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TWI641584B - α－取代甘胺醯胺衍生物 - Google Patents

α－取代甘胺醯胺衍生物 Download PDF

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Publication number
TWI641584B
TWI641584B TW103116211A TW103116211A TWI641584B TW I641584 B TWI641584 B TW I641584B TW 103116211 A TW103116211 A TW 103116211A TW 103116211 A TW103116211 A TW 103116211A TW I641584 B TWI641584 B TW I641584B
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TW
Taiwan
Prior art keywords
group
chloro
fluoroinden
alkyl
alkoxy
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TW103116211A
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English (en)
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TW201522288A (zh
Inventor
平澤秀明
川村直裕
小林淳一
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橘生藥品工業股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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Abstract

本發明提供一種新穎之α-取代甘胺醯胺衍生物、或其藥理學上所容許之鹽、含有其之醫藥組成物及其醫藥用途。
本發明提供具有TRPM8抑制作用的一般式(I)
[式中，A1為C6-10芳基等，A2為C6-10芳基等，X為CH等，Y為-CR1R2等，R1及R2獨立為氫原子等，R3及R4獨立為鹵原子等，n為1或2]所示化合物、或其藥理學上所容許之鹽。進而，本發明之化合物(I)可利用作為起因於傳入神經之過剩興奮或障礙的疾病或症狀的治療或預防藥。

Description

α-取代甘胺醯胺衍生物
本發明係關於可用於作為醫藥品之α-取代甘胺醯胺衍生物，或其藥理學上所容許之鹽、含有其之醫藥組成物及其醫藥用途。
瞬態受體電位(Transient Receptor Potential(TRP))通道係因溫度或化學物質等之各種刺激而被活性化的非選擇性陽離子通道，可分為TRPM、TRPA、TRPV、TRPC、TRPP、TRPML、TRPN家族。再者，TRPM家族中，已知有TRPM1、TRPM2、TRPM3、TRPM4a、TRPM4b、TRPM5、TRPM6、TRPM7、TRPM8(例如參照非專利文獻1)。
TRPM8係於2002年所選殖出之TRPM家族之第8個通道(例如參照非專利文獻2)，亦已知為CMR1(cold and menthol sensitive receptor-1)，藉由8℃~28℃之冷刺激或低溫感覺所誘發的化學物質(薄荷醇或Icilin)被活性化(例如參照非專利文獻1及2)。TRPM8係除了表現於初級傳入神經(Aδ纖維及C纖維)或三叉神經之外，尚報告有亦表現於味覺乳突、血管內皮、大動脈、肺動脈、前列腺、雄性生殖器(例如參照非專利文獻3)、支配人類膀胱上皮之神經纖維(例如參照非專利文獻4)、前列腺癌(例如參照非專利文獻5)、口腔扁平上皮癌(例如參照非專利文獻6)等。
於TRPM8剔除小鼠中，可見到寒冷知覺之欠缺、對於神經障礙或 炎症後之冷刺激的過敏症的欠缺等(例如參照非專利文獻3)。
於神經系統之疾病中，報告有在坐骨神經障礙模型鼠中TRPM8之表現增加、與低溫痛覺過敏呈相關(例如參照非專利文獻7)。又，顯示了於鼠及小鼠中因奧沙利鉑(oxaliplatin)所造成之末稍神經障礙而TRPM8之表現增加、TRPM8與因奧沙利鉑所造成之低溫痛覺過敏呈相關(例如參照非專利文獻8及9)。又，相較於健康人，服用奧沙利鉑之患者係對薄荷醇的反應性呈亢進，故可認為於人體中，與囓齒類同樣地TRPM8與因奧沙利鉑所造成之末稍神經障礙性疼痛呈相關(例如參照非專利文獻10)。
關於泌尿器系統之疾病，報告有於鼠中TRPM8與因低溫所誘發之頻尿症狀呈相關(例如參照非專利文獻11)。又，鼠中在雙重同時支配皮膚與膀胱之神經表現TRPM8，可認為與因低溫所誘發之排尿迫切感呈相關(例如參照非專利文獻12)。於貓及腦中風、脊髓損傷等之上位中樞神經疾病患者中，藉由對膀胱注入少量冷水可確認到正常情況下無法見到的排尿反射誘發，此排尿反射係因薄荷醇而增強(例如參照非專利文獻13及14)。又，貓中，由於因C纖維之去敏作用而減輕此排尿反射，故可認為與薄荷醇感受性之C纖維呈相關(例如參照非專利文獻13)。
另外，已報告有於特發性排尿肌過活動‧膀胱痛症候群患者之膀胱上皮下的神經纖維確認到TRPM8之表現量增加，TRPM8之表現量與排尿次數‧疼痛指數相關(例如參照非專利文獻15)，TRPM8係具有於膀胱傳入路徑中擔任與蓄尿呈相關的重要角色的可能性。
因此，藉由抑制TRPM8，可期待以TRPM8之活性化為起因的疾病或症狀的治療或預防。
另一方面，作為抑制TRPM8的物質，已知有N-(3-胺基丙基)-2-{[(3-甲基苯基)甲基]氧基}-N-(2-噻吩基甲基)苯并醯胺鹽酸鹽(以下有時稱為AMTB)。
已報告有於麻醉下之鼠中，AMTB使律動性膀胱收縮之頻率降低，抑制膀胱伸展所伴隨之內臟運動反射。然而，AMTB係於高濃度之藥效用量下確認到平均血壓之降低，而尚殘留著課題(例如參照非專利文獻16)。
AMTB亦揭示為以下一般式(A)：
[式中，R1、R2、R3、R4、R5、R6、R7及A係與專利文獻1之定義相同。]所示化合物的實施例(例如參照專利文獻1之實施例24)。
然而，一般式(A)除了與本發明之化合物於構造上相異之外，於專利文獻1中亦無與本發明之化合物相關的記載或教示。
另一方面，作為α-取代甘胺醯胺衍生物，揭示有一般式(B)：[化3]
[式中，R1、R2、R3、R5、n、y及z係與專利文獻2之定義相同。]所示化合物(例如參照專利文獻2)。
然而，專利文獻2記載之化合物係除了與本發明之化合物於構造上相異之外，進而相對於專利文獻2記載之化合物屬於催產素(oxytocin)抑制劑，本案發明之化合物屬於TRPM8抑制劑，此點亦完全相異。
[先前技術文獻] [專利文獻]
專利文獻1：國際公開2007/017093號
專利文獻2：國際公開2004/020414號
[非專利文獻]
非專利文獻1：富永真琴，「日本藥理學雜誌」，2004年，124卷，p.219-227
非專利文獻2：McKemy DD. et al., 「Nature」, 2002年，416卷，p.52-58
非專利文獻3：Broad LM. et al., 「Expert Opin Ther Targets」, 2009年，13卷，p.69-81
非專利文獻4：Andersson KE. et al., 「BJU Int」, 2010年，106卷，p.1114-1127
非專利文獻5：Zhang L. et al., 「Endocr Relat Cancer」, 2006年，13卷，p.27-38
非專利文獻6：Okamono Y. et al., 「Int J Oncol」, 2012年，40卷，p.1431-1440
非專利文獻7：Su L. et al., 「BMC Neurosci」, 2011年，12卷，p.120
非專利文獻8：Kawashiri T. et al., 「Mol Pain」, 2012年，8卷，p.7
非專利文獻9：Gauchan P. et al., 「Neurosci Lett」, 2009年，458卷，p.93-95
非專利文獻10：Kono T. et al., 「Brain Behav」, 2012年，2卷，68-73
非專利文獻11：Lei Z. et al., 「Neurourol Urodyn」, 2012年，doi:10.1002/nau.22325
非專利文獻12：Shibata Y. et al., 「Neuroreport」, 2011年，22卷，p.61-67
非專利文獻13：Lindstrom S. et al., 「Acta Physiol Scand」, 1991年，141卷，p.1-10
非專利文獻14：Geirsson G. et al.,「J Urol」, 1993年，150卷，427-430
非專利文獻15：Mukerji G. et al., 「BMC Urol」, 2006年，6卷，p.6
非專利文獻16：Lashinger ES. et al., 「Am J Physiol Renal Physiol」, 2008年，295卷，p.F803-F810
本發明之課題在於提供一種新穎之α-取代甘胺醯胺衍生物、或其藥理學上所容許之鹽、含有其之醫藥組成物及其醫藥用途。
本發明者等人為了發現α-取代甘胺醯胺衍生物而潛心研究。其結果發現，本發明之化合物(I)或其藥理學上所容許之鹽具有強力之TRPM8抑制作用，遂完成本發明。
亦即，用於解決上述課題的手段係如下述。
[1]一般式(I)所示之化合物、或其藥理學上所容許之鹽
[式中A1為由以下之a)~c)所構成群選擇之基：a)非取代或以由以下所構成群獨立選擇之1~2個基所取代的C6-10芳基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、C1-6烷氧基羰基、氰基、羥基C1-6烷基、胺甲醯基、硝基、胺基、C1-6烷氧基羰基胺基C1-6烷基、單(二)C1-6烷基胺基、(C1-6烷基)羰基胺基、C1-6烷基碸基(sulfonyl)胺基及C1-6烷基碸基；b)非取代或以由以下所構成群獨立選擇之1~2個基所取代的5員雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、氰基及鹵素C1-6烷氧基；及c)非取代或以由以下所構成群獨立選擇之1~2個基所取代的6員雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、氰基、及鹵素C1-6烷氧基；A2為由以下之d)~f)所構成群選擇之基： d)非取代或以由以下所構成群獨立選擇之1~2個基所取代的C6-10芳基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、羥基C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、胺基、硝基、羧基、(C1-6烷基)羰基胺基、(C1-6烷基)羰基氧基、(C1-6烷基)羰基及(C7-10芳烷基氧基)羰基；e)非取代或以由以下所構成群獨立選擇之1~2個基所取代的雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、單(二)C1-6烷基胺基、C1-6烷基硫基(sulfanyl)、胺基、(C7-10芳烷基氧基)羰基、羥基C1-6烷基、羥基C1-6烷氧基、C2-6烯基、啉基及(C1-6烷基)羰基；f)C3-6環烷基；X為CH或N；Y為-CR1R2-或氧原子；R1及R2獨立為氫原子、鹵原子或C1-6烷基；R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、羥基C1-6烷氧基、C3-6環烷基、C3-6環烷氧基、C2-6烯基或氰基(其中，在X為CH、且R1及R2均為氫原子時，R3及R4不同時為氫原子)；及n為1或2]。
[2]如[1]記載之化合物或其藥理學上所容許之鹽，其中，X為CH，n為1。
[3]如[2]記載之化合物或其藥理學上所容許之鹽，其中，一般式
所示之基，為下述一般式
[式中，R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、羥基C1-6烷氧基、C3-6環烷基、C3-6環烷氧基、C2-6烯基或氰基(其中，R3及R4不同時為氫原子)]所示。
[4]如[3]記載之化合物或其藥理學上所容許之鹽，其中，Y為-CR1R2-。
[5]如[4]記載之化合物或其藥理學上所容許之鹽，其中，一般式
所示之基，為下述一般式
[式中，A1為由以下之a1)、b)、c)所構成群選擇之基：a1)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、C1-6烷氧基羰基、氰基、羥基C1-6烷基、胺甲醯基、硝基、胺基、C1-6烷氧基羰基胺基C1-6烷基、單(二)C1-6烷基胺基、(C1-6烷基)羰基胺基、C1-6烷基碸基胺基及C1-6烷基碸基； b)非取代或以由以下所構成群獨立選擇之1~2個基所取代的5員雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、氰基及鹵素C1-6烷氧基；及c)非取代或以由以下所構成群獨立選擇之1~2個基所取代的6員雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、氰基、及鹵素C1-6烷氧基]所示。
[6]如[5]記載之化合物或其藥理學上所容許之鹽，其中，一般式
所示之基，為下述一般式
[式中，R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、羥基C1-6烷氧基、C3-6環烷基、C2-6烯基或氰基(其中，R3及R4不同時為氫原子)]所示。
[7]如[6]記載之化合物或其藥理學上所容許之鹽，其中，A2為由以下之d1)及e)所構成群選擇之基：d1)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、羥基C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、胺基、硝基、羧基、(C1-6烷基)羰基胺基、(C1-6烷基)羰基氧基、(C1-6烷基)羰基及(C7-10芳烷基氧基)羰基；以及 e)非取代或以由以下所構成群獨立選擇之1~2個基所取代的雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、單(二)C1-6烷基胺基、C1-6烷基硫基、胺基、(C7-10芳烷基氧基)羰基、羥基C1-6烷基、羥基C1-6烷氧基、C2-6烯基、啉基及(C1-6烷基)羰基。
[8]如[7]記載之化合物或其藥理學上所容許之鹽，其中，A1為由以下之a2)、b1)及c1)所構成群選擇之基：a2)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、羥基C1-6烷基、氰基、胺基、單(二)C1-6烷基胺基及C1-6烷氧基；b1)噻唑基；及c1)分別為非取代或以由以下所構成群獨立選擇之1~2個基所取代的吡啶基、嘧啶基或吡基：鹵原子、C1-6烷基、C1-6烷氧基及氰基；A2為由以下之d2)及e1)所構成群選擇之基：d2)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、羥基C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、(C1-6烷基)羰基氧基及胺基；及e1)非取代或以由以下所構成群獨立選擇之1~2個基所取代的雜環：鹵原子、C1-6烷基、C1-6烷氧基、氰基、單(二)C1-6烷基胺基、C1-6烷基硫基、胺基、羥基C1-6烷基及C2-6烯基；及R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、C3-6環烷基或氰基(其中，R3及R4不同時為氫原子)。
[9]如[8]記載之化合物或其藥理學上所容許之鹽，其中， A2為由以下之d2)及e2)所構成群選擇之基：d2)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、羥基C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、(C1-6烷基)羰基氧基及胺基；及e2)分別為非取代或以由以下所構成群獨立選擇之1~2個基所取代的吡啶基、嘧啶基、吡基、噻吩基、噻唑基、異噻唑基、2,3-二氫苯并呋喃基、吡唑基、咪唑基、異唑基、唑基、呋呫基或苯并[1,3]二呃基：鹵原子、C1-6烷基、C1-6烷氧基、氰基、單(二)C1-6烷基胺基、C1-6烷基硫基、胺基、羥基C1-6烷基及C2-6烯基。
[10]如[9]記載之化合物或其藥理學上所容許之鹽，其中，A1分別為非取代或以由以下所構成群所取代的苯基、吡啶基或吡基：鹵原子、胺基、單(二)C1-6烷基胺基、或羥基；A2為由以下之d3)及e3)所構成群選擇之基：d3)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、C1-6烷基、C1-6烷氧基及胺基；及e3)分別為非取代或以由以下所構成群獨立選擇之1~2個基所取代的吡啶基、嘧啶基、吡基、噻唑基、2,3-二氫苯并呋喃基、吡唑基、異唑基、唑基或苯并[1,3]二呃基：鹵原子、C1-6烷基、C1-6烷氧基、單(二)C1-6烷基胺基、C1-6烷基硫基及胺基；及R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷氧基、C3-6環烷基或氰基(其中，R3及R4不同時為氫原子)。
[11]如[9]記載之化合物或其藥理學上所容許之鹽，其中，A1分別為非取代或以由以下所構成群所取代的苯基、吡啶基或吡 基：鹵原子或羥基；A2為由以下之d4)及e3)所構成群選擇之基：d4)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、C1-6烷氧基及胺基；及e3)分別為非取代或以由以下所構成群獨立選擇之1~2個基所取代的吡啶基、嘧啶基、吡基、噻唑基、2,3-二氫苯并呋喃基、吡唑基、異唑基或苯并[1,3]二呃基：鹵原子、C1-6烷基、C1-6烷氧基、單(二)C1-6烷基胺基、C1-6烷基硫基及胺基；及R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷氧基、C3-6環烷基或氰基(其中，R3及R4不同時為氫原子)。
[12]如[1]記載之化合物或其藥理學上所容許之鹽，係選自由以下所組成之群：N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]菸鹼醯胺(實施例1-1)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-甲氧基茚-1-基]菸鹼醯胺(實施例1-6)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]苯甲醯胺(實施例2-2LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-甲氧基茚-1-基]苯甲醯胺(實施例2-4LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-環丙基茚-1-基]苯甲醯胺(實施例2-5LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-二氟甲氧基茚-1-基]苯甲醯胺 (實施例2-11LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-二氟甲氧基茚-1-基]菸鹼醯胺(實施例2-26LP)；2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-二氟甲氧基茚-1-基]菸鹼醯胺(實施例2-27LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]菸鹼醯胺(實施例2-31LP)；2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]菸鹼醯胺(實施例2-33LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟-6-甲氧基茚-1-基]菸鹼醯胺(實施例2-39LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟-6-甲基茚-1-基]菸鹼醯胺(實施例2-40LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟茚-1-基]菸鹼醯胺(實施例2-56LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺(實施例2-66LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]噻唑-5-甲醯胺(實施例2-71LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4,6-二氟茚-1-基]苯甲醯胺(實施例2-76LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5-氟菸鹼醯胺(實施例2-86LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]苯甲醯胺(實 施例2-221LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氰基茚-1-基]-2-羥基苯甲醯胺(實施例3-2)；N-[(R)-胺甲醯基苯基甲基]-N-[(S)-5-氯-2,3-二氫苯并呋喃-3-基]-2-羥基苯甲醯胺(實施例4-2)；2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]苯甲醯胺(實施例6-1)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺(實施例12)；2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]菸鹼醯胺(實施例1-3)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺(實施例2-6LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺(實施例2-23LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-2-甲氧基菸鹼醯胺(實施例2-36LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-2-甲氧基菸鹼醯胺(實施例2-46LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯茚-1-基]苯甲醯胺(實施例2-87LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-4-甲基噻唑-5-甲醯胺(實施例2-88LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基苯 甲醯胺(實施例2-89LP)；N-[(R)-胺甲醯基苯基甲基]-2-氯-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺(實施例2-93LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-2-氯-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺(實施例2-97LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基菸鹼醯胺(實施例2-100LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-(甲基胺基)菸鹼醯胺(實施例2-107LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2,3-二氫苯并呋喃-7-甲醯胺(實施例2-111LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基苯甲醯胺(實施例2-118LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-2-(甲基硫基)菸鹼醯胺(實施例2-125LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-(甲基硫基)菸鹼醯胺(實施例2-128LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-2-甲基菸鹼醯胺(實施例2-131LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-4-甲基噻唑-5-甲醯胺(實施例2-132LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基-2H-吡唑-3-甲醯胺(實施例2-133LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-2-甲基菸鹼醯胺 (實施例2-137LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5-甲基噻唑-4-甲醯胺(實施例2-147LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基異唑-5-甲醯胺(實施例2-150LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-甲基吡啶-2-甲醯胺(實施例2-152LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基嘧啶-5-甲醯胺(實施例2-154LP)；N-[(R)-胺甲醯基-(3-氟苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺(實施例2-161LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-甲基異菸鹼醯胺(實施例2-167LP)；N-[(R)-胺甲醯基-(3-羥基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺(實施例2-168LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯并[1,3]二呃-4-甲醯胺(實施例2-172LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯并[1,3]二呃-4-甲醯胺(實施例2-173LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-甲基吡-2-甲醯胺(實施例2-175LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-吡-2-甲醯胺(實施例2-179LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧 基菸鹼醯胺(實施例2-180LP)；N-[(RS)-胺甲醯基苯基甲基]-N-[(SR)-5-氯-7-氟-2,3-二氫苯并呋喃-3-基]苯甲醯胺(實施例2-252M)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺(實施例4-5、19-1LP)；N-[(R)-胺甲醯基吡-2-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺(實施例4-8)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-3-甲基苯甲醯胺(實施例4-9)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基菸鹼醯胺(實施例11)；2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺(實施例13)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺(實施例14LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基噻唑-5-甲醯胺(實施例15LP)；N-[(R)-胺甲醯基-(3-二甲基胺基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺(實施例18-13LP)；N-[(R)-胺甲醯基-(3-二甲基胺基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺(實施例19-6LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-4-甲基苯甲醯胺(實施例19-12LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-氟-6- 羥基苯甲醯胺(實施例19-15LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-氟-2-羥基苯甲醯胺(實施例19-16LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-4-氯-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺(實施例19-17LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-氟-2-羥基苯甲醯胺(實施例19-25LP)；N-[(R)-(3-胺基苯基)胺甲醯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺(實施例21-1)；N-[(R)-(3-胺基苯基)胺甲醯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺(實施例21-2)；N-[(R)-胺甲醯基(5-氟吡啶基-3-基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺(實施例19-31LP)；及N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-3-甲基苯甲醯胺(實施例19-41LP)。
[13]一種醫藥組成物，係含有上述[1]~[12]中任一項記載之化合物或其藥理學上所容許之鹽。
[14]如[13]記載之醫藥組成物，其係起因於傳入神經之過剩興奮或障礙的疾病或症狀的治療或預防用。
[15]一種起因於傳入神經之過剩興奮或障礙的疾病或症狀的治療或預防方法，係包括投予有效量之上述[1]~[12]中任一項記載之化合物或其藥理學上所容許之鹽。
[16]一種上述[1]~[12]中任一項記載之化合物或其藥理學上所容許 之鹽的使用，係用於製造起因於傳入神經之過剩興奮或障礙的疾病或症狀的治療或預防用的醫藥組成物。
作為其他態樣，
[17]一般式(I)所示之化合物、或其藥理學上所容許之鹽
[式中A1為由以下之aa)~cc)所構成群選擇之基：aa)非取代或以由以下所構成群獨立選擇之1~2個基所取代的C6-10芳基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、C1-6烷氧基羰基及C1-6烷基碸基；bb)非取代或以由以下所構成群獨立選擇之1~2個基所取代的5員雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基及鹵素C1-6烷氧基；及cc)非取代或以由以下所構成群獨立選擇之1~2個基所取代的6員雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基及鹵素C1-6烷氧基；A2為由以下之dd)、ee)、f)所構成群選擇之基：dd)非取代或以由以下所構成群獨立選擇之1~2個基所取代的C6-10芳基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、羥基C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、胺基、硝基、羧基及(C7-10芳烷基氧基)羰基；ee)非取代或以由以下所構成群獨立選擇之1~2個基所取代的雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6 烷氧基、氰基、單(二)C1-6烷基胺基、C1-6烷基硫基、胺基、(C7-10芳烷基氧基)羰基、羥基C1-6烷基、C2-6烯基、啉基及(C1-6烷基)羰基；f)C3-6環烷基；X為CH或N；Y為-CR1R2-或氧原子；R1及R2獨立為氫原子、鹵原子或C1-6烷基；R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、羥基C1-6烷氧基、C3-6環烷基、C3-6環烷氧基、C2-6烯基或氰基(其中，在X為CH、且R1及R2均為氫原子時，R3及R4不同時為氫原子)；及n為1或2]。
[18]如[17]記載之化合物或其藥理學上所容許之鹽，其中，X為CH，n為1。
[19]如[18]記載之化合物或其藥理學上所容許之鹽，其中，一般式
所示之基，為下述一般式
[式中，R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、羥基C1-6烷氧基、C3-6環烷基、C3-6環烷氧基、C2-6烯基或氰基(其中，R3及R4不同時為氫原子)]所示。
[20]如[19]記載之化合物或其藥理學上所容許之鹽，其中，Y為 -CR1R2-。
[21]如[20]記載之化合物或其藥理學上所容許之鹽，其中，一般式
所示之基，為下述一般式
[式中，A1為由以下之aa1)、bb)及cc)所構成群選擇之基：aa1)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、C1-6烷氧基羰基及C1-6烷基碸基；bb)非取代或以由以下所構成群獨立選擇之1~2個基所取代的5員雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基及鹵素C1-6烷氧基；及cc)非取代或以由以下所構成群獨立選擇之1~2個基所取代的6員雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基及鹵素C1-6烷氧基]所示。
[22]如[21]記載之化合物或其藥理學上所容許之鹽，其中，一般式
所示之基，為下述一般式
[式中，R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、羥基C1-6烷氧基、C3-6環烷基、C2-6烯基或氰基(其中，R3及R4不同時為氫原子)]所示。
[23]如[22]記載之化合物或其藥理學上所容許之鹽，其中，A2為由以下之dd1)及ee)所構成群選擇之基：dd1)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、羥基C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、胺基、硝基、羧基及(C7-10芳烷基氧基)羰基；ee)非取代或以由以下所構成群獨立選擇之1~2個基所取代的雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、單(二)C1-6烷基胺基、C1-6烷基硫基、胺基、(C7-10芳烷基氧基)羰基、羥基C1-6烷基、C2-6烯基、啉基及(C1-6烷基)羰基。
[24]如[23]記載之化合物或其藥理學上所容許之鹽，其中，A1為由以下之aa2)、bb1)及cc1)所構成群選擇之基：aa2)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基及C1-6烷氧基；bb1)噻唑基；及cc1)分別為非取代或以1~2個鹵原子所取代的吡啶基、嘧啶基或吡基； A2為由以下之dd2)及e1)所構成群選擇之基：dd2)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、羥基C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基及胺基；及e1)非取代或以由以下所構成群獨立選擇之1~2個基所取代的雜環：鹵原子、C1-6烷基、C1-6烷氧基、氰基、單(二)C1-6烷基胺基、C1-6烷基硫基、胺基、羥基C1-6烷基及C2-6烯基；及R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、C3-6環烷基或氰基(其中，R3及R4不同時為氫原子)。
[25]如[24]記載之化合物或其藥理學上所容許之鹽，其中，A2為由以下之dd2)及e2)所構成群選擇之基：dd2)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、羥基C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基及胺基；及e2)分別為非取代或以由以下所構成群獨立選擇之1~2個基所取代的吡啶基、嘧啶基、吡基、噻吩基、噻唑基、異噻唑基、2,3-二氫苯并呋喃基、吡唑基、咪唑基、異唑基、唑基、呋呫基或苯并[1,3]二呃基：鹵原子、C1-6烷基、C1-6烷氧基、氰基、單(二)C1-6烷基胺基、C1-6烷基硫基、胺基、羥基C1-6烷基及C2-6烯基。
[26]如[25]記載之化合物或其藥理學上所容許之鹽，其中，A1分別為非取代或以由以下所構成群所取代的苯基、吡啶基或吡基：鹵原子或羥基；A2為由以下之d4)及e3)所構成群選擇之基： d4)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、C1-6烷基及胺基；及e3)分別為非取代或以由以下所構成群獨立選擇之1~2個基所取代的吡啶基、嘧啶基、吡基、噻唑基、2,3-二氫苯并呋喃基、吡唑基、異唑基、唑基或苯并[1,3]二呃基：鹵原子、C1-6烷基、C1-6烷氧基、單(二)C1-6烷基胺基、C1-6烷基硫基及胺基；及R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷氧基、C3-6環烷基或氰基(其中，R3及R4不同時為氫原子)。
[27]如[17]記載之化合物或其藥理學上所容許之鹽，係選自由以下所組成之群：N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]菸鹼醯胺(實施例1-1)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-甲氧基茚-1-基]菸鹼醯胺(實施例1-6)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]苯甲醯胺(實施例2-2LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-甲氧基茚-1-基]苯甲醯胺(實施例2-4LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-環丙基茚-1-基]苯甲醯胺(實施例2-5LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-二氟甲氧基茚-1-基]苯甲醯胺(實施例2-11LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-二氟甲氧基茚-1-基]菸鹼醯胺 (實施例2-26LP)；2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-二氟甲氧基茚-1-基]菸鹼醯胺(實施例2-27LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]菸鹼醯胺(實施例2-31LP)；2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]菸鹼醯胺(實施例2-33LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟-6-甲氧基茚-1-基]菸鹼醯胺(實施例2-39LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟-6-甲基茚-1-基]菸鹼醯胺(實施例2-40LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟茚-1-基]菸鹼醯胺(實施例2-56LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺(實施例2-66LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]噻唑-5-甲醯胺(實施例2-71LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4,6-二氟茚-1-基]苯甲醯胺(實施例2-76LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5-氟菸鹼醯胺(實施例2-86LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]苯甲醯胺(實施例2-221LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氰基茚-1-基]-2-羥基苯甲醯 胺(實施例3-2)；N-[(R)-胺甲醯基苯基甲基]-N-[(S)-5-氯-2,3-二氫苯并呋喃-3-基]-2-羥基苯甲醯胺(實施例4-2)；2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]苯甲醯胺(實施例6-1)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺(實施例12)；2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]菸鹼醯胺(實施例1-3)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺(實施例2-6LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺(實施例2-23LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-2-甲氧基菸鹼醯胺(實施例2-36LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-2-甲氧基菸鹼醯胺(實施例2-46LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯茚-1-基]苯甲醯胺(實施例2-87LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-4-甲基噻唑-5-甲醯胺(實施例2-88LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基苯甲醯胺(實施例2-89LP)；N-[(R)-胺甲醯基苯基甲基]-2-氯-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯 胺(實施例2-93LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]--2-氯-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺(實施例2-97LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基菸鹼醯胺(實施例2-100LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-(甲基胺基)菸鹼醯胺(實施例2-107LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2,3-二氫苯并呋喃-7-甲醯胺(實施例2-111LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基苯甲醯胺(實施例2-118LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-2-(甲基硫基)菸鹼醯胺(實施例2-125LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-(甲基硫基)菸鹼醯胺(實施例2-128LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-2-甲基菸鹼醯胺(實施例2-131LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-4-甲基噻唑-5-甲醯胺(實施例2-132LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基-2H-吡唑-3-甲醯胺(實施例2-133LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-2-甲基菸鹼醯胺(實施例2-137LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5-甲基噻唑 -4-甲醯胺(實施例2-147LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基異唑-5-甲醯胺(實施例2-150LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-甲基吡啶-2-甲醯胺(實施例2-152LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基嘧啶-5-甲醯胺(實施例2-154LP)；N-[(R)-胺甲醯基-(3-氟苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺(實施例2-161LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-甲基異菸鹼醯胺(實施例2-167LP)；N-[(R)-胺甲醯基-(3-羥基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺(實施例2-168LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯并[1,3]二呃-4-甲醯胺(實施例2-172LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯并[1,3]二呃-4-甲醯胺(實施例2-173LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-甲基吡-2-甲醯胺(實施例2-175LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-吡-2-甲醯胺(實施例2-179LP)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基菸鹼醯胺(實施例2-180LP)；N-[(RS)-胺甲醯基苯基甲基]-N-[(SR)-5-氯-7-氟-2,3-二氫苯并呋喃 -3-基]苯甲醯胺(實施例2-252M)；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺(實施例4-5)；N-[(R)-胺甲醯基吡-2-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺(實施例4-8)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-3-甲基苯甲醯胺(實施例4-9)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基菸鹼醯胺(實施例11)；2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺(實施例13)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺(實施例14LP)；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基噻唑-5-甲醯胺(實施例15LP)。
[28]一種醫藥組成物，係含有上述[17]~[27]中任一項記載之化合物或其藥理學上所容許之鹽。
[29]如[28]記載之醫藥組成物，其係起因於傳入神經之過剩興奮或障礙的疾病或症狀的治療或預防用。
[30]一種起因於傳入神經之過剩興奮或障礙的疾病或症狀的治療或預防，係包括投予有效量之上述[17]~[27]中任一項記載之化合物或其藥理學上所容許之鹽。
[31]一種上述[17]~[27]中任一項記載之化合物或其藥理學上所容 許之鹽的使用，係用於製造起因於傳入神經之過剩興奮或障礙的疾病或症狀的治療或預防用的醫藥組成物。
本發明之化合物(I)或其藥理學上所容許之鹽，係根據例如國際公開2009/012430號記載之方法，於Icilin誘發wet-dog shake抑制作用確認試驗中，顯示了強力之抑制作用。因此，本發明之化合物(I)或其藥理學上所容許之鹽，可用於作為起因於傳入神經之過剩興奮或障礙的疾病或症狀的治療或預防藥。
針對本說明書中之用語進行說明。
所謂「鹵原子」，係指氟原子、氯原子、溴原子或碘原子。較佳為氟原子或氯原子。
所謂「C1-6烷基」，係指碳數1~6之亦可分枝的烷基。可舉例如甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基、異戊基、新戊基、第三戊基、1-甲基丁基、2-甲基丁基、1,2-二甲基丙基、正己基、異己基等。
所謂「C1-6烷氧基」，係指碳數1~6之亦可分枝的烷氧基。可舉例如甲氧基、乙氧基、丙氧基、異丙基、丁氧基、異丁氧基、第三丁氧基、第三丁氧基、戊氧基、己氧基等。
所謂「鹵素C1-6烷基」，係指以1~5個同種或異種之鹵原子所取代的上述C1-6烷基。可舉例如單氟甲基、二氟甲基、三氟甲基、2-氯乙基、2-氟乙基、2,2-二氟乙基、1,1-二氟乙基、1,2-二氟乙基、 2,2,2-三氟乙基、1,1,2,2,2-五氟乙基、2,2,2-三氯乙基、3-氟丙基、2-氟丙基、1-氟丙基、3,3-二氟丙基、2,2-二氟丙基、1,1-二氟丙基、1-氟丁基、1-氟戊基、1-氟己基等。
所謂「鹵素C1-6烷氧基」，係指以1~5個同種或異種之鹵原子所取代的上述C1-6烷氧基。可舉例如單氟甲氧基、二氟甲氧基、三氟甲氧基、2-氯乙氧基、2-氟乙氧基、2,2-二氟乙氧基、1,1-二氟乙氧基、1,2-二氟乙氧基、2,2,2-三氟乙氧基、1,1,2,2,2-五氟乙氧基、2,2,2-三氯乙氧基、3-氟丙氧基、2-氟丙氧基、1-氟丙氧基、3,3-二氟丙氧基、2,2-二氟丙氧基、1,1-二氟丙氧基、4-氟丁氧基、5-氟戊氧基、6-氟己氧基等。
所謂「羥基C1-6烷基」，係指以羥基所取代之上述C1-6烷基。可舉例如羥基甲基、1-羥基乙基、1-羥基-1,1-二甲基甲基、2-羥基乙基、2-羥基-2-甲基丙基、3-羥基丙基等。
所謂「羥基C1-6烷氧基」，係指以羥基所取代之上述C1-6烷氧基。可舉例如羥基甲氧基、1-羥基乙氧基、1-羥基-1,1-二甲基甲氧基、2-羥基乙氧基、2-羥基-2-甲基丙氧基、3-羥基丙氧基等。
所謂「C6-10芳基」，係指苯基或萘基。
所謂「(C7-10芳烷基氧基)羰基」，係指取代了以苯基所取代之碳數1~4個烷氧基的羰基。可舉例如苄基氧基羰基、苯乙基氧基羰基、1-苯基乙基氧基羰基、3-苯基丙基氧基羰基、4-苯基丁基氧基羰基等。
所謂「單(二)C1-6烷基胺基」，係指單取代或二取代了上述C1-6烷基的胺基。於二取代的情況之C1-6烷基亦可相異。
所謂「C1-6烷基硫基(sulfanyl)」，係指由(C1-6烷基)-S-所 示之基。可舉例如甲基硫基、乙基硫基、丙基硫基、異丙基硫基、丁基硫基、異丁基硫基、第二丁基硫基、戊基硫基、己基硫基等。
所謂「C1-6烷基碸基」，係指(C1-6烷基)-SO2-所示之基。可舉例如甲基碸基、乙基碸基、丙基碸基、異丙基碸基、丁基碸基、異丁基碸基、第二丁基碸基、戊基碸基、己基碸基等。
所謂「(C1-6烷基)羰基」，係指以上述C1-6烷基所取代的羰基。可舉例如乙醯基、乙基羰基、丙基羰基、異丙基羰基、異丁基羰基、丁基羰基、第二丁基羰基、第三丁基羰基、戊基羰基、己基羰基等。
所謂「C1-6烷氧基羰基」，係指以上述C1-6烷氧基所取代的羰基。可舉例如甲氧基羰基、乙氧基羰基、丙氧基羰基、異丙氧基羰基、異丁氧基羰基、丁氧基羰基、第二丁氧基羰基、第三丁氧基羰基、戊氧基羰基、己氧基羰基等。
所謂「C3-6環烷基」，係指碳數3~6個之單環性飽和脂環式烴。可舉例如環丙基、環丁基、環戊基、環己基。
所謂「C3-6環烷氧基」，係指碳數3~6個之具有單環性飽和脂環式烴的烷氧基。可舉例如環丙氧基、環丁氧基、環戊氧基、環己氧基。
所謂「雜環」，係指含有由硫原子、氧原子、氮原子中所選擇之1~4個原子的5或6員雜環，可舉例如呋喃基、噻吩基、吡咯基、氮呯基、吡唑基、咪唑基、唑基、異唑基、噻唑基、異噻唑基、1,2,3-三唑基、三唑基、四唑基、噻二唑基、哌喃基、吡啶基、1-氧離子基吡啶基、嗒基、嘧啶基、吡基、呋呫基等之芳香族雜環；吡咯啉基、咪唑啉基、吡唑啉基、二氫哌喃基、二氫硫基哌喃基、二 氫吡啶基等之不飽和雜環；及啉基、硫基啉基、吡咯啶基、咪唑啉基、吡唑啶基、哌啶基、哌基、四氫呋喃基等之飽和雜環。又，上述「雜環」亦可與其他環式基進行縮環，可舉例如異苯并呋喃基、苯并唑基、苯并異唑基、苯并噻唑基、苯并異噻唑基、烯基、醯基、基、啡噻基、吲基、異吲基、吲哚基、吲唑基、嘌呤基、喹基、異喹啉基、喹啉基、呔基、啶基、喹啉基、喹唑啉基、咔唑基、咔啉基、吖啶基、異吲哚啉基、2,3-二氫苯并呋喃基、咪唑并[1,2-a]吡啶、咪唑并[1,2-a]吡、苯并[1,3]二呃基、苯并噻吩基、5,6,7,8-四氫咪唑并[1,2-a]吡基等。
作為A2之「雜環」，較佳可舉例如噻吩基、吡唑基、咪唑基、唑基、異唑基、噻唑基、異噻唑基、吡啶基、嘧啶基、吡口基、呋呫基、2,3-二氫苯并呋喃基或苯并[1,3]二呃基；更佳可舉例如吡唑基、噻唑基、吡啶基或苯并[1,3]二呃基。
作為A1之「5員雜環」，較佳為異唑基或噻唑基。
作為A1之「6員雜環」，較佳為吡啶基、嗒基、嘧啶基或吡基，更佳為吡啶基、嘧啶基或吡基。
所謂「(C7-10芳烷基氧基)C1-6烷氧基」，係指取代了以苯基所取代之碳數1~4個烷氧基的上述C1-6烷氧基。
所謂「C2-6烯基」，係指具有至少1個雙鍵、直鏈或分枝鏈上之碳數2~6個的不飽和烴。可舉例如乙烯基、2-丙烯基、1-丙烯基、1-丁烯-1-基、1-丁烯-2-基、1-丁烯-3-基、1-丁烯-4-基、2-丁烯-1-基、2-丁烯-2-基、1-戊烯-1-基、1-戊烯-2-基、1-戊烯-3-基、2-戊烯-1-基、2-戊烯-2-基、2-戊烯-3-基、1-己烯-1-基、1-己烯-2-基、1-己烯-3-基、2-甲基-1-丙烯-1-基等。
所謂「(C1-6烷基)羰基胺基」，係指取代了上述(C1-6烷基)羰基的胺基。
所謂C1-6烷基碸基胺基，係指取代了上述C1-6烷基碸基的胺基。
所謂C1-6烷氧基羰基胺基C1-6烷基，係指以取代了上述C1-6烷氧基羰基之胺基所取代的上述C1-6烷基。
所謂(C1-6烷基)羰基氧基，係指取代了上述C1-6烷基的羰基氧基。
以下更詳細說明本發明。
本發明之化合物(I)，係包括光學異構物、幾何異構物等般之立體異構物。
本發明之化合物(I)的光學異構物，可為於各不對稱碳原子中之立體配置為R配置或S配置之任一種立體配置。又，任一光學異構物均包括於本發明中，此等光學異構物之混合物亦包括。再者，光學活性體之混合物中，由等量之光學異構物所構成的消旋體亦包括於本發明範圍內。在本發明之化合物(I)為消旋體之固體或結晶時，消旋化合物、消旋混合物及消旋固溶物亦包括於本發明範圍內。
本發明之化合物(I)中，於存在幾何異構物的情況，本發明亦包括該幾何異構物的任一種。
又，本發明之化合物(I)中，在存在構型異構物的情況，本發明亦包括其構型異構物之任一種。
再者，本發明之化合物(I)，視需要可依常法而作成為其藥理學上所容許之鹽。作為此種鹽，可舉例如酸加成鹽或與鹼的鹽。
作為酸加成鹽，可舉例如與鹽酸、氫溴酸、氫碘酸、硫 酸、硝酸、磷酸等無機酸的酸加成鹽，或與蟻酸、醋酸、三氟醋酸、甲磺酸、苯磺酸、對甲苯磺酸、丙酸、檸檬酸、琥珀酸、酒石酸、反丁烯二酸、丁酸、草酸、丙二酸、順丁烯二酸、乳酸、蘋果酸、碳酸、麩胺酸、天冬醯胺酸等有機酸的酸加成鹽。
作為與鹼之鹽，可舉例如鈉鹽、鉀鹽、鈣鹽、鎂鹽等之與無機鹼的鹽，與哌啶、啉、吡咯啶、精胺酸、離胺酸等有機鹼的鹽。
再者，本發明之化合物(I)或其藥理學上所容許之鹽，亦包括水合物或與乙醇等之作為醫藥品所容許之溶媒的溶媒合物。
TRPM8係確認於背根神經節或三叉神經節表現的陽離子通道。TRPM8抑制劑係使陽離子之經由TRPM8朝細胞內的流入量減少，抑制細胞內陽離子濃度的上昇。根據此作用，TRPM8抑制劑係藉由抑制過剩興奮的傳入神經活動，而可用於作為下泌尿道症狀(LUTS)、尤其是過動膀胱(OAB)等之症狀的治療或預防藥。
另外，TRPM8抑制作用可藉由對以屬於TRPM8促效劑的Icilin投予所誘發之wet-dog shake作用進行抑制的效力所評價。再者，藉由根據J.Urol.,2001,166,1142記載之方法、對醋酸誘發逼尿肌過動膀胱之排尿間隔的延長作用確認試驗，可評價對於過動膀胱(OAB)的效果。
作為本發明之一般式(I)所示化合物的其他態樣，A1為由以下之aa3)、bb2)及cc2)所構成群選擇之基：aa3)非取代或以由以下所構成群獨立選擇之1~2個基所取代的C6-10芳基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、C1-6烷氧基羰基及C1-6烷基碸基；bb2)異唑基或噻唑基；及 cc2)非取代或以由以下所構成群獨立選擇之1~2個基所取代的6員雜環：鹵原子及C1-6烷基；A2為由以下之dd)、ee)、f)所構成群選擇之基：dd)非取代或以由以下所構成群獨立選擇之1~2個基所取代的C6-10芳基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、羥基C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、胺基、硝基、羧基及(C7-10芳烷基氧基)羰基；ee)非取代或以由以下所構成群獨立選擇之1~2個基所取代的雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、單(二)C1-6烷基胺基、C1-6烷基硫基、胺基、(C7-10芳烷基氧基)羰基、羥基C1-6烷基、C2-6烯基、啉基及(C1-6烷基)羰基；f)C3-6環烷基X為CH或N；Y為-CR1R2-或氧原子；R1及R2獨立為氫原子、鹵原子或C1-6烷基；R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、羥基C1-6烷氧基、C3-6環烷基、C2-6烯基或氰基(其中，在X為CH、且R1及R2均為氫原子時，R3及R4不同時為氫原子)；及n為1或2。
本發明之化合物(I)之製造方法
本發明之化合物(I)或其藥理學上所容許之鹽，可依照以下詳述之方法或根據其之方法、或其他文獻記載之方法或根據其等之方法而製造。
(式中，A1、A2、R1~R4、X、Y及n係與上述同義；R5、R6係分別為C1-6烷基或R5、R6鍵結形成由-(CH2)m-(CHR7)m-(CH2)m-所示之基；m為1或2；R7表示氫原子或苯基。)
步驟1-1
將化合物(1)、化合物(2)、化合物(3)於溶媒中，使化合物(4)反應而得到化合物(5)。此種反應係本領域中具通常知識者所周知之Ugi反應，可例如使用Domling A.,Ugi I.Angewandte Chemie International Edition 2000,39,3168-3210記載之方法進行。反應溫度為-78℃~溶媒迴流溫度，反應時間係視所使用之原料物質、溶媒、反應溫度等而異，通常為10分鐘~6日。
步驟1-2
將化合物(5)於溶媒中、酸性條件下進行水解，得到化合物(I)。作為溶媒，可舉例如四氫呋喃、1,4-二烷等。作為酸，可舉例如氯化氫、硫酸、三氟醋酸等。反應溫度為室溫~溶媒迴流溫度，反應時間係視所使用之原料物質、溶媒、反應溫度等而異，通常為10分鐘~1日。
化合物(2)及化合物(3)係分別除了使用市售試藥之外，可藉由文獻記載之方法或根據其之方法而獲得。
化合物(1)係分別除了使用市售試藥之外，可藉由例如Jonathan A.Ellman et al.,Accounts of Chemical Research 2002,35,984-995記載之方法或根據其之方法而獲得。
化合物(4)係分別除了使用市售試藥之外，可藉由例如W.Maison et al.,Bioorganic Medicinal Chemistry 2000,8,1343-1360記載之方法或根據其之方法而獲得。
上述所示流程，係用於製造本發明之化合物(I)或其製造中間體之方法的例示，如本領域中具有通常知識者可理解般，此等流程可進行各種改變。
又，在視官能基之種類而需要保護基的情況，可依常法組合實施適宜導入及去除的操作。關於保護基之種類、導入、去除，可例示如Theodra W.Greene & Peter G.M.Wuts著編，「Greene's Protective Group in Organic Synthesis」，fourth edition,Wiley-Interscience,2006年之記載。
本發明之化合物(I)或其藥理學上所容許之鹽及用於製造該化合物所使用的製造中間體，視需要可藉由進行本領域中具有通常知識者所周知之屬於單離‧精製手段的溶媒萃取、晶析、再結晶、層析、分取高速液體層析等，而進行單離‧精製。
含有本發明之化合物(I)或其藥理學上所容許之鹽作為有效成分之醫藥組成物，可配合用法使用各種劑型者。作為此種劑型，可舉例如散劑、顆粒劑、細粒劑、乾糖漿劑、錠劑、膠囊劑、注射劑、液劑、軟膏劑、栓劑、貼劑、舌下劑等；以經口或非經口進行投予。
此等醫藥組成物係配合其劑型藉公知手法，與適當之賦形劑、崩解劑、結合劑、滑澤劑、稀釋劑、緩衝劑、等張化劑、防腐 劑、濕潤劑、乳化劑、分散劑、安定化劑、溶解輔助劑等之醫藥品添加物進行適當混合或稀釋‧溶解，而予以調製。又，在將本發明之化合物(I)或其藥理學上所容許之鹽與TRPM8抑制劑以外之藥劑組合使用時，可藉由將各別之活性成分同時或個別地、如同上述般進行製劑化而製造。
本發明之化合物(I)或其藥理學上所容許之鹽，係於Icilin誘發wet-dog shake抑制作用確認試驗中顯示根據TRPM8抑制的強力抑制作用。因此，含有本發明之化合物(I)或其藥理學上所容許之鹽作為有效成分的醫藥，係藉由TRPM8抑制作用，可使用作為起因於TRPM8活性化之疾病或症狀的治療或預防藥。
「起因於TRPM8活性化之疾病或症狀」係指起因於傳入神經之過剩興奮或障礙的疾病或症狀。
「起因於傳入神經之過剩興奮或障礙的疾病或症狀」，包括有不安、憂鬱症、下泌尿道症狀(LUTS)、疼痛、循環障礙、發癢、痲痺、蕁麻疹等。
所謂「下泌尿道症狀(LUTS)」，係指因下泌尿道機能障礙等所引起之症狀；作為「下泌尿道機能障礙」，可舉例如過動膀胱、逼尿機過動、夜間頻尿、間質性膀胱炎等之膀胱炎、慢性前列腺炎等之前列腺炎、膀胱痛症候群、過敏膀胱症候群、尿失禁、前列腺肥大症、尿道狹窄等。
所謂「循環障礙」，可舉例如寒冷性鼻炎、雷諾氏病等。
本發明之化合物(I)或其藥理學上所容許之鹽，亦可與TRPM8抑制劑以外之至少1種藥劑適當組合使用。
作為可與本發明之化合物(I)或其藥理學上所容許之鹽 組合使用的藥劑，可舉例如類鴉片鎮痛劑、非類固醇系抗炎症劑(NSAID)、巴比妥酸鹽系鎮靜劑、具有鎮靜作用之苯并二氮呯系藥劑、具有鎮靜作用之H1阻斷劑、鎮靜劑、骨骼肌鬆弛劑、NMDA受體拮抗劑、α腎上腺素作用藥、三環系抗憂鬱藥、抗痙攣劑、速激肽(tachykinis)拮抗劑(NK拮抗劑)、蕈毒鹼受體拮抗劑、COX-2選擇性抑制劑、焦煤鎮痛劑、神經阻斷劑、TRPV1促效劑、TRPV1抑制劑、β阻斷劑、局部麻醉劑、皮質類固醇、5-HT受體促效劑、5-HT2A受體拮抗劑、膽鹼促效性鎮痛劑、PDE5抑制劑、PDE9抑制劑、α2δ配體、大麻鹼、代謝型麩胺酸受體1拮抗劑(mGluR1拮抗劑)、代謝型麩胺酸受體5拮抗劑(mGluR5拮抗劑)、血清素再吸收抑制劑、降腎上腺素再吸收抑制劑、血清素‧降腎上腺素再吸收抑制劑、誘導型一氧化氮合成酵素抑制劑(iNOS抑制劑)、乙醯膽鹼酯酶抑制劑(AChE抑制劑)、EP4拮抗劑、白三烯B4拮抗劑、5-脂肪加氧酶抑制劑、鈉通道阻斷劑、5-HT3拮抗劑、用於化學療法之藥劑、EP1拮抗劑、β3腎上腺素促效劑、TRPA1抑制劑、TRPV3抑制劑、TRPV4抑制劑、T型鈣通道阻斷劑、ASIC抑制劑、P2X抑制劑、Trk抑制劑、FAAH抑制劑、肉毒桿菌毒素、5α還原酵素抑制劑、抗NGF抗體、NGF調節劑、IgE產生抑制劑、組織胺H2抑制劑、膀胱黏膜保護劑、NOS活性調節劑、膀胱肌鬆弛劑、GABA再吸收抑制劑、GABA受體調節劑、GABA胺基轉移酶抑制劑等。
又，所組合使用之藥劑具體係如下所例示，但本發明內容並不限定於此等。又，具體之化合物中，包括其游離體及其他藥理學上所容許之鹽。
作為「α腎上腺素作用藥」可舉例如多沙唑嗪(Doxazosin)、坦索羅辛(Tamsulosin)、西洛多辛(Silodosin)、克羅尼啶 (Clonidine)、胍法辛(Guanfacine)、右美托咪啶(Dexmedetomidine)、莫達非尼(Modafinil)、替札尼定(Tizanidine)、莫索尼定(moxonidine)等。
作為「蕈毒鹼受體拮抗劑」，可舉例如奧昔布寧(Oxybutynin)、托特羅定(Tolterodine)、丙哌維林(Propiverine)、達非那辛(Darifenacin)、索非那辛(Solifenacin)、替米維林(Temiverine)、溴化伊普托品(Ipratropium bromide)、曲司銨(Trospium)、丙胺太林(Propantheline)、替米維林(Temiverine)、咪達那辛(Imidafenacin)、弗斯特羅定(Fesoterodine)等。
作為「EP1拮抗劑」可舉例如GSK-269984A、ONO-8539等。
作為「β3腎上腺素促效劑」可舉例如米拉貝隆(Mirabegron)、索拉貝隆(Solabegron)、TRK-380等。
作為「膀胱黏膜保護劑」可舉例如聚硫酸戊聚糖、玻尿酸、硫酸軟骨素等。
在將本發明之化合物(I)或其藥理學上所容許之鹽、與上述藥劑之1種以上組合投予時，本發明包括以下1)~5)之任一種投予方法。
1)由配合劑所進行之同時投予；2)作為個別製劑，由同一投予路徑進行同時投予；3)作為個別製劑，由相異投予路徑進行同時投予；4)作為個別製劑，由同一投予路徑進行相異時間之投予；及5)作為個別製劑，由相異投予路徑進行相異時間之投予。
又，在如4)或5)般作為個別製劑於相異時間進行投予時，關於本發明之化合物(I)或其藥理學上所容許之鹽、與所組合投予之上述藥劑 的投予順序，並無特別限制。
又，本發明之化合物、或其藥理學上所容許之鹽，可藉由與1種以上之上述藥劑適當組合投予，而得到上述疾病之預防或治療上相加效果以上的有利效果。或者，同樣地可較單獨投予的情況使其使用量減少、或使所併用之TRPM8抑制劑以外之藥劑副作用減少、或可迴避或減輕所併用之TRPM8抑制劑以外之藥劑的副作用。
本發明之醫藥組成物，可全身性或局部性地、藉由經口或非經口(經鼻、經肺、靜脈內、直腸內、皮下、肌肉內、經皮等)進行投予。
在將本發明之醫藥組成物用於實際治療時，屬於其有效成分之本發明之化合物(I)或其藥理學上所容許之鹽的投予量，係視患者之年齡、性別、體重、疾病及治療程度等而適當決定。例如，在經口投予時，成人(體重設為60kg)每一日為約6~3000mg之範圍，可依1次或分為數次適當投予。作為經口劑之每1日的投予量，較佳為10~1000mg、更佳60~600mg。在非經口投予時，成人每一日為約0.6~300mg之範圍，可依1次或分為數次適當投予。作為經口劑之每1日的投予量，較佳為1~100mg、更佳6~60mg。又，本發明之屬於TRPM8抑制劑之有效成分的化合物(I)或其藥理學上所容許之鹽的投予量，可配合TRPM8抑制劑以外之藥劑的投予量進行減量。
以下，藉實施例、參考例及試驗例更詳細說明本發明，但本發明之範圍並不限定於此等。
各參考例、各實施例、各表中所使用之記號中，Ref.Ex.表示參考例編號，Ex.No.表示實施例編號，Strc.表示化學構造式，1H-NMR表示氫核磁共振質譜，CDCl3表示氯仿-d，DMSO-d6表示二甲 基亞碸-d6，CD3OD表示甲醇-d4。又，ESI-MS表示電噴灑游離化質量分析。RT表示高速液體管柱層析的保持時間。低極性生成物係指在將2種之非鏡像異構物混合物使用順相管柱層析法進行分離精製時，先洗提出之化合物；所謂高極性生成物，係指後洗提出之化合物。於實施例編號末端，LP表示低極性生成物、HP表示高極性生成物、M表示光學異構物之混合物。[α]D表示比旋光度。
各參考例中，微波之照射係使用Biotage公司Initiator。
各實施例中，高速液體管柱層析及質量分析係依下述條件所進行。
裝置：6520 Accurate-Mass Q-TOF instrument(Agilent)
管柱：Inertsil ODS-4(GL-science)2.1×50mm 3μm
流速：0.75mL/min.
梯度：
[實施例]
[參考例1-1]
6-環丙基茚-1-酮
於6-溴茚-1-酮(0.60g)、環丙基硼酸一水合物(0.47g)、三環己基膦(0.081g)及磷酸三鉀(2.11g)之甲苯(10mL)、蒸餾水(0.5mL)懸濁液中加入醋酸鈀(II)(0.064g)，將此混合物於微波照射下以150℃攪拌1 小時。將反應混合物冷卻至室溫後，加水，以醋酸乙酯萃取。將有機層以飽和食鹽水洗淨，以無水硫酸鎂乾燥，過濾。將濾液於減壓下濃縮。將此殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=0/100-20/80)精製，得到標題化合物(0.462g)。
1H-NMR(CDCl3)δ：0.68-0.75(2H,m),0.95-1.05(2H,m),1.90-2.00(1H,m),2.64-2.73(2H,m),3.05-3.13(2H,m),7.34-7.38(2H,m),7.40-7.43(1H,m).
[參考例1-2]
6-環丙基-4-氟茚-1-酮
使用對應之原料，依與參考例1-1相同的方法合成標題化合物。又，標題化合物之質譜數據如以下，構造式示於表2。
1H-NMR(CDCl3)δ：0.69-0.76(2H,m),0.99-1.07(2H,m),1.90-1.98(1H,m),2.67-2.75(2H,m),3.05-3.13(2H,m),7.02(1H,dd,J=1.3,9.9Hz),7.24(1H,d,J=1.3Hz).
[參考例2]
4-氟-6-乙烯基茚-1-酮
將6-溴-4-氟茚-1-酮(0.36g)、肆(三苯基膦)鈀(0)(0.182g)、三丁基乙烯錫(600μL)及甲苯(6mL)之混合物，於加熱迴流下攪拌整夜。將反應混合物冷卻至室溫後，加入0.5mol/L氟化鉀水溶液及醋酸乙酯，於室溫攪拌0.5小時。將不溶物以矽藻土過濾去除。將 濾液之有機層以水及飽和食鹽水依順洗淨，以無水硫酸鎂乾燥。將使溶媒減壓餾除而得到之殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=0/100-15/85)精製，得到標題化合物(0.235g)。構造式示於表2。
1H-NMR(CDCl3)δ：2.72-2.77(2H,m),3.11-3.17(2H,m),5.37(1H,d,J=10.8Hz),5.81(1H,d,J=17.5Hz),6.72(1H,dd,J=10.8,17.5Hz),7.33(1H,dd,J=1.2,9.8Hz),7.56-7.59(1H,m).
[參考例3-1]
(R)-6-氯-4-氟茚-1-基胺鹽酸鹽
於6-氯-4-氟茚-1-酮(0.43g)之甲苯(5mL)溶液中，加入(R)-第三丁基亞磺醯胺(0.29g)及鄰鈦酸四乙基酯(0.79g)，將其混合物於氬環境下以60℃攪拌23小時。將反應混合物注入至飽和碳酸氫鈉水溶液中，激烈攪拌所得之2層的混合物。將不溶物以矽藻土過濾去除，分取有機層後，對水層以甲苯萃取。合併有機層，以飽和食鹽水洗淨後，以無水硫酸鎂乾燥。將使溶媒減壓餾除而得到之殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=14/86-35/65)精製，得到(R)-N-(6-氯-4-氟茚-1-亞基)-第三丁基亞磺醯胺(0.18g)。於(R)-N-(6-氯-4-氟茚-1-亞基)-第三丁基亞磺醯胺(0.32g)之四氫呋喃(5.4mL)溶液中，以0℃加入水(0.11mL)及氫化硼鈉(0.13g)，於同溫度攪拌15分鐘、於室溫攪拌45分鐘。於反應混合物中加入二氯甲烷與水進行分液，將有機層減壓濃縮。將所得殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=19/81-40/60)精製，得到(R)-N-[(R)-6-氯-4-氟茚-1-基]-第三丁基亞磺醯胺(0.26g)。於(R)-N-[(R)-6-氯-4-氟茚-1-基]-第三丁基亞磺醯胺(0.39g) 之甲醇(3.4mL)溶液中依室溫加入4mol/L氯化氫1,4-二烷溶液(1.0mL)，以同溫度攪拌1小時。將二異丙基醚(約20mL)滴下至反應混合物，濾取所析出之鹽而得到標題化合物(0.26g)。構造式示於表2。
1H-NMR(DMSO-d6)δ：1.98-2.11(1H,m),2.44-2.59(1H,m),2.83-2.93(1H,m),3.00-3.11(1H,m),4.74-4.81(1H,m),7.44(1H,dd,J=1.6,9.0Hz),7.51-7.55(1H,m),8.25-8.55(3H,m).
[參考例3-2~3-6]
使用對應之原料，依與參考例3-1相同的方法合成參考例3-2~3-6。又，參考例3-2~3-6之質譜數據如以下，構造式示於表2。
[參考例3-2]
(R)-4-氟茚-1-基胺鹽酸鹽
1H-NMR(DMSO-d6)δ：1.95-2.15(1H,m),2.40-2.60(1H,m),2.80-3.00(1H,m),3.00-3.15(1H,m),4.70-4.80(1H,m),7.10-7.25(1H,m),7.30-7.55(2H,m),8.20-8.70(2H,m).
[參考例3-3]
(R)-5-氟茚-1-基胺鹽酸鹽
1H-NMR(DMSO-d6)δ：1.95-2.10(1H,m),2.40-2.60(1H,m),2.80-2.95(1H,m),3.00-3.15(1H,m),4.60-4.75(1H,m),7.05-7.25(2H,m),7.55-7.70(1H,m),8.20-8.65(2H,m).
[參考例3-4]
(R)-4,6-二氟茚-1-基胺鹽酸鹽
1H-NMR(DMSO-d6)δ：1.95-2.15(1H,m),2.40-2.60(1H,m),2.80-2.95(1H,m),2.95-3.10(1H,m),4.76(1H,dd,J=7.0Hz),7.20-7.40(2H,m),8.15-8.60(2H,m).
[參考例3-5]
(R)-3,3-二甲基茚-1-基胺鹽酸鹽
1H-NMR(DMSO-d6)δ：1.17(3H,s),1.38(3H,s),1.83(1H,dd,J=8.5,13.3Hz),2.38(1H,dd,J=7.5,13.3Hz),4.75-4.81(1H,m),7.27-7.40(3H,m),7.54-7.61(1H,m),8.47(3H,br s).
[參考例3-6]
(R)-6-環丙基茚-1-基胺鹽酸鹽
1H-NMR(DMSO-d6)δ：0.55-0.72(2H,m),0.90-1.00(2H,m),1.86-2.03(2H,m),2.37-2.52(1H,m),2.74-2.87(1H,m),2.92-3.05(1H,m),4.60-4.67(1H,m),7.08(1H,dd,J=1.6,8.0Hz),7.19(1H,d,J=8.0Hz),7.29(1H,s),8.33(3H,br s).
[參考例4-1]
(R)-N-[(R)-6-環丙基-4-氟茚-1-基)-第三丁基亞磺醯胺
於6-環丙基-4-氟茚-1-酮(0.083g)及(R)-第三丁基亞磺醯胺(0.053g)之四氫呋喃(1mL)溶液中依室溫加入鄰鈦酸四乙基酯(180μL)，將此混合物於加熱迴流下攪拌1日。將反應混合物冷卻至0℃，加入氫化硼鈉(0.017g)。將此混合物於冰冷下攪拌0.5小時後，於室溫攪拌1小時。於反應混合物加入水及甲醇，以醋酸乙酯萃取。將有機層以飽和食鹽水洗淨，以無水硫酸鎂乾燥，過濾。將濾液於減壓下濃縮。將此殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=2/8-1/1)精製，得到標題化合物(0.032g)。構造式示於表2。
1H-NMR(CDCl3)δ：0.61-0.73(2H,m),0.91-1.00(2H,m),1.23(9H,s),1.84-1.94(1H,m),1.95-2.05(1H,m),2.40-2.54(1H,m),2.71-2.82(1H,m),2.93-3.03(1H,m),3.39(1H,d,J=6.0Hz),4.80-4.90(1H,m),6.62(1H,d,J=10.4Hz),7.10(1H,s).
[參考例4-2]
(R)-N-[(R)-4-氟-6-乙烯基茚-1-基)-第三丁基亞磺醯胺
使用對應之原料，依與參考例4-1相同的方法合成標題化合物。又，標題化合物之質譜數據如以下，構造式示於表2。
1H-NMR(CDCl3)δ：1.24(9H,s),1.98-2.09(1H,m),2.45-2.57(1H,m),2.75-2.87(1H,m),2.97-3.08(1H,m),3.42(1H,d,J=6.2Hz),4.85-4.95(1H,m),5.26(1H,d,J=10.9Hz),5.74(1H,d,J=17.6Hz),6.68(1H,dd,J-10.9,17.6Hz),7.00(1H,d,J=10.0Hz),7.40(1H,s).
[參考例5]
[(R)-6-(2-苄氧基乙氧基)茚-1-基]胺甲酸第三丁酯
於N-[(R)-6-羥基茚-1-基]胺甲酸第三丁酯(0.148g)、碳酸銫(0.386g)及碘化鈉(0.018g)之N,N-二甲基甲醯胺(2mL)混合物中依室溫加入(2-溴乙氧基甲基)苯(117μL)，將此混合物以70℃攪拌3小時。將反應混合物冷卻至室溫後，加水，以醋酸乙酯萃取。將有機層以水及飽和食鹽水洗淨，以無水硫酸鎂乾燥。將使溶媒減壓餾除而得到之殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=1/9-9/1)精製，得到標題化合物(0.20g)。構造式示於表2。
1H-NMR(CDCl3)δ：1.49(9H,br s),1.71-1.85(1H,m),2.50-2.64(1H,m),2.69-2.95(2H,m),3.75-3.86(2H,m),4.08-4.20(2H,m),4.58-4.77(3H,m),5.06-5.21(1H,m),6.81(1H,dd,J=2.4,8.3Hz),6.88(1H,d,J=1.9Hz),7.10(1H,d,J=8.3Hz),7.24-7.42(5H,m).
[實施例1-1]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]菸鹼醯胺
於(R)-4,6-二氟茚-1-基胺(0.1g)之甲醇(1mL)溶液中加入苯醛(0.063g)，以60℃攪拌1小時。將反應混合物冷卻至室溫後，加入菸鹼酸(0.073g)及4-苯基環己烯-1-基異氰(0.108g)，以60℃攪拌整夜。將反應混合物冷卻至室溫後，於減壓下濃縮。於所得殘渣加入四氫呋喃(3mL)、水(12μL)及4mol/L氯化氫1,4-二烷溶液(440μL)，以室溫攪拌1.5小時。於反應混合物加入水及飽和碳酸氫鈉水溶液，以醋酸乙酯萃取粗製生成物。將有機層以水及飽和食鹽水洗淨，以無水硫酸鎂乾燥。將使溶媒減壓餾除而得到之殘渣以矽膠管析層析(洗提溶媒：甲醇/醋酸乙酯/正己烷=0/70/30-0/100/0-20/80/0)精製，得到標題化合物(0.076g)。構造式示於表3。
RT(min.)：2.727
MS(ESI,m/z)：406.1371(M-H)-
1H-NMR(CDCl3)δ：1.69-1.90(1H,m),1.93-2.15(1H,m),2.42-2.90(2H,m),4.54-4.88(1H,br),5.28-5.70(3H,m),6.65-6.79(1H,m),7.34-7.66(7H,m),7.77-7.97(1H,m),8.64-8.73(1H,m),8.82(1H,br s).
[實施例1-2~1-6]
使用對應之原料，依與實施例1-1相同的方法合成實施例1-2~1-6。又，實施例1-2~1-6之質譜數據如以下，構造式示於表3。
[實施例1-2]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氰基茚-1-基]菸鹼醯胺
RT(min.)：2.356
MS(ESI,m/z)：395.1513(M-H)-
1H-NMR(CDCl3)δ：1.74-2.19(2H,m),2.57-2.90(2H,m),4.56-5.78(4H,m),7.21-7.61(8H,m),7.81-7.92(1H,m),8.19-8.37(1H,m),8.64-8.75(1H,m),8.81(1H,br s).
[實施例1-3]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]菸鹼醯胺
RT(min.)：2.161
MS(ESI,m/z)：421.1480(M-H)-
1H-NMR(CDCl3)δ：1.61-1.82(1H,m),1.92-2.18(1H,m),2.43-2.80(2H,m),4.50-4.80(1H,br),5.23-5.62(5H,m),6.62-6.78(2H,m),7.35-7.55(7H,m),8.13(1H,dd,J=1.9,5.0Hz).
[實施例1-4]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氰基茚-1-基]菸鹼醯胺
RT(min.)：1.813
MS(ESI,m/z)：410.1621(M-H)-
1H-NMR(CDCl3)δ：1.63-1.86(1H,m),1.93-2.20(1H,m),2.58-2.90(2H,m),4.46-4.77(1H,br),5.08-5.81(5H,m),6.65-6.75(1H,m),7.35-7.62(8H,m),8.14(1H,dd,J=1.5,5.1Hz),8.21(1H,br s).
[實施例1-5]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-三氟甲基茚-1-基]菸鹼醯胺
RT(min.)：2.964
MS(ESI,m/z)：438.1435(M-H)-
1H-NMR(CDCl3)δ：1.76-1.94(1H,m),2.05-2.20(1H,m),2.58-2.90(2H,m),4.55-4.97(1H,br),5.20-5.81(3H,m),7.20-7.63(8H,m),7.78-7.97(1H,m),8.26(1H,br s),8.62-8.73(1H,m),8.82(1H,br s).
[實施例1-6]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-甲氧基茚-1-基]菸鹼醯胺(實施例1-6)；
RT(min.)：2.432
MS(ESI,m/z)：400.1663(M-H)-
1H-NMR(CDCl3)δ：1.67-1.82(1H,m),1.97-2.09(1H,m),2.47-2.75(2H,m),3.89(3H,s),4.66-4.82(1H,br),5.28-5.67(3H,m),6.81-6.88(1H,m),7.07(1H,d,J=8.4Hz),7.34-7.54(6H,m),7.60-7.65(1H,m),7.90-7.96(1H,m),8.69(1H,dd,J=1.6,5.0Hz),8.86-8.89(1H,m).
[實施例2-1]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-5-氟茚-1-基]苯甲醯胺
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-5-氟茚-1-基]苯甲醯胺
於(R)-5-氯茚-1-基胺鹽酸鹽(0.05g)之甲醇(1mL)溶液中加入三乙基胺(35μL)及苯醛(0.026g)，以50℃攪拌1.5小時。將反應混合物冷卻至室溫後，加入安息香酸(0.03g)及4-苯基環己烯-1-基異氰(0.045g)，以50℃攪拌3日。將反應混合物冷卻至室溫後，於減壓下濃縮。於所得殘渣加入四氫呋喃(2mL)、水(5μL)及4mol/L氯化氫1,4-二烷溶液 (185μL)，以室溫攪拌1小時。於反應混合物加入水及飽和碳酸氫鈉水溶液，以醋酸乙酯萃取粗製生成物。將有機層以水及飽和食鹽水洗淨，以無水硫酸鎂乾燥。將使溶媒減壓餾除而得到之殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=55/45-75/25-100/0)精製，得到N-[(R)-胺甲醯基苯基甲基]-N-[(R)-5-氯茚-1-基]苯甲醯胺(實施例2-1LP，0.040g)作為低極性生成物，得到N-[(R)-胺甲醯基苯基甲基]-N-[(R)-5-氯茚-1-基]苯甲醯胺(實施例2-1HP，0.023g)作為高極性生成物。構造式示於表4。
[實施例2-1LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-5-氯茚-1-基]苯甲醯胺
RT(min.)：3.627
MS(ESI,m/z)：403.1217(M-H)-
1H-NMR(CDCl3)δ：1.64-1.88(1H,m),1.95-2.15(1H,m),2.46-2.84(2H,m),4.63(1H,br s),5.20-5.90(3H,m),7.15(1H,br s),7.25-7.65(11H,m),7.91(1H,d,J=8.0Hz).
[實施例2-1HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-5-氯茚-1-基]苯甲醯胺
RT(min.)：3.534
MS(ESI,m/z)：403.1219(M-H)-
1H-NMR(CDCl3)δ：2.34-2.53(1H,m),2.58-2.86(2H,m),2.98-3.15(1H,m),4.35-4.53(1H,m),5.31-6.05(3H,m),6.51-6.70(1H,m),6.78(1H,dd,J=1.8,8.2Hz),7.16(1H,br s),7.27-7.63(10H,m).
[實施例2-2~2-260]
使用對應之原料，依與實施例2-1相同的方法合成實施例2-2~2-260。又，實施例2-2~2-260之質譜數據如以下，構造式示於表4~28。
[實施例2-2LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]苯甲醯胺；
RT(min.)：3.583
MS(ESI,m/z)：403.1219(M-H)-
1H-NMR(CDCl3)δ：1.70-1.86(1H,m),2.00-2.14(1H,m),2.48-2.78(2H,m),4.66(1H,s),5.23-5.93(3H,m),7.09(1H,d,J=7.8Hz),7.17-7.65(11H,m),7.97(1H,s).
[實施例2-2HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]苯甲醯胺；
RT(min.)：3.447
MS(ESI,m/z)：403.1213(M-H)-
1H-NMR(CDCl3)δ：2.35-2.56(1H,m),2.59-2.83(2H,m),2.95-3.13(1H,m),4.40(1H,br s),5.31-5.92(3H,m),6.49-6.64(1H,m),7.04-7.14(2H,m),7.27-7.63(10H,m).
[實施例2-3LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-三氟甲基茚-1-基]苯甲醯胺；
RT(min.)：3.760
MS(ESI,m/z)：437.1482(M-H)-
1H-NMR(CDCl3)δ：1.65-1.90(1H,m),2.00-2.20(1H,m),2.60-2.85(1H,m),2.85-3.05(1H,m),4.63(1H,br s),5.20-5.85(3H,m),7.30-7.65(12H,m),8.15-8.30(1H,m).
[實施例2-3HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-4-三氟甲基茚-1-基]苯甲醯胺；
RT(min.)：3.641
MS(ESI,m/z)：437.1483(M-H)-
1H-NMR(CDCl3)δ：2.40-2.60(1H,m),2.60-2.80(1H,m),2.80-3.00(1H,m),3.15-3.35(1H,m),4.30-4.55(1H,m),5.25-5.90(3H,m),6.75-6.95(2H,m),7.20-7.35(4H,m),7.35-7.50(5H,m),7.50-7.65(2H,m).
[實施例2-4LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-甲氧基茚-1-基]苯甲醯胺；
RT(min.)：3.332
MS(ESI,m/z)：399.1711(M-H)-
1H-NMR(CDCl3)δ：1.65-1.82(1H,m),1.96-2.11(1H,m),2.46-2.75(2H,m),3.90(3H,s),4.69(1H,br s),5.20-5.90(3H,m),6.78-6.87(1H,m),7.06(1H,d,J=8.3Hz),7.24-7.67(11H,m).
[實施例2-5LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-環丙基茚-1-基]苯甲醯胺；
RT(min.)：3.803
MS(ESI,m/z)：409.1919(M-H)-
1H-NMR(CDCl3)δ：0.74-1.06(4H,m),1.63-1.82(1H,m),1.91-2.11(2H,m),2.44-2.76(2H,m),4.65(1H,br s),5.19-5.98(3H,m),6.97-7.09(2H,m),7.29-7.68(11H,m).
[實施例2-5HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-環丙茚-1-基]苯甲醯胺；
RT(min.)：3.653
MS(ESI,m/z)：409.1913(M-H)-
1H-NMR(CDCl3)δ：-0.03-0.09(1H,m),0.26-0.36(1H,m),0.61-0.79(2H,m),1.46-1.59(1H,m),2.29-2.47(1H,m),2.56-2.78(2H,m),2.93-3.08(1H,m),4.45(1H,br s),5.25-5.95(3H,m),6.35(1H,br s),6.89(1H,dd,J=1.3,8.0Hz),7.02-7.08(1H,m),7.27-7.66(10H,m).
[實施例2-6LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺；
RT(min.)：3.720
MS(ESI,m/z)：421.1130(M-H)-
1H-NMR(CDCl3)δ：1.65-1.90(1H,m),1.90-2.20(1H,m),2.40-2.65(1H,m),2.65-2.90(1H,m),4.66(1H,br s),5.20-5.85(3H,m),6.75-7.05(1H,m),7.25-7.90(11H,m).
[實施例2-6HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺；
RT(min.)：3.595
MS(ESI,m/z)：421.1129(M-H)-
1H-NMR(CDCl3)δ：2.35-2.60(1H,m),2.60-2.90(2H,m),2.95-3.25(1H,m),4.30-4.50(1H,m),5.20-5.90(3H,m),6.25-6.45(1H,m),6.83(1H,d,J=8.3Hz),7.25-7.60(10H,m).
[實施例2-7LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氯茚-1-基]苯甲醯胺；
RT(min.)：3.627
MS(ESI,m/z)：403.1217(M-H)-
1H-NMR(CDCl3)δ：1.65-1.87(1H,m),1.99-2.16(1H,m),2.47-2.64(1H,m),2.74-2.92(1H,m),4.65(1H,br s),5.19-5.98(3H,m),7.23-7.62(12H,m),7.83-7.95(1H,m).
[實施例2-7HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-4-氯茚-1-基]苯甲醯胺；
RT(min.)：3.526
MS(ESI,m/z)：403.1216(M-H)-
1H-NMR(CDCl3)δ：2.34-3.23(4H,m),4.47(1H,br s),5.31-5.93(3H,m),6.52-6.68(1H,m),6.74-6.80(1H,m),7.11(1H,d,J=7.9Hz),7.23-7.63(10H,m).
[實施例2-8LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氯-6-氟茚-1-基]苯甲醯胺；
RT(min.)：3.779
MS(ESI,m/z)：421.1115(M-H)-
1H-NMR(CDCl3)δ：1.65-1.90(1H,m),1.90-2.15(1H,m),2.40-2.65(1H,m),2.65-2.85(1H,m),4.50-4.80(1H,m),5.20-5.85(3H,m),6.85-7.10(1H,m),7.25-7.80(11H,m).
[實施例2-8HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-4-氯-6-氟茚-1-基]苯甲醯胺；
RT(min.)：3.609
MS(ESI,m/z)：421.1121(M-H)-
1H-NMR(CDCl3)δ：2.40-2.60(1H,m),2.60-2.85(2H,m),2.95-3.20(1H,m),4.35-4.55(1H,m),5.30-5.90(3H,m),6.10-6.35(1H,m),6.75-6.95(1H,m),7.25-7.60(10H,m).
[實施例2-9LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(S)-2,3-二氫苯并呋喃-3-基]苯甲醯胺；
RT(min.)：2.882
MS(ESI,m/z)：371.1406(M-H)-
1H-NMR(CDCl3)δ：4.12(1H,dd,J=5.3,10.2Hz),4.26(1H,br s),4.66(1H,br s),5.28-5.88(3H,m),6.78(1H,d,J=8.1Hz),6.93-7.04(1H,m),7.19-7.73(12H,m).
[實施例2-9HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(S)-2,3-二氫苯并呋喃-3-基]苯甲醯胺；
RT(min.)：2.900
MS(ESI,m/z)：371.1402(M-H)-
1H-NMR(CDCl3)δ：4.48-4.61(2H,m),5.13-5.22(1H,m),5.43-5.70(3H,m),6.51(1H,t,J=7.5Hz),6.68(1H,br s),6.80(1H,d,J=8.2Hz),7.07-7.54(11H,m).
[實施例2-10LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-5-氯-6-甲氧基茚-1-基]苯甲醯胺；
RT(min.)：3.671
MS(ESI,m/z)：433.1329(M-H)-
1H-NMR(CDCl3)δ：1.60-1.80(1H,m),1.95-2.10(1H,m),2.45-2.70(2H,m),4.03(3H,s),4.55-4.70(1H,m),5.20-5.75(3H,m),7.17(1H,S),7.30-7.65(10H,m),7.75(1H,br s).
[實施例2-11LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-二氟甲氧基茚-1-基]苯甲醯胺；
RT(min.)：3.562
MS(ESI,m/z)：435.1535(M-H)-
1H-NMR(CDCl3)δ：1.75-1.95(1H,m),2.05-2.25(1H,m),2.50-2.85(2H,m),4.55-4.70(1H,m),5.25-5.65(2H,m),5.80-6.10(1H,m),6.67(1H,dd,J=74.6,74.6Hz),6.95-7.20(2H,m),7.30-7.65(10H,m),7.65-7.75(1H,m).
[實施例2-11HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-二氟甲氧基茚-1-基]苯甲醯胺；
RT(min.)：3.351
MS(ESI,m/z)：435.1527(M-H)-
1H-NMR(CDCl3)δ：2.40-2.60(1H,m),2.65-2.85(2H,m),3.00-3.15(1H,m),4.35-4.50(1H,m),5.30-5.90(4H,m),6.30-6.45(1H,m),6.87(1H,dd,J=2.0,8.0Hz),7.14(1H,d,J=8.3Hz),7.25-7.65(10H,m).
[實施例2-12LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-5,6-二氟茚-1-基]苯甲醯胺；
RT(min.)：3.469
MS(ESI,m/z)：405.1423(M-H)-
1H-NMR(CDCl3)δ：1.68-1.86(1H,m),1.99-2.19(1H,m),2.46-2.79(2H,m),4.55-4.77(1H,br),5.21-5.94(3H,m),6.83-7.01(1H,m),7.32-7.62(10H,m)7.71-7.88(1H,m).
[實施例2-12HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-5,6-二氟茚-1-基]苯甲醯胺；
RT(min.)：3.330
MS(ESI,m/z)：405.1424(M-H)-
1H-NMR(CDCl3)δ：2.36-2.56(1H,m),2.62-2.81(2H,m),2.94-3.15(1H,m),4.35-4.47(1H,br),5.32-5.87(3H,m),6.29-6.48(1H,m),6.88-7.00(1H,m),7.27-7.40(5H,m)7.41-7.60(5H,m).
[實施例2-13LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氰基茚-1-基]苯甲醯胺；
RT(min.)：3.144
MS(ESI,m/z)：394.1567(M-H)-
1H-NMR(CDCl3)δ：1.16-2.24(2H,m),2.56-3.22(2H,m),4.48-5.95(4H,m),7.12-7.64(12H,m),8.15-8.34(1H,m).
[實施例2-14LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-二氟甲氧基茚-1-基]苯甲醯胺；
RT(min.)：3.470
MS(ESI,m/z)：435.1531(M-H)-
1H-NMR(CDCl3)δ：1.65-1.85(1H,m),2.00-2.15(1H,m),2.45-2.65(1H,m),2.75-2.90(1H,m),4.66(1H,br s),5.20-6.00(3H,m),6.49(1H,dd,J=74.0,74.0Hz),6.95-7.10(1H,m),7.30-7.65(11H,m),7.80-7.90(1H,m).
[實施例2-14HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-4-二氟甲氧基茚-1-基]苯甲醯胺；
RT(min.)：3.382
MS(ESI,m/z)：435.1533(M-H)-
1H-NMR(CDCl3)δ：2.35-2.55(1H,m),2.60-2.85(2H,m),3.05-3.25(1H,m),4.40-4.55(1H,m),5.30-6.00(3H,m),6.49(1H,dd,J=73.9,73.9Hz),6.55-6.65(1H,m),6.75-6.95(2H,m),7.20-7.65(10H,m).
[實施例2-15LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(S)-5-氯-2,3-二氫苯并呋喃-3-基]苯甲醯胺；
RT(min.)：3.292
MS(ESI,m/z)：405.1019(M-H)-
1H-NMR(CDCl3)δ：3.61-5.90(6H,m),6.65(1H,d,J=8.6Hz),7.05-7.19(1H,m),7.36-7.80(11H,m).
[實施例2-15HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(S)-5-氯-2,3-二氫苯并呋喃-3-基]苯甲醯胺；
RT(min.)：3.215
MS(ESI,m/z)：405.1016(M-H)-
1H-NMR(CDCl3)δ：4.45-4.65(2H,m),5.07-5.21(1H,m),5.42-5.72(3H,m),6.51(1H,br s),6.65-6.74(1H,m),7.03(1H,d,J=8.2Hz),7.13-7.53(10H,m).
[實施例2-16LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-乙基茚-1-基]苯甲醯胺；
RT(min.)：3.752
MS(ESI,m/z)：397.1924(M-H)-
1H-NMR(CDCl3)δ：1.29(3H,t,J=7.6Hz),1.66-1.87(1H,m),1.97-2.13(1H,m),2.49-2.80(4H,m),4.67(1H,br s),5.20-6.05(3H,m),7.05-7.15(2H,m),7.30-7.53(8H,m),7.57-7.65(2H,m),7.77(1H,br s).
[實施例2-17LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-甲基茚-1-基]苯甲醯胺；
RT(min.)：3.516
MS(ESI,m/z)：383.1769(M-H)-
1H-NMR(CDCl3)δ：1.65-1.82(1H,m),1.98-2.11(1H,m),2.43(3H,s),2.48-2.78(2H,m),4.67(1H,br s),5.38-5.98(3H,m),7.02-7.12(2H,m),7.30-7.53(8H,m),7.58-7.66(2H,m),7.74(1H,br s).
[實施例2-18LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-甲基茚-1-基]苯甲醯胺；
RT(min.)：3.493
MS(ESI,m/z)：383.1766(M-H)-
1H-NMR(CDCl3)δ：1.66-1.83(1H,m),2.00-2.13(1H,m),2.20(3H,s),2.41-2.77(2H,m),4.70(1H,br s),5.21-6.01(3H,m),7.09(1H,d,J=7.2Hz),7.22-7.29(1H,m),7.31-7.64(10H,m),7.77(1H,d,J=7.2Hz).
[實施例2-19LP]
N-[(R)-6-溴茚-1-基]-N-[(R)-胺甲醯基苯基甲基]苯甲醯胺；
RT(min.)：3.654
MS(ESI,m/z)：447.0716(M-H)-
1H-NMR(CDCl3)δ：1.68-1.86(1H,m),1.97-2.14(1H,m),2.46-2.77(2H,m),4.66(1H,br s),5.25-5.94(3H,m),6.98-7.07(1H,m),7.30-7.63(11H,m),8.11(1H,br s).
[實施例2-20LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-三氟甲基茚-1-基]苯甲醯胺；
RT(min.)：3.737
MS(ESI,m/z)：437.1487(M-H)-
1H-NMR(CDCl3)δ：1.77-1.94(1H,m),2.06-2.26(1H,m),2.59-2.92(2H,m),4.56-4.74(1H,m),5.22-6.03(3H,m),7.17-7.65(12H,m),8.23(1H,br s).
[實施例2-21LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-三氟甲氧基茚-1-基]苯甲醯胺；
RT(min.)：3.822
MS(ESI,m/z)：453.1434(M-H)-
1H-NMR(CDCl3)δ：1.75-1.95(1H,m),2.00-2.20(1H,m),2.50-2.85(2H,m),4.55-4.80(1H,m),5.20-6.00(3H,m),7.05-7.20(2H,m),7.30-7.65(10H,m),7.85(1H,br s).
[實施例2-22LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-2-硝基苯甲醯胺；
RT(min.)：3.534
MS(ESI,m/z)：450.1273(M-H)-
1H-NMR(CDCl3)δ：1.65-1.85(1H,m),2.05-2.20(1H,m),2.35-2.50(1H,m),2.65-2.80(1H,m),4.63(1H,s),5.05-5.20(1H,m),5.35-5.50(2H,m),6.65-6.80(1H,m),7.35-7.85(9H,m),8.25(1H,d,J=8.2Hz).
[實施例2-23LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺；
RT(min.)：2.937
MS(ESI,m/z)：422.1074(M-H)-
1H-NMR(CDCl3)δ：1.70-1.90(1H,m),1.95-2.20(1H,m),2.40-2.65(1H,m),2.65-2.90(1H,m),4.55-4.90(1H,m),5.25-5.75(3H,m),6.90-7.10(1H,m),7.30-7.55(6H,m),7.70-7.95(2H,m),8.65-8.75(1H,m),8.82(1H,br s).
[實施例2-23HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺；
RT(min.)：2.767
MS(ESI,m/z)：422.1077(M-H)-
1H-NMR(CDCl3)δ：2.40-2.65(1H,m),2.65-2.85(2H,m),3.00-3.20(1H,m),4.30-4.55(1H,m),5.30-5.70(3H,m),6.20-6.40(1H,m),6.85(1H,d,J=8.3Hz),7.25-7.45(6H,m),7.80-7.95(1H,m),8.71(1H,dd,J=1.6,4.9Hz),8.75-8.85(1H,br s).
[實施例2-24LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(S)-5-氯-2,3-二氫苯并呋喃-3-基]菸鹼醯胺；
RT(min.)：2.486
MS(ESI,m/z)：406.0972(M-H)-
1H-NMR(CDCl3)δ：4.05-4.20(2H,m),5.00-5.90(4H,m),6.40-6.80(1H,m),7.00-7.95(9H,m),8.45-8.90(2H,m).
[實施例2-24HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(S)-5-氯-2,3-二氫苯并呋喃-3-基]菸鹼醯胺；
RT(min.)：2.507
MS(ESI,m/z)：406.0960(M-H)-
1H-NMR(CDCl3)δ：4.40-5.80(5H,m),6.35-6.80(2H,m),7.06(1H,d,J=1.7,8.6Hz),7.15-7.60(7H,m),7.65-7.90(1H,m),8.60-8.75(2H,m).
[實施例2-25LP]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(S)-5-氯-2,3-二氫苯并呋喃-3-基]菸鹼醯胺；
RT(min.)：1.824
MS(ESI,m/z)：421.1071(M-H)-
1H-NMR(CDCl3)δ：4.01(1H,dd,J=4.7,10.1Hz),5.35-5.65(5H,m),6.65-6.75(2H,m),7.16-7.23(1H,m),7.40-7.58(6H,m),7.70-7.72(1H,m),8.14(1H,dd,J=1.8,5.1Hz).
[實施例2-26LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-二氟甲氧基茚-1-基]菸鹼醯胺；
RT(min.)：2.778
MS(ESI,m/z)：436.1476(M-H)-
1H-NMR(CDCl3)δ：1.75-1.90(1H,m),2.05-2.20(1H,m),2.55-2.80(2H,m),4.55-4.85(1H,m),5.25-5.90(3H,m),6.65(1H,dd,J=74.1,74.1Hz),6.95-7.20(2H,m),7.35-7.55(6H,m),7.75(1H,br s),7.85-7.95(1H,m),8.65-8.75(1H,m),8.84(1H,br s).
[實施例2-27LP]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-二氟甲氧基茚-1-基]菸鹼醯胺；
RT(min.)：2.243
MS(ESI,m/z)：451.1583(M-H)-
1H-NMR(CDCl3)δ：1.40-1.90(1H,m),1.95-2.20(1H,m),2.50-2.80(2H,m),4.50-4.75(1H,m),5.30-5.60(5H,m),6.58(1H,dd,J=74.1,74.1Hz),6.68(1H,dd,J=5.0,7.3Hz),6.95-7.10(1H,m),7.16(1H,d,J=8.2Hz),7.35-7.55(6H,m),7.70(1H,br s),8.12(1H,dd,J=1.8,5.0Hz).
[實施例2-28LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(S)-5-氟-2,3-二氫苯并呋喃-3-基]苯甲醯胺；
RT(min.)：3.030
MS(ESI,m/z)：389.1307(M-H)-
1H-NMR(CDCl3)δ：4.10-5.84(6H,m),6.60-6.99(2H,m),7.32-7.66(11H,m).
[實施例2-28HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(S)-5-氟-2,3-二氫苯并呋喃-3-基]苯甲醯胺；
RT(min.)：2.979
MS(ESI,m/z)：389.1305(M-H)-
1H-NMR(CDCl3)δ：4.50-4.65(1H,m),5.11-5.23(1H,m),5.40-5.66(3H,m),6.25-6.36(1H,m),6.66-6.84(2H,m),7.17-7.34(4H,m),7.43-7.50(6H,m).
[實施例2-29LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(S)-5,7-二氟-2,3-二氫苯并呋喃-3-基]苯甲醯胺；
RT(min.)：3.239
MS(ESI,m/z)：407.1211(M-H)-
1H-NMR(CDCl3)δ：4.16-5.86(6H,m),6.64-6.81(1H,m),7.16-7.68(11H,m).
[實施例2-29HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(S)-5,7-二氟-2,3-二氫苯并呋喃-3-基]苯甲醯胺；
RT(min.)：3.165
MS(ESI,m/z)：407.1208(M-H)-
1H-NMR(CDCl3)δ：4.60-6.20(6H,m),6.60-6.68(1H,m),7.24-7.50(11H,m).
[實施例2-30LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟-6-甲氧基茚-1-基]苯甲醯胺；
RT(min.)：3.499
MS(ESI,m/z)：417.1614(M-H)-
1H-NMR(CDCl3)δ：1.66-1.81(1H,m),1.99-2.11(1H,m),2.41-2.53(1H,m),2.69-2.79(1H,m),3.89(3H,s),4.67(1H,br s),5.30-5.78(3H,m),6.54(1H,d,J=10.5Hz),7.33-7.52(9H,m),7.56-7.61(2H,m).
[實施例2-30HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-4-氟-6-甲氧基茚-1-基]苯甲醯胺；
RT(min.)：3.301
MS(ESI,m/z)：417.1618(M-H)-
1H-NMR(CDCl3)δ：2.39-2.51(1H,m),2.61-2.77(2H,m),2.99-3.11(1H,m),3.28(3H,s),4.47(1H,br s),5.37-5.54(2H,m),5.73(1H,br),5.95(1H,br s),6.40(1H,dd,J=2.0,10.4Hz),7.28-7.39(5H,m),7.42-7.48(3H,m),7.53-7.59(2H,m).
[實施例2-31LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]菸鹼醯胺；
RT(min.)：2.732
MS(ESI,m/z)：404.1171(M-H)-
1H-NMR(CDCl3)δ：1.70-1.90(1H,m),1.90-2.15(1H,m),2.50-2.80(2H,m),4.55-4.90(1H,m),5.20-5.75(3H,m),7.05-7.15(1H,m),7.15-7.30(1H,m),7.30-7.55(6H,m),7.85-8.05(2H,m),8.60-8.75(1H,m),8.84(1H,br s).
[實施例2-31HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]菸鹼醯胺；
RT(min.)：2.606
MS(ESI,m/z)：404.1170(M-H)-
1H-NMR(CDCl3)δ：2.40-2.60(1H,m),2.65-2.85(2H,m),2.95-3.15(1H,m),4.30-4.60(1H,m),5.25-5.75(3H,m),6.40-6.60(1H,m),7.10(2H,s),7.25-7.45(6H,m),7.80-7.95(1H,m),8.70(1H,dd,J=1.5,4.8Hz),8.83(1H,br s).
[實施例2-32LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]嘧啶-5-甲醯胺；
RT(min.)：2.715
MS(ESI,m/z)：407.1326(M-H)-
1H-NMR(CDCl3)δ：1.70-1.91(1H,m),1.94-2.14(1H,m),2.44-2.90(2H,m),4.45-5.00(1H,br),5.25-5.77(3H,m),6.63-6.86(1H,m),7.25-7.78(6H,m),8.77-9.02(2H,m),9.22-9.36(1H,m).
[實施例2-33LP]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]菸鹼醯胺；
RT(min.)：2.166
MS(ESI,m/z)：419.1276(M-H)-
1H-NMR(CDCl3)δ：1.45-1.80(1H,m),1.90-2.15(1H,m),2.45-2.75(2H,m),4.55-4.80(1H,m),5.25-5.65(5H,m),6.67(1H,dd,J=5.1,7.3Hz),7.10(1H,d,J=8.0Hz),7.20-7.30(1H,m),7.35-7.55(6H,m),7.87(1H,br s),8.12(1H,dd,J=1.7,5.0Hz).
[實施例2-34LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]吡-2-甲醯胺；
RT(min.)：2.944
MS(ESI,m/z)：407.1323(M-H)-
1H-NMR(DMSO-d6)δ：1.20-1.40(1H,m),2.00-2.15(1H,m),2.45-2.65(1H,m),2.80-2.95(1H,m),5.05-5.15(1H,m),5.54(1H,s),6.85-7.00(1H,m),7.20-7.55(9H,m),8.65-8.95(2H,m).
[實施例2-35LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟-6-甲基茚-1-基]苯甲醯胺；
RT(min.)：3.586
MS(ESI,m/z)：401.1671(M-H)-
1H-NMR(CDCl3)δ：1.68-1.82(1H,m),2.00-2.12(1H,m),2.39-2.56(4H,m),2.71-2.82(1H,m),4.65(1H,br s),5.25-5.85(3H,m),6.78(1H,d,J=9.6Hz),7.25-7.63(11H,m).
[實施例2-35HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-4-氟-6-甲基茚-1-基]苯甲醯胺；
RT(min.)：3.544
MS(ESI,m/z)：401.1669(M-H)-
1H-NMR(CDCl3)δ：1.93(3H,s),2.39-2.76(3H,m),3.02-3.14(1H,m),4.39(1H,br s),5.35-5.55(2H,m),5.67-5.79(1H,m),6.19(1H,br s),6.62(1H,d,J=9.9Hz),7.25-7.33(4H,m),7.42-7.47(3H,m),7.53-7.61(2H,m).
[實施例2-36LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-2-甲氧基菸鹼醯胺；
RT(min.)：3.204
MS(ESI,m/z)：436.1478(M-H)-
1H-NMR(CDCl3)δ：1.69-2.27(2H,m),2.44-3.08(2H,m),3.93-4.12(3H,m),4.49-4.85(1H,m),5.15-6.05(3H,m),6.51-6.79(1H,m),6.88-7.10(1H,m),7.30-7.88(7H,m),8.17-8.33(1H,m).
[實施例2-37LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氟茚-1-基]菸鹼醯胺；
RT(min.)：2.492
MS(ESI,m/z)：388.1465(M-H)-
1H-NMR(CDCl3)δ：1.69-1.88(1H,m),1.97-2.13(1H,m),2.46-2.78(2H,m),4.61-4.86(1H,br),5.28-5.75(3H,m),6.89-7.02(1H,m),7.05-7.16(1H,m),7.33-7.55(6H,m),7.66-7.79(1H,m),7.83-7.95(1H,m),8.69(1H,dd,J=1.5,4.9Hz),8.80-8.89(1H,m).
[實施例2-38LP]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氟茚-1-基]-2-甲氧基菸鹼醯胺；
RT(min.)：1.979
MS(ESI,m/z)：403.1574(M-H)-
1H-NMR(CDCl3)δ：1.50-2.11(2H,m),2.43-2.75(2H,m),4.54-4.79(1H,br),5.30-5.62(5H,m),6.67(1H,dd,J=5.0,7.4Hz),6.93-7.00(1H,m),7.09-7.15(1H,m),7.36-7.54(6H,m),7.59-7.64(1H,m),8.12(1H,dd,J=1.7,5.0Hz).
[實施例2-39LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟-6-甲氧基茚-1-基]菸鹼醯胺；
RT(min.)：2.674
MS(ESI,m/z)：418.1569(M-H)-
1H-NMR(CDCl3)δ：1.67-1.81(1H,m),1.97-2.10(1H,m),2.42-2.55(1H,m),2.68-2.80(1H,m),3.88(3H,s),4.72(1H,br s),5.32-5.61(3H,m),6.56(1H,d,J-10.5Hz),7.34-7.53(7H,m),7.86-7.95(1H,m),8.67-8.72(1H,m),8.86(1H,s).
[實施例2-39HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-4-氟-6-甲氧基茚-1-基]菸鹼醯胺；
RT(min.)：2.479
MS(ESI,m/z)：418.1570(M-H)-
1H-NMR(CDCl3)δ：2.43-2.55(1H,m),2.64-2.80(2H,m),2.98-3.11(1H,m),3.26(3H,s),4.50(1H,br),5.37-5.62(3H,m),5.88(1H,s),6.41(1H,dd,J=2.0,10.4Hz),7.30-7.44(6H,m),7.85-7.92(1H,m),8.69-8.73(1H,m),8.84(1H,s).
[實施例2-40LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟-6-甲基茚-1-基]菸鹼醯胺；
RT(min.)：2.744
MS(ESI,m/z)：402.1620(M-H)-
1H-NMR(CDCl3)δ：1.69-1.83(1H,m),2.00-2.10(1H,m),2.42(3H,s),2.45-2.57(1H,m),2.70-2.83(1H,m),4.72(1H,br s),5.33-5.64(3H,m),6.79(1H,d,J=9.7Hz),7.35-7.60(7H,m),7.91(1H,d,J=7.8Hz),8.69(1H,dd,J=1.6,4.9Hz),8.86(1H,s).
[實施例2-40HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-4-氟-6-甲基茚-1-基]菸鹼醯胺；
RT(min.)：2.672
MS(ESI,m/z)：402.1621(M-H)-
1H-NMR(CDCl3)δ：1.92(3H,s),2.40-2.58(1H,m),2.65-2.81(2H,m),3.00-3.15(1H,m),4.42(1H,br),5.37-5.64(3H,m),6.14(1H,s),6.63(1H,d,J=9.8Hz),7.25-7.44(6H,m),7.86-7.92(1H,m),8.70(1H,dd,J=1.7,4.9Hz),8.83(1H,s).
[實施例2-41LP]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(S)-5-氟-2,3-二氫苯并呋喃-3-基]菸鹼醯胺；
RT(min.)：1.545
MS(ESI,m/z)：405.1367(M-H)-
1H-NMR(CDCl3)δ：4.01(1H,dd,J=4.6,10.2Hz),4.07-4.85(1H,m),5.35-5.64(4H,m),6.65-6.78(2H,m),6.90-7.01(1H,m),7.39-7.60(7H,m),8.15(1H,dd,J=1.7,5.1Hz).
[實施例2-42LP]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(S)-5,7-二氟-2,3-二氫苯并呋喃-3-基]菸鹼醯胺；
RT(min.)：1.848
MS(ESI,m/z)：423.1271(M-H)-
1H-NMR(CDCl3)δ：4.07-4.80(2H,m),5.30-5.65(4H,m),6.67-6.87(2H,m),7.30-7.60(7H,m),8.13-8.17(1H,m).
[實施例2-43LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]吡啶-2-甲醯胺；
RT(min.)：3.085
MS(ESI,m/z)：406.1373(M-H)-
1H-NMR(CDCl3)δ：1.66-3.18(4H,m),4.69-6.24(4H,m),6.48-6.78(1H,m),6.97-8.06(9H,m),8.56-8.64(1H,m).
[實施例2-44LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]嗒-4-甲醯胺；
RT(min.)：2.633
MS(ESI,m/z)：407.1318(M-H)-
1H-NMR(CDCl3)δ：1.68-1.89(1H,m),1.95-2.13(1H,m),2.45-2.88(2H,m),4.48-5.76(4H,m),6.56-6.84(1H,m),7.37-7.72(7H,m),9.21-9.42(2H,m).
[實施例2-45LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-6-甲氧基菸鹼醯胺；
RT(min.)：3.324
MS(ESI,m/z)：436.1470(M-H)-
1H-NMR(CDCl3)δ：1.72-1.93(1H,m),1.95-2.20(1H,m),2.47-2.94(2H,m),3.97(3H,s),4.50-5.94(4H,m),6.64-6.77(1H,br),6.80(1H,d,J=8.7Hz),7.31-7.68(6H,m),7.74-7.86(1H,m),8.43(1H,d,J=1.7Hz).
[實施例2-46LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-2-甲氧基菸鹼醯胺；
RT(min.)：3.261
MS(ESI,m/z)：434.1276(M-H)-
1H-NMR(CDCl3)δ：1.65-1.85(1H,m),1.85-2.25(1H,m),2.45-2.80(2H,m),3.95-4.10(3H,m),4.55-4.90(1H,m),5.10-6.20(3H,m),6.90-7.15(2H,m),7.15-7.30(1H,m),7.30-8.05(7H,m),8.22(1H,dd,J=1.8,5.0Hz).
[實施例2-47LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]異菸鹼醯胺；
RT(min.)：2.620
MS(ESI,m/z)：406.1370(M-H)-
1H-NMR(CDCl3)δ：1.68-1.86(1H,m),1.93-2.12(1H,m),2.43-2.85(2H,m),4.50-5.05(1H,m),5.24-5.77(3H,m),6.53-6.80(1H,m),7.20-7.66(8H,m),8.66-8.80(2H,m).
[實施例2-48LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-7-氯-1,2,3,4-四氫萘-1-基]菸鹼醯胺；
RT(min.)：2.804
MS(ESI,m/z)：418.1329(M-H)-
1H-NMR(CDCl3)δ：1.34-1.64(2H,m),1.66-1.83(2H,m),2.55-2.65(2H,m),4.65(1H,br s),4.99-5.10(1H,m),5.28-5.69(2H,m),7.01(1H,d,J=8.2Hz),7.17-7.23(1H,m),7.35-7.45(4H,m),7.47-7.55(2H,m),7.89-7.95(1H,m),8.22(1H,d,J=1.3Hz),8.70(1H,dd,J=1.6,4.9Hz),8.86(1H,d,J=1.6Hz).
[實施例2-48HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-7-氯-1,2,3,4-四氫萘-1-基]菸鹼醯胺；
RT(min.)：2.701
MS(ESI,m/z)：418.1324(M-H)-
1H-NMR(CDCl3)δ：1.37-1.68(1H,m),1.90-2.07(1H,m),2.14-2.35(2H,m),2.58-2.83(2H,m),4.45(1H,br s),4.99-5.09(1H,m),5.34-5.72(2H,m),6.77(1H,br s),6.93-7.02(2H,m),7.22-7.43(6H,m),7.83-7.91(1H,m),8.70(1H,dd,J=1.5,4.9Hz),8.81-8.85(1H,m).
[實施例2-49LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-7-氯-1,2,3,4-四氫萘-1-基]苯甲醯胺；
RT(min.)：3.691
MS(ESI,m/z)：417.1379(M-H)-
1H-NMR(CDCl3)δ：1.32-1.55(2H,m),1.70-1.84(2H,m),2.54-2.63(2H,m),4.62(1H,br s),5.07-5.18(1H,m),5.24-5.99(2H,m),7.00(1H,d,J=8.2Hz),7.16-7.22(1H,m),7.32-7.61(10H,m),8.13-8.18(1H,m).
[實施例2-49HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-7-氯-1,2,3,4-四氫萘-1-基]苯甲醯胺；
RT(min.)：3.583
MS(ESI,m/z)：417.1376(M-H)-
1H-NMR(CDCl3)δ：1.40-1.53(1H,m),1.89-2.02(1H,m),2.13-2.33(2H,m),2.56-2.67(1H,m),2.70-2.83(1H,m),4.42(1H,br s),5.07-5.17(1H,m),5.31-5.93(2H,m),6.85(1H,br s),6.93-7.02(2H,m),7.28-7.32(5H,m),7.42-7.46(3H,m),7.53-7.57(2H,m).
[實施例2-50LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]噻吩-2-甲醯胺；
RT(min.)：3.682
MS(ESI,m/z)：427.0689(M-H)-
1H-NMR(CDCl3)δ：1.80-2.40(2H,m),2.55-2.70(1H,m),2.80-3.00(1H,m),4.40-6.30(4H,m),6.90-7.05(1H,m),7.07(1H,dd,J=3.8,5.0Hz),7.30-7.50(6H,m),7.52(1H,dd,J=1.0,5.0Hz),7.65-7.85(1H,m)．
[實施例2-51LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]噻唑-5-甲醯胺；
RT(min.)：3.173
MS(ESI,m/z)：428.0639(M-H)-
1H-NMR(CDCl3)δ：1.75-2.30(2H,m),2.50-2.70(1H,m),2.75-3.00(1H,m),4.50-6.05(4H,m),6.85-7.10(1H,m),7.30-7.55(5H,m),7.65-7.90(1H,m),8.20(1H,br s),8.92(1H,s).
[實施例2-52LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-異丙氧基茚-1-基]菸鹼醯胺；
RT(min.)：2.840
MS(ESI,m/z)：428.1983(M-H)-
1H-NMR(CDCl3)δ：1.34-1.42(6H,m),1.69-1.82(1H,m),1.96-2.07(1H,m),2.44-2.73(2H,m),4.60-4.85(2H,m),5.29-5.66(3H,m),6.77-6.86(1H,m),7.02-7.10(1H,m),7.33-7.62(7H,m),7.86-7.97(1H,m),8.64-8.72(1H,m),8.84-8.92(1H,m).
[實施例2-53LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-異丙氧基茚-1-基]苯甲醯胺；
RT(min.)：3.742
MS(ESI,m/z)：427.2028(M-H)-
1H-NMR(CDCl3)δ：1.34-1.43(6H,m),1.67-1.81(1H,m),1.97-2.08(1H,m),2.45-2.71(2H,m),4.61-4.76(2H,m),5.24-5.84(3H,m),6.77-6.84(1H,m),7.05(1H,d,J=8.1Hz),7.30-7.64(11H,m).
[實施例2-54LP]
N-[(R)-胺甲醯基苯基甲基]-6-氰基-N-[(R)-4,6-二氟茚-1-基]菸鹼醯胺；
RT(min.)：3.276
MS(ESI,m/z)：431.1326(M-H)-
1H-NMR(CDCl3)δ：1.67-2.16(2H,m),2.44-2.90(2H,m),4.50-5.85(4H,m),6.62-6.84(1H,m),7.37-8.09(8H,m),8.79-8.95(1H,m).
[實施例2-55LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]噻唑-5-甲醯胺；
RT(min.)：2.959
MS(ESI,m/z)：412.0941(M-H)-
1H-NMR(CDCl3)δ：1.77-1.98(1H,m),2.00-2.30(1H,m),2.54-2.69(1H,m),2.77-2.96(1H,m),4.37-5.14(1H,m),5.19-6.08(3H,m),6.55-6.88(1H,m),7.33-7.70(6H,m),8,17-8.24(1H,m),8.93(1H,s).
[實施例2-56LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟茚-1-基]菸鹼醯胺；
RT(min.)：2.502
MS(ESI,m/z)：388.1467(M-H)-
1H-NMR(CDCl3)δ：1.68-1.88(1H,m),1.97-2.15(1H,m),2.47-2.66(1H,m),2.72-2.92(1H,m),4.60-4.83(1H,br),5.29-5.73(3H,m),6.91-7.04(1H,m),7.29-7.55(7H,m),7.78(1H,d,J=7.7Hz),7.91(1H,d,J=7.7Hz),8.65-8.73(1H,m),8.80-8.90(1H,m).
[實施例2-57LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]噻唑-2-甲醯胺；
RT(min.)：3.495
MS(ESI,m/z)：412.0940(M-H)-
1H-NMR(CDCl3)δ：1.55-3.19(4H,m),4.50-5.90(2H,m),6.50-7.10(2H,m),7.32-7.68(8H,m),7.85-8.00(1H,m).
[實施例2-58LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氯-6-氟茚-1-基]菸鹼醯胺；
RT(min.)：2.986
MS(ESI,m/z)：422.1078(M-H)-
1H-NMR(CDCl3)δ：1.70-1.90(1H,m),1.95-2.15(1H,m),2.40-2.65(1H,m),2.65-2.85(1H,m),4.50-5.80(4H,m),6.85-7.10(1H,m),7.20-7.95(8H,m),8.65-8.75(1H,m),8.81(1H,br s).
[實施例2-59LP]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]噻唑-5-甲醯胺；
RT(min.)：2.752
MS(ESI,m/z)：443.0751(M-H)-
1H-NMR(CDCl3)δ：1.75-2.35(2H,m),2.45-2.75(1H,m),2.75-3.00(1H,m),4.20-6.30(6H,m),6.85-7.10(1H,m),7.10-7.80(7H,m).
[實施例2-60LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]噻唑-4-甲醯胺；
RT(min.)：3.294
MS(ESI,m/z)：428.0643(M-H)-
1H-NMR(CDCl3)δ：1.45-2.05(1H,m),2.10-2.45(1H,m),2.55-2.75(1H,m),2.75-3.20(1H,m),4.50-7.05(4H,m),7.10-7.85(7H,m),8.18(1H,br s),8.75-8.95(1H,m).
[實施例2-61LP]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]噻唑-5-甲醯胺；
RT(min.)：2.540
MS(ESI,m/z)：427.1046(M-H)-
1H-NMR(CDCl3)δ：1.78-2.36(2H,m),2.51-2.73(1H,m),2.80-2.95(1H,m),4.33-5.00(1H,m),5.21-6.30(5H,m),6.56-6.84(1H,m),7.31-7.58(7H,m).
[實施例2-62LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]對苯二甲醯胺酸苄酯；
RT(min.)：4.269
MS(ESI,m/z)：539.1791(M-H)-
1H-NMR(CDCl3)δ：1.63-2.12(2H,m),2.37-3.13(2H,m),4.50-5.07(1H,m),5.13-5.71(5H,m),6.53-6.73(1H,m),7.23-7.67(13H,m),8.08-8.22(2H,m).
[實施例2-63LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]噻吩-3-甲醯胺；
RT(min.)：3.586
MS(ESI,m/z)：427.0690(M-H)-
1H-NMR(CDCl3)δ：1.70-2.25(2H,m),2.45-2.65(1H,m),2.70-3.00(1H,m),4.50-5.95(4H,m),6.85-7.10(1H,m),7.20-7.90(9H,m).
[實施例2-64LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5-氟噻吩-2-甲醯胺；
RT(min.)：3.923
MS(ESI,m/z)：445.0597(M-H)-
1H-NMR(CDCl3)δ：1.22-1.34(1H,m),1.81-1.95(1H,m),2.56-2.69(1H,m),2.85-2.96(1H,m),4.10-6.30(4H,m),6.47(1H,dd,J=1.4,4.2Hz),6.94-7.03(1H,m),7.11-7.16(1H,m),7.34-7.43(5H,m),7.70-7.78(1H,m).
[實施例2-64HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5-氟噻吩-2-甲醯胺；
RT(min.)：3.747
MS(ESI,m/z)：445.0596(M-H)-
1H-NMR(CDCl3)δ：2.63-2.94(3H,m),3.13-3.23(1H,m),4.28-6.48(4H,m),6.49(1H,dd,J=1.4,4.2Hz),6.85-6.90(1H,m),7.13-7.18(1H,m),7.20-7.35(6H,m).
[實施例2-65LP]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟茚-1-基]菸鹼醯胺；
RT(min.)：1.997
MS(ESI,m/z)：403.1575(M-H)-
1H-NMR(CDCl3)δ：1.60-1.77(1H,m),1.97-2.16(1H,m),2.50-2.82(2H,m),4.52-4.82(1H,br),5.24-5.64(5H,m),6.67(1H,dd,J=5.0,7.4Hz),6.93-7.01(1H,m),7.25-7.55(7H,m),7.67(1H,d,J=7.4Hz),8.12(1H,d,J=1.8,5.0Hz).
[實施例2-66LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺；
RT(min.)：2.520
MS(ESI,m/z)：422.1078(M-H)-
1H-NMR(CDCl3)δ：1.74-1.94(1H,m),2.10-2.31(1H,m),2.48-2.68(1H,m),2.76-2.96(1H,m),4.63-4.77(1H,m),5.34-6.14(3H,m),6.95-7.06(1H,m),7.32-7.59(6H,m),7.70(1H,br s),7.85-8.02(1H,m),8.56-8.72(2H,m).
[實施例2-66HP]
N-[(S)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺；
RT(min.)：2.275
MS(ESI,m/z)：422.1079(M-H)-
1H-NMR(CDCl3)δ：2.42-3.20(4H,m),4.37-4.48(1H,m),5.41-5.92(3H,m),6.86-6.92(1H,m),7.28-7.34(1H,m),7.43-7.60(6H,m),7.86-7.94(1H,m),8.30-8.38(1H,m),8.56-8.63(1H,m).
[實施例2-67LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]異噻唑-5-甲醯胺；
RT(min.)：3.228
MS(ESI,m/z)：412.0937(M-H)-
1H-NMR(CDCl3)δ：1.71-1.93(1H,m),2.05-2.34(1H,m),2.48-2.66(1H,m),2.71-2.96(1H,m),4.45-5.90(4H,m),6.54-6.88(1H,m),7.32-7.65(7H,m),8.48(1H,br s).
[實施例2-68LP]
N-[(R)-胺甲醯基吡啶-2-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺；
RT(min.)：3.223
MS(ESI,m/z)：422.1075(M-H)-
1H-NMR(CDCl3)δ：1.90-2.09(1H,m),2.21-2.37(1H,m),2.50-2.69(1H,m),2.80-3.11(1H,m),4.66-5.95(4H,m),6.83-7.09(1H,m),7.40-7.83(9H,m),8.49-8.65(1H,m).
[實施例2-69LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]吡啶-2-甲醯胺；
RT(min.)：3.300
MS(ESI,m/z)：422.1077(M-H)-
1H-NMR(CDCl3)δ：1.60-2.10(1H,m),2.15-2.40(1H,m),2.45-3.20(2H,m),4.70-6.30(3H,m),6.80-7.00(1H,m),7.30-7.60(7H,m),7.60-8.00(3H,m),8.55-8.65(1H,m).
[實施例2-70LP]
N-[(R)-胺甲醯基吡啶-4-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺；
RT(min.)：2.385
MS(ESI,m/z)：422.1077(M-H)-
1H-NMR(CDCl3)δ：1.87-2.96(4H,m),4.56-4.73(1H,br),5.29-6.33(3H,m),6.94-7.09(1H,m),7.34-7.66(8H,m),8.62-8.68(2H,m).
[實施例2-71LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]噻唑-5-甲醯胺；
RT(min.)：2.972
MS(ESI,m/z)：410.0736(M-H)-
1H-NMR(CDCl3)δ：1.75-1.95(1H,m),2.00-2.30(1H,m),2.55-2.90(2H,m),4.50-4.90(1H,m),5.20-6.00(3H,m),7.05-7.30(2H,m),7.35-7.50(5H,m),7.90-8.00(1H,m),8.15-8.30(1H,m),8.92(1H,s).
[實施例2-72LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]噻吩-3-甲醯胺；
RT(min.)：3.440
MS(ESI,m/z)：409.0783(M-H)-
1H-NMR(CDCl3)δ：1.70-1.95(1H,m),1.95-2.20(1H,m),2.50-2.85(2H,m),4.55-4.80(1H,m),5.20-5.95(3H,m),7.05-7.30(2H,m),7.30-7.65(7H,m),7.71(1H,br s),7.90-8.05(1H,m).
[實施例2-73LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]吡啶-2-甲醯胺；
RT(min.)：3.112
MS(ESI,m/z)：404.1172(M-H)-
1H-NMR(CDCl3)δ：1.55-2.05(1H,m),2.15-2.40(1H,m),2.50-3.20(2H,m),4.60-5.25(1H,m),5.40-6.25(3H,m),7.00-7.25(2H,m),7.25-8.30(9H,m),8.61(1H,d,J=4.6Hz).
[實施例2-74LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]噻唑-4-甲醯胺；
RT(min.)：3.116
MS(ESI,m/z)：410.0738(M-H)-
1H-NMR(CDCl3)δ：1.45-2.05(1H,m),2.10-2.50(1H,m),2.55-3.20(2H,m),4.50-5.35(1H,m),5.35-6.85(3H,m),6.95-8.25(9H,m),8.75-8.95(1H,m).
[實施例2-75LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-噻唑-2-甲醯胺；
RT(min.)：3.711
MS(ESI,m/z)：428.0640(M-H)-
1H-NMR(CDCl3)δ：1.50-2.05(1H,m),2.10-2.45(1H,m),2.45-3.20(2H,m),4.50-7.10(4H,m),7.25-8.25(9H,m).
[實施例2-76LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4,6-二氟茚-1-基]苯甲醯胺；
RT(min.)：2.302
MS(ESI,m/z)：406.1371(M-H)-
1H-NMR(CDCl3)δ：1.74-1.92(1H,m),2.12-2.29(1H,m),2.50-2.66(1H,m),2.75-2.95(1H,m),4.59-4.84(1H,m),5.28-6.16(3H,m),6.62-6.83(1H,m),7.32-7.61(7H,m),7.86-8.04(1H,m),8.51-8.74(2H,m).
[實施例2-77LP]
N-[(R)-胺甲醯基吡啶-2-基甲基]-N-[(R)-4,6-二氟茚-1-基]苯甲醯胺；
RT(min.)：3.011
MS(ESI,m/z)：406.1373(M-H)-
1H-NMR(CDCl3)δ：1.90-2.04(1H,m),2.21-2.37(1H,m),2.50-2.68(1H,m),2.76-2.95(1H,m),4.69-4.86(1H,m),5.27-5.68(2H,m),6.61-6.79(1H,m),7.16-7.85(10H,m),8.54-8.62(1H,m).
[實施例2-77HP]
N-[(S)-胺甲醯基吡啶-2-基甲基]-N-[(R)-4,6-二氟茚-1-基]苯甲醯胺；
RT(min.)：2.800
MS(ESI,m/z)：406.1374(M-H)-
1H-NMR(CDCl3)δ：2.33-2.78(3H,m),2.95-3.14(1H,m),4.69-4.84(1H,m),5.40-5.72(2H,m),6.55-6.65(1H,m),6.95-7.06(1H,m),7.16-7.83(9H,m),8.49-8.60(1H,m).
[實施例2-78LP]
N-[(R)-胺甲醯基吡啶-2-基甲基]-N-[(R)-4,6-二氟茚-1-基]菸鹼醯胺；
RT(min.)：2.141
MS(ESI,m/z)：407.1324(M-H)-
1H-NMR(CDCl3)δ：1.87-2.06(1H,m),2.22-2.40(1H,m),2.52-2.69(1H,m),2.78-2.95(1H,m),4.75-4.95(1H,m),5.39-5.68(2H,m),6.61-6.80(1H,m),7.20-7.90(6H,m),7.92-8.08(1H,m),8.53-8.65(1H,m),8.66-8.81(1H,m),8.93(1H,br s).
[實施例2-79LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]噻唑-2-甲醯胺；
RT(min.)：3.543
MS(ESI,m/z)：410.0736(M-H)-
1H-NMR(CDCl3)δ：1.45-2.00(1H,m),2.15-2.45(1H,m),2.55-3.15(2H,m),4.60-5.90(2H,m),6.95-7.65(11H,m),7.80-8.00(1H,m).
[實施例2-80LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]異菸鹼醯胺；
RT(min.)：2.829
MS(ESI,m/z)：422.1075(M-H)-
1H-NMR(CDCl3)δ：1.30-3.20(4H,m),4.35-5.70(4H,m),6.80-7.90(9H,m),8.65-8.80(2H,m).
[實施例2-81LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4,6-二氟茚-1-基]菸鹼醯胺；
RT(min.)：1.447
MS(ESI,m/z)：407.1326(M-H)-
1H-NMR(CDCl3)δ：1.71-1.92(1H,m),2.08-2.27(1H,m),2.47-2.66(1H,m),2.74-2.94(1H,m),4.46-4.95(1H,m),5.33-5.84(3H,m),6.65-6.84(1H,m),7.35-7.62(3H,m),7.79-8.08(2H,m),8.57-8.91(4H,m).
[實施例2-82LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]異噻唑-5-甲醯胺；
RT(min.)：3.444
MS(ESI,m/z)：428.0640(M-H)-
1H-NMR(CDCl3)δ：1.70-1.95(1H,m),2.00-2.25(1H,m),2.50-2.65(1H,m),2.70-2.95(1H,m),4.50-5.90(4H,m),6.85-7.10(1H,m),7.30-7.90(7H,m),8.48(1H,s).
[實施例2-83LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺；
RT(min.)：1.774
MS(ESI,m/z)：423.1029(M-H)-
1H-NMR(CDCl3)δ：1.70-1.90(1H,m),2.05-2.30(1H,m),2.45-2.70(1H,m),2.70-2.95(1H,m),4.65-4.90(1H,m),5.30-5.85(3H,m),6.95-7.10(1H,m),7.25-7.50(2H,m),7.70-8.05(3H,m),8.60-8.85(4H,m).
[實施例2-84LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5-氟噻吩-2-甲醯胺；
RT(min.)：2.650
MS(ESI,m/z)：446.0547(M-H)-
1H-NMR(CDCl3)δ：1.85-1.98(1H,m),2.06-2.41(1H,m),2.64-2.78(1H,m),2.90-3.04(1H,m),4.41-6.23(4H,m),6.49(1H,dd,J=1.4,4.2Hz),7.04(1H,d,J=8.5Hz),7.15-7.19(1H,m),7.35(1H,dd,J=4.8,8.0Hz),7.67(1H,s),7.84-7.90(1H,m),8.59-8.64(2H,m).
[實施例2-85LP]
N-[(R)-胺甲醯基吡啶-2-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺；
RT(min.)：2.381
MS(ESI,m/z)：423.1031(M-H)-
1H-NMR(CDCl3)δ：1.87-3.16(4H,m),4.52-5.86(3H,m),6.79-8.09(8H,m),8.44-8.98(3H,m).
[實施例2-86LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5-氟菸鹼醯胺；
RT(min.)：3.319
MS(ESI,m/z)：440.0983(M-H)-
1H-NMR(CDCl3)δ：1.72-2.17(2H,m),2.44-2.86(2H,m),4.58-5.82(4H,m),6.87-7.09(1H,m),7.30-7.90(7H,m),8.50-8.70(2H,m).
[實施例2-87LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯茚-1-基]苯甲醯胺；
RT(min.)：2.318
MS(ESI,m/z)：404.1171(M-H)-
1H-NMR(CDCl3)δ：1.70-1.95(1H,m),2.10-2.30(1H,m),2.55-2.70(1H,m),2.70-2.90(1H,m),4.60-4.80(1H,m),5.20-6.30(3H,m),7.05-7.20(1H,m),7.20-7.30(1H,m),7.30-7.40(1H,m),7.40-7.50(3H,m),7.50-7.65(2H,m),7.80-7.90(1H,m),7.90-8.05(1H,m),8.55-8.70(2H,m),
[實施例2-88LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-4-甲基噻唑-5-甲醯胺；
RT(min.)：3.052
MS(ESI,m/z)：424.0892(M-H)-
1H-NMR(CDCl3)δ：1.65-2.20(2H,m),2.45-2.90(5H,m),4.50-4.90(1H,m),5.20-5.70(3H,m),7.05-7.15(1H,m),7.20-7.50(6H,m),7.90(1H,s),8.76(1H,s).
[實施例2-89LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基苯甲醯胺；
RT(min.)：3.654
MS(ESI,m/z)：451.1227(M-H)-
1H-NMR(CDCl3)δ：1.70-1.90(1H,m),1.95-2.25(1H,m),2.40-3.10(2H,m),3.85-3.95(3H,m),4.50-6.35(4H,m),6.80-7.15(3H,m),7.20-7.80(8H,m).
[實施例2-90LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]環己基甲醯胺；
RT(min.)：4.058
MS(ESI,m/z)：427.1595(M-H)-
1H-NMR(CDCl3)δ：1.05-3.04(15H,m),4.31-6.60(4H,m),6.90-7.06(1H,m),7.25-7.85(6H,m).
[實施例2-91LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-6-三氟甲基菸鹼醯胺；
RT(min.)：3.845
MS(ESI,m/z)：490.0953(M-H)-
1H-NMR(CDCl3)δ：1.69-1.87(1H,m),1.95-2.12(1H,m),2.45-3.15(2H,m),4.58-5.78(4H,m),6.84-7.06(1H,m),7.37-7.56(5H,m),7.69-7.88(2H,m),7.98-8.11(1H,m),8.89(1H,br s).
[實施例2-91HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-6-三氟甲基菸鹼醯胺；
RT(min.)：3.694
MS(ESI,m/z)：490.0953(M-H)-
1H-NMR(CDCl3)δ：2.46-2.61(1H,m),2.69-2.83(2H,m),3.02-3.17(1H,m),4.47(1H,br s),5.27-5.57(3H,m),6.26(1H,br s),6.86(1H,d,J=8.3Hz),7.25-7.43(5H,m),7.79(1H,d,J=8.0Hz),8.00-8.08(1H,m),8.89(1H,br s).
[實施例2-92LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-5,7-二氟茚-1-基]苯甲醯胺；
RT(min.)：3.970
MS(ESI,m/z)：405.1422(M-H)-
1H-NMR(CDCl3)δ：2.00-2.30(1H,m),2.30-2.65(1H,m),2.65-2.90(1H,m),2.90-3.15(1H,m),4.40-4.80(1H,m),5.00-6.20(2H,m),6.60-6.80(2H,m),6.90-7.15(1H,m),7.25-7.55(8H,m),7.55-7.65(2H,m).
[實施例2-92HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-5,7-二氟茚-1-基]苯甲醯胺；
RT(min.)：3.259
MS(ESI,m/z)：405.1422(M-H)-
1H-NMR(CDCl3)δ：2.40-2.60(1H,m),2.65-3.00(2H,m),3.15-3.40(1H,m),4.28(1H,br s),5.40-5.90(3H,m),6.10-6.20(1H,m),6.65-6.75(1H,m),7.15-7.30(5H,m),7.40-7.50(3H,m),7.55-7.65(2H,m).
[實施例2-93LP]
N-[(R)-胺甲醯基苯基甲基]-2-氯-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺；
RT(min.)：3.441
MS(ESI,m/z)：456.0688(M-H)-
1H-NMR(CDCl3)δ：1.72-1.86(1H,m),2.25-2.60(2H,m),2.75-3.13(1H,m),4.56(1H,br s),5.13-5.26(1H,m),5.34-5.50(2H,m),6.86-7.04(1H,m),7.34-7.94(8H,m),8.41-8.50(1H,m).
[實施例2-94LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-三氟甲基菸鹼醯胺；
RT(min.)：3.722
MS(ESI,m/z)：490.0951(M-H)-
1H-NMR(CDCl3)δ：1.67-2.15(2H,m),2.43-3.11(2H,m),4.56(1H,s),5.03-5.20(1H,m),5.31-5.53(2H,m),6.85-7.05(1H,m),7.35-8.14(8H,m),8.78-8.82(1H,m).
[實施例2-95LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]異噻唑-5-甲醯胺；
RT(min.)：3.551
MS(ESI,m/z)：410.0735(M-H)-
1H-NMR(CDCl3)δ：1.45-2.00(1H,m),2.15-2.45(1H,m),2.55-3.15(2H,m),4.60-5.90(2H,m),6.90-7.65(11H,m),7.80-8.00(1H,m).
[實施例2-96LP]
N-[(S)-胺甲醯基噻唑-2-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺；
RT(min.)：3.358
MS(ESI,m/z)：428.0639(M-H)-
1H-NMR(CDCl3)δ：1.85-2.04(1H,m),2.18-2.33(1H,m),2.48-2.67(1H,m),2.84-2.99(1H,m),4.94-5.07(1H,m),5.36-5.66(2H,m),6.83-7.05(2H,m),7.38-7.91(8H,m).
[實施例2-97LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-2-氯-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺；
RT(min.)：2.778
MS(ESI,m/z)：456.0686(M-H)-
1H-NMR(CDCl3)δ：1.66-2.96(4H,m),4.55-5.70(4H,m),6.80-7.07(1H,m),7.30-8.81(9H,m).
[實施例2-98LP]
N-[(R)-胺甲醯基苯基甲基]-3-氯-N-[(R)-6-氯-4-氟茚-1-基]異菸鹼醯胺；
RT(min.)：3.402
MS(ESI,m/z)：456.0687(M-H)-
1H-NMR(CDCl3)δ：1.71-3.17(4H,m),4.52-5.82(4H,m),6.83-7.07(1H,m),7.30-7.88(7H,m),8.50-8.80(2H,m).
[實施例2-99LP]
N-[(R)-胺甲醯基-(2-氯苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺；
RT(min.)：3.170
MS(ESI,m/z)：456.0685(M-H)-
1H-NMR(CDCl3)δ：1.60-3.18(4H,m),4.80-5.80(4H,m),6.79-7.01(1H,m),7.28-8.02(7H,m),8.57-8.89(2H,m).
[實施例2-100LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基菸鹼醯胺；
RT(min.)：2.796
MS(ESI,m/z)：436.1237(M-H)-
1H-NMR(CDCl3)δ：1.68-2.17(2H,m),2.40-2.62(4H,m),2.71-3.14(1H,m),4.58-5.11(1H,m),5.19-5.28(1H,m),5.36-5.53(2H,m),6.86-7.03(1H,m),7.17-7.60(6H,m),7.71-7.90(1H,m),8.48-8.72(2H,m).
[實施例2-101LP]
N-[(R)-胺甲醯基苯基甲基]-4-氯-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺；
RT(min.)：3.312
MS(ESI,m/z)：456.0687(M-H)-
1H-NMR(DMSO-d6)δ：1.30-1.44(1H,m),2.01-2.21(1H,m),2.48-2.66(1H,m),2.83-2.94(1H,m),4.92-5.00(0.5H,m),5.22-5.30(1H,m),5.40(0.5H,s),7.10-7.17(1H,m),7.35-7.81(9H,m),8.33(0.5H,s),8.62-8.68(1H,m),8.90(0.5H,s).
[實施例2-102LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-乙氧基菸鹼醯胺；
RT(min.)：3.596
MS(ESI,m/z)：466.1339(M-H)-
1H-NMR(CDCl3)δ：1.47(3H,t,J=7.1Hz),1.65-1.90(1H,m),2.10-2.30(1H,m),2.40-2.65(1H,m),2.65-3.10(1H,m),4.30-4.70(3H,m),5.20-5.80(3H,m),6.80-7.05(2H,m),7.30-7.90(7H,m),8.15-8.30(1H,m).
[實施例2-103LP]
N-[(R)-胺甲醯基-(2-氟苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺；
RT(min.)：3.039
MS(ESI,m/z)：440.0982(M-H)-
1H-NMR(CDCl3)δ：1.69-3.21(4H,m),4.82-5.82(4H,m),6.78-8.00(8H,m),8.62-8.86(2H,m).
[實施例2-104LP]
5-{N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]胺甲醯基}吡啶 -2-羧酸苄酯；
RT(min.)：3.976
MS(ESI,m/z)：556.1451(M-H)-
1H-NMR(CDCl3)δ：1.64-2.11(2H,m),2.40-2.87(2H,m),4.56-5.71(6H,m),6.80-7.10(1H,m),7.28-8.28(13H,m),8.85-8.99(1H,m).
[實施例2-105LP]
N-[(R)-胺甲醯基苯基甲基]-3-氯-N-[(R)-6-氯-4-氟茚-1-基]吡啶-2-甲醯胺；
RT(min.)：3.500
MS(ESI,m/z)：456.0688(M-H)-
1H-NMR(CDCl3)δ：1.61-3.17(4H,m),4.66-6.08(4H,m),6.78-7.01(1H,m),7.22-7.90(8H,m),8.48-8.62(1H,m).
[實施例2-106LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-6-甲氧基菸鹼醯胺；
RT(min.)：3.510
MS(ESI,m/z)：452.1181(M-H)-
1H-NMR(CDCl3)δ：1.68-2.23(2H,m),2.43-2.95(2H,m),3.97(3H,s),4.38-4.95(1H,m),5.22-5.88(3H,m),6.80(1H,d,J=8.6Hz),6.89-7.06(1H,m),7.31-7.53(5H,m),7.69-7.90(2H,m),8.38-8.48(1H,m).
[實施例2-106HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-6-甲氧基菸鹼醯胺；
RT(min.)：3.366
MS(ESI,m/z)：452.1187(M-H)-
1H-NMR(CDCl3)δ：2.48-2.83(3H,m),3.03-3.19(1H,m),3.97(3H,s),4.22-4.63(1H,m),5.32-5.83(3H,m),6.18-6.53(1H,m),6.75-6.89(2H,m),7.18-7.49(5H,m),7.73-7.85(1H,m),8.33-8.46(1H,m).
[實施例2-107LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-(甲基胺基)菸鹼醯胺；
RT(min.)：2.362
MS(ESI,m/z)：451.1341(M-H)-
1H-NMR(CDCl3)δ：1.62-2.14(2H,m),2.45-2.83(2H,m),3.00-3.13(3H,m),4.48-4.82(1H,m),5.19-5.67(3H,m),6.00-6.31(1H,m),6.57(1H,dd,J=5.1,7.2Hz),6.91-7.05(1H,m),7.34-7.68(7H,m),8.20(1H,dd,J=1.7,5.1Hz).
[實施例2-107HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-(甲基胺基)菸鹼醯胺；
RT(min.)：2.357
MS(ESI,m/z)：451.1343(M-H)-
1H-NMR(CDCl3)δ：2.49-2.90(3H,m),2.99-3.15(4H,m),4.21-4.56(1H,m),5.32-5.66(3H,m),5.89-6.32(1H,m),6.56(1H,dd,J=5.1,7.3Hz),6.81(1H,dd,J=1.3,8.6Hz),7.25-7.43(7H,m),8.20(1H,dd,J=1.7,5.1Hz).
[實施例2-108LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-三氟甲基菸鹼醯胺；
RT(min.)：3.616
MS(ESI,m/z)：490.0952(M-H)-
1H-NMR(CDCl3)δ：1.65-3.13(4H,m),4.56-4.78(1H,m),5.05-5.20(1H,m),5.30-6.03(2H,m),6.85-7.05(1H,m),7.33-7.56(5H,m),7.60-7.93(2H,m),8.76-9.10(2H,m).
[實施例2-109LP]
N-[(R)-胺甲醯基-(5-氟吡啶-3-基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺；
RT(min.)：3.217
MS(ESI,m/z)：440.0984(M-H)-
1H-NMR(CDCl3)δ：1.71-2.00(1H,m),2.13-2.40(1H,m),2.50-3.02(2H,m),4.64-4.86(1H,m),5.34-6.35(3H,m),6.92-7.08(1H,m),7.42-7.87(7H,m),8.40-8.56(2H,m).
[實施例2-110LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]咪唑并[1,2-a]吡-3-甲醯胺；
RT(min.)：2.970
MS(ESI,m/z)：462.1140(M-H)-
1H-NMR(CDCl3)δ：1.61-3.13(4H,m),4.40-6.40(4H,m),6.86-7.14(1H,m),7.36-8.22(8H,m),8.80-9.30(2H,m).
[實施例2-111LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2,3-二氫苯并呋喃-7-甲醯胺；
RT(min.)：3.737
MS(ESI,m/z)：463.1227(M-H)-
1H-NMR(CDCl3)δ：1.76-2.33(2H,m),2.45-2.90(2H,m),3.20-3.35(2H,m),4.56-6.17(6H,m),6.80-7.02(2H,m),7.19-7.72(8H,m).
[實施例2-112LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4-氯茚-1-基]菸鹼醯胺；
RT(min.)：1.615
MS(ESI,m/z)：405.1139(M-H)-
1H-NMR(CDCl3)δ：1.68-1.86(1H,m),2.07-2.23(1H,m),2.57-2.72(1H,m),2.79-2.99(1H,m),4.66-4.92(1H,m),5.26-5.91(3H,m),7.24-7.45(4H,m),7.77-8.05(3H,m),8.62-8.74(3H,m),8.81-8.87(1H,m).
[實施例2-113LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-氟苯甲醯胺；
RT(min.)：2.623
MS(ESI,m/z)：440.0983(M-H)-
1H-NMR(CDCl3)δ：1.74-1.89(1H,m),2.17-2.40(1H,m),2.54-2.67(1H,m),2.79-2.93(1H,m),4.57-4.87(1H,m),5.33-6.10(3H,m),6.98-7.04(1H,m),7.14-7.21(1H,m),7.24-7.68(5H,m),7.90-8.03(1H,m),8.59-8.72(2H,m).
[實施例2-114LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲氧基菸鹼醯胺；
RT(min.)：2.295
MS(ESI,m/z)：452.1177(M-H)-
1H-NMR(CDCl3)δ：1.68-2.21(2H,m),2.38-3.09(2H,m),3.89-4.03(3H,m),4.44-5.89(4H,m),6.80-7.05(2H,m),7.24-7.89(6H,m),8.40-8.66(2H,m).
[實施例2-115LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]咪唑并[1,2-a]吡啶-6-甲醯胺；
RT(min.)：2.250
MS(ESI,m/z)：461.1184(M-H)-
1H-NMR(CDCl3)δ：1.69-3.14(4H,m),4.45-6.60(4H,m),6.83-7.10(1H,m),7.27-8.00(10H,m),8.40-8.56(1H,m).
[實施例2-116LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基甲基菸鹼 醯胺；
RT(min.)：2.665
MS(ESI,m/z)：452.1184(M-H)-
1H-NMR(CDCl3)δ：1.69-1.82(1H,m),2.00-2.18(1H,m),2.45-3.12(2H,m),4.55-5.71(6H,m),6.85-7.04(1H,m),7.25-7.87(8H,m),8.59-8.67(1H,m).
[實施例2-117LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基苯甲醯胺；
RT(min.)：2.788
MS(ESI,m/z)：436.1235(M-H)-
1H-NMR(CDCl3)δ：1.68-1.81(1H,m),2.03-2.22(1H,m),2.37-2.58(4H,m),2.77-3.17(1H,m),4.61-4.70(1H,m),5.23-5.96(3H,m),6.85-7.03(1H,m),7.20-7.49(5H,m),7.61-7.82(1H,m),7.97-8.15(1H,m),8.51-8.74(2H,m).
[實施例2-118LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基苯甲醯胺；
RT(min.)：2.518
MS(ESI,m/z)：452.1183(M-H)-
1H-NMR(CDCl3)δ：1.75-1.91(1H,m),2.09-2.32(1H,m),2.52-2.67(1H,m),2.79-3.13(1H,m),3.90-3.97(3H,m),4.68-4.77(1H,m),5.31-6.75(3H,m),6.84-7.10(3H,m),7.25-7.58(4H,m),7.89-8.02(1H,m),8.50-8.76(2H,m).
[實施例2-119LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-三氟甲基苯甲醯胺；
RT(min.)：3.003
MS(ESI,m/z)：490.0953(M-H)-
1H-NMR(DMSO-d6)δ：1.22-2.22(2H,m),2.46-2.70(1H,m),2.82-2.94(1H,m),4.94-5.28(1H,m),5.31-5.36(1H,m),7.10-7.56(5H,m),7.63-8.03(5H,m),8.39-8.73(2H,m).
[實施例2-120LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-乙基苯甲醯胺；
RT(min.)：3.028
MS(ESI,m/z)：450.1387(M-H)-
1H-NMR(CDCl3)δ：1.28-1.35(3H,m),1.66-1.83(1H,m),2.01-2.25(1H,m),2.45-2.59(1H,m),2.70-3.14(3H,m),4.61-4.69(1H,m),5.18-6.04(3H,m),6.85-7.03(1H,m),7.19-7.84(6H,m),7.98-8.13(1H,m),8.53-8.73(2H,m).
[實施例2-121LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-6-側氧基-1,6-二氫嗒-3-甲醯胺；
RT(min.)：2.761
MS(ESI,m/z)439.0979(M-H)-
1H-NMR(CDCl3)δ：1.35-2.14(2H,m),2.51-2.64(1H,m),2.73-3.07(1H,m),5.04-6.35(4H,m),6.77-7.03(2H,m),7.35-7.79(7H,m),11.52(1H,br).
[實施例2-122LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-氰基苯甲醯胺；
RT(min.)：2.498
MS(ESI,m/z)：447.1031(M-H)-
1H-NMR(DMSO-d6)δ：1.29-2.14(2H,m),2.42-2.69(1H,m),2.84-2.97(1H,m),5.05-5.42(2H,m),7.11-8.09(10H,m),8.48-8.73(2H,m).
[實施例2-123LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-三氟甲氧基苯甲醯胺；
RT(min.)：3.072
MS(ESI,m/z)：506.0900(M-H)-
1H-NMR(CDCl3)δ：1.65-1.97(1H,m),2.13-2.24(1H,m),2.48-2.66(1H,m),2.77-3.16(1H,m),4.57-5.00(1H,m),5.20-5.78(3H,m),6.85-7.05(1H,m),7.32-7.77(6H,m),7.87-8.11(1H,m),8.59-8.69(2H,m).
[實施例2-124LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-5-甲氧基茚-1-基]菸鹼醯胺；
RT(min.)：0.998
MS(ESI,m/z)：401.1626(M-H)-
1H-NMR(CDCl3)δ：1.69-1.83(1H,m),2.08-2.25(1H,m),2.57-2.87(2H,m),3.81(3H,s),4.71-4.83(1H,m),5.24-6.05(3H,m),6.72-6.76(1H,m),6.86-6.91(1H,m),7.34-7.42(2H,m),7.73(1H,d,J=8.4Hz),7.87-7.94(1H,m),7.96-8.05(1H,m),8.60-8.73(3H,m),8.83-8.88(1H,m).
[實施例2-125LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-2-(甲基硫基)菸鹼醯胺；
RT(min.)：3.518
MS(ESI,m/z)：450.1050(M-H)-
1H-NMR(CDCl3)δ：1.65-1.90(1H,m),2.10-2.35(1H,m),2.45-2.75(5H,m),4.45-4.90(1H,m),5.10-5.65(3H,m),7.00-7.15(2H,m),7.20-7.30(1H,m),7.30-7.80(6H,m),7.95(1H,s),8.49(1H,dd,J=1.6,4.9Hz).
[實施例2-126LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]咪唑并[1,2-a]吡-2-甲醯胺；
RT(min.)：2.961
MS(ESI,m/z)：462.1148(M-H)-
1H-NMR(DMSO-d6)δ：1.19-1.36(1H,m),1.91-2.07(1H,m),2.42-2.64(1H,m),2.78-2.95(1H,m),5.06-5.17(1H,m),6.63(1H,s),7.08-7.15(1H,m),7.33-7.64(8H,m),7.96-8.01(1H,m),8.46(1H,s),8.60-8.67(1H,m),9.14(1H,s).
[實施例2-127LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2,3-二氫苯并呋喃-7-甲醯胺；
RT(min.)：2.574
MS(ESI,m/z)：464.1186(M-H)-
1H-NMR(CDCl3)δ：1.82-2.00(1H,m),2.26-2.43(1H,m),2.56-2.71(1H,m),2.80-2.96(1H,m),3.20-3.38(2H,m),4.60-4.86(3H,m),5.30-5.80(2H,m),6.87-7.07(2H,m),7.22-7.57(5H,m),7.85-7.98(1H,m),8.50-8.75(2H,m).
[實施例2-128LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-(甲基硫基)菸鹼醯胺；
RT(min.)：3.627
MS(ESI,m/z)：468.0959(M-H)-
1H-NMR(CDCl3)δ：1.70-1.90(1H,m),2.10-2.45(1H,m),2.45-2.60(1H,m),2.65(3H,s),2.65-3.15(1H,m),4.40-4.95(1H,m),5.00-5.75(3H,m),6.80-7.15(2H,m),7.35-7.85(7H,m),8.45-8.55(1H,m).
[實施例2-129LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基菸鹼醯胺；
RT(min.)：2.598
MS(ESI,m/z)：438.1035(M-H)-
1H-NMR(CDCl3)δ：1.35-2.00(2H,m),2.15-3.15(3H,m),4.70-5.20(1H,m),5.35-5.65(1H,m),6.05-6.80(2H,m),6.80-7.05(1H,m),7.25-7.85(9H,m).
[實施例2-130LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基噻唑-4-甲醯胺；
RT(min.)：3.464
MS(ESI,m/z)：442.0805(M-H)-
1H-NMR(CDCl3)δ：1.59-3.24(7H,m),4.44-7.06(4H,m),7.12-8.06(8H,m).
[實施例2-131LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：2.495
MS(ESI,m/z)：420.1532(M-H)-
1H-NMR(CDCl3)δ：1.56-2.22(2H,m),2.34-3.18(5H,m),4.46-5.68(4H,m),6.55-6.86(1H,m),7.14-7.83(8H,m),8.51-8.65(1H,m).
[實施例2-132LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-4-甲基噻唑-5-甲醯胺；
RT(min.)：3.005
MS(ESI,m/z)：426.1101(M-H)-
1H-NMR(CDCl3)δ：1.61-2.23(2H,m),2.44-2.95(5H,m),4.43-4.90(1H,m),5.27-5.84(3H,m),6.57-6.86(1H,m),7.28-7.81(6H,m),8.77(1H,s).
[實施例2-133LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基-2H-吡唑-3-甲醯胺；
RT(min.)：3.183
MS(ESI,m/z)：425.1189(M-H)-
1H-NMR(CDCl3)δ：1.68-2.25(2H,m),2.51-3.10(2H,m),3.86-4.18(3H,m),4.50-6.00(4H,m),6.46(1H,br s),6.80-7.11(1H,m),7.29-7.85(7H,m).
[實施例2-134LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-甲基-3H-咪唑-4-甲醯胺；
RT(min.)：2.272
MS(ESI,m/z)：425.1193(M-H)-
1H-NMR(CDCl3)δ：1.75-2.36(2H,m),2.51-3.00(2H,m),3.86(3H,br s),4.30-6.50(4H,m),6.88-7.07(1H,m),7.33-7.85(8H,m).
[實施例2-135LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5-甲基唑-4-甲醯胺；
RT(min.)：3.377
MS(ESI,m/z)：426.1032(M-H)-
1H-NMR(CDCl3)δ：1.69-2.25(2H,m),2.40-3.04(5H,m),4.38-5.10(1H,m),5.16-5.90(3H,m),6.87-7.13(1H,m),7.30-7.53(5H,m),7.61-7.87(1H,m),8.26(1H,br s).
[實施例2-136LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-2-氯-N-[(R)-6-氯茚-1-基]苯甲醯胺；
RT(min.)：2.567
MS(ESI,m/z)：438.0787(M-H)-
1H-NMR(CDCl3)δ：1.65-1.99(1H,m),2.11-2.34(1H,m),2.53-2.90(2H,m),4.60-4.85(1H,m),5.17-5.80(3H,m),7.07-8.22(9H,m),8.56-8.74(2H,m).
[實施例2-137LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：2.483
MS(ESI,m/z)：418.1332(M-H)-
1H-NMR(CDCl3)δ：1.60-1.85(1H,m),1.90-2.15(1H,m),2.40-2.60(1H,m),2.60-2.85(4H,m),4.55-4.80(1H,m),5.19(1H,dd,J=8.6,8.6Hz),5.25-5.65(2H,m),7.05-7.15(1H,m),7.15-7.30(2H,m),7.30-7.90(6H,m),7.90-8.05(1H,m),8.50-8.65(1H,m).
[實施例2-138LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯茚-1-基]-2-甲氧基苯甲醯胺；
RT(min.)：2.331
MS(ESI,m/z)：434.1285(M-H)-
1H-NMR(CDCl3)δ：1.70-1.90(1H,m),2.05-2.30(1H,m),2.55-2.70(1H,m),2.70-2.85(1H,m),3.94(3H,s),4.72(1H,s),5.20-5.80(2H,m),5.90-6.95(1H,m),6.97(1H,d,J=8.4Hz),7.06(1H,ddd,J=0.7,7.5,7.5Hz),7.11(1H,dd,J=8.0,17.4Hz),7.15-7.50(4H,m),7.68(1H,s),7.90-8.05(1H,m),8.50-8.80(2H,m).
[實施例2-139LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-乙基菸鹼醯胺；
RT(min.)：3.006
MS(ESI,m/z)：450.1399(M-H)-
1H-NMR(CDCl3)δ：1.35-1.45(3H,m),1.67-1.83(1H,m),1.97-2.08(1H,m),2.43-3.21(4H,m),4.53-4.72(1H,m),5.16-5.57(3H,m),6.84-7.04(1H,m),7.16-7.86(8H,m),8.58-8.66(1H,m).
[實施例2-140LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-乙烯基菸鹼醯胺；
RT(min.)：3.366
MS(ESI,m/z)：448.1238(M-H)-
1H-NMR(CDCl3)δ：1.64-1.85(1H,m),1.91-2.13(1H,m),2.40-3.18(2H,m),4.50-4.98(1H,m),5.13-5.78(4H,m),6.48-6.63(1H,m),6.85-7.87(10H,m),8.60-8.69(1H,m).
[實施例2-141LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基唑-5-甲醯胺；
RT(min.)：3.196
MS(ESI,m/z)：426.1034(M-H)-
1H-NMR(CDCl3)δ：1.82-2.32(2H,m),2.46(3H,br s),2.54-3.05(2H,m),4.46-5.27(1H,m),5.30-6.19(3H,m),6.84-7.05(1H,m),7.33-7.52(5H,m),7.54-7.87(2H,m).
[實施例2-142LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2,4-二甲基噻唑-5-甲醯胺；
RT(min.)：3.333
MS(ESI,m/z)：456.0961(M-H)-
1H-NMR(CDCl3)δ：1.67-1.93(1H,m),1.94-2.23(1H,m),2.45-2.96(8H,m),4.37-5.93(4H,m),6.87-7.08(1H,m),7.33-7.52(5H,m),7.63-7.79(1H,m).
[實施例2-143LP]
2-{N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]胺甲醯基}吡啶N氧化物；
RT(min.)：2.727
MS(ESI,m/z)：438.1036(M-H)-
1H-NMR(CDCl3)δ：1.75-2.25(1H,m),2.40-3.20(3H,m),4.60-6.00(4H,m),6.85-7.10(1H,m),7.25-7.70(9H,m),8.20-8.35(1H,m).
[實施例2-144LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]咪唑并[1,2-a]吡啶-8-甲醯胺；
RT(min.)：2.221
MS(ESI,m/z)：461.1193(M-H)-
1H-NMR(CDCl3)δ：1.90-3.20(4H,m),4.76-5.97(3H,m),6.78-6.99(2H,m),7.22-7.48(5H,m),7.49-7.82(4H,m),8.15-8.28(1H,m).
[實施例2-145LP]
3-{N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]胺甲醯基}吡啶N-氧化物；
RT(min.)：2.536
MS(ESI,m/z)：438.1030(M-H)-
1H-NMR(CDCl3)δ：1.65-1.85(1H,m),1.90-2.15(1H,m),2.45-3.20(2H,m),4.50-5.90(4H,m),6.80-7.20(1H,m),7.25-7.55(7H,m),7.60-7.90(1H,m),8.15-8.30(1H,m),8.36(1H,s).
[實施例2-146LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基噻唑-5-甲醯胺；
RT(min.)：2.101
MS(ESI,m/z)：443.0758(M-H)-
1H-NMR(CDCl3)δ：1.69-1.89(1H,m),1.99-2.29(1H,m),2.54-2.69(4H,m),2.80-2.97(1H,m),4.52-4.97(1H,m),5.32-5.75(3H,m),6.97-7.06(1H,m),7.39(1H,dd,J=4.8,8.0Hz),7.69(1H,br s),7.85-8.00(1H,br),8.59-8.71(2H,m),8.78(1H,s).
[實施例2-147LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5-甲基噻唑-4-甲醯胺；
RT(min.)：3.225
MS(ESI,m/z)：442.0803(M-H)-
1H-NMR(CDCl3)δ：1.69-1.92(1H,m),1.95-2.23(1H,m),2.47-2.70(4H,m),2.71-3.00(1H,m),4.45-4.91(1H,m),5.22-5.77(3H,m),6.85-7.08(1H,m),7.32-7.54(5H,m),7.72(1H,br s),8.77(1H,s).
[實施例2-148LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5-甲基唑-4-甲醯胺；
RT(min.)：3.435
MS(ESI,m/z)：426.1031(M-H)-
1H-NMR(CDCl3)δ：1.80-3.19(7H,m),4.26-6.11(2H,m),6.40-8.11(10H,m).
[實施例2-149LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-6-啉-4-基菸鹼醯胺；
RT(min.)：3.170
MS(ESI,m/z)：507.1618(M-H)-
1H-NMR(CDCl3)δ：1.76-2.25(2H,m),2.47-2.97(2H,m),3.54-3.64(4H,m),3.75-3.86(4H,m),4.42-6.08(3H,m),6.64(1H,d,J=8.8Hz),6.90-7.03(1H,m),7.30-7.51(6H,m),7.70-7.82(2H,m),8.45(1H,d,J=2.0Hz).
[實施例2-149HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-6-啉-4-基菸鹼醯胺；
RT(min.)：3.004
MS(ESI,m/z)：507.1613(M-H)-
1H-NMR(CDCl3)δ：2.48-2.81(3H,m),3.05-3.17(1H,m),3.56-3.63(4H,m),3.78-3.86(4H,m),4.27-4.71(1H,m),5.34-5.98(3H,m),6.19-6.51(1H,m),6.65(1H,d,J=8.9Hz),6.82-6.88(1H,m),7.27-7.37(5H,m),7.74(1H,dd,J=2.1,8.9Hz),8.42(1H,d,J=2.1Hz).
[實施例2-150LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5-甲基異唑-5-甲醯胺；
RT(min.)：3.507
MS(ESI,m/z)：426.1034(M-H)-
1H-NMR(CDCl3)δ：1.85-2.30(5H,m),2.50-2.67(1H,m),2.81-3.06(1H,m),4.82-5.92(4H,m),6.80-7.00(1H,m),7.34-7.72(6H,m),7.93-8.25(1H,m).
[實施例2-151LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-3-甲基吡啶-2-甲醯胺；
RT(min.)：3.205
MS(ESI,m/z)：418.1330(M-H)-
1H-NMR(CDCl3)δ：1.70-1.95(1H,m),2.10-2.30(1H,m),2.45-2.60(4H,m),2.60-2.75(1H,m),4.65-4.95(1H,m),5.17(1H,dd,J=8.5,8.5Hz),5.25-5.95(2H,m),7.00-7.50(6H,m),7.50-7.65(3H,m),7.92(1H,br s),8.40-8.50(1H,m).
[實施例2-152LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-甲基吡啶-2-甲醯胺；
RT(min.)：3.372
MS(ESI,m/z)：436.1240(M-H)-
1H-NMR(CDCl3)δ：1.70-2.00(1H,m),2.10-2.40(1H,m),2.40-3.20(5H,m),4.60-5.90(4H,m),6.80-7.00(1H,m),7.15-7.25(1H,m),7.25-7.70(6H,m),7.76(1H,s),8.40-8.50(1H,m).
[實施例2-153LP]
N-[(R)-胺甲醯基-(2-甲基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺；
RT(min.)：3.165
MS(ESI,m/z)：436.1241(M-H)-
1H-NMR(CDCl3)δ：1.79-3.13(7H,m),4.76-5.08(1H,m),5.26-5.73(3H,m),6.79-7.00(1H,m),7.17-7.50(5H,m),7.60-7.99(2H,m),8.54-8.90(2H,m).
[實施例2-154LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5-甲基嘧啶-5-甲醯胺；
RT(min.)：2.937
MS(ESI,m/z)：437.1192(M-H)-
1H-NMR(CDCl3)δ：1.68-1.84(1H,m),1.95-2.13(1H,m),2.44-2.92(5H,m),4.54-4.87(1H,m),5.09-5.62(3H,m),6.95-7.06(1H,m),7.38-7.61(5H,m),7.78(1H,s),8.50-8.80(1H,m),9.05-9.20(1H,m).
[實施例2-155LP]
N-[(R)-胺甲醯基-(3-甲基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：2.965
MS(ESI,m/z)：450.1399(M-H)-
1H-NMR(CDCl3)δ：1.38-1.87(1H,m),1.94-2.14(1H,m),2.38(3H,s),2.41-3.13(5H,m),4.52-5.00(1H,m),5.14-5.68(3H,m),6.84-7.40(6H,m),7.51-7.83(2H,m),8.52-8.60(1H,m).
[實施例2-156LP]
N-[(R)-胺甲醯基-(4-甲基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：2.975
MS(ESI,m/z)：450.1395(M-H)-
1H-NMR(CDCl3)δ：1.39-1.88(1H,m),1.94-2.14(1H,m),2.35-2.41(3H,m),2.42-2.55(1H,m),2.61-3.13(4H,m),4.49-5.62(4H,m),6.84-7.02(1H,m),7.13-7.28(3H,m),7.34-7.82(4H,m),8.51-8.60(1H,m).
[實施例2-157LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-6-(2,2,2-三氟乙氧基)菸鹼醯胺；
RT(min.)：3.951
MS(ESI,m/z)：502.1156(M-H)-
1H-NMR(CDCl3)δ：1.65-2.20(2H,m),2.50-2.85(2H,m),4.55-4.90(3H,m),5.25-5.80(3H,m),6.92(1H,d,J=8.5Hz),7.05-7.15(1H,m),7.15-7.30(1H,m),7.30-7.55(5H,m),7.88(1H,dd,J-2.0,8.6Hz),7.97(1H,br s),8.37-8.45(1H,m).
[實施例2-158LP]
3-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]吡-2-甲醯胺；
RT(min.)：2.928
MS(ESI,m/z)：420.1241(M-H)-
1H-NMR(CDCl3)δ：1.70-1.95(1H,m),2.05-2.35(1H,m),2.50-2.90(2H,m),4.55-4.95(1H,m),5.30-5.95(5H,m),7.08(1H,d,J=8.0Hz),7.10-7.25(1H,m),7.30-7.55(5H,m),7.70-7.95(2H,m),7.95-8.15(1H,m).
[實施例2-159LP]
N-[(R)-胺甲醯基-(2-氟苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：2.815
MS(ESI,m/z)：454.1144(M-H)-
1H-NMR(CDCl3)δ：1.40-2.20(2H,m),2.40-3.20(5H,m),4.85-5.65(4H,m),6.80-8.10(8H,m),8.50-8.60(1H,m).
[實施例2-160LP]
N-[(R)-胺甲醯基-(2-三氟甲基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：3.031
MS(ESI,m/z)：504.1114(M-H)-
1H-NMR(CDCl3)δ：1.40-1.75(1H,m),1.80-2.10(1H,m),2.35-2.55(1H,m),2.55-2.85(4H,m),4.80-5.60(4H,m),6.90-7.05(1H,m),7.15-7.30(1H,m),7.50-7.90(5H,m),8.15-8.40(1H,m),8.50-8.70(1H,m).
[實施例2-161LP]
N-[(R)-胺甲醯基-(3-氟苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：2.836
MS(ESI,m/z)：454.1147(M-H)-
1H-NMR(CDCl3)δ：1.64-1.83(1H,m),2.00-2.15(1H,m),2.45-2.87(5H,m),4.53-4.74(1H,m),5.21(1H,t,J=8.7Hz),5.37-5.67(2H,m),6.86-7.82(8H,m),8.54-8.62(1H,m).
[實施例2-162LP]
N-[(R)-胺甲醯基-(4-氟苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：2.839
MS(ESI,m/z)：454.1147(M-H)-
1H-NMR(CDCl3)δ：1.40-1.85(1H,m),1.96-2.13(1H,m),2.44-3.16(5H,m),4.52-4.96(1H,m),5.16-5.66(3H,m),6.86-7.34(4H,m),7.46-7.81(4H,m),8.53-8.62(1H,m).
[實施例2-163LP]
N-[(R)-胺甲醯基-(3-甲氧基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：2.785
MS(ESI,m/z)：466.1347(M-H)-
1H-NMR(CDCl3)δ：1.68-1.88(1H,m),1.97-2.15(1H,m),2.42-3.16(5H,m),3.82(3H,s),4.50-4.99(1H,m),5.15-5.62(3H,m),6.77-7.40(6H,m),7.51-7.83(2H,m),8.53-8.61(1H,m).
[實施例2-164LP]
N-[(R)-胺甲醯基-(4-甲氧基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：2.760
MS(ESI,m/z)：466.1347(M-H)-
1H-NMR(CDCl3)δ：1.42-1.90(1H,m),1.94-2.11(1H,m),2.42-3.14(5H,m),3.84(3H,s),4.46-4.95(1H,m),5.13-5.60(3H,m),6.84-7.03(3H,m),7.14-7.81(5H,m),8.52-8.61(1H,m).
[實施例2-165LP]
N-[(R)-胺甲醯基-(3-三氟甲基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2- 甲基菸鹼醯胺；
RT(min.)：3.239
MS(ESI,m/z)：504.1115(M-H)-
1H-NMR(CDCl3)δ：1.61-1.75(1H,m),2.03-2.14(1H,m),2.46-2.58(1H,m),2.61-2.87(4H,m),4.65-4.83(1H,m),5.23(1H,t,J=8.7Hz),5.33-5.70(2H,m),6.99-7.05(1H,m),7.20-7.30(1H,m),7.48-7.94(6H,m),8.55-8.63(1H,m).
[實施例2-166LP]
N-[(R)-胺甲醯基-(4-三氟甲基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：3.298
MS(ESI,m/z)：504.1113(M-H)-
1H-NMR(CDCl3)δ：1.62-1.77(1H,m),2.03-2.15(1H,m),2.46-2.58(1H,m),2.61-3.15(4H,m),4.62-4.98(1H,m),5.15-5.73(3H,m),6.86-7.30(2H,m),7.41-7.83(6H,m),8.54-8.64(1H,m).
[實施例2-167LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-甲基異菸鹼醯胺；
RT(min.)：2.769
MS(ESI,m/z)：436.1235(M-H)-
1H-NMR(CDCl3)δ：1.67-1.84(1H,m),1.92-2.12(1H,m),2.35-3.12(5H,m),4.52-4.72(1H,m),5.09-5.62(3H,m),6.83-7.65(7H,m),7.69-7.87(1H,m),8.50-8.60(2H,m).
[實施例2-168LP]
N-[(R)-胺甲醯基-(3-羥基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：2.314
MS(ESI,m/z)：452.1191(M-H)-
1H-NMR(DMSO-d6)δ：1.36-1.57(1H,m),2.02-2.15(1H,m),2.35-2.69(4H,m),2.85-2.97(1H,m),4.93-5.30(2H,m),6.66-7.49(8H,m),7.57-7.86(2H,m),8.51-8.59(1H,m),9.65(1H,br).
[實施例2-169LP]
N-[(R)-胺甲醯基-(4-羥基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：2.212
MS(ESI,m/z)：452.1178(M-H)-
1H-NMR(DMSO-d6)δ：1.31-1.51(1H,m),1.98-2.10(1H,m),2.35-2.68(4H,m),2.84-2.95(1H,m),4.91-5.27(2H,m),6.75-6.86(2H,m),7.02-7.17(3H,m),7.25-7.90(5H,m),8.50-8.58(1H,m),9.68(1H,br).
[實施例2-170LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基呋呫-3-甲醯胺；
RT(min.)：3.830
MS(ESI,m/z)：427.0986(M-H)-
1H-NMR(CDCl3)δ：1.80-3.05(7H,m),5.06-5.87(4H,m),6.76-6.97(1H,m),7.40-7.55(5H,m),7.58-7.67(1H,m).
[實施例2-171LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-氰基菸鹼醯胺；
RT(min.)：3.372
MS(ESI,m/z)：447.1035(M-H)-
1H-NMR(CDCl3)δ：1.78-1.91(1H,m),2.12-2.33(1H,m),2.45-3.16(2H,m),4.50-5.64(4H,m),6.85-7.02(1H,m),7.36-7.66(6H,m),7.72-8.12(2H,m),8.72-8.81(1H,m).
[實施例2-172LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯并[1,3]二呃-4-甲醯胺；
RT(min.)：2.594
MS(ESI,m/z)：466.0982(M-H)-
1H-NMR(CDCl3)δ：1.79-1.99(1H,m),2.21-2.42(1H,m),2.58-2.71(1H,m),2.79-2.98(1H,m),4.65-4.82(1H,m),5.37-5.78(2H,m),5.98-6.36(3H,m),6.85-7.08(4H,m),7.31-7.39(1H,m),7.49-7.62(1H,m),7.82-7.97(1H,m),8.55-8.70(2H,m).
[實施例2-173LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯并[1,3]二呃-4-甲醯胺；
RT(min.)：3.674
MS(ESI,m/z)：465.1034(M-H)-
1H-NMR(CDCl3)δ：1.69-1.92(1H,m),2.10-2.31(1H,m),2.50-2.63(1H,m),2.71-2.89(1H,m),4.56-5.95(4H,m),5.98-6.12(2H,m),6.81-7.03(4H,m),7.29-7.80(6H,m).
[實施例2-174LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-5-甲氧基茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：0.838
MS(ESI,m/z)：415.1781(M-H)-
1H-NMR(CDCl3)δ：1.61-1.76(1H,m),2.01-2.14(1H,m),2.51-2.87(5H,m),3.80(3H,s),4.61-4.80(1H,m),5.14-5.83(3H,m),6.70-6.76(1H,m),6.84-6.91(1H,m),7.17-7.24(1H,m),7.32-8.22(4H,m),8.50-8.73(3H,m).
[實施例2-175LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-甲基吡-2-甲醯胺；
RT(min.)：3.170
MS(ESI,m/z)：437.1194(M-H)-
1H-NMR(CDCl3)δ：1.80-2.30(2H,m),2.40-2.55(1H,m),2.60-2.85(4H,m),5.10-5.25(1H,m),5.35-5.80(2H,m),6.85-7.00(1H,m),7.35-7.50(4H,m),7.50-7.60(2H,m),7.77(1H,s),8.30-8.60(2H,m).
[實施例2-176LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2,2-二甲基-2,3-二氫苯并呋喃-7-甲醯胺；
RT(min.)：4.092
MS(ESI,m/z)：491.1551(M-H)-
1H-NMR(CDCl3)δ：1.29-1.65(6H,m),1.76-1.94(1H,m),2.12-2.36(1H,m),2.47-2.66(1H,m),2.73-2.88(1H,m),2.94-3.14(2H,m),4.58-4.77(1H,m),5.24-6.33(3H,m),6.87-7.01(2H,m),7.17-7.23(1H,m),7.28-7.76(7H,m).
[實施例2-177LP]
3-[(R)-胺甲醯基-{[(R)-6-氯-4-氟茚-1-基]-(2-甲基吡啶-3-羰基)胺基}甲基]安息香酸甲酯；
RT(min.)：2.776
MS(ESI,m/z)：494.1296(M-H)-
1H-NMR(CDCl3)δ：1.60-1.78(1H,m),2.00-2.12(1H,m),2.43-2.56(1H,m),2.62-2.87(4H,m),3.94(3H,m),4.63-4.85(1H,m),5.26-5.76(3H,m),6.92-7.27(2H,m),7.43-7.92(4H,m),7.95-8.27(2H,m),8.54-8.64(1H,m).
[實施例2-177HP]
3-[(S)-胺甲醯基-{[(R)-6-氯-4-氟茚-1-基]-(2-甲基吡啶-3-羰基)胺基}甲基]安息香酸甲酯；
RT(min.)：2.513
MS(ESI,m/z)：494.1294(M-H)-
1H-NMR(CDCl3)δ：2.30-3.23(7H,m),3.93(3H,m),4.35-4.45(1H,m),5.06-5.76(3H,m),6.80-8.14(8H,m),8.60(1H,dd,J=1.6,5.0Hz).
[實施例2-178LP]
N-[(R)-胺甲醯基-(3-甲磺醯基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：2.342
MS(ESI,m/z)：514.1018(M-H)-
1H-NMR(CDCl3)δ：1.40-1.80(1H,m),2.05-2.25(1H,m),2.45-2.90(5H,m),3.10(3H,s),4.70-4.90(1H,m),5.25(1H,dd,J=8.5,8.5Hz),5.30-6.10(2H,m),6.99-7.06(1H,m),7.20-7.32(1H,m),7.53-8.22(6H,m),8.55-8.67(1H,m).
[實施例2-179LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]吡-2-甲醯胺；
RT(min.)：3.081
MS(ESI,m/z)：423.1028(M-H)-
1H-NMR(CDCl3)δ：1.85-2.30(2H,m),2.45-2.70(1H,m),2.70-3.15(1H,m),4.50-6.70(4H,m),6.80-7.05(1H,m),7.30-7.85(6H,m),8.40-9.20(3H,m).
[實施例2-180LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基菸鹼醯胺；
RT(min.)：2.219
MS(ESI,m/z)：453.1144(M-H)-
1H-NMR(CDCl3)δ：1.70-3.10(4H,m),3.97-4.10(3H,m),4.60-6.50(4H,m),6.95-8.75(9H,m).
[實施例2-181LP]
3-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]吡-2-甲醯胺；
RT(min.)：3.074
MS(ESI,m/z)：438.1146(M-H)-
1H-NMR(CDCl3)δ：1.70-2.35(2H,m),2.45-3.20(2H,m),4.50-6.00(6H,m),6.85-7.00(1H,m),7.35-7.55(6H,m),7.80-7.92(1H,m),7.95-8.13(1H,m).
[實施例2-182LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯并[b]噻吩-2-甲醯胺；
RT(min.)：4.158
MS(ESI,m/z)：477.0856(M-H)-
1H-NMR(CDCl3)δ：1.79-2.35(2H,m),2.54-3.06(2H,m),4.39-4.97(1H,m),5.26-6.33(3H,m),6.84-7.09(1H,m),7.32-7.54(7H,m),7.64(1H,s),7.77-7.91(3H,m).
[實施例2-183LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]萘-2-甲醯胺；
RT(min.)：4.087
MS(ESI,m/z)：471.1290(M-H)-
1H-NMR(CDCl3)δ：1.73-2.22(2H,m),2.35-2.87(2H,m),4.45-5.88(4H,m),6.83-7.04(1H,m),7.34-7.99(12H,m),8.05(1H,s).
[實施例2-184LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]喹啉-3-甲醯胺；
RT(min.)：3.463
MS(ESI,m/z)：472.1243(M-H)-
1H-NMR(CDCl3)δ：1.73-2.22(2H,m),2.37-3.17(2H,m),4.50-5.89(4H,m),6.80-7.09(1H,m),7.35-7.69(6H,m),7.75-7.98(3H,m),8.14(1H,d,J=8.6Hz),8.37(1H,s),9.09(1H,s).
[實施例2-185LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]異喹啉-4-甲醯胺；
RT(min.)：3.206
MS(ESI,m/z)：472.1239(M-H)-
1H-NMR(CDCl3)δ：1.73-1.82(1H,m),2.10-2.18(1H,m),2.38-2.48(1H,m),2.69-2.76(1H,m),4.70(1H,br),5.50(2H,br),5.23-5.27(1H,m),6.93-6.96(1H,m),7.43-7.75(7H,m),7.93-8.04(2H,m),8.52-8.57(2H,m),9.31(1H,br).
[實施例2-186LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]萘-1-甲醯胺；
RT(min.)：4.078
MS(ESI,m/z)：471.1294(M-H)-
1H-NMR(CDCl3)δ：1.67-1.75(1H,m),2.00-2.08(1H,m),2.28-2.41(1H,m),2.28-2.41(1H,m),2.64-2.70(1H,m),4.67(1H,br),5.19-5.28(2H,m),6.90-6.92(1H,m),7.34-7.92(12H,m),8.48-8.51(1H,m).
[實施例2-187LP]
4-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]噻唑-5-甲醯胺；
RT(min.)：3.131
MS(ESI,m/z)：443.0761(M-H)-
1H-NMR(CDCl3)δ：1.82-3.08(4H,m),4.45-6.40(6H,m),6.94-7.05(1H,m),7.30-7.56(5H,m),7.64(1H,s),8.56(1H,s).
[實施例2-187HP]
4-胺基-N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]噻唑-5-甲醯胺；
RT(min.)：3.009
MS(ESI,m/z)：443.0759(M-H)-
1H-NMR(CDCl3)δ：2.67-2.97(3H,m),3.12-3.27(1H,m),4.33-4.60(1H,m),5.34-5.56(1H,br),5.92-6.23(3H,m),6.39-6.56(1H,br),6.87(1H,dd,J=1.5,8.6Hz),7.24-7.45(6H,m),8.58(1H,s).
[實施例2-188LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基-3-甲基苯甲醯胺；
RT(min.)：3.939
MS(ESI,m/z)：465.1397(M-H)-
1H-NMR(CDCl3)δ：1.63-3.18(7H,m),3.69-4.01(3H,m),4.55-5.96(4H,m),6.80-7.89(10H,m).
[實施例2-189LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-5-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：0.979
MS(ESI,m/z)：403.1590(M-H)-
1H-NMR(CDCl3)δ：1.62-1.80(1H,m),2.01-2.16(1H,m),2.54-2.88(5H,m),4.56-4.83(1H,m),5.17-5.89(3H,m),6.86-6.94(1H,m),6.98-7.07(1H,m),7.18-7.24(1H,m),7.32-8.23(4H,m),8.50-8.74(3H,m).
[實施例2-190LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-5-氟茚-1-基]-4-甲基噻唑-5-甲醯胺；
RT(min.)：1.527
MS(ESI,m/z)：409.1151(M-H)-
1H-NMR(CDCl3)δ：1.68-1.83(1H,m),2.10-2.27(1H,m),2.60-2.89(5H,m),4.59-4.85(1H,m),5.24-5.79(3H,m),6.89-6.94(1H,m),6.99-7.06(1H,m),7.35-7.40(1H,m),7.75-7.81(1H,m),7.94-8.00(1H,m),8.61(1H,d,J=2.3Hz),8.64(1H,dd,J=1.5,4.8Hz),8.78(1H,s).
[實施例2-191LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-5-氟茚-1-基]苯甲醯胺；
RT(min.)：2.057
MS(ESI,m/z)：388.1475(M-H)-
1H-NMR(CDCl3)δ：1.74-1.90(1H,m),2.11-2.28(1H,m),2.60-2.89(2H,m),4.62-4.82(1H,m),5.21-6.25(3H,m),6.85-6.94(1H,m),6.96-7.07(1H,m),7.32-7.39(1H,m),7.41-7.50(3H,m),7.53-7.61(2H,m),7.77-7.84(1H,m),7.91-8.00(1H,m),8.61(1H,dd,J=1.6,4.8Hz),8.65(1H,d,J=2.3Hz).
[實施例2-192LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氰基茚-1-基]苯甲醯胺；
RT(min.)：1.908
MS(ESI,m/z)：395.1525(M-H)-
1H-NMR(CDCl3)δ：1.67-1.78(1H,m),1.84-1.94(1H,m),2.20-2.28(1H,m),2.86-2.95(1H,m),4.66(1H,br),5.43-6.11(3H,m),7.34-7.55(8H,m),8.17(1H,s),8.62(3H,br).
[實施例2-192HP]
N-[(S)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氰基茚-1-基]苯甲醯胺；
RT(min.)：1.749
MS(ESI,m/z)：395.1524(M-H)-
1H-NMR(CDCl3)δ：2.51-2.60(1H,m),2.68-2.77(1H,m),2.85-2.93(1H,m),3.18-3.26(1H,m),4.33-4.41(1H,m),5.53-5.74(3H,m),6.89(1H,br),7.31-7.57(8H,m),7.91-7.93(1H,m),8.21(1H,br),8.61-8.62(1H,m).
[實施例2-193LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氟茚-1-基]苯甲醯胺；
RT(min.)：2.078
MS(ESI,m/z)：388.1474(M-H)-
1H-NMR(CDCl3)δ：1.78-1.92(1H,m),2.13-2.27(1H,m),2.56-2.68(1H,m),2.71-2.89(1H),4.63-4.80(1H,m),5.26-6.25(3H,m),6.92-7.03(1H,m),7.09-7.17(1H,m),7.32-7.37(1H,m),7.42-7.50(3H,m),7.53-7.62(3H,m),7.91-8.02(1H,m),8.59-8.68(2H,m).
[實施例2-193HP]
N-[(S)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氟茚-1-基]苯甲醯胺；
RT(min.)：1.895
MS(ESI,m/z)：388.1473(M-H)-
1H-NMR(CDCl3)δ：2.43-2.54(1H,m),2.62-2.83(2H,m),3.05-3.16(1H,m),4.41-4.57(1H,m),5.35-5.73(2H,m),5.83-6.18(1H,m),6.35-6.53(1H,m),6.85-6.91(1H,m),7.13-7.19(1H,m),7.25-7.31(1H,m),7.44-7.50(3H,m),7.52-7.59(2H,m),7.87-7.93(1H,m),8.30(1H,s),8.53-8.58(1H,m).
[實施例2-194LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氟茚-1-基]菸鹼醯胺；
RT(min.)：1.139
MS(ESI,m/z)：389.1429(M-H)-
1H-NMR(CDCl3)δ：1.75-1.88(1H,m),2.09-2.23(1H,m),2.56-2.86(2H,m),4.64-4.94(1H,m),5.28-5.95(3H,m),6.93-7.04(1H,m),7.09-7.19(1H,m),7.34-7.44(2H,m),7.58-7.68(1H,m),7.84-8.07(2H,m),8.60-8.73(3H,m),8.83(1H,s).
[實施例2-195LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：0.987
MS(ESI,m/z)：403.1586(M-H)-
1H-NMR(CDCl3)δ：1.66-1.81(1H,m),2.04-2.14(1H,m),2.52-2.85(5H,m),4.56-4.83(1H,m),5.07-5.90(3H,m),6.93-7.04(1H,m),7.10-7.25(2H,m),7.32-8.25(4H,m),8.50-8.75(3H,m).
[實施例2-196LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氟茚-1-基]-4-甲基噻唑-5-甲醯胺；
RT(min.)：1.539
MS(ESI,m/z)：409.1147(M-H)-
1H-NMR(CDCl3)δ：1.73-1.83(1H,m),2.08-2.27(1H,m),2.60-2.85(5H,m),4.57-4.95(1H,m),5.24-5.86(3H,m),6.95-7.04(1H,m),7.12-7.19(1H,m),7.34-7.40(1H,m),7.53-7.60(1H,m),7.90-8.04(1H,m),8.61(1H,d,J=2.2Hz),8.64(1H,dd,J=1.3,4.8Hz),8.78(1H,s).
[實施例2-197LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氰基茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：0.834
MS(ESI,m/z)：410.1634(M-H)-
1H-NMR(CDCl3)δ：1.71-1.80(1H,m),2.09-2.16(1H,m),2.65-2.86(5H,m),4.59-4.70(1H,m),5.26(1H,t,J=8.6Hz),5.37-5.79(2H,m),7.21-7.80,(5H,m),8.00-8.25(2H,m),8.59-8.67(3H,m).
[實施例2-198LP]
N-[(R)-胺甲醯基-(2-甲基吡啶-3-基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺；
RT(min.)：2.367
MS(ESI,m/z)：436.1249(M-H)-
1H-NMR(CDCl3)δ：1.00-3.22(7H,m),4.65-5.78(4H,m),6.75-8.16(9H,m),8.49-8.61(1H,m).
[實施例2-199LP]
N-[(R)-胺甲醯基-(2-甲基吡啶-3-基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：1.566
MS(ESI,m/z)：451.1357(M-H)-
1H-NMR(CDCl3)δ：1.38-1.62(1H,m),1.93-2.08(1H,m),2.24-2.88(8H,m),4.76-5.06(1H,m),5.14-5.62(3H,m),6.96-7.07(1H,m),7.17-7.34(2H,m),7.48-7.88(2H,m),8.02-8.29(1H,m),8.51-8.66(2H,m).
[實施例2-200LP]
N-[(R)-胺甲醯基-(6-甲基吡啶-3-基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺；
RT(min.)：2.317
MS(ESI,m/z)：436.1246(M-H)-
1H-NMR(CDCl3)δ：1.75-1.99(1H,m),2.06-2.30(1H,m),2.40-2.96(5H,m),4.53-4.82(1H,m),5.21-6.07(3H,m),6.88-7.24(2H,m),7.39-7.60(5H,m),7.64-7.93(2H,m),8.39-8.60(1H,m).
[實施例2-201LP]
N-[(R)-胺甲醯基-(6-甲基吡啶-3-基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺；
RT(min.)：1.643
MS(ESI,m/z)：437.1196(M-H)-
1H-NMR(CDCl3)δ：1.75-1.93(1H,m),2.05-2.23(1H,m),2.48-2.93(5H,m),4.53-4.93(1H,m),5.28-5.81(3H,m),6.91-7.08(1H,m),7.23(1H,d,J=8.1Hz),7.35-7.44(1H,m),7.68-7.96(3H,m),8.44-8.56(1H,m),8.66-8.74(1H,m),8.76-8.83(1H,m).
[實施例2-202LP]
N-[(R)-胺甲醯基-(6-甲基吡啶-3-基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：1.545
MS(ESI,m/z)：451.1353(M-H)-
1H-NMR(CDCl3)δ：1.66-1.86(1H,m),2.00-2.17(1H,m),2.44-2.89(8H,m),4.52-4.78(1H,m),5.14-5.71(3H,m),6.96-7.07(1H,m),7.13-7.31(2H,m),7.43-8.08(3H,m),8.41-8.66(2H,m).
[實施例2-203LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：1.378
MS(ESI,m/z)：419.1290(M-H)-
1H-NMR(CDCl3)δ：1.62-1.81(1H,m),2.00-2.14(1H,m),2.50-2.87(5H,m),4.60-4.80(1H,m),5.17-5.76(3H,m),7.09-7.16(1H,m),7.17-8.23(6H,m),8.51-8.74(3H,m).
[實施例2-204LP]
N-[(R)-胺甲醯基嗒-4-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基苯甲醯胺；
RT(min.)：2.708
MS(ESI,m/z)：453.1148(M-H)-
1H-NMR(CDCl3)δ：1.50-3.02(4H,m),3.89-4.07(3H,m),4.61-4.74(1H,m),5.32-5.82(3H,m),6.96-7.72(7H,m),9.17-9.23(2H,m).
[實施例2-205LP]
N-[(R)-胺甲醯基嗒-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基苯甲醯胺；
RT(min.)：2.807
MS(ESI,m/z)：453.1147(M-H)-
1H-NMR(CDCl3)δ：1.49-3.31(4H,m),3.93-3.99(3H,m),4.93-5.05(1H,m),5.24-5.82(2H,m),6.93-7.72(8H,m),7.94-8.14(1H,m),9.08-9.17(1H,m).
[實施例2-206LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-5-氯茚-1-基]苯甲醯胺；
RT(min.)：2.349
MS(ESI,m/z)：404.1182(M-H)-
1H-NMR(CDCl3)δ：1.71-1.87(1H,m),2.06-2.26(1H,m),2.58-2.88(2H,m),4.60-4.79(1H,m),5.27-6.20(3H,m),7.17-7.21(1H,m),7.25-7.40(2H,m),7.40-7.50(3H,m),7.52-7.62(2H,m),7.81(1H,d,J=8.0Hz),7.91-8.02(1H,m),8.58-8.68(2H,m).
[實施例2-207LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-5-氯茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：1.496
MS(ESI,m/z)：419.1294(M-H)-
1H-NMR(CDCl3)δ：1.61-1.80(1H,m),2.00-2.16(1H,m),2.50-2.88(5H,m),4.56-4.77(1H,m),5.15-5.77(3H,m),7.13-7.34(3H,m),7.34-8.20(4H,m),8.52-8.73(3H,m).
[實施例2-208LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-5-氯茚-1-基]-4-甲基噻唑-5-甲醯胺；
RT(min.)：1.901
MS(ESI,m/z)：425.0856(M-H)-
1H-NMR(CDCl3)δ：1.66-1.81(1H,m),2.02-2.23(1H,m),2.60-2.89(5H,m),4.54-4.86(1H,m),5.31-5.75(3H,m),7.18-7.23(1H,m),7.28-7.33(1H,m),7.35-7.40(1H,m),7.75-7.81(1H,m),7.92-8.00(1H,m),8.59-8.67(2H,m),8.78(1H,s).
[實施例2-209LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯茚-1-基]菸鹼醯胺；
RT(min.)：1.490
MS(ESI,m/z)：405.1134(M-H)-
1H-NMR(CDCl3)δ：1.67-2.26(2H,m),2.54-2.98(2H,m),4.64-4.92(1H,m),5.28-6.05(3H,m),7.09-7.15(1H,m),7.18-7.44(3H,m),7.85-8.05(3H,m),8.61-8.67(2H,m),8.71(1H,dd,J=1.6,5.0Hz),8.81-8.86(1H,m).
[實施例2-210LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯茚-1-基]-4-甲基噻唑-5-甲醯胺；
RT(min.)：1.819
MS(ESI,m/z)：425.0851(M-H)-
1H-NMR(CDCl3)δ：1.71-1.84(1H,m),2.07-2.27(1H,m),2.57-2.87(5H,m),4.57-4.95(1H,m),5.31-5.81(3H,m),7.10-7.17(1H,m),7.23-7.30(1H,m),7.34-7.40(1H,m),7.82(1H,s),7.90-8.00(1H,m),8.61(1H,d,J=2.3Hz),8.64(1H,dd,J=1.5,4.8Hz),8.78(1H,s).
[實施例2-211LP]
N-[(R)-胺甲醯基嘧啶-5-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基苯甲醯胺；
RT(min.)：2.770
MS(ESI,m/z)：453.1147(M-H)-
1H-NMR(CDCl3)δ：1.58-3.00(4H,m),3.92-4.04(3H,m),4.64-4.79(1H,m),5.04-6.00(3H,m),6.96-7.56(6H,m),8.82-8.95(2H,m),9.16-9.24(1H,m).
[實施例2-212LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-甲氧基茚-1-基]苯甲醯胺；
RT(min.)：2.046
MS(ESI,m/z)：400.1679(M-H)-
1H-NMR(CDCl3)δ：1.70-1.84(1H,m),2.06-2.22(1H,m),2.52-2.80(2H,m),3.88(3H,s),4.67-4.82(1H,m),5.28-6.20(3H,m),6.85(1H,dd,J=2.3,8.3Hz),7.10(1H,d,J=8.3Hz),7.32-7.37(1H,m),7.41-7.51(4H,m),7.55-7.64(2H,m),7.92-8.04(1H,m),8.60(1H,dd,J=1.5,4.8Hz),8.65(1H,d,J=2.3Hz).
[實施例2-213LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-甲氧基茚-1-基]菸鹼醯胺；
RT(min.)：1.154
MS(ESI,m/z)：401.1633(M-H)-
1H-NMR(CDCl3)δ：1.67-1.82(1H,m),2.05-2.18(1H,m),2.53-2.79(2H,m),3.88(3H,s),4.72-4.87(1H,m),5.28-5.83(3H,m),6.83-6.90(1H,m),7.07-7.14(1H,m),7.34-7.44(2H,m),7.50-7.56(1H,m),7.88-8.05(2H,m),8.61-8.73(3H,m),8.84-8.89(1H,m).
[實施例2-214LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-甲氧基茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：1.017
MS(ESI,m/z)：415.1790(M-H)-
1H-NMR(CDCl3)δ：1.61-1.77(1H,m),1.99-2.11(1H,m),2.47-2.89(5H,m),3.80-3.94(3H,m),4.64-4.83(1H,m),5.15-5.85(3H,m),6.81-6.89(1H,m),7.04-7.14(1H,m),7.18-7.24(1H,m),7.32-8.23(4H,m),8.50-8.72(3H,m).
[實施例2-215LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-甲氧基茚-1-基]-4-甲基噻唑-5-甲醯胺；
RT(min.)：1.517
MS(ESI,m/z)：421.1352(M-H)-
1H-NMR(CDCl3)δ：1.64-1.79(1H,m),2.07-2.22(1H,m),2.55-2.81(5H,m),3.86(3H,s),4.68-4.83(1H,m),5.32-5.70(3H,m),6.84-6.89(1H,m),7.08-7.14(1H,m),7.33-7.40(1H,m),7.43-7.48(1H,m),7.93-8.03(1H,m),8.60-8.65(2H,m),8.77(1H,s).
[實施例2-216LP]
N-[(R)-胺甲醯基吡-2-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基苯甲醯胺；
RT(min.)：2.973
MS(ESI,m/z)：453.1152(M-H)-
1H-NMR(CDCl3)δ：1.78-3.09(4H,m),3.92-4.04(3H,m),4.72-4.80(1H,m),5.20-5.80(2H,m),6.92-7.64(7H,m),8.48-8.58(2H,m),8.90-9.13(1H,m).
[實施例2-217LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4-氯茚-1-基]苯甲醯胺；
RT(min.)：2.344
MS(ESI,m/z)：404.1180(M-H)-
1H-NMR(CDCl3)δ：1.69-1.89(1H,m),2.08-2.27(1H,m),2.56-2.99(2H,m),4.60-4.80(1H,m),5.20-6.21(3H,m),7.22-7.33(2H,m),7.33-7.40(1H,m),7.41-7.50(3H,m),7.53-7.62(2H,m),7.73-7.83(1H,m),7.87-8.01(1H,m),8.62(1H,dd,J=1.4,4.8Hz),8.64-8.68(1H,m).
[實施例2-218LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氟茚-1-基]苯甲醯胺；
RT(min.)：4.044
MS(ESI,m/z)：387.1521(M-H)-
1H-NMR(CDCl3)δ：1.70-1.90(1H,m),1.95-2.20(1H,m),2.45-2.80(2H,m),4.67(1H,br s),5.15-6.00(3H,m),6.85-7.20(2H,m),7.30-7.80(11H,m).
[實施例2-218HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-氟茚-1-基]苯甲醯胺；
RT(min.)：3.879
MS(ESI,m/z)：387.1516(M-H)-
1H-NMR(CDCl3)δ：2.35-2.55(1H,m),2.60-2.85(2H,m),2.95-3.15(1H,m),4.46(1H,br s),5.30-5.65(2H,m),5.70-6.05(1H,m),6.25-6.45(1H,m),6.75-6.90(1H,m),7.10(1H,dd,J=5.1,8.1Hz),7.25-7.35(5H,m),7.40-7.50(3H,m),7.50-7.60(2H,m).
[實施例2-219LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟茚-1-基]苯甲醯胺；
RT(min.)：4.008
MS(ESI,m/z)：387.1520(M-H)-
1H-NMR(CDCl3)δ：1.65-1.90(1H,m),2.00-2.20(1H,m),2.45-2.65(1H,m),2.70-2.95(1H,m),4.66(1H,br s),5.20-5.95(3H,m),6.85-7.05(1H,m),7.25-7.65(11H,m),7.70-7.85(1H,m).
[實施例2-219HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-4-氟茚-1-基]苯甲醯胺；
RT(min.)：3.946
MS(ESI,m/z)：387.1517(M-H)-
1H-NMR(CDCl3)δ：2.35-2.55(1H,m),2.60-2.85(2H,m),3.05-3.25(1H,m),4.47(1H,br s),5.25-6.10(3H,m),6.40-6.65(1H,m),6.75-6.85(2H,m),7.20-7.35(5H,m),7.40-7.50(3H,m),7.50-7.65(2H,m).
[實施例2-220LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-5-氟茚-1-基]苯甲醯胺；
RT(min.)：4.027
MS(ESI,m/z)：387.1521(M-H)-
1H-NMR(CDCl3)δ：1.65-1.90(1H,m),2.00-2.20(1H,m),2.50-2.85(2H,m),4.65(1H,br s),5.20-5.95(3H,m),6.80-6.90(1H,m),6.95-7.10(1H,m),7.30-7.55(8H,m),7.55-7.65(2H,m),7.85-7.95(1H,m).
[實施例2-220HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-5-氟茚-1-基]苯甲醯胺；
RT(min.)：3.932
MS(ESI,m/z)：387.1517(M-H)-
1H-NMR(CDCl3)δ：2.35-2.55(1H,m),2.60-2.85(2H,m),3.00-3.20(1H,m),4.44(1H,br s),5.35-5.65(2H,m),5.75-6.00(1H,m),6.45-6.55(1H,m),6.55-6.70(1H,m),6.86(1H,dd,J=2.0,8.8Hz),7.25-7.35(5H,m),7.40-7.50(3H,m),7.50-7.60(2H,m).
[實施例2-221LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]苯甲醯胺；
RT(min.)：4.171
MS(ESI,m/z)：405.1424(M-H)-
1H-NMR(CDCl3)δ：1.65-1.90(1H,m),1.90-2.20(1H,m),2.40-2.65(1H,m),2.65-2.90(1H,m),4.66(1H,br s),5.20-5.85(3H,m),6.60-6.80(1H,m),7.30-7.65(11H,m).
[實施例2-221HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]苯甲醯胺；
RT(min.)：4.022
MS(ESI,m/z)：405.1426(M-H)-
1H-NMR(CDCl3)δ：2.35-2.65(1H,m),2.65-2.85(2H,m),2.95-3.20(1H,m),4.45(1H,br s),5.30-6.00(3H,m),6.05-6.25(1H,m),6.45-6.65(1H,m),7.25-7.40(5H,m),7.40-7.60(5H,m).
[實施例2-222LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2,6-二甲基菸鹼醯胺；
RT(min.)：2.439
MS(ESI,m/z)：450.1406(M-H)-
1H-NMR(CDCl3)δ：1H-NMR(CDCl3)δ ppm：1.34-1.85(1H,m),1.95-2.11(1H,m),2.41-3.13(8H,m),4.52-5.00(1H,m),5.17-5.61(3H,m),6.83-7.84(9H,m).
[實施例2-223LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4-氯茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：1.514
MS(ESI,m/z)：419.1298(M-H)-
1H-NMR(CDCl3)δ：1.61-1.81(1H,m),2.02-2.16(1H,m),2.53-2.95(5H,m),4.60-4.83(1H,m),5.22-5.89(3H,m),7.15-7.24(1H,m),7.24-8.20(6H,m),8.52-8.75(3H,m).
[實施例2-224LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4-氯茚-1-基]-4-甲基噻唑-5-甲醯胺；
RT(min.)：1.911
MS(ESI,m/z)：425.0858(M-H)-
1H-NMR(CDCl3)δ：1.65-1.81(1H,m),2.07-2.25(1H,m),2.59-2.98(5H,m),4.56-4.91(1H,m),5.27-5.80(3H,m),7.25-7.33(2H,m),7.34-7.42(1H,m),7.72-7.80(1H,m),7.91-8.00(1H,m),8.60-8.69(2H,m),8.77(1H,s).
[實施例2-225LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4-氟茚-1-基]苯甲醯胺；
RT(min.)：2.070
MS(ESI,m/z)：388.1485(M-H)-
1H-NMR(CDCl3)δ：1.74-1.92(1H,m),2.11-2.28(1H,m),2.54-2.70(1H,m),2.85-3.00(1H,m),4.64-4.82(1H,m),5.21-6.20(3H,m),6.94-7.02(1H,m),7.25-7.39(2H,m),7.41-7.50(3H,m),7.53-7.70(3H,m),7.87-8.01(1H,m),8.58-8.70(2H,m).
[實施例2-226LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4-氟茚-1-基]菸鹼醯胺；
RT(min.)：1.207
MS(ESI,m/z)：389.1432(M-H)-
1H-NMR(CDCl3)δ：1.70-1.87(1H,m),2.07-2.25(1H,m),2.56-2.98(2H,m),4.65-4.87(1H,m),5.28-5.93(3H,m),6.96-7.04(1H,m),7.29-7.45(3H,m),7.66-7.76(1H,m),7.85-8.05(2H,m),8.62-8.74(3H,m),8.82-8.89(1H,m).
[實施例2-227LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4-氟茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：1.052
MS(ESI,m/z)：403.1592(M-H)-
1H-NMR(CDCl3)δ：1.63-1.82(1H,m),2.01-2.17(1H,m),2.52-2.96(5H,m),4.60-4.80(1H,m),5.20-5.85(3H,m),6.95-7.04(1H,m),7.17-7.24(1H,m),7.29-8.20(5H,m),8.52-8.76(3H,m).
[實施例2-228LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4-氟茚-1-基]-4-甲基噻唑-5-甲醯胺；
RT(min.)：1.577
MS(ESI,m/z)：409.1155(M-H)-
1H-NMR(CDCl3)δ：1.68-1.84(1H,m),2.09-2.27(1H,m),2.60-2.74(4H,m),2.84-2.99(1H,m),4.62-4.85(1H,m),5.32-5.79(3H,m),6.95-7.04(1H,m),7.27-7.42(2H,m),7.63(1H,d,J=7.7Hz),7.92-8.01(1H,m),8.60-8.67(2H,m),8.78(1H,s).
[實施例2-229LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-7-氟茚-1-基]苯甲醯胺；
RT(min.)：1.868
MS(ESI,m/z)：388.1492(M-H)-
1H-NMR(CDCl3)δ：2.08-2.23(1H,m),2.38-2.63(1H,m),2.79-3.21(2H,m),4.50-4.82(1H,m),5.21-6.00(3H,m),6.87-6.97(1H,m),7.01-7.09(1H,m),7.24-7.37(2H,m),7.43-7.63(5H,m),7.79-7.91(1H,m),8.52-8.58(1H,m),8.60-8.67(1H,m).
[實施例2-230LP]
N-[(R)-胺甲醯基吡啶-2-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基噻唑-5-甲醯胺；
RT(min.)：2.698
MS(ESI,m/z)：443.0770(M-H)-
1H-NMR(CDCl3)δ：1.90-2.45(2H,m),2.55-3.00(5H,m),4.60-5.10(1H,m),5.35-5.75(2H,m),6.90-7.05(1H,m),7.20-7.85(5H,m),8.50-8.65(1H,m),8.78(1H,s).
[實施例2-231LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-5-甲氧基茚-1-基]-4-甲基噻唑-5-甲醯胺；
RT(min.)：1.394
MS(ESI,m/z)：421.1347(M-H)-
1H-NMR(CDCl3)δ：1.65-1.79(1H,m),2.11-2.24(1H,m),2.59-2.85(5H,m),3.81(3H,s),4.67-4.80(1H,m),5.21-5.84(3H,m),6.73-6.78(1H,m),6.85-6.91(1H,m),7.33-7.40(1H,m),7.67(1H,d,J=8.6Hz),7.94-8.00(1H,m),8.58-8.65(2H,m),8.77(1H,s).
[實施例2-232LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-7-氯茚-1-基]苯甲醯胺；
RT(min.)：2.034
MS(ESI,m/z)：404.1175(M-H)-
1H-NMR(CDCl3)δ：2.28-2.40(1H,m),2.55-2.72(1H,m),2.92-3.04(1H,m),3.20-3.33(1H,m),4.49-4.61(1H,m),5.08-5.88(2H,m),7.17-7.34(4H,m),7.43-7.68(6H,m),7.79-7.88(1H,m),8.50-8.55(1H,m),8.64-8.70(1H,m).
[實施例2-233LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4-甲基茚-1-基]苯甲醯胺；
RT(min.)：2.163
MS(ESI,m/z)：384.1723(M-H)-
1H-NMR(CDCl3)δ：1.71-1.89(1H,m),2.12-2.31(4H,m),2.47-2.86(2H,m),4.65-4.83(1H,m),5.26-6.48(3H,m),7.08-7.15(1H,m),7.20-7.30(1H,m),7.31-7.38(1H,m),7.40-7.50(3H,m),7.54-7.68(3H,m),7.92-8.00(1H,m),8.60(1H,dd,J=1.5,4.9Hz),8.65(1H,d,J=2.3Hz).
[實施例2-234LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4-甲基茚-1-基]菸鹼醯胺；
RT(min.)：1.303
MS(ESI,m/z)：385.1676(M-H)-
1H-NMR(CDCl3)δ：1.70-1.84(1H,m),2.07-2.28(4H,m),2.47-2.83(2H,m),4.71-4.89(1H,m),5.25-6.03(3H,m),7.10-7.16(1H,m),7.23-7.30(1H,m),7.34-7.42(2H,m),7.65-7.74(1H,m),7.85-8.05(2H,m),8.60-8.74(3H,m),8.82-8.89(1H,m).
[實施例2-235LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-2-甲基-N-[(R)-4-甲基茚-1-基]菸鹼醯胺；
RT(min.)：1.128
MS(ESI,m/z)：399.1831(M-H)-
1H-NMR(CDCl3)δ：1.62-1.77(1H,m),2.00-2.15(1H,m),2.22(3H,s),2.44-2.97(5H,m),4.63-4.87(1H,m),5.19-5.94(3H,m),7.09-8.23(7H,m),8.50-8.75(3H,m).
[實施例2-236LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4-甲基茚-1-基]-4-甲基噻唑-5-甲醯胺；
RT(min.)：1.654
MS(ESI,m/z)：405.1397(M-H)-
1H-NMR(CDCl3)δ：1.67-1.80(1H,m),2.11-2.30(4H,m),2.51-2.83(5H,m),4.69-4.83(1H,m),5.28-5.93(3H,m),7.10-7.16(1H,m),7.22-7.29(1H,m),7.33-7.39(1H,m),7.59-7.65(1H,m),7.94-8.00(1H,m),8.57-8.65(2H,m),8.76(1H,s).
[實施例2-237LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-5-甲基茚-1-基]苯甲醯胺；
RT(min.)：2.198
MS(ESI,m/z)：384.1725(M-H)-
1H-NMR(CDCl3)δ：1.71-1.87(1H,m),2.08-2.25(1H,m),2.35(3H,s),2.57-2.86(2H,m),4.64-4.80(1H,m),5.17-6.47(3H,m),7.00-7.07(1H,m),7.10-7.17(1H,m),7.30-7.37(1H,m),7.40-7.49(3H,m),7.54-7.63(2H,m),7.65-7.72(1H,m),7.92-8.00(1H,m),8.56-8.68(2H,m).
[實施例2-238LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-2-甲基-N-[(R)-5-甲基茚-1-基]菸鹼醯胺；
RT(min.)：1.207
MS(ESI,m/z)：399.1832(M-H)-
1H-NMR(CDCl3)δ：1.60-1.74(1H,m),2.00-2.12(1H,m),2.35(3H,s),2.52-2.86(5H,m),4.59-4.82(1H,m),5.16-5.89(3H,m),7.03(1H,s),7.10-7.18(1H,m),7.18-7.23(1H,m),7.32-7.43(1H,m),7.50-7.87(2H,m),7.95-8.20(1H,m),8.50-8.72(3H,m).
[實施例2-239LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-5-甲基茚-1-基]-4-甲基噻唑-5-甲醯胺；
RT(min.)：1.695
MS(ESI,m/z)：405.1396(M-H)-
1H-NMR(CDCl3)δ：1.65-1.78(1H,m),2.09-2.22(1H,m),2.36(3H,),2.60-2.83(5H,m),4.67-4.81(1H,m),5.27-5.91(3H,m),7.05(1H,s),7.12-7.17(1H,m),7.33-7.39(1H,m),7.66(1H,d,J=7.9Hz),7.94-8.00(1H,m),8.58-8.61(1H,m),8.62(1H,dd,J=1.5,4.8Hz),8.77(1H,s).
[實施例2-240LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-甲基茚-1-基]苯甲醯胺；
RT(min.)：2.168
MS(ESI,m/z)：384.1725(M-H)-
1H-NMR(CDCl3)δ：1.72-1.87(1H,m),2.07-2.23(1H,m),2.42(3H,s),2.55-2.84(2H,m),4.66-4.78(1H,m),5.28-6.30(3H,m),7.06-7.14(2H,m),7.31-7.36(1H,m),7.42-7.50(3H,m),7.55-7.65(3H,m),7.90-8.00(1H,m),8.59(1H,dd,J=1.6,5.0Hz),8.64(1H,d,J=2.3Hz).
[實施例2-241LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-甲基茚-1-基]菸鹼醯胺；
RT(min.)：1.328
MS(ESI,m/z)：385.1678(M-H)-
1H-NMR(CDCl3)δ：1.67-1.82(1H,m),2.06-2.18(1H,m),2.42(3H,s),2.53-2.83(2H,m),4.70-4.85(1H,m),5.28-5.95(3H,m),7.06-7.16(2H,m),7.33-7.44(2H,m),7.64-7.70(1H,m),7.88-8.04(2H,m),8.60-8.75(3H,m),8.84-8.91(1H,m).
[實施例2-242LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-2-甲基-N-[(R)-6-甲基茚-1-基]菸鹼醯胺；
RT(min.)：1.141
MS(ESI,m/z)：399.1833(M-H)-
1H-NMR(CDCl3)δ：1.60-1.75(1H,m),1.98-2.12(1H,m),2.41(3H,s),2.50-2.90(5H,m),4.62-4.80(1H,m),5.15-5.87(3H,m),7.05-7.15(2H,m),7.17-7.24(1H,m),7.32-8.22(4H,m),8.50-8.74(3H,m).
[實施例2-243LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-甲基茚-1-基]-4-甲基噻唑-5-甲醯胺；
RT(min.)：1.648
MS(ESI,m/z)：405.1398(M-H)-
1H-NMR(CDCl3)δ：1.66-1.78(1H,m),2.09-2.21(1H,m),2.41(3H,s),2.59-2.82(5H,m),4.67-4.81(1H,m),5.27-5.86(3H,m),7.08-7.15(2H,m),7.33-7.39(1H,m),7.55-7.60(1H,m),7.94-8.00(1H,m),8.58-8.64(2H,m),8.77(1H,s).
[實施例2-244LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4-氟-6-甲基茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：1.471
MS(ESI,m/z)：417.1740(M-H)-
1H-NMR(CDCl3)δ：1.61-1.78(1H,m),2.03-2.13(1H,m),2.33-2.88(8H,m),4.63-4.81(1H,m),5.14-5.84(3H,m),6.81(1H,d,J=9.9Hz),7.18-7.24(1H,m),7.32-8.23(4H,m),8.52-8.76(3H,m).
[實施例2-245LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4-氟-6-甲氧基茚-1-基]-2-甲基菸鹼醯胺；
RT(min.)：1.445
MS(ESI,m/z)：433.1691(M-H)-
1H-NMR(CDCl3)δ：1.61-1.77(1H,m),2.00-2.13(1H,m),2.43-2.87(5H,m),3.78-3.93(3H,m),4.63-4.83(1H,m),5.14-5.75(3H,m),6.56(1H,dd,J=1.7,10.5Hz),7.18-7.24(1H,m),7.31-8.21(4H,m),8.52-8.75(3H,m).
[實施例2-246LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2,6-二甲基菸鹼醯胺；
RT(min.)：1.520
MS(ESI,m/z：451.1355(M-H)-
1H-NMR(CDCl3)δ：1.64-1.81(1H,m),2.03-2.15(1H,m),2.47-3.17(8H,m),4.58-4.98(1H,m),5.25(1H,t,J=8.7Hz),5.32-5.78(2H,m),6.85-7.13(2H,m),7.33-7.79(3H,m),7.94-8.16(1H,m),8.60-8.72(2H,m).
[實施例2-247LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-異丙氧基苯甲醯胺；
RT(min.)：2.925
MS(ESI,m/z)：480.1508(M-H)-
1H-NMR(CDCl3)δ：1.38-1.49(6H,m),1.71-1.97(1H,m),2.14--2.37(1H,m),2.50-2.97(2H,m),4.62-4.79(2H,m),5.26-6.18(3H,m),6.92-7.08(3H,m),7.18-7.47(3H,m),7.56-7.63(1H,m),7.87-8.10(1H,m),8.54-8.67(1H,m),8.72-8.83(1H,m).
[實施例2-248LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-(2-羥基乙氧基)苯甲醯胺；
RT(min.)：2.232
MS(ESI,m/z)：482.1302(M-H)-
1H-NMR(CDCl3)δ：1.55-1.83(1H,m),1.98--2.37(1H,m),2.44-2.88(2H,m),3.89-4.41(4H,m),4.61-4.79(1H,m),5.22-5.69(3H,m),6.94-7.13(3H,m),7.31-7.46(3H,m),7.50-8.07(2H,m),8.48-8.69(1.4H,m),9.12-9.23(0.6H,m).
[實施例2-249LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2,5-二甲基菸鹼醯胺；
RT(min.)：2.675
MS(ESI,m/z)：450.1399(M-H)-
1H-NMR(CDCl3)δ：1.35-1.83(1H,m),1.93-2.13(1H,m),2.30-3.16(8H,m),4.52-4.97(1H,m),5.21(t,1H,J=8.7Hz),5.31-5.60(2H,m),6.84-7.03(1H,m),7.24-7.61(6H,m),7.71-7.84(1H,m),8.34-8.43(1H,m).
[實施例2-250LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2,5-二甲基菸鹼醯胺；
RT(min.)：1.746
MS(ESI,m/z)：451.1354(M-H)-
1H-NMR(CDCl3)δ：1.65-1.81(1H,m),2.00-2.16(1H,m),2.26-2.39(3H,m),2.47-3.21(5H,m),4.58-4.97(1H,m),5.24(t,1H,J=8.7Hz),5.32-5.78(2H,m),6.87-7.05(1H,m),7.21-7.80(3H,m),7.95-8.17(1H,m),8.35-8.45(1H,m),8.54-8.72(2H,m).
[實施例2-251LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6,7-二氫-5H-[1]吡啶-5-基]苯甲醯胺；
RT(min.)：0.978
MS(ESI,m/z)：370.1559(M-H)-
1H-NMR(CDCl3)δ：1.68-1.91(1H,m),2.05-2.21(1H,m),2.65-2.98(2H,m),4.52-4.67(1H,m),5.20-5.80(3H,m),7.31-7.66(11H,m),8.20-8.55(2H,m).
[實施例2-251HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6,7-二氫-5H-[1]吡啶-5-基]苯甲醯胺；
RT(min.)：0.811
MS(ESI,m/z)：370.1551(M-H)-
1H-NMR(CDCl3)δ：2.41-2.62(1H,m),2.65-3.00(2H,m),3.10-3.31(1H,m),4.37-4.53(1H,m),5.31-5.82(3H,m),6.65-6.73(1H,m),6.80-6.98(1H,m),7.24-7.64(10H,m),8.33(1H,d,J=4.4Hz).
[實施例2-252M]
N-[(RS)-胺甲醯基苯基甲基]-N-[(SR)-5-氯-7-氟-2,3-二氫苯并呋喃-3-基]苯甲醯胺；
RT(min.)：3.489
MS(ESI,m/z)：423.0914(M-H)-
1H-NMR(CDCl3)δ：3.60-4.41(2H,m),5.20-5.88(4H,m),6.91-6.99(1H,m),7.15-7.68(11H,m).
[實施例2-253M]
N-(胺甲醯基苯基甲基)-N-[(R)-3,3-二甲基茚-1-基]苯甲醯胺；
RT(min.)：3.623
MS(ESI,m/z)：397.1920(M-H)-
1H-NMR(CDCl3)δ：0.94(2H,s),1.02(1H,s),1.19(2H,s),1.45(1H,s),1.64-1.73(0.67H,m),1.83-1.92(0.67H,m),2.19-2.29(0.33H,m),2.47-2.59(0.33H,m),4.52(0.33H,s),4.68(0.67H,s),5.25-6.10(3H,m),6.68(0.33H,d,J=7.5Hz),6.81-6.87(0.33H,m),7.10-7.66(12.67H,m),7.96(0.67H,d,J=7.5Hz).
[實施例2-254M]
N-(胺甲醯基苯基甲基)-N-(3-甲基茚-1-基)苯甲醯胺；
RT(min.)：3.483
MS(ESI,m/z)：383.1767(M-H)-
1H-NMR(CDCl3)δ：1.00-1.43(3H,m),1.67-3.21(3H,m),4.50-4.63(0.3H,br),4.71(0.7H,br s),5.20-6.16(3H,m),6.68-8.10(14H,m).
[實施例2-255M]
N-(胺甲醯基苯基甲基)-N-[(R)-4-甲氧基茚-1-基]苯甲醯胺；
RT(min.)：3.203
MS(ESI,m/z)：399.1708(M-H)-
RT(min.)：3.259
MS(ESI,m/z)：399.1715(M-H)-
1H-NMR(CDCl3)δ：1.65-3.15(4H,m),3.80(1.4H,s),3.81(1.6H,s),4.45-4.75(1H,m),5.35-6.90(4H,m),7.20-8.15(12H,m).
[實施例2-256M]
N-(胺甲醯基苯基甲基)-N-(3,3-二氟茚-1-基)苯甲醯胺；
RT(min.)：3.180
MS(ESI,m/z)：405.1431(M-H)-
RT(min.)：3.229
MS(ESI,m/z)：405.1432(M-H)-
1H-NMR(CDCl3)δ：2.16-3.46(2H,m),4.20-4.55(1H,m),4.93-5.84(3H,m),6.64-7.11(1H,m),7.17-7.72(12H,m),7.90-8.17(1H,m).
[實施例2-257M]
N-(胺甲醯基吡啶-3-基甲基)-N-[(R)-7-氟茚-1-基]菸鹼醯胺；
RT(min.)：0.759
MS(ESI,m/z)：389.1434(M-H)-
1H-NMR(CDCl3)δ：2.08-2.24(0.5H,m),2.42-3.40(3.5H,m),4.30-4.41(0.5H,m),4.56-4.80(0.5H,m),5.24-5.86(2.5H,m),6.43-6.53(0.5H,m),6.88-7.48(4.5H,m),7.80-8.01(3H,m),8.45-8.92(3.5H,m).
[實施例2-258M]
N-(胺甲醯基吡啶-3-基甲基)-N-[(R)-7-氟茚-1-基]-4-甲基噻唑-5-甲醯胺；
RT(min.)：1.046
MS(ESI,m/z)：409.1141(M-H)-
RT(min.)：1.166
MS(ESI,m/z)：409.1146(M-H)-
1H-NMR(CDCl3)δ：2.08-2.22(0.6H,m),2.42-3.40(6.4H,m),4.32-4.37(0.4H,m),4.58-4.80(0.6H,m),5.32-5.88(2.6H,m),6.40-6.48(0.4H,m),6.88-7.40(4H,m),7.80-7.98(1.4H,m),8.46-8.62(1.6H,m),8.80(0.4H,s),8.82(0.6H,s).
[實施例2-259M]
N-(胺甲醯基吡啶-3-基甲基)-N-[(R)-7-氯茚-1-基]菸鹼醯胺；
RT(min.)：0.838
MS(ESI,m/z)：405.1122(M-H)-
RT(min.)：1.016
MS(ESI,m/z：405.1126(M-H)-
1H-NMR(CDCl3)δ：2.27-2.49(4H,m),4.18-4.26(0.4H,m),4.53-4.64(0.6H,m),5.18-5.70(2.6H,m),6.70-6.78(0.4H,m),7.08-7.51(5H,m),7.75-8.11(2.4H,m),8.43-8.93(3.6H,m).
[實施例2-260HP]
2-胺基-N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺；
RT(min.)：2.295
MS(ESI,m/z)：437.1187(M-H)-
1H-NMR(CDCl3)δ：2.50-2.85(3H,m),2.95-3.20(1H,m),4.25-4.55(1H,m),5.20-5.65(4H,m),6.10-6.35(1H,m),6.67(1H,dd,J=5.0,7.3Hz),6.81(1H,dd,J=1.3,8.5Hz),7.20-7.40(6H,m),7.47(1H,dd,J=1.8,7.2Hz),8.13(1H,dd,J=1.8,5.0Hz).
[實施例3-1]
N-[(R)-胺甲醯基苯基甲基]-2-羥基-N-[(R)-6-三氟甲基茚-1-基]苯甲醯胺；
於(R)-6-三氟甲基茚-4-基胺(0.06g)之甲醇(1mL)溶液加入苯醛(0.032g)，將此混合物於加熱迴流下攪拌20分鐘。將反應混合物冷卻至室溫後，加入乙醯基水楊酸(0.054g)及4-苯基環己烯-1-基異氰(0.055g)，於加熱迴流下攪拌整夜。將反應混合物冷卻至室溫後，於減壓下濃縮。對所得殘渣加入四氫呋喃(2mL)、水(6μL)及4mol/L氯化氫1,4-二烷溶液(225μL)，以室溫攪拌3小時。於反應混合物加入水及飽和碳酸氫鈉水溶液，以醋酸乙酯萃取粗製生成物。將有機層以水及飽和食鹽水洗淨，以無水硫酸鎂乾燥。將使溶媒減壓餾除而得到之殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=55/45-75/25-100/0)精製，得到2-{N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-三氟甲基茚-1-基]胺甲醯基}乙酸苯酯作為低極性生成物。將此生成物以胺基丙基矽膠管析層 析(洗提溶媒：甲醇/醋酸乙酯=0/100-35/65)精製，得到標題化合物(0.039g)。構造式示於表29。
RT(min.)：3.397
MS(ESI,m/z)：453.1431(M-H)-
1H-NMR(CDCl3)δ：1.67-2.33(2H,m),2.61-3.00(2H,m),4.29-6.00(4H,m),6.89-6.95(1H,m),7.01-7.07(1H,m),7.22-7.57(9H,m),8.13(1H,s),8.67-8.86(1H,m).
[實施例3-2~3-3]
使用對應之原料，依與實施例3-1相同的方法合成實施例3-2~3-3。又，實施例3-2~3-3之質譜數據如以下，構造式示於表29。
[實施例3-2]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氰基茚-1-基]-2-羥基苯甲醯胺；
RT(min.)：2.837
MS(ESI,m/z)：410.1510(M-H)-
1H-NMR(CDCl3)δ：1.48-1.99(2H,m),2.61-3.07(2H,m),4.40-6.21(4H,m),6.90-6.97(1H,m),7.00-7.07(1H,m),7.22-7.65(9H,m),8.15(1H,s),8.50-8.94(1H,br).
[實施例3-3]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-2-羥基苯甲醯胺；
RT(min.)：3.165
MS(ESI,m/z)：421.1370(M-H)-
1H-NMR(CDCl3)δ：1.64-2.25(2H,m),2.47-2.90(2H,m),4.30-5.00(1H,br),5.27-6.00(3H,m),6.62-6.78(1H,m),6.88-6.95(1H,m),7.00-7.06(1H,m),7.30-7.54(8H,m),8.54-8.84(1H,br).
[實施例4-1]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺；
於(R)-6-氯-4-氟茚-1-基胺鹽酸鹽(98mg)之甲醇(2.2mL)溶液加入苯醛(47mg)與三乙基胺(45mg)。將此混合物以60℃攪拌3小時，冷卻至室溫。將乙醯基水楊酸(79mg)及4-苯基環己烯-1-基異氰(81mg)加入至此混合物中，以60℃攪拌19小時。將反應混合物減壓濃縮，對所得殘渣懸浮於四氫呋喃(2.2mL)，加入水(9μL)及4mol/L氯化氫1,4-二烷溶液(0.33mL)，將此混合物以室溫攪拌1.5小時。於反應混合物加入飽和碳酸氫鈉水溶液與二氯甲烷，激烈攪拌所生成之2層的混合液。使用ISOLUTE(註冊商標)Phase Separator分離有機層，予以減壓濃縮。將殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=52/48-73/27)精製，得到2-{N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]胺甲醯基}乙酸苯酯作為低極性生成物。將此生成物以胺基丙基矽膠管析層析(洗提溶媒：甲醇/醋酸乙酯=14/86-20/80)精製，得到標題化合物(69mg)。構造式示於表30。
RT(min.)：3.364
MS(ESI,m/z)：437.1070(M-H)-
1H-NMR(CDCl3)δ：1.65-2.30(2H,m),2.50-2.95(2H,m),4.35-5.05(1H,m),5.20-6.00(3H,m),6.85-7.10(3H,m),7.30-7.55(7H,m),7.66(1H,br s),8.50-9.00(1H,m).
[實施例4-2~4-9]
使用對應之原料，依與實施例4-1相同的方法合成實施例4-2~4-9。又，實施例4-2~4-9之質譜數據如以下，構造式示於表30及31。
[實施例4-2]
N-[(R)-胺甲醯基苯基甲基]-N-[(S)-5-氯-2,3-二氫苯并呋喃-3-基]-2-羥基苯甲醯胺；
RT(min.)：2.974
MS(ESI,m/z)：421.0959(M-H)-
1H-NMR(CDCl3)δ：4.06(1H,dd,J=4.7,9.9Hz),4.40-6.00(4H,m),6.65-6.80(1H,m),6.90-7.00(1H,m),7.05(1H,dd,J=0.6,8.3Hz),7.10-7.70(10H,m),8.60-9.00(1H,m).
[實施例4-3]
N-[(R)-胺甲醯基苯基甲基]-N-[(S)-5-氟-2,3-二氫苯并呋喃-3-基]-2-羥基苯甲醯胺；
RT(min.)：2.721
MS(ESI,m/z)：405.1253(M-H)-
1H-NMR(CDCl3)δ：4.02-5.00(2H,m),5.45-5.75(3H,m),6.70-6.78(1H,m),6.90-6.99(2H,m),7.02-7.08(1H,m),7.23-7.30(1H,m),7.33-7.65(8H,m),8.73(1H,br).
[實施例4-4]
N-[(R)-胺甲醯基苯基甲基]-N-[(S)-5,7-二氟-2,3-二氫苯并呋喃-3-基]-2-羥基苯甲醯胺；
RT(min.)：2.910
MS(ESI,m/z)：423.1162(M-H)-
1H-NMR(CDCl3)δ：3.70-4.40(2H,m),5.38-5.88(3H,m),6.73-6.83(1H,m),6.91-6.97(1H,m),7.02-7.07(1H,m),7.25-7.31(2H,m),7.34-7.68(7H,m),8.70(1H,br).
[實施例4-5]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺；
RT(min.)：2.155
MS(ESI,m/z)：438.1031(M-H)-
1H-NMR(CDCl3)δ：1.70-2.38(2H,m),2.53-2.94(2H,m),4.43-5.10(1H,m),5.27-6.41(3H,m),6.88-7.04(3H,m),7.28-7.35(2H,m),7.39(1H,dd,J=4.8,7.9Hz),7.50-7.55(1H,m),7.86-8.07(1H,m),8.62(1H,dd,J=1.5,4.8Hz),8.69-8.86(1H,m),8.89-9.79(1H,m).
[實施例4-6]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯茚-1-基]-2-羥基苯甲醯胺；
RT(min.)：1.984
MS(ESI,m/z)：420.1128(M-H)-
1H-NMR(CDCl3)δ：1.67-1.87(1H,m),2.00-2.38(1H,m),2.54-2.86(2H,m),4.57-4.98(1H,m),5.30-6.35(3H,m),6.87-7.02(2H,m),7.13(1H,d,J=8.0Hz),7.22-7.42(4H,m),7.70(1H,br s),7.96-8.06(1H,m),8.57-8.64(1H,m),8.66-8.72(1H,m),8.81-9.76(1H,br).
[實施例4-7]
N-[(R)-胺甲醯基嘧啶-5-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺；
RT(min.)：2.463
MS(ESI,m/z)：439.0998(M-H)-
1H-NMR(DMSO-d6)δ：1.25-2.96(4H,m),4.64-5.61(2H,m),6.72-7.79(8H,m),8.64-8.93(2H,m),9.01-9.26(1H,m),10.09-10.49(1H,m).
[實施例4-8]
N-[(R)-胺甲醯基吡-2-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺；
RT(min.)：2.691
MS(ESI,m/z)：439.0998(M-H)-
1H-NMR(CDCl3)δ：1.88-2.02(1H,m),2.45-2.98(3H,m),4.80-4.96(1H,m),5.52-5.94(2H,m),6.94-7.07(3H,m),7.34-7.43(3H,m),7.86-8.28(1H,m),8.51-8.54(1H,m),8.60-8.64(1H,m),8.88(1H,s),9.22(1H,s).
[實施例4-9]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-3-甲基苯甲醯胺；
RT(min.)：3.811
MS(ESI,m/z)：451.1236(M-H)-
1H-NMR(CDCl3)δ：1.67-2.22(2H,m),2.30(3H,s),2.49-2.62(1H,m),2.63-2.94(1H,m),4.46-4.91(1H,m),5.28-5.95(3H,m),6.82(1H,t,J=7.6Hz),6.91-7.06(1H,m),7.18-7.25(2H,m),7.34-7.52(5H,m),7.61-7.71(1H,m),8.60-8.95(1H,br).
[實施例5-1]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-三氟甲基茚-1-基]苯甲醯胺；
於(R)-6-三氟甲基茚-1-基胺(0.06g)之甲醇(1mL)溶液加入苯醛(0.032g)，於加熱迴流下攪拌20分鐘。將反應混合物冷卻至室溫後，加入2-硝基安息香酸(0.049g)及4-苯基環己烯-1-基異氰(0.055g)，加熱迴流下攪拌整夜。將反應混合物冷卻至室溫後，於減壓下濃縮。對所得殘渣加入四氫呋喃(2mL)、水(6μL)及4mol/L氯化氫1,4-二烷溶液(225μL)，以室溫攪拌3小時。於反應混合物加入水及飽和碳酸氫鈉水溶液，以醋酸乙酯萃取粗製生成物。將有機層以水及飽和食鹽水洗淨，以無水硫酸鎂乾燥。將溶媒減壓餾除，對所得殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=55/45-75/25-100/0)精製，得到N-[(R)-胺甲醯基苯基甲基]-2-硝基-N-[(R)-6-三氟甲基茚-1-基]苯甲醯胺。對N-[(R)-胺甲醯基苯基甲基]-2-硝基-N-[(R)-6-三氟甲基茚-1-基]苯甲醯胺於室溫加入乙醇(2mL)及10%鈀碳(0.030g)，於氫環境下攪拌4小時。過濾去除觸媒，將濾液減壓濃縮。對此殘渣以胺基丙基矽膠管 析層析(洗提溶媒：醋酸乙酯/正己烷=45/55-65/35)精製得到標題化合物(0.015g)。構造式示於表32。
RT(min.)：3.695
MS(ESI,m/z)：452.1591(M-H)-
1H-NMR(CDCl3)δ：1.63-1,86(1H,m),2.00-2.25(1H,m),2.50-2.88(2H,m),4.29-4.74(3H,m),5.15-5.73(3H,m),6.67-6.80(2H,m),7.12-7.57(9H,m),8.17-8.29(1H,br).
[實施例5-2]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氰基茚-1-基]苯甲醯胺
使用對應之原料，依與實施例5-1相同的方法合成標題化合物。又，標題化合物之質譜數據如以下，構造式示於表32。
RT(min.)：3.124
MS(ESI,m/z)：409.1668(M-H)-
1H-NMR(CDCl3)δ：1.59-1.82(1H,m),1.91-2.22(1H,m),2.48-2.90(2H,m),4.22-5.80(6H,m),6.64-6.88(2H,m),7.12-7.62(9H,m),8.13-8.34(1H,m).
[實施例6-1]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]苯甲醯胺
於(R)-4,6-二氟茚-1-基胺鹽酸鹽(0.13g)之甲醇(1.6mL)溶液加入苯醛(67mg)與三乙基胺(64mg)。將此混合物以60℃攪拌2小時，冷卻至室溫。將2-硝基安息香酸(0.11g)及4-苯基環己烯-1-基異氰(0.12g)加入至此混合物中，以60℃攪拌15小時。將反應混合物減壓濃縮，對 所得殘渣懸浮於四氫呋喃(3.2mL)，加入水(13μL)及4mol/L氯化氫1,4-二烷溶液(0.47mL)，將此混合物以室溫攪拌2小時。於反應混合物加入飽和碳酸氫鈉水溶液與二氯甲烷，激烈攪拌所生成之2層的混合液。使用ISOLUTE(註冊商標)Phase Separator分離有機層，予以減壓濃縮。將殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=55/45-76/24)精製，得到N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-2-硝基苯甲醯胺(0.16g)。將N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-2-硝基苯甲醯胺(0.16g)、10%鈀碳(16mg)及四氫呋喃(3.5mL)的混合物於氫環境下以室溫激烈攪拌18小時。以矽藻土過濾去除觸媒，將濾液減壓濃縮。對殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=53/47-74/26)精製，得到標題化合物(0.11g)。構造式示於表33。
RT(min.)：3.462
MS(ESI,m/z)：420.1531(M-H)-
1H-NMR(CDCl3)δ：1.30-2.85(6H,m),4.50-4.75(1H,m),5.30-5.65(3H,m),6.60-6.80(3H,m),7.15-7.25(2H,m),7.30-7.60(6H,m).
[實施例6-2~6-5]
使用對應之原料，依與實施例6-1相同的方法合成實施例6-2~6-5。又，實施例6-2~6-5之質譜數據如以下，構造式示於表33及34。
[實施例6-2]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺
RT(min.)：3.664
MS(ESI,m/z)：436.1232(M-H)-
1H-NMR(CDCl3)δ：1.35-1.85(3H,m),1.90-2.25(1H,m),2.40-2.60(1H,m),2.60-2.80(1H,m),4.50-4.75(1H,m),5.30-5.70(3H,m),6.65-6.80(2H,m),6.90-7.05(1H,m),7.15-7.25(2H,m),7.30-7.60(5H,m),7.65-7.85(1H,m).
[實施例6-3]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(S)-5-氯-2,3-二氫苯并呋喃-3-基]苯甲醯胺
RT(min.)：3.239
MS(ESI,m/z)：420.1117(M-H)-
1H-NMR(CDCl3)δ：3.99-4.70(5H,m),5.28-5.80(3H,m),6.66-6.80(3H,m),7.07-7.24(3H,m),7.36-7.65(5H,m),7.72-7.77(1H,m).
[實施例6-4]
2-胺基-N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺
RT(min.)：2.498
MS(ESI,m/z)：437.1196(M-H)-
1H-NMR(CDCl3)δ：1.50-1.81(1H,m),1.99-2.27(1H,m),2.48-2.96(2H,m),4.00-5.00(3H,m),5.28-5.80(3H,m),6.67-6.82(2H,m),6.93-7.06(1H,m),7.12-7.24(2H,m),7.38(1H,dd,J=5.0,8.0Hz),7.70(1H,br s),7.92-8.17(1H,br),8.58-8.68(2H,m).
[實施例6-5]
2-胺基-N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺
RT(min.)：1.243
MS(ESI,m/z)：438.1144(M-H)-
1H-NMR(CDCl3)δ：1.55-1.79(1H,m),1.96-2.24(1H,m),2.50-2.63(1H,m),2.68-2.87(1H,m),4.51-4.94(1H,m),5.27-5.79(5H,m),6.69(1H,dd,J=5.0,7.3Hz),6.98-7.05(1H,m),7.39(1H,ddd,J=0.5,4.7,8.0Hz),7.47(1H,dd,J=1.6,4.7Hz),7.67(1H,s),7.95-8.10(1H,m),8.14(1H,dd,J=1.8,5.0Hz),8.60-8.63(1H,m),8.66(1H,dd,J=1.6,4.7Hz).
[實施例7]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-(2-羥基乙氧基)茚-1-基]苯甲醯胺
於[(R)-6-(2-苄基氧基乙氧基)茚-1-基]胺甲酸第三丁酯(0.20g)之二氯甲烷(1mL)溶液以室溫加入三氟醋酸(1mL)，以同溫度攪拌1小時。將反應混合物減壓濃縮。對此殘渣加入飽和碳酸氫鈉水溶液，以醋酸乙酯萃取。將有機層以飽和食鹽水洗淨，以無水硫酸鎂乾燥。將溶媒減壓餾除。將所得殘渣與三乙基胺(145μL)及苯醛(0.056g)之甲醇(1mL)混合液以60℃攪拌2小時。將反應混合物冷卻至室溫後，加入安息香酸(0.064g)及4-苯基環己烯-1-基異氰(0.095g)，以外溫60℃攪拌5日。將反應混合物於減壓下濃縮。對所得殘渣加入四氫呋喃(3mL)使其溶解。於此混合物加入水(11μL)及4mol/L氯化氫1,4-二烷溶液(0.39mL)，以室溫攪拌1.5小時。於反應混合物加入水及飽和碳酸氫鈉水溶液與二氯甲烷，以醋酸乙酯萃取粗製生成物。將有機層以水及飽和食鹽水洗淨，以無水硫酸鎂乾燥。將溶媒減壓餾除，對所得殘渣以 矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=55/45-75/25)精製，得到N-[(R)-胺甲醯基苯基甲基]-N-[6-(2-苄基氧基乙氧基)茚-1-基]苯甲醯胺(0.62g)。於N-[(R)-胺甲醯基苯基甲基]-N-[6-(2-苄基氧基乙氧基)茚-1-基]苯甲醯胺(0.62g)之四氫呋喃(1mL)溶液以室溫加入10%鈀碳(0.02g)，於氫環境下攪拌2小時。過濾去除觸媒，將濾液減壓濃縮。對此殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/甲醇=100/0-85/15)精製，得到標題化合物(0.019g)。構造式示於表34。
RT(min.)：2.832
MS(ESI,m/z)：429.1823(M-H)-
1H-NMR(CDCl3)δ：1.65-1.82(1H,m),1.97-2.13(1H,m),2.40-2.74(3H,m),3.90-4.00(2H,m),4.16-4.32(2H,m),4.67(1H,br s),5.34-5.90(3H,m),6.82-6.91(1H,m),7.04-7.10(1H,m),7.32-7.68(11H,m).
[實施例8-1]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-環丙基-4-氟茚-1-基]苯甲醯胺
於(R)-N-[(R)-6-環丙基-4-氟茚-1-基]-第三丁烷亞磺醯胺(0.03g)之甲醇(1mL)溶液以室溫加入4mol/L氯化氫1,4-二烷溶液(35μL)，於同溫攪拌3小時。將反應混合物於減壓下濃縮。將所得殘渣與三乙基胺(14μL)及苯醛(0.011g)之甲醇(2mL)混合液加熱迴流0.5小時。將反應混合物冷卻至室溫後，加入安息香酸(0.013g)及4-苯基環己烯-1-基異氰(0.019g)，加熱迴流2日。將反應混合物於減壓下濃縮。對所得殘渣加入四氫呋喃(2mL)使其溶解。於混合物加入水(3μL)及 4mol/L氯化氫1,4-二烷溶液(75μL)，以室溫攪拌1小時。於反應混合物加入水及飽和碳酸氫鈉水溶液，以醋酸乙酯萃取粗製生成物。將有機層以水及飽和食鹽水洗淨，以無水硫酸鎂乾燥。將溶媒減壓餾除，對所得殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=55/45-75/25-100/0)精製，得到標題化合物(0.006g)。構造式示於表34。
RT(min.)：3.848
MS(ESI,m/z)：427.1832(M-H)-
1H-NMR(CDCl3)δ：0.72-1.07(4H,m),1.66-1.79(1H,m),1.90-2.12(2H,m),2.42-2.87(2H,m),4.63(1H,br s),5.28-5.86(3H,m),6.64-6.74(1H,m),7.29-7.63(11H,m).
[實施例8-2]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟-6-乙烯基茚-1-基]苯甲醯胺
使用對應之原料，依與實施例8-1相同的方法合成標題化合物。又，標題化合物之質譜數據如以下，構造式示於表34。
RT(min.)：3.712
MS(ESI,m/z)：413.1676(M-H)-
1H-NMR(CDCl3)δ：1.68-1.84(1H,m),2.00-2.14(1H,m),2.44-2.88(2H,m),4.60-4.73(1H,m),5.21-5.96(5H,m),6.76(1H,dd,J=11.0,17.2Hz),6.96-7.04(1H,m),7.32-7.65(10H,m),7.89(1H,br s).
[實施例9]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-乙基-4-氟茚-1-基]苯甲醯胺
於N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟-6-乙烯基茚-1-基]苯甲醯胺(0.04g，實施例8-2)之四氫呋喃(1mL)溶液中以室溫10%鈀碳(0.01g)，於氫環境下攪拌3小時。將觸媒過濾去除，將濾液減壓濃縮。將此殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=55/45-75/25-100/0)精製，得到標題化合物(0.030g)。構造式示於表34。
RT(min.)：3.803
MS(ESI,m/z)：415.1832(M-H)-
1H-NMR(CDCl3)δ：1.28(3H,t,J=7.6Hz),1.69-1.91(1H,m),2.00-2.16(1H,m),2.44-2.87(4H,m),4.66(1H,br s),5.26-5.93(3H,m),6.80(1H,d,J=9.8Hz),7.32-7.66(11H,m).
[實施例10]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]對苯二甲醯胺
於N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]對苯二甲醯胺酸苄酯(0.068g，實施例2-62LP)之四氫呋喃(2mL)溶液中以室溫10%鈀碳(0.02g)，於氫環境下攪拌2小時。將觸媒過濾去除，將濾液減壓濃縮。將此殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/甲醇=100/0-80/20)精製，得到標題化合物(0.032g)。構造式示於表34。
RT(min.)：3.057
MS(ESI,m/z)：449.1322(M-H)-
1H-NMR(DMSO-d6)δ：1.11-1.28(1H,m),1.88-2.08(1H,m),2.43-2.64(1,m),2.75-2.94(1H,m),4.96-5.08(1H,m),5.37(1H,br s),6.88-6.98(1H,m),7.21-7.62(10H,m),7.99-8.12(2H,m),13.08-13.33(1H,br).
[實施例11]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基菸鹼醯胺
於(R)-6-氯-4-氟茚-1-基胺鹽酸鹽(0.33g)之甲醇(7.5mL)溶液加入苯醛(0.16g)與三乙基胺(0.15g)。將此混合物以65℃攪拌1小時，冷卻至室溫。將2-甲氧基菸鹼酸(0.24g)及4-苯基環己烯-1-基異氰(0.27g)加入至此混合物中，以65℃攪拌23小時。將反應混合物減壓濃縮，對所得殘渣懸浮於四氫呋喃(7.5mL)，加入水(30μL)及4mol/L氯化氫1,4-二烷溶液(1.1mL)，將此混合物以室溫攪拌1小時。於反應混合物加入飽和碳酸氫鈉水溶液與二氯甲烷，激烈攪拌所生成之2層的混合液。使用ISOLUTE(註冊商標)Phase Separator分離有機層，予以減壓濃縮。將殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=64/36-85/15)精製，得到粗製生成物。將此粗製生成物以胺基丙基矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=58/42-100/0)精製，得到標題化合物(0.20g)。構造式示於表34。
RT(min.)：3.409
MS(ESI,m/z)：452.1182(M-H)-
1H-NMR(CDCl3)δ：1.70-3.10(4H,m),3.95-4.10(3H,m),4.50-6.10(4H,m),6.80-7.10(2H,m),7.30-7.90(7H,m),8.20-8.30(1H,m).
[實施例12]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺
於(R)-6-氯-4-氟茚-1-基胺鹽酸鹽(103mg)之甲醇(2.3mL)溶液加入3-吡啶甲醛(50mg)與三乙基胺(47mg)。將此混合物以65℃攪拌2小時，冷卻至室溫。將二甲基菸鹼酸(67mg)與4-苯基環己烯-1-基異氰(85mg)加入至此混合物中，以65℃攪拌5小時。將反應混合物減壓濃縮，對所得殘渣懸浮於四氫呋喃(2.3mL)，加入水(9μL)及4mol/L氯化氫1,4-二烷溶液(0.46mL)，將此混合物以室溫攪拌1小時。於反應混合物加入飽和碳酸氫鈉水溶液與二氯甲烷，激烈攪拌所生成之2層的混合液。使用ISOLUTE(註冊商標)Phase Separator分離有機層，予以減壓濃縮。將殘渣以胺基丙基矽膠管析層析(洗提溶媒：甲醇-醋酸乙酯=0/100-9/91)精製，得到非鏡像異構物混合物。將此混合物以逆相分離液體層析(Inertsil ODS-3，洗提溶媒：乙腈/水=10/90-90/10)精製，得到標題化合物(32mg)。構造式示於表34。
RT(min.)：1.694
MS(ESI,m/z)：437.1191(M-H)-
1H-NMR(CDCl3)δ：1.65-1.85(1H,m),2.00-2.20(1H,m),2.45-2.90(5H,m),4.55-5.00(1H,m),5.23(1H,dd,J=8.8,8.8Hz),5.30-5.80(2H,m),7.02(1H,dd,J=0.8,8.6Hz),7.15-7.30(1H,m),7.35-7.90(3H,m),7.90-8.25(1H,m),8.50-8.80(3H,m).
[α]25 D：+54.4°(c=0.40、MeOH)
[實施例13]
2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺
於(R)-6-氯-4-氟茚-1-基胺鹽酸鹽(0.1g)之甲醇(3mL)溶液加入三乙基胺(0.046g)及苯醛(0.048g)，以65℃攪拌0.5小時，將反應 混合物冷卻至室溫後，加入2-硝基菸鹼酸(0.083g)及4-苯基環己烯-1-基異氰(0.083g)，以65℃攪拌整夜。將反應混合物冷卻至室溫後，於減壓下濃縮，對所得殘渣加入四氫呋喃(4mL)、水(40μL)及4mol/L氯化氫1,4-二烷溶液(340μL)，以室溫攪拌1小時。於反應混合物加入水及飽和碳酸氫鈉水溶液，以醋酸乙酯萃取粗製生成物。將有機層以水及飽和食鹽水洗淨，以無水硫酸鎂乾燥。將溶媒減壓餾除，對所得殘渣以矽膠管析層析(洗提溶媒：甲醇/醋酸乙酯/正己烷=0/6040-0/100/0-20/80/0)精製，得到2-硝基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺(0.090g)。如以下般調製雷氏觸媒之懸浮液。將Raney(註冊商標)2800 nickel,slurry in water,active catalyst(Sigma-Aldrich)之懸濁液(200μL)與乙醇的混合物進行攪拌，以傾析去除溶媒。將觸媒以乙醇洗淨3次，加入乙醇(1mL)，作成懸浮液。將此雷氏觸媒懸浮液於氬環境下，以室溫加入2-硝基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺(0.090g)之乙醇(1mL)溶液，於氫環境下攪拌5小時。過濾去除觸媒，將濾液減壓濃縮。對此殘渣以胺基丙基矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=90/10-100/0)精製，得到標題化合物(0.071g)。構造式示於表34。
RT(min.)：2.330
MS(ESI,m/z)：437.1182(M-H)-
1H-NMR(CDCl3)δ：1.60-1.85(1H,m),1.90-2.20(1H,m),2.45-2.85(2H,m),4.50-4.85(1H,m),5.20-5.65(5H,m),6.69(1H,dd,J=5.1,7.3Hz),6.90-7.05(1H,m),7.35-7.55(6H,m),7.70(1H,br s),8.13(1H,dd,J=1.7,5.1Hz).
[α]26 D：+44.9°(c=1.08、MeOH)
[實施例14]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺
於(R)-6-氯-4-氟茚-1-基胺鹽酸鹽(444mg)及苯醛(212mg)之甲醇(8mL)混合物中加入三乙基胺(202mg)，將此混合物以60℃攪拌2小時，將反應混合物冷卻至室溫，加入2-甲基菸鹼酸(274mg)及4-苯基環己烯-1-基異氰(366mg)，以60℃攪拌整夜。將溶媒減壓餾除。於此殘渣以室溫加入1,4-二烷(3.5mL)、水(0.5mL)、4mol/L氯化氫1,4-二烷溶液(0.5mL)，攪拌3小時。於反應混合物加入飽和碳酸氫鈉水溶液，以醋酸乙酯萃取粗製生成物。將有機層以水及飽和食鹽水洗淨，以無水硫酸鎂乾燥。將溶媒減壓餾除，對所得殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=5/1)精製，得到非鏡像異構物之粗製生成物。對此等粗製生成物以胺基丙基矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=3/1)精製，得到N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼(實施例14LP，279mg)作為低極性生成物，得到N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼(實施例14HP，166mg)作為高極性生成物。構造式示於表34及35。
[實施例14LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺
RT(min.)：2.728
MS(ESI,m/z)：436.1233(M-H)-
1H-NMR(CDCl3)δ：1.65-1.85(1H,m),1.96-2.11(1H,m),2.41-2.55(1H,m),2.61-3.14(4H,m),4.55-5.00(1H,m),5.17-5.24(1H,m),5.30-5.57(2H,m),6.84-7.04(1H,m),7.15-7.84(8H,m),8.53-8.61(1H,m).
[α]20 D：+24.9°(c=0.58、MeOH)
[實施例14HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺
RT(min.)：2.569
MS(ESI,m/z)：436.1240(M-H)-
1H-NMR(CDCl3)δ：2.31-3.17(7H,m),4.36(1H,br s),5.07-5.61(3H,m),6.12-6.28(1H,m),6.76-6.87(1H,m),7.17-7.73(7H,m),8.56-8.61(1H,m).
[α]25 D：+85.3°(c=1.18、MeOH)
[實施例15LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基噻唑-5-甲醯胺
於(R)-6-氯-4-氟茚-1-基胺鹽酸鹽(0.45g)之甲醇(10mL)溶液加入苯醛(0.22g)與三乙基胺(0.21g)。將此混合物以65℃攪拌2.5小時，冷卻至室溫。將4-甲基噻唑-5-羧酸(0.31g)及4-苯基環己烯-1-基異氰(0.37g)加入至此混合物中，以65℃攪拌20小時。將反應混合物減壓濃縮，對所得殘渣懸浮於四氫呋喃(5mL)，加入水(40μL)及4mol/L氯化氫1,4-二烷溶液(1.5mL)，將此混合物以室溫攪拌1小時。於反應 混合物加入飽和碳酸氫鈉水溶液與二氯甲烷，激烈攪拌所生成之2層的混合液。使用ISOLUTE(註冊商標)Phase Separator分離有機層，予以減壓濃縮。將殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=71/29-92/8)精製，得到標題化合物(0.35g)。構造式示於表35。
RT(min.)：3.241
MS(ESI,m/z)：442.0800(M-H)-
1H-NMR(CDCl3)δ：1.65-2.30(2H,m),2.45-3.05(5H,m),4.40-6.00(4H,m),6.85-7.10(1H,m),7.30-7.60(5H,m),7.72(1H,br s),8.77(1H,s).
[α]26 D：+33.6°(c=1.07、MeOH)
[實施例15HP]
N-[(S)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基噻唑-5-甲醯胺
依與實施例15LP相同的方法合成高極性非鏡相異構物之標題化合物。又，標題化合物之質譜數據如以下，構造式示於表35。
RT(min.)：3.046
MS(ESI,m/z)：442.0802(M-H)-
1H-NMR(CDCl3)δ：2.24-2.85(6H,m),3.05-3.20(1H,m),4.20-4.70(1H,m),5.20-5.75(3H,m),6.00-6.45(1H,m),6.84(1H,dd,J=1.0,8.6Hz),7.20-7.45(5H,m),8.79(1H,s).
[α]25 D：+72.3°(c=1.04、MeOH)
[實施例16]
7-乙醯基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5,6,7,8-四氫咪唑并[1,2-a]吡-3-甲醯胺
於5,6,7,8-四氫咪唑并[1,2-a]吡-3-甲酸乙酯(0.225g)之四氫呋喃(3mL)溶液中加入醋酸酐(130μL)，於室溫攪拌1小時。將反應混合物於減壓下濃縮，對所得殘渣以胺基丙基矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=60/40-85/15)精製，得到7-乙醯基-5,6,7,8-四氫咪唑并[1,2-a]吡-3-甲酸乙酯(0.12g)。於7-乙醯基-5,6,7,8-四氫咪唑并[1,2-a]吡-3-甲酸乙酯(0.12g)之乙醇(3mL)溶液中加入2mol/L氫氧化鈉水溶液(330μL)，於加熱迴流下攪拌30分鐘。將反應混合物冷卻後，加入2mol/L鹽酸(330μL)，於減壓下濃縮，得到7-乙醯基-5,6,7,8-四氫咪唑并[1,2-a]吡-3-甲酸(0.106g)。於(R)-6-氯-4-氟茚-1-基胺鹽酸鹽(0.112g)及三乙基胺(0.051g)之甲醇(2mL)混合液中加入苯醛(0.054g)，以65℃攪拌30分鐘。將反應混合物冷卻至室溫後，加入7-乙醯基-5,6,7,8-四氫咪唑并[1,2-a]吡-3-甲酸(0.106g)及4-苯基環己烯-1-基異氰(0.093g)加入至此混合物中，以65℃攪拌整夜。將反應混合物冷卻至室溫後，於減壓下濃縮。對所得殘渣加入四氫呋喃(4mL)、水(100μL)及4mol/L氯化氫1,4-二烷溶液(500μL)，以室溫攪拌30分鐘。於反應混合物加入水及飽和碳酸氫鈉水溶液，以醋酸乙酯萃取粗製生成物。將有機層以水及飽和食鹽水洗淨，以無水硫酸鎂乾燥。將溶媒減壓餾除，對所得殘渣以胺基丙基矽膠管析層析(洗提溶媒：甲醇/醋酸乙酯=4/96)精製，得到標題化合物(0.033g)作為低極性非鏡像異構物。構造式示於表35。
RT(min.)：2.458
MS(ESI,m/z)：508.1561(M-H)-
1H-NMR(CDCl3)δ：1.75-2.28(5H,m),2.55-2.97(2H,m),3.70-5.08(7H,m),5.23-6.26(3H,m),6.89-7.10(1H,m),7.33-7.49(6H,m),7.57-7.81(1H,m).
[實施例17]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5,6,7,8-四氫咪唑并[1,2-a]吡-3-甲醯胺
咪唑并[1,2-a]吡-3-甲酸乙酯(0.21g)及4mol/L氯化氫醋酸乙酯溶液(360μL)之乙醇(3mL)懸浮液中以室溫加入10%鈀碳(0.080g)，於氫環境下攪拌整夜。以過濾去除觸媒，將濾液減壓濃縮。於此殘渣加入四氫呋喃(3mL)、三乙基胺(460μL)及氯化苄基氧基羰基(250μL)，於室溫攪拌整夜。於反應混合物加入水及飽和碳酸氫鈉水溶液，以醋酸乙酯萃取粗製生成物。將有機層以水及飽和食鹽水洗淨，以無水硫酸鎂乾燥。將溶媒減壓餾除，對所得殘渣以胺基丙基矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=60/40-85/15)精製，得到5,6-二氫-8H-咪唑并[1,2-a]吡-3,7-二甲酸7-苄基-3-乙酯(0.16g)。於5,6-二氫-8H-咪唑并[1,2-a]吡-3,7-二甲酸7-苄基-3-乙酯(0.16g)之乙醇(3mL)溶液中加入2mol/L氫氧化鈉水溶液(315μL)，於加熱迴流下攪拌30分鐘。將反應混合物冷卻至室溫後，加入2mol/L鹽酸(315μL)，於減壓下濃縮，得到5,6-二氫-8H-咪唑并[1,2-a]吡-3,7-二甲酸7-苄酯(0.146g)。於(R)-6-氯-4-氟茚-1-基胺鹽酸鹽(0.108g)及三乙基胺(0.049g)之甲醇(2mL)溶液加入苯醛(0.052g)，以65℃攪拌30分鐘。將反應混合物冷卻 至室溫後，加入5,6-二氫-8H-咪唑并[1,2-a]吡-3,7-二甲酸7-苄酯(0.146g)及4-苯基環己烯-1-基異氰(0.089g)，以65℃攪拌整夜。將反應混合物冷卻至室溫後，於減壓下濃縮。對所得殘渣加入四氫呋喃(4mL)、水(100μL)及4mol/L氯化氫1,4-二烷溶液(500μL)，以室溫攪拌30分鐘。於反應混合物加入水及飽和碳酸氫鈉水溶液，以醋酸乙酯萃取粗製生成物。將有機層以水及飽和食鹽水洗淨，以無水硫酸鎂乾燥。將溶媒減壓餾除，對所得殘渣以胺基丙基矽膠管析層析(洗提溶媒：甲醇/醋酸乙酯=4/96)精製，得到3-{N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]胺甲醯基}-5,6-二氫-8H-咪唑并[1,2-a]吡-7-甲酸苄酯(0.038g)作為低極性非鏡像異構物。於3-{N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]胺甲醯基}-5,6-二氫-8H-咪唑并[1,2-a]吡-7-甲酸苄酯(0.038g)之四氫呋喃(3mL)懸浮液中以室溫加入10%鈀碳(0.020g)，於氫環境下攪拌1日。過濾去除觸媒，將濾液減壓濃縮。將此殘渣以胺基丙基矽膠管析層析(洗提溶媒：甲醇/醋酸乙酯=0/100-20/80)精製，得到標題化合物(0.23g)。構造式示於表35。
RT(min.)：2.045
MS(ESI,m/z)：466.1450(M-H)-
1H-NMR(CDCl3)δ：1.76-2.36(2H,m),2.50-3.00(2H,m),3.16-3.33(2H,m),3.56-5.00(6H,m),5.20-6.34(3H,m),6.86-7.09(1H,m),7.30-7.48(6H,m),7.55-7.81(1H,m).
[參考例6-1]
2-乙醯基氧基-3-三氟甲氧基安息香酸
於3-三氟甲氧基水楊酸(0.5g)與醋酸酐(2mL)之混合物以室溫加入硫酸(2滴)，將此混合物以80℃攪拌1小時。將反應混合物冷卻至室溫，加入冰。濾取不溶物，減壓乾燥，得到標題化合物(0.519g)。將構造式示於表36。
1H-NMR(CDCl3)δ ppm：2.38(3H,s),7.36-7.42(1H,m),7.56-7.61(1H,m),8.05(1H,dd,J=1.6,8.0Hz).
[參考例6-2]
2-乙醯基氧基-3-三氟甲基安息香酸
使用對應之原料，依與參考例6-1相同的方法合成標題化合物。又，標題化合物之質譜數據如以下，構造式示於表36。
1H-NMR(CDCl3)δ ppm：2.38(3H,s),7.44-7.50(1H,m),7.90-7.94(1H,m),8.29-8.34(1H,m).
[實施例18-1~18-16]
使用對應之原料，依與實施例2-1相同的方法合成實施例18-1~18-16。又，實施例18-1~18-16之質譜數據如以下，構造式示於表37及38。
[實施例18-1LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-二氟甲氧基苯甲醯胺
RT(min.)：2.793
MS(ESI,m/z)：488.0998(M-H)-
1H-NMR(DMSO-d6)δ ppm：1.22-1.37(1H,m),1.92-2.17(1H,m),2.50-2.70(1H,m),2.78-2.95(1H,m),4.78-5.45(3H,m),7.00-7.82(10H,m),8.43-8.67(2H,m).
[實施例18-2LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-6-羥基-2-甲基菸鹼醯胺
RT(min.)：2.671
MS(ESI,m/z)：452.1191(M-H)-
1H-NMR(DMSO-d6)δ ppm：1.05-1.35(1H,m),1.80-2.93(6H,m),4.88-5.19(1H,m),5.47-5.70(1H,m),6.23-6.31(1H,m),7.07-7.90(10H,m),11.70-12.04(1H,m).
[實施例18-3LP]
N-[(R)-胺甲醯基-(3-氰基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基苯甲醯胺
RT(min.)：3.565
MS(ESI,m/z)：476.1190(M-H)-
1H-NMR(CDCl3)δ ppm：1.71-1.87(1H,m),2.26-2.40(1H,m),2.52-2.68(1H,m),2.79-2.93(1H,m),3.92(1H,s),4.04(2H,m),4.67-4.81(1H,m),5.33-6.81(3H,m),6.94-7.15(3H,m),7.37-7.57(4H,m),7.60-7.78(2H,m),8.03(1H,br s).
[實施例18-4LP]
N-[(R)-胺甲醯基-(3-氰基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺
RT(min.)：2.655
MS(ESI,m/z)：461.1196(M-H)-
1H-NMR(CDCl3)δ ppm：1.56-1.78(1H,m),2.06-2.18(1H,m),2.47-2.89(5H,m),4.59-4.82(1H,m),5.19-5.80(3H,m),6.98-7.08(1H,m),7.19-7.29(1H,m),7.50-7.98(6H,m),8.53-8.68(1H,br).
[實施例18-5LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-氰基苯甲醯胺
RT(min.)：2.539
MS(ESI,m/z)：447.1042(M-H)-
1H-NMR(CDCl3)δ ppm：1.70-1.90(1H,m),2.00-2.22(1H,m),2.50-2.94(2H,m),4.62-4.93(1H,m),5.25-5.77(3H,m),6.96-7.09(1H,m),7.37-7.45(1H,m),7.54-7.65(1H,m),7.70-8.06(5H,m),8.58-8.75(2H,m).
[實施例18-6LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-氰基苯甲醯胺
RT(min.)：3.598
MS(ESI,m/z)：446.1086(M-H)-
1H-NMR(CDCl3)δ ppm：1.67-2.13(2H,m),2.45-2.88(2H,m),4.53-5.80(4H,m),6.88-7.08(1H,m),7.35-7.65(6H,m),7.67-7.89(4H,m).
[實施例18-7LP]
N-[(R)-胺甲醯基吡-2-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-氰基苯甲 醯胺
RT(min.)：2.931
MS(ESI,m/z)：448.0990(M-H)-
1H-NMR(CDCl3)δ ppm：2.00-2.15(1H,m),2.32-2.53(1H,m),2.61-2.74(1H,m),2.84-3.04(1H,m),4.73-4.93(1H,m),5.36-5.77(3H,m),6.97-7.07(1H,m),7.50-7.68(2H,m),7.75-7.82(1H,m),7.83-7.95(2H,m),8.52-8.63(2H,m),8.81(1h,br s).
[實施例18-8LP]
N-[(R)-胺甲醯基-(3-羥基甲基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺
RT(min.)：2.195
MS(ESI,m/z)：512.1410(M+HCO2)-
1H-NMR(CDCl3)δ ppm：1.38-2.18(3H,m),2.38-3.13(5H,m),4.55-5.00(3H,m),5.15-5.24(1H,m),5.37-5.72(2H,m),6.83-7.03(1H,m),7.16-7.83(7H,m),8.52-8.60(1H,m).
[實施例18-9LP]
N-[(R)-胺甲醯基-(3-胺甲醯基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺
RT(min.)：1.969
MS(ESI,m/z)：525.1359(M+HCO2)-
1H-NMR(CDCl3)δ ppm：1.36-1.78(1H,m),2.00-2.12(1H,m),2.43-3.13(5H,m),4.62-4.98(1H,m),5.17-5.28(1H,m),5.32-6.50(4H,m),6.84-7.05(1H,m),7.17-7.32(1H,m),7.41-7.89(5H,m),7.94-8.11(1H,m),8.52-8.64(1H,m).
[實施例18-10LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟基茚-1-基]-4-氰基噻吩-2-甲醯胺
RT(min.)：2.485
MS(ESI,m/z)：453.0600(M-H)-
1H-NMR(CDCl3)δ ppm：1.80-1.93(1H,m),2.08-2.36(1H,m),2.64-2.79(1H,m),2.89-3.00(1H,m),4.57-4.98(1H,m),5.41-5.99(3H,m),7.00-7.12(1H,m),7.34-7.43(1H,m),7.57(1H,s),7.73(1H,s),7.85-7.95(1H,m),8.08-8.13(1H,m),8.61-8.70(2H,m).
[實施例18-11LP]
{3-[(R)-胺甲醯基-{N-[(R)-6-氯-4-氟茚-1-基]-N-(2-甲基吡啶-3-羰基)胺基}甲基]苄基}胺甲酸第三丁酯
RT(min.)：3.089
MS(ESI,m/z)：611.2092(M+HCO2)-
1H-NMR(CDCl3)δ ppm：1.45(9H,s),1.63-1.82(1H,m),1.95-2.11(1H,m),2.41-3.13(5H,m),4.25-4.42(2H,m),4.55-5.05(2H,m),5.15-5.23(1H,m),5.38-5.65(2H,m),6.85-7.03(1H,m),7.15-7.53(5H,m),7.59-7.83(2H,m),8.53-8.61(1H,m).
[實施例18-12LP]
N-[(R)-胺甲醯基-(3-硝基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺
RT(min.)：2.836
MS(ESI,m/z)：481.1092(M-H)-
1H-NMR(CDCl3)δ ppm：1.63-1.79(1H,m),2.09-2.22(1H,m),2.49-2.89(5H,m),4.72-4.89(1H,m),5.22-5.32(1H,m),5.38-6.00(2H,m),6.87-7.07(1H,m),7.56-7.97(4H,m),8.20-8.67(3H,m).
[實施例18-13LP]
N-[(R)-胺甲醯基-(3-二甲基胺基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺
RT(min.)：2.572
MS(ESI,m/z)：479.1655(M-H)-
1H-NMR(CDCl3)δ ppm：1.73-2.20(2H,m),2.41-2.55(1H,m),2.60-2.86(4H,m),2.92-3.02(6H,m),4.45-5.70(4H,m),6.44-7.05(4H,m),7.15-7.32(2H,m),7.48-7.84(2H,m),8.52-8.60(1H,m).
[實施例18-14LP]
N-[(R)-胺甲醯基苯基甲基]-N-[(S)-5,7-二氟-2,3-二氫苯并呋喃-3-基]-2-甲基菸鹼醯胺
RT(min.)：2.298
MS(ESI,m/z)：422.1331(M-H)-
1H-NMR(CDCl3)δ ppm：2.35-2.83(3H,m),3.81-4.95(3H,m),5.22-5.81(3H,m),6.64-6.88(1H,m),7.09-7.73(8H,m),8.44-8.65(1H,m).
[實施例18-15M]
N-(胺甲醯基吡啶-3-基甲基)-N-[(S)-5,7-二氟-2,3-二氫苯并呋喃-3-基]-2-甲基菸鹼醯胺
RT(min.)：0.838
MS(ESI,m/z)：423.1277(M-H)-
RT(min.)：0.937
MS(ESI,m/z)：423.1278(M-H)-
1H-NMR(CDCl3)δ ppm：2.36-2.90(3H,m),4.08-4.88(2H,m),5.20-6.22(4H,m),6.68-6.91(1H,m),7.08-8.95(8H,m).
[實施例18-16LP]
N-[(R)-胺甲醯基苯-3-基甲基]-N-[(S)-5-氯-7-氟-2,3-二氫苯并呋喃-3-基]-2-甲基菸鹼醯胺
RT(min.)：2.576
MS(ESI,m/z)：438.1034(M-H)-
1H-NMR(CDCl3)δ ppm：2.38-2.83(3H,m),3.84-4.31(2H,m),5.20-5.63(4H,m),6.90-7.72(9H,m),8.43-8.63(1H,m).
[實施例19-1LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
於(R)-6-氯-4-氟茚-1-基胺鹽酸鹽(6.66g)之甲醇(100mL)溶液加入三乙基胺(4.80mL)及3-甲醯基吡啶(3.24g)，以60℃攪拌1小時。將反應混合物冷卻至室溫後，將乙醯基水楊酸(5.14g)及4-苯基環己烯-1-基異氰(5.50g)加入至此混合物中，以60℃攪拌整夜。將反應混合物冷卻至室溫後，於減壓下濃縮。對所得殘渣加入1,4-二烷(150mL)、水(30mL)及4mol/L氯化氫1,4-二烷溶液(30mL)，以室溫攪拌3小時。於反應混合物加入飽和碳酸氫鈉水溶液，以醋酸乙酯萃取粗製生成物。將有機層以水及飽和食鹽水洗淨，以無水硫酸鎂乾燥。將溶媒減 壓餾除，對所得殘渣以胺基丙基矽膠管析層析(洗提溶媒：醋酸乙酯/甲醇=5/1)精製，得到非鏡像異構物混合物。將此混合物以矽膠管析層析(洗提溶媒：二氯甲烷/二乙基醚/甲醇=10/10/1)精製，得到標題化合物(4.20g)作為低極性生成物。構造式示於表39。
1H-NMR(CDCl3)δ ppm：1.70-2.38(2H,m),2.53-2.94(2H,m),4.45-5.10(1H,m),5.27-6.41(3H,m),6.88-7.04(3H,m),7.27-7.35(2H,m),7.36-7.42(1H,m),7.51-7.54(1H,m),7.88-8.05(1H,m),8.62(1H,dd,J=1.5,4.8Hz),8.71-8.77(1H,m),9.10-9.75(1H,m).
[實施例19-2~19-41]
使用對應之原料，依與實施例19-1相同的方法合成實施例19-2~19-41。又，實施例19-2~19-41之質譜數據如以下，構造式示於表39~42。
[實施例19-2LP]
N-[(R)-胺甲醯基-(3-氰基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：3.220
MS(ESI,m/z)：462.1035(M-H)-
1H-NMR(CDCl3)δ ppm：1.67-1.83(1H,m),1.98-2.33(1H,m),2.55-2.92(2H,m),4.54-5.07(1H,m),5.31-6.00(3H,m),6.92-7.07(3H,m),7.31-7.40(2H,m),7.50-7.61(2H,m),7.65-7.76(2H,m),7.78-7.90(1H,m),8.23-8.60(1H,br).
[實施例19-3LP]
N-[(R)-胺甲醯基-(3-胺甲醯基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：2.588
MS(ESI,m/z)：480.1143(M-H)-
1H-NMR(DMSO-d6)δ ppm：1.09-1.21(1H,m),1.97-2.11(1H,m),2.46-2.59(1H,m),2.76-2.87(1H,m),5.01-5.11(1H,m),5.45(1H,br s),6.85-6.95(2H,m),7.06-7.30(4H,m),7.37-7.69(5H,m),7.82-7.93(2H,m),8.05(1H,br s),10.09(1H,br s).
[實施例19-4LP]
N-[(R)-胺甲醯基-(3-羥基甲基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：2.774
MS(ESI,m/z)：467.1188(M-H)-
1H-NMR(DMSO-d6)δ ppm：1.10-1.27(1H,m),1.99-2.12(1H,m),2.46-2.58(1H,m),2.76-3.02(1H,m),4.51(2H,d,J=5.6Hz),5.00-5.11(1H,m),5.26(1H,t,J=5.6Hz),5.41(1H,br s),6.82-6.95(2H,m),6.98-7.63(10H,m),10.04(1H,br s).
[實施例19-5LP]
N-[(R)-胺甲醯基-(3-硝基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：3.369
MS(ESI,m/z)：482.0940(M-H)-
1H-NMR(DMSO-d6)δ ppm：1.14-1.33(1H,m),1.96-2.12(1H,m),2.46-2.62(1H,m),2.77-2.90(1H,m),4.97-5.58(2H,m),6.81-7.00(2H,m),7.06-8.45(10H,m),10.18-10.28(1H,m).
[實施例19-6LP]
N-[(R)-胺甲醯基-(3-二甲基胺基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：2.811
MS(ESI,m/z)：480.1507(M-H)-
1H-NMR(DMSO-d6)δ ppm：1.21-1.35(1H,m),2.03-2.17(1H,m),2.47-2.61(1H,m),2.78-2.96(7H,m),5.02-5.13(1H,m),5.33(1H,br s),6.57-6.76(3H,m),6.83-6.95(2H,m),7.02-7.28(5H,m),7.42(1H,br s),7.58(1H,br s),10.02(1H,br s).
[實施例19-7LP]
N-[(R)-胺甲醯基-(3-羥基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：2.916
MS(ESI,m/z)：453.1037(M-H)-
1H-NMR(DMSO-d6)δ ppm：1.21-1.34(1H,m),2.05-2.18(1H,m),2.46-2.61(1H,m),2.79-2.91(1H,m),5.01-5.11(1H,m),5.32(1H,br s),6.70-6.80(3H,m),6.84-6.94(2H,m),7.05-7.30(5H,m),7.46(1H,br s),7.56(1H,br s),9.56(1H,br s),10.03(1H,br s).
[實施例19-8LP]
{3-[(R)-胺甲醯基-{N-[(R)-6-氯-4-氟茚-1-基]-N-(2-羥基苄甲醯基)胺基}甲基]苄基}胺甲酸第三丁酯
RT(min.)：3.584
MS(ESI,m/z)：566.1879(M-H)-
1H-NMR(CDCl3)δ ppm：1.44(9H,s),1.71-1.89(1H,m),1.97-2.27(1H,m),2.49-2.93(2H,m),4.32(2H,d,J=5.9Hz),4.45-5.95(5H,m),6.89-7.08(3H,m),7.25-7.47(6H,m),7.64(1H,s),8.45-8.89(1H,m).
[實施例19-9HP]
N-[(S)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：2.021
MS(ESI,m/z)：438.1034(M-H)-
1H-NMR(CDCl3)δ ppm：2.47-2.68(2H,m),2.73-2.85(1H,m),3.08-3.19(1H,m),4.52(1H,br s),5.50-5.59(1H,m),5.84(1H,br s),6.04(1H,br s),6.46(1H,br s),6.83-7.02(3H,m),7.28-7.36(3H,m),7.92-7.97(1H,m),8.37-8.41(1H,m),8.54-8.58(1H,m),9.10(1H,br).
[實施例19-10M]
N-(胺甲醯基吡啶-3-基甲基)-N-[(S)-5,7-二氟-2,3-二氫苯并呋喃-3-基]-2-羥基苯甲醯胺
RT(min.)：1.537
MS(ESI,m/z)：424.1128(M-H)-
RT(min.)：1.614
MS(ESI,m/z)：424.1119(M-H)-
1H-NMR(CDCl3)δ ppm：4.30-5.15(3H,m),5.55-6.57(3H,m),6.66-6.88(1H,m),6.91-7.01(2H,m),7.04-7.44(4H,m),7.81-8.02(1H,m),8.25-8.86(2H,m).
[實施例19-11LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-5-甲基苯甲醯胺
RT(min.)：2.416
MS(ESI,m/z)：452.1193(M-H)-
1H-NMR(CDCl3)δ ppm：1.75-1.92(1H,m),2.17-2.40(4H,m),2.56-2.67(1H,m),2.73-2.93(1H,m),4.60-4.97(1H,m),5.46-5.95(2H,m),6.20-6.55(1H,m),6.81(1H,d,J=8.1Hz),6.94-7.03(1H,m),7.05-7.13(2H,m),7.35-7.41(1H,m),7.49(1H,s),7.96(1H,br s),8.58-8.63(1H,m),8.73(1H,s),9.20(1H,br).
[實施例19-12LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-4-甲基苯甲醯胺
RT(min.)：2.416
MS(ESI,m/z)：452.1195(M-H)-
1H-NMR(CDCl3)δ ppm：1.75-1.92(1H,m),2.00-2.41(4H,m),2.55-2.68(1H,m),2.78-2.94(1H,m),4.60-5.02(1H,m),5.46-6.31(3H,m),6.71-6.76(1H,m),6.79(1H,s),6.96-7.03(1H,m),7.23(1H,d,J=7.9Hz),7.35-7.40(1H,m),7.54(1H,s),7.94(1H,br s),8.59-8.64(1H,m),8.69(1H,s),9.22(1H,br).
[實施例19-13LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-3-甲氧基苯甲醯胺
RT(min.)：2.295
MS(ESI,m/z)：468.1145(M-H)-
1H-NMR(CDCl3)δ ppm：1.77-1.94(1H,m),2.22-2.42(1H,m),2.54-2.66(1H,m),2.77-2.95(1H,m),3.92(3H,s),4.66-4.83(1H,m),5.42-6.82(3H,m),6.90-7.03(4H,m),7.30-7.37(1H,m),7.53(1H,s),7.98(1H,br s),8.56-8.61(1H,m),8.67(1H,s).
[實施例19-14LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-3-異丙基苯甲醯胺
RT(min.)：3.092
MS(ESI,m/z)：480.1507(M-H)-
1H-NMR(CDCl3)δ ppm：1.25(6H,t,J=6.9Hz),1.69-2.38(2H,m),2.55-2.68(1H,m),2.75-2.94(1H,m),3.38(1H,septet,J=6.9Hz),4.59-4.92(1H,m),5.47-5.90(3H,m),6.80-6.92(1H,m),6.97-7.04(1H,m),7.18(1H,dd,J=1.6,7.7Hz),7.30(1H,dd,J=1.4,7.7Hz),7.36-7.40(1H,m),7.63(1H,s),7.99(1H,br s),8.60-8.83(3H,m).
[實施例19-15LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-氟-6-羥基苯甲醯胺
RT(min.)：2.311
MS(ESI,m/z)：456.0944(M-H)-
1H-NMR(CDCl3)δ ppm：1.50-2.00(1H,m),2.24-2.94(3H,m),4.60-4.88(1H,m),5.45-5.94(3H,m),6.58-6.84(2H,m),6.96-7.07(1H,m),7.12-7.56(3H,m),7.77-8.17(1H,m),8.51-9.07(2H,m).
[實施例19-16LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-氟-2-羥基苯甲醯胺
RT(min.)：2.361
MS(ESI,m/z)：456.0941(M-H)-
1H-NMR(CDCl3)δ ppm：1.70-1.90(1H,m),1.98-2.39(1H,m),2.56-2.69(1H,m),2.78-2.93(1H,m),4.64-5.05(1H,m),5.43-6.33(3H,m),6.60-6.71(2H,m),6.97-7.05(1H,m),7.31(1H,dd,J=6.4,8.4Hz),7.38-7.44(1H,m),7.51(1H,s),7.92-7.99(1H,m),8.63(1H,dd,J=1.4,4.9Hz),8.72-8.76(1H,m).
[實施例19-17LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-4-氯-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：2.589
MS(ESI,m/z)：472.0653(M-H)-
1H-NMR(CDCl3)δ ppm：1.70-1.90(1H,m),2.12-2.39(1H,m),2.56-2.69(1H,m),2.78-2.93(1H,m),4.64-5.00(1H,m),5.38-6.41(3H,m),6.87-7.06(3H,m),7.22-7.28(1H,m),7.42(1H,dd,J=4.9,8.0Hz),7.48(1H,s),7.91-8.00(1H,m),8.62(1H,dd,J=1.4,4.8Hz),8.76(1H,s).
[實施例19-18LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-4-硝基苯甲醯胺
RT(min.)：2.510
MS(ESI,m/z)：483.0887(M-H)-
1H-NMR(CDCl3)δ ppm：1.70-1.90(1H,m),2.25-2.42(1H,m),2.56-2.68(1H,m),2.75-2.89(1H,m),4.73-4.86(1H,m),5.33-5.47(1H,m),5.79-6.21(2H,m),6.97-7.06(1H,m),7.43-7.54(3H,m),7.75-7.83(2H,m),7.97-8.06(1H,m),8.66-8.70(1H,m),8.86(1H,br s).
[實施例19-19LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-4-甲氧基苯甲醯胺
RT(min.)：2.297
MS(ESI,m/z)：468.1145(M-H)-
1H-NMR(CDCl3)δ ppm：1.78-1.92(1H,m),1.97-2.33(1H,m),2.59-2.71(1H,m),2.84-2.96(1H,m),3.81(3H,s),4.67-5.07(1H,m),5.50-6.18(3H,m),6.47(1H,dd,J=2.5,8.7Hz),6.53(1H,d,J=2.5Hz),6.99-7.04(1H,m),7.32(1H,d,J=8.7Hz),7.37(1H,dd,J=4.8,7.9Hz),7.60(1H,s),7.85-7.96(1H,m),8.60-8.67(2H,m),9.69(1H,br s).
[實施例19-20LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-3-氯-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：2.523
MS(ESI,m/z)：472.0646(M-H)-
1H-NMR(CDCl3)δ ppm：1.50-2.40(2H,m),2.54-2.65(1H,m),2.76-2.90(1H,m),4.65-4.90(1H,m),5.30-5.52(1H,m),5.76-6.23(2H,m),6.90-7.03(2H,m),7.24-7.28(1H,m),7.36(1H,dd,J=4.8,7.9Hz),7.40(1H,dd,J=1.5,8.0Hz),7.56(1H,s),7.91-8.01(1H,m),8.56-8.61(1H,m),8.66-8.69(1H,m).
[實施例19-21LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-4-三氟甲基苯甲醯胺
RT(min.)：2.813
MS(ESI,m/z)：506.0924(M-H)-
1H-NMR(CDCl3)δ ppm：1.65-1.90(1H,m),2.22-2.42(1H,m),2.55-2.67(1H,m),2.73-2.89(1H,m),4.71-4.88(1H,m),5.37-5.51(1H,m),5.94-6.52(2H,m),6.95-7.05(1H,m),7.12-7.21(2H,m),7.37-7.46(2H,m),7.48(1H,s),7.91-8.02(1H,m),8.58-8.62(1H,m),8.82(1H,br s).
[實施例19-22LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5-氟-2-羥基苯甲醯胺
RT(min.)：2.341
MS(ESI,m/z)：456.0941(M-H)-
1H-NMR(CDCl3)δ ppm：1.65-1.91(1H,m),2.15-2.45(1H,m),2.56-2.69(1H,m),2.74-2.91(1H,m),4.65-4.86(1H,m),5.40-5.61(1H,m),5.83-6.46(2H,m),6.86(1H,dd,J=4.3,8.9Hz),6.94-7.04(3H,m),7.40(1H,dd,J=4.9,8.0Hz),7.48(1H,s),7.90-8.01(1H,m),8.57-8.63(1H,m),8.75(1H,br s).
[實施例19-23LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-3-三氟甲氧基苯甲醯胺
RT(min.)：2.789
MS(ESI,m/z)：522.0866(M-H)-
1H-NMR(CDCl3)δ ppm：1.65-1.93(1H,m),2.15-2.39(1H,m),2.55-2.67(1H,m),2.74-2.91(1H,m),4.66-4.90(1H,m),5.35-5.53(1H,m),5.70-6.21(2H,m),6.92-7.04(2H,m),7.25-7.33(2H,m),7.38(1H,dd,J=4.9,8.1Hz),7.52(1H,s),7.93-8.04(1H,m),8.59-8.63(1H,m),8.69-8.73(1H,m).
[實施例19-24LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-羥基異菸鹼醯胺
RT(min.)：1.394
MS(ESI,m/z)：439.0989(M-H)-
1H-NMR(DMSO-d6)δ ppm：1.21-2.13(2H,m),2.47-3.01(2H,m),5.01-5.45(2H,m),7.08-7.61(6H,m),7.68-7.92(1H,m),8.11-8.33(2H,m),8.47-8.67(2H,m),10.2-11.1(1H,m).
[實施例19-25LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-氟-2-羥基苯甲醯胺
RT(min.)：2.252
MS(ESI,m/z)：456.0941(M-H)-
1H-NMR(CDCl3)δ ppm：1.86-3.06(4H,m),4.06-5.36(2H,m),5.50(1H,br s),6.56(1H,br s),6.75-7.44(6H,m),7.80-8.08(1H,m),8.58-8.66(1H,m),8.69-8.76(1H,m).
[實施例19-26LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-5-甲氧基苯甲醯胺
RT(min.)：2.240
MS(ESI,m/z)：468.1144(M-H)-
1H-NMR(CDCl3)δ ppm：1.72-1.88(1H,m),2.00-2.39(1H,m),2.55-2.67(1H,m),2.74-2.92(1H,m),3.74(3H,s),4.60-4.95(1H,m),5.40-6.32(3H,m),6.82-6.89(3H,m),6.96-7.02(1H,m),7.35-7.41(1H,m),7.54(1H,s),7.92-8.01(1H,m),8.50-8.98(3H,m).
[實施例19-27LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-5-氯-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：2.525
MS(ESI,m/z)：472.0644(M-H)-
1H-NMR(CDCl3)δ ppm：1.70-1.90(1H,m),2.15-2.45(1H,m),2.57-2.70(1H,m),2.75-2.91(1H,m),4.60-4.97(1H,m),5.39-5.60(1H,m),5.70-6.38(2H,m),6.87(1H,d,J=8.6Hz),6.97-7.04(1H,m),7.21-7.28(2H,m),7.41(1H,dd,J=4.9,8.0Hz),7.46(1H,br s),7.93-8.05(1H,m),8.60-8.66(1H,m),8.72-8.76(1H,m).
[實施例19-28LP]
5-乙醯基-N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：2.083
MS(ESI,m/z)：480.1145(M-H)-
1H-NMR(CDCl3)δ ppm：1.75-1.92(1H,m),2.15-2.45(1H,m),2.52(3H,s),2.56-2.70(1H,m),2.75-2.91(1H,m),4.65-4.99(1H,m),5.39-5.58(1H,m),5.70-6.30(2H,m),6.96-7.03(2H,m),7.44(1H,dd,J=4.9,8.0Hz),7.50(1H,br s),7.86-8.08(3H,m),8.65(1H,d,J=4.5Hz),8.75(1H,br s).
[實施例19-29LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-乙氧基-2-羥基苯甲醯胺
RT(min.)：2.485
MS(ESI,m/z)：482.1299(M-H)-
1H-NMR(CDCl3)δ ppm：1.41(3H,t,J=7.0Hz),1.79-2.36(2H,m),2.59-2.72(1H,m),2.84-2.97(1H,m),4.03(2H,q,J=7.0Hz),4.65-5.14(1H,m),5.50-6.20(3H,m),6.45(1H,dd,J=2.4,8.7Hz),6.51(1H,d,J=2.4Hz),6.98-7.04(1H,m),7.30(1H,d,J=8.7Hz),7.36(1H,dd,J=4.8,8.0Hz),7.59(1H,s),7.85-7.94(1H,m),8.60-8.67(2H,m),9.67(1H,br).
[實施例19-30LP]
5-乙醯基胺基-N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：1.746
MS(ESI,m/z)：495.1254(M-H)-
1H-NMR(CD3OD)δ ppm：1.33-2.36(5H,m),2.55-3.06(2H,m),4.85-5.78(2H,m),6.83-7.61(5H,m),7.64(1H,s),7.91-8.09(1H,m),8.48-8.71(2H,m).
[實施例19-31LP]
N-[(R)-胺甲醯基(5-氟吡啶-3-基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：2.881
MS(ESI,m/z)：456.0943(M-H)-
1H-NMR(CDCl3)δ ppm：1.70-1.89(1H,m),2.14-2.38(1H,m),2.58-2.70(1H,m),2.79-2.92(1H,m),4.67-4.95(1H,m),5.49-6.34(3H,m),6.91-6.97(2H,m),6.99-7.04(1H,m),7.28-7.35(2H,m),7.50(1H,s),7.76-7.86(1H,m),8.46-8.51(2H,m),8.90(1H,br).
[實施例19-32LP]
N-[(R)-胺甲醯基(5-甲氧基吡啶-3-基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：2.520
MS(ESI,m/z)：468.1147(M-H)-
1H-NMR(CDCl3)δ ppm：1.73-1.91(1H,m),2.01-2.36(1H,m),2.55-2.68(1H,m),2.77-2.93(1H,m),3.88(3H,s),4.64-4.94(1H,m),5.47-6.10(3H,m),6.89-6.95(1H,m),6.96-7.05(2H,m),7.29-7.36(2H,m),7.53-7.63(2H,m),8.24(1H,d,J=1.8Hz),8.32(1H,d,J=2.8Hz),8.94(1H,br).
[實施例19-33LP]
N-[(R)-胺甲醯基(5-甲基吡啶-3-基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：2.185
MS(ESI,m/z)：452.1190(M-H)-
1H-NMR(CDCl3)δ ppm：1.77-1.93(1H,m),2.12-2.46(4H,m),2.55-2.68(1H,m),2.76-2.93(1H,m),4.60-4.98(1H,m),5.40-6.43(3H,m),6.88-7.04(3H,m),7.24-7.37(2H,m),7.51(1H,s),7.76(1H,br s),8.44(1H,s),8.54(1H,br s),9.57(1H,br).
[實施例19-34LP]
N-[(R)-胺甲醯基(5-三氟甲基吡啶-3-基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：3.266
MS(ESI,m/z)：506.0909(M-H)-
1H-NMR(CDCl3)δ ppm：1.71-1.87(1H,m),2.10-2.43(1H,m),2.59-2.72(1H,m),2.81-2.94(1H,m),4.79-5.00(1H,m),5.51-6.58(3H,m),6.89-6.98(2H,m),6.99-7.04(1H,m),7.27-7.35(2H,m),7.45(1H,s),8.20(1H,s),8.75-8.98(3H,m).
[實施例19-35LP]
N-[(R)-胺甲醯基(6-三氟甲基吡啶-3-基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：3.395
MS(ESI,m/z)：506.0911(M-H)-
1H-NMR(DMSO-d6)δ ppm：1.21-1.79(1H,m),2.00-2.17(1H,m),2.45-2.92(2H,m),4.89-5.62(2H,m),6.69-8.22(10H,m),8.65-8.87(1H,m),10.14-10.43(1H,m).
[實施例19-36LP]
N-[(R)-胺甲醯基(5-氯吡啶-3-基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：3.077
MS(ESI,m/z)：472.0647(M-H)-
1H-NMR(CDCl3)δ ppm：1.72-1.89(1H,m),2.16-2.38(1H,m),2.58-2.70(1H,m),2.81-2.94(1H,m),4.65-4.96(1H,m),5.47-6.45(3H,m),6.91-6.96(2H,m),6.98-7.03(1H,m),7.28-7.35(2H,m),7.48(1H,s),8.00(1H,br s),8.55-8.59(2H,m),9.00(1H,br).
[實施例19-37LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(S)-5-氯-7-氟-2,3-二氫苯并呋喃-3-基]-2-羥基苯甲醯胺
RT(min.)：1.942
MS(ESI,m/z)：440.0827(M-H)-
1H-NMR(CDCl3)δ ppm：4.32-5.01(3H,m),5.56-6.60(3H,m),6.92-7.00(2H,m),7.04-7.11(1H,m),7.26-7.37(3H,m),7.43(1H,dd,J=4.8,8.0Hz),7.89-8.02(1H,m),8.61-8.65(1H,m),8.84(1H,br s),10.25(1H,br).
[實施例19-38LP]
N-[(R)-胺甲醯基(5-羥基吡啶-3-基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：2.133
MS(ESI,m/z)：454.0983(M-H)-
1H-NMR(DMSO-d6)δ ppm：1.21-1.39(1H,m),2.02-2.17(1H,m),2.42-2.93(2H,m),4.97-5.44(2H,m),6.83-6.96(2H,m),7.05-7.70(7H,m),7.96-8.15(2H,m),10.12(1H,br).
[實施例19-39LP]
N-[(R)-胺甲醯基(5-氰基吡啶-3-基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：2.915
MS(ESI,m/z)：463.0988(M-H)-
1H-NMR(CDCl3)δ ppm：1.70-1.86(1H,m),2.21-2.45(1H,m),2.61-2.73(1H,m),2.81-2.94(1H,m),4.71-4.90(1H,m),5.47-5.64(1H,m),5.71-6.70(2H,m),6.88(1H,d,J=8.2Hz),6.94-7.06(2H,m),7.27-7.35(2H,m),7.41(1H,s),8.28(1H,br s),8.52-8.96(3H,m).
[實施例19-40LP]
N-[(S)-胺甲醯基吡啶-3-基甲基]-N-[(S)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：2.176
MS(ESI,m/z)：438.1033(M-H)-
1H-NMR(CDCl3)δ：1.70-2.40(2H,m),2.54-2.94(2H,m),4.48-5.03(1H,m),5.40-6.53(3H,m),6.88-7.04(3H,m),7.28-7.35(2H,m),7.39(1H,dd,J=4.8,7.9Hz),7.50-7.55(1H,m),7.88-8.05(1H,m),8.62(1H,dd,J=1.5,4.8Hz),8.69-8.78(1H,m),9.38(1H,br).
[實施例19-41LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-3-甲基苯甲醯胺
RT(min.)：2.536
MS(ESI,m/z)：452.1197(M-H)-
1H-NMR(CDCl3)δ ppm：1.69-1.87(1H,m),1.98-2.36(4H,m),2.54-2.66(1H,m),2.73-2.93(1H,m),4.58-4.97(1H,m),5.46-5.98(3H,m),6.80-6.87(1H,m),6.97-7.04(1H,m),7.15-7.24(2H,m),7.34-7.40(1H,m),7.61(1H,br s),7.98(1H,br s),8.59-8.75(3H,m).
[實施例20-1]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2,4-二羥基苯甲醯胺
4-{N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]胺甲醯基}-3-羥基苯基乙酸酯
於(R)-6-氯-4-氟茚-1-基胺鹽酸鹽(0.11g)之甲醇(4mL)溶液加入三乙基胺(68μL)及3-甲醯基吡啶(0.054g)，以60℃攪拌2小時。將反應混合物冷卻至室溫後，加入2,4-二乙醯氧基安息香酸(0.097g)及4-苯基環己烯-1-基異氰(0.092g)，以60℃攪拌整夜。將反應混合物冷卻至室溫後，於減壓下濃縮。對所得殘渣加入1,4-二烷(5mL)、水(0.5mL)及4mol/L氯化氫1,4-二烷溶液(0.5mL)，以室溫攪拌3小時。於反應混合物加入飽和碳酸氫鈉水溶液，將此混合物以逆相分離液體層析(CapcellPakC18 UG80，洗提溶媒：乙腈/水=1/9-7/3)精製，得到N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2,4-二羥基苯甲醯胺(實施例20-1-1LP，3mg)及4-{N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]胺甲醯基}-3-羥基苯基乙酸酯(實施例20-1-2LP，17mg)。構造式示於表43。
[實施例20-1-1LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2,4-二羥基苯甲醯胺
RT(min.)：1.798
MS(ESI,m/z)：454.0987(M-H)-
1H-NMR(CD3OD)δ ppm：1.10-2.10(2H,m),2.54-2.69(1H,m),2.80-3.00(1H,m),5.12-5.90(2H,m),6.37-6.42(2H,m),6.89-7.00(1H,m),7.06-7.14(1H,m),7.45-7.52(1H,m),7.60(1H,s),7.89-7.97(1H,m),8.50-8.56(1H,m),8.60(1H,br s).
[實施例20-1-2LP]
4-{N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]胺甲醯基}-3-羥基苯基乙酸酯
RT(min.)：2.215
MS(ESI,m/z)：496.1094(M-H)-
1H-NMR(CD3OD)δ ppm：1.30-2.36(5H,m),2.55-3.08(2H,m),5.14-5.80(2H,m),6.67-6.77(2H,m),6.85-7.11(1H,m),7.21-7.56(2H,m),7.61(1H,s),7.87-8.08(1H,m),8.48-8.72(2H,m).
[實施例20-2LP]
N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2,3-二羥基苯甲醯胺
使用對應之原料，依與實施例20-1相同的方法合成標題化合物。又，標題化合物之質譜數據如以下，構造式示於表43。
RT(min.)：1.885
MS(ESI,m/z)：454.0985(M-H)-
1H-NMR(CD3OD)δ ppm：1.22-3.08(4H,m),5.06-5.80(2H,m),6.59-7.14(4H,m),7.40-7.55(1H,m),7.64(1H,s),7.90-8.13(1H,m),8.45-8.72(2H,m).
[實施例21-1]
N-[(R)-(3-胺基苯基)胺甲醯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺
如以下般調製雷氏觸媒之懸浮液。將Raney(註冊商標)2800 nickel,slurry in water,active catalyst(Sigma-Aldrich)之懸濁液(200μL)與乙醇的混合物進行攪拌，以傾析去除溶媒。將觸媒以乙醇洗淨3次，加入乙醇(1mL)，作成懸浮液。將此雷氏觸媒懸浮液以室溫加入N-[(R)-胺甲醯基-(3-硝基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺(實施例18-12LP，55mg)之乙醇(5mL)溶液，將此混合物於氫環境下攪拌2小時。過濾去除觸媒，將濾液減壓濃縮，得到標題化合物(36mg)。構造式示於表43。
RT(min.)：1.959
MS(ESI,m/z)：451.1350(M-H)-
1H-NMR(DMSO-d6)δ ppm：1.40-1.58(1H,m),2.03-2.16(1H,m),2.29-2.95(5H,m),4.93-5.34(4H,m),6.34-6.60(3H,m),7.00-7.85(7H,m),8.48-8.56(1H,m).
[實施例21-2~21-3]
使用對應之原料，依與實施例21-1相同的方法合成實施例21-2~21-3。又，實施例21-2~21-3之質譜數據如以下，構造式示於表43。
[實施例21-2]
N-[(R)-(3-胺基苯基)胺甲醯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：2.395
MS(ESI,m/z)：452.1190(M-H)-
1H-NMR(DMSO-d6)δ ppm：1.27-1.41(1H,m),2.07-2.21(1H,m),2.46-2.61(1H,m),2.79-2.91(1H,m),5.03-5.13(1H,m),5.18(2H,br s),5.25(1H,br s),6.45-6.57(3H,m),6.81-6.93(2H,m),6.99-7.29(5H,m),7.41(1H,br s),7.58(1H,br s),10.00(1H,br s).
[實施例21-3]
4-胺基-N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺
RT(min.)：1.611
MS(ESI,m/z)：453.1149(M-H)-
1H-NMR(CD3OD)δ ppm：1.45-2.09(2H,m),2.54-2.67(1H,m),2.83-2.97(1H,m),5.22-5.84(2H,m),6.23(1H,d,J=2.0Hz),6.28(1H,dd,J=2.0,8.3Hz),6.91-6.97(1H,m),7.02(1H,d,J=8.3Hz),7.48(1H,dd,J=5.0,7.8Hz),7.57(1H,s),7.88-7.94(1H,m),8.50-8.54(1H,m),8.56-8.60(1H,m).
[實施例22]
N-[(R)-(3-乙醯基胺基苯基)胺甲醯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺
於N-[(R)-(3-胺基苯基)胺甲醯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺(實施例21-1，80mg)與N,N-二異丙基乙基胺(0.03mL)及二氯甲烷(3mL)的混合物，以室溫加入乙醯氯(14mg)，將此混合物攪拌2小時。對反應混合物中加水，以醋酸乙酯萃取粗製生成物。將有機層以水及飽和食鹽水洗淨，以無水硫酸鎂乾燥。將溶媒減壓餾除，對所得殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=5/1-醋酸乙酯/甲醇=10/1)精製，得到標題化合物(75mg)。構造式示於表43。
RT(min.)：2.267
MS(ESI,m/z)：539.1513(M+HCO2)-
1H-NMR(DMSO-d6)δ ppm：1.29-1.53(1H,m),1.99-2.15(4H,m),2.34-2.70(4H,m),2.84-2.97(1H,m),4.90-5.38(2H,m),6.88-7.94(10H,m),8.51-8.59(1H,m),10.07(1H,s).
[實施例23]
N-[(R)-胺甲醯基-(3-甲磺醯基胺基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺
於N-[(R)-(3-胺基苯基)胺甲醯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺(實施例21-1，80mg)與N,N-二異丙基乙基胺(0.03mL)及二氯甲烷(3mL)的混合物，以室溫加入甲磺醯氯(18mg)，將此混合物攪拌2小時。對反應混合物中加水，以醋酸乙酯萃取粗製生 成物。將有機層以水及飽和食鹽水洗淨，以無水硫酸鎂乾燥。將溶媒減壓餾除，對所得殘渣以矽膠管析層析(洗提溶媒：醋酸乙酯/正己烷=5/1-醋酸乙酯/甲醇=10/1)精製，得到標題化合物(34mg)。構造式示於表43。
RT(min.)：2.397
MS(ESI,m/z)：529.1127(M-H)-
1H-NMR(DMSO-d6)δ ppm：1.28-1.53(1H,m),1.98-2.15(1H,m),2.35-2.70(4H,m),2.84-3.05(4H,m),4.93-5.37(2H,m),6.97-7.87(10H,m),8.51-8.60(1H,m),9.93(1H,br s).
[表43]
[試驗例1]
Icilin誘發wet-dog shake抑制作用確認試驗
將試驗化合物溶解於二甲基乙醯胺(和光純藥)，依二甲基乙醯胺含量成為5%之方式添加0.5%甲基纖維素溶液(和光純藥)而調製溶解液或懸浮液後，對雌性SD鼠依3或10mg/kg/5mL進行經口投予。於1小時後將溶解於聚乙二醇400(和光純藥)之Icilin(1mg/kg)進行腹腔內投予，引起濕狗搖動(wet-dog shake)。於Icilin投予5分鐘後，計數5分鐘之濕狗搖動。作為比較試驗，同樣地投予媒體(二甲基 乙醯胺(和光純藥)：0.5%甲基纖維素溶液(和光純藥)=5：95的混合物)，同樣計數此等之濕狗搖動的次數。作為試驗化合物之濕狗搖動抑制率，藉下式算出：[1-(試驗化合物投予之濕狗搖動之計數/媒體投予之濕狗搖動的計數)]×100。結果示於表44及45。
[試驗例2]
對於醋酸誘發逼尿肌過動膀胱之排尿間隔的延長作用確認試驗
將胺甲基酸乙酯(Sigma)依25%w/v溶解於純水，對雌性SD鼠依1.25g/kg進行皮下投予而麻醉。於此鼠之膀胱及大腿靜脈插入導管，將膀胱導管連接至注射器泵與壓力轉換器。使用壓力轉換器監測膀胱內壓之同時，依3.6ml/小時持續對膀胱注入0.25%醋酸/生理食鹽水溶液，引起逼尿肌過動。由靜脈導管投予將試驗化合物溶解於二甲基乙醯胺與生理食鹽水的混合液(20：80)的溶液，將即將投予前之排尿3次之間隔的平均值設為100%，算出剛投予後3次之間隔的平均值作為排尿間隔延長率(Elongation of micturition interval(%))。將投予量及結果示於表46及47。
如表44及45所示般，本發明之化合物顯示了強力之TRPM8抑制作用。進而如表46及47所示般，本發明之化合物具有對於排尿間隔的延長作用，判明其有效抑制逼尿肌過動。
(產業上之可利用性)
本發明之化合物由於具有強力之TRPM8抑制作用，故可用於作為因TRPM8活性化所引起之疾病或症狀的治療或預防藥，其中可用於作為下泌尿道症狀(LUTS)、尤其是過動膀胱(OAB)的治療或預防藥。

Claims (15)

  1. 一種一般式(I)所示之化合物或其藥理學上所容許之鹽，
    Figure TWI641584B_C0001
    式中，A1為由以下之a)~c)所構成群選擇之基：a)非取代或以由以下所構成群獨立選擇之1~2個基所取代的C6-10芳基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、C1-6烷氧基羰基、氰基、羥基C1-6烷基、胺甲醯基、硝基、胺基、C1-6烷氧基羰基胺基C1-6烷基、單C1-6烷基胺基、二C1-6烷基胺基、(C1-6烷基)羰基胺基、C1-6烷基碸基(sulfonyl)胺基及C1-6烷基碸基；b)非取代或以由以下所構成群獨立選擇之1~2個基所取代的5員雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、氰基及鹵素C1-6烷氧基；及c)非取代或以由以下所構成群獨立選擇之1~2個基所取代的6員雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、氰基及鹵素C1-6烷氧基；A2為由以下之d)~f)所構成群選擇之基：d)非取代或以由以下所構成群獨立選擇之1~2個基所取代的C6-10芳基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、羥基C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、胺基、硝基、羧基、(C1-6烷基)羰基胺基、(C1-6烷基)羰基氧基、(C1-6烷基)羰基及(C7-10芳烷基氧基)羰基；e)非取代或以由以下所構成群獨立選擇之1~2個基所取代的雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、單C1-6烷基胺基、二C1-6烷基胺基、C1-6烷基硫基(sulfanyl)、胺基、(C7-10芳烷基氧基)羰基、羥基C1-6烷基、羥基C1-6烷氧基、C2-6烯基、
    Figure TWI641584B_C0002
    啉基及(C1-6烷基)羰基；及f)C3-6環烷基；X為CH或N；Y為-CR1R2-或氧原子；R1及R2獨立為氫原子、鹵原子或C1-6烷基；R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、羥基C1-6烷氧基、C3-6環烷基、C3-6環烷氧基、C2-6烯基或氰基，其中，在X為CH、且R1及R2均為氫原子時，R3及R4不同時為氫原子；及n為1或2。
  2. 如申請專利範圍第1項之化合物或其藥理學上所容許之鹽，其中，X為CH，n為1。
  3. 如申請專利範圍第2項之化合物或其藥理學上所容許之鹽，其中，一般式
    Figure TWI641584B_C0003
    所示之基，為下述一般式所示：[化3]
    Figure TWI641584B_C0004
    式中，R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、羥基C1-6烷氧基、C3-6環烷基、C3-6環烷氧基、C2-6烯基或氰基，其中，R3及R4不同時為氫原子。
  4. 如申請專利範圍第3項之化合物或其藥理學上所容許之鹽，其中，Y為-CR1R2-。
  5. 如申請專利範圍第4項之化合物或其藥理學上所容許之鹽，其中，一般式
    Figure TWI641584B_C0005
    所示之基，為下述一般式所示：
    Figure TWI641584B_C0006
    式中，A1為由以下之a1)、b)及c)所構成群選擇之基：a1)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、C1-6烷氧基羰基、氰基、羥基C1-6烷基、胺甲醯基、硝基、胺基、C1-6烷氧基羰基胺基C1-6烷基、單C1-6烷基胺基、二C1-6烷基胺基、(C1-6烷基)羰基胺基、C1-6烷基碸基胺基及C1-6烷基碸基；b)非取代或以由以下所構成群獨立選擇之1~2個基所取代的5員雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、氰基及鹵素C1-6烷氧基；及c)非取代或以由以下所構成群獨立選擇之1~2個基所取代的6員雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、氰基、及鹵素C1-6烷氧基。
  6. 如申請專利範圍第5項之化合物或其藥理學上所容許之鹽，其中，一般式
    Figure TWI641584B_C0007
    所示之基，為下述一般式所示：
    Figure TWI641584B_C0008
    式中，R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、羥基C1-6烷氧基、C3-6環烷基、C2-6烯基或氰基，其中，R3及R4不同時為氫原子。
  7. 如申請專利範圍第6項之化合物或其藥理學上所容許之鹽，其中，A2為由以下之d1)及e)所構成群選擇之基：d1)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、羥基C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、胺基、硝基、羧基、(C1-6烷基)羰基胺基、(C1-6烷基)羰基氧基、(C1-6烷基)羰基及(C7-10芳烷基氧基)羰基；及e)非取代或以由以下所構成群獨立選擇之1~2個基所取代的雜環：鹵原子、羥基、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、單C1-6烷基胺基、二C1-6烷基胺基、C1-6烷基硫基、胺基、(C7-10芳烷基氧基)羰基、羥基C1-6烷基、羥基C1-6烷氧基、C2-6烯基、
    Figure TWI641584B_C0009
    啉基及(C1-6烷基)羰基。
  8. 如申請專利範圍第7項之化合物或其藥理學上所容許之鹽，其中，A1為由以下之a2)、b1)及c1)所構成群選擇之基：a2)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、羥基C1-6烷基、氰基、胺基、單C1-6烷基胺基、二C1-6烷基胺基及C1-6烷氧基；b1)噻唑基；及c1)分別為非取代或以由以下所構成群獨立選擇之1~2個基所取代的吡啶基、嘧啶基或吡
    Figure TWI641584B_C0010
    基：鹵原子、C1-6烷基、C1-6烷氧基及氰基；A2為由以下之d2)及e1)所構成群選擇之基：d2)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、羥基C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、(C1-6烷基)羰基氧基及胺基；及e1)非取代或以由以下所構成群獨立選擇之1~2個基所取代的雜環：鹵原子、C1-6烷基、C1-6烷氧基、氰基、單C1-6烷基胺基、二C1-6烷基胺基、C1-6烷基硫基、胺基、羥基C1-6烷基及C2-6烯基；及R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、C3-6環烷基或氰基，其中，R3及R4不同時為氫原子。
  9. 如申請專利範圍第8項之化合物或其藥理學上所容許之鹽，其中，A2為由以下之d2)及e2)所構成群選擇之基：d2)非取代或以由以下所構成群獨立選擇之1~2個基所取代的苯基：鹵原子、羥基、C1-6烷基、C1-6烷氧基、羥基C1-6烷氧基、鹵素C1-6烷基、鹵素C1-6烷氧基、氰基、(C1-6烷基)羰基氧基及胺基；及e2)分別為非取代或以由以下所構成群獨立選擇之1~2個基所取代的吡啶基、嘧啶基、吡
    Figure TWI641584B_C0011
    基、噻吩基、噻唑基、異噻唑基、2,3-二氫苯并呋喃基、吡唑基、咪唑基、異
    Figure TWI641584B_C0012
    唑基、
    Figure TWI641584B_C0013
    唑基、呋呫基或苯并[1,3]二
    Figure TWI641584B_C0014
    呃基：鹵原子、C1-6烷基、C1-6烷氧基、氰基、單C1-6烷基胺基、二C1-6烷基胺基、C1-6烷基硫基、胺基、羥基C1-6烷基及C2-6烯基。
  10. 如申請專利範圍第9項之化合物或其藥理學上所容許之鹽，其中，A1分別為非取代或以由以下所構成群取代環的苯基、吡啶基或吡
    Figure TWI641584B_C0015
    基：鹵原子、胺基、單C1-6烷基胺基、二C1-6烷基胺基或羥基；A2為由以下之d3)及e3)所構成群選擇之基：d3)非取代或以由以下所構成群獨立選擇之1~2個基取代環的苯基：鹵原子、羥基、C1-6烷基、C1-6烷氧基及胺基；及e3)分別為非取代或以由以下所構成群獨立選擇之1~2個基所取代的吡啶基、嘧啶基、吡
    Figure TWI641584B_C0016
    基、噻唑基、2,3-二氫苯并呋喃基、吡唑基、異
    Figure TWI641584B_C0017
    唑基或苯并[1,3]二
    Figure TWI641584B_C0018
    呃基：鹵原子、C1-6烷基、C1-6烷氧基、單C1-6烷基胺基、二C1-6烷基胺基、C1-6烷基硫基及胺基；及R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷氧基、C3-6環烷基或氰基，其中，R3及R4不同時為氫原子。
  11. 如申請專利範圍第10項之化合物或其藥理學上所容許之鹽，其中，A1分別為非取代或以由以下所構成群取代環的苯基、吡啶基或吡
    Figure TWI641584B_C0019
    基：鹵原子或羥基；A2為由以下之d4)及e3)所構成群選擇之基：d4)非取代或以由以下所構成群獨立選擇之1~2個基取代環的苯基：鹵原子、羥基、C1-6烷氧基及胺基；及e3)分別為非取代或以由以下所構成群獨立選擇之1~2個基所取代的吡啶基、嘧啶基、吡
    Figure TWI641584B_C0020
    基、噻唑基、2,3-二氫苯并呋喃基、吡唑基、異
    Figure TWI641584B_C0021
    唑基或苯并[1,3]二
    Figure TWI641584B_C0022
    呃基：鹵原子、C1-6烷基、C1-6烷氧基、單C1-6烷基胺基、二C1-6烷基胺基、C1-6烷基硫基及胺基；及R3及R4獨立為氫原子、鹵原子、C1-6烷基、C1-6烷氧基、鹵素C1-6烷氧基、C3-6環烷基或氰基，其中，R3及R4不同時為氫原子。
  12. 如申請專利範圍第1項之化合物或其藥理學上所容許之鹽，其係選自由以下所組成之群：N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-甲氧基茚-1-基]菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]苯甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-甲氧基茚-1-基]苯甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-環丙基茚-1-基]苯甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-二氟甲氧基茚-1-基]苯甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-二氟甲氧基茚-1-基]菸鹼醯胺；2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-二氟甲氧基茚-1-基]菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]菸鹼醯胺；2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟-6-甲氧基茚-1-基]菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟-6-甲基茚-1-基]菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4-氟茚-1-基]菸鹼醯胺；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]噻唑-5-甲醯胺；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-4,6-二氟茚-1-基]苯甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5-氟菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]苯甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氰基茚-1-基]-2-羥基苯甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(S)-5-氯-2,3-二氫苯并呋喃-3-基]-2-羥基苯甲醯胺；2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]苯甲醯胺；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-2-甲氧基菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-2-甲氧基菸鹼醯胺；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯茚-1-基]苯甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-4-甲基噻唑-5-甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基苯甲醯胺；N-[(R)-胺甲醯基苯基甲基]-2-氯-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺；N-[(R)-胺甲醯基吡啶-3-基甲基]-2-氯-N-[(R)-6-氯-4-氟茚-1-基]苯甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-(甲基胺基)菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2,3-二氫苯并呋喃-7-甲醯胺；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基苯甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-2-(甲基硫基)菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-(甲基硫基)菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-2-甲基菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-4,6-二氟茚-1-基]-4-甲基噻唑-5-甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基-2H-吡唑-3-甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯茚-1-基]-2-甲基菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-5-甲基噻唑-4-甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基異
    Figure TWI641584B_C0023
    唑-5-甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-甲基吡啶-2-甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基嘧啶-5-甲醯胺；N-[(R)-胺甲醯基-(3-氟苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-甲基異菸鹼醯胺；N-[(R)-胺甲醯基-(3-羥基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯并[1,3]二
    Figure TWI641584B_C0024
    呃-4-甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]苯并[1,3]二
    Figure TWI641584B_C0025
    呃-4-甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-甲基吡
    Figure TWI641584B_C0026
    -2-甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]吡
    Figure TWI641584B_C0027
    -2-甲醯胺；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基菸鹼醯胺；N-[(RS)-胺甲醯基苯基甲基]-N-[(SR)-5-氯-7-氟-2,3-二氫苯并呋喃-3-基]苯甲醯胺；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺；N-[(R)-胺甲醯基吡
    Figure TWI641584B_C0028
    -2-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-3-甲基苯甲醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲氧基菸鹼醯胺；2-胺基-N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；N-[(R)-胺甲醯基苯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-甲基噻唑-5-甲醯胺；N-[(R)-胺甲醯基-(3-二甲基胺基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；N-[(R)-胺甲醯基-(3-二甲基胺基苯基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-4-甲基苯甲醯胺；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-氟-6-羥基苯甲醯胺；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-4-氟-2-羥基苯甲醯胺；N-[(R)-胺甲醯基吡啶-3-基甲基]-4-氯-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺；N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-3-氟-2-羥基苯甲醯胺；N-[(R)-(3-胺基苯基)胺甲醯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-甲基菸鹼醯胺；N-[(R)-(3-胺基苯基)胺甲醯基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺；N-[(R)-胺甲醯基(5-氟吡啶基-3-基)甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基苯甲醯胺；及N-[(R)-胺甲醯基吡啶-3-基甲基]-N-[(R)-6-氯-4-氟茚-1-基]-2-羥基-3-甲基苯甲醯胺。
  13. 一種醫藥組成物，其係含有申請專利範圍第1至12項中任一項記載之化合物或其藥理學上所容許之鹽。
  14. 如申請專利範圍第13項之醫藥組成物，其係起因於傳入神經之過剩興奮或障礙的疾病或症狀的治療或預防用。
  15. 一種申請專利範圍第1至12項中任一項記載之化合物或其藥理學上所容許之鹽的使用，係用於製造起因於傳入神經之過剩興奮或障礙的疾病或症狀的治療或預防用的醫藥組成物。
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