TW202208354A - ＰＩ３Ｋα抑制劑及其使用方法 - Google Patents

ＰＩ３Ｋα抑制劑及其使用方法 Download PDF

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Publication number
TW202208354A
TW202208354A TW110115674A TW110115674A TW202208354A TW 202208354 A TW202208354 A TW 202208354A TW 110115674 A TW110115674 A TW 110115674A TW 110115674 A TW110115674 A TW 110115674A TW 202208354 A TW202208354 A TW 202208354A
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Taiwan
Prior art keywords
nitrogen
sulfur
oxygen
independently selected
partially unsaturated
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TW110115674A
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English (en)
Inventor
亞歷山卓 波席歐
路西恩 Ｖ 迪彼埃特羅
凱瑞 葛莉芬 弗里德里奇
哈坎 谷奈丁
拉維 克魯克拉斯里亞
安德烈 蘭斯卡比
瑪莉 Ｍ 麥德
湯瑪士 Ｈ 麥林
李維 查理斯 湯瑪士 皮爾斯
凱文 大衛 雷諾
凱利 Ｃ 秀特李維斯
湧 湯
亞歷山大 Ｍ 泰勒
Ｗ 派翠克 華特斯
瀚墨 張
法比奇 佐丹尼多
雅寇 沛切司基
大可 王
布蘭 喬登 阿田札
拉伯勒 梅根 博傳
安德魯 Ｊ 伯尼
菲 陳
山帕達 奇塔勒
索倫娜 葛洛茲雅
琴 貝諾 基貴雷
依洛迪 蘭妲嘉雷
愛麗珊德雷 拉里維
湯瑪士 勒皮崔
蓋譚 梅坦斯
喬漢 澳汀
莫漢 柏
克勞蒂歐 司圖利諾
卡西夫 譚維爾
萊克什 索拉
納萊什 維木拉
依蘭 Ｂ 奎傑
潘越
麥寇 保羅 丹尼諾
依芙斯 包斯奎
德斯 勞里爾斯 安托尼 喬彬
碧瑩 李
塔雷 穆罕默德
Original Assignee
美商傳達治療有限公司
美商Ｄ Ｅ 蕭爾研究有限公司
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Application filed by 美商傳達治療有限公司, 美商Ｄ Ｅ 蕭爾研究有限公司 filed Critical 美商傳達治療有限公司
Publication of TW202208354A publication Critical patent/TW202208354A/zh

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    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
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Abstract

本發明係關於新穎化合物及其醫藥組合物，以及用本發明之化合物及組合物抑制PI3Kα酶活性的方法。本發明進一步關於但不限於用本發明之化合物及組合物治療與PI3Kα信號傳導相關之病症的方法。

Description

PI3Kα抑制劑及其使用方法
磷脂醯肌醇3-激酶(PI3K)包含脂質激酶家族，其催化磷酸酯向肌醇脂之D-3'位置轉移以產生磷酸肌醇-3-磷酸酯(PIP)、磷酸肌醇-3,4-二磷酸酯(PIP2 )及磷酸肌醇-3,4,5-三磷酸酯(PIP3 )，該等產物轉而藉由將含有普列克受質蛋白-同源域(pleckstrin-homology domain)、FYVE、Phox及其他磷脂結合域之蛋白質引入通常位於質膜處之各種信號傳導複合物中而在信號級聯中充當第二信使((Vanhaesebroeck等人, Annu. Rev. Biochem 70:535 (2001)；Katso等人, Annu. Rev. Cell Dev. Biol. 17:615 (2001))。在兩個1類PI3K子類中，1A類PI3K為由與調節次單位組成性相關之催化性p110次單位(α、β或δ同功異型物)構成的雜二聚體，該調節次單位可為p85α、p55α、p50α、p85β或p55γ。1B類亞類具有一個家族成員，亦即由與兩個調節次單位p101或p84中之一者相關之催化性p110γ次單位構成的雜二聚體(Fruman等人, Annu Rev. Biochem. 67:481 (1998)；Suire等人, Curr. Biol. 15:566 (2005))。p85/55/50次單位之模組域包括Src同源(SH2)域，其與活化受體及細胞質酪胺酸激酶上特定序列背景中之磷酸酪胺酸殘基結合，引起1A類PI3K之活化及定位。1B類PI3K藉由結合多種肽及非肽配位體之G蛋白偶聯受體直接活化(Stephens等人, Cell 89:105 (1997)；Katso等人, Annu. Rev. Cell Dev. Biol. 17:615-675 (2001))。
因此，I類PI3K之所得磷脂產物將上游受體與下游細胞活動聯繫起來，該等活動包括增殖、存活、趨化性、細胞遷移、運動性、代謝、發炎及過敏反應、轉錄及轉譯(Cantley等人, Cell 64:281 (1991)；Escobedo及Williams, Nature 335:85 (1988)；Fantl等人, Cell 69:413 (1992))。在許多情況下，PIP2 及PIP3 將Aid (病毒癌基因v-Akt之人類同源物的產物)募集至質膜，Aid在質膜中充當對生長及存活重要的許多胞內信號傳導路徑之節點(Fantl等人, Cell 69:413-423 (1992)；Bader等人, Nature Rev. Cancer 5:921 (2005)；Vivanco及Sawyer, Nature Rev. Cancer 2:489 (2002))。
通常經由Aid活化提高存活率之PI3K的異常調節為人類癌症中最普遍的現象之一且已顯示以多個層級發生。在肌醇環之3'位置處使磷酸肌醇去磷酸化且因此拮抗PI3K活性之腫瘤抑制基因PTEN在多種腫瘤中功能性缺失。在其他腫瘤中，p110α同功異型物、PIK3CA及Akt之基因經擴增，且已在若干人類癌症中證明其基因產物之蛋白質表現增加。此外，已在人類癌症中描述用以上調p85-p110複合物之p85α的突變及易位。最後，已在多種人類癌症中以顯著頻率描述活化下游信號傳導路徑之PIK3CA中的體細胞誤義突變(Kang等人, Proc. Natl. Acad. Sci. USA 102:802 (2005)；Samuels等人, Science 304:554 (2004)；Samuels等人, Cancer Cell 7:561-573 (2005))。此等觀測結果顯示，磷酸肌醇-3激酶及此信號傳導路徑之上游及下游組分的失調為與人類癌症及增生性疾病相關之最常見失調之一(Parsons等人, Nature 436:792 (2005)；Hennessey等人, Nature Rev. Drug Disc. 4:988-1004 (2005))。
鑒於上述，PI3Kα抑制劑在增殖性疾病及其他病症的治療中將具有特別價值。雖然已開發出多種PI3K抑制劑(例如塔瑟昔布(taselisib)、阿帕昔布(alpelisib)、布帕昔布(buparlisib)及其他)，但此等分子抑制多種1A類PI3K同功異型物。對多種1A類PI3K同功異型物有活性之抑制劑被稱為「泛PI3K」抑制劑。現有PI3K抑制劑臨床開發之一個主要障礙為無法在腫瘤中達成所需的靶標抑制水準，同時避免對癌症患者的毒性。泛PI3K抑制劑共有某些靶標相關毒性，包括腹瀉、皮疹、疲勞及高血糖症。PI3K抑制劑之毒性取決於其同功異型物選擇性概況。PI3Kα之抑制與高血糖症及皮疹相關，而PI3Kδ或PI3Kγ之抑制與腹瀉、骨髓抑制及轉胺酶升高相關(Hanker等人, Cancer Discovery (2019) PMID: 30837161。因此，PI3Kα之選擇性抑制劑可增加治療窗，使得在腫瘤中實現足夠的靶標抑制，同時避免癌症患者中之劑量限制性毒性。
在一些實施例中，本發明提供式I-1化合物：
Figure 02_image003
或其醫藥學上可接受之鹽，其中R1 、R2 、Q、E、X、Y及Z中之每一者如本文中之實施例及類別以及子類中所定義。
在一些實施例中，本發明提供式I化合物：
Figure 02_image005
或其醫藥學上可接受之鹽，其中R1 、R2 、Q、E、X、Y及Z中之每一者如本文中之實施例及類別以及子類中所定義。
在一些實施例中，本發明提供一種醫藥組合物，其包含式I化合物或其醫藥學上可接受之鹽及醫藥學上可接受之載劑、佐劑或稀釋劑。
在一些實施例中，本發明提供一種治療PI3Kα介導之病症的方法，其包含向有需要之患者投與式I化合物或包含該化合物之組合物。
在一些實施例中，本發明提供一種用於提供式I化合物或其合成中間物的方法。
在一些實施例中，本發明提供一種用於提供包含式I化合物之醫藥組合物的方法。
相關申請案之交叉參考
本申請案主張2020年4月29日申請之美國臨時申請案第63/017,571號及2020年8月17日申請之美國臨時申請案第63/066,489號之權益；其各自以全文引用之方式併入本文中。 1. 本發明之某些實施例的一般描述
本發明化合物及其醫藥組合物適用作PI3Kα抑制劑。在一些實施例中，本發明提供式I化合物：
Figure 02_image007
或其醫藥學上可接受之鹽，其中： E為-C(O)-、-C(RE )2 -、-C(RE )2 C(RE )2 -、-C(S)-、-S(O)2- 、-OC(O)-、-N(RE )C(O)-、-C(O)N(RE )-或-C(RE )2 C(O)-； Q為CH、C(RQ )或N； X為CH、C(RX )或N； Y為CH、C(RY )或N； Z為CH、C(RZ )或N； R1 為-L1 -R1A ； R2 為-L2 -R2A ； RE 之各實例獨立地為H或-LE -REA ； RQ 為-LQ -RQA ； RX 為-LX -RXA ； RY 為-LY -RYA ； RZ 為-LZ -RZA ；或 RE 之兩個實例與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的3-8員飽和或部分不飽和單環；或具有0-4個獨立地選自氮、氧及硫之雜原子的8-12員飽和或部分不飽和雙環；其中各環經REEC 之n個實例取代； RQ 及R1 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的4-8員飽和或部分不飽和單環；或具有0-4個獨立地選自氮、氧及硫之雜原子的8-12員飽和或部分不飽和雙環；其中各環經RQ1C 之p個實例取代； RY 及RZ 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的4-7員部分不飽和或芳族環；其中該環經RYZC 之q個實例取代； L1 、L2 、LE 、LQ 、LX 、LY 及LZ 中之每一者獨立地為共價鍵，或C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-N(R)C(NR)-、-N(R)C(NOR)-、-N(R)C(NCN)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -； R1A 為經R1C 之r1 個實例取代之RA 或RB ； R2A 為經R2C 之r2 個實例取代之RA 或RB ； REA 為經REC 之r3 個實例取代之RA 或RB ； RQA 為經RQC 之r4 個實例取代之RA 或RB ； RXA 為經RXC 之r5 個實例取代之RA 或RB ； RYA 為經RYC 之r6 個實例取代之RA 或RB ； RZA 為經RZC 之r7 個實例取代之RA 或RB ； RL 為經RLC 之r8 個實例取代之RA 或RB ； RA 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SF5 、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 ； RB 之各實例獨立地為C1-6 脂族鏈；苯基；萘基；立方烷基；金剛烷基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環； R1C 、R2C 、REC 、RQC 、RXC 、RYC 、RZC 、RLC 、REEC 、RQ1C 及RYZC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SF5 、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環； R之各實例獨立地為氫或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或 相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，具有0-3個獨立地選自氮、氧及硫之雜原子之4-7員飽和、部分不飽和或雜芳基環；且 n、p、q、r1 、r2 、r3 、r4 、r5 、r6 、r7 及r8 中之每一者獨立地為0、1、2、3或4。 2. 化合物及定義
本發明化合物包括在本文中一般描述且藉由本文所揭示之類別、子類及種類進一步說明之彼等化合物。如本文中所使用，除非另外指明，否則以下定義應適用。出於本發明之目的，化學元素係根據元素週期表(Periodic Table of the Elements), CAS版, Handbook of Chemistry and Physics, 第75版來鑑別。另外，有機化學之一般原理描述於「Organic Chemistry」, Thomas Sorrell, University Science Books, Sausalito:  1999及「March's Advanced Organic Chemistry」, 第5版, 編者：Smith, M.B.，及March, J., John Wiley & Sons, New York:  2001，其全部內容特此以引用之方式併入。
如本文所用，術語「脂族」或「脂族基」意謂完全飽和或含有一或多個不飽和單元之直鏈(亦即非分支鏈)或分支鏈之經取代或未經取代之烴鏈，或完全飽和或含有一或多個不飽和單元、但不為芳族之單環烴或雙環烴(本文中亦稱作「碳環」、「環脂族」或「環烷基」)，其與分子之其餘部分具有單一連接點。除非另外說明，否則脂族基含有1-6個脂族碳原子。在一些實施例中，脂族基含有1-5個脂族碳原子。在其他實施例中，脂族基含有1-4個脂族碳原子。在其他實施例中，脂族基團含有1-3個脂族碳原子，且在又其他實施例中，脂族基團含有1-2個脂族碳原子。在一些實施例中，「環脂族」(或「碳環」)係指完全飽和或含有一或多個不飽和單元，但不為芳族之單環C3 -C6 烴，其具有連至分子之其餘部分的單個連接點。適合脂族基包括但不限於直鏈或分支鏈、經取代或未經取代之烷基、烯基、炔基及其混合物，諸如(環烷基)烷基、(環烯基)烷基或(環烷基)烯基。
除非另外指明，否則如本文所用，術語「烷基」係指具有直鏈、分支鏈、單環部分或多環部分或其組合之單價脂族烴基，其中該基團視情況在直鏈、分支鏈、單環部分或多環部分或其組合之一或多個碳原子處經各碳處之一或多個取代基取代，其中該一或多個取代基獨立地為C1 -C10 烷基。「烷基」之實例包括甲基、乙基、丙基、異丙基、丁基、異丁基、二級丁基、三級丁基、戊基、己基、庚基、環丙基、環丁基、環戊基、環己基、環庚基、降冰片烷基及其類似基團。
術語「低碳數烷基」係指C1-4 直鏈或分支鏈烷基。例示性低碳烷基為甲基、乙基、丙基、異丙基、丁基、異丁基及三級丁基。
術語「低碳鹵烷基」係指經一或多個鹵素原子取代之C1-4 直鏈或分支鏈烷基。
術語「雜原子」意謂氧、硫、氮、磷或矽中之一或多者(包括：氮、硫、磷或矽之任何氧化形式；任何鹼性氮之季銨化形式；或雜環之可取代氮，例如N (如在3,4-二氫-2H -吡咯基中)、NH (如在吡咯啶基中)或NR+ (如在N經取代之吡咯啶基中))。
如本文所使用之術語「不飽和」意謂部分具有一或多個不飽和單元。
如本文所用，術語「C1-8 (或C1-6 或C1-4 )飽和或不飽和、直鏈或分支鏈二價烴鏈」係指如本文所定義為直鏈或分支鏈之二價伸烷基、伸烯基及伸炔基鏈。
術語「伸烷基」係指二價烷基。「伸烷基鏈」為聚亞甲基，亦即-(CH2 )n -，其中n為正整數，較佳為1至6、1至4、1至3、1至2或2至3。經取代之伸烷基鏈為其中一或多個亞甲基氫原子由取代基置換之聚亞甲基。適合的取代基包括下文關於經取代之脂族基所描述之取代基。
術語「伸烯基」係指二價烯基基團。經取代之伸烯基鏈為含有至少一個雙鍵且一或多個氫原子經取代基置換之聚亞甲基。適合的取代基包括下文關於經取代之脂族基所描述之取代基。
術語「鹵素」意謂F、Cl、Br或I。
如在「芳烷基」、「芳烷氧基」或「芳氧基烷基」中單獨使用或作為較大部分的一部分使用之術語「芳基」係指具有總共5至14個環成員之單環或雙環環系統，其中系統中之至少一個環為芳族且其中系統中之各環含有3至7個環成員。術語「芳基」可與術語「芳環」互換使用。在本發明之某些實施例中，「芳基」係指可具有一或多個取代基的芳環系統，包括(但不限於)苯基、聯苯、萘基、蒽基及其類似基團。
除非另外定義，否則如本文所用，術語「雜芳基」或「雜芳族」係指含有一或多個雜原子(例如一至三個雜原子，諸如氮、氧及硫)的5至6員單環芳族環，或含有一或多個雜原子的8至10員多環環系統，其中多環環系統中的至少一個環為芳族，且多環環系統的連接點係經由芳族環上的環原子。雜芳基環可以經由碳或氮連接至相鄰基團。雜芳基環之實例包括(但不限於)呋喃、噻吩、吡咯、噻唑、㗁唑、異噻唑、異㗁唑、咪唑、吡唑、三唑、吡啶、嘧啶、吲哚等。舉例而言，除非另外定義，否則1,2,3,4-四氫喹啉為雜芳基環，條件為其連接點經由苯并環，例如：
Figure 02_image009
。
除非另外定義，否則術語「雜環基」或「雜環基團」係指飽和或部分不飽和的3-10員單環或7-14員多環環系統，包括橋連或稠合環，且其環系統包括一至四個雜原子，諸如氮、氧及硫。雜環基環可經由碳或氮連接至相鄰基團。
除非另外定義，否則術語「部分不飽和」在環的上下文中係指單環，或多環(例如雙環、三環等)環系統內的組成環，其中該組成環含有至少一個除環自身所提供之不飽和度之外的不飽和度，但不為芳族。部分不飽和環之實例包括(但不限於) 3,4-二氫-2H-哌喃、3-吡咯啉、2-噻唑啉等。在部分不飽和環為多環環系統之一部分的情況下，多環環系統中的其他組成環可為飽和、部分不飽和的或芳族，但多環環系統的連接點位於部分不飽和組成環上。舉例而言，除非另外定義，否則1,2,3,4-四氫喹啉為部分不飽和環，條件為其連接點係經由哌啶基環，例如：
Figure 02_image011
。
除非另外定義，否則術語「飽和」在環的上下文中係指3至10員單環或7至14員多環(例如雙環、三環等)環系統，其中該單環或作為多環環系統之連接點的組成環不含除環自身所提供之不飽和度之外的額外不飽和度。單環飽和環之實例包括但不限於氮雜環丁烷、氧雜環丁烷、環己烷等。在飽和環為多環環系統之一部分的情況下，多環環系統中的其他組成環可為飽和、部分不飽和的或芳族，但多環環系統的連接點位於飽和組成環上。舉例而言，除非另外定義，否則2-氮雜螺[3.4]辛-6-烯為飽和環，條件為其連接點係經由N-氮雜環丁烷基環，例如：
Figure 02_image013
。
如本文所用，術語「伸烷基」、「伸芳基」、「伸環烷基」、「伸雜芳基」、「伸雜環烷基」及具有前綴「伸-」的其他類似術語係指由該前綴修飾之基團的二價鍵結形式。舉例而言，「伸烷基」為二價烷基，其使基團連接至其所連接者。
如本文所用，術語「橋連雙環」係指具有至少一個橋鍵的任何雙環系統，亦即碳環或雜環，飽和或部分不飽和。如IUPAC所定義，「橋鍵」為多個原子或一個原子之未分支鏈或連接兩個橋頭之價鍵，其中「橋頭」為與三個或更多個骨架原子(除氫以外)鍵合之環系統之任何骨架原子。在一些實施例中，橋連雙環基團具有7-12個環成員及0-4個獨立地選自氮、氧或硫之雜原子。此類橋聯雙環基團已在此項技術中熟知且包括在下文中闡述之基團，其中各基團在任何可取代碳或氮原子處連接至分子之其餘部分。除非另外規定，否則橋連雙環基團視情況經一或多個如關於脂族基闡述之取代基取代。另外或替代地，橋連雙環基團之任何可取代氮視情況經取代。例示性橋連雙環包括：
Figure 02_image015
Figure 02_image017
如本文所述，本發明化合物可含有「視情況經取代之」部分。一般而言，術語「經取代」無論前面是否有術語「視情況」均意謂指示部分之一或多個氫經適合之取代基替換。除非另有指示，否則「視情況經取代」之基團可在基團之各可取代位置處具有適合的取代基，且當任何既定結構中之一個以上位置可經一個以上選自指定基團之取代基取代時，在每一位置處之取代基可相同或不同。本發明所預想之取代基之組合較佳為形成穩定或化學可行的化合物之組合。如本文所用之術語「穩定」係指在經歷容許產生、偵測其，且在某些實施例中，回收、純化其及將其用於本文所揭示之目的中之一或多者的條件時不實質上改變之化合物。
「視情況經取代」之基團之可取代碳原子上之適合單價取代基獨立地為鹵素；-(CH2 )0-4 R°；-(CH2 )0-4 OR°；-O(CH2 )0-4 Ro , -O-(CH2 )0-4 C(O)OR°；-(CH2 )0-4 CH(OR°)2 ；-(CH2 )0-4 SR°；-(CH2 )0-4 Ph，其可經R°取代；-(CH2 )0-4 O(CH2 )0-1 Ph，其可經R°取代；-CH=CHPh，其可經R°取代；-(CH2 )0-4 O(CH2 )0-1 -吡啶基，其可經R°取代；-NO2 ；-CN；-N3 ；-(CH2 )0-4 N(R°)2 ；-(CH2 )0-4 N(R°)C(O)R°；-N(R°)C(S)R°；-(CH2 )0-4 N(R°)C(O)NR°2 ；-N(R°)C(S)NR°2 ；-(CH2 )0-4 N(R°)C(O)OR°；-N(R°)N(R°)C(O)R°；-N(R°)N(R°)C(O)NR°2 ；-N(R°)N(R°)C(O)OR°；-(CH2 )0-4 C(O)R°；-C(S)R°；-(CH2 )0-4 C(O)OR°；-(CH2 )0-4 C(O)SR°；-(CH2 )0-4 C(O)OSiR°3 ；-(CH2 )0-4 OC(O)R°；-OC(O)(CH2 )0-4 SR°；-SC(S)SR°；-(CH2 )0-4 SC(O)R°；-(CH2 )0-4 C(O)NR°2 ；-C(S)NR°2 ；-C(S)SR°；-SC(S)SR°、-(CH2 )0-4 OC(O)NR°2 ；-C(O)N(OR°)R°；-C(O)C(O)R°；-C(O)CH2 C(O)R°；-C(NOR°)R°；-(CH2 )0-4 SSR°；- (CH2 )0-4 S(O)2 R°；-(CH2 )0-4 S(O)2 OR°；-(CH2 )0-4 OS(O)2 R°；-S(O)2 NR°2 ；-(CH2 )0-4 S(O)R°；-N(R°)S(O)2 NR°2 ；-N(R°)S(O)2 R°；-N(OR°)R°；-C(NH)NR°2 ；-P(O)(OR°)R°；-P(O)R°2 ；-OP(O)R°2 ；-OP(O)(OR°)2 ；-SiR°3 ；-(C1-4 直鏈或分支鏈伸烷基)O-N(R°)2 ；或-(C1-4 直鏈或分支鏈伸烷基)C(O)O-N(R°)2 ，其中各R°可如下文所定義地經取代且獨立地為氫、C1-6 脂族基、-CH2 Ph、-O(CH2 )0-1 Ph、-CH2 -(5-6員雜芳環)或具有0至4個獨立地選自氮、氧或硫之雜原子的5-6員飽和、部分不飽和或芳環，或不管以上定義，兩個獨立出現之R°與其一或多個插入原子一起形成具有0至4個獨立地選自氮、氧或硫之雜原子的3-12員飽和、部分不飽和或芳基單環或雙環，其可如下文所定義地經取代。
R°(或由兩個獨立出現之R°與其等插入原子連在一起形成之環)上之適合單價取代基獨立地為鹵素、-(CH2 )0-2 R● 、-(鹵基R● )、-(CH2 )0-2 OH、-(CH2 )0-2 OR● 、-(CH2 )0-2 CH(OR● )2 ；-O(鹵基R● )、-CN、-N3 、-(CH2 )0-2 C(O)R● 、-(CH2 )0-2 C(O)OH、-(CH2 )0-2 C(O)OR● 、-(CH2 )0-2 SR● 、-(CH2 )0-2 SH、-(CH2 )0-2 NH2 、-(CH2 )0-2 NHR● 、-(CH2 )0-2 NR● 2 、-NO2 、-SiR● 3 、-OSiR● 3 、-C(O)SR● 、-(C1-4 直鏈或分支鏈伸烷基)C(O)OR● 或-SSR● ，其中各R● 未經取代或在前面有「鹵基」之情況下僅經一或多個鹵素取代，且獨立地選自C1-4 脂族、-CH2 Ph、-O(CH2 )0-1 Ph或具有0至4個獨立地選自氮、氧或硫之雜原子之5-6員飽和、部分不飽和或芳環。R°之飽和碳原子之適合之二價取代基包括=O及=S。
「視情況經取代」之基團之飽和碳原子上的適合二價取代基包括以下：=O、=S、=NNR* 2 、=NNHC(O)R* 、=NNHC(O)OR* 、=NNHS(O)2 R* 、=NR* 、=NOR* 、-O(C(R* 2 ))2-3 O-或-S(C(R* 2 ))2-3 S，其中R* 之各實例各自獨立地選自氫、可如下文所定義經取代之C1-6 脂族基，或具有0至4個獨立地選自氮、氧或硫之雜原子的未經取代之5至6員飽和、部分不飽和或芳基環。結合於「視情況經取代」之基團之鄰近可取代碳的適合二價取代基包括：-O(CR* 2 )2-3 O-，其中R* 之各實例各自獨立地選自氫、可如下文所定義經取代之C1-6 脂族基，或具有0至4個獨立地選自氮、氧或硫之雜原子的未經取代之5至6員飽和、部分不飽和或芳基環。
R* 之脂族基上之適合之取代基包括鹵素、-R● 、-(鹵基R● )、-OH、-OR● 、-O(鹵基R● )、-CN、-C(O)OH、-C(O)OR● 、-NH2 、-NHR● 、-NR● 2 或-NO2 ，其中各R● 未經取代或當前面具有「鹵基」時僅經一或多個鹵素取代，且獨立地為C1-4 脂族基、-CH2 Ph、-O(CH2 )0-1 Ph或具有0至4個獨立地選自氮、氧或硫之雜原子的5-6員飽和、部分不飽和或芳環。
「視情況經取代之」基團之可取代氮上之適合之取代基包括-R† 、-NR† 2 、-C(O)R† 、-C(O)OR† 、-C(O)C(O)R† 、-C(O)CH2 C(O)R† 、-S(O)2 R† 、-S(O)2 NR† 2 、-C(S)NR† 2 、-C(NH)NR† 2 或-N(R† )S(O)2 R† ；其中各R† 獨立地為氫；可如下文所定義地經取代之C1-6 脂族基；未經取代之-OPh；或具有0至4個獨立地選自氮、氧或硫之雜原子的未經取代之5-6員飽和、部分不飽和或芳環，或不管以上定義，兩個獨立出現之R† 與其一或多個插入原子一起形成具有0至4個獨立地選自氮、氧或硫之雜原子的未經取代之3-12員飽和、部分不飽和或芳基單環或雙環。
R† 之脂族基上之適合之取代基獨立地為鹵素、-R● 、-(鹵基R● )、-OH、-OR● 、-O(鹵基R● )、-CN、-C(O)OH、-C(O)OR● 、-NH2 、-NHR● 、-NR● 2 或-NO2 ，其中各R● 未經取代或當前面具有「鹵基」時僅經一或多個鹵素取代，且獨立地為C1-4 脂族基、-CH2 Ph、-O(CH2 )0-1 Ph或具有0至4個獨立地選自氮、氧或硫之雜原子的5-6員飽和、部分不飽和或芳環。
如本文所用，術語「異構體」係指具有相同化學式、但結構或光學組態不同的化合物。如本文所用，術語「立體異構體」係指且包括具有相同分子式、但原子及/或官能基在空間中定位不同的異構分子。本發明化合物之所有立體異構體(例如，由於各個取代基上之不對稱碳而可能存在的彼等立體異構體)，包括對映異構形式及非對映異構形式，涵蓋在本發明之範疇內。因此，除非另有說明，否則本發明化合物之單一立體化學異構體以及對映異構體、非對映異構體及幾何(或構象)異構體的混合物處於本發明之範疇內。
如本文所用，術語「互變異構體」為平衡存在且容易自一種異構形式轉化成另一種異構形式的兩種或更多種結構異構體之一。應理解，互變異構體涵蓋價態互變異構體及質子互變異構體(亦稱為質子移變的互變異構體)。價互變異構體包括藉由一些鍵結電子之重組相互轉化。質子互變異構體包括經由質子遷移發生的相互轉化，諸如酮-烯醇及亞胺-烯胺異構化。除非另外說明，否則本發明化合物之所有互變異構體均在本發明之範疇內。
如本文所用，術語「同位素取代」係指原子經其同位素取代。如本文所用，術語「同位素」係指與自然界中主要存在的原子具有相同原子數、但質量數(中子數)與自然界中主要存在的原子之質量數不同的原子。應理解，具有同位素取代的化合物係指其中所含有的至少一個原子經其同位素取代的化合物。可經其同位素取代之原子包括(但不限於)氫、碳及氧。氫原子同位素之實例包括2 H (亦表示為D)及3 H。碳原子同位素之實例包括13 C及14 C。氧原子同位素之實例包括18 O。除非另外說明，否則本發明化合物之所有同位素取代均在本發明之範疇內。此類化合物適用作例如分析工具、生物分析中之探針或根據本發明之治療劑。在某些實施例中，舉例而言，所提供之化合物的彈頭部分RW 包含一或多個氘原子。
如本文所用，術語「醫藥學上可接受之鹽」係指在合理醫學判斷範疇內適用於與人類及低等動物之組織接觸而無異常毒性、刺激、過敏反應及其類似情況且與合理益處/風險比相稱的彼等鹽。例示性醫藥學上可接受之鹽見於例如Berge等人(J. Pharm. Sci. 1977, 66(1), 1；及Gould, P.L.,Int. J. Pharmaceutics 1986, 33, 201-217中；(各自以全文引用之方式併入本文)。
本發明化合物之醫藥學上可接受之鹽包括來源於適合的無機及有機酸及鹼之鹽。醫藥學上可接受之無毒酸加成鹽之實例為胺基與無機酸(諸如鹽酸、氫溴酸、磷酸、硫酸及過氯酸)或有機酸(諸如乙酸、草酸、順丁烯二酸、酒石酸、檸檬酸、丁二酸或丙二酸)形成之鹽，或藉由使用此項技術中所用之其他方法(諸如離子交換)形成之鹽。其他醫藥學上可接受之鹽包括己二酸鹽、藻酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯磺酸鹽、苯甲酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、檸檬酸鹽、環戊烷丙酸鹽、二葡糖酸鹽、十二烷基硫酸鹽、乙烷磺酸鹽、甲酸鹽、反丁烯二酸鹽、葡庚糖酸鹽、甘油磷酸鹽、葡糖酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、氫碘酸鹽、2-羥基-乙烷磺酸鹽、乳糖酸鹽、乳酸鹽、月桂酸鹽、月桂基硫酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、甲烷磺酸鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、果膠酸鹽、過硫酸鹽、3-苯基丙酸鹽、磷酸鹽、特戊酸鹽、丙酸鹽、硬脂酸鹽、丁二酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、對甲苯磺酸鹽、十一烷酸鹽、戊酸鹽及其類似者。
衍生自適當鹼之鹽包括鹼金屬鹽、鹼土金屬鹽、銨鹽及N+ (C1-4 烷基)4 鹽。代表性鹼金屬或鹼土金屬鹽包括鈉鹽、鋰鹽、鉀鹽、鈣鹽、鎂鹽及其類似者。其他醫藥學上可接受之鹽包括(適當時)無毒性銨、四級銨及使用相對離子(諸如鹵離子、氫氧根、羧酸根、硫酸根、磷酸根、硝酸根、低碳烷基磺酸根及芳基磺酸根)形成之胺陽離子。
醫藥學上可接受之鹽亦意欲涵蓋半鹽，其中化合物:酸之比率分別為2:1。例示性半鹽為衍生自包含兩個羧酸基之酸的彼等鹽，該等酸諸如蘋果酸、反丁烯二酸、順丁烯二酸、丁二酸、酒石酸、戊二酸、草酸、己二酸及檸檬酸。其他例示性半鹽為衍生自二質子礦物酸(諸如硫酸)之彼等鹽。較佳例示性半鹽包括(但不限於)半順丁烯二酸鹽、半反丁烯二酸鹽及半丁二酸鹽。
如本文所用，術語「約」在本文中用於指大約、大致、在…左右或在…附近。當術語「約」與數值範圍結合使用時，其藉由向上或向下擴展所闡述數值之邊界來調整其範圍。一般而言，術語「約」在本文中用於修飾數值高於及低於所述值：向上或向下(更高或更低) 20%的偏差。
如本文所用，「有效量」、「足量」或「治療有效量」係足以實現有益或所要結果(包括臨床結果)之化合物的量。因此，有效量可足以例如減輕或改善與PI3Kα信號傳導有關的疾患之嚴重程度及/或持續時間或其一或多種症狀；預防與PI3Kα信號傳導有關的疾患相關病狀或症狀之進展；或者增強或以其他方式改善另一療法之預防或治療效果。有效量亦包括避免或實質上減弱非所要副作用之化合物的量。
如本文所用以及此項技術中所理解，「治療」為獲得有益或所需結果(包括臨床結果)之方法。有益或所需臨床結果可以包括(但不限於)一或多種症狀或病狀之緩解或改善、疾病或病痛之程度減輕、疾病或病痛之狀態穩定(亦即不惡化)、疾病或病痛擴散之預防、疾病或病痛進展之延遲或減緩、疾病或病痛狀態之改善或緩和，以及緩解(無論部分或全部)，無論可偵測或不可偵測。「治療」亦可意謂若不接受治療則相比於預期存活期會延長存活期。在一些實施例中，可在一或多種症狀已出現之後投與療法。在其他實施例中，治療可在症狀不存在時投與。舉例而言，可在症狀發作之前向易感個體投與治療(例如根據症狀史及/或根據遺傳或其他易感性因素)。亦可在症狀消退之後繼續治療，例如以預防或延緩其復發。
片語「有需要」係指需要自與PI3Kα信號傳導活性有關的病狀中出現有症狀的或無症狀的緩解，或可以其他方式藉由本發明之化合物及/或組合物緩解。 3. 例示性實施例之描述
如上文所述，在一些實施例中，本發明提供式I-1化合物：
Figure 02_image019
或其醫藥學上可接受之鹽，其中： E為-C(O)-、-C(RE )2 -、-C(RE )2 C(RE )2 -、-C(S)-、-S(O)2 -、-OC(O)-、-N(RE )C(O)-、-C(O)N(RE )-或-C(RE )2 C(O)-； Q為CH、C(RQ )或N； X為CH、C(RX )或N； Y為CH、C(RY )或N； Z為CH、C(RZ )或N； R1 為-L1 -R1A ； R2 為-L2 -R2A ； RE 之各實例獨立地為H或-LE -REA ； RQ 為-LQ -RQA ； RX 為-LX -RXA ； RY 為-LY -RYA ； RZ 為-LZ -RZA ；或 RE 之兩個實例與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的3-8員飽和或部分不飽和單環；或具有0-4個獨立地選自氮、氧及硫之雜原子的8-12員飽和或部分不飽和雙環；其中各環經REEC 之n個實例取代； RQ 及R1 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的4-8員飽和或部分不飽和單環；或具有0-4個獨立地選自氮、氧及硫之雜原子的8-12員飽和或部分不飽和雙環；其中各環經RQ1C 之p個實例取代； RY 及RZ 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的4-7員部分不飽和或芳族環；其中該環經RYZC 之q個實例取代； L1 、L2 、LE 、LQ 、LX 、LY 及LZ 中之每一者獨立地為共價鍵，或C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-N(R)C(NR)-、-N(R)C(NOR)-、-N(R)C(NCN)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -； R1A 為經R1C 之r1 個實例取代之RA 或RB ； R2A 為經R2C 之r2 個實例取代之RA 或RB ； REA 為經REC 之r3 個實例取代之RA 或RB ； RQA 為經RQC 之r4 個實例取代之RA 或RB ； RXA 為經RXC 之r5 個實例取代之RA 或RB ； RYA 為經RYC 之r6 個實例取代之RA 或RB ； RZA 為經RZC 之r7 個實例取代之RA 或RB ； RL 為經RLC 之r8 個實例取代之RA 或RB ； RA 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SF5 、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-S(O)(NCN)R、-S(NCN)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 ； RB 之各實例獨立地為C1-6 脂族鏈；苯基；萘基；立方烷基；金剛烷基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環； R1C 、R2C 、REC 、RQC 、RXC 、RYC 、RZC 、RLC 、REEC 、RQ1C 及RYZC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SF5 、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環； R之各實例獨立地為氫或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或 相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，具有0-3個獨立地選自氮、氧及硫之雜原子之4-7員飽和、部分不飽和或雜芳基環；且 n、p、q、r1 、r2 、r3 、r4 、r5 、r6 、r7 及r8 中之每一者獨立地為0、1、2、3、4或5。
在一些實施例中，本發明提供式I-1化合物，其中E、Q、X、Y、Z、R1 、R2 、RE 、RQ 、RX 、RY 、RZ 、R1A 、R2A 、REA 、RQA 、RXA 、RYA 、RZA 、RL 、RA 、RB 、R1C 、R2C 、REC 、RQC 、RXC 、RYC 、RZC 、RLC 、REEC 、RQ1C 、RYZC 、R、n、p、q、r1 、r2 、r3 、r4 、r5 、r6 、r7 及r8 中之每一者如下文所定義及本文實施例中所述，單獨及以組合形式。
在某些實施例中，RYA 為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-S(O)(NCN)R或-S(NCN)R。在某些實施例中，RYA 為-S(O)(NR)R、-S(O)(NCN)R或-S(NCN)R。在某些實施例中，RYA 為-S(O)(NCN)R或-S(NCN)R。在某些實施例中，RYA 為-S(O)(NCN)R。在某些實施例中，RYA 為-S(NCN)R。在一些實施例中，RYA 選自表1之化合物中所描繪之基團。
在某些實施例中，RA 為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-S(O)(NCN)R或-S(NCN)R。在某些實施例中，RA 為-S(O)(NR)R、-S(O)(NCN)R或-S(NCN)R。在某些實施例中，RA 為-S(O)(NCN)R或-S(NCN)R。在某些實施例中，RA 為-S(O)(NCN)R。在某些實施例中，RA 為-S(NCN)R。在一些實施例中，RA 選自表1之化合物中所描繪之基團。
在某些實施例中，n為1、2、3、4或5。在某些實施例中，n為2、3、4或5。在某些實施例中，n為3、4或5。在某些實施例中，n為4或5。在某些實施例中，n為5.在某些實施例中，n選自表1之化合物中所表示之值。
在某些實施例中，p為1、2、3、4或5。在某些實施例中，p為2、3、4或5。在某些實施例中，p為3、4或5。在某些實施例中，p為4或5。在某些實施例中，p為5。在某些實施例中，p選自表1之化合物中所表示之值。
在某些實施例中，q為1、2、3、4或5。在某些實施例中，q為2、3、4或5。在某些實施例中，q為3、4或5。在某些實施例中，q為4或5。在某些實施例中，q為5。在某些實施例中，q選自表1之化合物中所表示之值。
在某些實施例中，r1 為1、2、3、4或5。在某些實施例中，r1 為2、3、4或5。在某些實施例中，r1 為3、4或5。在某些實施例中，r1 為4或5。在某些實施例中，r1 為5。在某些實施例中，r1 選自表1之化合物中所表示之值。
在某些實施例中，r2 為1、2、3、4或5。在某些實施例中，r2 為2、3、4或5。在某些實施例中，r2 為3、4或5。在某些實施例中，r2 為4或5。在某些實施例中，r2 為5。在某些實施例中，r2 選自表1之化合物中所表示之值。
在某些實施例中，r3 為1、2、3、4或5。在某些實施例中，r3 為2、3、4或5。在某些實施例中，r3 為3、4或5。在某些實施例中，r3 為4或5。在某些實施例中，r3 為5。在某些實施例中，r3 選自表1之化合物中所表示之值。
在某些實施例中，r4 為1、2、3、4或5。在某些實施例中，r4 為2、3、4或5。在某些實施例中，r4 為3、4或5。在某些實施例中，r4 為4或5。在某些實施例中，r4 為5。在某些實施例中，r4 選自表1之化合物中所表示之值。
在某些實施例中，r5 為1、2、3、4或5。在某些實施例中，r5 為2、3、4或5。在某些實施例中，r5 為3、4或5。在某些實施例中，r5 為4或5。在某些實施例中，r5 為5。在某些實施例中，r5 選自表1之化合物中所表示之值。
在某些實施例中，r6 為1、2、3、4或5。在某些實施例中，r6 為2、3、4或5。在某些實施例中，r6 為3、4或5。在某些實施例中，r6 為4或5。在某些實施例中，r6 為5。在某些實施例中，r6 選自表1之化合物中所表示之值。
在某些實施例中，r7 為1、2、3、4或5。在某些實施例中，r7 為2、3、4或5。在某些實施例中，r7 為3、4或5。在某些實施例中，r7 為4或5。在某些實施例中，r7 為5。在某些實施例中，r7 選自表1之化合物中所表示之值。
在某些實施例中，r8 為1、2、3、4或5。在某些實施例中，r8 為2、3、4或5。在某些實施例中，r8 為3、4或5。在某些實施例中，r8 為4或5。在某些實施例中，r8 為5。在某些實施例中，r8 選自表1之化合物中所表示之值。
如上文所述，在一些實施例中，本發明提供式I化合物：
Figure 02_image021
或其醫藥學上可接受之鹽，其中： E為-C(O)-、-C(RE )2 -、-C(RE )2 C(RE )2 -、-C(S)-、-S(O)2- 、-OC(O)-、-N(RE )C(O)-、-C(O)N(RE )-或-C(RE )2 C(O)-； Q為CH、C(RQ )或N； X為CH、C(RX )或N； Y為CH、C(RY )或N； Z為CH、C(RZ )或N； R1 為-L1 -R1A ； R2 為-L2 -R2A ； RE 之各實例獨立地為H或-LE -REA ； RQ 為-LQ -RQA ； RX 為-LX -RXA ； RY 為-LY -RYA ； RZ 為-LZ -RZA ；或 RE 之兩個實例與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的3-8員飽和或部分不飽和單環；或具有0-4個獨立地選自氮、氧及硫之雜原子的8-12員飽和或部分不飽和雙環；其中各環經REEC 之n個實例取代； RQ 及R1 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的4-8員飽和或部分不飽和單環；或具有0-4個獨立地選自氮、氧及硫之雜原子的8-12員飽和或部分不飽和雙環；其中各環經RQ1C 之p個實例取代； RY 及RZ 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的4-7員部分不飽和或芳族環；其中該環經RYZC 之q個實例取代； L1 、L2 、LE 、LQ 、LX 、LY 及LZ 中之每一者獨立地為共價鍵，或C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-N(R)C(NR)-、-N(R)C(NOR)-、-N(R)C(NCN)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -； R1A 為經R1C 之r1 個實例取代之RA 或RB ； R2A 為經R2C 之r2 個實例取代之RA 或RB ； REA 為經REC 之r3 個實例取代之RA 或RB ； RQA 為經RQC 之r4 個實例取代之RA 或RB ； RXA 為經RXC 之r5 個實例取代之RA 或RB ； RYA 為經RYC 之r6 個實例取代之RA 或RB ； RZA 為經RZC 之r7 個實例取代之RA 或RB ； RL 為經RLC 之r8 個實例取代之RA 或RB ； RA 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SF5 、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 ； RB 之各實例獨立地為C1-6 脂族鏈；苯基；萘基；立方烷基；金剛烷基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環； R1C 、R2C 、REC 、RQC 、RXC 、RYC 、RZC 、RLC 、REEC 、RQ1C 及RYZC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SF5 、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環； R之各實例獨立地為氫或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或 相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，具有0-3個獨立地選自氮、氧及硫之雜原子之4-7員飽和、部分不飽和或雜芳基環；且 n、p、q、r1 、r2 、r3 、r4 、r5 、r6 、r7 及r8 中之每一者獨立地為0、1、2、3或4。
如上文一般所定義，E為-C(O)-、-C(RE )2 -、-C(RE )2 C(RE )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-C(S)-、-S(O)2 -、-OC(O)-、-N(RE )C(O)-、-C(O)N(RE )-或-C(RE )2 C(O)-。在一些實施例中，E為-C(O)-。在一些實施例中，E為-OC(O)-或-N(RE )C(O)-。在一些實施例中，E為-C(RE )2- 、C3-6 伸環烷基或C3-6 伸雜環烷基。
在一些實施例中，E為-C(O)-、-OC(O)-、-N(RE )C(O)-或-C(RE )2 C(O)-。在一些實施例中，E為-OC(O)-、-N(RE )C(O)-或-C(RE )2 C(O)-。在一些實施例中，E為-C(O)-或-N(RE )C(O)-。
在一些實施例中，E為-C(O)-、-C(RE )2 -、-C(S)-或-S(O)2 -。在一些實施例中，E為-C(O)-、-C(RE )2 -或-C(S)-。在一些實施例中，E為-C(O)-或-C(S)-。
在一些實施例中，E為-C(RE )2 C(RE )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-OC(O)-、-N(RE )C(O)-、-C(O)N(RE )-或-C(RE )2 C(O)-。在一些實施例中，E為C3-6 伸環烷基或C3-6 伸雜環烷基。在一些實施例中，E為-C(RE )2 C(RE )2 -、-OC(O)-、-N(RE )C(O)-、-C(O)N(RE )-或-C(RE )2 C(O)-。在一些實施例中，E為-OC(O)-、-N(RE )C(O)-、-C(O)N(RE )-或-C(RE )2 C(O)-。在一些實施例中，E為-OC(O)-、-N(RE )C(O)-或-C(O)N(RE )-。在一些實施例中，E為-N(RE )C(O)-或-C(O)N(RE )-。在一些實施例中，E為-N(H)C(O)-或-C(O)N(H)-。在一些實施例中，E為-N(CH3 )C(O)-或-C(O)N(CH3 )-。
在一些實施例中，E為-S(O)2- 、-OC(O)-、-N(RE )C(O)-或-C(O)N(RE )-。在一些實施例中，E為-C(O)-、-C(RE )2 -、-C(RE )2 C(RE )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-C(S)-或-C(RE )2 C(O)-。在一些實施例中，E為-C(O)-、-C(RE )2 -、-C(RE )2 C(RE )2 -、-C(S)-或-C(RE )2 C(O)-。在一些實施例中，E為-C(O)-、-C(S)-或-C(RE )2 C(O)-。在一些實施例中，E為-C(RE )2 -、-C(RE )2 C(RE )2 -或-C(RE )2 C(O)-。在一些實施例中，E為-C(RE )2 -或-C(RE )2 C(RE )2 -。
在一些實施例中，E為-C(RE )2 -。在一些實施例中，E為-C(RE )2 C(RE )2 -。在一些實施例中，E為C3-6 伸環烷基。在一些實施例中，E為C3-6 伸雜環烷基。在一些實施例中，E為-C(S)-。在一些實施例中，E為-S(O)2- 。在一些實施例中，E為-OC(O)-。在一些實施例中，E為-N(RE )C(O)-。在一些實施例中，E為-N(H)C(O)-。在一些實施例中，E為-N(CH3 )C(O)-。在一些實施例中，E為-C(O)N(RE )-。在一些實施例中，E為-C(O)N(H)-。在一些實施例中，E為-C(O)N(CH3 )-。在一些實施例中，E為-C(RE )2 C(O)-。
在一些實施例中，E選自表1之化合物中所描繪之基團。
如上文一般所定義，Q為CH、C(RQ )或N。在一些實施例中，Q為CH。在一些實施例中，Q為C(RQ )。在一些實施例中，Q為N。在一些實施例中，Q為CH或C(RQ )。在一些實施例中，Q為CH或N。在一些實施例中，Q為C(RQ )或N。在一些實施例中，Q選自表1之化合物中所描繪之基團。
如上文一般所定義，X為CH、C(RX )或N。在一些實施例中，X為CH。在一些實施例中，X為C(RX )。在一些實施例中，X為N。在一些實施例中，X為CH或C(RX )。在一些實施例中，X為CH或N。在一些實施例中，X為C(RX )或N。在一些實施例中，X選自表1之化合物中所描繪之基團。
如上文一般所定義，Y為CH、C(RY )或N。在一些實施例中，Y為CH。在一些實施例中，Y為C(RY )。在一些實施例中，Y係N。在一些實施例中，Y為CH或C(RY )。在一些實施例中，Y為CH或N。在一些實施例中，Y為C(RY )或N。在一些實施例中，Y選自表1之化合物中所描繪之基團。
如上文一般所定義，Z為CH、C(RZ )或N。在一些實施例中，Z為CH。在一些實施例中，Z為C(RZ )。在一些實施例中，Z為N。在一些實施例中，Z為CH或C(RZ )。在一些實施例中，Z為CH或N。在一些實施例中，Z為C(RZ )或N。在一些實施例中，Z選自表1之化合物中所描繪之基團。
如上文一般所定義，R1 為-L1 -R1A 或RQ 及R1 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的4-8員飽和或部分不飽和單環；或具有0-4個獨立地選自氮、氧及硫之雜原子的8-12員飽和或部分不飽和雙環；其中各環經RQ1C 之p個實例取代。在一些實施例中，R1 為-L1 -R1A 。在一些實施例中，R1 為-R1A 。
在一些實施例中，RQ 及R1 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的4-8員飽和或部分不飽和單環；或具有0-4個獨立地選自氮、氧及硫之雜原子的8-12員飽和或部分不飽和雙環；其中各環經RQ1C 之p個實例取代。在一些實施例中，RQ 及R1 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的4-8員飽和或部分不飽和單環；其中該環經RQ1C 之p個實例取代。在一些實施例中，RQ 及R1 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的8-12員飽和或部分不飽和雙環；其中該環經RQ1C 之p個實例取代。
在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image023
，其中R1C 及r1 如本文中之實施例及類別及子類中所定義。在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image025
，其中R1C 如本文中之實施例及類別及子類中所定義。在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image027
，其中R1C 如本文中之實施例及類別及子類中所定義。在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image029
，其中R1C 如本文中之實施例及類別及子類中所定義。在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image031
，其中R1C 如本文中之實施例及類別及子類中所定義。
在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image033
，其中R1C 之各實例獨立地為鹵素、-CN、-O-(視情況經取代之C1-6 脂族基)或視情況經取代之C1-6 脂族基。在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image035
，其中R1C 之各實例獨立地為鹵素或視情況經1-3個鹵素取代之C1-3 脂族基。在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image037
，其中R1C 之各實例獨立地為鹵素或視情況經1-3個鹵素取代之C1-3 脂族基。在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image039
，其中R1C 之各實例獨立地為鹵素或視情況經1-3個鹵素取代之C1-3 脂族基。在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image041
，其中R1C 之各實例獨立地為氟、氯、-CH3 、-CHF2 或-CF3 。在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image043
，其中R1C 為鹵素或視情況經1-3個鹵素取代之C1-3 脂族基。
在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image045
。在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image047
。
在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image049
，其中R1C 及r1 如本文中之實施例及類別及子類中所定義。在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image051
。在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image053
。在一些實施例中，R1 (亦即-L1 -R1A 在一起)為
Figure 02_image055
。
在一些實施例中，R1 選自表1之化合物中所描繪之基團。
如上文一般所定義，R2 為-L2 -R2A 。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為-N(R)C(O)-R2A 或-R2A ，其中R及R2A 如本文中之實施例及類別及子類中所定義。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為-N(R)C(O)-R2A ，其中R及R2A 如本文中之實施例及類別及子類中所定義。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為-N(H)C(O)-R2A ，其中R2A 如本文中之實施例及類別及子類中所定義。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為-N(H)C(O)-R2A ，其中R2A 為經R2C 之r2 個實例取代之RB 。在一些實施例中，R2 為-R2A 。
在一些實施例中，R2 為-N(H)C(O)-R2A 、-N(H)C(O)N(H)-R2A 、-C(O)N(H)-R2A 、-N(H)-R2A 、-S(O)2 CH2 -R2A 、-CH2 S(O)2 -R2A 或-C(H)(CH3 )OH。在一些實施例中，R2 為-N(H)C(O)-R2A 、-N(H)C(O)N(H)-R2A 或-N(H)-R2A 。在一些實施例中，R2 為-C(O)N(H)-R2A 、-CH2 S(O)2 -R2A 或-C(H)(CH3 )OH。在一些實施例中，R2 為-S(O)2 CH2 -R2A 或-CH2 S(O)2 -R2A 。
在一些實施例中，R2 為-N(H)C(O)N(H)-R2A 。在一些實施例中，R2 為-C(O)N(H)-R2A 。在一些實施例中，R2 為-N(H)-R2A 。在一些實施例中，R2 為-S(O)2 CH2 -R2A 。在一些實施例中，R2 為-CH2 S(O)2 -R2A 。在一些實施例中，R2 為-C(H)(CH3 )OH。
在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image057
，其中R2C 及r2 如本文中之實施例及類別及子類中所定義。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image059
，其中R2C 如本文中之實施例及類別及子類中所定義。
在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image061
，其中R2C 之各實例獨立地為鹵素、-CN、-O-(視情況經取代之C1-6 脂族基)或視情況經取代之C1-6 脂族基。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image063
，其中R2C 之各實例獨立地為鹵素或視情況經1-3個鹵素取代之C1-3 脂族基。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image065
，其中R2C 之各實例獨立地為氟、氯、-CH3 、-CHF2 或-CF3 。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image067
。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image069
。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image071
。
在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image073
，其中R2C 及r2 如本文中之實施例及類別及子類中所定義。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image075
。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image077
，其中R2C 如本文中之實施例及類別及子類中所定義。
在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image079
，其中R2C 及r2 如本文中之實施例及類別及子類中所定義。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image081
。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image083
，其中R2C 如本文中之實施例及類別及子類中所定義。
在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image085
，其中R2C 及r2 如本文中之實施例及類別及子類中所定義。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image087
。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image089
，其中R2C 如本文中之實施例及類別及子類中所定義。
在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image091
，其中R2C 及r2 如本文中之實施例及類別及子類中所定義。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image093
，其中R2C 如本文中之實施例及類別及子類中所定義。
在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image095
，其中R2C 及r2 如本文中之實施例及類別及子類中所定義。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image097
，其中R2C 如本文中之實施例及類別及子類中所定義。
在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image099
，其中R2C 及r2 如本文中之實施例及類別及子類中所定義。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image101
，其中R2C 如本文中之實施例及類別及子類中所定義。
在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image103
，其中R2C 及r2 如本文中之實施例及類別及子類中所定義。在一些實施例中，R2 (亦即-L2 -R2A 在一起)為
Figure 02_image105
，其中R2C 如本文中之實施例及類別及子類中所定義。
在一些實施例中，R2 為
Figure 02_image107
Figure 02_image109
Figure 02_image111
。
在一些實施例中，R2 為
Figure 02_image113
。在一些實施例中，R2 為
Figure 02_image115
。在一些實施例中，R2 為
Figure 02_image117
。在一些實施例中，R2 為
Figure 02_image119
。在一些實施例中，R2 為
Figure 02_image121
。在一些實施例中，R2 為
Figure 02_image123
。在一些實施例中，R2 為
Figure 02_image125
。
在一些實施例中，R2 為
Figure 02_image127
。在一些實施例中，R2 為
Figure 02_image129
。在一些實施例中，R2 為
Figure 02_image131
。在一些實施例中，R2 為
Figure 02_image133
。在一些實施例中，R2 為
Figure 02_image135
。在一些實施例中，R2 為
Figure 02_image137
。
在一些實施例中，R2 為
Figure 02_image139
。在一些實施例中，R2 為
Figure 02_image141
。在一些實施例中，R2 為
Figure 02_image143
。
在一些實施例中，R2 為
Figure 02_image145
。在一些實施例中，R2 為
Figure 02_image147
。在一些實施例中，R2 為
Figure 02_image149
。在一些實施例中，R2 為
Figure 02_image151
。在一些實施例中，R2 為
Figure 02_image153
。在一些實施例中，R2 為
Figure 02_image155
。
在一些實施例中，R2 選自表1之化合物中所描繪之基團。
如上文一般所定義，RE 之各實例獨立地為H或-LE -REA ；或RE 之兩個實例與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的3-8員飽和或部分不飽和單環；或具有0-4個獨立地選自氮、氧及硫之雜原子的8-12員飽和或部分不飽和雙環；其中各環經REEC 之n個實例取代。
在一些實施例中，RE 之各實例獨立地為H或-LE -REA 。在一些實施例中，RE 為H。在一些實施例中，RE 之各實例獨立地為-LE -REA 。在一些實施例中，RE 之各實例獨立地為REA 。在一些實施例中，RE 之各實例獨立地為RA 。在一些實施例中，RE 之各實例獨立地為經REC 之r3 個實例取代之RB 。
在一些實施例中，RE 之各實例獨立地為H或經REC 之r3 個實例取代之C1-6 脂族基。在一些實施例中，RE 之各實例獨立地為H或經REC 之r3 個實例取代之C1-3 脂族基。在一些實施例中，RE 之各實例獨立地為H或經鹵素之r3 個實例取代之C1-3 脂族基。在一些實施例中，RE 之各實例獨立地為H或C1-3 脂族基。在一些實施例中，RE 之各實例獨立地為H、-CH3 、-CH2 F、-CHF2 -或-CF3 。在一些實施例中，RE 之各實例獨立地為H或-CH3 。
在一些實施例中，RE 之各實例獨立地為經REC 之r3 個實例取代之C1-6 脂族基。在一些實施例中，RE 之各實例獨立地為經REC 之r3 個實例取代之C1-3 脂族基C1-3 。在一些實施例中，RE 之各實例獨立地為經鹵素之r3 個實例取代之C1-3 脂族基。在一些實施例中，RE 之各實例獨立地為C1-3 脂族基。在一些實施例中，RE 之各實例獨立地為-CH3 、-CH2 F、-CHF2 -或-CF3 。在一些實施例中，RE 為-CH3 。
在一些實施例中，RE 之兩個實例與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的3-8員飽和或部分不飽和單環；或具有0-4個獨立地選自氮、氧及硫之雜原子的8-12員飽和或部分不飽和雙環；其中各環經REEC 之n個實例取代。在一些實施例中，RE 之兩個實例與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的3-8員飽和或部分不飽和單環；其中該環經REEC 之n個實例取代。在一些實施例中，RE 之兩個實例與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的8-12員飽和或部分不飽和雙環；其中該環經REEC 之n個實例取代
在一些實施例中，RE 選自表1之化合物中所描繪之基團。
如上文一般所定義，RQ 為-LQ -RQA 或RQ 及R1 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的4-8員飽和或部分不飽和單環；或具有0-4個獨立地選自氮、氧及硫之雜原子的8-12員飽和或部分不飽和雙環；其中該環經RQ1C 之p個實例取代。在一些實施例中，RQ 為-LQ -RQA 。在一些實施例中，RQ 為-RQA 。
在一些實施例中，RQ 及R1 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的4-8員飽和或部分不飽和單環；或具有0-4個獨立地選自氮、氧及硫之雜原子的8-12員飽和或部分不飽和雙環；其中該環經RQ1C 之p個實例取代。在一些實施例中，RQ 及R1 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的4-8員飽和或部分不飽和單環；其中該環經RQ1C 之p個實例取代。在一些實施例中，RQ 及R1 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的8-12員飽和或部分不飽和雙環；其中該環經RQ1C 之p個實例取代。
在一些實施例中，RQ 為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RQ 為鹵素、-CN、-OH、-O-(視情況經取代之C1-6 脂族基)或視情況經取代之C1-6 脂族基。在一些實施例中，RQ 為鹵素、-OH或視情況經1-3個鹵素取代之C1-3 脂族基。在一些實施例中，RQ 為氟、氯、-OH或-CH3 。在一些實施例中，RQ 為氘。在一些實施例中，RQ 選自表1之化合物中所描繪之基團。
如上文一般所定義，RX 為-LX -RXA 。在一些實施例中，RX 為-RXA 。在一些實施例中，RX 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RX 為鹵素、-CN、-OH、-O-(視情況經取代之C1-6 脂族基)或視情況經取代之C1-6 脂族基。在一些實施例中，RX 為鹵素、-OH、-O-(C1-3 脂族基)或C1-3 脂族基，其中各C1-3 脂族基視情況經1-3個鹵素取代。在一些實施例中，RX 為氟、氯、-OCH3 或-CH3 。在一些實施例中，RX 選自表1之化合物中所描繪之基團。
如上文一般所定義，RY 為-LY -RYA 或RY 及RZ 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的4-7員部分不飽和或芳族環；其中該環經RYZC 之q個實例取代。在一些實施例中，RY 為-LY -RYA 。在一些實施例中，RY 及RZ 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的4-7員部分不飽和或芳族環；其中該環經RYZC 之q個實例取代。在一些實施例中，RY 選自表1之化合物中所描繪之基團。
如上文一般所定義，RZ 為-LZ -RZA 或RY 及RZ 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的4-7員部分不飽和或芳族環；其中該環經RYZC 之q個實例取代。在一些實施例中，RZ 為-LZ -RZA 。在一些實施例中，RY 及RZ 與其等插入原子一起形成具有0-4個獨立地選自氮、氧及硫之雜原子的4-7員部分不飽和或芳族環；其中該環經RYZC 之q個實例取代。在一些實施例中，RZ 選自表1之化合物中所描繪之基團。
如上文一般所定義，L1 為共價鍵或C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，L1 為共價鍵。在一些實施例中，L1 為C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一個或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，L1 為C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈。
在一些實施例中，L1 為C1-2 二價飽和或不飽和烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，L1 為C1-2 二價飽和或不飽和烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-或-O-。在一些實施例中，L1 為C1-2 二價飽和或不飽和烴鏈。在一些實施例中，L1 選自表1之化合物中所描繪之基團。
如上文一般所定義，L2 為共價鍵或C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，L2 為共價鍵。在一些實施例中，L2 為C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一個或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，L2 為C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈。
在一些實施例中，L2 為C1-2 二價飽和或不飽和烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，L2 為C1-2 二價飽和或不飽和烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-或-O-。在一些實施例中，L2 為C1-2 二價飽和或不飽和烴鏈。
在一些實施例中，L2 為-N(R)C(O)-或-N(R)C(O)N(R)-。在一些實施例中，L2 為-N(H)C(O)-或-N(H)C(O)N(H)-。在一些實施例中，L2 為-N(R)C(O)-。在一些實施例中，L2 為-N(H)C(O)-。在一些實施例中，L2 為-N(R)C(O)N(R)-。在一些實施例中，L2 為-N(H)C(O)N(H)-。在一些實施例中，L2 為-N(R)-。在一些實施例中，L2 為-N(H)-。在一些實施例中，L2 為共價鍵。在一些實施例中，L2 選自表1之化合物中所描繪之基團。
如上文一般所定義，LE 為共價鍵或C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LE 為共價鍵。在一些實施例中，LE 為C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一個或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LE 為C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈。
在一些實施例中，LE 為C1-2 二價飽和或不飽和烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LE 為C1-2 二價飽和或不飽和烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-或-O-。在一些實施例中，LE 為C1-2 二價飽和或不飽和烴鏈。在一些實施例中，LE 選自表1之化合物中所描繪之基團。
如上文一般所定義，LQ 為共價鍵或C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LQ 為共價鍵。在一些實施例中，LQ 為C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一個或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LQ 為C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈。
在一些實施例中，LQ 為C1-2 二價飽和或不飽和烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LQ 為C1-2 二價飽和或不飽和烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-或-O-。在一些實施例中，LQ1 為C1-2 二價飽和或不飽和烴鏈。在一些實施例中，LQ 選自表1之化合物中所描繪之基團。
如上文一般所定義，LX 為共價鍵或C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LX 為共價鍵。在一些實施例中，LX 為C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一個或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LX 為C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈。
在一些實施例中，LX 為C1-2 二價飽和或不飽和烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LX 為C1-2 二價飽和或不飽和烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-或-O-。在一些實施例中，LX 為C1-2 二價飽和或不飽和烴鏈。在一些實施例中，LX 選自表1之化合物中所描繪之基團。
如上文一般所定義，LY 為共價鍵或C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LY 為共價鍵。在一些實施例中，LY 為C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一個或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LY 為C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈。
在一些實施例中，LY 為C1-2 二價飽和或不飽和烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LY 為C1-2 二價飽和或不飽和烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-或-O-。在一些實施例中，LY 為C1-2 二價飽和或不飽和烴鏈。
在一些實施例中，LY 為-C(H)2 -、-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LY 為-C(H)2 -、-CH(RL )-、-C(RL )2 -、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-或-O-。在一些實施例中，LY 為-C(H)2 -、-N(R)-、-N(R)C(O)-或-C(O)N(R)-。在一些實施例中，LY 為-C(H)2 -、-N(H)-、-N(H)C(O)-或-C(O)N(H)-。在一些實施例中，LY 選自表1之化合物中所描繪之基團。
如上文一般所定義，LZ 為共價鍵或C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LZ 為共價鍵。在一些實施例中，LZ 為C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一個或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LZ 為C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈。
在一些實施例中，LZ 為C1-2 二價飽和或不飽和烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LZ 為C1-2 二價飽和或不飽和烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-或-O-。在一些實施例中，LZ 為C1-2 二價飽和或不飽和烴鏈。
在一些實施例中，LZ 為-C(H)2 -、-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -。在一些實施例中，LZ 為-C(H)2 -、-CH(RL )-、-C(RL )2 -、-N(R)-、-N(R)C(O)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-或-O-。在一些實施例中，LZ 為-C(H)2 -、-N(R)-、-N(R)C(O)-或-C(O)N(R)-。在一些實施例中，LZ 為-C(H)2 -、-N(H)-、-N(H)C(O)-或-C(O)N(H)-。在一些實施例中，LZ 選自表1之化合物中所描繪之基團。
如上文一般所定義，R1A 為經R1C 之r1 個實例取代之RA 或RB 。在一些實施例中，R1A 為RA 。在一些實施例中，R1A 為經R1C 之r1 個實例取代之RB 。
在一些實施例中，R1A 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其中R1A 經R1C 之r1 個實例取代。
在一些實施例中，R1A 為經R1C 之r1 個實例取代之苯基。在一些實施例中，R1A 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環，其中R1A 經R1C 之r1 個實例取代。在一些實施例中，R1A 為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環，其中R1A 經R1C 之r1 個實例取代。
在一些實施例中，R1A 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；或3-7員飽和或部分不飽和單環碳環，其中R1A 經R1C 之r1 個實例取代。
在一些實施例中，R1A 為經獨立地選自以下之基團之r1 個實例取代的苯基：側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 及視情況經取代之C1-6 脂族基。在一些實施例中，R1A 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環，其中R1A 經獨立地選自以下之基團之r1 個實例取代：側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 及視情況經取代之C1-6 脂族基。在一些實施例中，R1A 為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環，其中R1A 經獨立地選自以下之基團之r1 個實例取代：側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 及視情況經取代之C1-6 脂族基。
在一些實施例中，R1A 為經R1C 之1-3個實例取代之苯基。在一些實施例中，R1A 為經R1C 之2個實例取代之苯基。在一些實施例中，R1A 為經R1 C 之1個實例取代之苯基。
在一些實施例中，R1A 為經獨立地選自以下之基團之1-3個實例取代的苯基：鹵素、-CN-、-O-(視情況經取代之C1-6 脂族基)及視情況經取代之C1-6 脂族基。在一些實施例中，R1A 為經獨立地選自以下之基團之1-3個實例取代的苯基：鹵素及視情況經1-3個鹵素取代之C1-3 脂族基。在一些實施例中，R1A 為經獨立地選自以下之基團之1-3個實例取代的苯基：氟、氯、-CH3 、-CHF2 及-CF3 。
在一些實施例中，R1A 為經獨立地選自以下之基團之2個實例取代的苯基：鹵素、-CN-、-O-(視情況經取代之C1-6 脂族基)及視情況經取代之C1-6 脂族基。在一些實施例中，R1A 為經獨立地選自以下之基團之2個實例取代的苯基：鹵素及視情況經1-3個鹵素取代之C1-3 脂族基。在一些實施例中，R1A 為經獨立地選自以下之基團之2個實例取代的苯基：氟、氯、-CH3 、-CHF2 及-CF3 。
在一些實施例中，R1A 為經選自以下之一個基團取代之苯基：鹵素、-CN-、-O-(視情況經取代之C1-6 脂族基)及視情況經取代之C1-6 脂族基。在一些實施例中，R1A 為經以下者取代之苯基：一個鹵素或視情況經1-3個鹵素取代之C1-3 脂族基。在一些實施例中，R1A 為經一個氟、氯、-CH3 、-CHF2 或-CF3 取代之苯基。
在一些實施例中，R1A 為
Figure 02_image157
，其中R1C 及r1 如本文中之實施例及類別及子類中所定義。在一些實施例中，R1A 為
Figure 02_image159
，其中R1C 如本文中之實施例及類別及子類中所定義。在一些實施例中，R1A 為
Figure 02_image161
，其中R1C 如本文中之實施例及類別及子類中所定義。在一些實施例中，R1A 為
Figure 02_image163
，其中R1C 如本文中之實施例及類別及子類中所定義。在一些實施例中，R1A 為
Figure 02_image165
，其中R1C 如本文中之實施例及類別及子類中所定義。
在一些實施例中，R1A 為
Figure 02_image167
，其中R1C 之各實例獨立地為鹵素、-CN、-O-(視情況經取代之C1-6 脂族基)或視情況經取代之C1-6 脂族基。在一些實施例中，R1A 為
Figure 02_image169
，其中R1C 之各實例獨立地為鹵素或視情況經1-3個鹵素取代之C1-3 脂族基。在一些實施例中，R1A 為
Figure 02_image171
，其中R1C 之各實例獨立地為鹵素或視情況經1-3個鹵素取代之C1-3 脂族基。在一些實施例中，R1A 為
Figure 02_image173
，其中R1C 之各實例獨立地為鹵素或視情況經1-3個鹵素取代之C1-3 脂族基。在一些實施例中，R1A 為
Figure 02_image175
，其中R1C 之各實例獨立地為氟、氯、-CH3 、-CHF2 或-CF3 。在一些實施例中，R1A 為
Figure 02_image177
，其中R1C 為鹵素或視情況經1-3個鹵素取代之C1-3 脂族基。
在一些實施例中，R1A 為
Figure 02_image179
。在一些實施例中，R1A 為
Figure 02_image181
。
在一些實施例中，R1A 為
Figure 02_image183
，其中R1C 及r1 如本文中之實施例及類別及子類中所定義。在一些實施例中，R1A 為
Figure 02_image185
。在一些實施例中，R1A 為
Figure 02_image187
。在一些實施例中，R1A 為
Figure 02_image189
。
在一些實施例中，R1A 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 或氘。
在一些實施例中，R1A 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，R1A 為側氧基。在一些實施例中，R1A 為鹵素。在一些實施例中，R1A 為-CN。在一些實施例中，R1A 為-NO2 。在一些實施例中，R1A 為-OR。在一些實施例中，R1A 為-SR。在一些實施例中，R1A 為-NR2 。在一些實施例中，R1A 為-S(O)2 R。在一些實施例中，R1A 為-S(O)2 NR2 。在一些實施例中，R1A 為-S(O)2 F。在一些實施例中，R1A 為-S(O)R。在一些實施例中，R1A 為-S(O)NR2 。在一些實施例中，R1A 為-S(O)(NR)R。在一些實施例中，R1A 為-C(O)R。在一些實施例中，R1A 為-C(O)OR。在一些實施例中，R1A 為-C(O)NR2 。在一些實施例中，R1A 為-C(O)N(R)OR。在一些實施例中，R1A 為-OC(O)R。在一些實施例中，R1A 為-OC(O)NR2 。在一些實施例中，R1A 為-N(R)C(O)OR。在一些實施例中，R1A 為-N(R)C(O)R。在一些實施例中，R1A 為-N(R)C(O)NR2 。在一些實施例中，R1A 為-N(R)C(NR)NR2 。在一些實施例中，R1A 為-N(R)S(O)2 NR2 。在一些實施例中，R1A 為-N(R)S(O)2 R。在一些實施例中，R1A 為-P(O)R2 。在一些實施例中，R1A 為-P(O)(R)OR。在一些實施例中，R1A 為-B(OR)2 。在一些實施例中，R1A 為氘。
在一些實施例中，R1A 為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，R1A 為鹵素、-CN或-NO2 。在一些實施例中，R1A 為-OR、-SR或-NR2 。在一些實施例中，R1A 為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，R1A 為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，R1A 為-OC(O)R或-OC(O)NR2 。在一些實施例中，R1A 為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，R1A 為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，R1A 為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，R1A 為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，R1A 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，R1A 為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，R1A 為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，R1A 為-SR、-S(O)2 R或-S(O)R。在一些實施例中，R1A 為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，R1A 為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，R1A 為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，R1A 為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，R1A 為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，R1A 為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，R1A 為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，R1A 為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，R1A 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，R1A 為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，R1A 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，R1A 為C1-6 脂族鏈；苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經R1C 之r1 個實例取代。
在一些實施例中，R1A 為經R1C 之r1 個實例取代之C1-6 脂族基C 。在一些實施例中，R1A 為經R1 C 之r1 個實例取代之苯基。在一些實施例中，R1A 為經R1 C 之r1 個實例取代之萘基。在一些實施例中，R1A 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；其中該環經R1 C 之r1 個實例取代。在一些實施例中，R1A 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中該環經R1C 之r1 個實例取代。在一些實施例中，R1A 為經R1C 之r1 個實例取代之3-7員飽和或部分不飽和單環碳環。在一些實施例中，R1A 為經R1C 之r1 個實例取代之5-12員飽和或部分不飽和雙環碳環。在一些實施例中，R1A 為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其中該環經R1C 之r1 個實例取代。在一些實施例中，R1A 為具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其中該環經R1C 之r1 個實例取代。
在一些實施例中，R1A 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經R1C 之r1 個實例取代。在一些實施例中，R1A 為3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經R1C 之r1 個實例取代。
在一些實施例中，R1A 為苯基；萘基；3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經R1C 之r1 個實例取代。在一些實施例中，R1A 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經R1C 之r1 個實例取代。
在一些實施例中，R1A 為苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經R1C 之r1 個實例取代。在一些實施例中，R1A 為萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；5-12員飽和或部分不飽和雙環碳環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經R1C 之r1 個實例取代。
在一些實施例中，R1A 為苯基或萘基；其各自經R1C 之r1 個實例取代。在一些實施例中，R1A 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經R1C 之r1 個實例取代。在一些實施例中，R1A 為3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經R1C 之r1 個實例取代。在一些實施例中，R1A 為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經R1C 之r1 個實例取代。
在一些實施例中，R1A 為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；其各自經R1C 之r1 個實例取代。在一些實施例中，R1A 為3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經R1C 之r1 個實例取代。在一些實施例中，R1A 為萘基或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經R1C 之r1 個實例取代。在一些實施例中，R1A 為5-12員飽和或部分不飽和雙環碳環或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經R1C 之r1 個實例取代。
在一些實施例中，R1A 為苯基或3-7員飽和或部分不飽和單環碳環，其各自經R1C 之r1 個實例取代。在一些實施例中，R1A 為萘基或5-12員飽和或部分不飽和雙環碳環；其各自經R1C 之r1 個實例取代。在一些實施例中，R1A 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經R1C 之r1 個實例取代。在一些實施例中，R1A 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經R1C 之r1 個實例取代。
在一些實施例中，R1A 為C1-6 脂族鏈；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經R1C 之r1 個實例取代。在一些實施例中，R1A 為C1-6 脂族鏈；苯基；萘基；3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經R1C 之r1 個實例取代。在一些實施例中，R1A 為C1-6 脂族鏈；苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經R1C 之r1 個實例取代。
在一些實施例中，R1A 為C1-6 脂族鏈、3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經R1C 之r1 個實例取代。在一些實施例中，R1A 為C1-6 脂族鏈、3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經R1C 之r1 個實例取代。在一些實施例中，R1A 為C1-6 脂族鏈、苯基或3-7員飽和或部分不飽和單環碳環，其各自經R1C 之r1 個實例取代。
在一些實施例中，R1A 選自表1之化合物中所描繪之基團。
如上文一般所定義，R2A 為經R2C 之r2 個實例取代之RA 或RB 。在一些實施例中，R2A 為RA 。在一些實施例中，R2A 為經R2C 之r2 個實例取代之RB 。
在一些實施例中，R2A 為苯基；萘基；立方烷基；金剛烷基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其中R2A 經R2C 之r2 個實例取代。
在一些實施例中，R2A 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其中R2A 經R2C 之r2 個實例取代。在一些實施例中，R2A 為苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其中R2A 經R2C 之r2 個實例取代。在一些實施例中，R2A 為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中R2A 經R2C 之r2 個實例取代。
在一些實施例中，R2A 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其中R2A 經獨立地選自以下之基團之r2 個實例取代：側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 及視情況經取代之C1-6 脂族基。在一些實施例中，R2A 為苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其中R2A 經獨立地選自以下之基團之r2 個實例取代：側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 及視情況經取代之C1-6 脂族基。在一些實施例中，R2A 為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中R2A 經獨立地選自以下之基團之r2 個實例取代：側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 及視情況經取代之C1-6 脂族基。
在一些實施例中，R2A 為經R2C 之r2 個實例取代之苯基。在一些實施例中，R2A 為經獨立地選自以下之基團之r2 個實例取代的苯基：側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 及視情況經取代之C1-6 脂族基。
在一些實施例中，R2A 為經獨立地選自以下之基團之1-3個實例取代的苯基：鹵素、-CN-、-O-(視情況經取代之C1-6 脂族基)及視情況經取代之C1-6 脂族基。在一些實施例中，R2A 為經獨立地選自以下之基團之1-3個實例取代的苯基：鹵素及視情況經1-3個鹵素取代之C1-3 脂族基。在一些實施例中，R2A 為經獨立地選自以下之基團之1-3個實例取代的苯基：氟、氯、-CH3 、-CHF2 及-CF3 。
在一些實施例中，R2A 為經獨立地選自以下之基團之2個實例取代的苯基：鹵素、-CN-、-O-(視情況經取代之C1-6 脂族基)及視情況經取代之C1-6 脂族基。在一些實施例中，R2A 為經獨立地選自以下之基團之2個實例取代的苯基：鹵素及視情況經1-3個鹵素取代之C1-3 脂族基。在一些實施例中，R2A 為經獨立地選自以下之基團之2個實例取代的苯基：氟、氯、-CH3 、-CHF2 及-CF3 。
在一些實施例中，R2A 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中R2A 經R2C 之r2 個實例取代。在一些實施例中，R2A 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中R2A 經獨立地選自以下之基團之r2 個實例取代：側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 及視情況經取代之C1-6 脂族基。
在一些實施例中，R2A 為具有1-2個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中R2A 經R2C 之r2 個實例取代。在一些實施例中，R2A 為具有1-2個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中R2A 經獨立地選自以下之基團之r2 個實例取代：側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 及視情況經取代之C1-6 脂族基。
在一些實施例中，R2A 為具有1-2個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中R2A 經獨立地選自以下之基團之0-2個實例取代：鹵素、-CN-、-O-(視情況經取代之C1-6 脂族基)及視情況經取代之C1-6 脂族基。在一些實施例中，R2A 為具有1-2個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中R2A 經獨立地選自以下之基團之0-2個實例取代：鹵素及視情況經1-3個鹵素取代之C1-3 脂族基。在一些實施例中，R2A 為具有1-2個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中R2A 經獨立地選自以下之基團之0-2個實例取代：氟、氯、-CH3 、-CHF2 及-CF3 。
在一些實施例中，R2A 為
Figure 02_image191
Figure 02_image193
，其中R2C 及r2 如本文中之實施例及類別及子類中所定義。在一些實施例中，R2A 為
Figure 02_image195
。在一些實施例中，R2A 為
Figure 02_image197
。在一些實施例中，R2A 為
Figure 02_image199
。在一些實施例中，R2A 為
Figure 02_image201
。在一些實施例中，R2A 為
Figure 02_image203
。在一些實施例中，R2A 為
Figure 02_image205
。在一些實施例中，R2A 為
Figure 02_image207
。在一些實施例中，R2A 為
Figure 02_image209
。在一些實施例中，R2A 為
Figure 02_image211
。在一些實施例中，R2A 為
Figure 02_image213
。在一些實施例中，R2A 為
Figure 02_image215
。
在一些實施例中，R2A 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 或氘。
在一些實施例中，R2A 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，R2A 為側氧基。在一些實施例中，R2A 為鹵素。在一些實施例中，R2A 為-CN。在一些實施例中，R2A 為-NO2 。在一些實施例中，R2A 為-OR。在一些實施例中，R2A 為-SR。在一些實施例中，R2A 為-NR2 。在一些實施例中，R2A 為-S(O)2 R。在一些實施例中，R2A 為-S(O)2 NR2 。在一些實施例中，R2A 為-S(O)2 F。在一些實施例中，R2A 為-S(O)R。在一些實施例中，R2A 為-S(O)NR2 。在一些實施例中，R2A 為-S(O)(NR)R。在一些實施例中，R2A 為-C(O)R。在一些實施例中，R2A 為-C(O)OR。在一些實施例中，R2A 為-C(O)NR2 。在一些實施例中，R2A 為-C(O)N(R)OR。在一些實施例中，R2A 為-OC(O)R。在一些實施例中，R2A 為-OC(O)NR2 。在一些實施例中，R2A 為-N(R)C(O)OR。在一些實施例中，R2A 為-N(R)C(O)R。在一些實施例中，R2A 為-N(R)C(O)NR2 。在一些實施例中，R2A 為-N(R)C(NR)NR2 。在一些實施例中，R2A 為-N(R)S(O)2 NR2 。在一些實施例中，R2A 為-N(R)S(O)2 R。在一些實施例中，R2A 為-P(O)R2 。在一些實施例中，R2A 為-P(O)(R)OR。在一些實施例中，R2A 為-B(OR)2 。在一些實施例中，R2A 為氘。
在一些實施例中，R2A 為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，R2A 為鹵素、-CN或-NO2 。在一些實施例中，R2A 為-OR、-SR或-NR2 。在一些實施例中，R2A 為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，R2A 為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，R2A 為-OC(O)R或-OC(O)NR2 。在一些實施例中，R2A 為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，R2A 為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，R2A 為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，R2A 為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，R2A 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，R2A 為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，R2A 為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，R2A 為-SR、-S(O)2 R或-S(O)R。在一些實施例中，R2A 為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，R2A 為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，R2A 為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，R2A 為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，R2A 為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，R2A 為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，R2A 為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，R2A 為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，R2A 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，R2A 為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，R2A 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，R2A 為C1-6 脂族鏈；苯基；萘基；立方烷基；金剛烷基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經R2 C 之r2 個實例取代。
在一些實施例中，R2A 為經R2C 之r2 個實例取代之C1-6 脂族基。在一些實施例中，R2A 為經R2 C 之r2 個實例取代之苯基。在一些實施例中，R2A 為經R2C 之r2 個實例取代之萘基。在一些實施例中，R2A 經R2 C 之r2 個實例取代之立方烷基。在一些實施例中，R2A 為經R2C 之r2 個實例取代之金剛烷基。在一些實施例中，R2A 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；其中該環經R2C 之r2 個實例取代。在一些實施例中，R2A 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中該環經R2C 之r2 個實例取代。在一些實施例中，R2A 為經R2C 之r2 個實例取代之3-7員飽和或部分不飽和單環碳環。在一些實施例中，R2A 為經R2C 之r2 個實例取代之5-12員飽和或部分不飽和雙環碳環。在一些實施例中，R2A 為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其中該環經R2C 之r2 個實例取代。在一些實施例中，R2A 為具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其中該環經R2C 之r2 個實例取代。
在一些實施例中，R2A 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經R2C 之r2 個實例取代。在一些實施例中，R2A 為立方烷基；金剛烷基；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經R2 C 之r2 個實例取代。
在一些實施例中，R2A 為苯基；萘基；立方烷基；金剛烷基；3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經R2C 之r2 個實例取代。在一些實施例中，R2A 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經R2 C 之r2 個實例取代。
在一些實施例中，R2A 為苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經R2C 之r2 個實例取代。在一些實施例中，R2A 為萘基；立方烷基；金剛烷基；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；5-12員飽和或部分不飽和雙環碳環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經R2 C 之r2 個實例取代。
在一些實施例中，R2A 為苯基或萘基；其各自經R2C 之r2 個實例取代。在一些實施例中，R2A 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經R2C 之r2 個實例取代。在一些實施例中，R2A 為3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經R2C 之r2 個實例取代。在一些實施例中，R2A 為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經R2 C 之r2 個實例取代。
在一些實施例中，R2A 為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；其各自經R2 C 之r2 個實例取代。在一些實施例中，R2A 為3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經R2C 之r2 個實例取代。在一些實施例中，R2A 為萘基或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經R2C 之r2 個實例取代。在一些實施例中，R2A 為立方烷基；金剛烷基；5-12員飽和或部分不飽和雙環碳環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經R2 C 之r2 個實例取代。
在一些實施例中，R2A 為苯基或3-7員飽和或部分不飽和單環碳環；其各自經R2 C 之r2 個實例取代。在一些實施例中，R2A 為萘基；立方烷基；金剛烷基；或5-12員飽和或部分不飽和雙環碳環；其各自經R2C 之r2 個實例取代。在一些實施例中，R2A 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經R2C 之r2 個實例取代。在一些實施例中，R2A 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經R2 C 之r2 個實例取代。
在一些實施例中，R2A 為C1-6 脂族鏈；立方烷基；金剛烷基；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經R2C 之r2 個實例取代。在一些實施例中，R2A 為C1-6 脂族鏈；苯基；萘基；立方烷基；金剛烷基；3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經R2C 之r2 個實例取代。在一些實施例中，R2A 為C1-6 脂族鏈；苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經R2 C 之r2 個實例取代。
在一些實施例中，R2A 為C1-6 脂族鏈、立方烷基、金剛烷基、3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經R2C 之r2 個實例取代。在一些實施例中，R2A 為C1-6 脂族鏈、3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經R2C 之r2 個實例取代。在一些實施例中，R2A 為C1-6 脂族鏈、苯基或3-7員飽和或部分不飽和單環碳環，其各自經R2 C 之r2 個實例取代。
在一些實施例中，R2A 選自表1之化合物中所描繪之基團。
如上文一般所定義，REA 為經REC 之r3 個實例取代之RA 或RB 。在一些實施例中，REA 為RA 。在一些實施例中，REA 為經REC 之r3 個實例取代之RB 。
在一些實施例中，REA 之各實例獨立地為經REC 之r3 個實例取代之C1-6 脂族基。在一些實施例中，REA 之各實例獨立地為經REC 之r3 個實例取代之C1-3 脂族基。在一些實施例中，REA 之各實例獨立地為經鹵素之r3 個實例取代之C1-3 脂族基。在一些實施例中，REA 之各實例獨立地為C1-3 脂族基。在一些實施例中，RE 之各實例獨立地為-CH3 、-CH2 F、-CHF2 -或-CF3 。在一些實施例中，REA 為-CH3 。
在一些實施例中，REA 選自表1之化合物中所描繪之基團。
如上文一般所定義，RQA 為經RQC 之r4 個實例取代之RA 或RB 。在一些實施例中，RQA 為RA 。在一些實施例中，RQA 為經RQC 之r4 個實例取代之RB 。
在一些實施例中，RQA 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 或氘。
在一些實施例中，RQA 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RQA 為側氧基。在一些實施例中，RQA 為鹵素。在一些實施例中，RQA 為-CN。在一些實施例中，RQA 為-NO2 。在一些實施例中，RQA 為-OR。在一些實施例中，RQA 為-SR。在一些實施例中，RQA 為-NR2 。在一些實施例中，RQA 為-S(O)2 R。在一些實施例中，RQA 為-S(O)2 NR2 。在一些實施例中，RQA 為-S(O)2 F。在一些實施例中，RQA 為-S(O)R。在一些實施例中，RQA 為-S(O)NR2 。在一些實施例中，RQA 為-S(O)(NR)R。在一些實施例中，RQA 為-C(O)R。在一些實施例中，RQA 為-C(O)OR。在一些實施例中，RQA 為-C(O)NR2 。在一些實施例中，RQA 為-C(O)N(R)OR。在一些實施例中，RQA 為-OC(O)R。在一些實施例中，RQA 為-OC(O)NR2 。在一些實施例中，RQA 為-N(R)C(O)OR。在一些實施例中，RQA 為-N(R)C(O)R。在一些實施例中，RQA 為-N(R)C(O)NR2 。在一些實施例中，RQA 為-N(R)C(NR)NR2 。在一些實施例中，RQA 為-N(R)S(O)2 NR2 。在一些實施例中，RQA 為-N(R)S(O)2 R。在一些實施例中，RQA 為-P(O)R2 。在一些實施例中，RQA 為-P(O)(R)OR。在一些實施例中，RQA 為-B(OR)2 。在一些實施例中，RQA 為氘。
在一些實施例中，RQA 為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RQA 為鹵素、-CN或-NO2 。在一些實施例中，RQA 為-OR、-SR或-NR2 。在一些實施例中，RQA 為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RQA 為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，RQA 為-OC(O)R或-OC(O)NR2 。在一些實施例中，RQA 為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RQA 為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，RQA 為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，RQA 為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RQA 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，RQA 為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，RQA 為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RQA 為-SR、-S(O)2 R或-S(O)R。在一些實施例中，RQA 為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RQA 為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，RQA 為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，RQA 為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RQA 為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RQA 為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RQA 為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，RQA 為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RQA 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RQA 為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RQA 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RQA 為C1-6 脂族鏈；苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RQC 之r6 個實例取代。
在一些實施例中，RQA 為經RQC 之r4 個實例取代之C1-6 脂族基。在一些實施例中，RQA 為經RQC 之r4 個實例取代之苯基。在一些實施例中，RQA 為經RQC 之r4 個實例取代之萘基。在一些實施例中，RQA 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；其中該環經RQC 之r4 個實例取代。在一些實施例中，RQA 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中該環經RQC 之r4 個實例取代。在一些實施例中，RQA 為經RQC 之r4 個實例取代之3-7員飽和或部分不飽和單環碳環。在一些實施例中，RQA 為經RQC 之r4 個實例取代之5-12員飽和或部分不飽和雙環碳環。在一些實施例中，RQA 為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其中該環經RQC 之r4 個實例取代。在一些實施例中，RQA 為具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其中該環經RQC 之r4 個實例取代。
在一些實施例中，RQA 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RQC 之r4 個實例取代。
在一些實施例中，RQA 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經RQC 之r4 個實例取代。在一些實施例中，RQA 為3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RQC 之r4 個實例取代。
在一些實施例中，RQA 為苯基；萘基；3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RQC 之r4 個實例取代。在一些實施例中，RQA 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RQC 之r4 個實例取代。
在一些實施例中，RQA 為苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RQC 之r4 個實例取代。在一些實施例中，RQA 為萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；5-12員飽和或部分不飽和雙環碳環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RQC 之r4 個實例取代。
在一些實施例中，RQA 為苯基或萘基；其各自經RQC 之r4 個實例取代。在一些實施例中，RQA 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經RQC 之r4 個實例取代。在一些實施例中，RQA 為3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RQC 之r4 個實例取代。在一些實施例中，RQA 為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RQC 之r4 個實例取代。
在一些實施例中，RQA 為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；其各自經RQC 之r4 個實例取代。在一些實施例中，RQA 為3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RQC 之r4 個實例取代。在一些實施例中，RQA 為萘基或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經RQC 之r4 個實例取代。在一些實施例中，RQA 為5-12員飽和或部分不飽和雙環碳環或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RQC 之r4 個實例取代。
在一些實施例中，RQA 為苯基或3-7員飽和或部分不飽和單環碳環；其各自經RQC 之r4 個實例取代。在一些實施例中，RQA 為萘基或5-12員飽和或部分不飽和雙環碳環；其各自經RQC 之r4 個實例取代。在一些實施例中，RQA 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RQC 之r4 個實例取代。在一些實施例中，RQA 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RQC 之r4 個實例取代。
在一些實施例中，RQA 為C1-6 脂族鏈；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RQC 之r4 個實例取代。在一些實施例中，RQA 為C1-6 脂族鏈；苯基；萘基；3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RQC 之r4 個實例取代。在一些實施例中，RQA 為C1-6 脂族鏈；苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RQC 之r4 個實例取代。
在一些實施例中，RQA 為C1-6 脂族鏈、3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RQC 之r4 個實例取代。在一些實施例中，RQA 為C1-6 脂族鏈、3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RQC 之r4 個實例取代。在一些實施例中，RQA 為C1-6 脂族鏈、苯基或3-7員飽和或部分不飽和單環碳環；其各自經RQC 之r4 個實例取代。
在一些實施例中，RQA 選自表1之化合物中所描繪之基團。
如上文一般所定義，RXA 為經RXC 之r5 個實例取代之RA 或RB 。在一些實施例中，RXA 為RA 。在一些實施例中，RXA 為經RXC 之r5 個實例取代之RB 。
在一些實施例中，RXA 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 或氘。
在一些實施例中，RXA 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RXA 為側氧基。在一些實施例中，RXA 為鹵素。在一些實施例中，RXA 為-CN。在一些實施例中，RXA 為-NO2 。在一些實施例中，RXA 為-OR。在一些實施例中，RXA 為-SR。在一些實施例中，RXA 為-NR2 。在一些實施例中，RXA 為-S(O)2 R。在一些實施例中，RXA 為-S(O)2 NR2 。在一些實施例中，RXA 為-S(O)2 F。在一些實施例中，RXA 為-S(O)R。在一些實施例中，RXA 為-S(O)NR2 。在一些實施例中，RXA 為-S(O)(NR)R。在一些實施例中，RXA 為-C(O)R。在一些實施例中，RXA 為-C(O)OR。在一些實施例中，RXA 為-C(O)NR2 。在一些實施例中，RXA 為-C(O)N(R)OR。在一些實施例中，RXA 為-OC(O)R。在一些實施例中，RXA 為-OC(O)NR2 。在一些實施例中，RXA 為-N(R)C(O)OR。在一些實施例中，RXA 為-N(R)C(O)R。在一些實施例中，RXA 為-N(R)C(O)NR2 。在一些實施例中，RXA 為-N(R)C(NR)NR2 。在一些實施例中，RXA 為-N(R)S(O)2 NR2 。在一些實施例中，RXA 為-N(R)S(O)2 R。在一些實施例中，RXA 為-P(O)R2 。在一些實施例中，RXA 為-P(O)(R)OR。在一些實施例中，RXA 為-B(OR)2 。在一些實施例中，RXA 為氘。
在一些實施例中，RXA 為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RXA 為鹵素、-CN或-NO2 。在一些實施例中，RXA 為-OR、-SR或-NR2 。在一些實施例中，RXA 為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RXA 為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，RXA 為-OC(O)R或-OC(O)NR2 。在一些實施例中，RXA 為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RXA 為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，RXA 為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，RXA 為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RXA 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，RXA 為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，RXA 為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RXA 為-SR、-S(O)2 R或-S(O)R。在一些實施例中，RXA 為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RXA 為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，RXA 為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，RXA 為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RXA 為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RXA 為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RXA 為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，RXA 為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RXA 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RXA 為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RXA 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RXA 為C1-6 脂族鏈；苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RXC 之r5 個實例取代。
在一些實施例中，RXA 為經RXC 之r5 個實例取代之C1-6 脂族基。在一些實施例中，RXA 為經RXC 之r5 個實例取代之苯基。在一些實施例中，RXA 為經RXC 之r5 個實例取代之萘基。在一些實施例中，RXA 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；其中該環經RXC 之r5 個實例取代。在一些實施例中，RXA 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中該環經RXC 之r5 個實例取代。在一些實施例中，RXA 為經RXC 之r5 個實例取代之3-7員飽和或部分不飽和單環碳環。在一些實施例中，RXA 為經RXC 之r5 個實例取代之5-12員飽和或部分不飽和雙環碳環。在一些實施例中，RXA 為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其中該環經RXC 之r5 個實例取代。在一些實施例中，RXA 為具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其中該環經RXC 之r5 個實例取代。
在一些實施例中，RXA 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RXC 之r5 個實例取代。
在一些實施例中，RXA 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經RXC 之r5 個實例取代。在一些實施例中，RXA 為3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RXC 之r5 個實例取代。
在一些實施例中，RXA 為苯基；萘基；3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RXC 之r5 個實例取代。在一些實施例中，RXA 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RXC 之r5 個實例取代。
在一些實施例中，RXA 為苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RXC 之r5 個實例取代。在一些實施例中，RXA 為萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；5-12員飽和或部分不飽和雙環碳環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RXC 之r5 個實例取代。
在一些實施例中，RXA 為苯基或萘基；其各自經RXC 之r5 個實例取代。在一些實施例中，RXA 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經RXC 之r5 個實例取代。在一些實施例中，RXA 為3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RXC 之r5 個實例取代。在一些實施例中，RXA 為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RXC 之r5 個實例取代。
在一些實施例中，RXA 為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；其各自經RXC 之r5 個實例取代。在一些實施例中，RXA 為3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RXC 之r5 個實例取代。在一些實施例中，RXA 為萘基或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經RXC 之r5 個實例取代。在一些實施例中，RXA 為5-12員飽和或部分不飽和雙環碳環或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RXC 之r5 個實例取代。
在一些實施例中，RXA 為苯基或3-7員飽和或部分不飽和單環碳環，其各自經RXC 之r5 個實例取代。在一些實施例中，RXA 為萘基或5-12員飽和或部分不飽和雙環碳環；其各自經RXC 之r5 個實例取代。在一些實施例中，RXA 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RXC 之r5 個實例取代。在一些實施例中，RXA 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RXC 之r5 個實例取代。
在一些實施例中，RXA 為C1-6 脂族鏈；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RXC 之r5 個實例取代。在一些實施例中，RXA 為C1-6 脂族鏈；苯基；萘基；3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RXC 之r5 個實例取代。在一些實施例中，RXA 為C1-6 脂族鏈；苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RXC 之r5 個實例取代。
在一些實施例中，RXA 為C1-6 脂族鏈、3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RXC 之r5 個實例取代。在一些實施例中，RXA 為C1-6 脂族鏈、3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RXC 之r5 個實例取代。在一些實施例中，RXA 為C1-6 脂族鏈、苯基或3-7員飽和或部分不飽和單環碳環；其各自經RXC 之r5 個實例取代。
在一些實施例中，RXA 選自表1之化合物中所描繪之基團。
如上文一般所描述，RYA 為經RYC 之r6 個實例取代之RA 或RB 。在一些實施例中，RYA 為RA 。在一些實施例中，RYA 為經RYC 之r6 個實例取代之RB 。
在一些實施例中，RYA 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之RB ：C1-6 脂族鏈；苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環；及具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其中該RB 經RYC 之r6 個實例取代。
在一些實施例中，RYA 為鹵素、-CN、-OR、-NR2 、-C(O)R、-C(O)OR、-C(O)NR2 、-N(R)C(O)R，或選自以下之RB ：C1-6 脂族鏈；苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環；及具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其中該RB 經RYC 之r6 個實例取代。
在一些實施例中，RYA 為鹵素、-CN、-OR、-NR2 、-C(O)R、-C(O)OR、-C(O)NR2 、-N(R)C(O)R，或選自以下之RB ：C1-6 脂族鏈；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環；及具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其中該RB 經RYC 之r6 個實例取代。在一些實施例中，RYA 為鹵素或選自以下之RB ：C1-6 脂族鏈；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環；及具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其中該RB 經RYC 之r6 個實例取代。
在一些實施例中，RYA 為鹵素或選自以下之RB ：C1-4 脂族鏈；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-5員飽和或部分不飽和單環碳環；及具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中該RB 經RYC 之r6 個實例取代。在一些實施例中，RYA 為鹵素或選自以下之RB ：C1-4 脂族鏈；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-5員飽和或部分不飽和單環碳環；及具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中該RB 經獨立地選自以下之基團之r6 個實例取代：側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 及視情況經取代之C1-6 脂族基。
在一些實施例中，RYA 為鹵素或選自以下之RB ：C1-4 脂族鏈；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-5員飽和或部分不飽和單環碳環；及具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中該RB 經獨立地選自以下之基團之r6 個實例取代：鹵素、-CN-、-OH、-O-(視情況經取代之C1-3 脂族基)及視情況經取代之C1-3 脂族基。在一些實施例中，RYA 為鹵素或選自以下之RB ：C1-4 脂族鏈；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-5員飽和或部分不飽和單環碳環；及具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中該RB 經獨立地選自以下之基團之r6 個實例取代：鹵素、-OH、-O-(C1-3 脂族基)及C1-3 脂族基，其中各C1-3 脂族基視情況經1-3個鹵素取代。在一些實施例中，RYA 為鹵素或選自以下之RB ：C1-4 脂族鏈；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-5員飽和或部分不飽和單環碳環；及具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中該RB 經獨立地選自以下之基團之r6 個實例取代：氟、氯、-OH、-OCH3 、-OCF3 、-CH3 、-CHF2 及-CF3 。
在一些實施例中，RYA 為鹵素或選自以下之RB ：C1-4 脂族鏈及具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中該RB 經獨立地選自以下之基團之r6 個實例取代：鹵素、-OH、-O-(C1-3 脂族基)及C1-3 脂族基，其中各C1-3 脂族基視情況經1-3個鹵素取代。在一些實施例中，RYA 為鹵素或選自以下之RB ：C1-4 脂族鏈及具有1-2個獨立地選自氮及氧之雜原子的3-5員飽和或部分不飽和單環雜環；其中該RB 經獨立地選自以下之基團之r6 個實例取代：氟、氯、-OH、-OCH3 、-OCF3 、-CH3 、-CHF2 及-CF3 。
在一些實施例中，RYA 為鹵素或經-OH及0-3個氟取代之C1-4 脂族鏈。
在一些實施例中，RYA 為鹵素、-CN、-OR、-NR2 、-C(O)R、-C(O)OR、-C(O)NR2 或-N(R)C(O)R。在一些實施例中，RYA 為鹵素。
在一些實施例中，RYA 為C1-6 脂族鏈；苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其中RYA 經RYC 之r6 個實例取代。在一些實施例中，RYA 為C1-6 脂族鏈；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其中RYA 經RYC 之r6 個實例取代。
在一些實施例中，RYA 為C1-4 脂族鏈；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-5員飽和或部分不飽和單環碳環；或具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中RYA 經RYC 之r6 個實例取代。在一些實施例中，RYA 為C1-4 脂族鏈；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-5員飽和或部分不飽和單環碳環；或具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中RYA 經獨立地選自以下之基團之r6 個實例取代：側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 及視情況經取代之C1-6 脂族基。
在一些實施例中，RYA 為C1-4 脂族鏈；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-5員飽和或部分不飽和單環碳環；或具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中RYA 經獨立地選自以下之基團之r6 個實例取代：鹵素、-CN-、-OH、-O-(視情況經取代之C1-3 脂族基)及視情況經取代之C1-3 脂族基。在一些實施例中，RYA 為C1-4 脂族鏈；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-5員飽和或部分不飽和單環碳環；或具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中RYA 經獨立地選自以下之基團之r6 個實例取代：鹵素、-OH、-O-(C1-3 脂族基)及C1-3 脂族基，其中各C1-3 脂族基視情況經1-3個鹵素取代。在一些實施例中，RYA 為C1-4 脂族鏈；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-5員飽和或部分不飽和單環碳環；或具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中RYA 經獨立地選自以下之基團之r6 個實例取代：氟、氯、-OH、-OCH3 、-OCF3 、-CH3 、-CHF2 及-CF3 。
在一些實施例中，RYA 為C1-4 脂族鏈或具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中RYA 經獨立地選自以下之基團之r6 個實例取代：鹵素、-OH、-O-(C1-3 脂族基)及C1-3 脂族基，其中各C1-3 脂族基視情況經1-3個鹵素取代。在一些實施例中，RYA 為C1-4 脂族鏈或具有1-2個獨立地選自氮及氧之雜原子的3-5員飽和或部分不飽和單環雜環；其中RYA 經獨立地選自以下之基團之r6 個實例取代：氟、氯、-OH、-OCH3 、-OCF3 、-CH3 、-CHF2 及-CF3 。在一些實施例中，RYA 為經-OH及0-3個氟取代之C1-4 脂族鏈。
在一些實施例中，RYA 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 或氘。
在一些實施例中，RYA 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RYA 為側氧基。在一些實施例中，RYA 為鹵素。在一些實施例中，RYA 為-CN。在一些實施例中，RYA 為-NO2 。在一些實施例中，RYA 為-OR。在一些實施例中，RYA 為-SR。在一些實施例中，RYA 為-NR2 。在一些實施例中，RYA 為-S(O)2 R。在一些實施例中，RYA 為-S(O)2 NR2 。在一些實施例中，RYA 為-S(O)2 F。在一些實施例中，RYA 為-S(O)R。在一些實施例中，RYA 為-S(O)NR2 。在一些實施例中，RYA 為-S(O)(NR)R。在一些實施例中，RYA 為-C(O)R。在一些實施例中，RYA 為-C(O)OR。在一些實施例中，RYA 為-C(O)NR2 。在一些實施例中，RYA 為-C(O)N(R)OR。在一些實施例中，RYA 為-OC(O)R。在一些實施例中，RYA 為-OC(O)NR2 。在一些實施例中，RYA 為-N(R)C(O)OR。在一些實施例中，RYA 為-N(R)C(O)R。在一些實施例中，RYA 為-N(R)C(O)NR2 。在一些實施例中，RYA 為-N(R)C(NR)NR2 。在一些實施例中，RYA 為-N(R)S(O)2 NR2 。在一些實施例中，RYA 為-N(R)S(O)2 R。在一些實施例中，RYA 為-P(O)R2 。在一些實施例中，RYA 為-P(O)(R)OR。在一些實施例中，RYA 為-B(OR)2 。在一些實施例中，RYA 為氘。
在一些實施例中，RYA 為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RYA 為鹵素、-CN或-NO2 。在一些實施例中，RYA 為-OR、-SR或-NR2 。在一些實施例中，RYA 為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RYA 為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，RYA 為-OC(O)R或-OC(O)NR2 。在一些實施例中，RYA 為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RYA 為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，RYA 為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，RYA 為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RYA 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，RYA 為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，RYA 為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RYA 為-SR、-S(O)2 R或-S(O)R。在一些實施例中，RYA 為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RYA 為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，RYA 為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，RYA 為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RYA 為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RYA 為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RYA 為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，RYA 為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RYA 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RYA 為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RYA 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RYA 為C1-6 脂族鏈；苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RYC 之r6 個實例取代。
在一些實施例中，RYA 為經RYC 之r6 個實例取代之C1-6 脂族基。在一些實施例中，RYA 為經RYC 之r6 個實例取代之苯基。在一些實施例中，RYA 為經RYC 之r6 個實例取代之萘基。在一些實施例中，RYA 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；其中該環經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中該環經RYC 之r6 個實例取代。在一些實施例中，RYA 為經RYC 之r6 個實例取代之3-7員飽和或部分不飽和單環碳環。在一些實施例中，RYA 為經RYC 之r6 個實例取代之5-12員飽和或部分不飽和雙環碳環。在一些實施例中，RYA 為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其中該環經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其中該環經RYC 之r6 個實例取代。
在一些實施例中，RYA 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RYC 之r6 個實例取代。
在一些實施例中，RYA 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經RYC 之r6 個實例取代。在一些實施例中，RYA 為3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RYC 之r6 個實例取代。
在一些實施例中，RYA 為苯基；萘基；3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RYC 之r6 個實例取代。
在一些實施例中，RYA 為苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RYC 之r6 個實例取代。在一些實施例中，RYA 為萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；5-12員飽和或部分不飽和雙環碳環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RYC 之r6 個實例取代。
在一些實施例中，RYA 為苯基或萘基；其各自經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經RYC 之r6 個實例取代。在一些實施例中，RYA 為3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RYC 之r6 個實例取代。
在一些實施例中，RYA 為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；其各自經RYC 之r6 個實例取代。在一些實施例中，RYA 為3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RYC 之r6 個實例取代。在一些實施例中，RYA 為萘基或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經RYC 之r6 個實例取代。在一些實施例中，RYA 為5-12員飽和或部分不飽和雙環碳環或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RYC 之r6 個實例取代。
在一些實施例中，RYA 為苯基或3-7員飽和或部分不飽和單環碳環；其各自經RYC 之r6 個實例取代。在一些實施例中，RYA 為萘基或5-12員飽和或部分不飽和雙環碳環；其各自經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RYC 之r6 個實例取代。
在一些實施例中，RYA 為C1-6 脂族鏈；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RYC 之r6 個實例取代。在一些實施例中，RYA 為C1-6 脂族鏈；苯基；萘基；3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RYC 之r6 個實例取代。在一些實施例中，RYA 為C1-6 脂族鏈；苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RYC 之r6 個實例取代。
在一些實施例中，RYA 為C1-6 脂族鏈、3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RYC 之r6 個實例取代。在一些實施例中，RYA 為C1-6 脂族鏈、3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RYC 之r6 個實例取代。在一些實施例中，RYA 為C1-6 脂族鏈、苯基或3-7員飽和或部分不飽和單環碳環；其各自經RYC 之r6 個實例取代。
在一些實施例中，RYA 為具有1、2或3個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中該環經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有2或3個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中該環經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有1、2或3個氮原子之8-10員雙環雜芳基環；其中該環經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有2或3個氮原子之8-10員雙環雜芳基環；其中該環經RYC 之r6 個實例取代。
在某些實施例中，RYA 為咪唑并[1,2-a ]吡𠯤基，[1,2,4]三唑并[1,5-a ]吡啶基或吡唑并[1,5-a ]嘧啶基；其各自經RYC 之r6 個實例取代。在某些實施例中，RYA 為經RYC 之r6 個實例取代之咪唑并[1,2-a ]吡𠯤基。在某些實施例中，RYA 為經RYC 之r6 個實例取代之[1,2,4]三唑并[1,5-a ]吡啶基。在某些實施例中，RYA 為經RYC 之r6 個實例取代之吡唑并[1,5-a ]嘧啶基。
在某些實施例中，RYA 為咪唑并[1,2-a ]吡𠯤-6-基、[1,2,4]三唑并[1,5-a ]吡啶-6-基或吡唑并[1,5-a ]嘧啶-5-基；其各自經RYC 之r6 個實例取代。在某些實施例中，RYA 為經RYC 之r6 個實例取代之咪唑并[1,2-a ]吡𠯤-6-基。在某些實施例中，RYA 為經RYC 之r6 個實例取代之[1,2,4]三唑并[1,5-a ]吡啶-6-基。在某些實施例中，RYA 為經RYC 之r6 個實例取代之吡唑并[1,5-a ]嘧啶-5-基。
在某些實施例中，RYA 為咪唑并[1,2-a ]吡𠯤-6-基，[1,2,4]三唑并[1,5-a ]吡啶-6-基或吡唑并[1,5-a ]嘧啶-5-基。在某些實施例中，RYA 為咪唑并[1,2-a ]吡𠯤-6-基。在某些實施例中，RYA 為[1,2,4]三唑并[1,5-a ]吡啶-6-基。在某些實施例中，RYA 為吡唑并[1,5-a ]嘧啶-5-基。
在一些實施例中，RYA 為具有1、2或3個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1或2個獨立地選自氮、氧及硫之雜原子的5-7員飽和或部分不飽和單環雜環；其各自經RYC 之r6 個實例取代。
在一些實施例中，RYA 為具有1、2或3個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；其中該環經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有1、2或3個獨立地選自氮、氧及硫之雜原子的5員單環雜芳基環；其中該環經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有1或2個獨立地選自氮及氧之雜原子的5員單環雜芳基環；其中該環經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有1或2個氮原子之6員單環雜芳基環；其中該環經RYC 之r6 個實例取代。
在某些實施例中，RYA 為吡唑基或咪唑基，其各自經RYC 之r6 個實例取代。在某些實施例中，RYA 為經RYC 之r6 個實例取代之吡唑基。在某些實施例中，RYA 為經RYC 之r6 個實例取代之咪唑基。在某些實施例中，RYA 為吡唑-4-基或咪唑-4-基，其各自經RYC 之r6 個實例取代。在某些實施例中，RYA 為經RYC 之r6 個實例取代之吡唑-4-基。在某些實施例中，RYA 為經RYC 之r6 個實例取代之咪唑-4-基。
在一些實施例中，RYA 為具有1或2個獨立地選自氮、氧及硫之雜原子的3-7員部分不飽和單環雜環；其中該環經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有1或2個獨立地選自氮、氧及硫之雜原子的3-7員飽和單環雜環；其中該環經RYC 之r6 個實例取代。
在一些實施例中，RYA 為具有1或2個獨立地選自氮、氧及硫之雜原子的5-7員飽和或部分不飽和單環雜環；其中該環經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有1或2個獨立地選自氮、氧及硫之雜原子的5-7員飽和單環雜環；其中該環經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有1或2個獨立地選自氮、氧及硫之雜原子的5-7員部分不飽和單環雜環；其中該環經RYC 之r6 個實例取代。
在一些實施例中，RYA 為具有1或2個獨立地選自氮及氧之雜原子的6員飽和或部分不飽和單環雜環；其中該環經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有1或2個獨立地選自氮及氧之雜原子的6員飽和單環雜環；其中該環經RYC 之r6 個實例取代。在一些實施例中，RYA 為具有1或2個獨立地選自氮及氧之雜原子的6員部分不飽和單環雜環；其中該環經RYC 之r6 個實例取代。在一些實施例中，RYA 為經RYC 之0、1、2或3個實例取代之吡啶-2(1H )-酮基。在一些實施例中，RYA 為經RYC 之0、1、2或3個實例取代之吡啶-2(1H )-酮-5-基。
在一些實施例中，RYA 為
Figure 02_image217
，其中RYC 及r6 如本文中之實施例及類別及子類中所定義。在一些實施例中，RYA 為
Figure 02_image219
。在一些實施例中，RYA 為
Figure 02_image221
。在一些實施例中，RYA 為
Figure 02_image223
。
在一些實施例中，RYA 為
Figure 02_image225
Figure 02_image227
，其中RYC 如本文中之實施例及類別及子類中所定義。在一些實施例中，RYA 為
Figure 02_image229
Figure 02_image231
。在一些實施例中，RYA 為
Figure 02_image233
Figure 02_image235
。
在一些實施例中，RYA 為
Figure 02_image237
。在一些實施例中，RYA 為
Figure 02_image239
。在一些實施例中，RYA 為
Figure 02_image241
。在一些實施例中，RYA 為
Figure 02_image243
。在一些實施例中，RYA 為
Figure 02_image245
。在一些實施例中，RYA 為
Figure 02_image247
。
在一些實施例中，RYA 為
Figure 02_image249
Figure 02_image251
。在一些實施例中，RYA 為
Figure 02_image253
、
Figure 02_image255
或
Figure 02_image257
。在一些實施例中，RYA 為
Figure 02_image259
。在一些實施例中，RYA 為
Figure 02_image261
。在一些實施例中，RYA 為
Figure 02_image263
。在一些實施例中，RYA 為
Figure 02_image265
。
在一些實施例中，RYA 選自表1之化合物中所描繪之基團。
如上文一般所定義，RZA 為經RZC 之r7 個實例取代之RA 或RB 。在一些實施例中，RZA 為RA 。在一些實施例中，RZA 為經RZC 之r7 個實例取代之RB 。
在一些實施例中，RZA 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之RB ：C1-6 脂族鏈；苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環；及具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其中該RB 經RZC 之r7 個實例取代。
在一些實施例中，RZA 為鹵素、-CN、-OR、-NR2 、-C(O)R、-C(O)OR、-C(O)NR2 、-N(R)C(O)R，或選自以下之RB ：C1-6 脂族鏈；3-7員飽和或部分不飽和單環碳環；及具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其中該RB 經RZC 之r7 個實例取代。在一些實施例中，RZA 為鹵素或選自以下之RB ：C1-4 脂族鏈；3-5員飽和或部分不飽和單環碳環；及具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中該RB 經獨立地選自以下之基團之r7 個實例取代：側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 及視情況經取代之C1-6 脂族基。
在一些實施例中，RZA 為鹵素或選自以下之RB ：C1-4 脂族鏈；3-5員飽和或部分不飽和單環碳環；及具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中該RB 經獨立地選自以下之基團之r7 個實例取代：鹵素、-OH、-O-(C1-3 脂族基)及C1-3 脂族基，其中各C1-3 脂族基視情況經1-3個鹵素取代。在一些實施例中，RZA 為鹵素或選自以下之RB ：C1-4 脂族鏈；3-5員飽和或部分不飽和單環碳環；及具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中該RB 經獨立地選自以下之基團之r7 個實例取代：氟、氯、-OH、-OCH3 、-OCF3 、-CH3 、-CHF2 及-CF3 。
在一些實施例中，RZA 為鹵素、-CN、-OR、-NR2 、-C(O)R、-C(O)OR、-C(O)NR2 或-N(R)C(O)R。在一些實施例中，RZA 為鹵素。
在一些實施例中，RZA 為C1-6 脂族鏈；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其中RZA 經RZC 之r7 個實例取代。在一些實施例中，RZA 為C1-4 脂族鏈；3-5員飽和或部分不飽和單環碳環；或具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中RZA 經獨立地選自以下之基團之r7 個實例取代：側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 及視情況經取代之C1-6 脂族基。
在一些實施例中，RZA 為C1-4 脂族鏈；3-5員飽和或部分不飽和單環碳環；或具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中RZA 經獨立地選自以下之基團之r7 個實例取代：鹵素、-OH、-O-(C1-3 脂族基)及C1-3 脂族基，其中各C1-3 脂族基視情況經1-3個鹵素取代。在一些實施例中，RZA 為C1-4 脂族鏈；3-5員飽和或部分不飽和單環碳環；或具有1-2個獨立地選自氮、氧及硫之雜原子的3-5員飽和或部分不飽和單環雜環；其中RZA 經獨立地選自以下之基團之r7 個實例取代：氟、氯、-OH、-OCH3 、-OCF3 、-CH3 、-CHF2 及-CF3 。
在一些實施例中，RZA 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 或氘。
在一些實施例中，RZA 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RZA 為側氧基。在一些實施例中，RZA 為鹵素。在一些實施例中，RZA 為-CN。在一些實施例中，RZA 為-NO2 。在一些實施例中，RZA 為-OR。在一些實施例中，RZA 為-SR。在一些實施例中，RZA 為-NR2 。在一些實施例中，RZA 為-S(O)2 R。在一些實施例中，RZA 為-S(O)2 NR2 。在一些實施例中，RZA 為-S(O)2 F。在一些實施例中，RZA 為-S(O)R。在一些實施例中，RZA 為-S(O)NR2 。在一些實施例中，RZA 為-S(O)(NR)R。在一些實施例中，RZA 為-C(O)R。在一些實施例中，RZA 為-C(O)OR。在一些實施例中，RZA 為-C(O)NR2 。在一些實施例中，RZA 為-C(O)N(R)OR。在一些實施例中，RZA 為-OC(O)R。在一些實施例中，RZA 為-OC(O)NR2 。在一些實施例中，RZA 為-N(R)C(O)OR。在一些實施例中，RZA 為-N(R)C(O)R。在一些實施例中，RZA 為-N(R)C(O)NR2 。在一些實施例中，RZA 為-N(R)C(NR)NR2 。在一些實施例中，RZA 為-N(R)S(O)2 NR2 。在一些實施例中，RZA 為-N(R)S(O)2 R。在一些實施例中，RZA 為-P(O)R2 。在一些實施例中，RZA 為-P(O)(R)OR。在一些實施例中，RZA 為-B(OR)2 。在一些實施例中，RZA 為氘。
在一些實施例中，RZA 為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RZA 為鹵素、-CN或-NO2 。在一些實施例中，RZA 為-OR、-SR或-NR2 。在一些實施例中，RZA 為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RZA 為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，RZA 為-OC(O)R或-OC(O)NR2 。在一些實施例中，RZA 為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RZA 為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，RZA 為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，RZA 為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RZA 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，RZA 為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，RZA 為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RZA 為-SR、-S(O)2 R或-S(O)R。在一些實施例中，RZA 為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RZA 為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，RZA 為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，RZA 為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RZA 為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RZA 為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RZA 為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，RZA 為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RZA 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RZA 為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RZA 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RZA 為C1-6 脂族鏈；苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RZC 之r7 個實例取代。
在一些實施例中，RZA 為經RZC 之r7 個實例取代之C1-6 脂族基。在一些實施例中，RZA 為經RZC 之r7 個實例取代之苯基。在一些實施例中，RZA 為經RZC 之r7 個實例取代之萘基。在一些實施例中，RZA 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；其中該環經RZC 之r7 個實例取代。在一些實施例中，RZA 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中該環經RZC 之r7 個實例取代。在一些實施例中，RZA 為經RZC 之r7 個實例取代之3-7員飽和或部分不飽和單環碳環。在一些實施例中，RZA 為經RZC 之r7 個實例取代之5-12員飽和或部分不飽和雙環碳環。在一些實施例中，RZA 為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其中該環經RZC 之r7 個實例取代。在一些實施例中，RZA 為具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其中該環經RZC 之r7 個實例取代。
在一些實施例中，RZA 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RZC 之r7 個實例取代。
在一些實施例中，RZA 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經RZC 之r7 個實例取代。在一些實施例中，RZA 為3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RZC 之r7 個實例取代。
在一些實施例中，RZA 為苯基；萘基；3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RZC 之r7 個實例取代。在一些實施例中，RZA 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RZC 之r7 個實例取代。
在一些實施例中，RZA 為苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RZC 之r7 個實例取代。在一些實施例中，RZA 為萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；5-12員飽和或部分不飽和雙環碳環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RZC 之r7 個實例取代。
在一些實施例中，RZA 為苯基或萘基；其各自經RZC 之r7 個實例取代。在一些實施例中，RZA 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經RZC 之r7 個實例取代。在一些實施例中，RZA 為3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RZC 之r7 個實例取代。在一些實施例中，RZA 為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RZC 之r7 個實例取代。
在一些實施例中，RZA 為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；其各自經RZC 之r7 個實例取代。在一些實施例中，RZA 為3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RZC 之r7 個實例取代。在一些實施例中，RZA 為萘基或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經RZC 之r7 個實例取代。在一些實施例中，RZA 為5-12員飽和或部分不飽和雙環碳環或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RZC 之r7 個實例取代。
在一些實施例中，RZA 為苯基或3-7員飽和或部分不飽和單環碳環；其各自經RZC 之r7 個實例取代。在一些實施例中，RZA 為萘基或5-12員飽和或部分不飽和雙環碳環；其各自經RZC 之r7 個實例取代。在一些實施例中，RZA 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RZC 之r7 個實例取代。在一些實施例中，RZA 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RZC 之r7 個實例取代。
在一些實施例中，RZA 為C1-6 脂族鏈；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RZC 之r7 個實例取代。在一些實施例中，RZA 為C1-6 脂族鏈；苯基；萘基；3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RZC 之r7 個實例取代。在一些實施例中，RZA 為C1-6 脂族鏈；苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RZC 之r7 個實例取代。
在一些實施例中，RZA 為C1-6 脂族鏈、3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RZC 之r7 個實例取代。在一些實施例中，RZA 為C1-6 脂族鏈、3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RZC 之r7 個實例取代。在一些實施例中，RZA 為C1-6 脂族鏈、苯基或3-7員飽和或部分不飽和單環碳環；其各自經RZC 之r7 個實例取代。
在一些實施例中，RZA 選自表1之化合物中所描繪之基團。
如上文一般所定義，RL 為經RLC 之r8 個實例取代之RA 或RB 。在一些實施例中，RL 為RA 。在一些實施例中，RL 為經RLC 之r8 個實例取代之RB 。
在一些實施例中，RL 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 或氘。
在一些實施例中，RL 為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RL 為側氧基。在一些實施例中，RL 為鹵素。在一些實施例中，RL 為-CN。在一些實施例中，RL 為-NO2 。在一些實施例中，RL 為-OR。在一些實施例中，RL 為-SR。在一些實施例中，RL 為-NR2 。在一些實施例中，RL 為-S(O)2 R。在一些實施例中，RL 為-S(O)2 NR2 。在一些實施例中，RL 為-S(O)2 F。在一些實施例中，RL 為-S(O)R。在一些實施例中，RL 為-S(O)NR2 。在一些實施例中，RL 為-S(O)(NR)R。在一些實施例中，RL 為-C(O)R。在一些實施例中，RL 為-C(O)OR。在一些實施例中，RL 為-C(O)NR2 。在一些實施例中，RL 為-C(O)N(R)OR。在一些實施例中，RL 為-OC(O)R。在一些實施例中，RL 為-OC(O)NR2 。在一些實施例中，RL 為-N(R)C(O)OR。在一些實施例中，RL 為-N(R)C(O)R。在一些實施例中，RL 為-N(R)C(O)NR2 。在一些實施例中，RL 為-N(R)C(NR)NR2 。在一些實施例中，RL 為-N(R)S(O)2 NR2 。在一些實施例中，RL 為-N(R)S(O)2 R。在一些實施例中，RL 為-P(O)R2 。在一些實施例中，RL 為-P(O)(R)OR。在一些實施例中，RL 為-B(OR)2 。在一些實施例中，RL 為氘。
在一些實施例中，RL 為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RL 為鹵素、-CN或-NO2 。在一些實施例中，RL 為-OR、-SR或-NR2 。在一些實施例中，RL 為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RL 為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，RL 為-OC(O)R或-OC(O)NR2 。在一些實施例中，RL 為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RL 為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，RL 為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，RL 為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RL 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，RL 為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，RL 為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RL 為-SR、-S(O)2 R或-S(O)R。在一些實施例中，RL 為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RL 為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，RL 為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，RL 為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RL 為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RL 為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RL 為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，RL 為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RL 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RL 為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RL 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RL 為C1-6 脂族鏈；苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RLC 之r8 個實例取代。
在一些實施例中，RL 為經RLC 之r8 個實例取代之C1-6 脂族基。在一些實施例中，RL 為經RLC 之r8 個實例取代之苯基。在一些實施例中，RL 為經RLC 之r8 個實例取代之萘基。在一些實施例中，RL 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；其中該環經RLC 之r8 個實例取代。在一些實施例中，RL 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其中該環經RLC 之r8 個實例取代。在一些實施例中，RL 為經RLC 之r8 個實例取代之3-7員飽和或部分不飽和單環碳環。在一些實施例中，RL 為經RLC 之r8 個實例取代之5-12員飽和或部分不飽和雙環碳環。在一些實施例中，RL 為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其中該環經RLC 之r8 個實例取代。在一些實施例中，RL 為具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其中該環經RLC 之r8 個實例取代。
在一些實施例中，RL 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RLC 之r8 個實例取代。
在一些實施例中，RL 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經RLC 之r8 個實例取代。在一些實施例中，RL 為3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RLC 之r8 個實例取代。
在一些實施例中，RL 為苯基；萘基；3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RLC 之r8 個實例取代。在一些實施例中，RL 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RLC 之r8 個實例取代。
在一些實施例中，RL 為苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RLC 之r8 個實例取代。在一些實施例中，RL 為萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；5-12員飽和或部分不飽和雙環碳環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RLC 之r8 個實例取代。
在一些實施例中，RL 為苯基或萘基；其各自經RLC 之r8 個實例取代。在一些實施例中，RL 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經RLC 之r8 個實例取代。在一些實施例中，RL 為3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RLC 之r8 個實例取代。在一些實施例中，RL 為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RLC 之r8 個實例取代。
在一些實施例中，RL 為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；其各自經RLC 之r8 個實例取代。在一些實施例中，RL 為3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RLC 之r8 個實例取代。在一些實施例中，RL 為萘基或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；其各自經RLC 之r8 個實例取代。在一些實施例中，RL 5-12員飽和或部分不飽和雙環碳環或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RLC 之r8 個實例取代。
在一些實施例中，RL 為苯基或3-7員飽和或部分不飽和單環碳環；其各自經RLC 之r8 個實例取代。在一些實施例中，RL 為萘基或5-12員飽和或部分不飽和雙環碳環；其各自經RLC 之r8 個實例取代。在一些實施例中，RL 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RLC 之r8 個實例取代。在一些實施例中，RL 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RLC 之r8 個實例取代。
在一些實施例中，RL 為C1-6 脂族鏈；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環；其各自經RLC 之r8 個實例取代。在一些實施例中，RL 為C1-6 脂族鏈；苯基；萘基；3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RLC 之r8 個實例取代。在一些實施例中，RL 為C1-6 脂族鏈；苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RLC 之r8 個實例取代。
在一些實施例中，RL 為C1-6 脂族鏈、3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環；其各自經RLC 之r8 個實例取代。在一些實施例中，RL 為C1-6 脂族鏈、3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；其各自經RLC 之r8 個實例取代。在一些實施例中，RL 為C1-6 脂族鏈、苯基或3-7員飽和或部分不飽和單環碳環；其各自經RLC 之r8 個實例取代。
在一些實施例中，RL 選自表1之化合物中所描繪之基團。
如上文一般所定義，RA 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SF5 、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RA 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SF5 、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RA 為側氧基。在一些實施例中，RA 為鹵素。在一些實施例中，RA 為-CN。在一些實施例中，RA 為-NO2 。在一些實施例中，RA 為-OR。在一些實施例中，RA 為-SF5 。在一些實施例中，RA 為-SR。在一些實施例中，RA 為-NR2 。在一些實施例中，RA 為-S(O)2 R。在一些實施例中，RA 為-S(O)2 NR2 。在一些實施例中，RA 為-S(O)2 F。在一些實施例中，RA 為-S(O)R。在一些實施例中，RA 為-S(O)NR2 。在一些實施例中，RA 為-S(O)(NR)R。在一些實施例中，RA 為-C(O)R。在一些實施例中，RA 為-C(O)OR。在一些實施例中，RA 為-C(O)NR2 。在一些實施例中，RA 為-C(O)N(R)OR。在一些實施例中，RA 為-OC(O)R。在一些實施例中，RA 為-OC(O)NR2 。在一些實施例中，RA 為-N(R)C(O)OR。在一些實施例中，RA 為-N(R)C(O)R。在一些實施例中，RA 為-N(R)C(O)NR2 。在一些實施例中，RA 為-N(R)C(NR)NR2 。在一些實施例中，RA 為-N(R)S(O)2 NR2 。在一些實施例中，RA 為-N(R)S(O)2 R。在一些實施例中，RA 為-P(O)R2 。在一些實施例中，RA 為-P(O)(R)OR。在一些實施例中，RA 為-B(OR)2 。在一些實施例中，RA 為氘。
在一些實施例中，RA 為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RA 為鹵素、-CN或-NO2 。在一些實施例中，RA 為-OR、-SR或-NR2 。在一些實施例中，RA 為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RA 為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，RA 為-OC(O)R或-OC(O)NR2 。在一些實施例中，RA 為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RA 為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，RA 為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，RA 為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RA 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，RA 為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，RA 為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RA 為-SR、-S(O)2 R或-S(O)R。在一些實施例中，RA 為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RA 為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，RA 為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，RA 為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RA 為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RA 為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RA 為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，RA 為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RA 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RA 為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RA 為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RA 選自表1之化合物中所描繪之基團。
如上文一般所定義，RB 之各實例獨立地為C1-6 脂族鏈；苯基；萘基；立方烷基；金剛烷基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環。
在一些實施例中，RB 為C1-6 脂族鏈。在一些實施例中，RB 為苯基。在一些實施例中，RB 為萘基。在一些實施例中，RB 為立方烷基。在一些實施例中，RB 為金剛烷基。在一些實施例中，RB 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。在一些實施例中，RB 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環。在一些實施例中，RB 為3-7員飽和或部分不飽和單環碳環。在一些實施例中，RB 為5-12員飽和或部分不飽和雙環碳環。在一些實施例中，RB 為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RB 為具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環。
在一些實施例中，RB 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環。
在一些實施例中，RB 為苯基；萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環。在一些實施例中，RB 為3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環。
在一些實施例中，RB 為苯基；萘基；3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環。在一些實施例中，RB 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環。
在一些實施例中，RB 為苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RB 為萘基；具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；5-12員飽和或部分不飽和雙環碳環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環。
在一些實施例中，RB 為苯基或萘基。在一些實施例中，RB 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環。在一些實施例中，RB 為3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環。在一些實施例中，RB 為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環。
在一些實施例中，RB 為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。在一些實施例中，RB 為3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RB 為萘基或具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環。在一些實施例中，RB 為5-12員飽和或部分不飽和雙環碳環或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環。
在一些實施例中，RB 為苯基或3-7員飽和或部分不飽和單環碳環。在一些實施例中，RB 為萘基或5-12員飽和或部分不飽和雙環碳環。在一些實施例中，RB 為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RB 為具有1-4個獨立地選自氮、氧及硫之雜原子的8-10員雙環雜芳基環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環。
在一些實施例中，RB 為C1-6 脂族鏈；3-7員飽和或部分不飽和單環碳環；5-12員飽和或部分不飽和雙環碳環；具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1-4個獨立地選自氮、氧及硫之雜原子的7-12員飽和或部分不飽和雙環雜環。在一些實施例中，RB 為C1-6 脂族鏈；苯基；萘基；3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環。在一些實施例中，RB 為C1-6 脂族鏈；苯基；具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。
在一些實施例中，RB 為C1-6 脂族鏈、3-7員飽和或部分不飽和單環碳環或5-12員飽和或部分不飽和雙環碳環。在一些實施例中，RB 為C1-6 脂族鏈、3-7員飽和或部分不飽和單環碳環或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RB 為C1-6 脂族鏈、苯基或3-7員飽和或部分不飽和單環碳環。
在一些實施例中，RB 選自表1之化合物中所描繪之基團。
如上文一般所定義，R1C 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R1C 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R1C 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。在一些實施例中，R1C 之各實例獨立地為選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R1C 為側氧基。在一些實施例中，R1C 為氘。在一些實施例中，R1C 之各實例獨立地為鹵素。在一些實施例中，R1C 為-CN。在一些實施例中，R1C 為-NO2 。在一些實施例中，R1C 為-OR。在一些實施例中，R1C 為-SR。在一些實施例中，R1C 為-NR2 。在一些實施例中，R1C 為-S(O)2 R。在一些實施例中，R1C 為-S(O)2 NR2 。在一些實施例中，R1C 為-S(O)2 F。在一些實施例中，R1C 為-S(O)R。在一些實施例中，R1C 為-S(O)NR2 。在一些實施例中，R1C 為-S(O)(NR)R。在一些實施例中，R1C 為-C(O)R。在一些實施例中，R1C 為-C(O)OR。在一些實施例中，R1C 為-C(O)NR2 。在一些實施例中，R1C 為-C(O)N(R)OR。在一些實施例中，R1C 為-OC(O)R。在一些實施例中，R1C 為-OC(O)NR2 。在一些實施例中，R1C 為-N(R)C(O)OR。在一些實施例中，R1C 為-N(R)C(O)R。在一些實施例中，R1C 為-N(R)C(O)NR2 。在一些實施例中，R1C 為-N(R)C(NR)NR2 。在一些實施例中，R1C 為-N(R)S(O)2 NR2 。在一些實施例中，R1C 為-N(R)S(O)2 R。在一些實施例中，R1C 為-P(O)R2 。在一些實施例中，R1C 為-P(O)(R)OR。在一些實施例中，R1C 為-B(OR)2 。
在一些實施例中，R1C 之各實例獨立地為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，R1C 之各實例獨立地為鹵素、-CN或-NO2 。在一些實施例中，R1C 之各實例獨立地為-OR、-SR或-NR2 。在一些實施例中，R1C 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，R1C 之各實例獨立地為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，R1C 之各實例獨立地為-OC(O)R或-OC(O)NR2 。在一些實施例中，R1C 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，R1C 之各實例獨立地為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，R1C 之各實例獨立地為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，R1C 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，R1C 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，R1C 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，R1C 之各實例獨立地為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，R1C 之各實例獨立地為-SR、-S(O)2 R或-S(O)R。在一些實施例中，R1C 之各實例獨立地為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，R1C 之各實例獨立地為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，R1C 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，R1C 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，R1C 之各實例獨立地為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，R1C 之各實例獨立地為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，R1C 之各實例獨立地為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，R1C 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，R1C 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，R1C 之各實例獨立地為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，R1C 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，R1C 之各實例獨立地為視情況經取代之C1-6 脂族基。在一些實施例中，R1C 之各實例獨立地為視情況經取代之苯基。在一些實施例中，R1C 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，R1C 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，R1C 之各實例獨立地為視情況經取代之C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，R1C 之各實例獨立地為視情況經取代之苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，R1C 之各實例獨立地為視情況經取代之C1-6 脂族基或視情況經取代之苯基。在一些實施例中，R1C 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，R1C 之各實例獨立地為選自以下之視情況經取代之基團：苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R1C 之各實例獨立地為C1-6 脂族基。在一些實施例中，R1C 為苯基。在一些實施例中，R1C 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，R1C 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R1C 之各實例獨立地為C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，R1C 之各實例獨立地為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R1C 之各實例獨立地為C1-6 脂族基或苯基。在一些實施例中，R1C 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R1C 之各實例獨立地為苯基, 具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R1C 之各實例獨立地為鹵素、-CN、-O-(視情況經取代之C1-6 脂族基)或視情況經取代之C1-6 脂族基。在一些實施例中，R1C 之各實例獨立地為鹵素、-CN、-O-(C1-6 脂族基)或C1-6 脂族基；其中各C1-6 脂族基視情況經一或多個鹵素原子取代。在一些實施例中，R1C 之各實例獨立地為鹵素或視情況經1-3個鹵素取代之C1-3 脂族基。在一些實施例中，R1C 之各實例獨立地為氟、氯、-CH3 、-CHF2 或-CF3 。
在一些實施例中，R1C 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 或視情況經取代之C1-6 脂族基。
在一些實施例中，R1C 之各實例獨立地選自表1之化合物中所描繪之基團。
如上文一般所定義，R2C 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R2C 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R2C 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。在一些實施例中，R2C 之各實例獨立地為選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R2C 為側氧基。在一些實施例中，R2C 為氘。在一些實施例中，R2C 之各實例獨立地為鹵素。在一些實施例中，R2C 為-CN。在一些實施例中，R2C 為-NO2 。在一些實施例中，R2C 為-OR。在一些實施例中，R2C 為-SR。在一些實施例中，R2C 為-NR2 。在一些實施例中，R2C 為-S(O)2 R。在一些實施例中，R2C 為-S(O)2 NR2 。在一些實施例中，R2C 為-S(O)2 F。在一些實施例中，R2C 為-S(O)R。在一些實施例中，R2C 為-S(O)NR2 。在一些實施例中，R2C 為-S(O)(NR)R。在一些實施例中，R2C 為-C(O)R。在一些實施例中，R2C 為-C(O)OR。在一些實施例中，R2C 為-C(O)NR2 。在一些實施例中，R2C 為-C(O)N(R)OR。在一些實施例中，R2C 為-OC(O)R。在一些實施例中，R2C 為-OC(O)NR2 。在一些實施例中，R2C 為-N(R)C(O)OR。在一些實施例中，R2C 為-N(R)C(O)R。在一些實施例中，R2C 為-N(R)C(O)NR2 。在一些實施例中，R2C 為-N(R)C(NR)NR2 。在一些實施例中，R2C 為-N(R)S(O)2 NR2 。在一些實施例中，R2C 為-N(R)S(O)2 R。在一些實施例中，R2C 為-P(O)R2 。在一些實施例中，R2C 為-P(O)(R)OR。在一些實施例中，R2C 為-B(OR)2 。
在一些實施例中，R2C 之各實例獨立地為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，R2C 之各實例獨立地為鹵素、-CN或-NO2 。在一些實施例中，R2C 之各實例獨立地為-OR、-SR或-NR2 。在一些實施例中，R2C 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，R2C 之各實例獨立地為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，R2C 之各實例獨立地為-OC(O)R或-OC(O)NR2 。在一些實施例中，R2C 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，R2C 之各實例獨立地為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，R2C 之各實例獨立地為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，R2C 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，R2C 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，R2C 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，R2C 之各實例獨立地為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，R2C 之各實例獨立地為-SR、-S(O)2 R或-S(O)R。在一些實施例中，R2C 之各實例獨立地為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，R2C 之各實例獨立地為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，R2C 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，R2C 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，R2C 之各實例獨立地為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，R2C 之各實例獨立地為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，R2C 之各實例獨立地為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，R2C 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，R2C 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，R2C 之各實例獨立地為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，R2C 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，R2C 之各實例獨立地為視情況經取代之C1-6 脂族基。在一些實施例中，R2C 之各實例獨立地為視情況經取代之苯基。在一些實施例中，R2C 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，R2C 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，R2C 之各實例獨立地為視情況經取代之C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，R2C 之各實例獨立地為視情況經取代之苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，R2C 之各實例獨立地為視情況經取代之C1-6 脂族基或視情況經取代之苯基。在一些實施例中，R2C 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，R2C 之各實例獨立地為選自以下之視情況經取代之基團：苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R2C 之各實例獨立地為C1-6 脂族基。在一些實施例中，R2C 為苯基。在一些實施例中，R2C 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，R2C 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R2C 之各實例獨立地為C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，R2C 之各實例獨立地為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R2C 之各實例獨立地為C1-6 脂族基或苯基。在一些實施例中，R2C 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R2C 之各實例獨立地為苯基, 具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R2C 之各實例獨立地為鹵素、-CN、-O-(視情況經取代之C1-6 脂族基)或視情況經取代之C1-6 脂族基。在一些實施例中，R2C 之各實例獨立地為鹵素、-CN、-O-(C1-6 脂族基)或C1-6 脂族基；其中各C1-6 脂族基視情況經一或多個鹵素原子取代。在一些實施例中，R2C 之各實例獨立地為鹵素或視情況經1-3個鹵素取代之C1-3 脂族基。在一些實施例中，R2C 之各實例獨立地為氟、氯、-CH3 、-CHF2 或-CF3 。
在一些實施例中，R2C 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 或視情況經取代之C1-6 脂族基。
在一些實施例中，R2C 之各實例獨立地選自表1之化合物中所描繪之基團。
如上文一般所定義，REC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，REC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。在一些實施例中，REC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-NR2 、-C(O)R、-C(O)OR、-C(O)NR2 、-OC(O)R、-N(R)C(O)R或-N(R)S(O)2 R。在一些實施例中，REC 之各實例獨立地為氘、鹵素、-CN-、-OR或-NR2 。在一些實施例中，REC 之各實例獨立地為氘或鹵素。在一些實施例中，REC 之各實例獨立地為鹵素。
在一些實施例中，REC 之各實例獨立地為選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，REC 之各實例獨立地選自表1之化合物中所描繪之基團。
如上文一般所定義，RQC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RQC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RQC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。在一些實施例中，RQC 之各實例獨立地為選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RQC 為側氧基。在一些實施例中，RQC 為氘。在一些實施例中，RQC 之各實例獨立地為鹵素。在一些實施例中，RQC 為-CN。在一些實施例中，RQC 為-NO2 。在一些實施例中，RQC 為-OR。在一些實施例中，RQC 為-SR。在一些實施例中，RQC 為-NR2 。在一些實施例中，RQC 為-S(O)2 R。在一些實施例中，RQC 為-S(O)2 NR2 。在一些實施例中，RQC 為-S(O)2 F。在一些實施例中，RQC 為-S(O)R。在一些實施例中，RQC 為-S(O)NR2 。在一些實施例中，RQC 為-S(O)(NR)R。在一些實施例中，RQC 為-C(O)R。在一些實施例中，RQC 為-C(O)OR。在一些實施例中，RQC 為-C(O)NR2 。在一些實施例中，RQC 為-C(O)N(R)OR。在一些實施例中，RQC 為-OC(O)R。在一些實施例中，RQC 為-OC(O)NR2 。在一些實施例中，RQC 為-N(R)C(O)OR。在一些實施例中，RQC 為-N(R)C(O)R。在一些實施例中，RQC 為-N(R)C(O)NR2 。在一些實施例中，RQC 為-N(R)C(NR)NR2 。在一些實施例中，RQC 為-N(R)S(O)2 NR2 。在一些實施例中，RQC 為-N(R)S(O)2 R。在一些實施例中，RQC 為-P(O)R2 。在一些實施例中，RQC 為-P(O)(R)OR。在一些實施例中，RQC 為-B(OR)2 。
在一些實施例中，RQC 之各實例獨立地為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RQC 之各實例獨立地為鹵素、-CN或-NO2 。在一些實施例中，RQC 之各實例獨立地為-OR、-SR或-NR2 。在一些實施例中，RQC 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RQC 之各實例獨立地為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，RQC 之各實例獨立地為-OC(O)R或-OC(O)NR2 。在一些實施例中，RQC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RQC 之各實例獨立地為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，RQC 之各實例獨立地為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，RQC 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RQC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，RQC 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，RQC 之各實例獨立地為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RQC 之各實例獨立地為-SR、-S(O)2 R或-S(O)R。在一些實施例中，RQC 之各實例獨立地為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RQC 之各實例獨立地為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，RQC 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，RQC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RQC 之各實例獨立地為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RQC 之各實例獨立地為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RQC 之各實例獨立地為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，RQC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RQC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RQC 之各實例獨立地為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RQC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RQC 之各實例獨立地為視情況經取代之C1-6 脂族基。在一些實施例中，RQC 之各實例獨立地為視情況經取代之苯基。在一些實施例中，RQC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，RQC 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RQC 之各實例獨立地為視情況經取代之C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，RQC 之各實例獨立地為視情況經取代之苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RQC 之各實例獨立地為視情況經取代之C1-6 脂族基或視情況經取代之苯基。在一些實施例中，RQC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RQC 之各實例獨立地為選自以下之視情況經取代之基團：苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RQC 之各實例獨立地為C1-6 脂族基。在一些實施例中，RQC 為苯基。在一些實施例中，RQC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RQC 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RQC 之各實例獨立地為C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RQC 之各實例獨立地為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RQC 之各實例獨立地為C1-6 脂族基或苯基。在一些實施例中，RQC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RQC 之各實例獨立地為苯基, 具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RQC 之各實例獨立地選自表1之化合物中所描繪之基團。
如上文一般所定義，RXC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RXC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RXC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。在一些實施例中，RXC 之各實例獨立地為選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RXC 為側氧基。在一些實施例中，RXC 為氘。在一些實施例中，RXC 之各實例獨立地為鹵素。在一些實施例中，RXC 為-CN。在一些實施例中，RXC 為-NO2 。在一些實施例中，RXC 為-OR。在一些實施例中，RXC 為-SR。在一些實施例中，RXC 為-NR2 。在一些實施例中，RXC 為-S(O)2 R。在一些實施例中，RXC 為-S(O)2 NR2 。在一些實施例中，RXC 為-S(O)2 F。在一些實施例中，RXC 為-S(O)R。在一些實施例中，RXC 為-S(O)NR2 。在一些實施例中，RXC 為-S(O)(NR)R。在一些實施例中，RXC 為-C(O)R。在一些實施例中，RXC 為-C(O)OR。在一些實施例中，RXC 為-C(O)NR2 。在一些實施例中，RXC 為-C(O)N(R)OR。在一些實施例中，RXC 為-OC(O)R。在一些實施例中，RXC 為-OC(O)NR2 。在一些實施例中，RXC 為-N(R)C(O)OR。在一些實施例中，RXC 為-N(R)C(O)R。在一些實施例中，RXC 為-N(R)C(O)NR2 。在一些實施例中，RXC 為-N(R)C(NR)NR2 。在一些實施例中，RXC 為-N(R)S(O)2 NR2 。在一些實施例中，RXC 為-N(R)S(O)2 R。在一些實施例中，RXC 為-P(O)R2 。在一些實施例中，RXC 為-P(O)(R)OR。在一些實施例中，RXC 為-B(OR)2 。
在一些實施例中，RXC 之各實例獨立地為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RXC 之各實例獨立地為鹵素、-CN或-NO2 。在一些實施例中，RXC 之各實例獨立地為-OR、-SR或-NR2 。在一些實施例中，RXC 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RXC 之各實例獨立地為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，RXC 之各實例獨立地為-OC(O)R或-OC(O)NR2 。在一些實施例中，RXC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RXC 之各實例獨立地為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，RXC 之各實例獨立地為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，RXC 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RXC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，RXC 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，RXC 之各實例獨立地為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RXC 之各實例獨立地為-SR、-S(O)2 R或-S(O)R。在一些實施例中，RXC 之各實例獨立地為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RXC 之各實例獨立地為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，RXC 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，RXC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RXC 之各實例獨立地為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RXC 之各實例獨立地為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RXC 之各實例獨立地為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，RXC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RXC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RXC 之各實例獨立地為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RXC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RXC 之各實例獨立地為視情況經取代之C1-6 脂族基。在一些實施例中，RXC 之各實例獨立地為視情況經取代之苯基。在一些實施例中，RXC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，RXC 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RXC 之各實例獨立地為視情況經取代之C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，RXC 之各實例獨立地為視情況經取代之苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RXC 之各實例獨立地為視情況經取代之C1-6 脂族基或視情況經取代之苯基。在一些實施例中，RXC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RXC 之各實例獨立地為選自以下之視情況經取代之基團：苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RXC 之各實例獨立地為C1-6 脂族基。在一些實施例中，RXC 為苯基。在一些實施例中，RXC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RXC 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RXC 之各實例獨立地為C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RXC 之各實例獨立地為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RXC 之各實例獨立地為C1-6 脂族基或苯基。在一些實施例中，RXC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RXC 之各實例獨立地為苯基, 具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RXC 之各實例獨立地選自表1之化合物中所描繪之基團。
如上文一般所定義，RYC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RYC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RYC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。在一些實施例中，RYC 之各實例獨立地為選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RYC 為側氧基。在一些實施例中，RYC 為氘。在一些實施例中，RYC 之各實例獨立地為鹵素。在一些實施例中，RYC 為-CN。在一些實施例中，RYC 為-NO2 。在一些實施例中，RYC 為-OR。在一些實施例中，RYC 為-SR。在一些實施例中，RYC 為-NR2 。在一些實施例中，RYC 為-S(O)2 R。在一些實施例中，RYC 為-S(O)2 NR2 。在一些實施例中，RYC 為-S(O)2 F。在一些實施例中，RYC 為-S(O)R。在一些實施例中，RYC 為-S(O)NR2 。在一些實施例中，RYC 為-S(O)(NR)R。在一些實施例中，RYC 為-C(O)R。在一些實施例中，RYC 為-C(O)OR。在一些實施例中，RYC 為-C(O)NR2 。在一些實施例中，RYC 為-C(O)N(R)OR。在一些實施例中，RYC 為-OC(O)R。在一些實施例中，RYC 為-OC(O)NR2 。在一些實施例中，RYC 為-N(R)C(O)OR。在一些實施例中，RYC 為-N(R)C(O)R。在一些實施例中，RYC 為-N(R)C(O)NR2 。在一些實施例中，RYC 為-N(R)C(NR)NR2 。在一些實施例中，RYC 為-N(R)S(O)2 NR2 。在一些實施例中，RYC 為-N(R)S(O)2 R。在一些實施例中，RYC 為-P(O)R2 。在一些實施例中，RYC 為-P(O)(R)OR。在一些實施例中，RYC 為-B(OR)2 。
在一些實施例中，RYC 之各實例獨立地為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RYC 之各實例獨立地為鹵素、-CN或-NO2 。在一些實施例中，RYC 之各實例獨立地為-OR、-SR或-NR2 。在一些實施例中，RYC 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RYC 之各實例獨立地為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，RYC 之各實例獨立地為-OC(O)R或-OC(O)NR2 。在一些實施例中，RYC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RYC 之各實例獨立地為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，RYC 之各實例獨立地為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，RYC 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RYC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，RYC 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，RYC 之各實例獨立地為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RYC 之各實例獨立地為-SR、-S(O)2 R或-S(O)R。在一些實施例中，RYC 之各實例獨立地為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RYC 之各實例獨立地為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，RYC 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，RYC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RYC 之各實例獨立地為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RYC 之各實例獨立地為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RYC 之各實例獨立地為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，RYC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RYC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RYC 之各實例獨立地為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RYC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RYC 之各實例獨立地為視情況經取代之C1-6 脂族基。在一些實施例中，RYC 之各實例獨立地為視情況經取代之苯基。在一些實施例中，RYC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，RYC 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RYC 之各實例獨立地為視情況經取代之C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，RYC 之各實例獨立地為視情況經取代之苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RYC 之各實例獨立地為視情況經取代之C1-6 脂族基或視情況經取代之苯基。在一些實施例中，RYC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RYC 之各實例獨立地為選自以下之視情況經取代之基團：苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RYC 之各實例獨立地為C1-6 脂族基。在一些實施例中，RYC 為苯基。在一些實施例中，RYC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RYC 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RYC 之各實例獨立地為C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RYC 之各實例獨立地為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RYC 之各實例獨立地為C1-6 脂族基或苯基。在一些實施例中，RYC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RYC 之各實例獨立地為苯基, 具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RYC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 或視情況經取代之C1-6 脂族基。
在一些實施例中，RYC 之各實例獨立地為鹵素、-CN、-OH、-O-(視情況經取代之C1-3 脂族基)或視情況經取代之C1-3 脂族基。在一些實施例中，RYC 之各實例獨立地為鹵素、-OH、-O-(C1-3 脂族基)或C1-3 脂族基，其中各C1-3 脂族基視情況經1-3個鹵素取代。在一些實施例中，RYC 之各實例獨立地為氟、氯、-OH、-OCH3 、-OCF3 、-CH3 、-CHF2 或-CF3 。在一些實施例中，RYC 之各實例獨立地為氟或-OH。
在一些實施例中，RYC 之各實例獨立地為側氧基、鹵素、-CN、-OH、-O-(視情況經取代之C1-3 脂族基)或視情況經取代之C1-3 脂族基。在一些實施例中，RYC 之各實例獨立地為側氧基、鹵素、-CN、-OH、-O-(C1-3 脂族基)或C1-3 脂族基，其中各C1-3 脂族基視情況經一或多個鹵素原子取代。在一些實施例中，RYC 之各實例獨立地為側氧基、鹵素、-CN, -OH、-O-(C1-3 脂族基)或C1-3 脂族基，其中各C1-3 脂族基視情況經1-3個鹵素取代。在一些實施例中，RYC 之各實例獨立地為側氧基、氟、氯、-CN、-OH、-OCH3 、-OCF3 、-CH3 、-CHF2 或-CF3 。在一些實施例中，RYC 之各實例獨立地為側氧基、-CN、氟或-OH。在一些實施例中，RYC 之各實例獨立地為側氧基、-CN、-CH3 或-CHF2 。在一些實施例中，RYC 之各實例獨立地為-CN、-CH3 或-CHF2 。
在一些實施例中，RYC 之各實例獨立地選自表1之化合物中所描繪之基團。
如上文一般所定義，RZC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RZC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RZC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。在一些實施例中，RZC 之各實例獨立地為選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RZC 為側氧基。在一些實施例中，RZC 為氘。在一些實施例中，RZC 之各實例獨立地為鹵素。在一些實施例中，RZC 為-CN。在一些實施例中，RZC 為-NO2 。在一些實施例中，RZC 為-OR。在一些實施例中，RZC 為-SR。在一些實施例中，RZC 為-NR2 。在一些實施例中，RZC 為-S(O)2 R。在一些實施例中，RZC 為-S(O)2 NR2 。在一些實施例中，RZC 為-S(O)2 F。在一些實施例中，RZC 為-S(O)R。在一些實施例中，RZC 為-S(O)NR2 。在一些實施例中，RZC 為-S(O)(NR)R。在一些實施例中，RZC 為-C(O)R。在一些實施例中，RZC 為-C(O)OR。在一些實施例中，RZC 為-C(O)NR2 。在一些實施例中，RZC 為-C(O)N(R)OR。在一些實施例中，RZC 為-OC(O)R。在一些實施例中，RZC 為-OC(O)NR2 。在一些實施例中，RZC 為-N(R)C(O)OR。在一些實施例中，RZC 為-N(R)C(O)R。在一些實施例中，RZC 為-N(R)C(O)NR2 。在一些實施例中，RZC 為-N(R)C(NR)NR2 。在一些實施例中，RZC 為-N(R)S(O)2 NR2 。在一些實施例中，RZC 為-N(R)S(O)2 R。在一些實施例中，RZC 為-P(O)R2 。在一些實施例中，RZC 為-P(O)(R)OR。在一些實施例中，RZC 為-B(OR)2 。
在一些實施例中，RZC 之各實例獨立地為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RZC 之各實例獨立地為鹵素、-CN或-NO2 。在一些實施例中，RZC 之各實例獨立地為-OR、-SR或-NR2 。在一些實施例中，RZC 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RZC 之各實例獨立地為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，RZC 之各實例獨立地為-OC(O)R或-OC(O)NR2 。在一些實施例中，RZC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RZC 之各實例獨立地為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，RZC 之各實例獨立地為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，RZC 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RZC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，RZC 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，RZC 之各實例獨立地為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RZC 之各實例獨立地為-SR、-S(O)2 R或-S(O)R。在一些實施例中，RZC 之各實例獨立地為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RZC 之各實例獨立地為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，RZC 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，RZC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RZC 之各實例獨立地為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RZC 之各實例獨立地為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RZC 之各實例獨立地為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，RZC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RZC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RZC 之各實例獨立地為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RZC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RZC 之各實例獨立地為視情況經取代之C1-6 脂族基。在一些實施例中，RZC 之各實例獨立地為視情況經取代之苯基。在一些實施例中，RZC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，RZC 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RZC 之各實例獨立地為視情況經取代之C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，RZC 之各實例獨立地為視情況經取代之苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RZC 之各實例獨立地為視情況經取代之C1-6 脂族基或視情況經取代之苯基。在一些實施例中，RZC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RZC 之各實例獨立地為選自以下之視情況經取代之基團：苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RZC 之各實例獨立地為C1-6 脂族基。在一些實施例中，RZC 為苯基。在一些實施例中，RZC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RZC 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RZC 之各實例獨立地為C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RZC 之各實例獨立地為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RZC 之各實例獨立地為C1-6 脂族基或苯基。在一些實施例中，RZC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RZC 之各實例獨立地為苯基, 具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RZC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 或視情況經取代之C1-6 脂族基。
在一些實施例中，RZC 之各實例獨立地為鹵素、-CN、-OH、-O-(視情況經取代之C1-3 脂族基)或視情況經取代之C1-3 脂族基。在一些實施例中，RZC 之各實例獨立地為鹵素、-OH、-O-(C1-3 脂族基)或C1-3 脂族基，其中各C1-3 脂族基視情況經1-3個鹵素取代。在一些實施例中，RZC 之各實例獨立地為氟、氯、-OH、-OCH3 、-OCF3 、-CH3 、-CHF2 或-CF3 。在一些實施例中，RZC 之各實例獨立地為氟或-OH。
在一些實施例中，RZC 之各實例獨立地選自表1之化合物中所描繪之基團。
如上文一般所定義，RLC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RLC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RLC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。在一些實施例中，RLC 之各實例獨立地為選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RLC 為側氧基。在一些實施例中，RLC 為氘。在一些實施例中，RLC 之各實例獨立地為鹵素。在一些實施例中，RLC 為-CN。在一些實施例中，RLC 為-NO2 。在一些實施例中，RLC 為-OR。在一些實施例中，RLC 為-SR。在一些實施例中，RLC 為-NR2 。在一些實施例中，RLC 為-S(O)2 R。在一些實施例中，RLC 為-S(O)2 NR2 。在一些實施例中，RLC 為-S(O)2 F。在一些實施例中，RLC 為-S(O)R。在一些實施例中，RLC 為-S(O)NR2 。在一些實施例中，RLC 為-S(O)(NR)R。在一些實施例中，RLC 為-C(O)R。在一些實施例中，RLC 為-C(O)OR。在一些實施例中，RLC 為-C(O)NR2 。在一些實施例中，RLC 為-C(O)N(R)OR。在一些實施例中，RLC 為-OC(O)R。在一些實施例中，RLC 為-OC(O)NR2 。在一些實施例中，RLC 為-N(R)C(O)OR。在一些實施例中，RLC 為-N(R)C(O)R。在一些實施例中，RLC 為-N(R)C(O)NR2 。在一些實施例中，RLC 為-N(R)C(NR)NR2 。在一些實施例中，RLC 為-N(R)S(O)2 NR2 。在一些實施例中，RLC 為-N(R)S(O)2 R。在一些實施例中，RLC 為-P(O)R2 。在一些實施例中，RLC 為-P(O)(R)OR。在一些實施例中，RLC 為-B(OR)2 。
在一些實施例中，RLC 之各實例獨立地為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RLC 之各實例獨立地為鹵素、-CN或-NO2 。在一些實施例中，RLC 之各實例獨立地為-OR、-SR或-NR2 。在一些實施例中，RLC 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RLC 之各實例獨立地為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，RLC 之各實例獨立地為-OC(O)R或-OC(O)NR2 。在一些實施例中，RLC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RLC 之各實例獨立地為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，RLC 之各實例獨立地為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，RLC 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RLC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，RLC 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，RLC 之各實例獨立地為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RLC 之各實例獨立地為-SR、-S(O)2 R或-S(O)R。在一些實施例中，RLC 之各實例獨立地為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RLC 之各實例獨立地為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，RLC 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，RLC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RLC 之各實例獨立地為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RLC 之各實例獨立地為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RLC 之各實例獨立地為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，RLC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RLC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RLC 之各實例獨立地為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RLC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RLC 之各實例獨立地為視情況經取代之C1-6 脂族基。在一些實施例中，RLC 之各實例獨立地為視情況經取代之苯基。在一些實施例中，RLC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，RLC 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RLC 之各實例獨立地為視情況經取代之C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，RLC 之各實例獨立地為視情況經取代之苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RLC 之各實例獨立地為視情況經取代之C1-6 脂族基或視情況經取代之苯基。在一些實施例中，RLC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RLC 之各實例獨立地為選自以下之視情況經取代之基團：苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RLC 之各實例獨立地為C1-6 脂族基。在一些實施例中，RLC 為苯基。在一些實施例中，RLC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RLC 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RLC 之各實例獨立地為C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RLC 之各實例獨立地為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RLC 之各實例獨立地為C1-6 脂族基或苯基。在一些實施例中，RLC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RLC 之各實例獨立地為苯基, 具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RLC 之各實例獨立地選自表1之化合物中所描繪之基團。
如上文一般所定義，REEC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，REEC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。在一些實施例中，REEC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-NR2 、-C(O)R、-C(O)OR、-C(O)NR2 、-OC(O)R、-N(R)C(O)R或-N(R)S(O)2 R。在一些實施例中，REEC 之各實例獨立地為氘、鹵素、-CN-、-OR或-NR2 。在一些實施例中，REEC 之各實例獨立地為氘或鹵素。在一些實施例中，REEC 之各實例獨立地為鹵素。
在一些實施例中，REEC 之各實例獨立地為選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，REEC 之各實例獨立地選自表1之化合物中所描繪之基團。
如上文一般所定義，RQ1C 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RQ1C 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RQ1C 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。在一些實施例中，RQ1C 之各實例獨立地為選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RQ1C 為側氧基。在一些實施例中，RQ1C 為氘。在一些實施例中，RQ1C 之各實例獨立地為鹵素。在一些實施例中，RQ1C 為-CN。在一些實施例中，RQ1C 為-NO2 。在一些實施例中，RQ1C 為-OR。在一些實施例中，RQ1C 為-SR。在一些實施例中，RQ1C 為-NR2 。在一些實施例中，RQ1C 為-S(O)2 R。在一些實施例中，RQ1C 為-S(O)2 NR2 。在一些實施例中，RQ1C 為-S(O)2 F。在一些實施例中，RQ1C 為-S(O)R。在一些實施例中，RQ1C 為-S(O)NR2 。在一些實施例中，RQ1C 為-S(O)(NR)R。在一些實施例中，RQ1C 為-C(O)R。在一些實施例中，RQ1C 為-C(O)OR。在一些實施例中，RQ1C 為-C(O)NR2 。在一些實施例中，RQ1C 為-C(O)N(R)OR。在一些實施例中，RQ1C 為-OC(O)R。在一些實施例中，RQ1C 為-OC(O)NR2 。在一些實施例中，RQ1C 為-N(R)C(O)OR。在一些實施例中，RQ1C 為-N(R)C(O)R。在一些實施例中，RQ1C 為-N(R)C(O)NR2 。在一些實施例中，RQ1C 為-N(R)C(NR)NR2 。在一些實施例中，RQ1C 為-N(R)S(O)2 NR2 。在一些實施例中，RQ1C 為-N(R)S(O)2 R。在一些實施例中，RQ1C 為-P(O)R2 。在一些實施例中，RQ1C 為-P(O)(R)OR。在一些實施例中，RQ1C 為-B(OR)2 。
在一些實施例中，RQ1C 之各實例獨立地為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RQ1C 之各實例獨立地為鹵素、-CN或-NO2 。在一些實施例中，RQ1C 之各實例獨立地為-OR、-SR或-NR2 。在一些實施例中，RQ1C 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RQ1C 之各實例獨立地為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，RQ1C 之各實例獨立地為-OC(O)R或-OC(O)NR2 。在一些實施例中，RQ1C 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RQ1C 之各實例獨立地為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，RQ1C 之各實例獨立地為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，RQ1C 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RQ1C 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，RQ1C 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，RQ1C 之各實例獨立地為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RQ1C 之各實例獨立地為-SR、-S(O)2 R或-S(O)R。在一些實施例中，RQ1C 之各實例獨立地為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RQ1C 之各實例獨立地為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，RQ1C 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，RQ1C 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RQ1C 之各實例獨立地為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RQ1C 之各實例獨立地為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RQ1C 之各實例獨立地為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，RQ1C 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RQ1C 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RQ1C 之各實例獨立地為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RQ1C 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RQ1C 之各實例獨立地為視情況經取代之C1-6 脂族基。在一些實施例中，RQ1C 之各實例獨立地為視情況經取代之苯基。在一些實施例中，RQ1C 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，RQ1C 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RQ1C 之各實例獨立地為視情況經取代之C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，RQ1C 之各實例獨立地為視情況經取代之苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RQ1C 之各實例獨立地為視情況經取代之C1-6 脂族基或視情況經取代之苯基。在一些實施例中，RQ1C 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RQ1C 之各實例獨立地為選自以下之視情況經取代之基團：苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RQ1C 之各實例獨立地為C1-6 脂族基。在一些實施例中，RQ1C 為苯基。在一些實施例中，RQ1C 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RQ1C 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RQ1C 之各實例獨立地為C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RQ1C 之各實例獨立地為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RQ1C 之各實例獨立地為C1-6 脂族基或苯基。在一些實施例中，RQ1C 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RQ1C 之各實例獨立地為苯基, 具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RQ1C 之各實例獨立地選自表1之化合物中所描繪之基團。
如上文一般所定義，RYZC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RYZC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RYZC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。在一些實施例中，RYZC 之各實例獨立地為選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RYZC 為側氧基。在一些實施例中，RYZC 為氘。在一些實施例中，RYZC 之各實例獨立地為鹵素。在一些實施例中，RYZC 為-CN。在一些實施例中，RYZC 為-NO2 。在一些實施例中，RYZC 為-OR。在一些實施例中，RYZC 為-SR。在一些實施例中，RYZC 為-NR2 。在一些實施例中，RYZC 為-S(O)2 R。在一些實施例中，RYZC 為-S(O)2 NR2 。在一些實施例中，RYZC 為-S(O)2 F。在一些實施例中，RYZC 為-S(O)R。在一些實施例中，RYZC 為-S(O)NR2 。在一些實施例中，RYZC 為-S(O)(NR)R。在一些實施例中，RYZC 為-C(O)R。在一些實施例中，RYZC 為-C(O)OR。在一些實施例中，RYZC 為-C(O)NR2 。在一些實施例中，RYZC 為-C(O)N(R)OR。在一些實施例中，RYZC 為-OC(O)R。在一些實施例中，RYZC 為-OC(O)NR2 。在一些實施例中，RYZC 為-N(R)C(O)OR。在一些實施例中，RYZC 為-N(R)C(O)R。在一些實施例中，RYZC 為-N(R)C(O)NR2 。在一些實施例中，RYZC 為-N(R)C(NR)NR2 。在一些實施例中，RYZC 為-N(R)S(O)2 NR2 。在一些實施例中，RYZC 為-N(R)S(O)2 R。在一些實施例中，RYZC 為-P(O)R2 。在一些實施例中，RYZC 為-P(O)(R)OR。在一些實施例中，RYZC 為-B(OR)2 。
在一些實施例中，RYZC 之各實例獨立地為鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 。
在一些實施例中，RYZC 之各實例獨立地為鹵素、-CN或-NO2 。在一些實施例中，RYZC 之各實例獨立地為-OR、-SR或-NR2 。在一些實施例中，RYZC 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RYZC 之各實例獨立地為-C(O)R、-C(O)OR、-C(O)NR2 或-C(O)N(R)OR。在一些實施例中，RYZC 之各實例獨立地為-OC(O)R或-OC(O)NR2 。在一些實施例中，RYZC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RYZC 之各實例獨立地為-P(O)R2 或-P(O)(R)OR。
在一些實施例中，RYZC 之各實例獨立地為-OR、-OC(O)R或-OC(O)NR2 。在一些實施例中，RYZC 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RYZC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R。
在一些實施例中，RYZC 之各實例獨立地為-S(O)2 R、-S(O)2 NR2 或-S(O)2 F。在一些實施例中，RYZC 之各實例獨立地為-S(O)R、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RYZC 之各實例獨立地為-SR、-S(O)2 R或-S(O)R。在一些實施例中，RYZC 之各實例獨立地為-S(O)2 NR2 、-S(O)NR2 或-S(O)(NR)R。在一些實施例中，RYZC 之各實例獨立地為-S(O)2 NR2 或-S(O)NR2 。在一些實施例中，RYZC 之各實例獨立地為-SR、-S(O)2 R、-S(O)2 NR2 或-S(O)R。
在一些實施例中，RYZC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RYZC 之各實例獨立地為-N(R)S(O)2 NR2 或-N(R)S(O)2 R。在一些實施例中，RYZC 之各實例獨立地為-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RYZC 之各實例獨立地為-N(R)C(O)NR2 或-N(R)S(O)2 NR2 。在一些實施例中，RYZC 之各實例獨立地為-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RYZC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)C(O)NR2 。在一些實施例中，RYZC 之各實例獨立地為-NR2 、-N(R)C(O)OR或-N(R)C(O)R。在一些實施例中，RYZC 之各實例獨立地為-NR2 、-N(R)C(O)OR、-N(R)C(O)R或-N(R)S(O)2 R。
在一些實施例中，RYZC 之各實例獨立地為視情況經取代之C1-6 脂族基。在一些實施例中，RYZC 之各實例獨立地為視情況經取代之苯基。在一些實施例中，RYZC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，RYZC 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RYZC 之各實例獨立地為視情況經取代之C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，RYZC 之各實例獨立地為視情況經取代之苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RYZC 之各實例獨立地為視情況經取代之C1-6 脂族基或視情況經取代之苯基。在一些實施例中，RYZC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，RYZC 之各實例獨立地為選自以下之視情況經取代之基團：苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RYZC 之各實例獨立地為C1-6 脂族基。在一些實施例中，RYZC 為苯基。在一些實施例中，RYZC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RYZC 之各實例獨立地為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RYZC 之各實例獨立地為C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，RYZC 之各實例獨立地為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RYZC 之各實例獨立地為C1-6 脂族基或苯基。在一些實施例中，RYZC 之各實例獨立地為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RYZC 之各實例獨立地為苯基, 具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，RYZC 之各實例獨立地選自表1之化合物中所描繪之基團。
如上文一般所定義，R之各實例獨立地為氫，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環；或相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，具有0-3個獨立地選自氮、氧及硫之雜原子之4-7員飽和、部分不飽和或雜芳基環。
在一些實施例中，R為氫或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。在一些實施例中，相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，具有0-3個獨立地選自氮、氧及硫之雜原子之4-7員飽和、部分不飽和或雜芳基環。
在一些實施例中，R為氫。在一些實施例中，R為選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。在一些實施例中，R為氫、C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R為視情況經取代之C1-6 脂族基。在一些實施例中，R為視情況經取代之苯基。在一些實施例中，R為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，R為具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，R為視情況經取代之C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環。在一些實施例中，R為視情況經取代之苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，R為視情況經取代之C1-6 脂族基或視情況經取代之苯基。在一些實施例中，R為具有1-2個獨立地選自氮、氧及硫之雜原子的視情況經取代之3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的視情況經取代之5-6員單環雜芳基環。
在一些實施例中，R為選自以下之視情況經取代之基團：苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R為C1-6 脂族基。在一些實施例中，R為苯基。在一些實施例中，R為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，R為具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R為C1-6 脂族基或具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環。在一些實施例中，R為苯基或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R為C1-6 脂族基或苯基。在一些實施例中，R為具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，R為苯基, 具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環或具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環。
在一些實施例中，相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，具有1-3個獨立地選自氮、氧及硫之雜原子的4至7員飽和、部分不飽和或雜芳基環。在一些實施例中，相同氮上之兩個R基團與其等插入原子一起形成除該氮以外不具有額外雜原子之4-7員飽和、部分不飽和或雜芳基環。
在一些實施例中，相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，具有0-3個獨立地選自氮、氧及硫之雜原子的4-7員飽和環。在一些實施例中，相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，具有0-3個獨立地選自氮、氧及硫之雜原子的4-7員部分不飽和環。在一些實施例中，相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，具有0-3個獨立地選自氮、氧及硫之雜原子的4-7員雜芳基環。
在一些實施例中，相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，具有1-3個獨立地選自氮、氧及硫之雜原子的4-7員飽和環。在一些實施例中，相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，具有1-3個獨立地選自氮、氧及硫之雜原子的4-7員部分不飽和環。在一些實施例中，相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，具有1-3個獨立地選自氮、氧及硫之雜原子之4-7員雜芳基環。
在一些實施例中，相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，不具有額外雜原子之4-7員飽和環。在一些實施例中，相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，不具有額外雜原子之4-7員部分不飽和環。在一些實施例中，相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，不具有額外雜原子之4-7員雜芳基環。
在一些實施例中，R選自表1之化合物中所描繪之基團。
如上文一般所定義，n為0、1、2、3或4。在一些實施例中，n為0。在一些實施例中，n為1。在一些實施例中，n為2。在一些實施例中，n為3。在一些實施例中，n為4。在一些實施例中，n為0或1。在一些實施例中，n為0、1或2。在一些實施例中，n為0、1、2或3。在一些實施例中，n為1或2。在一些實施例中，n為1、2或3。在一些實施例中，n為1、2、3或4。在一些實施例中，n為2或3。在一些實施例中，n為2、3或4。在一些實施例中，n為3或4。在一些實施例中，n係選自表1中之化合物所示的值。
如上文一般所定義，p為0、1、2、3或4。在一些實施例中，p為0。在一些實施例中，p為1。在一些實施例中，p為2。在一些實施例中，p為3。在一些實施例中，p為4。在一些實施例中，p為0或1。在一些實施例中，p為0、1或2。在一些實施例中，p為0、1、2或3。在一些實施例中，p為1或2。在一些實施例中，p為1、2或3。在一些實施例中，p為1、2、3或4。在一些實施例中，p為2或3。在一些實施例中，p為2、3或4。在一些實施例中，p為3或4。在一些實施例中，p係選自表1中之化合物所示的值。
如上文一般所定義，q為0、1、2、3或4。在一些實施例中，q為0。在一些實施例中，q為1。在一些實施例中，q為2。在一些實施例中，q為3。在一些實施例中，q為4。在一些實施例中，q為0或1。在一些實施例中，q為0、1或2。在一些實施例中，q為0、1、2或3。在一些實施例中，q為1或2。在一些實施例中，q為1、2或3。在一些實施例中，q為1、2、3或4。在一些實施例中，q為2或3。在一些實施例中，q為2、3或4。在一些實施例中，q為3或4。在一些實施例中，q係選自表1中之化合物所示的值。
如上文一般所定義，r1 為0、1、2、3或4。在一些實施例中，r1 為0。在一些實施例中，r1 為1。在一些實施例中，r1 為2。在一些實施例中，r1 為3。在一些實施例中，r1 為4。在一些實施例中，r1 為0或1。在一些實施例中，r1 為0、1或2。在一些實施例中，r1 為0、1、2或3。在一些實施例中，r1 為1或2。在一些實施例中，r1 為1、2或3。在一些實施例中，r1 為1、2、3或4。在一些實施例中，r1 為2或3。在一些實施例中，r1 為2、3或4。在一些實施例中，r1 為3或4。在一些實施例中，r1 選自表1之化合物中所表示之值。
如上文一般所定義，r2 為0、1、2、3或4。在一些實施例中，r2 為0。在一些實施例中，r2 為1。在一些實施例中，r2 為2。在一些實施例中，r2 為3。在一些實施例中，r2 為4。在一些實施例中，r2 為0或1。在一些實施例中，r2 為0、1或2。在一些實施例中，r2 為0、1、2或3。在一些實施例中，r2 為1或2。在一些實施例中，r2 為1、2或3。在一些實施例中，r2 為1、2、3或4。在一些實施例中，r2 為2或3。在一些實施例中，r2 為2、3或4。在一些實施例中，r2 為3或4。在一些實施例中，r2 選自表1之化合物中所表示之值。
如上文一般所定義，r3 為0、1、2、3或4。在一些實施例中，r3 為0。在一些實施例中，r3 為1。在一些實施例中，r3 為2。在一些實施例中，r3 為3。在一些實施例中，r3 為4。在一些實施例中，r3 為0或1。在一些實施例中，r3 為0、1或2。在一些實施例中，r3 為0、1、2或3。在一些實施例中，r3 為1或2。在一些實施例中，r3 為1、2或3。在一些實施例中，r3 為1、2、3或4。在一些實施例中，r3 為2或3。在一些實施例中，r3 為2、3或4。在一些實施例中，r3 為3或4。在一些實施例中，r3 選自表1之化合物中所表示之值。
如上文一般所定義，r4 為0、1、2、3或4。在一些實施例中，r4 為0。在一些實施例中，r4 為1。在一些實施例中，r4 為2。在一些實施例中，r4 為3。在一些實施例中，r4 為4。在一些實施例中，r4 為0或1。在一些實施例中，r4 為0、1或2。在一些實施例中，r4 為0、1、2或3。在一些實施例中，r4 為1或2。在一些實施例中，r4 為1、2或3。在一些實施例中，r4 為1、2、3或4。在一些實施例中，r4 為2或3。在一些實施例中，r4 為2、3或4。在一些實施例中，r4 為3或4。在一些實施例中，r4 選自表1之化合物中所表示之值。
如上文一般所定義，r5 為0、1、2、3或4。在一些實施例中，r5 為0。在一些實施例中，r5 為1。在一些實施例中，r5 為2。在一些實施例中，r5 為3。在一些實施例中，r5 為4。在一些實施例中，r5 為0或1。在一些實施例中，r5 為0、1或2。在一些實施例中，r5 為0、1、2或3。在一些實施例中，r5 為1或2。在一些實施例中，r5 為1、2或3。在一些實施例中，r5 為1、2、3或4。在一些實施例中，r5 為2或3。在一些實施例中，r5 為2、3或4。在一些實施例中，r5 為3或4。在一些實施例中，r5 選自表1之化合物中所表示之值。
如上文一般所定義，r6 為0、1、2、3或4。在一些實施例中，r6 為0。在一些實施例中，r6 為1。在一些實施例中，r6 為2。在一些實施例中，r6 為3。在一些實施例中，r6 為4。在一些實施例中，r6 為0或1。在一些實施例中，r6 為0、1或2。在一些實施例中，r6 為0、1、2或3。在一些實施例中，r6 為1或2。在一些實施例中，r6 為1、2或3。在一些實施例中，r6 為1、2、3或4。在一些實施例中，r6 為2或3。在一些實施例中，r6 為2、3或4。在一些實施例中，r6 為3或4。在一些實施例中，r6 選自表1之化合物中所表示之值。
如上文一般所定義，r7 為0、1、2、3或4。在一些實施例中，r7 為0。在一些實施例中，r7 為1。在一些實施例中，r7 為2。在一些實施例中，r7 為3。在一些實施例中，r7 為4。在一些實施例中，r7 為0或1。在一些實施例中，r7 為0、1或2。在一些實施例中，r7 為0、1、2或3。在一些實施例中，r7 為1或2。在一些實施例中，r7 為1、2或3。在一些實施例中，r7 為1、2、3或4。在一些實施例中，r7 為2或3。在一些實施例中，r7 為2、3或4。在一些實施例中，r7 為3或4。在一些實施例中，r7 選自表1之化合物中所表示之值。
如上文一般所定義，r8 為0、1、2、3或4。在一些實施例中，r8 為0。在一些實施例中，r8 為1。在一些實施例中，r8 為2。在一些實施例中，r8 為3。在一些實施例中，r8 為4。在一些實施例中，r8 為0或1。在一些實施例中，r8 為0、1或2。在一些實施例中，r8 為0、1、2或3。在一些實施例中，r8 為1或2。在一些實施例中，r8 為1、2或3。在一些實施例中，r8 為1、2、3或4。在一些實施例中，r8 為2或3。在一些實施例中，r8 為2、3或4。在一些實施例中，r8 為3或4。在一些實施例中，r8 選自表1之化合物中所表示之值。
在一些實施例中，本發明提供式I化合物，其中E為-C(O)-，由此形成式II化合物：
Figure 02_image267
或其醫藥學上可接受之鹽，其中Q、R1 、R2 、X、Y及Z中之每一者如本文中之實施例及類別以及子類中所定義。
在一些實施例中，本發明提供式II化合物，其中Q為CH，由此形成式III化合物：
Figure 02_image269
或其醫藥學上可接受之鹽，其中R1 、R2 、X、Y及Z中之每一者如本文中之實施例及類別以及子類中所定義。
在一些實施例中，本發明提供式II化合物，其中Q為N，由此形成式IV化合物：
Figure 02_image271
或其醫藥學上可接受之鹽，其中R1 、R2 、X、Y及Z中之每一者如本文中之實施例及類別以及子類中所定義。
在一些實施例中，本發明提供式II化合物，其中X、Y或Z為CH，由此形成式V、VI或VII化合物：
Figure 02_image273
或其醫藥學上可接受之鹽，其中R1 、R2 、Q、X、Y及Z中之每一者如本文中之實施例及類別以及子類中所定義。
在一些實施例中，本發明提供式II化合物，其中X、Y或Z為N，由此形成式VIII、IX或X化合物：
Figure 02_image275
或其醫藥學上可接受之鹽，其中R1 、R2 、Q、X、Y及Z中之每一者如本文中之實施例及類別以及子類中所定義。
在一些實施例中，本發明提供式III化合物，其中X、Y或Z為CH，由此形成式XI、XII或XIII化合物：
Figure 02_image277
或其醫藥學上可接受之鹽，其中R1 、R2 、X、Y及Z中之每一者如本文中之實施例及類別以及子類中所定義。
在一些實施例中，本發明提供式III化合物，其中X、Y或Z為N，由此形成式XIV、XV或XVI化合物：
Figure 02_image279
或其醫藥學上可接受之鹽，其中R1 、R2 、X、Y及Z中之每一者如本文中之實施例及類別以及子類中所定義。
在一些實施例中，本發明提供式XII、XIII、XV及XVI化合物，其中X為CH，由此形成式XVII、XVIII、XIX或XX化合物：
Figure 02_image281
或其醫藥學上可接受之鹽，其中R1 、R2 、X、Y及Z中之每一者如本文中之實施例及類別以及子類中所定義。
在一些實施例中，本發明提供式I化合物，其中E為-OC(O)-、-N(RE )C(O)-或-C(RE )2 C(O)-，由此分別形成式XXI、XXII或XXIII化合物：
Figure 02_image283
或其醫藥學上可接受之鹽，其中Q、R1 、R2 、RE 、X、Y及Z中之每一者如本文中之實施例及類別以及子類中所定義。
在一些實施例中，本發明提供式XXI、XXII或XXIII化合物，其中Q為CH，由此分別形成式XXIV、XXV或XXVI化合物：
Figure 02_image285
或其醫藥學上可接受之鹽，其中R1 、R2 、RE 、X、Y及Z中之每一者如本文中之實施例及類別以及子類中所定義。
在一些實施例中，本發明提供式III、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXIV、XXV或XXVI化合物，其在Q為CH時具有Q處描繪之立體化學，由此分別形成式XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物：
Figure 02_image287
Figure 02_image289
或其醫藥學上可接受之鹽，其中R1 、R2 、RE 、X、Y及Z中之每一者如本文中之實施例及類別以及子類中所定義。
在一些實施例中，本發明提供式XXVIII化合物：
Figure 02_image291
或其醫藥學上可接受之鹽，其中R1 、R2 、Y及Z中之每一者如本文中之實施例及類別以及子類中所定義。
在一些實施例中，本發明提供式XXXV化合物：
Figure 02_image293
或其醫藥學上可接受之鹽，其中R1 、R2 及Y中之每一者如本文中之實施例及類別以及子類中所定義。
在一些實施例中，本發明提供式XXXVII化合物：
Figure 02_image295
或其醫藥學上可接受之鹽，其中R1 、R2 及Y中之每一者如本文中之實施例及類別以及子類中所定義。
在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中L1 為共價鍵，且R2 為-N(R)C(O)-R2A 、-N(R)-R2A 或-R2A 。
在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中L1 為共價鍵，且R2 為-N(R)C(O)-R2A 。在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中L1 為共價鍵，且R2 為-N(R)-R2A 。在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中L1 為共價鍵，且R2 為-R2A 。
在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中L1 為共價鍵，且R2 為-N(H)C(O)-R2A 、-N(H)-R2A 或-R2A 。在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中L1 為共價鍵，且R2 為-N(H)C(O)-R2A 。在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中L1 為共價鍵，且R2 為-N(H)-R2A 。
在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中Y為C(RYA )、L1 為共價鍵，且R2 為-N(R)C(O)-R2A 。在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中Y為C(RYA )、L1 為共價鍵，且R2 為-N(R)-R2A 。在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中Y為C(RYA )、L1 為共價鍵，且R2 為-R2A 。
在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中Y為C(RYA )、L1 為共價鍵，且R2 為-N(H)C(O)-R2A 、-N(H)-R2A 或-R2A 。在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中Y為C(RYA )、L1 為共價鍵，且R2 為-N(H)C(O)-R2A 。在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中Y為C(RYA )、L1 為共價鍵，且R2 為-N(H)-R2A 。
在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中Y為C(RYA )。
在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中L1 為共價鍵(亦即R1 為-R1A )。
在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中R2 為-N(R)C(O)-R2A 、-N(R)-R2A 或-R2A 。在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中R2 為-N(R)C(O)-R2A 。在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中R2 為-N(R)-R2A 。在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中R2 為-R2A 。
在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中R2 為-N(H)C(O)-R2A 、-N(H)-R2A 或-R2A 。在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中R2 為-N(H)C(O)-R2A 。在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中R2 為-N(H)-R2A 。
在一些實施例中，本發明提供式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，其中Y為C(RYA )。
本發明之化合物之實例包括本文中之表及範例中所列的彼等化合物或其醫藥學上可接受之鹽、立體異構體或立體異構體混合物。在一些實施例中，本發明包含選自下表1中所描繪之化合物的化合物或其醫藥學上可接受之鹽、立體異構體或立體異構體混合物。在一些實施例中，本發明提供下表1中所示之化合物或其醫藥學上可接受之鹽。在一些實施例中，本發明提供下表1中所示的化合物。表 1. 具有生物活性資料的本發明代表性化合物。
實例編號 結構 SMILES 1 H NMR MS ADP-Glo IC50 MCF10A IC50
I-1
Figure 02_image297
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3csc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  10.09 (s, 1H), 9.02 (s, 1H), 7.94-8.07 (m, 2H), 7.52 - 7.72 (m, 4H), 7.32-7.46 (m, 2H), 7.04-7.15 (m, 1H), 6.91-7.00 (m, 2H), 6.62 (br s, 1H), 6.02 (s, 1H), 2.07-2.30 (m, 3 H) 399.2 B B
I-2
Figure 02_image299
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.37 (s, 1 H) 9.06 (s, 1H) 7.88 (br d, 8.59 Hz, 1 H) 7.65 - 7.69 (m, 1 H) 7.61 (t,  7.58 Hz, 1 H) 7.51 (d, 7.58 Hz, 1 H) 7.47 (br d,  8.84 Hz, 1 H) 7.33 (br d,  1.26 Hz, 1 H) 7.02 - 7.08 (m, 1 H) 6.91 - 7.00 (m, 2H) 5.89 (br s, 1 H) 1.93 - 2.35 (m, 3H) 429.3 B   
I-3
Figure 02_image301
 O=C(Nc1cccc2C(=O)NCc12)c1csc2ccccc12 1H NMR (400 MHz, DMSO-d6)  10.33 (s, 1 H) 8.53 - 8.67 (m, 2 H) 8.31 - 8.47 (m, 1 H) 8.09 (br d,  6.57 Hz, 1 H) 7.79 (br dd, 3.54, 2.53 Hz, 1 H) 7.36 - 7.63 (m, 4 H) 4.43 (s, 2 H) 309.17 E   
I-4
Figure 02_image303
 Cc1ccccc1[C@H]1NC(=O)c2cccc(NC(=O)c3csc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 10.10 (s, 1 H) 9.04 (s, 1 H) 7.96 - 8.14 (m, 2 H) 7.54 - 7.74 (m, 4 H) 7.31 - 7.53 (m, 2 H) 6.89 - 7.16 (m, 3H) 6.46 - 6.83 (m, 1 H) 6.04 (s, 1 H) 2.19 (br s, 2 H) 399.23 C   
I-5
Figure 02_image305
 Cc1ccccc1[C@@H]1NC(=O)c2cccc(NC(=O)c3csc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 10.10 (s, 1 H) 9.04 (s, 1 H) 7.99 - 8.09 (m, 2 H) 7.57 - 7.69 (m, 4 H) 7.37 - 7.45 (m, 2 H) 7.07 - 7.13 (m, 1H) 7.02 (d,  7.33 Hz, 1 H) 6.95 - 7.01 (m, 1 H) 6.53 - 6.72 (m, 1 H) 6.04 (s, 1 H) 2.05 - 2.32 (m, 3 H) 399.23 A B
I-6
Figure 02_image307
 CNC(=O)c1cc2C(=O)NC(c2c(NC(=O)c2csc3ccccc23)c1)c1ccccc1C 1H NMR (400 MHz, DMSO-d6) 10.15-10.31 (m, 1H), 9.11-9.22 (m, 1H), 8.63-8.81 (m, 1H), 8.12-8.15 (m, 1H), 8.08-8.18 (m, 2H), 8.04-8.10 (m, 2H), 8.04-8.09 (m, 2H), 7.97-8.03 (m, 1H), 7.70 (s, 1H), 7.33-7.49 (m, 2H), 6.91-7.17 (m, 5H), 5.96-6.18 (m, 1H), 2.73-3.00 (m, 4H), 2.11-2.26 (m, 3H) 456 A A
I-7
Figure 02_image309
 Cc1ccccc1C1NC(=O)c2nccc(NC(=O)c3csc4ccccc34)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.41 (s, 1H), 9.43 (s, 1H), 8.77 (d,J = 5.3 Hz, 1H), 8.01-8.06 (m, 1H), 7.98 (br d,J = 7.1 Hz, 1H), 7.75 (s, 1H), 7.64 (d,J = 5.3 Hz, 1H), 7.36-7.45 (m, 2H), 6.98-7.16 (m, 4H), 6.09 (s, 1H), 2.26 (br s, 3H)。 400.3 B   
I-8
Figure 02_image311
 O=C(Nc1cccc2C(=O)NC(c12)c1ccccc1)c1csc2ccccc12 1H NMR (400 MHz, DMSO-d6) 10.13 (s, 1 H), 9.06 (s, 1 H), 8.16-8.25 (m, 1 H), 8.03-8.11 (m, 1 H), 7.94 (s, 1 H), 7.55-7.71 (m, 3 H), 7.40-7.51 (m, 2 H), 7.12-7.26 (m, 3 H), 6.98-7.10 (m, 2 H), 5.86 (s, 1 H) 385.3 B   
I-9
Figure 02_image313
 Clc1ccccc1C1NC(=O)c2nccc(NC(=O)c3csc4ccccc34)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.50 (s, 1H), 9.46 (br s, 1H), 8.76 (d,J = 5.3 Hz, 1H), 8.08-8.14 (m, 1H), 8.02-8.07 (m, 1H), 7.95 (s, 1H), 7.58 (d,J = 5.3 Hz, 1H), 7.39-7.47 (m, 2H), 7.29-7.33 (m, 1H), 7.24 (td,J = 7.6, 1.6 Hz, 1H), 7.10-7.17 (m, 1H), 6.16-6.27 (m, 1H), 5.75 (s, 1H)。 420.2 B   
I-10
Figure 02_image315
 Cc1ccccc1C1NC(=O)Oc2cccc(Br)c12    318.2 E   
I-11
Figure 02_image317
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cccc4OCCCc34)c12 1H NMR (400 MHz, DMSO-d6) 9.94 (s, 1H), 9.03 (s, 1H), 7.63-7.54 (m, 3H), 7.24-7.16 (m, 2H), 7.05 (td, 7.3, 1.4 Hz, 1H), 6.94 (t, 7.8 Hz, 1H), 6.76 (dd, 8.2, 1.2 Hz, 1H), 6.53 (br. s, 1H), 6.10 (dd, 7.5, 1.1 Hz, 1H), 6.05 (br. s, 1H), 4.14-3.99 (m, 2H), 2.30 (br. s, 3H), 2.17 (t, 5.9 Hz, 1H), 2.13 (t, 5.7 Hz, 1H), 1.80-1.62 (m, 2H)。 399.3 E   
I-12
Figure 02_image319
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cccc(c3F)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.32 (s, 1H), 9.07 (s, 1H), 7.87 (t,  6.8 Hz, 1H), 7.68 (dd, 7.5, 1.1 Hz, 1H), 7.61 (t, 7.6 Hz, 1H), 7.52 (dd, 7.7, 0.8 Hz, 1H), 7.35 (t, 7.8 Hz, 1H), 7.19 (td, 7.4, 1.3 Hz, 1H), 7.13 (d, 6.9 Hz, 1H), 7.08-6.96 (m, 2H), 6.59 (br s, 1H), 5.96 (s, 1H), 2.43-2.08 (br s, 3H)。 429.3 E   
I-13
Figure 02_image321
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 10.15 (s, 1H), 9.05 (s, 1H), 8.58 (d, 8.2 Hz, 1H), 8.29 (d, 8.2 Hz, 1H), 7.80 (dd, 7.6, 1.2 Hz, 1H), 7.74-7.55 (m, 4H), 7.06-6.93 (m, 2H), 6.89 (t, 13.3 Hz, 1H), 6.68 (br s, 1H), 6.12 (s, 1H), 2.40-2.10 (br s, 3H)。 400.3 B B
I-14
Figure 02_image323
 COc1cccc(n1)-c1cccc2C(=O)NC(c12)c1ccccc1C    331.4 E   
I-15
Figure 02_image325
 Fc1cccc(C2NC(=O)c3nccc(NC(=O)c4csc5ccccc45)c23)c1F 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.61 (s, 1H), 9.49 (s, 1H), 8.76 (d,J = 5.1 Hz, 1H), 8.11-8.17 (m, 1H), 8.05-8.09 (m, 1H), 8.05 (s, 1H), 7.61 (d,J = 5.3 Hz, 1H), 7.41-7.48 (m, 2H), 7.25-7.34 (m, 1H), 6.98-7.05 (m, 1H), 6.82 (br t,J = 7.1 Hz, 1H), 6.11 (s, 1H)。 422.5 B   
I-16
Figure 02_image327
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 11.05 (s, 1H), 9.08 (s, 1H), 7.71 (d, 7.3 Hz, 1H), 7.61 (t, 7.6 Hz, 1H), 7.48 (dd, 7.8, 0.8 Hz, 1H), 7.24-7.08 (m, 2H), 7.10-6.95 (m, 1H), 6.53 (br. s, 1H), 5.86 (s, 1H), 2.27 (br. s, 3H)。 335 E   
I-17
Figure 02_image329
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3nn(C)c4ccccc34)c12 1H NMR (400 MHz,  DMSO-d6) 9.35 (s, 2H), 9.02 (s, 2H), 8.07 (d, 8.3 Hz, 2H), 7.98 (p, 3.8 Hz, 2H), 7.72 (d, 8.6 Hz, 2H), 7.60-7.52 (m, 4H), 7.45 (dd, 11.4, 4.0 Hz, 2H), 7.31-7.25 (m, 2H), 7.13-7.01 (m, 4H), 6.98 (t, 7.3 Hz, 2H), 6.87-6.49 (m, 2H), 6.12 (s, 2H), 4.08 (s, 6H), 2.30 (br s, 3H) 397 E   
I-18
Figure 02_image331
 COc1ccccc1C1NC(=O)c2cccc(NC(=O)c3csc4ccccc34)c12 1H NMR (400 MHz,  DMSO-d6) 10.00 (br s, 1H), 8.86 (s, 1H), 8.38 (br s, 1H), 8.18 (dd, 6.1, 3.0 Hz, 1H), 8.01-8.07 (m, 1H), 7.98 (s, 1H), 7.59-7.65 (m, 2H), 7.50-7.58 (m, 1H), 7.35-7.44 (m, 2H), 7.07-7.21 (m, 1H), 6.80 (d, 8.3 Hz, 1H), 6.63-6.76 (m, 2H), 6.15 (s, 1H), 3.20-3.50 (m, 3H) 415.4 D   
I-19
Figure 02_image333
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3coc4ccc(F)cc34)c12    401.4 C B
I-20
Figure 02_image335
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3coc4cc(F)ccc34)c12    401.5 C   
I-21
Figure 02_image337
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3noc4ccc(F)cc34)c12    402.5 D   
I-22
Figure 02_image339
 Fc1cccc([C@@H]2NC(=O)c3nccc(NC(=O)c4csc5ccccc45)c23)c1F 1 H NMR (400 MHz, DMSO-d6 ) δ 10.60 (s, 1H), 9.49 (s, 1H), 8.77 (d,J = 5.4 Hz, 1H), 8.11-8.16 (m, 1H), 8.05-8.09 (m, 1H), 8.05 (s, 1H), 7.60 (d,J = 5.4 Hz, 1H), 7.41-7.48 (m, 2H), 7.25-7.34 (m, 1H), 6.98-7.05 (m, 1H), 6.82 (br t,J = 7.0 Hz, 1H), 6.12 (s, 1H)。 422.4 C B
I-23
Figure 02_image341
 Fc1cccc([C@H]2NC(=O)c3nccc(NC(=O)c4csc5ccccc45)c23)c1F 1 H NMR (400 MHz, DMSO-d6 ) δ 10.60 (br s, 1H), 9.49 (s, 1H), 8.76 (br d,J = 5.4 Hz, 1H), 8.10-8.18 (m, 1H), 8.07 (br d,J = 3.9 Hz, 1H), 8.05 (s, 1H), 7.61 (br d,J = 5.1 Hz, 1H), 7.44 (dt,J = 4.6, 2.3 Hz, 2H), 7.24-7.35 (m, 1H), 6.97-7.06 (m, 1H), 6.82 (br t,J = 6.8 Hz, 1H), 6.12 (s, 1H)。 422.4 D   
I-24
Figure 02_image343
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3n[nH]c4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 13.65 (s, 1H), 9.62 (s, 1H), 9.00 (s, 1H), 8.07 (d, 8.2 Hz, 1H), 7.87 (dd, 6.7, 2.2 Hz, 1H), 7.62-7.52 (m, 3H), 7.44-7.37 (m, 1H), 7.28-7.20 (m, 1H), 7.02-6.96 (m, 2H), 6.96-6.88 (br s, 1H), 6.66 (br s, 1H), 6.15 (s, 1H), 2.30 (br s,3H) (甲酸鹽) 383.3 E   
I-25
Figure 02_image345
 [2H]C1(NC(=O)c2cccc(NC(=O)c3csc4ccccc34)c12)c1ccccc1C 1H NMR (400 MHz, DMSO-d6) 10.09 (s, 1H), 9.01 (s, 1H), 8.03-7.95 (m, 2H), 7.66-7.51 (m, 4H), 7.43-7.32 (m, 2H), 7.07 (td, 7.4, 1.4 Hz, 1H), 7.02-6.88 (m, 2H), 6.55 (br s, 1H), 2.16 (br s, 3H)。 400.4 A B
I-26
Figure 02_image347
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3csc4ccc(F)cc34)c12    417.5 B B
I-27
Figure 02_image349
 Cc1ccccc1C1NC(=O)c2cccc(Nc3cc4ccccc4nn3)c12    367.4 E   
I-28
Figure 02_image351
 Cc1ccccc1C1NC(=O)c2cccc(Nc3nc(C)c4ccccc4n3)c12    381.4 E   
I-29
Figure 02_image353
 Cc1ccccc1C1NC(=O)c2cc(Br)cc(NC(=O)c3csc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 10.12-10.35 (m, 1H), 9.13-9.35 (m, 1H), 7.96-8.08 (m, 2H), 7.80-7.87 (m, 1H), 7.71-7.78 (m, 1H), 7.56-7.68 (m, 1H), 7.32-7.49 (m, 2H), 7.05-7.14 (m, 1H), 6.88-7.05 (m, 2H), 6.44-6.82 (m, 1H), 5.91-6.11 (m, 1H), 1.82-2.38 (m, 3H) 477 A A
I-30
Figure 02_image355
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cc(=O)[nH]c4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  11.91 (s, 1H), 10.54 (s, 1H), 9.10 (s, 1H), 7.69 (dd, 7.5, 1.1 Hz, 1H), 7.62 (t, 7.6 Hz, 1H), 7.55-7.46 (m, 2H), 7.30 (d, 7.7 Hz, 1H), 7.27- 7.15 (m, 3H), 7.12-7.02 (m, 2H), 6.55 (br. s, 1H), 6.06 (s, 1H), 5.63 (d, 2.0 Hz, 1H), 2.33 (br. s, 3H)。 410 E   
I-31
Figure 02_image357
 OC1(NC(=O)c2nccc(NC(=O)c3csc4ccccc34)c12)c1cccc(F)c1F    438.5 E   
I-32
Figure 02_image359
 Clc1ccccc1[C@H]1NC(=O)c2nccc(NC(=O)c3csc4ccccc34)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.50 (s, 1H), 9.46 (br s, 1H), 8.76 (d,J = 5.3 Hz, 1H), 8.08-8.14 (m, 1H), 8.02-8.07 (m, 1H), 7.95 (s, 1H), 7.58 (d,J = 5.3 Hz, 1H), 7.39-7.47 (m, 2H), 7.29-7.33 (m, 1H), 7.24 (td,J = 7.6, 1.6 Hz, 1H), 7.10-7.17 (m, 1H), 6.16-6.27 (m, 1H), 5.75 (s, 1H)。 420.5 D   
I-33
Figure 02_image361
 Clc1ccccc1[C@@H]1NC(=O)c2nccc(NC(=O)c3csc4ccccc34)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.50 (s, 1H), 9.46 (br s, 1H), 8.76 (d,J = 5.3 Hz, 1H), 8.08-8.14 (m, 1H), 8.02-8.07 (m, 1H), 7.95 (s, 1H), 7.58 (d,J = 5.3 Hz, 1H), 7.39-7.47 (m, 2H), 7.29-7.33 (m, 1H), 7.24 (td,J = 7.6, 1.6 Hz, 1H), 7.10-7.17 (m, 1H), 6.16-6.27 (m, 1H), 5.75 (s, 1H)。 420.4 B B
I-34
Figure 02_image363
 Cc1ccccc1C1NC(=O)c2cc(N)cc(NC(=O)c3csc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.70-9.85 (m, 1H), 8.68-8.80 (m, 1H), 8.42-8.56 (m, 1H), 7.93-8.08 (m, 2H), 7.55 (s, 1H), 7.31-7.45 (m, 2H), 6.87-7.11 (m, 3H), 6.73-6.85 (m, 2H), 6.56-6.73 (m, 1H), 5.76-5.90 (m, 1H), 5.38-5.61 (m, 2H), 2.03-2.24 (m, 2H) 414 A B
I-35
Figure 02_image365
 COc1ccc(NC(=O)c2csc3ccccc23)c2C(NC(=O)c12)c1ccccc1C    429.4 A B
I-36
Figure 02_image367
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3csc4c(F)cccc34)c12 1H NMR (400 MHz, DMSO-d6) 10.20 (s, 1H), 9.02 (s, 1H), 7.85 (br d,  8.34 Hz, 1H), 7.76 (s, 1H), 7.64-7.67 (m, 1H), 7.60 (t,  7.45 Hz, 1H), 7.53-7.57 (m, 1H), 7.43 (dt,  5.43, 8.02 Hz, 1H), 7.30 (dd,  7.83, 10.10 Hz, 1H), 7.05-7.10 (m, 1H), 6.94-7.01 (m, 2H), 6.55-6.67 (m, 1H), 6.00 (s, 1H) 417.303 B   
I-37
Figure 02_image369
 Cc1ccccc1[C@H]1NC(=O)c2cccc(NC(=O)c3csc4c(F)cccc34)c12 1H NMR (400 MHz, DMSO-d6) 10.20 (s, 1H), 9.02 (s, 1H), 7.85 (br d,  8.34 Hz, 1H), 7.76 (s, 1H), 7.63-7.68 (m, 1H), 7.59-7.62 (m, 1H), 7.51-7.57 (m, 1H), 7.43 (dt,  5.43, 8.02 Hz, 1H), 7.28-7.34 (m, 1H), 7.04-7.11 (m, 1H), 6.93-7.02 (m, 2H), 6.55-6.66 (m, 1H), 6.00 (s, 1H), 2.07-2.25 (m, 3H) 417.25 E   
I-38
Figure 02_image371
 Cc1ccccc1[C@@H]1NC(=O)c2cccc(NC(=O)c3csc4c(F)cccc34)c12 1H NMR (400 MHz, DMSO-d6) 10.20 (s, 1H), 9.02 (s, 1H), 7.85 (br d,  8.34 Hz, 1H), 7.76 (s, 1H), 7.63-7.68 (m, 1H), 7.59-7.62 (m, 1H), 7.51-7.57 (m, 1H), 7.43 (dt,  5.43, 8.02 Hz, 1H), 7.28-7.34 (m, 1H), 7.04-7.11 (m, 1H), 6.93-7.02 (m, 2H), 6.55-6.66 (m, 1H), 6.00 (s, 1H), 2.07-2.25 (m, 3H) 417.25 B B
I-39
Figure 02_image373
 CNc1cc2C(=O)NC(c2c(NC(=O)c2csc3ccccc23)c1)c1ccccc1C 1H NMR (400 MHz, DMSO-d6) 9.76-9.94 (m, 1H), 8.71-8.85 (m, 1H), 8.39-8.52 (m, 1H), 7.93-8.08 (m, 2H), 7.52-7.66 (m, 1H), 7.26-7.46 (m, 3H), 6.90-7.16 (m, 4H), 6.59-6.85 (m, 4H), 6.00-6.18 (m, 2H), 5.77-5.90 (m, 1H), 2.70-2.85 (m, 3H), 2.03-2.29 (m, 3H) 428 A B
I-40
Figure 02_image375
 Cc1ccccc1C1NC(=O)c2cc(N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 9.98-10.14 (m, 1H), 8.68-8.84 (m, 1H), 8.44-8.59 (m, 1H), 7.75-7.93 (m, 1H), 7.36-7.51 (m, 1H), 7.22-7.36 (m, 1H), 6.98-7.08 (m, 1H), 6.85-6.97 (m, 1H), 6.68-6.85 (m, 2H), 6.43-6.68 (m, 2H), 5.62-5.79 (m, 1H), 5.42-5.60 (m, 1H), 2.01-2.26 (m, 3H) 444 A B
I-41
Figure 02_image377
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3noc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.07 (s, 1H), 7.86 (d, 8.8 Hz, 2H), 7.77-7.67 (m, 2H), 7.63 (d, 4.3 Hz, 2H), 7.49 (t, 7.8 Hz, 1H), 7.03-6.84 (m, 3H), 6.61 (br s, 1H), 6.05 (s, 1H), 2.42-1.87 (m, 3H)。 384.3 E   
I-42
Figure 02_image379
 COc1ccc2scc(C(=O)Nc3cccc4C(=O)NC(c34)c3ccccc3C)c2c1 1H NMR (400 MHz, DMSO-d6) 10.08 (s, 1H), 9.04 (s, 1H), 7.89 (d, 8.9 Hz, 1H), 7.78 (d, 2.5 Hz, 1H), 7.66 (dd, 7.1, 1.5 Hz, 1H), 7.62 (s, 1H), 7.60 (d, 7.2 Hz, 1H), 7.57 (dd, 7.7, 1.5 Hz, 1H), 7.12-7.03 (m, 2H), 7.03-6.90 (m, 2H), 6.61 (s, 1H), 6.03 (s, 1H), 3.79 (s, 3H), 2.18 (br s, 3H)。 429.3 D   
I-43
Figure 02_image381
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)N3CCc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 8.95 (s, 1H), 8.37 (s, 1H), 7.68 (d, 8.0 Hz, 1H), 7.60-7.50 (m, 2H), 7.47-7.35 (m, 1H), 7.19-7.06 (m, 3H), 7.02 (d, 7.3 Hz, 1H), 6.95 (t, 7.1 Hz, 1H), 6.88 (td, 7.4, 1.0 Hz, 1H), 6.54 (s, 1H), 5.88 (s, 1H), 3.68-3.50 (m, 1H), 3.01-2.80 (m, 3H), 2.07 (s, 3H)。 384.3 A B
I-44
Figure 02_image383
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)N3CC(=O)Nc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 10.63 (s, 1H), 8.87 (s, 1H), 7.52 (dd, 7.4, 1.2 Hz, 1H), 7.47 (t, 7.5 Hz, 1H), 7.32 (dd, 7.6, 1.0 Hz, 1H), 7.19-7.06 (m, 3H), 7.01-6.94 (m, 1H), 6.90 (dd, 8.0, 1.4 Hz, 1H), 6.60 (t, 7.8 Hz, 1H), 5.91 (s, 1H), 5.84 (d, 7.3 Hz, 1H), 4.30 (d, 16.3 Hz, 1H), 3.75 (t, 12.4 Hz, 1H), 2.42-2.10 (m, 3H) 411.4 E   
I-45
Figure 02_image385
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)N3CC(C)(C)c4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 8.96 (s, 1H), 8.31 (s, 1H), 7.71 (d, 8.1 Hz, 1H), 7.56-7.51 (m, 2H), 7.50-7.44 (m, 1H), 7.19-7.07 (m, 3H), 7.03 (d, 7.4 Hz, 1H), 6.99-6.89 (m, 2H), 6.56 (br. s, 1H), 5.93 (s, 1H), 3.36 (d, 9.9 Hz, 1H), 2.78 (d, 9.8 Hz, 1H), 2.19 (br. s, 3H), 1.17 (s, 3H), 1.13 (s, 3H)。 412.3 D D
I-46
Figure 02_image387
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3csc4cnccc34)c12    400 B D
I-47
Figure 02_image389
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cnc4ccc(Cl)cn34)c12    417.2 E   
I-48
Figure 02_image391
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cnn4ccc(Cl)cc34)c12    417.2 D   
I-49
Figure 02_image393
 Cc1cccnc1C1NC(=O)c2cccc(NC(=O)c3csc4ccccc34)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.13 (s, 1H), 9.03 (s, 1H), 8.18 (dd,J = 4.7, 1.4 Hz, 1H), 8.11-8.16 (m, 1H), 8.01-8.07 (m, 1H), 7.89 (s, 1H), 7.78-7.85 (m, 3H), 7.60-7.65 (m, 1H), 7.51-7.59 (m, 2H), 7.13 (dd,J = 7.7, 4.7 Hz, 1H), 6.18 (s, 1H), 2.17-2.26 (m, 3H) 400.4 D   
I-50
Figure 02_image395
 Cc1ccccc1C1NC(=O)c2cc(N)cc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.6-9.9 (m, 1H), 8.7-8.9 (m, 1H), 8.4-8.6 (m, 1H), 8.2-8.3 (m, 1H), 7.6-7.8 (m, 1H), 7.5-7.6 (m, 1H), 7.1-7.2 (m, 1H), 6.9-7.0 (m, 3H), 6.7-6.8 (m, 1H), 6.5-6.7 (m, 1H), 5.8-6.0 (m, 1H), 5.4-5.6 (m, 2H), 2.1-2.4 (m, 3H) 415 A A
I-51
Figure 02_image397
 Cc1ccccc1C1NC(=O)c2cc(NC3COC3)cc(NC(=O)c3csc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.8-9.9 (m, 1H), 8.8-9.0 (m, 1H), 7.9-8.1 (m, 2H), 7.6-7.7 (m, 1H), 7.3-7.5 (m, 2H), 6.9-7.1 (m, 2H), 6.7-6.9 (m, 2H), 6.5-6.7 (m, 2H), 5.8-5.9 (m, 1H), 4.8-5.0 (m, 2H), 4.6-4.7 (m, 1H), 4.4-4.5 (m, 1H), 3.9-4.3 (m, 2H), 2.1-2.3 (m, 3H) 470 A A
I-52
Figure 02_image399
 CC(=O)Nc1cc2C(=O)NC(c2c(NC(=O)c2csc3ccccc23)c1)c1ccccc1C 1H NMR (400 MHz, DMSO-d6) 10.2-10.4 (m, 1H), 10.0-10.2 (m, 1H), 8.9-9.1 (m, 1H), 8.0-8.1 (m, 1H), 7.9-8.0 (m, 1H), 7.8-7.9 (m, 1H), 7.5-7.7 (m, 2H), 7.3-7.5 (m, 1H), 6.9-7.2 (m, 1H), 6.5-6.8 (m, 1H), 5.9-6.0 (m, 1H), 2.3-2.4 (m, 1H), 2.1-2.2 (m, 1H), 2.1-2.1 (m, 1H), 2.1-2.2 (m, 6H) 456 A A
I-53
Figure 02_image401
 CC(C)Nc1cc2C(=O)NC(c2c(NC(=O)c2csc3ccccc23)c1)c1ccccc1C 1H NMR (400 MHz, DMSO-d6) 9.8-9.9 (m, 1H), 8.7-8.8 (m, 1H), 8.2-8.4 (m, 1H), 7.9-8.1 (m, 3H), 7.6-7.8 (m, 3H), 7.3-7.5 (m, 2H), 6.9-7.2 (m, 2H), 6.5-6.7 (m, 1H), 5.7-6.0 (m, 2H), 2.1-2.3 (m, 3H), 1.0-1.2 (m, 6H) 456 A A
I-54
Figure 02_image403
 Cc1ccccc1C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.0-10.1 (m, 1H), 8.6-8.8 (m, 1H), 7.7-7.9 (m, 1H), 7.4-7.5 (m, 1H), 7.2-7.3 (m, 1H), 6.9-7.1 (m, 3H), 6.8-6.8 (m, 1H), 6.7-6.8 (m, 1H), 6.5-6.6 (m, 1H), 5.6-5.8 (m, 1H), 1.8-2.3 (m, 3H) 507 B B
I-55
Figure 02_image405
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)N3CCCc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  8.92 (s, 1H), 8.57 (s, 1H), 7.52-7.41 (m, 2H), 7.41-7.32 (m, 1H), 7.22-6.99 (m, 4H), 6.86 (td, 7.4, 1.2 Hz, 1H), 6.78 (t, 7.7 Hz, 1H), 6.47 (br s, 1H), 6.32 (d, 8.0 Hz, 1H), 5.90 (s, 1H), 3.44-3.35 (m, 1H), 3.15-3.06 (m, 1H), 2.67-2.49 (m, 2H), 2.40-2.07 (br s, 3H), 1.74-1.47 (m, 2H)。 397.9 D   
I-56
Figure 02_image407
 Cc1ccccc1C1NC(=O)c2cc(NS(C)(=O)=O)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz,  DMSO-d6) 10.2-10.5 (m, 1H), 8.8-9.1 (m, 1H), 8.3-8.5 (m, 1H), 7.7-7.9 (m, 1H), 7.4-7.5 (m, 1H), 7.3-7.4 (m, 1H), 7.2-7.3 (m, 1H), 7.0-7.1 (m, 1H), 6.9-7.0 (m, 2H), 6.6-6.7 (m, 2H), 5.7-5.9 (m, 1H), 2.8-3.1 (m, 3H), 2.1-2.3 (m, 3H) 522 B   
I-57
Figure 02_image409
 Clc1cccnc1C1NC(=O)c2cccc(NC(=O)c3csc4ccccc34)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.14 (s, 1H), 9.08 (s, 1H), 8.28 (dd,J = 1.52, 4.55 Hz, 1H), 8.17-8.24 (m, 1H), 7.98-8.06 (m, 2H), 7.72 (dd,J = 1.39, 8.21 Hz, 1H), 7.60-7.66 (m, 1H), 7.56 (t,J = 7.58 Hz, 1H), 7.47 (dd,J = 1.01, 7.58 Hz, 1H), 7.38-7.44 (m, 2H), 7.25 (dd,J = 4.55, 8.08 Hz, 1H), 6.30-6.57 (m, 1H)。 420.3 D   
I-58
Figure 02_image411
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3coc4c(F)cc(F)cc34)c12    419.4 B   
I-59
Figure 02_image413
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(OC(F)F)c3)c12    427.4 D   
I-60
Figure 02_image415
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)N3CCNC(C3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 8.93 (d, 3.3 Hz, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 7.52-7.45 (m, 2H), 7.32-7.24 (m, 1H), 7.21-7.11 (m, 2H), 7.07-6.97 (m, 1H), 6.47 (br s, 1H), 5.89 (s, 1H), 3.72-3.59 (m, 1H), 3.53 (d, 10.8 Hz, 1H), 3.20-3.40 (m., 2 H), 2.85-2.70 (m, 1H), 2.70-2.62 (m, 1H), 2.62-2.52 (m, 1H), 2.40-2.25 (m, 3H)。 418.9 E   
I-61
Figure 02_image417
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3ccn4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  9.24 (s, 1H), 8.97 (s, 1H), 8.36 (dt, 6.9, 1.1 Hz, 1H), 8.04 (d, 9.1 Hz, 1H), 7.68 (dd, 6.2, 2.7 Hz, 1H), 7.56 (s, 1H), 7.58-7.53 (m, 1H), 7.45 (d, 3.0 Hz, 1H), 7.05-7.00 (m, 2H), 6.99-6.96 (m, 1H), 6.92 (td, 7.4, 1.4 Hz, 1H), 6.89 (d, 3.1 Hz, 1H), 6.77 (td, 6.8, 1.3 Hz, 1H), 6.61 (br s, 1H), 6.15 (s, 1H), 2.22 (br s, 3H) 382.3 B   
I-62
Figure 02_image419
 Cc1ccccc1C1NC(=O)c2cccc(N)c12 1H NMR (400 MHz, DMSO-d6)  8.79 (s, 1H), 7.23 (t, 7.6 Hz, 1H), 7.21-7.19 (m, 2H), 7.09 (dt, 8.5, 4.3 Hz, 1H), 6.96 (dd, 7.4, 0.8 Hz, 1H), 6.79 (dd, 7.9, 0.8 Hz, 1H), 6.78 (br s, 1H), 5.68 (s, 1H), 4.62 (s, 2H), 2.35 (br s, 3H)。 239.2 E   
I-63
Figure 02_image421
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3csc4cncnc34)c12 1H NMR (400 MHz, DMSO-d6) 10.53 (s, 1H), 9.63 (s, 1H), 9.19 (s, 1H), 9.13 (s, 1H), 8.91 (s, 1H), 8.25 (d, 5.8 Hz, 1H), 7.76-7.58 (m, 2H), 7.13 (d, 7.5 Hz, 1H), 7.04 (t, 7.5 Hz, 1H), 6.90 (t, 7.2 Hz, 1H), 6.54 (br s, 1H), 6.12 (s, 1H), 2.49-2.24 (br s, 3H)。 400.46 E   
I-64
Figure 02_image423
 Cc1ccccc1-n1[nH]c(=O)c2cccc(N)c12 1H NMR (400 MHz, CDCl3)  8.03 (s, 1H), 7.43-7.37 (m, 1H), 7.36-7.33 (m, 1H), 7.29 (d, 3.5 Hz, 2H), 7.21 (dd, 7.9, 0.7 Hz, 1H), 6.96 (t, 7.5 Hz, 1H), 6.62 (dd, 7.4, 0.7 Hz, 1H), 2.19 (s, 3H)。 239.9 D   
I-65
Figure 02_image425
 Cc1ccccc1[C@H]1NC(=O)c2cc(N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.0-10.1 (m, 1H), 8.7-8.9 (m, 1H), 8.3-8.6 (m, 1H), 7.7-8.0 (m, 2H), 7.2-7.5 (m, 2H), 7.0-7.1 (m, 1H), 6.9-7.0 (m, 1H), 6.81 (s, 1H), 6.72 (br s, 1H), 6.6-6.7 (m, 1H), 5.6-5.7 (m, 1H), 5.4-5.6 (m, 1H), 2.1-2.3 (m, 3H) 444 D   
I-66
Figure 02_image427
 Cc1ccccc1[C@@H]1NC(=O)c2cc(N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.0-10.1 (m, 1H), 8.7-8.9 (m, 1H), 8.3-8.6 (m, 1H), 7.7-8.0 (m, 2H), 7.2-7.5 (m, 2H), 7.0-7.1 (m, 1H), 6.9-7.0 (m, 1H), 6.81 (s, 1H), 6.72 (br s, 1H), 6.6-6.7 (m, 1H), 5.6-5.7 (m, 1H), 5.4-5.6 (m, 1H), 2.1-2.3 (m, 3H) 444 A   
I-67
Figure 02_image429
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3csc4cccc(F)c34)c12 1H NMR (400 MHz, DMSO-d6) 10.22 (s, 1H), 9.05 (s, 1H), 7.87 (d, 8.1 Hz, 1H), 7.64 (t, 7.4 Hz, 1H), 7.60 (d, 7.4 Hz, 1H), 7.54 (d, 7.4 Hz, 1H), 7.44 (td, 8.0, 4.8 Hz, 1H), 7.23 (dd, 9.3, 6.3 Hz, 2H), 7.18 (t, 6.0 Hz,1H), 7.08 (t, 7.5 Hz, 1H), 6.70 (br s, 1H), 6.65 (br s, 1H), 6.00 (s, 1H), 2.22 (br s, 3H)。 417.2 D   
I-68
Figure 02_image431
 Cc1ccccc1-n1[nH]c(=O)c2cccc(NC(=O)c3csc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 11.01 (s, 1H), 9.70 (s, 1H), 8.23-8.12 (m, 1H), 8.02-7.93 (m, 1H), 7.70 (dd, 8.0, 0.9 Hz,1H), 7.59 (s, 1H), 7.44-7.34 (m, 2H), 7.31 (d, 7.1 Hz, 1H), 7.18-7.11 (m, 2H), 7.09-7.04 (m, 1H), 7.03-6.93 (m, 2H), 2.06 (s, 3H)。 400.2 C   
I-69
Figure 02_image433
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cc(Cl)n4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  9.43 (s, 1H), 8.98 (s, 1H), 8.24 (d, 6.9 Hz, 1H), 8.14 (d, 8.9 Hz, 1H), 7.64-7.54 (m, 3H), 7.15 (dd, 9.0, 6.6 Hz, 1H), 7.05-6.89 (m, 5H), 6.60 (br s, 1H), 6.11 (s, 1H), 2.20 (br s, 3H)。 416.2 B   
I-70
Figure 02_image435
 FC(F)(F)Oc1ccccc1C1NC(=O)c2nccc(NC(=O)c3csc4ccccc34)c12 1H NMR(400 MHz, CD3CN) 8.75 (d, 5.3 Hz, 1H), 8.53 (s, 1H), 8.27-8.21 (m, 1H), 7.99-7.93 (m, 1H), 7.72 (d, 5.4 Hz, 1H), 7.66 (s, 1H), 7.50-7.42 (m, 3H), 7.38-7.32 (m, 1H), 7.27-7.18 (m, 2H), 7.15 (td, 7.6, 1.2 Hz, 1H), 6.11 (s, 1H)。 470.2 D   
I-71
Figure 02_image437
 Fc1ccc(F)c(c1)C1NC(=O)c2nccc(NC(=O)c3csc4ccccc34)c12 1H NMR (400 MHz, CD3CN)  8.76 (dd, 5.2, 0.5 Hz, 1H), 8.70 (s, 1H), 8.29-8.26 (m, 1H), 7.99-7.96 (m, 1H), 7.81 (s, 1H), 7.64 (d, 5.3 Hz, 1H), 7.51-7.45 (m, 3H), 7.01-6.96 (m, 2H), 6.85-6.79 (m, 1H), 6.09 (s, 1H)。 422.2 C   
I-72
Figure 02_image439
 Cc1ccccc1[C@@H]1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 10.15 (s, 1H), 9.05 (s, 1H), 8.58 (d, 8.2 Hz, 1H), 8.29 (d, 8.2 Hz, 1H), 7.80 (dd, 7.6, 1.2 Hz, 1H), 7.74-7.55 (m, 4H), 7.06-6.93 (m, 2H), 6.89 (t, 13.3 Hz, 1H), 6.68 (br s, 1H), 6.12 (s, 1H), 2.40-2.10 (br s, 3H)。 400.2 A   
I-73
Figure 02_image441
 Cc1ccccc1[C@H]1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  10.15 (s, 1H), 9.05 (s, 1H),  8.58 (d, 8.2 Hz, 1H), 8.29 (d, 8.2 Hz, 1H), 7.80 (dd, 7.6, 1.2 Hz, 1H), 7.74-7.55 (m, 4H), 7.06-6.93 (m, 2H), 6.89 (t, 13.3 Hz, 1H), 6.68 (br s, 1H), 6.12 (s, 1H), 2.40-2.10 (br s, 3H)。 400.2 C   
I-74
Figure 02_image443
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3csc4ccncc34)c12 1H NMR (400 MHz, DMSO-d6)  10.27 (s, 1H), 9.29 (d, 0.7 Hz, 1H), 9.04 (s, 1H), 8.46 (d, 5.6 Hz, 1H), 8.10 (dd, 5.6, 1.0 Hz, 1H), 7.85 (s, 1H), 7.68 (dd, 7.4, 1.2 Hz, 1H), 7.62 (t, 7.5 Hz, 1H), 7.54 (dd, 7.7, 1.2 Hz, 1H), 7.07-7.00 (m, 1H), 6.95 (dt, 11.5, 5.2 Hz, 2H), 6.62 (br s, 1H), 6.01 (s, 1H), 2.06 (m,  3H)+89%純，根據LC 400.3 D   
I-75
Figure 02_image445
 CNC(=O)c1cc2C(=O)N[C@@H](c2c(NC(=O)c2csc3ccccc23)c1)c1ccccc1C 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H) 9.17 (s, 1H) 8.76 (q, J=4.21 Hz, 1H) 8.15 (d, J=1.52 Hz, 1H) 8.06 - 8.10 (m, 2H) 8.01 - 8.05 (m, 1H) 7.71 (s, 1H) 7.36 - 7.48 (m, 2H) 7.08 - 7.13 (m, 1H) 6.96 - 7.05 (m, 2H) 6.08 (s, 1H) 2.84 (d, J=4.55 Hz, 3H) 1.99 - 2.34 (m, 2H) 456.1 D   
I-76
Figure 02_image447
 CNC(=O)c1cc2C(=O)N[C@H](c2c(NC(=O)c2csc3ccccc23)c1)c1ccccc1C 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H) 9.17 (s, 1H) 8.76 (q, J=4.21 Hz, 1H) 8.15 (d, J=1.52 Hz, 1H) 8.06 - 8.10 (m, 2H) 8.01 - 8.05 (m, 1H) 7.71 (s, 1H) 7.36 - 7.48 (m, 2H) 7.08 - 7.13 (m, 1H) 6.96 - 7.05 (m, 2H) 6.08 (s, 1H) 2.84 (d, J=4.55 Hz, 3H) 1.99 - 2.34 (m, 2H) 456.1 A A
I-77
Figure 02_image449
 CNc1cc(Nc2csc3ccccc23)cc2C(NC(=O)c12)c1ccccc1C 1H NMR(400 MHz, DMSO-d6)  8.35 (s, 1H), 8.15 (s, 1H), 7.93-7.85 (m, 1H), 7.82-7.76 (m, 1H), 7.37-7.29 (m, 2H), 7.19 (s, 1H), 7.16-7.07 (m, 3H), 6.97 (d, 7.0 Hz, 1H), 6.51 (q, 5.1 Hz, 1H), 6.17 (d, 1.5 Hz, 1H), 6.02 (s, 1H), 5.64 (s, 1H), 2.74 (d, 5.1 Hz, 3H), 2.33 (s, 3H)。 400.3 D   
I-78
Figure 02_image451
 COc1cccc2scc(C(=O)Nc3cccc4C(=O)NC(c34)c3ccccc3C)c12 1H NMR (400 MHz, DMSO-d6)  9.96 (s, 1H), 9.04 (s, 1H), 7.66-7.58 (m, 2H), 7.55 (ddd, 5.2, 4.5, 1.1 Hz, 2H), 7.36 (t, 8.0 Hz, 1H), 7.28-7.18 (m, 2H), 7.10 (t, 7.1 Hz, 1H), 6.94 (d, 7.6 Hz, 1H), 6.67 (s, 1H), 6.44 (s, 1H), 6.04 (s, 1H), 3.81 (s, 3H), 2.41-2.00 (m, 3H)。 429.3 E   
I-79
Figure 02_image453
 COc1ccc2c(csc2c1)C(=O)Nc1cccc2C(=O)NC(c12)c1ccccc1C 1H NMR (400 MHz, DMSO-d6) 10.04 (s, 1H), 9.03 (s, 1H), 7.92 (d, 8.9 Hz, 1H), 7.65 (dd, 6.5, 2.2 Hz, 1H), 7.61 (d, 7.7 Hz, 1H), 7.57 (m,2H), 7.48 (s, 1H), 7.09 (td, 7.4, 1.3 Hz, 1H), 6.98 (m, 3H), 6.60 (br s, 1H), 6.03 (s, 1H), 3.82 (s, 3H), 2.34-1.92 (m, 3H)。 429.3 E   
I-80
Figure 02_image455
 Cc1ccccc1C1(C)NC(=O)c2cccc(NC(=O)c3csc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 8.96 (s, 1H), 8.88 (s, 1H), 8.11-8.05 (m, 1H), 8.05-7.99 (m, 1H), 7.73 (dd, 7.8, 0.7 Hz, 1H), 7.71-7.65 (m, 3H), 7.58 (t, 7.6 Hz, 1H), 7.43-7.37 (m, 2H), 7.12-7.05 (m, 2H), 7.05-7.00 (m, 1H), 1.98 (s, 3H), 1.63 (s, 3H)。 413.3 E   
I-81
Figure 02_image457
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3coc4c(F)cc(Cl)cc34)c12 1H NMR (400 MHz, DMSO-d6) 10.20 (s, 1H), 9.05 (s, 1H), 8.28 (s, 1H), 7.68 (dd, 7.5, 1.1 Hz, 1H), 7.62 (t, 7.6 Hz, 1H), 7.57 (dd, 10.6, 1.9 Hz, 1H), 7.49 (m,  2H), 7.04 (td, 7.5, 1.3 Hz, 1H), 6.94 (dd, 12.8, 6.9 Hz, 2H), 6.60 (br s, 1H), 5.96 (s, 1H), 2.16 (br s, 3H)。 435.2 A   
I-82
Figure 02_image459
 CN1C(c2c(cccc2NC(=O)c2csc3ccccc23)C1=O)c1ccccc1C 1H NMR (400 MHz, DMSO-d6)  10.18 (s, 1H), 10.10 (s, 0.62H), 8.31-8.16 (m, 0.65H), 8.13-7.97 (m, 13.1, 7.0, 2.5 Hz, 3H), 7.78 (s, 0.64 H), 7.76 (s, 1H), 7.68 (td, 7.2, 0.9 Hz, 1.78H), 7.64-7.55 (m, 1.8H), 7.51 (d, 7.0 Hz, 0.67H), 7.49-7.35 (m, 5H), 7.21-6.94 (m, 5H), 6.83 (t, 7.5 Hz, 0.65 H), 6.29 (dd, 7.7, 1.2 Hz, 1H), 6.00 (s, 1H), 5.78 (s, 0.65H), 2.77 (s, 1.84H), 2.74 (s, 3H), 2.32 (s, 3H), 1.39 (s, 1.87H)。 413.3 E   
I-83
Figure 02_image461
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.38 (br s, 1H), 9.12 (br s, 1H), 8.63 (d,J = 8.08 Hz, 1H), 8.30 (d,J = 8.34 Hz, 1H), 7.53-7.82 (m, 6H), 7.16-7.31 (m, 1H), 6.92-7.06 (m, 1H), 6.07-6.29 (m, 1H)。 438.3 A A
I-84
Figure 02_image463
 Fc1cccc(F)c1C1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.49 (s, 1H), 9.01 (s, 1H), 8.64 (d,J =8.1 Hz, 1H), 8.30 (d,J =8.3 Hz, 1H), 7.50-7.76 (m, 5H), 7.18 (tt,J =8.3, 6.6 Hz, 1H), 6.78 (br t,J =7.8 Hz, 2H), 6.21 (s, 1H)。 422.3 D   
I-85
Figure 02_image465
 Cn1ncc(C2NC(=O)c3cccc(NC(=O)c4nsc5ccccc45)c23)c1C(F)(F)F 1 H NMR (400 MHz, DMSO-d6 ) δ 10.45 (s, 1H), 9.08 (s, 1H), 8.61 (d,J =8.1 Hz, 1H), 8.16-8.39 (m, 1H), 7.47-7.81 (m, 5H), 7.01 (s, 1H), 6.07 (s, 1H), 3.69 (d,J =0.8 Hz, 3H)。 458.4 D   
I-86
Figure 02_image467
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3c[nH]c(=O)c(F)c3)c12 1H NMR (400 MHz, DMSO-d6) 12.48 (br s, 1H), 9.85 (s, 1H), 9.00 (s, 1H), 7.50-7.70 (m, 2H), 7.26-7.47 (m, 3H), 6.88-7.14 (m, 3H), 6.53 (br d, 3.90 Hz, 1H), 5.84 (br s, 1H), 1.86-2.35 (m, 3H) 378.28 E   
I-87
Figure 02_image469
 Cc1ccccc1C1NC(=O)c2cc(CNC(=O)OC(C)(C)C)cc(NC(=O)c3csc4ccccc34)c12    528 A B
I-88
Figure 02_image471
 Cc1ccccc1C1NC(=O)c2cc(CN)cc(NC(=O)c3csc4ccccc34)c12    428 A   
I-89
Figure 02_image473
 C[C@@H](NC(=O)OC(C)(C)C)c1cc2C(=O)NC(c2c(NC(=O)c2csc3ccccc23)c1)c1ccccc1C    542 B   
I-90
Figure 02_image475
 C[C@@H](N)c1cc2C(=O)NC(c2c(NC(=O)c2csc3ccccc23)c1)c1ccccc1C    442 A   
I-91
Figure 02_image477
 Cc1ccccc1[C@H]1NC(=O)c2cc(N)cc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.6-9.9 (m, 1H), 8.7-8.9 (m, 1H), 8.4-8.6 (m, 1H), 8.2-8.3 (m, 1H), 7.6-7.8 (m, 1H), 7.5-7.6 (m, 1H), 7.1-7.2 (m, 1H), 6.9-7.0 (m, 3H), 6.7-6.8 (m, 1H), 6.5-6.7 (m, 1H), 5.8-6.0 (m, 1H), 5.4-5.6 (m, 2H), 2.1-2.4 (m, 3H) 415 C   
I-92
Figure 02_image479
 Cc1ccccc1[C@@H]1NC(=O)c2cc(N)cc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.6-9.9 (m, 1H), 8.7-8.9 (m, 1H), 8.4-8.6 (m, 1H), 8.2-8.3 (m, 1H), 7.6-7.8 (m, 1H), 7.5-7.6 (m, 1H), 7.1-7.2 (m, 1H), 6.9-7.0 (m, 3H), 6.7-6.8 (m, 1H), 6.5-6.7 (m, 1H), 5.8-6.0 (m, 1H), 5.4-5.6 (m, 2H), 2.1-2.4 (m, 3H) 415 A A
I-93
Figure 02_image481
 Clc1cc(NC(=O)c2nsc3ccccc23)c2C(NC(=O)c2n1)c1ccccc1Cl 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 9.65 (s, 1H), 8.67 (d, 1H), 8.32 (d, 1H), 7.98 (s, 1H), 7.69 (t, 1H), 7.62 (t, 1H), 7.33 (d, 1H), 7.22 (t, 1H), 7.14 (t, 1H)。 455.26 A   
I-94
Figure 02_image483
 Clc1ccccc1C1NC(=O)c2nc(cc(NC(=O)c3nsc4ccccc34)c12)-c1cn[nH]c1 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.20 (br s, 1H), 10.48 (s, 1H), 9.46 (s, 1H), 8.69 (d,J = 8.1 Hz, 1H), 8.41 (br s, 1H), 8.33 (d,J = 8.1 Hz, 1H), 8.10 (br s, 1H), 8.07 (s, 1H), 7.60-7.73 (m, 3H), 7.30 (d,J = 7.8 Hz, 1H), 7.15-7.21 (m, 1H), 7.09-7.14 (m, 1H), 6.29 ppm (br s, 1H)。 487.33 B   
I-95
Figure 02_image485
 CC1CN(C(=O)Nc2cccc3C(=O)NC(c23)c2ccccc2C)c2ccccc12 1H NMR (400 MHz, DMSO-d6) 8.92 (s, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 7.70 (d, 8.1 Hz, 1H), 7.62 (m, 1H), 7.53-7.48 (m, 2H), 7.46-7.32 (m, 2H), 7.22 (t, 7.4 Hz, 1H), 7.15-7.03 (m, 3H), 6.99 (d, 7.4 Hz, 1H), 6.96-6.84 (m, 2H), 6.79 (d, 8.7 Hz, 1), 6.54 (br s, 1H), 6.25 (t, 12.4 Hz, 1H), 6.17 (s, 0.24H), 5.87 (s, 1H), 3.79 (t, 9.8 Hz, 1H), 3.74 (s, 1H), 3.66 (s, 1H), 3.22-3.01 (m, 2H), 2.04 (s, 3H), 1.33 (d, 6.8 Hz, 1H), 1.18 (d, 6.2 Hz, 1H), 1.11 (d, 6.4 Hz, 2H), 1.07 (d, 6.7 Hz, 1H)。 398.3 B   
I-96
Figure 02_image487
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)N3CCc4ccc(F)cc34)c12 1H NMR (400 MHz, DMSO-d6) 8.97 (s, 1H), 8.49 (s, 1H), 7.60-7.51 (m, 2H), 7.43 (dd, 11.1, 2.1 Hz, 1H), 7.39 (dd, 7.1, 1.7 Hz, 1H), 7.13 (ddd, 7.4, 6.7, 3.5 Hz, 2H), 7.02 (d, 7.4 Hz, 1H), 6.95 (t, 7.3 Hz, 1H), 6.69 (ddd, 9.2, 8.3, 2.5 Hz, 1H), 6.57 (br s, 1H), 5.86 (s, 1H), 3.83-3.55 (m, 1H), 3.01-2.78 (m, 3H), 2.15 (m,  3H)。 402.3 B   
I-97
Figure 02_image489
 Cc1ccccc1[C@H]1NC(=O)c2cccc(NC(=O)c3coc4c(F)cc(F)cc34)c12 1H NMR (400 MHz, DMSO-d6)  10.08 (s, 1H), 8.98 (s, 1H), 8.18 (s, 1H), 7.61 (d, 7.6 Hz, 1H), 7.55 (t, 7.6 Hz, 1H), 7.45 (d, 7.6 Hz, 1H), 7.37 (t, 7.6 Hz, 1H), 7.25 (d, 7.6 Hz, 1H), 6.99-6.87 (m, 3H), 5.90 (s, 1H), 2.10 (s, 3H) 417.3 E   
I-98
Figure 02_image491
 Cc1ccccc1[C@@H]1NC(=O)c2cccc(NC(=O)c3coc4c(F)cc(F)cc34)c12 1H NMR (400 MHz,  DMSO-d6) 10.08 (s, 1H), 8.98 (s, 1H), 8.18 (s, 1H), 7.61 (d, 7.6 Hz, 1H), 7.55 (t, 7.6 Hz, 1H), 7.45 (d, 7.6 Hz, 1H), 7.37 (t, 7.6 Hz, 1H), 7.25 (d, 7.6 Hz, 1H), 6.99 - 6.87 (m, 3H), 5.90 (s, 1H), 2.10 (s, 3H) 417.3 B   
I-99
Figure 02_image493
 Fc1cccc(Cl)c1C1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.25-10.42 (m, 1H), 8.82-9.15 (m, 1H), 8.22-8.71 (m, 2H), 7.47-7.73 (m, 4H), 6.77-7.24 (m, 3H), 6.25-6.42 (m, 1H), 3.97-4.18 (m, 1H)。 438.2 C   
I-100
Figure 02_image495
 Cc1ccccc1C1NC(=O)c2cc(C=C)cc(NC(=O)c3csc4ccccc34)c12 1H NMR (400 MHz, CD3CN) 8.27 (brs, 1H), 8.23-8.14 (m, 1H), 8.00-7.91 (m, 1H), 7.83-7.76 (m, 2H), 7.49-7.40 (m, 2H), 7.34 (s, 1H), 7.28 (s, 1H), 7.16 (m, 1H), 7.05 (m, 2H), 6.91 (dd, 17.6, 11.0 Hz, 1H), 6.04 (s, 1H), 5.97 (d, 17.6 Hz, 1H), 5.41 (d, 10.9 Hz, 1H), 2.18 (s, 3H)。 425.3 A C
I-101
Figure 02_image497
 Clc1cnccc1C1NC(=O)c2cccc(NC(=O)c3csc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 10.23 (s, 1H), 9.13 (s, 1H), 8.40 (s, 1H), 8.24 (d, 4.9 Hz, 1H), 8.18-8.13 (m, 1H), 8.04-7.99 (m, 1H), 7.97 (s, 1H), 7.67 (dd, 7.5, 1.2 Hz, 1H), 7.61 (t, 7.6 Hz, 1H), 7.49 (dd, 7.7, 1.1 Hz, 1H), 7.42-7.37 (m, 2H), 6.86 (br s, 1H), 6.09 (s, 1H)。 420.2 D   
I-102
Figure 02_image499
 Fc1ccc(C2NC(=O)c3cccc(NC(=O)c4csc5ccccc45)c23)c(Cl)c1 1H NMR (400 MHz, DMSO-d6) 10.19 (s, 1H), 9.06 (s, 1H), 8.36 (s, 1H), 8.12-8.06 (m, 1H), 8.03-7.98 (m, 1H), 7.96 (s, 1H), 7.66-7.55 (m, 2H), 7.49 (dd, 7.8, 1.0 Hz, 1H), 7.42-7.34 (m, 2H), 7.22 (dd, 8.9, 2.7 Hz, 1H), 6.97 (s, 1H), 6.11 (s, 1H)。 437.2 A   
I-103
Figure 02_image501
 Nc1cccc2c1n(Cc1ccccc1)[nH]c2=O 1H NMR (400 MHz, DMSO-d6) 10.57 (s, 1H), 7.26-7.14 (m, 3H), 7.14-7.09 (m, 2H), 6.85 (dd, 7.9, 0.9 Hz, 1H), 6.77 (t, 7.6 Hz, 1H), 6.61 (d, 7.5 Hz, 1H), 5.32 (s, 2H), 5.16 (s, 2H)。 240.2 E   
I-104
Figure 02_image503
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)N3CCc4c3cc(F)cc4F)c12 1H NMR (400 MHz,  DMSO-d6) 8.94 (s, 1H), 8.58 (s, 1H), 7.54 (dd, 7.5, 1.5 Hz, 1H), 7.51 (t, 7.4 Hz, 1H), 7.34 (dd, 7.4, 1.5 Hz, 1H), 7.27 (d, 10.5 , 1.8 Hz,  1H), 7.10 (td, 8.3, 4.1 Hz, 1H), 7.01 (d, 7.3 Hz, 1H), 6.93 (t, 7.8 Hz, 1H), 6.70 (td, 9.5, 2.2 Hz, 1H), 6.61-6.38 (m, 1H), 5.80 (s, 1H), 3.75-3.62 (m, 1H), 2.97-2.78 (m, 3H), 2.34-1.80 (m, 3H)。 420.3 B   
I-105
Figure 02_image505
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3nsc4ccc(F)cc34)c12    418 B   
I-106
Figure 02_image507
 Cc1c(F)cccc1C1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.17 (s, 1H), 9.07 (s, 1H), 8.56 (br d,J =8.1 Hz, 1H), 8.29 (d,J =8.3 Hz, 1H), 7.78 (br d,J =7.3 Hz, 1H), 7.50-7.70 (m, 4H), 6.76-7.01 (m, 2H), 6.30-6.65 (m, 1H), 6.02-6.25 (m, 1H), 1.67-2.42 (m, 3H)。 418.3 B   
I-107
Figure 02_image509
 CCOc1ncc(cc1F)C(=O)Nc1cccc2C(=O)NC(c12)c1ccccc1C 1H NMR (400 MHz, DMSO-d6) 10.10 (s, 1H), 9.02 (s, 1H), 7.96 (s, 1H), 7.45-7.70 (m, 4H), 7.03-7.10 (m, 1H), 6.91-7.02 (m, 2H), 6.47-6.67 (m, 1H), 5.89 (br s, 1H), 4.42 (q,  6.91 Hz, 2H), 1.98-2.31 (m, 3H), 1.34 (t, 7.08 Hz, 3H) 406.39 E   
I-108
Figure 02_image511
 Cn1cc(cn1)-c1cc(NC(=O)c2nsc3ccccc23)c2C(NC(=O)c2n1)c1ccccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.44 (s, 1H), 9.46 (br s, 1H), 8.68 (br d,J = 8.1 Hz, 1H), 8.40 (s, 1H), 8.33 (br d,J = 8.5 Hz, 1H), 8.04 (d,J = 7.3 Hz, 2H), 7.35-7.75 (m, 3H), 7.31 (br d,J = 7.8 Hz, 1H), 7.19 (br t,J = 8.3 Hz, 1H), 7.08-7.15 (m, 1H), 6.30 (br s, 1H), 3.94 (s, 3H)。 501.4 B   
I-109
Figure 02_image513
 CC(C)Oc1ncc(cc1F)C(=O)Nc1cccc2C(=O)NC(c12)c1ccccc1C 1H NMR (400 MHz, DMSO-d6) 10.09 (s, 1H), 9.02 (s, 1H), 7.95 (s, 1H), 7.63-7.68 (m, 1H), 7.59 (t,  7.57 Hz, 1H), 7.46-7.55 (m, 2H), 7.03-7.10 (m, 1H), 6.90-7.02 (m, 2H), 6.45-6.68 (m, 1H), 5.89 (br s, 1H), 5.34 (td, 6.13, 12.39 Hz, 1H), 1.94-2.28 (m, 3H), 1.33 (d,  6.10 Hz, 6H) 420.45 E   
I-110
Figure 02_image515
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)N3CCc4ccc(Cl)cc34)c12 1H NMR (400 MHz,  DMSO-d6)  8.93 (s, 1H), 8.48 (s, 1H), 7.63 (d, 1.5 Hz, 1H), 7.55-7.47 (m, 2H), 7.35 (dd, 7.2, 1.7 Hz, 1H), 7.14-7.06 (m, 2H), 6.98 (d, 7.4 Hz, 1H), 6.95-6.86 (m, 2H), 6.60 (br s, 1H), 5.82 (s, 1H), 3.71-3.56 (m, 1H), 2.96-2.76 (m, 3H), 2.11 (s, 3H)。 418.3 B   
I-111
Figure 02_image517
 CC(C)COc1ncc(cc1F)C(=O)Nc1cccc2C(=O)NC(c12)c1ccccc1C 1H NMR (400 MHz, DMSO-d6) 10.10 (s, 1H), 9.02 (s, 1H), 7.96 (s, 1H), 7.62-7.67 (m, 1H), 7.47-7.62 (m, 3H), 7.04-7.12 (m, 1H), 6.89-7.02 (m, 2H), 6.42-6.68 (m, 1H), 5.89 (br s, 1H), 4.16 (d,  6.83 Hz, 2H), 1.93-2.29 (m, 4H), 0.97 (d,  6.59 Hz, 6H) 434.45 E   
I-112
Figure 02_image519
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.25 (s, 1H), 9.04 (s, 1H), 7.64-7.69 (m, 1H), 7.55-7.62 (m, 2H), 7.52 (d, 7.57 Hz, 1H), 7.39 (s, 1H), 7.15-7.26 (m, 1H), 6.86-7.10 (m, 4H), 6.59 (br d, 7.08 Hz, 1H), 5.91 (br s, 1H), 3.31 (s, 1H), 1.94-2.35 (m, 3H) 411.39 D   
I-113
Figure 02_image521
 Cn1cc(cn1)-c1cc(NC(=O)c2nsc3ccccc23)c2[C@@H](NC(=O)c2n1)c1ccccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.43 (br s, 1H), 9.45 (br s, 1H), 8.67 (br d,J = 5.9 Hz, 1H), 8.39 (s, 1H), 8.32 (br d,J = 8.1 Hz, 1H), 8.04 (d,J = 11.5 Hz, 2H), 7.66-7.74 (m, 1H), 7.62 (br d,J = 7.1 Hz, 1H), 7.31 (br d,J = 7.8 Hz, 1H), 7.16-7.23 (m, 1H), 7.13 (br t,J = 7.1 Hz, 1H), 6.29 (br s, 1H), 3.94 (s, 3H)。 501.3 B   
I-114
Figure 02_image523
 Cn1cc(cn1)-c1cc(NC(=O)c2nsc3ccccc23)c2[C@H](NC(=O)c2n1)c1ccccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.44 (br s, 1H), 9.46 (br s, 1H), 8.68 (br d,J = 7.6 Hz, 1H), 8.39 (s, 1H), 8.32 (br d,J = 8.3 Hz, 1H), 8.04 (d,J = 9.0 Hz, 2H), 7.66-7.74 (m, 1H), 7.57-7.66 (m, 1H), 7.31 (br d,J = 7.8 Hz, 1H), 7.16-7.23 (m, 1H), 7.13 (br t,J = 7.3 Hz, 1H), 6.30 (br s, 1H), 3.94 (s, 3H)。 501.4 D   
I-115
Figure 02_image525
 Cc1ccccc1C1NC(=O)c2cc(cc(NC(=O)c3csc4ccccc34)c12)-c1cnn(C)c1 1H NMR (400 MHz, CDCl3)  8.46 (br s, 1H), 8.26 (br s, 1H), 7.88 (s, 1H), 7.86 (d, 1.4 Hz, 1H), 7.76 (s, 1H), 7.49-7.40 (m, 3H), 7.36 (d, 7.3 Hz, 1H), 7.24-7.21 (m, 1H), 6.85 (s, 1H), 6.35 (s, 1H), 5.87 (s, 1H), 3.97 (s, 3H), 1.55 (s, 3H) 479.6 A   
I-116
Figure 02_image527
 Cc1ccccc1C1NC(=O)c2cc(cc(NC(=O)c3nsc4ccccc34)c12)C#N 1H NMR (400 MHz, DMSO-d6)  10.37 (s, 1H), 9.38 (s, 1H), 8.61 (d, 8.2 Hz, 1H), 8.31 (d, 8.2 Hz, 1H), 8.22 (d, 1.4 Hz, 1H), 8.11 (d, 1.3 Hz, 1H), 7.73-7.64 (m, 1H), 7.63-7.57 (m, 1H), 7.02-6.95 (m, 2H), 6.91 (t, 7.0 Hz, 1H), 6.63 (br s, 1H), 6.23 (s, 1H), 2.27 (br s, 3H)。 425.2 A   
I-117
Figure 02_image529
 Cc1ccccc1-n1[nH]c(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  11.71-11.31 (m, 1H), 9.89 (s, 1H), 8.57-8.50 (m, 1H), 8.24 (dt, 8.3, 0.8 Hz, 1H), 7.70 (dd, 8.0, 0.7 Hz, 1H), 7.63 (ddd, 8.2, 7.0, 1.2 Hz, 1H), 7.55 (ddd, 7.0, 4.7, 1.1 Hz, 2H), 7.18 (dd, 7.7, 1.4 Hz, 1H), 7.13 (t, 7.7 Hz, 1H), 6.98 (d, 7.4 Hz, 1H), 6.88 (dt, 7.6, 3.9 Hz, 1H), 6.83 (td, 7.4, 1.4 Hz, 1H), 2.06 (s, 3H)。 401.2 D   
I-118
Figure 02_image531
 O=C(Nc1cccc2c1n(Cc1ccccc1)[nH]c2=O)c1csc2ccccc12 1H NMR (400 MHz, DMSO-d6)  11.05 (br s, 1H), 10.48 (s, 1H), 8.54 (s, 1H), 8.42-8.33 (m, 1H), 8.11-8.03 (m, 1H), 7.60 (dd, 8.0, 1.0 Hz, 1H), 7.48-7.42 (m, 2H), 7.28 (d, 7.0 Hz, 1H), 7.19-7.11 (m, 3H), 7.10-7.03 (m, 1H), 7.01-6.94 (m, 2H), 5.34 (s, 2H)。 400.3 E   
I-119
Figure 02_image533
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1csc3ccccc13)ccc2CCO 1H NMR (400 MHz, DMSO-d6)  9.97 (s, 1H), 8.96 (s, 1H), 8.06-7.98 (m, 2H), 7.60 (s, 1H), 7.45 (d, 8.0 Hz, 1H), 7.43-7.35 (m, 3H), 7.09 (td, 7.5, 1.3 Hz, 1H), 6.99 (dd, 16.6, 7.3 Hz, 2H), 6.62 (s, 1H), 5.94 (s, 1H), 4.68 (t, 5.3 Hz, 1H), 3.75-3.63 (m, 2H), 3.39 (dt, 13.3, 6.8 Hz, 1H), 3.30-3.21 (m, 1H), 2.18 (s, 2H)。 443.3 A   
I-120
Figure 02_image535
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1csc3ccccc13)ccc2C(O)CO 1H NMR (400 MHz, DMSO-d6) 10.04 (s, 0.8 H), 10.03 (s, 1H), 9.21 (s, 1H), 9.16 (s, 0.8H), 8.02 (dd, 6.5, 2.5 Hz, 4H), 7.68-7.57 (m, 4H), 7.52 (dd, 8.1, 4.3 Hz, 2H), 7.45-7.35 (m, 4H), 7.16-7.06 (m, 2H), 6.99 (dd, 16.2, 7.3 Hz, 4H), 6.61 (br s, 1H), 6.00 (d, 6.7 Hz, 2H), 5.77 (d, 5.9 Hz, 1H), 5.68 (d, 6.3 Hz, 0.8H), 5.56 (td, 6.6, 4.6 Hz, 0.8H), 5.47 (td, 6.7, 4.9 Hz, 1H), 4.77 (dd, 9.8, 5.6 Hz, 2H), 4.57 (s, 1H), 3.66-3.56 (m, 2H), 3.56-3.42 (m, 2H), 2.19 (br s, 5H)。 459.2 B   
I-121
Figure 02_image537
 Cc1ccccc1C1NC(=O)c2cc(cc(NC(=O)c3nsc4ccccc34)c12)C(=O)NCC(F)F 1H NMR (400 MHz, DMSO-d6) 10.25 (s, 1H), 9.16 (s, 1H), 8.69-8.81 (m, 1H), 8.54-8.62 (m, 1H), 8.24-8.34 (m, 2H), 8.13 (d,  1.22 Hz, 1H), 7.63-7.71 (m, 1H), 7.53-7.62 (m, 1H), 6.85-7.02 (m, 3H), 6.60-6.79 (m, 1H), 6.15 (br s, 1H), 2.82 (d, 4.39 Hz, 3H), 2.10-2.41 (m, 3H) 507.38 A A
I-122
Figure 02_image539
 FC(F)c1ccccc1C1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.14 (s, 1H), 9.16 (s, 1H), 8.56 (d,J =8.08 Hz, 1H), 8.22-8.33 (m, 1H), 7.82 (dd,J =1.14, 7.71 Hz, 1H), 7.59-7.72 (m, 3H), 7.56 (ddd,J =0.88, 7.07, 8.21 Hz, 1H), 7.39-7.59 (m, 1H), 7.35 (d,J =7.83 Hz, 1H), 7.21-7.32 (m, 2H), 6.75 (br s, 1H), 6.18 (s, 1H)。 436.3 A B
I-123
Figure 02_image541
 CNC(=O)c1cc2C(=O)NC(c2c(NC(=O)c2nsc3ccccc23)c1)c1ccccc1C 1H NMR (400 MHz, DMSO-d6) 10.28 (s, 1H), 9.13-9.25 (m, 2H), 8.52-8.64 (m, 1H), 8.26-8.36 (m, 2H), 8.20 (s, 1H), 7.67 (br t, 7.57 Hz, 1H), 7.54-7.61 (m, 1H), 6.86-7.01 (m, 3H), 6.66-6.78 (m, 1H), 6.10-6.24 (m, 2H), 3.72 (tt, 4.76, 15.38 Hz, 2H), 2.10-2.40 (m, 3H) 457.41 A   
I-124
Figure 02_image543
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.3-11.0 (m, 1H), 9.0-9.4 (m, 1H), 8.3-8.6 (m, 1H), 7.5-8.1 (m, 3H), 7.2-7.4 (m, 1H), 7.0-7.2 (m, 1H), 6.5-6.9 (m, 2H), 5.7-6.1 (m, 1H) 545 A B
I-125
Figure 02_image545
 Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO-d6) 10.1-10.3 (m, 1H), 8.8-8.9 (m, 1H), 7.9-8.0 (m, 1H), 7.6-7.8 (m, 1H), 7.6-7.6 (m, 1H), 7.2-7.4 (m, 2H), 7.0-7.1 (m, 1H), 6.8-6.9 (m, 1H), 6.66 (s, 1H), 5.7-5.9 (m, 1H), 5.5-5.7 (m, 2H) 482 A A
I-126
Figure 02_image547
 NCc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.3-10.6 (m, 1H), 9.0-9.3 (m, 1H), 7.9-8.0 (m, 1H), 7.7-7.8 (m, 1H), 7.6-7.7 (m, 2H), 7.4-7.5 (m, 1H), 7.2-7.3 (m, 2H), 7.0-7.1 (m, 1H), 6.6-6.8 (m, 1H), 5.8-6.1 (m, 1H), 5.3-5.6 (m, 1H), 4.4-4.8 (m, 2H) 496 A   
I-127
Figure 02_image549
 CC(=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.5-10.8 (m, 1H), 9.2-9.5 (m, 1H), 8.4-8.6 (m, 1H), 8.2-8.3 (m, 1H), 7.93 (br d, 1H,  8.1 Hz), 7.6-7.8 (m, 2H), 7.2-7.5 (m, 1H), 6.9-7.2 (m, 1H), 6.6-6.9 (m, 1H), 5.9-6.2 (m, 1H), 2.7-2.8 (m, 3H) 509 A   
I-128
Figure 02_image551
 CC(C)(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.4-10.6 (m, 1H), 8.9-9.2 (m, 1H), 7.9-8.0 (m, 1H), 7.7-7.8 (m, 2H), 7.6-7.7 (m, 1H), 7.5-7.6 (m, 1H), 7.2-7.4 (m, 1H), 6.9-7.1 (m, 1H), 6.3-6.9 (m, 1H), 5.9-6.1 (m, 1H), 5.2-5.4 (m, 1H), 1.4-1.6 (m, 6H) 525 A   
I-129
Figure 02_image553
 COc1ccc2snc(C(=O)Nc3cccc4C(=O)NC(c34)c3ccccc3C)c2c1 1H NMR (400 MHz, DMSO-d6)  10.07 (s, 1H), 9.05 (s, 1H), 8.17 (d, 9.0 Hz, 1H), 8.10 (d, 2.4 Hz, 1H), 7.83 (dd, 7.6, 1.1 Hz, 1H), 7.68-7.55 (m, 2H), 7.32 (dd, 9.0, 2.5 Hz, 1H), 7.02-6.83 (m, 3H), 6.69 (br s, 1H), 6.13 (s, 1H), 3.86 (s, 3H), 2.42-2.02 (m, 3H)。 430.2 E   
I-130
Figure 02_image555
 CC1(NC(=O)c2cccc(NC(=O)c3csc4ccccc34)c12)c1ccccc1 1H NMR (400 MHz, DMSO-d6)  9.23 (s, 1H), 9.13 (s, 1H), 8.14-8.09 (m, 2H), 8.07-8.02 (m, 1H), 7.68 (dd, 7.0, 1.6 Hz, 1H), 7.64-7.56 (m, 2H), 7.43-7.39 (m, 2H), 7.28-7.18 (m, 5H), 1.97 (s, 3H)。 399.3 E   
I-131
Figure 02_image557
 Cc1ccccc1C1NC(=O)c2cc(CO)cc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  10.11 (s, 1H), 9.02 (s, 1H), 8.57 (d, 8.2 Hz, 1H), 8.29 (d, 8.2 Hz, 1H), 7.78 (s, 1H), 7.67 (ddd, 8.2, 7.1, 1.1 Hz, 1H), 7.61 (s, 1H), 7.58 (t,  7.6 Hz, 1H), 7.02-6.95 (m, 2H), 6.91 (t, 7.1 Hz, 1H), 6.68 (br s, 1H), 6.09 (s, 1H), 5.45 (s, 1H), 2.25 (br s, 3H)。 430.2 A   
I-132
Figure 02_image559
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1csc3ccccc13)ccc2C#N 1H NMR (400 MHz, DMSO-d6)  10.45 (br s, 1H), 9.48 (s, 1H), 8.08 (d, 8.2 Hz, 1H), 8.02 (dd, 12.5, 5.5 Hz, 2H), 7.81 (d, 8.2 Hz, 1H), 7.65 (s, 1H), 7.46 7.33 (m, 2H), 7.12 (dd, 13.8, 6.8 Hz, 1H), 7.01 (dd, 15.2, 7.3 Hz, 1H), 6.58 (br s, 1H), 6.10 (s, 1H), 2.23 (br s, 3H)。 424.2 A   
I-133
Figure 02_image561
 Cc1cc(Cl)ccc1C1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  10.27 (s, 1H), 9.06 (s, 1H), 8.55 (d, 8.2 Hz, 1H), 8.31 (d, 8.3 Hz, 1H), 7.75 (dd, 7.6, 1.1 Hz, 1H), 7.73-7.55 (m, 4H), 7.01 (d, 2.0 Hz, 1H), 6.95 (d, 7.3 Hz, 1H), 6.65 (br s, 1H), 6.07 (s, 1H), 2.22 (br s, 3H)。 433.7 D   
I-134
Figure 02_image563
 COCc1cc2C(=O)NC(c2c(c1)N(C)C(=O)c1nsc2ccccc12)c1ccccc1C 1H NMR (400 MHz, CD3OD) (s, 1H), 8.13 (d, 7.8 Hz, 0.40H), 7.98 (d, 7.9 Hz, 1H), 7.90 (s, 0.33H), 7.66 (s, 1H), 7.64-7.47 (m, 2H), 7.44-7.01 (m, 4H), 6.73 (br s, 0.55H), 6.37 (br s, 0.53H), 6.03 (br s, 0.31H), 4.67 (s, 0.35H), 4.58-4.48 (m, 0.34H), 4.36 (s, 1.37H), 3.50 (d, 8.6 Hz, 1H), 3.08 (br s, 2H), 2.94 (br s, 0.56H), 2.64 (br s, 2H), 1.29 (s, 1.12H)。 458.3 E   
I-135
Figure 02_image565
 CC(=O)c1cc2C(=O)NC(c2c(NC(=O)c2nsc3ccccc23)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.1-10.5 (m, 1H), 8.9-9.2 (m, 1H), 8.5-8.7 (m, 1H), 8.2-8.3 (m, 1H), 7.8-7.9 (m, 1H), 7.7-7.8 (m, 1H), 7.6-7.7 (m, 1H), 7.5-7.6 (m, 1H), 7.1-7.3 (m, 1H), 6.9-7.0 (m, 1H), 6.0-6.3 (m, 1H), 5.6-5.8 (m, 1H), 2.5 (m, 3H) 480 C   
I-136
Figure 02_image567
 CC(C)(O)c1cc2C(=O)NC(c2c(NC(=O)c2nsc3ccccc23)c1)c1cc(F)ccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.1-10.5 (m, 1H), 8.9-9.2 (m, 1H), 8.5-8.7 (m, 1H), 8.2-8.3 (m, 1H), 7.8-7.8 (m, 1H), 7.6-7.7 (m, 1H), 7.5-7.6 (m, 1H), 7.2-7.3 (m, 1H), 6.9-7.0 (m, 1H), 6.4-6.9 (m, 1H), 6.0-6.2 (m, 1H), 5.6-5.7 (m, 1H), 5.1-5.3 (m, 1H), 1.3-1.6 (m, 6H)。 496 A   
I-137
Figure 02_image569
 FC(F)c1ccc(F)cc1C1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.25 (s, 1H), 9.17 (s, 1H), 8.54 (d,J =8.05 Hz, 1H), 8.26 (d,J =8.30 Hz, 1H), 7.11-8.09 (m, 7H), 7.05 (dt,J =2.44, 8.42 Hz, 1H), 6.35-6.65 (m, 1H), 6.13 (s, 1H)。 454.4 A   
I-138
Figure 02_image571
 FC(F)c1ccc(F)cc1C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.44 (s, 1H), 9.14 (s, 1H), 7.90-8.00 (m, 1H), 7.83-7.90 (m, 1H), 7.67-7.74 (m, 1H), 7.58-7.67 (m, 2H), 7.52-7.57 (m, 1H), 7.47-7.52 (m, 1H), 7.40-7.47 (m, 1H), 7.16 (dt,J =2.44, 8.42 Hz, 1H), 6.24-6.62 (m, 1H), 5.77-6.15 (m, 1H)。 483.4 A   
I-139
Figure 02_image573
 Cc1ccccc1C1NC(=O)c2cc(cc(NC(=O)c3csc4ccccc34)c12)C(O)CO 1H NMR (400 MHz, DMSO-d6) 10.09 (s, 0.5H), 10.07 (s, 0.5H), 8.95 (s, 1H), 7.98 (m, 2H), 7.64 (s, 0.5H), 7.62 (s, 0.5H), 7.55 (d, 14.9 Hz, 2H), 7.36 (m, 2H), 7.05 (d, 7.5 Hz, 1H), 6.96 (m, 12.5, 5.3 Hz, 2H), 6.56 (br s, 1H), 5.97 (s, 1H), 5.46 (d, 4.4 Hz, 1H), 4.80 (d之集合, 5.8 Hz, 1H), 4.65 (m, 1H), 3.50 (m, 2H), 2.15 (s, 3H)。 458.7 A   
I-140
Figure 02_image575
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1csc3ccccc13)ccc2CN 1H NMR (400 MHz, DMSO-d6)  10.25-10.10 (m, 1H), 9.38 (s, 1H), 8.02 (d, 7.2 Hz, 2H), 7.62 (d, J = 16.0 Hz, 3H), 7.46-7.35 (m, 2H), 7.11 (t, 7.2 Hz, 1H), 7.06-6.95 (m, 2H), 6.61 (s, 1H), 6.07 (s, 1H), 4.47 (s, 2H), 2.23 (s, 3H)。 429.3 A   
I-141
Figure 02_image577
 Cc1ccccc1C1NC(=O)c2cc(cc(NC(=O)c3csc4ccccc34)c12)-c1cnoc1 1H NMR (400 MHz, DMSO-d6)  10.19 (s, 1H), 9.61 (s, 1H), 9.29 (s, 1H), 9.08 (s, 1H), 8.09-8.03 (m, 1H), 8.02-7.97 (m, 2H), 7.84 (d, 1.5 Hz, 1H), 7.66 (s, 1H), 7.42-7.34 (m, 2H), 7.05 (td, 7.4, 1.3 Hz, 1H), 7.01-6.91 (m, 2H), 6.00 (s, 1H), 1.20 (s, 3H)。 465.8 A   
I-142
Figure 02_image579
 Cc1ccccc1C1NC(=O)c2nccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    430.4 B   
I-143
Figure 02_image581
 CN(C)c1ncc(NC(=O)c2nsc3ccccc23)c2C(NC(=O)c12)c1ccccc1C    444.45 B   
I-144
Figure 02_image583
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 10.3-10.6 (m, 1H), 9.2-9.4 (m, 1H), 8.5-8.7 (m, 1H), 8.2-8.3 (m, 1H), 7.9-8.0 (m, 1H), 7.75 (s, 1H), 7.6-7.7 (m, 1H), 7.5-7.6 (m, 1H), 7.2-7.3 (m, 1H), 6.9-7.0 (m, 1H), 6.5-6.9 (m, 1H), 6.0-6.2 (m, 1H) 518.29 A C
I-145
Figure 02_image585
 Cc1ccccc1C1NC(=O)c2cccc(NCc3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  8.87 (s, 1H), 8.13 (d, 8.2 Hz, 1H), 7.83 (d, 8.2 Hz, 1H), 7.55 (t, 7.7 Hz, 1H), 7.31 (t, 7.7 Hz, 2H), 7.23 (d, 4.2 Hz, 2H), 7.04-7.02 (m, 2 Hz, 2H), 6.89 (d, 8.2 Hz, 1H), 6.74 (m, 1H), 6.82-6.60 (m, 1H), 5.80 (s, 1H), 5.30 (s, 1H), 4.71 (ddd, 21.1, 16.1, 5.4 Hz, 2H), 2.40 (br s, 3H)。 386.3 E   
I-146
Figure 02_image587
 COCc1cc2C(=O)NC(c2c(NC(=O)c2nsc3ccccc23)c1)c1ccccc1C 1H NMR (400 MHz, CDCl3)  8.93 (d, 7.5 Hz, 1H), 8.81 (s, 1H), 8.45 (s, 1H), 7.95 (d, 7.8 Hz, 1H), 7.77 (s, 1H), 7.56 (dtd, 16.2, 7.0, 1.2 Hz, 2H), 7.23 (s, 1H), 7.15 (s, 1H), 6.52 (s, 1H), 5.98 (br s, 1H), 4.62 (s, 2H), 3.47 (s, 3H), 1.78 (br s, 3H)。 444.2 A C
I-147
Figure 02_image589
 Cc1ccccc1C1NC(=O)c2nccc(NC(=O)N3CCc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  9.34 (s, 1H), 8.83 (br s, 1H), 8.64 (d, 5.3 Hz, 1H), 7.64 (d, 7.8 Hz, 1H), 7.42 (d, 5.4 Hz, 1H), 7.18-7.07 (m, 3H), 7.04-6.95 (m, 2H), 6.92 (t, 7.1 Hz, 1H), 6.55 (br s, 1H), 5.90 (s, 1H), 3.62-3.52 (m, 1H), 3.01-2.78 (m, 3H), 2.11 (br s, 3H) 385.4 B   
I-148
Figure 02_image591
 Cc1ccccc1C1NC(=O)c2nccc(NC(=O)N3CCc4c3cc(F)cc4F)c12 1H NMR (400 MHz, DMSO-d6)  9.33 (s, 1H), 9.06 (br s, 1H), 8.63 (d, 5.3 Hz, 1H), 7.33 (d, 5.3 Hz, 1H), 7.26 (d, 10.3 Hz, 1H), 7.12 (td, 7.4, 1.0 Hz, 1H), 6.96 (dd, 17.5, 7.5 Hz, 2H), 6.75 (td, 9.5, 2.2 Hz, 1H), 6.63-6.40 (m, 1H), 5.82 (s, 1H), 3.74-3.57 (m, 1H), 3.02-2.82 (m, 2H), 2.76 (m, 1H), 2.13 (m, 3H)。 421.2 C   
I-149
Figure 02_image593
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1csc3ccccc13)ccc2C(N)=O 1H NMR (400 MHz, DMSO-d6) 10.78 (s, 1H), 10.25 (Br s, 1H), 9.80 (s, 1H), 8.33 (d, 8.3 Hz, 1H), 8.06-8.01 (m, 2H), 7.78 (d, 8.4 Hz, 1H), 7.73 (s, 1H), 7.68-7.58 (m, 1H), 7.45-7.36 (m, 2H), 7.12 (td, 7.7, 0.9 Hz, 1H), 7.07-6.97 (m, 2H), 6.60 (Br s, 1H), 6.12 (s, 1H), 2.23 (Br s, 3H)。 442.3 A   
I-150
Figure 02_image595
 CNC(=O)c1ccc(NC(=O)c2csc3ccccc23)c2C(NC(=O)c12)c1ccccc1C 1H NMR (400 MHz, DMSO-d6)  11.20 (s, 1H), 10.22 (s, 1H), 9.82 (s, 1H), 8.33 (d, 7.9 Hz, 1H), 8.03 (d, 6.2 Hz, 2H), 7.77 (d, 8.1 Hz, 1H), 7.62 (s, 1H), 7.41 (s, 2H), 7.11 (d, 7.1 Hz, 1H), 7.07-6.93 (m, 2H), 6.61 (Br s, 1H), 6.13 (s, 1H), 2.91 (s, 3H), 2.23 (br s, 3H)。 456.3 A   
I-151
Figure 02_image597
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3ncc4ccc(Cl)cn34)c12 1H NMR (400 MHz, DMSO-d6) 9.90 (s, 1H), 9.31 (dt, 1.7, 0.8 Hz, 1H), 9.03 (s, 1H), 7.87 (dd, 9.6, 0.9 Hz, 1H), 7.82 (dd, 7.5, 1.3 Hz, 1H), 7.64-7.56 (m, 3H), 7.19 (dd, 9.5, 1.8 Hz, 1H), 6.99-6.93 (m, 2H), 6.91-6.86 (m, 1H), 6.67 (br s, 1H), 6.11 (s, 1H), 2.26 (br. s, 3H)。 417.2 E   
I-152
Figure 02_image599
 Cc1ccccc1-n1[nH]c(=O)c2cccc(NC(=O)c3nsc4ccc(F)cc34)c12 1H NMR (400 MHz, DMSO-d6)  11.12 (br s, 1H), 9.98 (s, 1H), 8.28 (dd, 9.1, 4.8 Hz, 1H), 8.11 (dd, 9.7, 2.5 Hz, 1H), 7.66 (dd, 8.0, 0.7 Hz, 1H), 7.55 (td, 8.8, 2.6 Hz, 1H), 7.45 (d, 7.2 Hz, 1H), 7.15-7.08 (m, 2H), 6.92 (d, 7.5 Hz, 1H), 6.81 (td, 7.5, 1.3 Hz, 1H), 6.74 (td, 7.5, 1.3 Hz, 1H), 2.04 (s, 3H)。 419.2 D   
I-153
Figure 02_image601
 Cc1ccc(NC(=O)c2csc3ccccc23)c2C(NC(=O)c12)c1ccccc1C 1H NMR (400 MHz, DMSO-d6)  9.98 (s, 1H), 8.93 (s, 1H), 8.06-7.99 (m, 2H), 7.61 (s, 1H), 7.45-7.35 (m, 3H), 7.34 (d, 8.0 Hz, 1H), 7.08 (td, 7.5, 1.3 Hz, 1H), 6.98 (m, 2H), 6.62 (br s, 1H), 5.95 (s, 1H), 2.69 (s, 3H), 2.19 (br s, 3H)。 413.3 B   
I-154
Figure 02_image603
 OCc1cc2C(=O)NC(c2c(NC(=O)c2nsc3ccccc23)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.2-10.6 (m, 1H), 8.9-9.3 (m, 1H), 8.5-8.8 (m, 1H), 8.2-8.3 (m, 1H), 8.1-8.4 (m, 1H), 7.5-7.8 (m, 4H), 7.2-7.4 (m, 1H), 6.9-7.1 (m, 1H), 5.9-6.3 (m, 1H), 5.4-5.6 (m, 1H), 4.5-4.8 (m, 2H) 468 A   
I-155
Figure 02_image605
 COc1ccc(CNCc2cc3C(=O)NC(c3c(NC(=O)c3nsc4ccccc34)c2)c2cc(F)ccc2Cl)cc1 1H NMR (500 MHz, DMSO-d6) 3.64-3.77 (m, 2H), 3.79-3.91 (m, 1H), 5.98-6.24 (m, 1H), 6.78-6.95 (m, 1H), 6.95-7.06 (m, 1H), 7.17-7.33 (m, 1H), 7.48-7.63 (m, 1H), 7.63-7.81 (m, 1H), 8.05-8.19 (m, 1H), 8.23-8.37 (m, 1H), 8.53-8.74 (m, 1H), 8.93-9.22 (m, 1H) 10.21-10.57 (m, 1H) 587 A B
I-156
Figure 02_image607
 CNC(=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1ccccc1C 1H NMR (400 MHz, CDCl3) 8.60 (s, 1H), 8.15 (d, 1.4 Hz, 1H), 7.51-7.42 (m, 2H), 7.34 (d, 7.5 Hz, 1H), 7.22 (d, 8.3 Hz, 5H), 6.43 (s, 1H), 6.33 (s, 1H), 5.93 (s, 1H), 3.06 (d, 4.8 Hz, 3H) 486.37 A   
I-157
Figure 02_image609
 Clc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.17-10.60 (m, 1H), 8.89-9.28 (m, 1H), 8.65 (br d,J =8.05 Hz, 1H), 8.30 (d,J =8.05 Hz, 1H), 6.82-8.02 (m, 7H), 5.74-6.69 (m, 2H)。 454.3 A   
I-158
Figure 02_image611
 Clc1ncccc1C1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.32-10.59 (m, 1H), 8.97-9.31 (m, 1H), 8.62 (br d,J =8.30 Hz, 1H), 8.22-8.37 (m, 1H), 8.04-8.22 (m, 1H), 6.82-7.88 (m, 7H), 5.87-6.53 (m, 1H)。 421.3 D   
I-159
Figure 02_image613
 Fc1cc(Cl)c(cc1F)C1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.21-10.54 (m, 1H), 8.95-9.30 (m, 1H), 8.62 (d,J =8.05 Hz, 1H), 8.31 (d,J =8.30 Hz, 1H), 6.86-7.83 (m, 7H), 6.00-6.27 (m, 1H)。 456.4 A   
I-160
Figure 02_image615
 Clc1ccncc1C1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.53 (s, 1H), 9.10 (br s, 1H), 8.63 (d,J =8.30 Hz, 1H), 7.91-8.40 (m, 3H), 7.44-7.78 (m, 5H), 7.30 (d,J =5.13 Hz, 1H), 6.01-6.31 (m, 1H)。 421.3 C   
I-161
Figure 02_image617
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn[nH]c1 1 H NMR (400 MHz, DMSO-d6 ) δ 13.21 (br s, 1H), 10.85 (br s, 1H), 9.44 (br s, 1H), 8.43 (br s, 1H), 8.12 (br s, 1H), 7.97 (br d,J = 4.1 Hz, 1H), 7.63-7.87 (m, 3H), 7.34 (br dd,J = 8.8, 5.1 Hz, 1H), 7.09 (td,J = 8.4, 2.9 Hz, 1H), 6.75-6.96 (m, 1H), 5.98 (br s, 1H)。 534.4 A B
I-162
Figure 02_image619
 Cn1cc(cn1)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.84 (br s, 1H), 9.44 (br s, 1H), 8.40 (s, 1H), 8.05 (s, 1H), 7.97 (br d,J = 6.6 Hz, 1H), 7.62-7.79 (m, 3H), 7.34 (br dd,J = 8.8, 5.1 Hz, 1H), 7.09 (td,J = 8.4, 2.9 Hz, 1H), 6.81-6.97 (m, 1H), 5.98 (br s, 1H), 3.93 (s, 3H)。 548.4 A   
I-163
Figure 02_image621
 CNC(=O)c1cc2C(=O)N[C@H](c2c(NC(=O)c2nsc3ccccc23)c1)c1ccccc1C 1H NMR (400 MHz, DMSO-d6) 10.28 (s, 1H), 9.13-9.25 (m, 2H), 8.52-8.64 (m, 1H), 8.26-8.36 (m, 2H), 8.20 (s, 1H), 7.67 (br t, 7.57 Hz, 1H), 7.54-7.61 (m, 1H), 6.86-7.01 (m, 3H), 6.66-6.78 (m, 1H), 6.10-6.24 (m, 2H), 3.72 (tt,  4.76, 15.38 Hz, 2H), 2.10-2.40 (m, 3H) 457.41 A   
I-164
Figure 02_image623
 CNC(=O)c1cc2C(=O)N[C@@H](c2c(NC(=O)c2nsc3ccccc23)c1)c1ccccc1C 1H NMR (400 MHz, DMSO-d6) 10.28 (s, 1H), 9.13-9.25 (m, 2H), 8.52-8.64 (m, 1H), 8.26-8.36 (m, 2H), 8.20 (s, 1H), 7.67 (br t, 7.57 Hz, 1H), 7.54-7.61 (m, 1H), 6.86-7.01 (m, 3H), 6.66-6.78 (m, 1H), 6.10-6.24 (m, 2H), 3.72 (tt, 4.76, 15.38 Hz, 2H), 2.10-2.40 (m, 3H) 457.41 D D
I-165
Figure 02_image625
 Cc1ccccc1[C@H]1NC(=O)c2cc(cc(NC(=O)c3nsc4ccccc34)c12)C(=O)NCC(F)F    507.38 B   
I-166
Figure 02_image627
 Cc1ccccc1[C@@H]1NC(=O)c2cc(cc(NC(=O)c3nsc4ccccc34)c12)C(=O)NCC(F)F    507.38 A A
I-167
Figure 02_image629
 FC(F)c1ccc(F)cc1[C@H]1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  10.25 (s, 1H), 9.17 (s, 1H), 8.54 (d, 8.05 Hz, 1H), 8.26 (d, 8.30 Hz, 1H), 7.74 (d, 7.32 Hz, 1H), 7.65 (td, 7.38, 15.01 Hz, 2H), 7.47-7.56 (m, 1H), 7.35 (br dd, 5.61, 8.54 Hz, 1H), 7.05 (dt,  2.44, 8.42 Hz, 1H), 6.34-6.62 (m, 1H), 6.13 (s, 1H) 452 A B
I-168
Figure 02_image631
 FC(F)c1ccc(F)cc1[C@@H]1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  10.25 (s, 1H), 9.17 (s, 1H), 8.54 (d, 8.05 Hz, 1H), 8.26 (d, 8.30 Hz, 1H), 7.74 (d, 7.32 Hz, 1H), 7.65 (td, 7.38, 15.01 Hz, 2H), 7.47-7.56 (m, 1H), 7.35 (br dd, 5.61, 8.54 Hz, 1H), 7.05 (dt, 2.44, 8.42 Hz, 1H), 6.34-6.62 (m, 1H), 6.13 (s, 1H) 452 A   
I-169
Figure 02_image633
 FC(F)c1ccc(F)cc1[C@H]1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.44 (s, 1H), 9.14 (s, 1H), 7.90-8.00 (m, 1H), 7.83-7.90 (m, 1H), 7.67-7.74 (m, 1H), 7.58-7.67 (m, 2H), 7.52-7.57 (m, 1H), 7.47-7.52 (m, 1H), 7.40-7.47 (m, 1H), 7.16 (dt, 2.44, 8.42 Hz, 1H), 6.24-6.62 (m, 1H), 5.77-6.15 (m, 1H) 483 D   
I-170
Figure 02_image635
 FC(F)c1ccc(F)cc1[C@@H]1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.44 (s, 1H), 9.14 (s, 1H), 7.90-8.00 (m, 1H), 7.83-7.90 (m, 1H), 7.67-7.74 (m, 1H), 7.58-7.67 (m, 2H), 7.52-7.57 (m, 1H), 7.47-7.52 (m, 1H), 7.40-7.47 (m, 1H), 7.16 (dt, 2.44, 8.42 Hz, 1H), 6.24-6.62 (m, 1H), 5.77-6.15 (m, 1H) 483 A   
I-171
Figure 02_image637
 Fc1cc(Cl)cc(c1)C(=O)Nc1ccnc2C(=O)NC(c12)c1ccccc1Cl    416.2 D   
I-172
Figure 02_image639
 Clc1ccccc1C1NC(=O)c2nccc(NC(=O)c3nsc4ccccc34)c12    421 B   
I-173
Figure 02_image641
 Fc1cc(Cl)cc(c1)C(=O)Nc1ccnc2C(=O)NC(c12)c1cccc(F)c1F    418 D   
I-174
Figure 02_image643
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1ccnc2C(=O)NC(c12)c1cccc(F)c1F    452.2 D   
I-175
Figure 02_image645
 Fc1cccc(C2NC(=O)c3nccc(NC(=O)c4nsc5ccccc45)c23)c1F    421 C   
I-176
Figure 02_image647
 Cc1ccccc1C1NC(=O)c2ccnc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.45 (s, 1H), 8.70 (d, 4.9 Hz, 1H), 8.42 (d, 8.4 Hz, 1H), 8.37 (s, 1H), 8.30 (d, 8.2 Hz, 1H), 7.72 (d, 4.9 Hz, 1H), 7.67 (t, 7.0 Hz, 1H), 7.58 (t, 7.7 Hz, 1H), 7.04-6.92 (m, 2H), 6.92-6.83 (m, 1H), 6.60 (br s, 1H), 6.23 (s, 1H), 2.22 (br s, 3H)。 401.2 D   
I-177
Figure 02_image649
 Cc1ccccc1C1NC(=O)c2nccc(NC(=O)N3CCc4ccc(F)cc34)c12 1H NMR (400 MHz, DMSO-d6)  9.35 (s, 1H), 8.95 (br s, 1H), 8.66 (d, 5.3 Hz, 1H), 7.43-7.38 (m, 2H), 7.20-7.09 (m, 2H), 7.01-6.96 (m, 2H), 6.79-6.70 (m, 1H), 6.55(br s, 1H), 5.88 (s, 1H), 3.68-3.61 (m, 1H), 3.03-2.75 (m, 3H), 2.29-2.00 (m, 3H)。 403.3 C   
I-178
Figure 02_image651
 Cc1ccccc1-n1[nH]c(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  11.08 (s, 1H), 10.13 (s, 1H), 7.84 (d, 8.5 Hz, 1H), 7.72 (dd, 8.0, 0.9 Hz, 1H), 7.48 (s, 1H), 7.44 (d, 9.1 Hz, 1H), 7.25 (dd, 7.3, 0.8 Hz, 1H), 7.14 (t, 7.8 Hz, 1H), 7.11-7.06 (m, 2H), 7.01-6.92 (m, 2H), 2.03 (s, 3H)。 428.3 C   
I-179
Figure 02_image653
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)C34CCC(CC3)CC4)c12 1H NMR (400 MHz, DMSO-d6) 8.97 (s, 1H), 8.75 (s, 1H), 7.57-7.54 (m, 1H), 7.53-7.49 (m, 1H), 7.45 (dd, 7.5, 1.4 Hz, 1H), 7.18 (d, 4.0 Hz, 2H), 7.06-6.98 (m, 1H), 6.47 (br. s, 1H), 5.94 (s, 1H), 2.32 (br. s, 3H), 1.50-1.45 (m, 1H), 1.42-1.33 (m, 6H), 1.32-1.21 (m, 6H)。 375.3 D   
I-180
Figure 02_image655
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3ncc4c(F)cc(F)cn34)c12 1H NMR (400 MHz, DMSO-d6)  10.02 (br s, 1H), 9.14 (d, 4.0 Hz, 1H), 9.03 (s, 1H), 7.84 (d, 0.8 Hz, 1H), 7.78 (dd, 7.6, 1.2 Hz, 1H), 7.65-7.62 (m, 1H), 7.62-7.57 (m, 1H), 7.44 (ddd, 10.6, 8.8, 1.8 Hz, 1H), 6.99-6.92 (m, 2H), 6.90-6.85 (m, 1H), 6.68 (br s, 1H), 6.10 (s, 1H), 2.23 (br s, 3H)。 419.3 E   
I-181
Figure 02_image657
 Cc1ccccc1C1NC(=O)c2cc(CCO)cc(NC(=O)c3csc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 10.06 (s, 1H), 8.93 (s, 1H), 8.62-8.38 (m, 2H), 8.03-7.95 (m, 2H), 7.62 (s, 1H), 7.47 (s, 1H), 7.41-7.32 (m, 3H), 7.05 (t, 7.8 Hz, 1H), 6.99-6.90 (m, 1H), 6.57 (br s, 1H), 5.95 (s, 1H), 4.71 (br s, 1H), 3.71-3.61 (m, 2H), 2.92-2.77 (m, 2H), 2.14 (s, 3H)。 442.8 A   
I-182
Figure 02_image659
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)-c1cn[nH]c1 1 H NMR (500 MHz, DMSO-d6 ) δ 13.20 (br s, 1H), 10.69 (br s, 1H), 9.44 (br s, 1H), 8.42 (br s, 1H), 8.11 (br s, 1H), 7.88 (br s, 1H), 7.57-7.83 (m, 3H), 7.36-7.43 (m, 2H), 7.14 (td,J = 8.4, 3.1 Hz, 1H), 5.99 (br s, 1H)。 500.4 B   
I-183
Figure 02_image661
 CSc1nc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)n1)c1ccccc1Cl 1H NMR (400 MHz, DMSO-d6) 9.63 (br s, 1H), 7.84 (br d, 7.58 Hz, 1H), 7.64 (br d, 9.09 Hz, 1H), 7.59 (s, 1H), 7.15-7.23 (m, 1H),7.07-7.15 (m, 1H), 7.03 (br t, 6.95 Hz, 1H), 6.83-6.97 (m, 1H), 6.51 (s, 1H), 5.98 (br s, 1H), 2.60 (s, 3H) 497.3 D   
I-184
Figure 02_image663
 Nc1nc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)n1)c1ccccc1Cl    466.4 C   
I-185
Figure 02_image665
 OCc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz) 10.4-10.6 (m, 1H), 9.0-9.2 (m, 1H), 7.9-8.0 (m, 1H), 7.7-7.8 (m, 1H), 7.5-7.7 (m, 2H), 7.4-7.5 (m, 1H), 7.2-7.4 (m, 1H), 7.0-7.1 (m, 1H), 6.5-6.8 (m, 1H), 5.9-6.2 (m, 1H), 5.3-5.6 (m, 1H), 4.4-4.9 (m, 2H) 497 A   
I-186
Figure 02_image667
 Cn1cc(cn1)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2[C@H](NC(=O)c2n1)c1cc(F)ccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.84 (br s, 1H), 9.44 (br s, 1H), 8.40 (s, 1H), 8.05 (s, 1H), 7.97 (br d,J = 6.6 Hz, 1H), 7.62-7.79 (m, 3H), 7.34 (br dd,J = 8.8, 5.1 Hz, 1H), 7.09 (td,J = 8.4, 2.9 Hz, 1H), 6.81-6.97 (m, 1H), 5.98 (br s, 1H), 3.93 (s, 3H)。 548.3 C   
I-187
Figure 02_image669
 Cn1cc(cn1)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2[C@@H](NC(=O)c2n1)c1cc(F)ccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.84 (br s, 1H), 9.44 (br s, 1H), 8.40 (s, 1H), 8.05 (s, 1H), 7.97 (br d,J = 6.6 Hz, 1H), 7.62-7.79 (m, 3H), 7.34 (br dd,J = 8.8, 5.1 Hz, 1H), 7.09 (td,J = 8.4, 2.9 Hz, 1H), 6.81-6.97 (m, 1H), 5.98 (br s, 1H), 3.93 (s, 3H)。 548.4 A   
I-188
Figure 02_image671
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC3(CCc4ccccc34)c12 1H NMR (500 MHz, DMSO-d6) 11.55 (s, 1H), 9.47 (s, 1H), 8.34 (d, 8.24 Hz, 1H), 8.12 (s, 1H), 8.06 (br dd, 6.71, 7.93 Hz, 2H), 7.57 (t, 7.93 Hz, 1H), 7.40 (d, 7.63 Hz, 1H), 7.26-7.33 (m, 1H), 7.15 (t, 7.32 Hz, 1H), 7.01 (d, 7.32 Hz, 1H), 6.79 (d, 7.32 Hz, 1H), 3.12-3.27 (m, 2H), 2.51-2.57 (m, 1H), 2.39-2.46 (m, 1H) 441.07 E   
I-189
Figure 02_image673
 CC(C)(O)c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.4-10.6 (m, 1H), 8.9-9.2 (m, 1H), 7.9-8.0 (m, 1H), 7.7-7.8 (m, 2H), 7.6-7.7 (m, 1H), 7.5-7.6 (m, 1H), 7.2-7.4 (m, 1H), 6.9-7.1 (m, 1H), 6.3-6.9 (m, 1H), 5.9-6.1 (m, 1H), 5.2-5.4 (m, 1H), 1.4-1.6 (m, 6H) 525 A A
I-190
Figure 02_image675
 CC(C)(O)c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.4-10.6 (m, 1H), 8.9-9.2 (m, 1H), 7.9-8.0 (m, 1H), 7.7-7.8 (m, 2H), 7.6-7.7 (m, 1H), 7.5-7.6 (m, 1H), 7.2-7.4 (m, 1H), 6.9-7.1 (m, 1H), 6.3-6.9 (m, 1H), 5.9-6.1 (m, 1H), 5.2-5.4 (m, 1H), 1.4-1.6 (m, 6H) 525 D   
I-191
Figure 02_image677
 CC(C)(O)c1cc2C(=O)N[C@@H](c2c(NC(=O)c2nsc3ccccc23)c1)c1cc(F)ccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.1-10.5 (m, 1H), 8.9-9.2 (m, 1H), 8.5-8.7 (m, 1H), 8.2-8.3 (m, 1H), 7.8-7.8 (m, 1H), 7.6-7.7 (m, 1H), 7.5-7.6 (m, 1H), 7.2-7.3 (m, 1H), 6.9-7.0 (m, 1H), 6.4-6.9 (m, 1H), 6.0-6.2 (m, 1H), 5.6-5.7 (m, 1H), 5.1-5.3 (m, 1H), 1.3-1.6 (m, 6H)。 496 C   
I-192
Figure 02_image679
 CC(C)(O)c1cc2C(=O)N[C@H](c2c(NC(=O)c2nsc3ccccc23)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.1-10.5 (m, 1H), 8.9-9.2 (m, 1H), 8.5-8.7 (m, 1H), 8.2-8.3 (m, 1H), 7.8-7.8 (m, 1H), 7.6-7.7 (m, 1H), 7.5-7.6 (m, 1H), 7.2-7.3 (m, 1H), 6.9-7.0 (m, 1H), 6.4-6.9 (m, 1H), 6.0-6.2 (m, 1H), 5.6-5.7 (m, 1H), 5.1-5.3 (m, 1H), 1.3-1.6 (m, 6H) 496 A A
I-193
Figure 02_image681
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn[nH]c1 1 H NMR (400 MHz, DMSO-d6 ) δ 13.21 (br s, 1H), 10.85 (br s, 1H), 9.44 (br s, 1H), 8.43 (br s, 1H), 8.12 (br s, 1H), 7.97 (br d,J = 4.1 Hz, 1H), 7.63-7.87 (m, 3H), 7.34 (br dd,J = 8.8, 5.1 Hz, 1H), 7.09 (td,J = 8.4, 2.9 Hz, 1H), 6.75-6.96 (m, 1H), 5.98 (br s, 1H)。 534.4 D   
I-194
Figure 02_image683
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn[nH]c1 1 H NMR (400 MHz, DMSO-d6 ) δ 13.21 (br s, 1H), 10.85 (br s, 1H), 9.44 (br s, 1H), 8.43 (br s, 1H), 8.12 (br s, 1H), 7.97 (br d,J = 4.1 Hz, 1H), 7.63-7.87 (m, 3H), 7.34 (br dd,J = 8.8, 5.1 Hz, 1H), 7.09 (td,J = 8.4, 2.9 Hz, 1H), 6.75-6.96 (m, 1H), 5.98 (br s, 1H)。 534.4 A   
I-195
Figure 02_image685
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)-c1cn[nH]c1 1 H NMR (500 MHz, DMSO-d6 ) δ 13.20 (br s, 1H), 10.69 (br s, 1H), 9.44 (br s, 1H), 8.42 (br s, 1H), 8.11 (br s, 1H), 7.88 (br s, 1H), 7.57-7.83 (m, 3H), 7.36-7.43 (m, 2H), 7.14 (td,J = 8.4, 3.1 Hz, 1H), 5.99 (br s, 1H)。 500.4 D   
I-196
Figure 02_image687
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)-c1cn[nH]c1 1 H NMR (500 MHz, DMSO-d6 ) δ 13.20 (br s, 1H), 10.69 (br s, 1H), 9.44 (br s, 1H), 8.42 (br s, 1H), 8.11 (br s, 1H), 7.88 (br s, 1H), 7.57-7.83 (m, 3H), 7.36-7.43 (m, 2H), 7.14 (td,J = 8.4, 3.1 Hz, 1H), 5.99 (br s, 1H)。 500.4 A   
I-197
Figure 02_image689
 O=C(Nc1cccc2C(=O)NC(c12)c1ccccc1C#N)c1nsc2ccccc12 1H NMR (400 MHz, DMSO-d6) 10.46 (s, 1H), 9.21 (s, 1H), 8.65 (dt, 8.1, 0.9 Hz, 1H), 8.31 (dt, 8.2, 0.9 Hz, 1H), 7.72-7.62 (m, 4H), 7.62-7.56 (m, 2H), 7.35 (td, 7.6, 1.2 Hz, 1H), 7.27 (td, 7.6, 1.3 Hz, 1H), 7.23-7.12 (br s), 6.15 (s)。 411.2 D   
I-198
Figure 02_image691
 COc1cccc2c(csc12)C(=O)Nc1cccc2C(=O)NC(c12)c1ccccc1C 1H NMR (400 MHz, DMSO-d6) 10.10 (s, 1H), 9.03 (s, 1H), 7.70-7.52 (m, 5H), 7.35 (t, 8.0 Hz, 1H), 7.09 (td, 7.4, 1.0, 1H), 7.01-6.95 (m, 3H), 6.55 (br s, 1H), 6.00 (s, 1H), 3.96 (s, 3H), 2.12 (br s, 3H)。 429.3 E   
I-199
Figure 02_image693
 Cc1ccccc1C1NC(=O)c2nccc(NC(=O)N3CCc4ncccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.35 (s, 1H), 9.00 (br s, 1H), 8.66 (d, 5.3 Hz, 1H), 8.04 (dd, 4.9, 1.4 Hz, 1H), 7.85 (d, 7.8 Hz, 1H), 7.39 (d, 5.3 Hz, 1H), 7.22-7.07 (m, 2H), 6.98 (d, 7.5 Hz, 2H), 6.54 (br s, 1H), 5.87 (s, 1H), 3.71-3.60 (m, 1H), 3.10-2.81 (m, 3H), 2.29-1.94 (m, 3H)。 386.3 E   
I-200
Figure 02_image695
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3noc4ccc(Cl)cc34)c12 1H NMR (400 MHz, DMSO-d6)  10.72 (br s, 1H), 9.07 (s, 1H), 7.94 (dd, 9.0, 0.4 Hz, 1H), 7.79 (dd, 9.0, 2.1 Hz, 1H), 7.73 (br s, 1H), 7.71 (dd, 7.2, 1.3 Hz, 1H), 7.63 (t, 7.5 Hz, 1H), 7.59 (dd, 7.8, 1.2 Hz, 1H), 7.02-6.93 (m, 2H), 6.93-6.85 (m, 1H), 6.64 (br s, 1H), 6.02 (s, 1H), 2.20 (br s, 3H)。 835.3 D   
I-201
Figure 02_image697
 Cc1ccccc1C1NCc2cccc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  8.85-8.80 (m, 1H), 8.77 (s, 1H), 8.10 (dt, 8.2, 0.8 Hz, 1H), 7.90 (d, 8.2 Hz, 1H), 7.62 (ddd, 8.2, 7.0, 1.2 Hz, 1H), 7.56 (ddd, 8.2, 7.0, 1.2 Hz, 1H), 7.40 (t, 7.5 Hz, 1H), 7.23 (dd, 7.5, 0.8 Hz, 1H), 7.14-7.02 (m, 3 H), 6.96 (dd, 7.5, 1.2 Hz, 1H), 5.91 (s, 1H), 4.42 (d, 14.0 Hz, 1H), 4.32 (d, 14.0 Hz, 1H), 2.42 (s, 3H)。 386.2 D   
I-202
Figure 02_image699
 Cc1ccccc1C1NC(=O)c2cc(CS(C)(=O)=O)cc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400MHz, CDCl3)  8.90 (d, 7.7 Hz, 1H), 8.87 (s, 1H), 8.59 (s, 1H), 7.94 (d, 7.8 Hz, 1H), 7.79 (d, 1.2 Hz, 1H), 7.72-7.62 (m, 1H), 7.60-7.50 (m, 3H), 7.46 (td, 7.4, 3.0 Hz, 1H), 7.17 (br s, 1H), 6.65 (s, 1H), 6.00 (br s, 1H), 4.41 (s, 2H), 2.89 (s, 3H), 2.16 (s, 1H), 1.24 (br s, 3H)。 492.3 A A
I-203
Figure 02_image701
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1nsc3ccccc13)ccc2Br 1H NMR (400 MHz, DMSO-d6)  10.10 (s, 1H), 9.22 (s, 1H), 8.58 (d, 8.2 Hz, 1H), 8.30 (d, 8.2 Hz, 1H), 7.76 (dd, 21.4, 8.4 Hz, 2H), 7.70-7.64 (m, 1H), 7.61-7.54 (m, 1 H), 7.01-6.94 (m, 2H), 6.91 (m, 1 H), 6.69 (br s, 1H), 6.08 (s, 1H), 2.24 (br s, 3H)。 480.1 A   
I-204
Figure 02_image703
 O=C(Nc1cccc2C(=O)NC(C3CCCCC3)c12)c1nsc2ccccc12 1H NMR (400 MHz, DMSO-d6) 10.90 (s, 1H), 8.72 (s, 1H), 8.70 (d, 8.3 Hz, 1H), 8.37 (d, 8.2 Hz, 1H), 7.75-7.69 (m, 2H), 7.64 (t, 7.6 Hz, 1H), 7.57-7.50 (m, 2H), 4.89 (s, 1H), 2.09-1.97 (m, 1H), 1.62 (m, 2H), 1.48 (d, 8.6 Hz, 2H), 1.34 (qd, 12.2, 9.4 Hz, 1H), 0.91 (t, 8.6 Hz, 2H), 0.87 (m, 1H), 0.71 (t, 8.7 Hz, 2H)。 392.2 B   
I-205
Figure 02_image705
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1nsc3ccccc13)ccc2C=C 1H NMR (400 MHz, DMSO-d6) 10.03 (br s, 1H), 9.06 (s, 1H), 8.59 (d, 8.1 Hz, 1H), 8.29 (d, 8.2 Hz, 1H), 8.11 (dd, 17.9, 11.2 Hz, 1H), 7.90 (d, 8.4 Hz, 1H), 7.79 (d, 8.3 Hz, 1H), 7.67 (t, 7.2 Hz, 1H), 7.58 (t, 7.4 Hz, 1 H), 7.06-6.94 (m, 2H), 6.93-6.90 (m, 1H), 6.71 (br s, 1H), 6.14-5.98 (m, 2H), 5.45 (d, 11.9 Hz, 1H), 2.25 (br s, 3H)。 426.3 B   
I-206
Figure 02_image707
 FC(F)c1ccc(F)cc1C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.55 (s, 1H), 9.33 (s, 1H), 7.94 (d, 8.2 Hz, 1H), 7.87 (d, 1.7 Hz, 1H), 7.78 (d, 1.7 Hz, 1H), 7.67 (d, 8.9 Hz, 1H), 7.58 (s, 1H), 7.50 (dd, 8.8, 5.6 Hz, 1H), 7.22 (td, 8.4, 2.7 Hz, 1H), 7.11 (s, 1H), 6.57 (s, 1H), 6.02 (s, 1H)。 561.05 A   
I-207
Figure 02_image709
 CC(=O)NCc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.3-10.7 (m, 1H), 8.8-9.3 (m, 1H), 7.9-8.0 (m, 1H), 7.7-7.8 (m, 1H), 7.6-7.7 (m, 2H), 7.4-7.5 (m, 2H), 7.3-7.3 (m, 1H), 7.0-7.1 (m, 1H), 5.8-6.1 (m, 1H), 5.2-5.6 (m, 1H), 4.4-4.8 (m, 2H), 2.0-2.1 (m, 3H) 538 B   
I-208
Figure 02_image711
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1ccnc2C(=O)NC(c12)c1ccccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.75 (br s, 1H), 9.48 (br s, 1H), 8.78 (d, 5.13 Hz, 1H), 7.94 (br d, 8.54 Hz, 1H), 7.63 (br d, 8.79 Hz, 1H), 7.48-7.57 (m, 2H), 7.26-7.33 (m, 1H), 7.18-7.25 (m, 1H), 7.11 (br t, 7.20 Hz, 1H), 6.70-6.99 (m, 1H), 6.06 (br s, 1H) 450.36 C   
I-209
Figure 02_image713
 Fc1cc(F)c2occ(C(=O)Nc3ccnc4C(=O)NC(c34)c3ccccc3Cl)c2c1 1H NMR (400 MHz, DMSO-d6) 10.55 (s, 1H), 9.46 (br s, 1H), 8.72-8.85 (m, 1H), 8.45 (s, 1H), 7.38-7.56 (m, 4H), 7.22-7.29 (m, 1H), 7.15-7.21 (m, 1H), 7.09 (br t, 7.20 Hz, 1H), 6.15 (br s, 1H) 440.35 C   
I-210
Figure 02_image715
 Fc1cc(F)c2occ(C(=O)Nc3ccnc4C(=O)NC(c34)c3cccc(F)c3F)c2c1 1H NMR (400 MHz, DMSO-d6) 10.62 (br s, 1H), 9.49 (s, 1H), 8.77 (d, 5.37 Hz, 1H), 8.53 (s, 1H), 7.54 (d, 5.37 Hz, 1H), 7.39-7.50 (m, 2H), 7.19-7.30 (m, 1H), 6.93-7.01 (m, 1H), 6.82 (br t, 6.96 Hz, 1H), 6.06 (s, 1H) 442.4 D   
I-211
Figure 02_image717
 CNC(=O)c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1ccccc1C    486.37 E   
I-212
Figure 02_image719
 CNC(=O)c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1ccccc1C    486.37 A   
I-213
Figure 02_image721
 Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  5.43-5.68 (m, 2H), 5.74-5.91 (m, 1H), 6.37-6.60 (m, 1H), 6.63-6.72 (m, 1H), 6.76-6.87 (m, 1H), 6.93-7.17 (m, 1H), 7.21-7.44 (m, 3H), 7.51-7.79 (m, 1H), 8.70-8.97 (m, 1H), 9.84-10.17 (m, 1H) 448 A A
I-214
Figure 02_image723
 CC(C)(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.2-10.4 (m, 1H), 9.0-9.2 (m, 1H), 7.7-7.8 (m, 1H), 7.66 (br d, 8.3 Hz, 2H), 7.5-7.6 (m, 1H), 7.3-7.5 (m, 2H), 7.0-7.2 (m, 1H), 6.6-6.7 (m, 1H), 5.8-6.1 (m,1H), 5.2-5.4 (m, 1H), 1.4-1.6 (m, 6H) 491 A   
I-215
Figure 02_image725
 CC(=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.3-10.7 (m, 1H), 9.1-9.4 (m, 1H), 8.4-8.6 (m, 1H), 8.0-8.3 (m, 1H), 7.6-7.8 (m, 1H), 7.3-7.5 (m, 3H), 7.0-7.2 (m, 1H), 6.5-6.9 (m, 1H), 5.8-6.2 (m, 1H), 3.8-4.3 (m, 3H) 475 B   
I-216
Figure 02_image727
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(Cl)c3)c12 1H NMR (400 MHz, DMSO-d6) 10.2-10.7 (m, 1H), 9.1-9.5 (m, 1H), 8.3-8.5 (m, 1H), 7.6-8.0 (m, 2H), 7.3-7.4 (m, 2H), 7.0-7.2 (m, 1H), 6.5-6.8 (m, 1H), 5.5-6.3 (m, 2H) 513 A   
I-217
Figure 02_image729
 Nc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO-d6) 10.1-10.3 (m, 1H), 8.8-8.9 (m, 1H), 7.9-8.0 (m, 1H), 7.6-7.8 (m, 1H), 7.6-7.6 (m, 1H), 7.2-7.4 (m, 2H), 7.0-7.1 (m, 1H), 6.8-6.9 (m, 1H), 6.66 (s, 1H), 5.7-5.9 (m, 1H), 5.5-5.7 (m, 2H) 482 D   
I-218
Figure 02_image731
 Nc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO-d6) 10.1-10.3 (m, 1H), 8.8-8.9 (m, 1H), 7.9-8.0 (m, 1H), 7.6-7.8 (m, 1H), 7.6-7.6 (m, 1H), 7.2-7.4 (m, 2H), 7.0-7.1 (m, 1H), 6.8-6.9 (m, 1H), 6.66 (s, 1H), 5.7-5.9 (m, 1H), 5.5-5.7 (m, 2H) 482 A A
I-219
Figure 02_image733
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1nsc3ccccc13)ccc2C(=O)N1CC(C1)C#N 1H NMR (400 MHz, DMSO-d6)  10.20 (br s, 1H), 9.25 (s, 1H), 8.59 (d, 8.3 Hz, 1H), 8.30 (d, 8.2 Hz, 1H), 7.88 (dd, 8.1, 2.2 Hz, 1H), 7.71-7.64 (m, 1H), 7.59 (t, 7.5 Hz, 1H), 7.53 (d, 8.1 Hz, 1H), 7.03-6.95 (m, 2H), 6.92 (s, 1H), 6.68 (br s, 1H), 6.15 (s, 1H), 4.37 (t, 9.4 Hz, 1H), 4.23 (dd, 9.6, 6.2 Hz, 1H), 4.20-4.07 (m, 2H), 3.91-3.81 (m, 1H), 2.27 (br s, 3H)。 508.2 C   
I-220
Figure 02_image735
 Cn1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1C(F)F 1H NMR (400 MHz, DMSO-d6) δ 10.53 (br s, 1H) 9.14 (s, 1H) 8.33 (s, 1H) 8.00 (s, 1H) 7.85 - 7.94 (m, 2H) 7.65 - 7.74 (m, 2H) 7.62 (s, 1H) 7.47 (dd, J=8.72, 5.68 Hz, 1H) 7.19 (td, J=8.46, 2.53 Hz, 1H) 6.46 - 6.61 (m, 1H) 5.98 (s, 1H) 3.74 - 4.02 (m, 1H) 3.88 (s, 2H) 563.1 A A
I-221
Figure 02_image737
 FC(F)(F)c1ccccc1C1NC(=O)c2cccc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 11.10 (s, 1H), 9.24 (s, 1H), 8.77 (d, 8.1 Hz, 1H), 8.39 (t, 4.4 Hz, 1H), 8.36 (d, 8.2 Hz, 1H), 7.99 (dt, 15.6, 7.8 Hz, 1H), 7.83 (d, 7.9 Hz, 1H), 7.76-7.68 (m, 1H), 7.67-7.63 (m, 1H), 7.61 (dd, 11.0, 4.2 Hz, 1H), 7.53 (t, 7.4 Hz, 1H), 7.18 (d, 8.2 Hz, 1H), 7.09 (d, 7.7 Hz, 1H), 5.91 (s, 1H)。 454.2 E   
I-222
Figure 02_image739
 COC(=O)c1cc(NC(=O)c2nsc3ccccc23)c2C(NC(=O)c2n1)c1ccccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.61 (br s, 1H), 9.70 (br s, 1H), 8.70 (d, 7.9 Hz, 1H), 8.60 (s, 1H), 8.33 (d, 8.2 Hz, 1H), 7.70 (ddd, 8.3, 7.0, 1.2 Hz, 1H), 7.67-7.52 (m, 1H), 7.33 (d, 7.7 Hz, 1H), 7.23 (td, 7.9, 1.6 Hz, 1H), 7.15 (td, 7.4, 1.1 Hz, 1H), 6.40 (br s, 1H), 3.97 (s, 3H)。 479.2 B   
I-223
Figure 02_image741
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1csc3ccccc13)ccc2CNC(=O)C(F)(F)F 1H NMR (400 MHz, DMSO-d6)  10.11-10.04 (m, 2H), 9.17 (s, 1H), 8.05-7.97 (m, 2H), 7.62 (s, 1H), 7.55 (d, 8.1 Hz, 1H), 7.42-7.37 (m, 3 H), 7.10 (td, 7.6, 1.1 Hz, 1H), 7.05-6.95 (m, 2H), 6.62 (br s, 1H), 6.02 (s, 1H), 5.02 (d, 5.8 Hz, 2H), 2.20 (br s, 3H)。 524.2 B   
I-224
Figure 02_image743
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1csc3ccccc13)ccc2CO 1H NMR (400 MHz, DMSO-d6)  10.07 (s, 1H), 9.11 (s, 1H), 8.08-7.99 (m, 2H), 7.63 (d, 8.0 Hz, 2H), 7.53 (d, 8.1 Hz, 1H), 7.43-7.35 (m, 2H), 7.09 (t, 7.4 Hz, 1H), 7.03-6.94 (m, 2H), 6.62 (br s, 1H), 6.02 (s, 1H), 5.04 (s, 2H), 2.19 (br s, 3H)。 429.3 A   
I-225
Figure 02_image745
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1nsc3ccccc13)ccc2C(=O)N1CC(C1)S(C)(=O)=O 1H NMR (400 MHz, DMSO-d6)  10.22 (br s, 1H), 9.26 (d, 5.2 Hz, 1H), 8.59 (d, 8.1 Hz, 1H), 8.30 (d,  8.2 Hz, 1H), 7.89 (t, 8.1 Hz, 1H), 7.71-7.64 (m, 1H), 7.59 (t, 7.6 Hz, 1H), 7.52 (dd, 8.1, 4.1 Hz, 1H), 7.06-6.95 (m, 2H), 6.92 (br s, 1H), 6.67 (br s, 1H), 6.15 (s, 1H), 4.43-4.32 (m, 2H), 4.23-4.19 (m, 2H), 4.06 (ddd, 13.1, 9.2, 3.5 Hz, 1H), 3.08 (d, 6.8 Hz, 3H), 2.27 (br s, 3H)。 561.3 B   
I-226
Figure 02_image747
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)C34CCC(C3)c3ccccc43)c12 1H NMR (400 MHz, DMSO-d6) 9.02 (br s, 1H), 8.99 (br s, 1H), 8.80 (br s, 2H), 7.67-7.53 (m, 6H), 7.23-7.10 (m, 6H), 7.09-6.91 (m, 6H), 6.85 (d, 7.2 Hz, 1H), 6.66-6.58 (m, 3H), 6.07 (s, 2H), 3.31 (dd, 11.4, 3.4 Hz, 2H), 2.29 (br. s, 6H), 1.93-1.84 (m, 2H), 1.81-1.76 (m, 1H), 1.76-1.64 (m, 3H), 1.44 (d, 8.7 Hz, 1H), 1.36 (d, 8.7 Hz, 1H), 1.22-1.14 (m, 1H), 1.14-1.08 (m, 1H), 1.08-0.99 (m, 2H)。光譜記錄於70℃ (343K)下。 409.4 D   
I-227
Figure 02_image749
 Cc1ccccc1[C@@H]1NC(=O)c2nccc(NC(=O)N3CCc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  9.34 (s, 1H), 8.83 (br s, 1H), 8.64 (d, 5.3 Hz, 1H), 7.64 (d, 7.8 Hz, 1H), 7.42 (d, 5.4 Hz, 1H), 7.18-7.07 (m, 3H), 7.04-6.95 (m, 2H), 6.92 (t, 7.1 Hz, 1H), 6.55 (br s, 1H), 5.90 (s, 1H), 3.62-3.52 (m, 1H), 3.01-2.78 (m, 3H), 2.11 (br s, 3H) 385.2 B   
I-228
Figure 02_image751
 Cc1ccccc1[C@H]1NC(=O)c2nccc(NC(=O)N3CCc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  9.34 (s, 1H), 8.83 (br s, 1H), 8.64 (d, 5.3 Hz, 1H), 7.64 (d, 7.8 Hz, 1H), 7.42 (d, 5.4 Hz, 1H), 7.18-7.07 (m, 3H), 7.04-6.95 (m, 2H), 6.92 (t, 7.1 Hz, 1H), 6.55 (br s, 1H), 5.90 (s, 1H), 3.62-3.52 (m, 1H), 3.01-2.78 (m, 3H), 2.11 (br s, 3H) 385.4 E   
I-229
Figure 02_image753
 Cc1ccccc1[C@@H]1NC(=O)c2nccc(NC(=O)N3CCc4c3cc(F)cc4F)c12 1H NMR (400 MHz, DMSO-d6)  9.33 (s, 1H), 9.06 (br s, 1H), 8.63 (d, 5.3 Hz, 1H), 7.33 (d, 5.3 Hz, 1H), 7.26 (d, 10.3 Hz, 1H), 7.12 (td, 7.4, 1.0 Hz, 1H), 6.96 (dd, 17.5, 7.5 Hz, 2H), 6.75 (td, 9.5, 2.2 Hz, 1H), 6.63-6.40 (m, 1H), 5.82 (s, 1H), 3.74-3.57 (m, 1H), 3.02-2.82 (m, 2H), 2.76 (ddd, 25.2, 16.0, 11.6 Hz, 1H), 2.13 (m, 3H)。 421.2 C   
I-230
Figure 02_image755
 Cc1ccccc1[C@H]1NC(=O)c2nccc(NC(=O)N3CCc4c3cc(F)cc4F)c12 1H NMR (400 MHz, DMSO-d6)  9.33 (s, 1H), 9.06 (br s, 1H), 8.63 (d, 5.3 Hz, 1H), 7.33 (d, 5.3 Hz, 1H), 7.26 (d, 10.3 Hz, 1H), 7.12 (td, 7.4, 1.0 Hz, 1H), 6.96 (dd, 17.5, 7.5 Hz, 2H), 6.75 (td, 9.5, 2.2 Hz, 1H), 6.63-6.40 (m, 1H), 5.82 (s, 1H), 3.74-3.57 (m, 1H), 3.02-2.82 (m, 2H), 2.76 (ddd, 25.2, 16.0, 11.6 Hz, 1H), 2.13 (m, 3H)。 421.3 E   
I-231
Figure 02_image757
 CS(=O)(=O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  2.84-3.03 (m, 3H), 3.97-4.15 (m, 1 H), 4.59-4.78 (m, 2H), 5.81-6.08 (m, 1H), 6.54-6.76 (m, 1H), 7.05-7.17 (m, 1H), 7.31-7.36 (m, 1H), 7.36-7.40 (m, 2H), 7.49-7.69 (m, 5H), 7.71-7.79 (m, 1H), 8.99-9.36 (m, 1 H), 10.24-10.55 (m, 1H) 525 A   
I-232
Figure 02_image759
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)cnc2Cl    464.36 B   
I-233
Figure 02_image761
 Cc1ccccc1C1NC(=O)c2cncc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.65 (s, 1H), 9.28 (s, 1H), 8.88 (s, 1H), 8.69 (s, 1H), 7.91 (br d, 8.54 Hz, 1H), 7.53 (br d, 8.54 Hz, 1H), 7.40 (br s, 1H), 7.03-7.11 (m, 1H), 6.93-7.02 (m, 2H), 6.50-6.64 (m, 1H), 5.95 (br s, 1H), 2.01-2.33 (m, 3H) 430.45 B   
I-234
Figure 02_image763
 Fc1cc(OC(F)(F)F)cc(c1)C(=O)Nc1ccnc2C(=O)NC(c12)c1ccccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.48-10.87 (m, 1H), 9.35-9.58 (m, 1H), 8.77 (d,J =5.13 Hz, 1H), 7.65 (br d,J =8.79 Hz, 1H), 7.54 (d,J =5.37 Hz, 1H), 6.57-7.42 (m, 6H), 5.91-6.20 (m, 1H)。 466.3 D   
I-235
Figure 02_image765
 Fc1cc(cc(c1)C(=O)Nc1ccnc2C(=O)NC(c12)c1ccccc1Cl)C#N 1 H NMR (400 MHz, DMSO-d6 ) δ 10.49-10.99 (m, 1H), 9.46 (br s, 1H), 8.75 (d,J =5.13 Hz, 1H), 8.08 (br d,J =7.81 Hz, 1H), 7.46-7.75 (m, 3H), 6.63-7.39 (m, 4H), 5.86-6.20 (m, 1H)。 407.3 E   
I-236
Figure 02_image767
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)cnc2C#N 1H NMR (400 MHz, DMSO-d6) 10.99 (br s, 1H), 9.67 (s, 1H), 8.84 (s, 1H), 7.93 (br d, 8.30 Hz, 1H), 7.51 (br d, 8.79 Hz, 1H), 7.35 (br s, 1H), 7.05-7.12 (m, 1H), 6.93-7.03 (m, 2H), 6.61 (br s, 1H), 6.01 (s, 1H), 2.07-2.37 (m, 3H) 455.41 D   
I-237
Figure 02_image769
 FC(F)c1ccc(F)cc1C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C#N       A   
I-238
Figure 02_image771
 CC(=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1C(F)F 1 H NMR (400 MHz, DMSO-d6 ) δ 10.61 (s, 1 H) 9.33 (s, 1 H) 8.24 (d,J =1.52 Hz, 1 H) 8.07 (d,J =1.52 Hz, 1 H) 7.92 (br d,J =8.34 Hz, 1 H) 7.69 (br d,J =9.09 Hz, 1 H) 7.60 (s, 1 H) 7.49 (dd,J =8.84, 5.56 Hz, 1 H) 7.21 (td,J =8.40, 2.65 Hz, 2 H) 6.50 (br s, 1 H) 6.10 (s, 1 H) 2.71 (s, 3 H)。    A   
I-239
Figure 02_image773
 CC(C)(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1C(F)F 1 H NMR (400 MHz, DMSO-d6 ) δ 10.47 (s, 1 H) 9.10 (s, 1 H) 7.89 (br d,J =8.08 Hz, 1 H) 7.80 (s, 1 H) 7.68 (br d,J =9.09 Hz, 1 H) 7.55 - 7.63 (m, 2 H) 7.47 (dd,J =8.59, 5.56 Hz, 1 H) 7.19 (td,J =8.46, 2.53 Hz, 1 H) 6.44 (br d,J =2.53 Hz, 1 H) 5.95 (s, 1 H) 5.31 (s, 1 H) 1.51 (s, 6 H)。    A   
I-240
Figure 02_image775
 Clc1ccccc1C1NC(=O)c2nccc(NC(=O)c3ccnc4CCCc34)c12 1 H NMR (500 MHz, DMSO-d6 ) δ 10.36-10.57 (m, 1H), 8.66-8.87 (m, 1H), 8.30-8.47 (m, 1H), 7.44-7.54 (m, 1H), 7.24-7.39 (m, 2H), 6.79-7.09 (m, 2H), 6.38-6.57 (m, 2H), 5.67-5.83 (m, 1H), 4.68-4.91 (m, 1H), 2.74-3.00 (m, 3H), 2.25-2.44 (m, 1H), 1.78-2.07 (m, 2H)。 405.3 E   
I-241
Figure 02_image777
 Cn1ncc(C2NC(=O)c3cccc(NC(=O)c4nsc5ccccc45)c23)c1C(F)F 1 H NMR (400 MHz, DMSO-d6 ) δ 10.23-10.40 (m, 1H), 8.83-9.08 (m, 1H), 8.61 (d,J =8.30 Hz, 1H), 8.31 (d,J =8.30 Hz, 1H), 7.80 (dd,J =1.22, 7.08 Hz, 1H), 7.49-7.73 (m, 4H), 6.90-7.32 (m, 2H), 6.08 (s, 1H), 3.67 (s, 3H)。 440.4 E   
I-242
Figure 02_image779
 CC(C)(O)c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.86 (s, 1H), 9.46 (s, 1H), 7.97 (d, 7.4 Hz, 1H), 7.80 (s, 1H), 7.75 (d, 8.8 Hz, 1H), 7.64 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.17-7.02 (m, 1H), 6.77 (br s, 1H), 5.99 (br s, 1H), 5.47 (s, 1H), 1.56 (s, 3H), 1.51 (s, 3H)。 526.4 B   
I-243
Figure 02_image781
 CN(C)c1ncc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c12)c1ccccc1C 1H NMR (400 MHz, DMSO-d6) 10.12 (s, 1H), 8.82 (s, 1H), 8.43 (br s, 1H), 8.13 (s, 1H), 7.86 (br d,  8.54 Hz, 1H), 7.48 (br d, 9.27 Hz, 1H), 7.37 (s, 1H), 7.00-7.08 (m, 1H), 6.89-6.98 (m, 1H), 6.66 (br s, 1H), 6.61 (br s, 1H), 5.74 (s, 1H), 3.19 (s, 3H), 2.11 (br s, 3H) 473.52 C   
I-244
Figure 02_image783
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)cnc2C 1H NMR (400 MHz, DMSO-d6) 10.50 (br s, 1H), 9.16 (br s, 1H), 8.48-8.54 (m, 1H), 7.89 (br d, 8.30 Hz, 1H), 7.51 (br d, 8.54 Hz, 1H), 7.39 (br s, 1H), 7.03-7.10 (m, 1H), 6.91-7.02 (m, 2H), 6.58 (br s, 1H), 5.86 (br s, 1H), 3.29 (s, 3H), 2.83 (s, 3H) 444.45 B   
I-245
Figure 02_image785
 Fc1ccc(NC(=O)Nc2ccnc3C(=O)NC(c23)c2ccccc2Cl)c(F)c1 1 H NMR (400 MHz, DMSO-d6 ) δ 9.39 (br s, 1H), 8.79 (br s, 2H), 8.63 (br d,J = 5.4 Hz, 1H), 7.79-7.87 (m, 1H), 7.76 (br d,J = 3.9 Hz, 1H), 7.46 (br d,J = 7.6 Hz, 1H), 7.32-7.37 (m, 1H), 7.20-7.31 (m, 2H), 7.04 (br t,J = 8.2 Hz, 1H), 6.76-6.91 (m, 1H), 6.10 ppm (br s, 1H)。 415.3 D   
I-246
Figure 02_image787
 Cc1ccccc1[C@@H]1NC(=O)c2nccc(NC(=O)N3CCc4ccc(F)cc34)c12 1H NMR (400 MHz, DMSO-d6)  9.35 (s, 1H), 8.95 (br s, 1H), 8.66 (d, 5.3 Hz, 1H), 7.43-7.38 (m,  2H), 7.20-7.09 (m, 2H), 7.01-6.96 (m, 2H), 6.79-6.70 (m, 1H), 6.55(br s, 1H), 5.88 (s, 1H), 3.68-3.61 (m, 1H), 3.03-2.75 (m, 3H), 2.29-2.00 (br s, 3H)。 403.3 B   
I-247
Figure 02_image789
 Cc1ccccc1[C@H]1NC(=O)c2nccc(NC(=O)N3CCc4ccc(F)cc34)c12 1H NMR (400 MHz, DMSO-d6)  9.35 (s, 1H), 8.95 (br s, 1H), 8.66 (d, 5.3 Hz, 1H), 7.43-7.38 (m,  2H), 7.20-7.09 (m, 2H), 7.01-6.96 (m, 2H), 6.79-6.70 (m, 1H), 6.55(br s, 1H), 5.88 (s, 1H), 3.68-3.61 (m, 1H), 3.03-2.75 (m, 3H), 2.29-2.00 (br s, 3H)。 403.3 E   
I-248
Figure 02_image791
 Cc1ccccc1C1NC(=O)c2nccc(NC(=O)N3CCc4cnccc34)c12 1H NMR (400 MHz, DMSO-d6)  9.36 (s, 1H), 9.10 (br s, 1H), 8.67 (d, 5.3 Hz, 1H), 8.27 (s, 1H), 8.24 (d, 5.4 Hz, 1H), 7.50 (d, 5.4 Hz, 1H), 7.41 (d, 5.3 Hz, 1H), 7.14 (td, 7.5, 1.1 Hz, 1H), 7.01 (d, 7.7 Hz, 1H), 6.97 (t, 7.4 H, 1Hz), 6.55 (br s, 1H), 5.86 (s,1H), 370-3.63 (m, 1H), 3.11-2.79 (m, 3H), 2.16 (br s, 3H)。 386.3 E   
I-249
Figure 02_image793
 CC1CN(C(=O)Nc2ccnc3C(=O)NC(c23)c2ccccc2C)c2ccccc12 1H NMR (400 MHz, DMSO-d6)  9.31 (s, 2H), 8.78 (br s, 1H), 8.67 (br s, 1H), 8.61 (s, 1H), 8.60 (s, 1H), 7.64 (d, 8.0 Hz, 1H), 7.59 (d, 8.1 Hz, 1H), 7.46 (d, 5.4 Hz, 1H), 7.40 (d, 5.3 Hz, 1H), 7.17-7.05 (m, 6H), 7.03-6.87 (m, 6H), 6.49 (br s, 2H), 5.89 (s, 1H), 5.88 (s, 1H), 3.79-3.65 (m, 2H), 3.25-3.08 (m, 2H), 2.99 (dd, 8.9, 5.9 Hz, 1H), 2.51 (dd, 10.0, 6.7 Hz, 1H), 2.15 (br s, 6H), 1.09 (d, 7.6 Hz, 3H), 1.04 (d, 6.8 Hz, 3H)。 397.4 B   
I-250
Figure 02_image795
 CC(C)(O)c1cc(NC(=O)c2nsc3ccccc23)c2C(NC(=O)c2n1)c1ccccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.40 (s, 1H), 9.47 (s, 1H), 8.65 (d, 8.1 Hz, 1H), 8.32 (d, 8.2 Hz, 1H), 8.23 (s, 1H), 7.72-7.66 (m, 1H), 7.65-7.59 (m, 1H), 7.58-7.54 (m, 1H), 7.33 (d, 7.7 Hz, 1H), 7.22 (td, 7.7, 1.8 Hz, 1H), 7.15 (td, 7.6, 1.2 Hz, 1H), 6.31 (br s, 1H), 5.44 (s, 1H), 1.56 (s, 3H), 1.52 (s, 3H)。 479.2 A   
I-251
Figure 02_image797
 Cc1ccccc1C1NC(=O)c2nccc(NC(=O)N3CCc4ccncc34)c12 1H NMR (400 MHz, DMSO-d6)  9.36 (s, 1H), 9.02 (s, 1H), 8.84 (s, 1H), 8.67 (d, 5.3 Hz, 1H), 8.15 (d, 4.9 Hz, 1H), 7.39 (d, 5.4 Hz, 1H), 7.24 (d, 4.7 Hz, 1H), 7.13 (td, 7.5, 1.2 Hz, 1H), 6.97 (m,, 2H), 6.54 (br s, 1H), 5.88 (s, 1H), 3.71-3.55 (m, 1H), 3.09-2.77 (m, 3H), 2.11 (br s, 3H)。 386.4 E   
I-252
Figure 02_image799
 Cc1ccccc1-n1[nH]c(=O)c2cccc(NC(=O)c3coc4c(F)cc(Cl)cc34)c12 1H NMR (400 MHz, DMSO-d6)  11.15 (br s, 1H), 9.85 (s, 1H), 8.17 (s, 1H), 7.72 (dd, 8.0, 3.9 Hz, 1H), 7.59 (d, 1.8 Hz, 1H), 7.53 (dd, 10.7, 1.9 Hz, 1H), 7.26 (d, 7.0 Hz, 1H), 7.14 (dd, 7.9, 7.4 Hz, 1H), 7.07 (dd, 7.7, 1.1 Hz, 1H), 6.97-6.92(m, 2H), 6.87 (td, 7.5, 1.1 Hz, 1H), 2.06 (s, 3H)。 436.1 B   
I-253
Figure 02_image801
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)cnc2N1CCOCC1 1H NMR (400 MHz, DMSO-d6)  10.19 (s, 1H), 8.98 (s, 1H), 8.17 (s, 1H), 7.85 (d, 8.4 Hz, 1H), 7.45 (d, 8.8 Hz, 1H), 7.33 (s, 1H), 7.06-6.83 (m, 3H), 6.60 (s, J, 1H), 5.75 (s), 3.80-3.66 (m, 6H), 3.63-3.51 (m, 2H), 2.15 (s, 3H)。 515.3 D   
I-254
Figure 02_image803
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)cnc2-c1cnn(C)c1 1H NMR (400 MHz, DMSO-d6)  9.24 (s, 1H), 8.90 (s, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 7.87 (d, 8.7 Hz, 1H), 7.49 (d, 8.8 Hz, 1H), 7.36 (s, 1H), 7.08-7.01 (m, 1H), 7.0-6.90 (m, 2H), 6.64 (s, 1H), 5.88 (s, 1H), 3.91 (s, 3H), 2.33-2.00 (m, 60.5 Hz, 3H)。 510.2 B   
I-255
Figure 02_image805
 Fc1ccc(Cl)c(c1)C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)cnc2N1CCOCC1 1H NMR (400 MHz, CD3OD) 8.16 (s, 1H), 7.74-7.55 (m, 3H), 7.24 (dd, 8.9, 5.0 Hz, 1H), 7.10-6.91 (m, 1H), 6.80-6.61 (bs, 1H), 6.03 (bs, 1H), 3.93-3.71 (m, 6H), 3.71-3.57 (m, 2H), 553.3 D   
I-256
Figure 02_image807
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)C3CCc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  9.87 (s, 0.6H), 9.85 (s, 0.4H), 9.01 (s, 0.4H), 8.98 (s, 0.6H), 7.65-7.53 (m, 2.4H), 7.47 (d, 1.2 Hz, 0.6H), 7.28-7.16 (m, 2.4H), 7.16-7.09 (m, 1.7H), 7.08-6.91 (m, 2H), 6.61 (d, 7.5 Hz, 0.4H), 6.45 (br s, 1.3H), 6.02 (s, 1H), 3.79-3.68 (m, 1H), 2.95-2.82 (m, 1H), 2.81-2.66 (m, 1H), 2.33 (br s, 1H), 2.16 (s, 2H), 2.06-1.94 (m, 1H), 1.94-1.82 (m, 1H)。 383.3 D   
I-257
Figure 02_image809
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nccc(NC(=O)N3CCc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  9.37 (s, 1H), 9.11 (s, 1H), 8.64 (s, 1H), 8.50 (s, 1H), 7.67 (d, 7.7 Hz, 1H), 7.41 (s, 1H), 7.35 (dd, 8.8, 5.2 Hz, 1H), 7.21-7.14 (m, 2H), 7.14-7.07 (m, 1H), 6.92 (t, 7.1 Hz, 1H), 6.72 (br s, 1H), 5.97 (br s, 1H), 3.89-3.75 (m, 1H), 3.25-3.16 (m, 1H), 3.08-2.87 (m, 2H) 423.6 C   
I-258
Figure 02_image811
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3ncn4ccc(Cl)cc34)c12 1H NMR (400 MHz, DMSO-d6)  9.29 (s, 1H), 9.02 (s, 1H), 8.52 (dd, 7.4, 0.8 Hz, 1H), 8.42 (s, 1H), 8.03-7.98 (m, 2H), 7.56 (d, 1.7 Hz, 1H), 7.55 (s, 1H), 7.09-7.02 (m, 2H), 7.01-6.94 (m, 2H), 6.69 (br. s, 1H), 6.15 (s, 1H), 2.35 (br. s, 3H)。 417.2 D   
I-259
Figure 02_image813
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(C3CC3)c12 1H NMR (400 MHz, DMSO-d6)  10.68 (s, 1H), 8.70 (s, 1H), 8.23 (s, 1H), 8.16 (d, 9.2 Hz, 1H), 8.04 (d, 8.5 Hz, 1H), 7.62 (dd, 6.9, 2.1 Hz, 1H), 7.58-7.54 (m, 2H), 4.37 (d, 7.4 Hz, 1H), 0.84-0.74 (m, 1H), 0.42-0.24 (m, 3H), 0.16 (m, 1H)。 379.2 E   
I-260
Figure 02_image815
 Cc1ccccc1C1NC(=O)c2cc(CN)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, CD3OD)  7.89 (s, 1H), 7.67-7.65 (m, 2H), 7.40-7.37 (m, 2H), 7.13 (td, 1.2, 7.7 Hz, 1H), 7.04 (d, 7.5 Hz, 1H), 6.99 (br t, 6.0 Hz, 1H), 6.60 (br s, 1H), 6.05 (s, 1H), 4.29 (br s, 2H), 2.30 (br s, 3H)。 458.3 B   
I-261
Figure 02_image817
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1nsc3ccccc13)ccc2C(=O)NCC(N)=O 1H NMR (400 MHz, DMSO-d6)  10.59 (t, 5.8 Hz, 1H), 10.14 (br s, 1H), 9.66 (s, 1 H), 8.60 (d, 8.1 Hz, 1H), 8.31 (d, 8.2 Hz, 1H), 8.05 (d, 8.3 Hz, 1H), 7.96 (d, 8.3 Hz, 1H), 7.91 (s, 1H), 7.68 (ddd, 8.2, 7.0, 1.2 Hz, 1H), 7.59 (ddd, 8.0, 7.0, 0.9 Hz, 1H), 7.18 (s, 1 H), 7.04-6.97 (m, 2H), 6.97-6.90 (m, 1 H), 6.70 (br s, 1H), 6.22 (s, 1H), 3.90 (d, 6.2 Hz, 2H), 2.35 (br s, 3H)。 500.3 A   
I-262
Figure 02_image819
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)cnc2N 1H NMR (400 MHz, DMSO-d6) 10.03 (s, 1H), 8.83 (s, 1H), 7.90-8.00 (m, 1H), 7.79 (br d,  8.34 Hz, 1H), 7.41-7.52 (m, 1H), 7.36 (s, 1H), 6.97-7.04 (m, 1H), 6.84-6.95 (m, 2H), 6.58-6.75 (m, 3H), 5.73 (s, 1H), 1.97-2.19 (m, 3H) 445.35 B   
I-263
Figure 02_image821
 CC(C)(O)c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1C(F)F 1 H NMR (400 MHz, DMSO-d6 ) δ 10.47 (s, 1 H) 9.10 (s, 1 H) 7.89 (br d,J =8.08 Hz, 1 H) 7.80 (s, 1 H) 7.68 (br d,J =9.09 Hz, 1 H) 7.55 - 7.63 (m, 2 H) 7.47 (dd,J =8.59, 5.56 Hz, 1 H) 7.19 (td,J =8.46, 2.53 Hz, 1 H) 6.44 (br d,J =2.53 Hz, 1 H) 5.95 (s, 1 H) 5.31 (s, 1 H) 1.51 (s, 6 H)。    E   
I-264
Figure 02_image823
 CC(C)(O)c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1C(F)F 1 H NMR (400 MHz, DMSO-d6 ) δ 10.47 (s, 1 H) 9.10 (s, 1 H) 7.89 (br d,J =8.08 Hz, 1 H) 7.80 (s, 1 H) 7.68 (br d,J =9.09 Hz, 1 H) 7.55 - 7.63 (m, 2 H) 7.47 (dd,J =8.59, 5.56 Hz, 1 H) 7.19 (td,J =8.46, 2.53 Hz, 1 H) 6.44 (br d,J =2.53 Hz, 1 H) 5.95 (s, 1 H) 5.31 (s, 1 H) 1.51 (s, 6 H)。    A B
I-265
Figure 02_image825
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)cnc2C(N)=O 1H NMR (400 MHz, DMSO-d6) 10.68 (br s, 1H), 9.47 (s, 1H), 8.79-8.91 (m, 1H), 8.71 (br s, 1H), 7.90 (br d, 6.83 Hz, 1H), 7.70 (br s, 1H), 7.53 (br d, 9.03 Hz, 1H), 7.39 (br s, 1H), 6.94-7.12 (m, 2H), 6.52-6.65 (m, 1H), 5.95 (br s, 1H), 2.07-2.35 (m, 3H) 473.4 B   
I-266
Figure 02_image827
 CC(C)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1ccccc1C 1H NMR (400 MHz, DMSO-d6)  1.29 (d, 6.82 Hz, 6H), 2.17 (br d, 1.26 Hz, 3H), 3.02-3.14 (m, 1H), 5.85 (s, 1H), 6.60 (s, 1H), 6.87-6.99 (m, 2H), 7.01-7.09 (m, 1H), 7.33-7.41 (m, 2H), 7.49 (br d, 8.84 Hz, 1H), 7.55 (d, 1.26 Hz, 1H), 7.87 (br d, 8.59 Hz, 1H), 8.99 (s, 1H), 10.33 (s, 1H) 471.4 B   
I-267
Figure 02_image829
 CC(C)(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(Cl)n3ccccc23)c1)c1cc(F)ccc1C(F)F 1 H NMR (400 MHz, DMSO-d6 ) δ 9.67 (s, 1 H) 9.05 (s, 1 H) 8.15 - 8.28 (m, 2 H) 7.72 (d,J =1.52 Hz, 1 H) 7.62 (d,J =1.52 Hz, 1 H) 7.38 (dd,J =8.72, 5.68 Hz, 1 H) 7.07 - 7.24 (m, 4 H) 7.00 (td,J =6.95, 1.26 Hz, 1 H) 6.39 (br d,J =9.35 Hz, 1 H) 6.08 (s, 1 H) 5.27 (s, 1 H) 1.51 (s, 6 H)。    A   
I-268
Figure 02_image831
 CC(C)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1ccccc1C 1H NMR (400 MHz, DMSO-d6)  0.91 (dd, 6.57, 1.26 Hz, 6H), 1.91 (tt, 13.45, 6.63 Hz, 1H), 2.04-2.24 (m, 2H), 2.51-2.70 (m, 3H), 5.85 (br s, 1H), 6.62 (s, 1H), 6.90-7.07 (m, 3H), 7.30 (s, 1H), 7.36 (br s, 1H), 7.42-7.50 (m, 2H), 7.86 (br d, 8.59 Hz, 1H), 8.98 (s, 1H), 10.30 (s, 1H) 485.4 A   
I-269
Figure 02_image833
 Nc1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)cc2C(=O)NC(c12)c1cc(F)ccc1C(F)F       E   
I-270
Figure 02_image835
 OC(c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)C(F)(F)F 1H NMR (400 MHz, DMSO-d6) 5.44 (dt, 13.07, 6.47 Hz, 1H), 5.97 (br s, 1H), 7.05-7.15 (m, 2H), 7.30 (dd, 8.84, 5.31 Hz, 1H), 7.60-7.68 (m, 2H), 7.74 (br d, 8.59 Hz, 1H), 7.82 (br d, 4.29 Hz, 1H), 7.93 (br d, 8.34 Hz, 1H), 9.19 (br s, 1H), 10.57 (br d, 8.34 Hz, 1H) 565 A   
I-271
Figure 02_image837
 CC(C)(O)c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2[C@H](NC(=O)c2n1)c1cc(F)ccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.86 (s, 1H), 9.46 (s, 1H), 7.97 (d,J = 7.4 Hz, 1H), 7.80 (s, 1H), 7.75 (d,J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.33 (dd,J = 8.9, 5.2 Hz, 1H), 7.17 - 7.02 (m, 1H), 6.77 (br s, 1H), 5.99 (br s, 1H), 5.47 (s, 1H), 1.56 (s, 3H), 1.51 (s, 3H)。 526.4 D   
I-272
Figure 02_image839
 CC(C)(O)c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2[C@@H](NC(=O)c2n1)c1cc(F)ccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.86 (s, 1H), 9.46 (s, 1H), 7.97 (d,J = 7.4 Hz, 1H), 7.80 (s, 1H), 7.75 (d,J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.33 (dd,J = 8.9, 5.2 Hz, 1H), 7.17 - 7.02 (m, 1H), 6.77 (br s, 1H), 5.99 (br s, 1H), 5.47 (s, 1H), 1.56 (s, 3H), 1.51 (s, 3H)。 526.4 B   
I-273
Figure 02_image841
 Nc1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.47 (s, 1H), 9.14 (br s, 1H), 7.94 (br d,J = 8.3 Hz, 1H), 7.67 (br d,J = 8.8 Hz, 1H), 7.56 (s, 1H), 7.31 (dd,J = 8.8, 5.1 Hz, 1H), 7.07 (td,J = 8.1, 2.4 Hz, 1H), 6.76-6.89 (m, 1H), 6.41-6.67 (m, 3H), 5.83 (br s, 1H)。 483.4 B   
I-274
Figure 02_image843
 Fc1ccc(Cl)c(c1)C1(Cl)NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)cnc2N1CC(F)(F)C1 1H NMR (400 MHz, CD3OD)  8.71 (s, 1H), 7.87 (s, 1H), 7.77 (d, 8.6 Hz, 1H), 7.68-7.58 (m, 2H), 7.49-7.32 (m, 1H), 7.14-6.97 (m, 1H), 3.82-3.56 (m, 4H)。 593.1 D   
I-275
Figure 02_image845
 FC(F)CNc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  3.49-3.66 (m, 2H), 5.82 (br s, 1H), 5.98-6.31 (m, 2H), 6.52 (br t, 6.35 Hz, 1H), 6.80 (s, 1H), 6.94 (d,  1.71 Hz, 1H), 7.05 (td, 8.36, 3.05 Hz, 1H), 7.27 (dd, 8.79, 5.13 Hz, 1H), 7.61 (s, 1H), 7.69 (br d, 8.79 Hz, 1H), 7.90 (br d, 8.30 Hz, 1H), 8.92 (br s, 1H), 10.29 (s, 1H) 546.26 A   
I-276
Figure 02_image847
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1nsc3ccccc13)ccc2C(=O)NCC(F)F 1H NMR (400 MHz, DMSO-d6)  11.78 (t, 5.5 Hz, 1H), 10.09 (s, 1H), 9.91 (s, 1H), 8.60 (d, 8.3 Hz, 1H), 8.38 (d, 8.4 Hz, 1H), 8.33-8.29 (m, 1H), 8.08 (d, 8.5 Hz, 1H), 7.68 (ddd, 8.2, 7.0, 1.2 Hz, 1H), 7.59 (ddd, 8.0, 7.0, 0.9 Hz, 1H), 7.05-7.00 (m, 2H), 6.98-6.90 (m, 1H), 6.64 (br s, 1H), 6.26 (s, 1H), 6.23 (tt, 55.7, 3.7 Hz, 1H), 3.85 (tdd, 16.4, 5.5, 4.0 Hz, 2H), 2.29 (br s, 3H)。 507.2 A   
I-277
Figure 02_image849
 Cc1nc(C(=O)Nc2cccc3C(=O)NC(c23)c2ccccc2C)c2cc(Cl)ccn12 1H NMR (400 MHz, DMSO-d6)  9.05 (s, 1H), 9.04 (s, 1H), 8.33 (dd, 7.6, 0.5 Hz, 1H), 8.17 (dd, 7.4, 1.3 Hz, 1H), 7.98 (dd, 2.1, 0.7 Hz), 7.59-7.50 (m, 2H), 7.17 (br. d, 7.4 Hz, 1H), 7.14-7.08 (m, 1H), 7.03 (br. t, 7.2 Hz, 1H), 6.97 (dd, 7.5, 2.1 Hz, 1H), 6.72 (br. s, 1H), 6.12 (s, 1H), 2.61 (s, 3H), 2.45 (br. s, 3H)。 431.3 E   
I-278
Figure 02_image851
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1nsc3ccccc13)ccc2C(O)=O 1H NMR (400 MHz, DMSO-d6)  10.31 (br s, 1H), 8.61 (d, 8.1 Hz, 1 H), 8.31 (d, 8.2 Hz, 1H), 8.28 (d, 8.2 Hz, 1H), 8.10 (d, 8.3 Hz, 1H), 7.68 (ddd, 8.2, 7.0, 1.1 Hz, 1H), 7.63-7.57 (m, 1H), 7.43-7.27 (m), 7.11-7.02 (m , 2 H), 6.96 (d, 6.1 Hz, 1H), 6.85 (br s, 1H), 6.38 (s, 1H), 2.39 (br s, 3H)。 444.2 C   
I-279
Figure 02_image853
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)ccc2Br 1H NMR (400 MHz, DMSO-d6)  10.37 (s, 1H), 9.25 (s, 1H), 7.89 (d, 8.5 Hz, 1H), 7.79 (d, 8.3 Hz, 1 H), 7.46 ( 8.4 Hz, 1H), 7.31 (s, 1H), 7.07 (td, 7.5, 1.2 Hz, 1H), 7.03-6.91 (m, 2H), 6.53 (br s, 1H), 5.87 (s, 1H), 2.22 (br s, 3H)。 507.2 B   
I-280
Figure 02_image855
 CC(O)c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.84 (br s, 1H), 9.41 (s, 1H), 8.08 -7.84 (m, 1H), 7.85-7.70 (m, 2H), 7.67 (s, 1H), 7.34 (dd, 8.8, 5.2 Hz, 1H), 7.09 (td, 8.3, 3.0 Hz, 1H), 6.78 (br s, 1H), 5.98 (s, 1H), 5.61 (br s, 1H), 4.96-4.76 (m, 1H), 1.46 (d, 6.5 Hz, 1.5H), 1.42 (d, 6.6 Hz, 1.5H)。 512.2 B   
I-281
Figure 02_image857
 Cc1ccc(F)cc1C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.47 (s, 1H), 9.11 (s, 1H), 7.92 (d, 8.5 Hz, 1H), 7.70 (m, 1H), 7.65 (t, 7.6 Hz, 1H), 7.60 (d, 8.8 Hz, 1H), 7.52 (dd, 7.7, 1.1 Hz, 1H), 7.45 (s, 1H), 7.02 (dd, 8.5, 6.0 Hz, 1H), 6.89 (td, 8.5, 2.8 Hz, 1H), 6.35 (br s, 1H), 5.85 (s, 1H), 2.01 (br s, 3H)。 445.3 B   
I-282
Figure 02_image859
 Cc1ccccc1C1NC(=O)c2nccc(NC(=O)N3CCc4cccnc34)c12 1H NMR (400 MHz, DMSO-d6)  11.04 (s, 1H), 9.47 (s, 1H), 8.68 (d, 5.9 Hz, 1H), 8.41 (d, 5.6 Hz, 1H), 7.59 (d, 6.4 Hz, 1H), 7.46 (br s, 1H), 7.32 (d, 10.7,1H), 7.17 (t, 7.2 Hz, 1H), 7.01 (t, 7.5 Hz, 1H), 6.88 (dd, 7.1, 5.7 Hz, 1H), 6.56 (br s, 1H), 6.10 (s, 1H), 3.96 (t, 8.6 Hz, 2H), 3.02 (t, 8.6 Hz, 2H), 2.64 (br s, 3H)。 386.3 D   
I-283
Figure 02_image861
 FC(F)c1ccc(F)cc1C1NC(=O)c2ccc(F)c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, CD3CN)  8.53 (s, 1H), 7.83 (dd, 8.4, 4.6 Hz, 1H), 7.64 (d, 8.7 Hz, 1H), 7.59-7.40 (m, 4H), 7.24 (s, 1H), 7.10 (td, 8.9, 2.8 Hz, 1H), 6.62 (s, 1H), 6.02 (s, 1H)。 499.2 C   
I-284
Figure 02_image863
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(NC3CC(F)(F)C3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.49 (br s, 1H), 9.15 (br s, 1H), 7.93 (br s, 1H), 7.68 (d, 8.9 Hz, 1H), 7.58 (br s, 1H), 7.33 (dd, 8.9, 5.1 Hz, 1H), 7.07 (td, 8.4, 3.1 Hz, 1H), 6.85-6.45 (m, 2H), 5.84 (br s, 1H), 4.38-4.15 (m, 1H), 3.13-2.88 (m, 2H), 2.65-2.52 (m, 2H)。 573.2 A   
I-285
Figure 02_image865
 Cc1nc(C(=O)Nc2cccc3C(=O)NC(c23)c2ccccc2C)n2cc(Cl)ccc12 1H NMR (400 MHz, DMSO-d6)  9.60 (s, 1H), 9.24 (dd, 1.7, 0.9 Hz, 1H), 9.04 (s, 1H), 7.94 (dd, 6.1, 2.8 Hz, 1H), 7.86 (dd, 9.5, 0.9 Hz, 1H), 7.61-7.57 (m, 2H), 7.10 (dd, 9.6, 1.7 Hz, 1H), 7.07-7.00 (m, 2H), 6.98-6.92 (m, 1H), 6.69 (br s, 1H), 6.11 (s, 1H), 2.47 (s, 3H), 2.34 (br s, 3H)。 431.2 E   
I-286
Figure 02_image867
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CC(F)(F)C1 1H NMR (400 MHz, DMSO-d6)  10.72 (br s, 1H), 9.30 (br s, 1H), 7.94 (d, 6.5 Hz, 1H), 7.71 (d, 9.0 Hz, 1H), 7.62 (s, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.17-6.97 (m, 1H), 6.94-6.56 (m, 2H), 5.91 (br s, 1H), 4.65-4.33 (m, 4H)。 559.3 A   
I-287
Figure 02_image869
 Fc1ccc(Cl)c(c1)C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)cnc2-c1cn[nH]c1 1H NMR (400 MHz, CD3OD)  8.80 (s, 1H), 8.92-8.44 (bs, 2H), 8.57 (s, 1H), 7.71-7.62 (m, 3H), 7.27 (dd, 8.9, 5.1 Hz, 1H), 6.99 (td, 7.9, 3.0 Hz, 1H), 6.83-6.65 (bs, 1H), 6.30-6.02 (bs, 1H)。 534.2 B   
I-288
Figure 02_image871
 COCCNc1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.49 (s, 1H), 9.14 (s, 1H), 7.95 (d,J = 8.6 Hz, 1H), 7.67 (d,J = 8.7 Hz, 1H), 7.55 (s, 1H), 7.31 (dd,J = 8.9, 5.2 Hz, 1H), 7.21 (br s, 1H), 7.07 (td,J = 8.4, 3.1 Hz, 1H), 6.82 (br s, 1H), 6.65 (s, 1H), 5.82 (br s, 1H), 3.60 - 3.44 (m, 4H), 3.30 (s, 3H)。 541.2 B   
I-289
Figure 02_image873
 Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1C(F)F 1 H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H) 8.89 (s, 1H) 7.88 (br d, J=8.24 Hz, 1H) 7.61 (br d, J=8.85 Hz, 1H) 7.38 - 7.58 (m, 2H) 7.15 (td, J=8.31, 2.29 Hz, 1H) 6.86 (d, J=1.83 Hz, 1H) 6.69 (d, J=1.22 Hz, 1H) 6.50 (br s, 1H) 5.77 (br s, 1H) 5.66 (s, 2H) 498.1 A A
I-290
Figure 02_image875
 CC(C)(O)c1cc2C(=O)NC(c2c(NC(=O)c2coc3c(F)cc(F)cc23)c1)c1cc(F)ccc1C(F)F 1 H NMR (500 MHz, DMSO-d6 ) δ 10.28 (s, 1 H) 9.11 (s, 1 H) 8.46 (s, 1 H) 7.78 (s, 1 H) 7.60 (d,J =1.22 Hz, 1 H) 7.36 - 7.49 (m, 2 H) 7.16 (td,J =8.31, 2.29 Hz, 1 H) 6.42 (br s, 1 H) 6.03 (s, 1 H) 5.31 (s, 1 H) 1.51 (s, 6 H)。    A   
I-291
Figure 02_image877
 CN1CCN(CC1)c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.63 (br s, 1H), 9.22 (br s, 1H), 8.34 (br s, 1H), 7.93 (br d,J = 8.1 Hz, 1H), 7.71 (br d,J = 8.8 Hz, 1H), 7.63 (s, 1H), 7.31 (br dd,J = 8.8, 5.1 Hz, 1H), 7.06 (td,J = 8.3, 2.9 Hz, 1H), 6.92 (br s, 1H), 6.63-6.79 (m, 1H), 5.87 (br s, 1H), 3.47-3.66 (m, 4H), 2.32-2.47 (m,J = 4.6 Hz, 3H), 2.24 (s, 3H)。 566.5 B   
I-292
Figure 02_image879
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3noc4CCCCCc34)c12    402.4 E   
I-293
Figure 02_image881
 CC(C)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  0.71-1.13 (m, 6H), 1.91 (dt, 13.36, 6.62 Hz, 1H), 2.55-2.67 (m, 2H), 5.92 (br s, 1H), 7.07 (td, 8.36, 3.05 Hz, 1H), 7.18-7.37 (m, 2H), 7.47 (s, 1H), 7.65 (s, 1H), 7.72 (br d, 9.03 Hz, 1H), 7.92 (br d, 8.54 Hz, 1H), 9.06 (br s, 1H), 10.44 (s, 1H) 523.4 A   
I-294
Figure 02_image883
 Cc1ccccc1C1NC(=O)Oc2cccc(NC(=O)c3csc4ccccc34)c12       B   
I-295
Figure 02_image885
 Cc1ccccc1C1NC(=O)Nc2cccc(OC(=O)c3csc4ccccc34)c12       D   
I-296
Figure 02_image887
 Clc1ccccc1NC(=O)Nc1ccnc2C(=O)NC(c12)c1ccccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 9.40 (br s, 1H), 9.25 (br s, 1H), 8.65 (br d,J = 5.4 Hz, 1H), 8.47 (br s, 1H), 7.87 (br d,J = 7.8 Hz, 1H), 7.66 (br d,J = 5.1 Hz, 1H), 7.44 (br d,J = 8.1 Hz, 2H), 7.27-7.36 (m, 2H), 7.22 (br t,J = 7.4 Hz, 1H), 7.04-7.11 (m, 1H), 6.81-6.95 (m, 1H), 6.15 (br s, 1H)。 413.3 D   
I-297
Figure 02_image889
 CS(=O)(=O)CC(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO-d6) 2.89-3.11 (m, 3H), 3.56-3.86 (m, 1H), 5.06-5.29 (m, 1H), 5.79-6.06 (m, 1H), 6.12-6.28 (m, 1H), 6.54-6.72 (m, 1H), 7.00-7.21 (m, 1H), 7.26-7.44 (m, 2H), 7.48-7.96 (m, 4H), 8.93-9.42 (m, 2H), 10.18-10.55 (m, 1H) 555 B   
I-298
Figure 02_image891
 CC(C)(O)c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO-d6) 10.3-10.4 (m, 1H), 8.9-9.2 (m, 1H), 7.7-7.8 (m, 1H), 7.6-7.7 (m, 1H), 7.5-7.6 (m, 1H), 7.3-7.5 (m, 3H), 7.1-7.2 (m, 1H), 6.3-6.9 (m, 1H), 5.6-6.2 (m, 1H), 5.2-5.4 (m, 1H), 1.4-1.6 (m, 6H) 492 A A
I-299
Figure 02_image893
 CC(C)(O)c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz DMSO-d6) 10.3-10.4 (m, 1H), 8.9-9.2 (m, 1H), 7.7-7.8 (m, 1H), 7.6-7.7 (m, 1H), 7.5-7.6 (m, 1H), 7.3-7.5 (m, 3H), 7.1-7.2 (m, 1H), 6.3-6.9 (m, 1H), 5.6-6.2 (m, 1H), 5.2-5.4 (m, 1H), 1.4-1.6 (m, 6H) 492 E   
I-300
Figure 02_image895
 C[C@H]1CN(C(=O)Nc2ccnc3C(=O)N[C@H](c23)c2ccccc2C)c2ccccc12 1H NMR (400 MHz, DMSO-d6)  9.31 (s, 2H), 8.78 (br s, 1H), 8.67 (br s, 1H), 8.61 (s, 1H), 8.60 (s, 1H), 7.64 (d, 8.0 Hz, 1H), 7.59 (d, 8.1 Hz, 1H), 7.46 (d, 5.4 Hz, 1H), 7.40 (d, 5.3 Hz, 1H), 7.17-7.05 (m, 6H), 7.03-6.87 (m, 6H), 6.49 (br s, 2H), 5.89 (s, 1H), 5.88 (s, 1H), 3.79-3.65 (m, 2H), 3.25-3.08 (m, 2H), 2.99 (dd, 8.9, 5.9 Hz, 1H), 2.51 (dd, 10.0, 6.7 Hz, 1H), 2.15 (br s, 6H), 1.09 (d, 7.6 Hz, 3H), 1.04 (d, 6.8 Hz, 3H) 398.5 B   
I-301
Figure 02_image897
 C[C@@H]1CN(C(=O)Nc2ccnc3C(=O)N[C@@H](c23)c2ccccc2C)c2ccccc12 1H NMR (400 MHz, DMSO-d6)  9.31 (s, 2H), 8.78 (br s, 1H), 8.67 (br s, 1H), 8.61 (s, 1H), 8.60 (s, 1H), 7.64 (d, 8.0 Hz, 1H), 7.59 (d, 8.1 Hz, 1H), 7.46 (d, 5.4 Hz, 1H), 7.40 (d, 5.3 Hz, 1H), 7.17-7.05 (m, 6H), 7.03-6.87 (m, 6H), 6.49 (br s, 2H), 5.89 (s, 1H), 5.88 (s, 1H), 3.79-3.65 (m, 2H), 3.25-3.08 (m, 2H), 2.99 (dd, 8.9, 5.9 Hz, 1H), 2.51 (dd, 10.0, 6.7 Hz, 1H), 2.15 (br s, 6H), 1.09 (d, 7.6 Hz, 3H), 1.04 (d, 6.8 Hz, 3H) 398.5 C   
I-302
Figure 02_image899
 C[C@H]1CN(C(=O)Nc2ccnc3C(=O)N[C@H](c23)c2ccccc2C)c2ccccc12 1H NMR (400 MHz, DMSO-d6)  9.31 (s, 2H), 8.78 (br s, 1H), 8.67 (br s, 1H), 8.61 (s, 1H), 8.60 (s, 1H), 7.64 (d, 8.0 Hz, 1H), 7.59 (d, 8.1 Hz, 1H), 7.46 (d, 5.4 Hz, 1H), 7.40 (d, 5.3 Hz, 1H), 7.17-7.05 (m, 6H), 7.03-6.87 (m, 6H), 6.49 (br s, 2H), 5.89 (s, 1H), 5.88 (s, 1H), 3.79-3.65 (m, 2H), 3.25-3.08 (m, 2H), 2.99 (dd, 8.9, 5.9 Hz, 1H), 2.51 (dd, 10.0, 6.7 Hz, 1H), 2.15 (br s, 6H), 1.09 (d, 7.6 Hz, 3H), 1.04 (d, 6.8 Hz, 3H) 398.5 C   
I-303
Figure 02_image901
 C[C@@H]1CN(C(=O)Nc2ccnc3C(=O)N[C@H](c23)c2ccccc2C)c2ccccc12 1H NMR (400 MHz, DMSO-d6)  9.31 (s, 2H), 8.78 (br s, 1H), 8.67 (br s, 1H), 8.61 (s, 1H), 8.60 (s, 1H), 7.64 (d, 8.0 Hz, 1H), 7.59 (d, 8.1 Hz, 1H), 7.46 (d, 5.4 Hz, 1H), 7.40 (d, 5.3 Hz, 1H), 7.17-7.05 (m, 6H), 7.03-6.87 (m, 6H), 6.49 (br s, 2H), 5.89 (s, 1H), 5.88 (s, 1H), 3.79-3.65 (m, 2H), 3.25-3.08 (m, 2H), 2.99 (dd, 8.9, 5.9 Hz, 1H), 2.51 (dd, 10.0, 6.7 Hz, 1H), 2.15 (br s, 6H), 1.09 (d, 7.6 Hz, 3H), 1.04 (d, 6.8 Hz, 3H) 398.5 E   
I-304
Figure 02_image903
 CN1CCN(CC1)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  2.87 (br s, 2 H), 3.02-3.25 (m, 3H), 3.53 (br s, 2H), 3.98 (br d, 4.15 Hz, 2H), 5.73 - 6.03 (m, 2H) 6.53 (br s, 1H), 7.00-7.19 (m, 2H), 7.22-7.40 (m, 2H), 7.60-7.80 (m, 2H) 7.95 (br d,  8.30 Hz, 1H) 9.07 (br s, 1H) 9.69 (br s, 1H) 10.41 (s, 1H) 565.36 A   
I-305
Figure 02_image905
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.75 (br s, 1H), 9.46 (s, 1H), 8.75 (d, 4.4 Hz, 1H), 7.94 (d, 7.0 Hz, 1H), 7.73 (d, 9.1 Hz, 1H), 7.64 (s, 1H), 7.58 (s, 1H), 7.35 (dd, 8.9, 5.2 Hz, 1H), 7.10 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 7.02-6.55 (br s, 1H), 6.06-5.92 (br s, 1H) 468.2 B   
I-306
Figure 02_image907
 Cc1ccccc1[C@@H]1NC(=O)c2cc(CO)cc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  10.12 (s, 1H), 9.01 (s, 1H), 8.55 (d, 7.8 Hz, 1H), 8.29 (d, 8.3 Hz, 1H), 7.78 (s, 1H), 7.66 (t, 7.2 Hz, 1H), 7.59 (s, 1H), 7.55 (m, 1H), 7.02-6.95 (m, 2H), 6.91 (t, 6.5 Hz, 1H), 6.68 (br s, 1H), 6.09 (s, 1H), 5.45 (s, 1H), 4.65 (s, 2H), 2.25 (br s, 3H)。 430.3 A   
I-307
Figure 02_image909
 Cc1ccccc1[C@H]1NC(=O)c2cc(CO)cc(NC(=O)c3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  10.12 (s, 1H), 9.02 (s, 1H), 8.56 (d, 8.2 Hz, 1H), 8.29 (d, 8.2 Hz, 1H), 7.78 (d, 0.9 Hz, 1H), 7.67 (ddd, 8.2, 7.0, 1.1 Hz, 1H), 7.60 (s, 1H), 7.57 (t, 7.6 Hz, 1H), 7.02-6.95 (m, 2H), 6.91 (t, 6.6 Hz, 1H), 6.69 (br s, 1H), 6.09 (s, 1H), 5.46 (t, 5.7 Hz, 1H), 4.65 (d, 5.1 Hz, 2H), 2.26 (br s, 3H)。 430.3 D   
I-308
Figure 02_image911
 CC(C)(O)c1cc2C(=O)NC(c2c(NC(=O)N2CCc3ccccc23)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  8.99 (s, 1H), 8.55 (s, 1H), 7.71 (d, 7.9 Hz, 1H), 7.65 (d, 1.4 Hz, 1H), 7.49 (d, 1.4 Hz, 1H), 7.36 (dd, 8.9, 5.2 Hz, 1H), 7.20-7.11 (m, 2H), 7.09 (t, 7.7 Hz, 1H), 6.88 (td, 7.4, 1.0 Hz, 1H), 6.54 (br s, 1H), 5.97 (br s, 1H), 5.25 (br s, 1H), 3.93-3.83 (m, 1H), 3.09-2.93 (m, 3H), 1.49 (s, 6H)。 480.5 A   
I-309
Figure 02_image913
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  9.20 (s, 1H), 8.66 (s, 1H), 7.74-7.64 (m, 2H), 7.59 (s, 1H), 7.37 (dd, 8.8, 5.3 Hz, 1H), 7.22-7.05 (m, 3H), 6.90 (t, 7.4 Hz, 1H), 6.64 (br s, 1H), 5.99 (br s, 1H), 3.80 (dd, 17.2, 9.7 Hz, 1H), 3.27-3.13 (m, 1H), 3.10-2.92 (m, 2H) 500.1 A   
I-310
Figure 02_image915
 CS(=O)(=O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.62 (s, 1H), 9.22 (s, 1H), 7.95 (d, 8.5 Hz, 1H), 7.77 (s, 1H), 7.74 (d, 8.9 Hz, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.4, 3.0 Hz, 1H), 6.65 (br s, 1H), 5.98 (br s, 1H), 4.72 (s, 2H), 2.98 (s, 3H)。 559 A   
I-311
Figure 02_image917
 CN1CC[C@@H](C1)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.28 (s, 1H), 8.91 (br. s, 1H), 7.92 (dt, 8.4及1.6 Hz, 1H), 7.69 (d, 9.4 Hz, 1H), 7.60 (s, 1H), 7.28 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.3, 3.1 Hz, 1H), 6.77 (t, 1.7 Hz, 1H), 6.68 - 6.64 (m, 1H), 6.36 (d, 6.6 Hz, 1H), 5.82 (br. s, 1H), 3.96-3.89 (m, 1H), 2.76-2.72 (m, 1H), 2.64-2.59 (m, 1H), 2.43-2.36 (m, 2H), 2.27 (s, 3H), 2.27-2.20 (m, 1H), 1.67-1.58 (m, 1H)。 565.4 A   
I-312
Figure 02_image919
 CN1CC[C@H](C1)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.27 (s, 1H), 8.91 (br s, 1H), 8.22 (s, 1H), 7.92 (dt, 8.4及1.6 Hz, 1H), 7.69 (d, 9.2 Hz, 1H), 7.60 (s, 1H), 7.28 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.4, 3.0 Hz, 1H), 6.77 (t, 1.7 Hz, 1H), 6.71-6.59 (m, 1H), 6.57 (br. s, 1H), 6.37 (d, 6.6 Hz, 1H), 5.82 (br. s, 1H), 3.98-3.90 (m, 1H), 2.77 (ddd, 9.1, 6.7, 2.4 Hz, 1H), 2.69-2.57 (m, 1H), 2.47-2.39 (m, 2H), 2.28 (s, 3H), 2.27-2.20 (m, 1H), 1.68-1.59 (m, 1H)。 565.3 A   
I-313
Figure 02_image921
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)ccc2C#N 1H NMR (400 MHz, DMSO-d6)  10.64 (br s, 1H), 9.48 (s, 1H), 8.08 (d, 8.1 Hz, 1H), 7.90 (d, 8.3 Hz, 1H), 7.77 (d, 8.0 Hz, 1H), 7.49 - 7.43 (m, 1H), 7.30 (br s, 1H), 7.08 (td, 7.5, 1.2 Hz, 1H), 7.01 (d, 7.2 Hz, 1H), 6.97 (t, 7.3 Hz, 1H), 6.52 (br s, 1H), 5.96 (s, 1H), 2.28 (s, 3 H)。 454.2 B   
I-314
Figure 02_image923
 COC(=O)c1cc2C(=O)NC(c2c(NC(=O)c2nsc3ccccc23)c1)c1ccccc1C 1H NMR (400 MHz, DMSO-d6)  10.28 (s, 1H), 9.29 (s, 1H), 8.62 (d, 8.2 Hz, 1H), 8.45 (d, 1.4 Hz, 1H), 8.31 (dt, 8.2, 0.8 Hz, 1H), 8.13 (d, 1.4 Hz, 1H), 7.68 (ddd, 8.2, 7.0, 1.2 Hz, 1H), 7.59 (ddd, 8.1, 7.0, 1.0 Hz, 1H), 7.02-6.98 (m, 2H), 6.96-6.87 (m, 2H), 6.22 (br s, 1H), 3.94 (s, 3H), 2.26 (br s, 3H)。 458.3 C   
I-315
Figure 02_image925
 Cc1ccccc1C1NC(=O)c2cc(cc(NC(=O)c3nsc4ccccc34)c12)C1(O)CC1 1H NMR (400 MHz, DMSO-d6)  10.13 (s, 1H), 9.00 (s, 1H), 8.56 (d, 8.1 Hz, 1H), 8.28 (dd, 5.0, 4.1 Hz, 1H), 7.66 (ddd, 8.2, 7.0, 1.2 Hz, 1H), 7.64 (d, 1.5 Hz, 1H), 7.57 (ddd, 8.1, 7.0, 1.0 Hz, 1H), 7.49 (d, 1.6 Hz, 1H), 7.01-6.85 (m, 3H), 6.67 (brs, 1H), 6.18 (s, 1H), 6.07 (br s, 1H), 2.23 (br s, 3H), 1.24-1.16 (m, 2H), 1.09-1.03 (m, 2H)。 456.3 A   
I-316
Figure 02_image927
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cc(F)n4ccccc34)c12 1H NMR (400 MHz, CD3CN)  8.09 (d, 9.2 Hz, 1H), 7.93 (d, 7.0 Hz, 1H), 7.88 (d, 7.9 Hz, 1H), 7.66-7.54 (m, 3H), 7.19-7.08 (m, 3H), 7.05 (t, 7.6 Hz, 1H), 6.99 (ddd, 9.3, 6.6, 1.0 Hz, 1H), 6.83 (td, 6.9, 1.2 Hz, 1H), 6.06 (br s, 1H), 5.94 (d, 3.1 Hz, 1H), 2.15 (br s, 3H) 400.1 C   
I-317
Figure 02_image929
 COc1cc(cc(F)c1F)C(=O)Nc1cccc2C(=O)NC(c12)c1ccccc1C 1H NMR (400 MHz, DMSO-d6)  10.14 (s, 1H), 9.05 (s, 1H), 7.67 (dd, 7.4, 1.2 Hz, 1H), 7.61 (t, 7.5 Hz, 1H), 7.53 (dd, 7.7, 1.1 Hz, 1H), 7.10 (td, 7.4, 1.3 Hz, 1H), 7.03 (d, 7.1 Hz, 1H), 7.00-6.96 (m, 2H), 6.94-6.89 (mt, 1H), 6.57 (br. s, 1H), 5.92 (s, 1H), 3.84 (s, 3H), 2.19 (br. s, 3H)。 409.2 C   
I-318
Figure 02_image931
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(OC(F)(F)F)c3)c12 1H NMR (400 MHz, DMSO-d6)  10.29 (s, 1H), 9.06 (s, 1H), 7.68 (dd, 7.5, 1.1 Hz, 1H), 7.61 (t, 7.5 Hz, 1H), 7.61 (mt, 1H, 1H), 7.53 (dd, 7.6, 0.7 Hz, 1H), 7.19 (br. d, 8.6 Hz, 1H), 7.11 (br. s, 1H), 7.07 (td, 7.5, 1.3 Hz, 1H), 7.00 (d, 7.0 Hz, 1H), 6.95 (br. t, 7.2 Hz, 1H), 6.55 (br. s, 1H), 5.90 (s, 1H), 2.19 (br. s, 3H)。 445.2 C   
I-319
Figure 02_image933
 CCCNc1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.45 (br s, 1H), 9.12 (br s, 1H), 7.93 (d, 8.4 Hz, 1H), 7.67 (d, 9.4 Hz, 1H), 7.57 (s, 1H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.11 (br s, 1H), 7.06 (ddd, 8.8, 8.1, 3.1 Hz, 1H), 6.74 (br s, 1H), 6.62 (s, 1H), 5.82 (br s, 1H), 3.28-3.25 (m, 2H), 1.59 (sx, 7.4 Hz, 2H), 0.95 (t, 7.4 Hz, 3H)。 525.2 A   
I-320
Figure 02_image935
 Fc1ccc(Cl)c(c1)C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)cnc2N1CC(F)(F)C1 1H NMR (400 MHz, CD3 CN)  8.46 (br s, 1H), 8.20 (s, 1H), 7.66-7.58 (m, 3H), 7.23 (dd, 8.9, 5.1 Hz, 1H), 7.05 (br s, 1H), 6.98 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.76 (br s, 1H), 6.05 (br s, 1H), 4.80-4.31 (m, 4H)。 559.2 B   
I-321
Figure 02_image937
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(NCC(F)(F)F)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.38 (br s, 1H), 9.22 (s, 1H), 7.93 (d, 8.3 Hz, 1H), 7.73-7.66 (m, 2H), 7.57 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.07 (ddd, 8.7, 8.0, 3.1 Hz, 1H), 6.83 (s, 1H), 6.75 (br s, 1H), 5.85 (br s, 1H), 4.43-4.16 (m, 2H)。 565.1 A   
I-322
Figure 02_image939
 CC1(O)CN(C1)c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.59 (s, 1H), 9.22 (s, 1H), 8.10-7.84 (m, 1H), 7.70 (d, 9.6 Hz, 1H), 7.61 (s, 1H), 7.45-7.22 (m, 1H), 7.07 (t, 7.9 Hz, 1H), 6.71 (br s, 1H), 6.61-6.30 (m, 1H), 5.87 (br s, 1H), 5.66 (s, 1H), 3.94-3.85 (m, 4H), 1.47 (s, 3H)。 553.2 B   
I-323
Figure 02_image941
 Fc1ccc(Cl)c(c1)-n1[nH]c(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  11.43 (br s, 1H), 10.42 (s, 1H), 7.92 (d, 8.1 Hz, 1H), 7.73 (d, 8.0 Hz, 1H), 7.70-7.62 (m, 2H), 7.37 (dd, 8.8, 5.6 Hz, 1H), 7.30 (d, 7.3 Hz, 1H), 7.25 (dd, 9.0, 2.9 Hz, 1H), 7.20 (t, 7.6 Hz, 1H), 6.97 (td, 8.4, 3.0 Hz, 1H)。 466.2 D   
I-324
Figure 02_image943
 COc1cc2CCN(C(=O)Nc3ccnc4C(=O)NC(c34)c3ccccc3C)c2cn1 1H NMR (400 MHz, DMSO-d6)  9.37 (s, 1H), 8.94 (s, 1H), 8.65 (d, 5.4 Hz, 1H), 8.36 (s, 1H), 7.39 (d, 5.4 Hz, 1H), 7.14 (td, 7.6, 1.2 Hz, 1H), 7.03-6.94 (m, 2H), 6.68 (s, 1H), 6.54 (br s, 1H), 5.89 (s, 1H), 3.80 (s, 3H), 3.65-3.55 (m, 1H), 3.02-2.78 (m, 3H), 2.13 (br s, 3H) 416.3 E   
I-325
Figure 02_image945
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1ccccc1Br 1H NMR (400 MHz, DMSO-d6)  10.43 (s, 1H), 9.19 (br s, 1H), 7.92 (d, 8.6 Hz, 1H), 7.74-7.59 (m, 3H), 7.54 (s, 1H), 7.48 (d, 6.7 Hz, 1H), 7.42 (d, 8.6 Hz, 1H), 7.24-7.08 (m, 2H, 6.56 (br s, 1H), 6.15 (br s, 1H)。 493.3 B   
I-326
Figure 02_image947
 CN(C)\C=N\c1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl       E   
I-327
Figure 02_image949
 Cc1cc(F)ccc1C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, CD3CN)  8.52 (s, 1H), 7.74 (dd, 7.5, 1.2 Hz, 1H), 7.64-7.62 (m, 3H), 7.57 (dd, 7.5, 1.2 Hz, 1H), 7.47 (d, 9.1 Hz, 1H), 7.37 (s, 1H), 7.16 (s, 1H), 6.78 (dd, 9.9, 2.1 Hz, 1H), 6.73 (s, 1H), 5.94 (s, 1H), 2.22 (s, 3H)。 445.3 C   
I-328
Figure 02_image951
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3nnc4ccccn34)c12 1H NMR (400 MHz, DMSO-d6)-10.61 (br. s, 1H), 9.07 (dt, 7.0, 1.1 Hz, 1H), 9.05 (s, 1H), 7.98 (dt, 9.3, 1.1 Hz, 1H), 7.69 (dd, 2.7, 1.2 Hz, 1H), 7.67 (dd, 3.0, 1.2 Hz, 1H), 7.64-7.58 (m, 2H), 7.24 (td, 6.9, 1.1 Hz, 1H), 6.93-6.86 (m, 2H), 6.82 (br. s, 1H), 6.66 (br. s, 1H), 6.09 (s, 1H), 2.19 (br. s, 3H)。 384.3 E   
I-329
Figure 02_image953
 C[C@@]1(O)C[C@@H](C1)Nc1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.49 (s, 1H), 9.14 (s, 1H), 7.94 (d, 8.5 Hz, 1H), 7.67 (d, 8.9 Hz, 1H), 7.56 (s, 1H), 7.34 (br s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.4, 3.1 Hz, 1H), 6.68 (br s, 1H), 6.55 (s, 1H), 5.82 (br s, 1H), 5.01 (s, 1H), 4.04-3.77 (m, 1H), 2.40 (dd, 11.0, 7.2 Hz, 2H), 2.03-1.87 (m, 2H), 1.30 (s, 3H)。 567.3 B   
I-330
Figure 02_image955
 FC(F)c1cc(F)c(F)cc1C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.47 (s, 1H), 9.16 (s, 1H), 7.87-8.05 (m, 3H), 7.64-7.77 (m, 2H), 7.42-7.58 (m, 2H), 6.64-7.38 (m, 2H), 5.96 (s, 1H)。 501.4 A   
I-331
Figure 02_image957
 FC(F)c1cc(F)c(F)cc1C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(Cl)c3)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.31 (s, 1H), 9.15 (s, 1H), 7.61-7.79 (m, 3H), 7.47-7.58 (m, 2H), 7.29-7.38 (m, 2H), 6.59-7.24 (m, 2H), 5.90-6.01 (m, 1H)。 467.4 B   
I-332
Figure 02_image959
 FC(F)c1cc(F)c(F)cc1C1NC(=O)c2cccc(NC(=O)c3nsc4ccc(F)cc34)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.36 (s, 1H), 9.20 (s, 1H), 8.37 (br dd,J =4.88, 9.03 Hz, 1H), 8.20 (br dd,J =2.20, 9.52 Hz, 1H), 6.95-7.98 (m, 6H), 6.65-6.91 (m, 1H), 5.97-6.17 (m, 1H)。 490.4 A   
I-333
Figure 02_image961
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(C=O)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1 H NMR (400 MHz, DMSO-d 6 ) δ　10.67 (s, 1H), 10.08-10.21 (m, 1H), 9.26-9.52 (m, 1H), 8.18-8.32 (m, 1H), 7.88-7.89 (m, 1H), 7.84-8.09 (m, 1H), 7.63-7.79 (m, 1H), 7.56-7.82 (m, 1H), 7.25-7.38 (m, 1H), 6.98-7.15 (m, 1H), 5.90-6.23 (m, 2H)。 495.3 A   
I-334
Figure 02_image963
 OC(CN1CC(F)(F)C1)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 500 MHz) 10.3-10.5 (m, 1H), 8.9-9.3 (m, 1H), 8.3-8.5 (m, 1H), 7.6-7.8 (m, 1H), 7.2-7.6 (m, 3H), 7.0-7.2 (m, 1H), 6.5-6.8 (m, 1H), 5.8-6.2 (m, 2H), 5.4-5.6 (m, 1H), 4.4-4.9 (m, 2H), 3.5-3.8 (m, 3H), 2.7-3.0 (m, 2H) 568 B   
I-335
Figure 02_image965
 COc1ncc2C(=O)NC(c2c1NC(=O)c1cc(F)cc(c1)C(F)(F)F)c1ccccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.24 (s, 1H), 9.05 (br s, 1H), 8.54 (s, 1H), 7.91 (br d, 8.30 Hz, 1H), 7.63 (br d, 8.79 Hz, 1H), 7.58 (br s, 1H), 7.19-7.31 (m, 2H), 7.03-7.17 (m, 1H), 6.60 (br s, 1H), 5.87-6.02 (m, 1H), 3.97 (s, 3H) 480.42 E   
I-336
Figure 02_image967
 Cn1cc(cn1)C(=O)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  3.91 (s, 3H), 5.81-6.04 (m, 2H), 7.08 (td, 8.36, 3.05 Hz, 1H), 7.31 (dd, 8.91, 5.25 Hz, 1H), 7.64 (s, 1H), 7.73 (br d, 8.79 Hz, 1H), 7.91-7.99 (m, 2H), 8.03-8.10 (m, 2H), 8.36 (s, 1H), 9.13 (br s, 1H), 10.16 (s, 1H), 10.52 (s, 1H) 590.28 A   
I-337
Figure 02_image969
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cc(ccn3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.07 (s, 1H), 9.08 (s, 1H), 8.83 (d, 7.1 Hz, 1H), 8.14 (s, 1H), 8.06-8.00 (m, 2H), 7.67-7.58 (m, 2H), 7.13-7.02 (m, 2H), 7.01-6.95 (m, 1H), 6.69 (br s, 1H), 6.08 (s, 1H), 2.26 (br s, 3H)。 412.3 E   
I-338
Figure 02_image971
 FC(F)CNc1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.55 (s, 1H), 9.21 (s, 1H), 7.96 (d, 8.1 Hz, 1H), 7.67 (d, 8.9 Hz, 1H), 7.55 (br s,2H), 7.32 (dd, 8.8, 5.2 Hz, 1H), 7.07 (td, 8.5, 3.0 Hz, 1H), 6.75 (s, 1H), 6.72 (br s, 1H), 6.18 (tt, 56.5, 4.0 Hz, 1H), 5.86 (br s, 1H), 4.09-3.55 (m, 2H)。 547.2 A   
I-339
Figure 02_image973
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)ccc2C(N)=O 1H NMR (400 MHz, DMSO-d6)  10.73 (s, 1H), 10.48 (br s, 1H), 9.80 (s, 1H), 8.33 (d, 8.3 Hz, 1H), 7.90 (d, 8.5 Hz, 1H), 7.75 (s, 1H), 7.71 (d, 8.3 Hz,1H), 7.47 (d, 8.6 Hz, 1H), 7.31 (br s, 1H), 7.09 (td, 7.6, 0.9 Hz, 1H), 7.01 (d, 7.3 Hz, 1 H), 6.99-6.93 (m, 1H), 6.47 (br s, 1H), 6.00 (br s, 1H), 2.30 (br s, 3H)。 472.3 B   
I-340
Figure 02_image975
 COc1cc(F)cc(c1)C(=O)Nc1cccc2C(=O)NC(c12)c1ccccc1C 1H NMR (400 MHz, DMSO-d6)  10.07 (s, 1H), 9.04 (s, 1H), 7.65 (dd, 7.4, 1.2 Hz, 1H), 7.60 (t, 7.5 Hz, 1), 7.53 (dd, 7.7, 1.1 Hz, 1H), 7.10 (td, 7.4, 1.4 Hz, 1H), 7.04 (br. d, 7.0 Hz, 1H), 6.99 (t, 2.3 Hz, 1H), 6.98-6.94 (m, 1H), 6.76 (s, 1H), 6.68 (br. d, 8.4 Hz, 1H), 6.56 (br s, 1H), 5.94 (s, 1H), 3.75 (s, 3H), 2.20 (br s, 3H) 391.3 D   
I-341
Figure 02_image977
 COc1cc(F)c(F)c(c1)C(=O)Nc1cccc2C(=O)NC(c12)c1ccccc1C 1H NMR (400 MHz, DMSO-d6)  10.26 (s, 1H), 9.07 (s, 1H), 7.67 (dd, 7.5, 1.0 Hz, 1H), 7.60 (t, 7.6 Hz, 1H), 7.49 (dd, 7.7, 0.5 Hz, 1H), 7.21-7.14 (m, 3H), 7.03 (td, 7.6, 1.6 Hz, 1H), 6.55 (br. s, 1H), 6.02 (s, 1H), 5.97 (s, 1H), 3.69 (s, 3H), 2.26 (br s, 3H) 409.3 E   
I-342
Figure 02_image979
 Cc1nc(C(=O)Nc2cccc3C(=O)NC(c23)c2ccccc2C)n2cc(F)cc(F)c12 1H NMR (400 MHz, DMSO-d6)  9.69 (s, 1H), 9.06 (dd, 5.1, 1.7 Hz, 1H), 9.05 (s, 1H), 7.91 (dd, 7.0, 1.7 Hz, 1H), 7.62-7.56 (m, 2H), 7.30 (ddd, 10.7, 8.8, 1.6 Hz, 1H), 7.07-7.01 (m, 2H), 6.97-6.92 (m, 1H), 6.69 (br s, 1H), 6.10 (s, 1H), 2.55 (s, 3H), 2.32 (br. s, 3H)。 433.3 E   
I-343
Figure 02_image981
 CN1C[C@@H](CC1=O)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.29 (d, 4.0 Hz, 1H), 8.95 (s, 1H), 7.92 (d, 8.6 Hz, 1H), 7.69 (d, 9.3 Hz, 1H), 7.60 (s, 1H), 7.28 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.5, 3.1 Hz, 1H), 6.80 (d, 1.9 Hz, 1H), 6.69 (s, 1H), 6.62 (br. s, 1H), 6.58 (d, 6.2 Hz, 1H), 5.84 (br. s, 1H), 4.19-4.08 (m, 1H), 3.79-3.74 (m, 1H), 3.24-3.16 (m, 1H), 2.79-2.73 (m, 1H), 2.75 (s, 3H), 2.22-2.15 (m, 1H)。 579.3 A   
I-344
Figure 02_image983
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(NC(=O)C3COC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  2.87 (br s, 1H), 3.99 (dt, 14.89, 7.44 Hz, 2H), 4.68-4.81 (m, 2H), 5.84-6.04 (m, 2H), 6.51 (br s, 1H), 7.03-7.13 (m, 1H), 7.30 (br dd, 8.79, 5.13 Hz, 1H), 7.62 (br s, 1H), 7.67-7.76 (m, 1H), 7.82 (br s, 1H), 7.93 (br d, 11.71 Hz, 1H), 9.13 (s, 1H), 10.32 (br s, 1H), 10.50 (br s, 1H) 566.31 A   
I-345
Figure 02_image985
 OCC(=O)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  4.04 (br d, 4.39 Hz, 2H), 5.73 (br s, 1H), 5.79-6.03 (m, 2H), 6.63 (br s, 1H), 7.07 (td, 8.24, 2.81 Hz, 1H), 7.29 (br dd, 8.91, 5.25 Hz, 1H), 7.62 (s, 1H), 7.71 (br d, 9.03 Hz, 1H), 7.83-8.00 (m, 2H), 8.06 (s, 1H), 8.47 (s, 1H), 9.10 (br s, 1H), 10.13(br s, 1H), 10.52 (s, 1H) 540.25 A   
I-346
Figure 02_image987
 COCC(=O)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  2.53 (s, 3H), 4.06 (s, 2H), 5.85-5.96 (m, 1H), 7.07 (br d, 2.68 Hz, 2H), 7.29 (br dd, 8.79, 5.13 Hz, 1 H)7.62 (s, 1H) 7.71 (br d, 9.27 Hz, 1 H), 7.88-7.93 (m, 1H) 8.02 (s, 1 H) 9.01 - 9.21 (m, 2 ) 10.20 (s, 1 H) 10.51 (s, 1 H) 554.31 A   
I-347
Figure 02_image989
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(NC(=O)C3CCOCC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)   1.54 - 1.91 (m, 4H) 2.56 - 2.71 (m, 2H) 3.91 (br d,  11.23 Hz, 2 H) 5.84 - 5.99 (m, 1H) 7.07 (td, 8.30, 2.93 Hz, 1H) 7.29 (br dd,  8.79, 5.13 Hz, 1H) 7.62 (s, 1H) 7.68 - 7.78 (m, 1H) 7.82 (s, 1H) 7.89 - 7.94 (m, 1H) 9.10 (br s, 2H) 10.27 (s, 1H) 10.48 (s, 1H) 594.28 A   
I-348
Figure 02_image991
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CN3CC(F)(F)C3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.33-10.66 (m, 1H), 9.11 (br s, 1H), 8.43 (br s, 1H), 6.17-8.11 (m, 7H), 5.80-6.08 (m, 1H), 3.76-3.99 (m, 1H), 3.58-3.72 (m, 1H), 3.13-3.31 (m, 4H)。 572.2 A   
I-349
Figure 02_image993
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CNC3CC(F)(F)C3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.48 (s, 1H), 9.09 (br s, 1H), 8.33 (s, 1H), 7.40-7.97 (m, 3H), 7.25-7.35 (m, 1H), 7.07 (dt,J = 3.05, 8.36 Hz, 1H), 6.24-6.89 (m, 2H), 5.79-6.10 (m, 1H), 3.77 (s, 1H), 3.01-3.23 (m, 2H), 2.61-2.93 (m, 2H), 2.15-2.44 (m, 2H)。 586.2 A   
I-350
Figure 02_image995
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CN3CCNCC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.49 (br s, 1H), 9.10 (br s, 1H), 8.34 (s, 1H), 6.11-8.09 (m, 6H), 5.68-6.05 (m, 1H), 3.33-3.74 (m, 10H), 2.60-2.85 (m, 1H), 2.24-2.44 (m, 1H)。 565.2 A   
I-351
Figure 02_image997
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(NC(=O)C3CS(=O)(=O)C3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  3.48-3.62 (m, 2H), 4.35-4.49 (m, 3H), 5.92 (br d,  6.35 Hz, 1H), 7.07 (td, 8.30, 2.93 Hz, 1H), 7.30 (br dd, 8.79, 5.13 Hz, 1H), 7.61 (s, 1H), 7.71 (br d, 8.79 Hz, 1H), 7.79 (s, 1H), 7.93 (s, 1H), 9.14 (br s, 3H), 10.51 (s, 1H), 10.64 (s, 1H) 614.34 A   
I-352
Figure 02_image999
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CNC3COC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.47 (br s, 1H), 9.08 (br s, 1H), 8.36 (br d,J =4.88 Hz, 1H), 6.19-8.08 (m, 7H), 5.74-6.11 (m, 1H), 4.45-4.63 (m, 1H), 4.16-4.38 (m, 1H), 3.82-3.99 (m, 1H), 3.66-3.82 (m, 1H), 2.83-3.30 (m, 3H)。 552.1 A   
I-353
Figure 02_image1001
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CN3CCC(F)(F)C3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1 H NMR (400 MHz, DMSO-d6 ) δ 10.33-10.72 (m, 1H), 8.96-9.33 (m, 1H), 8.27-8.55 (m, 1H), 6.32-8.09 (m, 6H), 5.62-6.23 (m, 2H), 3.66-3.90 (m, 1H), 3.12-3.30 (m, 2H), 2.81-3.02 (m, 1H), 2.62-2.81 (m, 1H), 2.13-2.37 (m, 1H), 1.18-1.61 (m, 2H)。 586.2 A   
I-354
Figure 02_image1003
 Fc1cnn(c1)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 9.34 (br s, 1H), 8.68 (br d,J = 3.9 Hz, 1H), 8.59 (br s, 1H), 8.25 (br s, 1H), 7.92 (br d,J = 3.7 Hz, 1H), 7.65-7.84 (m, 3H), 7.41 (br dd,J = 8.7, 5.0 Hz, 1H), 7.12 (td,J = 8.4, 2.9 Hz, 1H), 6.77-6.93 (m, 1H), 6.00 (br s, 1H)。 552.4 B   
I-355
Figure 02_image1005
 CC(C)(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1ccccc1C(F)F 1H NMR (DMSO-d6, 400 MHz)偏移10.4-10.5 (m, 1H), 9.0-9.2 (m, 1H), 7.88 (br d, 1H,  8.3 Hz), 7.78 (d, 1H,  1.2 Hz), 7.5-7.7 (m, 2H), 7.4-7.5 (m, 1H), 7.3-7.4 (m, 2H), 6.5-6.8 (m, 2H), 5.9-6.1 (m, 1H), 5.2-5.4 (m, 1H), 1.4-1.7 (m, 6H) 523 A   
I-356
Figure 02_image1007
 CC(C)(O)c1cc2C(=O)NC(c2c(NC(=O)c2nsc3ccccc23)c1)c1ccccc1C(F)F 1 H NMR (400 MHz, DMSO-d6 ) δ 10.0-10.3 (m, 1H), 9.1-9.2 (m, 1H), 9.0-9.2 (m, 1H), 8.5-8.7 (m, 1H), 8.2-8.4 (m, 1H), 8.1-8.1 (m, 1H), 7.94 (s, 1H), 7.7-7.8 (m, 1H), 7.7-7.7 (m, 1H), 7.6-7.7 (m, 1H), 7.5-7.4 (m, 1H), 7.2-7.3 (m, 1H), 6.7-6.8 (m, 1H), 6.1-6.2 (m, 1H), 5.2-5.4 (m, 1H), 1.4-1.6 (m, 6H)。 494 A   
I-357
Figure 02_image1009
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCC(F)(F)C1 1 H NMR (400 MHz, DMSO-d6 ) δ 10.61-10.73 (m, 1H), 9.08-9.25 (m, 1H), 8.42 (s, 1H), 7.82-7.98 (m, 1H), 7.72 (br d,J = 9.0 Hz, 1H), 7.65 (s, 1H), 7.33 (br dd,J = 8.5, 5.1 Hz, 1H), 7.07 (td,J = 8.3, 2.9 Hz, 1H), 6.62-6.73 (m, 1H), 5.88 (s, 1H), 3.82-4.02 (m, 2H), 3.60-3.77 (m, 2H), 2.54-2.63 (m, 2H)。 573.5 A   
I-358
Figure 02_image1011
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCOCC1 1 H NMR (400 MHz, DMSO-d6 ) δ 10.57-10.72 (m, 1H), 9.16-9.28 (m, 1H), 8.42 (br s, 1H), 7.85-8.00 (m, 1H), 7.71 (br d,J = 8.5 Hz, 1H), 7.65 (br s, 1H), 7.32 (br dd,J = 8.9, 5.2 Hz, 1H), 7.07 (td,J = 8.4, 3.1 Hz, 1H), 6.88-6.99 (m, 1H), 5.88 (br s, 1H), 3.65-3.79 (m, 4H), 3.54 (br s, 4H)。 553.5 A   
I-359
Figure 02_image1013
 OC1CCC(C1)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  1.23 (br s, 1 H) 1.39 (td,  12.45, 5.86 Hz, 1 H) 1.62 (br dd,  14.64, 7.08 Hz, 1 H) 1.73 (br d,  3.66 Hz, 1H) 1.96 (br d,  6.35 Hz, 1 H) 2.28 (br d,  6.59 Hz, 1 H) 3.64 - 3.76 (m, 1 H) 4.12 (br d,  4.88 Hz, 1 H) 4.63 (br d,  2.68 Hz, 1 H) 5.76 - 5.90 (m, 1 H) 6.19 (br d, 6.83 Hz, 1 H) 6.47 - 6.59 (m, 1 H) 6.65 (br s, 1 H) 6.77 (br d, 1.71 Hz, 1 H) 7.05 (td,  8.42, 2.93 Hz, 1 H) 7.26 (br dd,  8.79, 5.13 Hz, 1 H) 7.60 (br s, 1 H) 7.68 (br d,  9.27 Hz, 1 H) 7.90 (br d,  8.05 Hz, 1 H) 8.87 (br s, 1 H) 10.23 (s, 1 H)    A   
I-360
Figure 02_image1015
 FC(F)CCC(=O)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  2.06 - 2.25 (m, 3H) 2.52 - 2.57 (m, 2 H) 5.91 (br d, 9.27 Hz, 2H) 7.07 (td, 8.36, 2.81 Hz, 1H) 7.29 (br dd, 8.91, 5.25 Hz, 1H) 7.61 (s, 1H) 7.71 (br d,8.79 Hz, 1 H) 7.78 (s, 1H) 7.86 - 7.96 (m, 2 H) 9.11 (br s, 1H) 10.40 (s, 1H) 10.49 (s, 1H) 588.22 A   
I-361
Figure 02_image1017
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(NC(=O)C3CCO3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  2.92 - 3.05 (m, 2 H) 4.66 (br t,  7.81 Hz, 2H) 5.13 (ddd, 9.09, 6.41, 2.81 Hz, 1H) 5.86 - 5.97 (m, 1H) 7.08 (br d, 2.68 Hz, 1H) 7.30 (dd, 8.79, 5.13 Hz, 1 H) 7.63 (s, 1H) 7.71 (br d, 9.03 Hz, 1H) 7.91 - 8.00 (m, 2H) 8.09 (br d, 5.12 Hz, 1H) 9.13 (br s, 1H) 10.32 (s, 1H) 10.52 (s, 1H) 566.16 A   
I-362
Figure 02_image1019
 OB(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  5.81 - 6.14 (m, 2H) 6.45 - 6.63 (m, 1H) 6.90 - 7.13 (m, 2H) 7.20 - 7.37 (m, 1 H) 7.57 - 7.78 (m, 2H) 7.84 (s, 1 H) 7.88 - 7.98 (m, 1H) 8.10 - 8.23 (m, 1H) 8.37 - 8.54 (m, 2H) 8.99 - 9.19 (m, 1H) 10.41 - 10.54 (m, 1H) 511 A   
I-363
Figure 02_image1021
 Oc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz) 10.3-10.5 (m, 1H), 10.0-10.2 (m, 1H), 8.9-9.1 (m, 1H), 7.9-8.0 (m, 1H), 7.6-7.8 (m, 1H), 7.5-7.6 (m, 1H), 7.2-7.4 (m, 1H), 7.0-7.1 (m, 1H), 6.8-6.9 (m, 1H), 6.4-6.7 (m, 1H), 6.3-6.8 (m, 1H), 5.5-6.0 (m, 1H) 483 A   
I-364
Figure 02_image1023
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CCCO1 1H NMR (400 MHz, CD3CN)  8.63 (s, 1H), 7.69 (dd, 8.3, 0.8 Hz, 1H), 7.64 (dd, 8.4, 1.6 Hz, 1H), 7.61-7.52 (m, 3H), 7.25 (ddd, 8.9, 5.1, 1.2 Hz, 2H), 7.01-6.92 (m, 1H), 6.62 (br s, 1H), 6.11 (br s, 1H), 5.00 (q, 7.4 Hz, 1H), 4.12-4.04 (m, 1H), 3.95-3.86 (m, 1H), 2.48-2.38 (m, 1H), 2.06-1.97 (m, 2H), 1.84-1.72 (m, 1H)。 537.2 A   
I-365
Figure 02_image1025
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)ccc2P(C)(C)=O 1H NMR (400 MHz, DMSO-d6)  10.48 (br s, 1 H), 9.38 (s, 1 H), 8.17 (dd, 11.6, 8.1 Hz, 1 H), 7.88 (d, 8.5 Hz, 1 H), 7.70 (d, 8.0 Hz, 1 H), 7.44 (d, 8.2 Hz, 1 H), 7.28 (s, 1 H), 7.06 (td, 7.5, 1.2 Hz, 1 H), 7.00 - 6.90 (m, 2 H), 6.47 (br s, 1H), 5.94 (s, 1 H), 2.25 (br s, 3 H), 1.91 (d, 6.9 Hz, 3 H), 1.87 (d, 6.9 Hz, 3 H)。 503.3 D   
I-366
Figure 02_image1027
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CC(F)(F)C1 1 H NMR (400 MHz, DMSO-d6 ) δ 10.72 (br s, 1H), 9.30 (br s, 1H), 7.94 (d,J = 6.5 Hz, 1H), 7.71 (d,J = 9.0 Hz, 1H), 7.62 (s, 1H), 7.34 (dd,J = 8.9, 5.2 Hz, 1H), 7.17 - 6.97 (m, 1H), 6.94 - 6.56 (m, 2H), 5.91 (br s, 1H), 4.65 - 4.33 (m, 4H)。 559.3 A   
I-367
Figure 02_image1029
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CC(F)(F)C1 1 H NMR (400 MHz, DMSO-d6 ) δ 10.72 (br s, 1H), 9.30 (br s, 1H), 7.94 (d,J = 6.5 Hz, 1H), 7.71 (d,J = 9.0 Hz, 1H), 7.62 (s, 1H), 7.34 (dd,J = 8.9, 5.2 Hz, 1H), 7.17 - 6.97 (m, 1H), 6.94 - 6.56 (m, 2H), 5.91 (br s, 1H), 4.65 - 4.33 (m, 4H)。 559.2 D   
I-368
Figure 02_image1031
 CC1(F)CN(C1)c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.64 (s, 1H), 9.27 (s, 1H), 7.96 (d, 8.1 Hz, 1H), 7.70 (d, 8.9 Hz, 1H), 7.60 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.13-7.00 (m, 1H), 6.75 (br s, 1H), 6.53 (s, 1H), 5.89 (s, 1H), 4.27-4.01 (m, 4H), 1.67 (d, 22.2 Hz, 3H)。 555.3 B   
I-369
Figure 02_image1033
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cc(ccc3F)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.42 (s, 1H), 9.09 (s, 1H), 7.90 (mt, 1H), 7.68 (dd, 7.5, 1.0 Hz, 1H), 7.62 (t, 7.6 Hz, 1H), 7.58-7.45 (m, 2H), 7.17 (td, 7.2, 0.8 Hz, 1H), 7.12 (d, 6.8 Hz, 1H), 7.03 (td, 7.6, 1.2 Hz, 1H), 6.76 (s, 1H), 6.56 (br. s, 1H), 5.95 (s, 1H), 2.26 (br. s, 3H)。 429.3 D   
I-370
Figure 02_image1035
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CC(F)(F)C1 1H NMR (400 MHz, CD3CN)  8.55 (s, 1H), 7.66 (d, 8.9 Hz, 1H), 7.60 (d, 8.9 Hz, 1H), 7.57 (s, 1H), 7.27 (dd, 8.9, 5.1 Hz, 1H), 7.18 (s, 1H), 7.01-6.94 (m, 1H), 6.92 (d, 2.2 Hz, 1H), 6.78 (d, 2.2 Hz, 1H), 6.66 (br s, 1H), 6.05 (br s, 1H), 4.37 (t, 12.1 Hz, 4H)。 558.3 A   
I-371
Figure 02_image1037
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1ccc2ccccc2c1 1H NMR (400 MHz, DMSO-d6)  10.35 (s, 1H), 9.18 (s, 1H), 7.84 (d, 8.1 Hz, 1H), 7.78 (d, 8.0 Hz, 1H), 7.72 (dd, 7.2, 0.4 Hz, 1H), 7.70 (d, 8.4 Hz, 1H), 7.66-7.55 (m, 3H), 7.52 (s, 1H), 7.49-7.39 (m, 3H), 7.35 (m, 1H), 6.87 (dd, 8.6, 1.4 Hz, 1H), 5.88 (s, 1H) 465.2 E   
I-372
Figure 02_image1039
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, CD3CN )  8.63 (s, 1H), 7.77 (dd, 7.5, 0.9 Hz, 1H), 7.67-7.52 (m, 5H), 7.25 (dd, 8.9, 5.1 Hz, 2H), 6.97 (ddd, 8.9, 8.0, 3.1 Hz, 1H), 6.62 (br s, 1H), 6.13 (br s, 1H)。 467 A   
I-373
Figure 02_image1041
 COC(=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, d6-DMSO)  10.66 (s, 1H), 9.35 (br s, 1H), 8.13 (dd, 16.4, 1.2 Hz, 2H), 7.96 (d, 8.3 Hz, 1H), 7.76 (d, 8.8 Hz, 1H), 7.68 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.5, 3.1 Hz, 1H), 6.04 (br s, 1H), 3.93 (s, 3H)。 525.3 A   
I-374
Figure 02_image1043
 OC1(CC1)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, CD3CN)  8.61 (s, 1H), 7.67-7.56 (m, 4H), 7.55 (d, 1.6 Hz, 1H), 7.51 (d, 1.3 Hz, 1H), 7.25 (dd, 8.9, 5.1 Hz, 1H), 7.20 (br s, 1H), 6.96 (ddd, 8.9, 8.0, 3.1 Hz, 1H), 6.63 (br s, 1H), 6.09 (s, 1H), 1.30-1.26 (m, 2H), 1.14-1.10 (m, 2H)。 523.4 A   
I-375
Figure 02_image1045
 CN1C[C@H](CC1=O)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, )  10.30 (br. s, 1H), 8.95 (br. s, 1H), 7.93 (d, 8.5 Hz, 1H), 7.69 (d, 9.0 Hz, 1H), 7.60 (s, 1H), 7.28 (dd, 8.7, 5.1 Hz, 1H), 7.07 (td, 8.1, 2.8 Hz, 1H), 6.80 (d, 1.3 Hz, 1H), 6.69 (s, 1H), 6.58 (d, 6.2 Hz, 1H), 5.84 (br. s, 1H), 4.17 - 4.12 (m, 1H), 3.79-3.74 (m, 1H), 3.21 (m, 1H), 2.79-2.73 (m, 1H), 2.75 (s, 3H), 2.25-2.13 (m, 1H) 579.4 A   
I-376
Figure 02_image1047
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3nsc4ccc(Br)cc34)c12    478.3 C   
I-377
Figure 02_image1049
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3nsc4ccc(cc34)C#N)c12    425.4 D   
I-378
Figure 02_image1051
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3nsc4ccc(cc34)-c3ccccc3)c12    476.5 D   
I-379
Figure 02_image1053
 Cn1cc(cn1)-c1cc(NC(=O)c2cc(F)cc(Cl)c2)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.67 (s, 1H), 9.43 (br s, 1H), 8.38 (s, 1H), 8.03 (s, 1H), 7.63-7.76 (m, 2H), 7.27-7.43 (m, 3H), 7.13 (td, 8.4, 3.1 Hz, 1H), 6.79-6.95 (m, 1H), 5.98 (br s, 1H), 3.92 (s, 3H) 514.4 B   
I-380
Figure 02_image1055
 Cc1nn(C)cc1-c1cc(NC(=O)c2cc(F)cc(Cl)c2)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz) 10.65 (br s, 1H), 9.43 (br s, 1H), 8.26 (s, 1H), 7.61-7.75 (m, 2H), 7.29-7.44 (m, 3H), 7.15 (td, 8.4, 3.1 Hz, 1H), 6.81-6.97 (m, 1H), 6.00 (br s, 1H), 3.84 (s, 3H), 3.30 (br s, 3H) 528.4 B   
I-381
Figure 02_image1057
 Cc1c(cnn1C)-c1cc(NC(=O)c2cc(F)cc(Cl)c2)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz) 10.66 (br s, 1H), 9.33-9.45 (m, 1H), 7.90 (br s, 1H), 7.57-7.76 (m, 2H), 7.38 (br d, 8.8 Hz, 3H), 7.13 (td, 8.4, 3.1 Hz, 1H), 6.80-6.90 (m, 1H), 5.98 (s, 1H), 3.81 (s, 3H), 2.70 (s, 3H) 528.4 B   
I-382
Figure 02_image1059
 CC(O)(CO)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz)偏移10.4-10.7 (m, 1H), 8.9-9.2 (m, 1H), 7.8-8.0 (m, 1H), 7.7-7.8 (m, 1H), 7.66 (s, 1H), 7.5-7.6 (m, 1H), 7.2-7.4 (m, 1H), 6.9-7.2 (m, 1H), 6.5-6.7 (m, 1H), 5.8-6.1 (m, 2H), 5.1-5.3 (m, 1H), 4.7-5.0 (m, 1H), 3.4-3.7 (m, 2H), 1.3-1.6 (m, 3H) 541 B   
I-383
Figure 02_image1061
 Oc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  5.43 - 6.14 (m, 2H), 6.82 - 6.95 (m, 1H), 7.00 (d, 1.95 Hz, 1H), 7.10 (td,  8.36, 3.05 Hz, 1H), 7.25 - 7.47 (m, 2H), 7.53 - 7.88 (m, 1 H), 8.82 - 9.39 (m, 2H), 10.00 - 10.41 (m, 2H) 450 A   
I-384
Figure 02_image1063
 Cn1cc(cn1)-c1cc(NC(=O)c2cc(F)cc(Cl)c2)c2[C@H](NC(=O)c2n1)c1cc(F)ccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.67 (s, 1H), 9.43 (br s, 1H), 8.38 (s, 1H), 8.03 (s, 1H), 7.63-7.76 (m, 2H), 7.27-7.43 (m, 3H), 7.13 (td,J = 8.4, 3.1 Hz, 1H), 6.79-6.95 (m, 1H), 5.98 (br s, 1H), 3.92 (s, 3H)。 514.4 D   
I-385
Figure 02_image1065
 OB(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)   5.78 - 6.22 (m, 1H), 6.46-6.65 (m, 1H), 6.93 - 7.22 (m, 1H), 7.25-7.49 (m, 1H), 7.55-7.71 (m, 1H), 7.81 - 7.91 (m, 1H), 8.11 - 8.23 (m, 1H), 8.36 - 8.58 (m, 1H), 8.88 - 9.35 (m, 1H), 10.16 - 10.67 (m, 1H) 478 A   
I-386
Figure 02_image1067
 Cn1cc(cn1)-c1cc(NC(=O)c2cc(F)cc(Cl)c2)c2[C@@H](NC(=O)c2n1)c1cc(F)ccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.67 (s, 1H), 9.43 (br s, 1H), 8.38 (s, 1H), 8.03 (s, 1H), 7.63-7.76 (m, 2H), 7.27-7.43 (m, 3H), 7.13 (td,J = 8.4, 3.1 Hz, 1H), 6.79-6.95 (m, 1H), 5.98 (br s, 1H), 3.92 (s, 3H)。 514.4 A   
I-387
Figure 02_image1069
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (DMSO-d6, 500 MHz) 10.4-10.7 (m, 1H), 9.1-9.4 (m, 1H), 7.9-8.0 (m, 1H), 7.8-7.9 (m, 1H), 7.7-7.8 (m, 2H), 7.6-7.7 (m, 1H), 7.2-7.4 (m, 1H), 7.0-7.1 (m, 1H), 6.3-6.8 (m, 1H), 5.8-6.1 (m, 1H) 546 D   
I-388
Figure 02_image1071
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (DMSO-d6, 500 MHz) 10.4-10.7 (m, 1H), 9.1-9.4 (m, 1H), 7.9-8.0 (m, 1H), 7.8-7.9 (m, 1H), 7.7-7.8 (m, 2H), 7.6-7.7 (m, 1H), 7.2-7.4 (m, 1H), 7.0-7.1 (m, 1H), 6.3-6.8 (m, 1H), 5.8-6.1 (m, 1H) 546 A A
I-389
Figure 02_image1073
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(NC(=O)C3CNC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  3.73 - 3.81 (m, 1H), 3.94 - 4.21 (m, 4H), 5.80 - 6.02 (m, 2H) 6.52 (s, 1H), 7.08 (td,8.36, 2.81 Hz, 1 H), 7.31 (br dd,  8.79, 5.13 Hz, 1 H), 7.61 (s, 1H), 7.67 - 7.80 (m, 2H), 7.90 - 8.03 (m, 2H), 8.46 - 8.56 (m, 1H), 9.15 (br s, 1H), 10.49 (br d,  3.17 Hz, 1H) 565.5 B   
I-390
Figure 02_image1075
 Fc1cccc(c1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.44 (s, 1H), 9.12 (s, 1H), 8.01- 7.93(m, 1H), 7.77-7.72(m, 1H), 7.69 (dd, 7.5, 1.0 Hz, 1H), 7.66 (br s, 1H), 7.61 (t, 7.6 Hz, 1H), 7.54-7.49 (m, 1H), 7.19 (td, 8.0, 6.0 Hz, 1H), 7.07-6.98 (m, 1H), 6.83-6.74 (m, 2H), 5.74 (s, 1H)。 431.3 D   
I-391
Figure 02_image1077
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(Br)c3)c12 1H NMR (400 MHz, DMSO-d6)  10.22 (s, 1H), 9.06 (s, 1H), 7.74 (td, 8.3, 2.0 Hz, 1H), 7.67 (dd, 7.4, 1.1 Hz, 1H), 7.61 (t, 7.5 Hz, 1H), 7.53 (dd, 7.7, 0.9 Hz, 1H), 7.21 -7.14  (m, 2H), 7.10 (dd, 7.4, 1.2 Hz, 1H), 7.04 (d, 7.1 Hz, 1H), 6.98 (t, 7.2 Hz, 1H), 6.54 (br s, 1H), 5.90 (s, 1H), 2.20 (br s, 3H)。 439.2 C   
I-392
Figure 02_image1079
 O=C(Nc1cccc2C(=O)NC(c12)c1ccc2ccccc2c1)c1nsc2ccccc12 1H NMR (400 MHz, DMSO-d6)  10.22 (s, 1H), 9.18 (s, 1H), 8.56 (dt, 8.2, 1.0 Hz, 1H), 8.25 (dt, 8.3, 0.9 Hz, 1H), 7.85 (s, 1H), 7.77 (dd, 7.8, 0.9 Hz, 1H), 7.69 (d, 8.0 Hz, 1H), 7.66-7.60 (m, 3H), 7.57 (t, 7.7 Hz, 1H), 7.50 (ddd, 8.0, 7.0, 1.0 Hz, 1H), 7.39 (d, 8.1 Hz, 1H), 7.33 (ddd, 8.2, 6.9, 1.4 Hz, 1H), 7.26 (ddd, 8.1, 6.9, 1.2 Hz, 1H), 6.93 (dd, 8.5, 1.7 Hz, 1H), 6.09 (s, 1H) 436.3 E   
I-393
Figure 02_image1081
 Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1ccccc1Cl 1H NMR (400 MHz, CD3CN)  8.34 (s, 1H), 7.61 (d, 8.5 Hz, 1H), 7.52-7.44 (m, 3H), 7.28-7.23 (m, 2H), 7.19 (td, 7.6, 1.7 Hz, 1H), 7.12 (t, 7.4 Hz, 1H), 7.06 (s, 1H), 6.99-6.87 (m, 3H), 6.03 (s, 1H)。 464 A   
I-394
Figure 02_image1083
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1ccccc1Cl 1H NMR (400 MHz, CD3CN )  8.62 (br s, 1H), 7.88 (d, 1.7 Hz, 1H), 7.80 (br s, 1H), 7.67-7.61 (m, 1H), 7.53-7.46 (m, 2H), 7.32 (br s, 1H), 7.28 (dd, 8.0, 1.6 Hz, 1H), 7.24-7.19 (m, 1H), 7.12 (br t, 7.0 Hz, 1H), 6.90 (br s, 1H), 6.13 (br s, 1H)。 527 B   
I-395
Figure 02_image1085
 CP(C)(=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  9.29 (br s, 1 H), 8.34 (br s, 1 H), 8.08 (d, 10.5 Hz, 1 H), 7.96 (d, 8.6 Hz, 1 H), 7.91 (d, 11.5 Hz, 1 H), 7.76 (d, 8.8 Hz, 1 H), 7.69 (s, 1 H), 7.32 (dd, 8.9, 5.1 Hz, 1 H), 7.10 (td, 8.5, 3.0 Hz, 1 H), 6.67 (br s, 1H), 6.04 (br s, 1 H), 1.80-1.70 (m, 6H)。 543.3 A   
I-396
Figure 02_image1087
 Cc1ccccc1[C@@H]1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)ccc2C#N 1H NMR (400 MHz, DMSO-d6)  10.64 (br s, 1 H), 9.48 (s, 1 H), 8.08 (d, 8.1 Hz, 1 H), 7.90 (d, 8.3 Hz, 1 H), 7.77 (d, 8.0 Hz, 1 H), 7.49 - 7.43 (m, 1H), 7.30 (br s, 1 H), 7.08 (td, 7.5, 1.2 Hz, 1 H), 7.01 (d, 7.2 Hz, 1 H), 6.97 (t, 7.3 Hz, 1 H), 6.52 (br s, 1 H), 5.96 (s, 1 H), 2.28 (s, 3 H)。 454.3 A   
I-397
Figure 02_image1089
 Cc1ccccc1[C@H]1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)ccc2C#N (400 MHz, DMSO-D6)  10.64 (br s, 1 H), 9.48 (s, 1 H), 8.08 (d, 8.1 Hz, 1 H), 7.90 (d, 8.3 Hz, 1 H), 7.77 (d, 8.0 Hz, 1 H), 7.49 - 7.43 (m, 1 H), 7.30 (br s, 1 H), 7.08 (td, 7.5, 1.2 Hz, 1 H), 7.01 (d, 7.2 Hz, 1 H), 6.97 (t, 7.3 Hz, 1 H), 6.52 (br s, 1 H), 5.96 (s, 1 H), 2.28 (s, 3 H)。 454.3 B   
I-398
Figure 02_image1091
 Cc1ccccc1C1NC(=O)c2cccc(-c3nnc([nH]3)-c3ccccc3)c12 NMR (400 MHz, DMSO-d6)  8.29 (br. s, 1H), 8.02-8.01 (m, 2H), 7.82-7.81 (m, 2H), 7.58 (br. s, 1H), 7.28-7.24 (m, 4H), 7.21-7.15 (m, 4H), 6.67 (br. s, 1H), 2.10 (br. s, 3H) - 0.88-0.82 366.2 E   
I-399
Figure 02_image1093
 OC(=O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)  10.51 (br. s, 1H), 9.11 (s, 1H), 7.93 (dt, 8.5, 1.7 Hz, 1H), 7.73 (br. d, 8.8 Hz, 1H), 7.66 (s, 1H), 7.58 (s, 1H), 7.37 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.5, 3.1 Hz, 1H), 6.58 (br. s, 1H), 5.95 (br. s, 1H), 3.71 (d, AB之A, JAB = 15.9 Hz, 1H), 3.66 (d, AB之B, JAB = 15.6 Hz, 1H)。 525.3 A   
I-400
Figure 02_image1095
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3nnc4ccc(Cl)cn34)c12 1H-NMR (400 MHz, DMSO-d6)  10.70 (s, 1H), 9.08 (dd, 1.9, 0.9 Hz, 1H), 9.05 (s, 1H), 8.06 (dd, 9.7, 1.0 Hz, 1H), 7.71-7.66 (m, 3H), 7.65-7.59 (m, 1H), 6.94-6.86 (m, 2H), 6.85-6.79 (m, 1H), 6.67 (br. s, 1H), 6.07 (s, 1H), 2.18 (br. s, 3H)。 418.3 E   
I-401
Figure 02_image1097
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(Cl)cc(F)c1F 1H NMR (400 MHz, CD3CN )  8.84 (s, 1H), 7.77 (d, 7.5 Hz, 1H), 7.74-7.66 (m, 3H), 7.63 (t, 7.7 Hz, 1H), 7.50 (d, 7.7 Hz, 1H), 7.26-7.15 (m, 2H), 6.89-6.79 (m, 1H), 5.93 (s, 1H)。 485.2 B   
I-402
Figure 02_image1099
 Clc1ccc2occ(C(=O)Nc3cccc4C(=O)NCc34)c2c1       E   
I-403
Figure 02_image1101
 Cn1cc(C(=O)Nc2cccc3C(=O)NCc23)c2ccccc12       E   
I-404
Figure 02_image1103
 O=C(Nc1cccc2C(=O)NCc12)c1csc2CCCCc12       E   
I-405
Figure 02_image1105
 CN1Cc2c(cccc2NC(=O)N2CCc3ccc(C)cc23)C1=O       E   
I-406
Figure 02_image1107
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(NC(=O)C=C)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    536.25 A   
I-407
Figure 02_image1109
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(NC(=O)CCl)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    558.26 A   
I-408
Figure 02_image1111
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cc(F)cc4c(c[nH]c34)C(=O)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)偏移12.68 (br s, 1H), 10.36 (br s, 1H), 9.06 (s, 1H), 8.28 (br s, 1H), 8.01 (br d,  5.86 Hz, 1H), 7.47-7.72 (m, 3H), 6.84-7.06 (m, 3H), 6.44-6.73 (m, 2H), 6.00 (br s, 1H), 1.94-2.28 (m, 3H) 496.28 E   
I-409
Figure 02_image1113
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1ccc(Br)cc1Cl       D   
I-410
Figure 02_image1115
 Cc1nn(C)c(C)c1-c1cc(NC(=O)c2cc(F)cc(Cl)c2)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl    542.4 C   
I-411
Figure 02_image1117
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3n[nH]cc3Br)c12 1H NMR (400 MHz, DMSO-d6)  13.52 - 13.93 (m, 1H), 9.42 (br s, 1H), 8.98 (s, 1H), 8.03 (s, 1H), 7.79 (dd, 7.20, 1.10 Hz, 1H), 7.50 - 7.60 (m, 2H), 7.02 - 7.13 (m, 2H), 6.96 (dt, 7.87, 4.24 Hz, 1H), 6.54 - 6.73 (m, 1H), 6.06 (s, 1H), 2.14 - 2.40 (m, 3H) 411.19 E   
I-412
Figure 02_image1119
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3n[nH]cc3-c3ccccc3)c12 1H NMR (400 MHz, DMSO-d6)  13.43 (br s, 1 H), 9.37 (br s, 1H), 8.97 (s, 1H) 7.99 (s, 1H) 7.85 (br d, 5.37 Hz, 1H) 7.48-7.61 (m, 2 H), 7.43 (br s, 2H) 7.26 - 7.35 (m, 2H) 7.19 - 7.26 (m, 1H) 7.06 - 7.16 (m, 2H) 6.95 - 7.05 (m, 1H) 6.57 - 6.77 (m, 1H) 6.07 (s, 1H) 2.14 - 2.42 (m, 3H) 409.39 E   
I-413
Figure 02_image1121
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3nscc3-c3ccccc3)c12 1H NMR (400 MHz, DMSO-d6)  9.99 (s, 1 H), 9.05 (s, 1 H), 8.98 (s, 1 H), 7.68 (d, 7.32 Hz, 1 H) 7.50 - 7.62 (m, 2 H) 7.29 - 7.38 (m, 3 H), 7.17 - 7.27 (m, 2 H) 7.07 - 7.13 (m, 2 H), 6.97 - 7.04 (m, 1 H), 6.64 (br d,  3.17 Hz, 1 H), 6.03 (s, 1 H), 2.13 - 2.30 (m, 3 H) 426.3 D   
I-414
Figure 02_image1123
 Oc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(Br)ccc1Cl    525 B   
I-415
Figure 02_image1125
 Oc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(O)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  5.81 - 6.28 (m, 2 H), 6.47 - 6.72 (m, 1 H), 6.90 - 7.06 (m, 1 H), 7.17 (s, 1 H), 7.25 - 7.35 (m, 1 H), 7.38 - 7.52 (m, 1 H), 7.54 - 7.90 (m, 1 H), 8.90 - 9.20 (m, 1 H), 9.29 - 9.81 (m, 1 H), 10.09 - 10.38 (m, 1 H) 463 E   
I-416
Figure 02_image1127
 FC(F)(F)c1cc(Br)cc(c1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(Br)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 5.59 - 6.12 (m, 1 H), 6.47 - 6.69 (m, 1 H), 7.16 - 7.29 (m, 1 H), 7.31 - 7.52 (m, 1 H), 7.53 - 7.73 (m, 1 H), 7.75 - 7.86 (m, 1 H), 7.89 - 8.03 (m, 1 H), 8.14 - 8.32 (m, 1 H), 8.79 - 9.36 (m, 1 H), 10.34 - 10.85 (m, 1 H) 589 C   
I-417
Figure 02_image1129
 NC1CN(C1)c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.62 (br s, 1H), 9.23 (s, 1H), 8.25 (s, 1H), 7.95 (d, 8.2 Hz, 1H), 7.71 (d, 8.9 Hz, 1H), 7.61 (s, 1H), 7.32 (dd, 8.8, 5.1 Hz, 1H), 7.07 (td, 8.5, 3.0 Hz, 1H), 6.70 (br s, 1H), 6.46 (s, 1H), 5.88 (s, 1H), 4.22 (d, 8.1 Hz, 2H), 3.95-3.85 (m, 1H), 3.69 (dd, 14.1, 8.4 Hz, 2H)。 538.3 B   
I-418
Figure 02_image1131
 CS(=O)(=O)C1CN(C1)c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.51 (br s, 1H), 9.26 (s, 1H), 8.34 (s, 1H), 7.92 (d, 14.2 Hz, 1H), 7.71 (d, 9.0 Hz, 1H), 7.62 (s, 1H), 7.33 (dd, 8.8, 5.2 Hz, 1H), 7.08 (td, 8.3, 3.0 Hz, 1H), 6.75 (br s, 1H), 6.63 (s, 1H), 5.89 (s, 1H), 4.53-4.41 (m, 1H), 4.36 (q, 8.4 Hz, 2H), 4.24 (td, 8.9, 5.2 Hz, 2H), 3.10 (s, 1H)。 601.1 B   
I-419
Figure 02_image1133
 Cc1ccccc1C1NC(=O)c2cc(cc(NC(=O)c3nsc4ccccc34)c12)C1(O)CCC1 1H NMR (400 MHz, CD3CN)  8.93 (s, 1H), 8.85 (d, 8.1 Hz, 1H), 8.26 (t, 1.5 Hz, 1H), 8.13 (dt, 8.2, 1.0 Hz, 1H), 8.10 (s, 2.8 Hz, 1H), 7.65 (ddd, 7.1, 6.4, 1.3 Hz, 2H), 7.59 (ddd, 8.1, 7.0, 1.1 Hz, 1H), 7.23-7.10 (m, 4H), 7.05 (td, 8.2, 3.5 Hz, 1H), 6.05 (brs, 1H ), 1.01 (t, 6.1 Hz, 1H), 0.90 (t, 7.3 Hz, 1H), 0.82 (dd, 6.4, 1.6 Hz, 4H) 470.3 A   
I-420
Figure 02_image1135
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1COC1 1H NMR (400 MHz, DMSO-d6)   2.07 (s, 3 H) 4.43 (dt,  15.13, 7.32 Hz, 1 H) 4.59 - 4.76 (m, 2 H) 4.98 - 5.04 (m, 1 H) 5.98 (br d,  4.39 Hz, 1 H) 7.09 (td,  8.36, 3.05 Hz, 1 H) 7.31 (br dd,  8.79, 5.13 Hz, 1 H) 7.56 (s, 1 H) 7.65 - 7.78 (m, 2 H) 7.94 (br d,  8.30 Hz, 1 H) 9.15 (br s, 1 H) 10.52 (s, 1 H) 523.25 A   
I-421
Figure 02_image1137
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1ccc(cc1Cl)-c1ccccc1       D   
I-422
Figure 02_image1139
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1ccc(cc1Cl)C#N       E   
I-423
Figure 02_image1141
 CC(=O)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    524.25 A   
I-424
Figure 02_image1143
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1ccc(cc1Cl)C1CC1       D   
I-425
Figure 02_image1145
 Cn1cc(cn1)-c1ccc(C2NC(=O)c3cccc(NC(=O)c4cc(F)cc(c4)C(F)(F)F)c23)c(Cl)c1       E   
I-426
Figure 02_image1147
 CC(C)(CO)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 1.13 - 1.41 (m, 6 H), 4.66 - 4.88 (m, 1 H), 5.79 - 6.13 (m, 1 H), 6.61 - 6.80 (m, 1 H), 6.99 - 7.15 (m, 1 H), 7.18 - 7.35 (m, 1 H), 7.44 - 7.52 (m, 1 H), 7.58 - 7.81 (m, 4 H), 7.87 - 8.01 (m, 1 H), 8.41 - 8.54 (m, 1 H), 8.99 - 9.23 (m, 1 H), 10.39 - 10.63 (m, 1 H) 563 A   
I-427
Figure 02_image1149
 CC(C)(C(O)=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 1.41 - 1.64 (m, 6 H), 5.82 - 6.07 (m, 1 H), 7.02 - 7.14 (m, 1 H), 7.24 - 7.34 (m, 1 H), 7.41 - 7.48 (m, 1 H), 7.60 - 7.67 (m, 2 H), 7.70 - 7.80 (m, 1 H), 7.88 - 7.98 (m, 1 H), 8.32 - 8.45 (m, 1 H),  9.03 - 9.25 (m, 1 H), 10.42 - 10.65 (m, 1 H) 553 B   
I-428
Figure 02_image1151
 Oc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    465 D   
I-429
Figure 02_image1153
 Nc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    464 D   
I-430
Figure 02_image1155
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCC(CC3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  9.19 (s, 1H), 8.68 (s, 1H), 7.59 (d, 1.4 Hz, 1H), 7.50 (d, 1.4 Hz, 1H), 7.48-7.40 (m, 1H), 7.22 (td, 8.4, 3.0 Hz, 1H), 6.55 (br s, 1H), 6.03 (br s, 1H), 3.93 (d, 13.4 Hz, 1H), 3.78 (d, 13.6 Hz, 1H), 2.70 (d, 12.7 Hz, 1H), 2.55-2.38 (m, 2H), 1.72 (d, 12.3 Hz, 1H), 1.64 (d, 12.3 Hz, 1H), 1.25-1.09 (m, 1H), 0.89-0.65 (m, 1H)。 534.2 D   
I-431
Figure 02_image1157
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cccc2ccccc12 1H NMR (400 MHz, DMSO-d6)  10.03 (s, 1H), 8.99 (s, 1H), 8.01 (s, 1H), 7.92 (d, 7.9 Hz, 1H), 7.83-7.77 (m, 2H), 7.75 (d, 8.3 Hz, 2H), 7.68 (m, 1H), 7.63 (t, 7.6 Hz, 1H), 7.48 (d, 7.6 H, 1Hz), 7.39-7.19 (m, 4H), 6.48 (br s, 1H)。 463.3 D   
I-432
Figure 02_image1159
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCCC(C3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  9.20 (s, 2H), 8.80 (s, 1H), 8.77 (s, 1H), 7.57 (s, 1H), 7.57 (s, 1H), 7.54-7.42 (m, 4H), 7.25-7.15 (m, 2H), 6.52 (br s, 2H), 5.98 (br s, 2H), 4.03-3.87 (m, 2H), 3.71 (d, 13.0 Hz, 1H), 3.57 (d, 13.2 Hz, 1H), 2.70-2.54 (m, 2H), 2.36 (t, 12.3 Hz, 1H), 2.10 (br s, 1H), 1.83-1.70 (m, 2H), 1.68-1.11 (m, 7H), 0.6 (br s, 1H)。[非對映異構體之1:1混合物] 534.2 C   
I-433
Figure 02_image1161
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)N3CCCCC3)c12 1H NMR (400 MHz, DMSO-d6)  8.90 (s, 1H), 8.24 (s, 1H), 7.46-7.42 (m, 2H), 7.31 (dd, 6.2, 2.7 Hz, 1H), 7.19-7.12 (m, 2H), 7.07-6.98 (m, 1H), 6.53 (br s, 1H), 5.94 (s, 1H), 3.11-3.00 (m, 2H), 2.97-2.85 (m, 2H), 2.33 (br s, 3H), 1.43-1.32 (m, 2H), 1.28-1.14 (m, 2H), 1.13-0.98 (m, 2H)。 350.3 E   
I-434
Figure 02_image1163
 Cc1ccccc1C1NC(=O)c2c1c(NC(=O)c1nsc3ccccc13)ccc2CCO 1H NMR (400 MHz, DMSO-d6)  10.03 (s, 1 H), 8.96 (s, 1 H), 8.56 (d, 8.1 Hz, 1 H), 8.29 (d, 8.2 Hz, 1 H), 7.69-7.63 (m, 2 H), 7.57 (t, 7.6 Hz, 1 H), 7.39 (d, 8.1 Hz, 1 H), 6.99-6.84 (m, 3 H), 6.68 (br s, 1 H), 6.02 (s, 1 H), 4.69 (s, 1 H), 3.75 - 3.65 (m, 2 H), 3.43-3.22 (m, 2 H), 2.23 (s, 3 H)。 444.3 A   
I-435
Figure 02_image1165
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cccc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  10.29 (s, 1H), 9.05 (s, 1H), 7.87 (d, 7.6 Hz, 1H), 7.74 (d, 8.0 Hz, 1H), 7.69-7.58 (m, 3H), 7.53 (d, 7.8 Hz, 1H), 7.45 (s, 1H), 7.06 (td, 7.2及0.8 Hz, 1H), 6.99-6.93 (m, 2H), 6.55 (br. s, 1H), 5.94 (s, 1H), 2.18 (br. s, 3H)。 411.3 D   
I-436
Figure 02_image1167
 COc1cc(cc(F)c1F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1C(F)F 1H NMR (400 MHz, DMSO-d6)  10.33 (br. s, 1H), 9.32 (s, 1H), 7.84 (d, 1.7 Hz, 1H), 7.76 (d, 1.7 Hz, 1H), 7.53 (dd, 8.7, 5.7 Hz, 1H), 7.24 (td, 8.5, 2.6 Hz, 1H), 7.45-7.00 (1 H浸沒), 7.16-7.10 (m, 2H), 6.55 (br. s, 1H), 6.01 (s, 1H), 3.86 (s, 3H)。 539.2 B   
I-437
Figure 02_image1169
 CC(C)(O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)，呈旋轉異構體之約9:1混合物形式；主要旋轉異構體之分配-´ 10.49 (s, 1H), 9.07 (br. s, 1H), 7.93 (d, 8.6 Hz, 1H), 7.73 (d, 8.9 Hz, 1H), 7.65 (s, 1H), 7.56 (s, 1H), 7.34-7.31 (m, 1H), 7.31-7.28 (m, 1H), 7.09 (td, 8.4, 3.0 Hz, 1H), 6.60 (br. s, 1H), 5.94 (br. s, 1H), 4.47 (br. s, 1H), 2.83 (d, AB之A, JAB = 13.2 Hz, 1H), 2.78 (d, AB之B, JAB = 12.9 Hz), 1.12 (s, 3H), 1.10 (s, 3H)。 539.4 A   
I-438
Figure 02_image1171
 CNC(=O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)  10.52 (br. s, 1H), 9.13 (s, 1H), 8.10 (q, 4.0 Hz, 1H), 7.94 (d, 8.5 Hz, 1H), 7.73 (d, 9.1 Hz, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.37 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.4, 3.1 Hz, 1H), 6.58 (br. s, 1H), 5.95 (br. s, 1H), 3.59 (d, AB之A, JAB = 14.3 Hz, 1H), 3.55 (d, AB之B, JAB = 14.3 Hz, 1H), 2.60 (d, 4.6 Hz, 3H)。 538.3 A   
I-439
Figure 02_image1173
 CC(C)(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1ccccc1Cl NMR (400 MHz, CD3CN)  8.57 (br s, 1H), 7.81 (d, 1.5 Hz, 1H), 7.75 (br s, 1H), 7.67-7.63 (m, 1H), 7.62-7.58 (m, 1H), 7.54 (s, 1H), 7.51 (m, 2H), 7.26 (dd, 8.0, 1.4 Hz, 1H), 7.20 (td, 7.6, 1.7 Hz, 1H)與(s, 1H)重疊, 7.12 (t, 7.0 Hz, 1H), 6.87 (s, 1H), 6.15 (s, 1H), 1.57 (s, 3H), 1.56 (s, 3H)。 507 B   
I-440
Figure 02_image1175
 Fc1ccc(Cl)c(c1)C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)cnc2NC1COC1 NMR (400 MHz, MeOD4)  8.55 (s, 1H), 8.06 (s,1H), 7.74-7.58 (m, 3H), 7.28 (dd, 8.9, 5.1 Hz, 1H), 7.01 (ddd, 8.9, 5.1及3.0 Hz, 1H), 6.74 (br. s,1H), 6.12 (br. s,1H), 5.49 (s, 1H), 5.32-5.18 (m, 1H), 5.02 (td, 6.9, 2.0 Hz, 2H), 4.72 (q, 6.6 Hz, 2H)。 539.3 D   
I-441
Figure 02_image1177
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCC1 NMR (400 MHz, DMSO-d6)  10.57 (br. s, 1H), 9.22 (br. s, 1H), 7.95 (d, 8.6 Hz, 1H), 7.70 (d, 9.0 Hz, 1H), 7.60 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz 1H), 7.10-7.05 (m, 1H), 6.67 (br.s , 1H), 6.45 (br. s, 1H), 5.88 (br. s, 1H), 4.13-3.97 (m, 4H), 2.38 (qt, 8.9, 7.6 Hz, 2H)。 523.2 A   
I-442
Figure 02_image1179
 CC(C)CC1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6 )  10.78 (s, 1H), 8.93 (s, 1H), 8.18 (s, 1H), 8.12 (d, 8.9 Hz, 1H), 8.04 (d, 8.4 Hz, 1H), 7.62-7.50 (m, 3H), 4.81 (d, 9.0 Hz, 1H), 1.73 (m, 1H), 1.68-1.58 (ddd, 13.1, 10.4, 2.1Hz, 1H), 1.10 (ddd, 13.2, 6.4, 2.2 Hz, 1H), 0.78 (d, 6.3 Hz, 3H), 0.72 (d, 6.5 Hz, 3H)。 395.3 D   
I-443
Figure 02_image1181
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CC(C1)C#N 1H NMR (400 MHz, ACN-d3 )  8.62 (s, 1H), 7.66 (d, 8.4 Hz, 1H), 7.55 (d, 8.9 Hz, 1H), 7.52 (s, 1H), 7.42 (s, 1H), 7.31 (dd, 8.9, 5.1 Hz, 1H), 6.99 (td, 8.4, 3.0 Hz, 1H), 6.72 (s, 2H), 6.04 (s, 1H), 4.37 (td, 8.4, 3.9 Hz, 2H), 4.26 (ddd, 8.3, 5.9, 2.7 Hz, 2H), 3.75 (tt, 8.8, 5.9 Hz, 1H)。含有1.2及0.8之油脂及3.4至3.5之痕量雜質。 548.3 A   
I-444
Figure 02_image1183
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(CNCc3ccccc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, CD3CN)  8.10 (s, 1H), 7.76 (s, 1H), 7.66 (d, 8.3 Hz, 1H), 7.59 (d, 13.5 Hz, 3H), 7.41 (d, 7.3 Hz, 2H), 7.36 - 7.25 (m, 4H), 6.99 (td, 8.3, 2.8 Hz, 1H), 6.78 - 6.70 (m, 1 H), 6.15 (s, 1H), 4.08 (s, 2H), 3.89 (s, 2H)。 587.3 B   
I-445
Figure 02_image1185
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3nsc4ccc(cc34)-c3cnn(C)c3)c12    480.5 D   
I-446
Figure 02_image1187
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(Br)ccc1Cl    527 A   
I-447
Figure 02_image1189
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(Br)cc(c3)C(F)(F)F)c12    527 D   
I-448
Figure 02_image1191
 Oc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl    465 C   
I-449
Figure 02_image1193
 Nc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl    464 D   
I-450
Figure 02_image1195
 OB(O)c1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl    493 D   
I-451
Figure 02_image1197
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3ccsn3)c12 1H NMR (400 MHz, DMSO-d6)偏移9.87 (s, 1H), 9.11 (d,  4.64 Hz, 1H), 9.01 (s, 1H), 7.76 (d,  7.32 Hz, 1H), 7.67 (d,  4.64 Hz, 1H), 7.54-7.64 (m, 2H), 6.99-7.07 (m, 2H), 6.89-6.96 (m, 1H), 6.57-6.79 (m, 1H), 6.05 (br s, 1H), 2.10-2.39 (m, 3H) 350.31 E   
I-452
Figure 02_image1199
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3ncsc3Br)c12 1H NMR (400 MHz, DMSO-d6)偏移9.69 (s, 1H), 9.07 (s, 1H), 9.01 (s, 1H), 7.84 (d,  7.08 Hz, 1H), 7.49-7.64 (m, 2H), 7.07 (br d,  4.39 Hz, 2H), 6.92-7.02 (m, 1H), 6.57-6.79 (m, 1H), 6.03 (br s, 1H), 2.03-2.40 (m, 3H) 428.2 D   
I-453
Figure 02_image1201
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cc(Br)sn3)c12 1H NMR (400 MHz, DMSO-d6)偏移9.97 (s, 1H), 9.01 (s, 1H), 7.79 (s, 1H), 7.69 (d,  7.57 Hz, 1H), 7.61-7.66 (m, 1H), 7.54-7.61 (m, 1H), 6.99-7.08 (m, 2H), 6.94 (br t,  7.32 Hz, 1H), 6.50-6.80 (m, 1H), 6.01 (br s, 1H), 2.02-2.40 (m, 3H) 428.25 E   
I-454
Figure 02_image1203
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cc(F)cc4cc[nH]c34)c12 1H NMR (400 MHz, DMSO-d6)偏移11.17 (br s, 1H), 10.06 (s, 1H), 9.03 (s, 1H), 7.64-7.70 (m, 1H), 7.60 (d,  4.39 Hz, 1H), 7.50 (dd,  2.07, 9.40 Hz, 1H), 7.40 (br t,  2.68 Hz, 1H), 7.02-7.09 (m, 1H), 6.97 (br d,  7.32 Hz, 1H), 6.91 (br t,  7.20 Hz, 1H), 6.75 (br d,  9.52 Hz, 1H), 6.57-6.71 (m, 1H), 6.41-6.54 (m, 1H), 6.04 (s, 1H), 1.99-2.25 (m, 3H) 400.33 B   
I-455
Figure 02_image1205
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)-c1cccnc1    511.4 B   
I-456
Figure 02_image1207
 Cn1cc(ccc1=O)-c1cc(NC(=O)c2cc(F)cc(Cl)c2)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl    541.4 A   
I-457
Figure 02_image1209
 Cc1ncc(s1)-c1cc(NC(=O)c2cc(F)cc(Cl)c2)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl    531.3 A   
I-458
Figure 02_image1211
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)-c1ccncc1    511.4 B   
I-459
Figure 02_image1213
 Cc1nc(C)c(s1)-c1cc(NC(=O)c2cc(F)cc(Cl)c2)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl    545.3 A   
I-460
Figure 02_image1215
 Cc1ncc(cn1)-c1cc(NC(=O)c2cc(F)cc(Cl)c2)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl    526.4 B   
I-461
Figure 02_image1217
 CC(=O)Nc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    524.2 A   
I-462
Figure 02_image1219
 CC(=O)Nc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    524.2 D   
I-463
Figure 02_image1221
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3nscc3Br)c12 1H NMR (400 MHz, DMSO-d6)  10.05 (s, 1 H) 9.22 (s, 1 H) 9.01 (s, 1 H) 7.52 - 7.71 (m, 3 H) 7.02 - 7.10 (m, 2 H) 6.91 - 6.98 (m, 1 H) 6.58 -6.78 (m, 1 H) 6.03 (s, 1 H) 2.03 - 2.35 (m, 3 H) 428.2 D   
I-464
Figure 02_image1223
 Cc1ccccc1C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 甲醇-d4)  7.93 (d, 1.7 Hz, 1H), 7.80 (s, 1H), 7.47 (dd, 8.8, 5.0 Hz, 1H), 7.35 (td, 7.5, 1.4 Hz, 1H), 7.25 (d, 7.6 Hz, 1H), 7.22 - 7.09 (m, 2H), 6.74 (d, 7.7 Hz, 2H), 6.26 (s, 1H), 2.27 (s, 3H)。 475.15 E   
I-465
Figure 02_image1225
 COc1ccc(cc1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 甲醇-d4)  7.92 (d, 1.7 Hz, 1H), 7.74 (d, 1.7 Hz, 1H), 7.62 - 7.54 (m, 2H), 7.29 (dd, 8.9, 5.1 Hz, 1H), 7.00 (ddd, 8.9, 7.8, 3.1 Hz, 1H), 6.99 - 6.91 (m, 2H), 6.66 (s, 1H), 6.18 (s, 1H), 3.87 (s, 3H)。 491 E   
I-466
Figure 02_image1227
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccccc3F)c12 1H NMR (400 MHz, 甲醇-d4)  7.94 (d, 1.7 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.56 (dddd, 8.3, 7.2, 5.1, 1.9 Hz, 1H), 7.46 (td, 7.5, 1.9 Hz, 1H), 7.38 (dd, 8.9, 5.1 Hz, 1H), 7.25 (td, 7.6, 1.1 Hz, 1H), 7.17 (ddd, 11.0, 8.4, 1.1 Hz, 1H), 7.08 (ddd, 8.9, 7.8, 3.1 Hz, 1H), 6.71 (s, 1H), 6.22 (s, 1H)。 478.95 E   
I-467
Figure 02_image1229
 FC(F)C(=O)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)   5.93 (br s, 1 H) 6.29 - 6.51 (m, 2 H) 7.08 (td,  8.42, 2.93 Hz, 1 H) 7.30 (br dd,  8.79, 5.13 Hz, 1 H) 7.61 (s, 1 H) 7.71 (br d,  9.03 Hz, 1 H) 7.87 (s, 1 H) 7.93 (br d,  6.35 Hz, 1 H) 8.00 (s, 1 H) 9.19 (br s, 1 H) 10.56 (s, 1 H) 11.11 (s, 1 H) 560.26 A   
I-468
Figure 02_image1231
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(F)c3)c12 1H NMR (400 MHz, DMSO-d6)  10.39 (s, 1H), 9.29 (s, 1H), 7.82 (d, 1.7 Hz, 1H), 7.74 (t, 2.0 Hz, 1H), 7.52 (tt, 9.1, 2.4 Hz, 1H), 7.36 (dd, 8.9, 5.2 Hz, 1H), 7.24 (h, 4.8 Hz, 2H), 7.14 (td, 8.4, 3.1 Hz, 1H), 6.80 (s, 1H), 5.98 (s, 1H)。 495 B   
I-469
Figure 02_image1233
 COc1cccc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  9.79 (s, 1H), 9.27 (s, 1H), 7.87 (s, 1H), 7.75 (d, 1.8 Hz, 1H), 7.53 - 7.45 (m, 1H), 7.45 -7.35 (m, 2H), 7.18 (td, 8.4, 3.1 Hz, 1H), 7.10 (d, 8.4 Hz, 1H), 6.99 (t, 7.5 Hz, 1H), 6.74 (s, 1H), 6.11 (s, 1H), 3.74 (s, 3H)。 489 E   
I-470
Figure 02_image1235
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccccc3)c12 1H NMR (400 MHz, DMSO-d6)  10.22 (s, 1H), 9.27 (s, 1H), 7.80 - 7.73 (m, 2H), 7.55 (d, 8.0 Hz, 3H), 7.44 (t, 7.6 Hz, 2H), 7.35 (dd, 8.9, 5.2 Hz, 1H), 7.12 (td, 8.4, 3.1 Hz, 1H),7.00-6.55 (br,1H), 6.04 (s, 1H)。 459.1 E   
I-471
Figure 02_image1237
 COc1ccccc1C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 9.79 (s, 1H), 9.26 (s, 1H), 7.88 (t, 3.0 Hz, 1H), 7.75 (d, 1.8 Hz, 1H), 7.48 (ddd, 8.6, 7.3, 1.8 Hz, 1H), 7.45-7.34 (m, 2H), 7.18 (td, 8.4, 3.1 Hz, 1H), 7.10 (d, 8.3 Hz, 1H), 6.98 (t, 7.5 Hz, 1H), 6.74 (s, 1H), 6.11 (s, 1H), 3.73 (s, 3H)。 489 E   
I-472
Figure 02_image1239
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2c1C(=O)NS2(=O)=O NMR (400 MHz, DMSO)  12.14 (s, 1H), 8.57 (d, 8.2 Hz, 1H), 8.10-7.98 (m, 3H), 7.76 (t, 7.9 Hz, 1H), 7.58 (d, 7.5 Hz, 1H), 6.44 (br s, 1H)。 387.3 E   
I-473
Figure 02_image1241
 Cc1ccccc1C1NC(=O)c2cc(CO)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO)  10.33 (s, 1H), 9.00 (s, 1H), 7.84 (d, 8.3 Hz, 1H), 7.58 (s, 1H), 7.45 (t, 4.1 Hz, 2H), 7.32 (s, 1H), 7.01 (t, 7.7 Hz, 1H), 6.97-6.86 (m, 2H), 6.51 (br s, 1H), 5.84 (s, 1H), 5.41 (s, 1H), 4.62 (d, 2.4 Hz, 2H), 2.15 (br s, 3H)。 459.1 A   
I-474
Figure 02_image1243
 COc1cc(cc(F)c1N)C(=O)Nc1cc(N)cc2C(=O)NC(c12)c1cc(F)ccc1C(F)F 1H NMR (400 MHz, DMSO-d6)  8.08 (br. d, 7.4 Hz, 1H), 7.96 (ddd, 8.4, 7.0, 1.9 Hz, 1H), 7.85 (dd, 8.7, 5.4 Hz, 1H), 7.74 (s, 1H), 7.46 (td, 8.2, 2.3 Hz, 1H), 7.12 (d, 2.1 Hz, 1H), 7.09 (s, 2H), 7.06 (d, 2.5 Hz, 1H), 7.05 (t, 54.4 Hz, 1H), 6.99 (d, 2.2 Hz, 1H), 7.20-6.8 (2浸沒H), 6.72 (br. s, 2H), 3.97 (s, 3H)。 475.3 E   
I-475
Figure 02_image1245
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cccc(F)c3)c12 1H NMR (400 MHz, DMSO-d6)  10.09 (s, 1H), 9.04 (s, 1H), 7.66 (dd, 7.3, 1.3 Hz, 1H), 7.60 (t, 7.5 Hz, 1H), 7.54 (dd, 7.7, 1.3 Hz, 1H), 7.44 (td, 8.0, 5.9 Hz, 1H), 7.35 (tdd, 8.7, 2.6, 1.0 Hz, 1H), 7.25 (d, 7.6 Hz, 1H), 7.09 (td, 7.4, 1.3 Hz, 1H), 7.03-6.99 (m, 2H), 6.97 (t, 7.5 Hz, 1H), 6.58 (br. s, 1H), 5.95 (s, 1H), 2.18 (br. s, 3H)。 361.3 D   
I-476
Figure 02_image1247
 CN(C)C(=O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)-10.51 (br. s, 1H), 9.12 (s, 1H), 7.94 (d, 8.5 Hz, 1H), 7.73 (d, 9.1 Hz, 1H), 7.65 (s, 1H), 7.56 (s, 1H), 7.33 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.4, 3.1 Hz, 1H), 6.58 (br. s, 1H), 5.95 (br. s, 1H), 3.91 (d, AB之A, JAB = 15.6 Hz, 1H), 3.86 (d, AB之B, JAB = 15.6 Hz, 1H), 3.06 (s, 3H), 2.86 (s, 3H)。含有痕量正己烷(1.27及0.86)及油脂(1.54及1.03)。 552.3 A   
I-477
Figure 02_image1249
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccccc3Cl)c12 1H NMR (400 MHz, DMSO-d6)  10.42 (s, 1H), 9.30 (s, 1H), 7.8-7.75 (m, 2H), 7.55-7.43 (m, 3H), 7.38-7.24 (m, 2H), 6.82 (m, 2H), 6.11 (s, 1H)。 493 E   
I-478
Figure 02_image1251
 O[C@H]1C[C@H](C1)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.26 (br s, 1H), 8.90 (br s, 1H), 7.92 (d, 7.6 Hz, 1H), 7.69 (d, 8.0 Hz, 1H), 7.61 (s, 1H), 7.27 (dd, 8.7, 5.3 Hz, 1H), 7.06 (td, 8.3, 2.8 Hz, 1H), 6.73 (d, 1.7 Hz, 1H), 6.60 (s, 1H), 6.58 (br. s, 1H), 6.43 (d, 6.0 Hz, 1H), 5.82 (br s, 1H), 5.12 (d, 6.2 Hz, 1H), 3.95-3.86 (m, 1H), 3.39-3.30 (m, 1H), 2.75-2.67 (m, 2H), 1.75-1.66 (m, 2H)；2.67及2.33處之DMSO衛星；3.39-3.30處之多重峰與3.30處之水峰重疊。 552.3 A   
I-479
Figure 02_image1253
 Cc1ccccc1C1NC(=O)c2cccc(-c3cc4c(F)cc(F)cc4[nH]3)c12 1H NMR (400 MHz, DMSO-d6 )  11.87 (br. s, 1H), 9.15 (br. s, 1H), 7.87 (d, 7.6 Hz, 1H), 7.79 (d, 7.5 Hz, 1H), 7.71 (t, 7.5 Hz, 1H), 7.02-6.93 (m, 3H), 6.83 (t, 7.4 Hz, 1H), 6.74 (td, 10.2, 1.6 Hz, 1H), 6.46 (s, 1H), 6.43 (s, 1H), 2.36 (br. s, 3H)；2.67及2.33處之DMSO衛星；2.07處之殘餘乙腈；樣品含有18%甲酸鹽(8.51處之峰)。 375.3 D   
I-480
Figure 02_image1255
 NCc1ncc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, MeOD4)  8.68 (s, 1H), 8.54 (br. s, 1H), 7.76-7.65 (m, 3H), 7.31 (dd, 9.0, 5.0 Hz, 1H), 7.04 (ddd, 8.9, 7.9, 3.0 Hz, 1H), 6.76 (br. s, 1H), 6.25 (br. s, 1H), 4.82-4.69 (m, 2H)。 497.1 C   
I-481
Figure 02_image1257
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCCC3)c12 (400 MHz, DMSO-d6)  9.16 (br. s, 1H), 8.20 (s, 1H), 7.58 (d, 1.6 Hz, 1H), 7.49 (d, 1.6 Hz, 1H), 7.47 (br. s, 1H), 7.24 (td, 8.4, 3.0 Hz, 1H), 5.95 (br. s, 1H), 3.18 (m, 2H), 2.77 (m, 2H), 1.78-1.59 (m, 4H)。 452.2 E   
I-482
Figure 02_image1259
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCC(F)(F)C3)c12 (400 MHz, CD3CN)  7.73 (d, 1.5 Hz, 1H), 7.60 (s, 1H), 7.44 (dd, 8.5, 5.2 Hz, 1H), 7.24 (s, 1H), 7.10 (td, 8.5, 3.1 Hz, 1H), 6.76 (s, 1H), 6.08 (s, 1H), 3.59 (q, 13.4 Hz, 1H), 3.46-3.28 (m, 2H), 3.13 (s, 1H), 2.36-2.23 (m, 2H)。 488.2 D   
I-483
Figure 02_image1261
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OS(F)(=O)=O)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 5.73 - 6.32 (m, 1 H),  6.40 - 7.00 (m, 1 H), 7.04 - 7.16 (m, 1 H), 7.27 - 7.40 (m, 1 H), 7.59 - 7.66 (m, 1 H), 7.67 - 7.76 (m, 1 H), 7.77 - 7.85 (m, 1 H), 7.89 - 8.03 (m, 2 H), 9.05 - 9.62 (m, 1 H), 10.50 - 11.01 (m, 1 H) 565 A   
I-484
Figure 02_image1263
 OC(O)(c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)C(F)(F)F 1H NMR (400 MHz, DMSO-d6) 5.77 - 6.12 (m, 2 H), 6.41 - 6.62 (m, 1 H), 6.99 - 7.20 (m, 1 H), 7.25 - 7.46 (m, 2 H), 7.54 - 7.71 (m, 1 H), 7.79 - 7.92 (m, 1 H), 8.05 - 8.22 (m, 1 H), 8.30 - 8.54 (m, 2 H), 8.93 - 9.14 (m, 1 H), 10.28 - 10.43 (m, 1 H) 581 B   
I-485
Figure 02_image1265
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(ccc1Cl)C#N    474.3 E   
I-486
Figure 02_image1267
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(ccc1Cl)-c1ccccc1    525.4 D   
I-487
Figure 02_image1269
 FC(F)C1CN(C1)c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.62 (br s, 1H), 9.26 (br s, 1H), 7.96 (d, 7.9 Hz, 1H), 7.70 (d, 8.9 Hz, 1H), 7.60 (s, 1H), 7.32 (dd, 8.5, 5.1 Hz, 1H), 7.11-7.04 (m, 1H), 6.76 (br s,1 H), 6.50 (s, 1H), 6.42 (td, 56.3, 3.4 Hz, 1H), 5.88 (br s, 1H), 4.17 (q, 8.8 Hz, 1H), 4.00-3.95 (m, 2H), 3.56-3.37 (m, 1H)。 573.3 A   
I-488
Figure 02_image1271
 FC1CN(C1)c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6 )  10.64 (s, 1H), 9.27 (s, 1H), 7.97 (d, 8.2 Hz, 1H), 7.70 (d, 8.8 Hz, 1H), 7.60 (s, 1H), 7.32 (dd, 8.8, 5.1 Hz, 1H), 7.08 (td, 8.5, 3.0 Hz, 1H), 6.75 (br s, 1H), 6.54 (s, 1H), 5.89 (br s, 1H), 5.73-5.34 (m, 1H), 4.55-4.27 (m, 2H), 4.25-3.96 (m, 2H)。 541.1 A   
I-489
Figure 02_image1273
 Cn1cc(cn1)-c1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    529.4 E   
I-490
Figure 02_image1275
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C#N (400 MHz, CD3CN)  8.76 (br s, 1 H), 8.10 (d, 1.2 Hz, 1H), 7.90 (s, 1H), 7.67 (d, 8.4 Hz, 1H), 7.59 (d, 9.0 Hz, 1H), 7.55 (s, 1H), 7.45 (br s, 1H), 7.27 (dd, 8.9, 5.1 Hz, 1H), 6.99 (ddd, 8.8, 8.1, 3.1 Hz, 1H), 6.64 (br s, 1H), 6.18 (br s, 1H)。 490.3 A   
I-491
Figure 02_image1277
 FC1CCCN(C1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN )  7.69 (d, 1.6 Hz, 1H), 7.64-7.54 (m, 1H), 7.44 (dd, 8.2, 5.0 Hz, 1H), 7.23 (d, 1.3 Hz, 1H), 7.15-7.04 (m, 1H), 7.04-6.90 (m, 1H), 6.69 (br s, 1H), 6.06 (s, 1H), 4.72-4.05 (m, 1H), 3.52-2.79 (m, 4H), 1.89-1.68 (m, 2H), 1.67-1.16 (m, 2H)。 484.1 E   
I-492
Figure 02_image1279
 Cc1ccccc1C1NC(=O)c2cccc(NC3(COC3)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  8.92 (s, 1H), 7.69-7.62 (m, 1H), 7.48-7.45 (m, 2H), 7.26-7.23 (m, 2H), 7.20 (d, 7.7 Hz, 1H), 7.16-7.08 (m, 1H), 7.06 (d, 7.3 Hz, 1H), 6.72 (br s, 1H), 6.13 (d, 7.9 Hz, 1H), 5.90 (s, 1H), 5.38 (s, 1H), 5.18 (d, 6.8 Hz, 1H), 4.87 (d, 6.5 Hz, 1H), 4.67 (d, 6.2 Hz, 1H), 4.50 (d, 7.0 Hz, 1H), 2.40-2.27 (br s, 3H)。 457.2 D   
I-493
Figure 02_image1281
 CNC(=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, CD3CN)  8.82 (s, 1H), 8.09 (d, 1.4 Hz, 1H), 8.02 (s, 1H), 7.69 (d, 8.4 Hz 1H), 7.60 (d, 8.9 Hz 1H), 7.58 (s, 1H) 7.37 (s, 1H), 7.26 (dd, 8.9, 5.1 Hz, 1H), 7.26 (br s, 1H),  6.97 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.67 (br s, 1H), 6.16 (br s, 1H), 2.90 (d, 4.7 Hz, 3H)。 524.3 A A
I-494
Figure 02_image1283
 OC(=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, d6-DMSO)  10.64 (br s, 1H), 9.24 (br s,1H), 8.31 (br s, 1H), 8.13 (s, 1H), 8.03 (d, 10.0 Hz, 1H), 7.95 (d, 8.3 Hz, 1H), 7.76 (d, 8.9 Hz, 1H), 7.68 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.0, 2.7 Hz, 1H), 6.04 (br s, 1H)。 509.2 A   
I-495
Figure 02_image1285
 CC(C)(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc3cc[nH]c23)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 11.21 (br s, 1H), 10.21 (s, 1H), 9.06 (br s, 1H), 7.75 (s, 1H), 7.67 (s, 1H), 7.53 (br dd,  2.20, 9.27 Hz, 1H), 7.43 (br t,  2.56 Hz, 1H), 7.27 (br dd,  5.25, 8.91 Hz, 1H), 7.13 (br dd,  2.20, 10.25 Hz, 1H), 7.04 (dt,  2.93, 8.30 Hz, 1H), 6.58-6.76 (m, 1H), 6.45-6.51 (m, 1H), 6.10 (br s, 1H), 5.28 (s, 1H), 1.50 (d,  1.95 Hz, 3H), 0.75-1.19 (m, 3H) 496.38 A   
I-496
Figure 02_image1287
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)-c1cnc(s1)C(F)(F)F    585.4 A   
I-497
Figure 02_image1289
 Cc1ccc(cn1)-c1cc(NC(=O)c2cc(F)cc(Cl)c2)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl    525.4 B   
I-499
Figure 02_image1291
 Cn1ccc(cc1=O)-c1cc(NC(=O)c2cc(F)cc(Cl)c2)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl    541.4 B   
I-500
Figure 02_image1293
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (DMSO-d6, 400 MHz)偏移10.3-10.7 (m, 1H), 8.9-9.3 (m, 1H), 7.93 (br d, 1H,  8.5 Hz), 7.6-7.8 (m, 4H), 7.4-7.5 (m, 1H), 7.2-7.4 (m, 1H), 7.0-7.2 (m, 1H), 6.4-6.8 (m, 1H), 5.7-6.2 (m, 1H) 467.1 A A
I-501
Figure 02_image1295
 COc1cc(C)c(cn1)C(=O)Nc1cccc2C(=O)NC(c12)c1ccccc1C    388 E   
I-502
Figure 02_image1297
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)-c1ccncc1F    529.4 A   
I-503
Figure 02_image1299
 Cc1cnccc1-c1cc(NC(=O)c2cc(F)cc(Cl)c2)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl    525.4 A   
I-504
Figure 02_image1301
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3c[nH]c(=O)c(Br)c3C)c12    452 E   
I-505
Figure 02_image1303
 COc1cnccc1-c1cc(NC(=O)c2cc(F)cc(Cl)c2)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl    541.4 B   
I-506
Figure 02_image1305
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)-c1ccncc1C#N    536.4 A   
I-507
Figure 02_image1307
 NC(=O)c1cnccc1-c1cc(NC(=O)c2cc(F)cc(Cl)c2)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl    554.4 D   
I-508
Figure 02_image1309
 Cc1ccccc1[C@@H]1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)ccc2C(N)=O (400 MHz, DMSO-D6) 10.73 (s, 1 H), 10.48 (br s, 1 H), 9.80 (s, 1 H), 8.33 (d, 8.3 Hz, 1 H), 7.90 (d, 8.5 Hz, 1 H), 7.75 (s, 1 H), 7.71 (d, 8.3 Hz,1 H), 7.47 (d, 8.6 Hz, 1 H), 7.31 (br s, 1 H), 7.09 (td, 7.6, 0.9 Hz, 1 H), 7.01 (d, 7.3 Hz, 1 H), 6.99 - 6.93 (m, 1 H), 6.47 (br s, 1 H), 6.00 (br s, 1 H), 2.30 (br s, 3 H)。 472.3 A   
I-509
Figure 02_image1311
 Cc1ccccc1[C@H]1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)ccc2C(N)=O (400 MHz, DMSO-D6) 10.73 (s, 1 H), 10.48 (br s, 1 H), 9.80 (s, 1 H), 8.33 (d, 8.3 Hz, 1 H), 7.90 (d, 8.5 Hz, 1 H), 7.75 (s, 1 H), 7.71 (d, 8.3 Hz,1 H), 7.47 (d, 8.6 Hz, 1 H), 7.31 (br s, 1 H), 7.09 (td, 7.6, 0.9 Hz, 1 H), 7.01 (d, 7.3 Hz, 1 H), 6.99 - 6.93 (m, 1 H), 6.47 (br s, 1 H), 6.00 (br s, 1 H), 2.30 (br s, 3 H)。 472.3 B   
I-510
Figure 02_image1313
 FC(F)CNC(=O)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)   3.48 - 3.62 (m, 2 H) 5.92 - 6.26 (m, 3 H) 6.70 (br t,  5.86 Hz, 1 H) 7.08 (td,  8.30, 2.93 Hz, 1 H) 7.30 (br dd,  8.79, 5.13 Hz, 1 H) 7.61 (br d,  15.62 Hz, 2 H) 7.68 - 7.79 (m, 2 H) 7.93 (br d,  8.30 Hz, 1 H) 9.07 (br s, 1 H) 9.21 (s, 1 H) 10.46 (s, 1 H) 589.28 A   
I-511
Figure 02_image1315
 OCC(=O)Nc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    540.3 A   
I-512
Figure 02_image1317
 OCC(=O)Nc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    540.3 B   
I-513
Figure 02_image1319
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(NC(=O)N3CC(F)(F)C3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  4.41 (br t,  12.69 Hz, 4 H) 5.90 (br s, 1 H) 6.75 (br s, 1 H) 7.07 (td,  8.36, 3.05 Hz, 1 H) 7.29 (br dd,  8.91, 5.25 Hz, 1 H) 7.62 (br s, 1 H) 7.70 (br s, 1 H) 7.86 (br s, 1 H) 7.92 (br d,  7.57 Hz, 1 H) 8.50 (br s, 1 H) 9.07 (br s, 1 H) 9.26 (br s, 1 H) 10.48 (s, 1 H) 601.33 A   
I-514
Figure 02_image1321
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cccc(OC(F)(F)F)c3)c12 1H NMR (400 MHz, 甲醇-d4)  7.96 (d, 1.7 Hz, 1H), 7.77 - 7.72 (m, 1H), 7.61 (dt, 7.7, 1.5 Hz, 1H), 7.56 (dd, 8.7, 7.7 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.29 (dd, 8.9, 5.1 Hz, 1H), 7.01 (ddd, 8.9, 7.8, 3.1 Hz, 1H), 6.63 (s, 1H), 6.18 (s, 1H)。 541 C   
I-515
Figure 02_image1323
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(ccc3F)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.55 (s, 1H), 9.31 (s, 1H), 8.0 (s, 1H), 7.82 (d, 1.7 Hz, 1H), 7.73 (s, 1H), 7.56 (t, 9.2 Hz, 1H), 7.45 (dd, 8.9, 5.1 Hz, 1H), 7.38 (d, 5.8 Hz, 1H), 7.21 (td, 8.4, 3.1 Hz, 1H),6.67(s, 1H), 6.01 (s, 1H)。 545 D   
I-516
Figure 02_image1325
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccc(F)c(OC(F)(F)F)c3)c12 1H NMR (400 MHz, DMSO-d6)  10.44 (s, 1H), 9.28 (s, 1H), 7.82 (d, 1.8 Hz, 1H), 7.79 - 7.70 (m, 2H), 7.70 (d, 7.4 Hz, 1H), 7.70 - 7.61 (m, 1H), 7.31 (dd, 8.9, 5.1 Hz, 1H), 7.09 (td, 8.4, 3.0 Hz, 1H), 6.73 (s, 1H), 5.97 (s, 1H)。 561 B   
I-517
Figure 02_image1327
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccc(cc3)C#N)c12 1H NMR (400 MHz, DMSO-d6) 10.45 (s, 1H), 9.29 (s, 1H), 7.88 - 7.79 (m, 2H), 7.73 (d, 1.8 Hz, 1H), 7.49 (d, 1.9 Hz, 3H), 7.37 (dd, 8.9, 5.2 Hz, 1H), 7.15 (td, 8.5, 3.1 Hz, 1H), 6.77 (s, 1H), 5.97 (s, 1H)。 484 E   
I-518
Figure 02_image1329
 FC(F)c1ccccc1C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.50 (s, 1H), 9.30 (s, 1H), 7.81 (d, 9.4 Hz, 2H), 7.73 (d, 7.8 Hz, 1H), 7.66 (t, 7.6 Hz, 1H), 7.51 (q, 6.5, 5.6 Hz, 2H), 7.27 (td, 8.5, 3.2 Hz, 1H), 7.14 (s, 1H), 6.79 (d, 7.2 Hz, 2H), 6.04 (s, 1H)。 509 E   
I-519
Figure 02_image1331
 Cc1ccc(cc1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 甲醇-d4) 7.93 (d, 1.7 Hz, 1H), 7.75 (d, 1.7 Hz, 1H), 7.53-7.45 (m, 2H), 7.33-7.21 (m, 3H), 7.00 (ddd, 8.8, 7.7, 3.1 Hz, 1H), 6.66 (s, 1H), 6.18 (s, 1H), 2.41 (s, 3H)。 473 E   
I-520
Figure 02_image1333
 Cc1cccc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 氯仿-d) 8.53 (s, 1H), 7.92 (d, 1.7 Hz, 1H), 7.47 - 7.25 (m, 6H), 7.07 (ddd, 8.9, 7.3, 3.0 Hz, 1H), 6.72 (s, 1H), 6.56 (s, 1H), 6.18 (s, 1H), 2.40 (s, 3H)。 473 D   
I-521
Figure 02_image1335
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(Cl)cc(Cl)c3)c12 1H NMR (400 MHz, DMSO-d6)  10.49 (s, 1H), 9.28 (s, 1H), 7.96 (d, 8.2 Hz, 2H), 7.81 (d, 1.8 Hz, 1H), 7.71 (d, 8.3 Hz, 3H), 7.34 (dd, 8.9, 5.1 Hz, 1H), 7.12 (td, 8.4, 3.1 Hz, 1H), 6.00 (s, 1H)。 527 A   
I-522
Figure 02_image1337
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cccc(c3)C#N)c12 1H NMR (400 MHz, 氯仿-d)  8.52 (s, 1H), 7.97 (d, 1.7 Hz, 1H), 7.93-7.83 (m, 2H), 7.63 (t, 7.8 Hz, 1H), 7.58-7.50 (m, 2H), 7.37 (s, 1H), 7.15 (ddd, 8.9, 7.3, 3.0 Hz, 1H), 6.74 (s, 1H), 6.41 (s, 1H), 6.19 (s, 1H), 0.87 (s, 0H)。 486 D   
I-523
Figure 02_image1339
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccnc(c3)C(F)(F)F)c12 1H NMR (400 MHz, 甲醇-d4) 8.86 (d, 4.9 Hz, 1H), 7.99 (d, 1.7 Hz, 1H), 7.90-7.78 (m, 2H), 7.75 (s, 1H), 7.31 (dd, 8.9, 5.1 Hz, 1H), 7.03 (ddd, 8.9, 7.7, 3.1 Hz, 1H), 6.66 (s, 1H), 6.12 (s, 1H)。 528 E   
I-524
Figure 02_image1341
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccc(OC(F)(F)F)cc3)c12 1H NMR (400 MHz, 甲醇-d4) 7.95 (d, 1.7 Hz, 1H), 7.76-7.66 (m, 3H), 7.38-7.26 (m, 3H), 7.02 (ddd, 8.9, 7.8, 3.0 Hz, 1H), 6.79 (s, 1H), 6.17 (s, 1H)。 541 D   
I-525
Figure 02_image1343
 Fc1ccc(cc1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 甲醇-d4) 7.94 (d, 1.7 Hz, 1H), 7.73 (d, 1.7 Hz, 1H), 7.70-7.61 (m, 2H), 7.30 (dd, 8.9, 5.1 Hz, 1H), 7.22-7.12 (m, 2H), 7.01 (ddd, 8.9, 7.7, 3.0 Hz, 1H), 6.65 (s, 1H), 6.17 (s, 1H)。 477 E   
I-526
Figure 02_image1345
 Fc1cccc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.31 (s, 1H), 9.27 (s, 1H), 7.80 (d, 1.8 Hz, 1H), 7.74 (d, 1.9 Hz, 1H), 7.56 - 7.46 (m, 1H), 7.46 - 7.38 (m, 2H), 7.38 - 7.27 (m, 2H), 7.13 (td, 8.4, 3.1 Hz, 1H), 6.95 - 6.40 (br, 1H),  6.01 (s, 1H)。 476.9 D   
I-527
Figure 02_image1347
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccc(Cl)cc3)c12 1H NMR (400 MHz, 甲醇-d4)7.95 (d, 1.7 Hz, 1H), 7.73 (d, 1.7 Hz, 1H), 7.62-7.54 (m, 2H), 7.50-7.43 (m, 2H), 7.31 (dd, 8.9, 5.1 Hz, 1H), 7.02 (ddd, 8.8, 7.7, 3.0 Hz, 1H), 6.65 (s, 1H), 6.18 (s, 1H)。 492.9 D   
I-528
Figure 02_image1349
 Cc1ccccc1C1NC(=O)c2cc(Br)cc(NC(=O)c3cncc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.22 (br. s, 1H), 9.26 (s, 1H), 9.10 (s, 1H), 8.78 (s, 1H), 7.83 (重疊s, 1H), 7.80 (d, 1.7 Hz, 1H), 7.78 (d, 1.7 Hz, 1H), 7.07 (td, 7.5, 1.3 Hz, 1H), 7.00 (d, 6.8 Hz, 1H), 6.96 (br. t, 7.2 Hz, 1H), 6.57 (br. s, 1H), 5.89 (s, 1H), 2.23 (br. s, 3H)，1.98、1.23及0.85處之10%雜質 488.3 D   
I-529
Figure 02_image1351
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(CCC(F)(F)F)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.61 (br s, 1H), 9.47 (s, 1H), 7.96 (d, 7.8 Hz, 1H), 7.73 (d, 8.5 Hz, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.4, 3.1 Hz, 1H), 6.81 (br s, 1H), 5.97 (br s, 1H), 3.22-3.09 (m, 2H), 2.94-2.70 (m, 2H)。含有5%-10% 564.3 A   
I-530
Figure 02_image1353
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(NC3CCC3(F)F)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.32 (d, 4.5 Hz, 1H), 8.96 (s, 1H), 7.92 (d, 8.4 Hz, 1H), 7.69 (d, 9.2 Hz, 1H), 7.60 (s, 1H), 7.28 (ddd, 8.8, 5.2, 1.7 Hz, 1H), 7.14-7.00 (m, 1H), 6.90 (d, 1.8 Hz, 1H), 6.77 (s, 1H), 6.74 (d, 7.3 Hz, 1H), 6.57 (br s, 1H), 5.82 (br s, 1H), 4.57-4.22 (m, 1H), 2.47-2.32 (m, 2H), 2.31-2.17 (m, 1H), 1.71 (p, 9.9 Hz, 1H)。 572.5 A   
I-531
Figure 02_image1355
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)C#N NMR (400 MHz, DMSO-d6i)  9.42 (s, 1H), 8.10 (s, 1H), 8.03 (s, 1H), 7.69 (d, 8.5 Hz, 1H), 7.44-7.33 (m, 4H), 7.16 (td, 8.3, 2.8 Hz, 1H), 6.77 (br s, 1H), 6.06 (s, 1H)。 458 A   
I-532
Figure 02_image1357
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(NC3CCC3(F)F)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6 )  10.55 (s, 1H), 9.21 (s, 1H), 7.96 (d, 8.3 Hz, 1H), 7.66 (d, 7.8 Hz, 2H), 7.54 (s, 1H), 7.31 (ddd, 8.7, 5.2, 1.9 Hz, 1H), 7.07 (td, 8.4, 3.0 Hz, 1H), 6.77 (br s, 1H), 6.73 (d, 1.9 Hz, 1H), 5.85 (br s, 1H), 5.09 (br s, 1H), 2.54-2.30 (m, 2H), 2.30-2.18 (m, 1H), 1.82-1.57 (m, 1H)。 573.4 A   
I-533
Figure 02_image1359
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CC#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.61 (br. s, 1H), 9.22 (br. s, 1H), 7.95 (d, 7.7 Hz, 1H), 7.74 (d, 8.8 Hz, 1H), 7.70-7.63 (m, 2H), 7.51 (, 1Hs), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.5, 3.1 Hz, 1H), 6.63 (br. s, 1H), 5.98 (br. s, 1H), 4.26 (s, 2H)。部分甲酸鹽(8.47處之峰)。 504.3 A   
I-534
Figure 02_image1361
 Cc1ccccc1C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C3CC3)c12 10.11 (s, 1H), 9.23 (s, 1H), 7.81 (d, 1.7 Hz, 1H), 7.76 (d, 1.7 Hz, 1H), 7.14-7.06 (m, 3H), 6.99 (td, 7.5, 1.3 Hz, 1H), 6.86 (br. d, 9.5 Hz, 1H), 6.74 (s, 1H), 6.55 (br. s, 1H), 5.95 (s, 1H), 2.28 (br. s, 3H), 1.95-1.85 (m, 1H), 1.03-0.95 (m, 2H), 0.71-0.62 (m, 2H),  1.98、1.23及0.85之痕量雜質。 479.3 D   
I-535
Figure 02_image1363
 Cc1ccccc1C1NS(=O)(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO)  10.41 (s, 1H), 8.45 (d, 4.5 Hz, 1H), 7.85 (dt, 8.3及1.6 Hz, 1H), 7.81 (d, 7.6 Hz, 1H), 7.72 (t, 7.7 Hz, 1H), 7.59 (d, 7.4 Hz, 1H), 7.39 (d, 8.8 Hz, 1H), 7.22 (s, 1H), 7.03 (t, 7.3 Hz, 1H), 6.90 - 6.99 (m, 2H), 6.55 (br s, 1H), 5.97 (s, 1H), 2.16 (br. s, 3H)。 465.1 D   
I-536
Figure 02_image1365
 Cc1ccccc1C1NC(=O)c2cc(CF)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO)  10.44 (s, 1H), 9.15 (s, 1H), 7.90 (d, 8.5 Hz, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.49 (d, 9.0 Hz, 1H), 7.36 (s, 1H), 7.07 (t, 7.5 Hz, 1H), 7.00 (d, 7.3 Hz, 1H), 6.95 (t, 7.0 Hz, 1H), 6.59 (br s, 1H), 5.93 (s, 1H), 5.61 (d, 47.4 Hz, 2H), 2.21 (br s, 3H)。 461.2 A   
I-537
Figure 02_image1367
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(N3CCCCC3)c12 NMR (400 MHz, DMSO-d6 )  10.48 (s, 1H), 8.96 (s, 1H), 8.26 (dd, 8.0, 0.7 Hz, 1H), 8.12 (s, 1H), 8.11-8.04 (m, 2H), 7.57 (t, 7.7 Hz, 1H), 7.47 (dd, 7.5, 0.9 Hz, 1H), 5.68 (s, 1H), 2.53 (m, 2H), 2.33-2.24 (m, 2H), 1.38 (m, 4H), 1.35-1.27 (m, 2H) 422.3 E   
I-538
Figure 02_image1369
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCCC(F)(F)C1 (400 MHz, CD3CN)  8.63 (s, 1H), 7.66 (d, 8.9 Hz, 1H), 7.57 (d, 8.5 Hz, 1H), 7.55 (br. s, 1H), 7.39 (br. s, 1H), 7.33-7.27 (m, 1H), 7.10 (s, 1H), 6.98 (td, 8.4, 3.1 Hz, 1H), 6.75 (br. s, 1H), 6.04 (s, 1H), 4.06-3.94 (m, 2H), 3.73-3.65 (m, 2H), 1.91-1.81 (m, 4H)。 587.3 A   
I-539
Figure 02_image1371
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCC(F)(F)CC1 (400 MHz, CD3CN)  8.64 (br. s, 1H), 7.66 (d, 8.4 Hz, 1H), 7.61-7.50 (m, 2H), 7.39 (s, 1H), 7.30 (dd, 8.9, 5.1 Hz, 1H), 7.13 (s, 1H),  6.98 (ddd, 8.9, 8.0, 3.0 Hz, 1H), 6.75 (br. s, 1H), 6.05 (s, 1H), 3.84-3.81 (m, 4 H), 2.10-2.03 (m, 4H)。 587.3 A   
I-540
Figure 02_image1373
 F[C@H]1C[C@@H](C1)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6 )  10.28 br. (s, 1H), 8.94 (br. s, 1H), 7.92 (d, 8.5 Hz, 1H), 7.69 (d, 9.0 Hz, 1H), 7.60 (s, 1H), 7.28 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.4, 3.1 Hz, 1H), 6.70 (d, 2.0 Hz, 1H), 6.61 (s, 1H), 6.58 (d, 4.3 Hz, 1H), 6.74 - 6.42 (1H浸沒), 5.83 (br. s, 1H), 5.38-5.18 (m, 1H), 4.07-4.03 (m, 1H), 2.64-2.54 (m, 2H), 2.37-2.26 (m, 2H) 554.3 A   
I-541
Figure 02_image1375
 F[C@H]1C[C@H](C1)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, )  10.28 (br. s, 1H), 8.93 (br. s, 1H), 7.92 (d, 8.5 Hz, 1H), 7.69 (d, 9.2 Hz, 1H), 7.61 (s, 1H), 7.28 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.4, 3.1 Hz, 1H), 6.75 (d, 2.0 Hz, 1H), 6.63 (d, 1.4 Hz, 1H), 6.55 (d, 6.8 Hz, 1H), 6.74 - 6.42 (1H浸沒), 5.82 (br. s, 1H), 4.92 (dp, 56.2, 6.8 Hz, 1H), 3.53-3.43 (m, 1H), 2.94-2.86 (m, 2H), 2.12-1.96 (m, 2H); 554.2 A   
I-542
Figure 02_image1377
 FC1CCN(C1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN )  7.74-7.60 (m, 2H), 7.47-7.37 (m, 1H), 7.25 (s, 1H), 7.13-7.03 (m, 1H), 6.68 (s, 1H), 6.10 (s, 1H), 5.31-5.08 (m, 1H), 3.65-2.89 (m, 5H), 2.09-2.02 (m, 1H), 1.90-1.80 (m, 1H): 旋轉異構體及非對映異構體+油脂的可能混合物 470.1 E   
I-543
Figure 02_image1379
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCC(C3)C(F)(F)F)c12 NMR (400 MHz, CD3CN )  7.73-7.69 (m, 1H), 7.66 (d, 7.3 Hz, 1H), 7.44 (dd, 8.7, 5.1 Hz, 1H), 7.25 (s,1H), 7.15-7.03 (m, 1H), 6.72 (br s, 1H), 6.67 (d, 14.4 Hz, 1H), 6.20-5.95 (m, 1H), 3.71-3.37 (m, 2H), 3.31-3.14 (m, 1H), 3.12-2.86 (m, 2H), 2.14-2.05 (m, 1H), 2.02-1.96 (m, 1H)。 518.2 D   
I-544
Figure 02_image1381
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCCC(F)(F)C3)c12 NMR (400 MHz, CD3CN)  7.71 (d, 1.7 Hz, 1H), 7.58 (d, 1.6 Hz, 1H), 7.42 (dd, 17.2, 8.7 Hz, 1H), 7.23 (d, 1.6 Hz, 1H), 7.08 (ddd, 8.9, 8.0, 3.1 Hz  1H), 7.03 (s, 1H), 6.71 (br s, 1H), 6.06 (br s, 1H), 3.60-3.46 (m, 1H), 3.46-3.31 (m, 1H), 3.22-3.10 (m, 1H), 3.05-2.91 (m, 1H), 2.13-2.09 (m, 1H), 2.02-1.97 (m, 1H), 1.66-1.45 (m, 2H)。根據NMR之約10%雜質 502.1 D   
I-545
Figure 02_image1383
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(Cl)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    502.3 A   
I-546
Figure 02_image1385
 Cc1ncc(s1)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl    565.4 A   
I-547
Figure 02_image1387
 Cn1cc(ccc1=O)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl    575.5 A   
I-548
Figure 02_image1389
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccncc1F    563.4 A   
I-549
Figure 02_image1391
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccncc1C#N    570.4 A   
I-550
Figure 02_image1393
 Fc1cc(cc(Cl)c1F)C(=O)Nc1ccnc2C(=O)NC(c12)c1ccccc1Cl    434.3 C   
I-551
Figure 02_image1395
 NC1(CC1)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN )  8.73 (s, 1H), 8.27 (d, 1.4 Hz, 1H), 8.12 (s, 1H), 7.66 (dd, 6.8, 1.8 Hz, 1H), 7.64-7.57 (m, 2H), 7.35 (s, 1H), 7.27 (dd, 8.9, 5.1 Hz, 1H), 6.98 (ddd, 8.9, 8.0, 3.1 Hz, 1H), 6.66 (br s, 1H), 6.17 (br s, 1H), 3.15 (qd, 7.1, 0.9 Hz, 2H), 1.19 (t, 7.2 Hz, 4H)。 523.1 A   
I-552
Figure 02_image1397
 CCC(=O)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  1.12 (t,  7.44 Hz, 3 H) 2.29 - 2.45 (m, 2 H) 5.91 (br s, 1 H) 6.83 (br s, 1 H) 7.08 (td,  8.30, 2.93 Hz, 1 H) 7.31 (br dd,  8.91, 5.25 Hz, 1 H) 7.58 - 7.97 (m, 4 H) 8.50 (s, 1 H) 9.10 (br s, 1 H) 10.28 (br s, 1 H) 10.52 (br s, 1 H) 538.25 A   
I-553
Figure 02_image1399
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cncc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  10.70 (br. s, 1H), 9.33 (s, 1H), 8.89 (s, 1H), 8.69 (s, 1H), 7.97 (d, 8.7 Hz, 1H), 7.76 (d, 9.1 Hz, 1H), 7.68 (s, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.16-7.05 (m, 1H), 6.85 (br. s, 1H), 6.02 (br. s, 1H)。 468 A   
I-554
Figure 02_image1401
 CCC(N)(CC)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, CD3CN)  8.65 (br s, 1H), 8.10 (s, 1H), 7.82 (d, 1.6 Hz, 1H), 7.64 (s, 1H), 7.64-7.59 (m, 1H), 7.57 (s, 1H), 7.25 (dd, 8.8, 5.1 Hz, 1H), 7.19 (s, 1H), 6.96 (ddd, 8.8, 7.9, 3.0 Hz, 1H), 6.61 (br s, 1H), 6.09 (br s, 1H), 3.93 (t, 6.0 Hz, 1H), 3.28 (t, 5.9 Hz, 1H), 1.87 (br q, 7.0 Hz, 2H), 1.71 (br q, 7.3 Hz, 2H), 0.73 (td, 7.4, 2.0 Hz, 6H)。 550.4 A   
I-555
Figure 02_image1403
 NC(=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, d6-DMSO)  10.63 (s, 1H), 9.26 (s, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 8.01 (d, 0.9 Hz, 1H), 7.96 (d, 8.5 Hz, 1H), 7.75 (d, 9.1 Hz, 1H), 7.68 (s, 1H), 7.59 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (ddd, 8.8, 3.2, 3.2 Hz, 1H), 6.02 (br s, 1H)。 510.2 A   
I-556
Figure 02_image1405
 CCOc1cc(ccc1F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 甲醇-d4)7.94 (d, 1.7 Hz, 1H), 7.73 (s, 1H), 7.32 (ddd, 10.1, 7.5, 3.5 Hz, 2H), 7.21-7.10 (m, 2H), 7.02 (ddd, 8.8, 7.7, 3.1 Hz, 1H), 6.42 (d, 201.1 Hz, 2H), 4.13 (qd, 7.0, 4.9 Hz, 2H), 1.46 (t, 7.0 Hz, 3H)。 520.95 D   
I-557
Figure 02_image1407
 Fc1cccc(c1)C1(CC1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 甲醇-d4) 7.85 (d, 1.8 Hz, 1H), 7.68 (s, 1H), 7.59 (s, 1H), 7.35-7.20 (m, 2H), 7.02 (td, 8.3, 2.6 Hz, 1H), 6.87 (dt, 7.7, 1.3 Hz, 1H), 6.76 (dt, 9.9, 2.1 Hz, 1H), 6.44 (s, 1H), 6.08 (s, 1H), 1.62 (s, 1H), 1.34 (ddd, 10.1, 7.0, 4.0 Hz, 1H), 1.20-1.11 (m, 1H), 0.98 (ddd, 9.6, 7.0, 3.8 Hz, 1H)。 516.9 D   
I-558
Figure 02_image1409
 FC(F)Oc1cc(ccc1F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 甲醇-d4)7.95 (d, 1.7 Hz, 1H), 7.72 (s, 1H), 7.61-7.48 (m, 2H), 7.41-7.24 (m, 2H), 7.11-6.50 (m, 3H), 6.16 (s, 1H)。 542.85 D   
I-559
Figure 02_image1411
 COc1cc(ccc1F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 氯仿-d) 8.41 (s, 1H), 7.95 (d, 1.6 Hz, 1H), 7.44-7.33 (m, 3H), 7.13-7.01 (m, 2H), 6.83 (s, 1H), 6.71 (s, 1H), 6.49 (s, 1H), 6.18 (s, 1H), 3.94 (s, 3H), 2.03 (s, 0H)。 508.9 D   
I-560
Figure 02_image1413
 Fc1ccc(c(CC(=O)Nc2cc(Br)cc3C(=O)NC(c23)c2cc(F)ccc2Cl)c1)C(F)(F)F 1H NMR (400 MHz, 氯仿-d) 8.38 (s, 1H), 7.90 (d, 1.7 Hz, 1H), 7.64 (dd, 8.8, 5.4 Hz, 1H), 7.45 (dd, 8.9, 4.9 Hz, 1H), 7.15-7.01 (m, 3H), 6.85 (s, 1H), 6.53 (d, 8.3 Hz, 1H), 6.38 (s, 1H), 6.02 (s, 1H), 3.76-3.65 (m , 2H), 3.50 (d, 16.0 Hz, 1H)。 561 D   
I-561
Figure 02_image1415
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cnn(c3)-c3ccccc3)c12 1H NMR (400 MHz, 氯仿-d) 8.52 (s, 1H), 8.36 (s, 1H), 7.93 (d, 1.7 Hz, 1H), 7.75-7.68 (m, 2H), 7.65 (s, 1H), 7.58-7.47 (m, 3H), 7.42 (t, 7.4 Hz, 1H), 7.09 (ddd, 12.2, 6.8, 3.1 Hz, 2H), 6.72 (s, 1H), 6.42 (s, 1H), 6.22 (s, 1H)。 527 E   
I-562
Figure 02_image1417
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cccn4ccnc34)c12 1H NMR (400 MHz, DMSO-d6)  11.99 (s, 1H), 9.41 (s, 1H), 8.83 - 8.77 (m, 2H), 8.12 - 8.05 (m, 2H), 7.73 (d, 1.8 Hz, 1H), 7.53 (s, 2H), 7.13 (t, 7.0 Hz, 1H), 7.12 (s, 1H), 6.54 (s, 1H), 6.19 (s, 1H)。 499 E   
I-563
Figure 02_image1419
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)Cc3c(F)ccc(F)c3F)c12 1H NMR (400 MHz, 甲醇-d4)  7.90 (d, 1.7 Hz, 1H), 7.68 (d, 1.6 Hz, 1H), 7.48 - 7.40 (m, 1H), 7.25 (qd, 9.4, 5.1 Hz, 1H), 7.13 (ddd, 8.9, 7.8, 3.1 Hz, 1H), 6.96 (ddt, 9.6, 6.6, 3.4 Hz, 1H), 6.14 (s, 1H), 3.64 - 3.51 (m, 2H)。 527 E   
I-564
Figure 02_image1421
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)c(F)c(Cl)c3)c12 1H NMR (400 MHz, 甲醇-d4) 7.96 (d, 1.7 Hz, 2H), 7.73 (s, 2H), 7.58 - 7.47 (m, 4H), 7.34 (dd, 8.9, 5.0 Hz, 2H), 7.06 (ddd, 8.9, 7.7, 3.1 Hz, 2H), 6.65 (s, 3H), 6.14 (s, 2H), 4.63 (s, 2H)。 530.9 A   
I-565
Figure 02_image1423
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccc(F)c(Cl)c3)c12 1H NMR (400 MHz, 氯仿-d) 8.45 (s, 1H), 7.94 (d, 1.6 Hz, 1H), 7.55-7.43 (m, 3H), 7.34 (s, 1H), 7.23 (t, 8.4 Hz, 1H), 7.10 (ddd, 8.9, 7.3, 3.0 Hz, 1H), 6.72 (s, 1H), 6.60 (s, 1H), 6.18 (s, 1H)。 510.95 C   
I-566
Figure 02_image1425
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccc(F)c(c3)C(F)(F)F)c12 1H NMR (400 MHz, 氯仿-d) 8.39 (s, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 7.68 (d, 6.3 Hz, 1H), 7.40 (s, 2H), 7.31 (d, 8.8 Hz, 1H), 7.07 (s, 1H), 6.70 (s, 2H), 6.21 (s, 1H)。 545 C   
I-567
Figure 02_image1427
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cccc(n3)C(F)(F)F)c12 1H NMR (400 MHz, 氯仿-d)  9.30 (s, 1H), 8.74 (s, 1H), 8.45 (d, 7.9 Hz, 1H), 8.13 (t, 7.8 Hz, 1H), 7.96 (d, 1.7 Hz, 1H), 7.87 (d, 7.8 Hz, 1H), 7.48 (dd, 8.8, 4.8 Hz, 1H), 7.03 (s, 1H), 6.60 (s, 1H), 6.47 (s, 1H), 6.22 (s, 1H)。 529.9 D   
I-568
Figure 02_image1429
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)Cc3ccccc3C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.01 (s, 1H), 9.22 (s, 1H), 7.75 - (m, 2H), 7.69 - 7.59 (m, 1H), 7.59 (d, 7.6 Hz, 1H), 7.47 (t, 7.5 Hz, 2H), 7.30 -7.21 (m, 2H), 7.23-6.08 (m, 1H),5.98 (s, 1H), 3.65 - 3.49 (m, 2H)。 541.05 D   
I-569
Figure 02_image1431
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cccc(c3)C3CC3)c12 1H NMR (400 MHz, DMSO-d6)  10.16 (s, 1H), 9.27 (s, 1H), 7.82- 7.73 (m, 2H), 7.37 (dd, 8.9, 5.2 Hz, 1H), 7.36 - 7.26 (m, 2H), 7.28 (s, 1H), 7.18 - 7.08 (m, 2H), 6.78 (s, 1H), 6.04 (s, 1H), 1.98 - 1.87 (m, 1H), 0.99 (dq, 8.3, 1.5 Hz, 2H), 0.73 - 0.60 (m, 2H)。 499.05 D   
I-570
Figure 02_image1433
 FC(F)c1cccc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.42 (s, 1H), 9.28 (s, 1H), 7.80 (d, 1.7 Hz, 1H), 7.78 - 7.69 (m, 4H), 7.60 (t, 7.8 Hz, 1H), 7.33 (dd, 8.8, 5.1 Hz, 1H), 7.15 - 7.05 (m, 2H), 6.71 (s, 1H), 6.02 (s, 1H)。 509 D   
I-571
Figure 02_image1435
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccccc3OC(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.40 (s, 1H), 9.29 (s, 1H), 7.79 (d, 1.7 Hz, 1H), 7.69 (d, 1.9 Hz, 1H), 7.67 - 7.59 (m, 1H), 7.48 (t, 8.4 Hz, 2H), 7.39 (td, 7.6, 1.1 Hz, 1H), 7.27 (td, 8.4, 3.1 Hz, 1H), 6.83 (dt, 7.7, 2.2 Hz, 2H), 6.05 (s, 1H)。 542.95 D   
I-572
Figure 02_image1437
 FC(F)c1ccc(cc1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 氯仿-d)  7.96 (d, 1.7 Hz, 1H), 6.72 (t, 56.1 Hz, 2H), 8.46 (s, 1H), 7.60 (s, 4H), 7.41 (dd, 8.1, 4.3 Hz, 2H), 7.12 - 7.03 (m, 1H), 6.45 (s, 1H), 6.20 (s, 1H)。 509 D   
I-573
Figure 02_image1439
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cccc(Cl)c3)c12 1H NMR (400 MHz, DMSO-d6)  10.36 (s, 1H), 9.29 (s, 1H), 7.80 (d, 1.8 Hz, 1H), 7.74 (d, 1.8 Hz, 1H), 7.64 (dt, 7.8, 1.6 Hz, 1H), 7.55 (dt, 7.9, 1.5 Hz, 1H), 7.52 - 7.45 (m, 2H), 7.36 (dd, 8.9, 5.2 Hz, 1H), 7.14 (td, 8.4, 3.1 Hz, 1H), 7.11 - 6.25 (br, 1H), 6.00 (s, 1H)。 492.85 C   
I-574
Figure 02_image1441
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCCOCC3)c12 (400 MHz, CDCl3)  8.14 (s, 1H),  7.81 (dd, 1.6, 0.4 Hz, 1H), 7.45 (dd, 8.9, 4.9 Hz, 1H), 7.06 (ddd, 8.9, 7.4, 3.0 Hz 1H), 6.62 (br s, 1H), 6.45 (dd, 20.1, 8.5 Hz, 1H), 6.11 (s, 1H), 5.89 (s, 1H), 3.69-3.52 (m, 4H), 3.44-3.36 (m, 2H), 3.32 (t, 5.2 Hz, 2H), 1.83-1.67 (m, 2H) 482.2 E   
I-575
Figure 02_image1443
 OC1CN(C1)c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.68 (br s, 1H), 9.16 (s, 1H), 8.45 (s, 1H), 7.88 (s, 1H), 7.72 (d, 9.2 Hz, 1H), 7.66 (s, 1H), 7.33 (dd, 8.8, 5.2 Hz, 1H), 7.07 (td, 8.5, 2.9 Hz, 1H), 6.60 (br s, 1H), 5.86 (s, 1H), 5.65 (br s, 1H), 4.69-4.58 (m, 1H), 4.23 (dd, 15.5, 8.3 Hz, 2H), 3.77-3074 (m, 2H)。 539.5 A   
I-576
Figure 02_image1445
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCOCC3)c12 NMR (400 MHz, CD3CN)  7.70 (d, 1.7 Hz, 1H), 7.52 (d, 1.6 Hz, 1H), 7.46 (dd, 7.8, 5.5 Hz, 1H), 7.24 (s, 1H), 7.11 (ddd, 8.9, 8.0, 3.1 Hz, 1H), 7.00 (s 1H), 6.69 (br s, 1H), 6.08 (s, 1H), 3.48 (ddd, 11.3, 6.5, 3.2 Hz, 2H), 3.42-3.34 (m, 2H), 3.19 (ddd, 13.1, 6.5, 3.3 Hz, 2H), 2.99 (ddd, 13.2, 6.5, 3.2 Hz, 2H)。 466.3 E   
I-577
Figure 02_image1447
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCCCCC3)c12 NMR (400 MHz, CD3CN )  7.68 (s, 2H), 7.44 (dd, 8.9, 5.2 Hz, 1H), 7.23 (s, 1H), 7.09 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.74 (s, 1H), 6.64 (br s, 1H), 6.16 (s, 1H), 3.33-2.98 (m, 4H), 1.54-1.44 (m, 4H), 1.43-1.36 (m, 2H), 1.33-1.22 (m, 2H)。 480.2 E   
I-578
Figure 02_image1449
 NC(=O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)  10.52 (s, 1H), 9.12 (br. s, 1H), 7.94 (d, 8.5 Hz, 1H), 7.73 (d, 9.0 Hz, 1H), 7.65 (s, 1H), 7.61 (s, 2H), 7.38 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.4, 3.0 Hz, 1H), 7.01 (br. s, 1H), 6.59 (br. s, 1H), 5.95 (br. s, 1H), 3.62-3.51 (m, 2H)。 524.2 A   
I-579
Figure 02_image1451
 OCCc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.49 (br. s, 1H), 9.09 (br. s, 1H), 7.94 (d, 8.5 Hz, 1H), 7.73 (d, 9.1 Hz, 1H), 7.65 (s, 1H), 7.56 (s, 1H), 7.34 (s, 1H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.4, 3.1 Hz, 1H), 6.58 (br. s, 1H), 5.94 (br. s, 1H), 4.74 (br. s, 1H), 3.70 (t, 6.4 Hz, 2H), 2.95-2.82 (m, 2H)。 511.2 A   
I-580
Figure 02_image1453
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(F)c(F)c(c3)C(F)(F)F)c12    485.1 A   
I-581
Figure 02_image1455
 CC(=O)c1cc(F)cc(c1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl    441.4 D   
I-582
Figure 02_image1457
 Cn1cc(Br)c(n1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl    463.22 E   
I-583
Figure 02_image1459
 Cn1ncc(Br)c1C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl    463.22 E   
I-584
Figure 02_image1461
 Cc1ncc(cn1)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz) 11.04 (br s, 1H), 9.63 (br s, 1H), 9.38 (s, 2H), 8.14 (s, 1H), 8.00 (br d, 8.1 Hz, 1H), 7.76 (br d, 8.8 Hz, 1H), 7.67 (s, 1H), 7.35 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.4, 2.9 Hz, 1H), 6.83-7.02 (m, 1H), 6.08 (br s, 1H), 2.74 (s, 3H) 560.5 A   
I-585
Figure 02_image1463
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cncc(F)c1 1H NMR (DMSO-d6, 400 MHz) 11.03 (s, 1H), 9.63 (br s, 1H), 9.21 (s, 1H), 8.74 (br d, 2.4 Hz, 1H), 8.39 (br d, 9.8 Hz, 1H), 8.19 (br s, 1H), 8.00 (br d, 7.6 Hz, 1H), 7.77 (br d, 9.0 Hz, 1H), 7.68 (br s, 1H), 7.36 (br dd, 8.8, 5.1 Hz, 1H), 7.11 (td, 8.4, 3.1 Hz, 1H), 6.83-7.03 (m, 1H), 6.08 (br s, 1H) 563.5 A   
I-586
Figure 02_image1465
 CCn1cc(ccc1=O)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz) 10.91 (s, 1H), 9.52 (br s, 1H), 8.62 (d, 2.2 Hz, 1H), 8.20 (dd, 9.5, 2.4 Hz, 1H), 7.99 (br d, 8.1 Hz, 1H), 7.90 (s, 1H), 7.76 (br d, 9.0 Hz, 1H), 7.68 (s, 1H), 7.34 (dd, 9.0, 5.1 Hz, 1H), 7.10 (td, 8.4, 2.9 Hz, 1H), 6.79-6.98 (m, 1H), 6.57 (d, 9.5 Hz, 1H), 6.02 (br s, 1H), 4.07 (q, 7.1 Hz, 2H), 1.30 (t, 7.1 Hz, 3H) 589.5 A   
I-587
Figure 02_image1467
 Cn1cc(ccc1=O)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2[C@H](NC(=O)c2n1)c1cc(F)ccc1Cl    575.2 D   
I-588
Figure 02_image1469
 Cn1cc(ccc1=O)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2[C@@H](NC(=O)c2n1)c1cc(F)ccc1Cl    575.2 A   
I-589
Figure 02_image1471
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1COC1    523.4 A   
I-590
Figure 02_image1473
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1COC1    523.4 A   
I-591
Figure 02_image1475
 CC(C)(O)C(=O)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    568.27 A   
I-592
Figure 02_image1477
 OC1(CC1)C(=O)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    566.21 A   
I-593
Figure 02_image1479
 CC(C)n1cc(ccc1=O)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz)  10.94 (br s, 1H), 9.51 (br s, 1H), 8.48 (br d, 2.2 Hz, 1H), 8.20 (br dd, 9.6, 2.3 Hz, 1H), 7.98 (br s, 2H), 7.76 (br d, 8.8 Hz, 1H), 7.69 (s, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.4, 2.9 Hz, 1H), 6.77-6.96 (m, 1H), 6.58 (d, 9.5 Hz, 1H), 6.01 (br s, 1H), 5.13 (dt, 13.6, 6.7 Hz, 1H), 1.41 (dd, 6.6, 4.9 Hz, 6H) 603.6 A   
I-594
Figure 02_image1481
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc4cn[nH]c34)c12    439.33 C   
I-595
Figure 02_image1483
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc4nc[nH]c34)c12    439.38 D   
I-596
Figure 02_image1485
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(Cl)cc4CCOc34)c12    457.4 D   
I-597
Figure 02_image1487
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCCC(C3)c3ccccc3)c12 (400 MHz, DMSO-d6)  9.19 (s, 1H), 8.71 (s, 0.5H), 8.67 (s, 0.5H), 7.61-7.57 (m, 1H), 7.56-7.50 (m, 1H), 7.47 (d, 1.6 Hz, 0.5H), 7.46 (d, 1.6 Hz, 0.5H) 7.38-7.28 (m, 3H), 7.28-7.19 (m, 3H), 7.12 (d, 7.1 Hz, 1H), 6.60 (br s, 1H), 6.07 (br s, 1H), 3.96 (d, 12.1 Hz, 0.5H), 3.86 (d, 7.6 Hz, 0.5H), 3.76 (t, 14.4 Hz, 1H), 2.75-2.57 (m, 1H), 2.48-2.40 (m, 1H), 1.99-1.82 (m, 0.5H), 1.82-1.68 (m, 1H), 1.68-1.43 (m, 2H), 1.43-1.27 (m, 0.5H) 542.3 D   
I-598
Figure 02_image1489
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCC(C3)c3ccccc3)c12 (400 MHz, DMSO-d6)  9.15 (s, 1H), 8.28 (s, 0.5H), 8.19 (s, 0.5H), 7.56 (dd, 2.7, 1.8 Hz, 1H), 7.51 (d, (t, 1.7 Hz, 1H), 7.46 (d, (t, 1.7 Hz, 1H), 7.31 (t, 7.7 Hz, 2H), 7.28-7.13 (m, 5H), 5.94 (br s, 1H), 3.79-3.57 (m, 0.5H), 3.56-3.37 (m, 1H), 3.25-3.11 (m, 2.5H), 3.10-2.99 (m, 1H), 2.17-2.04 (m, 1H), 1.89-1.65 (m, 1H) 528.3 D   
I-599
Figure 02_image1491
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)CC3CCc4ccccc34)c12 1H NMR (400 MHz, 氯仿-d)  8.46 (s, 1H), 7.89 (t, 1.9 Hz, 1H), 7.42 (ddd, 22.3, 8.9, 4.9 Hz, 1H), 7.26 (d, 8.7 Hz, 1H), 7.22 (d, 6.6 Hz, 1H), 7.19-6.97 (m, 3H),  6.88 (s, 1H), 6.66 (dd, 8.5, 3.0 Hz, 1H), 6.42 (d, 5.1 Hz, 1H),  6.06 (s, 1H), 3.59-3.51 (m, 1H),2.72-2.57 (m, 2H), 2.40 -2.30 (m, 1H), 2.34-2.23 (m, 2H), 1.69 (dt, 13.3, 7.4 Hz, 1H)。 515 E   
I-600
Figure 02_image1493
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)CCc3ccccc3C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  9.87 (s, 1H), 9.25 (s, 1H), 7.75 - 7.57 (m, 4H), 7.44 (q, 7.7 Hz, 2H), 7.37 (d, 7.7 Hz, 1H), 7.22 (ddd, 8.9, 7.9, 3.1 Hz, 1H), 6.71 (s, 1H), 6.00 (s, 1H), 2.81 (dd, 20.3, 10.4 Hz, 2H), 2.34- 2.19 (m, 2H)。 555 D   
I-601
Figure 02_image1495
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cccc4CCCOc34)c12 1H NMR (400 MHz, DMSO-d6)  9.73 (s, 1H), 9.27 (s, 1H), 7.89 (d, 16.6 Hz, 1H), 7.74 (d, 1.8 Hz, 1H), 7.44 (s, 1H), 7.27 - 7.15 (m, 3H), 6.85 (t, 7.6 Hz, 2H), 6.11 (s, 1H), 4.18 - 4.10 (m, 1H), 4.04 (dt, 10.6, 5.2 Hz, 1H), 2.76 (t, 6.5 Hz, 2H), 1.90 (q, 5.9 Hz, 2H)。 515.05 E   
I-602
Figure 02_image1497
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cccc4cccnc34)c12 1H NMR (400 MHz, DMSO-d6)  12.91 (s, 1H), 9.34 (s, 1H), 8.93 (s, 1H), 8.58 (ddd, 14.9, 7.9, 1.7 Hz, 2H), 8.39 (s, 1H), 8.26 (dd, 8.1, 1.6 Hz, 1H), 7.82 - 7.68 (m, 3H), 7.29 (dd, 8.8, 5.1 Hz, 1H), 6.98 (d, 8.9 Hz, 1H), 6.80 (s, 1H), 6.26 (s, 1H)。 510 D   
I-603
Figure 02_image1499
 Cc1nc2ccccn2c1CC(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.12 (s, 1H), 9.21 (s, 1H), 8.06 (d, 6.9 Hz, 1H), 7.71 (dd, 13.5, 1.8 Hz, 2H), 7.44 (d, 9.0 Hz, 1H), 7.34 (dd, 8.8, 5.1 Hz, 1H), 7.23 - 7.14 (m, 1H), 7.15 (s, 1H), 6.83 (td, 6.8, 1.2 Hz, 1H), 6.54 (s, 1H), 5.98 (s, 1H), 3.72 (s, 2H), 2.17 (s, 3H)。 527 E   
I-604
Figure 02_image1501
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C3(CCCC3)c3ccccc3)c12 1H NMR (400 MHz, DMSO-d6)  9.23 (s, 1H), 9.16 (s, 1H), 7.69 (d, 1.8 Hz, 1H), 7.53 (d, 1.8 Hz, 2H), 7.30 - 7.13 (m, 6H), 6.17 (s, 1H), 2.14 (s, 2H), 1.89 (d, 23.1 Hz, 1H), 1.68 (dt, 13.1, 7.1 Hz, 1H), 1.48 (s, 2H), 1.26 (s, 2H)。 527.05 D   
I-605
Figure 02_image1503
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C3CCOc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  10.21 -10.11 (m, 1H), 9.26 (d, 15.1 Hz, 1H), 7.82 -7.69 (m, 2H), 7.60 (s, 1H), 7.46-7.33 (m, 1H), 7.21-7.05 (m, 1H), 6.78- 6.67 (m, 3H), 6.56 (s, 1H), 6.08 (s, 1H), 4.23-3.97 (m, 2H), 3.65 -3.58 (m, 1H), 1.86 - 1.79 (m, 1H), 1.71 - 1.63 (m, 1H)。 515 E   
I-606
Figure 02_image1505
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccnc4ccc(Cl)cc34)c12 1H NMR (400 MHz, DMSO-d6)  10.30 (s, 1H), 9.34 (s, 1H), 8.99 (d, 4.3 Hz, 1H), 8.13 (d, 9.0 Hz, 1H), 7.92 (d, 2.3 Hz, 1H), 7.86 (ddd, 8.3, 3.4, 2.0 Hz, 3H), 7.49 (dd, 8.9, 5.1 Hz, 1H), 7.24 (td, 8.4, 3.1 Hz, 1H), 7.14 (s, 1H), 6.70 (s, 1H), 6.13 (s, 1H)。 543.95 E   
I-607
Figure 02_image1507
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccnc(c3F)C(F)(F)F)c12 1H NMR (400 MHz, 氯仿-d) 8.70 (d, 4.8 Hz, 1H), 8.45-8.40 (m, 1H), 8.10 (t, 5.0 Hz, 1H), 7.98 (d, 1.6 Hz, 1H), 7.86 (d, 11.0 Hz, 1H), 7.42 (dd, 8.9, 4.9 Hz, 1H), 7.08 (ddd, 8.9, 7.4, 3.0 Hz, 1H), 6.94 (s, 1H), 6.65 (s, 1H), 6.17 (s, 1H)。 545.95 E   
I-608
Figure 02_image1509
 CCc1cc(F)cc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1ccccc1C NMR (400 MHz, DMSO-d6)  10.12 (br. s, 1H), 9.23 (s, 1H), 7.85 (d, 1.7 Hz, 1H), 7.76 (d, 1.7 Hz, 1H), 7.25-7.21 (m, 1H), 7.12 (td, 7.6,  1.2 Hz, 1H), 7.07-7.06 (m, 1H), 6.99 (td, 7.6,  1.2 Hz, 1H), 6.91-6.88 (m, 2H), 6.58 (br. s, 1H), 5.96 (s, 1H), 2.58 (q, 7.5 Hz, 2H), 2.26 (br. s, 3H), 1.15 (t, 7.6 Hz, 3H)，3.63、1.99、1.22、0.86處之痕量雜質。 465.3 C   
I-609
Figure 02_image1511
 O[C@H]1C[C@@H](C1)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.25 (br. s, 1H), 8.88 (br. s, 1H), 8.43 (br. s, 1H), 7.88 (d, 8.4 Hz, 1H), 7.65 (d, 8.6 Hz, 1H), 7.56 (s, 1H), 7.24 (dd, 8.9, 5.2 Hz, 1H), 7.02 (td, 8.5, 2.4 Hz, 1H), 6.63 (d, 1.9 Hz, 1H), 6.54 (s, 1H), 6.44 (d, 5.1 Hz, 1H), 5.79 (br. s, 1H), 5.07 (br. s, 1H), 4.37-4.20 (m, 1H), 3.84 (ddd, 11.5, 7.6, 4.3 Hz, 1H), 2.24-2.01 (m, 3H)。 552.2 A   
I-610
Figure 02_image1513
 CC1(COC1)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.24 (s, 1H), 8.91 (br. s, 1H), 7.88 (td, 8.4, 1.6 Hz, 1H), 7.64 (d, 9.0 Hz, 1H), 7.55 (s, 1H), 7.25 (dd, 8.9, 5.2 Hz, 1H), 7.03 (td, 8.4, 3.1 Hz, 1H), 6.64 (s, 1H), 6.57 (br. s, 1.6 Hz, 1H), 6.52 (d, 2.1 Hz, 1H), 6.47 (br. d, 1H), 5.80 (s, 1H), 4.63 (d, 5.7 Hz, 2H), 4.48 (d, 5.8 Hz, 2H), 1.57 (s, 3H)。8.32處之6%甲酸鹽。 552.2 A   
I-611
Figure 02_image1515
 COCc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, ACN)  8.61 (s, 1H), 7.69 (s, 1H), 7.65 (d, 8.5 Hz, 1H), 7.61-7.55 (m, 2H), 7.53 (s, 1H), 7.25 (dd, 8.9, 5.1 Hz, 1H), 7.22 (br s, 1H), 6.97 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.64 (br s, 1H), 6.11 (br s, 1H), 4.59 (s, 2H), 3.41 (s, 3H)。 511.1 A   
I-612
Figure 02_image1517
 FC(F)c1ccc(F)cc1C1NC(=O)c2cc(Br)cc(NC(=O)c3nsc4ccccc34)c12 NMR (400 MHz, DMSO)  10.31 (br s, 1H), 9.38 (s, 1H), 8.60 (d, 8.2 Hz, 1H), 8.31 (dt, 8.3, 0.9 Hz, 1H), 8.01 (d, 1.7 Hz, 1H), 7.83 (d, 1.7 Hz, 1H), 7.67 (ddd, 8.2, 7.0, 1.2 Hz, 1H), 7.59 (ddd, 8.1, 7.0, 1.0 Hz, 1H), 7.42 (dd, 8.6, 5.7 Hz, 1H), 7.11 (td, 8.5, 2.6 Hz, 1H), 6.63 (br s, 1H), 6.16 (s, 1H)。含有9%甲酸鹽(8.34)及來自NMR管之殘餘丙酮(2.05)。 532.1 A   
I-613
Figure 02_image1519
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(NC3COC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6 )  10.30 (s, 1H), 8.95 (br. s, 1H), 7.92 (d, 8.6 Hz, 1H), 7.69 (d, 8.9 Hz, 1H), 7.60 (s, 1H), 7.28 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.4, 3.1 Hz, 1H), 6.94 (d, 6.3 Hz, 1H), 6.69 (d, 2.0 Hz, 1H), 6.62 (s, 1H), 6.57 (br. s, 1H), 5.82 (br. s, 1H), 4.89 (t, 6.5 Hz, 2H), 4.62 (dd, 12.7, 6.4 Hz, 1H), 4.45 (q, 6.1 Hz, 2H)。8.36處之6%甲酸鹽 538.2 A   
I-614
Figure 02_image1521
 CCn1cc(ccc1=O)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2[C@H](NC(=O)c2n1)c1cc(F)ccc1Cl    589.3 D   
I-615
Figure 02_image1523
 CCn1cc(ccc1=O)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2[C@@H](NC(=O)c2n1)c1cc(F)ccc1Cl    589.3 A   
I-616
Figure 02_image1525
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2nc(Cl)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    502.2 B   
I-617
Figure 02_image1527
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2nc(Cl)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    502.2 A   
I-618
Figure 02_image1529
 CS(=O)(=O)Cc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 500 MHz) 10.5-10.7 (m, 1H), 9.0-9.3 (m, 1H), 7.9-8.0 (m, 1H), 7.7-7.8 (m, 2H), 7.6-7.7 (m, 1H), 7.4-7.6 (m, 1H), 7.2-7.4 (m, 1H), 6.9-7.2 (m, 1H), 6.5-7.0 (m, 2H), 5.7-6.2 (m, 1H), 4.5-4.9 (m, 2H), 2.9-3.1 (m, 3H) 559 A   
I-619
Figure 02_image1531
 CS(=O)(=O)Cc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 500 MHz) 10.5-10.7 (m, 1H), 9.1-9.4 (m, 1H), 7.92 (br d, 1H,  8.2 Hz), 7.7-7.8 (m, 2H), 7.6-7.7 (m, 1H), 7.5-7.6 (m, 1H), 7.2-7.4 (m, 1H), 7.0-7.2 (m, 1H), 6.2-7.0 (m, 1H), 5.7-6.2 (m, 1H), 4.5-4.8 (m, 2H), 2.9-3.1 (m, 3H) 559 D   
I-620
Figure 02_image1533
 CC(=O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1C(F)F    539 A   
I-621
Figure 02_image1535
 CC(C)(O)Cc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    539 A   
I-622
Figure 02_image1537
 CC(C)(O)Cc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    539 B   
I-623
Figure 02_image1539
 CC(=O)Cc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    523 A   
I-624
Figure 02_image1541
 CC(=O)Cc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    523 B   
I-625
Figure 02_image1543
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(NC(=O)C3CC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (500 MHz, DMSO-d6)  0.81 - 0.87 (m, 4 H) 1.81 (dt,  12.53, 6.19 Hz, 1 H) 5.85 - 5.95 (m, 1 H) 6.56 (br s, 1 H) 7.06 (td,  8.35, 3.15 Hz, 1 H) 7.29 (dd,  8.83, 5.04 Hz, 1 H) 7.62 (s, 1 H) 7.70 (br d,  9.14 Hz, 1 H) 7.80 (s, 1 H) 7.88 - 7.96 (m, 2 H) 9.08 (br s, 1 H) 10.47 (s, 1 H) 10.56 (s, 1 H) 550.4 A   
I-626
Figure 02_image1545
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3csc4ccccc34)c12    517.3 A   
I-627
Figure 02_image1547
 CC(C)(O)c1cc(F)cc(c1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl    457.4 E   
I-628
Figure 02_image1549
 Fc1ccc(Br)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.34 (s, 1H), 8.99 (s, 1H), 7.86 (d, 8.5 Hz, 1H), 7.75-7.68 (m, 3H), 7.65 (t, 7.6 Hz, 1H), 7.51 (d, 7.5 Hz, 1H), 7.46 (dd, 8.9, 5.4 Hz, 1H), 7.00 (dt, 8.5, 3.1 Hz, 1H), 6.55 (br s, 1H), 6.01 (s, 1H)  [T = 60 ℃]。 509.3 A   
I-629
Figure 02_image1551
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2c1n([nH]c2=O)C1CCCCC1 NMR (400 MHz, DMSO-d6)  10.61 (s, 2H), 8.26 (s, 1H), 8.15 (d, 8.7 Hz, 1H), 8.05 (d, 8.6 Hz, 1H), 7.59 (d, 7.9, 0.7 Hz, 1H), 7.23 (d, 7.2 Hz, 1H), 7.01 (t, 17.2, 9.5 Hz, 1H), 4.40 (m, 1H), 1.88-1.77 (m, 2H), 1.77-1.64 (m, 4H), 1.56-1.43 (m,  1H), 1.15-1.00 (m, 1H), 1.00-0.81 (m, 2H)。 422.5 D   
I-630
Figure 02_image1553
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1ccnc(Cl)c1 (400 MHz, d6-DMSO)  10.52 (s, 1H), 9.17 (s, 1H), 8.19 (d, 5.1 Hz, 1H), 8.01 (d, 8.5 Hz, 1H), 7.86 (d, 8.5 Hz, 1H), 7.84 (s 1H), 7.72 (dd, 7.5, 1.0 Hz, 1H), 7.64 (t, 7.6 Hz, 1H), 7.51 (dd, 7.8, 1.0 Hz, 1H), 7.18 (s, 1H), 6.93 (dd, 5.2, 1.4 Hz, 1H), 5.75 (s, 1H)。具有痕量脂族雜質。 448.3 E   
I-631
Figure 02_image1555
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C3CCCc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  9.99 (d, 52.3 Hz, 1H), 9.25 (s, 1H), 7.79 (d, 12.1 Hz, 1H), 7.72 (s, 1H), 7.65 - 7.24 (m, 2H), 7.16 - 6.93 (m, 3H), 6.59 (d, 59.8 Hz, 1H), 6.10 (s, 1H), 3.59 (s, 1H), 2.66 (d, 6.3 Hz, 2H), 1.95 - 1.67 (m, 2H), 1.64 (s, 2H)。 512.95 D   
I-632
Figure 02_image1557
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C3(COC3)c3ccccc3)c12 1H NMR (400 MHz, DMSO-d6)  9.89 (s, 1H), 9.29 (s, 1H), 7.76 (d, 1.7 Hz, 1H), 7.51 (s, 2H), 7.39 - 7.18 (m, 6H), 6.11 (s, 1H), 4.87 (d, 6.4 Hz, 1H), 4.69 (d, 6.3 Hz, 1H), 4.62 (d, 6.4 Hz, 1H), 4.51 (s, 1H)。 514.95 E   
I-633
Figure 02_image1559
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)Cn3ncc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  10.19 (s, 1H), 9.22 (s, 1H), 8.06 (s, 1H), 7.75 (dd, 18.4, 8.9 Hz, 3H), 7.54 (s, 1H), 7.41 - 7.23 (m, 3H), 7.16 (t, 7.4 Hz, 1H), 5.95 (s, 1H), 4.99 (s, 2H)。 512.95 E   
I-634
Figure 02_image1561
 CC1(CCCc2ccccc12)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 氯仿-d)  855 - 8.25 (d, 111.5 Hz, 1H), 7.84 (dd, 9.8, 1.7 Hz, 1H), 7.44 (dt, 9.2, 4.9 Hz, 1H), 7.23 - 6.95 (m, 4H), 6.92 - 6.81 (m, 1H), 6.57 (d, 8.1 Hz, 1H), 6.41 (d, 7.0 Hz, 1H), 6.33 - 6.23 (m, 1H), 5.82 - 5.46 (m, 1H), 2.72 (ddt, 22.0, 10.5, 5.9 Hz, 2H), 2.24 - 2.05 (m, 1H), 1.89 - 1.72 (m, 1H), 1.71 - 1.61 (m, 1H), 1.51 (d, 6.8 Hz, 4H)。 527.1 D   
I-635
Figure 02_image1563
 Cc1cc2cccc(C(=O)Nc3cc(Br)cc4C(=O)NC(c34)c3cc(F)ccc3Cl)c2o1 1H NMR (400 MHz, DMSO-d6)  10.14 (s, 1H), 9.27 (s, 1H), 7.77 (dd, 17.9, 1.8 Hz, 2H), 7.69 (dd, 6.8, 2.3 Hz, 1H), 7.33 (dd, 8.9, 5.1 Hz, 1H), 7.28 -7.18 (m, 2H), 7.11 (td, 8.4, 3.1 Hz, 1H), 6.65 (d, 1.3 Hz, 2H), 6.06 (s, 1H), 2.41 (s, 3H)。 513 D   
I-636
Figure 02_image1565
 Cn1ccc2c(ccnc12)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.40 (s, 1H), 9.29 (s, 1H), 8.32 (d, 4.9 Hz, 1H), 7.80 (s, 2H), 7.63 (d, 3.5 Hz, 1H), 7.37 (dd, 8.8, 5.1 Hz, 1H), 7.14 (td, 8.5, 3.1 Hz, 1H), 7.01 (d, 4.9 Hz, 1H), 6.72 (s, 1H), 6.45 (d, 3.5 Hz, 1H), 6.10 (s, 1H), 3.85 (s, 3H)。 513 E   
I-637
Figure 02_image1567
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccc4nncn4c3)c12 1H NMR (400 MHz, DMSO-d6)  10.46 (s, 1H), 9.42 (d, 0.8 Hz, 1H), 9.29 (s, 1H), 8.94 (t, 1.4 Hz, 1H), 7.88 - 7.80 (m, 2H), 7.71 (d, 1.7 Hz, 1H), 7.46 (dd, 9.6, 1.7 Hz, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.4, 3.0 Hz, 1H), 6.70 (s, 1H), 6.00 (s, 1H)。 500 E   
I-638
Figure 02_image1569
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3nccc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 10.51 (s, 1H), 9.34 (s, 1H), 9.05 (d, 8.8 Hz, 1H), 8.50 (d, 5.5 Hz, 1H), 8.28 (d, 6.4 Hz, 1H), 8.12 (dd, 13.7, 6.9 Hz, 2H), 7.82 (dt, 40.5, 7.6 Hz, 3H), 7.45 (s, 1H), 7.15 (t, 8.5 Hz, 1H), 6.24 (s, 1H)。 510 E   
I-639
Figure 02_image1571
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccccc3C#N)c12 1H NMR (400 MHz, 氯仿-d) 8.20 (s, 1H), 7.93 (s, 1H), 7.73 (s, 4H), 6.96 (s, 1H), 6.73 (t, 8.3 Hz, 1H), 6.61 (s, 1H), 6.55 (s, 1H), 6.17 (s, 1H)。 484 E   
I-640
Figure 02_image1573
 CCc1cc(ccc1F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1ccccc1C NMR (400 MHz, DMSO-d6)  10.04 (s, 1H), 9.22 (s, 1H), 7.84 (d, 1.6 Hz, 1H), 7.75 (d, 1.6 Hz, 1H), 7.30 (ddd, 7.6, 5.0, 2.2 Hz, 1H), 7.16 (dd, 9.6, 8.4, Hz, 1H), 7.13-7.09 (m, 2H), 7.06 (br. d, 6.9 Hz, 1H), 6.99 (td, 7.3, 1.2  Hz, 1H), 6.57 (br. s, 1H), 5.96 (s, 1H), 2.57 (q, 7.6 Hz, 2H), 2.25 (br. s, 3H), 1.14 (t, 7.5 Hz, 3H)，3.7、1.2及0.9處之雜質。 467.4 D   
I-641
Figure 02_image1575
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(F)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6 )  10.59 (br. s, 1H), 9.30 (s, 1H), 7.96 (d, 7.6 Hz, 1H), 7.72 (d, 8.9 Hz, 1H), 7.63 (s, 1H), 7.49 (d, 6.5 Hz, 1H), 7.44 (d, 10.0 Hz, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.5, 2.5 Hz, 1H), 6.65 (br. s, 1H), 5.98 (br. s, 1H)。8.36處之9%甲酸鹽。 485.1 A   
I-642
Figure 02_image1577
 CN1CCN(CC1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)  9.17 (br. s, 1H), 8.64 (s, 1H), 7.58 (d, 1.7 Hz, 1H), 7.54-7.48 (m, 1H), 7.47 (d, 1.7 Hz, 1H), 7.25 (ddd, 8.7, 8.1, 3.1 Hz, 1H), 6.57 (br. s, 1H), 5.97 (br. s, 1H), 3.22-3.11 (m, 2H), 3.03-2.93 (m, 2H), 2.18-2.09 (m, 2H), 2.12 (s, 3H), 2.05-1.95 (m, 2H)。化合物為部分鹽(8.22處之峰)。 473.2 E   
I-643
Figure 02_image1579
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1=CCOC1 NMR (400 MHz, MeCN-d3)  8.64 (s, 1H), 7.74 (s, 1H), 7.63 (d, 8.7 Hz, 1H), 7.58 (d, 8.7 Hz, 1H),  7.58-7.53 (m, 2H), 7.26 (dd, 8.9, 5.2 Hz, 2H), 6.97 (td, 8.5, 2.9 Hz, 1H), 6.66 (br. s, 1H), 6.54 (s, 1H), 6.13 (br. s, 1H), 5.04-4.99 (m, 2H), 4.81 (t, 4.1 Hz, 2H)。 535.2 A   
I-644
Figure 02_image1581
 OC1(Cc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CC1 NMR (400 MHz, DMSO-d6)  10.51 (s, 1H), 9.09 (br. s, 1H), 7.94 (d, 8.5 Hz, 1H), 7.74 (d, 9.0 Hz, 1H), 7.66 (s, 1H), 7.64 (s, 1H), 7.40 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.3, 3.0 Hz, 1H), 6.58 (br. s, 1H), 5.96 (br. s, 1H), 5.29 (s, 1H), 2.93 (s, 2H), 0.66 - 0.62 (m, 2H), 0.60 - 0.56 (m, 2H)。 537.2 A   
I-645
Figure 02_image1583
 CC(C)(O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN)  8.46 (s, 1H), 7.60 (s, 1H), 7.42 (s, 1H), 7.39 (m, 1H), 7.32-7.27 (m, 3H), 7.24 (dd, 9.0, 1.8 Hz, 1H), 7.00 (ddd, 11.5, 5.7, 2.8 Hz, 1H), 6.63 (br s, 1H), 6.10 (br s, 1H), 2.92-2.82 (m, 2H), 1.19 (s, 3H), 1.17 (s, 3H)。 505 A   
I-646
Figure 02_image1585
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc4cc[nH]c34)c12    438.46 A   
I-647
Figure 02_image1587
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc(=O)n(c1)C1CC1 1H NMR (DMSO-d6, 500 MHz) 10.90 (br s, 1H), 9.50 (br s, 1H), 8.32 (d, 2.2 Hz, 1H), 8.18 (dd, 9.6, 2.7 Hz, 1H), 7.85-8.03 (m, 2H), 7.76 (br d, 9.1 Hz, 1H), 7.68 (s, 1H), 7.34 (dd, 8.8, 5.0 Hz, 1H), 7.09 (td, 8.4, 3.2 Hz, 1H), 6.76-6.99 (m, 1H), 6.55 (d, 9.5 Hz, 1H), 6.01 (br s, 1H), 3.39-3.45 (m, 1H), 1.04-1.12 (m, 2H), 0.90-1.01  (m, 2H) 601.6 A   
I-648
Figure 02_image1589
 Cn1cc(ccc1=O)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    574.5 A   
I-649
Figure 02_image1591
 CCn1cc(ccc1=O)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    588.5 A   
I-650
Figure 02_image1593
 CC(C)n1cc(ccc1=O)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2[C@H](NC(=O)c2n1)c1cc(F)ccc1Cl    603.4 C   
I-651
Figure 02_image1595
 CC(C)n1cc(ccc1=O)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2[C@@H](NC(=O)c2n1)c1cc(F)ccc1Cl    603.4 A   
I-652
Figure 02_image1597
 Cc1ncc(cn1)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2[C@H](NC(=O)c2n1)c1cc(F)ccc1Cl    560.2 C   
I-653
Figure 02_image1599
 Cc1ncc(cn1)-c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2[C@@H](NC(=O)c2n1)c1cc(F)ccc1Cl    560.2 A   
I-654
Figure 02_image1601
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CNC1    522.4 A   
I-655
Figure 02_image1603
 CC(=O)N1CC(C1)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    564.51 A   
I-656
Figure 02_image1605
 CC(C)(COS(C)(=O)=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    617 A   
I-657
Figure 02_image1607
 Cc1ccccc1C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C3COC3)c12    417.45 D   
I-658
Figure 02_image1609
 Oc1cc(ccn1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, d6-DMSO)  11.39 (br s, 1H), 10.58 (br s, 1H), 9.07 (s, 1H), 7.99 (d, 8.2 Hz, 1H), 7.91 (s, 1H), 7.87 (d, 9.1 Hz, 1H), 7.68 (dd, 7.4, 0.9 Hz, 1H), 7.62 (app t, 7.6 Hz, 1H), 7.53 (d, 6.8 Hz, 1H), 7.15 (d, 6.8 Hz, 1H), 6.06 (s, 1H), 5.52 (s, 1H), 5.45 (d, 6.6 Hz, 1H)。 430.4 E   
I-659
Figure 02_image1611
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cccc(c1)C#N (400 MHz, d6-DMSO)  10.44 (br s, 1H), 9.13 (s, 1H), 7.98 (d, 8.5 Hz, 1H), 7.77 (d, 8.9 Hz, 1H), 7.71 (dd, 7.5, 1.0 Hz, 1H), 7.67 (s, 1H), 7.66 (d, 7.2 Hz, 1H), 7.63 (app t, 6.6 Hz, 1H), 7.49 (dd, 7.7, 1.0 Hz, 1H), 7.45 (app t, 1.5 Hz, 1H), 7.38 (app t, 7.8 Hz, 1H), 7.22 (br d, 8.0 Hz, 1H), 5.77 (s, 1H)。 438.4 E   
I-660
Figure 02_image1613
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cccc2CCNc12 1H NMR (400 MHz, CD3CN )  8.93 (br. s, 1H), 7.90 (d, 7.8 Hz, 1H), 7.69-7.65 (m, 3H), 7.59-7.54 (m, 2H), 7.08 (br. s, 1H), 6.95 (dd, 7.2, 0.9 Hz, 1H), 6.62 (br. d, 7.3 Hz, 1H), 6.54 (t, 7.5 Hz, 1H), 5.74 (s, 1H), 4.21 (br. s, 1H), 3.30-3.22 (m, 1H), 2.93-2.79 (m, 2H), 2.54-2.44 (m, 1H)；2.11及1.77處之乙腈衛星。 456.2 E   
I-661
Figure 02_image1615
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CC(CC(C3)C(F)(F)F)C(F)(F)F)c12 (400 MHz, DMSO-d6)  9.18 (br s, 1H), 8.82 (s, 0.3 H), 8.65 (s, 0.6 H), 7.69-7.58 (m, 2H), 7.53-7.42 (m, 1H), 7.27-7.17 (m, 1H), 6.67 (br s, 1H), 5.98 (s, 1H), 3.45-3.34 (m, 4H), 2.65-2.53 (m, 2H), 1.92 (t, 6.5 Hz, 2H) 602.2 D   
I-662
Figure 02_image1617
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CCO1 (400 MHz, DMSO-d6)  10.53 (s, 1H), 9.09 (s, 1H), 7.94 (d, 8.4 Hz, 1H), 7.90 (d, 8.1 Hz, 1H), 7.73 (d, 8.4 Hz, 1H), 7.66 (s, 1H), 7.55 (d, 8.0 Hz, 1H), 7.30 (ddd, 7.7, 5.1, 2.8 Hz, 1H), 7.13-7.05 (m, 1H), 6.62 (t, 7.4 Hz, 0.3H), 6.57 (t, 7.4 Hz, 0.7H), 6.00 (br s, 1H), 4.74 (dd, 13.7, 7.9 Hz, 1H), 4.65-4.55 (m, 1H),  3.52-3.46 (m, 1H), 3.24-3.11 (m, 1H)。 523.4 B   
I-663
Figure 02_image1619
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cccc(Br)c1 (400 MHz, d6-DMSO)  10.47 (s, 1H), 9.10 (s, 1H), 7.98 (d, 8.5 Hz, 1H), 7.77 (d, 8.9 Hz, 1H), 7.72 (s, 1H), 7.69 (d, 7.3 Hz, 1H), 7.61 (app t, 7.6 Hz, 1H), 7.48 (d, 7.6 Hz, 1H), 7.38 (d, 7.9 Hz, 1H), 7.15 (d, 1.3 Hz, 1H), 7.13 (app t, 9.2 Hz, 1H), 6.89 (d, 7.8 Hz, 1H), 5.69 (s, 1H)。 493.3 E   
I-664
Figure 02_image1621
 CC(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.50 (2xs, 1H), 9.11 (s, 1H), 7.94 (d, 8.5 Hz, 1H), 7.74 (d, 8.6 Hz, 1H), 7.69-7.64 (m, 2H), 7.47 (2xs, 1H), 7.31 (dd, 8.9, 5.1 Hz, 1H), 7.09 (td, 8.4, 3.0 Hz, 1H), 6.60 (br. s, 1H), 5.96 (br. s, 1H), 5.44 (2xs, 1H), 4.94-4.83 (m, 1H), 1.40 (2xd, 2.1 Hz, 3H)。 511.1 A   
I-665
Figure 02_image1623
 CC(O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.47 (s, 1H), 9.08 (s, 1H), 7.93 (d, 8.3 Hz, 1H), 7.73 (d, 8.9 Hz, 1H), 7.65 (s, 1H), 7.54 (s, 1H), 7.36-7.26 (m, 2H), 7.09 (td, 8.4, 3.0 Hz, 1H), 6.61 (br. s, 1H), 5.94 (br. s, 1H), 4.68 (2xd, 1.2 Hz, 1H), 3.95-3.85 (m, 1H), 2.86-2.72 (m, 2H), 1.09 (2xd, 2.9 Hz, 3H)。 525.1 A   
I-666
Figure 02_image1625
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cccc2cn[nH]c12 1H NMR (400 MHz, DMSO-d6 )  13.02 (s, 1H), 10.28 (s, 1H), 9.16 (s, 1H), 7.86 (s, 1H), 7.78 (d, 8.5 Hz, 1H), 7.72 (d, 7.4 Hz, 1H), 7.63 (t, 7.7 Hz, 1H), 7.57 (d, 7.9 Hz, 1H), 7.45 (d, 7.7 Hz, 1H), 7.20 (d, 8.8 Hz, 1H), 7.14 (s, 1H), 6.89 (t, 7.6 Hz, 1H), 6.64 (d, 7.2 Hz, 1H), 6.31 (s, 1H) 455.3 E   
I-667
Figure 02_image1627
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cccc(F)c1Cl 1H NMR (400 MHz, DMSO-d6) 10.55 (s, 1H), 9.33 (s, 1H), 7.96 (d, 8.4 Hz, 1H), 7.84 (d, 1.7 Hz, 1H), 7.76 (s, 1H), 7.69 (d, 9.0 Hz, 1H), 7.56 (s, 1H), 7.26 (t, 8.7 Hz, 1H), 7.17 (s, 1H), 6.67 (s, 1H), 6.07 (s, 1H)。 545 D   
I-668
Figure 02_image1629
 Cn1ccc2ccc(cc12)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 氯仿-d)  7.80 (s, 1H), 7.64 (d, 8.3 Hz, 1H), 7.48 (d, 1.6 Hz, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 7.25 - 7.16 (m, 1H), 7.09 - 6.97 (m, 2H), 6.87 (d, 15.2 Hz, 2H), 6.66 - 6.26 (m, 1H), 3.85 (s, 3H)。 512.05 D   
I-669
Figure 02_image1631
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cccc(F)c1Cl 1H NMR (400 MHz, DMSO-d6) 10.55 (s, 1H), 9.33 (s, 1H), 7.96 (d, 8.4 Hz, 1H), 7.84 (d, 1.7 Hz, 1H), 7.76 (s, 1H), 7.69 (d, 9.0 Hz, 1H), 7.56 (s, 1H), 7.26 (t, 8.7 Hz, 1H), 7.17 (s, 1H), 6.67 (s, 1H), 6.07 (s, 1H)。 545 A   
I-670
Figure 02_image1633
 Cn1ccc2c(cccc12)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 甲醇-d4)  7.61 (dt, 8.2, 0.9 Hz, 1H), 7.56 - 7.35 (m, 2H), 7.35 - 7.16 (m, 3H), 7.18 - 6.50 (m, 5H), 3.86 (s, 3H)。 512.05 E   
I-671
Figure 02_image1635
 Fc1ccc(F)c(c1)[C@H]1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.59 (s, 1H), 9.27 (s, 1H), 7.98 (d, 8.6 Hz, 1H), 7.82 (d, 1.8 Hz, 1H), 7.78 - 7.70 (m, 2H), 7.68 (s, 1H), 7.09 (dt, 9.7, 4.0 Hz, 2H), 6.88 (dd, 8.1, 4.7 Hz, 1H), 5.85 (s, 1H)。 529 D   
I-672
Figure 02_image1637
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cccc(F)c1Cl 1H NMR (400 MHz, DMSO-d6) 10.55 (s, 1H), 9.33 (s, 1H), 7.96 (d, 8.4 Hz, 1H), 7.84 (d, 1.7 Hz, 1H), 7.76 (s, 1H), 7.69 (d, 9.0 Hz, 1H), 7.56 (s, 1H), 7.26 (t, 8.7 Hz, 1H), 7.17 (s, 1H), 6.67 (s, 1H), 6.07 (s, 1H)。 545 A   
I-673
Figure 02_image1639
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cncc4ccccc34)c12 1H NMR (400 MHz, 甲醇-d4)  9.35 (d, 0.8 Hz, 1H), 8.20 (dd, 7.7, 1.4 Hz, 1H), 8.10 (d, 8.5 Hz, 1H), 7.98 (d, 1.7 Hz, 2H), 7.82 (dddd, 26.6, 8.1, 6.9, 1.3 Hz, 3H), 7.45 (dd, 8.9, 5.0 Hz, 1H), 7.17 (ddd, 8.9, 7.7, 3.0 Hz, 1H), 6.69 (s, 1H), 6.30 (s, 1H)。 510 D   
I-674
Figure 02_image1641
 Fc1ccc(F)c(c1)[C@@H]1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.59 (s, 1H), 9.27 (s, 1H), 7.98 (d, 8.5 Hz, 1H), 7.82 (d, 1.7 Hz, 1H), 7.78 - 7.70 (m, 2H), 7.68 (s, 1H), 7.14- 7.02 (m, 2H), 6.92 - 6.84 (m, 1H), 5.85 (s, 1H)。 531 B   
I-675
Figure 02_image1643
 Fc1ccc(F)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.58 (s, 1H), 9.27 (s, 1H), 7.98 (d, 8.5 Hz, 1H), 7.82 (d, 1.8 Hz, 1H), 7.78- 7.71 (m, 2H), 7.68 (s, 1H), 7.09 (dq, 8.0, 3.0 Hz, 2H), 6.88 (s, 1H), 5.85 (s, 1H)。 529 A   
I-676
Figure 02_image1645
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cc(F)c(F)cc1Cl 1H NMR (400 MHz, DMSO-d6)  10.58 (s, 1H), 9.29 (s, 1H), 7.99 (d, 8.5 Hz, 1H), 7.83 (d, 1.7 Hz, 1H), 7.81 - 7.71 (m, 2H), 7.63 (s, 1H), 7.57 (dd, 10.4, 7.3 Hz, 1H), 6.98 (s, 1H), 5.94 (s, 1H)。 562.9 D   
I-677
Figure 02_image1647
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(F)c(F)cc1Cl 1H NMR (400 MHz, DMSO-d6)  10.58 (s, 1H), 9.32 - 9.27 (m, 1H), 7.98 (d, 8.8 Hz, 1H), 7.83 (d, 1.7 Hz, 1H), 7.81 - 7.71 (m, 2H), 7.63 (s, 1H), 7.57 (dd, 10.4, 7.2 Hz, 1H), 6.91 (s, 1H), 5.94 (s, 1H)。 562.9 A   
I-678
Figure 02_image1649
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)c(F)cc1Cl 1H NMR (400 MHz, DMSO-d6)  10.58 (s, 1H), 9.29 (s, 1H), 7.99 (d, 8.4 Hz, 1H), 7.86 -7.81 (m, 1H), 7.81 - 7.72 (m, 2H), 7.63 (s, 1H), 7.57 (dd, 10.4, 7.3 Hz, 1H), 6.91 (s, 1H), 5.93 (s, 1H)。 562.95 A   
I-679
Figure 02_image1651
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1c(F)cccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.61 (d, 15.9 Hz, 1H), 9.24 (d, 57.4 Hz, 1H), 8.00 - 7.93 (m, 1H), 7.83 (dd, 5.3, 1.7 Hz, 1H), 7.74 - 7.60 (m, 3H), 7.27 (qd, 8.2, 5.9 Hz, 1H), 7.20 - 6.91 (m, 2H), 6.16 (d, 1.9 Hz, 1H)。 544.9 D   
I-680
Figure 02_image1653
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1c(F)cccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.61 (d, 15.9 Hz, 1H), 9.24 (d, 57.5 Hz, 1H), 7.97 (d, 8.4 Hz, 1H), 7.83 (dd, 5.3, 1.7 Hz, 1H), 7.74 - 7.60 (m, 3H), 7.27 (qd, 8.1, 5.9 Hz, 1H), 7.20 - 6.92 (m, 2H), 6.16 (d, 2.0 Hz, 1H)。 544.9 A   
I-681
Figure 02_image1655
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1c(F)cccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.62 (d, 15.8 Hz, 1H), 9.25 (d, 57.4 Hz, 1H), 7.96 (d, 8.5 Hz, 1H), 7.83 (dd, 5.4, 1.8 Hz, 1H), 7.75 - 7.59 (m, 3H), 7.28 (td, 8.4, 6.1 Hz, 1H), 7.20 - 6.91 (m, 2H), 6.16 (s, 1H)。 544.95 D   
I-682
Figure 02_image1657
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cccc(F)c1F 1H NMR (400 MHz, DMSO-d6)  10.58 (s, 1H), 9.30 (s, 1H), 7.98 (d, 8.4 Hz, 1H), 7.84 (d, 1.7 Hz, 1H), 7.79 (d, 1.8 Hz, 1H), 7.73 (d, 9.0 Hz, 1H), 7.63 (s, 1H), 7.35 - 7.24 (m, 1H), 7.05 - 6.95 (m, 1H), 6.80 (t, 7.0 Hz, 1H), 5.95 (s, 1H)。 528.95 B   
I-683
Figure 02_image1659
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cccc(F)c1F 1H NMR (400 MHz, DMSO-d6)  10.58 (s, 1H), 9.30 (s, 1H), 8.02 - 7.95 (m, 1H), 7.84 (d, 1.8 Hz, 1H), 7.79 (d, 1.8 Hz, 1H), 7.73 (d, 8.8 Hz, 1H), 7.63 (s, 1H), 7.29 (q, 8.9 Hz, 1H), 7.00 (q, 7.9 Hz, 1H), 6.80 (t, 7.0 Hz, 1H), 5.95 (s, 1H)。 528.95 D   
I-684
Figure 02_image1661
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cccc(F)c1F 1H NMR (400 MHz, DMSO-d6)  10.58 (s, 1H), 9.31 (s, 1H), 7.99 (d, 8.5 Hz, 1H), 7.84 (d, 1.7 Hz, 1H), 7.79 (t, 2.2 Hz, 1H), 7.73 (d, 9.0 Hz, 1H), 7.62 (s, 1H), 7.29 (q, 8.8 Hz, 1H), 7.03 - 6.95 (m, 1H), 6.84 - 6.76 (m, 1H), 5.95 (s, 1H)。 528.95 D   
I-685
Figure 02_image1663
 CN1CCN(CC1(C)C)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)  9.16 (s, 1H), 8.49 (s, 1H), 7.59 (d, 1.4 Hz, 1H), 7.53 (d, 1.5 Hz, 1H), 7.51-7.44 (m, 1H), 7.23 (td, 8.4, 3.0 Hz, 1H), 6.61 (br. s, 1H), 6.01 (br. s, 1H), 3.23-3.16 (m, 1H), 3.02-2.96 (m, 1H), 2.92 (d, 13.4 Hz, 1H), 2.76 (d, 12.6 Hz, 1H), 2.32-2.20 (m, 2H), 2.06 (s, 3H), 0.84 (s, 3H), 0.69 (s, 3H)。部分甲酸鹽。存在來源於哌𠯤之外消旋雜質(可能為胺基甲酸)，包括-´ 4.01 (t, 6.2 Hz, 2H), 3.66 (t, 6.4 Hz, 2H), 2.10 (s, 3H), 0.90 (s, 3H)。 511.3 E   
I-686
Figure 02_image1665
 CC1CN(CCN1C)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)，呈非對映異構體之約1:1混合物形式，9.16 (br. s, 2H), 8.63 (br. s, 1H), 8.61 (br. s, 1H), 7.58 (d, 1.4 Hz, 2H), 7.49 (br. d, 1.5 Hz, 2H), 7.48 (br. d, 1.3 Hz, 2H), 7.25 (td, 8.5, 3.0 Hz, 2H), 6.56 (br. s, 2H), 5.97 (br. s, 2H), 3.69-3.64 (m, 1H), 3.64-3.43 (m, 4H), 2.79-2.70 (m, 1H), 2.62-2.52 (m, 1H), 2.34 (dd, 12.9, 10.6 Hz, 1H), 2.18-2.12 (m, 1H), 2.11 (s, 6H), 1.90-1.82 (m, 1H), 1.80-1.72 (m, 1H), 1.72-1.65 (m, 1H), 1.62-1.52 (m, 1H), 1.49-1.36 (m, 1H), 0.89 (d, 6.2 Hz, 3H), 0.87 (d, 6.3 Hz, 3H)。 497.3 E   
I-687
Figure 02_image1667
 COc1cccc(c1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSOd6)  10.42 (s, 1H), 9.07 (s, 1H), 7.96 (d, 8.5 Hz, 1H), 7.70 (d, 8.2 Hz, 1H), 7.67 (m, 2H), 7.59 (t, 7.6 Hz, 1H), 7.49 (d, 7.7 Hz, 1 H), 7.08 (t, 7.9 Hz, 1H), 6.75 (dd, 8.2, 2.4 Hz, 1H), 6.53 (bs, 1H), 6.48 (d, 7.7 Hz, 1H), 5.68 (s, 1H), 3.48 (s, 3H)。 445.2 E   
I-688
Figure 02_image1669
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Cl)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, CD3CN)  8.64 (br s,1H), 7.74 (d, 1.8 Hz, 1H), 7.63 (d,  6.0 Hz, 1H), 7.60 (s, 1H), 7.56 (d,  6.0 Hz, 1H), 7.53 (s, 1H), 7.30 (br s, 1H), 7.25 (dd, 8.8, 5.2 Hz, 1H), 6.96 (td, 8.4, 3.1 Hz, 1H), 6.66 (br s, 1H), 6.09 (br s, 1H)。 542.3 A   
I-689
Figure 02_image1671
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1COC1 1H NMR (400 MHz, DMSO-d6)  9.29 (s, 1H), 8.40 (s,1H), 7.89-7.64 (m, 4H), 7.37 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.4, 3.1 Hz, 1H), 6.75 (br s, 1H), 5.96 (s, 1H), 4.94 (dd, 8.5, 5.5 Hz , 2H), 4.89 (dd, 6.7, 5.7 Hz, 1H), 4.83 (dd, 6.7, 5.7 Hz, 1H), 4.53 -4.40 (m, 1H)。 524.1 B   
I-690
Figure 02_image1673
 COCc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, ACN)  8.61 (s, 1H), 7.69 (s, 1H), 7.65 (d, 8.5 Hz, 1H), 7.61-7.55 (m, 2H), 7.53 (s, 1H), 7.25 (dd, 8.9, 5.1 Hz, 1H), 7.22 (br s, 1H), 6.97 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.64 (br s, 1H), 6.11 (br s, 1H), 4.59 (s, 2H), 3.41 (s, 3H)。 511.2 B   
I-691
Figure 02_image1675
 COCc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, ACN)  8.61 (s, 1H), 7.69 (s, 1H), 7.65 (d, 8.5 Hz, 1H), 7.61-7.55 (m, 2H), 7.53 (s, 1H), 7.25 (dd, 8.9, 5.1 Hz, 1H), 7.22 (br s, 1H), 6.97 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.64 (br s, 1H), 6.11 (br s, 1H), 4.59 (s, 2H), 3.41 (s, 3H)。 511.2 A A
I-692
Figure 02_image1677
 Cc1ccccc1C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C(F)F NMR (400 MHz, DMSO)  10.49 (s, 1H), 9.24 (s, 1H), 7.87 (d, 8.6 Hz, 1H), 7.82 (d, 0.8 Hz, 1H), 7.73 (s, 1H), 7.46 (d, 8.5 Hz, 1H), 7.31 (s, 1H), 7.21 (t, 55.6 Hz, 1H), 7.04 (td, 7.5, 1.3 Hz, 1H), 6.97 (d, 6.7 Hz, 1H), 6.92 (t, 7.6 Hz, 1H), 6.48 (br s, 1H), 5.94 (s, 1H), 2.20 (br s, 3H)。 479.2 B   
I-693
Figure 02_image1679
 Cc1ccccc1C1NC(=O)c2cc(Br)cc(NC(=O)c3cncc(n3)C(F)(F)F)c12 NMR (400 MHz, CDCl3)  9.65 (s, 1H), 9.15 (s, 1H), 8.92 (s, 1H), 8.37 (br. d, 7.7 Hz, 1H), 7.86 (dd, 7.6, 0.8 Hz, 1H), 7.69 (t, 7.8 Hz, 1H), 7.42 (dd, 8.8, 4.9 Hz, 1H), 7.00 (ddd, 8.9, 7.5, 3.0 Hz, 1H), 6.68 (s, 1H), 6.59 (br. s, 1H), 6.26 (s, 1H), 1.63 (br. s, 3H)。 492.3 E   
I-694
Figure 02_image1681
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(Cl)cc(F)c3Cl)c12 NMR (400 MHz, DMSO-d6)  10.46 (br. s, 1H), 9.31 (br. s, 1H), 7.84 (d, 9.6 Hz, 1H), 7.80 (d, 1.6 Hz, 1H), 7.72 (d, 1.4 Hz, 1H), 7.46 (dd, 8.3, 5.3 Hz, 1H), 7.30 (d, 6.7 Hz, 1H), 7.24 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.67 (br. s, 1H), 5.98 (br. s, 1H), 547 D   
I-695
Figure 02_image1683
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(NCC3(CC3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.32 (s, 1H), 8.94 (s, 1H), 7.92 (d, 8.3 Hz, 1H), 7.70 (d, 8.9 Hz, 1H), 7.62 (s, 1H), 7.28 (dd, 8.8, 5.2 Hz, 1H), 7.06 (td, 8.5, 2.9 Hz, 1H), 6.92 (d, 1.6 Hz, 1H), 6.79 (s, 1H), 6.62 (br s, 1H), 6.57 (br t, 5.6 Hz, 1H), 5.84 (br s, 1H), 3.30 (m, 2H), 1.33-1.17 (m, 2H), 1.14-0.98 (m, 2H)。 559.5 A   
I-696
Figure 02_image1685
 CC(C)(O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(CC(C)(C)O)c2)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO)  10.13 (s, 1H), 9.03 (s, 1H), 7.52 (s, 1H), 7.37-7.28 (m, 3H), 7.22 (d, 9.7 Hz, 1H), 7.11 (m, 2H), 6.61 (s, 1H), 6.00 (s, 1H), 4.45 (s, 1H), 4.42 (s, 1H), 2.82 (d, 12.7 Hz, 1H), 2.77 (d, 13.4 Hz, 1H), 2.67 (s, 2H), 1.12 (s, 3H), 1.09 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H)。 543 E   
I-697
Figure 02_image1687
 CCOC(=O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(CC(=O)OCC)c2)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO)  10.23 (s, 1H), 9.12 (s, 1H), 7.59 (s, 1H), 7.41 (s, 1H), 7.36-7.32 (m, 3H), 7.18 (m, 1H), 7.12 (td, 8.5, 3.2 Hz, 1H), 6.58 (br s, 1H), 5.99 (br s, 1H), 4.12 (q,  7.1, 2H), 4.11 (q, 7.1, 2H), 3.90 (d, AB之A, 16 Hz, 1H), 3.85 (d, AB之B, 16 Hz, 1H), 3.74 (s, 2H), 1.21 (t, 7.1, 3H), 1.20 (tt, 7.1, 3H)。 571 D   
I-698
Figure 02_image1689
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCOCC(F)(F)C3)c12 1H-NMR (400 MHz, DMSO-d6)-9.22 (s, 1H), 8.66 (s, 1H), 7.66 (d, 1.6 Hz, 1H), 7.55 (d, 1.7 Hz, 1H), 7.53-7.47 (m, 1H), 7.23 (td, 8.4, 3.1 Hz, 1H), 6.57 (br. s, 1H), 6.04 (br s, 1H), 4.17 (dt, 15.4, 11.2 Hz, 1H), 3.77-3.53 (m, 4H), 3.52-3.41 (m, 2H), 3.19 (ddd, 14.6, 8.0, 3.6 Hz, 1H)。 518.2 E   
I-699
Figure 02_image1691
 CC(C)n1cc(ccc1=O)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 500 MHz):-´ = 10.54 (s, 1H), 9.17 (br s, 1H), 8.17 (d, 2.7 Hz, 1H), 7.94-7.98 (m, 2H), 7.88 (dd, 9.5, 2.6 Hz, 1H), 7.68-7.78 (m, 3H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.4, 3.1 Hz, 1H), 6.55-6.84 (m, 1H), 6.52 (d, 9.5 Hz, 1H), 6.00 (br s, 1H), 5.12 (quin, 6.8 Hz, 1H), 1.40  (dd, 6.9, 2.9 Hz, 6H) 602.1 A   
I-700
Figure 02_image1693
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc(=O)n(c1)C1CC1 1H NMR (DMSO-d6, 500 MHz) 10.53 (s, 1H), 9.16 (br s, 1H), 7.93-7.98 (m, 2H), 7.91 (d, 1.2 Hz, 1H), 7.88 (dd, 9.5, 2.7 Hz, 1H), 7.76 (br d, 8.2 Hz, 1H), 7.70 (s, 2H), 7.32 (dd, 8.9, 5.1 Hz, 1H), 7.10 (td, 8.4, 3.1 Hz, 1H), 6.54-6.76 (m, 1H), 6.51 (d, 9.3 Hz, 1H), 6.01 (br s, 1H), 3.38-3.43 (m, 1H), 0.99-1.05  (m, 4H) 600.1 A   
I-701
Figure 02_image1695
 Cn1cc(ccc1=O)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.90 (s, 1H), 9.52 (s, 1H), 8.62 (d,J = 1.5 Hz, 1H), 8.18 (dd,J = 8.6, 1.6 Hz, 1H), 7.98 (d,J = 8.7, 1H), 7.87 (s, 1H), 7.75 (d,J = 8.5, 1H), 7.67 (s, 1H), 7.35 (m, 1H), 7.10 (td, 8.6, 1.6 Hz, 1H), 6.57 (d,J = 8.8 Hz, 1H), 6.02 (s, 1H), 3.59 (s, 3H)。 574.3 C   
I-702
Figure 02_image1697
 Cn1cc(ccc1=O)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1 H NMR (400 MHz, DMSO-d6 ) δ 10.90 (s, 1H), 9.52 (s, 1H), 8.62 (d,J = 1.5 Hz, 1H), 8.18 (dd,J = 8.6, 1.6 Hz, 1H), 7.98 (d,J = 8.7, 1H), 7.87 (s, 1H), 7.75 (d,J = 8.5, 1H), 7.67 (s, 1H), 7.35 (m, 1H), 7.10 (td, 8.6, 1.6 Hz, 1H), 6.57 (d,J = 8.8 Hz, 1H), 6.02 (s, 1H), 3.59 (s, 3H)。 574.2 A   
I-703
Figure 02_image1699
 CCn1cc(ccc1=O)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    588.2 E   
I-704
Figure 02_image1701
 CCn1cc(ccc1=O)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    588.4 A   
I-705
Figure 02_image1703
 COc1ccc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    574 A   
I-706
Figure 02_image1705
 OC1(Cc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CCC1 1H NMR (500 MHz, DMSO-d6)  1.48 - 1.67 (m, 2H), 1.88 - 2.03 (m, 4H), 2.94 (d, 15.26 Hz, 2H), 5.10 (s, 1H), 5.79 - 6.05 (m, 1H), 7.07 (td, 8.32, 3.05 Hz, 1H), 7.29 (dd, 8.85, 5.19 Hz, 1H), 7.38 (s, 1H), 7.63 (d, 17.85 Hz, 2H), 7.72 (br d, 8.85 Hz, 1H), 7.91 (br d, 8.39 Hz, 1H), 9.04 (br s, 1H), 10.44 (s, 1H) 551.41 A   
I-707
Figure 02_image1707
 OCCNc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO-d6)  3.16 (q,  5.80 Hz, 2 H) 3.55 - 3.63 (m, 2 H) 4.75 (br t,  4.43 Hz, 1 H) 6.13 - 6.18 (m, 1 H) 6.69 (s, 1 H) 6.75 (br s, 1 H) 6.82 (d,  1.83 Hz, 1 H) 7.04 (td,  8.28, 2.98 Hz, 1 H) 7.26 (dd,  8.85, 5.19 Hz, 1 H) 7.61 (s, 1 H) 7.66 - 7.71 (m, 1 H) 7.89 (br d,  8.09 Hz, 1 H) 8.50 (s, 1 H) 8.87 (br s, 1 H) 10.26 (s, 1 H) 526.4 A   
I-708
Figure 02_image1709
 CC(=O)COc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 500 MHz) 10.3-10.6 (m, 1H), 9.0-9.2 (m, 1H), 7.8-8.0 (m, 1H), 7.63 (s, 2H), 7.2-7.4 (m, 1H), 7.1-7.2 (m, 1H), 7.0-7.1 (m, 2H), 5.8-6.1 (m, 1H), 4.9-5.2 (m, 2H), 2.1-2.3 (m, 3H), 1.0-1.3 (m, 3H) 539 A   
I-709
Figure 02_image1711
 CC(C)(O)COc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 500 MHz) 10.3-10.5 (m, 1H), 9.0-9.2 (m, 1H), 7.9-8.1 (m, 1H), 7.7-7.8 (m, 1H), 7.6-7.7 (m, 1H), 7.3-7.4 (m, 1H), 7.1-7.2 (m, 1H), 7.0-7.1 (m, 2H), 6.3-6.8 (m, 1H), 5.7-6.1 (m, 1H), 4.5-4.8 (m, 1H), 3.7-3.9 (m, 2H), 1.1-1.4 (m, 6H) 555 A   
I-710
Figure 02_image1713
 CC1(Cc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)COC1 1H NMR (400 MHz, DMSO-d6)  1.24 (s, 2 H) 1.25 - 1.25 (m, 1 H) 2.83 - 3.16 (m, 3 H) 4.23 (d,  5.56 Hz, 2 H) 4.58 (t,  5.68 Hz, 2 H) 5.76 - 6.07 (m, 1 H) 7.09 (td,  8.46, 3.03 Hz, 1 H) 7.28 - 7.33 (m, 2 H) 7.51 (s, 1 H) 7.65 (s, 1 H) 7.73 (br d,  8.59 Hz, 1 H) 7.94 (br d,  8.59 Hz, 1 H) 9.10 (br s, 1 H) 10.45 (s, 1 H) 551.41 A   
I-711
Figure 02_image1715
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc4cc[nH]c34)c12       A   
I-712
Figure 02_image1717
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ncc[nH]1 1H NMR (400 MHz, DMSO-d6)  12.83 (br. s, 1H), 10.65 (s, 1H), 9.22 (s, 1H), 8.37 (s, 1H), 8.27 (d, 0.7 Hz, 1H), 8.14 (d, 1.0 Hz, 1H), 7.96 (d, 8.3 Hz, 1H), 7.77 (d, 8.6 Hz), 7.69 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.34-7.07 (m, 1H), 7.09 (td, 8.5, 3.0 Hz, 1H), 6.66 (br. s, 1H), 6.02 (br. s, 1H)。 533.2 A   
I-713
Figure 02_image1719
 CC(C)(O)c1cc2C(=O)N[C@H](c2c(NC(=O)N2CCc3ccccc23)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6 )  8.99 (s, 1H), 8.55 (s, 1H), 7.71 (d, 7.9 Hz, 1H), 7.65 (d, 1.4 Hz, 1H), 7.49 (d, 1.4 Hz, 1H), 7.36 (dd, 8.9, 5.2 Hz, 1H), 7.20-7.11 (m, 2H), 7.09 (t, 7.7 Hz, 1H), 6.88 (td, 7.4, 1.0 Hz, 1H), 6.54 (br s, 1H), 5.97 (br s, 1H), 5.25 (br s, 1H), 3.93-3.83 (m, 1H), 3.09-2.93 (m, 3H), 1.49 (s, 6H)。 480.2 A   
I-714
Figure 02_image1721
 CC(C)(O)c1cc2C(=O)N[C@@H](c2c(NC(=O)N2CCc3ccccc23)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6 )  8.99 (s, 1H), 8.55 (s, 1H), 7.71 (d, 7.9 Hz, 1H), 7.65 (d, 1.4 Hz, 1H), 7.49 (d, 1.4 Hz, 1H), 7.36 (dd, 8.9, 5.2 Hz, 1H), 7.20-7.11 (m, 2H), 7.09 (t, 7.7 Hz, 1H), 6.88 (td, 7.4, 1.0 Hz, 1H), 6.54 (br s, 1H), 5.97 (br s, 1H), 5.25 (br s, 1H), 3.93-3.83 (m, 1H), 3.09-2.93 (m, 3H), 1.49 (s, 6H) 480.2 E   
I-715
Figure 02_image1723
 CC(C)c1cc(F)cc(c1)C(=O)Nc1cccc2C(=O)NC(c12)c1ccccc1C 1H NMR (400 MHz, DMSO-d6)  10.03 (s, 1H), 9.05 (s, 1H), 7.65 (dd, 6.8, 1.8 Hz, 1H), 7.62-7.55 (m, 2H), 7.24 (dt, 9.9, 2.0 Hz, 1H), 7.09 (td, 7.3, 1.2 Hz, 1H), 7.03 (d, 7.1 Hz, 1H), 7.00 - 6.94 (m, 2H), 6.92 (d, 9.1 Hz, 1H), 6.55 (br s, 1H), 5.96 (s, 1H), 2.86 (七重峰, 6.8 Hz, 1H), 2.21 (br s, 3H), 1.18 (d, 1.7 Hz, 3H), 1.16 (d, 1.7 Hz, 3H)。 403.3 D   
I-716
Figure 02_image1725
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCNc4ccccc34)c12 (400 MHz, DMSO-d6)  9.20 (br s, 1H), 8.70 (s, 1H), 7.66-7.57 (m, 2H), 7.48 (dd, 8.7, 5.0 Hz, 1H), 7.22 (td, 8.4, 2.9 Hz, 1H), 6.76 (ddd, 8.1, 7.3, 1.4 Hz, 1H), 6.54 (dd, 8.1, 1.3 Hz, 1H), 6.19 (ddd, 8.4, 7.4, 1.4 Hz, 1H), 6.12-5.97 (m, 3H), 4.07-3.95 (m, 1H), 3.31-3.24 (m, 2H), 3.03 (t, 9.0 Hz, 1H), 2.91 (t, 9.0 Hz, 1H)。 515.1 D   
I-717
Figure 02_image1727
 OB(O)c1cccc(c1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, d6-DMSO)  10.35 (s, 1H), 9.05 (s, 1H), 7.92 (s, 1H), 7.90 (s, 2H), 7.68 (dd, 7.4, 0.9 Hz, 1H), 7.66-7.61 (m, 3H), 7.58 (t, 7.6 Hz, 1H), 7.47 (d, 7.7 Hz, 1H), 7.44 (s, 1H), 7.07 (t, 7.5 Hz, 1H), 6.99 (m, 1H), 5.71 (s, 1H)。 457.4 E   
I-718
Figure 02_image1729
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cccc(c1)C1CC1 (400 MHz, d6-DMSO)  10.40 (s, 1H), 9.03 (s, 1H), 7.97 (d, 8.3 Hz, 1H), 7.70 (s, 1H ), 7.69-7.64 (m, 2H), 7.59 (app t, 7.6 Hz, 1H), 7.45 (d, 7.1 Hz, 1H), 7.03 (app t, 7.7 Hz, 1H), 6.85 (d, 7.7 Hz, 1H), 6.71 (s, 1H), 6.61 (d, 7.6 Hz, 1H), 5.65 (s, 1H), 1.63-1.52 (m, 1H), 0.75-0.60 (m, 2H), 0.40-0.30 (m, 1H), 0.23-0.13 (m, 1H)。 455.2 E   
I-719
Figure 02_image1731
 Nc1ccc(cc1C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  9.99 (s, 1H), 9.22 (s, 1H), 7.76 - 7.67 (m, 2H), 7.59 - 7.51 (m, 2H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.08 (td, 8.4, 3.1 Hz, 1H), 6.78 (d, 8.6 Hz, 2H), 6.27 (s, 2H), 5.99 (s, 1H)。 542 D   
I-720
Figure 02_image1733
 F[C@H]1CCN(C[C@@H]1F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)，呈非對映異構體之約1:1混合物形式-´ 9.18 (br. s, 2H), 8.74 (s, 1H), 8.70 (s, 1H), 7.62-7.59 (m, 2H), 7.55 (d, 1.7 Hz, 1H), 7.48 (d, 1.7 Hz, 1H), 7.51-7.43 (m, 2H), 7.27-7.18 (m, 2H), 6.64 (br. s, 2H), 5.96 (br. s, 2H), 4.98-4.86 (m, 1H), 4.85-4.61 (m, 2H), 4.60-4.39 (m, 1H), 3.67-3.57 (m, 1H), 3.57-3.47 (m, 1H), 3.28-3.18 (m, 2H), 3.12-3.02 (m, 1H), 2.96-2.88 (m, 1H), 1.85-1.66 (m, 3H), 1.63-1.50 (m, 1H)。 504.2 E   
I-721
Figure 02_image1735
 O[C@@H]1CC[C@H]1Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, CD3CN)  8.49 (d, 11.1 Hz, 1H), 7.63 (d, 8.6 Hz, 1H), 7.56 (m, 3H), 7.23 (dd, 8.8, 5.1 Hz, 1H), 7.08 (s, 1H), 7.00 (t, 1.9 Hz, 1H), 6.97-6.92 (m, 1H), 6.85 (s, 1H), 6.64 (s, 1H), 5.96 (s, 1H), 5.19 (d, 6.1 Hz, 1H), 3.90 (dd, 15.2, 7.9 Hz, 1H), 3.67 (m, 1H), 1.62-1.44 (m 1H), 1.35-1.18 (m, 3H)。 552.2 A   
I-722
Figure 02_image1737
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCCC4CCCC34)c12 1H NMR (400 MHz, CDCl3)  8.15 (d, 7.2 Hz, 1H), 7.78 (d, 1.3 Hz, 1H), 7.44 (dd, 8.7, 5.1 Hz, 1H), 7.08-7.04 (m, 1H), 6.64 (s, 1H), 6.42 (s, 1H), 6.09 (s, 1H), 5.99-5.96 (m, 1H), 3.81-3.61 (m, 2H), 2.72-2.58 (m, 1H), 1.86-1.71 (m, 3H), 1.69-1.52 (m, 11H), 1.51-1.39 (m, 4H), 1.37-1.24 (m, 3H), 1.21-1.12 (m, 1H)。 508 B   
I-723
Figure 02_image1739
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CC(C1)C#N NMR (400 MHz, CD3CN)  8.49 (s, 1H), 7.62 (d, 8.5 Hz, 1H), 7.55 (d, 8.9 Hz, 1H), 7.52 (s, 1H), 7.22 (dd, 8.9, 5.1 Hz, 1H), 7.12 (br s, 1H), 6.97-6.90 (m), 6.79 (d, 2.0 Hz, 1H), 6.65 (s, 1H), 6.59 (br s, 1H), 5.99 (br s, 1H), 4.24-4.17 (m, 2H), 4.13-4.07 (m, 2H), 3.68 (m, 1H)。 547.3 A   
I-724
Figure 02_image1741
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(cc(Cl)n3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.29 (br. s, 1H), 9.14 (br. s, 1H), 8.33 (s, 1H), 8.15 (s, 1H), 7.75 (dd, 7.5, 0.9 Hz, 1H), 7.70-7.60 (m, 1H), 7.32 (dd, 8.8, 5.0 Hz, 1H), 7.07 (td, 8.5, 2.9 Hz, 1H), 6.58 (br. s, 1H), 6.11 (br. s, 1H)。 484.2 D   
I-725
Figure 02_image1743
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(Cl)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.52 (br. s, 1H), 9.15 (br. s, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.76 (s, 1H), 7.71 (d, 7.1 Hz, 1H), 7.64 (t, 7.6 Hz, 1H), 7.49 (d, 7.5 Hz, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.4, 3.0 Hz, 1H), 6.52 (br. s, 1H), 5.98 (br. s, 1H)。 483.1 C   
I-726
Figure 02_image1745
 Nc1cc(cc(n1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(F)(F)F 1H NMR (400 MHz, DMSO-d6)  9.86 (s, 1H), 9.14 (s, 1H), 7.86 (dd, 6.7, 2.2 Hz, 1H), 7.64-7.60 (m, 2H), 7.41-7.32 (m, 1H), 7.22 (s, 1H), 7.11 (td, 8.4, 3.0 Hz, 1H), 6.97-6.95 (m, 1H), 6.63 (br. s, 2H), 6.63 (br. s, 1H), 6.12 (br. s, 1H)。 465.2 D   
I-727
Figure 02_image1747
 Cn1c2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)cc1=O)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  8.35 (s, 1H), 8.12-8.01 (m, 1H), 7.95 (d, 8.7 Hz, 1H), 7.83 (br. s, 2H), 7.57 (br. s, 1H), 7.27 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.42 (br. s, 1H), 5.68 (s, 1H), 3.56 (s, 3H) 498.3 E   
I-728
Figure 02_image1749
 COC1CN(C1)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN)  8.49 (s, 1H), 7.63 (d, 8.6 Hz, 1H), 7.57 (d, 9.2 Hz, 1H), 7.55 (s, 1H), 7.24 (dd, 8.8, 5.2 Hz, 1H), 7.11 (br s, 1H), 6.99-6.89 (m, 1H), 6.76 (d, 2.0 Hz, 1H), 6.63 (br s, 2H), 6.01 (br s, 1H), 4.39-4.33 (m, 1H), 4.27-4.07 (m, 2H), 3.95-3.65 (m, 2H), 3.31 (s, 3H)。 552.3 B   
I-729
Figure 02_image1751
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CC2(COC2)C1 NMR (400 MHz, DMSO-d6 )  10.35 (s, 1H), 9.00 (br. s, 1H), 7.93 (d, 8.4 Hz, 1H), 7.71 (d, 8.9 Hz, 1H), 7.64 (s, 1H), 7.29 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.3, 3.1 Hz, 1H), 6.67 (d, 2.0 Hz, 1H), 6.52 (d, 1.5 Hz, 1H), 6.63-6.44 (br. s, 1H) 5.87 (br. s, 1H), 4.77-4.71 (m, 4H), 4.12-4.03 (m, 4H)。 564.3 A   
I-730
Figure 02_image1753
 CC(C)(O)CNc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO-d6)  1.19 (s, 6 H) 3.02 (dd,  5.72, 1.30 Hz, 2 H) 5.82 (br s, 1 H) 5.96 (br t,  5.19 Hz, 1 H) 6.78 (d,  1.37 Hz, 1 H) 6.90 (d,  1.98 Hz, 1 H) 7.05 (td,  8.39, 3.05 Hz, 1 H) 7.27 (dd,  8.85, 5.19 Hz, 1 H) 7.63 (s, 1 H) 7.69 (br d,  9.77 Hz, 1 H) 7.90 (br d,  8.39 Hz, 1 H) 8.86 (br s, 1 H) 10.18 - 10.31 (m, 1 H) 554.36 A   
I-731
Figure 02_image1755
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3coc4c(F)cc(F)cc34)c12 1H NMR (500 MHz, DMSO-d6)  6.03 (br s, 1 H) 7.05 (td,  8.35, 3.13 Hz, 1 H) 7.29 (dd,  8.85, 5.19 Hz, 1 H) 7.38 - 7.55 (m, 2 H) 7.70 (s, 1 H) 7.80 (d,  1.53 Hz, 1 H) 8.48 (s, 1 H) 9.26 (br s, 1 H) 10.32 (br s, 1 H) 537.25 A   
I-732
Figure 02_image1757
 Cc1ncc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    559 A   
I-733
Figure 02_image1759
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(Br)cc(NC(=O)c3csc4ccccc34)c12    517.3 D   
I-734
Figure 02_image1761
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Br)cc(NC(=O)c3csc4ccccc34)c12    517.3 A   
I-735
Figure 02_image1763
 CS(=O)(=O)CCCOc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz)  10.3-10.4 (m, 1H), 10.0-10.1 (m, 1H), 7.8-8.0 (m, 1H), 7.6-7.7 (m, 1H), 7.5-7.6 (m, 1H), 7.2-7.3 (m, 1H), 7.1-7.1 (m, 1H), 7.0-7.0 (m, 1H), 6.9-7.0 (m, 1H), 6.8-6.9 (m, 1H), 6.2-6.6 (m, 1H), 5.8-6.1 (m, 1H), 4.3-4.5 (m, 2H), 3.2-3.5 (m,2H) 3.0-3.0 (m, 3H), 2.1-2.3 (m, 2H) 603 B   
I-736
Figure 02_image1765
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nccn2c1    583 A   
I-737
Figure 02_image1767
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncccc2c1    594 A   
I-738
Figure 02_image1769
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2OC(F)(F)Oc2c1    623 B   
I-739
Figure 02_image1771
 CC(C)(O)COc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz) 10.3-10.5 (m, 1H), 8.9-9.2 (m, 1H), 7.8-8.1 (m, 1H), 7.7-7.8 (m, 1H), 7.6-7.7 (m, 1H), 7.2-7.3 (m, 1H), 7.1-7.2 (m, 1H), 7.0-7.1 (m, 2H), 6.2-6.9 (m, 1H), 5.7-6.1 (m, 1H), 4.6-4.7 (m, 1H), 4.0-4.1 (m, 2H), 1.1-1.3 (m, 6H) 555 D   
I-740
Figure 02_image1773
 CC(C)(O)COc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz) 10.3-10.6 (m, 1H), 8.9-9.3 (m, 1H), 7.9-8.0 (m, 1H), 7.7-7.8 (m, 1H), 7.6-7.7 (m, 1H), 7.2-7.4 (m, 1H), 7.1-7.2 (m, 1H), 7.0-7.1 (m, 2H), 6.2-6.9 (m, 1H), 5.7-6.1 (m, 1H), 4.6-4.8 (m, 1H), 4.0-4.2 (m, 2H), 1.1-1.3 (m, 6H) 555 A   
I-741
Figure 02_image1775
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2OCOc2c1    587 A   
I-742
Figure 02_image1777
 CC(C)n1cc(ccc1=O)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    602.4 D   
I-743
Figure 02_image1779
 CC(C)n1cc(ccc1=O)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    602.3 A   
I-744
Figure 02_image1781
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc(=O)n(c1)C1CC1    600.4 D   
I-745
Figure 02_image1783
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc(=O)n(c1)C1CC1    600.4 A   
I-746
Figure 02_image1785
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc(=O)n(c1)C1CC1    601.3 D   
I-747
Figure 02_image1787
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc(=O)n(c1)C1CC1    601.3 A A
I-748
Figure 02_image1789
 CC1(COc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)COC1    567 A   
I-749
Figure 02_image1791
 Cc1c(F)cccc1[C@H]1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.51 (s, 1H), 9.28 (s, 1H), 7.97-7.90 (m, 1H), 7.84- 7.78 (m, 2H), 7.55 (d, 9.0 Hz, 1H), 7.34 (s, 1H), 7.02-6.93 (m, 2H), 6.36 (s, 1H), 5.93 (s, 1H), 2.19 (s, 3H)。 527 D   
I-750
Figure 02_image1793
 Cc1c(F)cccc1[C@@H]1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.50 (s, 1H), 9.28 (s, 1H), 7.93 (dt, 8.7, 2.0 Hz, 1H), 7.84-7.77 (m, 2H), 7.55 (d, 8.8 Hz, 1H), 7.35 (s, 1H), 7.03-6.92 (m, 2H), 6.38 (s, 1H), 5.93 (s, 1H), 2.17 (s, 3H)。 527 B   
I-751
Figure 02_image1795
 Cc1c(F)cccc1C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.50 (s, 1H), 9.28 (s, 1H), 7.93 (d, 8.4 Hz, 1H), 7.87-7.75 (m, 2H), 7.55 (d, 8.9 Hz, 1H), 7.35 (s, 1H), 7.08-6.90 (m, 2H), 6.38 (s, 1H), 5.94 (s, 1H), 2.17 (s, 3H)。 525.15 B   
I-752
Figure 02_image1797
 Fc1ccc(Cl)c(c1)-n1[nH]c(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, CD3CN)  8.65 (s, 1H), 7.92 (d, 1.7 Hz, 1H), 7.68-7.61 (m, 1H), 7.54 7.50 (m, 3H), 7.31 (dd, 9.0, 5.5 Hz, 1H), 7.25 (dd, 8.8, 3.0 Hz, 1H), 6.92 (ddd, 9.0, 8.0, 3.0 Hz, 1H) 544.3 D   
I-753
Figure 02_image1799
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=S)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  7.86 (d, 7.1 Hz, 1H), 7.69 (t, 7.7 Hz, 1H), 7.60 (app d, 8.2 Hz, 1H), 7.55 (app d, 8.3 Hz, 2H), 7.38 (s, 1H), 7.33 (dd, 8.9, 5.1 Hz, 1H), 7.28-7.19 (m, 1H), 7.06 (ddd, 8.8, 8.1, 3.1 Hz, 1H), 6.69 (br s, 1H), 6.15 (br s, 1H)。 481.3 C   
I-754
Figure 02_image1801
 Fc1ccc([C@H]2NC(=O)c3cc(Br)cc(NC(=O)c4cc(F)cc(c4)C(F)(F)F)c23)c(Cl)c1 1H NMR (400 MHz, 氯仿-d) 8.46 (s, 1H), 7.93 (d, 1.6 Hz, 1H), 7.58 - 7.49 (m, 2H), 7.47 (s, 1H), 7.38 (s, 1H), 7.25 - 7.18 (m, 1H), 7.00 (s, 2H), 6.70 (s, 1H), 6.19 (s, 1H)。 547 D   
I-755
Figure 02_image1803
 Fc1ccc([C@@H]2NC(=O)c3cc(Br)cc(NC(=O)c4cc(F)cc(c4)C(F)(F)F)c23)c(Cl)c1 1H NMR (400 MHz, 氯仿-d)  8.46 (s, 1H), 7.93 (d, 1.7 Hz, 1H), 7.58 - 7.49 (m, 2H), 7.45 (s, 1H), 7.38 (s, 1H), 7.21 (dd, 7.9, 1.9 Hz, 1H), 7.01 (s, 2H), 6.69 (s, 1H), 6.19 (s, 1H)。 547 B   
I-756
Figure 02_image1805
 Fc1ccc(C2NC(=O)c3cc(Br)cc(NC(=O)c4cc(F)cc(c4)C(F)(F)F)c23)c(Cl)c1 1H NMR (400 MHz, 甲醇-d4) 7.96 (d, 1.7 Hz, 1H), 7.81 - 7.68 (m, 2H), 7.69 - 7.50 (m, 2H), 7.11 (dd, 8.7, 2.5 Hz, 1H), 6.93 (s, 2H), 6.22 (s, 1H)。 547 B   
I-757
Figure 02_image1807
 Cc1ccc(F)cc1[C@H]1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.53 (s, 1H), 9.26 (s, 1H), 7.97-7.90 (m, 1H), 7.82 (d, 1.7 Hz, 1H), 7.77 (t, 2.0 Hz, 1H), 7.59 (d, 9.0 Hz, 1H), 7.46 (s, 1H), 7.04 (dd, 8.5, 5.9 Hz, 1H), 6.90 (td, 8.4, 2.8 Hz, 1H), 6.40 (s, 1H), 5.86 (s, 1H), 2.33 (s, 3H)。 525 D   
I-758
Figure 02_image1809
 Cc1ccc(F)cc1[C@@H]1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.53 (s, 1H), 9.26 (s, 1H), 7.97-7.90 (m, 1H), 7.82 (d, 1.7 Hz, 1H), 7.77 (t, 2.0 Hz, 1H), 7.59 (d, 9.0 Hz, 1H), 7.46 (s, 1H), 7.04 (dd, 8.5, 5.9 Hz, 1H), 6.90 (td, 8.4, 2.8 Hz, 1H), 6.40 (s, 1H), 5.86 (s, 1H), 2.33 (s, 3H)。 525 A   
I-759
Figure 02_image1811
 Cc1ccc(F)cc1C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.53 (s, 1H), 9.26 (s, 1H), 7.97-7.90 (m, 1H), 7.82 (d, 1.7 Hz, 1H), 7.77 (t, 2.0 Hz, 1H), 7.59 (d, 9.0 Hz, 1H), 7.46 (s, 1H), 7.04 (dd, 8.5, 5.9 Hz, 1H), 6.90 (td, 8.4, 2.8 Hz, 1H), 6.40 (s, 1H), 5.86 (s, 1H), 2.33 (s, 3H)。 525 A   
I-760
Figure 02_image1813
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3nncc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  11.16 - 9.18 (d, 750.6 Hz, 1H), 9.13 (d, 29.5 Hz, 1H), 8.02 (d, 8.5 Hz, 1H), 7.98 - 7.80 (m, 2H), 7.80 - 7.60 (m, 3H), 7.55 - 7.13 (m, 1H), 6.95 (s, 2H), 6.73 - 6.19 (m, 1H), 5.81 (s, 1H)。 483 E   
I-761
Figure 02_image1815
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3nccc4cccnc34)c12 1H NMR (400 MHz, DMSO-d6)  9.30 (s, 1H), 9.04 (s, 1H), 8.89 (s, 1H), 8.76 (dd, 4.2, 1.6 Hz, 1H), 8.31 (dd, 8.3, 1.7 Hz, 1H), 8.13 (dd, 5.8, 1.7 Hz, 1H), 7.78 (dd, 8.3, 4.2 Hz, 1H), 7.58 (d, 1.8 Hz, 1H), 7.47 (s, 1H), 7.27 (d, 5.8 Hz, 1H), 7.16 (td, 8.3, 3.0 Hz, 1H), 6.73 (s, 1H), 6.22 (s, 1H)。 483 E   
I-762
Figure 02_image1817
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3nccc4ccccc34)c12 1H NMR (400 MHz, 氯仿-d)  8.40 (s, 1H), 8.10 (s, 1H), 7.85 (d, 1.7 Hz, 1H), 7.77 (d, 8.3 Hz, 1H), 7.66 (ddd, 8.1, 6.8, 1.1 Hz, 1H), 7.45 (ddd, 8.3, 6.9, 1.3 Hz, 2H), 7.28 (s, 3H), 6.97 - 6.87 (m, 1H), 6.67 (dd, 8.7, 3.0 Hz, 1H), 6.49 (s, 1H), 6.17 (s, 1H)。 482 D   
I-763
Figure 02_image1819
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(Cl)ccc1Cl 1H NMR (400 MHz, 甲醇-d4) 7.97 (d, 1.7 Hz, 1H), 7.83-7.58 (m, 4H), 7.39 -7.18 (m, 2H), 7.00 (s, 1H), 6.07 (s, 1H)。 562.85 A   
I-764
Figure 02_image1821
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cc(Cl)ccc1Cl 1H NMR (400 MHz, 氯仿-d)  8.40 (s, 1H), 7.98 (d, 1.7 Hz, 1H), 7.59-7.50 (m, 2H), 7.43 (s, 2H), 7.39 (d, 8.6 Hz, 1H), 7.33 (dd, 8.6, 2.4 Hz, 1H), 6.98 (s, 1H), 6.52 (s, 1H), 6.17 (s, 1H)。 563.05 D   
I-765
Figure 02_image1823
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(Cl)ccc1Cl 1H NMR (400 MHz, 氯仿-d)  8.40 (s, 1H), 7.98 (d, 1.7 Hz, 1H), 7.55 (td, 8.4, 7.2, 4.1 Hz, 2H), 7.43 (s, 2H), 7.39 (d, 8.6 Hz, 1H), 7.33 (dd, 8.6, 2.4 Hz, 1H), 6.98 (s, 1H), 6.49 (s, 1H), 6.17 (s, 1H)。 563 A   
I-766
Figure 02_image1825
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CC4CCCN4C(=O)C3)c12 NMR (400 MHz, DMSO-d6)  9.19 (s, 1H), 8.75-8.71 (m, 1H), 7.63 (dd, 6.6, 1.6 Hz, 1H), 7.46 (d, 1.6 Hz, 1H), 7.24 (ddd, 8.9, 8.1, 3.1 Hz, 1H), 7.18 (ddd, 8.9, 8.1, 3.1 Hz, 1H), 6.59 (br. s, 1H), 5.96-5.91 (m, 1H), 4.20-3.98 (m, 2H), 3.46-3.25 (m, 5H在水峰下), 2.04-1.95 (m, 1H), 1.95-1.86 (m, 2H), 1.81-1.66 (m, 1H), 1.42-1.30 (m, 1H) 521.3 E   
I-767
Figure 02_image1827
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(Cl)cc(F)c3F)c12 NMR (400 MHz, DMSO-d6)  10.49 (br. s, 1H), 9.16 (s, 1H), 7.91 (ddd, 10.0, 6.6, 2.6 Hz, 1H), 7.70 (dd, 7.6, 0.8 Hz, 1H), 7.64 (t, 8.0 Hz, 1H), 7.50-7.46 (m, 2H), 7.25 (ddd, 8.8, 8.1, 3.1 Hz, 1H), 6.88 (dt, 4.8, 2.0 Hz, 1H), 6.56 (br. s, 1H), 6.02 (br. s, 1H) 451.2 B   
I-768
Figure 02_image1829
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cnc3NC3CCC3)c12 NMR (400 MHz, DMSO-d6)  10.16 (s, 1H), 9.14 (s, 1H), 8.20 (d, 2.9 Hz, 1H), 8.04 (d, 7.0 Hz, 1H), 7.69 (d, 6.9 Hz, 1H), 7.63 (t, 7.6 Hz, 1H), 7.46 (d, 7.7 Hz, 1H), 7.40 (br. d, 8.9 Hz, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.12 (ddd, 8.8, 8.1, 3.1 Hz, 1H), 6.59 (br. s浸沒, 1H),  6.01 (br. s, 1H), 4.47-4.36 (sx, 7.6 Hz, 1H), 2.36 - 2.25 (m, 2H), 1.91-1.77 (m, 2H), 1.77-1.62 (m, 2H)。 469.4 D   
I-769
Figure 02_image1831
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCCC3c3ccccc3)c12 NMR (400 MHz, DMSO)  9.37 (s, 1H), 9.24 - 9.16 (m, 1H), 7.81 (s, 1H), 7.67 (d, 1.6 Hz, 1H), 7.60 (d, 1.5 Hz, 1H), 7.58 (d, 1.6 Hz, 1H), 7.54-48 (m, 1H), 7.33-7.27 (m, 2H), 7.26-7.16 (m, 1H), 7.09-7.03 (m, 1H), 6.57 (s, 1H), 6.04 (s, 1H), 4.74 (s, 1H), 3.98 (t, 6.0 Hz, 1H), 3.62 (t, 6.3 Hz, 1H), 3.46-3.38 (m, 1H), 2.11-2.01 (m, 1H), 1.77-1.54 (m, 3H)。 528 D   
I-770
Figure 02_image1833
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C#N    490.3 A   
I-771
Figure 02_image1835
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C#N    490.3 A   
I-772
Figure 02_image1837
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCCCC3c3ccccc3)c12 NMR (400 MHz, DMSO)  9.19 (s, 2H), 8.67 (s, 1H), 8.59 (s, 1H), 7.68-7.64 (m, 1H), 7.60 (dt, 3.5, 1.8 Hz, 3H), 7.55 (br s, 1H), 7.40-7.31 (m, 4H), 7.30-7.19 (m, 4H), 7.13-7.05 (m, 4H), 6.12 (s, 1H), 5.46 (s, 1H), 5.07 (s, 1H), 3.77 (d, 12.9 Hz, 1H), 3.50 (d, 12.4 Hz, 1H), 2.71-2.58 (m, 1H), 2.46-2.42 (m, 1H), 2.32 (dd, 7.6, 5.8 Hz, 1H), 2.22 (dd, 9.9, 1.7 Hz, 1H), 1.77-1.55 (m, 2H), 1.51-1.13 (m, 8H), 0.95-0.77 (m, 1H)。 544 D   
I-773
Figure 02_image1839
 COc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.48 (br. s, 1H), 9.13 (s, 1H), 7.94 (d, 8.5 Hz, 1H), 7.72 (d, 9.0 Hz, 1H), 7.64 (s, 1H), 7.30 (dd, 8.8, 5.2 Hz, 1H), 7.21 (d, 2.1 Hz, 1H), 7.12-7.04 (m, 2H), 6.59 (br. s, 1H), 5.93 (br. s, 1H), 3.88 (s, 3H) 497.2 A   
I-774
Figure 02_image1841
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)S(F)(F)(F)(F)F)c12 NMR (400 MHz, DMSO D6 )  10.64 (s, 寬峰, 1H), 9.30 (s, 寬峰, 1H, ), 8.21 (dd, 8.7, 1.9 Hz, 1H), 7.83 (s, 2H), 7.76 (d, 8.5 Hz, 1H), 7.73 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.5, 3.0 Hz, 1H), 7.25-6.25 (m, 寬峰, 1H), 6.20-5.60 (m, 寬峰, 1H)。 603.1 A   
I-775
Figure 02_image1843
 CP(C)(=O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.55 (br. s, 1H), 9.14 (s, 1H), 7.94 (d, 8.6 Hz, 1H), 7.73 (d, 9.0 Hz, 1H), 7.63 (s, 1H), 7.60 (br. t, 2.0 Hz 1H), 7.37 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.4, 3.0 Hz, 1H), 6.66 (br. s, 1H), 5.95 (br. s, 1H), 3.45-3.23 (s, 2H), 1.40 (d, 7.7 Hz, 1H), 1.37 (d,  7.7 Hz, 1H)。 557.2 A   
I-776
Figure 02_image1845
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Cl)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, CD3CN)  8.64 (br s,1H), 7.74 (d, 1.8 Hz, 1H), 7.63 (d,  6.0 Hz, 1H), 7.60 (s, 1H), 7.56 (d,  6.0 Hz, 1H), 7.53 (s, 1H), 7.30 (br s, 1H), 7.25 (dd, 8.8, 5.2 Hz, 1H), 6.96 (td, 8.4, 3.1 Hz, 1H), 6.66 (br s, 1H), 6.09 (br s, 1H)。 542.3 A A
I-777
Figure 02_image1847
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(Cl)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, CD3CN)  8.64 (br s,1H), 7.74 (d, 1.8 Hz, 1H), 7.63 (d,  6.0 Hz, 1H), 7.60 (s, 1H), 7.56 (d,  6.0 Hz, 1H), 7.53 (s, 1H), 7.30 (br s, 1H), 7.25 (dd, 8.8, 5.2 Hz, 1H), 6.96 (td, 8.4, 3.1 Hz, 1H), 6.66 (br s, 1H), 6.09 (br s, 1H)。 542.3 D   
I-778
Figure 02_image1849
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CCOC1 NMR (400 MHz, CD3CN)  8.58 (s, 1H), 7.63-7.50 (m, 4H), 7.42 (s, 1H), 7.20 (dd, 8.9, 5.1 Hz, 1H), 7.16 (br s, 1H), 6.93 (ddd, 11.9, 8.9, 5.1 Hz, 1H), 6.56 (br s, 1H), 6.04 (br s, 1H), 4.10-4.03 (m, 1H), 3.99 (td, 8.5, 4.7 Hz, 1H), 3.82 (q, 7.5 Hz, 1H), 3.67 (dd, 14.9, 7.8 Hz, 1H), 3.58-3.49 (m, 1H), 2.39 (ddd, 12.4, 10.1, 6.1 Hz, 1H), 2.01-1.94 (m, 1H)。 537.3 A   
I-779
Figure 02_image1851
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CC(F)(F)C1 NMR (400 MHz, CD3CN)  8.62 (s, 1H), 7.71-7.54 (m, 4H), 7.47 (s, 1H), 7.25 (dd, 8.9, 5.1 Hz, 2H), 6.96 (ddd, 8.9, 8.0, 3.1 Hz, 1H), 6.59 (br s, 1H), 6.10 (br s, 1H), 3.66-3.54 (m, 1H), 3.15-3.02 (m, 2H), 2.85-2.67 (m, 2H)。 598.3 A   
I-780
Figure 02_image1853
 CO[C@@H]1CC[C@H]1Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.28 (s, 1H), 8.96 (s, 1H), 7.92 (d, 8.6 Hz, 1H), 7.67 (d, 16.1Hz, 1H), 7.61 (s, 1H), 7.28 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.4, 3.1 Hz, 1H), 6.69 (d, 2.0 Hz, 1H), 6.60 (s, 1H), 6.54 (d, 5.3 Hz, 1H), 5.88 (s, 1H), 4.10-3.99 (m, 1H), 3.95-3.87 (m, 1H), 3.16 (s, 3H), 2.31 (ddd, 12.5, 7.6, 4.8 Hz, 2H), 2.18-2.09 (m, 2H)。 566.3 A   
I-781
Figure 02_image1855
 CO[C@H]1CC(C1)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN)  8.46 (s, 1H), 7.63 (d, 8.5 Hz, 2.0 Hz, 1H), 7.59-7.53 (m, 2H), 7.23 (dd, 8.9, 5.1 Hz, 1H), 7.09 (s, 1H), 6.95 (ddd, 8.8 Hz, 8.1 Hz, 3.1 Hz, 1H), 6.84 (d, 2.1 Hz, 1H), 6.76 (s, 1H), 6.63 (br, s, 1H), 5.98 (s, 1H), 5.09 (d, 6.9 Hz, 1H), 3.69 (p, 7.3 Hz, 1H), 3.62-3.53 (m, 1H), 3.20 (s, 3H), 2.86-2.79 (m, 2H), 1.77-1.69 (m, 2H)。 566.3 A   
I-782
Figure 02_image1857
 COc1ncc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz) 10.63 (s, 1H), 9.24 (br s, 1H), 9.05 (s, 2H), 8.06 (d, 1.5 Hz, 1H), 7.96 (br d, 8.3 Hz, 1H), 7.84 (d, 1.3 Hz, 1H), 7.76 (br d, 8.8 Hz, 1H), 7.70 (s, 1H), 7.33 (dd, 8.8, 5.3 Hz, 1H), 7.11 (td, 8.5, 3.0 Hz, 1H), 6.43-6.91 (m, 1H), 6.04 (br s, 1H), 4.00 (s, 3H) 575 A   
I-783
Figure 02_image1859
 Cc1ncc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    559.2 D   
I-784
Figure 02_image1861
 Cc1ncc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    559.2 A   
I-785
Figure 02_image1863
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(Cl)cc(F)c1F 1H NMR (400 MHz, DMSO-d6)  10.61 (s, 1H), 9.28 (s, 1H), 8.01 (d, 8.5 Hz, 1H), 7.87 - 7.73 (m, 4H), 7.59 (ddd, 9.7, 6.7, 2.6 Hz, 1H), 6.99 (s, 1H), 5.86 (s, 1H)。 563 A   
I-786
Figure 02_image1865
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(Cl)cc(F)c1F 1H NMR (400 MHz, DMSO-d6)  10.61 (s, 1H), 9.28 (s, 1H), 8.00 (d, 8.5 Hz, 1H), 7.87 - 7.78 (m, 2H), 7.78 - 7.73 (m, 2H), 7.59 (ddd, 9.7, 6.6, 2.6 Hz, 1H), 6.99 (s, 1H), 5.86 (s, 1H)。 563 A   
I-787
Figure 02_image1867
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cc(Cl)cc(F)c1F 1H NMR (400 MHz, DMSO-d6)  10.61 (s, 1H), 9.28 (s, 1H), 8.01 (d, 8.4 Hz, 1H), 7.87 - 7.79 (m, 2H), 7.79 - 7.73 (m, 2H), 7.59 (ddd, 9.5, 6.7, 2.6 Hz, 1H), 6.99 (s, 1H), 5.86 (s, 1H)。 563 D   
I-788
Figure 02_image1869
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)ccc3OC(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.50 (s, 1H), 9.33 - 9.29 (m, 1H), 7.81 (d, 1.7 Hz, 1H), 7.72 (d, 1.8 Hz, 1H), 7.60 - 7.47 (m, 3H), 7.29 (td, 8.4, 3.1 Hz, 1H), 6.78 (s, 1H), 6.58 (dd, 8.2, 3.0 Hz, 1H), 6.03 (s, 1H)。 563 D   
I-789
Figure 02_image1871
 FC(F)c1ccccc1[C@@H]1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.50 (s, 1H), 9.29 (s, 1H), 7.92 (d, 8.7 Hz, 1H), 7.85 (d, 1.8 Hz, 1H), 7.78 (d, 1.8 Hz, 1H), 7.67-7.00 (m, 6H), 6.72 (s, 1H), 6.02 (s, 1H)。 545.15 A   
I-790
Figure 02_image1873
 FC(F)c1ccccc1[C@H]1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.50 (s, 1H), 9.29 (s, 1H), 7.92 (dt, 8.6, 1.9 Hz, 1H), 7.85 (d, 1.7 Hz, 1H), 7.78 (d, 1.8 Hz, 1H), 7.63-7.09 (m, 6H), 6.72 (s, 1H), 6.02 (s, 1H)。 545.15 D   
I-791
Figure 02_image1875
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)ccc3Cl)c12 1H NMR (400 MHz, 甲醇-d4) 7.95 (d, 1.7 Hz, 1H), 7.88 - 7.73 (m, 1H), 7.66 - 7.36 (m, 2H), 7.21 (dddd, 20.0, 8.8, 7.9, 3.0 Hz, 2H), 6.63 (d, 3.1 Hz, 1H), 6.61 (d, 3.1 Hz, 1H), 6.27 (s, 1H)。 512.95 E   
I-792
Figure 02_image1877
 FC(F)c1ccccc1C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.50 (s, 1H), 9.29 (s, 1H), 7.92 (d, 8.4 Hz, 1H), 7.85 (d, 1.8 Hz, 1H), 7.78 (d, 1.9 Hz, 1H), 7.62-7.04 (m, 6H), 6.72 (s, 1H), 6.02 (s, 1H)。 545.15 A   
I-793
Figure 02_image1879
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)ccc3F)c12 1H NMR (400 MHz, DMSO-d6)  10.36 (s, 1H), 9.30 (s, 1H), 7.80 (d, 1.7 Hz, 1H), 7.74 (d, 1.8 Hz, 1H), 7.45 (ddt, 11.9, 7.4, 3.1 Hz, 2H), 7.36 (td, 9.3, 4.3 Hz, 1H), 7.28-7.19 (m, 1H), 6.98 (ddd, 8.5, 5.4, 3.2 Hz, 1H), 6.74 (s, 1H), 6.02 (s, 1H)。 496.9 D   
I-794
Figure 02_image1881
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(Cl)ccc3F)c12 1H NMR (400 MHz, DMSO-d6) 10.43 (s, 1H), 9.30 (s, 1H), 7.80 (d, 1.7 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.63 (ddd, 8.9, 4.3, 2.8 Hz, 1H), 7.51 - 7.43 (m, 1H), 7.36 (t, 9.3 Hz, 1H), 7.25 (td, 8.4, 3.0 Hz, 1H), 7.06 (dd, 6.0, 2.8 Hz, 1H), 6.71 (s, 1H), 6.00 (s, 1H)。 512.95 D   
I-795
Figure 02_image1883
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(Cl)ccc3Cl)c12 1H NMR (400 MHz, 氯仿-d) 8.45 (s, 1H), 7.95 (d, 1.6 Hz, 1H), 7.64 (s, 1H), 7.45-7.32 (m, 4H), 7.08 (td, 8.9, 8.2, 3.0 Hz, 1H), 6.66-6.59 (m, 2H), 6.16 (s, 1H)。 528.85 D   
I-796
Figure 02_image1885
 COc1ccc(F)cc1C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 9.89 (s, 1H), 9.28 (s, 1H), 7.83 (d, 1.7 Hz, 1H), 7.77 (d, 1.8 Hz, 1H), 7.42 (dd, 8.8, 5.1 Hz, 1H), 7.35 (ddd, 9.1, 7.9, 3.3 Hz, 1H), 7.23 - 7.05 (m, 3H), 6.73 (s, 1H), 6.07 (s, 1H), 3.73 (s, 3H)。 509 D   
I-797
Figure 02_image1887
 FC(F)c1ccc(F)cc1[C@@H]1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.55 (s, 1H), 9.33 (s, 1H), 7.94 (d, 8.2 Hz, 1H), 7.87 (d, 1.7 Hz, 1H), 7.78 (d, 1.7 Hz, 1H), 7.67 (d, 8.9 Hz, 1H), 7.58 (s, 1H), 7.50 (dd, 8.8, 5.6 Hz, 1H), 7.22 (td, 8.4, 2.7 Hz, 1H), 7.11 (s, 1H), 6.57 (s, 1H), 6.02 (s, 1H)。 561.05 A   
I-798
Figure 02_image1889
 FC(F)c1ccc(F)cc1[C@H]1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.55 (s, 1H), 9.33 (s, 1H), 7.94 (d, 8.2 Hz, 1H), 7.87 (d, 1.7 Hz, 1H), 7.78 (d, 1.7 Hz, 1H), 7.67 (d, 8.9 Hz, 1H), 7.58 (s, 1H), 7.50 (dd, 8.8, 5.6 Hz, 1H), 7.22 (td, 8.4, 2.7 Hz, 1H), 7.11 (s, 1H), 6.57 (s, 1H), 6.02 (s, 1H)。 561.05 D   
I-799
Figure 02_image1891
 COc1ccc(Cl)cc1C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 9.95 (s, 1H), 9.28 (s, 1H), 7.82-7.74 (m, 2H), 7.52 (dd, 8.9, 2.8 Hz, 1H), 7.44 (dd, 8.8, 5.1 Hz, 1H), 7.21 (ddd, 8.9, 8.0, 3.1 Hz, 1H), 7.16 -7.10 (m, 2H), 6.74 (s, 1H), 6.06 (s, 1H), 3.74 (s, 3H)。 522.95 D   
I-800
Figure 02_image1893
 COc1cc(F)cc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.29 (s, 1H), 9.31-9.26 (m, 1H), 7.82-7.77 (m, 1H), 7.74 (d, 2.0 Hz, 1H), 7.37 (dd, 8.8, 5.1 Hz, 1H), 7.14 (td, 8.4, 3.0 Hz, 1H), 7.05 (dt,  10.7, 2.5 Hz, 1H), 6.97 (s, 1H), 6.92 (d, 9.0 Hz, 1H), 6.70 (s, 1H), 6.01 (s, 1H), 3.80 (s, 3H)。 506.9 C   
I-801
Figure 02_image1895
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cccc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.51 (s, 1H), 9.29 (s, 1H), 7.93 (t,  9.0 Hz, 2H), 7.81 (d, 1.7 Hz, 1H), 7.78-7.67 (m, 3H), 7.32 (dd, 8.8, 5.1 Hz, 1H), 7.09 (td, 8.3, 3.0 Hz, 1H), 6.91 - 6.24 (m, 1H), 5.99 (s, 1H)。 526.9 B   
I-802
Figure 02_image1897
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(Cl)cc4cccnc34)c12 1H NMR (400 MHz, 氯仿-d) 13.17 (s, 1H), 8.82 (d, 2.5 Hz, 2H), 8.61 (dd, 4.4, 1.8 Hz, 1H), 8.22 (dd, 8.4, 1.8 Hz, 1H), 8.00 (d, 2.5 Hz, 1H), 7.95 (d, 1.7 Hz, 1H), 7.51 (dd, 8.4, 4.3 Hz, 1H), 7.34 (dd, 8.8, 4.9 Hz, 1H), 6.89 -6.80 (m, 1H), 6.64 (s, 1H), 6.59 (dd, 8.8, 2.9 Hz, 1H), 6.27 (s, 1H)。 543.95 E   
I-803
Figure 02_image1899
 O[C@H](C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl)c1cc(F)cc(F)c1 1H NMR (400 MHz, DMSO-d6)  9.54 (s, 1H), 9.25 (s, 1H), 8.01 (s, 1H), 7.70 (d, 1.7 Hz, 1H), 7.41 (s, 1H), 7.16 - 7.04 (m, 2H), 6.84 (s, 1H), 6.81 - 6.74 (m, 2H), 6.56 (s, 1H), 6.18 (s, 1H), 5.04 (d, 3.1 Hz, 1H)。 525.15 E   
I-804
Figure 02_image1901
 O[C@@H](C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl)c1cc(F)cc(F)c1 1H NMR (400 MHz, DMSO-d6)  9.72 (s, 1H), 9.20 (s, 1H), 7.91 (s, 1H), 7.71 (d, 1.7 Hz, 1H), 7.31 (dd, 8.8, 5.1 Hz, 1H), 7.13 (ddt, 10.9, 8.5, 4.2 Hz, 2H), 6.92 (d, 7.6 Hz, 2H), 6.75 (d, 4.5 Hz, 1H), 6.51 (s, 1H), 6.06 (s, 1H), 4.97 (d, 4.2 Hz, 1H)。 525.15 E   
I-805
Figure 02_image1903
 Fc1cc(F)c(Cl)c(c1)[C@@H]1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.60 (s, 1H), 9.33 (s, 1H), 7.99 (dt, 8.6, 2.1 Hz, 1H), 7.85 (d, 1.7 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.68 (s, 1H), 7.41 (td, 8.9, 2.9 Hz, 1H), 6.63 (s, 1H), 6.02 (s, 1H)。 563 A   
I-806
Figure 02_image1905
 Fc1cc(F)c(Cl)c(c1)[C@H]1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.58 (s, 1H), 9.32 (s, 1H), 7.98 (dd, 8.5, 2.4 Hz, 1H), 7.85 (d, 1.7 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.68 (s, 1H), 7.41 (td, 9.0, 2.9 Hz, 1H), 6.66 (s, 1H), 6.01 (s, 1H)。 562.85 C   
I-807
Figure 02_image1907
 Fc1cc(F)c(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.58 (s, 1H), 9.32 (s, 1H), 7.98 (d, 8.4 Hz, 1H), 7.85 (d, 1.7 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.68 (s, 1H), 7.40 (td, 8.9, 2.9 Hz, 1H), 6.65 (s, 1H), 6.01 (s, 1H)。 562.9 A   
I-808
Figure 02_image1909
 CNC(=O)c1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2n([nH]c(=O)c2c1)-c1cc(F)ccc1Cl NMR (400 MHz, CD3CN)  8.78 (s, 1H), 8.38 (s, 1H), 7.81 (s, 1H), 7.63 (d, 8.3 Hz, 1H), 7.58-7.49 (m, 2H), 7.37 (br s, 1H), 7.33-7.18 (m, 2H), 6.89 (td, 9.2, 3.7 Hz, 1H), 2.87 (d, 4.5 Hz, 3H)。 523.3 D   
I-809
Figure 02_image1911
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3Cl)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.65 (br s, 1H), 9.33 (s, 1H), 7.97 (dd, 8.5, 3.0 Hz, 1H), 7.86 (d, 1.7 Hz, 1H), 7.81 (d, 1.5 Hz, 1H), 7.60-7.48 (m, 1H), 7.30 (td, 8.4, 3.0 Hz, 1H), 7.16 (d, 5.8 Hz, 1H), 6.67 (br s, 1H), 6.09 (br s, 1H) 577.3 D   
I-810
Figure 02_image1913
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cccc2CC(=O)Nc12 1H NMR (400 MHz, DMSO-d6)  10.53 (br. s, 1H), 10.37 (br. s, 1H), 9.00 (s, 1H), 7.91 (d, 8.5 Hz, 1H), 7.67 (dd, 7.5, 1.0 Hz, 1H), 7.61 (t, 7.6 Hz, 1H), 7.52-7.46 (m, 2H), 7.43 (s, 1H), 6.99 (d, 6.6 Hz, 1H), 6.76 (t, 7.6 Hz, 1H), 6.31 (d, 7.5 Hz, 1H), 5.94 (br. s, 1H), 3.38 (d, 22.7 Hz, 1H), 2.70 (d, 22.7 Hz, 1H)。 470.2 E   
I-811
Figure 02_image1915
 Cn1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1h NMR (400 MHz, DMSO-d6) 10.52 (s, 1H), 9.14 (br. s, 1H), 8.34 (s, 1H), 8.01 (s, 1H), 7.95 (dt, 9.9, 1.5 Hz, 1H), 7.88 (d, 1.0 Hz, 1H), 7.75 (d, 8.0 Hz, 1H), 7.71-7.66 (m, 8.8 Hz, 2H), 7.31 (dd, 8.9, 5.1 Hz, 1H), 7.09 (td, 8.5, 3.0 Hz, 1H), 6.61 (br. s, 1H), 5.96 (br. s, 1H), 3.89 (s, 3H)。 547.2 A A
I-812
Figure 02_image1917
 FC(F)Oc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, MeCN-d3)  8.70 (br. s, 1H), 7.68-7.63 (m, 1H), 7.61-7.57 (m, 1H), 7.56 (s, 1H), 7.49 (d, 2.1 Hz, 1H), 7.40 (d, 1.4 Hz, 1H), 7.34 (s, 1H), 7.27 (dd, 8.9, 5.1 Hz, 1H), 6.98 (ddd, 8.8, 8.1, 3.1 Hz, 1H), 6.91 (t, 73.6 Hz, 1H), 6.66 (br.s, 1H), 6.12 (br. s, 1H)。含有8.17處之4%甲酸鹽 531.4 A   
I-813
Figure 02_image1919
 CC1(COC1)Nc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.24 (s, 1H), 8.91 (br. s, 1H), 7.88 (td, 8.4, 1.6 Hz, 1H), 7.64 (d, 9.0 Hz, 1H), 7.55 (s, 1H), 7.25 (dd, 8.9, 5.2 Hz, 1H), 7.03 (td, 8.4, 3.1 Hz, 1H), 6.64 (s, 1H), 6.57 (br. s, 1.6 Hz, 1H), 6.52 (d, 2.1 Hz, 1H), 6.47 (br. d, 1H), 5.80 (s, 1H), 4.63 (d, 5.7 Hz, 2H), 4.48 (d, 5.8 Hz, 2H), 1.57 (s, 3H)。 552.1 A   
I-814
Figure 02_image1921
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(NC3COC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6 )  10.30 (s, 1H), 8.95 (br. s, 1H), 7.92 (d, 8.6 Hz, 1H), 7.69 (d, 8.9 Hz, 1H), 7.60 (s, 1H), 7.28 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.4, 3.1 Hz, 1H), 6.94 (d, 6.3 Hz, 1H), 6.69 (d, 2.0 Hz, 1H), 6.62 (s, 1H), 6.57 (br. s, 1H), 5.82 (br. s, 1H), 4.89 (t, 6.5 Hz, 2H), 4.62 (dd, 12.7, 6.4 Hz, 1H), 4.45 (q, 6.1 Hz, 2H)。 538.3 A A
I-815
Figure 02_image1923
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn[nH]1 NMR (400 MHz, CD3CN)  8.67 (br s, 1H), 8.10 (d, 1.3 Hz, 1H), 8.05 (s, 1H), 7.68 (d, 2.4 Hz, 1H), 7.63 (d, 8.5 Hz, 1H), 7.59 (d, 9.0 Hz, 1H), 7.57 (s, 1H), 7.24 (dd, 8.9, 5.1 Hz, 2H), 6.99-6.91 (m, 1H), 6.79 (d, 2.4 Hz, 1H), 6.68 (br s, 1H), 6.14 (br s, 1H)。 533.3 A   
I-816
Figure 02_image1925
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(Cl)c3Cl)c12 NMR (400 MHz, DMSO)  9.29 (s, 1H), 7.81 (d, 1.6 Hz, 1H), 7.75 (d, 1.6 Hz, 1H), 7.60 (m, 3H), 7.36 (dd, 8.7, 5.2 Hz, 1H), 7.17-7.11 (m, 1H), 5.96 (br s, 1H)。 545 B   
I-817
Figure 02_image1927
 CC1(Cc2cc3C(=O)N[C@@H](c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)COC1    551.31 D   
I-818
Figure 02_image1929
 CC1(Cc2cc3C(=O)N[C@H](c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)COC1    551.31 A   
I-819
Figure 02_image1931
 CC(C)(O)COc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl    521 A   
I-820
Figure 02_image1933
 COC(C)(C)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    553.31 A   
I-821
Figure 02_image1935
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nncn2c1 1H NMR (DMSO-d6, 400 MHz):-´ = 10.64 (s, 1H), 9.28 (d, 0.8 Hz, 1H), 9.22-9.27 (m, 1H), 9.14 (s, 1H), 8.05 (s, 1H), 7.97 (br d, 8.1 Hz, 1H), 7.88-7.94 (m, 2H), 7.83-7.88 (m, 1H), 7.78 (br d, 8.8 Hz, 1H), 7.73 (s, 1H), 7.35 (dd, 8.8, 5.3 Hz, 1H), 7.12 (td, 8.3, 3.0 Hz, 1H), 6.50-7.03 (m, 1H), 6.07  (br s, 1H) 584 A   
I-822
Figure 02_image1937
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc(nc1)C1CC1    585 A   
I-823
Figure 02_image1939
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc(nc1)C(F)(F)F    613.1 A   
I-824
Figure 02_image1941
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1    584 A   
I-825
Figure 02_image1943
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc2nccn2c1    584 A   
I-826
Figure 02_image1945
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nccn2c1       C   
I-827
Figure 02_image1947
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nccn2c1    583.3 A   
I-828
Figure 02_image1949
 Nc1cc(ccn1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, d6-DMSO)  10.51 (s, 1H), 9.06 (s, 1H), 8.35 (s, 1H), 7.97 (d, 8.3 Hz, 1H), 7.83 (br s, 1H), 7.79 (br d, 8.7 Hz, 1H), 7.66 (dd, 7.4, 1.0 Hz, 1H), 7.62 (dd, 5.7, 0.8 Hz,  1H) 7.58 (t, 7.5 Hz, 1H), 7.50 (dd, 7.7, 0.9 Hz, 1H), 6.06 (dd, 5.2, 1.4 Hz, 1H), 6.05 (s, 1H) 5.78 (br s, 2H), 5.54 (s, 1H)。 431.2 E   
I-829
Figure 02_image1951
 CC1(COC1)Nc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.24 (s, 1H), 8.91 (br. s, 1H), 7.88 (td, 8.4, 1.6 Hz, 1H), 7.64 (d, 9.0 Hz, 1H), 7.55 (s, 1H), 7.25 (dd, 8.9, 5.2 Hz, 1H), 7.03 (td, 8.4, 3.1 Hz, 1H), 6.64 (s, 1H), 6.57 (br. s, 1.6 Hz, 1H), 6.52 (d, 2.1 Hz, 1H), 6.47 (br. d, 1H), 5.80 (s, 1H), 4.63 (d, 5.7 Hz, 2H), 4.48 (d, 5.8 Hz, 2H), 1.57 (s, 3H)。 552.1 C   
I-830
Figure 02_image1953
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(NC3COC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6 )  10.30 (s, 1H), 8.95 (br. s, 1H), 7.92 (d, 8.6 Hz, 1H), 7.69 (d, 8.9 Hz, 1H), 7.60 (s, 1H), 7.28 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.4, 3.1 Hz, 1H), 6.94 (d, 6.3 Hz, 1H), 6.69 (d, 2.0 Hz, 1H), 6.62 (s, 1H), 6.57 (br. s, 1H), 5.82 (br. s, 1H), 4.89 (t, 6.5 Hz, 2H), 4.62 (dd, 12.7, 6.4 Hz, 1H), 4.45 (q, 6.1 Hz, 2H)。 538.3 D   
I-831
Figure 02_image1955
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(OC(F)(F)F)c3)c12 1H NMR (400 MHz, 氯仿-d) 8.40 (s, 1H), 7.94 (d, 1.6 Hz, 1H), 7.54-7.40 (m, 2H), 7.22-7.15 (m, 2H), 7.14-7.04 (m, 2H), 6.73 (d, 14.7 Hz, 2H), 6.18 (s, 1H)。 563.1 B   
I-832
Figure 02_image1957
 [O-][N+](=O)c1cc(F)cc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, CDCl3)  8.47 (s, 1H), 8.16 (dt, 7.7, 2.2 Hz, 1H), 8.03-7.97 (m, 2H), 7.82-7.75 (m, 1H), 7.51 (dd, 8.7, 4.3 Hz, 2H), 7.14 (ddd, 8.9, 7.3, 3.0 Hz, 1H), 6.74 (s, 1H), 6.46 (s, 1H), 6.21 (s, 1H)。 524 A   
I-833
Figure 02_image1959
 FC(F)Oc1cc(F)cc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 氯仿-d) 8.45 (s, 1H), 7.96 (d, 1.6 Hz, 1H), 7.45 (dd, 8.9, 4.9 Hz, 1H), 7.34 (s, 1H), 7.08 (dddd, 20.4, 10.1, 7.8, 2.5 Hz, 4H), 6.72 (s, 1H), 6.58-6.43 (m, 2H), 6.18 (s, 1H)。 545 B   
I-834
Figure 02_image1961
 COc1c(Cl)cc(F)cc1C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.29 (s, 1H), 9.31 (s, 1H), 7.84 (d, 1.8 Hz, 1H), 7.80 (d, 1.7 Hz, 1H), 7.70 (dd, 8.1, 3.1 Hz, 1H), 7.50 (t, 6.3 Hz, 1H), 7.27 (ddd, 8.9, 7.9, 3.1 Hz, 1H), 6.60 (dd, 8.3, 3.2 Hz, 2H), 6.07 (s, 1H), 3.64 (s, 3H), 1.59 (s, 1H)。 540.95 D   
I-835
Figure 02_image1963
 FC(F)c1cc(F)cc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 甲醇-d4)  7.96 (d, 1.6 Hz, 1H), 7.74 (s, 1H), 7.61-7.45 (m, 3H), 7.31 (dd, 8.9, 5.0 Hz, 1H), 7.08-6.95 (m, 1H), 6.84 (s, 1H), 6.71 (s, 1H), 6.19 (s, 1H)。 526.85 B   
I-836
Figure 02_image1965
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(Cl)c3F)c12 1H NMR (400 MHz, DMSO-d6)  10.51 (s, 1H), 9.31 (s, 1H), 7.86 (ddd, 8.4, 5.5, 3.2 Hz, 1H), 7.81 (d, 1.7 Hz, 1H), 7.74 (d, 1.8 Hz, 1H), 7.47 (t, 7.0 Hz, 1H), 7.25 (ddd, 8.8, 7.9, 3.1 Hz, 1H), 7.03 (ddd, 7.9, 4.5, 2.9 Hz, 1H), 6.84 (s, 1H), 6.00 (s, 1H)。 528.9 C   
I-837
Figure 02_image1967
 FC(F)c1ccc(F)cc1C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 甲醇-d4) 7.95 (d, 1.7 Hz, 1H), 7.84-7.72 (m, 2H), 7.47 (dd, 8.9, 5.0 Hz, 1H), 7.39 (td, 8.4, 2.7 Hz, 1H), 7.26- 6.93 (m, 2H), 6.54 (s, 2H), 6.19 (s, 1H)。 526.9 D   
I-838
Figure 02_image1969
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc[nH]1 NMR (400 MHz, DMSO-d6)：存在3:1比率之2種咪唑互變異構形式(4及5取代之咪唑)。主要互變異構體：-´ 12.32 (br. s, 1H), 10.55 (s, 1H), 9.12 (s, 1H), 8.07 (d, 0.8 Hz, 1H), 7.96 (s, 1H), 7.93 (s, 1H), 7.84 (br. s, 1H), 7.79-7.74 (m, 2H), 7.70 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.11-7.06 (m, 1H), 6.63 (br. s, 1H), 5.97 (br. s, 1H)。8.24處之24%甲酸鹽。 533.2 A   
I-839
Figure 02_image1971
 CNc1cc(cc(n1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(F)(F)F 1H-NMR (400 MHz, DMSO-d6)  9.90 (s, 1H), 9.13 (s, 1H), 7.80 (d, 6.2 Hz, 1H), 7.69-7.60 (m, 2H), 7.36-7.27 (m, 2H), 7.18 (d, 1.0 Hz, 1H), 7.07 (td, 8.4, 3.1 Hz, 1H), 6.93-6.91 (m, 1H), 6.62 (br. s, 1H), 6.17 (br. s, 1H), 2.84 (d, 4.4 Hz, 3H)。 479.3 E   
I-840
Figure 02_image1973
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1c[nH]nn1 NMR (400 MHz, DMSO-d6)  10.63 (br. s, 1H), 9.21 (br. s, 1H), 8.59 (br. s, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.96 (d, 8.5 Hz, 1H), 7.77 (d, 9.0 Hz, 1H), 7.70 (s, 1H), 7.32 (dd, 8.8, 5.1 Hz, 1H), 7.09 (td, 9.16, 9.02, 3.04 Hz, 1H), 6.69 (br. s, 1H), 6.02 (br. s, 1H)。 534.2 A A
I-841
Figure 02_image1975
 Cc1ccccc1CC1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSOd6)  10.75 (s, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 8.14 (d, 9.0 Hz, 1H), 8.03 (d, 8.4 Hz, 1H), 7.62 (m, 1H), 7.55 (d, 2.8 Hz, 1H), 7.54 (s, 1H), 7.01-6.92 (m, 4H), 5.14-5.06 (m, 1H), 3.16 (dd, 14.0, 4.4 Hz, 1H), 2.56 (dd, 14.0, 7.8 Hz, 1H), 2.12 (s, 3H)。 443.4 D   
I-842
Figure 02_image1977
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(-c3nc4c(cc(F)cc4[nH]3)C(F)(F)F)c12 NMR (400 MHz, DMSO-D6)  9.23 (br s, 1 H), 8.39-8.15 (m, 2 H), 7.92 (dd, 7.5, 0.7 Hz, 1 H), 7.82 (t, 7.6 Hz, 1 H), 7.61 (dd, 8.8, 2.1 Hz, 1 H), 7.43-7.12 (m, 2 H), 6.95 (ddd, 8.7, 8.2, 3.1 Hz, 1 H), 6.60 (br s, 1 H), 6.29 (br s, 1 H)。 464.2 B   
I-843
Figure 02_image1979
 Nc1c(Cl)cc(F)cc1C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.20 (br s, 1H), 9.29 (s, 1H), 7.78 (d, 1.4 Hz, 1H), 7.73 (d, 1.4 Hz, 1H), 7.48 (dd, 8.1, 2.9 Hz, 1H), 7.39 (dd, 8.8, 5.2 Hz, 1H), 7.16 (td, 8.4, 3.1 Hz, 1H), 6.97 - 6.47 (m, 1H), 6.71 (dd, 9.3, 2.1 Hz, 1H), 6.31 (s, 2H), 5.97 (br s, 1H)。 524.3 B   
I-844
Figure 02_image1981
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1ccc2cn[nH]c2c1 1H NMR (400 MHz, DMSO-d6 )  12.76 (s, 1H), 10.35 (s, 1H), 9.13 (s, 1H), 7.95 (s, 1H), 7.88 (d, 8.3 Hz, 1H), 7.70 (dd, 7.5, 0.9 Hz, 1H), 7.60 (t, 7.6 Hz, 1H), 7.53 (d, 8.4 Hz, 1H), 7.51-7.45 (m, 8.1 Hz, 2H), 7.42 (s, 1H), 7.15 (s, 1H), 6.56 (d, 8.4 Hz, 1H), 5.82 (s, 1H)。2.67及2.33處之DMSO衛星。 455.3 E   
I-845
Figure 02_image1983
 Oc1c(Cl)cc(F)cc1C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  12.35 (br s, 1H), 9.25 (s, 1H), 8.04 (s, 1H), 7.72 (s, 1H), 7.48 (d, 4.8 Hz, 1H), 7.38-7.26 (m, 2H), 7.10 (td, 8.4, 3.1 Hz, 1H), 6.90 (br s, 1H), 5.98 (s, 1H) 525.2 C   
I-846
Figure 02_image1985
 O\N=C(/Nc1cccc2C(=S)NC(c12)c1cc(F)ccc1Cl)c1cc(F)cc(c1)C(F)(F)F    498 C   
I-847
Figure 02_image1987
 Fc1ccc(Cl)c(c1)C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)cc(Br)c2Cl       A   
I-848
Figure 02_image1989
 CC(C)(O)CN(CC(C)(C)O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    626.39 D   
I-849
Figure 02_image1991
 Cc1ncc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl    525 A   
I-850
Figure 02_image1993
 COc1cc(C)c(cn1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)   2.17 (s, 3 H) 3.83 (s, 3 H) 6.03 (br d,  4.80 Hz, 1 H) 6.64 - 6.74 (m, 2 H) 7.20 - 7.32 (m, 1 H) 7.43 - 7.52 (m, 1 H) 7.57 (s, 1 H) 7.71 - 7.79 (m, 2 H) 9.27 (br s, 1 H) 10.25 (s, 1 H) 506.29 E   
I-851
Figure 02_image1995
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2OCCCOc2c1    615.39 A   
I-852
Figure 02_image1997
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cncc2ccccc12    594.33 A   
I-853
Figure 02_image1999
 Cn1ccc2cc(ccc12)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    596.33 B   
I-854
Figure 02_image2001
 COc1cncc(c1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    574.32 A   
I-855
Figure 02_image2003
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2cc[nH]c2c1    582.27 B   
I-856
Figure 02_image2005
 Cc1nocc1Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.36 (s, 1H), 9.02 (s, 1H), 9.01 (s, 1H), 7.96 (s, 1H), 7.93 (d, 8.4 Hz, 1H), 7.70 (d, 9.2 Hz, 1H), 7.60 (s, 1H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.07 (td, 8.4, 3.1 Hz, 1H), 6.99 (d, 2.0 Hz, 1H), 6.90 (d, 1.5 Hz, 1H), 6.63 (br s, 1H), 5.88 (br s, 1H), 2.20 (s, 3H)。 561.4 A A
I-857
Figure 02_image2007
 CC1(CCCCC1)n1[nH]c(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DSMO-d6) 10.66 (s, 1H), 10.52 (br s, 1H), 8.21 (s, 1H), 8.11 (d, 9.2 Hz. 1H), 8.03 (d, 8.6 Hz, 1H), 7.66 (d, 7.9 Hz, 1H), 7.24 (d, 7.2 Hz, 1H), 7.08 (t, 7.6 Hz, 1H), 2.45-2.34 (m, 2H), 1.81-1.70 (m, 1H), 1.55-1.21 (m, 6H), 1.40 (s, 3H)。 434.5 D   
I-858
Figure 02_image2009
 COc1c(F)cc(Cl)cc1C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 氯仿-d) 9.16 (s, 1H), 8.35 (s, 1H), 7.97 (d, 1.7 Hz, 1H), 7.85 (dd, 2.7, 1.7 Hz, 1H), 7.42 (dd, 8.9, 5.0 Hz, 1H), 7.31 (d, 2.7 Hz, 1H), 7.02 (ddd, 8.8, 7.4, 3.0 Hz, 1H), 6.58 (d, 11.2 Hz, 2H), 6.15 (s, 1H), 3.75 (d, 2.3 Hz, 3H)。 541 D   
I-859
Figure 02_image2011
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(Cl)ccc3OC(F)(F)F)c12 1H NMR (400 MHz, 氯仿-d)  8.28 (s, 1H), 7.98 (d, 1.7 Hz, 1H), 7.72 (s, 1H), 7.67 (d, 2.7 Hz, 1H), 7.55 (dd, 8.8, 2.7 Hz, 1H), 7.35 (dd, 8.9, 4.9 Hz, 1H), 7.27 (dt, 8.8, 1.5 Hz, 1H), 7.03 (ddd, 8.9, 7.4, 3.0 Hz, 1H), 6.66 (s, 1H), 6.55 (s, 1H), 6.17 (s, 1H)。 578.95 D   
I-860
Figure 02_image2013
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.49 (s, 1H), 9.14 (s, 1H), 7.99-7.91 (m, 1H), 7.77-7.69 (m, 2H), 7.69-7.61 (m, 2H), 7.50 (d, 7.8 Hz, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.4, 3.1 Hz, 1H), 6.60 (s, 1H), 5.99 (s, 1H)。 467.37 D   
I-861
Figure 02_image2015
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CCC(=O)N1 1H NMR (400 MHz, DMSO-d6) 10.55 (d, 5.1 Hz, 1H), 9.17 (s, 1H), 8.23 (d, 7.5 Hz, 1H), 7.95 (d, 8.5 Hz, 1H), 7.75 (d, 9.2 Hz, 1H), 7.70-7.62 (m, 2H), 7.45 (s, 1H), 7.32 (dd, 8.9, 5.1 Hz, 1H), 7.10 (td, 8.4, 2.9 Hz, 1H), 5.99 (s, 1H), 4.87 (q, 6.4 Hz, 1H), 2.59 (dd, 12.7, 7.4 Hz, 1H), 2.54 (s, 1H), 2.28 (dd, 10.6, 5.7 Hz, 2H), 1.88-1.80 (m, 1H)。 550.25 A   
I-862
Figure 02_image2017
 COc1ccc(cc1)[C@H](C)N1[C@@H](c2c(cc(Br)cc2N)C1=O)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  7.59 (dd, 8.9, 5.1 Hz, 1H), 7.35 -7.20 (m, 2H), 7.15 - 7.02 (m, 3H), 7.01 - 6.84 (m, 3H), 6.62 (dd, 9.3, 3.1 Hz, 1H), 5.64 -5.24 (m, 2H), 5.02 (d, 8.2 Hz, 1H), 4.77 (d, 13.1 Hz, 1H), 3.75 (d, 15.2 Hz, 3H), 1.18 (dd, 16.3, 7.3 Hz, 3H)。 491.05 D   
I-863
Figure 02_image2019
 COc1ccc(cc1)[C@H](C)N1[C@H](c2c(cc(Br)cc2N)C1=O)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  7.66 -7.43 (m, 1H), 7.15 - 6.95 (m, 4H), 6.91 (d, 1.7 Hz, 1H), 6.68 - 6.59 (m, 2H), 6.05 (dd, 9.3, 3.1 Hz, 1H), 5.97 -5.70 (m, 1H), 5.26 (q, 7.2 Hz, 1H), 5.11 (q, 7.2 Hz, 1H), 4.95-4.78 (m, 1H), 3.66 (d, 3.7 Hz, 3H), 1.65 (dd, 9.2, 7.2 Hz, 3H)。 491 D   
I-864
Figure 02_image2021
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3ncnc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  9.84 (s, 1H), 9.21 (d, 35.3 Hz, 1H), 8.52 (s, 1H), 7.96 (d, 8.3 Hz, 1H), 7.89 - 7.67 (m, 4H), 7.52 (td, 7.4, 6.7, 1.4 Hz, 1H), 7.24 - 6.86 (m, 2H), 6.77 - 6.39 (m, 1H), 6.03 (s, 1H)。 483 E   
I-865
Figure 02_image2023
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn[nH]1 NMR (400 MHz, CD3CN)  8.67 (br s, 1H), 8.10 (d, 1.3 Hz, 1H), 8.05 (s, 1H), 7.68 (d, 2.4 Hz, 1H), 7.63 (d, 8.5 Hz, 1H), 7.59 (d, 9.0 Hz, 1H), 7.57 (s, 1H), 7.24 (dd, 8.9, 5.1 Hz, 2H), 6.99-6.91 (m, 1H), 6.79 (d, 2.4 Hz, 1H), 6.68 (br s, 1H), 6.14 (br s, 1H)。 533.3 A A
I-866
Figure 02_image2025
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn[nH]1 1H NMR (400 MHz, CD3CN) 8.67 (br s, 1H), 8.10 (d, 1.3 Hz, 1H), 8.05 (s, 1H), 7.68 (d, 2.4 Hz, 1H), 7.63 (d, 8.5 Hz, 1H), 7.59 (d, 9.0 Hz, 1H), 7.57 (s, 1H), 7.24 (dd, 8.9, 5.1 Hz, 2H), 6.99-6.91 (m, 1H), 6.79 (d, 2.4 Hz, 1H), 6.68 (br s, 1H), 6.14 (br s, 1H)。 533.3 D   
I-867
Figure 02_image2027
 Cn1ccc(Nc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)n1 NMR (400 MHz, DMSO-d6)  10.41 (s, 1H), 8.98 (br. s, 1H), 8.92 (s, 1H), 7.92 (d, 8.4 Hz, 1H), 7.72 (d, 1.9 Hz, 1H), 7.70 (d, 8.6 Hz, 1H), 7.61 (s, 1H), 7.56 (d, 2.2 Hz, 1H), 7.39 (d, 1.5 Hz, 1H), 7.29 (dd, 8.9, 5.2 Hz, 1H), 7.07 (td, 8.4, 3.0 Hz, 1H), 6.59 (br. s, 1H), 5.85 (br. s, 1H), 5.82 (d, 2.2 Hz, 1H), 3.77 (s, 3H)。 562.3 A   
I-868
Figure 02_image2029
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(NCC3(CC3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.32 (s, 1H), 8.94 (s, 1H), 7.92 (d, 8.3 Hz, 1H), 7.70 (d, 8.9 Hz, 1H), 7.62 (s, 1H), 7.28 (dd, 8.8, 5.2 Hz, 1H), 7.06 (td, 8.5, 2.9 Hz, 1H), 6.92 (d, 1.6 Hz, 1H), 6.79 (s, 1H), 6.62 (br s, 1H), 6.57 (br t, 5.6 Hz, 1H), 5.84 (br s, 1H), 3.30 (m, 2H), 1.33-1.17 (m, 2H), 1.14-0.98 (m, 2H)。 561.4 A A
I-869
Figure 02_image2031
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(NCC3(CC3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.32 (s, 1H), 8.94 (s, 1H), 7.92 (d, 8.3 Hz, 1H), 7.70 (d, 8.9 Hz, 1H), 7.62 (s, 1H), 7.28 (dd, 8.8, 5.2 Hz, 1H), 7.06 (td, 8.5, 2.9 Hz, 1H), 6.92 (d, 1.6 Hz, 1H), 6.79 (s, 1H), 6.62 (br s, 1H), 6.57 (br t, 5.6 Hz, 1H), 5.84 (br s, 1H), 3.30 (m, 2H), 1.33-1.17 (m, 2H), 1.14-0.98 (m, 2H)。 561.4 B   
I-870
Figure 02_image2033
 Cn1cc2c(cc(F)cc2n1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN)  8.51 (s, 1H), 8.25 (s, 1H), 7.76 (dd, 7.2, 1.3 Hz, 1H), 7.65 (t, 7.4 Hz, 1H), 7.60 (dd, 7.7, 1.0 Hz, 1H), 7.46 (ddd, 9.8, 2.1, 1.0 Hz, 1H), 7.22 (dd, 8.9, 5.1 Hz, 1H), 7.24-7.20 (m, 1H), 6.98-6.91 (m, 2H), 6.64 (br. s, 1H), 6.18 (br. s, 1H), 4.15 (s, 3H)。 453.5 E   
I-871
Figure 02_image2035
 Cn1ncc2c(cc(F)cc12)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN)  8.54 (s, 1H), 8.06 (s, 1H), 7.76 (dd, 7.1, 1.3 Hz, 1H), 7.65 (t, 7.5 Hz, 1H), 7.61 (dd, 7.9, 1.4 Hz, 1H), 7.43 (ddd, 9.2, 2.0, 1.0 Hz, 1H), 7.24 (dd, 8.9, 5.2 Hz, 1H), 7.25-7.22 (浸沒信號, 1H), 6.99-6.92 (m, 2H), 6.66 (br. s, 1H), 6.20 (br. s, 1H), 4.02 (s, 3H)。 453.3 E   
I-872
Figure 02_image2037
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(F)ccc3NC3CCC3)c12 NMR (400 MHz, DMSO-d6)  10.02 (s, 1H), 9.11 (s, 1H), 7.66 (dd, 7.3, 0.7 Hz, 1H), 7.61 (t, 7.5 Hz, 1H), 7.47 (dd, 7.6, 0.9 Hz, 1H), 7.39 (d, 6.1 Hz, 1H), 7.36 (dd, 8.9, 5.2 Hz, 1H), 7.16-7.13 m, 2H), 6.82 (dd, 9.9, 2.2 Hz, 1H), 6.54 (dd, 9.3, 4.7 Hz, 1H), 6.70-6.40 (m, 1H), 6.01 (s, 1H), 3.94-3.81 (m, 1H), 2.44-2.29 (m, 2H), 1.82-1.68 (m, 4H) 468.4 D   
I-873
Figure 02_image2039
 CC1(C)CC(COc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)O1 1H NMR (400 MHz, DMSO-d6)  10.44 (s, 1H), 9.10 (s, 1H), 7.92 (d, 7.6 Hz, 1H), 7.72 (d, 8.8 Hz, 1H), 7.65 (s, 1H), 7.35-7.28 (m, 1H), 7.23 (s, 1H), 7.14 (s, 1H), 7.11-7.03 (m, 1H), 6.63 (s (br), 1H), 5.92 (s (br), 1H), 4.90-4.77 (m, 1H), 4.27-4.12 (m, 2H), 2.47-2.32 (m, 2H), 1.42 (s, 3H), 1.40-1.37 (m, 3H)。 581.2 B   
I-874
Figure 02_image2041
 CNc1cc(ccn1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, d6-DMSO)  9.05 (br s, 2H), 7.86 (s, 1H), 7.83 (d, 8.3 Hz, 1H), 7.79 (br d, 9.4 Hz, 1H), 7.71 (d, 5.2 Hz, 1H), 7.63-7.56 (m, 1H), 7.49 (s, 1H), 7.48 (d, 5.0 Hz, 1H), 6.28-6.21 (m, 1H), 6.09 (s, 1H), 6.04 (dd, 5.3, 1.0 Hz, 1H), 5.50 (s, 1H), 2.54 (d, 4.8 Hz, 3H)。 445.4 E   
I-875
Figure 02_image2043
 Cc1ccc(cc1C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN)  8.57 (s, 1H), 7.87 (d, 1.7 Hz, 1H), 7.75 (s, 1H), 7.72-7.66 (m, 2H), 7.44 (d, 7.9 Hz, 1H), 7.30 (br s, 1H), 7.25 (dd, 8.9, 5.1 Hz, 1H), 6.97 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.67 (br s, 1H), 6.09 (s, 1H), 2.52 (d, 1.6 Hz, 3H)。 541 B   
I-876
Figure 02_image2045
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)C34CC5CC(CC(C5)C3)C4)c12 1H NMR (400 MHz, DMSO-d6)  9.09 (s, 1H), 9.06 (br. s, 1H), 7.60-7.53 (m, 2H), 7.52-7.46 (m, 1H), 7.40 (dd, 7.4, 1.5 Hz, 1H), 7.24 (ddd, 8.7, 8.2, 3.1 Hz, 1H), 6.45 (br. s, 1H), 6.04 (br. s, 1H), 1.92-1.85 (m, 3H), 1.66-1.60 (m, 3H), 1.58-1.47 (m, 9H)。 439.4 B   
I-877
Figure 02_image2047
 COc1ccc(cc1C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.34 (s, 1H), 9.27 (br s, 1H), 7.93 (dd, 8.8, 1.9 Hz, 1H), 7.78 (d, 1.6 Hz, 1H), 7.74 (d, 2.0 Hz, 1H), 7.70 (d, 1.5 Hz, 1H), 7.34 (d, 8.9 Hz, 1H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.13-7.02 (m, 1H), 5.98 (s, 1H), 3.96 (s, 3H)。 555 C   
I-878
Figure 02_image2049
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn[nH]c1 NMR (400 MHz, DMSO-d6 )  13.07 (br.s, 1H), 10.56 (br. s, 1H), 9.12 (br. s, 1H), 8.41-8.11 (m, 2H), 7.95 (br. d, 6.5 Hz, 1H), 7.94 (s, 1H), 7.76 (br.d, 9.8 Hz, 1H), 7.73 (s, 1H), 7.71 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.5, 3.1 Hz, 1H), 6.65 (br. s, 1H), 5.97 (br. s, 1H)。 533.2 A A
I-879
Figure 02_image2051
 Cn1cc(nn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, MeCN-D3) 主要旋轉異構體：8.72 (s, 1H), 8.23 (s, 1H), 8.12 (d, 1.3 Hz, 1H), 8.10 (d, 1.3 Hz, 1H), 7.67 - 7.60 (m, 2H), 7.59 (s, 1H), 7.28 - 7.25 (m, 1H), 7.26 (dd, 8.9, 5.1 Hz, 1H), 6.98 (ddd, 8.9, 8.0, 3.1 Hz, 1H), 6.71 (br. s, 1H), 6.16 (br. s, 1H), 4.11 (s, 3H)。 548.1 A   
I-880
Figure 02_image2053
 Cn1c(Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)nnc1C1CC1 1H-NMR (400 MHz, DMSO-d6)  8.95 (br. s, 1H), 8.47 (br. s, 1H), 7.50 (t, 7.4 Hz, 1H), 7.44-7.38 (m, 2H), 7.32 (d, 7.7 Hz, 1H), 7.20 (td, 8.5, 3.1 Hz, 1H), 6.30-6.24 (m, 1H), 5.76 (br. s, 1H), 2.94 (s, 3H), 1.83-1.74 (m, 1H), 0.98-0.86 (m, 4H)。8.38處之峰疑似歸因於甲酸鹽的存在。0.83-0.75處之多重峰可歸因於油脂。 398.4 E   
I-881
Figure 02_image2055
 COc1ncc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    575.2 D   
I-882
Figure 02_image2057
 COc1ncc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    575.2 A A
I-883
Figure 02_image2059
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc2nccn2c1    584.2 D   
I-884
Figure 02_image2061
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc2nccn2c1    584.3 A A
I-885
Figure 02_image2063
 Nc1ncc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.50-10.59 (m, 1H), 9.13-9.21 (m, 1H), 8.66-8.71 (m, 2H), 7.90-7.96 (m, 2H), 7.71-7.80 (m, 2H), 7.69 (s, 1H), 7.31 (dd,  5.18, 8.97 Hz, 1H), 7.09 (dt,  3.03, 8.34 Hz, 1H), 6.90 (s, 2H), 2.92-3.04 (m, 2H) 560.31 A   
I-886
Figure 02_image2065
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc(nc1)C#N 1H NMR (400 MHz, DMSO-d6)偏移10.72 (br s, 1H), 9.44-9.55 (m, 2H), 9.30 (br s, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 7.95 (br d,  8.08 Hz, 1H), 7.76 (br d,  8.84 Hz, 1H), 7.70 (s, 1H), 7.33 (dd,  5.31, 8.84 Hz, 1H), 7.10 (dt,  3.16, 8.40 Hz, 1H), 5.97-6.15 (m, 1H) 570.31 A   
I-887
Figure 02_image2067
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccncc1F 1H NMR (400 MHz, DMSO-d6)偏移10.66 (br s, 1H), 9.29 (br s, 1H), 8.73 (d,  2.78 Hz, 1H), 8.56 (dd,  0.76, 5.05 Hz, 1H), 7.90-8.02 (m, 2H), 7.73-7.86 (m, 3H), 7.68 (s, 1H), 7.33 (dd,  5.18, 8.97 Hz, 1H), 7.11 (dt,  3.16, 8.40 Hz, 1H), 5.96-6.14 (m, 1H) 562.41 A A
I-888
Figure 02_image2069
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cccnc1 1H NMR (400 MHz, DMSO-d6)偏移10.62 (s, 1H), 9.24 (br s, 1H), 8.99 (d,  2.02 Hz, 1H), 8.63 (dd,  1.52, 4.80 Hz, 1H), 8.17-8.25 (m, 1H), 8.01 (d,  1.52 Hz, 1H), 7.95 (br d,  8.59 Hz, 1H), 7.86 (s, 1H), 7.76 (br d,  8.84 Hz, 1H), 7.69 (s, 1H), 7.57-7.67 (m, 2H), 7.49-7.57 (m, 3H), 7.33 (dd,  5.05, 8.84 Hz, 1H), 7.10 (dt,  3.16, 8.40 Hz, 1H), 5.95-6.15 (m, 1H) 544.45 A   
I-889
Figure 02_image2071
 Cn1ccc(cc1=O)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.59 (br s, 1H), 9.24 (br s, 1H), 7.92-7.97 (m, 2H), 7.84 (s, 1H), 7.82 (s, 1H), 7.75 (br d,  8.84 Hz, 1H), 7.69 (s, 1H), 7.32 (dd,  5.18, 8.97 Hz, 1H), 7.09 (dt,  3.03, 8.34 Hz, 1H), 6.75 (d,  2.02 Hz, 1H), 6.68 (dd,  2.02, 7.07 Hz, 1H), 5.97-6.10 (m, 1H), 3.47 (s, 3H) 574.36 A   
I-890
Figure 02_image2073
 Cc1cnccc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.59 (s, 1H), 9.25 (br s, 1H), 8.56 (s, 1H), 8.50 (d,  4.80 Hz, 1H), 8.26 (s, 1H), 7.94 (br d,  8.34 Hz, 1H), 7.73 (br d,  9.09 Hz, 1H), 7.62-7.69 (m, 2H), 7.52 (s, 1H), 7.28-7.38 (m, 2H), 7.10 (dt,  3.03, 8.34 Hz, 1H), 5.96-6.14 (m, 1H), 2.31 (s, 3H) 558.41 A   
I-891
Figure 02_image2075
 COc1cccc(n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.58 (s, 1H), 9.23 (br s, 1H), 8.53 (s, 1H), 8.33 (d,  4.80 Hz, 1H), 7.94 (br d,  8.34 Hz, 1H), 7.86 (d,  1.01 Hz, 1H), 7.70-7.80 (m, 2H), 7.67 (s, 1H), 7.46 (d,  4.80 Hz, 1H), 7.33 (dd,  5.18, 8.97 Hz, 1H), 7.10 (dt,  3.03, 8.46 Hz, 1H), 5.98-6.13 (m, 1H), 3.95 (s, 3H) 574.41 A   
I-892
Figure 02_image2077
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cccnc1C(F)(F)F 1H NMR (400 MHz, DMSO-d6)偏移10.62 (s, 1H), 9.21-9.35 (m, 1H), 8.83 (dd,  1.14, 4.67 Hz, 1H), 8.04 (d,  7.58 Hz, 1H), 7.93 (br d,  8.59 Hz, 1H), 7.83 (dd,  4.67, 7.96 Hz, 1H), 7.73 (br d,  8.84 Hz, 1H), 7.64 (br d,  6.06 Hz, 2H), 7.48 (br s, 1H), 7.34 (dd,  5.18, 8.97 Hz, 1H), 7.11 (dt,  3.16, 8.40 Hz, 1H), 5.94-6.12 (m, 1H) 612.38 A   
I-893
Figure 02_image2079
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncccc2c1    594.3 D   
I-894
Figure 02_image2081
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncccc2c1    594.3 A A
I-895
Figure 02_image2083
 Cc1ncc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl    525.2 E   
I-896
Figure 02_image2085
 Cc1ncc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl    525.2 A   
I-897
Figure 02_image2087
 OC1(Cc2cc3C(=O)N[C@@H](c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CCC1    549.2 D   
I-898
Figure 02_image2089
 OC1(Cc2cc3C(=O)N[C@H](c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CCC1    549.2 A   
I-899
Figure 02_image2091
 CC(C)(O)CNc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    554.3 E   
I-900
Figure 02_image2093
 CC(C)(O)CNc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    554.3 A A
I-901
Figure 02_image2095
 Cn1cccc(-c2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)c1=O 1H NMR (500 MHz, DMSO-d6) 10.57 (s, 1H), 9.10-9.18 (m, 1H), 8.04 (s, 1H), 7.89-7.99 (m, 2H), 7.83 (dt,  2.29, 4.65 Hz, 2H), 7.76 (br d,  8.85 Hz, 1H), 7.70 (s, 1H), 7.34 (dd,  5.19, 8.85 Hz, 1H), 7.08-7.14 (m, 1H), 6.40 (t,  6.87 Hz, 1H), 5.93-6.09 (m, 1H), 3.56 (s, 3H) 574.32 B B
I-902
Figure 02_image2097
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cccc2cnccc12 1H NMR (500 MHz, DMSO-d6) 10.63 (s, 1H), 9.45 (s, 1H), 9.25-9.32 (m, 1H), 8.58 (d,  6.10 Hz, 1H), 8.25 (d,  8.24 Hz, 1H), 7.93-7.98 (m, 1H), 7.87-7.90 (m, 1H), 7.84 (d,  7.93 Hz, 1H), 7.73-7.80 (m, 3H), 7.63-7.71 (m, 2H), 7.38 (dd,  5.19, 8.85 Hz, 1H), 7.11-7.17 (m, 1H), 6.08-6.18 (m, 1H) 594.32 A A
I-903
Figure 02_image2099
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(c1)C1CNC1 1H NMR (500 MHz, DMSO)  10.51 (s, 1H), 9.14 (s, 1H), 8.95 (d, 89.5 Hz, 2H), 8.54 (s, 1H), 8.28 (s, 1H), 7.98-7.89 (m, 2H), 7.76-7.68 (m, 3H), 7.31 (dd, 8.8, 5.2 Hz, 1H), 7.09 (td, 8.4, 3.1 Hz, 1H), 5.97 (s, 1H), 5.46-5.36 (m, 1H), 4.47-4.34 (m, 4H)。 588.375 A D
I-904
Figure 02_image2101
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(c1)C1COC1 1H NMR (500 MHz, DMSO)  10.51 (s, 1H), 9.12 (s, 1H), 8.60 (s, 1H), 8.17 (s, 1H), 7.98-7.90 (m, 2H), 7.79-7.67 (m, 3H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.09 (qd, 8.4, 2.0 Hz, 1H), 5.96 (s, 1H), 5.63-5.55 (m, 1H), 4.98-4.89 (m, 4H)。 589.38 A A
I-905
Figure 02_image2103
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nccn2n1 1H NMR (500 MHz, DMSO)  10.68 (s, 1H), 9.28 (s, 1H), 8.40-8.32 (m, 2H), 8.29-8.21 (m, 2H), 8.00-7.94 (m, 2H), 7.86 (d, 1.2 Hz, 1H), 7.78 (dd, 9.2, 2.5 Hz, 1H), 7.72 (s, 1H), 7.33 (dd, 8.9, 5.1 Hz, 1H), 7.10 (td, 8.4, 3.0 Hz, 1H), 6.08 (s, 1H)。 584.37 A A
I-906
Figure 02_image2105
 Cn1nccc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN)  8.76 (br. s, 1H), 7.84 (d, 1.5 Hz, 1H), 7.68-7.64 (m, 2H), 7.64-7.57 (m, 2H), 7.49 (d, 1.9 Hz, 1H), 7.36 (br. s, 1H), 7.27 (dd, 8.9, 5.1 Hz, 1H), 6.99 (ddd, 8.9, 8.0, 3.1 Hz, 1H), 6.70 (br. s, 1H), 6.47 (d, 1.9 Hz, 1H), 6.19 (br. s, 1H), 3.93 (s, 3H)。 547.4 A A
I-907
Figure 02_image2107
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1ccccc1C1COC1 1H NMR (400 MHz, DMSO-d6 )  10.44 (br. s, 1H), 9.06 (s, 1H), 7.90 (d, 8.4 Hz, 1H), 7.71 (d, 5.2 Hz, 1H), 7.63 (t, 7.6 Hz, 1H), 7.53-7.22 (m, 5H), 7.09 (br. s, 1H), 6.41 (br. s, 1H), 5.74 (s, 1H), 5.03-4.43 (m, 4H), 4.16 (m, 1H)；2.67及2.33處之DMSO衛星；TMS在0.08-0.03區域中含有少量雜質。 471.2 E   
I-908
Figure 02_image2109
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(cc(F)c3F)C(F)(F)F)c12 1H NMR (400 MHz, 甲醇-d4)  7.97 (d, 1.7 Hz, 1H), 7.90 (ddd, 9.5, 6.8, 2.3 Hz, 1H), 7.76 (s, 1H), 7.41 (dt, 8.2, 4.1 Hz, 2H), 7.11 (ddd, 8.9, 7.8, 3.1 Hz, 1H), 6.69 (s, 1H), 6.20 (s, 1H)。 565 D   
I-909
Figure 02_image2111
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cncc(Cl)c3)c12 1H NMR (400 MHz, 氯仿-d) 8.76 (s, 1H), 8.55 (s, 1H), 8.43 (s,1H), 7.97 (d, 1.6 Hz, 1H), 7.88 (s, 1H), 7.47 (dd, 8.4, 4.3 Hz, 2H), 7.11 (m, 1H),  6.72 (s, 1H), 6.53 (s, 1H), 6.20 (s, 1H)。 495.95 D   
I-910
Figure 02_image2113
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C#N)c12 1H NMR (400 MHz, 氯仿-d)  8.50 (s, 1H), 7.97 (d, 1.6 Hz, 1H), 7.57 (td, 10.5, 9.9, 6.3 Hz, 3H), 7.42-7.38 (m, 2H), 7.22-7.12 (m, 1H), 6.74 (s, 1H), 6.52 (s, 1H), 6.19 (s, 1H)。    D   
I-911
Figure 02_image2115
 FC(F)c1ccc(Cl)cc1C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 氯仿-d) 8.45 (s, 1H), 7.96 (q, 1.8 Hz, 1H), 7.73 (d, 8.4 Hz, 1H), 7.61 (dd, 8.4, 2.0 Hz, 1H), 7.45-7.22 (m, 2H), 7.18-7.06 (m, 2H), 6.95 (d, 4.1 Hz, 1H), 6.72 (d, 8.5 Hz, 1H), 6.58 (s, 1H), 6.17 (s, 1H)。 544.95 D   
I-912
Figure 02_image2117
 CS(=O)(=O)c1cc(F)cc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 氯仿-d) 8.34 (s, 1H), 7.94 (d, 1.6 Hz, 1H), 7.87-7.81 (m, 3H), 7.67 (ddd, 8.3, 2.4, 1.5 Hz, 1H), 7.46 (dd, 8.9, 4.9 Hz, 1H), 7.07 (ddd, 8.9, 7.4, 3.0 Hz, 1H), 6.73-6.64 (m, 2H), 6.21 (s, 1H), 3.12 (s, 3H)。 557 E   
I-913
Figure 02_image2119
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(I)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.54 (s, 1 H), 9.22 (s, 1 H), 8.03-7.80 (m, 3 H), 7.72 (d, 9.0 Hz, 1 H), 7.66 (s, 1 H), 7.32 (dd, 8.9, 5.2 Hz, 1 H), 7.09 (td, 8.5, 3.0 Hz, 1 H), 6.66 (br s, 1 H), 5.93 (br s, 1 H)。 591.3 A A
I-914
Figure 02_image2121
 CSCc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6 )  10.52 (s, 1H), 9.14 (s, 1H), 7.93 (t, 8.7 Hz, 1H), 7.74 (d, 9.2 Hz, 1H), 7.64 (d, 6.4 Hz, 2H), 7.44 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.4, 3.0 Hz, 1H), 5.97 (br, s, 1H), 4.00-3.75 (m, 2H), 1.99 (s,3H)。 527.3 A A
I-915
Figure 02_image2123
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ncco1 NMR (400 MHz, DMSO)  10.69 (s, 1H), 9.33 (s, 1H), 8.33 (s, 1H), 8.16 (s, 2H), 7.96 (d, 8.3 Hz, 1H), 7.77 (d, 8.9 Hz, 1H), 7.68 (s, 1H), 7.48 (s, 1H), 7.34 (dd, 8.8, 5.2 Hz, 1H), 7.10 (td, 8.5, 3.1 Hz, 1H), 6.08 (s, 1H)。B環之鄰質子缺失 534 A A
I-916
Figure 02_image2125
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc[nH]c1=O NMR (400 MHz, DMSO)  12.00 (s, 1H), 10.59 (s, 1H), 9.15 (s, 1H), 8.07 (m, 1H), 7.94 (m, 2H), 7.85 (dd, 7.0, 2.0 Hz, 1H), 7.75 (d, 8.7 Hz, 1H), 7.68 (s, 1H), 7.47 (dd, 6.3, 1.4 Hz, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.4, 3.1 Hz, 1H), 6.36 (t, 6.7 Hz, 1H), 5.99 (s, 1H)。B環之鄰質子缺失 560 A A
I-917
Figure 02_image2127
 Cn1cc(Nc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)cn1 NMR (400 MHz, DMSO-d6)  10.30 (s, 1H), 8.96 (bs, 1H), 7.95 (s, 1H), 7.92 (d, 8.5 Hz, 1H), 7.74 (s, 1H), 7.69 (d, 9.1 Hz, 1H), 7.60 (s, 1H), 7.38 (s, 1H), 7.28 (dd, 8.8, 5.1 Hz, 1H), 7.06 (td, 8.3, 2.9 Hz, 1H), 6.96 (d, 1.6 Hz, 1H), 6.84 (d, 1.5 Hz, 1H), 6.69 (bs, 1H), 5.85 (bs, 1H), 3.83 (s, 3H)。 262.4 A A
I-918
Figure 02_image2129
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ncc[nH]1 NMR (400 MHz, DMSO-d6 )  12.83 (br. s, 1H), 10.65 (s, 1H), 9.22 (s, 1H), 8.37 (s, 1H), 8.27 (d, 0.7 Hz, 1H), 8.14 (d, 1.0 Hz, 1H), 7.96 (d, 8.3 Hz, 1H), 7.77 (d, 8.6 Hz), 7.69 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.34-7.07 (m, 浸沒1H), 7.09 (td, 8.5, 3.0 Hz, 1H), 6.66 (br. s, 1H), 6.02 (br. s, 1H)。 533.2 C   
I-919
Figure 02_image2131
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ncc[nH]1 NMR (400 MHz, DMSO-d6 )  12.83 (br. s, 1H), 10.65 (s, 1H), 9.22 (s, 1H), 8.37 (s, 1H), 8.27 (d, 0.7 Hz, 1H), 8.14 (d, 1.0 Hz, 1H), 7.96 (d, 8.3 Hz, 1H), 7.77 (d, 8.6 Hz), 7.69 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.34-7.07 (m, 浸沒1H), 7.09 (td, 8.5, 3.0 Hz, 1H), 6.66 (br. s, 1H), 6.02 (br. s, 1H)。 533.2 A A
I-920
Figure 02_image2133
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cscn1 NMR (400 MHz, CD3CN)  9.01 (d, 1.9 Hz, 1H), 8.76 (br s, 1H), 8.29 (d, 1.4 Hz, 1H), 8.25 (s, 1H), 8.02 (d, 1.9 Hz, 1H), 7.70-7.59 (m, 3H), 7.32 (br s, 1H), 7.27 (dd, 8.9, 5.1 Hz, 1H), 6.98 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.72 (br s, 1H), 6.18 (br s, 1H)。 550.3 A A
I-921
Figure 02_image2135
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1nccs1 NMR (400 MHz, CD3CN)  8.76 (s, 1H), 8.20 (m, 2H), 7.93 (d, 3.6, 1H), 7.65-7.55 (m, 4H), 7.35 (br s, 1H), 7.25 (dd, 8.9, 5.1 Hz, 1H), 6.99 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.69 (br s, 1H), 6.16 (br s, 1H)。 550.3 A A
I-922
Figure 02_image2137
 Cn1nccc1Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSOd6)  10.37 (s, 1H), 9.04 (s, 1H), 8.45 (s, 1H), 7.93 (d, 8.5 Hz, 1H), 7.69 (d, 9.2 Hz, 1H), 7.59 (s, 1H), 7.42 (d, 1.9 Hz, 1H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.07 (td, 8.3, 3.1 Hz, 1H), 7.02 (d, 2.0 Hz, 1H), 6.93 (d, 1.64 Hz, 1H), 6.63 (bs, 未充分解析, 1H), 6.12 (d, 1.9 Hz, 1H), 5.90 (bs, 1H), 3.68 (s, 3H)。 562.3 A A
I-923
Figure 02_image2139
 Cc1noc(C)c1Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN)  8.47 (br s, 1H), 7.60 (br d, 1H), 7.55 (d, 12.2 Hz, 1H), 7.51 (s, 1H), 7.22 (dd, 8.9, 5.1 Hz, 1H), 7.15 (br s, 1H), 6.93 (ddd, 11.1, 7.0, 3.1 Hz, 1H), 6.86 (d, 2.1 Hz, 1H), 6.76 (d, 1.8 Hz, 1H), 6.62 (br s, 1H), 6.17 (s, 1H), 5.99 (br s, 1H), 2.26 (s, 3H), 2.08 (s, 3H)。 577.5 A A
I-924
Figure 02_image2141
 Cc1nn(C)cc1Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSOd6)  10.29 (s, 1H), 8.94 (s, 1H), 7.91 (d, 8.7 Hz, 1H), 7.68 (浸沒br. d, 1H), 7.67 (s, 1H), 7.60-7.58 (m, 1H), 7.28 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.3, 3.1 Hz, 1H), 6.82 (d, 2.0 Hz, 1H), 6.72 (d, 1.8 Hz, 1H), 6.60 (bs, 未充分解析, 1H), 5.83 (bs, 1H), 3.76 (s, 3H), 2.02 (s, 3H)。存在20%甲酸鹽(8.38)。 576.3 A A
I-925
Figure 02_image2143
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1ccccc1C1CC1 1H NMR (400 MHz, DMSO-d6 )  10.15 (br. s, 1H), 8.85 (s, 1H), 7.79 (d, 8.4 Hz, 1H), 7.69 (d, 7.5 Hz, 1H), 7.61 (t, 7.6 Hz, 1H), 7.54-7.47 (m, 3H), 7.08 (t, 7.8 Hz, 1H), 6.95 (t, 7.7 Hz, 1H), 6.85 (d, 7.6 Hz, 1H), 6.66 (br. s, 1H), 6.21 (br. s, 1H), 1.88 (s), 0.74-0.47 (m, 1H), 0.70 - 0.50 (m, 3H), 0.47-0.39 (m, 1H)；2.68及2.33處之DMSO衛星。 455.3 B   
I-926
Figure 02_image2145
 OC1(Cc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CNC1 NMR (400 MHz, DMSO-d6 )  10.54 (s, 1H), 9.07 (s, 1H), 8.34 (s, 1H), 7.90 (d, 8.6 Hz, 1H), 7.69 (d, 8.7 Hz, 1H), 7.59 (d, 4.4 Hz, 2H), 7.36 (s, 1H), 7.27 (dd, 8.9, 5.2 Hz, 1H), 7.05 (td, 8.4, 3.1 Hz, 1H), 6.58 (br., 1H), 6.21 (br, 1H), 5.90 (s, 1H), 3.65 (d, 9.6 Hz, 2H), 3.58 (d, 9.8 Hz, 2H)3.13 (dd, 13.9 Hz, 9.6Hz, 2H)。 552.3 A D
I-927
Figure 02_image2147
 Cc1cc(cc2cnn(C)c12)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl       B C
I-928
Figure 02_image2149
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc(nc1)C#N       A A
I-929
Figure 02_image2151
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc(nc1)N1CCOCC1       A A
I-930
Figure 02_image2153
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc(nc1)N1CCOCC1       A B
I-931
Figure 02_image2155
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cccc2ncccc12       A A
I-932
Figure 02_image2157
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2OCCOc2c1       B B
I-933
Figure 02_image2159
 Cc1cc2cnn(C)c2cc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl       B C
I-934
Figure 02_image2161
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccnc2ccccc12       A A
I-935
Figure 02_image2163
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnoc1       A A
I-936
Figure 02_image2165
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1n[nH]c2cccnc12       A A
I-937
Figure 02_image2167
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1n[nH]c2ccccc12       B B
I-938
Figure 02_image2169
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1n[nH]c2ccncc12       B   
I-939
Figure 02_image2171
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1n[nH]c2ncccc12       A A
I-940
Figure 02_image2173
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc2cnccn12       A A
I-941
Figure 02_image2175
 CC(C)(O)c1ncc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    603.5 B A
I-942
Figure 02_image2177
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(c1)C1CC1    573.4 A A
I-943
Figure 02_image2179
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1 1 H NMR (DMSO-d6 , 400 MHz): δ = 10.64 (s, 1H), 9.48 (s, 1H), 9.26 (br s, 1H), 8.58 (s, 1H), 8.10-8.19 (m, 2H), 7.99 (br d, J = 9.9 Hz, 3H), 7.75-7.83 (m, 1H), 7.73 (s, 1H), 7.35 (dd, J = 8.8, 5.3 Hz, 1H), 7.12 (td, J = 8.3, 3.0 Hz, 1H), 6.51-6.97 (m, 1H), 6.07 (br s, 1H)。 584.3 C   
I-944
Figure 02_image2181
 CC(C)(C)OC(=O)N1CC(C1)n1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    588.37 A C
I-945
Figure 02_image2183
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1 1 H NMR (DMSO-d6 , 400 MHz): δ = 10.64 (s, 1H), 9.48 (s, 1H), 9.26 (br s, 1H), 8.58 (s, 1H), 8.10-8.19 (m, 2H), 7.99 (br d, J = 9.9 Hz, 3H), 7.75-7.83 (m, 1H), 7.73 (s, 1H), 7.35 (dd, J = 8.8, 5.3 Hz, 1H), 7.12 (td, J = 8.3, 3.0 Hz, 1H), 6.51-6.97 (m, 1H), 6.07 ppm (br s, 1H)。 584.3 A A
I-946
Figure 02_image2185
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ccnc2cn1 1H NMR (500 MHz, DMSO)  10.64 (s, 1H), 9.51 (d, 1.5 Hz, 1H), 9.27-9.12 (m, 2H), 8.29 (d, 26.2 Hz, 2H), 8.15 (t, 0.9 Hz, 1H), 7.94 (d, 8.4 Hz, 1H), 7.91-7.84 (m, 1H), 7.78 (d, 9.0 Hz, 1H), 7.72 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.3, 3.1 Hz, 1H), 6.06 (s, 1H)。 584.37 A A
I-947
Figure 02_image2187
 Cn1ccc(n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO)  10.52 (s, 1H), 9.13 (s, 1H), 8.04 (d, 1.5 Hz, 1H), 7.98-7.88 (m, 2H), 7.83-7.66 (m, 3H), 7.31 (dd, 8.9, 5.1 Hz, 1H), 7.08 (td, 8.4, 3.2 Hz, 1H), 6.86 (d, 2.3 Hz, 1H), 5.99 (s, 1H), 3.91 (s, 3H)。 547.41 A A
I-948
Figure 02_image2189
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc2ccccc2n1 1H NMR (500 MHz, DMSO-d6)   6.04 - 6.18 (m, 1 H) 6.52 (br d,  1.53 Hz, 1 H) 7.12 (td,  8.32, 2.90 Hz, 1 H) 7.36 (dd,  9.00, 5.04 Hz, 1 H) 7.73 - 7.78 (m, 1 H) 7.82 (br d,  8.85 Hz, 1 H) 7.89 - 8.03 (m, 3 H) 8.19 (td,  7.55, 1.68 Hz, 2 H) 8.52 (s, 1 H) 8.67 (s, 1 H) 9.31 (br d,  3.05 Hz, 1 H) 9.77 (s, 1 H) 10.76 (s, 1 H) 595.33 A A
I-949
Figure 02_image2191
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc2cnccc2[nH]1 1H NMR (500 MHz, DMSO-d6)   7.09 - 7.14 (m, 1 H) 7.33 - 7.37 (m, 1 H) 7.66 (s, 1 H) 7.73 (s, 1 H) 7.78 (br d,  9.16 Hz, 1 H) 7.93 - 8.04 (m, 3 H) 8.18 (s, 1 H) 8.38 (s, 1 H) 8.45 (d,  6.71 Hz, 1 H) 9.27 - 9.38 (m, 2 H) 10.69 (s, 1 H) 13.57 (s, 1 H) 14.65 - 14.98 (m, 1 H) 583.32 A B
I-950
Figure 02_image2193
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2c1n([nH]c2=O)-c1cccc(Cl)c1 1H NMR (400 MHz, DMSO-d6)  11.50 (br s, 1H), 10.65 (s, 1H), 7.94 (d, 12.7 Hz. 1H), 7.74 (m, 3H), 7.38 (d, 7.4 Hz, 1H), 7.33 (d, 8.2 Hz, 1H), 7.23(m, 3H), 7.05 (d, 8.0 Hz, 1H)。 450.3 D   
I-951
Figure 02_image2195
 Cc1cc(F)cc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 氯仿-d)  8.52 (s, 1H), 7.94 (d, 1.7 Hz, 1H), 7.46 (dd, 8.9, 4.9 Hz, 1H), 7.32 (s, 1H), 7.15-7.04 (m, 3H), 6.97 (d, 8.7 Hz, 1H), 6.73 (s, 1H), 6.49 (s, 1H), 6.18 (s, 1H), 2.41 (d, 0.8 Hz, 3H)。 493 D   
I-952
Figure 02_image2197
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccc(Cl)c(c3)C(F)(F)F)c12 1H NMR (400 MHz, 氯仿-d)  8.41 (s, 1H), 7.98 (d, 1.7 Hz, 1H), 7.74 (d, 5.3 Hz, 2H), 7.63 (d, 8.9 Hz, 1H), 7.45 - 7.36 (m, 2H), 7.13 - 7.03 (m, 1H), 6.71 (s, 1H), 6.44 (s, 1H), 6.18 (s, 1H)。 560.85 B   
I-953
Figure 02_image2199
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)Cc3c[nH]c4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  10.87 (s, 1H), 9.71 (s, 1H), 9.20 (s, 1H), 7.71 (dd, 16.6, 1.7 Hz, 2H), 7.40 (dd, 8.9, 5.2 Hz, 1H), 7.36 - 7.30 (m, 1H), 7.35 - 7.25 (m, 1H), 7.15 (td, 8.5, 2.9 Hz, 1H), 7.11 - 7.03 (m, 1H), 7.01 (d, 2.4 Hz, 1H), 6.94 (ddd, 7.9, 6.9, 1.1 Hz, 1H), 6.65 (s, 1H), 6.02 (s, 1H), 3.46 (s, 2H)。 512 E   
I-954
Figure 02_image2201
 OC(=O)c1cc(F)cc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 13.51 (s, 1H), 10.53 (s, 1H), 9.28 (s, 1H), 8.00 (d, 1.5 Hz, 1H), 7.89 - 7.79 (m, 2H), 7.72 (d, 1.9 Hz, 1H), 7.60 (dt, 9.2, 2.0 Hz, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.4, 3.1 Hz, 1H), 6.73 (s, 1H), 5.99 (s, 1H)。 523 E   
I-955
Figure 02_image2203
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)Cc3n[nH]c4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  12.78 (s, 1H), 10.04 (s, 1H), 9.20 (s, 1H), 7.76 - 7.69 (m, 2H), 7.53 - 7.44 (m, 2H), 7.42 - 7.29 (m, 2H), 7.16 (t, 7.2 Hz, 1H), 7.10 - 6.30 (m, 2H), 6.00 (s, 1H), 3.70 (s, 2H)。 513.05 E   
I-956
Figure 02_image2205
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3c[nH]c4cccc(Cl)c34)c12 1H NMR (400 MHz, DMSO-d6)  11.89 (s, 1H), 9.93 (s, 1H), 9.23 (s, 1H), 7.80 (d, 1.9 Hz, 1H), 7.72 (d, 1.7 Hz, 1H), 7.49 - 7.40 (m, 2H), 7.27 - 7.10 (m, 4H), 6.78 (s, 1H), 6.11 (s, 1H)。 532 D   
I-957
Figure 02_image2207
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cncc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.68 (s, 1H), 9.31 (s, 1H), 9.18 (s, 1H), 9.02 (s, 1H), 8.18 (s, 1H), 7.85 (s, 1H), 7.75 (s, 1H), 7.33 (dd, 8.9, 5.0 Hz, 1H), 7.10 (dd, 8.7, 3.0 Hz, 1H), 6.82 (t, 9.0 Hz, 1H), 5.97 (s, 1H)。 530.1 D   
I-958
Figure 02_image2209
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cncc(F)c3)c12 1H NMR (400 MHz, DMSO-d6)  10.52 (s, 1H), 9.30 (s, 1H), 8.78 (d, 2.8 Hz, 1H), 8.56 (d, 1.8 Hz, 1H), 7.87 - 7.79 (m, 2H), 7.75 (d, 1.8 Hz, 1H), 7.36 (dd, 8.8, 5.2 Hz, 1H), 7.19 - 7.09 (m, 1H), 6.76 (s, 1H), 5.99 (s, 1H)。 479.95 E   
I-959
Figure 02_image2211
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3nccc4c(Cl)cc(F)cc34)c12 1H NMR (400 MHz, DMSO-d6) 9.27 (s, 1H), 9.14 (s, 1H), 8.09 (d, 6.0 Hz, 1H), 7.98 (dd, 8.6, 2.4 Hz, 1H), 7.73-7.66 (m, 2H), 7.65 (d, 9.8 Hz, 1H), 7.39 (d, 6.0 Hz, 1H), 7.06 (s, 1H), 6.93-6.84 (m, 1H), 6.30 (s, 1H), 5.80 (s, 1H)。 533.95 B A
I-960
Figure 02_image2213
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-n1cccn1 (400 MHz, DMSO-D6)  10.67 (s, 1 H), 9.29 (s, 1 H), 8.76 (d, 2.5 Hz, 1 H), 8.14 (d, 1.6 Hz, 1 H), 8.09 (d, 1.6 Hz, 1 H), 7.96 (d, 8.4 Hz, 1 H), 7.82 (d, 1.6 Hz, 1 H), 7.76 (d, 8.9 Hz, 1 H), 7.69 (s, 1 H), 7.33 (dd, 8.9, 5.2 Hz, 1 H), 7.10 (td, 8.5, 3.0 Hz, 1 H), 6.66-6.58 (m, 1 H), 6.03 (br s, 1 H)。B環之鄰質子缺失/浸沒。 533.3 A A
I-961
Figure 02_image2215
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Nc3ncco3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSOd6)  10.58 (s, 1H), 10.53 (s, 1H), 9.08 (存在甲酸鹽), 7.98 (s, 1H), 7.94 (d, 8.6 Hz, 1H), 7.76 (s, 1H), 7.69 (m, 2H including d,  1.01 Hz, 1H), 7.62 (s, 1H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.08 (浸沒td, 8.38, 3.04 Hz, 1H), 7.05 (浸沒s, 1H), 6.60 (bs, 1H), 5.90 (bs, 1H)。 549.3 A A
I-962
Figure 02_image2217
 CS(=O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, Cd3CN)  8.75 (s, 1H), 7.67 (s, 1H), 7.65 (d, 8.5 Hz, 1H), 7.61-7.55 (m, 2H), 7.51 (s, 1H), 7.32 (s, 1H), 7.25 (dd, 8.9, 5.1 Hz, 1H), 6.97 (td, 8.4, 3.0 Hz, 1H), 6.65 (br, s, 1H), 6.11 (s, 1H), 4.21 (dd, 13.0, 1.2 Hz, 1H), 4.01 (dd, 13.1, 1.1 Hz, 1H), 2.49 (d, 3.6 Hz, 3H)。 543.2 A A
I-963
Figure 02_image2219
 CC(C)(O)Cc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl    505 C   
I-964
Figure 02_image2221
 Cc1coc(Nc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)n1 NMR (400 MHz, DMSOd6)  10.53 (s, 1H), 10.47 (s, 1H), 9.10 (br s, 1H), 8.02 (d, 1.8 Hz, 1H), 7.94 (d, 8.2 Hz, 1H), 7.71 (d, 9.6 Hz, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.40 (d, 1.4 Hz, 1H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.08 (td, 8.5, 3.0 Hz, 1H), 6.61 (br s, 1H), 5.87 (br s, 1H), 2.07 (d, 1.3 Hz, 3H)。 563.4 A A
I-965
Figure 02_image2223
 Cn1cc(Nc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)nn1 1H-NMR (400 MHz, DMSO-d6)  10.42 (s, 1H), 9.01 (br. s, 1H), 8.98 (s, 1H), 7.93 (br. d, 8.4 Hz, 1H), 7.84 (s, 1H), 7.71 (br. d, 8.8 Hz, 1H), 7.62 (s, 1H), 7.39 (d, 2.0 Hz, 1H), 7.29 (dd, 8.9, 5.2 Hz, 1H), 7.24 (d, 1.8 Hz, 1H), 7.07 (app. td, 8.4, 3.1 Hz, 1H), 6.60 (br. s, 1H), 5.87 (br. s, 1H), 4.04 (s, 3H)。 563.4 A A
I-966
Figure 02_image2225
 Cc1nc(Nc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)oc1C NMR (400 MHz, DMSOd6)  10.52 (s, 1H), 10.33 (s, 1H), 9.08 (br s, 1H), 7.99 (d, 1.8 Hz, 1H), 7.93 (d, 8.2 Hz, 1H), 7.71 (d, 8.8 Hz, 1H), 7.66 (s, 1H), 7.61 (s, 1H), 7.29 (dd, 8.8, 5.2 Hz, 1H), 7.07 (td, 8.5, 3.1 Hz, 1H), 6.68 (br s, 1H), 5.88 (br s, 1H), 2.19 (d, 0.9 Hz, 3H), 2.00 (d, 0.9 Hz, 3H)。 577.4 A A
I-967
Figure 02_image2227
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cncnc1    545.4 A A
I-968
Figure 02_image2229
 CC(C)(O)Cn1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    605.6 A A
I-969
Figure 02_image2231
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc2ncnn2c1    585.4 A A
I-970
Figure 02_image2233
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc2ncccc2[nH]1    582.27 A A
I-971
Figure 02_image2235
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc2ccccc2[nH]1 1H NMR (400 MHz, DMSO-d6)   6.01 (br s, 1 H) 6.37 - 6.91 (m, 1 H) 6.99 - 7.15 (m, 4 H) 7.32 (dd,  8.84, 5.05 Hz, 1 H) 7.41 (dd,  8.08, 0.76 Hz, 1 H) 7.56 (d,  7.83 Hz, 1 H) 7.69 - 7.80 (m, 2 H) 7.92 - 8.02 (m, 2 H) 8.21 (s, 1 H) 9.20 (br s, 1 H) 10.60 (s, 1 H) 11.81 (s, 1 H) 582.27 A A
I-972
Figure 02_image2237
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc2cccnc2[nH]1 1H NMR (400 MHz, DMSO-d6)   5.90 - 6.12 (m, 1 H) 6.86 - 6.98 (m, 1 H) 7.05 - 7.13 (m, 3 H) 7.32 (dd,  8.84, 5.05 Hz, 1 H) 7.72 (s, 1 H) 7.77 (br d,  9.35 Hz, 1 H) 7.91 - 7.99 (m, 2 H) 8.08 (br s, 1 H) 8.24 (dd,  4.55, 1.52 Hz, 1 H) 8.29 (br s, 1 H) 8.47 (s, 1 H) 9.10 - 9.32 (m, 1 H) 10.68 (br s, 1 H) 12.24 - 12.42 (m, 1 H) 583.27 A A
I-974
Figure 02_image2239
 Cn1ncnc1Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.50 (br. s, 1H), 9.39 (s, 1H), 9.09 (br. s, 1H), 8.00 (d, 1.8 Hz, 1H), 7.94 (d, 8.5 Hz, 1H), 7.82 (d, 1.6 Hz, 1H), 7.72 (d, 9.1 Hz, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.08 (td, 8.5, 3.0 Hz, 1H), 6.61 (br. s, 1H), 5.91 (br. s, 1H), 3.37 (s, 3H) 563.3 A A
I-975
Figure 02_image2241
 Cc1cc2nccnc2cc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    609.3 B   
I-976
Figure 02_image2243
 Cn1cnc(Nc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)n1 1H NMR (400 MHz, DMSO-d6)  10.47 (s, 1H), 9.67 (s, 1H), 9.02 (br. s, 1H), 8.26 (s, 1H), 7.96 (d, 1.9 Hz, 1H), 7.93 (dt, 8.5 Hz, 1H), 7.71 (d, 8.7 Hz, 1H), 7.61 (s, 1H), 7.58 (d, 1.5 Hz, 1H), 7.28 (dd, 8.8, 5.2 Hz, 1H), 7.07 (td, 8.6, 3.0 Hz, 1H), 6.54 (br. s, 1H), 5.86 (br. s, 1H), 3.81 (s, 3H)； 563.3 A A
I-977
Figure 02_image2245
 COCCOc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.50 (br s, 1H), 9.13 (s, 1H), 7.94 (d, 8.5 Hz, 1H), 7.71 (d, 8.7 Hz, 1H), 7.63 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.25-7.16 (m, 1H), 7.08 (td, 8.9, 3.1 Hz, 2H), 5.92 (br s, 1H), 4.28-4.17 (m, 2H), 3.70 (t, 4.4 Hz, 2H), 3.33 (s, 3H) 541.3 B   
I-978
Figure 02_image2247
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3nccc4c(cc(F)cc34)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  9.40 (s, 1H), 9.15 (s, 1H), 8.20 - 8.10 (m, 2H), 7.95 (d, 9.9 Hz, 1H), 7.70 (dd, 14.7, 1.7 Hz, 2H), 7.28 (s, 1H), 7.03 (s, 1H), 6.91 - 6.82 (m, 1H), 6.29 (s, 1H), 5.76 (s, 1H)。 568.15 A A
I-979
Figure 02_image2249
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc(nc1)C#N    570.1 B   
I-980
Figure 02_image2251
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc(nc1)C#N    570.1 A A
I-981
Figure 02_image2253
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2OC(=O)NCc2c1 1H NMR (400 MHz, DMSO-d6)   4.49 (s, 2 H) 5.93 - 6.10 (m, 1 H) 7.05 - 7.17 (m, 2 H) 7.32 (dd,  8.84, 5.05 Hz, 1 H) 7.66 - 7.82 (m, 6 H) 7.89 - 7.98 (m, 2 H) 8.03 (s, 1 H) 9.19 (br s, 1 H) 10.57 (s, 1 H) 614.3 A A
I-982
Figure 02_image2255
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2CC(=O)Nc2c1    598.2 A A
I-983
Figure 02_image2257
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cccn2nccc12 1H NMR (400 MHz, DMSO-d6)   4.08 (q,  5.14 Hz, 1 H) 6.01 - 6.17 (m, 1 H) 6.83 (d,  1.52 Hz, 1 H) 7.04 (t,  6.95 Hz, 1 H) 7.11 (td,  8.46, 3.03 Hz, 1 H) 7.35 (dd,  8.84, 5.31 Hz, 1 H) 7.48 (dd,  6.82, 0.76 Hz, 1 H) 7.67 (s, 1 H) 7.75 (br d,  8.59 Hz, 1 H) 7.87 - 8.00 (m, 3 H) 8.12 (d,  2.27 Hz, 1 H) 8.76 (d,  7.07 Hz, 1 H) 9.26 (br s, 1 H) 10.60 (s, 1 H) 583.2 A A
I-984
Figure 02_image2259
 Cc1nc2ccc(cc2o1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)   2.65 (s, 3 H) 5.84 - 6.18 (m, 1 H) 6.50 - 6.94 (m, 1 H) 7.10 (td,  8.34, 3.03 Hz, 1 H) 7.33 (dd,  8.84, 5.05 Hz, 1 H) 7.70 (s, 1 H) 7.73 - 7.78 (m, 3 H) 7.86 (s, 1 H) 7.95 (br d,  8.34 Hz, 1 H) 7.99 (s, 1 H) 8.11 (s, 1 H) 9.15 - 9.25 (m, 1 H) 10.59 (s, 1 H) 598.2 A A
I-985
Figure 02_image2261
 Cc1ncncc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    559.4 A A
I-986
Figure 02_image2263
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccncc1F    562.1 A A
I-987
Figure 02_image2265
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccncc1F    562.15 D   
I-988
Figure 02_image2267
 O=C(Nc1cccc2C(=O)NCc12)N1CCCC[C@H]1Cc1ccccc1 1H NMR (400 MHz, DMSO-d6) 8.39 (d, 26.3 Hz, 2H), 7.37 - 7.31 (m, 3H), 7.27 (d, 6.2 Hz, 4H), 7.19 (tt, 5.4, 2.4 Hz, 1H), 4.53 (p, 4.1 Hz, 1H), 4.26 - 3.81 (m, 3H), 3.09 (td, 13.3, 2.7 Hz, 1H), 2.92 (qd, 13.3, 7.7 Hz, 2H), 1.86 - 1.61 (m, 2H), 1.60 (s, 2H), 1.57 - 1.51 (m, 3H), 1.40 (qt, 12.5, 3.9 Hz, 1H)。 350.15 E   
I-989
Figure 02_image2269
 O=C(Nc1cccc2C(=O)NCc12)N1CCCC[C@@H]1Cc1ccccc1 1H NMR (400 MHz, DMSO-d6) 8.39 (d, 26.3 Hz, 2H), 7.37 - 7.31 (m, 3H), 7.27 (d, 6.2 Hz, 4H), 7.19 (tt, 5.4, 2.4 Hz, 1H), 4.53 (p, 4.1 Hz, 1H), 4.26 - 3.81 (m, 3H), 3.09 (td, 13.3, 2.7 Hz, 1H), 2.92 (qd, 13.3, 7.7 Hz, 2H), 1.86 - 1.61 (m, 2H), 1.60 (s, 2H), 1.57 - 1.51 (m, 3H), 1.40 (qt, 12.5, 3.9 Hz, 1H)。 350.2 E   
I-990
Figure 02_image2271
 O=C(Nc1cccc2C(=O)NCc12)N1CCCCC1Cc1ccccc1 1H NMR (400 MHz, DMSO-d6) 8.39 (d, 26.3 Hz, 2H), 7.37 - 7.31 (m, 3H), 7.27 (d, 6.2 Hz, 4H), 7.19 (tt, 5.4, 2.4 Hz, 1H), 4.53 (p, 4.1 Hz, 1H), 4.26 - 3.81 (m, 3H), 3.09 (td, 13.3, 2.7 Hz, 1H), 2.92 (qd, 13.3, 7.7 Hz, 2H), 1.86 - 1.61 (m, 2H), 1.60 (s, 2H), 1.57 - 1.51 (m, 3H), 1.40 (qt, 12.5, 3.9 Hz, 1H)。 350.15 E   
I-991
Figure 02_image2273
 COc1cc(cc(Cl)c1F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.34 (s, 1H), 9.29 (s, 1H), 7.81 (d, 1.7 Hz, 1H), 7.74 (d, 1.8 Hz, 1H), 7.37 (td, 9.2, 5.9 Hz, 2H), 7.24 (dd, 6.1, 2.0 Hz, 1H), 7.15 (ddd, 8.9, 7.9, 3.1 Hz, 1H), 6.66 (s, 1H), 5.98 (s, 1H), 3.90 (s, 3H)。 541 B   
I-992
Figure 02_image2275
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCCc4ccc(Cl)cc34)c12 1H NMR (400 MHz, DMSO-d6) 11.59 (s, 1H), 10.32 (s, 1H), 8.11 (s, 1H), 8.03 (d, 9.1 Hz, 1H), 7.95 (d, 8.4 Hz, 1H), 7.75 (dd, 7.5, 1.8 Hz, 1H), 7.67 (dd, 7.8, 1.5 Hz, 1H), 7.50 - 7.39 (m, 3H), 7.16 (d, 7.3 Hz, 1H), 7.00 (t, 7.8 Hz, 1H), 6.75 (d, 2.0 Hz, 1H)。 550 D   
I-993
Figure 02_image2277
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Nc3nc4ccccc4[nH]3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)-11.36 (br. s, 1H), 10.55 (s, 1H), 10.10 (br. s, 1H), 9.09 (br. s, 1H), 8.19 (d, 1.8 Hz, 1H), 7.97-7.95 (m, 1H), 7.95-7.92 (m, 1H), 7.73 (br. d, 8.9 Hz, 1H), 7.64 (s, 1H), 7.40 (br. s, 1H), 7.32 (d, 5.2 Hz, 1H), 7.30 (d, 5.2 Hz, 1H), 7.09 (app. td, 8.5, 3.1 Hz, 1H), 7.04-7.00 (m, 2H), 6.61 (br. s, 1H), 5.91 (br. s, 1H)。 598.4 A B
I-994
Figure 02_image2279
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Nc3cn[nH]c3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  12.73 (br. s, 1H), 10.30 (br. s, 1H), 8.95 (s, 1H), 7.94-7.89 (m, 2H), 7.69 (br. d, 8.7 Hz, 1H), 7.73-7.52 (m, 2H), 7.59 (s, 1H), 7.28 (dd, 8.9, 5.2 Hz, 1H), 7.06 (app. td, 8.4, 3.1 Hz, 1H), 6.95 (d, 2.1 Hz, 1H), 6.84 (d, 2.0 Hz, 1H), 6.58 (br. s, 1H), 5.85 (br. s, 1H)。 548.3 A A
I-995
Figure 02_image2281
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-n1ccnn1 (400 MHz, DMSO-D6)  10.77 (br s, 1 H), 9.37 (s, 1 H), 8.26 (d, 1.5 Hz, 1 H), 8.23 (s, 2 H), 8.20 (d, 1.7 Hz, 1 H), 7.96 (d, 8.4 Hz, 1 H), 7.77 (d, 8.9 Hz, 1 H), 7.69 (s, 1 H), 7.34 (dd, 8.9, 5.2 Hz, 1 H), 7.10 (td, 8.5, 3.0 Hz, 1 H), 6.71 (br s, 1 H), 6.08 (br s, 1 H)。 532.4 A A
I-996
Figure 02_image2283
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc(nc1)C#N    569.3 C   
I-997
Figure 02_image2285
 Cn1cc(Nc2cc3C(=O)N[C@H](c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)cn1 1H NMR (400 MHz, DMSO-d6)  11.02 (br s, 1H), 10.44 (s, 1H), 9.19 (br s, 1H), 9.00 (s, 1H), 7.92 (d, 8.5 Hz, 1H), 7.75 (s, 1H), 7.71 (d, 9.2 Hz, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.29 (dd, 8.8, 5.2 Hz, 1H), 7.07 (td, 8.4, 2.9 Hz, 1H), 6.81 (s, 1H), 6.68 (s, 1H), 5.87 (br s, 1H)。 562.4 A A
I-998
Figure 02_image2287
 Cn1cc(Nc2cc3C(=O)N[C@@H](c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)cn1 1H NMR (400 MHz, DMSOD6)  10.33 (br s, 1H), 8.95 (br s, 1H), 8.54 (s, 殘餘鹽), 7.94 (浸沒s, 1H), 7.91 (浸沒d, 8.03 Hz, 1H), 7.73 (s, 1H), 7.69 (d, 9.3 Hz, 1H), 7.61 (s, 1H), 7.38 (s, 1H), 7.29 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.4, 3.2 Hz, 1H), 6.94 (br s, 1H), 6.86 (br s, 1H), 6.57 (br s, 1H), 5.85 (br s, 1H), 3.83 (s, 3H)。 562.4 C   
I-999
Figure 02_image2289
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Nc3ncc[nH]3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSOD6)  11.02 (br s, 1H), 10.44 (s, 1H), 9.19 (br s, 1H), 9.00 (s, 1H), 7.92 (d, 8.5 Hz, 1H), 7.75 (s, 1H), 7.71 (d, 9.2 Hz, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.29 (dd, 8.8, 5.2 Hz, 1H), 7.07 (td, 8.4, 2.9 Hz, 1H), 6.81 (s, 1H), 6.68 (s, 1H), 5.87 (br s, 1H)。 548.4 A B
I-1000
Figure 02_image2291
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc(nc1)C#N    569.3 A A
I-1001
Figure 02_image2293
 Cn1ccc(cc1=O)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    574.1 D   
I-1002
Figure 02_image2295
 Cn1ccc(cc1=O)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    574.15 A A
I-1003
Figure 02_image2297
 Nc1ncc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    560.15 A A
I-1004
Figure 02_image2299
 Nc1ncc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    560.15 D   
I-1005
Figure 02_image2301
 Cn1ccc2c(F)cc(cc12)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.19 (s, 1H), 9.27 (s, 1H), 7.79 (dt, 4.5, 2.1 Hz, 2H), 7.59 (d, 2.9 Hz, 2H), 7.34 (dd, 8.9, 5.1 Hz, 1H), 7.10 (td, 8.4, 3.1 Hz, 1H), 7.02 (d, 11.4 Hz, 1H), 6.78 -6.56 (s, 2H), , 6.08 (s, 1H), 3.85 (s, 3H)。 529.9 D   
I-1006
Figure 02_image2303
 COc1cccc(n1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    574.05 A A
I-1007
Figure 02_image2305
 COc1cccc(n1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    574.05 D   
I-1008
Figure 02_image2307
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cccnc1    544.1 D   
I-1009
Figure 02_image2309
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cccnc1    544.1 A A
I-1010
Figure 02_image2311
 Cc1cnccc1-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    558.15 A A
I-1011
Figure 02_image2313
 Cc1cnccc1-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    558.15 D   
I-1012
Figure 02_image2315
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nccnc2c1    595.4 A A
I-1013
Figure 02_image2317
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cccc2nccn12 1H NMR (400 MHz, DMSO-d6)   5.94 - 6.19 (m, 1 H) 6.96 - 7.17 (m, 2 H) 7.30 - 7.43 (m, 2 H) 7.62 - 7.82 (m, 5 H) 7.85 - 8.02 (m, 4 H) 8.68 (br d,  6.57 Hz, 1 H) 9.16 - 9.40 (m, 1 H) 10.68 (br s, 1 H) 583.27 A A
I-1014
Figure 02_image2319
 Fc1ccc(c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C(F)(F)F 1H NMR (400 MHz,氯仿-d) 8.63 (d, 1.7 Hz, 1H), 7.98 (d, 1.6 Hz, 1H), 7.85 (dd, 8.9, 5.1 Hz, 1H), 7.50 (dd, 13.0, 8.2 Hz, 2H), 7.26 (d, 22.8 Hz, 2H), 7.14 (s, 1H), 6.71 (dd, 8.8, 2.6 Hz, 1H), 6.58 (s, 1H), 6.05 (s, 1H)。 581.05 A A
I-1015
Figure 02_image2321
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-n1ccnc1 (400 MHz, DMSO-D6)  10.71 (br s, 1 H), 9.31 (s, 1 H), 8.45 (s, 1 H), 8.03 - 7.90 (m, 3 H), 7.84 (s, 1 H), 7.76 (d, 8.8 Hz, 1 H), 7.69 (s, 1 H), 7.33 (dd, 8.9, 5.1 Hz, 1 H), 7.16 (s, 1 H), 7.10 (td, 8.4, 2.9 Hz, 1 H), 6.67 (br s, 1 H), 6.02 (br s, 1 H)。 531.4 A A
I-1016
Figure 02_image2323
 Cn1cc(ncc1=O)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO)  10.59 (s, 1H), 9.19 (s, 1H), 8.67 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.95 (d, 8.3 Hz, 1H), 7.77 (d, 8.5 Hz, 1H), 7.70 (s, 1H), 7.32 (dd, 8.9, 5.1 Hz, 1H), 7.09 (td, 8.6, 2.9 Hz, 1H), 6.01 (s, 1H), 3.55 (s, 3H) 573 A A
I-1017
Figure 02_image2325
 Cc1[nH]ncc1Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.27 (s, 1H), 8.94 (s, 1H), 7.91 (d, 8.4 Hz, 1H), 7.68 (d, 8.8 Hz, 1H), 7.58 (d, 5.8 Hz, 2H), 7.32-7.24 (m, 1H), 7.06 (td, 8.4, 3.2 Hz, 1H), 6.81 (d, 1.9 Hz, 1H), 6.70 (s, 1H), 5.84 (s, 1H), 2.08 (s, 3H)。 562.3 A A
I-1018
Figure 02_image2327
 CS(=N)(=O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.60 (s, 1H), 9.19 (br. s, 1H), 7.94 (d, 8.5 Hz, 1H), 7.81 (d, 0.5 Hz, 1H), 7.73 (d, 9.1 Hz, 1H), 7.64 (d, 3.3 Hz, 1H), 7.54 (d, 2.1 Hz, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.14-7.06 (m, 1H), 6.65 (br. s, 1H), 5.98 (br. s, 1H), 4.66-4.47 (m, 2H), 3.77 (d, 4.4 Hz, 1H), 2.84 (s, 3H)。 558.2 A A
I-1019
Figure 02_image2329
 OC1CC(C1)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.42 (s, 1H), 9.07 (br. s, 1H), 7.90 (d, 8.5 Hz, 1H), 7.70 (d, 8.9 Hz, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.31 (s, 1H), 7.26 (dd, 8.9, 5.2 Hz, 1H), 7.04 (td, 8.4, 3.1 Hz, 1H), 6.61 (br. s, 1H), 5.91 (br. s, 1H), 5.12 (d, 7.5 Hz, 1H), 4.11-3.94 (m, 1H), 3.07-2.95 (m, 1H), 2.65 (ddd, 14.5, 7.2, 3.8 Hz, 2H), 1.93 (ddd, 21.2, 7.3, 2.2 Hz, 2H)。 537.1 A A
I-1020
Figure 02_image2331
 COCCc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN)  8.58 (br s, 1H), 7.64-7.52 (m, 4H), 7.39 (s, 1H), 7.21 (m, 2H), 6.94 (td, 8.4, 3.1 Hz, 1H), 6.58 (br s, 1H), 6.04 (br s, 1H), 3.63 (t, 6.5 Hz, 2H), 3.28 (s, 3H), 2.98 (td, 6.7, 1.7 Hz, 2H)。 525.4 A A
I-1021
Figure 02_image2333
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(c1)C1CC1    573.2 E   
I-1022
Figure 02_image2335
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(c1)C1CC1    573.3 A A
I-1023
Figure 02_image2337
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc2ncnn2c1    585.4 C   
I-1024
Figure 02_image2339
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc2ncnn2c1    585.2 A A
I-1025
Figure 02_image2341
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1nc2cnccc2[nH]1    584.32 A B
I-1026
Figure 02_image2343
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1nc2ncccc2[nH]1    584.32 A A
I-1027
Figure 02_image2345
 Cn1cnc2ccc(cc12)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    597.38 A   
I-1028
Figure 02_image2347
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cccc2NC(=O)CCc12    612.34 A A
I-1029
Figure 02_image2349
 Cn1cc2cc(ccc2n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    597.33 A A
I-1030
Figure 02_image2351
 Cn1nncc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    548.31 A A
I-1031
Figure 02_image2353
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cccc2nonc12    585.27 A A
I-1032
Figure 02_image2355
 Cc1cc2ncc(cn2n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    598.38 A A
I-1033
Figure 02_image2357
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2[nH]ncc2c1    583.37 A A
I-1034
Figure 02_image2359
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cccc2NC(=O)Cc12    598.38 A   
I-1035
Figure 02_image2361
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nc[nH]c2c1    583.32 A   
I-1036
Figure 02_image2363
 Cc1nc2cc(ccc2o1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    598.33 A   
I-1037
Figure 02_image2365
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccnn1C1COC1    589.33 A   
I-1038
Figure 02_image2367
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccnn1CC1CC1    587.32 A A
I-1039
Figure 02_image2369
 Cc1noc2ncc(cc12)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    599.33 A A
I-1040
Figure 02_image2371
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCn2ncnc2C1    589.33 A B
I-1041
Figure 02_image2373
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2NC(=O)Cc2c1    598.23 A   
I-1042
Figure 02_image2375
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cccc2C(=O)NCCc12    612.39 A A
I-1043
Figure 02_image2377
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2NC(=O)COCc2c1    628.34 A A
I-1044
Figure 02_image2379
 Cn1c2cc(ccc2[nH]c1=O)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    613.34 A   
I-1045
Figure 02_image2381
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cccc2cccnc12    594.33 A   
I-1046
Figure 02_image2383
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn2cccnc12    584.32 A A
I-1047
Figure 02_image2385
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc2ccnn2c1    584.32 A A
I-1048
Figure 02_image2387
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2OCCNC(=O)c2c1    628.34 A A
I-1049
Figure 02_image2389
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccnc2[nH]ccc12    583.32 A A
I-1050
Figure 02_image2391
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)Nc3ccc(F)cc3C(F)(F)F)c12 (400 MHz, DMSO-d6)  9.31 (br s, 1H), 9.21 (s, 1H), 8.56 (br s, 1H), 7.80 (d, 1.3 Hz, 1H), 7.62 (d, 1.3 Hz, 1H), 7.61-7.42 (m, 4H), 7.22 (td, 8.5, 3.0 Hz, 1H), 6.82 (br s, 1H), 6.06 (s, 1H) 558.3 B   
I-1051
Figure 02_image2393
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)Nc3cc(ccc3C(F)(F)F)C#N)c12 1H NMR (400 MHz, DMSO-d6, 60 Â℃)  9.06 (br s, 1H), 8.39 (s, 1H), 8.24 (s, 1H), 7.81 (d, 7.4 Hz, 2H), 7.64 (s, 2H), 7.44 (dd, 8.8, 5.1 Hz, 1H), 7.18 (td, 8.4, 3.1 Hz, 1H), 6.78 (br s, 1H), 6.05 (s, 1H) 565.3 D   
I-1052
Figure 02_image2395
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Oc3ccncn3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.52 (br s, 1H), 9.29 (s, 1H), 8.82 (s, 1H), 8.75 (d, 6.0 Hz, 1H), 7.95 (d, 8.4 Hz, 1H), 7.72 (d, 8.9 Hz, 1H), 7.64 (s, 1H), 7.54 (d, 1.9 Hz, 1H), 7.41 (s, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.28 (dd, 5.7, 0.7 Hz, 1H), 7.12 (td, 8.5, 3.0 Hz, 1H), 6.70 (br s, 1H), 6.01 (br s, 1H) 559.4 B   
I-1053
Figure 02_image2397
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(cc2C(=O)N[C@H](c12)c1cc(Cl)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, 氯仿-d) 8.96 (s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 8.09 (d, 1.6 Hz, 1H), 7.97-7.87 (m, 2H), 7.58-7.51(m , 4H), 7.43 (d, 8.6 Hz, 1H), 7.36 (dd, 8.6, 2.4 Hz, 1H), 7.06 (s, 1H), 6.50 (s, 1H), 6.30 (s, 1H) 600.05 C   
I-1054
Figure 02_image2399
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(cc2C(=O)N[C@@H](c12)c1cc(Cl)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, 氯仿-d) 8.96 (s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 8.09 (d, 1.5 Hz, 1H), 7.97-7.87 (m, 2H), 7.58-7.53 (m,3H), 7.49 (s, 1H), 7.43 (d, 8.6 Hz, 1H), 7.36 (dd, 8.7, 2.4 Hz, 1H), 7.06 (s, 1H), 6.51 (s, 1H), 6.30 (s, 1H)。 600.05 A A
I-1055
Figure 02_image2401
 FC(F)c1ccc(F)cc1[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 10.62 (s, 1H), 9.50 (s, 1H), 9.30 (s, 1H), 8.59 (s, 1H), 8.16 (dd, 11.3, 1.8 Hz, 2H), 8.00 (dd, 5.5, 3.8 Hz, 2H), 7.95 (d, 8.5 Hz, 1H), 7.72 (d, 8.9 Hz, 1H), 7.65 (s, 1H), 7.52 (dd, 8.9, 5.6 Hz, 1H), 7.23 (td, 8.4, 2.7 Hz, 1H), 6.57 (s, 1H), 6.11 (s, 1H)。 600.2 D   
I-1056
Figure 02_image2403
 FC(F)c1ccc(F)cc1[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 10.62 (s, 1H), 9.50 (s, 1H), 9.30 (s, 1H), 8.59 (s, 1H), 8.16 (dd, 11.3, 1.8 Hz, 2H), 8.00 (dd, 5.5, 3.8 Hz, 2H), 7.95 (d, 8.5 Hz, 1H), 7.72 (d, 8.9 Hz, 1H), 7.65 (s, 1H), 7.52 (dd, 8.9, 5.6 Hz, 1H), 7.23 (td, 8.4, 2.7 Hz, 1H), 6.57 (s, 1H), 6.11 (s, 1H)。 600.2 A A
I-1057
Figure 02_image2405
 FC(F)c1ccc(F)cc1C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 10.62 (s, 1H), 9.50 (s, 1H), 9.30 (s, 1H), 8.59 (s, 1H), 8.16 (dd, 11.3, 1.8 Hz, 2H), 8.00 (dd, 5.5, 3.8 Hz, 2H), 7.95 (d, 8.5 Hz, 1H), 7.72 (d, 8.9 Hz, 1H), 7.65 (s, 1H), 7.52 (dd, 8.9, 5.6 Hz, 1H), 7.23 (td, 8.4, 2.7 Hz, 1H), 6.57 (s, 1H), 6.11 (s, 1H)。 600.2 A A
I-1058
Figure 02_image2407
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3noc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.24 (s, 1H), 9.12 (s, 1H), 7.98 (d, 1.8 Hz, 1H), 7.65 (d, 1.7 Hz, 1H), 7.63-7.55 (m, 3H), 7.35-7.21 (m, 2H), 7.02 (td, 8.4, 3.0 Hz, 1H), 6.81 (s, 1H), 6.16 (s, 1H)。 472.05 E   
I-1059
Figure 02_image2409
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(cc2C(=O)N[C@H](c12)c1cc(F)c(F)cc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  10.65 (s, 1H), 9.48 (t, 1.4 Hz, 1H), 9.26 (s, 1H), 8.58 (s, 1H), 8.18 - 8.11 (m, 2H), 8.03 -7.95 (m, 3H), 7.84 (d, 9.0 Hz, 1H), 7.72 (s, 1H), 7.59 (dd, 10.4, 7.3 Hz, 1H), 7.00 (s, 1H) , 6.04 (s, 1H)。 602.1 D   
I-1060
Figure 02_image2411
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3nsc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.29 (s, 1H), 9.17 (s, 1H), 8.07-7.97 (m, 2H), 7.81 (d, 8.1 Hz, 1H), 7.65 (d, 1.7 Hz, 1H), 7.61-7.52 (m, 1H), 7.40 (dd, 8.2, 6.9 Hz, 1H), 7.21 (dd, 8.9, 5.1 Hz, 1H), 6.97 (td, 8.4, 3.1 Hz, 1H), 6.57 (s, 1H), 6.11-6.07 (m, 1H)。 488 E   
I-1061
Figure 02_image2413
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(cc2C(=O)N[C@@H](c12)c1cc(F)c(F)cc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  10.64 (s, 1H), 9.48 (t, 1.4 Hz, 1H), 9.26 (s, 1H), 8.58 (s, 1H), 8.18 - 8.11 (m, 2H), 8.03 - 7.95 (m, 3H), 7.83 (d, 8.9 Hz, 1H), 7.71 (s, 1H), 7.59 (dd, 10.4, 7.2 Hz, 1H), 7.00 (s, 1H), 6.04 (s, 1H)。 602.1 A A
I-1062
Figure 02_image2415
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(cc2C(=O)N[C@H](c12)c1cc(F)cc(F)c1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, 氯仿-d)  8.95 (s, 1H), 8.45 (s, 1H), 8.39 (s, 1H), 8.11 (d, 1.6 Hz, 1H), 7.97 - 7.86 (m, 2H), 7.58 (d, 8.1 Hz, 2H), 7.51 (d, 9.0 Hz, 2H), 6.99 (dd, 8.1, 2.9 Hz, 1H), 6.65 (s, 1H), 6.47 (s, 1H), 6.35 (s, 1H)。 602.1 A A
I-1063
Figure 02_image2417
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(cc2C(=O)N[C@@H](c12)c1cc(F)cc(F)c1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, 氯仿-d)  8.96 (s, 1H), 8.45 (s, 1H), 8.38 (s, 1H), 8.11 (s, 1H), 7.91 (q, 9.1 Hz, 2H), 7.61 - 7.52 (m, 3H), 7.50 (s, 1H), 6.99 (d, 8.0 Hz, 1H), 6.64 (s, 1H), 6.51 (s, 1H), 6.34 (s, 1H)。 602.1 E   
I-1064
Figure 02_image2419
 OCCOc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6 )  10.49-10.36 (s, 1H), 9.13 (s, 1H), 7.94 (d, 8.3 Hz, 1H), 7.71 (d, 8.7 Hz, 1H), 7.63 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.20 (s), 7.12-7.05 (m, 2H), 5.90 (br, s, 1H), 4.94 (t, 5.5 Hz, 1H), 4.15-4.08 (m, 2H), 3.76 (q, 5.0 Hz, 2H)。 527.2 A A
I-1065
Figure 02_image2421
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cncs1 NMR (400 MHz, CD3CN)  8.88 (s, 1H), 8.73 (br s, 1H), 8.25 (d, 5.4 Hz, 1H), 7.95 (br s, 1H), 7.80 (s, 1H), 7.68-7.52 (m, 3H), 7.31 (m, 1H), 7.26-7.19 (m, 1H), 6.95 (td, 8.8, 2.7 Hz, 1H), 6.67 (br s, 1H), 6.13 (br s, 1H)。 550 A A
I-1066
Figure 02_image2423
 COc1nc(cs1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN )  8.67 (br s, 1H), 8.16 (s,1H), 8.03 (s, 1H), 7.61 (dd, 18.1, 9.7 Hz, 3H), 7.29 (d, 1.3 Hz, 1H), 7.23 (dd, 8.9, 5.0 Hz, 2H), 6.94 (td, 8.5, 3.4 Hz, 1H), 6.67 (br s, 1H), 6.12 (br s, 1H), 4.12 (s, 3H)。 580 A B
I-1067
Figure 02_image2425
 NC(=O)c1nc(cs1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN/DMSO)  10.49 (br s, 1H), 8.88 (br s, 1H), 8.43 (br s, 1H), 8.36 (d, 14.5 Hz, 2H), 8.15 (br s, 1H), 7.97 (br s, 1H), 7.78-7.64 (m, 3H), 7.59 (m, 1H), 7.20 (dd, 8.7, 5.2 Hz, 1H), 6.94 (td, 8.4, 3.0 Hz, 1H), 6.06 (br s, 1H)。 591 A A
I-1068
Figure 02_image2427
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnsc1 NMR (400 MHz, CD3CN)  9.14 (s, 1H), 8.94 (s, 1H), 8.77 (br s, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.66 (br d, 8.2 Hz, 1H), 7.61 (浸沒br d, 8.3 Hz, 1H), 7.61-7.58 (m, 1H), 7.25 (dd, 8.2, 4.8 Hz), 7.29-7.26 (浸沒m, 1H), 7.01-6.95 (m, 1H), 6.69 (br s, 1H), 6.16 (br s, 1H)。 548 A A
I-1069
Figure 02_image2429
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-n1cccn1 (400 MHz, DMSO-D6)  10.67 (s, 1 H), 9.29 (s, 1 H), 8.76 (d, 2.5 Hz, 1 H), 8.14 (d, 1.6 Hz, 1 H), 8.09 (d, 1.6 Hz, 1 H), 7.96 (d, 8.4 Hz, 1 H), 7.82 (d, 1.6 Hz, 1 H), 7.76 (d, 8.9 Hz, 1 H), 7.69 (s, 1 H), 7.33 (dd, 8.9, 5.2 Hz, 1 H), 7.10 (td, 8.5, 3.0 Hz, 1 H), 6.66-6.58 (m, 1 H), 6.03 (br s, 1 H)。 533.3 A A
I-1070
Figure 02_image2431
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-n1cccn1 (400 MHz, DMSO-D6)  10.67 (s, 1 H), 9.29 (s, 1 H), 8.76 (d, 2.5 Hz, 1 H), 8.14 (d, 1.6 Hz, 1 H), 8.09 (d, 1.6 Hz, 1 H), 7.96 (d, 8.4 Hz, 1 H), 7.82 (d, 1.6 Hz, 1 H), 7.76 (d, 8.9 Hz, 1 H), 7.69 (s, 1 H), 7.33 (dd, 8.9, 5.2 Hz, 1 H), 7.10 (td, 8.5, 3.0 Hz, 1 H), 6.66-6.58 (m, 1 H), 6.03 (br s, 1 H)。 533.3 D   
I-1071
Figure 02_image2433
 Cn1ccc(Nc2cc3C(=O)N[C@H](c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)n1 1H-NMR (400 MHz, DMSO-d6)  10.41 (s, 1H), 8.96 (br. s, 1H), 8.90 (br. s, 1H), 7.91 (br. s, 1H), 7.73-7.68 (m, 2H), 7.62 (br. s, 1H), 7.56 (d, 2.1 Hz, 1H), 7.40 (br. s, 1H), 7.29 (dd, 8.9, 5.2 Hz, 1H), 7.07 (app. td, 8.6, 3.0 Hz, 1H), 6.60 (br. s, 1H), 5.85 (br. s, 1H), 5.82 (d, 2.3 Hz, 1H), 3.77 (s, 3H)。 562.4 A A
I-1072
Figure 02_image2435
 Cn1ccc(Nc2cc3C(=O)N[C@@H](c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)n1 1H-NMR (400 MHz, DMSO-d6)  10.43 (br. s, 1H), 8.97 (br. s, 1H), 8.90 (br. s, 1H), 7.91 (br. d, 6.5 Hz, 1H), 7.73-7.68 (m, 2H), 7.62 (br. s, 1H),7.56 (d, 2.2 Hz, 1H), 7.41 (br. s, 1H), 7.29 (dd, 8.9, 5.2 Hz, 1H), 7.07 (app. td, 8.5, 3.0 Hz, 1H), 6.58 (br. s, 1H), 5.85 (s, 1H), 5.82 (d, 2.3 Hz, 1H), 3.77 (s, 3H)。 562.4 C   
I-1073
Figure 02_image2437
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)C34CC5CC(C3)CC(C5)(C4)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  9.37 (s, 1H), 9.09 (br. s, 1H), 7.61 (dd, 7.4, 1.1 Hz, 1H), 7.57 (t, 7.5 Hz, 1H), 7.52-7.45 (m, 1H), 7.36 (dd, 7.4, 1.0 Hz, 1H), 7.21 (app. td, 8.4, 3.1 Hz, 1H), 6.39 (br. s, 1H), 6.01 (br. s, 1H), 2.11-2.04 (m, 2H), 1.69-1.44 (m, 11H), 1.37-1.31 (m, 1H)。 507.4 A A
I-1074
Figure 02_image2439
 CC12CC3CC(C)(C1)CC(C3)(C2)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)  9.09 (s, 1H), 9.07 (br. s, 1H), 7.61-7.53 (m, 2H), 7.53-7.47 (m, 1H), 7.41 (dd, 7.3, 1.5 Hz, 1H), 7.24 (ddd, 8.8, 8.1, 3.1 Hz, 1H), 6.41 (br. s, 1H), 6.03 (br. s, 1H), 1.98 (dt, 6.0, 3.0 Hz, 1H), 1.44-1.35 (m, 2H), 1.35-1.18 (m, 5H), 1.16-0.95 (m, 5H), 0.75 (s, 3H), 0.75 (s, 3H)。 467.4 B   
I-1075
Figure 02_image2441
 Cn1ccnc1Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.42 (s, 1H), 9.01 (br. s, 1H), 8.75 (s, 1H), 8.15 (s, 1H), 7.93 (br. d, 8.9 Hz, 1H), 7.72 (d, 1.9 Hz, 1H), 7.71 (br. d, 8.9 Hz, 1H), 7.62 (s, 1H), 7.58 (d, 1.6 Hz), 1H, 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.1, 3.1 Hz, 1H), 6.91 (d, 1.4 Hz, 1H), 6.70 (d, 1.4 Hz, 1H), 5.88 (br. s, 1H), 3.54 (s, 3H) 562.3 A A
I-1076
Figure 02_image2443
 Cn1nc(ccc1=O)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO)  10.65 (s, 1H), 9.26 (br s, 1H), 8.23 (d, 9.8 Hz, 1H), 8.18 (d, 1.0 Hz, 1H), 8.04 (s, 1H), 7.96 (d, 8.2 Hz, 1H), 7.77 (d, 9.4 Hz, 1H), 7.70 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.14-7.06 (m, 2H), 6.04 (br s, 1H), 3.78 (s, 3H) 573 A A
I-1077
Figure 02_image2445
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Oc3ccccn3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, CD3CN)  8.62 (s, 1H), 8.17 (ddd, 5.0, 2.0, 0.8 Hz, 1H), 7.85 (ddd, 8.3, 7.2, 2.0 Hz, 1H), 7.67-7.62 (m, 1H), 7.60-7.54 (m, 2H), 7.49 (d, 2.1 Hz, 1H), 7.38-7.34 (m, 1H), 7.32-7.29 ( m與dd重疊, 1H), 7.28 (dd, 8.9, 5.1 Hz, 1H), 7.15 (ddd, 7.2, 5.0, 0.9 Hz, 1H), 7.09 (dt, 8.3, 0.8 Hz, 1H), 6.99 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.71 (br s, 1H), 6.14 (br s, 1H) 558 B   
I-1078
Figure 02_image2447
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn[nH]c1    533 A A
I-1079
Figure 02_image2449
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn[nH]c1    531 A   
I-1080
Figure 02_image2451
 CC(C)(O)Cc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl    505 A A
I-1081
Figure 02_image2453
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CS(=O)(=O)C3CC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  10.61 (br. s, 1H), 9.21 (br. s, 1H), 7.95 (br. d, 8.3 Hz, 1H), 7.79 (d, 0.5 Hz, 1H), 7.74 (br. d, 9.0 Hz, 1H), 7.65 (s, 1H), 7.54 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.5, 3.0 Hz, 1H), 6.59 (br. s, 1H), 5.98 (br. s, 1H), 4.77 (s, 2H), 2.71-2.61 (m, 1H), 1.02-0.91 (m, 2H), 0.89-0.79 (m, 2H)。存在2w% OPPh3 (信號在7.55與7.64之間)。8.41處之部分甲酸鹽。 585.2 A A
I-1082
Figure 02_image2455
 Cn1nccc1CNc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6 )  10.31 (s, 1H), 8.93 (br. s, 1H), 7.92 (br. d, 8.5 Hz, 1H), 7.69 (br. d, 9.0 Hz, 1H), 7.61 (s, 1H), 7.32 (d, 1.8 Hz, 1H), 7.28 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.4, 3.1 Hz, 1H), 6.91 (d, 2.0 Hz, 1H), 6.79 (d, 1.6 Hz, 1H), 6.66 (br. t, 5.4 Hz, 1H), 6.59 (br. s, 1H), 6.22 (d, 1.7 Hz, 1H), 5.82 (br. s, 1H), 4.40 (d, 5.6 Hz, 2H), 3.83 (s, 3H)。 576.2 A A
I-1083
Figure 02_image2457
 Cn1cnnc1Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6 )  10.50 (s, 1H), 9.12 (s, 1H), 9.08 (br. s, 1H), 8.22 (s, 1H), 7.93 (br. d, 9.5 Hz, 1H), 7.92 (d, 1.9 Hz, 1H), 7.84 (d, 1.8 Hz, 1H), 7.72 (br. d, 9.5 Hz, 1H), 7.63 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.08 (td, 8.5, 3.0 Hz, 1H), 6.59 (br. s, 1H), 5.91 (br. s, 1H), 3.59 (s, 3H)。 563.3 A B
I-1084
Figure 02_image2459
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cscn1 NMR (400 MHz, CD3CN)  9.01 (d, 1.9 Hz, 1H), 8.76 (br s, 1H), 8.29 (d, 1.4 Hz, 1H), 8.25 (s, 1H), 8.02 (d, 1.9 Hz, 1H), 7.70-7.59 (m, 3H), 7.32 (br s, 1H), 7.27 (dd, 8.9, 5.1 Hz, 1H), 6.98 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.72 (br s, 1H), 6.18 (br s, 1H)。 550.3 A A
I-1085
Figure 02_image2461
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cscn1 NMR (400 MHz, CD3CN)  9.01 (d, 1.9 Hz, 1H), 8.76 (br s, 1H), 8.29 (d, 1.4 Hz, 1H), 8.25 (s, 1H), 8.02 (d, 1.9 Hz, 1H), 7.70-7.59 (m, 3H), 7.32 (br s, 1H), 7.27 (dd, 8.9, 5.1 Hz, 1H), 6.98 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.72 (br s, 1H), 6.18 (br s, 1H)。 550.3 D   
I-1086
Figure 02_image2463
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-n1cncn1 (400 MHz, DMSO-D6)  10.73 (s, 1 H), 9.55 (s, 1 H), 9.35 (s, 1 H), 8.32 (s, 1 H), 8.24 (d, 1.1 Hz, 1 H), 8.09 (s, 1 H), 7.96 (d, 8.5 Hz, 1 H), 7.76 (d, 8.9 Hz, 1 H), 7.68 (s, 1 H), 7.34 (dd, 8.9, 5.2 Hz, 1 H), 7.11 (td, 8.4, 3.1 Hz, 1 H), 6.65 (br s, 1 H), 6.05 (br s, 1 H)。 532.3 A A
I-1087
Figure 02_image2465
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(CC#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    504.2 B   
I-1088
Figure 02_image2467
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(CC#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    506.2 A A
I-1089
Figure 02_image2469
 Nc1cc(ncn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO)  10.64 (s, 1H), 9.24 (s, 1H), 8.48 (d, 1.1 Hz, 1H), 8.19 (s, 2H), 7.94 (d, 8.4 Hz, 1H), 7.76 (d, 9.0 Hz, 1H), 7.70 (s, 1H), 7.65-7.51 (m, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.3, 3.1 Hz, 1H), 7.06-6.99 (m, 3H), 6.65 (s, 1H), 6.05 (s, 1H)。 560.36 A   
I-1090
Figure 02_image2471
 Nc1nccc(n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO)  10.67 (s, 1H), 9.23 (s, 1H), 8.42-8.31 (m, 2H), 8.22 (s, 1H), 7.94 (d, 8.5 Hz, 1H), 7.77 (d, 9.2 Hz, 1H), 7.71 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.27 (d, 5.2 Hz, 1H), 7.09 (td, 8.4, 3.1 Hz, 1H), 6.77 (s, 3H)。 560.31 A   
I-1091
Figure 02_image2473
 COc1ncccc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO)  10.62 (s, 1H), 9.23 (s, 1H), 8.28 (d, 5.3 Hz, 1H), 8.01 (d, 1.6 Hz, 1H), 7.94 (d, 5.5 Hz, 2H), 7.75 (dd, 8.8, 2.4 Hz, 1H), 7.70 (s, 1H), 7.41 (dd, 5.4, 1.6 Hz, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.20 (d, 1.8 Hz, 1H), 7.09 (ddd, 8.8, 7.9, 3.1 Hz, 1H), 6.63 (s, 1H), 6.04 (s, 1H), 3.91 (s, 3H)。 574.32 A A
I-1092
Figure 02_image2475
 Cc1ncc(c(C)n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    573 B   
I-1093
Figure 02_image2477
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncncc2c1    595.5 A A
I-1094
Figure 02_image2479
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cncnc1    545.2 C   
I-1095
Figure 02_image2481
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cncnc1    545.2 A A
I-1096
Figure 02_image2483
 CC(C)(O)Cn1cc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    605.4 E   
I-1097
Figure 02_image2485
 CC(C)(O)Cn1cc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    605.4 A A
I-1098
Figure 02_image2487
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccncc1C#N    569.26 A A
I-1099
Figure 02_image2489
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Nc3nnco3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  11.00 (br. s, 1H), 10.59 (br. s, 1H), 9.15 (br. s, 1H), 8.82 (s, 1H), 7.94 (br. d, 8.7 Hz, 1H), 7.92 (d, 1.5 Hz, 1H), 7.77 (s, 1H), 7.73 (br. d, 9.0 Hz, 1H), 7.62 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (app. td, 8.4, 3.0 Hz, 1H), 6.62 (br. s, 1H), 5.93 (br. s, 1H)。 550.3 A A
I-1100
Figure 02_image2491
 O\N=C(/Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)c1cc(F)cc(c1)C(F)(F)F    482.4 A   
I-1101
Figure 02_image2493
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1nc2ccccc2[nH]1 1H NMR (500 MHz, DMSO)  13.23 (s, 1H), 10.68 (s, 1H), 9.28 (s, 1H), 8.52-8.38 (m, 2H), 7.95 (d, 8.5 Hz, 1H), 7.79 (d, 8.8 Hz, 1H), 7.75-7.52 (m, 4H), 7.34-7.30 (m, 1H), 7.23 (s, 2H), 7.10 (dt, 8.7, 4.4 Hz, 1H), 6.64 (s, 1H), 6.08 (s, 1H)。 583.27 A A
I-1102
Figure 02_image2495
 Nc1cnc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO)  10.55 (s, 1H), 9.14 (s, 1H), 8.66 (d, 1.5 Hz, 1H), 8.19 (d, 1.6 Hz, 1H), 8.08 (d, 1.6 Hz, 1H), 7.98 (d, 1.5 Hz, 1H), 7.93 (d, 8.6 Hz, 1H), 7.76 (d, 9.2 Hz, 1H), 7.70 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.08 (td, 8.4, 3.1 Hz, 1H), 6.70 (s, 2H), 6.01 (s, 1H)。 560.36 A A
I-1103
Figure 02_image2497
 COc1cnc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO)  10.64 (s, 1H), 9.21 (s, 1H), 8.98 (d, 1.5 Hz, 1H), 8.44 (d, 1.4 Hz, 1H), 8.32 (d, 1.6 Hz, 1H), 8.20 (s, 1H), 7.94 (d, 8.5 Hz, 1H), 7.76 (d, 9.1 Hz, 1H), 7.70 (s, 1H), 7.32 (dd, 8.9, 5.1 Hz, 1H), 7.09 (td, 8.4, 3.1 Hz, 1H), 6.68 (s, 1H), 6.04 (s, 1H), 3.99 (s, 3H)。 575.31 A   
I-1104
Figure 02_image2499
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CN(C1)c1ccncn1    600.33 A A
I-1105
Figure 02_image2501
 COc1nccc(n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO)  10.68 (s, 1H), 9.27 (s, 1H), 8.73 (d, 5.2 Hz, 1H), 8.47-8.31 (m, 2H), 7.92 (dd, 23.2, 6.7 Hz, 2H), 7.80-7.65 (m, 2H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.4, 3.0 Hz, 1H), 6.59 (s, 1H), 6.05 (s, 1H), 4.02 (s, 3H)。 575.31 A A
I-1106
Figure 02_image2503
 Nc1ncncc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    560.5 A   
I-1107
Figure 02_image2505
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3ccc(F)c(OC(F)(F)F)c3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 10.50 (s, 1H), 9.48 (t, 1.4 Hz, 1H), 9.25 (s, 1H), 8.58 (s, 1H), 8.18 - 8.10 (m, 2H), 8.02 - 7.92 (m, 2H), 7.85 - 7.74 (m, 2H), 7.67 (dd, 10.1, 8.7 Hz, 1H), 7.34 (dd, 8.9, 5.1 Hz, 1H), 7.11 (td, 8.4, 3.1 Hz, 1H), 6.68 (s, 1H), 6.08 (s, 1H)。 600.1 B   
I-1108
Figure 02_image2507
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3ccc(F)c(OC(F)(F)F)c3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 10.50 (s, 1H), 9.48 (t, 1.4 Hz, 1H), 9.25 (s, 1H), 8.58 (s, 1H), 8.18 - 8.10 (m, 2H), 8.02 - 7.92 (m, 2H), 7.85 - 7.74 (m, 2H), 7.67 (dd, 10.1, 8.7 Hz, 1H), 7.34 (dd, 8.9, 5.1 Hz, 1H), 7.11 (td, 8.4, 3.1 Hz, 1H), 6.68 (s, 1H), 6.08 (s, 1H)。 600.05 D   
I-1109
Figure 02_image2509
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Br)cc(Nc3nccc4c(cc(F)cc34)C(F)(F)F)c12 1H NMR (400 MHz, 氯仿-d) 8.35 (s, 1H), 8.21 (s, 1H), 7.88-7.83 (m, 2H), 7.50 (s, 1H), 7.34 (s, 1H), 7.10 (s, 1H), 6.99 (s, 1H), 6.68 (dd, 8.7, 3.0 Hz, 1H), 6.57-6.44 (m, 2H), 6.14 (s, 1H)。 569.9 A A
I-1110
Figure 02_image2511
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(Br)cc(Nc3nccc4c(cc(F)cc34)C(F)(F)F)c12 1H NMR (400 MHz, 氯仿-d) 8.34 (s, 1H), 8.22 (d, 6.2 Hz, 1H), 7.90-7.85(s,1H),7.80-7.85(s,1H) 7.53-7.46 (m, 1H), 7.32 (dd, 8.9, 4.9 Hz, 1H), 7.14-7.07 (m, 1H), 6.99 (s, 1H), 6.67-6.57 (m, 3H), 6.14 (s, 1H) 569.9 D   
I-1111
Figure 02_image2513
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(OC(F)(F)F)c3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 10.55 (s, 1H), 9.48 (dd, 1.9, 1.0 Hz, 1H), 9.26 (s, 1H), 8.58 (s, 1H), 8.18-8.03 (m, 2H), 8.03-7.95 (m, 2H), 7.68 (d, 8.8 Hz, 1H), 7.53 (d, 8.8 Hz, 1H), 7.46-7.42 (m, 1H), 7.36 (dd, 8.9, 5.2 Hz, 1H), 7.13 (td, 8.4, 3.1 Hz, 1H), 6.08 (s, 1H)。 600.1 A A
I-1112
Figure 02_image2515
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Nc3cc[nH]n3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6 )  12.12 (s, 1H), 10.39 (s, 1H), 8.96 (br. s, 1H), 8.91 (s, 1H), 7.92 (d, 8.5 Hz, 1H), 7.74 (d, 0.9 Hz, 1H), 7.71 (br. d, 8.5 Hz, 1H), 7.62 (s, 1H), 7.47 (br. s, 1H), 7.29 (dd, 8.9, 5.2 Hz, 1H), 7.07 (td, 8.4, 3.1 Hz, 1H), 6.63 (br. s, 1H), 5.90 (m, 1H) 548.3 A A
I-1113
Figure 02_image2517
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OCC3(CC3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-D6)  10.51 (br s, 1 H), 9.15 (br s, 1 H), 7.94 (d, 8.5 Hz, 1 H), 7.71 (d, 9.1 Hz, 1 H), 7.64 (s, 1 H), 7.31 (dd, 8.9, 5.2 Hz, 1 H), 7.22 (d, 2.1 Hz, 1 H), 7.13 (s, 1 H), 7.08 (td, 8.4, 3.1 Hz, 1 H), 6.61 (br s, 1 H), 5.93 (br s, 1 H), 4.18 (dd, 28.4, 10.4 Hz, 2 H), 1.40 (dd, 7.3, 4.7 Hz, 2 H), 1.20 (dd, 7.4, 4.9 Hz, 2 H)。 562.4 A   
I-1114
Figure 02_image2519
 OC1(COC1)c1c(F)cc(cc1C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(F)(F)F NMR (400 MHz, DMSO-d6)  10.62 (br. s, 1H), 9.16 (br. s, 1H), 7.90 (d, 10.6 Hz, 1H), 7.70 (d, 7.4 Hz, 1H), 7.65 (t, 7.5 Hz, 1H), 7.55-7.44 (m, 2H), 7.23 (td, 8.4, 2.9 Hz, 1H), 6.51 (s, 1H), 6.33 (br. s, 1H), 6.00 (br. s, 1H), 4.91 (dd, 7.3, 1.8 Hz, 1H), 4.79 (d, 7.5 Hz, 1H), 4.65 (d, 7.4 Hz, 1H), 4.43 (d, 7.5 Hz, 1H) 539.2 D   
I-1115
Figure 02_image2521
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Nc3ccno3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.65 (br. s, 1H), 9.28 (br. s, 1H), 8.00 (br. d, 10.2 Hz, 1H), 7.95 (d, 8.1 Hz, 1H), 7.79 (d, 4.4 Hz, 1H), 7.74 (br. d, 8.3 Hz, 1H), 7.67 (br. s, 1H), 7.64 (s, 1H), 7.58 (s, 1H), 7.32 (dd, 8.7, 5.1 Hz, 1H), 7.10 (app. td, 8.4, 3.0 Hz, 1H), 6.63 (br. s, 1H), 5.99 (br. s, 1H), 5.33 (s, 1H)。 549.2 A   
I-1116
Figure 02_image2523
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cccc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 10.57 (s, 1H), 9.48 (t, 1.3 Hz, 1H), 9.25 (s, 1H), 8.58 (s, 1H), 8.18 - 8.04 (m, 2H), 8.03-7.90 (m, 4H), 7.83 (s, 1H), 7.74 (t, 7.8 Hz, 1H), 7.34 (dd, 8.9, 5.1 Hz, 1H), 7.11 (td, 8.4, 3.1 Hz, 1H), 6.11 (s, 1H), 1.24 (s, 1H)。 566.05 E   
I-1117
Figure 02_image2525
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(OC(F)(F)F)c3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 10.55 (s, 1H), 9.48 (dd, 1.9, 1.0 Hz, 1H), 9.26 (s, 1H), 8.58 (s, 1H), 8.18-8.03 (m, 2H), 8.03-7.95 (m, 2H), 7.68 (d, 8.8 Hz, 1H), 7.53 (d, 8.8 Hz, 1H), 7.46-7.42 (m, 1H), 7.36 (dd, 8.9, 5.2 Hz, 1H), 7.13 (td, 8.4, 3.1 Hz, 1H), 6.08 (s, 1H)。 600.1 D   
I-1118
Figure 02_image2527
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3ncc(cc3F)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.10 (s, 1H), 10.04 (s, 1H), 9.06 (s, 1H), 8.72 (dd, 11.2, 2.1 Hz, 1H), 8.58-8.50 (m, 2H), 8.12 (dd, 8.9, 5.1 Hz, 1H), 7.90 (ddd, 8.8, 7.9, 3.1 Hz, 1H), 7.34 (s, 1H), 6.76 (s, 1H)。 518 C   
I-1119
Figure 02_image2529
 FCc1cc(F)cc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 氯仿-d)  8.49 (s, 1H), 7.96 (s, 1H), 7.45 (dd, 8.9, 4.9 Hz, 2H), 7.38 (s, 1H), 7.26 -7.18 (m, 2H), 7.14 - 7.05 (m, 1H), 6.72 (s, 1H), 6.50 (s, 1H), 6.19 (s, 1H), 5.48 (s, 1H), 5.37 (s, 1H)。 509 C   
I-1120
Figure 02_image2531
 Cn1cc(Oc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)cn1 NMR (400 MHz, DMSO)  10.50 (s, 1H), 8.52 (s, 1H), 7.98 (s, 1H), 7.84 (d, 9.2 Hz, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.54 (d, 0.6 Hz, 1H), 7.51 (dd, 9.2, 3.0 Hz, 1H), 7.22 (dd, 8.8, 5.2 Hz, 1H), 7.08 (d, 1.7 Hz, 1H), 7.02 (td, 8.5, 3.1 Hz, 1H), 6.92 (br s, 1H), 6.04 (s, 1H), 3.74 (s, 3H)。 563 D   
I-1121
Figure 02_image2533
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cccc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)10.57 (s, 1H), 9.48 (t, 1.3 Hz, 1H), 9.25 (s, 1H), 8.58 (s, 1H), 8.18 - 8.04 (m, 2H), 8.03-7.90 (m, 4H), 7.83 (s, 1H), 7.74 (t, 7.8 Hz, 1H), 7.34 (dd, 8.9, 5.1 Hz, 1H), 7.11 (td, 8.4, 3.1 Hz, 1H), 6.11 (s, 1H), 1.24 (s, 1H)。 566.05 A   
I-1122
Figure 02_image2535
 Cc1ncc(c(N)n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    574.4 A   
I-1123
Figure 02_image2537
 Cc1nc2ccc(cn2n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    598.6 A A
I-1124
Figure 02_image2539
 Cc1nc2ncc(cn2n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    599.5 A A
I-1125
Figure 02_image2541
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-n1ccnc1 (400 MHz, DMSO-D6)  10.71 (br s, 1 H), 9.31 (s, 1 H), 8.45 (s, 1 H), 8.03 - 7.90 (m, 3 H), 7.84 (s, 1 H), 7.76 (d, 8.8 Hz, 1 H), 7.69 (s, 1 H), 7.33 (dd, 8.9, 5.1 Hz, 1 H), 7.16 (s, 1 H), 7.10 (td, 8.4, 2.9 Hz, 1 H), 6.67 (br s, 1 H), 6.02 (br s, 1 H)。 533.3 B   
I-1126
Figure 02_image2543
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-n1ccnc1 (400 MHz, DMSO-D6)  10.71 (br s, 1 H), 9.31 (s, 1 H), 8.45 (s, 1 H), 8.03 - 7.90 (m, 3 H), 7.84 (s, 1 H), 7.76 (d, 8.8 Hz, 1 H), 7.69 (s, 1 H), 7.33 (dd, 8.9, 5.1 Hz, 1 H), 7.16 (s, 1 H), 7.10 (td, 8.4, 2.9 Hz, 1 H), 6.67 (br s, 1 H), 6.02 (br s, 1 H)。 533.3 A   
I-1127
Figure 02_image2545
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-n1cnc(c1)C#N (400 MHz, DMSO-D6)  9.36 (s, 1 H), 8.90 (d, 1.1 Hz, 1 H), 8.67 (d, 0.9 Hz, 1 H), 8.06 (s, 1 H), 7.94 (d, 6.7 Hz, 2 H), 7.79-7.62 (m, 3 H), 7.34 (dd, 8.9, 5.2 Hz, 1 H), 7.11 (td, 8.4, 3.0 Hz, 1 H), 6.67 (br s, 1 H), 6.03 (br s, 1 H)。 556.3 A   
I-1128
Figure 02_image2547
 Fc1cncn1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-D6)  9.33 (s, 1 H), 8.39 (br s, 1 H), 8.23 (s, 1 H), 8.00 (s, 1 H), 7.96 (d, 8.3 Hz, 1 H), 7.88 (s, 1 H), 7.80-7.73 (m, 2 H), 7.71 (s, 1 H), 7.33 (dd, 8.8, 5.1 Hz, 1 H), 7.10 (td, 8.4, 2.7 Hz, 1 H), 6.71 (br s, 1 H), 6.03 (br s, 1 H)。 551.3 A   
I-1129
Figure 02_image2549
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OC3CC(C3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6 )  10.44 (s, 1H), 9.14 (s, 1H), 7.94 (dt, 8.5, 1.2 Hz, 1H), 7.71 (br. d, 8.9 Hz, 1H), 7.62 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.12-7.05 (m, 2H), 7.03 d, 1.6 Hz, 1H), 6.58 (br. s, 1H), 5.92 (br. s, 1H), 5.19-5.08 (m, 1H), 3.53-3.44 (m, 1H), 2.92-2.80 (m, 2H), 2.62-2.52 (m, 2H) 562.3 A   
I-1130
Figure 02_image2551
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Oc3ccnc(c3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.68 (br s, 1H), 9.31 (s, 1H), 8.67 (d, 5.7 Hz, 1H), 7.91 (d, 6.8 Hz, 1H), 7.86 (s, 1H), 7.71 (d, 8.4 Hz, 1H), 7.63 (s, 1H), 7.52 - 7.43 (m, 2H), 7.40 - 7.31 (m, 2H), 7.11 (td, 8.5, 3.0 Hz, 1H), 6.87 (br s, 1H), 6.05 (s, 1H)。 583.4 A   
I-1131
Figure 02_image2553
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OC3COC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.52 (br s, 1H), 9.15 (s, 1H), 7.94 (d, 8.4 Hz, 1H), 7.71 (d, 8.9 Hz, 1H), 7.63 (s, 1H), 7.30 (dd, 8.8, 5.2 Hz, 1H), 7.08 (td, 8.5, 3.0 Hz, 1H), 7.00 (s, 1H), 6.97 (d, 2.1 Hz, 1H), 6.65 (br s, 1H), 5.92 (s, 1H), 5.44 (p, 5.2 Hz, 1H), 4.98 (t, 6.6 Hz, 2H), 4.64-4.57 (m, 2H)。 537.3 A   
I-1132
Figure 02_image2555
 OC1CC(C1)Oc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  8.60 (br. d, 7.9 Hz, 1H), 7.67-7.55 (m, 3H), 7.30-7.23 (m, 2H), 7.21 (br. s, 1H), 7.13 (dd, 5.6, 2.1 Hz, 2H), 6.96 (ddd, 8.8, 8.0, 3.1 Hz), 6.64 (br. s, 1H), 6.05 (br. s, 1H), 4.77-4.68 (m, 1H), 3.69-3.62 (m, 1H), 1.36 (dd, 6.0, 5.2 Hz, 2H), 1.28-1.25 (m, 1H), 1.19 (d, 6.2 Hz, 1H) 555.3 B   
I-1133
Figure 02_image2557
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)C34CC5CC(CC(F)(C5)C3)C4)c12 1H-NMR (400MHz, DMSO-d6)-9.29 (s, 1H), 9.08 (br. s, 1H), 7.61 (dd, 7.3, 1.1 Hz, 1H), 7.57 (t, 7.5 Hz, 1H), 7.54-7.47 (m, 1H), 7.37 (dd, 7.5, 1.3 Hz, 1H), 7.24 (ddd, 8.8, 8.1, 3.1 Hz, 1H), 6.42 (br. s, 1H), 6.02 (br. s, 1H), 2.24-2.15 (m, 2H), 1.78 (d, 2.8 Hz, 1H), 1.77-1.72 (m, 1H), 1.71-1.64 (m, 3H), 1.62-1.56 (m, 1H), 1.53-1.39 (m, 5H), 1.37-1.31 (m, 1H)。 457.4 C   
I-1134
Figure 02_image2559
 OCCOCC(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6 )  10.55 (br s, 1H), 9.19 (br s 1H), 7.91 (d, 7.1 Hz, 1H), 7.79-7.69 (m, 2H), 7.66 (s, 2H), 7.54-7.48 (m, 1H), 7.31 (dd, 8.8, 5.2 Hz, 1H), 7.09 (tt, 8.7, 4.3 Hz, 1H), 5.96 (br s, 1H), 5.62 (d, 8.0 Hz, 1H), 4.88 (ddd, 16.6, 11.5, 5.0 Hz, 1H), 4.60 (dd, 5.0, 3.7 Hz, 1H), 3.62-3.52 (m, 2H), 3.52-3.43 (m, 4H)。 571.3 B   
I-1135
Figure 02_image2561
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OC3CCOCC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  10.41 (br. s, 1H), 9.12 (s, 1H), 7.94 (dt, 8.4, 1.6 Hz, 1H), 7.71 (br. d, 9.2 Hz), 7.63 (s, 1H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.26 (d, 2.2 Hz, 1H), 7.11-7.07 (m, 2H), 6.64 (br. s, 1H), 5.92 (br. s, 1H), 4.75 (tt, 8.4, 4.0 Hz, 1H), 3.93-3.81 (m, 2H), 3.57-3.46 (m, 2H), 2.07-1.94 (m, 2H), 1.72-1.54 (m, 2H)。 567.3 A   
I-1136
Figure 02_image2563
 Cn1nccc1-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.61 (s, 1H), 9.27 (br. s, 1H), 7.96 (br. d, 7.6 Hz, 1H), 7.79 (s, 1H), 7.74 (br. d, 7.9 Hz, 1H), 7.67 (s, 2H), 7.53 (d, 1.9 Hz, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.4, 3.1 Hz, 1H), 6.80 (s, 1H), 6.57 (d, 1.9 Hz, 1H), 6.05 (s, 1H), 3.94 (s, 3H)。 547.4 A   
I-1137
Figure 02_image2565
 Cn1nccc1-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.60 (s, 1H), 9.28 (br. s, 1H), 7.96 (br. d, 8.5 Hz, 1H), 7.80 (d, 1.3 Hz, 1H), 7.74 (br. d, 9.4 Hz, 1H), 7.66-7.65 (m, 2H), 7.53 (d, 1.9 Hz, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.5, 3.0 Hz, 1H), 6.75 (s, 1H), 6.57 (d, 1.9 Hz, 1H), 6.05 (s, 1H), 3.94 (s, 3H)。 547.4 D   
I-1138
Figure 02_image2567
 CNC1(NC(=O)c2cc(CS(C)=O)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)c1cc(F)ccc1Cl NMR (400 MHz, MeCNd3)  9.81 (br. s, 1H), 8.46 (dd, 1.6, 2.0 Hz, 1H), 7.78 (s, 1H), 7.70 (d, 0.8 Hz, 1H), 7.68 (d, 0.8 Hz, 1H), 7.51 (dd, 1.6, 2.0 Hz, 1H), 7.43 (dd, 8.8, 5.4 Hz, 1H), 7.30 (dt, 10.4, 3.1 Hz, 1H), 7.20 (br. s, 1H), 7.06 (dddd, 10.8, 7.2, 2.8, 0.4 Hz, 1H), 4.20 (dd, 12.9, 1.2 Hz, 1H), 4.03 (d, 12.9 Hz, 1H), 3.31 (br. s, 1H) 2.49 (d, 2.5 Hz, 3H), 2.18 (s, 3H)。 572.2 D   
I-1139
Figure 02_image2569
 CC(C)(C)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H-NMR (400 MHz, 溶劑)  9.30 (s, 1H), 9.24 (br. s, 1H), 7.71 (d, 1.7 Hz, 1H), 7.58 (d, 1.7 Hz, 1H), 7.54-7.47 (m, 1H), 7.24 (ddd, 8.8, 8.1, 3.1 Hz, 1H), 6.56 (br. s, 1H), 6.03 (s, 1H), 0.89 (s, 9H)。 439.3 D   
I-1140
Figure 02_image2571
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-n1cc(cn1)C#N (400 MHz, DMSO-D6)  10.71 (br s, 1 H), 9.57 (s, 1 H), 9.36 (s, 1 H), 8.44 (s, 1 H), 8.18 (s, 1 H), 8.12 (s, 1 H), 7.96 (d, 7.8 Hz, 1 H), 7.76 (d, 8.6 Hz, 1 H), 7.68 (s, 1 H), 7.34 (dd, 8.9, 5.2 Hz, 1 H), 7.11 (td, 8.5, 3.1 Hz, 1 H), 6.66 (br s, 1 H), 6.05 (br s, 1 H)。 556.3 A   
I-1141
Figure 02_image2573
 OC1COCC1(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.65 (br s, 1H), 9.13 (br s, 1H), 7.94 (d, 8.7 Hz, 1H), 7.85 (s, 1H) 7.77 (d , 8.7 Hz, 1H), 7.69 (s, 1H), 7.64-7.62 (m, 1H), 7.30 (dd, 8.9, 5.1 Hz, 1H), 7.11-7.06 (m, 1H), 6.58 (br s, 1H), 5.99 (br s, 1H), 5.51-5.46 (m, 1H), 5.40 (d, 6.0 Hz, 1H), 4.31 (ddd, 20.5, 13.2, 6.7 Hz, 1H), 4.14-4.01 (m, 1H), 3.98 (d, 9.3 Hz, 1H), 3.90 (dd, 9.3, 4.6 Hz, 1H), 3.70-3.59 (m, 1H)。 569.3 B   
I-1142
Figure 02_image2575
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CCCOC1 NMR (400 MHz, DMSO-d6)  9.11 (br s, 1H), 8.44 (br s, 1H), 7.94 (d, 8.4 Hz, 1H), 7.74 (d, 9.1 Hz, 1H), 7.67 (s, 1H), 7.61 (s, 1H), 7.40 (s, 1H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.08 (td, 8.5, 2.9 Hz, 1H), 6.61 (br s, 1H), 5.95 (br s, 1H), 3.92-3.86 (m, 2H), 3.47-3.3 (m. 2H), 3.10-2.94 (m. 1H), 2.05-1.99 (m, 1H), 1.89-1.74 (m, 1H), 1.77-1.65 (m, 2H)。 551.3 A   
I-1143
Figure 02_image2577
 COc1ccnc(Oc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)n1 NMR (400 MHz, CD3CN)  8.76 (br s, 1H), 8.21 (d, 5.7 Hz, 1H), 7.66-7.62 (m, 1H), 7.60-7.53 (m, 3H), 7.42 (d, 1.6 Hz, 1H), 7.40 (br s, 1H), 7.26 (dd, 8.9, 5.1 Hz, 1H), 6.98 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.68 (br s, 1H), 6.58 (d, 5.7 Hz, 1H), 6.13 (s, 1H), 3.90 (s, 3H)。 591 B   
I-1144
Figure 02_image2579
 Cn1nccc1Nc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-D6)  10.37 (s, 1H), 9.04 (s, 1H), 8.45 (s, 1H), 7.92 (d, 8.5 Hz, 1H), 7.69 (d, 8.9 Hz, 1H), 7.59 (s, 1H), 7.42 (d, 1.4 Hz, 1H), 7.30 (dd, 8.9, 5.1 Hz, 1H), 7.07 (td, 8.4, 2.9 Hz, 1H), 7.02 (d, 1.6 Hz, 1H), 6.94 (s, 1H), 6.66 (br s, 1H), 6.12 (d, 1.6 Hz, 1H), 5.89 (br s, 1H), 3.68 (s, 3H)。 562.3 A   
I-1145
Figure 02_image2581
 Cn1nccc1Nc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.36 (s, 1H), 9.04 (br s, 1H), 8.44 (s, 1H), 7.93 (d, 8.6 Hz, 1H), 7.69 (d, 9.0 Hz, 1H), 7.59 (s, 1H), 7.42 (d, 1.9 Hz, 1H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.07 (td, 8.4, 3.1 Hz, 1H), 7.02 (d, 2.0 Hz, 1H), 6.93 (br s, 1H), 6.64 (br s, 1H), 6.12 (d, 1.8 Hz, 1H), 5.89 (br s, 1H), 3.68 (s, 3 H)。 562.3 D   
I-1146
Figure 02_image2583
 Fc1cnn(c1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-D6)  10.69 (br s, 1 H), 9.30 (br s, 1 H), 8.96 (d, 4.4 Hz, 1 H), 8.12 - 8.02 (m,  2 H), 7.96 (d, 8.7 Hz, 1 H), 7.93 (d, 4.3 Hz, 1 H), 7.76 (d, 8.9 Hz, 1 H), 7.68 (s, 1 H), 7.33 (dd, 8.9, 5.2 Hz, 1 H), 7.10 (td, 8.5, 3.0 Hz, 1 H), 6.66 (br s, 1 H), 6.02 (br s, 1 H)。 549.3 A A
I-1147
Figure 02_image2585
 COc1ccc(Oc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)nn1 NMR (400 MHz, DMSO)  10.66 (br s, 1H), 9.24 (br s, 1H), 8.49 (s, 1H), 7.92 (br d, 7.0 Hz, 1H), 7.73 (br d, 8.9 Hz, 1H), 7.65 (s, 1H), 7.57 (d, 9.4 Hz, 1H), 7.41-7.39 (m, 2H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.3, 3.0 Hz, 1H), 6.71 (br s, 1H), 6.01 (br s, 1H), 3.97 (s, 3H)。 591 A   
I-1148
Figure 02_image2587
 COc1nccc(Oc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)n1 NMR (400 MHz, CD3CN)  8.72 (br s, 1H), 8.42 (d, 5.6 Hz, 1H), 7.65 (d, 8.4 Hz, 1H), 7.62-7.54 (m, 3H), 7.42 (d, 1.2 Hz, 1H), 7.35 (s, 1H), 7.28 (dd, 8.9, 5.1 Hz, 1H), 7.02-6.96 (m, 1H), 6.71 (br d, 5.6 Hz, 2H), 6.15 (br s, 1H), 3.86 (s, 3H)。 591 A   
I-1149
Figure 02_image2589
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OC3CS(=O)(=O)C3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6) 主要旋轉異構體:-´ 10.40 (br. s, 1H), 10.32 (br. s, 1H), 7.98 (br. d, 8.2 Hz, 1H), 7.78 (br. d, 8.8 Hz, 1H), 7.69 (s, 1H), 7.36-7.31 (m, 2H), 7.14-7.08 (m, 1H), 7.03 (d, 2.2 Hz, 1H), 6.86 (d, 2.2 Hz, 1H), 5.83 (s, 1H), 4.88-4.81 (m, 1H), 4.81-4.74 (m, 1H), 4.38-4.27 (m, 2H), 4.20-4.11 (m, 1H) 587.1 D   
I-1150
Figure 02_image2591
 CS(=O)c1ccccc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)   2.53 - 2.56 (m, 4 H) 5.98 - 6.19 (m, 1 H) 7.12 - 7.20 (m, 1 H) 7.39 (ddd,  8.84, 5.18, 2.15 Hz, 1 H) 7.50 - 7.62 (m, 2 H) 7.68 - 7.75 (m, 3 H) 7.76 - 7.83 (m, 2 H) 7.99 (br d,  8.34 Hz, 1 H) 8.09 (ddd,  7.77, 2.97, 1.14 Hz, 1 H) 9.31 (br s, 1 H) 10.65 (br d,  16.67 Hz, 1 H) 605.28 A   
I-1151
Figure 02_image2593
 COc1ncc(c(N)n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    590.5 B   
I-1152
Figure 02_image2595
 Cc1ncccc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    558.36 A   
I-1153
Figure 02_image2597
 Nc1ncc(cn1)C#Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz):-´ = 10.53 (s, 1H), 9.26 (br s, 1H), 8.49 (s, 2H), 7.96 (br d, 8.3 Hz, 1H), 7.60-7.77 (m, 4H), 7.33 (dd, 8.8, 5.3 Hz, 1H), 7.22 (s, 2H), 7.10 (td, 8.3, 3.0 Hz, 1H), 6.02 (br s, 1H), 2.99  (br s, 1H) 584.5 A   
I-1154
Figure 02_image2599
 OC1(COC1)C#Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz):-´ = 10.52 (s, 1H), 9.28 (br s, 1H), 7.96 (br d, 8.3 Hz, 1H), 7.69-7.76 (m, 2H), 7.66 (s, 1H), 7.61 (d, 1.0 Hz, 1H), 7.33 (dd, 8.8, 5.3 Hz, 1H), 7.10 (td, 8.4, 3.2 Hz, 1H), 6.70 (s, 1H), 6.01 (br s, 1H), 4.80 (d, 6.6 Hz, 2H), 4.63 (d, 6.6 Hz, 2H), 4.31-4.58 (m, 1H), 3.13  (s, 1H) 563.4 A   
I-1155
Figure 02_image2601
 Cn1cc(cn1)C#Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz):-´ = 10.51 (s, 1H), 9.26 (br s, 1H), 8.13 (s, 1H), 7.96 (br d, 8.6 Hz, 1H), 7.71-7.77 (m, 2H), 7.69 (d, 1.0 Hz, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.33 (dd, 9.0, 5.2 Hz, 1H), 7.10 (td, 8.3, 3.0 Hz, 1H), 6.01 (br s, 1H), 3.87 (s, 3H), 2.98  (br s, 1H) 571.4 A   
I-1156
Figure 02_image2603
 COc1c(F)cccc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO-d6)   3.74 (d,  1.37 Hz, 3 H) 6.06 (br s, 1 H) 6.74 (br d,  3.36 Hz, 1 H) 7.09 (td,  8.39, 3.05 Hz, 1 H) 7.21 - 7.27 (m, 1 H) 7.28 - 7.37 (m, 3 H) 7.66 (s, 1 H) 7.69 - 7.81 (m, 3 H) 7.88 (br d,  8.39 Hz, 1 H) 9.09 (s, 1 H) 10.47 (br s, 1 H) 591.33 A A
I-1157
Figure 02_image2605
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CN(C1)C#N 1H NMR (500 MHz, DMSO-d6)   4.14 - 4.21 (m, 1 H) 4.23 - 4.32 (m, 2 H) 4.53 - 4.62 (m, 2 H) 6.00 (br s, 1 H) 6.56 - 6.72 (m, 1 H) 7.07 (td,  8.39, 3.05 Hz, 1 H) 7.30 (dd,  8.85, 5.19 Hz, 1 H) 7.54 (d,  1.22 Hz, 1 H) 7.67 - 7.76 (m, 3 H) 7.89 (br d,  8.39 Hz, 1 H) 9.04 (s, 1 H) 10.42 (s, 1 H) 547.31 A C
I-1158
Figure 02_image2607
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CN(CC#N)C1 1H NMR (500 MHz, DMSO-d6)   3.34 - 3.40 (m, 2 H) 3.70 (s, 2 H) 3.74 - 3.80 (m, 2 H) 3.80 - 3.87 (m, 1 H) 5.97 (br s, 1 H) 6.50 - 6.72 (m, 1 H) 7.06 (td,  8.39, 3.05 Hz, 1 H) 7.28 (dd,  8.85, 5.19 Hz, 1 H) 7.49 (s, 1 H) 7.66 - 7.75 (m, 3 H) 7.87 (br d,  8.39 Hz, 1 H) 8.99 (s, 1 H) 10.40 (br s, 1 H) 534.4 A A
I-1159
Figure 02_image2609
 CS(=O)(=O)Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)   3.07 (s, 3 H) 5.92 (br s, 1 H) 6.58 (br s, 1 H) 7.08 (td,  8.40, 3.16 Hz, 1 H) 7.27 - 7.36 (m, 2 H) 7.49 (d,  1.77 Hz, 1 H) 7.60 (s, 1 H) 7.71 (br d,  9.09 Hz, 1 H) 7.94 (br d,  8.34 Hz, 1 H) 9.15 (br s, 1 H) 10.18 - 10.47 (m, 1 H) 10.54 (br s, 1 H) 560.31 A A
I-1160
Figure 02_image2611
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OCC#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    522.4 A A
I-1161
Figure 02_image2613
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc4c(Cl)c[nH]c34)c12    472 B B
I-1162
Figure 02_image2615
 COc1nccc(n1)N1CC(C1)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)   3.80 (s, 3 H) 4.08 (ddd,  11.87, 8.72, 5.94 Hz, 2 H) 4.15 - 4.25 (m, 1 H) 4.45 - 4.55 (m, 2 H) 6.16 (d,  5.81 Hz, 1 H) 6.70 - 6.82 (m, 1 H) 7.10 (td,  8.40, 2.91 Hz, 1 H) 7.32 (dd,  8.97, 5.18 Hz, 1 H) 7.56 (s, 1 H) 7.64 - 7.79 (m, 3 H) 7.94 (br d,  8.08 Hz, 1 H) 8.03 (d,  5.56 Hz, 1 H) 8.47 (s, 1 H) 9.16 (br s, 1 H) 10.53 (br s, 1 H) 630.39 A A
I-1163
Figure 02_image2617
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccccc1C#C 1H NMR (400 MHz, DMSO-d6)   4.22 (s, 1 H) 5.99 - 6.12 (m, 1 H) 7.11 (td,  8.46, 3.03 Hz, 1 H) 7.34 (dd,  8.84, 5.05 Hz, 1 H) 7.43 - 7.49 (m, 1 H) 7.51 - 7.59 (m, 2 H) 7.63 - 7.70 (m, 3 H) 7.75 (br d,  9.09 Hz, 1 H) 7.86 (d,  1.26 Hz, 1 H) 7.95 (br d,  8.34 Hz, 1 H) 9.23 (br s, 1 H) 10.60 (s, 1 H) 567.32 A A
I-1164
Figure 02_image2619
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCOCC1 1H NMR (400 MHz, DMSO-d6)   3.22 (q,  4.46 Hz, 4 H) 3.76 (t,  4.80 Hz, 4 H) 5.83 - 5.94 (m, 1 H) 7.02 - 7.10 (m, 2 H) 7.17 (d,  2.02 Hz, 1 H) 7.28 (dd,  8.84, 5.05 Hz, 1 H) 7.65 (s, 1 H) 7.71 (br d,  8.84 Hz, 1 H) 7.92 (br d,  8.59 Hz, 1 H) 9.01 (br s, 1 H) 10.38 (s, 1 H) 552.36 A A
I-1165
Figure 02_image2621
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  10.50 (s, 1H), 9.48 (dd, 1.9, 1.0 Hz, 1H), 9.27 (s, 1H), 8.58 (s, 1H), 8.18 - 8.10 (m, 2H), 8.03 - 7.94 (m, 2H), 7.72 (dt, 8.6, 2.2 Hz, 1H), 7.48 - 7.36 (m, 3H), 7.17 (td, 8.4, 3.1 Hz, 1H), 6.08 (s, 1H)。 550.1 A   
I-1166
Figure 02_image2623
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  10.50 (s, 1H), 9.48 (d, 1.6 Hz, 1H), 9.27 (s, 1H), 8.58 (s, 1H), 8.14 (dd, 9.4, 1.8 Hz, 2H), 8.03 - 7.94 (m, 2H), 7.75 - 7.68 (m, 1H), 7.47 - 7.36 (m, 3H), 7.17 (td, 8.4, 3.1 Hz, 1H), 6.08 (s, 1H), 1.24 (s, 0H)。 550.1 D   
I-1167
Figure 02_image2625
 Cc1ccc(cc1C(F)(F)F)C(=O)Nc1cc(cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, 氯仿-d) 8.96 (t, 1.4 Hz, 1H), 8.60 (s, 1H), 8.44 (s, 1H), 8.05 (d, 1.6 Hz, 1H), 7.91 (t, 1.3 Hz, 2H), 7.77 - 7.67 (m, 2H), 7.52 (s, 1H), 7.49 -7.40 (m, 2H), 7.10 (ddd, 8.9, 7.3, 3.0 Hz, 1H), 6.79 (d, 8.3 Hz, 1H), 6.56 (s, 1H), 6.31 (s, 1H), 2.60 (d, 1.9 Hz, 3H)。 580.15 A   
I-1168
Figure 02_image2627
 Cc1ccc(cc1C(F)(F)F)C(=O)Nc1cc(cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, 氯仿-d)  8.97 (s, 1H), 8.60 (s, 1H), 8.44 (s, 1H), 8.05 (d, 1.6 Hz, 1H), 7.92 (s, 2H), 7.76 - 7.68 (m, 2H), 7.54 (s, 1H), 7.49 - 7.40 (m, 2H), 7.10 (ddd, 8.9, 7.2, 3.0 Hz, 1H), 6.79 (d, 8.4 Hz, 1H), 6.62 (s, 1H), 6.31 (s, 1H), 2.60 (q, 1.9 Hz, 3H)。 580.05 E   
I-1169
Figure 02_image2629
 FC(F)Oc1cc(F)cc(c1)C(=O)Nc1cc(cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  10.45 (s, 1H), 9.47 (t, 1.3 Hz, 1H), 9.25 (s, 1H), 8.58 (s, 1H), 8.17 - 8.10 (m, 2H), 8.02 - 7.94 (m, 2H), 7.44 - 7.27 (m, 5H), 7.14 (td, 8.9, 8.0, 3.1 Hz, 1H), 6.10 (s, 2H)。 582.1 B   
I-1170
Figure 02_image2631
 FC(F)Oc1cc(F)cc(c1)C(=O)Nc1cc(cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  10.45 (s, 1H), 9.48 (d, 1.3 Hz, 1H), 9.25 (s, 1H), 8.58 (s, 1H), 8.17 - 8.10 (m,2H), 8.02 - 7.94 (m, 2H), 7.42 - 7.27 (m, 5H), 7.14 (td, 8.8, 8.1, 3.0 Hz, 1H), 6.10 (s, 2H)。 582.05 E   
I-1171
Figure 02_image2633
 FC(F)c1cc(F)cc(c1)C(=O)Nc1cc(cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  10.55 (s, 1H), 9.48 (s, 2H), 9.26 (s, 1H), 8.58 (d, 1.3 Hz, 1H), 8.14 (d, 10.2 Hz, 2H), 8.02 - 7.94 (m, 1H), 7.70 (d, 2.1 Hz, 1H), 7.68 (s, 2H), 7.58 (d, 9.3 Hz, 1H), 7.36 (dd, 9.0, 5.1 Hz, 1H), 7.12 (d, 5.7 Hz, 2H), 6.73 (s, 1H) ,6.10 (s, 1H)。 566.15 B   
I-1172
Figure 02_image2635
 FC(F)c1cc(F)cc(c1)C(=O)Nc1cc(cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  10.55 (s, 1H), 9.48 (s, 1H), 9.25 (s, 1H), 8.58 (s, 1H), 8.14 (d, 10.1 Hz, 2H), 8.02 - 7.94 (m, 2H), 7.69 (d, 9.4 Hz, 2H), 7.58 (d, 9.2 Hz, 1H), 7.36 (dd, 8.9, 5.1 Hz, 1H), 7.12 (d, 8.0 Hz, 2H), 6.73 (s, 1H), 6.09 (s, 1H)。 566.2 E   
I-1173
Figure 02_image2637
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)c(F)c(Cl)c3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 10.49 (s, 1H), 9.47 (t, 1.4 Hz, 1H), 9.28-9.23 (m, 1H), 8.58 (s, 1H), 8.17-8.10 (m, 2H), 8.02-7.94 (m, 2H), 7.75-7.66 (m, 1H), 7.63 (dt, 6.1, 1.9 Hz, 1H), 7.39 (dd, 8.9, 5.2 Hz, 1H), 7.16 (td, 8.4, 3.1 Hz, 1H), 6.65 (s, 1H), 6.07 (s, 1H)。 568.1 A   
I-1174
Figure 02_image2639
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)c(F)c(Cl)c3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 10.49 (s, 1H), 9.47 (t, 1.4 Hz, 1H), 9.28-9.23 (m, 1H), 8.58 (s, 1H), 8.17-8.10 (m, 2H), 8.02-7.94 (m, 2H), 7.75-7.66 (m, 1H), 7.63 (dt, 6.1, 1.9 Hz, 1H), 7.39 (dd, 8.9, 5.2 Hz, 1H), 7.16 (td, 8.4, 3.1 Hz, 1H), 6.65 (s, 1H), 6.07 (s, 1H)。 568.1 D   
I-1175
Figure 02_image2641
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CC(C1)C#N NMR (400 MHz, CD3CN)  8.64 (s,1H), 7.68-7.56 (m, 4H), 7.42 (d, 6.9 Hz,1H), 7.30-7.22 (m, 2H), 7.02-6.92 (m,1H), 6.60 (br, s,1H), 6.09 (br, s, 1H), 3.78-3.67 (m,1H), 3.31-3.19 (m,1H), 2.88-2.80 (m,1H), 2.78-2.70 (m,1H), 2.69-2.59 (m,1H), 2.56-2.44 (m,1H)。 546.3 A   
I-1176
Figure 02_image2643
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)Nc3cc(ccc3Cl)C(F)(F)F)c12 (400 MHz, DMSO-d6)  9.27 (s, 1H), 9.09 (s, 1H), 8.46 (s, 1H), 8.35 (d, 1.9 Hz, 1H), 7.74-7.66 (m, 3H), 7.46-7.36 (m, 2H), 7.17 (dt,  8.6, 2.3 Hz, 1H), 6.71 (br s, 1H), 6.06 (br s, 1H)。 574.2 B   
I-1177
Figure 02_image2645
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1ccc2C(NC(=O)Cc2c1)c1ccccc1Cl NMR (400 MHz, DMSO)  10.56 (s, 1H), 8.45 (d, 2.3 Hz, 1H), 8.16 (s, 1H), 8.10 (d, 9.1 Hz, 1H), 7.98 (d, 8.5 Hz, 1H), 7.67 (d, 2.0 Hz, 1H), 7.53 (dd, 8.5, 2.1 Hz, 1H), 7.51-7.47 (m, 1H), 7.36-7.26 (m, 3H), 7.00 (d, 8.6 Hz, 1H), 6.07 (d, 1.7 Hz, 1H), 3.79 (d, 20.4 Hz, 1H), 3.61 (d, 19.6 Hz, 1H)。 463.1 D   
I-1178
Figure 02_image2647
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2CC(=O)NC(c3ccccc3Cl)c12 NMR (400 MHz, DMSO)  10.18 (s, 1H), 8.59 (d, 3.8 Hz, 1H), 7.98-7.91 (m, 2H), 7.87 (d, 9.0 Hz, 1H), 7.40 (t, 7.7 Hz, 1H), 7.31-7.25 (m, 2H), 7.20 (td, 7.6, 1.7 Hz, 1H), 7.18-7.09 (m, 2H), 6.90 (dd, 7.7, 1.4 Hz, 1H), 6.23 (d, 3.7 Hz, 1H), 3.90 (d, 20.6 Hz, 1H), 3.62 (d, 20.7 Hz, 1H)。 463.1 D   
I-1179
Figure 02_image2649
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C34CC5CC(CC(Cl)(C5)C3)C4)c12 1H-NMR (400 MHz, DMSO-d6)  9.38 (s, 1H), 9.24 (br. s, 1H), 7.72 (d, 1.7 Hz, 1H), 7.58 (d, 1.7 Hz, 1H), 7.55-7.47 (m, 1H), 7.25 (ddd, 8.8, 8.1, 3.1 Hz, 1H), 6.52 (br. s, 1H), 6.00 (br. s, 1H), 2.15-2.09 (m, 2H), 2.06-1.99 (m, 2H), 1.95-1.85 (m, 3H), 1.81-1.75 (m, 1H), 1.61-1.55 (m, 1H), 1.52-1.40 (m, 5H)。 551.3 A   
I-1180
Figure 02_image2651
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)C34CC5CC(F)(CC(F)(C5)C3)C4)c12 1H-NMR (400 MHz, DMSO-d6)  9.45 (s, 1H), 9.11 (br. s, 1H), 7.63 (d, 6.8 Hz, 1H), 7.58 (t, 7.6 Hz, 1H), 7.56-7.49 (m, 1H), 7.39-7.35 (m, 1H), 7.25 (app. td, 8.4, 3.0 Hz, 1H), 6.38 (br. s, 1H), 6.01 (br. s, 1H), 2.42-2.35 (m, 1H), 2.07-1.99 (m, 1H), 1.94-1.87 (m, 1H), 1.81-1.73 (m, 2H), 1.71-1.59 (m, 5H), 1.58-1.52 (m, 1H), 1.42-1.29 (m, 2H)。 473.4 B   
I-1181
Figure 02_image2653
 OC1(CNc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CC1 (400 MHz, CD3CN)  8.48 (s, 1 H), 7.63 (d, 8.4 Hz, 1 H), 7.57 (d, 9.0 Hz, 1 H), 7.54 (s, 1 H), 7.23 (dd, 8.9, 5.1 Hz, 1 H), 7.09 (s, 1 H), 6.98-6.91 (m, 2 H), 6.86 (d, 1.9 Hz, 1 H), 6.64 (br s, 1 H), 5.98 (br s, 1 H), 5.08 (t, 5.5 Hz, 1 H), 3.60 (br s, 1 H), 3.28 (d, 5.6 Hz, 2 H), 0.73 - 0.69 (m, 2 H), 0.63 - 0.59 (m, 2 H)。含有0.86及1.27處之小油脂峰。 552.4 A   
I-1182
Figure 02_image2655
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C34C5C6C7C5C3C7C46)c12 1H-NMR (400MHz, DMSO-d6)  9.44 (s, 1H), 9.22 (br. s, 1H), 7.71 (d, 1.5 Hz, 1H), 7.62 (d, 1.7 Hz, 1H), 7.52-7.43 (m, 1H), 7.24 (app. td, 8.4, 3.1 Hz, 1H), 6.69 (br. s, 1H), 5.97 (br. s, 1H), 3.94-3.90 (m, 4H), 3.89-3.84 (m, 3H)。 485.3 D   
I-1183
Figure 02_image2657
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C34CC5CC(C3)CC(C5)(C4)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  9.44 (s, 1H), 9.25 (br. s, 1H), 7.72 (d, 1.6 Hz, 1H), 7.57 (d, 1.7 Hz, 1H), 7.52-7.44 (m, 1H), 7.22 (app. td, 8.4, 3.1 Hz, 1H), 6.48 (br. s, 1H), 5.99 (br. s, 1H), 2.11-2.04 (m, 2H), 1.69-1.62 (m, 2H), 1.61-1.41 (m, 9H), 1.38-1.32 (m, 1H)。 585.3 A   
I-1184
Figure 02_image2659
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OC3CCOC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO)  10.49 (br s, 1H), 9.14 (br s, 1H), 7.94 (d, 8.1 Hz, 1H), 7.71 (d, 9.0 Hz, 1H), 7.63 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.18 (s, 1H), 7.09 (td與s重疊, 8.2, 2.9 Hz, 1H), 7.06 (s與td重疊, 1H), 6.64 (br s, 1H), 5.93 (br s, 1H), 5.20 (m, 1H), 3.90 (m, 3H), 3.79 (td, 8.4, 4.6 Hz, 1H), 2.34-2.21 (m, 1H), 2.09-1.97 (m, 1H)。 553 A   
I-1185
Figure 02_image2661
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C#Cc1ccccn1 NMR (400 MHz, DMSO-d6)  10.53 (br. s, 1H), 9.31 (s, 1H), 8.65 (ddd, 4.8, 1.7, 0.9 Hz, 1H), 7.96 (br. d, 8.5 Hz, 1H), 7.90 (td, 7.7, 1.8 Hz, 1H), 7.85 (d, 0.9 Hz, 1H), 7.77-7.70 (m, 3H), 7.67 (s, 1H), 7.46 (ddd, 7.6, 4.9, 1.2 Hz, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.4, 3.0 Hz, 1H), 6.74 (br. s, 1H), 6.03 (br. s, 1H)。 568.3 A   
I-1186
Figure 02_image2663
 CCCCC(C)(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.53 (s, 1H), 9.09 (s, 1H), 7.93 (br. d, 8.4 Hz, 1H), 7.76 (br. d, 8.9 Hz, 1H), 7.73-7.70 (m, 1H), 7.68 (s, 1H), 7.54 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.4, 3.0 Hz, 1H), 6.57 (br. s, 1H), 5.93 (br. s, 1H), 5.14 (s, 1H), 1.81-1.64 (m, 2H), 1.50 (s, 3H), 1.33-1.12 (m, 3H), 1.05-0.89 (m, 1H), 0.84 - 0.76 (m, 3H)。 567.2 A   
I-1187
Figure 02_image2665
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CCOCC1 NMR (400 MHz, DMSO-D6)  10.52 (br s, 1H), 9.12 (br s, 1H), 7.94 (d, 9.2 Hz, 1H), 7.74 (d, 8.3 Hz, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.38 (s, 1H), 7.30 (dd, 8.8, 5.2 Hz, 1H), 7.08 (td, 8.2, 2.6 Hz, 1H), 6.61 (br s, 1H), 5.97 (br s, 1H), 3.98 (dd, 11.1, 3.6 Hz, 2H), 3.47 (t, 11.5 Hz, 2H), 3.01-2.95 (m, 1H), 1.89-1.56 (m, 4H)。 551.3 A   
I-1188
Figure 02_image2667
 CC(O)(c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)c1ccccn1 NMR (400 MHz, DMSO-d6 )  10.50 (br. s, 1H), 9.10 (s, 1H), 8.55 - 8.50 (m, 1H), 7.93 (br. d, 8.5 Hz, 1H), 7.82-7.77 (m, 2H), 7.76-7.70 (m, 2H), 7.64 (s, 1H), 7.60 (s, 1H), 7.31-7.22 (m, 2H), 6.55 (br. s, 1H), 6.25 (s, 1H), 5.90 (br. s, 1H), 1.94 (s, 3H)。 588.2 A   
I-1189
Figure 02_image2669
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCOc2ccccc12    600.38 A   
I-1190
Figure 02_image2671
 Cc1cnc2ccc(nn12)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    598.38 A   
I-1191
Figure 02_image2673
 CC(C)(O)C#Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    549.4 A   
I-1192
Figure 02_image2675
 O[C@@H]1COC[C@H]1Oc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    569.4 A   
I-1193
Figure 02_image2677
 Cn1ccnc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  9.15 (s, 1H), 8.51 (s, 1H), 8.08 (br s, 1H), 7.87-7.70 (m, 4H), 7.35 (dd, 8.8, 5.2 Hz, 1H), 7.31 (s, 1H), 7.09 (td, 8.4, 2.9 Hz, 1H), 7.03 (s, 1H), 6.70 (br s, 1H), 6.04 (s, 1H), 3.85 (s, 3H) 547.2 B   
I-1194
Figure 02_image2679
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C#CC1CC(F)(F)C1    581.5 B   
I-1195
Figure 02_image2681
 CS(=O)(=O)c1ccccc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)   2.97 (s, 3 H) 6.05 (br s, 1 H) 7.11 (td,  8.34, 3.03 Hz, 1 H) 7.34 (dd,  8.97, 5.18 Hz, 1 H) 7.46 - 7.54 (m, 2 H) 7.63 - 7.83 (m, 5 H) 7.93 (br d,  8.34 Hz, 1 H) 8.13 (dd,  7.83, 1.26 Hz, 1 H) 9.25 (br s, 1 H) 10.62 (s, 1 H) 621.34 A   
I-1196
Figure 02_image2683
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CS(=O)(=O)C1 1H NMR (500 MHz, DMSO-d6)   4.04 - 4.14 (m, 1 H) 4.32 - 4.49 (m, 2 H) 4.62 - 4.73 (m, 2 H) 5.98 (br d,  1.98 Hz, 1 H) 6.73 - 6.89 (m, 1 H) 7.09 (td,  8.39, 2.90 Hz, 1 H) 7.31 (dd,  8.85, 5.19 Hz, 1 H) 7.51 - 7.57 (m, 1 H) 7.67 (s, 1 H) 7.71 - 7.81 (m, 2 H) 7.94 (br d,  8.24 Hz, 1 H) 9.17 (br s, 1 H) 10.59 (br s, 1 H) 571.32 A   
I-1197
Figure 02_image2685
 COc1ccccc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO-d6)   3.81 (s, 3 H) 6.02 (br s, 1 H) 7.04 - 7.14 (m, 2 H) 7.18 (d,  8.24 Hz, 1 H) 7.32 (dd,  8.85, 5.19 Hz, 1 H) 7.36 - 7.44 (m, 2 H) 7.60 (s, 1 H) 7.67 (s, 1 H) 7.70 - 7.80 (m, 2 H) 7.93 (br d,  8.24 Hz, 1 H) 9.16 (br s, 1 H) 10.51 (s, 1 H) 573.37 B   
I-1198
Figure 02_image2687
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OC3CCC3(F)F)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO)  10.55 (br. s, 1H), 9.24 (s, 1H), 7.95 (d, 8.2 Hz, 1H), 7.72 (d, 9.7 Hz, 1H), 7.64 (s, 1H), 7.43 (s, 1H), 7.37-7.26 (m, 2H), 7.09 (td, 8.5, 3.1 Hz, 1H), 6.61 (浸沒br. s, 1H), 6.43 (ddd, 59.9, 16.9, 11.9 Hz, 1H), 5.96 (s, 1H), 1.37-1.14 (m, 2H), 1.15-0.99 (m, 2H) 573.2 A   
I-1199
Figure 02_image2689
 Cn1ccnc1C(C)(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.56 (br. s, 1H), 9.13 (br. s, 1H), 8.26 (s, 1H), 7.92 (br. d, 8.3 Hz, 1H), 7.72 (app. t, 8.4 Hz, 1H), 7.64-7.59 (m, 1H), 7.43 (s, 1H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.11-7.04 (m, 2H), 6.85-6.82 (m, 1H), 6.43 (br. s, 1H), 5.93 (br. s, 1H), 3.33 (s, 3H), 1.90 (s, 3H)。 591.2 A   
I-1200
Figure 02_image2691
 OC(Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)C(F)(F)F NMR (400 MHz, DMSO-d6)  10.50 (br s, 1H), 9.12 (br s, 1H), 7.94 (d, 8.3 Hz, 1H), 7.74 (d, 8.7 Hz, 1H), 7.70-7.63 (m, 2H), 7.43 (s, 1H), 7.31 (dd, 8.9, 5.1 Hz, 1H), 7.10 (td, 8.9, 2.1 Hz, 1H), 6.65 (浸沒br s, 1H), 6.35 (br s, 1H), 5.94 (br s, 1H), 4.28 (br s, 1H), 3.18-3.03 (m, 1H), 2.97-2.79 (m, 1H)。 579.2 A   
I-1201
Figure 02_image2693
 OC(=O)c1nc(cs1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.65 (br s, 1H), 9.20 (br s, 1H), 8.43 (br s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 7.94 (dd, 9.0, 1.2 Hz, 1H), 7.79 (dd, 9.0, 1.2 Hz, 1H), 7.72 (br s, 1H), 7.32 (dd, 9.0, 5.1 Hz, 1H), 7.17 (br s, 1H), 7.13-7.05 (m, 1H), 6.03 (br s, 1H)。 594.1 A   
I-1202
Figure 02_image2695
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Oc3ncccn3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  10.56 (s, 1H), 9.27 (s, 1H), 8.71 (d, 4.8 Hz, 2 X 1H), 7.95 (dt, 8.4, 2.0 Hz, 1H), 7.72 (br. d, 9.2 Hz, 1H), 7.64 (s, 1H), 7.52 (d, 1.9 Hz, 1H), 7.37 (s, 1H), 7.36-7.32 (m, 2H), 7.12 (td, 8.5, 3.1 Hz, 1H), 6.69 (br. s, 1H), 6.00 (br. s, 1H)。 561.1 B   
I-1203
Figure 02_image2697
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C34CC5CC(C3)C(F)(F)C(C5)C4)c12 1H-NMR (400 MHz, DMSO-d6)  9.42 (s, 1H), 9.25 (br. s, 1H), 7.72 (d, 1.6 Hz, 1H), 7.59 (d, 1.7 Hz, 1H), 7.55-7.45 (m, 1H), 7.25 (app. td, 8.4, 3.0 Hz, 1H), 6.56 (br. s, 1H), 5.99 (br. s, 1H), 2.18-2.10 (m, 2H), 1.92-1.86 (m, 1H), 1.79-1.66 (m, 3H), 1.65-1.57 (m, 5H), 1.56-1.51 (m, 2H)。 555.2 B   
I-1204
Figure 02_image2699
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C3(CC3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  9.51 (br. s, 1H), 9.25 (s, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 7.55-7.44 (m, 1H), 7.25 (app. td, 8.5, 3.1 Hz, 1H), 6.55 (br. s, 1H), 5.90 (br. s, 1H), 1.22-1.08 (m, 3H), 0.81-0.73 (m, 1H)。 493.1 E   
I-1205
Figure 02_image2701
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OC3CN(C3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO)  10.47 (s, 1H), 9.17 (s, 1H), 7.95 (d, 8.5 Hz, 1H), 7.70 (d, 9.6 Hz, 1H), 7.62 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.5, 3.3 Hz, 1H), 7.02 (s, 2H), 5.92 (s, 1H), 5.27-5.20 (m, 1H), 4.68-4.64 (m, 2H), 4.24 (m, 2H)。B袋鄰質子缺失。根據LC，約12-13%雜質，其為氧化產物。 563 A   
I-1206
Figure 02_image2703
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)Oc3ccc4CCNc4n3)c12 1H NMR (400 MHz, DMSO-d6)  10.65 (s, 1H), 9.26 (s, 1H), 7.89 (s, 1H), 7.71 (s, 1H), 7.47 (d, 8.0 Hz, 1H), 7.29 (dd, 9.0, 5.1 Hz, 1H), 7.04 (t, 8.5 Hz, 1H), 6.18 (d, 8.1 Hz, 2H), 3.92 (q, 9.3 Hz, 1H), 3.80 (q, 10.3, 9.6 Hz, 1H), 2.89 (t, 8.6 Hz, 2H)。 517.1 E   
I-1207
Figure 02_image2705
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(Cl)cc(Cl)c3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  10.51 (s, 1H), 9.47 (dd, 1.9, 1.0 Hz, 1H), 9.25 (s, 1H), 8.58 (s, 1H), 8.13 (dd, 9.1, 1.8 Hz, 2H), 8.03 - 7.93 (m, 2H), 7.86 (t, 1.9 Hz, 1H), 7.57 (d, 1.9 Hz, 2H), 7.40 (dd, 8.9, 5.1 Hz, 1H), 7.17 (td, 8.3, 3.0 Hz, 1H), 6.71 (s, 1H), 6.08 (s, 1H)。 565.8 D   
I-1208
Figure 02_image2707
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(Cl)cc(Cl)c3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  10.51 (s, 1H), 9.47 (dd, 1.9, 0.9 Hz, 1H), 9.25 (s, 1H), 8.58 (s, 1H), 8.13 (dd, 9.2, 1.8 Hz, 2H), 8.03 - 7.93 (m, 2H), 7.86 (t, 1.9 Hz, 1H), 7.57 (d, 1.9 Hz, 2H), 7.40 (dd, 8.9, 5.1 Hz, 1H), 7.17 (td, 8.4, 3.0 Hz, 1H), 6.08 (s, 1H)。 565.95 A   
I-1209
Figure 02_image2709
 Cn1c(Cl)cc(cc1=O)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.44 (s, 1H), 9.30 (s, 1H), 7.82 (d, 1.7 Hz, 1H), 7.71 (d, 1.6 Hz, 1H), 7.43 (d, 8.2 Hz, 1H), 7.19 (td, 8.5, 8.1, 2.8 Hz, 1H), 6.86 (s, 1H), 6.47 (q, 1.9 Hz, 2H), 5.97 (s, 1H), 3.57 (d, 1.3 Hz, 3H) 525.85 E   
I-1210
Figure 02_image2711
 O[C@@H]1CC[C@@H]1Oc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.45 (s, 1H), 9.11 (s, 1H), 7.94 (d, 8.4 Hz, 1H), 7.71 (d, 8.2 Hz, 1H), 7.62 (s, 1H), 7.31 (dd, 8.5, 5.0 Hz, 1H), 7.11 (d, 2.2 Hz, 1H), 7.07 (td, 8.5, 2.9 Hz, 1H), 7.04 (br. s, 1H), 6.49 (br. s, 1H), 5.92 (br. s, 1H), 5.23 (t,  7.35 Hz, 1H), 4.88-4.72 (m, 1H), 4.44 (br. s, 1H), 2.23-2.02 (m, 3H), 2.01-1.86 (m, 1H); 553.2 A   
I-1211
Figure 02_image2713
 CC(O)(CC#N)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.56 (s, 1H), 9.16 (s, 1H), 7.94 (d, 8.4 Hz, 1H), 7.84 (s, 1H), 7.75 (d, 9.0 Hz, 1H), 7.68 (s, 2H), 7.31 (dd, 8.8, 5.2 Hz, 1H), 7.10 (td, 8.4, 3.0 Hz, 1H), 6.58 (br s, 1H), 6.08 (s, 1H), 5.96 (br s, 1H), 3.14-3.07 (m, 2H), 1.63 (s, 3H) 550.2 A   
I-1212
Figure 02_image2715
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2NC(=O)NC(c3ccccc3Cl)c12 NMR (400 MHz, DMSO)  10.15 (s, 1H), 9.49 (d, 1.7 Hz, 1H), 8.00-7.91 (m, 2H), 7.89 (d, 9.2 Hz, 1H), 7.55-7.49 (m, 2H), 7.31-7.23 (m, 2H), 7.23-7.16 (m, 2H), 7.06 (dd, 5.9, 3.5 Hz, 1H), 6.89 (d, 7.3 Hz, 1H), 6.80 (d, 7.8 Hz, 1H), 6.14 (d, 3.0 Hz, 1H)。 464.1 D   
I-1213
Figure 02_image2717
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Nc3ccccc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    558.36 A   
I-1214
Figure 02_image2719
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cccnc1C#N    569.31 A   
I-1215
Figure 02_image2721
 NC(=O)c1cnccc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    587.27 B   
I-1216
Figure 02_image2723
 OC(=O)c1ccccc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO-d6)   5.95 - 6.11 (m, 1 H) 7.10 (td,  8.32, 2.90 Hz, 1 H) 7.33 (dd,  8.85, 5.04 Hz, 1 H) 7.44 - 7.53 (m, 3 H) 7.56 - 7.63 (m, 2 H) 7.66 (s, 1 H) 7.76 (br dd,  15.49, 8.32 Hz, 2 H) 7.93 (br d,  8.39 Hz, 1 H) 9.18 (br s, 1 H) 10.58 (s, 1 H) 587.37 B   
I-1217
Figure 02_image2725
 OC(=O)c1cnccc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO-d6)   5.96 - 6.12 (m, 1 H) 7.10 (td,  8.32, 2.90 Hz, 1 H) 7.33 (dd,  8.85, 5.19 Hz, 1 H) 7.49 - 7.57 (m, 5 H) 7.58 - 7.68 (m, 6 H) 7.74 (br d,  8.39 Hz, 1 H) 7.93 (br d,  8.39 Hz, 1 H) 8.75 (d,  5.04 Hz, 1 H) 8.90 - 8.95 (m, 1 H) 9.23 (br s, 1 H) 10.62 (s, 1 H) 588.32 B   
I-1218
Figure 02_image2727
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CCCN1 1H NMR (500 MHz, DMSO-d6)   1.54 - 1.65 (m, 1 H) 1.73 - 1.93 (m, 2 H) 2.25 (quind,  7.78, 7.78, 7.78, 7.78, 4.43 Hz, 1 H) 2.96 - 3.13 (m, 3 H) 4.25 - 4.34 (m, 1 H) 5.95 (br s, 1 H) 7.01 - 7.14 (m, 1 H) 7.29 (ddd,  8.66, 5.23, 1.68 Hz, 1 H) 7.51 (br d,  9.77 Hz, 1 H) 7.61 - 7.78 (m, 3 H) 7.92 (br d,  7.93 Hz, 1 H) 8.24 (s, 1 H) 9.08 (br s, 1 H) 10.50 (br d,  3.97 Hz, 1 H) 536.45 A   
I-1219
Figure 02_image2729
 COc1cnccc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO-d6)   3.95 (s, 3 H) 6.04 (br s, 1 H) 7.10 (td,  8.35, 2.98 Hz, 1 H) 7.33 (dd,  8.93, 5.11 Hz, 1 H) 7.47 (d,  4.88 Hz, 1 H) 7.57 - 7.65 (m, 1 H) 7.65 - 7.76 (m, 3 H) 7.88 (s, 1 H) 7.94 (br d,  8.39 Hz, 1 H) 8.33 (d,  4.88 Hz, 1 H) 8.54 (s, 1 H) 9.22 (br s, 1 H) 10.57 (s, 1 H) 574.37 A   
I-1220
Figure 02_image2731
 OC(=O)Cc1ccncc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO-d6)   2.33 (s, 2 H) 5.94 - 6.13 (m, 1 H) 7.11 (td,  8.35, 2.98 Hz, 1 H) 7.34 (dd,  8.85, 5.34 Hz, 1 H) 7.37 - 7.40 (m, 1 H) 7.51 (s, 1 H) 7.65 - 7.69 (m, 2 H) 7.74 (br d,  8.85 Hz, 1 H) 7.94 (br d,  8.39 Hz, 1 H) 8.45 - 8.51 (m, 2 H) 9.23 (br s, 1 H) 10.56 (s, 1 H) 602.33 A   
I-1221
Figure 02_image2733
 Cn1ncnc1COc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz):-´ = 10.48 (s, 1H), 9.15 (br s, 1H), 7.97 (s, 1H), 7.92-7.96 (m, 1H), 7.71 (br d, 9.1 Hz, 1H), 7.63 (s, 1H), 7.43 (d, 2.0 Hz, 1H), 7.31 (dd, 8.8, 5.1 Hz, 1H), 7.17 (d, 1.8 Hz, 1H), 7.09 (td, 8.3, 3.0 Hz, 1H), 5.92 (br s, 1H), 5.46 (d, 2.0 Hz, 2H), 3.94  (s, 3H) 578.1 A   
I-1222
Figure 02_image2735
 CN(C)c1ncc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz):  10.59 (s, 1H), 9.19 (br s, 1H), 8.80 (s, 2H), 7.91-7.98 (m, 2H), 7.72-7.78 (m, 2H), 7.69 (s, 1H), 7.32 (dd, 8.8, 5.1 Hz, 1H), 7.10 (td, 8.3, 3.3 Hz, 1H), 5.99 (br s, 1H), 3.19 (s, 6H), 2.84-3.07 (m, 1H) 588.1 A   
I-1223
Figure 02_image2737
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C#CC1COC1    547.4 A   
I-1224
Figure 02_image2739
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C#Cc1ccncc1    568.4 A   
I-1225
Figure 02_image2741
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C#Cc1cccnc1    568.1 A   
I-1226
Figure 02_image2743
 Fc1ccc(Cl)c(c1)C1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1    585.4 A   
I-1227
Figure 02_image2745
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCCc2ncccc12 1H NMR (400 MHz, DMSO-d6)  2.06 (quin,  6.13 Hz, 2 H) 2.92 (t,  6.57 Hz, 2 H) 3.63 - 3.76 (m, 2 H) 5.84 - 6.14 (m, 1 H) 7.00 (dd,  8.08, 4.55 Hz, 1 H) 7.09 (td,  8.46, 3.03 Hz, 1 H) 7.16 (br d,  7.58 Hz, 1 H) 7.28 - 7.38 (m, 2 H) 7.46 (d,  1.77 Hz, 1 H) 7.62 (s, 1 H) 7.70 (br d,  9.09 Hz, 1 H) 7.87 - 7.99 (m, 2 H) 9.15 (br s, 1 H) 10.46 (s, 1 H) 599.33 A   
I-1228
Figure 02_image2747
 CS(=O)(=O)N1CC(C1)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)   3.09 (s, 3 H) 3.92 - 4.09 (m, 3 H) 4.25 - 4.33 (m, 2 H) 5.98 (br s, 1 H) 7.09 (td,  8.34, 3.03 Hz, 1 H) 7.31 (dd,  8.97, 5.18 Hz, 1 H) 7.52 (s, 1 H) 7.66 (s, 1 H) 7.70 - 7.77 (m, 2 H) 7.95 (br d,  8.34 Hz, 1 H) 9.16 (br s, 1 H) 10.55 (s, 1 H) 600.33 A   
I-1229
Figure 02_image2749
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1    585.4 A   
I-1230
Figure 02_image2751
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2nc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1    585.4 B   
I-1231
Figure 02_image2753
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccncc1C#N       C   
I-1232
Figure 02_image2755
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccncc1C#N    569.08 A   
I-1233
Figure 02_image2757
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-n1cnc2ncccc12    584.32 A   
I-1234
Figure 02_image2759
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OCCCC=C)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6 )  10.43 (s, 1H), 9.12 (br. s, 1H), 7.94 (d, 8.4 Hz, 1H), 7.71 (d, 9.2 Hz, 1H), 7.63 (s, 1H), 7.31 (dd, 8.7, 5.2 Hz, 1H), 7.18 (d, 1.8 Hz, 1H), 7.14-7.01 (m, 2H), 6.63 (br. s, 1H), 5.89 (ddt, 17.0, 10.3, 6.6 Hz, 2H), 5.08 (ddd, 17.3, 3.4, 1.7 Hz, 1H), 5.01 (ddd, 10.3, 3.0, 1.4 Hz, 1H), 4.22-3.98 (m, 2H), 2.21 (dd, 14.5, 6.7 Hz, 2H), 1.92-1.80 (m, 1H)。 551.2 C   
I-1235
Figure 02_image2761
 CN1CCN(Cc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CC1=O NMR (400 MHz, CD3CN)  8.73 (s, 1H), 7.72-7.50 (m, 5H), 7.28 (s, 1H), 7.24 (dd, 8.9, 5.1 Hz, 1H), 6.96 (ddd, 8.8, 8.1, 3.1 Hz, 1H), 6.61 (br, s, 1H), 6.11 (br, s, 1H), 3.70 (s, 2H), 3.32-3.27 (m,, 2H), 3.04 (s, 2H), 2.86 (s, 3H), 2.75-2.70 (m, 2H)。 593.3 B   
I-1236
Figure 02_image2763
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCn2ccnc2C1 (400 MHz, CD3CN)  8.83 (s, 1 H), 8.08 (s, 1 H), 7.66 - 7.55 (m, 4 H), 7.37 - 7.17 (m, 4 H), 6.95 (td, 8.4, 2.9 Hz, 1 H), 6.63 (br s, 1 H), 6.04 (br s, 1 H), 4.55 (app d, 9.3 Hz, 2 H), 4.20 - 4.12 (m, 2 H), 3.83 (t, 5.1 Hz, 2 H)。 586.3 A   
I-1237
Figure 02_image2765
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCn2cncc2C1 (400 MHz, CD3CN)  8.66 (s, 1 H), 8.09 (s, 1 H), 7.67 - 7.56 (m, 4 H), 7.32 (d, 2.0 Hz, 1 H), 7.26-7.17 (m, 3 H), 6.95 (td, 8.4, 3.0 Hz, 1 H), 6.64 (br s, 1 H), 6.04 (br s, 1 H), 4.57 (s, 2 H), 4.19 (t, 5.2 Hz, 2 H), 3.80 (t, 5.3 Hz, 2 H)。 588.3 A   
I-1238
Figure 02_image2767
 COC(=O)c1cc(Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)ncc1C(F)(F)F (400 MHz, CD3CN)  8.88 (s, 1 H), 8.61 (s, 1 H), 7.78-7.71 (m, 1 H), 7.49 (br s, 1 H), 7.46 (dd, 5.0, 1.8 Hz, 1 H), 7.37 (t, 7.6 Hz, 1 H), 7.30 (d, 7.3 Hz, 1 H), 7.01 (app t, 7.0 Hz, 1 H), 6.94 (d, 7.8 Hz, 1 H), 6.85 (br s, 1 H), 6.65 (br s, 1 H), 4.19 (s, 1 H), 3.93 (s, 3 H)。 480.3 D   
I-1239
Figure 02_image2769
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OC3CCCOC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6 )  10.43 (br. s, 1H), 9.13 (br. s, 1H), 7.94 (d, 8.5 Hz, 1H), 7.71 (d, 9.1 Hz, 1H), 7.63 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.22 (d, 1.2 Hz, 1H), 7.13-7.03 (m, 2H), 6.64 (br. s, 1H), 5.91 (br. s, 1H), 4.64-4.43 (m, 1H), 3.84 (dd, 11.6, 2.4 Hz, 1H), 3.68-3.49 (m, 3H), 2.05 (m, 1H), 1.88-1.68 (m, 2H), 1.64-1.47 (m, 1H) 567.3 A   
I-1240
Figure 02_image2771
 Cc1cc(=O)[nH]cc1C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  11.75 (s, 1H), 10.06 (s, 1H), 9.26 (s, 1H), 7.75 (d, 1.7 Hz, 1H), 7.64 (s, 1H), 7.46 (dd, 8.8, 5.1 Hz, 1H), 7.21 (ddd, 8.9, 7.9, 3.1 Hz, 1H), 6.89 (s, 1H), 6.65 (s, 1H), 6.16 (s, 1H), 5.96 (s, 1H), 2.13 - 2.06 (m, 3H)。 489.9 E   
I-1241
Figure 02_image2773
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(COC(F)(F)F)c3)c12 1H NMR (400 MHz, DMSO-d6) 10.40 (s, 1H), 9.28 (s, 1H), 7.81 (d, 1.7 Hz, 1H), 7.74 (d, 1.9 Hz, 1H), 7.57-7.46 (m, 2H), 7.38-7.30 (m, 2H), 7.11 (td, 8.4, 3.1 Hz, 1H), 6.76 (s, 1H), 6.03-5.97 (m, 1H), 5.22 (s, 2H)。 575 D   
I-1242
Figure 02_image2775
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(Cl)cc4OCCNc34)c12 1H NMR (400 MHz, 氯仿-d) 8.46 (s, 1H), 7.92 (d, 1.6 Hz, 1H), 7.55 (dd, 9.0, 4.9 Hz, 1H),7.4-7.3(S,1H), 7.18 (s, 1H), 7.13 (ddd, 8.9, 7.4, 3.0 Hz, 1H), 6.87 (d, 2.3 Hz, 1H), 6.70 (s, 1H), 6.42 (s, 1H), 6.28 (d, 2.3 Hz, 1H), 6.16 (s, 1H), 4.22 (t, 4.5 Hz, 2H), 3.54-3.47 (m, 2H)。 551.9 D   
I-1243
Figure 02_image2777
 OC(CC#N)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.58 (s, 0.5H), 10.56 (s, 0.5H), 9.16 (s, 1H), 7.96 (s, 0.5H), 7.94 (s, 0.5H), 7.79 (s, 0.5H), 7.77-7.71 (m, 1.5H), 7.66 (s, 1H), 7.59 (s, 0.5H), 7.52 (s, 0.5H), 7.32 (dd, 5.2, 1.4 Hz, 0.5H), 7.30 (dd, 5.2, 1.4 Hz, 0.5H), 7.13-7.06 (m, 1H), 6.55 (br s, 1H), 6.24 (s, 0.5H), 6.22 (s, 0.5H), 5.97 (br s, 1H), 5.12 (q, 5.0 Hz, 0.5H), 5.07 (q, 5.1 Hz, 0.5H), 3.07-2.90 (m, 4H) 536.2 A   
I-1244
Figure 02_image2779
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C#Cc1ccn[nH]1 NMR (400 MHz, ACN-d3) : 8.79 (br. s, 1H), 7.89 (d, 0.8 Hz, 1H), 7.69 (s, 1H), 7.66-7.64 (m, 2H), 7.59 (mt, 1H), 7.57 (s, 1H), 7.41 (br. s, 1H), 7.26 (dd, 8.8, 5.1 Hz, 1H), 6.98 (td, 8.6, 3.0 Hz, 1H), 6.70 (br. s, 1H), 6.57 (s, 1H), 6.15 (br. s, 1H) 557.1 A   
I-1245
Figure 02_image2781
 Cc1ncc(Nc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)cn1 1H-NMR (400 MHz, DMSO-d6)  10.39 (br. s, 1H), 9.09 (br. s, 1H), 8.78 (s, 1H), 8.60 (s, 2H), 7.94 (br. d, 8.3 Hz, 1H), 7.71 (br. d, 8.9 Hz, 1H), 7.61 (br. s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.23 (d, 2.0 Hz, 1H), 7.19 (d, 1.7 Hz, 1H), 7.11-7.05 (m, 1H), 6.67 (br. s, 1H), 5.93 (br. s, 1H), 2.56 (s, 3H)。 574.4 A   
I-1246
Figure 02_image2783
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Oc3ncncc3F)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, CD3CN)  8.71 (br. s, 1H), 8.61 (d, 2.9 Hz, 1H), 8.51 (d, 1.4 Hz, 1H), 7.66-7.64 (m, 1H), 7.63 (d, 2.1 Hz, 1H), 7.61-7.58 (m, 1H), 7.57 (s, 1H), 7.51 (d, 1.5 Hz, 1H), 7.36 (br. s, 1H), 7.29 (dd, 8.9, 5.1 Hz, 1H), 7.00 (ddd, 8.6, 8.2, 3.1 Hz, 1H), 6.73 (br. s, 1H), 6.17 (br. s, 1H) 577.3 A   
I-1247
Figure 02_image2785
 Cn1cncc1C#Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, ACN-d3) : 8.80 (br. s, 1H), 7.89 (s, 1H), 7.69 (s, 1H), 7.66 (dt, 24.4, 8.4 Hz, 1H), 7.61-7.58 (m, 2H), 7.57 (s, 1H), 7.43 (br. s, 1H), 7.34 (br. s, 1H), 7.26 (dd, 9.0, 5.0 Hz, 1H), 6.98 (td, 8.7, 3.0 Hz, 1H), 6.69 (br. s, 1H), 6.14 (br. s, 1H), 3.75 (s, 3H)。 571.4 A   
I-1248
Figure 02_image2787
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCS(=O)(=O)CC1 (400 MHz, CD3CN)  8.59 (br. s, 1H), 7.64 (br. d, 8.0 Hz, 1H), 7.58 (br. d, 8.0 Hz, 1H), 7.57 (br. s, 1H), 7.32 (d, 2.3 Hz, 1H), 7.25 (dd, 8.9, 5.1 Hz, 1H), 7.17 (d, 2.0 Hz, 2H), 6.96 (td, 8.0, 3.1 Hz, 1H), 6.64 (br. s, 1H), 6.06 (br. s, 1H), 3.97-3.88 (m, 4H), 3.14-3.07 (m, 4H)。 600.2 A   
I-1249
Figure 02_image2789
 CN1CCN(CC1=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, CD3CN)  8.54 (br. s, 1H), 7.65-7.53 (m, 3H), 7.23-7.19 (m, 2H), 7.13 (s, 1H), 7.05 (d, 2.1 Hz, 1H), 6.93 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.60 (br. s, 1H), 6.00 (br. s, 1H), 3.84 (s, 2H), 3.62-3.50 (m, 2H), 3.49-3.39 (m, 2H), 2.93 (s, 3H)。 579.4 A   
I-1250
Figure 02_image2791
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-n1ccc2ncccc2c1=O (400 MHz, CD3CN)  8.92 (dd, 4.6, 1.7 Hz, 1H), 8.75 (br. s, 1H), 8.60 (dd, 8.0, 1.3 Hz, 1H), 7.80 (d, 1.8 Hz, 1H), 7.71 (s, 1H), 7.65-7.57 (m, 3H), 7.56-7.53 (m, 1H), 7.49 (dd, 8.1, 4.6 Hz, 1H), 7.34 (s, 1H), 7.26 (dd, 8.9, 5.2 Hz, 1H), 7.00-6.94 (m, 1H), 6.82 (d, 7.6 Hz, 1H), 6.71 (br. s, 1H), 6.18 (br. s, 1H)。 611.3 A   
I-1251
Figure 02_image2793
 CC(=O)N1CC(C1)Oc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN)  8.68 (s, 1H), 7.64 (br d, 8.3 Hz, 1H), 7.58 (d與m重疊, 8.3 Hz, 1H), 7.56 (s, 1H) 7.31 (s, 1H), 7.25 (dd, 8.9, 5.1 Hz, 1H), 7.08 (s, 2H), 6.96 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.64 (br s, 1H), 6.07 (br s, 1H), 5.13-5.06 (m, 1H), 4.61-4.53 (m, 1H), 4.33 (dd, 10.5, 6.6 Hz, 1H), 4.16 (ddd, 6.6, 5.6, 2.7 Hz, 1H), 3.88 (dd, 10.6, 3.5 Hz, 1H), 1.81 (s, 3H)。 580 B   
I-1252
Figure 02_image2795
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OC3CNC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, CD3CN)  9.04 (s, 1H), 7.72-7.54 (m, 4H), 7.45 (s, 1H), 7.24 (dd, 8.9, 5.1 Hz, 1H), 7.11 (d, 5.8 Hz, 1H), 6.95 (td, 8.4, 3.0 Hz, 1H), 6.65 (br s, 1H), 6.08 (br s, 1H), 5.30-5.18 (m, 1H), 4.64-4.47 (m, 2H), 4.30-4.10 (m, 2H), 3.89 (dd, 11.8, 5.3 Hz)。 538 B   
I-1253
Figure 02_image2797
 CC(C)Oc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.41 (s, 1H), 9.11 (s, 1H), 7.94 (d, 8.0 Hz, 1H), 7.71 (d, 9.6 Hz, 1H), 7.62 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.17 (d, 2.1 Hz, 1H), 7.08 (td, 8.5, 3.1 Hz, 1H), 7.02 (s, 1H), 6.59 (br. s, 1H), 5.92 (br. s, 1H), 4.75 (m, 1H), 1.32 (dd, 6.0, 3.5 Hz, 6H) 525.2 A   
I-1254
Figure 02_image2799
 CS(C)(=O)=Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.40 (br. s, 1H), 9.03 (br. s, 1H), 7.93 (br. d, 8.5 Hz, 1H), 7.71 (br. d, 9.0 Hz, 1H), 7.61 (s, 1H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.19 (d, 1.8 Hz, 1H), 7.07 (td, 8.4, 3.0 Hz, 1H), 7.02 (d, 1.8 Hz, 1H), 6.62 (br. s, 1H), 5.89 (br. s, 1H), 3.29 (s, 6H)。 558.2 B   
I-1255
Figure 02_image2801
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CNCCS1(=O)=O NMR (400 MHz, CD3CN)  8.71 (br s, 1H), 7.77 (d, 2.6 Hz, 1H), 7.71-7.56 (m, 5H), 7.38-7.29 (m, 1H), 7.25 (dd, 8.9, 5.1 Hz, 1H), 6.97 (td, 8.4, 3.0 Hz, 1H), 6.65 (br s, 1H), 6.14 (br s, 1H), 4.33-4.38 (m, 1H), 3.43-3.51 (m, 3H), 3.24-3.26 (m, 1H), 3.12-3.14 (m, 2H)。 600.2 A   
I-1256
Figure 02_image2803
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)NC34CC5CC(C3)CC(C5)(C4)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  9.14 (br. s, 1H), 7.99 (s, 1H), 7.66 (br. s, 1H), 7.53 (d, 1.7 Hz, 1H), 7.46 (dd, 8.2, 5.0 Hz, 1H), 7.23 (ddd, 8.8, 8.1, 3.1 Hz, 1H), 6.68 (br. s, 1H), 6.24 (s, 1H), 6.02 (br. s, 1H), 2.18-2.12 (m, 2H), 1.96 (d, 11.9 Hz, 1H), 1.93-1.84 (m, 2H), 1.80 (d, 11.8 Hz, 1H), 1.66-1.54 (m, 8H)。 602.2 B   
I-1257
Figure 02_image2805
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)NC34CC5CC(CC(C5)C3)C4)c12 1H-NMR (400 MHz, DMSO-d6)  9.12 (br. s, 1H), 8.24 (br. s, 1H), 7.70 (br. s, 1H), 7.49 (d, 1.7 Hz, 1H), 7.46 (dd, 8.2, 5.2 Hz, 1H), 7.23 (ddd, 8.7, 8.4, 3.1 Hz, 1H), 6.76 (br. s, 1H), 6.23 (s, 1H), 6.03 (br. s, 1H), 2.02-1.95 (m, 3H), 1.86-1.77 (m, 6H), 1.64-1.55 (m, 6H)。 534.2 B   
I-1258
Figure 02_image2807
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Nc3cn[nH]c3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  12.73 (br. s, 1H), 10.30 (s, 1H), 8.94 (br. s, 1H), 7.94-7.86 (m, 2H), 7.69 (br. d, 9.0 Hz, 1H), 7.60 (s, 1H), 7.65-7.55 (m, 2H), 7.29 (dd, 8.9, 5.2 Hz, 1H), 7.06 (app. td, 8.4, 3.1 Hz, 1H), 6.93 (br. s, 1H), 6.86 (br. s, 1H), 6.58 (br. s, 1H), 5.85 (br. s, 1H)。 548.3 A   
I-1259
Figure 02_image2809
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(Nc3cn[nH]c3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  12.73 (br. s, 1H), 10.29 (s, 1H), 8.95 (br. s, 1H), 7.94-7.88 (m, 2H), 7.69 (br. d, 9.3 Hz, 1H), 7.78-7.43 (m, 2H), 7.60 (s, 1H), 7.29 (dd, 8.9, 5.2 Hz, 1H), 7.06 (app. td, 8.4, 3.1 Hz, 1H), 6.94 (s, 1H), 6.85 (br. s, 1H), 6.59 (br. s, 1H), 5.85 (br. s, 1H)。 548.4 D   
I-1260
Figure 02_image2811
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCc2ncccc12       A   
I-1261
Figure 02_image2813
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCc2cnccc12       A   
I-1262
Figure 02_image2815
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCCc2cc(ccc12)C#N       A   
I-1263
Figure 02_image2817
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCc2cc(ccc12)C#N       A   
I-1264
Figure 02_image2819
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccccc1S(F)(=O)=O 1H NMR (400 MHz, DMSO-d6)   5.96 - 6.13 (m, 1 H) 7.12 (td,  8.46, 3.03 Hz, 1 H) 7.34 (dd,  8.84, 5.05 Hz, 1 H) 7.48 (s, 1 H) 7.65 (s, 2 H) 7.69 - 7.76 (m, 2 H) 7.85 (t,  7.71 Hz, 1 H) 7.93 (br d,  8.08 Hz, 1 H) 8.02 (td,  7.58, 1.26 Hz, 1 H) 8.29 (dd,  8.08, 1.01 Hz, 1 H) 9.28 (br s, 1 H) 10.63 (s, 1 H) 625.29 A   
I-1265
Figure 02_image2821
 OC(=O)Cc1ccccc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)   3.56 - 3.60 (m, 2 H) 5.93 - 6.14 (m, 1 H) 7.11 (td,  8.34, 3.03 Hz, 1 H) 7.30 - 7.45 (m, 7 H) 7.57 (d,  1.26 Hz, 1 H) 7.65 (s, 1 H) 7.73 (br d,  9.09 Hz, 1 H) 7.94 (br d,  8.34 Hz, 1 H) 9.21 (br s, 1 H) 10.57 (s, 1 H) 601.28 B   
I-1266
Figure 02_image2823
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CC11CC1 1H NMR (400 MHz, DMSO-d6)   0.68 (br d,  4.29 Hz, 1 H) 0.95 - 1.03 (m, 3 H) 1.15 (dt,  15.22, 4.39 Hz, 1 H) 1.61 (dt,  8.08, 4.04 Hz, 1 H) 2.43 (s, 1 H) 5.83 - 6.05 (m, 1 H) 7.04 - 7.12 (m, 1 H) 7.24 (br d,  6.82 Hz, 1 H) 7.30 (dt,  8.91, 5.40 Hz, 1 H) 7.42 (dd,  4.29, 1.26 Hz, 1 H) 7.65 (br s, 1 H) 7.72 (br d,  8.84 Hz, 1 H) 7.94 (br d,  8.34 Hz, 1 H) 9.08 (br s, 1 H) 10.42 (d,  6.82 Hz, 1 H) 533.35 A   
I-1267
Figure 02_image2825
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCC2(CNC(=O)C2)C1 (400 MHz, DMSO-d6)  10.37 (s, 1 H), 8.96 (s, 1 H), 7.92 (d, 8.6 Hz, 1 H), 7.72 (d, 8.9 Hz, 1 H) 7.68 (s, 1 H), 7.65 (s, 1 H), 7.29 (dd, 8.9, 5.2 Hz, 1 H), 7.06 ((ddd, 8.8, 8.1, 3.1 Hz), 1 H), 6.74 (d, 1.9 Hz, 1 H), 6.71-6.51 (浸沒br. s, 1H), 6.63 (d, 1.3 Hz, 1 H), 5.87 (br s, 1 H), 3.33 - 3.25 (m, 6 H,浸沒在水峰下), 3.35 - 2.20 (m, 2 H), 2.12 - 1.98 (m, 2 H。部分甲酸鹽。 603.4 A   
I-1268
Figure 02_image2827
 CC(C)(C#N)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.64 (s, 1H), 9.22 (s, 1H), 7.93 (d, 7.5 Hz, 1H), 7.84-7.72 (m, 2H), 7.72-7.63 (m, 2H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.5, 3.1 Hz, 1H), 6.67 (br s, 1H), 5.98 (br s, 1H), 1.79 (s, 3H), 1.78 (s, 3H)。 534.3 A   
I-1269
Figure 02_image2829
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCc4cc(Cl)ccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.21 (s, 1H), 8.72 (s, 1H), 7.73 - 7.67 (m, 2H), 7.57 (d, 1.8 Hz, 1H), 7.39 (dd, 8.9, 5.2 Hz, 1H), 7.24 (d, 2.2 Hz, 1H), 7.22 - 7.12 (m, 2H), 6.69 (s, 1H), 5.97 (s, 1H), 3.84 (td, 10.1, 7.0 Hz, 2H), 3.03 (dqd, 20.1, 10.0, 4.8 Hz, 2H)。 536 D   
I-1270
Figure 02_image2831
 Fc1ccc2N(CCc2c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 9.20 (s, 1H), 8.67 (s, 1H), 7.69 (p, 4.4 Hz, 2H), 7.58 (d, 1.8 Hz, 1H), 7.38 (dd, 8.9, 5.1 Hz, 1H), 7.17 (ddd, 8.8, 7.9, 3.1 Hz, 1H), 7.06 (dd, 8.5, 2.7 Hz, 1H), 6.94 (td, 9.0, 2.8 Hz, 1H), 6.70 (s, 1H), 5.97 (s, 1H), 3.84 (td, 10.1, 7.0 Hz, 1H), 3.33 (s, 1H), 3.13 - 2.89 (m, 2H)。 520.05 A   
I-1271
Figure 02_image2833
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cccc4c(Cl)c[nH]c34)c12 1H NMR (400 MHz, DMSO-d6)  11.40 (s, 1H), 10.31 (s, 1H), 9.27 (s, 1H), 7.85 (dd, 2.8, 1.8 Hz, 1H), 7.79 (d, 1.8 Hz, 1H), 7.71 (d, 7.9 Hz, 1H), 7.51 (d, 2.6 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.13 (t, 7.7 Hz, 1H), 7.06 (td, 8.4, 3.0 Hz, 1H),6.92 (s, 1H), 6.12 (s, 1H)。 533.9 C   
I-1272
Figure 02_image2835
 Cn1cncc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO)  10.60 (br s, 1H), 9.23 (br s, 1H), 7.96 (d, 8.3 Hz, 1H), 7.80-7.72 (m, , 3H), 7.67 (s, 1H), 7.62 (s, 1H), 7.33 (dd, 8.8, 5.1 Hz, 1H), 7.23 (s, 1H), 7.10 (td, 8.3, 2.8 Hz, 1H), 6.70 (br s, 1H), 6.03 (br s, 1H), 3.78 (s, 3H)。在8.30處含有0.48莫耳當量甲酸鹽。 547.1 A   
I-1273
Figure 02_image2837
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCCC1=O NMR (400 MHz, ACN)  8.65 (s, 1H), 8.02 (d, 1.9 Hz, 1H), 7.89 (d, 1.9 Hz, 1H), 7.64-7.59 (m, 1H), 7.59-7.53 (m, 2H), 7.26-7.19 (m, 2H), 6.93 (ddd, 8.9, 8.0, 3.1 Hz, 1H), 6.62 (br s, 1H), 6.06 (br s, 1H), 3.95-3.88 (m, 2H), 2.53 (t, 8.0 Hz, 2H), 2.12-2.08 (m, 2H)。被水信號遮蔽之2.10峰。 550 A   
I-1274
Figure 02_image2839
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2OC(=O)NC(c3ccccc3Cl)c12 NMR (400 MHz, DMSO)  10.26 (s, 1H), 8.70 (d, 2.8 Hz, 1H), 7.97 (br. d, 8.2 Hz, 1H), 7.91 (s, 1H), 7.87 (d, 9.1 Hz, 1H), 7.44 (t, 8.1 Hz, 1H), 7.31 (dd, 8.0, 1.3 Hz, 1H), 7.27-7.23 (m, 1H), 7.18-7.13 (m, 2H), 7.07 (br. d, 7.8 Hz, 1H), 7.02 (dd, 7.7, 1.4 Hz, 1H), 6.15 (d, 2.7 Hz, 1H)。 465.1 C   
I-1275
Figure 02_image2841
 CN(C)S(=O)(=O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.60 (br. s, 1H), 9.21 (br. s, 1H), 7.95 (dt, 8.5, 2.0 Hz, 1H), 7.77 (s, 1H), 7.75 (br. d, 8.4 Hz, 1H) 7.66 (s, 1H), 7.55 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.5, 3.1 Hz, 1H), 6.58 (br. s, 1H), 5.97 (br. s, 1H), 4.70-4.58 (m, 2H), 2.76 (s, 6H)。 588.2 A   
I-1276
Figure 02_image2843
 CS(=O)(=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN)  8.81 (br s, 1H), 8.21 (d, 1.5 Hz, 1H), 8.14 (s, 1H), 7.70-7.65 (m, 1H), 7.63-7.58 (m, 1H), 7.55-7.58 (m, 1H), 7.46 (br s, 1H), 7.29 (dd, 8.9, 5.1 Hz, 1H), 7.00 (ddd, 8.9, 8.0, 3.1 Hz, 1H), 6.69 (br s, 1H), 6.23 (br s, 1H), 3.18 (s, 3H)。 543 A   
I-1277
Figure 02_image2845
 CN1CC(NCC1=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN)  8.85 (br s, 1H), 7.76 (s,1H), 7.68-7.56 (m, 4H), 7.39 (s, 1H), 7.25 (dd, 8.9, 5.1 Hz, 1H), 6.96 (td, 8.4, 3.0 Hz, 1H), 6.60 (br s, 1H), 6.11 (br s, 1H), 4.27 (dt, 10.2, 4.0 Hz, 1H), 3.55-3.43 (m, 3H), 3.37 (dd, 20.5, 10.7 Hz, 1H), 2.89 (s, 3H。在2.5處觀測到的DMSO峰 579.2 A   
I-1278
Figure 02_image2847
 OC(c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)c1ccccn1 NMR (400 MHz, DMSO-d6 ) 主要非對映異構體之描述。-´ 10.49 (br. s, 1Hs), 9.12 (br. s, 1H), 8.50 (ddd, 4.8, 1.7, 0.9 Hz, 1H), 7.93 (br. d, 8.3 Hz, 1H), 7.83 (td, 7.7, 1.8 Hz, 1H), 7.72 ( app. d, 9.8 Hz, 2H), 7.66-7.62 (m, 5.9 Hz, 2H), 7.50 (s, 1H), 7.33-7.24 (m, 2H), 7.08 (td, 8.5, 3.1 Hz, 1H), 6.60 (br. s, 1H), 6.40 (br. s, 1H), 5.92 (浸沒br. s, 1H), 5.87 (s, 1H)。2種非對映異構體中之2:1混合物。脂族區域中存在油脂。 574.2 A   
I-1279
Figure 02_image2849
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CC3COC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)   3.12 (dd,  7.71, 4.42 Hz, 2 H) 3.32 - 3.38 (m, 2 H) 4.38 (td,  6.06, 3.79 Hz, 2 H) 4.65 (ddd,  7.64, 6.00, 1.26 Hz, 2 H) 5.83 - 5.97 (m, 1 H) 7.07 (td,  8.46, 3.03 Hz, 1 H) 7.26 - 7.31 (m, 2 H) 7.50 (s, 1 H) 7.63 (s, 1 H) 7.71 (br d,  8.84 Hz, 1 H) 7.93 (br d,  8.59 Hz, 1 H) 9.09 (br s, 1 H) 10.45 (s, 1 H) 537.35 A   
I-1280
Figure 02_image2851
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CN(C1)C1COC1 1H NMR (400 MHz, DMSO-d6)   2.29 (s, 1 H) 3.56 - 3.82 (m, 2 H) 3.92 - 4.31 (m, 4 H) 4.42 - 4.52 (m, 2 H) 4.67 (br t,  6.57 Hz, 2 H) 5.97 (br s, 1 H) 7.03 - 7.13 (m, 1 H) 7.30 (dd,  8.84, 5.31 Hz, 1 H) 7.50 (s, 1 H) 7.66 (s, 1 H) 7.69 - 7.82 (m, 2 H) 7.94 (br d,  8.34 Hz, 1 H) 9.15 (br s, 1 H) 10.53 (s, 1 H) 578.22 A   
I-1281
Figure 02_image2853
 OC1(COC1)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.56 (br. s, 1H), 9.15 (s, 1H), 7.93 (浸沒br. d, 8.7 Hz, 1H), 7.91 (d, 1.5 Hz, 1H), 7.76 (d, 1.4 Hz, 1H), 7.75 (浸沒br. d, 1H), 7.68 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.4, 3.1 Hz, 1H), 6.82 - 6.50 (m, 2H), 6.01 (br. s, 1H), 4.86 (d, 6.6 Hz, 2H), 4.76 (d, 6.5 Hz, 1H), 4.71 (d, 6.5 Hz, 1H)。 539.2 A   
I-1282
Figure 02_image2855
 Oc1cc(Cl)cc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.24 (s,2H), 9.26 (s, 1H), 7.78-7.73 (d, 1.8 Hz, 2H), 7.38 (dd, 8.8, 5.2 Hz, 1H), 7.15 (ddd, 8.8, 7.9, 3.1 Hz, 1H), 6.96 (d, 1.6 Hz, 2H), 6.87 (t, 1.7 Hz, 1H), 6.66 (s, 1H), 6.00 (s, 1H) 510.09 B   
I-1283
Figure 02_image2857
 Oc1cc(F)cc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.24-10.19 (m, 2H), 9.26 (s, 1H), 7.78-7.72 (m, 2H), 7.38 (dd, 8.9, 5.1 Hz, 1H), 7.14 (ddd, 8.8, 7.9, 3.1 Hz, 1H), 6.90-6.84 (m, 1H), 6.79-6.66 (m, 2H), 6.00 (s, 1H)。 495 D   
I-1284
Figure 02_image2859
 [O-][n+]1cccc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.51 (s, 1H), 9.29 (s, 1H), 8.40-8.34 (m, 1H), 8.29-8.24 (m, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.56-7.43 (m, 2H), 7.38 (dd, 8.9, 5.2 Hz, 1H), 7.20-7.10 (m, 1H), 5.97 (s, 1H)。 477.85 E   
I-1285
Figure 02_image2861
 FC(F)OCc1cc(F)cc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 9.37 (d, 60.3 Hz, 1H), 8.08 (s, 2H), 7.59 (s, 1H), 7.44-7.00 (m, 4H), 6.80 (d, 53.5 Hz, 1H), 6.30 (d, 149.1 Hz, 1H), 5.46 (t, 5.6 Hz, 1H), 4.51 (d, 5.7 Hz, 2H)。 557 E   
I-1286
Figure 02_image2863
 FC(F)Oc1ccc(cc1F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.33 (s, 1H), 9.28 (s, 1H), 7.81 (d, 1.7 Hz, 1H), 7.73 (d, 1.7 Hz, 1H), 7.59 - 7.31 (m, 5H), 7.13 (td, 8.4, 3.1 Hz, 1H), 6.34 - 6.87(s, 1H), 6.00 (s, 1H)。 544.9 D   
I-1287
Figure 02_image2865
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NS(=O)(=O)N3CCc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  9.93 (s, 1H), 9.24 (s, 1H), 7.61 (s, 1H), 7.48 (s, 1H), 7.27 - 7.16 (m, 3H), 7.04 - 6.90 (m, 3H), 6.76 (s, 1H), 6.08 (s, 1H), 3.81 - 3.72 (m, 1H), 3.65 (td, 10.1, 6.6 Hz, 1H), 3.09 - 2.88 (m, 2H)。 536 E   
I-1288
Figure 02_image2867
 CC(F)c1cc(F)cc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.38 (s, 1H), 9.28 (s, 1H), 7.81 (d, 1.7 Hz, 1H), 7.75 (d, 1.7 Hz, 1H), 7.43 (dd, 19.9, 9.3 Hz, 2H), 7.38 - 7.27 (m, 2H), 7.12 (tt, 8.7, 3.2 Hz, 1H), 6.72 (s, 2H), 6.00 (s, 1H), 5.85 - 5.65 (m, 1H), 2.08 (s, 0H), 1.59 (ddd, 24.4, 6.4, 1.9 Hz, 3H)。 523 B   
I-1289
Figure 02_image2869
 O[C@H]1CC[C@@H]1Oc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.46 (br. s, 1H), 9.12 (br. s, 1H), 7.95 (d, 8.4 Hz, 1H), 7.71 (d, 9.1 Hz, 1H), 7.62 (s, 1H), 7.33 - 7.28 (m, 2H), 7.15-7.01 (m, 2H), 6.58 (br. s, 1H), 5.91 (br. s, 1H), 5.75 (t, 8.0 Hz, 1H), 4.44 (q, 7.5 Hz, 1H), 4.15-3.95 (m, 1H), 2.25-2.19 (m, 1H), 2.12 - 2.03 (m, 1H), 1.56-1.35 (m, 2H) 553.2 B   
I-1290
Figure 02_image2871
 NCC(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO)  10.58 (br s, 1H), 9.13 (br s, 1H), 8.23 (s, 1H), 7.91 (d, 8.3 Hz, 1H), 7.75-7.68 (m, 1 H), 7.64 (d, 7.5 Hz, 1 H), 7.49 (d, 16.8 Hz, 1H), 7.31-7.25 (m, 1 H), 7.35-6.94 (m, 2 H), 7.09-7.02 (m, 1 H), 5.96 (br s, 1H), 4.87 (ddd, 12.6, 8.9, 3.1 Hz, 1H), 3.10-2.99 (m, 1H), 2.88-2.78 (m, 1H)。 526.1 B   
I-1291
Figure 02_image2873
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CC2CNCC2C1=O (400 MHz, CD3CN)  8.70 (br. s, 1H), 8.14 (s, 1H), 8.11 (dd, 6.0, 1.9 Hz, 1H), 7.93 (dd, 9.9, 1.8 Hz, 1H), 7.65 (d, 7.5 Hz, 1H), 7.59 (d, 7.5 Hz, 1H), 7.58 (s, 1H), 7.27 (br. s, 1H), 7.25 (dd, 9.0, 5.1 Hz, 1H), 6.96 (td, 8.5, 3.0 Hz, 1H), 6.65 (br. s, 1H), 6.09 (br. s, 1H), 4.17 (dd, 17.2, 9.0 Hz, 1H), 3.65 (ddd, 9.8, 6.7, 2.8 Hz, 1H), 3.28 (d, 10.8 Hz, 1H), 3.18 (t, 8.3 Hz, 1H), 3.04-2.91 (m, 4H)。 591.3 A   
I-1292
Figure 02_image2875
 CC(c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)S(C)(=O)=O NMR (400 MHz, CD3 CN ) 8.68 (s, 1H), 7.79 - 7.72 (m, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.62 - 7.56 (m, 3H), 7.32 - 7.22 (m, 2H), 6.97 (td, J = 8.4, 2.6 Hz, 1H), 6.63 (br, s, 1H), 6.11 (br, s, 1H), 5.55- 5.46 (m, 1H), 2.68- 2.61 (m, 3H), 1.68-1.63 (m, 3H)。 573 A   
I-1293
Figure 02_image2877
 Cn1nccc1Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)  10.51 (br. s, 1H), 9.15 (br. s, 1H), 7.94 (br. d, 9.0 Hz, 1H), 7.71 (br. d, 9.7 Hz, 1H), 7.62 (br. s, 1H), 7.53 (br. s, 1H), 7.34 (d, 1.8 Hz, 1H), 7.31 (dd, 8.9, 5.1 Hz, 1H), 7.30-7.28 (m, 1H), 7.08 (app. td, 8.5, 3.1 Hz, 1H), 6.59 (br. s, 1H), 6.09 (s, 1H), 5.94 (br. s, 1H), 4.27-4.18 (m, 2H), 3.71 (s, 3H)。 561.3 A   
I-1294
Figure 02_image2879
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)NC3(CC3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  9.19 (br. s, 1H), 8.11 (s, 1H), 7.72 (br. s, 1H), 7.59 (d, 1.6 Hz, 1H), 7.53-7.43 (m, 1H), 7.36 (s, 1H), 7.23 (app. td, 8.5, 3.1 Hz, 1H), 6.69 (br. s, 1H), 5.97 (br. s, 1H), 1.22-1.17 (m, 1H), 1.16-1.09 (m, 1H), 1.07-0.99 (m, 1H), 0.87-0.78 (m, 1H)。 506.2 D   
I-1295
Figure 02_image2881
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(O[C@H]3C[C@H](C3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO)  10.44 (br. s, 1H), 9.14 (br. s, 1H), 7.94 (br. d, 8.5 Hz, 1H), 7.73-7.68 (m, 1H), 7.62 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.13-7.04 (m, 2H), 7.01 (d, 1.9 Hz, 1H), 6.62 (br. s, 1H), 5.91 (s, 1H), 4.90-4.80 (m, 1H), 3.22-3.05 (m, 1H), 3.02-2.89 (m, 2H), 2.48-2.32 (m, 2H) 562.2 A   
I-1296
Figure 02_image2883
 CS(=O)(=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)(c1cc(F)ccc1Cl)S(O)(=O)=O (400 MHz, DMSO-d6)  10.93 (s, 1 H), 9.87 (s, 1 H), 8.77 (dd, 11.7, 3.1 Hz, 1 H), 8.66 (d, 1.5 Hz, 1 H), 8.02 (d, 8.5 Hz, 1 H), 8.00 (d, 1.6 Hz, 1 H), 7.79 (s, 1 H), 7.71 (d, 9.0 Hz, 1 H), 7.26 (dd, 8.8, 5.6 Hz, 1 H), 7.24-7.16 (m, 1 H), 7.10 (ddd, 8.8, 7.5, 3.1 Hz, 1 H), 6.95 (br s, 1 H), 3.35 (s, 3 H)。 623.3 D   
I-1297
Figure 02_image2885
 CC(C)(C)OC(=O)NCCSc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN)  8.70 (brs, 1H), 7.70 (d, 1.4 Hz, 1H), 7.64 (br d, 8.3 Hz, 1H), 7.59 (br d, 8.4 Hz, 1H), 7.58 (s, 1H), 7.27 (br s, 1H), 7.25 (dd, 8.9, 5.1 Hz, 1H), 6.96 (td, 8.4, 3.0 Hz, 1H), 6.67 (brs, 1H), 6.09 (brs, 1H), 5.57 (brs, 1H), 3.30 (q, 6.5 Hz, 2H), 3.18-3.11 (m, 2H), 1.39 (s, 9H)。 642.2 B   
I-1298
Figure 02_image2887
 NCCOc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.47 (br s, 1H), 9.12 (s, 1H), 7.94 (d, 8.3 Hz, 1H), 7.71 (d, 8.9 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.22 (d, 2.2 Hz, 1H), 7.12-7.03 (m, 2H), 6.57 (br s, 1H), 5.93 (br s, 1H), 4.19-4.06 (m, 2H), 3.35 (br s, 3H), 3.02 (t, 5.3 Hz, 2H) 526.2 B   
I-1299
Figure 02_image2889
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CC2(CNC2)C1 NMR (400 MHz, DMSO-d6)  10.46 (br. s, 1H), 9.00 (br. s, 1H), 7.92 (br. d, 9.2 Hz, 1H), 7.72 (br. d, 8.3 Hz, 1H), 7.64 (s, 1H), 7.28 (dd, 8.7, 5.1 Hz, 1H), 7.06 (td, 8.3, 3.2 Hz, 1H), 6.66 (d, 1.7 Hz, 1H), 6.52 (d, 1.2 Hz, 1H), 6.75-6.40 (br. s, 1H), 5.87 (br. s, 1H), 4.04-3.99 (m, 4H), 3.94-3.86 (m, 4H) 561.3 B   
I-1300
Figure 02_image2891
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ccncc2n1 NMR (400 MHz, ACN-d3)  9.00 (s, 1H), 8.88 (br. s, 1H), 8.41 (s, 1H), 8.32 (dd, 4.5, 1.1 Hz, 1H), 8.29 (m, 2H), 7.86 (d, 4.6 Hz, 1H), 7.68-7.61 (m, 2H), 7.60 (s, 1H), 7.41 (s, 1H), 7.27 (dd, 8.9, 5.1 Hz, 1H), 6.98 (td, 8.5, 3.1 Hz, 1H), 6.73 (br. s, 1H), 6.18 (br. s, 1H) 582.4 A   
I-1301
Figure 02_image2893
 CC(=O)N1CC2(C1)CN(C2)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.43 (br. s, 1H), 9.02 (br. s, 1H), 7.93 (br. d, 8.6 Hz, 1H), 7.72 (br. d, 9.2 Hz, 1H), 7.64 (s, 1H), 7.29 (dd, 9.0, 5.1 Hz, 1H), 7.07 (td, 8.3, 3.3 Hz, 1H), 6.67 (d, 1.7 Hz, 1H), 6.54 (br. s, 1H), 6.75-6.40 (br. s, 1H), 5.87 (br. s, 1H), 4.35-4.29 (m, 2H), 4.10-4.01 (m, 6H), 1.76 (s, 3H) 603.3 B   
I-1302
Figure 02_image2895
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CC3CCO3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)   2.37 - 2.45 (m, 1 H) 2.59 - 2.69 (m, 1 H) 3.04 - 3.22 (m, 2 H) 4.38 (tt,  9.00, 5.78 Hz, 1 H) 4.45 - 4.56 (m, 1 H) 4.92 - 5.04 (m, 1 H) 5.79 - 6.08 (m, 1 H) 7.09 (td,  8.34, 3.03 Hz, 1 H) 7.26 - 7.39 (m, 2 H) 7.55 - 7.79 (m, 3 H) 7.95 (br d,  8.59 Hz, 1 H) 9.12 (br s, 1 H) 10.45 - 10.56 (m, 1 H) 537.25 A   
I-1303
Figure 02_image2897
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccnn1CC#N 1H NMR (400 MHz, DMSO-d6)   5.57 (s, 2 H) 5.91 - 6.22 (m, 1 H) 6.66 (d,  2.02 Hz, 1 H) 7.11 (td,  8.40, 2.91 Hz, 1 H) 7.33 (dd,  8.84, 5.05 Hz, 1 H) 7.59 - 7.67 (m, 2 H) 7.70 - 7.76 (m, 2 H) 7.79 (d,  1.52 Hz, 1 H) 7.96 (br d,  8.34 Hz, 1 H) 9.23 - 9.40 (m, 1 H) 572.17 A   
I-1304
Figure 02_image2899
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(O[C@H]3C[C@@H](C3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12       D   
I-1305
Figure 02_image2901
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(O[C@H]3C[C@@H](C3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12       A   
I-1306
Figure 02_image2903
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ncccc2n1 NMR (400 MHz, DMSO-d6)  10.65 (br. s, 1H), 9.22 (br. s, 1H), 9.11 (s, 1H), 8.54 (dd, 4.5, 1.6 Hz, 1H), 8.37 (s, 1H), 8.25 (d, 0.8 Hz, 1H), 8.17 (ddd, 9.6, 1.2, 0.8 Hz, 1H), 7.97 (br. d, 8.3 Hz, 1H), 7.79 (br. d, 9.6 Hz, 1H), 7.72 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.28 (dd, 9.2, 4.5 Hz, 1H), 7.10 (td, 8.6, 3.0 Hz, 1H), 6.68 (br. s, 1H), 6.03 (br. s, 1H) 584.3 A   
I-1307
Figure 02_image2905
 CC(C)(O)C(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO d6) 10.50 (br. s, 1H), 9.09 (br. s, 1H), 7.94 (br. d, 8.2 Hz, 1H), 7.73 (br. d, 7.6 Hz, 1H), 7.70 (s, 1H), 7.64 (s,1H), 7.46 (s, 1H), 7.32-7.28 (m, 1H), 7.09 (td, 8.4, 3.0 Hz, 1H), 6.50 (br s, 1H), 5.97 (br s, 1H), 5.54 (d, 4.5 Hz, 1H), 4.45-4.44 (m, 2H), 1.15 (s, 3H), 0.97 (s, 3H) 555.3 B   
I-1308
Figure 02_image2907
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CNC(=O)CO1 NMR (400 MHz, MeOD)  8.54 (s, 1H), 7.90 (d, 3.7 Hz, 1H), 7.73-7.59 (m, 4H), 7.28 (dd, 8.9, 5.1 Hz, 1H), 7.03-6.96 (m, 1H), 6.57 (br s, 1H) 6.19 (br s, 1H), 5.08-5.00 (m, 1H), 4.40 (s, 2H), 3.68-3.62 (m, 1H), 3.52-3.42 (m, 1H)。 566.1 A   
I-1309
Figure 02_image2909
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CC2CNC(=O)C2C1 NMR (400 MHz, CD3CN)  8.53 (br. s, 1H), 7.64 (d, 8.3 Hz, 1H), 7.58 (d, 8.3 Hz, 1H),  7.57 (s, 1H), 7.26-7.21(m, 1H), 7.11 (br. s, 1H), 6.98-6.90 (m, 2H), 6.81 (s, 1H), 6.62 (br. s, 1H), 6.09 (s, 1H), 6.01 (br. s, 1H), 3.68-3.61  (m, 2H), 3.58 (dd, 9.9, 6.6 Hz, 1H), 3.45 (t, 7.8 Hz, 1H), 3.32-3.17 (m, 3H), 3.08 (t, 7.7 Hz, 1H) 591.3 A   
I-1310
Figure 02_image2911
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CC2(CCO2)C1 NMR (400 MHz, DMSO-d6 )  10.40 (s, 1H), 9.01 (br. s, 1H), 7.93 (br. d, 8.3 Hz, 1H), 7.71 (br. d, 8.6 Hz, 1H), 7.64 (s, 1H), 7.29 (dd, 8.8, 5.1 Hz, 1H), 7.06 (td, 8.5, 3.0 Hz, 1H), 6.69 (d, 1.6 Hz, 1H), 6.55 (浸沒br. s, 1H), 6.53 (s, 1H), 5.86 (br. s, 1H), 4.46 (t, 7.4 Hz, 2H), 4.18 (dd, 14.8, 9.0 Hz, 2), 3.96 (dd, 15.1, 8.9 Hz, 2H), 2.90 (t, 7.5 Hz, 2H)。 564.3 B   
I-1311
Figure 02_image2913
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1csc(n1)C#N NMR (400 MHz, CDC3CN/DMSO-d6)  10.27 (br s, 1H), 8.59 (br s, 1H), 8.53 (s, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 7.69-7.77 (m, 2H), 7.67 (br d, 1H), 7.24 (dd, 8.6, 5.3 Hz, 1H), 6.95 (td, 7.9, 3.1 Hz, 1H), 6.66 (br s, 1H), 6.16 (br s, 1H)。 575 A   
I-1312
Figure 02_image2915
 CS(=O)(Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)=NC#N NMR (400 MHz, DMSO-d6)  10.68 (br. s, 1H), 9.29 ( s, 1H), 7.95 (br. d, 8.3 Hz, 1H), 7.84 (s, 1H), 7.73 (br. d, 8.9 Hz, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.4, 2.9 Hz, 1H), 6.65 (br. s, 1H), 6.03 (br. s, 1H), 5.29-5.18 (m, 2H), 3.45 (s, 3H)。 583.1 A   
I-1313
Figure 02_image2917
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccc(OC(F)(F)F)c(F)c3)c12 1H NMR (400 MHz, DMSO-d6)  10.41 (s, 1H), 9.27 (s, 1H), 7.81 (d, 1.7 Hz, 1H), 7.75 - 7.67 (m, 2H), 7.62 (dd, 11.0, 2.1 Hz, 1H), 7.54 (dd, 8.3, 2.0 Hz, 1H), 7.35 (dd, 8.9, 5.2 Hz, 1H), 7.12 (td, 8.4, 3.1 Hz, 1H), 6.75 (s, 1H), 5.97 (s, 1H)。 560.8 D   
I-1314
Figure 02_image2919
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cccc(SC(F)(F)F)c3)c12 1H NMR (400 MHz, DMSO-d6)  10.44 (s, 1H), 9.27 (s, 1H), 7.91 (d, 7.6 Hz, 1H), 7.86 - 7.77 (m, 3H), 7.74 (d, 1.8 Hz, 1H), 7.63 (t, 7.8 Hz, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.4, 3.1 Hz, 1H), 6.69 (s, 1H), 6.01 (s, 1H)。 558.95 D   
I-1315
Figure 02_image2921
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3n[nH]c4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 12.28 (s, 1H), 9.13 (s, 1H), 8.18 (s, 1H), 8.08-8.03 (m, 1H), 7.42-7.35 (m, 2H), 7.31 (ddt, 7.7, 4.7, 2.1 Hz, 3H), 7.14-7.02 (m, 1H), 6.97 (ddd, 7.9, 6.8, 0.9 Hz, 1H), 6.79 (s, 1H), 6.08 (s, 1H)。 471 E   
I-1316
Figure 02_image2923
 COCc1cc(F)cc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.34 (s, 1H), 9.27 (s, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.40 - 7.31 (m, 3H), 7.23 (d, 9.4 Hz, 1H), 7.14 (td, 8.4, 3.0 Hz, 1H), 6.66 (s, 1H), 6.00 (s, 1H), 4.44 (s, 2H), 3.29 - 3.32 (m, 3H) 521 D   
I-1317
Figure 02_image2925
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(-c3cc4c(Cl)cc(F)cc4[nH]3)c12 1H NMR (400 MHz, DMSO-d6) 11.85 (s, 1H), 9.28 (s, 1H), 7.90 (d, 7.4 Hz, 1H), 7.82 (dd, 7.6, 1.2 Hz, 1H), 7.75 (t, 7.5 Hz, 1H), 7.31 (s, 1H), 7.09 (ddd, 9.4, 2.2, 0.9 Hz, 1H), 7.05-6.95 (m, 2H), 6.56-6.50 (m, 2H), 6.35 (s, 1H)。 428.95 B   
I-1318
Figure 02_image2927
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)n3ccc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 10.07 (s, 1H), 9.30 (s, 1H), 8.02 (d, 8.1 Hz, 1H), 7.82 (m, 2H), 7.76 (s, 1H), 7.59 (d, 7.6 Hz, 1H), 7.38 - 7.06 (m, 5H), 6.65 (d, 3.7 Hz, 1H), 6.05 (s, 1H)。 499.9 A   
I-1319
Figure 02_image2929
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc4oc(=O)[nH]c34)c12 1H NMR (400 MHz, DMSO-d6) 11.85 (s, 1H), 10.40 (s, 1H), 9.27 (s, 1H), 8.52 - 7.59 (m, 3H), 7.30 (s, 1H), 7.10 - 6.90 (m, 3H), 5.98 (s, 1H)。 535.95 D   
I-1320
Figure 02_image2931
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OC3CN(C3)C(=O)C(F)(F)F)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.48 (s, 1H), 9.20 (br s, 1H), 7.96 (d, 8.5 Hz, 1H), 7.71 (d, 8.9 Hz, 1H), 7.61 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.12-7.06 (m, 2H), 7.06-7.01 (m, 1H), 6.56 (br s, 1H), 5.94 (br s, 1H), 5.33-5.24 (m, 1H), 5.00-4.90 (m, 1H), 4.62 (dd, 11.3, 6.7 Hz, 1H), 4.52-4.41 (m, 1H), 4.19-4.10 (m, 1H)。 634.2 B   
I-1321
Figure 02_image2933
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(C[n+]3ccccc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, CD3CN)  8.95 (d, 6.0 Hz, 2H), 8.52 (t, 7.8 Hz, 1H), 8.39 (s, 2H), 8.05 (t, 6.9 Hz, 2H), 7.85 (s, 1H), 7.80 (s, 1H), 7.76-7.70 (m, 2H), 7.60 (d, 8.4 Hz, 1H), 7.55 (s, 1H), 7.20 (dd, 8.8, 5.1 Hz, 1H), 6.91 (td, 8.4, 2.9 Hz, 1H), 6.67 (br s, 1H), 6.19 (s, 1H), 5.86 (s, 2H)。 558.3 A   
I-1322
Figure 02_image2935
 CC(=O)NCCOc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.47 (s, 1H), 9.14 (s, 1H), 8.16 (t, 5.2 Hz, 1H), 7.95 (d, 8.1 Hz, 1H), 7.71 (d, 8.7 Hz, 1H), 7.63 (s, 1H), 7.31 (dd, 8.8, 5.1 Hz, 1H), 7.20 (s, 1H), 7.08 (d, 8.3 Hz, 2H), 6.54 (br s, 1H), 5.92 (br s, 1H), 4.18-4.04 (m, 2H), 3.45 (dd, 11.0, 5.6 Hz, 2H), 1.83 (s, 3H)。 568.1 B   
I-1323
Figure 02_image2937
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C3CCCC(C3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)，呈非對映異構體之約1:1混合物形式-´ 9.98 (br. s, 1H), 9.91 (br. s, 1H), 9.26 (br. s, 2H), 7.72-7.69 (m, 2H), 7.61 (d, 1.7 Hz, 1H), 7.58 (d, 1.7 Hz, 1H), 7.53-7.41 (m, 2H), 7.25-7.17 (m, 2H), 6.54 (br. s, 2H), 6.01 (br. s, 2H), 2.30-2.20 (m, 2H), 2.19-2.09 (m, 2H), 1.81-1.68 (m, 4H), 1.58 (d, 12.8 Hz, 1H), 1.50 (d, 12.8 Hz, 1H), 1.42-1.31 (m, 2H), 1.27-1.16 (m, 2H), 1.13-0.93 (m, 6H)。 533.2 B   
I-1324
Figure 02_image2939
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C3CCC(CC3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  9.78 (br. s, 1H), 9.26 (br. s, 1H), 7.75 (d, 1.6 Hz, 1H), 7.69 (d, 1.6 Hz, 1H), 7.53-7.45 (m, 1H), 7.23 (app. td, 8.4, 3.1 Hz, 1H), 6.52 (br. s, 1H), 6.08 (br. s, 1H), 2.38-2.34 (m, 1H), 2.24-2.12 (m, 1H), 1.66-1.58 (m, 1H), 1.57-1.31 (m, 5H), 1.29-1.14 (m, 2H)。 533.2 D   
I-1325
Figure 02_image2941
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)[C@H]1C[C@@H](C1)C#N NMR (400 MHz, CD3CN)  8.64 (s,1H), 7.68-7.56 (m, 4H), 7.42 (d, 6.9 Hz,1H), 7.30-7.22 (m, 2H), 7.02-6.92 (m,1H), 6.60 (br, s,1H), 6.09 (br, s, 1H), 3.78-3.67 (m,1H), 3.31-3.19 (m,1H), 2.88-2.80 (m,1H), 2.78-2.70 (m,1H), 2.69-2.59 (m,1H), 2.56-2.44 (m,1H) 546 B   
I-1326
Figure 02_image2943
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)[C@H]1C[C@@H](C1)C#N NMR (400 MHz, CD3CN)  8.64 (s,1H), 7.68-7.56 (m, 4H), 7.42 (d, 6.9 Hz,1H), 7.30-7.22 (m, 2H), 7.02-6.92 (m,1H), 6.60 (br, s,1H), 6.09 (br, s, 1H), 3.78-3.67 (m,1H), 3.31-3.19 (m,1H), 2.88-2.80 (m,1H), 2.78-2.70 (m,1H), 2.69-2.59 (m,1H), 2.56-2.44 (m,1H) 546 A   
I-1327
Figure 02_image2945
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)[C@@H]1C[C@@H](C1)C#N NMR (400 MHz, CD3CN)  8.64 (s,1H), 7.68-7.56 (m, 4H), 7.42 (d, 6.9 Hz,1H), 7.30-7.22 (m, 2H), 7.02-6.92 (m,1H), 6.60 (br, s,1H), 6.09 (br, s, 1H), 3.78-3.67 (m,1H), 3.31-3.19 (m,1H), 2.88-2.80 (m,1H), 2.78-2.70 (m,1H), 2.69-2.59 (m,1H), 2.56-2.44 (m,1H) 546 A   
I-1328
Figure 02_image2947
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)[C@@H]1C[C@@H](C1)C#N NMR (400 MHz, CD3CN)  8.64 (s,1H), 7.68-7.56 (m, 4H), 7.42 (d, 6.9 Hz,1H), 7.30-7.22 (m, 2H), 7.02-6.92 (m,1H), 6.60 (br, s,1H), 6.09 (br, s, 1H), 3.78-3.67 (m,1H), 3.31-3.19 (m,1H), 2.88-2.80 (m,1H), 2.78-2.70 (m,1H), 2.69-2.59 (m,1H), 2.56-2.44 (m,1H) 546 B   
I-1329
Figure 02_image2949
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ccnc2cn1    584.2 D   
I-1330
Figure 02_image2951
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ccnc2cn1    584.2 A   
I-1331
Figure 02_image2953
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nccn2n1    584.2 D   
I-1332
Figure 02_image2955
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nccn2n1    584.2 A   
I-1333
Figure 02_image2957
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(O[C@H]3C[C@H](C3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    561 D   
I-1334
Figure 02_image2959
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(O[C@H]3C[C@H](C3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    561 A   
I-1335
Figure 02_image2961
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ncnc2cn1    585.5 A   
I-1336
Figure 02_image2963
 CS(=O)(=O)Cn1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO-d6)  3.06 (s, 3 H) 5.77 (d,  0.92 Hz, 2 H) 5.89 - 6.10 (m, 1 H) 7.08 (td,  8.35, 2.98 Hz, 1 H) 7.31 (dd,  8.85, 5.19 Hz, 1 H) 7.69 (s, 1 H) 7.71 - 7.78 (m, 2 H) 7.94 (br s, 2 H) 8.27 (s, 1 H) 8.47 (s, 1 H) 9.14 (br s, 1 H) 10.53 (s, 1 H) 625.24 A   
I-1337
Figure 02_image2965
 OC(c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)C1(O)COC1    569.22 B   
I-1338
Figure 02_image2967
 OC1(COc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)COC1    569.17 B   
I-1339
Figure 02_image2969
 OCC1(Cc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)COC1 1H NMR (500 MHz, DMSO)  10.45 (s, 1H), 9.08 (s, 1H), 7.92 (dt, 8.6, 2.1 Hz, 1H), 7.72 (d, 9.1 Hz, 1H), 7.64 (s, 1H), 7.54 (d, 1.5 Hz, 1H), 7.35-7.25 (m, 2H), 7.12-6.98 (m, 1H), 6.59 (s, 1H), 5.93 (s, 1H), 5.02 (s, 1H), 4.45 (dd, 12.2, 5.8 Hz, 2H), 4.28 (dd, 20.6, 5.8 Hz, 2H), 3.52 (d, 10.9 Hz, 1H), 3.47 (d, 11.0 Hz, 1H), 3.13 (d, 13.4 Hz, 1H), 3.06 (d, 13.4 Hz, 1H)。 567.22 A   
I-1340
Figure 02_image2971
 OCCn1nccc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    577.22 A   
I-1341
Figure 02_image2973
 OCC(O)COc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DSMO-d6)  10.50 (br s, 1H), 9.17 (s, 1H), 7.95 (d, 9.2 Hz, 1H), 7.71 (d, 8.8 Hz, 1H), 7.63 (s, 1H), 7.31 (dd, 8.8, 5.2 Hz, 1H), 7.19 (d, 1.9 Hz, 1H), 7.13-7.04 (m, 2H), 6.49 (br s, 1H), 5.97 (br s, 1H), 5.05 (d, 5.1 Hz, 1H), 4.74 (t, 5.4 Hz, 1H), 4.13 (td, 9.5, 3.9 Hz, 1H), 4.06-3.90 (m, 1H), 3.90-3.75 (m, 1H), 3.47 (t, 5.5 Hz, 2H)。 557.2 A   
I-1342
Figure 02_image2975
 OCN1C(c2c(cc(cc2NC(=O)c2cc(F)cc(c2)C(F)(F)F)-c2ccc3ncnn3c2)C1=O)c1cc(F)ccc1Cl (400 MHz, DMSO)  10.67 (d, 35.5 Hz, 1H), 9.50 (s, 1H), 8.58 (s, 1H), 8.30-8.11 (m, 2H), 8.07-7.91 (m, 3H), 7.89-7.74 (m, 2H), 7.42-7.27 (m, 1H), 7.19-7.07 (m, 1H), 6.47-6.37 (m, 1H), 6.18 (t, 7.0 Hz, 1H), 6.09-5.98 (m, 1H), 5.30-5.17 (m, 1H), 4.18-4.07 (m, 1H)。 614.4 B   
I-1343
Figure 02_image2977
 CC(C)[C@H](N)C(=O)N1C(c2c(cc(cc2NC(=O)c2cc(F)cc(c2)C(F)(F)F)-c2ccc3ncnn3c2)C1=O)c1cc(F)ccc1Cl (400 MHz, DMSO-d6, 60Â℃)  9.48-9.40 (m, 1H), 8.57-8.51 (m, 1H), 8.34-8.24 (m, 1H), 8.16-8.07 (m, 2H), 8.00-7.73 (m, 4H), 7.25 (dd, 8.9, 5.2 Hz, 1H), 7.10-7.00 (m, 1H), 6.63-6.41 (m, 1H), 6.14-6.02 (m, 1H), 4.54 (d, 3.7 Hz, 0.5H), 4.44 (d, 4.9 Hz, 0.5H), 2.14-1.93 (m, 1H), 1.01 (d, 6.7 Hz, 1.5H), 0.94 (d, 6.5 Hz, 1.5H), 0.85 (d, 6.6 Hz, 1.5H), 0.42 (br d, 5.5 Hz, 1.5H) 683.4 A   
I-1344
Figure 02_image2979
 C[C@@](O)(C#N)c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.69 (br s, 1H), 9.10 (br s, 1H), 7.95-7.83 (m, 1H), 7.82 - 7.66 (m, 4H), 7.32 (dd, 8.8, 5.2 Hz, 1H), 7.09 (td, 8.4, 3.0 Hz, 1H), 6.52 (br s, 1H), 6.07 (br s, 1H), 5.95 (br s, 1H), 3.08 (s, 2H), 1.60 (s, 3H)。 550.3 C   
I-1345
Figure 02_image2981
 C[C@](O)(C#N)c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.66 (br s, 1H), 9.13 (br s, 1H), 8.02-7.88 (m, 1H), 7.88-7.80 (m, 1H), 7.76 (d, 9.1 Hz, 1H), 7.73-7.62 (m, 2H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.4, 2.9 Hz, 1H), 6.52 (br s, 1H), 6.09 (s, 1H), 5.95 (br s, 1H), 3.09 (s, 2H), 1.60 (s, 3H) [ 550.2 A   
I-1346
Figure 02_image2983
 CS(=O)(=O)N1CC(C1)Oc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, )  10.47 (s, 1H), 9.18 (br s, 1H), 7.95 (d, 7.8 Hz, 1H), 7.71 (d, 8.5 Hz, 1H), 7.62 (s, 1H), 7.31 (dd, 8.8, 5.2 Hz, 1H), 7.14-7.00 (m, 3H), 6.58 (br s, 1H), 5.94 (br s, 1H), 5.21 (p, 5.3 Hz, 1H), 4.37 (t, 6.6 Hz, 2H), 4.00 (td, 9.7, 4.6 Hz, 2H), 3.10 (s, 3H)。 616.3 A   
I-1347
Figure 02_image2985
 CN1C(COc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CCC1=O 1H NMR (400 MHz, DMSO-d6)  10.44 (s, 1H), 9.14 (s, 1H), 7.95 (d, 8.3 Hz, 1H), 7.72 (d, 8.6 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, 8.8, 5.1 Hz, 1H), 7.27 (s, 1H), 7.16-7.02 (m, 2H), 6.61 (br. s, 1H), 5.94 (br. s, 1H), 4.35 - 4.26 (m, 1H), 4.21 - 4.13 (m, 1H), 3.97-3.85 (m, 1H), 2.79 (s, 3H), 2.46-2.27 (m, 1H), 2.28-2.08 (m, 2H), 1.96-1.77 (m, 1H) 594.2 A   
I-1348
Figure 02_image2987
 CN1CC(COc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CC1=O 1H NMR (400 MHz, DMSO-d6 ) 非對映異構體之混合物：-´ 10.44 (br. s, 1H), 9.11 (br. s, 1H), 7.92 (br. d, 7.1 Hz, 1H), 7.71 (br. d, 8.9 Hz, 1H), 7.65 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.20 (s, 1H), 7.13 (s, 1H), 7.08 (dt, 5.6, 3.0 Hz, 1H), 6.58 (br. s, 1H), 5.92 (br. s, 1H), 4.20-3.98 (m, 2H), 3.54 (dd, 9.7, 8.3 Hz, 1H), 3.24 (dd, 9.6, 5.0 Hz, 1H), 2.90-2.76 (m, 1H), 2.73 (s, 3H), 2.44 (dd, 與溶劑峰重疊, 17.0, 9.2 Hz, 1H), 2.17 (dd, 16.8, 6.4 Hz, 1H) 594.2 A   
I-1349
Figure 02_image2989
 Cn1nc(Nc2cc(Br)cc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccccc12 1H NMR (400 MHz, DMSO-d6) 9.14 (s, 1H), 8.39 (s, 1H), 7.87 (s, 1H), 7.47 (d, 8.5 Hz, 1H), 7.39 (d, 1.7 Hz, 1H), 7.33 (ddd, 8.3, 6.8, 1.1 Hz, 1H), 7.27 (d, 8.1 Hz, 1H), 7.20 (dd, 8.9, 5.1 Hz, 1H), 7.05-6.91 (m, 2H), 6.67 (s, 1H), 6.01 (s, 1H), 3.91 (s, 3H)。 485 E   
I-1350
Figure 02_image2991
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(CC4CCC4)c3)c12 1H NMR (400 MHz, DMSO-d6) 10.25 (s, 1H), 9.28 (s, 1H), 7.81-7.74 (m, 2H), 7.36 (dd, 8.9, 5.1 Hz, 1H), 7.22 (dt, 9.7, 1.8 Hz, 1H), 7.13 (ddt, 9.4, 4.7, 2.5 Hz, 3H), 6.71 (s, 1H), 6.01 (s, 1H), 2.69 (d, 7.7 Hz, 2H), 2.02-1.89 (m, 2H), 1.89-1.77 (m, 2H), 1.74-1.61 (m, 2H)。 545 D   
I-1351
Figure 02_image2993
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(c3)C3CCC3)c12 1H NMR (400 MHz, DMSO-d6) 10.30 (s, 1H), 9.28 (s, 1H), 7.79 (d, 1.7 Hz, 1H), 7.74 (d, 1.8 Hz, 1H), 7.36 (dd, 8.8, 5.1 Hz, 1H), 7.26 (dd, 9.8, 2.3 Hz, 1H), 7.20-7.09 (m, 3H), 6.73 (s, 1H), 6.00 (s, 1H), 3.53 (p, 8.6 Hz, 1H), 2.30 (qt, 7.7, 2.5 Hz, 2H), 2.15-2.06 (m, 1H), 2.06 (ddd, 8.4, 6.9, 2.3 Hz, 1H), 2.05-1.89 (m, 1H), 1.88-1.73 (m, 1H)。 531 D   
I-1352
Figure 02_image2995
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NS(=O)(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.42 (s, 1H), 9.21 (s, 1H), 8.13-8.03 (s, 1H), 7.92-7.61 (m, 3H), 7.52-7.34 (s, 1H), 7.31-7.12 (tt, 8.5, 4.9 Hz, 2H) , 6.39-6.71 (s, 1H), 6.02 (s, 1H)。 581.15 E   
I-1353
Figure 02_image2997
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(C(=O)Nc3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.84 (s, 1H), 9.30 (s, 1H), 8.00 - 7.90 (m, 2H), 7.77 (t, 7.6 Hz, 1H), 7.63 (s, 1H), 7.57 (d, 11.3 Hz, 1H), 7.38 (d, 8.7 Hz, 2H), 7.10 (td, 8.4, 3.1 Hz, 1H), 6.39 (s, 1H)。 467.05 D   
I-1354
Figure 02_image2999
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CCn2cnnc2C1 (400 MHz, DMSO-d6)  10.50 (br s, 1 H), 8.78 (br s, 1 H), 8.51 (d, 13.2 Hz, 1 H), 8.50 (s, 1 H), 7.83 (s, 1 H), 7.75 (d, 9.1 Hz,  1 H), 7.55 (br s, 1 H), 7.36 (dd, 8.8, 5.2 Hz, 1 H), 7.06 (td, 8.4, 3.1 Hz, 1 H), 6.87 (br s, 1 H), 6.51 (br s, 1 H), 5.87 (s, 1 H), 4.57 (s, 2 H), 4.18 (t, 5.2 Hz, 2 H), 3.80 - 3.72 (m, 2 H)。 589.3 A   
I-1355
Figure 02_image3001
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2cccnc2n1 NMR (400 MHz, DMSO-d6)  10.70 (br. s, 1H), 9.23 (br. s, 1H), 9.00 (dd, 6.8, 1.9 Hz, 1H), 8.61 (s, 1H), 8.57 (dd, 4.1, 2.0 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 7.96 (br. d, 8.3 Hz, 1H), 7.79 (br. d, 9.1 Hz, 1H), 7.72 (s, 1H), 7.33 (dd, 8.8, 5.1 Hz, 1H), 7.13-7.08 (m, 2H), 6.60 (br. s, 1H), 6.07 (br. s, 1H)。 584.1 A   
I-1356
Figure 02_image3003
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(NC(=O)c3cccnc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO)  10.86 (s, 1H), 10.63 (s, 1H), 9.19 (s, 1H), 9.15 (d, 2.1 Hz, 1H), 8.79 (dd, 4.8, 1.6 Hz, 1H), 8.37-8.30 (m, 1H), 8.15 (d, 1.4 Hz, 1H), 8.03 (d, 1.1 Hz, 1H), 7.95 (d, 8.0 Hz, 1H), 7.74 (d, 8.6 Hz, 1H), 7.65 (s, , 1H), 7.61 (dd, 8.5, 4.8 Hz, 1H), 7.32 (dd, 8.8, 5.2 Hz, 1H), 7.10 (td, 8.4, 2.9 Hz 1H), 6.57 (br s, 1H), 5.96 (br s, 1H)。 587.3 A   
I-1357
Figure 02_image3005
 OCC1(COc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)COC1 NMR (400 MHz, DMSO)  10.45 (br s, 1H), 9.15 (br s, 1H), 7.95 (d, 7.8 Hz, 1H), 7.72 (d, 8.8 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, 8.8, 5.2 Hz, 1H), 7.26 (d, 2.0 Hz, 1H), 7.13 (d, 1.6 Hz, 1H), 7.09 (td, 8.5, 3.1 Hz, 1H), 6.59 (br s, 1H), 5.94 (br s, 1H), 5.04 (s, 1H), 4.50-4.38 (m, 4H), 4.30 (d, 9.5 Hz, 1H), 4.25 (d, 9.5 Hz, 1H), 3.74 (s, 2H)。 583.3 A   
I-1358
Figure 02_image3007
 CC1(CCCC(C1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)，呈非對映異構體之混合物形式-´ 9.58 (br. s, 2H), 9.30 (br. s, 2H), 7.74 (br. d, 1.3 Hz, 2H), 7.66 (d, 1.7 Hz, 1H), 7.64 (d, 1.7 Hz, 1H), 7.57-7.48 (m, 2H), 7.27-7.22 (m, 1H), 7.22-7.17 (m, 1H), 6.40 (br. s, 2H), 6.22 (br. s, 1H), 6.15 (br. s, 1H), 2.22-2.13 (m, 2H), 2.10-2.00 (m, 2H), 1.58-1.44 (m, 5H), 1.36-1.29 (m, 1H), 1.10-0.93 (m, 8H), 0.93 (s, 3H), 0.89 (s, 3H)。 547.2 B   
I-1359
Figure 02_image3009
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CNC(=O)O1 NMR (400 MHz, DMSO)  10.60 (s, 1H), 9.23 (s, 1H), 7.95 (d, 8.4 Hz, 1H), 7.82 (s, 0.5H), 7.81 (s, 0.5H), 7.74 (d, 9.1 Hz, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.54 (s, 0.5H), 7.53 (s, 0.5H), 7.32 (dd, 8.8, 5.1 Hz, 1H), 7.14-7.06 (m, 1H), 6.59 (br s, 1H), 6.00 (br s, 1H), 5.81 (dd, 15.3, 7.8 Hz, 1H), 3.99 (td, 8.8, 6.7 Hz, 1H), 3.45-3.37 (m, 1H) 552.1 A   
I-1360
Figure 02_image3011
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1CNC(=O)C1 (400 MHz, CD3CN)  8.65 (br. s, 1H), 7.88-7.55 (m, 5H), 7.48 (s, 1H), 7.32-7.23 (m, 2H), 7.04-6.92 (m, 1H), 6.61 (br. s, 1H), 6.11 (br. s, 1H), 3.91-3.72 (m, 2H), 3.44-3.33 (m, 1H), 2.66 (dtd, 11.2, 8.6, 2.5 Hz, 1H), 2.46-2.33 (m, 1H)。 548.3 A   
I-1361
Figure 02_image3013
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1COCCO1 NMR (400 MHz, CD3CN)  8.60 (br s, 1H), 7.77 (d, 8.0 Hz, 1H), 7.65 (d, 7.9 Hz, 1H), 7.62-7.46 (m, 3H), 7.24 (dd, 9.7, 4.5 Hz, 2H), 7.09-6.92 (m, 1H), 6.63 (br s, 1H), 6.08 (br s, 1H), 5.75 (d, 7.7 Hz, 1H), 4.09 (t, 15.0 Hz, 1H), 3.95 (dd, 11.0, 4.4 Hz, 2H), 3.79 (d, 11.4 Hz, 1H), 3.69 (dt, 12.1, 4.0 Hz, 1H), 3.27 (dt, 16.6, 11.2 Hz, 1H)。 553.3 B   
I-1362
Figure 02_image3015
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C3CC4(CCC4)C3)c12 1H-NMR (400 MHz, DMSO-d6)  9.58 (s, 1H), 9.22 (br. s, 1H), 7.68 (d, 1.5 Hz, 1H), 7.58 (d, 1.6 Hz, 1H), 7.52-7.45 (m, 1H), 7.24 (app. td, 8.4, 3.1 Hz, 1H), 6.64 (br. s, 1H), 6.00 (br. s, 1H), 2.74 (p, 8.5 Hz, 1H), 1.96-1.64 (m, 10H)。 477.3 D   
I-1363
Figure 02_image3017
 OC12CC3CC(C1)CC(C3)(C2)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)  9.24 (br. s, 2H), 7.70 (d, 1.6 Hz, 1H), 7.59 (d, 1.7 Hz, 1H), 7.53-7.45 (m, 1H), 7.24 (app. td, 8.5, 3.1 Hz, 1H), 6.51 (br. s, 1H), 6.01 (br. s, 1H), 4.48 (br. s, 1H), 2.07-2.01 (m, 2H), 1.53-1.29 (m, 12H)。 533.3 D   
I-1364
Figure 02_image3019
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CS(=O)(=O)N3CCOCC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  10.61 (s, 1H), 9.23 (br. s, 1H), 7.96 (br. d, 8.3 Hz, 1H), 7.79 (s, 1H), 7.75 (br. d, 9.2 Hz, 1H), 7.65 (s, 1H), 7.55 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.5, 2.9 Hz, 1H), 6.44 (br. s, 1H), 5.98 (br. s, 1H), 4.71 (d, 13.7 Hz, 1H), 4.67 (d, 13.6 Hz, 1H), 3.64-3.53 (m, 4H), 3.21-3.09 (m, 4H)。 630.2 A   
I-1365
Figure 02_image3021
 CNS(=O)(=O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN)  8.74 (s,1H), 7.75 (d, 1.4 Hz,1H), 7.68-7.53 (m, 1H), 7.62--7.54 (m,3H)7.32-7.23 (m, 2H), 6.98 (ddd, 8.9, 8.0, 3.1 Hz,1H), 6.64 (br, s,1H), 6.25-6.04 (br, s,1H), 5.22 (q, 4.8Hz,1H), 4.45 (s,2H), 2.71 (d, 5.0 Hz,3H)。 574 A   
I-1366
Figure 02_image3023
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OCC3CCO3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6 )  10.47 (br. s, 1H), 9.14 (br. s, 1H), 7.95 (d, 8.4 Hz, 1H), 7.72 (d, 9.1 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.26 (s, 1H), 7.13 (s, 1H), 7.09 (td, 8.5, 3.0 Hz, 1H), 6.58 (br. s, 1H), 5.93 (br. s, 1H), 5.10 - 5.00 (m, 1H), 4.61-4.41 (m, 2H), 4.27 m, 2H), 2.79 - 2.65 ( m, 1H), 2.63-2.53 (m, 1H)。 553.1 A   
I-1367
Figure 02_image3025
 NS(=O)(=O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.65 (br. s, 1H), 9.20 (br. s, 1H), 7.94 (br. d, 8.3 Hz, 1H), 7.74 (br. d, 8.9 Hz, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 7.47 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.6, 3.0 Hz, 1H), 6.97 (s, 2H), 6.60 (br. s, 1H), 6.00 (br. s, 1H), 4.51 (d, 13.7 Hz, 1H), 4.45 (d, 13.6 Hz, 1H)。 560.1 A   
I-1368
Figure 02_image3027
 Nc1nc2ccc(cn2n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1 H NMR (500 MHz, DMSO) δ 10.79 (s, 1H), 9.21 (s, 1H), 9.03 (dd, J = 2.0, 0.9 Hz, 1H), 8.01 (d, J = 1.7 Hz, 1H), 7.97 - 7.92 (m, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.86 (dd, J = 9.2, 1.9 Hz, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.48 - 7.45 (m, 1H), 7.31 (dd, J = 8.9, 5.1 Hz, 1H), 7.08 (td, J = 8.3, 3.0 Hz, 1H), 6.13 (s, 2H), 6.08 (s, 1H)。 599.23 A   
I-1369
Figure 02_image3029
 Cc1ncc(C#N)c(n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl       A   
I-1370
Figure 02_image3031
 Nc1nc2cc(ccn2n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1 H NMR (500 MHz, DMSO) δ 10.61 (s, 1H), 9.25 (s, 1H), 8.64 (d, J = 7.0 Hz, 1H), 8.06 (d, J = 1.8 Hz, 1H), 7.98 - 7.91 (m, 2H), 7.79 - 7.66 (m, 4H), 7.37 - 7.27 (m, 2H), 7.10 (td, J = 8.3, 3.2 Hz, 1H), 6.10 (s, 2H)。 599.13 A   
I-1371
Figure 02_image3033
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2ncnc2c1       A   
I-1372
Figure 02_image3035
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2ccnc2c1       A   
I-1373
Figure 02_image3037
 Nc1nnc2ccc(cn12)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl       A   
I-1374
Figure 02_image3039
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nnnn2c1    585.4 A   
I-1375
Figure 02_image3041
 CS(=O)(=O)N1CCC[C@H]1COc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.45 (s, 1H), 9.14 (br. s, 1H), 7.95 (br. d, 8.5 Hz, 1H), 7.72 (br. d, 8.7 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.21 (d, 1.6 Hz, 1H), 7.11-7.05 (m, 2H), 6.57 (br. s, 1H), 5.94 (br. s, 1H), 4.16-4.00 (m, 3H), 3.32-3.30 (m, 2H), 2.99 (d, 0.8 Hz, 3H), 2.09-1.87 (m, 4H)。 644.2 A   
I-1376
Figure 02_image3043
 OCC(O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.48 (br s, 1H), 9.09 (s, 1H), 7.94 (d, 8.3 Hz, 1H), 7.73 (d, 8.9 Hz, 1H), 7.65 (s, 1H), 7.56 (s, 1H), 7.37-7.26 (m, 2H), 7.08 (td, 13.5, 6.7 Hz, 1H), 6.59 (br s, 1H), 5.95 (br s, 1H), 4.73 (d, 4.5 Hz, 1H), 4.67 (br s, 1H), 3.70 (br s, 1H), 3.31-3.25 (m, 2H), 3.01-2.89 (m, 1H), 2.67 (tt, 17.1, 8.5 Hz, 1H)。 541.3 A   
I-1377
Figure 02_image3045
 OCc1cc(Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)ncc1C(F)(F)F (400 MHz, CD3CN)  8.92 (s, 1 H), 8.41 (s, 1 H), 7.48 (br s, 1 H), 7.35 (app t, 7.6 Hz, 1 H), 7.31 - 7.26 (m, 1 H), 6.99 (br t, 7.1 Hz, 1 H), 6.92 (d, 7.8 Hz, 1 H), 6.88 (br s, 1 H), 6.75 - 6.48 (br s, 1 H), 6.69 - 6.61 (m, 1 H), 4.80 (d, 16.2 Hz, 1 H), 4.80 (d, 16.2 Hz, 1 H), 4.18 (s, 1 H), 3.68 (s, 1 H)。 452.2 E   
I-1378
Figure 02_image3047
 CS(=O)(=O)N1CCC[C@@H]1COc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.45 (s, 1H), 9.14 (br. s, 1H), 7.95 (br. d, 8.5 Hz, 1H), 7.72 (br. d, 8.7 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.21 (d, 1.6 Hz, 1H), 7.13-7.03 (m, 2H), 6.58 (br. s, 1H), 5.93 (br. s, 1H), 4.19-3.98 (m, 3H), 3.32-3.30 (m, 2H), 2.99 (d, 0.8 Hz, 3H), 2.10-1.84 (m, 4H)。 644.2 A   
I-1379
Figure 02_image3049
 Cn1nccc1C(F)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)，呈非對映異構體之約1.2:1混合物形式-´ 10.59 (br. s, 2H), 9.27 (br. s, 2H), 7.95 (br. d, 8.2 Hz, 2H), 7.77-7.68 (m, 4H), 7.64 (s, 2H), 7.59 (s, 1H), 7.55 (s, 1H), 7.43 (dd, 6.9, 1.8 Hz, 2H), 7.34 (dd, 5.2, 1.8 Hz, 1H), 7.33-7.29 (m, 2H), 7.22 (d, 7.7 Hz, 1H), 7.13-7.07 (m, 3H), 6.69 (br. s, 2H), 6.12-5.93 (m, 4H), 3.90 (s, 3H), 3.89 (s, 3H)。 579.3 A   
I-1380
Figure 02_image3051
 Cn1nccc1C(=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)  10.71 (br. s, 1H), 9.38 (br. s, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.97 (br. d, 8.3 Hz, 1H), 7.76 (br. d, 9.1 Hz, 1H), 7.67 (br. s, 1H), 7.66 (d, 2.0 Hz, 1H), 7.35 (dd, 8.9, 5.1 Hz, 1H), 7.12 (td, 8.5, 3.1 Hz, 1H), 6.90 (s, 1H), 6.58 (br. s, 1H), 6.10 (br. s, 1H), 4.14 (s, 3H)。 575.3 A   
I-1381
Figure 02_image3053
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc4c3NC(=O)C4(F)F)c12 1H NMR (400 MHz, DMSO-d6) 11.11 (s, 1H), 10.49 (s, 1H), 9.30 (s, 1H), 7.99 (s, 1H), 7.79 (d, 21.8 Hz, 2H), 7.23 (d, 87.9 Hz, 4H), 6.0(s, 1H) 570 B   
I-1382
Figure 02_image3055
 CN(Cc1cccc(O)c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 氯仿-d) 8.16 (s, 1H), 7.77 (d, 1.6 Hz, 1H), 7.36 (dd, 8.9, 4.9 Hz, 1H), 7.19 (t, 7.8 Hz, 1H), 7.02 (ddd, 8.9, 7.4, 3.1 Hz, 1H), 6.78 (ddd, 8.2, 2.6, 0.9 Hz, 1H), 6.65 (dd, 16.5, 7.1 Hz, 3H), 6.57 (s, 1H), 6.04 (s, 1H), 5.93 (d, 6.8 Hz, 2H), 4.41- 4.12 (m, 2H), 2.74 (s, 3H)。 520 E   
I-1383
Figure 02_image3057
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CC4(CCC4)c4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  9.21 (s, 1H), 8.64 (s, 1H), 7.69 - 7.62 (m, 3H), 7.46 (dd, 7.6, 1.3 Hz, 1H), 7.37 (dd, 8.9, 5.1 Hz, 1H), 7.14 (ddt, 11.0, 6.2, 3.1 Hz, 2H), 7.00 (td, 7.4, 1.1 Hz, 1H), 5.99 (s, 1H), 3.86 (d, 10.5 Hz, 1H), 3.40 (d, 10.4 Hz, 1H), 2.37 - 2.25 (m, 2H), 2.15 - 2.01 (m, 1H), 2.04 - 1.87 (m, 3H)。 540.05 B   
I-1384
Figure 02_image3059
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(Cl)c(Cl)s3)c12 1H NMR (400 MHz, DMSO-d6) 10.42 (s, 1H), 9.29 (s, 1H), 7.82 (d, 1.7 Hz, 1H), 7.71 (d, 1.7 Hz, 1H), 7.55 (s, 1H), 7.37 (dd, 8.9, 5.1 Hz, 1H), 7.14 (ddd, 8.8, 7.9, 3.1 Hz, 1H), 7.01-5.62 (m, 2H)。 534.85 C   
I-1385
Figure 02_image3061
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc4CCCNc34)c12 1H NMR (400 MHz, DMSO-d6)  9.95 (s, 1H), 9.28 (s, 1H), 7.97 - 7.67 (m, 2H), 7.39 (t, 7.0 Hz, 1H), 7.30 (s, 1H), 7.16 (td, 8.4, 3.1 Hz, 1H), 6.92 (dd, 8.9, 2.9 Hz, 1H), 6.56 (dd, 10.1, 3.0 Hz, 1H), 6.01 (s, 1H), 3.28 (s, 2H), 2.70 (q, 6.2 Hz, 2H), 1.83 - 1.67 (m, 2H)。 534.05 C   
I-1386
Figure 02_image3063
 FC(F)Sc1cccc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.37 (s, 1H), 9.27 (s, 1H), 7.85-7.80 (s, 1H), 7.80-7.72 (m, 2H),7.71-7.69 (s, 1H), 7.67 (s, 1H), 7.54 (s, 1H), 7.49-7.31 (m, 1H), 7.30-7.15 (m, 1H), 7.10 (ddd, 8.8, 7.9, 3.1 Hz, 1H), 6.99-6.23 (s, 1H), 6.16 (s, 1H)。 540.95 D   
I-1387
Figure 02_image3065
 CC(=O)N1CCC11CN(C1)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6), 10.39 (br. s, 1H), 9.01 (br. s, 1H), 7.93 (br. d, 8.5 Hz, 1H), 7.72 (br. d, 8.8 Hz, 1H), 7.64 (s, 1H), 7.29 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.4, 3.0 Hz, 1H), 6.67 (d, 2.0 Hz, 1H), 6.51 (d, 1.4 Hz, 1H), 6.9-6.4 (br. s, 1H), 5.87 (br. s, 1H), 4.47 (dd, 7.8, 3.4 Hz, 2H), 4.04-4.00 (m, 4H), 2.54 (t, 7.4 Hz, 2H), 1.76 (s, 3H)。 603.3 B   
I-1388
Figure 02_image3067
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)N1CC2(CCN2)C1 NMR (400 MHz, DMSO-d6)  10.35 (s, 1H), 8.99 (s, 1H), 7.93 (br. d, 8.4 Hz, 1H), 7.71 (br. d, 8.8 Hz, 1H), 7.63 (s, 1H), 7.28 (dd, 8.9, 5.2 Hz, 1H), 7.06 (td, 8.5, 3.0 Hz, 1H), 6.65 (d, 1.9 Hz, 1H), 6.50 (d, 0.7 Hz), 6.70-6.40 (浸沒br. s, 1H), 5.86 (br. s, 1H), 4.08 (dd, 12.3, 8.0 Hz, 2H), 3.83 (t, 8.3 Hz, 2H), 3.32 (t, 6.9 Hz, 2H), 2.48-2.46 (m, 2H) 563.2 B   
I-1389
Figure 02_image3069
 Cn1nccc1C(O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)  10.53 (br. s, 2H), 9.17 (br. s, 2H), 7.94 (br. d, 8.4 Hz, 2H), 7.73 (d, 9.2 Hz, 2H), 7.72 (s, 2H), 7.65 (d, 10.6 Hz, 2H), 7.64 (s, 2H), 7.50 (s, 12.6 Hz, 1H), 7.47 (br. s, 1H), 7.34-7.28 (m, 4H), 7.13-7.05 (m, 2H), 6.40-6.34 (m, 2H), 6.09 (d, 5.1 Hz, 1H), 6.06 (d, 4.6 Hz, 1H), 5.99 (br. s, 1H), 5.97 (br. s, 2H), 5.95 (br. s, 1H), 3.78 (s, 3H), 3.76 (s, 3H)。 577.3 A   
I-1390
Figure 02_image3071
 OC(=O)COc1ncc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, CD3CN)  8.86 (s, 3H), 8.00 (s, 1H), 7.77 (s, 1H), 7.70-7.57 (m, 4H), 7.32 (br. s, 1H), 7.26 (dd, 9.0, 5.0 Hz, 1H), 6.98 (td, 8.3, 2.8 Hz, 1H), 6.66 (br. s, 1H), 6.16 (br. s, 1H), 4.92 (s, 2H)。 619.2 A   
I-1391
Figure 02_image3073
 O[C@H](CC#N)c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.58 (s, 1H), 9.16 (br s, 1H), 7.94 (d, 7.4 Hz, 1H), 7.81-7.70 (m, 2H), 7.66 (s, 1H), 7.54 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.5, 3.0 Hz, 1H), 6.52 (br s, 1H), 6.23 (d, 4.0 Hz, 1H), 5.96 (br s, 1H), 5.07 (app q, 4.9 Hz, 1H), 3.03 (dd, 16.8, 4.7 Hz, 1H), 2.95 (dd, 16.8, 6.5 Hz, 1H)。 536.2 D   
I-1392
Figure 02_image3075
 O[C@@H](CC#N)c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.60 (s, 1H), 9.15 (s, 1H), 7.93 (d, 7.8 Hz, 1H), 7.79-7.69 (m, 2H), 7.67 (s, 1H), 7.61 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.5, 2.9 Hz, 1H), 6.55 (br s, 1H), 6.24 (d, 3.5 Hz, 1H), 5.97 (br s, 1H), 5.12 (app q, 3.6 Hz, 1H), 3.01 (dd, 16.8, 4.9 Hz, 1H), 2.94 (dd, 16.7, 6.4 Hz, 1H)。 536.2 D   
I-1393
Figure 02_image3077
 O[C@H](CC#N)c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.58 (s, 1H), 9.16 (br s, 1H), 7.94 (d, 7.4 Hz, 1H), 7.83-7.70 (m, 2H), 7.66 (s, 1H), 7.54 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.5, 3.0 Hz, 1H), 6.54 (br s, 1H), 6.23 (d, 4.0 Hz, 1H), 5.96 (br s, 1H), 5.07 (app q, 5.0 Hz, 1H), 3.02 (dd, 16.8, 4.7 Hz, 1H), 2.95 (dd, 16.8, 6.5 Hz, 1H)。 536.2 A   
I-1394
Figure 02_image3079
 O[C@@H](CC#N)c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.59 (s, 1H), 9.15 (br s, 1H), 7.93 (d, 7.9 Hz, 1H), 7.78-7.69 (m, 2H), 7.67 (s, 1H), 7.61 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.5, 3.0 Hz, 1H), 6.51 (br s, 1H), 6.23 (d, 3.3 Hz, 1H), 5.97 (br s, 1H), 5.11 (app q, 4.2 Hz, 1H), 3.00 (dd, 16.7, 4.9 Hz, 1H), 2.93 (dd, 16.7, 6.4 Hz, 1H)。 536.2 A   
I-1395
Figure 02_image3081
 C[C@@](O)(CC#N)c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.69 (br s, 1H), 9.10 (br s, 1H), 7.95-7.83 (m, 1H), 7.81 (br s, 1H), 7.76 - 7.66 (m, 3H), 7.32 (dd, 8.8, 5.2 Hz, 1H), 7.09 (td, 8.4, 3.0 Hz, 1H), 6.52 (br s, 1H), 6.07 (br s, 1H), 5.95 (br s, 1H), 3.08 (s, 2H), 1.60 (s, 3H)。 550.3 A   
I-1396
Figure 02_image3083
 C[C@](O)(CC#N)c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.59 (s, 1H), 9.14 (br s, 1H), 7.98-7.87 (m, 1H), 7.81 (s, 1H), 7.78-7.64 (m, 3H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.6, 2.9 Hz, 1H), 6.53 (br s, 1H), 6.07 (s, 1H), 5.96 (br s, 1H), 3.08 (s, 2H), 1.62 (s, 3H)。 550.3 D   
I-1397
Figure 02_image3085
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(CCC#N)c1 NMR (400 MHz, DMSO-d6)  10.56 (s, 1H), 9.17 (br s, 1H), 8.48 (s, 1H), 8.14 (s, 1H), 7.96 (br d, 8.4 Hz, 1H), 7.91 (s, 1H), 7.76 (br d, 9.1 Hz, 1H), 7.70 (s, 2H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.5, 2.9 Hz, 1H), 6.65 (br s, 1H), 5.99 (br s, 1H), 4.44 (t, 6.3 Hz, 2H), 3.13 (t, 6.3 Hz, 2H)。 586.3 A   
I-1398
Figure 02_image3087
 CS(=O)(=O)CCn1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.58 (br s, 1H), 9.15 (br s, 1H), 8.48 (s, 1H), 8.12 (s, 1H), 7.96 (br d, 8.4 Hz, 1H), 7.90 (s, 1H), 7.76 (br d, 8.9 Hz, 1H), 7.70 (s, 2H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.5, 3.0 Hz, 1H), 6.68 (br s, 1H), 5.96 (br s, 1H), 4.60 (t, 6.8 Hz, 2H), 3.76 (t, 6.8 Hz, 2H), 2.90 (s, 3H)。 639.2 A   
I-1399
Figure 02_image3089
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CS(=O)(=O)N3CCC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSOd6)  10.63 (br. s, 1H), 9.22 (br. s, 1H), 7.95 (br. d, 8.3 Hz, 1H), 7.80 (s, 1H), 7.75 (br. d, 8.7 Hz, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 7.32 (dd, 8.8, 5.2 Hz, 1H), 7.10 (td, 8.3, 2.8 Hz, 1H), 6.55 (br. s, 1H), 5.97 (br. s, 1H), 4.81-4.69 (m, 2H), 3.90 (t, 7.7 Hz, 4H), 2.19 (p, 7.8, 2H)。 600.3 A   
I-1400
Figure 02_image3091
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CN3CCn4ncnc4C3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-D6)  10.58 (br s, 1 H), 9.16 (s, 1 H), 7.94 (d, 9.7 Hz, 1 H), 7.74 (d, 8.9 Hz, 1 H), 7.69 (s, 1 H), 7.65 (s, 1 H), 7.52 (s, 1 H), 7.31 (dd, 8.9, 5.2 Hz, 1 H), 7.08 (td, 8.5, 3.0 Hz, 1 H), 6.64 (br s, 1 H), 5.98 (br s, 1 H), 4.17 (t, 5.3 Hz, 2 H), 3.99 - 3.87 (m, 2 H), 3.75 (s, 2 H), 3.10-3.01 (m, 2 H)。 603.4 A   
I-1401
Figure 02_image3093
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CN3CCn4cnnc4C3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-D6)  10.61 (br s, 1 H), 9.17 (s, 1 H), 8.45 (s, 1 H), 7.95 - 7.91 (m, 1 H), 7.74 (d, 8.9 Hz, 1 H), 7.69 (s, 1 H), 7.65 (s, 1 H), 7.51 (s, 1 H), 7.31 (dd, 8.9, 5.2 Hz, 1 H), 7.09 (td, 8.5, 3.0 Hz, 1 H), 6.67 (br s, 1 H), 5.99 (br s, 1 H), 4.08(t, 5.4 Hz, 2 H), 3.97 - 3.86 (m, 2 H), 3.76 (s, 2 H), 2.98-2.89 (m, 2 H)。 603.4 A   
I-1402
Figure 02_image3095
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CS(=O)(=O)Nc3cccnc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6 )  10.61 (s, 1H), 10.47 (br. s, 1H), 9.20 (br. s, 1H), 8.37 (d, 2.4 Hz, 1H), 8.24 (dd, 4.6, 1.2 Hz, 1H), 7.95 (br. d, 8.3 Hz, 1H), 7.73 (br. d, 8.7 Hz, 1H), 7.66 (d, 0.8 Hz, 1H), 7.62 (s, 1H), 7.56 (ddd, 8.3, 2.7, 1.4 Hz, 1H), 7.46 (s, 1H), 7.36-7.28 (m, 2H), 7.11 (td, 8.5, 3.0 Hz), 6.48 (br. s, 1H), 5.98 (br. s, 1H), 4.79 (d, 13.9 Hz, 1H), 4.74 (d, 14.1 Hz, 1H)。 637.3 A   
I-1403
Figure 02_image3097
 CC(O)(c1ccncc1)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6) 10.53 (s, 0.5H), 10.51 (s, 0.5H) 9.15 (br. s, 1H), 8.53-8.50 (m, 2H), 7.93 (br. d, 8.5 Hz, 1H), 7.78 (d, 1.3 Hz, 0.5H), 7.74 (d, 1.3 Hz, 0.5H) 7.73 (br. d, 9.0, 1H), 7.64 (d, 6.4 Hz, 1H), 7.56 (s, 0.5H), 7.52 (s, 0.5H), 7.51 (s, 1H), 7.49 (s, 1H), 7.29 (dd, 8.9, 5.2 Hz, 1H), 7.08 (td, 8.6, 3.0 Hz, 1H), 6.54 (br. s, 1H), 6.29 (br. s, 1H), 5.92 (br. s, 1H), 1.94 (s, 1.5H), 1.93 (s, 1.5H)。 588.2 A   
I-1404
Figure 02_image3099
 Cn1cc(cnc1=O)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.61 (s, 1H), 9.22 (br. s, 1H), 9.03 (d, 5.8 Hz, 1H), 8.84 (d, 3.4 Hz, 1H), 7.98 (s, 1H), 7.96 (浸沒br.d, 5.8 Hz, 1H), 7.77 (s, 1H), 7.76 (浸沒br. d, 5.5 Hz, 1H), 7.70 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.6, 3.0 Hz, 1H), 6.63 (br. s, 1H), 5.99 (br. s, 1H), 3.54 (s, 3H)； 575.2 A   
I-1405
Figure 02_image3101
 COCCn1nccc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    606.23 B   
I-1406
Figure 02_image3103
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccnn1C[C@H]1CCOC1    617.24 A   
I-1407
Figure 02_image3105
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccnn1C[C@@H]1CCOC1    617.29 A   
I-1408
Figure 02_image3107
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ncccc1C#N    569.27 A   
I-1409
Figure 02_image3109
 Nc1cnc2ccc(cn12)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    598.28 A   
I-1410
Figure 02_image3111
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncc(C#N)n2c1    608.23 A   
I-1411
Figure 02_image3113
 Nc1cn2cc(ccc2n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    598.28 A   
I-1412
Figure 02_image3115
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OCc3cccnc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    574.27 A   
I-1413
Figure 02_image3117
 [2H]C1(NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO-d6)   6.50 (s, 1 H) 7.10 (td,  8.20, 3.13 Hz, 1 H) 7.33 (dd,  8.85, 5.19 Hz, 1 H) 7.70 - 7.72 (m, 1 H) 7.74 - 7.79 (m, 1 H) 7.96 (d,  8.70 Hz, 2 H) 7.98 (s, 1 H) 8.11 - 8.15 (m, 2 H) 8.56 (s, 1 H) 9.46 (d,  0.76 Hz, 1 H) 10.62 (s, 1 H) 585.23 A   
I-1414
Figure 02_image3119
 OCCC(O)COc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.48 (br s, 1H), 9.15 (br s, 1H), 7.96 (d, 7.5 Hz, 1H), 7.72 (d, 8.9 Hz, 1H), 7.63 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.20 (s, 1H), 7.13-7.03 (m, 2H), 6.57 (br s, 1H), 5.93 (br s, 1H), 4.93 (d, 3.8 Hz, 1H), 4.52-4.43 (m, 1H), 4.07-3.89 (m, 3H), 3.63-3.50 (m, 2H), 1.77-1.50 (m, 2H)。 571.2 A   
I-1415
Figure 02_image3121
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ocnc2c1 NMR (400 MHz, DMSO-d6 )  10.62 (br s, 1H), 9.24 (s, 1H), 8.84 (s, 1H), 8.19 (d, 1.5 Hz, 1H), 8.00 (d, 1.5 Hz, 1H), 7.97 (d, 8.4 Hz, 1H), 7.92 (d, 8.6 Hz, 1H), 7.90-7.84 (m, 1H), 7.78 (d, 9.1 Hz, 1H), 7.71 (s, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.4, 3.1 Hz, 1H), 6.86-6.56 (br s), 1H, 6.07 (br s, 1H)。 582.2 A   
I-1416
Figure 02_image3123
 NC(=O)COc1ncc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.66 (br s, 1H), 9.25 (br s, 1H), 9.05 (s, 2H), 8.06 (s, 1H), 7.97 (d, 8.5 Hz, 1H), 7.86 (s, 1H), 7.76 (d, 9.0 Hz, 1H), 7.69 (s, 1H), 7.55 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.25 (s, 1H), 7.11 (td, 8.4, 3.1 Hz, 1H), 6.67 (br s, 1H), 6.04 (br s, 1H), 4.80 (s, 2H)。 618.1 A   
I-1417
Figure 02_image3125
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3csc(Cl)c3Cl)c12 1H NMR (400 MHz, DMSO-d6)  10.35 (s, 1H), 9.28 (s, 1H), 7.85-7.79 (s, 1H), 7.78 (d, 1.8 Hz, 1H), 7.70 (s, 1H), 7.56-7.39 (s, 1H), 7.30-7.12 (s, 1H), 7.09-6.20 (s, 1H), 6.00 (s, 1H)。 534.9 D   
I-1418
Figure 02_image3127
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(c1)-c1ncccn1 NMR (400 MHz, DMSO-d6)  10.57 (br s, 1H), 9.29 (s, 1H), 9.20 (br s, 1H), 8.93 (s, 1H), 8.92 (s, 1H), 8.54 (s, 1H), 8.14 (s, 1H), 7.99 (br d, 7.1 Hz, 1H), 7.96 (s, 1H), 7.78 (br d, 9.6 Hz, 1H), 7.73 (s, 1H), 7.53 (t, 4.8 Hz, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.5, 3.1 Hz, 1H), 6.65 (br s, 1H), 6.01 (br s, 1H)。 611.2 A A
I-1419
Figure 02_image3129
 COc1ncc(cc1F)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.64 (br. s, 1H), 9.25 (s, 1H), 8.45 (d, 1.9 Hz, 1H), 8.22 (dd, 11.8, 1.9 Hz, 1H), 8.01 (s, 1H), 7.97 (d, 8.8 Hz, 1H), 7.84 (s, 1H), 7.76 (d, 9.0 Hz, 1H), 7.70 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.5, 3.0 Hz, 1H), 6.69 (br. s, 1H), 6.04 (br. s, 1H), 4.01 (s, 3H) 592.2 A   
I-1420
Figure 02_image3131
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(CC#N)c1 NMR (400 MHz, DMSO-d6)  10.64 (br s, 1H), 9.18 (br s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 7.95 (d, 8.5 Hz, 1H), 7.92 (s, 1H), 7.76 (d, 8.0 Hz, 1H), 7.73 (重疊d, 12.0 Hz, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.09 (td, 8.4, 2.9 Hz, 1H), 6.61 (br s, 1H), 5.98 (br s, 1H), 5.55 (s, 2H)。 570.3 A   
I-1421
Figure 02_image3133
 CC(C)(O)COc1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl NMR (400 MHz, DMSOd6)  9.35 (s, 1H), 7.92 (d, 8.3 Hz, 1H), 7.70 (d, 9.0 Hz, 1H), 7.61 (s, H), 7.35 (dd, 8.9, 5.2 Hz, 1H), 7.17-7.00 (td, 1H, 8.3, 3.0 Hz), 7.09 (s, 1H), 6.83 (br s, 1H), 5.95 (s, 1H), 4.73 (br s, 1H), 4.20-4.10 (m, 2H), 1.23 (s, 6H)。 556.3 B   
I-1422
Figure 02_image3135
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C(=O)NCCC=C (400 MHz, DMSO-d6)  10.64 (br s, 1 H), 9.27 (s, 1 H), 8.85 (t, 5.6 Hz, 1 H), 8.21 (s, 1 H), 7.99 (d, 0.7 Hz, 1 H), 7.96 (d, 8.4 Hz, 1 H), 7.76 (d, 8.9 Hz, 1 H), 7.68 (s, 1 H), 7.32 (dd, 8.9, 5.2 Hz, 1 H), 7.09 (td, 8.5, 3.0 Hz, 1 H), 6.53 (br s, 1 H), 6.03 (br s, 1 H), 5.85 (ddt, 17.0, 10.3, 6.7 Hz, 1 H), 5.15-5.07 (m, 1 H), 5.06-5.01 (m, 1 H), 3.37 (app dd, 12.9, 6.8 Hz, 2 H), 2.32 (app q, 6.9 Hz, 2 H)。 564.3 A   
I-1423
Figure 02_image3137
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccc(o3)C(F)(F)F)c12 1H NMR (400 MHz, 氯仿-d) 8.58 (s, 1H), 7.94 (d, 1.7 Hz, 1H), 7.57 (s, 1H), 7.50 (dd, 9.0, 4.9 Hz, 1H), 7.27 (dd, 3.6, 0.9 Hz, 1H), 7.07 (ddd, 8.9, 7.4, 3.0 Hz, 1H), 6.95 (dt, 3.7, 1.1 Hz, 1H), 6.70 - 6.65 (m, 2H), 6.23 (s, 1H)。 518.95 D   
I-1424
Figure 02_image3139
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc4ccc(=O)[nH]c34)c12 1H NMR (400 MHz, DMSO-d6) 11.53 (s, 1H), 10.62 (s, 1H), 9.33 (s, 1H), 7.98 (d, 9.7 Hz, 1H), 7.86 (d, 11.8 Hz, 3H), 7.32 (s, 2H), 7.10 (s, 1H), 6.70 (d, 9.7 Hz, 1H), 6.03 (s, 1H)。 544 D   
I-1425
Figure 02_image3141
 Nc1csnc1C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 9.98 (s, 1H), 9.27 (s, 1H), 7.97 (s, 1H), 7.70 (d, 16.1 Hz, 2H), 7.35 (s, 1H), 7.12 (dt, 9.4, 4.8 Hz, 1H), 6.12 (s, 1H), 5.75 (s, 2H)。 480.95 E   
I-1426
Figure 02_image3143
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3nsc(Cl)c3Cl)c12 1H NMR (400 MHz, DMSO-d6) 10.51 (s, 1H), 9.30 (s, 1H), 7.81 (q, 1.8 Hz, 2H), 7.42 -7.34 (m, 1H), 7.15 (ddd, 8.9, 7.9, 3.1 Hz, 1H), 6.95- 6.20 (s, 1H), 6.05 (s, 1H)。 535.9 D   
I-1427
Figure 02_image3145
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3ccc(s3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.60 (s, 1H), 9.30 (s, 1H), 7.83 (d, 1.7 Hz, 1H), 7.79 - 7.70 (m, 2H), 7.60 (dt, 4.0, 1.4 Hz, 1H), 7.33 (dd, 8.9, 5.1 Hz, 1H), 7.10 (ddd, 8.9, 7.9, 3.1 Hz, 1H), 6.82 (s, 1H),  5.99 (s, 1H)。 534.95 D   
I-1428
Figure 02_image3147
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(cs3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.43 (s, 1H), 9.29 (s, 1H), 8.56-8.51 (m, 1H), 7.81 (d, 1.7 Hz, 1H), 7.73 (dd, 2.7, 1.5 Hz, 2H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.13-7.03 (m, 1H), 7.00-6.10(s, 1H),5.98 (s, 1H)。 534.9 D   
I-1429
Figure 02_image3149
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCc4ccc(=O)[nH]c34)c12 1H NMR (400 MHz, DMSO-d6)  10.66 (s, 2H), 9.27 (s, 1H), 7.89 (s, 1H), 7.76 - 7.63 (m, 1H), 7.47 (d, 8.0 Hz, 1H), 7.29 (dd, 8.9, 5.1 Hz, 1H), 7.04 (td, 8.4, 3.0 Hz, 1H), 6.18 (d, 8.1 Hz, 2H), 3.92 (q, 9.3 Hz, 1H), 3.80 (q, 10.0, 9.3 Hz, 1H), 3.17 (d, 5.2 Hz, 1H), 2.89 (t, 8.6 Hz, 1H)。 519 E   
I-1430
Figure 02_image3151
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Cn3ccnc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.55 (br. s, 1H), 9.19 (br. s, 1H), 7.94 (br. d, 8.5 Hz, 1H), 7.84 (s, 1H), 7.71 (br. d, 8.7 Hz, 1H), 7.62 (s, 1H), 7.58 (d, 0.6 Hz, 1H), 7.34 (s, 1H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.28 (s, 1H), 7.09 (app. td, 8.4, 3.1 Hz, 1H), 6.95 (s, 1H), 6.57 (br. s, 1H), 5.95 (br. s, 1H), 5.44-5.33 (m, 2H)。 547.3 A   
I-1431
Figure 02_image3153
 CC(=O)N1CCC[C@H](C1)Oc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.43 (br s, 1H), 9.14 (s, 1H), 7.95 (d, 8.4 Hz, 1H), 7.71 (d, 8.2 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, 8.8, 5.2 Hz, 1H), 7.25 (ddd, 13.6, 6.3, 2.1 Hz, 1H), 7.13-7.02 (m, 2H), 6.54 (br s, 1H), 5.91 (br s, 1H), 4.79-4.68 (m, 0.5H), 4.54-4.43 (m, 0.5H), 4.00-3.87 (m, 0.5H), 3.83-3.46 (m, 2.5H), 3.24-3.10 (m, 1H), 2.09-1.40 (m, 7H) 608.3 A   
I-1432
Figure 02_image3155
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(NC(=O)c3cccnc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.46 (br s, 1H), 9.16 (s, 1H), 7.95 (d, 8.4 Hz, 1H), 7.70 (d, 8.9 Hz, 1H), 7.62 (s, 1H), 7.35-7.28 (m, 1H), 7.26-7.19 (m, 1H), 7.12-7.03 (m, 2H), 6.60 (br s, 1H), 5.93 (br s, 1H), 5.34-5.24 (m, 0.5H), 5.22-5.14 (m, 0.5H), 3.85 (dd, 11.9, 4.4 Hz, 0.5H), 3.69-3.51 (m, 3.5H), 2.29-2.06 (m, 2H), 1.98 (s, 1.8H), 1.96 (s, 0.6H), 1.95 (s, 0.6H) 594.2 A   
I-1433
Figure 02_image3157
 Cc1ccccc1S(=O)(=O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN )  8.64 (s,1H), 7.70 (d, 7.8, 0.9 Hz,1H), 7.65 (dt, 8.8 Hz, 1.5Hz,1H), 7.61-7.56 (m, 2H), 7.55 (d,  0.8 Hz, 1H), 7.41 (d.,  7.0Hz, 1H), 7.33 (app. t, 7.7 Hz, 1H), 7.26 (dd, 8.9, 5.1 Hz, 1H), 7.25 - 7.22 (浸沒m, 1H), 6.57 (br, s, 1H), 6.13 (br, s, 1H), 4.60 (s, 2H), 2.63 (s,3H)。 635 A   
I-1434
Figure 02_image3159
 CN=S(C)(=O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.60 (s, 1H), 9.20 (br. s, 1H), 7.95 (br. d, 8.2 Hz, 1H), 7.79 (s, 1H), 7.74 (br. d, 8.7 Hz, 1H), 7.64 (s, 1H), 7.51 (s, 0.5H), 7.50 (s, 0.5H), 7.32 (dd, 8.7, 5.1 Hz, 1H), 7.13-7.06 (m, 1H), 6.73 (br. s, 1H), 5.98 (br. s, 1H), 4.70 (d, 13.5 Hz, 1H), 4.64 (d, 13.6 Hz, 1H), , 2.83 (s, 1.5H), 2.82 (s, 1.5H), 2.69 (s, 1.5H), 2.67 (s, 1.5H)。 572.1 A   
I-1435
Figure 02_image3161
 CS(=O)(Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)=Nc1ccccc1 NMR (400 MHz, DMSO-d6 )  10.63 (br. s, 1H), 9.21 (br. s, 1H), 7.96 (br. d, 8.3 Hz, 1H), 7.81 (s, 0.5H), 7.79 (s, 0.5H), 7.73 (br. d, 8.9 Hz, 1H), 7.64 (s, 1H), 7.56 (s, 0.5H), 7.50 (s, 0.5H), 7.32 (dd, 8.3, 5.2 Hz, 2 x 0.5H), 7.21-7.15 (m, 2H), 7.10 (td, 8.2, 2.3 Hz, 1H), 7.01-6.94 (m, 2H), 6.90-6.85 (m, 1H), 6.61 (br. s, 1H), 5.98 (br. s, 1H), 4.99-4.81 (m, 2H), 3.07 (s, 3H)。 634.2 A   
I-1436
Figure 02_image3163
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CS(=O)(=O)c3ccccc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, CD3CN )  8.72 (d, 23.5 Hz, 1H), 7.75-7.71 (m, 2H), 7.69 (dt, 2.5, 1.5Hz, 1H) 7.67 - 7.63 (m, 1H) 7.61-7.52 (m, 4H), 7.46 (s, 1H), 7.43-7.39 (s, 1H), 7.34-7.29 (m, 1H), 7.26 (dd, 8.9, 5.1 Hz, 1H), 7.01-6.95 (m, 1H), 6.61 (br, s, 1H), 6.15 (br, s, 1H), 4.69-4.33 (m, 2H)。 621 A   
I-1437
Figure 02_image3165
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ccnc2cc1C#N 1H NMR (400 MHz, DMSO-d6)  10.71 (br. s, 1H), 9.33 (br. s, 1H), 8.98 (d, 0.8 Hz, 1H), 8.55 (app.t, 0.8 Hz 1H), 8.19 (s, 1H), 7.98 (d, 8.1 Hz, 1H), 7.95 - 7.92 (浸沒m, 1H), 7.93 (d, 1.1 Hz, 1H), 7.81-7.70 (m, 2H), 7.68 (s, 1H), 7.36 (dd, 8.9, 5.2 Hz, 1H), 7.13 (td, 8.1, 2.9 Hz, 1H), 6.68 (br. s, 1H), 6.07 (br. s, 1H) 608.1 A   
I-1438
Figure 02_image3167
 COc1ccc(nn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6 )  10.70 (s, 1H), 9.29 (br. s, 1H), 8.40-8.30 (m, 2H), 8.26 (s, 1H), 7.96 (br. d, 8.2 Hz, 1H), 7.76 (br. d, 8.9 Hz, 1H), 7.68 (s, 1H), 7.38 (d, 9.3 Hz, 1H), 7.33 (dd, 9.0, 5.2 Hz, 1H), 7.10 (td, 8.4, 2.7 Hz, 1H), 6.61 (br. s, 1H), 6.06 (br. s, 1H), 4.10 (s, 3H) 575.2 A   
I-1439
Figure 02_image3169
 CN(C)S(=O)(=O)n1nccc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    640.24 A   
I-1440
Figure 02_image3171
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ncnc2cn1    585.4 D   
I-1441
Figure 02_image3173
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ncnc2cn1    585.4 A A
I-1442
Figure 02_image3175
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncc(C#N)n2c1    608.2 B   
I-1443
Figure 02_image3177
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncc(C#N)n2c1    608.2 A   
I-1444
Figure 02_image3179
 Nc1nc2ccc(cn2n1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    599.2 A   
I-1445
Figure 02_image3181
 Nc1nc2ccc(cn2n1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    599.2 A   
I-1446
Figure 02_image3183
 Nc1nc2cc(ccn2n1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    599.2 A   
I-1447
Figure 02_image3185
 Nc1nc2cc(ccn2n1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    599.2 A   
I-1448
Figure 02_image3187
 Nc1nnc2ccc(cn12)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl       C   
I-1449
Figure 02_image3189
 Nc1nnc2ccc(cn12)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1 H NMR (500 MHz, DMSO) δ 10.65 (s, 1H), 9.25 (s, 1H), 8.66 (t, J = 1.4 Hz, 1H), 8.04 (d, J = 1.7 Hz, 1H), 7.96 (dt, J = 8.6, 2.0 Hz, 1H), 7.83 (s, 1H), 7.77 (d, J = 9.1 Hz, 1H), 7.70 (s, 1H), 7.55 (qd, J = 9.7, 1.4 Hz, 2H), 7.33 (dd, J = 8.9, 5.2 Hz, 1H), 7.10 (td, J = 8.4, 3.1 Hz, 1H), 6.53 (s, 2H), 6.04 (s, 1H)。 599.19 A   
I-1450
Figure 02_image3191
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2ccnc2c1       A   
I-1451
Figure 02_image3193
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2ccnc2c1       B   
I-1452
Figure 02_image3195
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nnnn2c1    585.5 D   
I-1453
Figure 02_image3197
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nnnn2c1    585.5 A   
I-1454
Figure 02_image3199
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1nccn1CC#N    572.22 B   
I-1455
Figure 02_image3201
 CS(=O)(=O)c1ccc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    622.19 A   
I-1456
Figure 02_image3203
 CS(=O)(=O)c1ccc(nc1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    622.14 A   
I-1457
Figure 02_image3205
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OC[C@H]3CCCN3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  10.53 (br. s, 1H), 9.15 (br. s, 1H), 7.95 (br. d, 8.3 Hz, 1H), 7.73 (br. d, 9.1 Hz, 1H), 7.65 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.22 (br. t, 2.1 Hz, 1H), 7.11-7.06 (m, 2H), 6.57 (br. s, 1H), 5.93 (br. s, 1H), 4.17-4.03 (m, 2H), 3.65 (m, 1H), 3.06-2.93 (m, 2H), 2.04-1.91 (m, 1H), 1.91-1.69 (m, 2H), 1.65-1.56 (m, 1H) 566.3 B   
I-1458
Figure 02_image3207
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2n1 (400 MHz, DMSO-d6)  10.74 (s, 1H), 9.34 (br s, 1H), 8.76 (s, 1H), 8.61 (d, 9.5 Hz, 1H), 8.47 (d, 9.5 Hz, 1H), 8.42 (s, 1H), 8.33 (s, 1H), 7.98 (d, 8.3 Hz, 1H), 7.80 (d, 8.9 Hz, 1H), 7.72 (s, 1H), 7.35 (dd, 8.8, 5.1 Hz, 1H), 7.12 (td, 8.4, 2.9 Hz, 1H), 6.62 (br s, 1H), 6.10 (br s, 1H)。 583.3 A   
I-1459
Figure 02_image3209
 CC(N(C)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl)c1ccccc1O 1H NMR (400 MHz, DMSO-d6)  9.73 (s, 1H), 9.12 (d, 9.4 Hz, 1H), 8.42 (s, 1H), 7.76-7.67 (m, 1H), 7.58 (td, 9.7, 8.9, 5.1 Hz, 1H), 7.50-7.44 (s, 1H), 7.29-7.18 (m, 2H), 7.19-7.08 (s, 1H), 6.92-6.68 (m, 3H), 6.15-5.71 (s, 1H), 5.20 (q, 7.0 Hz, 1H), 2.45 (s, 2H), 2.25 (s, 1H), 1.40-1.15 (m, 3H)。 534 E   
I-1460
Figure 02_image3211
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3nccc4cc[nH]c34)c12 1H NMR (400 MHz, DMSO-d6) 10.78 (s, 1H), 9.09 (s, 1H), 8.42 (s, 1H), 7.78 (d, 1.8 Hz, 1H), 7.67 (d, 5.6 Hz, 1H), 7.55 (d, 1.7 Hz, 1H), 7.39 (t, 2.7 Hz, 1H), 7.18 (dd, 8.8, 5.2 Hz, 1H), 7.08 (d, 5.6 Hz, 1H), 6.95 (td, 8.4, 3.1 Hz, 1H), 6.42-6.36 (m, 1H), 6.28 (d, 9.2 Hz, 1H), 6.02 (s, 1H)。 471 E   
I-1461
Figure 02_image3213
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3nccc4ccsc34)c12 1H NMR (400 MHz, DMSO-d6) 9.10 (s, 1H), 8.88 (s, 1H), 8.03 (d, 5.6 Hz, 1H), 7.92 (d, 5.3 Hz, 1H), 7.72 (d, 1.7 Hz, 1H), 7.60 (d, 1.8 Hz, 1H), 7.43 (d, 5.3 Hz, 1H), 7.36 (d, 5.5 Hz, 1H), 7.12 (dd, 8.8, 5.1 Hz, 1H), 6.94 (td, 8.3, 3.1 Hz, 1H), 6.25 (s, 1H), 5.85 (s, 1H)。 487.95 E   
I-1462
Figure 02_image3215
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CC4(CC4)c4ccccc34)c12 1H NMR (400 MHz, DMSO-d6)  9.19 (s, 1H), 8.58 (s, 1H), 7.69 - 7.60 (m, 3H), 7.37 (dd, 8.9, 5.1 Hz, 1H), 7.17 (td, 8.4, 3.0 Hz, 1H), 7.07 (t, 7.8 Hz, 1H), 6.89 - 6.42 (m, 3H), 5.96 (s, 1H), 3.78 (d, 9.9 Hz, 1H), 3.22 (s, 1H), 1.09 - 0.89 (m, 4H)。 526 B   
I-1463
Figure 02_image3217
 OCCC(O)Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6 )  10.48 (br s, 1H), 9.08 (s, 1H), 7.93 (d, 8.4 Hz, 1H), 7.73 (dd, 8.9 Hz, 1H), 7.65 (s, 1H), 7.55 (s, 1H), 7.32 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.13-7.05 (m, 1H), 6.61 (br s, 1H), 5.95 (br s, 1H), 4.62 (d, 4.7 Hz, 1H), 4.38 (br t, 4.3 Hz, 1H), 3.92-3.82 (m, 1H), 3.57-3.49 (m, 2H), 2.92-2.71 (m, 2H), 1.65-1.43 (m, 2H)。 555.3 A   
I-1464
Figure 02_image3219
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc(nc1)-c1ncco1 NMR (400 MHz, DMSO-d6)  10.74 (br s, 1H), 9.44 (s, 2H), 9.31 (br s, 1H), 8.43 (s, 1H), 8.25 (d, 0.7 Hz, 1H), 8.03 (s, 1H), 7.98 (d, 8.4 Hz, 1H), 7.78 (d, 9.3 Hz, 1H), 7.71 (s, 1H), 7.59 (s, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.12 (td, 8.7, 3.0 Hz, 1H), 6.64 (br s), 6.07 (br s)。 612.2 A   
I-1465
Figure 02_image3221
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(c1)-c1ccncn1 NMR (400 MHz, DMSO-d6 )  10.59 (br s, 1H), 9.37 (s, 1H), 9.21 (br s, 1H), 9.15 (d, 0.8 Hz,  1H), 8.94 (d, 5.6 Hz, 1H), 8.66 (s, 1H), 8.18 (s, 1H), 8.00 (dd, 5.9, 0.9, 1H), 8.00-7.95 (m, 2H), 7.78 (d, 8.8 Hz, 1H), 7.73 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.5, 3.1 Hz, 1H), 6.81 (br s, 1H), 6.01 (br s, 1H)。 611.3 A   
I-1466
Figure 02_image3223
  		 CC(=O)N1CCC[C@H]1COc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN), ´ 8.63 (br. s, 1H), 7.64 (br. d, 8.5 Hz, 1H), 7.58 (br. d, 9.8 Hz, 1H),7.55 (s, 1H), 7.37 (d, 1.9 Hz, 1H), 7.36 (d, 2.1 Hz, 1H), 7.24 (dd, 8.8, 5.2 Hz, 1H), 7.19-7.11 (m, 1H), 6.96 (td, 8.4, 2.8 Hz, 1H), 6.63 (br. s, 1H), 6.05 (br. s, 1H), 4.34-4.30 (m, 1H), 4.29-4.24 (m, 1H), 4.09-4.00 (m, 2H), 3.55-3.31 (m, 2H), 2.12-2.01(m, 4H), 1.98 (s, 3H) 608.3 A   
I-1467
Figure 02_image3225
 CC(=O)N1CCC[C@@H]1COc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN) 旋轉異構體之混合物, ´ 8.94 (br. s, 1H), 7.63 (br. d, 8.5 Hz, 1H), 7.59-7.56 (m, 2H), 7.36 (d, 1.9 Hz, 1H), 7.35 (d, 2.1 Hz, 1H), 7.24 (dd, 8.8, 5.2 Hz, 1H), 7.19-7.11 (m, 1H), 6.95 (td, 8.4, 2.8 Hz, 1H), 6.63 (br. s, 1H), 6.04 (br. s, 1H), 4.35-4.27 (m, 1H), 4.25 (dd, 9.8, 2.9 Hz, 1H), 4.03 (dd, 9.6, 7.8 Hz, 1H), 3.55-3.31 (m, 2H), 2.14-1.98 (m, 4H), 1.97 (s, 3H) 608.3 A   
I-1468
Figure 02_image3227
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OC[C@@H]3CCCN3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  10.58 (br. s, 1H), 9.16 (br. s, 1H), 8.34 (s, 1H), 7.95 (br. d, 8.3 Hz, 1H), 7.73 (br. d, 9.1 Hz, 1H), 7.65 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.22 (br. t, 2.1 Hz, 1H), 7.11-7.06 (m, 2H), 6.54 (浸沒br. s, 1H), 5.93 (br. s, 1H), 4.20-4.03 (m, 2H), 3.72-3.66 (m, 1H), 3.07-2.96 (m, 2H), 2.04-1.91 (m, 1H), 1.91-1.72 (m, 2H), 1.65-1.56 (m, 1H) 566.1 B   
I-1469
Figure 02_image3229
 NS(=O)(=O)CCNC(=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-D6)  10.67 (br s, 1 H), 9.29 (br s, 1 H), 8.99 (t, 5.5 Hz, 1 H), 8.21 (s, 1 H), 7.99 (s, 1 H), 7.96 (br d, 8.6 Hz, 1 H), 7.76 (br d, 8.9 Hz, 1 H), 7.68 (s, 1 H), 7.33 (dd, 8.8, 5.2 Hz, 1 H), 7.10 (td, 8.5, 2.8 Hz, 1 H), 6.98 (s, 2 H), 6.50 (br s, 1 H), 6.03 (br s, 1 H), 3.72 - 3.65 (m, 2 H), 3.28 (t, 7.2 Hz, 2H)。 615.2 A   
I-1470
Figure 02_image3231
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CS(=O)(=O)Cc3ccncc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  10.64 (br s, 1H), 9.24 (br s, 1H), 8.60 (d, 4.6 Hz, 2H), 7.95 (d, 8.3 Hz, 1H), 7.74 (s, 1H), 7.74 (br d, 7.8 Hz, 1H), 7.64 (s, 1H), 7.51 (s, 1H), 7.41 (d, 4.8 Hz, 2H), 7.32 (dd, 8.8, 5.0 Hz, 1H), 7.11 (td, 8.0, 3.6 Hz, 1H), 6.60 (br s, 1H), 5.99 (br s, 1H), 4.79 (s, 2H), 4.64 (s, 2H) 636 A   
I-1471
Figure 02_image3233
 [O-][n+]1ccc(CS(=O)(=O)Cc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)cc1 NMR (400 MHz, DMSO-d6 )  10.62 (br s, 1H), 9.24 (br s, 1H), 8.25 (m, 2H), 7.95 (d, 8.5 Hz, 1H), 7.73 (m, 2H), 7.64 (s, 1H), 7.50 (s, 1H), 7.41 (m, 2H), 7.32 (dd, 8.8, 5.2 Hz, 1H), 7.11 (td, 8.4, 2.9 Hz, 1H), 6.65 (br s, 1H), 6.00 (br s, 1H), 4.81-4.69 (m, 2H), 4.64 (s, 2H)。 652 A   
I-1472
Figure 02_image3235
 CC(c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)S(C)=O NMR (400 MHz, DMSO-d6) 10.67 (br. s, 1H), 9.20 (s, 1H), 7.95 (br. d, 8.3 Hz, 1H), 7.74 (br. d, 9.1 Hz, 1H), 7.70-7.63 (m, 2H), 7.44 (s, 0.5H), 7.41 (s, 0.5H), 7.35-7.28 (m, 1H), 7.14-7.06 (m, 1H), 6.6 (br. s, 1H), 5.98 (br, s, 1H), 4.30-4.23 (m, 0.5H), 4.22-4.15 (m, 0.5H), 2.42-2.37 (m, 1.5H), 2.27-2.21 (m, 1.5H), 1.67-1.63 (m, 1.5H), 1.63-1.58 (m, 1.5H) 557 B   
I-1473
Figure 02_image3237
 CC(c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)S(C)(=O)=O NMR (400 MHz, DMSO-d6) 10.64 (s, 1H), 9.28 (s, 1H), 7.95 (d, 8.1 Hz, 1H), 7.80 (d, 2.7 Hz, 1H), 7.74 (d, 9.3 Hz, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 7.32 (dd, 8.8, 5.1 Hz, 1H), 7.10 (m, 1H), 6.59 (br, s, 1H), 6.00 (br, s, 1H), 4.87- 4.78 (m, 1H), 2.91 (s, 3H), 1.71 (d, 7.1 Hz, 3H) 573 A   
I-1474
Figure 02_image3239
 OCCOc1ncc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)  10.54 (br. s, 1H), 9.26 (br. s, 1H), 9.04 (s, 2H), 8.05 (d, 0.8 Hz, 1H), 7.96 (br. d, 7.9 Hz, 1H), 7.86 (s, 1H), 7.77 (br. d, 8.8 Hz, 1H), 7.70 (s, 1H), 7.33 (dd, 8.8, 5.2 Hz, 1H), 7.11 (app. td, 8.4, 3.0 Hz, 1H), 6.63 (br. s, 1H), 6.04 (br. s, 1H), 4.96 (br. s, 1H), 4.42-4.38 (t, 5.0 Hz, 2H), 3.76 (t, 5.0 Hz, 2H)。 605.3 A   
I-1475
Figure 02_image3241
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Cc3ccc4C(=O)NCCc4c3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  9.13 (br. s, 1H), 8.36 (br. s, 1H), 7.93 (br. d, 8.4 Hz, 1H), 7.88 (t, 2.5 Hz 1H), 7.79 (d, 7.9 Hz, 1H), 7.72 (br. d, 8.9 Hz, 1H), 7.63 (s, 1H), 7.60 (s, 1H), 7.35 (s, 1H), 7.32-7.27 (m, 2H), 7.25 (s, 1H), 7.08 (app. td, 8.5, 3.1 Hz, 1H), 6.58 (br. s, 1H), 5.92 (br. s, 1H), 4.17 (d, AB之A, JAB = 14.6 Hz, 1H), 4.12 (d, AB之B, JAB = 14.7 Hz, 1H), 3.35 (td, 6.6, 2.7 Hz, 2H), 2.87 (t, 6.5 Hz, 2H)。 626.3 A   
I-1476
Figure 02_image3243
 CS(=O)(=O)CCc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO)  10.53 (br s, 1H), 9.14 (br s, 1H), 7.95 (d, 8.2 Hz, 1H), 7.73 (d, 9.1 Hz, 1H), 7.68 (s, 1H), 7.66 (s, 1H)。7.44 (s, 1H), 7.31 (dt, 9.7, 4.9 Hz, 1H), 7.09 (td, 8.3, 3.0 Hz, 1H), 6.59 (br s, 1H), 5.96 (br s, 1H), 3.54 (t, 7.9 Hz, 2H), 3.22-3.15 (m, 2H), 3.02 (s, 2H)。 573.1 A   
I-1477
Figure 02_image3245
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(NC(=O)c3cccnc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO)  10.86 (s, 1H), 10.63 (s, 1H), 9.19 (s, 1H), 9.15 (d, 2.1 Hz, 1H), 8.79 (dd, 4.8, 1.6 Hz, 1H), 8.37-8.30 (m, 1H), 8.15 (d, 1.4 Hz, 1H), 8.03 (d, 1.1 Hz, 1H), 7.95 (d, 8.0 Hz, 1H), 7.74 (d, 8.6 Hz, 1H), 7.65 (s, , 1H), 7.61 (dd, 8.5, 4.8 Hz, 1H), 7.32 (dd, 8.8, 5.2 Hz, 1H), 7.10 (td, 8.4, 2.9 Hz 1H), 6.57 (br s, 1H), 5.96 (br s, 1H)。 587.2 A   
I-1478
Figure 02_image3247
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(NC(=O)c3cccnc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO)  10.86 (s, 1H), 10.63 (s, 1H), 9.19 (s, 1H), 9.15 (d, 2.1 Hz, 1H), 8.79 (dd, 4.8, 1.6 Hz, 1H), 8.37-8.30 (m, 1H), 8.15 (d, 1.4 Hz, 1H), 8.03 (d, 1.1 Hz, 1H), 7.95 (d, 8.0 Hz, 1H), 7.74 (d, 8.6 Hz, 1H), 7.65 (s, , 1H), 7.61 (dd, 8.5, 4.8 Hz, 1H), 7.32 (dd, 8.8, 5.2 Hz, 1H), 7.10 (td, 8.4, 2.9 Hz 1H), 6.57 (br s, 1H), 5.96 (br s, 1H)。 587.3 B   
I-1479
Figure 02_image3249
 NS(=O)(=O)Cc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.65 (br. s, 1H), 9.20 (br. s, 1H), 7.94 (br. d, 8.3 Hz, 1H), 7.74 (浸沒br. d, 8.9 Hz, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 7.47 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.6, 3.0 Hz, 1H), 6.97 (s, 2H), 6.60 (br. s, 1H), 6.00 (br. s, 1H), 4.48 (app. q, 13.6 Hz, 2H)。 560.1 D   
I-1480
Figure 02_image3251
 NS(=O)(=O)Cc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.65 (br. s, 1H), 9.20 (br. s, 1H), 7.94 (br. d, 8.3 Hz, 1H), 7.74 (浸沒br. d, 8.9 Hz, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 7.47 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.6, 3.0 Hz, 1H), 6.97 (s, 2H), 6.60 (br. s, 1H), 6.00 (br. s, 1H), 4.48 (app. q, 13.6 Hz, 2H)。 560.1 A   
I-1481
Figure 02_image3253
 NC(=O)Cn1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.56 (br s, 1H), 9.15 (br s, 1H), 8.33 (s, 1H), 8.05 (s, 1H), 7.95 (br d, 8.6 Hz, 1H), 7.89 (s, 1H), 7.76 (br d, 9.5 Hz, 1H), 7.70 (s, 1H), 7.66-7.51 (m, 10H), 7.32 (dd, 8.8, 5.2 Hz, 2H), 7.09 (td, 8.7, 3.0 Hz, 1H), 6.61 (br s, 1H), 5.98 (br s, 1H), 4.80 (s, 2H)。 590.2 A   
I-1482
Figure 02_image3255
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc(nc1)-n1ccnc1 NMR (400 MHz, DMSO-d6)  10.76 (br s, 1H), 9.32 (s, 2H), 9.29 (浸沒br s, 1H), 8.67 (s, 1H), 8.19 (s, 1H), 8.03 (s, 1H), 7.97 (s, 1H), 7.96 (浸沒br d, 8.1 Hz, 1H), 7.77 (br d, 8.1 Hz, 1H), 7.71 (s, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.20 (s, 1H), 7.11 (td, 8.5, 3.0 Hz, 1H), 6.68 (br s, 1H), 6.04 (br s, 1H)。 611.2 A   
I-1483
Figure 02_image3257
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc(nc1)-n1cccn1 NMR (400 MHz, DMSO-d6)  10.73 (br s, 1H), 9.32 (s, 2H), 9.29 (浸沒br s, 1H), 8.74 (d, 2.4 Hz, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.97 (浸沒br d, 7.7 Hz, 1H), 7.92 (d, 0.9 Hz, 1H), 7.78 (br d, 9.0 Hz, 1H), 7.71 (s, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.6, 3.1 Hz, 1H), 6.75 (浸沒br s, 1H), 6.65 (dd, 2.6, 1.6 Hz, 1H), 6.07 (br s, 1H)。 611.2 A   
I-1484
Figure 02_image3259
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(CS(=O)(=O)N3CCOCC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  10.61 (s, 1H), 9.23 (br. s, 1H), 7.96 (br. d, 8.3 Hz, 1H), 7.79 (s, 1H), 7.75 (br. d, 9.2 Hz, 1H), 7.65 (s, 1H), 7.55 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.5, 2.9 Hz, 1H), 6.44 (br. s, 1H), 5.98 (br. s, 1H), 4.69 (s, 2H), 3.64-3.53 (m, 4H), 3.21-3.09 (m, 4H)。 630.2 D   
I-1485
Figure 02_image3261
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(CS(=O)(=O)N3CCOCC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  10.61 (s, 1H), 9.23 (br. s, 1H), 7.96 (br. d, 8.3 Hz, 1H), 7.79 (s, 1H), 7.75 (br. d, 9.2 Hz, 1H), 7.65 (s, 1H), 7.55 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.5, 2.9 Hz, 1H), 6.44 (br. s, 1H), 5.98 (br. s, 1H), 4.69 (s, 2H), 3.64-3.53 (m, 4H), 3.21-3.09 (m, 4H)。 630.2 A   
I-1486
Figure 02_image3263
 CS(=O)(Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)=Nc1cccnc1 NMR (400 MHz, DMSO-d6)  10.61 (br. s, 1H), 9.21 (br. s, 1H), 8.20 (d, 1.6 Hz, 0.5H), 8.19 (d, 1.7 Hz, 0.5H), 8.07 (app br. t, 4.0 Hz, 1H), 7.96 (br. d, 8.3 Hz, 1H), 7.81 (s, 0.5H), 7.79 (s, 0.5H), 7.73 (br. d, 8.4 Hz, 1H), 7.63 (s, 1H), 7.57 (s, 0.5H), 7.53 (s, 0.5H), 7.36-7.31 (浸沒m, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.21-7.14 (m, 1H), 7.10 (td, 8.5, 2.7 Hz, 1H), 6.66 (br. s, 1H), 5.97 (br. s, 1H), 5.05-4.90 (m, 2H), 3.16 (s, 3H)。 635.3 A   
I-1487
Figure 02_image3265
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CS(=O)c3cccc(c3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, CD3CN) ´ 8.63 (br. s 0.5H), 8.58 (br. s, 0.5H), 7.84 (dt, 3.3, 1.5 Hz, 0.5H), 7.82 (dt, 3.2, 1.6 Hz, 0.5H), 7.80 (br. t, 1.2 Hz, 0.5H), 7.77 (br. t, 1.2 Hz, 0.5H), 7.69-7.61 (m, 3H), 7.61-7.55 (m, 1H), 7.54 (s, 0.5H), 7.53 (s, 0.5H), 7.34 (d, 0.8 Hz, 0.5 H), 7.30-7.20 (m, 3.5H), 6.98 (dt, 8.8, 2.8 Hz, 0.5H), 6.97 (dt, 8.8, 2.8 Hz, 0.5H), 6.61 (br, s, 1H), 6.08 (br, s, 1H), 4.40 (d, 12.8 Hz, 0.5H), 4.37 (d, 12.8 Hz, 0.5H), 4.17 (d, 12.7 Hz, 0.5H), 4.14 (d, 12.9 Hz, 0.5H)。 630 A   
I-1488
Figure 02_image3267
 CN(C)S(=O)(=O)Cc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.60 (br. s, 1H), 9.21 (br. s, 1H), 7.95 (dt, 8.5, 2.0 Hz, 1H), 7.77 (s, 1H), 7.75 (br. d, 8.4 Hz, 1H) 7.66 (s, 1H), 7.55 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.5, 3.1 Hz, 1H), 6.58 (br. s, 1H), 5.97 (br. s, 1H), 4.70-4.58 (m, 2H), 2.76 (s, 6H)。 588.2 D   
I-1489
Figure 02_image3269
 CN(C)S(=O)(=O)Cc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.60 (br. s, 1H), 9.21 (br. s, 1H), 7.95 (dt, 8.5, 2.0 Hz, 1H), 7.77 (s, 1H), 7.75 (浸沒br. d, 8.4 Hz, 1H) 7.66 (s, 1H), 7.55 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.5, 3.1 Hz, 1H), 6.58 (br. s, 1H), 5.97 (br. s, 1H), 4.70-4.58 (m, 2H), 2.76 (s, 6H)。    A   
I-1490
Figure 02_image3271
 CSC(C)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6) ´ 10.51 (br. s, 0.5 H), 10.5 (br. s, 0.5 H), 9.11 (br. s, 1H), 7.90 (br. d, 8.7 Hz, 1H), 7.70 (br. d, 9.2 Hz, 1H), 7.62-7.60 (m, 2H), 7.44 (br. s, 0.5H), 7.42 (br. s, 0.5 H), 7.27 (dd, 8.9, 5.1 Hz, 1H), 7.05 (td, 8.6, 3.1 Hz, 1H), 6.59 (br. s, 1H), 5.90 (br. s, 1H), 4.12 (q, 6.9 Hz, 0.5H), 4.12 (q, 6.9 Hz, 0.5H), 1.88 (s, 1.5H), 1.87 (s, 1.5H), 1.54 (d, 6.9 Hz, 1.5H), 1.53 (d, 6.9 Hz, 1.5H)。 541 A   
I-1491
Figure 02_image3273
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CS(=O)(=O)c3cccc(c3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, CD3CN)  8.62 (s, 1H), 8.13 (t, 1.1Hz, 1H), 8.03 (dt, 7.9, 1.2 Hz, 1H), 7.94 (dt, 8.0, 1.3Hz, 1H), 7.70 (t, 7.9 Hz, 1H), 7.66 (br, d, 8.5 Hz, 1H), 7.58 (td, 9.1 Hz, 1.7Hz, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 7.42 (s, 1H), 7.27 (dd, 8.9, 5.1 Hz, 1H), 7.27 (NH, 1H), 6.98 (td, 8.1, 3.0 Hz, 1H), 6.62 (br, s, 1H), 6.12 (br, s, 1H), 4.66 (s, 2H)。 646 A   
I-1492
Figure 02_image3275
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc(OC2CC2)nc1 1H NMR (400 MHz, DMSO-d6)  10.66 (br. s, 1H), 9.26 (br. s, 1H), 9.06 (s, 2H), 8.06 (d, 1.3 Hz, 1H), 7.97 (d, 8.5 Hz, 1H), 7.85 (s, 1H), 7.76 (d, 8.8 Hz, 1H), 7.69 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.4, 3.0 Hz, 1H), 6.59 (br. s, 1H), 6.02 (br. s, 1H), 4.38 (tt, 6.2, 3.2 Hz, 1H), 0.86-0.80 (m, 2H), 0.80 - 0.74 (m, 2H)。 601.2 A   
I-1493
Figure 02_image3277
 OCC(O)CCNC(=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-D6)  10.65 (br s, 1 H), 9.27 (br s, 1 H), 8.79 (t, 5.3 Hz, 1 H), 8.21 (s, 1 H), 7.99 (s, 1 H), 7.96 (d, 8.5 Hz, 1 H), 7.76 (d, 8.8 Hz, 1 H), 7.68 (s, 1 H), 7.32 (dd, 8.9, 5.2 Hz, 1 H), 7.09 (td, 8.5, 2.9 Hz, 1 H), 6.52 (br s, 1 H), 6.03 (br s, 1 H), 4.64 - 4.50 (m, 2 H), 3.57-3.49 (m, 1 H), 3.47-3.23 (m, 4 H), 1.84-1.72 (m, 1 H), 1.54 - 1.43 (m, 1 H)。 598.2 A   
I-1494
Figure 02_image3279
 C\S(Cc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)=N/C#N NMR (400 MHz, DMSOO-d6)  10.64 (br. s, 1H), 9.26 (br. s, 1H), 7.95 (br. d, 8.4 Hz, 1H), 7.77 (s, 0.5H), 7.76 (s, 0.5H), 7.73 (br. d, 9.0 Hz, 1H), 7.63 (s, 1H), 7.55 (s, 0.5H), 7.53 (s, 0.5H), 7.33 (dd, 5.3, 2.6 Hz, 0.5H), 7.31 (dd, 5.2, 2.6 Hz, 0.5H), 7.15-7.06 (m, 1H), 6.59 (br. s, 1H), 6.01 (br. s, 1H), 4.71 (d, 12.9 Hz, 0.5H), 4.67 (d, 13.0 Hz, 0.5H), 4.50 (d, 11.9 Hz, 0.5H), 4.47 (d, 12.2 Hz, 0.5H), 2.90 (s, 1.5H), 2.89 (s, 1.5H)。 567.2 A   
I-1495
Figure 02_image3281
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CS(=O)(=O)c3ccncc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6 )  10.59 (s, 1H), 9.19 (br. s, 1H), 8.89 (dd, 4.5, 1.6 Hz, 2H), 7.95 (br. d, 8.5 Hz, 1H), 7.76 (dd, 5.8, 1.9 Hz, 2H), 7.73 (br. d, 9.1 Hz, 1H), 7.63 (s, 1H), 7.52 (br. s, 1H), 7.44 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.5, 2.9 Hz, 1H), 6.53 (br. s, 1H), 5.95 (br. s, 1H), 5.08 (s, 2H)。 622.1 A   
I-1496
Figure 02_image3283
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Cc3ccc4C(=O)NCc4c3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.48 (br. s, 1H), 9.13 (br. s, 1H), 8.50 (s, 1H), 7.93 (br. d, 8.5 Hz, 1H), 7.71 (br. d, 8.8 Hz, 1H), 7.65-7.61 (m, 3H), 7.52 (s, 1H), 7.44 (d, 7.9 Hz, 1H), 7.36 (s, 1H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.08 (app. td, 8.4, 3.0 Hz, 1H), 6.57 (br. s, 1H), 5.93 (br. s, 1H), 4.35 (s, 2H), 4.26 (d, AB之A, JAB = 14.5 Hz, 1H), 4.22 (d, JAB = 14.7 Hz, 1H)。 612.3 A   
I-1497
Figure 02_image3285
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Cn3cccn3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.52 (br. s, 1H), 9.17 (br. s, 1H), 7.97-7.93 (m, 1H), 7.93 (d, 2.0 Hz, 1H), 7.71 (br. d, 8.8 Hz, 1H), 7.62 (s, 1H), 7.52 (d, 1.6 Hz, 1H), 7.50 (s, 1H), 7.32-7.28 (m, 2H), 7.09 (app. td, 8.3, 2.9 Hz, 1H), 6.56 (br. s, 1H), 6.32 (t, 2.0 Hz, 1H), 5.94 (br. s, 1H), 5.57-5.48 (m, 2H)。 547.3 A   
I-1498
Figure 02_image3287
 CS(=O)(=O)n1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    610.99 A   
I-1499
Figure 02_image3289
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ccnn2c1    583.126 A   
I-1500
Figure 02_image3291
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2cncn2c1    583.12 A   
I-1501
Figure 02_image3293
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2cnnc2c1    584.17 A   
I-1502
Figure 02_image3295
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(N\C(Nc3ccc(F)cc3C(F)(F)F)=N\C#N)c12    584.3 D   
I-1503
Figure 02_image3297
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2cncc2c1    583.12 A   
I-1504
Figure 02_image3299
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn2ccnc2c1    584.17 A   
I-1505
Figure 02_image3301
 CNC(=O)n1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    590.13 A   
I-1506
Figure 02_image3303
 CNC(=O)c1ncc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.59 (br s, 1H), 9.39 (s, 2H), 9.31 (br s, 1H), 9.01 (q, 4.6 Hz, 1H), 8.24 (d, 1.1 Hz, 1H), 8.02 (s, 1H), 7.98 (d, 8.5 Hz, 1H), 7.78 (d, 8.3 Hz, 1H), 7.71 (s, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.12 (td, 8.5, 2.9 Hz, 1H), 6.65 (br s, 1H), 6.07 (br s, 1H), 2.85 (d, 4.8 Hz, 2H)。 602.2 B   
I-1507
Figure 02_image3305
 CC(C)(CNC(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl)C1(O)CCC1 1H NMR (400 MHz, DMSO-d6) 9.16 (s, 1H), 8.13 (s, 1H), 7.83 (s, 1H), 7.52 (d, 1.7 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.21 (td, 8.4, 3.1 Hz, 1H), 6.70 (s, 1H), 6.20 (t, 6.1 Hz, 1H), 5.99 (s, 1H), 4.86 (s, 1H), 3.03 (d, 8.7 Hz, 1H), 2.82 (dd, 13.5, 5.2 Hz, 1H), 2.16 - 2.06 (m, 3H), 1.82 - 1.71 (m, 2H), 1.44 - 1.34 (m, 1H), 0.69 (d, 10.8 Hz, 6H)。 526.25 E   
I-1508
Figure 02_image3307
 CC1(O)CN(C(=O)Nc2cc(Br)cc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccccc12 1H NMR (400 MHz, DMSO-d6) 9.20 (s, 1H), 8.68 (s, 1H), 7.82 (d, 8.1 Hz, 1H), 7.68 (d, 1.8 Hz, 1H), 7.59 (d, 1.8 Hz, 1H), 7.37 (dd, 8.8, 5.1 Hz, 1H), 7.31 (d, 7.4 Hz, 1H), 7.27 - 7.12 (m, 2H), 7.00 (t, 7.4 Hz, 1H), 6.68 (s, 1H), 5.97 (s, 1H), 5.53 (s, 1H), 3.78 (d, 10.7 Hz, 1H), 2.96 (s, 1H), 1.39 (s, 3H)。 532 D   
I-1509
Figure 02_image3309
 Fc1ccc2N(CC3(CC3)c2c1)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  9.19 (s, 1H), 8.61 (s, 1H), 7.66 (s, 2H), 7.59 (d, 1.8 Hz, 1H), 7.37 (dd, 8.9, 5.0 Hz, 1H), 7.18 (t, 7.7 Hz, 1H), 6.89 (t, 8.9 Hz, 1H), 6.67 (dd, 8.8, 2.7 Hz, 1H), 5.94 (s, 1H), 3.81 (d, 10.0 Hz, 1H), 3.18 (s, 1H), 1.09 (s, 2H), 0.97 (t, 9.6 Hz, 2H)。 544 A   
I-1510
Figure 02_image3311
 Fc1ccc2N(CC3(CC3)c2c1)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  9.19 (s, 1H), 8.61 (s, 1H), 7.65 (d, 10.6 Hz, 2H), 7.59 (d, 1.8 Hz, 1H), 7.37 (dd, 9.0, 5.1 Hz, 1H), 7.18 (td, 8.3, 3.0 Hz, 1H), 6.88 (td, 9.1, 2.6 Hz, 1H), 6.67 (dd, 8.7, 2.7 Hz, 1H), 5.93 (s, 1H), 3.81 (d, 10.0 Hz, 1H), 3.18 (s, 1H), 1.09 (d, 3.0 Hz, 2H), 1.02 - 0.90 (m, 2H)。 544 D   
I-1511
Figure 02_image3313
 C[C@@]1(O)CN(C(=O)Nc2cc(Br)cc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccccc12 1H NMR (400 MHz, DMSO-d6) 9.20 (s, 1H), 8.68 (s, 1H), 7.82 (d, 8.1 Hz, 1H), 7.68 (d, 1.8 Hz, 1H), 7.59 (d, 1.8 Hz, 1H), 7.37 (dd, 8.8, 5.1 Hz, 1H), 7.31 (d, 7.4 Hz, 1H), 7.27 - 7.12 (m, 2H), 7.00 (t, 7.4 Hz, 1H), 6.68 (s, 1H), 5.97 (s, 1H), 5.53 (s, 1H), 3.78 (d, 10.7 Hz, 1H), 2.96 (s, 1H), 1.39 (s, 3H)。 514 A   
I-1512
Figure 02_image3315
 Fc1ccc2N(CC3(CC3)c2c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  9.20 (s, 1H), 8.61 (s, 1H), 7.63 (dd, 29.2, 1.7 Hz, 3H), 7.38 (dd, 8.8, 5.1 Hz, 1H), 7.18 (td, 8.4, 3.1 Hz, 1H), 7.06 - 6.24 (m, 3H), 5.94 (s, 1H), 3.81 (d, 10.0 Hz, 1H), 3.19 (s, 1H), 1.15 - 1.04 (m, 2H), 1.03 - 0.91 (m, 2H)。 543.95 B   
I-1513
Figure 02_image3317
 O[C@H]1CN(C(=O)Nc2cc(Br)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccccc12 1H NMR (400 MHz, DMSO-d6) 9.20 (s, 1H), 8.72 (s, 1H), 7.82 (d, 8.2 Hz, 1H), 7.71 - 7.66 (m, 1H), 7.60 (d, 1.8 Hz, 1H), 7.40 - 7.30 (m, 2H), 7.24 (t, 7.8 Hz, 1H), 7.16 (td, 8.4, 3.1 Hz, 1H), 6.99 (t, 7.4 Hz, 1H), 6.67 (s, 1H), 5.98 (s, 1H), 5.66 (d, 6.0 Hz, 1H), 5.12 - 5.03 (m, 1H), 3.62 (dd, 11.2, 3.5 Hz, 1H), 3.23 (s, 1H)。 518 B   
I-1514
Figure 02_image3319
 O[C@@H]1CN(C(=O)Nc2cc(Br)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccccc12 1H NMR (400 MHz, DMSO-d6) 9.20 (s, 1H), 8.72 (s, 1H), 7.82 (d, 8.2 Hz, 1H), 7.71 - 7.66 (m, 1H), 7.60 (d, 1.8 Hz, 1H), 7.40 - 7.30 (m, 2H), 7.24 (t, 7.8 Hz, 1H), 7.16 (td, 8.4, 3.1 Hz, 1H), 6.99 (t, 7.4 Hz, 1H), 6.67 (s, 1H), 5.98 (s, 1H), 5.66 (d, 6.0 Hz, 1H), 5.12 - 5.03 (m, 1H), 3.62 (dd, 11.2, 3.5 Hz, 1H), 3.23 (s, 1H)。 518 A B
I-1515
Figure 02_image3321
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cccc4c(Cl)n[nH]c34)c12 1H NMR (400 MHz, DMSO-d6) 13.44 (s, 1H), 10.49 (s, 1H), 9.29 (s, 1H), 7.90 (d, 8.1 Hz, 1H), 7.81 (q, 1.8 Hz, 2H), 7.59 (d, 7.3 Hz, 1H), 7.31-7.21 (m, 2H), 7.08-6.99 (m, 1H), 6.08 (s, 1H)。 522.95 D   
I-1516
Figure 02_image3323
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(c12)-n1cnc2ccccc2c1=O 1H NMR (400 MHz, DMSO-d6)  9.30 (s, 1H), 8.60-8.05 (s, 1H), 8.02-7.31 (m, 7H), 7.32-6.80(m, 2H), 6.80-5.39 (m, 2H)。 406.05 E   
I-1517
Figure 02_image3325
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(OC[C@@H]3CCO3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6 )  10.47 (br. s, 1H), 9.14 (br. s, 1H), 7.95 (d, 8.4 Hz, 1H), 7.72 (d, 9.1 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.26 (s, 1H), 7.13 (s, 1H), 7.09 (dt, 8.5, 3.0 Hz, 1H), 6.58 (br. s, 1H), 5.93 (br. s, 1H), 5.10 - 5.00 (m, 1H), 4.61-4.41 (m, 2H), 4.27 m, 2H), 2.79 - 2.65 ( m, 1H), 2.63-2.53 (m, 1H)。 553.1 A   
I-1518
Figure 02_image3327
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(OC[C@H]3CCO3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.47 (br. s, 1H), 9.14 (br. s, 1H), 7.95 (d, 8.4 Hz, 1H), 7.72 (d, 9.1 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.26 (s, 1H), 7.13 (s, 1H), 7.09 (dt, 8.5, 3.0 Hz, 1H), 6.58 (br. s, 1H), 5.93 (br. s, 1H), 5.10 - 5.00 (m, 1H), 4.61-4.41 (m, 2H), 4.27 m, 2H), 2.79 - 2.65 ( m, 1H), 2.63-2.53 (m, 1H)。 553.1 A   
I-1519
Figure 02_image3329
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(OC[C@@H]3CCO3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6 )  10.47 (br. s, 1H), 9.14 (br. s, 1H), 7.95 (d, 8.4 Hz, 1H), 7.72 (d, 9.1 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.26 (s, 1H), 7.13 (s, 1H), 7.09 (dt, 8.5, 3.0 Hz, 1H), 6.58 (br. s, 1H), 5.93 (br. s, 1H), 5.10 - 5.00 (m, 1H), 4.61-4.41 (m, 2H), 4.27 m, 2H), 2.79 - 2.65 ( m, 1H), 2.63-2.53 (m, 1H)。 553.1 E   
I-1520
Figure 02_image3331
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(OC[C@H]3CCO3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.47 (br. s, 1H), 9.14 (br. s, 1H), 7.95 (d, 8.4 Hz, 1H), 7.72 (d, 9.1 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.26 (s, 1H), 7.13 (s, 1H), 7.09 (dt, 8.5, 3.0 Hz, 1H), 6.58 (br. s, 1H), 5.93 (br. s, 1H), 5.10 - 5.00 (m, 1H), 4.61-4.41 (m, 2H), 4.27 m, 2H), 2.79 - 2.65 ( m, 1H), 2.63-2.53 (m, 1H)。 553.1 E   
I-1521
Figure 02_image3333
 CN1C[C@H](COc2cc3C(=O)N[C@@H](c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CC1=O 1H NMR (400 MHz, DMSO-d6) 10.44 (br. s, 1H), 9.11 (br. s, 1H), 7.92 (br. d, 7.1 Hz, 1H), 7.71 (br. d, 8.9 Hz, 1H), 7.65 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.20 (s, 1H), 7.13 (s, 1H), 7.08 (dt, 5.6, 3.0 Hz, 1H), 6.58 (br. s, 1H), 5.92 (br. s, 1H), 4.20-3.98 (m, 2H), 3.54 (dd, 9.7, 8.3 Hz, 1H), 3.24 (dd, 9.6, 5.0 Hz, 1H), 2.90-2.76 (m, 1H), 2.73 (s, 3H), 2.44 (dd, 17.0, 9.2 Hz, 1H), 2.17 (dd, 16.8, 6.4 Hz, 1H) 594.2 A   
I-1522
Figure 02_image3335
 CN1C[C@H](COc2cc3C(=O)N[C@H](c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CC1=O 1H NMR (400 MHz, DMSO-d6) 10.44 (br. s, 1H), 9.11 (br. s, 1H), 7.92 (br. d, 7.1 Hz, 1H), 7.71 (br. d, 8.9 Hz, 1H), 7.65 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.20 (s, 1H), 7.13 (s, 1H), 7.08 (dt, 5.6, 3.0 Hz, 1H), 6.58 (br. s, 1H), 5.92 (br. s, 1H), 4.20-3.98 (m, 2H), 3.54 (dd, 9.7, 8.3 Hz, 1H), 3.24 (dd, 9.6, 5.0 Hz, 1H), 2.90-2.76 (m, 1H), 2.73 (s, 3H), 2.44 (dd, 與溶劑峰重疊, 17.0, 9.2 Hz, 1H), 2.17 (dd, 16.8, 6.4 Hz, 1H)；2.67及2.33處之DMSO衛星；7.13 (s, 1H)處之信號與7.08  (dt, 5.6, 3.0 Hz, 1H)處之信號部分重疊。 594.2 A   
I-1523
Figure 02_image3337
 CN1C[C@@H](COc2cc3C(=O)N[C@@H](c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CC1=O 1H NMR (400 MHz, DMSO-d6) 10.44 (br. s, 1H), 9.11 (br. s, 1H), 7.92 (br. d, 7.1 Hz, 1H), 7.71 (br. d, 8.9 Hz, 1H), 7.65 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.20 (s, 1H), 7.13 (s, 1H), 7.08 (dt, 5.6, 3.0 Hz, 1H), 6.58 (br. s, 1H), 5.92 (br. s, 1H), 4.20-3.98 (m, 2H), 3.54 (dd, 9.7, 8.3 Hz, 1H), 3.24 (dd, 9.6, 5.0 Hz, 1H), 2.90-2.76 (m, 1H), 2.73 (s, 3H), 2.44 (dd, 與溶劑峰重疊, 17.0, 9.2 Hz, 1H), 2.17 (dd, 16.8, 6.4 Hz, 1H)；2.67及2.33處之DMSO衛星；7.13 (s, 1H)處之信號與7.08  (dt, 5.6, 3.0 Hz, 1H)處之信號部分重疊。 594.2 D   
I-1524
Figure 02_image3339
 CN1C[C@@H](COc2cc3C(=O)N[C@H](c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CC1=O 1H NMR (400 MHz, DMSO-d6) 10.44 (br. s, 1H), 9.11 (br. s, 1H), 7.92 (br. d, 7.1 Hz, 1H), 7.71 (br. d, 8.9 Hz, 1H), 7.65 (s, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.20 (s, 1H), 7.13 (s, 1H), 7.08 (dt, 5.6, 3.0 Hz, 1H), 6.58 (br. s, 1H), 5.92 (br. s, 1H), 4.20-3.98 (m, 2H), 3.54 (dd, 9.7, 8.3 Hz, 1H), 3.24 (dd, 9.6, 5.0 Hz, 1H), 2.90-2.76 (m, 1H), 2.73 (s, 3H), 2.44 (dd, 17.0, 9.2 Hz, 1H), 2.17 (dd, 16.8, 6.4 Hz, 1H) 594.2 E   
I-1525
Figure 02_image3341
 CC(=O)N1CCC[C@@H](C1)Oc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-D6)  10.44 (s, 1 H), 9.14 (s, 1 H), 7.95 (d, 8.3 Hz, 1 H), 7.71 (d, 8.4 Hz, 1 H), 7.64 (s, 1 H), 7.31 (dd, 8.8, 5.2 Hz, 1 H), 7.26 (ddd, 13.7, 6.3, 2.1 Hz, 1 H), 7.14-7.02 (m, 2 H), 6.60 (br s, 1 H), 5.92 (br s, 1 H), 4.78-4.68 (m, 0.5 H), 4.54-4.43 (m, 0.5 H), 3.93 (ddd, 15.8, 12.7, 2.6 Hz, 0.5 H), 3.84-3.35 (m, 2.5 H), 3.25-3.09 (m, 1 H), 2.10 - 1.85 (m, 4.5 H), 1.84 - 1.40 (m, 2.5 H)。 608.3 B   
I-1526
Figure 02_image3343
 CS(=O)(=O)N1CCC[C@@H](C1)Oc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-D6)  10.47 (s, 0.5 H), 10.45 (s, 0.5 H), 9.15 (s, 1 H), 7.95 (br d, 8.5 Hz, 1 H), 7.71 (br d, 8.9 Hz, 1 H), 7.63 (s, 1 H), 7.31 (ddd, 8.8, 5.2, 0.7 Hz, 1 H), 7.27 (dd, 4.6, 2.1 Hz, 1 H), 7.13-7.04 (m, 2 H), 6.56 (br s, 1 H), 5.92 (br s, 1 H), 4.78-4.62 (m, 1 H), 3.54-3.44 (m, 1 H), 3.32 - 3.10 (m, 3 H), 2.93 (s, 1.5 H), 2.92 (s, 1.5 H), 2.02 - 1.96 (m, 1 H), 1.92-1.80 (m, 1 H), 1.78 - 1.68 (m, 1 H), 1.67 - 1.59 (m, 1 H)。 644.2 B   
I-1527
Figure 02_image3345
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(O[C@H]3CCCNC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-D6+D2O)  7.92 (d, 8.5 Hz, 1 H), 7.66 (d, 9.1 Hz, 1 H), 7.57 (s, 1 H), 7.35 (app dd, 3.3, 2.3 Hz, 1 H), 7.30 (dd, 8.7, 5.2 Hz, 1 H), 7.17 (dd, 7.0, 1.5 Hz, 1 H), 7.07 (td, 8.3, 2.8 Hz, 1 H), 6.62 (br s, 1 H), 5.90 (br s, 1 H), 4.87 (s, 1 H), 3.37 - 3.27 (m, 2 H), 3.18-3.09 (m, 1 H), 3.09-2.98 (m, 1 H), 1.98 - 1.82 (m, 3 H), 1.76-1.61 (m, 1 H)。 566.3 B   
I-1528
Figure 02_image3347
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Cc3ccc4nncn4c3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.48 (br. s, 1H), 9.24 (s, 1H), 9.14 (br. s, 1H), 8.55 (s, 1H), 7.93 (br. d, 8.6 Hz, 1H), 7.74 (d, 9.5 Hz, 1H), 7.70 (br. d, 8.7 Hz, 1H), 7.68 (s, 1H), 7.65-7.59 (m, 1H), 7.39 (s, 1H), 7.31 (d, 9.6 Hz, 1H), 7.30 (dd, 8.9, 5.3 Hz, 1H), 7.08 (app. td, 8.3, 2.9 Hz, 1H), 6.58 (br. s, 1H), 5.94 (br. s, 1H), 4.17 (d, AB之A, JAB = 16.1 Hz, 1H), 4.12 (d, AB之B, JAB = 15.6 Hz, 1H)。 598.3 A   
I-1529
Figure 02_image3349
 CC(C)(O)COc1ncc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)  10.50 (br. s, 1H), 9.26 (br. s, 1H), 9.04 (s, 2H), 8.06 (d, 1.4 Hz, 1H), 7.97 (br. d, 8.4 Hz, 1H), 7.86 (s, 1H), 7.77 (br. d, 8.8 Hz, 1H), 7.70 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.11 (app. td, 8.5, 3.1 Hz, 1H), 6.61 (br. s, 1H), 6.04 (br. s, 1H), 4.74 (br. s, 1H), 4.15 (s, 2H), 1.23 (s, 6H)。 633.3 A   
I-1530
Figure 02_image3351
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc(OCC#N)nc1 (400 MHz, DMSO-d6)  10.75 (br s, 1H), 9.26 (br s, 1H), 9.17 (s, 1H), 9.16 (s, 1H), 8.10 (s, 1H), 7.96 (d, 7.5 Hz, 1H), 7.91 (s, 1H), 7.77 (d, 8.7 Hz, 1H), 7.71 (s, 1H), 7.37-7.29 (m, 1H), 7.11 (t, 8.2 Hz, 1H), 6.68 (br s, 1H), 6.04 (br s, 1H), 5.35 (s, 2H) 598.3 A   
I-1531
Figure 02_image3353
 Nc1nc2cc(ccc2o1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, CD3CN)  8.73 (s, 1H), 7.99 (d, 1.4 Hz, 1H), 7.80 (s, 1H), 7.69-7.59 (m, 4H), 7.40 (s, 2H), 7.30 (br. s, 1H), 7.27 (dd, 8.9, 5.1 Hz, 1H), 6.98 (ddd, 8.7, 8.1, 3.1 Hz, 1H), 6.68 (br. s, 1H), 6.18 (br. s, 1H), 5.85 (br. s, 2H)。 599.2 A   
I-1532
Figure 02_image3355
 CN(C)C(=O)OCc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO)  10.54 (br s, 1H), 9.19 (br s, 1H), 7.95 (d, 8.6 Hz, 1H), 7.73 (d, 8.9 Hz, 1H), 7.67 (s, 1H), 7.64 (s, 1H), 7.47 (s, 1H), 7.31 (dd, 8.7, 5.2 Hz, 1H), 7.09 (td, 8.5, 2.7 Hz, 1H), 6.61 (br s, 1H), 5.97 (br s, 1H), 5.23 (s, 2H), 2.92 (s, 3H), 2.86 (s, 3H)。 568.1 A   
I-1533
Figure 02_image3357
 CNS(=O)(=O)Cc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, CD3CN)  8.74 (s,1H), 7.75 (d, 1.4 Hz,1H), 7.68-7.53 (m, 1H), 7.62--7.54 (m,3H)7.32-7.23 (m, 2H), 6.98 (ddd, 8.9, 8.0, 3.1 Hz,1H), 6.64 (br, s,1H), 6.25-6.04 (br, s,1H), 5.22 (q, 4.8Hz,1H), 4.45 (s,2H), 2.71 (d, 5.0 Hz,3H)。 574 B   
I-1534
Figure 02_image3359
 CNS(=O)(=O)Cc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    574 A   
I-1535
Figure 02_image3361
 Cn1cc(NS(=O)(=O)Cc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)cn1 NMR (400 MHz, CD3CN)  8.78 (s, 1H), 7.71 (s, 1H), 7.65 (d, 8.4 Hz, 1H), 7.61 (s, 1H), 7.58 (d, 9.0 Hz, 1H), 7.55 (s, 1H)7.52 (s, 1H), 7.34 (s, 1H), 7.30 (br, s, 1H), 7.27 (dd, 8.9, 5.1 Hz, 1H), 6.98 (td, 8.4, 3.0 Hz, 1H), 6.67 (br, s, 1H), 6.11 (br, s, 1H), 4.49 (d, 14.1 Hz, 1H), 4.45 (d, 14.1 Hz, 1H), 3.82 (s, 3H)。 640 A   
I-1536
Figure 02_image3363
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CS(=O)(=O)c3cccnc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, CD3CN)  8.84 (s, 1H), 8.83 (s, 1H), 8.65 (s, 1H), 8.03 (d, 7.9 Hz, 1H), 7.65 (d, 8.2 Hz, 1H), 7.58 (d, 9.1 Hz, 1H), 7.55-7.50 (m, 2H), 7.48 (s, 2H), 7.27 (dd, 8.8, 5.1 Hz, 1H), 7.27 (NH, s, 1H), 6.98 (td, 8.4, 3.0 Hz, 1H), 6.68 (br, s, 1H), 6.11 (br, s, 1H), 4.68 (s, 2H)。 622 A   
I-1537
Figure 02_image3365
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnccc1C#N       A   
I-1538
Figure 02_image3367
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1C#N       A   
I-1539
Figure 02_image3369
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ncnc2cc1C#N       A   
I-1540
Figure 02_image3371
 CC(C)(O)c1cnc2ccc(cc2c1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    652.6 A   
I-1541
Figure 02_image3373
 CC(=O)N1CC[C@@H](C1)Oc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-D6)  9.17 (s, 1 H), 7.94 (br d, 8.4 Hz, 1 H), 7.72 (br d, 9.0 Hz, 1 H), 7.64 (s, 1 H), 7.31 (dd, 8.8, 5.2 Hz, 1 H), 7.24 (app t, 2.0 Hz, 0.5 H), 7.22 (d, 2.1 Hz, 0.25 H), 7.21 (d, 2.1 Hz, 0.25 H), 7.12 - 7.04 (m, 2 H), 6.54 (br s, 1 H), 5.94 (br s, 1 H), 5.27 (s, 0.5 H), 5.18 (s, 0.5 H), 3.85 (dd, 11.8, 4.4 Hz, 0.5 H), 3.69-3.62 (m, 1 H), 3.62-3.51 (m, 2 H), 3.33 (td, 10.4, 2.3 Hz, 0.5 H), 2.34 - 2.18 (m, 1 H), 2.17-2.01 (m, 1 H), 1.98 (s, 1.5 H), 1.96 (s, 0.75 H), 1.94 (s, 0.75 H)。 594.3 B   
I-1542
Figure 02_image3375
 OCC(O)c1ncc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMS-d6)  10.75 (br s, 1H), 9.27 (br s, 1H), 9.24 (s, 2H), 8.14 (s, 1H), 7.97 (d, 8.8 Hz, 1H), 7.94 (s, 1H), 7.77 (d, 8.4 Hz), 7.70 (s, 1H), 7.34 (dd, 8.9, 5.1 Hz, 1H), 7.11 (td, 8.6, 3.0 Hz, 1H), 6.63 (br s, 1H), 6.04 (br s, 1H), 5.36 (d, 6.2 Hz, 1H), 4.75-4.69 (m, 2H), 3.91-3.67 (m, 2H)。 605.2 A   
I-1543
Figure 02_image3377
 CS(=O)(=O)Oc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-D6)  10.68 (br s, 1 H), 9.36 (br s, 1 H), 7.96 (br d, 8.4 Hz, 1 H), 7.73 (br d, 9.0 Hz, 1 H), 7.66 (d, 1.8 Hz, 1 H), 7.64 (s, 1 H), 7.52 (s, 1 H), 7.33 (dd, 8.9, 5.2 Hz, 1 H), 7.11 (td, 8.5, 3.0 Hz, 1 H), 6.71 (br s, 1 H), 6.02 (br s, 1 H), 3.50 (s, 3 H)。 559.2 A   
I-1544
Figure 02_image3379
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc2ocnc2c1 NMR (400 MHz, DMSO-d6)  10.65 (br s, 1H), 9.26 (br s, 1H), 9.00 (s, 1H), 8.84 (d, 2.2 Hz, 1H), 8.72 (d, 2.1 Hz, 1H), 8.09 (d, 1.3 Hz, 1H), 7.97 (d, 8.4 Hz, 1H), 7.93 (s, 1H), 7.77 (d, 9.0 Hz, 1H), 7.71 (s, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.6, 3.0 Hz, 1H), 6.66 (br s, 1H), 6.06 (br s, 1H)。 583.2 A   
I-1545
Figure 02_image3381
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc4CCC(=O)Nc34)c12 1H NMR (400 MHz, DMSO-d6) 10.35 (s, 1H), 10.16 (s, 1H), 9.15 (s, 1H), 7.72 (d, 7.4 Hz, 1H), 7.65 (t, 7.6 Hz, 1H), 7.51 (d, 7.7 Hz, 1H), 7.40-7.32 (m, 2H), 7.13 (td, 8.4, 3.1 Hz, 1H), 6.97-6.89 (m, 1H), 6.53 (s, 1H), 6.01 (s, 1H), 2.96 (q, 9.6, 8.6 Hz, 2H), 2.52 (s, 2H)。 468.1 E   
I-1546
Figure 02_image3383
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc4CCC(=O)Nc34)c12 1H NMR (400 MHz, DMSO-d6) 10.41 (s, 1H), 10.08 (s, 1H), 9.30 (s, 1H), 7.83 (s, 1H), 7.78 (d, 1.7 Hz, 1H), 7.37 (dt, 8.5, 4.3 Hz, 2H), 7.15 (td, 8.4, 3.1 Hz, 1H), 6.84 (d, 9.4 Hz, 1H), 6.68 (s, 1H), 5.99 (s, 1H), 2.96 (q, 8.5, 8.0 Hz, 2H), 2.52 (s, 2H)。 546 E   
I-1547
Figure 02_image3385
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc4c3NC(=O)C4(F)F)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)11.30-10.90(s,1H),10.56 (s, 1H), 9.48 (d, 1.7 Hz, 1H), 9.27 (s, 1H), 8.59 (s, 1H), 8.17-8.10 (m, 2H), 8.00 (d, 9.6 Hz, 3H), 7.38 (d, 9.1 Hz, 2H), 7.14 (s, 1H),6.20-5.90 (s, 1H)。 607.05 A   
I-1548
Figure 02_image3387
 CNC(=O)c1cc2C(=O)NC(c2c(NC(=O)c2ccccc2)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)10.27 (s, 1H), 9.22 (s, 1H), 8.76 (d, 4.8 Hz, 1H), 8.16 (d, 1.5 Hz, 1H), 8.02 (d, 1.6 Hz, 1H), 7.62-7.51 (m, 3H), 7.44 (t, 7.6 Hz, 2H), 7.35 (dd, 8.9, 5.1 Hz, 1H), 7.12 (td, 8.3, 3.0 Hz, 1H), 6.70 (s, 1H), 6.10 (s, 1H), 2.83 (d, 4.4 Hz, 3H)。 438.1 E   
I-1549
Figure 02_image3389
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3CCCCC3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.70 (s, 1H), 9.43 (dd, 1.9, 0.9 Hz, 1H), 9.19 (s, 1H), 8.57 (s, 1H), 8.09 (dd, 9.3, 1.9 Hz, 1H), 8.02 - 7.94 (m, 2H), 7.81 (d, 1.7 Hz, 1H), 7.51 (s, 1H), 7.25 (td, 8.4, 3.1 Hz, 1H), 6.13 (s, 1H), 2.06 (s, 1H), 1.62 (d, 16.2 Hz, 3H), 1.48 (s, 1H), 1.33 (s, 1H), 1.17 (d, 10.8 Hz, 1H), 1.13 (s, 4H)。 504.2 D   
I-1550
Figure 02_image3391
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3ccccc3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  10.28 (s, 1H), 9.47 (d, 1.7 Hz, 1H), 9.23 (s, 1H), 8.58 (s, 1H), 8.14 (dd, 9.3, 2.0 Hz, 1H), 8.09 (d, 1.7 Hz, 1H), 8.02-7.95 (m, 2H), 7.66-7.59 (m, 2H), 7.56 (t, 7.3 Hz, 1H), 7.45 (t, 7.6 Hz, 2H), 7.37 (dd, 8.9, 5.2 Hz, 1H), 7.14 (td, 8.3, 3.1 Hz, 1H), 6.15 (s, 1H)。 498 D   
I-1551
Figure 02_image3393
 [2H]C([2H])(c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)S(C)(=O)=O NMR (400 MHz, CD3CN)  8.72 (br, s, 1H), 7.78 (d, 1.4 Hz, 1H), 7.65 (br, d, 8.5 Hz, 1H), 7.63 (s, 1H), 7.60 (br, d, 9.1 Hz, 1H), 7.56 (s, 1H), 7.30 (br, s, 1H), 7.26 (dd, 8.9, 5.1 Hz, 1H), 6.98 (ddd, 8.8, 8.1, 3.1 Hz,1H), 6.66 (br, s, 1H), 6.14 (br, s, 1H), 2.89 (s, 3H)。 561 A   
I-1552
Figure 02_image3395
 Oc1ccc(nc1NC=O)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-D6)  10.59 (br s, 1 H), 9.92 (br s, 1 H), 9.40 (s, 1 H), 9.18 (s, 1 H), 8.21 (s, 1 H), 8.15 (s, 1 H), 7.95 (d, 8.4 Hz, 1 H), 7.79 - 7.73 (m, 2 H), 7.68 (s, 1 H), 7.35-7.30 (m, 1 H), 7.29 (d, 10.0 Hz, 1 H), 7.09 (td, 8.4, 3.0 Hz, 1 H), 6.67 (br s, 1 H), 6.00 (br s, 1 H)。 601.2 A   
I-1553
Figure 02_image3397
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ocnc2n1 (400 MHz, DMSO-D6)  9.26 (br s, 1 H), 9.12 (s, 1 H), 8.70 (br s, 1 H), 8.41 (d, 8.5 Hz, 1 H), 8.40 (s, 1 H), 8.36 (d, 1.2 Hz, 1 H), 8.29 (d, 8.6 Hz, 1 H), 7.96 (d, 8.4 Hz, 1 H), 7.80 (d, 9.1 Hz, 1 H), 7.74 (s, 1 H), 7.34 (dd, 8.9, 5.2 Hz, 1 H), 7.11 (td, 8.5, 3.0 Hz, 1 H), 6.69 (br s, 1 H), 6.07 (br s, 1 H)。 585.2 A   
I-1554
Figure 02_image3399
異構體 1 		Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(c1)-c1ncccn1 NMR (400 MHz, DMSO-d6)  10.57 (br s, 1H), 9.29 (s, 1H), 9.20 (br s, 1H), 8.93 (d, 4.8 Hz, 2H), 8.54 (s, 1H), 8.14 (s, 1H), 7.97 (br d, 7.1 Hz, 1H), 7.96 (s, 1H), 7.78 (br d, 9.6 Hz, 1H), 7.73 (s, 1H), 7.53 (t, 4.8 Hz, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.5, 3.1 Hz, 1H), 6.65 (br s, 1H), 6.01 (br s, 1H)。 611 D   
I-1555
Figure 02_image3401
異構體 2 		Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(c1)-c1ncccn1 NMR (400 MHz, DMSO-d6)  10.57 (br s, 1H), 9.29 (s, 1H), 9.20 (br s, 1H), 8.93 (d, 4.8 Hz, 2H), 8.54 (s, 1H), 8.14 (s, 1H), 7.97 (br d, 7.1 Hz, 1H), 7.96 (s, 1H), 7.78 (br d, 9.6 Hz, 1H), 7.73 (s, 1H), 7.53 (t, 4.8 Hz, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.5, 3.1 Hz, 1H), 6.65 (br s, 1H), 6.01 (br s, 1H)。 611 A   
I-1556
Figure 02_image3403
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CS(=O)(=O)N3CC(C3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  10.60 (s, 1H), 9.22 (br. s, 1H), 7.95 (br. d, 8.5 Hz, 1H), 7.79 (s, 1H), 7.74 (br. d, 8.8 Hz, 1H), 7.65 (s, 1H), 7.55 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.4, 3.0 Hz, 1H), 6.66 (br. s, 1H), 5.97 (br. s, 1H), 4.85 (s, 2H), 4.22-4.11 (m, 3H), 4.10-4.04 (m, 1H), 3.87-3.78 (m, 1H)。 625.2 A   
I-1557
Figure 02_image3405
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Cn3ccnc3C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.57 (br. s, 1H), 9.24 (br. s, 1H), 7.95 (br. d, 8.5 Hz, 1H), 7.85 (d, 1.0 Hz, 1H), 7.71 (br. d, 8.9 Hz, 1H), 7.62-7.59 (m, 2H), 7.37-7.33 (m, 1H), 7.31 (dd, 8.9, 5.2 Hz, 1H), 7.31 (d, 1.0 Hz, 1H), 7.09 (td, 8.4, 3.1 Hz, 1H), 6.58 (br. s, 1H), 5.97 (br. s, 1H), 5.66-5.58 (m, 2H)。 572.1 A   
I-1558
Figure 02_image3407
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)[C@H]1CNC(=O)O1 NMR (400 MHz, DMSO)  10.60 (s, 1H), 9.23 (s, 1H), 7.95 (d, 8.4 Hz, 1H), 7.82 (s, 0.5H), 7.81 (s, 0.5H), 7.74 (d, 9.1 Hz, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.54 (s, 0.5H), 7.53 (s, 0.5H), 7.32 (dd, 8.8, 5.1 Hz, 1H), 7.14-7.06 (m, 1H), 6.59 (br s, 1H), 6.00 (br s, 1H), 5.81 (dd, 15.3, 7.8 Hz, 1H), 3.99 (td, 8.8, 6.7 Hz, 1H), 3.45-3.37 (m, 1H)。 552.1 B   
I-1559
Figure 02_image3409
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)[C@H]1CNC(=O)O1 NMR (400 MHz, DMSO)  10.60 (s, 1H), 9.23 (s, 1H), 7.95 (d, 8.4 Hz, 1H), 7.82 (s, 0.5H), 7.81 (s, 0.5H), 7.74 (d, 9.1 Hz, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.54 (s, 0.5H), 7.53 (s, 0.5H), 7.32 (dd, 8.8, 5.1 Hz, 1H), 7.14-7.06 (m, 1H), 6.59 (br s, 1H), 6.00 (br s, 1H), 5.81 (dd, 15.3, 7.8 Hz, 1H), 3.99 (td, 8.8, 6.7 Hz, 1H), 3.45-3.37 (m, 1H)。 552.1 A   
I-1560
Figure 02_image3411
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)[C@@H]1CNC(=O)O1 NMR (400 MHz, DMSO)  10.60 (s, 1H), 9.23 (s, 1H), 7.95 (d, 8.4 Hz, 1H), 7.82 (s, 0.5H), 7.81 (s, 0.5H), 7.74 (d, 9.1 Hz, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.54 (s, 0.5H), 7.53 (s, 0.5H), 7.32 (dd, 8.8, 5.1 Hz, 1H), 7.14-7.06 (m, 1H), 6.59 (br s, 1H), 6.00 (br s, 1H), 5.81 (dd, 15.3, 7.8 Hz, 1H), 3.99 (td, 8.8, 6.7 Hz, 1H), 3.45-3.37 (m, 1H)。 552.1 C   
I-1561
Figure 02_image3413
 CS(=O)(Cc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)=NC#N NMR (187) (400 MHz, DMSO-d6)  10.68 (br. s, 1H), 9.29 ( s, 1H), 7.95 (br. d, 8.3 Hz, 1H), 7.84 (s, 1H), 7.73 (br. d, 8.9 Hz, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.4, 2.9 Hz, 1H), 6.65 (br. s, 1H), 6.03 (br. s, 1H), 5.29-5.18 (m, 2H), 3.45 (s, 3H)。 583.1 B   
I-1562
Figure 02_image3415
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)[C@@H]1CNC(=O)O1 NMR (400 MHz, DMSO)  10.60 (s, 1H), 9.23 (s, 1H), 7.95 (d, 8.4 Hz, 1H), 7.82 (s, 0.5H), 7.81 (s, 0.5H), 7.74 (d, 9.1 Hz, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.54 (s, 0.5H), 7.53 (s, 0.5H), 7.32 (dd, 8.8, 5.1 Hz, 1H), 7.14-7.06 (m, 1H), 6.59 (br s, 1H), 6.00 (br s, 1H), 5.81 (dd, 15.3, 7.8 Hz, 1H), 3.99 (td, 8.8, 6.7 Hz, 1H), 3.45-3.37 (m, 1H)。 552.1 A   
I-1563
Figure 02_image3417
 CS(=O)(Cc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)=NC#N NMR (187) (400 MHz, DMSO-d6)  10.68 (br. s, 1H), 9.29 ( s, 1H), 7.95 (br. d, 8.3 Hz, 1H), 7.84 (s, 1H), 7.73 (br. d, 8.9 Hz, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.4, 2.9 Hz, 1H), 6.65 (br. s, 1H), 6.03 (br. s, 1H), 5.29-5.18 (m, 2H), 3.45 (s, 3H)。 583.1 A   
I-1564
Figure 02_image3419
 CS(=O)(Cc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)=NC#N NMR (187) (400 MHz, DMSO-d6)  10.68 (br. s, 1H), 9.29 ( s, 1H), 7.95 (br. d, 8.3 Hz, 1H), 7.84 (s, 1H), 7.73 (br. d, 8.9 Hz, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.4, 2.9 Hz, 1H), 6.65 (br. s, 1H), 6.03 (br. s, 1H), 5.29-5.18 (m, 2H), 3.45 (s, 3H)。 583.1 A   
I-1565
Figure 02_image3421
 CS(=O)(Cc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)=NC#N NMR (187) (400 MHz, DMSO-d6)  10.68 (br. s, 1H), 9.29 ( s, 1H), 7.95 (br. d, 8.3 Hz, 1H), 7.84 (s, 1H), 7.73 (br. d, 8.9 Hz, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.4, 2.9 Hz, 1H), 6.65 (br. s, 1H), 6.03 (br. s, 1H), 5.29-5.18 (m, 2H), 3.45 (s, 3H)。 583.1 A   
I-1566
Figure 02_image3423
 CN1[C@H](COc2cc3C(=O)N[C@H](c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CCC1=O 1H NMR (400 MHz, DMSO-d6)  10.44 (s, 1H), 9.14 (s, 1H), 7.95 (d, 8.3 Hz, 1H), 7.72 (d, 8.6 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, 8.8, 5.1 Hz, 1H), 7.27 (s, 1H), 7.16-7.02 (m, 2H), 6.61 (br. s, 1H), 5.94 (br. s, 1H), 4.35 - 4.26 (m, 1H), 4.21 - 4.13 (m, 1H), 3.97-3.85 (m, 1H), 2.79 (s, 3H), 2.46-2.27 (m, 1H), 2.28-2.08 (m, 2H), 1.96-1.77 (m, 1H) 594.2 A   
I-1567
Figure 02_image3425
 CN1[C@@H](COc2cc3C(=O)N[C@H](c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CCC1=O 1H NMR (400 MHz, DMSO-d6)  10.44 (s, 1H), 9.14 (s, 1H), 7.95 (d, 8.3 Hz, 1H), 7.72 (d, 8.6 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, 8.8, 5.1 Hz, 1H), 7.27 (s, 1H), 7.16-7.02 (m, 2H), 6.61 (br. s, 1H), 5.94 (br. s, 1H), 4.35 - 4.26 (m, 1H), 4.21 - 4.13 (m, 1H), 3.97-3.85 (m, 1H), 2.79 (s, 3H), 2.46-2.27 (m, 1H), 2.28-2.08 (m, 2H), 1.96-1.77 (m, 1H) 594.2 A   
I-1568
Figure 02_image3427
 CN1[C@H](COc2cc3C(=O)N[C@@H](c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CCC1=O 1H NMR (400 MHz, DMSO-d6)  10.44 (s, 1H), 9.14 (s, 1H), 7.95 (d, 8.3 Hz, 1H), 7.72 (d, 8.6 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, 8.8, 5.1 Hz, 1H), 7.27 (s, 1H), 7.16-7.02 (m, 2H), 6.61 (br. s, 1H), 5.94 (br. s, 1H), 4.35 - 4.26 (m, 1H), 4.21 - 4.13 (m, 1H), 3.97-3.85 (m, 1H), 2.79 (s, 3H), 2.46-2.27 (m, 1H), 2.28-2.08 (m, 2H), 1.96-1.77 (m, 1H) 594.2 D   
I-1569
Figure 02_image3429
 CN1[C@@H](COc2cc3C(=O)N[C@@H](c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)CCC1=O 1H NMR (400 MHz, DMSO-d6)  10.44 (s, 1H), 9.14 (s, 1H), 7.95 (d, 8.3 Hz, 1H), 7.72 (d, 8.6 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, 8.8, 5.1 Hz, 1H), 7.27 (s, 1H), 7.16-7.02 (m, 2H), 6.61 (br. s, 1H), 5.94 (br. s, 1H), 4.35 - 4.26 (m, 1H), 4.21 - 4.13 (m, 1H), 3.97-3.85 (m, 1H), 2.79 (s, 3H), 2.46-2.27 (m, 1H), 2.28-2.08 (m, 2H), 1.96-1.77 (m, 1H) 594.2 E   
I-1570
Figure 02_image3431
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(CS(=O)(=O)c3ncccn3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, CD3CN)  8.99 (s, 1H), 8.98 (s, 1H), 8.68 (s, 1H), 7.69 (t, 4.9 Hz, 2H), 7.70 (br, s, 1H), 7.67-7.63 (m, 1H), 7.60 (s, 1H), 7.60-7.56 (m, 1H), 7.55 (m, 1H), 7.32 (s, 1H), 7.24 (dd, 8.9, 5.1 Hz, 1H), 6.97 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.54 (br, s, 1H), 6.09 (br, s, 1H), 5.00 (d, 2.1 Hz, 2H)。 623 A   
I-1571
Figure 02_image3433
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(c1)-c1cscn1 NMR (400 MHz, DMSO-d6)  10.57 (br s, 1H), 9.24 (d, 2.2 Hz, 1H), 9.17 (br s, 1H), 9.04 (s, 1H), 8.44 (s, 1H), 8.10 (s, 1H), 7.96 (br d, 8.4 Hz, 1H), 7.91 (s, 1H), 7.81 (d, 2.2 Hz, 1H), 7.77 (br d, 8.9 Hz, 1H), 7.73 (s, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.5, 3.0 Hz, 1H), 6.61 (br s, 1H), 6.00 (br s, 1H)。 616 A   
I-1572
Figure 02_image3435
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(c1)-c1nccs1 NMR (400 MHz, DMSO-d6)  10.59 (br s, 1H), 9.20 (s, 1H), 9.20 (br s, 1H), 8.55 (s, 1H), 8.16 (s, 1H), 7.97 (br d, 8.6 Hz, 1H), 7.94 (br s, 1H), 7.77 (br d, 9.1 Hz, 1H), 7.72 (br s, 1H), 7.71 (d, 3.5 Hz, 1H), 7.60 (d, 3.5 Hz, 1H), 7.32 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.5, 3.0 Hz, 1H), 6.62 (br s, 1H), 6.01 (br s, 1H)。 616 A   
I-1573
Figure 02_image3437
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nc(Cl)nn2c1 1H NMR (500 MHz, DMSO)  10.65 (s, 1H), 9.46 (d, 1.9 Hz, 1H), 9.25 (s, 1H), 8.22 (dd, 9.3, 1.9 Hz, 1H), 8.12 (s, 1H), 7.99-7.91 (m, 3H), 7.76 (d, 9.2 Hz, 1H), 7.71 (s, 1H), 7.33 (dd, 8.8, 5.2 Hz, 1H), 7.10 (td, 8.3, 3.0 Hz, 1H), 6.61 (s, 1H), 6.06 (s, 1H)。 618.18 A   
I-1574
Figure 02_image3439
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nnc(Cl)n2c1    618.04 A   
I-1575
Figure 02_image3441
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2nc(Cl)nc2c1 1H NMR (500 MHz, DMSO)  10.68 (s, 1H), 9.26 (s, 1H), 9.05 (d, 7.0 Hz, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.94 (s, 1H), 7.78-7.71 (m, 3H), 7.34 (dd, 8.9, 5.1 Hz, 1H), 7.10 (td, 8.4, 3.1 Hz, 1H), 6.70 (s, 1H), 6.27 (s, 1H), 6.08 (s, 1H)。 618.13 A   
I-1576
Figure 02_image3443
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-c2ccc3ncnn3c2)c2ccccc12 1H NMR (400 MHz, DMSO-d6) 9.43 (dd, 1.9, 0.9 Hz, 1H), 9.17 (s, 1H), 8.76 (s, 1H), 8.58 (s, 1H), 8.11 (dd, 9.3, 1.9 Hz, 1H), 8.05-7.91 (m, 2H), 7.87 (d, 8.1 Hz, 1H), 7.82 (d, 1.7 Hz, 1H), 7.43-7.31 (m, 2H), 7.30-7.21 (m, 1H), 7.24-7.13 (m, 1H), 7.00 (td, 7.4, 1.0 Hz, 1H), 6.66 (s, 1H), 6.11 (s, 1H), 5.68 (d, 6.0 Hz, 1H), 5.12 (td, 8.3, 7.0, 3.5 Hz, 1H), 3.72 (dd, 11.3, 3.6 Hz, 1H), 3.31 (s, 1H)。 555.35 B   
I-1577
Figure 02_image3445
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-c2ccc3ncnn3c2)c2ccccc12 1H NMR (400 MHz, DMSO-d6) 9.43 (dd, 1.9, 0.9 Hz, 1H), 9.17 (s, 1H), 8.76 (s, 1H), 8.58 (s, 1H), 8.11 (dd, 9.3, 1.9 Hz, 1H), 8.05-7.91 (m, 2H), 7.87 (d, 8.1 Hz, 1H), 7.82 (d, 1.7 Hz, 1H), 7.43-7.31 (m, 2H), 7.30-7.21 (m, 1H), 7.24-7.13 (m, 1H), 7.00 (td, 7.4, 1.0 Hz, 1H), 6.66 (s, 1H), 6.11 (s, 1H), 5.68 (d, 6.0 Hz, 1H), 5.12 (td, 8.3, 7.0, 3.5 Hz, 1H), 3.72 (dd, 11.3, 3.6 Hz, 1H), 3.31 (s, 1H)。 555.3 A   
I-1578
Figure 02_image3447
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-c2ccc3ncnn3c2)c2ccccc12 1H NMR (400 MHz, DMSO-d6) 9.43 (dd, 1.9, 0.9 Hz, 1H), 9.17 (s, 1H), 8.76 (s, 1H), 8.58 (s, 1H), 8.11 (dd, 9.3, 1.9 Hz, 1H), 8.05-7.91 (m, 2H), 7.87 (d, 8.1 Hz, 1H), 7.82 (d, 1.7 Hz, 1H), 7.43-7.31 (m, 2H), 7.30-7.21 (m, 1H), 7.24-7.13 (m, 1H), 7.00 (td, 7.4, 1.0 Hz, 1H), 6.66 (s, 1H), 6.11 (s, 1H), 5.68 (d, 6.0 Hz, 1H), 5.12 (td, 8.3, 7.0, 3.5 Hz, 1H), 3.72 (dd, 11.3, 3.6 Hz, 1H), 3.31 (s, 1H)。 555.1 E   
I-1579
Figure 02_image3449
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-c2ccc3ncnn3c2)c2ccccc12 1H NMR (400 MHz, DMSO-d6) 9.43 (dd, 1.9, 0.9 Hz, 1H), 9.17 (s, 1H), 8.76 (s, 1H), 8.58 (s, 1H), 8.11 (dd, 9.3, 1.9 Hz, 1H), 8.05-7.91 (m, 2H), 7.87 (d, 8.1 Hz, 1H), 7.82 (d, 1.7 Hz, 1H), 7.43-7.31 (m, 2H), 7.30-7.21 (m, 1H), 7.24-7.13 (m, 1H), 7.00 (td, 7.4, 1.0 Hz, 1H), 6.66 (s, 1H), 6.11 (s, 1H), 5.68 (d, 6.0 Hz, 1H), 5.12 (td, 8.3, 7.0, 3.5 Hz, 1H), 3.72 (dd, 11.3, 3.6 Hz, 1H), 3.31 (s, 1H)。 555.35 C   
I-1580
Figure 02_image3451
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(c12)-n1cc2ccccc2cc1=O 1H NMR (400 MHz, 氯仿-d) 8.10 (d, 7.6 Hz, 1H), 7.77-7.53 (m, 3H), 7.39 (s, 1H), 7.23 (s, 1H), 7.01-6.90 (m, 2H), 6.85 (t, 7.4 Hz, 1H), 6.76 (s, 1H), 6.65 (s, 2H), 6.44 (s, 1H), 6.20 (s, 1H)。 405.15 E   
I-1581
Figure 02_image3453
 CC(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 氯仿-d) 8.10 (d, 7.9 Hz, 1H), 7.76 (d, 7.5 Hz, 1H), 7.58 (t, 7.8 Hz, 1H), 7.48 (dd, 8.9, 4.9 Hz, 1H), 7.06 (ddd, 8.9, 7.3, 3.0 Hz, 1H), 6.99 (s, 1H), 6.69 (d, 8.8 Hz, 1H), 6.63 (s, 1H), 6.19 (s, 1H), 2.03 (s, 3H)。 319 E   
I-1582
Figure 02_image3455
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(CC(F)(F)F)c3)c12 1H NMR (400 MHz, DMSO-d6) 10.35 (s, 1H), 9.28 (s, 1H), 7.81 (d, 1.7 Hz, 1H), 7.75 (d, 1.8 Hz, 1H), 7.47 (s, 2H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.28 (d, 9.2 Hz, 1H), 7.12 (td, 8.4, 3.1 Hz, 1H), 5.99 (s, 1H), 3.78-3.72 (d, 2H)。 560.9 C   
I-1583
Figure 02_image3457
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc4c3NC(=O)C4(F)F)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 11.08 (s, 1H), 10.55 (s, 1H), 9.47 (dd, 1.9, 1.0 Hz, 1H), 9.26 (s, 1H), 8.58 (s, 1H), 8.17-8.10 (m, 2H), 8.03-7.95 (m, 3H), 7.38 (t, 7.0 Hz, 2H), 7.19-7.10 (m, 1H), 6.07 (s, 1H), 1.29-1.24 (m, 2H), 1.20-1.12 (m, 1H),1.00-0.70 (s,1H) 607 D   
I-1584
Figure 02_image3459
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc4c3NC(=O)C4(F)F)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 11.08 (s, 1H), 10.57 (s, 1H), 9.47 (t, 1.4 Hz, 1H), 9.26 (s, 1H), 8.58 (s, 1H), 8.17-8.10 (m, 2H), 8.03-7.95 (m, 3H), 7.80-7.50 (m,2H),7.50-7.30 (m,2H),7.30-7.00 (m,2H),6.08 (s, 1H),1.30-1.22 (s, 3H), 1.20-1.13 (m, 1H),0.90-0.80 (m,1H)。 607 B   
I-1585
Figure 02_image3461
  		 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ccnc2cc1C#N 1H NMR (400 MHz, DMSO-d6)  10.71 (br. s, 1H), 9.33 (br. s, 1H), 8.98 (d, 0.8 Hz, 1H), 8.55 (app.t, 0.8 Hz 1H), 8.19 (s, 1H), 7.98 (d, 8.1 Hz, 1H), 7.95 - 7.92 (m, 1H), 7.93 (d, 1.1 Hz, 1H), 7.81-7.70 (m, 2H), 7.68 (s, 1H), 7.36 (dd, 8.9, 5.2 Hz, 1H), 7.13 (td, 8.1, 2.9 Hz, 1H), 6.68 (br. s, 1H), 6.07 (br. s, 1H) 608.1 C   
I-1586
Figure 02_image3463
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ccnc2cc1C#N 1H NMR (400 MHz, DMSO-d6)  10.71 (br. s, 1H), 9.33 (br. s, 1H), 8.98 (d, 0.8 Hz, 1H), 8.55 (t, 0.8 Hz 1H), 8.19 (s, 1H), 7.98 (d, 8.1 Hz, 1H), 7.95 - 7.92 (m, 1H), 7.93 (d, 1.1 Hz, 1H), 7.81-7.70 (m, 2H), 7.68 (s, 1H), 7.36 (dd, 8.9, 5.2 Hz, 1H), 7.13 (td, 8.1, 2.9 Hz, 1H), 6.68 (br. s, 1H), 6.07 (br. s, 1H) 608.1 A   
I-1587
Figure 02_image3465
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1=CC(=O)OC1 (400 MHz, DMSO-d6)  10.68 (s, 1H), 9.32 (br s, 1H), 8.06 (s, 1H), 7.98 (d, 8.5 Hz, 1H), 7.83 (s, 1H), 7.79-7.71 (m, 1H), 7.69 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.4, 3.1 Hz, 1H), 6.95 (s, 1H), 6.50 (br s, 1H), 6.04 (br s, 1H), 5.55-5.43 (m, 2H)。 547.2 A   
I-1588
Figure 02_image3467
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Cn3cc(cn3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.53 (br. s, 1H), 9.21 (br. s, 1H), 8.79 (d, 0.4 Hz, 1H), 8.15 (d, 0.5 Hz, 1H), 7.95 (br. d, 8.3 Hz, 1H), 7.71 (br. d, 8.8 Hz, 1H), 7.62 (s, 1H), 7.61 (s, 1H), 7.37 (br. s, 1H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.09 (app. td, 8.4, 3.1 Hz, 1H), 6.57 (br. s, 1H), 5.95 (br. s, 1H), 5.64-5.56 (m, 2H)。 570.2 A   
I-1589
Figure 02_image3469
 [2H]c1nc2ccc(cn2n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.64 (s, 1H), 9.51-9.46 (m, 1H), 9.26 (s, 1H), 8.18 -8.07 (m, 2H), 8.03 - 7.94 (m, 3H), 7.78 (d, 9.3 Hz, 1H), 7.73 (s, 1H), 7.35 (dd, 8.9, 5.2 Hz, 1H), 7.12 (td, 8.4, 3.0 Hz, 1H), 6.67 (s, 1H), 6.08 (s, 1H)。 585.15 A   
I-1590
Figure 02_image3471
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(c12)-n1ccc2ccccc2c1=O 1H NMR (400 MHz, DMSO-d6)  9.21 (s, 1H), 8.26 (d, 8.0 Hz, 1H), 7.90 (d, 7.5 Hz, 1H), 7.76 (dt, 19.1, 7.6 Hz, 2H), 7.62 (dd, 22.6, 7.7 Hz, 2H), 7.55 (d, 7.5 Hz, 1H), 7.14 (s, 1H), 6.99 (s, 1H), 6.83 (d, 7.4 Hz, 1H), 6.66 (s, 1H), 6.49 (s, 1H), 6.34 (d, 7.4 Hz, 1H), 6.01 (s, 1H)。 405.05 E   
I-1591
Figure 02_image3473
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(CS(=O)(=O)c3ccccc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, CD3CN )  8.72 (br s, 1H), 7.75-7.71 (m, 2H), 7.69 (dt, 2.5, 1.5Hz, 1H) 7.67 - 7.63 (m, 1H) 7.61-7.52 (m, 4H), 7.46 (s, 1H), 7.43-7.39 (s, 1H), 7.34-7.29 (m, 1H), 7.26 (dd, 8.9, 5.1 Hz, 1H), 7.01-6.95 (m, 1H), 6.61 (br, s, 1H), 6.15 (br, s, 1H), 4.69-4.33 (m, 2H)。 621 A   
I-1592
Figure 02_image3475
 CN(C)S(=O)(=O)n1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-D6)  10.56 (br s, 1 H), 9.18 (br s, 1 H), 8.97 (s, 1 H), 8.57 (s, 1 H), 8.14 (s, 1 H), 7.97 (br d, 8.4 Hz, 1 H), 7.92 (s, 1 H), 7.77 (br d, 8.7 Hz, 1 H), 7.73 (s, 1 H), 7.32 (dd, 8.9, 5.2 Hz, 1 H), 7.10 (td, 8.5, 2.8 Hz, 1 H), 6.58 (br s, 1 H), 6.00 (br s, 1 H), 2.90 (s, 6 H)。 638.2 A   
I-1593
Figure 02_image3477
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(CS(=O)(=O)c3ccccc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, CD3CN )  8.72 (d, 23.5 Hz, 1H), 7.75-7.71 (m, 2H), 7.69 (dt, 2.5, 1.5Hz, 1H) 7.67 - 7.63 (m, 1H) 7.61-7.52 (m, 4H), 7.46 (s, 1H), 7.43-7.39 (s, 1H), 7.34-7.29 (m, 1H), 7.26 (dd, 8.9, 5.1 Hz, 1H), 7.01-6.95 (m, 1H), 6.61 (br, s, 1H), 6.15 (br, s, 1H), 4.69-4.33 (m, 2H)。 621 D   
I-1594
Figure 02_image3479
  		 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(CS(=O)(=O)c3cccc(c3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, CD3CN)  8.62 (s, 1H), 8.13 (t, 1.1Hz, 1H), 8.03 (dt, 7.9, 1.2 Hz, 1H), 7.94 (dt, 8.0, 1.3Hz, 1H), 7.70 (t, 7.9 Hz, 1H), 7.66 (br, d, 8.5 Hz, 1H), 7.58 (td, 9.1 Hz, 1.7Hz, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 7.42 (s, 1H), 7.27 (dd, 8.9, 5.1 Hz, 1H), 7.27 (NH, 1H), 6.98 (td, 8.1, 3.0 Hz, 1H), 6.62 (br, s, 1H), 6.12 (br, s, 1H), 4.66 (s, 2H)。 646 A   
I-1595
Figure 02_image3481
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(CS(=O)(=O)c3cccc(c3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, CD3CN)  8.62 (s, 1H), 8.13 (t, 1.1Hz, 1H), 8.03 (dt, 7.9, 1.2 Hz, 1H), 7.94 (dt, 8.0, 1.3Hz, 1H), 7.70 (t, 7.9 Hz, 1H), 7.66 (br, d, 8.5 Hz, 1H), 7.58 (td, 9.1 Hz, 1.7Hz, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 7.42 (s, 1H), 7.27 (dd, 8.9, 5.1 Hz, 1H), 7.27 (NH, 1H), 6.98 (td, 8.1, 3.0 Hz, 1H), 6.62 (br, s, 1H), 6.12 (br, s, 1H), 4.66 (s, 2H)。 646 D   
I-1596
Figure 02_image3483
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2ncnc2c1    584.2 D   
I-1597
Figure 02_image3485
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2ncnc2c1    584.2 A   
I-1598
Figure 02_image3487
 CN(C)S(=O)(=O)n1nccc1-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    640.14 C   
I-1599
Figure 02_image3489
 CN(C)S(=O)(=O)n1nccc1-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    640.14 A   
I-1600
Figure 02_image3491
 [2H][C@@]1(NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1)c1cc(F)ccc1Cl    585.08 A   
I-1601
Figure 02_image3493
 [2H][C@]1(NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1)c1cc(F)ccc1Cl    585.08 A   
I-1602
Figure 02_image3495
 COc1cnc2ccc(cc2c1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    624.5 A   
I-1603
Figure 02_image3497
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncc(cc2c1)C#N 1H NMR (DMSO-d6, 500 MHz) 10.66 (s, 1H), 9.24-9.33 (m, 1H), 9.21 (d, 2.1 Hz, 1H), 9.14 (d, 1.8 Hz, 1H), 8.59 (d, 2.0 Hz, 1H), 8.43 (dd, 8.8, 2.1 Hz, 1H), 8.26 (d, 8.7 Hz, 1H), 8.16 (d, 1.1 Hz, 1H), 8.00 (s, 1H), 7.97 (br d, 8.2 Hz, 1H), 7.78 (br d, 9.0 Hz, 1H), 7.72 (s, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.4, 3.0 Hz, 1H), 6.42-6.97 (m, 1H), 5.95-6.25 (m, 1H) 619.5 A   
I-1604
Figure 02_image3499
 CC(C)(O)c1cnc2ccc(cc2c1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    652.2 A   
I-1605
Figure 02_image3501
 CC(C)(O)c1cnc2ccc(cc2c1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    652.2 E   
I-1606
Figure 02_image3503
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2nc(Cl)nc2c1    619.2 B   
I-1607
Figure 02_image3505
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(nc2C(=O)NC(C3CCCCC3)c12)-c1ccc2ncnn2c1       C   
I-1608
Figure 02_image3507
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(c1)-c1cnccn1 NMR (400 MHz, DMSO-d6 )  10.57 (s, 1H), 9.30 (s, 1H), 9.29 (s, 1H), 9.19 (s, 1H), 8.67 (d, 2.5 Hz, 1H), 8.63-8.60 (m, 2H), 8.17 (s, 1H), 8.00-7.94 (m, 2H), 7.78 (d, 9.3 Hz, 1H), 7.73 (s, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.4, 2.8 Hz, 1H), 6.58 (br s, 1H), 5.96 (br s, 1H)。 609.1 A   
I-1609
Figure 02_image3509
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc4ccccc4[nH]3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, )  11.72 (s, 1H), 10.29 (s, 1H), 9.49 (s, 1H), 9.25 (s, 1H), 8.58 (s, 1H), 8.15 (dd, 9.3, 1.5 Hz, 1H), 8.09 (d, 0.9 Hz, 1H), 8.02-9.98 (m, 2H), 7.62 (d, 8.0 Hz, 1H), 7.44 (d, 8.2 Hz, 1H), 7.32 (dd, 8.8, 5.2 Hz, 1H), 7.21 (t, 7.5 Hz, 1H), 7.12-6.98 (m, 3H), 6.72 (br s, 1H), 6.26 (br s, 1H)。 535.2 D   
I-1610
Figure 02_image3511
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc4ccccc4[nH]3)c12 NMR (400 MHz, DMSO-d6 )  11.71 (s, 1H), 10.18 (s, 1H), 9.28 (s, 1H), 7.81 (d, 1.5 Hz, 1H), 7.78 (d, 1.4 Hz, 1H), 7.61 (d, 7.9 Hz, 1H), 7.42 (d, 8.2 Hz, 1H), 7.30 (dd, 8.8, 5.2 Hz, 1H), 7.20 (td, 11.7, 4.4 Hz, 1H), 7.09-7.01 (m, 2H), 6.93 (d, 1.4 Hz, 1H), 6.64 (br s, 1H), 6.13 (br s, 1H)。 496.1 D   
I-1611
Figure 02_image3513
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(C3CCCCC3)c12 NMR (400 MHz, DMSO-d6)  10.74 (br. s, 1H), 8.74 (s, 1H), 8.13 (s, 1H), 8.08 (br. d, 9.0 Hz, 1H), 8.04 (br. d, 8.5 Hz, 1H), 7.62-7.49 (m, 3H), 4.73 (d, 1.3 Hz, 1H), 1.90-1.80 (m, 1H), 1.73-1.64 (m, 1H), 1.59 - 1.50 (m, 3H), 1.39-1.27 (m, 1H), 1.06-0.86 (m, 3H), 0.79-0.61 (m, 2H)。 421.2 D   
I-1612
Figure 02_image3515
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Cc3ccc4C(=O)NCc4c3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.57 (br. s, 1H), 9.07 (br. s, 1H), 8.49 (s, 1H), 7.87 (br. d, 7.9 Hz, 1H), 7.71 (br. d, 8.6 Hz, 1H), 7.66 (s, 1H), 7.62 (d, 7.7 Hz, 1H), 7.56-7.50 (m, 2H), 7.46-7.41 (m, 2H), 7.30 (dd, 8.9, 5.2 Hz, 1H), 7.07 (app. td, 8.4, 3.1 Hz, 1H), 6.62 (br. s, 1H), 5.92 (br. s, 1H), 4.34 (s, 2H), 4.24 (d, AB之A, JAB = 14.9 Hz, 1H), 4.20 (d, AB之B, JAB = 14.7 Hz, 1H)。 612.2 A   
I-1613
Figure 02_image3517
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(Cc3ccc4C(=O)NCc4c3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.47 (br. s, 1H), 9.11 (br. s, 1H), 8.48 (s, 1H), 7.92 (br. d, 8.4 Hz, 1H), 7.71 (br. d, 8.8 Hz, 1H), 7.64-7.60 (m, 3H), 7.52 (s, 1H), 7.44 (d, 7.8 Hz, 1H), 7.37 (s, 1H), 7.29 (dd, 8.9, 5.2 Hz, 1H), 7.08 (app. td, 8.4, 3.0 Hz, 1H), 6.60 (br. s, 1H), 5.92 (br. s, 1H), 4.35 (s, 2H), 4.26 (d, AB之A, JAB = 14.5 Hz, 1H), 4.22 (d, AB之B, JAB = 14.4 Hz, 1H)。 612.2 B   
I-1614
Figure 02_image3519
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(Cn3cccn3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.63 (br. s, 1H), 9.09 (br. s, 1H), 7.91 (d, 2.0 Hz, 1H), 7.88-7.82 (m, 1H), 7.72 (br. d, 9.7 Hz, 1H), 7.67 (s, 1H), 7.51 (d, 1.8 Hz, 1H), 7.47-7.35 (m, 2H), 7.31 (dd, 8.8, 5.2 Hz, 1H), 7.08 (app. td, 8.5, 3.0 Hz, 1H), 6.60 (br. s, 1H), 6.31 (t, 2.0 Hz, 1H), 5.93 (br. s, 1H), 5.53-5.45 (m, 2H)。 547.2 B   
I-1615
Figure 02_image3521
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Cn3cccn3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.68 (br. s, 1H), 9.08 (br. s, 1H), 7.91 (d, 2.1 Hz, 1H), 7.87-7.81 (m, 1H), 7.72 (br. d, 9.4 Hz, 1H), 7.68 (s, 1H), 7.51 (d, 1.7 Hz, 1H), 7.49-7.43 (m, 1H), 7.37 (br. s, 1H), 7.31 (dd, 8.8, 5.2 Hz, 1H), 7.07 (app. td, 8.5, 3.1 Hz, 1H), 6.62 (br. s, 1H), 6.31 (t, 2.0 Hz, 1H), 5.93 (br. s, 1H), 5.53-5.44 (m, 2H)。 547.2 A   
I-1616
Figure 02_image3523
 Fc1cnc(nc1)-n1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6 )  9.25 (s, 1H), 9.19 (br s, 1H), 9.04-9.01 (m, 2H), 8.54 (s, 1H), 8.36 (br s, 1H), 8.14 (s, 1H), 7.98-7.92 (m. 2H), 7.78 (br d, 8.6 Hz, 1H), 7.73 (s 1H), 7.32 (dd, 8.8, 5.1 Hz, 1H), 7.10 (td, 8.3, 2.7 Hz, 1H), 6.60 (br s, 1H), 6.02 (br s, 1H)。 629 A   
I-1617
Figure 02_image3525
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3nc4ccccc4[nH]3)c12 NMR (400 MHz, DMSO-d6)  9.32 (br s,1H), 8.38 (s, 1H), 7.99 (br s, 1H), 7.78 (s, 1H), 7.65-7.60 (m, 2H), 7.32 (dd, 6.0, 3.1 Hz, 3H), 7.07 (td, 8.5, 2.9 Hz, 1H), 6.93-6.72 (m, 1H), 6.19 (br s, 1H) 501 D   
I-1618
Figure 02_image3527
 CC(C)(C#N)n1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-D6)  10.56 (br s, 1 H), 9.16 (br s, 1 H), 8.77 (s, 1 H), 8.25 (s, 1 H), 8.04 (s, 1 H), 7.96 (br d, 8.3 Hz, 1 H), 7.79 (s, 1 H), 7.77 (br d, 13.5 Hz, 1 H), 7.72 (s, 1 H), 7.32 (dd, 8.8, 5.2 Hz, 1 H), 7.09 (td, 8.5, 2.8 Hz, 1 H), 6.60 (br s, 1 H), 5.97 (br s, 1 H), 2.03 (s, 6 H)。 598.3 A   
I-1619
Figure 02_image3529
 CC(C)(CC(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO):-´ 9.40 (s, 1H), 9.28 (s, 1H), 7.75 (d, 1.2 Hz, 1H), 7.59 (d, 1.5 Hz, 1H), 7.51 (br s, 1H), 7.24 (td, 8.4, 3.0 Hz, 1H), 6.07 (br s, 1H), 2.52-2.47 (m, 2H), 0.98 (s, 3H), 0.90 (s, 3H)。 509.1 E   
I-1620
Figure 02_image3531
 CC(C)(C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(F)(F)F 1H NMR (400 MHz, DMSO):-´ 9.73 (s, 1H), 9.29 (s, 1H), 7.79 (d, 1.6 Hz, 1H), 7.59 (s, 1H), 7.52 (br s, 1H), 7.25 (td, 8.4, 3.0 Hz, 1H), 6.00 (br s, 1H), 1.12 (s, 6H)。 495.1 E   
I-1621
Figure 02_image3533
 FC(F)C1CCCC1C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO):-´ 10.26 (s, 0.5H), 10.16 (s, 0.5H), 9.25 (s, 1H), 7.77 (d, 1.5 Hz, 0.5H), 7.70 (d, 1.4 Hz, 0.5H), 7.68 (d, 1.3 Hz, 0.5H), 7.62 (d, 1.6 Hz, 0.5H), 7.47 (br s, 1H), 7.26-7.19 (m, 1H), 6.14 (s, 0.5H), 6.10 (br s, 0.5H), 5.89 ( td, 57.0, 3.9 Hz, 1H), 2.68-2.30 (m, 2H), 1.77-0.92 (m, 6H)。 503 E   
I-1622
Figure 02_image3535
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C3CC4(C3)CC(F)(F)C4)c12 1H NMR (400 MHz, DMSO):-´ 9.70 (s, 1H), 9.24 (s, 1H), 7.70 (d, 1.5 Hz, 1H), 7.57 (d, 1.7 Hz, 1H), 7.50 (br s, 1H), 7.24 (td, 8.4, 3.1 Hz, 1H), 6.00 (br s, 1H), 2.84 (五重峰, 8.4 Hz, 1H), 2.59 (td, 12.6, 2.0 Hz, 2H), 2.43 (td, 12.5, 1.9 Hz, 2H), 2.10-1.94 (m, 3H), 1.82 (br s, 1H)。 515 D   
I-1623
Figure 02_image3537
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C3CCC4C(C3)C4(F)F)c12 1H NMR (400 MHz, DMSO):-´ 9.82 (s, 0.5H), 9.77 (d, 5.7 Hz, 0.5H), 9.25 (s, 1H), 7.71-7.68 (m, 1H), 7.66 (d, 1.3 Hz, 0.25H), 7.61 (d, 1.5 Hz, 0.25H), 7.58 (d, 1.7 Hz, 0.25H), 7.57 (d, 1.7 Hz, 0.25H), 7.49 (br s, 1H), 7.29-7.20 (m, 1H), 6.00 (br s, 1H), 2.03-0.72 (m, 9H)。 515.1 D   
I-1624
Figure 02_image3539
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nc(nn2c1)C1CC1       A   
I-1625
Figure 02_image3541
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Cc3ccc4C(=O)NCCc4c3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.49 (br. s, 1H), 9.12 (br. s, 1H), 7.92 (br. d, 8.1 Hz, 1H), 7.87 (t, 2.7 Hz, 1H), 7.79 (d, 7.9 Hz, 1H), 7.71 (br. d, 9.1 Hz, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.36 (s, 1H), 7.32-7.27 (m, 2H), 7.25 (s, 1H), 7.08 (app. td, 8.5, 3.0 Hz, 1H), 6.61 (br. s, 1H), 5.92 (br. s, 1H), 4.17 (d, AB之A, JAB = 14.7 Hz, 1H), 4.12 (d, AB之B, JAB = 14.6 Hz, 1H), 3.36 (td, 6.8, 2.8 Hz, 2H), 2.87 (t, 6.5 Hz, 2H)。 626.3 C   
I-1626
Figure 02_image3543
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(Cc3ccc4C(=O)NCCc4c3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.48 (s, 1H), 9.13 (br. s, 1H), 7.93 (br. d, 8.5 Hz, 1H), 7.88 (br. t, 2.5 Hz, 1H), 7.79 (d, 7.9 Hz, 1H), 7.71 (br. d, 9.1 Hz, 1H), 7.63 (s, 1H), 7.59 (s, 1H), 7.35 (br. s, 1H), 7.33-7.27 (m, 2H), 7.25 (s, 1H), 7.08 (app. td, 8.4, 3.0 Hz, 1H), 6.57 (br. s, 1H), 5.92 (br. s, 1H), 4.17 (d, AB之A, JAB = 14.6 Hz, 1H), 4.12 (d, AB之B JAB = 14.6 Hz, 1H), 3.35 (td, 6.5, 2.8 Hz, 2H), 2.87 (t, 6.5 Hz, 2H)。 626.2 A   
I-1627
Figure 02_image3545
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)CC3CCCCC3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6 )  9.78 (s, 1H), 9.44 (s, 1H), 9.22 (s, 1H), 8.58 (s, 1H), 8.08 (dd, 9.3, 1.6 Hz, 1H), 7.97 (d, 9.3 Hz, 1H), 7.87 (d, 1.4 Hz, 1H), 7.58-7.49 (m, 1H), 7.24 (tt, 5.8, 2.9 Hz, 1H), 6.53 (br s, 1H), 6.16 (s, 1H), 1.93 (d, 6.9 Hz, 2H), 1.56 (d, 9.0 Hz, 3H), 1.51-1.44 (m, 1H), 1.38 (t, 13.5 Hz, 2H), 1.16-1.01 (m, 3H), 0.80-0.65 (m, 2H)。 518.2 D   
I-1628
Figure 02_image3547
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)CCc3ccccc3)c12)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)  9.88 (br. s, 1H), 9.44 (s, 1H), 9.23 (br. s, 1H), 8.57 (s, 1H), 8.08 (d, 9.1 Hz, 1H), 8.02 (s, 1H), 7.97 (d, 9.2 Hz, 1H), 7.78 (s, 1H), 7.58-7.49 (m, 1H), 7.33-7.23 (m, 3H), 7.22-7.09 (m, 3H), 6.65 (br. s, 1H), 6.09 (br. s, 1H), 2.69-2.55 (m, 2H), 2.41-2.19 (m, 2H)。 526.3 D   
I-1629
Figure 02_image3549
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)C1=CCCCC1 NMR (400 MHz, DMSO-d6 )  10.58 (s, 1H), 8.66 (s, 1H), 8.11 (s, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 7.63-7.50 (m, 3H), 5.69-5.64 (m, 1H), 5.12 (s, 1H), 1.90-1.78 (m, 1H), 1.52-1.27 (m, 5H), 1.26-1.16 (m, 1H), 1.13-1.01 (m, 1H)。 419.2 D   
I-1630
Figure 02_image3551
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C(Cl)c3ccccc3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  10.43 (br s, 1H), 9.47 (d, 6.0 Hz, 1H), 9.23 (br s, 1H), 8.57 (d, 3.1 Hz, 1H), 8.10 (ddd, 9.2, 7.3, 1.7 Hz, 1H), 8.05 (dd, 5.9, 1.6 Hz, 1H), 7.99-7.94 (m, 1H), 7.93-7.88 (m, 1H), 7.43 (br s, 1H), 7.40-7.29 (m, 6H), 7.16 (dtd, 11.6, 8.6, 3.0 Hz, 1H), 6.49 (br s, 1H), 6.14 (br s, 1H), 5.54 (s, 0.5H), 5.49 (s, 0.5 H)。 546 D   
I-1631
Figure 02_image3553
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3nc4ccccc4s3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.48 (s, 1H), 9.30 (br s, 1H), 8.58 (s, 1H), 8.30-8.23 (m, 2H), 8.21-8.07 (m, 4H), 7.99 (d, 9.2 Hz, 1H), 7.76-7.52 (m, 2H), 7.33 (dd, 8.8, 5.2 Hz, 1H), 7.06 (td, 8.5, 3.0 Hz, 1H), 6.62 (br s, 1H), 6.24 (br s, 1H)。 555 D   
I-1632
Figure 02_image3555
 NC1(CC(C1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(F)(F)F 1H NMR (400 MHz, DMSO):-´ 9.79 (s, 0.4H), 9.76 (s, 0.6H), 9.22 (s, 1H), 7.71-7.64 (m, 1H), 7.61 (d, 1.7 Hz, 0.6H), 7.59 (d, 1.7 Hz, 0.4H), 7.51-7.39 (m, 1H), 7.19 (td, 8.3, 3.1 Hz, 1H), 7.09-6.10 (br m, 1H), 5.95 (br s, 1H), 3.13-3.00 (m, 0.4H), 2.69-2.61 (m, 0.6H), 2.32-2.14 (m, 2.4H), 2.10-1.80 (m, 2H), 1.72-1.54 (m, 0.6H)。 520.1 E   
I-1633
Figure 02_image3557
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)CC3CC(F)(F)C3(F)F)c12 1H NMR (400 MHz, DMSO):-´ 10.00 (s, 1H), 9.25 (s, 1H), 7.74-7.69 (m, 1H), 7.65 (d, 1.7 Hz, 0.5H), 7.62 (d, 1.4 Hz, 0.5H), 7.56-7.41 (m, 1H), 7.29-7.19 (m, 1H), 7.12-6.14 (br m, 1H), 5.95 (br s, 1H), 2.95 (br s, 1H), 2.80-2.63 (m, 1H), 2.49-2.05 (m, 3H)。 523 D   
I-1634
Figure 02_image3559
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C3CC4(CC4(F)F)C3)c12 1H NMR (400 MHz, DMSO):-´ 9.87 (s, 1H), 9.27 (s, 1H), 7.74-7.68 (m, 1H), 7.62 (d, 1.7 Hz, 0.5H), 7.60 (d, 1.7 Hz, 0.5H), 7.57-7.39 (m, 1H), 7.19 (td, 8.8, 3.1 Hz, 1H), 7.12-6.22 (br m, 1H), 6.03 (br s, 1H), 3.17-2.96 (m, 1H), 2.20-1.77 (m, 4H), 1.38 (t, 8.7 Hz, 1H), 1.29 (td, 8.7, 2.3 Hz, 1H)。 499 E   
I-1635
Figure 02_image3561
 CC12CC3CC(F)(C1)CC(C3)(C2)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO):-´ 9.38 (s, 0.5H), 9.37 (s, 0.5H), 9.26 (s, 1H), 7.72 (d, 1.6 Hz, 1H), 7.59 (d, 1.7 Hz, 0.5H), 7.58 (d, 1.7 Hz, 0.5H), 7.52 (br s, 1H), 7.26 (td, 8.4, 3.1 Hz, 1H), 7.11-6.18 (br m, 1H), 5.99 (br s, 1H), 2.22 (br s, 1H), 1.72-1.47 (m, 5H), 1.45-0.94 (m, 7H), 0.84 (s, 1.5H), 0.83 (s, 1.5H)。 549.2 B   
I-1636
Figure 02_image3563
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C3(CCCC3)c3ccc(Cl)c(Cl)c3)c12 1H NMR (400 MHz, DMSO):-´ 9.37 (s, 1H), 9.25 (s, 1H), 7.71 (d, 1.7 Hz, 1H), 7.55 (d, 1.7 Hz, 1H), 7.49-7.42 (m, 2H), 7.40 (d, 2.2 Hz, 1H), 7.18 (td, 8.4, 3.0 Hz, 1H), 7.07 (dd, 8.5, 2.2 Hz, 1H), 6.70-6.16 (br m, 1H), 6.10 (s, 1H), 2.33-2.12 (m, 2H), 1.84-1.63 (m, 2H), 1.56-1.41 (m, 2H), 1.40-1.22 (m, 2H)。 595.1 E   
I-1637
Figure 02_image3565
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C3(CCCC3)c3cccc(Cl)c3)c12 1H NMR (400 MHz, DMSO):-´ 9.30 (s, 1H), 9.25 (s, 1H), 7.70 (d, 1.6 Hz, 1H), 7.51 (d, 1.7 Hz, 1H), 7.51-7.46 (m, 1H), 7.29-7.26 (m, 2H), 7.26-7.24 (m, 1H), 7.21 (dt, 8.3, 2.9 Hz, 1H), 7.10-7.03 (m, 1H), 6.82-6.22 (br m, 1H), 6.11 (br s, 1H), 2.25-2.09 (m, 2H), 1.86-1.75 (m, 1H), 1.74-1.62 (m, 1H), 1.54-1.40 (m, 2H), 1.33-1.19 (m, 2H)。 561.1 E   
I-1638
Figure 02_image3567
 Fc1cccc(c1)C1(CCCC1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO)  9.35-9.19 (m, 2H), 7.69 (d, 1.6 Hz, 1H), 7.52 (d, 1.7 Hz, 1H), 7.52-7.46 (m, 1H), 7.28 (dd, 14.4, 7.9 Hz, 1H), 7.22 (td, 8.5, 3.1 Hz, 1H), 7.07-6.97 (m, 2H), 6.95 (d, 7.9 Hz, 1H), 6.72-6.23 (br m, 1H), 6.14 (br s, 1H), 2.23-2.09 (m, 2H), 1.88-1.77 (m, 1H), 1.73-1.63 (m, 1H), 1.54-1.40 (m, 2H), 1.34-1.20 (m, 2H)。 545 E   
I-1639
Figure 02_image3569
 Cc1cccc(c1)C1(CCCC1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO):-´ 9.23 (s, 1H), 9.11 (s, 1H), 7.68 (d, 1.1 Hz, 1H), 7.53 (d, 1.2 Hz, 1H), 7.53-7.46 (m, 1H), 7.23 (td, 8.3, 2.9 Hz, 1H), 7.13 (t, 7.7 Hz, 1H), 7.05 (s, 1H), 7.01 (d, 7.3 Hz, 1H), 6.92 (d, 7.8 Hz, 1H), 6.76-6.24 (br s, 1H), 6.15 (br s, 1H), 2.27 (s, 3H), 2.19-2.08 (m, 2H), 1.87-1.75 (m, 1H), 1.72-1.62 (m, 1H), 1.53-1.38 (m, 2H), 1.31-1.14 (m, 2H)。 541.1 E   
I-1640
Figure 02_image3571
 C[C@@H](c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)S(C)(=O)=O NMR (400 MHz, DMSO-d6) ´ 10.64 (s, 1H), 9.28 (s, 1H), 7.95 (d, 8.1 Hz, 1H), 7.80 (d, 2.7 Hz, 1H), 7.74 (d, 9.3 Hz, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 7.32 (dd, 8.8, 5.1 Hz, 1H), 7.10 (m, 1H), 6.59 (br, s, 1H), 6.00 (br, s, 1H), 4.87- 4.78 (m, 1H), 2.91 (s, 3H), 1.71 (d, 7.1 Hz, 3H) 573 D   
I-1641
Figure 02_image3573
 C[C@@H](c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)S(C)(=O)=O NMR (400 MHz, DMSO-d6) 10.64 (s, 1H), 9.28 (s, 1H), 7.95 (d, 8.1 Hz, 1H), 7.80 (d, 2.7 Hz, 1H), 7.74 (d, 9.3 Hz, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 7.32 (dd, 8.8, 5.1 Hz, 1H), 7.10 (m, 1H), 6.59 (br, s, 1H), 6.00 (br, s, 1H), 4.87- 4.78 (m, 1H), 2.91 (s, 3H), 1.71 (d, 7.1 Hz, 3H) 573 A   
I-1642
Figure 02_image3575
 C[C@H](c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)S(C)(=O)=O NMR (400 MHz, DMSO-d6) 10.64 (s, 1H), 9.28 (s, 1H), 7.95 (d, 8.1 Hz, 1H), 7.80 (d, 2.7 Hz, 1H), 7.74 (d, 9.3 Hz, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 7.32 (dd, 8.8, 5.1 Hz, 1H), 7.10 (m, 1H), 6.59 (br, s, 1H), 6.00 (br, s, 1H), 4.87- 4.78 (m, 1H), 2.91 (s, 3H), 1.71 (d, 7.1 Hz, 3H) 573 A   
I-1643
Figure 02_image3577
 C[C@H](c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)S(C)(=O)=O NMR (400 MHz, DMSO-d6) 10.64 (s, 1H), 9.28 (s, 1H), 7.95 (d, 8.1 Hz, 1H), 7.80 (d, 2.7 Hz, 1H), 7.74 (d, 9.3 Hz, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 7.32 (dd, 8.8, 5.1 Hz, 1H), 7.10 (m, 1H), 6.59 (br, s, 1H), 6.00 (br, s, 1H), 4.87- 4.78 (m, 1H), 2.91 (s, 3H), 1.71 (d, 7.1 Hz, 3H) 573 D   
I-1644
Figure 02_image3579
 CS(=O)(=O)Cc1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2n1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.93 (br. s, 1H), 9.59 (s, 1H), 7.98 (d, 8.2 Hz, 1H), 7.74 (d, 8.9 Hz, 1H), 7.63 (s, 1H), 7.60 (s, 1H), 7.35 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.1, 3.1 Hz, 1H), 6.86 (br. s, 1H), 6.02 (br. s, 1H), 4.88 (s, 2H), 3.12 (s, 3H)。 560.1 A   
I-1645
Figure 02_image3581
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ncnc2cc1C#N 1 H NMR (500 MHz, DMSO-d6 ) δ 10.69 (s, 1H), 9.41 (d, J = 1.0 Hz, 1H), 9.31 (s, 1H), 8.85 (d, J = 0.9 Hz, 1H), 8.81 (s, 1H), 7.96 (d, J = 20.0 Hz, 2H), 7.76 (s, 2H), 7.68 (s, 1H), 7.35 (dd, J = 8.9, 5.2 Hz, 1H), 7.12 (s, 2H), 6.10 (s, 1H)。 609.2 D   
I-1646
Figure 02_image3583
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ncnc2cc1C#N 1 H NMR (500 MHz, DMSO-d6 ) δ 10.69 (s, 1H), 9.41 (d, J = 1.0 Hz, 1H), 9.31 (s, 1H), 8.85 (d, J = 0.9 Hz, 1H), 8.81 (s, 1H), 7.96 (d, J = 20.0 Hz, 2H), 7.76 (s, 2H), 7.68 (s, 1H), 7.35 (dd, J = 8.9, 5.2 Hz, 1H), 7.12 (s, 2H), 6.10 (s, 1H)。 609.2 A   
I-1647
Figure 02_image3585
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1C#N 1 H NMR (500 MHz, DMSO-d6 ) δ 10.71 (s, 1H), 9.33 (s, 1H), 8.80 (s, 1H), 8.34 (d, J = 9.2 Hz, 1H), 8.07 (s, 1H), 7.97 (t, J = 9.9 Hz, 2H), 7.83 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.68 (s, 1H), 7.35 (dd, J = 8.8, 5.1 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H)。 609.1 B B
I-1648
Figure 02_image3587
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1C#N 1 H NMR (500 MHz, DMSO-d6 ) δ 10.71 (s, 1H), 9.33 (s, 1H), 8.80 (s, 1H), 8.34 (d, J = 9.2 Hz, 1H), 8.07 (s, 1H), 7.97 (t, J = 9.9 Hz, 2H), 7.83 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.68 (s, 1H), 7.35 (dd, J = 8.8, 5.1 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H)。 609.1 A A
I-1649
Figure 02_image3589
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2n1 1H NMR (500 MHz, DMSO) δ 10.71 (s, 1H), 9.31 (s, 1H), 8.74 (s, 1H), 8.59 (d, J = 9.5 Hz, 1H), 8.45 (d, J = 9.5 Hz, 1H), 8.41 (d, J = 1.6 Hz, 1H), 8.32 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.72 (s, 1H), 7.34 (dd, J = 8.9, 5.2 Hz, 1H), 7.11 (td, J = 8.4, 3.0 Hz, 1H), 6.13 (s, 1H)。 585.2 D   
I-1650
Figure 02_image3591
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2n1 1H NMR (500 MHz, DMSO) δ 10.71 (s, 1H), 9.31 (s, 1H), 8.74 (s, 1H), 8.59 (d, J = 9.5 Hz, 1H), 8.45 (d, J = 9.5 Hz, 1H), 8.41 (d, J = 1.6 Hz, 1H), 8.32 (d, J = 1.7 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 8.9 Hz, 1H), 7.72 (s, 1H), 7.34 (dd, J = 8.9, 5.1 Hz, 1H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 6.08 (s, 1H)。 585.2 A   
I-1651
Figure 02_image3593
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2nc(nc2c1)C1CC1    624.24 A   
I-1652
Figure 02_image3595
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ncnc2cc1F    602.18 A   
I-1653
Figure 02_image3597
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc(F)c2ncnn2c1 1H NMR (400 MHz, DMSO)  10.65 (s, 1H), 9.39 (d, 7.1 Hz, 1H), 9.29 (s, 1H), 8.58 (s, 1H), 8.13 (s, 0.5H), 8.00 (s, 0.5H), 7.96 (d, 5.6 Hz, 2H), 7.75 (d, 8.7 Hz, 2H), 7.68 (s, 1H), 7.34 (dd, 8.9, 5.1 Hz, 1H), 7.12 (t, 6.8 Hz, 2H), 6.05 (s, 1H)。 602.13 A   
I-1654
Figure 02_image3599
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(nc2C(=O)NC(C3CCCC3)c12)-c1ccc2ncnn2c1    98 E   
I-1655
Figure 02_image3601
 Oc1ccc(F)cc1C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2ncnc2c1    566.22 D   
I-1656
Figure 02_image3603
 Cn1cc(c(n1)C#N)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    572.4 A   
I-1657
Figure 02_image3605
 FC(F)n1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    583.5 A   
I-1658
Figure 02_image3607
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NCc3ccccc3)c12 NMR (400 MHz, DMSO-d6)  9.10 (s, 1H), 7.57 (dd, 8.7, 5.1 Hz, 1H), 7.34-7.28 (m, 1H), 7.27-7.19 (m, 3H), 7.08-7.03 (m, 3H), 6.79 (d, 1.4 Hz, 1H), 5.86 (s, 1H), 5.65 (br s, 1H), 4.36-4.21 (m,, 2H)。 445 E   
I-1659
Figure 02_image3609
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(Nc3nc4ccccc4s3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  10.08 (br s, 1H), 9.48 (s, 1H), 9.25 (s, 1H), 8.58 (s, 1H), 8.14 (dd, 9.3, 1.8 Hz, 1H), 8.08 (br s, 1H), 8.00 (s, 1H), 7.98 (d, 9.3 Hz, 1H), 7.71 (br s, 1H), 7.53 (br s, 1H), 7.36 (dd, 8.8, 5.2 Hz, 1H), 7.29 (t, 7.7 Hz, 1H), 7.16-7.06 (m, 2H), 6.53 (br s, 1H), 6.26 (br s, 1H)。 525.2 B   
I-1660
Figure 02_image3611
 CC(C)(C#N)n1cc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-D6)  10.57 (s, 1 H), 9.16 (br s, 1 H), 8.77 (s, 1 H), 8.25 (s, 1 H), 8.04 (s, 1 H), 7.96 (d, 8.3 Hz, 1 H), 7.83-7.74 (m, 2 H), 7.72 (s, 1 H), 7.32 (dd, 8.9, 5.2 Hz, 1 H), 7.09 (td, 8.5, 2.8 Hz, 1 H), 6.57 (br s, 1 H), 5.98 (br s, 1 H), 2.03 (s, 6 H)。 598.3 C   
I-1661
Figure 02_image3613
 CC(C)(C#N)n1cc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-D6)  10.57 (s, 1 H), 9.16 (br s, 1 H), 8.77 (s, 1 H), 8.25 (s, 1 H), 8.04 (s, 1 H), 7.96 (d, 8.3 Hz, 1 H), 7.83-7.74 (m, 2 H), 7.72 (s, 1 H), 7.32 (dd, 8.9, 5.2 Hz, 1 H), 7.09 (td, 8.5, 2.8 Hz, 1 H), 6.57 (br s, 1 H), 5.98 (br s, 1 H), 2.03 (s, 6 H)。 598.3 A   
I-1662
Figure 02_image3615
 CC(C)OC(C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1)c1ccccc1 NMR (400 MHz, DMSO-d6)  9.60-9.53 (m, 1H), 9.45-9.40 (m, 1H), 9.31-9.21 (m, 1H), 8.57 (s, 1H), 8.49 (s, 2H), 8.15 (d, 1.4 Hz, 1H), 8.09-8.03 (m, 1H), 8.02-7.99 (m, 1H), 7.99-7.94 (m, 1H), 7.35-7.26 (m, 4H), 7.25-7.19 (m, 1H), 7.01 (br s, 1H), 6.27 (br s, 1H), 4.87-4.80 (m, 1H), 3.19-3.07 (m, 1H), 1.06-0.99 (m, 6H)。 570 D   
I-1663
Figure 02_image3617
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)N3CCCCC3)c12)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)  9.39-9.38 (m, 1H), 9.13 (br. s, 1H), 8.58-8.55 (m, 2H), 8.06 (dd, 9.3, 1.7 Hz, 1H), 7.97 (d, 9.3 Hz, 1H), 7.88 (d, 1.5 Hz, 1H), 7.69 (d, 1.4 Hz, 1H), 7.54-7.48 (m, 1H), 7.25 (app. td, 8.3, 3.0 Hz, 1H), 6.63 (br. s, 1H), 6.11 (br. s, 1H), 3.21 (ddd, 11.7, 7.2, 3.1 Hz, 2H), 3.07 (ddd, 12.6, 7.0, 3.3 Hz, 2H), 1.49-1.42 (m, 2H), 1.38-1.28 (m, 2H), 1.21-1.11 (m, 2H)。 505.3 D   
I-1664
Figure 02_image3619
 OC1CC(C1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.77 (s, 1H), 9.45-9.43 (m, 1H), 9.22 (br. s, 1H), 8.57 (s, 1H), 8.09 - 8.07 (m, 1H), 8.01 - 7.99 (m, 1H), 7.97 (dd, 3.0, 0.7 Hz, 1H), 7.78 (d, 1.6 Hz, 1H), 7.56-7.46 (m, 1H), 7.29-7.20 (m, 1H), 6.61 (br. s, 1H), 6.16 (br. s, 1H), 5.05 (d, 6.3 Hz, 1H), 4.17-4.03 (m, 1H), 2.81-2.74 (m, 1H), 2.39-2.18 (m, 1H), 2.07-2.15 (m, 1H), 1.93-1.82 (m, 2H)。 492 E   
I-1665
Figure 02_image3621
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)Cc3ccccc3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.46-9.43 (m, 1H), 8.57 (s, 1H), 8.09 (dd, 9.3, 1.8 Hz, 1H), 8.00 (d, 1.5 Hz, 1H), 7.96 (dd, 9.3, 0.7 Hz, 1H), 7.90 (d, 1.6 Hz, 1H), 7.54-7.43 (m, 1H), 7.34-7.15 (m, 5H), 7.04 (br d, 6.5 Hz, 2H), 6.63 (br s, 1H), 6.12 (br s, 1H), 3.45-3.33 (m, 2H)。 512 E   
I-1666
Figure 02_image3623
 OCC1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6 )  11.08 (br. s, 1H), 8.71 (s, 1H), 8.13 (s, 1H), 8.08 (dd, 7.6, 1.2 Hz, 1H), 8.07 (br. d, 8.4 Hz, 1H), 8.03 (br. d, 8.5 Hz, 1H), 7.57-7.49 (m, 2H), 6.21 (br. s, 1H), 4.83 (dd, 6.4, 5.7 Hz, 1H), 3.73 (dd, 10.5, 4.9 Hz, 1H), 3.49 (dd, 10.4, 7.2 Hz, 1H)。 369.2 E   
I-1667
Figure 02_image3625
 Fc1ccc(Cl)c(c1)C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)cc(c2Cl)-c1ccc2ncnn2c1 (400 MHz, DMSO-D6)  10.99-10.14 (br s, 1 H), 9.38 (br s, 1 H), 9.18 (s, 1 H), 8.60 (s, 1 H), 7.99 (app d, 9.2 Hz, 1 H), 7.98-7.92 (m, 1 H), 7.83 (dd, 9.2, 1.6 Hz, 1 H), 7.80-7.68 (m, 2 H), 7.66 (s, 1 H), 7.36 (dd, 8.9, 5.1 Hz, 1 H), 7.13 (td, 8.4, 2.9 Hz, 1 H), 6.77 (br s, 1 H), 6.05 (br s, 1 H)。 616.2 A   
I-1668
Figure 02_image3627
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(Nc3cn4ccccc4n3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6 )  9.40 (s, 1H), 9.12 (s, 1H), 8.57 (s, 1H), 8.37 (d, 6.7 Hz, 1H), 8.11 (br. s, 1H), 8.08 (dd, 9.3, 1.8 Hz, 1H), 8.00 (d, 1.5 Hz, 1H), 7.97 (dd, 9.2, 0.9 Hz, 1H), 7.66 (d, 1.0 Hz, 1H), 7.53 (s, 1H), 7.43 (dd, 8.8, 5.2 Hz, 1H), 7.36 (d, 8.9 Hz, 1H), 7.22-7.10 (m, 2H), 6.82 (t, 6.5 Hz, 1H), 6.69 (br. s, 1H), 6.21 (s, 1H) 510.2 D   
I-1669
Figure 02_image3629
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2nccc2c1 1H NMR (400 MHz, DMSO)  10.62 (s, 1H), 9.24 (s, 1H), 8.79 (dt, 7.3, 1.0 Hz, 1H), 8.22-8.17 (m, 1H), 8.11-8.04 (m, 2H), 7.95 (d, 9.6 Hz, 2H), 7.77 (d, 9.1 Hz, 1H), 7.71 (s, 1H), 7.36-7.30 (m, 2H), 7.10 (td, 8.4, 3.1 Hz, 1H), 6.70 (dd, 2.3, 0.9 Hz, 1H), 6.06 (s, 1H)。 583.126 A   
I-1670
Figure 02_image3631
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2nncc2c1 1H NMR (400 MHz, DMSO)  10.65 (s, 1H), 9.27 (s, 1H), 9.19 (d, 7.4 Hz, 1H), 8.50-8.41 (m, 1H), 8.27 (d, 1.0 Hz, 1H), 8.13 (s, 1H), 7.96 (dd, 13.1, 5.0 Hz, 2H), 7.77 (d, 9.0 Hz, 1H), 7.71 (s, 1H), 7.64 (dd, 7.4, 2.0 Hz, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.4, 3.0 Hz, 1H), 6.06 (s, 1H)。 584.127 A   
I-1671
Figure 02_image3633
 Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (500 MHz, DMSO)  9.24 (dd, 1.8, 1.0 Hz, 1H), 8.98 (s, 1H), 8.53 (s, 1H), 7.98 (dd, 9.3, 1.8 Hz, 1H), 7.92 (dd, 9.2, 1.0 Hz, 1H), 7.56 (dd, 8.9, 5.1 Hz, 1H), 7.34 (d, 1.5 Hz, 1H), 7.26 (ddd, 8.8, 7.9, 3.1 Hz, 1H), 7.19 (d, 1.6 Hz, 1H), 6.81 (s, 1H), 5.88 (s, 1H), 5.00 (s, 2H) 394.26 E   
I-1672
Figure 02_image3635
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(Br)c12)-c1ccc2ncnn2c1 1H NMR (500 MHz, DMSO)  9.52 (dd, 1.9, 0.9 Hz, 1H), 9.42 (s, 1H), 8.56 (s, 1H), 8.28 (s, 1H), 8.20-8.13 (m, 2H), 7.94 (dd, 9.2, 0.9 Hz, 1H), 7.62 (s, 1H), 7.28 (td, 8.4, 3.0 Hz, 1H), 6.55 (s, 1H), 6.09 (s, 1H)。 457.12 E   
I-1673
Figure 02_image3637
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(Cc3ccccc3)c12 NMR (400 MHz, DMSO-d6)  10.87 (s, 1H), 8.65 (s, 1H), 8.23 (s), 8.17 (d, 8.9 Hz, 1H), 8.01 (d, 8.2 Hz, 1H), 7.55 (dd, 7.8, 1.0 Hz, 1H), 7.42 (t, 7.6 Hz, 1H), 7.33 (dd, 7.4, 0.9 Hz, 1H), 7.00 (m, 3H), 6.91-6.87 (m, 2H), 5.10 (t, 4.6 Hz, 1H), 3.03 (dd, 13.7, 4.1 Hz, 1H), 2.81 (dd, 13.8, 4.7 Hz, 1H)。 429 E   
I-1674
Figure 02_image3639
 CC(=O)N1CCCCC1C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.67 (br s, 1H), 8.88 (s, 1H), 8.25 (s, 1H), 8.21 (d, 9.8 Hz, 1H), 7.98 (d, 8.2 Hz, 1H), 7.82 (d, 6.1 Hz, 1H), 7.65-7.52 (m, 2H), 5.11 (s, 1H), 4.79-4.70 (m, 1H), 3.74-3.54 (m, 2H), 1.98 (s, 3H), 1.61-1.36 (m, 4H), 1.29-1.18 (m, 1H), 1.03-0.91 (m, 1H) 464.3 E   
I-1675
Figure 02_image3641
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(C3CCCCN3)c12 (400 MHz, DMSO-d6)  8.87 (s, 1H), 8.76 (s, 1H), 8.52 (d, 8.0 Hz, 0.5H), 8.44 (d, 7.2 Hz, 0.5H), 8.06-7.95 (m, 3H), 7.52 (t, 7.7 Hz, 1H), 7.43 (d, 6.7 Hz, 1H), 4.74 (s, 0.5H), 4.53 (d, 7.1 Hz, 0.5H), 3.08-2.98 (m, 0.5H), 2.72 (br. d, 10.9 Hz, 0.5H), 2.65 - 2.60 (m, 0.5H), 2.59-2.54 (m, 1H), 1.83-1.74 (m, 0.5H), 1.74-1.66 (m, 0.5H), 1.60 - 1.54 (m, 0.5H), 1.46 (br. d, 9.7 Hz, 1H), 1.40-1.07 (m, 4H) 422.3 D   
I-1676
Figure 02_image3643
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nnc(Cl)n2c1    618.09 B   
I-1677
Figure 02_image3645
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2ncnc2n1    585.13 A   
I-1678
Figure 02_image3647
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(CN3CCCCC3)c12 NMR (400 MHz, DMSO-d6)  11.28 (s, 1H), 8.68 (s, 1H), 8.14-8.06 (m, 3H), 8.03 (br. d, 8.6 Hz, 1H), 7.56-7.48 (m, 2H), 4.96 (t, 6.1 Hz, 1H), 2.48 (浸沒d, 6.3 Hz, 2H), 2.44-2.24 (m, 4H), 1.21-1.13 (m, 6H)。 436.2 E   
I-1679
Figure 02_image3649
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(Nc3cc4ccccn4n3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.40 (s, 1H), 9.14 (s, 1H), 8.57 (s, 1H), 8.51-8.32 (m, 2H), 8.08 (td, 4.8, 1.8 Hz, 2H), 7.97 (d, 9.2 Hz, 1H), 7.72 (d, 1.5 Hz, 1H), 7.42-7.35 (m, 2H), 7.19-7.08 (m, 2H), 6.67 (td, 6.9, 1.3 Hz, 1H), 6.59 (br. s, 1H), 6.28 (s, 1H), 5.95 (s, 1H) 510.2 E   
I-1680
Figure 02_image3651
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)C3CCCCC3)c12    387.2 D   
I-1681
Figure 02_image3653
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3ccccc3)c12 1H NMR (400 MHz, DMSO-d6) 10.13 (s, 1H), 9.10 (s, 1H), 7.70-7.49 (m, 6H), 7.43 (t,  7.6 Hz, 2H), 7.34 (dd,  8.9, 5.2 Hz, 1H), 7.12 (td,  8.4, 3.1 Hz, 1H), 6.07 (s, 1H)。 381.15 E   
I-1682
Figure 02_image3655
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3cccc4ccccc34)c12 NMR (400 MHz, DMSO-d6)  9.09 (br s, 1H), 8.16 (s, 1H), 7.84 (d, 8.2 Hz, 1H), 7.59 (d, 8.2 Hz, 1H), 7.47 (d, 9.1 Hz, 1H), 7.45-7.37 (m, 3H), 7.28 (t, 7.3 Hz, 1H), 7.20 (s, 1H), 7.09-7.02 (m, 1H), 6.97 (d, 7.2 Hz, 1H), 6.93-6.84 (m, 1H), 6.31 (br s, 1H), 5.58 (br s, 1H)。 481.1 D   
I-1683
Figure 02_image3657
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3cc4ccccc4cn3)c12 NMR (400 MHz, DMSO-d6 )  9.17 (s, 1H), 8.97 (s, 1H), 8.69 (s, 1H), 7.92 (d, 8.2 Hz, 1H), 7.77 (d, 1.0 Hz, 1H), 7.68 (d, 8.4 Hz, 1H), 7.57 (t., 7.1 Hz, 1H), 7.54 (d, 0.9 Hz, 1H), 7.342 (app t, 7.6 Hz, 1H), 7.24 (dd, 8.8, 5.1 Hz, 1H), 7.03 (td, 8.3, 3.0 Hz, 1H), 6.83 (s, 1H), 6.52 (br s, 1H),  6.01 (s, 1H)。 482.1 E   
I-1684
Figure 02_image3659
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3csc4ccccc34)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  10.36 (s, 1H), 9.48 (t, 1.4 Hz, 1H), 9.24 (s, 1H), 8.58 (s, 1H), 8.29 - 8.22 (m, 1H), 8.15 (dd, 9.3, 1.8 Hz, 1H), 8.10 (d, 1.6 Hz, 1H), 8.06 (q, 3.2, 2.8 Hz, 2H), 8.06 - 7.96 (m, 2H), 7.49 - 7.40 (m, 2H), 7.36 (dd, 8.9, 5.2 Hz, 1H), 7.12 (td, 8.4, 3.1 Hz, 1H), 6.72 (s, 1H), 6.21 (s, 1H)。 554.1 A A
I-1685
Figure 02_image3661
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3csc4ccccc34)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  10.35 (s, 1H), 9.48 (t, 1.4 Hz, 1H), 9.24 (s, 1H), 8.58 (s, 1H), 8.30 - 8.22 (m, 1H), 8.15 (dd, 9.3, 1.9 Hz, 1H), 8.10 (d, 1.6 Hz, 1H), 8.06 (q, 3.3, 2.7 Hz, 2H), 8.06 - 7.96 (m, 2H), 7.49 - 7.40 (m, 2H), 7.36 (dd, 8.9, 5.2 Hz, 1H), 7.12 (td, 8.4, 3.1 Hz, 1H), 6.72 (s, 1H), 6.22 (s, 1H)。 554.1 D   
I-1686
Figure 02_image3663
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc4c(Cl)n[nH]c34)c12 1H NMR (400 MHz, DMSO-d6)  11.80 (s, 2H), 10.44 (s, 1H), 9.29 (s, 1H), 7.81 (d, 1.7 Hz, 1H), 7.74 (d, 1.8 Hz, 1H), 7.56 (d, 9.7 Hz, 1H), 7.46 (dd, 8.8, 5.1 Hz, 1H), 7.30 (d, 5.3 Hz, 1H), 7.23 (td, 8.4, 3.1 Hz, 1H), 6.73 (s, 1H), 6.05 (s, 1H)。 550.95 D   
I-1687
Figure 02_image3665
 CN1CC(CC1=O)c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.54 (br s, 1H), 9.15 (s, 1H), 7.95 (d, 8.9 Hz, 1H), 7.73 (d, 8.7 Hz, 1H), 7.65 (s, 1H), 7.62 (s, 1H), 7.42 (s, 1H), 7.31 (dd, 8.8, 5.1 Hz, 1H), 7.09 (td, 8.7, 3.5 Hz, 1H), 5.96 (br s, 1H), 3.83-3.72 (m, 2H), 2.79 (s, 3H), 2.77-2.70 (m, 1H), 2.45-2.37 (m, 2H) 564.1 A   
I-1688
Figure 02_image3667
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)COc3ccccc3)c12)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)  9.90 (s, 1H), 9.45 (dd, 1.7, 0.8 Hz, 1H), 9.24 (br. s, 1H), 8.58 (s, 1H), 8.10 (dd, 9.3, 1.8 Hz, 1H), 8.06 (d, 1.5 Hz, 1H), 8.00-7.96 (m, 2H), 7.50 (dd, 8.3, 5.1 Hz, 1H), 7.32-7.27 (m, 2H), 7.23 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.98 (tt, 7.3, 1.0 Hz, 1H), 6.86-6.82 (m, 2H), 6.68 (br. s, 1H), 6.17 (br. s, 1H), 4.42 (s, 2H)。 528.2 E   
I-1689
Figure 02_image3669
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C3CC(CCN3)C(F)(F)F)c12 1H NMR (400 MHz, CD3CN):-´ 8.48 (br s, 1H), 8.37 (d, 1.7 Hz, 0.5H), 8.24 (d, 1.7 Hz, 0.5H), 7.73 (d, 1.7 Hz, 0.5H), 7.72 (d, 1.7 Hz, 0.5H), 7.50 (br s, 1H), 7.32 (br s, 1H), 7.13 (td, 8.4, 3.1 Hz, 1H), 6.62 (br s, 1H), 6.09 (br s, 1H), 3.15-2.95 (m, 2H), 2.56 (td, 12.6, 2.9 Hz, 1H), 1.91-1.70 (m, 3H), 1.40-1.29 (m, 1H), 1.21-0.82 (m, 2H)。 534.1 E   
I-1690
Figure 02_image3671
 OC1CCC(CC1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.78 (br s, 1H),9.43 (dd, 1.7, 0.8 Hz, 1H), 9.20 (br s, 1H), 8.57 (s, 1H), 8.09 (dd, 9.3, 1.8 Hz, 1H), 8.01-7.94 (m, 2H), 7.80 (d, 1.6 Hz, , 1H), 7.57-7.45 (m, 1H), 7.32-7.19 (m, 1H), 6.58 (br s, 1H), 6.11 (br s, 1H), 4.57 (br s, 1H), 2.02-1.91 (m, 1H), 1.83-1.68 (m, 2H), 1.54-1.42 (m, 1H), 1.38-1.27 (m, 1H), 1.26-1.10 (m, 2H), 1.10-0.96 (m, 1H)。 520 E   
I-1691
Figure 02_image3673
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3coc4ccccc34)c12 (400 MHz, DMSO-D6)  9.17 (s, 1 H), 7.92 (s, 1 H), 7.65 (br s, 1 H), 7.54 (d, 8.3 Hz, 1 H), 7.37-7.28 (m, 3 H), 7.16 (t, 7.4 Hz, 1 H), 7.10 (td, 8.3, 3.0 Hz, 1 H), 7.08 (d, 8.1 Hz, 1 H), 7.05 (d, 1.2 Hz, 1 H), 6.67 (br s, 1 H), 5.88 (s, 1 H)。 469.2 D   
I-1692
Figure 02_image3675
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nc(Cl)nn2c1    618.4 D   
I-1693
Figure 02_image3677
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nc(Cl)nn2c1    618.2 A   
I-1694
Figure 02_image3679
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncc(Cl)n2c1    617.13 A   
I-1695
Figure 02_image3681
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2nc(Cl)nc2c1    618.2 D   
I-1696
Figure 02_image3683
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nc(Cl)cn2c1    617.08 A   
I-1697
Figure 02_image3685
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2nc(Cl)nc2c1    618.2 A   
I-1698
Figure 02_image3687
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2ncnc2c1F    602.18 A   
I-1699
Figure 02_image3689
 Cn1ncc(c1C#N)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    572.4 A   
I-1700
Figure 02_image3691
 COc1cc2ncnn2cc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    614.08 A   
I-1701
Figure 02_image3693
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ncnc2cc1F    602.2 D   
I-1702
Figure 02_image3695
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ncnc2cc1F    602.2 A   
I-1703
Figure 02_image3697
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc(F)c2ncnn2c1    602.2 E   
I-1704
Figure 02_image3699
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc(F)c2ncnn2c1    602.2 A   
I-1705
Figure 02_image3701
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(nc2C(=O)NC(C3CCOCC3)c12)-c1ccc2ncnn2c1    541.7 E   
I-1706
Figure 02_image3703
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(nc2C(=O)NC(C3CCCCO3)c12)-c1ccc2ncnn2c1    541.7 E   
I-1707
Figure 02_image3705
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nc(nn2c1)C#N    609.13 A   
I-1708
Figure 02_image3707
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nnc(C#N)n2c1    609.08 A   
I-1709
Figure 02_image3709
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)[C@@H]1CNC(=O)C1 (400 MHz, CD3CN)  8.79 (s, 1H), 7.68 (d, 1.2 Hz, 1H), 7.66-7.62 (m, 1H), 7.62-7.59 (m, 1H), 7.58 (s, 1H), 7.48 (s, 1H), 7.32 (br s, 1H), 7.24 (dd, 8.9, 5.1 Hz, 1H), 6.96 (td, 8.5, 3.2 Hz, 1H), 6.61 (br s, 1H), 6.19 (s, 1H), 6.10 (br s, 1H), 3.89-3.79 (m, 1H), 3.79-3.73 (m, 1H), 3.37 (dd, 9.2, 7.1 Hz, 1H), 2.66 (dd, 16.5, 8.6 Hz, 1H), 2.41 (dd, 16.5, 8.5 Hz, 1H)。 548.2 A   
I-1710
Figure 02_image3711
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)[C@H]1CNC(=O)C1 (400 MHz, CD3CN)  8.73 (s, 1H), 7.68 (d, 1.3 Hz, 1H), 7.65 (d, 8.4 Hz, 1H), 7.67-7.58 (m, 1H), 7.57 (s, 1H), 7.48 (s, 1H), 7.28 (s, 1H), 7.24 (dd, 8.9, 5.1 Hz, 1H), 6.96 (td, 8.5, 3.2 Hz, 1H), 6.60 (br s, 1H), 6.15 (s, 1H), 6.11 (s, 1H), 3.90-3.80 (m, 1H), 3.77 (t, 8.4 Hz, 1H), 3.39 (dd, 9.2, 6.9 Hz, 1H), 2.67 (dd, 16.5, 8.6 Hz, 1H), 2.39 (dd, 16.5, 8.3 Hz, 1H)。 548.2 A   
I-1711
Figure 02_image3713
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)[C@@H]1CNC(=O)C1 (400 MHz, CD3CN)  8.75 (s, 1H), 7.69 (d, 1.2 Hz, 1H), 7.67-7.63 (m, 1H), 7.63-7.59 (m, 1H), 7.58 (s, 1H), 7.48 (s, 1H), 7.30-7.22 (m, 2H), 6.96 (td, 8.5, 3.1 Hz, 1H), 6.63 (br s, 1H), 6.13 (br s, 2H), 3.90-3.80 (m, 1H), 3.77 (app t, 8.4 Hz, 1H), 3.37 (dd, 9.2, 7.1 Hz, 1H), 2.67 (dd, 16.5, 8.6 Hz, 1H), 2.42 (dd, 16.5, 8.5 Hz, 1H)。 548.2 D   
I-1712
Figure 02_image3715
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)[C@H]1CNC(=O)C1 (400 MHz, CD3CN)  8.74 (br s, 1H), 7.68 (d, 1.3 Hz, 1H), 7.67-7.63 (m, 1H), 7.63-7.59 (m, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.27-7.22(m, 2H), 6.96 (td, 8.6, 3.2 Hz, 1H), 6.61 (br s, 1H), 6.12 (br s, 2H), 3.90-3.80 (m, 1H), 3.77 (app t, 8.5 Hz, 1H), 3.39 (dd, 9.2, 6.9 Hz, 1H), 2.67 (dd, 16.5, 8.7 Hz, 1H), 2.39 (dd, 16.5, 8.4 Hz, 1H)。 548.3 D   
I-1713
Figure 02_image3717
 CN1CCCC[C@@H]1[C@@H]1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  8.60 (s, 1H), 8.35 (d, 7.2 Hz, 1H), 8.04 (d, 8.6 Hz, 1H), 7.92 (s, 1H), 7.89 (d, 8.4 Hz, 1H), 7.53 (t, 7.7 Hz, 1H), 7.45 (dd, 7.4, 1.0 Hz, 1H), 5.22 (s, 1H), 2.39-2.34 (m, 1H), 2.21 (s, 3H), 2.13-2.04 (m, 1H), 1.60-1.56 (m, 1H), 1.56-1.50 (m, 1H), 1.45-1.39 (m, 1H), 1.36-1.29 (m, 1H), 1.26-1.21 (m, 1H), 1.13-1.07 (m, 1H), 0.63 (qd, 14.3, 4.7 Hz, 1H) 436.2 E   
I-1714
Figure 02_image3719
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(c12)-n1[nH]c(=O)c2ccccc12 1H NMR (400 MHz, DMSO-d6)  10.97 (s, 1H), 9.17 (s, 1H), 7.82 (dd, 6.5, 2.5 Hz, 1H), 7.81-7.72 (m, 2H), 7.55 (d, 8.0 Hz, 1H), 7.30 (d, 3.9 Hz, 2H), 7.12 (s, 1H), 7.02 (dt, 7.8, 3.8 Hz, 1H), 6.81 (td, 8.4, 3.1 Hz, 1H), 6.36 (s, 1H), 6.25 (s, 1H)。 394.05 E   
I-1715
Figure 02_image3721
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)N3CCc4ccccc34)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.43 (dd, 1.9, 0.9 Hz, 1H), 9.16 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.10 (dd, 9.3, 1.9 Hz, 1H), 8.02-7.95 (m, 2H), 7.81 (d, 1.7 Hz, 1H), 7.73 (d, 8.0 Hz, 1H), 7.40 (dd, 8.8, 5.2 Hz, 1H), 7.22-7.14 (m, 2H), 7.17-7.07 (m, 1H), 6.91 (td, 7.4, 1.1 Hz, 1H), 6.69 (s, 1H), 6.10 (s, 1H), 3.88 (td, 10.0, 7.4 Hz, 1H), 3.04 (dt, 16.6, 7.5 Hz, 2H)。 539.3 A A
I-1716
Figure 02_image3723
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)N3CCc4ccccc34)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.42 (d, 1.8 Hz, 1H), 9.15 (s, 1H), 8.69 (s, 1H), 8.57 (s, 1H), 8.10 (dd, 9.3, 1.8 Hz, 1H), 8.04-7.95 (m, 2H), 7.82 (d, 2.0 Hz, 1H), 7.73 (d, 8.0 Hz, 1H), 7.40 (dd, 8.9, 5.1 Hz, 1H), 7.30 (d, 9.9 Hz, 1H), 7.28-7.15 (m, 3H),7.15-7.00 (m , 2H), 6.99-6.85(m,1H), 6.69 (s, 1H), 6.11 (s, 1H), 3.95-3.84 (m, 1H), 3.35-3.28(m,1H), 3.14-2.95 (m, 2H)。 539 D   
I-1717
Figure 02_image3725
 Fc1ccc2CCN(C(=O)Nc3cc(Br)cc4C(=O)NC(c34)c3cc(F)ccc3Cl)c2c1 1H-NMR (400 MHz, DMSO-d6)  9.23 (br. s, 1H), 8.79 (s, 1H), 7.69 (s, 1H), 7.57 (s, 1H), 7.45 (br. d, 10.6 Hz, 1H), 7.38 (dd, 8.8, 5.1 Hz, 1H), 7.19-7.13 (m, 2H), 6.71 (app. td, 9.0, 2.5 Hz, 1H), 6.65 (br. s, 1H), 5.97 (br. s, 1H), 3.87 (td, 10.0, 7.5 Hz, 1H), 3.29-3.17 (m, 1H), 3.07-2.89 (m, 2H)。 520.1 A   
I-1718
Figure 02_image3727
 OC1CCN(C1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)  9.38 (dd, 1.6, 0.9 Hz, 2H), 9.14 (br. s, 2H), 8.57 (s, 2H), 8.23 (br. s, 1H), 8.19 (br. s, 1H), 8.06 (dd, 9.3, 1.8 Hz, 2H), 7.97 (dd, 9.3, 0.5 Hz, 2H), 7.89 (s, 2H), 7.73 (br. s, 1H), 7.71 (br. s, 1H), 7.51-7.44 (m, 2H), 7.27-7.20 (m, 2H), 6.68 (br. s, 2H), 6.07 (br. s, 2H), 4.99 (br. s, 2H), 4.24-4.19 (m, 1H), 4.18-4.13 (m, 1H), 3.39-3.26 (m, 6H), 3.08-3.03 (m, 2H), 1.83-1.75 (m, 1H), 1.75-1.64 (m, 3H)。 507.3 E   
I-1719
Figure 02_image3729
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Cn3cnc(c3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.56 (br. s, 1H), 9.16 (br. s, 1H), 8.31(s, 1H), 8.12 (s), 7.93-7.85 (m, 1H), 7.71 (br. d, 8.6 Hz, 1H), 7.65 (s, 1H), 7.61 (br. s, 1H), 7.48 (br. s, 1H), 7.31 (dd, 8.9, 5.3 Hz, 1H), 7.08 (app. td, 8.5, 3.2 Hz, 1H), 6.62 (br. s, 1H), 5.95 (br. s, 1H), 5.47 (d, AB之A, JAB = 15.5 Hz, 1H), 5.42 (d, AB之B, JAB = 15.1 Hz, 1H)。 572.2 A   
I-1720
Figure 02_image3731
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)N3CCCC3)c12)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)  9.38 (dd, 1.7, 0.9 Hz, 1H), 9.13 (br. s, 1H), 8.57 (s, 1H), 8.25 (br. s, 1H), 8.05 (dd, 9.3, 1.8 Hz, 1H), 7.97 (dd, 9.3, 0.8 Hz, 1H), 7.89 (d, 1.6 Hz, 1H), 7.68 (d, 1.5 Hz, 1H), 7.53-7.46 (m, 1H), 7.25 (ddd, 8.7, 8.2, 3.1 Hz, 1H), 6.67 (br. s, 1H), 6.06 (br. s, 1H), 3.25-3.21 (m, 4H), 1.76-1.71 (m, 4H)。 491.3 E   
I-1721
Figure 02_image3733
 OC1CCCN(C1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)-9.38 (dd, 1.6, 0.8 Hz, 2H), 9.12 (br. s, 2H), 8.66 (br. s, 1H), 8.61 (br. s, 1H), 8.56 (s, 2H), 8.07 (d, 1.7 Hz, 1H), 8.05 (d, 1.7 Hz, 1H), 7.98 (d, 0.6 Hz, 1H), 7.96 (d, 0.7 Hz, 1H), 7.88 (d, 1.6 Hz, 2H), 7.69 (d, 1.6 Hz, 1H), 7.66 (d, 1.6 Hz, 1H), 7.54-7.47 (m, 2H), 7.28-7.21 (m, 2H), 6.59 (br. s, 1H), 6.08 (br. s, 2H), 4.85 (br. s, 2H), 3.82-3.73 (m, 2H), 3.63 (br. d, 12.8 Hz, 1H), 3.50 (br. d, 12.6 Hz, 1H), 2.99-2.89 (m, 1H), 2.63-2.54 (m, 1H), 2.44-2.34 (m, 2H), 2.27 (dd, 12.2, 9.9 Hz, 1H), 1.84-1.73 (m, 2H), 1.61-1.45 (m, 2H), 1.32-1.10 (m, 4H), 0.92-0.78 (m, 1H)。 521.3 E   
I-1722
Figure 02_image3735
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)N3CCC4(CC4(F)F)C3)c12)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)  ´ 9.39-9.38 (m, 1H), 9.16 (br. s, 1H), 8.57 (s, 1H), 8.41 (d, 2.2 Hz, 1H), 8.08-8.04 (m, 1H), 7.97 (dd, 9.3, 0.8 Hz, 1H), 7.92 (d, 1.4 Hz, 1H), 7.68 (dd, 5.4, 1.6 Hz, 1H), 7.53-7.45 (m, 1H), 7.30-7.20 (m, 1H), 6.66 (br. s, 1H), 6.06 (br. s, 1H), 3.54-3.37 (m, 2H), 3.11-3.02 (m, 1H), 3.00-2.86 (m, 1H), 2.02-1.85 (m, 2H), 1.64-1.49 (m, 2H)。 553.3 D   
I-1723
Figure 02_image3737
 OC1CCCC(C1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)  9.84 (br. s, 1H), 9.78 (br. s, 1H), 9.45-9.42 (m, 2H), 9.20 (br. s, 2H), 8.57 (s, 2H), 8.10 (dd, 3.8, 1.5 Hz, 1H), 8.07 (dd, 3.6, 1.5 Hz, 1H), 7.99-7.96 (m, 3H), 7.96 (s, 1H), 7.85 (d, 0.8 Hz, 1H), 7.76 (d, 0.6 Hz, 1H), 7.55-7.48 (m, 2H), 7.24 (app. td, 8.3, 2.9 Hz, 2H), 6.56 (br. s, 2H), 6.15 (br. s, 2H), 4.42 (br. s, 2H), 3.90-3.86 (m, 1H), 3.85-3.82 (m, 1H), 1.58-1.44 (m, 5H), 1.43-1.23 (m, 8H), 1.20-1.11 (m, 2H), 1.10-1.01 (m, 1H)。 520.3 E   
I-1724
Figure 02_image3739
 OC(C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1)c1ccccc1 NMR (400 MHz, DMSO-d6)  9.62 (br s, 1H), 9.41 (s, 1Hz), 9.20 (s, 1H), 8.57 (d, 1.7 Hz, 1H), 8.30 (s, 1H), 8.05 (td, 9.2, 1.6 Hz, 1H), 7.98 (d, 3.5 Hz, 1H), 7.62- 7.50 (m, 1H), 7.46-7.39 (m, 1H), 7.35-7.17 (m, 5H), 7.06 (d, 2.2 Hz, 1H), 6.63 (br s, 1H), 6.21 (br s, 1H), 4.95 (s, 1H)。 528 E   
I-1725
Figure 02_image3741
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3ccc4ccccc4c3)c12 NMR (400 MHz, DMSO-d6 )  9.15 (br s, 1H), 8.15 (s, 1H), 7.76 (d, 8.1 Hz, 1H), 7.71 (d, 8.8 Hz, 2H), 7.49-7.46 (m, 2H), 7.39 (t, 7.0 Hz, 1H), 7.32-7.24 (m,  2H), 7.13 (d, 1.7 Hz, 1H), 7.10-7.03 (m, 1H), 6.92 (dd, 8.8, 2.1 Hz, 1H), 6.48 (dd, 9.3, 2.8 Hz, 1H), 5.82 (s, 1H) 481.1 D   
I-1726
Figure 02_image3743
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NCC3CCCCC3)c12 NMR (400 MHz, DMSO-d6)  9.06 (s, 1H), 7.60-7.49 (m, 1H), 7.26 (td, 8.4, 3.1 Hz, 1H), 7.03 (d, 1.2 Hz, 1H), 6.87 (s, 1H), 6.76 (br s, 1H), 5.82 (s, 1H), 4.65-4.56 (m, 1H), 2.97-2.87 (m, 1H), 2.83-2.74 (m, 1H), 1.55 (d, 6.8 Hz, 3H), 1.45-1.24 (m, 3H), 1.15-0.96 (m, 3H), 0.78-0.58 (m, 2H)。 451.1 E   
I-1727
Figure 02_image3745
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(Nc3nc4ccccc4[nH]3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.41 (dd, 1.7, 0.9 Hz, 1H), 9.12 (br. s, 1H), 8.57 (s, 1H), 8.40 (d, 1.3 Hz, 1H), 8.35 (br. s, 2H), 8.10 (dd, 9.3, 1.8 Hz, 1H), 7.99 (dd, 9.3, 0.7 Hz, 1H), 7.81 (d, 1.6 Hz, 1H), 7.39 (dd, 8.8, 5.2 Hz, 1H), 7.21 (dd, 5.4, 2.9 Hz, 2H), 7.12 (ddd, 3.1, 8.0, 8.7 Hz, 1H), 7.00-6.87 (m, 2H), 6.61 (br. s, 1H), 6.38 (s, 1H)。 510.3 D   
I-1728
Figure 02_image3747
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(CS(=O)(=O)c3ccccc3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.33 (br. s, 1H), 9.23 (dd, 1.7, 0.9 Hz, 1H), 8.58 (s, 1H), 8.21 (s, 1H), 7.99 (d, 9.2 Hz, 1H), 7.83 - 7.74 (m, 1H), 7.83 - 7.74 (m, 1H), 7.74-7.60 (m, 5H), 7.45 (br. s, 1H), 7.30 (br. s, 1H), 6.47 (br. s, 1H), 6.07 (br. s, 1H), 4.71 (br. d, 13.4 Hz, 1H), 3.89 (d, 13.8 Hz, 1H) 533.1 E   
I-1729
Figure 02_image3749
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(c12)-c1ccc2ccccc2c1)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.63 (s, 1H), 9.34 (br s, 1H), 8.58 (s, 1H), 8.27 (d, 9.3 Hz, 1H), 8.21 (d, 1.5 Hz, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.97 (d, 9.3 Hz, 1H), 7.87 (t, 7.1 Hz, 2H), 7.82 (d, 8.5 Hz, 1H), 7.63 (d, 9.0 Hz, 1H), 7.56-7.44 (m, 2H), 7.07 (dd, 8.8, 5.2 Hz, 1H), 6.84 (td, 8.7, 2.8 Hz, 1H), 6.64 (br s, 1H), 6.39 (br s, 1H)。 505 D   
I-1730
Figure 02_image3751
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C(=O)c3ccccc3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  10.91 (br s, 1H), 9.51 (s, 1H), 9.31 (br s, 1H), 8.58 (s, 1H), 8.15 (dd, 9.3, 1.7 Hz, 1H), 8.12 (d, 1.2 Hz, 1H), 8.06 (d, 1.4 Hz, 1H), 7.99 (d, 9.2 Hz, 1H), 7.82-7.71 (m, 3H), 7.66-7.59 (m, 1H), 7.58-7.49 (m, 3H), 7.24 (td, 8.6, 2.9 Hz, 1H), 6.65 (br s, 1H), 6.21 (br s, 1H)。 526 D   
I-1731
Figure 02_image3753
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(C3CCC3)c12 NMR (400 MHz, DMSO-d6)  10.68 (s, 1H), 8.92 (s, 1H), 8.21 (s, 1H), 8.16 (d, 9.1 Hz, 1H), 8.04 (d, 8.4 Hz, 1H), 7.58-7.49 (m, 3H), 4.77 (d, 4.5 Hz, 1H), 2.77-2.64 (m, 1H), 2.07-1.95 (m, 1H), 1.90-1.80 (m, 1H), 1.76-1.66( m, 1H), 1.65-1.53(m, 1H), 1.39-1.30 (m, 2H)。 393 E   
I-1732
Figure 02_image3755
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(CC3CCCCC3)c12 NMR (400 MHz, DMSO-d6)  10.78 (s, 1H), 8.91 (s, 1H), 8.17 (s, 1H), 8.12 (d, 9.0 Hz, 1H), 8.05 (d, 8.4 Hz, 1H), 7.60-7.50 (m, 3H), 4.83 (br, d, 8.0 Hz, 1H), 1.83-1.66 (m, 2H), 1.57-1.37 (m, 5H), 1.18-0.90 (m, 4H), 0.81-0.58 (m, 2H)。 435 D   
I-1733
Figure 02_image3757
 CN1CCCC[C@H]1[C@@H]1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  11.17 (br s, 1H), 8.56 (s, 1H), 8.16 (s, 1H), 8.10 (d, 9.4 Hz, 1H), 8.04 (t, 7.8 Hz, 1H), 7.66 (dd, 7.0, 1.8 Hz, 1H), 7.58-7.50 (m, 2H), 5.26 (d, 3.6 Hz, 1H), 2.86 - 2.77 (app dt, 11.6 Hz, 2.5 H, 1H), 2.29-2.23 (m, 1H), 2.21 (s, 3H), 1.79 (td, 11.5, 2.4 Hz, 1H), 1.56-1.37 (m, 2H), 1.36-1.19 (m, 1H), 1.00-0.89 (m, 2H), 0.69 - 0.60 (m, 1H) 436.3 E   
I-1734
Figure 02_image3759
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2nnc(Cl)n2c1    618.09 A   
I-1735
Figure 02_image3761
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OCc3cncnc3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    575.12 A   
I-1736
Figure 02_image3763
 Nc1ccc(COc2cc3C(=O)NC(c3c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c2)c2cc(F)ccc2Cl)cn1    589.13 A   
I-1737
Figure 02_image3765
 Cn1cc(c(n1)C#N)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    572.4 E   
I-1738
Figure 02_image3767
 Cn1cc(c(n1)C#N)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    572.4 A   
I-1739
Figure 02_image3769
 FC(F)n1cc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1 H NMR (500 MHz, DMSO-d6 ) δ 10.55 (s, 1H), 9.17 (s, 1H), 8.94 (s, 1H), 8.44 (s, 1H), 8.06 (d, J = 1.5 Hz, 1H), 7.99 - 7.69 (m, 5H), 7.32 (dd, J = 8.9, 5.1 Hz, 1H), 7.09 (td, J = 8.4, 3.1 Hz, 1H), 6.92 - 6.41 (m, 1H), 5.99 (s, 1H)。 583.4 D   
I-1740
Figure 02_image3771
 FC(F)n1cc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1 H NMR (500 MHz, DMSO-d6 ) δ 10.55 (s, 1H), 9.17 (s, 1H), 8.94 (s, 1H), 8.44 (s, 1H), 8.06 (d, J = 1.5 Hz, 1H), 7.99 - 7.69 (m, 5H), 7.32 (dd, J = 8.9, 5.1 Hz, 1H), 7.09 (td, J = 8.4, 3.1 Hz, 1H), 6.92 - 6.41 (m, 1H), 5.99 (s, 1H)。 583.4 A A
I-1741
Figure 02_image3773
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2nc(nc2c1)C#N    609.23 A   
I-1742
Figure 02_image3775
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(c12)S(=O)(=O)Cc1ccccc1)-c1ccc2ncnn2c1 1H  NMR (400 MHz, DMSO-d )  9.59 (br. s, 1H), 9.49 (br. s, 1H), 8.62 (s, 1H), 8.50 (d, 1.5 Hz, 1H), 8.29 (br. s, 1H), 8.16 - 8.09 (m, 1H), 8.02 (d, 8.5 Hz, 1H), 7.62 (br. s, 1H), 7.40-7.28 (m, 3H), 7.24 (br. s, 1H), 7.02 (d, 6.4 Hz, 2H), 6.42 (br. s, 1H), 6.08 (s, 1H), 4.58 (d, 12.8 Hz, 1H), 4.25 (d, 12.5 Hz, 1H)。 533.1 D   
I-1743
Figure 02_image3777
 CC(=O)N1CCCC(C1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6 )  10.01 (br s, 1H), 9.45 (s, 1H), 9.23 (br s, 1H), 8.60-8.54 (m, 1H), 8.14-8.08 (m, 1H), 8.05-7.95 (m, 2H), 7.87-7.76 (m, 1H), 7.63-7.46 (m, 1H), 7.33-7.21 (m, 1H), 6.52 (br s, 1H), 6.12 (s, 1H), 4.35-4.07 (m, 1H), 3.79-3.61 (m, 1H), 3.00-2.81 (m, 1H), 2.28-2.07 (m, 1H), 1.95 (s, 3H), 1.74-1.09 (m, 5H)。 547.2 E   
I-1744
Figure 02_image3779
 CC(=O)N1CCC(CC1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.93 (s, 1H), 9.88 (s, 1H), 9.45 (br s, 2H), 9.23 (br s, 2H), 8.57 (s, 2H), 8.25 (s, 1H), 8.10 (dd, 9.3, 1.8 Hz, 2H), 8.02-8.01 (m, 2H), 7.98 (d, 9.3 Hz, 2H), 7.81 (dd, 12.1, 1.5 Hz, 2H), 7.58-7.49 (m, 2H), 7.31-7.20 (m, 2H), 6.61 (br s, 2H), 6.13 (br s, 2H), 4.30-4.13 (m, 2H), 3.81-3.65 (m, 2H), 3.05-2.88 (m, 2H), 2.37-2.26 (m, 2H), 2.46 (m, 1H), 1.98(s, 6H), 1.60-1.06 (m, 9H)。 547.1 E   
I-1745
Figure 02_image3781
 FC(F)Cc1cc(F)cc(c1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.31 (s, 1H), 9.29 (s, 1H),7.90-7.67 (m, 2H), 7.62-7.27 (m, 3H), 7.25-7.11 (m, 2H), 7.00-7.45 (m,1H), 7.45-6.10 (m,1H), 6.10-5.65 (m,1H), 3.26-3.13 (m, 2H)。 540.95 D   
I-1746
Figure 02_image3783
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(N3Cc4ccccc4CC3=O)c12 1H NMR (400 MHz, DMSO-d6) 9.08 (s, 1H), 7.77-7.65 (m, 2H), 7.59 (d, 7.5 Hz, 1H), 7.21 (t, 7.4 Hz, 1H), 7.18-7.07 (m, 2H), 6.88 (s, 2H), 6.49 (d, 173.5 Hz, 2H), 5.91-5.84 (m, 1H), 4.98 (d, 14.9 Hz, 1H), 3.86-3.59 (m, 2H), 3.45 (d, 18.3 Hz, 1H)。 407.25 E   
I-1747
Figure 02_image3785
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(C3CCCNC3)c12 (400 MHz, DMSO-d6)  10.79 (br s, 1H), 8.81 (s, 1H), 8.15 (s, 1H), 8.12 (d, 8.5 Hz, 1H), 8.04 (d, 8.4 Hz, 1H), 7.66 (dd, 6.5, 2.3 Hz, 1H), 7.61-7.50 (m, 2H), 4.78 (s, 1H), 2.78 (br d, 10.9 Hz, 1H), 2.25 (t, 11.3 Hz, 1H), 2.05 - 1.91 (m, 2H), 1.66 (br d, 12.7 Hz, 1H), 1.57 (br d, 12.1 Hz, 1H), 1.52-1.37 (m, 1H), 1.28-1.07 (m, 1H), 0.88-0.67 (m, 1H) 422.3 E   
I-1748
Figure 02_image3787
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Cn3cncc3C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.63 (br. s, 1H), 9.17 (br. s, 1H), 8.32 (d, 0.5 Hz, 1H), 7.93 (d, 0.8 Hz, 1H), 7.90-7.83 (m, 1H), 7.72 (br. d, 8.8 Hz, 1H), 7.65 (s, 1H), 7.53-7.40 (m, 2H), 7.32 (dd, 8.8, 5.2 Hz, 1H), 7.08 (app. td, 8.4, 3.0 Hz, 1H), 6.59 (br. s, 1H), 5.95 (br. s, 1H), 5.58 (d, AB之A, JAB = 16.1 Hz, 1H), 5.53 (d, AB之B, JAB = 15.9 Hz, 1H)。 572.3 A   
I-1749
Figure 02_image3789
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(Cn3cncc3C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)  10.67 (br. s, 1H), 9.20 (s, 1H), 8.32 (s, 1H), 7.94 (s, 1H), 7.91 (br. d, 7.6 Hz, 1H), 7.72 (br. d, 9.1 Hz, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.44-7.37 (m, 1H), 7.31 (dd, 8.8, 5.1 Hz, 1H), 7.09 (app. td, 8.5, 3.0 Hz, 1H), 6.64 (br. s, 1H), 5.96 (br. s, 1H), 5.60 (d, AB之A, JAB = 16.1 Hz, 1H), 5.55 (d, AB之B, JAB = 15.7 Hz, 1H)。 572.2 B   
I-1750
Figure 02_image3791
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3CCCC(F)(F)C3)c12)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)  9.98 (s, 2H), 9.45 (s, 2H), 9.23 (br. s, 2H), 8.57 (s, 2H), 8.12-8.08 (m, 2H), 8.03-8.01 (m, 2H), 7.98 (d, 9.2 Hz, 2H), 7.82 (dd, 6.8, 1.4 Hz, 2H), 7.56-7.50 (m, 2H), 7.31-7.23 (m, 2H), 6.58 (br. s, 2H), 6.11 (br. s, 2H), 2.42-2.30 (m, 2H), 2.02-1.91 (m, 2H), 1.90-1.58 (m, 8H), 1.56-1.49 (m, 1H), 1.41-1.28 (m, 3H), 1.24-1.08 (m, 2H)。 540.3 D   
I-1751
Figure 02_image3793
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3CCNCC3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  10.13 (br s, 1H), 9.44 (s, 1H), 9.24 (br s, 1H), 8.57 (s, 1H), 8.10 (dd, 9.3, 1.7 Hz, 1H), 8.01 (d, 1.2 Hz, 1H), 7.97 (d, 9.2 Hz, 1H), 7.85 (d, 1.4 Hz, 1H), 7.60-7.47 (m, 1H), 7.24 (td, 8.4, 3.0 Hz, 1H), 6.59 ( br s, 1H), 6.14 (br s, 1H), 3.14-2.97 (m, 2H), 2.63 (t, 10.8 Hz, 2H), 2.36-2.22 (m, 1H), 1.62-1.27 (m, 4H)。 505 E   
I-1752
Figure 02_image3795
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H]([C@@H]3CCCC(F)(F)C3)c12 1H NMR (400 MHz, DMSOd6)  10.89 (s, 1H), 8.81 (s, 1H), 8.08 (s, 1H), 8.05-7.99 (m, 2H), 7.65-7.53 (m, 3H), 4.88 (s, 1H), 2.25-2.13 (m, 1 H), 2.03-1.83 (m, 2H), 1.77 (d, 13.5 Hz, 1H), 1.69-1.51 (m, 2H), 1.43-1.28 (m, 1H), 1.28-1.11 (m, 2H), 1.06-0.92 (m, 1H)。 455.3 D   
I-1753
Figure 02_image3797
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CC4CC(F)(C4)C3)c12 1H NMR (400 MHz, DMSO):-´ 9.27 (br s, 1H), 8.38 (s, 1H), 7.63 (d, 1.5 Hz, 1H), 7.50 (br s, 1H), 7.48 (d, 1.7 Hz, 1H), 7.25 (td, 8.2, 2.7 Hz, 1H), 6.55 (br s, 1H), 5.97 (br s, 1H), 3.60-3.41 (m, 3H), 3.28-3.22 (m, 1H), 2.47-2.36 (m, 1H), 2.22 (dd, 18.0, 8.6 Hz, 2H), 1.62 (br s, 2H)。 496.2 E   
I-1754
Figure 02_image3799
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CC4CCC4(C3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO):-´ 9.21 (br s, 1H), 8.62 (s, 1H), 7.63 (s, 1H), 7.57 (d, 1.7 Hz, 0.5H), 7.56 (d, 1.7 Hz, 0.5H), 7.44 (br s, 1H), 7.22 (2個重疊td, 8.4, 3.1 Hz, 1H), 6.59 (br s, 1H), 6.02 (br s, 1H), 3.65 (d, 11.4 Hz, 0.5H), 3.46 (d, 11.0 Hz, 0.5H), 3.30 (d, 11.7 Hz, 1H), 3.24 (d, 11.8 Hz, 0.5H), 3.15 (dd, 11.1, 6.4 Hz, 0.5H), 3.05-2.94 (m, 1H), 2.94-2.86 (m, 0.5H), 2.76-2.65 (m, 0.5H), 2.36-2.24 (m, 1H), 2.19-2.05 (m, 1H), 1.90-1.81 (m, 0.5H), 1.81-1.71 (m, 0.5H), 1.66-1.54 (m, 0.5H), 1.51-1.39 (m, 0.5H)。 546.2 D   
I-1755
Figure 02_image3801
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)NC3(CC(F)(F)F)CC3)c12 1H NMR (400 MHz, DMSO):-´ 9.16 (s, 1H), 8.64 (br s, 0.5H), 8.49 (br s, 0.5H), 7.75 (s, 1H), 7.53 (s, 1H), 7.49-7.41 (m, 1H), 7.35 (s, 1H), 7.20 (td, 8.3, 2.8 Hz, 1H), 6.64 (br s, 1H), 6.11 (s, 1H), 2.49-2.34 (m, 2H), 0.76-0.52 (m, 4H)。 520.1 E   
I-1756
Figure 02_image3803
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCC4C(C3)C4C(F)(F)F)c12 1H NMR (400 MHz, DMSO):-´ 9.17 (br s, 1H), 8.40 (s, 0.5H), 8.36 (s, 0.5H), 7.58 (d, 1.7 Hz, 0.5H), 7.57 (d, 1.7 Hz, 0.5H), 7.51 (d, 1.7 Hz, 0.5H), 7.43 (br s及d, 1.7 Hz, 1.5H), 7.27-7.18 (m, 1H), 6.63 (br s, 1H), 5.90 (br s, 1H), 3.61-3.52 (m, 0.5H), 3.48-3.43 (m, 1.5H), 3.19-3.11 (m, 1H), 2.81-2.72 (m, 0.5H), 2.43-2.33 (m, 0.5H), 2.04-1.94 (m, 0.5H), 1.90-1.80 (m, 0.5H), 1.80-1.66 (m, 1H), 1.57-1.33 (m, 3H)。 546.1 D   
I-1757
Figure 02_image3805
 CC(C)(CC(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(F)(F)F 1H NMR (400 MHz, DMSO):-´ 9.95 (s, 1H), 9.27 (s, 1H), 7.74-7.70 (m, 2H), 7.51 (br s, 1H), 7.24 (td, 8.4, 3.1 Hz, 1H), 6.63 (br s, 1H), 6.04 (br s, 1H), 2.21 (2個重疊d, 13.9 Hz, 2H), 1.01 (br s, 3H), 0.94 (s, 3H)。 507 E   
I-1758
Figure 02_image3807
 CN1CCC(CC1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.88 (br s, 1H), 9.44 (s, 1H), 9.22 (br s, 1H), 8.57 (s, 1H), 8.09 (dd, 9.3, 1.7 Hz, 1H), 8.00 (d, 1.2 Hz, 1H), 7.97 (d, 9.2 Hz, 1H), 7.81 (d, 1.3 Hz, 1H), 7.60-7.40 (m, 1H), 7.25 (td, 8.4, 3.1 Hz, 1H), 6.56 (br s, 1H), 6.13 (br s, 1H), 2.72 (t, 11.2 Hz, 2H), 2.14 (s, 3H), 2.08-1.93 (m, 1H), 1.86-1.72 (m, 2H), 1.49-1.18 (m, 4H)。 519 E   
I-1759
Figure 02_image3809
 NC1CCC(CC1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.95 (br s, 1H), 9.44 (s, 1H), 9.21 (br s, 1H), 8.57 (s, 1H), 8.39 (br s, 2H), 8.00 (s, 1H), 7.97 (d, 9.0 Hz, 1H), 7.96 (s, 1H), 7.82 (br d, 4.7 Hz, 1H), 7.58-7.47 (m, 1H), 7.29-7.21 (m, 1H), 6.70 (br s, 1H), 6.11 (br s, 1H), 2.89-2.70 (m, 1H), 2.09-1.95 (m, 1H), 1.93-1.78 (m, 2H), 1.60-1.44 (m, 1H), 1.43-1.30 (m, 1H), 1.30-1.09 (m, 4H)。 519 E   
I-1760
Figure 02_image3811
 ON=C(C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1)c1ccccc1 NMR (400 MHz, DMSO-d6)  10.62 (br s, 1H), 9.45 (br s, 1H), 9.27 (br s, 1H), 8.59 (s, 1H), 8.15-7.95 (m, 5H), 7.63-7.50 (m, 1H), 7.42-7.37 (m, 1H), 7.32-7.24 (m, 3H), 7.14 (s, 1H), 7.12 (s, 1H), 6.60 (br s, 1H), 6.33 (br s, 1H)。 541 E   
I-1761
Figure 02_image3813
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(CN3CCCC3)c12 NMR (400 MHz, CD3CN)  12.43 (br. s, 1H), 8.45 (dd, 7.3, 1.6 Hz, 1H) 7.93 (s, 1H), 7.77 (br. d, 8.6 Hz, 1H), 7.68 (br. d, 8.6 Hz, 1H), 7.54-7.48 (m, 2H), 6.86 (br. s, 1H), 4.79 (ddd, 8.9, 4.5, 1.0 Hz, 1H), 2.79 (d, 4.9 Hz, 1H), 2.77 (s, 1H) 2.75-2.67 (m, 2H), 2.59-2.51 (m, 2H), 1.35  1.28 (m, 3H), 1.28-1.22 (m, 1H)。 422.2 E   
I-1762
Figure 02_image3815
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2ncc(C#N)c2c1 1H NMR (DMSO-d6, 400 MHz) 10.64 (s, 1H), 9.28 (br s, 1H), 9.07 (d, 7.3 Hz, 1H), 8.70 (s, 1H), 8.39 (d, 1.3 Hz, 1H), 8.24 (d, 1.5 Hz, 1H), 8.08-8.11 (m, 1H), 7.95-8.00 (m, 1H), 7.76-7.81 (m, 1H), 7.71-7.74 (m, 2H), 7.70 (d, 2.0 Hz, 1H), 7.32-7.37 (m, 1H), 7.09-7.15 (m, 1H), 6.02-6.14  (m, 1H) 608.4 A   
I-1763
Figure 02_image3817
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2nccc2n1 1H NMR (DMSO-d6, 400 MHz):-´ = 10.70 (s, 1H), 9.27-9.34 (m, 1H), 9.25 (dd, 7.3, 0.8 Hz, 1H), 8.48 (d, 1.0 Hz, 1H), 8.42 (d, 1.0 Hz, 1H), 8.29 (d, 2.3 Hz, 1H), 7.97 (br d, 8.6 Hz, 1H), 7.84 (d, 7.3 Hz, 1H), 7.80 (br d, 8.8 Hz, 1H), 7.74 (s, 1H), 7.34 (dd, 8.8, 5.3 Hz, 1H), 7.11 (td, 8.4, 3.2 Hz, 1H), 6.81 (dd, 2.3, 0.8 Hz, 1H), 6.02-6.20  (m, 1H) 584.4 A   
I-1764
Figure 02_image3819
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2ncnc2c1F 1H NMR (400 MHz, DMSO) δ 10.69 (s, 1H), 9.31 (s, 1H), 8.99 (d, J = 7.1 Hz, 1H), 8.65 (s, 1H), 8.00 (d, J = 1.4 Hz, 1H), 7.95 (dt, J = 8.6, 1.9 Hz, 1H), 7.85 (s, 1H), 7.76 (dd, J = 9.1, 2.5 Hz, 1H), 7.68 (s, 1H), 7.50 (q, J = 7.1 Hz, 1H), 7.34 (dd, J = 8.9, 5.2 Hz, 1H), 7.15 - 7.07 (m, 1H), 6.69 (s, 1H), 6.07 (s, 1H)。 602.18 D   
I-1765
Figure 02_image3821
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2ncnc2c1F 1H NMR (400 MHz, DMSO) δ 10.69 (s, 1H), 9.31 (s, 1H), 8.99 (d, J = 7.1 Hz, 1H), 8.65 (s, 1H), 8.00 (d, J = 1.4 Hz, 1H), 7.95 (dt, J = 8.6, 1.9 Hz, 1H), 7.85 (s, 1H), 7.76 (dd, J = 9.1, 2.5 Hz, 1H), 7.68 (s, 1H), 7.50 (q, J = 7.1 Hz, 1H), 7.34 (dd, J = 8.9, 5.2 Hz, 1H), 7.15 - 7.07 (m, 1H), 6.69 (s, 1H), 6.07 (s, 1H)。 602.18 A   
I-1766
Figure 02_image3823
 CC1(C)CC1C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6 )  10.56 (s, 1H), 8.77 (s, 1H), 8.20 (s, 1H), 8.14 (br. d, 9.2 Hz, 1H), 8.03 (br. d, 8.4 Hz, 1H), 7.66-7.51 (m, 3H), 4.48-4.41 (m, 1H), 1.14 (s, 3H), 0.93 (s, 3H), 0.34-0.24 (m, 3H)。 407.2 D   
I-1767
Figure 02_image3825
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2c(cnc2cn1)C#N    609.03 A   
I-1768
Figure 02_image3827
 FC(F)n1cc(ccc1=O)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    610.5 A   
I-1769
Figure 02_image3829
 CN1CCCC(C1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.80 (s, 1H), 8.79 (s, 1H), 8.15 (s, 1H), 8.09 (d, 9.1 Hz, 1H), 8.04 (d, 8.4 Hz, 1H), 7.62 (dd, 6.9, 1.9 Hz, 1H), 7.60-7.52 (m, 2H), 4.81 (d, 1.2 Hz, 1H), 2.60 (d, 10.4 Hz, 1H), 2.15-2.04 (m, 1H), 1.89 (s, 3H), 1.83 (d, 10.8 Hz, 1H), 1.64 - 1.56 (m, 3H), 1.39 (t, 10.9 Hz, 1H), 1.31-1.21 (m, 2H) 436.3 E   
I-1770
Figure 02_image3831
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(C3CCNCC3)c12 (400 MHz, DMSO-d6)  10.72 (br s, 1H), 8.78 (s, 1H), 8.14 (s, 1H), 8.10 (d, 9.0 Hz, 1H), 8.04 (d, 8.5 Hz, 1H), 7.61 (dd, 7.3, 1.4 Hz, 1H), 7.59-7.50 (m, 2H), 4.77 (d, 1.1 Hz, 1H), 2.98 (d, 11.8 Hz, 1H), 2.82 (d, 11.5 Hz, 1H), 2.35-2.20 (m, 2H), 2.00-1.87 (m, 1H), 1.55-1.43 (m, 2H), 0.93-0.80 (m, 1H), 0.57 (d, 10.8 Hz, 1H) 422.3 D   
I-1771
Figure 02_image3833
 CC(=O)N1CCCC(C1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.96 (br s, 0.5H), 10.85 (br s, 0.5H), 8.89 (s, 0.5H), 8.83 (s, 0.5H), 8.13-7.97 (m, 3H), 7.69-7.52 (m, 3H), 4.87 (d, 0.9 Hz, 0.5H), 4.77 (d, 1.4 Hz, 0.5H), 4.27 (d, 12.3 Hz, 0.5H), 3.68 (d, 12.3 Hz, 0.5H), 3.64 (d, 12.3 Hz, 0.5H), 2.77 (app t, 12.3 Hz, 1H), 2.55 -2.51 (m, 1H), 2.22 (t, 12.1 Hz, 0.5H), 1.94 (t, 12.1 Hz, 1H), 1.89 (s, 1.5H), 1.86-1.64 (m, 2.5H), 1.62 (s, 1.5H), 1.60-1.51 (m, 0.5H), 1.21-1.00 (m, 1H) 464.3 E   
I-1772
Figure 02_image3835
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(CC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1    583.2 B   
I-1773
Figure 02_image3837
 OCc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6 )  9.35 (s, 1H), 9.07 (s, 1H), 8.54 (s, 1H), 8.12 (s, 1H), 8.02 (dd, 9.3, 1.8 Hz, 1H), 7.99 (s, 1H), 7.89 (d, 9.2 Hz, 1H), 7.70 (s, 1H), 7.54 (dd, 8.3, 5.1 Hz, 1H), 7.40 (d, 1.3 Hz, 1H), 7.24 (td, 8.0, 3.0 Hz, 1H), 7.18 (s, 1H), 6.73 (br s, 1H), 5.96 (s, 1H), 5.69 (t, 6.2 Hz, 1H), 4.71 (dd, 16.1, 6.3 Hz, 1H), 4.53 (dd, 16.0, 5.5 Hz, 1H)。 596.3 E   
I-1774
Figure 02_image3839
 NC(=O)c1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 (400 MHz, DMSO-d6)  9.59 (d, 0.8 Hz, 1 H), 9.30 (s, 1 H), 8.59 (s, 1 H), 8.37 (s, 1 H), 8.29 (d, 1.5 Hz, 1 H), 8.26 (dd, 9.3, 1.8 Hz, 1 H), 8.11 (s, 1 H), 8.01 (d, 9.3 Hz, 1 H), 7.49 (br s, 1 H), 7.45 (s, 1 H), 7.18 (td, 8.4, 3.1 Hz, 1 H), 6.43 (br s, 1 H)。 422.1 D   
I-1775
Figure 02_image3841
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(ccc12)-c1ccc2ncnn2c1 (400 MHz, DMSO-d6)  9.42 (app d, 0.8 Hz, 1 H), 9.17 (s, 1 H), 8.56 (s, 1 H), 8.13 (d, 1.4 Hz, 1 H), 8.09 (dd, 9.3, 1.8 Hz, 1 H), 8.01 (dd, 8.0, 1.8 Hz, 1 H), 7.95 (dd, 9.3, 0.5 Hz, 1 H), 7.66 (dd, 8.9, 5.1 Hz, 1 H), 7.53 (d, 8.0 Hz, 1 H), 7.28 (ddd, 8.8, 8.1, 3.1 Hz, 1 H), 7.01 (dd, 9.3, 3.0 Hz, 1 H), 6.18 (s, 1 H)。 379.2 E   
I-1776
Figure 02_image3843
 CC(O)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6 )  11.29 (br. s, 1H), 8.72 (s, 1H), 8.44 (d, 7.5 Hz, 1H), 8.10 (s, 1H), 8.07-8.00 (m, 2H), 7.55 (t, 7.7 Hz, 1H), 7.48 (dd, 7.4, 0.8 Hz, 1H), 6.88 (br. s, 1H), 4.87 (d, 2.9 Hz, 1H), 4.29-4.22 (m, 1H), 0.73 (d, 6.3 Hz, 3H)。 383.2 D   
I-1777
Figure 02_image3845
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)CC3CCC3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.69 (s, 1H), 9.42 (d, 1.6 Hz, 1H), 9.16 (s, 1H), 8.57 (s, 1H), 8.08 (dd, 9.3, 1.9 Hz, 1H), 8.01-7.93 (m, 2H), 7.84 (d, 1.7 Hz, 1H), 7.53 (d, 7.7 Hz, 1H), 7.26 (td, 8.4, 3.1 Hz, 1H), 6.66 (s, 1H), 6.12 (s, 1H), 2.43-2.33 (m, 1H), 2.25-2.09 (m, 2H), 1.95-1.82 (m, 2H), 1.81-1.68 (m, 2H), 1.51 (p, 8.7 Hz, 2H)。 490.25 E   
I-1778
Figure 02_image3847
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3CCC3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.69 - 9.10 (m, 2H), 8.56 (s, 1H), 8.09 (dd, 9.3, 1.9 Hz, 1H), 8.03 - 7.91 (m, 2H), 7.80 (t, 1.8 Hz, 1H), 7.51 (dd, 9.0, 5.2 Hz, 1H), 7.24 (td, 8.4, 3.1 Hz, 1H), 6.67 (s, 1H), 6.13 (s, 1H), 2.96 (ddt, 12.4, 9.0, 4.9 Hz, 1H), 2.05 - 1.58 (m, 6H)。 476.1 E   
I-1779
Figure 02_image3849
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)[C@H]3CCCCN3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.41 (t, 1.3 Hz, 1H), 9.27 (s, 1H), 8.97 (s, 1H), 8.77 (q, 16.4, 13.1 Hz, 1H), 8.59 (s, 1H), 8.18 - 7.92 (m, 4H), 7.55 (t, 7.2 Hz, 2H), 7.28 (td, 8.4, 3.1 Hz, 1H), 6.11 (s, 1H), 3.93 - 3.71 (m, 1H), 3.23 (d, 12.7 Hz, 1H), 3.02 - 2.88 (m, 1H), 1.81 - 1.34 (m, 7H), 0.97 (q, 11.7 Hz, 1H)。 505.15 E   
I-1780
Figure 02_image3851
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)[C@@H]3CCCCN3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.41 (t, 1.3 Hz, 1H), 9.27 (s, 1H), 8.97 (s, 1H), 8.77 (q, 16.4, 13.1 Hz, 1H), 8.59 (s, 1H), 8.18 - 7.92 (m, 4H), 7.55 (t, 7.2 Hz, 2H), 7.28 (td, 8.4, 3.1 Hz, 1H), 6.11 (s, 1H), 3.93 - 3.71 (m, 1H), 3.23 (d, 12.7 Hz, 1H), 3.02 - 2.88 (m, 1H), 1.81 - 1.34 (m, 7H), 0.97 (q, 11.7 Hz, 1H)。 505.15 E   
I-1781
Figure 02_image3853
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)CC3CC3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.80 - 9.14 (m, 2H), 8.57 (s, 1H), 8.09 (dd, 9.3, 1.9 Hz, 1H), 8.02 - 7.92 (m, 2H), 7.85 (t, 1.9 Hz, 1H), 7.52 (dd, 8.9, 5.1 Hz, 1H), 7.24 (td, 8.4, 3.1 Hz, 1H), 6.66 (s, 1H), 6.13 (s, 1H), 2.03 - 1.87 (m, 2H), 0.77 (ddt, 12.4, 7.8, 3.7 Hz, 1H), 0.45 - 0.25 (m, 2H), 0.04 - -0.07 (m, 2H)。 476.1 E   
I-1782
Figure 02_image3855
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3CCCC3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.84 - 8.98 (m, 2H), 8.57 (s, 1H), 8.10 (dd, 9.3, 1.9 Hz, 1H), 8.03 - 7.93 (m, 2H), 7.81 (d, 1.7 Hz, 1H), 7.52 (dd, 9.1, 5.1 Hz, 1H), 7.25 (td, 8.4, 3.1 Hz, 1H), 6.63 (s, 1H), 6.14 (s, 1H), 2.68 (tt, 3.7, 1.8 Hz, 1H), 1.66 - 1.37 (m, 7H), 1.26 (d, 18.9 Hz, 1H)。 490.1 E   
I-1783
Figure 02_image3857
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)CN3CCCC3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.45 - 9.40 (m, 1H), 9.30 (d, 59.5 Hz, 1H), 8.57 (s, 1H), 8.21 (dd, 3.5, 1.7 Hz, 1H), 8.09 (dd, 9.3, 1.9 Hz, 1H), 8.02 - 7.95 (m, 2H), 7.57 (s, 1H), 7.29 (td, 8.4, 3.1 Hz, 1H), 6.67 (s, 1H), 6.18 (s, 1H), 3.11 - 2.94 (m, 2H), 2.38 - 2.11 (m, 4H), 1.72 - 1.59 (m, 4H)。 505.15 E   
I-1784
Figure 02_image3859
 OC(=O)c1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.49 - 9.27 (s, 1H), 8.57 (s, 1H), 8.44 (d, 1.9 Hz, 1H), 8.30 (d, 1.9 Hz, 1H), 8.15 (dd, 9.3, 1.9 Hz, 1H), 7.97 (d, 9.2 Hz, 1H), 7.51 (dd, 9.1, 5.2 Hz, 1H), 7.17 (td, 8.4, 3.1 Hz, 1H), 6.41 (s, 2H)。 422.95 E   
I-1785
Figure 02_image3861
 [2H]c1nc2ccc(cn2n1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, 甲醇-d4)  9.27 (dd, 1.9, 0.9 Hz, 1H), 8.22 - 8.12 (m, 2H), 7.99- 7.89 (m, 2H), 7.75-7.66 (m, 3H), 7.32 (dd, 8.9, 5.1 Hz, 1H), 7.04 (ddd, 8.8, 7.7, 3.0 Hz, 1H), 6.72 (s, 1H), 6.29 (s, 1H)。 585.05 A   
I-1786
Figure 02_image3863
 [2H]c1nc2ccc(cn2n1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, 甲醇-d4)  9.27 (dd, 1.9, 0.9 Hz, 1H), 8.22 - 8.12 (m, 2H), 7.99 - 7.89 (m, 2H), 7.76 - 7.66 (m, 3H), 7.32 (dd, 8.9, 5.1 Hz, 1H), 7.04 (ddd, 8.9, 7.7, 3.0 Hz, 1H), 6.72 (s, 1H), 6.29 (s, 1H)。 585.1 B   
I-1787
Figure 02_image3865
 NC(=O)C(C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1)c1ccccc1 NMR (400 MHz, DMSO-d6)  10.47 (br s, 0.6H), 10.13 (br s, 0.4H), 9.44-9.42 (m, 0.5H), 9.42-9.40 (m, 0.5H), 9.25 (br s, 0.6H), 9.21 (br s, 0.4H), 8.57 (s, 1H), 8.34 (d, 1.5 Hz, 0.5H), 8.10-8.04 (m, 1.5H), 8.01-7.94 (m, 2H), 7.75 (br s, 0.6H), 7.61 (br s, 0.4H), 7.54-7.36 (m, 2H), 7.31-7.14 (m, 5H), 7.04 (dd, 7.4, 1.5 Hz, 1H), 6.61 (br s, 1H), 6.14 (br s, 1H), 4.36 (br s, 0.6H), 4.35 (br s, 0.4H)。 555 D   
I-1788
Figure 02_image3867
 [2H]C([2H])(c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)S(C)(=O)=O NMR (400 MHz, CD3CN)  8.72 (br, s, 1H), 7.78 (d, 1.4 Hz, 1H), 7.65 (br, d, 8.5 Hz, 1H), 7.63 (s, 1H), 7.60 (br, d, 9.1 Hz, 1H), 7.56 (s, 1H), 7.30 (br, s, 1H), 7.26 (dd, 8.9, 5.1 Hz, 1H), 6.98 (ddd, 8.8, 8.1, 3.1 Hz,1H), 6.66 (br, s, 1H 561 B   
I-1789
Figure 02_image3869
 [2H]C([2H])(c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)S(C)(=O)=O NMR (400 MHz, CD3CN)  8.72 (br, s, 1H), 7.78 (d, 1.4 Hz, 1H), 7.65 (br, d, 8.5 Hz, 1H), 7.63 (s, 1H), 7.60 (br, d, 9.1 Hz, 1H), 7.56 (s, 1H), 7.30 (br, s, 1H), 7.26 (dd, 8.9, 5.1 Hz, 1H), 6.98 (ddd, 8.8, 8.1, 3.1 Hz,1H), 6.66 (br, s, 1H)。 561 A   
I-1790
Figure 02_image3871
 FC1=C(CCCC1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  10.62 (s, 1H), 8.66 (s, 1H), 8.14 (s, 1H), 8.07-8.00 (m, 2H), 7.62 (dd, 7.4, 1.4 Hz, 1H), 7.58 (t, 7.4 Hz, 1H), 7.51 (dd, 7.5, 1.3 Hz, 1H), 5.73 (s, 1H), 2.10-1.97 (m, , 1H), 1.64-1.40 (m, , 3H), 1.38-1.18 (m, 3H), 1.09 (m, 1H)。 437 C   
I-1791
Figure 02_image3873
 CC1(CC1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  10.59 (s, 1H), 8.72 (s, 1H), 8.24 (s, 1H), 8.16 (d, 9.2 Hz, 1H), 8.04 (d, 8.5 Hz, 1H), 7.63-7.53 (m, 3H), 4.04 (s, 1H), 0.54 (m, 2H), 0.43 (s, 3H), 0.32-0.23 (m, 1H), 0.19-0.11 (m, 1H)。 393 E   
I-1792
Figure 02_image3875
 CN1CCCC(C1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO -d6)  10.01 (br s, 0.5H), 9.97 (br s, 0.5H), 9.46-9.43 (m, 1H), 9.23 (br s, 1H), 8.57 (s, 1H), 8.10 (dt, 9.3, 1.8 Hz, 1H), 8.02-7.92 (m, 2.5H), 7.79 (d, 1.5 Hz, 0.5H), 7.62-7.46 (m, 1H), 7.32-7.22 (m, 1H), 6.50 (br s, 1H), 6.10 (br s, 1H), 2.67-2.54 (m, 1H), 2.44-2.37 (m, 0.5H), 2.36-2.26 (m, 1H), 2.25-2.13 (m, 0.5H), 2.09 (s, 1.5H), 2.06 (s, 1.5H), 1.83-1.59 (m, 2H), 1.57-1.29 (m, 3H), 1.23-1.06 (m, 1H)。 519 D   
I-1793
Figure 02_image3877
 Fc1cnc2ccc(cn12)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO)  10.61 (s, 1H), 9.22 (s, 1H), 8.75 (s, 1H), 8.09 (d, 1.6 Hz, 1H), 7.95 (d, 8.4 Hz, 1H), 7.91 (s, 1H), 7.77 (d, 9.0 Hz, 1H), 7.71 (s, 1H), 7.69 (dd, 9.5, 1.8 Hz, 1H), 7.66 (d, 1.7 Hz, 1H), 7.61 (ddt, 9.7, 6.9, 3.9 Hz, 2H), 7.57-7.52 (m, 1H), 7.42 (d, 7.2 Hz, 1H), 7.33 (dd, 8.9, 5.2 Hz, 1H), 7.10 (td, 8.3, 3.1 Hz, 1H), 6.05 (s, 1H)。 601.23 A   
I-1794
Figure 02_image3879
 Cn1ncc(c1C#N)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    572.4 D   
I-1795
Figure 02_image3881
 Cn1ncc(c1C#N)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    572.4 A   
I-1796
Figure 02_image3883
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc2ncc(C#N)n2c1    609.08 A   
I-1797
Figure 02_image3885
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc(F)c2ncc(C#N)n2c1    626.09 A   
I-1798
Figure 02_image3887
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2ncc(C#N)c2c1    608.5 D   
I-1799
Figure 02_image3889
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccn2ncc(C#N)c2c1    608.5 A   
I-1800
Figure 02_image3891
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(c1)C1(CC1)C#N (400 MHz, DMSO-d6)  10.57 (s, 1 H), 9.16 (s, 1 H), 8.74 (s, 1 H), 8.23 (s, 1 H), 8.01-7.93 (m, 2 H), 7.80 - 7.70 (m, 3 H), 7.32 (dd, 8.9, 5.2 Hz, 1 H), 7.09 (td, 8.5, 2.9 Hz, 1 H), 6.57 (br s, 1 H), 5.98 (s, 1 H), 1.98-1.85 (m, 4 H)。 596.3 A   
I-1801
Figure 02_image3893
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(C#N)c12)-c1ccc2ncnn2c1 (400 MHz, DMSO-d6)  9.60 (s, 1 H), 9.51 (s, 1 H), 8.63-8.57 (m, 2 H), 8.49 (s, 1 H), 8.22 (dd, 9.3, 1.7 Hz, 1 H), 7.98 (d, 9.3 Hz, 1 H), 7.69-7.49 (m, 1 H), 7.34 (td, 8.4, 2.6 Hz, 1 H), 6.35 (br s, 1 H)。 402.2 D   
I-1802
Figure 02_image3895
 Fc1ccc(Cl)c(c1)C1NC(=O)c2c1c(NC(=O)c1cc(F)cc(c1)C(F)(F)F)cc(-c1ccc3ncnn3c1)c2-c1ccc2ncnn2c1 (400 MHz, CD3CN)  8.83 (br s, 0.5 H), 8.75 - 8.67 (m, 0.5 H), 8.66 (s, 1 H), 8.27 (d, 2.6 Hz, 2 H), 8.10 (s, 1 H), 7.76 (s, 1 H), 7.66 (dd, 17.2, 8.7 Hz, 2 H), 7.61 (s, 1 H), 7.54 (dd,   18.1, 9.1 Hz, 2 H), 7.46 (br s, 1 H), 7.35 (dd, 9.2, 1.7 Hz, 2 H), 7.30 (dd, 8.9, 5.1 Hz, 1 H), 7.03 (td, 8.4, 3.0 Hz, 1 H), 6.84 (br s, 1 H), 6.21 (br s, 1 H) 701.2 B   
I-1803
Figure 02_image3897
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3CCCCO3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6 )  9.45-9.39 (m, 1H), 9.22 (s, 1H), 9.18 (s, 0.5H), 9.02 (s, 0.5 H), 8.57 (s, 1H), 8.20 (s, 0.5H), 8.17 (d, 1.3 Hz, 1H), 8.09 (d, 1.6 Hz, 1H), 8.09-8.04 (m, 1H), 8.01-7.93 (m, 2H), 7.51 ( br s, 1H), 7.34-7.21 (m, 1H), 7.00-6.35 (br s, 1H), 6.19 (br s, 1H), 3.88 (dd, 16.0, 13.5 Hz, 1H), 3.72 (dd, 12.8, 11.4, 2.4 Hz,  1H), 3.52-3.35 (m, 2H), 1.82-1.57 (m, 2H), 1.57-1.29 (m, 3H), 1.11-0.71 (m, 1H)。 506.3 E   
I-1804
Figure 02_image3899
 CC(=O)N1CCCCC1C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6 )  9.87 (s, 0.1H),  9.85 (s, 0.2H), 9.74 (s, 0.3H), 9.65 (s, 0.3H), 9.44-9.42 (s, 0.6H), 9.41-9.39(s, 0.5H), 9.24-9.14 (m, 1H), 8.56-8.51 (m, 1H), 8.10-8.03 (m, 1H), 8.03-7.99 (m, 1H), 7.98-7.91 (m, 2H), 7.86-7.78 (m, 0.5H), 7.57-7.46 (m, 1H), 7.26-7.17 (m, 1H), 6.50 (br s, 1H), 6.20 (br s, 0.6H), 6.16 (br s, 0.4H), 5.08-4.96 (m, 1H), 4.45-3.98 (m, 0.4H), 3.63-3.46 (m, 0.6H), 2.94-2.67 (m, 0.5H), 1.98 (s, 2H), 1.90 (s, 1H), 1.94-1.76 (浸沒m, 1H), 1.58-1.45 (m, 0.5 H), 1.43-1.14 (m, 4H), 1.14-0.48 (m, 1H)。非對映異構體及可能旋轉異構體之混合物 547.2 E   
I-1805
Figure 02_image3901
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1ccccc1 NMR (400 MHz, DMSO-d6 )  10.40 (s, 1H), 9.09 (s, 1H), 7.95 (br. d, 8.5 Hz, 1H), 7.69-7.65 (m, 2H), 7.62-7.57 (m, 2H), 7.52 (dd, 7.1, 0.7 Hz, 1H), 7.22-7.11 (m, 3H), 6.99-6.95 (m, 2H), 5.73 (s, 1H)。 415.3 D   
I-1806
Figure 02_image3903
 NC(=O)Cn1nc(Nc2cc(cc3C(=O)NC(c23)c2cc(F)ccc2Cl)-c2ccc3ncnn3c2)c2ccccc12 1H NMR (400 MHz, DMSO-d6)  9.35 (dd, 1.9, 0.9 Hz, 1H), 9.05 (s, 1H), 8.56 (s, 1H), 8.38 (s, 1H), 8.10 - 7.95 (m, 3H), 7.74 (d, 1.6 Hz, 1H), 7.59 (s, 1H), 7.47 (d, 8.4 Hz, 1H), 7.39 - 7.29 (m, 2H), 7.24 (dd, 8.8, 4.9 Hz, 2H), 7.08 - 6.95 (m, 2H), 6.72 (s, 1H), 6.12 (s, 1H), 5.00 - 4.82 (m, 2H)。 567.3 D   
I-1807
Figure 02_image3905
 OCCn1nc(Nc2cc(cc3C(=O)NC(c23)c2cc(F)ccc2Cl)-c2ccc3ncnn3c2)c2ccccc12 1H NMR (400 MHz, DMSO-d6)  9.34 (s, 1H), 9.07 (s, 1H), 8.56 (s, 1H), 8.33 (s, 1H), 8.09 - 8.02 (m, 2H), 7.97 (d, 9.3 Hz, 1H), 7.72 (d, 1.6 Hz, 1H), 7.50 (d, 8.5 Hz, 1H), 7.33 (dt, 9.3, 2.2 Hz, 2H), 7.26 (dd, 8.8, 5.2 Hz, 1H), 7.03 (td, 8.4, 3.2 Hz, 1H), 6.94 (d, 7.5 Hz, 1H), 6.65 (s, 1H), 6.13 (s, 1H), 4.83 (t, 5.4 Hz, 1H), 4.31 (t, 5.7 Hz, 2H), 3.80 (t, 5.8 Hz, 2H)。 554.35 D   
I-1808
Figure 02_image3907
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(Nc3nn(CC#N)c4ccccc34)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.39 (t, 1.4 Hz, 1H), 9.13 (s, 1H), 8.68 (s, 1H), 8.57 (s, 1H), 8.09 (dd, 9.3, 1.9 Hz, 1H), 8.02 (t, 2.1 Hz, 1H), 7.97 (d, 9.2 Hz, 1H), 7.83 (d, 1.6 Hz, 1H), 7.63 (d, 8.8 Hz, 1H), 7.51 - 7.41 (m, 2H), 7.21 (dd, 8.8, 5.1 Hz, 1H), 7.09 (dd, 8.2, 6.8 Hz, 1H), 7.00 (td, 8.3, 3.1 Hz, 1H), 6.57 (s, 1H), 6.18 (s, 1H), 5.63 (d, 2.8 Hz, 2H)。 549.1 D   
I-1809
Figure 02_image3909
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(Nc3nn(C4CC4)c4ccccc34)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.36 (t, 1.4 Hz, 1H), 9.08 (s, 1H), 8.57 (s, 1H), 8.40 (s, 1H), 8.10 - 8.02 (m, 2H), 7.98 (d, 9.0 Hz, 1H), 7.74 (d, 1.6 Hz, 1H), 7.53 (d, 8.4 Hz, 1H), 7.36 (dd, 14.1, 7.2 Hz, 2H), 7.25 - 7.20 (m, 1H), 7.07 - 6.98 (m, 2H), 6.60 (s, 1H), 6.10 (d, 2.8 Hz, 1H), 3.57 (p, 5.3 Hz, 1H), 1.08 (tq, 5.9, 1.9 Hz, 4H)。 550.25 D   
I-1810
Figure 02_image3911
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCOC(C3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 9.21 (s, 1H), 8.89 (s, 1H), 7.65 (d, 1.7 Hz, 1H), 7.53 (d, 1.7 Hz, 1H), 7.48 (dd, 4.5, 1.7 Hz, 1H), 7.27 (ddt, 11.2, 8.4, 2.7 Hz, 1H), 6.65 (s, 1H), 5.96 (s, 1H), 3.92 (dd, 19.6, 10.6 Hz, 2H), 3.58 (dd, 27.2, 13.5 Hz, 1H), 2.55 (s, 3H)。 535.95 D   
I-1812
Figure 02_image3913
 NC1(CCCC1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.46 (d, 2.1 Hz, 1H), 9.23 (s, 1H), 8.58 (s, 1H), 8.30 - 7.87 (m, 5H), 7.53 (s, 1H), 7.28 (td, 8.4, 3.1 Hz, 1H), 6.08 (s, 1H), 1.82 (d, 73.1 Hz, 8H)。 505.15 E   
I-1813
Figure 02_image3915
 OC1(CCCC1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.58 - 9.35 (m, 2H), 9.20 (s, 1H), 8.57 (s, 1H), 8.20 - 8.06 (m, 2H), 8.03 - 7.94 (m, 2H), 7.54 (d, 8.3 Hz, 1H), 7.26 (ddd, 8.8, 7.9, 3.1 Hz, 1H), 6.67 (s, 1H), 6.25 (s, 1H), 5.49 (s, 1H), 1.83 - 1.55 (m, 6H), 1.54 - 1.31 (m, 2H)。 506.15 E   
I-1814
Figure 02_image3917
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3CCCOC3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6 )  9.93 (br s, 0.5H), 9.91 (br s, 0.5H), 9.44 (s, 1H), 9.22 (br s, 1H), 8.57 (s, 1H), 8.09 (dd, 9.3, 1.8 Hz, 1H), 8.01 (s, 1H), 7.97 (d, 9.3 Hz, 1H), 7.81 (dd, 9.4, 1.4 Hz, 1H), 7.62-7.46 (m, 1H), 7.32-7.21 (m, 1H), 6.59 (br s, 1H), 6.09 (br s, 1H), 3.74 (d, 10.6 Hz, 1H), 3.61 (dd, 11.1, 3.7 Hz, 0.5H), 3.25-2.98 (m, 2H), 2.40-2.27 (m, 1H), 1.72-1.59 (m, 0.5H), 1.58-1.32 (m, 4H)。 506 E   
I-1815
Figure 02_image3919
 CN1CCC(CC1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.82 (br s, 1H), 8.80 (s, 1H), 8.13 (s, 1H), 8.09 (d, 8.9 Hz, 1H), 8.04 (d, 8.5 Hz, 1H), 7.65-7.48 (m, 3H), 4.79 (d, 1.5 Hz, 1H), 2.79 (d, 7.5 Hz, 1H), 2.65 (d, 11.6 Hz, 2H), 2.06 (s, 3H), 1.86-1.74 (m, 1H), 1.69-1.55 (m, 3H), 1.54-1.44 (m, 1H), 0.98 (qd, 12.4, 3.9 Hz, 1H), 0.59 (d, 12.5 Hz, 1H) 436.3 E   
I-1816
Figure 02_image3921
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)[C@H]3CCC[C@@H](C3)C(F)(F)F)c12)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)  9.90 (br. s, 1H), 9.84 (br. s, 1H), 9.45-9.43 (m, 2H), 9.23 (br. s, 2H), 8.58-8.57 (m, 2H), 8.10 (dd, 9.2, 0.9 Hz, 2H), 8.03-7.98 (m, 3H), 7.95 (dd, 12.1, 1.9 Hz, 2H), 7.82-7.80 (m, 1H), 7.56-7.50 (m, 2H), 7.28-7.20 (m, 2H), 6.51 (br. s, 2H), 6.22 (br. s, 1H), 6.20 (br. s, 1H), 2.61-2.55 (m, 2H), 1.93-1.83 (m, 2H), 1.68-1.59 (m, 2H), 1.56-1.48 (m, 2H), 1.44-1.30 (m, 6H), 1.27-1.14 (m, 4H), 1.04-0.77 (m, 2H)。 572.4 A   
I-1817
Figure 02_image3923
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)[C@H]3CCC[C@H](C3)C(F)(F)F)c12)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)  10.03 (br. s, 1H), 9.95 (br. s, 1H), 9.44 (s, 2H), 9.22 (br. s, 2H), 8.58-8.56 (m, 2H), 8.10 (dd, 9.3, 1.3 Hz, 2H), 8.01 (d, 1.1 Hz, 2H), 7.97 (d, 9.3 Hz, 2H), 7.80 (dd, 10.6, 0.9 Hz, 2H), 7.53-7.43 (m, 2H), 7.25-7.19 (m, 2H), 6.57 (br. s, 2H), 6.12 (br. s, 2H), 2.31-2.14 (m, 4H), 1.83-1.71 (m, 4H), 1.68-1.53 (m, 2H), 1.43-1.34 (m, 2H), 1.30-1.20 (m, 2H), 1.15-0.98 (m, 6H)。 572.3 B   
I-1818
Figure 02_image3925
 CC(=O)N1CCC(CC1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.73 (br s, 1H), 8.76 (s, 0.5H), 8.73 (s, 0.5H), 8.16 (s, 1H), 8.12 (d, 8.9 Hz, 1H), 8.04 (d, 8.5 Hz, 1H), 7.64 (dd, 3.0, 1.6 Hz, 0.5H), 7.62 (dd, 3.2, 1.7 Hz, 0.5H), 7.60-7.51 (m, 2H), 4.83 (s, 1H), 4.41 (d, 12.9 Hz, 0.5H), 4.25 (d, 13.0 Hz, 0.5H), 3.81 (d, 13.4 Hz, 0.5H), 3.67 (d, 13.3 Hz, 0.5H), 2.85-2.68 (m, 1H), 2.29-2.16 (m, 1H), 2.16-2.03 (m, 1H), 1.93 (s, 1.5H), 1.89 (s, 1.5H), 1.64-1.48 (m, 1.5H), 1.48-1.32 (m, 0.5H), 0.94-0.82 (m, 0.5H), 0.81-0.70 (m, 0.5H), 0.69-0.58 (m, 1H) 464.3 E   
I-1819
Figure 02_image3927
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)C3(CCCC3)c3cc(F)ccc3F)c12 1H NMR(400 MHz, DMSO):-´ 9.22 (s, 1H), 8.93 (s, 1H), 7.70 (d,  1.4 Hz, 1H), 7.57 (d,  1.4 Hz, 1H), 7.52 (dd,  8.1, 5.1 Hz, 1H), 7.24 (td,  8.4, 3.0 Hz, 1H), 7.19-7.02 (m, 3H), 6.50 (brs, 1H), 6.10 (s, 1H), 2.07-1.93 (m, 2H), 1.80-1.64 (m, 2H), 1.54-1.30 (m, 4H) 563.2 E   
I-1820
Figure 02_image3929
 OC1CCCCC1C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6) 10.66 (br. s, 1H), 8.60 (s, 1H), 8.16 (s, 1H), 8.11 (br. d, 9.1 Hz, 1H), 8.00 (br. d, 8.6 Hz, 1H), 7.73 (dd, 7.3, 1.0 Hz, 1H), 7.50-7.43 (m, 2H), 4.97 (d, 1.2 Hz, 1H), 4.34 (br. s, 1H), 3.27-3.16 (m, 1H), 1.82 (app. t, 11.2 Hz, 1H), 1.72-1.62 (m, 1H), 1.58-1.47 (m, 2H), 1.39 (app. d, 12.2 Hz, 1H), 1.29-1.20 (m, 1H), 1.05-0.96 (m, 2H), 0.84-0.71 (m, 1H)。 437.2 E   
I-1821
Figure 02_image3931
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3CCOCC3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6 )  9.88 (s, 1H), 9.45-9.43 (m, 1H), 9.22 (br s, 1H), 8.57 (s, 1H), 8.09 (dd, 9.3, 1.8 Hz, 1H), 8.01 (d, 1.5 Hz, 1H), 7.97 (dd, 9.2, 0.6 Hz, 1H), 7.81 (d, 1.5 Hz, 1H), 7.59-7.46 (m, 1H), 7.25 (td, 8.4, 3.1 Hz, 1H), 6.57 (br s, 1H), 6.13 (br s, 1H), 3.87-3.62 (m, 2H), 3.38-3.07 (m, 2H), 2.41-2.23 (m, 1H), 1.45-1.37 (m, 2H), 1.36-1.16 (m, 2H)。 506 E   
I-1822
Figure 02_image3933
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc(C#N)c2ncnn2c1    609.13 A   
I-1823
Figure 02_image3935
 FC(F)n1cnc(c1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    583.4 A   
I-1824
Figure 02_image3937
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn2ncnc2c1 1H NMR (500 MHz, DMSO) δ 10.68 (s, 1H), 9.29 (s, 1H), 9.27 (d, J = 2.4 Hz, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.73 (s, 1H), 8.30 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 1.7 Hz, 1H), 7.96 (dt, J = 8.5, 2.0 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.72 (s, 1H), 7.34 (dd, J = 8.9, 5.1 Hz, 1H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 6.08 (s, 1H)。 585.12 A   
I-1825
Figure 02_image3939
 Cc1c(ccc2ncnn12)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl       A   
I-1826
Figure 02_image3941
 FC(F)n1cc(c(n1)C#N)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    608.5 A   
I-1827
Figure 02_image3943
 Cc1cc2ncnn2cc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    598.08 A   
I-1828
Figure 02_image3945
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc2ncnn2cc1F    602.08 A   
I-1829
Figure 02_image3947
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3nsc4ccccc34)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 10.54 (s, 1H), 9.48 (dd, 1.9, 0.9 Hz, 1H), 9.26 (s, 1H), 8.70 (d, 8.2 Hz, 1H), 8.58 (s, 1H), 8.33 (dt, 8.3, 1.1 Hz, 1H), 8.19-8.12 (m, 2H), 8.11 (d, 1.7 Hz, 1H), 8.00 (dd, 9.3, 0.9 Hz, 1H), 7.70 (ddd, 8.3, 6.9, 1.2 Hz, 1H), 7.62 (ddd, 8.1, 7.0, 1.1 Hz, 1H), 7.33-7.24 (m, 1H), 7.04 (td, 8.4, 3.0 Hz, 1H), 6.82 (s, 1H), 6.29 (s, 1H)。 555.1 A   
I-1830
Figure 02_image3949
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3nsc4ccccc34)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 10.54 (s, 1H), 9.48 (dd, 1.9, 0.9 Hz, 1H), 9.26 (s, 1H), 8.70 (d, 8.2 Hz, 1H), 8.58 (s, 1H), 8.33 (dt, 8.3, 1.1 Hz, 1H), 8.19-8.12 (m, 2H), 8.11 (d, 1.7 Hz, 1H), 8.00 (dd, 9.3, 0.9 Hz, 1H), 7.70 (ddd, 8.3, 6.9, 1.2 Hz, 1H), 7.62 (ddd, 8.1, 7.0, 1.1 Hz, 1H), 7.33-7.24 (m, 1H), 7.04 (td, 8.4, 3.0 Hz, 1H), 6.82 (s, 1H), 6.29 (s, 1H)。 555.1 D   
I-1831
Figure 02_image3951
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3CCCO3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.57 (s, 1H), 9.445-9.44(m, 0.7H), 9.44-9.42 (m, 0.3H), 9.24 (s, 1H), 8.57 (s, 1H),  8.14-8.06 (m, 1.5H), 8.03 (s, 1.5 H), 8.02-7.94 (m, 1.5H), 7.63-7.49 (m, 1H), 7.33-7.17 (m, 1H), 6.67 (br s, 1H), 6.24 (s, 0.3H), 6.20 (s, 0.7H), 4.26-4.16 (m, 1H), 3.77-3.52 (m, 2H), 2.12-1.95 (m, 1H), 1.81-1.59 (m, 1H), 1.59-1.20 (m, 2H)。 492.3 E   
I-1832
Figure 02_image3953
 CN1CC(C1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, MeCN-d3)  9.46 (br. s, 1H), 8.68 (br. s, 1H), 8.16 (d, 0.4 Hz, 1H), 8.02 (dt, 9.1, 1.7 Hz, 1H), 7.73 (dt, 8.7, 1.5 Hz, 1H), 7.65 (dd, 7.2, 1.3 Hz, 1H), 7.61-7.52 (m , 2H), 5.07 (d, 2.9 Hz, 1H), 4.08 (dd, 10.2, 6.4 Hz, 1H), 3.84 ( t, 9.4 Hz, 1H), 3.43 (app. t, 1H), 3.38 (m, 1H), 3.23 (dd, 8.9, 5.8 Hz, 1H), 2.53 (s, 3H) 408.2 E   
I-1833
Figure 02_image3955
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(C3CNC3)c12 NMR (400 MHz, MeCN-d3 )  9.46 (br. s, 1H), 8.83 (br. s, 1H), 8.15 (s, 1H), 8.02 (d, 9.2 Hz, 1H), 7.73 (d, 8.5 Hz, 1H), 7.66 (dd, 7.1, 1.2 Hz, 1H), 7.61-7.51 (m, 2H), 5.07 (d, 1.3 Hz, 1H), 4.21-4.07 (m, 1H), 4.08-3.90 (m, 1H), 3.69-3.52 (m, 1H), 3.50-3.40 (m, 1H), 3.24 (m, 1H)。 394.1 E   
I-1834
Figure 02_image3957
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C(C#N)c3ccccc3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  10.59 (br s, 1H), 9.44 (br s, 1H), 9.21 (br s, 1H), 8.57 (s, 1H), 8.14-8.02 (m, 2H), 7.96 (d, 9.2 Hz, 1H), 7.86-6.71 (m, 8H), 6.70-6.22 (m, 1H), 6.10 (s, 1H), 5.20 (s, 0.3H), 5.13 (s,0.3H)。 537 D   
I-1835
Figure 02_image3959
 OC1CCC(CC1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  10.74 (br s, 1H), 8.70 (s, 1H), 8.14 (s, 1H), 8.09 (d, 8.9 Hz, 1H), 8.05 (d, 8.5 Hz, 1H), 7p.61-7.49 (m, 3H), 4.77 (s, 1H), 4.45 (d, 4.2 Hz, 1H), 3.24-3.12 (m, 1H), 1.92-1.68 (m, 2H), 1.64 (d, 11.9 Hz, 1H), 1.57 (d, 13.34 H, 1H), 1.39 (qd, 13.4, 3.2 Hz, 1H), 0.98-0.70 (m, 3H), 0.68-0.60 (m, 1H)。 437.1 E   
I-1836
Figure 02_image3961
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H](C3CCC(F)(F)CC3)c12 NMR (400 MHz, DMSOD6)  10.83 (br s, 1H), 8.79 (s, 1H), 8.15 (s, 1H), 8.13 (d, 9.2 Hz, 1H), 8.03 (d, 8.5 Hz, 1H), 7.64 (dd, 7.3, 1.5 Hz, 1H), 7.59-7.51 (m, 2H), 4.86 (br s, 1H), 2.09-1.95 (m, 2H), 1.90-1.80 (m, 1H), 1.7-1.51 (m, 4H), 1.05-0.90 (qd,  13.7, 3.6 Hz, 1H), 0.73 (app. Br d, 12.7 Hz, 1H)。 457.3 E   
I-1837
Figure 02_image3963
 CC(C#N)n1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.55 (br s, 1 H), 9.17 (br s, 1 H), 8.62 (s, 1 H), 8.23 (s, 1 H), 7.98 - 7.94 (m, 2 H), 7.79-7.68 (m, 3 H), 7.32 (dd, 8.9, 5.2 Hz, 1 H), 7.09 (td, 8.5, 2.9 Hz, 1 H), 6.58 (br s, 1 H), 5.98 (br s, 1 H), 5.88 (q, 7.1 Hz, 1 H), 1.86 (d, 7.1 Hz, 3 H)。 584.3 A   
I-1838
Figure 02_image3965
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2c(cnc2cc1F)C#N    626.14 A   
I-1839
Figure 02_image3967
 Cn1nc(cc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)C(F)F       A   
I-1840
Figure 02_image3969
 FC(F)c1nnc2ccc(cn12)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl       A   
I-1841
Figure 02_image3971
 Cn1nc2ccccc2c1Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.35 - 9.29 (m, 1H), 9.08 (s, 1H), 8.54 (s, 1H), 8.24 (s, 1H), 7.97 (dd, 9.3, 1.8 Hz, 1H), 7.92 (d, 9.2 Hz, 1H), 7.71 (d, 1.6 Hz, 1H), 7.50 (dd, 8.8, 5.5 Hz, 2H), 7.29 - 7.14 (m, 3H), 7.07 (d, 8.4 Hz, 1H), 6.88 (dd, 8.5, 6.5 Hz, 1H), 6.55 (d, 8.9 Hz, 1H), 5.59 (s, 1H), 3.55 (s, 3H)。 524.15 E   
I-1842
Figure 02_image3973
 CC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.85 - 9.56 (m, 1H), 9.44 (s, 1H), 9.19 (s, 1H), 8.57 (s, 1H), 8.14 - 8.06 (m, 1H), 8.03 - 7.94 (m, 2H), 7.82 - 7.77 (m, 1H), 7.67 (dd, 33.9, 7.4 Hz, 1H), 7.50 (s, 1H), 7.32 - 7.15 (m, 1H), 6.56 (s, 1H), 6.14 (s, 1H), 3.93 (s, 1H), 2.37 (s, 1H), 2.16 (t, 12.0 Hz, 1H), 1.86 - 1.76 (m, 3H), 1.69 (s, 1H), 1.62 (d, 17.6 Hz, 1H), 1.43 (s, 3H), 1.24 (s, 1H), 1.22 - 1.08 (m, 1H), 1.07 - 0.97 (m, 2H)。 561.2 E   
I-1843
Figure 02_image3975
 CC(=O)N[C@H]1CCC[C@@H](C1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.82 (s, 1H), 9.43 (dd, 1.9, 0.9 Hz, 1H), 9.18 (s, 1H), 8.57 (s, 1H), 8.09 (dd, 9.4, 1.9 Hz, 1H), 8.02 - 7.94 (m, 2H), 7.79 (d, 1.7 Hz, 1H), 7.70 (d, 8.0 Hz, 1H), 7.48 (td, 8.3, 3.1 Hz, 1H), 7.19 (td, 8.3, 3.1 Hz, 1H), 6.11 (s, 1H), 3.45 (s, 1H), 3.32 (s, 1H), 2.14 (d, 12.9 Hz, 1H), 1.81 (s, 3H), 1.69 (t, 12.3 Hz, 2H), 1.43 (s, 2H), 1.22 (d, 14.9 Hz, 1H), 1.15 (s, 1H), 1.05 (s, 2H)。 561.2 E   
I-1844
Figure 02_image3977
 N[C@@H]1CCC[C@@H](C1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.76 (d, 33.5 Hz, 1H), 9.43 (d, 2.0 Hz, 1H), 9.20 (s, 1H), 8.57 (d, 1.2 Hz, 1H), 8.14 - 8.05 (m, 1H), 8.03 - 7.98 (m, 1H), 7.98 - 7.67 (m, 1H), 7.52 (s, 1H), 7.25 (t, 8.5 Hz, 1H), 6.61 (s, 1H), 6.14 (s, 1H), 2.14 (s, 1H), 2.08 - 1.74 (m, 1H), 1.67 (s, 2H), 1.51 (s, 1H), 1.42 (d, 12.6 Hz, 1H), 1.21 (s, 5H), 1.02 - 0.88 (m, 1H)。 519.2 E   
I-1845
Figure 02_image3979
 N[C@H]1CCC[C@@H](C1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.76 (d, 33.5 Hz, 1H), 9.46 - 9.41 (m, 1H), 9.19 (s, 1H), 8.57 (s, 1H), 8.09 (dd, 9.3, 2.0 Hz, 1H), 8.03 - 7.94 (m, 2H), 7.86 - 7.76 (m, 1H), 7.52 (s, 1H), 7.25 (t, 8.6 Hz, 1H), 6.65 (s, 1H), 6.14 (s, 1H), 2.25 - 1.96 (m, 1H), 1.95 - 1.74 (m, 2H), 1.65 (s, 2H), 1.20 (d, 34.2 Hz, 4H), 1.09 - 0.38 (m, 3H)。 519.2 E   
I-1846
Figure 02_image3981
 CNC(=O)c1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)9.56 (t, 1.4 Hz, 1H), 9.29 (s, 1H), 8.60 (s, 1H), 8.54 (d, 4.8 Hz, 1H), 8.30-78.10 (m, 3H),8.10-7.90 (s,1H),7.52 (d, 9.1 Hz, 1H), 7.19 (td, 8.4, 3.1 Hz, 1H), 6.41 (s, 2H), 2.61-2.55 (m, 3H)。 436 E   
I-1847
Figure 02_image3983
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)[C@H]3CCCNC3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 10.12 - 9.12 (m, 2H), 8.57 (s, 1H), 8.09 (dd, 9.3, 1.9 Hz, 1H), 8.02 - 7.84 (m, 3H), 7.53 (d, 10.1 Hz, 1H), 7.35 - 7.10 (m, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 2.86 - 2.71 (m, 2H), 2.33 (s, 1H), 2.22 (d, 9.8 Hz, 1H), 1.51 -1.15 (m, 6H)。 505.15 E   
I-1848
Figure 02_image3985
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)[C@H]3CCCNC3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 10.12 - 9.12 (m, 2H), 8.57 (s, 1H), 8.09 (dd, 9.3, 1.9 Hz, 1H), 8.02 - 7.84 (m, 3H), 7.53 (d, 10.1 Hz, 1H), 7.35 - 7.10 (m, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 2.86 - 2.71 (m, 2H), 2.33 (s, 1H), 2.22 (d, 9.8 Hz, 1H), 1.51 -1.15 (m, 6H)。 505.15 E   
I-1849
Figure 02_image3987
 CC(=O)N[C@H]1CC[C@H](CC1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.45 - 9.40 (m, 1H), 9.38 (s, 1H), 9.23 (s, 1H), 8.57 (s, 1H), 8.21 (dd, 3.5, 1.7 Hz, 1H), 8.09 - 7.95 (m, 2H), 7.93 - 7.82 (s, 1H), 7.79 - 7.68 (s, 1H), 7.57 (s, 1H), 7.29 (td, 8.4, 3.1 Hz, 1H), 6.67 (s, 1H), 6.18 (s, 1H), 3.87 - 3.62 (s, 1H), 2.19 - 2.05 (m, 1H), 1.87 - 1.79 (m, 3H), 1.69 - 1.58 (m, 2H), 1.58 - 1.53 (m,1H), 1.45 - 1.37 (m,2H), 1.37 - 1.29 (m,1H), 1.29 - 1.17(m, 2H)。 561.05 E   
I-1850
Figure 02_image3989
 CC(=O)N[C@H]1CC[C@@H](CC1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.74 (s, 1H), 9.44 (t, 1.3 Hz, 1H), 9.20 (s, 1H), 8.58 (s, 1H), 8.09 (dd, 9.3, 1.9 Hz, 1H), 8.02 - 7.94 (m, 2H), 7.81 (d, 1.7 Hz, 1H), 7.70 (d, 7.8 Hz, 1H), 7.53 (s, 1H), 7.26 (td, 8.4, 3.1 Hz, 1H), 6.13 (s, 1H), 2.06 - 1.96 (m, 1H), 1.87 - 1.65 (m, 5H), 1.53 (dd, 8.8, 4.7 Hz, 1H), 1.36 (s, 1H), 1.32 - 1.23 (m, 3H), 1.21 - 0.98 (m, 2H)。 561.1 E   
I-1851
Figure 02_image3991
 OCc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.43 - 9.38 (m, 1H), 9.18 (s, 1H), 8.56 (s, 1H), 8.10 (dd, 9.3, 1.9 Hz, 1H), 8.05 (d, 1.8 Hz, 1H), 8.02 (d, 1.8 Hz, 1H), 7.97 (d, 9.3 Hz, 1H), 7.60 (s, 1H), 7.28 (td, 8.4, 3.1 Hz, 1H), 6.85 - 6.27 (m, 1H), 6.14 (s, 1H), 5.29 (t, 5.3 Hz, 1H), 4.42 (dd, 14.2, 5.6 Hz, 1H), 4.10 (dd, 14.4, 5.1 Hz, 1H)。 409.05 E   
I-1852
Figure 02_image3993
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC3CCc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.06 (d, 10.4 Hz, 1H), 7.48 (ddd, 24.1, 8.9, 5.2 Hz, 1H), 7.27-6.97 (m, 6H), 6.40 (d, 7.5 Hz, 1H), 5.86 (d, 22.4 Hz, 1H), 5.15-4.81 (m, 2H), 2.97-2.77 (m, 1H), 2.76-2.58 (m, 1H), 2.37-2.18 (m, 1H), 1.80-1.33 (m, 1H)。 471 E   
I-1853
Figure 02_image3995
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Br)cc(NC(=O)[C@H]3C[C@H]3C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.36 (s, 1H), 9.24 (s, 1H), 7.74 (d, 1.7 Hz, 1H), 7.65 (d, 1.8 Hz, 1H), 7.48 (dd, 9.0, 5.0 Hz, 1H), 7.24 (td, 8.4, 3.1 Hz, 1H), 6.92 - 6.21 (s, 1H), 5.94 (s, 1H), 2.06 (qd, 7.2, 4.2 Hz, 1H), 1.92 (td, 7.1, 4.1 Hz, 1H), 1.16 (t, 7.4 Hz, 2H)。 490.85 E   
I-1854
Figure 02_image3997
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(Br)cc(NC(=O)[C@H]3C[C@H]3C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.46 (s, 1H), 9.25 (s, 1H), 7.75 (d, 1.7 Hz, 1H), 7.57 (d, 1.8 Hz, 1H), 7.47 (t, 7.0 Hz, 1H), 7.23 (td, 8.4, 3.1 Hz, 1H), 6.72 (s, 1H), 5.95 (s, 1H), 2.03 (s, 1H), 1.92 (dt, 9.3, 5.0 Hz, 1H), 1.26 - 1.08 (m, 2H)。 490.8 E   
I-1855
Figure 02_image3999
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc(F)c2ncc(C#N)n2c1    626.2 C   
I-1856
Figure 02_image4001
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc(F)c2ncc(C#N)n2c1    626.2 A   
I-1857
Figure 02_image4003
 CN(C)C(=O)c1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1       E   
I-1858
Figure 02_image4005
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc2ncc(C#N)n2c1    609.2 C   
I-1859
Figure 02_image4007
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc2ncc(C#N)n2c1    609.2 A   
I-1860
Figure 02_image4009
 FC(F)n1cc(ccc1=O)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    610.5 D   
I-1861
Figure 02_image4011
 FC(F)n1cc(ccc1=O)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    610.5 A   
I-1862
Figure 02_image4013
 FC(F)n1ncc(c1C#N)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl       A   
I-1863
Figure 02_image4015
 FC(F)n1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl       A   
I-1864
Figure 02_image4017
 FC(F)c1cn2cc(ccc2n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    633.14 A   
I-1865
Figure 02_image4019
 Cn1nc(cc1-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)C(F)(F)F       A   
I-1866
Figure 02_image4021
 FC(F)c1cnc2ccc(cn12)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    633.19 A   
I-1867
Figure 02_image4023
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc2ncnn2cc1F 1H NMR (400 MHz, DMSO) δ 10.67 (s, 1H), 9.53 (d, J = 5.3 Hz, 1H), 9.31 (s, 1H), 8.61 (s, 1H), 8.19 (d, J = 7.3 Hz, 1H), 7.97 (d, J = 11.3 Hz, 2H), 7.82 (s, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.68 (s, 1H), 7.34 (dd, J = 8.9, 5.2 Hz, 1H), 7.15 - 7.09 (m, 1H), 6.08 (s, 1H)。 602.08 D   
I-1868
Figure 02_image4025
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc2ncnn2cc1F 1H NMR (400 MHz, DMSO) δ 10.67 (s, 1H), 9.53 (d, J = 5.3 Hz, 1H), 9.31 (s, 1H), 8.61 (s, 1H), 8.19 (d, J = 7.3 Hz, 1H), 7.97 (d, J = 11.3 Hz, 2H), 7.82 (s, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.68 (s, 1H), 7.34 (dd, J = 8.9, 5.2 Hz, 1H), 7.15 - 7.09 (m, 1H), 6.08 (s, 1H)。 602.08 A   
I-1869
Figure 02_image4027
 Fc1cnc2ccc(cn12)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO) δ 10.61 (s, 1H), 9.22 (s, 1H), 8.75 (s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.71 (s, 1H), 7.69 (dd, J = 9.5, 1.8 Hz, 1H), 7.66 (d, J= 1.7 Hz, 1H), 7.61 (ddt, J = 9.7, 6.9, 3.9 Hz, 2H), 7.57 - 7.52 (m, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.33 (dd, J = 8.9, 5.2 Hz, 1H), 7.10 (td, J = 8.3, 3.1 Hz, 1H), 6.05 (s, 1H)。 601.18 C   
I-1870
Figure 02_image4029
 Fc1cnc2ccc(cn12)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO) δ 10.61 (s, 1H), 9.22 (s, 1H), 8.75 (s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.71 (s, 1H), 7.69 (dd, J = 9.5, 1.8 Hz, 1H), 7.66 (d, J= 1.7 Hz, 1H), 7.61 (ddt, J = 9.7, 6.9, 3.9 Hz, 2H), 7.57 - 7.52 (m, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.33 (dd, J = 8.9, 5.2 Hz, 1H), 7.10 (td, J = 8.3, 3.1 Hz, 1H), 6.05 (s, 1H)。 601.18 A   
I-1871
Figure 02_image4031
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn2ncnc2c1 1H NMR (500 MHz, DMSO) δ 10.68 (s, 1H), 9.29 (s, 1H), 9.27 (d, J = 2.4 Hz, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.73 (s, 1H), 8.30 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 1.7 Hz, 1H), 7.96 (dt, J = 8.5, 2.0 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.72 (s, 1H), 7.34 (dd, J = 8.9, 5.1 Hz, 1H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 6.08 (s, 1H)。 585.12 B   
I-1872
Figure 02_image4033
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn2ncnc2c1 1H NMR (500 MHz, DMSO) δ 10.68 (s, 1H), 9.29 (s, 1H), 9.27 (d, J = 2.4 Hz, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.73 (s, 1H), 8.30 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 1.7 Hz, 1H), 7.96 (dt, J = 8.5, 2.0 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.72 (s, 1H), 7.34 (dd, J = 8.9, 5.1 Hz, 1H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 6.08 (s, 1H)。 585.12 A   
I-1873
Figure 02_image4035
 Cc1cc2ncnn2cc1-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl       D   
I-1874
Figure 02_image4037
 Cc1cc2ncnn2cc1-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl       A   
I-1875
Figure 02_image4039
 Cc1c(ccc2ncnn12)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl       D   
I-1876
Figure 02_image4041
 Cc1c(ccc2ncnn12)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl       A   
I-1877
Figure 02_image4043
 Fc1cnc2cnc(cn12)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO) δ 10.65 (s, 1H), 9.27 (d, J = 1.4 Hz, 1H), 9.26 - 9.21 (m, 1H), 9.17 (t, J = 1.7 Hz, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.33 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 9.1 Hz, 1H), 7.75 - 7.69 (m, 2H), 7.33 (dd, J = 8.9, 5.2 Hz, 1H), 7.10 (td, J = 8.4, 3.0 Hz, 1H)。 602.18 D   
I-1878
Figure 02_image4045
 Fc1cnc2cnc(cn12)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO) δ 10.65 (s, 1H), 9.27 (d, J = 1.4 Hz, 1H), 9.26 - 9.21 (m, 1H), 9.17 (t, J = 1.7 Hz, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.33 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 9.1 Hz, 1H), 7.75 - 7.69 (m, 2H), 7.33 (dd, J = 8.9, 5.2 Hz, 1H), 7.10 (td, J = 8.4, 3.0 Hz, 1H)。 602.18 A   
I-1879
Figure 02_image4047
 Cn1nc(cc1-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)C(F)F       D   
I-1880
Figure 02_image4049
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc(C#N)c2ncnn2c1    609.08 C   
I-1881
Figure 02_image4051
 Cn1nc(cc1-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)C(F)F 1H NMR (500 MHz, DMSO) δ 10.59 (s, 1H), 9.27 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 1.5 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.71 - 7.64 (m, 2H), 7.33 (dd, J = 8.9, 5.2 Hz, 1H), 7.15 - 7.06 (m, 2H), 7.02 (s, 1H), 6.83 (d, J = 1.3 Hz, 1H), 4.07 (q, J = 5.3 Hz, 1H), 3.96 (s, 3H), 3.16 (d, J = 5.2 Hz, 3H)。 597.18 A   
I-1882
Figure 02_image4053
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc(C#N)c2ncnn2c1 1H NMR (500 MHz, DMSO) δ 10.65 (s, 1H), 9.83 (d, J = 1.7 Hz, 1H), 9.26 (s, 1H), 8.94 (d, J = 1.7 Hz, 1H), 8.76 (s, 1H), 8.23 (d, J = 1.7 Hz, 1H), 8.03 (d, J = 1.8 Hz, 1H), 7.96 (dt, J = 8.6, 2.0 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.73 (s, 1H), 7.34 (dd, J = 8.9, 5.2 Hz, 1H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 6.07 (s, 1H) 609.08 A   
I-1883
Figure 02_image4055
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2c(cnc2cc1F)C#N 1H NMR (400 MHz,DMSO) δ 10.66 (s, 1H), 9.31 (s, 1H) ,9.22-9.16 (m, 1H), 8.55 (s, 1H), 8.20 (d, J=7.1 Hz, 1H), 7.97 (d, J=9.2 Hz, 2H), 7.82 (s, 1H), 7.76 (d, J=9.1 Hz, 1H), 7.68 (s, 1H), 7.34 (dd, J=8.9, 5.2 Hz, 1H), 7.12(td, J=8.4, 3.0 Hz,1H) 626.09 D   
I-1884
Figure 02_image4057
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2c(cnc2cc1F)C#N 1H NMR (400 MHz, DMSO) δ 10.66 (s, 1H), 9.31 (s, 1H) ,9.22-9.16 (m, 1H), 8.55 (s, 1H), 8.20 (d, J=7.1 Hz, 1H), 7.97 (d, J=9.2 Hz, 2H), 7.82 (s, 1H), 7.76 (d, J=9.1 Hz, 1H), 7.68 (s, 1H), 7.34 (dd, J=8.9, 5.2 Hz, 1H), 7.12(td, J=8.4, 3.0 Hz,1H) 626.09 A   
I-1885
Figure 02_image4059
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(c1)C1(CC1)C#N    598.2 C   
I-1886
Figure 02_image4061
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnn(c1)C1(CC1)C#N    598.2 A   
I-1887
Figure 02_image4063
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(OCC#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    523.07 C   
I-1888
Figure 02_image4065
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(OCC#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    523.07 A   
I-1889
Figure 02_image4067
 FC(F)n1cc(c(n1)C#N)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz): δ = 10.69 (s, 1H), 9.32 (br s, 1H), 9.23 (s, 1H), 7.89-8.22 (m, 3H), 7.86 (s, 1H), 7.74 (br d, J = 8.3 Hz, 1H), 7.66 (s, 1H), 7.34 (dd, J = 8.8, 5.1 Hz, 1H), 7.12 (td, J = 8.4, 2.9 Hz, 1H), 6.38-6.88 (m, 1H), 5.82-6.20 ppm (m, 1H)。 608.5 D   
I-1890
Figure 02_image4069
 FC(F)n1cc(c(n1)C#N)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz): δ = 10.69 (s, 1H), 9.32 (br s, 1H), 9.23 (s, 1H), 7.89-8.22 (m, 3H), 7.86 (s, 1H), 7.74 (br d, J = 8.3 Hz, 1H), 7.66 (s, 1H), 7.34 (dd, J = 8.8, 5.1 Hz, 1H), 7.12 (td, J = 8.4, 2.9 Hz, 1H), 6.38-6.88 (m, 1H), 5.82-6.20 ppm (m, 1H)。 608.4 A   
I-1891
Figure 02_image4071
 Oc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 (400 MHz, CD3CN)  9.01 -8.99 (m, 1 H), 8.35 (br s, 1 H), 7.93 (dd, 9.3, 1.8 Hz, 1 H), 7.82 (dd, 9.2, 0.6 Hz, 1 H), 7.64 (d, 1.4 Hz, 1 H), 7.49 (dd, 8.8, 5.1 Hz, 1 H), 7.32 (d, 1.5 Hz, 1 H), 7.22 (br s, 1 H), 7.09 (ddd, 8.8, 8.0, 3.1 Hz, 1 H), 6.76 (dd, 9.4, 3.1 Hz, 1 H), 6.11 (br s, 1 H)。 393.3 D   
I-1892
Figure 02_image4073
 CSc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1    425.05 E   
I-1893
Figure 02_image4075
  		 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Br)cc(N[C@H]3COCc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.05 (s, 1H), 7.40 (dd, 8.9, 5.2 Hz, 1H), 7.30-7.23 (m, 2H), 7.18 (td, 7.5, 1.3 Hz, 1H), 7.13 (d, 1.5 Hz, 1H), 7.05-6.92 (m, 2H), 6.84 (s, 1H), 6.55 (s, 1H), 5.80 (s, 1H), 4.88 (d, 9.3 Hz, 1H), 4.71 (q, 5.0 Hz, 1H), 4.67 (s, 2H), 3.84 (dd, 11.4, 4.2 Hz, 1H), 3.63 (dd, 11.4, 5.8 Hz, 1H)。 487 E   
I-1894
Figure 02_image4077
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Br)cc(N[C@@H]3COCc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.05 (s, 1H), 7.40 (dd, 8.9, 5.2 Hz, 1H), 7.30-7.23 (m, 2H), 7.18 (td, 7.5, 1.3 Hz, 1H), 7.13 (d, 1.5 Hz, 1H), 7.05-6.92 (m, 2H), 6.84 (s, 1H), 6.55 (s, 1H), 5.80 (s, 1H), 4.88 (d, 9.3 Hz, 1H), 4.71 (q, 5.0 Hz, 1H), 4.67 (s, 2H), 3.99 (dd, 11.4, 4.2 Hz, 1H), 3.70 (dd, 11.4, 5.8 Hz, 1H)。 487 E   
I-1895
Figure 02_image4079
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC3CCOc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.06 (d, 17.1 Hz, 1H), 7.48 (td, 9.3, 5.2 Hz, 1H), 7.34-7.20 (m, 2H), 7.20-7.10 (m, 2H), 7.10-7.02 (m, 1H), 6.95-6.80 (m, 1H), 6.80-6.36 (m, 2H), 5.88 (s, 1H), 5.10 (d, 7.5 Hz, 1H), 4.74 (dt, 9.3, 4.9 Hz, 1H), 4.00 (ddd, 9.9, 5.7, 3.2 Hz, 1H), 3.52-3.42 (m, 1H), 1.82 (ddd, 13.5, 8.9, 4.5 Hz, 1H), 1.62 (d, 13.7 Hz, 1H)。 486.95 B   
I-1896
Figure 02_image4081
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3c[nH]c4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 11.00 (d, 2.7 Hz, 1H), 9.08 (s, 1H), 7.47 (ddd, 8.8, 5.2, 1.4 Hz, 1H), 7.37 (d, 8.2 Hz, 1H), 7.25-7.15 (m, 2H), 7.15-7.03 (m, 3H), 6.98-6.91 (m, 1H), 6.91 (ddd, 7.8, 6.5, 0.9 Hz, 1H), 6.78 (dd, 3.4, 1.7 Hz, 2H), 5.86 (d, 1.2 Hz, 1H)。 470 E   
I-1897
Figure 02_image4083
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(C(=O)Nc3ccccc3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  10.39 (s, 1H), 9.61 (t, 1.3 Hz, 1H), 9.35 (s, 1H), 8.59 (s, 1H), 8.40 (s, 1H), 8.34 (d, 1.7 Hz, 1H), 8.28 (dd, 9.3, 1.9 Hz, 1H), 8.01 (d, 9.3 Hz, 1H), 7.49 - 7.38 (m, 3H), 7.30 (t, 7.9 Hz, 2H), 7.17 - 7.03 (m, 2H), 6.46 (s, 2H)。 498.15 E   
I-1898
Figure 02_image4085
 CS(=O)(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.33 (d, 98.3 Hz, 2H), 8.58 (s, 1H), 8.09 (dd, 9.3, 1.9 Hz, 1H), 7.98 (d, 9.5 Hz, 2H), 7.86 (d, 1.6 Hz, 1H), 7.53 (t, 7.2 Hz, 1H), 7.26 (td, 8.4, 3.1 Hz, 1H), 7.08-6.30 (s, 1H), 6.17 (s, 1H), 2.86 (m, 3H)。 472.05 D   
I-1899
Figure 02_image4087
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3(CCCC3)C#N)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  10.31 (s, 1H), 9.49 - 9.44 (m, 1H), 9.26 (s, 1H), 8.57 (s, 1H), 8.16 - 8.06 (m, 2H), 7.98 (d, 9.3 Hz, 1H), 7.86 (d, 1.8 Hz, 1H), 7.53 (s, 1H), 7.25 (td, 8.4, 3.1 Hz, 1H), 6.56 (s, 1H), 6.09 (s, 1H), 2.13 - 2.02 (m, 1H), 2.04 (s, 1H), 2.02 - 1.93 (m, 1H), 1.97 - 1.83 (m, 1H), 1.78 - 1.55 (m, 4H)。 515.15 E   
I-1900
Figure 02_image4089
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3CNCCO3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.42 (dd, 3.1, 1.3 Hz, 1H), 9.27 (br s, 0.4H), 9.23 (br s, 0.6H), 9.15 (br s, 0.4H), 8.57 (s, 1H), 8.31 (s, 2H), 8.14 (d, 1.4 Hz, 0.4H), 8.10-8.07 (m, 0.6H), 8.06 (d, 1.6 Hz, 0.6H), 8.01 (d, 1.5 Hz, 0.4H), 7.98 (dd, 3.7, 1.3 Hz, 0.5H), 7.96 (dd, 2.3, 0.8 Hz, 0.5H), 7.66-7.45 (m, 1H), 7.32-7.24 (m, 1H), 6.67 (br s, 1H), 6.27-6.08 (m, 1H), 3.84-3.69 (m, 2H), 3.49-3.39 (m, 1H), 2.88 (d, 12.0 Hz, 0.5H), 2.79 (d, 12.0 Hz, 0.5H), 2.67 (d, 12.0 Hz, 1H), 2.57-2.51 (浸沒m, 1H), 2.12 (br s, 0.5H), 2.03 (dd, 12.3, 10.3 Hz, 0.5H)。 507 E   
I-1901
Figure 02_image4091
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H]([C@@H]3COCCN3)c12 (400 MHz, CD3CN)  8.61 (dd, 7.9, 1.1 Hz, 1H), 8.04 (s, 1H), 7.92 (d, 9.1 Hz, 1H), 7.69 (d, 8.5 Hz, 1H), 7.57-7.47 (m, 2H), 6.93 (br s, 1H), 4.66 (s, 1H), 3.65 (dd, 11.6, 3.2 Hz, 1H), 3.49 (dd, 11.4, 3.0 Hz, 1H), 3.35 (dt, 10.5, 2.7 Hz, 1H), 3.28 (td, 11.7, 2.4 Hz, 1H), 3.06 (br s, 1H), 2.90 (td, 12.0, 3.4 Hz, 1H), 2.75 (t, 11.0 Hz, 1H), 2.63 (d, 12.0 Hz, 1H) 424.2 E   
I-1902
Figure 02_image4093
 O[C@H]1CN(C[C@@H]1C(F)(F)F)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)  9.40-9.38 (m, 2H), 9.16 (br. s, 2H), 8.57 (s, 2H), 8.45 (br. s, 1H), 8.39 (br. s, 1H), 8.09-8.04 (m, 2H), 7.99-7.95 (m, 2H), 7.93 (s, 2H), 7.73-7.70 (m, 2H), 7.51-7.44 (m, 2H), 7.28-7.19 (m, 2H), 6.65 (br. s, 2H), 6.09 (br. s, 2H), 5.72 (d, 5.4 Hz, 1H), 5.69 (d, 4.7 Hz, 1H), 4.32-4.26 (m, 1H), 4.24-4.18 (m, 1H), 3.72-3.55 (m, 2H), 3.39-3.29 (m, 2H), 3.15-3.09 (m, 2H), 3.02-2.82 (m, 4H)。 575.2 D   
I-1903
Figure 02_image4095
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)N3CCC(C3)C(F)(F)F)c12)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)  9.40-9.38 (m, 2H), 9.16 (br. s, 2H), 8.56 (s, 2H), 8.44 (br. s, 1H), 8.40 (br. s, 1H), 8.08-8.04 (m, 2H), 7.99-7.95 (m, 2H), 7.93-7.91 (m, 2H), 7.71-7.69 (m, 2H), 7.52-7.46 (m, 2H), 7.29-7.20 (m, 2H), 6.66 (br. s, 2H), 6.07 (br. s, 2H), 3.58 (dd, 10.5, 8.8 Hz, 1H), 3.49-3.40 (m, 1H), 3.36-3.29 (m, 3H), 3.27-3.12 (m, 3H), 3.01-2.88 (m, 2H), 2.14-2.02 (m, 2H), 1.93-1.77 (m, 2H)。 559.3 D   
I-1904
Figure 02_image4097
 OC1(CCN(C1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1)C(F)(F)F 1H-NMR (400 MHz, DMSO-d6)  9.40-9.38 (m, 2H), 9.15 (br. s, 2H), 8.57 (s, 2H), 8.46 (br. s, 1H), 8.36 (br. s, 1H), 8.08-8.04 (m, 2H), 7.99-7.95 (m, 2H), 7.93-7.91 (m, 2H), 7.73-7.71 (m, 1H), 7.70-7.68 (m,1H), 7.50-7.44 (m, 2H), 7.28-7.18 (m, 2H), 6.69 (br. s, 2H), 6.52 (s, 1H), 6.45 (s, 1H), 6.07 (br. s, 2H), 3.70-3.61 (m, 1H), 3.52 (d, 11.4 Hz, 1H), 3.42-3.35 (m, 3H), 3.25-3.15 (m, 2H), 3.03-2.89 (m, 1H), 2.01-1.90 (m, 4H)。 575.3 E   
I-1905
Figure 02_image4099
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(c12)S(=O)(=O)Cc1ccccc1)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.59 (br. s, 1H), 9.49 (br. s, 1H), 8.62 (s, 1H), 8.50 (d, 1.5 Hz, 1H), 8.29 (br. s, 1H), 8.16 - 8.09 (m, 1H), 8.02 (d, 8.5 Hz, 1H), 7.62 (br. s, 1H), 7.40-7.28 (m, 3H), 7.24 (br. s, 1H), 7.02 (d, 6.4 Hz, 2H), 6.42 (br. s, 1H), 6.08 (s, 1H), 4.58 (d, 12.8 Hz, 1H), 4.25 (d, 12.5 Hz, 1H)。 533.1 D   
I-1906
Figure 02_image4101
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(c12)S(=O)(=O)Cc1ccccc1)-c1ccc2ncnn2c1    533.1 E   
I-1907
Figure 02_image4103
 CC(O)c1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H  NMR (400 MHz, DMSO-d6) 9.43 (br. s, 1H), 9.23 (br. s, 1H), 8.57 (s, 1H), 8.14-8.10 (m, 1H), 8.09 (d, 1.8 Hz, 1H), 8.08-8.01 (m, 2H), 7.98 (br. s, 1H), 7.71 - 7.54 (m, 1H), 7.28 (td, 8.5, 2.9 Hz, 1H), 6.51 (br. s, 1H), 6.22 (br. s, 1H), 5.28 (d, 3.5 Hz, 1H), 4.54 - 4.41 (m, 1H), 1.25 (d, 5.0 Hz, 3H) 423.1 E   
I-1908
Figure 02_image4105
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(N3CCNCC3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.49  (dd-1.7, 0.8 Hz, 1H), 9.22 (s, 1H), 8.56 (s, 1H), 8.14 (dd, 9.3, 1.8 Hz, 1H), 7.94 (dd, 9.3, 0.7 Hz, 1H), 7.73 (d, 1.4 Hz, 1H), 7.57 (dd, 8.6, 5.5 Hz, 1H), 7.50 (d, 1.4 Hz, 1H), 7.28 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.67 (br s, 1H), 6.17 (s, 1H), 3.16-3.05 (m, 2H), 2.78 2.66 (m, 2H), 2.48-2.32 (m, 4H)。 463 E   
I-1909
Figure 02_image4107
 CC(=O)N1CC(C1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6 )  10.71 (br. s, 1H), 9.11 (d, 7.2 Hz, 1H), 8.20 (s, 1H), 8.17 (d, 9.0 Hz, 1H), 8.03 (d, 8.3 Hz, 1H), 7.64-7.54 (m, 3H), 5.00 (2 d, 3.6 Hz, 1H), 4.13 (t, 8.6 Hz, 0.5H), 4.07 (dd, 8.5, 5.9 Hz, 0.5H), 3.92-3.81 (m, 1H), 3.67-3.59 (m, 0.5H), 3.38 (m, 0.5H), 3.18-3.05 (m, 1.5H), 2.93-2.87 (m, 0.5H), 1.67 (s, 1.5H), 1.61 (s, 1.5H)。 436.2 E   
I-1910
Figure 02_image4109
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3COCCO3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.54 (br s, 0.5H), 9.43 (s, 1H), 9.43 (br s, 0.5H), 9.23 (br s, 1H), 8.57 (s, 1H), 8.12-7.94 (m, 5H), 7.64-7.46 (m, 1H), 7.29 (ddd, 8.2, 6.4, 4.0 Hz, 1H), 6.61 (br s, 1H), 6.18 (br s, 0.5H), 6.13 (br s, 0.5H), 4.00 (ddd, 19.6, 9.4, 3.1 Hz, 1H), 3.81-3.55 (m, 5H), 3.40-3.30 (m, 0.5H), 2.97-2.88 (m, 0.5H)。 508 E   
I-1911
Figure 02_image4111
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(N3CCOCC3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.50 (dd, 1.7, 0.8 Hz, 1H), 9.25 (s, 1H), 8.56 (s, 1H), 8.21-8.13 (m, 1H), 7.95 (dd, 9.3, 0.7 Hz, 1H), 7.78 (d, 1.4 Hz, 1H), 7.62-7.54 (m, 2H), 7.28 ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.77 (br s, 1H), 6.18 (s, 1H), 3.33-3.26 (m), 4H), 3.21-3.13 (m, 2H), 2.78-2.69 (m, 2H)。 464.2 E   
I-1912
Figure 02_image4113
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(C3CCCCC33CC3)c12 1H NMR (400 MHz, DMSO-d6)  10.77 (s, 0.3H), 10.74 (s, 0.7H), 8.70 (s, 0.3H), 8.61 (s, 0.7H), 8.15 (s, 4.0 Hz, 0.3H), 8.14 (s, 0.7H), 8.11 8.06 (br, d, 9.3Hz, 1H), 8.03 (br, d, 8.5Hz, 1H), 7.62-7.49 (m, 3H), 4.86 (d, 3.0 Hz, 0.3H), 4.63 (s, 0.7H), 1.87-1.75 (m, 0.7H), 1.75-1.61 (m, 0.3H), 1.61-1.45 (m, 1.4H), 1.45-1.31 (m, 2.1H), 1.27-1.19 (m, 0.7H), 1.18-1.06 (m, 0.7H), 1.05-0.96 (m, 0.7H), 0.95-0.85 (m, 1.4H), 0.76-0.64 (m, 0.3H), 0.59-0.52 (m, 0.7H), 0.34 (dt, 9.0, 4.5 Hz, 0.7H), 0.20 (dt, 9.9, 5.0 Hz, 0.7H), 0.06 (t, 3.8 Hz, 0.3H), -0.01- -0.14 (m, 1.2H), -0.14- -0.21 (m, 0.3H), -0.34 (t, 6.7 Hz, 0.3H)。 447 D   
I-1913
Figure 02_image4115
 OC1CCC(CC(=O)Nc2cc(cc3C(=O)NC(c23)c2cc(F)ccc2Cl)-c2ccc3ncnn3c2)CC1 1H NMR (400 MHz, DMSO-d6)  9.75 (br s, 0.2H), 9.74 (br s, 0.8H), 9.42-9.38 (m, 1H), 9.16 (br s, 1H), 8.53 (s, 1H), 8.04 (dt, 10.2, 5.1 Hz, 1H), 7.96 (m, 2H), 7.85-7.81 (m, 1H), 7.57-7.40 (m, 1H), 7.24-7.18 (m, 1H), 6.52 (br s, 1H), 6.16 (br s, 1H), 4.42 (s, 0.8H), 4.21 (s, 0.2H), 3.24-3.14 (m,  1H), 1.94-1.84 (m, 2H), 1.67 (d, 11.2 Hz, 2H), 1.45-1.23 (m, 3H), 1.06-0.90 (m, 2H), 0.82-0.65 (m, 2H)。 534.3 E   
I-1914
Figure 02_image4117
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(CC(=O)N3CCc4ccccc34)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.44 (dd, 1.1, 0.6 Hz, 1H), 9.25 (br s, 1H), 8.56 (s, 1H), 8.12 (dd, 9.3, 1.8 Hz, 2H), 7.97 (d, 9.4 Hz, 1H), 7.96 (br s, 1H), 7.83 (d, 8.0 Hz, 1H), 7.48 (br s, 1H), 7.23 (d, 7.4 Hz, 1H), 7.10 (t, 7.7 Hz, 1H), 7.07-7.02 (m, 1H), 6.98 (t, 7.4 Hz, 1H), 6.50 (br. d, 7.9 Hz, 1H), 6.17 (br. s, 1H), 4.00 (dd, 18.6, 8.5 Hz, 1H), 3.84 (m, 2H), 3.53 - 3.44 (m, 1H), 3.14 (t, 8.3 Hz, 2H)。 538.2 E   
I-1915
Figure 02_image4119
 C[C@H](C#N)n1cc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl       D   
I-1916
Figure 02_image4121
 C[C@H](C#N)n1cc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR(400 MHz, DMSO-d6) δ 10.82 (br s, 1 H), 9.16 (s, 1 H), 8.61 (s, 1 H), 8.22 (s, 1 H), 7.96 - 7.93 (m, 2 H), 7.83 - 7.70 (m, 3 H), 7.31 (dd,J = 8.9, 5.2 Hz, 1 H), 7.08 (td,J = 8.3, 3.0 Hz, 1 H), 6.62 (brs, 1 H), 5.99 (brs, 1 H), 5.89 (q,J = 7.1 Hz, 1 H), 1.86 (d,J = 7.1 Hz, 3 H)。 586.3 A   
I-1917
Figure 02_image4123
 CC1(CCCCC1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  10.75 (s, 1H), 8.75 (s, 1H), 8.15 (s, 1H), 8.08 (d, 9.0 Hz, 1H), 8.02 (d, 8.5 Hz, 1H), 7.60-7.49 (m, 3H), 4.69 (s, 1H), 1.47-1.10 (m, 9H), 1.06-0.98 (m, 1H), 0.51 (s, 3H)。 435 E   
I-1918
Figure 02_image4125
 FC(F)n1cnc(c1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 9.18 (s, 1H), 8.94 (s, 1H), 8.43 (s, 1H), 8.06 (d, J = 1.6 Hz, 1H), 8.02 - 7.79 (m, 3H), 7.75 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.31 (dd, J = 8.9, 5.1 Hz, 1H), 7.09 (td, J = 8.3, 3.1 Hz, 1H), 6.86 - 6.58 (m, 1H), 5.98 (s, 1H)。 583.2 D   
I-1919
Figure 02_image4127
 FC(F)n1cnc(c1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 9.18 (s, 1H), 8.94 (s, 1H), 8.43 (s, 1H), 8.06 (d, J = 1.6 Hz, 1H), 8.02 - 7.79 (m, 3H), 7.75 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.31 (dd, J = 8.9, 5.1 Hz, 1H), 7.09 (td, J = 8.3, 3.1 Hz, 1H), 6.86 - 6.58 (m, 1H), 5.98 (s, 1H)。 583.2 A   
I-1920
Figure 02_image4129
 FC(F)n1ncc(c1C#N)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO) δ 10.71 (s, 1H), 9.32 (s, 1H), 8.71 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.65 (s, 1H), 7.33 (dd, J = 8.9, 5.2 Hz, 1H), 7.11 (td, J = 8.8, 8.4, 3.0 Hz, 1H), 6.01 (s, 1H)。 608.13 D   
I-1921
Figure 02_image4131
 FC(F)n1ncc(c1C#N)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO) δ 10.71 (s, 1H), 9.32 (s, 1H), 8.71 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.65 (s, 1H), 7.33 (dd, J = 8.9, 5.2 Hz, 1H), 7.11 (td, J = 8.8, 8.4, 3.0 Hz, 1H), 6.01 (s, 1H)。 608.13 A   
I-1922
Figure 02_image4133
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2c(cnc2cn1)C#N 1H NMR (400 MHz, DMSO) δ 10.67 (s, 1H), 9.52 (d, J = 1.5 Hz, 1H), 9.46 (d, J = 1.5 Hz, 1H), 9.24 (s, 1H), 8.67 (s, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.43 - 8.34 (m, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 9.1 Hz, 1H), 7.72 (s, 1H), 7.33 (dd, J = 8.9, 5.2 Hz, 1H), 7.10 (td, J = 8.4, 3.1 Hz, 1H), 6.62 (s, 1H), 6.06 (s, 1H)。 609.18 D   
I-1923
Figure 02_image4135
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2c(cnc2cn1)C#N 1H NMR (400 MHz, DMSO) δ 10.67 (s, 1H), 9.52 (d, J = 1.5 Hz, 1H), 9.46 (d, J = 1.5 Hz, 1H), 9.24 (s, 1H), 8.67 (s, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.43 - 8.34 (m, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 9.1 Hz, 1H), 7.72 (s, 1H), 7.33 (dd, J = 8.9, 5.2 Hz, 1H), 7.10 (td, J = 8.4, 3.1 Hz, 1H), 6.62 (s, 1H), 6.06 (s, 1H)。 609.18 A   
I-1924
Figure 02_image4137
 FC(F)c1nnc2ccc(cn12)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO) δ 12.67 (s, 1H), 10.64 (s, 1H), 9.26 (s, 1H), 9.03 (t, J = 1.4 Hz, 1H), 8.12 (d, J = 1.7 Hz, 1H), 8.10 - 7.99 (m, 2H), 7.98 - 7.83 (m, 3H), 7.79 - 7.72 (m, 1H), 7.70 (s, 1H), 7.33 (dd, J = 8.9, 5.1 Hz, 1H), 7.10 (td, J = 8.3, 3.0 Hz, 1H), 6.07 (s, 1H) 634.19 D   
I-1925
Figure 02_image4139
 FC(F)c1nnc2ccc(cn12)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (500 MHz, DMSO) δ 12.67 (s, 1H), 10.64 (s, 1H), 9.26 (s, 1H), 9.03 (t, J = 1.4 Hz, 1H), 8.12 (d, J = 1.7 Hz, 1H), 8.10 - 7.99 (m, 2H), 7.98 - 7.83 (m, 3H), 7.79 - 7.72 (m, 1H), 7.70 (s, 1H), 7.33 (dd, J = 8.9, 5.1 Hz, 1H), 7.10 (td, J = 8.3, 3.0 Hz, 1H), 6.07 (s, 1H) 634.19 A   
I-1926
Figure 02_image4141
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc(F)n2ncnc2c1    602.03 D   
I-1927
Figure 02_image4143
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cc(F)n2ncnc2c1    602.03 A   
I-1928
Figure 02_image4145
 FC(F)c1cn2cc(ccc2n1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 9.26 (s, 1H), 9.18 (dd, J = 2.0, 1.1 Hz, 1H), 8.27 (t, J = 1.9 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.86 (s, 1H), 7.82 (dd, J = 9.5, 1.9 Hz, 1H), 7.79 - 7.69 (m, 3H), 7.33 (dd, J = 5.6, 3.3 Hz, 1H), 7.19 (s, 1H), 7.11 (td, J = 8.4, 3.0 Hz, 1H), 6.05 (s, 1H)。 633.24 D   
I-1929
Figure 02_image4147
 FC(F)c1cn2cc(ccc2n1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 9.26 (s, 1H), 9.18 (dd, J = 2.0, 1.1 Hz, 1H), 8.27 (t, J = 1.9 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.86 (s, 1H), 7.82 (dd, J = 9.5, 1.9 Hz, 1H), 7.79 - 7.69 (m, 3H), 7.33 (dd, J = 5.6, 3.3 Hz, 1H), 7.19 (s, 1H), 7.11 (td, J = 8.4, 3.0 Hz, 1H), 6.05 (s, 1H)。 633.24 A   
I-1930
Figure 02_image4149
 FC(F)n1cc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 9.18 (s, 1H), 8.94 (s, 1H), 8.43 (s, 1H), 8.06 (d, J = 1.6 Hz, 1H), 8.02 - 7.79 (m, 3H), 7.75 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.31 (dd, J = 8.9, 5.1 Hz, 1H), 7.09 (td, J = 8.3, 3.1 Hz, 1H), 6.86 - 6.58 (m, 1H), 5.98 (s, 1H)。 583.2 D   
I-1931
Figure 02_image4151
 FC(F)n1cc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(Cl)c2)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 9.18 (s, 1H), 8.94 (s, 1H), 8.43 (s, 1H), 8.06 (d, J = 1.6 Hz, 1H), 8.02 - 7.79 (m, 3H), 7.75 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.31 (dd, J = 8.9, 5.1 Hz, 1H), 7.09 (td, J = 8.3, 3.1 Hz, 1H), 6.86 - 6.58 (m, 1H), 5.98 (s, 1H)。 583.2 A   
I-1932
Figure 02_image4153
 FC(F)c1ccc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz): δ = 10.66 (s, 1H), 9.28 (br s, 1H), 9.13 (d, J = 2.0 Hz, 1H), 8.43 (dd, J = 8.1, 2.3 Hz, 1H), 8.10 (d, J = 1.3 Hz, 1H), 7.97 (br d, J = 8.6 Hz, 1H), 7.93 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.77 (br d, J = 9.1 Hz, 1H), 7.70 (s, 1H), 7.34 (dd, J = 8.8, 5.3 Hz, 1H), 6.90-7.22 (m, 2H), 6.46-6.84 (m, 1H), 5.85-6.25 ppm (m, 1H)。 594.4 B   
I-1933
Figure 02_image4155
 FC(F)c1cc(ccn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz): δ = 10.66 (s, 1H), 9.21-9.41 (m, 1H), 8.81 (d, J = 5.1 Hz, 1H), 8.17 (d, J = 1.3 Hz, 1H), 8.12 (s, 1H), 8.07 (br d, J = 5.3 Hz, 1H), 8.02 (s, 1H), 7.98 (br d, J = 8.6 Hz, 1H), 7.78 (br d, J = 9.1 Hz, 1H), 7.71 (s, 1H), 7.34 (dd, J = 9.0, 5.2 Hz, 1H), 6.90-7.20 (m, 2H), 6.39-6.71 (m, 1H), 5.92-6.26 ppm (m, 1H)。 594.4 A   
I-1934
Figure 02_image4157
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc2ncc(Cl)n2c1 1H NMR (400 MHz, DMSO) 10.67 (s, 1H), 9.28 (s, 1H), 9.18 (d, 2.5 Hz, 1H), 9.06 (d, 2.5 Hz, 1H), 8.21 (d, 1.6 Hz, 1H), 7.96 (d, 16.9 Hz, 2H), 7.77 (d, 9.4 Hz, 1H), 7.71 (s, 1H), 7.34 (dd, 8.9, 5.2 Hz, 1H), 7.11 (td, 8.3, 3.1 Hz, 1H), 6.06 (s, 1H)。 618.13 A   
I-1935
Figure 02_image4159
 CC(Oc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)C#N    523.07 A   
I-1936
Figure 02_image4161
 FC(F)c1cnc2ccc(cn12)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO) δ 10.65 (s, 1H), 9.27 (s, 1H), 8.90 (t, J = 1.4 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 8.00 (s, 1H), 8.01 - 7.85 (m, 3H), 7.89 - 7.80 (m, 2H), 7.76 (d, J = 9.1 Hz, 1H), 7.69 (s, 2H), 7.33 (dd, J = 8.9, 5.2 Hz, 1H), 7.10 (td, J = 8.4, 3.1 Hz, 1H), 6.06 (s, 1H) 633.19 C   
I-1937
Figure 02_image4163
 FC(F)c1cnc2ccc(cn12)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO) δ 10.65 (s, 1H), 9.27 (s, 1H), 8.90 (t, J = 1.4 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 8.00 (s, 1H), 8.01 - 7.85 (m, 3H), 7.89 - 7.80 (m, 2H), 7.76 (d, J = 9.1 Hz, 1H), 7.69 (s, 2H), 7.33 (dd, J = 8.9, 5.2 Hz, 1H), 7.10 (td, J = 8.4, 3.1 Hz, 1H), 6.06 (s, 1H) 633.19 A   
I-1938
Figure 02_image4165
 FC(F)c1nc2ccc(cn2n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO) δ 10.65 (s, 1H), 9.56 (dd, J = 1.9, 0.9 Hz, 1H), 9.27 (s, 1H), 8.25 (dd, J = 9.4, 1.8 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8.07 (dd, J = 9.3, 0.9 Hz, 1H), 8.00 - 7.93 (m, 2H), 7.76 (d, J = 9.1 Hz, 1H), 7.70 (s, 1H), 7.38 - 7.28 (m, 2H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 3.16 (d, J = 3.5 Hz, 1H)。 634.19 A   
I-1939
Figure 02_image4167
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3OCCc4ccccc34)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6 )  9.69 (br s, 1H), 9.56 (br s, 1H), 9.44 (dd, 1.7, 0.8 Hz, 1H), 9.42 (dd, 1.6, 0.8 Hz, 1H), 9.22 (br s, 1H), 9.15 (br s, 1H), 8.58 (s, 1H), 8.57 (s, 1H),  8.16-8.05 (m, 4H), 8.02-7.94 (m, 4H), 7.43-7.34 (m,  2H), 7.27-7.15 (m, 11.2, 5.8 Hz, 6H), 7.14-7.02 (m, 6H), 6.54 (br s, 1H), 6.22 (br s, 1H), 6.14 (br s, 1H), 5.13 (s, 1H), 5.10 (s, 1H),  3.98-3.89 (m, 1H), 3.80-3.71 (m, 2H), 3.71-3.63 (m, 1H),  2.82-2.64 (m, 4H)。 554.3 D   
I-1940
Figure 02_image4169
 CS(=O)c1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.61 (d, 17.7 Hz, 1H), 9.42 (s, 1H), 8.59 (s, 1H), 8.43 (s, 1H), 8.33 (d,  7.0 Hz, 1H), 8.20 (dd,  16.4, 9.4 Hz, 1H), 8.00 (d,  9.3 Hz, 1H), 7.62 (s, 1H), 7.33 (d,  12.4 Hz, 1H), 6.68 (s, 1H), 6.43-6.26 (s, 1H), 2.20 (s, 3H)。 441.2 E   
I-1941
Figure 02_image4171
 CS(=O)(=O)c1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.67 (s, 1H), 9.58 (s, 1H), 8.61 (s, 1H), 8.51 (s, 2H), 8.26 (d, 9.4 Hz, 1H), 8.02 (d, 9.3 Hz, 1H), 7.62 (s, 1H), 7.26 (s, 1H), 6.53 (s, 1H), 6.47-6.25 (s, 1H), 2.94 (s, 3H)。 456.95 E   
I-1942
Figure 02_image4173
 O[C@@H]1C[C@H](C(=O)Nc2cc(Br)cc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccccc12 1H NMR (400 MHz, DMSO-d6)  10.16 (d, 46.4 Hz, 1H), 9.25 (s, 1H), 7.81 (d, 51.4 Hz, 2H), 7.53 (d, 26.0 Hz, 1H), 7.40 - 7.20 (m, 3H), 7.11 (q, 6.8 Hz, 1H), 6.66 (d, 7.6 Hz, 1H), 6.09 (s, 1H), 5.40 (dd, 14.7, 6.9 Hz, 1H), 4.97 (dt, 14.0, 7.0 Hz, 1H), 3.63 (dd, 16.2, 8.2 Hz, 1H), 2.30 (dd, 14.3, 7.7 Hz, 1H), 1.98 (s, 1H), 1.80 - 1.65 (m, 1H)。 517.05 E   
I-1943
Figure 02_image4175
 O[C@H]1C[C@H](C(=O)Nc2cc(Br)cc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccccc12 1H NMR (400 MHz, DMSO-d6)  10.11 (d, 35.6 Hz, 1H), 9.22 (d, 22.3 Hz, 1H), 7.85 - 7.70 (m, 2H), 7.65 (d, 1.8 Hz, 2H), 7.37 - 7.28 (s, 1H), 7.22 (m, 2H), 7.16 - 7.07 (s, 1H), 6.72 - 6.18 (s, 1H), 6.82 (dd, 25.9, 7.5 Hz, 1H), 6.04 (m, 2H), 5.29 - 5.07 (s, 1H), 2.37 - 2.00 (s, 1H), 1.82 (ddd, 13.1, 8.2, 5.0 Hz, 1H)。 517.05 E   
I-1944
Figure 02_image4177
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(-c3nc4c(F)cc(cc4[nH]3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  9.33 (s, 1H), 8.31 (d, 7.6 Hz, 1H), 7.96 (d, 7.5 Hz, 1H), 7.85 (t, 7.6 Hz, 1H), 7.65 (s, 1H), 7.38 (d, 10.6 Hz, 2H), 6.95 (td, 8.4, 3.1 Hz, 1H), 6.69 (s, 1H), 6.21 (s, 1H)。 464.05 A   
I-1945
Figure 02_image4179
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Br)cc(NC(=O)Nc3ccccc3)c12 1H NMR (400 MHz, DMSO-d6) 9.26 - 8.26 (m, 2H), 7.85 - 7.76 (m, 1H), 7.62 (d, 1.7 Hz, 1H), 7.46 (dd, 8.9, 5.1 Hz, 1H), 7.39 - 7.31 (m, 2H), 7.31 - 7.14 (m, 3H), 6.98 (td, 7.3, 1.3 Hz, 1H), 6.88 - 6.59 (m, 1H), 6.06 (s, 1H)。 476 E   
I-1946
Figure 02_image4181
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(Br)cc(NC(=O)Nc3ccccc3)c12 1H NMR (400 MHz, DMSO-d6) 9.26 - 8.26 (m, 2H), 7.85 - 7.76 (m, 1H), 7.62 (d, 1.7 Hz, 1H), 7.46 (dd, 8.9, 5.1 Hz, 1H), 7.39 - 7.31 (m, 2H), 7.31 - 7.14 (m, 3H), 6.98 (td, 7.3, 1.3 Hz, 1H), 6.88 - 6.59 (m, 1H), 6.06 (s, 1H)。 476 D   
I-1947
Figure 02_image4183
 CN1CCCC[C@H]1C(=O)Nc1cc(cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.43 (d, 1.8 Hz, 2H), 8.57 (s, 1H), 8.18 (d, 1.7 Hz, 1H), 8.09 (dd, 9.3, 1.9 Hz, 1H), 8.03 - 7.94 (m, 2H), 7.55 (s, 1H), 7.26 (td, 8.4, 3.1 Hz, 1H), 6.16 (d, 69.1 Hz, 2H), 5.93 (d, 2H), 3.00 - 2.76 (m, 2H), 1.90 (s, 4H), 1.54 (d, 12.0 Hz, 2H), 1.38 (d, 13.2 Hz, 2H), 1.15 (s, 1H)。 519.25 E   
I-1948
Figure 02_image4185
 CN1CCCC[C@H]1C(=O)Nc1cc(cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.43 (d, 1.8 Hz, 2H), 8.57 (s, 1H), 8.18 (d, 1.7 Hz, 1H), 8.09 (dd, 9.3, 1.9 Hz, 1H), 8.03 - 7.94 (m, 2H), 7.55 (s, 1H), 7.26 (td, 8.4, 3.1 Hz, 1H), 6.16 (d, 69.1 Hz, 2H), 5.93 (d, 2H), 3.00 - 2.76 (m, 2H), 1.90 (s, 4H), 1.54 (d, 12.0 Hz, 2H), 1.38 (d, 13.2 Hz, 2H), 1.15 (s, 1H)。 519.2 E   
I-1949
Figure 02_image4187
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(Br)cc(NC(=O)N[C@@]3(CC(F)(F)F)CCCOC3)c12 1H NMR (400 MHz, DMSO):-´ 9.17 (s, 1H), 8.52 (s, 1H), 7.83 (d, 1.0 Hz, 1H), 7.52 (d, 1.7 Hz, 1H), 7.48 (dd, 8.3, 5.3 Hz, 1H), 7.22 (td, 8.4, 3.1 Hz, 1H), 6.71 (br s, 1H), 6.58 (s, 1H), 6.01 (s, 1H), 3.67-3.49 (m, 4H), 2.85-2.63 (m, 2H), 2.01-1.90 (m, 1H), 1.61-1.49 (m, 1H), 1.47-1.33 (m, 2H)。 564.2 E   
I-1950
Figure 02_image4189
 NCc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.45 (s, 1H), 9.19 (s, 1H), 8.56 (s, 1H), 8.15 (dd, 9.3, 1.9 Hz, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.97 (d, 9.3 Hz, 1H), 7.64 (s, 1H), 7.28 (s, 1H), 6.50 (s, 1H), 6.17 (s, 1H), 3.61 (d, 15.6 Hz, 2H)。 408.08 E   
I-1951
Figure 02_image4191
 CN1C(=O)NC(c2cc(F)ccc2Cl)c2c(NC(=O)c3cc(F)cc(c3)C(F)(F)F)cccc12 1H NMR (氯仿-d, 400 MHz) 7.62 (1H, dt,  8.8, 1.9 Hz), 7.51 (4H, q,  3.5, 2.6 Hz), 7.43 (1H, dd,  8.9, 4.9 Hz), 7.18 (1H, s), 7.03 (2H, ddt,  10.4, 6.0, 3.2 Hz), 6.60 (1H, dd,  8.7, 3.0 Hz), 6.14 (1H, dd,  3.1, 1.3 Hz), 5.55 (1H, d,  3.1 Hz), 3.41 (3H, s) 494.1 D   
I-1952
Figure 02_image4193
 CN1CCN(CC1)c1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 NMR (400 MHz, CD3CN)  9.09 (br s, 1H), 8.36 (br s, 1H), 8.04 (s, 0.5H), 8.00 (dd, 9.3, 1.9 Hz, 1H), 7.84 (br s, 0.5H), 7.82 (d, 1.5 Hz, 1H), 7.56-7.51 (m, 2H), 7.34-7.29 (m, 1H), 7.14 (ddd, 8.8, 8.0, 3.1 Hz, 1H), 6.62 (br s, 0.5H), 6.60 (br s, 0.5H), 6.20 (s, 1H), 3.41-3.33 (m, 2H), 3.05-2.96 (m, 2H), 2.74-2.54 (m, 4H), 2.44 (s, 3H)。 477 E   
I-1953
Figure 02_image4195
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)NC3(CC(F)(F)F)CCOCC3)c12 1H NMR (400 MHz, DMSO-d6) 9.19 (s, 1H), 8.07 (s, 1H), 7.76 (d, 1.7 Hz, 1H), 7.54 (d, 1.7 Hz, 1H), 7.49 (dd, 8.7, 5.0 Hz, 1H), 7.27-7.19 (m, 1H), 6.71 (br s, 1H), 6.48 (s, 1H), 6.06 (s, 1H), 3.65-3.50 (m, 2H), 3.30-3.14 (m, 2H), 2.80-2.65 (m, 2H), 1.96-1.86 (m, 2H), 1.67-1.50 (m, 2H)。 564.1 E   
I-1954
Figure 02_image4197
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CC4CC4(F)C3)c12 1H NMR (400 MHz, DMSO-d6) 9.19 (s, 1H), 8.38 (s, 1H), 7.62 (d, 1.5 Hz, 1H), 7.56-7.42 (m, 2H), 7.30-7.22 (m, 1H), 7.06-6.18 (m, 1H), 5.95 (br s, 1H), 3.95-3.84 (m, 0.5H), 3.81-3.49 (m, 1.5H), 3.24-3.15 (m, 1H), 3.12-2.70 (m, 1H), 2.05-1.92 (m, 1H), 1.55-1.40 (m, 1H), 0.46 (br s, 1H)。 482 E   
I-1955
Figure 02_image4199
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(OCc3ccccc3)c12)-c1ccc2ncnn2c1 (400 MHz, DMSO-d6)  9.52 - 9.50 (m, 1 H), 9.19 (s, 1 H), 8.57 (s, 1 H), 8.16 (dd, 9.3, 1.8 Hz, 1H), 7.96 (d, 9.4 Hz, 1 H), 7.75-7.70 (m, 2 H), 7.52 (dd, 8.9, 5.1 Hz, 1 H), 7.31-7.24 (m, 4 H), 7.02 - 6.96 (m, 2 H), 6.88 (br s, 1 H), 6.07 (s, 1 H), 5.28-5.18 (m, 2 H)。 485.2 E   
I-1956
Figure 02_image4201
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(C3CCCN3)c12 NMR (400 MHz, DMSO-d6)  8.87 (s, 1H), 8.46 (d, 7.9 Hz, 1H), 8.37 (m, 2H), 8.06 (d, 4.8 Hz, 1H), 8.01 (d, 8.0 Hz), 7.61-7.49 (m, 1H), 7.43 (d, 7.3 Hz, 1H), 4.58 (d, 10.2 Hz, 1H), 3.06-23.00 (m, 1H), 2.89-2.81 (m, 1H), 2.78-2.66 (m, 1H), 1.92-1.81 (m, 2H), 1.60-1.48 (m, 2H)。 408.1 E   
I-1957
Figure 02_image4203
 FC1CCCC(C1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.92 (br. s, 1H), 9.90-9.87 (m, 1H), 9.45-9.43 (m, 2H), 9.21 (s, 2H), 8.57 (s, 2H), 8.11-8.07 (m, 2H), 8.01-7.99 (m, 2H), 7.99-7.95 (m, 2H), 7.86-7.80 (m, 2H), 7.55-7.49 (m, 2H), 7.29-7.22 (m, 2H), 6.58 (br. s, 2H), 6.13 (br. s, 2H), 4.96-4.90 (m, 1H), 4.84-4.78 (m, 1H), 2.48-2.39 (m, 2H), 1.85-1.65 (m, 4H), 1.61-1.35 (m, 8H), 1.32-1.12 (m, 4H)。 522.3 D   
I-1958
Figure 02_image4205
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(C3CCCOC3)c12 (400 MHz, CD3CN)  9.13 (s, 0.6H), 9.06 (s, 0.4H), 8.11 (s, 1H), 7.96 (d, 9.1 Hz,1H), 7.74 (d, 8.4 Hz,1H), 7.67-7.57 (m , 2H), 7.57-7.51 (m, 7.6 Hz, 1H), 6.97 (s, 0.6H), 6.85 (s, 0.4H), 4.83 (s, 1H), 3.85 (dd, 11.1, 2.1 Hz, 0.4H), 3.77-3.63 (m, 1H), 3.32 (t, 10.9 Hz, 0.4H), 3.27-3.11 (m, 1H), 3.11-3.02 (m, 0.6H), 2.95 (t, 10.9 Hz, 0.6H), 2.12 (m, 1H), 1.88-1.78 (m, 0.6H), 1.61-1.32 (m, 3H), 1.12-0.99 (m, 0.6H), 0.96-0.84 (m, 0.4H) 423.1 E   
I-1959
Figure 02_image4207
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC3CNCc4ccccc34)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.47-9.42 (m, 1H), 9.01 (s, 1H), 8.55 (s, 1H), 8.14 (dd, 9.3, 1.9 Hz, 1H), 7.94 (d, 9.3 Hz, 1H), 7.48-7.37 (m, 3H), 7.26 (td, 8.4, 3.1 Hz, 1H), 7.13 (td, 7.5, 1.3 Hz, 1H), 7.02 (d, 7.6 Hz, 1H), 6.91 (t, 7.4 Hz, 1H), 6.61 (d, 7.7 Hz, 1H), 5.88 (s, 1H), 4.86-4.77 (m, 2H), 3.86 (s, 2H), 3.24 (dd, 12.0, 4.1 Hz, 1H), 2.87 (dd, 12.5, 5.8 Hz, 1H)。 525.1 D   
I-1960
Figure 02_image4209
 OC1CCCC(CC(=O)Nc2cc(cc3C(=O)NC(c23)c2cc(F)ccc2Cl)-c2ccc3ncnn3c2)C1 NMR (400 MHz, DMSO-d6) 9.79 (br s, 1H), 9.43 (br s, 1H), 9.26-9.13 (m, 1H), 8.57 (d, 2.5 Hz, 1H), 8.13-7.94 (m, 4H), 7.60-7.43 (m, 1H), 7.35-7.17 (m, 1H), 6.59 (br s, 1H), 6.16 (br s, 1H), 4.47 (br s, 1H), 3.81-3.57 (m, 1H), 2.01-1.90 (m, 2H), 1.48-1.08 (m, 9H)。 534.2 E   
I-1961
Figure 02_image4211
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Br)cc(NC(=O)N[C@@]3(CC(F)(F)F)CCCOC3)c12 1H NMR (400 MHz, DMSO-d6) 9.18 (s, 1H), 8.49 (s, 1H), 7.77 (d, 1.7 Hz, 1H), 7.53 (d, 1.7 Hz, 1H), 7.48 (dd, 8.6, 5.1 Hz, 1H), 7.21 (td, 8.4, 3.1 Hz, 1H), 6.65 (br s, 1H), 6.58 (s, 1H), 6. (s, 1H), 3.64 (dd, 10.8, 2.5 Hz, 2H), 3.44-3.35 (m, 2H), 2.92-2.75 (m, 1H), 2.69-2.53 (m, 1H), 2.17-2.05 (m, 1H), 1.59-1.47 (m, 1H), 1.47-1.32 (m, 2H)。 564.2 E   
I-1962
Figure 02_image4213
 CC(C=CC=C1)=C1C2NCCC3=CC=CC(NC(C4=CC(F)=CC(C(F)(F)F)=C4)=O)=C32    428.2 E   
I-1963
Figure 02_image4215
 CC(C=CC=C1)=C1C2NCCC3=C(Br)C=CC(NC(C4=CC(F)=CC(C(F)(F)F)=C4)=O)=C32    506.1 E   
I-1964
Figure 02_image4217
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3CCCN(CC(F)(F)F)C3)c12)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)，呈非對映異構體之約1:1混合物形式9.93 (br. s, 1H), 9.91 (br. s, 1H), 9.45-9.43 (m, 2H), 9.21 (br. s, 2H), 8.57 (s, 2H), 8.11-8.07 (m, 2H), 8.01 (d, J = 1.1 Hz, 2H), 7.97 (d, J = 9.3 Hz, 2H), 7.82-7.77 (m, 2H), 7.56-7.49 (m, 2H), 7.28-7.22 (m, 2H), 6.56 (br. s, 2H), 6.09 (br. s, 2H), 3.20-3.06 (m, 3H), 3.03-2.92 (m, 1H), 2.84-2.78 (m, 2H), 2.70-2.65 (m, 1H), 2.55-2.44 (m, 1H), 2.36-2.27 (m, 2H), 2.22 (m, 3H), 2.14-2.06 (m, 1H), 1.59-1.50 (m, 3H), 1.43-1.32 (m, 3H), 1.24-1.05 (m, 2H)。 587.3 E   
I-1965
Figure 02_image4219
 O[C@H]1CN(C[C@H]1O)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6) 9.38-9.37 (m, 1H), 9.13 (br. s, 1H), 8.56 (s, 1H), 8.19 (br. s, 1H), 8.05 (dd, J = 9.3, 1.8 Hz, 1H), 7.96 (dd, J = 9.2, 0.6 Hz, 1H), 7.89 (d, J = 1.5 Hz, 1H), 7.72 (br. s, 1H), 7.52-7.45 (m, 1H), 7.24 (app. td, J = 8.6, 3.2 Hz, 1H), 6.66 (br. s, 1H), 6.08 (br. s, 1H), 4.96-4.89 (m, 2H), 3.95-3.89 (m, 1H), 3.89-3.82 (m, 1H), 3.44-3.32 (m, 2H), 3.08 (dd, J = 10.1, 5.6 Hz, 1H), 3.02-2.94 (m, 1H)。3.44-3.32處之多重峰被H2O峰部分遮蔽。 523 E   
I-1966
Figure 02_image4221
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C34CCC(CC3)O4)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6 )  9.46-9.40 (m, 2H), 9.21 (br s, 1H), 8.57 (s, 1H), 8.10 (dd, J = 9.3, 1.8 Hz, 1H), 8.03-8.00 (m, 2H), 7.97 (dd, J = 9.3, 0.5 Hz, 1H), 7.59-7.44 (m, 1H), 7.29-7.21 (m, 1H), 6.61 (br s, 1H), 6.22 (br s, 1H), 4.60 (t, J = 4.9 Hz, 1H), 1.79-1.58 (m, 4H), 1.58-1.48 (m, 2H), 1.39-1.13 (m, 2H)。平均10%雜質 518.3 E   
I-1967
Figure 02_image4223
 OC1(CCCCC1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  10.70 (br. s, 1H), 8.71 (s, 1H), 8.09 (s, 1H), 8.04 (br. d, J = 9.0 Hz, 1H), 7.99 (br. d, J = 8.4 Hz, 1H), 7.58-7.45 (m, 3H), 4.71 (s, 1H), 4.18 (br. s, 1H), 3.69 (s, 1H), 1.85-1.66 (m, 2H), 1.61 (d, J = 13.4 Hz, 1H), 1.44 (d, J = 11.5 Hz, 1H), 1.28-1.17 (m, 1H), 1.16-1.02 (m, 3H), 0.32 (d, J = 10.8 Hz, 1H)。 437.1 E   
I-1968
Figure 02_image4225
 CN(C)S(=O)(=O)c1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.60 (d, J = 2.1 Hz, 1H), 9.57 (s, 1H), 8.61 (s, 1H), 8.47 (s, 1H), 8.24 (s, 1H), 8.19 (dd, J = 9.3, 1.9 Hz, 1H), 8.00 (d, J = 9.3 Hz, 1H), 7.59 (s, 1H), 7.22 (s, 1H), 6.25 (d, J = 103.6 Hz, 1H), 2.62 (s, 6H)。 486 E   
I-1969
Figure 02_image4227
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)C12CC3CC(CC(C3)C1)C2 NMR (400 MHz, DMSOd6)  10.78 (s, 1H), 8.72 (s, 1H), 8.14 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.59-7.50 (m, 3H), 4.50 (s, 1H), 1.81 (br s, 3H), 1.56 (d, J = 13.4 Hz, 3H), 1.52 (m, 3H), 1.44 (d, J = 11.5 Hz, 3H), 1.31 (d, J = 11.8 Hz, 3H)。在3.9處存在雜質  根據NMR為10-15%。 473.3 E   
I-1970
Figure 02_image4229
 NS(=O)(=O)c1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.55 (d, J = 1.8 Hz, 1H), 9.45 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H), 8.42 (d, J = 1.7 Hz, 1H), 8.20 (dd, J = 9.3, 1.9 Hz, 1H), 8.05 (d, J = 9.3 Hz, 1H), 7.53 (s, 1H), 7.20 (td, J = 8.4, 3.1 Hz, 1H), 7.10 (s, 1H), 6.37 (s, 1H)。 458 E   
I-1971
Figure 02_image4231
 [H][C@]1(CCCC[C@H]1O)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.74 (s, 1H), 8.12 (s, 1H), 8.08 (d, J = 9.0 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.65 (dd, J = 7.4, 1.2 Hz, 1H), 7.59-7.50 (m, 3H), 4.94-4.88 (m, 2H), 3.94-3.88 (m, 1H), 1.92 (d, J = 12.4 Hz, 1H), 1.66 (d, J = 13.6 Hz, 1H), 1.55-1.39 (m, 2H), 1.30-1.20 (m, 2H), 1.15 (d, J = 13.3 Hz, 1H), 1.03-0.89 (m, 1H), 0.47 (d, J = 10.5 Hz, 1H)   [單一非對映異構體]。 437.2 E   
I-1972
Figure 02_image4233
 [H][C@@]1(CCCC[C@@H]1O)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.64 (s, 1H), 8.59 (s, 1H), 8.14 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.59-7.48 (m, 3H), 5.30 (d, J = 1.1 Hz, 1H), 4.70 (d, J = 4.5 Hz, 1H), 3.44-3.35 (m, 1H), 1.85 (d, J = 8.9 Hz, 1H), 1.73 (t, J = 10.5 Hz, 1H), 1.54 (d, J = 12.7 Hz, 1H), 1.42 (d, J = 12.6 Hz, 1H), 1.14-0.86 (m, 3H), 0.75-0.66 (m, 1H), 0.66-0.55 (m, 1H) [單一非對映異構體] [約5wt%雜質形式之TBSOH]。 437.2 E   
I-1973
Figure 02_image4235
 COc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.51 (t, J=1.4 Hz, 1H), 9.15 (s, 1H), 8.57 (s, 1H), 8.17 (dd, J=9.3, 1.8 Hz, 1H), 7.96 (dd, J=9.3, 0.9 Hz, 1H), 7.72 (d, J=1.3 Hz, 1H), 7.62-7.53 (m, 2H), 7.24 (td, J=8.4, 3.1 Hz, 1H), 6.81 (s, 1H), 6.04 (s, 1H), 3.82 (s, 3H)。 409.05 E   
I-1974
Figure 02_image4237
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3cccc(=O)[nH]3)c12 1H NMR (400 MHz, DMSO-d6)  10.31 (s, 1H), 9.14 (s, 1H), 8.46 (s, 1H), 7.71 (d, J = 4.3 Hz, 1H), 7.53 (s, 1H), 7.41 - 7.23 (m, 2H), 7.13 (td, J = 8.4, 3.1 Hz, 1H), 6.49 (s, 1H), 6.11 (s, 1H), 6.00 (s, 1H), 5.90 (s, 1H)。 449.95 D   
I-1975
Figure 02_image4239
 O[C@H]1CC[C@H](C1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  9.68 (d, J = 17.2 Hz, 1H), 9.22 (s, 1H), 7.72 - 7.61 (m, 2H), 7.47 (d, J = 7.3 Hz, 1H), 7.24 (td, J = 8.4, 3.1 Hz, 1H), 6.67 (s, 1H), 6.01 (s, 1H), 4.62 (dd, J = 4.7, 2.8 Hz, 1H), 4.03 - 3.96 (m, 1H), 2.54 (s, 1H), 1.87 - 1.69 (m, 1H), 1.59 (dt, J = 10.3, 6.9 Hz, 1H), 1.56 - 1.29 (m, 4H)。 466.95 E   
I-1976
Figure 02_image4241
 O[C@@H]1CC[C@H](C1)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  9.75 (s, 1H), 9.23 (s, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.61 (dt, J = 6.0, 2.0 Hz, 1H), 7.48 (d, J = 6.9 Hz, 1H), 7.29 - 7.19 (m, 1H), 6.67 (s, 1H), 6.02 (s, 1H), 4.47 (t, J = 3.9 Hz, 1H), 4.09 (s, 1H), 2.54 (s, 1H), 1.73 - 1.60 (m, 1H), 1.64 (s, 2H), 1.50 (dd, J = 8.5, 3.9 Hz, 1H), 1.40 (s, 2H)。 467.05 E   
I-1977
Figure 02_image4243
 CNS(=O)(=O)c1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.56 (d, J = 1.9 Hz, 1H), 9.50 (s, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 8.40 (s, 1H), 8.19 (dd, J = 9.3, 1.9 Hz, 1H), 8.04 (d, J = 9.3 Hz, 1H), 7.55 (s, 2H), 7.21 (td, J = 8.4, 3.0 Hz, 1H), 6.38 (s, 2H) , 2.33 (s, 3H)。 472 E   
I-1978
Figure 02_image4245
 O[C@H]1CN(C[C@H]1C(F)(F)F)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)，呈非對映異構體之約1:1混合物形式  9.39-9.38 (m, 2H), 9.16 (br. s, 2H), 8.56 (s, 2H), 8.35 (br. s, 1H), 8.27 (br. s, 1H), 8.08-8.04 (m, 2H), 7.99-7.95 (m, 2H), 7.93-7.90 (m, 2H), 7.82-7.78 (m, 1H), 7.74 (d, J = 1.1 Hz, 1H), 7.53-7.46 (m, 2H), 7.23 (app. td, J = 8.4, 3.0 Hz, 2H), 6.68 (br. s, 2H), 6.10 (br. s, 2H), 5.58 (br. d, J = 4.3 Hz, 1H), 5.49 (d, J = 4.5 Hz, 1H), 4.44-4.36 (m, 2H), 3.67-3.51 (m, 1H), 3.47-3.40 (m, 3H), 3.31-3.20 (m, 2H), 3.16-3.03 (m, 1H), 3.02-2.86 (m, 3H)。 575.3 D   
I-1979
Figure 02_image4247
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(C(=O)NCc3ccccc3)c12 1H NMR (400 MHz, DMSO-d6) 9.34 (s, 1H), 9.08 (dd, J = 7.3, 4.7 Hz, 1H), 8.08 (s, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.49 (s, 1H), 7.30 - 7.17 (m, 4H), 6.87 (dd, J = 6.7, 2.9 Hz, 2H), 6.36 (s, 1H), 4.61 - 4.39 (m, 1H), 4.15 -3.88 (m, 1H)。 475 E   
I-1980
Figure 02_image4249
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(Cn3ccccc3=O)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.38 (br. s, 1H), 8.56 (s, 1H), 8.52 (br. s, 2H), 8.13 - 8.10 (m, 1H), 7.90 - 7.92 (m, 2H), 7.68 - 7.56 (m, 2H), 7.43-7.34 (m, 1H), 7.26 (ddd, J = 8.6, 8.0, 2.9 Hz, 1H), 6.51 (br. s, 1H), 6.37 (br. s, 1H), 6.33 (d, J = 9.3 Hz, 1H), 6.19 (app. t, J = 7.0 Hz, 1H), 4.88 (d, J = 14.5 Hz, 1H), 4.72 (d, J = 14.8 Hz, 1H)；含有乙腈(2.08)；含有一些雜質(根據LC為約10%)。 486.2 E   
I-1981
Figure 02_image4251
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(COc3cc4ccccc4cn3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6 )  9.49 (dd, J = 1.7, 0.8 Hz, 1H), 9.32 (br. s, 1H), 8.98 (s, 1H), 8.57 (s, 1H), 8.21 (br. s, 1H), 8.17 (浸沒br. s, 1H), 8.15 (重疊dd, J = 4.6, 1.8 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.65 (ddd, J = 8.2, 6.8, 1.0, 1H), 7.44 (ddd, J = 8.0, 6.8, 1.0 Hz, 1H), 7.38 (dd, J = 8.8, 5.2 Hz, 1H), 7.13 (br. s, 1H), 7.03 (br. s, 1H), 6.57 (br. s, 1H), 6.35 (br. s, 1H), 5.27 (d, J = 12.2 Hz, 1H), 5.15 (br. s, 1H)。含有8%甲酸銨(8.43)；含有殘餘乙腈(2.08)。 536.2 D   
I-1982
Figure 02_image4253
 NC1CCCCC1C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)9.43 (s, 1H), 9.22 (d, J = 9.8 Hz, 1H), 8.58 (s, 1H), 8.40-8.05 (m, 2H),8.05-7.98 (m, 2H), 7.53 (s, 1H), 7.32-7.20 (m, 1H), 6.90-6.35 (m,1H), 6.17 (s, 1H), 3.10-2.90 (m,1H), 2.25-1.90 (m,1H), 1.85-1.50 (m,2H), 1.50-1.35(m,2H),1.35-1.15(m,4H),1.15-0.80(m,2H) 519.1 E   
I-1983
Figure 02_image4255
 NC(=O)CC(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  10.05 (br s, 1H), 9.43 (d, J = 0.7 Hz, 1H), 9.21 (br s, 1H), 8.57 (s, 1H), 8.08 (dd, J = 9.3, 1.5 Hz, 1H), 8.01 (d, J = 0.9 Hz, 1H), 7.98-7.91 (m, 2H), 7.54-7.44 (m, 2H), 7.23 (td, J = 8.3, 3.0 Hz, 1H), 7.17-7.08 (m, 1H), 6.74 (br s, 1H), 6.07 (br s, 1H), 3.00 (d, J = 15.9 Hz, 1H), 2.96 (d, J = 16.2 Hz, 1H)。 479 E   
I-1984
Figure 02_image4257
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc2ncc(Cl)n2c1 1H NMR (400 MHz, DMSO) δ 10.67 (s, 1H), 9.28 (s, 1H), 9.18 (d, J = 2.5 Hz, 1H), 9.06 (d, J = 2.5 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 16.9 Hz, 2H), 7.77 (d, J = 9.4 Hz, 1H), 7.71 (s, 1H), 7.34 (dd, J = 8.9, 5.2 Hz, 1H), 7.11 (td, J = 8.3, 3.1 Hz, 1H), 6.06 (s, 1H)。 619.18 C   
I-1985
Figure 02_image4259
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cnc2ncc(Cl)n2c1 1H NMR (400 MHz, DMSO) δ 10.67 (s, 1H), 9.28 (s, 1H), 9.18 (d, J = 2.5 Hz, 1H), 9.06 (d, J = 2.5 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 16.9 Hz, 2H), 7.77 (d, J = 9.4 Hz, 1H), 7.71 (s, 1H), 7.34 (dd, J = 8.9, 5.2 Hz, 1H), 7.11 (td, J = 8.3, 3.1 Hz, 1H), 6.06 (s, 1H)。 619.18 A   
I-1986
Figure 02_image4261
 FC(F)c1nc2ccc(cn2n1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO) δ 10.65 (s, 1H), 9.56 (dd, J = 1.9, 0.9 Hz, 1H), 9.27 (s, 1H), 8.25 (dd, J = 9.4, 1.8 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8.07 (dd, J = 9.3, 0.9 Hz, 1H), 8.00 - 7.93 (m, 2H), 7.76 (d, J = 9.1 Hz, 1H), 7.70 (s, 1H), 7.38 - 7.28 (m, 2H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 3.16 (d, J = 3.5 Hz, 1H)。 634.19 D   
I-1987
Figure 02_image4263
 FC(F)c1nc2ccc(cn2n1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO) δ 10.65 (s, 1H), 9.56 (dd, J = 1.9, 0.9 Hz, 1H), 9.27 (s, 1H), 8.25 (dd, J = 9.4, 1.8 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8.07 (dd, J = 9.3, 0.9 Hz, 1H), 8.00 - 7.93 (m, 2H), 7.76 (d, J = 9.1 Hz, 1H), 7.70 (s, 1H), 7.38 - 7.28 (m, 2H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 3.16 (d, J = 3.5 Hz, 1H)。 634.19 A   
I-1988
Figure 02_image4265
 CC#Cc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.47 (d, J = 2.4 Hz, 1H), 9.29 (s, 0H), 8.56 (s, 1H), 8.17-8.08 (m, 2H), 8.00 (d, J = 1.7 Hz, 1H), 7.94 (d, J = 9.3 Hz, 1H), 7.58 (s, 1H), 7.27 (td, J = 8.4, 3.1 Hz, 1H), 6.12 (s, 1H), 2.96 (q, J = 2.1 Hz, 1H), 1.87 (s, 3H)。 417.05 E   
I-1989
Figure 02_image4267
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)[C@H]3C[C@H](C3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 9.78 (s, 1H), 9.24 (s, 1H), 7.72 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.23 (ddd, J = 8.8, 7.9, 3.1 Hz, 1H), 6.64 (s, 1H), 6.02 (s, 1H), 3.09 (dq, J = 18.2, 9.1 Hz, 1H), 2.91 (p, J = 9.0 Hz, 1H), 2.13-1.86 (m, 4H)。 506.9 D   
I-1990
Figure 02_image4269
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(N3C(=O)CCC3=O)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.45 (d, J = 0.8 Hz, 1H), 9.36 (br s, 1H), 8.58 (s, 1H), 8.32 (br s, 1H), 8.06 (dd, J = 9.3, 1.8 Hz, 1H), 8.01-7.95 (m, 2H), 7.70-7.48 (m, 1H), 7.25 (td, J = 8.6, 2.9 Hz, 1H), 6.56 (br s, 1h), 5.96 (br s, H), 2.92-2.76 (m, 1H), 2.76-2.60 (m, 2H), 2.44-2.11 (m, 1H)。 476 E   
I-1991
Figure 02_image4271
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3COCCN3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6 )  9.67-9.47 (m, 1H), 9.43-9.38 (m, 1H), 9.31-9.19 (m, 1H), 8.58 (s, 1H), 8.29 (s, 1H), 8.25 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.11-8.03 (m, 1H), 8.02-7.93 (m, 2H), 7.66-7.48(m, 1H), 7.36-7.22 (m, 1H), 6.14 (br s, 1H), 3.58-3.44 (m, 2H), 3.42-3.19 (m, 4H), 3.18-3.07 (m, 1H)。非對映異構體之混合物(1:1.6) 507.3 E   
I-1992
Figure 02_image4273
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3CCCC(N3)C(F)(F)F)c12)-c1ccc2ncnn2c1 NMR (400 MHz, ACN-d3 )  9.05 (s, 1H), 8.43-8.32 (m, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.96 (d, J = 11.0 Hz, 1H), 7.50 (s, 1H), 7.31 (, 1Hs), 7.23-7.04 (m, 1H), 6.62 (br s, 1H), 6.27 (br , 1H), 3.33-3.10 (m,  2H), 1.87-1.59 (m, 4H), 1.46-1.33 (m, 1H), 1.33-1.11 (m, 1H), 0.96-0.78 (m, 1H)。非對映異構體之混合物(3:1)；報導主要異構體 573.1 D   
I-1993
Figure 02_image4275
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(Nc3ccn(n3)C3CC3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.35-9.30 (m, 1H), 9.06 (s, 1H), 8.56 (s, 1H), 8.03 (dd, J=9.3, 1.8 Hz, 1H), 8.00-7.92 (m, 2H), 7.83 (s, 1H), 7.59 (dd, J=11.8, 1.9 Hz, 2H), 7.48 (dd, J=8.8, 5.2 Hz, 1H), 7.20 (td, J=8.3, 3.1 Hz, 1H), 6.62 (s, 1H), 6.09 (s, 1H), 5.75 (d, J=2.3 Hz, 1H), 3.57 (tt, J=7.3, 3.9 Hz, 1H), 1.02-0.85 (m, 4H)。 500.05 E   
I-1994
Figure 02_image4277
 OCCn1ccc(Nc2cc(cc3C(=O)NC(c23)c2cc(F)ccc2Cl)-c2ccc3ncnn3c2)n1 1H NMR (400 MHz, DMSO-d6)  9.32 (dd, J = 1.8, 1.0 Hz, 1H), 9.05 (s, 1H), 8.56 (s, 1H), 8.02 (dd, J = 9.3, 1.8 Hz, 1H), 8.00 -7.92 (m, 2H), 7.78 (s, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.49 (dd, J = 8.9, 5.2 Hz, 1H), 7.21 (ddd, J = 8.9, 7.9, 3.1 Hz, 1H), 6.69 (s, 1H), 6.11 (s, 1H), 5.76 (d, J = 2.3 Hz, 1H), 4.86 (t, J = 5.3 Hz, 1H), 4.02 (td, J = 5.5, 1.6 Hz, 2H), 3.72 (q, J = 5.7 Hz, 2H)。 504 E   
I-1995
Figure 02_image4279
 CS(=O)(=O)n1cc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.58 (br s, 1 H), 9.19 (br s, 1 H), 8.98 (s, 1 H), 8.64 (s, 1 H), 8.13 (s, 1 H), 7.99 - 7.91 (m, 2 H), 7.76 (d, J = 8.9 Hz, 1 H), 7.72 (s, 1 H), 7.32 (dd, J = 8.9, 5.1 Hz, 1 H), 7.10 (td, J = 8.5, 2.9 Hz, 1 H), 6.58 (br s, 1 H), 5.99 (br s, 1 H), 3.61 (s, 3 H)。 609.1 C   
I-1996
Figure 02_image4281
 CS(=O)(=O)n1cc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.58 (br s, 1 H), 9.18 (br s, 1 H), 8.97 (s, 1 H), 8.64 (s, 1 H), 8.13 (s, 1 H), 8.00-7.88 (m, 2 H), 7.76 (d, J = 8.9 Hz, 1 H), 7.73 (s, 1 H), 7.32 (dd, J = 8.9, 5.2 Hz, 1 H), 7.10 (td, J = 8.5, 3.0 Hz, 1 H), 6.61 (br s, 1 H), 5.99 (br s, 1 H), 3.61 (s, 3 H)。 609.1 A   
I-1997
Figure 02_image4283
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(c12)C1=CCNCC1)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.50 (d, J = 0.7 Hz, 1H), 9.27 (br s, 1H), 8.56 (s, 1H), 8.33 (br s, 1H), 8.16 (dd, J = 9.3, 1.8 Hz, 1H), 8.06 (d, J = 1.4 Hz, 1H), 7.95 (d, J = 9.3 Hz, 1H), 7.83 (s, 1H), 7.62-7.47 (m, 1H), 7.25 (td, J = 8.4, 3.1 Hz, 1H), 6.46 (br s, 1H), 6.29 (br s, 1H), 5.84 (br s, 1H), 3.46-3.08 (m, 2H), 2.98-2.71 (m, 1H), 2.58 (br d, J = 12.3 Hz, 1H), 2.39-2.16 (m, 1H), 1.47 (br d, J = 13.5 Hz, 1H)。 460 E   
I-1998
Figure 02_image4285
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(c12)C1=CCCNC1)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.53-9.51 (m, 1H), 9.27 (br s, 1H), 8.56 (s, 1H), 8.18 (dd, J = 9.3, 1.4 Hz, 1H), 8.06 (s, 1H), 7.94 (d, J = 9.3 Hz, 1H), 7.89 (s, 1H), 7.66-7.46 (m, 1H), 7.25 (td, J = 8.4, 3.0 Hz, 1H), 6.41 (br s, 1H), 6.29 (br s, 1H), 5.90 (br s, 1H), 3.69 (br d, J = 18.1 Hz, 1H), 2.92-2.72 (m, 1H), 2.47-2.34 (m, 1H), 2.17-1.87 (m, 3H)。一個質子缺失或浸沒。 460 E   
I-1999
Figure 02_image4287
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(CN3CCCCC3=O)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.42 - 9.40 (m, 1H), 9.36-9.18 (m, 1H), 8.57 (s, 1H), 8.10-8.03 (m, 2H), 7.97 (d, J = 9.3 Hz, 1H), 7.64 (s, 2H), 7.30 (td, J = 8.3, 3.1 Hz, 1H), 6.51 (br. s, 1H), 6.23 (br. s, 1H), 4.40 (d, J = 15.3 Hz, 1H), 4.07 (d, J = 15.3 Hz, 1H), 3.23-3.05 (m, 1H), 3.05-2.83 (m, 1H), 2.28-2.21 (m, 2H), 1.85-1.55 (m, 4H) 490.2 E   
I-2000
Figure 02_image4289
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)CC#N)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.45 (s, 1H), 9.24 (br s, H), 8.57 (s, 1H), 8.15-8.05 (m, 2H), 7.97 (d, J = 9.2 Hz, 1H), 7.81 (s, 1H), 7.66-7.44 (m, 1H), 7.25 (td, J = 8.4, 3.0 Hz, 1H), 6.68 (br s, 1H), 6.03 (br s, 1H), 3.66 (d, J = 18.6 Hz, 1H), 3.52 (d, J = 18.6 Hz, 1H)。醯胺NH缺失/浸沒。 461 E   
I-2001
Figure 02_image4291
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(N(CC(=O)N3CCCCC3)C(=O)C(F)(F)F)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6 )  11.47 (s, 1H), 9.98 (s, 1H), 9.58 (s, 1H), 9.40 (br s, 1H), 8.92 (dd, J = 9.4, 1.3 Hz, 1H), 8.56 (d, J = 9.4 Hz, 1H), 8.35 (s, 1H), 8.10 (s, 1H), 7.68-7.39 (m, 1H), 7.27 (td, J = 8.4, 3.1 Hz, 1H), 6.07 (br s, 1H), 5.72 (s, 2H), 3.57-3.40 (m, 4H), 1.75-1.58 (m, 4H), 1.56-1.39 (m,  2H)。 615 E   
I-2002
Figure 02_image4293
 FC(F)c1cc(ccn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz) δ 10.66 (s, 1H), 9.21-9.41 (m, 1H), 8.81 (d, J = 5.1 Hz, 1H), 8.17 (d, J = 1.3 Hz, 1H), 8.12 (s, 1H), 8.07 (br d, J = 5.3 Hz, 1H), 8.02 (s, 1H), 7.98 (br d, J = 8.6 Hz, 1H), 7.78 (br d, J = 9.1 Hz, 1H), 7.71 (s, 1H), 7.34 (dd, J = 9.0, 5.2 Hz, 1H), 6.90-7.20 (m, 2H), 6.39-6.71 (m, 1H), 5.92-6.26 ppm (m, 1H)。 594.2 D   
I-2003
Figure 02_image4295
 FC(F)c1cc(ccn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz) δ 10.66 (s, 1H), 9.21-9.41 (m, 1H), 8.81 (d, J = 5.1 Hz, 1H), 8.17 (d, J = 1.3 Hz, 1H), 8.12 (s, 1H), 8.07 (br d, J = 5.3 Hz, 1H), 8.02 (s, 1H), 7.98 (br d, J = 8.6 Hz, 1H), 7.78 (br d, J = 9.1 Hz, 1H), 7.71 (s, 1H), 7.34 (dd, J = 9.0, 5.2 Hz, 1H), 6.90-7.20 (m, 2H), 6.39-6.71 (m, 1H), 5.92-6.26 ppm (m, 1H)。 594.4 A   
I-2004
Figure 02_image4297
 FC(F)c1ccc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz) δ 10.66 (s, 1H), 9.28 (br s, 1H), 9.13 (d, J = 2.0 Hz, 1H), 8.43 (dd, J = 8.1, 2.3 Hz, 1H), 8.10 (d, J = 1.3 Hz, 1H), 7.97 (br d, J = 8.6 Hz, 1H), 7.93 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.77 (br d, J = 9.1 Hz, 1H), 7.70 (s, 1H), 7.34 (dd, J = 8.8, 5.3 Hz, 1H), 6.90-7.22 (m, 2H), 6.46-6.84 (m, 1H), 5.85-6.25 ppm (m, 1H)。 594.2 D   
I-2005
Figure 02_image4299
 C[C@H](Oc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)C#N    536.1 D   
I-2006
Figure 02_image4301
 C[C@@H](Oc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)C#N    536.1 A   
I-2007
Figure 02_image4303
 C[C@H](Oc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)C#N    536.1 D   
I-2008
Figure 02_image4305
 FC(F)c1ccc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (DMSO-d6, 400 MHz): δ = 10.66 (s, 1H), 9.28 (br s, 1H), 9.13 (d, J = 2.0 Hz, 1H), 8.43 (dd, J = 8.1, 2.3 Hz, 1H), 8.10 (d, J = 1.3 Hz, 1H), 7.97 (br d, J = 8.6 Hz, 1H), 7.93 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.77 (br d, J = 9.1 Hz, 1H), 7.70 (s, 1H), 7.34 (dd, J = 8.8, 5.3 Hz, 1H), 6.90-7.22 (m, 2H), 6.46-6.84 (m, 1H), 5.85-6.25 ppm (m, 1H)。 594.5 A   
I-2009
Figure 02_image4307
 C[C@@H](Oc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl)C#N    536.1 A   
I-2010
Figure 02_image4309
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC3CCS(=O)(=O)CC3)c12)-c1ccc2ncnn2c1    526 E   
I-2012
Figure 02_image4311
 [2H]c1nc2cnc(cn2n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.69 (s, 1H), 9.92 (s, 1H), 9.54 (s, 1H), 9.26 (s, 1H), 8.48 (s, 1H), 8.35 (s, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.71 (s, 1H), 7.37 - 7.30 (m, 1H), 7.11 (d, J = 8.7 Hz, 1H), 6.39 (br s, 1H)。 586.15 A   
I-2013
Figure 02_image4313
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Br)cc(N[C@@H]3CCOc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.08 (s, 0H), 7.49 (dd, J = 8.9, 5.1 Hz, 1H), 7.33-7.22 (m, 2H), 7.19-7.12 (m, 2H), 7.06 (ddd, J = 6.7, 4.8, 1.7 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 6.76 (dd, J = 8.3, 1.2 Hz, 2H), 5.89 (s, 1H), 5.10 (d, J = 7.5 Hz, 1H), 4.74 (dt, J = 9.3, 4.7 Hz, 1H), 4.00 (ddd, J = 10.2, 5.9, 3.3 Hz, 1H), 3.53-3.43 (m, 1H), 1.83 (tq, J = 8.0, 3.7 Hz, 1H), 1.63 (d, J = 14.6 Hz, 1H)。 486.9 E   
I-2014
Figure 02_image4315
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Br)cc(N[C@H]3CCOc4ccccc34)c12 1H NMR (400 MHz, DMSO-d6) 9.08 (s, 0H), 7.49 (dd, J = 8.9, 5.1 Hz, 1H), 7.33-7.22 (m, 2H), 7.19-7.12 (m, 2H), 7.06 (ddd, J = 6.7, 4.8, 1.7 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 6.76 (dd, J = 8.3, 1.2 Hz, 2H), 5.89 (s, 1H), 5.10 (d, J = 7.5 Hz, 1H), 4.74 (dt, J = 9.3, 4.7 Hz, 1H), 4.00 (ddd, J = 10.2, 5.9, 3.3 Hz, 1H), 3.53-3.43 (m, 1H), 1.83 (tq, J = 8.0, 3.7 Hz, 1H), 1.63 (d, J = 14.6 Hz, 1H)。 486.9 E   
I-2015
Figure 02_image4317
 [2H]c1nc2ccc(-c3cc4C(=O)NC(c4c(NC(=O)c4cc(F)cc(c4)C(F)(F)F)c3)c3cc(F)ccc3Cl)c(C#N)n2n1 1H NMR (400 MHz, DMSO-d6) 10.72 (d, J = 2.1 Hz, 1H), 9.35 (s, 1H), 8.34 (s, 1H), 8.08 (s, 1H), 7.96 (s, 2H), 7.85 (dd, J = 9.3, 1.9 Hz, 1H) , 7.69 (s, 1H), 7.38 (s, 1H), 7.22 (s, 1H), 7.14 (s, 1H), 6.64-7.08 (d, J = 9.3 Hz , 1H), 6.10 (br s, 1H)。 610 A   
I-2016
Figure 02_image4319
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(c12)-n1ccc2c(F)cc(cc2c1=O)C(F)(F)F)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.57 (d, J = 25.7 Hz, 1H), 9.37 (s, 1H), 8.58 (d, J = 4.1 Hz, 1H), 8.36 (d, J = 10.4 Hz, 2H), 8.29 - 8.07 (m, 3H), 7.99 (dd, J = 9.4, 6.2 Hz, 1H), 7.87 (s, 1H), 7.11 (dd, J = 134.1, 73.8 Hz, 3H), 6.52 (d, J = 7.7 Hz, 1H), 6.08 - 5.69 (m, 1H)。 608.1 D   
I-2017
Figure 02_image4321
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(COc3ccccc3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.49 (s, 1H), 9.29 (s, 1H), 8.57 (s, 1H), 8.22 - 8.12 (m, 3H), 7.98 (d, J = 9.3 Hz, 1H), 7.46 (s, 1H), 7.24 (t, J = 7.8 Hz, 2H), 7.19 (s, 1H), 6.92 (t, J = 7.3 Hz, 1H), 6.81 (d, J = 8.0 Hz, 2H), 6.57 (s, 1H), 6.27 (s, 1H), 4.91 (d, J = 11.4 Hz, 1H), 4.83 (s, 1H)。 485.15 E   
I-2018
Figure 02_image4323
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(N3CCn4ncnc4C3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6 )  9.57 (dd, J = 1.7, 0.8 Hz, 1H), 9.32-9.22 (m, 1H), 8.57 (s, 1H), 8.20 (dd, J = 9.3, 1.8 Hz, 1H), 7.97 (dd, J = 9.3, 0.6 Hz, 1H), 7.92 (s, 1H), 7.90 (d, J = 1.3 Hz, 1H), 7.81 (d, J = 1.3 Hz, 1H), 7.44 (dd, J = 8.8, 5.1 Hz, 1H), 7.21-7.15 (m, 1H), 6.85 (br s, 1H), 6.30 (s, 1H), 4.56 (d, J = 15.9 Hz, 1H), 4.09 (d, J = 15.9 Hz, 1H), 3.93-3.81 (m, 1H), 3.79-3.64 (m, 1H), 3.39-3.27 (m, 1H)。 501 E   
I-2019
Figure 02_image4325
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(N3CCn4cnnc4C3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.59-9.56 (m, 1H), 9.25 (s, 1H), 8.57 (s, 1H), 8.41 (s, 1H), 8.20 (dd, J = 9.3, 1.8 Hz, 1H), 7.99-7.95 (m, 1H), 7.89 (d, J = 1.3 Hz, 1H), 7.79 (d, J = 1.1 Hz, 1H), 7.44 (dd, J = 8.7, 5.4 Hz, 1H), 7.19 (ddd, J = 11.0, 6.8, 2.3 Hz, 1H), 6.75 (br s, 1H), 6.30 (s, 1H), 4.58 (d, J = 15.4 Hz, 1H), 4.15 (d, J = 15.5 Hz, 1H), 3.81-3.74 (m, 1H), 3.72-3.65 (m, 1H), 3.64- 3.56 (m, 1H), 3.27-3.20 (浸沒m, 1H)。 501 E   
I-2020
Figure 02_image4327
 CN1CCC=C(C1)c1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.59-9.47 (m, 1H), 9.25 (br s, 1H), 8.56 (s, 1H), 8.19 (d, J = 9.3 Hz, 1H), 8.06 (s, 1H), 8.02-7.84 (m, 1H), 7.70-7.42 (m, 1H), 7.24 (td, J = 8.4, 2.8 Hz, 1H), 6.41 (br s, 1H), 6.29 (br s, 1H), 5.86 (s, 1H), 3.42 (br d, J = 16.1 Hz, 1H), 2.24-2.08 (m, 2H), 2.04 (s, 3H), 2.04-1.93 (m, 1H), 1.90-1.72 (m, 1H), 1.63-1.47 (m, 1H)。 474 E   
I-2021
Figure 02_image4329
 CN1CCC(=CC1)c1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1    474 E   
I-2022
Figure 02_image4331
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(OCC#N)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.52 (br, s, 1H), 9.25 (br, s, 1H), 8.59 (s, 1H), 8.19 (dd, J = 9.3, 1.9 Hz, 1H), 8.00 (dd, J = 9.3, 0.8 Hz, 1H), 7.88 (d, J = 1.2 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.57 (dd, J = 8.8, 5.2 Hz, 1H), 7.28-7.22 (m, 1H), 6.87 (br, s, 1H), 6.10 (s, 1H), 5.27 (s, 2H)。 434 E   
I-2023
Figure 02_image4333
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(N[C@@H]3CCCNC3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.43 (s, 1H), 9.06 (s, 1H), 8.55 (s, 1H), 8.11 (d, J = 9.1 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.56 (dd, J = 8.3, 5.0 Hz, 1H), 7.38 (s, 1H), 7.32-7.22 (m, 2H), 6.87 (br s, 1H), 5.96 (s, 1H), 4.54 (d, J = 7.7 Hz, 1H), 3.93-3.70 (m, 1H), 3.28-3.07 (m, 1H), 2.99-2.74 (m, 1H), 2.72-2.53 (m, 1H), 1.61-1.17 (m, 4H)。 477 E   
I-2024
Figure 02_image4335
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC3CCNCC3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.41 (s, 1H), 9.06 (s, 1H), 8.57 (s, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.67-7.51 (m, 1H), 7.39 (s, 1H), 7.34-7.19 (m, 2H), 6.82 (br s, 1H), 5.97 (s, 1H), 4.55-4.24 (m, 1H), 3.92-3.55 (m, 1H), 3.49-2.54 (m, 3H), 1.77-0.99 (m, 4H)。 477 E   
I-2025
Figure 02_image4337
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3ccncc3)c12 1H NMR (400 MHz, DMS)-d6)  9.23 (s, 1H), 8.47 (br. s, 1H), 8.07 (br. s, 2H), 7.68 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 7.05 (td, J = 8.4, 3.1 Hz, 1H), 6.62 (br. s, 1H), 6.45 (d, J = 4.2 Hz, 2H), 5.86 (s, 1H) 432 E   
I-2026
Figure 02_image4339
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(Cn3ccc4ccccc4c3=O)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6 )  9.38 (s, 1H), 8.54 (s, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 1.1 Hz, 1H), 7.99 (dd, J = 9.3, 1.5 Hz, 1H), 7.92 (dd, J = 9.3, 0.6 Hz, 1H), 7.75 (br. s, 1H), 7.72-7.65 (m, 1H), 7.65-7.58 (m, 1H), 7.59-7.51 (m, 1H), 7.52-7.44 (m, 1H), 7.39 (br. s, 1H), 7.12 (br. s, 1H), 6.60 (d, J = 7.4 Hz, 1H), 6.56-6.27 (m, 1H), 5.54 (m, 2H), 4.94 (dd, J = 34.6, 15.0 Hz, 2H) 536.2 E   
I-2027
Figure 02_image4341
 O[C@@H]1C[C@@H](C[C@@H](C1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)，呈非對映異構體之約1:1混合物形式, 9.94 (br. s, 1H), 9.83 (br. s, 1H), 9.25 (br. s, 2H), 7.71 (s, 2H), 7.61 (d, J = 1.4 Hz, 1H), 7.55 (d, J = 0.9 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.22 - 7.16 (m, 2H), 6.51 (br. s, 2H), 6.01 (br. s, 2H), 4.90 - 4.87 (m, 2H), 3.47 - 3.38 (m, 2H), 2.40 - 2.29 (m, 3H), 2.24 - 2.13 (m, 2H), 1.96 - 1.89 (m, 1H), 1.77 - 1.69 (m, 1H), 1.62 - 1.54 (m, 1H), 1.54 - 1.46 (m, 1H), 1.10 - 0.80 (m, 6H)。 549.1 E   
I-2028
Figure 02_image4343
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)[C@H]3CCC[C@H](C3)C(F)(F)F)c12)-c1ccc2ncnn2c1    588.5 D   
I-2029
Figure 02_image4345
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)[C@H]3CCC[C@H](C3)C(F)(F)F)c12)-c1ccc2ncnn2c1    588.5 A A
I-2030
Figure 02_image4347
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)[C@@H]3CCC[C@@H](C3)C(F)(F)F)c12)-c1ccc2ncnn2c1    588.5 C   
I-2031
Figure 02_image4349
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)[C@@H]3CCC[C@@H](C3)C(F)(F)F)c12)-c1ccc2ncnn2c1    588.5 D   
I-2032
Figure 02_image4351
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)[C@@H]3CCC[C@H](C3)C(F)(F)F)c12)-c1ccc2ncnn2c1    588.5 D   
I-2033
Figure 02_image4353
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)[C@H]3CCC[C@@H](C3)C(F)(F)F)c12)-c1ccc2ncnn2c1    588.5 D   
I-2034
Figure 02_image4355
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)[C@@H]3CCC[C@H](C3)C(F)(F)F)c12)-c1ccc2ncnn2c1    588.5 A A
I-2035
Figure 02_image4357
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)[C@H]3CCC[C@@H](C3)C(F)(F)F)c12)-c1ccc2ncnn2c1    588.5 A   
I-2036
Figure 02_image4359
 [H][C@]1(CCCCC1=O)[C@@H]1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.60 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 8.09 (d, J = 9.1 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 7.4, 1.4 Hz, 1H), 7.60-7.51 (m, 2H), 5.43 (s, 1H), 2.93 (dd, J = 11.8, 5.1 Hz, 1H), 2.35-2.20 (m, 2H), 1.95-1.83 (m, 1H), 1.70-1.60 (m, 1H), 1.53-1.38 (m, 2H), 1.27-1.11 (m, 1H), 1.07-0.97 (m, 1H)。 435.3 E   
I-2037
Figure 02_image4361
 COC1CCCC(C1)C(=O)Nc1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.82 (s, 1H), 9.45-9.41 (m, , 1H), 9.20 (s, 1H), 8.57 (s, 1H), 8.09 (dd, J = 9.3, 1.8 Hz, 1H), 8.01-7.93 (m, 2H), 7.80 (dd, J = 6.6, 1.6 Hz, 1H), 7.56-7.48 (m, 1H), 7.31-7.16 (m, 1H), 6.73 (br s, 1H), 6.12 (s, 1H), 3.21 (s, 3H), 3.08-2.94 (m, 1H), 2.16-2.03 (m, 1H), 1.99-1.80 (m, 1.5H), 1.76-1.59 (m, 1.5H), 1.49-0.83 (m, 5H)。非對映異構體之1:1混合物(報導一種)；approx. 534.2 E   
I-2038
Figure 02_image4363
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NCC(=O)N3CCCCC3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.28 (s, 1H), 8.54 (s, 1H), 8.00 (d, J = 9.2, 1.5 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.68 (dd, J = 10.3, 5.1 Hz, 1H), 7.50-7.13 (m, 4H), 6.49 (d, J = 7.6 Hz, 1H), 6.07 (br. s, 1H), 5.05 - 4.92 (m, 2H), 4.94 (s, 1H), 4.63 (d, J = 17.1 Hz, 1H), 3.62-3.47 (m, 2H), 3.27-3.18 (浸沒m, 2H), 1.62-1.38 (m, 6H) 519.2 E   
I-2039
Figure 02_image4365
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(N3CCn4cc(nc4C3)C(F)(F)F)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.55 (dd, J = 1.8, 0.9 Hz, 1H), 9.23 (br s, 1H), 8.57 (s, 1H), 8.19 (dd, J = 9.3, 1.8 Hz, 1H), 7.96 (dd, J = 9.3, 0.7 Hz, 1H), 7.88 (d, J = 1.4 Hz, 1H), 7.76 (d, J = 1.3 Hz, 1H), 7.70 (d, J = 1.3 Hz, 1H), 7.43 (dd, J = 8.8, 5.2 Hz, 1H), 7.18 (ddd, J = 8.8, 8.0, 3.1 Hz, 1H), 6.72 (br s, 1H), 6.29 (br s, 1H), 4.48 (d, J = 15.6 Hz, 1H), 4.05 (d, J = 15.5 Hz, 1H), 3.77 (dd, J = 13.9, 6.4 Hz, 1H), 3.69-3.59 (m, 2H), 3.30-3.23 (浸沒m, 1H)。 568 E   
I-2040
Figure 02_image4367
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(N3CCn4c(C3)nnc4C(F)(F)F)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.57 (dd, J = 1.7, 0.8 Hz, 1H), 9.23 (br s, 1H), 8.57 (s, 1H), 8.20 (dd, J = 9.3, 1.8 Hz, 1H), 7.97 (dd, J = 9.3, 0.7 Hz, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.83 (d, J = 1.4 Hz, 1H), 7.37 (dd, J = 8.9, 5.1 Hz, 1H), 7.19-7.13 (m, 1H), 6.76 (br s, 1H), 6.27 (br s, 1H), 4.68 (d, J = 15.9 Hz, 1H), 4.17 (d, J = 15.9 Hz, 1H), 4.02-3.90 (m, 1H), 3.64 (q, J = 6.5 Hz, 2H), 3.40-3.34 (浸沒m, 1H)。 569 E   
I-2041
Figure 02_image4369
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(C(=O)N3CCCCC3)c12 NMR (400 MHz, DMSO-d6)  10.77 (br. s, 1H), 9.08 (s, 1H), 8.14 (s, 1H), 8.08 (br. d, J = 9.2 Hz, 1H), 8.04 (br. d, J = 8.5 Hz, 1H), 7.62-7.52 (m, 3H), 5.74 (s, 1H), 3.52-3.43 (m, 1H), 3.37-3.28 (浸沒m, 2H), 3.13-3.04 (m, 1H), 1.50-1.38 (m, 2H), 1.35-1.24 (m, 3H), 0.91-0.80 (m, 1H)。 450.2 E   
I-2042
Figure 02_image4371
 NC1CN(C(=O)Nc2cc(Br)cc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccccc12 1H NMR (400 MHz, DMSO-d6)  9.21 (s, 1H), 8.70 (d, J = 51.2 Hz, 1H), 7.78 - 7.56 (m, 3H), 7.43 - 7.33 (m, 2H), 7.17 (dddt, J = 16.9, 11.7, 8.6, 5.4 Hz, 2H), 7.05 - 6.95 (m, 1H), 6.70 (s, 1H), 6.08 - 5.85 (m, 1H), 4.46 (t, J = 7.3 Hz, 1H), 4.00 (dd, J = 10.8, 9.0 Hz, 1H), 3.76 - 3.64 (m, 1H), 3.52 (dd, J = 10.9, 5.8 Hz, 1H), 3.07 - 2.90 (m, 1H)。 515.05 D   
I-2043
Figure 02_image4373
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(OC3CCOc4ccccc34)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  9.56 (br, s, 1H), 9.13 (s, 1H), 8.58 (s, 1H), 8.23-8.18 (m, 1H), 7.97 (dd, J = 9.3, 0.7 Hz, 1H), 7.91 (d, J = 15.1 Hz, 1H), 7.75 (dd, J = 6.9, 1.2 Hz, 1H), 7.41 (dd, J = 8.9, 5.2 Hz, 0.6H), 7.29 (dd, J = 7.6, 1.6 Hz, 0.6H), 7.27-7.20 (m, 1.2H), 7.15 (ddd, J = 9.8, 3.9, 1.6 Hz, 1H), 7.10-7.04 (m, 0.4H), 6.90 (td, J = 7.5, 1.1 Hz, 0.6H), 6.83-6.79 (m, 1H), 6.77 (浸沒s, 1H), 6.73 (dd, J = 8.2, 0.9 Hz, 1H), 6.61 (td, J = 7.4, 1.1 Hz, 0.4H), 6.45 (dd, J = 7.6, 1.5 Hz, 0.4H), 5.96 (s, 0.4H), 5.87 (s, 0.6H), 5.84 (t, J = 2.9 Hz, 0.6H), 5.77 (m, 0.4H), 4.21 (m, 1H), 3.86 (m, 0.6H), 3.03 (m, 0.4H), 2.22 (m, 1H), 1.93 (m, 0.6H), 1.72 (m, 0.4H) 527 E   
I-2044
Figure 02_image4375
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)CC3(CC3)C(F)(F)F)c12)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)  9.88 (br. s, 1H), 9.43 (dd, J = 1.7, 0.8 Hz, 1H), 9.20 (br. s, 1H), 8.57 (s, 1H), 8.08 (dd, J = 9.3, 1.8 Hz, 1H), 8.01 (d, J = 1.5 Hz, 1H), 7.97 (dd, J = 9.3, 0.8 Hz, 1H), 7.89 (d, J = 1.5 Hz, 1H), 7.52 (dd, J = 8.0, 4.8 Hz, 1H), 7.24 (ddd, J = 8.7, 8.1, 3.1 Hz, 1H), 6.66 (br. s, 1H), 6.11 (s, 1H), 2.49-2.46 (m, 1H), 2.29 (d, J = 15.3 Hz, 1H), 0.93-0.88 (m, 1H), 0.85-0.78 (m, 3H)。多重峰2.49-2.46係被DMSO峰部分遮蔽之二重峰。 544.3 D   
I-2045
Figure 02_image4377
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3CCS(=O)(=O)CC3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO-d6)  10.17-10.01 (m, 1H), 9.44 (d, J = 0.7 Hz, 1H), 9.24 (br s, 1H), 8.57 (s, 1H), 8.10 (dd, J = 9.3, 1.8 Hz, 1H), 8.03 (d, J = 1.5 Hz, 1H), 7.98 (d, J = 9.3 Hz, 1H), 7.82 (s, 1H), 7.58-7.46 (m, 1H), 7.25 (td, J = 8.4, 3.1 Hz, 1H), 6.56 (br s, 1H), 6.16 (br s, 1H), 3.20-3.07 (m, 2H), 3.07-2.95 (m, 2H), 2.48-2.38 (m, 1H), 1.96-1.74 (m, 3H), 1.73-1.62 (m, 1H)。 554 E   
I-2046
Figure 02_image4379
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(N3CCN(CC3)C(=O)C(F)(F)F)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  9.51 (dd, J = 1.7, 0.8 Hz, 1H), 9.24 (s, 1H), 8.56 (s, 1H), 8.17 (dd, J = 9.3, 1.8 Hz, 1H), 7.95 (dd, J = 9.3, 0.6 Hz, 1H), 7.87 (d, J = 1.4 Hz, 1H), 7.72 (d, J = 1.3 Hz, 1H), 7.58 (dd, J = 8.3, 5.1 Hz, 1H), 7.27 (ddd, J = 8.9, 8.0, 3.1 Hz, 1H), 6.79 (br. s, 1H), 6.19 (s, 1H), 3.51-3.37 (m, 3H), 3.29-3.14 (m, 3H), 2.89-2.77 (m, 1H), 2.79-2.68 (m, 1H) 559.2 E   
I-2047
Figure 02_image4381
 CC(=O)N1CCN(CC1)c1cc(cc2C(=O)NC(c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)    9.50 (d, J = 0.8 Hz, 1H), 9.24 (s, 1H), 8.56 (s, 1H), 8.16 (dd, J = 9.3, 1.8 Hz, 1H), 7.95 (d, J = 9.3 Hz, 1H), 7.82 (d, J = 1.4 Hz, 1H), 7.62 (d, J = 1.4 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.27 (ddd, J = 8.71, 7.03, 3.10 Hz, 1H ), 6.74 (br. s, 1H), 6.20 (s, 1H), 3.29-3.04 (m, 6H), 2.85-2.68 (m, 1H), 2.71-2.57 (m, 1H), 1.98 (s, 3H)；3.29-3.04 6H處之多重峰與殘餘水峰重疊 505.2 E   
I-2048
Figure 02_image4383
 FC(F)n1cc(cn1)-c1cc2C(=O)NC(c2c(c1)-c1nc2cc(cc(F)c2[nH]1)C(F)(F)F)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 9.31 (s, 1H), 8.98 (s, 1H), 8.71 (s, 1H), 8.52 (s, 1H), 8.23 (s, 1H), 8.07-7.77 (m , 1H), 7.63 (s, 1H), 7.37 (s, 1H), 7.28 (d, J = 10.6 Hz, 1H), 6.95 (td, J = 8.4, 3.1 Hz, 1H), 6.70 (s, 1H), 1.23 (s, 1H)。 580 D   
I-2049
Figure 02_image4385
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(Nc3n[nH]c4c(cc(F)cc34)C(F)(F)F)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6)  12.89 (s, 1H), 9.41 (d, J = 1.7 Hz, 1H), 9.11 (s, 1H), 8.59 (d, J = 6.7 Hz, 2H), 8.10 (dd, J = 9.3, 1.8 Hz, 1H), 8.05 - 7.96 (m, 2H), 7.78 (d, J = 1.6 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.19 (dd, J = 8.8, 5.2 Hz, 1H), 7.00 (td, J = 8.4, 3.1 Hz, 1H), 6.55 (s, 1H), 6.03 (s, 1H)。 596.15 A   
I-2050
Figure 02_image4387
 Cn1nc(Nc2cc(cc3C(=O)NC(c23)c2cc(F)ccc2Cl)-c2ccc3ncnn3c2)c2cc(F)cc(c12)C(F)(F)F 1H NMR (400 MHz, DMSO-d6)  9.37 (d, J = 1.4 Hz, 1H), 9.13 (s, 1H), 8.55 (s, 1H), 8.36 (s, 1H), 8.06 - 7.99 (m, 1H), 7.93 (d, J = 9.3 Hz, 1H), 7.76 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.45 (dd, J = 9.0, 5.2 Hz, 1H), 7.31 (s, 1H), 7.21 (td, J = 8.3, 3.1 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.64 (s, 1H), 5.61 (s, 1H), 3.65 (s, 3H)。 610.2 C   
I-2051
Figure 02_image4389
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)C3CNCC(C3)C(F)(F)F)c12)-c1ccc2ncnn2c1 1H-NMR (400 MHz, DMSO-d6)，呈非對映異構體之約3:2:1:1混合物形式；對於主要非對映異構體  10.15 (br. s, 1H), 9.44 (s, 1H), 9.23 (br. s, 1H), 8.58 (s, 1H), 8.12-8.08 (m, 1H), 8.06-7.96 (m, 3H), 7.58-7.49 (m, 1H), 7.27-7.20 (m, 1H), 6.57 (br. s, 1H), 6.19 (br. s, 1H), 6.16 (br. s, 1H), 2.87-2.77 (m, 1H), 2.62-2.47 (m, 2H), 2.44-2.37 (m, 1H), 2.31-2.09 (m, 2H), 1.95-1.82 (m, 1H), 1.63-1.53 (m, 1H)。 573.3 E   
I-2052
Figure 02_image4391
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H](C3CCCCC3)c12 NMR (400 MHz, DMSO-d6)  10.74 (br. s, 1H), 8.74 (s, 1H), 8.13 (s, 1H), 8.08 (br. d, J = 9.0 Hz, 1H), 8.04 (br. d, J = 8.5 Hz, 1H), 7.62-7.49 (m, 3H), 4.73 (d, J = 1.3 Hz, 1H), 1.90-1.80 (m, 1H), 1.73-1.64 (m, 1H), 1.59 - 1.50 (m, 3H), 1.39-1.27 (m, 1H), 1.06-0.86 (m, 3H), 0.79-0.61 (m, 2H)。 421.2 D   
I-2053
Figure 02_image4393
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@H](C3CCCCC3)c12 NMR (400 MHz, DMSO-d6)  10.74 (br. s, 1H), 8.74 (s, 1H), 8.13 (s, 1H), 8.08 (br. d, J = 9.0 Hz, 1H), 8.04 (br. d, J = 8.5 Hz, 1H), 7.62-7.49 (m, 3H), 4.73 (d, J = 1.3 Hz, 1H), 1.90-1.80 (m, 1H), 1.73-1.64 (m, 1H), 1.59 - 1.50 (m, 3H), 1.39-1.27 (m, 1H), 1.06-0.86 (m, 3H), 0.79-0.61 (m, 2H)。 421.2 E   
I-2054
Figure 02_image4395
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(C(=O)NC3CCCCC3)c12 NMR (400 MHz, DMSO-d6 )  11.33 (s, 1H), 8.94 (d, J = 0.6 Hz, 1H), 8.27 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.17 (br. d, J = 9.3 Hz, 1H), 8.12 (dd, J = 7.6, 1.0 Hz, 1H), 8.04 (br. d, J = 8.7 Hz, 1H), 7.57 (d, J = 7.7 Hz), 7.53 (dd, J = 7.5, 1.2 Hz), 5.43 (d, J = 0.9 Hz, 1H), 3.56-3.41 (m, 1H), 1.62 - 1.46 (m, 4H), 1.24-1.10 (m, 4H), 1.09-0.93 (m, 2H)。2種旋轉異構體之9:1混合物。 464.1 E   
I-2055
Figure 02_image4397
 FC(F)S(=O)(=O)n1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.59 (s, 1 H), 9.27 (s, 1 H), 9.22 (br s, 1 H), 8.90 (s, 1 H), 8.23 (s, 1 H), 7.97 (重疊的s, 1 H), 7.97 (重疊的d, J = 10.8 Hz, 1 H), 7.76 (d, J = 9.0 Hz, 1 H), 7.73 (s, 1 H), 7.73 (t, J = 51.4 Hz, 1 H), 7.32 (dd, J = 8.9, 5.2 Hz, 1 H), 7.10 (td, J = 8.5, 3.0 Hz, 1 H), 6.60 (br s, 1 H), 6.01 (br s, 1 H)。 645.2 A   
I-2056
Figure 02_image4399
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(Nc3cn[nH]c3)c12 1H NMR (400 MHz, DMSO-d6)  12.75 (s, 1H), 9.09 (s, 1H), 7.59 (br. s, 1H), 7.51 (dd, J = 8.8, 5.2 Hz, 1H), 7.23 (ddd, J = 8.8, 8.0, 3.1 Hz, 2H), 7.15 (d, J = 1.6 Hz, 1H), 6.98 - 6.94 (m, 2H), 6.68 (br. s, 1H), 5.82 (s, 1H) 421 E   
I-2057
Figure 02_image4401
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@H](CC3CCCCC3)c12 NMR (400 MHz, DMSO-d6)  10.78 (s, 1H), 8.91 (s, 1H), 8.17 (s, 1H), 8.12 (d, J = 9.0 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.60-7.50 (m, 3H), 4.83 (br, d, J = 8.0 Hz, 1H), 1.83-1.66 (m, 2H), 1.57-1.37 (m, 5H), 1.18-0.90 (m, 4H), 0.81-0.58 (m, 2H)。 435 D   
I-2058
Figure 02_image4403
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H](CC3CCCCC3)c12 NMR (400 MHz, DMSO-d6)  10.78 (s, 1H), 8.91 (s, 1H), 8.17 (s, 1H), 8.12 (d, J = 9.0 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.60-7.50 (m, 3H), 4.83 (br, d, J = 8.0 Hz, 1H), 1.83-1.66 (m, 2H), 1.57-1.37 (m, 5H), 1.18-0.90 (m, 4H), 0.81-0.58 (m, 2H)。 435 C   
I-2059
Figure 02_image4405
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(Nc3nnc4CCCCn34)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6 )  9.32 (s, 1H), 8.92 (s, 1H), 8.52 (s), 8.22 (br. s, 1H), 8.04 (dd, J = 9.4, 1.4 Hz, 1H), 7.95 (d, J = 9.3 Hz, 1H), 7.81 - 7.70 (m, 2H), 7.44 (dd, J = 8.9, 5.2 Hz, 1H), 7.20 (td, J = 8.7, 2.9 Hz, 1H), 6.46 (d, J = 8.6 Hz, 1H), 5.92 (s, 1H), 3.53-3.40 (m, 1H), 2.92-2.79 (m, 1H), 2.77-2.69 (m, 2H), 1.87-1.63 (m, 4H)。 515.3 E   
I-2060
Figure 02_image4407
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(C3CCCCC3=O)c12 (400 MHz, DMSO-d6)  10.62 (br s, 0.65H), 10.37 (s, 0.35H), 8.55 (s, 0.35H), 8.25 (s, 0.65H), 8.15 (s, 0.35H), 8.13 (s, 0.65H), 8.10 (d, J = 10.4, 1.4 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.61 (td, J = 7.3, 1.1 Hz, 1H), 7.57-7.48 (m, 2H), 5.43 (s, 0.65H), 5.11 (d, J = 1.2 Hz, 0.35H), 2.97-2.89 (m, 0.65H), 2.84-2.77 (m, 0.35H), 2.30-2.19 (m, 1.3H), 1.96-1.78 (m, 1H), 1.76 - 1.56 (m, 2H), 1.53-1.39 (m, 2H), 1.38-1.27 (m, 0.35H), 1.25-1.11 (m, 1H), 1.07-0.97 (m, 0.65H)   [約2:1比率之非對映異構體]。 435.2 E   
I-2061
Figure 02_image4409
 FC(F)COc1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl       D   
I-2062
Figure 02_image4411
 FC(F)COc1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    547.1 A   
I-2063
Figure 02_image4413
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)-c1ccc2ncnn2c1C#N    576.2 C   
I-2064
Figure 02_image4415
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)-c1ccc2ncnn2c1C#N    576.2 A   
I-2065
Figure 02_image4417
 FC(F)c1cn2cc(ncc2n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl       A   
I-2066
Figure 02_image4419
 [2H]c1nc2ccc(-c3cc4C(=O)N[C@H](c4c(NC(=O)c4cc(F)cc(c4)C(F)(F)F)c3)c3cc(F)ccc3Cl)c(C#N)n2n1    610.00 D   
I-2067
Figure 02_image4421
 [2H]c1nc2ccc(-c3cc4C(=O)N[C@@H](c4c(NC(=O)c4cc(F)cc(c4)C(F)(F)F)c3)c3cc(F)ccc3Cl)c(C#N)n2n1    610.00 A   
I-2068
Figure 02_image4423
 [2H]c1nc2cnc(cn2n1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    586.15 D   
I-2069
Figure 02_image4425
 [2H]c1nc2cnc(cn2n1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    586.15 A   
I-2070
Figure 02_image4427
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Br)cc(NC(=O)C3(CCCC3)c3cc(F)cc(c3)C(F)(F)F)c12       E   
I-2071
Figure 02_image4429
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(Br)cc(NC(=O)C3(CCCC3)c3cc(F)cc(c3)C(F)(F)F)c12       E   
I-2072
Figure 02_image4431
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@H](C3CCC(F)(F)CC3)c12    457.3 E   
I-2073
Figure 02_image4433
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H](C3CCC(F)(F)CC3)c12    457.3 E   
I-2074
Figure 02_image4435
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@H](c12)C12C[C@H]3C[C@H](C[C@H](C3)C1)C2    473.3 E   
I-2075
Figure 02_image4437
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H](c12)C12C[C@H]3C[C@H](C[C@H](C3)C1)C2    473.3 D   
I-2076
Figure 02_image4439
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(C3NC4CCC3C4)c12 NMR (400 MHz, DMSOd6)  8.98 (s, 1H), 8.48 (dd, J = 8.0, 1.0 Hz, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.43 (dd, J = 7.4, 1.0 Hz, 1H), 4.64 (d, J = 10.0 Hz, 1H), 3.21 (s, 1H), 2.79 (d, J = 3.5 Hz, 1H), 2.03 (d, J = 9.4 Hz, 1H), 1.66-1.47 (m, 2H), 1.29 (m, 4H)。 434.3 E   
I-2077
Figure 02_image4441
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(N3CCC(F)(F)CC3)c12 NMR (400 MHz, DMSO d6)  10.35 (s, 1H), 8.97 (s, 1H), 8.14 - 8.12 (m, 1H), 8.11 (dd, J = 7.9, 0.9 Hz, 2H), 8.11 - 8.07 (浸沒寬dt, J = 9.3, 2 Hz, 1H), 8.05 (寬dt, J = 8.5, 1.4 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.51 (dd, J = 7.5, 0.9 Hz, 1H), 5.72 (s, 1H), 2.69-2.57 (m, 2H), 2.45-2.34 (m, 2H), 1.93-1.77 (m, 2H), 1.70 (m, 2H)。 458.3 D   
I-2078
Figure 02_image4443
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC3CCCS(=O)(=O)C3)c12)-c1ccc2ncnn2c1 NMR (400 MHz, DMSO)  9.49-9.47 (m, 0.6H), 9.47-9.45 (m, 0.4H), 9.09 (s, 0.6H), 9.08 (s. 0.4H), 8.56 (s, 1H), 8.12 (d, J = 1.8 Hz, 0.4H), 8.09 (d, J = 1.8 Hz, 0.6H), 7.95 (s, 0.6H), 7.93 (s, 0.4H), 7.62-7.54 (m, 1H), 7.43 (d, J = 1.2 Hz, 0.4H), 7.42 (d, J = 1.1 Hz, 0.6H), 7.31-7.18 (m, 3H), 7.12 (s, 1H), 6.99 (s, 1H), 6.81 (br s, 1H), 5.93 (s, 0.4H), 5.91 (s, 0.6H), 4.67 (d, J = 8.8 Hz, 0.4H), 4.63 (d, J = 9.5 Hz, 0.6H), 4.27-4.09 (m, 1H), 3.55-3.45 (m, 0.6H), 3.21-2.91 (m, 3H), 2.77-2.68 (m, 0.4H), 2.08-1.60 (m, 3H), 1.56-1.29 (m, 1H)。非對映異構體之約3:2混合物。 526 E   
I-2079
Figure 02_image4445
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)[C@H]3CCC[C@H](C3)C(F)(F)F)c12 1H-NMR (400 MHz, DMSO-d6)，呈非對映異構體之約1:1混合物形式,  9.82 (br. s, 1H), 9.73 (br. s, 1H), 9.09 (br. s, 2H), 7.63-7.54 (m, 4H), 7.51-7.42 (m, 2H), 7.41-7.34 (m, 2H), 7.25-7.16 (m, 2H), 6.42 (br. s, 2H), 6.04 (br. s, 2H), 2.30-2.08 (m, 4H), 1.85-1.68 (m, 4H), 1.64-1.50 (m, 2H), 1.40-0.92 (m, 10H)。 455.3 C   
I-2080
Figure 02_image4447
 O[C@H]1C[C@@H](C[C@@H](C1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)，呈非對映異構體之約1:1混合物形式,  9.98 (br. s, 1H), 9.87 (br. s, 1H), 9.25 (br. s, 2H), 7.71 (d, J = 1.5 Hz, 1H), 7.70 (d, J = 1.5 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 1.5 Hz, 1H), 7.50-7.41 (m, 2H), 7.23-7.17 (m, 2H), 6.53 (br. s, 2H), 6.01 (br. s, 2H), 4.84 (d, J = 2.6 Hz, 1H), 4.80 (d, J = 2.8 Hz, 1H), 4.04 (br. s, 1H), 4.02 (br. s, 1H), 2.61-2.53 (m, 2H), 2.47-2.38 (m, 2H), 1.80-1.72 (m, 2H), 1.58-1.51 (m, 1H), 1.50-1.44 (m, 1H), 1.41-1.17 (m, 7H), 1.11-1.00 (m, 1H)。 549.1 D   
I-2081
Figure 02_image4449
 FC(F)n1cc(cn1)-c1cc(N[C@H]2CCOc3ccccc23)c2[C@H](NC(=O)c2n1)c1cc(F)ccc1Cl    526.1 D   
I-2082
Figure 02_image4451
 FC(F)n1cc(cn1)-c1cc(N[C@H]2CCOc3ccccc23)c2[C@@H](NC(=O)c2n1)c1cc(F)ccc1Cl    526.1 E   
I-2083
Figure 02_image4453
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cccc(NC(=O)[C@H]3CC[C@H](C3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) ä 9.80 (s, 1H), 9.08 (s, 1H), 7.61 (dd, J = 7.4, 1.4 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.46 (s, 1H), 7.39 (dd, J = 7.5, 1.5 Hz, 1H), 7.22 (ddd, J = 8.9, 8.0, 3.1 Hz, 1H), 6.51 (s, 1H), 6.05 (s, 1H), 2.83 (d, J = 8.3 Hz, 1H), 2.78 (d, J = 8.9 Hz, 1H), 1.84-1.56 (dt, J = 12.9, 7.8 Hz, 4H), 1.55-1.24 (d, J = 12.4 Hz, 2H)。 441.05 E   
I-2084
Figure 02_image4455
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cccc(NC(=O)[C@@H]3CC[C@@H](C3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)9.78 (s, 1H), 9.10-9.06 (m, 1H), 7.61 (dd, J = 7.4, 1.5 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.49 (s, 1H), 7.39 (dd, J = 7.4, 1.5 Hz, 1H), 7.22 (ddd, J = 8.8, 8.0, 3.1 Hz, 1H), 6.47 (s, 1H), 6.07 (s, 1H), 2.80 (h, J = 8.9 Hz, 1H), 2.63 (p, J = 8.3 Hz, 1H), 1.87-1.57 (dt, J = 12.9, 7.8 Hz, 4H), 1.55-1.24 (d, J = 12.4 Hz, 2H)。 441.05 E   
I-2085
Figure 02_image4457
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cccc(NC(=O)[C@H]3CC[C@H](C3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) ä 9.81 (s, 1H), 9.08 (s, 1H), 7.65-7.53 (m, 2H), 7.47 (t, J = 7.2 Hz, 1H), 7.39 (dd, J = 7.4, 1.5 Hz, 1H), 7.22 (td, J = 8.4, 3.1 Hz, 1H), 6.43 (s, 1H), 6.05 (s, 1H), 2.81 (dq, J = 18.3, 9.1 Hz, 1H), 2.58 (q, J = 8.8, 8.1 Hz, 1H), 1.86-1.57 (dt, J = 12.9, 7.8 Hz, 4H), 1.56-1.24 (d, J = 12.4 Hz, 2H)。 441.05 D   
I-2086
Figure 02_image4459
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cccc(NC(=O)[C@@H]3CC[C@@H](C3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) ä 9.78 (s, 1H), 9.08 (s, 1H), 7.61 (dd, J = 7.5, 1.5 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.53-7.46 (m, 1H), 7.39 (dd, J = 7.4, 1.5 Hz, 1H), 7.22 (td, J = 8.4, 3.1 Hz, 1H), 6.48 (s, 1H), 6.06 (s, 1H), 2.80 (dq, J = 18.0, 9.0 Hz, 1H), 2.62 (dt, J = 10.1, 7.7 Hz, 1H), 1.84-1.57 (dt, J = 12.9, 7.8 Hz, 4H), 1.56-1.24 (d, J = 12.4 Hz, 2H)。 441.05 D   
I-2087
Figure 02_image4461
 OB(O)c1cc(F)cc(c1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  10.23 (br s, 0.8H), 10.10 (br s, 0.2H), 9.23-9.01 (m, 1H), 8.36 (s, 1H), 7.91 (br s, 0.6H), 7.89-7.83 (m, 0.6H), 7.75-7.39 (m, 5H), 7.33 (dd, J = 8.8, 5.2 Hz, 1H), 7.29-7.22 (m, 1H), 7.10 (td, J = 8.4, 2.4 Hz, 1H), 7.03-6.85 (m, 1H), 6.55 (br s, 1H), 6.10 (br s, 0.5H), 6.03 (br s, 0.5H)。 443 E   
I-2088
Figure 02_image4463
 OC1(CCCC(C1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, 乙腈-d3)  8.61 (br. s, 1H), 7.80 (dd, J = 7.8, 0.6 Hz, 1H), 7.65 (dd, J = 3.0, 1.0 Hz, 1H), 7.58 (ddd, J = 7.6, 1.4 Hz, 1H), 7.47 (dd, J = 8.9, 5.1 Hz, 1H), 7.24 (br. s, 1H), 7.10 (ddd, J = 8.7, 8.1, 3.1 Hz, 1H), 6.57 (br. s, 1H), 6.20 (br. s, 1H), 3.77 (s, 1H), 3.02-2.79 (m, 1H), 1.89-1.79 (m, 1H), 1.68-1.45 (m, 3H), 1.34-1.06 (m, 4H)。非對映異構體之1:1混合物 471.3 E   
I-2089
Figure 02_image4465
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(C#N)c12)-c1ccc(=O)[nH]c1       E   
I-2090
Figure 02_image4467
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1=CN2CCN=C2C=C1 1H NMR (400 MHz, DMSO-d6) 10.30 (s, 1H), 9.13 (s, 1H), 8.12 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.80-7.70 (m, 3H), 7.66 (s, 1H), 7.53 (d, J = 9.5 Hz, 1H), 7.33 (dd, J = 8.9, 5.1 Hz, 1H), 7.10 (td, J = 8.4, 3.1 Hz, 1H), 6.71 (s, 1H), 6.44 (d, J = 9.6 Hz, 1H), 5.99 (s, 1H), 4.16 (t, J = 10.3 Hz, 2H), 3.83 (t, J = 10.3 Hz, 2H)。 585.1 A   
I-2091
Figure 02_image4469
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)C1=CN2CCN=C2C=C1 1H NMR (400 MHz, DMSO-d6) 10.30 (s, 1H), 9.13 (s, 1H), 8.12 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.80-7.70 (m, 3H), 7.66 (s, 1H), 7.53 (d, J = 9.5 Hz, 1H), 7.33 (dd, J = 8.9, 5.1 Hz, 1H), 7.10 (td, J = 8.4, 3.1 Hz, 1H), 6.71 (s, 1H), 6.44 (d, J = 9.6 Hz, 1H), 5.99 (s, 1H), 4.16 (t, J = 10.3 Hz, 2H), 3.83 (t, J = 10.3 Hz, 2H)。 585.1 C   
I-2092
Figure 02_image4471
 FC(F)S(=O)(=O)n1cc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.60 (s, 1 H), 9.26 (s, 1 H), 9.22 (s, 1 H), 8.89 (s, 1 H), 8.22 (s, 1 H), 7.98 (s, 1 H), 7.97 (重疊的d, J = 11.0 Hz, 1 H), 7.76 (d, J = 8.9 Hz, 1 H), 7.73 (重疊的app t,  J = 51.3 Hz, 1 H)7.73 (s, 1 H), 7.32 (dd, J = 8.9, 5.2 Hz, 1 H), 7.10 (td, J = 8.5, 3.0 Hz, 1 H), 6.61 (br s, 1 H), 6.01 (s, 1 H)。 645.2 B   
I-2093
Figure 02_image4473
 FC(F)S(=O)(=O)n1cc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  10.60 (br s, 1 H), 9.27 (s, 1 H), 9.22 (s, 1 H), 8.90 (s, 1 H), 8.22 (s, 1 H), 7.98 (s, 1 H), 7.97 (重疊的d, J = 11.4 Hz, 1 H), 7.76 (d, J = 8.9 Hz, 1 H), 7.73 (重疊的app t, j = 51.6 Hz, 1 H), 7.73 (s, 1 H), 7.32 (dd, J = 8.9, 5.2 Hz, 1 H), 7.10 (td, J = 8.4, 3.0 Hz, 1 H), 6.61 (br s, 1 H), 6.00 (br s, 1 H)。 645.2 A   
I-2094
Figure 02_image4475
 OC(CCNC(=O)c1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(F)(F)F 1H NMR (400 MHz, DMSO-d6)9.19 (s, 1H), 8.54-8.47 (m, 1H), 7.87 (d, J = 7.4 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.14 (td, J = 8.4, 3.1 Hz, 1H), 6.37-6.31 (m, 2H), 6.10 (dd, J = 8.8, 6.6 Hz, 1H), 3.86-3.79 (m, 1H), 3.27-3.10 (m, 1H), 3.10-2.96 (m, 1H), 1.51-1.20 (m, 2H)。 431.15 E   
I-2095
Figure 02_image4477
 Cn1c(Cl)cc(cc1=O)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)10.43 (s, 1H), 9.30 (s, 1H), 7.82 (d, J = 1.7 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.47-7.39 (m, 1H), 7.19 (ddd, J = 8.8, 7.9, 3.1 Hz, 1H), 6.66-6.48 (m, 3H), 5.97 (s, 1H), 3.57 (s, 3H)。 525.9 E   
I-2096
Figure 02_image4479
 Cn1c(Cl)cc(cc1=O)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)10.43 (s, 1H), 9.30 (s, 1H), 7.82 (d, J = 1.7 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.43 (t, J = 7.1 Hz, 1H), 7.19 (ddd, J = 8.8, 7.9, 3.1 Hz, 1H), 6.70-6.48 (m, 3H), 5.97 (s, 1H), 3.57 (s, 3H)。 525.9 E   
I-2097
Figure 02_image4481
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(C#Cc3ccccc3)c12 1H NMR (400 MHz, DMSO-d6) 9.24 (s, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.52 (s, 1H), 7.45 - 7.37 (m, 3H), 7.28 (dt, J = 9.6, 3.2 Hz, 2H), 7.23 (dd, J = 8.6, 3.0 Hz, 1H), 6.16 (s, 1H)。 362 E   
I-2098
Figure 02_image4483
 CN(C)S(=O)(=O)c1cc(cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.61 (dd, J = 1.9, 0.9 Hz, 1H), 9.57 (s, 1H), 8.61 (s, 1H), 8.47 (s, 1H), 8.26-8.16 (m, 2H), 8.00 (d, J = 9.2 Hz, 1H), 7.60 (s, 1H), 7.22 (s, 1H), 6.39 (s, 1H), 2.62 (s, 6H)。 486.05 E   
I-2099
Figure 02_image4485
 CN(C)S(=O)(=O)c1cc(cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.61 (dd, J = 1.9, 0.9 Hz, 1H), 9.57 (s, 1H), 8.61 (s, 1H), 8.47 (s, 1H), 8.26-8.16 (m, 2H), 8.00 (d, J = 9.2 Hz, 1H), 7.60 (s, 1H), 7.22 (s, 1H), 6.39 (s, 1H), 2.62 (s, 6H)。 486.05 E   
I-2100
Figure 02_image4487
 NS(=O)(=O)c1cc(cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.56 (dd, J = 1.8, 0.9 Hz, 1H), 9.48 (s, 1H), 8.62 (s, 1H), 8.55 (s, 1H), 8.42 (d, J = 1.7 Hz, 1H), 8.20 (dd, J = 9.3, 1.9 Hz, 1H), 8.06 (d, J = 9.3 Hz, 1H), 7.56 (s, 2H), 7.21 (td, J = 8.4, 3.0 Hz, 1H), 6.37 (s, 2H)。 458 E   
I-2101
Figure 02_image4489
 NS(=O)(=O)c1cc(cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) 9.56 (dd, J = 1.8, 0.9 Hz, 1H), 9.48 (s, 1H), 8.62 (s, 1H), 8.55 (s, 1H), 8.42 (d, J = 1.7 Hz, 1H), 8.20 (dd, J = 9.3, 1.9 Hz, 1H), 8.06 (d, J = 9.3 Hz, 1H), 7.56 (s, 2H), 7.21 (td, J = 8.4, 3.0 Hz, 1H), 6.37 (s, 2H)。 458 E   
I-2102
Figure 02_image4491
 O[C@H]1CC[C@H](C1)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  9.71 (s, 1H), 9.23 (s, 1H), 7.70 (s, 1H), 7.64 (d, J = 1.7 Hz, 1H), 7.49 (s, 1H), 7.24 (td, J = 8.4, 3.1 Hz, 1H), 6.67 (s, 1H), 6.01 (s, 1H), 4.62 (d, J = 4.7 Hz, 1H), 4.04 - 3.96 (m, 1H), 2.42 (q, J = 8.2 Hz, 1H), 1.87 - 1.75 (m, 1H), 1.59 (d, J = 6.6 Hz, 1H), 1.43 (s, 3H), 1.34 (ddd, J = 13.8, 8.7, 6.3 Hz, 1H), 1.24 (s, 1H)。 467.05 E   
I-2103
Figure 02_image4493
 O[C@H]1CC[C@H](C1)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  9.67 (s, 1H), 9.23 (s, 1H), 7.72 - 7.61 (m, 2H), 7.48 (s, 1H), 7.24 (td, J = 8.5, 3.1 Hz, 1H), 6.67 (s, 1H), 6.01 (s, 1H), 4.61 (d, J = 4.6 Hz, 1H), 4.00 (q, J = 5.6 Hz, 1H), 2.42 (q, J = 8.3 Hz, 1H), 1.75 (dt, J = 13.9, 7.3 Hz, 1H), 1.64 - 1.37 (m, 2H), 1.42 (s, 3H), 1.24 (s, 1H)。 467.05 E   
I-2104
Figure 02_image4495
 O[C@@H]1CC[C@@H](C1)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  9.71 (s, 1H), 9.23 (s, 1H), 7.70 (d, J = 1.7 Hz, 1H), 7.64 (d, J = 1.7 Hz, 1H), 7.49 (s, 1H), 7.24 (td, J = 8.4, 3.0 Hz, 1H), 6.67 (s, 1H), 6.01 (s, 1H), 4.62 (d, J = 4.7 Hz, 1H), 3.99 (q, J = 5.6 Hz, 1H), 2.42 (q, J = 8.3 Hz, 1H), 1.81 (ddd, J = 14.0, 8.5, 6.2 Hz, 1H), 1.60 (s, 1H), 1.44 (s, 3H), 1.35 (ddd, J = 12.9, 8.6, 6.1 Hz, 1H)。 467.05 E   
I-2105
Figure 02_image4497
 O[C@@H]1CC[C@@H](C1)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  9.67 (s, 1H), 9.23 (s, 1H), 7.72 - 7.64 (m, 2H), 7.48 (s, 1H), 7.24 (td, J = 8.4, 3.1 Hz, 1H), 6.68 (s, 1H), 6.01 (s, 1H), 4.62 (d, J = 4.6 Hz, 1H), 4.00 (q, J = 5.6 Hz, 1H), 2.42 (q, J = 8.3 Hz, 1H), 1.75 (dt, J = 13.9, 7.1 Hz, 1H), 1.64 - 1.49 (m, 1H), 1.53 - 1.40 (m, 1H), 1.39 (dd, J = 9.4, 4.9 Hz, 3H), 1.17 (t, J = 7.2 Hz, 1H)。 467.05 E   
I-2106
Figure 02_image4499
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(\C=C\c3ccccc3)c12 1H NMR (400 MHz, DMSO-d6)  9.17 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.60 (m, 2H), 7.42 - 7.32 (m, 4H), 7.28 (td, J = 5.9, 2.6 Hz, 1H), 7.24 - 7.17 (m, 2H), 6.91 (d, J = 16.3 Hz, 1H), 6.76 - 6.40 (s, 1H), 6.28 (s, 1H)。 364.1 E   
I-2107
Figure 02_image4501
 Cc1cc(=O)[nH]cc1C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) ä 11.73 (s, 1H), 10.04 (s, 1H), 9.24 (s, 1H), 7.74 (d, J = 1.7 Hz, 1H), 7.67-7.62 (m, 1H), 7.46 (dd, J = 8.8, 5.1 Hz, 1H), 7.21 (td, J = 8.4, 3.1 Hz, 1H), 6.90 (s, 1H), 6.64 (s, 1H), 6.16 (s, 1H), 5.96 (s, 1H), 2.11 (s, 3H)。 492.15 E   
I-2108
Figure 02_image4503
 Cc1cc(=O)[nH]cc1C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) ä 11.72 (s, 1H), 10.05 (s, 1H), 9.24 (s, 1H), 7.74 (d, J = 1.7 Hz, 1H), 7.64 (s, 1H), 7.46 (dd, J = 8.7, 5.1 Hz, 1H), 7.21 (td, J = 8.4, 3.1 Hz, 1H), 6.90 (s, 1H), 6.65 (s, 1H), 6.16 (s, 1H), 5.97 (s, 1H), 2.11 (s, 3H)。 492.15 E   
I-2109
Figure 02_image4505
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(CC3CCCC3)c12 (400 MHz, DMSO-d6)  10.78 (s, 1H), 8.88 (s, 1H), 8.17 (s, 1H), 8.12 (d, J = 8.9 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.60-7.50 (m, 3H), 4.77 (d, J = 7.2 Hz, 1H), 1.93-1.81 (m, 1H), 1.81-1.72 (m, 1H), 1.69-1.60 (m, 1H), 1.51-1.41 (m, 1H), 1.39-1.22 (m, 5H), 1.04 (tt, J = 15.2, 7.4 Hz, 1H), 0.94-0.81 (m, 1H)。 421.4 D   
I-2110
Figure 02_image4507
 O[C@H]1CCCCC1[C@@H]1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6)  10.90 (s, 1H), 8.53 (s, 1H), 8.10 (s, 1H), 8.03 (t, J = 8.5 Hz, 2H), 7.71 (dd, J = 6.8, 2.1 Hz, 1H), 7.55-7.48 (m, 2H), 4.75 (d, J = 3.9 Hz, 1H), 4.25 (br s, 1H), 3.57 (s, 1H), 1.73-1.41 (m, 5H), 1.32-1.20 (m. 2H), 1.16-1.08 (m, 1H), 1.06 - 0.94 (m, 1H)   [單一非對映異構體] 437.4 E   
I-2111
Figure 02_image4509
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCn4c(C3)nnc4C(F)(F)F)c12 NMR (400 MHz, DMSO-d6)  9.05 (br s, 1H), 8.98 (br s, 1H), 7.56 (d, J = 2.2 Hz, 2H), 7.34-7.25 (m, 1H), 7.19 (dd, J = 7.6, 5.4 Hz, 1H), 6.98 (td, J = 8.1, 2.4 Hz, 1H), 6.37 (br s, 1H), 5.95 (br s, 1H), 4.74 (d, J = 17.1 Hz, 1H), 4.43 (d, J = 16.9 Hz, 1H), 4.13-3.98 (m, 1H), 3.97-3.87 (m, 1H), 3.86-3.74 (m, 1H), 3.68-3.55 (m, 1H)。 495 E   
I-2112
Figure 02_image4511
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3ncc(Br)s3)c12 NMR (400 MHz, DMSO-d6)  10.53 (br s, 1H), 9.13 (br s, 1H), 8.12 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.64-7.51 (m, 2H), 7.33 (dd, J = 8.7, 4.9 Hz, 1H), 7.09 (td, J = 8.1, 3.1 Hz, 1H), 6.51 (br s, 1H), 6.07 (br s, 1H)。 468 E   
I-2113
Figure 02_image4513
 O[C@@]1(CCCN(C1)C(=O)Nc1cccc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl)C(F)(F)F    472 E   
I-2114
Figure 02_image4515
 O[C@]1(CCCN(C1)C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)C(F)(F)F    472.1 E   
I-2115
Figure 02_image4517
 O[C@]1(CCCN(C1)C(=O)Nc1cccc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl)C(F)(F)F    472.1 E   
I-2116
Figure 02_image4519
 O[C@@]1(CCCN(C1)C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)C(F)(F)F    472.1 E   
I-2117
Figure 02_image4521
 CC(C)(O)C12CC(C1)(C2)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  9.38 (s, 1H), 9.05 (br s, 1H), 7.60 (dd, J = 7.4, 0.9 Hz, 1H), 7.55 (app. t, J = 7.5 Hz, 1H),  7.54-7.40 (m, 1H), 7.39 (dd, J = 7.6, 1.1 Hz, 1H), 7.24 (td, J = 8.4, 3.1 Hz, 1H), 6.56 (br s, 1H), 5.98 (br s, 1H), 4.17 (br s, 1H), 1.58 (s, 6H), 0.98 (s, 6H)。 429 E   
I-2118
Figure 02_image4523
 OC(C1CC1)(C1CC1)C12CC(C1)(C2)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl NMR (400 MHz, DMSO-d6)  9.34 (s, 1H), 9.04 (br s, 1H), 7.59 (dd, J = 7.4, 1.0 Hz, 1H), 7.55 (app. t, J = 7.5 Hz, 1H), 7.51-7.42 (m, 1H), 7.40 (dd, J = 7.6, 1.2 Hz, 1H), 7.27-7.20 (m, 1H), 6.60 (br s, 1H), 5.99 (br s, 1H), 3.51 (s, 1H), 1.70 (s, 6H), 0.72-0.60 (m, 2H), 0.32-0.21 (m, 4H), 0.22-0.09 (m, 4H)。 481 E   
I-2119
Figure 02_image4525
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cccc(NC(=O)CCC(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  9.85 (s, 1H), 9.09 (s, 1H), 7.63 (m, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.50 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.24 (td, J = 8.4, 3.1 Hz, 1H), 5.97 (s, 1H), 2.33 (dq, J = 14.9, 10.4, 8.9 Hz, 3H), 2.17 (q, J = 9.3, 8.6 Hz, 1H)。 401.15 E   
I-2120
Figure 02_image4527
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cccc(NC(=O)CCC(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6)  9.85 (s, 1H), 9.09 (s, 1H), 7.63 (m, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.50 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.24 (td, J = 8.4, 3.1 Hz, 1H), 5.97 (s, 1H), 2.33 (dq, J = 14.9, 10.4, 8.9 Hz, 3H), 2.17 (q, J = 9.3, 8.6 Hz, 1H)。 401.2 E   
I-2121
Figure 02_image4529
 CC(C)(O)c1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@H](O)c3ccccc23)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  9.01 (s, 1H), 8.50 (s, 1H), 7.74 - 7.63 (m, 2H), 7.56 (d, J = 1.7 Hz, 1H), 7.38 - 7.28 (m, 2H), 7.23 - 7.14 (m, 1H), 7.09 (td, J = 8.4, 3.1 Hz, 1H), 6.95 (t, J = 7.4 Hz, 1H), 6.53 (s, 1H), 6.07 (s, 1H), 5.60 (d, J = 5.0 Hz, 1H), 5.26 (s, 1H), 5.15 (dd, J = 8.4, 4.3 Hz, 1H), 3.98 (dd, J = 11.1, 8.0 Hz, 1H), 3.20 (dt, J = 10.7, 5.2 Hz, 1H), 1.50 (s, 6H)。 496.2 D   
I-2122
Figure 02_image4531
 CC(C)(O)c1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@@H](O)c3ccccc23)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  8.99 (s, 1H), 8.63 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.51 (s, 1H), 7.40 - 7.30 (m, 2H), 7.24 (t, J = 7.7 Hz, 1H), 7.16 (td, J = 8.4, 3.1 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.54 (s, 1H), 5.98 (s, 1H), 5.64 (d, J = 6.0 Hz, 1H), 5.27 (s, 1H), 5.09 (s, 1H), 3.72 (dd, J = 11.2, 3.5 Hz, 1H), 3.21 (s, 1H), 1.50 (s, 6H)。 496.2 E   
I-2123
Figure 02_image4533
 CC(C)(O)c1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@H](O)c3ccccc23)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 9.02 (s, 1H), 8.52 (s, 1H), 7.74 - 7.65 (m, 2H), 7.56 (d, J = 1.6 Hz, 1H), 7.38 - 7.28 (m, 2H), 7.23 - 7.14 (m, 1H), 7.10 (td, J = 8.4, 3.1 Hz, 1H), 6.99 - 6.91 (m, 1H), 6.53 (s, 1H), 6.08 (s, 1H), 5.62 (s, 1H), 5.27 (s, 1H), 5.15 (dd, J = 8.2, 3.9 Hz, 1H), 3.99 (dd, J = 11.1, 8.0 Hz, 1H), 3.21 (s, 1H), 1.50 (s, 6H)。 496.2 C   
I-2124
Figure 02_image4535
 CC(C)(O)c1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@@H](O)c3ccccc23)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  8.99 (s, 1H), 8.63 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.51 (s, 1H), 7.40 - 7.30 (m, 2H), 7.24 (t, J = 7.7 Hz, 1H), 7.16 (td, J = 8.3, 3.1 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 6.53 (s, 1H), 5.98 (s, 1H), 5.65 (s, 1H), 5.27 (s, 1H), 5.08 (s, 1H), 3.72 (dd, J = 11.4, 3.5 Hz, 1H), 3.21 (s, 1H), 1.50 (s, 6H)。 496.2 A B
I-2125
Figure 02_image4537
 CNc1nc2ccc(cn2n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 10.60 (s, 1H), 9.39-8.97 (m, 2H), 8.04 (d, J = 1.6 Hz, 1H), 7.97 (dt, J = 8.7, 2.1 Hz, 1H), 7.93-7.85 (m, 2H), 7.81-7.69 (m, 2H), 7.54-7.47 (m, 1H), 7.34 (dd, J = 8.9, 5.2 Hz, 1H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 6.58 (q, J = 4.9 Hz, 2H), 6.05 (s, 1H), 2.86 (d, J = 4.9 Hz, 3H) 613.15 A A
I-2126
Figure 02_image4539
 O[C@H]1CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 1H NMR (400 MHz, DMSO-d6) 9.06 (s, 1H), 8.50 (s, 1H), 7.70 (dd, J = 8.8, 4.7 Hz, 1H), 7.60-7.57 (t, J = 7.4 Hz, 2H), 7.44 (dd, J = 7.3, 1.6 Hz, 1H), 7.35 (dd, J = 8.9, 5.2 Hz, 1H), 7.15-7.03 (m, 3H), 6.57 (s, 1H), 6.09 (s, 1H), 5.73 (d, J = 5.1 Hz, 1H), 5.15 (dt, J = 8.4, 4.5 Hz, 1H), 3.97 (dd, J = 11.0, 8.1 Hz, 1H), 3.23 (dd, J = 11.1, 4.1 Hz, 1H)。 456.05 C   
I-2127
Figure 02_image4541
 O[C@@H]1CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 1H NMR (400 MHz, DMSO-d6) 9.04 (s, 1H), 8.62 (s, 1H), 7.83 (dd, J = 8.8, 4.7 Hz, 1H), 7.62-7.52 (m, 2H), 7.37 (dd, J = 8.8, 5.3 Hz, 2H), 7.21-7.10 (m, 2H), 7.08 (td, J = 9.0, 2.8 Hz, 1H), 6.53 (s, 1H), 6.00 (s, 1H), 5.76 (d, J = 6.0 Hz, 1H), 5.08 (s, 1H), 3.71 (dd, J = 11.3, 3.6 Hz, 1H), 3.31 (s, 1H)。 456.05 A A
I-2128
Figure 02_image4543
 O[C@H]1CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 1H NMR (400 MHz, DMSO-d6) 9.04 (s, 1H), 8.63 (s, 1H), 7.83 (dd, J = 8.9, 4.7 Hz, 1H), 7.62-7.52 (m, 2H), 7.37 (dd, J = 8.8, 5.6 Hz, 2H), 7.15-7.08 (m, 3H), 6.54 (s, 1H), 6.00 (s, 1H), 5.76 (d, J = 6.0 Hz, 1H), 5.08 (dt, J = 8.2, 4.4 Hz, 1H), 3.71 (dd, J = 11.3, 3.7 Hz, 1H), 3.25 (s, 1H)。 456.1 E   
I-2129
Figure 02_image4545
 O[C@@H]1CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 1H NMR (400 MHz, DMSO-d6) 9.06 (s, 1H), 8.50 (s, 1H), 7.70 (dd, J = 8.9, 4.7 Hz, 1H), 7.64-7.53 (m, 2H), 7.44 (dd, J = 7.3, 1.6 Hz, 1H), 7.35 (dd, J = 8.9, 5.2 Hz, 1H), 7.12-6.98 (m, 3H), 6.56 (s, 1H), 6.09 (s, 1H), 5.73 (d, J = 5.0 Hz, 1H), 5.15 (dt, J = 8.6, 4.5 Hz, 1H), 3.97 (dd, J = 11.1, 8.1 Hz, 1H), 3.23 (dd, J = 11.0, 4.1 Hz, 1H)。 456.05 E   
I-2130
Figure 02_image4547
 Nc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@H](O)c3ccccc23)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 8.80 (s, 1H), 8.16 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.36 - 7.26 (m, 2H), 7.22 - 7.13 (m, 1H), 7.06 (ddd, J = 8.8, 7.9, 3.1 Hz, 1H), 6.93 (td, J = 7.4, 1.1 Hz, 1H), 6.73 (dd, J = 16.6, 2.0 Hz, 2H), 6.53 (s, 1H), 5.94 (s, 1H), 5.59 (d, J = 5.3 Hz, 1H), 5.50 (s, 2H), 5.12 (dt, J = 8.7, 4.5 Hz, 1H), 3.85 (dd, J = 11.1, 8.0 Hz, 1H), 3.27 (dd, J = 11.0, 3.9 Hz, 1H)。 453.15 D   
I-2131
Figure 02_image4549
 Nc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@@H](O)c3ccccc23)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 8.77 (s, 1H), 8.30 (s, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.26 - 7.17 (m, 1H), 7.12 (td, J = 8.3, 3.1 Hz, 1H), 6.95 (t, J = 7.4 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 6.52 (s, 1H), 5.84 (s, 1H), 5.66 (s, 1H), 5.50 (s, 2H), 5.07 (dd, J = 8.1, 3.5 Hz, 1H), 3.63 (dd, J = 11.3, 3.6 Hz, 1H), 3.25 (d, J = 9.9 Hz, 1H)。 453.15 D   
I-2132
Figure 02_image4551
 Nc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@H](O)c3ccccc23)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  8.80 (s, 1H), 8.17 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.36 - 7.26 (m, 2H), 7.17 (td, J = 7.7, 1.4 Hz, 1H), 7.10 - 7.01 (m, 1H), 6.93 (td, J = 7.4, 1.0 Hz, 1H), 6.73 (dd, J = 16.7, 2.0 Hz, 2H), 6.53 (s, 1H),  5.94 (s, 1H), 5.59 (d, J = 5.3 Hz, 1H), 5.50 (s, 2H), 5.12 (dt, J = 8.4, 4.3 Hz, 1H), 3.85 (dd, J = 11.1, 8.0 Hz, 1H), 3.27 (dd, J = 11.0, 3.9 Hz, 1H)。 453.1 A   
I-2133
Figure 02_image4553
 Nc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@@H](O)c3ccccc23)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 8.76 (s, 1H), 8.28 (s, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.22 (t, J = 7.7 Hz, 1H), 7.12 (td, J = 8.3, 3.1 Hz, 1H), 7.00 - 6.91 (m, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 6.52 (s, 1H), 5.84 (s, 1H), 5.60 (d, J = 6.1 Hz, 1H), 5.49 (s, 2H), 5.07 (s, 1H), 3.62 (dd, J = 11.3, 3.6 Hz, 1H), 3.24 (s, 1H)。 453.1 A A
I-2134
Figure 02_image4555
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(OCC3CC3)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 1H NMR (400 MHz, DMSO-d6) 10.43 (s, 1H), 9.11 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 9.1 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, J = 8.9, 5.1 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.13 - 7.05 (m, 2H), 6.56 (s, 1H), 5.93 (s, 0H), 3.96 (d, J = 7.0 Hz, 2H), 1.27 (dd, J = 12.1, 7.1 Hz, 1H), 0.65 - 0.56 (m, 2H), 0.42 - 0.33 (m, 2H)。 537.15 B   
I-2135
Figure 02_image4557
 FC(F)n1cc(cn1)-c1cc2C(=O)NC(c2c(c1)-c1cn2ccc(cc2n1)C(F)(F)F)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) ä 9.28 (s, 1H), 9.04 (s, 1H), 8.72 (d, J = 7.2 Hz, 1H), 8.66 (s, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 8.14 (d, J = 1.7 Hz, 1H), 8.06 (s, 0H), 7.91 (s, 0H), 7.79 (d, J = 21.3 Hz, 1H), 7.38 (s, 1H), 7.17 (dd, J = 7.2, 1.9 Hz, 2H), 6.96 (td, J = 8.4, 3.1 Hz, 1H), 6.70 (s, 1H)。 562 D   
I-2136
Figure 02_image4559
 OC1(CCCC(C1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(F)(F)F    471.2 E   
I-2137
Figure 02_image4561
 OC(=O)c1cc(ccn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6)  10.65 (s, 1H), 9.30 (s, 1H), 8.44 (dd, J=51.6, 28.1 Hz, 2H), 8.26-7.91 (m, 5H), 7.78 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.34 (dd, J=8.9, 5.2 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H), 6.09 (s, 1H)。 588.25 A   
I-2138
Figure 02_image4563
 C[C@@H](CCC(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 9.80 (s, 1H), 9.10 (s, 1H), 7.65-7.55 (m, 2H), 7.47 (td, J = 7.5, 3.0 Hz, 2H), 7.21 (td, J = 8.4, 3.1 Hz, 1H), 6.43 (s, 1H), 6.15 (s, 1H), 2.28 (p, J = 6.9 Hz, 1H), 2.09-1.89 (s, 2H), 1.51-1.38 (m, 1H), 1.32 (tt, J = 12.2, 5.9 Hz, 1H), 0.85 (d, J = 6.8 Hz, 3H)。 429.2 D   
I-2139
Figure 02_image4565
 C[C@H](CCC(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 9.82 (s, 1H), 9.10 (s, 1H), 7.65-7.54 (m, 2H), 7.50 (dd, J = 8.9, 5.1 Hz, 1H), 7.43 (dd, J = 7.4, 1.5 Hz, 1H), 7.21 (td, J = 8.4, 3.1 Hz, 1H), 6.46 (s, 1H), 6.10 (s, 1H), 2.27 (dq, J = 13.9, 6.6 Hz, 1H), 2.15-1.85 (m, 2H), 1.60 (dddd, J = 13.1, 11.2, 8.3, 4.9 Hz, 1H), 1.39 (ddt, J = 13.3, 11.2, 5.5 Hz, 1H), 0.77 (d, J = 6.9 Hz, 3H)。 429.2 E   
I-2140
Figure 02_image4567
 C[C@H](CCC(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 9.80 (s, 1H), 9.10 (s, 1H), 7.65-7.55 (m, 2H), 7.47 (td, J = 8.3, 7.2, 3.5 Hz, 2H), 7.21 (ddd, J = 8.8, 8.0, 3.1 Hz, 1H), 6.43 (s, 1H), 6.15 (s, 1H), 2.27 (p, J = 6.9 Hz, 1H), 2.09-1.89 (s, 2H), 1.51-1.38 (m, 1H), 1.32 (tq, J = 12.3, 5.8 Hz, 1H), 0.85 (d, J = 6.9 Hz, 3H)。 429.2 E   
I-2141
Figure 02_image4569
 C[C@@H](CCC(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl 1H NMR (400 MHz, DMSO-d6) 9.82 (s, 1H), 9.10 (s, 1H), 7.65-7.54 (m, 2H), 7.50 (dd, J = 8.9, 5.1 Hz, 1H), 7.43 (dd, J = 7.4, 1.5 Hz, 1H), 7.21 (td, J = 8.4, 3.1 Hz, 1H), 6.46 (s, 1H), 6.10 (s, 1H), 2.27 (dq, J = 13.9, 6.6 Hz, 1H), 2.15-1.85 (m, 2H), 1.60 (dddd, J = 13.1, 11.2, 8.3, 4.9 Hz, 1H), 1.39 (ddt, J = 13.3, 11.2, 5.5 Hz, 1H), 0.77 (d, J = 6.9 Hz, 3H)。 429.2 E   
I-2142
Figure 02_image4571
 O[C@@H]1CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2cccc(F)c12 1H NMR (400 MHz, DMSO-d6) 9.05 (s, 1H), 8.71 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.64-7.53 (m, 2H), 7.43-7.33 (m, 2H), 7.31 (td, J = 8.2, 5.9 Hz, 1H), 7.17 (td, J = 8.4, 3.1 Hz, 1H), 6.78 (t, J = 8.6 Hz, 1H), 6.54 (s, 1H), 6.01 (s, 1H), 5.80 (d, J = 6.8 Hz, 1H), 5.24 (td, J = 7.2, 2.2 Hz, 1H), 3.80 (dd, J = 11.5, 2.3 Hz, 1H), 3.21 (s, 1H)。 456.2 A A
I-2143
Figure 02_image4573
 O[C@@H]1CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2cccc(F)c12 1H NMR (400 MHz, DMSO-d6) 9.09 (s, 1H), 8.59 (s, 1H), 7.65-7.54 (m, 2H), 7.53-7.42 (m, 2H), 7.35 (dd, J = 8.9, 5.1 Hz, 1H), 7.24 (td, J = 8.2, 5.9 Hz, 1H), 7.09 (td, J = 8.4, 3.1 Hz, 1H), 6.74 (t, J = 8.6 Hz, 1H), 6.56 (s, 1H), 6.10 (s, 1H), 5.75 (d, J = 5.6 Hz, 1H), 5.30 (ddd, J = 7.8, 5.7, 2.4 Hz, 1H), 3.92 (dd, J = 11.3, 7.5 Hz, 1H), 3.38 (dd, J = 11.3, 2.5 Hz, 1H)。 456.2 C   
I-2144
Figure 02_image4575
 O[C@H]1CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2cccc(F)c12 1H NMR (400 MHz, DMSO-d6) 9.08 (s, 1H), 8.59 (s, 1H), 7.61-7.58 (dd, J = 7.5, 1.5 Hz, 2H), 7.50-7.42 (t, J = 7.4 Hz, 2H), 7.35 (dd, J = 8.9, 5.1 Hz, 1H), 7.24 (td, J = 8.2, 5.9 Hz, 1H), 7.09 (td, J = 8.4, 3.1 Hz, 1H), 6.74 (t, J = 8.6 Hz, 1H), 6.56 (s, 1H), 6.10 (s, 1H), 5.75 (d, J = 5.6 Hz, 1H), 5.29 (ddd, J = 7.9, 5.5, 2.4 Hz, 1H), 3.92 (dd, J = 11.3, 7.5 Hz, 1H), 3.37 (dd, J = 11.5, 2.6 Hz, 1H)。 456.2 D   
I-2145
Figure 02_image4577
 O[C@H]1CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2cccc(F)c12 1H NMR (400 MHz, DMSO-d6) 9.05 (s, 1H), 8.71 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.64-7.53 (m, 2H), 7.43-7.35 (m, 2H), 7.31 (td, J = 8.2, 5.9 Hz, 1H), 7.17 (td, J = 8.4, 3.1 Hz, 1H), 6.78 (t, J = 8.6 Hz, 1H), 6.54 (s, 1H), 6.01 (s, 1H), 5.80 (d, J = 6.7 Hz, 1H), 5.28-5.20 (m, 1H), 3.80 (dd, J = 11.6, 2.3 Hz, 1H), 3.21 (s, 1H)。 456.2 D   
I-2146
Figure 02_image4579
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(cc(NC(=O)[C@H]3CCCCN3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) ä 9.40 (dd, J = 1.8, 0.9 Hz, 1H), 9.24 (s, 1H), 8.58 (s, 1H), 8.25 (d, J = 25.7 Hz, 1H), 8.06 (dd, J = 9.3, 1.8 Hz, 1H), 8.03 - 7.94 (m, 2H), 7.56 (s, 1H), 7.30 (td, J = 8.3, 3.1 Hz, 1H), 6.17 (s, 1H), 3.06 (d, J = 9.4 Hz, 1H), 2.82 - 2.64 (m, 1H), 2.43 (d, J = 11.3 Hz, 1H), 1.58 - 1.00 (m, 6H), 0.99 - 0.85 (m, 1H)。 505.35 E   
I-2147
Figure 02_image4581
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(cc(NC(=O)[C@@H]3CCCCN3)c12)-c1ccc2ncnn2c1 1H NMR (400 MHz, DMSO-d6) ä 9.40 (dd, J = 1.8, 0.9 Hz, 1H), 9.24 (s, 1H), 8.58 (s, 1H), 8.25 (d, J = 25.7 Hz, 1H), 8.06 (dd, J = 9.3, 1.8 Hz, 1H), 8.03 - 7.94 (m, 2H), 7.56 (s, 1H), 7.30 (td, J = 8.3, 3.1 Hz, 1H), 6.17 (s, 1H), 3.06 (d, J = 9.4 Hz, 1H), 2.82 - 2.64 (m, 1H), 2.43 (d, J = 11.3 Hz, 1H), 1.58 - 1.00 (m, 6H), 0.99 - 0.85 (m, 1H)。 505.35 E   
I-2148
Figure 02_image4583
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-n1ccnn1 1H NMR (400 MHz, DMSO-d6)  10.75 (s, 1H), 9.36 (s, 1H), 9.12 - 9.07 (m, 1H), 8.26 - 8.18 (m, 2H), 8.05 (d, J = 1.2 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 9.1 Hz, 1H), 7.71 (s, 1H), 7.36 (dd, J = 8.9, 5.2 Hz, 1H), 7.12 (td, J = 8.4, 3.1 Hz, 1H), 6.08 (s, 1H)。 534 A   
I-2149
Figure 02_image4585
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(NC(=O)C3(CNC3)C#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz,DMSO-d6 )  10.84 (br s, 1 H), 10.55 (s, 1 H), 9.20 (br s, 1 H), 8.14 (s, 1 H), 8.00 (d, J = 1.2 Hz, 1 H), 7.95 (d, J = 8.3 Hz, 1 H), 7.82 (d, J = 1.3 Hz, 1 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.63 (s, 1 H), 7.32 (dd, J = 8.9, 5.2 Hz, 1 H), 7.09 (td, J = 8.5, 3.0 Hz, 1 H), 6.60 (br s, 1 H), 5.96 (br s, 1 H), 4.05 (dd, J = 8.2, 3.1 Hz, 2 H), 3.91 (d, J = 8.2 Hz, 2 H)。 590.2 A D
I-2150
Figure 02_image4587
 O[C@@H]1C[C@H](C[C@H](C1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)  9.89 (br. s, 1H), 9.25 (br. s, 1H), 7.69 (d, J = 1.4 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.51-7.44 (m, 1H), 7.20 (app. td, J = 8.3, 3.0 Hz, 1H), 6.55 (br. s, 1H), 6.02 (br. s, 1H), 4.86 (br. s, 1H), 4.01 (br. s, 1H), 2.57 (tt, J = 12.2, 3.1 Hz, 1H), 2.48-2.39 (m, 1H), 1.80-1.73 (m, 1H), 1.51-1.44 (m, 1H), 1.41-1.34 (m, 1H), 1.34-1.28 (m, 1H), 1.27-1.17 (m, 1H), 1.11-1.00 (m, 1H)。 549.3 D   
I-2151
Figure 02_image4589
 O[C@@H]1C[C@H](C[C@H](C1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)  9.99 (br. s, 1H), 9.25 (br. s, 1H), 7.71 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.44 (dd, J = 8.5, 5.1 Hz, 1H), 7.20 (ddd, J = 8.8, 8.2, 3.1 Hz, 1H), 6.51 (br. s, 1H), 6.01 (br. s, 1H), 4.81 (br. d, J = 2.4 Hz, 1H), 4.04 (br. s, 1H), 2.56 (tt, J = 12.5, 3.3 Hz, 1H), 2.47-2.38 (m, 1H), 1.80-1.72 (m, 1H), 1.57-1.50 (m, 1H), 1.34-1.22 (m, 4H)。 549.3 D   
I-2152
Figure 02_image4591
 O[C@H]1C[C@@H](C[C@@H](C1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl 1H-NMR (400 MHz, DMSO-d6)  9.98 (br. s, 1H), 9.25 (br. s, 1H), 7.71 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.44 (dd, J = 8.5, 5.1 Hz, 1H), 7.20 (ddd, J = 8.7, 8.1, 3.1 Hz, 1H), 6.52 (br. s, 1H), 6.01 (br. s, 1H), 4.80 (br. d, J = 2.8 Hz, 1H), 4.04 (br. s, 1H), 2.56 (tt, J = 12.4, 3.3 Hz, 1H), 2.47-2.38 (m, 1H), 1.80-1.72 (m, 1H), 1.58-1.51 (m, 1H), 1.34-1.23 (m, 4H)。 549.3 D   
I-2153
Figure 02_image4593
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@H](CC3CCCC3)c12 (400 MHz, DMSO-d6)  10.78 (s, 1H), 8.88 (s, 1H), 8.17 (s, 1H), 8.12 (d, J = 8.9 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.60-7.50 (m, 3H), 4.77 (d, J = 7.2 Hz, 1H), 1.93-1.81 (m, 1H), 1.81-1.72 (m, 1H), 1.69-1.60 (m, 1H), 1.51-1.41 (m, 1H), 1.39-1.22 (m, 5H), 1.04 (tt, J = 15.2, 7.4 Hz, 1H), 0.94-0.81 (m, 1H)。 421.4 D   
I-2154
Figure 02_image4595
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H](CC3CCCC3)c12 (400 MHz, DMSO-d6)  10.78 (s, 1H), 8.88 (s, 1H), 8.17 (s, 1H), 8.12 (d, J = 8.9 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.60-7.50 (m, 3H), 4.77 (d, J = 7.2 Hz, 1H), 1.93-1.81 (m, 1H), 1.81-1.72 (m, 1H), 1.69-1.60 (m, 1H), 1.51-1.41 (m, 1H), 1.39-1.22 (m, 5H), 1.04 (tt, J = 15.2, 7.4 Hz, 1H), 0.94-0.81 (m, 1H)。 421.4 D   
I-2155
Figure 02_image4597
 OC1(CCC(CC1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(F)(F)F    471.2 E   
I-2156
Figure 02_image4599
 Fc1cc(F)cc(c1)C1NC(=O)c2cc(Br)cc(NC(=O)c3cc(F)cc(F)c3)c12 1H NMR (400 MHz, DMSO) 10.33 (s, 1H), 9.28-9.23 (m, 1H), 7.8-7.75 (m, 2H), 7.54 (tt, J = 9.1, 2.4 Hz, 1H), 7.33 (ddd, J = 6.9, 2.4, 1.3 Hz, 2H), 7.10 (tt, J = 9.3, 2.4 Hz, 1H), 6.79-6.69 (m, 2H), 5.75 (d, J = 1.1 Hz, 1H)。 480 D   
I-2157
Figure 02_image4601
 O=C1C2=C(C=C)C=CC(NC(C3=CSC4=C3C=CC=C4)=O)=C2C(C5=C(C)C=CC=C5)N1    425.3      
I-2158
Figure 02_image4603
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC3CCCNC3)c12)-c1ccc2ncnn2c1    477.0 E   
I-2159
Figure 02_image4605
 FC(F)n1cc(cn1)-c1cc(N[C@H]2CCOc3ccccc23)c2[C@H](NC(=O)c2n1)c1cc(F)ccc1Cl    526.1 D   
I-2160
Figure 02_image4607
 FC(F)n1cc(cn1)-c1cc(N[C@H]2CCOc3ccccc23)c2[C@@H](NC(=O)c2n1)c1cc(F)ccc1Cl    526.1 E   
I-2161
Figure 02_image4609
 FC(F)n1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(F)c2)c1)c1cc(F)cc(F)c1 (400 MHz, DMSO) δ 10.33 (s, 1H), 9.15 (d, J = 1.3 Hz, 1H), 8.90 (d, J = 0.7 Hz, 1H), 8.39 (d, J = 0.7 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.84 (d, J = 1.6 Hz, 1H), 7.60 - 7.43 (m, 2H), 7.42 - 7.34 (m, 2H), 7.10 (tt, J = 9.3, 2.4 Hz, 1H), 6.76 - 6.68 (m, 2H), 5.75 (s, 1H)。 517.0 B   
I-2162
Figure 02_image4611
 O[C@@H]1C[C@H](CC(F)(F)F)N(C1)C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl (400 MHz, CD3CN) δ 7.62 - 7.58 (m, 1H), 7.57 - 7.49 (m, 2H), 7.45 (dd, J = 8.9, 5.2 Hz, 1H), 7.16 (br s, 1H), 7.09 (ddd, J = 8.9, 8.0, 3.1 Hz, 1H), 6.62 (br s, 1H), 6.62 (br s [浸沒峰], 1H), 6.20 (br s, 1H), 4.37 - 4.33 (m, 1H), 4.04 - 3.96 (m, 1H), 3.23 (dd, J = 10.1, 4.7 Hz, 1H), 2.88 (d, J = 10.1 Hz, 1H), 2.85 - 2.75 (m, 1H), 2.54 - 2.42 (m, 1H), 2.03 - 1.97 (m, 2H), 1.91 - 1.84 (m, 1H) ppm 472.2 D   
I-2163
Figure 02_image4613
 O[C@@H]1C[C@H](CC(F)(F)F)N(C1)C(=O)Nc1cccc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl (400 MHz, CD3CN) δ 7.62 - 7.58 (m, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.46 - 7.38 (m, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.14 (br s, 1H), 7.07 (ddd, J = 8.8, 8.0, 3.1 Hz, 1H), 6.71 (br s, 1H), 6.62 (br s, 1H), 6.13 (br s, 1H), 4.27 (ddd, J = 7.7, 5.1, 2.7 Hz, 1H), 4.21 (d, J = 8.7 Hz, 1H), 3.05 (d, J = 10.5 Hz, 1H), 2.83 - 2.71 (m, 1H), 2.64 - 2.52 (m, 1H), 2.51 - 2.37 (m, 2H), 2.09 - 1.99 (m, 1H), 1.90 - 1.82 (m, 1H) ppm [約5:1非對映異構比-描述主要非對映異構體] 472.2 E   
I-2164
Figure 02_image4615
 O[C@H]1C[C@H](CC(F)(F)F)N(C1)C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl (400 MHz, CD3CN) δ 7.63 - 7.58 (m, 2H), 7.55 (d, J = 7.5 Hz, 1H), 7.46 (dd, J = 8.9, 5.1 Hz, 1H), 7.17 (br s, 1H), 7.10 (ddd, J = 8.8, 8.0, 3.1 Hz, 1H), 6.61 (br s, 1H), 6.61 (br s [浸沒], 1H), 6.21 (br s, 1H), 4.31 - 4.25 (m, 1H), 4.09 - 4.00 (m, 1H), 3.14 (dd, J = 9.8, 5.0 Hz, 1H), 3.05 - 2.92 (m, 1H), 2.88 (dd, J = 9.8, 3.0 Hz, 1H), 2.12 - 2.08 (m, 1H [浸沒在水峰下]), 2.03 - 1.97 (m, 1H), 1.92 - 1.83 (m, 2H) ppm 472.2 D   
I-2165
Figure 02_image4617
 O[C@H]1C[C@H](CC(F)(F)F)N(C1)C(=O)Nc1cccc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl (400 MHz, CD3CN ) δ 7.62 - 7.58 (m, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.13 (br s, 1H), 7.10 - 7.01 (m, 1H), 6.68 (br s, 1H), 6.58 (br s, 1H), 6.18 (br s, 1H), 4.33 - 4.25 (m, 1H), 4.20 - 4.12 (m, 1H), 3.30 (dd, J = 10.1, 4.8 Hz, 1H), 2.81 - 2.67 (m, 2H), 2.12 - 2.07 (m, 1H [浸沒在水峰下]), 2.07 - 1.98 (m, 1H), 1.92 - 1.83 (m, 2H) ppm [約4:1非對映異構比-描述主要非對映異構體] 472.2 E   
I-2166
Figure 02_image4619
 OC[C@@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccccc12 (400 MHz, DMSO-d6)  9.03 (s, 1H), 8.55 (s, 2H), 7.80 (d, J=8.1 Hz, 1H), 7.61-7.51 (m, 2H), 7.41 (dd, J=7.2, 1.8 Hz, 1H), 7.35 (dd, J=8.9, 5.1 Hz, 1H), 7.29 (d, J=7.4 Hz, 1H), 7.21 (t, J=7.7 Hz, 1H), 7.12 (td, J=8.4, 3.1 Hz, 1H), 7.00-6.91 (m, 1H), 6.08 (s, 1H), 5.51 (s, 1H), 4.90 (t, J=5.6 Hz, 1H), 3.68 (d, J=10.9 Hz, 1H), 3.53 (dd, J=11.0, 5.0 Hz, 1H), 3.46-3.36 (m, 2H)。 468.1 D   
I-2167
Figure 02_image4621
 OC[C@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccccc12 (400 MHz, DMSO-d6)  9.05 (s, 1H), 8.44 (s, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.57 (d, J=7.2 Hz, 2H), 7.50 (s, 1H), 7.37 (dd, J=8.8, 5.1 Hz, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 7.11 (dt, J=8.4, 4.2 Hz, 1H), 6.95 (t, J=7.4 Hz, 1H), 6.14 (s, 1H), 5.43 (s, 1H), 4.92 (s, 1H), 3.93 (d, J=10.9 Hz, 1H), 3.50 (s, 2H), 3.27 (d, J = 10.7 Hz, 2H)。 468.1 E   
I-2168
Figure 02_image4623
 OC[C@@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccccc12 (400 MHz, DMSO-d6)  9.03 (s, 1H), 8.56 (s, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.62-7.51 (m, 2H), 7.41 (dd, J=7.2, 1.8 Hz, 1H), 7.35 (dd, J=8.9, 5.2 Hz, 1H), 7.31-7.26 (m, 1H), 7.21 (t, J=7.7 Hz, 1H), 7.12 (td, J=8.3, 3.1 Hz, 1H), 6.95 (t, J=7.4 Hz, 1H), 6.54 (s, 1H), 6.08 (s, 1H), 5.52 (s, 1H), 4.92 (s, 1H), 3.68 (d, J=10.9 Hz, 1H), 3.53 (d, J=10.9 Hz, 1H), 3.41 (t, J=11.7 Hz, 2H)。 468.1 E   
I-2169
Figure 02_image4625
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(CCC#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6) 10.54 (s, 1H), 9.15 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 9.1 Hz, 1H), 7.67 (d, J = 9.8 Hz, 2H), 7.43 (s, 1H), 7.32 (dd, J = 8.9, 5.2 Hz, 1H), 7.10 (td, J = 8.4, 3.1 Hz, 1H), 5.96 (s, 1H), 3.13-2.99 (m, 2H), 2.94 (t, J = 7.1 Hz, 2H)。 520.2 A A
I-2170
Figure 02_image4627
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(CCC#N)cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6) 10.54 (s, 1H), 9.15 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 9.1 Hz, 1H), 7.67 (d, J = 9.8 Hz, 2H), 7.43 (s, 1H), 7.32 (dd, J = 8.9, 5.2 Hz, 1H), 7.10 (td, J = 8.4, 3.1 Hz, 1H), 5.96 (s, 1H), 3.13-2.99 (m, 2H), 2.94 (t, J = 7.1 Hz, 2H)。 520.2 E   
I-2171
Figure 02_image4629
 O[C@@H]1CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2cc(F)ccc12 (400 MHz, DMSO-d6) δ9.08 (s, 1H), 8.63 (s, 1H), 7.58 (q, J = 7.9, 7.4 Hz, 2H), 7.49 - 7.26 (m, 4H), 7.09 (td, J = 8.4, 3.1 Hz, 1H), 6.75 (td, J = 8.7, 2.5 Hz, 1H), 6.55 (s, 1H), 6.08 (s, 1H), 5.79 - 5.49 (m, 1H), 5.12 (dd, J = 7.7, 3.4 Hz, 1H), 3.97 (dd, J = 11.1, 7.9 Hz, 1H), 3.29 (dd, J = 11.1, 3.5 Hz, 1H)。 456.3 A A
I-2172
Figure 02_image4631
 O[C@H]1CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2cc(F)ccc12 (400 MHz, DMSO-d6) δ9.08 (s, 1H), 8.63 (s, 1H), 7.58 (q, J = 7.9, 7.4 Hz, 2H), 7.49 - 7.26 (m, 4H), 7.09 (td, J = 8.4, 3.1 Hz, 1H), 6.75 (td, J = 8.7, 2.5 Hz, 1H), 6.55 (s, 1H), 6.08 (s, 1H), 5.79 - 5.49 (m, 1H), 5.12 (dd, J = 7.7, 3.4 Hz, 1H), 3.97 (dd, J = 11.1, 7.9 Hz, 1H), 3.29 (dd, J = 11.1, 3.5 Hz, 1H)。 456.3 C   
I-2173
Figure 02_image4633
 O[C@@H]1CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2cc(F)ccc12 (400 MHz, DMSO-d6) δ9.08 (s, 1H), 8.63 (s, 1H), 7.58 (q, J = 7.9, 7.4 Hz, 2H), 7.49 - 7.26 (m, 4H), 7.09 (td, J = 8.4, 3.1 Hz, 1H), 6.75 (td, J = 8.7, 2.5 Hz, 1H), 6.55 (s, 1H), 6.08 (s, 1H), 5.79 - 5.49 (m, 1H), 5.12 (dd, J = 7.7, 3.4 Hz, 1H), 3.97 (dd, J = 11.1, 7.9 Hz, 1H), 3.29 (dd, J = 11.1, 3.5 Hz, 1H)。 456.3 D   
I-2174
Figure 02_image4635
 O[C@H]1CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2cc(F)ccc12 (400 MHz, DMSO-d6) δ9.08 (s, 1H), 8.63 (s, 1H), 7.58 (q, J = 7.9, 7.4 Hz, 2H), 7.49 - 7.26 (m, 4H), 7.09 (td, J = 8.4, 3.1 Hz, 1H), 6.75 (td, J = 8.7, 2.5 Hz, 1H), 6.55 (s, 1H), 6.08 (s, 1H), 5.79 - 5.49 (m, 1H), 5.12 (dd, J = 7.7, 3.4 Hz, 1H), 3.97 (dd, J = 11.1, 7.9 Hz, 1H), 3.29 (dd, J = 11.1, 3.5 Hz, 1H)。 456.3 E   
I-2175
Figure 02_image4637
 O[C@@H]1C[C@H](C[C@H](C1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) δ 9.93 (br. s, 1H), 9.08 (br. s, 1H), 7.62 - 7.54 (m, 2H), 7.44 (dd, J = 8.6, 4.8 Hz, 1H), 7.33 (dd, J = 7.4, 1.3 Hz, 1H), 7.18 (ddd, J = 8.8, 8.1, 3.1 Hz, 1H), 6.41 (br. s, 1H), 6.05 (br. s, 1H), 4.81 (br. s, 1H), 4.05 (br. s, 1H), 2.57 (tt, J = 12.1, 3.3 Hz, 1H), 2.46 - 2.38 (m, 1H), 1.80 - 1.72 (m, 1H), 1.60 - 1.54 (m, 1H), 1.37 - 1.19 (m, 3H), 0.98 - 0.88 (m, 1H)。 471.4 E   
I-2176
Figure 02_image4639
 O[C@@H]1C[C@H](C[C@H](C1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) δ 9.79 (br. s, 1H), 9.08 (br. s, 1H), 7.61 - 7.54 (m, 2H), 7.48 (dd, J = 7.4, 4.8 Hz, 1H), 7.43 (dd, J = 7.2, 0.9 Hz, 1H), 7.19 (app. td, J = 8.3, 3.0 Hz, 1H), 6.44 (br. s, 1H), 6.06 (br. s, 1H), 4.84 (br. s, 1H), 4.01 (br. s, 1H), 2.58 (tt, J = 13.3, 3.8 Hz, 1H), 2.46 - 2.39 (m, 1H), 1.81 - 1.74 (m, 1H), 1.53 - 1.46 (m, 1H), 1.39 - 1.18 (m, 3H), 1.08 (app. q, J = 12.8 Hz, 1H)。 471.4 E   
I-2177
Figure 02_image4641
 O[C@H]1C[C@@H](C[C@@H](C1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) δ 9.77 (br. s, 1H), 9.07 (br. s, 1H), 7.61 - 7.54 (m, 2H), 7.48 (dd, J = 7.7, 5.0 Hz, 1H), 7.43 (dd, J = 7.1, 1.5 Hz, 1H), 7.19 (td, J = 8.4, 3.1 Hz, 1H), 6.45 (br. s, 1H), 6.06 (br. s, 1H), 4.82 (d, J = 2.8 Hz, 1H), 4.01 (br. s, 1H), 2.59 (tt, J = 12.0, 3.4 Hz, 1H), 2.48 - 2.40 (m, 1H), 1.81 - 1.73 (m, 1H), 1.53 - 1.47 (m, 1H), 1.38 - 1.18 (m, 3H), 1.08 (app. q, J = 12.7 Hz, 1H)。 471.4 D   
I-2178
Figure 02_image4643
 O[C@H]1C[C@@H](C[C@@H](C1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) δ 9.91 (br. s, 1H), 9.08 (br. s, 1H), 7.62 - 7.54 (m, 2H), 7.44 (dd, J = 8.3, 5.1 Hz, 1H), 7.33 (dd, J = 7.4, 1.0 Hz, 1H), 7.19 (ddd, J = 8.8, 8.1, 3.1 Hz, 1H), 6.40 (br. s, 1H), 6.05 (br. s, 1H), 4.78 (br. s, 1H), 4.05 (br. s, 1H), 2.58 (tt, J = 12.4, 3.6 Hz, 1H), 2.47 - 2.37 (m, 1H), 1.80 - 1.73 (m, 1H), 1.60 - 1.53 (m, 1H), 1.38 - 1.19 (m, 2H), 0.93 (app. q, J = 11.8 Hz, 1H)。 471.4 E   
I-2179
Figure 02_image4645
 O[C@H]1C[C@@H](C[C@@H](C1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) δ 9.88 (br. s, 1H), 9.25 (br. s, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.48 (dd, J = 7.1, 4.6 Hz, 1H), 7.20 (ddd, J = 8.8, 8.1, 3.1 Hz, 1H), 6.56 (br. s, 1H), 6.02 (br. s, 1H), 4.85 (d, J = 2.4 Hz, 1H), 4.01 (br. s, 1H), 2.58 (tt, J = 12.6, 3.6 Hz, 1H), 2.48 - 2.39 (m, 1H), 1.80 - 1.73 (m, 1H), 1.51 - 1.45 (m, 1H), 1.40 - 1.34 (m, 1H), 1.34 - 1.29 (m, 1H), 1.28 - 1.20 (m, 1H), 1.11 - 1.00 (m, 1H)。 549.3 C   
I-2180
Figure 02_image4647
 CC(c1nn[nH]c1C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(F)(F)F (400 MHz, DMSO-d6) δ 11.20 (br s, 1H), 10.26 (br s, 1H), 10.18 (br s, 1H), 9.10 (br s, 1H), 9.08 (br s, 1H), 7.69 - 7.63 (m, 2H), 7.63 - 7.54 (m, 4H), 7.35 - 7.28 (m, 2H), 7.13 - 7.00 (m, 2H), 6.62 (br s, 2H), 6.12 (br s, 2H), 4.66 (br s, 1H), 4.55 (br s, 1H), 1.48 (d, J = 7.1 Hz, 3H), 1.42 (d, J = 7.3 Hz, 3H)。非對映異構體之1:1混合物(兩者皆報導) 468.0 E   
I-2181
Figure 02_image4649
 OCC1CN(CC1C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl (400 MHz, CD3CN) δ 7.59 (重疊dd J = 7.5, 1.3 Hz, 0.5H), 7.59 (重疊dd J = 7.5, 1.5 Hz, 0.5H), 7.52 (t, J = 7.6 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.18 (br s, 1H), 7.11 - 7.04 (m, 1H), 6.68 (br s, 0.5H), 6.65 (br s, 0.5H), 6.59 (浸沒br s, 1H), 6.15 (br s, 1H), 3.66 - 3.59 (m, 0.5H), 3.60 - 3.33 (m, 5.5H), 3.21 - 3.11 (m, 1H), 2.96 - 2.84 (m, 1H), 2.54 - 2.38 (浸沒m, 1H)。 472.0 E   
I-2182
Figure 02_image4651
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCc4ccncc34)c12 (400 MHz, DMSO-d6)  9.07 (s, 1H), 8.87 (s, 1H), 8.71 (s, 1H), 8.13 (d, J = 4.7 Hz, 1H), 7.65 - 7.53 (m, 2H), 7.42 - 7.33 (m, 2H), 7.29 - 7.23 (m, 1H), 7.15 (ddd, J = 8.9, 7.9, 3.1 Hz, 1H), 6.55 (s, 1H), 6.01 (s, 1H), 3.89 (q, J = 9.8 Hz, 1H), 3.20 - 2.99 (m, 3H)。 423.2 E   
I-2183
Figure 02_image4653
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(Br)cc(Nc3cn[nH]c3)c12 (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 9.09 (s, 1H), 7.59 (br. s, 1H), 7.51 (dd, J = 8.8, 5.2 Hz, 1H), 7.23 (ddd, J = 8.8, 8.0, 3.1 Hz, 2H), 7.15 (d, J = 1.6 Hz, 1H), 6.98 - 6.94 (m, 2H), 6.68 (br. s, 1H), 5.82 (s, 1H)；外消旋混合物。 421.1 E   
I-2184
Figure 02_image4655
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Br)cc(Nc3cn[nH]c3)c12 (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 9.09 (s, 1H), 7.59 (br. s, 1H), 7.51 (dd, J = 8.8, 5.2 Hz, 1H), 7.23 (ddd, J = 8.8, 8.0, 3.1 Hz, 2H), 7.15 (d, J = 1.6 Hz, 1H), 6.98 - 6.94 (m, 2H), 6.68 (br. s, 1H), 5.82 (s, 1H) 421.1 E   
I-2185
Figure 02_image4657
 FC(F)c1ccc(F)cc1C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ncnc2cn1       A A
I-2186
Figure 02_image4659
 CC(C)(CN)n1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    604.3 A B
I-2187
Figure 02_image4661
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(C#Cc3cc(F)cc(c3)C(F)(F)F)c12    448.2 E   
I-2188
Figure 02_image4663
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(C(=O)Nc3ccccc3)c12 (400 MHz, DMSO-d6)  10.32 (s, 1H), 9.25 (s, 1H), 7.93 (dd, J=7.7, 3.9 Hz, 2H), 7.74 (t, J=7.5 Hz, 1H), 7.41 (d, J=8.1 Hz, 3H), 7.27 (t, J=7.9 Hz, 2H), 7.16-7.01 (m, 2H), 6.41 (s, 1H)。 381.2 E   
I-2189
Figure 02_image4665
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(C(=O)Nc3cccc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6) 10.65 (s, 1H), 9.28 (s, 1H), 7.95 (t, J = 7.3 Hz, 2H), 7.81 (s, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.45-7.38 (m, 1H), 7.35 (dd, J = 8.9, 5.2 Hz, 1H), 7.10 (ddd, J = 8.9, 7.9, 3.1 Hz, 1H), 6.40 (s, 1H)。 449.2 D   
I-2190
Figure 02_image4667
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-n1ncccc1=O (400 MHz, DMSO-d6)  10.67 (s, 1H), 9.29 (s, 1H), 8.13 (dd, J = 3.8, 1.6 Hz, 1H), 7.92 (dd, J = 12.0, 5.2 Hz, 2H), 7.84 - 7.73 (m, 2H), 7.69 (s, 1H), 7.55 (dd, J = 9.5, 3.8 Hz, 1H), 7.35 (dd, J = 8.9, 5.2 Hz, 1H), 7.13 (ddd, J = 16.8, 9.0, 2.3 Hz, 2H), 6.73 (s, 1H), 6.04 (s, 1H)。 561.1 B   
I-2191
Figure 02_image4669
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCc4cnccc34)c12 (400 MHz, DMSO-d6) 9.09 (s, 1H), 8.81 (s, 1H), 8.31 - 8.26 (m, 1H), 8.23 (d, J = 5.4 Hz, 1H), 7.66 - 7.60 (m, 1H), 7.63 - 7.54 (m, 2H), 7.43 - 7.35 (m, 2H), 7.16 (ddd, J = 8.8, 7.9, 3.1 Hz, 1H), 6.59 (s, 1H), 6.00 (s, 1H), 3.92 (td, J = 10.1, 7.0 Hz, 1H), 3.19 - 3.08 (m, 2H), 3.08 (s, 1H)。 423.1 D   
I-2192
Figure 02_image4671
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-n1ccccc1=O (400 MHz, DMSO-d6)  10.68 (s, 1H), 9.32 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.82 - 7.71 (m, 2H), 7.71 - 7.65 (m, 2H), 7.62 - 7.53 (m, 2H), 7.36 (dd, J = 8.9, 5.2 Hz, 1H), 7.13 (td, J = 8.4, 3.0 Hz, 1H), 7.00 - 6.76 (s, 1H), 6.55 (dt, J = 9.2, 1.0 Hz, 1H), 6.38 (td, J = 6.7, 1.4 Hz, 1H), 6.06 (s, 1H)。 560.1 A B
I-2193
Figure 02_image4673
 CCC(CC(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(C)C(F)(F)F (400 MHz, DMSO-d6 ) δ , 9.74 (br. s, 1H), 9.08 (br. s, 1H), 7.65 - 7.52 (m, 2H), 7.53 - 7.46 (m, 1H), 7.42 (dd, J = 7.4, 1.4 Hz, 1H), 7.26 - 7.16 (m, 1H), 6.42 (br. s, 1H), 6.07 (br. s, 1H), 2.48 - 2.28 (m, 1H), 2.21 - 1.74 (m, 3H), 1.24 - 0.95 (m, 2H), 0.94 (d, J = 2.0 Hz, 3H), 0.75 (t, J = 7.3 H, 3Hz) 457.2 D   
I-2194
Figure 02_image4675
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3[nH]nnc3CC(F)(F)F)c12 (400 MHz, DMSO-d6) δ 10.19 (br s, 1H), 9.10 (br s, 1H), 7.68 - 7.62 (m, 1H), 7.62 - 7.56 (m, 2H), 7.31 (dd, J = 8.8, 5.2 Hz, 1H), 7.07 (td, J = 8.4, 3.1 Hz, 1H), 6.62 (br s, 1H), 6.12 (br s, 1H), 4.11 - 3.97 (m, 2H)。 454.0 E   
I-2195
Figure 02_image4677
 CC(C(CC(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)C=C)C(F)(F)F (400 MHz, DMSO-d6 ) δ 9.67 (br. s, 1H), 9.07 (br. s, 1H), 7.68 - 7.51 (m, 2H), 7.54 - 7.44 (m, 1H), 7.41 (dd, J = 7.5, 1.4 Hz, 1H), 7.32 - 7.10 (m, 1H), 6.59 (br. s, 1H), 6.04 (br. s, 1H), 5.58 (dd, J = 17.6, 8.5 Hz, 1H), 5.04 - 4.87 (m, 2H), 2.87 - 2.63 (m, 1H), 2.35 - 1.88 (m, 2H), 0.99 (d, J = 7.1 Hz, 3H)；非對映異構體之1:1混合物。 455.3 D   
I-2196
Figure 02_image4679
 CC(C)(C)CCC1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSOd6) δ 10.79 (s, 1H), 8.72 (s, 1H), 8.16 (s, 1H), 8.09 (d, J = 8.9 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.60 - 7.51 (m, 3H), 4.79 (dd, J = 6.4, 2.4 Hz, 1H), 1.88 - 1.76 (m, 1H), 1.43 - 1.28 (m, 1H), 0.99 - 0.81 (m, 2H), 0.68 (s, 9H)。 423.4 D   
I-2197
Figure 02_image4681
 CC(C(CO)CC(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(F)(F)F (400 MHz, DMSO-d6 ) δ 9.72 (s, 1H), 9.07 (s, 1H), 7.68 - 7.53 (m, 2H), 7.52 - 7.44 (m, 1H), 7.39 (dd, J = 7.5, 1.3 Hz, 1H), 7.27 - 7.15 (m, 1H), 6.59 (br. s, 1H), 6.01 (重疊br. s, 1H), 4.82 (重疊d, J = 5.0 Hz, 1H), 3.32 - 3.13 (m, 1H), 3.15 - 2.97 (m, 1H), 2.75 - 2.54 (m, 1H), 2.41 - 2.15 (m, 1H), 2.10 - 1.76 (m, 2H), 0.94 (d, J = 3.6 Hz, 3H)；非對映異構體之1:1混合物 459.2 E   
I-2198
Figure 02_image4683
 CC(O)C(CC(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(C)C(F)(F)F (400 MHz, DMSO-d6 ) δ 9.64 (br. s, 1H), 9.06 (br. s, 1H), 7.65 - 7.51 (m, 2H), 7.51 - 7.32 (m, 2H), 7.26 - 7.11 (m, 1H), 6.50 (br. s, 1H), 6.06 (br. s, 1H), 4.70 (d, J = 4.2 Hz, 1H), 3.71 - 3.38 (m, 1H), 3.00 - 2.57 (m, 1H), 2.39 - 1.84 (m, 3H), 1.00 - 0.93 (m, 3H), 0.89 (d, J = 6.2 Hz, 3H)；非對映異構體之1:1:0.85:0.75混合物。 473.3 E   
I-2199
Figure 02_image4685
 OC[C@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccccc12 (400 MHz, DMSO-d6)  9.05 (s, 1H), 8.43 (s, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.62-7.52 (m, 2H), 7.49 (dd, J=7.0, 2.0 Hz, 1H), 7.36 (dd, J=8.9, 5.1 Hz, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.23-7.15 (m, 1H), 7.10 (td, J=8.4, 3.1 Hz, 1H), 6.95 (t, J=7.5 Hz, 1H), 6.14 (s, 1H), 5.41 (s, 1H), 4.90 (t, J=5.4 Hz, 1H), 3.93 (d, J=10.8 Hz, 1H), 3.50 (d, J=5.5 Hz, 2H), 3.27 (d, J=10.7 Hz, 1H)。 468.1 E   
I-2200
Figure 02_image4687
 CN(C)c1nc2cc(ccn2n1)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (DMSO-d6, 400 MHz) 10.61 (1H, s), 9.23 (1H, s), 9.16 (1H, s), 8.04 (1H, s), 7.99-7.86 (3H, m), 7.78 (1H, d, J=9.0 Hz), 7.72 (1H, s), 7.56 (1H, d, J=9.2 Hz), 7.34 (1H, dd, J=8.9, 5.1 Hz), 7.16-7.08 (1H, m), 6.03 (1H, s), 3.08 (6H, s) 627.1 A A
I-2201
Figure 02_image4689
 FC(F)c1ccc(F)cc1C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)-c1cn2ncnc2cn1    567.2 A B
I-2202
Figure 02_image4691
 CN1CCO\C1=N/c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl    565.0 B   
I-2203
Figure 02_image4693
 C[C@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccccc12 (400 MHz, DMSO-d6)  9.07 (s, 1H), 8.39 (s, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.61-7.51 (m, 3H), 7.37 (dd, J=8.8, 5.2 Hz, 1H), 7.29 (dd, J=7.5, 1.4 Hz, 1H), 7.21-7.13 (m, 1H), 7.09 (td, J=8.4, 3.1 Hz, 1H), 7.00-6.92 (m, 1H),6.53(s, 1H) 6.14 (s, 1H), 5.46 (s, 1H), 3.59 (d, J=10.6 Hz, 1H), 3.51 (d, J=10.5 Hz, 1H), 1.45 (s, 3H)。 452.0 D   
I-2204
Figure 02_image4695
 C[C@@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccccc12    450.0 D   
I-2205
Figure 02_image4697
 C[C@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccccc12 (400 MHz, DMSO-d6)  9.04 (s, 1H), 8.58 (s, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.72-7.51 (m, 2H), 7.42-7.34 (m, 2H), 7.31 (dd, J=7.4, 1.3 Hz, 1H), 7.26-7.12 (m, 3H), 6.98 (td, J=7.4, 1.1 Hz, 1H), 6.58 (s, 1H), 6.01 (s, 1H), 5.52 (s, 1H), 3.84 (d, J=10.8 Hz, 1H), 1.41 (s, 3H)。 450.0 A A
I-2206
Figure 02_image4699
 C[C@@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccccc12 (400 MHz, DMSO-d6)  9.04 (s, 1H), 8.58 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.57 (d, J=7.3 Hz, 2H), 7.37 (dd, J=9.0, 5.5 Hz, 2H), 7.31 (d, J=7.4 Hz, 1H), 7.26-7.12 (m, 2H),6.53-6.98 (t, J=7.4 Hz, 1H), 6.01 (s, 1H), 5.51 (s, 1H), 3.84 (d, J=10.8 Hz, 1H), 2.97 (s, 1H), 1.41 (s, 3H)。 452.0 E   
I-2207
Figure 02_image4701
 O[C@H]1CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2c1cccc2F (400 MHz, DMSO-d6) 9.09 (s, 1H), 9.04 (s, 1H), 7.57 (d, J = 4.3 Hz, 2H), 7.49 (s, 1H), 7.43-7.37 (m, 1H), 7.26 (td, J = 8.4, 3.1 Hz, 1H), 7.16 (dd, J = 5.2, 3.4 Hz, 1H), 7.13-7.04 (m, 2H), 5.94 (s, 1H), 5.77 (d, J = 6.2 Hz, 1H), 5.15 (q, J = 6.7 Hz, 1H), 3.51 (dd, J = 11.3, 6.0 Hz, 1H), 3.24 (t, J = 9.6 Hz, 1H)。 456.1 D   
I-2208
Figure 02_image4703
 O[C@@H]1CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2c1cccc2F (400 MHz, DMSO-d6) 9.09 (s, 1H), 9.04 (s, 1H), 7.57 (d, J = 4.3 Hz, 2H), 7.49 (s, 1H), 7.43-7.37 (m, 1H), 7.26 (td, J = 8.4, 3.1 Hz, 1H), 7.16 (dd, J = 5.2, 3.4 Hz, 1H), 7.13-7.04 (m, 2H), 5.94 (s, 1H), 5.77 (d, J = 6.2 Hz, 1H), 5.15 (q, J = 6.7 Hz, 1H), 3.51 (dd, J = 11.3, 6.0 Hz, 1H), 3.24 (t, J = 9.6 Hz, 1H)。 456.1 E   
I-2209
Figure 02_image4705
 O[C@H]1CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2c1cccc2F (400 MHz, DMSO-d6) 9.09 (s, 1H), 9.04 (s, 1H), 7.57 (d, J = 4.3 Hz, 2H), 7.49 (s, 1H), 7.43-7.37 (m, 1H), 7.26 (td, J = 8.4, 3.1 Hz, 1H), 7.16 (dd, J = 5.2, 3.4 Hz, 1H), 7.13-7.04 (m, 2H), 5.94 (s, 1H), 5.77 (d, J = 6.2 Hz, 1H), 5.15 (q, J = 6.7 Hz, 1H), 3.51 (dd, J = 11.3, 6.0 Hz, 1H), 3.24 (t, J = 9.6 Hz, 1H)。 456.1 E   
I-2210
Figure 02_image4707
 O[C@@H]1CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2c1cccc2F (400 MHz, DMSO-d6) 9.09 (s, 1H), 9.04 (s, 1H), 7.57 (d, J = 4.3 Hz, 2H), 7.49 (s, 1H), 7.43-7.37 (m, 1H), 7.26 (td, J = 8.4, 3.1 Hz, 1H), 7.16 (dd, J = 5.2, 3.4 Hz, 1H), 7.13-7.04 (m, 2H), 5.94 (s, 1H), 5.77 (d, J = 6.2 Hz, 1H), 5.15 (q, J = 6.7 Hz, 1H), 3.51 (dd, J = 11.3, 6.0 Hz, 1H), 3.24 (t, J = 9.6 Hz, 1H)。 456.1 E   
I-2211
Figure 02_image4709
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cccc(NC(=O)[C@H]3CCC[C@@H](C3)OC(F)(F)F)c12 混合物(400 MHz, DMSO-d6) δ 9.79 (br s, 0.35H), 9.77 (br s, 0.15H), 9.76 (br s, 0.15H), 9.73 (br s, 0.35H), 9.09 (br s, 1H), 7.63 - 7.54 (m, 2H), 7.52 - 7.44 (m, 1H), 7.43 - 7.35 (m, 1H), 7.25 - 7.16 (m, 1H), 6.46 (br s, 1H), 6.03 (br s, 1H), 4.74 - 4.70 (m, 0.15H), 4.70 - 4.67 (m, 0.15H), 4.33 - 4.27 (m, 0.35H), 4.27 - 4.21 (m, 0.35H), 2.46 - 2.40 (m, 0.15H), 2.39 - 2.30 (m, 0.15H), 2.26-2.20 (m, 0.35H), 2.20-2.14 (m, 0.35H), 1.95 (br s, 1H), 1.84 - 1.38 (m, 4.3H), 1.37 - 1.16 (m, 2H), 1.13 - 1.00 (m, 0.3H), 0.99 - 0.86 (m, 0.3H)。 471.0 E   
I-2212
Figure 02_image4711
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cccc(NC(=O)[C@H]3CCC[C@@H](C3)OC(F)(F)F)c12 混合物(400 MHz, DMSO-d6) δ 9.79 (br s, 0.35H), 9.77 (br s, 0.15H), 9.76 (br s, 0.15H), 9.73 (br s, 0.35H), 9.09 (br s, 1H), 7.63 - 7.54 (m, 2H), 7.52 - 7.44 (m, 1H), 7.43 - 7.35 (m, 1H), 7.25 - 7.16 (m, 1H), 6.46 (br s, 1H), 6.03 (br s, 1H), 4.74 - 4.70 (m, 0.15H), 4.70 - 4.67 (m, 0.15H), 4.33 - 4.27 (m, 0.35H), 4.27 - 4.21 (m, 0.35H), 2.46 - 2.40 (m, 0.15H), 2.39 - 2.30 (m, 0.15H), 2.26-2.20 (m, 0.35H), 2.20-2.14 (m, 0.35H), 1.95 (br s, 1H), 1.84 - 1.38 (m, 4.3H), 1.37 - 1.16 (m, 2H), 1.13 - 1.00 (m, 0.3H), 0.99 - 0.86 (m, 0.3H)。 471.0 E   
I-2213
Figure 02_image4713
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cccc(NC(=O)[C@@H]3CCC[C@@H](C3)OC(F)(F)F)c12 混合物(400 MHz, DMSO-d6) δ 9.79 (br s, 0.35H), 9.77 (br s, 0.15H), 9.76 (br s, 0.15H), 9.73 (br s, 0.35H), 9.09 (br s, 1H), 7.63 - 7.54 (m, 2H), 7.52 - 7.44 (m, 1H), 7.43 - 7.35 (m, 1H), 7.25 - 7.16 (m, 1H), 6.46 (br s, 1H), 6.03 (br s, 1H), 4.74 - 4.70 (m, 0.15H), 4.70 - 4.67 (m, 0.15H), 4.33 - 4.27 (m, 0.35H), 4.27 - 4.21 (m, 0.35H), 2.46 - 2.40 (m, 0.15H), 2.39 - 2.30 (m, 0.15H), 2.26-2.20 (m, 0.35H), 2.20-2.14 (m, 0.35H), 1.95 (br s, 1H), 1.84 - 1.38 (m, 4.3H), 1.37 - 1.16 (m, 2H), 1.13 - 1.00 (m, 0.3H), 0.99 - 0.86 (m, 0.3H)。 471.0 E   
I-2214
Figure 02_image4715
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cccc(NC(=O)[C@@H]3CCC[C@@H](C3)OC(F)(F)F)c12 混合物(400 MHz, DMSO-d6) δ 9.79 (br s, 0.35H), 9.77 (br s, 0.15H), 9.76 (br s, 0.15H), 9.73 (br s, 0.35H), 9.09 (br s, 1H), 7.63 - 7.54 (m, 2H), 7.52 - 7.44 (m, 1H), 7.43 - 7.35 (m, 1H), 7.25 - 7.16 (m, 1H), 6.46 (br s, 1H), 6.03 (br s, 1H), 4.74 - 4.70 (m, 0.15H), 4.70 - 4.67 (m, 0.15H), 4.33 - 4.27 (m, 0.35H), 4.27 - 4.21 (m, 0.35H), 2.46 - 2.40 (m, 0.15H), 2.39 - 2.30 (m, 0.15H), 2.26-2.20 (m, 0.35H), 2.20-2.14 (m, 0.35H), 1.95 (br s, 1H), 1.84 - 1.38 (m, 4.3H), 1.37 - 1.16 (m, 2H), 1.13 - 1.00 (m, 0.3H), 0.99 - 0.86 (m, 0.3H)。 471.0 E   
I-2215
Figure 02_image4717
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cccc(NC(=O)[C@@H]3CCC[C@H](C3)OC(F)(F)F)c12 混合物(400 MHz, DMSO-d6) δ 9.79 (br s, 0.35H), 9.77 (br s, 0.15H), 9.76 (br s, 0.15H), 9.73 (br s, 0.35H), 9.09 (br s, 1H), 7.63 - 7.54 (m, 2H), 7.52 - 7.44 (m, 1H), 7.43 - 7.35 (m, 1H), 7.25 - 7.16 (m, 1H), 6.46 (br s, 1H), 6.03 (br s, 1H), 4.74 - 4.70 (m, 0.15H), 4.70 - 4.67 (m, 0.15H), 4.33 - 4.27 (m, 0.35H), 4.27 - 4.21 (m, 0.35H), 2.46 - 2.40 (m, 0.15H), 2.39 - 2.30 (m, 0.15H), 2.26-2.20 (m, 0.35H), 2.20-2.14 (m, 0.35H), 1.95 (br s, 1H), 1.84 - 1.38 (m, 4.3H), 1.37 - 1.16 (m, 2H), 1.13 - 1.00 (m, 0.3H), 0.99 - 0.86 (m, 0.3H)。 471.0 E   
I-2216
Figure 02_image4719
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cccc(NC(=O)[C@@H]3CCC[C@H](C3)OC(F)(F)F)c12 混合物(400 MHz, DMSO-d6) δ 9.79 (br s, 0.35H), 9.77 (br s, 0.15H), 9.76 (br s, 0.15H), 9.73 (br s, 0.35H), 9.09 (br s, 1H), 7.63 - 7.54 (m, 2H), 7.52 - 7.44 (m, 1H), 7.43 - 7.35 (m, 1H), 7.25 - 7.16 (m, 1H), 6.46 (br s, 1H), 6.03 (br s, 1H), 4.74 - 4.70 (m, 0.15H), 4.70 - 4.67 (m, 0.15H), 4.33 - 4.27 (m, 0.35H), 4.27 - 4.21 (m, 0.35H), 2.46 - 2.40 (m, 0.15H), 2.39 - 2.30 (m, 0.15H), 2.26-2.20 (m, 0.35H), 2.20-2.14 (m, 0.35H), 1.95 (br s, 1H), 1.84 - 1.38 (m, 4.3H), 1.37 - 1.16 (m, 2H), 1.13 - 1.00 (m, 0.3H), 0.99 - 0.86 (m, 0.3H)。 471.0 E   
I-2217
Figure 02_image4721
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cccc(NC(=O)[C@H]3CCC[C@H](C3)OC(F)(F)F)c12 混合物(400 MHz, DMSO-d6) δ 9.79 (br s, 0.35H), 9.77 (br s, 0.15H), 9.76 (br s, 0.15H), 9.73 (br s, 0.35H), 9.09 (br s, 1H), 7.63 - 7.54 (m, 2H), 7.52 - 7.44 (m, 1H), 7.43 - 7.35 (m, 1H), 7.25 - 7.16 (m, 1H), 6.46 (br s, 1H), 6.03 (br s, 1H), 4.74 - 4.70 (m, 0.15H), 4.70 - 4.67 (m, 0.15H), 4.33 - 4.27 (m, 0.35H), 4.27 - 4.21 (m, 0.35H), 2.46 - 2.40 (m, 0.15H), 2.39 - 2.30 (m, 0.15H), 2.26-2.20 (m, 0.35H), 2.20-2.14 (m, 0.35H), 1.95 (br s, 1H), 1.84 - 1.38 (m, 4.3H), 1.37 - 1.16 (m, 2H), 1.13 - 1.00 (m, 0.3H), 0.99 - 0.86 (m, 0.3H)。 471.0 E   
I-2218
Figure 02_image4723
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cccc(NC(=O)[C@H]3CCC[C@H](C3)OC(F)(F)F)c12 混合物(400 MHz, DMSO-d6) δ 9.79 (br s, 0.35H), 9.77 (br s, 0.15H), 9.76 (br s, 0.15H), 9.73 (br s, 0.35H), 9.09 (br s, 1H), 7.63 - 7.54 (m, 2H), 7.52 - 7.44 (m, 1H), 7.43 - 7.35 (m, 1H), 7.25 - 7.16 (m, 1H), 6.46 (br s, 1H), 6.03 (br s, 1H), 4.74 - 4.70 (m, 0.15H), 4.70 - 4.67 (m, 0.15H), 4.33 - 4.27 (m, 0.35H), 4.27 - 4.21 (m, 0.35H), 2.46 - 2.40 (m, 0.15H), 2.39 - 2.30 (m, 0.15H), 2.26-2.20 (m, 0.35H), 2.20-2.14 (m, 0.35H), 1.95 (br s, 1H), 1.84 - 1.38 (m, 4.3H), 1.37 - 1.16 (m, 2H), 1.13 - 1.00 (m, 0.3H), 0.99 - 0.86 (m, 0.3H)。 471.0 E   
I-2219
Figure 02_image4725
 OCC12CC(C1)(C2)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) δ 9.41 (br. s, 1H), 9.05 (br. s, 1H), 7.60 (dd, J = 7.4, 0.9 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.38 (dd, J = 7.6, 1.0 Hz, 1H), 7.24 (ddd, J = 8.8, 8.1, 3.1 Hz, 1H), 6.54 (br. s, 1H), 5.97 (br. s, 1H), 4.53 (t, J = 5.6 Hz, 1H), 3.33 - 3.31 (m, 2H), 1.65 - 1.59 (m, 6H)。 401.3 E   
I-2220
Figure 02_image4727
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@H](C3CC3)c12    379.4 E   
I-2221
Figure 02_image4729
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H](C3CC3)c12    379.3 E   
I-2222
Figure 02_image4731
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCNC(C3)C(F)(F)F)c12 (400 MHz, DMSO-d6) δ 9.03 (br s, 1H), 8.65 (s, 0.6H), 8.63 (s, 0.4H), 7.63 - 7.45 (m, 3H), 7.33 - 7.13 (m, 2H), 6.48 (br s, 1H), 5.99 (br s, 1H), 3.81 (br d, J = 11.4 Hz, 1H), 3.62 (浸沒br d, J = 12.0 Hz, 0.6H), 3.20 - 3.04 (m, 0.6H), 2.93 - 2.55 (m, 3.6H), 2.49 - 2.35 (浸沒m, 1H), 2.21 - 2.05 (m, 0.4H)。 457.0 E   
I-2223
Figure 02_image4733
 Nc1cc(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c2C(NC(=O)c2c1C#N)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) δ 10.42 (br s, 1 H), 9.16 (br s, 1 H), 7.94 - 7.82 (m, 1 H), 7.67 (d, J = 9.0 Hz, 1 H), 7.59 (s, 1 H), 7.31 (dd, J = 8.8, 5.2 Hz, 1 H), 7.07 (td, J = 8.4, 3.0 Hz, 1 H), 7.07 (浸沒s, 1 H) 6.66 (br s, 1 H), 6.40 (br s, 1 H), 6.40 (浸沒br s, 1 H), 5.82 (br s, 1 H)。 507.2 A A
I-2224
Figure 02_image4735
 O[C@@H]1CCC[C@@H](C1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6 ) δ 10.73 (s, 1H), 8.74 (s, 1H), 8.13 (s, 1H), 8.08 (d, J = 9.4 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.66 - 7.49 (m, 3H), 4.73 (s, 1H), 4.60 (d, J = 3.9 Hz, 1H), 3.25 - 3.02 (m, 1H), 1.99 - 1.82 (m, 1H), 1.81 - 1.58 (m, 2H), 1.59 - 1.35 (m, 1H), 1.23 (dd, J = 23.9, 12.0 Hz, 1H), 1.09 - 0.73 (m, 2H), 0.75 - 0.43 (m, 2H)；非對映異構體之2.5:1混合物；描述主要非對映異構體。 437.3 E   
I-2225
Figure 02_image4737
 O[C@H]1CCCC(C1)[C@H]1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6 ) δ 10.73 (s, 1H), 8.74 (s, 1H), 8.13 (s, 1H), 8.08 (d, J = 9.4 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.66 - 7.49 (m, 3H), 4.73 (s, 1H), 4.60 (d, J = 3.9 Hz, 1H), 3.25 - 3.02 (m, 1H), 1.99 - 1.82 (m, 1H), 1.81 - 1.58 (m, 2H), 1.59 - 1.35 (m, 1H), 1.23 (dd, J = 23.9, 12.0 Hz, 1H), 1.09 - 0.73 (m, 2H), 0.75 - 0.43 (m, 2H)；非對映異構體之2.5:1混合物；描述主要非對映異構體。 437.3 E   
I-2226
Figure 02_image4739
 O[C@@H]1CCC[C@H](C1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6 ) δ 10.73 (s, 1H), 8.74 (s, 1H), 8.13 (s, 1H), 8.08 (d, J = 9.4 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.66 - 7.49 (m, 3H), 4.73 (s, 1H), 4.60 (d, J = 3.9 Hz, 1H), 3.25 - 3.02 (m, 1H), 1.99 - 1.82 (m, 1H), 1.81 - 1.58 (m, 2H), 1.59 - 1.35 (m, 1H), 1.23 (dd, J = 23.9, 12.0 Hz, 1H), 1.09 - 0.73 (m, 2H), 0.75 - 0.43 (m, 2H)；非對映異構體之2.5:1混合物；描述主要非對映異構體。 437.3 E   
I-2227
Figure 02_image4741
 O[C@H]1CCC[C@H](C1)C1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6 ) δ 10.73 (s, 1H), 8.74 (s, 1H), 8.13 (s, 1H), 8.08 (d, J = 9.4 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.66 - 7.49 (m, 3H), 4.73 (s, 1H), 4.60 (d, J = 3.9 Hz, 1H), 3.25 - 3.02 (m, 1H), 1.99 - 1.82 (m, 1H), 1.81 - 1.58 (m, 2H), 1.59 - 1.35 (m, 1H), 1.23 (dd, J = 23.9, 12.0 Hz, 1H), 1.09 - 0.73 (m, 2H), 0.75 - 0.43 (m, 2H)；非對映異構體之2.5:1混合物；描述主要非對映異構體。 437.3 E   
I-2228
Figure 02_image4743
 C[C@H](O)c1cc(cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 (400 MHz, DMSO-d6 )  δ 9.43 (br. s, 1H), 9.23 (br. s, 1H), 8.57 (s, 1H), 8.14 - 8.10 (m, 1H), 8.09 (d, J = 1.8 Hz, 1H), 8.08 - 8.01 (m, 2H), 7.98 (br. s, 1H), 7.71 - 7.54 (m, 1H), 7.28 (td, J = 8.5, 2.9 Hz, 1H), 6.51 (br. s, 1H), 6.22 (br. s, 1H), 5.28 (d, J = 3.5 Hz, 1H), 4.54 - 4.41 (m, 1H), 1.25 (d, J = 5.0 Hz, 3H)；非對映異構體之3:1混合物；描述主要非對映異構體。 423.1 E   
I-2229
Figure 02_image4745
 C[C@H](O)c1cc(cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 (400 MHz, DMSO-d6 ) δ 9.43 (br. s, 1H), 9.23 (br. s, 1H), 8.57 (s, 1H), 8.14 - 8.10 (m, 1H), 8.09 (d, J = 1.8 Hz, 1H), 8.08 - 8.01 (m, 2H), 7.98 (br. s, 1H), 7.71 - 7.54 (m, 1H), 7.28 (td, J = 8.5, 2.9 Hz, 1H), 6.51 (br. s, 1H), 6.22 (br. s, 1H), 5.28 (d, J = 3.5 Hz, 1H), 4.54 - 4.41 (m, 1H), 1.25 (d, J = 5.0 Hz, 3H)；非對映異構體之3:1混合物；描述主要非對映異構體 423.1 E   
I-2230
Figure 02_image4747
 C[C@@H](O)c1cc(cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 (400 MHz, DMSO-d6 ) δ 9.43 (br. s, 1H), 9.23 (br. s, 1H), 8.57 (s, 1H), 8.14 - 8.10 (m, 1H), 8.09 (d, J = 1.8 Hz, 1H), 8.08 - 8.01 (m, 2H), 7.98 (br. s, 1H), 7.71 - 7.54 (m, 1H), 7.28 (td, J = 8.5, 2.9 Hz, 1H), 6.51 (br. s, 1H), 6.22 (br. s, 1H), 5.28 (d, J = 3.5 Hz, 1H), 4.54 - 4.41 (m, 1H), 1.25 (d, J = 5.0 Hz, 3H)；非對映異構體之3:1混合物；描述主要非對映異構體。 423.1 E   
I-2231
Figure 02_image4749
 C[C@@H](O)c1cc(cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)-c1ccc2ncnn2c1 (400 MHz, DMSO-d6 ) δ 9.43 (br. s, 1H), 9.23 (br. s, 1H), 8.57 (s, 1H), 8.14 - 8.10 (m, 1H), 8.09 (d, J = 1.8 Hz, 1H), 8.08 - 8.01 (m, 2H), 7.98 (br. s, 1H), 7.71 - 7.54 (m, 1H), 7.28 (td, J = 8.5, 2.9 Hz, 1H), 6.51 (br. s, 1H), 6.22 (br. s, 1H), 5.28 (d, J = 3.5 Hz, 1H), 4.54 - 4.41 (m, 1H), 1.25 (d, J = 5.0 Hz, 3H)；非對映異構體之3:1混合物；描述主要非對映異構體。 423.1 E   
I-2232
Figure 02_image4751
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3noc4CCOCc34)c12       E   
I-2233
Figure 02_image4753
 FC(F)c1ccc(F)cc1[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ncnc2cn1    601.3 D   
I-2234
Figure 02_image4755
 FC(F)c1ccc(F)cc1[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1cn2ncnc2cn1    603.1 A A
I-2235
Figure 02_image4757
 CC1(C)CCc2scc(C(=O)Nc3cccc4C(=O)NC(c34)c3cc(F)ccc3Cl)c2C1       D   
I-2236
Figure 02_image4759
 O[C@@H]1C[C@H](CN(C1)C(=O)Nc1cccc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl)C(F)(F)F    472.0 E   
I-2237
Figure 02_image4761
 O[C@@H]1C[C@H](CN(C1)C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)C(F)(F)F    472.0 D   
I-2238
Figure 02_image4763
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3noc4CCCCc34)c12       D   
I-2239
Figure 02_image4765
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3csc4CCCCc34)c12       A B
I-2240
Figure 02_image4767
 CN1CCN(CC1(C)C)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.49 (s, 1H), 7.59 (d, J = 1.4 Hz, 1H), 7.53 (d, J = 1.5 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.23 (td, J = 8.4, 3.0 Hz, 1H), 6.61 (br. s, 1H), 6.01 (br. s, 1H), 3.23 - 3.16 (m, 1H), 3.02 - 2.96 (m, 1H), 2.92 (d, J = 13.4 Hz, 1H), 2.76 (d, J = 12.6 Hz, 1H), 2.32 - 2.20 (m, 2H), 2.06 (s, 3H), 0.84 (s, 3H), 0.69 (s, 3H)。 511.3 E   
I-2241
Figure 02_image4769
 CN1CCN(CC1(C)C)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.49 (s, 1H), 7.59 (d, J = 1.4 Hz, 1H), 7.53 (d, J = 1.5 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.23 (td, J = 8.4, 3.0 Hz, 1H), 6.61 (br. s, 1H), 6.01 (br. s, 1H), 3.23 - 3.16 (m, 1H), 3.02 - 2.96 (m, 1H), 2.92 (d, J = 13.4 Hz, 1H), 2.76 (d, J = 12.6 Hz, 1H), 2.32 - 2.20 (m, 2H), 2.06 (s, 3H), 0.84 (s, 3H), 0.69 (s, 3H)。 511.3 E   
I-2242
Figure 02_image4771
 Fc1ccc(Cl)c(c1)[C@@H]1NC(=O)c2cc(Br)cc(NC(=O)N3CCOCC(F)(F)C3)c12 (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.66 (s, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.23 (td, J = 8.4, 3.1 Hz, 1H), 6.57 (br. s, 1H), 6.04 (br. s, 1H), 4.17 (dt, J = 15.4, 11.2 Hz, 1H), 3.77 - 3.53 (m, 4H), 3.52 - 3.41 (m, 2H), 3.19 (ddd, J = 14.6, 8.0, 3.6 Hz, 1H)。 520.3 E   
I-2243
Figure 02_image4773
 Fc1ccc(Cl)c(c1)[C@H]1NC(=O)c2cc(Br)cc(NC(=O)N3CCOCC(F)(F)C3)c12 (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.66 (s, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.23 (td, J = 8.4, 3.1 Hz, 1H), 6.57 (br. s, 1H), 6.04 (br. s, 1H), 4.17 (dt, J = 15.4, 11.2 Hz, 1H), 3.77 - 3.53 (m, 4H), 3.52 - 3.41 (m, 2H), 3.19 (ddd, J = 14.6, 8.0, 3.6 Hz, 1H)。 520.3 E   
I-2244
Figure 02_image4775
 CN1CCN(CC1)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) δ 9.17 (br. s, 1H), 8.64 (s, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.47 (d, J = 1.7 Hz, 1H), 7.25 (ddd, J = 8.7, 8.1, 3.1 Hz, 1H), 6.57 (br. s, 1H), 5.97 (br. s, 1H), 3.22 - 3.11 (m, 2H), 3.03 - 2.93 (m, 2H), 2.18 - 2.09 (m, 2H), 2.12 (s, 3H), 2.05 - 1.95 (m, 2H)。 483.3 E   
I-2245
Figure 02_image4777
 CN1CCN(CC1)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) δ 9.17 (br. s, 1H), 8.64 (s, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.47 (d, J = 1.7 Hz, 1H), 7.25 (ddd, J = 8.7, 8.1, 3.1 Hz, 1H), 6.57 (br. s, 1H), 5.97 (br. s, 1H), 3.22 - 3.11 (m, 2H), 3.03 - 2.93 (m, 2H), 2.18 - 2.09 (m, 2H), 2.12 (s, 3H), 2.05 - 1.95 (m, 2H)。 483.3 E   
I-2246
Figure 02_image4779
 FC(F)C1CN(C(=O)Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccccc12 (400 MHz, DMSO-d6) δ，呈非對映異構體之約1:1混合物形式, δ 9.07 (br. s, 2H), 8.67 (br. s, 1H), 8.66 (br. s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.61 - 7.54 (m, 4H), 7.43 - 7.34 (m, 4H), 7.30 (dd, J = 7.0, 4.5 Hz, 2H), 7.26 - 7.19 (m, 2H), 7.18 - 7.09 (m, 2H), 6.99 - 6.93 (m, 2H), 6.56 (br. s, 2H), 6.30 - 6.00 (m, 1H), 6.25 (td, J = 55.9, 3.5 Hz, 1H), 6.05 (br. s, 2H), 4.06 - 3.83 (m, 5H), 3.39 (dd, J = 10.2, 4.2 Hz, 1H)。 472.4 A B
I-2247
Figure 02_image4781
 CC(C)(C)N[C@@H]1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    410.2 E   
I-2248
Figure 02_image4783
 CC(C)(C)N[C@H]1NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12    410.2 E   
I-2249
Figure 02_image4785
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@H](NC3CCCC3)c12    422.2 E   
I-2250
Figure 02_image4787
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H](NC3CCCC3)c12    422.3 E   
I-2251
Figure 02_image4789
 Oc1cc2C(=O)NC(c2c(c1)N(CCC#N)C(=O)c1cc(F)cc(c1)C(F)(F)F)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 10.44 (s, 1H), 9.15 (d, J = 53.9 Hz, 1H), 8.00-7.44 (m, 3H), 7.38-6.99 (m, 3H), 6.86 (d, J = 47.8 Hz, 1H), 6.40 (dd, J = 78.9, 38.4 Hz, 1H), 6.02-5.06 (m, 1H), 4.68 (s, 1H), 3.69 (d, J = 151.1 Hz, 1H), 2.95-2.62 (m, 2H)。 536.3 E   
I-2252
Figure 02_image4791
 [H][C@@]1(NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)[C@@]1([H])CCCC(=O)C1 (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.89 (s, 1H), 8.15 - 8.05 (m, 2H), 8.02 (d, J = 8.5 Hz, 1H), 7.66 - 7.51 (m, 3H), 4.96 (s, 1H), 2.40 - 2.13 (m, 3H), 2.14 - 2.01 (m, 1H), 2.02 - 1.89 (m, 1H), 1.89 - 1.61 (m, 2H), 1.52 - 1.19 (m, 1H), 1.20 - 0.99 (m, 1H)；非對映異構體之約1.25:1混合物，描述主要非對映異構體 435.2 E   
I-2253
Figure 02_image4793
 [H][C@@]1(NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)[C@]1([H])CCCC(=O)C1 (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.89 (s, 1H), 8.15 - 8.05 (m, 2H), 8.02 (d, J = 8.5 Hz, 1H), 7.66 - 7.51 (m, 3H), 4.96 (s, 1H), 2.40 - 2.13 (m, 3H), 2.14 - 2.01 (m, 1H), 2.02 - 1.89 (m, 1H), 1.89 - 1.61 (m, 2H), 1.52 - 1.19 (m, 1H), 1.20 - 0.99 (m, 1H)；非對映異構體之約1.25:1混合物；描述主要非對映異構體。 435.2 E   
I-2254
Figure 02_image4795
 [H][C@]1(NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)[C@@]1([H])CCCC(=O)C1 (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.89 (s, 1H), 8.15 - 8.05 (m, 2H), 8.02 (d, J = 8.5 Hz, 1H), 7.66 - 7.51 (m, 3H), 4.96 (s, 1H), 2.40 - 2.13 (m, 3H), 2.14 - 2.01 (m, 1H), 2.02 - 1.89 (m, 1H), 1.89 - 1.61 (m, 2H), 1.52 - 1.19 (m, 1H), 1.20 - 0.99 (m, 1H)；非對映異構體之約1.25:1混合物；描述主要非對映異構體。 435.2 E   
I-2255
Figure 02_image4797
 [H][C@]1(NC(=O)c2cccc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)[C@]1([H])CCCC(=O)C1 在非對映異構體之混合物中：1H    (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.89 (s, 1H), 8.15 - 8.05 (m, 2H), 8.02 (d, J = 8.5 Hz, 1H), 7.66 - 7.51 (m, 3H), 4.96 (s, 1H), 2.40 - 2.13 (m, 3H), 2.14 - 2.01 (m, 1H), 2.02 - 1.89 (m, 1H), 1.89 - 1.61 (m, 2H), 1.52 - 1.19 (m, 1H), 1.20 - 0.99 (m, 1H)；非對映異構體之約1.25:1混合物；描述主要非對映異構體。 435.2 E   
I-2256
Figure 02_image4799
 FC(F)(C1=CC(F)=CC(C(NC2=C3C(NC(C3=CC(NC4=NCCO4)=C2)=O)C5=CC(F)=CC=C5Cl)=O)=C1)F (500 MHz, DMSO) δ 10.44 (s, 1H), 9.01 (s, 1H), 7.93 - 7.88 (m, 1H), 7.77 - 7.67 (m, 2H), 7.61 (s, 1H), 7.28 (dt, J = 8.9, 4.6 Hz, 1H), 7.06 (td, J = 8.3, 3.1 Hz, 1H), 5.87 (s, 1H), 4.30 (t, J = 8.5 Hz, 2H), 3.76 (s, 2H)。 551.0 A B
I-2257
Figure 02_image4801
 OC1CN(C(=O)Nc2cc(Br)cc3C(=O)NC(c23)c2cc(F)ccc2C(F)F)c2ccc(F)cc12    550.1 A B
I-2258
Figure 02_image4803
 FC(F)c1ccc(F)cc1[C@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)-c1cn2ncnc2cn1    567.3 D   
I-2259
Figure 02_image4805
 FC(F)c1ccc(F)cc1[C@@H]1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)-c1cn2ncnc2cn1    567.3 A A
I-2260
Figure 02_image4807
 C[C@]1(CCC[C@@H](C1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl    547.1 C   
I-2261
Figure 02_image4809
 C[C@@]1(CCC[C@H](C1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl    547.1 A A
I-2262
Figure 02_image4811
 C[C@]1(CCC[C@@H](C1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl    547.1 B B
I-2263
Figure 02_image4813
 C[C@@]1(CCC[C@H](C1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl    547.1 D   
I-2264
Figure 02_image4815
 C[C@]1(CCC[C@@H](C1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl    547.1 B   
I-2265
Figure 02_image4817
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3coc4COCc34)c12    98.0 E   
I-2266
Figure 02_image4819
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3csc4COCCc34)c12    98.0 B   
I-2267
Figure 02_image4821
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(Cl)c3)c12)-c1cn2ncnc2cn1       D   
I-2268
Figure 02_image4823
 C[C@H](c1nn[nH]c1C(=O)Nc1cccc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl)C(F)(F)F    468.0 E   
I-2269
Figure 02_image4825
 C[C@H](c1nn[nH]c1C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)C(F)(F)F    468.0 E   
I-2270
Figure 02_image4827
 C[C@@H](c1nn[nH]c1C(=O)Nc1cccc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl)C(F)(F)F    468.0 E   
I-2271
Figure 02_image4829
 C[C@@H](c1nn[nH]c1C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)C(F)(F)F    468.0 D   
I-2272
Figure 02_image4831
 O[C@@H]1C[C@@H](C[C@@H](C1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl    549.0 E   
I-2273
Figure 02_image4833
 O[C@@H]1C[C@@H](C[C@@H](C1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl    550.9 E   
I-2274
Figure 02_image4835
 O[C@H]1C[C@H](C[C@H](C1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl    550.9 E   
I-2275
Figure 02_image4837
 O[C@H]1C[C@H](C[C@H](C1)C(F)(F)F)C(=O)Nc1cc(Br)cc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl    551.0 E   
I-2276
Figure 02_image4839
 OC[C@@H]1CN(C[C@H]1C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl    470.2 E   
I-2277
Figure 02_image4841
 OC[C@@H]1CN(C[C@H]1C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl    470.2 D   
I-2278
Figure 02_image4843
 OC[C@H]1CN(C[C@@H]1C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl    470.2 E   
I-2279
Figure 02_image4845
 OC[C@H]1CN(C[C@@H]1C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl    470.2 E   
I-2280
Figure 02_image4847
 OC1c2ccccc2N(C(=O)Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)C11CC1 (400 MHz, DMS)-d6) δ 9.23 (s,, 1H), 9.07 (br. s, 1H), 7.52 (m, 2H), 7.38 (d, J = 5.2 Hz, 1H), 7.35 (d, J = 5.2 Hz, 1H), 7.28 - 7.21 (m, 1H), 7.16 - 6.99 (m, 1H), 6.96 - 6.83 (m, 2H), 6.42 (br. s, , 1H), 6.13 (br. s, 1H), 6.00 (br. s, 1H), 5.62 (d, J = 6.8 Hz, 1H), 5.04 (d, J = 5.3 Hz, 1H), 1.78 (dt, J = 10.3, 5.2 Hz, 1H), 1.33 (ddd, J = 12.0, 8.1, 4.5 Hz, 1H), 1.10 (dt, J = 9.7, 5.0 Hz, 1H), 0.46 (ddd, J = 10.0, 7.2, 4.7 Hz, 1H)；非對映異構體之混合物。 464.4 E   
I-2281
Figure 02_image4849
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@H](C[C@@H]3CCCCN3)c12    436.4 E   
I-2282
Figure 02_image4851
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H](C[C@@H]3CCCCN3)c12    426.4 E   
I-2283
Figure 02_image4853
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)C3CCc4ccccc4C3)c12 (400 MHz, DMSO-d6 ) δ 9.81 (s, 1H), 9.11 (br. s, 1H), 7.65 - 7.49 (m, 3H), 7.45 (ddd, J = 11.5, 7.2, 1.7 Hz, 1H), 7.34 - 7.23 (m, 1H), 7.11 - 7.03 (m, 3H), 7.02 - 6.88 (m, 1H), 6.48 (br. s, 1H), 6.09 (br. s, 1H), 2.80 - 2.59 (m, 2H), 2.61 - 2.52 (m, 1H), 2.48 - 2.22 (m, 2H), 1.55 (m, 2H)；非對映異構體之混合物。 435.4 E   
I-2284
Figure 02_image4855
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCSc4ccccc34)c12 (400 MHz, DMSO-d6) δ 9.07 (br s, 1H), 8.64 (s, 1H), 7.58 - 7.45 (m, 3H), 7.38 (d, J = 7.3 Hz, 1H), 7.26 (td, J = 8.4, 3.1 Hz, 1H), 7.16 (dd, J = 7.9, 1.4 Hz, 1H), 6.99 (td, J = 7.7, 1.3 Hz, 1H), 6.79 (td, J = 7.7, 1.3 Hz, 1H), 6.46 (br s, 1H), 6.20 (br s, 1H), 6.07 (br s, 1H), 4.37 (br d, J = 11.4 Hz, 1H ), 3.20 - 3.04 (m, 2H), 3.03 - 2.91 (m, 1H)。 454.0 E   
I-2285
Figure 02_image4857
 OC(C(F)(F)F)C12CCC(CC1)(C2)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) δ 9.29 (s, 0.5H), 9.28 (s, 0.5H), 9.08 (br s, 1H), 7.60 (dd, J = 7.4, 1.1 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.53 - 7.44 (m, 1H), 7.37 (dd, J = 7.4, 1.0 Hz, 1H), 7.22 (td, J = 8.4, 3.1 Hz, 1H), 6.44 (br s, 1H), 6.25 (d, J = 2.7 Hz, 0.5H), 6.24 (d, J = 2.8 Hz, 0.5H), 6.04 (br s, 1H), 4.02 - 3.93 (m, 1H), 1.82 - 1.68 (m, 1H), 1.62 - 1.15 (m, 9H)。非對映異構體之1:1混合物 473.0 E   
I-2286
Figure 02_image4859
 CC([C@@H]1C[C@@H](O)CN1C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(F)(F)F (400 MHz, CD3CN) δ 7.74 (d, J = 7.6 Hz, 0.4H), 7.65 - 7.44 (m, 3.6H), 7.17 (br s, 1H), 7.14 - 7.06 (m, 1H), 6.66 (br s, 0.4H), 6.57 (br s, 1H), 6.50 (br s, 0.6H), 6.31 - 6.24 (m, 1H), 4.34 - 4.24 (m, 0.6H), 4.16 (p, J = 6.9 Hz, 0.4H), 4.13 - 4.05 (m, 1H), 3.37-3.30 (m, 0.4H), 3.29 - 3.02 (m, 1H), 3.02 - 2.88 (m, 0.6H), 2.83 (dd, J = 10.1, 2.9 Hz, 0.6H), 2.77 (dd, J = 9.7, 6.9 Hz, 0.4H), 2.09 - 2.00 (m, 2H [浸沒在H2O中]), 1.04 (d, J = 7.3 Hz, 1.2H), 0.89 (d, J = 6.9 Hz, 1.8H) ppm [非對映異構體之約1.5-1混合物] 486.3 C   
I-2287
Figure 02_image4861
 CC([C@H]1C[C@@H](O)CN1C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(F)(F)F (400 MHz, CD3CN) δ 7.60 (s, 0.4H), 7.58 (s, 0.6H), 7.52 (t, J = 7.6 Hz, 1H), 7.48 - 7.38 (m, 1H), 7.32 (d, J = 8.0 Hz, 0.4H), 7.30 (d, J = 7.8 Hz, 0.6H), 7.15 (br s, 1H), 7.13 - 7.03 (m, 1H), 6.86 (br s, 0.6H), 6.82 (br s, 0.4H), 6.56 (br s, 1H), 6.11 (br s, 1H), 4.36 - 4.26 (m, 0.4H), 4.26 - 4.15 (m, 1H), 3.98 (p, J = 7.3 Hz, 0.4H), 3.22 - 3.08 (m, 0.4H), 3.00 (dd, J = 10.5, 3.0 Hz, 0.4H), 2.96 - 2.87 (m, 1H), 2.82 (dd, J = 9.8, 7.6 Hz, 1H), 2.75 (dd, J = 10.6, 5.9 Hz, 0.4H), 2.13 - 2.04 (m, 1H [浸沒在H2 O峰下]), 1.74 - 1.63 (m, 1H), 1.00 (d, J = 7.2 Hz, 1.2H), 0.97 (d, J = 7.1 Hz, 1.8H) ppm [非對映異構體之約1.5:1混合物] 486.3 E   
I-2288
Figure 02_image4863
 CC(O)c1cc2C(=O)NC(c2c(NC(=O)N2CC(O)c3ccccc23)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.02 (d, J = 10.9 Hz, 1H), 8.62-8.49 (m, 1H), 7.84-7.71 (m, 1H), 7.56 (ddd, J = 11.8, 4.1, 1.4 Hz, 1H), 7.49-7.30 (m, 3H), 7.30-7.05 (m, 2H), 6.96 (dtd, J = 9.8, 7.4, 1.0 Hz, 1H), 6.53 (s, 1H), 6.08-5.99 (m, 1H), 5.62 (ddd, J = 13.7, 5.6, 1.8 Hz, 1H), 5.39 (dd, J = 4.4, 2.6 Hz, 1H), 5.15-5.09 (m, 1H), 4.86 (dp, J = 12.3, 6.3 Hz, 1H), 4.01-3.70 m, 1H),3.30-3.15 (m, 1H), 1.40 (dd, J = 6.4, 2.0 Hz, 3H)。 482.3 A D
I-2289
Figure 02_image4865
 CC(C#N)c1cc2C(=O)N[C@@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)10.60 (s, 1H), 9.23 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 4.9 Hz, 2H), 7.66 (s, 1H), 7.57 (s, 1H), 7.33 (dd, J = 8.9, 5.1 Hz, 1H), 7.10 (td, J = 8.3, 3.1 Hz, 1H),7.10-5.99 (s, 1H), 5.99 (s, 1H), 4.57 (dd, J = 7.2, 4.1 Hz, 1H), 1.64 (dd, J = 7.3, 4.5 Hz, 3H)。 520.1 D   
I-2290
Figure 02_image4867
 CC(C#N)c1cc2C(=O)N[C@H](c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 10.60 (d, J = 10.8 Hz, 1H), 9.24 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.78-7.71 (m, 2H), 7.66 (s, 1H), 7.56 (d, J = 7.4 Hz, 1H), 7.33 (dd, J = 8.9, 5.1 Hz, 1H), 7.10 (td, J = 8.4, 3.1 Hz, 1H), 6.68 (s, 1H), 5.99 (s, 1H), 4.57 (q, J = 7.2 Hz, 1H), 1.64 (dd, J = 7.2, 4.6 Hz, 3H)。 520.1 A A
I-2291
Figure 02_image4869
 O[C@H]1CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2cc(F)c(F)cc12 (400 MHz, DMSO-d6) 9.09 (s, 1H), 8.65 (s, 1H), 7.67 - 7.53 (m, 3H), 7.42 (dd, J = 7.6, 1.3 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.14 - 7.05 (m, 1H), 6.56 (s, 1H), 6.08 (s, 1H), 5.76 (dt, J = 4.4, 1.8 Hz, 1H), 5.14 (dt, J = 8.6, 4.3 Hz, 1H), 3.99 (dd, J = 11.0, 8.1 Hz, 1H), 3.23 (dd, J = 11.2, 3.8 Hz, 1H)。 474.0 D   
I-2292
Figure 02_image4871
 O[C@H]1CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2cc(F)c(F)cc12 (400 MHz, DMSO-d6) 9.09 (s, 1H), 8.64 (s, 1H), 7.67 - 7.54 (m, 3H), 7.42 (dd, J = 7.5, 1.4 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.10 (ddd, J = 8.9, 7.9, 3.1 Hz, 1H), 6.55 (s, 1H), 6.07 (s, 1H), 5.76 (d, J = 5.0 Hz, 1H), 5.14 (dt, J = 8.4, 4.3 Hz, 1H), 3.99 (dd, J = 11.1, 8.0 Hz, 1H), 3.23 (dd, J = 11.0, 3.8 Hz, 1H)。 474.0 E   
I-2293
Figure 02_image4873
 O[C@@H]1CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2cc(F)c(F)cc12 (400 MHz, DMSO-d6) 9.07 (s, 1H), 7.79 (s, 1H), 7.64 - 7.53 (m, 2H), 7.42 - 7.33 (m, 3H), 7.16 (td, J = 8.3, 3.1 Hz, 1H), 6.05 (s, 2H), 5.09 - 5.02 (m, 1H), 3.74 (dd, J = 11.3, 3.3 Hz, 1H), 3.34 (s, 2H)。 474.0 A A
I-2294
Figure 02_image4875
 O[C@H]1CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2cc(F)c(F)cc12 (400 MHz, DMSO-d6) 9.07 (s, 1H), 8.75 (s, 1H), 7.79 (d, J = 6.1 Hz, 1H), 7.64 - 7.57 (m, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.38 (dt, J = 8.8, 4.9 Hz, 3H), 7.16 (ddd, J = 8.9, 7.9, 3.1 Hz, 1H), 6.54 (s, 1H), 5.98 (d, J = 6.9 Hz, 1H), 5.78 (dd, J = 6.0, 1.3 Hz, 1H), 5.05 (d, J = 8.4 Hz, 1H), 3.74 (dd, J = 11.4, 3.3 Hz, 1H), 3.23 (s, 1H)。 474.0 E   
I-2295
Figure 02_image4877
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(OCc3cc(F)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO-d6) δ9.10 (s, 1H), 7.65 - 7.59 (m, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.43 (dd, J = 8.9, 5.1 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.33 (s, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.20 (td, J = 8.4, 3.1 Hz, 1H), 7.08 (d, J = 9.5 Hz, 1H), 6.79 (s, 1H), 6.04 (s, 1H), 5.19 (s, 2H)。 454.0 E   
I-2296
Figure 02_image4879
 OCC1(NC(=O)c2cccc(-c3nc4cc(cc(F)c4[nH]3)C(F)(F)F)c12)c1cccc(F)c1 (400 MHz, DMSO-d6) δ9.05 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.61 (s, 1H), 7.33 (d, J = 10.6 Hz, 1H), 6.99 (q, J = 7.5 Hz, 1H), 6.89 - 6.75 (m, 3H), 4.75 (d, J = 10.6 Hz, 1H), 4.60 (s, 1H)。 460.3 D   
I-2297
Figure 02_image4881
 FC(F)(C1OC(NC(C=C23)=CC(NC(C4=CC(C(F)(F)F)=CC(F)=C4)=O)=C3C(NC2=O)C5=CC(F)=CC=C5Cl)=NC1)F (400 MHz, DMSO) δ 10.50 (d, J = 3.8 Hz, 1H), 10.16 - 10.11 (m, 1H), 9.08 (s, 1H), 7.98 (s, 0H), 7.92 (dt, J = 8.5, 1.9 Hz, 2H), 7.78 (s, 1H), 7.73 - 7.66 (m, 2H), 7.63 - 7.58 (m, 1H), 7.28 (ddd, J = 8.9, 5.2, 2.8 Hz, 1H), 7.11 - 7.01 (m, 0H), 7.06 (s, 1H), 6.64 (s, 2H), 5.87 (s, 1H), 5.32 (d, J = 8.4 Hz, 1H), 4.16 (t, J = 11.8 Hz, 1H), 3.98 - 3.90 (m, 1H)。 619.0 A B
I-2298
Figure 02_image4883
 FC(F)(C1=CC(F)=CC(C(NC2=C3C(NC(C3=CC(NC4=NCCN4C)=C2)=O)C5=CC(F)=CC=C5Cl)=O)=C1)F (400 MHz, DMSO) δ 10.53 (s, 1H), 9.25 (s, 1H), 7.96 (dt, J = 8.4, 2.1 Hz, 1H), 7.78 (s, 5H), 7.74 - 7.58 (m, 2H), 7.53 (d, J = 1.9 Hz, 1H), 7.39 - 7.28 (m, 2H), 7.27 - 7.10 (m, 1H), 7.08 (s, 2H), 6.62 (s, 1H), 6.02 (s, 1H), 3.75 - 3.65 (m, 2H), 3.65 - 3.49 (m, 3H), 3.03 (s, 3H), 1.25 (dd, J = 7.0, 2.2 Hz, 3H)。 564.0 B   
I-2299
Figure 02_image4885
 OC1CN(C(=O)Nc2cc(cc3C(=O)NC(c23)c2cc(F)ccc2Cl)-c2cnn(c2)C(F)F)c2ccc(F)cc12    572.2 A B
I-2300
Figure 02_image4887
 FC(F)n1cc(cn1)-c1cc2C(=O)NC(c2c(NC(=O)N2CCc3cc(F)ccc23)c1)c1cc(F)ccc1Cl    556.2 A B
I-2301
Figure 02_image4889
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3csc4cocc34)c12    98.0 E   
I-2302
Figure 02_image4891
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)C3COC4CCCCC34)c12    98.0 E   
I-2303
Figure 02_image4893
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)C34CC5CC(CC(C5)O3)C4)c12    98.0 E   
I-2304
Figure 02_image4895
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3csc4CNCCc34)c12    97.0 E   
I-2305
Figure 02_image4897
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCCc4ccccc4C3)c12 (400 MHz, DMSO-d6) 8.95 (s, 1H), 8.20 (s, 1H), 7.48 (q, J = 3.3, 2.4 Hz, 2H), 7.29 (td, J = 6.2, 5.6, 2.7 Hz, 2H), 7.20 - 7.10 (m, 3H), 7.07 (ddd, J = 11.5, 7.5, 3.4 Hz, 2H), 6.38 (s, 1H), 6.01 (s, 1H), 4.50 (d, J = 14.9 Hz, 1H), 4.25 (d, J = 14.9 Hz, 1H), 3.50 (d, J = 14.3 Hz, 1H), 2.82 (q, J = 6.1 Hz, 2H), 2.50 (p, J = 1.9 Hz, 1H), 1.55 - 1.47 (m, 2H)。 450.1 E   
I-2306
Figure 02_image4899
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCCCc4ccccc34)c12 (400 MHz, DMSO-d6) 9.04 - 9.00 (m, 1H), 7.55 (s, 5H), 7.49 (d, J = 4.3 Hz, 1H), 7.34 - 7.21 (m, 1H), 7.15 (td, J = 7.5, 1.4 Hz, 1H), 7.00 (s, 1H), 6.41 (s, 2H), 6.11 - 6.06 (m, 1H), 2.68 (d, J = 2.1 Hz, 2H), 2.51 (d, J = 1.9 Hz, 1H), 2.52 - 2.12 (m, 2H), 1.65 (s, 1H), 1.53 (s, 1H), 1.35 (s, 1H)。 450.1 E   
I-2307
Figure 02_image4901
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCc4ccccc4C3)c12 (400 MHz, DMSO-d6) 9.01 (s, 1H), 8.57 (s, 1H), 7.51 (q, J = 4.4, 3.7 Hz, 2H), 7.32 (dd, J = 5.9, 3.0 Hz, 1H), 7.17 (tdd, J = 9.2, 7.1, 4.3 Hz, 4H), 7.08 - 7.01 (m, 1H), 6.97 (t, J = 9.0 Hz, 1H), 6.40 (s, 1H), 6.01 (s, 1H), 4.41 (d, J = 16.4 Hz, 1H), 4.15 (d, J = 16.4 Hz, 1H), 3.45 (ddd, J = 12.2, 6.7, 4.7 Hz, 1H), 3.22 (ddd, J = 12.6, 7.4, 4.5 Hz, 1H), 2.77 - 2.67 (m, 1H), 2.55 (d, J = 5.6 Hz, 1H)。 436.1 E   
I-2308
Figure 02_image4903
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCc4ccccc4CC3)c12 (400 MHz, DMSO-d6) 9.04 (s, 1H), 8.56 (s, 1H), 7.53 (q, J = 4.4, 3.5 Hz, 2H), 7.40 - 7.30 (m, 2H), 7.11 (dd, J = 16.8, 3.0 Hz, 5H), 6.49 (s, 1H), 6.13 (s, 1H), 3.34 (s, 2H), 3.32 (s, 2H), 2.68 (d, J = 18.1 Hz, 2H), 2.47 (s, 2H)。 450.1 E   
I-2309
Figure 02_image4905
 NC(=O)CCN(C(=O)c1cc(F)cc(c1)C(F)(F)F)c1cc(O)cc2C(=O)NC(c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 10.26 (s, 1H), 9.13 (d, J = 53.2 Hz, 1H), 7.86-6.66 (m, 7H), 6.63-5.97 (m, 1H), 5.97-4.24 (m, 1H), 3.58 (d, J = 67.6 Hz, 1H), 2.48-2.12 (m, 2H)。 554.2 E   
I-2310
Figure 02_image4907
 O[C@H]1CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)c(F)c12 (400 MHz, DMSO-d6)  9.05 (s, 1H), 8.73 (s, 1H), 7.68 (s, 1H), 7.58 (d, J = 8.7 Hz, 2H), 7.49 - 7.27 (m, 3H), 7.17 (td, J = 8.4, 3.1 Hz, 1H),6.82 - 6.24 (s, 1H), 5.97 (s, 2H), 5.27 (d, J = 7.2 Hz, 1H), 3.81 (d, J = 11.4 Hz, 1H), 3.23 (s, 1H)。 474.1 A A
I-2311
Figure 02_image4909
 O[C@@H]1CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)c(F)c12 (400 MHz, DMSO-d6)  9.08 (s, 1H), 8.60 (s, 1H), 7.58 (dd, J = 12.9, 5.6 Hz, 2H), 7.45 (q, J = 6.9, 5.3 Hz, 2H), 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.27 (q, J = 9.4 Hz, 1H), 7.10 (td, J = 8.4, 3.1 Hz, 1H), 6.52 (s, 1H), 6.08 (s, 1H), 5.92 (d, J = 4.9 Hz, 1H), 5.34 (s, 1H), 3.96 (dd, J = 11.3, 7.6 Hz, 1H), 3.36 (d, J = 2.9 Hz, 1H)。 474.3 D   
I-2312
Figure 02_image4911
 O[C@H]1CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)c(F)c12 (400 MHz, DMSO-d6)  9.09 (s, 1H), 8.59 (s, 1H), 7.64 - 7.51 (m, 2H), 7.48 - 7.40 (m, 2H), 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.28 (dt, J = 11.0, 8.6 Hz, 1H), 7.10 (ddd, J = 8.9, 7.9, 3.1 Hz, 1H), 6.55 (s, 1H), 6.08 (s, 1H), 5.93 (d, J = 5.8 Hz, 1H), 5.39 - 5.30 (m, 1H), 3.96 (dd, J = 11.2, 7.7 Hz, 1H), 3.36 (d, J = 2.9 Hz, 1H)。 474.3 D   
I-2313
Figure 02_image4913
 O[C@@H]1CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)c(F)c12 (400 MHz, DMSO-d6)  9.06 (s, 1H), 8.73 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.62 - 7.49 (m, 2H), 7.44 - 7.25 (m, 3H), 7.17 (td, J = 8.3, 3.1 Hz, 1H), 6.50 (s, 1H), 5.98 (m, 2H), 5.28 (t, J = 7.1 Hz, 1H), 3.81 (dd, J = 11.5, 2.4 Hz, 1H), 3.21 (s, 1H)。 474.3 D   
I-2314
Figure 02_image4915
 OCC1CN(C(=O)Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccccc12 (400 MHz, DMSO-d6 ) δ 9.04 (br. s, 1H), 8.58 (br. s, 0.5H), 8.56 (br. s, 0.5H), 7.79 - 7.67 (m, 1H), 7.60 - 7.52 (m, 2H), 7.43 - 7.32 (m, 2H), 7.21 (d, J = 7.3 Hz, 1H), 7.18 - 7.07 (m, 2H), 6.89 (ddd, J = 7.4, 4.1, 0.9 Hz, 1H), 6.48 (br. s, 1H), 6.03 (br. s, 1H), 4.94 (br. s, 1H), 3.93 (t, J = 9.9 Hz, 0.5H), 3.74 (dd, J = 10.0, 4.6 Hz, 0.5H), 3.69 - 3.55 (m, 1H), 3.41 - 3.38 (浸沒m, 1H), 3.28 - 3.09 (m, 2H)；非對映異構體之1:1混合物。 452.3 D   
I-2315
Figure 02_image4917
 Oc1nn(C(=O)Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccccc12 (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.10 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 7.5, 1.1 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.56 - 7.50 (m, 1H), 7.34 - 7.21 (m, 2H), 7.01 (td, J = 8.5, 3.0 Hz, 1H), 6.66 (br s, 1H), 6.21 (br s, 1H)。 437.0 D   
I-2316
Figure 02_image4919
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(C(=O)Nc3ccc(cc3)C(F)(F)F)c12 (400 MHz, DMSO-d6) δ 10.71 (s, 1 H), 9.28 (s, 1 H), 7.95 (d, J = 7.5 Hz, 1 H), 7.75 (t, J = 7.6 Hz, 1 H), 7.64 (app s, 4 H), 7.37 (dd, J = 8.1, 5.1 Hz, 1 H), 7.14 - 7.07 (m, 1 H), 6.50 (浸沒br s, 1 H), 6.41 (重疊的br s, 1 H)。 449.2 E   
I-2317
Figure 02_image4921
 COC(=O)C1CN(C(=O)Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccccc12 (400 MHz, DMSO-d6 ) δ 9.05 (br. s, 1H), 8.71 (br. s, 0.5H), 8.68 (br. s, 0.5H), 7.73 (d, J = 8.0 Hz, 1H), 7.66 - 7.47 (m, 2H), 7.44 - 7.29 (m, 3H), 7.24 - 7.06 (m, 2H), 6.95 (ddd, J = 7.5, 3.3, 1.0 Hz, 1H), 6.57 (br. s, 1H), 6.04 (br. s, 1H), 4.41 (dd, J = 10.3, 6.2 Hz, 0.5H), 4.32 (dd, J = 10.3, 6.0 Hz, 0.5H), 4.22 (dd, J = 10.4, 6.1 Hz, 0.5H), 4.06 (t, J = 10.6 Hz, 0.5H), 3.74 - 3.69 (浸沒m, 0.5H), 3.74 (s, 1.5H), 3.72 (s, 0.5H), 3.42 - 3.32 (浸沒m, 0.5H)；非對映異構體之1:1混合物。 435.4 E   
I-2318
Figure 02_image4923
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H]([C@H]3CCCCCN3)c12 (400 MHz, CD3CN) δ 8.75 (dd, J = 7.6, 1.5 Hz, 0.5H), 8.55 (dd, J = 7.6, 1.4 Hz, 0.5H), 8.07 (s, 0.5H (甲酸鹽)), 8.03 (s, 0.5H), 8.01 (s, 0.5H), 7.94 - 7.86 (m, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.53 - 7.45 (m, 2H), 6.95 (br s, 0.5H), 6.87 (br s, 0.5H), 4.72 (d, J = 1.7 Hz, 0.5H), 4.53 (d, J = 9.8 Hz, 0.5H), 3.40 (dt, J = 9.0, 2.5 Hz, 0.5H), 2.77 - 2.69 (m, 1H), 2.65 - 2.36 (m, 2H,浸沒在H2O峰下)), 1.85 - 1.78 (m, 0.5H), 1.71 - 1.53 (m, 3H), 1.52 - 1.35 (m, 3H) ppm [約1:1 dr, 未觀測到NH質子]。 436.4 E   
I-2319
Figure 02_image4925
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)N[C@@H]([C@@H]3CCCCCN3)c12 (400 MHz, CD3CN) δ 8.55 (dd, J = 7.6, 1.5 Hz, 1H), 8.09 (s, 0.5H, 甲酸鹽)), 8.01 (s, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.55 - 7.45 (m, 2H), 6.95 (br s, 1H), 4.53 (dd, J = 9.6, 1.0 Hz, 1H), 2.77 - 2.68 (m, 1H), 2.60 - 2.51 (m, 1H), 2.44 - 2.36 (m, 1H (浸沒在H2O峰下)), 1.85 - 1.78 (m, 1H), 1.74 - 1.55 (m, 3H), 1.53 - 1.37 (m, 3H) ppm [單一非對映異構體, 未觀測到NH質子]。 436.4 E   
I-2320
Figure 02_image4927
 Nc1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cccc(F)c1 (400 MHz, DMSO-d6) δ 10.17 (s, 1 H), 8.84 (s, 1 H), 7.93 (d, J = 8.4 Hz, 1 H), 7.70 (d, J = 9.0 Hz, 1 H), 7.62 (s, 1 H), 7.20 - 7.12 (m, 1 H), 6.98 (td, J = 8.5, 2.4 Hz, 1 H), 6.81 (d, J = 1.8 Hz, 1 H), 6.78 (d, J = 7.7 Hz, 1 H), 6.74 - 6.68 (m, 2 H), 5.57 (br s, 2 H), 5.52 (s, 1 H)。 448.2 C   
I-2321
Figure 02_image4929
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCC3c3ccccc3)c12 (400 MHz, DMSO-d6) δ 9.05 (br s, 0.5H), 9.01 (br s, 0.5H), 8.51 (s, 0.5H), 8.04 (s, 0.5H), 7.58 - 7.53 (m, 1H), 7.53 - 7.47 (m, 2H), 7.38-7.27 (m, 3H), 7.26-7.20 (m, 4H), 6.61 (br s, 1H), 6.08 (br s, 0.5H), 6.03 (浸沒br s, 0.5H), 5.21 (t, J = 8.1 Hz, 0.5H), 4.92 (t, J = 7.7 Hz, 0.5H), 3.86 - 3.74 (m, 1H), 3.61 (dd, J = 16.0, 7.7 Hz, 0.5H), 3.04 (dd, J = 14.3, 7.6 Hz, 0.5H), 2.47 (浸沒m, 1H), 2.04 - 1.87 (m, 1H)。非對映異構體之1:1混合物 436.0 E   
I-2322
Figure 02_image4931
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(CC3CC=CC3)c12 (400 MHz, DMSO d6) δ 10.79 (s, 1H), 8.94 (s, 1H), 8.14 (s, 1H), 8.09 (d, J = 9.0 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.61 - 7.50 (m, 3H), 5.55 - 5.49 (m, 1H), 5.42-5.37 (m, 1H), 4.80 (d, J = 7.6 Hz, 1H), 2.40 - 2.28 (m, 2H), 2.28 - 2.16 (m, 1H), 2.00 - 1.86 (m, 2H), 1.78 - 1.66 (m, 1H), 1.34 - 1.24 (m, 1H)。 419.4 E   
I-2323
Figure 02_image4933
 FC(F)([C@@H]1OC(NC(C=C23)=CC(NC(C4=CC(C(F)(F)F)=CC(F)=C4)=O)=C3[C@@H](NC2=O)C5=CC(F)=CC=C5Cl)=NC1)F    619.0 B   
I-2324
Figure 02_image4935
  		 FC(F)([C@H]1OC(NC(C=C23)=CC(NC(C4=CC(C(F)(F)F)=CC(F)=C4)=O)=C3[C@@H](NC2=O)C5=CC(F)=CC=C5Cl)=NC1)F    619.0 A A
I-2325
Figure 02_image4937
 FC(F)([C@@H]1OC(NC(C=C23)=CC(NC(C4=CC(C(F)(F)F)=CC(F)=C4)=O)=C3[C@H](NC2=O)C5=CC(F)=CC=C5Cl)=NC1)F    619.0 D   
I-2326
Figure 02_image4939
 FC(F)([C@H]1OC(NC(C=C23)=CC(NC(C4=CC(C(F)(F)F)=CC(F)=C4)=O)=C3[C@H](NC2=O)C5=CC(F)=CC=C5Cl)=NC1)F    619.0 D   
I-2327
Figure 02_image4941
 FC(F)(C1=CC(F)=CC(C(NC2=C3C(NC(C3=CC(NC4=NCC5(CC5)O4)=C2)=O)C6=CC(F)=CC=C6Cl)=O)=C1)F (500 MHz, DMSO) δ 10.45 (s, 1H), 9.02 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 9.3 Hz, 1H), 7.63 (d, J = 15.0 Hz, 1H), 7.33 - 7.24 (m, 1H), 7.06 (qd, J = 8.1, 4.1 Hz, 1H), 6.67 (s, 2H), 5.87 (s, 1H), 3.87 - 3.80 (m, 2H), 1.15 - 1.09 (m, 2H), 0.77 (s, 2H)。 577.0 B   
I-2328
Figure 02_image4943
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCC4C3[C@H]4C(F)(F)F)c12    454.3 E   
I-2329
Figure 02_image4945
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCC4C3[C@@H]4C(F)(F)F)c12    454.2 D   
I-2330
Figure 02_image4947
 Fc1cc(cc(c1)C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c3nc(cs3)C(F)(F)F)c12 (400 MHz, DMSO-d6 ) δ 10.67 (s, 1H), 9.59 (d, J = 1.3 Hz, 1H), 8.42 (s, 1H), 8.05 - 7.98 (m, 3H), 7.73 - 7.63 (m, 3H), 6.34 (d, J = 1.3 Hz, 1H)。 490.2 E   
I-2331
Figure 02_image4949
 FC(F)[C@@H]1CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccccc12    470.2 D   
I-2332
Figure 02_image4951
 FC(F)[C@H]1CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccccc12    470.2 D   
I-2333
Figure 02_image4953
 FC(F)[C@H]1CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccccc12    470.2 A B
I-2334
Figure 02_image4955
 FC(F)[C@@H]1CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccccc12    470.2 A B
I-2335
Figure 02_image4957
 CC[C@H](CC(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)[C@@H](C)C(F)(F)F    455.2 D   
I-2336
Figure 02_image4959
 CC[C@@H](CC(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)[C@H](C)C(F)(F)F    455.2 D   
I-2337
Figure 02_image4961
 CC[C@@H](CC(=O)Nc1cccc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl)[C@H](C)C(F)(F)F    455.2 E   
I-2338
Figure 02_image4963
 CC[C@H](CC(=O)Nc1cccc2C(=O)N[C@@H](c12)c1cc(F)ccc1Cl)[C@@H](C)C(F)(F)F    455.2 E   
I-2339
Figure 02_image4965
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CC(Nc4ccccc34)C(F)(F)F)c12 (400 MHz, DMSO-d6) δ 9.06 (br s, 1H), 8.76 (s, 0.5H), 8.24 (s, 0.5H), 7.69 - 7.58 (m, 0.5H), 7.58 - 7.41 (m, 3H), 7.32 (d, J = 7.5 Hz, 0.5H), 7.27-7.18 (m, 1H), 6.94 - 6.80 (m, 2H), 6.78-6.74 (m, 1H), 6.40 (t, J = 7.6 Hz, 1H), 6.27 (dd, J = 15.2, 8.0 Hz, 1H), 6.09 (br s, 1H), 5.73 (br s, 1H), 4.79 (br d, J = 14.3 Hz, 0.5H), 4.39 - 4.23 (m, 0.5H), 4.21 - 4.00 (m, 1H), 3.35 (浸沒m, 0.5H), 2.75 (br d, J = 12.9 Hz, 0.5H)。非對映異構體之1:1混合物。 505.0 E   
I-2340
Figure 02_image4967
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCSC(C3)C(F)(F)F)c12 (400 MHz, DMSO-d6) δ 9.06 (br s, 0.5H), 9.04 (br s, 0.5H), 8.66 (br s, 0.5H), 8.64 (br s, 0.5H) 7.61 - 7.46 (m, 3H), 7.35 - 7.19 (m, 2H), 6.51 (br s, 1H), 6.03 (br s, 0.5H), 5.98 (br s, 0.5H), 4.19 (br d, J = 12.1 Hz, 0.5H), 3.93 (dd, J = 14.1, 2.7 Hz, 0.5H), 3.69 - 3.56 (m, 1H), 3.55 - 3.44 (m, 1H), 3.42 - 3.35 (浸沒m, 0.5H), 3.19 (dd, J = 11.3, 9.7 Hz, 0.5H), 3.13 - 2.97 (m, 1H), 2.79 - 2.66 (m, 1H), 2.60 (dd, J = 12.8, 9.0 Hz, 0.5H), 2.26 (br d, J = 12.4 Hz, 0.5H)。非對映異構體之1:1混合物 474.0 E   
I-2341
Figure 02_image4969
 C[C@H]([C@@H]1C[C@@H](O)CN1C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)C(F)(F)F (400 MHz, CD3CN) δ 7.63 - 7.58 (m, 2H), 7.57 - 7.45 (m, 2H), 7.21 (br s, 1H), 7.10 (ddd, J = 8.8, 8.0, 3.1 Hz, 1H), 6.69 (br s, 1H), 6.56 (br s, 1H), 6.28 (s, 1H), 4.16 (p, J = 7.0 Hz, 1H), 4.09 (td, J = 8.1, 3.9 Hz, 1H), 3.34 (dd, J = 9.5, 7.1 Hz. 1H), 3.29 - 3.16 (m, 1H), 2.77 (dd, J = 9.7, 6.9 Hz), 2.13 - 2.04 (m, 1H [浸沒在H2O中]), 1.73 - 1.63 (m, 1H), 0.89 (d, J = 7.1 Hz, 3H) ppm [95:5 dr, 85%純度]。 486.4 B   
I-2342
Figure 02_image4971
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2nccn2)c2ccc(F)cc12 (400 MHz, DMSO-d6)  9.27 (s, 1H), 8.93 (s, 1H), 8.22 (s, 2H), 8.16 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.86 (s, 1H), 7.38 (dd, J = 8.9, 5.1 Hz, 1H), 7.17 (ddd, J = 13.5, 8.1, 2.9 Hz, 2H), 7.10 (td, J = 9.0, 2.8 Hz, 1H), 6.07 (s, 1H), 5.78 (d, J = 6.0 Hz, 1H), 5.06 (d, J = 9.2 Hz, 1H), 3.73 (dd, J = 11.4, 3.6 Hz, 1H), 3.24 (s, 1H)。 523.3 B   
I-2343
Figure 02_image4973
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2nccn2)c2ccc(F)cc12 (400 MHz, DMSO-d6)  9.29 (s, 1H), 8.77 (s, 1H), 8.23 (d, J = 8.6 Hz, 3H), 8.09 (d, J = 1.9 Hz, 1H), 7.75 (dd, J = 8.7, 4.7 Hz, 1H), 7.37 (dd, J = 8.9, 5.1 Hz, 1H), 7.17-7.10 (m, 2H), 7.12-7.02 (m, 1H), 6.16 (s, 1H), 5.75 (d, J = 5.0 Hz, 1H), 5.15 (s, 1H), 4.03-3.93 (m, 1H), 3.26-3.19 (m, 1H)。 523.2 D   
I-2344
Figure 02_image4975
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2nccn2)c2ccc(F)cc12    523.1 D   
I-2345
Figure 02_image4977
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2nccn2)c2ccc(F)cc12 (400 MHz, DMSO-d6)  9.27 (s, 1H), 8.94 (s, 1H), 8.22 (s, 2H), 8.16 (s, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.38 (dd, J = 8.9, 5.1 Hz, 1H), 7.22-7.06 (m, 3H),6.16-5.95(s, 1H), 5.79 (d, J = 6.0 Hz, 1H), 5.07 (s, 1H), 3.77-3.69 (m, 1H)。 523.2 D   
I-2346
Figure 02_image4979
 O[C@H]1CN(C(=O)Nc2cc(CCC#N)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.05 (s, 1H), 8.66 (s, 1H), 7.83 (dd, J = 9.1, 4.7 Hz, 1H), 7.55 (d, J = 1.5 Hz, 1H), 7.37 (dd, J = 8.9, 5.1 Hz, 1H), 7.29 (s, 1H), 7.15 (ddd, J = 13.3, 8.0, 2.9 Hz, 2H), 7.08 (td, J = 9.0, 2.8 Hz, 1H), 6.53 (s, 1H), 5.97 (s, 1H), 5.76 (d, J = 6.0 Hz, 1H), 5.07 (s, 1H), 3.71 (dd, J = 11.4, 3.6 Hz, 1H), 3.23 (s, 1H), 3.11-2.95 (m, 2H), 2.91 (t, J = 7.6 Hz, 2H)。 509.1 A B
I-2347
Figure 02_image4981
 O[C@@H]1CN(C(=O)Nc2cc(CCC#N)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.05 (s, 1H), 8.66 (s, 1H), 7.83 (dd, J = 9.1, 4.7 Hz, 1H), 7.55 (d, J = 1.5 Hz, 1H), 7.37 (dd, J = 8.9, 5.1 Hz, 1H), 7.29 (s, 1H), 7.15 (ddd, J = 13.3, 8.0, 2.9 Hz, 2H), 7.08 (td, J = 9.0, 2.8 Hz, 1H), 6.53 (s, 1H), 5.97 (s, 1H), 5.76 (d, J = 6.0 Hz, 1H), 5.07 (s, 1H), 3.71 (dd, J = 11.4, 3.6 Hz, 1H), 3.23 (s, 1H), 3.11-2.95 (m, 2H), 2.91 (t, J = 7.6 Hz, 2H)。 509.1 B   
I-2348
Figure 02_image4983
 O[C@@H]1CN(C(=O)Nc2cc(CCC#N)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.05 (s, 1H), 8.66 (s, 1H), 7.83 (dd, J = 9.1, 4.7 Hz, 1H), 7.55 (d, J = 1.5 Hz, 1H), 7.37 (dd, J = 8.9, 5.1 Hz, 1H), 7.29 (s, 1H), 7.15 (ddd, J = 13.3, 8.0, 2.9 Hz, 2H), 7.08 (td, J = 9.0, 2.8 Hz, 1H), 6.53 (s, 1H), 5.97 (s, 1H), 5.76 (d, J = 6.0 Hz, 1H), 5.07 (s, 1H), 3.71 (dd, J = 11.4, 3.6 Hz, 1H), 3.23 (s, 1H), 3.11-2.95 (m, 2H), 2.91 (t, J = 7.6 Hz, 2H)。 509.1 D   
I-2349
Figure 02_image4985
 O[C@H]1CN(C(=O)Nc2cc(CCC#N)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.05 (s, 1H), 8.66 (s, 1H), 7.83 (dd, J = 9.1, 4.7 Hz, 1H), 7.55 (d, J = 1.5 Hz, 1H), 7.37 (dd, J = 8.9, 5.1 Hz, 1H), 7.29 (s, 1H), 7.15 (ddd, J = 13.3, 8.0, 2.9 Hz, 2H), 7.08 (td, J = 9.0, 2.8 Hz, 1H), 6.53 (s, 1H), 5.97 (s, 1H), 5.76 (d, J = 6.0 Hz, 1H), 5.07 (s, 1H), 3.71 (dd, J = 11.4, 3.6 Hz, 1H), 3.23 (s, 1H), 3.11-2.95 (m, 2H), 2.91 (t, J = 7.6 Hz, 2H)。 509.1 D   
I-2350
Figure 02_image4987
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2ccccc2=O)c2ccc(F)cc12 (400 MHz, DMSO-d6)9.23 (s, 1H), 8.84 (s, 1H), 7.85-7.77 (m, 2H), 7.60-7.51 (m, 2H), 7.46-7.36 (m, 2H), 7.15 (dddd, J = 34.3, 18.0, 8.6, 3.0 Hz, 3H), 6.80-6.51 (m, 2H), 6.37 (td, J = 6.7, 1.4 Hz, 1H), 6.09 (s, 1H), 5.77 (d, J = 6.0 Hz, 1H), 5.08 (s, 1H), 3.70 (dd, J = 11.3, 3.6 Hz, 1H), 3.30-3.10 (s, 1H)。 531.2 A C
I-2351
Figure 02_image4989
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2ccccc2=O)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.26 (s, 1H), 8.70 (s, 1H), 7.77-7.73 (m, 2H), 7.61-7.50 (m, 3H), 7.39 (dd, J = 8.9, 5.2 Hz, 1H), 7.14 (ddd, J = 11.2, 8.0, 3.0 Hz, 2H), 7.05 (td, J = 9.1, 2.8 Hz, 1H), 6.80-6.54 (m, 2H), 6.37 (td, J = 6.7, 1.3 Hz, 1H), 6.17 (s, 1H), 5.75 (d, J = 5.0 Hz, 1H), 5.15 (dt, J = 8.7, 4.5 Hz, 1H), 3.97 (dd, J = 11.1, 8.1 Hz, 1H), 3.22 (dd, J = 11.1, 4.0 Hz, 1H)。 531.1 B   
I-2352
Figure 02_image4991
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2ccccc2=O)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.26 (s, 1H), 8.70 (s, 1H), 7.81-7.69 (m, 2H), 7.60-7.50 (m, 3H), 7.39 (dd, J = 8.9, 5.2 Hz, 1H), 7.14 (ddd, J = 11.5, 8.0, 3.0 Hz, 2H), 7.05 (td, J = 9.0, 2.8 Hz, 1H), 6.80-6.54 (m, 2H), 6.37 (td, J = 6.7, 1.3 Hz, 1H), 6.17 (s, 1H), 5.75 (d, J = 5.0 Hz, 1H), 5.15 (dt, J = 8.7, 4.5 Hz, 1H), 3.97 (dd, J = 11.0, 8.0 Hz, 1H), 3.22 (dd, J = 11.2, 4.0 Hz, 1H)。 531.2 D   
I-2353
Figure 02_image4993
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2ccccc2=O)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.23 (s, 1H), 8.83 (s, 1H), 7.84 (dd, J = 8.5, 4.6 Hz, 1H), 7.77 (dd, J = 6.9, 2.1 Hz, 1H), 7.60-7.51 (m, 2H), 7.46-7.36 (m, 2H), 7.15 (dddd, J = 34.5, 18.1, 8.6, 3.0 Hz, 3H), 6.80-6.50 (m, 2H), 6.37 (td, J = 6.7, 1.4 Hz, 1H), 6.08 (s, 1H), 5.77 (d, J = 6.0 Hz, 1H), 5.08 (s, 1H), 3.70 (dd, J = 11.3, 3.6 Hz, 1H), 3.25 (s, 1H)。 531.2 D   
I-2354
Figure 02_image4995
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)\N=C1/OC[C@H]2CCCN12 (500 MHz, DMSO) δ 10.33 (d, J = 3.4 Hz, 1H), 8.98 (s, 1H), 7.90 (dt, J = 8.3, 2.0 Hz, 1H), 7.70 (d, J = 9.1 Hz, 1H), 7.64 (s, 1H), 7.31 - 7.22 (m, 2H), 7.06 (td, J = 8.2, 3.0 Hz, 1H), 7.03 (s, 1H), 5.89 (s, 1H), 5.74 (s, 1H), 4.63 - 4.55 (m, 1H), 4.27 (s, 1H), 3.97 (s, 1H), 3.62 (s, 1H), 3.16 (s, 2H), 2.03 - 1.95 (m, 2H), 1.93 - 1.86 (m, 1H), 1.53 - 1.40 (m, 1H)。 591.0 B   
I-2355
Figure 02_image4997
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)\N=C1/OC[C@@H]2CCCN12    591.0 B   
I-2356
Figure 02_image4999
 FC(F)n1cc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)N2CCc3cc(F)ccc23)c1)c1cc(F)ccc1Cl    556.3 D   
I-2357
Figure 02_image5001
 FC(F)n1cc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)N2CCc3cc(F)ccc23)c1)c1cc(F)ccc1Cl    556.3 A A
I-2358
Figure 02_image5003
 FC(F)(C1=CC(F)=CC(C(NC2=C3C(NC(C3=CC(NC4=NC(C)(C)CO4)=C2)=O)C5=CC(F)=CC=C5Cl)=O)=C1)F (500 MHz, DMSO) δ 10.43 (s, 1H), 9.01 (s, 1H), 8.13 (s, 1H), 7.91 (dd, J = 8.2, 2.2 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 7.27 (dd, J = 8.8, 5.2 Hz, 1H), 7.06 (tt, J = 8.6, 4.3 Hz, 1H), 6.59 (s, 1H), 5.85 (s, 1H), 3.98 (s, 2H), 1.26 (d, J = 3.3 Hz, 6H)。 579.0 B   
I-2359
Figure 02_image5005
 FC(F)(C1=CC(F)=CC(C(NC2=C3C(NC(C3=CC(NC4=NC5(CC5)CO4)=C2)=O)C6=CC(F)=CC=C6Cl)=O)=C1)F (500 MHz, DMSO) δ 10.45 (s, 1H), 9.03 (s, 1H), 8.12 (s, 1H), 7.94 - 7.87 (m, 2H), 7.68 (d, J = 9.4 Hz, 1H), 7.58 (s, 2H), 7.27 (dd, J = 8.8, 5.1 Hz, 1H), 7.06 (td, J = 8.4, 3.1 Hz, 1H), 6.50 (s, 1H), 5.84 (s, 1H), 4.25 (s, 2H), 1.22 (s, 0H), 0.95 - 0.90 (m, 2H), 0.75 - 0.68 (m, 2H)。 577.0 A B
I-2360
Figure 02_image5007
 FC(F)(C1=CC(F)=CC(C(NC2=C3C(NC(C3=CC(NC4=NC(C(F)(F)F)CO4)=C2)=O)C5=CC(F)=CC=C5Cl)=O)=C1)F (400 MHz, DMSO) δ 10.54 (d, J = 7.4 Hz, 1H), 10.14 (s, 1H), 9.09 (s, 1H), 8.47 (s, 1H), 8.03 (s, 1H), 7.98 - 7.88 (m, 2H), 7.72 - 7.63 (m, 2H), 7.58 (s, 1H), 7.28 (dd, J = 8.9, 5.1 Hz, 1H), 7.06 (s, 1H), 6.84 (s, 3H), 5.85 (s, 1H), 5.74 (s, 1H), 4.89 (s, 1H), 4.51 (t, J = 9.4 Hz, 1H), 4.44 - 4.35 (m, 1H)。 619.0 A C
I-2361
Figure 02_image5009
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cscc3C(F)(F)F)c12       D   
I-2362
Figure 02_image5011
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)CCc3ccccc3)c12 (400 MHz, DMSO-d6) 9.70 (s, 1H), 9.09 (s, 1H), 7.61 (dd, J = 7.6, 1.3 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.51 (s, 1H), 7.37 (dd, J = 7.5, 1.3 Hz, 1H), 7.32 - 7.10 (m, 6H), 6.02 (s, 1H), 2.70 - 2.57 (s, 1H), 2.57 - 2.52 (s, 1H), 2.34 - 2.16 (m, 2H)。 409.3 E   
I-2363
Figure 02_image5013
 Oc1ccc(cc1C(F)(F)F)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.95 (s, 1H), 9.09 (s, 1H), 7.61 (p, J = 7.9, 7.5 Hz, 5H), 7.49 (d, J = 7.4 Hz, 1H), 7.31 (dd, J = 8.9, 5.2 Hz, 1H), 7.08 (td, J = 8.5, 3.1 Hz, 1H), 6.81 (s, 1H), 6.60 (s, 1H), 6.02 (s, 1H)。 465.1 E   
I-2364
Figure 02_image5015
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2cccn2)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.18 (s, 1H), 8.85 (s, 1H), 8.71 (d, J = 2.6 Hz, 1H), 8.03 - 7.95 (m, 2H), 7.88 - 7.79 (m, 2H), 7.38 (dd, J = 9.0, 5.1 Hz, 1H), 7.22 - 7.05 (m, 3H), 6.63 - 6.57 (m, 1H), 6.02 (s, 1H), 5.78 (d, J = 6.0 Hz, 1H), 5.07 (s, 2H), 3.77 - 3.69 (m, 1H), 3.34 (s, 1H)。 522.3 A B
I-2365
Figure 02_image5017
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2cccn2)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.21 (s, 1H), 8.74 - 8.68 (m, 2H), 8.07 - 7.99 (m, 2H), 7.81 (d, J = 1.8 Hz, 1H), 7.74 (dd, J = 9.0, 4.7 Hz, 1H), 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.11 (td, J = 8.5, 3.0 Hz, 2H), 7.05 (td, J = 9.0, 2.8 Hz, 1H), 6.73 (s, 1H), 6.60 (t, J = 2.1 Hz, 1H), 6.12 (s, 1H), 5.75 (d, J = 5.0 Hz, 1H), 5.16 (dt, J = 8.3, 4.6 Hz, 1H), 3.99 (dd, J = 11.1, 8.1 Hz, 1H), 3.22 (dd, J = 11.2, 4.1 Hz, 1H)。 522.4 C   
I-2366
Figure 02_image5019
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2cccn2)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.21 (s, 1H), 8.74 - 8.68 (m, 2H), 8.07 - 7.99 (m, 2H), 7.81 (d, J = 1.7 Hz, 1H), 7.74 (dd, J = 8.9, 4.7 Hz, 1H), 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.11 (td, J = 8.4, 3.0 Hz, 3H), 6.60 (t, J = 2.1 Hz, 2H), 6.12 (s, 1H), 5.75 (d, J = 5.0 Hz, 1H), 5.16 (dt, J = 8.6, 4.5 Hz, 1H), 3.99 (dd, J = 11.1, 8.1 Hz, 1H), 3.22 (dd, J = 11.0, 4.1 Hz, 1H)。 522.3 D   
I-2367
Figure 02_image5021
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2cccn2)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.19 (s, 1H), 8.85 (s, 1H), 8.72 (d, J = 2.5 Hz, 1H), 7.99 (dd, J = 11.9, 2.0 Hz, 2H), 7.81 (d, J = 1.7 Hz, 1H), 7.38 (dd, J = 8.9, 5.1 Hz, 1H), 7.22 - 7.11 (m, 2H), 7.11 (dd, J = 8.9, 2.8 Hz, 2H), 6.63 - 6.57 (m, 1H), 6.02 (s, 1H), 5.78 (d, J = 6.0 Hz, 1H), 5.07 (s, 1H), 3.73 (dd, J = 11.3, 3.6 Hz, 1H), 3.24 (s, 1H), 1.13 (s, 1H)。 522.4 D   
I-2368
Figure 02_image5023
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2ccnn2)c2ccc(F)cc12 (400 MHz, DMSO-d6)9.30 (s, 1H), 9.07 (d, J = 1.2 Hz, 1H), 8.79 (s, 1H), 8.14 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 1.2 Hz, 1H), 7.75 (dd, J = 8.9, 4.7 Hz, 1H), 7.38 (dd, J = 8.9, 5.1 Hz, 1H), 7.20-7.11 (m, 2H), 7.06 (d, J = 2.9 Hz, 1H), 7.00-6.50 (m, 1H), 6.17 (s, 1H), 5.75 (s, 1H), 5.16 (s, 1H), 3.99 (dd, J = 11.1, 8.0 Hz, 1H), 3.24 (dd, J = 11.1, 4.0 Hz, 1H)。 523.1 D   
I-2369
Figure 02_image5025
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2ccnn2)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.29 (s, 1H), 9.08 (d, J = 1.2 Hz, 1H), 8.96 (s, 1H), 8.17-7.98 (m, 3H), 7.86 (s, 1H), 7.39 (dd, J = 8.9, 5.1 Hz, 1H), 7.27-7.03 (m, 3H), 7.00-6.50 (m, 1H), 6.30-5.90 (m, 1H), 5.79 (d, J = 6.0 Hz, 1H), 5.09 (d, J = 9.0 Hz, 1H), 3.73 (dd, J = 11.4, 3.5 Hz, 1H), 3.17 (d, J = 5.2 Hz, 1H)。 523.1 A B
I-2370
Figure 02_image5027
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2ccnn2)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.32 (s, 1H), 9.08 (s, 1H), 8.81 (s, 1H), 8.14 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 1.9 Hz, 1H), 8.04 (s, 1H), 7.75 (dd, J = 8.9, 4.7 Hz, 1H), 7.38 (dd, J = 8.9, 5.1 Hz, 1H), 7.17-7.10 (m, 2H), 7.07 (dd, J = 9.1, 2.8 Hz, 1H), 6.90-6.50 (m, 1H),6.17 (s, 1H), 5.76 (d, J = 4.9 Hz, 1H), 5.16 (dt, J = 8.7, 4.4 Hz, 1H), 4.16-3.90 (m, 1H), 3.23 (dd, J = 11.1, 4.0 Hz, 1H)。 523.1 C   
I-2371
Figure 02_image5029
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2ccnn2)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.28 (s, 1H), 9.07 (d, J = 1.2 Hz, 1H), 8.95 (s, 1H), 8.23-8.05 (m, 2H), 8.04 (d, J = 1.2 Hz, 1H), 7.86 (s, 1H), 7.39 (dd, J = 8.9, 5.1 Hz, 1H), 7.28-7.04 (m, 3H), 7.00-6.50 (m, 1H), 6.20-6.10 (m,1H), 5.78 (d, J = 6.0 Hz, 1H), 5.08 (s, 1H), 3.73 (dd, J = 11.3, 3.6 Hz, 1H), 3.30-3.20 (m,1H) 523.1 D   
I-2372
Figure 02_image5031
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)\C=C\c3ccccc3)c12 (400 MHz, DMSO-d6)  9.95 (s, 1H), 9.08 (s, 1H), 7.67-7.60 (m, 1H), 7.64-7.52 (m, 3H), 7.49-7.39 (m, 5H), 7.39 (s, 1H), 7.14 (td, J = 8.3, 2.9 Hz, 1H), 6.49 (d, J = 15.8 Hz, 1H), 6.06 (s, 1H)。 407.1 E   
I-2373
Figure 02_image5033
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)n3ncc4ccccc34)c12 (400 MHz, DMSO-d6) δ 9.15 (br s, 1H), 8.38 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.78 - 7.54 (m, 4H), 7.37 (t, J = 7.4 Hz, 1H), 7.23 (dd, J = 8.6, 5.1 Hz, 1H), 6.99 (td, J = 7.3, 1.4 Hz, 1H), 6.61 (br s, 1H), 6.21 (br s, 1H)。 421.0 B   
I-2374
Figure 02_image5035
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)C3CCc4ccccc4CC3)c12 (400 MHz, DMSO-d6) δ 9.63 (br. s, 1H), 9.04 (br. s, 1H), 7.58 - 7.49 (m, 2H), 7.49 - 7.41 (m, 1H), 7.37 (dd,J = 7.2, 1.7 Hz, 1H), 7.22 (ddd,J = 8.8, 8.1, 3.1 Hz, 1H), 7.09 - 7.00 (m, 4H), 6.51 (br. s, 1H), 6.01 (br. s, 1H), 2.75 - 2.53 (m, 4H), 2.37 (ddd,J = 11.2, 7.2, 3.0 Hz, 1H), 1.65 - 1.57 (m, 1H), 1.54 - 1.34 (m, 1H), 1.26 - 1.03 (m, 2H)。 449.2 E   
I-2375
Figure 02_image5037
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)C3CCCc4ccccc4C3)c12 (400 MHz, DMSO-d6) δ 9.70 (br. s, 0.5H), 9.68 (br. s, 0.5H), 9.11 (br. s, 1H), 7.67 - 7.51 (m, , 3H), 7.43 (dd, J = 3.2, 1.7 Hz, 0.5H), 7.41 (dd, J = 3.41, 1.6 Hz, 0.5H), 7.28 (兩個重疊ddd, J = 7.3, 3.3, 1.7 Hz, 1H), 7.12 - 6.99 (m, 3H), 7.05 - 6.94 (m, 0.5H), 6.93 - 6.80 (m, 0.5H), 6.10 (br. s, 1H), 2.88 - 2.62 (m, 3H), 2.39 (d, J = 14.0 Hz, 0.5H), 2.28 - 2.12 (m, 0.5H), 2.10 - 1.95 (m, 1H), 1.96 - 1.75 (m, 1H), 1.81 - 1.39 (m, 2H), 1.21 - 1.00 (m, 1H)；異構體之1:1混合物。 449.3 E   
I-2376
Figure 02_image5039
 OC1CN(C(=O)Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccc(Cl)cc12 (400 MHz, DMSO-d6) δ 9.08 (br s, 0.5 H), 9.06 (br s, 0.5 H), 8.70 (s, 0.5 H), 8.58 (s, 0.5 H), 7.83 (d, J = 8.5 Hz, 0.5 H), 7.70 (d, J = 8.7 Hz, 0.5 H), 7.64 - 7.52 (m, 2 H), 7.42 (dd, J = 7.4, 1.3 Hz, 0.5 H), 7.39 - 7.26 (m, 3 H), 7.24 (dd, J = 8.7, 2.3 Hz, 0.5 H), 7.19 - 7.13 (m, 0.5 H), 7.09 (td, J = 8.4, 3.1 Hz, 0.5 H), 6.51 (br s, 1 H), 6.07 (br s, 1 H), 5.99 (br s, 1 H), 5.76 (app dd, J = 10.6, 5.4 Hz, 1 H), 5.15 (dt, J = 8.1, 4.2 Hz, 0.5 H), 5.10 - 5.04 (m, 0.5 H), 3.96 (dd, J = 11.0, 8.1 Hz, 0.5 H), 3.71 (dd, J = 11.3, 3.4 Hz, 0.5 H), 3.21 (d, J = 3.8 Hz, 0.5 H), 3.19 (d, J = 3.7 Hz, 0.5 H)。非對映異構體之約1:1混合物。 472.2 D   
I-2377
Figure 02_image5041
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCCC33CCC3)c12    97.0 C   
I-2378
Figure 02_image5043
 C[C@@H]([C@H]1C[C@H](O)CN1C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)C(F)(F)F (400 MHz, CD3CN) δ 7.58 (dd, J = 7.4, 1.1 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.12 (br s, 1H), 7.04 (ddd, J = 8.8, 8.0, 3.1 Hz, 1H), 6.67 (br s, 1H), 6.57 (br s, 1H), 6.17 (br s, 1H), 4.36 - 4.30 (m, 1H), 4.26 - 4.19 (m, 1H), 3.31 (dd, J = 10.0, 5.3 Hz, 1H), 2.88 - 2.76 (m, 1H), 2.68 (dd, J = 9.8, 3.6 Hz, 1H), 2.07 - 2.00 (m, 1H), 1.91 - 1.82 (m, 1H), 1.01 (d, J = 7.3 Hz, 3H) ppm [單一非對映異構體] 486.4 E   
I-2379
Figure 02_image5045
 C[C@H]([C@H]1C[C@H](O)CN1C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)C(F)(F)F (400 MHz, CD3CN) δ 7.59 (dd, J = 7.4, 1.0 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.15 (br s, 1H), 7.04 (ddd, J = 8.8, 8.1, 3.1 Hz, 1H), 6.73 (br s, 1H), 6.56 (br s, 1H), 6.19 (br s, 1H), 4.34 (td, J = 8.2, 3.7 Hz, 1H), 4.30 - 4.23 (m, 1H), 3.26 (dd, J = 10.4, 4.2 Hz, 1H), 3.21 - 3.00 (m, 1H), 2.88 (d, J = 10.3 Hz, 1H), 2.13 - 2.07 (m, 1H [浸沒在H2O峰下]), 1.83 - 1.74 (m, 1H), 0.82 (d, J = 7.2 Hz, 3H) ppm。 486.4 E   
I-2380
Figure 02_image5047
 Cc1nn(C(=O)Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccccc12 (400 MHz, DMSO) δ 9.61 (s, 1H), 9.13 (s, 1H), 8.15 (dt, J = 8.4, 0.9 Hz, 1H), 7.84 (dt, J = 8.0, 1.0 Hz, 1H), 7.81 (dd, J = 6.6, 2.3 Hz, 1H), 7.65 - 7.60 (m, 2H), 7.57 (ddd, J = 8.3, 7.1, 1.1 Hz, 1H), 7.35 (ddd, J = 8.0, 7.1, 0.9 Hz, 1H), 7.30 (dd, J = 8.8, 5.1 Hz, 1H), 7.04 (ddd, J = 8.8, 7.9, 3.1 Hz, 1H), 6.82 - 6.50 (m, 1H), 6.21 (s, 1H), 2.54 (s, 3H) 435.0 C   
I-2381
Figure 02_image5049
 Nc1nn(C(=O)Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccccc12 (400 MHz, DMSO) δ 9.10 (s, 1H), 9.08 (s, 1H), 8.09 - 8.03 (m, 1H), 7.86 (dt, J = 8.0, 1.0 Hz, 1H), 7.78 (dd, J = 6.0, 3.0 Hz, 1H), 7.58 (q, J = 3.7, 3.0 Hz, 2H), 7.50 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.37 (t, J = 6.7 Hz, 1H), 7.24 (ddd, J = 8.0, 7.1, 0.9 Hz, 1H), 7.07 (ddd, J = 8.9, 7.9, 3.1 Hz, 1H), 6.86 - 6.50 (m, 1H), 6.20 (s, 1H), 6.13 (s, 2H) 436.0 B   
I-2382
Figure 02_image5051
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)Nc3n[nH]c4ccccc34)c12 (500 MHz, DMSO) δ 12.16 (s, 1H), 9.70 (s, 1H), 9.43 (s, 1H), 9.09 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.43 - 7.32 (m, 3H), 7.08 (td, J = 8.4, 3.1 Hz, 1H), 7.02 (ddd, J = 7.9, 6.7, 1.0 Hz, 1H), 6.78 - 6.42 (m, 1H), 6.10 (s, 1H) 436.0 D   
I-2383
Figure 02_image5053
 O[C@]1(CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)(F)F (400 MHz, DMSOd6) δ 9.08 (s, 1H), 8.80 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.39 (m, 3H), 7.31 (dd, J = 8.9, 5.2 Hz, 1H), 7.24 (s, 1H), 7.12 (td, J = 8.5, 3.0 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.52 (br s, 1H), 6.03 (s, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.48 (d, J = 11.5 H, 1Hz)。 506.3 E   
I-2384
Figure 02_image5055
 O[C@@]1(CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)(F)F (400 MHz, DMSOd6) δ 9.10 (s, 1H), 8.70 (, 1Hs), 7.81 (d, J = 8.2 H, 1Hz), 7.67 - 7.55 (m, 2H), 7.48 (dd, J = 7.3, 1.5 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.36 (td, J = 7.1 , 1.1 Hz, 1H), 7.33 (d, J = 5.3 Hz, 1H), 7.21 (s, 1H), 7.11 (td, J = 8.7, 3.2 Hz, 1H), 7.05 (td, J = 7.9, 0.9 Hz, 1H ), 6.53 (br s, 1H), 6.08 (s, 1H), 4.16 (d, J = 12.0 Hz, 1H), 3.44 (d, J = 12.0 Hz, 1H)。 506.3 D   
I-2385
Figure 02_image5057
 O[C@@]1(CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)(F)F (400 MHz, DMSOd6) δ 9.10 (s, 1H), 8.70 (, 1Hs), 7.81 (d, J = 8.2 H, 1Hz), 7.67 - 7.55 (m, 2H), 7.48 (dd, J = 7.3, 1.5 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.36 (td, J = 7.1 , 1.1 Hz, 1H), 7.33 (d, J = 5.3 Hz, 1H), 7.21 (s, 1H), 7.11 (td, J = 8.7, 3.2 Hz, 1H), 7.05 (td, J = 7.9, 0.9 Hz, 1H ), 6.53 (br s, 1H), 6.08 (s, 1H), 4.16 (d, J = 12.0 Hz, 1H), 3.44 (d, J = 12.0 Hz, 1H)。 506.3 D   
I-2386
Figure 02_image5059
 O[C@]1(CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)(F)F (400 MHz, DMSOd6) δ 9.08 (s, 1H), 8.80 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.39 (m, 3H), 7.31 (dd, J = 8.9, 5.2 Hz, 1H), 7.24 (s, 1H), 7.12 (td, J = 8.5, 3.0 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.52 (br s, 1H), 6.03 (s, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.48 (d, J = 11.5 H, 1Hz)。 506.3 A A
I-2387
Figure 02_image5061
 O=C1C2=CC(NC3=N[C@H](C(F)(F)F)CO3)=CC(NC(C4=CC(F)=CC(C(F)(F)F)=C4)=O)=C2[C@H](C5=C(Cl)C=CC(F)=C5)N1    619.0 A B
I-2388
Figure 02_image5063
 O=C1C2=CC(NC3=N[C@@H](C(F)(F)F)CO3)=CC(NC(C4=CC(F)=CC(C(F)(F)F)=C4)=O)=C2[C@H](C5=C(Cl)C=CC(F)=C5)N1    619.0 A B
I-2389
Figure 02_image5065
 O=C1C2=CC(NC3=N[C@H](C(F)(F)F)CO3)=CC(NC(C4=CC(F)=CC(C(F)(F)F)=C4)=O)=C2[C@@H](C5=C(Cl)C=CC(F)=C5)N1    619.0 D   
I-2390
Figure 02_image5067
 O=C1C2=CC(NC3=N[C@@H](C(F)(F)F)CO3)=CC(NC(C4=CC(F)=CC(C(F)(F)F)=C4)=O)=C2[C@@H](C5=C(Cl)C=CC(F)=C5)N1    619.0 D   
I-2391
Figure 02_image5069
 CCCCc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3cc(O)cc(c3)C(F)(F)F)c12 (400 MHz, DMSO) δ 10.81 (s, 1H), 10.26 (s, 1H), 8.99 (s, 1H), 8.49 (s, 1H), 7.66 - 7.61 (m, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.27 (s, 1H), 7.15 (d, J = 8.2 Hz, 2H), 7.08 (s, 1H), 7.00 (dd, J = 8.2, 2.2 Hz, 1H), 6.78 (s, 1H), 5.96 (s, 1H),  2.18 (s, 2H), 1.12 - 1.06 (m, 4H), 0.77 - 0.69 (m, 2H)。 503.0 D   
I-2392
Figure 02_image5071
 CC(C)N1C[C@H](O)C[C@H]1C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6 ) δ 9.23 (br. s, 1H), 9.16 (br. s, 1H), 8.07 (dd, J = 7.5, 1.4 Hz, 0.6H), 7.91 (dd, J = 7.1, 1.8 Hz, 0.3H), 7.69 - 7.43 (m, 3H), 7.33 - 7.29 (m, 0.6H), 7.29 - 7.25 (m, 0.4H), 6.42 (br. s, 1H), 6.14 (br. s, 1H), 4.84 (br. s, 1H), 4.01 - 3.93 (m, 0.3H), 3.70 - 3.61 (m, 0.7H), 3.28 (重疊dd, J = 5.8, 3.7 Hz, 1H), 3.03 (dd, J = 9.3, 5.3 Hz, 0.3H), 2.83 (dd, J = 9.4, 5.2 Hz, 0.7H), 2.43 (td, J = 12.9, 6.4 Hz, 1H), 2.37 - 2.24 (m, 1H), 1.88 - 1.79 (m, 0.3H), 1.80 - 1.68 (m, 0.7H), 1.65 - 1.48 (m, 0.3H), 1.33 (dt, J = 15.8, 4.8 Hz, 0.7H), 0.89 (重疊d, J = 5.0 Hz, 4H), 0.71 (d, J = 6.4 Hz, 1H), 0.68 (d, J = 6.3 Hz, 1H)；非對映異構體之2:1混合物 432.3 E   
I-2393
Figure 02_image5073
 C[C@@H]([C@@H]1C[C@H](O)CN1C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl)C(F)(F)F (400 MHz, CD3CN) δ 7.65 - 7.45 (m, 3H), 7.45 - 7.38 (m, 1H), 7.18 - 7.01 (m, 2H), 6.70 (d, J = 5.1 Hz, 1H), 6.57 (br s, 1H), 6.30 (br s, 0.5H), 6.19 (br s, 0.5H), 4.38 - 4.22 (m, 2H), 3.26 (dd, J = 10.4, 4.2 Hz, 1H), 3.16 (dd, J = 10.3, 4.3 Hz, 1H), 2.99 (d, J = 10.3 Hz, 1H), 2.87 (d, J = 10.1 Hz, 1H), 1.82 - 1.74 (m, 1H), 0.82 (d, J = 7.2 Hz, 1.25H), 0.78 (d, J = 7.2 Hz, 1.75H) ppm [dr = 60:40]。 486.3 C   
I-2394
Figure 02_image5075
 CCC1C(C)CCN1C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 呈1:1:非對映異構體之約1:1混合物形式 δ 9.00 (br. s, 4H), 8.13 (br. s, 1H), 8.08 (br. s, 1H), 7.78 (br. s, 1H), 7.69 (br. s, 1H), 7.55 - 7.44 (m, 14H), 7.30 - 7.18 (m, 6H), 6.59 (br. s, 4H), 6.13 (br. s, 2H), 6.06 (br. s, 1H), 6.02 (br. s, 1H), 3.83 (app. q, J = 6.8 Hz, 1H), 3.51 (dd, J = 12.2, 6.3 Hz, 1H), 3.32 - 3.28 (m, 1H), 3.28 - 3.01 (m, 6H), 3.00 - 2.92 (m, 1H), 2.45 - 2.35 (m, 1H), 2.13 - 1.68 (m, 8H), 1.65 - 1.56 (m, 1H), 1.56 - 1.13 (m, 12H), 0.97 - 0.91 (m, 9H), 0.82 (d, J = 6.8 Hz, 3H), 0.79 - 0.67 (m, 12H)。 416.4 D   
I-2395
Figure 02_image5077
 CCC1CCCN1C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)，呈非對映異構體之約1:1混合物形式 δ 9.00 (br. s, 2H), 8.13 (s, 1H), 7.79 (s, 1H), 7.51 - 7.44 (m, 7H), 7.26 - 7.18 (m, 3H), 6.58 (br. s, 2H), 6.08 (br. s, 1H), 6.01 (br. s, 1H), 3.80 - 3.73 (m, 1H), 3.48 - 3.38 (m, 1H), 3.23 - 3.16 (m, 1H), 3.12 (dd, J = 16.5, 8.0 Hz, 1H), 3.00 - 2.93 (m, 1H), 2.60 - 2.52 (m, 1H), 1.79 - 1.54 (m, 10H), 1.15 - 1.00 (m, 2H), 0.75 (t, J = 6.8 Hz, 3H), 0.72 (t, J = 6.7 Hz, 3H)。 402.4 D   
I-2396
Figure 02_image5079
 CC(C)C1CCCN1C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)，呈非對映異構體之約1:1混合物形式, δ 9.01 (br. s, 2H), 8.19 (s, 1H), 7.80 (s, 1H), 7.57 - 7.46 (m, 7H), 7.27 - 7.18 (m, 3H), 6.54 (br. s, 2H), 6.16 (br. s, 1H), 6.00 (br. s, 1H), 3.81 (dd, J = 11.5, 5.6 Hz, 1H), 3.54 - 3.49 (m, 1H), 3.21 - 3.11 (m, 2H), 3.03 (ddd, J = 10.1, 7.6, 4.6 Hz, 1H), 2.06 - 1.96 (m, 1H), 1.90 - 1.79 (m, 1H), 1.77 - 1.49 (m, 9H), 0.79 - 0.73 (m, 6H), 0.67 (d, J = 6.8 Hz, 3H), 0.62 (d, J = 6.8 Hz, 3H)。 416.4 D   
I-2397
Figure 02_image5081
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)c3ncsc3Br)c12 (400 MHz, DMSO-d6 ) δ 9.97 (br s, 1H), 9.12 (s, 1H), 9.10 (浸沒br s, 1H), 7.72 (dd, J = 7.3, 0.6 Hz, 1H), 7.67 - 7.50 (m, 2H), 7.35 (dd, J = 8.3, 5.1 Hz, 1H), 7.11 (td, J = 8.5, 3.0 Hz, 1H), 6.68 (br s, 1H), 6.10 (br s, 1H)。 466.0 D   
I-2398
Figure 02_image5083
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCC(C3)C3CC3)c12 (400 MHz, DMSO-d6 ) δ 9.00 (br s, 1H), 8.10 (s, 0.5H), 8.04 (s, 0.5H), 7.55 - 7.40 (m, 3H), 7.33 - 7.26 (m, 1H), 7.26 - 7.19 (m, 1H), 6.58 (br s, 1H), 5.99 (br s, 1H), 3.22 - 3.11 (重疊m, 1H), 3.10 - 2.65 (浸沒m, 2H), 2.94 - 2.84 (重疊m, 1H), 1.94 - 1.73 (m, 1H), 1.58 - 1.29 (m, 2H), 0.68 - 0.51 (m, 1H), 0.47 - 0.33 (m, 2H), 0.22 - 0.02 (m, 2H)。 414.0 E   
I-2399
Figure 02_image5085
 O[C@H]1CN(C(=O)Nc2cc(Cl)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ9.23 (s, 1H), 8.61 (s, 1H), 7.70 (dd, J = 8.9, 4.7 Hz, 1H), 7.56 (d, J = 11.8 Hz, 2H), 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.08 (dtd, J = 26.7, 9.0, 8.6, 2.9 Hz, 3H), 6.61 (s, 1H), 6.08 (s, 1H), 5.88 - 5.64 (m, 1H), 5.34 - 4.92 (m, 1H), 3.91 (dd, J = 11.0, 8.1 Hz, 1H), 3.24 (dd, J = 11.1, 3.9 Hz, 1H)。 490.0 D   
I-2400
Figure 02_image5087
 O[C@H]1CN(C(=O)Nc2cc(Cl)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ9.23 (s, 1H), 8.61 (s, 1H), 7.70 (dd, J = 8.9, 4.7 Hz, 1H), 7.56 (d, J = 11.8 Hz, 2H), 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.08 (dtd, J = 26.7, 9.0, 8.6, 2.9 Hz, 3H), 6.61 (s, 1H), 6.08 (s, 1H), 5.88 - 5.64 (m, 1H), 5.34 - 4.92 (m, 1H), 3.91 (dd, J = 11.0, 8.1 Hz, 1H), 3.24 (dd, J = 11.1, 3.9 Hz, 1H)。 490.0 B   
I-2401
Figure 02_image5089
 O[C@@H]1CN(C(=O)Nc2cc(Cl)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ9.23 (s, 1H), 8.61 (s, 1H), 7.70 (dd, J = 8.9, 4.7 Hz, 1H), 7.56 (d, J = 11.8 Hz, 2H), 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.08 (dtd, J = 26.7, 9.0, 8.6, 2.9 Hz, 3H), 6.61 (s, 1H), 6.08 (s, 1H), 5.88 - 5.64 (m, 1H), 5.34 - 4.92 (m, 1H), 3.91 (dd, J = 11.0, 8.1 Hz, 1H), 3.24 (dd, J = 11.1, 3.9 Hz, 1H)。 490.0 E   
I-2402
Figure 02_image5091
 O[C@@H]1CN(C(=O)Nc2cc(Cl)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ9.23 (s, 1H), 8.61 (s, 1H), 7.70 (dd, J = 8.9, 4.7 Hz, 1H), 7.56 (d, J = 11.8 Hz, 2H), 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.08 (dtd, J = 26.7, 9.0, 8.6, 2.9 Hz, 3H), 6.61 (s, 1H), 6.08 (s, 1H), 5.88 - 5.64 (m, 1H), 5.34 - 4.92 (m, 1H), 3.91 (dd, J = 11.0, 8.1 Hz, 1H), 3.24 (dd, J = 11.1, 3.9 Hz, 1H)。 487.9 A A
I-2403
Figure 02_image5093
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2cc(cn2)C#N)c2ccc(F)cc12 (400 MHz, DMSO-d6)  9.54 (s, 1H), 9.26 (s, 1H), 8.93 (s, 1H), 8.46 (d, J = 24.6 Hz, 1H), 8.29 - 7.70 (m, 3H), 7.45 (d, J = 23.9 Hz, 1H), 7.25 - 7.01 (m, 3H), 6.97 - 6.45 (s, 1H), 6.08 (s, 1H), 5.79 (s, 1H), 5.07 (s, 1H), 3.72 (d, J = 9.9 Hz, 1H), 3.42 (s, 1H)。 547.1 A B
I-2404
Figure 02_image5095
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2cc(cn2)C#N)c2ccc(F)cc12 (400 MHz, DMSO-d6)  9.54 (s, 1H), 9.29 (s, 1H), 8.86 (d, J = 63.1 Hz, 1H), 8.43 (s, 1H), 8.26 - 7.79 (m, 2H), 7.74 (dd, J = 8.8, 4.7 Hz, 1H), 7.38 (dt, J = 9.1, 4.7 Hz, 1H), 7.21 - 7.10 (m, 2H), 7.10 - 6.95 (s, 1H), 6.93 - 6.36 (m, 1H), 6.15 (s, 1H), 5.77 (s, 1H), 5.23 - 5.00 (m, 1H), 3.97 (dd, J = 11.0, 8.1 Hz, 1H), 3.26 - 3.16 (m, 1H)。 547.2 B   
I-2405
Figure 02_image5097
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2cc(cn2)C#N)c2ccc(F)cc12 (400 MHz, DMSO-d6)  9.54 (s, 1H), 9.29 (s, 1H), 8.86 (d, J = 63.1 Hz, 1H), 8.43 (s, 1H), 8.11 - 7.94 (m, 2H), 7.74 (dd, J = 8.8, 4.7 Hz, 1H), 7.38 (dt, J = 9.1, 4.7 Hz, 1H), 7.21 - 6.93 (m, 3H), 6.93 - 6.36 (m, 1H), 6.15 (s, 1H), 5.77 (s, 1H), 5.23 - 5.00 (m, 1H), 3.97 (dd, J = 11.0, 8.1 Hz, 1H), 3.26 - 3.16 (m, 1H)。 547.2 A   
I-2406
Figure 02_image5099
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2cc(cn2)C#N)c2ccc(F)cc12 (400 MHz, DMSO-d6)  9.54 (s, 1H), 9.26 (s, 1H), 8.93 (s, 1H), 8.46 (d, J = 24.6 Hz, 1H), 8.02 (d, J = 23.9 Hz, 2H), 7.86 (s, 1H), 7.39 (dd, J = 8.9, 5.1 Hz, 1H), 7.24 - 7.02 (m, 3H), 6.98 - 6.37 (m, 1H), 6.08 (s, 1H), 5.79 (s, 1H), 5.07 (s, 1H), 3.72 (d, J = 9.9 Hz, 1H), 3.17 (d, J = 4.5 Hz, 1H) 547.1 D   
I-2407
Figure 02_image5101
 CC(N1C[C@H](O)C[C@H]1C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(F)(F)F (400 MHz, DMSO-d6 ) δ 9.29 (br. s, 1H), 9.16 (br. s, 0.3H), 9.15 (br. s, 0.6H), 9.11 (br. s, 0.3H), 7.95 - 7.80 (m, 0.2H), 7.83 - 7.68 (m, 0.8H), 7.67 - 7.39 (m, 3H), 7.35 - 7.09 (m, 1H), 6.71 (br. s, 0.3H), 6.38 (br. s, 0.7H), 6.15 (br. s, 0.3H), 6.08 (br. s, 0.7H), 4.88 (br. s, 1H), 4.14 - 3.78 (m, 1H), 3.79 - 3.53 (m, 1H), 3.55 - 3.40 (m, 0.2H), 3.28 - 3.07 (m, 1H), 3.08 - 2.91 (m, 0.8H), 2.93 - 2.82 (m, 0.2H), 2.71 - 2.59 (m, 0.2H), 2.60 - 2.52 (m, 0.8H), 1.86 - 1.64 (m, 1H), 1.50 - 1.26 (m, 1H), 1.15 (d, J = 7.0 Hz, 0.7H), 1.08 (d, J = 7.0 Hz, 1.6H), 1.07 (d, J = 6.9 Hz, 0.2H), 1.05 (d, J = 6.8 Hz, 0.5H)；根據LCMS，非對映異構體之1.4:1:0.9:0.2混合物 486.3 E   
I-2408
Figure 02_image5103
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCCC3C3CC3)c12 (400 MHz, DMSO-d6) δ 9.00 (br s, 1H), 8.18 (br s, 0.6H), 7.74 (br s, 0.4H), 7.56 - 7.38 (m, 3H), 7.29 - 7.17 (m, 2H), 6.57 (浸沒br s, 1H), 6.04 (br s, 0.6H), 5.97 (浸沒br s, 0.4H), 3.64 (t, J = 7.3 Hz, 0.6H), 3.28 (dt, J = 15.1, 7.6 Hz, 1H), 3.04 (dd, J = 8.5, 5.3 Hz, 1H), 2.41 - 2.27 (m, 0.6H), 1.96 - 1.81 (m, 1H), 1.81 - 1.53 (m, 3.4H), 0.95 - 0.81 (m, 0.4H), 0.81 - 0.66 (m, 0.6H), 0.58 - 0.40 (m, 1H), 0.39 - 0.29 (m, 1H), 0.28 - 0.21 (m, 1H), 0.15 - -0.02 (m, 1H)。非對映異構體之3:2混合物 414.0 E   
I-2409   
Figure 02_image5105
 FC(F)(C1=CC(F)=CC(C(NC2=C3C(NC(C3=CC(NC4=NC5(CC(F)(F)C5)CO4)=C2)=O)C6=CC(F)=CC=C6Cl)=O)=C1)F (400 MHz, DMSO) δ 10.49 (s, 1H), 9.84 (s, 1H), 9.08 (s, 1H), 8.02 (s, 2H), 7.92 (d, J = 8.4 Hz, 1H), 7.72 - 7.61 (m, 3H), 7.58 (s, 1H), 7.28 (dd, J = 8.9, 5.1 Hz, 1H), 7.07 (td, J = 8.3, 3.0 Hz, 1H), 5.85 (s, 1H), 4.40 (s, 2H), 2.89 (dd, J = 14.3, 10.7 Hz, 5H), 2.06 (s, 2H), 1.06 (s, 1H)。 627.0 A C
I-2410
Figure 02_image5107
 Nc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@@H](O)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 8.79 (s, 1H), 8.33 (s, 1H), 7.81 (dd, J = 8.9, 4.7 Hz, 1H), 7.33 (dd, J = 8.8, 5.2 Hz, 1H), 7.12 (ddt, J = 8.5, 5.8, 3.1 Hz, 2H), 7.06 (td, J = 9.0, 2.7 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.51 (s, 1H), 5.82 (s, 1H), 5.74 (d, J = 6.0 Hz, 1H), 5.51 (s, 2H), 5.05 (s, 1H), 3.66 (dd, J = 11.4, 3.6 Hz, 1H), 3.27 - 3.19 (m, 1H)。 471.1 A A
I-2411
Figure 02_image5109
 Nc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@@H](O)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 8.81 (s, 1H), 8.20 (s, 1H), 7.70 (dd, J = 9.1, 4.7 Hz, 1H), 7.32 (dd, J = 8.8, 5.2 Hz, 1H), 7.13 - 6.98 (m, 3H), 6.75 (d, J = 2.0 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 6.52 (s, 1H), 5.92 (s, 1H), 5.71 (d, J = 5.2 Hz, 1H), 5.51 (s, 2H), 5.13 (s, 1H), 3.96 - 3.87 (m, 1H), 3.23 (d, J = 8.9 Hz, 1H)。 471.1 A D
I-2412
Figure 02_image5111
 Nc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@H](O)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 8.78 (s, 1H), 8.33 (s, 1H), 7.82 (dd, J = 8.8, 4.8 Hz, 1H), 7.34 (dd, J = 8.8, 5.2 Hz, 1H), 7.12 (ddt, J = 8.5, 5.5, 3.0 Hz, 2H), 7.06 (td, J = 9.1, 2.8 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.51 (s, 1H), 5.82 (s, 1H), 5.73 (d, J = 6.0 Hz, 1H), 5.51 (s, 2H), 5.05 (s, 1H), 3.66 (dd, J = 11.3, 3.6 Hz, 1H), 3.23 (s, 1H)。 471.2 D   
I-2413
Figure 02_image5113
 Nc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@H](O)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 8.81 (s, 1H), 8.20 (s, 1H), 7.70 (dd, J = 8.9, 4.8 Hz, 1H), 7.32 (dd, J = 8.8, 5.2 Hz, 1H), 7.13 - 7.07 (m, 1H), 7.06 (dd, J = 8.7, 5.6 Hz, 1H), 7.06 - 6.97 (m, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 6.53 (s, 1H), 5.92 (s, 1H), 5.71 (d, J = 5.1 Hz, 1H), 5.51 (s, 2H), 5.13 (dt, J = 8.7, 4.6 Hz, 1H), 3.91 (dd, J = 11.1, 8.1 Hz, 1H), 3.23 (dd, J = 11.1, 4.1 Hz, 1H)。 471.2 E   
I-2414
Figure 02_image5115
 OC1CN(C(=O)Nc2cc(cc3C(=O)NC(c23)c2cc(F)ccc2Cl)-n2cncn2)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ 9.51 (br s, 1 H), 9.28 (br s, 1 H), 8.94 (br s, 0.5 H), 8.79 (s, 0.5 H), 8.30 (s, 0.5 H), 8.30 (s, 0.5 H), 8.12 - 8.09 (m, 1 H), 8.03 (d, J = 1.8 Hz, 0.5 H), 7.96 (d, J = 1.6 Hz, 0.5 H), 7.85 (dd, J = 8.0, 4.4 Hz, 0.5 H), 7.73 (dd, J = 8.8, 4.7 Hz, 0.5 H), 7.41 - 7.33 (m, 1 H), 7.21 - 7.00 (m, 3 H), 6.67 (br s, 1 H), 6.14 (br s, 0.5 H), 6.06 (br s, 0.5 H), 5.15 (dd, J = 7.9, 3.9 Hz, 0.5 H), 5.07 (dd, J = 7.7, 3.2 Hz, 0.5 H), 3.98 (dd, J = 10.9, 8.2 Hz, 0.5 H), 3.72 (dd, J = 11.3, 3.4 Hz, 0.5 H), 3.21 (dd, J = 11.0, 3.8 Hz, 0.5 H)。0.5 H浸沒在水信號下。非對映異構體之約1:1混合物。 523.3 B D
I-2415
Figure 02_image5117
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)N3CC[C@@H](C3)C#N)c12)-c1ccc2ncnn2c1 (400 MHz, DMSO-d6) δ 9.39 (br s, 1H), 9.17 (br s, 1H), 8.56 (s, 1H), 8.44 (d, J = 7.6 Hz, 1H), 8.06 (dt, J = 9.3, 1.6 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.93 (s, 1H), 7.70 (dd, J = 2.4, 1.8 Hz, 1H), 7.51 (br s, 1H), 7.28 - 7.20 (m, 1H), 6.70 (br s, 1H), 6.07 (br s, 1H), 3.58 (dd, J = 10.6, 7.1 Hz, 1H), 3.47 - 3.36 (m, 4H[浸沒在H2O峰下]), 2.24 - 1.95 (m, 2H) ppm [非對映異構體之1:1混合物]。 516.4 E   
I-2416
Figure 02_image5119
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(cc(NC(=O)N3CC[C@H](C3)C#N)c12)-c1ccc2ncnn2c1 (400 MHz, DMSO-d6) δ 9.39 (br s, 1H), 9.17 (br s, 1H), 8.56 (s, 1H), 8.44 (d, J = 7.6 Hz, 1H), 8.06 (dt, J = 9.3, 1.6 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.93 (s, 1H), 7.70 (dd, J = 2.4, 1.8 Hz, 1H), 7.51 (br s, 1H), 7.28 - 7.20 (m, 1H), 6.70 (br s, 1H), 6.07 (br s, 1H), 3.58 (dd, J = 10.6, 7.1 Hz, 1H), 3.47 - 3.36 (m, 4H[浸沒在H2O峰下]), 2.24 - 1.95 (m, 2H) ppm [非對映異構體之1:1混合物]。 516.4 E   
I-2417
Figure 02_image5121
 OC1(CN(C1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)c1scnc1C(F)(F)F (400 MHz, DMSO-d6) δ 9.20 (m, 1H), 9.03 (br s, 1H), 8.51 (br s, 1H), 7.60 - 7.48 (m, 2H), 7.43 - 7.32 (m, 1H), 7.18 (dd, J = 8.3, 5.5 Hz, 1H), 6.99 (td, J = 8.4, 2.9 Hz, 1H), 6.90 (br s, 1H), 6.47 (br s, 1H), 6.03 (br s, 1H), 4.10 (d, J = 9.0 Hz, 1H), 4.03 (d, J = 9.1 Hz, 1H), 3.87 (d, J = 9.1 Hz, 1H), 3.66 (d, J = 10.5 Hz, 1H)。 527.0 E   
I-2418
Figure 02_image5123
 OC1(CN(C1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)c1nc(cs1)C(F)(F)F (400 MHz, DMSO-d6) δ 9.05 (br s, 1H), 8.51 (d, J = 0.9 Hz, 1H), 8.39 (br s, 1H), 7.56 - 7.50 (m, 2H), 7.50 - 7.42 (m, 2H), 7.39 (br s, 1H), 7.16 (ddd, J = 8.9, 8.0, 3.1 Hz, 1H), 6.57 (br s, 1H), 6.09 (br s, 1H), 4.11 (d, J = 8.5 Hz, 1H), 3.99 (d, J = 8.5 Hz, 1H), 3.92 (d, J = 8.5 Hz, 1H), 3.70 (d, J = 8.7 Hz, 1H)。 527.0 E   
I-2419
Figure 02_image5125
 CC(C)C1CCN(C1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6 ) δ 9.00 (br s, 1H), 8.12 (s, 0.5H), 8.02 (s, 0.5H), 7.65 - 7.36 (m, 3H), 7.43 - 7.15 (m, 2H), 6.56 (br s, 1H), 5.97 (br s, 1H), 3.61 - 3.38 (浸沒m, 2H), 3.23 - 3.02 (m, 1H), 2.84 - 2.64 (m, 1H), 1.88 (td, J = 12.2, 6.3 Hz, 1H), 1.77 - 1.51 (m, 1H), 1.47 - 1.16 (m, 2H), 0.89 (dd, J = 6.6, 1.6 Hz, 3H), 0.84 (d, J = 6.5 Hz, 3H)。8.22 ppm處之部分甲酸鹽。非對映異構體之1:1混合物 416.0 E   
I-2420
Figure 02_image5127
 CCC1CCN(C1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) δ 9.00 (br s, 1H), 8.09 (s, 0.5H), 8.03 (s, 0.5H), 7.55 - 7.42 (m, 3H), 7.35 - 7.17 (m, 2H), 6.55 (br s, 1H), 5.98 (br s, 1H), 3.58 - 3.35 (浸沒m, 2H), 3.26 - 3.08 (m, 1H), 2.82 - 2.64 (m, 1H), 2.02 - 1.78 (m, 2H), 1.44 - 1.10 (m, 3H), 0.95 - 0.80 (m, 3H)。8.23 ppm處之部分甲酸鹽。非對映異構體之1:1混合物。 402.0 E   
I-2421
Figure 02_image5129
 CC(C1CCN(C1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)C(F)(F)F (400 MHz, DMS)-d6) δ 9.01 (br. s, 1H), 8.26 (br. s, 0.2H), 8.24 (br. s, 0.3H), 8.14 (br. s, 0.3H), 8.11 (br. s, 0.2H), 7.54 - 7.42 (m, 3H), 7.33 - 7.15 (m, 2H), 6.59 (br. s, 1H), 5.97 (br. s, 1H), 3.69 - 3.53 (m, 1H), 3.53 - 3.39 (m, 1H), 3.24 - 3.04 (m, 1H), 2.99 - 2.88 (m, 1H), 2.47 - 2.24 (m, 1H), 2.24 - 1.99 (m, 1H), 2.02 - 1.81 (m, 1H), 1.67 - 1.30 (m, 1H), 1.10 (d, J = 6.9 Hz, 0.8H ), 1.09 (d, J = 6.9 Hz, 0.8H), 1.03 (d, J = 6.7 Hz, 0.7H), 1.02 (d, J = 6.7 Hz, 0.7H)；非對映異構體之約1.3:1.2:1:1混合物；含有約5%甲酸鹽-歸因於8.25 ppm處之峰 470.2 E   
I-2422
Figure 02_image5131
 [H][C@@]12CCN(C(=O)Nc3cccc4C(=O)NC(c34)c3cc(F)ccc3Cl)[C@]1([H])CCCC2 (400 MHz, DMSO-d6) δ，呈非對映異構體之約1:1混合物形式, δ 8.99 (br. s, 2H), 8.04 (br. s, 1H), 7.78 (br. s, 1H), 7.52 - 7.40 (m, 7H), 7.27 - 7.17 (m, 3H), 6.60 (br. s, 2H), 6.05 (br. s, 2H), 3.77 - 3.68 (m, 1H), 3.39 - 3.28 (m, 1H), 3.21 (dd, J = 17.4, 9.1 Hz, 1H), 3.05 - 2.95 (m, 1H), 2.15 - 1.97 (m, 2H), 1.90 - 1.72 (m, 3H), 1.71 - 1.47 (m, 8H), 1.44 - 1.32 (m, 4H), 1.32 - 1.17 (m, 3H), 1.12 - 0.87 (m, 4H)。3.39-3.28 ppm處之多重峰被殘餘H2O之峰遮蔽。 428.4 D   
I-2423
Figure 02_image5133
 OC1(CN(C(=O)Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)F (400 MHz, DMSO-d6) δ，呈非對映異構體之約1:1混合物形式 δ 9.11 - 9.04 (m, 2H), 8.72 (br. s, 1H), 8.62 (br. s, 1H), 7.86 (br. d, J = 8.1 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.62 - 7.54 (m, 4H), 7.48 (dd, J = 7.3, 1.7 Hz, 1H), 7.42 - 7.37 (m, 3H), 7.37 - 7.26 (m, 4H), 7.14 - 7.08 (m, 2H), 7.01 (tdd, J = 7.5, 5.0, 0.9 Hz, 2H), 6.55 (s, 1H), 6.63 - 6.43 (m, 2H), 6.49 (s, 1H), 6.38 - 6.07 (m, 2H), 6.11 (br. s, 1H), 6.05 (br. s, 1H), 4.06 (d, J = 11.7 Hz, 1H), 3.82 (br. d, J = 12.2 Hz, 1H), 3.45 (br. d, J = 11.3 Hz, 1H), 3.33 - 3.30 (m, 1H)。3.33-3.30 ppm處之多重峰被殘餘H2O之峰部分遮蔽。 488.3 A B
I-2424
Figure 02_image5135
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cc(Br)cc(NC(=O)N3CCCC33CCCC3)c12    98.0 C   
I-2425
Figure 02_image5137
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCc4c3cccc4C#N)c12    447.1 E   
I-2426
Figure 02_image5139
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCc4cc(ccc34)C#N)c12    446.9 E   
I-2427
Figure 02_image5141
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCc4ccc(cc34)C#N)c12    447.0 D   
I-2428
Figure 02_image5143
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCSC3)c12    391.8 E   
I-2429
Figure 02_image5145
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CC4C3C3CCC4C3)c12    426.0 E   
I-2430
Figure 02_image5147
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCCC33CCCCC3)c12    442.0 C   
I-2431
Figure 02_image5149
 Nc1nn(C(=O)Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccc(F)cc12    453.9 C   
I-2432
Figure 02_image5151
 CC(C)(C)[C@H]1CCCN1C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 呈非對映異構體之約19:1混合物形式, δ 9.02 (br. s, 1H), 7.77 (br. s, 1H), 7.74 (br. d, J = 7.1 Hz, 1H), 7.54 - 7.47 (m, 3H), 7.23 (ddd, J = 8.8, 8.1, 3.1 Hz, 1H), 6.63 (br. s, 1H), 6.16 (br. s, 1H), 3.74 - 3.70 (m, 1H), 3.15 - 3.07 (m, 1H), 3.05 - 2.96 (m, 1H), 1.82 - 1.65 (m, 2H), 1.58 - 1.48 (m, 2H), 0.78 (s, 9H)。 430.4 C   
I-2433
Figure 02_image5153
 CC(C)(C)[C@@H]1CCCN1C(=O)Nc1cccc2C(=O)N[C@H](c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) δ呈非對映異構體之約19:1混合物形式, δ 9.00 (br. s, 1H), 8.33 (br. s, 1H), 7.52 - 7.44 (m, 3H), 7.26 - 7.19 (m, 2H), 6.36 (br. s, 1H), 5.98 (br. s, 1H), 3.99 (d, J = 7.9 Hz, 1H), 3.21 - 3.13 (m, 1H), 2.45 - 2.36 (m, 1H), 1.78 - 1.61 (m, 3H), 1.53 - 1.44 (m, 1H), 0.75 (s, 9H)。 430.4 D   
I-2434
Figure 02_image5155
 CCN(C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)c1ccc(F)cc1 (400 MHz, DMSO-d6)  9.05 (s, 1H), 7.73 (s, 1H), 7.61 (s, 1H), 7.53-7.43 (m, 2H), 7.35 (ddd, J = 10.9, 7.2, 2.7 Hz, 2H), 7.09 (t, J = 8.6 Hz, 2H), 6.64 (dd, J = 8.7, 5.0 Hz, 2H), 6.42 (s, 1H), 6.08 (s, 1H), 3.64 (dt, J = 14.2, 7.1 Hz, 1H), 3.42 (dq, J = 13.9, 6.9 Hz, 1H), 0.90 (t, J = 7.0 Hz, 3H)。 442.3 E   
I-2435
Figure 02_image5157
 CN(C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl)c1ccc(F)cc1 (400 MHz, DMSO-d6) 9.04 (s, 1H), 7.91 (s, 1H), 7.58 (s, 1H), 7.54-7.45 (m, 2H), 7.33 (ddd, J = 11.7, 8.6, 4.7 Hz, 2H), 7.10 (t, J = 8.8 Hz, 2H), 6.85-6.75 (m, 2H), 6.43 (s, 1H), 6.04 (s, 1H), 3.05 (s, 3H)。 428.2 E   
I-2436
Figure 02_image5159
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCc4cc(ccc34)C(F)(F)F)c12 (400 MHz, DMSO-d6) 9.07 (s, 1H), 8.72 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 6.6 Hz, 1H), 7.61-7.54 (m, 2H), 7.54-7.45 (m, 2H), 7.43-7.35 (m, 2H), 7.16 (td, J = 8.4, 3.1 Hz, 1H), 6.01 (s, 1H), 3.95 (td, J = 10.1, 7.0 Hz, 1H), 3.12 (pt, J = 16.8, 7.8 Hz, 2H)。 490.3 E   
I-2437
Figure 02_image5161
 COc1ccc2N(CCc2c1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl    452.3 E   
I-2438
Figure 02_image5163
 Cc1cccc2N(CCc12)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.05 (s, 1H), 8.49 (s, 1H), 7.62 -7.50 (m, 3H), 7.45 -7.36 (m, 2H), 7.16 (td, J = 8.4, 3.1 Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 6.73 (d, J = 7.5 Hz, 1H), 6.57 (s, 1H), 6.03 (s, 1H), 3.87 (td, J = 10.1, 7.2 Hz, 1H), 3.27 (s, 1H), 2.96 (tp, J = 14.3, 7.0 Hz, 2H), 2.19 (s, 3H)。 436.2 D   
I-2439
Figure 02_image5165
 COc1ccc2CCN(C(=O)Nc3cccc4C(=O)NC(c34)c3cc(F)ccc3Cl)c2c1 (400 MHz, DMSO-d6) 9.06 (s, 1H), 8.54 (s, 1H), 7.63 - 7.52 (m, 2H), 7.43 - 7.33 (m, 3H), 7.16 (td, J = 8.4, 3.1 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.60 (s, 1H), 6.47 (dd, J = 8.2, 2.5 Hz, 1H), 6.02 (s, 1H), 3.87 (td, J = 9.9, 7.4 Hz, 1H), 3.70 (s, 3H), 3.28 (d, J = 17.2 Hz, 1H), 3.04 - 2.85 (m, 2H)。 452.2 D   
I-2440
Figure 02_image5167
 Cc1ccc2N(CCc2c1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.03 (s, 1H), 8.47 (s, 1H), 7.56 (q, J = 7.5 Hz, 3H), 7.43-7.34 (m, 2H), 7.15 (td, J = 8.4, 3.1 Hz, 1H), 6.98 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.58 (s, 1H), 6.02 (s, 1H), 3.83 (td, J = 9.9, 7.4 Hz, 1H), 3.23-3.15 (m, 1H), 2.98 (dt, J = 13.6, 7.0 Hz, 2H), 2.24 (s, 3H)。 436.2 E   
I-2441
Figure 02_image5169
 COc1cccc2N(CCc12)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.06 (s, 1H), 8.65 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.64 - 7.53 (m, 2H), 7.39 (td, J = 8.3, 7.4, 2.7 Hz, 2H), 7.22 - 7.12 (m, 2H), 6.97 (d, J = 7.9 Hz, 1H), 6.56 (s, 1H), 6.00 (s, 1H), 3.94 (td, J = 10.3, 7.0 Hz, 1H), 3.25 (s, 1H), 3.08 (tdd, J = 16.5, 10.3, 6.4 Hz, 2H)。 456.2 E   
I-2442
Figure 02_image5171
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCc4c3cccc4Cl)c12 (400 MHz, DMSO-d6) 9.06 (s, 1H), 8.65 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.64 - 7.53 (m, 2H), 7.39 (td, J = 8.3, 7.4, 2.7 Hz, 2H), 7.22 - 7.12 (m, 2H), 6.97 (d, J = 7.9 Hz, 1H), 6.56 (s, 1H), 6.00 (s, 1H), 3.94 (td, J = 10.3, 7.0 Hz, 1H), 3.25 (s, 1H), 3.08 (tdd, J = 16.5, 10.3, 6.4 Hz, 2H)。 456.2 D   
I-2443
Figure 02_image5173
 NCCc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@H](O)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.00 (s, 1H), 8.60 (s, 1H), 7.83 (dd, J = 8.9, 4.7 Hz, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.36 (dd, J = 8.9, 5.2 Hz, 1H), 7.21 (d, J = 1.5 Hz, 1H), 7.15 (tt, J = 8.2, 2.9 Hz, 2H), 7.08 (td, J = 9.0, 2.8 Hz, 1H), 6.55 (s, 1H), 5.96 (s, 1H), 5.77 (s, 1H), 5.07 (dd, J = 8.4, 3.5 Hz, 1H), 3.71 (dd, J = 11.3, 3.6 Hz, 1H), 3.27 (d, J = 32.4 Hz, 4H), 2.90-2.70 (m, 3H)。 499.2 A D
I-2444
Figure 02_image5175
 NCCc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@@H](O)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.00 (s, 1H), 8.60 (s, 1H), 7.83 (dd, J = 8.9, 4.7 Hz, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.36 (dd, J = 8.9, 5.2 Hz, 1H), 7.21 (d, J = 1.5 Hz, 1H), 7.15 (tt, J = 8.2, 2.9 Hz, 2H), 7.08 (td, J = 9.0, 2.8 Hz, 1H), 6.55 (s, 1H), 5.96 (s, 1H), 5.77 (s, 1H), 5.07 (dd, J = 8.4, 3.5 Hz, 1H), 3.71 (dd, J = 11.3, 3.6 Hz, 1H), 3.27 (d, J = 32.4 Hz, 4H), 2.90-2.70 (m, 3H)。 499.2 B   
I-2445
Figure 02_image5177
 NCCc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@H](O)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.00 (s, 1H), 8.60 (s, 1H), 7.83 (dd, J = 8.9, 4.7 Hz, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.36 (dd, J = 8.9, 5.2 Hz, 1H), 7.21 (d, J = 1.5 Hz, 1H), 7.15 (tt, J = 8.2, 2.9 Hz, 2H), 7.08 (td, J = 9.0, 2.8 Hz, 1H), 6.55 (s, 1H), 5.96 (s, 1H), 5.77 (s, 1H), 5.07 (dd, J = 8.4, 3.5 Hz, 1H), 3.71 (dd, J = 11.3, 3.6 Hz, 1H), 3.27 (d, J = 32.4 Hz, 4H), 2.90-2.70 (m, 3H)。 499.2 D   
I-2446
Figure 02_image5179
 NCCc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@@H](O)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.00 (s, 1H), 8.60 (s, 1H), 7.83 (dd, J = 8.9, 4.7 Hz, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.36 (dd, J = 8.9, 5.2 Hz, 1H), 7.21 (d, J = 1.5 Hz, 1H), 7.15 (tt, J = 8.2, 2.9 Hz, 2H), 7.08 (td, J = 9.0, 2.8 Hz, 1H), 6.55 (s, 1H), 5.96 (s, 1H), 5.77 (s, 1H), 5.07 (dd, J = 8.4, 3.5 Hz, 1H), 3.71 (dd, J = 11.3, 3.6 Hz, 1H), 3.27 (d, J = 32.4 Hz, 4H), 2.90-2.70 (m, 3H)。 499.2 D   
I-2447
Figure 02_image5181
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCc4ccc(cc34)C(F)(F)F)c12 (400 MHz, DMSO-d6) 9.08 (s, 1H), 8.73 (s, 1H), 8.00 (s, 1H), 7.66 - 7.59 (m, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.43 - 7.32 (m, 3H), 7.25 (d, J = 7.5 Hz, 1H), 7.13 (td, J = 8.4, 3.1 Hz, 1H), 6.56 (s, 1H), 6.03 (s, 1H), 3.95 (td, J = 10.0, 7.0 Hz, 1H), 3.21 (s, 1H), 3.13 (q, J = 10.1 Hz, 2H)。 490.2 D   
I-2448
Figure 02_image5183
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-c2ccc(=O)n(c2)C(F)F)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.12 (s, 1H), 8.73 (s, 1H), 8.16 (d, J = 2.6 Hz, 1H), 8.11 - 8.04 (m, 1H), 7.94 - 7.72 (m, 3H), 7.63 (d, J = 1.7 Hz, 1H), 7.38 (dd, J = 8.9, 5.2 Hz, 1H), 7.21 - 7.02 (m, 3H), 6.69 (d, J = 9.7 Hz, 2H), 6.05 (s, 1H), 5.79 (s, 1H), 5.12 - 5.05 (m, 1H), 3.73 (dd, J = 11.4, 3.6 Hz, 1H), 3.25 (dd, J = 11.0, 4.0 Hz, 1H)。 599.1 A B
I-2449
Figure 02_image5185
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-c2ccc(=O)n(c2)C(F)F)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.14 (s, 1H), 8.59 (s, 1H), 8.15 (d, J = 2.6 Hz, 1H), 8.12 - 8.03 (m, 1H), 7.92 (s, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.78 - 7.64 (m, 2H), 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.18 - 6.96 (m, 3H), 6.68 (d, J = 9.7 Hz, 2H), 6.13 (s, 1H), 5.74 (d, J = 4.9 Hz, 1H), 5.31 - 5.07 (m, 1H), 4.00 (dd, J = 11.1, 8.0 Hz, 1H), 3.25 (dd, J = 11.0, 4.0 Hz, 1H)。 599.1 B   
I-2450
Figure 02_image5187
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-c2ccc(=O)n(c2)C(F)F)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.14 (s, 1H), 8.60 (s, 1H), 8.15 (d, J = 2.6 Hz, 1H), 8.11 - 8.03 (m, 1H), 7.92 (s, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.80 - 7.66 (m, 2H), 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.18 - 6.95 (m, 3H), 6.68 (m, 2H), 6.13 (s, 1H), 5.75 (s, 1H), 5.16 (dd, J = 8.0, 4.0 Hz, 1H), 4.00 (dd, J = 11.1, 8.1 Hz, 1H), 3.25 (dd, J = 11.0, 4.0 Hz, 1H)。 599.0 D   
I-2451
Figure 02_image5189
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-c2ccc(=O)n(c2)C(F)F)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.12 (s, 1H), 8.73 (s, 1H), 8.16 (d, J = 2.6 Hz, 1H), 8.11 - 8.03 (m, 1H), 7.92 (s, 1H), 7.88 - 7.75 (m, 2H), 7.63 (d, J = 1.7 Hz, 1H), 7.38 (dd, J = 8.9, 5.2 Hz, 1H), 7.21 - 7.01 (m, 3H), 6.69 (d, J = 9.7 Hz, 2H), 6.13 (s, 1H), 5.86 (s, 1H), 5.09 (d, J = 7.6 Hz, 1H), 3.73 (dd, J = 11.3, 3.6 Hz, 1H), 3.25 (dd, J = 11.0, 4.0 Hz, 1H)。 599.2 D   
I-2452
Figure 02_image5191
 CC(C)[C@@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.05 (s, 1H), 8.60 (s, 1H), 7.89 (s, 1H), 7.63 - 7.53 (m, 2H), 7.42 (dd, J = 7.1, 1.8 Hz, 1H), 7.34 (dd, J = 8.9, 5.1 Hz, 1H), 7.14 (td, J = 8.4, 3.1 Hz, 1H), 7.09 - 7.02 (m, 2H), 6.55 (s, 1H), 6.11 (s, 1H), 5.54 (s, 1H), 3.64 (d, J = 11.2 Hz, 1H), 3.30 (s, 1H), 2.15 - 2.04 (m, 1H), 0.89 (d, J = 6.7 Hz, 3H), 0.55 (d, J = 6.8 Hz, 3H)。 498.3 D   
I-2453
Figure 02_image5193
 CC(C)[C@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.08 (s, 1H), 8.41 (s, 1H), 7.74 (dd, J = 8.8, 4.7 Hz, 1H), 7.58 (d, J = 1.9 Hz, 3H), 7.39 (dd, J = 8.9, 5.1 Hz, 1H), 7.13 (td, J = 8.5, 3.1 Hz, 1H), 7.08 - 6.97 (m, 2H), 6.55 (s, 1H), 6.17 (s, 1H), 5.48 (s, 1H), 3.78 (d, J = 11.1 Hz, 1H), 3.35 (s, 1H), 2.08 (s, 1H), 0.94 (d, J = 6.7 Hz, 3H), 0.57 (d, J = 6.8 Hz, 3H)。 498.3 D   
I-2454
Figure 02_image5195
 CC(C)[C@@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.05 (s, 1H), 8.60 (s, 1H), 7.89 (s, 1H),  7.63 - 7.53 (m, 2H), 7.42 (dd, J = 7.1, 1.8 Hz, 1H), 7.34 (dd, J = 8.9, 5.2 Hz, 1H), 7.14 (td, J = 8.3, 3.1 Hz, 1H), 7.06 (ddt, J = 6.9, 3.9, 2.1 Hz, 2H), 6.55 (s, 1H), 6.11 (s, 1H), 5.54 (s, 1H), 3.64 (d, J = 11.3 Hz, 1H), 3.35 (s, 1H), 2.15 - 2.04 (m, 1H), 0.89 (d, J = 6.7 Hz, 3H), 0.55 (d, J = 6.8 Hz, 3H)。 498.3 B   
I-2455
Figure 02_image5197
 CC(C)[C@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.08 (s, 1H), 8.41 (s, 1H), 7.74 (dd, J = 8.8, 4.8 Hz, 1H), 7.58 (d, J = 1.9 Hz, 3H), 7.39 (dd, J = 8.9, 5.1 Hz, 1H), 7.13 (td, J = 8.4, 3.1 Hz, 1H), 7.08 - 7.02 (m, 1H), 7.02 (dd, J = 9.0, 6.3 Hz, 1H), 6.55 (s, 1H), 6.17 (s, 1H), 5.48 (s, 1H), 3.78 (d, J = 11.1 Hz, 1H), 3.29 (s, 1H), 2.07 (q, J = 6.7 Hz, 1H), 0.94 (d, J = 6.7 Hz, 3H), 0.57 (d, J = 6.8 Hz, 3H)。 498.3 D   
I-2456
Figure 02_image5199
 CCC[C@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.62 (s, 1H), 7.86 (s, 1H), 7.62 - 7.52 (m, 2H), 7.41- 7.32 (m, 2H), 7.14 (td, J = 8.3, 3.1 Hz, 1H), 7.11 - 7.01 (m, 2H), 6.03 (s, 1H), 5.55 (s, 1H), 3.77 (d, J = 11.0 Hz, 1H), 3.12 (d, J = 11.0 Hz, 1H), 1.77 (td, J = 12.2, 11.2, 4.4 Hz, 1H), 1.52 (td, J = 13.3, 12.6, 4.4 Hz, 1H), 1.26 (d, J = 14.2 Hz, 1H), 1.07 - 0.88 (m, 4H)。 498.2 D   
I-2457
Figure 02_image5201
 CCC[C@@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.62 (s, 1H), 7.86 (s, 1H), 7.62 - 7.52 (m, 2H), 7.41- 7.32 (m, 2H), 7.14 (td, J = 8.3, 3.1 Hz, 1H), 7.11 - 7.01 (m, 2H), 6.03 (s, 1H), 5.55 (s, 1H), 3.77 (d, J = 11.0 Hz, 1H), 3.12 (d, J = 11.0 Hz, 1H), 1.77 (td, J = 12.2, 11.2, 4.4 Hz, 1H), 1.52 (td, J = 13.3, 12.6, 4.4 Hz, 1H), 1.26 (d, J = 14.2 Hz, 1H), 1.07 - 0.88 (m, 4H)。 498.2 C   
I-2458
Figure 02_image5203
 CCC[C@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.62 (s, 1H), 7.86 (s, 1H), 7.62 - 7.52 (m, 2H), 7.41- 7.32 (m, 2H), 7.14 (td, J = 8.3, 3.1 Hz, 1H), 7.11 - 7.01 (m, 2H), 6.03 (s, 1H), 5.55 (s, 1H), 3.77 (d, J = 11.0 Hz, 1H), 3.12 (d, J = 11.0 Hz, 1H), 1.77 (td, J = 12.2, 11.2, 4.4 Hz, 1H), 1.52 (td, J = 13.3, 12.6, 4.4 Hz, 1H), 1.26 (d, J = 14.2 Hz, 1H), 1.07 - 0.88 (m, 4H)。 498.2 D   
I-2459
Figure 02_image5205
 CCC[C@@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.62 (s, 1H), 7.86 (s, 1H), 7.62 - 7.52 (m, 2H), 7.41- 7.32 (m, 2H), 7.14 (td, J = 8.3, 3.1 Hz, 1H), 7.11 - 7.01 (m, 2H), 6.03 (s, 1H), 5.55 (s, 1H), 3.77 (d, J = 11.0 Hz, 1H), 3.12 (d, J = 11.0 Hz, 1H), 1.77 (td, J = 12.2, 11.2, 4.4 Hz, 1H), 1.52 (td, J = 13.3, 12.6, 4.4 Hz, 1H), 1.26 (d, J = 14.2 Hz, 1H), 1.07 - 0.88 (m, 4H)。 498.2 D   
I-2460
Figure 02_image5207
 CC[C@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.63 (s, 1H), 7.86 (dd, J = 8.7, 4.5 Hz, 1H), 7.64 - 7.52 (m, 2H), 7.42 - 7.33 (m, 2H), 7.15 (td, J = 8.4, 3.1 Hz, 1H), 7.11 - 7.01 (m, 2H), 6.55 (s, 1H), 6.04 (s, 1H), 5.56 (s, 1H), 3.76 (d, J = 11.0 Hz, 1H), 3.13 (d, J = 11.0 Hz, 1H), 1.80 (dq, J = 14.1, 7.1 Hz, 1H), 1.57 (dq, J = 14.6, 7.4 Hz, 1H), 0.76 (t, J = 7.3 Hz, 3H)。 484.2 D   
I-2461
Figure 02_image5209
 CC[C@@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.63 (s, 1H), 7.86 (dd, J = 8.7, 4.5 Hz, 1H), 7.64 - 7.52 (m, 2H), 7.42 - 7.33 (m, 2H), 7.15 (td, J = 8.4, 3.1 Hz, 1H), 7.11 - 7.01 (m, 2H), 6.55 (s, 1H), 6.04 (s, 1H), 5.56 (s, 1H), 3.76 (d, J = 11.0 Hz, 1H), 3.13 (d, J = 11.0 Hz, 1H), 1.80 (dq, J = 14.1, 7.1 Hz, 1H), 1.57 (dq, J = 14.6, 7.4 Hz, 1H), 0.76 (t, J = 7.3 Hz, 3H)。 484.2 A A
I-2462
Figure 02_image5211
 CC[C@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.63 (s, 1H), 7.86 (dd, J = 8.7, 4.5 Hz, 1H), 7.64 - 7.52 (m, 2H), 7.42 - 7.33 (m, 2H), 7.15 (td, J = 8.4, 3.1 Hz, 1H), 7.11 - 7.01 (m, 2H), 6.55 (s, 1H), 6.04 (s, 1H), 5.56 (s, 1H), 3.76 (d, J = 11.0 Hz, 1H), 3.13 (d, J = 11.0 Hz, 1H), 1.80 (dq, J = 14.1, 7.1 Hz, 1H), 1.57 (dq, J = 14.6, 7.4 Hz, 1H), 0.76 (t, J = 7.3 Hz, 3H)。 484.2 D   
I-2463
Figure 02_image5213
 CC[C@@]1(O)CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.63 (s, 1H), 7.86 (dd, J = 8.7, 4.5 Hz, 1H), 7.64 - 7.52 (m, 2H), 7.42 - 7.33 (m, 2H), 7.15 (td, J = 8.4, 3.1 Hz, 1H), 7.11 - 7.01 (m, 2H), 6.55 (s, 1H), 6.04 (s, 1H), 5.56 (s, 1H), 3.76 (d, J = 11.0 Hz, 1H), 3.13 (d, J = 11.0 Hz, 1H), 1.80 (dq, J = 14.1, 7.1 Hz, 1H), 1.57 (dq, J = 14.6, 7.4 Hz, 1H), 0.76 (t, J = 7.3 Hz, 3H)。 484.2 D   
I-2464
Figure 02_image5215
 OC1CN(C(=O)Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2cc(Cl)ccc12 (400 MHz, DMSO-d6) δ 9.08 (br s, 1 H), 8.74 (s, 0.5 H), 8.67 (s, 0.5 H), 7.83 (s, 0.5 H), 7.67 - 7.51 (m, 2.5 H), 7.47 - 7.26 (m, 3 H), 7.15 (td, J = 8.4, 3.0 Hz, 0.5 H), 7.08 (td, J = 8.5, 3.0 Hz, 0.5 H), 7.02 (dd, J = 8.1, 1.8 Hz, 0.5 H), 6.99 (dd, J = 8.0, 1.8 Hz, 0.5 H), 6.55 (br s, 1 H), 6.07 (br s, 0.5 H), 6.00 (br s, 0.5 H), 5.72 (s, 1 H), 5.12 (dd, J = 7.7, 3.1 Hz, 0.5 H), 5.06 (dd, J = 7.2, 2.5 Hz, 0.5 H), 3.96 (dd, J = 10.9, 8.0 Hz, 0.5 H), 3.71 (dd, J = 11.3, 3.2 Hz, 0.5 H), 3.26 (dd, J = 11.1, 3.3 Hz, 0.5 H)。非對映異構體之約1:1混合物 472.2 A C
I-2465
Figure 02_image5217
 CC(C)c1cc(N)n(n1)C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl    428.1 E   
I-2466
Figure 02_image5219
 CC(C)c1cc(N)nn1C(=O)Nc1cccc2C(=O)NC(c12)c1cc(F)ccc1Cl    428.0 E   
I-2467
Figure 02_image5221
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCCC33CC3)c12 (400 MHz, DMSO-d6) δ 8.98 (br s, 1H), 7.97 (s, 1H), 7.70 - 7.37 (m, 3H), 7.37 - 7.15 (m, 2H), 6.61 (br s, 1H), 5.89 (br s, 1H), 3.29 (浸沒m, 1H), 2.78 - 2.55 (m, 1H), 1.94 - 1.81 (m, 1H), 1.82 - 1.71 (m, 2H), 1.70 - 1.57 (m, 2H), 1.49 - 1.35 (m, 1H), 0.46 - 0.25 (m, 2H)。 400.0 D   
I-2468
Figure 02_image5223
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCC4(CC4)C3)c12 (400 MHz, DMSO-d6) δ 9.00 (br s, 1H), 8.06 (br s, 1H), 7.59 - 7.41 (m, 3H), 7.29 (p, J = 3.8 Hz, 1H), 7.24 (td, J = 8.4, 3.1 Hz, 1H), 6.59 (br s, 1H), 6.00 (br s, 1H), 3.39 (浸沒m, 1H), 3.17 (d, J = 9.8 Hz, 1H), 2.94 (br s, 1H), 2.70 (br s, 1H), 1.76 - 1.55 (m, 2H), 0.63 - 0.39 (m, 4H)。 400.0 E   
I-2469
Figure 02_image5225
 OC1(CN(C(=O)Nc2cc(cc3C(=O)NC(c23)c2cc(F)ccc2Cl)C#N)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) δ 9.40 (br. s, 1H), 8.99 (br. s, 2H), 8.05 (s, 2H), 7.92 (s, 2H), 7.85 (dd, J = 8.9, 4.6 Hz, 1H), 7.82 (s, 1H), 7.52 - 7.39 (m, 2H ), 7.36 (td, J = 8.3, 5.5 Hz, 2H), 7.31 - 7.25 (m, 2H), 7.25 - 7.18 (m, J = 7.8 Hz, 2H), 7.18 - 7.05 (m, 2H), 6.63 (br. s, 2H), 6.14 (s, 2H), 4.15 (d, J = 11.8 Hz, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.52 (d, J = 11.8 Hz, 1H), 3.45 (d, J = 11.8 Hz, 1H)；非對映異構體之1:1混合物 547.3 A A
I-2470
Figure 02_image5227
 Cc1ccc2CCN(C(=O)Nc3cccc4C(=O)NC(c34)c3cc(F)ccc3Cl)c2c1 (400 MHz, DMSO-d6)  9.05 (s, 1H), 8.55 (s, 1H), 7.61 - 7.52 (m, 2H), 7.46 (s, 1H), 7.42 - 7.34 (m, 2H), 7.15 (td, J = 8.4, 3.1 Hz, 1H), 7.04 (d, J = 7.5 Hz, 2H), 6.75 - 6.68 (m, 1H),6.20(s, 1H) 3.89 - 3.77 (m, 1H), 3.34 (s, 2H), 3.28 (s, 1H), 2.24 (s, 3H)。 436.2 B   
I-2471
Figure 02_image5229
 N[C@]1(CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) δ 9.08 (br s, 1H), 8.68 (s, 1H), 7.78 (dd, J = 8.9, 4.6 Hz, 1H), 7.63 - 7.54 (m, 2H), 7.45 (dd, J = 7.3, 1.4 Hz, 1H), 7.37 (dd, J = 8.7, 5.3 Hz, 1H), 7.28 (dd, J = 8.1, 2.5 Hz, 1H), 7.19 - 7.08 (m, 2H), 6.49 (br s, 1H), 6.06 (br s, 1H), 4.21 (d, J = 11.5 Hz, 1H), 3.30 - 3.25 (m, 1H [浸沒在H2O峰下-參見COSY]), 2.89 - 2.83 (br s, 2H) ppm [dr = 95:5, 外消旋]。 523.4 D   
I-2472
Figure 02_image5231
 N[C@@]1(CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) δ 9.08 (br s, 1H), 8.77 (s, 1H), 7.81 (dd, J = 8.6, 4.4 Hz, 1H), 7.63 - 7.54 (m, 2H), 7.36 (dd, J = 7.4, 1.3 Hz, 1H), 7.33 (dd, J = 8.9, 5.2 Hz, 1H), 7.26 (dd, J = 8.3, 2.5 Hz, 1H), 7.19 - 7.09 (m, 2H), 6.53 (br s, 1H), 6.04 (br s, 1H), 3.85 (d, J = 11.6 Hz, 1H), 3.54 (d, J = 11.5 Hz, 1H), 2.96 - 2.87 (br s, 2H) ppm [單一非對映異構體]。 523.4 C   
I-2473
Figure 02_image5233
 OC1(CN(C(=O)Nc2cc(cc3C(=O)NC(c23)c2cc(F)ccc2Cl)C#N)c2ccccc12)C(F)(F)F (400 MHz, DMSO-d6 ) δ 9.40 (br. s, 2H), 8.96 (br. s, 2H), 8.04 (s, 2H), 7.95 (d, J = 1.3 Hz, 1H), 7.83 (d, J = 1.3 Hz, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.60 (d, J = 1.2 Hz, 1H), 7.44 (d, J = 7.7 Hz, 2H), 7.42 - 7.31 (m, 4H), 7.32 - 7.22 (m, 2H), 7.23 - 7.01 (m, 4H), 6.71 (br. s, 2H), 6.16 (br. s, 2H), 4.08 (d, J = 12.0 Hz, 1H), 3.92 (d, J = 11.9 Hz, 1H), 3.50 (d, J = 11.6 Hz, 1H), 3.47 (d, J = 11.6 Hz, 1H)；非對映異構體之1:1混合物 529.3 A A
I-2474
Figure 02_image5235
 OC1(CN(C(=O)Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F    524.3 A B
I-2475
Figure 02_image5237
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-c2cnn(c2)C(F)F)c2ccc(F)cc12 (400 MHz, DMSO) δ9.08 (s, 1H), 8.87 (s, 1H), 8.68 (s, 1H), 8.38 (s, 1H), 8.01 - 7.65 (m, 4H), 7.37 (dd, J = 8.9, 5.1 Hz, 1H), 7.19 - 7.04 (m, 3H), 6.73 - 6.48 (m, 1H), 6.00 (s, 1H), 5.76 (d, J = 5.9 Hz, 1H), 5.12 - 5.03 (m, 1H), 3.69 (dd, J = 11.4, 3.6 Hz, 1H), 3.29 - 3.27 (m, 1H) 571.9 D   
I-2476
Figure 02_image5239
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-c2cnn(c2)C(F)F)c2ccc(F)cc12 (400 MHz, DMSO) δ9.10 (s, 1H), 8.87 (d, J = 0.8 Hz, 1H), 8.55 (s, 1H), 8.38 (d, J = 0.7 Hz, 1H), 8.00 - 7.68 (m, 4H), 7.34 (dd, J = 8.8, 5.2 Hz, 1H), 7.13 - 6.99 (m, 3H), 6.79 - 6.43 (m, 1H), 6.08 (s, 1H), 5.73 (d, J = 5.0 Hz, 1H), 5.15 (dt, J = 8.6, 4.5 Hz, 1H), 3.96 (dd, J = 11.1, 8.1 Hz, 1H), 3.28 - 3.20 (m, 1H) 571.9 E   
I-2477
Figure 02_image5241
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-c2cnn(c2)C(F)F)c2ccc(F)cc12 (400 MHz, DMSO) δ9.08 (s, 1H), 8.87 (d, J = 0.8 Hz, 1H), 8.68 (s, 1H), 8.38 (d, J = 0.8 Hz, 1H), 8.01 - 7.65 (m, 4H), 7.37 (dd, J = 8.9, 5.2 Hz, 1H), 7.18 - 7.03 (m, 3H), 6.76 - 6.40 (m, 1H), 6.00 (s, 1H), 5.76 (d, J = 5.9 Hz, 1H), 5.07 (t, J = 8.6 Hz, 1H), 3.69 (dd, J = 11.4, 3.6 Hz, 1H), 3.30 - 3.20 (m, 1H) 571.9 A A
I-2478
Figure 02_image5243
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-c2cnn(c2)C(F)F)c2ccc(F)cc12 (400 MHz, DMSO) δ9.10 (s, 1H), 8.87 (d, J = 0.8 Hz, 1H), 8.55 (s, 1H), 8.38 (d, J = 0.7 Hz, 1H), 8.01 - 7.67 (m, 4H), 7.34 (dd, J = 8.9, 5.1 Hz, 1H), 7.14 - 6.99 (m, 3H), 6.75 - 6.48 (m, 1H), 6.08 (s, 1H), 5.73 (d, J = 4.9 Hz, 1H), 5.15 (dt, J = 8.7, 4.5 Hz, 1H), 3.96 (dd, J = 11.1, 8.1 Hz, 1H), 3.27 - 3.20 (m, 1H) 571.9 B   
I-2479
Figure 02_image5245
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCc4ccccc34)c12 (400 MHz, DMSO-d6) 9.05 (s, 1H), 8.54 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.38 (dt, J = 8.3, 3.6 Hz, 2H), 7.20 - 7.11 (m, 2H), 7.14 - 7.05 (m, 1H), 6.89 (td, J = 7.5, 1.1 Hz, 1H), 6.57 (s, 1H), 6.02 (s, 1H), 3.85 (td, J = 10.0, 7.4 Hz, 1H), 3.34 (s, 1H), 3.12 - 2.93 (m, 2H)。 422.1 A B
I-2480
Figure 02_image5247
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCc4ccc(OC(F)(F)F)cc34)c12 (400 MHz, DMSO-d6) δ9.07 (s, 1H), 8.68 (s, 1H), 7.70 (s, 1H), 7.64 - 7.53 (m, 2H), 7.43 - 7.34 (m, 2H), 7.26 (d, J = 8.1 Hz, 1H), 7.14 (ddd, J = 8.9, 7.9, 3.1 Hz, 1H), 6.86 (ddd, J = 8.2, 2.4, 1.1 Hz, 1H), 6.55 (s, 1H), 6.02 (s, 1H), 3.94 (td, J = 10.1, 6.8 Hz, 1H), 3.29 (s, 1H), 3.15 - 2.96 (m, 2H)。 506.4 D   
I-2481
Figure 02_image5249
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCc4cc(OC(F)(F)F)ccc34)c12 (400 MHz, DMSO-d6) δ9.05 (s, 1H), 8.63 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.63 - 7.54 (m, 2H), 7.39 (dd, J = 8.0, 6.2 Hz, 2H), 7.22 - 7.08 (m, 3H), 6.47 (s, 1H), 6.00 (s, 1H), 3.92 (td, J = 10.1, 7.1 Hz, 1H), 3.25 (s, 1H), 3.09 (td, J = 19.3, 18.0, 8.3 Hz, 2H)。 506.2 D   
I-2482
Figure 02_image5251
 OC1(CN(C(=O)Nc2cc(Cl)cc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) δ 9.26 (br s, 1H), 8.93 (br s, 0.5H), 8.85 (br s, 0.5H), 7.60 (d, J = 1.5 Hz, 1H), 7.57 (d, J = 1.8 Hz, 0.5H), 7.47 (d, J = 1.8 Hz, 0.5H), 7.38 - 7.24 (m, 4H), 7.24 - 7.18 (m, 1H), 7.17 - 7.08 (m, 1H), 6.65 (br s, 1H), 6.03 (br s, 1H), 4.14 (d, J = 12.3 Hz, 1H), 3.95 (d, J = 12.0 Hz, 0.5H), 3.48 (浸沒dd, J = 28.0, 12.6 Hz, 1H)。非對映異構體之1:1混合物。 558.0 A A
I-2483
Figure 02_image5253
 OC1(CN(C(=O)Nc2cc(Cl)cc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)(F)F (400 MHz, DMSO-d6) δ 9.27 (br s, 1H), 8.91 (br s, 0.5H), 8.81 (br s, 0.5H), 7.60 (d, J = 1.1 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.40 - 7.30 (m, 3H), 7.19 - 7.02 (m, 3H), 6.68 (br s, 1H), 6.08 (br s, 0.5H), 6.03 (br s, 0.5H), 4.09 (d, J = 12.0 Hz, 0.5H), 3.92 (d, J = 12.0 Hz, 0.5H), 3.49 (浸沒的重疊的dd, J = 28.0, 12.6 Hz, 1H)。非對映異構體之1:1混合物。 540.0 A A
I-2484
Figure 02_image5255
 O[C@]1(CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)F    487.9 E   
I-2485
Figure 02_image5257
 O[C@@]1(CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)F    487.9 D   
I-2486
Figure 02_image5259
 O[C@@]1(CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)F    487.9 E   
I-2487
Figure 02_image5261
 O[C@]1(CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)F    487.9 A A
I-2488
Figure 02_image5263
 OC1(CN(C(=O)Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F (400 MHz, DMSO-d6) δ，呈非對映異構體之約1:1混合物形式, δ 9.09 (br. s, 1H), 9.07 (br. s, 1H), 8.75 (br. s, 1H), 8.65 (br. s, 1H), 7.88 (dd, J = 8.1, 4.0 Hz, 1H), 7.79 (dd, J = 8.9, 4.7 Hz, 1H), 7.62 - 7.54 (m, 4H), 7.46 (dd, J = 7.4, 1.5 Hz, 1H), 7.40 - 7.28 (m, 3H), 7.28 - 7.21 (m, 2H), 7.21 - 7.08 (m, 4H), 6.70 (s, 1H), 6.64 (s, 1H), 6.55 (br. s, 2H), 6.27 (td, J = 55.3, 3.1 Hz, 2H), 6.08 (br. s, 1H), 6.03 (br. s, 1H), 4.10 (d, J = 11.8 Hz, 1H), 3.86 (d, J = 11.8 Hz, 1H), 3.45 (d, J = 11.7 Hz, 1H), 3.32 - 3.28 (m, 1H)。3.32-3.28 ppm處之多重峰被殘餘H2O之峰部分遮蔽。 506.3 A B
I-2489
Figure 02_image5265
 OC1CN(C(=O)Nc2cc(OCC3(CC3)C#N)cc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ 9.05 (br s, 1 H), 8.60 (br s, 1 H), 7.81 (dd, J = 8.5, 4.7 Hz, 0.5 H), 7.69 (dd, J = 8.9, 4.7 Hz, 0.5 H), 7.35 (dt, J = 9.3, 4.8 Hz, 1 H), 7.18 - 6.98 (m, 5 H), 6.57 (br s, 1 H), 6.03 (br s, 0.5 H), 5.94 (br s, 0.5 H), 5.77 (br s, 1 H), 5.13 (dd, J = 7.9, 3.9 Hz, 0.5 H), 5.06 (dd, J = 7.8, 3.2 Hz, 0.5 H), 4.19 (dd, J = 10.4, 3.6 Hz, 1 H), 4.11 (dd, J = 10.4, 2.8 Hz, 1 H), 3.90 (dd, J = 11.0, 8.1 Hz, 0.5 H), 3.66 (dd, J = 11.2, 3.5 Hz, 0.5 H), 3.27 (d, J = 4.0 Hz, 0.5 H), 3.24 (d, J = 3.9 Hz, 0.5 H), 1.39 (app q, J = 4.5 Hz, 2 H), 1.19 (dd, J = 7.0, 4.7 Hz, 2 H)。非對映異構體之約1:1混合物。 551.3 A C
I-2490
Figure 02_image5267
 CC1(Cc2cc3C(=O)NC(c3c(NC(=O)N3CC(O)c4cc(F)ccc34)c2)c2cc(F)ccc2Cl)COC1    540.0 C   
I-2491
Figure 02_image5269
 O[C@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)C#N)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.37 (s, 1H), 8.76 (s, 1H), 8.02 (d, J = 1.4 Hz, 1H), 7.88 (d, J = 1.4 Hz, 1H), 7.70 (dd, J = 8.9, 4.7 Hz, 1H), 7.37 (dd, J = 8.9, 5.2 Hz, 1H), 7.12 (td, J = 8.3, 3.0 Hz, 2H), 7.05 (td, J = 9.1, 2.8 Hz, 1H), 6.17 (s, 1H), 5.76 (d, J = 5.0 Hz, 1H), 5.15 (dt, J = 8.5, 4.4 Hz, 1H), 3.92 (dd, J = 11.0, 8.0 Hz, 1H), 3.22 (d, J = 3.9 Hz, 1H), 3.09 (d, J = 7.0 Hz, 1H)。 481.1 B   
I-2492
Figure 02_image5271
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)C#N)c2ccc(F)cc12    482.3 C   
I-2493
Figure 02_image5273
 O[C@@H]1CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)C#N)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.37 (s, 1H), 8.89 (s, 1H), 8.75 (s, 1H), 8.04 - 7.99 (m, 2H), 7.87 (d, J = 1.4 Hz, 1H), 7.82 - 7.77 (m, 1H), 7.70 (dd, J = 8.9, 4.7 Hz, 1H), 7.38 (dt, J = 8.9, 5.5 Hz, 2H), 6.70 (s, 2H), 5.15 (dt, J = 8.6, 4.4 Hz, 1H), 3.92 (dd, J = 11.0, 8.0 Hz, 1H), 3.23 (dd, J = 11.0, 4.0 Hz, 1H)。 481.3 B   
I-2494
Figure 02_image5275
 O[C@@]1(CN(C(=O)Nc2ccc(c3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2cccn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.28 (s, 1H), 8.74 (s, 1H), 8.69 - 8.64 (m, 1H), 7.89 - 7.81 (m, 2H), 7.78 (d, J = 1.7 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.42 (s, 1H), 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.30 - 7.19 (m, 2H), 7.18 - 7.09 (m, 1H), 6.76 (s, 1H), 6.51 (t, J = 2.1 Hz, 1H), 6.11 (s, 1H), 4.23 (d, J = 12.0 Hz, 1H), 3.50 (d, J = 11.1 Hz, 1H)。 590.2 D   
I-2495
Figure 02_image5277
 O[C@]1(CN(C(=O)Nc2ccc(c3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2cccn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.26 (s, 1H), 8.82 (s, 1H), 8.65 (s, 1H), 7.93 (s, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 7.39 - 7.18 (m, 3H), 7.16 (td, J = 8.4, 3.1 Hz, 1H), 6.76 (s, 1H), 6.54 - 6.48 (m, 1H), 6.07 (s, 1H), 4.01 (d, J = 12.1 Hz, 1H), 3.54 (d, J = 12.0 Hz, 1H)。 590.2 E   
I-2496
Figure 02_image5279
 O[C@]1(CN(C(=O)Nc2ccc(c3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2cccn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.27 (s, 1H), 8.73 (s, 1H), 8.66 (s, 1H), 7.89 - 7.81 (m, 2H), 7.78 (d, J = 1.7 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.41 (s, 1H), 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.30 - 7.19 (m, 2H), 7.18 - 7.09 (m, 1H), 6.84 (s, 1H), 6.51 (dd, J = 2.5, 1.8 Hz, 1H), 6.11 (s, 1H), 4.22 (d, J = 12.0 Hz, 1H), 3.51 (s, 1H)。 590.2 D   
I-2497
Figure 02_image5281
 O[C@@]1(CN(C(=O)Nc2ccc(c3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2cccn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.27 (s, 1H), 8.83 (s, 1H), 8.65 (s, 1H), 7.93 (d, J = 6.6 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 1.7 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.43 (s, 1H), 7.35 (dd, J = 8.9, 5.1 Hz, 1H), 7.32 - 7.12 (m, 3H), 6.76 (s, 1H), 6.54 - 6.48 (m, 1H), 6.07 (s, 1H), 4.02 (d, J = 12.0 Hz, 1H), 3.55 (d, J = 12.1 Hz, 1H)。 590.2 A A
I-2498
Figure 02_image5283
 Fc1ccc(Cl)c(c1)C1NC(=O)c2cccc(NC(=O)N3CCc4c3cccc4C(F)(F)F)c12 (400 MHz, DMSO-d6) δ9.06 (s, 1H), 8.72 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.63 - 7.55 (m, 2H), 7.43 - 7.32 (m, 3H), 7.25 - 7.13 (m, 2H), 6.57 (s, 1H), 6.00 (s, 1H), 3.97 (td, J = 10.0, 6.6 Hz, 1H), 3.34 (s, 3H)。 490.1 D   
I-2499
Figure 02_image5285
 C[C@H](Cn1cc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@H](O)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl)C#N (400 MHz, DMSO-d6)  9.08 (s, 1H), 8.55 (s, 1H), 8.40 (d, J = 0.8 Hz, 1H), 8.10 (d, J = 0.7 Hz, 1H), 7.80 (d, J = 1.5 Hz, 1H), 7.73 (dd, J = 8.9, 4.7 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.35 (dd, J = 8.9, 5.2 Hz, 1H), 7.17 - 6.97 (m, 3H), 6.64 (s, 1H), 6.09 (s, 1H), 5.75 (d, J = 5.0 Hz, 1H), 5.16 (dt, J = 8.6, 4.6 Hz, 1H), 4.58 - 4.29 (m, 2H), 3.98 (dd, J = 11.1, 8.1 Hz, 1H), 3.52 - 3.40 (m, 1H), 3.24 (dd, J = 11.0, 4.1 Hz, 1H), 1.28 (d, J = 7.1 Hz, 3H)。 589.3 D   
I-2500
Figure 02_image5287
 C[C@@H](Cn1cc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@H](O)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl)C#N (400 MHz, DMSO-d6)  9.08 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.10 (s, 1H), 7.80 (d, J = 1.5 Hz, 1H), 7.73 (dd, J = 8.9, 4.7 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.35 (dd, J = 8.9, 5.1 Hz, 1H), 7.16 - 6.99 (m, 3H), 6.63 (s, 1H), 6.09 (s, 1H), 5.74 (d, J = 5.0 Hz, 1H), 5.16 (dt, J = 8.6, 4.5 Hz, 1H), 4.53 - 4.31 (m, 2H), 3.98 (dd, J = 11.1, 8.1 Hz, 1H), 3.53 - 3.42 (m, 1H), 3.24 (dd, J = 11.2, 4.1 Hz, 1H), 1.28 (d, J = 7.1 Hz, 3H)。 589.3 B   
I-2501
Figure 02_image5289
 C[C@H](Cn1cc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@H](O)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl)C#N (400 MHz, DMSO-d6)  9.08 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.80 (d, J = 1.5 Hz, 1H), 7.73 (dd, J = 8.9, 4.7 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.35 (dd, J = 8.9, 5.1 Hz, 1H), 7.16 - 6.97 (m, 3H), 6.63 (s, 1H), 6.09 (s, 1H), 5.74 (d, J = 5.0 Hz, 1H), 5.16 (dt, J = 8.6, 4.5 Hz, 1H), 4.53 - 4.33 (m, 2H), 3.98 (dd, J = 11.1, 8.1 Hz, 1H), 3.48 (h, J = 7.0 Hz, 1H), 3.25 (dd, J = 11.1, 4.1 Hz, 1H), 1.27 (d, J = 7.1 Hz, 3H)。 589.3 B   
I-2502
Figure 02_image5291
 C[C@@H](Cn1cc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@@H](O)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl)C#N (400 MHz, DMSO-d6)  9.08 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.80 (d, J = 1.5 Hz, 1H), 7.73 (dd, J = 8.9, 4.7 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.35 (dd, J = 8.9, 5.1 Hz, 1H), 7.16 - 6.93 (m, 3H), 6.63 (s, 1H), 6.09 (s, 1H), 5.74 (d, J = 5.0 Hz, 1H), 5.16 (dt, J = 8.7, 4.5 Hz, 1H), 4.51 - 4.35 (m, 2H), 3.98 (dd, J = 11.1, 8.1 Hz, 1H), 3.48 (p, J = 6.9 Hz, 1H), 3.25 (dd, J = 11.2, 4.1 Hz, 1H), 1.27 (d, J = 7.1 Hz, 3H)。 589.3 D   
I-2503
Figure 02_image5293
 C[C@H](Cn1cc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@@H](O)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl)C#N (400 MHz, DMSO-d6)  9.06 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 3.9 Hz, 1H), 7.79 (s, 1H), 7.60 - 7.55 (m, 1H), 7.37 (dd, J = 8.9, 5.1 Hz, 1H), 7.20 - 7.05 (m, 3H), 6.64 (s, 1H), 6.00 (s, 1H), 5.77 (d, J = 6.0 Hz, 1H), 5.09 (s, 1H), 4.51 - 4.31 (m, 2H), 3.71 (dd, J = 11.4, 3.6 Hz, 1H), 3.47 (p, J = 7.0 Hz, 1H), 3.28 (s, 1H), 1.28 (dd, J = 7.1, 1.7 Hz, 3H)。 589.2 A C
I-2504
Figure 02_image5295
 C[C@@H](Cn1cc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@@H](O)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl)C#N (400 MHz, DMSO-d6)  9.06 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.10 (s, 1H), 7.85 (dd, J = 8.9, 4.7 Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H), 7.58 (d, J = 1.5 Hz, 1H), 7.37 (dd, J = 8.9, 5.1 Hz, 1H), 7.19 - 7.06 (m, 3H), 6.62 (s, 1H),6.00 (s, 1H), 5.77 (d, J = 5.9 Hz, 1H), 5.16 - 4.99 (m, 1H), 4.47 - 4.34 (m, 2H), 3.71 (dd, J = 11.4, 3.6 Hz, 1H), 3.54 - 3.41 (m, 1H), 3.27 (s, 1H), 1.28 (d, J = 7.1 Hz, 3H)。 589.2 D   
I-2505
Figure 02_image5297
 C[C@H](Cn1cc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@@H](O)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl)C#N (400 MHz, DMSO-d6)  9.06 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.85 (dd, J = 8.8, 4.7 Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H), 7.58 (d, J = 1.5 Hz, 1H), 7.38 (dd, J = 8.9, 5.1 Hz, 1H), 7.21 - 7.05 (m, 3H), 6.62 (s, 1H), 6.00 (s, 1H), 5.77 (d, J = 5.9 Hz, 1H), 5.08 (q, J = 5.8, 3.6 Hz, 1H), 4.48 - 4.33 (m, 2H), 3.71 (dd, J = 11.4, 3.6 Hz, 1H), 3.48 (h, J = 7.0 Hz, 1H), 3.28 (s, 1H), 1.28 (d, J = 7.0 Hz, 3H)。 589.3 D   
I-2506
Figure 02_image5299
 O[C@]1(CN(C(=O)Nc2cc(Cl)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)(F)F       D   
I-2507
Figure 02_image5301
 O[C@@]1(CN(C(=O)Nc2cc(Cl)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)(F)F       D   
I-2508
Figure 02_image5303
 O[C@@]1(CN(C(=O)Nc2cc(Cl)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)(F)F       D   
I-2509
Figure 02_image5305
 O[C@]1(CN(C(=O)Nc2cc(Cl)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)(F)F       A A
I-2510
Figure 02_image5307
 O[C@]1(CN(C(=O)Nc2cc(Cl)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F       D   
I-2511
Figure 02_image5309
 O[C@@]1(CN(C(=O)Nc2cc(Cl)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F       B   
I-2512
Figure 02_image5311
 O[C@@]1(CN(C(=O)Nc2cc(Cl)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F       D   
I-2513
Figure 02_image5313
 O[C@]1(CN(C(=O)Nc2cc(Cl)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F       A A
I-2514
Figure 02_image5315
 O[C@]1(CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F       E   
I-2515
Figure 02_image5317
 O[C@@]1(CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F       D   
I-2516
Figure 02_image5319
 O[C@@]1(CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.00 (d, J = 17.4 Hz, 1H), 8.68 (s, 1H), 7.96-7.81 (m, 1H), 7.46 (s, 1H), 7.40-7.17 (m, 6H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 6.55 (s, 1H), 6.03 (s, 1H), 4.24 (d, J = 12.0 Hz, 1H), 3.41 (d, J = 12.1 Hz, 1H), 2.97-2.74 (m, 4H)。 524.1 D   
I-2517
Figure 02_image5321
 O[C@@]1(CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.00 (d, J = 17.4 Hz, 1H), 8.68 (s, 1H), 7.96-7.81 (m, 1H), 7.46 (s, 1H), 7.40-7.17 (m, 6H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 6.55 (s, 1H), 6.03 (s, 1H), 4.24 (d, J = 12.0 Hz, 1H), 3.41 (d, J = 12.1 Hz, 1H), 2.97-2.74 (m, 4H)。 524.1      
I-2518
Figure 02_image5323
 O[C@]1(CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F       A A
I-2519
Figure 02_image5325
 O[C@]1(CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.35 (s, 1H), 8.99 (s, 1H), 8.77 (s, 1H), 7.93-7.88 (m, 2H),7.88-7.70 (m,1H), 7.58 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.35 (dd, J = 8.9, 5.1 Hz, 1H), 7.29 (td, J = 9.0, 2.8 Hz, 1H), 7.23 (dd, J = 8.1, 2.7 Hz, 1H), 7.17 (td, J = 8.4, 3.1 Hz, 1H), 6.77 (s, 1H), 6.11 (s, 1H), 4.03 (d, J = 12.1 Hz, 1H), 3.54 (d, J = 12.2 Hz, 1H)。 591.1      
I-2520
Figure 02_image5327
 O[C@@]1(CN(C(=O)Nc2ccc(c3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2ccnn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.35 (s, 1H), 8.89 (s, 1H), 8.78 (s, 1H), 7.93-7.81 (m, 3H), 7.66 (d, J = 8.4 Hz, 1H), 7.42-7.37 (m, 2H), 7.26 (qd, J = 8.6, 8.2, 2.8 Hz, 2H), 7.15 (td, J = 8.4, 3.1 Hz, 1H), 6.77 (s, 1H), 4.24 (d, J = 12.0 Hz, 1H), 3.48 (d, J = 12.1 Hz, 1H), 2.87 (s, 1H)。 591.1 A A
I-2521
Figure 02_image5329
 O[C@@]1(CN(C(=O)Nc2ccc(c3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2ccnn2)c2ccc(F)cc12)C(F)(F)F       D   
I-2522
Figure 02_image5331
 O[C@@]1(CN(C(=O)Nc2ccc(c3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2ccnn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.35 (s, 1H), 8.98 (s, 1H), 8.77 (s, 1H), 7.93-7.84 (m, 2H), 7.80-7.70 (m,1H),7.61-7.54 (m, 1H), 7.44 (s, 1H), 7.40-7.30( m, 1H),7.30-7.25 (m, 1H),7.23 (dd, J = 8.0, 2.8 Hz, 1H), 7.17 (td, J = 8.4, 3.0 Hz, 1H),6.80 (s, 1H), 6.11 (s, 1H), 4.03 (d, J = 12.1 Hz, 1H), 3.54 (d, J = 12.0 Hz, 1H)。 591.1      
I-2523
Figure 02_image5333
 O[C@]1(CN(C(=O)Nc2ccc(c3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2ccnn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.35 (s, 1H), 8.89 (s, 1H), 8.78 (s, 1H), 7.93 (d, J = 1.1 Hz, 1H), 7.90-7.81 (m, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.42-7.37 (m, 2H), 7.26 (qd, J = 8.7, 2.8 Hz, 2H), 7.15 (td, J = 8.3, 3.1 Hz, 1H), 6.79 (s, 1H), 6.15 (s, 1H), 4.24 (d, J = 12.0 Hz, 1H), 3.48 (d, J = 12.2 Hz, 1H)。 591.1 D   
I-2524
Figure 02_image5335
 O[C@]1(CN(C(=O)Nc2ccc(c3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2ccnn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.18 (s, 1H), 9.02 (s, 1H), 8.10 (s, 2H), 8.00-7.85(m,1H),7.68 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.43 (s, 1H), 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.29 (td, J = 9.0, 2.8 Hz, 1H), 7.25-7.12 (m, 1H),7.12-6.90 (m, 1H), 6.70 (s, 1H), 6.07 (s, 1H), 4.02 (d, J = 12.0 Hz, 1H), 3.51 (d, J = 12.0 Hz, 1H)。 591.1 D   
I-2525
Figure 02_image5337
 O[C@@]1(CN(C(=O)Nc2ccc(c3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2nccn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.18 (s, 1H), 9.02 (s, 1H), 8.10 (s, 2H), 7.95 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.44 (s, 1H), 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.29 (td, J = 9.1, 2.8 Hz, 1H), 7.22 (dd, J = 8.1, 2.7 Hz, 1H), 7.16 (td, J = 8.3, 3.1 Hz, 1H), 6.69 (s, 1H), 6.07 (s, 1H), 4.02 (d, J = 12.1 Hz, 1H), 3.51 (d, J = 12.0 Hz, 1H), 0.99 (t, J = 7.2 Hz, 1H)。 591.1 A A
I-2526
Figure 02_image5339
 O[C@@]1(CN(C(=O)Nc2ccc(c3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2nccn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.19 (s, 1H), 8.91 (s, 1H), 8.10 (s, 2H), 7.87 (dd, J = 9.0, 4.7 Hz, 1H), 7.66 (q, J = 8.4 Hz, 2H), 7.43-7.34 (m, 2H), 7.32-7.20 (m, 2H), 7.15 (td, J = 8.3, 3.1 Hz, 1H), 6.64 (s, 1H), 6.11 (s, 1H), 4.21 (d, J = 12.0 Hz, 1H), 3.44 (d, J = 12.0 Hz, 1H)。 591.1 D   
I-2527
Figure 02_image5341
 O[C@]1(CN(C(=O)Nc2ccc(c3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2nccn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.19 (s, 1H), 8.92 (s, 1H), 8.10 (s, 2H), 7.87 (dd, J = 8.9, 4.7 Hz, 1H), 7.66 (q, J = 8.3 Hz, 2H), 7.44-7.34 (m, 2H), 7.32-7.20 (m, 2H), 7.15 (td, J = 8.3, 3.1 Hz, 1H), 6.71 (s, 1H), 6.11 (s, 1H), 4.21 (d, J = 12.1 Hz, 1H), 3.45 (d, J = 12.0 Hz, 1H)。 591.2 D   
I-2528
Figure 02_image5343
 O[C@]1(CN(C(=O)Nc2ccc(c3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2nccn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.27 (s, 1H), 9.03 (s, 1H), 7.94 (dd, J = 9.2, 4.6 Hz, 1H), 7.78 (dd, J = 7.0, 2.1 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.56 (ddd, J = 9.0, 6.6, 2.1 Hz, 1H), 7.52 - 7.40 (m, 2H), 7.36 (dd, J = 8.9, 5.2 Hz, 1H), 7.29 (td, J = 9.0, 2.8 Hz, 1H), 7.21 (dd, J = 8.1, 2.7 Hz, 1H), 7.16 (td, J = 8.4, 3.1 Hz, 1H), 6.55 (dt, J = 9.4, 1.0 Hz, 2H), 6.38 (td, J = 6.7, 1.4 Hz, 1H), 6.11 (s, 1H), 4.00 (d, J = 12.1 Hz, 1H), 3.52 (d, J = 12.1 Hz, 1H)。 617.2 D   
I-2529
Figure 02_image5345
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2ccccc2=O)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.27 (s, 1H), 8.92 (s, 1H), 7.87 (dd, J = 9.0, 4.7 Hz, 1H), 7.78 (dd, J = 7.0, 2.1 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.59 - 7.51 (m, 2H), 7.45 - 7.35 (m, 2H), 7.31 - 7.19 (m, 2H), 7.16 (td, J = 8.4, 3.1 Hz, 1H), 6.58 - 6.50 (m, 1H), 6.38 (td, J = 6.7, 1.4 Hz, 2H), 6.15 (s, 1H), 4.22 (d, J = 12.0 Hz, 1H), 3.52 (d, J = 12.1 Hz, 1H)。 617.2 D   
I-2530
Figure 02_image5347
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2ccccc2=O)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.27 (s, 1H), 8.92 (s, 1H), 7.87 (dd, J = 9.0, 4.7 Hz, 1H), 7.78 (dd, J = 6.9, 2.1 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.60 - 7.51 (m, 2H), 7.43 - 7.35 (m, 2H), 7.31 - 7.11 (m, 3H), 6.63 (s, 1H), 6.58 - 6.51 (m, 1H), 6.38 (td, J = 6.7, 1.4 Hz, 1H), 6.15 (s, 1H), 4.22 (d, J = 12.1 Hz, 1H), 3.43 (d, J = 12.0 Hz, 1H)。 617.2 D   
I-2531
Figure 02_image5349
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2ccccc2=O)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.26 (s, 1H), 9.03 (s, 1H), 7.94 (dd, J = 9.1, 4.6 Hz, 1H), 7.78 (dd, J = 6.9, 2.1 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.56 (ddd, J = 9.0, 6.6, 2.1 Hz, 1H), 7.48 - 7.40 (m, 2H), 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.28 (td, J = 9.1, 2.8 Hz, 1H), 7.24 - 7.12 (m, 2H), 6.58 - 6.51 (m, 2H), 6.38 (td, J = 6.7, 1.4 Hz, 1H), 6.11 (s, 1H), 4.00 (d, J = 12.1 Hz, 1H), 3.52 (d, J = 12.1 Hz, 1H)。 617.2 D   
I-2532
Figure 02_image5351
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2ccccc2=O)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.24 (s, 1H), 9.02 (s, 1H), 8.13 (dd, J = 3.8, 1.7 Hz, 1H), 7.95 (s, 1H), 7.84 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 1.9 Hz, 1H), 7.55 (dd, J = 9.5, 3.8 Hz, 1H), 7.41 (s, 1H), 7.35 (dd, J = 8.9, 5.2 Hz, 1H), 7.29 (td, J = 9.0, 2.8 Hz, 1H), 7.24 - 7.11 (m, 3H), 6.67 (s, 1H), 6.08 (s, 1H), 4.01 (d, J = 12.1 Hz, 1H), 3.52 (d, J = 12.1 Hz, 1H)。 618.2 A A
I-2533
Figure 02_image5353
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2ncccc2=O)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.25 (s, 1H), 8.92 (s, 1H), 8.13 (dd, J = 3.8, 1.7 Hz, 1H), 7.92 - 7.81 (m, 2H), 7.74 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 9.5, 3.8 Hz, 1H), 7.44 - 7.34 (m, 2H), 7.31 - 7.19 (m, 2H), 7.15 (ddd, J = 9.5, 5.3, 2.4 Hz, 2H), 6.63 (s, 1H), 6.12 (s, 1H), 4.24 (d, J = 12.1 Hz, 1H), 3.42 (d, J = 12.2 Hz, 1H)。 618.1 D   
I-2534
Figure 02_image5355
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2ncccc2=O)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.25 (s, 1H), 8.92 (s, 1H), 8.13 (dd, J = 3.8, 1.6 Hz, 1H), 7.92 - 7.81 (m, 2H), 7.74 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 9.5, 3.8 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.31 - 7.10 (m, 4H), 6.66 (s, 1H), 6.12 (s, 1H), 4.24 (d, J = 12.0 Hz, 1H), 3.42 (d, J = 12.1 Hz, 1H)。 618.1 C   
I-2535
Figure 02_image5357
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2ncccc2=O)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.24 (s, 1H), 9.02 (s, 1H), 8.13 (dd, J = 3.8, 1.7 Hz, 1H), 7.94 (d, J = 6.8 Hz, 1H), 7.84 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 1.9 Hz, 1H), 7.55 (dd, J = 9.5, 3.8 Hz, 1H), 7.41 (s, 1H), 7.35 (dd, J = 8.9, 5.1 Hz, 1H), 7.29 (td, J = 9.0, 2.8 Hz, 1H), 7.24 - 7.11 (m, 3H), 6.66 (s, 1H), 6.08 (s, 1H), 4.01 (d, J = 12.1 Hz, 1H), 3.52 (d, J = 12.0 Hz, 1H)。 618.2 D   
I-2536
Figure 02_image5359
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2ncccc2=O)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) δ9.15 (s, 1H), 8.61 (s, 1H), 7.72 (dd, J = 8.9, 4.7 Hz, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 7.36 (dd, J = 8.9, 5.2 Hz, 1H), 7.07 (dtd, J = 28.1, 9.0, 8.6, 2.9 Hz, 3H), 6.60 (s, 1H), 6.08 (s, 1H), 5.74 (d, J = 4.5 Hz, 1H), 5.16 (dd, J = 8.3, 4.2 Hz, 1H), 4.23 (s, 2H), 3.98 (dd, J = 11.1, 8.1 Hz, 1H), 3.21 (dd, J = 10.9, 4.1 Hz, 1H)。 495.2 A A
I-2537
Figure 02_image5361
 O[C@@H]1CN(C(=O)Nc2cc(CC#N)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ9.15 (s, 1H), 8.61 (s, 1H), 7.72 (dd, J = 8.9, 4.7 Hz, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 7.36 (dd, J = 8.9, 5.2 Hz, 1H), 7.07 (dtd, J = 28.1, 9.0, 8.6, 2.9 Hz, 3H), 6.60 (s, 1H), 6.08 (s, 1H), 5.74 (d, J = 4.5 Hz, 1H), 5.16 (dd, J = 8.3, 4.2 Hz, 1H), 4.23 (s, 2H), 3.98 (dd, J = 11.1, 8.1 Hz, 1H), 3.21 (dd, J = 10.9, 4.1 Hz, 1H)。 495.1 A A
I-2538
Figure 02_image5363
 O[C@@H]1CN(C(=O)Nc2cc(CC#N)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ9.15 (s, 1H), 8.61 (s, 1H), 7.72 (dd, J = 8.9, 4.7 Hz, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 7.36 (dd, J = 8.9, 5.2 Hz, 1H), 7.07 (dtd, J = 28.1, 9.0, 8.6, 2.9 Hz, 3H), 6.60 (s, 1H), 6.08 (s, 1H), 5.74 (d, J = 4.5 Hz, 1H), 5.16 (dd, J = 8.3, 4.2 Hz, 1H), 4.23 (s, 2H), 3.98 (dd, J = 11.1, 8.1 Hz, 1H), 3.21 (dd, J = 10.9, 4.1 Hz, 1H)。 495.1 A   
I-2539
Figure 02_image5365
 O[C@H]1CN(C(=O)Nc2cc(CC#N)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) δ9.15 (s, 1H), 8.61 (s, 1H), 7.72 (dd, J = 8.9, 4.7 Hz, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 7.36 (dd, J = 8.9, 5.2 Hz, 1H), 7.07 (dtd, J = 28.1, 9.0, 8.6, 2.9 Hz, 3H), 6.60 (s, 1H), 6.08 (s, 1H), 5.74 (d, J = 4.5 Hz, 1H), 5.16 (dd, J = 8.3, 4.2 Hz, 1H), 4.23 (s, 2H), 3.98 (dd, J = 11.1, 8.1 Hz, 1H), 3.21 (dd, J = 10.9, 4.1 Hz, 1H)。 495.2 D   
I-2540
Figure 02_image5367
 O[C@H]1CN(C(=O)Nc2cc(CC#N)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12 (400 MHz, DMSO-d6) 9.09 (s, 1H), 8.86 (s, 1H), 7.93 (s, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 7.38 - 7.23 (m, 3H), 7.20 (dd, J = 8.1, 2.8 Hz, 1H), 7.13 (td, J = 8.4, 3.1 Hz, 1H), 6.53 (s, 1H), 6.01 (s, 1H), 4.56 (s, 2H), 4.01 (d, J = 12.1 Hz, 1H), 3.50 (d, J = 12.0 Hz, 1H), 3.36 (s, 3H)。 568.3 B   
I-2541
Figure 02_image5369
 COCc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.10 (s, 1H), 8.76 (s, 1H), 7.86 (dd, J = 9.0, 4.7 Hz, 1H), 7.54 (s, 1H), 7.44 (d, J = 1.4 Hz, 1H), 7.40 (s, 1H), 7.35 (dd, J = 8.9, 5.1 Hz, 1H), 7.30 - 7.18 (m, 2H), 7.12 (td, J = 8.3, 3.1 Hz, 1H), 6.53 (s, 1H), 6.06 (s, 1H), 4.56 (s, 2H), 4.24 (d, J = 12.0 Hz, 1H), 3.41 (d, J = 12.0 Hz, 1H), 3.36 (s, 3H)。 568.3 A A
I-2542
Figure 02_image5371
 COCc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.10 (s, 1H), 8.75 (s, 1H), 7.86 (dd, J = 9.0, 4.7 Hz, 1H), 7.54 (s, 1H), 7.44 (d, J = 1.4 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.30 - 7.18 (m, 2H), 7.12 (td, J = 8.4, 3.1 Hz, 1H), 6.54 (s, 1H), 6.05 (s, 1H), 4.56 (s, 2H), 4.24 (d, J = 12.1 Hz, 1H), 3.41 (d, J = 12.0 Hz, 1H), 3.36 (s, 3H)。 568.3 D   
I-2543
Figure 02_image5373
 COCc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.09 (s, 1H), 8.85 (s, 1H), 7.93 (s, 1H), 7.54 (d, J = 1.4 Hz, 1H), 7.41 (s, 1H), 7.36 (d, J = 1.4 Hz, 1H), 7.32 (dd, J = 8.9, 5.2 Hz, 1H), 7.27 (td, J = 9.0, 2.7 Hz, 1H), 7.20 (dd, J = 8.1, 2.8 Hz, 1H), 7.13 (td, J = 8.3, 3.1 Hz, 1H), 6.54 (s, 1H), 6.01 (s, 1H), 4.56 (s, 2H), 4.01 (d, J = 12.1 Hz, 1H), 3.50 (d, J = 12.1 Hz, 1H), 3.36 (s, 3H)。 568.3 D   
I-2544
Figure 02_image5375
 COCc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) δ 9.26 (br s, 1H), 8.88 (s, 0.5H), 8.78 (s, 0.5H), 7.88 (dd, J = 8.0, 3.9 Hz, 0.5H), 7.81 (dd, J = 8.9, 4.7 Hz, 0.5H), 7.58 (s, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.39 - 7.30 (m, , 1H), 7.29 - 7.23 (m, 1H), 7.18 (dd, J = 8.9, 2.7 Hz, 1H), 7.16 - 7.08 (m, 1H), 6.66 (br s, 1H), 6.27 (app. t, J = 55.4, 3.6 Hz, 1H), 6.09 (重疊br s, 0.5H), 6.05 (重疊br s, 0.5H), 4.04 (d, J = 11.5 Hz, 0.5H), 3.82 (d, J = 11.9 Hz, 0.5H), 3.47 (d, J = 11.6 Hz, 0.5H), 3.33 (d, J = 11.3 Hz, 0.5H)。非對映異構體之1:1混合物。 540.0 D   
I-2545
Figure 02_image5377
 OC1(CN(C(=O)Nc2cc(Cl)cc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F (400 MHz, ) δ 9.39 (br. s, 2H), 8.99 (s, 1H), 8.89 (s, 1H), 8.03 (br. s, 2H), 7.91 (2個重疊s, 2H), 7.81 (2個重疊s, 2H), 7.45 - 7.30 (m, 2H), 7.32 - 7.21 (m, 3H), 7.22 - 7.17 (m, 2H), 7.17 - 7.08 (m, 3H), 6.74 (s, 1H), 6.67 (s, 1H), 6.28 (app. td, J = 55.2, 3.1 Hz, 2H (CHF2信號)), 6.15 (br. s, 2H), 4.03 (br. d, J = 11.2 Hz, 1H), 3.80 (br. d, J = 11.9 Hz, 1H), 3.46 (br. d, J = 11.4 Hz, 1H), 3.30 (浸沒br. d, J = 11.9 Hz, 1H)；非對映異構體之約1:1混合物 529.2 A A
I-2546
Figure 02_image5379
 OC1(CN(C(=O)Nc2cc(cc3C(=O)NC(c23)c2cc(F)ccc2Cl)C#N)c2ccc(F)cc12)C(F)F (400 MHz, DMSO-d6)  9.30 (s, 1H), 9.07 (s, 1H), 8.47 (s, 1H), 8.12 (s, 2H), 8.04 (s, 1H), 7.95 (s, 1H), 7.36 (dd, J=8.9, 5.1 Hz, 1H), 7.28 (s, 1H), 7.24-7.13 (m, 2H), 7.17-7.10 (m, 1H), 6.10 (s, 1H), 4.04 (s, 1H), 3.54 (s, 1H)。 591.2 A B
I-2547
Figure 02_image5381
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2ccnn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6)  9.32 (s, 1H), 9.07 (s, 2H), 8.20 (s, 1H), 8.10 (s, 1H), 8.04 (d, J=1.2 Hz, 1H), 7.90 (dd, J=9.0, 4.6 Hz, 1H), 7.38 (dd, J=8.9, 5.1 Hz, 2H), 7.31-7.19 (m, 2H), 7.15 (td, J=8.4, 3.1 Hz, 1H), 6.15 (s, 1H), 4.23 (d, J=12.1 Hz, 1H), 3.45 (d, J=11.7 Hz, 1H)。 591.1 A A
I-2548
Figure 02_image5383
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2ccnn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6)  9.33 (s, 1H), 9.08 (d, J=1.3 Hz, 1H), 9.03 (s, 1H), 8.19-8.07 (m, 2H), 8.04 (d, J=1.2 Hz, 1H), 7.90 (dd, J=9.0, 4.6 Hz, 1H), 7.42 (s, 1H), 7.38 (dd, J=8.9, 5.1 Hz, 1H), 7.32-7.20 (m, 2H), 7.15 (td, J=8.3, 3.1 Hz, 1H), 6.15 (s, 1H), 4.24 (d, J=12.0 Hz, 1H), 3.43 (d, J=11.8 Hz, 1H)。 591.2 D   
I-2549
Figure 02_image5385
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2ccnn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6)  9.31 (s, 1H), 9.15 (s, 1H), 9.07 (s, 1H), 8.11 (s, 2H), 8.04 (s, 1H), 7.94 (s, 1H), 7.46 (s, 1H), 7.36 (dd, J=8.9, 5.1 Hz, 1H), 7.28 (s, 1H), 7.22 (d, J=7.9 Hz, 1H), 7.15 (td, J=8.4, 3.1 Hz, 1H), 6.11 (s, 1H), 4.01 (s, 1H), 3.54 (s, 1H)。 591.1 B   
I-2550
Figure 02_image5387
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2ccnn2)c2ccc(F)cc12)C(F)(F)F       D   
I-2551
Figure 02_image5389
 O[C@@H]1CN(C(=O)Nc2cc(OCC3(CC3)C#N)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12       D   
I-2552
Figure 02_image5391
 O[C@@H]1CN(C(=O)Nc2cc(OCC3(CC3)C#N)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12       A B
I-2553
Figure 02_image5393
 O[C@H]1CN(C(=O)Nc2cc(OCC3(CC3)C#N)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12       B   
I-2554
Figure 02_image5395
 O[C@H]1CN(C(=O)Nc2cc(OCC3(CC3)C#N)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12       B   
I-2555
Figure 02_image5397
 O[C@]1(CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F       D   
I-2556
Figure 02_image5399
 O[C@]1(CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F       C   
I-2557
Figure 02_image5401
 O[C@@]1(CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F       D   
I-2558
Figure 02_image5403
 O[C@@]1(CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F       A A
I-2559
Figure 02_image5405
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)C#N)c2ccc(F)cc12)C(F)(F)F       D   
I-2560
Figure 02_image5407
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)C#N)c2ccc(F)cc12)C(F)(F)F       A A
I-2561
Figure 02_image5409
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)C#N)c2ccc(F)cc12)C(F)(F)F       D   
I-2562
Figure 02_image5411
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)C#N)c2ccc(F)cc12)C(F)(F)F       A A
I-2563
Figure 02_image5413
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)C#N)c2ccccc12)C(F)(F)F       D   
I-2564
Figure 02_image5415
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)C#N)c2ccccc12)C(F)(F)F       A A
I-2565
Figure 02_image5417
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)C#N)c2ccccc12)C(F)(F)F       D   
I-2566
Figure 02_image5419
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)C#N)c2ccccc12)C(F)(F)F (400 MHz, DMSO) δ 9.06 (s, 1H), 8.80 (s, 0.5H), 8.70 (s, 0.5H), 7.90 (dd, J = 8.9, 4.6 Hz, 0.5H), 7.82 (dd, J = 8.9, 4.7 Hz, 0.5H), 7.63 - 7.53 (m, 2H), 7.47 - 7.17 (m, 5H), 7.15 - 7.06 (m, 1H), 6.77 - 6.30 (m, 1H), 6.03 (s, 1H)。 526.3 A A
I-2567
Figure 02_image5421
 [2H]C1([2H])N(C(=O)Nc2cccc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccc(F)cc2C1(O)C(F)(F)F (400 MHz, DMSO d6) δ 9.08 (br. s, 1H), 8.89 (s, 1H), 8.31 (s, 1H), 7.97 - 7.87 (m, 1H), 7.67 (s, 1H), 7.47 (d, J = 3.3 Hz, 1H), 7.39 (d, J = 3.1 Hz, 1H), 7.37-7.29 (m, 1H), 7.28-7.17 (m, 3H), 7.16 - 7.06 (m, 1H), 6.52 (br. s, 1H), 6.04 (br. s, 1H), 4.23 (d, J = 11.6 Hz, 1H), 3.96 (d, J = 2.8 Hz, 2H), 3.50 (d, J = 10.2 Hz, 1H)。1:1混合物 553.4 A A
I-2568
Figure 02_image5423
 NCc1cc2C(=O)NC(c2c(NC(=O)N2CC(O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl    591.1 A D
I-2569
Figure 02_image5425
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2nccn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6)  9.30 (s, 1H), 8.99 (s, 1H), 8.28-8.20 (m, 3H), 8.12 (d, J=1.9 Hz, 1H), 7.90 (dd, J=8.9, 4.7 Hz, 1H), 7.41-7.33 (m, 2H), 7.32-7.19 (m, 2H), 7.14 (td, J=8.3, 3.1 Hz, 1H), 6.72 (s, 1H), 6.14 (s, 1H), 4.23 (d, J=12.0 Hz, 1H), 3.44 (d, J=12.1 Hz, 1H)。 591.1 A A
I-2570
Figure 02_image5427
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)-n2nccn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6)  9.30 (s, 1H), 8.99 (s, 1H), 8.28-8.20 (m, 3H), 8.12 (d, J=1.9 Hz, 1H), 7.90 (dd, J=9.0, 4.7 Hz, 1H), 7.41-7.33 (m, 2H), 7.26 (ddd, J=21.4, 8.9, 2.8 Hz, 2H), 7.14 (td, J=8.3, 3.1 Hz, 1H), 6.71 (s, 1H), 6.14 (s, 1H), 4.23 (d, J=12.0 Hz, 1H), 3.44 (d, J=11.9 Hz, 1H)。 591.1 D   
I-2571
Figure 02_image5429
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2nccn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6)  9.29 (s, 1H), 9.09 (s, 1H), 8.22 (s, 2H), 8.18 (d, J=2.0 Hz, 1H), 8.12 (d, J=1.9 Hz, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.42 (s, 1H), 7.39-7.25 (m, 2H), 7.22 (dd, J=8.0, 2.7 Hz, 1H), 7.14 (td, J=8.4, 3.1 Hz, 1H), 6.71 (s, 1H), 6.10 (s, 1H), 4.03 (d, J=12.2 Hz, 1H), 3.54 (d, J=12.0 Hz, 1H)。 591.4 D   
I-2572
Figure 02_image5431
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)-n2nccn2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 7.86 (s, 1H), 7.79 (s, 1H), 7.67 (dd, J = 6.4, 3.5 Hz, 1H), 7.28 (dt, J = 8.6, 4.2 Hz, 1H), 7.23 (s, 1H), 7.19 (dd, J = 8.1, 2.6 Hz, 1H), 7.07 (s, 1H), 6.58 (s, 1H), 5.91 (s, 1H), 4.00 (s, 1H), 3.42 (d, J = 12.1 Hz, 1H), 2.08 (d, J = 2.6 Hz, 3H)。 581.2 D   
I-2573
Figure 02_image5433
 CC(=O)Nc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 10.26 (s, 1H), 9.05 (s, 1H), 8.73 (s, 1H), 7.89 - 7.81 (m, 2H), 7.79 (d, J = 1.9 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.23 (ddd, J = 18.6, 9.4, 2.8 Hz, 2H), 7.11 (td, J = 8.3, 3.1 Hz, 1H), 6.57 (s, 1H), 5.99 (s, 1H), 4.22 (d, J = 12.0 Hz, 1H), 3.40 (d, J = 12.0 Hz, 1H), 2.11 (s, 3H)。 581.2 A A
I-2574
Figure 02_image5435
 CC(=O)Nc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 10.26 (s, 1H), 9.05 (s, 1H), 8.73 (s, 1H), 7.89 - 7.81 (m, 2H), 7.79 (d, J = 1.9 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.23 (ddd, J = 18.5, 9.3, 2.8 Hz, 2H), 7.11 (td, J = 8.3, 3.1 Hz, 1H), 6.56 (s, 1H), 5.99 (s, 1H), 4.22 (d, J = 12.0 Hz, 1H), 3.40 (d, J = 12.1 Hz, 1H), 2.11 (s, 3H)。 581.2 B   
I-2575
Figure 02_image5437
 CC(=O)Nc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 10.26 (s, 1H), 9.04 (s, 1H), 8.84 (s, 1H), 7.93 (dd, J = 9.3, 4.6 Hz, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.36 (s, 1H), 7.35 - 7.23 (m, 2H), 7.20 (dd, J = 8.1, 2.7 Hz, 1H), 7.12 (td, J = 8.4, 3.1 Hz, 1H), 6.57 (s, 1H), 5.95 (s, 1H), 4.02 (d, J = 12.2 Hz, 1H), 3.48 (d, J = 12.1 Hz, 1H), 2.11 (s, 3H)。 581.2 D   
I-2576
Figure 02_image5439
 CC(=O)Nc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.27 (s, 1H), 8.89 (s, 1H), 7.87 (dd, J = 9.0, 4.6 Hz, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.42-7.32 (m, 2H), 7.30-7.18 (m, 2H), 7.17-7.07 (m, 1H), 6.90-6.40 ( m, 1H),  6.12 (s, 1H), 4.21 (d, J = 12.0 Hz, 1H), 3.43 (d, J = 12.2 Hz, 1H 574.1 D   
I-2577
Figure 02_image5441
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)C(F)F)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.28 (s, 1H), 8.90 (s, 1H), 7.87 (dd, J = 9.0, 4.6 Hz, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.43-7.33 (m, 2H), 7.32-7.19 (m, 2H), 7.18-7.06 (m, 1H), 6.90-6.12 (m, 1H), 4.21 (d, J = 12.0 Hz, 1H), 3.43 (d, J = 12.1 Hz, 1H)。 574.0 D   
I-2578
Figure 02_image5443
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)C(F)F)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.27 (s, 1H), 9.00 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.61 (s, 1H), 7.43 (s, 1H), 7.41-7.18 (m, 4H), 7.15-7.07 (m, 1H), 6.90-6.40 ( m, 1H), 6.08 (s, 1H), 4.00 (d, J = 12.1 Hz, 1H), 3.51 (d, J = 12.1 Hz, 1H)。 574.1 D   
I-2579
Figure 02_image5445
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)C(F)F)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.26 (s, 1H), 8.99 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.61 (s, 1H), 7.42 (s, 1H), 7.37-7.32 (m, 1H), 7.28 (td, J = 9.0, 2.7 Hz, 1H), 7.25-7.07 (m, 3H), 6.90-6.40 ( m, 1H), 6.08 (s, 1H), 4.00 (d, J = 12.1 Hz, 1H), 3.52 (d, J = 12.1 Hz, 1H)。 574.1 A A
I-2580
Figure 02_image5447
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)C(F)F)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.00 (d, J = 17.4 Hz, 1H), 8.68 (s, 1H), 7.96-7.81 (m, 1H), 7.46 (s, 1H), 7.40-7.17 (m, 6H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 6.55 (s, 1H), 6.03 (s, 1H), 4.24 (d, J = 12.0 Hz, 1H), 3.41 (d, J = 12.1 Hz, 1H), 2.97-2.74 (m, 4H)。 567.2 D   
I-2581
Figure 02_image5449
 NCCc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.00 (d, J = 17.4 Hz, 1H), 8.68 (s, 1H), 7.96-7.81 (m, 1H), 7.46 (s, 1H), 7.40-7.17 (m, 6H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 6.55 (s, 1H), 6.03 (s, 1H), 4.24 (d, J = 12.0 Hz, 1H), 3.41 (d, J = 12.1 Hz, 1H), 2.97-2.74 (m, 4H)。 567.2 A D
I-2582
Figure 02_image5451
 NCCc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.00 (d, J = 17.4 Hz, 1H), 8.68 (s, 1H), 7.96-7.81 (m, 1H), 7.46 (s, 1H), 7.40-7.17 (m, 6H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 6.55 (s, 1H), 6.03 (s, 1H), 4.24 (d, J = 12.0 Hz, 1H), 3.41 (d, J = 12.1 Hz, 1H), 2.97-2.74 (m, 4H)。 567.2 B   
I-2583
Figure 02_image5453
 NCCc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.00 (d, J = 17.4 Hz, 1H), 8.68 (s, 1H), 7.96-7.81 (m, 1H), 7.46 (s, 1H), 7.40-7.17 (m, 6H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 6.55 (s, 1H), 6.03 (s, 1H), 4.24 (d, J = 12.0 Hz, 1H), 3.41 (d, J = 12.1 Hz, 1H), 2.97-2.74 (m, 4H)。 567.1 D   
I-2584
Figure 02_image5455
 NCCc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)，呈非對映異構體之約1:1混合物形式, δ 9.15 (br. s, 1H), 9.13 (br. s, 1H), 8.89 (br. s, 1H), 8.77 (br. s, 1H), 7.90 (br. d, J = 7.8 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.59 - 7.57 (m, 1H), 7.51 - 7.49 (m, 1H), 7.45 - 7.29 (m, 7H), 7.22 (s, 1H), 7.20 (s, 1H), 7.14 - 7.04 (m, 4H), 6.58 (br. s, 2H), 6.08 (br. s, 1H), 6.03 (br. s, 1H), 4.24 (s, 4H), 4.17 (d, AB之A, JAB = 12.1 Hz, 1H), 3.97 (d, AB之A, JAB = 12.4 Hz, 1H), 3.48 (d, AB之B, JAB = 11.8 Hz, 1H), 3.43 (d, AB之B, JAB = 11.9 Hz, 1H)。 545.4 D   
I-2585
Figure 02_image5457
 OC1(CN(C(=O)Nc2cc(CC#N)cc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)(F)F (400MHz, DMSO-d6) δ 呈非對映異構體之約3:2混合物形式；對於兩種非對映異構體, δ 9.16 (br. s, 1H), 9.15 (br. s, 1H), 8.86 (br. s, 1H), 8.75 (br. s, 1H), 7.89 (dd, J = 8.4, 3.9 Hz, 1H), 7.81 (dd, J = 8.9, 4.7 Hz, 1H), 7.57 (br. s, 2H), 7.47 (d, J = 1.2 Hz, 1H), 7.39 (d, J = 1.2 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.28 - 7.21 (m, 2H), 7.20 - 7.16 (m, 2H), 7.15 - 7.08 (m, 2H), 6.71 (s, 1H), 6.64 (s, 1H), 6.58 (br. s, 1H), 6.42 - 6.12 (m, 2H), 6.07 (br. s, 1H), 6.03 (br. s, 1H), 4.23 (s, 4H), 4.11 (d, AB之A, JAB = 11.8 Hz, 1H), 3.86 (d, AB之A, JAB = 11.3 Hz, 1H), 3.44 (d, AB之B JAB = 11.4 Hz, 1H), 3.29 (d, AB之B JAB = 12.3 Hz, 1H)。 545.3 A A
I-2586
Figure 02_image5459
 OC1(CN(C(=O)Nc2cc(CC#N)cc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F (400 MHz, DMSO-d6) δ 9.18 (br s, 1 H), 8.85 (br s, 2 H), 7.95 - 7.80 (m, 1 H), 7.35 - 7.23 (m, 2 H), 7.23 - 7.17 (m, 1 H), 7.14 - 7.05 (m, 1 H), 6.81 (s, 0.5 H), 6.74 (s, 0.5 H), 6.65 (br s, 1 H), 6.52 - 6.44 (m, 1 H), 5.90 (br s, 1 H), 4.19 (d, J = 12.0 Hz, 0.5 H), 3.97 (d, J = 12.1 Hz, 0.5 H), 3.45 (浸沒d, J = 12.0 Hz, 0.5 H), 3.30 (浸沒d, J = 12.2 Hz, 0.5 H), 2.90 - 2.72 (m, 3 H)。非對映異構體之約1:1混合物。 578.3 A B
I-2587
Figure 02_image5461
 CNc1cc(NC(=O)N2CC(O)(c3cc(F)ccc23)C(F)(F)F)c2C(NC(=O)c2c1C#N)c1cc(F)ccc1Cl       A B
I-2588
Figure 02_image5463
 O[C@]1(CN(C(=O)Nc2cc(Cl)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F       D   
I-2589
Figure 02_image5465
 O[C@]1(CN(C(=O)Nc2cc(Cl)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F       D   
I-2590
Figure 02_image5467
 O[C@@]1(CN(C(=O)Nc2cc(Cl)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F       D   
I-2591
Figure 02_image5469
 O[C@@]1(CN(C(=O)Nc2cc(Cl)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F    525.9 A A
I-2592
Figure 02_image5471
 [2H]C1([2H])N(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc2[C@]1(O)C(F)(F)F    525.9 D   
I-2593
Figure 02_image5473
 [2H]C1([2H])N(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc2[C@@]1(O)C(F)(F)F    525.8 D   
I-2594
Figure 02_image5475
 [2H]C1([2H])N(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc2[C@@]1(O)C(F)(F)F (400 MHz, DMSO) δ 9.05 (s, 1H), 8.79 (s, 1H), 7.90 (dd, J = 8.9, 4.7 Hz, 1H), 7.63 - 7.53 (m, 2H), 7.39 - 7.35 (m, 2H), 7.31 (dd, J = 8.9, 5.1 Hz, 1H), 7.25 (td, J = 9.0, 2.8 Hz, 1H), 7.19 (dd, J = 8.1, 2.7 Hz, 1H), 7.15 - 7.08 (m, 1H), 6.65 - 6.38 (m, 1H), 6.01 (s, 1H)。 525.9 D   
I-2595
Figure 02_image5477
 [2H]C1([2H])N(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc2[C@]1(O)C(F)(F)F    525.9 A A
I-2596
Figure 02_image5479
 OC1(CN(C(=O)Nc2cc(CC#N)cc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) δ，呈非對映異構體之約1:1混合物形式, δ 9.17 (br. s, 2H), 8.94 (s, 1H), 8.83 (s, 1H), 7.95 - 7.90 (m, 1H), 7.86 (dd, J = 8.9, 4.7 Hz, 1H), 7.59 (br. s, 2H), 7.47 (d, J = 1.3 Hz, 1H), 7.42 - 7.38 (m, 3H), 7.37 - 7.30 (m, 2H), 7.30 - 7.19 (m, 5H), 7.16 - 7.09 (m, 2H), 6.56 (br. s, 2H), 6.11 - 5.97 (m, 2H), 4.24 (s, 4H), 4.23 - 4.20 (m, 1H), 4.01 (d, J = 12.1 Hz, 1H), 3.48 (d, J = 12.0 Hz, 1H), 3.39 (d, J = 12.1 Hz, 1H)。4.23-4.20 ppm處之多重峰被4.24 ppm處之4H單峰部分遮蔽。 563.3 A A
I-2597
Figure 02_image5481
 NCc1cc2C(=O)NC(c2c(NC(=O)N2CC(O)(C(F)F)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl (400 MHz, DMSOD6) δ 9.10 (s, 1H), 8.84 (s, 1H), 8.34 (s, 1H), 7.87 (dd, J = 8.4, 4.4 Hz, 1H), 7.67 (s, 1H), 7.49 (s, 1H), 7.34 (dd, J = 8.9, 5.2 Hz, 1H), 7.26 (dd, J = 6.2, 3.0 Hz, 1 H), 7.07-7.21 (m, 2H), 6.51 (br s, 1H), 6.28 (td, J = 55.4, 1.9 Hz, 1H), 6.08 (br. s, 1H), 4.12 (d, J = 11.8 Hz, 1H), 3.99 (s, 2H), 3.46 (d, J = 12.0 Hz, 1H)。 535.2 A D
I-2598
Figure 02_image5483
 O[C@@]1(CN(C(=O)Nc2cc(CC#N)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F       D   
I-2599
Figure 02_image5485
 O[C@]1(CN(C(=O)Nc2cc(CC#N)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F       B   
I-2600
Figure 02_image5487
 O[C@]1(CN(C(=O)Nc2cc(CC#N)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F       C   
I-2601
Figure 02_image5489
 O[C@@]1(CN(C(=O)Nc2cc(CC#N)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F       A A
I-2602
Figure 02_image5491
 O[C@]1(CN(C(=O)Nc2cc(CC#N)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)(F)F       D   
I-2603
Figure 02_image5493
 O[C@]1(CN(C(=O)Nc2cc(CC#N)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)(F)F       D   
I-2604
Figure 02_image5495
 O[C@@]1(CN(C(=O)Nc2cc(CC#N)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)(F)F       C   
I-2605
Figure 02_image5497
 O[C@@]1(CN(C(=O)Nc2cc(CC#N)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccccc12)C(F)(F)F       A A
I-2606
Figure 02_image5499
 CNc1cc(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c2[C@@H](NC(=O)c2c1C#N)c1cc(F)ccc1Cl       D   
I-2607
Figure 02_image5501
 CNc1cc(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c2[C@H](NC(=O)c2c1C#N)c1cc(F)ccc1Cl       D   
I-2608
Figure 02_image5503
 CNc1cc(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c2[C@@H](NC(=O)c2c1C#N)c1cc(F)ccc1Cl       D   
I-2609
Figure 02_image5505
 CNc1cc(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c2[C@H](NC(=O)c2c1C#N)c1cc(F)ccc1Cl       A A
I-2610
Figure 02_image5507
 CC(C)(C#N)n1cc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.10 (s, 1H), 8.78-8.73 m, 2H), 8.21 (s, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.88 (dd, J = 9.0, 4.7 Hz, 1H), 7.73 (d, J = 1.5 Hz, 1H), 7.40-7.35 (m, 2H), 7.25 (qd, J = 8.8, 2.8 Hz, 2H), 7.12 (ddd, J = 8.9, 7.8, 3.1 Hz, 1H), 6.59 (s, 1H), 6.06 (s, 1H), 4.27 (d, J = 12.1 Hz, 1H), 3.44 (d, J = 12.0 Hz, 1H), 2.04 (s, 6H)。 671.1 D   
I-2611
Figure 02_image5509
 CC(C)(C#N)n1cc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.10 (s, 1H), 8.78-8.73 m, 2H), 8.21 (s, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.88 (dd, J = 9.0, 4.7 Hz, 1H), 7.73 (d, J = 1.5 Hz, 1H), 7.40 (s, 1H), 7.35 (dd, J = 8.9, 5.2 Hz, 1H), 7.25 (qd, J = 8.8, 2.8 Hz, 2H), 7.12 (ddd, J = 8.9, 7.8, 3.1 Hz, 1H), 6.59 (s, 1H), 6.06 (s, 1H), 4.27 (d, J = 12.1 Hz, 1H), 3.44 (d, J = 12.0 Hz, 1H), 2.04 (s, 6H)。 671.2 B   
I-2612
Figure 02_image5511
 CC(C)(C#N)n1cc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.09 (s, 1H), 8.85 (s, 1H), 8.73 (s, 1H), 8.20 (s, 1H), 7.95 (d, J = 1.5 Hz, 2H), 7.67 (d, J = 1.5 Hz, 1H), 7.42 (s, 1H), 7.37-7.18 (m, 3H), 7.13 (td, J = 8.4, 3.1 Hz, 1H), 6.60 (s, 1H), 6.03 (s, 1H), 4.00 (d, J = 12.1 Hz, 1H), 3.59 (d, J = 12.1 Hz, 1H), 2.04 (s, 6H)。 671.1 D   
I-2613
Figure 02_image5513
 CC(C)(C#N)n1cc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)9.09 (s, 1H), 8.85 (s, 1H), 8.73 (s, 1H), 8.20 (s, 1H), 7.95 (d, J = 1.5 Hz, 2H), 7.67 (d, J = 1.5 Hz, 1H), 7.42 (s, 1H), 7.37-7.18 (m, 3H), 7.13 (td, J = 8.4, 3.1 Hz, 1H), 6.60 (s, 1H), 6.03 (s, 1H), 4.00 (d, J = 12.1 Hz, 1H), 3.59 (d, J = 12.1 Hz, 1H), 2.04 (s, 6H)。 657.1 A A
I-2614
Figure 02_image5515
 O[C@@]1(CN(C(=O)Nc2ccc(CC#N)c3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) δ9.23 (s, 1H), 8.75 (d, J = 7.2 Hz, 1H), 7.84 (dd, J = 8.9, 4.7 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.49 (dd, J = 8.1, 1.9 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.30 - 7.18 (m, 2H), 7.12 (td, J = 8.4, 3.1 Hz, 1H), 6.06 (s, 1H), 4.79 - 4.39 (m, 2H), 4.21 (d, J = 11.9 Hz, 1H), 3.45 (d, J = 12.1 Hz, 1H)。 563.4 A A
I-2615
Figure 02_image5517
 O[C@@]1(CN(C(=O)Nc2ccc(CC#N)c3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) δ9.23 (s, 1H), 8.75 (d, J = 7.2 Hz, 1H), 7.84 (dd, J = 8.9, 4.7 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.49 (dd, J = 8.1, 1.9 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.30 - 7.18 (m, 2H), 7.12 (td, J = 8.4, 3.1 Hz, 1H), 6.06 (s, 1H), 4.79 - 4.39 (m, 2H), 4.21 (d, J = 11.9 Hz, 1H), 3.45 (d, J = 12.1 Hz, 1H)。 563.4 D   
I-2616
Figure 02_image5519
 O[C@]1(CN(C(=O)Nc2ccc(CC#N)c3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) δ9.23 (s, 1H), 8.75 (d, J = 7.2 Hz, 1H), 7.84 (dd, J = 8.9, 4.7 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.49 (dd, J = 8.1, 1.9 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.30 - 7.18 (m, 2H), 7.12 (td, J = 8.4, 3.1 Hz, 1H), 6.06 (s, 1H), 4.79 - 4.39 (m, 2H), 4.21 (d, J = 11.9 Hz, 1H), 3.45 (d, J = 12.1 Hz, 1H)。 563.4 D   
I-2617
Figure 02_image5521
 O[C@]1(CN(C(=O)Nc2ccc(CC#N)c3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) δ9.23 (s, 1H), 8.75 (d, J = 7.2 Hz, 1H), 7.84 (dd, J = 8.9, 4.7 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.49 (dd, J = 8.1, 1.9 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.30 - 7.18 (m, 2H), 7.12 (td, J = 8.4, 3.1 Hz, 1H), 6.06 (s, 1H), 4.79 - 4.39 (m, 2H), 4.21 (d, J = 11.9 Hz, 1H), 3.45 (d, J = 12.1 Hz, 1H)。 563.4 D   
I-2618
Figure 02_image5523
 O[C@@]1(CN(C(=O)Nc2ccc(Cl)c3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.19 (s, 1H), 8.82 (s, 1H), 7.91 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.42 - 7.10 (m, 6H), 6.66 (s, 1H), 5.99 (s, 1H), 3.98 (d, J = 12.1 Hz, 1H), 3.50 (d, J = 12.1 Hz, 1H)。 558.1 A A
I-2619
Figure 02_image5525
 O[C@@]1(CN(C(=O)Nc2ccc(Cl)c3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.20 (s, 1H), 8.72 (s, 1H), 7.83 (dd, J = 8.9, 4.7 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.29 - 7.18 (m, 2H), 7.13 (td, J = 8.4, 3.1 Hz, 1H), 6.64 (s, 1H), 6.03 (s, 1H), 4.17 (d, J = 12.0 Hz, 1H), 3.44 (d, J = 12.1 Hz, 1H)。 558.1 D   
I-2620
Figure 02_image5527
 O[C@]1(CN(C(=O)Nc2ccc(Cl)c3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.19 (s, 1H), 8.81 (s, 1H), 7.90 (d, J = 6.3 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.34 (dd, J = 8.9, 5.2 Hz, 1H), 7.27 (td, J = 9.0, 2.8 Hz, 1H), 7.21 (dd, J = 8.1, 2.8 Hz, 1H), 7.14 (td, J = 8.4, 3.0 Hz, 1H), 6.63 (s, 1H), 5.99 (s, 1H), 3.97 (d, J = 12.1 Hz, 1H), 3.50 (d, J = 12.1 Hz, 1H)。 558.1 D   
I-2621
Figure 02_image5529
 O[C@]1(CN(C(=O)Nc2ccc(Cl)c3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.20 (s, 1H), 8.72 (s, 1H), 7.83 (dd, J = 8.9, 4.7 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.42 - 7.31 (m, 2H), 7.29 - 7.18 (m, 2H), 7.13 (ddd, J = 8.8, 7.9, 3.1 Hz, 1H), 6.64 (s, 1H), 6.03 (s, 1H), 4.17 (d, J = 12.0 Hz, 1H), 3.44 (d, J = 12.0 Hz, 1H)。 558.1 C   
I-2622
Figure 02_image5531
 OC1(CN(C(=O)Nc2cc(F)cc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F (400 MHz, DMSO-d6) δ 9.25 (br s, 1H), 8.85 (br s, 0.5H), 8.74 (br s, 0.5H), 7.87 (br dd, J = 8.1, 4.1 Hz, 0.5H), 7.80 (dd, J = 8.9, 4.5 Hz, 0.5H), 7.42 - 7.30 (m, 3H), 7.30 - 7.21 (m, 2H), 7.19 (dd, J = 8.8, 2.4 Hz, 1H), 7.16 - 7.08 (m, 1H), 6.72 (br s, 0.5H), 6.66 (br s, 0.5H), 6.27 (td, J = 55.3, 4.5 Hz, 1H), 6.04 (br s, 1H), 4.01 (d, J = 11.4 Hz, 0.5H), 3.79 (d, J = 12.0 Hz, 0.5H), 3.48 (d, J = 11.8 Hz, 0.5H)。非對映異構體之1:1混合物 524.0 A B
I-2623
Figure 02_image5533
 OC1(CN(C(=O)Nc2cc(F)cc3C(=O)NC(c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F    542.0 A A
I-2624
Figure 02_image5535
 O[C@]1(CN(C(=O)Nc2cc(CC#N)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F       D   
I-2625
Figure 02_image5537
 O[C@@]1(CN(C(=O)Nc2cc(CC#N)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F       D   
I-2626
Figure 02_image5539
 O[C@]1(CN(C(=O)Nc2cc(CC#N)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F       C   
I-2627
Figure 02_image5541
 O[C@@]1(CN(C(=O)Nc2cc(CC#N)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F       A A
I-2628
Figure 02_image5543
 O[C@]1(CN(C(=O)Nc2cc(F)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F       D   
I-2629
Figure 02_image5545
 O[C@]1(CN(C(=O)Nc2cc(F)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F       D   
I-2630
Figure 02_image5547
 O[C@@]1(CN(C(=O)Nc2cc(F)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F       D   
I-2631
Figure 02_image5549
 O[C@@]1(CN(C(=O)Nc2cc(F)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F       A A
I-2632
Figure 02_image5551
 O[C@]1(CN(C(=O)Nc2cc(F)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F       D   
I-2633
Figure 02_image5553
 O[C@]1(CN(C(=O)Nc2cc(F)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F       D   
I-2634
Figure 02_image5555
 O[C@@]1(CN(C(=O)Nc2cc(F)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F       D   
I-2635
Figure 02_image5557
 O[C@@]1(CN(C(=O)Nc2cc(F)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)F       A A
I-2636
Figure 02_image5559
 Cc1cn(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.23 (s, 1H), 8.96 (s, 1H), 8.26 (d, J = 1.5 Hz, 1H), 7.90 (d, J = 14.8 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.56 (t, J = 1.3 Hz, 1H), 7.44 (s, 1H), 7.34 (dd, J = 8.9, 5.1 Hz, 1H), 7.28 (td, J = 9.0, 2.8 Hz, 1H), 7.22 (dd, J = 8.0, 2.7 Hz, 1H), 7.14 (td, J = 8.4, 3.1 Hz, 1H), 6.77 (d, J = 81.8 Hz, 1H), 6.06 (s, 1H), 3.98 (d, J = 12.1 Hz, 1H), 3.57 (d, J = 11.9 Hz, 1H), 2.19 (d, J = 1.0 Hz, 3H)。 604.1 D   
I-2637
Figure 02_image5561
 Cc1cn(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.23 (s, 1H), 8.96 (s, 1H), 8.26 (d, J = 1.5 Hz, 1H), 7.90 (d, J = 14.8 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.56 (t, J = 1.3 Hz, 1H), 7.44 (s, 1H), 7.34 (dd, J = 8.9, 5.1 Hz, 1H), 7.28 (td, J = 9.0, 2.8 Hz, 1H), 7.22 (dd, J = 8.0, 2.7 Hz, 1H), 7.14 (td, J = 8.4, 3.1 Hz, 1H), 6.77 (d, J = 81.8 Hz, 1H), 6.06 (s, 1H), 3.98 (d, J = 12.1 Hz, 1H), 3.57 (d, J = 11.9 Hz, 1H), 2.19 (d, J = 1.0 Hz, 3H)。 604.4 A A
I-2638
Figure 02_image5563
 Cc1cn(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.23 (s, 1H), 8.96 (s, 1H), 8.26 (d, J = 1.5 Hz, 1H), 7.90 (d, J = 14.8 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.56 (t, J = 1.3 Hz, 1H), 7.44 (s, 1H), 7.34 (dd, J = 8.9, 5.1 Hz, 1H), 7.28 (td, J = 9.0, 2.8 Hz, 1H), 7.22 (dd, J = 8.0, 2.7 Hz, 1H), 7.14 (td, J = 8.4, 3.1 Hz, 1H), 6.77 (d, J = 81.8 Hz, 1H), 6.06 (s, 1H), 3.98 (d, J = 12.1 Hz, 1H), 3.57 (d, J = 11.9 Hz, 1H), 2.19 (d, J = 1.0 Hz, 3H)。 604.1 D   
I-2639
Figure 02_image5565
 Cc1cn(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.23 (s, 1H), 8.96 (s, 1H), 8.26 (d, J = 1.5 Hz, 1H), 7.90 (d, J = 14.8 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.56 (t, J = 1.3 Hz, 1H), 7.44 (s, 1H), 7.34 (dd, J = 8.9, 5.1 Hz, 1H), 7.28 (td, J = 9.0, 2.8 Hz, 1H), 7.22 (dd, J = 8.0, 2.7 Hz, 1H), 7.14 (td, J = 8.4, 3.1 Hz, 1H), 6.77 (d, J = 81.8 Hz, 1H), 6.06 (s, 1H), 3.98 (d, J = 12.1 Hz, 1H), 3.57 (d, J = 11.9 Hz, 1H), 2.19 (d, J = 1.0 Hz, 3H)。 604.4 E   
I-2640
Figure 02_image5567
 CNc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  8.83 (s, 1H), 8.57 (s, 1H), 7.90 (dd, J = 9.1, 4.7 Hz, 1H), 7.35 (s, 1H), 7.31-7.21 (m, 2H), 7.18 (dd, J = 8.1, 2.8 Hz, 1H), 7.09 (td, J = 8.3, 3.1 Hz, 1H), 6.70 (d, J = 2.1 Hz, 1H), 6.58 (d, J = 2.1 Hz, 1H), 6.52 (s, 1H), 6.21-6.05 (m, 1H), 5.87 (s, 1H), 3.98 (d, J = 12.1 Hz, 1H), 3.50 (d, J = 12.0 Hz, 1H), 2.75 (d, J = 4.9 Hz, 3H)。 553.1 A A
I-2641
Figure 02_image5569
 CNc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  8.85 (s, 1H), 8.49 (s, 1H), 7.84 (dd, J = 9.0, 4.7 Hz, 1H), 7.35-7.27 (m, 2H), 7.26-7.17 (m, 2H), 7.08 (ddd, J = 8.8, 7.8, 3.1 Hz, 1H), 6.68 (dd, J = 17.1, 2.1 Hz, 2H), 6.50 (s, 1H), 6.14 (d, J = 5.2 Hz, 1H), 5.91 (s, 1H), 4.20 (d, J = 12.0 Hz, 1H), 3.41 (d, J = 12.1 Hz, 1H), 2.75 (d, J = 4.9 Hz, 3H)。 553.1 C   
I-2642
Figure 02_image5571
 CNc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 8.85 (s, 1H), 8.49 (s, 1H), 7.84 (dd, J = 9.0, 4.7 Hz, 1H), 7.35-7.28 (m, 2H), 7.27-7.15 (m, 2H), 7.08 (ddd, J = 8.9, 7.9, 3.2 Hz, 1H), 6.68 (dd, J = 17.1, 2.1 Hz, 2H), 6.51 (s, 1H), 6.13 (d, J = 5.1 Hz, 1H), 5.91 (s, 1H), 4.20 (d, J = 12.1 Hz, 1H), 3.41 (d, J = 12.1 Hz, 1H), 2.75 (d, J = 4.9 Hz, 3H)。 553.1 B   
I-2643
Figure 02_image5573
 CNc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 8.83 (s, 1H), 8.57 (s, 1H), 7.90 (dd, J = 9.1, 4.6 Hz, 1H), 7.35 (s, 1H), 7.31-7.21 (m, 2H), 7.18 (dd, J = 8.1, 2.8 Hz, 1H), 7.09 (td, J = 8.3, 3.1 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 6.58 (d, J = 2.1 Hz, 1H), 6.51 (s, 1H), 6.14 (d, J = 5.1 Hz, 1H), 5.87 (s, 1H), 3.98 (d, J = 12.1 Hz, 1H), 3.50 (d, J = 12.1 Hz, 1H), 2.75 (d, J = 4.9 Hz, 3H)。 553.1 D   
I-2644
Figure 02_image5575
 CNc1cc(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c2[C@H](NC(=O)c2n1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.07 - 9.03 (m, 1H), 8.84 (s, 1H), 7.90 (dd, J = 9.0, 4.6 Hz, 1H), 7.38 (s, 1H), 7.34 - 7.23 (m, 2H), 7.19 (dd, J = 8.1, 2.7 Hz, 1H), 7.08 (td, J = 8.4, 3.1 Hz, 1H), 6.96 (d, J = 5.1 Hz, 1H), 6.66 (s, 1H), 6.49 (s, 1H), 5.87 (s, 1H), 3.93 (d, J = 12.1 Hz, 1H), 3.52 (d, J = 12.0 Hz, 1H), 2.86 (d, J = 4.8 Hz, 3H)。 554.4 A A
I-2645
Figure 02_image5577
 CNc1cc(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c2[C@H](NC(=O)c2n1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.06 (s, 1H), 8.74 (s, 1H), 7.85 (dd, J = 9.0, 4.6 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.30 - 7.17 (m, 2H), 7.10 (ddd, J = 8.9, 7.9, 3.1 Hz, 1H), 6.96 (d, J = 4.9 Hz, 1H), 6.66 (s, 1H), 6.59 (s, 1H), 5.89 (s, 1H), 4.11 (d, J = 12.0 Hz, 1H), 3.38 (d, J = 12.0 Hz, 1H), 2.86 (d, J = 4.7 Hz, 3H)。 554.4 D   
I-2646
Figure 02_image5579
 CNc1cc(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c2[C@@H](NC(=O)c2n1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.07 (s, 1H), 8.74 (s, 1H), 7.86 (dd, J = 9.0, 4.7 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.26 (td, J = 9.0, 2.8 Hz, 1H), 7.21 (dd, J = 8.0, 2.7 Hz, 1H), 7.10 (td, J = 8.4, 3.1 Hz, 1H), 6.96 (q, J = 4.8 Hz, 1H), 6.66 (s, 1H), 6.59 (s, 1H), 5.89 (s, 1H), 4.11 (d, J = 12.0 Hz, 1H), 3.38 (d, J = 12.0 Hz, 1H), 2.86 (d, J = 4.7 Hz, 3H)。 554.1 C   
I-2647
Figure 02_image5581
 CNc1cc(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c2[C@@H](NC(=O)c2n1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.05 (s, 1H), 8.84 (s, 1H), 7.90 (dd, J = 9.1, 4.7 Hz, 1H), 7.37 (s, 1H), 7.34 - 7.28 (m, 1H), 7.31 - 7.23 (m, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.08 (td, J = 8.3, 3.1 Hz, 1H), 6.96 (s, 1H), 6.66 (s, 1H), 6.49 (s, 1H), 5.86 (s, 1H), 3.92 (d, J = 12.2 Hz, 1H), 3.52 (d, J = 12.0 Hz, 1H), 2.85 (d, J = 4.7 Hz, 3H)。 554.3 B   
I-2648
Figure 02_image5583
 [2H]C1(NC(=O)c2cccc(NC(=O)N3CC(O)(c4cc(F)ccc34)C(F)(F)F)c12)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) δ 8.60 (br s, 1H), 8.36 (d, J = 8.1 Hz, 0.5H), 8.19 (d, J = 7.9 Hz, 0.5H), 7.88 (td, J = 10.1, 5.5 Hz, 1H), 7.47 - 7.36 (m, 1H), 7.17 (t, J = 7.9 Hz, 1H), 7.08 (ddd, J = 16.8, 8.5, 2.9 Hz, 1H), 6.98 - 6.80 (m, 3H), 6.70 (br s, 1H), 6.36 (br s, 1H), 3.98 (d, J = 14.0 Hz, 0.5H), 3.77 (d, J = 13.9 Hz, 0.5H), 3.56 (d, J = 12.6 Hz, 0.5H), 3.26 (浸沒d, J = 13.6 Hz, 0.5H)。 525.0 A A
I-2649
Figure 02_image5585
 CC(C)(CN)n1cc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)9.04 (s, 1H), 8.81 (s, 1H), 8.44 (s, 1H), 8.00 (s, 1H), 7.96-7.86 (m, 2H), 7.64-7.56 (m, 1H), 7.41 (s, 1H), 7.33-7.27 (m, 2H), 7.25-7.17 (m, 1H), 7.12 (td, J = 8.4, 3.1 Hz, 1H), 6.80-6.30 (s,1H), 6.01 (s, 1H),4.01 (d, J = 12.1 Hz, 1H), 3.58 (d, J = 12.1 Hz, 1H), 2.89 (s, 2H), 2.00 (s, 1H), 1.52 (s, 6H),1.25(m,1H)。 661.2 A B
I-2650
Figure 02_image5587
 CC(C)(CN)n1cc(cn1)-c1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.04 (s, 1H), 8.81 (s, 1H), 8.44 (s, 1H), 8.00 (s, 1H), 7.96-7.86 (m, 2H), 7.64-7.56 (m, 1H), 7.41 (s, 1H), 7.33-7.27 (m, 2H), 7.25-7.17 (m, 1H), 7.12 (td, J = 8.4, 3.1 Hz, 1H), 6.80-6.30 (s,1H), 6.01 (s, 1H), 4.01 (d, J = 12.1 Hz, 1H),3.58 (d, J = 12.1 Hz, 1H), 2.89 (s, 2H), 2.00 (s, 1H), 1.52 (s, 6H),1.25(m,1H)。 661.2 C   
I-2651
Figure 02_image5589
 CC(C)(CN)n1cc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)9.04 (s, 1H), 8.81 (s, 1H), 8.44 (s, 1H), 8.00 (s, 1H), 7.96-7.86 (m, 2H), 7.64-7.56 (m, 1H), 7.41 (s, 1H), 7.33-7.27 (m, 2H), 7.25-7.17 (m, 1H), 7.12 (td, J = 8.4, 3.1 Hz, 1H),6.80-6.30(s,1H),6.01 (s, 1H),4.01 (d, J = 12.1 Hz, 1H),3.58 (d, J = 12.1 Hz, 1H), 2.89 (s, 2H), 2.00 (s, 1H), 1.52 (s, 6H),1.25(m,1H)。 661.1 D   
I-2652
Figure 02_image5591
 CC(C)(CN)n1cc(cn1)-c1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)9.04 (s, 1H), 8.81 (s, 1H), 8.44 (s, 1H), 8.00 (s, 1H), 7.96-7.86 (m, 2H), 7.64-7.56 (m, 1H), 7.41 (s, 1H), 7.33-7.27 (m, 2H), 7.25-7.17 (m, 1H), 7.12 (td, J = 8.4, 3.1 Hz, 1H),6.80-6.30(s,1H),6.01 (s, 1H),4.01 (d, J = 12.1 Hz, 1H),3.58 (d, J = 12.1 Hz, 1H), 2.89 (s, 2H), 2.00 (s, 1H), 1.52 (s, 6H),1.25(m,1H)。 661.1 D   
I-2653
Figure 02_image5593
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)C2COC2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.11 (s, 1H), 8.77 (s, 1H), 7.87 (dd, J = 8.9, 4.7 Hz, 1H), 7.63-7.59 (m, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.41-7.31 (m, 2H), 7.24 (ddd, J = 18.3, 9.2, 2.7 Hz, 2H), 7.12 (td, J = 8.4, 3.1 Hz, 1H), 6.56 (s, 1H), 6.06 (s, 1H), 5.02 (dd, J = 8.3, 6.0 Hz, 2H), 4.67 (dt, J = 11.3, 6.3 Hz, 2H), 4.41 (p, J = 7.4 Hz, 1H), 4.26 (d, J = 12.1 Hz, 1H), 3.41 (d, J = 12.0 Hz, 1H)。 580.1 E   
I-2654
Figure 02_image5595
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)C2COC2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.09 (s, 1H), 8.86 (s, 1H), 7.92 (dd, J = 9.0, 4.6 Hz, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.41 (s, 1H), 7.32 (dd, J = 8.9, 5.2 Hz, 1H), 7.28 (td, J = 9.0, 2.8 Hz, 1H), 7.21 (dd, J = 8.0, 2.7 Hz, 1H), 7.13 (td, J = 8.4, 3.1 Hz, 1H), 6.56 (s, 1H), 6.02 (s, 1H), 5.02 (ddd, J = 8.3, 6.0, 1.1 Hz, 2H), 4.66 (dt, J = 10.8, 6.3 Hz, 2H), 4.46-4.35 (m, 1H), 4.02 (d, J = 12.1 Hz, 1H), 3.52 (d, J = 12.0 Hz, 1H)。 580.1 D   
I-2655
Figure 02_image5597
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)C2COC2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6)9.08 (s, 1H), 8.85 (s, 1H), 7.92 (dd, J = 9.1, 4.6 Hz, 1H), 7.61 (d, J = 1.5 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.40 (s, 1H), 7.36-7.18 (m, 3H), 7.12 (td, J = 8.3, 3.1 Hz, 1H), 6.56 (s, 1H), 6.02 (s, 1H), 5.02 (ddd, J = 8.3, 5.9, 1.1 Hz, 2H), 4.66 (dt, J = 10.6, 6.3 Hz, 2H), 4.40 (p, J = 7.2 Hz, 1H), 4.02 (d, J = 12.1 Hz, 1H), 3.53 (d, J = 12.0 Hz, 1H), 1.45-1.20 (m, 1H)。 580.1 A A
I-2656
Figure 02_image5599
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)C2COC2)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6)9.09 (s, 1H), 8.76 (s, 1H), 7.87 (dd, J = 9.0, 4.7 Hz, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 1.5 Hz, 1H), 7.40-7.31 (m, 2H), 7.30-7.21 (m, 1H), 7.25-7.18 (m, 1H), 7.12 (ddd, J = 8.9, 7.9, 3.1 Hz, 1H), 6.56 (s, 1H), 6.06 (s, 1H), 5.02 (dd, J = 8.3, 6.0 Hz, 2H), 4.67 (dt, J = 11.2, 6.3 Hz, 2H), 4.40 (ddd, J = 14.8, 8.4, 6.7 Hz, 1H), 4.26 (d, J = 12.0 Hz, 1H), 3.41 (d, J = 12.1 Hz, 1H)。 580.1 C   
I-2657
Figure 02_image5601
 CC1(Cc2cc3C(=O)N[C@@H](c3c(NC(=O)N3C[C@@](O)(c4cc(F)ccc34)C(F)(F)F)c2)c2cc(F)ccc2Cl)COC1 (400 MHz, DMSO-d6)  9.03 (s, 1H), 8.76 (s, 1H), 7.92 (dd, J = 8.8, 4.6 Hz, 1H), 7.44 - 7.35 (m, 2H), 7.35 - 7.23 (m, 2H), 7.20 (dd, J = 8.7, 2.2 Hz, 2H), 7.12 (td, J = 8.4, 3.1 Hz, 1H), 6.56 (s, 1H), 5.99 (s, 1H), 4.58 (t, J = 5.7 Hz, 2H), 4.24 (dd, J = 5.6, 3.3 Hz, 2H), 4.00 (d, J = 12.1 Hz, 1H), 3.51 (d, J = 12.1 Hz, 1H), 3.14 - 2.92 (m, 2H), 1.24 (s, 3H)。 608.4 A A
I-2658
Figure 02_image5603
 CC1(Cc2cc3C(=O)N[C@@H](c3c(NC(=O)N3C[C@](O)(c4cc(F)ccc34)C(F)(F)F)c2)c2cc(F)ccc2Cl)COC1 (400 MHz, DMSO-d6)  9.05 (s, 1H), 8.68 (s, 1H), 7.85 (dd, J = 8.9, 4.7 Hz, 1H), 7.41 (d, J = 1.3 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.29 - 7.18 (m, 3H), 7.11 (ddd, J = 8.9, 7.9, 3.1 Hz, 1H), 6.56 (s, 1H), 6.02 (s, 1H), 4.57 (t, J = 5.9 Hz, 2H), 4.33 - 4.02 (m, 3H), 3.41 (d, J = 12.0 Hz, 1H), 3.10 (d, J = 13.4 Hz, 1H), 3.01 (d, J = 13.4 Hz, 1H), 1.24 (s, 3H)。 608.4 D   
I-2659
Figure 02_image5605
 CC1(Cc2cc3C(=O)N[C@H](c3c(NC(=O)N3C[C@@](O)(c4cc(F)ccc34)C(F)(F)F)c2)c2cc(F)ccc2Cl)COC1 (400 MHz, DMSO-d6)  9.05 (s, 1H), 8.69 (s, 1H), 7.85 (dd, J = 9.0, 4.7 Hz, 1H), 7.41 (d, J = 1.4 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.30 - 7.17 (m, 3H), 7.11 (td, J = 8.3, 3.1 Hz, 1H), 6.56 (s, 1H), 6.02 (s, 1H), 4.57 (t, J = 5.9 Hz, 2H), 4.28 - 4.10 (m, 3H), 3.40 (d, J = 12.0 Hz, 1H), 3.10 (d, J = 13.4 Hz, 1H), 3.01 (d, J = 13.4 Hz, 1H), 1.24 (s, 3H)。 608.4 D   
I-2660
Figure 02_image5607
 CC1(Cc2cc3C(=O)N[C@H](c3c(NC(=O)N3C[C@](O)(c4cc(F)ccc34)C(F)(F)F)c2)c2cc(F)ccc2Cl)COC1 (400 MHz, DMSO-d6)  9.04 (s, 1H), 8.77 (s, 1H), 7.92 (dd, J = 9.0, 4.7 Hz, 1H), 7.40 (d, J = 10.1 Hz, 2H), 7.35 - 7.23 (m, 2H), 7.22 - 7.16 (m, 2H), 7.12 (td, J = 8.4, 3.1 Hz, 1H), 6.95 - 6.14 (m, 1H), 5.98 (s, 1H), 4.58 (t, J = 5.8 Hz, 2H), 4.24 (dd, J = 5.6, 3.4 Hz, 2H), 4.00 (d, J = 12.1 Hz, 1H), 3.51 (d, J = 12.1 Hz, 1H), 3.10 (d, J = 13.5 Hz, 1H), 3.01 (d, J = 13.4 Hz, 1H), 1.24 (s, 3H)。 608.1 E   
I-2661
Figure 02_image5609
 Cc1nccn1-c1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  9.28 (s, 1H), 8.99 (s, 1H), 7.92 (t, J = 6.0 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.51-7.39 (m, 3H), 7.43-7.32 (m, 1H), 7.29 (td, J = 9.0, 2.7 Hz, 1H), 7.22 (dd, J = 8.1, 2.7 Hz, 1H), 7.15 (td, J = 8.4, 3.1 Hz, 1H), 6.98 (d, J = 1.5 Hz, 1H), 6.74 (s, 2H), 6.11 (s, 1H), 3.99 (d, J = 11.8 Hz, 1H), 3.55 (d, J = 12.0 Hz, 1H), 2.37 (s, 3H)。 604.1 A A
I-2662
Figure 02_image5611
 Cc1nccn1-c1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  9.29 (s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 9.0, 4.6 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 1.4 Hz, 1H), 7.43-7.34 (m, 2H), 7.31-7.19 (m, 2H), 7.19-7.10 (m, 1H), 6.96 (d, J = 1.4 Hz, 1H), 6.72 (s, 1H), 6.15 (s, 1H), 4.18 (d, J = 12.0 Hz, 1H), 3.46 (d, J = 12.0 Hz, 1H), 2.37 (s, 3H)。 604.1 D   
I-2663
Figure 02_image5613
 Cc1nccn1-c1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  9.28 (s, 1H), 8.88 (s, 1H), 7.86 (dd, J = 9.0, 4.7 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H), 7.41-7.34 (m, 2H), 7.31-7.19 (m, 2H), 7.15 (td, J = 8.4, 3.1 Hz, 1H), 6.96 (d, J = 1.4 Hz, 1H), 6.14 (s, 1H), 4.18 (d, J = 11.9 Hz, 1H), 3.46 (d, J = 12.0 Hz, 1H), 2.37 (s, 3H)。 604.1 D   
I-2664
Figure 02_image5615
 Cc1nccn1-c1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  9.28 (s, 1H), 8.99 (s, 1H), 7.93 (dd, J = 8.9, 4.6 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.43 (dd, J = 14.4, 1.9 Hz, 3H), 7.41-7.19 (m, 3H), 7.15 (td, J = 8.4, 3.1 Hz, 1H), 6.96 (d, J = 1.4 Hz, 1H), 6.11 (s, 1H), 4.00 (d, J = 12.0 Hz, 1H), 3.55 (d, J = 12.0 Hz, 1H), 2.37 (s, 3H)。 604.1 D   
I-2665
Figure 02_image5617
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)N2CCCC2=O)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.11 (s, 1H), 8.95 (s, 1H), 7.93 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.40 (s, 1H), 7.36 - 7.24 (m, 2H), 7.21 (d, J = 8.2 Hz, 1H), 7.13 (td, J = 8.3, 3.1 Hz, 1H), 6.54 (s, 1H), 5.99 (s, 1H), 4.09 - 3.85 (m, 3H), 2.56 (d, J = 8.5 Hz, 3H), 2.11 (p, J = 7.5 Hz, 2H)。 607.2 A A
I-2666
Figure 02_image5619
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)N2CCCC2=O)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.10 (s, 1H), 8.83 (s, 1H), 7.91 - 7.80 (m, 3H), 7.38 - 7.30 (m, 2H), 7.30 - 7.19 (m, 2H), 7.11 (td, J = 8.3, 3.1 Hz, 1H), 6.54 (s, 1H), 6.01 (s, 1H), 4.29 (d, J = 12.0 Hz, 1H), 4.01 ¨C 3.86 (m, 2H), 3.32 (s, 1H), 2.57 (t, J = 8.0 Hz, 2H), 2.17 ¨C 2.05 (m, 2H)。 607.1 D   
I-2667
Figure 02_image5621
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)N2CCCC2=O)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.10 (s, 1H), 8.83 (s, 1H), 7.91 - 7.80 (m, 3H), 7.38 - 7.30 (m, 2H), 7.30 - 7.18 (m, 2H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 6.55 (s, 1H), 6.01 (s, 1H), 4.29 (d, J = 12.1 Hz, 1H), 4.01 - 3.86 (m, 2H), 3.32 (s, 1H), 2.57 (t, J = 8.0 Hz, 2H), 2.17 ¨C 2.05 (m, 2H)。 607.2 D   
I-2668
Figure 02_image5623
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)N2CCCC2=O)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.09 (s, 1H), 8.93 (s, 1H), 7.93 (s, 1H), 7.83 (dd, J = 18.0, 2.0 Hz, 2H), 7.38 (s, 1H), 7.33 (d, J = 5.2 Hz, 1H), 7.34 - 7.23 (m, 1H), 7.23 - 7.17 (m, 1H), 7.12 (td, J = 8.2, 3.0 Hz, 1H), 6.58 (s, 1H), 5.99 (s, 1H), 4.05 (d, J = 12.3 Hz, 1H), 4.02 - 3.85 (m, 2H), 3.51 - 3.41 (m, 1H), 2.58 (d, J = 8.0 Hz, 2H), 2.11 (dd, J = 14.4, 6.9 Hz, 2H)。 607.1 E   
I-2669
Figure 02_image5625
 O[C@@]1(CN(C(=O)Nc2cc(Cn3cc(cn3)C#N)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.14 (s, 1H), 8.87 (s, 1H), 8.79 (s, 1H), 8.15 (s, 1H), 7.91 (s, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 7.36 - 7.23 (m, 3H), 7.20 (d, J = 8.2 Hz, 1H), 7.13 (td, J = 8.4, 3.0 Hz, 1H), 6.51 (s, 1H), 6.00 (s, 1H), 5.58 (s, 2H), 4.00 (d, J = 12.0 Hz, 1H), 3.46 (d, J = 12.0 Hz, 1H) 629.2 A A
I-2670
Figure 02_image5627
 O[C@]1(CN(C(=O)Nc2cc(Cn3cc(cn3)C#N)cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.15 (s, 1H), 8.78 (d, J = 3.6 Hz, 2H), 8.15 (s, 1H), 7.84 (dd, J = 9.0, 4.7 Hz, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 7.37 - 7.30 (m, 2H), 7.30 - 7.19 (m, 2H), 7.12 (td, J = 8.3, 3.0 Hz, 1H), 6.51 (s, 1H), 6.04 (s, 1H), 5.57 (s, 2H), 4.22 (d, J = 12.0 Hz, 1H), 3.34 (s, 1H)。 629.2 C   
I-2671
Figure 02_image5629
 O[C@@]1(CN(C(=O)Nc2cc(Cn3cc(cn3)C#N)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.15 (s, 1H), 8.78 (d, J = 3.6 Hz, 2H), 8.15 (s, 1H), 7.84 (dd, J = 8.9, 4.7 Hz, 1H), 7.52 (s, 1H), 7.42 - 7.30 (m, 3H), 7.24 (ddd, J = 18.5, 9.3, 2.8 Hz, 2H), 7.12 (td, J = 8.3, 3.1 Hz, 1H), 6.51 (s, 1H), 6.03 (s, 1H), 5.57 (s, 2H), 4.22 (d, J = 12.1 Hz, 1H), 3.37 (s, 1H)。 629.2 C   
I-2672
Figure 02_image5631
 O[C@]1(CN(C(=O)Nc2cc(Cn3cc(cn3)C#N)cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.14 (s, 1H), 8.87 (s, 1H), 8.79 (s, 1H), 8.15 (s, 1H), 7.91 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.36 - 7.23 (m, 3H), 7.21 (d, J = 8.0 Hz, 1H), 7.13 (td, J = 8.3, 3.0 Hz, 1H), 6.51 (s, 1H), 6.00 (s, 1H), 5.58 (s, 2H), 3.99 (d, J = 12.1 Hz, 1H), 3.46 (d, J = 11.7 Hz, 1H)。 629.2 E   
I-2673
Figure 02_image5633
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)N2CCOC2=O)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.13 (s, 1H), 8.98 (s, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.40 (s, 1H), 7.36-7.24 (m, 2H), 7.21 (dd, J = 8.0, 2.7 Hz, 1H), 7.13 (td, J = 8.3, 3.1 Hz, 1H), 6.56 (s, 1H), 5.99 (s, 1H), 4.50 (t, J = 8.0 Hz, 2H), 4.17 (dq, J = 27.7, 8.3 Hz, 2H), 4.06 (d, J = 12.2 Hz, 1H), 3.46 (d, J = 12.1 Hz, 1H)。 609.4 A A
I-2674
Figure 02_image5635
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)N2CCOC2=O)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.13 (s, 1H), 8.98 (s, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.40 (s, 1H), 7.36-7.24 (m, 2H), 7.21 (dd, J = 8.0, 2.7 Hz, 1H), 7.13 (td, J = 8.3, 3.1 Hz, 1H), 6.56 (s, 1H), 5.99 (s, 1H), 4.50 (t, J = 8.0 Hz, 2H), 4.17 (dq, J = 27.7, 8.3 Hz, 2H), 4.06 (d, J = 12.2 Hz, 1H), 3.46 (d, J = 12.1 Hz, 1H)。 609.4 D   
I-2675
Figure 02_image5637
 O[C@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)N2CCOC2=O)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.13 (s, 1H), 8.98 (s, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.40 (s, 1H), 7.36-7.24 (m, 2H), 7.21 (dd, J = 8.0, 2.7 Hz, 1H), 7.13 (td, J = 8.3, 3.1 Hz, 1H), 6.56 (s, 1H), 5.99 (s, 1H), 4.50 (t, J = 8.0 Hz, 2H), 4.17 (dq, J = 27.7, 8.3 Hz, 2H), 4.06 (d, J = 12.2 Hz, 1H), 3.46 (d, J = 12.1 Hz, 1H)。 609.2 D   
I-2676
Figure 02_image5639
 O[C@@]1(CN(C(=O)Nc2cc(cc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)N2CCOC2=O)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.13 (s, 1H), 8.98 (s, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.40 (s, 1H), 7.36-7.24 (m, 2H), 7.21 (dd, J = 8.0, 2.7 Hz, 1H), 7.13 (td, J = 8.3, 3.1 Hz, 1H), 6.56 (s, 1H), 5.99 (s, 1H), 4.50 (t, J = 8.0 Hz, 2H), 4.17 (dq, J = 27.7, 8.3 Hz, 2H), 4.06 (d, J = 12.2 Hz, 1H), 3.46 (d, J = 12.1 Hz, 1H)。 609.2 E   
I-2677
Figure 02_image5641
 CNc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@](O)(C(F)F)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  8.82 (s, 1H), 8.49 (s, 1H), 7.87 (dd, J = 8.9, 4.7 Hz, 1H), 7.29 (dd, J = 8.9, 5.2 Hz, 1H), 7.24 (dd, J = 8.3, 2.8 Hz, 1H), 7.17 (td, J = 9.0, 2.8 Hz, 1H), 7.08 (td, J = 8.3, 3.1 Hz, 1H), 6.69 (d, J = 2.1 Hz, 1H), 6.65 (s, 1H), 6.59 (d, J = 2.1 Hz, 1H), 6.45 (d, J = 47.5 Hz, 1H), 6.25 (s, 1H), 6.15 - 6.07 (m, 1H), 5.89 (s, 1H), 3.87 - 3.79 (m, 1H), 3.46 (d, J = 11.7 Hz, 1H), 2.75 (d, J = 5.0 Hz, 3H)。 535.1 A A
I-2678
Figure 02_image5643
 CNc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@](O)(C(F)F)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  8.84 (s, 1H), 8.40 (s, 1H), 7.80 (dd, J = 9.0, 4.7 Hz, 1H), 7.32 (dd, J = 8.9, 5.2 Hz, 1H), 7.22 (dd, J = 8.2, 2.8 Hz, 1H), 7.15 (td, J = 9.1, 2.8 Hz, 1H), 7.08 (td, J = 8.3, 3.1 Hz, 1H), 6.70 - 6.64 (m, 2H), 6.60 (s, 1H), 6.45 (d, J = 47.1 Hz, 1H), 6.25 (s, 1H), 6.16 - 6.08 (m, 1H), 5.93 (s, 1H), 4.09 (d, J = 11.7 Hz, 1H), 3.30 (d, J = 3.6 Hz, 1H), 2.75 (d, J = 4.9 Hz, 3H)。 535.1 D   
I-2679
Figure 02_image5645
 CNc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@@](O)(C(F)F)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  8.84 (s, 1H), 8.40 (s, 1H), 7.80 (dd, J = 9.0, 4.7 Hz, 1H), 7.32 (dd, J = 8.8, 5.1 Hz, 1H), 7.22 (dd, J = 8.3, 2.8 Hz, 1H), 7.15 (td, J = 9.0, 2.8 Hz, 1H), 7.08 (td, J = 8.4, 3.1 Hz, 1H), 6.71 - 6.64 (m, 2H), 6.60 (s, 1H), 6.39 (s, 1H), 6.25 (s, 1H), 6.15 - 6.05 (m, 1H), 5.93 (s, 1H), 4.09 (d, J = 11.7 Hz, 1H), 3.29 (s, 1H), 2.75 (d, J = 5.0 Hz, 3H)。 535.1 E   
I-2680
Figure 02_image5647
 CNc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@@](O)(C(F)F)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6)  8.82 (s, 1H), 8.49 (s, 1H), 7.87 (dd, J = 8.9, 4.7 Hz, 1H), 7.29 (dd, J = 8.9, 5.1 Hz, 1H), 7.23 (dd, J = 8.2, 2.8 Hz, 1H), 7.17 (td, J = 9.1, 2.8 Hz, 1H), 7.08 (td, J = 8.4, 3.1 Hz, 1H), 6.69 (d, J = 2.1 Hz, 1H), 6.65 (s, 1H), 6.59 (d, J = 2.1 Hz, 1H), 6.45 (d, J = 46.0 Hz, 1H), 6.25 (s, 1H), 6.12 (d, J = 5.6 Hz, 1H), 5.89 (s, 1H), 3.83 (d, J = 11.8 Hz, 1H), 3.46 (d, J = 11.8 Hz, 1H), 2.75 (d, J = 4.9 Hz, 3H)。 535.2 E   
I-2681
Figure 02_image5649
 [2H][C@]1(NC(=O)c2cccc(NC(=O)N3C[C@@](O)(c4cc(F)ccc34)C(F)(F)F)c12)c1cc(F)ccc1Cl       D   
I-2682
Figure 02_image5651
 [2H][C@]1(NC(=O)c2cccc(NC(=O)N3C[C@](O)(c4cc(F)ccc34)C(F)(F)F)c12)c1cc(F)ccc1Cl       A A
I-2683
Figure 02_image5653
 [2H][C@@]1(NC(=O)c2cccc(NC(=O)N3C[C@](O)(c4cc(F)ccc34)C(F)(F)F)c12)c1cc(F)ccc1Cl       D   
I-2684
Figure 02_image5655
 [2H][C@@]1(NC(=O)c2cccc(NC(=O)N3C[C@@](O)(c4cc(F)ccc34)C(F)(F)F)c12)c1cc(F)ccc1Cl       E   
I-2685
Figure 02_image5657
 O[C@]1(CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2ccccc2Cl)c2ccc(F)cc12)C(F)(F)F       E   
I-2686
Figure 02_image5659
 O[C@@]1(CN(C(=O)Nc2cccc3C(=O)N[C@H](c23)c2ccccc2Cl)c2ccc(F)cc12)C(F)(F)F       E   
I-2687
Figure 02_image5661
 O[C@@]1(CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2ccccc2Cl)c2ccc(F)cc12)C(F)(F)F       D   
I-2688
Figure 02_image5663
 O[C@]1(CN(C(=O)Nc2cccc3C(=O)N[C@@H](c23)c2ccccc2Cl)c2ccc(F)cc12)C(F)(F)F       A A
I-2689
Figure 02_image5665
 OC1(CN(C(=O)Nc2cccc3C(=O)NC(c23)c2ccccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) δ 9.06 (br s, 1H), 8.75 (s, 0.5H), 8.66 (s, 0.5H), 7.90 (dd, J = 8.7, 4.7 Hz, 0.5H), 7.85 (dd, J = 8.4, 4.5 Hz, 0.5H), 7.59 (t, J = 7.0 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.48 - 7.34 (m, 2H), 7.32 - 7.17 (m, 5H), 7.17 - 7.05 (m, 1H), 6.09 (br s, 1H), 4.17 (d, J = 11.9 Hz, 0.5H), 3.97 (d, J = 12.1 Hz, 0.5H), 3.43 (d, J = 11.5 Hz, 0.5H), 3.31 (浸沒d, 0.5H)。非對映異構體之1:1混合物。 506.0      
I-2690
Figure 02_image5667
 CN(C)c1cc(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c2[C@@H](NC(=O)c2n1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.13 (s, 1H), 8.98 (s, 1H), 7.90 (dd, J = 9.1, 4.7 Hz, 1H), 7.41 (s, 1H), 7.34- 7.24 (m, 2H), 7.20 (dd, J = 8.1, 2.7 Hz, 1H), 7.08 (td, J = 8.3, 3.1 Hz, 1H), 6.60 (s, 2H), 5.90 (s, 1H), 3.98 (d, J = 12.1 Hz, 1H), 3.52 (d, J = 12.1 Hz, 1H), 3.11 (s, 6H)。 568.4 A A
I-2691
Figure 02_image5669
 CN(C)c1cc(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c2[C@@H](NC(=O)c2n1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.14 (s, 1H), 8.89 (s, 1H), 7.88 (dd, J = 9.0, 4.6 Hz, 1H), 7.36 (s, 1H), 7.33 (dd, J = 8.8, 5.1 Hz, 2H), 7.32 - 7.18 (m, 2H), 7.10 (ddd, J = 8.9, 7.8, 3.1 Hz, 1H), 6.68 (s, 1H), 5.91 (s, 1H), 4.21 (d, J = 12.1 Hz, 2H), 3.12 (s, 6H)。 568.4 D   
I-2692
Figure 02_image5671
 CN(C)c1cc(NC(=O)N2C[C@@](O)(c3cc(F)ccc23)C(F)(F)F)c2[C@H](NC(=O)c2n1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.14 (s, 1H), 8.90 (s, 1H), 7.88 (dd, J = 9.1, 4.6 Hz, 1H), 7.37 (s, 1H), 7.33 (dd, J = 8.8, 5.2 Hz, 1H), 7.26 (ddd, J = 16.8, 8.4, 2.8 Hz, 2H), 7.21 (d, J = 2.8 Hz, 1H), 7.10 (td, J = 8.3, 3.1 Hz, 1H), 6.74 (s, 1H), 6.68 (s, 1H), 5.92 (s, 1H), 4.21 (d, J = 12.1 Hz, 1H), 3.12 (s, 6H)。 568.4 E   
I-2693
Figure 02_image5673
 CN(C)c1cc(NC(=O)N2C[C@](O)(c3cc(F)ccc23)C(F)(F)F)c2[C@H](NC(=O)c2n1)c1cc(F)ccc1Cl (400 MHz, DMSO-d6) 9.13 (s, 1H), 8.98 (s, 1H), 7.89 (dd, J = 9.1, 4.7 Hz, 1H), 7.40 (s, 1H), 7.34 - 7.24 (m, 2H), 7.20 (dd, J = 8.1, 2.7 Hz, 1H), 7.07 (ddd, J = 8.8, 7.9, 3.1 Hz, 1H), 6.60 (s, 2H), 5.90 (s, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.52 (d, J = 12.0 Hz, 1H), 3.11 (s, 6H)。 568.0 E   
I-2694
Figure 02_image5675
 NCc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@@](O)(C(F)F)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl    533.3 A B
I-2695
Figure 02_image5677
 NCc1cc2C(=O)N[C@@H](c2c(NC(=O)N2C[C@](O)(C(F)F)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl    533.3 D   
I-2696
Figure 02_image5679
 NCc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@@](O)(C(F)F)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl    533.3 D   
I-2697
Figure 02_image5681
 NCc1cc2C(=O)N[C@H](c2c(NC(=O)N2C[C@](O)(C(F)F)c3cc(F)ccc23)c1)c1cc(F)ccc1Cl    533.3 D   
I-2698
Figure 02_image5683
 O[C@]1(CN(C(=O)Nc2ccnc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6)9.41 (s, 1H), 9.27 (s, 1H), 8.68 (s, 1H), 7.92 (d, J = 6.8 Hz, 1H), 7.42 (s, 2H), 7.34 - 7.29 (m, 2H), 7.21 (d, J = 7.5 Hz, 1H), 7.11 (td, J = 8.4, 3.1 Hz, 1H), 6.73 (s, 1H), 6.02 (s, 1H), 3.98 (s, 1H), 3.54 (d, J = 12.2 Hz, 1H)。 525.0 A B
I-2699
Figure 02_image5685
 O[C@@]1(CN(C(=O)Nc2ccnc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6)  9.42 (s, 1H), 9.17 (s, 1H), 8.70 (s, 1H), 7.88 (dd, J = 9.2, 4.5 Hz, 1H), 7.49 (d, J = 5.4 Hz, 1H), 7.40-7.32 (m, 2H), 7.28 (t, J = 8.9 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.12 (td, J = 8.9, 8.5, 3.1 Hz, 1H), 6.79 (s, 1H), 6.04 (s, 1H), 4.17 (d, J = 12.1 Hz, 1H), 3.37 (d, J = 11.9 Hz, 1H)。 525.0 D   
I-2700
Figure 02_image5687
 O[C@]1(CN(C(=O)Nc2ccnc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6)  9.42 (s, 1H), 9.18 (s, 1H), 8.70 (d, J = 5.4 Hz, 1H), 7.88 (dd, J = 9.1, 4.6 Hz, 1H), 7.49 (d, J = 5.4 Hz, 1H), 7.40-7.20 (m, 4H), 7.12 (td, J = 8.4, 3.1 Hz, 1H), 6.82 (s, 1H), 6.05 (s, 1H), 4.18 (d, J = 12.1 Hz, 1H), 3.37 (d, J = 12.1 Hz, 1H)。 525.0 D   
I-2701
Figure 02_image5689
 O[C@@]1(CN(C(=O)Nc2ccnc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.42 (s, 1H),9.27 (s, 1H), 8.70 (d, J = 5.3 Hz,1H),7.92 (s, 1H),7.50-7.40 (m,1H),7.40-7.37 (m, 1H),7.37-7.26 (m, 2H),7.22 (d, J = 8.4 Hz, 1H), 7.10 (td, J = 8.4, 3.0 Hz, 1H), 6.81 (s, 1H), 6.03 (s, 1H), 4.00 (d, J = 12.1 Hz, 1H), 3.52 (d, J = 12.0 Hz, 1H)。 524.9 D   
I-2702
Figure 02_image5691
 O[C@@]1(CN(C(=O)Nc2cc(Cl)nc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.57 (s, 1H), 9.34 (s, 1H), 7.88 (s, 1H), 7.63 (s, 1H), 7.38 (s, 2H), 7.28 (s, 1H), 7.22 (s, 1H), 7.14 (td, J = 8.4, 3.1 Hz, 1H), 7.01- 6.03 (s, 1H), 6.04 (s, 1H), 4.06 (s, 1H), 3.45 (s, 1H)。 559.1 D   
I-2703
Figure 02_image5693
 O[C@]1(CN(C(=O)Nc2cc(Cl)nc3C(=O)N[C@@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F (400 MHz, DMSO-d6) 9.58 (s, 1H), 9.43 (s, 1H), 7.90 (s, 1H), 7.51 (s, 1H), 7.46 (s, 1H), 7.33 (s, 2H), 7.22 (s, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.27 (s, 2H), 3.90 (s, 1H), 3.58 (s, 1H)。 559.1 A A
I-2704
Figure 02_image5695
 O[C@@]1(CN(C(=O)Nc2cc(Cl)nc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F    559.1 A A
I-2705
Figure 02_image5697
 O[C@]1(CN(C(=O)Nc2cc(Cl)nc3C(=O)N[C@H](c23)c2cc(F)ccc2Cl)c2ccc(F)cc12)C(F)(F)F    559.1 D   
I-2706
Figure 02_image5698
 Fc1cccc(c1)C1NC(=O)c2cc(cc(NC(=O)c3cc(F)cc(c3)C(F)(F)F)c12)-c1ccc2ncnn2c1C#N            
I-2707
Figure 02_image5699
 NC(=O)c1c(ccc2ncnn12)-c1cc2C(=O)NC(c2c(NC(=O)c2cc(F)cc(c2)C(F)(F)F)c1)c1cc(F)ccc1Cl            
在上表1及以下實施例中之化學結構中，立體對稱中心係根據增強立體表示格式(MDL/Biovia，例如使用標記「或1」、「或2」、「abs」、「及1」)描述。(參見例如化合物I-1、I-2、I-4、I-5、I-292及I-293之結構)。
在一些實施例中，本發明提供上表1中之化合物，其中化合物表示為具有「A」之ADP-Glo IC50 。在一些實施例中，本發明提供上表1中之化合物，其中化合物表示為具有「A」或「B」之ADP-Glo IC50 。在一些實施例中，本發明提供上表1中之化合物，其中化合物表示為具有「A」或「B」或「C」之ADP-Glo IC50 。在一些實施例中，本發明提供上表1中之化合物，其中化合物表示為具有「A」或「B」或「C」或「D」之ADP-Glo IC50 。
在一些實施例中，本發明提供上表1中之化合物，其中化合物表示為具有「A」之MCF10A IC50 。在一些實施例中，本發明提供上表1中之化合物，其中化合物表示為具有「A」或「B」之MCF10A IC50 。在一些實施例中，本發明提供上表1中之化合物，其中化合物表示為具有「A」或「B」或「C」之MCF10A IC50 。在一些實施例中，本發明提供上表1中之化合物，其中化合物表示為具有「A」或「B」或「C」或「D」之MCF10A IC50 。
在一些實施例中，本發明包含選自上表1中描繪之彼等化合物的式I化合物，或其醫藥學上可接受之鹽、立體異構體或立體異構體混合物。在一些實施例中，本發明提供選自上表1中描繪之彼等化合物的式I化合物，或其醫藥學上可接受之鹽。在一些實施例中，本發明提供選自上表1中描繪之彼等化合物的式I化合物。
在一些實施例中，本發明包含選自上表1中描繪之彼等化合物的式II化合物，或其醫藥學上可接受之鹽、立體異構體或立體異構體混合物。在一些實施例中，本發明提供選自以表1中描繪之彼等化合物的式II化合物，或其醫藥學上可接受之鹽。在一些實施例中，本發明提供選自上表1中描繪之彼等化合物的式II化合物。
在一些實施例中，本發明包含選自上表1中描繪之彼等化合物的式III化合物，或其醫藥學上可接受之鹽、立體異構體或立體異構體混合物。在一些實施例中，本發明提供選自上表1中描繪之彼等化合物的式III化合物，或其醫藥學上可接受之鹽。在一些實施例中，本發明提供選自上表1中描繪之彼等化合物的式III化合物。
在一些實施例中，本發明包含選自上表1中描繪之彼等化合物的式IV化合物，或其醫藥學上可接受之鹽、立體異構體或立體異構體混合物。在一些實施例中，本發明提供選自上表1中描繪之彼等化合物的式IV化合物，或其醫藥學上可接受之鹽。在一些實施例中，本發明提供選自上表1中描繪之彼等化合物的式IV化合物。
在一些實施例中，本發明包含選自上表1中描繪之彼等化合物的式V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，或其醫藥學上可接受之鹽、立體異構體或立體異構體混合物。在一些實施例中，本發明提供選自上表1中描繪之彼等化合物的式V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物，或其醫藥學上可接受之鹽。在一些實施例中，本發明提供選自上表1中描繪之彼等化合物的式V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX、XXX、XXXI、XXXII、XXXIII、XXXIV、XXXV、XXXVI、XXXVII、XXXVIII、XXXIX或XXXX化合物。 4. 提供本發明化合物之一般方法
本發明化合物可一般藉由熟習此項技術者已知之合成及/或半合成方法、以下流程中所說明之方法及以下實例中詳細描述之方法來製備或分離。然而，本發明之範疇不應解釋為限於此等流程中所揭示之特定實施例，該等實施例僅為說明性的。至少一些在本文中鑑別為「中間物」之化合物，例如在數字之前有「Int-」之化合物被視為本發明化合物。
在流程中，熟習有機合成技術者應瞭解，分子之各個部分上存在的官能基應與所提出之試劑及反應相容。與反應條件不相容的取代基對於熟習此項技術者而言將為顯而易見的，且因此指定替代方法(例如保護基團或替代反應的使用)。保護基化學及策略為此項技術中熟知的，例如如「Protecting Groups in Organic Synthesis」, T. W. Greene及P. G. M. Wuts, 第3版, John Wiley & Sons, 1999中所詳細描述，其全部內容以引用之方式併入本文中。流程之起始材料為市售的或易於由熟習有機合成技術者使用標準方法自已知材料製備。
此項技術中熟知的有機化學及合成之一般原理描述於例如以下各者中：「Organic Chemistry」, Thomas Sorrell, University Science Books, Sausalito:  1999；「March's Advanced Organic Chemistry」, 第5版, 編者：Smith, M.B.及March, J., John Wiley & Sons, New York:  2001；及「Comprehensive Organic Synthesis」, 第2版., 編者：Knochel, P.及Molander, G.A., Elsevier, Amsterdam:  2014；其各自之全部內容特此以引用之方式併入。舉例而言，以下某些實施例涉及離去基。適合之離去基為此項技術中所熟知，如例如前述參考文獻中所述。此類離去基團包括但不限於鹵素、烷氧基、磺醯基氧基、視情況經取代之烷基磺醯基氧基、視情況經取代之烯基磺醯基氧基、視情況經取代之芳基磺醯基氧基及重氮部分。適合之離去基之實例包括氯、碘、溴、氟、甲烷磺醯基(甲磺醯基)、甲苯磺醯基、三氟甲磺酸酯、硝基-苯磺醯基(硝基苯磺醯基)及溴-苯磺醯基(溴苯磺醯基)。流程 1
Figure 02_image5700
在一些實施例中，式A化合物(亦即式I化合物，其中Q為CH，且R2 為-N(H)C(O)-R2A )係根據以上流程1中描繪之一般程序製備。在一些實施例中，步驟1包含使Int-1與式PG-NH2 之一級胺縮合，由此形成式Int-2化合物，其中X、Y及Z如本文實施例中所定義，LG1 及LG2 為脫離基，且PG為保護基。在一些實施例中，LG1 及LG2 結合在一起為-O- (亦即Int-1為雙環酸酐)。在一些實施例中，LG1 及LG2 為Cl。在一些實施例中，PG為對甲氧基苯甲基(PMB)。在一些實施例中，PG為2,4-二甲氧基苯甲基(DMB)。
在一些實施例中，步驟2包含式Int-2化合物之還原，由此形成式Int-3化合物，其中X、Y及Z如本文實施例中所定義且PG為保護基。在一些實施例中，該還原係藉由鐵及氯化銨進行。
在一些實施例中，步驟3包含式R1 -M之有機金屬試劑與Int-3之親核加成，由此形成式Int-4化合物，其中X、Y、Z及R1 如本文實施例中所定義且PG為保護基。在一些實施例中，式R1 -M之有機金屬試劑為式R1 -MgBr或R1 -MgCl之格林納試劑。在一些實施例中，式R1 -M之有機金屬試劑為式R1 -MgBr之格林納試劑。在一些實施例中，R1 為經R1C 之r1 個實例取代之苯基。
在一些實施例中，步驟4包含式Int-4化合物之還原，由此形成式Int-5化合物，其中X、Y、Z及R1 如本文實施例中所定義且PG為保護基。在一些實施例中，該還原係藉由矽烷及酸進行。在一些實施例中，該還原係藉由三烷基矽烷及三氟乙酸進行。
在一些實施例中，步驟5包含使Int-5與包含R2A 之試劑偶合，由此形成式Int-6化合物，其中X、Y、Z、R1 及R2A 如本文實施例中所定義且PG為保護基。
在一些實施例中，包含R2A 之試劑為式R2A -C(O)Cl之化合物。在一些實施例中，包含R2A 之試劑為式R2A -C(O)OH之化合物，且步驟5進一步包含醯胺偶合試劑。在一些實施例中，醯胺偶合試劑為1-[雙(二甲胺基)亞甲基]-1H -1,2,3-三唑并[4,5-b ]吡錠3-氧化物六氟磷酸鹽(HATU)或四甲基氯甲脒六氟磷酸鹽(TCFH)及N -甲基咪唑(NMI)。在一些實施例中，醯胺偶合試劑為四甲基氯甲脒六氟磷酸鹽(TCFH)及N -甲基咪唑(NMI)。在一些實施例中，醯胺偶合試劑為1-[雙(二甲胺基)亞甲基]-1H -1,2,3-三唑并[4,5-b ]吡錠3-氧化物六氟磷酸鹽(HATU)。
在一些實施例中，包含R2A 之試劑包含一級或二級胺，且步驟5進一步包含羰基當量試劑。在一些實施例中，羰基當量試劑為三光氣。
在一些實施例中，步驟6包含式Int-6化合物之去除保護基，由此形成式A化合物，其中X、Y、Z、R1 及R2A 如本文實施例中所定義。在一些實施例中，該去除保護基係藉由酸進行。在一些實施例中，該去除保護基係藉由三氟乙酸進行。在一些實施例中，該去除保護基係藉由三氟乙酸及三氟甲磺酸進行。在一些實施例中，該去除保護基係藉由氧化劑進行。在一些實施例中，該去除保護基係藉由硝酸鈰(IV)銨進行。
在一些實施例中，使進行步驟5及步驟6之次序顛倒。流程 2
Figure 02_image5702
在一些實施例中，根據以上流程2中描繪之一般程序製備式Int-5化合物。在一些實施例中，步驟1包含Int-26與式R1 -CHO之醛、式PG-NH2 之一級胺及三級丁基異氰化物之烏吉反應(Ugi reaction)縮合，由此形成式Int-7化合物，其中R1 、X、Y及Z如本文實施例中所定義，LG為離去基且PG為保護基。在一些實施例中，LG為鹵素。在一些實施例中，LG為F。在一些實施例中，LG為Cl。在一些實施例中，PG為對甲氧基苯甲基(PMB)。在一些實施例中，PG為2,4-二甲氧基苯甲基(DMB)。
在一些實施例中，步驟2包含式Int-7化合物之環化，由此形成式Int-8化合物，其中R1 、X、Y及Z如本文實施例中所定義且PG為保護基。在一些實施例中，該環化係藉由鹼進行。在一些實施例中，該環化係藉由有機鹼進行。在一些實施例中，該環化係藉由2-(三級丁基)-1,1,3,3-四甲基胍進行。在一些實施例中，該環化係藉由無機鹼進行。在一些實施例中，該環化係藉由碳酸鉀進行。在一些實施例中，該環化係藉由相轉移試劑催化。在一些實施例中，該環化係藉由四烷基銨相轉移試劑催化。
在一些實施例中，步驟3包含式Int-8化合物之還原，由此形成式Int-9化合物，其中R1 、X、Y及Z如本文實施例中所定義且PG為保護基。在一些實施例中，該還原係藉由矽烷及酸進行。在一些實施例中，該還原係藉由三烷基矽烷及三氟乙酸進行。
在一些實施例中，步驟4包含式Int-9化合物之還原，由此形成式Int-5化合物，其中R1 、X、Y及Z如本文實施例中所定義且PG為保護基。在一些實施例中，該還原係藉由鐵及氯化銨進行。流程 3
Figure 02_image5704
在一些實施例中，式A化合物(亦即式I化合物，其中Q為CH，且R2 為-N(H)C(O)-R2A )係根據以上流程4中描繪之一般程序製備。在一些實施例中，步驟1包含式Int-10化合物之還原，由此形成式Int-11化合物，其中X、Y及Z如本文實施例中所定義。在一些實施例中，該還原係藉由金屬氫化物進行。在一些實施例中，該還原係藉由硼氫化鈉進行。
在一些實施例中，步驟2包含式Int-11化合物之還原，由此形成式Int-12化合物，其中X、Y及Z如本文實施例中所定義。在一些實施例中，該還原係藉由鐵及氯化銨進行。
在一些實施例中，步驟3包含式Int-12化合物之活化，由此形成式Int-13化合物，其中X、Y及Z如本文實施例中所定義且LG為離去基。在一些實施例中，該活化為醇解反應。在一些實施例中，離去基為烷氧基。在一些實施例中，該活化為甲醇解。在一些實施例中，離去基為甲氧基。
在一些實施例中，步驟4包含式R1 -M之有機金屬試劑與Int-13之親核加成，由此形成式Int-14化合物，其中X、Y、Z及R1 如本文實施例中所定義。。在一些實施例中，式R1 -M之有機金屬試劑為式R1 -MgBr或R1 -MgCl之格林納試劑。
在一些實施例中，步驟5包含使Int-14與包含R2A 之試劑偶合，由此形成式A化合物，其中X、Y、Z、R1 及R2A 如本文實施例中所定義。
在一些實施例中，包含R2A 之試劑為式R2A -C(O)Cl之化合物。在一些實施例中，包含R2A 之試劑為式R2A -C(O)OH之化合物，且步驟5進一步包含醯胺偶合試劑。在一些實施例中，醯胺偶合試劑為四甲基氯甲脒六氟磷酸鹽(TCFH)及N -甲基咪唑(NMI)或1-[雙(二甲胺基)亞甲基]-1H -1,2,3-三唑并[4,5-b ]吡錠3-氧化物六氟磷酸鹽(HATU)。
在一些實施例中，包含R2A 之試劑包含一級或二級胺，且步驟5進一步包含羰基當量試劑。在一些實施例中，羰基當量試劑為三光氣。流程 4
Figure 02_image5706
在一些實施例中，根據以上流程4中描繪之一般程序製備式Int-5或Int-6化合物。在一些實施例中，步驟1包含使Int-15與式PG-NH2 之一級胺偶合，由此形成式Int-16化合物，其中X、Y及Z如本文實施例中所定義，LG1 為離去基且PG為保護基。在一些實施例中，X、Y或Z中之一或多者為氮。在一些實施例中，X為氮。在一些實施例中，Z為氮。在一些實施例中，LG1 為鹵素。在一些實施例中，LG1 為Cl。在一些實施例中，PG為2,4-二甲氧基苯甲基(DMB)。在一些實施例中，PG為對甲氧基苯甲基(PMB)。
在一些實施例中，步驟2包含將Int-16與式R1 -C(O)-LG2 之化合物縮合，由此形成式Int-17化合物，其中R1 、X、Y及Z如本文實施例中所定義，LG1 為離去基，且PG為保護基。在一些實施例中，LG2 為Cl。在一些實施例中，該縮合係藉由強鹼進行。在一些實施例中，該縮合係藉由丁基鋰進行。在一些實施例中，該縮合係藉由LHMDS進行。
在一些實施例中，步驟3包含式Int-17化合物之還原，由此形成式Int-18化合物，其中R1 、X、Y及Z如本文實施例中所定義，LG1 為離去基，且PG為保護基。在一些實施例中，該還原係藉由矽烷及酸進行。在一些實施例中，該還原係藉由三烷基矽烷及三氟乙酸進行。
在一些實施例中，步驟4包含使Int-18與式PG2 -N(H)-PG3 化合物偶合，由此形成式Int-19化合物，其中R1 、X、Y及Z如本文實施例中所定義，且PG、PG2 及PG3 為保護基。在一些實施例中，PG2 為2,4-二甲氧基苯甲基(DMB)。在一些實施例中，PG2 為對甲氧基苯甲基(PMB)。在一些實施例中，PG3 為H。在一些實施例中，PG3 為2,4-二甲氧基苯甲基(DMB)。在一些實施例中，PG3 為對甲氧基苯甲基(PMB)。在一些實施例中，PG2 -N-PG3 在一起表示疊氮化物(N3 )。
在一些實施例中，該偶合係藉由鹼進行：。在一些實施例中，該偶合係藉由有機鹼進行。在一些實施例中，該偶合係藉由三烷基胺鹼進行。在一些實施例中，該偶合係藉由無機鹼進行。在一些實施例中，該偶合係藉由過渡金屬催化劑進行。在一些實施例中，該偶合係藉由鈀催化劑進行。
在一些實施例中，步驟5包含式Int-19化合物之去除保護基，由此形成式Int-5化合物，其中R1 、X、Y及Z如本文實施例中所定義，且PG為保護基。在一些實施例中，該去除保護基係藉由酸進行。在一些實施例中，該去除保護基係藉由鹽酸進行。在一些實施例中，該去除保護基係藉由三氟乙酸進行。在一些實施例中，該去除保護基係藉由還原劑進行(例如，當PG2 -N-PG3 在一起表示疊氮化物時)。在一些實施例中，該去除保護基係藉由膦還原劑進行。
在一些實施例中，步驟6包含使Int-18與式R2A -C(O)NH2 之化合物偶合，由此形成式Int-6化合物，其中R1 、R2A 、X、Y及Z如本文實施例中所定義，且PG為保護基。在一些實施例中，該偶合為過渡金屬介導之偶合反應。在一些實施例中，該偶合為Pd催化之偶合反應。流程 5
Figure 02_image5708
在一些實施例中，根據以上流程5中描繪之一般程序製備式Int-5化合物。在一些實施例中，步驟1包含Int-20與式R1 -CHO之醛、式PG-NH2 之一級胺及三級丁基異氰化物之烏吉反應縮合，由此形成式Int-21化合物，其中R1 、X、Y及Z如本文實施例中所定義，LG為離去基且PG為保護基。在一些實施例中，LG為鹵素。在一些實施例中，LG為Br。在一些實施例中，LG為Cl。在一些實施例中，PG為2,4-二甲氧基苯甲基(DMB)。在一些實施例中，PG為對甲氧基苯甲基(PMB)。
在一些實施例中，步驟2包含式Int-21化合物之環化，由此形成式Int-22化合物，其中R1 、X、Y及Z如本文實施例中所定義，LG為離去基，且PG為保護基。在一些實施例中，該環化係藉由鹼進行。在一些實施例中，該環化係藉由無機鹼進行。在一些實施例中，該環化係藉由氫化鈉進行。在一些實施例中，該環化係藉由碳酸鉀進行。在一些實施例中，該環化係藉由相轉移試劑催化。在一些實施例中，該環化係藉由四烷基銨相轉移試劑催化。在一些實施例中，該環化係藉由有機鹼進行。在一些實施例中，該環化係藉由2-(三級丁基)-1,1,3,3-四甲基胍進行。
在一些實施例中，步驟3包含式Int-22化合物之還原，由此形成式Int-23化合物，其中R1 、X、Y及Z如本文實施例中所定義，LG為離去基且PG為保護基。在一些實施例中，該還原係藉由矽烷及路易斯酸進行。在一些實施例中，該還原係藉由三烷基矽烷及三氟硼二乙基醚合物進行。在一些實施例中，該還原係藉由矽烷及酸進行。在一些實施例中，該還原係藉由三烷基矽烷及三氟乙酸進行。
在一些實施例中，步驟4包含式Int-23化合物之偶合，由此形成式Int-5化合物，其中R1 、X、Y及Z如本文實施例中所定義且PG為保護基。在一些實施例中，該偶合為過渡金屬介導之偶合反應。在一些實施例中，該偶合為Pd催化之偶合反應。在一些實施例中，該偶合為用二苯甲酮亞胺進行之Pd催化之偶合反應。流程 6
Figure 02_image5710
在一些實施例中，式B化合物(亦即式I化合物，其中Q為C(RQ )，且R2 為-N(H)C(O)-R2A )係根據以上流程6中描繪之一般程序製備。在一些實施例中，步驟1包含式RQ -M之有機金屬試劑與Int-4之親核加成，由此形成式Int-24化合物，其中X、Y、Z、R1 及RQ 如本文實施例中所定義且PG為保護基。在一些實施例中，PG為對甲氧基苯甲基(PMB)。在一些實施例中，PG為2,4-二甲氧基苯甲基(DMB)。在一些實施例中，式RQ -M之有機金屬試劑為式RQ -MgBr或RQ -MgCl之格林納試劑。在一些實施例中，該親核加成係藉由路易斯酸進行。在一些實施例中，該親核加成係藉由三氟硼二乙基醚合物進行。
在一些實施例中，步驟2包含使Int-24與包含R2A 之試劑偶合，由此形成式Int-25化合物，其中X、Y、Z、R1 及R2A 如本文實施例中所定義且PG為保護基。
在一些實施例中，包含R2A 之試劑為式R2A -C(O)Cl之化合物。在一些實施例中，包含R2A 之試劑為式R2A -C(O)OH之化合物，且步驟2進一步包含醯胺偶合試劑。在一些實施例中，醯胺偶合試劑為四甲基氯甲脒六氟磷酸鹽(TCFH)及N -甲基咪唑(NMI)。在一些實施例中，醯胺偶合試劑為1-[雙(二甲胺基)亞甲基]-1H -1,2,3-三唑并[4,5-b ]吡錠3-氧化物六氟磷酸鹽(HATU)。
在一些實施例中，包含R2A 之試劑包含一級或二級胺，且步驟2進一步包含羰基當量試劑。在一些實施例中，羰基當量試劑為三光氣。
在一些實施例中，步驟3包含式Int-25化合物之去除保護基，由此形成式B化合物，其中X、Y、Z、R1 、RQ 及R2A 如本文實施例中所定義。在一些實施例中，該去除保護基係藉由酸進行。在一些實施例中，該去除保護基係藉由三氟乙酸進行。在一些實施例中，該去除保護基係藉由三氟乙酸及三氟甲磺酸進行。在一些實施例中，該去除保護基係藉由氧化劑進行。在一些實施例中，該去除保護基係藉由硝酸鈰(IV)銨進行。
在一些實施例中，使進行步驟2及步驟3之次序顛倒。
額外式B化合物可藉由進行親核加成來製備，如關於以上流程6之步驟1所描述，而非藉由以上流程2、流程4及流程5之還原步驟3。其餘步驟如流程2、流程4及流程5中所述地進行，以製備Int-24 (而非Int-5)或Int-25 (而非Int-6)之化合物。流程 7
Figure 02_image5712
在一些實施例中，式C化合物(亦即式I化合物，其中Q為N，且R2 為-N(H)C(O)-R2A )係根據以上流程7中描繪之一般程序製備。在一些實施例中，步驟1包含使式Int-26與式R1 -N(H)-NH2 之肼偶合，由此形成式Int-27化合物，其中R1 、X、Y及Z如本文實施例中所定義且LG為離去基。在一些實施例中，LG為鹵素。在一些實施例中，LG為Cl。在一些實施例中，LG為F。在一些實施例中，步驟5進一步包含醯胺偶合試劑。在一些實施例中，醯胺偶合試劑為1-[雙(二甲胺基)亞甲基]-1H -1,2,3-三唑并[4,5-b ]吡錠3-氧化物六氟磷酸鹽(HATU)。
在一些實施例中，步驟2包含式Int-27化合物之環化，由此形成式Int-28化合物，其中R1 、X、Y及Z如本文實施例中所定義。在一些實施例中，該環化係藉由鹼進行。在一些實施例中，該環化係藉由無機鹼進行。在一些實施例中，該環化係藉由三級丁醇鉀進行。在一些實施例中，該環化係藉由碳酸鉀進行。在一些實施例中，該環化係藉由相轉移試劑催化。在一些實施例中，該環化係藉由四烷基銨相轉移試劑催化。在一些實施例中，該環化係藉由有機鹼進行。在一些實施例中，該環化係藉由2-(三級丁基)-1,1,3,3-四甲基胍進行。
在一些實施例中，步驟3包含式Int-28化合物之還原，由此形成式Int-29化合物，其中R1 、X、Y及Z如本文實施例中所定義。在一些實施例中，該還原係藉由鐵及氯化銨進行。
在一些實施例中，步驟4包含使Int-29與包含R2A 之試劑偶合，由此形成式C化合物，其中X、Y、Z、R1 及R2A 如本文實施例中所定義。
在一些實施例中，包含R2A 之試劑為式R2A -C(O)Cl之化合物。在一些實施例中，包含R2A 之試劑為式R2A -C(O)OH之化合物，且步驟4進一步包含醯胺偶合試劑。在一些實施例中，醯胺偶合試劑為四甲基氯甲脒六氟磷酸鹽(TCFH)及N -甲基咪唑(NMI)。在一些實施例中，醯胺偶合試劑為1-[雙(二甲胺基)亞甲基]-1H -1,2,3-三唑并[4,5-b ]吡錠3-氧化物六氟磷酸鹽(HATU)。
在一些實施例中，包含R2A 之試劑包含一級或二級胺，且步驟4進一步包含羰基當量試劑。在一些實施例中，羰基當量試劑為三光氣。
在一些實施例中，步驟4之偶合亦引起吲唑酮(indazalonyl)氮原子之醯化。在該等實施例中，非所需醯基取代基可在鹼性條件下選擇性移除。因此，在一些實施例中，步驟4之偶合之後為用鹼處理產物，由此形成式C化合物，其中X、Y、Z、R1 及R2A 如本文實施例中所定義。在一些實施例中，步驟4之偶合之後為用含無機鹼之醇溶劑處理產物。在一些實施例中，步驟4之偶合之後為用含碳酸鉀之甲醇處理。官能基轉化
在一些實施例中，式I化合物之合成進一步包含官能基轉化。官能基轉化為此項技術中熟知的，如例如以下各者中所述：「Organic Chemistry」, Thomas Sorrell, University Science Books, Sausalito:  1999；「March's Advanced Organic Chemistry」, 第5版, 編者.:  Smith, M.B.及March, J., John Wiley & Sons, New York:  2001；及「Comprehensive Organic Synthesis」, 第2版, 編者: Knochel, P.及Molander, G.A., Elsevier, Amsterdam:  (2014)。
在一些實施例中，官能基轉化係對Int-5進行。在一些實施例中，官能基轉化係對Int-6進行。在一些實施例中，官能基轉化係對式A化合物進行。在一些實施例中，官能基轉化係對Int-14進行。在一些實施例中，官能基轉化係對Int-24進行。在一些實施例中，官能基轉化係對Int-25進行。在一些實施例中，官能基轉化係對式B化合物進行。在一些實施例中，官能基轉化係對Int-28進行。在一些實施例中，官能基轉化係對Int-29進行。在一些實施例中，官能基轉化係對式C化合物進行
在一些實施例中，當X、Y或Z為經鹵素取代之碳時，式I化合物之合成進一步包含鹵素之官能基轉化。在一些實施例中，鹵素為溴。
在一些實施例中，官能基轉化為過渡金屬介導之偶合反應。在一些實施例中，官能基轉化為鈴木偶合。在一些實施例中，官能基轉化為Ni介導之光氧化還原偶合。在一些實施例中，官能基轉化為Pd介導之C-N偶合。在一些實施例中，官能基轉化為施蒂勒偶合。在一些實施例中，官能基轉化為Pd介導之氰化。在一些實施例中，官能基轉化為赫克偶合(Heck coupling)。在一些實施例中，官能基轉化為羰基化。在一些實施例中，該羰基化係在醇存在下進行且形成酯。在一些實施例中，該羰基化係在胺存在下進行且形成醯胺。在一些實施例中，羰基化為Pd催化的。在一些實施例中，羰基化為Co介導的。
在一些實施例中，當X、Y或Z為經包含烯烴之基團取代之碳時，式I化合物之合成進一步包含烯烴之官能基轉化。在一些實施例中，官能基轉化為烯烴之氧化。在一些實施例中，官能基轉化為烯烴之硼氫化。在一些實施例中，官能基轉化為烯烴之二羥基化。在一些實施例中，官能基轉化為烯烴之氧化裂解。在一些實施例中，官能基轉化為烯烴之還原。
在一些實施例中，當X、Y或Z為經包含酯之基團取代之碳時，式I化合物之合成進一步包含酯之官能基轉化。在一些實施例中，官能基轉化為酯還原為醇。在一些實施例中，官能基轉化為酯皂化為羧酸。在一些實施例中，將所得羧酸進一步轉化為醯胺。在一些實施例中，官能基轉化為酯之環丙烷化。
在一些實施例中，當X、Y或Z為經包含醛或酮之基團取代之碳時，式I化合物之合成進一步包含醛或酮之官能基轉化。在一些實施例中，官能基轉化為醛或酮之親核加成。在一些實施例中，官能基轉化為醛或酮之有機金屬加成。在一些實施例中，官能基轉化為醛或酮之格林納加成。在一些實施例中，官能基轉化為醛或酮還原為醇。在一些實施例中，官能基轉化為醛或酮之還原胺化。 5. 用途、調配物及投與 醫藥學上可接受之組合物
根據另一實施例，本發明提供一種組合物，其包含本發明化合物或其醫藥學上可接受之衍生物，及醫藥學上可接受之載劑、佐劑或媒劑。在一些實施例中，本發明提供一種醫藥組合物，其包含本發明化合物及醫藥學上可接受之載劑。本發明組合物中之化合物之量為使得有效地可量測地抑制生物樣品中或患者中之PI3Kα蛋白激酶或其突變體。。在某些實施例中，本發明組合物中之化合物之量為使得有效地可量測地抑制生物樣品中或患者中之PI3Kα蛋白激酶或其突變體。在某些實施例中，本發明之組合物經調配以用於投與需要此類組合物之患者。在一些實施例中，本發明之組合物經調配以用於向患者口服投藥。
如本文所用，術語「個體」及「患者」意謂動物(亦即，動物界成員)，較佳為哺乳動物，且最佳為人類。在一些實施例中，個體為人類、小鼠、大鼠、貓、猴、犬、馬或豬。在一些實施例中，個體為人類。在一些實施例中，個體為小鼠、大鼠、貓、猴、犬、馬或豬。
術語「醫藥學上可接受之載劑、佐劑或媒劑」係指不破壞與其一起調配之化合物之藥理學活性的無毒載劑、佐劑或媒劑。可用於本發明組合物中之醫藥學上可接受之載劑、佐劑或媒劑包括但不限於離子交換劑、氧化鋁、硬脂酸鋁、卵磷脂、血清蛋白(諸如人類血清白蛋白)、緩衝物質(諸如磷酸鹽)、甘胺酸、山梨酸、山梨酸鉀、飽和植物脂肪酸之部分甘油酯混合物、水、鹽或電解質(諸如魚精蛋白硫酸鹽、磷酸氫二鈉、磷酸氫鉀、氯化鈉、鋅鹽)、膠態二氧化矽、三矽酸鎂、聚乙烯基吡咯啶酮、基於纖維素之物質、聚乙二醇、羧甲基纖維素鈉、聚丙烯酸酯、蠟、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇及羊毛脂。
「醫藥學上可接受之衍生物」意謂在向接受者投與時能夠直接或間接提供本發明化合物或其抑制活性代謝物或殘餘物的本發明化合物之任何無毒的鹽、酯、酯之鹽或其他衍生物。
如本文所用，術語「其抑制活性代謝物或殘餘物」意謂其代謝物或殘餘物亦為PI3Kα蛋白激酶或其突變體之抑制劑。
本發明組合物可經口、非經腸、藉由吸入噴霧、局部、經直腸、經鼻、經頰、經陰道或藉助於植入式貯器投與。如本文所用，術語「非經腸」包括皮下、靜脈內、肌肉內、關節內、滑膜內、胸骨內、鞘內、肝內、病灶內及顱內注射或輸注技術。較佳地，組合物經口、腹膜內或靜脈內投與。
本發明之組合物之無菌可注射形式可為水性或油性懸浮液。此等懸浮液可根據此項技術中已知之技術使用適合的分散劑或濕潤劑及懸浮劑來調配。無菌可注射製劑亦可為於無毒非經腸可接受之稀釋劑或溶劑中之無菌可注射溶液或懸浮液，例如於1,3-丁二醇中之溶液。在可採用之可接受媒劑及溶劑中有水、林格氏溶液(Ringer's solution)及等張氯化鈉溶液。另外，無菌不揮發性油習用作溶劑或懸浮介質。
出於此目的，可採用任何溫和的不揮發性油，包括合成單甘油酯或二甘油酯。諸如油酸之脂肪酸及其甘油酯衍生物適用於製備可注射劑，如天然醫藥學上可接受之油，諸如橄欖油或蓖麻油，尤其呈其聚氧乙烯化形式。此等油溶液或懸浮液亦可含有長鏈醇稀釋劑或分散劑，諸如羧甲基纖維素或常用於通常用於調配醫藥學上可接受之劑型(包括乳液及懸浮液)的類似分散劑。其他常用界面活性劑(諸如Tween、Span及其他乳化劑)或常用於製造醫藥學上可接受之固體、液體或其他劑型之生物可用性增進劑亦可用於調配之目的。
本發明之醫藥學上可接受之組合物可以任何經口可接受之劑型經口投與，包括(但不限於)膠囊、錠劑、水性懸浮液或溶液。在用於經口使用之錠劑之情況下，常用載劑包括乳糖及玉米澱粉。亦典型地添加潤滑劑，諸如硬脂酸鎂。就膠囊形式之經口投與而言，適用的稀釋劑包括乳糖及乾燥玉米澱粉。當需要水性懸浮液用於經口使用時，使活性成分與乳化劑及懸浮劑組合。若需要，亦可添加某些甜味劑、調味劑或著色劑。
或者，本發明之醫藥學上可接受之組合物可以直腸投與之栓劑形式投與。此等栓劑可藉由將藥劑與適合的無刺激性賦形劑混合來製備，該賦形劑在室溫下為固體，但在直腸或陰道溫度下為液體且因此將在直腸或陰道中熔融以釋放藥物。此類材料包括可可脂、蜂蠟及聚乙二醇。
本發明之醫藥學上可接受之組合物亦可局部投與，尤其當治療目標包括藉由局部施用容易達到之區域或器官(包括眼睛、皮膚或低位腸道之疾病)時。容易製備適合的局部調配物用於此等區域或器官中之每一者。
用於低位腸道之局部施用可以直腸栓劑調配物(參見上文)形式或以適合的灌腸調配物形式實現。亦可使用局部經皮貼片。
對於局部施用，所提供的醫藥學上可接受之組合物可調配為含有懸浮或溶解於一或多種載劑中之活性組分的適合的軟膏形式。用於本發明化合物之局部投與的載劑包括(但不限於)礦物油、液體石蠟脂、白石蠟脂、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蠟及水。或者，所提供的醫藥學上可接受之組合物可以含有懸浮或溶解於一或多種醫藥學上可接受之載劑中的活性組分的適合的洗劑或乳膏形式調配。適合載劑包括但不限於礦物油、去水山梨醇單硬脂酸酯、聚山梨醇酯60、鯨蠟酯蠟、鯨蠟硬脂醇、2-辛基十二醇、苯甲醇及水。
對於經眼使用，所提供的醫藥學上可接受之組合物可調配為具有或不具有防腐劑(諸如苯紮氯銨(benzylalkonium chloride))、於等張pH值經調整之無菌生理食鹽水中之微米尺寸化懸浮液，或較佳為於等張pH值經調整之無菌生理食鹽水中的溶液。或者，對於經眼使用，醫藥學上可接受之組合物可在軟膏(諸如石蠟脂)中調配。
本發明之醫藥學上可接受之組合物亦可藉由經鼻氣霧劑或吸入來投與。此類組合物係根據醫藥調配技術中熟知之技術製備，且可使用苯甲醇或其他適合的防腐劑、增強生物可用性之吸收促進劑、碳氟化合物及/或其他習知溶解劑或分散劑製備成於生理食鹽水中之溶液。
本發明之醫藥學上可接受之組合物較佳經調配以便經口投與。此類調配物可在存在或不存在食品之情況下投與。在一些實施例中，本發明之醫藥學上可接受之組合物在不存在食品之情況下投與。在其他實施例中，本發明之醫藥學上可接受之組合物在存在食品之情況下投與。
本發明化合物為了產生單一劑型之組合物而可與載劑物質合併的量將視所治療的患者、特定投藥模式而變化。較佳地，所提供之組合物應調配為使得可向接受此等組合物之患者投與0.01-100毫克/公斤體重/天之間的劑量之抑制劑。
亦應理解，任何特定患者之特定劑量及治療方案將視多種因素而定，該等因素包括所採用之特定化合物之活性、年齡、體重、一般健康、性別、膳食、投與時間、排泄率、藥物組合及治療醫師之判斷及所治療之特定疾病之嚴重強度。本發明化合物在組合物中之量亦視組合物中之特定化合物而定。
組合物中所採用之精確劑量亦將視投藥途徑而定，且應根據醫師判斷及各個體之情況決定。在本發明之特定實施例中，適於經口投與本發明化合物之劑量範圍通常為每天約1毫克至每天約1000毫克。在一些實施例中，口服劑量為每天約1毫克至每天約800毫克。在一些實施例中，口服劑量為每天約1毫克至每天約500毫克。在一些實施例中，口服劑量為每天約1毫克至每天約250毫克。在一些實施例中，口服劑量為每天約1毫克至每天約100毫克。在一些實施例中，口服劑量為每天約5毫克至每天約50毫克。在一些實施例中，口服劑量為每天約5毫克。在一些實施例中，口服劑量為每天約10毫克。在一些實施例中，口服劑量為每天約20毫克。在一些實施例中，口服劑量為每天約30毫克。在一些實施例中，口服劑量為每天約40毫克。在一些實施例中，口服劑量為每天約50毫克。在一些實施例中，口服劑量為每天約60毫克。在一些實施例中，口服劑量為每天約70毫克。在一些實施例中，口服劑量為每天約100毫克。應認識到，本文所列劑量中之任一者可構成上限或下限劑量範圍，且可與任何其他劑量組合以構成包含上限及下限之劑量範圍。
在一些實施例中，醫藥學上可接受之組合物含有濃度在以下範圍內的所提供化合物及/或其醫藥學上可接受之鹽：約0.01至約90 wt%、約0.01至約80 wt%、約0.01至約70 wt%、約0.01至約60 wt%、約0.01至約50 wt%、約0.01至約40 wt%、約0.01至約30 wt%、約0.01至約20 wt%、約0.01至約2.0 wt%、約0.01至約1 wt%、約0.05至約0.5 wt%、約1至約30 wt%，或約1至約20 wt%。組合物可調配為溶液、懸浮液、軟膏或膠囊及其類似者。醫藥組合物可製備成水溶液，且可含有其他組分，諸如防腐劑、緩衝劑、張力劑、抗氧化劑、穩定劑、黏度調節成分及其類似者。
醫藥學上可接受之載劑為熟習此項技術者所熟知，且包括例如佐劑、稀釋劑、賦形劑、填充劑、潤滑劑及媒劑。在一些實施例中，載劑為稀釋劑、佐劑、賦形劑或媒劑。在一些實施例中，載劑為稀釋劑、佐劑或賦形劑。在一些實施例中，載劑為稀釋劑或佐劑。在一些實施例中，載劑為賦形劑。
醫藥學上可接受之載劑之實例可包括例如水或生理鹽水溶液、聚合物(諸如聚乙二醇)、碳水化合物及其衍生物、油、脂肪酸或醇。作為醫藥載劑之油的非限制性實例包括石油、動物油、植物油或合成來源之油，諸如花生油、大豆油、礦物油、芝麻油及其類似者。醫藥載劑亦可為生理鹽水、阿拉伯膠(gum acacia)、明膠、澱粉糊、滑石、角蛋白、膠態二氧化矽、尿素及其類似者。此外，亦可使用助劑、穩定劑、增稠劑、潤滑劑及著色劑。適合的醫藥載劑之其他實例描述於例如以下各者中：Remington's: The Science and Practice of Pharmacy, 第22版 (Allen, Loyd V., Jr 編, Pharmaceutical Press (2012))；Modern Pharmaceutics, 第5版 (Alexander T. Florence, Juergen Siepmann, CRC Press (2009))；Handbook of Pharmaceutical Excipients, 第7版 (Rowe, Raymond C.; Sheskey, Paul J.；Cook, Walter G.；Fenton, Marian E. 編, Pharmaceutical Press (2012)) (其各自以全文引用之方式併入本文中)。
本文所用的醫藥學上可接受之載劑可選自各種有機或無機物質，該等物質用作醫藥調配物之物質且作為鎮痛劑、緩衝劑、黏合劑、崩解劑、稀釋劑、乳化劑、賦形劑、增量劑、滑動劑、增溶劑、穩定劑、懸浮劑、張力劑、媒劑及黏度增加劑併入。亦可添加醫藥添加劑，諸如抗氧化劑、芳香劑、著色劑、風味改善劑、防腐劑及甜味劑。可接受的醫藥載劑之實例包括羧甲基纖維素、結晶纖維素、甘油、阿拉伯膠、乳糖、硬脂酸鎂、甲基纖維素、散劑、生理鹽水、褐藻酸鈉、蔗糖、澱粉、滑石及水以及其他。在一些實施例中，術語「醫藥學上可接受」意謂經聯邦政府或州政府之管制機構批准或在美國藥典或其他公認之藥典中列出適用於動物且更尤其適用於人類。
諸如洗滌劑之界面活性劑亦適用於調配物中。界面活性劑之特定實例包括聚乙烯吡咯啶酮、聚乙烯醇、乙酸乙烯酯及乙烯吡咯啶酮之共聚物、聚乙二醇、苯甲醇、甘露糖醇、甘油、山梨糖醇或脫水山梨糖醇之聚氧乙烯化酯；卵磷脂或羧甲基纖維素鈉；或丙烯酸衍生物，諸如甲基丙烯酸酯及其他；陰離子界面活性劑，諸如鹼性硬脂酸鹽，特定言之硬脂酸鈉、硬脂酸鉀或硬脂酸銨；硬脂酸鈣或硬脂酸三乙醇胺；烷基硫酸鹽，特定言之月桂基硫酸鈉及鯨蠟基硫酸鈉；十二烷基苯磺酸鈉或二辛基磺基丁二酸鈉；或脂肪酸，特定言之衍生自椰子油之彼等脂肪酸；陽離子界面活性劑，諸如具有式N+ R'R''R'''R''''Y- 之水溶性四級銨鹽，其中R基團相同或不同，視情況為羥化烴基，且Y- 為強酸之陰離子，諸如鹵素、硫酸根及磺酸根陰離子；溴化鯨蠟基三甲銨為可使用的陽離子界面活性劑中之一者，其為具有式N+ R'R''R'''之胺鹽，其中R基團相同或不同，視情況為羥化烴基；鹽酸十八烷基胺為可使用的陽離子界面活性劑中之一者；非離子界面活性劑，諸如脫水山梨糖醇之視情況聚氧乙烯化酯，特定言之聚山梨醇酯80或聚氧乙烯化烷基醚；硬脂酸聚乙二醇、蓖麻油之聚氧乙烯化衍生物、聚甘油酯、聚氧乙烯化脂肪醇、聚氧乙烯化脂肪酸或環氧乙烷及環氧丙烷之共聚物；兩性界面活性劑，諸如甜菜鹼之經取代月桂基化合物。
適合的醫藥載劑亦可包括賦形劑，諸如澱粉、葡萄糖、乳糖、蔗糖、明膠、麥芽、稻米、麵粉、白堊、矽膠、硬脂酸鈉、單硬脂酸甘油酯、滑石、氯化鈉、脫脂奶粉、甘油、丙烯、乙二醇、聚乙二醇300、水、乙醇、聚山梨醇酯20及其類似者。必要時，本發明組合物亦可含有少量濕潤劑或乳化劑，或pH緩衝劑。
錠劑及膠囊調配物可進一步含有一或多種佐劑、黏合劑、稀釋劑、崩解劑、賦形劑、填充劑或潤滑劑，其各自為此項技術中已知的。此類實例包括碳水化合物(諸如乳糖或蔗糖)、無水磷酸氫鈣、玉米澱粉、甘露糖醇、木糖醇、纖維素或其衍生物、微晶纖維素、明膠、硬脂酸鹽、二氧化矽、滑石、乙醇酸澱粉鈉、阿拉伯膠、調味劑、防腐劑、緩衝劑、崩解劑及著色劑。經口投與之組合物可含有一或多種視情況存在的藥劑，例如甜味劑，諸如果糖、阿斯巴甜糖(aspartame)或糖精；調味劑，諸如胡椒薄荷、冬青油或櫻桃；著色劑；及防腐劑，以提供醫藥學上適口的製劑。 化合物及醫藥學上可接受之組合物之用途
本文所述的化合物及組合物通常適用於抑制激酶或其突變體。在一些實施例中，由本文所述之化合物及組合物抑制之激酶為磷脂醯肌醇3-激酶(PI3K)。在一些實施例中，由本文所述之化合物及組合物抑制之激酶為PI3Kα、PI3Kδ及PI3Kγ中之一或多者。。在一些實施例中，由本文所述之化合物及組合物抑制之激酶為PI3Kα。在一些實施例中，由本文所述之化合物及組合物抑制之激酶為含有以下突變中之至少一者之PI3Kα：H1047R、E542K及E545K。
本發明之化合物或組合物可適用於受益於PI3K酶之抑制的應用。舉例而言，本發明之PI3K抑制劑總體上適用於治療細胞增生性疾病。本發明之化合物或組合物可適用於受益於PI3Kα酶之抑制的應用。舉例而言，本發明之PI3Kα抑制劑總體上適用於治療細胞增生性疾病。
通常經由Aid活化提高存活率之PI3K的異常調節為人類癌症中最普遍的現象之一且已顯示以多個層級發生。在肌醇環之3'位置處使磷酸肌醇去磷酸化且因此拮抗PI3K活性之腫瘤抑制基因PTEN在多種腫瘤中功能性缺失。在其他腫瘤中，p110α同功異型物、PIK3CA及Akt之基因經擴增，且已在若干人類癌症中證明其基因產物之蛋白質表現增加。此外，已在人類癌症中描述用以上調p85-p110複合物之p85α的突變及易位。最後，已在多種人類癌症中以顯著頻率描述活化下游信號傳導路徑之PIK3CA中的體細胞誤義突變(Kang等人, Proc. Natl. Acad. Sci. USA 102:802 (2005)；Samuels等人, Science 304:554 (2004)；Samuels等人, Cancer Cell 7:561-573 (2005))。此等觀測結果顯示，磷酸肌醇-3激酶及此信號傳導路徑之上游及下游組分的失調為與人類癌症及增生性疾病相關之最常見失調之一(Parsons等人, Nature 436:792 (2005)；Hennessey等人, Nature Rev. Drug Disc. 4:988-1004 (2005))。
本發明中所用之化合物作為PI3K激酶(例如PI3Kα)或其突變體之抑制劑的活性可在活體外、活體內或細胞株中進行分析。活體外分析包括測定磷酸化活性及/或後續功能性結果或活化PI3Kα或其突變體之ATP酶活性之抑制的分析。替代的活體外分析對抑制劑結合至PI3Kα之能力進行定量。可藉由在結合之前對抑制劑進行放射性標記、分離抑制劑/PI3Kα複合物及測定放射性標記結合量來量測抑制劑結合。或者，可藉由運作競爭實驗來測定抑制劑結合，其中將新抑制劑與結合至已知放射性配位體之PI3Kα一起培育。適用於分析PI3Kα抑制劑之代表性活體外及活體內分析包括本文所述之專利及科學出版物中所描述及揭示之彼等分析。用於分析在本發明中用作PI3Kα或其突變體之抑制劑之化合物的詳細條件闡述於以下實例中。病症治療
所提供之化合物為PI3Kα抑制劑且因此適用於治療一或多種與PI3Kα或其突變體之活性相關的病症。因此，在某些實施例中，本發明提供一種治療個體之PI3Kα介導之病症的方法，其包含向有需要之個體投與治療有效量之本發明化合物或其醫藥學上可接受之鹽，或前述任一者的醫藥學上可接受之組合物。在某些實施例中，本發明提供一種治療個體之PI3Kα介導之病症的方法，其包含向有需要之個體投與治療有效量之本發明化合物或其醫藥學上可接受之組合物。在一些實施例中，個體具有突變PI3Kα。在一些實施例中，個體具有含有以下突變中之至少一者的PI3Kα：H1047R、E542K及E545K。
如本文所用，術語「PI3Kα介導之」病症、疾病及/或病狀意謂其中已知PI3Kα或其突變體起作用的任何疾病或其他有害病狀。因此，本發明之另一實施例係關於治療已知PI3Kα或其突變體起作用之一或多種疾病或減輕其嚴重程度。此類PI3Kα介導之病症包括但不限於細胞增生性病症(例如癌症)。在一些實施例中，PI3Kα介導之病症為由突變PI3Kα介導之病症。在一些實施例中，PI3Kα介導之病症為由含有以下突變中之至少一者之PI3Kα介導之病症：H1047R、E542K及E545K。
在一些實施例中，本發明提供一種治療細胞增生性疾病之方法，該方法包含向有需要之患者投與治療有效量之本發明化合物或其醫藥學上可接受之鹽或前述任一者之醫藥學上可接受之組合物。在一些實施例中，本發明提供一種治療細胞增生性疾病之方法，該方法包含向有需要之患者投與治療有效量之本發明化合物或其醫藥學上可接受之組合物。
在一些實施例中，治療方法包含以下步驟：i)鑑別需要此類治療之個體；(ii)提供所揭示化合物或其醫藥學上可接受之鹽；及(iii)投與治療有效量之所提供之該化合物以治療、抑制及/或預防需要此類治療之個體的疾病病況或病狀。在一些實施例中，個體具有突變PI3Kα。在一些實施例中，個體具有含有以下突變中之至少一者的PI3Kα：H1047R、E542K及E545K。
在一些實施例中，治療方法包含以下步驟：i)鑑別需要此類治療之個體；(ii)提供包含所揭示化合物或其醫藥學上可接受之鹽的組合物；及(iii)投與治療有效量之該組合物以治療、抑制及/或預防需要此類治療之個體的疾病病況或病狀。。在一些實施例中，個體具有突變PI3Kα。在一些實施例中，個體具有含有以下突變中之至少一者的PI3Kα：H1047R、E542K及E545K。
本發明之另一態樣提供根據本文中之定義的化合物或其醫藥學上可接受之鹽，或前述任一者之醫藥組合物，其用於治療本文所述之病症。本發明之另一態樣提供根據本文中之定義的化合物或其醫藥學上可接受之鹽或前述任一者之醫藥組合物用於治療本文所述病症的用途。類似地，本發明提供根據本文中之定義的化合物或其醫藥學上可接受之鹽用於製備供治療本文所述病症之藥劑的用途。細胞增生性病症
在一些實施例中，病症為細胞增生性疾病。在一些實施例中，細胞增生性疾病為癌症。在一些實施例中，癌症為腫瘤。在一些實施例中，癌症為實體腫瘤。在一些實施例中，細胞增生性疾病為腫瘤及/或癌細胞生長。在一些實施例中，細胞增生性疾病為腫瘤。在一些實施例中，細胞增生性疾病為實體腫瘤。在一些實施例中，細胞增生性疾病為癌細胞生長。
在一些實施例中，癌症選自肉瘤；肺；支氣管；前列腺；乳房(包括散發性乳癌及考登氏病(Cowden disease)患者)；胰臟；胃腸道；結腸；直腸；癌瘤；結腸癌；腺瘤；結腸直腸腺瘤；甲狀腺；肝；肝內膽管；肝細胞；腎上腺；胃；胃；神經膠質瘤；神經膠母細胞瘤；子宮內膜；黑色素瘤；腎；腎盂；膀胱；子宮體；子宮頸；陰道；卵巢(包括透明細胞卵巢癌)；多發性骨髓瘤；食道；白血病；急性骨髓性白血病；慢性骨髓性白血病；淋巴細胞性白血病；骨髓白血病；腦；腦癌；口腔及咽；喉；小腸；非霍奇金氏淋巴瘤(non-Hodgkin lymphoma)；絨毛狀結腸腺瘤；瘤形成；上皮特徵瘤形成；淋巴瘤；乳癌；基底細胞癌；鱗狀細胞癌；光化性角化症；頸部；頭部；真性紅血球增多症；原發性血小板增多症；骨髓纖維化伴骨髓化生；及瓦爾登斯特倫巨球蛋白血症(Waldenstrom macroglobulinemia)。
在一些實施例中，癌症選自肺；支氣管；前列腺；乳房(包括散發性乳癌及考登氏病)；胰臟；胃腸道；結腸；直腸；甲狀腺；肝；肝內膽管；肝細胞；腎上腺；胃；胃；子宮內膜；腎；腎盂；膀胱；子宮體；子宮頸；陰道；卵巢(包括透明細胞卵巢癌)；食道；白血病；急性骨髓性白血病；慢性骨髓性白血病；淋巴細胞性白血病；骨髓白血病；腦；口腔及咽；喉；小腸；頸部；及頭部。在一些實施例中，癌症選自肉瘤；癌瘤；結腸癌；腺瘤；結腸直腸腺瘤；神經膠質瘤；神經膠母細胞瘤；黑色素瘤；多發性骨髓瘤；腦癌；非霍奇金氏淋巴瘤；絨毛狀結腸腺瘤；瘤形成；上皮特徵瘤形成；淋巴瘤；乳癌；基底細胞癌；鱗狀細胞癌；光化性角化症；真性紅血球增多症；原發性血小板增多症；骨髓纖維化伴骨髓化生；及瓦爾登斯特倫巨球蛋白血症。
在一些實施例中，癌症選自肺；支氣管；前列腺；乳房(包括散發性乳癌及考登氏病)；胰臟；胃腸道；結腸；直腸；甲狀腺；肝；肝內膽管；肝細胞；腎上腺；胃；胃；子宮內膜；腎臟；腎盂；膀胱；子宮體；子宮頸；陰道；卵巢(包括透明細胞卵巢癌)；食道；腦；口腔及咽；喉；小腸；頸部；及頭部。在一些具體實例中，癌症為白血病。在一些實施例中，癌症為急性骨髓性白血病；慢性骨髓性白血病；淋巴細胞性白血病；或骨髓白血病。
在一些實施例中，癌症為乳癌(包括散發性乳癌及考登氏病)。在一些實施例中，癌症為乳癌。在一些實施例中，癌症為ER+/HER2-乳癌。在一些實施例中，癌症為ER+/HER2-乳癌，且該個體不耐受或不適於用阿普昔布(alpelisib)治療。在一些實施例中，癌症為散發性乳癌。在一些實施例中，癌症為考登氏病。
在一些實施例中，癌症為卵巢癌。在一些實施例中，卵巢癌為透明細胞卵巢癌。
在一些實施例中，細胞增生性疾病具有突變PI3Kα。在一些實施例中，癌症具有突變PI3Kα。在一些實施例中，乳癌具有突變PI3Kα。在一些實施例中，卵巢癌具有突變PI3Kα。在一些實施例中，透明細胞卵巢癌具有突變PI3Kα。
在一些實施例中，細胞增生性疾病具有含有以下突變中之至少一者的PI3Kα：H1047R、E542K及E545K。在一些實施例中，癌症具有含有以下突變中之至少一者的PI3Kα：H1047R、E542K及E545K。在一些實施例中，乳癌具有含有以下突變中之至少一者的PI3Kα：H1047R、E542K及E545K。在一些實施例中，卵巢癌具有含有以下突變中之至少一者的PI3Kα：H1047R、E542K及E545K。在一些實施例中，透明細胞卵巢癌具有含有以下突變中之至少一者的PI3Kα：H1047R、E542K及E545K。
在一些實施例中，癌症為腺瘤；癌瘤；肉瘤；神經膠質瘤；神經膠母細胞瘤；黑色素瘤；多發性骨髓瘤；或淋巴瘤。在一些實施例中，癌症為結腸直腸腺瘤或絨毛狀結腸腺瘤。在一些實施例中，癌症為結腸癌；腦癌；乳癌；基底細胞癌；或鱗狀細胞癌。。在一些實施例中，癌症為瘤形成或上皮特徵瘤形成。在一些實施例中，癌症為非霍奇金氏淋巴瘤。在一些實施例中，癌症為光化性角化症；真性紅血球增多症；原發性血小板增多症；骨髓纖維化伴骨髓化生；或瓦爾登斯特倫巨球蛋白血症。
在一些實施例中，細胞增生性疾病顯示PI3Kα之過度表現或擴增、PIK3CA之體細胞突變、PTEN之生殖系突變或體細胞突變，或用以上調p85-p110複合物之p85α之突變及易位。在一些實施例中，細胞增生性疾病顯示PI3Kα之過度表現或擴增。在一些實施例中，細胞增生性疾病顯示PIK3CA之體細胞突變。在一些實施例中，細胞增生性疾病顯示PTEN之生殖系突變或體細胞突變。在一些實施例中，細胞增生性疾病顯示用以上調p85-p110複合物之p85α之突變及易位。額外病症
在一些實施例中，PI3Kα介導之病症選自由以下組成之群：真性紅血球增多症、原發性血小板增多症、骨髓纖維化伴骨髓化生、哮喘、COPD、ARDS、PROS (PI3K相關過度生長症候群)、靜脈畸形、呂氏症候群(Loffler's syndrome)、嗜酸性球性肺炎、寄生蟲(詳言之後生動物)感染(包括熱帶嗜酸性球增多症)、支氣管肺麯黴病、結節性多動脈炎(包括查格-施特勞斯症候群(Churg-Strauss syndrome))、嗜酸性球性肉芽腫、由藥物反應引起之影響氣管之嗜酸性球相關病症、牛皮癬、接觸性皮膚炎、異位性皮膚炎、斑禿、多形性紅斑、疱疹樣皮炎、硬皮病、白斑病、過敏性脈管炎、蕁麻疹、大皰性類天疱瘡、紅斑性狼瘡、天疱瘡、後天大皰性表皮鬆懈、自體免疫血液病症(例如溶血性貧血、再生不全性貧血、純紅血球貧血及特發性血小板減少症)、全身性紅斑性狼瘡症、多軟骨炎、韋格納肉芽腫病(Wegener granulomatosis)、皮肌炎、慢性活動性肝炎、重症肌無力、史蒂芬-約翰遜症候群(Steven-Johnson syndrome)、特發性口炎性腹瀉、自體免疫發炎性腸病(例如潰瘍性結腸炎及克羅恩氏病(Crohn's disease))、內分泌眼病變、葛瑞夫茲氏病(Graves' disease)、類肉瘤病、肺泡炎、慢性過敏性肺炎、多發性硬化症、原發性膽汁性肝硬化、葡萄膜炎(前部及後部)、肺間質纖維化、牛皮癬性關節炎、腎小球腎炎、心血管疾病、動脈粥樣硬化、高血壓、深靜脈血栓形成、中風、心肌梗塞、不穩定絞痛、血栓栓塞、肺栓塞、溶栓性疾病、急性動脈缺血、周邊血栓性閉塞、及冠狀動脈疾病、再灌注損傷、視網膜病變(諸如糖尿病性視網膜病變或高壓氧誘導之視網膜病變)及由眼內壓升高或眼房水分泌表徵之病狀，諸如青光眼。
在一些實施例中，PI3Kα介導之病症為真性紅血球增多症、原發性血小板增多症或骨髓纖維化伴骨髓化生。在一些實施例中，PI3Kα介導之病症為哮喘、COPD、ARDS、PROS (PI3K相關過度生長症候群)、靜脈畸形、呂氏症候群、嗜酸性球性肺炎、寄生蟲(詳言之後生動物)感染(包括熱帶嗜酸性球增多症)或支氣管肺麯黴病。在一些實施例中，PI3Kα介導之病症為結節性多動脈炎(包括查格-施特勞斯症候群)、嗜酸性球性肉芽腫、由藥物反應引起之影響氣管之嗜酸性球相關病症、牛皮癬、接觸性皮膚炎、異位性皮膚炎、斑禿、多形性紅斑、疱疹樣皮炎或硬皮病。在一些實施例中，PI3Kα介導之病症為白斑病、過敏性脈管炎、蕁麻疹、大皰性類天疱瘡、紅斑性狼瘡、天疱瘡、後天大皰性表皮鬆懈或自體免疫血液病症(例如溶血性貧血、再生不全性貧血、純紅血球貧血及特發性血小板減少症)。在一些實施例中，PI3Kα介導之病症為全身性紅斑性狼瘡症、多軟骨炎、硬皮病、韋格納肉芽腫病、皮肌炎、慢性活動性肝炎、重症肌無力、史蒂芬-約翰遜症候群、特發性口炎性腹瀉或自體免疫發炎性腸病(例如潰瘍性結腸炎及克羅恩氏病)。
在一些實施例中，PI3Kα介導之病症為內分泌眼病變、葛瑞夫茲氏病、類肉瘤病、肺泡炎、慢性過敏性肺炎、多發性硬化症、原發性膽汁性肝硬化、葡萄膜炎(前部及後部)、肺間質纖維化或牛皮癬性關節炎。在一些實施例中，PI3Kα介導之病症為腎小球腎炎、心血管疾病、動脈粥樣硬化、高血壓、深靜脈血栓形成、中風、心肌梗塞、不穩定絞痛、血栓栓塞、肺栓塞、溶栓性疾病、急性動脈缺血、周邊血栓性閉塞及冠狀動脈疾病，或再灌注損傷。在一些實施例中，PI3Kα介導之病症為視網膜病變，諸如糖尿病性視網膜病變或高壓氧誘導之視網膜病變，及由眼內壓升高或眼房水分泌表徵之病狀，諸如青光眼。投藥途徑及劑型
根據本發明之方法，化合物及組合物可使用有效治療病症(例如增生性病症)或減輕其嚴重程度的任何量及任何投藥途徑投與。所需精確量將隨各個體而變化，視個體之物種、年齡及一般狀況、感染之嚴重度、特定藥劑其投藥模式及其類似因素而定。本發明之化合物較佳調配成容易投藥及均一給藥的單位劑型。如本文所用，表述「單位劑型」係指適於待治療患者之藥劑的實體不連續單元。然而，應瞭解，本發明之化合物及組合物之每日總用量將由主治醫師在合理醫學判斷範疇內決定。用於任何特定患者或生物之特定有效劑量水準將視多種因素而定，該等因素包括待治療病症及病症嚴重強度；所用特定化合物之活性；所用特定組合物；患者之年齡、體重、一般健康、性別及膳食；投與時間、投與途徑及所用特定化合物之排泄比率；治療持續時間；與所用特定化合物組合或同時使用之藥物；及如醫學技術中熟知之因素。
本發明之醫藥學上可接受之組合物可經口、直腸、非經腸、腦池內、陰道內、腹膜內、體表(如藉由散劑、軟膏或滴劑)、經頰、作為口服或鼻用噴霧或其類似方式投與人類及其他動物。在某些實施例中，本發明化合物可按以下劑量水準經口或非經腸投與以獲得所要治療效應：每天、每天一或多次每公斤個體體重約0.01 mg至約50 mg，且較佳約1 mg至約25 mg。
用於經口投與之液體劑型包含(但不限於)醫藥學上可接受之乳液、微乳液、溶液、懸浮液、糖漿及酏劑。除活性化合物之外，液體劑型可含有此項技術中常用之惰性稀釋劑，諸如水或其他溶劑；增溶劑及乳化劑，諸如乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、二甲基甲醯胺、油(尤其棉籽油、花生油、玉米油、胚芽油、橄欖油、蓖麻油及芝麻油)、甘油、四氫糠醇、聚乙二醇及脫水山梨糖醇之脂肪酸酯；及其混合物。除惰性稀釋劑之外，經口組合物亦可包括佐劑，諸如濕潤劑、乳化劑及懸浮劑、甜味劑、調味劑及芳香劑。
可根據已知技術使用適合之分散劑或潤濕劑及懸浮劑調配可注射製劑，例如無菌可注射水性或油性懸浮液。無菌可注射製劑亦可為無毒非經腸可接受之稀釋劑或溶劑中之無菌可注射溶液、懸浮液或乳液，例如呈1,3-丁二醇中之溶液形式。在可接受之媒劑及溶劑中，可使用的有水、林格氏溶液(Ringer's solution)、U.S.P.及等張氯化鈉溶液。另外，無菌不揮發性油習用作溶劑或懸浮介質。出於此目的，可採用任何溫和的不揮發性油，包括合成單甘油酯或二甘油酯。另外，諸如油酸之脂肪酸用於製備可注射劑。
可注射調配物可例如藉由經由細菌截留過濾器過濾或藉由併入殺菌劑來滅菌，呈可在使用前溶解或分散於無菌水或其他無菌可注射介質中之無菌固體組合物形式。
為延長本發明化合物之效果，通常需要減緩來自皮下或肌肉內注射之化合物之吸收。此可藉由使用具有不良水溶性之結晶或非晶形材料之液體懸浮液來達成。則化合物之吸收率視其溶解率而定，溶解率又可視晶體尺寸及結晶形態而定。或者，藉由將化合物溶解或懸浮於油媒劑中來實現非經腸投與之化合物之延遲吸收。藉由在諸如聚丙交酯-聚乙交酯之生物可降解聚合物中形成化合物之微膠囊基質來製造可注射積存形式。視化合物與聚合物之比率及所使用之特定聚合物的性質而定，可控制化合物釋放速率。其他可生物降解之聚合物的實例包括聚(原酸酯)及聚(酸酐)。亦藉由將化合物覆埋於與身體組織相容之脂質體或微乳液中來製備儲槽式可注射調配物。
用於經直腸或經陰道投與之組合物較佳為可藉由將本發明化合物與適合的非刺激賦形劑或載劑(諸如可可脂、聚乙二醇)混合而製備之栓劑；或在環境溫度下為固體但在體溫下為液體且因此在直腸或陰道腔中熔融且釋放活性化合物的栓劑蠟。
用於經口投與之固體劑型包括膠囊劑、錠劑、丸劑、散劑及粒劑。在此類固體劑型中，活性化合物可與至少一種惰性、醫藥學上可接受之賦形劑或載劑，諸如檸檬酸鈉或磷酸二鈣，及/或a)填充劑或擴充劑，諸如澱粉、乳糖、蔗糖、葡萄糖、甘露醇及矽酸，b)黏合劑，諸如羧甲基纖維素、海藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖及阿拉伯膠，c)保濕劑，諸如甘油，d)崩解劑，諸如瓊脂-瓊脂，碳酸鈣、馬鈴薯或木薯澱粉、褐藻酸、某些矽酸鹽及碳酸鈉，e)阻溶劑，諸如石蠟，f)吸收促進劑，諸如第四銨化合物，g)濕潤劑，諸如十六醇及單硬脂酸甘油酯，h)吸收劑，諸如高嶺土及膨潤土，及i)潤滑劑，諸如滑石、硬脂酸鈣、硬脂酸鎂、固態聚乙二醇、月桂基硫酸鈉及其混合物混合。在膠囊、錠劑及丸劑之情況下，該劑型亦可包含緩衝劑。
類似類型之固體組合物亦可用作使用諸如乳糖(lactose或milk sugar)以及高分子量聚乙二醇及其類似物之賦形劑之軟填充及硬填充明膠膠囊中的填充劑。錠劑、糖衣藥丸、膠囊、丸劑及粒劑之固體劑型可製備有包衣及外殼，諸如腸溶包衣及醫藥調配技術中熟知之其他包衣。其可視情況含有乳濁劑，且亦可具有僅在或優先在腸道之某一部分中釋放或視情況以延遲方式釋放活性成分之組合物。可使用之包埋組成物之實例包括聚合物質及蠟。類似類型之固體組合物亦可用作使用如乳糖以及高分子量聚乙二醇及其類似物之賦形劑之軟及硬填充明膠膠囊中之填充劑。
活性化合物亦可與一或多種如上文所指出之賦形劑一起以微囊封形式存在。錠劑、糖衣藥丸、膠囊、丸劑及粒劑之固體劑型可製備有包衣及殼層，諸如腸溶衣、釋放控制包衣及醫藥調配技術中熟知之其他包衣。在此類固體劑型中，活性化合物可與至少一種惰性稀釋劑(諸如蔗糖、乳糖或澱粉)混雜。如正常實務，此類劑型亦可包含除惰性稀釋劑之外的額外物質，例如製錠潤滑劑及其他製錠助劑，諸如硬脂酸鎂及微晶纖維素。在膠囊、錠劑及丸劑之情況下，劑型亦可包含緩衝劑。其可視情況含有乳濁劑，且亦可具有僅在或優先在腸道之某一部分中釋放或視情況以延遲方式釋放活性成分之組合物。可使用之包埋組成物之實例包括聚合物質及蠟。
用於局部或經皮投與本發明化合物之劑型包括軟膏、糊劑、乳膏、洗劑、凝膠、散劑、溶液、噴霧劑、吸入劑或貼片。活性組分係在無菌條件下與醫藥學上可接受之載劑及如可為所需之任何所需防腐劑或緩衝劑摻合。眼用調配物、滴耳劑和滴眼劑也涵蓋於本發明的範圍內。另外，本發明涵蓋使用經皮貼片，其具有向身體提供控制遞送化合物之附加優點。此類劑型可藉由在適當介質中溶解或分配化合物來製備。亦可使用吸收強化劑來增加化合物之透皮量。可藉由提供速率控制膜或藉由將化合物分散於聚合物基質或凝膠中來控制速率。給藥的量及療法
根據本發明之方法，向個體投與治療有效量之本發明之化合物，例如以減少或改善個體之病症之症狀。此量容易藉由熟習此項技術者基於已知程序判定，該等程序包括活體內確立之滴定曲線的分析以及本文所揭示的方法及分析。
在一些實施例中，方法包含投與治療有效劑量的本發明化合物。在一些實施例中，治療有效劑量為每公斤體重至少約0.0001 mg、每公斤體重至少約0.001 mg、每公斤體重至少約0.01 mg、每公斤體重至少約0.05 mg、每公斤體重至少約0.1 mg、每公斤體重至少約0.25 mg、每公斤體重至少約0.3 mg、每公斤體重至少約0.5 mg、每公斤體重至少約0.75 mg、每公斤體重至少約1 mg、每公斤體重至少約2 mg、每公斤體重至少約3 mg、每公斤體重至少約4 mg、每公斤體重至少約5 mg、每公斤體重至少約6 mg、每公斤體重至少約7 mg、每公斤體重至少約8 mg、每公斤體重至少約9 mg、每公斤體重至少約10 mg、每公斤體重至少約15 mg、每公斤體重至少約20 mg、每公斤體重至少約25 mg、每公斤體重至少約30 mg、每公斤體重至少約40 mg、每公斤體重至少約50 mg、每公斤體重至少約75 mg、每公斤體重至少約100 mg、每公斤體重至少約200 mg、每公斤體重至少約250 mg、每公斤體重至少約300 mg、每公斤體重至少約350 mg、每公斤體重至少約400 mg、每公斤體重至少約450 mg、每公斤體重至少約500 mg、每公斤體重至少約550 mg、每公斤體重至少約600 mg、每公斤體重至少約650 mg、每公斤體重至少約700 mg、每公斤體重至少約750 mg、每公斤體重至少約800 mg、每公斤體重至少約900 mg，或每公斤體重至少約1000 mg。應認識到，本文所列劑量中之任一者可構成上限或下限劑量範圍，且可與任何其他劑量組合以構成包含上限及下限之劑量範圍。
在一些實施例中，治療有效劑量的範圍為每公斤體重約0.1 mg至約10 mg、每公斤體重約0.1 mg至約6 mg、每公斤體重約0.1 mg至約4 mg或每公斤體重約0.1 mg至約2 mg之範圍內。
在一些實施例中，治療有效劑量的範圍為約1至500 mg、約2至150 mg、約2至120 mg、約2至80 mg、約2至40 mg、約5至150 mg、約5至120 mg、約5至80 mg、約10至150 mg、約10至120 mg、約10至80 mg、約10至40 mg、約20至150 mg、約20至120 mg、約20至80 mg、約20至40 mg、約40至150 mg、約40至120 mg或約40至80 mg。
在一些實施例中，方法包含單次給藥或投藥(例如單次注射或沈積)。或者，在一些實施例中，方法包含每日一次、每日兩次、每日三次或每日四次投與有需要之個體，歷時約2至約28天，或約7至約10天，或約7至約15天，或更久。在一些實施例中，方法包含長期投藥。在又其他實施例中，方法包含在數週、數月、數年或數十年之期間內投藥。在另其他實施例中，方法包含在數週之期間內投藥。在另其他實施例中，方法包含在數月之期間內投藥。在另其他實施例中，方法包含在數年之期間內投藥。在又其他實施例中，方法包含在數十年之期間內投藥。
投藥劑量可視已知因素而變化，諸如活性成分之藥效學特徵以及其投藥模式及途徑；活性成分之投與時間；接受者之年齡、性別、健康狀況及體重；症狀之性質及程度；並行治療之種類、治療頻率及所需效果；以及排出速率。此等因素皆容易確定且熟習此項技術者可利用此等因素來調整或滴定劑量及/或給藥方案。蛋白激酶的抑制
根據一個實施例，本發明係關於抑制生物樣品中之蛋白質激酶活性之方法，其包含使該生物樣品與本發明化合物或包含該化合物之組合物接觸的步驟。根據另一實施例，本發明係關於抑制PI3K或其突變體於生物樣品中之活性的方法，該方法包含使生物樣品與本發明化合物或包含該化合物之組合物接觸的步驟。根據另一實施例，本發明係關於抑制PI3Kα或其突變體於生物樣品中之活性的方法，該方法包含使生物樣品與本發明化合物或包含該化合物之組合物接觸的步驟。在一些實施例中，PI3Kα為突變PI3Kα。在一些實施例中，PI3Kα含有以下突變中之至少一者：H1047R、E542K及E545K。
在另一實施例中，本發明提供相比於PI3Kδ及PI3Kγ中之一或兩者，選擇性抑制PI3Kα之方法。在一些實施例中，本發明化合物相比於PI3Kδ及PI3Kγ具有大於5倍之選擇性。在一些實施例中，本發明化合物相比於PI3Kδ及PI3Kγ具有大於10倍之選擇性。在一些實施例中，本發明化合物相比於PI3Kδ及PI3Kγ具有大於50倍之選擇性。在一些實施例中，本發明化合物相比於PI3Kδ及PI3Kγ具有大於100倍之選擇性。在一些實施例中，本發明化合物相比於PI3Kδ及PI3Kγ具有大於200倍之選擇性。在一些實施例中，PI3Kα為突變PI3Kα。在一些實施例中，PI3Kα含有以下突變中之至少一者：H1047R、E542K及E545K。
在另一實施例中，本發明提供相比於野生型PI3Kα，選擇性抑制突變PI3Kα之方法。在一些實施例中，相比於野生型PI3Kα，本發明化合物對突變PI3Kα具有大於5倍之選擇性。在一些實施例中，相比於野生型PI3Kα，本發明化合物對突變PI3Kα具有大於10倍之選擇性。在一些實施例中，相比於野生型PI3Kα，本發明化合物對突變PI3Kα具有大於50倍之選擇性。在一些實施例中，相比於野生型PI3Kα，本發明化合物對突變PI3Kα具有大於100倍之選擇性。在一些實施例中，相比於野生型PI3Kα，本發明化合物對突變PI3Kα具有大於200倍之選擇性。在一些實施例中，突變PI3Kα含有以下突變中之至少一者：H1047R、E542K及E545K。
如本文所用之術語「生物樣品」包括但不限於細胞培養物或其提取物；由哺乳動物所獲得之活組織檢查材料或其提取物；及血液、唾液、尿液、糞便、精液、眼淚或其他體液或其提取物。
抑制PI3K (例如PI3Kα，或其突變體)於生物樣品中之活性適用於熟習此項技術者已知之多種目的。此類目的之實例包括但不限於輸血、器官移植、生物標本儲存及生物分析。
本發明之另一實施例係關於一種抑制患者中之蛋白激酶活性的方法，其包含向該患者投與本發明化合物或包含該化合物之組合物的步驟。
根據另一實施例，本發明係關於抑制PI3K或其突變體於患者中之活性的方法，該方法包含向該患者投與本發明化合物或包含該化合物之組合物的步驟。。在一些實施例中，本發明係關於抑制PI3Kα或其突變體於患者中之活性的方法，該方法包含向該患者投與本發明化合物或包含該化合物之組合物的步驟。。在一些實施例中，PI3Kα為突變PI3Kα。在一些實施例中，PI3Kα含有以下突變中之至少一者：H1047R、E542K及E545K。
根據另一實施例，本發明提供一種治療有需要之患者的由PI3K或其突變體介導之病症的方法，該方法包含向該患者投與根據本發明之化合物或其醫藥學上可接受之組合物的步驟。在一些實施例中，本發明提供治療有需要之患者的由PI3Kα或其突變體介導之病症之方法，該方法包含向該患者投與根據本發明之化合物或其醫藥學上可接受之組合物的步驟。在一些實施例中，PI3Kα為突變PI3Kα。在一些實施例中，PI3Kα含有以下突變中之至少一者：H1047R、E542K及E545K。
根據另一實施例，本發明提供一種抑制PI3Kα或其突變體於個體中之信號傳導活性的方法，該方法包含向有需要之個體投與治療有效量之根據本發明之化合物或其醫藥學上可接受之組合物。在一些實施例中，本發明提供一種抑制個體中之PI3Kα信號傳導活性的方法，該方法包含向有需要之個體投與治療有效量之根據本發明之化合物或其醫藥學上可接受之組合物。在一些實施例中，PI3Kα為突變PI3Kα。在一些實施例中，PI3Kα含有以下突變中之至少一者：H1047R、E542K及E545K。在一些實施例中，個體具有突變PI3Kα。在一些實施例中，個體具有含有以下突變中之至少一者的PI3Kα：H1047R、E542K及E545K。
本文所述之化合物亦可經由併入至催化PI3Kα破壞之藥劑中來抑制PI3Kα功能。舉例而言，可將化合物併入靶向蛋白水解的嵌合體(PROTAC)中。PROTAC為雙官能分子，其中一個部分能夠接合E3泛蛋白連接酶且另一部分能夠結合意欲藉由細胞蛋白品質控制機制進行降解的目標蛋白。目標蛋白募集至特定E3連接酶使得其經標記用於毀壞(亦即，泛素化)且隨後藉由蛋白酶體降解。可使用任何E3連接酶。PROTAC中之與E3接合酶接合的部分經由連接子連接至PROTAC中之與目標蛋白接合的部分，該連接子由可變原子鏈組成。PI3Kα募集至E3連接酶因此將導致PI3Kα蛋白質破壞。可變原子鏈可包括例如環、雜原子及/或重複聚合物單元。其可為剛性或撓性的。其可使用有機合成技術中之標準技術連接至上述兩個部分。 組合療法
視待治療之特定病症、病狀或疾病而定，可將通常為了治療該病狀而投與的其他治療劑與本發明之化合物及組合物組合投與。如本文所用，通常經投與以治療特定疾病或病狀之額外治療劑係稱為「適於所治療之疾病或病狀」。
另外，PI3K充當整合平行信號傳導路徑之第二信使節點，且有證據表明PI3K抑制劑與其他路徑之抑制劑之組合將適用於治療癌症及細胞增生性疾病。
因此，在某些實施例中，治療方法包含將本發明的化合物或組合物與一或多種其他治療劑組合投與。在某些其他實施例中，治療方法包含將本發明的化合物或組合物作為單獨的治療劑投與。
大致20%-30%之人類乳癌過度表現Her-2/neu-ErbB2，其為藥物曲妥珠單抗之靶標。儘管曲妥珠單抗已在一些表現Her2/neu-ErbB2之患者中證實持久反應，但此等患者中僅一部分有反應。近來的研究已指示此有限反應率可藉由曲妥珠單抗與PI3K或PI13K/AKT路徑抑制劑之組合顯著改良(Chan等人, Breast Can. Res. Treat. 91:187 (2005)，Woods Ignatoski等人, Brit. J. Cancer 82:666 (2000)，Nagata等人, Cancer Cell 6:117 (2004))。因此，在某些實施例中，治療方法包含投與本發明之化合物或組合物與曲妥珠單抗之組合。在某些實施例中，該癌症為過度表現Her-2/neu-ErbB2之人類乳癌。
多種人類惡性腫瘤表現活化突變或Her1/EGFR含量增加，且已針對此受體酪胺酸激酶開發出多種抗體及小分子抑制劑，包括得舒(tarceva)、吉非替尼(gefitinib)及艾必妥(erbitux)。然而，儘管EGFR抑制劑在某些人類腫瘤(例如NSCLC)中展示抗腫瘤活性，但其未能在所有患有表現EGFR之腫瘤的患者中增加總體患者存活率。此可藉由Her1/EGFR之許多下游靶標在包括PI3K/Akt路徑之多種惡性腫瘤中以高頻率突變或失調之事實來合理化。
舉例而言，吉非替尼抑制活體外分析中腺癌細胞株之生長。然而，可選擇對吉非替尼具有耐藥性之此等細胞株之亞純系，其表明PI3/Akt路徑之活化增加。此路徑之下調或抑制使得耐藥性亞純系對吉非替尼敏感(Kokubo等人, Brit. J. Cancer 92:1711 (2005))。此外，在具有攜帶PTEN突變且過度表現PI3K/Akt路徑及EGFR兩者之EGFR抑制之細胞株的乳癌之活體外模型中產生協同作用(She等人, Cancer Cell 8:287-297 (2005))。此等結果表明吉非替尼與PI3K/Akt路徑抑制劑之組合將為癌症中有吸引力的治療策略。
因此，在某些實施例中，治療方法包含投與本發明之化合物或組合物與Her1/eGFR抑制劑之組合。在某些實施例中，治療方法包含投與本發明之化合物或組合物與得舒、吉非替尼及艾必妥中之一或多者之組合。在某些實施例中，治療方法包含投與本發明之化合物或組合物與吉非替尼之組合。在某些實施例中，癌症表現活化突變或Her1/EGFR含量增加。
AEE778 (Her-2/neu/ErbB2、VEGFR及EGFR之抑制劑)及RAD001 (mTOR之抑制劑，Akt之下游靶標)之組合在神經膠母細胞瘤異種移植模型中產生比任一單獨藥劑更大的組合功效(Goudar等人, Mol. Cancer. Ther. 4:101-112 (2005))。
抗雌激素(諸如他莫昔芬)經由誘導需要細胞週期抑制劑p27Kip之作用的細胞週期停滯來抑制乳癌生長。最近，已展示Ras-Raf-MAP激酶路徑之活化改變p27Kip之磷酸化狀態，使得其遏制細胞週期之抑制活性減弱，藉此導致抗雌激素耐受性(Donovan等人, J. Biol. Chem. 276:40888, (2001))。如由Donovan等人報導，經由用MEK抑制劑治療來抑制MAPK信號傳遞，逆轉激素難治性乳癌細胞株中p27之磷酸化狀態且因此恢復激素敏感性。類似地，p27Kip經Aid之磷酸化亦消除其遏制細胞週期之作用(Viglietto等人, Nat. Med. 8:1145 (2002))。
因此，在某些實施例中，治療方法包含投與本發明之化合物或組合物與激素依賴性癌症治療之組合。在某些實施例中，治療方法包含投與本發明之化合物或組合物與他莫昔芬之組合。在某些實施例中，癌症為激素依賴性癌症，諸如乳癌及前列腺癌。藉由此用途，旨在藉由習知抗癌劑逆轉此等癌症中通常可見之激素耐受性。
在血液癌，諸如慢性骨髓性白血病(CML)中，染色體易位造成組成性活化之BCR-Abl酪胺酸激酶。罹病患者由於Abl激酶活性之抑制而對小分子酪胺酸激酶抑制劑伊馬替尼有反應。然而，許多晚期疾病患者最初對伊馬替尼有反應，但隨後由於Abl激酶域中賦予耐藥性之突變而稍後復發。活體外研究已證明BCR-Ab1採用Ras-Raf激酶路徑引發其作用。另外，抑制一種以上之相同路徑激酶提供針對賦予耐藥性之突變的額外保護。
因此，在另一態樣中，本發明之化合物及組合物與至少一種選自激酶抑制劑之群的額外藥劑(諸如伊馬替尼)組合用於治療血液癌，諸如慢性骨髓性白血病(CML)。藉由此用途，旨在逆轉或防止對該至少一種額外藥劑之耐藥性。
由於PI3K/Akt路徑之活化驅動細胞存活，因此與驅動癌細胞凋亡之療法(包括放射線療法及化學療法)組合之路徑抑制將引起反應改良(Ghobrial等人, CA Cancer J. Clin 55:178-194 (2005))。舉例而言，PI3激酶抑制劑與卡鉑之組合在活體外增殖及凋亡分析以及卵巢癌異種移植模型中之活體內腫瘤功效方面展現協同效應(Westfall及Skinner, Mol. Cancer Ther. 4:1764-1771 (2005))。
在一些實施例中，一或多種其他治療劑係選自抗體、抗體-藥物結合物、激酶抑制劑、免疫調節劑及組蛋白去乙醯酶抑制劑。與PIK3CA抑制劑及其他治療劑之協同組合描述於例如Castel等人, Mol. Cell Oncol. (2014)1(3) e963447中。
在一些實施例中，一或多種額外治療劑選自以下藥劑或其醫藥學上可接受之鹽：BCR-ABL抑制劑(參見例如Ultimo等人 Oncotarget (2017) 8 (14) 23213-23227.)，例如伊馬替尼(imatinib)、伊羅替尼(inilotinib)、尼羅替尼(nilotinib)、達沙替尼(dasatinib)、伯舒替尼(bosutinib)、普納替尼(ponatinib)、巴氟替尼(bafetinib)、達魯舍替(danusertib)、塞卡替尼(saracatinib)、PF03814735；ALK抑制劑(參見例如Yang等人 Tumour Biol. (2014) 35 (10) 9759-67)，例如克卓替尼(crizotinib)、NVP-TAE684、塞利替尼(ceritinib)、阿來替尼(alectinib)、布加替尼(brigatinib)、恩特希尼(entrecinib)、勞拉替尼(lorlatinib)；BRAF抑制劑(參見例如Silva等人 Mol. Cancer Res. (2014) 12, 447-463)，例如維羅非尼(vemurafenib)、達拉非尼(dabrafenib)；FGFR抑制劑(參見例如Packer等人 Mol. Cancer Ther. (2017) 16(4) 637-648)，例如英非替尼(infigratinib)、多韋替尼(dovitinib)、厄達替尼(erdafitinib)、TAS-120、培米替尼(pemigatinib)、BLU-554、AZD4547；FLT3抑制劑，例如舒尼替尼(sunitinib)、米哚妥林(midostaurin)、塔努替尼(tanutinib)、索拉非尼(sorafenib)、來他替尼(lestaurtinib)、喹雜替尼(quizartinib)及克拉尼布(crenolanib)；MEK抑制劑(參見例如Jokinen等人 Ther. Adv. Med. Oncol. (2015) 7(3) 170-180)，例如曲美替尼(trametinib)、考比替尼(cobimetinib)、畢尼替尼(binimetinib)、司美替尼(selumetinib)；ERK抑制劑，例如優立替尼(ulixertinib)、MK 8353、LY 3214996；KRAS抑制劑，例如AMG-510、MRTX849、ARS-3248；酪胺酸激酶抑制劑(參見例如Makhov等人 Mol. Cancer. Ther. (2012) 11(7) 1510-1517)，例如埃羅替尼(erlotinib)、立尼法尼(linifanib)、舒尼替尼(sunitinib)、帕佐泮尼(pazopanib)；表皮生長因子受體(EGFR)抑制劑(參見例如She等人 BMC Cancer (2016) 16, 587)：吉非替尼(gefitnib)、奧希替尼(osimertinib)、西妥昔單抗(cetuximab)、帕尼單抗(panitumumab)；HER2受體抑制劑(參見例如Lopez等人 Mol. Cancer Ther. (2015) 14(11) 2519-2526)，例如曲妥珠單抗(trastuzumab)、帕妥珠單抗(pertuzumab)、來那替尼(neratinib)、拉帕替尼(lapatinib)、拉帕替尼(lapatinib)；MET抑制劑(參見例如Hervieu等人 Front. Mol. Biosci. (2018) 5, 86)，例如克卓替尼(crizotinib)、卡博替尼(cabozantinib)；CD20抗體，例如利妥昔單抗(rituximab)、托西莫單抗(tositumomab)、奧伐木單抗(ofatumumab)；DNA合成抑制劑，例如卡培他濱(capecitabine)、吉西他濱(gemcitabine)、奈拉濱(nelarabine)、羥基脲；抗腫瘤劑(參見例如Wang等人 Cell Death & Disease (2018) 9, 739)，例如奧沙利鉑(oxaliplatin)、卡鉑(carboplatin)、順鉑(cisplatin)；免疫調節劑，例如阿托珠單抗(afutuzumab)、來那度胺(lenalidomide)、沙立度胺(thalidomide)、泊利度胺(pomalidomide)；CD40抑制劑，例如達西珠單抗(dacetuzumab)；促細胞凋亡受體促效劑(PARA)，例如杜拉樂明(dulanermin)；熱休克蛋白(HSP)抑制劑(參見例如Chen等人 Oncotarget (2014) 5 (9), 2372-2389)，例如坦螺旋黴素(tanespimycin)；刺蝟拮抗劑(參見例如Chaturvedi等人 Oncotarget (2018) 9 (24), 16619-16633)，例如維莫德吉(vismodegib)；蛋白酶體抑制劑(參見例如Lin等人 Int. J. Oncol. (2014) 44 (2), 557-562)，例如硼替佐米(bortezomib)；PI3K抑制劑，例如皮克立西(pictilisib)、達托利塞(dactolisib)、阿普昔布(alpelisib)、布帕昔布(buparlisib)、塔瑟昔布(taselisib)、艾德昔布(idelalisib)、德衛利昔(duvelisib)、厄布利塞(umbralisib)；SHP2抑制劑 (參見例如Sun等人 Am. J. Cancer Res. (2019) 9 (1), 149-159，例如SHP099、RMC-4550、RMC-4630)；BCL-2抑制劑(參見例如Bojarczuk等人 Blood (2018) 133 (1), 70-80)，例如維納妥拉(venetoclax)；芳香酶抑制劑(參見例如Mayer等人Clin. Cancer Res. (2019) 25 (10), 2975-2987)：依西美坦(exemestane)、來曲唑(letrozole)、阿那曲唑(anastrozole)、氟維司群(fulvestrant)、他莫昔芬(tamoxifen)；mTOR抑制劑(參見例如Woo等人 Oncogenesis (2017) 6, e385)，例如坦羅莫司(temsirolimus)、地磷莫司(ridaforolimus)、依維莫司(everolimus)、西羅莫司(sirolimus)；CTLA-4抑制劑(參見例如O'Donnell等人 (2018) 48, 91-103)，例如曲美單抗(tremelimumab)、伊匹單抗(ipilimumab)；PD1抑制劑(參見O'Donnell, 前述)，例如納武單抗(nivolumab)、派立珠單抗(pembrolizumab)；免疫黏附素；其他免疫檢查點抑制劑(參見例如Zappasodi等人 Cancer Cell (2018) 33, 581-598，其中術語「免疫檢查點」係指CD4及CD8 T細胞之細胞表面上的一組分子。免疫檢查點分子包括但不限於計劃性死亡1 (PD-1)、細胞毒性T淋巴細胞抗原4 (CTLA-4)、B7H1、B7H4、OX-40、CD 137、CD40及LAG3。可充當適用於本發明之方法之免疫檢查點抑制劑的免疫治療劑包括但不限於PD-L1、PD-L2、CTLA4、TIM3、LAG3、VISTA、BTLA、TIGIT、LAIR1、CD 160、2B4及/或TGFRβ之抑制劑)：例如匹立珠單抗(pidilizumab)、AMP-224；PDL1抑制劑(參見例如O'Donnell，前述)：例如MSB0010718C；YW243.55.S70、MPDL3280A；MEDI-4736、MSB-0010718C或MDX-1105；組蛋白脫乙醯基酶抑制劑(HDI，參見例如Rahmani等人 Clin. Cancer Res. (2014) 20(18), 4849-4860)，例如伏立諾他(vorinostat)；雄激素受體抑制劑(參見例如Thomas等人 Mol. Cancer Ther. (2013) 12(11), 2342-2355)，例如恩雜魯胺(enzalutamide)、乙酸阿比特龍(abiraterone acetate)、奧特羅那(orteronel)、加利特隆(galeterone)、司維特奈(seviteronel)、比卡魯胺(bicalutamide)、氟他胺(flutamide)；雄激素，例如氟甲睾酮(fluoxymesterone)；CDK4/6抑制劑(參見例如Gul等人 Am. J. Cancer Res. (2018) 8(12), 2359-2376)，例如阿伏西地(alvocidib)、帕柏西利(palbociclib)、利波西利(ribociclib)、曲拉西利(trilaciclib)、阿貝西利(abemaciclib)。
在一些實施例中，一或多種額外治療劑選自以下藥劑：抗FGFR抗體；FGFR抑制劑、細胞毒性劑；雌激素受體靶向或其他內分泌療法、免疫檢查點抑制劑、CDK抑制劑、受體酪胺酸激酶抑制劑、BRAF抑制劑、MEK抑制劑、其他PI3K抑制劑、SHP2抑制劑及SRC抑制劑。(參見Katoh, Nat. Rev. Clin. Oncol. (2019), 16:105-122；Chae等人 Oncotarget (2017), 8:16052-16074；Formisano等人, Nat. Comm. (2019), 10:1373-1386；及其中所引用之參考文獻)。
以編碼序號、類屬或商標名識別之活性化合物之結構可自正版標準概要「默克索引(The Merck Index)」或自資料庫，例如專利國際(Patents International)(例如IMS世界公開案(IMS World Publications))獲得。
本發明化合物亦可與已知治療方法(例如投與激素或輻射)組合使用。在某些實施例中，所提供化合物用作放射增敏劑，尤其用於治療對於放射線療法展現不佳敏感性之腫瘤。
本發明化合物可單獨或與一或多種其他治療化合物組合投與，可能的組合療法採用的形式為本發明化合物及一或多種其他治療化合物的固定組合或交錯或彼此獨立的投與，或固定組合與一或多種其他治療化合物的組合投與。此外或另外，本發明化合物可與化學療法、放射療法、免疫療法、光療法、手術介入或其組合進行組合，尤其用於腫瘤療法。如上文所描述，與其他治療策略之情形下的輔助療法相同，長期療法亦為可能的。其他可能的治療為在腫瘤消退後維持患者狀態之療法，或甚至為化學預防療法(例如對處於風險下之患者)。
彼等額外藥劑可與含本發明化合物之組合物分開投與，作為多次給藥方案之一部分。或者，彼等藥劑可為單一劑型之一部分，與本發明化合物一起混合成單一組合物。若作為多次給藥方案的一部分投與，則兩種活性劑可同時、依次或彼此間隔一定時段(通常彼此間隔在5小時以內)提供。
如本文所使用，術語「組合(combination/combined)」及相關術語係指同時或依次投與根據本發明之治療劑。舉例而言，本發明化合物可與另一治療劑以單獨的單位劑型或共同呈單一單位劑型同時或依次投與。因此，本發明提供一種包含本發明化合物、額外治療劑及醫藥學上可接受之載劑、佐劑或媒劑之單一單位劑型。
可與載劑物質組合產生單一劑型之本發明化合物及額外治療劑(在包含如上文所描述之額外治療劑之彼等組合物中)的量將視所治療之宿主及特定投與模式而變化。優選地，應調配本發明組合物以使得可投與0.01-100毫克/公斤體重/天之間的劑量的本發明化合物。
在包含額外治療劑之彼等組合物中，該額外治療劑及本發明化合物可協同作用。因此，此類組合物中額外治療劑之量將小於僅利用該治療劑之單一療法中所需之量。在此類組合物中，可投與劑量介於0.01-1,000微克/公斤體重/天之間的額外治療劑。
存在於本發明組合物中之額外治療劑的量將不超過通常將以包含該治療劑作為唯一活性劑之組合物形式投與的量。目前所揭示之組合物中額外治療劑之量較佳將在占通常存在於包含該藥劑作為唯一治療活性劑之組合物中之量約50%至100%的範圍內。
本發明化合物或其醫藥組合物亦可併入用於包覆可植入醫療裝置的組合物中，該等可植入醫療裝置諸如假體、人工瓣膜、血管移植物、支架及導管。血管內支架例如已用於克服再狹窄(損傷後的血管壁再狹窄)。然而，使用支架或其他可植入裝置之患者具有凝塊形成或血小板活化之風險。可藉由用包含激酶抑制劑之醫藥學上可接受之組合物預包覆該裝置來預防或減輕此等非所需作用。用本發明化合物包覆之可植入裝置為本發明之另一實施例。
本發明之化合物及/或組合物中之任一者可提供於包含該等化合物及/或組合物之套組中。因此，在一些實施例中，本發明之化合物及/或組合物提供於套組中。
藉由以下非限制性實例進一步描述本發明。 實例
本文提供實例以促進對本發明之更透徹理解。以下實例用於說明製備及實施本發明之標的的例示性方式。然而，本發明之範疇不應理解為限於此等實例中所揭示之特定實施例，該等實例僅具說明性。
如在以下實例中所描繪，在某些例示性實施例中，根據以下通用程序來製備化合物。應瞭解，儘管通用方法描繪本發明之某些化合物之合成，但以下通用方法及一般熟習此項技術者已知之其他方法可應用於如本文所述之此等化合物中之每一者的其他類別及子類及種類。本發明之其他化合物係藉由與本文在實例中所述之方法基本上類似的方法及熟習此項技術者已知之方法製備。
在下述合成方法之描述中，除非另有說明，否則應瞭解，所有反應條件(例如反應溶劑、氛圍、溫度、持續時間及處理程序)選自標準反應條件，除非另外指明。實例之起始材料可為市售的或易於藉由標準方法自已知材料製備。縮寫清單 aq：水溶液 Ac：乙醯基 ACN或MeCN：乙腈 AmF：甲酸銨 anhyd.：無水 BINAP：(±)-2,2'-雙(二苯膦基)-1,1'-聯二萘 Bn：苯甲基 conc.：濃 DBU：1,8-二氮雜雙環[5.4.0]十一碳-7-烯 DCE：二氯乙烷 DCM：二氯甲烷 DIPEA：二異丙胺 DMF：N,N-二甲基甲醯胺 DMP：戴斯-馬丁高碘烷 DMPU：N,N'-二甲基丙烯脲 DMSO：二甲基甲醯胺 DIPEA：二異丙基乙胺 EA或EtOAc：乙酸乙酯 EDCI、EDC或EDAC：1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺 equiv或eq：莫耳當量 Et：乙基 HATU：1-[雙(二甲胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]吡錠3-氧化物六氟磷酸鹽 HPLC：高壓液相層析 LCMS或LC-MS：液相層析-質譜 Ms：甲烷磺醯基 NBS：N-溴丁二醯亞胺 NMR：核磁共振 PE：石油醚 PMB：對甲氧基苯甲基 rt或RT：室溫 sat：飽和 TBS：三級丁基二甲基矽烷基 TEA：三乙胺 Tf：三氟甲烷磺酸酯 TFA：三氟乙酸 THF：四氫呋喃 TLC：薄層層析 Tol：甲苯 UV：紫外線LC-MS 方法概述 LCMS 方法 1 儀器 LC：      Waters Acquity UPLC UV偵測：    Waters Acquity PDA (198-360nm)，20 pts/s，220及254nm MS偵測：    Waters SQD，ESI (ES+/ES-, 120-1200 amu) 移動相 溶離劑A1： Milli-Q H2 O + 10mM甲酸銨pH: 3.8 (AmF) 溶離劑B1：  ACN 管柱 Waters Acquity UPLC CSH C18，1.8µm，2.1×30mm，在40℃下 梯度 5%至100% B於2.0分鐘內；保持100% B 0.7分鐘 流量 0.9 mL/min 運行時間 2.7分鐘LCMS 方法 2 儀器 LC：      Waters Acquity UPLC UV偵測：    Waters Acquity PDA (198-360nm)，20 pts/s，220及254nm MS偵測：    Waters SQD，ESI (ES+/ES-, 120-1200 amu) 移動相 溶離劑A1： Milli-Q H2 O + 10mM甲酸銨pH: 3.8 (AmF) 溶離劑B1：  ACN 管柱 Waters Acquity UPLC CSH C18，1.8µm，2.1×30mm，在40℃下 梯度 5%至100% B於5.2分鐘內；保持100% B 1.2分鐘 流量 0.9 mL/min 運行時間 7分鐘實例 1 N -(1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [b ] 噻吩 -3- 甲醯胺 (I-1)
Figure 02_image5714
2-(4- 甲氧基苯甲基 )-4- 硝基異吲哚啉 -1,3- 二酮
Figure 02_image5716
步驟 1 ：在25℃下向4-硝基異苯并呋喃-1,3-二酮(40.0 g，207 mmol, 1.00當量)於HOAc (500 mL)中之混合物中添加PMBNH2 (36.9 g，269 mmol，34.9 mL，1.30當量)，接著加熱至85℃且在85℃下攪拌10小時。將兩批混合物倒入水(1.00 L)中，接著過濾且用石油醚(200 mL)洗滌濾餅，在真空中乾燥，得到呈淡黃色固體狀之2-(4-甲氧基苯甲基)-4-硝基異吲哚啉-1,3-二酮(120 g，383 mmol，92.6%產率，100%純度)。MS:m/z = 334.9 [M+Na]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (d,J = 8.0 Hz, 1H), 8.17 (d,J = 7.2 Hz, 1H), 8.05 (t,J = 8.0 Hz, 1H), 7.27 (d,J = 8.4 Hz, 2H), 6.88 (d,J = 8.4 Hz, 2H), 4.70 (s, 2H), 3.72 (s, 3H)。4- 胺基 -2-(4- 甲氧基苯甲基 ) 異吲哚啉 -1,3- 二酮
Figure 02_image5718
步驟 2 ：在25℃下向2-(4-甲氧基苯甲基)-4-硝基異吲哚啉-1,3-二酮(48.8 g，156 mmol，1.00當量)於EtOH (700 mL)/H2 O (200 mL)中之溶液中添加NH4 Cl (33.4 g，625 mmol，4.00當量)。將混合物加熱至40℃且在40℃下將Fe (26.2 g，469 mmol，3.00當量)添加至混合物中。隨後將混合物加熱至80℃且在80℃下攪拌1小時。過濾兩批混合物，且用乙酸乙酯(5×800 mL)洗滌濾餅。在真空中濃縮濾液，得到殘餘物。向殘餘物中添加水(400 mL)且用乙酸乙酯(3×800 mL)萃取。合併之有機層用鹽水(800 mL)洗滌，經Na2 SO4 乾燥且過濾。濃縮濾液，得到呈黃色固體狀之4-胺基-2-(4-甲氧基苯甲基)異吲哚啉-1,3-二酮(85.5 g，298 mmol，95.5%產率，98.5%純度)。MS:m/z = 283.1 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 7.43 (t,J = 6.0 Hz, 1H), 7.22 (d,J = 8.4Hz, 2H), 6.99-6.96 (m, 2H), 6.87 (d,J = 8.4 Hz, 2H), 6.46 (s, 2H), 4.61 (s, 2H), 3.71 (s, 3H)。4- 胺基 -3- 羥基 -2-(4- 甲氧基苯甲基 )-3-( 鄰甲苯基 ) 異吲哚啉 -1- 酮
Figure 02_image5720
步驟 3 ：在0℃下向4-胺基-2-(4-甲氧基苯甲基)異吲哚啉-1,3-二酮(50.0 g，174 mmol，1.00當量)於DCM (1.50 L)中之溶液中逐滴添加鄰甲苯基溴化鎂(1.00 M於Et2 O中，436 mL，2.50當量)，接著升溫至20℃且在20℃下攪拌1小時。將混合物倒入NH4 Cl飽和水溶液(1.50 L)中且用乙酸乙酯(3×800 mL)萃取。合併之有機層用鹽水(800 mL)洗滌，經Na2 SO4 乾燥且過濾。濃縮濾液，得到呈黃色固體狀之4-胺基-3-羥基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(72.4 g，粗物質)。MS:m/z = 357.4 [M-OH]+ 。4- 胺基 -2-(4- 甲氧基苯甲基 )-3-( 鄰甲苯基 ) 異吲哚啉 -1- 酮
Figure 02_image5722
步驟 4 ：在25℃下向4-胺基-3-羥基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(67.4 g，180 mmol，1.00當量)於DCM (680 mL)中之溶液中添加TFA (205 g，1.80 mol，133 mL，10.0當量)。將混合物冷卻至0℃，隨後在0℃下添加三乙基矽烷(41.9 g，360 mmol，57.5 mL，2.00當量)。使混合物升溫至25℃且在25℃下攪拌1小時。在真空中濃縮混合物，得到殘餘物。向殘餘物中添加水(500 mL)，藉由添加氨將pH調節至8，且用DCM (3×500 mL)萃取混合物。合併之有機層用鹽水(500 mL)洗滌，經Na2 SO4 乾燥且過濾。濃縮濾液，得到粗產物。粗產物藉由管柱層析(SiO2 ，石油醚/乙酸乙酯=1:0至0:1)純化，得到呈黃色固體狀之4-胺基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(30.0 g，81.7 mmol，45.4%產率，97.6%純度)。MS:m/z = 359.1 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 7.56-7.55 (m, 1H), 7.28-7.24 (m, 6H), 7.10-7.00 (m, 8H), 6.99-6.74 (m, 6H), 6.48 (d,J = 7.6 Hz, 1H), 5.52 (s, 1H), 5.39 (s, 1H), 5.00-4.94 (m, 2H), 4.56 (s, 2H), 4.43 (s, 2H), 3.72 (s, 6H), 3.57 (d,J = 14.8 Hz, 1H), 3.48 (d,J = 15.2 Hz, 1H), 2.26 (s, 3H), 1.50 (s, 2H)。 N -{2-[(4- 甲氧基苯基 ) 甲基 ]-3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 }-1- 苯丙噻吩 -3- 甲醯胺
Figure 02_image5724
步驟 5 ：在室溫下向4-胺基-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-2,3-二氫-1H-異吲哚-1-酮(50 mg，0.14 mmol)於DCM (2.0 mL)中之溶液中添加吡啶(56 μL, 0.70 mmol，5當量)、1-苯丙噻吩-3-甲醯氯(27 mg，0.14 mmol，1當量)，且在室溫下攪拌混合物1.5小時。藉由旋轉蒸發濃縮溶液。所得粗混合物藉由製備型HPLC (40-80% ACN/水)純化，得到呈白色固體狀之所需產物(45 mg，63%產率)。MS:m/z = 519.3 [M+H]+ 。 N -[3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H- 異吲哚 -4- 基 ]-1- 苯丙噻吩 -3- 甲醯胺 (I-1)
Figure 02_image5726
步驟 6 ：將N -{2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基}-1-苯丙噻吩-3-甲醯胺(40 mg，0.077 mmol)溶解於TFA (2.0 mL)中。在微波反應器中，在100℃下攪拌溶液45分鐘。藉由旋轉蒸發濃縮溶液。所得粗混合物藉由製備型HPLC (30-70% ACN/水)純化，得到呈白色固體狀之所需產物(18 mg，60%產率)。MS:m/z = 399.2 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 10.09 (s, 1H), 9.02 (s, 1H), 7.94-8.07 (m, 2H), 7.52-7.72 (m, 4H), 7.32-7.46 (m, 2H), 7.04-7.15 (m, 1H), 6.91-7.00 (m, 2H), 6.62 (br s, 1H), 6.02 (s, 1H), 2.07-2.30 (m, 3H)。實例 2 N -(1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 雙環 [2.2.2] 辛烷 -1- 甲醯胺 (I-179)
Figure 02_image5728
N -(2-(4- 甲氧基苯甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 雙環 [2.2.2] 辛烷 -1- 甲醯胺
Figure 02_image5730
步驟 1 ：在氮氣下向配備有磁性攪拌棒之火焰乾燥圓底燒瓶中裝入4-胺基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(50.0 mg，139 µmol)於無水吡啶(0.70 mL)中之溶液，且在攪拌下將溶液冷卻至0℃。接著逐滴添加雙環[2.2.2]辛烷-1-甲醯氯(47.9 mg，278 µmol)於DCM (1.30 mL)中之溶液，且將反應混合物升溫至環境溫度且攪拌16小時。隨後將反應混合物分配於NaHCO3 飽和水溶液(10 mL)與DCM (10 mL)之間，且使混合物穿過相分離器。隨後在真空中濃縮有機相，得到粗產物。藉由C18逆相層析純化(用含55-80% ACN之10 mmol AmF水溶液溶離)，得到呈非晶形橙色固體狀之N -(2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)雙環[2.2.2]辛烷-1-甲醯胺(43 mg，86.4 µmol，62%產率)。LC-MS (方法1):  1.60 min,m/z = 495.4 [M+H]+ 。 N -(1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 雙環 [2.2.2] 辛烷 -1- 甲醯胺 (I-179)
Figure 02_image5732
步驟 2 ：將N -(2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)雙環[2.2.2]辛烷-1-甲醯胺(40.0 mg，80.8 µmol)於TFA (0.54 mL)中之溶液在90℃下在密封管中攪拌加熱18小時。接著將反應混合物冷卻至環境溫度且在真空中濃縮。殘餘物藉由C18逆相急驟層析直接純化(用含40-65% ACN之10 mmol AmF水溶液溶離)，得到呈非晶形橙色固體狀之N -(1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)雙環[2.2.2]辛烷-1-甲醯胺(21.0 mg，56.0 µmol，70%產率)。LC-MS (方法2):  2.45 min,m/z = 375.3 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 8.97 (s, 1H), 8.75 (s, 1H), 7.57-7.54 (m, 1H), 7.53-7.49 (m, 1H), 7.45 (dd,J = 7.5, 1.4 Hz, 1H), 7.18 (d,J = 4.0 Hz, 2H), 7.06-6.98 (m, 1H), 6.47 (br. s, 1H), 5.94 (s, 1H), 2.32 (br. s, 3H), 1.50-1.45 (m, 1H), 1.42-1.33 (m, 6H), 1.32-1.21 (m, 6H)。實例 3 N -(1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 )-[1,2,4] 三唑并 [4,3-a ] 吡啶 -3- 甲醯胺 (I-328)
Figure 02_image5734
[1,2,4] 三唑并 [4,3-a ] 吡啶 -3- 甲醯氯
Figure 02_image5736
步驟 1 ：在0℃下將亞硫醯氯(20.0 µL，275 µmol)逐滴添加至[1,2,4]三唑并[4,3-a ]吡啶-3-甲酸(34.0 mg，208 µmol)及DIPEA (0.15 mL，858 µmol)於DCM (0.83 mL)中之攪拌溶液中。在此溫度下攪拌反應混合物15分鐘，隨後升溫至環境溫度且再攪拌1.5小時。隨後在真空中移除揮發物，且將粗[1,2,4]三唑并[4,3-a ]吡啶-3-甲醯氯直接用於下一步驟，假定定量產率。 N -(2-(4- 甲氧基苯甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 )-[1,2,4] 三唑并 [4,3-a ] 吡啶 -3- 甲醯胺
Figure 02_image5738
步驟 2 ： 在氮氣下向配備有磁性攪拌棒之火焰乾燥圓底燒瓶中裝入4-胺基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(50 mg，139 µmol)於無水吡啶(0.70 mL)中之溶液，且在攪拌下將溶液冷卻至0℃。隨後逐滴添加[1,2,4]三唑并[4,3-a ]吡啶-3-甲醯氯(37.7 mg，208 µmol)於DCM (1.30 mL)中之溶液。將反應混合物升溫至環境溫度且攪拌16小時。隨後將反應混合物分配於NaHCO3 飽和水溶液(10 mL)與DCM (10 mL)之間，且使混合物穿過相分離器。隨後在真空中濃縮有機相，得到粗產物。藉由C18逆相層析純化(用含37-57% ACN之10 mmol AmF水溶液溶離)，獲得呈非晶形黃色固體狀之N -(2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)-[1,2,4]三唑并[4,3-a ]吡啶-3-甲醯胺(39 mg，58.0 µmol，56%產率)。LC-MS (方法1):  1.20 min,m/z = 504.3 [M+H]+ 。 N -(1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 )-[1,2,4] 三唑并 [4,3-a ] 吡啶 -3- 甲醯胺 (I-328)
Figure 02_image5740
步驟 3 ：將N -(2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)-[1,2,4]三唑并[4,3-a ]吡啶-3-甲醯胺(39.0 mg，58.0 µmol)於TFA (0.55 mL)中之溶液在90℃下在密封管中攪拌加熱42小時。接著將反應混合物冷卻至環境溫度且在真空中濃縮。殘餘物藉由C18逆相急驟層析直接純化(用含18-38% ACN之10 mmol AmF水溶液溶離)，得到呈非晶形白色固體狀之N -(1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)-[1,2,4]三唑并[4,3-a ]吡啶-3-甲醯胺(16.7 mg，43.5 µmol，75%產率)。
LC-MS (方法2):  1.51 min,m/z = 384.3 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 10.61 (br. s, 1H), 9.07 (dt,J = 7.0, 1.1 Hz, 1H), 9.05 (s, 1H), 7.98 (dt,J = 9.3, 1.1 Hz, 1H), 7.69 (dd,J = 2.7, 1.2 Hz, 1H), 7.67 (dd,J = 3.0, 1.2 Hz, 1H), 7.64-7.58 (m, 2H), 7.24 (td,J = 6.9, 1.1 Hz, 1H), 6.93-6.86 (m, 2H), 6.82 (br. s, 1H), 6.66 (br. s, 1H), 6.09 (s, 1H), 2.19 (br. s, 3H)。基於在8.42 ppm處存在單峰，化合物似乎已分離為部分甲酸鹽。實例 4 7- 氯 -N -[3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ] 咪唑并 [1,5-a ] 吡啶 -1- 甲醯胺 (I-258)
Figure 02_image5742
2-(4- 氯吡啶 -2- 基 )-2-( 羥亞胺基 ) 乙酸甲酯
Figure 02_image5744
步驟 1 ：在環境溫度下將亞硝酸鈉(242 mg，3.51 mmol)於水(1.10 mL)中之溶液逐滴添加至2-(4-氯吡啶-2-基)乙酸甲酯(652 mg，3.51 mmol)於乙酸(4.30 mL)中之攪拌溶液中，且將反應混合物在環境溫度下攪拌4小時。接著在真空中移除揮發物，且將殘餘物懸浮於水(25 mL)中。藉由添加固體K2 CO3 將pH調節至7至8，且將所得懸浮液傾入分液漏斗中且萃取至EtOAc (3×10 mL)中。合併之有機相用飽和NaCl溶液洗滌，乾燥(無水MgSO4 )，過濾且真空濃縮，得到定量產率之黃綠色膠狀之2-(4-氯吡啶-2-基)-2-(羥亞胺基)乙酸甲酯(762 mg，3.55 mmol)，呈幾何異構體之3:1混合物形式。粗產物未經進一步純化即直接用於下一步驟中。LC-MS (方法1):  0.68 min (次要異構體), 0.80 min (主要異構體),m/z = 215.1 [M+H]+ ；次要異構體1 H NMR (400 MHz, CDCl3 ) δ 8.53 (d,J = 5.5 Hz, 1H), 7.87 (d,J = 1.8 Hz, 1H), 7.34 (dd,J = 5.4, 2.0 Hz, 1H), 3.99 (s, 3H)；主要異構體1 H NMR (400 MHz, CDCl3 ) δ 8.49-8.46 (m, 1H), 8.24 (dd,J = 2.0, 0.5 Hz, 1H), 7.53 (dd,J = 5.5, 2.0 Hz, 1H), 3.96 (s, 3H)。2- 胺基 -2-(4- 氯吡啶 -2- 基 ) 乙酸甲酯
Figure 02_image5746
步驟 2 ：在環境溫度下向2-(4-氯吡啶-2-基)-2-(羥亞胺基)乙酸甲酯(762 mg，3.55 mmol)於乙酸(18.0 mL)中之劇烈攪拌溶液中一次性添加鋅粉(1.15 g，17.7 mmol)。在環境溫度下攪拌反應混合物2.5小時。隨後在真空中移除揮發物，且將殘餘物分配於EtOAc (20 mL)與飽和NaHCO3 水溶液(25 mL)之間。將兩相上清液傾析至分液漏斗中，且分離各相。用EtOAc (2×20 mL)萃取水相。合併之有機物用飽和NaCl溶液洗滌，乾燥(無水MgSO4 )，過濾且在真空中濃縮，得到粗2-胺基-2-(4-氯吡啶-2-基)乙酸甲酯，其不經進一步純化即立即用於下一步驟，假定定量產率。7- 氯咪唑并 [1,5-a ] 吡啶 -1- 甲酸甲酯
Figure 02_image5748
步驟 3 ：向配備有磁性攪拌棒之微波小瓶中裝入2-胺基-2-(4-氯吡啶-2-基)乙酸甲酯(712 mg，3.55 mmol)及原甲酸三乙酯(0.88 mL，5.29 mmol)之混合物。密封小瓶，且將反應混合物在150℃下在微波反應器中照射10分鐘，隨後冷卻至環境溫度。真空濃縮反應混合物，且殘餘物藉由C18逆相急驟層析純化(用含18-38% ACN之10 mmol AmF水溶液溶離)，得到呈非晶形米色固體狀之7-氯咪唑并[1,5-a ]吡啶-1-甲酸甲酯(17 mg，80.7 µmol，2.3%產率)。LC-MS (方法1):  0.75 min,m/z = 211.0 [M+H]+ 。7- 氯咪唑并 [1,5-a ] 吡啶 -1- 甲酸
Figure 02_image5750
步驟 4 ：將2M NaOH水溶液(0.05 mL，0.10 mmol)一次性添加至7-氯咪唑并[1,5-a ]吡啶-1-甲酸甲酯(17.0 mg，80.7 µmol)於甲醇(0.12 mL)及水(0.12 mL)中之攪拌懸浮液中，且將混合物在環境溫度下攪拌20小時。隨後在真空中濃縮反應混合物以移除揮發物，且用水(10 mL)稀釋殘餘物。將混合物用濃HCl酸化至pH 2-3，且用CHCl3 :IPA之4:1混合物(3×10 mL)萃取。合併之有機相用NaCl飽和水溶液洗滌，乾燥(無水MgSO4 )，過濾且在真空中濃縮，得到呈淡黃色固體狀之粗7-氯咪唑并[1,5-a ]吡啶-1-甲酸(13.0 mg，66.1 µmol，82%產率)。粗酸不經進一步純化即直接用於下一步驟中。LC-MS (方法1):  0.55 min,m/z = 415.2 [2M+Na]+ 。7- 氯咪唑并 [1,5-a ] 吡啶 -1- 甲醯氯
Figure 02_image5752
步驟 5 ：在0℃下將亞硫醯氯(10.0 µL，137 µmol)逐滴添加至7-氯咪唑并[1,5-a ]吡啶-1-甲酸(13.0 mg，66.1 µmol)及DIPEA (40.0 µL，230 µmol)於DCM (0.27 mL)中之攪拌溶液中。在此溫度下攪拌反應混合物15分鐘，隨後升溫至環境溫度且再攪拌1.5小時。隨後在真空中移除揮發物，且將粗7-氯咪唑并[1,5-a ]吡啶-1-甲醯氯直接用於下一步驟，假定定量產率。7- 氯 -N -(2-(4- 甲氧基苯甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 咪唑并 [1,5-a ] 吡啶 -1- 甲醯胺
Figure 02_image5754
步驟 6 ：在氮氣下向配備有磁性攪拌棒之火焰乾燥圓底燒瓶中裝入4-胺基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(28.4 mg，79.3 µmol)於無水吡啶(0.33 mL)中之溶液，且在攪拌下將溶液冷卻至0℃。接著逐滴添加7-氯咪唑并[1,5-a ]吡啶-1-甲醯氯(14.2 mg，66.1 µmol)於DCM (0.80 mL)中之溶液，且將反應混合物升溫至環境溫度且攪拌16小時。隨後將反應混合物分配於NaHCO3 飽和水溶液(10 mL)與DCM (10 mL)之間，且使混合物穿過相分離器。隨後在真空中濃縮有機相，得到粗產物。藉由C18逆相急驟層析純化(用含50-75% ACN之10 mmol AmF水溶液溶離)，得到呈非晶形橙棕色固體狀之7-氯-N -(2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)咪唑并[1,5-a ]吡啶-1-甲醯胺(8.0 mg，14.8 µmol，23%產率)。LC-MS (方法1):  1.46 min,m/z = 537.3 [M+H]+ 。 7- 氯 -N -[3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ] 咪唑并 [1,5-a ] 吡啶 -1- 甲醯胺 (I-258)
Figure 02_image5756
步驟 7 ：將7-氯-N -(2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)咪唑并[1,5-a ]吡啶-1-甲醯胺(8.0 mg，14.8 µmol)於TFA (0.10 mL)中之溶液在90℃下在密封管中攪拌加熱18小時。接著將反應混合物冷卻至環境溫度且在真空中濃縮。殘餘物藉由C18逆相急驟層析直接純化(用含35-55% ACN之10 mmol AmF水溶液溶離)，得到呈非晶形灰白色固體狀之7-氯-N -(1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)咪唑并[1,5-a ]吡啶-1-甲醯胺(5.0 mg，11.9 µmol，81%產率)。LC-MS (方法2):  2.17 min,m/z = 417.2 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 9.29 (s, 1H), 9.02 (s, 1H), 8.52 (dd,J = 7.4, 0.8 Hz, 1H), 8.42 (s, 1H), 8.03-7.98 (m, 2H), 7.56 (d,J = 1.7 Hz, 1H), 7.55 (s, 1H), 7.09-7.02 (m, 2H), 7.01-6.94 (m, 2H), 6.69 (br. s, 1H), 6.15 (s, 1H), 2.35 (br. s, 3H)。實例 5 7- 氯 -N -(1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 )-3- 甲基咪唑并 [1,5-a ] 吡啶 -1- 甲醯胺 (I-277)
Figure 02_image5758
N -((4- 氯吡啶 -2- 基 ) 甲基 ) 乙醯胺
Figure 02_image5760
步驟 1 ：在0℃下將乙醯氯(0.43 mL，6.05 mmol)逐滴添加至(4-氯吡啶-2-基)甲胺(684 mg，4.79 mmol)及吡啶(0.78 mL，9.64 mmol)之攪拌溶液中。在0℃下攪拌反應混合物15分鐘，隨後升溫至環境溫度且攪拌2小時。隨後在真空中濃縮反應混合物且粗N -((4-氯吡啶-2-基)甲基)乙醯胺不經進一步純化即直接用於下一步驟，假定定量產率。LC-MS (方法1):  0.47 min,m/z = 185.0 [M+H]+ 。1-(7- 氯 -3- 甲基咪唑并 [1,5-a ] 吡啶 -1- 基 )-2,2,2- 三氟乙酮
Figure 02_image5762
步驟 2 ：將粗N -((4-氯吡啶-2-基)甲基)乙醯胺(884 mg，4.78 mmol)溶解於DCM (16.0 mL)中，添加吡啶(1.20 mL，14.7 mmol)，且在攪拌下將所得溶液冷卻至-5℃。隨後緩慢逐滴添加三氟乙酸酐(1.50 mL，10.7 mmol)。使反應混合物在攪拌下經3小時緩慢升溫至環境溫度。隨後用NaHCO3 飽和水溶液(20 mL)淬滅反應物，且用DCM (3×20 mL)萃取混合物。合併之有機物用NaCl飽和水溶液洗滌，乾燥(無水MgSO4 )，過濾且在真空中濃縮。藉由C18逆相急驟層析純化(用含30-55% ACN之10 mmol AmF水溶液溶離)，得到呈黃色固體狀之1-(7-氯-3-甲基咪唑并[1,5-a ]吡啶-1-基)-2,2,2-三氟乙酮(1.02 g，3.89 mmol，82%產率經兩個步驟)。1 H NMR (400 MHz, CDCl3 ) δ 8.41 (dd,J = 2.0, 0.9 Hz, 1H), 7.91 (dd,J = 7.3, 0.8 Hz, 1H), 7.00 (dd,J = 7.3, 2.1 Hz, 1H), 2.74 (s, 3H)。7- 氯 -3- 甲基咪唑并 [1,5-a ] 吡啶 -1- 甲酸
Figure 02_image5764
步驟 3 ：向配備有磁性攪拌棒之微波小瓶中裝入1-(7-氯-3-甲基咪唑并[1,5-a ]吡啶-1-基)-2,2,2-三氟乙酮(400 mg，1.52 mmol)於2M NaOH水溶液(4.50 mL，9.00 mmol)中之懸浮液。小瓶經密封且在微波反應器中在110℃下照射10分鐘。使反應混合物冷卻至環境溫度，用水(30 mL)稀釋且用EtOAc (2×10 mL)萃取。隨後用濃HCl將水相酸化至pH 2-3，在此期間沈澱物析出。沈澱物藉由真空過濾收集，用水洗滌，且藉由抽吸乾燥，得到呈非晶形米色固體狀之7-氯-3-甲基咪唑并[1,5-a ]吡啶-1-甲酸(260 mg，1.23 mmol，81%產率)。LC-MS (方法1):  0.58 min,m/z = 211.1 [M+H]+ 。7- 氯 -3- 甲基咪唑并 [1,5-a ] 吡啶 -1- 甲醯氯
Figure 02_image5766
步驟 4 ：在0℃下將亞硫醯氯(20.0 µL，275 µmol)逐滴添加至7-氯-3-甲基咪唑并[1,5-a ]吡啶-1-甲酸(44.0 mg，0.21 mmol)及DIPEA (0.15 mL，0.86 mmol)於DCM (1.10 mL)中之攪拌溶液中。在此溫度下攪拌反應混合物15分鐘，隨後升溫至環境溫度且再攪拌1.5小時。隨後在真空中移除揮發物，且將粗7-氯-3-甲基咪唑并[1,5-a ]吡啶-1-甲醯氯直接用於下一步驟，假定定量產率。7- 氯 -N -(2-(4- 甲氧基苯甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 )-3- 甲基咪唑并 [1,5-a ] 吡啶 -1- 甲醯胺
Figure 02_image5768
步驟 5 ：在氮氣下向配備有磁性攪拌棒之火焰乾燥圓底燒瓶中裝入4-胺基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(50.0 mg，139 µmol)於無水吡啶(0.70 mL)中之溶液，且在攪拌下將溶液冷卻至0℃。接著逐滴添加7-氯-3-甲基咪唑并[1,5-a ]吡啶-1-甲醯氯(47.6 mg，208 µmol)於DCM (1.40 mL)中之溶液，且將反應混合物升溫至環境溫度且攪拌16小時。隨後將反應混合物分配於NaHCO3 飽和水溶液(10 mL)與DCM (10 mL)之間，且使混合物穿過相分離器。隨後在真空中濃縮有機相，得到粗產物。藉由C18逆相急驟層析純化(用含55-75% ACN之10 mmol AmF水溶液溶離)，得到呈非晶形橙棕色固體狀之7-氯-N -(2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)-3-甲基咪唑并[1,5-a ]吡啶-1-甲醯胺(62 mg，0.11 mmol，79%產率)。LC-MS (方法1):  1.54 min,m/z = 551.3 [M+H]+ 。7- 氯 -N -(1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 )-3- 甲基咪唑并 [1,5-a ] 吡啶 -1- 甲醯胺 (I-277)
Figure 02_image5770
步驟 6 ：將7-氯-N -(2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)-3-甲基咪唑并[1,5-a ]吡啶-1-甲醯胺(62 mg，109 µmol)於TFA (0.73 mL)中之溶液在90℃下在密封管中攪拌加熱18小時。接著將反應混合物冷卻至環境溫度且在真空中濃縮。殘餘物藉由C18逆相急驟層析直接純化(用含36-56% ACN之10 mmol AmF水溶液溶離)，得到呈非晶形灰白色固體狀之7-氯-N -(1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)咪唑并[1,5-a ]吡啶-1-甲醯胺(6.0 mg，13.9 µmol，13%產率)。LC-MS (方法2):  2.17 min,m/z = 417.2 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 9.05 (s, 1H), 9.04 (s, 1H), 8.33 (dd,J = 7.6, 0.5 Hz, 1H), 8.17 (dd,J = 7.4, 1.3 Hz, 1H), 7.98 (dd,J = 2.1, 0.7 Hz, 1H), 7.59-7.50 (m, 2H), 7.17 (br. d,J = 7.4 Hz, 1H), 7.14-7.08 (m, 1H), 7.03 (br. t,J = 7.2 Hz, 1H), 6.97 (dd,J = 7.5, 2.1 Hz, 1H), 6.72 (br. s, 1H), 6.12 (s, 1H), 2.61 (s, 3H), 2.45 (br. s, 3H)。2.45 ppm處之寬單峰與DMSO-d 5 峰重疊。
根據實例1-5之方法製備之額外化合物列於下表2中。此等化合物之對應1 H NMR及質譜表徵描述於表1中。下表2中之某些化合物係藉由用其他化合物置換如實例1-5中所述之4-胺基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮製備，該等其他化合物之製備進一步描述於以下實例中。表 2. 額外例示性化合物
化合物 化合物 化合物
I-2    I-61    I-216
I-4    I-62    I-279
I-5    I-67    I-292
I-11    I-69    I-316
I-16    I-74    I-317
I-19    I-78    I-318
I-20    I-79    I-340
I-21    I-81    I-341
I-25    I-86    I-369
I-26    I-97    I-376
I-30    I-98    I-377
I-36    I-105    I-378
I-37    I-107    I-387
I-38    I-109    I-388
I-42    I-111    I-612
I-46    I-112    I-638
I-47    I-124    I-693
I-48    I-144    I-752
I-54    I-198    I-850
I-58    I-203    I-1610
I-59    I-206    I-1617
實例 6 6,8- 二氟 -N -(1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 咪唑并 [1,5-a] 吡啶 -3- 甲醯胺 (I-180)
Figure 02_image5772
2-(((3,5- 二氟吡啶 -2- 基 ) 甲基 ) 胺基 )-2- 側氧基乙酸乙酯
Figure 02_image5774
步驟 1 ：向配備有磁性攪拌棒之火焰乾燥圓底燒瓶中裝入(3,5-二氟吡啶-2-基)甲胺(500 mg，3.46 mmol)及三乙胺(0.97 mL，6.95 mmol)於DCM (7.00 mL)中之溶液，且在攪拌下將混合物冷卻至0℃。緩慢逐滴添加氯側氧基乙酸乙酯(0.39 mL，3.49 mmol)，且使反應混合物升溫至環境溫度且攪拌3天。用水(20 mL)淬滅反應物且用DCM (3×20 mL)萃取混合物。合併之有機相用NaCl飽和水溶液洗滌，乾燥(無水MgSO4 )，過濾且在真空中濃縮。藉由矽膠急驟層析純化(用5-80% EtOAc/己烷溶離)，得到呈黃色膠狀之2-(((3,5-二氟吡啶-2-基)甲基)胺基)-2-側氧基乙酸乙酯(452 mg，1.85 mmol，53%產率)。LC-MS (方法1):  0.61 min,m/z = 245.1 [M+H]+ ;1 H NMR (400 MHz, CDCl3 ) δ 8.32 (d, 2.3 Hz, 1H), 8.21 (br. s, 1H), 7.27-7.22 (m, 1H), 4.69 (dt, 5.1, 1.6 Hz, 1H), 4.39 (q, 7.1 Hz, 2H), 1.40 (t, 7.2 Hz, 3H)。6,8- 二氟咪唑并 [1,5-a ] 吡啶 -3- 甲酸乙酯
Figure 02_image5776
步驟 2 ：向配備有磁性攪拌棒及回流冷凝器之圓底燒瓶中裝入2-(((3,5-二氟吡啶-2-基)甲基)胺基)-2-側氧基乙酸乙酯(412 mg，1.68 mmol)於DCE (4.10 mL)中之溶液，隨後在環境溫度下在攪拌下逐滴添加POCl3 (1.50 mL，16.0 mmol)。隨後在攪拌下將反應混合物加熱至120℃後維持18小時，之後冷卻至環境溫度。在真空中移除揮發物，且藉由添加NaHCO3 飽和水溶液(20 mL)小心地淬滅殘餘物。用EtOAc (3×25 mL)萃取混合物，且合併之有機相經乾燥(無水MgSO4 )，過濾且在真空中濃縮。殘餘物藉由矽膠急驟層析純化(用5-20% EtOAc/己烷溶離)，獲得呈極淺黃色固體狀之6,8-二氟咪唑并[1,5-a ]吡啶-3-甲酸乙酯(306 mg，1.35 mmol，80%產率)。LC-MS (方法1):  0.94 min,m/z = 227.7 [M+H]+ 。6,8- 二氟咪唑并 [1,5-a ] 吡啶 -3- 甲酸
Figure 02_image5778
步驟 3 ：將2M NaOH水溶液(0.25 mL，0.50 mmol)一次性添加至6,8-二氟咪唑并[1,5-a ]吡啶-3-甲酸乙酯(100 mg，0.44 mmol)於乙醇(0.67 mL)及水(0.67 mL)中之攪拌溶液中，且將混合物在環境溫度下攪拌18小時。隨後在真空中濃縮反應混合物以移除揮發物，且用水(10 mL)稀釋殘餘物。用濃HCl將混合物酸化至pH 2-3。所得沈澱物藉由真空過濾收集，用水洗滌，且藉由抽吸乾燥，得到呈淡黃色固體狀之6,8-二氟咪唑并[1,5-a ]吡啶-3-甲酸(73 mg，0.37 mmol，83%產率)。LC-MS (方法1):  0.48 min,m/z = 197.1 [M-H]- 。6,8- 二氟咪唑并 [1,5-a ] 吡啶 -3- 甲醯氯
Figure 02_image5780
步驟 4 ：在0℃下將亞硫醯氯(30.0 µL，41.4 µmol)逐滴添加至6,8-二氟咪唑并[1,5-a ]吡啶-3-甲酸(55.0 mg，278 µmol)及DIPEA (0.20 mL，1.14 mmol)於DCM (1.10 mL)中之攪拌溶液中。在此溫度下攪拌反應混合物15分鐘，隨後升溫至環境溫度且再攪拌1.5小時。隨後在真空中移除揮發物，且將粗6,8-二氟咪唑并[1,5-a ]吡啶-3-甲醯氯直接用於下一步驟，假定定量產率。6,8- 二氟 -N -(2-(4- 甲氧基苯甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 咪唑并 [1,5-a ] 吡啶 -3- 甲醯胺
Figure 02_image5782
步驟 5 ：在氮氣下向配備有磁性攪拌棒之火焰乾燥圓底燒瓶中裝入4-胺基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(50 mg，139 µmol)於無水吡啶(0.70 mL)中之溶液，且在攪拌下將溶液冷卻至0℃。接著逐滴添加6,8-二氟咪唑并[1,5-a ]吡啶-3-甲醯氯(60.2 mg，278 µmol)於DCM (1.30 mL)中之溶液，且將反應混合物升溫至環境溫度且攪拌16小時。隨後將反應混合物分配於NaHCO3 飽和水溶液(10 mL)與DCM (10 mL)之間，且使混合物穿過相分離器。隨後在真空中濃縮有機相，得到粗產物。藉由矽膠急驟層析純化(用10% EtOAc/己烷溶離)，得到呈非晶形橙棕色固體狀之6,8-二氟-N -(2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)咪唑并[1,5-a ]吡啶-3-甲醯胺(77 mg，142 µmol，定量產率)。LC-MS (方法1):  1.60 min,m/z = 539.3 [M+H]+ 。6,8- 二氟 -N -(1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 咪唑并 [1,5-a] 吡啶 -3- 甲醯胺 (I-180)
Figure 02_image5784
步驟 6 ：將6,8-二氟-N -(2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)咪唑并[1,5-a ]吡啶-3-甲醯胺(57.0 mg，105 µmol)於TFA (0.70 mL)中之溶液在75℃下在密封管中攪拌加熱40小時。接著將反應混合物冷卻至環境溫度且在真空中濃縮。殘餘物藉由C18逆相急驟層析直接純化(用含40-65% ACN之10 mmol AmF水溶液溶離)，得到呈非晶形橙色固體狀之6,8-二氟-N -(1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)咪唑并[1,5-a ]吡啶-3-甲醯胺(17.0 mg，40.6 µmol，39%產率)。LC-MS (方法2):  2.51 min,m/z = 419.3 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 10.02 (br. s, 1H), 9.14 (d, 4.0 Hz, 1H), 9.03 (s, 1H), 7.84 (d, 0.8 Hz, 1H), 7.78 (dd, 7.6, 1.2 Hz, 1H), 7.65-7.62 (m, 1H), 7.62-7.57 (m, 1H), 7.44 (ddd, 10.6, 8.8, 1.8 Hz, 1H), 6.99-6.92 (m, 2H), 6.90-6.85 (m, 1H), 6.68 (br. s, 1H), 6.10 (s, 1H), 2.23 (br. s, 3H)。
根據實例6之方法製備之額外化合物列於下表3中。表 3. 額外例示性化合物
化合物
I-151
I-285
I-342
實例 7 N -(1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 )-1,2,3,4- 四氫 -1,4- 甲橋萘 -1- 甲醯胺 (I-226)
Figure 02_image5786
N -(2-(4- 甲氧基苯甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 )-1,2,3,4- 四氫 -1,4- 甲橋萘 -1- 甲醯胺
Figure 02_image5788
步驟 1 ：在環境溫度下向配備有磁性攪拌棒之旋蓋式玻璃反應管中裝入4-胺基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(50.0 mg，139 µmol)及1,2,3,4-四氫-1,4-甲橋萘-1-甲酸(31.2 mg，166 µmol)於DCM (0.50 mL)中之劇烈攪拌混合物。逐滴添加N -甲基咪唑(40.0 µL，500 µmol)，接著一次性添加四甲基氯甲脒六氟磷酸鹽(TCFH，46.5 mg，166 µmol)，且將反應混合物在環境溫度下攪拌24小時。隨後將反應混合物分配於DCM (10 mL)與水(10 mL)之間，且使混合物穿過相分離器。真空濃縮有機相，且殘餘物藉由C18逆相急驟層析純化(用含55-80% ACN之10 mmol AmF水溶液溶離)，得到呈非晶形灰白色固體狀之N -(2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)-1,2,3,4-四氫-1,4-甲橋萘-1-甲醯胺(57.0 mg，107 µmol，78%產率)。LC-MS (方法1):  1.58 min,m/z = 529.4 [M+H]+ 。 N -(1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 )-1,2,3,4- 四氫 -1,4- 甲橋萘 -1- 甲醯胺 (I-226)
Figure 02_image5790
步驟 2 ：將N -(2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)-1,2,3,4-四氫-1,4-甲橋萘-1-甲醯胺(57.0 mg，107 µmol)於TFA (0.71 mL)中之溶液在90℃下在密封管中攪拌加熱18小時。接著將反應混合物冷卻至環境溫度且在真空中濃縮。殘餘物藉由C18逆相急驟層析直接純化(用含40-60% ACN之10 mmol AmF水溶液溶離)，得到呈非晶形灰白色固體狀之N -(1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)-1,2,3,4-四氫-1,4-甲橋萘-1-甲醯胺(37.0 mg，90.5 µmol，85%產率)。LC-MS (方法2):  2.49 min,m/z = 409.4 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 )，呈非對映異構體之1:1混合物形式 δ 9.02 (br. s, 1H), 8.99 (br. s, 1H), 8.80 (br. s, 2H), 7.67-7.53 (m, 6H), 7.23-7.10 (m, 6H), 7.09-6.91 (m, 6H), 6.85 (d,J = 7.2 Hz, 1H), 6.66-6.58 (m, 3H), 6.07 (s, 2H), 3.31 (dd,J = 11.4, 3.4 Hz, 2H), 2.29 (br. s, 6H), 1.93-1.84 (m, 2H), 1.81-1.76 (m, 1H), 1.76-1.64 (m, 3H), 1.44 (d,J = 8.7 Hz, 1H), 1.36 (d,J = 8.7 Hz, 1H), 1.22-1.14 (m, 1H), 1.14-1.08 (m, 1H), 1.08-0.99 (m, 2H)。光譜記錄於70℃ (343K)下。實例 8 N -(1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [d ] 異噻唑 -3- 甲醯胺 (I-13)
Figure 02_image5792
N -(2-(4- 甲氧基苯甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [d ] 異噻唑 -3- 甲醯胺
Figure 02_image5794
步驟 1 ：向4-胺基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(100 mg，0.278 mmol)、1-[雙(二甲胺基)亞甲基]-1H -1,2,3-三唑并[4,5-b]吡錠3-氧化物六氟磷酸鹽(HATU，127 mg，0.336 mmol)及1,2-苯并噻唑-3-甲酸(50 mg，0.27 mmol)於無水DMF (1.5 mL)中之溶液中添加NaHCO3 (70 mg，0.83 mmol)。在氮氣氛圍下在22℃下攪拌所得混合物。18小時後，反應混合物用NaHCO3 飽和水溶液處理且用EtOAc (3×10 mL)萃取。合併之有機層經硫酸鈉乾燥，過濾且藉由旋轉蒸發濃縮。所得物質藉由C18管柱層析純化(用20%至100% MeCN/10 mM AmF溶離)。含產物之溶離份經合併且凍乾以獲得呈白色粉末狀之標題化合物(105 mg，72%產率)。m/z = 520.4 [M+H]+ 。 N -(1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [d ] 異噻唑 -3- 甲醯胺 (I-13)
Figure 02_image5796
步驟 2 ：N -(2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[d ]異噻唑-3-甲醯胺(105 mg，0.202 mmol)用三氟乙酸(5.0 mL)處理，且在120℃下攪拌所得混合物。2小時後，藉由旋轉蒸發濃縮反應混合物，且所得物質藉由C18管柱層析純化(用20%至100% MeCN/10 mM AmF溶離)。含產物之溶離份經合併且凍乾以獲得呈白色粉末狀之標題化合物(45 mg，58%產率)。m/z = 400.3 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) 10.15 (s, 1H), 9.05 (s, 1H), 8.58 (d,J = 8.2 Hz, 1H), 8.29 (d,J = 8.2 Hz, 1H), 7.80 (dd,J = 7.6, 1.2 Hz, 1H), 7.74-7.55 (m, 4H), 7.06-6.93 (m, 2H), 6.89 (t,J = 13.3 Hz, 1H), 6.68 (br s, 1H), 6.12 (s, 1H), 2.40-2.10 (br s, 3H)。
根據實例7及8之方法製備之額外化合物列於下表4中。下表4中之某些化合物係藉由用其他化合物置換如實例7及8中所述之4-胺基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮製備，該等其他化合物之製備進一步描述於以下實例中。表 4. 額外例示性化合物
化合物 化合物 化合物
I-12    I-2177    I-2225
I-17    I-2178    I-2226
I-24    I-2179    I-2227
I-41    I-2180    I-2232
I-63    I-2193    I-2235
I-72    I-2194    I-2238
I-73    I-2195    I-2239
I-129    I-2196    I-2247
I-133    I-2197    I-2248
I-197    I-2198    I-2249
I-200    I-2211    I-2250
I-256    I-2212    I-2252
I-337    I-2213    I-2253
I-612    I-2214    I-2254
I-638    I-2215    I-2255
I-693    I-2216    I-2260
I-752    I-2217    I-2261
I-850    I-2218    I-2262
I-1610    I-2219    I-2263
I-1617    I-2220    I-2264
I-2175    I-2221    I-2265
I-2176    I-2224    I-2266
I-2268    I-2301    I-2338
I-2269    I-2302    I-2361
I-2270    I-2303    I-2362
I-2271    I-2304    I-2363
I-2272    I-2318    I-2372
I-2273    I-2319    I-2374
I-2274    I-2322    I-2375
I-2275    I-2330    I-2391
I-2281    I-2335    I-2392
I-2282    I-2336    I-2397
I-2283    I-2337    I-2407
I-2285            
實例 9 N -[3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-2,3- 二氫 -1H - 吲哚 -1- 甲醯胺 (I-43)
Figure 02_image5798
N -{2-[(4- 甲氧基苯基 ) 甲基 ]-3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 }-2,3- 二氫 -1H - 吲哚 -1- 甲醯胺
Figure 02_image5800
步驟 1 ：向4-胺基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(50 mg，139 μmol，1.00當量)於無水THF (0.7 mL)中之溶液中添加DIPEA (19.2 μL, 139 μmol，1.00當量)。攪拌混合物且冷卻至0℃。在0℃下逐滴添加三光氣(41.8 mg，141 μmol，1.01當量)於無水THF (0.7 mL)中之溶液。在室溫下攪拌混合物隔夜。隨後將溶液添加至2,3-二氫-1H -吲哚(116 mg，973 µmol，7.00當量)於吡啶(1.5 mL)及DMAP (催化量)之溶液中。在室溫下攪拌所得混合物隔夜。反應混合物用NH4 Cl水溶液稀釋且用二氯甲烷萃取。濃縮有機層以獲得呈棕色油狀之N -{2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基}-2,3-二氫-1H -吲哚-1-甲醯胺(35 mg)，其不經進一步純化即用於下一步驟中。LC-MS (方法1):  1.42 min,m/z = 504.4 [M+H]+ 。 N -[3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-2,3- 二氫 -1H - 吲哚 -1- 甲醯胺 (I-43)
Figure 02_image5802
步驟 2 ：將N -{2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基}-2,3-二氫-1H -吲哚-1-甲醯胺(35 mg，粗物質)於三氟乙酸(10 ml, 130 mmol)中之溶液在80℃下攪拌隔夜。濃縮反應混合物。所得殘餘物藉由逆相管柱層析(C18：12 g管柱；含10mM AmF之水/乙腈)純化且凍乾，得到呈白色固體狀之N -[3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-2,3-二氫-1H -吲哚-1-甲醯胺(18.8 mg，49.0 µmol，35%產率)。LC-MS (方法1):  1.51 min, ＞99%純度,m/z = 383.9 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 8.95 (s, 1H), 8.37 (s, 1H), 7.68 (d,J = 8.0 Hz, 1H), 7.60-7.50 (m, 2H), 7.47-7.35 (m, 1H), 7.19-7.06 (m, 3H), 7.02 (d,J = 7.3 Hz, 1H), 6.95 (t,J = 7.1 Hz, 1H), 6.88 (td,J = 7.4, 1.0 Hz, 1H), 6.54 (s, 1H), 5.88 (s, 1H), 3.68-3.50 (m, 1H), 3.01-2.80 (m, 3H), 2.07 (s, 3H)。
根據實例9之方法製備之額外化合物列於下表5中。下表5中之某些化合物係藉由用其他化合物置換如實例9中所述之4-胺基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮製備，該等其他化合物之製備進一步描述於以下實例中。表 5. 額外例示性化合物
化合物 化合物 化合物
I-43    I-597    I-1051
I-44    I-598    I-1176
I-45    I-612    I-1256
I-55    I-638    I-1257
I-60    I-642    I-1269
I-95    I-661    I-1270
I-96    I-685    I-1294
I-104    I-686    I-1318
I-110    I-693    I-1382
I-308    I-698    I-1383
I-309    I-713    I-1429
I-405    I-714    I-1459
I-430    I-716    I-1462
I-432    I-720    I-1507
I-433    I-722    I-1508
I-481    I-752    I-1509
I-482    I-766    I-1510
I-491    I-769    I-1511
I-542    I-772    I-1512
I-543    I-988    I-1513
I-544    I-989    I-1514
I-574    I-990    I-1576
I-576    I-992    I-1577
I-577    I-1050    I-1578
I-1579    I-2121    I-2204
I-1610    I-2122    I-2205
I-1663    I-2123    I-2206
I-1715    I-2124    I-2207
I-1716    I-2126    I-2208
I-1717    I-2127    I-2209
I-1718    I-2128    I-2210
I-1720    I-2129    I-2222
I-1721    I-2130    I-2236
I-1722    I-2131    I-2237
I-1753    I-2132    I-2240
I-1754    I-2133    I-2241
I-1755    I-2142    I-2242
I-1756    I-2143    I-2243
I-1810    I-2144    I-2244
I-1902    I-2145    I-2245
I-1903    I-2162    I-2246
I-1904    I-2163    I-2257
I-1945    I-2164    I-2276
I-1946    I-2165    I-2277
I-1949    I-2166    I-2278
I-1953    I-2167    I-2279
I-1954    I-2168    I-2280
I-1961    I-2171    I-2284
I-1965    I-2172    I-2286
I-1978    I-2173    I-2287
I-2042    I-2174    I-2288
I-2111    I-2181    I-2291
I-2113    I-2182    I-2292
I-2114    I-2191    I-2293
I-2115    I-2199    I-2294
I-2116    I-2203    I-2299
I-2300    I-2352    I-2402
I-2305    I-2353    I-2403
I-2306    I-2356    I-2404
I-2307    I-2357    I-2405
I-2308    I-2364    I-2406
I-2310    I-2365    I-2408
I-2311    I-2366    I-2410
I-2312    I-2367    I-2411
I-2313    I-2368    I-2412
I-2314    I-2369    I-2413
I-2315    I-2370    I-2414
I-2317    I-2371    I-2415
I-2321    I-2373    I-2416
I-2328    I-2376    I-2417
I-2329    I-2377    I-2418
I-2331    I-2378    I-2419
I-2332    I-2379    I-2420
I-2333    I-2380    I-2421
I-2334    I-2381    I-2422
I-2339    I-2382    I-2423
I-2340    I-2383    I-2424
I-2341    I-2384    I-2425
I-2342    I-2385    I-2426
I-2343    I-2386    I-2427
I-2344    I-2393    I-2428
I-2345    I-2394    I-2429
I-2346    I-2395    I-2430
I-2347    I-2396    I-2431
I-2348    I-2398    I-2432
I-2349    I-2399    I-2433
I-2350    I-2400    I-2434
I-2351    I-2401    I-2435
I-2436    I-2468    I-2500
I-2437    I-2469    I-2501
I-2438    I-2470    I-2502
I-2439    I-2471    I-2503
I-2440    I-2472    I-2504
I-2441    I-2473    I-2505
I-2442    I-2474    I-2506
I-2443    I-2475    I-2507
I-2444    I-2476    I-2508
I-2445    I-2477    I-2509
I-2446    I-2478    I-2510
I-2447    I-2479    I-2511
I-2448    I-2480    I-2512
I-2449    I-2481    I-2513
I-2450    I-2482    I-2514
I-2451    I-2483    I-2515
I-2452    I-2484    I-2516
I-2453    I-2485    I-2517
I-2454    I-2486    I-2518
I-2455    I-2487    I-2519
I-2456    I-2488    I-2520
I-2457    I-2489    I-2521
I-2458    I-2490    I-2522
I-2459    I-2491    I-2523
I-2460    I-2492    I-2524
I-2461    I-2493    I-2525
I-2462    I-2494    I-2526
I-2463    I-2495    I-2527
I-2464    I-2496    I-2528
I-2465    I-2497    I-2529
I-2466    I-2498    I-2530
I-2467    I-2499    I-2531
I-2532    I-2564    I-2596
I-2533    I-2565    I-2597
I-2534    I-2566    I-2598
I-2535    I-2567    I-2599
I-2536    I-2568    I-2600
I-2537    I-2569    I-2601
I-2538    I-2570    I-2602
I-2539    I-2571    I-2603
I-2540    I-2572    I-2604
I-2541    I-2573    I-2605
I-2542    I-2574    I-2606
I-2543    I-2575    I-2607
I-2544    I-2576    I-2608
I-2545    I-2577    I-2609
I-2546    I-2578    I-2610
I-2547    I-2579    I-2611
I-2548    I-2580    I-2612
I-2549    I-2581    I-2613
I-2550    I-2582    I-2614
I-2551    I-2583    I-2615
I-2552    I-2584    I-2616
I-2553    I-2585    I-2617
I-2554    I-2586    I-2618
I-2555    I-2587    I-2619
I-2556    I-2588    I-2620
I-2557    I-2589    I-2621
I-2558    I-2590    I-2622
I-2559    I-2591    I-2623
I-2560    I-2592    I-2624
I-2561    I-2593    I-2625
I-2562    I-2594    I-2626
I-2563    I-2595    I-2627
I-2628    I-2653    I-2674
I-2629    I-2654    I-2675
I-2630    I-2655    I-2676
I-2631    I-2656    I-2677
I-2632    I-2657    I-2678
I-2633    I-2658    I-2679
I-2634    I-2659    I-2680
I-2635    I-2660    I-2681
I-2636    I-2661    I-2682
I-2637    I-2662    I-2683
I-2638    I-2663    I-2684
I-2639    I-2664    I-2685
I-2640    I-2665    I-2686
I-2641    I-2666    I-2687
I-2642    I-2667    I-2688
I-2643    I-2668    I-2689
I-2648    I-2669    I-2694
I-2649    I-2670    I-2695
I-2650    I-2671    I-2696
I-2651    I-2672    I-2697
I-2652    I-2673      
實例 10 N -[6- 溴 -3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-1- 苯丙噻吩 -3- 甲醯胺 (I-29) 及 N -[6-(1- 甲基 -1H - 吡唑 -4- 基 )-3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-1- 苯丙噻吩 -3- 甲醯胺 (I-115)
Figure 02_image5804
5- 溴 -3- 硝基鄰苯二甲酸
Figure 02_image5806
步驟 1 ：在25℃下向5-溴-2-甲基-3-硝基苯甲酸(290 g，1.12 mol，1.00當量)於H2 O (2.90 L)中之溶液中添加KOH (313 g，5.58 mol，5.00當量)。在70℃下向混合物中添加KMnO4 (881 g，5.58 mol，5.00當量)，且隨後在70℃下攪拌反應混合物16小時。向反應混合物中添加Na2 SO3 (10%，3.00 L)，隨後過濾混合物。向濾液中添加6 M HCl以將pH調節至1，且用乙酸乙酯萃取水相三次。合併之有機相經Na2 SO4 乾燥，過濾且減壓濃縮，得到呈黃色固體狀之5-溴-3-硝基鄰苯二甲酸(173 g)。LC-MS (方法1, 220 nm):  1.73 min, 73.4%純度;1 H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (s, 1H), 8.34 (s, 1H)。5- 溴 -3- 硝基鄰苯二甲醯二氯
Figure 02_image5808
步驟 2 ：在25℃下向5-溴-3-硝基鄰苯二甲酸(75.0 g，259 mmol，1.00當量)於甲苯(130 mL)中之溶液中添加SOCl2 (245 g，2.06 mol，149 mL，7.97當量)，隨後將混合物加熱至100℃且在100℃下攪拌3.5小時。兩批混合物經濃縮且接著溶解於甲苯(3×100 mL)中且自其濃縮，得到呈棕色油狀之5-溴-3-硝基鄰苯二甲醯二氯(165 g)。產物未經進一步純化即用於下一步驟中。對於LCMS分析，用MeOH淬滅產物：LC-MS (方法1, 220 nm):  0.21 min,m/z = 318.0 [M+H]+ 。6- 溴 -2-(4- 甲氧基苯甲基 )-4- 硝基異吲哚啉 -1,3- 二酮
Figure 02_image5810
步驟 3 ：在0℃下向5-溴-3-硝基鄰苯二甲醯二氯(82.3 g，252 mmol，1.00當量)於THF (140 mL)中之溶液中添加PMBNH2 (41.4 g，302 mmol，39.1 mL，1.20當量)及Et3 N (83.7 g，827 mmol，115 mL，3.28當量)於THF (50 mL)中之混合物，接著將混合物加熱至70℃，且在70℃下攪拌15小時。混合物經濃縮且接著溶解於AcOH (189 g，3.15 mol，180 mL，12.5當量)中。將混合物加熱至90℃且在90℃下攪拌4.5小時。兩批混合物用DCM (200 mL)稀釋且濃縮。將殘餘物溶解於甲苯(2×200 mL)中，接著自甲苯濃縮，得到殘餘物。將殘餘物溶解於乙酸乙酯(500 mL)中且倒入水(500 mL)中。用乙酸乙酯(3×500 mL)萃取水相。合併之有機層用鹽水(500 mL)洗滌，經Na2 SO4 乾燥且過濾。濃縮濾液，得到呈黃色固體狀之6-溴-2-(4-甲氧基苯甲基)-4-硝基異吲哚啉-1,3-二酮(204 g)。LC-MS (方法1, 220 nm):  0.99 min,m/z = 415.2 [M+Na]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 8.58 (d,J = 1.6 Hz, 1H), 8.41 (d,J = 1.6 Hz, 1H), 7.27 (d,J = 8.8 Hz, 2H), 6.88 (d,J = 8.8 Hz, 2H), 4.69 (s, 2H), 3.72 (s, 3H)。4- 胺基 -6- 溴 -2-(4- 甲氧基苯甲基 ) 異吲哚啉 -1,3- 二酮
Figure 02_image5812
步驟 4 ：在25℃下向6-溴-2-(4-甲氧基苯甲基)-4-硝基異吲哚啉-1,3-二酮(100 g，256 mmol，1.00當量)於EtOH (1.00 L) / H2 O (200 mL)中之溶液中添加NH4 Cl (54.7 g，1.02 mol，4.00當量)。將混合物加熱至40℃，且隨後在40℃下將Fe (42.8 g，767 mmol，3.00當量)添加至混合物中。將所得混合物加熱至80℃且在80℃下攪拌1.5小時。將兩批混合物倒入水(200 mL)中，過濾，且在真空中濃縮濾液。用乙酸乙酯(3×200 mL)萃取所得殘餘物。合併之有機層用鹽水(200 mL)洗滌，經Na2 SO4 乾燥，過濾且濃縮濾液。殘餘物藉由管柱層析(SiO2 ，石油醚/乙酸乙酯=1/0至0/1，產物Rf =0.5於3/1石油醚/乙酸乙酯中)純化，得到呈黃色固體狀之4-胺基-6-溴-2-(4-甲氧基苯甲基)異吲哚啉-1,3-二酮(63.3 g，145.5 mmol，83.0%純度)。LC-MS (方法1, 220 nm):  0.99 min,m/z = 361.1 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 7.22-7.18 (m, 3H), 7.06 (d,J = 2.0 Hz, 1H), 6.87 (d,J = 8.8 Hz, 2H), 6.65 (s, 2H), 4.61 (s, 2H), 3.71 (s, 3H)。4- 胺基 -6- 溴 -3- 羥基 -2-(4- 甲氧基苯甲基 )-3-( 鄰甲苯基 ) 異吲哚啉 -1- 酮
Figure 02_image5814
步驟 5 ：在0℃下向4-胺基-6-溴-2-(4-甲氧基苯甲基)異吲哚啉-1,3-二酮(77.3 g，178 mmol，1.00當量)於DCM (1.00 L)中之溶液中逐滴添加鄰甲苯基溴化鎂(0.9 M於二乙醚中，493 mL，2.50當量)，接著將混合物升溫至25℃且在25℃下攪拌1.5小時。將混合物倒入NH4 Cl飽和水溶液(800 mL)中且用乙酸乙酯(3×800 mL)萃取。合併之有機層用鹽水(800 mL)洗滌，經Na2 SO4 乾燥且過濾。濃縮濾液，得到呈黑棕色油狀之4-胺基-6-溴-3-羥基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(145.4 g，粗物質)。產物未經進一步純化即用於下一步驟中。LC-MS (方法1, 220 nm):  0.99 min,m/z = 437.2 [M-OH]+ 。4- 胺基 -6- 溴 -2-(4- 甲氧基苯甲基 )-3-( 鄰甲苯基 ) 異吲哚啉 -1- 酮
Figure 02_image5816
步驟 6 ：在25℃下向4-胺基-6-溴-3-羥基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(131 g，289 mmol，1.00當量)於DCM (1.00 L)中之溶液中添加TFA (330 g，2.89 mol，214 mL，10.0當量)，隨後在0℃下向混合物中添加三乙基矽烷(67.2 g，578 mmol，92.3 mL，2.00當量)。使混合物升溫至25℃且在25℃下攪拌1小時。在真空中濃縮兩批混合物，得到殘餘物。向殘餘物中添加水(500 mL)，且藉由添加氨將pH調節至8。用DCM (3×500 mL)萃取混合物。合併之有機層用鹽水(500 mL)洗滌，經Na2 SO4 乾燥，過濾且濃縮濾液。殘餘物藉由管柱層析(SiO2 ，石油醚/乙酸乙酯=1/0至0/1)及製備型HPLC純化，得到呈紅棕色固體狀之4-胺基-6-溴-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(41.0 g，86.3 mmol，94.4%純度)及呈黃色固體狀之7-胺基-5-溴-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(29.0 g，61.7 mmol，93.1%純度)。
4-胺基-6-溴-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮之表徵資料：LC-MS (方法1, 220 nm):  1.00 min,m/z = 437.2 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 7.54 - 7.53 (m, 1H), 7.28 -7.23 (m, 4H), 7.15 (d,J = 1.2 Hz, 1H), 6.99 - 6.97 (m, 8H), 6.93 - 6.83 (m, 5H), 6.48 (d,J = 7.6 Hz, 1H), 5.52 (s, 1H), 5.39 (s, 1H), 4.95 - 4.87 (m, 3H), 4.74 (s, 1H), 3.71 (s, 6H), 3.58 (d,J = 14.8 Hz 1H), 3.49 (d,J = 15.6 Hz, 1H), 2.25 (s, 3H), 1.51 (s, 2H)。 N -[6- 溴 -3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-1- 苯丙噻吩 -3- 甲醯胺 (I-29)
Figure 02_image5818
步驟 7 及 8 ：根據實例1，步驟5及6之程序，將4-胺基-6-溴-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮轉化為N -[6-溴-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1-苯丙噻吩-3-甲醯胺。MS:m/z = 477.0 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 10.12-10.35 (m, 1H), 9.13-9.35 (m, 1H), 7.96-8.08 (m, 2H), 7.80-7.87 (m, 1H), 7.71-7.78 (m, 1H), 7.56-7.68 (m, 1H), 7.32-7.49 (m, 2H), 7.05-7.14 (m, 1H), 6.88-7.05 (m, 2H), 6.44-6.82 (m, 1H), 5.91-6.11 (m, 1H), 1.82-2.38 (m, 3H)。 N -[6-(1- 甲基 -1H - 吡唑 -4- 基 )-3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-1- 苯丙噻吩 -3- 甲醯胺 (I-115)
Figure 02_image5820
步驟 9 ：在配備有攪拌棒之旋蓋式玻璃反應管中將N -[6-溴-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1-苯丙噻吩-3-甲醯胺(40 mg，83.7 µmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-1H -吡唑(19.1 mg)及Na2 CO3 (26 mg)懸浮於二㗁烷(0.5 mL)中。使懸浮液經受冷凍-泵送-解凍循環(3個循環)，且隨後使氮氣鼓泡通過懸浮液10分鐘。隨後將雙(三苯膦)二氯化鈀(II) (1.8 mg，2.56 µmol)添加至懸浮液。將玻璃反應管密封且在攪拌下置於預加熱油浴(110℃，外部)中5小時。反應混合物經由矽藻土過濾且用乙酸乙酯洗滌。在減壓下濃縮合併之濾液，且殘餘物藉由逆相急驟管柱層析純化(用具有10 mM AmF之0-100%乙腈/水溶離)，以在凍乾之後得到呈白色固體狀之N -[6-(1-甲基-1H -吡唑-4-基)-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1-苯丙噻吩-3-甲醯胺(3.3 mg，7.8%產率)。MS:m/z = 479.3 [M+H]+ ;1 H NMR (400 MHz, CDCl3 ) δ 8.46 (br s, 1H), 8.26 (br s, 1H), 7.88 (s, 1H), 7.86 (d,J = 1.4 Hz, 1H), 7.76 (s, 1H), 7.49 - 7.40 (m, 3H), 7.36 (d,J = 7.3 Hz, 1H), 7.24 - 7.21 (m, 1H), 6.85 (s, 1H), 6.35 (s, 1H), 5.87 (s, 1H), 3.97 (s, 3H), 1.55 (s, 3H)。
根據實例10之方法製備之額外化合物列於下表6中。下表6中之某些化合物係藉由用其他化合物置換如實例10中所述之N -[6-溴-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1-苯丙噻吩-3-甲醯胺製備，該等其他化合物之製備進一步描述於以下實例中。表 6. 額外例示性化合物
化合物
I-220
I-141
實例 11 3- 氟 -N -[3-(2- 甲基苯基 )-6-( 異丙基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-5-( 三氟甲基 ) 苯甲醯胺 (I-266)
Figure 02_image5822
4- 胺基 -2-[(4- 甲氧基苯基 ) 甲基 ]-3-(2- 甲基苯基 )-6-( 丙 -2- 基 )-2,3- 二氫 -1H - 異吲哚 -1- 酮
Figure 02_image5824
步驟 1 ：將4 mL小瓶中之二氯化鎳(II) 1,2-二甲氧基乙烷(6.25 mg)及4,4'-二-三級丁基-2,2'-二吡啶基(8.75 mg)於二㗁烷(0.5 mL)中之儲備溶液用氮氣鼓泡15分鐘(直至溶液變為淺藍色)。在具有攪拌棒之獨立4 mL小瓶中，將4-胺基-6-溴-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-2,3-二氫-1H-異吲哚-1-酮(50 mg，114 µmol)及[Ir{dFCF3 ppy}2 (bpy)]PF6 (28.3 mg，1.0當量)於二㗁烷(0.6 mL)中之溶液在攪拌下用氮氣吹掃。向此溶液中依序添加1,1,1,3,3,3-六甲基-2-(三甲基矽基)三矽烷(35.1 µL，1.0當量)、氫氧化鋰(5.46 mg，2當量)、100 µL鎳/配位體儲備溶液及2-溴丙烷(12.7 µL，1.2當量)。將反應混合物鼓泡10分鐘，接著密封。將反應混合物在攪拌下置於藍色LED光前方6 cm處持續72小時。濃縮反應混合物，且殘餘物藉由矽膠管柱層析純化(用0-100% EtOAc/庚烷溶離)，以產生4-胺基-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-6-(丙-2-基)-2,3-二氫-1H -異吲哚-1-酮(30 mg，74.9 µmol，65.7%)。3- 氟 -N -[3-(2- 甲基苯基 )-6-( 異丙基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-5- ( 三氟甲基 ) 苯甲醯胺 (I-266)
Figure 02_image5826
步驟 2 ：向3-氟-5-(三氟甲基)苯甲酸(39.9 mg，192 µmol)於DCE (0.2 mL)中之懸浮液中添加1-氯-N ,N ,2-三甲基-1-丙烯基胺(25.3 µL，2當量)。將混合物在室溫下攪拌5分鐘，直至溶液變透明，接著添加至4-胺基-2-[(4-甲氧基苯基)甲基]-3-(異丙基)-6-(2-甲基丙基)-2,3-二氫-1H -異吲哚-1-酮(40 mg，96.4 µmol)、DMAP (3.70 mg，9.64 µmol)及吡啶(38.9 µL，5當量)於1,1-二氯乙烷(1 mL)中之溶液中。攪拌反應混合物約20分鐘，隨後濃縮。
殘餘物用1 mL TFA處理且在100℃下攪拌2小時。反應物用甲苯稀釋，隨後濃縮三次。殘餘物藉由製備型HPLC純化，以產生3-氟-N -[3-(2-甲基苯基)-6-(異丙基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-5-(三氟甲基)苯甲醯胺(9.7 mg，20.0 µmol，20.7 %)。MS:m/z = 471.4 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 1.29 (d,J = 6.82 Hz, 6H), 2.17 (br d,J = 1.26 Hz, 3H), 3.02-3.14 (m, 1H), 5.85 (s, 1H), 6.60 (s, 1H), 6.87-6.99 (m, 2H), 7.01-7.09 (m, 1H), 7.33-7.41 (m, 2H), 7.49 (br d,  8.84 Hz, 1H), 7.55 (d,J = 1.26 Hz, 1H), 7.87 (br d,J = 8.59 Hz, 1H), 8.99 (s, 1H), 10.33 (s, 1H)。
根據實例11之方法製備之額外化合物列於下表7中。下表7中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 7. 額外例示性化合物
化合物
I-268
I-293
實例 12 N -(6- 溴 -3-(2- 氯 -5- 氟苯基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5828
步驟 1 ：在20℃下向化合物1 (185 g，999 mmol)於H2 SO4 (1.20 L)中之溶液中添加1,3-二溴-5,5-二甲基乙內醯脲(143 g，500 mmol)，將混合物在85℃下攪拌2小時。將混合物冷卻至20℃，隨後將其倒入冰水(5.00 L)中且過濾。真空濃縮濾餅，得到呈黃色固體狀之化合物2 (240 g，84.5%產率)。1 H NMR (400 MHz, DMSO-d 6 ) δ 14.15 (br, 1H), 8.55 (d,J = 3.2 Hz, 1H), 8.32 - 8.29 (m, 1H)。
步驟 2 ： 在20℃下在N2 下向2-氯-5-氟苯甲醛(67.0 g，423 mmol)於MeOH (1.20 L)中之溶液中依序添加以下試劑：(4-甲氧基苯基)甲胺(58.0 g，423 mmol)、化合物2 (120 g，423 mmol)及三級丁胩(35.1 g，423 mmol)。在20℃下攪拌混合物2小時。直接濃縮混合物。殘餘物藉由管柱層析(SiO2 ，石油醚/乙酸乙酯=50:1至5:1，Rf =0.40)純化，得到呈黃色固體狀之化合物3 (248 g，88.6%產率)。MS:m/z = 648.1 [M+Na]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 8.52 (br, 1H), 8.26 - 8.20 (m, 1H), 7.90 (s, 1H), 7.61 - 7.51 (m, 1H), 7.28 - 7.08 (m, 3H), 6.89 - 6.77 (m, 2H), 6.62 - 6.60 (m, 2H), 5.39 - 5.13 (m, 1H), 4.55 - 4.27 (m, 1H), 3.65 (s, 3H), 1.30 - 1.25 (m, 9H)。
步驟 3 ： 在20℃下向化合物3 (243 g，367 mmol)於ACN (1.50 L)中之溶液中添加2-三級丁基-1,1,3,3-四甲基胍(94.3 g，550 mmol)。在50℃下攪拌混合物2小時。濃縮混合物，得到呈黑色油狀之化合物4 (191 g，粗物質)。MS:m/z = 522.9 [M+H]+ 。
步驟 4 ： 在20℃下向化合物4 (191 g，367 mmol)於TFA (1.50 L)中之溶液中添加三乙基矽烷(213 g，1.83 mol)。在90℃下攪拌混合物5小時。直接濃縮混合物，得到呈綠色油狀之化合物5 (186 g，粗物質)。MS:m/z = 505.9 [M+H]+ 。
步驟 5 ： 在20℃下向化合物5 (186 g，367 mmol)於EtOH (1.20 L)及AcOH (150 mL)中之溶液中添加NH4 Cl (137 g，2.57 mol)。將混合物加熱至50℃且逐份添加Fe (143 g，2.57 mol)。在80℃下攪拌混合物1小時。用MeOH (2.00 L)及乙酸乙酯(2.00 L)稀釋混合物。隨後將混合物倒入水(4.00 L)中。用乙酸乙酯(2.00 L×3)萃取混合物。合併之有機層用鹽水(2.50 L)洗滌，經Na2 SO4 乾燥，過濾且濃縮。藉由矽膠管柱層析(石油醚/乙酸乙酯=50/1至5/1，Rf =0.40)純化粗產物。隨後藉由製備型HPLC (管柱：Phenomenex luna C18 250，50mm，10 μm；移動相：[水(0.225% FA)-ACN]；B%：40%-70%，30分鐘)純化粗產物，得到呈灰白色固體狀之化合物6 (30.5 g，14.2%產率)。MS:m/z = 476.8 [M+H]+ ;1 H NMR (400 MHz, CDCl3 ) δ 7.49 (d,J = 1.6 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.12 - 7.08 (m, 2H), 7.05 - 7.00 (m, 1H), 6.88 (d,J = 1.6 Hz, 1H), 6.83 - 6.79 (m, 2H), 6.52 (dd,J = 3.2, 3.2 Hz, 1H), 5.70 (d,J = 1.6 Hz, 1H), 5.17 (d,J = 14.8 Hz, 1H), 3.79 (s, 3H), 3.68 (d,J = 14.8 Hz, 1H)。
步驟 6 ： 將4-胺基-6-溴-3-(2-氯-5-氟苯基)-2-[(4-甲氧基苯基)甲基]-2,3-二氫-1H-異吲哚-1-酮(7.0 g，14.7 mmol)溶解於500 mL ACN中且用吡啶(2.32 g，29.4 mmol)及3-氟-5-(三氟甲基)苯甲醯氯(3.33 g，14.7 mmol)處理。一小時後，添加3-氟-5-(三氟甲基)苯甲醯氯(0.833 g，3.67 mmol)之第二等分試樣且攪拌反應物72小時。用EtOAc及水稀釋混合物。有機層用鹽水洗滌，經硫酸鈉乾燥，過濾，接著濃縮，以產生N-[6-溴-3-(2-氯-5-氟苯基)-2-[(4-甲氧基苯基)甲基]-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(11 g，16.5 mmol)
步驟 7 ： 將化合物7 (8.5 g，12.7 mmol)添加至燒瓶中且溶解於甲磺酸(35 mL)中且加熱至60℃後維持16小時。向混合物中添加碳酸鈉水溶液(10%)。水層用EtOAc萃取，有機物接著用鹽水洗滌，經硫酸鈉乾燥，過濾且濃縮，得到N -[6-溴-3-(2-氯-5-氟苯基)-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(6 g，86.5%產率)。
根據實例12之方法製備之額外化合物列於下表8中。表8中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 8. 額外例示性化合物
化合物 化合物 化合物
I-49    I-138    I-221
I-57    I-157    I-241
I-83    I-158    I-281
I-84    I-159    I-325
I-85    I-160    I-330
I-99    I-167    I-331
I-101    I-168    I-332
I-102    I-169    I-371
I-122    I-170    I-372
I-137            
實例 13 N-[4- 氯 -1-(2- 甲基苯基 )-3- 側氧基 -1H,2H,3H- 吡咯并 [3,4-c] 吡啶 -7- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-232)
Figure 02_image5830
步驟 1 ： 在0℃下向化合物1 (30.0 g，127 mmol)及2,4-二甲氧基苯甲基胺(22.3 g，133 mmol)於DMF (180 mL)中之溶液中添加HOBt (25.7 g，190 mmol)、EDCI (36.5 g，190 mmol)及DIPEA (41.0 g，317 mmol)。在10-20℃下攪拌混合物4小時。將混合物在攪拌下倒入900 mL水中且用乙酸乙酯(1.00 L×3)萃取。有機層用0.5 N HCl調節至pH 6-7，用飽和NaHCO3 溶液(200 mL)及鹽水(200 mL×2)洗滌，乾燥且濃縮。殘餘物用石油醚/乙酸乙酯=20/1 (300 mL)濕磨2小時。過濾混合物，且乾燥濾餅，得到呈淺黃色固體狀之化合物2 (32.0 g，粗物質)。1 H NMR (400 MHz, CDCl3 ) δ 8.47 (d,J = 2.4 Hz, 1H), 8.23 (d,J = 2.8 Hz, 1H), 7.25 (d,J = 8.0 Hz, 1H), 7.07 (br, s, 1H), 6.48 - 6.45 (m, 2H), 4.57 (d,J = 5.6 Hz, 2H), 3.85 (s, 3H), 3.81 (s, 3H)。
步驟 2 ： 在0℃下向化合物2 (32.0 g，83.0 mmol)於THF (320 mL)中之溶液中添加NaH (4.98 g，124 mmol，60%純度，1.50當量)。在0℃下攪拌混合物0.5小時且接著逐滴添加對甲苯甲醯氯(17.5 g，113 mmol，14.7 mL，1.36當量)。在0-25℃下再攪拌混合物2小時。混合物藉由添加150 mL NH4 Cl水溶液淬滅且用乙酸乙酯(150 mL×3)萃取。乾燥且濃縮有機層。藉由管柱層析(SiO2，石油醚/乙酸乙酯=1/0至5/1，Rf =0.50)純化殘餘物，得到呈黃色固體狀之化合物3 (12.8 g)。1 H NMR (400 MHz, CDCl3 ) δ 8.24 (d,J = 2.4 Hz, 1H), 7.43 (d,J = 2.4 Hz, 1H), 7.31 (d,J = 8.4 Hz, 1H), 7.25 - 7.19 (m, 2H), 7.13 (d,J = 7.2 Hz, 1H), 7.00 (d,J = 7.6 Hz, 1H), 6.50 - 6.47 (m, 1H), 6.43 (d,J = 2.4 Hz, 1H), 5.12 (s, 2H), 3.81 (s, 3H), 3.69 (s, 3H), 2.20 (s, 3H)。
步驟 3 ： 在-50℃下向化合物3 (12.8 g，25.4 mmol，1.00當量)於THF (128 mL)中之溶液中添加LiHMDS (1 M，38.1 mL，1.50當量)。在-50℃下再攪拌混合物4小時。混合物藉由650 mL飽和NH4 Cl溶液淬滅且用650 mL×2之乙酸乙酯萃取。有機層經合併，用鹽水(650 mL)洗滌，乾燥且濃縮，得到呈黃色固體狀之化合物4 (12.0 g，粗物質)。1 H NMR (400 MHz, CDCl3 ) δ 8.48 (s, 1H), 8.21 (d,J = 7.6 Hz, 1H), 7.43 (d,J = 8.4 Hz, 1H), 7.39 (t,J = 7.2 Hz, 1H), 7.30 (t,J = 7.0 Hz, 1H), 7.02 (d,J = 7.6 Hz, 1H), 6.43 - 6.41 (m, 1H), 6.34 (d,J = 2.0 Hz, 1H), 5.34 (br, s, 1H), 4.54 (d,J = 14.4 Hz, 1H), 4.05 (d,J = 14.8 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 1.63 (s, 3H)。
步驟 4 ： 向化合物4 (12.0 g，23.8 mmol)及TFA (67.9 g，596 mmol)於DCM (120 mL)中之溶液中添加Et3 SiH (27.7 g，238 mmol，38.1 mL，10.0當量)。在10-20℃下攪拌混合物16小時。混合物用飽和Na2 CO3 溶液調整至pH 7-8且用DCM (200 mL×3)萃取。有機層用鹽水(100 mL)洗滌，經Na2 SO4 乾燥，過濾且濃縮。殘餘物用石油醚/乙酸乙酯=20/1 (50.0 mL)之溶液濕磨12小時，且隨後過濾，得到濾餅。在真空下乾燥濾餅，得到呈黃色固體狀之化合物5 (8.58 g，66.2%產率)。MS:m/z = 488.9 [M+H]+ ;1 H NMR (400 MHz, CDCl3 ) δ 8.48 - 8.47 (m, 1H), 7.24 - 7.19 (m, 2H), 7.12 - 7.08 (m, 1H), 7.04 (d,J = 8.0 Hz, 1H), 6.54 (d,J = 7.6 Hz, 1H), 6.44 - 6.41 (m, 2H), 5.59 (s, 1H), 5.03 - 4.96 (m, 1H), 3.84 - 3.80 (m, 4H), 3.74 - 3.72 (m, 3H), 2.33 (s, 3H)。
步驟 5 ： 向反應小瓶中裝入7-溴-4-氯-2-[(2,4-二甲氧基苯基)甲基]-1-(2-甲基苯基)-1H,2H,3H-吡咯并[3,4-c]吡啶-3-酮(250 mg，0.512 mmol)、3-氟-5-(三氟甲基)苯甲醯胺(81.6 mg，0.394 mmol)、三級丁醇鈉(56.8 mg，0.591 mmol)、Pd2 (dba)3 (21.6 mg，23.6 umol)及Xanthphos (4.56 mg，7.88 umol)。抽空反應容器且用氮氣回填3次，接著添加無水甲苯(5 mL)。加熱至100℃後維持16小時。用1N HCl淬滅。用水(5 mL)稀釋且用EtOAc (2×10 mL)萃取，經硫酸鈉乾燥且乾燥至SiO2上。使用0-60% EtOAc/庚烷在CombiFlash® EZ Prep閃蒸管柱(40 mm管柱)上純化。合併之溶離份經濃縮，得到呈橙色固體狀之N-{4-氯-2-[(2,4-二甲氧基苯基)甲基]-1-(2-甲基苯基)-3-側氧基-1H,2H,3H-吡咯并[3,4-c]吡啶-7-基}-3-氟-5-(三氟甲基)苯甲醯胺(321 mg，25.6%)。MS:m/z = 614.28 [M+H]+ 。
步驟 6 ： 將N-{4-氯-2-[(2,4-二甲氧基苯基)甲基]-1-(2-甲基苯基)-3-側氧基-1H,2H,3H-吡咯并[3,4-c]吡啶-7-基}-3-氟-5-(三氟甲基)苯甲醯胺(15 mg，0.02443 mmol)於TFA (500 uL)中之溶液在100℃下加熱16小時。混合物經濃縮且藉由逆相HPLC純化(20-40%乙腈/水，含0.1%甲酸)純化，得到N-[4-氯-1-(2-甲基苯基)-3-側氧基-1H,2H,3H-吡咯并[3,4-c]吡啶-7-基]-3-氟-5-(三氟甲基)苯甲醯胺(5 mg，0.01078 mmol)。實例 14 N -(4- 胺基 -3- 側氧基 -1-( 鄰甲苯基 )-2,3- 二氫 -1H - 吡咯并 [3,4-c] 吡啶 -7- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-262)
Figure 02_image5832
步驟 1 ： 將N-{4-氯-2-[(2,4-二甲氧基苯基)甲基]-1-(2-甲基苯基)-3-側氧基-1H,2H,3H-吡咯并[3,4-c]吡啶-7-基}-3-氟-5-(三氟甲基)苯甲醯胺(75 mg，0.1221 mmol)溶解於DMF中。用N2 鼓泡5分鐘。添加1-(2,4-二甲氧基苯基)甲胺(20.1 µL，0.1343 mmol)，接著添加乙基雙(丙-2-基)胺(31.8 µL，0.1831 mmol)。在100℃下攪拌16小時。混合物用EtOAc稀釋，用水萃取(2次)，用鹽水洗滌，經Na2 SO4 乾燥且濃縮。在製備型HPLC上使用0-50% EtOAc/庚烷純化濃縮物，得到N-{2-[(2,4-二甲氧基苯基)甲基]-4-{[(2,4-二甲氧基苯基)甲基]胺基}-1-(2-甲基苯基)-3-側氧基-1H,2H,3H-吡咯并[3,4-c]吡啶-7-基}-3-氟-5-(三氟甲基)苯甲醯胺(59.0 mg，65%)。MS:m/z = 745.53 [M+H]+ 。
步驟 2 ： 將N-{2-[(2,4-二甲氧基苯基)甲基]-4-{[(2,4-二甲氧基苯基)甲基]胺基}-1-(2-甲基苯基)-3-側氧基-1H,2H,3H-吡咯并[3,4-c]吡啶-7-基}-3-氟-5-(三氟甲基)苯甲醯胺(59.0 mg，0.07922 mmol)溶解於TFA (1 mL)中且在室溫下攪拌1小時。將混合物加熱至100℃後維持16小時，且濃縮。將濃縮物溶解於DCM (1 mL)中且向溶液中添加Et3 SiH (3當量)及TFA (10當量)，在80℃下攪拌1小時。藉由逆相HPLC純化，得到N-(4-胺基-3-側氧基-1-(鄰甲苯基)-2,3-二氫-1H -吡咯并[3,4-c]吡啶-7-基)-3-氟-5-(三氟甲基)苯甲醯胺(5 mg，0.011 mmol)。實例 15 N -[3-(2- 甲基苯基 )-1- 側氧基 -1H,2H,3H- 吡咯并 [3,4-c] 吡啶 -4- 基 ]-1,2- 苯并噻唑 -3- 甲醯胺 (I-176)
Figure 02_image5834
步驟 1 ： 在N2 氛圍下向2,6-二氯-N-[(4-甲氧基苯基)甲基]吡啶-4-甲醯胺(2.0 g，6.42 mmol)於THF (32.0 mL)中之攪拌-50℃溶液中緩慢添加LiHMDS (7.05 mL 之1.0 M溶液於THF中)。在-78℃下攪拌橙色溶液1小時。經2分鐘向反應物中逐滴添加2-甲基苯甲醯氯溶液(919 µL，7.06 mmol)。反應物在-78℃下攪拌0.5小時且接著在環境溫度下攪拌16小時。使混合物重新冷卻至-50至-78℃且緩慢添加1.1當量含1M LiHMDS之THF (7.05 mL)。在-50至-78℃下攪拌反應物1小時。將混合物用水緩慢淬滅且濃縮以移除THF。用EtOAc稀釋懸浮液。分離各層，且用EtOAc萃取水層兩次。有機層經合併，用鹽水洗滌，經Na2 SO4 乾燥且過濾。藉由急驟層析(50 g，固體負載，0-50% EtOAc/己烷)純化粗產物，得到4,6-二氯-3-羥基-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-1H,2H,3H-吡咯并[3,4-c]吡啶-1-酮(812 mg，29.5%產率)。
步驟 2 ：在氮氣下向4,6-二氯-3-羥基-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-1H,2H,3H-吡咯并[3,4-c]吡啶-1-酮(812.8 mg，1.89 mmol)於DCM (8.45 mL)中之攪拌0℃溶液中添加TFA (2.89 mL)，接著添加三乙基矽烷(3.00 mL，18.9 mmol)。接著使反應物升溫至環境溫度且攪拌16小時。混合物用DCM (20 mL)稀釋且用NaHCO3 飽和水溶液淬滅，直至pH 6-7。有機層經再次萃取，用鹽水洗滌，經Na2 SO4 乾燥，過濾且濃縮。藉由正相層析(50 g，30-70% EtOAc/己烷)純化粗產物。濃縮溶離份，以產生4,6-二氯-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-1H,2H,3H-吡咯并[3,4-c]吡啶-1-酮(502 mg，64.2%產率)。
步驟 3 ： 將含有4,6-二氯-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-1H,2H,3H-吡咯并[3,4-c]吡啶-1-酮(243 mg，0.5879 mmol)、雙[(2,4-二甲氧基苯基)甲基]胺(205 mg，0.6466 mmol)、乙基雙(丙-2-基)胺(1.52 mL，8.81 mmol)及2-丙醇(2.35 mL)之管密封且在150℃下攪拌30小時，且接著冷卻至環境溫度。將混合物稀釋於水/EtOAc中。用NH4 Cl將水層之pH調節至pH 7-8。水層用EtOAc萃取兩次。合併有機層，用鹽水洗滌且濃縮。藉由逆相層析(30 g，30%-100% ACN/甲酸銨(水溶液))純化粗產物。濃縮含有產物之溶離份，以產生4-{雙[(2,4-二甲氧基苯基)甲基]胺基}-6-氯-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-1H,2H,3H-吡咯并[3,4-c]吡啶-1-酮(24 mg，6.1%產率)。
步驟 4 ：將4-{雙[(2,4-二甲氧基苯基)甲基]胺基}-6-氯-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-1H,2H,3H-吡咯并[3,4-c]吡啶-1-酮(25 mg，0.03601 mmol)及無水NaOAc (12.3 mg)溶解於甲醇(1.2 mL)中。用N2 吹掃溶液且添加9.6 mg Pd/C 10% wt。再次用N2 吹掃混合物，隨後用H2 吹掃。在室溫下在H2 氛圍下攪拌混合物16小時。用N2 吹掃混合物且添加5 mg Pd/C 10% wt。再次用N2 吹掃混合物，隨後用H2 吹掃。在室溫下在H2 氛圍下攪拌混合物16小時。混合物經由Celite® 過濾，用EtOAc/MeOH洗滌，濃縮且真空乾燥，以產生4-{雙[(2,4-二甲氧基苯基)甲基]胺基}-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-1H,2H,3H-吡咯并[3,4-c]吡啶-1-酮(3 mg)。
步驟 5 ：將固體4-{雙[(2,4-二甲氧基苯基)甲基]胺基}-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-1H,2H,3H-吡咯并[3,4-c]吡啶-1-酮(24 mg，0.03637 mmol)用三氟乙酸(0.70 mL，0.08289 mmol)處理且在環境溫度下攪拌。20分鐘後，濃縮混合物。含有4-胺基-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-1H,2H,3H-吡咯并[3,4-c]吡啶-1-酮(13 mg)之粗混合物直接用於下一步驟。
步驟 6 ：將4-胺基-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-1H,2H,3H-吡咯并[3,4-c]吡啶-1-酮(13.0 mg，0.03616 mmol)溶解於吡啶(0.36 mL)中且添加1,2-苯并噻唑-3-甲醯氯(10.7 mg，0.05424 mmol)。將混合物在環境溫度下攪拌2小時。將約10.7 mg 1,2-苯并噻唑-3-甲醯氯添加至混合物中，且將其再攪拌一小時。將水(0.4 mL)及5 mg K2 CO3 添加至反應物中。在環境溫度下攪拌混合物0.5小時。混合物經濃縮，用DCM及水稀釋。將pH調節至7-8且分離各層。用DCM萃取水層兩次。有機層經合併，用鹽水洗滌，經Na2 SO4 乾燥，過濾且濃縮。將含有N-(2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)-2,3-二氫-1H-吡咯并[3,4-c]吡啶-4-基)苯丙[d]異噻唑-3-甲醯胺(18.8 mg)之粗產物直接用於下一步驟。
步驟 7 ：在氮氣下向N-(2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)-2,3-二氫-1H-吡咯并[3,4-c]吡啶-4-基)苯丙[d]異噻唑-3-甲醯胺(19.4 mg，0.03615 mmol)於DCM (0.18 mL)中之攪拌0℃溶液中添加具有0.2%三氟甲磺酸之TFA (55.3 uL)，接著添加三乙基矽烷(57.6 µL，0.3615 mmol)。使反應物升溫至環境溫度且攪拌16小時。混合物經濃縮，用DCM/水稀釋且用NaHCO3 飽和水溶液緩慢淬滅，直至pH 6-7。有機層經再次萃取，用鹽水洗滌且濃縮。藉由逆相層析(10 g，10-75% ACN/甲酸銨10 mM)純化粗產物。純溶離份經合併、濃縮且凍乾，以產生N-[3-(2-甲基苯基)-1-側氧基-1H,2H,3H-吡咯并[3,4-c]吡啶-4-基]-1,2-苯并噻唑-3-甲醯胺(1 mg，6.6%產率)。實例 16 N-[5-(2- 氯苯基 )-2-( 甲基硫基 )-7- 側氧基 -5H,6H,7H- 吡咯并 [3,4-d] 嘧啶 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5836
步驟 1 ：向圓底燒瓶中添加6-羥基-2-(甲基硫基)嘧啶-4-甲酸(1.29 g，6.95 mmol)，將其懸浮於POCl3 (15 mL)中且加熱至95℃。2小時後，使反應物冷卻，濃縮，且再溶解於THF (10 mL)中。在獨立燒瓶中，將含2-氯-N-[(4-甲氧基苯基)甲基]苯甲醯胺(1.6 g，5.80 mmol)之THF (15 mL)冷卻至-78℃且裝填鋰基雙(三甲基矽基)胺(5.80 mL，5.80 mmol)。將來自燒瓶一之溶液逐滴添加至第二燒瓶中。30分鐘後，反應物用水淬滅且用乙酸乙酯萃取。濃縮有機層，以產生6-氯-N-(2-氯苯甲醯基)-N-[(4-甲氧基苯基)甲基]-2-(甲基硫基)嘧啶-4-甲醯胺(550 mg，20.5%產率)。
步驟 2 ： 將6-氯-N-(2-氯苯甲醯基)-N-[(4-甲氧基苯基)甲基]-2-(甲基硫基)嘧啶-4-甲醯胺(547 mg，1.18 mmol)於THF中之混合物冷卻至-78℃且裝填鋰基雙(三甲基矽基)胺(1.18 mL，1.18 mmol)。在-78℃下攪拌反應物1小時，且使溶液升溫至-20℃。隨後用飽和NH4 Cl淬滅反應物，且用乙酸乙酯萃取水層。濃縮有機層，以產生4-氯-5-(2-氯苯基)-5-羥基-6-[(4-甲氧基苯基)甲基]-2-(甲基硫基)-5H,6H,7H-吡咯并[3,4-d]嘧啶-7-酮(418 mg，0.90 mmol，76%)。
步驟 3 ： 向小瓶中添加含4-氯-5-(2-氯苯基)-5-羥基-6-[(4-甲氧基苯基)甲基]-2-(甲基硫基)-5H,6H,7H-吡咯并[3,4-d]嘧啶-7-酮(350 mg，0.7570 mmol)之THF (5 mL)，接著向其中裝入三乙胺(315 µL，L，2.27 mmol)及1-(2,4-二甲氧基苯基)甲胺(151 mg，0.9084 mmol)且在環境溫度下攪拌。6小時後，將反應物倒入鹽水溶液中且用乙酸乙酯萃取。濃縮有機層，以產生5-(2-氯苯基)-4-{[(2,4-二甲氧基苯基)甲基]胺基}-5-羥基-6-[(4-甲氧基苯基)甲基]-2-(甲基硫基)-5H,6H,7H-吡咯并[3,4-d]嘧啶-7-酮(484 mg，粗物質)。
步驟 4 ： 向小瓶中添加5-(2-氯苯基)-4-{[(2,4-二甲氧基苯基)甲基]胺基}-5-羥基-6-[(4-甲氧基苯基)甲基]-2-(甲基硫基)-5H,6H,7H-吡咯并[3,4-d]嘧啶-7-酮(450mg，0.7587 mmol)，接著添加TFA (4 mL)，接著添加三乙基矽烷(1.21 mL，7.58 mmol)，且將混合物加熱至80℃。4小時後，濃縮反應物。將粗物質溶解於DCM中，用飽和碳酸氫鈉洗滌，接著經硫酸鈉乾燥。有機層經過濾且濃縮，以產生4-胺基-5-(2-氯苯基)-6-[(4-甲氧基苯基)甲基]-2-(甲基硫基)-5H,6H,7H-吡咯并[3,4-d]嘧啶-7-酮(265 mg，82%產率)。
步驟 5 ： 向含有含3-氟-5-(三氟甲基)苯甲酸(36.5 mg，0.1756 mmol)之甲苯(1 mL)的小瓶中添加(1-氯-2-甲基丙-1-烯-1-基)二甲胺(23.1 µL，0.1756 mmol)，且將混合物在環境溫度下攪拌30分鐘以產生儲備溶液。在獨立小瓶中，將含4-胺基-5-(2-氯苯基)-6-[(4-甲氧基苯基)甲基]-2-(甲基硫基)-5H,6H,7H-吡咯并[3,4-d]嘧啶-7-酮(50 mg，0.1171 mmol)之THF (3mL)冷卻至0℃，且裝填鋰基雙(三甲基矽基)胺(175 µL，0.1756 mmol)。在15分鐘之後，添加酸氯化物之儲備溶液且攪拌30分鐘。移除溶劑，且藉由製備型HPLC純化殘餘物，以產生N-[5-(2-氯苯基)-6-[(4-甲氧基苯基)甲基]-2-(甲基硫基)-7-側氧基-5H,6H,7H-吡咯并[3,4-d]嘧啶-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(15 mg，20%產率)。
步驟 6 ： 向微波小瓶中添加含N-[5-(2-氯苯基)-6-[(4-甲氧基苯基)甲基]-2-(甲基硫基)-7-側氧基-5H,6H,7H-吡咯并[3,4-d]嘧啶-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(15 mg，0.02431 mmol)之TFA + 1% TfOH (1.5 mL)，將其在微波中在75℃下加熱50分鐘。移除溶劑，且藉由製備型HPLC純化殘餘物，以產生N-[5-(2-氯苯基)-2-(甲基硫基)-7-側氧基-5H,6H,7H-吡咯并[3,4-d]嘧啶-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(6.5 mg，54%產率)。實例 17 3- 氟 -N-[1-(1- 甲基環己基 )-3- 側氧基 -2,3- 二氫 -1H- 吲唑 -7- 基 ]-5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5838
步驟 1 ：向2-氯-3-硝基苯甲酸(1 g，4.96 mmol)、(1-甲基環己基)肼(635 mg，4.96 mmol)及HATU (2.82 g，7.44 mmol)於DMF (50 mL)中之溶液中添加碳酸氫鈉(1.24 g，14.8 mmol)。在環境溫度下攪拌混合物隔夜，且接著用飽和NaHCO3 及鹽水洗滌混合物。反應混合物經濃縮且藉由逆相層析(30 g管柱，10 mM甲酸銨於水/乙腈系統(5-100%)中)純化且凍乾，得到2-氯-N'-(1-甲基環己基)-3-硝基苯并醯肼(500 mg，26.9 %產率)。
步驟 2 ： 向圓底燒瓶中添加2-氯-N'-(1-甲基環己基)-3-硝基苯并醯肼(500 mg，1.60 mmol)、三級丁醇鈉(230 mg，2.40 mmol)及DMF (20 mL)。在90℃下在惰性氛圍下攪拌混合物2小時。反應混合物經濃縮且藉由逆相層析(30 g管柱，10 mM甲酸銨於水/乙腈系統(5-100%)中)純化且溶離份經凍乾，得到1-(1-甲基環己基)-7-nitro-2,3-二氫-1H-吲唑-3-酮(180 mg，39.9 %產率)。
步驟 3 ： 向30 mL小瓶中裝入1-(1-甲基環己基)-7-硝基-2,3-二氫-1H-吲唑-3-酮(180 mg，653 µmol)、鐵(364 mg，6.52 mmol)及乙酸(668 µL，11.7 mmol)。將混合物懸浮於4:1 MeOH/水(15 mL)中且在90℃下劇烈攪拌30分鐘。經由Celite® 墊過濾混合物。在減壓下濃縮濾液，得到7-胺基-1-(1-甲基環己基)-2,3-二氫-1H-吲唑-3-酮(70 mg，43.7 %產率)。
步驟 4 ： 向7-胺基-1-(1-甲基環己基)-2,3-二氫-1H-吲唑-3-酮(70 mg，285 µmol)於DCM (5 mL)中之溶液中添加吡啶(112 mg，1.42 mmol)及3-氟-5-(三氟甲基)苯甲醯氯(129 mg，570 µmol)，且將所得混合物在環境溫度下攪拌1小時。反應混合物經濃縮，用NH4 Cl水溶液洗滌，用DCM萃取。濃縮有機層，獲得黏性粗殘餘物(150 mg)，其不經進一步純化即用於下一步驟中。假設產率為定量的。
步驟 5 ： 將3-氟-N-{2-[3-氟-5-(三氟甲基)苯甲醯基]-1-(1-甲基環己基)-3-側氧基-2,3-二氫-1H-吲唑-7-基}-5-(三氟甲基)苯甲醯胺(180 mg，287 µmol)溶解於甲醇(10 mL)中，接著添加碳酸鉀(395 mg，2.86 mmol)，且將反應混合物在60℃下攪拌1小時。反應混合物經濃縮且藉由逆相層析(30 g管柱，10mM甲酸銨於水/乙腈系統(5-100%)中)純化，得到3-氟-N-[1-(1-甲基環己基)-3-側氧基-2,3-二氫-1H-吲唑-7-基]-5-(三氟甲基)苯甲醯胺(80 mg，181 µmol，63.8%)。
根據實例17之方法製備之額外化合物列於下表9中。表9中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 9. 額外例示性化合物
化合物 化合物 化合物
I-68    I-152    I-252
I-117    I-178    I-323
實例 18 N-(1,1- 二氧離子基 -3-( 鄰甲苯基 )-2,3- 二氫苯丙 [d] 異噻唑 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5840
步驟 1 ： (A)向冷卻至0℃之水(36 mL)中添加亞硫醯氯(6.08 mL，4.3當量，14.2 mmol)，將溫度保持在0-7℃下(極其放熱，用滴液漏斗緩慢小心添加)。使混合物升溫至室溫後維持1小時，其後添加CuCl (191 mg，0.1當量)且使用鹽水/冰浴將溶液冷卻至-3℃。(B)將濃氯化氫(30 mL，1.0當量，36% w/w)添加至2-胺基-6-硝基苯甲酸甲酯(3.8 g，19.3 mmol)中，藉由冰/鹽水混合物冷卻保持溫度低於30℃，且將混合物冷卻至-5℃。將亞硝酸鈉(1.52 g，1.15當量)溶解於水(5 mL)中(放熱，需要用滴液漏斗緩慢小心添加)，將溫度保持在-5℃與0℃之間且再攪拌15分鐘。將來自(B)之漿液逐滴添加至溶液(A)中，同時將兩種溶液之溫度保持在0與-5℃之間，且將此混合物攪拌30分鐘，過濾，用水沖洗且風乾，產生濕濾餅。在真空下乾燥物質，得到2-(氯磺醯基)-6-苯硝基苯甲酸甲酯(5.34 g，99%產率)。
步驟 2 ： 向圓底燒瓶中裝入2-(氯磺醯基)-6-苯硝基苯甲酸甲酯(1 g，3.57 mmol)及二㗁烷(5 mL)，且使用冰浴將混合物冷卻至0℃。逐滴添加氫氧化銨(5 mL，濃度35 wt%)，且將混合物經90分鐘升溫至室溫。將混合物冷卻至0℃，且添加濃HCl (約4 mL)以達到pH 1。添加水(30 mL)且在燒結漏斗上過濾反應混合物，用水沖洗且風乾，得到呈灰白色固體狀之4-硝基苯丙[d]異噻唑-3(2H)-酮1,1-二氧化物(560 mg，68.7 %產率)。
步驟 3 ： 向反應小瓶中裝載4-硝基苯丙[d]異噻唑-3(2H)-酮1,1-二氧化物(500 mg，2.19 mmol)、氫氧化鈀、20重量%濕鈀/碳(100 mg，0.429當量)，且用氮氣吹掃。添加無水甲醇(8 mL)，且繼續氮氣吹掃2分鐘，接著用氫氣(來自氣球)吹掃5分鐘。在環境溫度下攪拌混合物16小時。混合物用氮氣吹掃，且經由燒結漏斗上之小矽藻土墊過濾。將濾液濃縮至乾燥，得到呈茶色粉末狀之4-胺基苯丙[d]異噻唑-3(2H)-酮1,1-二氧化物(368 mg，1.81 mmol，82.9 %)。
步驟 4 ： 向圓底燒瓶中裝入4-胺基苯丙[d]異噻唑-3(2H)-酮1,1-二氧化物(236 mg，1.19 mmol)、4-二甲胺基吡啶(14.5 mg，0.1當量)及無水吡啶(3 mL)，接著逐滴添加3-氟-5-(三氟甲基)苯甲醯氯(403 mg，1.78 mmol)。在環境溫度下攪拌混合物1小時。反應混合物用DCM (50 mL)及水(10 mL)稀釋，且用1 MHCl (約30 mL)酸化至pH 1。分離出DCM相，且用EtOAc (30 mL)萃取水相。將有機相合併，經硫酸鈉乾燥，且濃縮至乾燥。粗混合物用DCM (約8 mL)濕磨且過濾，得到呈茶色固體狀之N-(1,1-二氧離子基-3-側氧基-2,3-二氫苯丙[d]異噻唑-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(355 mg，0.9142 mmol，76.8 %)。
步驟 5 ： 在氮氣下向乾燥圓底燒瓶在裝入N-(1,1-二氧離子基-3-側氧基-2,3-二氫苯丙[d]異噻唑-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(100 mg，0.2575 mmol)及無水四氫呋喃(1.03 mL)，且將混合物冷卻至0℃。逐滴添加溴(2-甲基苯基)鎂(772 µL，0.7725 mmol，1 M於THF中)且經1小時升溫至環境溫度。1小時後，添加第二部分的溴(2-甲基苯基)鎂(257 μl，257 μM，1 M於THF中)，且在環境溫度下攪拌3小時，接著添加第三部分的溴(2-甲基苯基)鎂(257 μl，257 μM，1 M於THF中)且將混合物在環境溫度下攪拌隔夜。反應混合物用飽和NH4 Cl (5 mL)淬滅，用水(5 mL)稀釋，且用EtOAc (3×12 mL)萃取，經硫酸鈉乾燥且濃縮至乾燥，得到N-(1,1-二氧離子基-3-(鄰甲苯基)苯丙[d]異噻唑-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(120 mg，0.1038 mmol，40.3 %)。粗產物直接用於下一步驟。
步驟 6 ： 向圓底燒瓶中裝入粗N-(1,1-二氧離子基-3-(鄰甲苯基)苯丙[d]異噻唑-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(60 mg，0.1297 mmol)及無水甲醇(1.29 mL)，接著添加硼氫化鈉(14.7 mg，3當量) (即時氣體逸出)。攪拌反應混合物3小時。將反應混合物濃縮至乾燥且藉由逆相急驟層析(12 g C18濾筒，10至80% ACN/甲酸銨(水溶液))純化。雜質(Rt=1.80分鐘)與所需產物共溶離。將含有所需產物之所有溶離份濃縮在一起且藉由正相急驟層析(12 g濾筒，0至25% EtOAc/DCM)再純化，在凍乾之後得到呈白色固體狀之N-(1,1-二氧離子基-3-(鄰甲苯基)-2,3-二氫苯丙[d]異噻唑-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(17 mg，28.2%)。實例 19 (Z)-N-[3-(2- 氯 -5- 氟苯基 )-1- 亞硫基 -2,3- 二氫 -1H- 異吲哚 -4- 基 ]-3- 氟 -N'- 羥基 -5-( 三氟甲基 ) 苯甲脒
Figure 02_image5842
步驟 1 ： 將N-[3-(2-氯-5-氟苯基)-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(0.065 g，139 µmol)於甲苯(2 mL)中之懸浮液用雙(4-甲氧基苯基)-1,3,2,4-二硫雜二磷雜環丁烷-2,4-二硫酮(60.2 mg)處理。將混合物在100℃下攪拌3小時且接著藉由矽膠層析(0-100% EtOAc/己烷)純化，得到N-[3-(2-氯-5-氟苯基)-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯-1-硫代碳醯胺(0.038 g，78.6 µmol，56%)。
步驟 2 ： 將N-[3-(2-氯-5-氟苯基)-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯-1-硫代碳醯胺(0.038 g，78.6 µmol)於乙醇(3 mL)中之溶液用NaHCO3 (2當量)及羥胺鹽酸鹽(2當量)處理。將混合物在70℃下攪拌48小時且接著藉由逆相HPLC (20-70% ACN/水)純化，得到呈淡黃色粉末狀之(Z)-N-[3-(2-氯-5-氟苯基)-1-亞硫基-2,3-二氫-1H-異吲哚-4-基]-3-氟-N'-羥基-5-(三氟甲基)苯甲脒(0.005 g，7.02 µmol，9%產率)。實例 20 5- 溴 -4-(2- 甲基苯基 )-3,4- 二氫 -2H-1,3- 苯并㗁 𠯤 -2- 酮
Figure 02_image5844
步驟 1 ： 向含2-溴-6-羥基苯甲醛(1.72 g，8.55 mmol)及2-甲基丙烷-2-亞磺醯胺(1.23 g，10.2 mmol)之THF (25 mL)中添加四乙氧基鈦(5.35 mL，25.6 mmol)。將混合物在環境溫度下攪拌2小時。隨後將溶液用碳酸氫鈉水溶液淬滅。用DCM萃取水層。濃縮有機層，得到N-[(E)-(2-溴-6-羥基苯基)亞甲基]-2--甲基丙烷2-亞磺醯胺(2.6 g，8.55 mmol，99%)。
步驟 2 ： 在0℃下向N-[(E)-(2-溴-6-羥基苯基)亞甲基]-2-甲基丙烷2-亞磺醯胺(200 mg，0.6574 mmol)於THF (3 mL)中之溶液中添加溴(2-甲基苯基)鎂(985 µL，1.97 mmol，2 M於THF中)。在0℃下攪拌5分鐘之後，使反應物升溫至環境溫度。攪拌混合物15分鐘，隨後用飽和NH4 Cl淬滅。用乙酸乙酯萃取水層，且濃縮有機層，以產生N-[(2-溴-6-羥基苯基)(2-甲基苯基)甲基]-2-甲基丙烷2-亞磺醯胺(260 mg，0.650 mmol，99%)。
步驟 3 ： 向含N-[(2-溴-6-羥基苯基)(2-甲基苯基)甲基]-2-甲基丙烷2-亞磺醯胺(210 mg，0.5298 mmol)之2-MeTHF (3 mL)中添加1-(1H-咪唑-1-羰基)-1H-咪唑(170 mg，1.05 mmol)，且加熱至90℃後維持16小時。冷卻溶液，接著逐滴添加MTBE直至固體開始沈澱。隨後過濾固體且乾燥，得到5-溴-4-(2-甲基苯基)-3,4-二氫-2H-1,3-苯并㗁 𠯤-2-酮(95 mg，0.538 mmol，56.5%)。實例 21 N-(4-(2- 氯苯基 )-2- 側氧基 -1,2,3,4- 四氫喹唑啉 -5- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5846
步驟 1 ： 向圓底燒瓶中裝入3-胺基苯甲醯胺(500 mg，3.67 mmol)及4-二甲胺基吡啶(22.4 mg，0.05當量)，且用氮氣沖洗。添加無水吡啶(7.34 mL)，接著添加3-氟-5-(三氟甲基)苯甲醯氯(837 µL，5.50 mmol)，且將反應混合物在環境溫度下攪拌1.5小時。添加水(20 mL)，且攪拌反應混合物10分鐘。經由燒結漏斗過濾混合物，且用水及少量乙腈沖洗沈澱物，接著風乾，得到呈白色粉末狀之N-(3-胺甲醯基苯基)-3-氟-5-(三氟甲基)苯甲醯胺(726 mg，2.22 mmol，61.0 %)。
步驟 2 ： 在氮氣下使用冰浴將N-(3-胺甲醯基苯基)-3-氟-5-(三氟甲基)苯甲醯胺(175 mg，0.5867 mmol)及N,N-二異丙基乙胺(107 µL，1.05當量)於無水THF (2.93 mL)中之溶液冷卻至0℃，且逐滴添加三光氣(174 mg，0.5867 mmol)於THF (3 mL)中之溶液。在0℃下攪拌反應混合物1小時，接著逐滴添加氫氧化銨(390 µL，5.86 mmol，25 wt%於水中)且攪拌10分鐘。反應混合物用水(15 mL)稀釋，用EtOAc (2×15 mL)萃取，用飽和NH4 Cl洗滌，經硫酸鈉乾燥，過濾且濃縮，得到呈茶色固體狀之N- [3-(胺甲醯基胺基)苯基]-3-氟-5-(三氟甲基)苯甲醯胺(210 mg，0.5845 mmol，99.5 %)。
步驟 3 ： 向反應小瓶中裝入N-[3-(胺甲醯基胺基)苯基]-3-氟-5-(三氟甲基)苯甲醯胺(100 mg，0.2930 mmol)及2-氯苯甲醛(49.4 mg，0.3515 mmol)，且添加含五氧化磷之MeOH (7.7重量%，0.5 mL，1.0當量)。將反應混合物加熱至80℃後維持45分鐘，隨後倒入飽和NaHCO3 中。混合物用EtOAc (2×15 mL)萃取，用飽和NaHCO3 (10 mL)洗滌，經硫酸鈉乾燥且濃縮至乾燥。經由逆相層析(12 g C18濾筒，5至70% ACN/AmF)純化，獲得呈白色固體狀之N-(4-(2-氯苯基)-2-側氧基-1,2,3,4-四氫喹唑啉-5-基)-3-氟-5-(三氟甲基)苯甲醯胺(8 mg，5.65%)。實例 22 N-[1-(2- 氯苯基 )-3- 側氧基 -1,2,3,4- 四氫異喹啉 -8- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5848
步驟 1 ： 向圓底燒瓶中裝入2-(3-胺基苯基)乙醯胺(250 mg，1.66 mmol)及4-二甲胺基吡啶(10.1 mg，0.05當量)且用氮氣沖洗。添加無水吡啶(5.53 mL)，接著添加3-氟-5-(三氟甲基)苯甲醯氯(379 µL，2.48 mmol)，且將反應混合物在環境溫度下攪拌16小時。將水(20 mL)添加至反應混合物，攪拌10分鐘，且沈澱物經過濾且風乾。在高真空中乾燥殘餘物，得到呈茶色粉末狀之N-[3-(胺甲醯基甲基)苯基]-3-氟-5-(三氟甲基)苯甲醯胺(570 mg，1.40 mmol，84.7 %)。
步驟 2 ： 向反應小瓶中裝入N-[3-(胺甲醯基甲基)苯基]-3-氟-5-(三氟甲基)苯甲醯胺(100 mg，0.2938 mmol)及2-氯苯甲醛(45.4 mg，0.3231 mmol)，接著添加含P2 O5 之MeOH (7.7重量%，0.5 mL，1.0當量)，且將反應混合物加熱至80℃後維持2小時。冷卻後，將反應混合物緩慢倒入飽和NaHCO3 (20 mL)中。濾出沈澱物，將其溶解於EtOAc中且濃縮至乾燥。藉由逆相層析(12 g C18濾筒，10至70% ACN/AmF)純化，在凍乾之後獲得呈白色粉末狀之N-[1-(2-氯苯基)-3-側氧基-1,2,3,4-四氫異喹啉-8-基]-3-氟-5-(三氟甲基)苯甲醯胺(24 mg，0.05185 mmol，17.7 %)實例 23 N-[5-(2- 氯 -5- 氟苯基 )-1- 甲基 -2,7- 二側氧基 -1H,2H,5H,6H,7H- 吡咯并 [3,4-b] 吡啶 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5850
步驟 1 ： 在15℃下向4,6-二氯吡啶甲酸(58.0 g，302 mmol)於二氯甲烷(1.80 L)中之溶液中添加CDI (73.4 g，453 mmol，1.50當量)及DMAP (1.11 g，9.06 mmol，0.03當量)，且攪拌混合物12小時。接著在25℃下向反應混合物中添加(4-甲氧基苯基)甲胺(41.4 g，302 mmol，39.1 mL)，且將混合物攪拌1.5小時。將混合物倒入水(2.00 L)中。有機層用水(500 mL×2)及鹽水(500 mL)洗滌，經Na2 SO4 乾燥，過濾且濃縮。來自兩批前述程序之殘餘物藉由矽膠管柱層析純化，用石油醚:乙酸乙酯=1:0至10:1溶離(產物：P1：Rf =0.50)，得到呈棕色固體狀之4,6-二氯-N-(4-甲氧基苯甲基)吡啶甲醯胺(165 g，453 mmol，75.1%產率)。
步驟 2 ： 在25℃下向4,6-二氯-N-(4-甲氧基苯甲基)吡啶甲醯胺(88.0 g，282 mmol，1.00當量)於THF (800 mL)中之混合物中添加NaH (22.6 g，565 mmol)，且攪拌混合物2小時。隨後在25℃下向混合物中添加2-氯-5-氟苯甲醯氯(81.8 g，424 mmol)於THF (80.0 mL)中之溶液，且攪拌混合物2小時。合併兩批前述反應混合物且用水(2.00 L)淬滅。用乙酸乙酯(1.00 L×2)萃取所得溶液。合併之有機層用鹽水(500 mL)洗滌，經Na2 SO4 乾燥，過濾且濃縮。殘餘物藉由矽膠管柱層析純化，用石油醚:乙酸乙酯=1:0至80:1溶離(產物：P1：Rf =0.60)，得到呈黃色固體狀之4,6-二氯-N -(2-氯-5-氟苯甲醯基)-N -(4-甲氧基苯甲基)吡啶甲醯胺(160 g，57.4%產率)。
步驟 3 ： 在-50℃下向4,6-二氯-N-(2-氯-5-氟苯甲醯基)-N-(4-甲氧基苯甲基)吡啶甲醯胺(72.0 g，153 mmol，1.00當量)於THF (720 mL)中之溶液中添加LiHMDS (1.00 M，230 mL，1.50當量)。在-50℃下攪拌混合物3小時。將兩批前述混合物合併且用水(3.00 L)淬滅。用乙酸乙酯(1.50 L×2)萃取所得溶液。合併之有機層用鹽水(1.00 L)洗滌，經Na2 SO4 乾燥，過濾且濃縮。殘餘物藉由矽膠管柱層析純化，用石油醚:乙酸乙酯=1:0至1:1溶離(產物：P1：Rf =0.30)，得到呈白色固體狀之2,4-二氯-5-(2-氯-5-氟苯基)-5-羥基-6-(4-甲氧基苯甲基)-5,6-二氫-7H-吡咯并[3,4-b]吡啶-7-酮(34.0 g，68.3 mmol，14.8%產率)。
步驟 4 ： 在25℃下向2,4-二氯-5-(2-氯-5-氟苯基)-5-羥基-6-(4-甲氧基苯甲基)-5,6-二氫-7H-吡咯并[3,4-b]吡啶-7-酮(34.0 g，68.3 mmol)於二氯甲烷(340 mL)中之溶液中添加Et3 SiH (79.4 g，683 mmol，109 mL)及BF3 ·Et2 O (31.0 g，218 mmol)。接著在40℃下攪拌混合物15小時。用飽和NaHCO3 溶液將混合物調節為pH 6至7。所得混合物用二氯甲烷(400 mL×2)萃取。合併之有機層用鹽水(300 mL)洗滌，經Na2 SO4 乾燥，過濾且濃縮。殘餘物藉由矽膠管柱層析純化，用石油醚:乙酸乙酯=1:0至10:1溶離(產物：P1：Rf =0.50)，得到呈白色固體狀之2,4-二氯-5-(2-氯-5-氟苯基)-6-(4-甲氧基苯甲基)-5,6-二氫-7H-吡咯并[3,4-b]吡啶-7-酮(32.0 g，64.4 mmol，95.8%產率)。
步驟 5 ： 在密封管中向2,4-二氯-5-(2-氯-5-氟苯基)-6-(4-甲氧基苯甲基)-5,6-二氫-7H-吡咯并[3,4-b]吡啶-7-酮(6.40 g，13.5 mmol)於i-PrOH (40.3 mL)中之溶液中添加(2,4-二甲氧基苯基)甲胺(3.40 g，20.3 mmol)及DIEA (5.26 g，40.7 mmol)。在190℃下攪拌混合物5小時。反應混合物經合併且濃縮，得到粗產物。隨後將粗產物溶解於100 mL DCM中，用鹽酸(0.50 M，50.0 mL)及鹽水(100 mL)洗滌，經Na2 SO4 乾燥，過濾且濃縮。藉由製備型HPLC (管柱：Phenomenex Luna c18 250mm×100mm×10.0μm；移動相：[水(0.225% FA)-ACN]；B%：45.0%-75.0%，20min)純化殘餘物，得到4-氯-5-(2-氯-5-氟苯基)-2-((2,4-二甲氧基苯甲基)胺基)-6-(4-甲氧基苯甲基)-5,6-二氫-7H-吡咯并[3,4-b]吡啶-7-酮(2.6 g，4.4 mmol，32.9%產率)。
步驟 6 ：將4-氯-5-(2-氯-5-氟苯基)-2-((2,4-二甲氧基苯甲基)胺基)-6-(4-甲氧基苯甲基)-5,6-二氫-7H-吡咯并[3,4-b]吡啶-7-酮(13.0 g，22.3 mmol，1.00當量)於TFA (120 g，1.05 mol，78.0 mL，47.2當量)中之懸浮液在25℃下攪拌7小時。用飽和NaHCO3 溶液將反應混合物調節至pH 9.00。用乙酸乙酯(1.00 L×3)萃取所得混合物。合併之有機層用鹽水(500 mL)洗滌，經Na2 SO4 乾燥，過濾且濃縮，得到呈灰白色固體狀之2-胺基-4-氯-5-(2-氯-5-氟苯基)-6-[(4-甲氧基苯基)甲基]-5H,6H,7H-吡咯并[3,4-b]吡啶-7-酮(9.97 g，17.3 mmol，77.9%產率)。
步驟 7 ： 在0℃下向2-胺基-4-氯-5-(2-氯-5-氟苯基)-6-[(4-甲氧基苯基)甲基]-5H,6H,7H-吡咯并[3,4-b]吡啶-7-酮(1 g，2.31 mmol)於MeOH (10 mL)中之溶液中添加TFA (880 μL)，接著添加亞硝酸三級丁酯(1.35 mL，11.5 mmol)。在環境溫度下攪拌混合物5小時，且接著添加NaHCO3 飽和水溶液。混合物用AcOEt (3×)萃取，且合併之有機層用鹽水洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由矽膠層析(0至30%丙酮/庚烷)純化，獲得呈白色發泡體/固體狀之4-氯-5-(2-氯-5-氟苯基)-2-甲氧基-6-[(4-甲氧基苯基)甲基]-5H,6H,7H-吡咯并[3,4-b]吡啶-7-酮(725 mg，70%)。
步驟 8 ： 將4-氯-5-(2-氯-5-氟苯基)-2-甲氧基-6-[(4-甲氧基苯基)甲基]-5H,6H,7H-吡咯并[3,4-b]吡啶-7-酮(525 mg，1.17 mmol)溶解於HCl於二㗁烷(4M，15 mL)中之溶液中。在環境溫度下攪拌混合物24小時，且小心地添加NaHCO3 飽和水溶液。用DCM萃取混合物(3次)，且合併之有機層用鹽水洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮，得到呈透明油狀之4-氯-5-(2-氯-5-氟苯基)-6-(4-甲氧基苯甲基)-4a,5,6,7a-四氫-1H-吡咯并[3,4-b]吡啶-2,7-二酮(506 mg，1.17 mmol，100%)。
步驟 9 ： 在環境溫度下向4-氯-5-(2-氯-5-氟苯基)-6-(4-甲氧基苯甲基)-4a,5,6,7a-四氫-1H-吡咯并[3,4-b]吡啶-2,7-二酮(506 mg，1.17 mmol)於無水及脫氣DMF (5.8 mL)中之溶液中添加碘甲烷(88.5 µL，1.75 mmol)，接著添加碳酸二鉀(485 mg，3.51 mmol)。在環境溫度下攪拌混合物12小時，且接著添加NH4 Cl之脫氣飽和水溶液。用DCM (3×)萃取混合物，且合併之有機層用鹽水洗滌，經MgSO4 乾燥，過濾且在減壓下濃縮。藉由矽膠層析(0至20%丙酮/庚烷)純化，獲得呈油狀之4-氯-5-(2-氯-5-氟苯基)-6-(4-甲氧基苯甲基)-1-甲基-5,6-二氫-1H-吡咯并[3,4-b]吡啶-2,7-二酮(432 mg，83%)。
步驟 10 ： 將4-氯-5-(2-氯-5-氟苯基)-6-(4-甲氧基苯甲基)-1-甲基-5,6-二氫-1H-吡咯并[3,4-b]吡啶-2,7-二酮(432 mg，0.9658 mmol)稀釋於1-(4-甲氧基苯基)甲胺(6.5 mL，49.7 mmol)中且將混合物在120℃下攪拌12小時(密封管)。混合物接著用AcOEt稀釋且用1N HCl溶液洗滌。分離各層，且用AcOEt (3×)萃取水層。合併之有機層用1N HCl洗滌，隨後用鹽水洗滌，經MgSO4 乾燥，過濾且在減壓下濃縮。藉由矽膠層析(0至40%丙酮/己烷)純化，獲得呈白色固體發泡體狀之5-(2-氯-5-氟苯基)-6-(4-甲氧基苯甲基)-4-((4-甲氧基苯甲基)胺基)-1-甲基-5,6-二氫-1H-吡咯并[3,4-b]吡啶-2,7-二酮(489 mg，92%)。
步驟 11 ： 將5-(2-氯-5-氟苯基)-6-(4-甲氧基苯甲基)-4-((4-甲氧基苯甲基)胺基)-1-甲基-5,6-二氫-1H-吡咯并[3,4-b]吡啶-2,7-二酮(425 mg，0.7755 mmol)溶解於TFA (0.6 mL)中且在120℃下攪拌4小時。添加四滴TfOH且在80℃下繼續攪拌12小時。小心地將混合物倒入NaHCO3 飽和水溶液中且用DCM (3×)及2MeTHF (3×)萃取。合併之有機層用鹽水洗滌，經Na2SO4乾燥，過濾且在減壓下濃縮。所得固體在MeOH中沈澱且藉由過濾回收，得到呈橙色固體狀之4-胺基-5-(2-氯-5-氟苯基)-1-甲基-1H,2H,5H,6H,7H-吡咯并[3,4-b]吡啶-2,7-二酮(260 mg，粗物質)。
步驟 12 ： 在環境溫度下向4-胺基-5-(2-氯-5-氟苯基)-1-甲基-1H,2H,5H,6H,7H-吡咯并[3,4-b]吡啶-2,7-二酮(50 mg，0.1624 mmol)於無水DCM (2 mL)中之溶液中添加3-氟-5-(三氟甲基)苯甲酸(40.5 mg，0.1948 mmol), 1-甲基-1H-咪唑(40.0 mg，0.4872 mmol)及[氯(二甲胺基)亞甲基]二甲基銨氮六氟磷酸鹽(68.3 mg，0.2436 mmol)。在環境溫度下攪拌混合物12小時。反應混合物接著用DCM (10 mL)及H2 O (10 mL)稀釋且穿過相分離器濾筒。隨後在真空中濃縮有機部分。藉由逆相層析(12 g管柱，水/ACN；水溶劑為10 mM甲酸銨)純化產物，以產生N-[5-(2-氯-5-氟苯基)-1-甲基-2,7-二側氧基-1H,2H,5H,6H,7H-吡咯并[3,4-b]吡啶-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(8.79 mg，10.8%)。實例 24 4- 胺基 -3- 甲氧基異吲哚啉 -1- 酮
Figure 02_image5852
步驟 1 ： 在0℃下向4-硝基-2,3-二氫-1H-異吲哚-1,3-二酮(15 g，78.0 mmol)於DCM (150 mL)及甲醇(150 mL)中之溶液中逐份添加NaBH4 (2.95 g，78.0 mmol)。使混合物升溫至室溫且攪拌1小時。將混合物濃縮至約100 mL且在布赫納漏斗上過濾，得到8.6 g呈白色粉末狀之3-羥基-4-硝基異吲哚啉-1-酮。回收濾液且再濃縮，隨後再次過濾。重複此程序，獲得額外4.7 g呈白色固體狀之3-羥基-4-硝基異吲哚啉-1-酮(13.3 g，88%)。LC-MS (方法1):  0.4 min,m/z = 193.1 [M-H]- 。
步驟 2 ： 向3-羥基-4-硝基異吲哚啉-1-酮(7 g，36 mmol)於甲醇(150 mL)中之懸浮液中添加Pd/C (10% on carbon, 2.5 g)，接著添加NaHCO3 (5 g)。將混合物用氫氣脫氣(真空及填充)，且在室溫下在氫氣壓力下攪拌12小時。隨後將混合物在Celite® 塞上過濾(用MeOH洗滌)且在減壓下濃縮。粗4-胺基-3-羥基異吲哚啉-1-酮不經進一步純化即用於下一步驟。
步驟 3 ： 將粗4-胺基-3-羥基異吲哚啉-1-酮稀釋於MeOH (150 mL)中且接著添加4N HCl溶液(10 mL)。在60℃下攪拌混合物15分鐘且接著使其冷卻至室溫。在減壓下移除揮發物且用NaHCO3 飽和水溶液處理混合物。用DCM (3×)及MeTHF (3×)萃取混合物。合併之有機層用鹽水洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由矽膠層析(0至80%丙酮/己烷)純化，得到呈橙色固體狀之4-胺基-3-甲氧基異吲哚啉-1-酮(1 g，22%)。LC-MS (方法1):  0.38 min,m/z = 179.2 [M+H]+ 。實例 25 6-([1,2,4] 三唑并 [1,5-a] 吡啶 -6- 基 )-4- 溴 -3-(2- 氯 -5- 氟苯基 )-2-(4- 甲氧基苯甲基 ) 異吲哚啉 -1- 酮
Figure 02_image5854
步驟 1 ： 在20℃下向4-胺基-6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苯甲基)異吲哚啉-1-酮(125 g，263 mmol)於DCM (1.25 L)中之溶液中添加DMAP (38.5 g，315 mmol)及Boc2 O (86.0 g，394 mmol)，且將混合物在20℃下攪拌12小時。將反應物倒入H2 O (2.00 L)中且進行劃分。合併之有機層用飽和NH4 Cl溶液(1.50 mL×3)洗滌，用鹽水(1.50 L)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮，得到殘餘物。藉由管柱層析(SiO2 ，石油醚/乙酸乙酯=100/1至10/1，Rf =0.55)純化殘餘物，得到呈黃色固體狀之化合物1及1a (196 g，粗物質)。
步驟 2 ：向化合物1及1a (98.0 g，粗物質)於DMF (980 mL)中之溶液中添加6-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-[1,2,4]三唑并[1,5-a]吡啶(50.1 g，204 mmol)及K2 CO3 (2 M，255 mL)。用N2 吹掃混合物三次。隨後在20℃下將Pd(dppf)Cl2 (6.23 g，8.51 mmol，0.05當量)添加至混合物中。再次用N2 吹掃混合物三次。隨後將混合物加熱至90℃且在90℃下攪拌1小時。將反應物倒入H2 O (5.00 L)中，攪拌且過濾。用乙酸乙酯(3.00 L)稀釋濾餅且過濾。合併之有機層用飽和NH4 Cl溶液(1.50 L)洗滌，用鹽水(1.50 L)洗滌，經Na2 SO4 乾燥，過濾且減壓濃縮，得到呈黑棕色固體狀之化合物2及2a (85.0 g，粗物質)。
步驟 3 ： 在20℃下向化合物2及2a (85.0 g，粗物質)於DCM (850 mL)中之溶液中添加TFA (655 g，5.74 mol)，接著將混合物在20℃下攪拌3小時。在減壓下濃縮反應物，得到油狀物。將油狀物用DCM (1.00 L)稀釋，倒入2 N NaOH (2.00 L)及冰中，且用DCM (1.00 L×3)萃取。合併之有機層用鹽水(2.00 L)洗滌，經Na2 SO4 乾燥，過濾且減壓濃縮，得到殘餘物。殘餘物藉由管柱層析(SiO2 ，石油醚/乙酸乙酯=10/1至乙酸乙酯/二氯甲烷=4/1，Rf =0.40)純化，得到呈黃色非晶形固體狀之6-([1,2,4]三唑并[1,5-a]吡啶-6-基)-4-胺基-3-(2-氯-5-氟苯基)-2-(4-甲氧基苯甲基)異吲哚啉-1-酮(57.5 g)。
步驟 4 ： 在0℃下向6-([1,2,4]三唑并[1,5-a]吡啶-6-基)-4-胺基-3-(2-氯-5-氟苯基)-2-(4-甲氧基苯甲基)異吲哚啉-1-酮(11.6 g，22.6 mmol)於ACN (110 mL)及HBr (173 g，705 mmol)中之溶液中添加NaNO2 (1.71 g，24.8 mmol，1.10當量)。在0℃下再攪拌重氮溶液30分鐘，且接著將CuBr (3.89 g，27.1 mmol)添加至混合物中且在0℃下攪拌1小時。將混合物倒入冰水(2.00 L)中且用DCM (1.00 L×3)萃取。合併之有機層經Na2 SO4 乾燥，過濾且在減壓下濃縮，得到殘餘物。藉由管柱層析(SiO2 ，石油醚/乙酸乙酯=1/1至0/1，Rf =0.50)純化殘餘物。在25℃下用乙酸乙酯(200 mL)濕磨所得產物16小時，得到呈綠色固體狀之6-([1,2,4]三唑并[1,5-a]吡啶-6-基)-4-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苯甲基)異吲哚啉-1-酮(8.3 g，12.8 mmol，56.7%產率)。實例 26 N-(3-(2- 氯 -5- 氟苯基 )-1- 側氧基 -6-(4,4,5,5- 四甲基 -1,3,2- 二氧硼㖦 -2- 基 ) 異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5856
在25℃下向N-(6-溴-3-(2-氯-5-氟苯基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(160 g，261 mmol)及B2 Pin2 (79.5 g，313 mmol，1.20當量)於二㗁烷(1.60 L)中之溶液中添加KOAc (76.8 g，783 mmol)及Pd(dppf)Cl2 (9.55 g，13.1 mmol，0.05當量)。將混合物用N2 吹掃三次，加熱至90℃且在90℃下攪拌14小時。向反應混合物中添加半飽和鹽水(0.50 L)，接著添加飽和Na2 S2 O3 水溶液(0.80 L)。水層用EtOAc (1.0 L)萃取，接著過濾混合物。在分離有機層之後，再次用EtOAc (1.00 L)萃取水層。合併之有機層用鹽水(0.50 L)洗滌，經Na2 SO4 乾燥，過濾且濃縮。將粗產物溶解於MTBE (3.00 V粗物質，600 mL)中，緩慢滴入庚烷(10.0 V粗物質，2.00 L)中，隨後在25℃下攪拌混合物2小時。過濾混合物，且在真空中乾燥濾餅。在25℃下用石油醚:乙酸乙酯=5:1 (600 mL)濕磨所得產物10小時。過濾混合物，且在真空中乾燥濾餅。獲得呈茶色非晶形固體狀之N-(3-(2-氯-5-氟苯基)-1-側氧基-6-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(157 g，96.3%產率)。實例 27 N-(3-(2- 氯 -5- 氟苯基 )-6- 羥基 -1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5858
在25℃下在N2 氛圍下向N-(3-(2-氯-5-氟苯基)-1-側氧基-6-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(97.0 g，0.164 mol，1.00當量)於ACN (1.00 L)中之溶液中添加H2 O2 -脲(28.9 g，0.307 mol，1.88當量)，接著將混合物在25℃下攪拌12小時。向混合物中添加半飽和鹽水(0.50 L)，接著添加飽和Na2 S2 O3 水溶液(0.80 L)。水層用乙酸乙酯(1.00 L)萃取，且隨後過濾混合物。在分離有機層之後，再次用乙酸乙酯(1.00 L)萃取水層。合併之有機層用鹽水(0.50 L)洗滌，經Na2 SO4 乾燥，過濾且濃縮。藉由管柱層析(SiO2 ，乙酸乙酯:二氯甲烷=1:10-1:4-1:1，Rf =0.30)純化粗產物。將粗產物溶解於MTBE (150 mL，3.00 V粗物質)中，緩慢滴入庚烷(520 mL，10.0 V粗物質)中，隨後將混合物加熱至50℃，且在50℃下攪拌1小時。將混合物冷卻至25℃且過濾，且在真空中乾燥濾餅，得到呈黃色固體狀之N-(3-(2-氯-5-氟苯基)-6-羥基-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(51.0 g，61.7%產率)。實例 28 1-(2- 氯 -5- 氟苯基 )-7-(3- 氟 -5-( 三氟甲基 ) 苯甲醯胺基 )-3- 側氧基異吲哚啉 -5- 甲酸甲酯
Figure 02_image5860
在25℃下向N-(6-溴-3-(2-氯-5-氟苯基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(120 g，220 mmol)於MeOH (1.00 L)中之溶液中添加Et3 N (44.5 g，440 mmol，61.2 mL)及Pd(dppf)Cl2 (16.1 g，22.0 mmol)。混合物經脫氣且用CO吹掃三次。將混合物加熱至80℃且在80℃下在CO (50 psi)下攪拌16小時。濃縮混合物，且藉由管柱層析(SiO2 ，石油醚:乙酸乙酯=50:1至0:1，Rf =0.1)純化殘餘物，得到呈粉紅色固體狀之1-(2-氯-5-氟苯基)-7-(3-氟-5-(三氟甲基)苯甲醯胺基)-3-側氧基異吲哚啉-5-甲酸甲酯(58.0 g，103 mmol，47.0%產率，93.6%純度)。實例 29 N-(6-( 溴甲基 )-3-(2- 氯 -5- 氟苯基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5862
步驟 1 ：在0℃下向氫化鋰鋁(7.16 g，188 mmol，2.20當量)於THF (100 mL)中之溶液中添加溶解於THF (300 mL)中之1-(2-氯-5-氟苯基)-7-(3-氟-5-(三氟甲基) 苯甲醯胺基)-3-側氧基異吲哚啉-5-甲酸甲酯(45.0 g，85.7 mmol，1.00當量)。使混合物升溫至25℃且在25℃下攪拌2小時。將混合物冷卻至-10℃且在攪拌下倒入Na2 SO4 *10H2 O (110 g)中，隨後在減壓下過濾且在壓力下濃縮濾液。在25℃下用混合物溶液(石油醚:乙酸乙酯=5:1，300 mL)濕磨殘餘物30分鐘，且在壓力下過濾，獲得呈棕色固體狀之N-(3-(2-氯-5-氟苯基)-6-(羥甲基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(50.0 g，粗物質)。
步驟 2 ： 在-20℃下向N-(3-(2-氯-5-氟苯基)-6-(羥甲基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(36.0 g，72.5 mmol)於THF (1200 mL)中之溶液中添加PBr3 (23.5 g，86.96 mmol)，接著將混合物升溫至0℃且在0℃下攪拌2小時。將混合物緩慢升溫至10℃且在10℃下攪拌10小時。在-20℃下將混合物滴加至飽和NH4 Cl (200 mL)中，接著用乙酸乙酯(500 mL×3)萃取。合併之有機層用鹽水(200 mL×3)洗滌，經Na2 SO4 乾燥，過濾且減壓濃縮。在10℃下用混合溶劑(石油醚:乙酸乙酯=3:1，100 mL)濕磨殘餘物30分鐘，以獲得呈白色固體狀之N-(6-(溴甲基)-3-(2-氯-5-氟苯基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(27.6 g，46.9 mmol，64.7%產率)。實例 30 (1-(2- 氯 -5- 氟苯基 )-7-(3- 氟 -5-( 三氟甲基 ) 苯甲醯胺基 )-3- 側氧基異吲哚啉 -5- 基 ) 甲烷磺醯氯
Figure 02_image5864
向100 mL圓底燒瓶中裝入N-(6-(溴甲基)-3-(2-氯-5-氟苯基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(1.05 g，1.0當量)及硫脲(149 mg，1.05當量)。添加乙醇(30 mL)，且將反應介質加熱至80℃且在攪拌下保持3小時。將反應介質冷卻至環境溫度，且在減壓下移除乙醇，得到白色粉末。將混合物溶解於MeCN (6 mL)中且冷卻至0℃。向反應混合物中逐滴添加鹽酸(1N，1.3 mL)，在0℃下保持攪拌20分鐘，此時逐份添加N -氯丁二醯亞胺(998 mg，4當量)。使反應介質升溫至環境溫度。在攪拌30分鐘之後，將反應混合物濃縮以產生呈橙色固體狀之(1-(2-氯-5-氟苯基)-7-(3-氟-5-(三氟甲基)苯甲醯胺基)-3-側氧基異吲哚啉-5-基)甲烷磺醯氯(1.01 g，92%產率)實例 31 N-(3-(2- 氯 -5- 氟苯基 )-6- 甲醯基 -1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-333)
Figure 02_image5866
步驟 1 ：在25℃下向N-(6-溴-3-(2-氯-5-氟苯基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(200 g，367 mmol)於二㗁烷(2.00 L)及H2 O (400 mL)中之溶液中添加乙烯基
Figure 110115674-A0304-12-01
酸頻哪醇酯(113 g，733 mmol)、Pd(dppf)Cl2 (26.8 g，36.7 mmol)及NaHCO3 (154 g，1.83 mol)，接著將混合物加熱至80℃且在80℃下攪拌12小時。將混合物倒入水(2.50 L)中且用乙酸乙酯(1.00 L×2)萃取。合併之有機相用鹽水(1.00 L×2)洗滌，經無水Na2 SO4 乾燥，過濾且真空濃縮。藉由管柱層析(SiO2 ，石油醚:乙酸乙酯=50:1-0:1，Rf =0.25)純化所得殘餘物，得到呈棕色固體狀之N-(3-(2-氯-5-氟苯基)-1-側氧基-6-乙烯基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(135 g，70.1%產率)。
步驟 2 ： 在-78℃下將臭氧鼓泡至N-(3-(2-氯-5-氟苯基)-1-側氧基-6-乙烯基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(52.0 g，106 mmol)於DCM (2.00 L)中之溶液中持續0.5小時。在用N2 吹掃過量O3 之後，在-78℃下添加Me2 S (7.21 g，116 mmol)，且將混合物在-78℃下攪拌0.5小時。兩批反應混合物用飽和NaHCO3 溶液(2.00 L)淬滅，且用DCM (1.20 L×3)萃取混合物。合併之有機層用鹽水(1.00 L)洗滌，經Na2 SO4 乾燥，過濾且濃縮。所得殘餘物藉由製備型HPLC (管柱：Phenomenex luna C18 (250×70mm，15 μm)；移動相：[水(0.225% FA)-ACN]；B%：43ACN%-63ACN%，20分鐘)純化，得到呈灰白色固體狀之N-(3-(2-氯-5-氟苯基)-6-甲醯基-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(42.0 g，40.1%產率)。實例 32 N-(2-([1,2,4] 三唑并 [1,5-a] 吡啶 -6- 基 )-5-(2- 氯 -5- 氟苯基 )-7- 側氧基 -6,7- 二氫 -5H- 吡咯并 [3,4-b] 吡啶 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5868
步驟 1 ： 將2,4-二氯-5-(2-氯-5-氟苯基)-6-(4-甲氧基苯甲基)-5,6-二氫-7H-吡咯并[3,4-b]吡啶-7-酮(6.000 g，13.2 mmol)在二甲氧基乙烷(60 mL)及乙醇(30 mL)之混合物中漿化。向其中添加6-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-[1,2,4]三唑并[1,5-a]吡啶(3.23 g，13.2 mmol)，接著添加25 mL 1.5 M碳酸鈉水溶液。藉由使N2 直接鼓泡至漿液中來使混合物脫氣10分鐘。添加鈀(2+)雙(三苯膦)二氯化物(370 mg，528 µmol)，且將混合物加熱至80℃後維持3小時。將反應混合物冷卻至室溫且用乙酸乙酯(150 mL)及水(50 mL)稀釋。用乙酸乙酯(100 mL)萃取混合物。合併之有機層用鹽水(100 mL)洗滌，經Na2 SO4 乾燥，過濾且濃縮。殘餘物藉由矽膠管柱層析純化，用庚烷:乙酸乙酯=1:1至0:100溶離(產物：P1：Rf =0.50)，得到呈灰白色固體狀之2-([1,2,4]三唑并[1,5-a]吡啶-6-基)-4-氯-5-(2-氯-5-氟苯基)-6-(4-甲氧基苯甲基)-5,6-二氫-7H-吡咯并[3,4-b]吡啶-7-酮(3.1 g，42.9%產率)。
步驟 2 ： 將2-([1,2,4]三唑并[1,5-a]吡啶-6-基)-4-氯-5-(2-氯-5-氟苯基)-6-(4-甲氧基苯甲基)-5,6-二氫-7H-吡咯并[3,4-b]吡啶-7-酮(2.0 g，3.74 mmol)溶解於3 mL NMP中且用1-(2,4-二甲氧基苯基)甲胺(2.8 mL，18.7 mmol)處理。將混合物加熱至150℃後維持30分鐘。將反應物冷卻至室溫，用乙酸乙酯(50 mL)及LiCl水溶液(25 mL)稀釋。有機層用4×25 mL LiCl水溶液洗滌，經Na2 SO4 乾燥，過濾且濃縮，得到呈灰白色固體狀之2-([1,2,4]三唑并[1,5-a]吡啶-6-基)-5-(2-氯-5-氟苯基)-4-((2,4-二甲氧基苯甲基)胺基)-6-(4-甲氧基苯甲基)-5,6-二氫-7H-吡咯并[3,4-b]吡啶-7-酮(2.5 g，3.60 mmol，96.7%產率)。
步驟 3 ： 將2-([1,2,4]三唑并[1,5-a]吡啶-6-基)-5-(2-氯-5-氟苯基)-4-((2,4-二甲氧基苯甲基)胺基)-6-(4-甲氧基苯甲基)-5,6-二氫-7H-吡咯并[3,4-b]吡啶-7-酮(2.5 g，3.75 mmol)溶解於DCM (2 mL)中且滴加至三氟乙酸(5.7 mL，75 mmol，20當量)中。在室溫下攪拌混合物16小時。混合物經真空濃縮，隨後用二氯甲烷(50 mL)稀釋。將其緩慢添加至冰冷的碳酸氫鈉飽和水溶液(50 mL)之攪拌混合物中。隨後經由添加2 N氫氧化鈉將pH調節至pH 10。攪拌混合物5小時。有機層用水(50 mL)、鹽水(50 mL)洗滌，經Na2 SO4 乾燥，過濾且濃縮。所得殘餘物用MTBE (25 mL)濕磨60分鐘且接著過濾，得到呈灰白色固體狀之2-([1,2,4]三唑并[1,5-a]吡啶-6-基)-4-胺基-5-(2-氯-5-氟苯基)-6-(4-甲氧基苯甲基)-5,6-二氫-7H-吡咯并[3,4-b]吡啶-7-酮(1.6 g，82.9%產率)。
步驟 4 ： 將2-([1,2,4]三唑并[1,5-a]吡啶-6-基)-4-胺基-5-(2-氯-5-氟苯基)-6-(4-甲氧基苯甲基)-5,6-二氫-7H-吡咯并[3,4-b]吡啶-7-酮(2.50 g，4.85 mmol)溶解於乙腈(30 mL)中。添加吡啶(3.9 mL，48.5 mmol)，接著添加3-氟-5-(三氟甲基)苯甲醯氯(1.31 g，5.81 mmol，1.2當量)。將反應物加熱至80℃後維持16小時。將反應物冷卻至室溫且用乙酸乙酯(100 mL)稀釋。將其小心地用10%碳酸鈉水溶液(3×50 mL)，接著用鹽水(50 mL)洗滌。溶液經Na 2SO4 乾燥，過濾且濃縮。將殘餘物在MTBE (25 mL)中濕磨2小時且過濾，得到N-(2-([1,2,4]三唑并[1,5-a]吡啶-6-基)-5-(2-氯-5-氟苯基)-6-(4-甲氧基苯甲基)-7-側氧基-6,7-二氫-5H-吡咯并[3,4-b]吡啶-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(2.5 g，73.3%產率)。
步驟 5 ： 將N-(2-([1,2,4]三唑并[1,5-a]吡啶-6-基)-5-(2-氯-5-氟苯基)-6-(4-甲氧基苯甲基)-7-側氧基-6,7-二氫-5H-吡咯并[3,4-b]吡啶-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(1.00 g，1.41 mmol)溶解於乙腈(18 mL)中。添加水溶液(2 mL)形式之硝酸鈰銨(1.54 g，2.82 mmol)。使反應物升溫至40℃後維持30分鐘。將反應物冷卻至室溫且小心地用亞硫酸氫鈉於水中之溶液淬滅。用MeTHF (3×20 mL)萃取混合物。合併之有機物接著用水(20 mL)、鹽水(30 mL)洗滌，經Na2 SO4 乾燥，過濾且濃縮。殘餘物藉由矽膠管柱層析純化，用二氯甲烷:甲醇=100:0至85:15溶離，得到呈白色固體狀之N-(2-([1,2,4]三唑并[1,5-a]吡啶-6-基)-5-(2-氯-5-氟苯基)-7-側氧基-6,7-二氫-5H-吡咯并[3,4-b]吡啶-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(514 mg，62.3%產率)。實例 33 N-[3-(2- 氯 -5- 氟苯基 )-6-(1H- 吲哚 -2- 基 )-1- 側氧基 -2,3- 二氫 -1H- 異吲哚 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5870
向8 mL小瓶中添加N-[6-溴-3-(2-氯-5-氟苯基)-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(100 mg，183 µmol)、2-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-1H-吲哚(44.4 mg，1當量)、碳酸鈉(48.4 mg，2.5當量)及雙(三苯膦)二氯化鈀(10.5 mg，0.15當量)。小瓶用氮氣吹掃且密封。隨後將固體溶解於二㗁烷(1.6 mL)及水(0.4 mL)中。接著攪拌反應物且將其加熱至90℃後維持1小時，隨後經由LCMS檢查反應進程。冷卻反應混合物且經由二氧化矽墊過濾。濃縮濾液，且將所得物質在AccQ Prep系統上純化，用含0.1%甲酸之30-60%水溶離。濃縮含產物之溶離份，以產生-[3-(2-氯-5-氟苯基)-6-(1H-吲哚-2-基)-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(87.6 mg，82.6%)。實例 34 N-[3-(2- 氯 -5- 氟苯基 )-6-[3-( 二氟甲基 ) 咪唑并 [1,2-a] 吡啶 -6- 基 ]-1- 側氧基 -2,3- 二氫 -1H- 異吲哚 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5872
向小瓶中添加N-[3-(2-氯-5-氟苯基)-1-側氧基-6-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(381 mg，644 µmol)、6-溴-3-(二氟甲基)咪唑并[1,2-a]吡啶(145 mg，586 µmol)、雙(三苯膦)二氯化鈀(2+) (61.6 mg，87.8 µmol)及碳酸二鈉(185 mg，1.75 mmol)。小瓶經吹掃且用氮氣回填，且接著添加水(250 µL)及二㗁烷(1 mL)。隨後將反應混合物加熱至90℃後維持20分鐘。接著經由LCMS檢查反應進程，其顯示完全轉化為產物。接著將混合物冷卻，過濾且置於AccQ prep系統上。濃縮含有產物之溶離份，以產生N-[3-(2-氯-5-氟苯基)-6-[3-(二氟甲基)咪唑并[1,2-a]吡啶-6-基]-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(145 mg，39.1%)。
根據實例33及實例34之方法製備之額外化合物列於下表10中。表10中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 10. 額外例示性化合物
化合物 化合物 化合物
I-705    I-741    I-822
I-712    I-782    I-823
I-732    I-783    I-824
I-736    I-784    I-825
I-737    I-815    I-826
I-738    I-821    I-827
I-838    I-928    I-1006
I-849    I-929    I-1007
I-851    I-930    I-1008
I-852    I-931    I-1009
I-853    I-932    I-1010
I-854    I-933    I-1011
I-855    I-934    I-1012
I-865    I-940    I-1023
I-866    I-941    I-1024
I-881    I-943    I-1025
I-882    I-945    I-1026
I-883    I-946    I-1027
I-884    I-948    I-1028
I-885    I-949    I-1030
I-886    I-967    I-1032
I-887    I-969    I-1033
I-888    I-970    I-1034
I-890    I-971    I-1035
I-891    I-972    I-1036
I-892    I-975    I-1037
I-893    I-979    I-1038
I-894    I-980    I-1039
I-895    I-981    I-1041
I-896    I-982    I-1042
I-902    I-984    I-1043
I-905    I-985    I-1044
I-906    I-986    I-1045
I-915    I-987    I-1047
I-918    I-996    I-1048
I-919    I-1000    I-1049
I-921    I-1003    I-1053
I-927    I-1004    I-1054
I-1055    I-1150    I-1272
I-1056    I-1151    I-1303
I-1057    I-1152    I-1329
I-1059    I-1156    I-1330
I-1061    I-1163    I-1331
I-1062    I-1165    I-1332
I-1063    I-1166    I-1335
I-1065    I-1167    I-1340
I-1089    I-1168    I-1342
I-1090    I-1169    I-1343
I-1091    I-1170    I-1368
I-1092    I-1171    I-1369
I-1093    I-1172    I-1373
I-1094    I-1173    I-1374
I-1095    I-1174    I-1390
I-1098    I-1190    I-1405
I-1101    I-1193    I-1406
I-1102    I-1195    I-1407
I-1103    I-1197    I-1408
I-1105    I-1207    I-1409
I-1106    I-1208    I-1410
I-1107    I-1214    I-1411
I-1108    I-1215    I-1413
I-1111    I-1216    I-1415
I-1116    I-1217    I-1416
I-1117    I-1219    I-1419
I-1121    I-1220    I-1437
I-1122    I-1222    I-1438
I-1123    I-1231    I-1439
I-1124    I-1232    I-1440
I-1136    I-1264    I-1441
I-1137    I-1265    I-1442
I-1443    I-1553    I-1665
I-1444    I-1573    I-1667
I-1445    I-1574    I-1676
I-1448    I-1583    I-1684
I-1449    I-1584    I-1685
I-1452    I-1585    I-1688
I-1453    I-1586    I-1690
I-1454    I-1589    I-1692
I-1455    I-1598    I-1693
I-1456    I-1599    I-1694
I-1458    I-1600    I-1696
I-1464    I-1601    I-1700
I-1474    I-1602    I-1701
I-1482    I-1603    I-1702
I-1483    I-1604    I-1703
I-1492    I-1605    I-1704
I-1499    I-1609    I-1707
I-1500    I-1624    I-1708
I-1506    I-1627    I-1723
I-1529    I-1628    I-1724
I-1530    I-1630    I-1730
I-1531    I-1631    I-1734
I-1537    I-1645    I-1743
I-1538    I-1646    I-1744
I-1539    I-1647    I-1750
I-1540    I-1648    I-1751
I-1542    I-1649    I-1758
I-1544    I-1650    I-1759
I-1547    I-1652    I-1760
I-1549    I-1653    I-1767
I-1550    I-1662    I-1773
I-1552    I-1664    I-1777
I-1778    I-1842    I-1913
I-1779    I-1843    I-1922
I-1780    I-1844    I-1923
I-1781    I-1845    I-1924
I-1782    I-1847    I-1925
I-1783    I-1848    I-1928
I-1785    I-1849    I-1929
I-1786    I-1850    I-1932
I-1787    I-1855    I-1933
I-1792    I-1856    I-1934
I-1793    I-1858    I-1936
I-1796    I-1859    I-1937
I-1797    I-1864    I-1938
I-1802    I-1865    I-1939
I-1803    I-1866    I-1947
I-1804    I-1869    I-1948
I-1812    I-1870    I-1957
I-1813    I-1873    I-1960
I-1814    I-1874    I-1964
I-1816    I-1875    I-1966
I-1817    I-1876    I-1982
I-1821    I-1877    I-1983
I-1822    I-1878    I-1984
I-1825    I-1879    I-1985
I-1827    I-1880    I-1986
I-1829    I-1881    I-1987
I-1830    I-1882    I-1990
I-1831    I-1883    I-1991
I-1834    I-1884    I-1992
I-1838    I-1899    I-2000
I-1839    I-1900    I-2001
I-1840    I-1910    I-2002
I-2003    I-2045    I-2170
I-2004    I-2051    I-2185
I-2008    I-2063    I-2185
I-2012    I-2064    I-2186
I-2015    I-2065    I-2200
I-2028    I-2066    I-2201
I-2029    I-2067    I-2233
I-2030    I-2068    I-2234
I-2031    I-2069    I-2258
I-2032    I-2125    I-2259
I-2033    I-2137    I-2267
I-2034    I-2146    I-2289
I-2035    I-2147    I-2290
I-2037    I-2161    I-2706
I-2044    I-2169    I-2707
實例 35 N-[3-(2- 氯 -5- 氟苯基 )-6-[( 氧雜環丁烷 -2- 基 ) 甲基 ]-1- 側氧基 -2,3- 二氫 -1H- 異吲哚 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5874
向4 mL小瓶中添加4,4'-二-三級丁基-2,2'-二吡啶基(3.67 mg，0.05當量)及NiCl2 (3.07 mg，0.01當量)，及二㗁烷(1.0 mL)。攪拌溶液且用氮氣鼓泡15分鐘，直至其變為淡藍色。在攪拌鎳配位體儲備溶液的同時，向具有攪拌棒之8 mL小瓶中添加溶解於二㗁烷(2.73 mL)中之N-[6-溴-3-(2-氯-5-氟苯基)-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(150 mg，274 µmol)及[Ir{dF(CF3 )ppy}2 (dtbpy)]PF6 (3.07 mg，0.01當量)。將混合物用氮氣吹掃且攪拌。向含Ir之混合物中依序添加二甲基吡啶(95.1 µL，3當量)、1,1,1,3,3,3-六甲基二矽氮烷(68.1 mg，1.0當量)、鎳配位體儲備溶液，接著添加2-(溴甲基)氧雜環丁烷(39.5 µL，1.5當量)。將反應物鼓泡10分鐘，隨後用封口膜及真空油脂密封。將反應物置放於Merck光反應器中以在100%強度(波長：365nm至450nm)下運行3小時，隨後經由LCMS檢查反應進程。反應物經濃縮且在AccQ系統上純化，用含0.1%甲酸之30%-60%水溶離。含產物之溶離份經凍乾，以產生N-[3-(2-氯-5-氟苯基)-6-[(氧雜環丁烷-2-基)甲基]-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(94 mg，63.9%)。
根據實例35之方法製備之額外化合物列於下表11中。表11中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 11. 額外例示性化合物
化合物
I-529
I-1376
實例 36 N-[3-(2- 氯 -5- 氟苯基 )-1- 側氧基 -6-(5- 側氧基 -5,6- 二氫 -1,6- 㖠啶 -6- 基 )-2,3- 二氫 -1H- 異吲哚 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5876
向可再密封之反應小瓶中裝入5,6-二氫-1,6-㖠啶-5-酮(20 mg，0.1368 mmol)、N-[6-溴-3-(2-氯-5-氟苯基)-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(74.6 mg，0.1368 mmol)、碘化銅(I) (3.90 mg，0.15當量)、碳酸二鉀(8.50 mg，0.45當量)及攪拌棒，隨後抽空且用氮氣吹掃三次。添加二甲基甲醯胺(0.5 mL)，且在130℃下攪拌混合物隔夜。隨後使反應混合物冷卻且用水稀釋。用乙酸乙酯萃取水層3次。有機層用鹽水洗滌，經硫酸鈉乾燥，過濾且濃縮。所得物質藉由製備型HPLC (乙腈/水/0.1%甲酸)純化。含產物之溶離份經凍乾，以產生產物N-[3-(2-氯-5-氟苯基)-1-側氧基-6-(5-側氧基-5,6-二氫-1,6-㖠啶-6-基)-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(3.91 mg，4.4%)。實例 37 N-[3-(2- 氯 -5- 氟苯基 )-1- 側氧基 -6-[( 嘧啶 -5- 基 ) 甲氧基 ]-2,3- 二氫 -1H- 異吲哚 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5878
向20 mL小瓶中添加溶解於四氫呋喃(5 mL)中之N-[3-(2-氯-5-氟苯基)-6-羥基-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(100 mg，207 µmol)、(嘧啶-5-基)甲醇(22.7 mg，207 µmol)、三苯膦(70.5 mg，1.3當量)及偶氮二甲酸二異丙酯(52.8 µL，1.3當量)。攪拌反應物且在回流下加熱20分鐘。經由LCMS檢查反應進程且展示完全轉化為產物。用AccQ prep系統純化反應混合物，以產生N-[3-(2-氯-5-氟苯基)-1-側氧基-6-[(嘧啶-5-基)甲氧基]-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(46.4 mg，38.9%)。
根據實例37之方法製備之額外化合物列於下表12中。表12中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 12. 額外例示性化合物
化合物 化合物 化合物
I-708    I-1132    I-1366
I-709    I-1135    I-1375
I-735    I-1149    I-1378
I-739    I-1160    I-1412
I-740    I-1184    I-1414
I-748    I-1192    I-1421
I-773    I-1198    I-1431
I-812    I-1205    I-1432
I-819    I-1210    I-1457
I-873    I-1221    I-1466
I-977    I-1234    I-1467
I-1064    I-1239    I-1468
I-1113    I-1251    I-1517
I-1129    I-1252    I-1518
I-1131    I-1253    I-1519
I-1132    I-1289    I-1520
I-1135    I-1295    I-1521
I-1149    I-1298    I-1522
I-1160    I-1304    I-1523
I-1184    I-1305    I-1524
I-1192    I-1320    I-1525
I-1198    I-1322    I-1526
I-1205    I-1333    I-1527
I-1210    I-1334    I-1541
I-873    I-1338    I-1566
I-977    I-1341    I-1567
I-1064    I-1346    I-1568
I-1113    I-1347    I-1569
I-1129    I-1348    I-1735
I-1131    I-1357    I-1736
I-1887    I-2006    I-2061
I-1888    I-2007    I-2062
I-1935    I-2009    I-2134
I-2005            
實例 38 N-[3-(2- 氯 -5- 氟苯基 )-1- 側氧基 -6-{[(1r*,3r**)-3- 羥基環丁基 ] 胺基 }-2,3- 二氫 -1H- 異吲哚 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5880
在微波小瓶中，N-[6-溴-3-(2-氯-5-氟苯基)-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(70 mg，128 µmol)、(1r*,3r**)-3-胺基環丁-1-醇鹽酸鹽(31.6 mg)及BrettPhos Pd G4 (35.3 mg)於甲苯(1.5 mL)中之溶液藉由使氮氣穿過該溶液而脫氣。向反應混合物中添加雙(三甲基矽基)胺基化鋰(512 µL，512 µmol)。將管密封且在110℃下加熱1小時。用水(2 mL)淬滅反應物且使混合物穿過Celite®。在C18逆相管柱(12 g濾筒)上使用含5-60% ACN之水作為溶離劑來純化粗混合物。收集含有所需產物之溶離份且凍乾，以產生N-[3-(2-氯-5-氟苯基)-1-側氧基-6-{[(1r*,3r**)-3-羥基環丁基]胺基}-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(2 mg，2.8%)。
根據實例38之方法製備之額外化合物列於下表13中。表13中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 13. 額外例示性化合物
化合物 化合物 化合物
I-39    I-723    I-1164
I-51    I-728    I-1181
I-53    I-729    I-1189
I-275    I-730    I-1227
I-284    I-780    I-1233
I-288    I-781    I-1236
I-304    I-814    I-1237
I-311    I-830    I-1248
I-312    I-848    I-1249
I-310    I-868    I-1250
I-321    I-869    I-1260
I-329    I-899    I-1261
I-338    I-900    I-1262
I-343    I-960    I-1263
I-359    I-1015    I-1267
I-370    I-1040    I-1273
I-375    I-1069    I-1291
I-478    I-1070    I-1299
I-530    I-1082    I-1301
I-532    I-1086    I-1309
I-540    I-1125    I-1310
I-541    I-1126    I-1354
I-609    I-1127    I-1387
I-613    I-1128    I-1388
I-695    I-1140    I-2148
I-707    I-1146    I-2192
I-721            
實例 39 N -(6-( 胺基甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [b ] 噻吩 -3- 甲醯胺 (I-88)
Figure 02_image5882
向反應容器中裝入N -[6-溴-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1-苯丙噻吩-3-甲醯胺(20 mg，0.04189 mmol)、2-{[(三級丁氧基)羰基]胺基}乙酸(22.0 mg，0.1256 mmol)、Cs2 CO3 (40.8 mg，0.1256 mmol)、NiCl2 ∙DME (1.37 mg，0.006283 mmol)、4,4'-二-三級丁基-2,2'-二吡啶基(1.68 mg，0.006283 mmol)及[Ir{dF(CF3 )ppy}2 (dtbpy)]PF6 (0.02 mol%)。反應容器經密封，抽空且用N2 吹掃。隨後添加0.3 mL DMAC，且混合物在環境溫度下攪拌16小時，同時用Kessel燈照射。反應混合物用EtOAc稀釋且經由矽膠塞過濾。
濾液經濃縮，接著用1:1 TFA及DCM稀釋且攪拌4小時。反應物經濃縮，且藉由逆相HPLC使用如下之梯度純化產物：水(0.1% FA)及乙腈(0.1% FA) 80/20至30/70於13分鐘內，接著5/95。含產物之溶離份經合併且凍乾，得到N -(6-(胺基甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[b ]噻吩-3-甲醯胺(2 mg，10%)。
根據實例39之方法製備之額外化合物列於下表14中。下表14中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 14. 額外例示性化合物
化合物 化合物 化合物
I-87    I-126    I-207
I-89    I-140    I-223
I-90    I-155    I-260
實例 40 N -[6- 胺基 -3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-1,2- 苯并噻唑 -3- 甲醯胺 (I-50)
Figure 02_image5884
向反應容器中裝入N -[6-溴-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-1,2-苯并噻唑-3-甲醯胺(50 mg，0.1 mmol)及Pd(t Bu)3 P-G4 (13.7 mg，0.017 mmol)。將反應容器抽成真空且用N2 吹掃。隨後添加0.6 mL甲苯，且在環境溫度下攪拌混合物5分鐘。隨後添加LiHMDS (0.5 mL，0.5 mmol)，且在50℃下攪拌混合物16小時。混合物用2 mL MeOH (0.1% FA)稀釋，攪拌且接著濃縮。所得殘餘物用2 mL DMSO稀釋且藉由逆相HPLC使用如下之梯度純化：水(0.1% FA)及乙腈(0.1% FA) 70/30至35/65於13分鐘內，接著5/95。含產物之溶離份經合併且凍乾，得到N -[6-胺基-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1,2-苯并噻唑-3-甲醯胺(10 mg，20 %)。
根據實例40之方法製備之額外化合物列於下表15中。下表15中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 15. 額外例示性化合物
化合物 化合物 化合物
I-34    I-91    I-217
I-40    I-92    I-218
I-65    I-125    I-289
I-66    I-213      
實例 41 N -[6- 乙烯基 -3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-1- 苯丙噻吩 -3- 甲醯胺 (I-100)
Figure 02_image5886
向配備有攪拌棒之旋蓋式玻璃反應小瓶中添加N -[6-溴-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1-苯丙噻吩-3-甲醯胺(80 mg，167.0 μmol)、1,4-二㗁烷(1.5 mL)、三丁基(乙烯基)錫(80 μL, 273 umol)、DABCO (2.00 mg，17.8 μmol)及TBAF (500 μL)。懸浮液藉由冷凍-泵送-解凍循環(3個循環)脫氣，接著用氮氣鼓泡10分鐘。接著將乙酸鈀(2.00 mg，8.90 μmol)引入至懸浮液中。密封懸浮液，且將小瓶置於預加熱油浴(110℃，外部)中直至認為反應完成(約16小時)。反應混合物經由矽藻土過濾且用乙酸乙酯洗滌。在減壓下蒸發合併之有機溶離份，得到粗殘餘物。此粗殘餘物經由小矽膠墊過濾，且首先用己烷且接著用乙酸乙酯溶離。在減壓下蒸發合併之有機溶離份，得到粗產物。將大約一半此粗產物藉由正相急驟管柱層析(用20% EtOAc/己烷至100%乙酸乙酯之梯度溶離)純化，得到呈灰白色固體狀之N -[6-乙烯基-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1-苯丙噻吩-3-甲醯胺(9 mg)。實例 42 N -[6-(2- 羥乙基 )-3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-1- 苯丙噻吩 -3- 甲醯胺 (I-181)
Figure 02_image5888
步驟 1 ：向配備有攪拌棒之圓底燒瓶中裝入粗N -[6-乙烯基-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1-苯丙噻吩-3-甲醯胺(約25 mg，約59 μmol)於THF (1.0 mL)中之溶液。在室溫下向此溶液中添加過量BH3 ∙THF (1.0 M THF溶液，0.2 mL，200 μmol)。接著在室溫下攪拌溶液4小時。向此溶液中添加過硼酸鈉四水合物(30.7 mg，200 μmol)，且攪拌混合物5分鐘。隨後向溶液中添加水(1.0 mL)，且攪拌混合物隔夜。在減壓下蒸發溶液，得到粗殘餘物。藉由逆相急驟管柱層析(12 g，C18，用增加量之乙腈(0-100%)自初始10 mM碳酸氫銨/水中溶離)純化粗殘餘物，在凍乾之後得到呈白色粉末狀之所需醇及少量雜質之混合物。使用製備型HPLC (梯度20%至100%乙腈於0.1% FA/水中)進一步純化此白色粉末，以在凍乾純溶離份之後得到3.2 mg呈白色固體狀之N -[6-(2-羥乙基)-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1-苯丙噻吩-3-甲醯胺。
根據實例42之方法製備之額外化合物列於下表16中。下表16中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 16. 額外例示性化合物
化合物
I-119
I-434
I-579
實例 43 N -[6-(1,2- 二羥乙基 )-3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-1- 苯丙噻吩 -3- 甲醯胺 (I-139)
Figure 02_image5890
步驟 1 ：向配備有攪拌棒之圓底燒瓶中裝入粗N -[6-乙烯基-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1-苯丙噻吩-3-甲醯胺(約25 mg，約59 μmol)於THF (1.5 mL)及水(0.4 mL)中之溶液。向此反應混合物中添加NMO (6.6 mg，56 μmol)及鋨酸鉀(VI)二水合物(1.9 mg，5 μmol)。將溶液攪拌兩小時。在減壓下蒸發揮發物，得到殘餘物，其藉由正相急驟管柱層析(用20% EtOAc/己烷至100% EtOAc之梯度，接著10% MeOH/EtOAc溶離)純化，自MeOH/EtOAc溶離份獲得所需二醇非對映異構體之1:1混合物。在減壓下蒸發溶劑，得到經濃縮之二醇混合物。進一步藉由逆相急驟管柱層析(用10mM碳酸氫銨/水至100%乙腈之梯度溶離)純化二醇混合物。凍乾純溶離份，獲得4.8 mg呈白色固體狀之非對映異構體之1:1混合物形式之所需二醇N -[6-(1,2-二羥乙基)-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1-苯丙噻吩-3-甲醯胺。
根據實例43之方法製備之額外化合物列於下表17中。下表17中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 17. 額外例示性化合物
化合物
I-120
I-382
實例 44 N -[6-( 羥甲基 )-3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-1,2- 苯并噻唑 -3- 甲醯胺 (I-131)
Figure 02_image5892
7- 胺基 -2-(4- 甲氧基苯甲基 )-3- 側氧基 -1-( 鄰甲苯基 ) 異吲哚啉 -5- 甲酸甲酯及 2-(4- 甲氧基苯甲基 )-7-(( 甲氧羰基 ) 胺基 )-3- 側氧基 -1-( 鄰甲苯基 ) 異吲哚啉 -5- 甲酸甲酯
Figure 02_image5894
步驟 1 ：向4-胺基-6-溴-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(17.1 g，39.1 mmol，1.00當量)於MeOH (500 mL)中之溶液中添加DPPF (2.17 g，3.91 mmol，0.10當量)、Pd(OAc)2 (1.76 g，7.82 mmol，0.20當量)及KOAc (11.5 g，117 mmol，3.00當量)。混合物經脫氣且用CO吹掃三次。將混合物加熱至80℃且在80℃下在CO (50 psi)下攪拌10小時。LCMS顯示大量未消耗的4-胺基-6-溴-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮。在80℃下攪拌混合物120小時。過濾混合物，且真空濃縮濾液，得到粗產物。粗產物藉由管柱層析(SiO2 ，石油醚/乙酸乙酯=1/0至0/1)純化，得到呈淡黃色固體狀之7-胺基-2-(4-甲氧基苯甲基)-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲酸甲酯(MS:m/z = 417.2 [M+H]+ )及2-(4-甲氧基苯甲基)-7-((甲氧羰基)胺基)-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲酸甲酯(11.5 g，22.9 mmol，58.6%產率，94.5%純度)。
2-(4-甲氧基苯甲基)-7-((甲氧羰基)胺基)-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲酸甲酯之表徵資料：MS:m/z = 475.3 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 9.17 (d,J = 16.4 Hz, 1H), 8.13 (dd,J = 23.6, 1.2 Hz, 1H), 7.94 (d,J = 1.2 Hz, 1H), 7.60 (d,J = 19.4 Hz, 1H), 6.93 - 6.83 (d,J = 19.4 Hz, 1H), 7.45 (d,J = 24 Hz, 1H), 7.28 - 7.22 (m, 5H), 7.07 - 7.00 (m, 6H), 6.91 - 6.87 (m, 4H), 6.46 (d,J = 7.6 Hz, 1H), 6.29 (d,J = 7.6 Hz, 1H), 5.97 (s, 1H), 5.73 (s, 1H), 5.63 (s, 1H), 5.50 (s, 1H), 5.01 - 4.91 (m, 2H), 4.77 (s, 1H), 3.92 (d,J = 4.8 Hz, 4H), 3.87 (d,J = 4.8 Hz, 2H), 3.74 (d,J = 8.0 Hz, 6H), 3.62(d,J = 14.8 Hz, 1H), 3.49 (d,J = 9.6 Hz, 5H), 2.25 (d,J = 18.4 Hz, 3H), 1.48 (s, 1H), 1.34 (s, 2H)。4- 胺基 -6-( 羥甲基 )-2-[(4- 甲氧基苯基 ) 甲基 ]-3-(2- 甲基苯基 )-2,3- 二氫 -1H - 異吲哚 -1- 酮
Figure 02_image5896
步驟 2 ：將7-胺基-2-(4-甲氧基苯甲基)-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲酸甲酯(516 mg，1.24 mmol)於THF (6.19 mL)中之溶液在氮氣氛圍下攪拌且使用冰浴冷卻至0℃。隨後添加硼烷氫化鋰(930 µL，1.86 mmol，2 M於THF中)之溶液，且使混合物升溫至室溫後維持隔夜。反應混合物用水(20 mL)淬滅，用DCM (3×20 mL)萃取，且在減壓下濃縮合併之有機相。所得殘餘物藉由逆相層析(60 g管柱C18，10至100% ACN/AmF 10 mM)純化，在凍乾之後得到呈白色粉末狀之4-胺基-6-(羥甲基)-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-2,3-二氫-1H -異吲哚-1-酮(188 mg，0.484 mmol，39%產率)。MS:m/z = 389.3 [M+H]+ 。 N -[6-( 羥甲基 )-2-[(4- 甲氧基苯基 ) 甲基 ]-3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-1,2- 苯并噻唑 -3- 甲醯胺
Figure 02_image5898
步驟 3 ：向4-胺基-6-(羥甲基)-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-2,3-二氫-1H -異吲哚-1-酮(150 mg，0.3861 mmol)於DCM (1.93 mL)中之溶液中添加1H -咪唑(65.7 mg，0.9652 mmol)，且使用冰浴將反應混合物冷卻至0℃。接著添加三級丁基(氯)二甲基矽烷(69.8 mg，0.4633 mmol)，且在室溫下攪拌反應混合物2小時。
向反應混合物中添加1,2-苯并噻唑-3-甲醯氯(76.3 mg，0.3861 mmol)，且在室溫下攪拌反應混合物3天。將反應混合物濃縮至乾燥且藉由逆相層析(60 g C18管柱，10至100% ACN/AmF 10 mM)純化，以在凍乾之後得到呈橙色粉末狀之N -[6-(羥甲基)-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1,2-苯并噻唑-3-甲醯胺(80.5 mg，0.1466 mmol，38%產率)。MS:m/z = 550.3 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 10.18 (s, 0.31H), 10.06 (s, 0.48H), 8.58 (d,J = 8.2 Hz, 0.32H), 8.52 (d,J = 8.2 Hz, 0.53H), 8.29 (d,J = 8.3 Hz, 1H), 7.72 (d,J = 4.5 Hz, 1H), 7.71 - 7.67 (m, 1H), 7.67 - 7.63 (m, 1H), 7.60 - 7.52 (m, 1H), 7.27 (d,J = 7.0 Hz, 0.38H), 7.11 - 6.81 (m, 7H), 6.74 (t,J = 6.7 Hz, 0.36H), 6.42 - 6.35 (m, 0.57H), 5.96 (s, 0.51H), 5.76 (s, 0.33H), 5.45 (td,J = 5.8, 2.9 Hz, 1H), 5.00 (dd,J = 15.0, 11.1 Hz, 1H), 4.65 (t,J = 5.2 Hz, 2H), 3.73 (s, 3H), 3.61 (d,J = 14.9 Hz, 0.40H), 3.47 (d,J = 15.5 Hz, 0.71H), 2.10 (s, 2H), 1.44 (s, 1H)。化合物似乎在環境溫度下以非互換旋轉異構體形式存在於DMSO溶液中。 N -[6-( 羥甲基 )-3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-1,2- 苯并噻唑 -3- 甲醯胺
Figure 02_image5900
步驟 4 ：在密封管中，將N -[6-(羥甲基)-2-[(4-甲氧基苯基)甲基]-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1,2-苯并噻唑-3-甲醯胺(231 mg，0.420 mmol)溶解於三氟乙酸(6.42 mL，84.0 mmol)中。將所得混合物在90℃下加熱24小時。用DCM (50 mL)稀釋反應物，用水(2×5 mL)洗滌有機層，且在減壓下濃縮有機相。殘餘物藉由逆相層析(60 g C18濾筒，10至100% ACN/AmF 10 mM)純化，在凍乾之後得到呈棕色粉末狀之N -[6-(羥甲基)-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1,2-苯并噻唑-3-甲醯胺(123 mg，0.288 mmol，68%產率)。
根據實例44之方法製備之額外化合物列於下表18中。下表18中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 18. 額外例示性化合物
化合物 化合物 化合物
I-154    I-306    I-314
I-185    I-307    I-373
I-224            
實例 45 N -(6-(( 甲磺醯基 ) 甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [d ] 異噻唑 -3- 甲醯胺 (I-202)
Figure 02_image5902
N -(6-( 溴甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [d ] 異噻唑 -3- 甲醯胺
Figure 02_image5904
步驟 1 ：向燒瓶中裝入N -(6-(羥甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[d ]異噻唑-3-甲醯胺(7 mg，0.0163 mmol)、二氯甲烷(0.13 mL)、三苯膦(4.69 mg，0.0179 mmol)及四溴甲烷(5.93 mg，0.0179 mmol)。在室溫下攪拌反應混合物1.5小時。在減壓下濃縮反應混合物且藉由逆相層析(30 g C18濾筒，10至100% ACN/AmF 10 mM)純化，得到呈米色粉末狀之N -(6-(溴甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[d ]異噻唑-3-甲醯胺(9.00 mg，0.0183 mmol)。MS:m/z = 492.2 [M+H]+ 。 N -(6-(( 甲磺醯基 ) 甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [d ] 異噻唑 -3- 甲醯胺
Figure 02_image5906
步驟 2 ：向密封管中裝入N -(6-(溴甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[d ]異噻唑-3-甲醯胺(9.00 mg，0.01827 mmol)、DMF (0.09 mL)及甲烷亞磺酸鈉(4.66 mg，0.04567 mmol)。將反應混合物加熱至70℃後維持6小時。將反應混合物冷卻至室溫，隨後經逆相層析(30 g C18濾筒，10至100% ACN/AmF 10 mM)直接純化，以在凍乾之後得到呈白色粉末狀之N -(6-((甲磺醯基)甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[d ]異噻唑-3-甲醯胺(5.44 mg，0.0111 mmol，60%產率)。MS:m/z = 492.3 [M+H]+ ;1 H NMR (400 MHz, CDCl3 ) δ 8.90 (d,J = 7.7 Hz, 1H), 8.87 (s, 1H), 8.59 (s, 1H), 7.94 (d,J = 7.8 Hz, 1H), 7.79 (d,J = 1.2 Hz, 1H), 7.72 - 7.62 (m, 1H), 7.60 - 7.50 (m, 3H), 7.46 (td,J = 7.4, 3.0 Hz, 1H), 7.17 (br s, 1H), 6.65 (s, 1H), 6.00 (br s, 1H), 4.41 (s, 2H), 2.89 (s, 3H), 2.16 (s, 1H), 1.24 (br s, 3H)。
根據實例45之方法製備之額外化合物列於下表19中。下表19中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 19. 額外例示性化合物
化合物
I-231
I-310
實例 46 N -(6-( 甲氧基甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 )-N - 甲基苯丙 [d ] 異噻唑 -3- 甲醯胺 (I-134)
Figure 02_image5908
N -(2-(4- 甲氧基苯甲基 )-6-( 甲氧基甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 )-N - 甲基苯丙 [d ] 異噻唑 -3- 甲醯胺
Figure 02_image5910
步驟 1 ：向使用冰浴冷卻至0℃之N -(6-(羥甲基)-2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[d ]異噻唑-3-甲醯胺(20 mg，0.036 mmol)於DMF (0.18 mL)中之溶液中添加氫化鈉(3.05 mg，0.0764 mmol)，且攪拌混合物30分鐘。添加碘甲烷(2.71 µL，0.0437 mmol)，且使反應混合物升溫至室溫後維持2小時。用水(10 mL)淬滅反應物，用DCM (3×10 mL)萃取水層，且在減壓下濃縮合併之有機層。殘餘物藉由逆相層析(30 g C18 Biotage，10至100% ACN/AmF 10 mM)純化，在凍乾之後得到呈米色粉末狀之N -(2-(4-甲氧基苯甲基)-6-(甲氧基甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)-N -甲基苯丙[d ]異噻唑-3-甲醯胺(10.5 mg，0.0183 mmol，50%產率)。MS:m/z = 578.4 [M+H]+ 。 N -(6-( 甲氧基甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 )-N - 甲基苯丙 [d ] 異噻唑 -3- 甲醯胺
Figure 02_image5912
步驟 2 ：向密封管中裝入N -(2-(4-甲氧基苯甲基)-6-(甲氧基甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)-N -甲基苯丙[d ]異噻唑-3-甲醯胺(10.5 mg，0.0183 mmol)及三氟乙酸(317 µL，4.15 mmol)，且將反應混合物加熱至90℃後維持24小時。所得混合物用DCM (20 mL)稀釋，用水(2×50 mL)洗滌，且在減壓下濃縮。殘餘物藉由逆相層析(30 g C18濾筒，10至100% ACN/AmF 10 mM)純化，在凍乾之後得到呈米色粉末狀之N -(6-(甲氧基甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)-N -甲基苯丙[d ]異噻唑-3-甲醯胺(3.84 mg，0.00839 mmol，40%產率)。實例 47 N -(6-( 甲氧基甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [d ] 異噻唑 -3- 甲醯胺 (I-146)
Figure 02_image5914
甲磺酸 (7-( 苯丙 [d ] 異噻唑 -3- 甲醯胺基 )-2-(4- 甲氧基苯甲基 )-3- 側氧基 -1-( 鄰甲苯基 ) 異吲哚啉 -5- 基 ) 甲酯
Figure 02_image5916
步驟 1 ：向N -(6-(羥甲基)-2-(4-甲氧基苯甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[d ]異噻唑-3-甲醯胺(25 mg，0.036 mmol)於無水DCM (0.23 mL)中之溶液中添加三乙胺(19.0 µL，0.14 mmol)，且使用冰浴將混合物冷卻至0℃。添加甲磺酸甲磺醯酯(11.8 mg，0.0682 mmol)，且在室溫下攪拌反應混合物30分鐘。用水(20 mL)淬滅混合物。分離各層，且水層用DCM (3×20 mL)進一步萃取。將合併之有機物用鹽水洗滌，經硫酸鈉乾燥且濃縮，得到甲磺酸(7-(苯丙[d ]異噻唑-3-甲醯胺基)-2-(4-甲氧基苯甲基)-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-基)甲酯，其直接用於下一步驟。MS:m/z = 628.2 [M+H]+ 。 N -(2-(4- 甲氧基苯甲基 )-6-( 甲氧基甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [d ] 異噻唑 -3- 甲醯胺
Figure 02_image5918
步驟 2 ：向甲磺酸(7-(苯丙[d ]異噻唑-3-甲醯胺基)-2-(4-甲氧基苯甲基)-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-基)甲酯於甲醇(1 mL)中之溶液中添加甲醇鈉(1.0 mL，4.36 mmol，25% w/w於MeOH中)，且在室溫下攪拌混合物18小時。在減壓下濃縮混合物，且粗物質藉由逆相層析(30 g C18濾筒，10至100% ACN/AmF 10mM)純化，以在凍乾之後得到呈米色粉末狀之N -(2-(4-甲氧基苯甲基)-6-(甲氧基甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[d ]異噻唑-3-甲醯胺(13.0 mg，0.0231 mmol，50%產率經兩個步驟)。MS:m/z = 564.3 [M+H]+ 。 N -(6-( 甲氧基甲基 )-1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [d ] 異噻唑 -3- 甲醯胺
Figure 02_image5920
步驟 3 ：向密封管中裝入N -(2-(4-甲氧基苯甲基)-6-(甲氧基甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[d ]異噻唑-3-甲醯胺(13.0 mg，0.0231 mmol)及三氟乙酸(352 µL，4.61 mmol)，且將反應混合物加熱至90℃後維持24小時。所得混合物用DCM (20 mL)稀釋，用水(2×50 mL)洗滌，且在減壓下濃縮。殘餘物藉由逆相層析(30 g C18濾筒，10至100% ACN/AmF 10 mM)純化，在凍乾之後得到呈米色粉末狀之N -(6-(甲氧基甲基)-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[d ]異噻唑-3-甲醯胺(6 mg，0.013 mmol，55%產率)。實例 48 7-( 苯丙 [b ] 噻吩 -3- 甲醯胺基 )-N - 甲基 -3- 側氧基 -1-( 鄰甲苯基 ) 異吲哚啉 -5- 甲醯胺 (I-6) 、 (R )-7-( 苯丙 [b ] 噻吩 -3- 甲醯胺基 )-N - 甲基 -3- 側氧基 -1-( 鄰甲苯基 ) 異吲哚啉 -5- 甲醯胺 (I-75) 及 (S )-7-( 苯丙 [b ] 噻吩 -3- 甲醯胺基 )-N - 甲基 -3- 側氧基 -1-( 鄰甲苯基 ) 異吲哚啉 -5- 甲醯胺 (I-76)
Figure 02_image5922
7- 胺基 -2-(4- 甲氧基苯甲基 )-3- 側氧基 -1-( 鄰甲苯基 ) 異吲哚啉 -5- 甲酸
Figure 02_image5924
步驟 1 ：在25℃下向2-(4-甲氧基苯甲基)-7-((甲氧羰基)胺基)-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲酸甲酯(10.0 g，19.9 mmol，1.00當量)於MeOH (200 mL)中之混合物中添加NaOH (2 M，99.6 mL，10.0當量)。隨後將混合物加熱至60℃且在60℃下攪拌4小時。在真空中濃縮混合物，得到殘餘物。用水(200 mL)稀釋殘餘物，且用乙酸乙酯(3×200 mL)洗滌。將水層調節至pH=3，隨後用乙酸乙酯(3×20.0 mL)萃取。合併之有機層用鹽水(20.0 mL)洗滌，經Na2 SO4 乾燥，過濾且濃縮濾液。藉由管柱層析(SiO2 ，0至5% MeOH/DCM)純化粗產物，得到呈黃色固體狀之7-胺基-2-(4-甲氧基苯甲基)-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲酸(3.50 g，7.89 mmol，39.6%產率，90.7%純度)。MS:m/z = 401.1 [M-H]- ;1 H NMR (400 MHz, DMSO-d 6 ) δ 12.93 (s, 1H), 7.60 -7.54 (m, 3H), 7.44 - 7.39 (m, 2H), 7.31 - 7.21(m, 4H), 7.03 - 6.99 (m, 6H), 6.88 - 6.86 (m, 4H), 6.46 (d,J = 8.0 Hz, 1H), 5.60 (s, 1H), 5.48 (s, 1H), 4.99 - 4.93 (m, 1H), 4.85 (s, 1H), 4.71 (s, 2H), 3.73 (s, 6H), 3.65 (d,J = 8.0 Hz, 1H), 3.60 (d,J = 14.8 Hz, 1H), 3.51 (d,J = 15.6 Hz, 1H), 2.26 (s, 3H), 1.48 (s, 2H)。7- 胺基 -2-(4- 甲氧基苯甲基 )-N - 甲基 -3- 側氧基 -1-( 鄰甲苯基 ) 異吲哚啉 -5- 甲醯胺
Figure 02_image5926
步驟 2 ：在25℃下向7-胺基-2-(4-甲氧基苯甲基)-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲酸(844 mg，2.10 mmol，1.00當量)於DMF (10 mL)中之溶液中添加DIPEA (2.17 g，16.8 mmol，2.92 mL，8.00當量)。將混合物冷卻至0℃，接著在0℃下添加HOBt (567 mg，4.19 mmol，2.00當量)及EDCI (804 mg，4.19 mmol，2.00當量)。使混合物升溫至25℃且在25℃下攪拌0.5小時。隨後向反應混合物中添加MeNH2 ∙HCl (708 mg，10.5 mmol，5.00當量)，且在25℃下攪拌混合物4小時。將混合物倒入水(40.0 mL)中且用乙酸乙酯(3×40.0 mL)萃取。合併之有機層用鹽水(40.0 mL)洗滌，經Na2 SO4 乾燥，過濾且濃縮。藉由管柱層析(SiO2 ，石油醚/乙酸乙酯=1:0至0:1)純化殘餘物，得到呈淡黃色固體狀之化合物7-胺基-2-(4-甲氧基苯甲基)-N -甲基-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲醯胺(340 mg)。MS:m/z = 414.3 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 8.50 - 8.47 (m, 2H), 7.57 - 7.52 (m, 2H), 7.44 (d,J = 1.2 Hz, 1H), 7.37 - 7.20 (m, 7H), 7.10 - 7.00 (m, 4H), 6.90 - 6.85 (m, 7H), 6.62 (d,J = 8.4 Hz, 2H), 6.46 (d,J = 8.0 Hz, 1H), 5.58 (s, 1H), 5.45 (s, 1H), 5.00 - 4.94 (m, 1H), 4.68 (t,J = 19.2 Hz, 4H), 3.72 (s, 3H), 3.65 (s, 3H), 3.59 (d,J = 14.8 Hz, 1H), 3.51 (d,J = 15.2 Hz, 1H), 2.78 - 2.75 (m, 6H), 2.26 (s, 2H), 1.30 (s, 2H)。7-( 苯丙 [b ] 噻吩 -3- 甲醯胺基 )-2-(4- 甲氧基苯甲基 )-N - 甲基 -3- 側氧基 -1-( 鄰甲苯基 ) 異吲哚啉 -5- 甲醯胺
Figure 02_image5928
步驟 3 ：向7-胺基-2-(4-甲氧基苯甲基)-N -甲基-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲醯胺(340 mg，818 μmol，1.00當量)及苯丙[b ]噻吩-3-甲醯氯(241 mg，1.23 mmol，1.50當量)於THF (8.00 mL)中之混合物中添加Et3 N (248.42 mg，2.45 mmol，342 μL, 3.00當量)。在50℃下攪拌混合物8小時。在真空中濃縮混合物，得到粗產物。粗產物藉由製備型HPLC (管柱：Waters X bridge BEH C18 250*50mm*10μm；移動相：42%-72% ACN/水(10mM NH4 HCO3 ))純化，得到呈白色固體狀之7-(苯丙[b ]噻吩-3-甲醯胺基)-2-(4-甲氧基苯甲基)-N -甲基-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲醯胺(130 mg，224 μmol，99.2%純度)。MS:m/z = 576.4 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 10.18 (d,J = 43.2 Hz, 1H), 8.80 - 8.77 (m, 1H), 8.24 (d,J = 21.2 Hz, 1H), 8.16 - 8.13 (m, 1H), 8.07 - 7.96 (m, 3H), 7.79 (d,J = 20.0 Hz, 7H), 6.62 (d,J = 8.4 Hz, 2H), 6.46 (d,J = 8.0 Hz, 1H), 5.58 (s, 1H), 5.45 (s, 1H), 5.00 - 4.94 (m, 1H), 7.42 - 7.36 (m, 2H), 7.18 - 7.00 (m, 5H), 6.92 - 6.86 (m, 3H), 6.34 (d,J = 7.2 Hz, 1H), 5.94 (s, 1H), 5.71 (s, 1H), 5.00 (dd,J = 14.8, 3.6 Hz, 1H), 3.73 (s, 3H), 3.63 (d,J = 15.2 Hz, 1H), 3.53 (d,J = 15.6 Hz, 1H), 2.83 (t,J = 4.8 Hz, 3H), 1.94 (s, 2H), 1.39 (s, 1H)。7-( 苯丙 [b ] 噻吩 -3- 甲醯胺基 )-N - 甲基 -3- 側氧基 -1-( 鄰甲苯基 ) 異吲哚啉 -5- 甲醯胺
Figure 02_image5930
步驟 4 ：將7-(苯丙[b ]噻吩-3-甲醯胺基)-2-(4-甲氧基苯甲基)-N -甲基-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲醯胺(130 mg，226 μmol，1.00當量)於TFA (4.00 g，35.1 mmol，2.60 mL，156當量)中之溶液在100℃下攪拌75小時。在真空中濃縮混合物，得到殘餘物。將殘餘物溶解於乙酸乙酯(20.0 mL)中，倒入NaHCO3 飽和水溶液(20.0 mL)中，用乙酸乙酯(3×20.0 mL)萃取。合併之有機層用鹽水(20.0 mL)洗滌，經Na2 SO4 乾燥，過濾且濃縮。粗產物藉由製備型HPLC (管柱：Waters Xbridge 150*25mm*5μm；移動相：28%-58% ACN/水(10mM NH4 HCO3 ))純化，得到呈白色固體狀之7-(苯丙[b ]噻吩-3-甲醯胺基)-N -甲基-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲醯胺(76.0 mg，167 μmol，73.8%產率，100%純度)。MS:m/z = 456.2 [M+H]+ ;1 H NMR (400 MHz, CD3 OD) δ 8.18 (d,J = 1.2 Hz, 1H), 8.13 (t,J = 5.6 Hz, 1H), 8.02 (d,J = 1.6 Hz, 1H), 7.92 -7.89 (m, 1H), 7.42 -7.39 (m, 3H), 7.16 - 7.12 (m, 1H), 7.03 - 7.00 (m, 2H), 6.15 (s, 1H), 2.98(s, 3H), 2.21 - 2.18 (m, 3H)。(R )-7-( 苯丙 [b ] 噻吩 -3- 甲醯胺基 )-N - 甲基 -3- 側氧基 -1-( 鄰甲苯基 ) 異吲哚啉 -5- 甲醯胺及 (S )-7-( 苯丙 [b ] 噻吩 -3- 甲醯胺基 )-N - 甲基 -3- 側氧基 -1-( 鄰甲苯基 ) 異吲哚啉 -5- 甲醯胺
Figure 02_image5932
步驟 5 ：7-(苯丙[b ]噻吩-3-甲醯胺基)-N -甲基-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲醯胺之對映異構體係藉由SFC (管柱：REGIS (S ,S )-WHELK-O1 (250 mm*50 mm，10 μm)；移動相：50% [0.1% NH3 H2 O於MeOH中])拆分，得到呈白色固體狀之(S )-7-(苯丙[b ]噻吩-3-甲醯胺基)-N -甲基-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲醯胺(27.7 mg，60.2 μmol，36.0%產率，99.0%純度，99.6%ee )及呈灰白色固體狀之(R )-7-(苯丙[b ]噻吩-3-甲醯胺基)-N -甲基-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲醯胺(25.8 mg，55.9 μmol，33.4%產率，98.5%純度，99.8%ee )。
根據實例48之方法製備之額外化合物列於下表20中。下表20中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 20. 額外例示性化合物
化合物 化合物 化合物
I-121    I-163    I-166
I-123    I-164    I-211
I-156    I-165    I-212
實例 49 N -[6-(1- 羥基環丙基 )-3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-1,2- 苯并噻唑 -3- 甲醯胺 (I-315)
Figure 02_image5934
7-(1,2- 苯并噻唑 -3- 醯胺基 )-2-[(4- 甲氧基苯基 ) 甲基 ]-1-(2- 甲基苯基 )-3- 側氧基 -2,3- 二氫 -1H - 異吲哚 -5- 甲酸甲酯
Figure 02_image5936
步驟 1 ：在0℃下，將1,2-苯并噻唑-3-甲醯氯(110 mg，0.56 mmol)於DCM (2.0 mL)中之溶液添加至7-胺基-2-(4-甲氧基苯甲基)-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲酸甲酯(154 mg，0.372 mmol)於DCM (2.0 mL)中之溶液中。在0℃下攪拌反應混合物10-15分鐘，隨後使其達到室溫後維持隔夜。反應混合物用飽和碳酸氫鈉(1.0 mL)淬滅，且攪拌30分鐘。反應混合物用DCM (10 mL)稀釋，且用飽和碳酸氫鈉(15 mL×3)、水(15 mL)且接著用鹽水(15 mL)洗滌。有機層經Na2 SO4 乾燥，且過濾。在減壓下蒸發濾液，得到7-(1,2-苯并噻唑-3-醯胺基)-2-[(4-甲氧基苯基)甲基]-1-(2-甲基苯基)-3-側氧基-2,3-二氫-1H -異吲哚-5-甲酸甲酯，其未經進一步純化即用於下一步驟中。MS:m/z = 578.2 [M+H]+ 。7-( 苯丙 [d ] 異噻唑 -3- 甲醯胺基 )-3- 側氧基 -1-( 鄰甲苯基 ) 異吲哚啉 -5- 甲酸甲酯
Figure 02_image5938
步驟 2 ：在室溫下，在配備有攪拌棒及隔片之旋蓋式玻璃反應小瓶中，在氮氣氛圍下將7-(1,2-苯并噻唑-3-醯胺基)-2-[(4-甲氧基苯基)甲基]-1-(2-甲基苯基)-3-側氧基-2,3-二氫-1H -異吲哚-5-甲酸甲酯溶解於三氟乙酸(2.0 mL，17.5 μmol)中。添加過量三乙基矽烷(100 μL，625 μmol)，且在室溫下攪拌溶液30分鐘。用塑膠蓋快速替換隔片，且密封反應混合物以與氧氣氛圍隔絕。將反應混合物置於預加熱油浴(105℃，外部)中且攪拌隔夜。反應混合物用DCM (10 mL)稀釋，且接著蒸發所有揮發物，得到粗殘餘物。向粗殘餘物中添加乙醚(3 mL)及MeOH (10 mL)。振盪所得懸浮液，且使不可溶部分沈降。緩慢過濾上清液，隨後過濾固體，且用MeOH (3 mL×3)洗滌剩餘固體。再重複洗滌及過濾步驟兩次，得到93 mg呈淡棕色固體狀之7-(苯丙[d ]異噻唑-3-甲醯胺基)-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲酸甲酯，其未經進一步純化即用於下一步驟中。MS:m/z = 458.1 [M+H]+ 。 N -[6-(1- 羥基環丙基 )-3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-1,2- 苯并噻唑 -3- 甲醯胺
Figure 02_image5940
步驟 3 ：向配備有攪拌棒之火焰乾燥的圓底燒瓶中裝入7-(苯丙[d ]異噻唑-3-甲醯胺基)-3-側氧基-1-(鄰甲苯基)異吲哚啉-5-甲酸甲酯(30 mg，65.5 μmol)。使固體懸浮於THF (5.0 mL)中，且在室溫下劇烈攪拌10分鐘。添加四異丙醇鈦(50 μL，168 μmol)，且在室溫下攪拌混合物10分鐘。經3小時向所得溶液中逐滴添加乙基溴化鎂(0.8 mL，3.0 M，2.40 mmol)。溶液藉由逐滴添加1M HCl (1 mL)淬滅，接著用DCM (20 mL)稀釋。用水(20 mL×3)，接著用鹽水(20 mL×3)洗滌混合物。蒸發溶劑。所得殘餘物藉由逆相急驟管柱層析(用含0至100%乙腈之10 mM AmF/水溶離)純化，以在凍乾之後得到呈白色粉末狀之N -[6-(1-羥基環丙基)-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1,2-苯并噻唑-3-甲醯胺(13 mg)。實例 50 N -(7- 氰基 -1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [b ] 噻吩 -3- 甲醯胺 (I-132)
Figure 02_image5942
6- 溴 -2- 甲基 -3- 硝基苯甲酸
Figure 02_image5944
步驟 1 ：在0℃下向2-溴-6-甲基苯甲酸(240 g，1.12 mol，1.00當量)於H2 SO4 (1.20 L)中之溶液中逐滴添加HNO3 (76.5 g，1.21 mol，54.7 mL，1.09當量)於H2 SO4 (100 mL)中之混合物。在0℃下攪拌混合物45分鐘。將混合物倒入冰水(5.00 L)中，且固體沈澱。過濾懸浮液。在減壓下乾燥濾餅，得到呈淡黃色固體狀之6-溴-2-甲基-3-硝基苯甲酸及區位異構體(339 g，粗物質)之大致當量克分子混合物。MS:m/z = 261.9 [M+H]+ ;1 H NMR (400 MHz, CDCl3 ) δ 7.84 (d,J = 8.8 Hz, 1H), 7.81 (d,J = 8.0 Hz, 0.5H), 7.65 (d,J = 8.8 Hz, 1H), 7.37 (d,J = 8.4 Hz, 0.9H), 2.61 (s, 3H), 2.52 (s, 1.5H)。4- 胺基 -7- 溴 -2-(4- 甲氧基苯甲基 )-3-( 鄰甲苯基 ) 異吲哚啉 -1- 酮
Figure 02_image5946
步驟 2 至 7 ：使用實例10，步驟1至6中所述之程序，將6-溴-2-甲基-3-硝基苯甲酸在6個步驟中轉化為4-胺基-7-溴-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮，產率為2%。(步驟1中產生之非所需區位異構體係在步驟5之鐵介導之硝基還原之後藉由逆相層析移除)。4-胺基-7-溴-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮產物在藉由逆相HPLC純化之後分離為白色固體。MS:m/z = 439.2 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 7.57 - 7.55 (m, 0.5H), 7.39 - 7.34 (m, 1H), 7.30 - 7.20 (m, 2H), 7.11 - 6.99 (m, 3H), 6.88 - 6.85(m, 2H) 6.76 - 6.68(m, 1H), 6.49 (d,J = 7.6 Hz, 0.5H), 5.50 (s, 0.5H), 5.38 (s, 0.5H), 4.96 - 4.90 (m, 1H), 4.72 (s, 1H), 4.57 (s, 1H), 3.72 (s, 3H), 3.58 (d,J = 14.8 Hz, 0.5H), 3.48 (d,J = 15.2 Hz, 0.5H), 2.25 (s, 1.7H), 1.52 (s, 1.3H)。 N -(7- 溴 -1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [b ] 噻吩 -3- 甲醯胺
Figure 02_image5948
步驟 8 及 9 ：根據實例1，步驟5及6之程序，將4-胺基-7-溴-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮轉化為N -(7-溴-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[b ]噻吩-3-甲醯胺。 N -(7- 氰基 -1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [b ] 噻吩 -3- 甲醯胺
Figure 02_image5950
步驟 10 ：向配備有塗有特氟隆(Teflon)之攪拌棒及橡膠隔片的微波小瓶中裝入N -(7-溴-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[b ]噻吩-3-甲醯胺(30 mg，0.0628 mmol)，接著裝入Pd2 (dba)3 (11.5 mg，0.0126 mmol)、dppf (6.96 mg，0.0126 mmol)、Zn(CN)2 (14.7 mg，0.126 mmol)、鋅(821 µg，0.0126 mmol)、DMF (1.9 mL)及水(0.1 mL)。在室溫下在適度攪拌下，藉由用氮氣鼓泡約5分鐘使深色混濁溶液脫氣。隨後將小瓶置於預加熱油浴(105℃，外部)中，且劇烈攪拌3小時。將混合物冷卻至室溫且直接裝載至C18管柱(24 g)上，用含10%-60%乙腈之10 mM AmF水溶液溶離。含有純產物之溶離份經合併，在減壓下移除乙腈，且將剩餘水溶液凍乾，得到呈茶色非晶形固體狀之N -(7-氰基-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[b ]噻吩-3-甲醯胺(18 mg)。
根據實例50之方法製備之額外化合物列於下表21中。下表21中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 21. 額外例示性化合物
化合物
I-116
I-237
I-313
實例 51 N -[7- 乙烯基 -3-(2- 甲基苯基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-1- 苯丙噻吩 -3- 甲醯胺 (I-2157)
Figure 02_image5952
向配備有塗有特氟隆之攪拌棒及橡膠隔片的50 mL圓底燒瓶中裝入N -(7-溴-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[b ]噻吩-3-甲醯胺(100 mg，0.209 mmol)，接著裝入乙烯基三氟硼酸鉀(139 mg，1.04 mmol)、K2 CO3 (201 mg，1.46 mmol)及THF:水(10 mL，9:1)。在緩慢攪拌下，藉由用氮氣鼓泡約五分鐘使棕色混濁溶液脫氣。隨後添加Pd(dppf)Cl2 (29 mg，0.042 mmol)，且將橡膠隔片快速更換為回流冷凝器。在室內真空下抽空該系統，且用氮氣回填。隨後將燒瓶置於預加熱油浴(63℃，外部)中，且攪拌混合物40小時。混合物用乙酸乙酯(20 mL)稀釋，且用水(2×20 mL)洗滌。用乙酸乙酯(20 mL)萃取合併之水層。合併之有機物用鹽水(20 mL)洗滌，經硫酸鈉乾燥，過濾，且減壓移除溶劑，得到茶色糊狀物。殘餘物藉由矽膠急驟層析(乙酸乙酯/己烷)純化，得到呈茶色粉末狀之N -[7-乙烯基-3-(2-甲基苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-1-苯丙噻吩-3-甲醯胺(65 mg)。MS:m/z = 425.3 [M+H]+ 。
根據實例51之方法製備之額外化合物列於下表22中。下表22中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 22. 額外例示性化合物
化合物
I-205
實例 52 7-( 苯丙 [b ] 噻吩 -3- 甲醯胺基 )-3- 側氧基 -1-( 鄰甲苯基 ) 異吲哚啉 -4- 甲醯胺 (I-149)
Figure 02_image5954
向配備有塗有特氟隆之攪拌棒及橡膠隔片的微波小瓶中裝入N -(7-溴-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[b ]噻吩-3-甲醯胺(20 mg，0.0419 mmol)，接著裝入Pd(OAc)2 (1.88 mg，0.00838 mmol)、Xantphos (4.84 mg，0.00838 mmol)、4-二甲胺基吡啶(10.2 mg，0.0838 mmol)、Co2 (CO)8 (3.6 mg，0.010 mmol)及二㗁烷(2 mL)。在適度攪拌下，藉由用氮氣鼓泡5分鐘使此深色混濁溶液脫氣，且隨後添加氨於異丙醇(0.1 mL，0.20 mmol)中之2 M溶液。將橡膠隔片快速更換為微波小瓶蓋且密封。接著將小瓶置於Biotage微波反應器中且在90℃下照射一小時。將混合物直接裝載至C18管柱(24 g，使用1 mL DMF沖洗小瓶)上，且管柱用含10-60%乙腈之10mM AmF水溶液溶離。將含有純產物之溶離份凍乾，得到呈灰白色非晶形固體狀之7-(苯丙[b ]噻吩-3-甲醯胺基)-3-側氧基-1-(鄰甲苯基)異吲哚啉-4-甲醯胺(9 mg)。
根據實例52之方法製備之額外化合物列於下表23中。下表23中之某些化合物係藉由其他化合物製備，該等其他化合物之製備描述於實例中之他處。表 23. 額外例示性化合物
化合物 化合物 化合物
I-150    I-261    I-278
I-219    I-276    I-339
I-225            
實例 53 N -(7- 甲基 -1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [b ] 噻吩 -3- 甲醯胺 (I-153)
Figure 02_image5956
向配備有塗有特氟隆之攪拌棒及橡膠隔片的微波小瓶中裝入N -(7-溴-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[b ]噻吩-3-甲醯胺(20 mg，0.0419 mmol)，接著裝入Pd2 (dba)3 (3.83 mg，0.00419 mmol)、DABAL-Me3 (10.7 mg，0.0419 mmol)、Xphos (3.99 mg，0.00838 mmol)及THF (2 mL)。隨後將深色反應混合物加熱至回流且劇烈攪拌9小時。將混合物冷卻至室溫且再添加DABAL-Me3 (5 mg)。將混合物再次加熱至回流且劇烈攪拌18小時。將混合物冷卻至室溫，用乙酸乙酯(20 mL)稀釋，且用水(2×20 mL)洗滌。用乙酸乙酯(10 mL)萃取合併之水層。合併之有機相經硫酸鈉乾燥，過濾，且在減壓下移除溶劑。所得殘餘物藉由逆相層析(負載於DMF中，C18管柱，24 g，10-50%乙腈/10 mM AmF水溶液)純化。將含有純產物之溶離份凍乾，得到呈白色非晶形固體狀之N -(7-甲基-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[b ]噻吩-3-甲醯胺(2.6 mg)。實例 54 N -(6- 乙醯基 -3-(2- 氯 -5- 氟苯基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-127)
Figure 02_image5958
將N -[6-溴-3-(2-氯-5-氟苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(600 mg，1.09 mmol)、三丁基(1-乙氧基乙烯基)錫烷(787 mg，2.18 mmol)及雙(三苯膦)二氯化鈀(II) (153 mg，0.218 mmol)合併且抽空/用氮氣吹掃。添加二㗁烷(4 mL)，且將混合物加熱至90℃後維持4小時。混合物用EtOAc稀釋，經由矽膠塞過濾，且濃縮濾液，得到N -(3-(2-氯-5-氟苯基)-6-(1-乙氧基乙烯基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺。
將所得殘餘物在TFA (2.5 mL)及水(0.5 mL)中攪拌2小時，隨後濃縮且藉由逆相HPLC純化，得到N -(6-乙醯基-3-(2-氯-5-氟苯基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(0.42 g，72%)。實例 55 N -(3-(2- 氯 -5- 氟苯基 )-6-(2- 羥基丙 -2- 基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-128)
Figure 02_image5960
在0℃下向N -(6-乙醯基-3-(2-氯-5-氟苯基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(400 mg，0.7 mmol)於THF (5 mL)中之溶液中逐滴添加MeMgBr，3.0 M於Et2 O (3.5 mmol，1.16 mL)中。反應完成後，用NH4 Cl水溶液淬滅反應物，且用EtOAc萃取混合物。有機物用鹽水洗滌，乾燥且濃縮。殘餘物藉由逆相HPLC，使用如下之梯度純化：水(0.1% FA)及乙腈(0.1% FA) 70/30至35/65於13分鐘內，接著5/95。含產物之溶離份經合併且凍乾，得到N -(3-(2-氯-5-氟苯基)-6-(2-羥基丙-2-基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(0.25 g，67%)。
根據實例54及55之方法製備之額外化合物列於下表24中。表 24. 額外例示性化合物
化合物 化合物 化合物
I-135    I-238    I-272
I-136    I-239    I-280
I-189    I-242    I-290
I-190    I-250    I-298
I-191    I-263    I-299
I-192    I-264    I-308
I-214    I-267    I-355
I-215    I-271    I-356
實例 56 N -(3-(2- 氯 -5- 氟苯基 )-1- 側氧基 -6-(2,2,2- 三氟 -1- 羥乙基 ) 異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-270)
Figure 02_image5962
向含N -[3-(2-氯-5-氟苯基)-6-甲醯基-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(110 mg，0.2223 mmol)之0.5 mL DMF中添加K2 CO3 (28 mg，0.2 mmol)及三甲基(三氟甲基)矽烷(80 mg，0.5626 mmol)。將混合物在室溫下攪拌16小時。隨後將混合物放入1 mL MeOH中且添加50 μL濃HCl且攪拌1小時。將混合物放入2 mL DMSO中且藉由逆相HPLC，使用如下之梯度純化：水(0.1% FA)及乙腈(0.1% FA) 70/30至35/65於13分鐘內，接著5/95。含產物之溶離份經合併且凍乾，得到N -(3-(2-氯-5-氟苯基)-1-側氧基-6-(2,2,2-三氟-1-羥乙基)異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(35 mg，27%)。
根據實例56之方法製備之額外化合物列於下表25中。表 25. 額外例示性化合物
化合物
I-297
I-334
實例 57 N -(3-(2- 氯 -5- 氟苯基 )-6-((3,3- 二氟氮雜環丁烷 -1- 基 ) 甲基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-348)
Figure 02_image5964
將N -[3-(2-氯-5-氟苯基)-6-甲醯基-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(15 mg，0.030 mmol)於THF (1 mL)中之溶液用3,3-二氟氮雜環丁烷鹽酸鹽(8 mg，0.061 mmol)及聚合物結合之Biotage® MP-三乙醯氧基硼氫化物(2 mmol/g，40 mg)處理。在45℃下攪拌混合物12小時且接著用EtOAc稀釋。將其過濾且隨後藉由旋轉蒸發濃縮。對殘餘物進行逆相HPLC純化(15-60%乙腈/水)，得到呈灰白色粉末狀之N -(3-(2-氯-5-氟苯基)-6-((3,3-二氟氮雜環丁烷-1-基)甲基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(5 mg，29%產率)。
根據實例57之方法製備之額外化合物列於下表26中。表 26. 額外例示性化合物
化合物
I-349
I-350
I-352
I-353
實例 58 N -[3-(2- 氯 -5- 氟苯基 )-6-(1- 羥基環丙基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-374)
Figure 02_image5966
1-(2- 氯 -5- 氟苯基 )-7-[3- 氟 -5-( 三氟甲基 ) 苯甲醯胺基 ]-3- 側氧基 -2,3- 二氫 -1H - 異吲哚 -5- 甲酸甲酯
Figure 02_image5968
步驟 1 ：向配備有攪拌棒及橡膠隔片之旋蓋式玻璃反應小瓶中裝入N -[6-溴-3-(2-氯-5-氟苯基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(90 mg，164 µmol)、乙酸鈀(II) (7.36 mg，32.8 µmol)、甲醇(1.58 g，49.3 mmol)、Co2 (CO)8 (16.6 mg，48.8 µmol)、Xantphos (18.8 mg，32.6 µmol)及4-二甲胺基吡啶(20 mg，164 µmol)。藉由在劇烈攪拌下用氮氣(氣球)鼓泡兩分鐘使反應混合物脫氣，用塑膠蓋快速替換橡膠隔片，且密封反應混合物以自大氣隔絕。接著將小瓶置於預加熱油浴(85℃，外部)中，且劇烈攪拌混合物7小時。在減壓下蒸發揮發物以得到殘餘物，其藉由正相急驟管柱層析純化(用0-100% EtOAc/庚烷之梯度溶離)，得到呈灰白色固體狀之1-(2-氯-5-氟苯基)-7-[3-氟-5-(三氟甲基)苯甲醯胺基]-3-側氧基-2,3-二氫-1H -異吲哚-5-甲酸甲酯(73 mg)。MS:m/z = 525.3 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 10.66 (s, 1H), 9.35 (br s, 1H), 8.13 (dd,J = 16.4, 1.2 Hz, 2H), 7.96 (d,J = 8.3 Hz, 1H), 7.76 (d,J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.33 (dd,J = 8.9, 5.2 Hz, 1H), 7.10 (td,J = 8.5, 3.1 Hz, 1H), 6.04 (br s, 1H), 3.93 (s, 3H)。未觀測到預期在約6.8 ppm處之一個質子。 N -[3-(2- 氯 -5- 氟苯基 )-6-(1- 羥基環丙基 )-1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image5970
步驟 2 ：根據實例49，步驟3之程序，1-(2-氯-5-氟苯基)-7-[3-氟-5-(三氟甲基)苯甲醯胺基]-3-側氧基-2,3-二氫-1H -異吲哚-5-甲酸甲酯轉化為N -[3-(2-氯-5-氟苯基)-6-(1-羥基環丙基)-1-側氧基-2,3-二氫-1H -異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺，其在逆相層析(10 mM AmF，以0-100% CH3 CN於水中之梯度)之後分離為灰白色固體。實例 59 N -(3- 環己基 -1- 側氧基異吲哚啉 -4- 基 ) 苯丙 [d ] 異噻唑 -3- 甲醯胺 (I-204)
Figure 02_image5972
4- 胺基 -3- 環己基異吲哚啉 -1- 酮
Figure 02_image5974
步驟 1 ：在0℃下在氮氣氛圍下向4-胺基-3-甲氧基異吲哚啉-1-酮(50 mg，0.28 mmol)於無水THF (0.35 mL)中之溶液中添加溴(環己基)鎂(841 µL，0.841 mmol)於THF中之1M溶液。在室溫下攪拌混合物15分鐘。添加另一份溴(環己基)鎂(560 μL，0.56 mmol)之1M溶液且繼續在室溫下攪拌15分鐘。隨後添加NH4 Cl之飽和水溶液，且用EtOAct (3×)萃取混合物。合併之有機層用鹽水洗滌，經Na2 SO4 乾燥，過濾且減壓濃縮。呈棕色油狀之所得4-胺基-3-環己基異吲哚啉-1-酮不經進一步純化即用於下一步驟中。 N -(3- 環己基 -1- 側氧基異吲哚啉 -4- 基 ) 苯丙 [d ] 異噻唑 -3- 甲醯胺
Figure 02_image5976
步驟 2 ：在室溫下在氮氣氛圍下將來自前一步驟之4-胺基-3-環己基異吲哚啉-1-酮溶解於無水DMF (0.94 mL)中，且添加1,2-苯并噻唑-3-甲酸(60.3 mg，0.337 mmol)，接著添加HATU (159 mg，0.421 mmol)，且最後添加DIPEA (197 µL，1.12 mmol)。在室溫下攪拌混合物12小時。混合物接著用水稀釋且用AcOEt (3×)萃取。合併之有機層用鹽水洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由逆相層析(5至70% ACN/AmF水溶液10 mM)純化，接著藉由正相層析(0至60%丙酮/己烷)純化，在凍乾之後得到呈黃色粉末狀之N -(3-環己基-1-側氧基異吲哚啉-4-基)苯丙[d ]異噻唑-3-甲醯胺(10 mg，10%)。
根據實例59之方法製備之額外化合物列於下表27中。表 27. 額外例示性化合物
化合物 化合物
I-8    I-259
I-18    I-327
I-106      
實例 60 N -(7- 側氧基 -5-( 鄰甲苯基 )-6,7- 二氫 -5H - 吡咯并 [3,4-b ] 吡啶 -4- 基 ) 吲哚啉 -1- 甲醯胺 (I-147)
Figure 02_image5978
4- 氯 -N -(2,4- 二甲氧基苯甲基 ) 吡啶甲醯胺
Figure 02_image5980
步驟 1 ：在15℃下持續0.5小時向4-氯吡啶甲酸(200 g，1.27 mol，1.00當量)於DCM (2.00 L)中之溶液中添加CDI (216 g，1.33 mol，1.05當量)及DMAP (4.65 g，38.1 mmol，0.03當量)。接著添加(2,4-二甲氧基苯基)甲胺(212 g，1.27 mol，191 mL，1.00當量)於DCM (400 mL)中之溶液，且將混合物在25℃下攪拌1小時。濃縮反應混合物。殘餘物藉由快速急驟管柱層析(SiO2 ，石油醚/乙酸乙酯=3/1)純化，獲得呈白色固體狀之4-氯-N -(2,4-二甲氧基苯甲基)吡啶甲醯胺(316 g，1.03 mol，81.1%產率)。4- 氯 -6-(2,4- 二甲氧基苯甲基 )-5- 羥基 -5-( 鄰甲苯基 )-5,6- 二氫 -7H - 吡咯并 [3,4-b ] 吡啶 -7- 酮
Figure 02_image5982
步驟 2 ：在-78℃下向n -BuLi (2.50 M，391 mL，3.00當量)於THF (1.20 L)中之溶液中添加4-氯-N -(2,4-二甲氧基苯甲基)吡啶甲醯胺(100 g，326 mmol，1.00當量)於THF (200 mL)中之溶液。在-40至-50℃下攪拌混合物將近3小時。隨後使反應物重新冷卻至-78℃。經15分鐘向反應物中逐滴添加2-甲基苯甲醯氯(101 g，652 mmol，84.7 mL，2.00當量)於THF (200 mL)中之溶液。在-78℃下攪拌反應物1小時，隨後移除乾冰/乙酸乙酯浴。隨後在25℃下攪拌反應物2小時。將混合物倒入水(2.00 L)中且用乙酸乙酯(3×500 mL)萃取。合併之有機層用鹽水(500 mL)洗滌，經Na2 SO4 乾燥且濃縮。所得黃色油藉由管柱層析(SiO2 ，石油醚/乙酸乙酯=50/1至1/1)純化一次，且藉由管柱層析(SiO2 ，DCM/MeOH=1/0至50/1)純化兩次，獲得呈白色固體狀之4-氯-6-(2,4-二甲氧基苯甲基)-5-羥基-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(125 g)。MS:m/z = 425.0 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 9.02 (t,J = 6.4 Hz, 1H), 8.73 (d,J = 5.2 Hz, 1H), 7.94 (d,J = 5.2 Hz, 1H), 7.44 - 7.47 (m, 1H), 7.36 (d,J = 7.2 Hz, 1H), 7.21 (d,J = 4.0 Hz, 1H), 6.91 (d,J = 8.4 Hz, 1H), 6.52 (d,J = 2.4 Hz, 1H), 6.39 (dd,J =2.4, 8.4 Hz, 1H), 4.25 (d,J = 6.0 Hz, 2H), 3.76 (s, 3H), 3.72 (s, 3H), 2.65 (s, 3H)。4- 氯 -6-(2,4- 二甲氧基苯甲基 )-5-( 鄰甲苯基 )-5,6- 二氫 -7H - 吡咯并 [3,4-b ] 吡啶 -7- 酮
Figure 02_image5984
步驟 3 ：在25℃下向4-氯-6-(2,4-二甲氧基苯甲基)-5-羥基-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(75.0 g，177 mmol，1.00當量)於DCM (1.10 L)中之攪拌溶液中添加TFA (503 g，4.41 mol，327 mL，25.0當量)。將混合物冷卻至0℃，隨後添加三乙基矽烷(205 g，1.77 mol，282 mL，10.0當量)。使混合物升溫至25℃，在25℃下攪拌12小時，且接著濃縮。殘餘物藉由逆相HPLC (0.1% FA條件)純化，得到呈白色固體狀之4-氯-6-(2,4-二甲氧基苯甲基)-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(62.0 g，152 mmol，85.9%產率)。MS:m/z = 409.1 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 8.73 (d,J = 5.2 Hz, 1H), 7.66 (d,J = 5.6 Hz, 1H), 7.20 - 7.28 (m, 2H), 7.04 - 7.08 (m, 1H), 6.95 (d,J = 8.4 Hz, 1H), 6.45 - 6.50 (m, 4H), 5.78 (s, 1H), 4.82 (dd,J =3.6, 14.8 Hz, 1H), 3.73 (s, 3H), 3.64 (s, 3H), 2.24 (s, 3H)。6-(2,4- 二甲氧基苯甲基 )-4-((2,4- 二甲氧基苯甲基 ) 胺基 )-5-( 鄰甲苯基 )-5,6- 二氫 -7H - 吡咯并 [3,4-b ] 吡啶 -7- 酮
Figure 02_image5986
步驟 4 ：將4-氯-6-(2,4-二甲氧基苯甲基)-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(70.0 g，171 mmol，1.00當量)、(2,4-二甲氧基苯基)甲胺(42.9 g，256 mmol，38.6 mL，1.50當量)、Cs2 CO3 (55.7 g，171 mmol，1.00當量)、Pd2 (dba)3 (15.6 g，17.1 mmol，0.10當量)及BRETTPHOS (18.3 g，34.2 mmol，0.20當量)於二㗁烷(700 mL)中之混合物脫氣且用N2 吹掃三次，且接著將混合物在90℃下在N2 氛圍下攪拌12小時。添加額外(2,4-二甲氧基苯基)甲胺(14.3 g，85.6 mmol，12.8 mL，0.50當量)，用N2 吹掃混合物三次，且隨後在90℃下在N2 氛圍下攪拌混合物18小時。反應混合物用H2 O (600 mL)稀釋且用乙酸乙酯(3×400 mL)萃取。合併之有機層用NaCl飽和水溶液(800 mL)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。所得殘餘物藉由管柱層析(SiO2 ，石油醚/乙酸乙酯=1/0至0/1，乙酸乙酯/甲醇=20/1)純化，得到呈棕色油狀之6-(2,4-二甲氧基苯甲基)-4-((2,4-二甲氧基苯甲基)胺基)-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(60.0 g，94.1 mmol，55.0%產率，84.7%純度)。MS:m/z = 540.0 [M+H]+ ;1 H NMR (400 MHz, CDCl3 ) δ 8.39 - 8.42 (m, 1H), 7.29 - 7.30 (m, 1H), 7.21 - 7.23 (m, 1H), 7.17 - 7.18 (m, 1H), 7.14 (s, 1H), 7.12 (s, 1H), 7.07 - 7.09 (m, 1H), 6.91 - 6.94 (m, 1H), 6.78 - 6.80 (m, 1H), 6.70 (d,J = 8.4 Hz, 1H), 6.54 (d,J = 6.0 Hz, 1H), 6.29 - 6.32 (m, 2H), 5.36 (s, 1H), 3.76 - 3.80 (m, 12H), 3.66 (s, 2H), 3.63 (s, 2H), 2.08 (s, 3H)。4- 胺基 -6-(2,4- 二甲氧基苯甲基 )-5-( 鄰甲苯基 )-5,6- 二氫 -7H - 吡咯并 [3,4-b ] 吡啶 -7- 酮
Figure 02_image5988
步驟 5 ：將6-(2,4-二甲氧基苯甲基)-4-((2,4-二甲氧基苯甲基)胺基)-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(60.0 g，111 mmol，1.00當量)於HCl/MeOH (4.00 M，600 mL，21.6當量)中之溶液在35℃下攪拌7小時。將額外HCl/MeOH (4.00 M，600 mL，21.6當量)添加至混合物中，接著將混合物在35℃下攪拌16小時。將額外HCl/MeOH (4.00 M，600 mL，21.6當量)添加至混合物中，接著將混合物在35℃下攪拌22小時。真空濃縮反應混合物，且將殘餘物溶解於DCM (2.00 L)中。用飽和NaHCO3 (1.00 L)將混合物調節至pH=8且在25℃下攪拌0.5小時。用DCM (2×2.00 L)萃取混合物。合併之有機層用鹽水(2×200 mL)洗滌，經Na2 SO4 乾燥，過濾且濃縮。所得棕色膠狀物藉由逆相HPLC (0.1% FA條件)純化，得到呈白色固體狀之4-胺基-6-(2,4-二甲氧基苯甲基)-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(20.4 g，50.4 mmol，45.3%產率，96.0%純度)。MS:m/z = 390.2 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 - 8.23 (m, 1H), 7.52 - 7.54 (m, 1H), 7.18 - 7.27 (m, 2H), 7.06 - 7.09 (m, 1H), 6.97 (d,J = 8.4 Hz, 1H), 6.84 (d,J = 8.4 Hz, 1H), 6.59 - 6.65 (m, 1H), 6.44 - 6.53 (m, 3H), 5.39 - 5.48 (m, 2H), 4.69 - 4.82 (m, 1H), 3.69 - 3.78 (m, 6H), 2.25 (s, 2H), 1.15 (s, 1H)。 N -(6-(2,4- 二甲氧基苯甲基 )-7- 側氧基 -5-( 鄰甲苯基 )-6,7- 二氫 -5H - 吡咯并 [3,4-b ] 吡啶 -4- 基 ) 吲哚啉 -1- 甲醯胺
Figure 02_image5990
步驟 6 ：將4-胺基-6-(2,4-二甲氧基苯甲基)-5-(鄰甲苯基)-5H -吡咯并[3,4-b ]吡啶-7(6H )-酮(1.00 g，1.87 mmol)及羰基二咪唑(457 mg，2.82 mmol)溶解於DCM (25 mL)中。向所得混合物中添加N,N -二異丙基乙胺(0.54 mL，3.08 mmol)及4-二甲胺基吡啶(2.5 mg，0.020mmol)。在40℃下攪拌所得混合物。24小時後，使反應混合物冷卻至22℃，且將吲哚啉(457 mg，3.84 mmol)添加至溶液中。所得混合物在22℃下攪拌1小時且接著用NH4 Cl飽和水溶液稀釋且用DCM萃取。有機層經硫酸鈉乾燥，過濾，且藉由旋轉蒸發濃縮。所得N -(6-(2,4-二甲氧基苯甲基)-7-側氧基-5-(鄰甲苯基)-6,7-二氫-5H -吡咯并[3,4-b ]吡啶-4-基)吲哚啉-1-甲醯胺不經進一步純化即直接進行後續反應。 N -(7- 側氧基 -5-( 鄰甲苯基 )-6,7- 二氫 -5H - 吡咯并 [3,4-b ] 吡啶 -4- 基 ) 吲哚啉 -1- 甲醯胺
Figure 02_image5992
步驟 7 ：來自前一步驟之N -(6-(2,4-二甲氧基苯甲基)-7-側氧基-5-(鄰甲苯基)-6,7-二氫-5H -吡咯并[3,4-b ]吡啶-4-基)吲哚啉-1-甲醯胺(約1.00 mmol)用三氟乙酸(14.2 mL)及三氟甲磺酸(0.41 mL，4.67 mmol)處理。在40℃下攪拌所得混合物。1小時後，反應混合物經濃縮，用飽和NaHCO3 水溶液稀釋且用DCM萃取。有機層經硫酸鈉乾燥，過濾，且藉由旋轉蒸發濃縮。所得混合物藉由C18矽膠管柱層析(20%至100% MeCN/10 mM AmF (水溶液))純化。含產物之溶離份經合併且凍乾，獲得呈白色粉末狀之N -(7-側氧基-5-(鄰甲苯基)-6,7-二氫-5H -吡咯并[3,4-b ]吡啶-4-基)吲哚啉-1-甲醯胺(38 mg，5.3%經兩個步驟)。
根據實例60之方法製備之額外化合物列於下表28中。表 28. 額外例示性化合物
化合物 化合物 化合物
I-148    I-245    I-282
I-177    I-246    I-296
I-199    I-247    I-300
I-227    I-248    I-301
I-228    I-249    I-302
I-229    I-251    I-303
I-230    I-257    I-324
實例 61 N -(5-(2,3- 二氟苯基 )-7- 側氧基 -6,7- 二氫 -5H - 吡咯并 [3,4-b ] 吡啶 -4- 基 ) 苯丙 [b ] 噻吩 -3- 甲醯胺 (I-15)
Figure 02_image5994
4- 胺基 -5-(2,3- 二氟苯基 )-6-(2,4- 二甲氧基苯甲基 )-5,6- 二氫 -7H - 吡咯并 [3,4-b ] 吡啶 -7- 酮
Figure 02_image5996
步驟 1 至 5 ：根據實例60，步驟1至5之程序合成4-胺基-5-(2,3-二氟苯基)-6-(2,4-二甲氧基苯甲基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮。 N -(5-(2,3- 二氟苯基 )-6-(2,4- 二甲氧基苯甲基 )-7- 側氧基 -6,7- 二氫 -5H - 吡咯并 [3,4-b ] 吡啶 -4- 基 ) 苯丙 [b ] 噻吩 -3- 甲醯胺
Figure 02_image5998
步驟 6 ：向1-氯-2-甲基丙-1-烯-1-基)二甲胺(257 mg，1.93 mmol，4當量)於甲苯(1.6 mL) 中之攪拌溶液中添加1-苯丙噻吩-3-甲酸(343 mg，1.93 mmol，4當量)。懸浮液快速變為透明淺粉色溶液，將其攪拌30分鐘。將約0.4 mL此溶液添加至4-胺基-5-(2,3-二氟苯基)-6-(2,4-二甲氧基苯甲基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(200 mg，0.483 mmol)於吡啶(1 mL)中之攪拌溶液中。向此溶液中添加催化DMAP (24 mg，0.19 mmol，0.4當量)。將混合物在室溫下攪拌5分鐘，且接著在75-80℃下攪拌5小時。每小時將額外0.4 mL預先形成之酸氯化物於甲苯中之溶液添加至混合物中，直至反應幾乎完成。將混合物冷卻至室溫且用甲醇(2 mL)淬滅。在淬滅之後將混合物攪拌10分鐘且隨後濃縮。殘餘物在12 g管柱上溶離，用10:90:1 MeOH/DCM/NH4 OH於DCM中之梯度溶離，得到呈淺黃色泡沫狀固體之N -(5-(2,3-二氟苯基)-6-(2,4-二甲氧基苯甲基)-7-側氧基-6,7-二氫-5H -吡咯并[3,4-b ]吡啶-4-基)苯丙[b ]噻吩-3-甲醯胺(214 mg，約95%純度, 73.5%產率)。在純化之後仍存在少量殘餘吡啶。MS:m/z = 572.5 [M+H]+ 。 N -(5-(2,3- 二氟苯基 )-7- 側氧基 -6,7- 二氫 -5H - 吡咯并 [3,4-b ] 吡啶 -4- 基 ) 苯丙 [b ] 噻吩 -3- 甲醯胺
Figure 02_image6000
步驟 7 ：向N -(5-(2,3-二氟苯基)-6-(2,4-二甲氧基苯甲基)-7-側氧基-6,7-二氫-5H -吡咯并[3,4-b ]吡啶-4-基)苯丙[b ]噻吩-3-甲醯胺(197 mg，0.342 mmol)於乙腈(6.8 mL)中之溶液中添加硝酸銨鈰(IV) (559 mg，1.02 mmol，3.0當量)之溶液。在室溫下攪拌混合物15分鐘。用NaHCO3 飽和水溶液(25 mL)小心地處理混合物。所得固體藉由過濾分離，乾燥且以矽膠漿料形式裝載至24公克矽膠管柱上，用10:90:1 MeOH/DCM/NH4 OH於DCM中之梯度溶離。含產物之溶離份(在6.7%與7.5% MeOH/DCM之間溶離)經合併，濃縮且乾燥。隨後用二氯甲烷(2 mL)處理所得黃色固體(93 mg)。藉由過濾分離淡黃色固體且乾燥，以產生N -(5-(2,3-二氟苯基)-7-側氧基-6,7-二氫-5H -吡咯并[3,4-b ]吡啶-4-基)苯丙[b ] 噻吩-3-甲醯胺(84.5 mg，58%產率)。
根據實例60及61之方法製備之額外化合物列於下表29中。表 29. 額外例示性化合物
化合物 化合物 化合物
I-7    I-71    I-208
I-9    I-142    I-209
I-22    I-171    I-210
I-23    I-172    I-234
I-32    I-173    I-235
I-33    I-174    I-240
I-70    I-175    I-305
實例 62 3- 氟 -N -(4- 甲基 -3- 側氧基 -1-( 鄰甲苯基 )-2,3- 二氫 -1H - 吡咯并 [3,4-c ] 吡啶 -7- 基 )-5-( 三氟甲基 ) 苯甲醯胺 (I-244)
Figure 02_image6002
N -(2-(2,4- 二甲氧基苯甲基 )-4- 甲基 -3- 側氧基 -1-( 鄰甲苯基 )-2,3- 二氫 -1H - 吡咯并 [3,4-c ] 吡啶 -7- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image6004
步驟 1 ：向N -(4-氯-2-(2,4-二甲氧基苯甲基)-3-側氧基-1-(鄰甲苯基)-2,3-二氫-1H -吡咯并[3,4-c ]吡啶-7-基)-3-氟-5-(三氟甲基)苯甲醯胺(50 mg，0.0814 mmol)於二㗁烷(500 µL)及水(50 µL)中之溶液中添加碳酸鉀(33.7 mg，0.2442 mmol)、三甲基-1,3,5,2,4,6-三氧硼𠮿(12.4 µL，0.0896 mmol)及肆(三苯基膦)鈀(4.70 mg，0.00407 mmol)。將混合物在100℃下攪拌16小時，隨後用1 N HCl (100 µL)淬滅，隨後用水稀釋。所得混合物用EtOAc萃取三次。合併之有機物經Na2 SO4 乾燥，過濾且濃縮。所得殘餘物未經進一步純化即直接用於下一步驟中。3- 氟 -N -(4- 甲基 -3- 側氧基 -1-( 鄰甲苯基 )-2,3- 二氫 -1H - 吡咯并 [3,4-c ] 吡啶 -7- 基 )-5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image6006
步驟 2 ：根據實例13, 步驟6之程序，N -(2-(2,4-二甲氧基苯甲基)-4-甲基-3-側氧基-1-(鄰甲苯基)-2,3-二氫-1H -吡咯并[3,4-c ]吡啶-7-基)-3-氟-5-(三氟甲基)苯甲醯胺轉化為3-氟-N -(4-甲基-3-側氧基-1-(鄰甲苯基)-2,3-二氫-1H -吡咯并[3,4-c ]吡啶-7-基)-5-(三氟甲基)苯甲醯胺。實例 63 N -(1- 氯 -1-(2- 氯 -5- 氟苯基 )-4-(3,3- 二氟氮雜環丁烷 -1- 基 )-3- 側氧基 -2,3- 二氫 -1H - 吡咯并 [3,4-c ] 吡啶 -7- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-274)
Figure 02_image6008
N -[4- 氯 -1-(2- 氯 -5- 氟苯基 )-3- 側氧基 -1H ,2H ,3H - 吡咯并 [3,4-c ] 吡啶 -7- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image6010
步驟 1-6 ：類似於實例13，步驟1-6之程序，製備N -[4-氯-1-(2-氯-5-氟苯基)-3-側氧基-1H ,2H ,3H -吡咯并[3,4-c ]吡啶-7-基]-3-氟-5-(三氟甲基)苯甲醯胺。 N -(1- 氯 -1-(2- 氯 -5- 氟苯基 )-4-(3,3- 二氟氮雜環丁烷 -1- 基 )-3- 側氧基 -2,3- 二氫 -1H - 吡咯并 [3,4-c ] 吡啶 -7- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image6012
步驟 7 ：向錐形微波反應管中裝入N -[4-氯-1-(2-氯-5-氟苯基)-3-側氧基-1H ,2H ,3H -吡咯并[3,4-c ]吡啶-7-基]-3-氟-5-(三氟甲基)苯甲醯胺(11 mg，21.9 µmol，1.0當量)、3,3-二氟氮雜環丁烷鹽酸鹽(3.65 mg，28.4 µmol，1.3當量)及碳酸銫(17.8 mg，54.7 µmol，2.5當量)，且用氮氣吹掃5分鐘。隨後將無水DMF (0.5 mL)添加至反應介質，將其密封且在85℃下攪拌2小時。使反應介質冷卻至室溫，用EtOAc (4 mL)稀釋，且有機相用半飽和NaHCO3 (水溶液)洗滌4次。有機層接著經無水MgSO4 乾燥且在真空下濃縮。粗混合物經C18管柱純化，用水(10mM甲酸鹽):乙腈95:5至0:100溶離。純溶離份經凍乾，得到N -(1-氯-1-(2-氯-5-氟苯基)-4-(3,3-二氟氮雜環丁烷-1-基)-3-側氧基-2,3-二氫-1H -吡咯并[3,4-c ]吡啶-7-基)-3-氟-5-(三氟甲基)苯甲醯胺(3.2 mg)。MS:m/z = 593.1 [M+H]+ ;1 H NMR (400 MHz, CD3 OD) δ 8.71 (s, 1H), 7.87 (s, 1H), 7.77 (d,J = 8.6 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.49 - 7.32 (m, 1H), 7.14 - 6.97 (m, 1H), 3.82 - 3.56 (m, 4H)。
藉由類似於實例13、14、62、63及本文中之其他實例之方法製備的額外化合物列於下表30中。表 30. 額外例示性化合物
化合物 化合物 化合物
I-143    I-253    I-265
I-233    I-254    I-287
I-236    I-255    I-320
I-243            
實例 64 N -(3-(2-( 二氟甲基 )-5- 氟苯基 )-5- 氟 -1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-283)
Figure 02_image6014
2-[1-(3- 溴 -2,4- 二氟苯基 )-N -[(2,4- 二甲氧基苯基 ) 甲基 ] 甲醯胺基 ]-N - 三級丁基 -2-[2-( 二氟甲基 )-5- 氟苯基 ] 乙醯胺
Figure 02_image6016
步驟 1 ：向2-(二氟甲基)-5-氟苯甲醛(405 mg，2.33 mmol)於甲醇(5 mL)中之溶液中添加1-(2,4-二甲氧基苯基)甲胺(350 µL，2.33 mmol)，接著添加3-溴-2,4-二氟苯甲酸(500 mg，2.10 mmol)及2-異氰基-2-甲基丙烷(193 mg，2.33 mmol)。混合物在室溫下攪拌隔夜。在真空中濃縮反應混合物，獲得黃色固體。所得2-[1-(3-溴-2,4-二氟苯基)-N -[(2,4-二甲氧基苯基)甲基]甲醯胺基]-N -三級丁基-2-[2-(二氟甲基)-5-氟苯基]乙醯胺不經進一步純化即用於下一步驟中。LC-MS (方法1):  1.62 min,m/z = 644.2 [M+H]+ 。4- 溴 -3-[2-( 二氟甲基 )-5- 氟苯基 ]-2-[(2,4- 二甲氧基苯基 ) 甲基 ]-5- 氟 -2,3- 二氫 -1H - 異吲哚 -1- 酮
Figure 02_image6018
步驟 2 ：將2-[1-(3-溴-2,4-二氟苯基)-N -[(2,4-二甲氧基苯基)甲基]甲醯胺基]-N -三級丁基-2-[2-(二氟甲基)-5-氟苯基]乙醯胺(1.0 g，1.55 mmol)於DMF (6.2 mL)中之溶液抽空且用氮氣吹掃三次，且將反應混合物在-78℃下攪拌5分鐘。隨後在氮氣氛圍下添加NaH (92.8 mg，3.87 mmol)，且將反應物在-78℃至22℃攪拌隔夜。反應混合物經飽和NH4 Cl中和且接著用EtOAc (10 mL)萃取。用EtOAc (3×5 mL)萃取水相。合併之有機層用鹽水溶液洗滌，經硫酸鈉乾燥，過濾且在真空中濃縮。所得殘餘物含有4-溴-3-[2-(二氟甲基)-5-氟苯基]-2-[(2,4-二甲氧基苯基)甲基]-5-氟-2,3-二氫-1H -異吲哚-1-酮及氧化產物4-溴-3-[2-(二氟甲基)-5-氟苯基]-2-[(2,4-二甲氧基苯基)甲基]-5-氟-3-羥基-2,3-二氫-1H-異吲哚-1-酮。藉由正相層析(50 g管柱，己烷/丙酮)純化混合物。純化之所需4-溴-3-[2-(二氟甲基)-5-氟苯基]-2-[(2,4-二甲氧基苯基)甲基]-5-氟-2,3-二氫-1H -異吲哚-1-酮用於步驟3中。
對純化之氧化產物進行還原反應：將4-溴-3-[2-(二氟甲基)-5-氟苯基]-2-[(2,4-二甲氧基苯基)甲基]-5-氟-3-羥基-2,3-二氫-1H -異吲哚-1-酮(500 mg，0.9253 mmol)於DCM (2 mL)中之溶液冷卻至-78℃且添加BF3 ∙OEt2 (182 µL，1.48 mmol)。15分鐘後，添加三乙基矽烷(1.46 mL，9.25 mmol)。混合物在-78℃下再攪拌15分鐘且接著升溫至22℃且攪拌3小時。混合物用NaHCO3 水溶液稀釋且用DCM萃取。有機物經硫酸鈉乾燥，過濾且在真空中濃縮。所得4-溴-3-[2-(二氟甲基)-5-氟苯基]-2-[(2,4-二甲氧基苯基)甲基]-5-氟-2,3-二氫-1H -異吲哚-1-酮與前一部分組合且不經進一步純化即用於下一步驟中。4- 胺基 -3-[2-( 二氟甲基 )-5- 氟苯基 ]-2-[(2,4- 二甲氧基苯基 ) 甲基 ]-5- 氟 -2,3- 二氫 -1H - 異吲哚 -1- 酮
Figure 02_image6020
步驟 3 ：向4-溴-3-[2-(二氟甲基)-5-氟苯基]-2-[(2,4-二甲氧基苯基)甲基]-5-氟-2,3-二氫-1H -異吲哚-1-酮(20 mg，0.03814 mmol)於甲苯(0.4 mL)中之溶液中添加二苯甲酮亞胺(8.29 mg，0.04576 mmol)，接著添加(S )-BINAP (7.12 mg，0.01144 mmol)、Pd2 (dba)3 (3.49 mg，0.003814 mmol)及NaOt Bu (5.49 mg，0.05721 mmol)。在80℃下攪拌混合物16小時。反應混合物用1 M HCl淬滅且在22℃下攪拌隔夜。隨後，用DCM (10 mL)及NaHCO3 (15 mL)稀釋反應混合物，且用DCM (3×5 mL)萃取水相。合併之有機層用鹽水溶液洗滌，經硫酸鈉乾燥，過濾且在真空中濃縮。殘餘物藉由逆相層析(30 g管柱，水/ACN；水溶劑為10mM甲酸銨)純化，得到4-胺基-3-[2-(二氟甲基)-5-氟苯基]-2-[(2,4-二甲氧基苯基)甲基]-5-氟-2,3-二氫-1H -異吲哚-1-酮。LC-MS (方法1):  1.30 min,m/z = 461.3 [M+H]+ 。 N -{3-[2-( 二氟甲基 )-5- 氟苯基 ]-2-[(2,4- 二甲氧基苯基 ) 甲基 ]-5- 氟 -1- 側氧基 -2,3- 二氫 -1H - 異吲哚 -4- 基 }-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image6022
步驟 4 ：向4-胺基-3-[2-(二氟甲基)-5-氟苯基]-2-[(2,4-二甲氧基苯基)甲基]-5-氟-2,3-二氫-1H -異吲哚-1-酮(10 mg，0.0217 mmol)於DCM (1 mL)中之溶液中添加3-氟-5-(三氟甲基)苯甲醯氯(7.37 mg，0.0326 mmol)及K2 CO3 (15 mg，0.108 mmol)。在50℃下攪拌反應混合物3小時。用EtOAc (10 mL)及NaHCO3 (15 mL)稀釋反應混合物，且用EtOAc (3×5 mL)萃取水相。合併之有機層用鹽水溶液洗滌，經硫酸鈉乾燥，過濾且在真空中濃縮。藉由逆相層析(30 g管柱，水/ACN；水溶劑為10 mM甲酸銨)純化所得殘餘物。LC-MS (方法1):  1.52 min,m/z = 651.7 [M+H]+ 。 N -(3-(2-( 二氟甲基 )-5- 氟苯基 )-5- 氟 -1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image6024
步驟 5 ：在密封管中將N -{3-[2-(二氟甲基)-5-氟苯基]-2-[(2,4-二甲氧基苯基)甲基]-5-氟-1-側氧基-2,3-二氫-1H-異吲哚-4-基}-3-氟-5-(三氟甲基)苯甲醯胺(10 mg，0.01537 mmol)於TFA (2 mL)中之混合物加熱至40℃後維持1小時。接著將反應混合物冷卻至環境溫度且在真空中濃縮。藉由逆相層析(30 g管柱，水/ACN；水溶劑為10 mM甲酸銨)純化所得殘餘物，得到N -(3-(2-(二氟甲基)-5-氟苯基)-5-氟-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(0.79 mg，5 %產率經2個步驟)。實例 65 N -(3- 甲基 -1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [b ] 噻吩 -3- 甲醯胺 (I-80)
Figure 02_image6026
4- 胺基 -2-(4- 甲氧基苯甲基 )-3- 甲基 -3-( 鄰甲苯基 ) 異吲哚啉 -1- 酮
Figure 02_image6028
步驟 1 ：在室溫下在氮氣氛圍下向4-胺基-3-羥基-2-(4-甲氧基苯甲基)-3-(鄰甲苯基)異吲哚啉-1-酮(300 mg，0.801 mmol)於無水THF (3 mL)中之溶液中添加BF3 ∙OEt2 (295 μL, 2.40 mmol)。隨後將紫色溶液在室溫下攪拌12小時，隨後添加氯(甲基)鎂(4.8 mL，3 M於THF中，14.3 mmol)之溶液。再攪拌混合物1小時，且接著緩慢添加NH4 Cl之飽和(水)溶液(20 mL)。混合物用EtOAc稀釋且用EtOAc (3×)萃取。合併之有機層用鹽水洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮，得到橙色發泡體。所得4-胺基-2-(4-甲氧基苯甲基)-3-甲基-3-(鄰甲苯基)異吲哚啉-1-酮不經進一步純化即使用。LC-MS (方法1):  1.24 min,m/z = 373.3 [M+H]+ 。4- 胺基 -3- 甲基 -3-( 鄰甲苯基 ) 異吲哚啉 -1- 酮
Figure 02_image6030
步驟 2 ：將4-胺基-2-(4-甲氧基苯甲基)-3-甲基-3-(鄰甲苯基)異吲哚啉-1-酮(150 mg，0.282 mmol)於TFA (15 mL)中之溶液在170℃下在微波照射下加熱80分鐘。分析指示主要產物為2,2,2-三氟-N -(3-甲基-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)乙醯胺。隨後在減壓下濃縮混合物且溶解於MeOH (10 mL)中。添加碳酸鉀(500 mg，3.56 mmol)，且在60℃下加熱混合物12小時。混合物接著用NH4 Cl飽和(水)溶液稀釋且用DCM (4×)萃取。合併之有機層用鹽水洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮，得到4-胺基-3-甲基-3-(鄰甲苯基)異吲哚啉-1-酮，其不經進一步純化即用於下一步驟中。 N -(3- 甲基 -1- 側氧基 -3-( 鄰甲苯基 ) 異吲哚啉 -4- 基 ) 苯丙 [b ] 噻吩 -3- 甲醯胺
Figure 02_image6032
步驟 3 ：將來自前一步驟之4-胺基-3-甲基-3-(鄰甲苯基)異吲哚啉-1-酮溶解於吡啶(6 mL)中且添加1-苯丙噻吩-3-甲醯氯(110 mg，0.563 mmol)。在室溫下攪拌混合物12小時。混合物接著用CuSO4 之飽和(水)溶液稀釋且用EtOAc (3×)萃取。合併之有機層用水，隨後用飽和NaHCO3 (水溶液)，且最後用鹽水洗滌，隨後經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由逆相層析(5至70% ACN/水[AmF 10 mM])純化，接著藉由正相層析(0至60%丙酮/庚烷)純化，在凍乾之後得到呈白色粉末狀之N -(3-甲基-1-側氧基-3-(鄰甲苯基)異吲哚啉-4-基)苯丙[b ]噻吩-3-甲醯胺(43 mg，37%經兩個步驟)。
藉由類似於實例65及本文中之其他實例之方法製備的額外化合物列於下表31中。表 31. 額外例示性化合物
化合物
I-130
實例 66 N -(1-(2- 氯苯基 )-6- 甲氧基 -3- 側氧基 -2,3- 二氫 -1H - 吡咯并 [3,4-c ] 吡啶 -7- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-335)
Figure 02_image6034
2- 氯 -N -(2,4- 二甲氧基苯甲基 ) 苯甲醯胺
Figure 02_image6036
步驟 1 ：向1-(2,4-二甲氧基苯基)甲胺(4.76 g，28.5 mmol)於DCM (30 mL)中之溶液中添加DIPEA (9.91 mL，57.0 mmol)。將溶液冷卻至0-5℃，接著逐滴添加2-氯苯甲醯氯(3.61 mL，28.5 mmol)。使混合物升溫至室溫且攪拌2小時。用DCM稀釋混合物且用水洗滌。乾燥且濃縮有機層。添加庚烷，且音波處理混合物直至分離固體。混合物經過濾且風乾，得到呈白色固體狀之2-氯-N -(2,4-二甲氧基苯甲基)苯甲醯胺(7.89 g，25.8 mmol，90.5%產率)。MS:m/z = 306.3 [M+H]+ 。1-(2- 氯苯基 )-2-(2,4- 二甲氧基苯甲基 )-6- 甲氧基 -7- 硝基 -1,2- 二氫 -3H - 吡咯并 [3,4-c ] 吡啶 -3- 酮
Figure 02_image6038
步驟 2 ：在-50℃下經15分鐘向2-氯-N -(2,4-二甲氧基苯甲基)苯甲醯胺(1.51 g，4.97 mmol)於THF (25 mL)中之溶液中逐滴添加LHMDS (4.97 mL，4.97 mmol)，將溫度保持在-50℃。將混合物在-50℃下攪拌15分鐘，接著經15分鐘逐滴添加6-氯-5-硝基吡啶-3-甲醯氯(1.1 g，4.97 mmol)。添加完成後，經30分鐘將混合物升溫至-20℃。30分鐘後，將混合物冷卻至-50℃且經15分鐘逐滴添加第二當量之LHMDS (4.97 mL，4.97 mmol)。經45分鐘將混合物升溫至室溫。在室溫下用MeOH (25 mL)淬滅反應混合物。將溶液濃縮至SiO2 上，且藉由正相層析(0-100%乙酸乙酯/庚烷)純化，得到1-(2-氯苯基)-2-(2,4-二甲氧基苯甲基)-6-甲氧基-7-硝基-1,2-二氫-3H -吡咯并[3,4-c ]吡啶-3-酮(1.24 g，0.638 mmol，12.8%, 30%純，根據HPLC)。MS:m/z = 486.12 [M+H]+ 。7- 胺基 -1-(2- 氯苯基 )-2-(2,4- 二甲氧基苯甲基 )-1- 羥基 -6- 甲氧基 -1,2- 二氫 -3H - 吡咯并 [3,4-c ] 吡啶 -3- 酮
Figure 02_image6040
步驟 3 ：將前一步驟中製備之1-(2-氯苯基)-2-(2,4-二甲氧基苯甲基)-6-甲氧基-7-硝基-1,2-二氫-3H-吡咯并[3,4-c]吡啶-3-酮(300 mg，0.6174 mmol)於MeOH (4 mL)及AcOH (2 mL)中之溶液冷卻至0℃，且添加鐵(172 mg，3.08 mmol)。使混合物升溫至室溫，接著在80℃下加熱1小時。將混合物分配於EtOAc與水之間，接著經由矽藻土墊過濾以移除任何固體。各層為分離層，且有機層用鹽水洗滌，經Na2 SO4 乾燥，過濾且濃縮。所得7-胺基-1-(2-氯苯基)-2-(2,4-二甲氧基苯甲基)-1-羥基-6-甲氧基-1,2-二氫-3H -吡咯并[3,4-c ]吡啶-3-酮(35%純，根據LCMS)不經進一步純化即直接用於下一步驟。 N -(1-(2- 氯苯基 )-2-(2,4- 二甲氧基苯甲基 )-1- 羥基 -6- 甲氧基 -3- 側氧基 -2,3- 二氫 -1H - 吡咯并 [3,4-c ] 吡啶 -7- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image6042
步驟 4 ：將3-氟-5-(三氟甲基)苯甲酸(94.6 mg，0.4546 mmol)於DCE (5 mL)中之懸浮液用(1-氯-2-甲基丙-1-烯-1-基)二甲胺(60.7 mg，0.4546 mmol)處理。將混合物在室溫下攪拌15分鐘，隨後將其轉移至前一步驟之製備之7-胺基-1-(2-氯苯基)-2-(2,4-二甲氧基苯甲基)-1-羥基-6-甲氧基-1,2-二氫-3H -吡咯并[3,4-c ]吡啶-3-酮(100 mg，0.2273 mmol)、DMAP (8.74 mg，0.0227 mmol)及吡啶(90.9 µL，1.13 mmol)於DCE (5 mL)中之溶液中。將混合物在60℃下攪拌16小時。混合物經濃縮且所得N -(1-(2-氯苯基)-2-(2,4-二甲氧基苯甲基)-1-羥基-6-甲氧基-3-側氧基-2,3-二氫-1H -吡咯并[3,4-c ]吡啶-7-基)-3-氟-5-(三氟甲基)苯甲醯胺不經進一步純化即用於下一步驟中。 N -(1-(2- 氯苯基 )-6- 甲氧基 -3- 側氧基 -2,3- 二氫 -1H - 吡咯并 [3,4-c ] 吡啶 -7- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image6044
步驟 5 ：將前一步驟中製備之N -(1-(2-氯苯基)-2-(2,4-二甲氧基苯甲基)-1-羥基-6-甲氧基-3-側氧基-2,3-二氫-1H -吡咯并[3,4-c ]吡啶-7-基)-3-氟-5-(三氟甲基)苯甲醯胺溶解於TFA (1 mL)中且在80℃下攪拌30分鐘。將混合物冷卻至室溫，添加三乙基矽烷(108 µL，0.682 mmol)，且將混合物在80℃下加熱30分鐘。濃縮混合物，     且藉由逆相純化來純化殘餘物，得到呈白色固體狀之N -(1-(2-氯苯基)-6-甲氧基-3-側氧基-2,3-二氫-1H -吡咯并[3,4-c ]吡啶-7-基)-3-氟-5-(三氟甲基)苯甲醯胺(6 mg，0.01250 mmol，5.50 %來自步驟2)。實例 67 6-([1,2,4] 三唑并 [1,5-a] 吡啶 -6- 基 )-3-(2- 氯 -5- 氟苯基 )-4-( 哌啶 -3- 基胺基 ) 異吲哚啉 -1- 酮 (I-2158)
Figure 02_image6046
3-((6-([1,2,4] 三唑并 [1,5-a] 吡啶 -6- 基 )-3-(2- 氯 -5- 氟苯基 )-2-(4- 甲氧基苯甲基 )-1- 側氧基異吲哚啉 -4- 基 ) 胺基 ) 哌啶 -1- 甲酸三級丁酯
Figure 02_image6048
步驟 1 ：向配備有攪拌棒之25 mL微波小瓶中裝入4-溴-3-(2-氯-5-氟苯基)-2-[(4-甲氧基苯基)甲基]-6-{[1,2,4]三唑并[1,5-a]吡啶-6-基}-2,3-二氫-1H-異吲哚-1-酮(300 mg，0.5191 mmol)、Pd2 dba3 (47.5 mg，0.05191 mmol)、DavePhos (40.8 mg，0.1038 mmol)、三級丁醇鈉(148 mg，1.55 mmol)及3-胺基哌啶-1-甲酸三級丁酯(187 µL，2當量)，隨後用甲苯(4 mL)稀釋。混合物用氮氣鼓泡，隨後密封且在110℃下加熱1小時。在真空濃縮之後，對混合物進行逆相C18層析且凍乾，得到3-((6-([1,2,4]三唑并[1,5-a]吡啶-6-基)-3-(2-氯-5-氟苯基)-2-(4-甲氧基苯甲基)-1-側氧基異吲哚啉-4-基)胺基)哌啶-1-甲酸三級丁酯(150 mg，0.22 mmol，41.5%產率)。6-([1,2,4] 三唑并 [1,5-a] 吡啶 -6- 基 )-3-(2- 氯 -5- 氟苯基 )-4-( 哌啶 -3- 基胺基 ) 異吲哚啉 -1- 酮
Figure 02_image6050
步驟 2 ：向配備有攪拌棒之20 mL密封管中裝入3-{[3-(2-氯-5-氟苯基)-2-[(4-甲氧基苯基)甲基]-1-側氧基-6-{[1,2,4]三唑并[1,5-a]吡啶-6-基}-2,3-二氫-1H-異吲哚-4-基]胺基}哌啶-1-甲酸三級丁酯(150 mg，0.2151 mmol)，接著稀釋於三氟乙酸(20 mL)中且添加三氟甲磺酸(28.4 µL，1.5當量)。將小瓶密封且在90℃下加熱1小時。混合物用DCM稀釋且濃縮，進行逆相層析(C18-30 g)且凍乾，得到6-([1,2,4]三唑并[1,5-a]吡啶-6-基)-3-(2-氯-5-氟苯基)-4-(哌啶-3-基胺基)異吲哚啉-1-酮(20 mg，0.042 mmol，19.6%產率)。MS:m/z = 477.0 [M+H]+ 。實例 68 (S)-N-[3-(2- 氯 -5- 氟苯基 )-1- 側氧基 -6-{[1,2,4] 三唑并 [1,5-a] 吡啶 -6- 基 }-2,3- 二氫 -1H- 異吲哚 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-943) 及 (R)-N-[3-(2- 氯 -5- 氟苯基 )-1- 側氧基 -6-{[1,2,4] 三唑并 [1,5-a] 吡啶 -6- 基 }-2,3- 二氫 -1H- 異吲哚 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-945)
Figure 02_image6052
N-[3-(2- 氯 -5- 氟苯基 )-1- 側氧基 -6-{[1,2,4] 三唑并 [1,5-a] 吡啶 -6- 基 }-2,3- 二氫 -1H- 異吲哚 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image6054
步驟 1 ：將N-[6-溴-3-(2-氯-5-氟苯基)-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(32.1 mg)、6-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-[1,2,4]三唑并[1,5-a]吡啶(23.0 mg)、雙(三苯膦)二氯化鈀(II) (6.18 mg)、碳酸二鈉(18.6 mg)於乙腈(1.17 mL) /水(0.4 mL)中之經N2 脫氣之混合物在密封管中在110℃下攪拌40分鐘。混合物經冷卻，用THF (10 mL)及鹽水(8 mL)稀釋，且分離各層。濃縮有機層。將粗產物以矽膠漿料形式裝載至12 g矽膠管柱上，以DCM至10:90:1 MeOH/DCM/NH4 OH梯度經25分鐘溶離。產物在5.5%與6.2% MeOH/DCM之間溶離。含有產物之溶離份經合併，真空濃縮且乾燥，以產生泡沫狀白色固體(25.0 mg)。MS:m/z = 584.0 [M+H]+ 。1 H NMR (400 MHz, DMSO-d6 ) δ 10.65 (s, 1H), 9.48 (s, 1H), 9.34 - 9.26 (br s, 1H), 8.58 (s, 2H), 8.34 (s, 2H), 8.00 (m, 3H), 7.97 (m, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.59 (s, 1H), 7.42(t, J = 7.7 Hz, 1H), 6.04 (br s, 1H)。(S)-N-[3-(2- 氯 -5- 氟苯基 )-1- 側氧基 -6-{[1,2,4] 三唑并 [1,5-a] 吡啶 -6- 基 }-2,3- 二氫 -1H- 異吲哚 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-943) 及 (R)- N-[3-(2- 氯 -5- 氟苯基 )-1- 側氧基 -6-{[1,2,4] 三唑并 [1,5-a] 吡啶 -6- 基 }-2,3- 二氫 -1H- 異吲哚 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-945)
步驟 2 ：90.3 mg來自步驟1之外消旋體(經多個反應運行組合)藉由SFC進行對掌性分離(方法：管柱：ChiralPak AS-H 30×250 mm 移動相：55%甲醇於CO2 中；流動速率：80 mL/min；樣品：將90.3 mg樣品溶解於10 mL甲醇+10 mL二氯甲烷中；注射：2.5 mL；偵測：220 nm)。分離產生兩個峰。
峰1 (滯留時間：0.66分鐘)：(S)-N-[3-(2-氯-5-氟苯基)-1-側氧基-6-{[1,2,4]三唑并[1,5-a]吡啶-6-基}-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺分離為白色固體，100% LC純度及100%對掌性純度(38.8 mg)。MS:m/z = 584.3 [M+H]+ 。1 H NMR (DMSO-d6 , 400 MHz): δ = 10.64 (s, 1H), 9.48 (s, 1H), 9.26 (br s, 1H), 8.58 (s, 1H), 8.10-8.19 (m, 2H), 7.99 (br d, J = 9.9 Hz, 3H), 7.75-7.83 (m, 1H), 7.73 (s, 1H), 7.35 (dd, J = 8.8, 5.3 Hz, 1H), 7.12 (td, J = 8.3, 3.0 Hz, 1H), 6.51-6.97 (m, 1H), 6.07 (br s, 1H)。
峰2 (滯留時間：2.48分鐘)：(R)-N-[3-(2-氯-5-氟苯基)-1-側氧基-6-{[1,2,4]三唑并[1,5-a]吡啶-6-基}-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺分離為白色固體，100% LC純度及99.89%對掌性純度(37.6 mg)。MS:m/z = 584.3 [M+H]+ 。1 H NMR (DMSO-d6 , 400 MHz): δ = 10.64 (s, 1H), 9.48 (s, 1H), 9.26 (br s, 1H), 8.58 (s, 1H), 8.10-8.19 (m, 2H), 7.99 (br d, J = 9.9 Hz, 3H), 7.75-7.83 (m, 1H), 7.73 (s, 1H), 7.35 (dd, J = 8.8, 5.3 Hz, 1H), 7.12 (td, J = 8.3, 3.0 Hz, 1H), 6.51-6.97 (m, 1H), 6.07 ppm (br s, 1H)。實例 69 (S)-N-(3-(2- 氯 -5- 氟苯基 )-6-(5- 氰基 -[1,2,4] 三唑并 [1,5-a] 吡啶 -6- 基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-1647) 及 (R)-N-(3-(2- 氯 -5- 氟苯基 )-6-(5- 氰基 -[1,2,4] 三唑并 [1,5-a] 吡啶 -6- 基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-1648)
Figure 02_image6056
N-(3-(2- 氯 -5- 氟苯基 )-6-(5- 氰基 -[1,2,4] 三唑并 [1,5-a] 吡啶 -6- 基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image6058
步驟 1 ：向裝配有攪拌棒之密封管中添加[1-(2-氯-5-氟苯基)-7-[3-氟-5-(三氟甲基)苯甲醯胺基]-3-側氧基-2,3-二氫-1H-異吲哚5-基]
Figure 110115674-A0304-12-01
酸(50 mg，0.09792 mmol)、6-溴-[1,2,4]三唑并[1,5-a]吡啶-5-甲腈(21.8 mg，0.09792 mmol)、雙(三苯膦)二氯化鈀(II) (10.3 mg，0.01468 mmol)、乙腈(2 mL，0.05M)及碳酸二鈉(31.1 mg，0.2937 mmol)於水(0.65 mL)中之溶液。用氮氣使混合物脫氣30秒，且密封該管。在90℃下加熱反應物45分鐘。將反應物冷卻至室溫，經由Celite® 墊過濾，且濃縮。在製備型HPLC (AccQ Prep；用含0.1%甲酸之30%-60%乙腈/水溶離)上純化殘餘物。將含有產物之合併之溶離份真空濃縮，以產生固體(10 mg，15.9%產率)。MS:m/z = 609.08 [M+H]+ 。1 H NMR (500 MHz, DMSO-d6 ) δ 10.71 (s, 1H), 9.33 (s, 1H), 8.79 (s, 1H), 8.33 (d, J = 9.2 Hz, 1H), 8.06 (s, 1H), 7.98 (d, J = 9.3 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.83 (s, 1H), 7.75 (d, J = 9.1 Hz, 1H), 7.68 (s, 1H), 7.35 (dd, J = 8.9, 5.1 Hz, 1H), 7.12 (td, J = 8.4, 3.1 Hz, 1H), 6.54 (s, 1H), 6.08 (s, 1H)。(S)-N-(3-(2- 氯 -5- 氟苯基 )-6-(5- 氰基 -[1,2,4] 三唑并 [1,5-a] 吡啶 -6- 基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-1647) 及 (R)-N-(3-(2- 氯 -5- 氟苯基 )-6-(5- 氰基 -[1,2,4] 三唑并 [1,5-a] 吡啶 -6- 基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-1648)
步驟 2 ：100.0 mg來自步驟1之外消旋體(經多個反應運行組合)藉由SFC進行對掌性分離(方法：管柱：UniChiral AS-5H 21×250 mm；移動相：60%甲醇於CO2 中；流動速率：70 mL/min；樣品：將100.0 mg樣品溶解於5 mL甲醇+5 mL二氯甲烷中；注射：2.5 mL；偵測：254 nm)。分離產生兩個峰。
峰1 (滯留時間：0.83分鐘)：(S)-N-(3-(2-氯-5-氟苯基)-6-(5-氰基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺分離為固體(40 mg)。MS:m/z = 609.1 [M+H]+ 。1 H NMR (500 MHz, DMSO-d6 ) δ 10.71 (s, 1H), 9.33 (s, 1H), 8.80 (s, 1H), 8.34 (d, J = 9.2 Hz, 1H), 8.07 (s, 1H), 7.97 (t, J = 9.9 Hz, 2H), 7.83 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.68 (s, 1H), 7.35 (dd, J = 8.8, 5.1 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H)。
峰2 (滯留時間：3.11分鐘)：(R)-N-(3-(2-氯-5-氟苯基)-6-(5-氰基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺分離為固體(43 mg)。MS:m/z = 609.1 [M+H]+ 。1 H NMR (500 MHz, DMSO-d6 ) δ 10.71 (s, 1H), 9.33 (s, 1H), 8.80 (s, 1H), 8.34 (d, J = 9.2 Hz, 1H), 8.07 (s, 1H), 7.97 (t, J = 9.9 Hz, 2H), 7.83 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.68 (s, 1H), 7.35 (dd, J = 8.8, 5.1 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H)。實例 70 (S)-N-(3-(2- 氯 -5- 氟苯基 )-6-(1-( 二氟甲基 )-1H- 吡唑 -4- 基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-1739) 及 (R)-N-(3-(2- 氯 -5- 氟苯基 )-6-(1-( 二氟甲基 )-1H- 吡唑 -4- 基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-1740)
Figure 02_image6060
N-(3-(2- 氯 -5- 氟苯基 )-6-(5- 氰基 -[1,2,4] 三唑并 [1,5-a] 吡啶 -6- 基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image6062
步驟 1 ：向裝配有攪拌棒之密封管中添加N-[6-溴-3-(2-氯-5-氟苯基)-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(350 mg，0.641 mmol，1當量)、1-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-1H-吡唑(211 mg，0.865 mmol，1.35當量)、雙(三苯膦)二氯化鈀(II) (67.4 mg，0.096 mmol，0.15當量)、二㗁烷(4.3 mL，0.15M)及碳酸鈉(203 mg，1.92 mmol，3.0當量)於水(1.4 mL)中之溶液。用氮氣使混合物脫氣30秒，且密封該管。在100℃下攪拌反應物總共55分鐘。將反應物冷卻至室溫且用水(30 mL)處理。藉由過濾分離深棕色固體。將粗物質(＞400 mg)以矽膠漿料形式裝載於24 g矽膠管柱上，以DCM至10:90:1 MeOH/DCM/NH4 OH梯度經25分鐘溶離。產物以約3.8% MeOH/DCM溶離。將含有所需產物之溶離份合併、濃縮且乾燥，得到茶色固體(94.0 mg)。MS:m/z = 583.4 [M+H]+ 。1 H NMR (400 MHz, DMSO-d6 ) δ 10.56 (s, 1H), 9.18 (s, 1H), 8.94 (s, 1H), 8.43 (s, 1H), 8.06 (d, J = 1.6 Hz, 1H), 8.02 - 7.79 (m, 3H), 7.75 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.31 (dd, J = 8.9, 5.1 Hz, 1H), 7.09 (td, J = 8.3, 3.1 Hz, 1H), 6.86 - 6.58 (m, 1H), 5.98 (s, 1H)。(S)-N-(3-(2- 氯 -5- 氟苯基 )-6-(1-( 二氟甲基 )-1H- 吡唑 -4- 基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-1739) 及 (R)-N-(3-(2- 氯 -5- 氟苯基 )-6-(1-( 二氟甲基 )-1H- 吡唑 -4- 基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-1740)
步驟 2 ：來自步驟1之85.1 mg外消旋體藉由SFC進行對掌性分離(管柱：UniChiral AS-5H 21×250 mm；移動相：45%甲醇於CO2 中；流動速率：70 mL/min；樣品：將85.1 mg樣品溶解於10 mL甲醇+5 mL二氯甲烷中；注射：2.5 mL；偵測：254 nm)。分離產生兩個峰。
峰1 (滯留時間：0.45分鐘)：(S)-N-(3-(2-氯-5-氟苯基)-6-(1-(二氟甲基)-1H-吡唑-4-基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺分離為固體(42.8 mg)。MS:m/z = 583.4 [M+H]+ 。1 H NMR (500 MHz, DMSO-d6 ) δ 10.55 (s, 1H), 9.17 (s, 1H), 8.94 (s, 1H), 8.44 (s, 1H), 8.06 (d, J = 1.5 Hz, 1H), 7.99 - 7.69 (m, 5H), 7.32 (dd, J = 8.9, 5.1 Hz, 1H), 7.09 (td, J = 8.4, 3.1 Hz, 1H), 6.92 - 6.41 (m, 1H), 5.99 (s, 1H)。
峰2 (滯留時間：0.74分鐘)：呈固體形式之(R)-N-(3-(2-氯-5-氟苯基)-6-(1-(二氟甲基)-1H-吡唑-4-基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(23.4 mg)。MS:m/z = 583.4 [M+H]+ 。1 H NMR (500 MHz, DMSO-d6 ) δ 10.55 (s, 1H), 9.17 (s, 1H), 8.94 (s, 1H), 8.44 (s, 1H), 8.06 (d, J = 1.5 Hz, 1H), 7.99 - 7.69 (m, 5H), 7.32 (dd, J = 8.9, 5.1 Hz, 1H), 7.09 (td, J = 8.4, 3.1 Hz, 1H), 6.92 - 6.41 (m, 1H), 5.99 (s, 1H)。實例 71 (S )-N-(3-(2- 氯 -5- 氟苯基 )-6-(1- 甲基 -6- 側氧基 -1,6- 二氫吡啶 -3- 基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-701) 及 (R )-N-(3-(2- 氯 -5- 氟苯基 )-6-(1- 甲基 -6- 側氧基 -1,6- 二氫吡啶 -3- 基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-702)
Figure 02_image6064
N-[3-(2- 氯 -5- 氟苯基 )-2-[(4- 甲氧基苯基 ) 甲基 ]-6-(1- 甲基 -6- 側氧基 -1,6- 二氫吡啶 -3- 基 )-1- 側氧基 -2,3- 二氫 -1H- 異吲哚 -4- yl]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image6066
步驟 1 ：將N-[6-溴-3-(2-氯-5-氟苯基)-2-[(4-甲氧基苯基)甲基]-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5- (三氟甲基)苯甲醯胺(140 mg)、1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-1,2-二氫吡啶-2-酮(83.6 mg)、雙(三苯膦)二氯化鈀(II) (22.0 mg)、碳酸二鈉(66.7 mg)於乙腈(4.19 mL) /水(1.40 mL)中之經N2 脫氣之混合物在105℃下在密封管中攪拌40分鐘。混合物經冷卻，用THF (7-8 mL)及鹽水(10 mL)稀釋，且分離各層。濃縮有機層。將粗物質以矽膠漿料形式裝載至24 g矽膠管柱上，以DCM至10:90:1 MeOH/DCM/NH4 OH梯度經20分鐘溶離。產物在4.7%與5.2% MeOH/DCM之間溶離。合併之溶離份在真空中濃縮且乾燥，以產生稱重為114.1 mg之灰白色/淺灰綠色泡沫狀固體。MS:m/z = 694.7 [M+H]+ 。N-[3-(2- 氯 -5- 氟苯基 )-6-(1- 甲基 -6- 側氧基 -1,6- 二氫吡啶 -3- 基 )-1- 側氧基 -2,3- 二氫 -1H- 異吲哚 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image6068
步驟 2 ：將N-[3-(2-氯-5-氟苯基)-2-[(4-甲氧基苯基)甲基]-6-(1-甲基-6-側氧基-1,6-二氫吡啶-3-基)-1-側氧基-2,3-二氫-1H-異吲哚-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(114.1 mg)及10% TFA於DCM (5.5 mL)中之混合物在100℃下在微波中加熱14小時。冷卻後，混合物經濃縮且在12公克矽膠管柱上以DCM至10:90:1 MeOH/DCM/NH4 OH溶離。將產物在6.1%與6.7% MeOH/DCM之間溶離，真空濃縮且乾燥，以產生61.6 mg。MS:m/z = 574.5 [M+H]+ ;1 H NMR (400 MHz, DMSO-d6 ) δ 10.90 (s, 1H), 9.52 (s, 1H), 8.62 (d,J = 1.5 Hz, 1H), 8.18 (dd,J = 8.6, 1.6 Hz, 1H), 7.98 (d,J = 8.7, 1H), 7.87 (s, 1H), 7.75 (d,J = 8.5, 1H), 7.67 (s, 1H), 7.35 (m, 1H), 7.10 (td, 8.6, 1.6 Hz, 1H), 6.57 (d,J = 8.8 Hz, 1H), 6.02 (s, 1H), 3.59 (s, 3H)。(S )-N-(3-(2- 氯 -5- 氟苯基 )-6-(1- 甲基 -6- 側氧基 -1,6- 二氫吡啶 -3- 基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-701) 及 (R )-N-(3-(2- 氯 -5- 氟苯基 )-6-(1- 甲基 -6- 側氧基 -1,6- 二氫吡啶 -3- 基 )-1- 側氧基異吲哚啉 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-702)
步驟 3 ：55 mg來自步驟2之外消旋體藉由SFC進行對掌性分離(方法：管柱：ChiralPak IC-H 21×250 mm 移動相：40%甲醇於CO2 中；流動速率：70 mL/min；樣品：將54.8 mg樣品溶解於4 mL甲醇+4 mL二氯甲烷中；注射：1 mL；偵測：220 nm)。分離產生兩個峰。
峰1 (滯留時間：2.4分鐘)：(S )-N-(3-(2-氯-5-氟苯基)-6-(1-甲基-6-側氧基-1,6-二氫吡啶-3-基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺分離為白色固體，100% LC純度及100%對掌性純度(20.2 mg)。MS:m/z = 574.3 [M+H]+ ;1 H NMR (400 MHz, DMSO-d6 ) δ 10.90 (s, 1H), 9.52 (s, 1H), 8.62 (d,J = 1.5 Hz, 1H), 8.18 (dd,J = 8.6, 1.6 Hz, 1H), 7.98 (d,J = 8.7, 1H), 7.87 (s, 1H), 7.75 (d,J = 8.5, 1H), 7.67 (s, 1H), 7.35 (m, 1H), 7.10 (td, 8.6, 1.6 Hz, 1H), 6.57 (d,J = 8.8 Hz, 1H), 6.02 (s, 1H), 3.59 (s, 3H)。
峰2 (滯留時間：3.72分鐘)：(R )-N-(3-(2-氯-5-氟苯基)-6-(1-甲基-6-側氧基-1,6-二氫吡啶-3-基)-1-側氧基異吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲醯胺分離為白色固體，100% LC純度及100%對掌性純度(20.1 mg)。MS:m/z = 574.2 [M+H]+ ;1 H NMR (400 MHz, DMSO-d6 ) δ 10.90 (s, 1H), 9.52 (s, 1H), 8.62 (d,J = 1.5 Hz, 1H), 8.18 (dd,J = 8.6, 1.6 Hz, 1H), 7.98 (d,J = 8.7, 1H), 7.87 (s, 1H), 7.75 (d,J = 8.5, 1H), 7.67 (s, 1H), 7.35 (m, 1H), 7.10 (td, 8.6, 1.6 Hz, 1H), 6.57 (d,J = 8.8 Hz, 1H), 6.02 (s, 1H), 3.59 (s, 3H)。實例 72 4- 胺基 -2- 氯 -6-(2,4- 二甲氧基苯甲基 )-5-( 鄰甲苯基 )-5,6- 二氫 -7H - 吡咯并 [3,4-b ] 吡啶 -7- 酮
Figure 02_image6070
4,6- 二氯 -N -(2,4- 二甲氧基苯甲基 ) 吡啶甲醯胺
Figure 02_image6072
步驟 1 ：向4,6-二氯吡啶甲酸(50.0 g，260 mmol，1.00當量)於DCM (250 mL)中之溶液中添加CDI (44.3 g，273 mmol，1.05當量)及DMAP (1.59 g，13.02 mmol，0.05當量)，且將混合物在45℃下攪拌2小時。接著將混合物冷卻至15℃，且添加2,4-二甲氧基苯甲基胺(43.5 g，260 mmol，39.2 mL，1.00當量)於DCM (50 mL)中之溶液。在15℃下攪拌混合物5小時。添加水(700 mL)且用DCM (3×300 mL)萃取混合物。用1M HCl將有機相調節至pH=4，且用DCM (300 mL)萃取。合併之有機層用飽和NaCl (50 mL)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮，得到呈白色固體狀之4,6-二氯-N -(2,4-二甲氧基苯甲基)吡啶甲醯胺(68.0 g，165 mmol，63.5%產率，83.0%純度)。MS:m/z = 341.0 [M+H]+ ;1 H NMR (400 MHz, CDCl3 ) δ 8.15 (s, 1H), 8.14 (s, 1H), 7.45 (d,J = 0.8 Hz, 1H), 7.26 (t,J = 7.2 Hz, 1H), 6.50 - 6.42 (m, 2H), 3.88 (s, 3H), 3.80 (s, 3H)。4,6- 二氯 -N -(2,4- 二甲氧基苯甲基 )-N -(2- 甲基苯甲醯基 ) 吡啶甲醯胺
Figure 02_image6074
步驟 2 ：在0℃下在N2 下向NaH (10.6 g，264 mmol，60%純度, 1.50當量)於THF (300 mL)中之懸浮液中添加含4,6-二氯-N -(2,4-二甲氧基苯甲基)吡啶甲醯胺(60.0 g，176 mmol，1.00當量)之THF (100 mL)。將混合物在0℃下攪拌0.5小時。接著在0℃下逐滴添加2-甲基苯甲醯氯(28.8 g，186 mmol，24.2 mL，1.06當量)，且將混合物在0℃下攪拌2小時。混合物用1.0 L NH4 Cl淬滅且用乙酸乙酯(3×500 mL)萃取。合併之有機層用鹽水洗滌，經Na2 SO4 乾燥，且濃縮。殘餘物藉由矽膠管柱層析(石油醚:乙酸乙酯=100:0至100:6)純化，得到呈棕色油狀之4,6-二氯-N -(2,4-二甲氧基苯甲基)-N -(2-甲基苯甲醯基)吡啶甲醯胺(35.0 g，64.7 mmol，36.8產率，84.9%純度)。MS:m/z = 483.1 [M+Na]+ ;1 H NMR (400 MHz, CDCl3 ) δ 7.40 (d,J = 4.2 Hz, 1H), 7.37 (d,J = 0.8 Hz, 1H), 7.18 - 7.16 (m, 3H), 7.02 - 7.00 (m, 2H), 6.48 (d,J = 4.2 Hz, 1H), 6.41 (d,J = 1.2 Hz, 1H), 5.12 (s, 2 H), 3.80 (s, 3H), 3.66 (s, 3H), 2.44 (s, 3H)。2,4- 二氯 -6-(2,4- 二甲氧基苯甲基 )-5- 羥基 -5-( 鄰甲苯基 )-5,6- 二氫 -7H - 吡咯并 [3,4-b ] 吡啶 -7- 酮
Figure 02_image6076
步驟 3 ：在-50℃下向4,6-二氯-N -(2,4-二甲氧基苯甲基)-N -(2-甲基苯甲醯基)吡啶甲醯胺(44.8 g，97.4 mmol，1.00當量)於THF (450 mL)中之溶液中添加LiHMDS (1 M，146 mL，1.50當量)。在-50℃下攪拌溶液3小時。混合物用飽和NH4 Cl溶液(1.0 L)淬滅且用乙酸乙酯(2×500 mL)萃取。有機層經合併，用鹽水(500 mL)洗滌，乾燥且濃縮。殘餘物藉由矽膠管柱層析(石油醚:乙酸乙酯=100:1至100:11)純化，得到呈黃色油狀之2,4-二氯-6-(2,4-二甲氧基苯甲基)-5-羥基-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(29.0 g，33.5 mmol，34.3%產率，53.0%純度)。MS:m/z = 459.0 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 8.99 (t,J = 6.2 Hz, 1H), 8.21 (s, 1H), 7.35 (s, 1H), 7.23 (d,J = 3.6 Hz, 1H), 7.16 (d,J = 4.0 Hz, 1H) 6.88 (d,J = 4.0 Hz, 1H), 6.55 (d,J = 1.2 Hz, 1H), 6.53 - 6.50 (m, 3H), 4.24 (d,J = 3.2 Hz, 2H), 3.80 (s, 3H), 3.70 (s, 3H), 2.64 (s, 3H)。2,4- 二氯 -6-(2,4- 二甲氧基苯甲基 )-5-( 鄰甲苯基 )-5,6- 二氫 -7H - 吡咯并 [3,4-b ] 吡啶 -7- 酮
Figure 02_image6078
步驟 4 ：在20℃下向2,4-二氯-6-(2,4-二甲氧基苯甲基)-5-羥基-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(28.0 g，32.3 mmol，1.00當量)及TFA (92.1 g，808 mmol，59.8 mL，25.0當量)於DCM (280 mL)中之溶液中添加Et3 SiH (37.6 g，323 mmol，51.6 mL，10.0當量)。在25℃下攪拌溶液12小時。濃縮混合物。粗產物藉由製備型HPLC (TFA條件)純化，得到呈棕色固體狀之2,4-二氯-6-(2,4-二甲氧基苯甲基)-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(7.85 g，17.5 mmol，54.3%產率，99.0%純度)。MS:m/z = 443.0 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 7.95 (s, 1H), 7.23, (s, 1H), 7.09 - 7.08 (m, 1H), 6.95 (d,J = 4.2 Hz, 1H), 6.57 (d,J = 5.8 Hz, 1H) 6.51 (s, 1H), 6.50 - 6.44 (m, 1H), 5.78 (s, 1H), 4.80 (d,J = 7.6 Hz, 1H), 3.77 (s, 1H), 3.74 (s, 3H), 3.65 (s, 3H), 2.22 (s, 3H)。2- 氯 -6-(2,4- 二甲氧基苯甲基 )-4-((2,4- 二甲氧基苯甲基 ) 胺基 )-5-( 鄰甲苯基 )-5,6- 二氫 -7H - 吡咯并 [3,4-b ] 吡啶 -7- 酮及 4- 氯 -6-(2,4- 二甲氧基苯甲基 )-2-((2,4- 二甲氧基苯甲基 ) 胺基 )-5-( 鄰甲苯基 )-5,6- 二氫 -7H - 吡咯并 [3,4-b ] 吡啶 -7- 酮
Figure 02_image6080
步驟 5 ：在密封管中向2,4-二氯-6-(2,4-二甲氧基苯甲基)-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(3.92 g，8.84 mmol，1.00當量)於i-PrOH (25.0 mL)中之溶液中添加化合物2,4-二甲氧基苯甲基胺(2.22 g，13.3 mmol，2.00 mL，1.50當量)及DIPEA (3.43 g，26.5 mmol，4.62 mL，3.00當量)。在160℃下攪拌混合物5小時。濃縮混合物。殘餘物藉由製備型HPLC (管柱：Phenomenex Luna C18 (250*80 mm*15 μm)；移動相：含56%-86% CH3 CN之水(0.1% TFA)，經20分鐘)純化，得到呈淡黃色固體狀之2-氯-6-(2,4-二甲氧基苯甲基)-4-((2,4-二甲氧基苯甲基)胺基)-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(4.79 g，8.20 mmol，46.4%產率，98.24%純度)及呈黃色固體狀之4-氯-6-(2,4-二甲氧基苯甲基)-2-((2,4-二甲氧基苯甲基)胺基)-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(1.35 g，2.28 mmol，12.9%產率，97.0%純度)。
2-氯-6-(2,4-二甲氧基苯甲基)-4-((2,4-二甲氧基苯甲基)胺基)-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮：MS:m/z = 574.2 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 7.50 (d,J = 3.4 Hz, 1H), 7.29 - 7.25 (m, 2H), 7.14 - 7.10 (m, 1H), 7.00 - 6.84 (m, 1H), 6.70 - 6.63 (m, 2H) 6.52 - 6.43 (m, 4H), 5.76 - 5.38 (m, 2H), 4.79 - 4.67 (m, 1H), 4.16 - 4.14 (m,2H), 3.74 (s, 3H), 3.70 (s, 3H), 3.69 (s, 3H), 3.66 (s, 3H), 2.21 (s, 2H), 1.55 (s, 1H)。
4-氯-6-(2,4-二甲氧基苯甲基)-2-((2,4-二甲氧基苯甲基)胺基)-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮：MS:m/z = 574.4 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 7.41 (s, 1H), 8.21 (s, 1H), 7.20 - 7.18 (m, 3H), 7.11 - 7.07 (m, 1H), 6.78 (d,J = 3.2 Hz, 1H), 6.58 (s, 1H), 6.54 (s, 1H), 6.52 - 6.50 (m, 4H), 5.52 (s, 1H), 4.75 (d,,J = 7.6 Hz, 3H), 4.43 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.73 (s, 3H), 3.65 (s, 3H), 2.19 (s, 2H), 1.61 (s, 1H)。4- 胺基 -2- 氯 -6-(2,4- 二甲氧基苯甲基 )-5-( 鄰甲苯基 )-5,6- 二氫 -7H - 吡咯并 [3,4-b ] 吡啶 -7- 酮
Figure 02_image6082
步驟 6 ：將2-氯-6-(2,4-二甲氧基苯甲基)-4-((2,4-二甲氧基苯甲基)胺基)-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(3.60 g，6.27 mmol，1.00當量)及TFA (17.9 g，157 mmol，11.6 mL，25.0當量)之溶液在25℃下攪拌2小時。將混合物倒入飽和Na2 CO3 (200 mL)中且過濾。用乙酸乙酯(2×150 mL)萃取濾液。合併之有機物經Na2 SO4 乾燥且濃縮。殘餘物藉由逆相HPLC (0.1% NH3 •H2 O)純化，得到呈白色固體狀之4-胺基-2-氯-6-(2,4-二甲氧基苯甲基)-5-(鄰甲苯基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(1.18 g，2.76 mmol，43.9%產率，99.1%純度)。MS:m/z = 424.3 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 7.51 (t,J = 2.6 Hz, 1H), 7.28 - 7.20 (m, 2H), 7.11 - 7.08 (s, 1H), 6.98 - 6.84 (m, 1H), 6.86 (d,J = 9.0 Hz, 1H) 6.53 - 6.51 (m, 1H), 6.46 - 6.44 (m, 1H), 5.87 - 5.80 (m, 2H), 5.48 (d,J = 10.8 Hz, 1H), 4.80 - 4.66 (m, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 2.24 (s, 2H), 1.59 (s, 1H)。實例 73 N -(5-(2- 氯苯基 )-7- 側氧基 -2-(1H - 吡唑 -4- 基 )-6,7- 二氫 -5H - 吡咯并 [3,4-b ] 吡啶 -4- 基 ) 苯丙 [d ] 異噻唑 -3- 甲醯胺 (I-94)
Figure 02_image6084
4- 胺基 -2- 氯 -5-(2- 氯苯基 )-6-(4- 甲氧基苯甲基 )-5,6- 二氫 -7H- 吡咯并 [3,4-b] 吡啶 -7- 酮
Figure 02_image6086
步驟 1 至 6 ：根據實例68，步驟1至6之程序，將4,6-二氯吡啶甲酸、4-甲氧基苯甲基胺及2-氯苯甲醯氯轉化為4-胺基-2-氯-5-(2-氯苯基)-6-(4-甲氧基苯甲基)-5,6-二氫-7H-吡咯并[3,4-b]吡啶-7-酮。MS:m/z = 414.3 [M+H]+ 。N-[2- 氯 -5-(2- 氯苯基 )-6-[(4- 甲氧基苯基 ) 甲基 ]-7- 側氧基 -5H,6H,7H- 吡咯并 [3,4-b] 吡啶 -4- 基 ]-1,2- 苯并噻唑 -3- 甲醯胺
Figure 02_image6088
步驟 7 ：向(1-氯-2-甲基丙-1-烯-1-基)二甲胺(624 mg，4.67 mmol)於甲苯(3.89 mL)中之攪拌溶液中添加1,2-苯并噻唑-3-甲酸(836 mg，4.67 mmol)。懸浮液極快速變為透明淺粉色溶液，將其攪拌30分鐘，隨後添加1.3 mL至4-胺基-2-氯-5-(2-氯苯基)-6-[(4- 甲氧基苯基)甲基]-5H,6H,7H-吡咯并[3,4-b]吡啶-7-酮(323 mg，0.779 mmol)於吡啶(2.6 mL)中之溶液中。向此反應溶液中添加催化DMAP。將溶液在室溫下攪拌5分鐘，且隨後在65℃下攪拌30分鐘。分數份添加總共6當量之酸氯化物。反應物最終冷卻至室溫且用MeOH (3 mL)淬滅，接著濃縮且裝載於12 g矽膠管柱上，以DCM至10:90:1 MeOH/DCM/NH4 OH梯度經25分鐘溶離。產物在3%與3.5% MeOH/DCM之間溶離，以產生淺黃色泡沫狀固體(316 mg，70.5%產率)。MS:m/z = 575.5 [M+H]+ 。 N -[2- 氯 -5-(2- 氯苯基 )-7- 側氧基 -5H ,6H ,7H - 吡咯并 [3,4-b ] 吡啶 -4- 基 ]-1,2- 苯并噻唑 -3- 甲醯胺 (I-93)
Figure 02_image6090
步驟 8 ：向N-[2-氯-5-(2-氯苯基)-6-[(4-甲氧基苯基)甲基]-7-側氧基-5H,6H,7H-吡咯并[3,4-b]吡啶-4-基]-1,2-苯并噻唑-3-甲醯胺(251 mg，0.436 mmol)於乙腈(8.7 mL)中之溶液中添加硝酸鈰(712 mg，1.30 mmol)於水(0.87 mL)中之溶液。在室溫下攪拌混合物1小時。反應物用NaHCO3 飽和水溶液(25 mL)處理。黃色沈澱物藉由過濾分離，乾燥且在12 g矽膠管柱上用DCM溶離至10:90:1 MeOH/DCM/NH4 OH梯度，歷時25分鐘。主要產物峰在5.5%與6.7% MeOH/DCM之間溶離。含有純產物之溶離份經合併、濃縮且乾燥，以產生N-[2-氯-5-(2-氯苯基)-7-側氧基-5H,6H,7H-吡咯并[3,4-b]吡啶-4-基]-1,2-苯并噻唑-3-甲醯胺(44 mg，21.8%產率)。MS:m/z = 455.3 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 9.65 (s, 1H), 8.67 (d, 1H), 8.32 (d, 1H), 7.98 (s, 1H), 7.69 (t, 1H), 7.62 (t, 1H), 7.33 (d, 1H), 7.22 (t, 1H), 7.14 (t, 1H)。 N -(5-(2- 氯苯基 )-7- 側氧基 -2-(1H - 吡唑 -4- 基 )-6,7- 二氫 -5H - 吡咯并 [3,4-b ] 吡啶 -4- 基 ) 苯丙 [d ] 異噻唑 -3- 甲醯胺 (I-94)
Figure 02_image6092
步驟 9 ：在密封管中向N-[2-氯-5-(2-氯苯基)-7-側氧基-5H,6H,7H-吡咯并[3,4-b]吡啶-4-基]-1,2-苯并噻唑-3-甲醯胺(18.3 mg，0.04 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-1H-吡唑-1-甲酸三級丁酯(17.6 mg，0.06 mmol，1.5當量)、雙(三苯膦)二氯化鈀(II) (4.2 mg，0.006 mmol，0.15當量)之混合物中添加乙腈(0.8 mL)及碳酸鈉(12.7 mg，0.12 mmol，3當量)於水(0.27 mL)中之溶液。在密封管之前，用氮氣使反應混合物短暫脫氣。接著在115℃下攪拌反應混合物20分鐘，隨後重新冷卻至室溫。用THF (5 mL)及鹽水(3 mL)稀釋反應混合物，且分離各層。有機層經硫酸鈉乾燥，過濾且濃縮。將粗物質以矽膠漿料形式裝載至12公克矽膠管柱上，且以如下之梯度溶離：DCM至10:90:1 MeOH/DCM/NH4 OH經20分鐘。將在7%與9% MeOH/DCM之間溶離之溶離份合併，濃縮，且乾燥，以產生呈淡黃色固體狀之外消旋N-[5-(2-氯苯基)-7-側氧基-2-(1H-吡唑-4-基)-5H,6H,7H吡咯并[3,4-b]吡啶-4-基]-1,2-苯并噻唑-3-甲醯胺(6.8 mg，35%產率)。MS:m/z = 487.3 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 13.20 (br s, 1H), 10.48 (s, 1H), 9.46 (s, 1H), 8.69 (d,J = 8.1 Hz, 1H), 8.41 (br s, 1H), 8.33 (d,J = 8.1 Hz, 1H), 8.10 (br s, 1H), 8.07 (s, 1H), 7.60-7.73 (m, 3H), 7.30 (d,J = 7.8 Hz, 1H), 7.15-7.21 (m, 1H), 7.09-7.14 (m, 1H), 6.29 ppm (br s, 1H)。
根據實例68及69之方法製備之額外化合物列於下表32中。表 32. 額外例示性化合物
化合物 化合物 化合物
I-108    I-186    I-379
I-113    I-187    I-380
I-114    I-193    I-381
I-161    I-194    I-384
I-162    I-195    I-386
I-182    I-196      
實例 74 N -[5-(2- 氯 -5- 氟苯基 )-2-(3,3- 二氟氮雜環丁烷 -1- 基 )-7- 側氧基 -5H ,6H ,7H - 吡咯并 [3,4-b ] 吡啶 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-286)
Figure 02_image6094
4- 胺基 -2- 氯 -5-(2- 氯 -5- 氟苯基 )-6-(2,4- 二甲氧基苯甲基 )-5,6- 二氫 -7H - 吡咯并 [3,4-b ] 吡啶 -7- 酮
Figure 02_image6096
步驟 1 至 6 ：根據實例68，步驟1至6之程序，將4,6-二氯吡啶甲酸、2,4-二甲氧基苯甲基胺及2-氯-5-氟苯甲醯氯轉化為4-胺基-2-氯-5-(2-氯-5-氟苯基)-6-(2,4-二甲氧基苯甲基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮。 N -(2- 氯 -5-(2- 氯 -5- 氟苯基 )-6-(2,4- 二甲氧基苯甲基 )-7- 側氧基 -6,7- 二氫 -5H - 吡咯并 [3,4-b ] 吡啶 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image6098
步驟 7 ：在氮氣下向4-胺基-2-氯-5-(2-氯-5-氟苯基)-6-(2,4-二甲氧基苯甲基)-5,6-二氫-7H -吡咯并[3,4-b ]吡啶-7-酮(1.00 g，2.31 mmol)於無水吡啶(14.7 mL)中之混合物中逐滴添加3-氟-5-(三氟甲基)苯甲醯氯(530.4 μL, 3.47 mmol)。隨後添加4-二甲胺基吡啶(14 mg，0.115 mmol)，且在環境溫度下攪拌混合物6小時。用水淬滅混合物，且用飽和NaHCO3 水溶液調節pH。用DCM萃取產物。有機相接著經硫酸鈉乾燥，過濾且藉由旋轉蒸發濃縮。藉由正相二氧化矽層析(0%至70% EtOAc/己烷)純化，得到呈白色固體狀之N -(2-氯-5-(2-氯-5-氟苯基)-6-(2,4-二甲氧基苯甲基)-7-側氧基-6,7-二氫-5H -吡咯并[3,4-b ]吡啶-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(67%產率)。 N -(5-(2- 氯 -5- 氟苯基 )-2-(3,3- 二氟氮雜環丁烷 -1- 基 )-6-(2,4- 二甲氧基苯甲基 )-7- 側氧基 -6,7- 二氫 -5H - 吡咯并 [3,4-b ] 吡啶 -4- 基 )-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺
Figure 02_image6100
步驟 8 ：將含有N -(2-氯-5-(2-氯-5-氟苯基)-6-(2,4-二甲氧基苯甲基)-7-側氧基-6,7-二氫-5H -吡咯并[3,4-b ]吡啶-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(1.00 g，1.61 mmol)、3,3-二氟氮雜環丁烷鹽酸鹽(416.24 mg，3.21 mmol)及BrettPhos Pd Gen.4 (728.3 mg，0.803 mmol)之小瓶在真空中抽空且用氮氣吹掃。添加甲苯(10.7 mL，0.15 M)，且再次用氮氣吹掃混合物。隨後向混合物中添加LiHMDS (1M於THF中，8.03 mL，8.03 mmol)，且在105℃下攪拌混合物2小時。將混合物冷卻至22℃且在惰性氛圍下用DCM及水淬滅。雙相溶液接著用NH4 Cl飽和水溶液稀釋且用DCM萃取。有機層經硫酸鈉乾燥，過濾，且藉由旋轉蒸發濃縮。所得產物混合物不經進一步純化即直接進行後續反應。 N -[5-(2- 氯 -5- 氟苯基 )-2-(3,3- 二氟氮雜環丁烷 -1- 基 )-7- 側氧基 -5H ,6H ,7H - 吡咯并 [3,4-b ] 吡啶 -4- 基 ]-3- 氟 -5-( 三氟甲基 ) 苯甲醯胺 (I-286)
Figure 02_image6102
步驟 9 ：含有N -(5-(2-氯-5-氟苯基)-2-(3,3-二氟氮雜環丁烷-1-基)-6-(2,4-二甲氧基苯甲基)-7-側氧基-6,7-二氫-5H -吡咯并[3,4-b ]吡啶-4-基)-3-氟-5-(三氟甲基)苯甲醯胺(約1.00 mmol)之來自前一步驟之產物混合物用三氟乙酸(22 mL)及三氟甲磺酸(0.1 mL，1 mmol)處理。所得混合物在90℃下攪拌1小時。將混合物冷卻至室溫且濃縮。藉由C18矽膠管柱層析(30%至80% MeCN/10 mM碳酸氫銨水溶液)純化殘餘物。含產物之溶離份經合併且凍乾，以獲得呈白色粉末狀之N -[5-(2-氯-5-氟苯基)-2-(3,3-二氟氮雜環丁烷-1-基)-7-側氧基-5H ,6H ,7H -吡咯并[3,4-b ]吡啶-4-基]-3-氟-5-(三氟甲基)苯甲醯胺(64.8 mg，11.5%經兩個步驟)。MS:m/z = 559.3 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 10.72 (br s, 1H), 9.30 (br s, 1H), 7.94 (d,J = 6.5 Hz, 1H), 7.71 (d,J = 9.0 Hz, 1H), 7.62 (s, 1H), 7.34 (dd,J = 8.9, 5.2 Hz, 1H), 7.17 - 6.97 (m, 1H), 6.94 - 6.56 (m, 2H), 5.91 (br s, 1H), 4.65 - 4.33 (m, 4H)。
根據實例68-70之方法製備之額外化合物列於下表33中。表 33. 額外例示性化合物
化合物 化合物 化合物
I-273    I-321    I-357
I-284    I-322    I-356
I-288    I-329    I-366
I-291    I-338    I-367
I-319    I-354    I-368
實例 75 4-(1,2- 苯并噻唑 -3- 醯胺基 )-5-(2- 氯苯基 )-7- 側氧基 -5H ,6H ,7H - 吡咯并 [3,4-b ] 吡啶 -2- 甲酸甲酯 (I-222)
Figure 02_image6104
4- 氯 -6-( 甲氧羰基 ) 吡啶 -2- 甲酸
Figure 02_image6106
步驟 1 ：將4-氯吡啶-2,6-二甲酸(8.15 g，40.4 mmol)與亞硫醯氯(58.8 mL，807 mmol)混合且升溫至回流。在攪拌5小時之後，將混合物冷卻至室溫且攪拌16小時。藉由旋轉蒸發移除過量亞硫醯氯。殘餘物用無水二氯乙烷(161 mL)溶解且接著冷卻至0-5℃。將甲醇(1.87 mL，46.4 mmol)及DIPEA (8.07 mL，46.4 mmol)逐滴添加至混合物(放熱)。在室溫下攪拌混合物2.5小時。藉由旋轉蒸發移除揮發物。含有單甲酯、二甲酯及起始物質之混合物的殘餘物藉由正相層析(0-50%乙腈/DCM)純化。將純溶離份合併、濃縮且在真空中乾燥，得到呈灰白色固體狀之4-氯-6-(甲氧羰基)吡啶-2-甲酸(2.28 g，26%產率，90%純度，根據LC/MS)。4- 氯 -6-{[(4- 甲氧基苯基 ) 甲基 ] 胺甲醯基 } 吡啶 -2- 甲酸甲酯
Figure 02_image6108
步驟 2 ：在室溫下將亞硫醯氯(15.2 mL，10 mmol)逐滴添加至4-氯-6-(甲氧羰基)吡啶-2-甲酸(2.28 g，10.5 mmol)於DMF (10 mL)中之攪拌懸浮液中。在25分鐘後且在氣體逸出之後，使混合物升溫至40℃後維持20分鐘。藉由旋轉蒸發移除過量亞硫醯氯，且將殘餘物溶解於無水二氯乙烷(42.0 mL)中且冷卻至0℃。將三乙胺(3.12 mL，22.5 mmol)及1-(4-甲氧基苯基)甲胺(2.04 mL，15.7 mmol)添加至溶液。將混合物在室溫下攪拌1小時。用水緩慢淬滅混合物。分離各層，且用EtOAc萃取水層。有機層經合併，經Na2 SO4 乾燥，且蒸發溶劑。殘餘物經由正相矽膠層析(20-75% EtOAc/己烷)純化，得到呈黃色固體狀之4-氯-6-{[(4-甲氧基苯基)甲基]胺甲醯基}吡啶-2-甲酸甲酯(2.56 g，73%產率)。4- 氯 -5-(2- 氯苯基 )-5- 羥基 -6-[(4- 甲氧基苯基 ) 甲基 ]-7- 側氧基 -5H ,6H ,7H - 吡咯并 [3,4-b ] 吡啶 -2- 甲酸甲酯
Figure 02_image6110
步驟 3 ：在氮氣氛圍下向4-氯-6-{[(4-甲氧基苯基)甲基]胺甲醯基}吡啶-2-甲酸甲酯(1.53 g，4.57 mmol)於THF (22.8 mL)中之攪拌-50℃溶液中緩慢添加LiHMDS (1.0 M溶液於THF中，5.0 mL，5.0 mmol)。在-78℃下攪拌溶液1小時。經2分鐘向混合物中逐滴添加2-氯苯甲醯氯(635 µL，5.02 mmol)。將混合物在-78℃下攪拌0.5小時且接著在室溫下攪拌2.5小時。使混合物重新冷卻至-50℃與至-78℃之間，且隨後緩慢添加LiHMDS (1M於THF中，5.0 mL，5.0 mmol)。在-50℃與-78℃之間攪拌混合物1小時。用AcOH (0.6 mL)於MeOH (25 mL)中之溶液緩慢淬滅混合物。接著將溶液稀釋於水及EtOAc中。分離各層，且用EtOAc萃取水層三次。有機層經合併，用鹽水洗滌，經Na2 SO4 乾燥，過濾且濃縮。殘餘物藉由正相二氧化矽層析(0-60%丙酮/庚烷)純化，得到呈灰白色固體狀之4-氯-5-(2-氯苯基)-5-羥基-6-[(4-甲氧基苯基)甲基]-7-側氧基-5H ,6H ,7H -吡咯并[3,4-b ]吡啶-2-甲酸甲酯(1.03 g，38%產率)。4- 氯 -5-(2- 氯苯基 )-6-[(4- 甲氧基苯基 ) 甲基 ]-7- 側氧基 -5H ,6H ,7H - 吡咯并 [3,4-b ] 吡啶 -2- 甲酸甲酯
Figure 02_image6112
步驟 4 ：在氮氣下向4-氯-5-(2-氯苯基)-5-羥基-6-[(4-甲氧基苯基)甲基]-7-側氧基-5H ,6H ,7H -吡咯并[3,4-b ]吡啶-2-甲酸甲酯(1.03 g，2.17 mmol)於DCM (10.8 mL)中之攪拌0℃溶液中添加TFA (3.31 mL，43.4 mmol)，接著添加三乙基矽烷(3.46 mL，21.7 mmol)。隨後使混合物升溫至室溫且攪拌16小時。將混合物冷卻至0℃且添加第二份TFA (1.65 mL，21.7 mmol)及三乙基矽烷(1.73 mL，10.9 mmol)。將混合物升溫至室溫且攪拌16小時。混合物用DCM稀釋且用NaHCO3 飽和水溶液淬滅直至獲得pH 6-7。分離各層，且用DCM萃取水層一次。有機層經合併，用鹽水洗滌，經Na2 SO4 乾燥，過濾且濃縮。殘餘物藉由正相矽膠管柱(30-100%丙酮/己烷)純化，得到呈黃色固體狀之4-氯-5-(2-氯苯基)-6-[(4-甲氧基苯基)甲基]-7-側氧基-5H ,6H ,7H -吡咯并[3,4-b ]吡啶-2-甲酸甲酯(684.8 mg，69%產率)。4- 疊氮基 -5-(2- 氯苯基 )-5- 羥基 -6-[(4- 甲氧基苯基 ) 甲基 ]-7- 側氧基 -5H ,6H ,7H - 吡咯并 [3,4-b ] 吡啶 -2- 甲酸甲酯
Figure 02_image6114
步驟 5 ：向圓底燒瓶中添加含4-氯-5-(2-氯苯基)-6-[(4-甲氧基苯基)甲基]-7-側氧基-5H ,6H ,7H -吡咯并[3,4-b ]吡啶-2-甲酸甲酯(500 mg，1.09 mmol)之DMF (5.7 mL)。添加疊氮化鈉(105 mg，1.63 mmol)，且在70℃下攪拌混合物1.5小時。將混合物冷卻至室溫，接著用水稀釋且用DCM萃取。再次用DCM萃取水層。有機層經合併，用鹽水洗滌，經Na2 SO4 乾燥，過濾且濃縮。所得4-疊氮基-5-(2-氯苯基)-5-羥基-6-[(4-甲氧基苯基)甲基]-7-側氧基-5H ,6H ,7H -吡咯并[3,4-b ]吡啶-2-甲酸甲酯不經進一步純化即直接進行後續反應。4- 胺基 -5-(2- 氯苯基 )-5- 羥基 -6-[(4- 甲氧基苯基 ) 甲基 ]-7- 側氧基 -5H ,6H ,7H - 吡咯并 [3,4-b ] 吡啶 -2- 甲酸甲酯
Figure 02_image6116
步驟 6 ：向4-疊氮基-5-(2-氯苯基)-5-羥基-6-[(4-甲氧基苯基)甲基]-7-側氧基-5H ,6H ,7H -吡咯并[3,4-b ]吡啶-2-甲酸甲酯(505 mg，1.05 mmol)於THF (10.5 mL)及水(2.10 mL)中之溶液中添加三苯膦(826 mg，3.15 mmol)。在60℃下加熱混合物2小時。將混合物冷卻至室溫且逐滴添加濃鹽酸(2.62 mL，31.5 mmol) (放熱添加)。將混合物在60℃下加熱2小時且接著冷卻至室溫。藉由旋轉蒸發濃縮揮發物，且將殘餘物稀釋於DCM及水中。水層用NaHCO3 飽和水溶液鹼化。分離各層，且用DCM萃取水層兩次。有機層經合併，用鹽水洗滌，經Na2 SO4 乾燥，過濾且濃縮。殘餘物藉由正相二氧化矽層析(0-15% MeOH/DCM)純化，隨後藉由正相二氧化矽層析(0-80%丙酮/庚烷)進行第二純化，得到呈黃色固體狀之4-胺基-5-(2-氯苯基)-5-羥基-6-[(4-甲氧基苯基)甲基]-7-側氧基-5H ,6H ,7H -吡咯并[3,4-b ]吡啶-2-甲酸甲酯(100.7 mg，21%產率經2個步驟)。4- 胺基 -5-(2- 氯苯基 )-6-[(4- 甲氧基苯基 ) 甲基 ]-7- 側氧基 -5H ,6H ,7H - 吡咯并 [3,4-b ] 吡啶 -2- 甲酸甲酯
Figure 02_image6118
步驟 7 ：在氮氣下向4-胺基-5-(2-氯苯基)-5-羥基-6-[(4-甲氧基苯基)甲基]-7-側氧基-5H ,6H ,7H -吡咯并[3,4-b ]吡啶-2-甲酸甲酯(87.6 mg，0.193 mmol)於DCE (2.57 mL)中之攪拌溶液中添加三氟硼烷二乙基醚合物(76.1 µL，0.618 mmol)，接著添加三乙基矽烷(307 µL，1.93 mmol)。將混合物加熱至80℃，攪拌15小時，且接著冷卻至室溫。添加第二部分之三氟硼烷二乙基醚合物(76.1 µL，0.618 mmol)及三乙基矽烷(307 µL，1.93 mmol)，且將混合物加熱至80℃且攪拌15小時。將混合物冷卻至室溫且用DCM及水稀釋。用NaHCO3 飽和水溶液將pH調節至8-9。分離各層，且用DCM萃取水層兩次。有機層經合併，用鹽水洗滌，經Na2 SO4 乾燥，過濾且濃縮。殘餘物不經任何進一步純化即直接用於下一步驟中。4-(1,2- 苯并噻唑 -3- 醯胺基 )-5-(2- 氯苯基 )-6-[(4- 甲氧基苯基 ) 甲基 ]-7- 側氧基 -5H ,6H ,7H - 吡咯并 [3,4-b ] 吡啶 -2- 甲酸甲酯
Figure 02_image6120
步驟 8 ：將含有4-胺基-5-(2-氯苯基)-6-[(4-甲氧基苯基)甲基]-7-側氧基-5H ,6H ,7H -吡咯并[3,4-b ]吡啶-2-甲酸甲酯(84.5 mg，0.193 mmol)及1,2-苯并噻唑-3-甲酸(44.9 mg，0.251 mmol)之來自前一步驟之殘餘物溶解於DCM (0.96 mL)中。添加N -甲基咪唑(53.7 μL，0.675 mmol)，接著添加四甲基氯甲脒六氟磷酸鹽(64.9 mg，0.231 mmol)。將混合物在室溫下攪拌16小時且接著用DCM及水稀釋。用NaHCO3 飽和水溶液將pH調節至7-8。分離各層，且用DCM萃取水層。合併之有機物用鹽水洗滌，經Na2 SO4 乾燥，過濾且濃縮。所得殘餘物不經進一步純化即直接進行後續反應。4-(1,2- 苯并噻唑 -3- 醯胺基 )-5-(2- 氯苯基 )-7- 側氧基 -5H ,6H ,7H - 吡咯并 [3,4-b ] 吡啶 -2- 甲酸甲酯 (I-222)
Figure 02_image6122
步驟 9 ：根據實例37，步驟7之程序，將4-(1,2-苯并噻唑-3-醯胺基)-5-(2-氯苯基)-6-[(4-甲氧基苯基)甲基]-7-側氧基-5H ,6H ,7H -吡咯并[3,4-b ]吡啶-2-甲酸甲酯轉化為4-(1,2-苯并噻唑-3-醯胺基)-5-(2-氯苯基)-7-側氧基-5H ,6H ,7H -吡咯并[3,4-b ]吡啶-2-甲酸甲酯。藉由正相二氧化矽層析(0%至10% MeOH/DCM)純化殘餘物。將殘餘物懸浮於水中且過濾沈澱物。固體接著用乙腈/水之混合物溶解且凍乾，獲得呈灰白色粉末狀之4-(1,2-苯并噻唑-3-醯胺基)-5-(2-氯苯基)-7-側氧基-5H ,6H ,7H -吡咯并[3,4-b ]吡啶-2-甲酸甲酯(4.62 mg，13%產率經3個步驟)。MS:m/z = 479.2 [M+H]+ ;1 H NMR (400 MHz, DMSO-d 6 ) δ 10.61 (br s, 1H), 9.70 (br s, 1H), 8.70 (d,J = 7.9 Hz, 1H), 8.60 (s, 1H), 8.33 (d,J = 8.2 Hz, 1H), 7.70 (ddd,J = 8.3, 7.0, 1.2 Hz, 1H), 7.67 - 7.52 (m, 1H), 7.33 (d,J = 7.7 Hz, 1H), 7.23 (td,J = 7.9, 1.6 Hz, 1H), 7.15 (td,J = 7.4, 1.1 Hz, 1H), 6.40 (br s, 1H), 3.97 (s, 3H)。實例 76
在ADP-Glo生物化學PIK3CA激酶分析中測試本發明之所選化合物。將待分析之化合物以1:2連續稀釋之16個劑量(各孔20 nL體積)接種於1536孔培養盤上，且使培養盤升溫至室溫。添加PIK3CA酶(例如H1047R、E542K、E545K或野生型) (1 μL於酶分析緩衝液(包含50 mM HEPES pH 7.4、50mM NaCl、6mM MgCl2 、5mM DTT及0.03% CHAPS)中之2 nM溶液)，且振盪10秒且預培育30分鐘。向孔中添加1 μL含200 μM ATP及20 μM diC8-PIP2之受質分析緩衝液(50 mM HEPES pH7.4、50mM NaCl、5mM DTT及0.03% CHAPS)以起始反應，且將培養盤振盪10秒，接著以1500 rpm短暫旋轉，且接著在室溫下培育60分鐘。藉由添加2 μL ADP-Glo試劑(Promega)停止反應，且以1500 rpm短暫旋轉，且接著培育40分鐘。添加ADP-Glo偵測試劑(Promega)且將培養盤以1500 rpm短暫旋轉，接著培育30分鐘。在Envision 2105 (Perkin Elmer)上讀取培養盤，且使用Genedata軟體計算IC50 值。
使用H1047R PIK3CA酶之ADP-Glo生物化學PIK3CA激酶分析之結果呈現於表1中。具有小於或等於100 nM之IC50 的化合物表示為「A」；具有大於100 nM但小於或等於500 nM之IC50 的化合物表示為「B」；具有大於500 nM但小於或等於1 μM之IC50 的化合物表示為「C」；具有大於1 μM但小於或等於10 μM之IC50 的化合物表示為「D」；且具有大於10 μM但小於或等於100 μM之IC50 的化合物表示為「E」。實例 77
在基於MCF10A細胞之PIK3CA激酶分析，亦即CisBio Phospho-AKT (Ser473) HTRF分析中測試本發明之所選化合物，以量測PIK3CA介導之AKT磷酸化程度。使用過度表現熱點PIK3CA突變(包括H1047R、E542K及E545K突變)之MCF10A細胞(永生化非轉化乳房細胞株)。細胞以5,000個細胞/孔接種於補充有0.5 mg/mL氫化可體松、100 ng/mL霍亂毒素、10 μg/mL胰島素及0.5%馬血清之DMEM/F12 (Thermo Fisher Scientific)中。塗鋪後，將細胞置於5% CO2 、37℃培育箱中以黏附隔夜。
第二天，以1:3連續稀釋之12個劑量將化合物添加至細胞培養盤中。劑量反應曲線一式兩份地運行。利用Echo 55 Liquid Handler聲學分配器(Labcyte)進行化合物添加。在5% CO2 、37℃培育箱中培育細胞培養盤2小時。在化合物培育之後，將細胞在室溫下溶解60分鐘。最後，在室溫下進行與HTRF抗體一起培育4小時。所有試劑(溶解緩衝液及抗體)均根據製造商方案自CisBio pAKT S473 HTRF分析套組使用。在Envision 2105 (Perkin Elmer)上讀取培養盤，且使用Genedata軟體計算IC50 值。
基於MCF10A細胞之PIK3CA激酶分析的結果呈現於表1中。具有小於或等於1 μM之IC50 的化合物表示為「A」；具有大於1 μM但小於或等於5 μM之IC50 的化合物表示為「B」；具有大於5 μM但小於或等於10 μM之IC50 的化合物表示為「C」；具有大於10 μM但小於或等於36 μM之IC50 的化合物表示為「D」；且具有大於36 μM但小於或等於100 μM之IC50 的化合物表示為「E」。參考文獻併入
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Figure 110115674-A0101-11-0002-1

Claims (42)

  1. 一種式I-1化合物，
    Figure 03_image6124
    或其醫藥學上可接受之鹽，其中： E為-C(O)-、-C(RE )2 -、-C(RE )2 C(RE )2 -、-C(S)-、-S(O)2 -、-OC(O)-、-N(RE )C(O)-、-C(O)N(RE )-或-C(RE )2 C(O)-； Q為CH、C(RQ )或N； X為CH、C(RX )或N； Y為CH、C(RY )或N； Z為CH、C(RZ )或N； R1 為-L1 -R1A ； R2 為-L2 -R2A ； RE 之各實例獨立地為H或-LE -REA ； RQ 為-LQ -RQA ； RX 為-LX -RXA ； RY 為-LY -RYA ； RZ 為-LZ -RZA ；或 RE 之兩個實例與其等插入原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的3至8員飽和或部分不飽和單環；或具有0至4個獨立地選自氮、氧及硫之雜原子的8至12員飽和或部分不飽和雙環；其中各環經REEC 之n個實例取代； RQ 及R1 與其等插入原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至8員飽和或部分不飽和單環；或具有0至4個獨立地選自氮、氧及硫之雜原子的8至12員飽和或部分不飽和雙環；其中各環經RQ1C 之p個實例取代； RY 及RZ 與其等插入原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和或芳族環；其中該環經RYZC 之q個實例取代； L1 、L2 、LE 、LQ 、LX 、LY 及LZ 中之每一者獨立地為共價鍵，或C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-N(R)C(NR)-、-N(R)C(NOR)-、-N(R)C(NCN)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -； R1A 為經R1C 之r1 個實例取代之RA 或RB ； R2A 為經R2C 之r2 個實例取代之RA 或RB ； REA 為經REC 之r3 個實例取代之RA 或RB ； RQA 為經RQC 之r4 個實例取代之RA 或RB ； RXA 為經RXC 之r5 個實例取代之RA 或RB ； RYA 為經RYC 之r6 個實例取代之RA 或RB ； RZA 為經RZC 之r7 個實例取代之RA 或RB ； RL 為經RLC 之r8 個實例取代之RA 或RB ； RA 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SF5 、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-S(O)(NCN)R、-S(NCN)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 ； RB 之各實例獨立地為C1-6 脂族鏈；苯基；萘基；立方烷基(cubanyl)；金剛烷基；具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環；具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環雜芳基環；3至7員飽和或部分不飽和單環碳環；5至12員飽和或部分不飽和雙環碳環；具有1至2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環；或具有1至4個獨立地選自氮、氧及硫之雜原子的7至12員飽和或部分不飽和雙環雜環； R1C 、R2C 、REC 、RQC 、RXC 、RYC 、RZC 、RLC 、REEC 、RQ1C 及RYZC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SF5 、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1-2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1-4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環； R之各實例獨立地為氫，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環；或 相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，具有0至3個獨立地選自氮、氧及硫之雜原子之4至7員飽和、部分不飽和或雜芳基環；且 n、p、q、r1 、r2 、r3 、r4 、r5 、r6 、r7 及r8 中之每一者獨立地為0、1、2、3、4或5。
  2. 一種式I化合物，
    Figure 03_image6126
    或其醫藥學上可接受之鹽，其中： E為-C(O)-、-C(RE )2 -、-C(RE )2 C(RE )2 -、-C(S)-、-S(O)2 -、-OC(O)-、-N(RE )C(O)-、-C(O)N(RE )-或-C(RE )2 C(O)-； Q為CH、C(RQ )或N； X為CH、C(RX )或N； Y為CH、C(RY )或N； Z為CH、C(RZ )或N； R1 為-L1 -R1A ； R2 為-L2 -R2A ； RE 之各實例獨立地為H或-LE -REA ； RQ 為-LQ -RQA ； RX 為-LX -RXA ； RY 為-LY -RYA ； RZ 為-LZ -RZA ；或 RE 之兩個實例與其等插入原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的3至8員飽和或部分不飽和單環；或具有0至4個獨立地選自氮、氧及硫之雜原子的8至12員飽和或部分不飽和雙環；其中各環經REEC 之n個實例取代； RQ 及R1 與其等插入原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至8員飽和或部分不飽和單環；或具有0至4個獨立地選自氮、氧及硫之雜原子的8至12員飽和或部分不飽和雙環；其中各環經RQ1C 之p個實例取代； RY 及RZ 與其等插入原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和或芳族環；其中該環經RYZC 之q個實例取代； L1 、L2 、LE 、LQ 、LX 、LY 及LZ 中之每一者獨立地為共價鍵，或C1-4 二價飽和或不飽和、直鏈或分支鏈烴鏈，其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下者置換：-CH(RL )-、-C(RL )2 -、C3-6 伸環烷基、C3-6 伸雜環烷基、-N(R)-、-N(R)C(O)-、-N(R)C(NR)-、-N(R)C(NOR)-、-N(R)C(NCN)-、-C(O)N(R)-、-N(R)S(O)2 -、-S(O)2 N(R)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -； R1A 為經R1C 之r1 個實例取代之RA 或RB ； R2A 為經R2C 之r2 個實例取代之RA 或RB ； REA 為經REC 之r3 個實例取代之RA 或RB ； RQA 為經RQC 之r4 個實例取代之RA 或RB ； RXA 為經RXC 之r5 個實例取代之RA 或RB ； RYA 為經RYC 之r6 個實例取代之RA 或RB ； RZA 為經RZC 之r7 個實例取代之RA 或RB ； RL 為經RLC 之r8 個實例取代之RA 或RB ； RA 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SF5 、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR或-B(OR)2 ； RB 之各實例獨立地為C1-6 脂族鏈；苯基；萘基；立方烷基；金剛烷基；具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環；具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環雜芳基環；3至7員飽和或部分不飽和單環碳環；5至12員飽和或部分不飽和雙環碳環；具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環；或具有1至4個獨立地選自氮、氧及硫之雜原子的7至12員飽和或部分不飽和雙環雜環； R1C 、R2C 、REC 、RQC 、RXC 、RYC 、RZC 、RLC 、REEC 、RQ1C 及RYZC 之各實例獨立地為側氧基、氘、鹵素、-CN、-NO2 、-OR、-SF5 、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)2 F、-S(O)R、-S(O)NR2 、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R、-P(O)R2 、-P(O)(R)OR、-B(OR)2 ，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3-7員飽和或部分不飽和單環雜環及具有1至4個獨立地選自氮、氧及硫之雜原子的5-6員單環雜芳基環； R之各實例獨立地為氫，或選自以下之視情況經取代之基團：C1-6 脂族基、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環；或 相同氮上之兩個R基團與其等插入原子一起形成除該氮以外，具有0-3個獨立地選自氮、氧及硫之雜原子之4至7員飽和、部分不飽和或雜芳基環；且 n、p、q、r1 、r2 、r3 、r4 、r5 、r6 、r7 及r8 中之每一者獨立地為0、1、2、3或4。
  3. 如請求項1或2之化合物，其中該化合物為式III化合物：
    Figure 03_image6128
    或其醫藥學上可接受之鹽。
  4. 如請求項1或2之化合物，其中該化合物為式IV化合物：
    Figure 03_image6130
    或其醫藥學上可接受之鹽。
  5. 如請求項1或2之化合物，其中該化合物為式V、VI或VII化合物：
    Figure 03_image6132
    或其醫藥學上可接受之鹽。
  6. 如請求項1或2之化合物，其中該化合物為式VIII、IX或X化合物：
    Figure 03_image6134
    或其醫藥學上可接受之鹽。
  7. 如請求項1或2之化合物，其中該化合物為式XI、XII或XIII化合物：
    Figure 03_image6136
    或其醫藥學上可接受之鹽。
  8. 如請求項1或2之化合物，其中該化合物為式XIV、XV或XVI化合物：
    Figure 03_image6138
    或其醫藥學上可接受之鹽。
  9. 如前述請求項中任一項之化合物，其中X為CH。
  10. 如請求項1或2之化合物，其中該化合物為式XXVIII化合物：
    Figure 03_image6140
    或其醫藥學上可接受之鹽。
  11. 如前述請求項中任一項之化合物，其中Z為CH或N。
  12. 如前述請求項中任一項之化合物，其中L1 為共價鍵。
  13. 如前述請求項中任一項之化合物，其中R1A 為經R1C 之r1 個實例取代之RB 。
  14. 如前述請求項中任一項之化合物，其中R1A 為苯基或具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環雜芳基環，其中R1A 經R1C 之r1 個實例取代。
  15. 如前述請求項中任一項之化合物，其中R1A 為經R1C 之r1 個實例取代之苯基。
  16. 如前述請求項中任一項之化合物，其中R1 為
    Figure 03_image6142
    。
  17. 如前述請求項中任一項之化合物，其中R1C 之各實例獨立地為鹵素、-CN、-O-(C1-6 脂族基)或C1-6 脂族基；其中各C1-6 脂族基視情況經一或多個鹵素原子取代。
  18. 如前述請求項中任一項之化合物，其中R1C 之各實例獨立地為鹵素或視情況經1至3個鹵素取代之C1-3 脂族基。
  19. 如前述請求項中任一項之化合物，其中R2 為-N(H)C(O)-R2A 、-N(H)C(O)N(H)-R2A 、-C(O)N(H)-R2A 、-N(H)-R2A 、-S(O)2 CH2 -R2A 、-CH2 S(O)2 -R2A 或-C(H)(CH3 )OH。
  20. 如前述請求項中任一項之化合物，其中R2 為-N(H)C(O)-R2A 。
  21. 如前述請求項中任一項之化合物，其中R2A 為經R2C 之r2 個實例取代之RB 。
  22. 如前述請求項中任一項之化合物，其中R2A 為苯基；萘基；具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環雜芳基環；或具有1至4個獨立地選自氮、氧及硫之雜原子的7至12員飽和或部分不飽和雙環雜環；其中R2A 經R2C 之r2 個實例取代。
  23. 如請求項1至20中任一項之化合物，其中R2A 為
    Figure 03_image6144
    Figure 03_image6146
    Figure 03_image6148
    。
  24. 如請求項1至18中任一項之化合物，其中R2 為
    Figure 03_image6150
    Figure 03_image6152
    Figure 03_image6154
    Figure 03_image6156
    。
  25. 如前述請求項中任一項之化合物，其中R2C 之各實例獨立地為鹵素、-CN、-O-(C1-6 脂族基)或C1-6 脂族基；其中各C1-6 脂族基視情況經一或多個鹵素原子取代。
  26. 如前述請求項中任一項之化合物，其中R2C 之各實例獨立地為鹵素或視情況經1至3個鹵素取代之C1-3 脂族基。
  27. 如前述請求項中任一項之化合物，其中Y為C(RYA )。
  28. 如前述請求項中任一項之化合物，其中RYA 為C1-4 脂族鏈；3至5員飽和或部分不飽和單環碳環；或具有1至2個獨立地選自氮、氧及硫之雜原子的3至5員飽和或部分不飽和單環雜環；其中RYA 經獨立地選自以下之基團之r6 個實例取代：鹵素、-CN-、-OH、-O-(視情況經取代之C1-3 脂族基)及視情況經取代之C1-3 脂族基。
  29. 如請求項1至27中任一項之化合物，其中RYA 為具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環雜芳基環；其中該環經RYC 之r6 個實例取代。
  30. 如請求項1至27中任一項之化合物，其中RYA 為具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環；或具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環；其各自經RYC 之r6 個實例取代。
  31. 如請求項1至27中任一項之化合物，其中RYA 為
    Figure 03_image6158
    Figure 03_image6160
    Figure 03_image6162
    。
  32. 如請求項1至27或29至31中任一項之化合物，其中RYC 之各實例獨立地為側氧基、鹵素、-CN、-OH、-O-(C1-3 脂族基)或C1-3 脂族基，其中各C1-3 脂族基視情況經一或多個鹵素原子取代。
  33. 一種化合物，其選自表1中所闡述之化合物，或其醫藥學上可接受之鹽。
  34. 一種醫藥組合物，其包含如前述請求項中任一項之化合物及醫藥學上可接受之載劑。
  35. 一種抑制個體中PI3Kα信號傳導活性之方法，其包含向有需要個體投與治療有效量之如請求項1至33中任一項之化合物或如請求項34之醫藥組合物。
  36. 一種治療個體中PI3Kα介導之病症的方法，其包含向有需要個體投與治療有效量之如請求項1至33中任一項之化合物或如請求項34之醫藥組合物。
  37. 一種治療個體中細胞增生性疾病之方法，其包含向有需要個體投與治療有效量之如請求項1至33中任一項之化合物或如請求項34之醫藥組合物。
  38. 如請求項37之方法，其中該細胞增生性疾病為癌症。
  39. 如請求項38之方法，其中該癌症為乳癌。
  40. 如請求項38之方法，其中該癌症為卵巢癌。
  41. 如請求項40之方法，其中該卵巢癌為透明細胞卵巢癌。
  42. 如請求項35至41中任一項之方法，其中該個體具有含有以下突變中之至少一者的PI3Kα：H1047R、E542K及E545K。
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