TW201143771A - Polycyclic compound - Google Patents

Polycyclic compound Download PDF

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TW201143771A
TW201143771A TW100115874A TW100115874A TW201143771A TW 201143771 A TW201143771 A TW 201143771A TW 100115874 A TW100115874 A TW 100115874A TW 100115874 A TW100115874 A TW 100115874A TW 201143771 A TW201143771 A TW 201143771A
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amino
compound
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phenyl
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TW100115874A
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Takuya Ikeda
Takanori Yamazaki
Takaaki Jojima
Nana Takagi
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Daiichi Sankyo Co Ltd
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Abstract

The subject of present invention is related to a compound with excellent antagonistic effect to neurokinin NK1 receptor, neurokinin NK2 receptor and muscarine M3 receptor, or excellent antagonistic effect to neurokinin NK1 recepto and muscarine M3 receptor, so as to be useful as a therapeutic drug of bronchus asthma, chronic obstructive pulmonary disease and the like; or a pharmacologically acceptable salt thereof. The mean of solution is a compound having general formula (I) or pharmacologically acceptable salt thereof [In formula, Y is a part structure having antagonistic effect to neurokinin NK1 receptor and neurokinin NK2 receptor, or a part structure having antagonistic effect to neurokinin NK1 receptor; A is a single bond, triple bond, oxygen atom, carbonyl and the like; E is a part structure having antagonistic effect to muscarine M3 receptor; m is an integer of 0 to 4; n is an integer of 1 to 8].

Description

201143771 六、發明說明： ， 【發明所屬之技術領域】 本發明係關於具有優異神經激肽（neur〇kinin ) NK,、神經激肽NK：2及蕈毒鹼m3受體拮抗作用、或具有 神經激肽NK,及蕈毒鹼Μ〗受體拮抗作用，而有用於作 為支氣管氣喘、慢性阻塞性肺病等之治療藥的化合物或 其藥理上可容許的鹽。 【先前技術】 支氣管氣°而或慢性阻塞性肺病（C 〇 p D )係支氣管收 縮、呼吸道炎症、黏液分泌、咳嗽等為亢進的。基質p (substance P )或神經激肽A與呼吸道收縮作用、炎症 作用、咳、黏液分泌有關，對基質p或神經激肽A之兩 文體（神經激肽NK,及神經激肽NK：2受體）拮抗的化合 物有抑制上述生理作用的可能性（非專利文獻丨、非專 利文獻2)。已揭示對神經激肽ΝΚι及神經激肽nk2兩 党體拮抗的非胜肽性低分子化合物（專利文獻丨、專利 文獻2 )，但尚未獲得作為藥劑使用的認可。另一方面， 乙醯基膽鹼藉由使蕈毒鹼性％受體作用，而引起強的呼 吸道收縮作用（非專利文獻3)。對孽毒驗性A受體拮 抗的化合物有具有支氣管擴張作用的化合 :、專:文獻4、專利文獻5)，可被使用作為支氣』 非專利文獻4)。已揭示藉由拮Μ “性^ 營撼^ * &amp;升各個早獨戶斤發揮的支氣 s擴張作用而發揮強的支翁瞢 又札官擴張作用（專利文獻6 )。 201143771 然而，對神經激肽NK!及神經激肽NK：2兩受體抬抗的化 合物、或對神經激肽ΝΚ!受體拮抗的化合物因尚未被上 市作為支氣管氣喘或COPD治療藥，而有所謂無法併用 早劑的問題點。藉由枯抗神經激狀Ν Κ1、神經激肽ν κ 2 及蕈毒鹼性Ms受體、或拮抗神經激肽ΝΚ,及簟毒驗性 Ms受體，而具有強的支氣管擴張作用、抗炎症作用、鎮 咳去痰作用的單一化合物正被企望。 [先前技術文獻] [專利文獻] [專利文獻1]US65 1 1 975號公報 [專利文獻2] US7365067號公報 [專利文獻3]US2004/167167號公報 [專利文獻4]US2005/203 1 3 1號公報 [專利文獻5]US2006/28 1740號公報 [專利文獻6]特開2006-160639號公報 [非專利文獻] [非專利文獻 1 ] American Review Of Respiratory Disease,1991, vol.144, pages 11 87-11 98 [非專利文獻 2] American Review Of Respiratory Disease, 1991, vol. 144, pages 1 39 1 -1 399 [非專利文獻 3] Life Sciences, 1993, vol. 52, pages521-527 [I卜專利文獻 4] European Journal of Pharmacology, 2006，vol. 533，pages36-39 鍵、氧原子 201143771 【發明内容】 [發明概要] [發明所欲解決的課題] 本發明者等長期專心進行研究關於具有對神經激 NKl、神經激肽NKi及蕈毒驗吣受體全部拮抗的作用 單一化合物之合成及其藥理活性的結果，發現單一化 物對全部的受體顯示结抗作用、或對油 柏机1 p w 喊對神絚激肽NK丨及 毒鹼M3兩受體顯示拮抗作用，且持續顯示藥效的化 物，遂而完成本發明。 [用以解決課題的手段] 本發明係關於（丨）具有通式（！）的化合物或其 理上可容許的鹽，201143771 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to an excellent neurokinin (neur〇kinin) NK, a neurokinin NK:2 and a muscarinic m3 receptor antagonism, or a nerve The kinin NK, and muscarinic receptor antagonism, and a compound for use as a therapeutic drug for bronchial asthma, chronic obstructive pulmonary disease, or the like, or a pharmacologically acceptable salt thereof. [Prior Art] Bronchial tract or chronic obstructive pulmonary disease (C 〇 p D) is hyperthyroidism, respiratory inflammation, mucus secretion, cough, etc. Matrix p (substance P) or neurokinin A is associated with respiratory contraction, inflammation, cough, mucus secretion, and two forms of matrix p or neurokinin A (neurokinin NK, and neurokinin NK: 2 receptor) The compound which is antagonistic has a possibility of inhibiting the above physiological action (Non-Patent Document 2, Non-Patent Document 2). A non-peptidic low molecular compound which antagonizes both neurokinin ΝΚι and neurokinin nk2 has been disclosed (Patent Document 2, Patent Document 2), but has not yet been approved as a pharmaceutical use. On the other hand, acetylcholine causes a strong respiratory contraction by acting on a scorpion basophilic receptor (Non-Patent Document 3). A compound having bronchodilating action for a compound which antagonizes sputum A receptors has a bronchodilating action: Patent Document 4, Patent Document 5), which can be used as a tributary gas. Non-Patent Document 4). It has been revealed that the stagnation of "sexual ^ 撼 撼 * * 各个 各个 各个 各个 各个 各个 各个 各个 各个 各个 各个 各个 各个 各个 各个 各个 各个 各个 各个 各个 各个 各个 ( ( ( ( ( ( ( 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 Neurokinin NK! and neurokinin NK: 2 two receptor antagonist compounds, or compounds that antagonize neurokinin ΝΚ! receptors have not been marketed as bronchial asthma or COPD therapeutic drugs, but there is a so-called inability to use The problem of the agent is strong by anti-neurospinal Ν1, neurokinin ν κ 2 and scorpion basal Ms receptor, or antagonizing neurokinin ΝΚ, and scorpion venom Ms receptor A single compound which has a bronchodilating action, an anti-inflammatory action, and an antitussive and antispasmodic effect is expected. [Prior Art] [Patent Document 1] [Patent Document 1] US Pat. No. 6, 1 975 (Patent Document 2) US Pat. No. 7,365,067 [Patent Document 3 [Patent Document 4] US Patent Publication No. 2005/203 1 3 1 [Patent Document 5] US 2006/28 1740 (Patent Document 6) JP-A-2006-160639 [Non-Patent Document] [Non-patent Literature 1 ] American Review Of Respiratory Disease, 1991, vol .144, pages 11 87-11 98 [Non-Patent Document 2] American Review Of Respiratory Disease, 1991, vol. 144, pages 1 39 1 -1 399 [Non-Patent Document 3] Life Sciences, 1993, vol. 52, pages521 -527 [Ib Patent Document 4] European Journal of Pharmacology, 2006, vol. 533, pages 36-39 Key, oxygen atom 201143771 [Summary of the Invention] [Problems to be Solved by the Invention] The present inventors have long-term concentration The results of the study on the synthesis and pharmacological activity of a single compound having an effect on the total antagonism of nerve shock NK1, neurokinin NKi, and scorpion venom receptors were found to show nocturnal effects on all receptors, or The cypress machine 1 pw screams for the antagonism of the two receptors of the sensitizing peptide NK 丨 and the muscarinic M3, and continues to display the medicinal properties, and the present invention has been completed. [Means for Solving the Problem] The present invention relates to (丨) a compound having the formula (!) or a physiologically acceptable salt thereof,

EW (I) [式中， Y表示具有神經激肽NK!及神經激肽NK2受體拮 作用的部分構造或具有神經激肽ΝΚι受體拮抗作用的 分構造； A录不單鍵 '•八災η文在 基羰基、4 (II)所代表之基、式（m)所代表之 式（IV)所代表之基； 肽 之 合 蕈 合 藥 抗 部 胺 或 201143771EW (I) [wherein, Y represents a partial structure with neurokinin NK! and neurokinin NK2 receptor antagonism or a sub-structure with neurokinin ΝΚ1 receptor antagonism; A recording is not a single bond '• eight disasters The base represented by the formula (IV) represented by the formula (IV) in the carbonyl group, the group represented by the formula (IV), and the anti-partial amine of the peptide compound or 201143771

CECE

3 C——N ο3 C——N ο

CY RIN 基 基基數數 苯烷整整 ,伸伸之之 原子子羰基或C664 氫原原基}鍵1-至至 示氫氫氧基單 C 1 ο 表示示示胺示示示-下 R1表表表基表表表表 2 3 12 3 CRRL 曱 LL p q 羰 »3/ 或 基 羰 »3/ \ly 基 安 月 基 ’ 甲 κίν 基 ， ， 、 院基基基 C6烷烷氧:'c c J C - - 山厌 1. n^ 或 c C 、 子或或基 示 表 8 8 數 整 之CY RIN, base number, benzene, neat, extended atomic carbonyl or C664 hydrogenogen primordium, bond 1- to hydrohydroloxy, mono C 1 ο, indicating amine display - lower R1 table Table 2 Table 3 3 3 3 CRRL 曱LL pq carbonyl »3/ or carbonyl carbonyl »3/ \ly keetyl ' 甲 ίί base , , , 院 基 基 基 C6 alkane oxygen: 'cc JC - - 山厌1 . n^ or c C , sub or or base table 8 8

基 之 表 代 所 E 式 與 E C 合 結 ，， 基 數數，之 整整鍵表 之之單代 4 示所 至至至表 Y 1 1 10£式 示示及與 表表Y Y s t c C 合 結The formula of the base is combined with E C , and the number of bases, the single generation of the whole key table is shown in the table Y 1 1 10 10 and is combined with the table Y Y s t c C

形 情 的 基 烷 6 C I C, 為 2 RFormal base 6 C I C, 2 R

2 R 3 L 與 可 子 原碳 意 任 之任意碳原子結合）； 201143771 E表不具有蕈毒鹼A受體拮抗作用的部分構造； m表示〇至4之整數； η表示1至8之整數]。 於本發明，較佳可舉例·· (2 )如（1 )之化合物或其藥理上可容許的鹽，其 中Υ表示式（V)所代表之基、式（VI)所代表之基或 式（VII )所代表之基 cm cm2 R 3 L binds to any carbon atom of the protonic carbon;) 201143771 E has no partial structure of muscarinic A receptor antagonism; m represents an integer from 〇 to 4; η represents an integer from 1 to 8 ]. In the present invention, a compound of (1) or a pharmacologically acceptable salt thereof, wherein Υ represents a group represented by the formula (V), or a group represented by the formula (VI), is preferred. (VII) the base represented by cm cm

CIN ν,)CIN ν,)

3 4 H R 基基 的的 A A 群群 基基 代代 取取 選選 立立 獨獨 個個 5 3 至至 1 1 有有 具具 可可， 示或基 表基環 R4苯雜表基環 { 之之R5苯雜 代代 之之 取取 代代 至至 1 1 有有 具具 可可， 示或基 3 取取 基基 勺 勺 白 白. A A 群群 基基 代代 取取 自 ΑΘ 選選 立立 獨獨 個個 201143771 R6表示氫原子或CVC6烷基， R7表示可具有1至5個獨立選自取代基群A的基取 代之苯基或可具有1至3個獨立選自取代基群A的基取 代之雜環基， u表示1或2， 取代基群A表示由鹵素原子、C^-Ce烷基、CVC6鹵 化烷基、羥基、烷氧基、CVC6鹵化烷氧基、氰基、 羧基、C2-C7烷基羰基氧基、C2-C7烷氧基羰基氧基、胺 甲醯基、硝基及胺基組成之群，3 4 HR base group of AA group bases are selected and selected individually. 5 3 to 1 1 has a ring of R4 benzene with a cocoa, a base or a base ring { The R5 benzene heterogeneous substitution is substituted to 1 1 and there is a cocoa, or the base 3 is taken from the base spoon. The AA group base is taken from the generation and the singularity is selected. Each of 201143771 R6 represents a hydrogen atom or a CVC6 alkyl group, and R7 represents a phenyl group which may have 1 to 5 substituents independently selected from the substituent group A or may have 1 to 3 radical substituents independently selected from the substituent group A. a heterocyclic group, u represents 1 or 2, and a substituent group A represents a halogen atom, a C^-Ce alkyl group, a CVC6 halogenated alkyl group, a hydroxyl group, an alkoxy group, a CVC6 halogenated alkoxy group, a cyano group, a carboxyl group, a C2 group. a group of -C7 alkylcarbonyloxy, C2-C7 alkoxycarbonyloxy, aminemethantyl, nitro and amine groups,

Cm表示單鍵，且與式-(CH2) m•所代表之基結合）。 (3 )如（1 )或（2 )之化合物或其藥理上可容許的 鹽，其中E表示式（VIII)所代表之基、式（IX)所代 表之基、式（X)所代表之基、式（XI)所代表之基或 式（XII)所代表之基 201143771Cm represents a single bond and is combined with a group represented by the formula -(CH2) m•). (3) The compound of (1) or (2) or a pharmacologically acceptable salt thereof, wherein E represents a group represented by the formula (VIII), a group represented by the formula (IX), and a formula (X) The base represented by formula (XI) or the base represented by formula (XII) 201143771

N—CrN-Cr

'Cr'Cr

'Cn'Cn

〇〇

,Cr (XII) (Cn表示單鍵，且與式-(CH2) n-所代表之基結合）。 (4 )如選自（1 )至（3 )任一項之化合物或其藥理 上可容許的鹽，其中通式（I)為通式（la), Cr (XII) (Cn represents a single bond and is bonded to a group represented by the formula -(CH2) n-). (4) A compound selected from any one of (1) to (3) or a pharmacologically acceptable salt thereof, wherein the formula (I) is a formula (la)

-10- 201143771 (5 )如（4 )之化合物或其藥理上可容許的鹽，其 中R1為氫原子或曱基，L1為氧基羰基、羰基氧基、（甲 基胺基）羰基或羰基（曱基胺基）基，L2為單鍵或伸苯 基，p為2至4之整數，q為0或l，r為1至5之整數。 (6 )如選自（1 )至（3)任一項之化合物或其藥理 上可容許的鹽，其中通式（I)為通式（lb)The compound of (4), wherein R1 is a hydrogen atom or a fluorenyl group, and L1 is an oxycarbonyl group, a carbonyloxy group, a (methylamino)carbonyl group or a carbonyl group, or a pharmacologically acceptable salt thereof. (mercaptoamino) group, L2 is a single bond or a phenyl group, p is an integer from 2 to 4, q is 0 or 1, and r is an integer from 1 to 5. (6) A compound of any one of (1) to (3) or a pharmacologically acceptable salt thereof, wherein the formula (I) is a formula (lb)

(lb) CF, (7)如（6)之化合物或其藥理上可容許的鹽，其 中η為2至5之整數。 (8 )如選自（1 )至（3 )任一項之化合物或其藥理 上可容許的鹽，其中通式（I )為通式（Ic )(lb) CF, (7) A compound of (6) or a pharmacologically acceptable salt thereof, wherein η is an integer of from 2 to 5. (8) A compound according to any one of (1) to (3) or a pharmacologically acceptable salt thereof, wherein the formula (I) is a formula (Ic)

(9 )如（8 )之化合物或其藥理上可容許的鹽，其 中s為3至6之整數，m為2至4之整數。 (10)如選自（1)至（3)任一項之化合物或其藥 理上可容許的鹽，其中通式（I )為通式（Id ) -11 - 201143771(9) A compound according to (8) or a pharmacologically acceptable salt thereof, wherein s is an integer of from 3 to 6, and m is an integer of from 2 to 4. (10) A compound according to any one of (1) to (3) or a pharmacologically acceptable salt thereof, wherein the formula (I) is a formula (Id) -11 - 201143771

(11 )如（1 ο)之化合物或其藥理上可容許的鹽， 其中R3為氫原子或甲基，t為1至4之整數，m為1至 4之整數，η為1至4之整數。 (12) —種化合物或其藥理上可容許的鹽，其為： (3R) -1- { 7-[ { 5-[ { 2-[3,5-雙（三氟甲基）苯基]-2-曱基丙醯基}(甲基）胺基]-4- ( 2-甲基苯基）。比啶-2-基} (曱基）胺基]庚-5-炔-l-基}吡咯啶-3-基羥基（二-2-噻吩基）乙酸酯、 (3R) -1-{ 5-[{ 5-[{ 2-[3,5-雙（三氟曱基）苯基]-2-曱基丙醯基}(甲基）胺基]-4- ( 2-曱基苯基）吼啶-2-基} (曱基）胺基]戍-3-块-1-基}。比洛。定-3-基輕基（二-2_ 噻吩基）乙酸酯、 (3尺）-1-{6-[{5-[{2-[3,5-雙（三氟曱基）苯基]-2-曱基丙醯基丨（甲基）胺基]-4- ( 2-甲基苯基）吼啶-2-基} (曱基）胺基]己-4-炔-1-基丨吡咯啶-3-基羥基（二-2-噻吩基）乙酸酯、 4_ { [ { 4-[ ( 2- { 4-[(聯苯基-2-基胺曱酸基）氧基] 哌啶-1 -基}乙基）（甲基）胺曱醯基]苄基}(曱基）胺 -12- 201143771 基]甲基}苯基4-[ ( N- { 5-[ { 2-[3:，5-雙（三氟甲基）苯 基]-2 -甲基丙酿基}(曱基）胺基]-.4-(2-甲基苯基）。比 啶-2-基} -N-甲基甘胺醯基）（曱基）胺基]丁酸酯、 4-[ ( { 4-[ ( 2- { 4-[(聯苯基-2-基胺甲醯基）氧基] 哌啶-1 -基}乙基）（曱基）胺曱醯基]苄基}胺基）甲基] 苯基 4-[ ( N- { 5-[ { 2-[3,5-雙（三氟曱基）苯基]-2-曱 基丙醯基}(曱基）胺基]-4- ( 2-甲基苯基）。比啶-2-基} -N-曱基甘胺醯基）（曱基）胺基]丁酸酯、 (3R) - l-{ 2-[{ 6-[4-( { 3-[( { [( 2S) -Γ-{ 2-[( 5R) -3- { [3，5-雙（三氟曱基）苯基]羰基} -5- ( 4-氟苯基） -1，3-噚唑啶-5-基]乙基}-2,3-二氫螺[茚-1,4’-哌啶]-2-基] 氧基}乙醯基）胺基]丙基}胺曱醯基）哌啶-1 -基]己醯 基}(甲基）胺基]乙基} π比略α定_ 3 -基經基（二。塞吩-2 _ 基）乙酸酯、 Ν- ( 2 - { [2-( 4-{ 2-[( 3S ) -3 - ( 2.·胺基-2-側氧基-1,1-二苯基乙基）。比咯啶-1-基]乙基}苯基）乙基](曱基） 胺基}乙基）-2- { [ ( 2S ) -Γ- { 2-[ ( 5R) -3- { [3,5-雙 (三氟曱基）苯基]羰基} -5- ( 4-氟苯基）-1，3-噚唑啶-5-基]乙基} -2,3-二氫螺[茚-1,4’-哌啶]-2-基]氧基丨-Ν-曱 基乙醯胺、 N-( 2-{ [2-( 4-{ 2-[( 3S) -3-( 2-胺基-2-側氧基-1，1-二苯基乙基）α比ρ各。定-1-基]乙基}苯基）乙基]胺基}乙 基）-2- { [ ( 2S) -1’- { 2-[ ( 5R) -3&quot; { [3,5-雙（三氟曱 基）苯基]羰基} -5- ( 4-氟苯基）-1,3··嘮唑啶-5-基]乙基} -2,3-二氳螺[茚-1,4’-哌啶]-2-基]氧基丨-Ν-甲基乙醯胺、 201143771 N- ( 3,3,3-三苯基丙醯基）甘胺醯基-!^-({1-[6-({ 4-[ ({ [ ( 2S) -1，- { 2-[ ( 5R) -3- { [3,5-雙（三氟曱 基）苯基]羰基} -5 - ( 4-氟苯基）-1，3-嘮唑啶-5-基]乙基} -2,3-二氫螺[茚-1，4’-哌啶]-2-基]氧基}乙醯基）（曱基） 胺基]丁醯基}胺基）己基]哌啶-3-基}曱基）-β-丙胺酸 醯胺、 (3R) -1-{ 8-[{ 5-[{ 2-[3,5-雙（三氟曱基）苯基]-2-曱基丙醯基}(甲基）胺基]-4- ( 2-甲基苯基）。比啶-2-基} (曱基）胺基]辛-6-炔-l-基}。比咯啶-3-基羥基（二噻 吩-2-基）乙酸酯、 (3R) -1-[2- ( 4- { 5-[ { 2-[3,5-雙（三氟甲基）苯 基]-2-曱基丙醯基丨（曱基）胺基]-4- ( 2-曱基苯基）吼 。定-2 -基} α底σ井-1 -基）乙基]。比σ各。定-3 -基經基（二α塞吩-2 _ 基）乙酸酯、 (3R) -1-[3- ( 4- { 5-[ { 2-[3,5-雙（三氟甲基）苯 基]-2-曱基丙醯基}(曱基）胺基]-4- ( 2-曱基苯基）吼 σ定-2 -基} α底听-1-基）-3 -側氧基丙基]。比σ各α定-3 -基經基 (二噻吩-2-基）乙酸酯、 (31〇-1-(3-{2-[{5-[{2-[3,5-雙（三氟曱基）苯基]-2-曱基丙醯基}(甲基）胺基]-4-( 2-甲基苯基）。比啶-2-基} (曱基）胺基]乙氧基丨丙基）°比咯啶-3-基羥基（二-2-噻吩基）乙酸酯、 1- ( 2- { [6- ( { 4-[{3-[ ( N-{5-[ { 2-[3,5-雙（三氟 曱基）苯基]-2-曱基丙醯基}(曱基）胺基]-4- ( 2-甲基 苯基）。比啶-2-基} -N-曱基甘胺醯基）（曱基）胺基]丙基} -14- 201143771 (甲基）胺甲醯基]苯基}胺基）己醯基](曱基）胺基}乙 基）哌啶-4-基聯苯基-2-基胺基曱酸酯、 1- { 2-[ ( { 4-[ ( { 4-[ { 3-[ ( N- { 5-[ { 2-[3,5-雙（三 氟甲基）苯基]-2-曱基丙醯基丨（曱基）胺基]-4-(2-曱 基苯基）α比σ定-2-基} -N -曱基甘胺酿i基）（甲基）胺基] 丙基}(曱基）胺甲醯基]苯基}胺基）甲基]苯基}羰 基）（曱基）胺基]乙基}哌啶-4-基聯苯基-2-基胺基曱 酸I旨、 (3R) -1- { 4-[ ({ [ ( 2S) -Γ- { 2-[ ( 5R) -3-[3,5-雙（三氟甲基）苯曱醯基]-5- ( 4-氟苯基）-1，3-嘮唑啶-5-基]乙基}-2,3-二氫螺[茚-1,4’-哌啶]..2-基]氧基}乙醯基） (曱基）胺基]丁基} °比咯啶-3-基羥基（二-2-噻吩基） 乙酸酯、或 8- { 4-[ ({ [ ( 2S) -1，- { 2-[ ( 5R) -3-[3,5-雙（三氟 甲基）苯甲醯基]-5-( 4-氟苯基）-1，3-嘮唑啶-5-基]乙基} -2,3-二氫螺[茚-1，4’-哌啶]-2-基]氧基}乙醯基）（曱基） 胺基]丁基} -8-氮雜雙環[3.2.1]辛-3-基羥基（二-2-噻吩 基）乙酸酯。 (1 3 )如上述（1 2 )記載的化合物或其藥理上可容 許的鹽中之化合物。 (1 4 ) 一種化合物或其藥理上可容許的鹽，其為： 4-[ ( { 4-[ ( 2- { 4-[(聯苯基-2-基胺曱醯基）氧基]哌啶 -l-基}乙基）（曱基）胺甲醯基]苄基}胺基）甲基]苯 基 4-[ ( Ν- { 5-[ { 2-[3,5-雙（三氟甲基）苯基]-2-甲基 丙醯基}(甲基）胺基]-4- ( 2-曱基苯基）吼啶-2-基} -Ν-甲基甘胺醯基）（甲基）胺基]丁酸酯、 -15- 201143771 (3R) - l-{ 2-[{ 6-[4-( { 3-[( { [( 2S) -Γ-{ 2-[( 5R) -3-{ [3,5-雙（三氟曱基）苯基]羰基} -5-( 4-氟苯基） _l，3_〇f唑啶-5-基]乙基}-2,3-二氫螺[茚-1，4’-哌啶]-2-基] 氧基丨乙醯基）胺基]丙基}胺甲醯基）哌啶-1 -基]己醯 基}(曱基）胺基]乙基} °比咯啶-3-基羥基（二噻吩-2-基）乙酸酯、 N-( 2-{ [2-( 4-{ 2-[( 3S) -3-( 2 -胺基-2-側氧基-1,1-二苯基乙基）。比咯啶-1-基]乙基}苯基）乙基]胺基}乙 基）-2- { [ ( 2S) -1’- { 2-[ ( 5R) -3- { [3,5-雙（三氟曱 基）苯基]羰基} -5- ( 4-氟笨基）-1,3-嘮唑啶-5-基]乙基} -2，3-二氫螺[茚-1,4’-哌啶]-2-基]氧基} -N-甲基乙醯胺、 1- ( 2- { [6- ( { 4-[{3-[ ( N-{5-[ { 2-[3,5-雙（三氟 曱基）苯基]-2-曱基丙醯基丨（曱基）胺基]-4-( 2-曱基 苯基）。比啶-2-基} -N-曱基甘胺醯基）（甲基）胺基]丙基} (曱基）胺曱醯基]苯基}胺基）己醯基](甲基）胺基}乙 基）π底。定-4-基聯苯基-2-基胺基甲酸S旨、 1- { 2-[ ( M-[ ( { 4-[ { 3-[ ( Ν- { 5-[ { 2-[3,5-雙（三 氟曱基）苯基]-2-甲基丙醯基}(曱基）胺基]-4-( 2-甲 基苯基）吼啶-2-基} -N-曱基甘胺醯基）（甲基）胺基] 丙基}(曱基）胺甲醯基]苯基}胺基）甲基]苯基}羰 基）（曱基）胺基]乙基}°底。定-4 -基聯苯基-2-基胺基曱 酸S旨、或 (3R) -1- { 4-[ ({ [ ( 2S) -Γ- { 2-[ ( 5R) -3-[3,5-雙（三氟甲基）苯甲醯基]-5-( 4-氟苯基）-1,3-嘮唑啶-5-基]乙基} -2,3-二氫螺[茚-1,4’-哌啶]-2-基]氧基}乙醯基） 201143771 (甲基）胺基]丁基}吡咯啶_3_基羥基（二_2_噻吩基） 乙酸酯。 (1 5 )如上述（丨4 )記載的化合物或其藥理上可容 許的鹽中的化合物。 (16)種醫藥組成物’其含有選自如（1)至（15) 項中任一項s己載之化合物或其藥理上可容許的鹽為有效 成分。 (1 7 )如（1 6 )記載的醫藥組成物，其中該醫藥組 成物具有支氣管擴張作用及抗炎症作用。 (1 8 )如（1 6 )記載的醫藥組成物，其中該醫藥組 成物係用於治療及/或預防神經激肽NKl、神經激肽nk2 及/或蕈毒驗Ms受體參與的疾病或神經激肽NKl及/或蕈 毒驗M3受體參與的疾病。 (1 9 )如（1 6 )記載的醫藥組成物，其中該醫藥組 成物係用於治療及/或預防呼吸器官疾病、過敏性疾病及 /或神經系統疾病。 (20 )如（1 6 )記載的醫藥組成物，其中該醫藥組 成物係用於治療及/或預防呼吸器官疾病及/或神經系統 疾病。 (2 1 )如（1 6 )記載的醫藥組成物，其中該醫藥組 成物係用於·治療及/或預防支氣管氣喘、支氣管炎、慢性 阻塞性肺病、咳嗽、喀痰過度分泌、鼻炎、疼痛 '焦慮、 抑鬱、痙攣、帕金森氏症、尿失禁、過敏性腸症候群、 刖列腺肥大、嘔吐、消化性潰瘍、網膜檢查、急性虹彩 炎、角膜炎、縮瞳、由於麻醉藥導致的過度唾液分泌、 呼吸道分泌及/或潰癌。 -17- 201143771 (22)如（16)記載的醫藥組成物，其中該醫藥組 成物 阻塞 痙攣 成物 肺病 成物 合物 組成 具有 用於 簟毒 m3受 用於 經系 用於 用於 係用於治療及/或預防支氣管氣喘、支氣管炎、慢性 性肺病、咳嗷、喀痰過度分泌、疼痛、焦慮、抑鬱、 、帕金森氏症、過敏性腸症候群及/或前列腺肥大。 (23 )如（16 )記載的醫藥組成物，其中該醫藥組 係用於治療及/或預防支氣管氣喘及/或慢性阻塞性 〇 (24 )如（丨9 )至（23 )項中任一項記載之醫藥組 ’其中S亥醫藥組成物係經肺投與及/或點鼻投與。 (2 5 ) 一種選自（1 )至（1 5 )項中任一項記載之化 或其藥理上可容許的鹽之用途，係其用於製造醫藥 物。 (26 )如（25 )記載之用途，其中該醫藥組成物係 支氣管擴張作用及抗炎症作用的醫藥組成物。 (27 )如（25 )記載之用途，其中該醫藥組成物係 治療及/或預防神經激肽NK,、神經激肽NK2及/或 驗Μ〗受體參與的疾病或神經激肽NK,及/或簟毒鹼 體參與的疾病。 (28 )如（25 )記載之用途，其中該醫藥組成物係 治療及/或預防呼吸器官疾病、過敏性疾病及/或神 統疾病。 (29 )如（25 )記載之用途，其中該醫藥組成物係 治療及/或預防呼吸器官疾病及/或神經系統疾病。 (30 )如（25 )記載之用途，其中該醫藥組成物係 治療及/或預防支氣管氣喘、支氣管炎、慢性阻塞性 •18- 201143771 肺病、咳嗷、喀痰過度分泌、鼻[疼痛、焦慮、抑鬱、 痙攣、帕金森氏症、尿失禁、過敏性腸症候群、前列腺 肥大、嘔吐、消化性潰瘍、網膜檢查、急性虹彩炎、角 膜炎、縮瞳、由於麻醉藥導致的過度唾液分泌、呼吸道 分泌及/或潰瘍。 (3 1 )如（25 )記載之用途，其中該醫藥組成物係 用於治療及/或預防支氣管氣喘、支氣管炎、慢性阻塞性 肺病、咳嗽、喀痰過度分泌、疼痛、焦慮、抑鬱、痙攣、 帕金森氏症、過敏性腸症候群及/或前列腺肥大。 (32 )如（25 )記載之用途，其中該醫藥組成物係 用於治療及/或預防支氣管氣喘及/或慢性阻塞性肺病。 (33 )如選自（28 )至（32 )中任一項記載之用途， 其中該醫藥組成物係用於經肺投與及/或點鼻投與。 (3 4 ) —種疾病之治療及/或預防方法，其係將藥理 的有效量之選自（1 )至（15 )中任一項記載之化合物或 其藥理上可容許的鹽投與溫血動物。 (35 )如（34 )記載之方法，其中疾病為神經激肽 、神經激肽NKz及/或蕈毒鹼受體參與的疾病、 或神經激肽N K!及/或蕈毒驗μ 3受體參與的疾病。 (36)如（34)記載之方法’其中疾病為呼吸器官 疾病、過敏性疾病及/或神經系統疾病。 (3 7 )如（3 4 )記載之方法，其中疾病為呼吸器官 疾病及/或神經系統疾病。 (38 )如（34 )記載之方法’其中疾病為支氣管氣 喘、支氣管炎、慢性阻塞性肺病、咳嗷、喀痰過度分泌、 -19- 201143771 鼻炎、疼痛、焦慮、抑鬱 ,a ., 林K症、尿生禁、 過敏性腸症候群、前列腺肥大、 ’、 眩户杏 4 匕土 '肩化性潰瘍、嫻 的… 彩炎、角膜炎、縮曈、由於麻醉藥導致 的匕度垂液分泌、呼吸道分泌及/或潰瘍。 ’、 (39)如（34)記載之方法，复中 而支氣g炎、慢性阻塞性肺病、咳嗽、喀 夜、虐、隹南 秋各疫過度分泌、 疼痛‘、、、慮、抑鬱、痙攣、帕金森氏症、^ ^ 群及/或前列腺肥大。 W㈣症候 其中疾病為支氣管氣 (4 〇 )如（3 4 )記載之方法 喘及/或慢性阻塞性肺病。 (41)如選自（36)至（4G)中任-項記載之方法， 其特徵為經肺投與及/或點鼻投與具有通式 物或其藥理上可容許的鹽；及 ° (42 )如選自（34 )至（4 i )中 ^ . 項记載之方法， 其中溫血動物為人類。 ，_素原子」為氟原子、氣原子、溴原子 佳為氟原子或氣原子’更佳為氟原子。 ，「CrC6烷基」係碳數為！至6個之直鏈 。例如，曱基、乙基、丙基、異丙基、丁 二級丁基、三級丁基、戊基、異戊基、2_ 於本發明 或硬原子。較 於本發明 或分枝鏈烷基 基 '異丁基、 甲基丁基、新戊基或己基，較佳為碳數為丨至4個之直 鏈或分枝鏈烷基（Cl_C4烷基），更佳為曱基或乙基（c]_c 烧基）’再更佳為甲基。 於本發明，「Ci_C6齒化烷基」係相同或相異之i至 5個前述「函素原子」與前述「Cl_C6烷基」結；的基。 -20- 201143771 例如，三氟f基' 三氣 溴曱基、氟甲基或基 '二氟甲基、二氯甲基、二 2,2,2 -三蠢 7 苴 之1至5個前述「南素原— 土’較佳為相同或相異 的基（CVC4鹵化烷基），、子」與前述「C!-C4烷基j結合 前述「鹵素原子」邀&amp; 為相同或相異之1至5個 」與刖述「c 鹵化烷基），再更佳兔_ 1 2 ’元基J結合的基（C丨-C2 為二氟甲基。(11) A compound of (1) or a pharmacologically acceptable salt thereof, wherein R3 is a hydrogen atom or a methyl group, t is an integer of 1 to 4, m is an integer of 1 to 4, and η is 1 to 4 Integer. (12) A compound or a pharmacologically acceptable salt thereof, which is: (3R) -1- { 7-[ { 5-[ { 2-[3,5-bis(trifluoromethyl)phenyl] -2-mercaptopropyl}(methyl)amino]-4-(2-methylphenyl). Bis-2-yl}(indenyl)amino]hept-5-yne-1-yl}pyrrolidin-3-ylhydroxy(di-2-thienyl)acetate, (3R)-1-{ 5-[{ 5-[{ 2-[3,5-bis(trifluoromethyl)phenyl]-2-mercaptopropyl}(methyl)amino]-4-(2-mercaptobenzene) Acridine-2-yl}(indenyl)amino]indol-3-block-1-yl}. Bilo. Din-3-yl light (2--2-thienyl) acetate, (3 ft)-1-{6-[{5-[{2-[3,5-bis(trifluoromethyl)phenyl) ]-2-mercaptopropyl hydrazino (methyl)amino]-4-(2-methylphenyl)acridin-2-yl}(indenyl)amino]hex-4-yn-1- Pyridoxin-3-ylhydroxy (di-2-thienyl) acetate, 4_ { [ { 4-[ ( 2- { 4-[(biphenyl-2-ylamine decanoyl)oxy) Piperidine-1-yl}ethyl)(methyl)amine fluorenyl]benzyl}(indenyl)amine-12- 201143771 yl]methyl}phenyl 4-[ ( N- { 5-[ { 2-[3:,5-bis(trifluoromethyl)phenyl]-2-methylpropyl](indenyl)amino]-.4-(2-methylphenyl). 2-yl}-N-methylglycine indenyl)(indenyl)amino]butyrate, 4-[( { 4-[ ( 2- { 4-[4-[(biphenyl-2-ylamine) Thio)oxy]piperidin-1 -yl}ethyl)(fluorenyl)amine hydrazino]benzyl}amino)methyl]phenyl 4-[(N- { 5-[ { 2-[ 3,5-bis(trifluoromethyl)phenyl]-2-mercaptopropyl}(indenyl)amino]-4-(2-methylphenyl).pyridin-2-yl} N-mercaptosylamino)(fluorenyl)amino]butyrate, (3R) - l-{ 2-[{ 6-[4-( { 3-[( { [( 2S) -Γ- { 2-[( 5 R) -3- { [3,5-bis(trifluoromethyl)phenyl]carbonyl} -5-(4-fluorophenyl)-1,3-oxazolidine-5-yl]ethyl}- 2,3-Dihydrospiro[茚-1,4'-piperidinyl]-2-yl]oxy}ethinyl)amino]propyl}aminoindolyl)piperidin-1 -yl]hexidine }}(methyl)amino]ethyl} π ratio slightly α _ 3 -yl-based (di-cepan-2-yl) acetate, Ν- ( 2 - { [2-( 4-{ 2-[( 3S ) -3 - ( 2.. Amino-2-sidedoxy-1,1-diphenylethyl).Byrrolidin-1-yl]ethyl}phenyl)ethyl] (fluorenyl)amino}ethyl)-2-{ [( 2S ) -Γ- { 2-[ ( 5R) -3- { [3,5-bis(trifluoromethyl)phenyl]carbonyl} 5-(4-Fluorophenyl)-1,3-oxazolidin-5-yl]ethyl}-2,3-dihydrospiro[茚-1,4'-piperidin]-2-yl]oxy Base Ν-Ν-mercaptoacetamide, N-( 2-{ [2-( 4-{ 2-[( 3S) -3-( 2-amino-2-yloxy-1,1-di) Phenylethyl)α ratio ρ.dine-1-yl]ethyl}phenyl)ethyl]amino}ethyl)-2- { [ ( 2S) -1'- { 2-[ ( 5R) -3&quot; { [3,5-Bis(trifluoromethyl)phenyl]carbonyl} -5-(4-fluorophenyl)-1,3··oxazolidine-5-yl]ethyl} -2 ,3-di-spiro[茚-1,4'-piperidinyl]-2-yl]oxyindole-indole-methyl Indoleamine, 201143771 N-(3,3,3-triphenylpropanyl)glycine-based-!^-({1-[6-({ 4-[ ({ [ ( 2S) -1,- { 2-[ ( 5R) -3- { [3,5-Bis(trifluoromethyl)phenyl]carbonyl} -5 - (4-fluorophenyl)-1,3-oxazolidine-5-yl Ethyl} -2,3-dihydrospiro[茚-1,4'-piperidinyl]-2-yl]oxy}ethenyl)(fluorenyl)amino]butanyl}amino)hexyl]piperidin Acridine-3-yl}fluorenyl)-β-alanine decylamine, (3R)-1-{ 8-[{ 5-[{ 2-[3,5-bis(trifluoromethyl)phenyl]- 2-mercaptopropyl}(methyl)amino]-4-(2-methylphenyl). Bis-2-yl}(fluorenyl)amino]oct-6-yne-l-yl}. Bilobidine-3-ylhydroxy (dithien-2-yl)acetate, (3R)-1-[2-(4-{ 5-[ { 2-[3,5-bis(trifluoromethyl) Phenyl]-2-mercaptopropyl fluorenyl (indenyl)amino]-4-(2-indolylphenyl) fluorene. Defen-2-yl} α- bottom σ well-1 -yl)ethyl ]. More than σ. -3 -yl-based (di-α-cepan-2-yl)acetate, (3R)-1-[3-(4- { 5-[ { 2-[3,5-bis(trifluoromethyl) Phenyl]-2-mercaptopropenyl}(fluorenyl)amino]-4-(2-mercaptophenyl)indole-2-yl} α-endyl-1-yl)-3 - pendant oxypropyl]. Σσ α α-yl-based (dithien-2-yl) acetate, (31〇-1-(3-{2-[{5-[{2-[3,5-double ( Trifluoromethyl)phenyl]-2-mercaptopropyl}(methyl)amino]-4-(2-methylphenyl).pyridin-2-yl}(indenyl)amino] Ethoxy propyl propyl) ° pyridin-3-ylhydroxy (di-2-thienyl) acetate, 1- ( 2- { [6- ( { 4-[{3-[ ( N-{ 5-[ { 2-[3,5-bis(trifluoromethyl)phenyl]-2-mercaptopropyl}(indenyl)amino]-4-(2-methylphenyl). Acridine-2-yl}-N-mercaptosylamino)(indenyl)amino]propyl} -14- 201143771 (methyl)amine-methylphenyl]phenyl}amino)hexanyl] Mercapto)amino}ethyl)piperidin-4-ylbiphenyl-2-ylamino phthalate, 1- { 2-[ ( { 4-[ ( { 4-[ { 3-[ ( - { 5-[ { 2-[3,5-bis(trifluoromethyl)phenyl]-2-mercaptopropyl fluorenyl (fluorenyl)amino]-4-(2-mercaptophenyl)比βσ-2-yl}-N-mercaptoamine amide i)) (methyl)amino] propyl} (fluorenyl)amine carbhydryl]phenyl}amino)methyl]phenyl }carbonyl)(fluorenyl)amino]ethyl}piperidin-4-ylbiphenyl-2-ylamino decanoic acid I, (3R) -1- { 4-[ ({ [ ( 2S) - Γ- { 2-[ ( 5R) -3-[3,5-Bis(trifluoromethyl)phenyl)-5-(4-fluorophenyl)-1,3-oxazolidine-5- (ethyl)-2,3-dihydrospiro[茚-1,4'-piperidine]..2-yl]oxy}ethenyl)(fluorenyl)amino]butyl} ° Pyridin-3-ylhydroxy (di-2-thienyl) acetate, or 8-{ 4-[ ({ [ ( 2S) -1,- { 2-[ ( 5R) -3-[3,5- Bis(trifluoromethyl)benzylidene]-5-(4-fluorophenyl)-1,3-oxazolidin-5-yl]ethyl}-2,3-dihydrospiro[茚-1 , 4'-piperidinyl]-2-yl]oxy}ethinyl)(fluorenyl)amino]butyl}-8-azabicyclo[3.2.1]oct-3-ylhydroxy (2-2) (1) A compound according to the above (1 2) or a pharmacologically acceptable salt thereof. (1 4 ) A compound or a pharmacologically acceptable salt thereof, which is : 4-[ ( { 4-[ ( 2- { 4-[(Biphenyl-2-ylaminoindolyl)oxy)piperidine-1-yl}ethyl)(indenyl)aminecarboxamide Benzyl}amino)methyl]phenyl 4-[( Ν- { 5-[ { 2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanyl} Methyl)amino]-4-(2-mercaptophenyl)acridin-2-yl}-indole-methylglycine fluorenyl) Amino]butyrate, -15- 201143771 (3R) - l-{ 2-[{ 6-[4-( { 3-[( { [( 2S) -Γ-{ 2-[( 5R) -3-{[3,5-bis(trifluoromethyl)phenyl]carbonyl}-5-(4-fluorophenyl) _l,3_〇foxaridin-5-yl]ethyl}-2, 3-Dihydrospiro[茚-1,4'-piperidinyl]-2-yl]oxyindolyl)amino]propyl}aminecarboxyl)piperidin-1 -yl]hexanyl} (fluorenyl)amino]ethyl} °pyrrolidin-3-ylhydroxy (dithien-2-yl)acetate, N-( 2-{ [2-( 4-{ 2-[( 3S)) -3-(2-Amino-2-oxo-1,1-diphenylethyl). Bilobidine-1-yl]ethyl}phenyl)ethyl]amino}ethyl)-2- { [ ( 2S) -1'- { 2-[ ( 5R) -3- { [3,5 - bis(trifluoromethyl)phenyl]carbonyl} -5-(4-fluorophenyl)-1,3-oxazolidin-5-yl]ethyl}-2,3-dihydrospiro[茚- 1,4'-piperidinyl]-2-yl]oxy}-N-methylacetamide, 1-(2-{ [6- ( { 4-[{3-[ ( N-{5-[ {2-[3,5-Bis(trifluoromethyl)phenyl]-2-mercaptopropyl fluorenyl (indenyl)amino]-4-(2-indolylphenyl). -N-mercaptosylamino)(methyl)amino]propyl}(fluorenyl)amine fluorenyl]phenyl}amino)hexanyl](methyl)amino} Base) π bottom. 1,4--4-biphenyl-2-ylaminocarboxylic acid S, 1- { 2-[ ( M-[ ( { 4-[ { 3-[ ( Ν- { 5-[ { 2-[ 5-bis(trifluoromethyl)phenyl]-2-methylpropanyl}(indenyl)amino]-4-(2-methylphenyl)acridin-2-yl}-N-indole (Glysylamine) (methyl)amino] propyl} (indenyl) amine indenyl] phenyl} amino) methyl] phenyl} carbonyl) (fluorenyl) amino] ethyl} ° bottom. -4-4 -ylbiphenyl-2-ylamino decanoic acid S, or (3R) -1- { 4-[ ({ [ 2S) -Γ- { 2-[ ( 5R) -3-[ 3,5-bis(trifluoromethyl)benzylidene]-5-(4-fluorophenyl)-1,3-oxazolidin-5-yl]ethyl}-2,3-dihydrospiro [茚-1,4'-piperidinyl]-2-yl]oxy}ethenyl) 201143771 (methyl)amino]butyl}pyrrolidinyl-3-ylhydroxy (di-2-thiophenyl) Acid ester. (1) A compound as described in the above (丨4) or a pharmaceutically pharmacologically acceptable salt thereof. (16) A pharmaceutical composition comprising a compound selected from any one of (1) to (15) or a pharmacologically acceptable salt thereof as an active ingredient. (1) The pharmaceutical composition according to (1), wherein the pharmaceutical composition has a bronchodilating action and an anti-inflammatory action. (1) The pharmaceutical composition according to (1), wherein the pharmaceutical composition is for treating and/or preventing a disease in which the neurokinin NK1, the neurokinin nk2, and/or the scorpion venom Ms receptor are involved or Neurokinin NKl and/or scorpion venom is a disease in which the M3 receptor is involved. (1) The pharmaceutical composition according to (1), wherein the pharmaceutical composition is for treating and/or preventing a respiratory disease, an allergic disease, and/or a nervous system disease. (20) The pharmaceutical composition according to (16), wherein the pharmaceutical composition is for treating and/or preventing a respiratory disease and/or a nervous system disease. (2) The pharmaceutical composition according to (1), wherein the pharmaceutical composition is used for treating and/or preventing bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, hyperextension, rhinitis, and pain. Anxiety, depression, delirium, Parkinson's disease, urinary incontinence, irritable bowel syndrome, mastitis, vomiting, peptic ulcer, omental examination, acute iridotonitis, keratitis, migraine, excessive saliva due to anesthetics Secretion, respiratory secretion and / or ulceration. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; And/or prevent bronchial asthma, bronchitis, chronic lung disease, cough, excessive secretion of sputum, pain, anxiety, depression, Parkinson's disease, irritable bowel syndrome, and/or prostatic hypertrophy. (23) The pharmaceutical composition according to (16), wherein the pharmaceutical composition is for treating and/or preventing bronchial asthma and/or chronic obstructive convulsion (24) as in any one of (丨9) to (23) The medical group described in the 'Shai Pharmaceutical Composition is administered by the lung and/or nose. (2) A use of the compound according to any one of (1) to (1), or a pharmacologically acceptable salt thereof, for use in the manufacture of a medicament. (26) The use according to (25), wherein the pharmaceutical composition is a pharmaceutical composition for bronchodilating action and anti-inflammatory action. (27) The use according to (25), wherein the pharmaceutical composition is a disease or neurokinin NK which is involved in the treatment and/or prevention of neurokinin NK, neurokinin NK2 and/or test receptors, and / or scorpion venom involved in the disease. (28) The use according to (25), wherein the pharmaceutical composition is for treating and/or preventing a respiratory disease, an allergic disease, and/or a pancreatic disease. (29) The use according to (25), wherein the pharmaceutical composition is for treating and/or preventing a respiratory disease and/or a nervous system disease. (30) The use according to (25), wherein the pharmaceutical composition is for treating and/or preventing bronchial asthma, bronchitis, chronic obstructiveness, 18-201143771 lung disease, coughing, excessive sputum secretion, nasal [pain, anxiety, Depression, sputum, Parkinson's disease, urinary incontinence, irritable bowel syndrome, prostatic hypertrophy, vomiting, peptic ulcer, omental examination, acute iridotonitis, keratitis, migraine, excessive salivation due to anesthetics, respiratory secretion And / or ulcers. (3) The use of (25), wherein the pharmaceutical composition is for treating and/or preventing bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, hyperextension, pain, anxiety, depression, paralysis, Parkinson's disease, irritable bowel syndrome and/or prostatic hypertrophy. (32) The use of (25), wherein the pharmaceutical composition is for treating and/or preventing bronchial asthma and/or chronic obstructive pulmonary disease. (33) The use according to any one of (28) to (32), wherein the pharmaceutical composition is for pulmonary administration and/or nasal administration. (3) A method for the treatment and/or prevention of a disease, which comprises administering a pharmacologically effective amount of a compound according to any one of (1) to (15) or a pharmacologically acceptable salt thereof to the temperature. Blood animals. (35) The method according to (34), wherein the disease is a disease in which a neurokinin, a neurokinin NKz and/or a muscarinic receptor is involved, or a neurokinin NK! and/or a scorpion venom μ 3 receptor Participation in the disease. (36) The method according to (34) wherein the disease is a respiratory disease, an allergic disease, and/or a nervous system disease. (3) The method according to (3), wherein the disease is a respiratory disease and/or a nervous system disease. (38) The method according to (34) wherein the disease is bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, hyperextension, -19-201143771 rhinitis, pain, anxiety, depression, a., K disease , urinary suffocation, allergic bowel syndrome, prostatic hypertrophy, ', spleen apricot 4 匕 ' 'shoulder ulcer, sputum ... color inflammation, keratitis, sputum, due to anesthesia caused by sputum secretion, Respiratory secretion and / or ulcers. ', (39) as described in (34), re-integration and stagnation of g-inflammation, chronic obstructive pulmonary disease, cough, night, abuse, excessive secretion, pain, ',, worry, depression,痉挛, Parkinson's disease, ^ ^ group and / or prostate hypertrophy. W (4) Symptoms The disease is bronchial gas (4 〇) as described in (3 4), asthma and / or chronic obstructive pulmonary disease. (41) A method according to any one of (36) to (4G), characterized by pulmonary administration and/or nasal administration of a compound having a general formula or a pharmacologically acceptable salt thereof; (42) A method as described in (34) to (4 i ) wherein the warm-blooded animal is a human. The _ atom is a fluorine atom, a gas atom, a bromine atom, preferably a fluorine atom or a gas atom, and more preferably a fluorine atom. , "CrC6 alkyl" is the carbon number! Up to 6 straight chains. For example, mercapto, ethyl, propyl, isopropyl, butyl secondary butyl, tert-butyl, pentyl, isopentyl, 2 - in the present invention or a hard atom. Compared with the present invention or the branched alkyl group 'isobutyl, methylbutyl, neopentyl or hexyl, a straight or branched alkyl group having a carbon number of from 4 to 4 (Cl_C4 alkyl) is preferred. More preferably, it is a mercapto group or an ethyl group (c]_c alkyl group), and more preferably a methyl group. In the present invention, the "Ci_C6 dentate alkyl group" is a group of the same or different i to 5 of the aforementioned "elemental atom" and the above "Cl_C6 alkyl". -20- 201143771 For example, 1 to 5 of the above-mentioned trifluoro-f-'trioxalanium bromide, fluoromethyl or keto-difluoromethyl, dichloromethyl, di 2, 2, 2 - 3 stupid 7 苴"Nansuyuan-soil" is preferably the same or a different base (CVC4 halogenated alkyl group), and the "C!-C4 alkyl group j is combined with the aforementioned "halogen atom" and the same or different 1 to 5" and "C-halogenated alkyl", and more preferably rabbit _ 1 2 'membery J-bonded group (C丨-C2 is difluoromethyl.

於本發明，「C „ ^ 埃·氧基」為前述「err宜 ^ 氧原子結合的基，係碳 J ^ C丨-C6院基」與 氧基。例如，曱氧基、為1至6個之直鏈或分枝鏈烷 氧基、異丁氧基、二級基、丙氧基、異丙氧基、丁 較佳係碳數為1至4個乳基、三級丁氧基或戊氧基，In the present invention, "C „ ^ 埃·oxyl group” is the above-mentioned "err should be an oxygen atom-bonding group, and is a carbon J^C丨-C6 yard group" and an oxy group. For example, a methoxy group, 1 to 6 straight or branched alkoxy groups, isobutoxy groups, a secondary group, a propoxy group, an isopropoxy group, and a butyl group preferably have a carbon number of 1 to 4 Lactic, tertiary butoxy or pentyloxy,

燒氧幻，更佳為甲氧義之直鏈或分枝㈣氧基（CA (C】-C3烧氧基），再更^乙乳基、丙氧基或異丙氧基 丹文佳為曱氧基。 於本發明，「C, _「上 ^ 5 ^ -i· -+· Γ Λ * 6 ·’化烷氧基」係相同或相異之工 主5個刖逸「鹵素原子 Α。&amp;口 , 」與削述「C丨-C6烷氧基」結合的 基。例如，三氟甲氧基、二 氣甲氧基、二漠甲氧基、；氣甲乳基、二氟甲氧基、二 較佳為相同或相異：U 5甲氧基或2,2,2-三敗乙氧基’ 述「W燒氧基」結合的二前广？素原子」與前 4Η π , 、基（Cl-C4鹵化烧氧基），更佳 两相同或柏異之丨至 y ^ 「Cr 個之前述「iS素原子」與前述Oxygen igniting, more preferably a linear or branched (tetra)oxy group (CA (C)-C3 alkoxy), and more ethyl lactate, propoxy or isopropoxy In the present invention, "C, _"上^5^-i·-+· Γ Λ * 6 · 'alkoxy" is the same or different workers, five 「 「 "halogen atom Α. &amp; mouth," a group that binds to the "C丨-C6 alkoxy group". For example, trifluoromethoxy, dimethoxymethoxy, dimethyl methoxy, methoxymethyl, difluoro The oxy group and the second group are preferably the same or different: U 5 methoxy group or 2,2,2-tris ethoxy group, the "W alkoxy group" bonded with the "ww alkoxy group" and the first 4 Η π , base (Cl-C4 halogenated alkoxy), better two identical or different 丨 to y ^ "Cr of the aforementioned "iS atom" and the foregoing

Ci-C2烷氧基」結合的美Γ 〇 ^上 」”引乩 為三氟曱氡某。 土（ C1-C2画化烷氧基），再更佳 於本發明，「c r 「c _Γ 7、元基羰基氧基」係1個之前述 1 6燒基」結合的銷发Λ 醯氧芙、a /、氧原子結合的基。例如，乙 乳巷丙醯虱基、丁醯β 〜氣基、異丁醯氧基、戊醯氧基、 -21- 201143771 三甲基乙醯氧基、戊醯氧基或異戊醯氧基，較佳為！個 之前述「C丨-C4烷基」結合的羰基與氧原子結合的基 (C^C：5烷基羰基氧基），更佳為乙醯氧基。 於本發明’「CrC7烷氧基羰基氧基」係i個之前述 「c, -C6烧氧基」結合的羰基與氧原子結合的基^例如， 甲氧基羰基氧基、乙氧基羰基氧基、丙氧基羰基氧基、 異丙氧基羰基氧基、丁氧基幾基氧基、二級丁氧基幾基 氧基或三、級丁氧基幾基氧基，較佳為丨個之前述「CA 烷氧基」結合的羰基與氧原子結合的基（c”c5烷氧基羰 基氧基）’更佳為曱氧基羰基氧基。 於本發明，雜1衣基」係含有1至3個硫原子、氧原 子或/及氮原+’可再含有】或2個之氮原子且該硫原 子可與2個氧原子結合的4至7員雜環基。例如&quot;夫喃 基、噻吩基、吡咯基、吖庚因基、吡唑基、咪唑基、噚 嗤基、異崎錄…塞唾基、異嗔唾基、U，4巧二唾基、 “3,4-噻二唑基、三唑基、四唑基、。塞二唑基、哌喃基、 比疋基、。合啩基、嘧啶基或吡啩基之類的「芳香族雜環 基」、或四氫哌喃基、㈤氫噻吩基、味啉基、硫咮啉基： 吡咯咬基、吡咯啉基、咪嗤咬基…比唑。定基、哌咬基、 旅啡基，琳基，咬基、異^定基十坐琳基、 塞疋基比唾。疋基、二氧戊環基、二0f烧基或5,6-二 氫-4H-U-号听基之類的「部分或完全還原型之飽和雜^ 基」，上述雜環基可盥笼昏 ^ 合二環式料基」），例如，苯并切基、苯μ。坐基‘ 苯并0f唑基、異苯并咕4 1 南基、1，3-—氧異苯并呋喃基、 -22- 201143771 °查嚇·基、1，3 -苯并二氧戊環夷、 基、異。弓卜朵基或t朵。林基。1，4'笨并二污炫基、°引哚 於本發明，「可具有1至Ci-C2 alkoxy""""""""""""""""""""""""""""""""""""""""" And a ketone carbonyl group is a group in which the above-mentioned 16 ketone group is bonded to the oxime, a /, oxygen atom-bonded group. For example, propyl ketone, butyl hydrazine, butyl hydrazine, isobutyl methoxy, pentyloxy, -21- 201143771 trimethyl ethoxycarbonyl, pentyloxy or isoamyloxy , preferably! The above-mentioned "C丨-C4 alkyl group"-bonded group in which a carbonyl group is bonded to an oxygen atom (C^C:5-alkylcarbonyloxy group) is more preferably an ethoxy group. In the present invention, "CrC7 alkoxycarbonyloxy group" is a group in which the above-mentioned "c, -C6 alkoxy group"-bonded carbonyl group is bonded to an oxygen atom, for example, a methoxycarbonyloxy group or an ethoxycarbonyl group. An oxy group, a propoxycarbonyloxy group, an isopropoxycarbonyloxy group, a butoxy oxyoxy group, a 2,4-butoxyoxy group or a tris-butoxyoxy group, preferably Further, the "CA alkoxy"-bonded carbonyl group and the oxygen atom-bonded group (c"c5 alkoxycarbonyloxy group)' are more preferably an oxooxycarbonyloxy group. In the present invention, a hetero-1-yl group" A 4- to 7-membered heterocyclic group containing 1 to 3 sulfur atoms, an oxygen atom or/and a nitrogen former + 'may be further contained] or 2 nitrogen atoms and which may be bonded to 2 oxygen atoms. For example, &quot;fumyl, thienyl, pyrrolyl, azepine, pyrazolyl, imidazolyl, fluorenyl, sulphate, succinyl, isoindolyl, U, 4 succinyl, "Aromatic hybrids such as 3,4-thiadiazolyl, triazolyl, tetrazolyl, oxadiazolyl, piperidyl, fluorenyl, fluorenyl, pyrimidinyl or pyridyl Cyclo", or tetrahydropyranyl, (5) thiophenyl, morpholinyl, thioporphyrin: pyrrolebityl, pyrrolinyl, imidazole, azole. Fixed base, piperidine base, british base, Linji, bite base, different bases, ten bases, and sulki. a "partially or fully reduced saturated heterocyclic group" such as a fluorenyl group, a dioxolanyl group, a dioxin group or a 5,6-dihydro-4H-U-yl group, the above heterocyclic group Cage 合 ^ bicyclic material base"), for example, benzo-cut group, benzene μ. Sodium-benzo-3-fazolyl, isobenzopyrene 4 1 South, 1, 3-oxobenzofuranyl, -22- 201143771 °, scare base, 1,3 -benzodioxolane Yi, base, and difference. Bow Buduki or t. Lin Ke. 1,4' stupid and dilute base, ° cited in the present invention, "can have 1 to

的基取代之笨基」為苯基或經個獨立選自取代基群A 群A之基取代的苯基。較戶至5個獨立選自取代基 Μ-雙（三氣甲基）笨基二44^笨基、2_甲基笨基、 於本發明，「可…至广三甲氧基苯基。The base-substituted stupid group is a phenyl group or a phenyl group independently substituted with a group selected from the group A of the substituent group A. From the household to 5 independently selected from the group consisting of a substituent Μ-bis(trimethylmethyl) phenyl 2 44^, and a 2-methyl group, in the present invention, "may be ... to a wide trimethoxyphenyl group.

的基取代之雜環基」為前C立選自取代基群A 立選自取代基群A之基取代？衣基」或經1至3個獨 於本發明，「cvC述「雜環基」。 之直誠純鏈飽和碳化氫可自碳數為1至6個 例如，亞甲基、甲基亞氣原子的2價基。 基、四亞甲基、”基甲：乙基、伸丙基、三亞甲 肀基、2_曱基=¾甲其 ， 甲基三亞甲基、五亞甲基 土-亞甲基、3- 伸乙基、三亞甲基、四亞ψΑ亞甲基’較佳為亞曱基、 於本發明，「伸笨美#%五亞甲基或六亞甲基。 r Α ά 1 ? ^ ^ 土」糸可自苯除去2個氫原子的2 饧基，為1，2-伸苯基、^ 丁旳2 1，3-伸苯基或^伸笨基。Μ·伸笨基。較佳為 本發明之具有通式⑴的化合物或其藥理 ^ 的鹽包含全部之異構物（嗣·烯醇異構物、 Μ 物、光學異構物、回轉異構物等）。 、異構 本發明之具有通式⑴的化合物 的鹽於其分子内存有不對稱碳原+，故、：里上可各許 物。於本發明之化合物，此等異構物及此等：異構 合物全部以單一十主_ 寺’、構物之混 式表示’即以通式⑴表示。因此，本The radically substituted heterocyclic group is a radical selected from the group consisting of the substituent group A and the substituent group A. The "clothing group" or one to three are unique to the present invention, "cvC describes "heterocyclic group". The straight chain pure hydrocarbon saturated hydrocarbon can be from 1 to 6 carbon atoms, for example, a methylene group, a methyl group of a methylene atom. Base, tetramethylene, "methyl: ethyl, propyl, trimethylene, 2 - fluorenyl = 3⁄4, methyl methylene, penta methylene - methylene, 3- The exoethyl, trimethylene, and tetramethylene methylene group is preferably an anthracene group, in the present invention, "extension" #% pentamethylene or hexamethylene. r Α ά 1 ? ^ ^ soil糸 A 2-mercapto group capable of removing two hydrogen atoms from benzene, which is a 1,2-phenylene group, a butyl group, a 1,3-phenylene group or a phenyl group. Μ·Standing base. Preferably, the compound of the present invention having a compound of the formula (1) or a pharmacologically acceptable salt thereof comprises all of the isomers (indole enol isomers, anthracene, optical isomers, rotatory isomers, etc.). Isomerization The salt of the compound of the present invention having the formula (1) has an asymmetric carbonogen + in its molecule, so that it can be exemplified. In the compound of the present invention, these isomers and the like: all of the isomers are represented by a single ternary structure and a mixture of the structures, i.e., represented by the general formula (1). Therefore, this

C •23- 201143771 發明亦包含此等異構物及此等異構物之任 物全部。 干的匕合 如上述之立體異構物係可使用光學活性原料 物，或使用丨對稱合成或不對稱誘導的手法來。 明有關之化合物，或所合成 σ战本％ 所欲可使用通常之光學分割法或分離法單物依 本發明之具有通式⑴的化合物或其藥理： 的鹽亦可於構成此等化合物的原子之i個以 ：终 同位素之非天然比率。就屌 ’原子 干犹原子冋位素而言，例如，飞谢 例氘（2h)、氚（4)、碘_12 可舉 ^ I)或石反-14(14(^、隹 又，前述化合物，例如，可έ ) 4 〇 、及矾（3Η)、碘-125 (丨25Τ、 或碳-14 ( C)等放射性同你| ) 戌丨j位素作放射性標識而得。 放射性標識的化合物有用於作 ！ 戸马治療或預防劑、 办 藥，例如’分析試藥及診斷鈿 Μ九试 Μ ’例如’活體内哥;；偟 劑。本發明之化合物之全部 〜像杉斷 主口Ρ冋位素變異體不管是不达 射性’皆包含於本發明之範嘴。 疋古為放 「其藥理上可容許的_ 土 |」思指不具有顯荖主 使用作為醫藥的鹽。本發明之Β ‘者母性且可 &lt;具有通式（I )的仆人此 具有胺基之類的鹼性基的愔I J化合物於 月形’經由與酸反鹿， 有羧基之類的酸性基的情形，奸 ^ 又於具 就基於驗性基的鹽而言由與驗反應’可作成鹽。 鹽酸鹽、溴化氫酸鹽、碘化彳舉例氟化氫酸鹽、 il酸鹽之類的-化新 硝酸鹽、過氣酸鹽、硫酸醆、 因化風 烷磺酸鹽、三氟曱烷磺醆_ “夂鹽等之無機酸鹽；甲C • 23- 201143771 The invention also includes all such isomers and all such isomers. Dry kneading The stereoisomers as described above may be used as optically active starting materials, or by ruthenium symmetric synthesis or asymmetric induction. A compound of the formula (1) or a pharmacologically acceptable salt thereof may be used in the compound of the formula (1) or a salt thereof. The atomic i is the unnatural ratio of the final isotope. In the case of 原子 'atomic dry helium atomic pheromone, for example, fly 氘 氘 (2h), 氚 (4), iodine _12 can be ^ I) or stone anti-14 (14 (^, 隹 ,, the aforementioned Compounds, for example, έ, 4 〇, and 矾 (3Η), iodine-125 (丨25Τ, or carbon-14 (C), etc. are radioactively labeled with you )j. The compound is used for the treatment or prophylaxis of hummer, such as 'analytical reagents and diagnosis 钿Μ Μ Μ ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' The ubiquitin variant, whether it is non-radial or not, is included in the mouth of the present invention. The sputum is "the pharmacologically permissible _ soil|" thinking that it does not have the main use of the salt as a medicine. The 愔IJ compound having a basic group such as an amine group of the servant of the formula (I) is in the form of an acid group such as a carboxyl group via an anti-deer with an acid. In the case of rape, and in the case of a salt based on the test, the salt can be used as a salt. Hydrochloride, hydrogen bromide, iodide For example the hydrogen fluoride salts, such salts IL - nitrate of new, off gas, sulfated 醆, because mineral acid salts of alkyl sulfonates wind, trifluoromethyl Yue alkylsulfonyl 醆 _ "Fan salts, etc.; A

炫基續酸鹽、苯績酸鹽、二燒續酸鹽之類的CA r本磺酸鹽之類的芳基磺酸 -24- 201143771 鹽、乙酸鹽、蘋果酸鹽、反丁烯二酸鹽、琥 檬酸鹽、抗壞血酸鹽、酒石酸鹽、蓚酸鹽、 鹽等之有機酸鹽；及甘胺酸鹽、離胺鹽、精 胺酸鹽、麩胺酸鹽、天冬胺酸鹽之類的胺基 另一方面，就基於酸性基之鹽而言，例 鈉盘、鉀鹽、鐘鹽之類的驗金屬鹽、妈鹽、 鹼土類金屬鹽、鋁鹽、鐵鹽等之金屬鹽；銨 機鹽、三級辛基胺鹽、二苄基胺鹽、味啉鹽 鹽、苯基甘胺酸烷基酯鹽、伸乙基二胺鹽、 葡糖胺鹽、胍鹽、二乙基胺鹽、三乙基胺鹽 胺鹽、N，N’-二苄基伸乙基二胺鹽、氣普鲁卡 卡因鹽、二乙醇胺胺鹽、N-苄基苯乙基胺鹽 四曱基銨鹽、參（羥基曱基）胺基甲烷鹽之 等之胺鹽；及甘胺酸鹽、離胺酸鹽、精胺酸 鹽、麩胺酸鹽、天冬胺酸鹽之類的胺基酸鹽 本發明之具有通式（I)的化合物或其藥 的鹽經由放置於大氣中、或再結晶，有吸收 為水合物的情形’如此水合物亦包含於本發 本發明之具有通式（I )的化合物或其藥 的鹽有吸收其他各種溶媒而成為溶媒合物的 之〉谷媒合物亦包含於本發明之鹽。 「具有神經激肽NK!、神經激肽NK2及蕈 结抗作用的化合物」係具有神經激肽NKl 用、神經激肽NK2受體拮抗作用及簟毒鹼m3 用之全部的拮抗作用的化合物。 ϊ白酸鹽、檸 順丁稀二酸 胺酸鹽、鳥 酸鹽。 如’可舉例 鎂鹽之類的 鹽之類的無 '葡萄糖胺 N•曱基還原 、二環己基 因鹽、普鲁 、°底听鹽、 類的有機鹽 鹽、鳥胺酸 〇 理上可容許 水分子而成 明之鹽。 理上可容許 情形，如此 毒驗M3受體 受體拮抗作 受體拮抗作 -25- 201143771 具有神經激肽NK!及蕈毒鹼M3受體拮抗作用的化 合物」係亦具有神經激肽ΝΚι受體拮抗作用及簟毒鹼％ 受體枯抗作用兩者之拮抗作用的化合物。 「具有神經激肽NK,受體拮抗作用」係指具有對神 經激狀NKl受體表現細胞粗膜標本具特異的結合能力， 且藉由阻礙或抑制基質P誘發呼吸道收縮等之神經激肽 受體激動劑之作用而被評價的神經激肽NKi受體拮 抗作用’特定的化合物是否具有如此拮抗作用，只要熟 悉本項技術領域之人士即可依據例如，以下之方法而容 易地判別。 有關方法係依據文獻（European Journal ofArylsulfonate such as CA sulfonate, such as chlorinated acid salt, phthalic acid salt, or bis-sodium sulphonate.-24- 201143771 Salt, acetate, malate, fumaric acid An organic acid salt of a salt, a succinate, an ascorbate, a tartrate, a citrate or a salt; and a glycinate, an amine salt, a arginine, a glutamate, an aspartate or the like On the other hand, in the case of a salt based on an acidic group, a metal salt such as a metal salt such as a sodium disk, a potassium salt or a clock salt, a mother salt, an alkaline earth metal salt, an aluminum salt or an iron salt; Ammonium machine salt, tertiary octylamine salt, dibenzylamine salt, porphyrin salt, alkyl phenylglycine, ethyl diamine salt, glucosamine salt, sulfonium salt, diethyl Amine salt, triethylamine salt amine salt, N,N'-dibenzylethylidene diamine salt, gas procacaine salt, diethanolamine amine salt, N-benzylphenethylamine salt tetradecyl An amine salt of an ammonium salt, a hydroxy(hydroxy)aminomethane salt; and an amine group such as a glycinate, an amidate, a arginine, a glutamate or an aspartate; Acid salt of the present invention The compound of (I) or a salt thereof is placed in the atmosphere or recrystallized, and is absorbed as a hydrate. Thus, the hydrate is also included in the compound of the present invention having the formula (I) or a drug thereof. The salt of the salt which is a solvent which absorbs other various solvents and is a solvent is also included in the salt of the present invention. The "compound having neurokinin NK!, neurokinin NK2, and sputum anti-effect" is a compound having antagonism of neurokinin NK1, neurokinin NK2 receptor antagonism, and muscarinic m3. Leucate, cis-succinic acid, aminate, acinate. Such as 'can be exemplified by salts such as magnesium salts, such as no-glucosamine N• thiol reduction, dicyclohexyl gene salt, prolu, sulphate salt, organic salt of the class, ornithine Allow water molecules to form a clear salt. In principle, it is permissible to test the M3 receptor receptor antagonism as a receptor antagonist. -25-201143771 A compound with neurokinin NK! and muscarinic M3 receptor antagonism also has neurokinin ΝΚι Compounds that antagonize both antagonism and muscarinic receptor receptors. "There is a neurokinin NK, receptor antagonism" refers to a neurokinin receptor that has a specific binding ability to a neuronal NK1 receptor-expressing cell crude membrane specimen, and which induces respiratory contraction by blocking or inhibiting matrix P. The neurokinin NKi receptor antagonism evaluated by the action of a agonist 'whether a specific compound has such an antagonistic effect can be easily discriminated according to, for example, the following method as long as it is familiar to those skilled in the art. The relevant methods are based on the literature (European Journal of

Pharmacology’ 2008，vol.5 86，pages 306-3 12 )記載之測 定法（2 · 3受體結合試驗），測量神經激肽Νκ^受體結合能 力’並依據預先設定的一定値（Ki = ΙμΜ，較佳Ki = 1〇ηΜ) 以下’及依據文獻（將 British Journal of Pharmacology and Chemotherapy, 1962, vol. 19, p age s 1 6 8 - 1 8 2, European Journal of Pharmacology, 1992 vol 231 p a g e s 3 1 - 3 8作變化）’測量呼吸道收縮，其抑制效果若為 氣管内投與之其用量為預先設定的一定値（id5〇 = lmg/kg，較佳為ID5Q= 50pg/kg )以下，即可判定為具有 拮抗作用的方法。 「具有神經激肽NK2受體拮抗作用」意指具有對神 經激肽NK2受體表現細胞粗膜標本具有特異的結合能 力，且藉由阻礙或抑制神經激肽A誘發呼吸道收縮等之神 經激肽NK：2受體激動劑之作用而被評價的神經激狀Νκ -26- 201143771 受體拮抗作用，特定化合物是否具有此等拮抗作用只要 為本項技術領域之人士可依據例如，以下之方法容易地 判別。 有關方法可皋例依據文獻（European Journal of Pharmacology，2008, vol.5 86, pages306-3 12 )記載之測定 法（2.3受體結合試驗），測量神經激肽NK：2受體結合能 力’並依據預先設定的一定値（Κί=1μΜ，較佳為Ki = 10nM)以下，及依據測定法（2 6於天竺鼠之支氣管收 縮），測量呼吸道收縮，其抑制效果只要氣管内投與時其 用里為預先設定的一定値（ΙΕ&gt;5〇== lmg/kg ’較佳為 =50gg/kg)以下，即可判定為具有拮抗作用。 「具有簟毒鹼Ms受體拮抗作用」意指具有對蕈毒鹼Pharmacology' 2008, vol. 5 86, pages 306-3 12) The assay described (2 · 3 receptor binding assay), measuring neurokinin Ν κ ^ receptor binding capacity ' and based on a predetermined set of 値 (Ki = ΙμΜ, preferably Ki = 1〇ηΜ) following 'and according to the literature (British Journal of Pharmacology and Chemotherapy, 1962, vol. 19, p age s 1 6 8 - 18 2, European Journal of Pharmacology, 1992 vol 231 pages 3 1 - 3 8 for change) 'Measure the contraction of the airway, if the inhibitory effect is less than a predetermined amount of 气 (id5〇= lmg/kg, preferably ID5Q=50pg/kg). It can be judged as a method having an antagonistic action. "The neurokinin NK2 receptor antagonism" means a neurokinin having a specific binding ability to a neuroblastin NK2 receptor expressing a crude cell membrane specimen, and which induces respiratory contraction by blocking or inhibiting neurokinin A. Neurokinetic Ν κ -26- 201143771 receptor antagonism evaluated by the action of NK:2 receptor agonist, whether a specific compound has such antagonism as long as the person skilled in the art can, for example, according to the following method Ground discrimination. The method can be used to measure the binding capacity of neurokinin NK:2 receptor by the method described in the literature (European Journal of Pharmacology, 2008, vol. 5 86, pages 306-3 12) (2.3 receptor binding assay). According to the pre-set 値 (Κί = 1μΜ, preferably Ki = 10nM) below, and according to the measurement method (2 6 in the bronchoconstriction of guinea pigs), the contraction of the airway is measured, and the inhibitory effect is as long as it is administered intratracheally. It is judged to have an antagonistic action by setting a predetermined 値 (ΙΕ&gt;5〇== lmg/kg 'preferably = 50 gg/kg) or less. "with muscarinic Ms receptor antagonism" means having a muscarine

Ms受體表現細胞粗膜標本具有特異的結合能力，且藉由 阻礙或抑制乙醯基膽鹼誘發呼吸道收縮等之蕈毒鹼％受 體激動劑之作用而被評價的蕈毒鹼&amp;受體拮抗作用，特 定化合物是否具有此等拮抗作用只要為本項㈣領域之 人士可依據例如’以下之方法容易地判別。 有關方法可舉例依據文獻「T . f c . ^ ^ m. I Life Sciences, 1993, vol.52，pages537-544)記載之、'目η 八、』， 戟（測疋法（人類蕈毒鹼受體 研究）’測量蕈毒鹼Ms受體結合能六 σ此力，依據預先設定的一 定値（Ki = 1 μΜ，較佳為 Ki = 1 〇ηλ/Γ Λ ^ ιυηΜ)以下，及依據測定 法（將於麻醉犬之解除支氣管痙蠻Γ . 手 V b r ο n c h 〇 s p a s m ο 1 y s 1 s ) 作改變），而測量呼吸道收縮，i 〃抑制效果若於氣管内投 與時其用量為預先設定的一定信r 心値（1])50= img/kg，較佳 為1D5Q=5(Wkg)以下者即可判定為具有结抗作用。 -27- 201143771 鑑定該「具有神經激肽NK,、神經激肽ΝΚ2及蕈毒鹼 %受體拮抗作用的化合物」的方法亦包含本發明。該方 法係包含（1 )判斷被驗化合物是否具有神經激肽NKi受 體拮抗作用的步驟、（i i )判斷該被驗化合物是否具有神 經激肽NK2受體拮抗作用的步驟、及（iU )判斷該被驗 化合物是否具有蕈毒驗M3受體拮抗作用的步驟。於該方 法，步驟（i )至（iii )可以任意之順序進行、或同時並 行進行2個以上之步驟。將於步驟（丨）至（Hi )任一者， 被判定為具有各受體拮抗作用的被驗化合物認定為「具 有神經激肽NK,、神經激肽NK2及蕈毒鹼μ〗受體拮抗作用 的化合物」。 鑑定該「具有神經激肽NKl及蕈毒鹼％受體拮抗作 用的化合物」的方法亦包含於本發明。該方法係包含（i) 判斷被驗化合物是否具有神經激肽ΝΚι受體拮抗作用的 步驟及（iii)判斷該被驗化合物是否具有蕈毒鹼受體 拮抗作用的步驟。於該方法之步驟（i)或（iH)，可以 任意之順序進行或同時並行進行2個步驟。將於步驟（i ) 或（iii)任一者被判定為具有各受體拮抗作用的被驗化 合物認定為「具有神經激肽NKl及蕈毒鹼…受體拮抗作 用的化合物j。 步驟（i)包含“）測量被驗化合物之神經激肽狐丨 受體結合能力的步驟及（b)判斷該化合物是否阻礙或抑 制神經激肽NKl受體激動劑之作用的步驟。就神經激肽 NI受體激動劑而言，例如，可舉例基 狀叫受體激動劑之作用而言，例如，可舉4例= 呼吸道收縮等。 -28- 201143771 步驟（ii)包含（C)測量被驗化合物之神經激肽NK2 受體結合能力的步驟及（d)判斷該化合物是否阻礙或抑 制神經激狀NK2受體激動劑之作用的步驟。就神經激肽 NK2受體激動劑而言，例如，可舉例神經激肽八等。就神 經激狀NK2受體激動劑之作用而言，例如，可舉例神經 激肽A誘發呼吸道收縮等。 步驟（m )包含（e )測量被驗化合物之簟毒鹼 受體結合能力的步驟及（f)判斷該化合物是否阻礙或抑 制蕈毒鹼M3受體激動劑之作用的步驟。就簟毒鹼M3受體 激動劑而言，例如，可舉例乙醯基膽鹼、乙醯曱膽鹼 (methachohne)等。就蕈毒鹼％受體激動劑之作用而 言，例如，可舉例乙醯基膽鹼誘發呼吸道收縮等。 於測量上述之各受體結合能力的步驟，可使用内在 性表現該受體多胜肽的動物組織或細胞，或導入表現重 組受體多胜肽的基因的動物或細胞之膜劃分、無傷的細 胞（完整細胞）等、及經標識的各受體結合物質。 又本毛明之方法中被鑑定為「具有神經激肽1、 神經激肽nk2及蕈毒鹼m3受體拮抗作用的化合n 「具有神經激肽NKl及蕈毒鹼％受體拮抗作用的化合 物」的化合物，如後述’有用於作為醫藥，尤其，有用 於作為支氣管氣喘、支氣管炎、慢性阻塞性肺病、咳嗽、 :痰過度分泌、鼻炎、疼痛、焦慮、抑營、痙攣、帕金 ^氏症、尿失禁、過敏性腸症候群、前列腺肥大”區吐、 責瘍、網膜檢查、急性虹彩炎、角膜炎、縮瞳、 由於转料致的過度钱分泌、呼料分減/ -29- 201143771 之預防劑或治療劑。因此，鑑定本發明之「具有神 肽NKl、神經激肽NK2及蕈毒鹼M3受體拮抗作、用的 物」的方法作為鑑定該疾病之預防或治療劑 含於本發明。 [發明之效果] 本發明之具有通式（I )的化合物或其藥理上玎 的鹽對神經激肽NK〗、神經激肽NK：2及蕈毒鹼M3受 或對神經激肽NL及蕈毒鹼M3受體，顯示拮抗作 故有用於作為醫藥，尤其，有用於作為支氣管氣喘 氣管炎、慢性阻塞性肺病、咳嗽、喀痰過度分泌、鼻 疼痛、焦慮 '抑鬱、痙攣、帕金森氏症、尿失禁、 性腸症候群、前列腺肥大、嘔吐 '消化性潰瘍、網 查、急性虫工彩炎、角膜炎、縮瞳、由於麻醉藥導致 度唾液分泌、呼吸道分泌及/或潰瘍之預防劑或治療 【實施方式】 [用以實施發明之形態] 本發明之具有通式（I )的化合物可依據以下記 文獻及實施例來製造。 具有神經激肽NK】及神經激肽NK2受體拮抗作 部分構造或具有神經激‘肽N K!受體拮抗作用的部分 可依據US7365067號公報、US2003/4 157號公報等 的方法或類似此等之方法而被製造。 具有蕈毒鹼M3受體拮抗作用的部分構造係 US2004/1671 67 號公報、US2005/203 167 號公 EP 1 2 1 328 1號公報等記載的方法或類似此等之方法 製造。 經激 化合 亦包 容許 :體， 用’ 、支 .炎、 過 膜檢 的過 .劑。 載之 用的 構造 記載 依據 報、 而被 -30- 201143771 結合2個部分構造的部位可依據Tetrahedron Lett· 1991,32, 4505、J.Org.Chem. 1989, 54, 5522 &gt; Organic Letters, Vol.4, No.5, 2002, 73 7-740 等、或下述記載之實 施例來製造。又，胺基、羥基及/或羧基可因應必要使用 保護基而保護。保護•脱保護為必要的步驟係依據既知 之方法（例如，”Protective Groups in Organic Synthesis” (Theodora W. Greene、Peter G. M.Wuts 著，1 999 年， Wiley-Interscience Publication 發行）等記載之方法）來 進行。 本發明之具有通式（I )的化合物或其藥理上可容許 的鹽之投與形態可為例如’經由錠劑、膠囊劑、顆粒劑、 散劑或糖漿劑等之經口投與、或經由注射劑或栓劑等之 非經口投與。再者，本發明之具有通式（的化合物或 其藥理上可容許的鹽亦可作為粉末 '溶液或懸浮液之形 態經肺投與。此等用之製劑係使用賦形劑、潤滑劑、結 合劑、崩解劑、安定劑、矯味矯臭劑、稀釋劑等之添力: 劑而以周知方法製造。 賦形劑可為例如，乳糖、白糖、葡萄糖、甘露糖 或山梨糖醇之類的糖衍生物、玉米澱粉、馬鈐薯澱粉、 澱粉、糊精或羧曱基澱粉之類的澱粉衍生物；結晶 素、低取代度經基丙基纖維素、經基丙基甲基：：素 羧甲基纖維素、羧甲基纖維素 素納之類的纖維素衍生物、阿拉伯耀.、； =基纖 魯蘭多糖（pullulan)等之有機糸时 . A 或 酸、合成矽酸鋁或偏_ _ 、 / ，或輕質無水 4 1场矽酸鋁酸鎂之類的^ 欠装I頰的矽酸鹽衍生物 -31- 201143771 磷酸鈣之類的磷酸鹽；碳酸鈣之類的碳酸鹽；或硫酸鈣 之類的硫酸鹽等之無機系賦形劑。 潤滑劑，例如，硬脂酸、硬脂酸鈣或硬脂酸鎂之類 的硬脂酸金屬鹽；滑石；勝狀石夕石；B e g u m或録堪之類 的蠟類；硼酸；己二酸；硫酸鈉之類的硫酸鹽；二醇； 反丁烯二酸；苯甲酸鈉；DL-白胺酸；脂肪酸鈉鹽；月桂 基硫酸鈉或月桂基硫酸鎂之類的月桂基硫酸鹽；無水矽 酸或矽酸水合物之類的矽酸類；或上述澱粉衍生物。 結合劑可為例如，聚乙烯吡咯啶酮或聚乙二醇 (macrogol )、或與前述賦形劑相同的化合物。 崩解劑可為例如，與前述賦形劑相同的化合物、或 交聯羧甲基纖維素鈉、羧甲基澱粉鈉或交聯聚乙烯吡咯 啶酮之類的經化學修飾的澱粉•纖維素類。 安定劑可為例如，對羥基苯曱酸甲酯或對羥基苯曱 酸丙酯之類的對羥基苯曱酸酯類；氣丁醇、苄基醇或苯 基乙基醇之類的醇類；氯化烷基二曱基苄基銨；酚或甲 S分之類的酴類；硫柳汞（t h i m e r 〇 s a 1 );去氫乙酸；或山 梨酸。 嬌味矯臭劑可為通常使用的甘味料、酸味料或香料 等。 於製造用以經肺投與本發明之具有通式（I )的化合 物或其藥理上可容許的鹽的溶液或懸浮液的情形，例 如，經由使本發明之化合物溶解或懸浮於水、或水及輔 助溶媒（例如，乙醇、丙二醇、聚乙二醇等）之混合物 可製造。此等溶液或懸浮液可進一步含有防腐劑（例如， -32- 201143771 氣化烷基二曱基苄基銨）、可溶化劑（例如，Tween 8〇 或Span 80之類的聚山梨酸酯、或氯化烷基二曱基节基 銨之類的表面活性劑）、緩衝劑、等張化劑（何如，氣化 鈉）、吸收促進劑及/或增黏劑。又，懸浮液可進一步含 有懸浮化劑（例如’微結晶質纖維素、羧基甲基纖維素 鈉等）。 如上述製造的用以經肺投與的組成物可藉由吸入劑 領域中一般的手段（例如使用注射器、吸量管、插管或 喷霧器）而直接投與鼻腔或口腔。使用噴霧器的情形， 可將本發明之化合物與適當喷射劑（例如，二氣I甲院、 二氣氟曱烷或二氣四氟乙烷之類的氯氟化碳、或二氧化 碳等氣體等）一起作為加壓包的形式的氣溶膠喷霧或 使用噴霧器投與。 本發明之具有通式（I )的化合物或其藥理上可容許 的鹽之使用量依患者（溫血動物，尤其是人）之症狀、 年齡等而異，例如經口投與的情形，對成人每丨日之下 限為〇_lmg (較佳為img，更佳為5mg)，上 r Μ ^ 上限為 lOOOmg 較佳為lOOmg，更佳為50mg)，j次 痛r . 力乂歎次，因康 史與者為所企望的。靜脈内投盥的情F 〜 之下限為O.Olmg(較佳為〇 (較佳為10mg)，i次或分成、 上限為lOOmg % ^ X刀成數次，因库、荇此 為所企望的。 U愿症狀而投與者 又’將本發明之具有通式 可衮飞（1)的化合物或兑蕴捉Η 泎的鹽經肺投與的情形之 ，、柰里上 物，尤复人）之佇曲^ ^ 用里依心者（溫血動 /、人）之症狀、年齡蓉而® ,,， “而異，例如，斜成人每！ -33- 201143771 曰之下限為〇. 1 pg/kg (較佳為0.5pg/kg )，上限為 lOOOOpg/kg (較佳為lOOOpg/kg)，1次或分成數次，因 應症狀而投與者為所企望的。 [實施例] 以下，舉貫施例及試驗例以進一步詳細說明本發 明，但本發明之範圍並未限定於此等例。 實施例之管柱層析中的溶出係藉由TLC (薄層層析 (Thin Layer Chromatography))觀察下進行。於 TLC 觀 察，將作為TLC盤之Merck公司製之石夕膠60F254、或富士 SILYSIA公司製之TLC plates NH，使用展開溶媒作為管 柱層析的溶出溶媒的溶媒，使用UV檢測器作為檢測法。 管柱用石夕膠係相同的Kishida化學公司製之石夕膠sk-85 (23 0〜400網目）、SK-34 ( 70〜230網目）、關東化學公 司製之矽膠60N ( 40〜50μηι )、富士 SILYSIA公司製之 Chromatorex NH DM1020 ( 100 〜200 網目）' DM2035SG (200〜350網目）或富士 SILYSIA化學公司製之石夕膠 FL1 00 B。通常之管柱層析之外，適宜使用山善公司之自 動層析裝置（YFLC-prep4)及可拋棄式管柱（Molitec公 司、山善公司、和光純藥公司）。經由preparative TLC的 純化係使用Merck公司製之矽膠60F2 5 4、〇.5mm厚、盤 20X20cm。又，實施例所使用的代號具有如下意義。 mg :毫克；g :克；mL :毫升；MHz :死赫；HATU : 〇-(7-氮雜苯并三唑-1-基）-Ν，Ν，&gt;Γ，Ν'-四曱基脲六氟磷 酸酯；WSC · HC1 : 1-乙基-3-(二曱基胺基丙基）碳化 二亞胺鹽酸鹽；HOBT· Η20: 1-羥基苯并三唑-水合物。 -34- 201143771 於以下之實施例，核磁共振（以下，1H NMR)光譜 係將四甲基矽烷作為標準物質，化學位移値記載為δ値 (ppm)。分裂樣式係單線以s表示，雙線以d表示，三重線 以t表示，四重線以q表示，平廣以br表示。 質量分析（以下，MS)以FAB(快速原子撞擊，Fast Atom Bombardment)法、EI(電離，Electron Ionization) 法、APCI (大氣壓化學 '電離源，Atmospheric Pressure Chemical Ionization)或 ESI (電灑法，Electron Spray Ionization)法進行。 [實施例1 ] (3R) - l-{ 7-[{ 5-[{ 2-[3,5-雙（三氟曱基）苯基]-2-甲基丙醯基}(甲基）胺基]_4_ ( 2-曱基苯基）。比啶-2-基} (曱基）胺基]庚-5-炔-l-基}吡咯啶-3-基羥基（二-2- °塞吩基）乙酸酉旨The Ms receptor exhibits a specific binding ability of the cell crude membrane specimen, and is evaluated by the action of a muscarinic receptor agonist which inhibits or inhibits acetylcholine-induced respiratory contraction and the like. The antagonism of the specific compound, whether or not the specific compound has such antagonism, can be easily discriminated by a person in the field of the above (4) according to, for example, the following method. The method can be exemplified by the literature "T. fc. ^ ^ m. I Life Sciences, 1993, vol. 52, pages 537-544), 'mesh VIII, 』, 戟 (testing method (human muscarinic Body study) 'Measure the scorpion basal Ms receptor binding energy sigma sigma, according to a predetermined 値 (Ki = 1 μΜ, preferably Ki = 1 〇ηλ / Γ Λ ^ ιυηΜ), and according to the assay (The bronchial sputum will be removed from the anesthetized dog. The hand V br ο nch 〇spasm ο 1 ys 1 s ) is changed), and the airway contraction is measured, and the i 〃 inhibition effect is preset if it is administered in the trachea. A certain letter r (1)) 50 = img / kg, preferably 1D5Q = 5 (Wkg) or less can be judged to have a nodgic effect. -27- 201143771 identified the "with neurokinin NK, The method of the compound of neurokinin ΝΚ2 and muscarinic receptor antagonism also encompasses the present invention. The method comprises the steps of: (1) determining whether the test compound has neurokinin NKi receptor antagonism, (ii) determining whether the test compound has neurokinin NK2 receptor antagonism, and (iU) determining Whether the test compound has a step of detecting M3 receptor antagonism by scorpion venom. In this method, steps (i) to (iii) may be carried out in any order or simultaneously in two or more steps. In any of the steps (丨) to (Hi), the test compound determined to have each receptor antagonism was identified as "having neurokinin NK, neurokinin NK2, and muscarinic μ" receptor antagonism Compound of action". A method for identifying the "compound having neurokinin NK1 and muscarinic receptor antagonistic action" is also included in the present invention. The method comprises the steps of (i) determining whether the test compound has neurokinin ΝΚ1 receptor antagonism and (iii) determining whether the test compound has muscarinic receptor antagonism. In step (i) or (iH) of the method, two steps can be performed in any order or simultaneously in parallel. The test compound which is determined to have each receptor antagonism in either of the steps (i) or (iii) is identified as "the compound j having neurokinin NK1 and muscarinic receptor antagonism. Step (i And a step of (b) determining whether the compound inhibits or inhibits the action of a neurokinin NK1 receptor agonist. In the case of a neurokinin NI receptor agonist, for example, a role called a receptor agonist can be exemplified, for example, 4 cases = respiratory contraction or the like. -28- 201143771 Step (ii) comprises the steps of (C) measuring the ability of the neurokinin NK2 receptor binding ability of the test compound and (d) determining whether the compound inhibits or inhibits the action of the neurokinetic NK2 receptor agonist . As the neurokinin NK2 receptor agonist, for example, neurokinin octapeptide can be exemplified. For the action of a neurokinetic NK2 receptor agonist, for example, neurokinin A induces airway contraction and the like. Step (m) comprises the steps of (e) measuring the ability of the test compound to bind to the muscarinic receptor and (f) determining whether the compound inhibits or inhibits the action of the muscarinic M3 receptor agonist. As the muscarinic M3 receptor agonist, for example, acetylcholine, methachohne and the like can be exemplified. With regard to the action of the muscarinic receptor agonist, for example, acetylcholine induces airway contraction and the like. In the step of measuring the binding ability of each of the above receptors, an animal tissue or a cell which expresses the polypeptide of the receptor intrinsically, or a membrane or an animal which is introduced into a gene representing a recombinant receptor polypeptide can be used, and is not damaged. Cells (intact cells), etc., and labeled receptor binding substances. In the method of Maoming, it was identified as "the compound with neurokinin 1, neurokinin nk2 and muscarinic m3 receptor antagonism n "compound with neurokinin NKl and muscarinic receptor antagonism" The compound, as described later, is used as a medicine, especially for use as bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, excessive secretion of sputum, rhinitis, pain, anxiety, depression, phlegm, Parkin's disease. , urinary incontinence, irritable bowel syndrome, prostatic hypertrophy, vomiting, blame, omentum examination, acute iridotonitis, keratitis, deflation, excessive money secretion due to material transfer, call loss reduction / -29- 201143771 A prophylactic or therapeutic agent. Therefore, the method for identifying the "antagonist NK1, neurokinin NK2, and muscarinic M3 receptor antagonistic action" of the present invention is identified as a prophylactic or therapeutic agent for identifying the disease. invention. [Effects of the Invention] The compound of the formula (I) or a pharmacologically acceptable salt thereof of the present invention acts on neurokinin NK, neurokinin NK:2 and muscarinic M3 or on neurokinin NL and 蕈The muscarinic M3 receptor, which shows antagonism, is used as a medicine, especially for bronchial asthmatic bronchitis, chronic obstructive pulmonary disease, cough, excessive sputum secretion, nasal pain, anxiety 'depression, convulsions, Parkinson's disease, Urinary incontinence, septic syndrome, prostatic hypertrophy, vomiting, peptic ulcer, net examination, acute worm, keratitis, sputum, salivation due to anesthesia, respiratory secretion and/or ulcer prophylaxis or treatment [Embodiment] [Formation for Carrying Out the Invention] The compound of the present invention having the formula (I) can be produced according to the following documents and examples. The portion having the neurokinin NK] and the neurokinin NK2 receptor antagonistic partial construct or having the neurokinetic 'peptide NK! receptor antagonism can be used according to the method of US Pat. No. 7,365,067, US 2003/4 157, or the like. It is manufactured by the method. A part of the structure having a muscarinic M3 receptor antagonism is produced by a method described in, for example, US Patent Publication No. 2004/1671, US Pat. Excited combination also allows for: body, using ', inflammation, and membrane test. The structure used for the record is based on the report, and the part constructed by combining the two parts by -30-201143771 can be based on Tetrahedron Lett. 1991, 32, 4505, J. Org. Chem. 1989, 54, 5522 &gt; Organic Letters, Vol .4, No. 5, 2002, 73 7-740, etc., or the examples described below. Further, the amine group, the hydroxyl group and/or the carboxyl group may be protected by the use of a protecting group as necessary. Protection and deprotection are necessary steps according to well-known methods (for example, "Protective Groups in Organic Synthesis" (Theodora W. Greene, Peter GMWuts, 1985, published by Wiley-Interscience Publication). get on. The administration form of the compound of the formula (I) or a pharmacologically acceptable salt thereof of the present invention may be, for example, 'oral administration via a tablet, capsule, granule, powder or syrup, or the like, or via Injectables or suppositories are administered orally. Furthermore, the compound of the present invention having a general formula or a pharmacologically acceptable salt thereof can also be administered as a powder in the form of a solution or suspension. These preparations use excipients, lubricants, A binding agent, a disintegrating agent, a stabilizer, a flavoring agent, a diluent, etc., may be produced by a known method. The excipient may be, for example, lactose, white sugar, glucose, mannose or sorbitol. Starch derivatives such as sugar derivatives, corn starch, horse starch starch, starch, dextrin or carboxymethyl starch; crystallization, low degree of substitution by propyl cellulose, propyl propyl methyl: Carboxymethylcellulose, cellulose derivatives such as carboxymethylcellulose sodium, arabic.;; organic ruthenium such as pullulan. A or acid, synthetic aluminum citrate or Partial _ _, /, or light anhydrous, 1 1 field magnesium silicate, etc. ^ Under-packed I buccal phthalate derivative -31- 201143771 Phosphate such as calcium phosphate; Carbonic acid such as calcium carbonate An inorganic excipient such as a salt; or a sulfate such as calcium sulfate. For example, stearic acid, calcium stearate or magnesium stearate such as stearic acid; talc; Shengshi Shishi; B egum or recorded wax; boric acid; adipic acid; Sulfate such as sodium; diol; fumaric acid; sodium benzoate; DL-leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate or lauryl magnesium sulfate; anhydrous citric acid or a tannic acid such as a citric acid hydrate; or a starch derivative as described above. The binding agent may be, for example, polyvinylpyrrolidone or macrogol, or the same compound as the aforementioned excipient. For example, the same compound as the aforementioned excipient, or chemically modified starch/cellulosic such as croscarmellose sodium, sodium carboxymethyl starch or cross-linked polyvinylpyrrolidone. For example, p-hydroxybenzoic acid esters such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate; alcohols such as gas butanol, benzyl alcohol or phenylethyl alcohol; chlorine Alkyl dimercaptobenzylammonium; anthraquinones such as phenol or in S; thimerosal (thimer 〇sa) 1); dehydroacetic acid; or sorbic acid. The flavoring agent may be a commonly used sweetener, sour or flavor, etc. to produce a compound of the formula (I) for administration to the present invention via the lung or A solution or suspension of a pharmacologically acceptable salt, for example, by dissolving or suspending the compound of the present invention in water, or a mixture of water and an auxiliary solvent (for example, ethanol, propylene glycol, polyethylene glycol, etc.) These solutions or suspensions may further contain a preservative (for example, -32-201143771 vaporized alkyldimercaptobenzylammonium), a solubilizing agent (for example, polysorbate such as Tween 8® or Span 80). Or a surfactant such as alkyl diindenyl quaternary ammonium chloride, a buffering agent, an isotonic agent (such as sodium hydride), an absorption enhancer, and/or a tackifier. Further, the suspension may further contain a suspending agent (e.g., 'microcrystalline cellulose, sodium carboxymethylcellulose, etc.). The composition for pulmonary administration as described above can be directly administered to the nasal cavity or the oral cavity by means of a general means in the field of inhalation, for example, using a syringe, a pipette, a cannula or a nebulizer. In the case of a nebulizer, the compound of the present invention may be mixed with a suitable propellant (for example, a chlorofluorocarbon such as a gas, a fluorocarbon or a gas such as carbon dioxide, or the like). Together, they are administered as an aerosol spray in the form of a pressurized pack or using a spray. The amount of the compound of the formula (I) of the present invention or a pharmacologically acceptable salt thereof varies depending on the symptoms, age, and the like of the patient (warm-blooded animal, especially human), for example, in the case of oral administration, The lower limit of adult per day is 〇_lmg (preferably img, more preferably 5mg), upper r Μ ^ upper limit is lOOOOg, preferably lOOmg, more preferably 50mg), j times pain r. force sigh, Because Kang history and the people are looking forward to it. The lower limit of the intravenous F 〜 F 〜 is O.Olmg (preferably 〇 (preferably 10mg), i times or divided, the upper limit is lOOmg % ^ X knife into several times, because the library, 荇 this is expected U wants the symptoms and the donor also 'injects the compound of the present invention with the formula (1) or the salt of the cockroach, and the salt of the cockroach, and the sputum, especially ) 伫 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ Pg/kg (preferably 0.5 pg/kg), the upper limit is 1000 pg/kg (preferably 1000 pg/kg), once or divided into several times, and the donor is expected to respond to the symptoms. [Examples] The present invention will be further described in detail by way of examples and test examples, but the scope of the present invention is not limited to the examples. The dissolution in the column chromatography of the examples is by TLC (thin layer chromatography). Chromatography)) Under observation, TLC was used as a TLC disc, or a TLC plates, manufactured by Merck, Inc., or a TLC plates, manufactured by Fuji SILYSIA. As a solvent for the elution solvent of the column chromatography, a UV detector was used as the detection method. The same column was used for the Shika gum, the same Kishida Chemical Co., Ltd., Shishijiao sk-85 (23 0 to 400 mesh), SK-34 (70~230 mesh), Silicone 60N (40~50μηι) made by Kanto Chemical Co., Ltd., Chromatorex NH DM1020 (100~200 mesh) made by Fuji SILYSIA Co., Ltd.' DM2035SG (200~350 mesh) or stone made by Fuji SILYSIA Chemical Co., Ltd.夕胶 FL1 00 B. In addition to the usual column chromatography, it is suitable to use Yamagata's automatic chromatography device (YFLC-prep4) and disposable column (Molitec, Shanshan, and Wako Pure Chemical Co., Ltd.). For the purification of TLC, a silicone resin 60F2 5 4, 〇.5 mm thick, and a disk 20×20 cm manufactured by Merck Co., Ltd. was used. Further, the codes used in the examples have the following meanings: mg: mg; g: gram; mL: ML; ;HATU : 〇-(7-azabenzotriazol-1-yl)-indole, hydrazine, &gt; hydrazine, Ν'-tetradecylurea hexafluorophosphate; WSC · HC1 : 1-ethyl-3 -(didecylaminopropyl)carbodiimide hydrochloride; HOBT·Η20: 1-hydroxybenzotriazole- Thereof. -34-201143771 of the following examples, nuclear magnetic resonance (hereinafter, 1H NMR) spectra were tetramethylammonium Silane as a standard substance, as described in the chemical shift Zhi Zhi δ (ppm). The split pattern is represented by s, the double line is represented by d, the triple line is represented by t, the quadruple line is represented by q, and the flat line is represented by br. Mass analysis (hereinafter, MS) is FAB (Fast Atom Bombardment), EI (Electron Ionization), APCI (Atmospheric Pressure Chemical Ionization) or ESI (Electron) Spray Ionization). [Example 1] (3R) - l-{ 7-[{ 5-[{ 2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanyl} (methyl) Amino]_4_(2-nonylphenyl). Bis-2-yl}(fluorenyl)amino]hept-5-yne-l-yl}pyrrolidin-3-ylhydroxy (di-2-(secenyl)acetate)

[實施例la]6-[苄基（甲基）胺基]-4- ( 2-曱基苯基）°比啶 -3-羧醯胺 將文獻（US6297375B1)記載的N-三級丁基-6-氣-4-(2 -曱基苯基）〇比咬-3-叛醯胺（32_3g，99.7mmol)及 N-节基曱基胺（64.3mL，498.5mmol)之混合物於100C 加熱攪拌2 0小時。反應液以乙酸乙酯稀釋，加入水後， 以乙酸乙酯（X 2 )提取，有機層以飽和食鹽水洗淨。以 無水硫酸鈉乾燥後，減壓下，餾除溶劑所獲得的殘渣使 -35- 201143771 用石夕膠管柱層析純化（己烧：乙酸乙g旨=3 : 1 - 3 : 2 )， 獲得粗製之胺基化體（4 1. 5 g )。 將獲得的粗製胺基化體溶解於曱烷磺酸（84mL， 1.30mmol) ’於6 〇 C加熱搜择11小時。反應液中冰冷 下，緩慢地將水加入’以1 0N氫氧化鈉水溶液將反應液 作成pH8-9。以乙酸乙酯（χ2 )提取，有機層以飽和食 鹽水洗淨。以無水硫酸鈉乾燥後’減壓下，餾除溶劑所 獲得的殘渣使用矽膠管柱層析純化（己烷：乙酸乙 1:1-乙酸乙酯：甲醇= 10:1)，獲得呈黃色固體之 題目的化合物（12.4g，產率36%)。獲得呈黃色固體之 作為副生成物的脱Bn體的6-(甲基胺基）-4- ( 2 -甲&amp; 苯基）吡啶-3-羧醯胺（15.6g，產率62% ) 。 土 標題化合物 H NMR (CDC13, 400MHz): δ 2.13 (3H，s)，3.09 (3tl s)，4.80-4.97 (2Η，m)，5.08 (2Η，brs)，6.19 (1Η ，s)= 7.18-7.36 (9H, m), 8.96 (1H, s). MS (ESI) m/z: 331 (M + ). 脱811體.6-(曱基胺基）-4-(2-曱基苯基）11比。定3 羧醯胺 'H NMR (CDC13j 400MHz): δ 2.16 (3H, s), 2.96 〇H d，J = 5.1 Hz)，4.98 (1H，brs)，5.09 (2H，brs)，6.09 (iH : 7.20-7.22 (1H, m)} 7.29-7.38 (3H, m), 8.89 (1H, s). MS (ESI) m/z: 241 (M + ).[Example la] 6-[benzyl(methyl)amino]-4-(2-mercaptophenyl) ° pyridine-3-carboxamide The N-tertiary butyl group described in the document (US6297375B1) Mixture of -6-gas-4-(2-mercaptophenyl)anthracene with a mixture of 3--3-treazone (32_3g, 99.7mmol) and N-nodal mercaptoamine (64.3mL, 498.5mmol) at 100C Stir for 20 hours. The reaction mixture was diluted with EtOAc. EtOAc (EtOAc) After drying over anhydrous sodium sulfate, the residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on silica gel column chromatography (hexanes: ethyl acetate = 3:1 - 3 : 2 ). Crude aminated body (4 1. 5 g). The obtained crude aminated compound was dissolved in decanesulfonic acid (84 mL, 1.30 mmol While the reaction mixture was ice-cooled, water was slowly added to pH 8-9 with a 10 N aqueous sodium hydroxide solution. It was extracted with ethyl acetate (χ2), and the organic layer was washed with brine. After drying over anhydrous sodium sulfate, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 1:1-ethyl acetate:methanol = 10:1) to give a yellow solid. The title compound (12.4 g, yield 36%). De-Bn-formed 6-(methylamino)-4-(2-methyl&amp;phenyl)pyridine-3-carboxamide as a by-product as a yellow solid (15.6 g, yield 62%) . Soil title compound H NMR (CDC13, 400MHz): δ 2.13 (3H, s), 3.09 (3 s s), 4.80-4.97 (2 Η, m), 5.08 (2 Η, brs), 6.19 (1Η, s) = 7.18- 7.36 (9H, m), 8.96 (1H, s). MS (ESI) m/z: 331 (M + ). 811 s. 6-(decylamino)-4-(2-mercaptophenyl) ) 11 ratio. 3 carboxy guanamine 'H NMR (CDC13j 400MHz): δ 2.16 (3H, s), 2.96 〇H d, J = 5.1 Hz), 4.98 (1H, brs), 5.09 (2H, brs), 6.09 (iH: 7.20-7.22 (1H, m)} 7.29-7.38 (3H, m), 8.89 (1H, s). MS (ESI) m/z: 241 (M + ).

[實施例lb]6-[苄基（甲基）胺基]-4- ( 2-甲基苯基）％啤 -3-羧醯胺 -36- 201143771 實施例la所獲得的副生成物6-(甲基胺基）-4- ( 2-甲基本基）。比咬_3_叛酿胺（I5.6g，64.7mmol)之N，N-二曱基甲醯胺溶液（130mL )中加入碳酸鉀（13.4g， 97.2mmol)、，及节基漠（ii.gniL，97.2mmol)，於 80。(^ 搜 拌4小時。反應液以乙酸乙酯稀釋，有機層依序以水 (x 3 )、飽和食鹽水洗淨。以無水硫酸鈉乾燥後，減壓下， 顧除溶劑所獲得的殘渣使用矽膠管柱層析純化（己烷： 乙酸乙酯=1 : 1 _丨：2 )，獲得呈黃色固體之標題目的化 合物（1 1.3g，產率53% )。 ]H NMR (CDC13, 400MHz): δ 2.13 (3Η, s), 3.09 (3H, s), 4.80-4.97 (2H, m), 5.08 (2H, brs), 6.19 (1H, s), 7-18-7.36 (9H, m), 8.96 (1H, s). MS (ESI) m/z: 331 (M + ).[Example lb] 6-[Benzyl(methyl)amino]-4-(2-methylphenyl)% beer-3-carboxamide-36-201143771 The by-product 6 obtained in Example la -(Methylamino)-4-(2-methylphenyl). Potassium carbonate (13.4 g, 97.2 mmol), and jieji desert (II) were added to the N,N-dimercaptocaramine solution (130 mL) of the bite_3_ acetoamine (I5.6g, 64.7 mmol). .gniL, 97.2 mmol) at 80. (^) Mix for 4 hours. The reaction solution was diluted with ethyl acetate. The organic layer was washed with water (x 3 ) and brine, then dried over anhydrous sodium sulfate. The title compound (1 1.3 g, yield 53%) was obtained as a yellow solid (yield: hexanes: EtOAc: EtOAc: ): δ 2.13 (3Η, s), 3.09 (3H, s), 4.80-4.97 (2H, m), 5.08 (2H, brs), 6.19 (1H, s), 7-18-7.36 (9H, m) , 8.96 (1H, s). MS (ESI) m/z: 331 (M + ).

[實施例lc] { 6-[苄基（甲基）胺基]_4_ ( 2_甲基苯基）。比 啶-3 -基}胺基曱酸甲酯 將N-溴琥珀醯亞胺（19. lg，i〇7.4mmol )溶解於二 氣曱烧（107mL)，冰冷下’加入甲醇鈉（65mL，28%甲 醇溶液，336.5mmol)後，於同溫攪拌i小時。冰冷下， 於反應液中加入實施例la及lb所獲得的6_[苄基（甲基） 月女基]-4-( 2-甲基苯基）吡啶-3-羧醯胺（23 7g，71 6mm〇1 ) 之二氣甲烧-甲醇混合溶液（4: i，477mL)後，於室溫攪 拌1小時。於反應液中加入1N鹽酸，將反應液作成pH89 後，以二氯甲烷（x3)提取，有機層以飽和食鹽水洗淨。 以無水硫酸鈉乾燥後，減壓下，餾除溶劑所獲得的殘渣 使用石夕勝管柱層析純化（己烷：乙酸乙酯=3 :丨_丨 -37- 201143771 獲得呈黃色油狀物之標題目的化合物（19.7g，產率 76 % )。 'H NMR (CDC13, 400ΜΗζ): δ 2.08 (3Η, s), 3.05 (3H, s), 3.66 (3H, s), 4.72-4.87 (2H, m), 5.82 (1H, brs), 6.30 (1H, s), 7.10 (1H, d, J = 6.7 Hz), 7.23-7.32 (9H, m).[Example lc] { 6-[Benzyl(methyl)amino]_4_(2-methylphenyl). Methylpyridin-3-yl}amino decanoate N-bromosuccinimide (19. lg, i 7.4 mmol) was dissolved in dioxane (107 mL), and MgSO4 (65 mL, After 28% methanol solution, 336.5 mmol), it was stirred at the same temperature for 1 hour. 6-[benzyl(methyl)urephetyl]-4-(2-methylphenyl)pyridine-3-carboxamide (23 g, obtained in Examples la and lb) was added to the reaction mixture under ice cooling. 71 6 mm 〇 1 ) A gas-methanol-methanol mixed solution (4: i, 477 mL) was stirred at room temperature for 1 hour. 1N hydrochloric acid was added to the reaction mixture, and the reaction mixture was made to pH 89, then extracted with dichloromethane (x3), and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the residue obtained by distilling the solvent under reduced pressure was purified by chromatography (hexane: ethyl acetate = 3: 丨 丨 37 - 37 - 201143771) as a yellow oil. The title compound (19.7 g, yield 76%). 'H NMR (CDC13, 400 ΜΗζ): δ 2.08 (3 Η, s), 3.05 (3H, s), 3.66 (3H, s), 4.72-4.87 (2H , m), 5.82 (1H, brs), 6.30 (1H, s), 7.10 (1H, d, J = 6.7 Hz), 7.23-7.32 (9H, m).

[實施例ld]N2-苄基-N2，N5-二曱基-4- ( 2-曱基苯基）。比啶 2,5 -二胺 於雙（乙氧基曱氧基）氫化鋁鈉（75.8mL，3.6M甲 苯溶液，272.8mmol )，於室溫，緩慢將實施例lc所獲得 的{ 6-[苄基（曱基）胺基]-4- ( 2-甲基苯基）。比啶-3-基} 胺基甲酸曱酯（19.7g，54.6mmol)之曱苯溶液（182mL) 加入後，於室溫攪拌10分鐘。接著於50°C攪拌2小時 後，將反應液冷卻至0°C，緩慢將1N氫氧化鈉水溶液 (163.8mL)加入。以甲苯（χ3 )提取，有機層依序以水、 飽和食鹽水洗淨。以無水硫酸鈉乾燥後，減壓下，餾除 溶劑所獲得的殘渣使用矽膠管柱層析純化（己烷：乙酸 乙酯=4 : 1 -3 : 1 )，獲得呈黃色油狀物之標題目的化合 物（16.2g，產率 93% )。 'H NMR (CDC13, 400ΜΗζ): δ 2.11 (3Η, s), 2.77 (3H, s), 2.86 (1H, brs), 3.00 (3H, s), 4.65-4.80 (2H, m), 6.33 (1H, s), 7.13 (1H, d, J = 7.0 Hz), 7.21-7.31 (8H, m), 7.75 (1H, s).[Example ld] N2-benzyl-N2,N5-dimercapto-4-(2-mercaptophenyl). Bisidine 2,5-diamine in sodium bis(ethoxymethoxy)aluminum hydride (75.8 mL, 3.6 M in toluene, 272.8 mmol), slowly obtained at room temperature, s. Benzyl (indenyl)amino]-4-(2-methylphenyl). After the addition of decyl-3-yl} guanidinium carbamate (19.7 g, 54.6 mmol) in benzene (182 mL), the mixture was stirred at room temperature for 10 min. After stirring at 50 ° C for 2 hours, the reaction solution was cooled to 0 ° C, and 1N aqueous sodium hydroxide (163.8 mL) was slowly added. The mixture was extracted with toluene (χ3), and the organic layer was washed successively with water and saturated brine. After drying over anhydrous sodium sulfate, the residue obtained by distilling the solvent under reduced pressure was purified using silica gel column chromatography (hexane: ethyl acetate = 4 : 1 - 3 : 1 ) The compound of interest (16.2 g, yield 93%). 'H NMR (CDC13, 400ΜΗζ): δ 2.11 (3Η, s), 2.77 (3H, s), 2.86 (1H, brs), 3.00 (3H, s), 4.65-4.80 (2H, m), 6.33 (1H , s), 7.13 (1H, d, J = 7.0 Hz), 7.21-7.31 (8H, m), 7.75 (1H, s).

[實施例le]2-[3,5-雙（三氟曱基）苯基]-N，2-二曱基-N-[6-(曱基胺基）-4- ( 2-曱基苯基）。比啶-3-基]丙醯胺 -38- 201143771 於實施例Id所獲得的N2-苄基_N2，N5_二甲基_4_ ( h 甲基苯基）他。定_2,5.二胺（l6.2g’ 51 之二氯甲 烷溶液（140mL)中加入N，N_二異丙基乙基胺（9 4mL, 54.0mmol) ’冰冷下，緩慢逐滴加入2_[3,5_雙（三氟甲基） 苯基]·2-甲基丙酿基氯（l5.6g，49 lmm〇1)，於室溫授摔 3〇分鐘。減壓下，潑除溶劑所獲得的殘㈣乙酸乙酿稀 釋，加人水後，以乙酸乙(x2)提取，有機層以飽和 食鹽水洗淨。以無水硫酸鈉乾燥後，減屋下，顧除溶劑 而獲得粗製之醯胺體。 於10%鈀-破（9.3g)，加入獲得的粗製醯胺體之乙 醇溶液（255mL )及4N鹽酸-二嘮烷（乃〇mL， 101.9mm〇l)，系統内置換為氫氣環境後，於6〇〇c攪拌 3 ·5小時。系統内置換為氮氣環境後，於氮氣環境下，追 加丨〇%鈀-碳（4.6g )及4Ν鹽酸二噚烷（12 5mL， 5 1 .Ommol) ’再將系統内置換為氫氣環境後，於6(rc攪 拌1.5小時。將系統内置換為氮氣環境後，使用賽利特 石夕藻土（ C e 1 i t e )過渡反應液。減壓下，鶴除溶劑所獲得 的殘渣以乙酸乙酯稀釋’追加飽和碳酸氫鈉水後，以乙 酸乙酯（χ2 )提取，有機層以飽和食鹽水洗淨。以無水 硫酸鈉乾燥後，減壓下，餾除溶劑而使用NH矽膠管柱 層析（己烷：乙酸乙酯=2 : 1 )純化，獲得呈黃色固體 之標題目的化合物（22.lg，產率85%)。 MS (FAB) m/z: 509(M + H) + . IR(KBr) vmax 3258，1659，1611，1372，1281，1182, 1 144, 1082, 898, 683 cm'1. -39- 201143771 [實施例lf]2-[3,5·雙（三氟甲基）苯基]-N- { 6-[ ( 7- {[三 級丁基（二苯基）矽烷基]氧基}庚-2-炔-1-基）（曱基） 胺基]-4- ( 2-甲基苯基）吡啶-3-基} -N，2-二甲基丙醯胺 將文獻（Chemistry-A European Journal 2004，10, 2759)記載的7_{[三級丁基（二苯基）矽烷基]氧基}庚 -2-快-1-醇（719mg’ 196mm〇1)溶解於乙酸乙酯（2〇niL)， 冰冷下，加入乙基胺（〇.328mL，2.35mmol)及甲烷磺醯 氣（〇.182mL ’ 2.35mmol)後，同溫下攪拌15分鐘。不溶 物以賽利特矽藻土過濾’減壓下，將餾除溶劑所獲得的 殘造溶解於N，N-二甲基乙醯胺（1 5 mL )，將實施例1 e所 獲得的2-[3,5-雙（三氟曱基）苯基]_n，2-二曱基-N-[6-(甲 基胺基）-4- ( 2-甲基苯基）吡啶-3 —基]丙醯胺（500mg， 0.981mmol)、碳酸鉀（271mg，1 ·96ηιιηο1 )及埃化钟 (3 25mg，1.96mmol)加入後，於80°C攪拌4 5小時。反 應液以乙酸乙酯稀釋，有機層依序以水（χ3 )、飽和食鹽 水洗淨。以無水硫酸鈉乾燥後，減壓下，餾除溶劑所獲 得的殘渣使用矽膠管柱層析純化（己烷：乙酸乙酯=8 5 : 15) ’獲得呈褐色油狀物之標題目的化合物（649mg， 產率77% )。 *H NMR (CDC13, 400MHz): δ 1.03 (6Η, s), 1.05 (9H, s), 1.57- 1.66 (4H, m), 2.14-2.18 (2H, m), 2.20-2.24 (2H, m), 2.28-2.32 (1H, m), 3.07 (3H, s), 3.63-3.69 (5H, m)5 4.22-4.25 (1H, m), 4.27-4.33 (1H, m), 6.43 (1H, s), 7.34-7.44 (9H, m), 7.64-7.67 (7H, m), 7.75 (1H, s), 8.00 (1H, s). -40- 201143771 [實施例lg]2-[3,5-雙（三氟曱基）苯基]-N- { 6-[ ( 7-羥基 庚-2-炔-1-基）（甲基）胺基]-4- ( 2-甲基苯基）。比啶-3_ 基} -N,2-二甲基丙醯胺 將實施例If所獲得的化合物（ 649mg，〇.756mmol) 溶解於四氫呋喃（8mL)，加入氟化四丁基銨（iM -四氫 °夫喃溶液，0 _ 9 0 8 m L，0 · 9 0 8 m m ο 1 )後，於室溫搜拌 15 小時。於反應液中加入水，以乙酸乙酯提取，有機磨以 飽和食鹽水洗淨。以無水硫酸鈉乾燥後，減壓下，儲除 溶劑所獲得的殘渣使用矽膠分取薄層層析純化（己烷： 乙酸乙酯=1 : 1 )，獲得呈黃色油狀物之標題目的化合 物（255mg，產率 54% )。 MS (FAB) m/z: 620(M + H) + . IR(液態膜）vmax 2939, 2236, 1746, 1650, 1597, 1 501， U73，1282，1 184，1 137 cm·1.[Example le] 2-[3,5-bis(trifluoromethyl)phenyl]-N,2-diindenyl-N-[6-(decylamino)-4-(2-fluorenyl) Phenyl). Bibi-3-yl]propanamine -38- 201143771 N2-benzyl-N2,N5-dimethyl-4-(-(methylphenyl)) obtained in Example Id. Add _2,5. diamine (16.2g' of methylene chloride solution (140mL), add N,N-diisopropylethylamine (9 4mL, 54.0mmol), and add it slowly and slowly. 2_[3,5_bis(trifluoromethyl)phenyl]·2-methylpropanyl chloride (l5.6g, 49 lmm〇1), and allowed to fall for 3 minutes at room temperature. The residue obtained from the solvent (4) was diluted with acetic acid, and after adding human water, it was extracted with ethyl acetate (x2), and the organic layer was washed with saturated brine. After drying with anhydrous sodium sulfate, the mixture was reduced and the solvent was obtained. Crude guanamine. In 10% palladium-broken (9.3g), add the obtained crude guanamine solution in ethanol (255mL) and 4N hydrochloric acid-dioxane (Nanjing, 101.9mm 〇l), within the system After replacing with a hydrogen atmosphere, the mixture was stirred at 6 ° C for 3 · 5 hours. After replacing the system with a nitrogen atmosphere, 丨〇 % palladium-carbon (4.6 g) and 4 噚 dioxane hydrochloride (12 5 mL) were added under a nitrogen atmosphere. , 5 1 .Ommol) ' After replacing the system with a hydrogen atmosphere, stir at 1.5 (rc for 1.5 hours. After replacing the system with a nitrogen atmosphere, use the Celite celite (C e ite ) transition reaction. Liquid The residue obtained by removing the solvent from the hexanes was diluted with ethyl acetate. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The solvent was evaporated to give the title compound (yield: ield: 85%). /z: 509 (M + H) + . IR (KBr) vmax 3258, 1659, 1611, 1372, 1281, 1182, 1 144, 1082, 898, 683 cm'1. -39- 201143771 [Example lf] 2 -[3,5·bis(trifluoromethyl)phenyl]-N- { 6-[ ( 7- {[tris-butyl(diphenyl)decyl]oxy}hept-2-yne-1 -yl)(indenyl)amino]-4-(2-methylphenyl)pyridin-3-yl}-N,2-dimethylpropanamine will be the literature (Chemistry-A European Journal 2004, 10, 7_{[Tributyl(diphenyl)decyl]oxy}heptan-2-propanol (719 mg '196 mm〇1) as described in 2759) was dissolved in ethyl acetate (2 〇niL), icy cold Next, add ethylamine (〇.328mL, 2.35mmol) and methanesulfonate (〇.182mL ' 2.35mmol), stir at the same temperature 15 minutes. The insoluble matter was filtered with Celite, and the residue obtained by distilling off the solvent was dissolved in N,N-dimethylacetamide (15 mL) under reduced pressure. Example 1 e 2-[3,5-Bis(trifluoromethyl)phenyl]-n,2-dimercapto-N-[6-(methylamino)-4-(2-methylphenyl) obtained Pyridine-3-ylpropanamide (500 mg, 0.981 mmol), potassium carbonate (271 mg, 1 · 96 ηιιηο1), and Anhuahua (3 25 mg, 1.96 mmol) were added, and the mixture was stirred at 80 ° C for 45 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water (3) and brine. After drying over anhydrous sodium sulfate, the residue obtained by distilling the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 8 5: 15). 649 mg, yield 77%). *H NMR (CDC13, 400MHz): δ 1.03 (6Η, s), 1.05 (9H, s), 1.57- 1.66 (4H, m), 2.14-2.18 (2H, m), 2.20-2.24 (2H, m) , 2.28-2.32 (1H, m), 3.07 (3H, s), 3.63-3.69 (5H, m)5 4.22-4.25 (1H, m), 4.27-4.33 (1H, m), 6.43 (1H, s) , 7.34-7.44 (9H, m), 7.64-7.67 (7H, m), 7.75 (1H, s), 8.00 (1H, s). -40- 201143771 [Example lg]2-[3,5-double (Trifluoromethyl)phenyl]-N-{ 6-[(7-hydroxyhept-2-yn-1-yl)(methyl)amino]-4-(2-methylphenyl). The compound obtained in Example If (649 mg, 〇.756 mmol) was dissolved in tetrahydrofuran (8 mL), and tetrabutylammonium fluoride (iM -4) was added. After the hydrogen solution, 0 _ 9 0 8 m L, 0 · 9 0 8 mm ο 1 ), mix at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the residue obtained by the solvent was purified by silica gel chromatography (hexane: ethyl acetate = 1 : 1 ) (255 mg, yield 54%). MS (FAB) m/z: 620 (M + H) + . IR (liquid film) vmax 2939, 2236, 1746, 1650, 1597, 1 501, U73, 1282, 1 184, 1 137 cm·1.

[實施例lh] ( 3R) -3- {[羥基（二噻吩-2-基）乙醯基]氧 基}吡咯啶-1 -甲酸三級丁酯 於氫化鈉（4.09g，55%，93.8mm〇l)之曱苯懸浮液 (1 8 8 m L )中，儘快地加入經基（二。塞吩-2 -基）乙酸甲 酯（3 5.8g，1 40.7mmol )及（3R ) -3 -經基0比 口各。定-1 -甲酸 二級丁醋甲酸三級丁醋（1 7 · 6 g，9 3.8 m m ο 1 )之混合物之 曱本溶液（3 7 6 m L )，一邊將系統内於2 0 0 - 3 0 0 m m H g減 壓一邊於8 0 °C攪拌2.5小時。減壓下，餾除溶劑所獲得 的殘渣使用矽膠層析純化（己烷：乙酸乙酯=4 : 1 -1 : 1 )， 獲得呈褐色油狀物之標題目的化合物（3 3 · 9 g，產率8 8 % )。 201143771 ]H NMR (CDC13s 400MHz): δ 1.45 (9H, s), 2.04-2.07 (1H，m)，3.24.3.29 (1H，m)，3.34-3.40 (1H，m)，3.44-3.48 (1 H，m)，3 · 5 3 - 3.5 7 (2 H, m)，4 · 6 4 (1 H，s)，5.4 0 - 5.4 3 (1 jj m), 6.96-6.98 (2H, m), 7.13-7.15 (2H, m), 7.26-7.29 (2H m).[Example lh] (3R)-3-{[Hydroxy(dithien-2-yl)ethenyl]oxy}pyrrolidin-1-carboxylic acid tert-butyl acrylate in sodium hydride (4.09 g, 55%, 93.8) Mm〇l) in the benzene suspension (1 8 8 m L), as soon as possible, add methyl (dithiophene-2-yl)acetate (3 5.8 g, 1 40.7 mmol) and (3R ) - 3 - The base is 0 to each. Ding-1 - formic acid dibutyl vinegar formic acid grade III vinegar (1 7 · 6 g, 9 3.8 mm ο 1 ) mixture of bismuth solution (3 7 6 m L), while the system is within 2 0 0 - 3 0 0 mm H g was stirred at 80 ° C for 2.5 hours under reduced pressure. The residue obtained by distilling the solvent under reduced pressure was purified by silica gel chromatography (hexane: ethyl acetate = 4:1 -1 : 1 ) to give the title compound (3 3 · 9 g, Yield 8 8 %). 201143771 ]H NMR (CDC13s 400MHz): δ 1.45 (9H, s), 2.04-2.07 (1H, m), 3.24.3.29 (1H, m), 3.34-3.40 (1H, m), 3.44-3.48 (1 H ,m),3 · 5 3 - 3.5 7 (2 H, m),4 · 6 4 (1 H,s),5.4 0 - 5.4 3 (1 jj m), 6.96-6.98 (2H, m), 7.13 -7.15 (2H, m), 7.26-7.29 (2H m).

[實施例li] ( 3R)-吡咯啶-3-基羥基（二噻吩-2-基）乙 酸酉旨 將實施例lh所獲得的（3R) -3- {[羥基（二噻吩_2_ 基）乙醯基]氧基}吡咯啶-1 -甲酸三級丁酯（3 3.9 g， 82.7mmol)及 p -甲氧苯胺（1.02g，8.27mmol)溶解於 ι，4_ 二0f·烧（166mL)，冰冷下，加入4N鹽酸-二烧（207mL， 827.0mmol)，於室溫攪拌2.5小時。於反應液中加入飽和 碳酸氫鈉水及碳酸鉀而作成鹼性，以乙酸乙酯（X 3 )提 取後，有機層以飽和食鹽水洗淨。以無水硫酸鈉乾燥後， 減壓下，餾除溶劑所獲得的殘渣使用NH矽膠管柱層析純 化（己烷：乙酸乙酯=4 : 1 -乙酸乙酯：曱醇=20 : 1 )， 獲得呈紫色固體之標題目的化合物（1 7.9 g ’產率7 0 % )。 'H NMR (CDC13, 400MHz): δ 1.85- 1.92 (1Η, m)5 2.00-2.09 (1H，m)，2.87-2.94 (1H，m), 2.99-3.07 (3H，m), 5.36-5.40 (1H，m)，6.96-6.98 (2H，m)，7.15-7.17 (2H，m), 7.28 (2H, dd, J = 5.1,1.2 Hz).[Example li] (3R)-pyrrolidin-3-ylhydroxy (dithien-2-yl)acetic acid hydrazine (3R) -3-{[hydroxy(dithien-2-yl) group obtained in Example lh Ethyl methoxy]pyrrolidine-1 -carboxylic acid tert-butyl butyl ester (3 3.9 g, 82.7 mmol) and p-methoxyaniline (1.02 g, 8.27 mmol) were dissolved in ι, 4 _ 2 0 ·· (166 mL) 4N Hydrochloric acid-di-burn (207 mL, 827.0 mmol) was added and the mixture was stirred at room temperature for 2.5 hr. Saturated sodium hydrogencarbonate water and potassium carbonate were added to the reaction mixture to make a basic solution. After extracting with ethyl acetate (X3), the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the residue obtained by distilling the solvent under reduced pressure was purified by chromatography using EtOAc (hexane: ethyl acetate = 4:1 - ethyl acetate: methanol = 20:1). The title compound (1 7.9 g 'yield 70%) was obtained as a purple solid. 'H NMR (CDC13, 400MHz): δ 1.85- 1.92 (1Η, m)5 2.00-2.09 (1H,m), 2.87-2.94 (1H,m), 2.99-3.07 (3H,m), 5.36-5.40 ( 1H, m), 6.96-6.98 (2H, m), 7.15-7.17 (2H, m), 7.28 (2H, dd, J = 5.1, 1.2 Hz).

[實施例 lj] ( 3R) -1- { 7-[ { 5-[ { 2-[3,5-雙（三氟甲基） 苯基]-2-甲基丙醯基}(甲基）胺基]-4- ( 2-曱基苯基）。比 啶-2-基}(曱基）胺基]庚-5-炔-l-基}吡咯啶-3-基羥基 (二-2-噻吩基）乙酸酯 -42- 201143771 將貫把例1 g所獲得的化合物（1 〇 〇 m g，〇 1 6 1 m m ο 1 ) 溶解於乙酸乙酯（3mL )，冰冷下，加入三乙基胺 〇.194mmol)及甲烷磺醯氯（3〇μί，〇194mm〇1)後，於 相同溫度下攪拌1 5分鐘。不溶物以赛利特矽藻土過濾， 減壓下’將餾除溶劑所獲得的殘渣溶解於N，N_二曱基曱 醯胺（6 m L )，將實施例1 i所獲得的（3 R ) _吼洛咬-3 _基經 基（二°塞吩-2-基）乙酸酯（55mg，0.177mmol)、碳酸舒 (33mg，0.242mmol)、及峨化鉀（：29mg，0-177 mmol ) 加入後’於8 0 °C攪拌6小時。反應液以乙酸乙酯稀釋，有 機層依序以水（X 3 )、飽和食鹽水洗淨。以無水硫酸鈉乾 燥後’減壓下，餾除溶劑所獲得的殘渣使用矽膠分取薄 層層析純化（二氣曱烷：曱醇==20 : 1 )。再使用矽膠分 取薄層層析純化（二氯甲烷：曱醇=40 : 1、V/V、5次展 開）’獲得呈褐色固體之標題目的化合物（14mg，產率 10% )。 MS (FAB) m/z: 911 (M + H) + . IR(KBr) vmax 2933，1738，1 65 1:, 1 596，1499，1 373, 1281，1 184，1 1 37, 708 cnT1· [實施例2] (3R) - l-{ 5-[{ 5-[{ 2-[3,5-雙（三氟甲基）苯基]-2-曱基丙醯基丨（曱基）胺基]-4- ( 2-曱基笨基）&quot;比啶-2-基} (曱基）胺基]戊-3-炔-l-基}吡咯啶-3-基羥基（二-2- 噻吩基）乙酸酯 -43- 201143771[Example lj] ( 3R) -1- { 7-[ { 5-[ { 2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanyl} (methyl) Amino]-4-(2-mercaptophenyl). Bis-2-yl}(indenyl)amino]hept-5-yne-1-yl}pyrrolidin-3-ylhydroxy(di-2-thienyl)acetate-42- 201143771 1 g of the obtained compound (1 〇〇mg, 〇1 6 1 mm ο 1 ) was dissolved in ethyl acetate (3 mL), ice-cooled, triethylamine 〇.194 mmol) and methane sulfonium chloride (3〇μί After 〇194 mm〇1), stir at the same temperature for 15 minutes. The insoluble matter was filtered with Celite, and the residue obtained by distilling off the solvent was dissolved in N,N-didecylamine (6 m L ) under reduced pressure, and obtained in Example 1 i ( 3 R ) _ 吼 咬 -3 - carbyl (2°-sec-2-yl) acetate (55 mg, 0.177 mmol), hydrazide (33 mg, 0.242 mmol), and potassium hydride (: 29 mg, 0-177 mmol) After the addition, the mixture was stirred at 80 ° C for 6 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water (X 3 ) and brine. After drying with anhydrous sodium sulfate, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel fractionation (di-hexane: decyl alcohol == 20:1). The title compound (14 mg, yield 10%) was obtained from the title compound (yield: methylene chloride: hexanes: 40:1, V/V, 5 times). MS (FAB) m/z: 911 (M + H) + . IR(KBr) vmax 2933,1738,1 65 1:, 1 596,1499,1 373, 1281,1 184,1 1 37, 708 cnT1· [Example 2] (3R) - l-{ 5-[{ 5-[{ 2-[3,5-bis(trifluoromethyl)phenyl]-2-mercaptopropyl fluorenyl (fluorenyl) Amino]-4-(2-indolyl)&quot;bipyridin-2-yl}(indenyl)amino]pent-3-yne-l-yl}pyrrolidin-3-ylhydroxy (di- 2-thienyl)acetate-43- 201143771

[實施例2a]2-[3,5-雙（三氟曱基）苯*]_ν·{6_[( 5·{[三 級丁基（二苯基）矽烷基]氧基}戊-2_炔-丨_基）（甲基） 胺基]-4- ( 2 -甲基苯基）°比啶-3-基} -Ν，2-二曱基丙醯胺 將文獻（J.Org.Chem. 1989’ 54,5522 )記載的 5·{[三 級丁基（二苯基）矽烷基]氧基}戊-2-炔-ΐ_醇（399mg， 1.18mmol)溶解於乙酸乙酯（12mL)，冰冷下，將=乙 基胺（0.197mL，l_41mmol)及甲烷磺醯氣（〇 u〇mL， 1.4 1 mmol )加入後’於相同溫度下攪拌丨5分鐘。於反應 液中加入水’以乙酸乙S旨提取，有機層以飽和食鹽水洗 淨。以無水硫酸鈉乾燥後，減壓下，將餾除溶劑所獲得 的殘渣溶解於N，N-二曱基乙醯胺（6mL)，添加實施例le 所獲得的化合物（300mg’ 0.589mmol)、碳酸鉀（i63mg， 1.18mmol)、及峨化钟（147mg，0.884mmol)後，於5〇°c 攪拌6小時。反應液以乙酸乙酯稀釋，有機層依序以水 (X 3 )、飽和食鹽水洗淨。以無水硫酸鈉乾燥後，減壓下， 餾除溶劑所獲得的殘渣使用矽膠管柱層析純化（己烷： 乙酸乙酯=9 : 1 - 4 : 1 )，獲得呈黃色油狀物之標題目的 化合物（321 mg，產率66% )。 NMR (CDC13, 400ΜΗζ): δ 1.03 (9Η, s), l.〇6 (6Η, s), 2.08-2.10 (1Η, m), 2.27-2.33 (2H, m), 2.42-2.50 (2H, m), 3.05 (3H, s), 3.66-3.79 (5H, m), 4.20-4.22 (1H, m), 4.24-4.33 (1H, m), 6.41 (1H, s), 7.34-7.43 (8H, m), -44- 201143771 7_65_7.68 (7H，m)，7.70-7.73 (1H，m)，7.75 (1H，s)，8.00 (1H, S). &gt;雙（三氟甲基）苯基]_N_ { 6_[ ( 5漠戊 块-1_基）（甲基）胺基]-4- ( 2-曱基苯基）。比啶-3-基} _N，2_二曱基丙醯胺 將實施例2a所獲得的化合物（321mg，0.387mmol ) '备解於四氫。夫喃（4mL )，加入氟化四丁基銨（1M-四氫 夫喃浴液’ 0.581mL ’ 〇.581mmol)後，於室溫攪拌1小 蚪。於反應液中加入水，以乙酸乙酯提取。有機層以飽 和食鹽水洗淨’以無水硫酸鈉乾燥後，減壓下，餾除溶 劑所獲得的殘渣使用矽膠分取薄層層析純化（己烷：乙 酸乙_ = 2 : 1 ) ’獲得呈黃色油狀物之醇體（149mg， 產率65% )。 將所獲得的醇體（68mg，0.Π 5 mmol)溶解於二氯 曱燒（5mL)，將三苯基膦（36mg，0.138mmol)及四漠 化碳（46.mg ’ 〇.13 8mmol )加入後，於室溫攪拌30分鐘。 減壓下，餾除溶劑所獲得的殘渣使用矽膠管柱層析純化 (己院：乙酸乙酯==2 : 1 )，獲得呈褐色油狀物之標題 目的化合物（75mg，產率100%)。 MS (ESI) m/z: 654 (M + ).[Example 2a] 2-[3,5-bis(trifluoromethyl)benzene*]_ν·{6_[(5·{[tri-butyl(diphenyl)decyl)oxy}pent-2 _ alkyne-丨-yl)(methyl)amino]-4-(2-methylphenyl) °pyridin-3-yl}-indole,2-dimercaptopropionamide (J.Org) .Chem. 1989 ' 54,5522 ) 5·{[Tributyl(diphenyl)decyl]oxy}pent-2-yne-indole-ol (399 mg, 1.18 mmol) dissolved in ethyl acetate (12 mL), under ice-cooling, = ethylamine (0.197 mL, l_41 mmol) and methanesulfonium sulfonate (〇u〇mL, 1.4 1 mmol) were added and then stirred at the same temperature for 5 minutes. Water was added to the reaction solution to extract with acetic acid, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the residue obtained by distilling off the solvent was dissolved in N,N-dimercaptoacetamide (6 mL) under reduced pressure, and the compound obtained in Example (300 mg '0.589 mmol), Potassium carbonate (i63 mg, 1.18 mmol) and a hydrazine clock (147 mg, 0.884 mmol) were stirred at 5 ° C for 6 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water (X 3 ) and brine. After drying over anhydrous sodium sulfate, the residue obtained by distilling the solvent under reduced pressure was purified using silica gel column chromatography (hexane: ethyl acetate = 9 : 1 - 4 : 1 ) The compound of interest (321 mg, yield 66%). NMR (CDC13, 400ΜΗζ): δ 1.03 (9Η, s), l.〇6 (6Η, s), 2.08-2.10 (1Η, m), 2.27-2.33 (2H, m), 2.42-2.50 (2H, m ), 3.05 (3H, s), 3.66-3.79 (5H, m), 4.20-4.22 (1H, m), 4.24-4.33 (1H, m), 6.41 (1H, s), 7.34-7.43 (8H, m ), -44- 201143771 7_65_7.68 (7H, m), 7.70-7.73 (1H, m), 7.75 (1H, s), 8.00 (1H, S). &gt; bis(trifluoromethyl)phenyl] _N_ { 6_[ (5 戊 块 -1 - yl) (methyl)amino]-4-(2-mercaptophenyl). Bibi-3-yl} _N,2-dimercaptopropionamide The compound obtained in Example 2a (321 mg, 0.387 mmol) was prepared in tetrahydrogen. After the addition of tetrabutylammonium fluoride (1M-tetrahydrofuran bath '0.581 mL' 〇.581 mmol), the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel fractionation (hexane:ethyl acetate = s: 2:1). The alcohol was yellow oil (149 mg, yield 65%). The obtained alcohol (68 mg, 0. Π 5 mmol) was dissolved in dichlorohydrazine (5 mL), triphenylphosphine (36 mg, 0.138 mmol) and four desertified carbon (46. mg ' 〇.13 8 mmol). After the addition, the mixture was stirred at room temperature for 30 minutes. The residue obtained by distilling the solvent under reduced pressure was purified by silica gel column chromatography (hexanes: ethyl acetate == 2 : 1 ) to give the title compound (75 mg, yield 100%) . MS (ESI) m/z: 654 (M + ).

[實施例 2c] ( 3R) -1- { 5-[ { 5-[ { 2-[3,5-雙（三氟甲基） 苯基]-2-甲基丙醯基}(曱基）胺基]~4_ ( 2-甲基苯基）。比 啶_2-基}(曱基）胺基]戊-3-炔-1-基丨。比咯啶-3-基羥基 (二-2-噻吩基）乙酸酯 -45- 201143771 將實施例2b所獲得的化合物（75mg，0.11 5mmo 1 ) 溶解於N，N-二曱基乙醯胺（3mL )，添加實施例li所獲得 的（3R )-吡咯啶-3-基羥基（二噻吩-2-基）乙酸酯 (39mg，〇.l27mmol)及石炭酸氫納（20mg，0.230mmol)， 於5 0°C攪拌4小時。於反應液中加入碘化鉀（38mg， 〇.23Ommol )，再於50°C攪拌9小時。反應液以乙酸乙酯稀 釋’有機層依序以水（χ3 )、飽和食鹽水洗淨。以無水硫 酸鈉乾燥後，減壓下，餾除溶劑所獲得的殘渣使用ΝΗ矽 膠管柱層析純化（己烷：乙酸乙酯=2 : 1 -1 : 1 )。再使 用逆相分取管柱層析（Waters，MS C18 OBD，5μηι， 30x100mm)(乙腈：〇·1% 乙酸銨水溶液= 20: 80-100: 〇) 純化’獲得呈黃色固體之標題目的化合物（7 m g，產率7 % )。 MS (FAB) m/z: 883(M + H) + . IR(KBr) vmax 2935，1 738，1651，1596，1499，1 373, 1281，1184，1 1 36, 708 cm1.[Example 2c] ( 3R) -1- { 5-[ { 5-[ { 2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanyl}(fluorenyl) Amino]~4_(2-methylphenyl). Bisidine-2-yl}(indenyl)amino]pent-3-yn-1-ylindole. Biloxidin-3-ylhydroxy (di-2-thienyl) acetate-45- 201143771 The compound obtained in Example 2b (75 mg, 0.11 5 mmo 1 ) was dissolved in N,N-dimercaptoacetamide (3 mL), (3R)-pyrrolidin-3-ylhydroxy (dithien-2-yl)acetate (39 mg, 〇.l27 mmol) obtained in Example li and sodium hydrogencarbonate (20 mg, 0.230 mmol) , stirred at 50 ° C for 4 hours. Potassium iodide (38 mg, 〇. 23 mmol) was added to the reaction mixture, followed by stirring at 50 ° C for 9 hours. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water (3) and brine. After drying with anhydrous sodium sulfate, the residue obtained by distilling the solvent under reduced pressure was purified using hexane column chromatography (hexane: ethyl acetate = 2 : 1 -1 : 1 ). Purification by reverse phase fractionation column chromatography (Waters, MS C18 OBD, 5μηι, 30x100mm) (acetonitrile: 〇·1% aqueous ammonium acetate = 20: 80-100: 〇) Purified to give the title compound as a yellow solid (7 mg, yield 7%). MS (FAB) m/z: 883 (M + H) + . IR (KBr) vmax 2935,1 738,1651,1596,1499,1 373, 1281,1184,1 1 36, 708 cm1.

[貫施例3 ] (3R) - l-{ 6-[{ 5-[{ 2-[3,5-雙（三氟曱基）笨基]·2_ 曱基丙醯基}(甲基）胺基]-4-(2 -甲基苯基）D比啶_2_基} (曱基）胺基]己-4-炔- l-基}吡咯啶-3-基羥基（二_2_ 噻吩基）乙酸酯[Example 3] (3R) - l-{ 6-[{ 5-[{ 2-[3,5-bis(trifluoromethyl)phenyl]·2_ decylpropenyl} (methyl) Amino]-4-(2-methylphenyl)D-pyridyl-2-yl}(indenyl)amino]hex-4-yne-l-yl}pyrrolidin-3-ylhydroxy (2_2_) Thienyl) acetate

46- 201143771 [實施例3a]2-[3,5-雙（三氟甲基）苯基]_N_ ( 6_[ ( 6_羥j 己-2-炔-1-基）（甲基）胺基]-4- (2 -甲基苯基）0比咬_3 基} -N,2-二甲基丙醯胺 將文獻（Tetrahedron Lett. 1991，32，4505 )記載的 6- {[三級丁基（二苯基）矽烷基]氧基}己-2_炔醇 (277mg，0.7 8 5mmol)溶解於乙酸乙酯（8mL)，冰冷下， 加入三乙基胺（0.131mL，〇.942mmol)及甲烷石黃酿氯 (73pL，0.942mmol)後，於相同溫度下攪拌2〇分鐘。 於反應液中添加水，並以乙酸乙酯提取，有機層以飽和 食鹽水洗淨。以無水硫酸鈉乾燥後，減壓下，館除溶劑 而獲得粗製之甲磺酸酯體。 將獲得的粗製甲磺酸酯體溶解於N，N_二曱基乙醯胺 (4mL )，添加實施例16所獲得的化合物（，女 0.393mm〇l)、碳酸鉀（13〇mg，〇 785議〇1)、及磁化卸 (l〇9mg，〇.785mmo丨）後，於5〇1：攪拌5.5小時。反應液 以乙酸乙酯稀釋’有機層依序以水（χ3)、飽和食鹽2洗 淨。以無水硫酸鈉乾燥後’減壓下，餾除溶劑所；得的 殘渣使用矽膠管柱層析純化（己烷：乙酸乙_ = 6:丨）， 獲得粗製之胺基化體。 將獲得的粗製胺基化體溶解於四氣。夫喃（Μ)，添 加氟化四丁基銨（1M-四氫咬喃溶液，〇 983mL，，、、 〇、.983mm〇1 )後，於室溫攪拌i小時。於反應液中加入水， 以乙m日提取。有機層以飽和食鹽水洗淨，並以益水 納乾燥後，減壓下，館除溶劑所獲得的殘清使用球 ::石夕膠管桎層析純化（己烷：乙酸乙m_1:1)， 獲付’白色固體之標題目的化合物（9〇mg，產率30% )。 -47- 201143771 MS (FAB) m/z: 606(M + H) + . IR(KBr) vmax 2932，1 650，1 597，1 500, 1 373，1 282, 1 185，1 1 37, 896, 683 cm·1· [實施例 3b] ( 3R) -1- { 6-[ { 5-[ { 2-[3,5-雙（三氟甲基） 苯基]-2-甲基丙醯基}(曱基）胺基]-4- ( 2-曱基苯基）吼 °定-2-基}(曱基）胺基]己-4 -炔- l-基}&quot;比洛°定-3-基經基 (二-2-噻吩基）乙酸酯 將實施例3 a所獲得的化合物（7 0 m g，0.11 8 m m ο 1 ) 溶解於乙酸乙酯（5mL )，冰冷下，加入三乙基胺（40pL， 0.284mmol)及甲烷磺醯氯（22pL，0.284mmol)後，於 相同溫度下搜掉1 5分鐘。於反應液中加入水，以乙酸乙 酯提取’有機層以飽和食鹽水洗淨。以無水硫酸鈉乾燥 後’減壓下’餾除溶劑所獲得的殘渣溶解於N，N-二甲基 乙醯胺（4mL )，加入實施例1 i所獲得的化合物（3 7mg， 0.118mmol)、碳酸氫鈉（20mg，0.23 6mmol )、及碘化鉀 (3 9mg，0.23 6mmol )後，於50°C攪拌5小時。反應液以 乙酸乙酯稀釋’有機層依序以水（x 3 )、飽和食鹽水洗淨。 以無水硫酸鈉乾燥後，減壓下’餾除溶劑所獲得的殘渣 使用NH石夕膠管柱層析純化（己烧：乙酸乙酯=2 : 1 -1 : 1 )。再使用逆相分取管柱層析純化（Waters，MS C1 8 OBD，5μπι ’ 3〇xl〇〇mm)(乙腈：〇·ι% 乙酸銨水溶液= 70 : 30-100 : 0 )，獲得呈淡黃色固體之標題目的化合物 (41mg，產率 39% )。 MS (FAB) m/z: 897(M + H) + . IR(KBr) vmax 293 1，1732，1651，1499，1373，1281， 1 184，1 137，1081，708 cm'1. -48 - 201143771 [實施例4 ] 4_ { [ { 4_[ ( 2_ { 4-[(聯苯基-2-基胺甲醯基）氧基] 哌啶- l-基}乙基）（甲基）胺甲醯基]苄基}(曱基）胺 基]甲基}苯基4-[(N-{5-[{2-[3,5-雙（三氟曱基）笨 基]-2-曱基丙醯基}(甲基）胺基]-4- ( 2-甲基苯基）吼 啶-2-基} -N-曱基甘胺醯基）（甲基）胺基]丁酸酯46-201143771 [Example 3a] 2-[3,5-Bis(trifluoromethyl)phenyl]_N_(6-[(6-hydroxyj hex-2-yn-1-yl)(methyl)amino group ]-4-(2-methylphenyl)0 than bite_3 base} -N,2-dimethylpropionamide 6- {[third grade) as described in the literature (Tetrahedron Lett. 1991, 32, 4505) Butyl (diphenyl)decyl]oxy}hexan-2-alkynol (277 mg, 0.78 5 mmol) was dissolved in ethyl acetate (8 mL), EtOAc (EtOAc) And methane-brown-brown chlorine (73 pL, 0.942 mmol), and stirred at the same temperature for 2 minutes. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated brine. After drying the sodium, the solvent was removed under reduced pressure to obtain a crude mesylate. The obtained methanesulfonate was dissolved in N,N-dimercaptoacetamide (4 mL), and Example 16 was added. The obtained compound (, female 0.393 mm 〇l), potassium carbonate (13 〇 mg, 〇 785 〇 〇 1), and magnetized unloading (l 〇 9 mg, 〇.785 mmo 丨), after 5 〇 1 : stirring for 5.5 hours The reaction solution was diluted with ethyl acetate. The organic layer was sequentially water (χ3), saturated. The salt 2 was washed, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure; the residue obtained was purified by chromatography on silica gel column (hexane: ethyl acetate = 6: hexane) to obtain crude amination. The obtained crude aminated body was dissolved in four gas. Furuan (Μ), tetrabutylammonium fluoride (1M-tetrahydrogenate solution, 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 . . . . . . After that, the mixture was stirred at room temperature for 1 hour, and water was added to the reaction mixture, and the mixture was extracted with a m-day. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried under reduced pressure, and the residue obtained by removing the solvent under reduced pressure. Purification using a ball: purified by chromatography on silica gel (hexane: ethyl acetate m_1:1), titled title compound (9 mg, yield 30%) of white solid. -47- 201143771 MS (FAB) m/z: 606(M + H) + . IR(KBr) vmax 2932,1 650,1 597,1 500, 1 373,1 282, 1 185,1 1 37, 896, 683 cm·1· [ Example 3b] ( 3R) -1- { 6-[ { 5-[ { 2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanyl}(indenyl)amine -4-(2-mercaptophenyl) 吼 定 -2-yl}(fluorenyl)amino]hex-4-yne-l-yl}&quot; The compound obtained in Example 3a (70 mg, 0.11 8 mm ο 1 ) was dissolved in ethyl acetate (5 mL) under ice-cooling. After adding triethylamine (40 pL, 0.284 mmol) and methanesulfonium chloride (22 pL, 0.284 mmol), it was taken for 15 minutes at the same temperature. Water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The residue obtained by distilling off the solvent under reduced pressure of anhydrous sodium sulfate was dissolved in N,N-dimethylacetamide (4 mL), and the compound obtained in Example 1 i (3 7 mg, 0.118 mmol) was added. After sodium hydrogencarbonate (20 mg, 0.23 6 mmol) and potassium iodide (3 9 mg, 0.23 6 mmol), the mixture was stirred at 50 ° C for 5 hours. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water (x 3 ) and brine. After drying over anhydrous sodium sulfate, the residue obtained by distilling solvent under reduced pressure was purified using NH.sub.2. Purification by reverse phase separation column chromatography (Waters, MS C1 8 OBD, 5μπι '3〇xl〇〇mm) (acetonitrile: 〇·ι% ammonium acetate aqueous solution = 70: 30-100: 0), obtained The title compound (41 mg, yield 39%) MS (FAB) m/z: 897 (M + H) + . IR (KBr) vmax 293 1,1732,1651,1499,1373,1281, 1 184,1 137,1081,708 cm'1. -48 - 201143771 [Example 4] 4_ { [ { 4_[ ( 2_ { 4-[(Biphenyl-2-ylaminocarbamoyl)oxy] piperidine-1-yl}ethyl)(methyl)amine A Mercapto]benzyl}(indenyl)amino]methyl}phenyl 4-[(N-{5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-indole (Methyl)amino]-4-(2-methylphenyl)acridin-2-yl}-N-mercaptosylamino)(methyl)amino]butyrate

[實施例4a] 4- {[( 4-羥基苄基）胺基；1曱基}苯曱酸曱酯 將4-(胺基曱基）苯曱酸曱酯（6.88g，34.2mmol) 及4-經基苯甲酸· （ 4.60g，37.7mmol)溶解於乙醇 (3 00mL )，加熱回流下攪拌6小時。於室溫，於反應液 中加入氫化棚鈉（1.39g，37.3mmol)，並於相同溫度下 授拌1小時。於反應液加入飽和碳酸氫納水，以二氣曱院 提取後’有機層以飽和食鹽水洗淨。以無水硫酸納乾燥 後，減壓下，由己烷及二氣曱烷之混合溶媒將餾除溶劑 所獲得的殘渣再沉澱，獲得呈白色固體之標題目的化合 物（4.90g，產率 52% )。 MS (El) m/z: 271(M + ). IR(KBr) vmax 2949, 171 8，1612: 1518，1444，1 282, 1251，1 109, 820, 759 cm]· [實施例4b]4- {[(三級丁氧基羰基）（4-羥基苄基）胺 基]曱基}苯曱酸 -49- 201143771 將實施例4a所獲得的4-{ [( 4-羥基苄基）胺基]甲基} 苯甲酸甲酯（1.07g’ 3.94mmol)溶解於二氣曱烷（39mL)， 加入二碳酸二（三級丁基）酯（947mg，4 34mm〇1 )之 二氣甲烷溶液（8mL) ’於室溫攪拌4.5小時。減壓下，餾 除溶劑而獲得粗製之B 〇 c體。 將獲得的粗製Boc體溶解於甲醇（39mL)，加入4N 氫氧化鈉水溶液（3.94m，15.8mmol)，於室溫授掉17小 時、50°C攪拌1.5小時。於反應液中加入二氣甲烷，以⑺ 鹽酸作成pH為1後’以二氯甲烷（x2)提取。有機層以 無水硫酸鈉乾燥後，減壓下’餾除溶劑所獲得的殘逢由 己烷及少量的二乙基醚濾取，獲得呈白色固體之標題目 的化合物（1.23g，產率80% )。 'H NMR (DMSO-d6, 500ΜΗζ): δ 1.35-1.42 (9Η, m), 4.21-4.36 (4H, m), 6.72 (2H, d, J = 8.6 Hz), 7.04.7 05 (2H m), 7.28-7.29 (2H, m), 7.90 (2H, d, J = 8.6 Hz), 9.35 (1H brs). MS (FAB) m/z: 3 5 8(M + H) + .[Example 4a] 4-{[(4-hydroxybenzyl)amino group; 1 fluorenyl} benzoic acid decyl ester 4-(aminomercapto) benzoic acid decyl ester (6.88 g, 34.2 mmol) and 4-Benzylbenzoic acid ( 4.60 g, 37.7 mmol) was dissolved in ethanol (300 mL), and stirred under reflux for 6 hours. Hydrogenated sodium hydride (1.39 g, 37.3 mmol) was added to the reaction mixture at room temperature and stirred at the same temperature for one hour. After adding saturated sodium hydrogencarbonate to the reaction mixture, the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the residue obtained by distilling solvent from hexane and dioxane was re-precipitated to give the title compound (4.90 g, yield 52%) as a white solid. MS (El) m/z: 271 (M + ). IR (KBr) vmax 2949, 171 8,1612: 1518,1444,1 282, 1251,1 109, 820, 759 cm]· [Example 4b] 4 - {[(Tris-butoxycarbonyl)(4-hydroxybenzyl)amino]] decyl}benzoic acid-49- 201143771 4-{[(4-Hydroxybenzyl)amine obtained in Example 4a Methyl benzoate (1.07 g ' 3.94 mmol) was dissolved in dioxane (39 mL), and a di-methane solution of di(tert-butyl) dicarbonate (947 mg, 4 34 mm 〇 1 ) was added. (8 mL) 'Stir at room temperature for 4.5 hours. The solvent was distilled off under reduced pressure to give a crude material. The obtained crude Boc was dissolved in methanol (39 mL), and 4N aqueous sodium hydroxide (3.94 m, 15.8 mmol) was added, and the mixture was allowed to stand at room temperature for 17 hours and at 50 ° C for 1.5 hours. Dioxethane was added to the reaction mixture, and (7) hydrochloric acid was used to make a pH of 1 and then extracted with dichloromethane (x2). The organic layer was dried over anhydrous sodium sulfate (MgSO4). . 'H NMR (DMSO-d6, 500ΜΗζ): δ 1.35-1.42 (9Η, m), 4.21-4.36 (4H, m), 6.72 (2H, d, J = 8.6 Hz), 7.04.7 05 (2H m) , 7.28-7.29 (2H, m), 7.90 (2H, d, J = 8.6 Hz), 9.35 (1H brs). MS (FAB) m/z: 3 5 8 (M + H) + .

[實施例4c] 1- ( 2- {[ ( 4- {[(三級丁氧基羰基）（4經 基苄基）胺基]甲基}苯基）幾基](曱基）胺基丨乙基） 哌啶-4-基聯苯基-2-基胺基曱酸酯 將1-[2-(曱基胺基）乙基]略。定-4 -基聯苯基-2-基胺 基甲酸酯（1 94mg，0.550mmol )及實施例4b所獲得的4- {[(三級丁氧基羰基）（4-羥基苄基）胺基]曱基丨苯甲 酸（197mg ’ 0_5 50mmol )溶解於二氣甲烷（5.5mL)， 加入WSC · HC1( 127mg’ 0.660mmol)，於室溫搜拌整夜。 -50- 201143771 減壓下，餾除溶劑所獲得的殘渣使用nh矽膠管柱層析純 化（己烷：乙酸乙酯=1: 1-乙酸乙酯：甲醇= 40: 1)， 獲得呈白色固體之標題目的化合物（373mg ,產率98 % )。 MS (APCI) m/z: 693(M + H) + . IR(KBr) vmax 2932，1735，1691，1613，1517，1450, 1237, 1 162, 1045, 751 cm·1.[Example 4c] 1-(2-{[(4-{[(tert-butoxycarbonyl))(4-benzyl)amino]methyl}phenyl)alkyl](indenyl)amine Ethylethyl)piperidin-4-ylbiphenyl-2-ylamino phthalate is slightly 1-[2-(indolyl)ethyl]. 4-[4-Benzyl-2-ylcarbamate (1 94 mg, 0.550 mmol) and 4-{[(tertiary butoxycarbonyl) (4-hydroxybenzyl) obtained in Example 4b Amino]mercaptobenzoic acid (197 mg '0_5 50 mmol) was dissolved in di-methane (5.5 mL), and then WSC·HC1 (127 mg &lt; -50- 201143771 The residue obtained by distilling the solvent under reduced pressure was purified by mhhhhhhhhhhhhhhhhhhhhhhhhhh The title compound (373 mg, yield 98%). MS (APCI) m/z: 693 (M + H) + . IR (KBr) vmax 2932, 1735, 1691, 1613, 1517, 1450, 1237, 1 162, 1045, 751 cm·1.

[實施例4d]l- ( 2- { [ ( 4- { [ ( 4-羥基苄基）（曱基）胺 基]曱基}苯基）羰基](甲基）胺基}乙基）哌啶_4基聯 苯基-2 -基胺基曱酸g旨 將實施例4c所獲得的化合物（100mg，〇 145mm〇1 ) 溶解於曱醇（3mL )，加入4N鹽酸-二嘮烷（9〇0， 0.3 61mmol)，於室溫攪拌丨小時。再於反應液中加入4N 鹽酸-二脅烧（363 pL，1.44mmol )，於室溫授拌i 5小時。 減壓下，將餾除溶劑所獲得的殘渣溶解於乙腈（3mL )， 加入37%福馬林水溶液（〇 29〇mL)及氫化氰基硼鈉 (55mg，0_870mmol)，於室溫攪拌整夜。於反應液中 加入飽和碳酸氫鈉，以乙酸乙酯提取後，有機層依序以 水、飽和食鹽水洗淨。以無水硫酸鈉乾燥後，減壓下， 餾除溶劑所獲得的殘渣使用NH矽膠管柱層析純化（己 烷：乙酸乙酯=1 : 2-乙酸乙酯：曱醇=6〇 : j )，獲得 王κ色油狀物之標題目的化合物（5〇mg，產率η%) 0 MS (ESI) m/z: 60 6 (M + ).[Example 4d] 1-(2-{[(4-{[(4-hydroxybenzyl)(indolyl)amino]] yl}phenyl)carbonyl](methyl)amino}ethyl)piper Pyridin-4-ylbiphenyl-2-ylaminofurfuric acid g The compound obtained in Example 4c (100 mg, 〇145 mm〇1) was dissolved in methanol (3 mL), and 4N hydrochloric acid-dioxane (9) was added. 〇0, 0.361 mmol), stirred at room temperature for hrs. Further, 4N hydrochloric acid-di-flavor (363 pL, 1.44 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours. The residue obtained by distilling off the solvent was dissolved in acetonitrile (3 mL), and a 37% aqueous solution of sulphate (29 〇mL) and sodium cyanoborohydride (55 mg, 0-870 mmol) were added and stirred at room temperature overnight. Saturated sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the residue obtained by distilling off the solvent under reduced pressure was purified using NH?? </ RTI> column chromatography (hexane: ethyl acetate = 1: 2-ethyl acetate: decyl alcohol = 6 〇: j) The title compound (5 〇 mg, yield η%) was obtained as the title product of yd.

[實施例4e]4-[(溴乙醯基）（曱基）胺基]丁酸曱酯 -51 · 201143771 將4-(曱基胺基）丁酸曱酯鹽酸鹽（[ο。，6 〇〇mm〇1) 溶解於二氯曱烷（30mL )，冰冷下，添加三乙基胺 (2_08mL，15.0mmol )及溴乙醯基氣（〇 5〇〇mL， 6.00mmol )，於室溫攪拌1小時。於反應液中加入iN鹽 酸’以乙酸乙酯提取。有機層依序以水、飽和食鹽水洗 淨’以無水硫酸鈉乾燥後’減壓下，鶴除溶劑而獲得呈 褐色油狀物之標題目的化合物（688mg，產率45%)。 Ή NMR (CDC13, 500MHz): δ 1.86- 1.98 (2Η, m), 2.34-2.39 (2Η，m)，2.9 及 3.09 (共 3Η，各 s), 3.38-3.45 (2H，m)，3.68 及 3.71 (共 3H, s), 4.06 及 4.12 (2H，各 s). [實施例 4f]4-[ ( N- { 5-[ { 2-[3,5-雙（三 I 曱基）苯基]·2_ 曱基丙醯基}(甲基）胺基]-4- ( 2-曱基苯基）吼啶-2-基}-1^ -甲基甘胺醯基）（曱基）胺基]丁酸甲酯 將實施例1 e所獲得的化合物（2 7 8 m g，0.5 4 6 m m ο 1) 溶解於甲苯（5.5mL)，冰冷下，逐滴加入〇.5M六曱基二 矽氮烷鉀之曱苯溶液（4.37mL，2.1 8mmol )，於室溫攪拌 1 0分鐘。於反應液中加入實施例4 e所獲得的4 -[(溴乙醯 基）（甲基）胺基]丁酸曱酯（68 8mg，2.73mmol )之曱 苯溶液（5 · 5 mL )後，於7 5 °C攪拌4 1小時》於反應液中加 入飽和碳酸氫鈉水，以乙酸乙酯（X 3 )提取後，有機層 以飽和食鹽水洗淨。以無水硫酸鈉乾燥後，減壓下，鶴 除溶劑所獲得的殘渣使用矽膠管柱層析純化（己烷：乙 酸乙酯=3 : 2-1 : 2 )，獲得呈黃色油狀物之標題目的化 合物（129mg，產率34%)。 MS (APCI) m/z: 681(M + H) + . -52- 201143771 IR(KBr) vmax 1734，1648，1 502，1371，1 278，1170, 1 130，1079, 896, 682 cnT1· [實施例4g]4-[ ( N- { 5-[ { 2-[3,5-雙（三氟曱基）苯基]_2-曱基丙醯基}(甲基）胺基]-4- ( 2-曱基苯基）。比啶-2-基} -N -曱基甘胺酿基）（甲基）胺基]丁酸 將實施例4f所獲得的化合物（i29nig，〇」9〇nimol ) 溶解於曱醇（2mL ) ’添加in氫氧化鈉水溶液（〇 569mL， 〇.569mmol)後，於室溫攪拌24小時。反應液中加入⑶ 鹽酸（0.569mL)，以二氯曱烷（x3)提取後，以無水硫 酸鈉乾燥。減壓下，餾除溶劑所獲得的殘渣以四氫呋喃 (χ2 )共彿’獲得呈淡綠色固體之標題目的化合物 (120mg，產率 95% )。 MS (APCI) m/z: 667(M + H) + .[Example 4e] 4-[(bromoethyl)(indenyl)amino]butyrate-butyrate-51 · 201143771 4-(decylamino)butyrate decanoate hydrochloride ([ο., 6 〇〇mm〇1) Dissolved in dichloromethane (30mL), added with triethylamine (2_08mL, 15.0mmol) and bromoethane (5〇mL, 6.00mmol) in the room under ice cooling Stir for 1 hour. iN hydrochloric acid was added to the reaction solution to extract with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride (yield: EtOAc (yield: 45%). NMR NMR (CDC13, 500MHz): δ 1.86- 1.98 (2Η, m), 2.34-2.39 (2Η, m), 2.9 and 3.09 (3 total, each s), 3.38-3.45 (2H, m), 3.68 and 3.71 (3H, s), 4.06 and 4.12 (2H, each s). [Example 4f] 4-[(N- { 5-[ { 2-[3,5-bis(tri-indolyl)phenyl] ·2_ mercaptopropyl}(methyl)amino]-4-(2-mercaptophenyl)acridin-2-yl}-1^-methylglycine decyl)(fluorenyl)amine Methyl butyrate The compound obtained in Example 1 e (2 7 8 mg, 0.5 4 6 mm ο 1) was dissolved in toluene (5.5 mL), and ice-cooled, 〇.5M hexamethylene diazide was added dropwise. A solution of the potassium benzene in benzene (4.37 mL, 2.18 mmol) was stirred at room temperature for 10 min. After adding 4 -[(bromoethyl)(methyl)amino]butyrate decanoate (68 8 mg, 2.73 mmol) obtained in Example 4 e to a solution of benzene (5 · 5 mL) The mixture was stirred at 75 ° C for 4 1 hour. To the reaction mixture was added saturated aqueous sodium bicarbonate and extracted with ethyl acetate (x 3 ), and the organic layer was washed with brine. After drying over anhydrous sodium sulfate, the residue obtained by removing the solvent was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 2-1: 2) to give a yellow oily title. The compound of interest (129 mg, yield 34%). MS (APCI) m/z: 681 (M + H) + . -52- 201143771 IR(KBr) vmax 1734,1648,1 502,1371,1 278,1170, 1 130,1079, 896, 682 cnT1· [ Example 4g] 4-[(N- { 5-[ { 2-[3,5-bis(trifluoromethyl)phenyl]_2-mercaptopropyl}(methyl)amino]-4- (2-nonylphenyl).pyridin-2-yl}-N-mercaptoamine-based (meth)amino]butyric acid The compound obtained in Example 4f (i29nig, 〇"9〇 Nimol) was dissolved in decyl alcohol (2 mL). After adding aqueous sodium hydroxide solution (〇 569 mL, 569. 569 mmol), the mixture was stirred at room temperature for 24 hours. (3) Hydrochloric acid (0.569 mL) was added to the reaction mixture, which was extracted with dichloromethane (x3) and dried over anhydrous sodium sulfate. The title compound (120 mg, yield: 95%) was obtained from m. MS (APCI) m/z: 667 (M + H) + .

[實施例4h]4- { [ { 4-[ ( 2- { 4-[(聯苯基-2_基胺曱醯基） 氧基]旅。定- l-基}乙基）（曱基）胺甲醯基]苄基}(曱 基）胺基]曱基}苯基4-[(N-{5-[{2-[3,5-雙（三氟曱 基）苯基]-2-甲基丙醯基丨（曱基）胺基]-4-(2-曱基苯 基）°比啶-2-基} -N-甲基甘胺醯基）（甲基）胺基]丁酸 酉旨 將貝施例4 d所獲得的化合物（5 〇 m g，0.0 8 2 4 m m ο 1 ) 及實施例4g所獲得的化合物（6〇rng，〇 0906ιηιη〇1 )溶解 於N，N-二曱基甲醯胺（3mL ) ’加入三乙基胺（34μί， 0.246mmol)、WSC · HC1 ( 18mg，〇.124mmol)、及 4-二 甲基胺基。比。定（1片）’於室溫攪拌1.5小時。再於反應液 中加入三乙基胺（68pL，0_496mmol )、WSC · HC1( 18mg， -53- 201143771 0_124mmol )、及4-二甲基胺基吡啶（1片），於室溫整夜 攪拌。於反應液中加入水，以乙酸乙酯提取後，有機層 依序以水（X 2 )、飽和食鹽水洗淨。以無水硫酸鈉乾燥後， 減壓下，餾除溶劑所獲得的殘渣使用逆相分取管柱層析 純化（Waters，MS C18 0BD，5μπι，3〇xlO〇mm)(乙腈： 0.1%乙酸銨水溶液= 30: 70-100: 0)，獲得呈黃色固 體之標題目的化合物（22mg，產率21 % )。 MS (FAB) m/z: 1255(M + H) + . IR(KBr) vmax 2932，1734，1649，1 506，1 398，1 372, 128 1, 1 184, 1 136, 753 cm*1.[Example 4h] 4-{ [ { 4-[ ( 2- { 4-[(biphenyl-2-ylamino)indolyloxy]]]-l-yl}ethyl) Aminomethyl]benzyl}(indenyl)amino]indenyl}phenyl 4-[(N-{5-[{2-[3,5-bis(trifluoromethyl)phenyl]-) 2-methylpropionyl fluorenyl (fluorenyl)amino]-4-(2-mercaptophenyl) ° pyridine-2-yl}-N-methylglycinyl) (methyl)amino group ] Butyric acid is prepared by dissolving the compound obtained in the 4th step of the shell of Example 4 (5 〇mg, 0.0 8 2 4 mm ο 1 ) and the compound obtained in Example 4g (6〇rng, 〇0906ιηιη〇1 ) in N, N-Dimercaptocarbamide (3 mL) 'Addition of triethylamine (34 μί, 0.246 mmol), WSC · HC1 (18 mg, 〇.124 mmol), and 4-dimethylamino group. ratio. The solution (1 tablet) was stirred at room temperature for 1.5 hours. Further, triethylamine (68 pL, 0_496 mmol), WSC · HC1 (18 mg, -53-201143771 0-124 mmol) and 4-dimethylaminopyridine (one tablet) were added to the reaction mixture, and the mixture was stirred overnight at room temperature. After adding water to the reaction mixture and extracting with ethyl acetate, the organic layer was washed with water (X 2 ) and brine. After drying over anhydrous sodium sulfate, the residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase column chromatography (Waters, MS C18 0 BD, 5 μπι, 3 〇 x 10 〇mm) (acetonitrile: 0.1% ammonium acetate) Aqueous solution = 30: 70-100: 0)m. MS (FAB) m/z: 1255 (M + H) + . IR (KBr) vmax 2932,1734,1649,1 506,1 398,1 372, 128 1,1 184, 1 136, 753 cm*1.

[實施例5 ] 4-[({4-[(2-{4-[(聯苯基-2-基胺曱酿基）氧基] 哌啶- l-基}乙基）（甲基）胺曱醯基]苄基}胺基）曱基] 苯基 4-[(N-{5-[{2-[3,5-雙（三氟甲基）苯基]_2_曱 基丙醯基}(曱基）胺基]-4- ( 2-曱基苯基）°比啶-2-基} -N-曱基甘胺醯基）（曱基）胺基]丁酸酯[Example 5] 4-[({4-[(2-{4-[(biphenyl-2-ylamine))oxy]piperidin-1-yl}ethyl)(methyl) Amidino]benzyl}amino)indenyl]phenyl 4-[(N-{5-[{2-[3,5-bis(trifluoromethyl)phenyl]_2-indenyl) (indenyl)amino]-4-(2-mercaptophenyl) °pyridin-2-yl}-N-mercaptosylamino)(indenyl)amino]butyrate

[實施例5a]4- { [ { 4-[ ( 2- { 4-[(聯苯基-2-基胺甲醯基） 氧基]哌啶-1-基}乙基）（曱基）胺曱醯基]苄基丨（三 級丁氧基羰基）胺基]曱基}苯基4-[ ( N- { 5-[ { 2-[3,5-雙（三氟曱基）苯基]-2-曱基丙醯基丨（曱基）胺基]-4-(2-甲基苯基）吡啶-2-基} -N-甲基甘胺醯基）（甲基） 胺基]丁酸酯 -54- 201143771 將貫施例4c所獲得的化合物（1 25mg，〇_ 1 80mmol ) 及實施例4g所獲得的化合物（i2〇mg，0.180mmol )溶解 於二氣甲烷（2mL)，加入 WSC · HC1( 42mg，〇.216mmol)， 於至溫授拌4小時。於反應液中加入4 -二甲基胺基《比。定 (Img ’ 〇_〇〇9mmol)，於室溫攪拌2.5日。再加入4-二曱 基胺基。比咬（2mg，〇 .〇 1 8mmol )，於室溫攪拌23小時。 於反應液中加入飽和碳酸氫鈉水，以乙酸乙酯提取後， 有機層以飽和食鹽水洗淨。以無水硫酸鈉乾燥後，減壓 下’餾除溶劑所獲得的殘渣使用矽膠管柱層析純化（二 氣甲烷：曱醇=50 : 1 -30 : 1 )，獲得呈黃色固體之標題 目的化合物（135 mg，產率56%)。 MS (FAB) m/z: 1341(M + H) + . IR(KBr) vmax 2930，1694，1649，1 507，14〇3，1 367, !2813 1183, 1137, 752 cm&quot;1.[Example 5a] 4- { [ { 4-[ ( 2- { 4-[(biphenyl-2-ylaminocarbamoyl)oxy]piperidin-1-yl}ethyl)(fluorenyl) Amidino]benzyl hydrazine (tertiary butoxycarbonyl)amino]indenyl}phenyl 4-[(N-{ 5-[ { 2-[3,5-bis(trifluoromethyl)benzene) 2-mercaptopropyl fluorenyl (indenyl)amino]-4-(2-methylphenyl)pyridin-2-yl}-N-methylglycinyl) (methyl)amine Butyl-butyrate-54- 201143771 The compound obtained in Example 4c (1 25 mg, 〇 1 80 mmol) and the compound obtained in Example 4 g (i2 〇mg, 0.180 mmol) were dissolved in di-methane (2 mL). ), WSC · HC1 (42 mg, 〇. 216 mmol) was added, and the mixture was stirred for 4 hours. A 4-dimethylamino group "ratio was added to the reaction solution. (Img 〇 〇〇 〇〇 9 mmol) was stirred at room temperature for 2.5 days. Further, a 4-didecylamino group is added. More than a bite (2 mg, 〇.〇 18 mmol), stirred at room temperature for 23 hours. Saturated sodium hydrogencarbonate water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the residue obtained by distilling off the solvent under reduced pressure was purified using silica gel column chromatography (di- methane: decyl alcohol = 50 : 1 -30 : 1 ) to give the title compound as a yellow solid. (135 mg, yield 56%). MS (FAB) m/z: 1341 (M + H) + . IR (KBr) vmax 2930,1694,1649,1 507,14〇3,1 367, !2813 1183, 1137, 752 cm&quot;1.

[實施例5b]4-[ ( { 4-[ ( 2- {4-[(聯苯基-2-基胺曱醯基） 氧基]哌啶-l-基}乙基）（曱基）胺曱醯基]苄基丨胺基） 甲基]苯基4-[( N-丨5-[{ 2-[3,5-雙（三氟甲基）苯基]_2· 甲基丙醯基}(甲基）胺基]-4- ( 2·曱基苯基）D比啶_2_ 基} -N-曱基甘胺醯基）（甲基）胺基]丁酸酯 於實施例5a所獲得的化合物（41mg，〇 〇3〇6mm〇l) 之丨，4-二嘮烧溶液（3mL)中，冰冷下，添加4N鹽酸-二 噚烷（77gL，0.3 0 6mmol)，於相同溫度下攪拌1〇分鐘， 再於室溫整夜攪拌。於反應液中添加飽和碳酸氫鈉水 後，以乙酸乙酯提取，有機層依序以水、飽和食鹽水洗 淨後，以無水硫酸鈉乾燥。減壓下，餾除溶劑所獲得的 -55- 201143771 殘渣使用逆相分取管柱層析純化（Waters，MS Cl 8 OBD，5μηι，3〇xl〇Omm)(乙腈：0.1% 乙酸銨水溶液= 20 ： 80-100 ： 0 )，獲得呈黃色固體之標題目的化合物 (7mg，產率 18% )。 MS (FAB) m/z: 1241(M + H) + . IR(KBr) vmax 2929，1 733, 1 649，1 506，1 373，1281， 1 1 84, 1 1 37, 838, 752 cm'1.[Example 5b] 4-[( { 4-[ ( 2- {4-[(biphenyl-2-ylaminoindolyl)oxy]piperidine-1-yl}ethyl)(fluorenyl) Amidino]benzyl benzylamino)methyl]phenyl 4-[(N-丨5-[{ 2-[3,5-bis(trifluoromethyl)phenyl]_2]methylpropionamidine (})(methyl)amino]-4-(2·nonylphenyl) D-pyridin-2-yl}-N-mercaptoglycaninyl)(methyl)amino]butyrate in the examples 5a obtained compound (41mg, 〇〇3〇6mm〇l), 4-diindole solution (3mL), 4N hydrochloric acid-dioxane (77gL, 0.30 6mmol) was added under ice cooling, the same Stir at a temperature for 1 minute, then stir at room temperature overnight. After adding saturated sodium hydrogencarbonate water to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The residue of -55-201143771 obtained by distilling off the solvent under reduced pressure was purified by reverse phase column chromatography (Waters, MS Cl 8 OBD, 5μηι, 3〇xl〇Omm) (acetonitrile: 0.1% aqueous ammonium acetate solution = 20: 80-100: 0), the title compound (7 mg, yield 18%) MS (FAB) m/z: 1241 (M + H) + . IR (KBr) vmax 2929,1 733, 1 649,1 506,1 373,1281, 1 1 84, 1 1 37, 838, 752 cm' 1.

[實施例6 ] (3R) - l-{ 2-[{ 6-[4-( { 3-[( { [( 2S) - r-{ 2-[( 5R) -3- { [3,5-雙（三氟曱基）苯基]羰基} -5- ( 4-氟苯基） -1，3-嘮唑啶-5-基]乙基}-2,3-二氫螺[茚-1,4’-哌啶]-2-基] 氧基}乙醯基）胺基]丙基}胺曱醯基）哌啶-1 -基]己醯 基}(甲基）胺基]乙基}。比咯啶-3-基羥基（二噻吩-2-[Example 6] (3R) - l-{ 2-[{ 6-[4-( { 3-[( { [( 2S) - r-{ 2-[( 5R) -3- { [3,5 -Bis(trifluoromethyl)phenyl]carbonyl} -5-(4-fluorophenyl)-1,3-oxazolidin-5-yl]ethyl}-2,3-dihydrospiro[茚- 1,4'-piperidinyl]-2-yl]oxy}ethinyl)amino]propyl}aminoindenyl)piperidine-1-yl]hexyl}}(methyl)amino] base}. Biropyridin-3-ylhydroxy (dithiophene-2-

[實施例6a] ( 5R) -3-[3,5-雙（三氟曱基）苯甲醯基]-5-(2- {[三級丁基（二甲基）矽烷基]氧基}乙基）-5-( 4-氟苯基）-1,3-嘮唑啶 於（2R) -1-胺基_4- {[三級丁基（二曱基）矽烷基] 氧基} -2-(4-氟苯基）丁-2_醇（i2892g、〇411rn〇i)之 苯（1000mL)溶液中添加三聚曱醛（18 5〇g、〇 617rnol)， 設置水分分離器而攪拌回流4小時。減壓濃縮反應混合物 -56- 201143771 而獲得呈褐色油狀之（5R) _5_ (2 {[三級丁基（二曱基） 矽炫•基]氣基丨乙基）-5-(4-氟苯基）-1，3-嘮唑啶之粗製 物 1 39.43g。 於獲得的粗製（5R) _5· ( 2·丨[三級丁基（二曱基） 矽烷基]氧基}乙基）-5_(4_氟笨基）-1，3-嘮唑啶 (139.43g)二乙基胺（69mL，0.49 5mol)、4-(二甲基 胺基）°比0定（5.〇2g、〇.〇41mol)之二氯甲烧（l〇〇〇mL) 溶液中，冰冷下，逐滴加入3，5 -雙（三氟曱基）苯曱醯 基氣（l〇〇g、〇.43 4mol)，於室溫攪拌18小時。反應混合 物以水、飽和食鹽水洗淨’以無水硫酸納乾燥後’減壓 濃縮。所獲得的殘留物使用矽膠管柱層析純化（丨〇 %乙 酸乙醋/η -己烧）’獲得呈淡黃色油狀物之標題目的化合 物 131.76g (產率 62% )。 [實施例6b]2-[ ( 5R) -3-[3,5-雙（三氟曱基）苯曱醯基]_5_ (4 -氟苯基）-l，3-«f唑唆-5-基]乙醇 於實施例6a所獲得的化合物（l3l76g’ 〇 254m〇i) 之四氫吱喃（50()mL)溶液中添加氟化四丁基敍之四氮 咬喃溶液（1.0M，508mL)及乙酸（7〇mL，i π—), 於室溫檀拌2小時。於反應思合物中加入乙酸乙醋 ( 1000mL)’ U飽和碳酸氫納水溶液 '水、飽和食鹽水 洗淨，以無水硫酸納乾燥後，减壓濃縮。所獲得的殘留 物使用石夕膠管柱層析純化（3〇 %乙酸乙賴&amp;己烷—5〇 %)，獲得呈無色油狀物之標題目的化合物i〇2 ug (產 率 99% )。 -57- 201143771 [實施例6c]2_[( 5R) -3-[3,5_雙（三ι甲基）苯曱醯基]_5_ (4-氟苯基）-1,3-嘮唑啶_5_基]乙基γ烷磺酸酯 於實施例6b所獲得的2_[ (5R) _3_[3,5_雙（三氟甲 基 )苯甲醯基]-5_ ( 4·氟笨基）·1，3-噚唑啶-5-基]乙醇 102.11g、0_226mol)、三乙基胺（63mL，〇.452m〇1)， 4-(二甲基胺基）吡啶 (1000mL )溶液中， (2.76g、〇.〇273mol)之二氯曱烷 冰冷下，逐滴加入甲烷磺醯氯 26mL、0.336mol)，冰冷下攪拌H、時。反應混合物以 水、飽和食鹽水洗淨’以無水硫酸鈉乾燥後，減壓濃縮。 殘留物使用石夕膠管柱層析純化（3〇 %乙酸乙酯/n_己烧 —50%)’獲得呈白色固體之標題目的化合物1〇821g(產 率 90% )。 'H NMR(CDC13, 4〇〇ΜΗζ): δ 2.30-2.50(2H, m), 2.91(3Η, brs), 3.8 0-4.2 1 (3 Η, m), 4.25-4.3 5 ( 1 Η, m), 4.90-5.10(1Η, m), 5.20-5.40( 1 Η, m), 7.11(2Η, brs), 7.20-7.47(2Η, m), 7.91(2Η, s), 8.00(1Η, s); MS(FAB) m/z: 530(M + H) + ; IR(ATR) vmax 1734, 1646, 1356, 1278, 1 171, 1 129, 957, 906, 837, 681，527cm-1· [實施例6d] ( 2S ) -2-(烯丙氧基）-2,3-二氫- ΓΗ-螺[茚 -1，4，-哌啶]-Γ·曱酸三級丁酯 於（2S) -2-羥基-2,3-二氫-l’H-螺[茚-1，4，-哌啶]-1’-甲酸三級丁酯（50_0g，164.8mmol)之Ν，Ν-二曱基甲醯 胺（1 50mL )溶液中，冰冷攪拌下緩慢添加氫化鈉（含 量55%、10.79g、247.2mmol)。添加後’逐滴加入漠、丙 -58- 201143771 烯（28.5mL、329_6mmol)，冰冷下撥拌1小時。逐滴加入 水（400mL )後，以乙酸乙酯（300mL、80mLx2 )提取。 有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥後，減壓 濃縮。所獲得的殘留物使用矽膠管柱層析純化（0%乙酸 乙酯/η-己烷—20% )，獲得呈無色油狀物之標題目的化合 物 5 7.1 5 g。 'H NMR (CDC13, 400MHz): δ 1.45 (9Η, s), 1.65-1.75 (2H, m), 2.05-2.12 (1H, m), 2.95-3.25 (4H, m), 3.80-4.20 (5H, m), 5.13-5.31 (2H, m), 5.86-5.98 ( 1 H, m)5 7.11-7.25 (4H, m). MS (FAB + ) m/z: 344 ((M + H) + ). IR (液態膜）：2976，2929，1694，1479，1425, 1 366, 1278, 1237, 1 17 1, 1 080, 759 cm'1.[Example 6a] (5R) -3-[3,5-bis(trifluoromethyl)benzimidyl]-5-(2-{[tris-butyl(dimethyl)decyl]oxy Ethyl)-5-(4-fluorophenyl)-1,3-oxazolidine to (2R)-1-amino-_4-{[tertiary butyl(diindenyl)decyl]oxy Add melamine (18 5〇g, 〇617rnol) to a solution of -2-(4-fluorophenyl)butan-2-ol (i2892g, 〇411rn〇i) in benzene (1000mL), set up a water separator The mixture was stirred under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure -56-201143771 to obtain (5R) _5_ (2 {[tris-butyl(di-decyl) fluorene)-] thiol ethyl)-5-(4- Fluorophenyl)-1,3-oxazolidine crude 1 39.43 g. Obtained crude (5R) _5· (2·丨[tris-butyl(didecyl)decyl]oxy}ethyl)-5-(4-fluorophenyl)-1,3-oxazolidine ( 139.43g) Diethylamine (69mL, 0.49 5mol), 4-(dimethylamino) ° 0 (5. 〇 2g, 〇. 〇 41mol) of dichloromethane (l 〇〇〇 mL) To the solution, 3,5-bis(trifluoromethyl)benzoquinone (1 〇〇g, 〇.43 4 mol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography (yield: EtOAc EtOAc (EtOAc). [Example 6b] 2-[( 5R) -3-[3,5-bis(trifluoromethyl)benzoinyl]_5_(4-fluorophenyl)-l,3-«foxazol-5 -Based on a solution of the compound obtained in Example 6a (13.76 g' 〇 254 〇i) in tetrahydrofuran (50 () mL), tetrabutyl sulfonate solution (1.0 M, 508 mL) and acetic acid (7 mL, i π-) were mixed at room temperature for 2 hours. Ethyl acetate (1000 mL) was added to the reaction mixture, and the mixture was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by silica gel column chromatography (3% EtOAc / hexane hexane - 5%) to give the title compound i 〇 2 ug (yield 99%) as a colorless oil. . -57- 201143771 [Example 6c] 2_[( 5R) -3-[3,5_bis(trimethyl)benzoyl]_5_(4-fluorophenyl)-1,3-oxazolidinium 2-[(5R) _3_[3,5-bis(trifluoromethyl)benzylidene]-5_ (4·fluorophenyl) obtained in Example 6b · 1,3-oxazolidin-5-yl]ethanol 102.11g, 0_226mol), triethylamine (63mL, 〇.452m〇1), 4-(dimethylamino)pyridine (1000mL) solution (2.76 g, 〇. 〇 273 mol) of dichloromethane was ice-cooled, and methanesulfonyl chloride (26 mL, 0.336 mol) was added dropwise, and H was stirred under ice cooling. The reaction mixture was washed with water and saturated brine. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 'H NMR(CDC13, 4〇〇ΜΗζ): δ 2.30-2.50(2H, m), 2.91(3Η, brs), 3.8 0-4.2 1 (3 Η, m), 4.25-4.3 5 ( 1 Η, m ), 4.90-5.10(1Η, m), 5.20-5.40( 1 Η, m), 7.11(2Η, brs), 7.20-7.47(2Η, m), 7.91(2Η, s), 8.00(1Η, s) MS(FAB) m/z: 530(M + H) + ; IR(ATR) vmax 1734, 1646, 1356, 1278, 1 171, 1 129, 957, 906, 837, 681, 527 cm-1· Example 6d] ( 2S ) -2-(allyloxy)-2,3-dihydro-indole-spiro[茚-1,4,-piperidine]-indole decanoic acid tert-butyl ester in (2S) 2-Hydroxy-2,3-dihydro-l'H-spiro[茚-1,4,-piperidine]-1'-carboxylic acid tert-butyl butyl ester (50_0g, 164.8mmol), Ν-曱In a solution of carbamide (1 50 mL), sodium hydride (content 55%, 10.79 g, 247.2 mmol) was slowly added under ice-cooling stirring. After the addition, Mo, C-58-201143771 olefin (28.5 mL, 329-6 mmol) was added dropwise, and the mixture was stirred for 1 hour under ice cooling. After adding water (400 mL) dropwise, it was extracted with ethyl acetate (300 mL, 80 mL×2). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue obtained was purified by silica gel column chromatography (yield: 0% ethyl acetate / hexanes - 20%) to afford the title compound 5 7.1 5 g as colorless oil. 'H NMR (CDC13, 400MHz): δ 1.45 (9Η, s), 1.65-1.75 (2H, m), 2.05-2.12 (1H, m), 2.95-3.25 (4H, m), 3.80-4.20 (5H, m), 5.13-5.31 (2H, m), 5.86-5.98 ( 1 H, m) 5 7.11-7.25 (4H, m). MS (FAB + ) m/z: 344 ((M + H) + ). IR (liquid film): 2976, 2929, 1694, 1479, 1425, 1 366, 1278, 1237, 1 17 1, 1 080, 759 cm'1.

[實施例6e] ( 2S ) -2- ( 2-側氧基乙氧基）-2,3-二氫-1，H-螺[茚-1，4 哌啶]_ 1、甲酸三級丁酯 將實施例6d所獲得的（2S ) -2-(烯丙氧基）-2,3-二氫- ΓΗ-螺[茚-1，4’-哌啶]-Γ -曱酸三級丁酯（57.15g ) 溶解於丙酮（400 mL)、三級丁醇（200 mL)及水（200 mL) 之混合溶媒，冰冷下加入N-甲基咪啉N-氧化物（2 1.2 g、 18 lmmol)及四氧化餓（2_5wt%三級丁醇溶液、8.39g、 0.825mmol )，於室溫攪拌4小時。於反應液中加入硫代硫 酸鈉水溶液（26g、l〇〇mL )後，攪拌10分鐘，減壓餾除 有機溶媒。加入乙酸乙酯作提取並以無水硫酸鈉乾燥 後’減壓濃縮而獲得粗製之呈淡黃色非晶形之（2S ) -2-(2,3 -二羥基丙氧基）-2,3 -二氫- l’H-螺[茚-1，4’ -哌 啶]-1’ -甲酸三級丁酯69.58g。 -59- 201143771 將所獲得的粗製物溶解於四氫吱喃（4 〇 〇 m l )及水 (400mL )之混合溶媒，冰冷攪拌下，逐步少量添加過 碘酸鈉（ 52.87g、247mmol )。添加後’於室溫授拌i 5小 時。於反應溶液中加入水（400mL)並以乙酸乙酿（3〇〇、 1 50、1 OOmL )提取，合併有機層並以飽和食鹽水洗淨。 以無水硫酸鈉乾燥後，減壓濃縮，獲得粗製之呈無色非 晶形之標題目的化合物59.52g。 !H NMR (CDC13, 400MHz): δ 1.50 (9H, s), 1.62-1.85 (2H，m)，2.15-2.24 (1H，m)，2.92-4.25 (l〇H，m)， 7.19-7.26 (4H，m)，9.74 (1H，s). MS (FAB + ) m/z: 346 ((M + H) + ). IR (液態膜）：2976,293 1，1 686，1479，1428,1367,1239, 10 1 0,756 cm'1.[Example 6e] (2S)-2-(2-Sideoxyethoxy)-2,3-dihydro-1,H-spiro[茚-1,4 piperidine]-1, formic acid tert-butyl The ester of (2S)-2-(allyloxy)-2,3-dihydro-indole-spiro[茚-1,4'-piperidine]-indole-decanoic acid obtained in Example 6d The ester (57.15g) was dissolved in a mixed solvent of acetone (400 mL), tertiary butanol (200 mL) and water (200 mL), and N-methylmorpholine N-oxide (2 1.2 g, 18 was added under ice cooling). Lmmol) and tetraoxide (2_5 wt% tertiary butanol solution, 8.39 g, 0.825 mmol) were stirred at room temperature for 4 hours. After adding a sodium thiosulfate aqueous solution (26 g, 10 mL) to the reaction mixture, the mixture was stirred for 10 minutes, and the organic solvent was evaporated under reduced pressure. Ethyl acetate was added for extraction and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give (2S)-2-(2,3-dihydroxypropyloxy)-2,3 - Hydrogen-l'H-spiro[茚-1,4'-piperidinyl]-1'-carboxylic acid tert-butyl butyl ester 69.58 g. -59- 201143771 The obtained crude product was dissolved in a mixed solvent of tetrahydrofuran (4 〇 〇 m l ) and water (400 mL), and sodium iodate (52.87 g, 247 mmol) was gradually added thereto under ice-cooling stirring. After the addition, the mixture was stirred at room temperature for 5 hours. Water (400 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 EtOAc, EtOAc, EtOAc). After drying over anhydrous sodium sulfate, the residue was evaporated. !H NMR (CDC13, 400MHz): δ 1.50 (9H, s), 1.62-1.85 (2H, m), 2.15-2.24 (1H, m), 2.92-4.25 (l〇H,m), 7.19-7.26 ( 4H,m),9.74 (1H,s). MS (FAB + ) m/z: 346 ((M + H) + ). IR (liquid film): 2976,293 1,1 686,1479,1428,1367 ,1239, 10 1 0,756 cm'1.

[實施例6f] { [ ( 2S ) -1，-(三級丁氧基羰基）_2,3_二氫 螺[茚-M’-哌啶]-2-基]氧基}乙酸 將實施例6e獲得的粗製（2S ) -2- ( 2-側氧基乙氧基） -2，3 -二氫-1 ’ Η -螺[茚_ 1，4 ’ -娘啶]_ 1 ’ _甲酸三級丁酯5 9 5 2 g 溶解於四氫呋喃（200mL )及三級丁醇（4〇〇mL )之混合 溶媒’添加2-甲基-2-丁烯（87.3mL)。冰冷攪拌下，依 序添加填I 一虱納一水合物（ 64.27g、412mmol)水溶液 (100mL)及亞氯酸鈉（44.7g、494mmol )，水冷下攪拌 2 · 5小時。將反應液冰冷，逐滴添加4N氫氧化鈉水溶液 (20 6mL)。加入水（200mL)及乙酸乙酯（200mL)後， 過濾生成的白色沉澱’殘渣以水（l00mL )及乙酸乙酯 (1 OOmL )洗淨。將濾液冰冷’添加4N鹽酸（1 60mL ) -60- 201143771 作分液提取。有機層以飽和食鹽水洗淨，以無水硫酸鈉 乾燥後’減壓濃縮，獲得粗製之呈淡黃色非晶形之標題 目的化合物5 9.5 8 g。由二乙基醚及η-己烷之混合溶媒將 所獲得的粗製物再結晶，獲得呈白色固體之標題目的化 合物 5 0.6 4 g。 'H NMR (CD3OD5 400ΜΗζ): δ 1.48 (9Η, s), 1.52-1.64 (2H, m), 1.68-1.75 (1H, m), 2,12-2.20 (1H, m), 3.00 (1H, dd, J = 16.5, 3.0 Hz), 3.15 (1H, dd, J = 16.5, 5.4 Hz), 3.20-3.40 ( 1 H, m), 3.41-3.60 (1H, m), 3.86-3.99 (2H, m), 4.15-4.17 (2H, m), 4.32-4.37 (1H, m), 7.10-7.20 (4H, m). MS (FAB + ) m/z: 362 ((M + H) + ). IR (KBr): 2976, 2932, 1756, 1 690, 1 643, 1479, 1430, 1 366, 1279, 1 1 69, 1 1 1 9, 759 cm·1· [實施例6§]乙基[(28)-2,3-二氫螺[茚-1，4，-哌啶]-2-基 氧基]乙酸酯 與實施例6f所獲得的{[ ( 2S ) .1’-(三級丁氧基羰 基）-2,3 -二氫螺[茚-1，4，-哌啶]-2-基]氧基}乙酸 ( 28.20g、78.0mmol)之乙醇溶液（ 280mL)中，冰冷攪 拌下，逐滴添加亞硫酿氣（12.3mL、156mmol)，加熱回 流2小時》放冷後，減壓餾除反應液之乙醇。於所獲得的 黃色油狀物中添加乙酸乙酯後，以碳酸氫鈉水溶液洗 淨。分離有機層後，於水層中加入乙酸乙酯作提取。合 併有機層並以無水硫酸鎂乾燥後，減壓餾除溶媒。於所 獲得的殘留物中加入甲苯而溶解後，減壓餾除溶媒，獲 得粗製之呈淡黃色油狀物之標題目的化合物32.1 g。 201143771 MS (FAB + ) m/z: 290 ((M + H) + ).[Example 6f] { [( 2S ) -1,-(tertiary butoxycarbonyl)-2,3-dihydrospiro[indo-M'-piperidinyl]-2-yl]oxy}acetic acid Example 6e obtained crude (2S)-2-(2-sided ethoxyethoxy)-2,3-dihydro-1 ' Η-spiro[茚_ 1,4 '-Nantidyl]_ 1 ' _carboxylic acid Butyl methoxide 5 9 5 2 g A mixed solvent dissolved in tetrahydrofuran (200 mL) and tertiary butanol (4 〇〇 mL) was added 2-methyl-2-butene (87.3 mL). Under ice-cooling, an aqueous solution of I-sodium monohydrate (64.27 g, 412 mmol) (100 mL) and sodium chlorite (44.7 g, 494 mmol) were added, and the mixture was stirred under water cooling for 2.5 hours. The reaction solution was ice-cooled, and a 4N aqueous sodium hydroxide solution (20 6 mL) was added dropwise. After adding water (200 mL) and ethyl acetate (200 mL), the resulting white solid residue was washed with water (100 mL) and ethyl acetate (100 mL). The filtrate was ice-cooled and 4N hydrochloric acid (1 60 mL) -60 - 201143771 was added for liquid separation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The obtained crude product was recrystallized from a mixed solvent of diethyl ether and hexanes to afford the title compound 50.6 4 g. 'H NMR (CD3OD5 400ΜΗζ): δ 1.48 (9Η, s), 1.52-1.64 (2H, m), 1.68-1.75 (1H, m), 2,12-2.20 (1H, m), 3.00 (1H, dd , J = 16.5, 3.0 Hz), 3.15 (1H, dd, J = 16.5, 5.4 Hz), 3.20-3.40 ( 1 H, m), 3.41-3.60 (1H, m), 3.86-3.99 (2H, m) , 4.15-4.17 (2H, m), 4.32-4.37 (1H, m), 7.10-7.20 (4H, m). MS (FAB + ) m/z: 362 ((M + H) + ). IR (KBr ): 2976, 2932, 1756, 1 690, 1 643, 1479, 1430, 1 366, 1279, 1 1 69, 1 1 1 9, 759 cm·1· [Example 6 §] Ethyl [(28)- 2,3-Dihydrospiro[茚-1,4,-piperidinyl]-2-yloxy]acetate and {[(2S).1'-(tri-butoxy) obtained in Example 6f a solution of carbonyl)-2,3-dihydrospiro[茚-1,4,-piperidinyl]-2-yl]oxy}acetic acid (28.20 g, 78.0 mmol) in ethanol (280 mL) Thionite gas (12.3 mL, 156 mmol) was added dropwise, and the mixture was heated under reflux for 2 hours. After cooling, the ethanol in the reaction mixture was evaporated under reduced pressure. Ethyl acetate was added to the obtained yellow oil, and then washed with aqueous sodium hydrogen carbonate. After separating the organic layer, ethyl acetate was added to the aqueous layer for extraction. The organic layer was combined and dried over anhydrous magnesium sulfate and evaporated. After the toluene was added to the obtained residue and dissolved, the solvent was evaporated under reduced pressure to give 32.1 g of the title compound as a pale yellow oil. 201143771 MS (FAB + ) m/z: 290 ((M + H) + ).

[實施例 6h]{ [ ( 2S ) -Γ- { 2-[ ( 5R) -3-[3,5-雙（三氟曱 基）本甲酿基]-5- (4 -說苯基）唾σ定-5_基]乙基} -2,3-二氫螺[茚-丨〆’-哌啶]-2-基]氧基}乙酸乙酯 於實施例6g獲得的粗製[(2S) -2,3-二氮螺[茚-M，-派咬]-2-基氧基]乙酸乙酯（32.1g)及實施例6(：所獲得的 化合物（37.6g、70.9mmol )之乙腈溶液（i6〇mL)中’ 室溫攪拌下’添加碳酸氫鈉（7.1 5g、8 5.11 mmol)，氮氣 環境下，攪拌回流1 4小時。將反應液放冷至室溫後，減 壓德除有機溶媒。於所獲得的殘渣中添加碳酸氫鈉水溶 液，以乙酸乙酯提取。合併有機層並以無水硫酸鎂乾燥， 減壓館除溶媒。所獲得的殘渣使用矽膠層析純化（己烷： 乙酸乙酯=2 : 1 _〇/1 )，獲得呈白色固體之標題目的化 合物47.8g (產率93% )。 MS (APCI) m/z: 723 ((M + H) + ).[Example 6h] { [( 2S ) -Γ- { 2-[ ( 5R) -3-[3,5-bis(trifluoromethyl)benyl]-5- (4-phenyl)唾 定 -5 -5 - yl] ethyl} -2,3-dihydrospiro[茚-丨〆'-piperidinyl]-2-yl]oxy} ethyl acetate obtained in Example 6g of crude [[2S -2,3-diazaspiro[茚-M,-pyro]-2-yloxy]acetate (32.1 g) and Example 6 (: compound obtained (37.6 g, 70.9 mmol) Add sodium bicarbonate (7.1 5g, 8 5.11 mmol) in acetonitrile solution (i6〇mL) under stirring at room temperature, and stir under reflux for 14 hours under nitrogen atmosphere. After cooling the reaction solution to room temperature, decompression The organic solvent was added to the obtained residue, and aqueous sodium hydrogencarbonate was added to ethyl acetate. The organic layer was combined and dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. : (ethyl acetate = 2: 1 _ 〇 / 1 ), obtained titled compound (yield: 93%) as a white solid. MS (APCI) m/z: 723 ((M + H) + ).

[實施例 6i]{[(2S) -1，-{M(5R) _3_[3,5•雙（三氟曱 基）笨曱醯基]-5-(4-氟苯基）-u-嘮唑啶_5_基]乙基） _2,3-二氫螺[茚·ι，4’_哌啶基]氧基}乙酸 於實施例6h所獲得的化合物（34.1g、47_lmm〇1 )之 曱醇/容液（340mL)中，冰冷授拌下，逐滴加入1N氫氧 化鈉水溶液（71mL、71mm〇l)，於室溫攪拌2小時。冰冷 授掉下，添加1N鹽酸（71mL，71mm〇l)加以中和後， 減壓餾除曱醇。於殘留物中添加水後，以乙酸乙酯提取， 以無水硫酸鎂乾燥。減壓餾除溶媒，將所獲得的殘渣溶 解於乙酸乙酯後，以賽利特矽藻土過濾。減壓餾除濾液， 獲得呈白色非晶形之標題目的化合物32 6g(產率Μ% )。 -62- 201143771 *H NMR (CD3OD, 400MHz): δ 1.70-2.08(3H5 m)5 2.25-2.65(3H, m), 2.82-3.03 (2H, m), 3.1 0-3.62(5H, m)5 3.85-4.21(5H, m), 4.25-4.40(1 H, m), 5.04-5.50(2H, m), 7.05-7.25(6H, m), 7.40-7.62(2H, m);( 7.9 7 - 8.20 (3 H, m), MS (FAB + ) m/z: 695 ((M + H) + ). IR (KBr): 2935, 1 65 1, 1 605, 1 5 1 1, 1432, 1 360, 128 1, 1 179, 1 138, 907, 682 cm'1.[Example 6i] {[(2S) -1, -{M(5R) _3_[3,5• bis(trifluoromethyl) adenyl]-5-(4-fluorophenyl)-u- The compound obtained in Example 6h (34.1 g, 47-lmm〇1) of oxazolidine-5-yl]ethyl) _2,3-dihydrospiro[茚·ι,4′-piperidinyl]oxy}acetic acid The sterol/liquid (340 mL) was stirred under ice-cooling, and a 1N aqueous sodium hydroxide solution (71 mL, 71 mm) was added dropwise, and the mixture was stirred at room temperature for 2 hours. After ice-cold was added, 1N hydrochloric acid (71 mL, 71 mm 〇l) was added and neutralized, and decyl alcohol was distilled off under reduced pressure. After adding water to the residue, it was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in ethyl acetate and filtered over Celite. The filtrate was evaporated under reduced pressure to give the title compound (yield: 5%). -62- 201143771 *H NMR (CD3OD, 400MHz): δ 1.70-2.08(3H5 m)5 2.25-2.65(3H, m), 2.82-3.03 (2H, m), 3.1 0-3.62(5H, m)5 3.85-4.21(5H, m), 4.25-4.40(1 H, m), 5.04-5.50(2H, m), 7.05-7.25(6H, m), 7.40-7.62(2H, m); (7.9 7 - 8.20 (3 H, m), MS (FAB + ) m/z: 695 ((M + H) + ). IR (KBr): 2935, 1 65 1, 1 605, 1 5 1 1, 1432, 1 360 , 128 1, 1 179, 1 138, 907, 682 cm'1.

[實施例6j] 4-[ ( 3- U (苄基氧基）羰基]胺基}丙基） 胺曱醯基]哌啶-1 -曱酸三級丁酯 將1-(三級丁氧基裁基）旅咬.-4-曱酸（ 200mg， 0.872mmol )及（3-胺基丙基）胺基曱酸苄基酯鹽酸鹽 (213mg ’ 0.872mmol)溶解於二氣曱烷（2mL)，添加 三乙基胺（〇.145mL’ 1.05mmol)及 WSC · HC1( 201mg， 1.0 5mmol ) ’於室溫攪拌4日。於反應液中添加水，以乙 酸乙酯提取後，有機層以飽和食鹽水洗淨。以無水硫酸 鈉乾燥後，減壓下，镏除溶劑所獲得的殘渣使用石夕膝管 柱層析純化（己烧：乙酸乙酯=1 : 2)，獲得呈無色油 狀物之標題目的化合物（182mg，產率50%)。 MS (APCI) m/z: 320(M + H)+ :(脱 B0C體）. IR(KBr) vmax 2932, 1649, 153 1.. 1424, 1247, 1162 1 129，1026, 736, 696 cm·1.[Example 6j] 4-[(3-U(benzyloxy)carbonyl]amino}propyl)aminoindolyl]piperidine-1-decanoic acid tert-butyl butyl 1-(tri-butoxy) Baseline) BTS. 4-decanoic acid (200mg, 0.872mmol) and (3-aminopropyl)aminobenzyl phthalate hydrochloride (213mg '0.872mmol) are dissolved in dioxane ( 2 mL), triethylamine (〇.145 mL '1.05 mmol) and WSC · HC1 (201 mg, 1.0 5 mmol) were added and stirred at room temperature for 4 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine. After drying over anhydrous sodium sulfate, the residue obtained by the solvent was purified under reduced pressure. (182 mg, yield 50%). MS (APCI) m/z: 320(M + H)+ : (de-B0C). IR(KBr) vmax 2932, 1649, 153 1.. 1424, 1247, 1162 1 129,1026, 736, 696 cm· 1.

[實施例6 k ] 4 - [ (3 -胺基丙基）胺甲醢基]娘n定_ 1 _曱酸三級 丁酯 於10%纪-碳（乾燥’ 18mg)中，添加實施例6j所獲 得的化合物（182mg，0.434mmol)之曱醇溶液（4 5mL) 201143771 系統内置換為氫氣環境後，於室溫攪拌2小時。系統内置 換為氮氣環境後’使用賽利特矽藻土將反應液過濾。減 壓下，餾除溶劑所獲得的殘渣以四氫呋喃（χ2)共沸， 獲付呈白色固體之標題目的化合物（12〇mg，農率97 % )。 'H NMR (CDC13, 500ΜΗζ)： δ 1.46 (9Η, m), 1.59-1.65 (5H, m), 1.80- 1.84 (3H, m), 2.17-2.24 (1H, m), 2.71-2.77 (2H, m), 2.81-2.84 (2H, m), 3.37 (2H, q, J = 6.3 Hz)s 4.10-4.18 (2H, m), 6.71 (1H, brs). MS (FAB) m/z: 286(M + H) + .[Example 6 k ] 4 - [(3 -Aminopropyl)amine-carbyl]N-butyl butyl decanoate in 10%-carbon (dried '18 mg), addition example A solution of the compound (182 mg, 0.434 mmol) obtained in 6j (4 5 mL) was replaced with a hydrogen atmosphere in the system. After the system is replaced with a nitrogen atmosphere, the reaction solution is filtered using Celite. The residue obtained by distilling off the solvent was azeotroped with tetrahydrofuran (χ2), and the title compound (12 〇mg, 97%) was obtained as a white solid. 'H NMR (CDC13, 500ΜΗζ): δ 1.46 (9Η, m), 1.59-1.65 (5H, m), 1.80- 1.84 (3H, m), 2.17-2.24 (1H, m), 2.71-2.77 (2H, m), 2.81-2.84 (2H, m), 3.37 (2H, q, J = 6.3 Hz)s 4.10-4.18 (2H, m), 6.71 (1H, brs). MS (FAB) m/z: 286 ( M + H) + .

[實施例 6L] 4 - ( { 3-[ ( { [ ( 2S ) - l，- { 2-[ ( 5R ) -3 - { [3,5- 雙（二氟甲基）苯基]幾基} -5-(4_氟苯基）_1，3_今唾。定 -5 -基]乙基} - 2，3 -二氫螺[茚-1，4，-哌啶卜2 -基]氧基丨乙醯 基）胺基]丙基}胺曱醯基）哌啶-1 _甲酸三級丁酯 將實施例6i所獲得的化合物（i53mg，0.221mmol ) 溶解於二氣曱烷（2mL)，冰冷下，添加三乙基胺（35μί， 0.2 5 2mmol )及三甲基乙醯基氣（27μί，0_219mmol )， 於室溫攪拌2 5分鐘。於反應液中，冰冷下，添加實施例 6k所獲得的化合物（60mg，0.210mmol)之二氣曱烧溶 液（2mL)’於室溫攪拌16小時。減壓下，餾除溶劑所 獲得的殘渣使用NH矽膠管柱層析純化（乙酸乙酯：甲 醇=50 : 1 )，獲得呈白色固體之標題目的化合物 (175mg，產率 87% )。 MS (APCI) m/z: 962(M + H) + . IR(KBr) vmax 293 1，1659，1 533，1430，1360，1281， 1174，1 1 38, 848, 758 cm·1· -64- 201143771 [實施例 6m]N- { 3-[ ( { [ ( 2S) _1M 2_[ ( 5R) _3_ { [3,5_ 雙（二氟甲基）苯基]羰基} -5-(4 -氟苯基）-i，3-«f唑啶 -5-基]乙基} _2,3-二氫螺[茚_；ι，4，-哌啶]_2_基]氧基丨乙醯 基）胺基]丙基}派啶-4-羧醯胺 於實施例6L所獲得的化合物（]75mg，〇182rnmol) 中添加2N鹽酸-曱醇（l.82mL，3.64mmol)，於室溫授拌 3小時。於反應液中添加1 n氫氧化鈉水溶液，以乙酸乙酯 提取後’有機層以飽和食鹽水洗淨。以無水硫酸鈉乾燥 後’減壓下’餾除溶劑所獲得的殘渣使用NH矽膠管柱層 析純化（乙酸乙酯：甲醇=20 : 1 -二氣曱烧：曱醇=1 〇 : 1)，獲得呈白色固體之標題目的化合物（147mg，產率 94% ) 〇 MS (APCI) m/z: 842(M + H) + . IR(KBr) vmax 293 1, 1 738, 1654, 1 534, 1439, 1 359, 1281, 1181，1 139, 682 cnT1.[Example 6L] 4 - ( { 3-[ ( { [ ( 2S ) - l, - { 2-[ ( 5R ) -3 - { [3,5-bis(difluoromethyl)phenyl]) } -5-(4_fluorophenyl)_1,3_this saliva. Ding-5-yl]ethyl}-2,3-dihydrospiro[茚-1,4,-piperidin-2-yl] The compound obtained in Example 6i (i53 mg, 0.221 mmol) was dissolved in dioxane (2 mL), m.p. Under ice cooling, triethylamine (35 μί, 0.252 mmol) and trimethylacetonitrile gas (27 μί, 0-219 mmol) were added and stirred at room temperature for 25 minutes. In the reaction mixture, a solution of the compound obtained in Example 6k (60 mg, 0.210 mmol. The residue obtained by distilling the solvent under reduced pressure was purified eluting eluting elut elut elut elut elut eluting MS (APCI) m/z: 962 (M + H) + . IR (KBr) vmax 293 1,1659,1 533,1430,1360,1281, 1174,1 1 38, 848, 758 cm·1· -64 - 201143771 [Example 6m] N- { 3-[ ( { [ 2S) _1M 2_[ ( 5R) _3_ { [3,5_bis(difluoromethyl)phenyl]carbonyl} -5-(4-fluoro Phenyl)-i,3-«foxazol-5-yl]ethyl} _2,3-dihydrospiro[茚_;ι,4,-piperidine]_2-yl]oxyindolyl) Amino]propyl}pyridin-4-carboxyguanamine A 2N hydrochloric acid-decyl alcohol (1.82 mL, 3.64 mmol) was added to the compound obtained in Example 6L (75 mg, 〇 182 rnmol), and stirred at room temperature. 3 hours. After adding 1 n aqueous sodium hydroxide solution to the reaction mixture and extracting with ethyl acetate, the organic layer was washed with saturated brine. The residue obtained by distilling off the solvent under reduced pressure of anhydrous sodium sulfate and then evaporated under reduced pressure was purified by column chromatography using EtOAc (ethyl acetate:methanol = 20:1 - two gas: decyl alcohol = 1 〇: 1) The title compound was obtained as a white solid (147 mg, yield: 94%) 〇MS (APCI) m/z: 842 (M + H) + . IR (KBr) vmax 293 1, 1 738, 1654, 1 534, 1439, 1 359, 1281, 1181, 1 139, 682 cnT1.

[實施例6n] ( 3R)-吡咯啶-3-基羥基（二噻吩-2-基）乙 酸酯 4-曱基苯磺酸鹽 將實施例lh所獲得的（3R) -3- {[羥基（二噻吩-2-基）乙醯基]氧基} 0比咯啶-1-曱酸三級丁酯（150mg， 0.367mmol)溶解於四氫0夫喃（4mL)，添加p -甲苯續酸 • 1水合物（126mg，0.733mmol)，於 50°C 攪拌 15小時。 再於反應液中添加P-曱苯磺酸· 1水合物（63mg， 0.3 67mmol)，於50°C攪拌5小時。自系統中過濾沉澱的白 色固體，獲得呈白色固體之標題目的化合物（149mg， 產率84% )。 -65- 201143771 Ή NMR (CDC13j 500MHz): δ 2.13-2.21 (2H, m), 2.38 (3H, s), 3.30-3.36 (2H, m), 3.44-3.49 (2H, m), 3.53-3.59 (1H, m), 5.46-5.48 (1H, m), 6.87-6.90 (2H, m), 7.12-7.15 (2H, m), 7.18 (2H, d, J = 8.0 Hz), 7.20-7.22 (2H, m), 7.67 (2H, d, J = 8.0 Hz). MS (FAB + ) m/z: 309(M + H)+ ((3R)-n比 p各咬-3 基經 基（二噻吩-2-基）乙酸酯） MS (FAB-) m/z: 171(M-H)_ (4 -曱基苯石黃酸）.[Example 6n] (3R)-pyrrolidin-3-ylhydroxy (dithien-2-yl)acetate 4-mercaptobenzenesulfonate The (3R)-3-{[ obtained in Example lh] Hydroxy(dithiophen-2-yl)ethenyl]oxy} 0 is dissolved in tetrahydrofuran (4 mL) with triethyl bromo-1-pyrucylate (150 mg, 0.367 mmol), and p-toluene is added. The acid hydrate 1 hydrate (126 mg, 0.733 mmol) was stirred at 50 ° C for 15 hours. Further, P-toluenesulfonic acid·1 hydrate (63 mg, 0.367 mmol) was added to the reaction mixture, and the mixture was stirred at 50 ° C for 5 hours. The precipitated white solid was filtered from EtOAc (EtOAc: EtOAc Compound: -65- 201143771 Ή NMR (CDC13j 500MHz): δ 2.13-2.21 (2H, m), 2.38 (3H, s), 3.30-3.36 (2H, m), 3.44-3.49 (2H, m), 3.53-3.59 ( 1H, m), 5.46-5.48 (1H, m), 6.87-6.90 (2H, m), 7.12-7.15 (2H, m), 7.18 (2H, d, J = 8.0 Hz), 7.20-7.22 (2H, m), 7.67 (2H, d, J = 8.0 Hz). MS (FAB + ) m/z: 309(M + H)+ ((3R)-n ratio p each bite-3 base group (dithiophene- 2-based) acetate) MS (FAB-) m/z: 171 (MH) _ (4-mercaptophthalic acid).

[實施例6〇] ( 3R) -1- { 2-[(三級丁氧基羰基）（曱基） 胺基]乙基} °比洛咬-3 -基經基（二°塞吩-2 -基）乙酸酯 將實施例6n所獲得的（3R)-吡咯啶-3-基羥基（二 噻吩-2-基）乙酸酯4 -曱基苯磺酸鹽（728mg，1.5 lmmol ) 溶解於二氣甲烷（15 mL) ’添加三乙基胺（0.231 mL， 1.66mmol)、曱基（2-側氧基乙基）胺基曱酸三級丁酯 ( 288mg，1.66mmol)、氫化三乙醯氧基硼鈉（48〇mg， 2.27mmol)、及乙酸（ 0.265mL)，於室溫攪拌17小時。 於反應液中添加飽和碳酸氫納水，以乙酸乙酯（χ 3 )提 取後’有機層以飽和食鹽水洗淨。以無水硫酸鈉乾燥後， 減壓下，餾除溶劑所獲得的殘渣使用ΝΗ矽膠管柱層析純 化（己烷：乙酸乙酯=；!:丨），獲得呈淡黃色油狀物之 標題目的化合物（706 mg，產率100%)。 Ή NMR (CDC13, 500MHz): δ 1.45 (9Η, m), 1.84-1.89 (1Η, m), 2.17-2.26 (1H, m), 2.49-2.54 (1H, m), 2.56-2.59 (2H, m), 2.65-2.70 (1H, m), 2.75-2.79 (1H, m), 2.86-2.92 (4H, m), 3.24-3.35 (1H, m), 4.79-4.85 (1H, m), 5.30-5.53 -66 - 201143771 (1H, m), 6.96-6.99 (2H, m), 7.17-7.20 (2H, m), 7.27-7.28 (2H, m). MS (FAB) m/z: 467(M + H) + .[Example 6 〇] ( 3R) -1- { 2-[(tertiary butoxycarbonyl)(fluorenyl)amino]ethyl} ° piroxime-3 -yl thiol (di- thiophene - (3-R)acetate (3R)-pyrrolidin-3-ylhydroxy (dithien-2-yl)acetate 4-mercaptobenzenesulfonate (728 mg, 1.5 lmmol) obtained in Example 6n Dissolved in di-hydrogen methane (15 mL) 'Addition of triethylamine (0.231 mL, 1.66 mmol), decyl (2-o-oxyethyl)amino decanoic acid tert-butyl ester (288 mg, 1.66 mmol), hydrogenation Sodium triethoxyborohydride (48 mg, 2.27 mmol) and acetic acid (0.265 mL) were stirred at room temperature for 17 h. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate (?3). After drying over anhydrous sodium sulfate, the residue obtained by distilling the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate=;!: 丨) to give a pale yellow oil. Compound (706 mg, yield 100%). NMR NMR (CDC13, 500MHz): δ 1.45 (9Η, m), 1.84-1.89 (1Η, m), 2.17-2.26 (1H, m), 2.49-2.54 (1H, m), 2.56-2.59 (2H, m ), 2.65-2.70 (1H, m), 2.75-2.79 (1H, m), 2.86-2.92 (4H, m), 3.24-3.35 (1H, m), 4.79-4.85 (1H, m), 5.30-5.53 -66 - 201143771 (1H, m), 6.96-6.99 (2H, m), 7.17-7.20 (2H, m), 7.27-7.28 (2H, m). MS (FAB) m/z: 467 (M + H ) + .

[實施例6p]( 3 R ) -1 - [2 -(曱基胺基）乙基]°比洛咬-3 -基羥 基（二噻吩-2-基）乙酸酯 將實施例6〇所獲得的（3R) -1- { 2-[(三級丁氧基羰 基）（甲基）胺基]乙基} °比**各咬-3 -基經基（二β塞吩-2 -基）乙酸酯（706mg，1.51mmol)溶解於四氫吱喃（i5mL)， 添加p-甲苯確酸一水合物（863mg，4_54mmol )，於50°C 攪拌1 5小時。於反應液中添加飽和碳酸氫鈉水，以二氯 曱烷（X 3 )提取後，有機層以無水硫酸鈉乾燥。減壓下， 餾除溶劑所獲得的殘渣使用NH矽膠管柱層析純化（乙酸 乙酯：甲醇=1 0 : 1 )，獲得呈褐色油狀物之標題目的化 合物（479mg，產率87%)。 MS (APCI) m/z: 367(M + H) + . IR(ATR) Vmax 2795，1732，1435，1224，1141，1〇89, 1041，849，789, 698 cm·1· [實施例6q] ( 3R) ]_ { 2_[ ( 6_溴己醯基）（曱基）胺基] 乙基} °比η各。定-3-基羥基（二噻吩-2-基）乙酸酯 將實施例6Ρ所獲得的（3R)-l-[2-(甲基胺基）乙基] 。比嘻。定-3-基經基（二噻吩-2-基）乙酸酯（67mg， 0.182mmol)溶解於乙酸乙酯（2mL)，冰冷下，添加三 乙基胺（30μΕ ’ 0.218mmol )及6-漠己醯基氯（29μί， 0.1 9 lmmol) ’於室溫攪拌i小時。不溶物以賽利特矽藻土 過遽’減麼下’顧除溶劑而獲得呈淡黃色油狀物之標題 目的化合物（99mg ’產率100% )。 -67- 201143771 MS (APCI) m/z: 543(M + H) + .[Example 6p] ( 3 R ) -1 - [2 -(decylamino)ethyl] ° piroxime-3-ylhydroxy (dithien-2-yl)acetate Example 6 Obtained (3R)-1-{2-[(tertiary butoxycarbonyl)(methyl)amino]ethyl} ° ratio ** each bite-3-yl-based (di-β-beta-2) Acetate (706 mg, 1.51 mmol) was dissolved in tetrahydrofuran (i5 mL), and p-toluene acid monohydrate (863 mg, 4 - 54 mmol) was added and stirred at 50 ° C for 15 hours. Saturated sodium hydrogencarbonate water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The residue obtained by the solvent was evaporated to dryness crystals eluted eluted elut elut elut elut elut elut elut elut elut elut elut . MS (APCI) m/z: 367 (M + H) + . IR (ATR) Vmax 2795,1732,1435,1224,1141,1〇89, 1041,849,789, 698 cm·1· [Example 6q ] ( 3R) ]_ { 2_[ ( 6 —Bromohexyl)(fluorenyl)amino] Ethyl} ° ratio η. Ding-3-ylhydroxy (dithien-2-yl)acetate (3R)-l-[2-(methylamino)ethyl] obtained in Example 6A. Than. Dilute-3-yltransyl (dithiophen-2-yl)acetate (67 mg, 0.182 mmol) was dissolved in ethyl acetate (2 mL), EtOAc (EtOAc) The mixture was stirred at room temperature for 1 hour. The insoluble material was obtained from the title compound (99 mg y yield 100%) of the title compound as a pale yellow oil. -67- 201143771 MS (APCI) m/z: 543 (M + H) + .

[實施例 6r] ( 3R) -1- { 2-[ { 6-[4- ( { 3-[ ( { [ ( 2S ) -1 ,-ί 2-[ ( 5R) -3- { [3,5-雙 （三氟 曱基） 苯基]羰基 } -5- ( 4-氟苯基）-1，3-嘮唑啶-5-基]乙基} -2,3-二氫螺[茚-1，4’-哌啶]-2·基]氧基}乙醯基）胺基]丙基}胺曱醯基）哌啶 -1 -基]己醯基}(甲基）胺基]乙基} °比咯啶-3 -基羥基 (二噻吩-2-基）乙酸酯 將實施例6q所獲得的化合物（99mg，0.182mmol) 溶解於乙腈（2mL )，添加實施例6m所獲得的化合物 (147mg，0.171mmol)、碳酸氫納（23mg，0.267mmol)、 及碘化鉀（43mg，0.267mmol)，於50°C攪拌45.5小時。 反應液以乙酸乙酯稀釋，添加水後，以乙酸乙酯（X 3 ) 提取。有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥後， 減壓下，餾除溶劑所獲得的殘渣使用NH矽膠管柱層析純 化（乙酸乙酯：甲醇= 50: 1-15: 1)。再使用逆相分取 管柱層析純化（Waters，MS C18 OBD，5μηι，30x100mm) (乙腈：0.1 %曱酸銨水溶液=60 : 40 )，獲得呈白色固 體之標題目的化合物（56mg，產率25%)。 MS (FAB) m/z: 1324(M + H) + . IR(KBr) vmax 2932，1 73 8，1 649，1 533，1438，1 359, 1281，1 180，1 139, 706 crrT1.[Example 6r] ( 3R) -1- { 2-[ { 6-[4- ( { 3-[ ( { [ ( 2S ) -1 , -ί 2-[ ( 5R) -3- { [3, 5-bis(trifluoromethyl)phenyl]carbonyl} -5-(4-fluorophenyl)-1,3-oxazolidin-5-yl]ethyl}-2,3-dihydrospiro[茚-1,4'-piperidine]-2-yl]oxy}ethenyl)amino]propyl}aminoindenyl)piperidine-1-yl]hexyl}}(methyl)amino] Ethyl} °-r-pyridin-3-ylhydroxy (dithien-2-yl)acetate The compound obtained in Example 6q (99 mg, 0.182 mmol) was dissolved in acetonitrile (2 mL). The compound (147 mg, 0.171 mmol), sodium hydrogencarbonate (23 mg, 0.267 mmol), and potassium iodide (43 mg, 0.267 mmol) were stirred at 50 ° C for 45.5 hours. The reaction mixture was diluted with ethyl acetate. Water was added and then ethyl acetate (?? The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and evaporated. . Purification by reverse phase column chromatography (Waters, MS C18 OBD, EtOAc, EtOAc, EtOAc (EtOAc) 25%). MS (FAB) m/z: 1324 (M + H) + . IR (KBr) vmax 2932,1 73 8,1 649,1 533,1438,1 359, 1281,1 180,1 139, 706 crrT1.

[實施例7] N-( 2-{ [2-( 4-{ 2-[( 3S) -3-( 2-胺基-2-側氧基-1，1-二苯基乙基）。比咯啶-1-基]乙基}苯基）乙基](甲基） 胺基}乙基）-2-{[(2S) -l，-{2-[(5R) -3-{[3,5-雙 -68- 201143771 (三氟曱基）苯基]羰基} -5-( 4-氟苯基）-1，3-嘮唑啶-5- 基]乙基} -2,3-二氫螺[茚-1，4’-哌啶]-2-基]氧基} 基乙酿胺[Example 7] N-(2-{[2-(4-{2-[(3S)-3-(2-amino-2-yloxy-1,1-diphenylethyl)). Bilobidine-1-yl]ethyl}phenyl)ethyl](methyl)amino}ethyl)-2-{[(2S) -l,-{2-[(5R) -3-{ [3,5-bis-68- 201143771 (trifluoromethyl)phenyl]carbonyl} -5-(4-fluorophenyl)-1,3-oxazolidin-5-yl]ethyl} -2, 3-Dihydrospiro[茚-1,4'-piperidinyl]-2-yl]oxy}yl ethanoamine

-N-甲 [實施例7a]2-[ ( 3S ) -1- ( 2- { 4-[2-(曱基胺基）乙基] 苯基}乙基）吡咯啶-3-基]-2,2-二苯基乙醯胺鹽酸鹽 於文獻（US2005/20 3167A1)記載的 2-{(3S)-l-[2-(4-{2-[苄基（曱基）胺基]乙基}苯基）乙基]。比咯啶 -3-基}-2,2-二苯基乙醯胺（1.118，2.09111111〇1)及20% 氫氧化i巴（1 〇〇mg )之乙醇懸浮液（21 mL )中添加4N 鹽酸-二今烧（1.30mL，5.22mmol)，將系統内置換為氫 氣環境後，於50°C攪拌1小時。將系統内置換為氮氣環 境後，使用賽利特矽藻土過濾反應液。減壓下，餾除溶 劑而獲得呈白色固體之標題目的化合物（1 · 1 2g，產率1 〇〇 % )。 MS (FAB) m/z: 599(M + H) + . IR(KBr) vmax 2930，2795，169 1: 1446，1391，1 365, 1155，1046, 754, 702 cm'1.-N-A [Example 7a] 2-[( 3S ) -1-( 2- { 4-[2-(decylamino)ethyl]phenyl}ethyl)pyrrolidin-3-yl]- 2,2-Diphenylacetamidine hydrochloride 2-{(3S)-l-[2-(4-{2-[benzyl(indenyl))amine group described in the literature (US2005/20 3167A1) ]ethyl}phenyl)ethyl]. Add 4N to an ethanol suspension (21 mL) of bromidin-3-yl}-2,2-diphenylacetamide (1.118, 2.09111111〇1) and 20% iodine (1 〇〇mg) Hydrochloric acid-dijinchao (1.30 mL, 5.22 mmol) was replaced with a hydrogen atmosphere, and then stirred at 50 ° C for 1 hour. After replacing the system with a nitrogen atmosphere, the reaction solution was filtered using Celite. The title compound (1 · 1 2 g, yield 1%) was obtained as a white solid. MS (FAB) m/z: 599 (M + H) + . IR (KBr) vmax 2930,2795,169 1: 1446,1391,1 365, 1155,1046, 754, 702 cm'1.

[實施例 7b] ( 2- { [2- ( 4- { 2-[ ( 3S ) -3- ( 2-胺基-2-側氧 基-1，1-二笨基乙基）吡咯啶-1-基]乙基}苯基）乙基](曱 基）胺基}乙基）甲基胺基甲酸三級丁酯 -69- 201143771 將實施例7 a所獲得的2 - [ ( 3 S ) -1 - ( 2 - { 4 - [ 2 -(曱基 胺基）乙基]苯基}乙基）°比°各咬基]-2,2 -二笨基乙醯 胺鹽酸鹽（300mg，0_680mmol )溶解於1，2-二氣乙烧 (7mL)，添加三乙基胺（ 0.284mL，2.04mmol)、曱基 (2-側氧基乙基）胺基甲酸三級丁酯（I77mg， 1.02mmol)、及氫化三乙驢氧基硼鈉 （2l6mg， 1.0 2 m m ο 1 )，於室溫攪拌5 5小時。於反應液中添加飽和 碳酸氫鈉水’以二氣曱烷-曱醇（3 : 1，X 3 )提取後，以 無水硫酸納乾燥。減壓下，館除溶劑所獲得的殘渣使用 NH矽膠管柱層析純化（己烷：乙酸乙酯=1 : 2 -乙酸乙 醋：甲醇=20 : 1 )，獲得呈白色固體之標題目的化合物 (307mg，產率 75% )。 MS (FAB) m/z: 599(M + H) + . IR(KBr) vmax 2930，2795，1691，1446，1391，1 365, 1 1 55, 1046, 754, 702 cm'1.[Example 7b] (2-{ [2-(4-{2-[(3S)-3-(2-amino-2-yloxy-1,1-diphenylethyl)pyrrolidine- 3-yl]ethyl}phenyl)ethyl](fluorenyl)amino}ethyl)methylaminocarbamic acid tert-butyl butyl ester-69- 201143771 2 - [ ( 3 S obtained in Example 7 a) ) -1 - ( 2 - { 4 - [ 2 -(decylamino)ethyl]phenyl}ethyl) °°°bite]-2,2-di-p-acetylacetamide hydrochloride ( 300 mg, 0-680 mmol) was dissolved in 1,2-diethylene b (7 mL), and triethylamine (0.284 mL, 2.04 mmol), decyl (2-o-oxyethyl) carbamic acid tert-butyl butyl ester ( I77 mg, 1.02 mmol), and sodium triethoxysulfonium hydride (2l6 mg, 1.0 2 mm ο 1 ) were stirred at room temperature for 5 hr. Saturated sodium hydrogencarbonate water was added to the reaction mixture, and extracted with dioxane-nonanol (3:1, X3), and then dried over anhydrous sodium sulfate. The residue obtained by solvent removal under reduced pressure was purified by column chromatography eluting with EtOAc (hexane: ethyl acetate = hexanes: ethyl acetate:methanol = 20:1) (307 mg, yield 75%). MS (FAB) m/z: 599 (M + H) + . IR (KBr) vmax 2930,2795,1691,1446,1391,1 365, 1 1 55, 1046, 754, 702 cm'1.

[實施例 7c]2-[ ( 3S ) -1- { 2-[4- ( 2- {甲基[2-(曱基胺基） 乙基]胺基}乙基）苯基]乙基丨n比咯啶_3•基]_2,2_二苯基 乙醯胺 於實施例7b所獲得的化合物（296mg，〇.494mmol) 之甲醇洛液（2mL )中添加4N鹽酸-二嘮烷（j 24mL ’ 4.94mmol )，於室溫攪拌！小時再於4〇&lt;&gt;c攪拌i小時。 於反應液中添加飽和碳酸氫鈉水後，以二氯甲烷-甲醇 (4 . 1 ’ X 3 )提取’以無水硫酸鈉乾燥。減壓下，餾除 ，劑所獲得的殘渣使用NH矽膠管柱層析純化（乙酸乙 Ss .甲醇=100: 10 : 1)，獲得呈黃色固體之標題目 的化合物（240mg，產率97% )。 -70- 201143771 MS (FAB) m/z: 499(M + H) + . IR(KBr) vmax 2942，2795，1681，1445，1372，1152, 1045, 818, 754, 702 cm&quot;1.[Example 7c] 2-[( 3S ) -1- { 2-[4-( 2-{methyl[2-(decylamino)ethyl]amino}ethyl)phenyl]ethyl hydrazine N-r-pyridyl-3·yl]_2,2-diphenylacetamide was added to the compound obtained in Example 7b (296 mg, 〇.494 mmol) in MeOH (2 mL). j 24mL ' 4.94mmol ), stir at room temperature! The hour is further stirred at 4 〇 &lt;&gt;c for 1 hour. After adding saturated sodium hydrogencarbonate water to the reaction mixture, it was extracted with dichloromethane-methanol (4. 1 'X 3 ) and dried over anhydrous sodium sulfate. The residue obtained by distillation under reduced pressure was purified by EtOAc EtOAc EtOAc EtOAc EtOAc . -70- 201143771 MS (FAB) m/z: 499 (M + H) + . IR (KBr) vmax 2942,2795,1681,1445,1372,1152, 1045, 818, 754, 702 cm&quot;1.

[實施例 7d]N- ( 2- { [2- ( 4- { 2-[ ( 3S ) -3- ( 2-胺基-2- 側氧基-1，1 -二苯基乙基）。比咯啶-:l •基]乙基丨苯基）乙 基](甲基）胺基}乙基）-2-{[(2S) -l，-{2-[(5R) -3- {[3,5-雙（三氟曱基）苯基]羰基丨_54_氟苯基） -1，3-嘮唑啶-5-基]乙基}-2,3-二氫螺[茚_1，4，-哌啶]-2-基] 氧基} -N -曱基乙酿胺 將實施例6i所獲得的化合物（ 244mg，〇.351mmol) 浴解於二氣曱烧（5mL)’冰冷下’添加三乙基胺（67pL， 〇.47 9mmol )及氣曱酸異丁酯（5〇μΧ，0 383mmol )，於 室溫攪拌15分鐘。於實施例7c所獲得的2-[( 3S ) -l-丨 2-[4-(2- {曱基[2-(甲基胺基）乙基]胺基丨乙基）苯基]乙 基}°比°各。定-3-基]-2,2-二苯基乙醯胺（i59mg，〇.319mmol) 之二氣甲烷溶液（5mL )中，冰冷下，添加反應液，並 於室溫攪拌3 · 5小時》減壓下，餾除溶劑所獲得的殘渣使 用NH矽膠管柱層析純化（己烷：乙酸乙酯=丨：2_乙酸 乙酿：甲醇= 20: U ，獲得呈白色固體之標題目的化合 物（3 17mg ’ 產率 77% )。 MS (FAB) m/z: 1175(M + H) + . IR(KBr) vmax 293 1，2800，1649:, 1443，1 3 5 8，1281， 1181, 1139, 757, 702 cm-1.[Example 7d] N-(2-{ [2-(4-{2-[(3S)-3-(2-amino-2-yloxy-1,1-diphenylethyl)). Bilobidine-:l•yl]ethyl phenyl)ethyl](methyl)amino}ethyl)-2-{[(2S) -l,-{2-[(5R) -3- {[3,5-Bis(Trifluoromethyl)phenyl]carbonylindole_54_fluorophenyl)-1,3-oxazolidin-5-yl]ethyl}-2,3-dihydrospiro[茚_1,4,-Piperidine]-2-yl]oxy}-N-mercaptoethylamine The compound obtained in Example 6i (244 mg, 〇.351 mmol) was dissolved in dioxane (5 mL) Under ice cooling, triethylamine (67 pL, 〇.47 9 mmol) and isobutyl phthalate (5 〇μΧ, 0 383 mmol) were added and stirred at room temperature for 15 minutes. 2-[( 3S ) -l-丨2-[4-(2- {曱yl[2-(methylamino)ethyl]aminopurinylethyl)phenyl]B obtained in Example 7c The base}° is different from °. To a solution of dimethyl-3-yl]-2,2-diphenylacetamide (i59 mg, 319. 319 mmol) in m. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography using EtOAc (EtOAc: EtOAc: EtOAc: (3 17 mg 'yield 77%) MS (FAB) m/z: 1175 (M + H) + . IR (KBr) vmax 293 1,2800,1649:, 1443,1 3 5 8,1281, 1181, 1139, 757, 702 cm-1.

[實施例8] -71- 201143771 N_(2_{[2_(4_{2_[(3S)_3_(2_ 胺基 _2_ 側氧基 U· 二苯基乙基）料咬-1·基]乙基丨笨基）〔基]胺基}乙 基）-2-{[(2S) _3、{[3,5_ 雙（三說甲 基）苯基]截基} -5-( 4-氟苯基）4 i，3-号唑啶-5-基]乙基} _2,3·二氣螺[節-1，4，·㈣]义基]氣基卜N-甲基乙酿胺[Example 8] -71- 201143771 N_(2_{[2_(4_{2_[(3S)_3_(2_Amino-2-)-oxyl U.diphenylethyl)-biter-1·yl]ethyl丨基基)[yl]amino}ethyl)-2-{[(2S) _3, {[3,5_bis(tri-methyl)phenyl]-) ) 4 i,3-oxazolidine-5-yl]ethyl} _2,3·dioxaspiro[jie-1,4,·(tetra)]yryl]qijib N-methylethramine

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cf3 CF-,Cf3 CF-,

[t.^，J8a]{2-[( {[(2S) -PM2.[(5R) .3.{[35. 雙（三氣甲基）苯基m基丨-5_(4i苯基卜^十坐咬 .5-基]乙基}-2,3·二氫螺[節·^呢。定]_2基]氧基}乙酿 基）（曱基）胺基]乙基丨胺基甲酸三級丁醋 將實施例6i所獲得的化合物（l35mg，〇 ι94_〇ι) 溶解於二氣曱烧（3mL)，冰冷下，添加三乙基胺（81_， 〇.583mm〇1)及三曱基乙酿基氯（25吣，〇 2〇4薦〇1)， 於室溫攪拌1 5分鐘。於反應液中添加[2_ (曱基胺基） 乙基]胺基曱酸三級丁酯鹽酸鹽（45mg，〇 214mm〇1)， 於室溫攪拌整夜。減壓下’餾除溶劑所獲得的殘渣使用 NH矽膠管柱層析純化（己烷：乙酸乙唣二^ _ 1 : 2 )， 獲得呈白色固體之標題目的化合物（i 5〇爪旦，產率9丄 % )。 MS (APCI) m/z: 851 (M + H) +.[t.^,J8a]{2-[( {[(2S) -PM2.[(5R) .3.{[35. Bis(trimethyl)methylphenyl]-5-(4iphenyl) ^十坐咬.5-yl]ethyl}-2,3·dihydrospiro[节·^呢]_2基]oxy}ethyl aryl)(fluorenyl)amino]ethyl guanamine The compound obtained in Example 6i (l35 mg, 〇ι 94_〇ι) was dissolved in dioxane (3 mL) under ice-cooling, and triethylamine (81_, 〇.583 mm〇1) was added and Trimethyl sulfonyl chloride (25 吣, 〇 2 〇 4 recommended 〇 1), stirred at room temperature for 15 minutes. Add [2_ (decylamino) ethyl] amide decanoic acid to the reaction solution Butyl ester hydrochloride (45 mg, 〇 214 mm 〇1) was stirred at room temperature overnight. The residue obtained by distillation of the solvent under reduced pressure was purified by NH?? 1 : 2 ), the title compound (i 5 〇 旦, yield 9 丄 %) was obtained as a white solid. MS (APCI) m/z: 851 (M + H) +.

[實施例 8b]N-(2-胺基乙基）_2_{[(2S) i，丨 2[(5R) -3-{[3,5-雙（三敗曱基）苯基]幾基} _5_(4_氟苯基） -72- 201143771 _1，3-噚唑啶-5-基]乙基卜2,3-二氫螺[茚- i，4，-哌啶]-2-基] 氧基} -N-曱基乙醯胺 將實施例8a所獲得的化合物（！ 5〇Ing , 〇_ 176mmol ) 溶解於甲醇（〇.9mL)’添加4N鹽酸-二噚烷（〇.883mL， 3.53mmol)後，於室溫攪拌i小時，減壓下，餾除溶劑所 獲得的殘渣使用NH矽膠管柱層析純化（乙酸乙酯：曱醇 = 10: 1) ’獲得呈白色固體之標題目的化合物（i25rng， 產率95% )。 MS (APCI) m/z: 751 (M + H) +.[Example 8b] N-(2-Aminoethyl)_2_{[(2S) i, 丨2[(5R)-3-{[3,5-bis(tris-decyl)phenyl]) } _5_(4_fluorophenyl) -72- 201143771 _1,3-oxazolidin-5-yl]ethyl b 2,3-dihydrospiro[茚-i,4,-piperidinyl]-2-yl ]oxy}-N-mercaptoacetamide The compound obtained in Example 8a (! 5 〇 Ing, 〇 _ 176 mmol) was dissolved in methanol (〇. 9 mL), and 4N hydrochloric acid-dioxane (〇.883 mL) was added. After stirring at room temperature for 1 hour, the residue obtained by distilling the solvent under reduced pressure was purified by chromatography using ethylamine (ethyl acetate: decyl alcohol = 10:1). The title compound (i25rng, yield 95%). MS (APCI) m/z: 751 (M + H) +.

[實施例8c]2-[ ( 3S ) -1- { 2-[4- ( 2-羥基乙基）苯基]乙基} °比略。定-3 -基]-2，2 -二苯基乙醯胺 於文獻（US2004/254219 A1)記載的2,2-二笨基 -2-[ ( 3S )-吡咯啶-3-基]乙醯胺（i.22g，4_34mmol)之 乙腈溶液（40mL)中，添加文獻（US2005/203 1 67 A1) s己載的2-[4- (2 -經基乙基）笨基]乙基4-甲基苯績酸酯 (1 _39g ’ 4_34mmol )、及 N，N-二異丙基乙基胺（2.27mL， 13.0mmol)，於60°C加熱攪拌12.5小時。於反應液中添 加水後’以乙酸乙酯（X 2 )提取，有機層以飽和食鹽水 洗淨。以無水硫酸鈉乾燥後，減壓下，餾除溶劑所獲得 的殘渣使用NH矽膠管柱層析純化（乙酸乙酯：曱醇= 100 : 0-20 : 1 )，獲得呈白色固體之標題目的化合物 (1.53g，產率 82% )。 】H NMR (CDC13，400MHz): δ 1.76-1.86 (1H，m)， 1.88- 1.95 (1Η, m), 2.15-2.13 (1H, m);, 2.26-2.33 (1 H, m), 2.62 (1H, t, J = 6.0 Hz), 2.68-2.76 (4H, m), 2.82-2.90 (4H, -73- 201143771 m), 3.28-3.35 (1H, m), 3.86-3.89 (2H, m), 5.24 (1H, brs), 7.07-7.22 (8H，m)，7·23_7·31 (4H，m)，7.35 (2H, d, J = 7.0 Hz), 8.16 (1H, brs). MS (APCI) m/z: 429(M + H) + .[Example 8c] 2-[(3S)-1-{2-[4-(2-Hydroxyethyl)phenyl]ethyl} ° ratio. 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]B described in the literature (US2004/254219 A1) In a solution of guanamine (i.22g, 4_34mmol) in acetonitrile (40mL), add the literature (US2005/203 1 67 A1) s-loaded 2-[4-(2-propionyl)phenyl]ethyl 4 Methyl benzoate (1 - 39 g '4 - 34 mmol) and N,N-diisopropylethylamine (2.27 mL, 13.0 mmol) were stirred and stirred at 60 ° C for 12.5 hours. After adding water to the reaction mixture, it was extracted with ethyl acetate (X 2 ), and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the residue obtained by distilling the solvent under reduced pressure was purified by chromatography on ethylamine (ethyl acetate: decyl alcohol = 100 : 0 - 20 : 1 ) to give a white solid. Compound (1.53 g, yield 82%). H NMR (CDC13, 400MHz): δ 1.76-1.86 (1H, m), 1.88- 1.95 (1Η, m), 2.15-2.13 (1H, m);, 2.26-2.33 (1 H, m), 2.62 ( 1H, t, J = 6.0 Hz), 2.68-2.76 (4H, m), 2.82-2.90 (4H, -73- 201143771 m), 3.28-3.35 (1H, m), 3.86-3.89 (2H, m), 5.24 (1H, brs), 7.07-7.22 (8H, m), 7·23_7·31 (4H, m), 7.35 (2H, d, J = 7.0 Hz), 8.16 (1H, brs). MS (APCI) m/z: 429 (M + H) + .

[實施例8d]2-[ ( 3S ) -1- { 2-[4- ( 2-側氧基乙基）苯基] 乙基}吡咯啶-3-基]-2,2-二苯基乙醯胺 將實施例8c所獲得的2-[ ( 3S ) -1- { 2-[4- ( 2-羥基 乙基）苯基]乙基}吡咯啶-3 -基]-2,2 -二苯基乙醯胺 (150mg，0.350mmol)、二甲基亞石風（〇.i49mL， 2.10mmol )、及 Ν，Ν·二異丙基乙基胺（〇· i 83mL， l_05mmol)溶解於二氣曱烷（4mL)，冰冷下，添加三氡 化硫-。比°定複合物（164mg，l_05mmol)，於相同溫度下撥 拌5_5小時。再於反應液中添加二甲基亞砜（， 1.05mm〇l)、N，N_:異丙基乙基胺（92μί，〇 525匪〇1)、 及三氧化硫_。比啶複合物（82mg，〇 525mm〇1)，於相同溫 度下攪拌1小時，於室溫攪拌整夜。於反應液中添加水， 以二氯曱烷（χ3 )提取，以無水硫酸鈉乾燥。減壓下， 餾除溶劑而獲得粗製之呈黃色油狀物之標題目的化合物 (218mg、含有二曱基亞砜）。 'H NMR (CDC13, 400MHz): δ 1.40-1.42 (lHj m), !-47-1.50 (1H, m), ι.99-2.05 (2H, m), 2.74-2.86 (2H, m), 3.04-3.13 (4H，m)，3.62 (2H，s)，3 75_3 84 (2H，吨 7 〇7 OH, d, J = 7.8 Hz), 7.17 (1H, d, J = 7.8 Hz), 7.23-7.30 (9H，m)，7.65-7.70 (1H，m)，8.61-8.62 (2H，m)，9.68 (1H， s). ， -74- 201143771 [貫施例 8e]N- (2- { [2- (4- { 2-[ (3S) -3- (2 -胺基 _2_ 側氧基-1,1-二苯基乙基）°比洛咬-1-基]乙基}苯基）乙 基]胺基}乙基）-2- { [ ( 2S) -1，- { 2-[ ( 5R) ·3_ { [3,5_ 雙（三氟甲基）苯基]数基} -5- ( 4-氟笨基）_丨，3_号嗤咬 -5-基]乙基} -2,3-二氫螺[茚-1，4’-哌啶]_2_基]氧基} _Ν_ 曱基乙醯胺 將實施例8 d所獲得的化合物（5 0 m g，〇 _ 1 1 7 m m ο 1 ) 及實施例8b所獲得的化合物（88mg，〇· 1 1 7mm〇i )溶解 於1，2-二氯乙烷（3mL)-甲醇（0.5mL)，添加氫化三乙 醯氧基棚鈉（50mg，0.234mmol)，並於室溫授拌3小時。 於反應液中添加飽和碳酸氫納水，以乙酸乙醋提取後， 有機層以飽和食鹽水洗淨。以無水硫酸納乾燥後，減壓 下’餾除溶劑所獲得的殘渣使用NH矽膠管柱層析純化 (己烷：乙酸乙酯=1: 2-0: 100)，獲得呈白色固體之 標題目的化合物（20mg，產率15% )。 MS (FAB) m/z: 1161(M + H) + . IR(KBr) vmax 2929, 2802, 1677, 15 1 1, 1444, 1358, 128 1, 1 1 39, 757, 702 cm'1.[Example 8d] 2-[(3S)-1-{2-[4-(2-Sideoxyethyl)phenyl]ethyl}pyrrolidin-3-yl]-2,2-diphenyl Acetylamine 2-[(3S)-1-{2-[2-(2-hydroxyethyl)phenyl]ethyl}pyrrolidin-3-yl]-2,2- obtained in Example 8c Diphenylacetamidine (150 mg, 0.350 mmol), dimethyl succinite (〇.i49 mL, 2.10 mmol), and hydrazine, hydrazine diisopropylethylamine (〇· i 83 mL, l_05 mmol) were dissolved in Dioxane (4 mL), added with trisulfide-- under ice cooling. The compound (164 mg, l_05 mmol) was mixed at the same temperature for 5-5 hours. Further, dimethyl sulfoxide (1.05 mm 〇l), N, N_: isopropylethylamine (92 μί, 匪〇 525 匪〇 1), and sulfur trioxide _ were added to the reaction liquid. The pyridine complex (82 mg, 525 525 mm 〇 1) was stirred at the same temperature for 1 hour and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane (??) and dried over anhydrous sodium sulfate. The title compound (218 mg, containing dimercaptosulfoxide) was obtained as a crude yellow oil. 'H NMR (CDC13, 400MHz): δ 1.40-1.42 (lHj m), !-47-1.50 (1H, m), ι.99-2.05 (2H, m), 2.74-2.86 (2H, m), 3.04 -3.13 (4H,m), 3.62 (2H,s),3 75_3 84 (2H, ton 7 〇7 OH, d, J = 7.8 Hz), 7.17 (1H, d, J = 7.8 Hz), 7.23-7.30 (9H,m), 7.65-7.70 (1H,m),8.61-8.62 (2H,m),9.68 (1H, s). , -74- 201143771 [Example 8e]N- (2- { [2 - (4- { 2-[ (3S) -3- (2-amino-2-ylideneoxy-1,1-diphenylethyl) ° pirate-1-yl]ethyl}phenyl) Ethyl]amino}ethyl)-2- { [( 2S) -1,- { 2-[ ( 5R) ·3_ { [3,5_bis(trifluoromethyl)phenyl]number} -5 - (4-Fluorophenyl)_丨, 3_嗤嗤-5-yl]ethyl}-2,3-dihydrospiro[茚-1,4'-piperidinyl]-2-yl]oxy} _Ν_Mercaptoacetamide The compound obtained in Example 8d (50 mg, 〇_1 1 7 mm ο 1 ) and the compound obtained in Example 8b (88 mg, 〇·1 1 7 mm〇i) were dissolved in 1,2-Dichloroethane (3 mL)-methanol (0.5 mL), EtOAc (EtOAc) Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine. After drying over anhydrous sodium sulfate, the residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on EtOAc (hexane: ethyl acetate = 1: 2 - 0: 100). Compound (20 mg, yield 15%). MS (FAB) m/z: 1161 (M + H) + . IR (KBr) vmax 2929, 2802, 1677, 15 1 1, 1444, 1358, 128 1, 1 1 39, 757, 702 cm'1.

[實施例9] N- ( 3,3,3 -三苯基丙醯基）甘胺醯基·ν_ ( { Ι-Ι^-Ο 4-[ ({ [ ( 2S) -1’- { 2-[ ( 5R) -3- { [3,5-雙 （ 三氟甲 基）本基]幾基}-5-(4-氟苯基）-1，3_今。坐11定-5_基]乙基} -2,3-二氫螺[茚-1，4’-哌啶]-2-基]氧基丨乙醯基）（曱基） 胺基]丁醯基}胺基）己基]哌啶-3-基丨甲基）-β-丙胺酸 醯胺 -75- 201143771[Example 9] N-(3,3,3-triphenylpropanyl)glycine · group·ν_ ( { Ι-Ι^-Ο 4-[ ({ [ ( 2S) -1'- { 2 -[ ( 5R) -3- { [3,5-bis(trifluoromethyl)benzyl]yl}-5-(4-fluorophenyl)-1,3_今. Sitting 11 定-5_ Ethyl]ethyl}-2,3-dihydrospiro[茚-1,4'-piperidinyl]-2-yl]oxyindolyl)(fluorenyl)amino]butanyl}amino)hexyl] Piperidin-3-ylindole methyl)-β-alanine decylamine-75- 201143771

[實施例93]&gt;^(3,3,3-三苯基丙醯基）甘胺醯基-：^-(哌 啶-3-基甲基）·β·丙胺酸醯胺 使用3 ·(胺基甲基）哌啶-1 -曱酸三級丁酯（1 · 1 g、 5.2mmol )替代（3S ) -3-(胺基曱基）哌啶-1-曱酸三級 丁酯，依據 EP12 1328 1 A1 ( 2002/06/12 )記載的方法， 獲得呈白色固體之標題目的化合物（203mg、產率 43 % )。 MS (ESI) : m/z 527 ((M + Η ) + );(游離體）· [實施例9b]N-(3,3,3 -三苯基丙酿基）甘胺醯基_&amp;[(1_ { 6-[(三級丁氧基羰基）胺基]己基}哌啶-3-基）曱基 丙胺酸醯胺 將貫施例9 a所獲得的Ν - ( 3，3，3 -三苯基丙醯基）甘 胺醯基-N- ( D底。定-3-基甲基）-β-丙胺酸醯胺（2〇3mg 0.3 9mmol )溶解於乙腈（5mL)，於室溫添加已知化人物 6-[(三級丁氧基羰基）胺基]己基曱烷磺酸酿（287 0.96mmol ) ( Organic Letters ' Vol.4 ' No 5 , 2〇〇2 乳軋環境下，於 737-740)、蛾化钟（64mg 50度攪拌16小時。反應終了後，添加水， 丹添加乙酸 乙酯作分液。分離所獲得的有機層，以飽和 艮義水洗淨 後’以無水硫酸鈉乾燥，減壓下，餾除溶取丨 # $』。殘洁伟田 NH矽膠管柱層析純化（乙酸乙酯—乙酸 Q Θ曰.甲醇 . -76- 201143771 5)’獲付呈白色固體之標題目的化合物（i92mg、產率 69% ) 〇 MS (FAB) : m/z 726 ((Μ + Η ) + )； IR (KBr) vmax 3313, 2932，1655, 1531，1446, 1365, 1246, 1 171, 753, 702 cm'1.[Example 93] &gt;^(3,3,3-triphenylpropanyl)glycidyl-:^-(piperidin-3-ylmethyl)·β·alanine guanamine was used 3 · (Aminomethyl) piperidine-1 - decanoic acid tert-butyl ester (1 · 1 g, 5.2 mmol) instead of (3S)-3-(aminomercapto)piperidine-1-decanoic acid tert-butyl ester According to the method described in EP 12 1328 1 A1 (2002/06/12), the title compound (203 mg, yield 43%) was obtained as white solid. MS (ESI): m/z 527 ((M + Η ) + ); (free) · [Example 9b] N-(3,3,3-triphenylpropyl)glycine _&amp ;[(1_ { 6-[(Tris-butoxycarbonyl)amino]hexyl}piperidin-3-yl) decyl propylamine decylamine will be obtained by the Ν - (3,3, obtained in Example 9a) 3-triphenylpropanyl)glycine fluorenyl-N-(D-d.d--3-ylmethyl)-β-alanine decylamine (2〇3mg 0.3 9mmol) was dissolved in acetonitrile (5mL) Adding a known person 6-[(tris-butoxycarbonyl)amino]hexyl decane sulfonic acid (287 0.96 mmol) at room temperature (Organic Letters ' Vol.4 ' No 5 , 2〇〇2 milk rolling environment Next, at 737-740), moth clock (64 mg 50 degree stirring for 16 hours. After the reaction is finished, add water, add ethyl acetate as a liquid separation. Separate the obtained organic layer and wash it with saturated hydrazine water. 'Dry with anhydrous sodium sulfate, distillate under reduced pressure, distillate 丨# $』. Residue cleansing by NH column chromatography (ethyl acetate-acetic acid Q Θ曰.methanol. -76- 201143771 5)' The title compound (i92mg, yield 69%) was obtained as a white solid. 〇MS (FAB): m/z 726 ((Μ + Η ) + ); R (KBr) vmax 3313, 2932,1655, 1531,1446, 1365, 1246, 1 171, 753, 702 cm'1.

[實施例9 c ] N - ( 3，3，3 -三苯基丙酿基）甘胺醢基_ n - { [ 1 -(6 -胺基己基）派咬-3 -基]甲基} - β ··丙胺酸酸胺二鹽酸 鹽 將貫施例9 b所獲得的化合物（1 9 2 m g、0 · 2 6 m m ο 1 ) 溶解於乙醇（2mL )，冰冷下，添加4N鹽酸/1，4-二号院 溶液（2mL )，氮氣環境下，於室溫攪拌4 5小時。反應 終了後，減壓下，德除溶劑。冰冷下添加乙酸乙酯，再 添加飽和碳酸氫鈉水作中和而分液》分離所獲得的有機 層，獲得粗製之呈薄黃色固體之標題目的化合物 (183mg)。 [實施例9(1]4-[({[(23)-1’-{2-[(51〇-3-{[3,5-雙 (二氣甲基）本基]氣基} -5-( 4 -氣苯基）-1，坐咬-5_ 基]乙基} -2,3-二氫螺[茚-1，4，-哌啶]-2-基]氧基}乙醯基） (曱基）胺基]丁酸甲酯 將貫施例6 i所獲得的化合物（].5 〇 m g、0 · 2 2 m m ο 1 ) 溶解於二氣甲烷（5mL) ’冰冷下，添加三乙基胺（72μί、 0.52mm〇l)、三甲基乙醯基氯（27pL、0.22mmol)，氮氣 環境下，於相同溫度下攪拌1 5分鐘。接著於冰冷下，添 加已知化合物4 -(曱基胺基）丁酸曱|旨鹽酸鹽（44mg、 〇·2 6 mmol )( US5886143 Al( 1999/0 3/23))，氮氣環境下， -77- 201143771 於室/皿攪4半2日。反應終了後，添加飽和碳酸氫鈉水， 再添加乙酸乙酯作分液。分離所獲得的有機層，以飽和 艮鹽水洗淨後，以無水硫酸鈉乾燥，減壓下，德除溶劑。 殘渣使用NH矽膠官柱層析純化（己烷：乙酸乙酯、j : 5)，獲得呈白色固體之標題目的化合物（133mg、產率 76% ) 〇 [貫知例 9e]4-[({ [( 2S) - l’-{ 2-[( 5R) -3-{ [3,5-雙（三 氟曱基）苯基]羰基} -5- (4-氟苯基）q，〗·嘮唑啶-5-基] 乙基卜2,3-二氫螺[茚-1，4，-哌啶卜2_基]氧基丨乙醯基）（曱 基）胺基]丁酸 將實施例9d所獲得的化合物（n3mg、〇丨6mmol ) 溶解於乙醇（5mL )，冰冷下，添加1 n氫氧化鈉水溶液 (〇.3 3mL、〇.3 3mmol) ’於室溫攪拌3 5小時。反應終了 後’減壓下，餾除乙醇後’添加1N鹽酸水溶液（〇.33mL、 0.33mmol )，再添加乙酸乙酯作分液。分離所獲得的有機 層以飽和食鹽水洗淨後’以無水硫酸鈉乾燥，減壓下， 餾除溶劑’獲得粗製之呈白色固體之標題目的化合物 (114mg、產率 87% )。 [貫施例9f]N-( 3,3,3-三苯基丙醯基）甘胺醯基_Ν_( { ((4-[({[(2S) -l’-{2-[(5R) _3_{[3,5_雙（三氟曱 基）本基]幾基} -5-( 4 -氟苯基）-1，3-〇^·。坐n定-5-基]乙基} -2,3-二氫螺[茚q〆’-哌啶]-2-基]氧基丨乙醯基甲基） 胺基]丁醯基}胺基）己基]哌啶_3-基}曱基）_β_丙胺酸 醯胺 -78- 201143771 將實施例9e所獲得的化合物（ll4mg 〇i4mm〇i) /合解於一氣甲烷（5mL)，冰冷下，添加三乙基胺（ι〇〇μ[、 0.72mmol )、三曱基乙醢 ri。τ 基亂（18μ£、〇.14mmol)，氮氣 環境下，於相同溫度下措技】$八# 又广償件15分鐘。接著冰冷下，添加 實施例9c合成的N- ( 3 3飞=贫：a t姑请、 * « 二本基丙醯基）甘胺醯基-N_ { [1-( 6-胺基己基）略π含&quot;^ | 1田甘、 ^取疋-3·基]曱基丨-β-丙胺酸醯胺二 鹽酸鹽（183mg、〇.27nm0丨），氮氣環境下，於室溫攪拌 1 8小時。反應終了後，添加飽和碳酸氫鈉水，再添加乙 酸乙酯作分液^分離所獲得的有機層，並以飽和食鹽水 洗淨後，以無水硫酸鈉乾燥，減壓下，餾除溶劑。殘渣 使用NH碎膠官柱層析純化（乙酸乙g旨—乙酸乙g旨：曱 醇、1 : 5 )後’以逆相分取管柱層析純化（XTerra Prep ms C18 OBD 5μιη 30Φ x l〇〇mm)(乙腈·· 〇」％ 乙酸銨水溶 液、50 : 50-乙腈）’獲得呈白色固體之標題目的化合物 (53mg、產率 26% )。 MS (FAB) : m/z 1401 (M + H) + IR(KBr)vmax 33 14,293 1, 1650, 1 5 1 1, 1359, 128 1, 1181，1 1 39, 757, 702 cm-1.[Example 9 c ] N -( 3,3,3 -triphenylpropyl aryl)glyoximeyl _ n - { [ 1 -(6 -aminohexyl) keto-3 -yl]methyl} -β ··Alanine diamine hydrochloride The compound obtained in Example 9 b (1 2 2 mg, 0 · 2 6 mm ο 1 ) was dissolved in ethanol (2 mL), and 4N hydrochloric acid was added under ice cooling. The solution of 1,4-yard 2 (2 mL) was stirred at room temperature for 45 hours under nitrogen. After the end of the reaction, the solvent was removed under reduced pressure. The title compound (183 mg) was obtained from the title compound. [Example 9(1] 4-[({[(23)-1'-{2-[(51〇-3-{[3,5-bis(dimethyl)))]]] 5-(4-(phenylene)-1, sit-n-5-yl]ethyl}-2,3-dihydrospiro[indol-1,4,-piperidinyl]-2-yl]oxy} acetamidine Methyl (butyryl)amino]butyric acid The compound obtained in Example 6 i (5. 〇mg, 0 · 2 2 mm ο 1 ) was dissolved in di-methane (5 mL) under ice cooling. Add triethylamine (72 μί, 0.52 mm 〇l), trimethyl ethinyl chloride (27 pL, 0.22 mmol), and stir at the same temperature for 15 minutes under nitrogen atmosphere. Then add known compounds under ice cooling. 4 -(decylamino)butyric acid ruthenate|Identified hydrochloride (44mg, 〇·6 6mmol) (US5886143 Al(1999/0 3/23)), under nitrogen atmosphere, -77- 201143771 in room/dish After stirring for 4 and a half days, the reaction was completed, and saturated sodium hydrogencarbonate water was added thereto, and ethyl acetate was added for liquid separation. The obtained organic layer was separated, washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc (EtOAc:EtOAc) (133 mg, yield 76%) 〇 [Knowledge Example 9e] 4-[({ [(2S) - l'-{ 2-[( 5R) -3-{ [3,5-bis(trifluoromethyl) Phenyl]carbonyl} -5-(4-fluorophenyl)q, 〗 oxazolidin-5-yl] ethyl b 2,3-dihydrospiro[茚-1,4,-piperidin 2 _ 丨 丨 ) ) ) ) ) ) ) ) ) ) ) ) ) ) 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 丁 实施 丁 丁 实施 实施 实施 实施 实施 实施The aqueous solution (〇3 3 mL, 〇.3 3 mmol) was stirred at room temperature for 35 hours. After the reaction was completed, the ethanol was distilled off under reduced pressure, and then 1N aqueous hydrochloric acid (〇.33 mL, 0.33 mmol) was added, and then acetic acid was added. Ethyl acetate was used as a liquid. The obtained organic layer was washed with EtOAc (EtOAc). %). [Example 9f] N-( 3,3,3-triphenylpropanyl)glycine Ν Ν_( { ((4-[({[(2S) -l'-{2 -[(5R) _3_{[3,5_bis(trifluoromethyl)benzyl]yl} -5-(4-fluorophenyl)-1,3-〇^·. Sitting n--5- Ethyl]ethyl}-2,3-dihydrospiro[茚q〆'-piperider ]-2-yl]oxyindenylmethyl)amino]butanyl}amino)hexyl]piperidine-3-yl}mercapto)_β-alanine decylamine-78- 201143771 Example 9e The obtained compound (ll4 mg 〇i 4 mm 〇i) was dissolved in mono-methane (5 mL), and under ice cooling, triethylamine (ι〇〇μ[, 0.72 mmol) and tridecyl hydrazine ri were added. Τ-based chaos (18μ£, 〇.14mmol), under the nitrogen atmosphere, at the same temperature, the technique is as follows: $8# and the parts are replenished for 15 minutes. Then, under ice cooling, the N-(3 3 fly = lean: atu, * « di-propyl propyl) glycine thiol-N_ { [1-( 6-aminohexyl) slightly synthesized in Example 9c was added. π containing &quot;^ | 1 Tiangan, ^ 疋-3·yl] fluorenyl-β-alanine decylamine dihydrochloride (183mg, 〇.27nm0丨), under nitrogen atmosphere, stirring at room temperature 1 8 hours. After the reaction was completed, a saturated aqueous solution of sodium hydrogencarbonate was added, and ethyl acetate was added to separate the organic layer, and the organic layer was separated, washed with saturated aqueous sodium sulfate, and dried over anhydrous sodium sulfate. The residue was purified by NH colloidal column chromatography (ethyl acetate-ethyl acetate: sterol, 1:5) and then purified by reverse phase column chromatography (XTerra Prep ms C18 OBD 5μιη 30Φ xl〇) 〇mm)(acetonitrile·· 〇%% aqueous ammonium acetate, 50:50-acetonitrile) was obtained as the title compound (53 mg, yield 26%). MS (FAB): m/z 1401 (M + H) + IR (KBr) vmax 33 14,293 1, 1650, 1 5 1 1, 1359, 128 1, 1181,1 1 39, 757, 702 cm-1.

[實施例10] (31〇-1-{8-[{5-[{2-[3,5-雙（三氟甲基）苯基]-2-曱基丙醯基}(甲基）胺基]-4-( 2-甲基苯基）吼啶-2-基} (甲基）胺基]辛-6-炔-l-基}吡咯啶-3·基羥基（二噻 吩-2-基）乙酸酯 -79- 201143771[Example 10] (31〇-1-{8-[{5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-mercaptopropyl}} (methyl) Amino]-4-(2-methylphenyl)acridin-2-yl}(methyl)amino]oct-6-yne-l-yl}pyrrolidin-3-ylhydroxy (dithiophene-2) -base) acetate-79- 201143771

00

[實施例10a] 8- {[三級丁基（二苯基）矽烷基]氧基}辛 -2-炔-1-醇 將三級 (12.7g 、 基（庚-6-炔-1-基氧基）二苯基矽烷 36_2mm〇l )( Tetrahedron，61, 5，2005, 1127-1140 )溶解於四氫呋喃（180mL )，於-78度逐滴加 入2.67N正丁基鐘/己烧溶液（i6.3mL、43.5mmol)，氮 氣環丨兄下於相同溫度下搜拌1小時。之後，添加三聚 曱醛（3.5g、〇.1〇9m〇1)並花i 5小時升溫至室溫。反應 終了後，添加飽和氣化銨水，再添加乙酸乙酯作分液。 为離所獲得的有機層，以飽和食鹽.水洗淨後，以無水硫 酸納乾燥’減壓下’餾除溶劑。殘渣使用NH矽膠管柱 層析純化（己烷：乙酸乙酯、5 : 1 )，獲得呈無色油狀物 質之標題化合物（11.5g、產率84%)。 [實施例10b]8- {[三級丁基（二苯基）矽烷基]氧基}辛 -2-炔-1-基甲烷磺酸酯 將實施例10a所獲得的8- {[三級丁基（二苯基）石夕 烧基]氧基}辛-2 -炔_1_醇（Yoomg、1.8mmol)溶解於二 乳甲烧（10mL )，冰冷下，添加三乙基胺（〇 39mL、 2.8mmol )、甲烷磺醯氯（〇 2imL、2 8爪爪〇1 )，氮氣環境 下：於：同溫度下攪掉1.2 +日夺。反應終了後，添加飽 和妷酸氫鈉水，再添加乙酸乙酯作分液。分離所獲得的 $機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥，減 壓下’顧除溶劑而獲得粗製之標題化合物（75〇rng )。 -80- 201143771 [實施例10c]2-[3,5-雙（三氟曱基）苯基]_N_{ 6·[( 8_{[三 級丁基（二苯基）石夕烧基]氧基}辛-2-快-1-基）（甲基） 胺基]-4- ( 2-曱基苯基）吡啶-3-基} -Ν，2-二甲基丙醯胺 將貫施例1 e合成的化合物（3 0 0 m g、〇 · 5 5 m m ο 1 )溶 解於N，N -二曱基乙醯胺（6mL)’室溫下’添加實施例i〇b 合成的8- {[三級丁基（二苯基）矽烷基]氧基丨辛_2·炔 -1-基甲院續酸酯（750mg、1,64mm 〇1)、碳酸鉀（226 mg、 1.64mmol)及蛾化針（i〇9mg、0.67mm〇l)，氮氣環境下， 於7 〇度搜拌1 7小時。反應終了後’添加飽和碳酸氫納水， 再添加乙酸乙酯作分液。分離所獲得的有機層，以飽和 食鹽水洗淨後，以無水硫酸鈉乾燥，減壓下，餾除溶劑。 殘渣使用NH矽膠管柱層析純化（己烷：乙酸乙酯、5 : 1 )， 獲得呈無色油狀物質之標題化合物（320mg、產率67 % )。 [實施例10d]2-[3,5-雙（三曱基）苯基]{ 6-[ ( 8-經基辛-2-炔-1-基）（曱基）胺基]_4_ ( 2_曱基苯基）。比啶 -3-基} -N，2-二甲基丙醯胺 將實施例l〇c所獲得的化合物（320mg、0.37mmol ) 溶解於四氫呋喃（5mL)，冰冷下，添加1 ·〇μ氟化四丁 基銨/四氫吱喃溶液（〇 5 5 m L，〇 · 5 5 ηι ο 1 )，氮氣環境下， 於室溫攪拌1小時。反應終了後’冰冷下，於反應液中 添加飽和氣化銨水’再添加乙酸乙酯作分液。分離所獲 得的有機層’以飽和食鹽水洗淨後，以無水硫酸鈉乾燥， 減麼下’顧除溶劑。使用矽膠管柱層析純化（己烷：乙 酸乙醋、3 : 2 )，獲得呈無色油狀物質之標題化合物 (193mg、產率 83% )。 -81- 201143771 MS (FAB) : m/z 634 ((Μ + Η ) + );(游離體） IR (Thin Film) vmax 2936，1597，1500，1398，1373, 1281，1185，1 1 38, 1 082, 756 cm'1.[Example 10a] 8-{[Tributyl(diphenyl)decyl]oxy}oct-2-yn-1-ol will be tertiary (12.7 g, yl (hept-6-alkyn-1-) Alkoxy)diphenylnonane 36_2mm〇l (Tetrahedron, 61, 5, 2005, 1127-1140) was dissolved in tetrahydrofuran (180 mL), and 2.67 N n-butyl clock/hexane solution was added dropwise at -78 °C. I6.3mL, 43.5mmol), and the nitrogen ring was mixed for 1 hour at the same temperature. Thereafter, trimeraldehyde (3.5 g, 〇.1〇9m〇1) was added and the temperature was raised to room temperature over 5 hours. After the reaction was completed, saturated aqueous vaporized ammonium water was added, and ethyl acetate was added for liquid separation. After the organic layer obtained was washed with saturated salt and water, the solvent was distilled off under anhydrous sodium sulfate to dryness under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjjjjj [Example 10b] 8-{[Tributyl(diphenyl)decyl]oxy}oct-2-yn-1-ylmethanesulfonate 8-{[Class 3] obtained in Example 10a Butyl (diphenyl) succinyl] oxy} octyl-2-alkyn-1-ol (Yoomg, 1.8 mmol) was dissolved in ketone (10 mL), and triethylamine was added under ice cooling. 39mL, 2.8mmol), methane sulfonium chloride (〇2imL, 2 8 claw 〇1), under nitrogen atmosphere: at the same temperature, 1.2 + day smash. After the end of the reaction, saturated sodium hydrogen hydride was added, and ethyl acetate was added for liquid separation. The obtained layer was separated and washed with brine, dried over anhydrous sodium sulfate, and evaporated to give the title compound (75 〇rng). -80- 201143771 [Example 10c] 2-[3,5-bis(trifluoromethyl)phenyl]_N_{ 6·[( 8_{[tris-butyl(diphenyl))) oxygen } 辛 -2- -1-yl-1-yl)(methyl)amino]-4-(2-mercaptophenyl)pyridin-3-yl}-indole, 2-dimethylpropanamide Example 1 The compound synthesized by e (300 mg, 〇·5 5 mm ο 1 ) was dissolved in N,N-dimercaptoacetamide (6 mL) at room temperature 'Addition of Example i〇b synthesized 8- {[Tri-tert-butyl(diphenyl)decyl]oxyindole-2-alkyn-1-yl-methoxylate (750 mg, 1,64 mm 〇1), potassium carbonate (226 mg, 1.64 mmol) And moth needle (i〇9mg, 0.67mm〇l), under nitrogen atmosphere, mix for 7 hours at 7 degrees. After the completion of the reaction, saturated aqueous sodium hydrogencarbonate was added, and ethyl acetate was added for liquid separation. The obtained organic layer was separated, washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified with EtOAc EtOAcjjjjjjjjj [Example 10d] 2-[3,5-bis(trimethylene)phenyl]{ 6-[(8-octyl-2-yn-1-yl)(indenyl)amino]_4_ ( 2 _mercaptophenyl). The compound obtained in Example l〇c (320 mg, 0.37 mmol) was dissolved in tetrahydrofuran (5 mL) under ice-cooling, and 1·〇μF Tetrabutylammonium/tetrahydrofuran solution (〇5 5 m L, 〇·5 5 ηι ο 1 ) was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the completion of the reaction, 'saturated vaporized ammonium water was added to the reaction mixture under ice cooling, and ethyl acetate was added for liquid separation. The organic layer obtained was separated and washed with saturated brine, and dried over anhydrous sodium sulfate to reduce solvent. The title compound (193 mg, yield: 83%) was obtained. -81- 201143771 MS (FAB) : m/z 634 ((Μ + Η ) + ); (free body) IR (Thin Film) vmax 2936,1597,1500,1398,1373, 1281,1185,1 1 38, 1 082, 756 cm'1.

[實施例 lOe] ( 3R) -1- { 8-[ { 5-[ { 2-[3,5-雙（三氟曱基） 苯基]-2-曱基丙醯基}(甲基）胺基]-4- ( 2-甲基苯基）。比 °定-2-基}(曱基）胺基]辛-6-炔-1-基}。比〇各π定-3-基經基 (二噻吩-2-基）乙酸酯 將實施例1 0 d所獲得的化合物（1 8 0 m g、0.2 8 m m ο 1 ) 溶解於乙酸乙酯（5mL )，冰冷下，添加三乙基胺（60μί、 0.43mmol)、曱院項酿氣（33pL、0.43mmol)，氣氣環境 下，於相同溫度下授摔1 · 2小時。之後，過滤反應液，減 壓濃縮，將所獲得的殘渣溶解於N，N-二曱基乙醯胺 (5 m L ) ’室溫下，添加實施例1 i合成的（3 R ) - °比》各咬-3 -基經基（二°塞吩-2-基）乙酸S旨（176mg、0.59mmol)、 碳酸氫納 （48mg、0.57mmol )及蛾化斜 （57mg、 0.341mmol)’氮氣環境下，於70度攪拌2小時。反應終了 後，添加飽和碳酸氫鈉水，再添加乙酸乙酯作分液。分 離所獲得的有機層，以飽和食鹽水洗淨後，以無水硫酸 鈉乾燥，減壓下，餾除溶劑。殘渣使用NH矽膠管柱層析 純化（己烷：乙酸乙酯、1 : 1 )後，以逆相分取管柱層 析純化（InertsilODS-3、3.0cmx25cm)(乙腈：0.1% 乙 酸銨水溶液、50 : 50-1 00 : 0 )，獲得呈白色固體之標題 目的化合物（112mg、產率43%)。 MS (FAB) : m/z 925 ((M + Η ) + );(游離體） IR (KC1) vmax 2934, 1737, 1650, 1596, 1499, 1372 128 1, 1 1 84, 1 136, 108 1 cm-1. -82- 201143771 [實施例i1] ·[Example lOe] ( 3R) -1- { 8-[ { 5-[ { 2-[3,5-bis(trifluoromethyl)phenyl]-2-mercaptopropyl}} (methyl) Amino]-4-(2-methylphenyl). Ratio °-2-yl}(fluorenyl)amino]oct-6-yn-1-yl}. The compound obtained in Example 10 d (1 800 mg, 0.28 mm ο 1 ) was dissolved in ethyl acetate (n.sub.1). 5mL), under ice cooling, adding triethylamine (60μί, 0.43mmol), broth (33pL, 0.43mmol), in a gas atmosphere, at the same temperature for 1 · 2 hours. Thereafter, the reaction solution was filtered, concentrated under reduced pressure, and the obtained residue was dissolved in N,N-dimercaptoacetamide (5 m L ) at room temperature, and (3 R ) - ° synthesized in Example 1 i was added. Ratios of each bite-3-yl-based (di-sept-2-yl)acetic acid S (176 mg, 0.59 mmol), sodium hydrogencarbonate (48 mg, 0.57 mmol) and moth (57 mg, 0.341 mmol) Stir at 70 °C for 2 hours under a nitrogen atmosphere. After the completion of the reaction, saturated sodium hydrogencarbonate water was added, and ethyl acetate was added for liquid separation. The obtained organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by column chromatography on EtOAc (hexane: ethyl acetate, 1:1), and purified by reverse column chromatography (Inertsil ODS-3, 3.0 cm x 25 cm) (acetonitrile: 0.1% aqueous ammonium acetate solution, 50: 50-1 00: 0), the title compound (112 mg, yield 43%) MS (FAB): m/z 925 ((M + Η ) + ); (free body) IR (KC1) vmax 2934, 1737, 1650, 1596, 1499, 1372 128 1, 1 1 84, 1 136, 108 1 Cm-1. -82- 201143771 [Embodiment i1]

(3R) -l-[2- ( 4- { 5-[ { 2-[3,5·雙（三氟曱基）笨 基]-2-甲基丙醯基丨（曱基）胺基]..4_ ( 2-曱基苯基）。比 °定-2 -基}娘σ井_ 1-基）乙基]°比洛°定-3 -基經基（二售吩_ 2 · 基）乙酸酯 [實施例 lla]2-[3,5-雙（二氟甲基）笨基]-Ν- { 6-[4- ( 2-羥基乙基）哌啩-1-基]-4-( 2_甲基苯基）吡啶-3-基} -N，2_ 二曱基丙醯胺 將文獻（US2003/4 1 57 A1)記載的2-[3,5-雙（三氣 曱基）苯基]-N，2-二甲基-N-[4- ( 2-曱基苯基）-6-(哌听 -1-基）**比。定-3-基]丙醞胺（150mg，0.266mmol)溶解於 乙腈（3mL)，添加碳酸卸（45mg，0.320mmol)及2-、;臭 乙醇（24μί，0.320mmol )後，於60°C攪拌1 8小時。於 反應液中加入水’以乙酸乙酯提取’有機層以飽和食鹽 水洗淨。以無水硫酸鈉乾燥後，減壓下，館除溶劑所獲 得的殘渣使用矽膠分取薄層層析純化（二氣曱烷：甲醇 =20 . 1 ) ’獲得呈育色油狀物之標題目的化合物 (121mg，產率 75% )。 MS (FAB) m/z: 609(M+H) + . IR(KBr) vmax 1649，1596，1487，1373，1281，1185, 1 137，1082，896, 683 cm·1. -83- 201143771 [實施例 lib] ( 3R) -l-[2- ( 4- { 5-[ { 2_[3,5_雙（三氟甲 基）苯基]-2 -甲基丙醯基丨（曱基）胺基]_4_(2甲基苯 基）°比啶-2 -基}哌听-1 _基）乙基]吡咯啶_ 3 _基羥基（二 噻吩-2 -基）乙酸酯 將實施例11a所獲得的化合物（92mg，0_i51mmol) 溶解於乙酸乙酯（2mL)，冰冷下，添加三乙基胺（25μί， 〇.18 1mmol)及曱烷磺醯氯（Ι3μί，O.l66mm〇1)後’於 相同溫度下搜拌2小時。不溶物以赛利特石夕藻土過濾，減 壓下，將餾除溶劑所獲得的殘渣溶解於乙腈（4mL )，添 加實施例1 i所獲得的（3R )-吡咯啶-3-基經基（二噻吩(3R) -l-[2-( 4- { 5-[ { 2-[3,5·bis(trifluoromethyl)phenyl]-2-methylpropenyl (fluorenyl)amino] ..4_ (2-indolylphenyl). Ratio ° -2 - base} Niang 井 well _ 1-yl) Ethyl] ° Biluo ° -3 base group (second sale 吩 _ 2 · base )acetate [Example lla] 2-[3,5-bis(difluoromethyl) phenyl]-indole-{ 6-[4-( 2-hydroxyethyl)piperazin-1-yl]- 4-(2-Methylphenyl)pyridin-3-yl}-N,2-dimercaptopropionamide 2-[3,5-double (three gas enthalpy) described in the literature (US 2003/4 1 57 A1) Phenyl]-N,2-dimethyl-N-[4-(2-mercaptophenyl)-6-(piperazin-1-yl)** ratio. Din-3-yl]propanamide (150 mg, 0.266 mmol) was dissolved in acetonitrile (3 mL), then added with carbonic acid (45 mg, 0.320 mmol) and 2-, odorous ethanol (24 μί, 0.320 mmol) at 60 ° C Stir for 18 hours. Water was added to the reaction mixture to extract with ethyl acetate. The organic layer was washed with saturated brine. After drying with anhydrous sodium sulfate, the residue obtained by removing the solvent under reduced pressure was purified by thin layer chromatography using silica gel (dioxane: methanol = 20.1). Compound (121 mg, yield 75%). MS (FAB) m/z: 609 (M+H) + . IR (KBr) vmax 1649,1596,1487,1373,1281,1185,1 137,1082,896, 683 cm·1. -83- 201143771 [ Example lib] ( 3R) -l-[2-( 4- { 5-[ { 2_[3,5-bis(trifluoromethyl)phenyl]-2-methylpropenyl fluorene (fluorenyl) Amino]_4_(2methylphenyl) ° pyridine-2-yl}piperazin-1 yl)ethyl]pyrrolidine _ 3 _ hydroxy (dithiophen-2-yl) acetate will be an example The compound obtained in 11a (92 mg, 0 - i 51 mmol) was dissolved in ethyl acetate (2 mL), and, under ice cooling, triethylamine (25 μί, 〇.18 1 mmol) and decanesulfonium chloride (Ι3μί, O.l66mm〇1) were added. After 'mixing at the same temperature for 2 hours. The insoluble matter was filtered through Celite, and the residue obtained by distilling off the solvent was dissolved in acetonitrile (4 mL) under reduced pressure, and the (3R)-pyrrolidin-3-yl group obtained in Example 1 i was added. Dithiophene

-2-基）乙酸酯（47mg，0.151mmol)、碳酸鉀（25mg， 0.181mmol)、及碘化鉀（23mg，0_151mmol)後，於6(TC 授拌1 0小時。於反應液中添加水，以乙酸乙酯提取，有 機層以飽和食鹽水洗淨。以無水硫酸鈉乾燥後，減壓下， 餾除溶劑所獲得的殘渣使用矽膠分取薄層層析純化（二 氣甲烷：曱醇= 20:1)，獲得呈褐色固體之標題目的化 合物（65mg，產率48%)。 MS (FAB) m/z: 900(M + H) + . IR(KBr) vmax 1 738，1651，1 596，1486，1372，1281， 1 184，1 1 37, 896, 708 cm·1.-2-yl)acetate (47 mg, 0.151 mmol), potassium carbonate (25 mg, 0.181 mmol), and potassium iodide (23 mg, 0-151 mmol), and then stirred for 10 hours at 6 (TC). Water was added to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel fractionation (di-methane: decyl alcohol = The title compound (65 mg, yield 48%) was obtained as a brown solid. MS (FAB) m/z: 900 (M + H) + . IR (KBr) vmax 1 738,1651,1 596 , 1486, 1372, 1281, 1 184, 1 1 37, 896, 708 cm·1.

[實施例12] (3R) -l-[3- ( 4· { 5-[ { 2-[3,5-雙（三氟曱基）苯 基]·2-甲基丙醯基}(甲基）胺基]-4- ( 2-甲基苯基）。比 啶-2-基}哌啡-l-基）-3-側氧基丙基]吡咯啶-3-基羥基 (二噻吩-2-基）乙酸酯 -84 - 201143771[Example 12] (3R) -l-[3-( 4· { 5-[ { 2-[3,5-bis(trifluoromethyl)phenyl]·2-methylpropanyl} (a Amino]-4-(2-methylphenyl).pyridin-2-yl}piperidin-l-yl)-3-oxopropyl propyl]pyrrolidin-3-ylhydroxy (dithiophene) -2-yl)acetate-84 - 201143771

[實施例12a]2-[3,5-雙（三氟甲基）苯基]-N- { 6-[4- ( 3-氣丙醯基）哌畊-1-基]-4-( 2-曱基苯基）°比啶-3-基} -N，2-二曱基丙醯胺 將文獻（US2003/41 57 A1)記載的2-[3,5-雙（三氟 曱基）苯基]-N，2-二曱基-N-[4- ( 2-甲基苯基）-6-(哌听 -1-基）α比咬-3-基]丙醯胺（ 200mg，0.354mmol)溶解於 二氯曱烧（4mL)，添加三乙基胺（.59μί，0.425mmol) 及3-氣丙醯基氣（4hL，0.3 90mmol )後，於室溫攪拌整 夜。於反應液中添加水，以乙酸乙酯提取，有機層以飽 和食鹽水洗淨。以無水硫酸鈉乾燥後，減壓下，餾除溶 劑所獲得的殘渣使用矽膠分取薄層層析純化（二氣曱 烷：曱醇=30 : 1 )，獲得呈白色固體之標題目的化合物 (203mg，產率 88% ) 〇 'H NMR (CDC13, 400ΜΗζ): δ 1.34 (6Η, brs), 1.48-1.51 (1H, m), 2.11-2.15 (2H, m), 2.31-2.35 (2H, m), 2.53-2.58 (1H, m), 2.86 (2H, t, J = 7.0 Hz), 3.52-3.54 (2H, m), 3.61-3.63 (2H, m), 3.68-3.69 (2H, m), 3.76-3.78 (2H, m), 3.86 (2H, t, J = 7.0 Hz), 6.52 (1H; brs), 7.25-7.29 (4H, m)5 7.66 (2H, brs), 7.76 (1H, s), 8.02 (1H, s). MS (FAB) m/z: 655(M + H) + .[Example 12a] 2-[3,5-Bis(trifluoromethyl)phenyl]-N-{6-[4-(3-acetonyl)piperidin-1-yl]-4-( 2-Mercaptophenyl) ° pyridine-3-yl}-N,2-dimercaptopropionamide 2-[3,5-bis(trifluoromethyl) group described in the literature (US 2003/41 57 A1) Phenyl]-N,2-dimercapto-N-[4-(2-methylphenyl)-6-(piperazin-1-yl)α butyl-3-yl]propanamide (200mg) , 0.354 mmol) was dissolved in dichlorohydrazine (4 mL), triethylamine (.59 μί, 0.425 mmol) and 3-propanone (3hL, 0.3 90 mmol) were added, and then stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine. After drying with anhydrous sodium sulfate, the residue obtained by distilling the solvent under reduced pressure was purified by silica gel chromatography (dichlorobenzene: decyl alcohol = 30:1) to give the title compound ( 203 mg, yield 88%) 〇'H NMR (CDC13, 400 ΜΗζ): δ 1.34 (6 Η, brs), 1.48-1.51 (1H, m), 2.11-2.15 (2H, m), 2.31-2.35 (2H, m ), 2.53-2.58 (1H, m), 2.86 (2H, t, J = 7.0 Hz), 3.52-3.54 (2H, m), 3.61-3.63 (2H, m), 3.68-3.69 (2H, m), 3.76-3.78 (2H, m), 3.86 (2H, t, J = 7.0 Hz), 6.52 (1H; brs), 7.25-7.29 (4H, m)5 7.66 (2H, brs), 7.76 (1H, s) , 8.02 (1H, s). MS (FAB) m/z: 655 (M + H) + .

[實施例 12b] ( 3R) -l-[3- ( 4- { 5-[ { 2-[3,5-雙（三氟曱 基）苯基]-2-曱基丙醯基丨（曱基）胺基]-4- ( 2-曱基苯 -85- 201143771 基）吡啶-2-基}哌畔_ι_基）_3_側氧基丙基]吡咯啶_3_ 基經基（二噻吩-2 -基）乙酸酯 將實施例12a所獲得的化合物（2〇3mg , 〇.3l〇mm〇1 ) 溶解於乙腈（6 m L )，添加實施例1 i所獲得的（3 R ) _吡咯 啶-3-基羥基（二噻吩-2-基）乙酸酯（96mg， 〇.310mmol )、碳酸鉀（52mg ’ 0.372mmol )及峨化納 (47mg，0.3 10mmol )後，於60°C攪拌10小時。於反應 液中添加水’以乙酸乙醋提取’有機層以飽和食鹽水洗 淨。以無水硫酸鈉乾燥後，減壓下，餾除溶劑所獲得的 殘渣使用矽膠分取薄層層析純化（二氯曱烷：甲醇=2〇 : 1 )，獲得呈褐色固體之標題目的化合物（1 12mg，產率 39% )。 MS (FAB) m/z: 928(M + H)+. IR(KBr) vmax 1740，1 648，1485，1439，1 373，1282, 1229，1 184，1 136, 708 cm·1.[Example 12b] (3R) -l-[3-(4-{ 5-[ { 2-[3,5-bis(trifluoromethyl)phenyl]-2-mercaptopropyl fluorenyl) Amino]-4-(2-mercaptobenzene-85- 201143771 yl)pyridin-2-yl}piperazine_ι_yl)_3_sideoxypropyl]pyrrolidine_3_ylcarbyl Thiophen-2-yl)acetate The compound obtained in Example 12a (2〇3 mg, 〇.3l〇mm〇1) was dissolved in acetonitrile (6 m L), and the obtained (3 R) obtained in Example 1 i was added. _ Pyrrrolidin-3-ylhydroxy (dithiophen-2-yl) acetate (96 mg, 〇.310 mmol), potassium carbonate (52 mg '0.372 mmol) and sodium hydride (47 mg, 0.3 10 mmol), after 60 Stir at °C for 10 hours. Water was added to the reaction solution to extract with ethyl acetate. The organic layer was washed with saturated brine. After drying with anhydrous sodium sulfate, the residue obtained by distilling the solvent under reduced pressure was purified by silica gel chromatography (dichloromethane:methanol = 2 〇: 1 ) to give the title compound ( 1 12 mg, yield 39%). MS (FAB) m/z: 928 (M + H) +. IR (KBr) vmax 1740,1 648,1485,1439,1 373,1282, 1229,1 184,1 136, 708 cm·1.

[實施例13] (3R)-l-( 3-{ 2-[{ 5-[{ 2-[3,5-雙（三氟曱基）苯基]_2_ 曱基丙醯基}(甲基）胺基]-4- ( 2-甲基苯基）&quot;比啶_2-基} (曱基）胺基]乙氧基丨丙基）吡咯啶-3-基羥基（二-2-噻吩基）乙酸酯[Example 13] (3R)-l-( 3-{ 2-[{ 5-[{ 2-[3,5-bis(trifluoromethyl)phenyl]_2- fluorenyl)} Amino]-4-(2-methylphenyl)&quot;pyridin-2-yl}(indenyl)amino]ethoxypropyl)pyrrolidin-3-ylhydroxy (2--2-) Thienyl) acetate

[實施例13a]2-[3,5-雙（三氟曱基）苯基]-Ν-[6-{ [2-( 3-{[三 級丁基（二曱基）矽烷基]氧基丨丙氧基）乙基](曱基） 胺基} -4- ( 2-曱基苯基）吡啶-3-基]-Ν，2-二曱基丙醯胺 -86- 201143771 於2-[3,5-雙（三氟甲基）苯基]-N- { 6-[ ( 2-羥基乙基） (曱基）胺基]-4- ( 2-曱基苯基）吼啶_3_基} -N，2-二甲 基丙醯胺（300mg、0.361mmol)之Ν,Ν-二甲基曱醢胺溶 液（4mL )中添加氫化鈉（38mg、55%於油中、 0.866mmol)’於室溫攪拌20分鐘。添加（3-溴丙氧基） (二級丁基）一甲基碎烧（250μί、l.〇8mmol)，並於 90°C 攪拌4 · 5小時。追加（3 -溴丙氧基）（三級丁基）二曱基 矽烷（167μί、0.721 mmo 1 ) ’於9 0 °C:攪拌3小時。於反應 液中加入乙酸乙酯而稀釋後，以水及飽和食鹽水洗淨， 且有機層以無水硫酸鈉乾燥。減壓餾除溶劑所獲得的殘 渣使用石夕膠分取薄層層析純化（η -己院：乙酸乙酯=4 : 1 )，獲得呈無色油狀物之標題化合物（244mg、產率93 % )。 ]Η NMR (CDC13, 400ΜΗζ): δ 0.03 (6Η, s), 0.88 (9Η, s), 1.30-1.33 (4H, m), 1.48-1.51 (2H, m), 1.73-1.80 (2H, m), 2.13-2.15 (2H, m), 2.29-2.33 (2H, m), 2.55-2.5 8 ( 1 H, m), 3.09 (3H, s), 3.51 (2H, t, J = 6.3Hz), 3.61-3.64 (2H, m)5 3.6 8 (2H, t, J = 6.3Hz), 3.70-3.7 8 (2H, m), 3.79-3.86 (1H, m)5 6.36 ( 1 H, s), 7.21-7.31 (4H, m), 7.65-7.68 (2H, m), 7.75 (1H, s), 7.96 (1H, s).[Example 13a] 2-[3,5-Bis(trifluoromethyl)phenyl]-indole-[6-{[2-( 3-{[tris-butyl(diindenyl)decyl)oxy] Propyloxy)ethyl](indenyl)amino}-4-(2-mercaptophenyl)pyridin-3-yl]-indole, 2-dimercaptopropanamide-86- 201143771 at 2 -[3,5-bis(trifluoromethyl)phenyl]-N- { 6-[(2-hydroxyethyl)(indolyl)amino]-4-(2-indolylphenyl)acridine _3_基}-N,2-dimethylpropanamide (300mg, 0.361mmol), sodium hydride (38mg, 55% in oil, added to Ν-dimethyl decylamine solution (4mL) 0.866 mmol)' was stirred at room temperature for 20 minutes. (3-Bromopropoxy) (secondary butyl)-methyl ketone (250 μί, l. 〇 8 mmol) was added and stirred at 90 ° C for 4.5 hours. (3 -Bromopropoxy)(tertiary butyl)didecyl decane (167 μί, 0.721 mmo 1 ) was added at 90 ° C: stirring for 3 hours. Ethyl acetate was added to the reaction mixture, and the mixture was diluted with water and brine, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified using EtOAc (EtOAc (EtOAc) %). Η NMR (CDC13, 400ΜΗζ): δ 0.03 (6Η, s), 0.88 (9Η, s), 1.30-1.33 (4H, m), 1.48-1.51 (2H, m), 1.73-1.80 (2H, m) , 2.13-2.15 (2H, m), 2.29-2.33 (2H, m), 2.55-2.5 8 ( 1 H, m), 3.09 (3H, s), 3.51 (2H, t, J = 6.3Hz), 3.61 -3.64 (2H, m)5 3.6 8 (2H, t, J = 6.3Hz), 3.70-3.7 8 (2H, m), 3.79-3.86 (1H, m)5 6.36 ( 1 H, s), 7.21- 7.31 (4H, m), 7.65-7.68 (2H, m), 7.75 (1H, s), 7.96 (1H, s).

[實施例1 3b]2-[3，5-雙（三氟甲基）苯基]-N-[6- { [2- ( 3-羥基丙氧基）乙基](甲基）胺基} -4- ( 2-甲基苯基）。比 啶-3-基]-N，2-二曱基丙醯胺 於貫施例1 3 a所獲得的化合物（2 4 4 m g、0.3 3 6 m m ο 1 ) 之四氫呋喃溶液（4mL)中添加〇·ιμ氟化四丁基銨/四氫 -87- 201143771 。夫喊溶液（403卟），並於室溫攪拌3〇分鐘。追加〇 1Μι 化四丁基銨/四氫呋喃溶液（4〇3 μΐ^ )，於室溫攪拌2〇分 鐘。於反應液中添加水後’以乙酸乙酯提取。所獲得的 有機層以飽和食鹽水洗淨後’以無水硫酸鈉乾燥，減壓 餾除溶劑。所獲得的殘渣使用矽膠管柱層析純化（n己 院：乙酸乙酯=2 : 1 -1 : 2 )’獲得呈白色固體之標題化 合物（189mg、產率92% ) » MS (FAB) m/z: 612(M + H) + . IR(KBr) vmax 293 1，1651，1 597，1 505，1 373，1282, 1 1 84, 1 1 36, 896, 683 cm'1.[Example 1 3b] 2-[3,5-Bis(trifluoromethyl)phenyl]-N-[6-{[2-(3-hydroxypropoxy)ethyl](methyl)amino group } -4- (2-methylphenyl). Addition of the compound (2 4 4 mg, 0.33 6 mm ο 1 ) in tetrahydrofuran (4 mL) of the compound obtained in Example 1 3 a (1 mL) 〇·ιμ tetrabutylammonium fluoride/tetrahydro-87- 201143771. The solution was called (403 卟) and stirred at room temperature for 3 minutes. Add 1 Μ 1 Μ tetrabutylammonium / tetrahydrofuran solution (4 〇 3 μΐ ^ ), and stir at room temperature for 2 〇 minutes. After adding water to the reaction liquid, it was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained was purified using EtOAc EtOAc EtOAc (EtOAc (EtOAc) /z: 612(M + H) + . IR(KBr) vmax 293 1,1651,1 597,1 505,1 373,1282, 1 1 84, 1 1 36, 896, 683 cm'1.

[實施例 13c] ( 3R) -1- ( 3- { 2-[ { 5-[ { 2-[3,5-雙（三氟曱 基）苯基]-2-甲基丙醯基}(甲基）胺基]-4-(2-曱基苯基） Dt匕咬-2-基}(曱基）胺基]乙氧基}丙基）°比洛咬-3 -基經 基（二-2-噻吩基）乙酸酯 使用實施例13b所獲得的化合物 （142mg、 0.232mmol)及實施例li所獲得的（3R )-吡咯啶-3-基羥 基（二噻吩-2-基）乙酸酯（55mg，0.177mmol)，依據實 施例3b記載的方法，而獲得呈白色固體之標題化合物 (99mg，產率 47% ) 〇 MS (FAB) m/z: 903(M + H) + . IR(KBr) vmax 2934，1738，1651，1 597，1 505，1 373, 1282，1 136, 896, 708 cm·1.[Example 13c] ( 3R) -1- ( 3- { 2-[ { 5-[ { 2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanyl} Methyl)amino]-4-(2-mercaptophenyl) Dt(R)-2-yl}(indenyl)amino]ethoxy}propyl)°Bilidine-3-yl-based Di-2-thienyl)acetate The compound obtained in Example 13b (142 mg, 0.232 mmol) and (3R)-pyrrolidin-3-ylhydroxy (dithiophen-2-yl) obtained in Example li were used. The title compound (99 mg, yield 47%) mp. MS (FAB) m/z: 903 (M + H) + IR(KBr) vmax 2934,1738,1651,1 597,1 505,1 373, 1282,1 136, 896, 708 cm·1.

[實施例14] 1- ( 2- { [6- ( { 4-[{3-[ ( N-{5-[ { 2-[3,5-雙（三氟 曱基）苯基]-2-曱基丙醯基}(甲基）胺基]-4- ( 2-甲基 -88 - 201143771 苯基）吼啶-2-基} -N-甲基甘胺醯基）（曱基）胺基]丙基} (甲基）胺曱醯基]苯基}胺基）己醯基](曱基）胺基丨乙 基）$啶-4-基聯苯基-2-基胺基甲酸賴[Example 14] 1-(2-{ [6-( { 4-[{3-[ ( N-{5-[ { 2-[3,5-bis(trifluoromethyl)phenyl]-2) -mercaptopropyl}(methyl)amino]-4-(2-methyl-88 - 201143771 phenyl) acridine-2-yl}-N-methylglycinyl) (fluorenyl) Amino]propyl}(methyl)amine fluorenyl]phenyl}amino)hexyl decyl](fluorenyl)amino oxime ethyl))acrid-4-ylbiphenyl-2-ylamino Formic acid

II

[實施例I4a]乙基N-{5-[{2-[3,5-雙（三氟曱基）苯基]_2_ 甲基丙醯基}(曱基）胺基]-4-(2-甲基苯基）。比啶_2_基}_心 甲基甘胺酸酯 於貫施例le所獲得的化合物（2 5〇g、4 91mm〇i )之 甲苯溶液（49mL)中，冰冷攪拌下，逐滴加入〇 5M六亞 甲基二矽氮烷鉀/甲苯溶液（39.3mL)，於室溫攪拌1〇分 鐘。再冰冷後，逐滴加入溴乙酸乙酯（5 44mL、 49.1mm〇l)’並於75°C加熱攪拌4日。於反應液中添加水 後，以乙酸乙酯提取（2次），所獲得的有機層以飽和食 鹽水洗淨。以無水硫酸鈉乾燥，減壓餾除溶劑而所獲得 的殘潰使用NH矽膠管柱層析（n_己烷：乙酸乙酯=6 及矽膠管柱層析（η-己烷：乙酸乙醋：=9 :丨_4 :丨）純化 獲得呈黃色油狀物之標題化合物（1 · 3 5 g、4 6 % )。 ]H NMR (CDC13, 500ΜΗζ): δ 1.27 (3Η, t, J = 7.5 Hz) 1.47-1.56 (6H, m), 2.12-2.16 (2H, m), 2.25-2.33 (3H, m) 2.53-2.57 (1H, m), 3.10 (3H, s), 3.66 (2H, s), 4.18 (2H q J = 7.5 Hz), 6·42 (1H，s)，7.23-7.28 (4H, m), 7.64-7.66 (2H, m), 7.75 (1H, s), 7.96 (1H, s). MS (APCI) m/z: 596 (M + H) + . -89- 201143771 [實施例14b]N-{5-[{2-[3,5-雙（三氟曱基）苯基]_2_曱基丙 醯基}(甲基）胺基]-4-(2-甲基苯基）D比啶_2_基}_氺甲基甘 胺酸 於實施例14a所獲得的化合物（1 35g、2 27mm〇1) 之乙醇溶液（23mL)中添加1N氫氧化鈉水溶液 (6 · 80mL ) ’於至溫攪拌} 5小時。於反應液中添加丨N鹽 酸水溶液（6.80mL)後，減壓餾除乙醇。添加二氣曱烷 而提取後，以無水硫酸鈉乾燥。減壓乾固溶劑，獲得粗 製之呈育綠固體之標題化合物（l.〇5g、產率μ%)。 H NMR (CDC13，500MHz): δ 1.18-1.38 (6H，m)， 2.12-2.27 (4Η, m)5 2.34-2.3 8 ( 1 H, m), 2.55-2.61 (1H, m), 3.15 (3H, s), 4.19-4.23 (1HS m), 4.38-4.43 (1H, m), 6.54 (1H, s), 7.23-7.27 (3H, m), 7.31-7.34 (1H, m), 7.63 (2H, s), 7.76 (1H, s), 7.95 (1H, s). MS (APCI) m/z: 568 (M + H) + .[Example I4a] Ethyl N-{5-[{2-[3,5-bis(trifluoromethyl)phenyl]_2-methylpropenyl}(indenyl)amino]-4-(2) -methylphenyl).比 _2 _ _ 心 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 〇 5M hexamethylene diazoxide potassium / toluene solution (39.3 mL), stir at room temperature for 1 Torr. After further ice-cooling, ethyl bromoacetate (5 44 mL, 49.1 mm )l) was added dropwise and heated at 75 ° C for 4 days. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate (2 times), and the obtained organic layer was washed with saturated brine. The residue was dried over anhydrous sodium sulfate and the solvent was evaporated evaporated evaporated. m m m m m m m m m m m m m m m m m m m m m m m m m m m The title compound (1 · 3 5 g, 4 6 %) was obtained as a yellow oil.]H NMR (CDC13, 500 ΜΗζ): δ 1.27 (3 Η, t, J = 7.5 Hz) 1.47-1.56 (6H, m), 2.12-2.16 (2H, m), 2.25-2.33 (3H, m) 2.53-2.57 (1H, m), 3.10 (3H, s), 3.66 (2H, s ), 4.18 (2H q J = 7.5 Hz), 6.42 (1H, s), 7.23-7.28 (4H, m), 7.64-7.66 (2H, m), 7.75 (1H, s), 7.96 (1H, s). MS (APCI) m/z: 596 (M + H) + . -89 - 201143771 [Example 14b] N-{5-[{2-[3,5-bis(trifluoromethyl)benzene) ] _2 _2 } } } } } } } } } } } } } } } } } } } } } } 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施To a solution of the compound (1 35 g, 2 27 mm 〇1) in ethanol (23 mL) was added 1N aqueous sodium hydroxide (6·80 mL), and stirred at room temperature for 5 hours. A solution of 丨N hydrochloric acid (6.80 mL) was added to the mixture. After that, the ethanol was distilled off under reduced pressure, and after adding dioxane and extracting, Drying over anhydrous sodium sulfate, the title compound was obtained (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , 2.12-2.27 (4Η, m)5 2.34-2.3 8 ( 1 H, m), 2.55-2.61 (1H, m), 3.15 (3H, s), 4.19-4.23 (1HS m), 4.38-4.43 (1H , m), 6.54 (1H, s), 7.23-7.27 (3H, m), 7.31-7.34 (1H, m), 7.63 (2H, s), 7.76 (1H, s), 7.95 (1H, s). MS (APCI) m/z: 568 (M + H) + .

[貫施例14c]N- { 5-[ { 2-[3,5-雙（三氟曱基）苯基]_2_甲 基丙醯基丨（曱基）胺基]-4- (2 -曱基苯基）η比咬_2_基} -Ν-曱基甘胺酸一鹽酸鹽 於實施例14b所獲得的化合物（50mg、〇.088 1mm〇i) 之'一污院浴液（2mL)中’冰冷下’添加4N鹽酸/二号 烷溶液（66 μι)。減壓乾固反應液，而獲得粗製之呈藍色 固體之標題化合物（46mg、產率87% )。 MS (FAB) m/z: 568(Μ + Η) + ·(游離體） IR(KBr) V— 298 1，1734，1 648，1471，ι 373, 1 282, 1 185，1 1 36, 897, 683 cm·1. -90- 201143771 [實施例14d] 4-[( 6-乙氧基-6-側氧基己基）胺基]苯曱酸 三級丁酯 將6-溴己烷酸乙基（5.55g、24.9mmol)及4-胺基苯 曱酸三級丁酯（4.37g、22.6mm〇l)溶解於ν,Ν-二曱基甲 醯胺（23mL) ’添加N，N-二異丙基乙基胺（4.72mL、 27.1mmol )及碘化鉀（4.13g、24.9mmol )，並於 65°C 攪 拌4日。於反應液中添加乙酸乙酯而稀釋後，以水及飽和 食鹽水洗淨，所獲得的有機層以無水硫酸鎂乾燥。減壓 餾除溶劑，所獲得的殘渣使用矽膠管柱層析純化（n-己 烷：乙酸乙酯=9 : 1 -1 : 1 )，獲得呈白色固體之標題化 合物（5.61g、產率74% )。 !H NMR (CDC13, 500 MHz): 61.26 (2Η, t, J = 7.32 Hz), 1.39-1.48 (2H, m)5 1.56 (9H, s), 1.59-1.73 (4H, m), 2.32 (2H, t, J = 7.32 Hz), 3.17 (2H, t, J = 7.〇8 Hz), 4.04 (1H, s), 4.13 (2H, q, J = 7.00 Hz), 6.52 (2H, d, J = 8.79 Hz), 7.81 (2H, d, J = 8.79 Hz). MS (FAB) m/z: 33 5 (M) + ; IR (KBr) vmax 3385, 1727, 1682, 1 602, 1288, 1269, 1 1 58, 1 1 1 3, 842, 772 cm'1.[Example 14c] N- { 5-[ { 2-[3,5-bis(trifluoromethyl)phenyl]_2-methylpropenyl fluorenyl (fluorenyl)amino]-4- (2) - mercaptophenyl) η than bite 2_yl} - fluorenyl-glycolic acid monohydrochloride salt of the compound obtained in Example 14b (50 mg, 〇.088 1mm〇i) A solution of 4N hydrochloric acid / dioxane (66 μm) was added to the solution under ice cooling (2 mL). The title compound (46 mg, yield: 87%). MS (FAB) m/z: 568 (Μ + Η) + · (free body) IR(KBr) V— 298 1,1734,1 648,1471,ι 373, 1 282, 1 185,1 1 36, 897 , 683 cm·1. -90- 201143771 [Example 14d] 4-[(6-Ethoxy-6-oxooxyhexyl)amino]benzoic acid tert-butyl butyl 6-bromohexaneate Base (5.55g, 24.9mmol) and 4-aminobutyl 4-aminobenzoate (4.37g, 22.6mm〇l) were dissolved in ν, Ν-dimercaptocarboxamide (23mL) 'Add N, N- Diisopropylethylamine (4.72 mL, 27.1 mmol) and potassium iodide (4.13 g, 24.9 mmol) were stirred at 65 ° C for 4 days. Ethyl acetate was added to the reaction mixture, and the mixture was diluted with water and brine, and the obtained organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. EtOAcjjjjjjjjjjjj %). !H NMR (CDC13, 500 MHz): 61.26 (2Η, t, J = 7.32 Hz), 1.39-1.48 (2H, m)5 1.56 (9H, s), 1.59-1.73 (4H, m), 2.32 (2H , t, J = 7.32 Hz), 3.17 (2H, t, J = 7.〇8 Hz), 4.04 (1H, s), 4.13 (2H, q, J = 7.00 Hz), 6.52 (2H, d, J = 8.79 Hz), 7.81 (2H, d, J = 8.79 Hz). MS (FAB) m/z: 33 5 (M) + ; IR (KBr) vmax 3385, 1727, 1682, 1 602, 1288, 1269, 1 1 58, 1 1 1 3, 842, 772 cm'1.

[實施例14e] 4- ( { 6-[ ( 2- { 4-[(聯苯基-2-基胺甲醯基） 氧基]哌啶-l-基}乙基）（甲基）胺基]-6-側氧基己基} 胺基）苯甲酸三級丁酯 於實施例14d所獲得的化合物（3.56g、10.6mmol) 之乙醇溶液（40mL )中，添加1N氫氧化鈉水溶液 (1 5.6mL )，於 5 0攪拌 1.5小時。添加乙酸乙酯 -91- 201143771 (2.0mL、1.5mmol)後，減壓濃縮反應液，冰冷下’添 加1N鹽酸水溶液（16mL )。過濾生成的沉澱，以水、 η-己烷、及二異丙基醚洗淨，獲得呈白色固體之6- { [4- (二級丁氧基裁基）本基]胺基丨己烧酸（3.〇ig、產率 92% ) 〇 將所獲得的化合物（3.01g、9.79mmol )及1-[2-(曱 基胺基）乙基]哌啶-4 -基聯苯基-2 -基胺基曱酸酯 (3_14g、8.90mmol)溶解於二氣甲烷（89mL)，冰冷下 添加 WSC · HC1 ( 2_25mg、11.8mmol)及 4-Ν,Ν-二曱基 胺基吡啶（12mg、0.098mmol )，於室溫攪拌20分鐘。 減壓濃縮反應液後’添加乙酸乙酯並以碳酸氫鈉水溶液 洗淨，所獲得的有機層以無水硫酸鎂乾燥。減壓餾除溶 劑而所獲得的殘渣使用NH矽膠管柱層析純化（己烷： 乙酸乙酯=2 : 8-0 : 1 〇 )’獲得呈白色固體之標題化合物 (5.63g、產率 98% )。 MS (FAB) m/z: 643 (M + H) + ; IR (KBr) vmax 2932, 1696, 1605, 1 523, 1292, 1 160, 1045, 772, 749, 702 cm-丨.[Example 14e] 4-( { 6-[ ( 2- { 4-[(biphenyl-2-ylaminocarbamoyl)oxy]piperidine-1-yl}ethyl)(methyl)amine A solution of the compound obtained in Example 14d (3.56 g, 10.6 mmol) in ethanol (40 mL) was added 1N aqueous sodium hydroxide (1) 5.6 mL), stirred at 50 for 1.5 hours. After ethyl acetate-91-201143771 (2.0 mL, 1.5 mmol) was added, the mixture was evaporated. The precipitate formed was filtered, washed with water, η-hexane, and diisopropyl ether to give 6-{[4-(2-butoxy-based) benzyl] carbazide as a white solid. Acid (3. 〇ig, yield 92%) 化合物 obtained compound (3.01 g, 9.79 mmol) and 1-[2-(decylamino)ethyl]piperidin-4-ylbiphenyl- 2-Amino decanoic acid ester (3_14g, 8.90mmol) was dissolved in di-methane (89mL), and WSC · HC1 (2_25mg, 11.8mmol) and 4-indole-indole-didecylaminopyridine (12mg) were added under ice cooling. , 0.098 mmol), stirred at room temperature for 20 minutes. After the reaction mixture was concentrated under reduced pressure, ethyl acetate was added and washed with aqueous sodium hydrogen carbonate, and the organic layer obtained was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to drynessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessness %). MS (FAB) m/z: 643 (M + H) + ; IR (KBr) vmax 2932, 1696, 1605, 1 523, 1292, 1 160, 1045, 772, 749, 702 cm-丨.

[實施例14f]l- ( 2- { [6- ({ 4_[ { 3_[(三級丁氧基羰基） (曱基）胺基]丙基}(曱基）胺甲醯基]苯基丨胺基）己 醯基](甲基）胺基}乙基）哌啶-4-基聯苯基_2_基胺基 甲酸酯 於實施例14e所獲得的化合物（丨.0^、丨68mmQi) 中添加4N鹽酸/二噂烷溶液（40mL)，於室溫攪拌i3 5 小時。於反應液中添加甲苯後，減壓餾除溶劑，獲得粗 -92- 201143771 製之4-({6-[(2-{4-[(聯苯基_2-基胺甲醯基）氧基] 派咬-l-基}乙基）（甲基）胺基]6側氧基己基}胺基） 苯甲酸二鹽酸鹽。 於獲得的粗製羧酸體中添加二氯曱烷（25mL )及三 乙基胺（938pL、6.73mmol )而溶解，冰冷攪拌下，逐 滴添加三甲基乙醯基氯（213mg、i 77mm〇1)之二氯曱 烧溶液（4mL )。於室溫攪拌1 5分鐘後，逐滴添加甲基 [3-(曱基胺基）丙基]胺基甲酸三級丁酯（3 57rng、 l_77mmol)，並於室溫攪拌3〇分鐘。於反應液中添加飽 和碳酸氫納水溶液並洗淨後，再於分離的水層中加入乙 酸乙酿作提取（2次）。合併有機層並以無水硫酸鎂乾燥， 減壓鶴除溶劑《所獲得的殘渣使用Νίί矽膠管柱層析純 化（η-己烷：乙酸乙酯=1 : · i 1 )，獲得呈白色固體 之標題化合物（948mg、產率89%)。 MS (FAB) m/z: 771 (M + H) + . IR (KBr) vmax 3340, 2932, 1694, 1 609, 1 523, 1 396, 1045, 83 1,765, 748, 703 cm'1.[Example 14f] l-(2-{ [6-({ 4_[ { 3_[(tertiary-butoxycarbonyl)(indenyl)amino]propyl}(indenyl)amine-methyl)]phenyl The compound obtained in Example 14e (丨.0^, 丨amino)hexyl]hexyl](methyl)amino}ethyl)piperidin-4-ylbiphenyl-2-ylaminoformate 4N Hydrochloric acid/dioxane solution (40 mL) was added to 丨68mmQi), and i3 was stirred at room temperature for 5 hours. After adding toluene to the reaction liquid, the solvent was distilled off under reduced pressure to give 4-({6-[(2-{4-[(biphenyl-2-ylaminocarbamoyl))). Base] l-l-yl}ethyl)(methyl)amino]6-oxo-hexyl}amino) benzoic acid dihydrochloride. Dichloromethane (25 mL) and triethylamine (938 pL, 6.73 mmol) were added to the obtained crude carboxylic acid to dissolve, and trimethylethyl sulfonyl chloride (213 mg, i 77 mm 〇) was added dropwise with stirring under ice cooling. 1) Dichlorohydrazine solution (4 mL). After stirring at room temperature for 15 minutes, methyl [3-(decylamino)propyl]carbamic acid tert-butyl butyl ester (3 57 ng, 1 - 77 mmol) was added dropwise and stirred at room temperature for 3 min. After adding a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture and washing it, acetic acid was added to the separated aqueous layer for extraction (2 times). The organic layer was combined and dried over anhydrous magnesium sulfate, and then evaporated, and then evaporated to the solvent to the residue (yield: hexane: ethyl acetate = 1 : · i 1 ) to give a white solid. The title compound (948 mg, yield 89%). MS (FAB) m/z: 771 (M + H) + . IR (KBr) vmax 3340, 2932, 1694, 1 609, 1 523, 1 396, 1045, 83 1,765, 748, 703 cm'1.

[實施例14g]l-[2-(曱基{ 6-[ ( 4-丨甲基[3-(曱基胺基） 丙基]胺曱醯基丨苯基）胺基]己醯基}胺基）乙基]哌啶 -4-基聯苯基-2-基胺基甲酸酯 於貫施例1 4 f所獲得的化合物（1 〇 3 m g、0. 〇 7 6 m m ο 1 ) 中添加2N鹽酸/甲醇溶液（4.9mL )，於室溫攪拌一晚。 於反應液中添加1Ν氫氧化鈉水溶液而作成鹼性後，以乙 酸乙酯提取，以無水硫酸鈉乾燥^減壓餾除溶劑，所獲 得的殘渣使用ΝΗ矽膠管柱層析純化（乙酸乙酯：甲醇= -93- 201143771 20: 1 —二氯甲烷：曱醇= l〇: 1)，獲得呈白色固體之標 題化合物（310mg、95%)。 MS(FAB) m/z: 671(M+H)+.[Example 14g] 1-[2-(indenyl{6-[(4-indolylmethyl[3-(decylamino)propyl))]indolylphenyl)amino]hexyl]} Amino)ethyl]piperidin-4-ylbiphenyl-2-ylcarbamate in the compound of Example 1 4 f (1 〇 3 mg, 0. 〇7 6 mm ο 1 ) A 2N hydrochloric acid/methanol solution (4.9 mL) was added and stirred at room temperature overnight. After adding 1 NaOH aqueous solution to the reaction mixture to make a basic solution, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness. Methanol = -93-201143771 20: 1 - dichloromethane: decyl alcohol = 1 〇: 1), the title compound (310 mg, 95%) MS(FAB) m/z: 671(M+H)+.

[實施例 14h]l- ( 2- { [6- ( { 4-[ { 3_[ ( N- { 5_[ { 2-[3,5-雙（三氟甲基）苯基]-2·曱基丙醯基}(甲基）胺基]-4-(2-甲基苯基）吼啶-2-基} -N-曱基甘胺醯基）（甲基） 胺基]丙基}(曱基）胺甲醯基]苯基}胺基）己醯基](甲 基）胺基}乙基）°底咬-4 -基聯笨基-2-基胺基曱酸酯 將貫施例14 g所獲得的化合物（3 1 〇 m g、〇 · 4 6 2 m m ο 1 ) 及實施例1 4c所獲得的化合物（5 1 〇mg、〇 796mmol )溶 解於二氯甲烧（5mL)，添加三乙基胺（192μί、 1.39mmol )、二曱基胺基吡啶（2mg )及 WSC · HC1 (133mg、0.6 94mmol )並於室溫攪拌18小時。減壓濃 縮反應液後，添加飽和碳酸氫鈉水溶液，以乙酸乙酯提 取。有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥。減 壓餾除溶劑而所獲得的殘渣使用NH矽膠管柱層析純化 (乙酸乙酯：曱醇=60 : 1 -50 : 1 )，獲得粗製之呈淡褐 色固體之標題化合物（27 1 mg )。所獲得的粗製物使用 逆相分取管柱層析（日本Waters，MSC180BD，5μιη， 30 x 1 00mm)(乙腈：0.1%曱酸銨水溶液=60 : 40 )純 化，獲得呈淡黃色固體之標題目的化合物（1 80mg，產 率 54% ) 〇 MS (FAB) m/z: 1220 (M + H) + . IR(KBr) vmax 2933，1731，1647，1 495，1 3 98，1281， 1 181，1 136，1080, 765 cm·1. -94- 201143771 [實施例15] 1-{2-[( {4-[( {4-[{3-[(]^-{5-[{2-[3,5-雙（三 氟曱基）苯基]-2 -曱基丙醯基}(甲基）胺基]-4- (2·曱 基笨基）吡啶-2-基丨-N-曱基甘胺醯基）（曱基）胺基] 丙基}(甲基）胺曱醯基]苯基}胺基）曱基]苯基}羰 基）（曱基）胺基]乙基}哌啶-4-基聯苯基-2-基胺基曱[Example 14h] l-(2- { [6-( { 4-[ { 3_[ ( N- { 5_[ { 2-[3,5-bis(trifluoromethyl)phenyl]-2·曱) (Methyl)amino]-4-(2-methylphenyl)acridin-2-yl}-N-mercaptosylamino)(methyl)amino]propyl} (Mercapto)Aminomethyl]phenyl}amino)hexanyl](methyl)amino}ethyl)°Bottom-4-based phenyl-2-ylamino phthalate will The compound obtained in Example 14 g (3 1 〇mg, 〇· 4 6 2 mm ο 1 ) and the compound obtained in Example 1 4c (5 1 〇mg, 〇796 mmol) were dissolved in dichloromethane (5 mL). Triethylamine (192 μί, 1.39 mmol), dimercaptoaminopyridine (2 mg) and WSC · HC1 (133 mg, 0.6 94 mmol) were added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to drynessnessnessnessnessnessnessnessnesssssssssssssssssssssssssss . The obtained crude product was purified by reverse phase separation column chromatography (Waters, MSC 180 BD, 5 μιη, 30 x 100 mm) (acetonitrile: 0.1% aqueous ammonium citrate = 60:40) to give a pale yellow solid title. The compound of interest (1 80 mg, yield 54%) 〇MS (FAB) m/z: 1220 (M + H) + . IR (KBr) vmax 2933,1731,1647,1 495,1 3 98,1281, 1 181 ,1 136,1080, 765 cm·1. -94- 201143771 [Embodiment 15] 1-{2-[( {4-[( {4-[{3-[(]^-{5-[{2 -[3,5-bis(trifluoromethyl)phenyl]-2-mercaptopropyl}(methyl)amino]-4-(2·indolyl)pyridin-2-ylindole- N-mercaptosylamino)(fluorenyl)amino]propyl}(methyl)amine fluorenyl]phenyl}amino)indolyl]phenyl}carbonyl)(indenyl)amino]B哌}piperidin-4-ylbiphenyl-2-ylamino hydrazine

[實施例15a] 1- ( 2- {[( 4-曱醯基苯基）羰基](甲基） 胺基}乙基）哌啶-4-基聯苯基-2-基胺基甲酸酯 將1-[2-(曱基胺基）乙基]〇底咬-4 -基聯苯基基 胺基曱酸酯（400mg、l.l3mm〇l )及4-曱醯基苯甲酸 (187mg、1.24mmol)溶解於二氣甲烷（llniL)，於室温 添加 WSC · HC1( 260mg、l.SGmmol)'1 直接.授拌 14 小時。 減壓德除反應液之溶劑，添加飽和碳酸氫鈉水溶液’以 乙酸乙自旨取。有機層以飽和食鹽水洗淨，以無水硫酉久 鈉乾燥後’減壓餾除溶劑。所獲得的殘渣使用矽膠管枉 層析純化（二氣曱炫&gt;:曱醇= 30: 1)，獲得呈白色固體 之標題化合物（433mg、產率79%)。 4 NMR (CDC13，500MHz): δ 1.24-1.31 (1H，m)， 1.64-1.70 (1H，m)，1.82- 1.87 ( 1H，m)，1.92-1.9“lH，m)， 2.07-2.12 (1H，m)，2.30-2.35 ( 1H，m)，2.43-2.46 (1H，m)， -95- 201143771 2.63- 2.65 (1 H, m), 2.77-2.82 (1H, m), 2.95 (1.5H, m), 3.11 (1.5H, m), 3.29-3.32 (1H, m), 3.65-3.67 ( 1H, m), 4.64- 4.68 (1H, m), 4.74-4.76 (1H, m), 6.59 (2H, s), 7.12-7.15 (1H, m), 7.22 (1H, d, J = 7.5 Hz), 7.34-7.38 (2H, m), 7.41-7.44 (1H, m), 7.47-7.51 (2H, m), 7.54-7.58 (2H, m)，7.92 (2H，d，J = 8.0 Hz)，8.08-8.12 (1H，m)，10.05 (1H， s)· MS (APCI) m/z: 486 (M + H) + .[Example 15a] 1-(2-{[(4-Mercaptophenyl)carbonyl](methyl)amino}ethyl)piperidin-4-ylbiphenyl-2-ylaminocarboxylic acid The ester will be 1-[2-(fluorenylamino)ethyl]indole Bite-4-ylbiphenylylamino decanoate (400 mg, 1.1 mm) and 4-mercaptobenzoic acid ( 187 mg, 1.24 mmol) was dissolved in di-methane (llniL), and WSC · HC1 (260 mg, 1.SGmmol) '1 was added at room temperature. The solvent of the reaction mixture was removed under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was then taken from ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) 4 NMR (CDC13, 500MHz): δ 1.24-1.31 (1H, m), 1.64-1.70 (1H, m), 1.82- 1.87 (1H, m), 1.92-1.9"lH,m), 2.07-2.12 (1H , m), 2.30-2.35 ( 1H, m), 2.43 - 2.46 (1H, m), -95- 201143771 2.63- 2.65 (1 H, m), 2.77-2.82 (1H, m), 2.95 (1.5H, m), 3.11 (1.5H, m), 3.29-3.32 (1H, m), 3.65-3.67 ( 1H, m), 4.64- 4.68 (1H, m), 4.74-4.76 (1H, m), 6.59 (2H , s), 7.12-7.15 (1H, m), 7.22 (1H, d, J = 7.5 Hz), 7.34-7.38 (2H, m), 7.41-7.44 (1H, m), 7.47-7.51 (2H, m ), 7.54-7.58 (2H, m), 7.92 (2H, d, J = 8.0 Hz), 8.08-8.12 (1H, m), 10.05 (1H, s)· MS (APCI) m/z: 486 (M + H) + .

[實施例15b]4-( {4-[(2-丨4-[(聯苯基-2-基胺曱醯基） 氧基]哌啶-1 -基}乙基）（甲基）胺曱醯基]苄基丨胺基） 苯曱酸三級丁酯 將實施例15a所獲得的化合物（433mg、0.892mmol) 及4-胺基苯曱酸三級丁酯（157mg、〇.811mmol)溶解於 一氣甲烧（9mL)，於室溫添加乙酸（42pL)及氫化三乙 醯氧基硼鈉（258mg、1.22mmol)，並攪拌一晚。減壓館 除反應液之溶劑，所獲得的殘渣使用NH石夕膠管柱層析 純化（η -己烧·乙酸乙自旨=1. 1-1: 2)，獲得呈白色固 體之標題化合物（399mg、產率74% )。 'H NMR (CDC13, 500MHz): δ 1.55 (9Η, s), 1.65-1.68 (1H, m), 1.82-1.87 (1H, m), 1.91-1.96 (1H, m), 2.08-2 11 (1H, m), 2.30-2.33 (1H, m), 2.42-2.52 (1H, m), 2.60-2.64 (1H, m), 2.76-2.80 (1H, m), 2.97-3.09 (3H, m) 3.32-3 37 (2H, m), 3.63-3.66 (2H, m), 4.41 (1H, d, J = 5.2 Hz) 4.46-4.48 (1H, m), 4.66-4.76 (2H, m), 6.55-6.59 (3H, m), 7.11-7.15 (2H, m), 7.21 (1H, d, J = 7.5 Hz), 7.35-7.40 (5h, -96- 201143771 m)，7.42 (1H，d，J = 7.5Hz)，7.49 (2H，t，J = 7.5 Hz)，7.81 (2H, d, J = 8.6 Hz), 8.08-8.12 (2H, m). MS (APCI) m/z: 663 (M + H) + .[Example 15b] 4-( {4-[(2-丨4-[(biphenyl-2-ylaminoindolyl)oxy]piperidin-1 -yl}ethyl)(methyl)amine The compound obtained in Example 15a (433 mg, 0.892 mmol) and the 4-tert-butyl 4-aminobenzoate (157 mg, 〇.811 mmol) were obtained as the benzyl benzylamino) benzoic acid tert-butyl ester. It was dissolved in a gas-fired (9 mL), and acetic acid (42 pL) and hydrogenated sodium triacetoxyborate (258 mg, 1.22 mmol) were added at room temperature and stirred overnight. The residue obtained in the decompression chamber was purified by NH.sub.2 chromatography (n-hexane, ethyl acetate = 1. 1-1: 2). 399 mg, yield 74%). 'H NMR (CDC13, 500MHz): δ 1.55 (9Η, s), 1.65-1.68 (1H, m), 1.82-1.87 (1H, m), 1.91-1.96 (1H, m), 2.08-2 11 (1H , m), 2.30-2.33 (1H, m), 2.42-2.52 (1H, m), 2.60-2.64 (1H, m), 2.76-2.80 (1H, m), 2.97-3.09 (3H, m) 3.32- 3 37 (2H, m), 3.63-3.66 (2H, m), 4.41 (1H, d, J = 5.2 Hz) 4.46-4.48 (1H, m), 4.66-4.76 (2H, m), 6.55-6.59 ( 3H, m), 7.11-7.15 (2H, m), 7.21 (1H, d, J = 7.5 Hz), 7.35-7.40 (5h, -96- 201143771 m), 7.42 (1H, d, J = 7.5Hz) , 7.49 (2H, t, J = 7.5 Hz), 7.81 (2H, d, J = 8.6 Hz), 8.08-8.12 (2H, m). MS (APCI) m/z: 663 (M + H) + .

[貫施例 15c]l-{2-[( {4_[( {4_[{3_[(三級丁 氧基羰 基）（甲基）胺基]丙基丨（甲基）胺曱醯基]苯基}胺 基）曱基]苯基}羰基）（曱基）胺基]乙基丨哌啶_4_基聯 本基-2 -基胺基曱酸酿 於實施例15b所獲得的化合物（399mg、〇.602mmol) 之二0f烧溶液（3mL )中添加4N鹽酸-二噚烷（1 2mL )， 並於室溫擾拌14.5小時。於反應液中添加甲苯後，減壓 乾固溶劑’獲得粗製之呈白色固體之4_({ 4_[( 2_{ 4_K聯 苯基-2-基胺曱醯基）氧基]哌啶-卜基丨乙基曱基）胺 甲醯基]苄基}胺基）苯曱酸二鹽酸鹽。 於所獲得的粗製物之二氣曱烷溶液（6mL )中加入 三乙基胺（418 μί、3.01 mmol)、曱基[3_(曱基胺基）丙 基]胺基曱酸三級丁酯（122rng、〇_6〇2mmol )、及WSC · HC1 ( 138mg、0.722mmol )，於室溫攪拌3.5小時。添加 4-二曱基胺基。比啶（4mg )，於室溫攪拌2_5日。於反應 液中添加乙酸乙酯加以稀釋，有機層以飽和碳酸氫鈉水 溶液及飽和食鹽水洗淨。有機層以無水硫酸鈉乾燥後， 減壓餾除溶劑而所獲得的殘渣使用NH矽膠管柱層析純 化（乙酸乙醋：曱醇=60 : 1 )’獲得呈白色固體之標題 化合物（392mg、產率82% )。 MS (APCI) m/z: 791 (M + H) + . IR(KBr) vmax 2932，1693，1609，1 522，1449，1398: 1222, 1045, 833, 765 cm'1. -97- 201143771 [實施例15d]l - ( 2- {曱基[(4_ { [ ( 4- {甲基[3-(甲基 胺基）丙基]胺甲醯基}苯基）胺基]甲基}苯基）羰基] 胺基}乙基）哌啶-4-基聯苯基-2-基胺基甲酸酯 於實施例15c所獲得的化合物（39〇mg、〇.493mmol) 中添加2N鹽酸一甲醇溶液（4·93mL)並溶解’室溫攪拌。 於反應液中添加1N氫氧化鈉水溶液後’以乙酸乙龍提 取。有機層以無水硫酸鈉乾燥後，減壓餾除溶劑而所萑 得的殘渣使用NH矽膠管柱層析純化（乙酸乙酿.^ 甲酉 固體之 = 20: 1 —二氣甲烷：甲醇=10: 1)，獲得呈白色 標題化合物（306mg、產率90%)。 (6H，m)， (1 H，m)， 〇H，m)， (1H，m)， (1H，m)， (3H，m)， (3H，m)， (2H，t，j NMR (CDC13, 500MHz): δ 1.54-i.6l 1.64-1.69 (lH，m)，1.77- 1.86 (3Η，m)，1.91] 95 2.07-2.11 (1H，m)，2.31-2.64 (8H，m)，2,76-2.80 2.97-3.02 (3H, m), 3.07-3.10 (1H, m), 3.33-3 37 3.47-3.51 (2H，m)，3.63-3.66 (1H，m)，4.3〇_4 33 4.39-4.40 (1H，m)，4.69-4.75 (1H，m)，6.56-6.58 7.11-7.15 (1H, m), 7.21-7.73 (2H，m)，7.26-7 27 7.3 5-7.40 (5H, m), 7.43 (1H, d, J = 7.5Hz), 7 49 =7.5 Hz), 8.07-8.11 (1H, m). MS (APCI) m/z: 691 (M + H) + .[Example 15c] 1-{2-[( {4_[( {4_[{3_[(Tris-butoxycarbonyl)(methyl)amino]propyl propyl (methyl)amine fluorenyl] Phenyl}amino)indenyl]phenyl}carbonyl)(indenyl)amino]ethylpiperidinyl-4-yl-2-ylaminophosphonic acid The compound obtained in Example 15b was obtained. 4N Hydrochloric acid-dioxane (1 2 mL) was added to a solution of (399 mg, 〇. 602 mmol) of EtOAc (3 mL), and the mixture was stirred at room temperature for 14.5 hours. After adding toluene to the reaction mixture, the solvent was dried under reduced pressure to give a crude white solid (yield of 4-({4_[(2_{4_K biphenyl-2-ylamino) hydrazino))). Ethyl decyl)amine carbaryl]benzyl}amino)benzoic acid dihydrochloride. Triethylamine (418 μί, 3.01 mmol), decyl [3_(decylamino)propyl]amino decanoic acid tert-butyl ester was added to the obtained crude dioxane solution (6 mL). (122rng, 〇_6〇2mmol), and WSC · HC1 (138mg, 0.722mmol) were stirred at room temperature for 3.5 hours. 4-Didecylamino group is added. Bisidine (4 mg) was stirred at room temperature for 2-5 days. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate (MgSO4), EtOAcjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Yield 82%). MS (APCI) m/z: 791 (M + H) + . IR (KBr) vmax 2932,1693,1609,1 522,1449,1398: 1222, 1045, 833, 765 cm'1. -97- 201143771 [ Example 15d] l - (2-{Mercapto[(4_{[(4-{methyl[3-(methylamino)propyl))aminomethyl)}phenyl)amino]methyl}benzene To the compound obtained in Example 15c (39 mg, 〇.493 mmol), 2N hydrochloric acid was added to the carbonyl group]amino}ethyl)piperidin-4-ylbiphenyl-2-ylcarbamate. Methanol solution (4.93 mL) was dissolved and stirred at room temperature. After adding 1 N aqueous sodium hydroxide solution to the reaction mixture, it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue obtained was purified using NH </ br> </ br> column chromatography : 1) The title compound (306 mg, yield 90%) was obtained. (6H,m), (1 H,m), 〇H,m), (1H,m), (1H,m), (3H,m), (3H,m), (2H,t,j NMR (CDC13, 500MHz): δ 1.54-i.6l 1.64-1.69 (lH,m), 1.77- 1.86 (3Η,m),1.91] 95 2.07-2.11 (1H,m),2.31-2.64 (8H,m) , 2,76-2.80 2.97-3.02 (3H, m), 3.07-3.10 (1H, m), 3.33-3 37 3.47-3.51 (2H,m),3.63-3.66 (1H,m),4.3〇_4 33 4.39-4.40 (1H, m), 4.69-4.75 (1H, m), 6.56-6.58 7.11-7.15 (1H, m), 7.21-7.73 (2H, m), 7.26-7 27 7.3 5-7.40 (5H , m), 7.43 (1H, d, J = 7.5Hz), 7 49 =7.5 Hz), 8.07-8.11 (1H, m). MS (APCI) m/z: 691 (M + H) + .

[實施例 1 5e] 1 - { 2-[ ( { 4- [ ( { 4-[ { 3 - [ ( N- { 5_[ ( 2 雙（二親*曱基）本基]-2 -甲基丙酿基丨（&quot;甲且、 f ; 、T基）胺基]-4_ (2-曱基苯基）。比啶-2-基} -N-曱基甘胺酿基）（ 胺基]丙基}(曱基）胺甲醯基]苯基丨胺基）甲其]—土） 幾基）（曱基）胺基]乙基}〇底。定-4 -基聯絮：a： 。 ^ ^ 甲酸_ .本基I基胺基 -98- 201143771 使用實施例 15 d所獲得的化合物Γ , ς r v 丄 5 6 m g、 0.2 2 6 m m ο 1 )及實施例1 4 c所獲得的化合物r 7 W89nig、 0.452mmol )，而依據實施例14h記载的方法 θ ^ 後件呈淡 黃色固體之標題化合物（lOlmg、產率36%)。 MS (FAB) m/z: 1240 (M + H) + . IR(KBr) vmax 293 1, 1 733, 1609, 1495, 1 398, 1 28 1, 1 1 82, 1 136, 1079, 752 cm·1· [實施例16] (3R) -1- { 4-[ ( { [ ( 2S ) -Γ- { 2-[ ( 5R) -3-[3,5-雙（三氟曱基）苯曱醯基]-5 - ( 4-氟笨基）-1，3-嘮唑啶- 5-基]乙基} -2,3-二氫螺[茚-1，4’-哌啶]_·2-基]氧基}乙醯基） (甲基）胺基]丁基}吡咯啶-3-基羥基（二-2·噻吩基） 乙酸酯二鹽酸鹽[Example 1 5e] 1 - { 2-[ ( { 4- [ ( { 4-[ { 3 - [ ( N- { 5_[ ( 2 bis (indolyl)-yl)]-2-methyl Alkyl (&quot;methyl, f; , T-based) amino]-4_(2-mercaptophenyl).pyridin-2-yl}-N-mercaptoamine-based (amino group) ]]]}}}}]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]] : ^ ^ Formic acid _. The present group I-amino group-98- 201143771 obtained using the compound obtained in Example 15 d, ς rv 丄 5 6 mg, 0.2 2 6 mm ο 1 ) and Example 1 4 c The title compound (10 mg, yield 36%) of the title compound (yield: 36%). MS (FAB) m/z: 1240 (M + H) + . IR(KBr) vmax 293 1, 1 733, 1609, 1495, 1 398, 1 28 1, 1 1 82, 1 136, 1079, 752 cm· 1· [Example 16] (3R) -1- { 4-[ ( { [ ( 2S ) -Γ- { 2-[ ( 5R) -3-[3,5-bis(trifluoromethyl)phenylhydrazine) Mercapto]-5-(4-fluorophenyl)-1,3-oxazolidine-5-yl]ethyl}-2,3-dihydrospiro[茚-1,4'-piperidine]_· 2-yl]oxy}ethenyl) (methyl)amino]butyl}pyrrolidin-3-ylhydroxy (di-2·thienyl) acetate dihydrochloride

CF, [實施例 16a]2- { [ ( 2S) -Γ- { 2-[ ( 5R) -3-[3,5-雙（三 氟曱基）苯曱醯基]-5- ( 4-氟苯基）.,l，3- 唑啶-5-基]乙 基} -2,3-二氳螺[茚-1,4’-哌啶]-2-基]氧基} -Ν- ( 4-羥基 丁基）-Ν-曱基乙醯胺 使用實施例 6i所獲得的化合物 （250mg、 0.360mmol )、4-(甲基胺基）丁 -1 -醇（44.6mg、 0.43 2mmol )，並依據實施例6£記載的方法，獲得呈白色 固體之標題化合物（204mg、產率73% )。 -99- 5 201143771 MS (FAB) m/z: 781 (M + H) + . IR(KBr) vmax 3426，2932，1648，1359，1281，1181， 1 1 39, 907, 758, 682 cm'1.CF, [Example 16a] 2- { [ ( 2S) -Γ- { 2-[ ( 5R) -3-[3,5-bis(trifluoromethyl)phenylindenyl]-5- ( 4- Fluorophenyl).,l,3-oxazolidin-5-yl]ethyl}-2,3-dioxaspiro[茚-1,4'-piperidinyl]-2-yl]oxy} -Ν- (4-Hydroxybutyl)-indole-mercaptoacetamide The compound obtained in Example 6i (250 mg, 0.360 mmol), 4-(methylamino)butan-1-ol (44.6 mg, 0.43 2 mmol) The title compound (204 mg, yield: 73%) -99- 5 201143771 MS (FAB) m/z: 781 (M + H) + . IR(KBr) vmax 3426,2932,1648,1359,1281,1181, 1 1 39, 907, 758, 682 cm'1 .

[實施例 16b]4-[ ({ [ ( 2S) -1’ - { 2-[ ( 5R) -3-[3,5-雙（三 氟曱基）苯曱醯基]-5- ( 4-氟苯基）-1，3- 唑啶-5-基]乙 基}-2,3-二氫螺[茚-1，4’-哌啶]-2-基]氧基}乙醯基）（曱 基）胺基]丁基甲烷磺酸酯 將實施例1 6 a所獲得的化合物（3 0 0 m g、0 · 3 8 5 m m ο 1 ) 之二氯曱烷溶液（5mL )冷卻，添加三乙基胺（64μί、 0.462mmol)及甲院石黃醯氣（36pL、0.462mmol)，並直 接攪拌1小時。於反應液中添加水，以二氣曱烷提取。 使用矽膠管柱層析純化（乙酸乙酯：二氣曱烷：曱醇=5 : 5: 0-5·· 5: 1)，獲得標題化合物（327mg、產率99%)。 MS(FAB) m/z : 8 5 8 ((M + H) + ,游離體） IR(KBr) vmax: 3437，1651，1511，1436，1 359, 1 282, 1 225，1174，1138，1108, 848, 760, 682, 529 cm.1.[Example 16b] 4-[ ({ [(2S) -1' - { 2-[( 5R) -3-[3,5-bis(trifluoromethyl)phenyl)]-5- ( 4 -fluorophenyl)-1,3-oxazolidin-5-yl]ethyl}-2,3-dihydrospiro[indol-1,4'-piperidinyl]-2-yl]oxy}ethenyl ((mercapto)amino]butyl butyl sulfonate The solution of the compound obtained in Example 166 (3 0 0 mg, 0 · 3 8 5 mm ο 1 ) in dichloromethane (5 mL) was cooled. Triethylamine (64 μί, 0.462 mmol) and scutellaria (36 pL, 0.462 mmol) were added and stirred directly for 1 hour. Water was added to the reaction liquid, and the mixture was extracted with dioxane. The title compound (327 mg, yield: 99%) was obtained. MS (FAB) m/z: 8 5 8 ((M + H) + , free) IR (KBr) vmax: 3437,1651,1511,1436,1 359, 1 282, 1 225,1174,1138,1108 , 848, 760, 682, 529 cm.1.

[實施例 16c] ( 3R) -1- { 4-[ ({ [ ( 2S) -1，- { 2-[ ( 5R) -3-[3,5-雙（三氟曱基）苯曱醯基]_5_(4_氟苯基）_i，3_ 噚唑啶-5-基]乙基} -2,3-二氫螺[茚- l，4’-哌啶]-2-基]氧 基}乙醯基）（甲基）胺基]丁基}吼咯啶-3-基羥基（二 -2 -β塞吩基）乙酸S旨二鹽酸鹽 將實施例1 6b所獲得的化合物（1 50mg、0 · 1 7 5 mmo 1) 及實施例1 i所獲得的化合物（6 5 m g、0.2 1 m m ο 1)溶解於 乙腈（5mL)，添加碳酸鉀（48mg、〇.35mmol )並於80°C 攪拌20小時。減壓濃縮反應液後，添加水，並以二氯甲 -100- 201143771 烷提取。使用NH矽膠管柱層析純化（乙醆乙酯.二氣 甲烷= 0:100-50: 50)，獲得標題化合物之游離體^ 5img'、 產率27% )。將所獲得的游離體溶解於乙酸乙酷，以in 鹽酸水溶液洗淨。分離有機層並減壓乾固，獲得呈白色 固體之標題化合物。 IR(KBr) vmax: 3259, 2935，256 5，1742，1652，1510, 1434, 1 359, 1282, 1228, 1 180, 1 1 39, 848, 760, 707, 682 cm'1. MS(FAB) m/z : 1071 ((M + H) +，游離體） [實施例17] 8- { 4-[ ({ [ ( 2S) -1’- { 2-[ ( 5R) _3-[3,5-雙（三氟 曱基）苯曱醯基]-5-( 4 -氟苯基）-1,3 -号嗤σ定_5_基]乙基} -2,3-二氫螺[茚-1，4’-哌啶]-2-基]氧基}乙醯基）（曱基） 胺基]丁基} -8-氮雜雙環[3.2.1]辛-3-基羥基（二-2_嘆吩 基）乙酸酯二鹽酸鹽[Example 16c] ( 3R) -1- { 4-[ ({ [ (2S) -1,- { 2-[( 5R) -3-[3,5-bis(trifluoromethyl)phenylhydrazine) _5_(4_fluorophenyl)_i,3_oxazolidin-5-yl]ethyl}-2,3-dihydrospiro[茚-l,4'-piperidinyl]-2-yl]oxy Ethyl hydrazide) (methyl)amino] butyl} fluoren-3-yl hydroxy (di-2 - β-sepyl) acetic acid S dihydrochloride The compound obtained in Example 166 ( 1 50 mg, 0 · 1 7 5 mmo 1) and the compound obtained in Example 1 i (6 5 mg, 0.2 1 mm ο 1) was dissolved in acetonitrile (5 mL), potassium carbonate (48 mg, 〇.35 mmol) was added and Stir at 80 ° C for 20 hours. After concentrating the reaction mixture under reduced pressure, water was added and extracted with methylene chloride -100 - 201143771. Purification by column chromatography on EtOAc (EtOAc EtOAc (EtOAc:EtOAc) The obtained free body was dissolved in ethyl acetate and washed with an aqueous solution of hydrochloric acid. The title compound was obtained as a white solid. IR(KBr) vmax: 3259, 2935,256 5,1742,1652,1510, 1434, 1 359, 1282, 1228, 1 180, 1 1 39, 848, 760, 707, 682 cm'1. MS(FAB) m/z : 1071 ((M + H) +, free form) [Example 17] 8- { 4-[ ({ [ ( 2S) -1'- { 2-[ ( 5R) _3-[3,5 - bis(trifluoromethyl)phenylhydrazino]-5-(4-fluorophenyl)-1,3-form 嗤σ定_5_yl]ethyl} -2,3-dihydrospiro[茚-1,4'-piperidinyl]-2-yl]oxy}ethenyl)(fluorenyl)amino]butyl}-8-azabicyclo[3.2.1]oct-3-ylhydroxy (two -2_story phenyl) acetate dihydrochloride

[實施例17a] 3-[2-羥基（二-2-噻吩基）乙醯氧基]_8_氮 雜雙環[3.2.1]辛烷-8-甲酸三級丁酯 氮氣環境下，於氫化鈉（450mg (含量55%、礦物 油分散物）、1 0 _ 3 mmo 1)之甲苯懸浮溶液（6.7mL )中， 室溫攪拌下逐滴添加羥基（二-2-噻吩基）乙酸甲酯 (2.54g、l〇_〇mmol)及 3-羥基-8-氮雜雙環[3.2.1]辛烷-8- -101 - 201143771 曱酸三級丁酯（2.27g、lO.Ommol)之曱笨（20mL)-四 鼠咳喃（1 0 m L )混合溶液。於室溫授摔1 0分鐘後，一 邊將系統内以200-300mmHg減壓一邊於75°C攪拌1小 時’再加熱回流3.5小時。放冷後’添加1 〇 %檸檬酸水 溶液及水，以乙酸乙酯提取。有機層以無水硫酸鈉乾燥， 減壓餾除溶劑。所獲得的殘渣使用矽膠管柱層析純化（η· 己烧：乙酸乙酯=1 0 ·· 1 - 5 : 1 )，獲得呈白色固體之標題 化合物（3.75g、產率83%)。 *H NMR (CDC13, 400ΜΗζ): δ 1.20-1,54(2H, m), 1.44(9H,s), 1.66-1.82(4H, m), 2.01 -2.25(2H, m)， 3.95-4.25(2H, m), 5.24(lH,dd, J = 4.7, 5.1 Hz), 7.00(2H, dd, J = 3.9, 4.7 Hz), 7.16(2H, d, J = 3.9 Hz), 7.31(2H, d, J = 4.7 Hz). MS(FAB) m/z: 450 (M + H) + . ，1686， 1401， 1274, 基羥基（二-2-噻吩 IR(KBr) vmax 3453, 2974, 1 7 1 7 1026, 794, 706 cm' [實施例17b]8-氮雜雙環[3.2.1]辛_3_ 基）乙酸酯 於實施例17a所獲得的化合物（3 4 、乂 4 3 g、7 · 6 3 m m ο 1 ) 之二烷溶液（20mL)中添加4N_醅卜 烷溶液（20mL) 並於室溫攪拌5小時。減壓濃縮溶劑[Example 17a] 3-[2-Hydroxy(di-2-thienyl)ethyloxy]-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl hydride under hydrogenation Add sodium hydroxy(di-2-thienyl)acetate dropwise at room temperature with stirring in a suspension of sodium (450 mg (55% in mineral oil dispersion), 1 0 _ 3 mmo 1) in toluene (6.7 mL) (2.54g, l〇_〇mmol) and 3-hydroxy-8-azabicyclo[3.2.1]octane-8- -101 - 201143771 三 butyl citrate (2.27g, lO.Ommol) Stupid (20 mL) - four mouse cough (10 m L) mixed solution. After dropping for 10 minutes at room temperature, the system was further stirred at 75 ° C for 1 hour while depressurizing at 200-300 mmHg, and then heated under reflux for 3.5 hours. After cooling, '1 〇% citric acid water solution and water were added, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc *H NMR (CDC13, 400ΜΗζ): δ 1.20-1, 54 (2H, m), 1.44 (9H, s), 1.66-1.82 (4H, m), 2.01 -2.25 (2H, m), 3.95-4.25 ( 2H, m), 5.24 (lH, dd, J = 4.7, 5.1 Hz), 7.00 (2H, dd, J = 3.9, 4.7 Hz), 7.16 (2H, d, J = 3.9 Hz), 7.31 (2H, d , J = 4.7 Hz). MS(FAB) m/z: 450 (M + H) + . , 1686, 1401, 1274, hydroxy (di-2-thiophene IR (KBr) vmax 3453, 2974, 1 7 1 7 1026, 794, 706 cm' [Example 17b] 8-Azabicyclo[3.2.1]octyl-3-yl)acetate The compound obtained in Example 17a (3 4 , 乂 4 3 g, 7 · A 4 N_decane solution (20 mL) was added to a solution of 6 3 mm EtOAc (20 mL) and stirred at room temperature for 5 hr. Concentrated solvent under reduced pressure

^冷Μ杰加乙酸乙酯及1N 氫氧化鈉水溶液加以提取（3。女』、 .. 有機層以無水硫酸鎖 乾烯，減壓餾除溶劑。所獲得的 坟盈使用NH矽膠管柱層 析純化（乙酸乙酯：甲醇=1〇 1 υ . 1 )，獲得呈淡音 色固體之標題化合物（2.22g、產率83% )。 、 -102- 201143771 MS(FAB) m/z: 350 (M + H) + . IR(KBr) vmax 2947, 1732, 1494, 1244, 1233, 1080, 1034, 850, 703 cm'1.^Cold ΜJia ethyl acetate and 1N aqueous sodium hydroxide solution (3. Female), .. organic layer with anhydrous sulfuric acid lock dry olefin, solvent distillation under reduced pressure. The obtained grave is using NH 矽 rubber tube column The title compound (2.22 g, yield: 83%) was obtained eluted eluted eluted eluted eluted eluted M + H) + . IR(KBr) vmax 2947, 1732, 1494, 1244, 1233, 1080, 1034, 850, 703 cm'1.

[實施例 17c]8- { 4-[ ( { [ ( 2S ) -1， { 2-[ ( 5R ) -3-[3,5-雙（二氣曱基）苯曱醯基]-5-(4-氟苯基）-1,3-°^·。坐。定- 5-基]乙基} -2,3-二氫螺[茚-1，4，-哌啶]-2-基]氧基}乙醯基） (甲基）胺基]丁基}-8-氮雜雙環[3.2.1]辛-3-基羥基（二 -2-噻吩基）乙酸酯二鹽酸鹽 將貫施例1 6 b所獲得的化合物（2 3 6 m g、0.2 5 6 m m ο 1 ) 及實施例17b所獲得的化合物（i〇7mg、〇 3〇7mm〇i)溶 解於乙猜（5mL)’添加碳酸針（71mg、〇,512mmol)及 蛾化钾（8 5 m g、〇 . 5 1 2 m m ο 1 )並於8 0 °C授拌2 0小時。減 壓濃縮反應液後，添加水，並以二氣曱烧提取。使用NH 矽膠管柱層析（乙酸乙酯：二氣甲烷=〇 : 1〇〇_1〇〇 : 〇 ) 及逆相管柱純化，獲得標題化合物之游離體（42mg、產 率1 5 % )。將所獲得的游離體溶解於乙酸乙酯，以1 n鹽 酸水溶液洗淨。分離有機層並減壓乾固，獲得呈白色固 體之標題化合物。 IR(KBr) vmax： 3416, 2954, 257 1, 1737, 1650, 15 10, 1434, 1360, 1282, 1225, 1 176, 1 139, 848, 759, 707, 682 cm'1. MS(FAB) m/z : 1111 ((M + H) +，游離體）. (試驗例1 ) [天竺鼠NK!受體結合試驗] C： -103- 201143771 y以竺鼠粗膜標.本可實施受體結合試驗。即將NKl 受體高表現部位的肺組織摘出後製作粗膜桿|，使[3H] 物質P“UbSUnCeP)及被驗物質與粗膜標本液反應後， 藉由膜成分回收後測量放射活性，可算出 竺鼠NK丨受體之親和性。 負耵大 (試驗例2 ) [天竺鼠NK2受體結合試驗] =竺鼠粗膜標本可實施受體結合試驗。即將％ =表現部位的回腸組織摘出後製作粗膜標本，使 3 ΤΙ或神經激肽A及被驗物質與粗膜標本液反 :後，猎由膜成分回收後測量放射活性 質對天竺鼠NK2受體之親和，卜 ”出被驗物 (試驗例3 ) [天竺鼠Μ〗受體結合試驗] 受二=粗膜標本可實施受體結合試驗。即將吣 [N·;: 4°:…腺組織摘出後製作粗膜標本，使 反二二二·“胺甲基氣及被驗物質與粗膜標本液 物質對天竺鼠m3受體之親和性舌性，可算出被驗 (試驗例4) [人類NK,受體結合試驗] 合試二Γ對T1人受體表現細胞的粗膜標本可實施受體結 標本使=ζΝΚ1受體表現咖細胞調製的粗膜 +使[Η]物i Ρ及被驗物f與粗膜標本液反應 ,藉由膜成分回收後測量放射活性，可算出： 對人類NK丨受體之親和性。 了异出破驗物質 -104- 201143771 (試驗例5 ) [人類NK：2受體結合試驗] (a )粗膜標本之製作 將人型NK：2受體表現COS細胞之冷凍保存細胞液以 緩衝液（含0.04%牛血清白蛋白（BSA)的50 mM參-鹽酸， PH7 ·4 )稀釋而作成5 · Ox 1 05個細胞/ml，作為粗膜標本來 使用。 (b )受體結合試驗 將[3H]Sil 48968 ( GE Healthcare . Japan (股））以 混合液（50mM參-鹽酸（pH7.4) 、6mM氯化猛4水合 物、800 μ g/mL BSA、8 /z g/m:L糜蛋白酶抑制素[Example 17c] 8-{ 4-[( { [ ( 2S ) -1, { 2-[( 5R ) -3-[3,5-bis(dimethyl)phenyl)]-5- (4-fluorophenyl)-1,3-°^·. Sodium. 5-Benzyl]ethyl}-2,3-dihydrospiro[茚-1,4,-piperidinyl]-2-yl ]oxy}ethinyl)(methyl)amino]butyl}-8-azabicyclo[3.2.1]oct-3-ylhydroxy(di-2-thienyl)acetate dihydrochloride The compound obtained in Example 1 6 b (2 3 6 mg, 0.256 mm ο 1 ) and the compound obtained in Example 17b (i〇7 mg, 〇3〇7 mm〇i) were dissolved in B guess (5 mL). ) Add carbonate needles (71 mg, cesium, 512 mmol) and potassium moth (85 mg, 〇 5 1 2 mm ο 1 ) and mix for 20 hours at 80 °C. After the reaction mixture was concentrated under reduced pressure, water was added and extracted with a second gas. The title compound was obtained as a free compound (42 mg, yield: 15%) using EtOAc (EtOAc: EtOAc: EtOAc: . The obtained free body was dissolved in ethyl acetate and washed with a 1 n aqueous hydrochloric acid solution. The organic layer was separated and dried <RTI ID=0.0> IR(KBr) vmax: 3416, 2954, 257 1, 1737, 1650, 15 10, 1434, 1360, 1282, 1225, 1 176, 1 139, 848, 759, 707, 682 cm'1. MS(FAB) m /z : 1111 ((M + H) +, free body). (Test Example 1) [Guinea NK! Receptor Binding Test] C: -103- 201143771 y The squirrel was used as a rough membrane label. test. The lung tissue of the high-performance part of the NK1 receptor is extracted to prepare a crude membrane rod, and the [3H] substance P "UbSUnCeP" and the test substance are reacted with the crude membrane sample solution, and the radioactivity is measured by recovering the membrane component. Calculate the affinity of the NK 丨 receptor in the squirrel. Negative 耵 (Test Example 2) [Guineus NK2 receptor binding assay] = 竺 粗 粗 粗 可 可 受体 受体 受体 受体 粗 粗 粗 粗 粗 粗 粗 粗 % % % % % % % % % % % % % % % % % Make a crude membrane specimen, so that the 3 ΤΙ or neurokinin A and the test substance are opposite to the crude membrane specimen: after the recovery of the membrane component, the radioactive substance is measured for the affinity of the NK2 receptor of the guinea pig, and the test object is taken out. (Test Example 3) [Scorpio sputum receptor binding assay] The receptor binding assay can be carried out by the second = crude membrane specimen. Coming soon [N·;: 4°: ... glandular tissue is removed to make a crude membrane specimen, so that the anti-two-two-two "amine methyl gas and the substance of the test substance and the crude membrane sample substance on the scorpion m3 receptor affinity tongue Sex, can be calculated (Test Example 4) [Human NK, Receptor Binding Test] Co-division of crude membrane specimens of T1 human receptor-expressing cells can be performed on receptor-bound specimens to make ζΝΚ1 receptors exhibit coffee cell modulation The crude film + reacts the [Η] substance i Ρ and the test object f with the crude film sample solution, and the radioactivity is measured by recovering the film component, and the affinity for the human NK 丨 receptor can be calculated. Test substance-104- 201143771 (Test Example 5) [Human NK:2 receptor binding assay] (a) Preparation of crude membrane specimens Human NK:2 receptors express cryopreserved cell fluid of COS cells in buffer (including 0.04% bovine serum albumin (BSA) was diluted with 50 mM ginseng-hydrochloric acid (pH 7.4) to prepare 5 · Ox 195 cells/ml, which was used as a crude membrane specimen. (b) Receptor binding assay will be [3H ]Sil 48968 (GE Healthcare . Japan) is a mixture (50 mM ginseng-HCl (pH 7.4), 6 mM chlorinated tetrahydrate, 800 μg/mL BSA, 8 /z g/m: L-protease

(chymostatin)、8 pg/mL 亮肽素（leupeptin)、80 pg/mL 枯草菌素（bacitracin )、20 // g/mL 膦醯二狀 (phosphoramidon ))稀釋。於此混合液250 pL中添加 被驗物質及粗膜標本液250 μί，於室溫培育35分鐘 ([3H]SR 48968為最終濃度1 ηΜ)。反應後，使用自動 過遽裝置（Brandel , Biomedical Research and Development Laboratories, Inc.)，於 GF/B 玻璃纖維淚 紙(Whatman，Biomedical Research and Development Laboratories, Inc.)上回收膜成分。又，玻璃纖維渡紙因 低度抑制非特異結合，故以0 · 1 %聚伸乙基亞胺液作4小 時以上前處理來使用。將膜成分回收過濾器移到含 Picofluor 3 mL的小塑膠瓶，以液體閃爍•讀數器（perkin Elmer, Tri-Carb 2 900TR 或 23 00TR)測量放射活性。 -105- 201143771 NK2受體結合作用由5〇%結合藥用量（π”）及對 NK2受體的[3H]SR 48968之親和性（Kd)，算出被驗物 質對NK2受體之親和性（Ki )。 結果示於表1。 (表1 ) 實施例 Ki ( nM ) 6 1.0 7 1.2 8 1.2 9 2.0 由上述結果可知，本發明之化合物具有優異的神經 激肽NK2受體結合作用。 (試驗例6) [人類M3受體結合試驗] (a )粗膜標本之製作 將人型A受體表現CHO細胞之冷束保存細胞液以 緩衝液（含0.5 mM EDTA的50 mM參-鹽酸，pH7 稀 釋而作成5.0x1 05個細胞/nU，作為粗犋標本來使用。 (b )受體結合試驗 將[N-曱基l-3H]-(-)-莨菪胺曱基氣（ge Healthcare • Japan (股））以含 0·5 mM EDTA 的 50 mM 參-鹽酸 (pH7.4 )稀釋，於此混合液250 pL中添加被驗物質及 粗膜標本液250 μί，於室溫培育60分鐘。反應後，使 用自動過濾裝置（Brandel，Biomedical Research and(chymostatin), 8 pg/mL leupeptin, 80 pg/mL bacitracin, 20 // g/mL phosphoramidide dilution. 250 μL of the test substance and the crude membrane sample solution were added to 250 pL of the mixture, and the mixture was incubated at room temperature for 35 minutes ([3H]SR 48968 was a final concentration of 1 η Μ). After the reaction, the membrane fraction was recovered on GF/B glass fiber tear paper (Whatman, Biomedical Research and Development Laboratories, Inc.) using an automatic perforating device (Brandel, Biomedical Research and Development Laboratories, Inc.). Further, since the glass fiber paper was low-inhibited by non-specific binding, it was used in a 0. 1% polyethylenimine solution for 4 hours or more. The membrane component recovery filter was transferred to a small plastic bottle containing Picofluor 3 mL and the radioactivity was measured with a liquid scintillation • reader (perkin Elmer, Tri-Carb 2 900TR or 23 00TR). -105- 201143771 NK2 receptor binding is determined by the affinity of 〇2 receptor for the NK2 receptor by the binding amount of 〇2药用(π)) and the affinity of NK2 receptor for [3H]SR 48968 (Kd). (Ki) The results are shown in Table 1. (Table 1) Example Ki (nM) 6 1.0 7 1.2 8 1.2 9 2.0 From the above results, it is understood that the compound of the present invention has excellent neurokinin NK2 receptor binding. Test Example 6) [Human M3 receptor binding assay] (a) Preparation of a crude membrane specimen The human A receptor expresses a cold-cell preservation cell fluid of CHO cells in a buffer solution (50 mM gins-hydrochloric acid containing 0.5 mM EDTA, Diluted to pH 5.0 and made 5.0x1 05 cells/nU for use as a crude sputum specimen. (b) Receptor binding assay [N-mercapto l-3H]-(-)- amidoxime-based gas (ge Healthcare • Japan (stock)) diluted with 50 mM ginseng-hydrochloric acid (pH 7.4) containing 0.5 mM EDTA, 250 μL of the test substance and the crude membrane sample solution were added to the mixture at 250 μL, and incubated at room temperature for 60 minutes. After the reaction, use an automatic filter device (Brandel, Biomedical Research and

Development Laboratories, Inc.)，於 GF/B 玻璃纖維滤 -106- 201143771 紙（Whatman，Biomedical Research and Development Laboratories，Inc.)上回收膜成分（[N-曱基-3H]-(-)-莨 菪胺甲基氯為最終濃度0 · 5 nM )。又，玻璃纖維濾紙因 低度抑制非特異結合，故以0.1 %聚伸乙基亞胺液作4小 時以上前處理來使用。將膜成分回收過濾器移到含 Picofluor 3 mL的小塑膠瓶，以液體閃燦•讀數器（perkin Elmer，Tri-Carb 2900TR 或 23 00TR)測量放射活性。 Μ;受體結合作用由50%結合藥用量（IC5〇)及對A 受體的[N-曱基」莨菪胺甲基氯之親和性（Kd)， 算出被驗物質對M3受體之親和性（JCi )。 結果示於表2。 (表2) 貫施例 Ki ( nM) 2 33.3 4 23.4 5 3.9 6 23.8 7 31.1 8 29.1 9 36.6 11 14.6 12 23.3 13 32.7 14 1.1 15 6.8 16 28.8 -107- 201143771 由上述結果可知’本發明之化合物具有優異的簟毒 鹼m3受體結合作用。 (試驗例7) [乙醯甲膽驗呼吸道收縮之抑制作用（活體内，氣管内投 與）] 使用健康天竺鼠’將對為蕈毒鹼受體激動劑的乙醯 甲膽鹼的呼吸道收縮的抑制作用，使用Konzett-Roessler (Naunyn-Schmiedebergs Arch. Exp. Pathol· pharmakol. 1 9 5，7 1 (1 9 4 0))之變化法，可以呼吸道内壓作為指標來 調查。 (試驗例8 ) [A管透過性亢進之抑制作用（活體内，氣管内投與）] 血管透過性亢進之抑制作用係使用健康天竺鼠（體 重400g左右，Hartley系雄性天竺鼠），將對抗由NK1受 體激動藥物質P ( SP )之血管透過性亢進的抑制作用，以 漏出色素量作為指標來調查。 於以戊巴比妥（pentobarbital )( 30mg/kg，i.p_ )麻 醉的天竺鼠之大腿靜脈内投與色素（伊凡斯藍（Evans blue) : 40mg/kg，i.v.)，經由立即將SP(lpg/kg)靜脈 注射，而誘發血管透過性之亢進。1 5分鐘後，天竺鼠於 二氧化碳下使致死’於主氣管部位漏出的色素量依據 Harada法（J. Pharm. Pharmacol. 23, 21 8(1971))來測量。 被驗藥物溶解於5 %葡萄糖溶液，使用氣管内投與器 具（Penn-Century. lnc·，model 1A-1B)投與 0.5 mL/kg之溶 液，於S P誘發1小時前經氣管内投與。 -108- 201143771 抑制作用以被驗藥物投與天竺鼠之漏出色素量作 指標來判斷。 &quot; 結果示於表3。 (表3 ) ----------------- 實施例 抑制率（100ug/kg ) --_______ 3 94.5% 由上述結果可知，本發明之化合物具有對神經激肽 NKl受體的優異拮抗作用。 (試驗例9 ) [物負P誘發呼吸道收縮之抑制作用（活體内，氣管内投 與）] 使用健康天竺鼠，對經由NKi受體激動劑物質p( sp ) 的呼吸道收縮的抑制作用，使用Konzett-RoessUr (Naunyn-Schmiedebergs Arch. Exp. Pathol, pharmakol. 195，7 1 (1 940))的改變法，將呼吸道内壓作為指標可加 以調查。 (試驗例1 0 ) [神經激肽A誘發呼吸道收縮之抑制作用（活體内，氣管 内投與）] 使用健康天竺鼠’對經由為NK2受體激動劑的神經 激肽A ( NKA )的呼吸道收縮的抑制作用，使用 Konzett-Roessler ( Naunyn-Schmiedebergs Arch. Exp. Pathol, pharmakol. 1 95, 71(1940))之變化法，可將呼吸 道内壓作為指標來調查。 -109- 201143771 由表1至表3之結果可知，本發明之化合物對於神 經激肽NK】、神經激肽NK2及蕈毒鹼Μ〗受體，或對神經 激肽NK,及蕈毒鹼M3受體，具有優異的拮抗作用，而 有用於作為選自下列疾病組成之群之治療劑及/或預防 劑：支氣管氣喘、支氣管炎、慢性阻塞性肺病、咳嗽、 喀痰過度分泌、鼻炎、疼痛、焦慮、抑鬱、痙攣、帕金 森氏症、尿失禁、過敏性腸症候群、前列腺肥大、呕吐、 消化性潰瘍、網膜檢查、急性虹彩炎、角膜炎、縮瞳、 由於麻醉藥導致的過度唾液分泌、呼吸道分泌及潰瘍。 製劑例 製劑例1散劑 將實施例1之化合物5g、乳糖895g及玉米澱粉100g 以混合器混合而獲得散劑。 製劑例2顆粒劑 混合實施例1之化合物5g、乳糖865g及低取代度 羥基丙基纖維素1 〇〇g後，添加丨〇%羥基丙基纖維素水 溶液3〇Og加以混練。將其押出並使用造粒機造粒，乾 餘而獲得顆粒劑。 製劑例3銘:劑 將實施例4之化合物5g、乳糖9〇g、玉米澱粉、 結晶纖維素20g及硬脂酸鎂lg以混合器混合後，藉由以 錠劑機打錠而獲得銳齊丨。 製劑例4吸入用液劑i 調製貫施例9之化合物成為丨〇 % ( W/W )、氣化烷 基二曱基苄基銨成為0.04% (W/W)、苯乙基醇成為040 % (W/W)、純水成 4 89.56% (W/W)的液劑。 -110- 201143771 製劑例5吸入用液劑2 調製實施例7之彳μ入仏 基二曱基节基錄成為。。:二成：1〇%(W/W)、氯化烧 _(價）、丙二醇/^(靖）、聚伸乙基二醇成為 0/ , 、 ％ 成為 30% ( W/W)、純水成為 39.96 % ( W/W)的液劑。 製劑例6吸入用散劑 調製實施例9之化人私七Λ / / 々化《物成為40% ( W/W)、乳糖成 為60% ( W/W)的散劑。 製劑例7喷霧劑 調製實施例7之化合物成4 10% ( W/W)、印填脂 成為 0.5% ( W/W) ' Freon u 成為 34 5% ( w/w)、Fre〇n 12成為55% (W/W)的喷霧劑。 [產業上之利用可能性] 本發明之具有通式（I )的化合物或其藥理上可容許 的鹽，係對於神經激肽NK,、神經激肽nK2及蕈毒鹼M3 文體’或對於神經激肽NK!及蕈毒鹼m3受體，顯示拮 抗作用’且毒性少、體内動態優異，故有用於作為醫藥， 尤其’有用於作為呼吸器官疾病、過敏性疾病及/或神經 系統疾病之預防劑或治療劑。 【圖式簡單説明】 無。 【主要元件符號說明】 無。 -111-Development Laboratories, Inc., Recovering Membrane Components ([N-Mercapto-3H]-(-)-莨菪 on GF/B Glass Fiber Filter-106- 201143771 Paper (Whatman, Biomedical Research and Development Laboratories, Inc.) The amine methyl chloride is the final concentration of 0 · 5 nM ). Further, since the glass fiber filter paper suppresses non-specific binding at a low level, it is used by pretreatment with a 0.1% polyethylenimine solution for 4 hours or more. The membrane component recovery filter was transferred to a small plastic bottle containing Picofluor 3 mL and the radioactivity was measured with a liquid flash reader (perkin Elmer, Tri-Carb 2900TR or 23 00TR).受体; receptor binding is calculated from the 50% binding amount (IC5〇) and the affinity for the [N-mercapto] guanamine methyl chloride of the A receptor (Kd), and the test substance is calculated for the M3 receptor. Affinity (JCi). The results are shown in Table 2. (Table 2) Example Ki (nM) 2 33.3 4 23.4 5 3.9 6 23.8 7 31.1 8 29.1 9 36.6 11 14.6 12 23.3 13 32.7 14 1.1 15 6.8 16 28.8 -107- 201143771 From the above results, the compound of the present invention is known. It has excellent muscarinic m3 receptor binding. (Test Example 7) [Inhibition of airway contraction by inhalation of anthraquinone (in vivo, intratracheal administration)] Using healthy guinea pigs to contract the airway of methotrexate, which is a muscarinic receptor agonist. Inhibition, using the variation of Konzett-Roessler (Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 195, 7 1 (1 904)), can be investigated by using the internal pressure of the respiratory tract as an indicator. (Test Example 8) [Inhibition of A-tube hyperactivity (in vivo, intratracheal administration)] The inhibition of vascular hyperactivity is the use of healthy guinea pigs (about 400 g in weight, Hartley male guinea pig), which will be confronted by NK1. The inhibitory effect of the agonistic drug substance P (SP) on vascular hyperactivity was investigated by using the amount of leakage pigment as an index. In the thigh vein of guinea pig anesthetized with pentobarbital (30 mg/kg, i.p_), the pigment (Evans blue: 40 mg/kg, iv) was administered via SP ( Lpg/kg) is administered intravenously to induce hypervascular permeability. After 1 minute, the amount of pigment that guinea pigs caused to death at the main airway portion was measured according to the Harada method (J. Pharm. Pharmacol. 23, 21 8 (1971)). The test drug was dissolved in a 5% glucose solution, and 0.5 mL/kg of the solution was administered using an intratracheal administration device (Penn-Century. lnc·, model 1A-1B), and administered intratracheally 1 hour before the induction of S P . -108- 201143771 The inhibitory effect was judged by the amount of the test substance administered to the guinea pig. &quot; The results are shown in Table 3. (Table 3) ----------------- Example inhibition rate (100 ug/kg) --_______ 3 94.5% From the above results, the compound of the present invention has a neurokinin Excellent antagonism of NK1 receptors. (Test Example 9) [Inhibition of respiratory contraction induced by negative P (in vivo, intratracheal administration)] Using natural guinea pig, the inhibition of respiratory contraction via the NKi receptor agonist substance p(sp) was used, using Konzett The change method of -RoessUr (Naunyn-Schmiedebergs Arch. Exp. Pathol, Pharmakol. 195, 7 1 (1 940)) can be investigated by using the internal pressure of the respiratory tract as an indicator. (Test Example 10) [Inhibition of neurokinin A-induced respiratory contraction (in vivo, intratracheal administration)] Respiratory contraction of neurokinin A (NKA) via NK2 receptor agonist using healthy guinea pig ' The inhibitory effect was investigated using the variation of the Konzett-Roessler (Naunyn-Schmiedebergs Arch. Exp. Pathol, Pharmakol. 1 95, 71 (1940)). -109- 201143771 It can be seen from the results of Tables 1 to 3 that the compounds of the present invention are directed to neurokinin NK], neurokinin NK2 and muscarinic receptors, or to neurokinin NK, and muscarinic M3. The receptor has excellent antagonism, and has therapeutic agents and/or prophylactic agents for use as a group consisting of bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, hyperextension, rhinitis, pain, Anxiety, depression, delirium, Parkinson's disease, urinary incontinence, irritable bowel syndrome, prostatic hypertrophy, vomiting, peptic ulcer, omental examination, acute iridotonitis, keratitis, migraine, excessive salivation due to anesthetics, Respiratory secretions and ulcers. Formulation Example Formulation Example 1 Powder 5 g of the compound of Example 1, 895 g of lactose and 100 g of corn starch were mixed by a mixer to obtain a powder. Formulation Example 2 Granules After mixing 5 g of the compound of Example 1, 865 g of lactose and 1 〇〇g of a low degree of substitution of hydroxypropylcellulose, a 丨〇% hydroxypropylcellulose aqueous solution of 3 〇Og was added and kneaded. This was extruded and granulated using a granulator, and dried to obtain granules. Formulation Example 3: Agent 5 g of the compound of Example 4, 9 g of lactose, corn starch, 20 g of crystalline cellulose, and lg of magnesium stearate were mixed in a mixer, and then obtained by tableting with a tablet machine. Hey. Formulation Example 4 Inhalation Liquid Solution i The compound of Example 9 was prepared to have 丨〇% (W/W), vaporized alkyldimercaptobenzylammonium was 0.04% (W/W), and phenethyl alcohol was 040. % (W/W), pure water into 4 89.56% (W / W) liquid agent. -110- 201143771 Formulation Example 5 Liquid preparation for inhalation 2 Preparation of the thiol into the oxime of Example 7 was carried out. . :20%: 1〇% (W/W), chlorinated _(valence), propylene glycol/^(jing), polyethylene glycol becomes 0/, , % becomes 30% (W/W), pure The water became a liquid of 39.96 % (w/w). Formulation Example 6 Powder for inhalation A modified powder of Example 9 was prepared. / / The powder became 40% (w/w), and the lactose was 60% (W/W). Formulation Example 7 Spray The compound of Example 7 was prepared to 4 10% (w/w), and the printing fat became 0.5% (W/W) 'Freon u became 34 5% (w/w), Fre〇n 12 Become a 55% (W/W) spray. [Industrial Applicability] The compound of the present invention having a formula (I) or a pharmacologically acceptable salt thereof is for neurokinin NK, neurokinin nK2 and muscarinic M3 stylistics or for nerves The kinin NK! and muscarinic m3 receptors show antagonism' and are less toxic and have excellent in vivo dynamics. Therefore, they are used as medicines, especially for use as respiratory diseases, allergic diseases and/or neurological diseases. Prophylactic or therapeutic agent. [Simple description of the diagram] None. [Main component symbol description] None. -111-

Claims (1)

201143771 七、申請專利範圍： 1. 一種具有通式（I)之化合物或其藥理上可容許的鹽， 丫 [式中， Y為具有神經激肽（neur〇kinin) NL及神經激肽ΝΚ2 受體拮抗作用的部分構造或具有神經激肽NK,受體 结抗作用的部分構造； A為單鍵、三鍵、氧原子、羰基、羰基胺基、胺基羰 基、式（π)所代表之基、式（ΠΙ)所代表之基或式 (IV )所代表之基 L1、，/CY201143771 VII. Scope of application: 1. A compound of the formula (I) or a pharmacologically acceptable salt thereof, wherein Y is a neurokinin (neur〇kinin) NL and a neurokinin ΝΚ2 Partial structure of antagonism or partial structure with neurokinin NK, receptor nociation; A is a single bond, triple bond, oxygen atom, carbonyl group, carbonyl amine group, aminocarbonyl group, represented by formula (π) The base represented by the formula (ΠΙ) or the base L1, / CY represented by the formula (IV) (R表示氫原子或Cl-c6烷基； R2表示氫原子或Cl_c6烷基； R3表示氫原子或Cl_c6烷基； L1表示氧基羰基、羰基氧基、（甲基胺基）羰基或羰 基（曱基胺基）基；(R represents a hydrogen atom or a Cl-c6 alkyl group; R2 represents a hydrogen atom or a Cl_c6 alkyl group; R3 represents a hydrogen atom or a Cl_c6 alkyl group; and L1 represents an oxycarbonyl group, a carbonyloxy group, a (methylamino)carbonyl group or a carbonyl group ( Mercaptoalkyl) group; p表示1至6之整數. q表示0至4之整數； -112- 201143771 r表示1至8之整數； s表示1至8之整數； t表示1至4之整數； CY及CE表示單鍵； CY與式Y所表示的基結合，而CE與式E所表示的基 結合； R2為Ci-C^烷基之情形，R2之任意之碳原子可與L3 之任意之碳原子結合）； E表示具有蕈毒鹼M3受體拮抗作用的部分構造； m表示0至4之整數； η表示1至8之整數]。 2.如申請專利範圍第1項之化合物或其藥理上可容許的 鹽，於通式中，Υ為式（V)所代表之基、式（VI) 所代表之基或式（VII)所代表之基p represents an integer from 1 to 6. q represents an integer from 0 to 4; -112- 201143771 r represents an integer from 1 to 8; s represents an integer from 1 to 8; t represents an integer from 1 to 4; CY and CE represent a single bond CY is bonded to a group represented by Formula Y, and CE is bonded to a group represented by Formula E; R2 is a Ci-C^ alkyl group, and any carbon atom of R2 may be bonded to any carbon atom of L3); E represents a partial structure having muscarinic M3 receptor antagonism; m represents an integer of 0 to 4; η represents an integer of 1 to 8]. 2. A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein in the formula, Υ is a group represented by formula (V), a group represented by formula (VI) or a formula (VII) Representative base 113- 201143771 (R表示可具有1至5個獨立選自取代基群A的基 取代之笨基或可具有1至3個獨立選自取代基群A的 基取代之雜環基； R5表不可具有1至5個獨立選自取代基群A的基取 代之苯基或可具有1至3個獨立選自取代基群A的基 取代之雜環基； R6表示氫原子或CVC6烷基； R7表示可具有1至5個獨立選自取代基群A的基取 代之苯基或可具有1至3個獨立選自取代基群A的基 取代之雜環基； u表示1或2 ; 取代基群A表示鹵素原子、烷基、鹵化烷 基、羥基、CVC6烷氧基、CVC6鹵化烷氧基、氰基、 雖基、C2_C7烧基叛基氧基、〇2_(:7炫&gt;氧基幾基氧基、 胺甲醯基、硝基及胺基組成之群； Cm表示單鍵，且與式-(CH2) m-表示之基結合）。 3.如申請專利範圍第1或2項之化合物或其藥理上可容 許的鹽，其中E為式（VIII)所代表之基、式（ιχ) 所代表之基、式（X )所代表之基、式（ΧΙ )所代表 之基或式（XII)所代表之基 -114- 201143771113- 201143771 (R represents a heterocyclic group which may have 1 to 5 substituents independently selected from the substituent group A or a heterocyclic group which may have 1 to 3 substituents independently selected from the substituent group A; a phenyl group having 1 to 5 groups independently selected from the group of substituents A or a heterocyclic group which may have 1 to 3 groups independently selected from the group of substituents A; R6 represents a hydrogen atom or a CVC6 alkyl group; a phenyl group which may have 1 to 5 substituents independently selected from the substituent group A or a heterocyclic group which may have 1 to 3 substituents independently selected from the substituent group A; u represents 1 or 2; Group A represents a halogen atom, an alkyl group, a halogenated alkyl group, a hydroxyl group, a CVC6 alkoxy group, a CVC6 halogenated alkoxy group, a cyano group, a C2_C7 alkyl group, a ruthenium group, and a ruthenium group. a group consisting of a benzyloxy group, an amine carbaryl group, a nitro group and an amine group; Cm represents a single bond and is bonded to a group represented by the formula -(CH2) m-) 3. As claimed in claim 1 or 2 a compound or a pharmacologically acceptable salt thereof, wherein E is a group represented by the formula (VIII), a group represented by the formula (ι), a group represented by the formula (X), and a formula (ΧΙ) Group or a group represented by the formula of (XII) -114- 201143771 Or N—CrOr N-Cr (XII) (cn表示單鍵，且與式-(CH2) n-表示的基結合）。 4.如申請專利範圍第1至3項中任一項之化合物或其藥 理上可容許的鹽，其中通式（I)為通式（la)(XII) (cn represents a single bond and is bonded to a group represented by the formula -(CH2)n-). 4. A compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein the formula (I) is a formula (la) -115- 201143771 5. 如申請專利範圍第4項之化合物或其藥理上可容許的 鹽，其中R1為氫原子或曱基，L1為氧基羰基、羰基 氧基、（甲基胺基）羰基或羰基（甲基胺基）基；L2 為單鍵或伸苯基；p為2至4之整數；q為0或l;r 為1至5之整數。 6. 如申請專利範圍第1至3項中任一項之化合物或其藥 理上可容許的鹽，其中通式（I)為通式（lb)-115- 201143771 5. A compound according to claim 4 or a pharmacologically acceptable salt thereof, wherein R1 is a hydrogen atom or a fluorenyl group, and L1 is an oxycarbonyl group, a carbonyloxy group or a (methylamino)carbonyl group. Or a carbonyl (methylamino) group; L2 is a single bond or a phenyl group; p is an integer from 2 to 4; q is 0 or 1; r is an integer from 1 to 5. 6. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the formula (I) is a formula (lb) 7 ·如申請專利範圍第6項之化合物或其藥理上可容許的 鹽，其中η為2至5之整數。 8.如申請專利範圍第1至3項中任一項之化合物或其藥 理上可容許的鹽，其中通式（I)為通式（Ic)7. A compound as claimed in claim 6 or a pharmacologically acceptable salt thereof, wherein η is an integer from 2 to 5. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein the formula (I) is a formula (Ic) 9.如申請專利範圍第8項之化合物或其藥理上可容許的 鹽，其中s為3至6之整數，m為2至4之整數。 -116- 201143771 1 ο.如申請專利範圍第1至3項中任一項之化合物或其藥 理上可容許的鹽，其中通式（I)為通式（Id)9. A compound according to claim 8 or a pharmacologically acceptable salt thereof, wherein s is an integer from 3 to 6, and m is an integer from 2 to 4. The compound of any one of claims 1 to 3, or a pharmacologically acceptable salt thereof, wherein the formula (I) is of the formula (Id) 11. 如申請專利範圍第1 0項之化合物或其藥理上可容許 的鹽，其中R3為氫原子或甲基，t為1至4之整數， m為1至4之整數，η為1至4之整數。 12. —種化合物或其藥理上可容許的鹽，其為： 4-[ ( { 4-[ ( 2- { 4-[(聯苯基-2-基胺甲醯基）氧基] 哌啶-1 -基}乙基）（甲基）胺曱醯基]苄基}胺基） 甲基]苯基 4-[ ( Ν- { 5-[ { 2-[3,5-雙（三氟甲基）苯 基]-2-曱基丙醯基}(曱基）胺基]-4- ( 2-曱基苯基） 吡啶-2-基} -Ν-曱基甘胺醯基）（曱基）胺基]丁酸酯、 (3R) - l-{ 2-[{ 6-[4-( { 3-[( { [( 2S) -l5-{ 2-[( 5R) -3-{ [3，5-雙（三氟甲基）苯基]羰基} -5-(4-氟苯基） -l，3-〇f唑啶-5-基]乙基}-2,3-二氫螺[茚-1，4’-哌啶]-2-基]氧基}乙醯基）胺基]丙基}胺曱醯基）哌啶-1 -基]己醯基}(曱基）胺基]乙基}。比咯啶-3-基羥基 (二噻吩-2-基）乙酸酯、 N- ( 2 - { [2- ( 4- { 2-[ ( 3S ) -3- ( 2-胺基-2-側氧基-1,1-二苯基乙基）。比咯啶-1 -基]乙基}苯基）乙基]胺基} 乙基）-2- {[ ( 2S) -1，- { 2-[ ( 5R) -3- { [3,5-雙（三 -117- 201143771 氟曱基）苯基]羰基} -5- ( 4-氟苯基）-1，3-噚唑啶-5-基]乙基} -2,3-二氫螺[茚-1，4’-哌啶]-2-基]氧基} -N-曱基乙醯胺、 1- ( 2- { [6- ( { 4-[{3-[ ( N-{5-[ { 2-[3,5-雙（三氟曱 基）苯基]-2-甲基丙醯基}(甲基）胺基]-4- ( 2-曱基 苯基）。比啶-2-基} -N-曱基甘胺醯基）（甲基）胺基] 丙基}(曱基）胺甲醯基]苯基}胺基）己醯基](曱基） 胺基}乙基）α底π定-4-基聯苯基-2-基胺基曱酸自旨、 1- { 2-[ ( { 4-[ ( { 4-[ { 3-[ ( Ν- { 5-[ { 2-[3,5-雙（三 氟甲基）苯基]-2-曱基丙醯基}(曱基）胺基]-4-(2-甲基苯基）°比啶-2-基} -N-曱基甘胺醯基）（甲基） 胺基]丙基}(甲基）胺曱醯基]苯基}胺基）曱基] 苯基}羰基）（甲基）胺基]乙基}哌啶-4-基聯苯基 -2-基胺基甲酸酯、或 (3R)小{ 4-[ ({ [ ( 2S) -Γ- { 2-[ ( 5R) -3-[3,5-雙 (三氟曱基）苯甲醯基]-5- ( 4-氟苯基）-1，3-嘮唑啶 -5-基]乙基} -2,3-二氫螺[茚-1，4’-哌啶]-2-基]氧基} 乙醯基）（曱基）胺基]丁基}。比咯啶-3-基羥基（二 -2 -噻吩基）乙酸酯。 1 3 . —種醫藥組成物，其含有如申請專利範圍第1至1 2 項中任一項之化合物或其藥理上可容許的鹽作為有 效成分。 14.如申請專利範圍第13項之醫藥組成物，該醫藥組成 物具有支氣管擴張作用及抗炎症作用。 1 5 _如申請專利範圍第1 3項之醫藥組成物，該醫藥組成 物係用於治療及/或預防神經激肽NK,、神經激肽NK2 -118- 201143771 及^或孽毒鹼m3受體參與的疾病或神經激肽ΝΚι及/ 或蕈毒鹼M3受體參與的疾病。 16. 如申請專利範圍第13項之醫藥組成物’該醫藥組成 物係用於治療及/或預防呼吸器官疾病、過敏性疾病及 /或神經糸統疾病。 17. 如申請專利範圍帛13帛《醫藥組成物，胃醫藥組成 物係用於治療及/或預防支氣管氣喘、支氣管炎、慢性 阻塞性肺病、咳嗽、喀痰過分泌、鼻炎、疼痛、焦慮、 抑營，痙擎、帕金森氏症、尿失禁、過敏性腸症候群、 =腺肥大、嘔吐、消化性潰瘍、網膜檢查、急性虹 衫炎、角膜炎、縮瞳、由於麻醉藥導致的過度唾液分 泌、呼吸道分泌及/或潰瘍。 18. 如申請專利範圍第13項之醫藥組成物，該醫藥組成 物係用於治療及/或預防支氣管氣喘及/或慢性阻塞性 肺病。 19. 如申請專利範圍第16至18項中任一項之醫藥組成 物’ a亥醫藥組成物係用於經肺投與及/或點鼻投與。 2 0 _ —種如申請專利範圍第1至丨2項中任一項之化合物 或其藥理上可容許的鹽之用途，其係用於製造醫藥組 成物。 2 1 _如申請專利範圍第2〇項之用途，其中該醫藥組成物 係具有支氣管擴張作用及抗炎症作用的醫藥組成物。 22.如申請專利範圍第2〇項之用途，其中該醫藥組成物 係用以治療及/或預防神經激肽NK!、神經激肽NK2 及/或蕈毒鹼M3受體參與的疾病、或神經激肽NK,及 /或蕈毒鹼M3受體參與的疾病之組成物。 -119- 201143771 2 3 .如申請專利範圍第2 0項之用途，其中該醫藥組成物 係用以治療及/或預防支氣管氣喘、支氣管炎、慢性阻 塞性肺病、咳漱、嗓痰過分泌、鼻炎、疼痛、焦慮、 抑鬱、痙攣、帕金森氏症、尿失禁、過敏性腸症候群、 前列腺肥大、嘔吐、消化性潰瘍、網膜檢查、急性虹 彩炎、角膜炎、縮曈、由於麻醉藥導致的過度唾液分 泌、呼吸道分泌及/或潰瘍。 24. 如申請專利範圍第23項之用途，其中該醫藥組成物 係用於經肺投與及/或點鼻投與。 25. —種疾病之治療及/或預防方法，其係將如申請專利範 圍第1至1 2項中任一項之化合物或其藥理上可容許 的鹽之藥理上的有效量投與溫血動物。 26. 如申請專利範圍第25項之方法，其中疾病為神經激 肽ΝΚ,、神經激肽ΝΚ2及/或蕈毒鹼μ3受體參與的疾 病 '或神經激肽ΝΚ,及/或簟毒鹼μ3受體參與的疾病。 27. 如申請專利範圍第25項之方法，其中疾病為支氣管氣 喘、支氣管炎、慢性阻塞性肺病、咳嗽、喀痰過度分 泌、鼻炎、疼痛、焦慮、抑鬱、痙攣、帕金森氏症、 尿失禁、過敏性腸症候群、前列腺肥大、嘔吐、消化 性潰瘍、網膜檢查、急性虹彩炎、角膜炎、縮瞳、由 於麻醉藥導致的過度唾液分泌、呼吸道分泌及/或潰瘍。 28 ·如申請專利範圍第27項之方法，其經肺投與及/或點 鼻投與具有通式（I)的化合物或其藥理上可容許的鹽。 29.如申請專利範圍第25至28項中任一項之方法，其中 溫血動物為人類。 ί：; -120- 201143771 四、指定代表圖： (一） 本案指定代表圖為：無。 (二） 本代表圖之元件符號簡單說明: 無0 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式:11. A compound according to claim 10 or a pharmacologically acceptable salt thereof, wherein R3 is a hydrogen atom or a methyl group, t is an integer from 1 to 4, m is an integer from 1 to 4, and η is 1 to An integer of 4. 12. A compound or a pharmacologically acceptable salt thereof, which is: 4-[({4-[(2-{4-[(biphenyl-2-ylaminocarbamoyl)oxy)piperidine) -1 -yl}ethyl)(methyl)amine fluorenyl]benzyl}amino)methyl]phenyl 4-[( Ν- { 5-[ { 2-[3,5-bis(trifluoro Methyl)phenyl]-2-mercaptopropyl}}(fluorenyl)amino]-4-(2-mercaptophenyl)pyridin-2-yl}-indole-mercaptoamine thiol) Mercapto)amino]butyrate, (3R) - l-{ 2-[{ 6-[4-( { 3-[( { [( 2S) -l5-{ 2-[( 5R) -3- {[3,5-Bis(trifluoromethyl)phenyl]carbonyl}-5-(4-fluorophenyl)-1,3-indyrazolidine-5-yl]ethyl}-2,3- Dihydrospiro[茚-1,4'-piperidinyl]-2-yl]oxy}ethenyl)amino]propyl}aminoindolyl)piperidin-1 -yl]hexyl}} Amino)ethyl}. Bilobidine-3-ylhydroxy (dithien-2-yl)acetate, N-( 2 - { [2-( 4- { 2-[ ( 3S ) -3- ( 2-amino-2-) Sideoxy-1,1-diphenylethyl).Byrrolidin-1 -yl]ethyl}phenyl)ethyl]amino}ethyl)-2- {[ ( 2S) -1,- { 2-[ ( 5R) -3- { [3,5-bis(tri-117- 201143771 fluoroindolyl)phenyl]carbonyl} -5-(4-fluorophenyl)-1,3-oxazolidine -5-yl]ethyl}-2,3-dihydrospiro[茚-1,4'-piperidinyl]-2-yl]oxy}-N-mercaptoacetamide, 1- (2- { [6-( { 4-[{3-[ ( N-{5-[ { 2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanyl}} (methyl) Amino]-4-(2-mercaptophenyl).pyridin-2-yl}-N-mercaptosylamino)(methyl)amino]propyl}(indenyl)aminecarboxyl Phenyl}amino)hexanyl](fluorenyl)amino}ethyl)ethyl π 定-4-ylbiphenyl-2-ylamino decanoic acid, 1- { 2-[ ( { 4-[ ( { 4-[ { 3-[( Ν- { 5-[ { 2-[3,5-bis(trifluoromethyl)phenyl)-2-mercaptopropyl)} Amino]-4-(2-methylphenyl)-pyridin-2-yl}-N-mercaptosylamino)(methyl)amino]propyl}(methyl)amine oxime Phenyl]amino}amino) Phenyl}carbonyl)(methyl)amino]ethyl}piperidin-4-ylbiphenyl-2-ylcarbamate, or (3R) small { 4-[ ({ [ ( 2S) -Γ-{2-[(5R)-3-[3,5-bis(trifluoromethyl)benzimidyl]-5-(4-fluorophenyl)-1,3-oxazolidine-5 -yl]ethyl}-2,3-dihydrospiro[indolyl-1,4'-piperidinyl]-2-yl]oxy}ethenyl)(indenyl)amino]butyl}. Bilpyridin-3-ylhydroxy (di-2-thienyl) acetate. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof as an active ingredient. 14. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition has a bronchodilating action and an anti-inflammatory action. 1 5 _If the pharmaceutical composition of claim 13 of the patent scope is used for the treatment and/or prevention of neurokinin NK, neurokinin NK2 -118- 201143771 and or muscarinic m3 A disease in which the body is involved or a neuropeptide ΝΚι and/or muscarinic M3 receptor is involved in the disease. 16. The pharmaceutical composition of claim 13 wherein the pharmaceutical composition is for the treatment and/or prevention of respiratory diseases, allergic diseases and/or neurological diseases. 17. For the scope of patent application 帛13帛 “Pharmaceutical composition, gastric medicine composition is used for the treatment and/or prevention of bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, sputum secretion, rhinitis, pain, anxiety, depression Camp, Ai Qing, Parkinson's disease, urinary incontinence, irritable bowel syndrome, = gland hypertrophy, vomiting, peptic ulcer, omental examination, acute rainbow uritis, keratitis, sputum, excessive salivation due to anesthetics , respiratory secretions and / or ulcers. 18. The pharmaceutical composition of claim 13 for use in the treatment and/or prevention of bronchial asthma and/or chronic obstructive pulmonary disease. 19. The pharmaceutical composition of any one of claims 16 to 18, wherein the pharmaceutical composition is used for pulmonary administration and/or nasal administration. The use of a compound according to any one of claims 1 to 2, or a pharmacologically acceptable salt thereof, for the manufacture of a pharmaceutical composition. 2 1 _ The use of the second aspect of the patent application, wherein the pharmaceutical composition is a pharmaceutical composition having a bronchodilating action and an anti-inflammatory action. 22. The use of the second aspect of the patent application, wherein the pharmaceutical composition is for treating and/or preventing a disease involving neurokinin NK!, neurokinin NK2 and/or muscarinic M3 receptor, or A composition of a disease in which neurokinin NK, and/or muscarinic M3 receptor is involved. -119- 201143771 2 3. The use of the scope of claim 20, wherein the pharmaceutical composition is for treating and/or preventing bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, sputum secretion, Rhinitis, pain, anxiety, depression, cramps, Parkinson's disease, urinary incontinence, irritable bowel syndrome, prostatic hypertrophy, vomiting, peptic ulcer, omental examination, acute iridotonitis, keratitis, deflation, due to anesthetics Excessive saliva secretion, respiratory secretion and/or ulceration. 24. The use of claim 23, wherein the pharmaceutical composition is for pulmonary administration and/or nasal administration. 25. A method for the treatment and/or prevention of a disease, which comprises administering a pharmacologically effective amount of a compound of any one of claims 1 to 12 or a pharmacologically acceptable salt thereof to warm blood. animal. 26. The method of claim 25, wherein the disease is a neurokinin ΝΚ, a neurokinin ΝΚ 2 and/or a muscarinic μ3 receptor involved in a disease 'or a neurokinin ΝΚ, and/or a muscarinic bacterium; A disease in which the μ3 receptor is involved. 27. The method of claim 25, wherein the disease is bronchial asthma, bronchitis, chronic obstructive pulmonary disease, cough, hyperextension, rhinitis, pain, anxiety, depression, cramps, Parkinson's disease, urinary incontinence, Allergic bowel syndrome, prostatic hypertrophy, vomiting, peptic ulcer, omental examination, acute iridotonitis, keratitis, migraine, excessive salivation due to anesthetics, respiratory secretion and/or ulceration. 28. The method of claim 27, wherein the compound of formula (I) or a pharmacologically acceptable salt thereof is administered pulmonaryly and/or nasally. The method of any one of claims 25 to 28, wherein the warm-blooded animal is a human. ί:; -120- 201143771 IV. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: None 0. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention:
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