TW200529835A - Calcitonin gene related deptide receptor antagonists - Google Patents

Calcitonin gene related deptide receptor antagonists Download PDF

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TW200529835A
TW200529835A TW093137052A TW93137052A TW200529835A TW 200529835 A TW200529835 A TW 200529835A TW 093137052 A TW093137052 A TW 093137052A TW 93137052 A TW93137052 A TW 93137052A TW 200529835 A TW200529835 A TW 200529835A
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keto
piperidine
dihydro
methyl
quinazoline
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TW093137052A
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TWI284534B (en
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Prasad Chaturvedula
Ling Chen
Rita L Civiello
Charles Mark Conway
Andrew P Degnan
Gene Michael Dubowchik
Xiaojun Han
Xiang Jun J Jiang
George N Karageorge
Guanglin Luo
John E Macor
Graham Poindexter
George Tora
Shikha Vig
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Bristol Myers Squibb Co
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Abstract

The present invention relates to compounds of Formula (I), as antagonists of calcitonin gene-related peptide receptors ("CGRP-receptor"), pharmaceutical compositions comprising them, methods for identifying them, methods of treatment using them and their use in therapy for treatment of neurogenic vasodilation, neurogenic inflammation, migraine and other headaches, thermal injury, circulatory shock, flushing associated with menopause, airway inflanimatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and other conditions the treatment of which can be effected by the antagonism of CGRP- receptors.

Description

200529835 ⑴ 九、發明說明 【發明所屬之技術領域】 本發明關於降鈣素基因相關肽受體（C G R P受體）$ 新穎小分子掊抗劑，包含彼之醫藥組成物、鑑定彼之方法 、利用彼之治療方法及彼於治療神經源性血管擴張、神經 源性發炎、偏頭痛、叢集性頭痛及其他頭痛、熱損傷、循 環性休克、與停經有關之潮紅、呼吸道發炎疾病（諸如氣 喘和慢性阻塞性肺疾病（COPD ))及其他可藉由拮抗 CGRP受體完成治療之病症上的治療用途。 【先前技術】 降鈣素基因相關肽（CGRP )係天然存在之37個胺基 酸的肽，其係於1982年首先被鑑定（Amara，S· G. et al·， Science 1 982，298，240-244 )。該肽之兩種型式（ a CGRP和0 CGRP )被表現，其於鼠和人體內分別爲1個 和3個胺基酸之差異。該肽廣泛地分佈於周圍神經系統（ PN S )和中樞神經系統（CN S )，主要係位於感覺傳入神 經元和中樞神經元，且顯現許多功效，其包括血管擴張。 當CGRP自細胞釋出時，CGRP與特定之細胞表面G蛋 白質偶合受體結合並顯現其生物上之作用，其主要係藉由 活化細胞內之腺苷酸環化酶（Poyner，D· R. et al·，Br. J·200529835 九 IX. Description of the invention [Technical field to which the invention belongs] The present invention relates to a calcitonin gene-related peptide receptor (CGRP receptor) His method of treatment and treatment of neurogenic vasodilation, neurogenic inflammation, migraine, cluster headache and other headaches, heat injury, circulatory shock, flushing associated with menopause, respiratory inflammatory diseases (such as asthma and chronic Obstructive pulmonary disease (COPD)) and other therapeutic uses that can be accomplished by antagonizing the CGRP receptor. [Prior art] Calcitonin gene-related peptide (CGRP) is a naturally occurring amino acid peptide of 37 amino acids, which was first identified in 1982 (Amara, S.G. et al., Science 1 982, 298, 240-244). Two forms of the peptide (a CGRP and 0 CGRP) are expressed, which are different in mice and humans by 1 and 3 amino acids, respectively. The peptide is widely distributed in the peripheral nervous system (PNS) and central nervous system (CNS), mainly in sensory afferent neurons and central neurons, and exhibits many effects, including vasodilation. When CGRP is released from cells, CGRP binds to specific cell surface G protein-coupled receptors and displays its biological effects, mainly by activating adenylate cyclase (Poyner, D.R. et al ·, Br. J ·

Pharmacol. 1 9 92， 105，44 卜7 ; Van Vain, F. et al·，Pharmacol. 1 9 92, 105, 44 Bu 7; Van Vain, F. et al.,

Neurosci. Lett. 1990，119，195-8)。已提出 2 種 CGRP 矣體 (CGRPi fP CGRP2 )，其係基於 CGRP肽片段（8 — 37 )之 200529835 (2) 拮抗性質和CGRP之線型類似物活化CGRP2受體之能力（ Juaneda，C. e t a1.5 TiPS 2 0 0 0, 2 1，432-438 )。然而，缺 少 CGRP2受體之分子證據（Brain, S. D. et al·，TiPS 2002, 23，51-53) 。體具有3個成份：（i) 1個7跨膜似 降鈣素受體之受體（CRLR) 、（ii)單跨膜受體活性改質 第1型蛋白質（RAMP1)、及（iii)胞內受體成份蛋白質 (RCP ) ( Evans Β· N. et al” J. Biol· Cliem·，2000，275, 3 1 43 8-43 )。轉運CRLR至細胞膜及配體與CGRP受體結合 需要 RAMP1 ( McLatchie，L. M. et al.，Nature 1 99 8, 3 93? 333-339)。訊號轉導需要 RCP (Evans B. N. et al·，J· Biol. Chem·，2000，275，31438-43)。在小分子拮抗劑與 CGRP受體之結合上存有已知之種特異性差異，觀察到拮 抗人類受體比其他物種受體具有典型之較大親和性（ Brain，S. D· et al·，TiPS 2002，23，5 卜53) 。RAMP1 之胺 基酸序列決定物種之選擇性，特別是胺基酸殘基Trp 74負 責人類受體之表現型（Mallee et al·，J. Biol· Chem·， 2002，2 77，1 4294-8 ) 〇 在受體層次上對C G RP之抑制劑被視爲可用於發生過 量CGRP受體活化之病理生理症狀上。某些該症狀包括神 經源性血管擴張、神經源性發炎、偏頭痛' 叢集性頭痛及 其他頭痛、熱損傷、循環性休克、停經性潮紅及氣喘。 CGRP受體活化涉及偏頭痛之發病（Edvinsson L·，CNS Drugs, 2001, 15 ( 10) ： 74 5 - 5 3 ； Williamson, D. J.Neurosci. Lett. 1990, 119, 195-8). Two types of CGRP carcass (CGRPi fP CGRP2) have been proposed, which are based on 200529835 of the CGRP peptide fragment (8-37) (2) Antagonistic properties and the ability of linear analogues of CGRP to activate the CGRP2 receptor (Juaneda, C. et a1 .5 TiPS 2 0 0 0, 2 1,432-438). However, there is a lack of molecular evidence for the CGRP2 receptor (Brain, S. D. et al., TiPS 2002, 23, 51-53). The body has three components: (i) a 7-transmembrane calcitonin-like receptor (CRLR), (ii) a single-transmembrane receptor-modified type 1 protein (RAMP1), and (iii) Intracellular receptor component protein (RCP) (Evans Β · N. Et al "J. Biol · Cliem ·, 2000, 275, 3 1 43 8-43). Transport of CRLR to the cell membrane and the binding of the ligand to the CGRP receptor are required RAMP1 (McLatchie, LM et al., Nature 1 99 8, 3 93? 333-339). Signal transduction requires RCP (Evans BN et al., J. Biol. Chem., 2000, 275, 31438-43). There are known species specific differences in the binding of small molecule antagonists to CGRP receptors, and it has been observed that antagonistic human receptors have a typically greater affinity than other species of receptors (Brain, S. D. et al., TiPS 2002, 23, 5 and 53). The amino acid sequence of RAMP1 determines species selectivity, especially the amino acid residue Trp 74 is responsible for the phenotype of human receptors (Mallee et al., J. Biol · Chem · , 2002, 2 77, 1 4294-8). Inhibitors of CG RP at the receptor level are considered to be useful for pathophysiological symptoms of excessive CGRP receptor activation. Some of these Symptoms include neurogenic vasodilation, neurogenic inflammation, migraine 'cluster headaches and other headaches, heat damage, cyclic shock, menopausal flushing, and asthma. CGRP receptor activation is involved in the onset of migraine (Edvinsson L., CNS Drugs, 2001, 15 (10): 74 5-5 3; Williamson, DJ

Mic rose. Res. Tech.，2001，53， 167-178 ; Grant，A· D.; 200529835 (3)Mic rose. Res. Tech., 2001, 53, 167-178; Grant, A.D .; 200529835 (3)

Brit. J. Pharmacol., 2 0 02, 1 3 5, 3 5 6- 3 62 )。偏頭痛期間， 血淸 CGRP量升高（Goodsby Ρ· J. et al·，Ann. Neurol·， 1 9 90，28，1 83-7 )，且經抗偏頭痛藥物治療後，CGRP量返 回至正常値並伴隨頭痛症狀之減輕（Gallai V. et al.， Cephalalgia 1 995，1 5 : 3 84-3 9 0 )。與對照組相比較，偏 頭痛患者顯現升高之基礎CGRP量（Ashina M.，et al.， Pain 2000，86 ( 1— 2) : 133-8· 2000)。靜脈內輸入 CGRP於偏頭痛患者產生持續性頭痛(Lassen L. H. et al.5 Cephalalgia, 2002 Feb， 22 ( 1) : 54-61)。狗和鼠之臨床 前硏究報告顯示，利用肽拮抗劑CGRP ( 8 — 3 7 )系統性阻 斷CGRP不會改變靜止系統性血液動力情況，亦不會改變 區域性血流（Shen，Y-T et al.，J· Pharmacol. Exp· Ther. 200 1，2 98，551-8)。因此，CGRP受體拮抗劑可爲偏頭痛 之新穎治療藥物，其避免與非選擇性5 - HT1B/1D激動劑（ triptans，例如sumatriptan )有關之活性血管收縮的心血 管負擔。 自文獻可知存有各種不同之活體內偏頭痛模式（參閱 Dv Vries, P. et al.? Eur. J. Pharmacol. 1 999? 3 7 5, 6 1 -74 ) 。某些電刺激三叉神經節並測量其神經分佈之顱內脈管的 擴張（例如 William son et al., Cephalalgia 1997，17 : 518- 5 24 )。基於面動脈亦爲三叉神經所分佈，其他模式硏究 藉由電刺激三叉神經之活化所誘導之面部血流之改變（例 如 Escott et al·，Brain Res· 1995，669 : 93)。另一方面， 亦硏究其他周圍神經（例如隱靜脈神經）和血管床（例如 >8- 200529835 (4) 異常血流）（例如 E s c o 11 e t a 1 ·，B r · J · P h a r m a c ο 1. 1 9 9 3 5 110,772-6)。已顯示藉由利用肽拮抗劑CGRP( 8— 37) (即缺少首7個殘基之肽片段）或小分子c GRP受體拮抗劑 之預處理可阻斷所有之模式。於某些實例，已使用外源性 CGRP作爲朿U激源。然而，所有前揭模式係侵入性終端處 置，且沒有一個前揭模式已顯示逆轉經利用C GRP受體拮 抗劑之後處理所形成之動脈擴張增加或血流增加的臨床上 重要失敗效果。Williamson et al.，Cephalalgia 1997 17 : 518-24 和 Williamson et al.，Cephalalgia 1997 17 : 5 25-3 1 於經由終端 ''活體內〃處置之經戊巴比妥鈉麻醉之鼠體內 ’特別使用靜脈內注射之C G R P作爲剌激源以增加顱內硬 腦膜動脈徑’該終端 ''活體內〃處置涉及鑽孔使顱骨變薄 並創造一個封閉之顱視窗以目視硬腦膜動脈。藉由靜脈內 注射CGRP ( 8 — 37 )之前處理可阻斷該效果·。Escott et al· Brain Res 1 995 669 : 93特別揭示鑽孔至鼠顱骨，並使 用腦電極以電刺激三叉神經節且對終端處置之經戊巴比妥 鈉麻醉之鼠（涉及神經肌肉阻斷、氣管插管及人工通氣） 測量其雷射D ο p p 1 e r面部血流。藉由C G R P ( 8 — 3 7 )之前 處理可阻斷該效果。Esott et al., Br. J. Pharmacol. 1993 1 1 0 : 7 7 2 - 6對備有頸靜脈插套管以利用於麻醉和藥物投遞 之經戊巴比妥鈉麻醉之動物，特別使用皮內注射之CGRP 作爲刺激源以增加鼠腹部皮膚之血流。藉由靜脈內注射 CGRP ( 8 — 37 )之前處理可阻斷該效果。Chu et al· Neurosci. Lett. 200 1 3 1 0: 1 6 9-172 特別使用皮內注射之 200529835 (5) C GRP作爲刺激源並對終端處置之經戊巴比妥鈉麻醉且氣 管插套管之動物測量鼠背部皮膚血流之雷射Doppler改變 ，且自皮下植入之滲透泵連續釋出CGRP ( 8 - 37 )顯示前 處理之阻斷效果。Hall et al. Br. J. Pharmacol. 1995 114 :592-7 和 Hall et al. Br. J. Pharmacol. 1 9 9 9 126 : 280-4 特 別揭示局部投遞C GRP以增加倉鼠面頰窩之小動脈徑及皮 下注射C GRP以增加備有頸靜脈插套管以利用麻醉和藥物 投遞之戊巴比妥鈉麻醉之鼠背部皮膚血流。藉由靜脈內注 射CGRP ( 8 — 37 )之前處理可阻斷該效果。Doods et al. Br. J. Pharmacol. 2000 Feb. 129(3) ： 420-3特別揭示鑽 孔至狨（即新世界猴）之顱骨，並對經浸入性終端處置之 神經肌肉阻斷和人工通氣的戊巴比妥鈉麻醉之靈長類，利 用腦電極以產生三叉神經節之電刺激並測量其面部血流。 藉由小分子CGRP拮抗劑之前處理可阻斷增加之血流。參 閱 WO 03 /272252，標題爲lS0lated DNA MoleculesBrit. J. Pharmacol., 2 02, 1 3 5, 3 5 6- 3 62). During migraine, the amount of CGRP in blood was increased (Goodsby P. J. et al., Ann. Neurol., 1 90, 28, 1 83-7), and after treatment with anti-migraine drugs, the amount of CGRP returned to Normal sickness accompanied by a reduction in headache symptoms (Gallai V. et al., Cephalalgia 1 995, 15: 3 84-3 9 0). Compared with the control group, patients with migraine showed elevated basal CGRP levels (Ashina M., et al., Pain 2000, 86 (1-2): 133-8 · 2000). Intravenous infusion of CGRP produces persistent headache in patients with migraine (Lassen L. H. et al. 5 Cephalalgia, 2002 Feb, 22 (1): 54-61). Preclinical research reports in dogs and mice have shown that systematic blockade of CGRP with the peptide antagonist CGRP (8-37) does not alter resting systemic hemodynamics and regional blood flow (Shen, YT et al. al., J. Pharmacol. Exp. Ther. 200 1, 2 98, 551-8). Therefore, CGRP receptor antagonists can be a novel treatment for migraine, which avoids the cardiovascular burden of active vasoconstriction associated with non-selective 5-HT1B / 1D agonists (triptans, such as sumatriptan). From the literature, it is known that there are various in vivo migraine modes (see Dv Vries, P. et al.? Eur. J. Pharmacol. 1 999? 3 7 5, 6 1 -74). Certain intracranial vasodilators that electrically stimulate the trigeminal ganglion and measure its nerve distribution (eg William son et al., Cephalalgia 1997, 17: 518-5 24). Because the facial artery is also distributed by the trigeminal nerve, other models investigate changes in facial blood flow induced by electrical stimulation of trigeminal nerve activation (eg, Escott et al., Brain Res. 1995, 669: 93). On the other hand, other peripheral nerves (such as saphenous vein nerves) and vascular beds (such as> 8- 200529835 (4) abnormal blood flow) (such as Esco 11 eta 1 ·, B · J · P harmac ο 1. 1 9 9 3 5 110,772-6). It has been shown that all modes can be blocked by pretreatment with the peptide antagonist CGRP (8-37) (i.e. the peptide fragment lacking the first 7 residues) or a small molecule c GRP receptor antagonist. In some instances, exogenous CGRP has been used as a 激 U exciter. However, all of the antecedent patterns are invasive terminal treatments, and none of them have been shown to reverse clinically important failed effects of increased arterial dilatation or increased blood flow resulting from treatment with C GRP receptor antagonists. Williamson et al., Cephalalgia 1997 17: 518-24 and Williamson et al., Cephalalgia 1997 17: 5 25-3 1 'Special use' in sodium pentobarbital-anesthetized mice treated via terminal `` in vivo '' treatment Intravenous injection of CGRP as a stimulus source to increase the diameter of the intracranial dura mater arteries. The "in-terminal" in vivo treatment involves drilling holes to thin the skull and creating a closed cranial window to visualize the dural arteries. This effect can be blocked by pre-treatment with intravenous injection of CGRP (8-37). Escott et al · Brain Res 1 995 669: 93 specifically revealed that sodium pentobarbital-anesthetized rats (involving neuromuscular blockage, Tracheal intubation and artificial ventilation) Measure the laser blood flow on the face. This effect can be blocked by pre-treatment of C G R P (8 — 3 7). Esott et al., Br. J. Pharmacol. 1993 1 1 0: 7 7 2-6 For sodium anesthetized animals with jugular vein cannula for anesthesia and drug delivery, especially skin Intravenous injection of CGRP acts as a stimulus to increase blood flow in the abdominal skin of rats. This effect can be blocked by pre-treatment with intravenous injection of CGRP (8-37). Chu et al. Neurosci. Lett. 200 1 3 1 0: 1 6 9-172 200529835 using intradermal injection (5) C GRP as stimulation source and terminally treated with sodium pentobarbital anesthesia and tracheal intubation Controlled animals measure the laser Doppler changes in skin blood flow on the back of rats, and continuous release of CGRP (8-37) from subcutaneously implanted osmotic pumps shows the blocking effect of pretreatment. Hall et al. Br. J. Pharmacol. 1995 114: 592-7 and Hall et al. Br. J. Pharmacol. 1 9 9 9 126: 280-4 specifically disclosed the local delivery of C GRP to increase the arterioles of hamster cheek sockets C GRP was injected subcutaneously to increase blood flow on the back skin of rats anesthetized with sodium pentobarbital using anesthesia and drug delivery. This effect can be blocked by pretreatment with intravenous CGRP (8-37). Doods et al. Br. J. Pharmacol. 2000 Feb. 129 (3): 420-3 specifically reveals the skull bone drilled into the tadpole (that is, the New World Monkey), and the neuromuscular blocking and artificial The ventilated primates of sodium pentobarbital use brain electrodes to generate electrical stimulation of the trigeminal ganglia and measure their facial blood flow. Pre-treatment with small molecule CGRP antagonists can block increased blood flow. See WO 03/272252, titled lS0lated DNA Molecules

Encoding Η υ m a n i g e d Clcitonin Gene-Rolated Related Peptide Receptor, Related Non-Hum an TransogenicEncoding Η υ m a n i g e d Clcitonin Gene-Rolated Related Peptide Receptor, Related Non-Hum an Transogenic

Animals and Assay MethodsA 。因此，本發明之方法特別 是一種非浸入性之靈長類存活模式，其測量外源性C GRP 誘發之面部血流改變，並證實對自發性吸入異氟醚（ isoflurane)麻醉且隨後恢復之狨、肽和小分子CGRP拮抗 劑之前處理和後處理功效能提供顯著之利益。 近來已報告許多非肽之小分子C G RP受體拮抗劑。 WO 97/0 904 6及其對應案特別揭示作爲CGRP受體之配體（ 200529835 (6) 特別是拮抗劑）之奎寧和奎尼定相關化合物。 WO 98/09630和WO 98/56779及其對應案特別揭示作爲 C G RP受體拮抗劑之各種之各種不同經取代之硝基苯醯胺 化合物。WO 0 1 /3 2649、WO 0 1 /49676 及 WO 0 1 /3 264 8 及彼 之對應案特別揭示作爲CGRP受體拮抗劑之一系統4-酮基 丁醯胺及相關環丙烷衍生物。WO 00/ 1 8 7 64、 WO 9 8/ 1 1 1 2 8及WO 00/5 5 1 54及彼之對應案特別揭示作爲 CGRP受體拮抗劑之苯並咪唑啉基哌啶。與CGRP無關之一 · 系列促生長素抑制素拮抗劑已揭示於WO 99/52 8 75和 WO 01 /25228及彼之對應案中。參閱USP 6,344,449、 USP 6,313,097、USP 6,512,609、USP 6,552,043、 USP 2003181462、 USP 20030191068及 WO 03/076432及相 關申請案。因此，有效治療神經源性發炎、偏頭痛及其他 病症之新穎CGRP受體拮抗劑係非常有益的。Animals and Assay MethodsA. Therefore, the method of the present invention is particularly a non-immersive primate survival mode, which measures facial blood flow changes induced by exogenous C GRP, and confirms the spontaneous inhalation of isoflurane anesthesia and subsequent recovery. The pre- and post-treatment effects of tritium, peptides, and small molecule CGRP antagonists can provide significant benefits. Many non-peptide small molecule C G RP receptor antagonists have recently been reported. WO 97/0 904 6 and its counterparts specifically disclose quinine and quinidine related compounds as ligands for CGRP receptors (200529835 (6) especially antagonists). WO 98/09630 and WO 98/56779 and their counterparts specifically disclose a wide variety of different substituted nitrobenzamide compounds as C G RP receptor antagonists. WO 0 1/3 2649, WO 0 1/49676 and WO 0 1/3 264 8 and their counterparts specifically disclose the system 4-ketobutylamidine and related cyclopropane derivatives as one of the CGRP receptor antagonists. WO 00/1 8 7 64, WO 9 8/1 1 1 2 8 and WO 00/5 5 1 54 and their counterparts specifically disclose benzimidazoline piperidines as CGRP receptor antagonists. One unrelated to CGRP · A series of somatostatin antagonists have been disclosed in WO 99/52 8 75 and WO 01/25228 and their counterparts. See USP 6,344,449, USP 6,313,097, USP 6,512,609, USP 6,552,043, USP 2003181462, USP 20030191068 and WO 03/076432 and related applications. Therefore, novel CGRP receptor antagonists that are effective in treating neurogenic inflammation, migraine, and other conditions are very beneficial.

【發明內容】 發明簡述 本發明之第一方面的第一較佳體系係提供式（I )之 化合物SUMMARY OF THE INVENTION The first preferred system of the first aspect of the present invention is to provide a compound of formula (I)

及其藥學上可接受之鹽和溶劑化物，其φ V係—N ( R1 ) ( R2 )或 OR4 ; - 11 - 200529835 (7) R4係Η、C ] — 6 j：完基、c】-4鹵院基或 (c】-4伸院基）〇-’ R4'係C3-7環烷基、苯基、金剛烷基、奎寧環基、氮雜 雙環〔2.2.1〕庚基、吖丁啶基、四氫呋喃基、呋喃基、 二噁茂烷基、噻嗯基、四氫噻嗯基、吡咯基、吡咯啉基、 吡咯烷基、咪唑基、咪哩啉基、咪D坐烷基、吡唑基、毗唑 啉基、吡唑烷基、噁唑基、異噁唑基、噻唑基、異噻唑基 、噁二唑基、噻二唑基、三唑基、吡喃基、吡啶基、嘧啶 · 基、吡嗪基、噠嗪基、三嗪基、哌啶基、哌嗪基、嗎啉代 、硫化嗎啉代或二噁茂烷基；且 R4 /係可選擇經1或2個相同或不同之取代基取代，該取 代基係選自鹵、氰基、C】—4院基、C 1 - 4鹵烷基、C】—4烷 氧基、經基、胺基、C 3 - 7 Ϊ哀；t元基、C 1 — 3院基胺基、C 1 — 3 二j：完胺基、（C】—3院基）0_2脲基、苯基或节基；且 R4'可選擇地含有1或2個羰基，其中該羰基之碳原子係 Ri環結構之一員； _ R1和R2係各別獨立之L1，其中L1選自Η、C】-6烷基、 C2— 6烯基、C2- 6炔基、—C!- 6伸烷基一胺基 (C! _ 3烷基）2、C3- 7環烷基、苯基、吖丁啶基、金剛烷 基、四氫呋喃基、呋喃基、二噁茂烷基、噻嗯基、四氫噻 嗯基、吡咯基、哦咯啉基、吼咯烷基、咪唑基、咪唑啉基 、咪唑烷基、吡唑基、吡咪啉基、吡唑烷基、噁唑基、異 0惡哇基、噻唑基、異噻唑基、噁二唑基、噻二唑基、三唑 基、吡喃基、吡啶基、嘧啶基、吡嗪基、噠嗪基、三嗉基 -12 - 200529835 (8) 、哌啶基、哌嗦基 '嗎啉代、硫代嗎啉代或二噁茂烷基； 且 R1和R2係各別可選擇且獨立經}或2個相同或不同之取代 基取代，該取代基選自鹵 '氰基、Cl-4烷基、Ci_ 4鹵烷基 、C]-4烷氧基、羥基、胺基、C3—7環烷基、Ci 3烷基胺 基、C ! - 3二烷基胺基、（C ! _ 3烷基）Q _ 2脲基、苯基或苄 基；且 R和R係可―擇各別含1或2個擬基，其中該鑛基之碳原 · 子係包含R1和R2之雜環的一員； 其中L1係可選擇各別由n中斷，該N係由L2連接，其中 L2係各別爲！：！— 3伸烷基或C】_3烷叉基；或 R1和R2與其連接之N—起形成χ，其中X係吖丁啶基、吡 咯基、吡咯啉基、吡咯烷基、咪唑啉基、咪唑烷基、D比唑 啉基、吡唑烷基、吖庚因基、二吖庚因基、哌嗪基、哌啶 基、嗎啉代或硫代嗎啉代； 其中X可選擇經Y取代，其中Y係二噁茂烷基、C! - 9烷基 · 、C2 - 9烯基、C2 - 9炔基、C! _ 4烷基胺基、C, - 4二烷胺基 、C] - 4烷氧基、C3- 7環院基、苯基、吖丁啶基、呋喃基、 噻嗯基、吡咯基、吡咯啉基、吡咯烷基、吡咯烷酮基、咪 唑基、咪唑啉基、咪唑院基、咪唑烷酮基、吡唑基、毗唑 啉基、吡唑烷基、吖庚因基、二吖庚因基、吡啶基、嘧啶 基、二氫苯並咪唑酮基、哌嗪基、哌啶基、嗎啉代、苯並 噻唑基、苯並異噻唑基或硫代嗎啉代·’且 其中X和Y係可選擇由z中斷，其中Z係一 N H C ( Ο ) 0 — -13- 200529835 (9) 、- NHC(O) NH-、- NC(O) NH2、_NH—、__c] 伸院基一、一 c I - 3伸丨兀基 、—C】-3伸燒基 — NHC(O) Ο — Ci-3伸院基；且 X和Y係可選擇地各別經1或2個相同或不同之取代基取 代，該取代基選自Ci- 4烷基、胺基、3院基胺基、 —Ci - 6伸烷基一胺基（C】-3院基）2、（ I _ 3烷基）〇 - 2脲 基、苯基或苄基； X和Y係可選擇地各別含有1或2個羰基，其中該鑛基之 碳原子係包含X和Y之雜環的一員； 唯其若X係經Y取代且若X和Y不經由Z中斷，則X和Y可 選擇地共有1個碳原子且一起形成螺環部份； Q係Q /或Q〃 ； 其中Q /係（Sy ) SR3 ;且 Q"係 NH ( Sy) SR3、NHC ( Ο) ( Sy ) sr3、 NHC ( O ) O ( Sy ) SR3 > NHC ( O ) NH ( Sy) SR3、 〇 ( Sy) SR3、( Sy) SNHR3、( Sy) SNHC ( 〇) R3、 (Sy ) SNHC ( O ) OR3、( Sy ) SNHC ( O) NHR3 或 (Sy ) s〇R3 ； 其中84系Ci - 3伸烷基或C] - 3烷叉基且s係0或1 ; U係（：心或NH ; 唯其若（^係Q〃 ，則U係CH2 ; R3係尺33或R3b， 其中r3 a係（i )具有2個稠合環之雜環，每1個該稠合環 具有5至7員，該雜環含有1至5個選自Ο、N或S之相同或不 -14 - 200529835 (10) 口#離芦πτ -燁地含有〗或2個碳基，其中該 同的雜原子，且該雑Σ我可进擇见 羰基之碳原子係該稠合環之一員； (ii) 4至6員環，其含有1至3個選自〇、Ν 或S之相同不同之的雜原子且可選擇地曰有1或2個羰基， 其中該羰基之碳原子係該4至6員雜環之一貝’ (iii) C3-7環院基， (iv) 咔唑基.、芴基、苯基、一 〇 一本基、And pharmaceutically acceptable salts and solvates thereof, φ V is —N (R1) (R2) or OR4;-11-200529835 (7) R4 is Η, C] — 6 j: end group, c]- 4-halogenoyl or (c) -4 Shenyuanji) 0-'R4 'is C3-7 cycloalkyl, phenyl, adamantyl, quinuclidinyl, azabicyclo [2.2.1] heptyl, Azetidinyl, tetrahydrofuranyl, furanyl, dioxoalkylene, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidolinyl, imidazolyl, Pyrazolyl, pyrazoline, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl , Pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, morpholino sulfide, or dioxocene alkyl; and R4 / series can be selected via 1 or 2 With the same or different substituents, the substituent is selected from halogen, cyano, C] -4 alkyl, C 1-4 haloalkyl, C] -4 alkoxy, meridian, amine, C 3-7 mourning; t-membered group, C 1-3 alkylamino group, C 1-3 two j: end Group, (C) -3 phenyl group, 0_2 ureido group, phenyl group or benzyl group; and R4 ′ may optionally contain 1 or 2 carbonyl groups, wherein the carbon atom of the carbonyl group is a member of the Ri ring structure; _ R1 and R2 Is an independent L1, wherein L1 is selected from fluorene, C] -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C! -6 alkylene monoamine (C! _3 alkyl ) 2, C3-7 cycloalkyl, phenyl, azetidinyl, adamantyl, tetrahydrofuranyl, furanyl, dioxoalkylene, thienyl, tetrahydrothienyl, pyrrolyl, ohrolyl, Rotyl, imidazolyl, imidazolinyl, imidazolyl, pyrazolyl, pyrimidyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazole Base, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triamyl-12-200529835 (8), piperidinyl, piperidinyl'morpholine And thiomorpholino or dioxoalkylene; and R1 and R2 are each independently selectable and independently substituted by} or 2 identical or different substituents, the substituents being selected from halogen 'cyano, Cl- 4 alkyl, Ci_ 4 haloalkyl, C] -4 alkoxy, hydroxyl, Group, C3-7 cycloalkyl group, Ci3 alkylamino group, C! -3 dialkylamino group, (C! _3 alkyl group) Q_2 urea group, phenyl group or benzyl group; and R and R The system can be selected to contain 1 or 2 pseudogroups, in which the carbon atom of the mineral base contains a member of the heterocyclic ring of R1 and R2; where L1 can be selected to be interrupted by n, and the N system is interrupted by L2 Connection, which L2 series are each for! :! — 3-alkylene or C] -3 alkylidene; or R1 and R2 to which N is attached to form χ, where X is azetidinyl, pyrrolyl, pyrrolyl, pyrrolidinyl, imidazolinyl, imidazolyl D, pyrazoline, pyrazolidinyl, azepine, diazepine, piperazinyl, piperidinyl, morpholino or thiomorpholino; where X may be optionally substituted by Y, where Y-based dioxoalkylene, C! -9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C! _4 alkylamino, C, -4 dialkylamino, C]-4 Alkoxy, C3- 7 cycloalkyl, phenyl, azetidinyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolyl, imidazole Alkanone, pyrazolyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepine, pyridyl, pyrimidinyl, dihydrobenzimidazolone, piperazinyl, piperidinyl , Morpholino, benzothiazolyl, benzoisothiazolyl, or thiomorpholino · 'and where X and Y are optionally interrupted by z, where Z is a NHC (〇) 0 — -13- 200529835 ( 9),-NHC (O) NH-,-NC (O) NH2, _NH—, __c] Shenyuan Jiyi, one c I-3 Wuxiji, —C] -3 Yanjiji — NHC (O) 〇 — Ci-3 Shenyuanji; and X and Y are optional Substituted by 1 or 2 identical or different substituents, the substituents are selected from Ci-4 alkyl, amine, 3-alkylamino, —Ci-6 alkylene monoamine (C) -3 (Chenyl) 2, (I_3 alkyl) 0-2 ureido, phenyl, or benzyl; X and Y each optionally contain 1 or 2 carbonyl groups, wherein the carbon atom system of the mineral group contains X A member of the heterocyclic ring with Y; only if X is substituted by Y and X and Y are not interrupted by Z, then X and Y may optionally have 1 carbon atom and together form a spiro ring moiety; Q is Q / Or Q〃; where Q / is (Sy) SR3; and Q " is NH (Sy) SR3, NHC (O) (Sy) sr3, NHC (O) O (Sy) SR3 > NHC (O) NH (Sy ) SR3, 〇 (Sy) SR3, (Sy) SNHR3, (Sy) SNHC (〇) R3, (Sy) SNHC (O) OR3, (Sy) SNHC (O) NHR3 or (Sy) s〇R3; of which 84 Is Ci-3 alkylene or C] -3 alkylidene and s is 0 or 1; U is (heart or NH; only if Q is Q〃, U is CH2; R3 is 33 or R3b , among them r3 a (i) heterocyclic ring having 2 fused rings, each of which has 5 to 7 members, and the heterocyclic ring contains 1 to 5 members which are the same or not -14 selected from 0, N or S -200529835 (10) 口 # 离 芦 πτ -Episode contains two or more carbon groups, the same heteroatom, and the 雑 Σ I can see that the carbon atom of the carbonyl group is a member of the fused ring; ( ii) a 4- to 6-membered ring containing 1 to 3 heteroatoms of the same different type selected from 0, N, or S and optionally having 1 or 2 carbonyl groups, wherein the carbon atom of the carbonyl group is the 4 to 6 One of the 6-membered heterocycles' (iii) a C3-7 ring group, (iv) a carbazolyl group, a fluorenyl group, a phenyl group, a benzoyl group,

一0〜C】-4伸烷基一苯基或萘基；或 (Λ〇 C]」烷基、C2- 7 烯基、—C(〇) R3 、CHc(O) 0—r3，、ch(CH3) C(O) 0 - r3 、 —C ( O) 0〜R3,或c2_ 7炔基；且-0 ~ C] -4 alkylene phenyl or naphthyl; or (Λ〇C] "alkyl, C2- 7 alkenyl, -C (〇) R3, CHc (O) 0-r3, ch (CH3) C (O) 0-r3, —C (O) 0 ~ R3, or c 2_ 7 alkynyl; and

其中R 3 a係可選擇經1至3個相同或不同之取代基取代， 以取代基選自苄基、苯基、一 〇一苯基、—〇— C】—3伸烷 基苯_、一 Ci— 3伸烷基一 〇c ( 〇) -苯基、氰基、胺基、 硝基、鹵、C】—6烷基、Ci— 3單、二或三鹵烷基、C】-3單 〜或三鹵烷氧基、（c】-3烷基）ι一 2胺基、一0r3 、 (0)R3、— c(0)0 - R3、- 〇-C(〇)r3、 N ( R3 ) 2、— c ( 0 ) N ( R3 ' ) 2、 一 MW) C(〇) (R3') 2、Wherein R 3 a is optionally substituted by 1 to 3 substituents which are the same or different, and the substituent is selected from benzyl, phenyl, 100-phenyl, -0-C] -3 alkylbenzene, -Ci-3 alkylene-10c (〇) -phenyl, cyano, amine, nitro, halogen, C] -6 alkyl, Ci-3 mono, di or trihaloalkyl, C]- 3 mono- or trihaloalkoxy, (c) -3 alkyl) 1-2 amine, -0r3, (0) R3,-c (0) 0-R3, -〇-C (〇) r3, N (R3) 2,-c (0) N (R3 ') 2, one MW) C (〇) (R3') 2,

NN

RR

c ( 0 ) N ( R 一（R3 一）C ( O ) OR: ^°-C(〇) N(R3 - ) 2. n(R3^ ) S02R· S〇2K[ ( - \ r 1 R ) 2、或—S02R·；c (0) N (R one (R3 one) C (O) OR: ^ ° -C (〇) N (R3-) 2. n (R3 ^) S02R · S〇2K [(-\ r 1 R) 2. Or—S02R ·;

R 係11或匚卜6烷基；R is 11 or 6 alkyl;

R 唯其若 RJ a 係—c ( 〇 ) R3 '、C H C ( 0 )〇一 _ 15- 200529835 (11) CH(CH3) C(O) O— R3'或一 C(O) O— R3 ，則該 -C ( Ο ) R3 ’、CHC ( 0 ) 0 — R3 '、 CH ( CH3 ) C ( O ) O — R3 '或一C ( O ) O — R3 係未經取代 9 R3b係R3a但不爲苯基、1 一萘基、2 -萘基、1，2，3，4 —四氫一1—萘基、1H — D引D朵一 3—基、1 一甲基一 1H〜〇弓[ 哚一3 —基、1 —甲醯基—1 Η —吲哚一 3 —基、1 一 （ 1，】 —二甲基乙氧羰基）一 1Η -吲哚一 3-基、4 —咪唑基、1 鲁 一甲基一 4 —咪哇基、2 -噻嗯基、3 -噻嗯基、噻唑基、 1 U —吲唑一 3 —基、1 一甲基一 1 Η —吲哚唑一 3 —基、苯並 〔b〕呋喃3 —基、苯並〔b〕噻嗯一 3 -基、咐D定基、D奎啉 基或異喹啉基； 且可選擇地於碳骨架經由取代基之單、二或三取代，該 取代基係F、C 1、B r、直鏈或支鏈烷基、C 3 - 8環烷基、苯 基烷基、烯基、烷氧基、苯基、苯基烷氧基、三氟甲基、 烷氧羰基烷基、羰基烷基、烷氧羰基、羧基、二烷基胺基 鲁 院基、一院基胺基院氧基、淫基、硝基、胺基、乙醒胺基 、丙醯胺基、苯甲醯基、苯甲醯胺基、苯甲醯甲基胺基、 甲基磺醯氧基、胺基羰基、烷基胺基羰基、二烷基胺基羰 基、烷醯基、氰基、四唑基、苯基、吡啶基、噻唑基、呋 喃基、三氟甲氧基、三氟甲硫基、三氟甲基亞磺醯基或三 氟甲基磺醯基； 其中該取代基可爲相同或不同且上述之苯甲醯基、苯甲 醯胺基及苯甲醯甲基胺基可額外地於苯基部份藉由F、C1 -16 - 200529835 (12) 、Br、烷基、三氟甲基、胺基或乙醯胺基加以取代 D係 0、NCN 或 NS02 (^-3烷基； A 係 C、N 或 C Η ; m和η係各別爲0、1或2 ; 唯其若m和η係0，則Α不爲Ν ; 若m係2，則η不爲2 ;或 若η係2，則m不爲2 ; E 係 N、C Η 或 C ;R only if RJ a is —c (〇) R3 ′, CHC (0) 〇 一 _ 15- 200529835 (11) CH (CH3) C (O) O— R3 ′ or -C (O) O— R3, Then -C (Ο) R3 ', CHC (0) 0 — R3', CH (CH3) C (O) O — R3 'or one C (O) O — R3 is unsubstituted 9 R3b is R3a but not Phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1naphthyl, 1H-D [Indole-3-yl, 1-methylfluorenyl-1, fluorene-indole-3-yl, 1- (1,]-dimethylethoxycarbonyl)-1fluorene-indolyl 3-yl, 4-imidazole 1-methyl-1, 4-imidyl, 2-thienyl, 3-thienyl, thiazolyl, 1 U-indazole-3-yl, 1-methyl-1, 1-pyridyl-indole A 3-yl group, a benzo [b] furan 3-yl group, a benzo [b] thien- 3-yl group, a d-Dyl group, a D-quinolinyl group, or an isoquinolinyl group; and optionally via a substitution on the carbon skeleton Mono, di or tri-substituted, the substituent is F, C 1, B r, straight or branched alkyl, C 3-8 cycloalkyl, phenylalkyl, alkenyl, alkoxy, benzene Phenyl Alkoxy, trifluoromethyl, alkoxycarbonylalkyl, carbonylalkyl, alkoxycarbonyl, carboxyl, dialkylaminoalkyl, monoamineamino, oxo, nitro, nitro, amine Methyl, ethylamine, propylamino, benzamidine, benzamidine, benzamidinemethylamino, methylsulfonyloxy, aminocarbonyl, alkylaminocarbonyl, dioxane Aminoaminocarbonyl, alkylfluorenyl, cyano, tetrazolyl, phenyl, pyridyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl, or Fluoromethylsulfonyl; wherein the substituents may be the same or different and the above-mentioned benzamidine, benzamidine and benzamidine methylamine groups may additionally be added to the phenyl moiety by F, C1 -16-200529835 (12), Br, alkyl, trifluoromethyl, amine or acetamido substituted with D system 0, NCN or NS02 (^ -3 alkyl; A system C, N or C C; m and η are 0, 1, or 2 respectively; only if m and η are 0, A is not N; if m is 2, η is not 2; or if η is 2, m is not 2 ; E is N, C Η or C;

Ρ係〇或1 ; 若Ρ係1，則G、J及Ε—起形成Αχ或Ay ;P is 0 or 1; if P is 1, G, J and E together form Aχ or Ay;

Ax係具有2個稠合環之稠合雜環，每一個該稠合環具 至7員，該雜環含有1至4個選自〇、N或S之相同或不同白勺 雜原子；且，係可選擇地含有1或2個羰基，其中該幾基之 碳原子係該稠合雜環之一員；Ax is a fused heterocyclic ring having 2 fused rings, each of which has 7 members, the heterocyclic ring contains 1 to 4 heteroatoms of the same or different groups selected from 0, N or S; and , Optionally contains 1 or 2 carbonyl groups, in which the carbon atom of the several groups is a member of the fused heterocyclic ring;

Ay係含有1至3個選自Ο、N或S之雜原子的4至6員雜環； 且，係可選擇地有1至2個羰基，其中該羰基之碳原子係該 4至6員雜環之一員； 其中Ax和Ay可選擇地經C】-4烷基、C! - 4烷氧基、Cl _ 4 鹵烷基、氰基、C3_7環烷基、苯基、鹵苯基、鹵、呋喃基 、吡咯基、吡略啉基、吡咯烷基、咪唑基、咪η坐啉基、味 唑烷基、吡唑基、吡唑啉基、吡唑烷基、吡啶基、嘧π定基 、哌啶基、哌嗪基或嗎啉代取代；或 若Ρ係〇使得G和.Τ係與Α連接，則Α係C且G、·丨及Α-起形 成螺環系統，該環系統含有A，且其中G、J及A —起係 -17 - (13) 200529835 G J A / 或 G J A "; 其中GJA —係Ax或Ay;且，OJA"係Ax或Ay; 唯其Αλ不爲1，3一二氮雜—稠合雜環；且，Ay不爲！，3 一二氮雜一雜環；且 進一步唯其若Q係Q〃，則义3係R3a ;且，若q係q / ，則 R3係R3b、或们係R3a，p係〇且〇、：及a一起形成gja" 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另—較佳體系，其中q係q /且 · R3 係 R3b。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q / 、R3 係R3a且p係0，使得G、J及A —起形成GJA，，。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q / 、 Q 係（sy ) s R3 且 S 係 0。 依據本發明之第一方面的第一較佳體系之化合物，提 · 供本發明之第一方面的另一較佳體系，其中Q係Q / 、 Q Μ系（sy) sR3、sy係C〗—3伸烷基且S係1。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q / 、 Q >係（Sy ) sR3、sy係C] — 3烷叉基且S係1。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q/且U 係 CH2。 -18 - 200529835 (14) 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中（3係Q / 、 Q / 係（sy ) sR3、S 係 0 且 U 係 ch2。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q / 、 Q ’係（Sy ) sR3、Sy係C】—3伸烷基、s係1且U係CH2 〇 依據本發明之第一方面的第一較佳體系之化合物，提 · 供本發明之第一方面的另一較佳體系，其中Q係Q / 、 Q Μ系（Sy ) SR3、sy係C】-3烷叉基、S係1且U係ch2 〇 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q /且U 係NH 〇 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q / 、 φ Q〆係(Sy ) SR3、 s係〇且u係NH 〇 依據本發明之第一方面的第~較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q / 、 Q係（s》）s R3、sy係C】—3伸院基、s係1且u係N Η。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中q係q > 、 Q係（S. ) s R 、s y係C】-3院叉基、s係1且υ係Ν Η。 依據本發明之第一方面的第一較佳體系之化合物，提 -19- 200529835 (15) 供本發明之第一方面的另一較佳體系，其中Q係Q 〃 。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q 〃且 Q"係 NH ( Sy ) SR3 〇 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q〃 、 Q"係 NH ( sy ) SR3 且 S 係 〇。 依據本發明之第一方面的第一較佳體系之化合物，提 鲁 供本發明之第一方面的另一較佳體系，其中Q係Q 〃 、 Q"係NH ( sy ) SR3、sy係C】-3伸烷基且S係1 〇 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中卩係（^〃 、 Q々係N H ( Sy ) s R3、S y係C ! - 3烷叉基且s係1。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q 〃且 Q"係 NHC ( Ο ) ( sy ) SR3。 · 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q 〃 、 (T 係 NHC ( 0) ( Sy) SR3 且 s 係 〇 〇 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q 〃 、 Q"係NHC ( Ο ) ( Sy ) SR3、Sy係C】-3伸烷基且s係1。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q 〃 、 -20- 200529835 (16) Q"係 NHC ( Ο ) ( Sy ) SR3、Sy 係 C! — 3 烷叉基且 s 係 1。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q 〃且 Q"係 NHC ( 0 ) 0 ( Sy ) SR3。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q 〃 、 (T 係 NHC ( 0 ) 〇 ( Sy ) SR3 且 s 係 〇 〇 依據本發明之第一方面的第一較佳體系之化合物，提 φ 供本發明之第一方面的另一較佳體系，其中〇係（5〃 、 Q”係NHC ( 0 ) 0 ( Sy ) SR3、Sy係C】—3伸烷基且s係1 〇 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中（^係卩〃、 Q"係 NHC ( 0 ) 0 ( Sy ) SR3、Sy 係 C! — 3 烷叉基且 s 係 i 〇 依據本發明之第一方面的第一較佳體系之化合物，提 φ 供本發明之第一方面的另一較佳體系，其中Q係Q 〃且 Q"係 NHC ( Ο) NH ( Sy) SR3 〇 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q 〃 、 Q"係 NHC ( 0 ) NH ( Sy ) SR3 且 S 係 0。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q 〃 、 (T 係 NHC(0)NH(S>')sR3、sy 係 C】-3 伸烷基且 s 係 1。 -21 - 200529835 (17) 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q 〃 、 係NHC ( Ο ) NH ( Sy ) SR3、Sy係C】-3烷叉基且s係 1 ° 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中V係OR4。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中V係OR4且 春 R4係C】-6烷基。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中V係 一 N ( R】）(R2) 〇 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中 V係—N ( R1 ) ( R2 )或 OR4 ; R4係Η、C!— 6烷基、C!- 4鹵烷基或 _ (C】-4伸烷基）g - π4'; R4'係C3- 7環烷基、苯基、金剛烷基、奎寧環基、氮雜 雙環〔2.2.1〕庚基、吖丁啶基、四氫呋喃基、呋喃基、 二噁茂烷基、噻嗯基、四氫噻嗯基、吡咯基、吡咯啉基、 吡咯烷基、咪唑基、咪唑啉基、咪唑烷基、吡唑基、吡唑 啉基、吡唑烷基、噁唑基、異噁唑基、噻唑基、異噻唑基 、噁二唑基、噻二唑基、三唑基、吡喃基、吡啶基、嘧啶 基、吡嗉基、噠嗪基、三嗪基、哌啶基、哌嗉基、嗎啉代 -22- 200529835 (18) 、硫化嗎啉代或二噁茂烷基；且 R4'係可選擇經1或2個相同或不同之取代基取代，該取 代基係選自鹵、氰基、C〗-4烷基、C ! - 4鹵烷基、C 1 _ 4院 氧基、羥基、胺基、C3 - 7環烷基、C i — 3烷基胺基、C ! _ 3 二烷胺基、（Ci-3烷基）〇— 2脲基、苯基或苄基；且Ay is a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms selected from 0, N or S; and, optionally, has 1 to 2 carbonyl groups, wherein the carbon atom of the carbonyl group is the 4 to 6 members A member of a heterocyclic ring; wherein Ax and Ay are optionally via C] -4 alkyl, C! -4 alkoxy, Cl_4 haloalkyl, cyano, C3_7 cycloalkyl, phenyl, halophenyl, Halo, furyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazoline, amidazolyl, pyrazolyl, pyrazolinyl, pyrazolyl, pyridyl, pyrimidine Phenyl, piperidinyl, piperazinyl or morpholino substitution; or if P is 0 such that G and .T are linked to A, then A is C and G, · and A form a spiro ring system, the ring The system contains A, and G, J, and A are from -17-(13) 200529835 GJA / or GJA " where GJA is Ax or Ay; and OJA " is Ax or Ay; except that Aλ is not 1,3-diaza-fused heterocycle; and, Ay is not! , 3 is a diaza-heterocyclic ring; and further, if Q is Q〃, it means R3a; and if q is q /, then R3 is R3b, or R3a, and p is 0 and 0, : A compound that forms gja " according to the first preferred system of the first aspect of the present invention together with a provides another preferred system of the first aspect of the present invention, wherein q is q / and R3 is R3b. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Q is Q /, R3 is R3a, and p is 0, such that G, J, and A — Form GJA ,,. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Q is Q /, Q is (sy) s R3 and S is 0. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Q is Q /, QM is (sy) sR3, and sy is C. —3 alkyl and S is 1. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Q is Q /, Q > (Sy) sR3, sy is C] — 3alkylidene and S is 1. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Q is Q / and U is CH2. -18-200529835 (14) The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, in which (3 series Q /, Q / system (sy) sR3, S is 0 and U is ch2. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Q is Q /, Q 'is ( Sy) sR3, Sy-based C] -3 alkylene, s-based 1 and U-based CH2 〇 The compound according to the first preferred system of the first aspect of the present invention provides another aspect of the first aspect of the present invention Preferred system, wherein Q is Q /, QM is (Sy) SR3, sy is C] -3 alkylidene, S is 1 and U is ch2. According to the first preferred system of the first aspect of the present invention, A compound, which provides another preferred system of the first aspect of the present invention, wherein Q is Q / and U is NH. The compound of the first preferred system according to the first aspect of the present invention provides the first aspect of the present invention. Another preferred system, wherein Q is Q /, φ Q〆 is (Sy) SR3, s is 〇 and u is NH 〇 According to the first aspect of the first aspect of the present invention Compound, which provides another preferred system of the first aspect of the present invention, wherein Q is Q /, Q is (s) s R3, sy is C] —3 Nobuyoshi, s is 1 and u is N Η The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein q is q >, Q is (S.) s R, and sy is C ] -3 prostheses, s is 1 and υ is N Η. Compounds according to the first preferred system of the first aspect of the present invention, -19-200529835 (15) Another for the first aspect of the present invention Preferred system, wherein Q is Q 〃. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Q is Q 〃 and Q " is NH (Sy) SR3. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Q is Q〃, Q " is NH (sy) SR3, and S is 0. The compound according to the first preferred system of the first aspect of the present invention, Tiru provides another preferred system of the first aspect of the present invention, Wherein Q is Q 〃, Q " is NH (sy) SR3, sy is C] -3 alkylene and S is 1 0. The compound according to the first preferred system of the first aspect of the present invention provides the first Another preferred system in one aspect, wherein 卩 is (^ 〃, Q々 is NH (Sy) s R3, S y is C! -3 alkylidene and s is 1). The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Q is Q 〃 and Q " is NHC (0) (sy) SR3. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Q is Q 〃, (T is NHC (0) (Sy) SR3 and s Compounds according to the first preferred system of the first aspect of the present invention provide another preferred system of the first aspect of the present invention, wherein Q is Q 、, Q " is NHC (〇) (Sy) SR3 , Sy is C] -3 alkyl and s is 1. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Q is Q 〃 , -20- 200529835 (16) Q " is NHC (O) (Sy) SR3, Sy is C! -3 alkylidene and s is 1. Compounds according to the first preferred system of the first aspect of the present invention, Another preferred system of the first aspect of the present invention is provided, wherein Q is Q〃 and Q " is NHC (0) 0 (Sy) SR3. A compound according to the first preferred system of the first aspect of the present invention provides Another preferred system of the first aspect of the present invention, wherein Q is Q 〃, (T is NHC (0) 〇 (Sy) SR3 and s is 〇〇 According to the compound of the first preferred system of the first aspect of the present invention, φ provides another preferred system of the first aspect of the present invention, wherein 0 (5〃, Q "is NHC (0) 0 (Sy) SR3, Sy is C] -3 alkyl and s is 1 0. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein卩 〃, Q " is NHC (0) 0 (Sy) SR3, Sy is C!-3 alkylidene and s is i 〇 Compound according to the first preferred system of the first aspect of the present invention, φ is provided Another preferred system of the first aspect of the invention, wherein Q is Q and Q " is NHC (0) NH (Sy) SR3. The compound according to the first preferred system of the first aspect of the invention provides the present invention Another preferred system of the first aspect, wherein Q is Q〃, Q " is NHC (0) NH (Sy) SR3 and S is 0. A compound according to the first preferred system of the first aspect of the present invention, Another preferred system of the first aspect of the present invention is provided, wherein Q is Q〃, (T is NHC (0) NH (S > ') sR3, sy is C) -3 And s is 1. -21-200529835 (17) The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Q is Q 〃 and NHC (Ο) NH (Sy) SR3, Sy is C] -3 alkylidene and s is 1 ° The compound according to the first preferred system of the first aspect of the present invention provides another comparison of the first aspect of the present invention. Best system, of which V is OR4. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein V is OR4 and R4 is C] -6 alkyl. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein V is -N (R)) (R2). According to the first aspect of the present invention, A compound of the first preferred system provides another preferred system of the first aspect of the present invention, wherein V is —N (R1) (R2) or OR4; R4 is Η, C! -6 alkyl, C! -4 haloalkyl or _ (C) -4 alkylene) g-π4 '; R4' is C3- 7 cycloalkyl, phenyl, adamantyl, quinuclidinyl, azabicyclo [2.2.1 ] Heptyl, azetidinyl, tetrahydrofuryl, furyl, dioxoalkyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolyl , Pyrazolyl, pyrazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridine And pyrimidinyl, pyrimidinyl, pyridazinyl, triazinyl, piperidinyl, piperidinyl, morpholino-22-200529835 (18), morpholinosulfide or dioxocene alkyl; and R4 ' Department can choose via 1 or 2 The same or different substituents are substituted, and the substituent is selected from the group consisting of halo, cyano, C〗 -4 alkyl, C! -4 haloalkyl, C1-4 hydroxyl, hydroxy, amine, C3-7 Cycloalkyl, Ci-3 alkylamino, C! -3 dialkylamino, (Ci-3 alkyl) 0-2 ureido, phenyl or benzyl; and

Ri可選擇地含有1或2個羰基，其中該羰基之碳原子係 Rf環結構之一員； R1和R2係各別獨立之L1，其中L1選自Η、Cl - 6烷基、 φ 一 C]— 6伸院基一胺基（Ci-3院基）2、匚3-7丨哀院基、苯基 、金剛烷基、吖丁啶基、四氫呋喃基、呋喃基、二噁茂烷 基、噻嗯基、四氫噻嗯基、吡咯基、吡咯啉基、吡咯烷基 、咪唑基、咪唑啉基、咪唑烷基、吡唑基、吡咪啉基、吡 唑烷基、噁唑基、異噁唑基、噻唑基、異噻唑基、噁二唑 基、噻二唑基、三唑基、吡喃基、吡啶基、嘧啶基、毗嗪 基、噠嗪基、三嗪基、哌啶基、哌嗪基、嗎啉代、硫代嗎 啉代或二噁茂烷基；且 · R 1和R2係各別可選擇且獨立經1或2個相同或不同之取代 基取代，該取代基選自鹵、氰基、C4烷基、C ! - 4鹵烷基 、C ! - 4烷氧基、羥基、胺基、c 3 — 7環烷基、C ! - 3垸基胺 基、C!— 3二烷基胺基、（C!-3烷基脲基、苯基或苄 基；且 R 1和R2係可選擇各別含I或2個羰基，其中該羰基之碳原 子係包含R 1和R2之雜環的一員； 其中L1係可選擇由N中斷，該N係由L2連接，其中L2係 -23- 200529835 (19) C I - 3伸烷基；或 R和R與其連接之N —起形成X，其中X係吖丁啶基、吡 略卩林基、卩Η* π夕k Κ略烷基、咪唑啉基、咪唑烷基、吡唑啉基、吡 口i k基、D丫庚因基、二吖庚因基、哌嗪基、哌啶基、嗎啉 代或硫代嗎啉代； 其中X可選擇經Y取代，其中Y係二噁茂烷基、C! - 4烷基 、Cl~ 4院基胺基、C,- 4二烷胺基、C!- 4烷氧基、C3- 7環 k基、本基 '吖丁啶基、吡咯基、吡咯啉基、吡咯烷基、 · D比略垸酮基、咪唑基、咪唑啉基、咪唑烷基、咪唑烷酮基 、D比η坐基、吡唑啉基、吡唑烷基、吖庚因基、二吖庚因基 、吼Π定基、嘧啶基、二氫苯並咪唑酮基 '哌嗪基、哌啶基 、嗎啉代、苯並噻唑基、苯並異噻唑基或硫代嗎啉代；且 其中X和Υ係可選擇由Ζ中斷，其中Ζ係一 NHC(O) 〇 — 、-NHC(〇)㈣一、一 NC(O) NH2' - NH-、一 C丨-3 伸烷基一或一 C】—3伸烷基—NH C ( 0 ) 0 - C 1 - 3伸烷基一 ’ φ X和Y係可選擇地各別經i或2個相同或不同之取代基取 代’該取代基選自C ! - 4烷基、胺基、C ! - 3烷基胺基、 一 C丨-6伸烷基一胺基（C〗-3烷基）2、（ C丨-3烷基）G _ 2脲 基、苯基或苄基； X和Y係可選擇地各別含有1或2個羰基，其中該羰基之 碳原子係包含X和Y之雜環的一員； 唯其若X係經Y取代且若X和Y不經由z中斷，則X 和γ可選擇地共有1個碳原子且一起形成螺環部份。 -24- 200529835 (20) 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中R4係Η、 6 ；!：完基、Cl _ 4鹵烷基或（Cl _ 4伸烷基）G_ π4 ' ; Ri 係C3 -7環烷基、苯基、金剛烷基、奎寧環基、氮雜雙環 〔2·2·1〕庚基、吖丁啶基、四氫呋喃基、呋喃基、二噁 茂院基、噻嗯基、四氫噻嗯基、吡咯基、吡咯啉基、毗咯 院基、咪唑基、咪唑啉基、咪唑烷基、吡唑基、吡唑啉基 、D比哩烷基、噁唑基、異噁唑基、噻唑基、異噻唑基、噁 φ 二D坐基、噻二唑基、三唑基、吡喃基、吡啶基、嘧啶基、 D比嗪基、噠嗪基、三嗪基、哌啶基、哌嗪基、嗎啉代、硫 化嗎琳代或二噁茂烷基；且R4 '係可選擇經1或2個相同 或不同之取代基取代，該取代基係選自鹵、氰基、C! - 4 院基、C】—*鹵烷基、4烷氧基、羥基、胺基、C3_ 7環 院基、C丨1烷基胺基、c3二烷胺基、 (C】-3纟兀基）G_2脈基、苯基或；基。 依據本發明之第一方面的第一較佳體系之化合物，提 · 供本發明之第一方面的另一較佳體系，其中R4係Η、 C】-6院基、Cl_ 4鹵烷基或（Cl - 4伸烷基）。叫R4' ; R4 — 係C3 — 7環烷基、苯基、金剛烷基、奎寧環基、氮雜雙環 〔2 ·2 ·1〕庚基、吖丁啶基、四氫呋喃基、呋喃基、二噁 茂院基、噻嗯基、四氫噻嗯基、吡咯基、吡咯啉基、吡咯 院基、咪唑基、咪唑啉基、咪唑烷基、吡唑基、吡唑啉基 、吼唑院基、噁唑基、異噁唑基、噻唑基、異噻唑基、噁 二哗基、噻二唑基、三唑基、吡喃基、吡啶基、嘧啶基、 -25- 200529835 (21) 吡嗪基、噠嗦基、三嗉基、哌啶基、哌嗪基、嗎啉代、硫 化嗎啉代或二噁茂烷基 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中R4係Η、Ri optionally contains 1 or 2 carbonyl groups, wherein the carbon atom of the carbonyl group is a member of the Rf ring structure; R1 and R2 are each independently L1, where L1 is selected from fluorene, Cl-6 alkyl, φ-C] — 6Yenyl-amino group (Ci-3), 2, 3-7 丨 Arylidene, phenyl, adamantyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxoalkyl, thion Group, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolyl, pyrazolyl, pyrimidyl, pyrazolyl, oxazolyl, isoxazole Oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, Piperazinyl, morpholino, thiomorpholino or dioxocene alkyl; and R 1 and R 2 are each independently selectable and independently substituted by 1 or 2 identical or different substituents, the substituents being selected Self-halogen, cyano, C4 alkyl, C! -4 haloalkyl, C! -4 alkoxy, hydroxyl, amine, c 3-7 cycloalkyl, C! -3 amidino, C! — 3 dialkylamino, (C! -3 alkylureido Phenyl or benzyl; and R 1 and R 2 may each contain I or 2 carbonyl groups, wherein the carbon atom of the carbonyl group includes a member of the heterocyclic ring of R 1 and R 2; wherein L 1 is optionally interrupted by N, The N is connected by L2, wherein L2 is -23-200529835 (19) CI-3 alkylene; or R and R are connected with N to form X, wherein X is azetidinyl, pyrrolidinyl, hydrazone Η * π alkene alkyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrikyl, Daheptinyl, diazepine, piperazinyl, piperidinyl, morpholine Or thiomorpholino; where X can be optionally substituted by Y, where Y is dioxoalkyl, C! -4 alkyl, Cl ~ 4 alkylamino, C, -4 dialkylamino, C !-4 alkoxy, C3- 7 ring k group, the base 'azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, D than slightly fluorenone, imidazolyl, imidazolinyl, imidazolyl Imidazolidinone, D-ratio, pyrazolinyl, pyrazolidinyl, azepine, diazepine, pyridinyl, pyrimidinyl, dihydrobenzimidazolone 'piperazinyl , Piperidinyl, morpholino, benzothiazolyl, benzoiso Oxazolyl or thiomorpholino; and where X and Υ are optionally interrupted by Z, where Z is -NHC (O) 0-, -NHC (〇) ㈣-1, -NC (O) NH2 '-NH- , -C 丨 -3 alkylene or C] -3 alkylene -NH C (0) 0-C 1-3 alkylene-φ X and Y are optionally via i or 2 respectively The same or different substituents are substituted. The substituent is selected from the group consisting of C! -4 alkyl, amine, C! -3 alkylamine, and C-6 alkylene monoamine (C〗 -3 alkyl Group) 2, (C 丨 -3 alkyl) G_2 ureido, phenyl or benzyl; X and Y each optionally contain 1 or 2 carbonyl groups, wherein the carbon atom system of the carbonyl group contains X and A member of the heterocycle of Y; only if X is substituted by Y and if X and Y are not interrupted by z, then X and γ may optionally have 1 carbon atom and together form a spiro ring moiety. -24- 200529835 (20) The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein R4 is Η, 6;!: Endyl, Cl _ 4 haloalkyl or (Cl _ 4 alkyl) G_ π4 '; Ri is C3-7 cycloalkyl, phenyl, adamantyl, quinuclidinyl, azabicyclo [2 · 2 · 1] heptane Radical, azetidinyl, tetrahydrofuryl, furyl, dioxoyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolyl, pyrrolyl, imidazolyl, imidazolinyl, imidazolyl, Pyrazolyl, pyrazolinyl, d-pyridyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl , Pyridyl, pyrimidinyl, D-pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, morpholino, or dioxocene alkyl; and R4 'is optional 1 or 2 substituents which are the same or different, the substituent is selected from the group consisting of halo, cyano, C!-4 alkyl, C]-* haloalkyl, 4 alkoxy, hydroxyl, amine, C3_ 7 Cycloalkyl, C 丨 1 alkylamino c3 dialkylamino, (C Wu-yl] -3 Si) of G_2 veins, phenyl, or; group. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein R4 is fluorene, C] -6 alkyl, Cl_4 haloalkyl or (Cl-4 alkylene). Called R4 '; R4 — is C3-7 cycloalkyl, phenyl, adamantyl, quinuclidinyl, azabicyclo [2 · 2 · 1] heptyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxane Molybdenyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolyl, imidazolyl, imidazolinyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazinyl, Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, -25- 200529835 (21) pyrazinyl , Pyridinyl, trifluorenyl, piperidinyl, piperazinyl, morpholino, morpholino, or dioxocene alkyl compounds according to the first preferred system of the first aspect of the present invention, to provide the present invention Another preferred system of the first aspect, wherein R4 is Η,

Ci - 6烷基或（C】—4伸烷基）iRi係C3 — 7環烷基。Ci-6 alkyl or (C] -4 alkylene) iRi is C3-7 cycloalkyl.

依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中V係 -NCR1) ( R2)，且The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein V is -NCR1) (R2), and

Rl和R2係各別獨立之L1，其中L1選自H、C】-6烷基、 一 c! - 6伸烷基一胺基（C】_ 3烷基）2、C3_ 7環烷基、苯基 、印丁啶基、金剛烷基、四氫呋喃基、呋喃基、二噁茂烷 基、噻嗯基、四氫噻嗯基、吡咯基、吡咯啉基、吡咯烷基 咪唑基、咪唑啉基、咪唑烷基、吡唑基、吡咪啉基、吡 哩院基、B惡哩基、異噁唑基、噻唑基、異噻唑基、噁二哗 基、噻二唑基、三唑基、吡喃基、吡啶基、嘧啶基、毗嗪R1 and R2 are each independently L1, wherein L1 is selected from the group consisting of H, C] -6 alkyl, -c! -6 alkylene monoamine (C) _3 alkyl), C3_7 cycloalkyl, Phenyl, butadiidyl, adamantyl, tetrahydrofuranyl, furanyl, dioxoalkyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl imidazolyl, imidazolinyl, imidazole Alkyl, pyrazolyl, pyrimidinyl, pyrimidinyl, B-oxazyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazyl, thiadiazolyl, triazolyl, pyran , Pyridyl, pyrimidinyl, pyrazine

基、噠嗪基、三嗪基、哌啶基、哌嗪基、嗎啉 11八 硫代嗎 啉代或二噁茂烷基；或 “Group, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholine 11 octathiomorpholino or dioxoalkylene; or "

Rl和R2與其連接之Ν—起形成X，其中X係吖丁啶基、吡 咯基、吡咯啉基、吡咯烷基、咪唑啉基、咪D坐烷基、咁_ 琳基、w π坐院基、口丫庚因基、二卩丫庚因基哩 矛、盎、哌啶 基、嗎啉代或硫代嗎啉代； 其中X係經Y取代，其中¥係二噁茂烷基、烷基、 C3-7環烷基、苯基、吖丁啶基、吡咯基、吡咯啉基、吡咯 k基、咄咯烷酮基、咪唑基、咪唑啉基、咪唑 匕丨休D坐 -26- 200529835 (22) 烷酮基、吡唑基、吡唑啉基、吡唑烷基、吖庚因基、二吖 庚因基、吡啶基、嘧啶基、二氫苯並咪唑酮基、哌嗪基' 哌啶基、嗎啉代、苯並噻唑基、苯並異噻唑基或硫代嗎啉 代；且 其中X和Y可選擇地共有1個碳原子且一起形成螺環 部份。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中V係 · —NCR1) (R2)且Ri和各別獨立爲其中^選 自H、C】-6烷基，或Ri和R2與其連接之N—起形成X， 其中X係哌啶基或嗎啉代；其中X係經γ取代，其中Y 係一嚼戊垸基、c 1 — 4院基或脈D定基；且其中X和Y可選 擇地共有1個碳原子且一起形成螺環部份。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中V係 —N ( R1 ) ( R2 )且其中Rl和R2各別獨立爲L1，其中φ 選自Η或c】—6烷基。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中V係 . 一 N(R】） （R2)且其中r^dr2與其連接之^^—起形成 X ’其中X係哌啶基或嗎啉代；其中X係經Y取代，其中 Y係一噁茂烷基、c卜4烷基或哌啶基；且其中χ和Y可 選擇地共有1個碳原子且一起形成螺環部份。 依據本發明之第一方面的第一較佳體系之化合物，提 - 21 - 200529835 (23) 供本發明之第一方面的另一較佳體系，其中V係 —N(R]) (R2)且其中與其連接之n 一起形成 X，其中X係哌啶基；其中χ係經γ取代，其中Y係哌 啶基。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中V係 一 N ( R1 ) ( R2 )且其中Ri和R2與其連接之ν 一起形成 X，其中X係嗎啉代；其中X係經γ取代，其中γ係 · C 1 - 4院基。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中V係 一 NCR1) (R2)且其中R1和R2與其連接之N 一起形成 X，其中X係哌啶基；其中X係經γ取代，其中γ係 C ! - 4烷基。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中V係 · 一 NCR1) (R2)且其中和與其連接之n —起形成 X，其中X係哌啶基；其中X係經γ取代，其中Y係二 噁茂烷基；且其中X和Y共有1個碳原子且一起形成螺 環部份。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中X和Y不爲 Z中斷。 依據本發明之第一方面的第一·較佳體系之化合物’挂 -28- 200529835 (24) 供本發明之第一方面的另一較佳體系，其中χ和γ不爲 Ζ中斷；且X和Υ共有丨個碳原子且一起形成螺環部份 〇 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中R3係R3a。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中R3係R3b。 依據本發明之第一方面的第—較佳體系之化合物，提 春 供本發明之第一方面的另一較佳體系，其中R3a係具有2 個稠合環之雜環，每一個稠合環具有5至7員，該雜環含 有1至5個選自〇、N或S之相同或不同的雜原子。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中R3 a係具有2 個稠合環之雜環，每一個稠合環具有5至7員，該雜環含 有1至5個選自〇、N或S之相同或不同的雜原子且該雜 環可選擇地含有1或2個羰基，其中該羰基之碳原子係該 · 稠合環之一員。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中係具有2 個稠合環之雜環，每一個稠合環具有5至7員，該雜環含 有1至5個選自〇、N或S之相同或不同的雜原子且該雜 環可選擇地含有1或2個羰基’其中該羰基之碳原子係該 稠合環之一員；其中R3a可選擇地經1至3個相同或不同 之取代基取代，該取代基選自爷基、苯基、一 〇 -苯基、 -29- (25) (25)200529835 _〇—C】—3烷基苯基、一 d_3伸烷基—〇c(o) —苯基、 氰基、胺基、硝基、鹵、Ci-3單一、二—或三鹵院基、 C】—3單一、二一或三鹵烷氧基、Cl_6烷氧基、（Ci-3烷 基）1-2 胺基、一 OR^、- c ( 0 ) R3 ^、一 C(0) OR3. 、-0 - C(0) R3' — N(R3」2、 -C(0)N(、R3’）2、—n(R3」C(0) (r3')2、 -N ( R3' ) c ( 0) n ( R3' ) 2、 -N(R3 )C(〇)〇R3'— 〇c(0)N(R3')2、 · -N(R3’）S02R3' — s〇2N(R3’）2 或-S02R3-; R3係H或C】-6烷基。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中係4至6 員雜環’其含有1至3個選自0、N或S之相同或不同的 雜原子。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中]133係4至6 φ 員雜環，其含有1至3個選自0、N或S之相同或不同的 雜原子且可選擇地含有1至2個羰基，其中該羰基之碳原 子係該4至6員雜環之一員。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中R3 a係4至6 員雜環，其含有1至3個選自0、N或S之相同或不同的 雜原子且可選擇地含有1至2個羰基，其中該羰基之碳原 子係該4至6員雜環之一員；其中R3a可選擇地經]至3 -30- (26) (26)200529835 或不同之取代基取代，該取代基選自苄基、苯基、 本*毫、一 〇__Ci-3院基苯基、—C】—3伸院基 (〇) —苯基、氰基、胺基、硝基、鹵、Ci-3單— 、一 —鹵烷基、Ci-3單一、二一或三鹵烷氧基、R1 and R2 form an X with the N to which they are attached, where X is azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolyl, hydrazone, wπradyl, Methylheptyl, dipyheptimyl, hydrazine, piperidinyl, morpholino, or thiomorpholino; where X is substituted by Y, where ¥ is dioxoalkyl, alkyl, C3-7 cycloalkyl, phenyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolium 26-200529835 (22) Alkanone, pyrazolyl, pyrazolinyl, pyrazolyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihydrobenzimidazolone, piperazinyl 'piperidinyl , Morpholino, benzothiazolyl, benzoisothiazolyl, or thiomorpholino; and wherein X and Y optionally share 1 carbon atom and together form a spiro ring moiety. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, in which V is -NCR1) (R2), and Ri and each are independently selected X is formed from H, C] -6 alkyl, or N to which Ri and R2 are connected, wherein X is piperidinyl or morpholino; wherein X is substituted by γ, wherein Y is a glutamyl group, c 1-4 radicals or D-based radicals; and wherein X and Y may optionally have a total of 1 carbon atom and together form a spiro ring moiety. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein V is -N (R1) (R2) and wherein R1 and R2 are each independently L1, wherein φ is selected from fluorene or c] -6 alkyl. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein V is a N (R)) (R2) and wherein r ^ dr2 is connected thereto ^^ — from which X 'is formed, wherein X is piperidinyl or morpholino; wherein X is substituted by Y, wherein Y is an oxocene alkyl, c4-alkyl or piperidinyl; and wherein χ and Y Optionally there is a total of 1 carbon atom and together forms a spiro ring moiety. The compound according to the first preferred system of the first aspect of the present invention provides-21-200529835 (23) Another preferred system of the first aspect of the present invention, wherein V is -N (R)) (R2) Wherein, X is formed together with n connected to it, wherein X is piperidinyl; wherein χ is substituted by γ, and Y is piperidinyl. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein V is a N (R1) (R2) and wherein Ri and R2 are connected to ν Together, X is formed, wherein X is a morpholino; wherein X is substituted by γ, and γ is a C 1-4 radical. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein V is an NCR1) (R2) and wherein R1 and R2 are formed together with the N to which they are attached. X, wherein X is piperidinyl; wherein X is substituted by γ, wherein γ is C! -4 alkyl. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, in which V is a NCR1) (R2) and is formed by neutralization with n connected thereto. X, wherein X is piperidinyl; wherein X is substituted by γ, wherein Y is dioxocene alkyl; and wherein X and Y share 1 carbon atom and together form a spiro ring moiety. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, in which X and Y are not interrupted by Z. Compounds of the first preferred system according to the first aspect of the present invention 'Hang-28- 200529835 (24) Another preferred system for the first aspect of the present invention, wherein χ and γ are not interrupted by Z; and X A compound having 丨 carbon atoms and forming a spiro ring moiety together with Υ. A compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein R3 is R3a. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein R3 is R3b. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein R3a is a heterocyclic ring having two fused rings, each of which is a fused ring Having 5 to 7 members, the heterocyclic ring contains 1 to 5 heteroatoms which are the same or different and are selected from 0, N or S. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein R3a is a heterocyclic ring having 2 fused rings, each of which has 5 to 7 members, the heterocyclic ring contains 1 to 5 same or different heteroatoms selected from 0, N or S and the heterocyclic ring optionally contains 1 or 2 carbonyl groups, wherein the carbon atom of the carbonyl group is · One of the fused rings. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein the heterocyclic ring has 2 fused rings, each fused ring has 5 to 7 members, the heterocyclic ring contains 1 to 5 same or different heteroatoms selected from 0, N or S and the heterocyclic ring optionally contains 1 or 2 carbonyl groups wherein the carbon atom of the carbonyl group is the fused ring One member; wherein R3a is optionally substituted with 1 to 3 substituents which are the same or different, the substituent is selected from the group consisting of hexyl, phenyl, 10-phenyl, -29- (25) (25) 200529835 _〇 —C] —3-alkylphenyl, mono-d_3-alkylene—oc (o) —phenyl, cyano, amine, nitro, halogen, Ci-3 single, di- or trihalo, C ] —3 single, di- or trihaloalkoxy, Cl-6 alkoxy, (Ci-3 alkyl) 1-2 amino, mono-OR ^, -c (0) R3 ^, mono-C (0) OR3 ., -0-C (0) R3 '— N (R3 ″ 2, -C (0) N (, R3') 2, —n (R3 ″ C (0) (r3 ') 2, -N (R3 ') c (0) n (R3') 2, -N (R3) C (〇) 〇R3'— 〇c (0) N (R3 ') 2, · -N (R3') S02R3 '— s〇 2N (R3 ') 2 or -S02R3-; R 3 is H or C] -6 alkyl. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein it is a 4- to 6-membered heterocyclic ring. It contains 1 to 3 identical or different heteroatoms selected from 0, N or S. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention. Where] 133 is a 4 to 6 φ membered heterocyclic ring, which contains 1 to 3 same or different heteroatoms selected from 0, N or S and optionally contains 1 to 2 carbonyl groups, wherein the carbon atoms of the carbonyl group Is a member of the 4- to 6-membered heterocyclic ring. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein R 3 a is a 4- to 6-membered heterocyclic ring. A ring containing 1 to 3 same or different heteroatoms selected from 0, N or S and optionally containing 1 to 2 carbonyl groups, wherein the carbon atom of the carbonyl group is one of the 4 to 6 membered heterocyclic ring; Wherein R3a is optionally substituted by] to 3-30- (26) (26) 200529835 or a different substituent selected from the group consisting of benzyl, phenyl, 〇__Ci-3 phenyl group, —C] -3 phenyl group (〇) —phenyl, cyano, amine, nitro, halo, Ci-3 mono—, monohaloalkyl, Ci -3 single, di- or trihaloalkoxy,

Cl - 6院氧基、（c]_ 3烷基）卜2胺基、—〇R3’、 -C(O) R3' — c(〇) 〇R3、一 〇— c(〇) r3、 -N ( R3- ) 2、- C ( Ο) N ( R3,）2、 —N ( R3 - ) C ( O ) ( R3 / ) 2、 φ -N ( R3 - ) c ( 〇 ) N ( R3 ' ) 2、 -N(R3-) C(O) OR3' -OC(O) N(R3，）2、 -N ( V ) S02R3' - S02N ( R3 - ) 2 或—sow ; r3係H或c】-6烷基。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中R3a係C3_7 環烷基。 依據本發明之第一方面的第一較佳體系之化合物，提 · 供本發明之第一方面的另一較佳體系，其中R3 a係C3 一 7 環院基；其中R3a可選擇地經1至3個相同或不同之取代 基取代，該取代基選自平基、苯基、一 〇一苯基、 —〇 一 Cl— 3院基苯基、一 Ci-3伸院基一 〇C(〇)—苯基、 氰基、胺基、硝基、鹵、單一、二一或三鹵院基、 C]-3單—、二—或三鹵烷氧基、C】—6烷氧基、 (C】—3 烷基）】—2 胺基、—OR3 ' 一 C ( 0 ) R3 ' —c(0) 〇R3— 、 - 〇 - c ( Ο ) R3 ^ Ν ( R3 ") -31 - (27)200529835 -C ( Ο ) N -N ( R3,） 、一〇c ( 〇 —so2N ( R 依據本 供本發明之 、芴基、苯 基。 依據本 供本發明之 、荀基、苯 基；其中 R 代’該取代 烷基苯基、 基、硝基、 、二一或三 基、— OR3 一 〇 〜C ( 〇 、-N ( R3 ^ 一 N ( R3_ ) -N ( R3 - } 一 N ( R3-) R 3係Η或 依據本 (R3 ' ) 2、- N ( R3 ' ) C ( 〇 ) ( R3' ) 2、 C ( 0 ) N ( R3’）2、- N ( R3 - ) C ( 0 ) 〇R3 一 )N ( R3,）2、- N ( Ri ) SOW、 3 )2 或—SO2R3 ;R3 係 Η 或 Ci-6 院基。 發明之第一方面的第一較佳體系之化合物，提 第一方面的另一較佳體系，其中1133係昨唑基 基、一 0—苯基、—0 - C〗-4伸烷基苯基或萘 發明之第一方面的第一較佳體系之化合物，提 第一方面的另一較佳體系，其中1133係咔唑基 基、一 0 一苯基、一 0一 Cl_4伸烷基苯基或萘 3a可選擇地經1至3個相同或不同之取代基取 基選自苄基、苯基、一 〇 —苯基、—〇 一 C卜3 一 c】-3伸院基—〇c(o) -苯基、氰基、胺 鹵、Ci-3單一、二一或三鹵院基、3單— 鹵烷氧基、c 1 - 6烷氧基、（c丨—3烷基）】-2胺 · 、-C(0)R3'— C(〇)〇R3'、 )R3 ^、- N(R3-) 2、- C(0) n(R3') 2 )C ( 0) ( R”）2、 C ( 0 ) N ( R3 ' ) 1、 C ( 0 ) OR3 一、— 0C ( 〇 ) N ( R3 ' ) 2、 S02R3'、一 S02N(R3') 2 或—SOW ； c 1 - 6院基。 發明之第一方面的第一較佳體系之化合物，提 '32- (28) (28)200529835 供本‘發明之第一方面的另一較佳體系，其中R3a係C!- 8 烷基、c2— 7 烯基、—C(O) R3’、一 c(0) OR3’或 C2-7 炔基。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中R3a係Ci- 8 烷基、C2-7 烯基、一 C(0) R3'、一 c(0) OR3’ 或 C2-7 炔基；其中RSa可選擇地經1至3個相同或不同之取代基 取代’該取代基選自节基、苯基、一 〇 一苯基、 —0— C卜3烷基苯基、—Ci_3伸烷基—〇c(〇) —苯基、 氰基、胺基、硝基、鹵、d-3單一、二一或三鹵烷基、 C】-3單一、二—或三鹵烷氧基、Cl_6烷氧基、（C】-3烷 基）1 - 2 胺基、—OR3 '、一 C(0)R3’、— C(0) OR3 一 、-〇〜C(〇) R3’、- N(R3') 2、 -c(〇)N(R3-)2、— n(r3，）c(o) (r3，）2、 - N ( R3 - ) C ( 0 ) N ( R3 ' ) 2、 - N(R3 ) c ( 0 ) OR3 、- 〇C(0) N(R3') 2、 - N(R3」S02R3 ' - S02N(R3 一）2 或-S02R3- ; 係H或C卜6烷基；唯其若R3a係—C ( 0 ) R3 ' - CHC(〇) 〇r3'、_ CH ( CH3 ) C ( 0 ) OR3'或 一 C ( 〇 ) 〇r3 ' 則該一 c ( 〇 ) R3 '、— CHC ( 0 ) 〇R3 -、-CH ( CHs ) c ( 0 ) OR3 '或—c ( 0 ) OR3 '係未經取代 ο i衣據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中R3係RSa且 -33 - (29) (29)200529835 R 3 a係苯基、羥基苯基、吖丁啶基、萘基、C i - 6烷基、 C 2 — 6烯基、C 2 - 6炔基、二氫喹諾酮基、氫喧諾酮基、〇奎 啉基、二氣異喹諾酮基、氫異喹諾酮基、異喹啉基、一氫 D奎D坐啉酮基、氫喹唑啉酬|基、喹Π坐啉基、二氫D奎D惡啉酮基 、氫喹噁啉酮基、喹噁啉基、苯並咪唑基、吲唑基、二氫 苯並咪唑啉酮基、氫苯並咪唑啉酮基、苯並咪唑啉基、二 氫苯並噻唑啉酮基、氫苯並噻唑啉酮基、苯並噻11坐基、二 氫苯並噁唑基、苯並三唑基、二氫苯並噻吩酮基、氫苯並 · 噻吩酮基、苯並噻嗯基、二氫苯並呋喃酮基、氫苯並咲喃 酮基、苯並呋喃基、苯並二噁茂烷基、二氫吲哚滿酮基、 氫吲哚滿酮基、吲哚基、吲哚嗪滿基、異吲哚基 '吲13朵滿 基、吲D坐基、吡唑基、吡唑啉基、吡唑烷基、咲喃基、噻 嗯基、吡咯基、吡咯啉基、吡咯烷基、咪唑基、咪唑啉基 、咪唑烷基、吡啶基、嘌呤基、咔唑基、嘧啶基、哌啶基 、三唑並嘧啶基、四氫吡唑並吡啶基、哌嗪基或嗎啉代； 且可選擇地如前揭第一方面之第一較佳體系經取代。 參 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中R3係R3a且 R3a係苯基、萘基、吲唑基、苯並咪唑啉基、二氫苯並噁 唑基、苯並三唑基、苯並噻嗯基、苯並二噁茂烷基、二氫 吲哚滿酮基、吲哚基、呋喃基、噻嗯基、吡啶基、嘌呤基 、咔唑基、哌啶基、三唑並嘧啶基、四氫吡唑並吡啶基； 且可選擇地如前揭第一方面之第一較佳體系經取代。 依據本發明之第一方面的第一較佳體系之化合物，提 -34 - 200529835 (30) 供本發明之第一方面的另一較佳體系，其中R3係R3a且 R3 a係二氫苯並噻唑啉酮基、氫苯並噻唑啉酮基、苯並噻 唑基、二氫苯並噻吩酮基、氫苯並噻吩酮基、苯並噻嗯基 、二氫苯並呋喃酮基、氫苯並呋喃酮基、苯並呋喃基、二 氫吲哚滿酮基、氫吲哚滿酮基、吲哚基、吲哚嗪滿基、異 吲哚基、吲哚滿基或吲唑基；且可選擇地如前揭第一方面 之第一較佳體系經取代。 依據本發明之第一方面的第一較佳體系之化合物，提 φ 供本發明之第一方面的另一較佳體系，其中R3係R3a且 R3 a係二氫苯並噁唑基、苯並三唑基、吲哚基、鹵硝基苯 基、鹵嘧啶基、鹵嘌呤基、C ! - 3烷基硝基胺基嘧啶基、 三唑並嘧啶基、吡啶基、吲唑基、苯基或苯並二噁茂烷基 ;且可選擇地如前揭第一方面之第一較佳體系經取代。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中R3係1133且 R3 a係萘基、苯基一 Ο -苯基或噻嗯基；且可選擇地如前 鲁 揭第一方面之第一較佳體系經取代。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中R3係R3b。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中R3係R3b且 R3b係 1 Η —吲哚—5 —基 -35- 200529835 (31)Cl-6 oxo, (c) _3 alkyl) p 2 amine, -〇R3 ', -C (O) R3'-c (〇) 〇R3, 〇- c (〇) r3,- N (R3-) 2,-C (Ο) N (R3,) 2, --N (R3-) C (O) (R3 /) 2, φ -N (R3-) c (〇) N (R3 ' ) 2, -N (R3-) C (O) OR3 '-OC (O) N (R3,) 2, -N (V) S02R3'-S02N (R3-) 2 or --sow; r3 is H or c ] -6 alkyl. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein R3a is a C3_7 cycloalkyl group. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein R3 a is C3-7 ring base; wherein R3a is optionally selected by 1 To 3 identical or different substituents, the substituent is selected from the group consisting of a phenyl group, a phenyl group, a 10-phenyl group, a -0-Cl-3 alkyl phenyl group, a Ci-3 alkyl group-10C ( 〇) —phenyl, cyano, amine, nitro, halogen, mono, di- or tri-halo, C] -3 mono-, di- or trihaloalkoxy, C] -6 alkoxy , (C) —3 alkyl)]-2 amine group, —OR3'-C (0) R3 '-c (0) 〇R3—,-〇- c (Ο) R3 ^ Ν (R3 ")- 31-(27) 200529835 -C (0) N-N (R3,), 10c (0-so2N (R according to the present invention, fluorenyl, phenyl. According to the present invention, fluorenyl , Phenyl; wherein R is substituted for the substituted alkylphenyl, phenyl, nitro, bis or triyl, —OR3 〇 ～ C (〇, -N (R3 ^ -N (R3_) -N (R3 -) -N (R3-) R 3 is based on (R3 ') 2,-N (R3') C (〇) (R3 ') 2, C (0) N (R3 ') 2,-N (R3-) C (0) 〇R3 a) N (R3,) 2,-N (Ri) SOW, 3) 2 or -SO2R3; R3 is Or Ci-6. Based on the compound of the first preferred system of the first aspect of the invention, another preferred system of the first aspect is mentioned, in which 1133 is oxazolyl, -0-phenyl, -0- C〗 -4 The compound of the first preferred system of the first aspect of the invention of naphthylphenyl or naphthalene, another preferred system of the first aspect, wherein 1133 is a carbazolyl group, a 0-phenyl group, 0-0 Cl_4 alkylene phenyl or naphthalene 3a is optionally selected from benzyl, phenyl, 0-phenyl, -〇-C 3 3 c via 1 to 3 substituents which are the same or different 】 -3 Shenyuanji—Oc (o) -phenyl, cyano, amine halide, Ci-3 single, dione or trihaloyl, 3 mono-haloalkoxy, c 1-6 alkoxy , (C 丨 -3 alkyl)]-2 amine, -C (0) R3'-C (〇) 〇R3 ',) R3 ^, -N (R3-) 2,-C (0) n ( R3 ') 2) C (0) (R ”) 2, C (0) N (R3') 1, C (0) OR3 one, — 0C (〇) N (R3 ') 2, S02R3', one S02N (R3 ') 2 or—SOW; c 1-6 base. The compound of the first preferred system of the first aspect of the invention provides another preferred system of the first aspect of the invention of '32-(28) (28) 200529835, wherein R3a is a C! -8 alkyl group, c2-7 alkenyl, -C (O) R3 ', a c (0) OR3' or C2-7 alkynyl. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein R3a is Ci-8 alkyl, C2-7 alkenyl, -C (0) R3 ', a c (0) OR3', or C2-7 alkynyl; wherein RSa is optionally substituted with 1 to 3 identical or different substituents, the substituent being selected from benzyl, phenyl, and benzene , —0—C 3 alkylphenyl, —Ci_3 alkylene — 0c (〇) —phenyl, cyano, amino, nitro, halogen, d-3 single, dione or trihalane Group, C] -3 single, di- or trihaloalkoxy group, Cl-6 alkoxy group, (C] -3 alkyl) 1-2 amino group, -OR3 ', one C (0) R3', -C (0) OR3 I, -〇 ~ C (〇) R3 ',-N (R3') 2, -c (〇) N (R3-) 2,-n (r3,) c (o) (r3,) 2,-N (R3-) C (0) N (R3 ') 2,-N (R3) c (0) OR3,-〇C (0) N (R3') 2,-N (R3``S02R3 ' -S02N (R3 one) 2 or -S02R3-; is H or C 6 alkyl; only if R3a is -C (0) R3 '-CHC (〇) 〇r3', _ CH (CH3) C (0 ) OR3 'or a C (〇) 〇r3 ′ then the c (〇) R3 ′, — CHC (0) 〇 R3-, -CH (CHs) c (0) OR3 ′ or —c (0) OR3 ′ is unsubstituted. I The compound according to the first preferred system of the first aspect of the present invention provides the first Another preferred system in one aspect, wherein R3 is RSa and -33-(29) (29) 200529835 R 3a is phenyl, hydroxyphenyl, azetidinyl, naphthyl, Ci-6 alkyl, C 2 — 6 alkenyl, C 2-6 alkynyl, dihydroquinolone, hydronorolone, 0 quinolinyl, digas isoquinolyl, hydrogen isoquinolone, isoquinolinyl, monohydroquinone Quinolinone, hydroquinazoline group, quinolinyl group, dihydroquinone, oxaquinone group, hydroquinoxaline group, quinoxaline group, benzimidazolyl group, indazolyl group, Hydrobenzimidazolone, Hydrobenzimidazolone, Benzimidazoline, Dihydrobenzothiazolinone, Hydrobenzothiazolinone, Benzothiazine, Dihydrobenzo Oxazolyl, benzotriazolyl, dihydrobenzothienone, hydrobenzo · thienone, benzothienyl, dihydrobenzofuranone, hydrobenzofuranone, benzo Furyl, benzodioxoalkyl, indoline Radical, indolinyl, indolyl, indolazinyl, isoindolyl, indolinyl, indyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyrene Uranyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolyl, pyridyl, purinyl, carbazolyl, pyrimidinyl, piperidinyl, triazolopyrimidine Group, tetrahydropyrazolopyridyl, piperazinyl or morpholino; and optionally the first preferred system of the first aspect is substituted as previously disclosed. The compound according to the first preferred system according to the first aspect of the present invention provides another preferred system according to the first aspect of the present invention, wherein R3 is R3a and R3a is phenyl, naphthyl, indazolyl, benzo Imidazolinyl, dihydrobenzoxazolyl, benzotriazolyl, benzothienyl, benzodioxoalkyl, dihydroindolinone, indolyl, furanyl, thienyl , Pyridyl, purinyl, carbazolyl, piperidinyl, triazolopyrimidinyl, tetrahydropyrazolopyridyl; and optionally the first preferred system of the first aspect is substituted as previously disclosed. The compound according to the first preferred system of the first aspect of the present invention provides -34-200529835 (30) Another preferred system of the first aspect of the present invention, wherein R3 is R3a and R3a is dihydrobenzo Thiazolinone, hydrobenzothiazolinone, benzothiazolyl, dihydrobenzothienone, hydrobenzothienone, benzothienyl, dihydrobenzofuranone, hydrobenzo Furanone, benzofuranyl, dihydroindolone, hydroindolone, indolyl, indolazinyl, isoindolyl, indolyl, or indazolyl; and The first preferred system, which was selected as previously disclosed, was replaced. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein R3 is R3a and R3a is dihydrobenzoxazolyl, benzo Triazolyl, indolyl, halonitrophenyl, halopyrimidinyl, halopurinyl, C! -3 alkylnitroaminopyrimidinyl, triazolopyrimidinyl, pyridyl, indazolyl, phenyl Or benzodioxoalkylene; and optionally substituted as described above in the first preferred system of the first aspect. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein R3 is 1133 and R3a is naphthyl, phenyl-10-phenyl or thio Umji; and optionally the first preferred system of the first aspect has been replaced. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein R3 is R3b. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein R3 is R3b and R3b is 1 Η —indole-5 —yl-35- 200529835 (31)

1H-苯並三唑一 5-基1H-benzotriazole-5yl

HN 一 NHN a N

1，3 —二氫一D引D朵滿—2 —酮一5 —基 〇1,3-dihydro-D-introduction D Duo-2-2-keto-5-yl.

3H-苯並噁唑一 2 —酮—6 —基 〇3H-benzoxazole- 2-keto-6-yl.

1，3—二氫—苯並咪11坐—2-酮—5—基 〇1,3-dihydro-benzimidyl 11--2-keto-5-yl.

-36- 200529835 (32)-36- 200529835 (32)

1，4一二氫—苯並[d][l，3]噁嗪一 2 —酮一 6—基1,4-dihydro-benzo [d] [l, 3] oxazine- 2-keto-6-yl

4 —二氫—1H —喹唑啉—2 —酮一 6-基 4 Η —苯並[1，4 ] Π惡嗪—3 —酮—7 -基 -37- 200529835 (33) ο4 -dihydro-1H -quinazolin-2 -one- 6-yl 4 Η -benzo [1,4] Πoxazin-3 -one -7 -yl -37- 200529835 (33) ο

其中Ty係Η、C!-4烷基、f、Cl、Br或腈。 依據本發明之第~方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中R3係R3b且 R3b係吖丁啶基、C】—6烷基、C2„ 6烯基、C2 — 6炔基、二 氫喹諾酮基、氫喹諾酮基、二氫異咱諾酮基、氫異喹諾酮 基、二氫喹唑啉酮基、氫喹唑啉酮基、喹唑啉基、二氫D奎 噁啉酮基、氫喹噁啉酮基、喹噁啉基、苯並咪唑基、1Η 一吲唑一 5 —基、二氫苯並咪唑啉酮基、氫苯並咪唑啉酮 基、苯並咪唑啉基、二氫苯並噻唑啉酮基、氫苯並噻唑啉 酮基、苯並噻唑基、二氫苯並噻吩酮基、氫苯並噻吩酮基 、二氫苯並呋喃酮基、氫苯並呋喃酮基、苯並二噁茂烷基 、二氫苯並噁唑基、苯並三唑基、二氫吲哚滿酮基、氫吲 哚滿酮基、吲哚嗪滿基、異吲哚基、吲哚滿基、吡唑基、 吡唑啉基 '吡唑烷基、呋喃基、吡咯基、吡咯啉基、吡咯 烷基、咪唑啉基、咪唑烷基、嘌呤基、咔唑基、嘧啶基、 哌啶基、哌嗪基或嗎啉代；且可選擇地如前揭第一方面之 第一較佳體系經取代。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中R3係R3b且 R3 b係二氫苯並咪唑啉酮基、氫苯並咪唑啉酮基、苯並咪 D坐啉基、二氫苯並噻唑啉酮基、氫苯並噻唑啉酮基、苯並 -38- (34) 200529835 噻唑基、二氫苯並噻吩酮基、氫苯並噻吩酮基、二氫苯並 口夫喃酮1基、氫苯並咲喃酮基、1H—吲唑一 5 -基、苯並二 並三唑基、二氫吲哚滿酮 、異吲哚基、吲哚滿基、 呋喃基、吡咯基、吡咯啉 烷基、嘌呤基、咔唑基、 代；且可選擇地如前揭第Among them, Ty is fluorene, C! -4 alkyl, f, Cl, Br or nitrile. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein R3 is R3b and R3b is azetidinyl, C] -6 alkyl, C2. 6 Alkenyl, C2-6 alkynyl, dihydroquinolone, hydroquinolone, dihydroisozanolone, hydrogen isoquinolone, dihydroquinazolinone, hydroquinazolinone, quinazolinyl , Dihydro D quinoxalinone, hydroquinoxalinone, quinoxaline, benzimidazolyl, 1Η-indazol-5-yl, dihydrobenzimidazolone, hydrobenzimidazoline Keto, benzimidazolyl, dihydrobenzothiazolinone, hydrobenzothiazolinone, benzothiazyl, dihydrobenzothienone, hydrobenzothienone, dihydrobenzo Furanone, hydrobenzofuranone, benzodioxoalkyl, dihydrobenzoxazolyl, benzotriazolyl, indolinone, indolone, indole Azazinyl, isoindolyl, indolyl, pyrazolyl, pyrazolinyl'pyrazolyl, furyl, pyrrolyl, pyrrolidyl, pyrrolidyl, imidazolinyl, imidazole Group, purinyl, carbazolyl, pyrimidinyl, piperidinyl, piperazinyl, or morpholino; and optionally substituted as described in the first preferred system of the first aspect. According to the first aspect of the present invention The compound of the first preferred system provides another preferred system of the first aspect of the present invention, wherein R3 is R3b and R3b is dihydrobenzimidazolinone, hydrobenzimidazolinone, benzo Imidazoline, dihydrobenzothiazolinone, hydrobenzothiazolinone, benzo-38- (34) 200529835 thiazolyl, dihydrobenzothiophenone, hydrobenzothiophenone, Dihydrobenzoxanthone 1 group, hydrobenzopyranone group, 1H-indazol-5-yl group, benzoditriazole group, dihydroindolone, isoindolyl, indole Manganyl, furyl, pyrrolyl, pyrrolidinyl, purinyl, carbazolyl, substituted; and optionally as described above

一較佳體系之化合物，提 體系，其中R3係R3b且 h 6烯基、C2 - 6炔基、二 噁茂烷基、二氫苯並噁唑基、苯 基、氫吲哚滿酮基、吲哚嗪滿基 吡唑基、吡唑啉基、吡唑烷基、 基、吡咯烷基、咪唑啉基、咪唑 嘧啶基、哌啶基、哌嗪基或嗎啉 一方面之第一較佳體系經取代。A preferred system compound is a system in which R3 is R3b and h 6 alkenyl, C2-6 alkynyl, dioxoalkyl, dihydrobenzoxazolyl, phenyl, indolinone, Indolazinylpyrazolyl, pyrazolinyl, pyrazolidinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholine is the first preferred The system was replaced.

依據本發明之第一方面的第 供本發明之第一方面的另一較佳 R3b係吖丁啶基、C!- 6烷基、CAccording to the first aspect of the present invention, another preferred R3b is azetidinyl, C! -6 alkyl, C

氫喹諾酮基、氫喹諾酮基、二氫異喹諾酮基、氫異喹諾酮 基、二氫D奎唑啉酮基、氫喹唑啉酮基、喹唑啉基、二氫[I奎 噁啉酮基、氫喹噁啉酮基、D|噁啉基、苯並咪唑基、1 Η 一吲π坐一 5 —基、二氫苯並咪Β坐啉酮基、氫苯並咪{]坐啉酮 基、苯並咪唑啉基、二氫苯並噻唑啉酮基、氫苯並噻唑啉 酮基、苯並噻唑基、二氫苯並噻吩酮基、氫苯並噻吩酮基 、二氫苯並呋喃酮基、氫苯並呋喃酮基、苯並二噁茂烷基 、二氫苯並噁唑基、苯並三唑基、嘌呤基、咔唑基、嘧啶 基、哌啶基、哌嗪基或嗎啉代；且可選擇地如前揭第一方 面之第一較佳體系經取代。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另〜較佳體系，其中R3係R3b且 R3b係吖丁啶基、C】-6烷基、c2 - 6烯基、C2 — 6炔基、二 -39- 200529835 (35) 氫喹諾酮基、氫喹諾酮基、二氫異喹諾酮基、氫異喹諾_ 基、二氫喹唑啉酮基、氫喹唑啉酮基、D奎唑啉基、二氫 噁啉酮基、氫喹噁啉酮基、喹噁啉基、苯並咪唑基、苯# 二噁茂烷基、二氫苯並噁唑基、苯並三唑基、二氫吲D朵滿 酮基、氫吲哚滿酮基、1 Η —吲唑一 5 —基、吲哚嗪滿基、 異吲哚基、吲哚滿基、吡唑基、吡唑啉基、吡唑烷基、％ 喃基' 吡咯基、吡咯啉基、吡咯烷基、咪唑啉基、咪U坐@ 基、嘌呤基、咔唑基、嘧啶基、哌啶基、哌嗪基或嗎n林# ;且可選擇地如前揭第一方面之第一較佳體系經取代。 ® 依據本發明之第一方面的第一較佳體系之化合物，_ 供本發明之第一方面的另一較佳體系，其中R3係R3b且 R3 b係苯並二噁茂烷基、二氫苯並噁唑基、苯並三π坐基、 嘌呤基或咔唑基；且可選擇地如前揭第一方面之第〜較佳 體系經取代。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中R3係R3b且 φ R3b係二氫苯並噁唑基 '苯並三唑基、吲哚基、鹵硝基苯 基、鹵Cfe Π疋基、鹵嘌D令基、C】-3垸基硝基胺基嘧、D定基、 三唑並嘧啶基、吡啶基、1 Η -吲唑一 5 —基、苯基或苯並 二噁茂烷基。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q，且其 中該化合物具有絕對R構形。 依據本發明之第一方面的第一較佳體系之化合物，提 -40- 200529835 (36) 供本發明之第一方面的另一較佳體系，其中Q係Q -且其 中該化合物具有絕對S構形。 依據本發明之第一方面的第一較佳體系之化合物，冑 供本發明之第一方面的另一較佳體系，其中Q係Q〃且其 中該化合物具有絕對R構形。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Q係Q〃且其 中該化合物具有絕對S構形。 φ 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中111和Π皆爲1 Ο 依據本發明之第一方面的第一較佳體系之.化合物，提 供本發明之第一方面的另一較佳體系，其中D係〇。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Α係C。 依據本發明之桌一方面的第一較佳體系之化合物，提 · 供本發明之第一方面的另一較佳體系，其中A係CH。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中A係N。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中^係N。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中E係CH。 依據本發明之第一方面的第一較佳體系之化合物，提 -41 - (37) (37)200529835 供本發明之第一方面的另一較佳體系，其中E係C。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中該化合物具有 如本文所述之低於10 nM之CGRP結合1C 50値。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中該化合物具有 如本文所述之低於100 nM之CGRP結合ic 50値。 依據本發明之第一方面的第一較佳體系之化合物，提 鲁 供本發明之第一方面的另一較佳體系，其中該化合物具有 如本文所述之低於1 000 nM之CGRP結合IC 5G値。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中p係1且G、 J及E —起形成Αχ或Ay。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中p係1且G、 J及E —起形成Αχ。 φ 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中p係1且G、 J及E —起形成Ay。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Ax係具有2 個稠合環之稠合雜環，每一個該稠合環具有5至7員，該 雜環含有1至4個選自〇、N或S之相同或不同的雜原子 且該雜環可選擇地含有1或2個羰基，其中該羰基之碳原 -42 - 200529835 (38) 子係該稠合雜環之一員。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Ax係具有2 個稠合環之稠合雜環，每一個該稠合環具有5至7員，該 雜環含有1至4個選自〇、N或S之相同或不同的雜原子 〇 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Ax係具有2 φ 個稠合環之稠合雜環，每一個該稠合環具有5至7員，該 雜環含有1至4個選自〇、N或S之相同或不同的雜原子 且其中Ax係經苯基取代。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Ax係本文所 述之稠合雜環。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Ay係4至6 · 員雜環，其含有1至3個選自0、N或S之雜原子且其可 選擇地含有1或2個羰基，其中該羰基之碳原子係該4至 6員雜環之一員。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Ay係4至6 員雜環，其含有1至3個選自〇、N或S之雜原子。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Ay係4至6 -43 - (39) (39)200529835 員雜環，其含有1至3個選自〇、N或S之雜原子且其可 選擇地含有1或2個羰基，其中該羰基之碳原子係該4至 6員雜環之一員，且其中Ay係經苯基取代。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中Ay係本文所 述之4至6員雜環。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中p係〇以便g 和J皆與A連接’則G、j及A —起形成螺環系統，且該 環系統之環含有A，其中G、J及A —起係GJA /或 GJA〃 。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中P係0以便^ 和J皆與A連接，則G、j及A —起形成螺環系統，且該 環系統之環含有A，其中G、J及A —起係GJA /。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中p係〇以便〇 和J皆與A連接，則G、j及A —起形成螺環系統，且該 環系統之環含有A，其中G、J及A —起係G J A"。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中P係〇以便Q 和J皆與A連接，則G、j及A —起形成螺環系統，且該 環系統之環含有A，其中G、J及A —起係G J A /且 G A，係 a X。 200529835 (40) 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中p係0以使G 和J皆與A連接，則G、J及A —起形成螺環系統，且該 環系統之環含有A，其中G、J及A —起係GJA /且 GJA / 係 Ay。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中p係0以使G 和J皆與A連接，則G、j及A —起形成螺環系統，且該 鲁 環系統之環含有A，其中G、J及A —起係GJA 〃且 GJA"係 Ax。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中p係0以使G 和J皆與A連接，則G、j及A —起形成螺環系統，且該 環系統之環含有A，其中G、J及A —起係GJA 〃且 GJA"係 Ay。 依據本發明之第一方面的第一較佳體系之化合物，提 · 供本發明之第一方面的另一較佳體系，其中p係〇以使G 和J皆與A連接，則G、]及A —起形成螺環系統，且該 環系統之環含有A，其中G、J及A —起形成雜環，該雜 環選自咪唑啉酮基、咪唑烷酮基、二氫D奎諾酮基、二氫異 鸣諾酮基、二氫D奎唑啉酮基、二氫喹噁啉酮基、二氫苯並 11惡嗪基、氫苯並噁嗪基、二氫苯並噁嗪酮基、二氫苯並咪 唑啉酮基、二氫苯並咪唑基、二氫苯並噻唑啉酮基、二氫 苯並噻唑基、二氫苯並噻吩酮基、二氫苯並呋喃酮基、二 -45 - 200529835 (41) 氫吲哚滿酮基、吲哚滿基、吡唑啉基、吡唑烷基、吡咯啉 基、吡咯烷基、咪唑啉基、咪唑烷基、哌啶基、哌嗪基或 嗎啉代；其中該雜環可選擇地經C ! - 4烷基、C】-4院氧基 、Cl— 4鹵院基、氰基、C3—7環院基、苯基、鹵苯基、口夫 喃基、吡咯基、吡咯啉基、吡咯烷基、咪唑基、咪唑D林基 、咪唑烷基、吡唑基、吡唑啉基、吡唑烷基、吡啶基、哺 啶基、哌啶基、哌嗪基或嗎啉代取代。 依據本發明之第一方面的第一較佳體系之化合物，提 φ 供本發明之第一方面的另一較佳體系，其中p係〇以使G 和：T皆與A連接，則G、J及A —起形成螺環系統，且該 環系統之環含有A，其中G、J及A —起形成雜環，該雜 環選自咪嗤啉酮基、咪唑烷酮基、二氫喹諾酮基、二氫異 喹諾酮基、二氫喹唑啉酮基、二氫喹噁啉酮基、二氫苯並 噁嗪基、氫苯並噁嗪基、二氫苯並噁嗪酮基、二氫苯並咪 唑啉酮基、二氫苯並咪唑基、二氫苯並噻唑啉酮基、二氫 苯並噻唑基、二氫苯並噻吩酮基、二氫苯並呋喃酮基、二 鲁 氫吲哚滿酮基、吲哚滿基、吡唑啉基、吡唑烷基、吡咯啉 基、吡咯烷基、咪唑啉基、咪唑烷基、哌啶基、哌嗪基或 嗎啉代；其中該雜環可選擇地經C ! — 4烷基、C】-4烷氧基 、C!—4鹵烷基、氰基、c3_7環烷基、苯基、鹵苯基、呋 喃基、毗唑基、吡唑啉基、吡唑烷基、吡啶基、嘧啶基、 脈陡基、哌嗪基或嗎啉代取代。Hydroquinolones, Hydroquinolones, Dihydroisoquinolones, Hydroisoquinolones, Dihydro D-Quazolinones, Hydroquinolones, Quinazolines, Dihydro [I Quinoxalinone, Hydroquinoxalinone, D | oxolinyl, benzimidazolyl, 1 hydrazine, 1-indol, 5-benzyl, dihydrobenzimidin, B, and benzoimidin , Benzimidazoline, dihydrobenzothiazolinone, hydrobenzothiazolinone, benzothiazolyl, dihydrobenzothiophenone, hydrobenzothiophenone, dihydrobenzofuranone Base, hydrobenzofuranone, benzodioxoalkyl, dihydrobenzoxazolyl, benzotriazolyl, purinyl, carbazolyl, pyrimidinyl, piperidinyl, piperazinyl, or And substituted with the first preferred system of the first aspect. The compound according to the first preferred system of the first aspect of the present invention provides another ~ preferred system of the first aspect of the present invention, wherein R3 is R3b and R3b is azetidinyl, C] -6 alkyl, c2-6 Alkenyl, C2-6 alkynyl, di-39- 200529835 (35) Hydroquinolone, Hydroquinolone, Dihydroisoquinolyl, Hydroisoquinolyl, Dihydroquinazolinone, Hydroquinazoline Keto, D-Quazolinyl, Dihydrooxolinone, Hydroquinoxalinone, Quinoxaline, Benzimidazolyl, Benzene Dioxocene, Dihydrobenzoxazolyl, Benzene Benzotriazolyl, dihydroindolinone, hydroindolinone, 1H-indazol-5-yl, indolazinyl, isoindolinyl, indolyl, pyrazolyl , Pyrazolinyl, pyrazolidinyl,% anyl 'pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolyl, purinyl, carbazolyl, pyrimidinyl, piperidinyl, Piperazinyl or morpholinyl; and optionally substituted as described in the first preferred system of the first aspect. ® Compounds according to the first preferred system of the first aspect of the present invention, _ Another preferred system for the first aspect of the present invention, wherein R3 is R3b and R3b is benzodioxoalkyl, dihydrogen Benzooxazolyl, benzotriπyl, purinyl, or carbazolyl; and optionally, the first to the preferred systems of the first aspect are substituted as previously disclosed. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein R3 is R3b and φR3b is dihydrobenzoxazolyl'benzotriazole. Group, indolyl, halonitrophenyl, haloCfe, hydrazone, halopurenyl, C] -3amidonitroaminopyrimidyl, Damido, triazolopyrimidyl, pyridyl, 1 -Indazole-5yl, phenyl or benzodioxocene. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Q is Q, and wherein the compound has an absolute R configuration. The compound according to the first preferred system of the first aspect of the present invention provides -40-200529835 (36) Another preferred system of the first aspect of the present invention, wherein Q is Q-and wherein the compound has an absolute S Configuration. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Q is Q 系 and wherein the compound has an absolute R configuration. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Q is Q〃 and wherein the compound has an absolute S configuration. φ The compound according to the first preferred system according to the first aspect of the present invention provides another preferred system according to the first aspect of the present invention, wherein both 111 and Π are 1 0 according to the first comparison of the first aspect of the present invention. A compound of the preferred system provides another preferred system of the first aspect of the invention, wherein D is 0. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein A is C. The compound according to the first preferred system of the one aspect of the table of the present invention provides another preferred system of the first aspect of the present invention, wherein A is CH. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein A is N. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein ^ is N. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein E is CH. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system according to the first aspect of the present invention, wherein E is C. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein the compound has a CGRP of less than 10 nM in combination with 1C 501 as described herein. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein the compound has a CGRP binding ic 50% lower than 100 nM as described herein. The compound according to the first preferred system of the first aspect of the present invention is another preferred system of the first aspect of the present invention, wherein the compound has a CGRP binding IC of less than 1,000 nM as described herein 5G 値. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein p is 1 and G, J and E together form Aχ or Ay. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein p is 1 and G, J and E together form Aχ. φ The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein p is 1 and G, J and E together form Ay. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Ax is a fused heterocyclic ring having 2 fused rings, each of which is fused The ring has 5 to 7 members, the heterocyclic ring contains 1 to 4 same or different heteroatoms selected from 0, N or S and the heterocyclic ring optionally contains 1 or 2 carbonyl groups, wherein the carbon atom of the carbonyl group is- 42-200529835 (38) One member of this fused heterocyclic ring. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Ax is a fused heterocyclic ring having 2 fused rings, each of which is fused The ring has 5 to 7 members, and the heterocyclic ring contains 1 to 4 same or different heteroatoms selected from 0, N or S. The compound according to the first preferred system of the first aspect of the present invention provides the present invention. Another preferred system of the first aspect, wherein Ax is a fused heterocyclic ring having 2 φ fused rings, each of which has 5 to 7 members, and the heterocyclic ring contains 1 to 4 members selected from 0, N or S is the same or different heteroatom and wherein Ax is substituted with phenyl. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Ax is a fused heterocyclic ring as described herein. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Ay is a 4 to 6 membered heterocyclic ring containing 1 to 3 selected from 0 , N, or S heteroatoms and which optionally contain 1 or 2 carbonyl groups, wherein the carbon atom of the carbonyl group is one of the 4 to 6 membered heterocyclic ring. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Ay is a 4- to 6-membered heterocyclic ring containing 1 to 3 selected from 0, A heteroatom of N or S. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Ay is 4 to 6 -43-(39) (39) 200529835 membered heterocyclic ring, It contains 1 to 3 heteroatoms selected from 0, N or S and it optionally contains 1 or 2 carbonyl groups, wherein the carbon atom of the carbonyl group is one of the 4 to 6 membered heterocyclic ring, and wherein Ay is Phenyl substituted. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein Ay is a 4- to 6-membered heterocyclic ring described herein. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein p is 0 so that both g and J are connected to A ', then G, j, and A — It forms a spiral ring system, and the ring of the ring system contains A, where G, J, and A are all GJA / or GJA〃. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein P is 0 so that ^ and J are connected to A, then G, j, and A — It forms a spiral ring system, and the ring of the ring system contains A, where G, J, and A are together GJA /. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein p is 0 such that 0 and J are connected to A, then G, j and A — It forms a spiral ring system, and the ring of the ring system contains A, where G, J, and A—from GJ A ". The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein P is 0 such that Q and J are connected to A, then G, j and A — It forms a spiral ring system, and the ring of the ring system contains A, where G, J and A — starting from GJA / and GA — a X. 200529835 (40) A compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein p is 0 such that G and J are both connected to A, then G , J, and A together form a spiral ring system, and the ring of the ring system contains A, where G, J, and A—are GJA / and GJA / Ay. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein p is 0 such that G and J are connected to A, then G, j and A -It forms a spiral ring system, and the ring of the ring system contains A, where G, J, and A-start from GJA, and GJA " is Ax. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein p is 0 such that G and J are connected to A, then G, j and A — Form a spiral ring system, and the ring of the ring system contains A, where G, J, and A — start from GJA 〃 and GJA " Ay. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein p is 0 such that G and J are both connected to A, then G,] And A together form a spiro ring system, and the ring of the ring system contains A, wherein G, J, and A together form a heterocyclic ring selected from the group consisting of imidazolinone, imidazolidinyl, and dihydro D quinol Keto, dihydronorsonone, dihydro D quinazolinone, dihydroquinoxalinone, dihydrobenzo 11 oxazinyl, hydro benzoxazinyl, dihydro benzoxazine Keto, dihydrobenzimidazolone, dihydrobenzimidazolyl, dihydrobenzothiazolinone, dihydrobenzothiazolyl, dihydrobenzothiophenone, dihydrobenzofuranone , Bi-45-200529835 (41) Indolanone, indolanyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl , Piperazinyl or morpholino; wherein the heterocyclic ring is optionally via C! -4 alkyl, C] -4 alkyloxy, Cl-4 halogen alkyl, cyano, C3-7 cycloalkyl, benzene Radical, halophenyl, haloyl, Rotyl, pyrrolidinyl, pyrrolidinyl, imidazolyl, imidazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolyl, pyridyl, pyridyl, piperidinyl, piperazine Or morpholino. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein p is 0 such that G and T are both connected to A, then G, J and A together form a spiro ring system, and the ring of the ring system contains A, wherein G, J, and A together form a heterocyclic ring selected from the group consisting of imidazolinone, imidazolidinone, and dihydroquinolone Base, dihydroisoquinolone, dihydroquinazolinone, dihydroquinoxalinone, dihydrobenzoxazinyl, hydrobenzoxazinyl, dihydrobenzoxazinone, dihydro Benzimidazolone, dihydrobenzimidazolyl, dihydrobenzothiazolinone, dihydrobenzothiazyl, dihydrobenzothiophenone, dihydrobenzofuranone, diluin Indolone, indolyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholino; wherein the Heterocycles are optionally via C! -4 alkyl, C] -4 alkoxy, C! -4 haloalkyl, cyano, c3_7 cycloalkyl, phenyl, halophenyl, furanyl, pyrazolyl Pyrazolinyl , Pyrazolyl, pyridyl, pyrimidinyl, venosyl, piperazinyl or morpholino.

依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中P係〇以使G -46- 200529835 (42) 和J皆與A連接，則G、j及A —起形成螺環系統，且該 環系統之環含有A，其中G、J及A —起形成雜環，該雜 環選自咪唑啉酮基、咪唑烷酮基、二氫喹諾酮基、二氫異 口奎諾酮基、二氫H奎唑啉酮基、二氫苯並呋喃酮基、二氫吲 噪滿酮基、吲哚滿基、吡唑啉基、吡唑烷基、吡咯啉基、 口比咯烷基、咪唑啉基、咪唑烷基、哌啶基、哌嗪基或嗎啉 代；其中該雜環可選擇地經C ! — 4烷基、c】—4烷氧基、 C】-4鹵烷基、氰基、C3-7環烷基、苯基、鹵苯基、哌嗪 基或嗎啉代取代。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中P係0以使G 和J皆與A連接，則G、J及A —起形成螺環系統，且該 環系統之環含有A，其中G、J及A —起形成雜環，該雜 環選自咪唑啉酮基、咪唑烷酮基 '二氫唾諾酮基、二氫異 喹諾酮基、二氫喹唑啉酮基、二氫喹噁啉酮基、二氫苯並 噁嗪基、氫苯並噁嗪基、二氫苯並噁嗪酮基、二氫苯並咪 φ 唑啉酮基、二氫苯並咪唑基、二氫苯並噻唑啉酮基、二氫 苯並噻唑基、二氫苯並噻吩酮基、二氫苯並呋喃酮基、二 氫吲哚滿酮基、吲哚滿基、吡唑啉基、吡唑烷基、吡咯啉 基、吡咯烷基、咪唑啉基、咪唑烷基、哌啶基、哌嗪基或 嗎啉代。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中p係0以使G 和：！皆與A連接，則G、j及A —起形成螺環系統，且該 -47 - (43) (43)200529835 環系統之環含有A，其中G、J及A —起形成雜環，該雜 環選自咪唑啉酮基、咪唑烷酮基、二氫D奎諾酮基、二氫異 口奎諾酮基、二氫喹唑啉酮基、二氫喹噁啉酮基、二氫苯並 噁嗪基、氫苯並噁嗪基或二氫苯並噁嗪酮基。 依據本發明之第一方面的第一較佳體系之化合物，提 供本發明之第一方面的另一較佳體系，其中P係〇以使G 和J皆與A連接，則G、j及A —起形成螺環系統，且該 環系統之環含有A，其中G、J及A —起形成雜環，該雜 φ 環選自咪唑啉酮基、咪唑烷酮基、二氫喹諾酮基、二氫異 曈諾酮基、二氫喹唑啉酮基、二氫喹噁啉酮基或二氫苯並 噁嗪基。 本發明之第二方面的各種不同之較佳體系提供醫藥組 成物，其包含本文界定之式（I)化合物。 本發明之第三方面的各種不同之較佳體系提供治療發 炎（特別是神經源性發炎）、頭痛（特別是偏頭痛）、疼 痛、熱損傷、循環性休克、糖尿病、Reynaud氏徵候、周 馨 圍動脈機能不足、蝌網膜下/顱內出血、腫瘤生長、與停 經有關之潮紅及其他藉由拮抗CGRP受體可達成治療之病 症之方法，其係經由投遞包含本文所界定之式（I )化合 物的醫藥組成物。 本發明之第四方面的各種不同之較佳體系係本發明之 化合物的用途，其係選自（a )腸黏膜之免疫調控、（b ) 拮抗心臟過敏性損傷之保護功效、（c )刺激或預防骨再 吸收之間白素—】b ( I L - 1 b )刺激作用、（d )調控N K 1 -48 - 200529835 (44) 受體於脊柱神經元中之表現、及（e )呼吸道發炎疾病和 慢性阻塞性肺疾病，其包括氣喘。參閱文獻（a ) Clacitonin Receptor-Like Receptor Is Expressed oil Gastrointestinal Immune Cells. H a g n e r ? Stefanie ； Knauer , Jens ； Haberberger, Rainer ； Goeke， B urkhard ； Voigt, Karlheinz ; McGregor， Gerard Patrick. Institute of Physiology, Philipps University, Marburg, Germany. Digestion ( 2002 )，66 ( 4)，1 97-203 ； ( b ) Protective effects of calcitonin gene-redated peptide-mediated evodiamine on guinea-pig cardiac anaphylaxis. Rang，W e i -Qing ； Du, Yan-Hua ； Hu， Chang-Ping ; Ye，Feng ； Tan, Gui-Shan ； Deng, Han-Wu ; Li， Yuan-Jian. School of Pharmaceutical Sciences， Department of Pharmacology, Central South University, Xiang-Ya Road 88，Changsha， Hunan, Naunyn-Schmiedeberg*s Archives of Pharmacology (2 0 0 3 ) ，3 6 7 ( 3) ? 3 06-3 1 1 ； ( c ) The experimental study on the effect calcitonin gene-related peptide on bone resorption mediated by interleuki-l . L i an 5 K a i ; D u , Jingyuan ； Rao， Zhenyu ; Luo, H u a i c a n. Depatment of Orthopedics， Xiehe Hospital, Tonji Medical College, Huazhong University of Science and Technology, Wuhan, P e p o. Rep. China. Journal of Tongji Medical University ( 2 0 0 1 ) ，21 (4)，304-307， ( d ) Calcitnin gene -relatedThe compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein P is 0 such that G-46-200529835 (42) and J are both connected to A G, j, and A together form a spiro ring system, and the ring of the ring system contains A, wherein G, J, and A together form a heterocyclic ring selected from the group consisting of imidazolinone, imidazolidinyl, Dihydroquinolone, dihydroisoquinolyl, dihydroH quinazolinone, dihydrobenzofuranone, dihydroindolone, indolyl, pyrazolinyl, pyridine Azolidinyl, pyrrolinyl, orbitalyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholino; wherein the heterocyclic ring is optionally via C! -4 alkyl, c ] -4 alkoxy, C] -4 haloalkyl, cyano, C3-7 cycloalkyl, phenyl, halophenyl, piperazinyl or morpholino substituted. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein P is 0 such that G and J are connected to A, then G, J and A — Forming a spiro ring system, and the ring of the ring system containing A, wherein G, J, and A — form a heterocyclic ring selected from the group consisting of imidazolinone, imidazolidinyl 'dihydrosialone, Dihydroisoquinolone, dihydroquinazolinone, dihydroquinoxalinone, dihydrobenzoxazinyl, hydrobenzoxazinyl, dihydrobenzoxazinone, dihydrobenzo Imidazolone, dihydrobenzimidazolyl, dihydrobenzothiazolinone, dihydrobenzothiazolyl, dihydrobenzothiophenone, dihydrobenzofuranone, dihydroindole Perketone, indolyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholino. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein p is 0 such that G and:! Are all connected to A, then G, j and A together form a spiro ring system, and the ring of the -47-(43) (43) 200529835 ring system contains A, where G, J and A together form a heterocyclic ring, the The heterocyclic ring is selected from the group consisting of imidazolinone, imidazolidinone, dihydro D quinolone, dihydroisoquinolyl, dihydroquinazolinone, dihydroquinoxalinone, and dihydrobenzene And benzoxazinyl, hydrobenzoxazinyl or dihydrobenzoxazinone. The compound according to the first preferred system of the first aspect of the present invention provides another preferred system of the first aspect of the present invention, wherein P is 0 such that G and J are connected to A, then G, j and A — Forming a spiro ring system, and the ring of the ring system containing A, wherein G, J and A — forming a heterocyclic ring, the hetero φ ring is selected from the group consisting of imidazolinone, imidazolidinone, dihydroquinolone, di Hydroisonordone, dihydroquinazolinone, dihydroquinoxalinone, or dihydrobenzoxazinyl. Various preferred systems of the second aspect of the invention provide pharmaceutical compositions comprising a compound of formula (I) as defined herein. Various preferred systems of the third aspect of the present invention provide treatment for inflammation (especially neurogenic inflammation), headache (especially migraine), pain, heat damage, circulatory shock, diabetes, Reynaud's sign, Zhou Xin Periarterial insufficiency, subomentum / intracranial hemorrhage, tumor growth, flushing associated with menopause, and other methods that can be treated by antagonizing the CGRP receptor, are delivered by delivery including compounds of formula (I) as defined herein Medical composition. Various preferred systems of the fourth aspect of the present invention are the use of the compounds of the present invention, which are selected from (a) immune regulation of the intestinal mucosa, (b) protection against antagonistic cardiac allergic damage, and (c) stimulation Or prevent interleukins between bone resorption —] b (IL-1 b) stimulation, (d) regulation of NK 1 -48-200529835 (44) receptor expression in spinal neurons, and (e) respiratory inflammation Diseases and chronic obstructive pulmonary diseases, which include asthma. (A) Clacitonin Receptor-Like Receptor Is Expressed oil Gastrointestinal Immune Cells. H agner? Stefanie; Knauer, Jens; Haberberger, Rainer; Goeke, Burkhard; Voigt, Karlheinz; McGregor, Gerard Patrick. Institute of Physics , Marburg, Germany. Digestion (2002), 66 (4), 1 97-203; (b) Protective effects of calcitonin gene-redated peptide-mediated evodiamine on guinea-pig cardiac anaphylaxis. Rang, Wei-Qing; Du, Yan-Hua; Hu, Chang-Ping; Ye, Feng; Tan, Gui-Shan; Deng, Han-Wu; Li, Yuan-Jian. School of Pharmaceutical Sciences, Department of Pharmacology, Central South University, Xiang-Ya Road 88 , Changsha, Hunan, Naunyn-Schmiedeberg * s Archives of Pharmacology (2 0 0 3), 3 6 7 (3)? 3 06-3 1 1; (c) The experimental study on the effect calcitonin gene-related peptide on bone resorption mediated by interleuki-l. L i an 5 K ai; Du, Jingyuan; Rao, Zhenyu; Luo, H uaica n. Depa tment of Orthopedics, Xiehe Hospital, Tonji Medical College, Huazhong University of Science and Technology, Wuhan, Pepo. Rep. China. Journal of Tongji Medical University (2 0 0 1), 21 (4), 304-307, ( d) Calcitnin gene -related

Peptide regulates expression of neu】.okininl receptors by -49- 200529835 (45)Peptide regulates expression of neu】 .okininl receptors by -49- 200529835 (45)

McCarson KE, LG. J. Neurosci. of Neuroscience, Minnesota 55455, Toxicology， and Medical Center, nation of antigen- rat spinal neurons. Seybold V S, Me l. melstein PG， Grot h RD， Abrahams 2003 2 3 ( 5 ) : 1 8 1 6 - 1 8 24. epartmentMcCarson KE, LG. J. Neurosci. Of Neuroscience, Minnesota 55455, Toxicology, and Medical Center, nation of antigen- rat spinal neurons. Seybold VS, Me l. Melstein PG, Grot h RD, Abrahams 2003 2 3 (5): 1 8 1 6-1 8 24.epartment

University of Minnesota，Minneapolis， and Department of Pharmacology, Therapeutics, University of Kansas Kansas City, Kansas 66 1 60 ( e ) Atten induced airway hyperresponsi venes in CGRP-deficient mice. Aoki-Nagase， Tomoko ; Nagase， Takahide ; Oh-Hashi， Yoshio ; Shindo， Takayuki ； Kurihara, Yukiko ; Yamaguchi， Yasuhiro ; Yamamoto， Hiroshi ; Tomita, Tetsuji ; Ohga，Eijiro ; Nagai, Ryozo ; Kurihara，Hiroki ； Ouchi， Yasuyoshi. Department of Geriatric Medicine， Graduate School of Medicine, University of Tokyo, Tokyo, Japan. American Journal of Physiology ( 2002 )， 2 8 3 ( 5 5 P t. 1 ) ? L963-L970 ； ( f) Calcitonin gene- related peptide as inflammatory mediator. Springer, Jochen ； Geppetti，Pierangelo ； Fischer, Axel ； Groneberg， David A. Charite Campus-Virchow, Department of Pediatric Pneumology and Immunology, Divison of Allergy Research, Humboldt-University Berlin, Berlin, Germany. Pulmonary Pharmacology & Therapeutics ( 2003 )，16 ( 3) ，121-130;及(g ) Pharmacological targets for the inhibition of neurogenic inflammation. H e 1 y e s, -50- 200529835 (46)University of Minnesota, Minneapolis, and Department of Pharmacology, Therapeutics, University of Kansas Kansas City, Kansas 66 1 60 (e) Atten induced airway hyperresponsi venes in CGRP-deficient mice. Aoki-Nagase, Tomoko; Nagase, Takahide; Oh-Hashi , Yoshio; Shindo, Takayuki; Kurihara, Yukiko; Yamaguchi, Yasuhiro; Yamamoto, Hiroshi; Tomita, Tetsuji; Ohga, Eijiro; Nagai, Ryozo; Kurihara, Hiroki; Ouchi, Yasuyoshi. Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. American Journal of Physiology (2002), 2 8 3 (5 5 P t. 1)? L963-L970; (f) Calcitonin gene-related peptide as inflammatory mediator. Springer, Jochen; Geppetti, Pierangelo ; Fischer, Axel; Groneberg, David A. Charite Campus-Virchow, Department of Pediatric Pneumology and Immunology, Divison of Allergy Research, Humboldt-University Berlin, Berlin, Germany. Pulmonary Pharmacology & Therapeutics (2003), 16 (3), 121- 130; and (g) Pharmacological targets for the inhibition of neurogenic inflammation. H e 1 y e s, -50- 200529835 (46)

Zsuzsanna ； Pinter, Erika ； Nemeth, Jozsef ； Szolanyi， Janos. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pecs, Pecs, Hung. Current Medicinal Chemistry * Anti-Inflammatory & Anti-Allergy Agents ( 2003)，2 ( 2)，191-218，其皆倂入本文 作爲參考。 本發明之第五方面的各種不同之較佳體系提供本發明 之化合物與一或多種藥劑之組合物，該藥劑選自 C 〇χ 一 2 抑制齊11、NSAIDS、阿斯匹林、醋氨酚、triptans ( 5 —羥 色胺5 - HTIB/ ID激動劑）' 麥角胺或咖啡因，其係用 於治療偏頭痛。 本發明之第六方面提供活體內鑑別抗偏頭痛之化合物 的非終端方法。 本發明之第六方面的第一較佳.體系提供一種活體內鑑 別抗偏頭痛之化合物的非終端方法，其包含投遞至哺乳動 物體內CGRP受體激動劑，其量能引起血流增加，隨後投 遞測試化合物，其量能逆轉該CGRP引起之血流增加，其 中該哺乳動物係轉基因哺乳動物，其含有具有Trp 74之人 類化RAMP1，或係內源性表現具有Trp74之RAMP1的哺 乳動物。 本發明之第六方面的另一較佳體系提供一種活體內鑑 別抗偏頭痛之化合物的非終端方法，其包含於投遞至哺乳 動物體內CGRP受體激動劑之前投遞測試化合物，其中該 CGRP受體激動劑之投遞量係能引起血流增加，且其中該 ~ 51 - 200529835 (47) 測試化合物之投遞量係能壓制該C GRP引起之血流增加， 其中該哺乳動物係轉基因哺乳動物，其含有具有Trp 74之 人類化RAMP1，或係內源性表現具有Trp74之RAMP1的 哺乳動物。 本發明之第六方面的另一較佳體系提供一種活體內鑑 別抗偏頭痛之化合物的非終端方法，其包含投遞至哺乳動 物體內CGRP受體激動劑，其量能引起周圍動脈徑增加， 隨後投遞測試化合物，其量能逆轉該CGRP引起之周圍動 φ 脈徑的增加，其中該哺乳動物係轉基因哺乳動物，其含有 具有Trp74之人類化RAMP1，或係內源性表現具有Trp74 之RAMP1的哺乳動物。 本發明之第六方面的另一較佳體系提供一種活體內鑑 別抗偏頭痛之化合物的非終端方法，其包含於投遞至哺乳 動物體內CGRP受體激動劑之前投遞測試化合物，其中該 CGRP受體激動劑之投遞量係能引起周圍動脈徑增加，且 其中該測試化合物之投遞量係能壓制該CGRP引起之周圍 · 動脈徑的增加，其中該哺乳動物係轉基因哺乳動物，其含 有具有Trp74之人類化RAMP1，或係內源性表現具有 Trp74之RAMP1的哺乳動物。 本發明之第六方面的其他較佳體系提供活體內鑑別本 文所描述之抗偏頭痛之化合物的非終端方法，其中該血流 係面部血流。 本發明之第六方面的其他較佳體系提供活體內鑑別本 文所描述之抗偏頭痛之化合物的非終端方法，其中該內源 -52- 200529835 (48) 性表現具有Trp74之RAMP1的哺乳動物係非人之靈長類 〇 本發明之第六方面的其他較佳體系提供活體內鑑別本 文所描述之抗偏頭痛之化合物的非終端方法，其中該內源 性表現具有Trp74之RAMP1的哺乳動物係人。 本發明之第六方面的其他較佳體系提供活體內鑑別本 文所描述之抗偏頭痛之化合物的非終端方法，其中該內源 性表現具有Trp74之RAMP1的哺乳動物係非人之靈長類 且該非人之靈長類係狨。 本發明之第六方面的其他較佳體系提供活體內鑑別本 文所描述之抗偏頭痛之化合物的非終端方法，其中該抗偏 頭痛之化合物係CGRP受體拮抗劑。 本發明之其他較佳體系可包含本文所揭示之兩個或多 個較佳體系及/或方面的適當結合。 本發明之其他較佳體系亦可包含本文所揭示之較佳體 系及/或方面的適當子集。 Φ 本發明之其他較佳體系及方面依據下文之敘述係顯而 易見的。 發明詳述 本發明之敘述應以符合化學鍵結之定律和解釋。例如 ，於任一指定之位置必須除去一個氫原子方能容納一個取 代基。 本文所使用之「雜環」包括含有1或多個雜原子（例 -53- 200529835 (49) 如〇、N或s )之環部份，除非另有說明，該雜環包括芳 香族環和非芳香族環（例如脂肪族環）。 當描述例如一個含有1至4個氮原子之5，6—稠合 雙環系統，本文所使用之「稠合雙環系統」包括芳香族環 系統和脂肪族環系統，例如吲哚嗪滿、吲哚、異吲哚、 3 Η —吲哚、吲哚滿、吲唑或苯並咪唑。 若取代基係以通稱表示，則該通稱範圍內任一和所有 之基團係涵蓋於本發明中。例如，通稱爲「吡咯酮基」（ 鲁 D比略酮之基團，該吡咯酮係含有羰基之吡咯）之取代基包 括批咯一 2 -酮基（其中羰基係與氮連接）和吡咯一 3 一酮 基（其中羰基與氮之間插入有亞甲基）。 同樣地’除非另有說明，本發明包含取代基可連接於 任一和所有適當連接該取代基之位置上。 然而’亦明瞭的是，本發明包含之化合物具有化學安 定性’即不應連接本發明之雜脂肪族環取代基使得該雜脂 肪族環取代基上之雜原子對連接位置α位置，其中該連接 · 位置亦爲雜環子。 依附另一較佳體系或方面的一個較佳體系或方面僅描 述具有不同於其依附之較佳體或方面之値或前題的變數。 例如，若依附之較佳體系僅描述R2，則與R2無關之變數 或前題係表示所依附之較佳體系的變數或前題。 若變數係以數値0定量表示，則連接該變數之鍵結不 再存在。 本文所使用之「伸烷基」表示二價烷，即2個氫原子 -54- 200529835 (50) 自烷除去（當該烷含有1個以上之碳原子時，該氫原子係 自2個不同之碳原子除去），例如—CH2CH2CH2-。 本文所使用之「烷叉基」表示烷之2個氫原子係自1Zsuzsanna; Pinter, Erika; Nemeth, Jozsef; Szolanyi, Janos. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pecs, Pecs, Hung. Current Medicinal Chemistry * Anti-Inflammatory & Anti-Allergy Agents (2003), 2 (2), 191-218, all of which are incorporated herein by reference. Various different preferred systems of the fifth aspect of the present invention provide a combination of a compound of the present invention and one or more agents selected from the group consisting of C 0χ-2, Inhibitory AIDS 11, NSAIDS, Aspirin, Acetaminophen , Triptans (5-hydroxytryptamine 5-HTIB / ID agonist) 'ergotamine or caffeine, which is used to treat migraine. A sixth aspect of the present invention provides a non-terminal method for in vivo identification of anti-migraine compounds. The first preferred system of the sixth aspect of the present invention provides a non-terminal method for in vivo identification of anti-migraine compounds, which comprises delivery to a mammalian CGRP receptor agonist in an amount that causes an increase in blood flow and subsequent delivery A test compound in an amount that reverses the increase in blood flow caused by the CGRP, wherein the mammal is a transgenic mammal that contains humanized RAMP1 with Trp 74 or a mammal that endogenously expresses RAMP1 with Trp74. Another preferred system of the sixth aspect of the present invention provides a non-terminal method for in vivo identification of anti-migraine compounds, which comprises delivering a test compound before delivery to a mammalian CGRP receptor agonist, wherein the CGRP receptor agonists The delivery amount of the agent can cause an increase in blood flow, and the ~ 51-200529835 (47) test compound delivery amount can suppress the blood flow increase caused by the C GRP, wherein the mammal is a transgenic mammal, which contains Humanized RAMP1 of Trp 74, or mammals that endogenously express RAMP1 with Trp74. Another preferred system of the sixth aspect of the present invention provides a non-terminal method for in vivo identification of anti-migraine compounds, which comprises delivery to a mammalian CGRP receptor agonist in an amount that causes an increase in peripheral arterial diameter and subsequent delivery A test compound in an amount that reverses the increase in peripheral pulse diameter caused by the CGRP. The mammal is a transgenic mammal that contains humanized RAMP1 with Trp74, or a mammal with endogenous expression of RAMP1 with Trp74. . Another preferred system of the sixth aspect of the present invention provides a non-terminal method for in vivo identification of anti-migraine compounds, which comprises delivering a test compound before delivery to a mammalian CGRP receptor agonist, wherein the CGRP receptor agonists The delivery amount of the agent can cause an increase in the peripheral arterial diameter, and the delivery amount of the test compound can suppress the increase in the peripheral arterial diameter caused by the CGRP. The mammal is a transgenic mammal that contains a humanized Trp74. RAMP1, or a mammal that endogenously expresses RAMP1 with Trp74. Other preferred systems of the sixth aspect of the present invention provide a non-terminal method for in vivo identification of anti-migraine compounds described herein, wherein the blood flow is facial blood flow. Other preferred systems of the sixth aspect of the present invention provide a non-terminal method for in vivo identification of anti-migraine compounds described herein, wherein the endogenous -52- 200529835 (48) mammalian with RAMP1 having Trp74 is non-terminal Human primates. Other preferred systems of the sixth aspect of the present invention provide a non-terminal method for in vivo identification of anti-migraine compounds described herein, wherein the mammalian endogenously expresses RAMP1 with Trp74. Other preferred systems of the sixth aspect of the present invention provide a non-terminal method for in vivo identification of migraine-resistant compounds described herein, wherein the mammal endogenously expressing RAMP1 with Trp74 is a non-human primate and the non-primate Human Primates Other preferred systems of the sixth aspect of the present invention provide a non-terminal method for in vivo identification of anti-migraine compounds described herein, wherein the anti-migraine compound is a CGRP receptor antagonist. Other preferred systems of the invention may include appropriate combinations of two or more of the preferred systems and / or aspects disclosed herein. Other preferred systems of the present invention may also include a suitable subset of the preferred systems and / or aspects disclosed herein. Φ Other preferred systems and aspects of the invention will be apparent from the description below. DETAILED DESCRIPTION OF THE INVENTION The description of the present invention should conform to the laws and interpretations of chemical bonding. For example, a hydrogen atom must be removed at any given position to accommodate a substituent. As used herein, a "heterocyclic ring" includes a ring portion containing one or more heteroatoms (eg, -53-200529835 (49) such as 0, N, or s). Unless otherwise specified, the heterocyclic ring includes an aromatic ring and Non-aromatic rings (such as aliphatic rings). When describing, for example, a 5,6-fused bicyclic ring system containing 1 to 4 nitrogen atoms, the "fused bicyclic ring system" as used herein includes aromatic ring systems and aliphatic ring systems such as indolazine, indole , Isoindole, 3 Η-indole, indole, indazole or benzimidazole. If a substituent is represented by a generic term, any and all groups within the generic term are encompassed by the present invention. For example, the substituents commonly known as "pyrrolidone" (a pyridone group, the pyrrolidone is a pyrrole containing a carbonyl group) include pyrrolyl 2-keto (where the carbonyl group is connected to nitrogen) and pyrrolyl-1 3 Monoketone (where a methylene is inserted between the carbonyl and nitrogen). Likewise, unless stated otherwise, the invention encompasses substituents which can be attached at any and all positions where such substituents are suitably attached. However, it is also clear that the compounds included in the present invention are chemically stable, that is, the heteroalicyclic ring substituents of the present invention should not be attached such that the heteroatoms on the heteroalicyclic ring substituents are connected to the position α, where The connection and position are also heterocyclic. A preferred system or aspect that depends on another preferred system or aspect describes only variables that have a different aspect or proposition than the preferred aspect or aspect that it depends on. For example, if the attached preferred system only describes R2, then the variable or previous question that is not related to R2 indicates the variable or previous question of the preferred system that it depends on. If the variable is quantitatively represented by the number 値 0, the bond connecting the variable no longer exists. As used herein, "alkylene" means a divalent alkane, that is, two hydrogen atoms -54- 200529835 (50) is removed from the alkane (when the alkane contains more than one carbon atom, the hydrogen atom is different from two Carbon atoms are removed), for example -CH2CH2CH2-. As used herein, "alkylidene" means that the two hydrogen atoms of an alkane are from 1

個碳原子除去，例如 。 應瞭解的是，式（I )之5，6 -員稠合結構的6員環 中之間隔雙鍵命名係相對的且代表該環之定域7Γ軌道電子 〇 本文所使用之「芳基」或「芳-」包括苯基或萘基。 本文所使用之「雜環基」或「雜環」包括雜芳基和雜 脂肪族環基。 本文所使用之「鹵」或「鹵素」包括氟、氯、溴及碘 且進一步表示1或多個相同或不同之鹵素可於各別之部份 被取代。 除非另有說明，非環狀烴（諸如烷基、烷氧基、烯基 及炔基）可爲支鏈或直鏈。 除非另有特別指明，本發明可包括任一和所有可能之 立體異構物、幾何異構物、非對映異構物、對映異構物、 反構體及光學異構物。 本文所使用之「Trp74」表示RAMP1上第74個殘基 係色胺酸（參閱 Mallee et al.，J. Biol. Chem. 2002，277, 1 42 94 - 8，其內容倂入文本作爲參考）。 本文所使用之「抗偏頭痛化合物」包括任何能夠逆轉 或減輕CGRP受體媒介之血管擴張的化合物、肽或肽片段 (經修飾或未經修飾），例如c G RP受體拮抗劑。 -55- (51) (51)200529835 本文所使用之「測試化合物」包括被測試之任何化合 物、肽或肽片段（經修飾或未經修飾），以測定其是否能 夠逆轉或減輕CGRP受體媒介之血管擴張，例如推定之 CGRP受體拮抗劑。 本文所使用之「CGRP受體剌激動劑」包括任何化合 物、肽或肽片段（經修飾或未經修飾），其能誘發CGRP 受體媒介之血管擴張，特別係例如a C G R P或/3 C G R P ;降 鈣素族群之其他成員，例如腎上腺髓質素；CGRP之Ν端 片段，例如 CGRP(1— 12) 、CGRP(1— 15)及 CGRP( 1 一 22 ) ； CGRP之G端醯胺（NH2 )片段，例如CGRP ( 1 一 8+NH2) 、、CGRP ( 1— 13+NH2)及 CGRP ( 1— 14 + NH2 );及非天然之CGRP類似物，例如 (Ala1 Ψ ( CH2NH ) Cys2〕hCGRP，其於 Ala1 與 Cys2 之 間存有 1個假肽鍵。參閱文獻 Maggi CA，Rovero P5 Giuliani S，Evangelista S，Regoli D，Meli A. Biological activty of N-terminal fragments of calcitonin gene-related peptide. E u r J Pharmacol. 1 990 Apr 10 ； 179 ( 1-2) * 217-9； Qing X5 Wimalawansa SJ? Keith IM. Specific N-terminal CGRP fragments mitigate chronic hypoxic pulmonary hypertension i n rats. R e g u 1 P ep t. 2 003 Jan 31 ;110(2) : 93-9 及 Dennis T，Fournier A，St Pierr S，Carbon atoms, such as. It should be understood that the nomenclature of spaced double bonds in a 6-membered ring of the 5,6-membered fused structure of formula (I) is relative and represents the local 7Γ orbital electron of the ring. "Aryl" as used herein Or "aryl-" includes phenyl or naphthyl. As used herein, "heterocyclyl" or "heterocyclic" includes heteroaryl and heteroalicyclic. As used herein, "halogen" or "halogen" includes fluorine, chlorine, bromine, and iodine and further indicates that one or more of the same or different halogens may be substituted in separate sections. Unless stated otherwise, acyclic hydrocarbons such as alkyl, alkoxy, alkenyl, and alkynyl can be branched or straight chained. Unless specifically stated otherwise, the present invention may include any and all possible stereoisomers, geometric isomers, diastereomers, enantiomers, isomers, and optical isomers. "Trp74" as used herein refers to the 74th residue of tryptophan on RAMP1 (see Mallee et al., J. Biol. Chem. 2002, 277, 1 42 94-8, the content of which is incorporated by reference) . As used herein, "anti-migraine compounds" include any compound, peptide, or peptide fragment (modified or unmodified), such as a cG RP receptor antagonist, that can reverse or reduce vasodilation of the CGRP receptor mediator. -55- (51) (51) 200529835 As used herein, a "test compound" includes any compound, peptide or peptide fragment (modified or unmodified) that is tested to determine whether it can reverse or reduce the CGRP receptor mediator Vasodilation, such as putative CGRP receptor antagonists. As used herein, "CGRP receptor 剌 agonist" includes any compound, peptide or peptide fragment (modified or unmodified), which can induce vasodilation of the CGRP receptor mediator, especially for example a CGRP or / 3 CGRP; Other members of the calcitonin family, such as adrenomedullin; N-terminal fragments of CGRP, such as CGRP (1-12), CGRP (1-15), and CGRP (1-222); G-terminal amine (NH2) of CGRP Fragments, such as CGRP (1-8 + NH2), CGRP (1-3-13 + NH2) and CGRP (1-1-14 + NH2); and non-natural CGRP analogs, such as (Ala1 Ψ (CH2NH) Cys2] hCGRP, It has a pseudo-peptide bond between Ala1 and Cys2. See the literature Maggi CA, Rovero P5 Giuliani S, Evangelista S, Regoli D, Meli A. Biological activty of N-terminal fragments of calcitonin gene-related peptide. E ur J Pharmacol. 1 990 Apr 10; 179 (1-2) * 217-9; Qing X5 Wimalawansa SJ? Keith IM. Specific N-terminal CGRP fragments mitigate chronic hypoxic pulmonary hypertension in rats. R egu 1 P ep t. 2 003 Jan 31; 110 (2): 93-9 and Dennis T, Fournier A, St Pierr S,

Quirion R. Structure-activity profile of calcitonin gene-related peptide in peripheral and brain tissues. Evidence for receptor multiplicity. J Pharmacol Exp Ther. 1 9 8 9 Nov -56- 200529835 (52) :2 5 1 ( 2 ) : 7 1 8 - 2 5，其倂入本文作爲參考。 本發明之化合物可爲藥學上可接受之鹽的型式。該鹽 可包括與無機酸（諸如，例如，氫氯酸和硫酸）之加成鹽 和與有機酸（諸如，例如，乙酸、檸檬酸、甲烷磺酸、甲 苯磺酸、酒石酸及馬來酸）之加成鹽。再者，若本發明之 化合物含有酸基，該酸基可爲鹼金屬鹽（諸如，例如，鉀 鹽和鈉鹽）、鹼土金屬鹽（諸如，例如，鎂鹽和鈣鹽）及 有機鹼鹽（諸如三乙基銨鹽和精氨酸鹽）之型式。若爲舌 φ 下調製劑，糖精鹽或馬來酸鹽係特別有益的。本發明之化 合物可經水合或未經水合。 投遞本發明之化合物可藉由口服劑型（諸如藥片、膠 .囊（每一個膠囊包括維持釋出型或適時適出型調製劑）、 藥九、粉末、顆粒、酏劑、酊劑、懸浮液、糖漿及乳化劑 )。本發明之化合物亦可經由靜脈內、腹膜內、皮下或肌 內投遞，前揭投遞途徑所使用之劑型係爲熟習藥學領域之 人士所習知者。該化合物可經單獨投遞，但通常係與藥學 鲁 載體一起投遞’該藥學載體之選擇係基於所選擇之投遞途 徑和標準藥學實務。投遞本發明之化合物亦可藉由鼻內途 徑’其係藉由局部使用適當之鼻內載體，或藉由穿皮途徑 ’其使用穿皮皮膚貼藥。當經由穿皮投遞本發明之化合物 時’其劑重係持I買地攝入。 當本發明之化合物的劑量係〇 . 〇 1至3 0 m g / k g時， 對每一個個案本發明之化合物的劑量、劑量攝取及排定時 間必須小心調整’其利用習知之專業調整方法並考慮接受 -57- 200529835 (53) 者之年齡、體重及病狀，投遞途徑及疾病狀態之本性和程 度。依據良好之臨床實務’適宜地投遞本發明之化合物於 能產生有效有益功效但未造成任何有害或不欲之副作用的 濃度。 合成 依據下述之一般反應圖，可合成本發明之化合物。除 非另有說明，依據上式化合物之敘述，界定下述反應圖中 之變數。依據反應圖1或2，可製備本發明之化合物。亦 可利用該反應圖之變化以製備本發明之化合物，該變化係 熟習此技藝之人士所習知。Quirion R. Structure-activity profile of calcitonin gene-related peptide in peripheral and brain tissues. Evidence for receptor multiplicity. J Pharmacol Exp Ther. 1 9 8 9 Nov -56- 200529835 (52): 2 5 1 (2): 7 1 8-2 5 which is incorporated herein by reference. The compounds of the invention may be in the form of a pharmaceutically acceptable salt. The salt may include addition salts with inorganic acids such as, for example, hydrochloric acid and sulfuric acid, and with organic acids such as, for example, acetic acid, citric acid, methanesulfonic acid, toluenesulfonic acid, tartaric acid, and maleic acid. Addition of salt. Furthermore, if the compound of the present invention contains an acid group, the acid group may be an alkali metal salt (such as, for example, potassium and sodium salts), an alkaline earth metal salt (such as, for example, magnesium and calcium salts), and an organic base salt (Such as triethylammonium and arginine). Saccharin salts or maleate salts are particularly beneficial for tongue φ modulators. The compounds of the invention may be hydrated or unhydrated. The compounds of the present invention can be delivered by oral dosage forms (such as tablets, capsules, capsules (each capsule includes a sustained release or timely release preparation), medicine nine, powder, granules, tinctures, elixirs, suspensions, Syrup and emulsifier). The compounds of the present invention can also be delivered intravenously, intraperitoneally, subcutaneously, or intramuscularly. The dosage forms used in the pre-delivery route are known to those skilled in the pharmaceutical field. The compound can be delivered separately, but is usually delivered with a pharmaceutical carrier. The choice of the pharmaceutical carrier is based on the chosen delivery route and standard pharmaceutical practice. The compounds of the present invention can also be delivered via the intranasal route 'which is by topical application of an appropriate intranasal carrier, or by a transdermal route' which uses a transdermal patch. When the compound of the present invention is delivered through the skin, its dosage is taken as I buy it. When the dosage of the compound of the present invention is 0.001 to 30 mg / kg, the dosage, dose intake and scheduling time of the compound of the present invention must be carefully adjusted for each case. Accept -57- 200529835 (53) The age, weight and condition of the person, the nature and extent of the delivery route and disease state. The compounds of the present invention are suitably delivered according to good clinical practice at a concentration that produces effective beneficial effects without causing any harmful or undesired side effects. Synthesis The compounds of the present invention can be synthesized according to the following general reaction scheme. Unless otherwise stated, the variables in the following reaction diagrams are defined based on the description of the compounds of the above formula. The compounds of the present invention can be prepared according to Reaction Schemes 1 or 2. Changes in this reaction scheme can also be used to prepare the compounds of the present invention, which changes are known to those skilled in the art.

-•58 ~ 200529835 (54) 反應圖1 ·合成式I化合物-• 58 ~ 200529835 (54) Scheme 1 · Synthesis of compound of formula I

IV 反應圖1描述之合成方法起始自式II化合物，其係 胺基終端經保護之胺基酸。一般胺基保護基（P G )包括 BOC、CBZ及FMOC且其加入和除去已爲此技藝所習知。 利用標準肽偶合劑使式II化合物之羧酸部份與式HNR]R2 之胺偶合以生成式III之醯胺。除去胺基保護基以生成式 IV化合物。。隨後於混合脲或脲排物反應中，令式IV化 合物與式V之胺（如下所示）偶合以生成式I化合物。利 鲁 用光氣、硫酸二琥珀醯亞胺酯、羧基二咪唑或其他對等物 ，可方便地進行混合脲之生成。脲等排物（諸如氰基胍和 磺酿基胍）之生成係爲文獻所記載。 -59- (55) 200529835 反應圖2.合成式I化合物IV Reaction The synthetic method described in Figure 1 starts from a compound of formula II, which is an amino acid with a protected amino group terminal. General amine protecting groups (P G) include BOC, CBZ and FMOC and their addition and removal are known in the art. The carboxylic acid moiety of the compound of formula II is coupled to the amine of formula HNR] R2 using a standard peptide coupling agent to form amidine of formula III. Removal of the amine protecting group to produce a compound of formula IV. . The compound of formula IV is then coupled with an amine of formula V (shown below) to form a compound of formula I in a mixed urea or urea discharge reaction. Lilu can use phosgene, disuccinimidyl sulfate, carboxydiimidazole, or other equivalents to easily produce mixed urea. The formation of urea and other compounds (such as cyanoguanidine and sulfoguanidine) is well documented in the literature. -59- (55) 200529835 Scheme 2. Synthesis of compound of formula I

VV

反應圖2描述之合成方法起始自式V化合物，其係 竣基終端保護之胺基酸。該保護基通常係甲酯，但是亦可 使用其他之保護基’諸如乙酯、特丁酯及苄酯。如上述於 混合脲或脲等排物反應中，令式V化合物與式VIII之胺 (如下所示）偶合以生成式VI化合物。將式！ V化合物轉 化爲自由之式VII酸化合物，隨後該式VII酸化合物與式 hnWr2之胺偶合以生成式I化合物。The synthetic method described in Reaction Figure 2 starts from a compound of formula V, which is an end-protected amino acid. The protecting group is usually a methyl ester, but other protecting groups such as ethyl ester, tert-butyl ester and benzyl ester may be used. Compounds of formula V and an amine of formula VIII (shown below) are coupled to form a compound of formula VI in a mixed urea or urea discharge reaction as described above. Will! Compound V is converted to a free acid compound of formula VII, which is then coupled with an amine of formula hnWr2 to form a compound of formula I.

反應圖3描述之合成方法起始自反應圖2之式vn化 合物。令式V化合物與醇r4〇h偶合。該形成酯之反應係 爲此技藝所習知且可藉由利用例如羰二醯亞胺偶合劑（諸 如N ’ N —二環己基羰二醯亞胺）進行。此外，特別對二 (56) (56)200529835 級醇和三級醇之酯，通常有期的是包括加速醯化反應之添 加劑，諸如4 一二甲基胺基吡啶。 製備HNR]R2和式VIH胺 式VIII和HNWr2胺係爲可購得之商品，藉由文獻方 法或本文描述之方法可製得。The synthetic method described in Reaction Scheme 3 begins with the reaction of the compound of formula vn in Reaction Scheme 2. The compound of formula V is coupled with the alcohol r40h. This ester-forming reaction is well known in the art and can be carried out by using, for example, a carbonyldiamidoimine coupling agent (such as N'N-dicyclohexylcarbonyldiamidoimine). In addition, especially for the esters of bis (56) (56) 200529835 and tertiary alcohols, it is common to include additives that accelerate the tritiation reaction, such as 4-dimethylaminopyridine. Preparation of HNR] R2 and formula VIH amines Formula VIII and HNWr2 amines are commercially available products and can be prepared by literature methods or methods described herein.

製備式Π和V胺基酸Preparation of Π and V amino acids

Q RS H0yVPG 11 細/叫 vQ RS H0yVPG 11 fine / call v

s H I 式11和v胺基酸係爲可購得之商品或依反應圖4之 方法可製得。The s H I formula 11 and v amino acids are commercially available or can be prepared according to the method shown in FIG. 4.

-61 - 200529835 (57) 反應圖4.合成式π和V化合物-61-200529835 (57) Reaction Figure 4. Synthesis of compounds of formula π and V

反應圖4描述之合成方法起始自式IX之醛，該醛係 於Wads worth-Emmons偶合反應中與式X之甘氨酸磷酸酯 反應。利用鹼（諸如二氮雜環雙環十一碳烯或四甲基胍或 此技藝習知之其他有機鹼或無機鹼）使式X化合物去質 子。還原所生成之式XI化合物的雙鍵以生成式XII化合 物。可進行還原反應以生成消旋物或藉由利用立體選擇性 觸媒以生成任一之式ΧΠ之對映異構物。該還原反應可起 始於自氫供給者（諸如甲酸或環己二烯）之轉移氫化反應 或利用氣體氫之氫化反應，其皆於適當之觸媒存之存在下 。藉由酸或鹼水解該酯以製備式11化合物。利用此技藝 習知之方法，藉由除去保護基（P G )以製備式 V化1合物 -62 - 200529835 (58) 如示於反應圖5，可製備式XII之其他胺基酸衍生物 反應圖5.合成式XII化合物 r3h r3、 r4oThe synthetic method described in Reaction Figure 4 begins with an aldehyde of formula IX which is reacted with a glycine phosphate of formula X in a Wads worth-Emmons coupling reaction. The compound of formula X is deprotonated using a base such as a diazacyclobicycloundecene or tetramethylguanidine or other organic or inorganic bases known in the art. The double bond of the resulting compound of formula XI is reduced to form a compound of formula XII. Reduction reactions can be performed to generate racemates or by using stereoselective catalysts to generate any of the enantiomers of formula XII. The reduction reaction can begin with a transfer hydrogenation reaction from a hydrogen supplier (such as formic acid or cyclohexadiene) or a hydrogenation reaction with gaseous hydrogen, both in the presence of a suitable catalyst. The ester is hydrolyzed by acid or base to prepare a compound of formula 11. Using a method known in the art, by removing the protecting group (PG) to prepare a compound of Formula V-62-200529835 (58) As shown in Reaction Figure 5, other amino acid derivatives of Formula XII can be prepared. 5. Synthesis of compounds of formula XII r3h r3, r4o

ΧΙΠXII

.PG.PG

XIVXIV

Ν〆 Η PG XII οΝ〆 Η PG XII ο

其中爲反應圖5之目的，式XIV化合物係親核性化 合物（諸如胺或醇），能與所示之式X ΠI化合物參與 Michael 反應。 依據反應圖6或7可製備其他之式I化合物。亦可利 用該等反應圖之變化以製備本發明之化合物，該變化係熟 習此技藝之人士所習知。Among them, for the purpose of reaction of Fig. 5, the compound of formula XIV is a nucleophilic compound (such as an amine or an alcohol), and can participate in the Michael reaction with the compound of formula XIII as shown. Other compounds of formula I can be prepared according to reaction schemes 6 or 7. Changes in these reaction schemes can also be used to prepare the compounds of the present invention, which changes are known to those skilled in the art.

-63- (59) 200529835 反應圖6 . R3、-63- (59) 200529835 Reaction Figure 6. R3,

CHO IX 合成式I化合物 -一" r3CHO IX Synthetic Compound of Formula I -A " r3

、COOHCOOH

\^C〇OH一 XV\ ^ C〇OH- XV

反應圖6描述之合成方法起始自可購得或合成之醛。 該二碳同系化反應和雙鍵還原反應係爲文獻所記載且產生 式X V化合物。某些式X v化合物亦爲可購得之商品，且 其他式XV化合物可藉由此技藝習知之其他方法加以製備 。製備式X V I和X V 11之化合物係記載於文獻中，其作爲 Evans對掌性不對稱合成反應之基質和產物。水解生成式 XVIII化合物。如與反應圖2之式VII化合物，利用習知 之醯胺偶合反應途徑，該羧酸可與式之胺反應以 生成式XIX化合物。水解該特丁酯以生成式X χ之化合物 ，其可進一步與式VIII化合物偶合以生成式I化合物。 -64- 200529835 (60) 反應圖7.合成式I化合物The synthetic method described in Reaction Figure 6 starts from commercially available or synthesized aldehydes. This two-carbon homologous reaction and double bond reduction reaction are described in the literature and produce a compound of formula X V. Certain compounds of formula Xv are also commercially available, and other compounds of formula XV can be prepared by other methods known in the art. The compounds of the formulae X V I and X V 11 are described in the literature as the substrate and product of Evans's asymmetric synthetic reaction on palms. Hydrolysis produces a compound of formula XVIII. If reacting with the compound of formula VII of Figure 2, the carboxylic acid can be reacted with an amine of formula to form a compound of formula XIX using the conventional amidine coupling reaction pathway. The tert-butyl ester is hydrolyzed to form a compound of formula Xx, which can be further coupled with a compound of formula VIII to form a compound of formula I. -64- 200529835 (60) Reaction Figure 7. Synthesis of Compound of Formula I

反應圖7亦起始自可購得或合成之醛。該醛於鹼之存 在下與琥珀酸二甲酯反應以生成式XXI化合物。還原式 XXI化合物之雙鍵以生成式ΧΧΠ化合物。可進行該還原 Φ 反應以生成消旋物或藉由使用立體選擇性觸媒以產生任一 之式XXII之對映異構物。該還原反應可起始於自氫供給 者（諸如甲酸或環己二烯）之轉移氫化反應或利用氣體氫 之氫化反應，其皆於適當之觸媒之存在下。利用習知醯胺 合成途徑，令該醯胺與式VIII胺偶合以生成式XXIII化 合物。水解甲酯生成式XXIV化合物，其係進一步與各種 不同之胺或醇偶合以分別生成式I之醯胺和式I之酯。 亦可依據反應圖8之方法製備式I化合物。 -65- (61) 200529835 反應圖8.合成式I化合物Reaction Figure 7 also starts from commercially available or synthesized aldehydes. This aldehyde is reacted with dimethyl succinate in the presence of a base to form a compound of formula XXI. The double bond of the compound of formula XXI is reduced to produce a compound of formula XXI. This reduction Φ reaction can be carried out to produce a racemate or by using a stereoselective catalyst to produce any of the enantiomers of formula XXII. The reduction reaction can be initiated by a transfer hydrogenation reaction from a hydrogen supplier (such as formic acid or cyclohexadiene) or a hydrogenation reaction using gaseous hydrogen, both in the presence of a suitable catalyst. Using the conventional amidine synthesis route, this amidine is coupled with an amine of formula VIII to form a compound of formula XXIII. Hydrolysis of the methyl ester yields a compound of formula XXIV, which is further coupled with a variety of different amines or alcohols to form amidine and formula I esters, respectively. Compounds of formula I can also be prepared according to the method of Reaction Scheme 8. -65- (61) 200529835 Scheme 8. Synthesis of compound of formula I

xx vmxx vm

反應圖8描述之合成方法起始自可購得之N —特丁氧 羰基- L -門冬氨酸苄酯。爲方便合成反應亦可使用經不 同保護之門冬氨酸衍生物。利用標準之肽偶合反應方法， 令々羧基與式VIII胺偶合。藉由氫解反應除去式XXV化 合物之α羧基保護基以生成式XXVI化合物。該式XXVI 化合物進一步與式HNWR2之胺偶合以生成式XXVII化合 物。藉由於有機溶劑中與強酸（諸如三氟乙酸或HC1 )反 應以除去胺基保護基。隨後令所生成之式XXVIII化合物 與各種不同之親電子性反應劑反應以生成式I化合物。例 如，利用涉及於不同溫度下加熱或藉由與化學反應計量或 作爲觸媒之過渡金屬（諸如鈀或銅）的催化反應之習知方 法，該式XXVIII化合物可與_芳香族化合物偶合。於此 技藝習知之還原烷化反應條件下，該式XXVIII化合物亦 -66- 200529835 (62) 可與不同之醛或酮反應。該式XXVIII化合物亦可與異氰 酸酯、醯基氯或氨基甲醯氯反應以分別生成脲、醯胺或氨 基甲酸酯衍生物。取決於所選擇之保護基和除去保護基之 次序，可改變上述修飾之順序。 亦可依據反應圖9之方法製備式I化合物。 反應圖9.合成式I化合物 〇〇γ^Η + OEtThe synthetic method described in reaction Figure 8 starts from the commercially available N-tert-butoxycarbonyl-L-aspartic acid benzyl ester. To facilitate the synthesis reaction, differently protected aspartic acid derivatives can also be used. The amidine carboxyl group is coupled to an amine of formula VIII using a standard peptide coupling reaction method. The α-carboxy protecting group of the compound of formula XXV is removed by a hydrogenolysis reaction to produce a compound of formula XXVI. This compound of formula XXVI is further coupled with an amine of formula HNWR2 to form a compound of formula XXVII. Removal of amine protecting groups by reaction with strong acids such as trifluoroacetic acid or HC1 in organic solvents. The resulting compound of formula XXVIII is then reacted with various electrophilic reactants to form a compound of formula I. For example, the compound of formula XXVIII can be coupled with an aromatic compound using conventional methods involving heating at different temperatures or by catalytic reaction with a chemical reaction or a catalytic transition metal such as palladium or copper. Under the conditions of reductive alkylation reaction known in the art, the compound of formula XXVIII can also react with different aldehydes or ketones. The compound of formula XXVIII can also be reacted with isocyanate, fluorenyl chloride or carbamate chloride to form urea, sulfonamide or urethane derivatives, respectively. The order of the above modifications may be changed depending on the order of the protecting group selected and the protecting group being removed. Compounds of formula I can also be prepared according to the method of Reaction Scheme 9. Reaction Figure 9. Synthesis of Compound of Formula I 〇〇γ ^ Η + OEt

CIZn^A 又。七\ho ,CIZn ^ A again. Seven \ ho,

OEtOEt

HOHO

反應圖9描述之合成方法起始自式xxix之亞胺，其 係藉由乙醛酸乙酯與式r3nh2之胺的縮合反應力α以製備 。該式XXIX之亞胺與2-特丁氧基一 2-酮基乙基氯化鋅 反應以生成式XXX化合物。利用與強酸反應以除去特丁 酯保護基以生成自由之式XXXI之酸，其係與式VIII胺 偶合以生成式ΧΧΧΠ之化合物。利用氫氧化物金屬鹽或 水溶性鹼水解該乙酯以生成自由之式X X X π 1之*“酸。該 -67- 200529835 (63) α酸再與式hnWr2之胺偶合以生成式I化合物。 脲基醯胺中間產物和實施例 全體適用：利用Bruker 5 00或3 00 MHz儀器分析1Η 和13C-NMR光譜且化學位移係相對於四甲基矽烷以ppm (δ )記錄（（5 = 0.0 )。所有蒸發係於減壓下進行。除 非另有說明，藉由Shimadzu儀器利用YMC C1 8管柱（3 X 5 0 mm ) 、2分鐘線性梯度之0至1 〇〇 %溶劑B於A中 之3分鐘分析期間，進行LC/MS分析。對LC/MS和 Shimadzia製備性HPLC系統，溶劑AT係10%甲醇/ 90% 水/ 0. 1 %三氟乙酸，且溶劑B係9 0 %甲醇/ 1 〇 %水/ 0 · 1 %三氟乙酸，UV偵測器設定爲220 nm。 1 一苄基一2，，3 / -二氫—2，一酮基螺一[哌啶一 4， 4 ^ ( 1 / Η )—喧唑啉The synthetic method described in Reaction Figure 9 starts from an imine of formula xxix, which is prepared by the condensation reaction power α of ethyl glyoxylate and an amine of formula r3nh2. The imine of formula XXIX is reacted with 2-tertoxy-2-ketoethylzinc chloride to form a compound of formula XXX. The reaction with a strong acid to remove the tert-butyl protecting group to form a free acid of the formula XXXI is coupled with an amine of the formula VIII to form a compound of the formula XXXXX. This ethyl ester is hydrolyzed with a hydroxide metal salt or a water-soluble base to form a * "acid of the free formula XXX π 1. The -67- 200529835 (63) alpha acid is then coupled with an amine of the formula hnWr2 to form a compound of formula I. Ureamidamide intermediates and examples are applicable in general: 1 分析 and 13C-NMR spectra are analyzed using a Bruker 5 00 or 3 00 MHz instrument and chemical shifts are recorded in ppm (δ) relative to tetramethylsilane ((5 = 0.0) All evaporations were performed under reduced pressure. Unless otherwise stated, YMC C1 8-column (3 X 50 mm) with a 2-minute linear gradient of 0 to 1000% of solvent B in A was used by Shimadzu instrument. During the 3-minute analysis, LC / MS analysis was performed. For LC / MS and Shimadzia preparative HPLC systems, the solvent AT was 10% methanol / 90% water / 0.1% trifluoroacetic acid, and the solvent B was 90% methanol / 10% water / 0 · 1% trifluoroacetic acid, UV detector set to 220 nm. 1 monobenzyl-2, 3 / -dihydro-2, monoketospiro-1 [piperidine-4, 4 ^ (1 / Η)-oxazoline

加熱多磷酸（1 1 3 g )至1 〇 〇至1 1 0 °C，並於攪拌下加 入1 一卡基—暖卩定一 4 一酮（9.27 ml’ 50毫莫耳）。隨後 立即以小部分添加之方法加入苯脲（9 · 5 5 g，7 0毫莫耳） ，該小部分添加之方式可避免產生過多之泡沬。於1 5 0至 1 6 0 °C下隔夜加熱該混合物。令該混合物冷卻至1 0 0至 ]1 〇 °C (該混合物於較低之溫度下變得黏稠而不易攪拌） ，隨後緩慢地加入水（2 0 〇 m 1 )。利用1 0 N N a Ο Η中和所 200529835 (64) 生成之溶液至約pH 8，隨後利用氯仿進行萃取。將有機 層置於Mg S 04上乾燥並經濃縮後生成粗產物，其係經矽 膠閃蒸管柱層析（6 : 4乙酸乙酯/己烷）純化以生成所 欲之產物（9.0g，58%)。 質譜：3 08.2 5 ( MH ) +。 2 > ，3 / -二氫—2 / —酮基螺一[哌啶—4，4 / ( 1 ^ Η )Heat polyphosphoric acid (1 13 g) to 100 to 110 ° C, and add 1-carboxyl-warmthidine-4-one (9.27 ml '50 millimoles) with stirring. Immediately afterwards, phenylurea (9.55 g, 70 mmol) was added in a small portion. This small portion was added to avoid excessive foaming. The mixture was heated overnight at 150 to 160 ° C. The mixture was allowed to cool to 100 to 100 ° C (the mixture became viscous at a lower temperature without being easily stirred), and then water (200 m 1) was added slowly. The resulting solution was neutralized with 10 N N a Η Η 200529835 (64) to about pH 8 and then extracted with chloroform. The organic layer was dried on Mg S 04 and concentrated to produce a crude product, which was purified by silica gel flash column chromatography (6: 4 ethyl acetate / hexane) to produce the desired product (9.0 g, 58%). Mass spectrum: 3 08.2 5 (MH) +. 2 >, 3 / -dihydro-2 / --- ketospiro- [piperidine-4,4 / (1 ^ Η)

一喹唑啉Quinazoline

將1 〇 %含鈀之木炭（1 5 0 mg )加入至1 —苄基一2 /10% palladium-containing charcoal (150 mg) was added to 1-benzyl-2 /

，3 / —二氫一 2 / — 酮基螺—哌啶—4，一 （1—H) —喧啉（1 ·00 g )之脫氣甲醇（50 ml )和 6N HC1 ( 2.0 ml )溶液中。於60 psi氫氣壓下且在Parr裝置上隔夜搖晃 該混合物。LC/ MS分析顯示反應未完全。加入超過10% 含鈀之木炭（200 mg)，並以超過2天之時間搖晃該混合 物。此時所有起始物係已消耗。過濾該混合物並濃縮濾液 以生成所欲之化合物（53 1 mg，64% )。 質譜：218·12(ΜΗ) +。 4 —胺基一 4 一氰基一哌啶一羧酸特丁酯 -69- 200529835 (65) NC NH2, 3 / -dihydro-1 / 2-—ketospiro-piperidine-4, mono (1-H) -quinoline (1.00 g) in degassed methanol (50 ml) and 6N HC1 (2.0 ml) solution in. The mixture was shaken overnight at 60 psi hydrogen on a Parr device. LC / MS analysis showed incomplete reaction. Add more than 10% palladium-containing charcoal (200 mg) and shake the mixture for more than 2 days. At this point all starting materials have been consumed. The mixture was filtered and the filtrate was concentrated to give the desired compound (53 1 mg, 64%). Mass spectrum: 218 · 12 (MΗ) +. 4-amino-tetrabutyl cyano-piperidine monocarboxylate -69- 200529835 (65) NC NH2

室溫下將氯化銨（2·66 g，49,8毫莫耳）加入至4_ 酮基一哌Π定一1 一殘酸特丁醋（9.0 g, 45.3毫莫耳）之充 分攪拌甲醇溶液中並攪拌丨小時。加入氰化鈉（2>44 g， 4 9 · 8毫莫耳）並持續攪拌1 6小時。藉由5 %碳酸氫鈉水 溶液（5 0 m 1 )驟止該反應混合物，經水稀釋並藉由旋轉 修 蒸發以除去甲醇。利用一氯甲院（3xl〇〇 mi)萃取該氰 胺，置於N a2 S Ο 4上乾燥’經蒸發溶劑後生成所欲之油狀 化合物（9 1 %產率）。 ]H-NMR(300MHz，CDC13) ·· 53.95 - 3.90 (m，lH) 3.80—3.71 (m5 1 Η ) J 3.42 — 3.06 ( m » 2H) > 2.04 — 1·9 4(ηι，1Η) ，1·71— 1.50(m，3H)。 質譜·· 2 2 6 ( Μ Η ) +。 2—苯基—1，38—二氮雜一螺[4.5]癸一 1 一烯一 4 —酮，鹽 酸鹽Ammonium chloride (2.66 g, 49,8 mmol) was added to 4_ keto-piperidine-1 1 t-butyl vinegar (9.0 g, 45.3 mmol) in methanol at room temperature and stirred well The solution was stirred for 丨 hours. Add sodium cyanide (2> 44 g, 4 9 · 8 mmol) and continue stirring for 16 hours. The reaction mixture was quenched with a 5% aqueous solution of sodium bicarbonate (50 ml), diluted with water and evaporated by rotary evaporation to remove methanol. The cyanamide was extracted with monochloromethane (3x100 mi) and dried over Na 2 S 0 4 'after evaporation of the solvent to yield the desired oily compound (91% yield). ] H-NMR (300MHz, CDC13) · 53.95-3.90 (m, lH) 3.80—3.71 (m5 1 Η) J 3.42 — 3.06 (m »2H) > 2.04 — 1 · 9 4 (ηι, 1Η), 1.71— 1.50 (m, 3H). Mass spectrum · 2 2 6 (ΜΗ) +. 2-phenyl-1,38-diaza-spiro [4.5] decane-1, ene-1,4-one, hydrochloride

將三乙胺（1·24 ml，8.88莫耳）加入至4一胺基一 4 一氰基一哌啶一 1 一羧酸特丁酯（1 . 0 g，4.4 4毫莫耳）之 二氯甲烷（3 0 m 1 )溶液中，隨後加入苯甲醯氯（9 3 6 m g -70 - 200529835 (66) ，6.6 6毫莫耳）。經3 0分鐘後’加入4 一（二甲基胺基 )吡啶（4 0 m g，0 · 3 3毫莫耳）並持續攪拌1 2小時。藉由 1 Μ N a Ο Η ( 1 0 m 1 )驟止該反應混合物，經由乙酸乙酯（ 100 ml)稀釋並進行分離。先後利用1M NaOH (40 ml) 、硫酸氫鈉水溶液（5 0 m 1 )及鹽水（5 0 m 1 )沖洗有機層 ，隨後置於Na2S04上乾燥。經由結晶，利用30%乙酸乙 酯之己烷溶液作爲溶劑，得到90%產率之所欲產物4 -苯 甲醯基胺基一 4 一氰基—哌啶一 1 一羧酸特丁酯。 φ 將6M NaOH(1.5 ml)加入至4 一苯甲醯基胺基—4 一氰基一哌啶一 1—羧酸特丁酯（1.3 g，4毫莫耳）之乙 醇（1 0 m 1 )溶液中，隨後加入 3 0 %過氧化氫。迴流該反 應混合物3小時。利用水（3 0 m 1 )稀釋該反應混合物’ 隨後除去乙醇。利用乙酸乙酯（1 〇〇 ml )稀釋殘餘物。利 用鹽水（30 ml )沖洗有機層並置於Na2S〇4上乾燥。經由 結晶，自3 0 %乙酸乙酯之己烷溶液，得到8 0 %產率之所 欲產物4 -酮基—2 -苯基一 1，3，8 -三氮雜—螺[4.5]癸 φ —1 一烯一 8 —羧酸特丁酯。令該特丁酯溶解於二氯甲烷（ 5 m 1 )中並加入H C1之二噁烷飽和溶液（2 5 m 1 )。經2 小時後，除去溶劑以生成白色粉末之2 -苯基一 1 ’ 3 ’ 8 一三氮雜一螺[4.5]癸一 1 一烯—4 —酮鹽酸鹽（95%產率） 〇 ]H-NMR ( 5 00MHz，CD30D ) ： ά 8.23 - 8.2 1 ( m，2Η )7.96 — 7.9 2 ( m 5 1 Η ) ，7.79 — 7.7 6 ( πι 5 2Η) ’ j.68 — 3.6 4 ( m，3 Η ) ，3 . 3 1 — 3 · 3 0 ( m，1 Η ) ，2.4 7 — 2 · 4 4 ( m -71 - (67) (67)200529835 ，4H)。質譜：230(MH)+。 5 —甲醯基一吲唑一 1 一羧酸特丁酯 ΟTriethylamine (1.24 ml, 8.88 moles) was added to two of 4-monoamino-4, 4-cyano-piperidine-1, tert-butyl carboxylate (1.0 g, 4.4 4 mmol) To a solution of methyl chloride (30 m 1), benzamidine chloride (9 36 mg -70-200529835 (66), 6.66 mmol) was subsequently added. After 30 minutes, 4-mono (dimethylamino) pyridine (40 mg, 0.33 mmol) was added and stirring was continued for 12 hours. The reaction mixture was quenched by 1 M N a 0 Η (10 m 1), diluted with ethyl acetate (100 ml) and separated. The organic layer was washed with 1M NaOH (40 ml), an aqueous sodium hydrogen sulfate solution (50 m 1), and brine (50 m 1), and then dried on Na2S04. Through crystallization, a 30% ethyl acetate in hexane solution was used as a solvent to obtain the desired product 4-benzylaminoamino-4,4-cyano-piperidine-1,1-butylcarboxylic acid tert-butyl ester in 90% yield. φ 6M NaOH (1.5 ml) was added to 4-benzylaminoamino-4, 4-cyano-piperidine-1, tert-butyl carboxylic acid (1.3 g, 4 mmol) in ethanol (1 0 m 1 ) Solution, followed by 30% hydrogen peroxide. The reaction mixture was refluxed for 3 hours. The reaction mixture was diluted with water (30 m 1) and then ethanol was removed. The residue was diluted with ethyl acetate (100 ml). The organic layer was washed with brine (30 ml) and dried over Na2SO4. Through crystallization, from 30% ethyl acetate in hexane solution, the desired product 4-keto-2-phenyl-1,3,8-triaza-spiro [4.5] decane was obtained in 80% yield. φ — 1-ene-8-carboxylic acid tert-butyl ester. The tert-butyl ester was dissolved in dichloromethane (5 m 1) and a saturated solution of H C1 in dioxane (25 m 1) was added. After 2 hours, the solvent was removed to give 2-phenyl-1'3'8-triaza-spiro [4.5] decane-1-ene-4-one hydrochloride (95% yield) as a white powder. ] H-NMR (500 MHz, CD30D): ά 8.23-8.2 1 (m, 2Η) 7.96 — 7.9 2 (m 5 1 Η), 7.79 — 7.7 6 (π5 5 2Η) 'j.68 — 3.6 4 (m , 3 Η), 3.3 1 — 3 · 3 0 (m, 1 Η), 2.4 7 — 2 · 4 4 (m -71-(67) (67) 200529835, 4H). Mass spectrum: 230 (MH) +. 5-Methenyl-indazole- 1-tert-butyl carboxylate 〇

將二碳酸二特丁酯（3 8 8 mg，1.78毫莫耳）之二氯甲 烷（2 ml )溶液於室溫下逐滴地加入至1 Η —吲唑一 5 —醛 (273 mg，1.87毫莫耳）、4 —二甲基胺基吡啶（114 mg ，〇·94毫莫耳）及三乙胺（0·26 ml，1.87毫莫耳）之二氯 甲烷（1 0 ml )溶液中。室溫下攪拌所生成之亮黃色溶液 達1 6小時。真空下除去溶劑，並利用含有％三乙胺之乙酸 乙酯/己烷（1 : 1 )作爲流洗液以矽膠（2 5 g )閃蒸層析 殘餘物，生成呈褐黃色液體之標的化合物（4 1 4 m g，9 0 % )° 】H-NMR ( CDC13，5 0 0MHz ) ά 10.08 ( s，1 Η ) 8.38 ( s ，1H) ，8.34(s，lH) ，8.25(d，J=8.5Hz，lH)， 8.04(d，J=8.8Hz，lH) ，：1.71(s，9H)。 13CNMR ( CDC13， 1 25MHz ) δ 1 9 1 . 8， 1 4 9 · 0， 1 4 2.5， 140.6，133.0，128.3，126.4，125.8，115.3，85.7，27.8 5 — （ 2 —苄氧羰基胺基一 2 —甲氧羰基一乙烯基）一吲唑 一 1 一羧酸特丁酯 -72 - 200529835 (68)A solution of ditert-butyl dicarbonate (3.88 mg, 1.78 mmol) in dichloromethane (2 ml) was added dropwise at room temperature to 1 Η -indazole-5 -aldehyde (273 mg, 1.87 Mmol), 4-dimethylaminopyridine (114 mg, 0.94 mmol) and triethylamine (0.26 ml, 1.87 mmol) in dichloromethane (10 ml) . The resulting bright yellow solution was stirred at room temperature for 16 hours. The solvent was removed under vacuum, and the residue was flash-chromatographed with silica gel (25 g) using ethyl acetate / hexane (1: 1) containing% triethylamine as a flow wash to produce the target compound as a brown-yellow liquid. (4 1 4 mg, 90%) °] H-NMR (CDC13, 50 MHz) ά 10.08 (s, 1 Η) 8.38 (s, 1H), 8.34 (s, 1H), 8.25 (d, J = 8.5Hz, 1H), 8.04 (d, J = 8.8Hz, 1H), 1.71 (s, 9H). 13CNMR (CDC13, 1 25MHz) δ 1 9 1 .8, 1 4 9 · 0, 1 4 2.5, 140.6, 133.0, 128.3, 126.4, 125.8, 115.3, 85.7, 27.8 5 — (2-benzyloxycarbonylamino-1 2-methoxycarbonyl monovinyl) -indazole-1 mono-butyl carboxylate-72-200529835 (68)

於一 78 °C下攪拌N- （苄氧羰基）一 α -亞磷羧基甘 胺酸三甲酯（5.50 g，16.6毫莫耳）和四甲基胍（1.99 ml ，15·9毫莫耳）之無水四氫呋喃（50 ml )溶液達20分鐘 。隨後藉由注射器以超過1 0分鐘之時間緩慢地加入5 -甲 醯基一吲唑一 1 一羧酸特丁酯（3.72 g，15.1毫莫耳）之四 氫呋喃（2 5 ml )溶液。於一 7 8 °C下攪拌該反應混合物4小 時，隨後隔夜回溫至室溫。蒸發溶劑並經由矽膠閃蒸管柱 層析（1 : 2乙酸乙酯/己烷）處理殘餘物以生成白色泡 沬之標的化合物（5.7 7 g，8 5 % )。Stir N- (benzyloxycarbonyl) -α-phosphorous carboxyglycinate (5.50 g, 16.6 mmol) and tetramethylguanidine (1.99 ml, 15.9 mmol) at -78 ° C. ) In anhydrous tetrahydrofuran (50 ml) for 20 minutes. Subsequently, a solution of tetramethylfurfuryl (5-methylpyridinyl-indazole-1) -tetrahydrobutyrate (3.72 g, 15.1 mmol) in tetrahydrofuran (25 ml) was slowly added via a syringe over 10 minutes. The reaction mixture was stirred at 78 ° C for 4 hours and then allowed to warm to room temperature overnight. The solvent was evaporated and the residue was subjected to silica gel flash column chromatography (1: 2 ethyl acetate / hexane) to give a white foamy target compound (5.7 7 g, 85%).

】H-NMR ( CDC13，5 00MHz ) (5 8 · 0 9 ( d，J = 9 · 0 Η z，1 H )8.08 ( s ^ 1H ) ，7.84(s，1 H ) ，7.67(d，J=9.0Hz， 1 H ) ，7.47 ( s，1 H ) ，7.30 ( brs，5H ) ，6.43 ( brs， 1 H ) ，5.09(s，2H) ，3.84(s，3H) ，1.72(s，9H) o 質譜：452 ( MH ) +。 (±) — 5 — （2 —胺基一 2 —甲氧羰基一乙基）一吲唑一 1 -羧酸特丁酯 -73- 200529835 (69)] H-NMR (CDC13, 500 MHz) (5 8 · 0 9 (d, J = 9 · 0 Η z, 1 H) 8.08 (s ^ 1H), 7.84 (s, 1 H), 7.67 (d, J = 9.0Hz, 1 H), 7.47 (s, 1 H), 7.30 (brs, 5H), 6.43 (brs, 1 H), 5.09 (s, 2H), 3.84 (s, 3H), 1.72 (s, 9H) ) o Mass spectrum: 452 (MH) +. (±) — 5 — (2-amino- 2 -methoxycarbonyl monoethyl) -indazole- 1-tert-butyl carboxylate-73- 200529835 (69)

氧羰 丁酯 醇（ 用氮 並利 合物 7.55 一 3 . ，5. (s， (士 氫一 乙基Oxobutyl alcohol (using nitrogen benzoate

利用Parr氫化器且於50 psi氫氣下，搖晃5 — ( 2 —苄 基胺基一 2—甲氧鑛基一乙嫌基）一 D引Π坐一 1 一殘酸特 (524 mg，1·16 毫莫耳）和 10%Pd/C(60mg)之甲 2 0 ml )混合物達4.5小時。使該反應混合物真空並利 氣進行淸洗。經由通過寅氏鹽墊過濾該反應混合物， 用數份甲醇輕洗該墊。蒸發該甲醇濾液以生成標的化 (351 mg，95%)。 -NMR ( CDC13，500MHz ) 5 8 · 1 2 — 8 · 1 0 ( ηι，2 Η )， (brs，1 Η ) ，7.37(dd，J=8.9，1.5Hz，1H ) 3.77 75(m，lH) ，3.70(s，3H) ，3.19(dd，J=13.7 5Hz，1 H ) ，2.99 (dd，J=13.7，8.0Hz，1 H ) ，1.72Using a Parr hydrogenator and shaking at 50 psi hydrogen, 5- (2-benzylamino-2-methoxyxanthyl-ethanyl) -D-addition- 1-residual acid (524 mg, 1 · 16 millimoles) and 10% Pd / C (60 mg) in 20 ml of formazan for 4.5 hours. The reaction mixture was evacuated and rinsed in air. The reaction mixture was filtered through a pad of Yin's salt, and the pad was gently washed with several portions of methanol. The methanol filtrate was evaporated to give the target compound (351 mg, 95%). -NMR (CDC13, 500MHz) 5 8 · 1 2 — 8 · 10 (η, 2 Η), (brs, 1 Η), 7.37 (dd, J = 8.9, 1.5 Hz, 1H) 3.77 75 (m, lH ), 3.70 (s, 3H), 3.19 (dd, J = 13.7 5Hz, 1 H), 2.99 (dd, J = 13.7, 8.0Hz, 1 H), 1.72

2H )。質譜：320(MH) )—5— (2—甲氧羯基一 2- {[2-嗣基一1，4 一 一 2 Η —喹Π坐琳一 3 —基）—呢D定一 1 一類基]一胺基} _ )一吲唑—1 一羧酸特丁酯2H). Mass spectrum: 320 (MH)) —5 -— (2-methoxyfluorenyl-2-([2-fluorenyl-1,4—1-2] Η—quinoloxaline-3—yl) —? D fixed-1 One kind of group] monoamine} _) -indazole-1 monobutyl carboxylate

ΟΟ

室溫下攪拌5 - （ 2 —胺基一 2 -甲氧羰基一己基）一 -74- 200529835 (70)Stir at room temperature 5-(2 -amino- 2 -methoxycarbonyl-hexyl)--74- 200529835 (70)

吲唑—1 —羧酸特丁酯（3 07 mg，0.96毫莫耳），、N，N — 二琥珀醯亞胺碳酸酯（246 mg，0.961毫莫耳）及N，N — 二異丙基乙胺（0.67 m卜384毫莫耳）之二氯甲烷溶液30 分鐘。加入3 — _D定一 4 一基—3，4一二氫一 1H — D奎D坐啉 一 2 —酮（238 mg，1.03毫莫耳），並於室溫下攪拌該反 應混合物1 6小時。蒸發溶劑並藉由閃蒸層析且利用二氯甲 烷/甲醇/三乙胺（93 : 5 : 2 )作爲流洗液以純化殘餘物 ，生成產物（259 mg，47% )。 ]H-NMR ( CDC13 5 3 00MHz) 5 8.13— 8.10( m，2H)， 7.48 ( brs，1H) ，7.3 1 ( dd，J 二 8 · 8，1 ·6Ηζ，1 H ) 7. 1 6 (t，J=8.0Hz，1H ) ，7.05 (d，J=7.0Hz，1H ) ，6.94 (t，J=7,7Hz，1 H ) ，6.82 (s，1H ) ，6.66 (d，J = 8.0Hz，1H ) ，4.98 (d，J=7.7Hz，1 H ) ，4.87-4.81 ( m，lH) ，4.58—4.49 (m，lH) ，4.26(s，2H) ，4.05 —3.97(m，2H) ，3.74— 3.67 ( ni，4H) ，3.29— 3.23 (Indazole-1-tert-butyl carboxylate (3 07 mg, 0.96 mmol), N, N-disuccinimide carbonate (246 mg, 0.961 mmol) and N, N-diisopropyl Solution of methylethylamine (0.67 m @ 384 mmol) in dichloromethane for 30 minutes. Add 3 — —D-A-4, 4-A, 3, 4 — dihydro — 1H — D, quinoline, and 2 ketoline (238 mg, 1.03 mmol) and stir the reaction mixture at room temperature for 16 hours. . The solvent was evaporated and the residue was purified by flash chromatography using dichloromethane / methanol / triethylamine (93: 5: 2) as a flow wash to yield the product (259 mg, 47%). ] H-NMR (CDC13 5 3 00MHz) 5 8.13— 8.10 (m, 2H), 7.48 (brs, 1H), 7.3 1 (dd, J 2 8 · 8, 1 · 6Ηζ, 1 H) 7. 1 6 ( t, J = 8.0Hz, 1H), 7.05 (d, J = 7.0Hz, 1H), 6.94 (t, J = 7, 7Hz, 1H), 6.82 (s, 1H), 6.66 (d, J = 8.0 Hz, 1H), 4.98 (d, J = 7.7Hz, 1 H), 4.87-4.81 (m, lH), 4.58-4.49 (m, lH), 4.26 (s, 2H), 4.05-3.97 (m, 2H ), 3.74— 3.67 (ni, 4H), 3.29— 3.23 (

m，2H) ，2.93— 2.84 (m，2H) ，：1.76— 1.62 (m，1H) ，1.70(s，9H) ，1.48 — 1.42 (m，lH)。 質譜：5 77 ( ΜΗ ) +。 2 —三甲基甲矽烷基一乙烷磺醯氯 對經火焰乾燥之三頸圓底燒瓶內之三苯膦（]2 9 g， 49 0毫莫耳）之二氯甲烷（2 00 ml )澄淸溶液，於0°C下在 3分鐘內加入硫醯氯（4 3 m 1，5 3 9毫莫耳）。於0 t下經攪 -75- (71) (71)200529835 拌5分鐘後，除去冰水浴並以超過1 〇分鐘之時間分數份加 入2 —三甲基甲矽烷基乙烷磺酸鈉（5〇 g，245毫莫耳）。 室溫下攪拌所生成之白色懸浮液1 6小時，隨後經由寅氏鹽 墊過濾。濃縮濾液至約5 0 m 1，隨後加入乙酸乙酯/己烷 (1:3，1000 ml)及寅氏鹽（40 g)。室溫下攪拌該混 合物1 5分鐘，並通過寅氏鹽墊過濾。真空下除去溶劑並將 殘餘物載入已潤濕之矽膠（3 00 ml )管柱中，且利用1 : 3 乙酸乙醋/己院作爲流洗液。除去溶劑以得到亮黃褐色液 體之標的化合物（4 1 . 9 g，8 5 % )。若未立即使用，經產 物應於氮氣下貯存於冰箱或冷凍庫中以使分解最少。 ^-NMR ( CDC13 5 500MHz ) 53.61— 3.57(m，2H) ’ 1.3 2 - 1.27 ( m > 2H ) ，0.10(s，9H)。 1 一 （ 2 —三甲基甲矽烷基—乙烷磺醯基）一 1 η 一吲哚_ 5 一羧酸乙酯m, 2H), 2.93—2.44 (m, 2H), 1.76—1.62 (m, 1H), 1.70 (s, 9H), 1.48—1.42 (m, 1H). Mass spectrum: 5 77 (ΜΗ) +. 2-Trimethylsilyl-ethanesulfonyl chloride on triphenylphosphine (2 9 g, 49 0 mol) in dichloromethane (2 00 ml) in a flame-dried three-neck round bottom flask Clear the solution and add thionine chloride (4 3 m 1,5 3 9 mmol) at 0 ° C over 3 minutes. After stirring at -75- (71) (71) 200529835 for 5 minutes, remove the ice water bath and add sodium 2-trimethylsilylethane sulfonate (5 (G, 245 mmol). The resulting white suspension was stirred at room temperature for 16 hours and then filtered through a Yin's salt pad. The filtrate was concentrated to about 50 ml, and then ethyl acetate / hexane (1: 3, 1000 ml) and Yin's salt (40 g) were added. The mixture was stirred at room temperature for 15 minutes and filtered through a Yin's salt pad. The solvent was removed under vacuum and the residue was loaded into a wet silica gel (300 ml) column, and 1: 3 ethyl acetate / hexane was used as the flow wash. The solvent was removed to obtain the target compound (41. 9 g, 85%) as a bright yellow-brown liquid. If not used immediately, the product should be stored in a refrigerator or freezer under nitrogen to minimize decomposition. ^ -NMR (CDC13 5 500 MHz) 53.61-3.57 (m, 2H) '1.3 2-1.27 (m > 2H), 0.10 (s, 9H). 1- (2-trimethylsilyl-ethanesulfonyl)-1 η-indole-5 ethyl carboxylate

於〇 °C下逐滴地將1 Η —吲哚—5 —羧酸乙酯（1 〇 . 3 1 g1Η-indole-5-carboxylic acid ethyl ester (10.3 1 g) was dropped dropwise at 0 ° C.

，58.8毫莫耳）之二甲基甲醯胺（50 ml )溶液加入至NaH (1·83 g’ 76.4毫莫耳）之二甲基甲醯胺（150 ml)溶液 中。於〇 °C下攪拌所生成之混合物3 0分鐘，隨後於〇。(：下緩 慢地加入2 —三甲基甲矽烷基—乙烷磺醯氯（1 7.7 g，8 8.2 毫莫耳）之二甲基甲醯胺（1 〇 〇 m 1 )溶液。經2小時後， -76- 200529835 (72) 加入飽和氯化銨水溶液（2 0 0 ml )，並利用乙酸乙酯（ 3 00 ml )萃取該混合物。經分離後，利用乙酸乙酯（2 x 1 5 0 m 1 )萃取水層。利用鹽水（3 X 1 5 0 m 1 )冲洗結合之有 機層，並置於無水硫酸鈉上乾燥。真空下除去溶劑，並藉 由矽膠閃蒸層析且利用1 : 1 · 5二氯甲烷/己烷作爲流洗液 以純化殘餘物，生成白色固體之標的化合物（1 5 . 8 g，7 9 % )。58.8 millimoles) of dimethylformamide (50 ml) was added to a solution of NaH (1.83 g '76.4 millimoles) of dimethylformamide (150 ml). The resulting mixture was stirred at 0 ° C for 30 minutes, and then at 0 ° C. (: Slowly add a solution of 2-trimethylsilyl-ethanesulfonyl chloride (1 7.7 g, 8 8.2 mmol) in dimethylformamide (1000 m 1). Over 2 hours After that, -76- 200529835 (72) was added a saturated aqueous ammonium chloride solution (200 ml), and the mixture was extracted with ethyl acetate (300 ml). After separation, ethyl acetate (2 x 1 5 0 m 1) extract the aqueous layer. Rinse the combined organic layers with brine (3 × 1 500 m 1) and dry over anhydrous sodium sulfate. Remove the solvent under vacuum and use silica gel flash chromatography and use 1: 1 • 5 dichloromethane / hexane as a flow wash to purify the residue to yield the target compound as a white solid (15.8 g, 79%).

]H-NMR ( CDC13，5 00MHz ) 5 8 · 3 6 ( d，J 二 ι · 5 Η z，1 H )’ 8.03 (dd，J = 9.0 5 2.0Hz 5 1 H ) ，7.92 (d，J = 8.5Hz » 1 H ) ，7.50 ( d ^ J=3.5Hz，1 H ) ， 6.75 (d，J 二 3.5Ηζ» 1 H ) ，3.94(s，3H) ，3.21—3.18 (m，2H)， 0.84 — 0.80 (m，2H) ，-0.06(s，9H)。 13C-NMR ( CDC13，1 25MHz ) 5 1 6 7 · 3，1 3 7 · 7，1 3 0 · 3， 128.3 ， 125.9 ， 125.5 ， 124.0 ， 112.8 ， 108.3 ， 52·2 ， 51.2 ，1 0 · 1 ’ - 2 · 1。質譜 3 5 4 · 1 2 ( Μ H ) +。] H-NMR (CDC13, 5000 MHz) 5 8 · 3 6 (d, J 2 · 5 Η z, 1 H) '8.03 (dd, J = 9.0 5 2.0 Hz 5 1 H), 7.92 (d, J = 8.5Hz »1 H), 7.50 (d ^ J = 3.5Hz, 1 H), 6.75 (d, J 2 3.5Ηζ» 1 H), 3.94 (s, 3H), 3.21—3.18 (m, 2H), 0.84 — 0.80 (m, 2H), -0.06 (s, 9H). 13C-NMR (CDC13, 1 25MHz) 5 1 6 7 ' - twenty one. Mass spectrum 3 5 4 · 1 2 (MH) +.

類似之方法製備 1 一 （ 2 —三甲基甲矽烷基—乙烷磺醯基）一 1 H 一吲哚_ 5 -羧酸乙酯Preparation of 1- (2-trimethylsilyl-ethanesulfonyl)-1 H-indole-5 -carboxylic acid ethyl ester in a similar manner

H-NMR(CDC13，500 MHz) (58.51 ( s ^ 1H ) , 8.34 ( s ]Η ) ，8.2 1 ( d d，J = 8.9，1 · 5 Η z，1 Η ) ，8 · 1 2 ( d , J = -77- 200529835 (73) 9.2Hz，lH) ，3.96(s，3H) ，3.42—3.39(m，2H)， 0.86-0.82 (m，2H) ，-0.02(s，9H) 0 13C-NMR ( CDC13，i 25MHz ) (5 1 6 6.4，1 4 3 · 1 ’ 1 4 1 · 2， 130.1，126.5，125.0，124.2，112.9，52.5，51.3，9.8，-2·1。質譜 3 5 5.1 3 ( MH) +。 〔1 一 （ 2 —三甲基甲矽烷基—乙烷磺醯基）一 1 H —吲哚 一 5 —基〕一甲醇H-NMR (CDC13, 500 MHz) (58.51 (s ^ 1H), 8.34 (s) Η), 8.2 1 (dd, J = 8.9, 1 · 5 Η z, 1 Η), 8 · 1 2 (d, J = -77- 200529835 (73) 9.2Hz, lH), 3.96 (s, 3H), 3.42-3.39 (m, 2H), 0.86-0.82 (m, 2H), -0.02 (s, 9H) 0 13C- NMR (CDC13, i 25MHz) (5 1 6 6.4, 1 4 3 · 1 '1 4 1 · 2, 130.1, 126.5, 125.0, 124.2, 112.9, 52.5, 51.3, 9.8, -2.1. Mass spectrum 3 5 5.1 3 (MH) +. [1 mono (2-trimethylsilyl-ethanesulfonyl)-1 H-indole-5-yl] -methanol

於〇 °C下將二異丁基氫化鋁（8 2.9 ml，1 Μ甲苯溶液， 82· 9毫莫耳）溶液緩慢地加入至1—( 2 一三甲基甲矽烷基 一乙烷磺醯基）一 1 Η —吲哚一 5 —羧酸乙酯（8 · 8 1 g， 25.9毫莫耳）之甲苯（20〇1111)溶液。經於0。(：下攪拌45 φ 分鏟後’藉由添加甲醇（2 6 m 1 )，粉末狀硫酸鈉+水合 物（1 94 g )乃寅氏鹽（26 mi )以驟止該反應。於1小時 Θ令該混合物回溫至室溫並通過寅氏鹽墊過濾。真空下除 $ '溶齊!1以生成非常黏稠液體狀之標的化合物，其係冷卻固 化。白色固體（8.08g，100%產率）。 】H-NMR ( CDC13，5 00MHz ) 5 7.8 7 ( d，J = 8 · 5 Η z，1 Η )5 7.62 ( s ^ 1 H )，7.44(d，J=3.7Hz，lH)，7.35( dd’ J 二 8.6，1.5 Hz，1H)，6‘66(d，J=3.7Hz，】H)， 4.7 9 ( s ’ 2 H ) ，3 · 1 8 - 3 · 1 4 ( m，2 H ) ，1 . 7 3 ( s，I H ) -78- 200529835 (74) ，0.85— 0.82( m，2H) ，-〇.〇6(s，9H)。質譜 312.14( Μ Η ) + 。 〔1 一 （ 2 —三甲基甲矽烷基一乙烷磺醯基）一 1 η —吲哚 —5 —基〕一甲醇Slowly add a solution of diisobutylaluminum hydride (8 2.9 ml, 1 M toluene solution, 82.9 mmol) at 0 ° C to 1- (2-trimethylsilyl-ethanesulfonium) A solution of 1) fluorene-indole-5-carboxylic acid ethyl ester (8.81 g, 25.9 mmol) in toluene (201111). After 0. (: After stirring under 45 φ for shovelling, by adding methanol (2 6 m 1), powdered sodium sulfate + hydrate (1 94 g) Nayin's salt (26 mi) to stop the reaction. In 1 hour Θ The mixture was allowed to warm to room temperature and filtered through a Yin's salt pad. The solvent was removed under vacuum to dissolve! 1 to produce a very viscous liquid-like target compound, which was cooled and solidified. White solid (8.08g, 100% product Rate).] H-NMR (CDC13, 500 MHz) 5 7.8 7 (d, J = 8 · 5 Η z, 1 Η) 5 7.62 (s ^ 1 H), 7.44 (d, J = 3.7 Hz, 1H) , 7.35 (dd 'J, 8.6, 1.5 Hz, 1H), 6'66 (d, J = 3.7Hz,】 H), 4.7 9 (s' 2 H), 3 · 1 8-3 · 1 4 (m , 2 H), 1. 7 3 (s, IH) -78- 200529835 (74), 0.85-0.82 (m, 2H), -0.06 (s, 9H). Mass spectrum 312.14 (Μ Η) +. [1- (2-trimethylsilyl-ethanesulfonyl)-1 η-indole-5-yl] -methanol

於〇 °C下將1 一 （ 2 -三甲基矽烷基一乙烷磺醯基）一 1 Η — D引哚一 5 —羧酸乙酯（經由甲苯（2 χ )共沸乾燥， 5.77 g ’ 16.9毫莫耳）之四氫呋喃（5〇 ml )溶液加入至氫 硼化鋰（3·68 g，169毫莫耳）之四氫呋喃（1〇〇 ml)溶液 中。令該混合物回溫至室溫，並攪拌1 4小時。隨後冷卻至 0 °C並加入氫硼化鋰（3 · 5 g )。令該混合物回溫至室溫並 攪拌1 4小時。隨後再冷卻至〇艺並緩慢地加入飽和氯化銨 水溶液（2 5 m 1 )。通過寅氏鹽墊以過濾所生成之白色懸 浮液，經除去溶劑後，藉由閃蒸層析並利用含有1 %三乙 胺之乙酸乙酯/己烷（1 : 1 . 5 )純化殘餘物以生成白色固 體之標的化合物（3.8 g，72% )。 j-NMR ( CD3OD，5 00MHz ) 5 8 · 1 4 ( s，1 Η ) ，8.04 ( d，J=8.5Hz，lH) ，7.85(s，lH) ，7.61(dd，J=8.5 ，1·2Ηζ，1H) ，4.76(s，2H) ，3.49 — 3.46 (m，1H) ，0.76—0.72 (n]，2H) ，-0.03(s，9H)； i3C-NMR ( CD3OD，125 MHz) o 141.2，140.9，138.3， 200529835 (75) 129.2， 125.8， 119·6， 112.7， 63.8， 50.8， 9.9， -3.2。質 譜 313.12 (ΜΗ) +。 1 一 （ 2 —三甲基甲矽烷基一乙烷磺醯基）一 1 Η —吲哚一 5 一醛At 0 ° C, 1- (2-trimethylsilyl-ethanesulfonyl)-1-fluorene-Dindole-5-carboxylic acid ethyl ester (via toluene (2χ) azeotropically dried, 5.77 g A solution of 16.9 millimoles) in tetrahydrofuran (50 ml) was added to a solution of lithium borohydride (3.68 g, 169 millimoles) in tetrahydrofuran (100 ml). The mixture was allowed to warm to room temperature and stirred for 14 hours. It was then cooled to 0 ° C and lithium borohydride (3.5 g) was added. The mixture was allowed to warm to room temperature and stirred for 14 hours. It was then cooled to 0 ° C and a saturated aqueous ammonium chloride solution (2 5 m 1) was slowly added. The resulting white suspension was filtered through a Yin's salt pad, and after removing the solvent, the residue was purified by flash chromatography using ethyl acetate / hexane (1: 1.5) containing 1% triethylamine To give the target compound as a white solid (3.8 g, 72%). j-NMR (CD3OD, 500 MHz) 5 8 · 1 4 (s, 1 Η), 8.04 (d, J = 8.5Hz, 1H), 7.85 (s, 1H), 7.61 (dd, J = 8.5, 1 · 2Ηζ, 1H), 4.76 (s, 2H), 3.49-3.46 (m, 1H), 0.76-0.72 (n), 2H), -0.03 (s, 9H); i3C-NMR (CD3OD, 125 MHz) o 141.2 , 140.9, 138.3, 200529835 (75) 129.2, 125.8, 119.6, 112.7, 63.8, 50.8, 9.9, -3.2. Mass spectrum 313.12 (ΜΗ) +. 1- (2-trimethylsilyl-ethanesulfonyl)-1-fluorene-indole-5-aldehyde

對5 0 0 m 1圓底燒瓶內之活化二氧化猛（2 2 g，經甲苯 (2x )共沸乾燥）和二氯甲烷（70 ml )之混合物，於0°C 下加入〔1 一 （ 2 —三甲基甲矽烷基—乙烷磺醯基）一 1 Η 一吲哚一5 —基〕一甲醇（2·1 g，6·74毫莫耳）之二氯甲 烷（30 ml )溶液。於0°C下攪拌該反應混合物30分鐘，並 通過寅氏鹽墊過濾。真空下除去溶劑以生成白色固體之標 的化合物（1 · 8 g，8 0 % ) 。 β 】H-NMR ( CDC13，5 00ΜΗζ ) ό 1 0 · 0 6 ( s，1 Η ) ，8·15 (s，lH) ，8.01(d，J=8.6Hz，lH) ，7.8 7(dd，J = 8.6，1·5Ηζ，1H) ，7.54(d，J=3.4Hz，1H) ，6.80(d ，J=3.6Hz，1 H ) ，3·24— 3·20(ηι，2H) ，0.86— 0.82 (m，2 H ) ，- 0 · 0 6 ( s，9 H )。 】3C-NMR ( CDC13，] 25MHz ) (5 1 9 1 · 9，1 3 8 · 5，1 3 2 · 3， 130.7，128.8，125.3，125.1，1134.6，108.4，51.4， 1 0 2.2，- 2 · 1。質譜 3 1 0 . 1 2 ( Μ H )—。 -80- (76) (76)200529835 類似之方法製備 1 一 （2〜二甲基甲石夕垸基一乙院礦酿基）一 iH — D引卩坐一 5 一醛To a mixture of activated dioxide (2 2 g, azeotropically dried with toluene (2x)) and dichloromethane (70 ml) in a 500 m 1 round-bottomed flask, [1 1 ( 2-trimethylsilyl-ethanesulfonyl)-1 Η-indole-5-yl] -methanol (2.1 g, 6.74 mmol) in dichloromethane (30 ml) . The reaction mixture was stirred at 0 ° C for 30 minutes and filtered through a Yin's salt pad. The solvent was removed in vacuo to give the title compound (1.8 g, 80%) as a white solid. β] H-NMR (CDC13, 500MΗζ) 1 0 · 0 6 (s, 1 Η), 8.15 (s, 1H), 8.01 (d, J = 8.6Hz, 1H), 7.87 (dd, J = 8.6, 1.5Ηζ, 1H), 7.54 (d, J = 3.4Hz, 1H), 6.80 (d, J = 3.6Hz, 1H), 3.24-3.20 (η, 2H), 0.86 — 0.82 (m, 2 H),-0 · 0 6 (s, 9 H). ] 3C-NMR (CDC13,] 25MHz) (5 1 9 1 · 9, 1 3 8 · 5, 1 3 2 · 3, 130.7, 128.8, 125.3, 125.1, 1134.6, 108.4, 51.4, 1 0 2.2,-2 · 1. Mass spectrum 3 1 0. 1 2 (MH) —. -80- (76) (76) 200529835 A similar method was used to prepare 1- (2 ~ dimethylmethyazene-Yiyuan mine base) One iH — D induces sitting one 5 one aldehyde

質譜 3 1 1 · 1 〇 ( MH ) +。 2氧鑛基胺基—3 — 〔1— (2 —三甲基甲石夕院基一乙垸 醯基）一 1 Η —吲哚—5 —基〕一丙烯酸甲酯Mass spectrum 3 1 1 · 10 (MH) +. 2-oxoaminoamine—3— [1— (2-trimethylmethoxineyl-ethylfluorenyl) —1 1-pyridine—indole-5 —yl] monoacrylate

於室溫下將1，1，3，3 —四甲基胍（0.6 8 ml，5 · 4 3毫 莫耳）加入至N—（苄氧羰基）-亞磷羧基甘胺酸三 甲酯（1 · 8 8 g，5 · 6 9毫莫耳）之四氫呋喃（4 0 m 1 )溶液中 。室溫下攪拌該混合物〗5分鐘並冷卻至-7 8 °C，隨後緩慢 地加入1 一 （ 2 一三甲基甲矽烷基一乙烷磺醯基）一 1 Η -D引[1朵—5 -醒（1 . 6 g，5 . 1 7毫莫耳）之四氫咲喃（1 5 m 1 ) 溶液。於一 7 8 C下擾泮所生成之反應混合物2小時，隨後 -81 - 200529835 並藉由矽膠閃 於3小時內回溫至室溫。真空下除去溶劑 蒸層析且利用含有1 %三乙胺之二氯甲烷/己院（1 : ^ 5 )作爲流洗液以純化殘餘物，生成標的化合物，其爲9 2 : 8 Z/ E混合物（其測定係藉由c〇2CH3之整合，對Z異構物 係於3 _ 7 9 p p m，而對E異構物係於3.6 5 p p m )。對Z異構物 ]H-NMR ( CD3CN » 5 0 0MHz ) 6 7 · 9 6 ( s，2 Η ) ，7.91 ( d，J=8.5Hz，1H) ’ 7.66(d，j=8.5Hz，1H) ，7.56( d，J=3.7Hz，1 H ) ，7.51 (s，i h ) ，7.43— 7.35 (m， 5H) ，7.67(d，J=3.7Hz，lH) ，5.16(s，2H) > 3.79At room temperature, 1,1,3,3-tetramethylguanidine (0.6 8 ml, 5.3 mmol) was added to N- (benzyloxycarbonyl) -phosphorous carboxyglycine trimethyl ester ( 1 · 8 8 g, 5 · 6 9 mmol) in a solution of tetrahydrofuran (40 m 1). The mixture was stirred at room temperature for 5 minutes and cooled to -7 8 ° C, followed by the slow addition of 1- (2-trimethylsilyl-ethanesulfonyl)-1-fluorene [1 朵 — 5-Awake (1.6 g, 5.17 millimolar) solution in tetrahydrofuran (15 m 1). The resulting reaction mixture was disturbed at 78 C for 2 hours, then -81-200529835 and warmed up to room temperature within 3 hours by flashing silicone gel. The solvent was removed under vacuum and the chromatography was performed and the residue was purified using dichloromethane / hexane (1: ^ 5) containing 1% triethylamine as a flow wash to produce the target compound, which was 9 2: 8 Z / E Mixture (the measurement was by the integration of co2CH3, the Z isomer was at 3-7 9 ppm, and the E isomer was at 3.6 5 ppm). To the Z isomer] H-NMR (CD3CN »500 MHz) 6 7 · 9 6 (s, 2 Η), 7.91 (d, J = 8.5Hz, 1H) '7.66 (d, j = 8.5Hz, 1H ), 7.56 (d, J = 3.7Hz, 1H), 7.51 (s, ih), 7.43-7.35 (m, 5H), 7.67 (d, J = 3.7Hz, 1H), 5.16 (s, 2H) > 3.79

(s，3H) ，3.42— 3.38 (m，2H) ，0.87—0.83 (m，2H )，-0.04 ( s，9H )。質譜 515.20 ( Mh) +。 類似之方法製備 2 —苄氧羰基胺基—3— 〔1 一 （2%三甲基甲矽烷基一乙烷 擴釀基）一 1 Η - D引η坐一 5 —基〕巧燒酸甲酯(s, 3H), 3.42--3.38 (m, 2H), 0.87-0.83 (m, 2H), -0.04 (s, 9H). Mass spectrum 515.20 (Mh) +. A similar method to prepare 2-benzyloxycarbonylamino-3-[[1- (2% trimethylsilyl-ethane expanded group)-1 Η-D-introduction _ 5 -yl] succinic acid methyl ester

藉由矽膠閃蒸層析，利用含有1%三乙胺之二氯甲烷 作爲流洗液’生成標的化合物’其爲9 5 : 5 z / Ε混合物（ 其測疋/[尔錯由—C H = C ( C Ο 2 Vi e ) ( ν η C Β ζ )之整合， •82、 200529835 (78) 3.72 g，92% )。對 Z異構物： W-NMR ( CD3CN，5 0 0MHz ) 5 8.39 ( s，1 H ) ，8 · 1 2 ( s，1 H ) ，8.03(d，J=8.8Hz，1H) ，7.84(dd，J=8.8 ，1.2Hz，1H) ，7.51 (s，1H) ，7.43—7.35 (m，lH)By silica gel flash chromatography, dichloromethane containing 1% triethylamine was used as a flow wash to 'generate the target compound' which was a 9 5: 5 z / Ε mixture (its test / [尔 ault 由 —CH = Integration of C (C Ο 2 Vi e) (ν η C Β ζ), • 82, 200529835 (78) 3.72 g, 92%). For Z isomers: W-NMR (CD3CN, 500 MHz) 5 8.39 (s, 1 H), 8.12 (s, 1 H), 8.03 (d, J = 8.8 Hz, 1H), 7.84 ( dd, J = 8.8, 1.2Hz, 1H), 7.51 (s, 1H), 7.43-7.35 (m, lH)

，5.14(s，2H) ，3.81(s，3H) ，3.51—3.47(m，2H )，0.83-0.79(m，2H) ，-0.02(s，9H)。 質譜 516.18 (ΜΗ) +。 (土）一 2—胺基一 3— 〔 1— (2 —二甲基甲5夕院基一乙少兀 磺醯基）一1 Η -吲哚一 5 —基〕一丙酸甲酯, 5.14 (s, 2H), 3.81 (s, 3H), 3.51-3.47 (m, 2H), 0.83-0.79 (m, 2H), -0.02 (s, 9H). Mass spectrum 516.18 (ΜΗ) +. (Earth) 2-Amine- 3— [1- (2-Dimethylformyl-5-ethylsulfofluorenyl) -1 1-indole- 5-yl] monopropionate

將2—苄氧羰基胺基一 3—〔1 一 （2—三甲基甲矽烷基 一乙烷磺醯基）一 1 Η —吲哚一 5 —基〕一丙烯酸甲酯（ 2.24 g，4.36 毫莫耳）、甲醇（100 ml)及 10%Pd/C( 〇· 52 g )加入至經火焰乾燥之5 00 ml圓底燒瓶中。令該混 合物脫氣並利用氫氣淸洗5次。室溫下攪拌1小時，隨後通 過寅氏鹽過濾。除去溶劑，並藉由閃蒸層析且利用含有1 %三乙胺之乙酸乙酯/己烷（1 : 1和2 : 1 )純化殘餘物， 生成無色黏稠液體之標的化合物（1 .2 7 g，7 6 % )，其係 冷卻固化。 -83- 200529835 (79) • 2Hz，1H ，1.5Hz， 1H-NMR ( CD3CN ， 5 00MHz ) 5 7 · 8 2 ( dAdd 2-benzyloxycarbonylamino-3- [1- (2-trimethylsilyl-ethanesulfonyl)-1 hydrazone-indole-5-yl] -methyl acrylate (2.24 g, 4.36 Millimoles), methanol (100 ml) and 10% Pd / C (0.52 g) were added to a flame-dried 500 ml round bottom flask. The mixture was degassed and washed 5 times with hydrogen. After stirring at room temperature for 1 hour, it was filtered through Yin's salt. The solvent was removed and the residue was purified by flash chromatography and using 1% triethylamine in ethyl acetate / hexane (1: 1 and 2: 1) to give the title compound (1.2 7 as a colorless viscous liquid) g, 76%), which is solidified by cooling. -83- 200529835 (79) • 2Hz, 1H, 1.5Hz, 1H-NMR (CD3CN, 5 00MHz) 5 7 · 8 2 (d

，7.51-7.49 (m，2H) ，7.22(dd，J 1H ) 6.72 ( d • 7Hz， 1 H ) .70 ( dd 6·1Ηζ，1H) ，3.65(s，3H) ，3·38— 3.34 (m，2H) 3.08(dd，J=13.4，5.8Hz，lH) ，2.95(dd，J=13.4 7.3Hz，lH) ，0.82-0.79(m，2H) ，-0.05(s，9H) ^ 13C-NMR ( CDC13，125MHz ) 5 176.0，134.4，133.4 56.6 ， 51.7 131.1 ， 127.9， 126.4， 122.4， 113.1 ， 107. 50.8， 41.3， 10· .2.7。質譜 3 8 3.1 6 ( MH ) 類似之方法製備= (±) — 2 —胺基一3— 〔1 一 （2—三甲基甲矽烷基一乙烷 磺醯基）一1 Η -吲唑一 5 —基〕一丙酸甲酯, 7.51-7.49 (m, 2H), 7.22 (dd, J 1H) 6.72 (d • 7Hz, 1 H). 70 (dd 6. · 1Ηζ, 1H), 3.65 (s, 3H), 3.38— 3.34 ( m, 2H) 3.08 (dd, J = 13.4, 5.8Hz, lH), 2.95 (dd, J = 13.4 7.3Hz, lH), 0.82-0.79 (m, 2H), -0.05 (s, 9H) ^ 13C- NMR (CDC13, 125MHz) 5 176.0, 134.4, 133.4 56.6, 51.7 131.1, 127.9, 126.4, 122.4, 113.1, 107. 50.8, 41.3, 10. · 2.7. Mass spectrum 3 8 3.1 6 (MH) Prepared in a similar way = (±) — 2 —amino — 3 — [1- (2-trimethylsilyl-ethanesulfonyl) — 1 fluorene — indazole — 5 —yl] methyl propionate

W-NMR ( CD3CN，5 00MHz ) 5 8 · 3 4 ( s，1 Η ) ，7.98 ( d，J 二 8·6Ηζ，1 Η ) ，7.69 ( s ^ 1 Η ) ，7.46 ( dd ^ J = 8.6 ，1.5Hz，1Η) ，3.71 (dd，J二 7.3，5·8Ηζ，1Η) ，3.65 (s，3H) ，3.48-3.44( m，2H) ，3.12(dd，J=13.7 ，5.8Hz，1H) ，2.97 (dd，J = 13.7，7·6Ηζ，1H) ，0.83 —0.7 9 ( m，2 H ) ，- 0.0 2 ( s，9 H )。 -84- 200529835 (80) 13C-NMR ( CDC13 ? 125MHz ) (5 1 7 5 · 9， 1 4 1 . 1，1 4 0.5， 134.6，131.5，126.0，122.2，112.7，56.4，51.8，51.1 ，40.9，9.8，-2.6。質譜 384·15(ΜΗ) +。 (R) — 2 —苄氧羰基胺基一 3-〔1一 （2 —三甲基甲矽烷 基一乙烷磺醯基）一 1 Η —吲唑一 5 —基〕一丙酸甲酯W-NMR (CD3CN, 5000 MHz) 5 8 · 3 4 (s, 1 Η), 7.98 (d, J 2 8. 6 Η ζ, 1 Η), 7.69 (s ^ 1 Η), 7.46 (dd ^ J = 8.6 , 1.5Hz, 1Η), 3.71 (dd, J 2 7.3, 5 · 8Ηζ, 1Η), 3.65 (s, 3H), 3.48-3.44 (m, 2H), 3.12 (dd, J = 13.7, 5.8Hz, 1H ), 2.97 (dd, J = 13.7, 7.6 Ηζ, 1H), 0.83-0.79 (m, 2H), -0.02 (s, 9H). -84- 200529835 (80) 13C-NMR (CDC13-125MHz) (5 1 7 5 · 9, 1 4 1. 1, 1 4 0.5, 134.6, 131.5, 126.0, 122.2, 112.7, 56.4, 51.8, 51.1, 40.9 , 9.8, -2.6. Mass spectrum 384 · 15 (ΜΗ) +. (R) — 2-benzyloxycarbonylamino — 3- [1- (2-trimethylsilyl-ethanesulfonyl) —1 Η —Indazole-5 —yl] monopropionate

於經3次真空/氮氣淸洗循環處理之手套袋中，對配 備有攪拌磁石之AIRFREE ® ( Schlenk )反應燒瓶載入（ 一）一1，2 -雙（2R，5R) - 2，5 —二乙基磷烷並（ phospholano )苯（環辛二烯）铑（I )三氟甲基磺酸酯（ 123 mg，0.1 7毫莫耳，5莫耳％ )，並以橡膠隔板密封， 隨後自該手套袋中取出。將2-苄氧羰基胺基一 3 - 〔1 - (2 —三甲基甲矽烷基一乙烷磺醯基）一 1 Η —吲唑一 5 -基〕一丙烯酸甲酯（1.75 g，3.40毫莫耳）載入第2個配備 有攪拌磁石之AIRFREE ® ( Schlenk )反應燒瓶中並以橡 膠隔板密封。經3次真空/氮氣淸洗循環後，令其溶解於 無水甲醇（75 ml )和無水二氯甲烷（；[5 mi )之混合物中 。該2種溶劑於加入前藉由噴佈氮氣至少1小時以除去氧。 一旦於溶液中’令該混合物再次經3次真空/氮氣淸洗循 -85- 200529835 (81) 環處理。藉由插管將該脫氫胺基酸溶液導入含有該觸媒之 AIRFREE ® ( Schlenk )反應燒瓶中。令該反應混合物經5 次真空/氫氣淸洗循環處理，隨後打開該燒瓶至1大氣壓 氫氣（球形瓶）下。經1 6小時後，藉由3次真空/氮氣淸 洗循環淸洗該反應混合物。蒸發溶劑並藉由管柱層析（梯 度1 : 4乙酸乙酯/己烷至1 : 2乙酸乙酯/己烷）純化殘餘 物以生成白色固體之標的化合物（1.5 g，85%)，其具 有98.4%之對映體過量，其測定係藉由HPLC分析（利用 φ Chirocel OD管柱，80%己烷/20%乙醇爲流洗液；滯留 時間：標的化合物爲13.9分而S對映異構物爲1 1 .2分）。 ]H-NMR ( CDCls J 3 00MHz) 5 8·17 ( s，1H) ，7·98 ( d，J二 8·8Ηζ，1 Η ) ，7.47(s，1 Η ) ，7.35— 7.25 ( m， 6Η ) ，5.29-5.24(m，lH) ，5.08(dd，J=19.0， 12·1Ηζ，1H) ，4·73— 4.67 (m，lH) ，3.73(s，3H)，In a glove bag treated with 3 vacuum / nitrogen purging cycles, load an AIRFREE ® (Schlenk) reaction flask equipped with a stirring magnet into (a) -1,2-double (2R, 5R)-2,5 — Diethylphosphanono benzene (cyclooctadiene) rhodium (I) trifluoromethanesulfonate (123 mg, 0.1 7 millimoles, 5 mole%), and sealed with a rubber separator, It was then removed from the glove bag. 2-Benzyloxycarbonylamino- 3-[1- (2-trimethylsilyl-ethanesulfonyl)-1 fluorene-indazole-5 -yl] monoacrylate (1.75 g, 3.40 Millimoles) were loaded into a second AIRFREE® (Schlenk) reaction flask equipped with a stirring magnet and sealed with a rubber septum. After three vacuum / nitrogen purging cycles, it was dissolved in a mixture of anhydrous methanol (75 ml) and anhydrous dichloromethane (; [5 mi)). The two solvents were sprayed with nitrogen for at least one hour before being added to remove oxygen. Once in the solution ', the mixture was subjected to 3 vacuum / nitrogen purging cycles -85- 200529835 (81). The dehydroamino acid solution was introduced into the AIRFREE ® (Schlenk) reaction flask containing the catalyst through a cannula. The reaction mixture was subjected to 5 vacuum / hydrogen purge cycles, and then the flask was opened to 1 atmosphere of hydrogen (spherical flask). After 16 hours, the reaction mixture was washed by 3 vacuum / nitrogen purge cycles. The solvent was evaporated and the residue was purified by column chromatography (gradient 1: 4 ethyl acetate / hexane to 1: 2 ethyl acetate / hexane) to give the title compound (1.5 g, 85%) as a white solid, which It has an enantiomeric excess of 98.4%, and its determination was performed by HPLC (using a φ Chirocel OD column, 80% hexane / 20% ethanol as the flow eluent; retention time: the target compound is 13.9 points and the S enantiomer The structure is 1 1.2 points). ] H-NMR (CDCls J 3 00MHz) 5 8 · 17 (s, 1H), 7.98 (d, J 2 8.8Ηζ, 1 Η), 7.47 (s, 1)), 7.35-7.25 (m, 6Η), 5.29-5.24 (m, lH), 5.08 (dd, J = 19.0, 12.1 · ζ, 1H), 4.73-4.67 (m, lH), 3.73 (s, 3H),

3.38— 3.32( m，2H) ，3.29(dd，J=14.2，5.6Hz，lH )，3.19(dd，J=13.9，5·6Ηζ，1H) ，0.91- 0.85 (m， · 2H ) ，-0.02(s，9H)。質譜：518(MH) +。 (R) — 2—胺基一3— 〔1— (2 —三甲基甲矽烷基一乙烷 磺醯基）一 1 Η —吲唑一 5 -基〕丙酸甲酯3.38— 3.32 (m, 2H), 3.29 (dd, J = 14.2, 5.6Hz, 1H), 3.19 (dd, J = 13.9, 5. · 6Ηζ, 1H), 0.91-0.85 (m, · 2H), -0.02 (s, 9H). Mass spectrum: 518 (MH) +. (R) — 2—Amine—3— [1— (2-trimethylsilyl monoethanesulfonyl) — 1 1 —Indazole—5-yl] propanoic acid methyl ester

於5 0 p s i氫氣下，利用P a 1· 1·氣化器’搖動（R ) — 2 — -86- 200529835 (82) 苄氧羰基胺基一 3 — 〔1 一 （2—三甲基甲矽烷基一乙烷磺 醯基）一1H —吲唑一 5 —基〕—丙酸甲酯（1.24 g，2.40 毫莫耳）和10%Pd/C(124mg)之甲醇（50 ml)混合物 2 /J、時。利用3次真空/氮氣淸洗循環淸洗該反應混合物。 經由通過寅氏鹽墊過濾該反應混合物，隨後利用數份甲醇 輕洗該寅氏鹽墊。蒸發甲醇濾液生成黏性膠之標的化合物 (879mg，96%) 0 】H-NMR ( CDC13，3 00MHz ) 5 8.21 ( s，1H) ，8.02 ( · d，J=8.8Hz，1H) ，7.59(s，1H) ，7.38( d，J=8.8Hz ，：IH) ，3.72(s，lH) ，3.38—3.32(m，2H) ，3.21( dd，J=13.9，5.1Hz，1H) ，2.98(dd，J=13.9，7.9Hz ，1H) ，〇·91— 0.85(m，2H) ，-0.02(s，9H)。質譜 :3 84 ( ΜΗ ) +。 7 —甲基一 2— (2—三甲基甲矽烷基一乙烷磺醯基一 2H — 吲唑—5 -醛 ®Under 50 psi hydrogen, use a Pa 1 · 1 · gasifier to shake (R) — 2 — -86- 200529835 (82) benzyloxycarbonylamino — 3 — [1 1 (2-trimethylformyl) Mixture of silyl monoethane sulfonyl) -1H-indazole-5-yl] -propionate (1.24 g, 2.40 mmol) and 10% Pd / C (124 mg) in methanol (50 ml) 2 / J 、 时. The reaction mixture was purged with 3 vacuum / nitrogen purging cycles. The reaction mixture was filtered by passing through a Yin's salt pad, and then the Yin's salt pad was gently washed with several portions of methanol. Evaporation of the methanol filtrate yielded the target compound of viscous gum (879 mg, 96%). 0] H-NMR (CDC13, 3 00MHz) 5 8.21 (s, 1H), 8.02 (· d, J = 8.8Hz, 1H), 7.59 ( s, 1H), 7.38 (d, J = 8.8Hz ,: IH), 3.72 (s, lH), 3.38-3.32 (m, 2H), 3.21 (dd, J = 13.9, 5.1Hz, 1H), 2.98 ( dd, J = 13.9, 7.9 Hz, 1H), 0.91-0.85 (m, 2H), -0.02 (s, 9H). Mass spectrum: 3 84 (ΜΗ) +. 7-methyl-1 2- (2-trimethylsilyl-ethanesulfonyl-2H-indazole-5-aldehyde ®

將三乙胺（7.83 ml，56.2毫莫耳，3當量）加入至7 — 甲基吲唑一 5—醛（3.0 g，18.7毫莫耳）之二氯甲烷（150 懸浮液中，隨後逐滴地加入純2 —三甲基甲矽烷基-乙烷磺醯氯（5.60 g，28.1毫莫耳’ 1.5當量）。該混合物 逐漸地呈均質狀並於室溫下攪拌]6小時。濃縮該溶液至最 少量之二氯甲烷，隨後經矽膠閃蒸管柱層析（1 : 4乙酸乙 -87 - (83) (83)200529835 酯/己烷），生成灰黃色固體之產物（4.7 g，77% )。 】H-NMR ( CDC13，3 00MHz) δ 9.98 ( s，1Η ) ，8.77 ( s ，1 H ) ，8.09(s，1 H ) ，7.64(s，1 H ) ，3.64-3.58( m，2H) ，2.65(s，3H) ，0·88— 0.82 ( m，2H) ，0.〇l (s ， 9H)。 2 —苄氧羰基胺基一3— 〔7 —甲基一2 — （2—三甲基甲矽 烷基一乙烷磺醯基）一 2H —吲唑—5 -基〕一丙烯酸甲酯Triethylamine (7.83 ml, 56.2 mmol, 3 equivalents) was added to a suspension of 7-methylindazole-5aldehyde (3.0 g, 18.7 mmol) in methylene chloride (150 suspension, followed by dropwise Add pure 2-trimethylsilyl-ethanesulfonyl chloride (5.60 g, 28.1 millimoles' 1.5 equivalents). The mixture is gradually homogeneous and stirred at room temperature] for 6 hours. The solution is concentrated To a minimum amount of dichloromethane, and then subjected to silica gel flash column chromatography (1: 4 ethyl acetate-87-(83) (83) 200529835 ester / hexane) to give the product as an off-white solid (4.7 g, 77 %).] H-NMR (CDC13, 3 00MHz) δ 9.98 (s, 1Η), 8.77 (s, 1 H), 8.09 (s, 1 H), 7.64 (s, 1 H), 3.64-3.58 (m , 2H), 2.65 (s, 3H), 0.88—0.82 (m, 2H), 0.01 (s, 9H). 2—Benzyloxycarbonylamino—3— [7—Methyl—2— (2-trimethylsilyl-ethanesulfonyl)-2H-indazole-5 -yl] monoacrylate

將四甲基胍（1.78 ml，1.05當量）加入至N—(苄氧 羰基）一 α —亞磷羧基甘胺酸三甲酯（4.93 g，14·9毫莫 耳，1.4當量）之無水四氫呋喃（75 ml )·.溶液中。於室溫 和氮氣下，攪拌該混合物5分鐘並隨後冷卻至一 7 8 °經 於一 7 8 °C。經於—Μ °C下攪拌1 5分鐘後，加入7 —甲基一 2 一 （2—三甲基甲石夕院基一乙院擴釀基）一 2H—卩引卩朵一 5 -醛之四氫呋喃（2 5 ml )溶液。令該反應混合物隔夜緩 慢地回溫至室溫。雖然反應未完全’蒸發溶劑。令所生成 殘餘物溶解於乙酸乙酯中並利用1 Μ硫酸進行冲洗。分離 有機層，置於MgS〇4上乾燥’並進行過濾和蒸發。經閃蒸 管柱層析（】：4乙酸乙酯/己丨完）生成白色玻璃狀'泡沬之 產物（2.66g，37%)。 }H-NMR ( CDCh ^ 3 00MHz ) δ 8.48 ( s，1 Η ) ，7.62 ( s 200529835 (84) ，1Η) ，7·38— 7.25 (m，7H) ，6.48(bs，lH) ，5·10 (s，2H) ，3.83(s，3H) ，3.58-3.52(m，2H)， 2.51(s，3H) ，0.89-0.83( m，2H) ，0.02(s，9H) 。質譜：530(MH)+。 (R) —2 —苄氧羰基胺基_3— 〔7 —甲基一 2 — （2—三甲 基甲矽烷基一乙烷磺醯基）—2H —吲唑一 5 -基〕丙酸甲Tetramethylguanidine (1.78 ml, 1.05 eq.) Was added to anhydrous tetrahydrofuran N- (benzyloxycarbonyl) -α-phosphorous carboxyglycine trimethyl ester (4.93 g, 14.9 mmol, 1.4 eq.) (75 ml) .. in solution. The mixture was stirred at room temperature under nitrogen for 5 minutes and then cooled to 178 ° C over 178 ° C. After stirring at -M ° C for 15 minutes, 7-methyl-1 2- (2-trimethylmethylate and 1st ethyl alcohol)-2H-pyridine-5-aldehyde Tetrahydrofuran (25 ml) solution. The reaction mixture was allowed to slowly warm to room temperature overnight. Although the reaction was not complete 'the solvent was evaporated. The resulting residue was dissolved in ethyl acetate and washed with 1 M sulfuric acid. The organic layer was separated, dried over MgS04 and filtered and evaporated. After flash column chromatography (]: 4 ethyl acetate / hexane), a white glassy product (2.66 g, 37%) was obtained. } H-NMR (CDCh ^ 3 00MHz) δ 8.48 (s, 1 Η), 7.62 (s 200529835 (84), 1 Η), 7.38-7.25 (m, 7H), 6.48 (bs, 1H), 5. · 10 (s, 2H), 3.83 (s, 3H), 3.58-3.52 (m, 2H), 2.51 (s, 3H), 0.89-0.83 (m, 2H), 0.02 (s, 9H). Mass spectrum: 530 (MH) +. (R) —2 —Benzyloxycarbonylamino — 3 — [7 —Methyl-2 — (2-trimethylsilylmonoethanesulfonyl) —2H —indazol-5-yl] propanoic acid A

於經3次真空/氮氣淸洗循環處理之手套袋中，對配 備有攪拌磁石之AIRFREE ® ( Schlenk )反應燒瓶載入（ —)-1，2 -雙（2R，5R ) — 2，5 - 二乙基磷院並（ phospholano )苯（環辛二烯）铑（I )三氟甲基磺酸酯（ 2 5 9 mg，0.36毫莫耳，9莫耳％ )，並以橡膠隔板密封， 隨後自該手套袋中取出。將2-苄氧羰基胺基一 3 - 〔7-甲基一 2 — （2 —三甲基甲矽烷基一乙烷磺醯基）一 1H — 吲唑一 5 —基〕一丙烯酸甲酯（2.03 g，3.83毫莫耳）載入 第2個配備有攪拌磁石之AIRFREE ® ( Schlenk )反應燒瓶 中並以橡膠隔板密封。經3次真空/氮氣淸洗循環後，令 其溶解於無水甲醇（8 0 ml，其於加入前藉由噴佈氮氣至 少1小時以除去氧）。一旦於溶液中，令該混合物再次經3 次真空/氮氣淸洗循環處理。藉由插管將該脫氫胺基酸溶 -89- 200529835 (85) 液轉移至含有該觸媒之AIRFREE ® ( Schlenk )反應燒瓶 中。令該反應混合物經5次真空/氫氣淸洗循環處理，隨 後打開該燒瓶至1大氣壓氫氣球形瓶下。經2.5小時後，藉 由3次真空/氮氣淸洗循環淸洗該反應混合物。蒸發溶劑 並藉由管柱層析（梯度1: 4乙酸乙酯/己烷至1: 2乙酸乙 酯/己烷）純化殘餘物以生成白色固體之標的化合物（ 1.4 g，68%，99.2% 對映體過量）。In a glove bag treated with 3 vacuum / nitrogen purging cycles, load (—)-1, 2-double (2R, 5R) — 2, 5-into an AIRFREE ® (Schlenk) reaction flask equipped with a stirring magnet. Diethylphosphine (phosphoolano) benzene (cyclooctadiene) rhodium (I) trifluoromethanesulfonate (259 mg, 0.36 mmol, 9 mole%) and sealed with a rubber separator Then remove it from the glove bag. 2-benzyloxycarbonylamino- 3-[7-methyl-2-(2-trimethylsilyl-ethanesulfonyl)-1H-indazole-5 -yl] methyl acrylate ( 2.03 g, 3.83 mmol) was loaded into a second AIRFREE ® (Schlenk) reaction flask equipped with a stirring magnet and sealed with a rubber septum. After 3 vacuum / nitrogen purging cycles, it was dissolved in anhydrous methanol (80 ml, which was removed by spraying nitrogen for at least 1 hour before adding oxygen). Once in solution, the mixture was again subjected to 3 vacuum / nitrogen purge cycles. The dehydroamino acid-soluble-89-200529835 (85) solution was transferred into a AIRFREE® (Schlenk) reaction flask containing the catalyst by cannula. The reaction mixture was subjected to 5 vacuum / hydrogen purge cycles, and then the flask was opened under a 1-atmospheric hydrogen balloon. After 2.5 hours, the reaction mixture was purged by 3 vacuum / nitrogen purging cycles. The solvent was evaporated and the residue was purified by column chromatography (gradient 1: 4 ethyl acetate / hexane to 1: 2 ethyl acetate / hexane) to give the title compound as a white solid (1.4 g, 68%, 99.2% Enantiomeric excess).

j-NMR ( CDC13，3 00MHz ) 5 8.43 ( s，1H ) ，7.34 ( s ，5H) ，7.19(s，lH) ，6.87(s，lH) ，5.24(d，J = 8.1Hz，1 H ) ，5.08(dd，J=18.3，12·1Ηζ，1 H ) ，4.67 (dd，J=13.9，6·2Ηζ，1 H ) ，3.73 (s，1 H ) ，3.57 - 3.51(ni，2H) ，3.16(dd，J=14.0，5.9Hz，lH)， 3.06 (dd，J=13.9，6.6Hz，1H) ，2.55 (s，3H ) ，0.89 —0.83(m，2H) ，0.01(s，9H)。j-NMR (CDC13, 3 00MHz) 5 8.43 (s, 1H), 7.34 (s, 5H), 7.19 (s, lH), 6.87 (s, lH), 5.24 (d, J = 8.1 Hz, 1 H) , 5.08 (dd, J = 18.3, 12.1Ηζ, 1 H), 4.67 (dd, J = 13.9, 6. · 2Ηζ, 1 H), 3.73 (s, 1 H), 3.57-3.51 (ni, 2H), 3.16 (dd, J = 14.0, 5.9Hz, 1H), 3.06 (dd, J = 13.9, 6.6Hz, 1H), 2.55 (s, 3H), 0.89-0.83 (m, 2H), 0.01 (s, 9H) .

】3C-NMR ( CDC13，75MHz ) δ 1 7 2 · 0，1 5 5.7，1 5 1 · 7， 136.2，132.2，129.8，129.5，1 2 8 · 6，1 2 8 · 4，1 2 8 · 2， 125.1 ， 121.1 ， 118.1 ， 67.1 ， 54·7， 52.5 ， 51.1 ， 38.6， 17.1，9.7，-2.0。質譜：532(^[11) +。 (R) — 2—胺基一 3—〔7—甲基—2 — （2 —三甲基矽烷基 一乙烷磺醯基）一 2H -吲唑一 5 —基〕丙酸甲酯] 3C-NMR (CDC13, 75MHz) δ 1 7 2 · 0, 1 5 5.7, 1 5 1 · 7, 136.2, 132.2, 129.8, 129.5, 1 2 8 · 6, 1 2 8 · 4, 1 2 8 · 2, 125.1, 121.1, 118.1, 67.1, 54.7, 52.5, 51.1, 38.6, 17.1, 9.7, -2.0. Mass spectrum: 532 (^ [11) +. (R) — 2-aminoamino 3- [7-methyl-2 — (2-trimethylsilyl monoethanesulfonyl)-2H-indazol 5-yl] propanoic acid methyl ester

-90-· 200529835 (86) 於55 psi氫氣壓下，利用Parr裝置搖動2—苄氧羰基胺 基一 3 — 〔7—甲基一 2 — （2—三甲基甲砂院基一乙院磺醯 基）一2H—吲唑一 5 —基〕一丙烯甲酯（1.35 g，2.54毫 莫耳）和10%Pd/C(135 mg)之甲醇（40 ml)溶液3小 時。利用3次真空/氮氣淸洗循環淸洗該反應混合物。經 由通過寅氏鹽墊過濾該反應混合物並利用數份甲醇輕洗該 墊。蒸發該甲醇濾液以生成黏性膠之標的化合物（1.0 1 g ，定量產率）。 j-NMR ( CDC13，3 00MHz ) 5 8.45 ( s，1 Η ) ，7·29 ( s ，：ΙΗ) ，6.97(s，lH) ，3.79—3.73 (m，lH) ，3·73( s，3H) ，3.56— 3.50(m，2H) ，5.12(dd，J=13.5， 5·12Ηζ，1H) ，4.85(dd，J=13.5，8·1Ηζ，1 H ) ，2,58 (s，3H) ，0.87—0.81 (m，2H) ，0.01(s，9H)。 13C-NMR ( CDC13，75MHz ) 5 175.5， 151.8， 133.7， 129.9，129.4，125.0，121.3，117.9，55.5，52.1，51.1 ，41.4，17.1，9.8，-2.1。質譜：398(1\411) +。 _ (R) — 3— 〔7—甲基一2— (2—三甲基甲砂院基一乙院 磺醯基）一2H —吲唑一 5 —基〕一 2— { 〔4— (2—酮基 —1，4 一二氫一 2H —喹唑啉—3 —基）—哌啶—1 一羰基 〕一胺基} 一丙酸甲酯 200529835 (87)-90- · 200529835 (86) Under 55 psi hydrogen pressure, shake the 2-benzyloxycarbonylamino group 3-[7-methyl-2-(2-trimethylmethanamine, 1st-2nd) with Parr device. A solution of sulfofluorenyl) -2H-indazol-5-yl] -propenyl methyl ester (1.35 g, 2.54 mmol) and 10% Pd / C (135 mg) in methanol (40 ml) for 3 hours. The reaction mixture was purged with 3 vacuum / nitrogen purging cycles. The reaction mixture was filtered through a Yin's salt pad and the pad was gently washed with several portions of methanol. The methanol filtrate was evaporated to give the target compound of viscous gum (1.0 1 g, quantitative yield). j-NMR (CDC13, 3 00MHz) 5 8.45 (s, 1 Η), 7.29 (s ,: 1Η), 6.97 (s, 1H), 3.79-3.73 (m, 1H), 3.73 (s, 3H), 3.56-3.50 (m, 2H), 5.12 (dd, J = 13.5, 5.12Ηζ, 1H), 4.85 (dd, J = 13.5, 8 · 1Ηζ, 1H), 2,58 (s, 3H ), 0.87—0.81 (m, 2H), 0.01 (s, 9H). 13C-NMR (CDC13, 75MHz) 5 175.5, 151.8, 133.7, 129.9, 129.4, 125.0, 121.3, 117.9, 55.5, 52.1, 51.1, 41.4, 17.1, 9.8, -2.1. Mass spectrum: 398 (1 \ 411) +. _ (R) — 3— [7-methyl-1 2- (2-trimethylmethanyl, 1B, sulfonyl), 2H —indazole, 5 —yl], 2— {〔4— ( 2-keto-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 monocarbonyl] monoamino} methyl propionate 200529835 (87)

och3 室溫下攪拌2 —胺基一 3— 〔7 —甲基一 2— (2—三甲 基甲矽烷基一乙烷磺醯基）一 2H -吲唑一 5 —基〕一丙酸 甲酯（500 mg，1.26毫莫耳）、N，N —二異丙基乙胺（ 0.66 ml，3.77毫莫耳）及二琥珀醯亞胺碳酸酯（322 mg， 1.26毫莫耳）之二氯甲院（20 ml)混合物30分鐘。隨後 加入3 —[根B定一4 一基一3，4 一 一^氯一1H —喧口坐琳一 2-嗣 (4 44 mg，1.3 5毫莫耳）並於室溫下隔夜攪拌該反應混合 物。蒸發溶劑並藉由閃蒸管柱層析（1 : 4丙酮/乙酸乙酯 )純化殘餘物以生成白色固體之標的化合物（490 mg，60 %產率）。 j-NMR ( CDC13，3 00MHz ) δ 8·47 ( s，1 Η ) ，7.23 ( s ，：ΙΗ) ，7.19—7.14(m，lH) ，7.04(d，J=7.3Hz，1Ηoch3 Stir at room temperature 2-amino-3- [7-methyl-2- (2-trimethylsilyl-ethanesulfonyl)-2H-indazole-5-yl] monopropionate Dichloride (500 mg, 1.26 mmol), N, N-diisopropylethylamine (0.66 ml, 3.77 mmol) and disuccinimide carbonate (322 mg, 1.26 mmol) of dichloride A hospital (20 ml) mixture for 30 minutes. Then add 3— [root B, a 4-base, a 3-, 4-a, chloro-1H, and a saurian sorrel—2— 嗣 (4 44 mg, 1.35 mmol) and stir the mixture overnight at room temperature. Reaction mixture. The solvent was evaporated and the residue was purified by flash column chromatography (1: 4 acetone / ethyl acetate) to give the title compound (490 mg, 60% yield) as a white solid. j-NMR (CDC13, 3 00MHz) δ 8.47 (s, 1 Η), 7.23 (s ,: 1Η), 7.19-7.14 (m, lH), 7.04 (d, J = 7.3Hz, 1Η

)，6·97— 6·93(ηι，2Η) ，6.77(s，lH) ，6.65(d，J = 7·7Ηζ，1H ) ，4.99 ( d ^ J=7.3Hz，1 H ) ，4.8 1 (dd， J=13.5，6·2Ηζ，1H) ，4.58— 4.46( m，1H) ^ 4.27 ( s ，2H) ，4.10-3.98(m，2H) ，3.73(s，2H) ，3.57- 3 . 5 1 ( ni，2 H ) ，3 . 1 4 — 3 . 1 1 ( m，2 H ) ，2 · 9 5 — 2.8 3 ( m ，2H) ，2.58(s，3H) ，1·77— 1·65(ηι，4Η) ，0·92 — -92- (88) 200529835 0.84( m，2H) ，-0.01(s，9H)。質譜：655(MH)4。 類似之方法製備： (±) — 2— { 〔4— (2 —酮基一1，4 —二氫一2H — D奎唑 啉一3 —基）—哌啶一 1—羰基〕—胺基} 一3—〔1 一（2 一三甲基甲矽烷基一乙烷磺醯基）一1 Η —吲哚一 5 —基〕 一丙酸甲酯), 6.97-6.93 (η, 2Η), 6.77 (s, 1H), 6.65 (d, J = 7.7Ηζ, 1H), 4.99 (d ^ J = 7.3Hz, 1H), 4.81 (dd, J = 13.5, 6.2Ηζ, 1H), 4.58—4.46 (m, 1H) ^ 4.27 (s, 2H), 4.10-3.98 (m, 2H), 3.73 (s, 2H), 3.57-3. 5 1 (ni, 2 H), 3. 1 4 — 3.. 1 1 (m, 2 H), 2. 9 5 — 2.8 3 (m, 2H), 2.58 (s, 3H), 1.77— 1 65 (η, 4 ，), 0.92 — -92- (88) 200529835 0.84 (m, 2H), -0.01 (s, 9H). Mass spectrum: 655 (MH) 4. Prepared in a similar way: (±) — 2— {[4 -— (2-keto-1,4-dihydro-2H—D quinazoline-3—yl) —piperidine-1—carbonyl] —amino } —3- (1— (2-trimethylsilyl-ethanesulfonyl) —1—fluorene-indole-5—yl] monopropionate

HH

】H-NMR ( CD3OD，5 00ΜΗζ ) ό 7.85 ( d，J= 8·2Ηζ， 1 Η ) ，7.55(s，lH) ，7.51(d，J=3.7Hz，lH) ，7.27 (dd，J=8.6，1·5Ηζ，]H) ，7.16(t，J二 7.6Hz，1H) ，7.10 (d，J 二 7.6Hz，1 H ) ，6.95 (t，J 二 7.6Hz，1 Η ) ，6.79 (d，J - 8.0Hz ^ 1 H ) ，6.73 (d，J=3.7Hz，1 H ) ，4.44— 4.38 (m，1 H ) ，4.26 (s，2H ) ，4.13- 4.08 ( m，2H) ，3.73(s，lH) ，3.34-3.29 (m，4H) ，3·13 (dd，J=13.5，9.4Hz，]H) ，2.89-2.79( ηι，2H )， 1.76— 1.70(m，lH) ，：1.63— 1.59(m，3H) ，0·76 — 0.72 (m，2H) ，-0.07(s，9H)。質譜：640.40 (MH ) -93- 200529835 (89) (R) — 2- {4— (2 —酮基一 1，4 —二氫一2H —喹唑啉 =3—基）一 P底 D定一 1 一 基〕一胺基} 一 3—〔1— (2 — 三甲基甲矽烷基一乙烷磺醯基）一 1 Η —吲唑一 5 —基〕— 丙酸甲酯] H-NMR (CD3OD, 500M 00ζ) 7.85 (d, J = 8.2Ηζ, 1 ，), 7.55 (s, 1H), 7.51 (d, J = 3.7Hz, 1H), 7.27 (dd, J = 8.6, 1.5Ηζ,] H), 7.16 (t, J 7.6Hz, 1H), 7.10 (d, J 7.6Hz, 1H), 6.95 (t, J 7.6Hz, 1 Η), 6.79 ( d, J-8.0Hz ^ 1 H), 6.73 (d, J = 3.7Hz, 1 H), 4.44— 4.38 (m, 1 H), 4.26 (s, 2H), 4.13- 4.08 (m, 2H), 3.73 (s, lH), 3.34-3.29 (m, 4H), 3.13 (dd, J = 13.5, 9.4Hz,] H), 2.89-2.79 (η, 2H), 1.76-1.70 (m, lH) : 1.63— 1.59 (m, 3H), 0.76—0.72 (m, 2H), -0.07 (s, 9H). Mass spectrum: 640.40 (MH) -93- 200529835 (89) (R) — 2- {4 -— (2-keto-1,4-dihydro-1H—quinazoline = 3-yl) -1-1 -yl] -amino}-3-[1-(2-trimethylsilyl-ethanesulfonyl)-1-fluorene-indazole-5 -yl]-methyl propionate

室溫下攪拌（R) — 2 —胺基一 3 - 〔1 一 （2 —三甲基 甲矽烷基一乙烷磺醯基）一 1 Η -吲唑一 5 —基〕一丙酸甲 酯（764 mg，1.99毫莫耳）、N，N —二異丙基乙胺（1·10 ml，5·97毫莫耳）及二琥珀醯亞胺碳酸酯（ 509 mg，1.99 毫莫耳）之二氯甲烷（20 ml)溶液40分鐘。隨後加入3 — 定一 4 一基—3，4 一二氫—1H - D奎 D坐啉一 2 —酮（70% 純度，7 03 mg，2.13毫莫耳），並於室溫下隔夜攪拌該反 應以生成標的化合物（1.15 g，90% )。 'H-NMR ( CDCI3 5 3 00MHz ) ά 8.21 ( s，ih ) ，8.01 ( d，J=8.5Hz，1H) ，7.53 (s，1H) ，7.32(d，J=8.5Hz ’ 1H) ’ 7.16(t，J=7.8Hz，IH) ，7.〇6(d，J=7.6Hz ，：IH) ，6.95(d，J=7.6Hz，lH) ，6.76(s，1H)， 6.65 (d，J=7.9Hz，1 H ) ，5.01 (d，J = 7.6 Hz ? IH)， -94- 200529835 (90)Stir at room temperature (R) — 2-aminoamino-3-[1-mono (2-trimethylsilyl-ethanesulfonyl)-1 hydrazone-indazole-5-yl] monopropionate (764 mg, 1.99 mmol), N, N-diisopropylethylamine (1 · 10 ml, 5.97 mmol) and disuccinimidyl carbonate (509 mg, 1.99 mmol) Dichloromethane (20 ml) solution for 40 minutes. Then add 3-dichloro-4, 3-dihydro-3, 4-dihydro-1H-D, quinoline, and 2-sitolin-2-one (70% purity, 7 03 mg, 2.13 mmol), and stir overnight at room temperature. This reaction yielded the target compound (1.15 g, 90%). 'H-NMR (CDCI3 5 3 00MHz) ά 8.21 (s, ih), 8.01 (d, J = 8.5Hz, 1H), 7.53 (s, 1H), 7.32 (d, J = 8.5Hz' 1H) '7.16 (t, J = 7.8Hz, IH), 7.06 (d, J = 7.6Hz ,: IH), 6.95 (d, J = 7.6Hz, 1H), 6.76 (s, 1H), 6.65 (d, J = 7.9Hz, 1 H), 5.01 (d, J = 7.6 Hz? IH), -94- 200529835 (90)

4.84(dd，J 二 13.1，6.0Hz，1H) ，4.56-4.49( m，lH )，4.28(s，2H) ，4.13-3.98 (m，2H) ，3.73(s， 3H ) ，3.3 9 - 3.3 5 (m，2H ) ，3.28 (dd，J 二 14.0， 6.1Hz，1 H ) ，3.24 ( dd ^ J=13.7，5.8Hz，1 H ) ^ 2.94- 2.87(m，2H) ，1.75— 1.67(m，4H) ，0·91 — 0.87(m ，2H) ，-0.02(s，9H)。質譜：641(MH)+。 類似之方法製備： (±) — 2{ 〔4— (2 —酮基一2，3 —二氫一苯並咪唑一 1 一基）一哌啶一 1—羰基〕一胺基} — 3 —〔1 一（2 —三甲 基甲矽烷基一乙烷磺醯基）一1 Η —吲哚一5 —基〕丙酸甲 酯4.84 (dd, J, 13.1, 6.0Hz, 1H), 4.56-4.49 (m, lH), 4.28 (s, 2H), 4.13-3.98 (m, 2H), 3.73 (s, 3H), 3.3 9-3.3 5 (m, 2H), 3.28 (dd, J 2 14.0, 6.1 Hz, 1 H), 3.24 (dd ^ J = 13.7, 5.8 Hz, 1 H) ^ 2.94- 2.87 (m, 2H), 1.75-1.67 ( m, 4H), 0.91-0.87 (m, 2H), -0.02 (s, 9H). Mass spectrum: 641 (MH) +. Prepared in a similar manner: (±) — 2 {[4- (2-keto-2,3-dihydro-benzimidazole-1 1-yl) -piperidine-1—carbonyl] -amino}} 3— [1- (2-trimethylsilyl-ethanesulfonyl)-1-fluorene-indole-5-yl] methyl propionate

】H-NMR ( CD3CN，5 00MHz ) ά 9 · 7 8 ( s，1 Η ) ，7.86 ( d，J=8.8Hz，lH) ，7.56(s，lH) ，7.49(d，J=3.7Hz ，1H) ，7.28(dd，J=8.5，1.5Hz，lH) ，7·10— 7.08( m，1 H ) ，7.05— 7.03 (m，1H) ，6.99— 6·97 (ni，2H) ，6.70 (d，J=3.7Hz，1 H ) ，5.9 1 (d，J=7.9Hz，1 H ) ，4.66(q，J=8.2Hz，1 H ) ，4.45— 4.39( ni，1 H )， -95- (91) 200529835 4.14(brs，lH) ，3.68(s，3H) ，3.36—3.32 )，3.27(dd，J=14.0，5.5Hz，lH) ，3.18( 13.7，8.5Hz，1H) ，2.90— 2.84 (m，2H) ，2.5 1 H ) ，2.36—2.21 (m，2H) ^ 1 .74 - 1 .70 ( m 0.82— 0.78 (m，2H) ，-0.09(s，9H)。質譜： (ΜΗ ) + 。 (±) — 2— { 〔4 —酮基一2，3 —二氫一苯並明 基）—哌啶一 1 一羰基〕一胺基} — 3—〔1 一（2 甲矽烷基一乙烷磺醯基）一 1 Η —吲唑—5 -基〕 酯 (m，2H dd，J = ;5 ( b r s， ，2H )， 626.26 :口坐—i _ 一三甲基 一丙酸甲] H-NMR (CD3CN, 500 MHz) ά 9 · 7 8 (s, 1 Η), 7.86 (d, J = 8.8Hz, lH), 7.56 (s, lH), 7.49 (d, J = 3.7Hz, 1H), 7.28 (dd, J = 8.5, 1.5Hz, 1H), 7.10—7.08 (m, 1H), 7.05—7.03 (m, 1H), 6.99-6.97 (ni, 2H), 6.70 (d, J = 3.7Hz, 1 H), 5.9 1 (d, J = 7.9Hz, 1 H), 4.66 (q, J = 8.2Hz, 1 H), 4.45-4.39 (ni, 1 H),- 95- (91) 200529835 4.14 (brs, lH), 3.68 (s, 3H), 3.36-3.32, 3.27 (dd, J = 14.0, 5.5Hz, lH), 3.18 (13.7, 8.5Hz, 1H), 2.90 — 2.84 (m, 2H), 2.5 1 H), 2.36—2.21 (m, 2H) ^ 1.74-1.70 (m 0.82—0.78 (m, 2H), -0.09 (s, 9H). Mass spectrum: (ΜΗ) +. (±) — 2— {[4-keto-2,3-dihydro-benzobenzyl) —piperidine-1 monocarbonyl] monoamino} — 3— [1 Silyl-ethane-sulfonyl)-1 fluorene-indazol-5-yl] ester (m, 2H dd, J =; 5 (brs,, 2H), 626.26: 口 坐 —i _ one trimethyl one Methyl propionate

W-NMR ( CD3CN，5 00MHz ) 5 9.61 ( brs，1 Η (s，lH) ，8.00(d，J=8.5Hz，lH) ，7.74( ，7.51 ( dd，J - 8.8 ^ 1.5Hz，1 H ) ，7.10- 7.06 )，7.05— 7.02 (m，1H) ，7.00 — 6.97 ( ni， 5.90n(d，J 二 7·9Ηζ，1H) ，4.67— 4.62 (m， 4.42— 4.36 (m，]H) ，4.13— 4.07(brs，lH)， ，3 H ) ，3.4 5 - 3 . 4 2 ( m，2 H )， )，8.35 s，1 Η ) (m，1 Η 2Η )， 1 Η )， 3.68 ( s 3.30 ( dd，J 二 1 4.0， -96- 200529835 (92) 5.8Hz，1 Η ) ，3.20 ( dd ^ J=13.7，8·8Ηζ，1H) ，2.89 —W-NMR (CD3CN, 500 MHz) 5 9.61 (brs, 1 Η (s, 1H), 8.00 (d, J = 8.5Hz, 1H), 7.74 (, 7.51 (dd, J-8.8 ^ 1.5Hz, 1H ), 7.10-7.06), 7.05-7.02 (m, 1H), 7.00-6.97 (ni, 5.90n (d, J 2 7.9.9Ηζ, 1H), 4.67- 4.62 (m, 4.42--4.36 (m,) H ), 4.13—4.07 (brs, 1H),, 3 H), 3.4 5-3.4. 2 (m, 2 H),), 8.35 s, 1 Η) (m, 1 1 2Η), 1 Η), 3.68 (s 3.30 (dd, J 2 1 4.0, -96- 200529835 (92) 5.8Hz, 1 Η)), 3.20 (dd ^ J = 13.7, 8 · 8Ηζ, 1H), 2.89 —

2·84(ηι，2Η) ，2.52(brs，lH) ，2.33—2.23 (m，2H )，：1.72— 1.69( m，2H) ，0.80— 0.76( m，2H)， -0·07 ( s，9H)。質譜：627.2 5 ( MH) +。 (±) 2— { 〔4— (2 —酮基一1，4 —二氫一2H — D奎唑啉 —3 -基）一哌啶一1 一羰基〕一胺基} — 3- 〔1 一 （2 — 三甲基甲矽烷基一乙烷磺醯基）一 1 Η -吲哚一 5 —基〕一 丙酸甲酯2.84 (ηι, 2Η), 2.52 (brs, lH), 2.33—2.23 (m, 2H), 1.72—1.69 (m, 2H), 0.80—0.76 (m, 2H), -0 · 07 (s , 9H). Mass spectrum: 627.2 5 (MH) +. (±) 2— {[4 -— (2-keto-1,4-dihydro-1H—D-quinazolin-3-yl) -piperidine-1 monocarbonyl] monoamine} — 3- [1 Mono (2-trimethylsilyl-ethanesulfonyl)-1 fluorene-indole-5-yl] monopropionate

1 H-NMR ( CD3OD，5 00MHz ) 5 7.85 ( d，J= 8·2Ηζ， 1 Η ) ，7.55(s，lH) ，7.51(d，J=3.7Hz，lH) ，7·27 (dd，J二 8.6，1·5Ηζ，1H) ，7.16(t，J二 7·6Ηζ，1H) ，7.10 (d，J=7.6Hz，1 H ) ，6.95 (t，J=7.6Hz，1 H ) ，6.79(d，J=8.0Hz，lH) ，6.73(d，J=3.7Hz，lH) ，4.44— 4.38 (m，1 H ) ，4.26 ( s ^ 2H ) ，4.13- 4.08 ( m，2 H ) ，3 · 7 3 ( s，3 H ) ，3 · 3 4 — 3.2 9 ( m，4 H ) ，3 . ] 3 (dd，J=13.5，9.4Hz，lH) ，2·89— 2.79( ni，2H)， 1.76— 1.70( m， 1H) ， 1.63— 1.59( m，3H) ，0.7 6 — -97- 200529835 (93) 0.72(m，2H) ，-0.07(s，9H)。質譜：640.40 (ΜΗ ) +。 (±) — 2 — { 〔4— (2 —酮基一 1，4 —二氫一2Η — 口奎唑 啉一3 -基）—哌啶一 1 一羰基〕—胺基} 一 3 —〔 1 — ( 2 —三甲基甲矽烷基一乙烷磺醯基）一 1 Η —吲唑—5 —基〕 丙酸甲酯1 H-NMR (CD3OD, 500 MHz) 5 7.85 (d, J = 8 · 2Ηζ, 1 Η), 7.55 (s, 1H), 7.51 (d, J = 3.7Hz, 1H), 7.27 (dd, J 8.6, 1.5 Ηζ, 1H), 7.16 (t, J 7.6 Η ζ, 1H), 7.10 (d, J = 7.6 Hz, 1 H), 6.95 (t, J = 7.6 Hz, 1 H), 6.79 (d, J = 8.0Hz, lH), 6.73 (d, J = 3.7Hz, lH), 4.44— 4.38 (m, 1 H), 4.26 (s ^ 2H), 4.13-4.08 (m, 2 H) , 3 · 7 3 (s, 3 H), 3 · 3 4 — 3.2 9 (m, 4 H), 3.] 3 (dd, J = 13.5, 9.4 Hz, 1H), 2.89— 2.79 (ni , 2H), 1.76— 1.70 (m, 1H), 1.63— 1.59 (m, 3H), 0.7 6 — -97- 200529835 (93) 0.72 (m, 2H), -0.07 (s, 9H). Mass spectrum: 640.40 (ΜΗ) +. (±) — 2 — {[4— (2 —keto-1,4-dihydro-1, 2Η — or quinazolin-3 —yl) —piperidine — 1 —carbonyl] — amine} — 3 — [ 1 — (2-trimethylsilyl monoethanesulfonyl) — 1 hydrazone —indazol — 5-yl] methyl propionate

HH

S^° )··〜、\〇 】Η - N M R ( C D 3 Ο D，5 0 0 Μ Η ζ ) 5 8 · 3 9 ( d，J 二 0 · 5 Η ζ， 1 Η ) ，8.02(d，J=8.5Hz，1Η) ，7.75(s，1 H ) ，7.52 (dd，J=8」，1.5Hz，1 H ) ，7.14— 7.10 (m，2H)， 6.94 ( t ^ J=7.5Hz，1 H ) ，6.78 (d，J 二 7.5Hz，1 H )， 4.63-4.60 (m，1 H ) ，4.43— 4.37 (m，1 H ) ，4.27 ( s ，2H) ，4.41(brs，lH) ，4.08(brs，lH) ，3.71(s， 1 H ) ，3.47— 3.43 (m，lH) ，3·37— 3.33 (m，lH)，S ^ °) · ~~, \ 〇】 Η-NMR (CD 3 Ο D, 50 0 Μ Η ζ) 5 8 · 3 9 (d, J 2 0 · 5 Η ζ, 1 Η), 8.02 (d , J = 8.5Hz, 1Η), 7.75 (s, 1 H), 7.52 (dd, J = 8 ″, 1.5Hz, 1 H), 7.14— 7.10 (m, 2H), 6.94 (t ^ J = 7.5Hz , 1 H), 6.78 (d, J 7.5 Hz, 1 H), 4.63-4.60 (m, 1 H), 4.43— 4.37 (m, 1 H), 4.27 (s, 2H), 4.41 (brs, lH ), 4.08 (brs, lH), 3.71 (s, 1H), 3.47-3.43 (m, lH), 3.37-3.33 (m, lH),

3.18 (dd，J 二 13.5，10_0Hz，1H) ，2.8 7— 2.79( m，2H )，1.73— 1.59( m，4H) ，0.80— 0.75 ( m，2H)， -0.05 ( s，9H )； 13C-NMR(CD3〇D， 125 MHz) o 173.7， 155.5， 158.]， ]41·0 ， 140.6 ， 137.2 ， ]34.4 ， 131.3 ， ]28.2 ， 126.]， -98- (94) 200529835 9，52.1 47.9， ，-3.2。 125.8，122.2，121.9，118.3，113.4，112,6’ 55· ，51·7，50·8，48·9，48.6，48.4，48.2，48·〇 ’ 47.7 ， 47.5 ， 43·8 ， 43.7 ， 43.1 ， 37.2 ， 28.5 ， 9·8 ： 質譜·· 641.40(ΜΗ) +。 【實施方式】 實施例1 一酮基 一羰基 (±) — 3— (1H—吲唑一5 —基）2— { 〔4〆（2 —1，4 —二氫一 1 Η —喹唑啉一 3 —基）一哌啶一 1 〕胺基丨一丙酸3.18 (dd, J 2 13.5, 10_0 Hz, 1H), 2.8 7— 2.79 (m, 2H), 1.73— 1.59 (m, 4H), 0.80—0.75 (m, 2H), -0.05 (s, 9H); 13C -NMR (CD3OD, 125 MHz) o 173.7, 155.5, 158.],] 41.0, 140.6, 137.2,] 34.4, 131.3,] 28.2, 126.], -98- (94) 200529835 9, 52.1 47.9,, -3.2. 125.8, 122.2, 121.9, 118.3, 113.4, 112, 6 '55 ·, 51 · 7, 50 · 8, 48 · 9, 48.6, 48.4, 48.2, 48 · 〇' 47.7, 47.5, 43.8, 43.7, 43.1 , 37.2, 28.5, 9 · 8: Mass spectrum · 641.40 (ΜΗ) +. [Embodiment] Example 1 Monoketo-carbonyl (±)-3-(1H-indazol 5-yl) 2- {[4〆 (2 -1,4 -dihydro-1 Η -quinazoline -3-yl) -piperidine- 1] amino-monopropionic acid

令溶解於四氫呋喃（5 m 1 )和甲醇（5 ml ) β 一甲氧鑛基一2— { 〔4— (2 —酮基一1，4一/氫 口奎唑啉一 3 -基）一哌啶一 1 一羰基〕一胺基} 一乙 吲唑一 1 一羧酸特丁酯（1 68 mg，0.29毫莫耳）溶 至〇°C。加入LiOH單水合物（49 mg，2.04毫莫其） 5 ml )溶液。於下攪拌該反應混合物6小時’隨 冰箱中1 6小時。真空下除去溶劑並令殘餘物溶解於 ml )中。利用IN HC1調整該水溶液之pH至約1。藉 以收集所生成之沈澱白色固體。真空下乾燥該固體 的化合物（1 0 8 m g，8 0 % )。 5 -（ 2 一 2H — 基）一 液冷卻 之水（ 後置入 水（I 5 由過濾 以生成 • 46 ( (95) 200529835 ]H-NMR ( DMSO-d6，300MHz) δ 12.94 ( bs，1 H 9.19(s，lH) ，8.01(s，lH) ，7.61(s，lH) ，7Let dissolve in tetrahydrofuran (5 m 1) and methanol (5 ml) β-methoxide- 2-{[4-(2 -keto-1,4-/ hydroquinazoline -3 -yl)- Piperidine-1 monocarbonyl] monoamino} monoethylindazole-1 tert-butyl carboxylate (168 mg, 0.29 mmol) was dissolved to 0 ° C. A solution of LiOH monohydrate (49 mg, 2.04 mmol) in 5 ml) was added. The reaction mixture was stirred for 6 hours' in the refrigerator for 16 hours. The solvent was removed under vacuum and the residue was dissolved in ml). The pH of the aqueous solution was adjusted to about 1 using IN HC1. The resulting precipitated white solid was collected. The solid compound was dried under vacuum (108 mg, 80%). 5-(2-2H — based), a liquid-cooled water (after placing in water (I 5 by filtration to generate • 46 ((95) 200529835) H-NMR (DMSO-d6, 300MHz) δ 12.94 (bs, 1 H 9.19 (s, lH), 8.01 (s, lH), 7.61 (s, lH), 7

d，J=8.4Hz，1 H ) ，7.28 ( dd ^ J = 8.5 ^ 1.5Hz，1 H 7.13— 7.06 (m，2H) ，6.86(t，J=7.0Hz，lH)， —6.72(m，2H) ，4.32-4.24 (m，2H) ，4.09— 4. m，2H) ，3.17-2.97 (m，2H) ，2.72— 2.59 ( m， ，1.57 — 1.35 (m，4H) 。IR(KBr，cm—】）3424, ，2930 ， 1660 ， 1628 ， 1505 ， 1474 ， 1446 ， 753 ° 質 463 ( ΜΗ ) + 。 (R ) — 2- { 〔4— (2 —酮基—1，4 —二氫一2H — 啉—3 —基）一丨派Π定—1 —簾基〕一胺基} — 3 — 〔 1 · 一三甲基甲矽烷基一乙烷磺醯基）一1 Η —吲唑一5 — 一丙酸 [)， 6.76 .02 ( 2H ) 29 63 譜： 口奎口坐 -(2 基〕d, J = 8.4Hz, 1 H), 7.28 (dd ^ J = 8.5 ^ 1.5 Hz, 1 H 7.13—7.06 (m, 2H), 6.86 (t, J = 7.0 Hz, 1H), —6.72 (m, 2H), 4.32-4.24 (m, 2H), 4.09— 4. m, 2H), 3.17-2.97 (m, 2H), 2.72— 2.59 (m,, 1.57 — 1.35 (m, 4H)) IR (KBr, cm—]) 3424,, 2930, 1660, 1628, 1505, 1474, 1446, 753 ° mass 463 (ΜΗ) +. (R) — 2- {[4— (2 —keto —1, 4 —dihydro 1 2H —Phenyl — 3 —yl) — π — 1 — curtain] monoamine} — 3 — [1-trimethylsilyl monoethanesulfonyl)-1 fluorene — indazole One 5-monopropionic acid [), 6.76 .02 (2H) 29 63 Spectrum: Kou Kui mouth sitting-(2 base)

冷卻（R) — 2 — { 〔4— 2 —酬基—1’ 4 —二氧—2 Η 唑啉一 3 -基）—哌啶一 1 一羰基〕一胺基）一 3 —〔 1 2 —三甲基甲矽烷基一乙烷磺醯基）—1 Η —吲唑一 5 〕—丙酸甲酯（7 7 5 mg，1.2]毫莫耳）之四氫呋喃（ )和甲醇（3 ml )溶液至0°C。加入LiOH單水合物（ 一喹 -( 一基 9 ml '115 -100 > (96) 200529835 m g，4 · 8 4毫莫耳）之水（3 m 1 )溶液。〇 °C下攪拌該反應 混合物2小時，隨後置入—1 5 °C冰箱1 6小時。當利用冰浴 冷卻該反應混合物時，藉由加入IN HC1 ( 3.8 ml )令其PH 增加至約7。真空下移除有機溶劑。經加入IN HC1 ( 0.5 m 1 )後，利用乙酸乙酯萃取水層。將結合之萃取液置於 MgSCU上乾燥，經過濾和蒸發發生成白色固體之標的化合 物（684 mg，9 0 % )。 W-NMR ( DMSO-d6，3 00MHz ) δ 9.21 ( s ^ 1 Η ) ，8.58 (S，1H) ，7.90(d，J=8.4Hz，lH) ，7.78(S，1H) ，7.56(d，J=8.1Hz’lH) ，7·13 — 7.09(m，2H)， 6.88— 6.83 (m，1H) ，6.76— 6·74 (m，2H) ，4.33 — 4.27 (m，2H) ，4.18 (s，2H) ，4.09 — 3.96 (m，3H) ，3.57— 3.5l(m，2H) ，3.25— 3.04 (m，2H) ，2.74 — 2·6〇 (ηι，2H) ，1.54 — 1.43 (m，4H) ，0·70 — 0.64 (m ，2H) ，-〇.〇8(s，9H)。質譜：627(MH) +。Cooling (R) — 2 — {[[4-2 —Paxyl — 1 '4 —dioxo-2 oxazoline — 3-yl) — piperidine — 1 —carbonyl] — amine) — 3 — [1 2 —Trimethylsilyl monoethanesulfonyl) —1 Η —Indazole-5] —methyl propionate (7 7 5 mg, 1.2] mol) tetrahydrofuran () and methanol (3 ml) Solution to 0 ° C. A solution of LiOH monohydrate (monoquinol- (monoyl 9 ml '115 -100 > (96) 200529835 mg, 4.84 mmol) was added in water (3 ml). The reaction was stirred at 0 ° C The mixture was allowed to stand for 2 hours and then placed in a refrigerator at -15 ° C for 16 hours. When the reaction mixture was cooled with an ice bath, its pH was increased to about 7 by adding IN HC1 (3.8 ml). The organic solvent was removed under vacuum. After adding IN HC1 (0.5 m 1), the aqueous layer was extracted with ethyl acetate. The combined extract was dried on MgSCU, filtered and evaporated to form the target compound as a white solid (684 mg, 90%) W-NMR (DMSO-d6, 300 MHz) δ 9.21 (s ^ 1 Η), 8.58 (S, 1H), 7.90 (d, J = 8.4Hz, 1H), 7.78 (S, 1H), 7.56 (d , J = 8.1Hz'lH), 7.13 — 7.09 (m, 2H), 6.88 — 6.83 (m, 1H), 6.76 — 6.74 (m, 2H), 4.33 — 4.27 (m, 2H), 4.18 (s, 2H), 4.09 to 3.96 (m, 3H), 3.57 to 3.5l (m, 2H), 3.25 to 3.04 (m, 2H), 2.74 to 2.60 (η, 2H), 1.54 to 1.43 ( m, 4H), 0.70 to 0.64 (m, 2H), -0.08 (s, 9H). Mass spectrum: 627 (MH) +.

類似之方法製備： (土）— 2〜{ 〔4— (2 —酮基一 2，3 -二氫一 2H —苯並 咪唑一 1 一基）一哌啶一 1 一羰基〕一胺基丨一 3 -〔1 一（ 2 —三甲基甲矽烷基，乙烷磺醯基）一 1 Η —吲唑一5 —基 -101 - 200529835 (97)Prepared in a similar way: (Earth) — 2 ~ {[4 -— (2-keto-2,3-dihydro-2H-benzimidazole-1 1-yl) -piperidine-1 1-carbonyl] -amine group 丨-3-[1 mono (2-trimethylsilyl, ethanesulfonyl)-1 fluorene-indazole-5-yl-101-200529835 (97)

質譜61 2.25 (± ) — 2 — 一基）—哌 基甲矽烷基 質譜6 1 3.2 6 (± ) — 2 — 琳一3 —基 ) 一三甲基甲 一丙酸 MH ) +。 {4一（2-酮基—2，3 —二氫一苯並咪唑—1 :―1 一羰基〕一胺基} — 3— 〔1— (2 —三甲 乙烷磺醯基）一 1 Η —吲唑—5 —基〕一丙酸 ηMass spectrum 61 2.25 (±) — 2 — 1-yl) -piperidylsilyl mass spectrum 6 1 3.2 6 (±) — 2 — Lin — 3 —yl)-trimethylformyl monopropionate MH) +. {4-mono (2-keto-2,3-dihydromonobenzimidazole-1: -1 monocarbonyl] monoamine} — 3— [1— (2-trimethylethanesulfonyl) —1 Η —Indazol-5-yl] monopropionic acid η

ΜΗ ) { 〔4— (2— 酮基一1，4 —二氫一2H — D奎唑 —哌Π定一1—羰基〕一胺基} 一 3— 〔1— (2 7院基一乙院擴釀基）一 1 Η - D引哗一 5 —基〕 -102 - 200529835 (98) ΗΜΗ) {[4- (2-keto-1,4-dihydro-2H-D-quinazole-piridine-1-carbonyl] -amino group}-3— [1— (27 Enlargement of the base of the hospital)-1 Η-D Initiation-5-〕] -102-200529835 (98) Η

1 H-NMR ( CD3CN，5 00MHz ) (5 8 · 3 7 ( s，1 H ) ，8.08 ( s，lH) ，8.01(d，J=8.5Hz，lH) ，7.77(s，lH)， 7.53 (dd，J=8.5，1.5Hz，1H) ，7.19(t，J=7.3Hz， 1 H ) ，7.14(d，J=7.3Hz，1H) ，6.98(td，J=7.6, 1.2Hz，1 H ) ，6.79 ( d，J = 8.0Hz，1 H ) ，6.28 ( brs， 3H ) ，4.54-4.49(m，lH) ，4·37— 4.32(m，lH)， 4.30 (s，2H) ，3.98-3.92 (m，2H) ^ 3.45-3.41 (m1 H-NMR (CD3CN, 500 MHz) (5 8 · 37 (s, 1 H), 8.08 (s, 1H), 8.01 (d, J = 8.5Hz, 1H), 7.77 (s, 1H), 7.53 (dd, J = 8.5, 1.5Hz, 1H), 7.19 (t, J = 7.3Hz, 1H), 7.14 (d, J = 7.3Hz, 1H), 6.98 (td, J = 7.6, 1.2Hz, 1 H), 6.79 (d, J = 8.0 Hz, 1 H), 6.28 (brs, 3H), 4.54-4.49 (m, lH), 4.37-4.32 (m, lH), 4.30 (s, 2H), 3.98-3.92 (m, 2H) ^ 3.45-3.41 (m

，2H ) ，3.37 ( dd ^ J=14.0，4.9Hz，1 H ) ，3.20(dd，J = 14.0，9·7Ηζ，1H) ，2.84— 2.77 (m，2H) ^ 1.65- 1.57 (m，4H) ，0.79—0.76 (m，2H) ，-0.05(s，9H) 。質譜：627.30(MH) +。 (R ) — 4 — (2 —嗣基一1 ’ 4 — 一 氣一2 Η — D 奎 口坐琳一3 — 基）—哌啶一 1 —羧酸{ 2 -〔 1，4 /〕聯哌啶_ 1 / —基 一 2 —酮基一 1 一 〔1 一 （2 —三甲基甲矽烷基一乙烷磺醯基 )一 1H—吲唑一 5 —基甲基一乙基〕一醯胺 -103- 200529835 (99), 2H), 3.37 (dd ^ J = 14.0, 4.9 Hz, 1 H), 3.20 (dd, J = 14.0, 9.7 Ηζ, 1H), 2.84— 2.77 (m, 2H) ^ 1.65- 1.57 (m, 4H ), 0.79-0.76 (m, 2H), -0.05 (s, 9H). Mass spectrum: 627.30 (MH) +. (R) — 4 — (2 —fluorenyl-1 ′ 4 — one gas one 2 Η — D quetialine 3 —yl) —piperidine 1 —carboxylic acid {2-[1,4 /] bipipe Pyridinyl 1 / -yl 2-keto 1 1 [1 ((2-trimethylsilyl-ethanesulfonyl)-1H-indazole- 5-methylmethyl-ethyl]-1 Amine-103- 200529835 (99)

將4 一哌啶並哌啶（1 64 mg，0.9 7毫莫耳）和 PyBOP® (460 mg，0.88 毫莫耳）之二氯甲烷（15 液加入至（R) - 2— { 〔4— (2 —酮基—1，4一 2H - Π奎琳琳一 3 —基）一呢Π定一 1 一幾基〕—胺基 〔1 一 （2 —三甲基甲矽烷基一乙烷磺醯基）一 —5 —〕一丙酸（554 mg，0.88 毫莫耳）和 N，N — 基乙胺（0.62 ml，3.54毫莫耳）之二氯甲烷（20 液中。室溫下攪拌該反應混合物1 6小時。隨後濃| ml，並藉由閃蒸管柱層析，利用二氯甲烷/甲醇/ (95 : 4 : 1 )作爲流洗液以進行純化，生成白色固 的化合物（5 9 9 m g，8 7 % )。 】H-NMR ( CD3CN，3 00MHz ) (5 8 · 3 7 ( s，0.5H ) (s，0.5H) ，8.02— 7.96( m，lH) ，7.74(s， ，7.71(s，0.5H) ，7.55— 7.46(m，lH) ，7.2 (m，2H) ，6·9 7— 6.92 (m，lH) ，6.79(d，J: ，1H) ，5.71(d，J=8.1Hz，lH) ，5.00(dd， ，8.1Hz，1H) ，4.63— 4.51 (m，1H) ，4.39— 4 ，1 H ) ，4.2 9 ( s，2 H ) ，4 · 1 0 — 3.9 6 ( m，3 H )， ml)溶 二氫― } - 3 - [-D引D坐 二異丙 ml )溶 宿至約2 三乙胺 體之標 ，8.36 0.5H ) 1 - 7.12 =8.1Hz J = 15.0 .2 9 ( m 3.46 — -104 - 200529835 (100) 3·40( ηι，2Η) ，2.92-2.70 (m，8H) ，2.58-2.37(m ，5H ) ，1.74-1.40( m，13H) ，0.80— 0.74( m，2H ) ，-0.04(s，9H)。質譜：778(MH)+。 類似之方法製備= (±) — 4— (2 —酮基一2，3 —二氫一苯並咪唑一1—基 )一脈H定一 1 —殘酸{ 2 -〔 1，4 〕聯哌D定一 1 —基—2 一酮基一 1 一 〔1 一 （2—三甲基甲矽烷基一乙烷磺醯基） —1 Η —吲哚一5 —基甲基〕一乙基}—醯胺 〇Add 4 piperidine and piperidine (1 64 mg, 0.9 7 mmol) and PyBOP® (460 mg, 0.88 mmol) in dichloromethane (15) to (R)-2— {〔4— (2-Keto-1,4-2H-Π 琳琳琳 3- 基)-? Π 定 一 1 一 基基] -amino [1-(2-trimethylsilyl-ethanesulfonate Fluorenyl) mono-5 —] monopropionic acid (554 mg, 0.88 mmol) and N, N-ethylethylamine (0.62 ml, 3.54 mmol) in dichloromethane (20 solutions. Stir at room temperature The reaction mixture was for 16 hours. It was then concentrated | ml and purified by flash column chromatography using dichloromethane / methanol / (95: 4: 1) as a flow wash to produce a white solid compound ( 5 99 mg, 87%).] H-NMR (CD3CN, 300MHz) (5 8 · 37 (s, 0.5H) (s, 0.5H), 8.02-7.96 (m, lH), 7.74 ( s,, 7.71 (s, 0.5H), 7.55-7.46 (m, lH), 7.2 (m, 2H), 6.9 7-6.92 (m, lH), 6.79 (d, J :, 1H), 5.71 (d, J = 8.1Hz, lH), 5.00 (dd,, 8.1Hz, 1H), 4.63—4.51 (m, 1H), 4.39-4, 1H), 4.29 (s, 2H), 4 · 1 0 3.9 6 (m, 3 H), ml) dissolve dihydrogen}-3-[-D lead D sit diisopropyl ml) solvate to about 2 triethylamine standard, 8.36 0.5H) 1-7.12 = 8.1Hz J = 15.0.2 9 (m 3.46 — -104-200529835 (100) 3.40 (η, 2Η), 2.92-2.70 (m, 8H), 2.58-2.37 (m, 5H), 1.74-1.40 ( m, 13H), 0.80—0.74 (m, 2H), -0.04 (s, 9H). Mass spectrum: 778 (MH) +. Prepared by similar method = (±) — 4— (2 —keto-2, 3 —Dihydro-benzimidazole—1-yl) —Hydron 1—Residual acid {2-[1,4] Bipipedidine D—1—yl—2—Keto-1—1— [1— (2 —Trimethylsilyl monoethanesulfonyl) —1 hydrazine —indole 5 —ylmethyl] monoethyl} —fluorenamine.

】Η-ΝΜΙΙ ( CD3CN，5 00MHz ) 5 9·42 ( brs，1 Η ) ，7.80 (d，8·5Ηζ，1 Η ) ，7.78 ( d，J= 8.2Hz，0.4H )，Η-NMILI (CD3CN, 500 MHz) 5 9 · 42 (brs, 1 Η), 7.80 (d, 8 · 5 Ηζ, 1 Η), 7.78 (d, J = 8.2 Hz, 0.4H),

7.50 (s，1 Η ) ，7.43 (t，J = 3.0Hz ^ 1 H ) ，7.27 (d，J = 8·5Ηζ，0.6H) ，7.23 (d，J=8.5Hz，0.4H) ，7.10 — .07 ( m，1 H ) ，7. 0 2 — 6 · 95 (m， 3H ) ，6.69 ( s ，0. 4H 6. 68 ( s 5 0.6H ：)，5 • 88 (d， J = 8 . 5Hz，0.6H ) .85 ( d，J 二 8. ,4Hz ，1 H ) ，f ;.04 — 4.98 ( m，1 H ) ，4. 49 (s， -C I.4H ) 4.46 (s，0 .6H )， 4.36 - 4.30 ( m ，1 H ) > 4. 11 -4.07 ( m ? 1 H )， 3.97- 3 , .91 ( m ，1 H )， η o 1 J . J I 一 .28 ( m，2H ) ，3. 11-3. 05 (m j 6H )， 2.87 - 2. 80 ( m -105- (101) (101)200529835 ，2H ) ，2.43— 2.07 (m，8H ) ，1.7 8 - 1.74 ( m ^ 4H ) ，1.71— 1.65( m，2H ) ，1.46 - 1.40 (m^ 2H ) ，1.37-1.31 (m，2H) ，0.80— 0.74 ( m，2H) ，-0.10(s，9H) 。：LC/MS: tR=2.47 分，762·37(ΜΗ) +。 (±) — 4— (2 —酮基一2，3 —氫一苯並咪唑一1 一基） —_ 陡—1—錢酸{2—〔1’ 4 〕聯_0定—1 —基一 2 — 酮基一 1 一 〔1 一 （2—三甲基甲矽烷基一乙烷磺醯基）— 1H —吲唑一 5 —基甲基〕—乙基}—醯胺7.50 (s, 1 Η), 7.43 (t, J = 3.0Hz ^ 1 H), 7.27 (d, J = 8.5Ηζ, 0.6H), 7.23 (d, J = 8.5Hz, 0.4H), 7.10 — .07 (m, 1 H), 7. 0 2 — 6 · 95 (m, 3 H), 6.69 (s, 0.4 H 6. 68 (s 5 0.6 H :), 5 • 88 (d, J = 8 5Hz, 0.6H) .85 (d, J 2 8., 4Hz, 1 H), f; .04 — 4.98 (m, 1 H), 4.49 (s, -C I.4H) 4.46 (s , 0. 6H), 4.36-4.30 (m, 1 H) > 4. 11 -4.07 (m? 1 H), 3.97- 3, .91 (m, 1 H), η o 1 J. JI 1. 28 (m, 2H), 3. 11-3.05 (mj 6H), 2.87-2.80 (m -105- (101) (101) 200529835, 2H), 2.43-2.07 (m, 8H), 1.7 8-1.74 (m ^ 4H), 1.71-1.65 (m, 2H), 1.46-1.40 (m ^ 2H), 1.37-1.31 (m, 2H), 0.80-0.74 (m, 2H), -0.10 (s, 9H) :: LC / MS: tR = 2.47 minutes, 762 · 37 (ΜΗ) +. (±) — 4— (2-keto-2,3-hydro-benzimidazole-1 1-yl) —_ steep —1—Chrysanoic acid {2— [1 '4] Associated 0—1 —yl — 2 — keto — 1 — [1 — (2-trimethylsilyl—ethanesulfonyl) 1H - indazol-5 - yl methyl] - ethyl} - Amides

j-NMR ( CD3CN，5 0 0MHz ) 5 9 · 6 7 ( s，1 Η ) ，8.32 ( s，1 Η ) ，7.96 ( d ^ J=8.7Hz，0.55H ) ，7.93 (d，J - 8·6Ηζ，0.45H ) ，7.70 ( s ^ 1 H ) ，7.5 1 (d，J=8.6Hz， 0.55H) ， 7.47 (d， J=8.8Hz， 0.45H ) ， 7.08-7.05 (m ，1 H ) ，7.03— 6.99 (m，1 H ) ，6.98-6.94 (m，2H) ，6.01(d，J=7.9Hz，0.45H) ，5.96(d，J=7.9Hz， 0.55H ) ，5.05-5.00 (m，1 H ) ，4.49— 4.46 (m，1 H ) ，4.35-4.29 (m，1 H ) ，4.10— 4.05 (in，1 H ) ^ 4.00- 3.93( in，1H) ，3·40— 3.36 ( m，2H) ，3.17— 3.30( m ，6 H ) ，2 · 9 ] - 2 · 7 1 ( m，2 H ) ，2.5 2 — 2 . 1 3 ( m，8 H ) -106- 200529835 (102) ，1.76(brs，4H) ，1.69— 1.65 (m，2H) ，1.44—1.41j-NMR (CD3CN, 500 MHz) 5 9 · 6 7 (s, 1 Η), 8.32 (s, 1 Η), 7.96 (d ^ J = 8.7Hz, 0.55H), 7.93 (d, J-8 6Ηζ, 0.45H), 7.70 (s ^ 1H), 7.51 (d, J = 8.6Hz, 0.55H), 7.47 (d, J = 8.8Hz, 0.45H), 7.08-7.05 (m, 1H ), 7.03--6.99 (m, 1 H), 6.98-6.94 (m, 2H), 6.01 (d, J = 7.9Hz, 0.45H), 5.96 (d, J = 7.9Hz, 0.55H), 5.05-5.00 (m, 1 H), 4.49— 4.46 (m, 1 H), 4.35—4.29 (m, 1 H), 4.10— 4.05 (in, 1 H) ^ 4.00— 3.93 (in, 1H), 3.40— 3.36 (m, 2H), 3.17— 3.30 (m, 6 H), 2 · 9]-2 · 7 1 (m, 2 H), 2.5 2-2.. 1 3 (m, 8 H) -106- 200529835 (102), 1.76 (brs, 4H), 1.69-1.65 (m, 2H), 1.44-1.41

(m，2H ) ，1.34— 1.30( m，2H ) ，0.77 - 0.7 1 (m，2H )，-0.08(s，9H) °LC/MS:tR=2.35 分，763.35 (ΜΗ ) + 。 (±) — 4— (2 —酮基一1，4 —二氫一2H—口奎唑啉一3 — 基）一哌啶一 1 —羧酸{ 2 — 〔 1，4 /〕聯哌啶—1 / 一基 一 2—酮基一1 一 〔1= (2—三甲基甲矽烷基一乙烷磺醯基 )—1 Η —吲哚一 5 _基甲基〕一乙基}—醯胺(m, 2H), 1.34— 1.30 (m, 2H), 0.77-0.7 1 (m, 2H), -0.08 (s, 9H) ° LC / MS: tR = 2.35 minutes, 763.35 (ΜΗ) +. (±) — 4 -— (2-keto-1,4-dihydro-2H—orthoquinazolin-3—yl) -piperidine-1—carboxylic acid {2 — [1,4 /] bipiperidine —1 / 1-yl-2—keto-1 1- [1 = (2-trimethylsilyl-ethanesulfonyl) —1 Η—indole-5—methylmethyl] -ethyl} — Amidine

!H-NMR ( CD3CN，5 00MHz ) 5 8 · 1 7 ( s，0 · 6 Η ) ，8.16! H-NMR (CD3CN, 5000MHz) 5 8 · 1 7 (s, 0 · 6 Η), 8.16

(s，0.4H) ，7.84(d，J=8.5Hz，0.6H) ，7.81(d，J =8.5Hz，0.4H) ，7.54 ( s，0.4H ) ，7.5 3 ( s，0 · 6 H )， 7.48(t，J二 4·1Ηζ，1H) ，7.31 (dd，J=8.5，1.5Hz， 0.6H )， 7.28 ( dd，J 二 :8.5，1 .5Hz ，0.4H ) ，7.18 ( t ， 二 7·4Ηζ ，1 H ) ，7.09 —7.06 ( m ? 1 H )， 6.93 ( t ， J = 7.3Hz， 1 H )，（ 5.83 ( d ，J = 7·9Ηζ， 1 H )， 6.7 2 ( d，J 二 3.6Hz， 1 H )，丨 5.09 ( d ，J = 8·2Ηζ， 1 H )， 5.0 5 - 4.99 ( m， 1 H ) ^ 4.53 -4.50 (m， 1 H ) 5 4.40 - 4.34 ( m . 1 H ) -107- (103) (103)200529835 ，4.26(s，i.2H) ，4.24(s，0.8H) ，3·99— 3.94( m， 1 H ) ，3.35-3.30 (m，2H) ，3·15— 3.07(m，3H)， 3.08— 3.03 (m，1H) ，2.81-2.73 (m，3H) ，2.55 — 2·37( m，6H) ，2·21— 2·16( ni，lH) ，2.13-2.08 (m ，1H) ，1.69-1.57 (m，4H) ，1.51— 1.45 (m，4H) ，：1.41— 1.35(m，4H) ，0·83— 0.74 (m，2H) ，-0.06 (s，9H )。質譜：776.44 ( MH ) +。 (±) — 4— (2 —酮基一 1，4 -二氫一2H—D奎唑啉一 3- 基）一哌啶一 1 —羧酸{ 2 — 〔 1，4 /〕聯哌啶一 1 / 一基 一 2—酮基一1 一〔1 一 （2—三甲基甲矽烷基—乙烷磺醯基 )一 1 Η —吲唑—5 —基甲基〕一乙基} 一醯胺(s, 0.4H), 7.84 (d, J = 8.5Hz, 0.6H), 7.81 (d, J = 8.5Hz, 0.4H), 7.54 (s, 0.4H), 7.5 3 (s, 0 · 6 H ), 7.48 (t, J = 4 · 1Ηζ, 1H), 7.31 (dd, J = 8.5, 1.5Hz, 0.6H), 7.28 (dd, J: 8.5, 1.5Hz, 0.4H), 7.18 (t , 7 · 4Ηζ, 1 H), 7.09—7.06 (m? 1 H), 6.93 (t, J = 7.3Hz, 1 H), (5.83 (d, J = 7.9Ηζ, 1 H), 6.7 2 (d, J 3.6Hz, 1 H), 5.09 (d, J = 8 · 2Ηζ, 1 H), 5.0 5-4.99 (m, 1 H) ^ 4.53 -4.50 (m, 1 H) 5 4.40- 4.34 (m. 1 H) -107- (103) (103) 200529835, 4.26 (s, i.2H), 4.24 (s, 0.8H), 3.99— 3.94 (m, 1 H), 3.35-3.30 (m, 2H), 3.15—3.07 (m, 3H), 3.08—3.03 (m, 1H), 2.81-2.73 (m, 3H), 2.55—2.37 (m, 6H), 2.21— 2.16 (ni, lH), 2.13-2.08 (m, 1H), 1.69-1.57 (m, 4H), 1.51-1.45 (m, 4H), 1.41- 1.35 (m, 4H), 0.83- 0.74 (m, 2H), -0.06 (s, 9H). Mass spectrum: 776.44 (MH) +. (±) — 4— (2-keto-1,4-dihydro-2H—D quinine Phenyl-3-yl) -piperidine-1 1-carboxylic acid {2 — [1,4 /] bipiperidine-1 / 1-yl-2 2-keto-1-1 1 [1-(2-trimethylsilane -Ethanesulfonyl)-1 fluorene-indazole-5 -ylmethyl] monoethyl} monofluorenylamine

藉由矽膠層析，利用二氯甲烷/甲醇/三乙胺（90 : 10 : 0.5 )作爲流洗液進行純化。 j-NMR ( CD3CN，5 00MHz ) 5 8 · 3 6 ( s，1 Η ) ，8.04 ( s，lH) ，8.01(d，J=8.8Hz，0.6H) ，7.97(dd，J = 8·8Ηζ，0.4H) ，7.74 ( s，1H) ，7.5 4 ( d d，J = 8.5， 1.5Ηζ，0·6Η) ，7.51(dd，J=8.5，1.5Hz，0.4H)， -108 (104) (104)200529835 7.18(t，J=7.4Hz，1 H ) ，7.11 (t，J=7.3Hz，1 H )， 6.94 (t，J=7.3Hz，1 H ) ，6.83 (d，J=7.9Hz，1 H )，Purified by silica gel chromatography using dichloromethane / methanol / triethylamine (90: 10: 0.5) as a flow wash. j-NMR (CD3CN, 5000MHz) 5 8 · 3 6 (s, 1 Η), 8.04 (s, 1H), 8.01 (d, J = 8.8Hz, 0.6H), 7.97 (dd, J = 8 · 8Ηζ , 0.4H), 7.74 (s, 1H), 7.5 4 (dd, J = 8.5, 1.5Ηζ, 0.6Η), 7.51 (dd, J = 8.5, 1.5Hz, 0.4H), -108 (104) ( 104) 200529835 7.18 (t, J = 7.4Hz, 1 H), 7.11 (t, J = 7.3Hz, 1 H), 6.94 (t, J = 7.3Hz, 1 H), 6.83 (d, J = 7.9Hz , 1 H),

6.05 ( d，J二 8.5Hz，0.4H ) ，6 · 0 2 ( d，J 二 8 · 5 Η z，0.6H )，5.06-5.01 (m，lH) ，4·52— 4.50 (m，lH) ，4.39 —4.34(m，1H) ，4.27(s，1.2H) ，4.25(s，0.8H) ，4·00— 3.97 (m，2H) ，3.45— 3.40 (m，2H) ，3.20 — 3.08(m，2H) ，2.81-2.74 (m，2H) ^ 2.56-2.3 9 (m ，8H) ，2.27— 2.24 (m，1H) ，2.20-2.16 (m，1H) ，1.68 — 1.57 ( m，4H) ，1.52 — 1.45 (m，4H) ，1.41- 1.34(m，4H) ，：1.06-1.01 (m，1H) ，0.80— 0.75 (m ，2H) ，-0.07(s，9H)。質譜：777.40(MH)+。 (±) — 4 — （2 —酮基一2，3 —二氫一 2H—苯並咪唑一1 一基）一暖Π定—1 一殘酸{ 2 — ( 4 -異丁基一 _嗪一 1 一基 )一 2 —酮基一1— 〔1 一（2 -三甲基甲矽烷基一乙烷磺醯 基）—1 Η —吲哚一 5 —基甲基〕一乙基丨一醯胺6.05 (d, J = 8.5Hz, 0.4H), 6.02 (d, J = 8.5 * z, 0.6H), 5.06-5.01 (m, lH), 4.52-4.50 (m, lH ), 4.39 — 4.34 (m, 1H), 4.27 (s, 1.2H), 4.25 (s, 0.8H), 4.00 — 3.97 (m, 2H), 3.45 — 3.40 (m, 2H), 3.20 — 3.08 (m, 2H), 2.81-2.74 (m, 2H) ^ 2.56-2.3 9 (m, 8H), 2.27— 2.24 (m, 1H), 2.20-2.16 (m, 1H), 1.68 — 1.57 (m, 4H) ), 1.52-1.45 (m, 4H), 1.41- 1.34 (m, 4H), 1.06-1.01 (m, 1H), 0.80-0.75 (m, 2H), -0.07 (s, 9H). Mass spectrum: 777.40 (MH) +. (±) — 4 — (2-keto-2,3-dihydro-2H-benzimidazole-1 1-yl) -Nondidine-1 1-residual acid {2 — (4 -isobutyl-_azine 1 1 1 group) 2 2 -keto 1 1 [1 1 (2-trimethylsilyl monoethanesulfonyl) 1 1-indole 5 -ylmethyl] 1 ethyl 丨 1 Amidine

】H-NMR(CD3CN，500MHz) J 9.75 ( s ^ 1 H ) ，7.82 ( d，J=8.2Hz，]H) ，7.54(s，lH) ，7.48(d，J二 3.6Hz -109- (105) (105)200529835] H-NMR (CD3CN, 500MHz) J 9.75 (s ^ 1 H), 7.82 (d, J = 8.2Hz,] H), 7.54 (s, 1H), 7.48 (d, J = 3.6Hz -109- ( 105) (105) 200529835

，1 Η ) ，7.28(d，J=8.5Hz，1 Η ) ，7.12— 7.09( m，1H )，7.04— 7.02 (m，lH) ，7.00—6.97 (m，2H) ，6·72 (d，J 二 3.7Hz，1 H ) ，5.97 (d，J=8.2Hz，1 H ) ，5.0 1 (dd，J=14.6，7.2Hz，1 H ) ，4.40-4.34( m，1 H )， 4.15-4.08 (m，2H) ，3.58— 3.54 (m，1H) ，3.36- 3.32(m，2H) ，3.14— 3.10( m，8H) ^ 2.89-2.83 (m ，2H) ，2.34-2.23 (m，4H) ，2.17-2.13 (m，1H) ，0.85(d，J=6.7Hz，6H) ，0.83-0.80 (m，2H)， -0.06(s，9H)。質譜 736.40 (MH) +。 (±) — 4— (2 —酮基一 2，3 —二氫一苯並咪唑一1 一基 )一哌D定一 1—殘酸{2- （1，4 —二氧雜一 8 -氮雜一螺 〔4.5〕癸一 8 —基）—2—酮基一1 一 〔1 一 （2 —三甲基甲 矽烷基一乙烷磺醯基）一 1 Η -吲哚一 5 —基甲基〕一乙基 }醯胺, 1 Η), 7.28 (d, J = 8.5Hz, 1 Η), 7.12— 7.09 (m, 1H), 7.04— 7.02 (m, 1H), 7.00—6.97 (m, 2H), 6.72 (d , J 2 3.7Hz, 1 H), 5.97 (d, J = 8.2Hz, 1 H), 5.0 1 (dd, J = 14.6, 7.2Hz, 1 H), 4.40-4.34 (m, 1 H), 4.15 -4.08 (m, 2H), 3.58—3.54 (m, 1H), 3.36- 3.32 (m, 2H), 3.14— 3.10 (m, 8H) ^ 2.89-2.83 (m, 2H), 2.34-2.23 (m, 4H), 2.17-2.13 (m, 1H), 0.85 (d, J = 6.7Hz, 6H), 0.83-0.80 (m, 2H), -0.06 (s, 9H). Mass spectrum 736.40 (MH) +. (±) — 4— (2-keto-2,3-dihydro-benzimidazole-1 1-yl) -piperidine D- 1-residual acid {2- (1,4-dioxa-8- Aza-spiro [4.5] decy-8-yl) -2-keto-1 1- [1- (2-trimethylsilyl-ethanesulfonyl)-1 hydrazone-indole-5-yl Methyl] -ethyl} amidamine

]H-NMR ( CD3CN ^ 500ΜΗζ) δ 9 ·2Ί ( s，1 Η ) ，7.82 ( d，J=8.5Hz，lH) ，7.55(s，lH) ，7.48(d，J=3.6Hz ，1H) ，7.28(dd，J二 8.5，].5Hz，1H) ，7.13-7.10( -110- (106) (106)200529835 m，1 Η ) ，7 · 0 6 - 7 · 0 3 ( m，1 Η ) ，7 · 0 1 — 6 · 9 8 ( m，2 Η ) ，6.72 (d，J=3.6Hz，1 H ) ，5.95 (d，J=8.0Hz，1 H ) ，5.05 (dd，J=15.0，7·3Ηζ，1H) ，4.41-4.34( m， 1 H ) ，4.14-4.08 (m，2H) ，3·90— 3.86 (m，3H)， 3.68— 3.64 (m，1 H ) ，3.60-3.56 (m，2H) ，3.45 — 3.40 (m，1H) ，3.35— 3.31 (m，2H) ，3.15(dd，J = 13.4，7·1Ηζ，1H) ，3.05 (dd，J=13.4，7·0Ηζ，1 H )， 2.8 9 - 2.8 3 ( m ^ 2H ) ，2·34— 2.19(m，3H) ，1.73 — 1.70(m，2H) ，1.73— 1.70(m，2H) ^ 1.64 - 1 .5 6 ( m ，2H) ，1.53— 1.49(m，1H) ，1.29— 1.26 (m，1H) ，0.84—0.80 (m，2H) ，-0.05(s，9H)。質譜：737.37 (Μ H ) +。 (±) — 4— (2 —酮基一 2，3 —二氫一苯並咪唑一1—基 )—哌啶一 1 —羧酸{ 2 — （ 4 一異丁基一哌嗪一 1 —基）一 2 —酮基一 1 一〔1 一（2 —三甲基甲矽烷基—乙烷磺醯基） 一 1H—吲唑一 5-基甲基〕—乙基}—醯胺] H-NMR (CD3CN ^ 500MΗζ) δ 9 · 2Ί (s, 1 Η), 7.82 (d, J = 8.5Hz, 1H), 7.55 (s, 1H), 7.48 (d, J = 3.6Hz, 1H) , 7.28 (dd, J 8.5,] .5 Hz, 1H), 7.13-7.10 (-110- (106) (106) 200529835 m, 1 Η), 7 · 0 6-7 · 0 3 (m, 1 Η ), 7 · 0 1 — 6 · 9 8 (m, 2 Η), 6.72 (d, J = 3.6Hz, 1 H), 5.95 (d, J = 8.0Hz, 1 H), 5.05 (dd, J = 15.0, 7 · 3Ηζ, 1H), 4.41-4.34 (m, 1 H), 4.14-4.08 (m, 2H), 3.90— 3.86 (m, 3H), 3.68— 3.64 (m, 1 H), 3.60 -3.56 (m, 2H), 3.45 — 3.40 (m, 1H), 3.35 — 3.31 (m, 2H), 3.15 (dd, J = 13.4, 7. · 1Ηζ, 1H), 3.05 (dd, J = 13.4, 7 · 0Ηζ, 1 H), 2.8 9-2.8 3 (m ^ 2H), 2.34— 2.19 (m, 3H), 1.73— 1.70 (m, 2H), 1.73— 1.70 (m, 2H) ^ 1.64-1 .5 6 (m, 2H), 1.53 to 1.49 (m, 1H), 1.29 to 1.26 (m, 1H), 0.84 to 0.80 (m, 2H), -0.05 (s, 9H). Mass spectrum: 737.37 (MH) +. (±) — 4 -— (2-keto-2,3-dihydro-benzimidazole-1-yl) —piperidine-1—carboxylic acid {2 — (4-isobutyl-piperazine-1— A) 2 -keto 1-1 [1 (2-trimethylsilyl-ethanesulfonyl)-1H-indazol 5-ylmethyl] -ethyl} -amidamine

H-NMR ( CD3CN，5 0 0MHz ) ό 9.8 4 ( s，1 Η ) ，8.37 ( -111 - (107) (107)200529835 s，lH) ，7.98(d，J=8.5Hz，lH) ，7.74(s，lH)， 7.52(dd，J二 8.8，1.5Hz，1H) ，7.71— 7.09( m，1H ) ，7.06-7.03 (m，1 H ) ，7.02— 6.98 (m，2H ) ，5.97 ( d，J= 8.2Hz，1 H ) ，5.02 ( dd，J = 14.3，7·3Ηζ，1 H ) ，4.39-4.33 (m，1H) ，4.14— 4.07 (m，2H) ，3.53 — 3.50(m，3H) ，3.46—3.42 (m，2H) ^ 3.4 5 - 3.3 9 ( m ，：IH) ，3.20— 3.06 (m，5H) ，2.89-2.83 (m，2H) ，2.30-2.27 (m，4H) ，2.21— 2.17 (m，1H) » 1.74- 1.70 (m，3H) ，0.86(d，J=6.7Hz，6H) > 0.8 1-0.77 (m，2H) ，-0.04(s，9H)。質譜：737.40(MH) +。 (土）一 4 一 （2—酮基一2，3 —二氫一苯並咪唑一1 一基 )—暖陡—1—殘酸{2— (1，4 一二氧雜—8 —氮雜一螺 〔4.5〕癸一8—基）一2 —酮基一1 一 〔1— (2—三甲基甲 矽烷基一乙烷磺醯基）—1 Η —吲唑一5 —基甲基〕一乙基 } 一酿胺H-NMR (CD3CN, 50 MHz) 9.8 9.8 (s, 1 Η), 8.37 (-111-(107) (107) 200529835 s, lH), 7.98 (d, J = 8.5Hz, lH), 7.74 (s, lH), 7.52 (dd, J 8.8, 1.5 Hz, 1H), 7.71—7.09 (m, 1H), 7.06-7.03 (m, 1 H), 7.02— 6.98 (m, 2H), 5.97 ( d, J = 8.2Hz, 1 H), 5.02 (dd, J = 14.3, 7 · 3Ηζ, 1 H), 4.39-4.33 (m, 1H), 4.14—4.07 (m, 2H), 3.53 — 3.50 (m , 3H), 3.46—3.42 (m, 2H) ^ 3.4 5-3.3 9 (m ,: IH), 3.20—3.06 (m, 5H), 2.89-2.83 (m, 2H), 2.30-2.27 (m, 4H) ), 2.21— 2.17 (m, 1H) »1.74- 1.70 (m, 3H), 0.86 (d, J = 6.7Hz, 6H) > 0.8 1-0.77 (m, 2H), -0.04 (s, 9H) . Mass spectrum: 737.40 (MH) +. (Soil) 4 4 (2-keto-2,3-dihydro-benzimidazole-1 1-yl)-warm steep-1-residual acid {2-(1,4-dioxa-8-nitrogen Hetero-spiro [4.5] decyl-8-yl) -2-keto-1 1- [1- (2-trimethylsilyl-ethanesulfonyl) -1 hydrazone-indazole-5-ylmethyl Propyl] monoethyl} monomethylamine

】Η-ΝΜΙΙ ( CD3CN，5 00ΜΗζ ) ά 9.34 ( s，1 Η ) ，8.36 ( s，]H) ，7.97(d，J=8.5Hz，lH) ，7.74(s，lH)， -112- (108) 200529835 7.52(dd，J二 8.5，1·5Ηζ，1H) ，7·11— 7.08(m，1H) ，7.06— 7·03 (m，1H ) ，7.02-6.98 (m，2H ) ，5.98 ( d，J= 8.2Hz，1 H ) ，5.06 ( dd，J = 14.6，7.3Hz，1 H ) ，4.39-4.32 (m，lH) ，4.13— 4.03(m，2H) ，3·92 — 3.88 (m，2H) ，3.71— 3.6 6(m，lH) ，3.63-3.53 (m ，2H ) ，3.48— 3.45 (m，1 H ) ，3.44-3.40 (m，2H ) ，3.19(dd，J=13.4，6.5Hz，lH) ，3.08(dd，J=]3.7Η-NMILI (CD3CN, 500M5ζ) ά 9.34 (s, 1 Η), 8.36 (s,] H), 7.97 (d, J = 8.5Hz, 1H), 7.74 (s, 1H), -112- ( 108) 200529835 7.52 (dd, J 8.5, 1.5Ηζ, 1H), 7.11—7.08 (m, 1H), 7.06—7.03 (m, 1H), 7.02-6.98 (m, 2H), 5.98 (d, J = 8.2Hz, 1 H), 5.06 (dd, J = 14.6, 7.3Hz, 1 H), 4.39-4.32 (m, lH), 4.13—4.03 (m, 2H), 3.92 — 3.88 (m, 2H), 3.71—3.6 6 (m, 1H), 3.63-3.53 (m, 2H), 3.48—3.45 (m, 1 H), 3.44-3.40 (m, 2H), 3.19 (dd, J = 13.4, 6.5Hz, lH), 3.08 (dd, J =) 3.7

，7.3Hz，1 H ) ，2.85 (t，J = 12.8Hz，2H ) ，2.32 - 2.20, 7.3Hz, 1 H), 2.85 (t, J = 12.8Hz, 2H), 2.32-2.20

(m，4H) ，1.73— 1.70 (m，2H) ，1·67 — K51(m，3H )，1·38— 1.33 (m，lH) ，0.81-0.77(m，2H)， -0.04 ( s，9H )。 質譜：7 3 8.3 2 ( ΜΗ ) +。 實施例2 (R) — 4 — ( 2 —酬基一1’4 — 一 氯一2H —哇 口坐琳一3 —(m, 4H), 1.73— 1.70 (m, 2H), 1.67—K51 (m, 3H), 1.38— 1.33 (m, 1H), 0.81-0.77 (m, 2H), -0.04 (s , 9H). Mass spectrum: 7 3 8.3 2 (ΜΗ) +. Example 2 (R) — 4 — (2 —Paxyl 1’4 — 1 Chlorine 2H — Wow

基）—哌啶一 1 —羧酸〔2 — ( 1，4 /〕聯哌啶一 1 / —基 —1 一（1H —吲唑一 5—基甲基）—2 —酮基乙基〕一醯胺) —Piperidine-1—carboxylic acid [2 — (1,4 /] bipiperidine-1 / —yl-1— (1H —indazol-5-ylmethyl) —2 —ketoethyl] Monoamine

令（R) — 4— (2 —酮基一】，4一二氫一 2H — D奎唑啉 -113- (109) (109)200529835 一 3 —基）—哌啶—1 一羧酸丨2 —〔 i，4 /〕聯哌啶—厂 —基一 2 —酮基一1—〔1 一 （2一三甲基甲矽烷基一乙烷磺 醯基）—1H —吲唑—5 —基甲基〕一乙基丨—醯胺（5.68 mg，0.73毫莫耳）和CsFCl.ll g，7.31毫莫耳）之乙腈（ 5 0 ml )溶液於80°C下加熱4.5小時。濃縮該反應混合物並 藉由閃蒸管柱層析（CH2C12/甲醇/三乙胺，94 : 5 : 1 ) 純化殘餘物，生成白色固體之標的化合物（2 80 mg，63% 產率），其具有98.2%之對映體過量，其測定係藉由 HPLC分析，利用Chirocel 0D管柱且20% B(A =乙醇， B = 0.05%二乙胺之己烷溶液）作爲流洗液（滯留時間： 標的化合物爲9.51分鐘，且S對映異構物爲15.9分鐘）。 】H-NMR ( CD30D，500MHz ) (5 8.04 ( s，0.75H )，Let (R) — 4 -— (2-keto), 4-dihydro-2H—D quinazoline-113- (109) (109) 200529835—3-yl) —piperidine-1 monocarboxylic acid 丨2 — [i, 4 /] piperidine—plant—yl—2—keto—1— [1 ((2-trimethylsilyl-ethanesulfonyl) —1H—indazole—5 — A solution of methylmethyl] -ethyl-amidine (5.68 mg, 0.73 mmol) and CsFCl.ll g, 7.31 mmol) in acetonitrile (50 ml) was heated at 80 ° C for 4.5 hours. The reaction mixture was concentrated and the residue was purified by flash column chromatography (CH2C12 / methanol / triethylamine, 94: 5: 1) to give the title compound (2 80 mg, 63% yield) as a white solid, which It has an enantiomeric excess of 98.2%, and its determination was performed by HPLC analysis using a Chirocel 0D column and 20% B (A = ethanol, B = 0.05% diethylamine in hexane solution) as the flow wash solution (retention time : The target compound is 9.51 minutes and the S enantiomer is 15.9 minutes). H-NMR (CD30D, 500MHz) (5 8.04 (s, 0.75H),

8.03 ( s，0.25H ) ，7.67 ( s，0.75H) ，7·65 ( s，0.25H )，7.56(d，J=8.5Hz，0.75H) ’ 7.41 (d’ J=8.5Hz’ 0.75H ) ，7.31 (d，J=8.5Hz，0.25H) ，7.19— 7.12( m8.03 (s, 0.25H), 7.67 (s, 0.75H), 7.65 (s, 0.25H), 7.56 (d, J = 8.5Hz, 0.75H) '7.41 (d' J = 8.5Hz '0.75H ), 7.31 (d, J = 8.5Hz, 0.25H), 7.19— 7.12 (m

，2H) ，6.97-6.94 (m，lH) ，6.80(d，J=7.9Hz，lH )，5_08-5.05(m，lH) ，4.60—4.53 (m，lH) ? 4.48 -4.40 (m，1H) ，4.37(m，1·5Η) ，4.26(s，0.5H) ，4·24— 4·14(ηι，2Η) ，4·06 — 3.97 (m，lH) ，3.15( d，J=7.9Hz，1·5Η) ，3.12—3.05(m，0.5H) ，2.94 - 2.86 (m，3H) ，2.57—2.51 (m，1.5H) ，2.47— 2.42 ( m，1H) ，2.37 - 2.33 (m，0·75Η) ，2.03 — 2.02 (m， 1 .5H ) ，1 .8 7 - 1 .7 5 ( m，3.75H ) ，1 · 7 3 — 1 · 6 8 ( ni，2 H )，1.67— 1.54( m，3H) ，1.53 — 1.44( m，4H) ，1.43 -114- 200529835 (110) 一 1.34(m，2H) ，1.30— 1.26( m，1H) ，0.83— 0.77( m，0.75H) ，-0.06 至- 0.24(s，0.75H)。質譜：613 (ΜΗ ) + 。 類似之方法製備： 實施例3 (±) — 4— (2 —酮基一2，3 —二氫一苯並咪唑一1—基 )一 _ B定一 1 一殘酸〔2 — 〔 1，4 〕聯哌卩定一 1 —基— (1H —吲哚一 5 —基甲基）一2—酮基一乙基〕一醯胺, 2H), 6.97-6.94 (m, lH), 6.80 (d, J = 7.9Hz, lH), 5_08-5.05 (m, lH), 4.60-4.53 (m, lH)? 4.48 -4.40 (m, 1H ), 4.37 (m, 1.5Η), 4.26 (s, 0.5H), 4.24-4.14 (η, 2Η), 4.06-3.97 (m, lH), 3.15 (d, J = 7.9 Hz, 1.5Η), 3.12—3.05 (m, 0.5H), 2.94-2.86 (m, 3H), 2.57—2.51 (m, 1.5H), 2.47—2.42 (m, 1H), 2.37-2.33 (m , 0 · 75Η), 2.03 — 2.02 (m, 1.5H), 1.8 8-1.75 (m, 3.75H), 1. 7 3 — 1 · 6 8 (ni, 2 H), 1.67 — 1.54 (m, 3H), 1.53 — 1.44 (m, 4H), 1.43 -114- 200529835 (110) — 1.34 (m, 2H), 1.30 — 1.26 (m, 1H), 0.83 — 0.77 (m, 0.75H) ), -0.06 to -0.24 (s, 0.75H). Mass spectrum: 613 (ΜΗ) +. Prepared by a similar method: Example 3 (±) — 4 — (2-keto-2,3-dihydro-benzimidazole-1-yl) -B-fixed-1 1 residual acid [2 — [1, 4] Bipiperidine- 1-yl- (1H-indole-5-ylmethyl)-2-keto-ethyl] -pyridamine

^-NMR ( DMSO- d6 5 5 00MHz) 5 10.99(s，0.6H)， 10.96 (s，0.4H) ，10.85 (s，lH) ，7.41(s，0.4H)， 7.36 ( s，0.6H ) ，7.33 ( d，J= 8·0Ηζ，0.6H ) ，7.29- 7.26 (m，1H) ，7.16-7.14 (m，1H) ，7.10(d，J =^ -NMR (DMSO- d6 5 5 00MHz) 5 10.99 (s, 0.6H), 10.96 (s, 0.4H), 10.85 (s, lH), 7.41 (s, 0.4H), 7.36 (s, 0.6H) , 7.33 (d, J = 8 · 0Ηζ, 0.6H), 7.29- 7.26 (m, 1H), 7.16-7.14 (m, 1H), 7.10 (d, J =

7·6Ηζ，0·4Η) ，7·02— 6.96 (m，4H) ，6.81(brs，IH )，6·37 — 6·35(ηι，1Η) ，4.86(q，J=8.0Hz，0.6H) ，4.80 (q，J 二 7.5Hz，0.4H ) ，4.45 (brs，1 H ) ，4.38 —4.3 2 ( m，1 H ) ，4 · 2 1 — 4 · 1 6 ( m，1 H ) ，3 · 9 8 ( b r s， 1 H ) ，3.18(d，J=5.2Hz，0.6H) ，3·04— 2.92 (m， -115- 200529835 (111) 2.4H ) ，2·82— 2.74 ( m，4H) ，2·37— 2.33 (m，2H)， 2.25-2.08 (m^ 4H) ，2.04-1.90 (m，2H) ^ 1.47- 1.24(m，10H) ，0.75 - 0.7 1 (m，1 H ) 〇 LC/MS: tR - 1 .90分，5 98.42 ( ΜΗ ) + 〇 實施例4 (±) — 4 — （2 —酮基-2，3 —二氫一苯並咪唑一 1 一基 )一哌啶—1 一羧酸〔2 —〔 1，4 /〕聯哌啶一 1 / —基〕 —1— (1H —卩引卩坐一5 —基甲基）—2 —酮[基一乙基〕釀胺7 · 6Ηζ, 0 · 4Η), 7.02— 6.96 (m, 4H), 6.81 (brs, IH), 6.37 — 6.35 (η, 1Η), 4.86 (q, J = 8.0Hz, 0.6 H), 4.80 (q, J 7.5Hz, 0.4H), 4.45 (brs, 1 H), 4.38 —4.3 2 (m, 1 H), 4 · 2 1 — 4 · 1 6 (m, 1 H) , 3 · 9 8 (brs, 1 H), 3.18 (d, J = 5.2Hz, 0.6H), 3.04— 2.92 (m, -115- 200529835 (111) 2.4H), 2.82— 2.74 ( m, 4H), 2.37— 2.33 (m, 2H), 2.25-2.08 (m ^ 4H), 2.04-1.90 (m, 2H) ^ 1.47- 1.24 (m, 10H), 0.75-0.7 1 (m, 1 H) 〇LC / MS: tR-1.90 minutes, 5 98.42 (ΜΗ) + 〇 Example 4 (±) — 4 — (2-keto-2,3-dihydromonobenzimidazole — 1 — 1 — ) -Piperidine-1 monocarboxylic acid [2- — [1,4 /] bipiperidine-1 / —yl] —1 — (1H — hydrazine — 5 —methylmethyl) — 2 — ketone [ Methyl ethyl

】H-NMR ( DMS0 — d6，5 00MHz ) ά 1 0 · 7 0 ( s，1 Η )， 8.22(d，J=8.2Hz，0.6H) ，8.11(s，0.4H) ^ 8.00 ( s ，0.6H) ，7.89(d，J=9.1Hz，0.4H) ，7.62-7.57 (m ，：IH) ，7.52— 7.43 (m，1H) ，7.30 - 7.26 (m，1H) ，7.14— 7.08 (m，1 H ) ，6.99-6.95 (m，2H) ，6·85 (] H-NMR (DMS0 — d6, 5 00MHz) ά 1 0 · 7 0 (s, 1 Η), 8.22 (d, J = 8.2 Hz, 0.6H), 8.11 (s, 0.4H) ^ 8.00 (s, 0.6H), 7.89 (d, J = 9.1Hz, 0.4H), 7.62-7.57 (m ,: IH), 7.52-7.43 (m, 1H), 7.30-7.26 (m, 1H), 7.14-7.08 (m , 1 H), 6.99-6.95 (m, 2H), 6.85 (

brs，1 H ) ，4.8 9 - 4.8 0 ( m » 1 H ) ，4.45-4.31 (m^ 2H )，4.18-4.00 (m，2H) ，3.26-3.16 (m，lH) ，3.09 —2.96(m，2H) ，2.82-2.73 (m，4H) ，2.38-2.34 ( m，2 H ) ，2.2 4 - 2 · 0 8 ( m，4 H ) ，2.0 3 — 1 . 8 8 ( m，2 H ) ，1.47 — 1.22 (m，1 OH ) ，0.90-0.84 (m，1 H ) 。LC/ -116- 200529835 (112) MS : tR 二 1.73 分，5 99.3 2 ( ΜΗ) + 〇 實施例5 (±) — 4一 （2 —酮基一 1，4 —二氫一 2Η — 口奎唑啉一3-基）—_ Π定一 1 一殘酸〔2 —〔 1，4 /〕聯 _ D定—1 / 一基 一 1— (1Η_吲哚一 5—基甲基）一 2一酮基一乙基〕—醯 胺brs, 1 H), 4.89-4.8 0 (m »1 H), 4.45-4.31 (m ^ 2H), 4.18-4.00 (m, 2H), 3.26-3.16 (m, lH), 3.09-2.96 (m , 2H), 2.82-2.73 (m, 4H), 2.38-2.34 (m, 2 H), 2.24-2 · 0 8 (m, 4 H), 2.0 3-1. 8 8 (m, 2 H) , 1.47—1.22 (m, 1 OH), 0.90-0.84 (m, 1 H). LC / -116- 200529835 (112) MS: tR di 1.73 points, 5 99.3 2 (ΜΗ) + 〇 Example 5 (±) — 4 — (2 — keto — 1, 4 — dihydro — 2 — — Kui Kui Oxazoline-3-yl) —_ Π 定 -1 1 residual acid [2- — [1, 4 /] bis-D din-1 / 1-based 1 — (1 Η_indole-5-ylmethyl) a 2-ketomonoethyl] -amidine

H /NH / N

N H 令4一（2-酮基—1，4一二氫一 2H —咱嗤啉一 3 -基 )一哌卩定一 1 一羧酸{ 2 -〔 1，4 /〕聯啦啶-1 / 一基一 2 一酮基一 1 一 〔1— (2—三甲基甲矽烷基一乙烷磺醯基） —1Η—吲哚一5 —基甲基〕一乙基} 一醯胺（52 mg，0.67 毫莫耳）和CsF ( 51 mg ’ 0·33毫莫耳）之乙腈（5 ml)溶 液於9 0 °C下加熱4小時。真空下除去溶劑並藉由矽膠層析 且利用CH2C12 /甲醇/三乙胺（93 : 5 : 2 )作爲流洗液以 純化殘餘物’生成白色固體之標的化合物（7 0 %產率）。 】H-NMR ( CD3CN，5 0 0MHz ) 5 9.30 ( s，1H ) ，7.48 ( s，lH) ，7.42(s，lH) ，7.39(d，J=8.2Hz，lH)， 7.36 ( d ^ J=8.2Hz，0.4H ) ’ 7.24 - 7.2 1 (m，1 H )， 7.]9(t，J二 7.9 Hz， 1 H ) ，7·12— 7.09( m，1H) ，7.06 -117- (113) 200529835 (d，J=8.2Hz，0.6H) ，7.02(d，J=8.2Hz，0.4H)， 6.95 (t，J=7.4Hz，1 H ) ，4.04-3.93 (m，1 H ) ，3.07 -3.02(m，1.6H) ，2.95(dd，J=13.7，7·1Ηζ，0.4H) ，2·85— 2.72 (m，3H) ，2·56— 2.37 ( m，3H) ，2.42- 2.37 ( m ^ 1H ) ，：1.99— 1.95 (m，7H) » 1.76 - 1.51 (m ，8H) ，1.45-1.40 (m，3H) °LC/MS:tR=1.91 分， 6 1 2·44 ( ΜΗ ) +。NH Let 4- (2-keto-1,4-dihydro-2H-oxanolin-3-yl) -piperidine-1 monocarboxylic acid {2-[1,4 /] biratidine-1 / One group one 2 one keto group one one [1- (2-trimethylsilyl monoethanesulfonyl) —1 Η—indole 5-ylmethyl] monoethyl} monofluorene ( A solution of 52 mg, 0.67 mmoles) and CsF (51 mg '0.33 mmoles) in acetonitrile (5 ml) was heated at 90 ° C for 4 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using CH2C12 / methanol / triethylamine (93: 5: 2) as a flow wash to yield the title compound as a white solid (70% yield). ] H-NMR (CD3CN, 500 MHz) 5 9.30 (s, 1H), 7.48 (s, lH), 7.42 (s, lH), 7.39 (d, J = 8.2 Hz, lH), 7.36 (d ^ J = 8.2Hz, 0.4H) '7.24-7.2 1 (m, 1 H), 7.] 9 (t, J 2 7.9 Hz, 1 H), 7.12— 7.09 (m, 1H), 7.06 -117- (113) 200529835 (d, J = 8.2Hz, 0.6H), 7.02 (d, J = 8.2Hz, 0.4H), 6.95 (t, J = 7.4Hz, 1 H), 4.04-3.93 (m, 1 H ), 3.07-3.02 (m, 1.6H), 2.95 (dd, J = 13.7, 7.1 · ζ, 0.4H), 2.85-2.72 (m, 3H), 2.56-2.37 (m, 3H), 2.42- 2.37 (m ^ 1H), 1.99—1.95 (m, 7H) »1.76-1.51 (m, 8H), 1.45-1.40 (m, 3H) ° LC / MS: tR = 1.91 points, 6 1 2 · 44 (ΜΗ) +.

實施例6 (±) - 4— (2 —酮基一1，4 -二氫一2H— 喧唑啉 一3 — 基）—哌啶—1 一羧酸〔2 —〔 1，4 /〕聯哌啶一 1 / 一基 一 1一 （1H —吲唑一5 —基甲基）一2 —酮基一乙基〕一醯Example 6 (±)-4- (2-keto-1,4-dihydro-2H-oxazolin-3-yl) -piperidine-1 monocarboxylic acid [2-[1, 4 /] Piperidine-1 / 1-yl-1 1 (1H-indazol-5-ylmethyl)-2 -ketomonoethyl]-

藉由矽膠層析且利用CH2C12 :甲醇：三乙胺（93 : 5 :2 )作爲流洗液以進行純化，生成白色固體之標的化合 物（9 0 %產率）。 】H-NMR ( CD3OD，5 00MHz ) 5 8·04 ( s，0.7H ) ，8.02 (s，0.3H) ，7.67(s，0.7H) ，7.65(s，0.3H) > 7.56 (d，J=8.5Hz，0.7H) ，7.5I(d，J=8.5Hz，0.3H)， -118- (114) (114)200529835 7.40 ( d， ，J= 8.5Hz，0.7H) ，7 · 3 3 ( d，J 二 8 · 5 H z， 0.3H) ，7.19—7.12 (m，2H) ，6·97— 6.94 (m，lH)， 6.80(d，J=8.0Hz，1H) ，5.08— 5.05 (m，1H) ，4.59Purification was performed by silica gel chromatography using CH2C12: methanol: triethylamine (93: 5: 2) as a flow wash to produce the target compound as a white solid (90% yield). ] H-NMR (CD3OD, 500 MHz) 5 8 · 04 (s, 0.7H), 8.02 (s, 0.3H), 7.67 (s, 0.7H), 7.65 (s, 0.3H) > 7.56 (d, J = 8.5Hz, 0.7H), 7.5I (d, J = 8.5Hz, 0.3H), -118- (114) (114) 200529835 7.40 (d,, J = 8.5Hz, 0.7H), 7 · 3 3 (d, J 2 8. 5 Hz, 0.3H), 7.19—7.12 (m, 2H), 6.97— 6.94 (m, 1H), 6.80 (d, J = 8.0Hz, 1H), 5.08— 5.05 (m, 1H), 4.59

-4.54 (m，1H) ，4.48— 4.42 (m，1H) ，4.37(s，IH-4.54 (m, 1H), 4.48—4.42 (m, 1H), 4.37 (s, IH

)，4.27— 4.20(m，2H) ，4.04(d，J=13.4Hz，0.3H), 4.27— 4.20 (m, 2H), 4.04 (d, J = 13.4Hz, 0.3H

)，3.99(d，J=13.4Hz，0.7H) ，3.19— 3.08(m，2H )，2.94-2.86 (m，3H) ，2.57(brs，2H) » 2.51 - 2.36 (m，2H) ，2.07— 2.05 (m，1H) ^ 1.90-1.31 (m ，16H) 。LC/MS: tR=1.85 分，613.44(MH) +。 藉由利用下述之條件進行消旋混合物之旋光分離，得 到（R )對映異構物，彼之個別合成係描述於上述實施例1. 中：Chiracel OD製備管柱，50x500 mm，20// m; A = EtOH，B二 0.05% 二乙胺 / 己院；20%B@65ml/ 分達 45 分 鐘；滯留時間：R對映異構物爲20.5分鐘且S對映異構物爲 3 2.8分鐘。 實施例7 (±) — 4— (2 —酮基一2，3 —二氫一苯並咪唑一 1 一基 )—喊B定—1—殘酸〔1— (1H—D引D朵一 5 -基甲基）—2 一 （4 一異丁基一哌嗪—1—基）一 2 —酮基—乙基〕一醯 胺 -119- (115) 200529835), 3.99 (d, J = 13.4Hz, 0.7H), 3.19—3.08 (m, 2H), 2.94-2.86 (m, 3H), 2.57 (brs, 2H) »2.51-2.36 (m, 2H), 2.07 — 2.05 (m, 1H) ^ 1.90-1.31 (m, 16H). LC / MS: tR = 1.85 points, 613.44 (MH) +. By optically separating the racemic mixture using the following conditions, the (R) enantiomer was obtained, and its individual synthesis is described in the above Example 1. Chiracel OD preparation column, 50x500 mm, 20 / / m; A = EtOH, B di 0.05% diethylamine / hexahedron; 20% B @ 65ml / min for 45 minutes; retention time: R enantiomer is 20.5 minutes and S enantiomer is 3 2.8 minutes. Example 7 (±) — 4— (2-keto-2,3-dihydro-benzimidazole-1 1-yl) —B-Ding-1—Residual acid [1-—1H—D 5-Methyl) -2 (4-isobutyl-piperazin-1-yl) -2-keto-ethyl] monofluorenamine-119- (115) 200529835

LC/MS: tR=2.05 分，572.31 (ΜΗ)LC / MS: tR = 2.05 points, 572.31 (ΜΗ)

實施例8 (±) — 4— (2—酮基一2，3 —二氫一苯並咪唑一1 一基 )一呢D定一 1 一殘酸〔2— (1，4一二氧雜一 8 —氮雜一螺 〔4.5〕癸一8 —基）一1— (1Η —吲哚一5 —基甲基）一 2 一酮基一乙基〕一醯胺Example 8 (±) — 4 — (2-keto-2,3-dihydro-benzimidazole- 1-yl) -N-D-D-1—A residual acid [2-—1,4-Dioxane -8-aza-spiro [4.5] decyl-8-yl)-1- (1fluorene-indole-5-ylmethyl) -2 2-ketomonoethyl] -amidine

LC/MS: tR=2.35 分，573.26 (MH) +。LC / MS: tR = 2.35 points, 573.26 (MH) +.

實施例9 (±) — 4— (2 —酮基一 2，3 —二氫一苯並咪唑一 1—基 )—哌啶一 1 —羧酸〔1 — ( 1 Η —吲唑一5 —基甲基）一 2 一 （4 一異丁基—暖嗪一]—基）一2 —酮1基—乙基〕一釀 胺 - 120- (116) (116)200529835Example 9 (±) — 4 — (2-keto-2,3-dihydro-benzimidazole-1 —yl) —piperidine — 1 —carboxylic acid [1 — (1 Η —indazole — 5 — Methyl)-2-(4-isobutyl-warmazine-]-yl)-2 -keto-1yl-ethyl] -methylamine-120- (116) (116) 200529835

LC/MS : tR= 1.86分，5 7 3.2 8 ( ΜΗ) +。 實施例1 〇 (土）一 4 一 （2 —嗣基一2，3 — 一氯一苯並咏口坐一1—基 )—哌啶一 1 —羧酸〔2 - （ 1，4 —二氮雜—8 —氮雜—螺 〔4.5〕癸一8 —基）一 1— (1H —吲哚一 5 —基甲基）一 2 一酮基一乙基〕一醯胺LC / MS: tR = 1.86 minutes, 5 7 3.2 8 (ΜΗ) +. Example 1 〇 (土) 一 4-(2-Amino-2,3- 3-chloro-benzobenzo- 1-yl) -piperidine-1 -carboxylic acid [2-(1,4 -2 Aza-8-aza-spiro [4.5] decyl-8-yl)-1- (1H-indole-5-ylmethyl) -2 2-keto-ethyl] -pyridamine

LC/MS: tR=2.18 分，574.23 (MH) +。 實施例1 1 (土） 一 4 — (2 —酬基一1，4 — 一 氨一2 Η — 口奎哇琳 一 3 — 基）一哌啶一 1 一羧酸〔2— （1，4 一二氧雜一 8—氮雜— 螺〔4.5〕癸一 8—基）一 1— (1Η—Π引D坐一5 —基甲基）一 2 —酮基一乙基〕一醯胺 -121 - (117) 200529835LC / MS: tR = 2.18 points, 574.23 (MH) +. Example 1 1 (Earth)-4-(2 -Amino-1,4--Ammonia-2 Η-Moxaquinaline-3 -yl) -piperidine-1 -carboxylic acid [2-(1,4 Dioxa-8-aza-spiro [4.5] decyl-8-yl)-1- (1Η-ΠΠD-S-5-ylmethyl) -2-ketomonoethyl] -amidine- 121-(117) 200529835

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將1，4 —二氧雜一 8 —氮雜螺〔4.5〕癸烷（32 mg， 0·23毫莫耳）和PyBOP® (107 mg，0.21毫莫耳）之二氯 甲 烷 (5 m 1 )溶液加入至3 — (1 Η —吲 哚—5 - -基）_ -2 - { 4 - -(2 :一酮基- -1，4 —二氫一2Η — D奎唑啉- - 3 -基 )_ 哌 啶 一 1 - -羰基〕 一胺基}— 丙酸（95 mg，0 .21毫莫 耳） 和 N ，N - -二異丙 基乙胺（〇 · 14 ml，0· .82毫莫 耳）之 二甲 基 甲 醯胺 (5 ml) 溶液中。室溫下攪拌 :該反應 混合物 1 6小 時 〇 局真 空下除去所有溶劑 。藉由閃 蒸管柱 層析並 利用 CH2丨 Cl2/ 甲醇/三 ί乙胺（93 : 5 : 2 )以 純水殘 餘物， 生成 白 色 固體 之標的化合物（67 mg，56%產率）。 iH-NMR ( CDC13，5 00MHz ) 5 1 0 · 5 2 ( s， 1 Η )， 7.9 7 ( s ，1 Η )，7.54 (s , 1 Η ) ，7.37 ( d ，J = 8 • 6Hz， 1H ) ? 7. 20 ( d，J - 10.7Hz ^ 1 Η ) ，7·16 ( t，J = 7 • 2Hz， 1H) 5 7. 04 ( d，J = 7· 6Ηζ，1 Η ) ，7.01 ( s ，1 H ) ，6·94 (t， J = :8 .6Hz ，1 Η )， 6·67 ( d ，： 7·6Ηζ， 1 H )， 5.64 ( d，J = 7. 9Hz， 1 Η )， 5·16 ( dd，. J = 1 5 ·0，< 6.7Hz， 1 Η )， 4.56 — 4. ,49 ( m 7 1 Η )，4·25 ( s，2H ) ，4· 1 1 (brt， J - 15 • 6Hz， 2Η ) ，3 .92 - 3.8 4 ( m，4 H ) ，3.73- -3.69 ( m 5 1H ) ，3 .60-3.5 6 ( s，2H ) ，3.48— 3.43 ( m， 1 Η )， -122 - 200529835 (118) 3·22— 3.17( m，1H) ，3.11 (d，J=6.7Hz，2H) ，2.90 -2.85 (m，2H) ，2.68-2.60 (m，4H) ，1·67 — 1.61 ( m，2H) ，：1·54— 1.49(m，2H)。質譜：588(MH)+。 4一溴一 2’ 6-二甲基苯基重氮基一特丁基硫化物Mix 1,4-dioxa-8-azaspiro [4.5] decane (32 mg, 0.23 mmol) and PyBOP® (107 mg, 0.21 mmol) in dichloromethane (5 m 1 ) Solution was added to 3-(1 Η-indole-5--yl) _ -2-{4--(2: monoketo--1,4-dihydro-2 Η-D quinazoline--3 -Yl) -piperidine- 1--carbonyl] monoamino} -propionic acid (95 mg, 0.21 mmol) and N, N--diisopropylethylamine (0.14 ml, 0.1 .82 mmol) in dimethylformamide (5 ml). Stir at room temperature: the reaction mixture was removed for 16 hours under vacuum. Chromatography on a flash column and the use of CH2 丨 Cl2 / methanol / triethylamine (93: 5: 2) with pure water residues yielded the target compound as a white solid (67 mg, 56% yield). iH-NMR (CDC13, 5 00MHz) 5 1 0 · 5 2 (s, 1 Η), 7.9 7 (s, 1 Η), 7.54 (s, 1 Η), 7.37 (d, J = 8 • 6Hz, 1H )? 7. 20 (d, J-10.7 Hz ^ 1 Η), 7 · 16 (t, J = 7 • 2 Hz, 1H) 5 7. 04 (d, J = 7 · 6 Η ζ, 1 Η), 7.01 ( s, 1 H), 6.94 (t, J =: 8.6 Hz, 1 Η), 6.67 (d ,: 7 · 6 Ηζ, 1 H), 5.64 (d, J = 7.9 Hz, 1 Η ), 5.16 (dd,. J = 1 5 · 0, < 6.7Hz, 1 Η), 4.56 — 4., 49 (m 7 1 Η), 4.25 (s, 2H), 4.1.1 1 (brt, J-15 • 6Hz, 2Η), 3.92-3.8 4 (m, 4 H), 3.73-3.69 (m 5 1H), 3.60-3.5 6 (s, 2H), 3.48— 3.43 (m, 1 Η), -122-200529835 (118) 3.22— 3.17 (m, 1H), 3.11 (d, J = 6.7Hz, 2H), 2.90-2.85 (m, 2H), 2.68-2.60 (m, 4H), 1.67 — 1.61 (m, 2H), 1.54 — 1.49 (m, 2H). Mass spectrum: 588 (MH) +. 4-bromo- 2 ′ 6-dimethylphenyldiazo-tert-butyl sulfide

利用碾缽和杵將4 —溴一 2，6—二甲基苯胺（20.00 g ’ 1 〇 〇毫莫耳）硏磨成粉末，隨後懸浮於2 4 % HC1 ( 41 m 1 )中。冷卻該攪拌混合物至-2 0 °C並與亞硝酸鈉（7.24 g，1·〇5當量）之水（16 ml )溶液反應（該亞硝酸鈉水溶 液係以超過4 0分鐘之時間逐滴地加入），同時保持溫度低 於一 5°C。經於—5°C至一20°C下3 0分鐘後，利用乙酸鈉固 體緩衝該混合物至約pH 5。於0 °C下以超過約1 〇分鐘時間 ，將該混合物（保持在約-1 下）分數份地加入至特丁 基硫赶（1 1 . 3 m 1，1當量）之乙醇（1 〇 〇 in 1 )攪拌溶液中 。經添加後，於〇 t下攪拌該混合物3 0分鐘，隨後加入碎 冰（約1 5 0 ml )。將該混合物置入冰箱隔夜貯存。藉由過 濾收集所生成淡褐色固體，經水冲洗後，於高真空下乾燥 數小時（26.90 g，89%)。該化合物爲安定之固體，但 當自乙醇中再結晶析出時，顯現顯著的分解。 】H-NMR ( CDC13，5 0 0MHz ) <5 1·58 ( 9H，s) ，].99 ( - 123- 200529835 (119) 6H，s) ，7.21(2H，s)。質譜：303·05(ΜΗ) +。 5 _漠一7 —甲基D引口坐4-Bromo-2,6-dimethylaniline (20.00 g '100 mmol) was pulverized into a powder using a mortar and pestle, and then suspended in 24% HC1 (41 m 1). The stirred mixture was cooled to -20 ° C and reacted with a solution of sodium nitrite (7.24 g, 1.05 equivalents) in water (16 ml) (the aqueous sodium nitrite solution was dripped over 40 minutes) Add) while keeping the temperature below -5 ° C. After 30 minutes at -5 ° C to -20 ° C, the mixture was buffered to approximately pH 5 with sodium acetate solids. This mixture (maintained at about -1) was added in portions to tert-butylthiophene (1 1.3 m 1.1 equivalents) of ethanol (1 0) at 0 ° C over a period of about 10 minutes. 〇in 1) Stir the solution. After the addition, the mixture was stirred at 0 t for 30 minutes, followed by the addition of crushed ice (about 150 ml). The mixture was stored in the refrigerator overnight. The resulting light brown solid was collected by filtration, rinsed with water, and dried under high vacuum for several hours (26.90 g, 89%). This compound is a stable solid, but when recrystallized from ethanol, it shows significant decomposition. H-NMR (CDC13, 500 MHz) < 5 1.58 (9H, s),]. 99 (-123-200529835 (119) 6H, s), 7.21 (2H, s). Mass spectrum: 303.05 (ΜΗ) +. 5 _ Mo 7-methyl D mouth sitting

將4一溴一 2，6-二甲基苯基重氮基一特丁基硫化物 (12.50 g，41.5毫莫耳）和特丁氧化鉀（46·56 g，10當 量）置入經火焰乾燥之圓底燒瓶中。加入攪拌棒並將該混 合物置於氮氣下。隨後加入乾DMSO( 120 ml)。室溫下 隔夜劇烈攪拌該混合物。將該反應混合物小心地倒入至碎 冰（400 ml )和10% HC1 ( 200 ml )之混合物中。於4°C 下隔夜靜置所生成長之懸浮液，並藉由過濾以收集固體且 以水冲洗。令粗固體溶解於5 ·· 1二氯甲烷/甲醇中，將該 溶液置於MgS04上乾燥且經蒸發後生成灰白色固體之產物 (7.60 g，87% )。 】H-NMR ( CDC13/ CD3OD，5 0 0MHz ) 5 2.51 ( 3H，s) ，7.22 ( 1H，s) ，7.69 ( 1H，s) ，7.94 ( 1H，s)。質 譜：2·11·03(ΜΗ) +。 7 —甲基吲唑—5 —醛Place 4-bromo-2,6-dimethylphenyldiazo-tert-butyl sulfide (12.50 g, 41.5 mmol) and tert-butoxide (46.56 g, 10 equivalents) in a flame Dry in a round bottom flask. A stir bar was added and the mixture was placed under nitrogen. Then dry DMSO (120 ml) was added. The mixture was stirred vigorously overnight at room temperature. The reaction mixture was carefully poured into a mixture of crushed ice (400 ml) and 10% HC1 (200 ml). The resulting long suspension was left to stand overnight at 4 ° C, and the solid was collected by filtration and rinsed with water. The crude solid was dissolved in 5 ·· 1 dichloromethane / methanol, and the solution was dried over MgS04 and evaporated to give the product as an off-white solid (7.60 g, 87%). H-NMR (CDC13 / CD3OD, 500 MHz) 5 2.51 (3H, s), 7.22 (1H, s), 7.69 (1H, s), 7.94 (1H, s). Mass spectrum: 2.11.03 (ΜΗ) +. 7-methylindazole-5-aldehyde

Η -124- 200529835 (120) 將5 —溴一 7 —甲基吲唑（6 · 1 0 g，2 8 · 9毫莫耳）和 NaH (60%礦物油液，1.27 g，1」當量）載入含有磁石攪 拌棒之經火焰乾燥的圓底燒瓶中。於室溫和氮氣下’加入 乾四氫咲喃（3 0 m 1 )。室溫下攪拌該混合物1 5分鐘，期 間該混合物呈均質狀。冷卻該攪拌混合物至- 70 °C，隨後 以超高數分鐘之時間加入另丁基鋰之環己烷溶液（1 .4 Μ ，4 5 ml，2 · 2當量）。經1小時後，於一 7 0 °C下以超過數 分鐘之時間，加入二甲基甲醯胺（1 0 m 1 )。令該混合物 回溫至室溫並隔夜攪拌。隨後冷卻至0 °C並小心地加入i n HC1 (60 ml )。經數分鐘後，加入NaHC〇3固體以驗化該 混合物至P Η 9 — 1 0。分離相層並利用乙酸乙酯冲洗水層2 次。利用〇 · 8 Μ N a H S Ο 4 ( 3 X 1 2 5 m 1 )萃取結合之有機層。 利用乙酸乙醋（1 00 ml )冲洗結合之水層，隨後利用 NaOH固體調整pH至約1〇。利用乙酸乙醋（3χ 1 5〇 ml ) 萃取所生成之懸浮液。利用鹽水冲洗結合之有機層，經乾 燥（M g S Ο4 )和蒸發後生成淡黃褐色固體之產物（3 . 〇 I g ，65% )。 】H-NMR ( CDC13，500MHz) 5 2·63 ( 3H，s)，7 7 3 ( 1H，s ) ，8.12 ( 1H，s ) ，8.25 ( 1H，〇 λ ) I ，s ) ，10·03 ( 1H， s )。質譜：161 .06 ( MH ) +。 2—苄氧羰基胺基一 3 -一丙烯酸甲酯Η -124- 200529835 (120) 5-Bromo-7-methylindazole (6 · 10 g, 2 8 · 9 mmol) and NaH (60% mineral oil, 1.27 g, 1 "equivalent) Load into a flame-dried round bottom flask containing a magnetic stir bar. At room temperature and under nitrogen, dry tetrahydrofuran (30 m 1) was added. The mixture was stirred at room temperature for 15 minutes, during which time the mixture was homogeneous. The stirred mixture was cooled to -70 ° C, and then a solution of another butyl lithium in cyclohexane (1.4 M, 45 ml, 2.2 equivalents) was added over a few minutes. After 1 hour, add dimethylformamide (10 m 1) at -70 ° C for more than a few minutes. The mixture was allowed to warm to room temperature and stirred overnight. Then cool to 0 ° C and carefully add in HC1 (60 ml). After a few minutes, NaHC03 solid was added to test the mixture to P Η 9-10. The phases were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were extracted with 0.8 M Na H S 0 4 (3 X 1 2 5 m 1). The combined aqueous layer was washed with ethyl acetate (100 ml), and then the pH was adjusted to about 10 using NaOH solids. The resulting suspension was extracted with ethyl acetate (3 × 150 ml). The combined organic layers were washed with brine, dried (M g S 0 4) and evaporated to give the product as a pale yellow-brown solid (3.0 I g, 65%). H-NMR (CDC13, 500MHz) 5 2.63 (3H, s), 7 7 3 (1H, s), 8.12 (1H, s), 8.25 (1H, 0λ) I, s), 10.03 (1H, s). Mass spectrum: 161.06 (MH) +. 2-benzyloxycarbonylamino-methyl 3-acrylate

吲唑—5 —基 -125- (121) 200529835Indazole-5-yl-125- (121) 200529835

HN 一 NHN a N

室溫下令N—苄氧羰基- α -亞磷羧基甘胺酸三甲酯 (5.51 g，1.2當量）之四氫呋喃（30 ml)攪拌溶液與四 甲基胍（1.91 ml，1·1當量）反應。經10分鐘後’加入7 -甲基吲唑一 5 —醛（2.22 g，13.86毫莫耳）之四氫呋喃（ 2 0 m 1 )溶液。藉由T L C和L C / M S監控起始物之消耗。於 室溫下經5天後，蒸發溶劑並令殘餘物溶解於乙酸乙酯中 。利用2 %磷酸和鹽水冲洗該溶液，置於M g S Ο 4上乾燥並 進行蒸發。藉由矽膠閃蒸層析且利用1 : 1和2 : 1之乙酸乙 酯/己烷作爲流洗液以純化殘餘物’生成無色泡沬狀之產 物（4.93 g’ 97%)。 j-NMR ( CDC13，500MHz ) 5 2·43 ( 3H，s) ，3.80 ( 3H，s) ，5.12(2H，s) ，6.66( 1H，S) ，7.28(5H， brs ) ，7.33(lH，s) ，7.47(lH，s) ，7.7 4(lH，s) ，7.96 ( 1H，s )。質譜：3 66. 1 6 ( MH ) +。 (±) — 2 —胺基一 3 — （7 — 甲基一 1H — D 引 口坐一 5 —基）一 丙酸甲酯 -126- (122) (122)200529835Tetrahydrofuran (30 ml) stirred solution of N-benzyloxycarbonyl-α-phosphorous carboxyglycine trimethyl ester (5.51 g, 1.2 equivalents) was reacted with tetramethylguanidine (1.91 ml, 1.1 equivalents) at room temperature. . After 10 minutes', a solution of 7-methylindazole-5 -aldehyde (2.22 g, 13.86 mmol) in tetrahydrofuran (20 m 1) was added. Consumption of starting materials was monitored by T L C and L C / M S. After 5 days at room temperature, the solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was rinsed with 2% phosphoric acid and brine, dried over MgS04 and evaporated. The residue was purified by silica gel flash chromatography using 1: 1 and 2: 1 ethyl acetate / hexane as a flow wash to produce a colorless foamy product (4.93 g '97%). j-NMR (CDC13, 500MHz) 5 2.43 (3H, s), 3.80 (3H, s), 5.12 (2H, s), 6.66 (1H, S), 7.28 (5H, brs), 7.33 (lH, s), 7.47 (lH, s), 7.74 (lH, s), 7.96 (1H, s). Mass spectrum: 3 66. 1 6 (MH) +. (±) — 2 —Amine — 3 — (7 —Methyl — 1H — D — 5 —yl) — Methyl propionate -126- (122) (122) 200529835

藉由冒出氮氣通過30分鐘以使2 -节氧鑛基胺基- 3-(7 —甲基一1H —吲唑一 5—基）一丙烯酸甲酯（4.93 g， 1 3 J9毫莫耳）之甲醇（125 ml )溶液脫氣，隨後小心地 加入10%Pd/C(0.6 g)。於40 psi下在par r搖動裝置中 隔夜氫化該混合物。藉由通過寅氏鹽墊以過濾除去觸媒， 隨後真空濃縮濾液以生成無色泡沫之產物（3.6 2 g，定量 】H-NMR ( CD3OD，5 00MHz ) (5 2 · 4 5 ( 3 Η，s ) ，2.99 ( lH，Abq) ，3.22(lH，Abq) ，3.74(3H，s) ,3.89( lH，m) ，6.91(lH，s) ，7.31(1H，s) ，7.73(1H，s )。質譜：234·11(ΜΗ) +。 實施例1 2 (±) — 3— (7— 甲基一1H —吲唑一5 —基）一2— { 〔4 —(2 —嗣基一 1，4 — 一氯—2H-唁卩坐琳一3 —基）—喊 啶一 1一羰基〕—胺基} 一丙酸甲酯Pass 2-nitrogenaminoamine-3- (7-methyl-1H-indazole-5-yl) monoacrylate (4.93 g, 1 3 J9 mmol) by passing nitrogen through for 30 minutes. ) In methanol (125 ml), followed by careful addition of 10% Pd / C (0.6 g). The mixture was hydrogenated overnight in a par r shaker at 40 psi. The catalyst was removed by filtration through a Yin's salt pad, and the filtrate was then concentrated in vacuo to produce a colorless foam product (3.6 2 g, quantitative) H-NMR (CD3OD, 5000 MHz) (5 2 · 4 5 (3 Η, s ), 2.99 (lH, Abq), 3.22 (lH, Abq), 3.74 (3H, s), 3.89 (lH, m), 6.91 (lH, s), 7.31 (1H, s), 7.73 (1H, s) Mass spectrum: 234 · 11 (ΜΗ) +. Example 1 2 (±) — 3— (7-methyl-1H—indazole-5 —yl) —2 — {[4 — (2 —fluorenyl-1 , 4-chloro- 2H-pyridinyl-3-yl)-oxidine-1-carbonyl]-amino} methyl propionate

-127- (123) (123)200529835 室溫下令羰基二咪唑（113.2 mg，1當量）與（±) 一 2 —胺基一3 — （7 —甲基—1H — D引D坐一 5 —基）—丙酸 甲酯（162.9 mg，0.698毫莫耳）之二氯甲烷（3 ml)攪拌 溶液反應。於宝溫下經〗.5小時後，加入3 —哌啶一 4 一基 —3，4 —二氫一1H—D奎 Π坐啉一2 —酮（161.5 mg，1 當量） 。室溫下隔夜攪拌該混合物。生成白色沈澱物，其爲所欲 之產物。蒸發溶劑並利用CH2C12碾製殘餘物。藉由過濾以 收集產物，經由CHeh冲洗並於真空下乾燥，生成白色固 體（24 1 ·5 mg，71 % )。某些產物殘留於母液中。 】Η-ΝΜΙΙ(二甲基甲醯胺一d6，500MHz) (5ΐ·75(4Η， m ) ，2.78(3H，s) ，2.7—3.1(4H，s) ? 3.35 ( 2 H > m )，3.86(3H，s) ，4.57(lH，m) ，4.72(lH，m)， 7.11 (3H，m) ，7.31(1H，s) ，7.34(2H，m) ，772 (1H，s) ，9·34(1Η，s)。質譜：491.13(MH) +。 類似之方法製備： 實施例1 3 3 — （7—甲基一 1H— 吲唑一 5 —基）—2— 〔2 一 ，3^一 二氫一 2 / —酮基螺一（哌啶一 4，4 / 一 （ 1 Η ) 一 d奎π坐琳 )羰基胺基〕一丙酸甲酯-127- (123) (123) 200529835 Order carbonyldiimidazole (113.2 mg, 1 equivalent) with (±) 2 -amino 3-(7 -methyl-1H-) at room temperature Group)-A solution of methyl propionate (162.9 mg, 0.698 mmol) in dichloromethane (3 ml) was reacted. After 5 minutes at Bao Wen, add 3-piperidine-4-diyl-3,4-dihydro-1H-D-quinoline to 2-one (161.5 mg, 1 equivalent). The mixture was stirred overnight at room temperature. A white precipitate was formed, which was the desired product. The solvent was evaporated and the residue was milled with CH2C12. The product was collected by filtration, rinsed through CHeh and dried under vacuum to give a white solid (24 1 · 5 mg, 71%). Some products remain in the mother liquor. ] Η-NMILI (dimethylformamide-d6, 500MHz) (5ΐ · 75 (4Η, m), 2.78 (3H, s), 2.7-3.1 (4H, s)? 3.35 (2H > m) , 3.86 (3H, s), 4.57 (lH, m), 4.72 (lH, m), 7.11 (3H, m), 7.31 (1H, s), 7.34 (2H, m), 772 (1H, s), 9. · 34 (1Η, s). Mass spectrum: 491.13 (MH) +. Prepared in a similar manner: Example 1 3 3 — (7-methyl-1H-indazol-5-yl) — 2 — [2 1, 3 ^ -dihydro-2 / -ketospiro- (piperidine-4,4 /-(1 Η) -d-quineline) carbonylamino] monopropionate methyl ester

1 Η · N M R ( D M S 0 - d 6 ) 5 1 . 5 9 ( 4 Η，m ) ，2.4 6 ( 3 η，s (124) 200529835 )，3.00— 3.08(4H，s) ，3.6(3H，s) ，3.78-3.81( 2Η，ιιι) ，4·30— 4.32 ( lH，m) ，6.78-6.88 (4H，m) ，7_03(lH，s) ，7.10(lH，m) ，7.13(lH，s)， 7.41 (lH，s) ，7.96(lH，s) ，9.12(lH，s)。質譜 :477· 1 1 ( ΜΗ ) +。 實施例1 4 3— (7 —甲基一 1H — D 引唑一5 —基）一 2— (1，2 —二氫 一 2 —酮基螺—4H— 3，1一二氫—苯並噁嗪—4，，4一哌 啶一羰基胺基）一丙酸甲酯 〇1 Η NMR (DMS 0-d 6) 5 1. 5 9 (4 Η, m), 2.46 (3 η, s (124) 200529835), 3.00—3.08 (4H, s), 3.6 (3H, s ), 3.78-3.81 (2Η, ιιι), 4.30-4.32 (lH, m), 6.78-6.88 (4H, m), 7_03 (lH, s), 7.10 (lH, m), 7.13 (lH, s) ), 7.41 (lH, s), 7.96 (lH, s), 9.12 (lH, s). Mass spectrum: 477 · 1 1 (Μ +) +. Example 1 4 3- (7-methyl-1H-D Indazole-5-yl) -2- (1,2-dihydro-2 2-ketospiro-4H-3,1-dihydro-benzo Oxazine-4,4,4-piperidine-carbonylamino) methyl propionate.

h3co '〇 質譜：4 7 8 · 1 5 ( Μ Η ) +。 厂，r —二 一 D奎啉羰基胺 3— (7 — 甲基一1Η — D 引唑一5 —基）一2{ 氨—2 -醒基螺（_D定一 4，4 — ( 1 Η ) 基} 一丙酸甲酯h3co '〇 mass spectrum: 4 7 8 · 15 (ΜΗ) +. Plant, r-di-D-quinolinylcarbonylamine 3- (7-methyl-1, 1-diazole, 5-azole), 2 {ammonia-2, 2-spirospiro (_D 定 一 4, 4 — (1 Η ) Group} methyl propionate

]H-NMR ( DM SO - d6) (5 1.42 - 1.56 (4H^ m) ，2.47 (3H，s) ，2.50— 2.54 ( lH，d) ，2.60— 2.64 ( lH，d -129- (125) 200529835 )，2·98— 3.06(4H，m) ，3.60(3H，s) ，3.80(2H， m ) ，4.30(lH，m) ，6.86(2H，d) ，6.95(2H，m) ，7.15(lH，m) ，7.40(lH，s) ，7.95(lH，s)， 8.32(lH，s) ，10.14(lH，s) ，13.05(lH，s)。質 譜：476·17(ΜΗ) +。 3 — ( 7 —甲基 一 1 Η — D 引口坐一5 —基）一2 — 〔2 —苯基一 1，，3# ，8，—三氮雜一螺（4，，5^)癸—1—烯—8 一羰基胺基〕一丙酸甲酯] H-NMR (DM SO-d6) (5 1.42-1.56 (4H ^ m), 2.47 (3H, s), 2.50—2.54 (lH, d), 2.60— 2.64 (lH, d -129- (125) 200529835), 2.98—3.06 (4H, m), 3.60 (3H, s), 3.80 (2H, m), 4.30 (lH, m), 6.86 (2H, d), 6.95 (2H, m), 7.15 (lH, m), 7.40 (lH, s), 7.95 (lH, s), 8.32 (lH, s), 10.14 (lH, s), 13.05 (lH, s). Mass spectrum: 476 · 17 (ΜΗ) + . 3 — (7 —methyl-1 1 Η — D inlet sits a 5 —yl) — 2 — [2 —phenyl-1, 3 #, 8, —triaza-spiro (4 ,, 5 ^ ) Dec-1-ene-8 monocarbonylamino] methyl propionate

h3^u u 1 H-NMR ( DMSO - d6 ) 5 1.50(2H，m) ，1·68(2Η， m ) ，2.46(3H，s 重疊 DMSO) ，3.05(2H，m) ，3.30h3 ^ u u 1 H-NMR (DMSO-d6) 5 1.50 (2H, m), 1.68 (2Η, m), 2.46 (3H, s overlap DMSO), 3.05 (2H, m), 3.30

(2H，m) ，3.60(3H，s) ，3.86(2H，m) ，4.28(1H ，m) ，6.98(lH，d) ，7.04(lH，s) ，7.40(lH，s) ，7.58(2H，m) ，7.65(lH，m) ，8.00(lH，s)， 8.04(2H，m)。質譜：489.15 (MH) +。 實施例1 5 (±) — 3— (7 —甲基一1H — 口引唑一5 —基）一2{ 〔4 — (2 —嗣基_ 1，4 —氯一2 Η — D奎口坐琳一3 —基）一呢D定—1 一羰基〕一胺基丨一丙酸 -130- (126) (126)200529835(2H, m), 3.60 (3H, s), 3.86 (2H, m), 4.28 (1H, m), 6.98 (lH, d), 7.04 (lH, s), 7.40 (lH, s), 7.58 ( 2H, m), 7.65 (lH, m), 8.00 (lH, s), 8.04 (2H, m). Mass spectrum: 489.15 (MH) +. Example 1 5 (±) — 3 — (7 —methyl-1H — oxazole-5 —yl) — 2 {[4 — (2 —fluorenyl_ 1,4 —chloro-1 2 hydrazine — D-quinol Zirin- 3 -yl) -D-D-1 -carbonyl] -amino group 丨 -propionic acid-130- (126) (126) 200529835

室溫下令LiOH(140.5 mg，7當量）之水（1〇 ηιι)溶 液與（±) — 3 — （7 —甲基一1H —卩引 _ — 5 —基）一2— { 〔4一（2 —酮基一 1,4 —二氫—2H—喹唑啉一 3 —基）— 哌啶一 1 一羰基〕一胺基}—丙酸甲酯（240.0 mg，0.489 毫莫耳）之1: 1四氫咲喃/甲醇（20 ml)懸浮液反應。 於1分鐘內，該混合物呈均質狀，隨後於4 °C下隔夜靜置。 於約30°C下蒸發溶劑並利用IN HC1調整其pH至約1。於4 °C下貯存所生成之白色懸浮液達數小時，隨後藉由過濾以 收集產物，利用少量水進行冲洗，並於真空下乾燥（ 169.0 mg’ 73% )。加入NaCI固體至濾液中，生成較多產 物之沈澱（5.2 m g，總產率7 5 % )。At room temperature, make a solution of LiOH (140.5 mg, 7 eq.) In water (10 μm) and (±) — 3 — (7 —methyl-1H — hydrazine — — 5 —yl) — 2 — {[4 一 ( 2-keto-1,4-dihydro-2H-quinazoline-3-yl) -piperidine-1 monocarbonyl] monoamino} -methyl propionate (240.0 mg, 0.489 mmol) : 1 Tetrahydrofuran / methanol (20 ml) suspension reaction. Within 1 minute, the mixture was homogeneous and then allowed to stand overnight at 4 ° C. The solvent was evaporated at about 30 ° C and its pH was adjusted to about 1 with IN HC1. The resulting white suspension was stored at 4 ° C for several hours, and then the product was collected by filtration, rinsed with a small amount of water, and dried under vacuum (169.0 mg '73%). Adding NaCI solids to the filtrate resulted in precipitation of more products (5.2 mg, total yield 75%).

W-NMR ( CD3OD，5 00MHz ) 5 1 · 2 - 1 .7 ( 4 Η，m )， 2.58 (3Η，s ) ’ 2.5— 3.2 (4H，m) ，3.35 ( 2 Η 5 m )， 4.15 (2H，m) ’ 4.36 ( 1H，m) ，4.60 ( 1H，m) 5 6.79 (lH，d) ，6.96(lH，t) ，7.18(3H，m) ^ 7.49 ( 1H ，s) ，8.〇〇(lH，s)。質譜：477.13(MH)+。 類似之方法製備： 3— (7 〜甲基一 1 H —吲唑—5 —基）—2— [ 2 ^ ，3^ — 氫一2 / —酮基螺一（哌啶一 4，4 / — ( I Η ) — D奎唑啉羰 基胺基〕〜丙酸 -131 - (127) (127)200529835W-NMR (CD3OD, 500 MHz) 5 1 · 2-1. 7 (4 Η, m), 2.58 (3 Η, s) '2.5— 3.2 (4H, m), 3.35 (2 Η 5 m), 4.15 ( 2H, m) '4.36 (1H, m), 4.60 (1H, m) 5 6.79 (lH, d), 6.96 (lH, t), 7.18 (3H, m) ^ 7.49 (1H, s), 8. O (lH, s). Mass spectrum: 477.13 (MH) +. Prepared in a similar way: 3- (7 ~ methyl-1H-indazol-5-yl) -2- [2 ^, 3 ^ -hydrogen-2 / -ketospiro-1 (piperidine-4, 4 / — (I Η) — D quinazoline carbonylamino] ~ propionic acid -131-(127) (127) 200529835

1 H-NMR ( DMSO - d6 ) 51.58(4H，m) ，2.46(3H，s )，3.00—3.23 (3H，m) ，3.78— 3.91(3H，m) ^ 3.88 (2H，m) ，4.28(lH，s) ，6.70(lH，d) ，6.75 — 6.85(3H，m) ，7.04(lH，d) ，7.11(lH，m) ，7.18 (lH，s) ，7.96(lH，s) ，13.02(lH，m)。質譜： 4 63.09 ( ΜΗ ) +。 3— (7 —甲基—1H — 口引唑一5 —基）一2— (1，2 —二氫 一 2 一醒基螺—4H—3，1— ^氯—苯並卩惡嗦一 4 ，4 —喊 啶一羰基胺基）一丙酸甲酯1 H-NMR (DMSO-d6) 51.58 (4H, m), 2.46 (3H, s), 3.00-3.23 (3H, m), 3.78-3.91 (3H, m) ^ 3.88 (2H, m), 4.28 ( lH, s), 6.70 (lH, d), 6.75-6.85 (3H, m), 7.04 (lH, d), 7.11 (lH, m), 7.18 (lH, s), 7.96 (lH, s), 13.02 (lH, m). Mass spectrum: 4 63.09 (ΜΗ) +. 3— (7—Methyl—1H—orazol-5—yl) —2— (1,2, dihydro—2—Axylspiro-4H—3,1— chloro—benzopyrene] 4,4—Methylidine-carbonylamino) monopropionate

】H-NMR(DMS0— d6) 5 1.63-1.98 (4H，m) ，2·46 (3H，s，7-Me 重疊 DSM0) ，2·98-3·32(4Η，ηι)， 3.90(2H，m) ，4·28(1Η，ηι) ，6.78(lH，d) ，6.87 (2H，m) ，6·96(1Η，ηι) ，7.05(lH，s) ，7·24(1Η ，m) ，7.41(]H，s) ，7.96(lH，s) ，：10,22(lH，s )，：1 2.4 2 ( 1 H，b r. ) ，1 3.0 2 ( ] H，m )。質譜：4 6 4 · 0 7 (ΜΗ) -132 - (128) 200529835 3— (7 -甲基一1H — D 引唑一5 —基）一2{3〆，4〆一二 氯一 2 -酬基螺—（喊D定一 4，4 — (1H) —ti奎琳—羯 基胺基丨-丙酸H-NMR (DMS0-d6) 5 1.63-1.98 (4H, m), 2.46 (3H, s, 7-Me overlap DSM0), 2.98-3.32 (4Η, η), 3.90 (2H M), 4.28 (1Η, η), 6.78 (lH, d), 6.87 (2H, m), 6.96 (1Η, η), 7.05 (lH, s), 7.24 (1Η, m ), 7.41 (] H, s), 7.96 (lH, s) ,: 10,22 (lH, s) ,: 1 2.4 2 (1 H, b r.), 1 3.0 2 (] H, m). Mass spectrum: 4 6 4 · 0 7 (ΜΗ) -132-(128) 200529835 3— (7-methyl-1H—D indazole-5—yl) —2 {3〆, 4〆—dichloro—2- Stilbyl Spiro— (Should D be a 4,4— (1H) —ti quinine—fluorenylamino 丨 -propionic acid

N-NHN-NH

】H-NMR(DMSO—d6) 5 1.39-1.45 (2H，m) ，1·53 -1.56(2H，m) ，2.46(3H，s) ，2.50-2.54(lH，d )，2·60— 2.63 ( lH，d) ，2.83— 3.03 (3H，m) ，3.09 一 3.11(lH，m) ，3.78—3.81 (2H，m) ，4.27( lH，m )，6.69— 6.70(lH，d) ，6.86— 6.87(lH，d) > 6.93 —6.94( lH，m) ，6.99-7.00( lH，m) ，7.05(lH，m )，7.41(lH，s) ，7_95(lH，s) ，10.13(lH，s)， 12.50(lH，m) ，：!3.03(lH，m)。質譜：462(MH) + 3— (7 一甲基—1H — D弓 I 唑一5— 基）一2{2 / — 苯基一 1 ^ ，3， ，8，一三氮雜一螺（4^ ，5^)癸一1—烯一8 一羰基胺基〕-丙酸] H-NMR (DMSO-d6) 5 1.39-1.45 (2H, m), 1.53-1.56 (2H, m), 2.46 (3H, s), 2.50-2.54 (lH, d), 2.60- 2.63 (lH, d), 2.83-3.03 (3H, m), 3.09-3.11 (lH, m), 3.78-3.81 (2H, m), 4.27 (lH, m), 6.69-6.70 (lH, d), 6.86— 6.87 (lH, d) > 6.93—6.94 (lH, m), 6.99-7.00 (lH, m), 7.05 (lH, m), 7.41 (lH, s), 7_95 (lH, s), 10.13 (lH, s), 12.50 (lH, m) ,: 3.03 (lH, m). Mass spectrum: 462 (MH) + 3— (7-methyl-1H—D archyl azole—5-yl) —2 {2 / —phenyl—1 ^, 3,, 8, 1, triaza-spiro ( 4 ^, 5 ^) decyl 1-ene-8 monocarbonylamino] -propionic acid

HO -133- 200529835 (129) 】H-NMR(DMSO— d6) 5 1.36(2H，m) ，：l.63(2H， m ) ，2.46(31^，5重疊031\40) ，2.98— 3.03 (2H，m) ，3.09—3.11 (2H，m) ，3.86(2H，m) ，4.21(lH，m )，7.04( lH，s) ，7.40(lH，s) ，7·52— 7·58(3Η， m) ，7.99(3H，m) ，：ll.55(lH，m) ，：!3.00(lH，m )。質譜：475.08( MH ) +。HO -133- 200529835 (129)】 H-NMR (DMSO- d6) 5 1.36 (2H, m), 1.63 (2H, m), 2.46 (31 ^, 5 overlap 031 \ 40), 2.98- 3.03 (2H, m), 3.09-3.11 (2H, m), 3.86 (2H, m), 4.21 (lH, m), 7.04 (lH, s), 7.40 (lH, s), 7.52-7.58 (3Η, m), 7.99 (3H, m), ll.55 (lH, m),! 3.00 (lH, m). Mass spectrum: 475.08 (MH) +.

實施例1 6 (±) 4— (2 —酮基一 1，4 -二氫一2H—喹唑啉一 3 —基 )—喊卩定一 1 —殘酸〔2 —〔 1，4 〕聯_ Π定一 1 —基— (7 —甲基一 1H —吲唑一 5 —基甲基）一2 —酮基一乙基） -醯胺Example 1 6 (±) 4- (2-keto-1,4-dihydro-2H-quinazoline-3-yl) -Hexidine-1-Residual acid [2-[1, 4] _ 定 a 1 -yl-(7 -methyl-1H-indazole-5-methyl)-2-keto-ethyl)-hydrazine

於〇°C下令（±) — 3— (7 —甲基一 1H —吲唑一 5 —基 )—2 — { 〔4 — (2 —嗣基一1，4 — 一氯一2 Η — 口 奎 口坐琳一 3 —基）—哌啶一 1 一羰基〕一胺基丨一丙酸（65.7 mg， 0.138毫莫耳）之2: 1 二甲基甲醯胺/CH2C12(1.5 ml) 攪拌溶液與4 一（ 1 一哌Π定基）一哌D定（4 6.5 m g，2當量） 、二異丙基乙胺（0.048 ml，2當量）及PyBOP® (75.5 m g，]. 0 5當量）反應。令冰浴溶解並於室溫下隔夜攪拌該 -134- (130) (130)200529835 混合物。高真空下除去溶劑，並藉由矽膠閃蒸層析（流洗 液爲含有1 %三乙胺之1 8 : 1 CH2C12/甲醇）純化殘餘物 ，生成灰黃色固體之產物（80.4 mg，93%)。 1 H-NMR ( CD3OD，5 00MHz ) 5 - 0 · 2 8 ( 1 Η，m ) ，0.7 5 (lH，m) ，1.2-2.0(12H，m) ，2.08(2H，m) ，2.4 —2.5(3H，m) ，2.59(3H，s) ，2.68(2H，m) ^ 2.90 (4H，m) ，3e〇8(4H，m) ，3.9-5.1 (4H，數 m)， 6.81 (lH，d) ，6.96(lH，t) ，7.16(3H，m) ^ 7.49 (lH，s) ，8.03(lH，s)。質譜：627.29(MH)+。 類似之方法製備： 實施例1 7 (±) — 4— (2 —酮基一1，4 —二氫一 2H — D奎唑啉一3 — 基）一哌啶一1 一羧酸〔1 — ( 7 —甲基一1 Η — D弓丨唑一 5 — 基甲基）一 2 —酮基一 2—哌啶—1—基—乙基〕一醯胺(±) — 3 — (7 —methyl-1H —indazol 5 —yl) — 2 — {〔4 — (2 —fluorenyl-1,4 —monochloro-2 2 — — at 0 ° C) Quekouline-3-yl) -piperidine-1 monocarbonyl] -amino group 丨 monopropionic acid (65.7 mg, 0.138 mmol) 2: 1 dimethylformamide / CH2C12 (1.5 ml) Stir The solution was mixed with 4 (1-piperidinyl)-piperidin (4 6.5 mg, 2 equivalents), diisopropylethylamine (0.048 ml, 2 equivalents), and PyBOP® (75.5 mg,]. 0 5 equivalents) reaction. The ice bath was allowed to dissolve and the -134- (130) (130) 200529835 mixture was stirred overnight at room temperature. The solvent was removed under high vacuum, and the residue was purified by silica gel flash chromatography (the washing solution was 1 8: 1 CH2C12 / methanol containing 1% triethylamine) to give the product as an off-white solid (80.4 mg, 93% ). 1 H-NMR (CD3OD, 500 MHz) 5-0 · 2 8 (1 Η, m), 0.7 5 (lH, m), 1.2-2.0 (12H, m), 2.08 (2H, m), 2.4-2.5 (3H, m), 2.59 (3H, s), 2.68 (2H, m) ^ 2.90 (4H, m), 3e〇8 (4H, m), 3.9-5.1 (4H, several m), 6.81 (lH, d), 6.96 (lH, t), 7.16 (3H, m) ^ 7.49 (lH, s), 8.03 (lH, s). Mass spectrum: 627.29 (MH) +. Prepared in a similar manner: Example 1 7 (±) — 4— (2-keto-1,4-dihydro-2H—D quinazoline-3-yl) -piperidine-1 1-carboxylic acid [1 — (7-methyl-1, 1-D-bendazole-5-methyl), 2-keto-2, piperidin-1-yl-ethyl] -ammonium

】H-NMR ( CD3OD，5 00ΜΗζ ) δ 0 · 8 7 ( 1Η，m ) ，1·33 (1 Η，m ) ，：1 . 4 7 ( 2 Η，m ) ，1 . 8 0 ( 6 Η，m ) ，2.5 7 ( 3H，s) ，2.89(2H，m) ，3.06(2H，m) ，3·18(4Η， m ) ，3 · 4 0 ( 2 H，m ) ，3 · 6 ] ( 1 H，m ) ，4 . 1 6 ( 1 H，m ) ，4 · 2 8 ( 1 H，A b q ) ，4 · 4 3 ( 1 H，m ) ，5 . 0 2 ( 1 H，m )， -135- (131) (131)200529835 6.51 (lH，d) ，6.79(lH，d) ，6.96(lH，t) ，7.11( lH，d) ，7.15(lH，t) ，7.48(lH，s) ，8.01(lH，s )。質譜：544.24(MH)+。 實施例1 8 (土）一 4 — ( 2 —酬基一1，4 一 一 氨—2 Η — D 奎 口坐琳一3 — 基）一哌啶—1 一羧酸〔1 一二甲基氨基甲醯基一 2 — （7- 甲基一1Η—吲唑一5-基）一乙基〕一醯胺H-NMR (CD3OD, 500MΗζ) δ 0 · 8 7 (1Η, m), 1.33 (1 Η, m): 1. 4 7 (2 Η, m), 1. 8 0 (6 Η , M), 2.5 7 (3H, s), 2.89 (2H, m), 3.06 (2H, m), 3.18 (4Η, m), 3 · 4 0 (2 H, m), 3 · 6] (1 H, m), 4. 1 6 (1 H, m), 4 · 2 8 (1 H, A bq), 4 · 4 3 (1 H, m), 5.0 2 (1 H, m ), -135- (131) (131) 200529835 6.51 (lH, d), 6.79 (lH, d), 6.96 (lH, t), 7.11 (lH, d), 7.15 (lH, t), 7.48 (lH , S), 8.01 (lH, s). Mass spectrum: 544.24 (MH) +. Example 1 8 (Earth)-4-(2 -Amino-1,4 -Ammonia-2 Η-D quetiazolin -3 -yl) -piperidine-1 -carboxylic acid [1 -dimethyl Carbamidyl-2- (7-methyl-1,1-indazole-5-yl) -ethyl] -amidine

】H-NMR ( CD3OD，5 00MHz ) 5 1·12 ( 2H，d) ，1.64(] H-NMR (CD3OD, 500 MHz) 5 1 · 12 (2H, d), 1.64 (

2H，m) ，2.57(3H，m) ，2.74(lH，m) ，2.87(3H ，s) ，2.89(3H，s) ，2.86(2H，m) ，3.07(2H，m )，3.20(lH，m) ，4.17(lH，m) ，4.25(lH，Abq) ，4.43(lH，m) ，4.97(lH，m) ，6.79(lH，d)， 6.95(lH，t) ，7·0— 7.4(3H，m) ，7.48(lH，d)， 8.01 (1H，s)。質譜：504.15(MH)+。 實施例1 9 (±) — 4 — （2— 酮基一1，4 —二氫一2H — D奎唑啉一3 — 基）一哌啶一1 —羧酸〔1 — ( 7 —甲基一1 Η — D引唑一5 — 基甲基）一2 — （ 4 —甲基—哌嗪一 1 —基）一2 —酮基一乙 -136- (132) (132)200529835 基〕一醯胺2H, m), 2.57 (3H, m), 2.74 (lH, m), 2.87 (3H, s), 2.89 (3H, s), 2.86 (2H, m), 3.07 (2H, m), 3.20 (lH , M), 4.17 (lH, m), 4.25 (lH, Abq), 4.43 (lH, m), 4.97 (lH, m), 6.79 (lH, d), 6.95 (lH, t), 7.0- 7.4 (3H, m), 7.48 (lH, d), 8.01 (1H, s). Mass spectrum: 504.15 (MH) +. Example 1 9 (±) — 4 — (2-keto-1,4-dihydro-2H—D quinazoline-3-yl) -piperidine-1—carboxylic acid [1 — (7-methyl 1 1 Η —D-azole- 5 -ylmethyl) 2 — (4-methyl-piperazine 1 -yl) 2 —keto-ethyl-136- (132) (132) 200529835 group] a Amidine

】H-NMR ( CD3OD，5 00MHz ) 5 1.30 ( 2H，m) ，1.66 (2H，m) ，1·78(1Η，χη) ，：l.90(lH，m) ，2.00( 3H，s) ，2.19(lH，m) ，2.35(lH，m) ，2·58(3Η，H-NMR (CD3OD, 500 MHz) 5 1.30 (2H, m), 1.66 (2H, m), 1.78 (1Η, χη), 1.90 (lH, m), 2.00 (3H, s) , 2.19 (lH, m), 2.35 (lH, m), 2.58 (3Η,

s ) ，2.88(2H，m) ，3.09(2H，d) » 3.10-3.45 (3H ，m) ，3.66( lH，m) ，4.19(2H，d) ，4.20(2H，s )，4.43(lH，m) ，4.98(lH，t) ，6.80(lH，d)， 6.95(lH，t) ，7.11(2H，m) ，7.16(lH，t) ^ 7.47 (lH，s) ，8.02(lH，s)。質譜：559·23(ΜΗ)+。 實施例2 0 (±) — 4— (2 —酮基一1，4 —二氫一2H — 口奎唑啉一3 — 基）—呢Π定—1 一殘酸〔1 一 （7 —甲基—1H — D引D坐—5 — 基甲基）一2 —酮基一 2 — 咯B定一 1 一基一乙基〕一酿胺s), 2.88 (2H, m), 3.09 (2H, d) »3.10-3.45 (3H, m), 3.66 (lH, m), 4.19 (2H, d), 4.20 (2H, s), 4.43 (lH , M), 4.98 (lH, t), 6.80 (lH, d), 6.95 (lH, t), 7.11 (2H, m), 7.16 (lH, t) ^ 7.47 (lH, s), 8.02 (lH, s). Mass spectrum: 559 · 23 (ΜΗ) +. Example 2 0 (±) — 4— (2-keto-1,4-dihydro-1H—quinazoline-3 —yl) —Nididine-1 1 residual acid [1 1 (7 — -1H — D — D — 5 — methyl — 2 — keto — 2 — pyridine, 1 — 1 — 1 —yl] amine

H-NMR ( CD3OD，500MHz) 5 1.4 0 - 1.90 ( 5H，m ) ，2.0 2 ( 3 Η，b r s ) ，2 . 5 7 ( 3 H，s ) -137- 200529835 (133) 2.89(2H，q) ，3.09(2H，m) ，3·16(1Η (2 Η，m ) ，3.4 0 ( 1 Η，m ) ，3 · 5 6 ( 1 Η， 2H，d) ，4.27(2H，s) ，4.40(lH，m)， )，6.80 ( 1H，d ) ，6.95 ( 1H，t ) ，7.10 7.16(lH，m) ，7.48(lH，s) ，7·53(1Η (1 H，s )。質譜：5 3 0.1 9 ( MH ) +。 實施例2 1 (土）一 4 — (2 —嗣基一1 ’ 4 一 __•氣一2 Η — 基）一哌啶一 1—羧酸〔1 一 （7 —甲基一1Η 基甲基）一 2_嗣基一2— (4 - D比π定_4 一基 基）一乙基〕一醯胺 ，m ) ，3.25 m ) ，4.1 7 ( 4.69 ( 1H，t (1 H，s )， ，m ) ? 8.01H-NMR (CD3OD, 500MHz) 5 1.4 0-1.90 (5H, m), 2.0 2 (3 Η, brs), 2. 5 7 (3 H, s) -137- 200529835 (133) 2.89 (2H, q ), 3.09 (2H, m), 3.16 (1Η (2 Η, m), 3.40 (1 Η, m), 3 · 5 6 (1 Η, 2H, d), 4.27 (2H, s), 4.40 (lH, m),), 6.80 (1H, d), 6.95 (1H, t), 7.10 7.16 (lH, m), 7.48 (lH, s), 7.53 (1Η (1 H, s)). Mass spectrum: 5 3 0.1 9 (MH) +. Example 2 1 (Earth)-4-(2 -fluorenyl-1 '4-_ •• gas-2 fluorenyl-1) -piperidine-1 -carboxylic acid [ 1- (7-methyl-1,1-methyl) -2-fluorenyl-2- (4-D than πdio_4-yl) -ethyl] -fluorenamine, m), 3.25 m), 4.1 7 (4.69 (1H, t (1 H, s),, m)? 8.01

D奎π坐啉一 3 — —D引卩坐一5 — —_ 嗪一1 —D quinine sitting on a 3 — —D on a sitting 5 — —_ hydrazine 1 —

!H-NMR ( CD3OD，5 00MHz ) 5 1·38 ( 1H， 2H，m) ，1.81(lH，m) ，2.30(lH，m) ，s) ，2.95(4H，m) ，3.13(2H，d)，： )，3.35— 3.65 (4H，m) ，3.79 ( 1H，m) ，d) ，4.31(2H，s) ，4.42(lH，m) ，4· ，6.64(2H，d) ，6.80(lH，d) ，6.89( 6.96( lH，t) ，7.14(lH，m) ，7. t) ^ 1.68( ，2.53 ( 3H !.22 ( 1H，m ，4.1 8 ( 2H 99 ( 1 Η，t ) 1 Η，m )， 5 ] ( 1 Η，s ) ，7.99 -138- (134) 200529835 (lH，s) ，8.10(2H，d) ，8·16(1Η，ηι)。質譜： 622.26 ( ΜΗ ) +。 實施例2 2 (±) — 4— (2 —酮基一1，4 —二氫一 2Η—α奎唑啉一3 — 基）一哌啶一 1 一羧酸〔1 — ( 7 —甲基—1 Η —吲唑一5 — 基甲基）一 2 —嗣基一 2 — ( 4 — D比π定一 2 —基一呢嗦一1 —! H-NMR (CD3OD, 500 MHz) 5 1 · 38 (1H, 2H, m), 1.81 (lH, m), 2.30 (lH, m), s), 2.95 (4H, m), 3.13 (2H, d) ,:), 3.35— 3.65 (4H, m), 3.79 (1H, m), d), 4.31 (2H, s), 4.42 (lH, m), 4. ·, 6.64 (2H, d), 6.80 (lH, d), 6.89 (6.96 (lH, t), 7.14 (lH, m), 7.t) ^ 1.68 (, 2.53 (3H! .22 (1H, m), 4.18 (2H 99 (1 Η, t) 1 Η, m), 5] (1 Η, s), 7.99 -138- (134) 200529835 (lH, s), 8.10 (2H, d), 8.16 (1 Η, η). Mass spectrum: 622.26 (ΜΗ) +. Example 2 2 (±) — 4 — (2-keto-1,4-dihydro- 2Η-αquinazoline-3-yl) -piperidine-1 1-carboxylic acid [1 — (7-methyl-1 fluorene-indazole-5-ylmethyl)-2-fluorenyl- 2— (4—D ratio π fixed 1 2—radical 1-methyl 1—

基）一乙基〕—醯胺) Monoethyl] -amidine

]H-NMR ( CD3OD，5 00MHz ) 5 1.27 ( 1H，m) ，1.38 (1Η，ηι) ，1.67(2H，m) ，：l.84(lH，m) ，2.54(] H-NMR (CD3OD, 500 MHz) 5 1.27 (1H, m), 1.38 (1Η, η), 1.67 (2H, m), 1.84 (lH, m), 2.54 (

3H，s) ，2.65(lH，m) ，2·88(2Η，ηι) ，3·15(4Η， m ) ，3 . 3 5 ( 1 H，in ) ，3 · 5 8 ( 3 H，m ) ，3 · 7 7 ( 1 H，m ) ，4.18 ( 2H，d ) ，4.30 ( 2H，s) ，4.42 ( 1H，m)， 5.01 (lH，t) ，6.62(lH，d) ，6.70(lH，t) ，6.80( lH，d) ，6.95(lH，t) ，7.10(3H，m) ，7.50(lH，s )，7.54(lH，t) ，7.99(lH，s) ，8.05(1H，7) 〇 質譜：622.25(MH) +。 實施例2 3 -139- (135) 200529835 (±) — 1— (7 —甲基一1H-D引唑一 5 -基甲基） 1，4 一聯呢卩定〕一 1 —基一嗣基乙基〕—2 ，3 —2 > —酮基螺—〔哌啶一 4，4 / — ( 1 Η )—喹 1 -羧醯胺 一 2-〔 —二氫 ί啉〕一3H, s), 2.65 (lH, m), 2.88 (2Η, η), 3.15 (4Η, m), 3. 3 5 (1 H, in), 3. 5 8 (3 H, m ), 3 · 7 7 (1 H, m), 4.18 (2H, d), 4.30 (2H, s), 4.42 (1H, m), 5.01 (lH, t), 6.62 (lH, d), 6.70 ( lH, t), 6.80 (lH, d), 6.95 (lH, t), 7.10 (3H, m), 7.50 (lH, s), 7.54 (lH, t), 7.99 (lH, s), 8.05 (1H 7) Mass spectrum: 622.25 (MH) +. Example 2 3 -139- (135) 200529835 (±) — 1— (7-methyl-1H-D-triazole-5-ylmethyl) 1,4-tribenzidine] 1-1-yl-fluorene Ethyl] -2,3--2 > --ketospiro- [piperidine-4,4 / — (1 Η) -quin 1 -carboxamidine 2-[-dihydroline]-

iH-NMR ( DMSO - d6，5 00MHz ) 5 1.2-1.73( )，2.46(3H，s) ，2.75— 3.24(12H，m) ，3 ，m) ，4.45(lH，m) ，4.78-4.85(lH，m) lH，m) ，6.86(lH，m) ，7.05(lH，m) ，7 ，m) ，7.21(lH，m) ，7.27(2H，ni) ，7.98 )，9.23(lH，m)。質譜：613·25(ΜΗ)+。 14Η，m .87 ( 2H ，6.80 ( • 12 ( 1H (1 Η，miH-NMR (DMSO-d6, 500 MHz) 5 1.2-1.73 (), 2.46 (3H, s), 2.75— 3.24 (12H, m), 3, m), 4.45 (lH, m), 4.78-4.85 ( lH, m) lH, m), 6.86 (lH, m), 7.05 (lH, m), 7, m), 7.21 (lH, m), 7.27 (2H, ni), 7.98), 9.23 (lH, m ). Mass spectrum: 613 · 25 (ΜΗ) +. 14Η, m .87 (2H, 6.80 (• 12 (1H (1 Η, m

實施例24 (±) — 1— (7 —甲基一1H —吲唑一5 —基甲基） 1 一哌啶基）—2 —酮基乙基〕—，3/ —二氫 嗣基螺一〔呢卩定一 4 ’ 4 — ( 1 Η ) — D奎Π坐琳〕一 胺 —2 —( —2 / — 1 一羧醯 -140- (136) (136)200529835Example 24 (±) — 1— (7-methyl-1H—indazol-5-ylmethyl) 1-piperidinyl) -2-ketoethyl] —, 3 / —dihydrofluorenylspiro 〔[卩 定 一一 4 '4 — (1 Η) — D Kui 坐 Xilin] monoamine — 2 — (— 2 / — 1 monocarboxamidine-140- (136) (136) 200529835

】H-NMR ( CD3OD，5 0 0MHz ) 5 0_87 ( 1H，m) ，1.28 —1.47(5H，m) ，1.74— 1.85(4H，m) ，2.53(3H，s] H-NMR (CD3OD, 50 MHz) 50-87 (1H, m), 1.28-1.47 (5H, m), 1.74-1.85 (4H, m), 2.53 (3H, s

)，3.02-3.28(8H，m) ，3.92(2H，m) ，5.02(1H ，m) ，6.82(lH，d) ，6.99(lH，d) ，7.04-7.09( 2H，m) ，7.17(lH，m) ，7.32(2H，s) ，7.45(1H， s ) ，7.96(lH，s)。質譜：530.17(MH)+。 實施例2 5 (土） 一 1 — (7 —甲基 一 1 Η — 口 引口坐一5 —基甲基）一2 —〔 1，4一聯暖啶〕一 1—基一酮基乙基〕一1，，2/ —二氫 —2 / —酮基螺一 〔4 Η — 3 /，1 一苯並噁嗪一 4，4 / —哌), 3.02-3.28 (8H, m), 3.92 (2H, m), 5.02 (1H, m), 6.82 (lH, d), 6.99 (lH, d), 7.04-7.09 (2H, m), 7.17 ( lH, m), 7.32 (2H, s), 7.45 (1H, s), 7.96 (lH, s). Mass spectrum: 530.17 (MH) +. Example 2 5 (Earth)-1-(7 -methyl-1 Η-mouth mouth sitting-5-methyl group)-2-[1, 4-diamidine]-1-yl-ketoethyl Yl] -1,2,2-dihydro-2 / 2-ketospiro-1 [4 Η — 3 /, 1 benzoxazine-4,4 / —piperone

】H-NMR ( DMSO - d6，5 0 0MHz ) 5 1.88( 14H，m)， 2.64(3H，s) ，2.78(]2H，m) ，4.0(2H，m) ，4.4( 1 H，m ) ，4.8 5 ( 1 H，m ) ，6 · 8 0 — 6.8 8 ( 2 H，m ) ，7.0 3 -141 - (137) (137)200529835 (2 Η，m ) ，7 · 1 1 ( 1 Η，in ) ，7.2 3 ( 1 Η，m ) ，7 · 3 6 ( 2 Η，m ) ，7 · 7 9 ( 1 Η，m )。質譜：6 1 4 · 7 3 ( Μ Η ) +。 實施例2 6 (±) — 1— (7 —甲基一1H-D 引唑一5 —基甲基）一2—( 1 一哌啶基）一2 —酮基乙基〕一 I，，2 / —二氫—— 爾I基螺—〔4H - 3 ’ 1—苯並卩惡嗦一 4，4 —呢D定〕—1 -羧醯胺] H-NMR (DMSO-d6, 500 MHz) 5 1.88 (14H, m), 2.64 (3H, s), 2.78 (] 2H, m), 4.0 (2H, m), 4.4 (1 H, m) , 4.8 5 (1 H, m), 6 · 8 0 — 6.8 8 (2 H, m), 7.0 3 -141-(137) (137) 200529835 (2 Η, m), 7 · 1 1 (1 Η , In), 7.23 (1 Η, m), 7 · 3 6 (2 m, m), 7 · 7 9 (1 Η, m). Mass spectrum: 6 1 4 · 7 3 (ΜΗ) +. Example 2 6 (±) — 1— (7-methyl-1H-D indazole—5-ylmethyl) —2— (1—piperidinyl) —2—ketoethyl] —I ,, 2 / --dihydro-hydrazyl spiro-[4H-3 '1-benzoxaoxine-1,4, -dehydro]-1 -carboxamide

】H-NMR ( DMSO— d6，500MHz) 5 1.15 - 1.91 ( 10H，] H-NMR (DMSO— d6, 500MHz) 5 1.15-1.91 (10H,

m) ，2.47(3H，s) ，2·95— 3.05 (6H，m) ，3.40(4H ，m) ，3.95(2H，d) ，4.81(lH，m) ，6.81(lH，d )，6.88(lH，d) ，6.94(lH，m) ，6.99(lH，m)， 7.04(lH，s) ，7.24(lH，m) ，7.37(lH，s) ^ 7.96 (lH，s)。質譜：531.23(MH)+。 實施例2 7 (±) — 〔1 一二甲基氨基甲醯基一 2 — （7 —甲基一 1H — 吲唑—5 —基）—乙基〕—]/ ，2/ —二氫—2> —酮基螺 —〔4 Η — 3 / ，1 —苯並噁嗪—4，4 / —哌啶〕一1 一羧醯 胺 -142- (138) (138)200529835m), 2.47 (3H, s), 2.95-3.05 (6H, m), 3.40 (4H, m), 3.95 (2H, d), 4.81 (lH, m), 6.81 (lH, d), 6.88 (lH, d), 6.94 (lH, m), 6.99 (lH, m), 7.04 (lH, s), 7.24 (lH, m), 7.37 (lH, s) ^ 7.96 (lH, s). Mass spectrum: 531.23 (MH) +. Example 2 7 (±) — [1-dimethylaminocarbamoyl-2 — (7-methyl-1H — indazole-5 —yl) —ethyl] —] /, 2 — —dihydro — 2 > —ketospiro— [4 Η — 3 /, 1 —benzoxazine — 4, 4 / —piperidine] —1 monocarboxamide-142- (138) (138) 200529835

^-NMR ( DMSO- d6 ^ 5 00MHz) 51.68— 1.88(4H，m )，2.47(3H，m) ，2.79(6H，s) ，2·89— 3·04(4Η， m ) ，3.96(2H，d) ，4·75(1Η，ηι) ，6.81(lH，d) ，6.88(lH，d) ，6.93(lH，m) ，6.98(lH，m)， 7.05 ( 1H，s) ，7.24 ( 1H，m) ，7.43 ( 1H，s) ，7.97 (lH，s) ，8.32(lH，s)。質譜：491.14(MH)+。 實施例2 8 (±) — 〔1 一 （2 —金剛烷基一氨基甲醯基）一 2— （7 — 甲基一1H —吲唑一 5 —基）—乙基〕一 I — ，2，一二氫— 2，—酮基螺—〔4 Η — 3 / ，1 —苯並噁嗪—4，4 / — _啶 〕一 1 一羧醯胺^ -NMR (DMSO- d6 ^ 5 00MHz) 51.68— 1.88 (4H, m), 2.47 (3H, m), 2.79 (6H, s), 2.89— 3.04 (4Η, m), 3.96 (2H , D), 4.75 (1Η, η), 6.81 (lH, d), 6.88 (lH, d), 6.93 (lH, m), 6.98 (lH, m), 7.05 (1H, s), 7.24 ( 1H, m), 7.43 (1H, s), 7.97 (lH, s), 8.32 (lH, s). Mass spectrum: 491.14 (MH) +. Example 2 8 (±) — [1- (2-Adamantyl-carbamoyl)-2- (7-methyl-1H-indazol-5-yl) -ethyl] -I-, 2 , -Dihydro-2, -ketospiro- [4 Η — 3 /, 1 -benzoxazine-4, 4 / — _pyridine]-1 -carboxamide

^-NMR ( DMSO- d6 5 5 00ΜΗζ) 5]·40-1.95 ( 15Η， in) ，2.46(3H，m) ，2·89— 3.07(4H，m) ，3.81(1H ，m ) ，3.90 ( 2 H 5 m ) ，4.48 ( 1 H 5 m ) ，6 · 7 4 ( 2 H，ni -143- (139) (139)200529835 )，6.86(lH，d) ，6.97(lH，m) ，7.11(lH，s)， 7·24(1Η，ηι) ，7.36(lH，s) ，7.44(lH，s) » 7.96 (lH，s)。質譜：597.27(MH) +。 實施例2 9 (±) — 1，，2> —二氫一2^ —酮基螺一〔4H— 3，，1 —苯並噁嗪—4，4 / —哌啶一1 —羧醯〔1 一 （ 7 —甲基一 1H — 口引唑一 5 —基甲基）一2 -酮基一2— (4 — 口比啶一4 — 基一哌嗪一 1 一基）一乙基〕一醯胺^ -NMR (DMSO- d6 5 5 00ΜΗζ) 5] · 40-1.95 (15Η, in), 2.46 (3H, m), 2.89—3.07 (4H, m), 3.81 (1H, m), 3.90 ( 2 H 5 m), 4.48 (1 H 5 m), 6. 7 4 (2 H, ni -143- (139) (139) 200529835), 6.86 (lH, d), 6.97 (lH, m), 7.11 (lH, s), 7.24 (lH, s), 7.36 (lH, s), 7.44 (lH, s) »7.96 (lH, s). Mass spectrum: 597.27 (MH) +. Example 2 9 (±) — 1, 2, 2> —dihydro — 2 ^ —ketospiro 1 [4H — 3 ,, 1 —benzoxazine — 4, 4 / —piperidine — 1 —carboxamidine [ 1- (7-methyl-1H-oripizole-5-ylmethyl) -2-keto-2- (4-oripidine-4-yl-piperazine-1 1-yl) -ethyl] Monoamine

LC/MS: tR: 1.56 分，609·14(ΜΗ) +。 實施例3 0 (±) — 1^ ，2^ —二氫一2，一酮基螺一〔4Η— 3^ ，1 一苯並噁嗪—4，4 / —哌啶一1 一羧酸{ 2 — （ 7 —甲基一 1 Η 一 D引口坐一 5 —基）一1 — 〔 （D比D定一 4 —基甲基）一氛基 甲醯基一乙基丨一醯胺 -144- (140) (140)200529835LC / MS: tR: 1.56 minutes, 609 · 14 (ΜΗ) +. Example 3 0 (±) — 1 ^, 2 ^ —dihydro-2, 1-ketospiro-1 [4Η—3 ^, 1—benzoxazine—4, 4 / —piperidine—1 monocarboxylic acid { 2 — (7 —methyl — 1 — 1 D — 5 — base) — 1 — [(D is more than 4 — methyl — D—D—methyl — 4 —methylmethyl) — carbamoyl — ethyl — amine — 144- (140) (140) 200529835

LC/MS: tR: 1.49 分，553.12 (ΜΗ) +。 實施例3 1 (±) — 1— (7 —甲基一1H —吲唑一5 —基甲基）一2—〔 1，4一聯暖啶〕一1—基—2 —酮基乙基〕一二氫 —2 一顚1基螺一〔呢D定一 4 5 4 一 ( 1 Η ) 一 D奎琳〕一1 -羧醯胺LC / MS: tR: 1.49 minutes, 553.12 (ΜΗ) +. Example 3 1 (±) — 1— (7-methyl-1H—indazol-5-ylmethyl) —2— [1,4-diazapiperidine] —1—yl-2-ketoethyl 〔〕 -Dihydro-2-1 螺 1 spiro 1 [? D fixed a 4 5 4 1 (1 Η)-D quinine]-1-Carboxamide

iH-NMR ( DMSO — d6，5 00MHz ) 5 1 · 2 0 — 2 · 0 0 ( 1 4 Η， m ) ，2.46(3H，s) ，2.38-3.03(12H，m) ，3·87(2Η ，m) ，4.34(lH，m) ，4.76-4.87(lH，m) ，6.65( lH，m) ，6·82— 7.64 (3H，m) ，7·13 — 7.23(2H，m) ，7.36(3H，m) ，7.96(lH，s)。質譜：612.32 (ΜΗ ) 實施例3 2 -145- (141) 200529835 (±) — 1— (7 -甲基一1H — D 引唑一5 —基甲基）一2—〔 1— I派D定基〕—2—醒基乙基〕3 ，4 — _•氨一 2 —酬 基螺一〔哌啶—4，4 / _ ( 1 Η )—喹啉〕一 1，一羧醯胺 ΗΝ—ΝiH-NMR (DMSO — d6, 500 MHz) 5 1 · 2 0 — 2 · 0 0 (1 4 Η, m), 2.46 (3H, s), 2.38-3.03 (12H, m), 3.87 (2Η , M), 4.34 (lH, m), 4.76-4.87 (lH, m), 6.65 (lH, m), 6.82-7.64 (3H, m), 7.13-7.23 (2H, m), 7.36 (3H, m), 7.96 (lH, s). Mass spectrum: 612.32 (ΜΗ) Example 3 2 -145- (141) 200529835 (±) — 1— (7-methyl-1H—D Izozol-5—methylmethyl) —2— [1-I group D (Amino group) —2—Axylethyl] 3,4 — —Ammonia 2 —Aminospirospira [Piperidine-4,4 / _ (1 Η) —quinoline] —1, 1 Carboxamide 醯 N — Ν

^-NMR ( DMSO- d6 J 5 00MHz) 5 1.10— 1.68( 10H， m ) ，2.46(3H，s) ，2·50— 2.60 (2H，m) ，2·82 — 2.97(4H，m) ，3.39(2H，m) ，3.85(2H，m) ，4.80^ -NMR (DMSO- d6 J 5 00MHz) 5 1.10— 1.68 (10H, m), 2.46 (3H, s), 2.50— 2.60 (2H, m), 2.82 — 2.97 (4H, m), 3.39 (2H, m), 3.85 (2H, m), 4.80

(lH，m) ，6.68(lH，m) ，6.87(lH，s) ，6.94(1H ，m) ，7.03(lH，s) ，7.06(lH，m) ，7.15(lH，m )，7.37(lH，s) ，7.40(lH，s) ，7.96(lH，s)。 質譜：529·25(ΜΗ) +。 實施例3 3 (±) — 〔1 一二甲基氨基甲醯基一 2— (7 —甲基一 1H — 吲唑一5 —基）一乙基〕一3 / ，4/ —二氫—2/ —酮基螺 一〔呢卩定一 4，4 一（ 1 Η ) - D奎琳〕一 1，一殘釀胺 ΗΝ—Ν(lH, m), 6.68 (lH, m), 6.87 (lH, s), 6.94 (1H, m), 7.03 (lH, s), 7.06 (lH, m), 7.15 (lH, m), 7.37 ( lH, s), 7.40 (lH, s), 7.96 (lH, s). Mass spectrum: 529 · 25 (ΜΗ) +. Example 3 3 (±) — [1-dimethylaminocarbamoyl-2— (7-methyl-1H—indazol-5-yl) -ethyl] —3 /, 4 / —dihydro— 2 / —Ketospiro [Nine-A-4,4- (1))-D Quilin] -1, A residual amine ΗN-Ν

H-NMR(DMS0— d6，500 ΜΗζ) δ1.43(2Η，ηι)， -146 ~ 200529835 (142) 1.56 (2H，m) ，2.46(3H，s) ，2.56(2H，m) -2.79H-NMR (DMS0- d6,500 ΜΗζ) δ1.43 (2Η, ηι), -146 ~ 200529835 (142) 1.56 (2H, m), 2.46 (3H, s), 2.56 (2H, m) -2.79

(3H，s) ，2.90(5H，m) ，3.84(2H，m) ，4.73(1H ，m) ，6.69(3H，m) ，2.69(lH，d) ，6·94(1Η，ιη )，7.05(2H，m) ，7.14(lH，m) ，7.37(lH，s)， 7.42(lH，s) ，7.96(lH，s)。質譜：489.2(MH) +(3H, s), 2.90 (5H, m), 3.84 (2H, m), 4.73 (1H, m), 6.69 (3H, m), 2.69 (lH, d), 6.94 (1Η, ιη), 7.05 (2H, m), 7.14 (lH, m), 7.37 (lH, s), 7.42 (lH, s), 7.96 (lH, s). Mass spectrum: 489.2 (MH) +

實施例3 4 (±) — 4—酮基一2—苯基一1，3，8—三氮雜一螺〔4, 5〕癸一1—烯—8 —羧酸{1— (7 —甲基—1H —吲唑—5 一基甲基）一 2- 〔1，4一聯哌啶一丨/一基一2 —酮基— 乙基丨一醯胺Example 3 4 (±) — 4-keto-2-phenyl-1,3,8-triaza-spiro [4, 5] decane-1-ene-8-carboxylic acid {1— (7 — Methyl-1H-indazole-5 monomethyl) 2- [1,4-bipiperidinyl- / mono-yl-2 -keto-ethyl-monomethylamine

HN—NHN-N

]H-NMR ( DMSO- d6 5 5 00ΜΗζ) ά 1 · 3 4 — 2.0 0 ( 1 4 Η， m ) ，2.48( 3Η，重疊 DMSO) ，2.70—3.30 ( 12H，m) ，3.90(2H，m) ，4.40(lH，m) ，4.82( lH，m)， 6.82(lH，m) ，7.04(lH，s) ，7·37(2Η，ηι) ，7.56 (3H，m) ，7.98(3H，s)。質譜：625.29(MH)+。 實施例3 5 -147- (143) 200529835 (±) — 4—酮基一2 —苯基一1，3，8—三氮雜一螺〔4, 5〕癸一1—嫌一8 —殘酸{1— (7 —甲基—1H — D引D坐—5 —基甲基）一 2 — 〔1 一哌啶基〕一 2 —酮基一乙基}—羧 醯胺] H-NMR (DMSO- d6 5 5 00ΜΗζ) ά 1 · 3 4 — 2.0 0 (1 4 Η, m), 2.48 (3Η, overlapping DMSO), 2.70—3.30 (12H, m), 3.90 (2H, m ), 4.40 (lH, m), 4.82 (lH, m), 6.82 (lH, m), 7.04 (lH, s), 7.37 (2Η, η), 7.56 (3H, m), 7.98 (3H, s). Mass spectrum: 625.29 (MH) +. Example 3 5 -147- (143) 200529835 (±) — 4-keto-1 2-phenyl-1,3,8-triaza-spiro [4, 5] decyl-1—supposedly 8—residue Acid {1- (7-Methyl-1H—Dihydrobenzyl-5- (methyl))-2-([1-piperidinyl] -2- (keto-ethyl)}-carboxamide

HN-NHN-N

!H-NMR (DMSO— d6，500MHz) 5 1.10 — 1.62 ( 6H，m )，1.73 ( 4H，m) ，2·48 ( 3H，s) ，3.00 ( 6H，m)， 3.39 (2H，m) ，3.93(2H，m) ，4.82( lH，m) ，6.78 (1 H ^ m ) ，7.05(lH，s) ，7.37(2H，s) ，7·40(1Η ，s) ，7.53(2H，m) ，7.98(2H，m)。質譜：543.26 (ΜΗ )! H-NMR (DMSO—d6, 500MHz) 5 1.10 — 1.62 (6H, m), 1.73 (4H, m), 2.48 (3H, s), 3.00 (6H, m), 3.39 (2H, m) , 3.93 (2H, m), 4.82 (lH, m), 6.78 (1H ^ m), 7.05 (lH, s), 7.37 (2H, s), 7.40 (1Η, s), 7.53 (2H, m), 7.98 (2H, m). Mass spectrum: 543.26 (ΜΗ)

實施例3 6 (±) — 4 —酮基一2 —苯基一1，3，8—三氮雜一螺〔4, 5〕癸一 1—烯一8 —羧酸〔1 一二甲基氨基甲醯基一2 —（7 —甲基一1H—吲唑一5 —基）一乙基〕醯胺Example 3 6 (±) — 4-keto-2-phenyl-1,3,8-triaza-spiro [4, 5] decane-1-ene-8-carboxylic acid [1-dimethyl Carbamidyl-2- (7-methyl-1H-indazol-5-yl) monoethyl] fluorenamine

HN 一 NHN a N

H-NMR ( DMSO— d6，500MHz) 5 1 . -148- (144) 200529835 )，2.78(4H，m) ，2.90(6H，m) ，3.94(2H，m)， 4.74(lH，m) ，6.77(lH，m) ，7.05(lH，s) ，7.37H-NMR (DMSO- d6, 500MHz) 5 1. -148- (144) 200529835), 2.78 (4H, m), 2.90 (6H, m), 3.94 (2H, m), 4.74 (lH, m), 6.77 (lH, m), 7.05 (lH, s), 7.37

(4H，s) ，7.42(lH，s) ，7.52(2H，m) ，7.98(2H ，：m )。質譜：5 02.2 1 ( MH ) +。 實施例3 7 4— (2 —酮基一1，4 —二氫_2H — D奎唑啉一3 —基）一哌 啶一1_羧酸{1_ (1H —吲唑一 5 —基甲基）一2 —酮基 —2〔4 一 （2 —嗣基一1，4 — 一 氯 一 2 Η — D奎哇琳一3 —基 )一哌啶一 1_基〕—乙基} 一醯胺(4H, s), 7.42 (lH, s), 7.52 (2H, m), 7.98 (2H,: m). Mass spectrum: 5 02.2 1 (MH) +. Example 3 7 4- (2-keto-1,4-dihydro_2H-D quinazoline-3-yl) -piperidine-1-carboxylic acid {1_ (1H-indazole-5-ylmethyl) A) 2 -keto-2 [4 a (2 -fluorenyl-1,4-monochloro-2 fluorene-D quinaline -3 -yl) -piperidine -1 -yl] -ethyl}- Amidine

LC/MS: tR 二 Κ51 分，674 (ΜΗ) 一。 Ν Η 實施例3 8 4一 （3— (1Η — D 引唑一5 —基）一2— {4— (2 —酮基一 1 ，4 — 一氣―2Η — D奎卩坐琳—3 —基）一呢卩定—1 一類基〕— 胺基丨一丙醯基）一哌嗪—1 一羧酸苄酯 -149- (145) (145)200529835LC / MS: tR two κ51 points, 674 (ΜΗ) one. Ν Η Example 3 8 4 1 (3- (1Η — D azole-5 —yl) — 2 — {4 — (2 —keto-1, 4 — one gas — 2 — — D quinazine — 3 — Group) monobenzidine-1, a kind of group] -amino group 丨 propionyl group) -piperazine-1 benzyl monocarboxylate-149- (145) (145) 200529835

LC/MS : tR= 1.74 分，66 5 ( ΜΗ)—。 實施例3 9 4— (2 —酮基一 1，4 —二氫一2Η — D奎唑啉一3 —基）—哌 啶一1 一羧酸〔1 一 （ 1 Η —吲唑一 5 —基甲基）一2 -酮基 —2 —酮基—2 —哌嗪一 1—基〕一乙基丨一醯胺LC / MS: tR = 1.74 points, 66 5 (ΜΗ) —. Example 3 9 4- (2-keto-1,4-dihydro-2H-D quinazolin-3-yl) -piperidine- 1-carboxylic acid [1 1- (1H-Indazole-5) Methyl)-2-keto-2 -keto-2 -piperazine-1 -yl] -ethyl

將 10% Pd / C ( 50 mg)加入至 4— ( 3— ( 1Η —吲唑 —5—基）一 2— { 〔4 —酮基一1，4一 二氫一 2H — D奎唑啉 —3 —基）—哌啶—1 一羰基〕一胺基丨一丙醯胺）—哌嗪 —1 —羧酸苄酯（280 mg，0.4 2毫莫耳）之甲醇（50 ml ) 脫氣溶液中。於50 psi氫氣壓下且在Parr裝置中，搖動該 混合物3小時。經由通過寅氏鹽，過濾該混合物。減壓下 濃縮濾液以生成所欲之產物（9 1 %產率）。 LC/MS: tR 二 1.22 分，531 (ΜΗ) Η·。 -150- (146) 200529835 實施例40a 4_ (2 -酮基一 1，4 —二氫—2H—喹唑啉—3—基）一哌 啶—1 一羧酸(1H -吲唑一 5—基甲基）一2—〔4一 (2 —甲基一丁基）一呢'嗪一 1 一基〕一 2—酮基一乙基} 一醯胺10% Pd / C (50 mg) was added to 4— (3— (1Η—indazol-5-yl) —2— {[4-ketone-1,4-dihydro-2H—D quinazoline —3 —yl) —piperidine — 1 monocarbonyl] monoamine — monopropylammonium — piperazine — 1 —benzyl carboxylate (280 mg, 0.4 2 mmol) degassed in methanol (50 ml) In solution. The mixture was shaken for 3 hours under 50 psi hydrogen pressure in a Parr apparatus. The mixture was filtered through yin's salt. The filtrate was concentrated under reduced pressure to give the desired product (91% yield). LC / MS: tR 1.22 points, 531 (ΜΗ) Η ·. -150- (146) 200529835 Example 40a 4- (2-keto-1,4-dihydro-2H-quinazolin-3-yl) -piperidine-1 monocarboxylic acid (1H-indazole-5- Methyl)-2-[4-((2-methyl-butyl) -n-'azine- 1-1 -yl]-2 -keto-ethyl} -monamine

令4— (2-酮基—1，4 —二氫-2H-喹唑啉一 3 -基 )一哌啶一 1 一羧酸〔1 — ( 1 Η —吲唑—5 —基甲基）一 2 一酮基—2 —哌嗪一 1 一基—乙基〕—醯胺（100 nig， 0.1 88毫莫耳）之甲醇（25 ml )攪拌溶液與2 —甲基一丁 醛（0.03ml，0.3 76毫莫耳）反應。於室溫下經1小時後， 加入三乙醯氧基氫硼化鈉（80 mg，0.316毫莫耳）。隔夜 攪拌該混合物。藉由通過sex筒以過濾該溶液。先後利用 ® 甲醇和1 Μ氨之甲醇溶液流洗該筒。真空下除去溶劑以生 成所欲之產物（50%產率）。 LC/ MS : tR 二 1.31 分，601 ( ΜΗ) +。 製備實施例至401"之一般實驗方法 將適當之醛（0·04毫莫耳）加入至實施例39之哌嗪（ 0.2 0.0 2毫莫耳）之甲醇（0 · 2 111】）溶液中，並於室溫下搖動 所生成之溶液1小時。隨後加入二乙醯氧基氫硼化物（ -151 > (147) (147)200529835 毫莫耳）並於室溫下隔夜攪拌該溶液。藉由通過sex筒過 濾該溶液並利用甲醇和氨/甲醇溶液冲洗該筒。真空下濃 縮該氨/甲醇溶液並藉由製備性Η P L C純化粗產物以生成 表1列示之產物。 表1. 實施例40b至40k 實施例 結構 HPLC 滯留時間 (分） 質譜 (MH)+ 40b HN-N h 〜Ο 2.62 629 40c ΗΝ-Ν ίγα^0 工。〇 Μβ>«3Ν^ 1.41 587 40d ΗΝ-Ν ^νΙ〇° 1.27 573 40e ΗΝ-Ν 0.0 0〇 1.74 611 -152 - (148)200529835 實施例 結構 HPLC 滯留時間 (分） 質譜 (MH)+ 40f HN-N h XvO" 1 O1 人。〇 1.89 643 40g HN-N 夕乂〇0 <X〇 0〇 H 1.48 610 40h HN-N ^入0 2.19 614 40i HN，N h 《vC?00 Et广人0 2.36 629 40j HN-N h 工。〇 Phv^^Nv^ 1.66 647 40k HN-N ¢/ Xv^ r-x〇° 2.61 545 - 153- (149) (149)200529835 實施例4 1 a 3 — ( 7 —甲基一1 Η — 口 引口坐一5 —基）一2 — { 〔4 — (2 — 嗣基一1，4 一 一氯一2 Η — D奎口坐琳一 3 —基）一 I概Π定一 1 — 羰基〕一胺基} 一丙酸環己酯Let 4- (2-keto-1,4-dihydro-2H-quinazoline-3-yl) -piperidine-1 monocarboxylic acid [1- (1 fluorene-indazole-5-ylmethyl) A solution of 2-monoketo-2-piperazine-1-yl-ethyl] -amidamine (100 nig, 0.1 88 mmol) in methanol (25 ml) and 2-methylmonobutyraldehyde (0.03ml) , 0.3 76 millimoles). After 1 hour at room temperature, sodium triacetoxyborohydride (80 mg, 0.316 mmol) was added. The mixture was stirred overnight. The solution was filtered by passing through a sex cartridge. The cartridge was washed with a methanol solution of ® methanol followed by 1 M ammonia. The solvent was removed under vacuum to produce the desired product (50% yield). LC / MS: tR II 1.31 points, 601 (ΜΗ) +. The general experimental method of Preparation Examples to 401 " The appropriate aldehyde (0.04 mmol) was added to a solution of piperazine (0.2 0.0 2 mmol) in methanol (0.2111) in Example 39, The resulting solution was shaken at room temperature for 1 hour. Diethylfluorenyl borohydride (-151 > (147) (147) 200529835 mmol) was then added and the solution was stirred overnight at room temperature. The solution was filtered by passing through a sex cartridge and the cartridge was rinsed with methanol and ammonia / methanol solutions. The ammonia / methanol solution was concentrated under vacuum and the crude product was purified by preparative ΗPLC to yield the products listed in Table 1. Table 1. Examples 40b to 40k Examples Structure HPLC retention time (minutes) Mass spectrum (MH) + 40b HN-N h ~ 0 2.62 629 40c cΝ-Ν ίγα ^ 0 work. 〇Μβ> «3N ^ 1.41 587 40d ΗΝ-Ν ^ νΙ〇 ° 1.27 573 40e ΗΝ-Ν 0.0 0〇1.74 611 -152-(148) 200529835 Example Structural HPLC Retention Time (Min) Mass Spectrum (MH) + 40f HN -N h XvO " 1 O1 person. 〇1.89 643 40g HN-N 乂 〇0 < X〇00〇H 1.48 610 40h HN-N ^ 0 2.19 614 40i HN, N h 《vC? 00 Et Guangren 0 2.36 629 40j HN-N h . 〇Phv ^^ Nv ^ 1.66 647 40k HN-N ¢ / Xv ^ rx〇 ° 2.61 545-153- (149) (149) 200529835 Example 4 1 a 3 — (7 —methyl-1 1 Η — mouth inlet Sat — 5 — radical — 2 — {[4 — (2 — amidin — 1, 4, 1 — chloro — 2 Η — D Kui Kou Lin — 3 — base) — I — 1 — carbonyl] — Amine} cyclohexyl monopropionate

將環己醇（13.3//1，0.126毫莫耳）加入至（±) — 2 —胺基一 3 — （7—甲基—1H —吲唑—5 —基）一丙酸（20 mg，0.042毫莫耳）、4一（二甲基胺基）吡啶（2.5 mg， 0·02毫莫耳）及1— 〔3 — （二甲基胺基〕一 3 —乙基羰二 醯亞胺氫氯化物（33 mg，0.17毫莫耳）之CH2C12 (2 ml )和二甲基甲醯胺（1 ml )之攪拌溶液中。於50至55 °C下 攪拌該反應混合物4小時。減壓下除去溶劑，並藉由製備 性矽膠TLC ( 9 : 1氯仿/甲醇）純化殘餘物以生成白色 固體之所欲產物（9 · 4 m g，4 0 % )。 j-NMR ( CD3OD，500MHz) 5 1·32 - 1.87 ( 14H，m) ，2.57(3H，s) ，2.86(2H，m) ，3·11— 3.26(2H，mCyclohexanol (13.3 // 1, 0.126 mmol) was added to (±) -2-amino-1- (7-methyl-1H-indazol-5-yl) monopropionic acid (20 mg, 0.042 millimoles), 4- (dimethylamino) pyridine (2.5 mg, 0.02 millimoles) and 1- [3- (dimethylamino) -3-ethylcarbonyldiamidoimine Hydrochloride (33 mg, 0.17 mmol) in a stirred solution of CH2C12 (2 ml) and dimethylformamide (1 ml). The reaction mixture was stirred at 50 to 55 ° C for 4 hours. The solvent was removed and the residue was purified by preparative silica TLC (9: 1 chloroform / methanol) to give the desired product (9.4 mg, 40%) as a white solid. J-NMR (CD3OD, 500MHz) 5 1.32-1.87 (14H, m), 2.57 (3H, s), 2.86 (2H, m), 3.11-3.26 (2H, m

)，4.13— 4.22(3H，m) ，4.46(lH，m) ^ 4.55 ( 1H ，m) ，4.80(lH，m) ，6.79(lH，d) ，6.97(lH，m )，7·08— 7.18(2H，m) ，7.35(lH，s) ，7·47( 1H， s ) ，8.0]— 8.02(]H，m)。質譜：559.22(MH)+。 -154- (150) (150)200529835 類似之方法製備： 實施例4 1 b 3— (7 —甲基—iH — 口引唑一5 —基）一2— { 〔4— (2 — 嗣基一1，4 — _•氯一2 Η — D奎口坐琳一 3 —基）一呢D定一 1 — 羰基〕一胺基} 一丙酸 1 一苄基—哌啶一 4一基酯), 4.13— 4.22 (3H, m), 4.46 (lH, m) ^ 4.55 (1H, m), 4.80 (lH, m), 6.79 (lH, d), 6.97 (lH, m), 7.08— 7.18 (2H, m), 7.35 (lH, s), 7.47 (1H, s), 8.0] —8.02 (] H, m). Mass spectrum: 559.22 (MH) +. -154- (150) (150) 200529835 Prepared in a similar manner: Example 4 1 b 3— (7 —methyl—iH — oxazole-5 —yl) — 2 — {〔4— (2 — fluorenyl -1,4 — _ • Chloro-2 D — D Kuizuline 3 —yl) 1 D D 1 — carbonyl] monoamino} monopropionic acid 1 benzyl-piperidine 4 4-yl ester

LC/MS : tR= 1.76 分，65 0.3 0 ( ΜΗ) +。 實施例4 1 c 3— (7 —甲基一1H — 口引唑一基）一2— { 〔4— (2 —酮基 —1，4 —: 一·氯一2 Η — D奎口坐琳一3 —基）一喊D定一1 —類基 〕一胺基} 一丙酸 1 一甲基一哌啶—4 一基酯LC / MS: tR = 1.76 minutes, 65 0.3 0 (ΜΗ) +. Example 4 1 c 3— (7-methyl-1H—orazolyl) —2— {[4— (2-keto-1,4—: 1 · chloro-1 2 Η—D Kuikou sit Lynn 3 -yl) y D D 1 -yl] monoamine} monopropionate 1 methyl 1-piperidine-4 monoyl ester

LC/MS : tR= 1.59 分，5 74.27 ( ΜΗ) +。 實施例4 1 d 3 — ( 7 —甲基一1 Η — 口引口坐一5 —基）一2 — { [ 4 — (2 — 嗣基一1，4 — 一氣一2 Η —喧口坐琳一3 —基）一呢Π定一1 — 羰基〕一胺基}丙酸 4 一苯基-環己酯 (151) 200529835LC / MS: tR = 1.59 minutes, 5 74.27 (ΜΗ) +. Example 4 1 d 3 — (7 —methyl-1 1 Η — mouth mouth sits a 5 — base) — 2 — {[4 — (2 — fluorenyl base 1, 1, 4 — one breath one 2 Η — sits loudly Lin-3-yl) -n-butyl- 1-carbonyl] -amino group} propanoic acid 4-monophenyl-cyclohexyl ester (151) 200529835

LC/MS: tR=2.69分，635·29(ΜΗ) +。 實施例4 1 e 3 - (7 —甲基一1H — 口引唑一5 —基）一2— { 〔4一 （2 — 醒[基一1，4 一 一·氯一 2H —喧口坐琳_ 3 —基）_喊D定一1 — 羰基〕一胺基丨—丙酸（R) - 吡啶—4 —基一乙酯 ΗΝ-ΝLC / MS: tR = 2.69 minutes, 635 · 29 (ΜΗ) +. Example 4 1 e 3-(7-methyl-1H—orazol-5-yl)-2— {[4 一 (2 — awake [yl-1,4—one · chlorine 2H—sit out Lynn — 3 —yl — _ D 1 — carbonyl] monoamino 丨 — propionic acid (R)-pyridin 4- 4-yl monoethyl ester ΗΝ-Ν

LC/ MS : iR = 1 .66分，5 82.22 ( ΜΗ ) 實施例4 1 f 3— (7 —甲基一1H — D 引唑一5 —基）一2- { 〔4— (2 — 酮基一1，4 —二氫一2 Η — D奎唑啉—3 —基）一哌啶一 1 一 羯基〕一胺基丨—丙酸（S) - 1—D比D定一 4 一基一乙酯LC / MS: iR = 1.66 minutes, 5 82.22 (ΜΗ) Example 4 1 f 3— (7-methyl-1H—D indazole-5-yl) -1 2- {[4— (2-one 1-4-dihydro-2 fluorenyl-D quinazoline-3-yl) -piperidine-1 1-fluorenyl] -amino group 丨 -propionic acid (S)-1-D than D fixed 4 1 Methyl ethyl

HN 一 NHN a N

-156- (152) 200529835 LC/MS : 1.65 分，5 8 2.23 ( ΜΗ) +。 >1 4 —溴—2 —氯—6 —甲基苯基重氮基—特丁基硫化物-156- (152) 200529835 LC / MS: 1.65 points, 5 8 2.23 (ΜΗ) +. > 1 4 -Bromo-2 -chloro-6 -methylphenyldiazo-tert-butyl sulfide

令4一溴一 2—氯一 6-甲基苯胺（4.0 g，18.3毫莫耳 )懸浮於24 % HC1 ( 5 m 1 )中。冷卻該攪拌混合物至一 2 〇 °C ，隨後以超過1 〇分鐘之時間逐滴地加入亞硝酸鈉（ 1 . 3 2 g，1 . 0 5當量）之水（2 m 1 )溶液以進行反應’同時 維持溫度低於—5°C。於—5°C至一 20°C之溫度下經30分鐘 後，利用乙酸鈉固體緩衝該混合物至約PH 5。於0 °C下以 超過約1 〇分鐘間，將該混合物（維持於約一 1 0 下）分數 剖份地加入至特丁基硫赶（2.06 ml，1當量）之乙醇（ 18.5 ml )攪拌溶液中。經添加後，於〇°C下攪拌該混合物 3 〇分鐘，隨後加入碎冰（約5 0 m 1 )。於冰箱中隔夜貯存 該混合物。藉由過濾以收集所生成之淡褐色固體，經水冲 洗並置於高真空下乾燥數小時（4.60 g ’ 78% )。質譜： 323.03 ( MH ) +。 5 -溴一 7 —氯吲唑 -157- (153) (153)2005298354-Bromo-2-chloro-6-methylaniline (4.0 g, 18.3 mmol) was suspended in 24% HC1 (5 m 1). The stirred mixture was cooled to -20 ° C, and then a solution of sodium nitrite (1.32 g, 1.05 equivalent) in water (2 m 1) was added dropwise over a period of 10 minutes to perform the reaction. 'While maintaining the temperature below -5 ° C. After 30 minutes at a temperature of -5 ° C to -20 ° C, the mixture was buffered to a pH of about 5 using sodium acetate solids. Add this mixture (maintained at about -10 ° C) in fractions to butylthiosulfate (2.06 ml, 1 equivalent) in ethanol (18.5 ml) at 0 ° C over about 10 minutes. In solution. After the addition, the mixture was stirred at 0 ° C. for 30 minutes, and then crushed ice (about 50 m 1) was added. The mixture was stored in the refrigerator overnight. The resulting light brown solid was collected by filtration, washed with water and dried under high vacuum for several hours (4.60 g '78%). Mass spectrum: 323.03 (MH) +. 5 -bromo- 7-chloroindazole -157- (153) (153) 200529835

將4一溴一 2—氯—6—甲基苯基重氮基一特丁基硫化 物（4.60 g，14.4毫莫耳）和特丁氧化鉀（16.1 g，10當 量）加入至火焰乾燥之圓底燒瓶中。加入攪拌棒並將該混 合物置於氮氣下。隨後加入乾DMSO (50 ml)。室溫下激 烈攪拌該混合物1 〇分鐘。小心地將該反應混合物倒入至碎 冰（1 50 ml )和1 0% HC1 ( 74 ml )之混合液中。於4°C下 隔夜靜置所生成之懸浮液，隨後藉由過濾以收集固體並利 用水進行冲洗。收集固體並置於真空下乾燥，生成亮灰褐 色固體（2.86 g，86% )。 ^-NMR ： ( CDC13，5 00MHz ) 5 7 · 5 2 ( d，J = 1 . 5，1 Η )，7.82(d，J=1.5，lH) ，8.08(s，lH)。質譜： 23 0.90 ( ΜΗ ) +。 7 -氯吲唑—5 -醛Add 4-bromo-2-chloro-6-methylphenyldiazo-tert-butyl sulfide (4.60 g, 14.4 millimoles) and tert-butoxide (16.1 g, 10 equivalents) to the flame-dried Round bottom flask. A stir bar was added and the mixture was placed under nitrogen. Then dry DMSO (50 ml) was added. The mixture was stirred vigorously at room temperature for 10 minutes. The reaction mixture was carefully poured into a mixture of crushed ice (150 ml) and 10% HC1 (74 ml). The resulting suspension was allowed to stand overnight at 4 ° C, and then the solid was collected by filtration and rinsed with water. The solid was collected and dried under vacuum to give a light gray-brown solid (2.86 g, 86%). ^ -NMR: (CDC13, 500 MHz) 5 7 · 5 2 (d, J = 1.5, 1 Η), 7.82 (d, J = 1.5, 1H), 8.08 (s, 1H). Mass spectrum: 23 0.90 (ΜΗ) +. 7-chloroindazole-5-aldehyde

將5 —溴一 7 —氮吲唑（2 · 0 g，8 . 7毫莫耳）和N aH ( 22 1 mg，1.1當量）載入含有磁石攪拌棒之經火焰乾燥的 圓底燒瓶中。於室溫和氮氣環境下，加入乾四氫呋喃（3 0 ml)。室溫下攪拌該混合物1 5分鐘，期間該混合物呈均質 -158- (154) (154)200529835 狀。冷卻該攪拌混合物至- 7 8 °C，且以超過數分鐘之時間 加入特丁基鋰之戊烷溶液（1.7M，10.5 ml，2·0當量）。 於- 7 8 °C下經3 0分鐘後，令該反應混合物逐漸地回溫至 —5 0 °C，並維持1 5分鐘，隨後再冷卻至一 7 8 °C。緩慢地加 入二甲基甲醯胺（2.8 ml)並令該混合物回溫至一 5CTC。 將該溶液迅速地轉移至含有二乙醚和水之分離漏斗中。藉 由加入1 Μ硫酸氫鉀溶液使該水溶液呈酸性，隨後加入 NaHC03進行中和。利用二乙醚（3χ )萃取水溶液，隨後 經水和鹽水冲洗，置於MgS04上乾燥，經濃縮後生成幾近 純水之物質（1 · 7 g，1 00 % )。自熱甲醇中藉由再結晶以 得到分析級之純樣品。 】H-NMR : ( CDC13，500MHz ) 5 7.97 ( s，1Η ) ，8·20 (s，lH) ，8.30(s，lH) ，：1〇.〇2(s，1H)。質譜： 1 8 1 ·09 ( ΜΗ ) + 〇 2 —卡氧鑛基胺基—3 — （7-氛一 1Η - D引π坐一 5 —基 丙烯酸甲酯5-Bromo-7-azindazole (2.0 g, 8.7 mmol) and NaH (22 1 mg, 1.1 equivalents) were charged into a flame-dried round bottom flask containing a magnetic stir bar. At room temperature and under nitrogen, dry tetrahydrofuran (30 ml) was added. The mixture was stirred at room temperature for 15 minutes, during which the mixture was homogeneous -158- (154) (154) 200529835. The stirred mixture was cooled to -78 ° C, and a solution of t-butyllithium in pentane (1.7M, 10.5 ml, 2.0 equivalents) was added over a period of several minutes. After 30 minutes at -78 ° C, the reaction mixture was gradually warmed to -50 ° C, maintained for 15 minutes, and then cooled to 78 ° C. Slowly add dimethylformamide (2.8 ml) and allow the mixture to warm to -5CTC. The solution was quickly transferred to a separation funnel containing diethyl ether and water. The aqueous solution was made acidic by adding a 1 M potassium hydrogensulfate solution, followed by neutralization by adding NaHC03. The aqueous solution was extracted with diethyl ether (3x), then washed with water and brine, dried over MgS04, and concentrated to form a substance close to pure water (1.7 g, 100%). An analytical grade pure sample was obtained by recrystallization from self-heating methanol. H-NMR: (CDC13, 500 MHz) 5 7.97 (s, 1H), 8.20 (s, 1H), 8.30 (s, 1H), 10.2 (s, 1H). Mass spectrum: 1 8 1 · 09 (ΜΗ) + 〇 2 —Carbonylamino — 3 — (7-Amine 1 1-D π π-5-based methyl acrylate

令特丁氧化鉀（375 mg，1.2當量）之二氯甲烷（20 ml )攪拌懸浮液冷卻至一 20 °C，隨後令其與N—苄氧羰基 一 α —亞磷羧基甘胺酸三甲酯（1 ·】1 g，1 · 2當量）之二氯 甲烷（5 ml )溶液反應。經1 0分鐘後’加入7 —氯吲唑—5 -159- 200529835 (155) —醛（0.50 g，2·79毫莫耳）之二氯甲烷（5 ml)溶液。 令該反應混合物逐漸地回溫至室溫並攪拌3天。將該反應 混合物倒入含有水和二乙醚之分離漏斗中。利用二乙醚（ 3 X )萃取水溶液，隨後經鹽水冲洗，置於μ g S Ο 4上乾燥， 並濃縮。管柱層析產生伴有起始物（0.20 g，40% )之產 物（0.40g，37%)。 'H-NMR ： ( CDC13，5 00MHz ) ά 3.64 ( s，3H ) ，5.11 (s，2H ) ， 6.44 ( bs，1H ) ，7.30 ( bs，5 H ) ，7.43 ( sLet the stirred suspension of potassium tetrabutoxide (375 mg, 1.2 equivalents) in dichloromethane (20 ml) cool to a temperature of 20 ° C, and then mix it with N-benzyloxycarbonyl-α-phosphorous carboxyglycine trimethyl A solution of the ester (1 ·] 1 g, 1 · 2 equivalents) in dichloromethane (5 ml) was reacted. After 10 minutes, a solution of 7-chloroindazole-5 -159- 200529835 (155) -aldehyde (0.50 g, 2.79 mmol) in dichloromethane (5 ml) was added. The reaction mixture was gradually warmed to room temperature and stirred for 3 days. The reaction mixture was poured into a separating funnel containing water and diethyl ether. The aqueous solution was extracted with diethyl ether (3X), then washed with brine, dried over μg S 04, and concentrated. Column chromatography produced a product (0.40 g, 37%) with a starting material (0.20 g, 40%). 'H-NMR: (CDC13, 5 00MHz) ά 3.64 (s, 3H), 5.11 (s, 2H), 6.44 (bs, 1H), 7.30 (bs, 5H), 7.43 (s

，1H) ，7.62(s，lH) ，7.80(s，ih) ，8.0 7(s，1H )。質譜·· 3 8 6.1 6 ( MH ) +。 (±) — 2 —胺基一 3 — （7 —氯一1H—吲唑—5—基）一丙 酸甲酯1H), 7.62 (s, 1H), 7.80 (s, ih), 8.07 (s, 1H). Mass spectrum ... 3 8 6.1 6 (MH) +. (±) — 2 —Amine — 3 — (7 —Chloro-1H-indazol-5-yl) monopropionate

令2 -苄氧羰基胺基—3— (7 -氯一 1H—吲唑—5 -基）一丙烯酸甲酯（300 mg，0.78毫莫耳）之甲醇（10 m 1 )溶液與三氟乙酸（〇. 2 m 1 )反應，隨後經氮氣冲洗並 與1 0 % P d / C ( 3 〇 m g )反應。利用氫氣冲洗該燒瓶並於 氫氣下攪拌。經4天後，所有起始物係已耗盡。利用氮氣 冲洗該反應混合物，通過寅氏鹽進行過濾，並進行濃縮。 管柱層析生成7 8 m g ( 4 0 % )。 -160- (156) 200529835 ]H-NMR ： (CDC13，500MHz) 5 1.31 (bs，3H)， 2.95 (dd，J=13.7，7.9，1H ) ，3.18 (dd，J=13.7，5.2 ，1H) ，3.48(s，3H) ，3.78(dd，J=7.9，5.2，lH) ，7.23(s，lH) ，7.46(s，lH) ，8.00(s，lH)。質 譜：2 5 4.06 ( ΜΗ ) +。 實施例4 2 (土） 一 3 — ( 7 —氯 一 1 Η — 口引口坐 _ 5 —基）一2 — { 〔4 — (2 —酮基一 1，4_二氫一2Η — D奎唑啉一3 —基）一哌啶 一 1 一羰基〕一胺基} 一丙酸甲酯Let a solution of 2-benzyloxycarbonylamino-3- (7-chloro-1H-indazol-5-yl) monoacrylate (300 mg, 0.78 mmol) in methanol (10 m 1) and trifluoroacetic acid (0.2 m 1), followed by flushing with nitrogen and reacting with 10% P d / C (30 mg). The flask was flushed with hydrogen and stirred under hydrogen. After 4 days, all starting lines have been consumed. The reaction mixture was flushed with nitrogen, filtered through yin salt, and concentrated. Column chromatography yielded 78 mg (40%). -160- (156) 200529835] H-NMR: (CDC13, 500MHz) 5 1.31 (bs, 3H), 2.95 (dd, J = 13.7, 7.9, 1H), 3.18 (dd, J = 13.7, 5.2, 1H) , 3.48 (s, 3H), 3.78 (dd, J = 7.9, 5.2, 1H), 7.23 (s, 1H), 7.46 (s, 1H), 8.00 (s, 1H). Mass spectrum: 2 5 4.06 (ΜΗ) +. Example 4 2 (Earth) 1 3 — (7 —Chloro-1 1 Η — Mouth Induction _ 5 —Base) 1 2 — {[4 — (2 —Keto-1,4_Dihydro-1 2Η — D Quinazoline-3-yl) -piperidine-1 monocarbonyl] monoamino} methyl propionate

H3CO \〇 於0 t：下令（± ) — 2 —胺基一 3 — ( 7 —氯一 1 Η —吲唑 一 5—基）—丙酸甲酯（78 mg，0.31毫莫耳）之四氫呋喃 (2 ml )攪拌溶液與羰基二咪唑（50 mg，1當量）反應。 攪拌該反應混合物5分鐘，回溫至室溫，再攪拌1 0分鐘， 隨後令其與3 —哌'II定—4 一基一 3 ’ 4 一 一氯—1 Η —喧D坐琳 —2—酮（78 mg，1.1當量）反應。室溫下隔夜攪拌該混 合物。蒸發溶劑並藉由管柱層析純化殘餘物以生成白色粉 末（148 mg，94%) 〇 】H-NMR : ( DMSO— d6，5 00MHz ) 5 1 .4 6 ( ηι，4H )， 2.55— 2.80( m，2 Η ) ，3.05 (dd，J=13.7，10.7，1Η) ，3 . ] 5 ( m，1 H ) ，3.6 2 ( s，3 H ) ，4 · 0 4 ( d，J = ] 3 · 4， -161 - 200529835 (157) 2H ) ，4.11(s，2H) ，4·22 — 4.39 (m，2H) ，6.76(d ，J=7.9，1 H ) ，6.87 (dd，J=7.3，7.3，1 H ) ，6.90 (H3CO \ 0 at 0 t: Order (±) — 2 —Amine 3 — (7 —Chloro 1 Η —Indazole 5 —yl) — methyl propionate (78 mg, 0.31 mmol) tetrahydrofuran (2 ml) The stirred solution was reacted with carbonyldiimidazole (50 mg, 1 equivalent). The reaction mixture was stirred for 5 minutes, warmed to room temperature, and stirred for another 10 minutes, and then allowed to react with 3-piperidine-4, a base, 3'4, a chlorine, 1 Η, 喧 Dazolin-2 -Ketone (78 mg, 1.1 equivalents). The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by column chromatography to give a white powder (148 mg, 94%). H] NMR: (DMSO—d6, 500 MHz) 5 1.4. 6 (η, 4H), 2.55— 2.80 (m, 2 Η), 3.05 (dd, J = 13.7, 10.7, 1Η), 3.] 5 (m, 1 H), 3.6 2 (s, 3 H), 4 · 0 4 (d, J = ] 3 · 4, -161-200529835 (157) 2H), 4.11 (s, 2H), 4.22 — 4.39 (m, 2H), 6.76 (d, J = 7.9, 1 H), 6.87 (dd, J = 7.3, 7.3, 1 H), 6.90 (

d，J=8.2，lH) ，7.08(d，J=7.6，lH) ，7.12(dd，J =7.6，7.6，1H) ，7.40 ( s，1H) ，7.60 ( s，1H)， 8.15(s，lH) ，9.18(s，lH) ，：13.48(s，1H)。質譜 :51 1 · 18 ( ΜΗ ) +。d, J = 8.2, lH), 7.08 (d, J = 7.6, lH), 7.12 (dd, J = 7.6, 7.6, 1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.15 (s 1H), 9.18 (s, 1H), 13.48 (s, 1H). Mass spectrum: 51 1 · 18 (ΜΗ) +.

實施例4 3 (土） 一 4 — (2 —酬基一1，4 — 一 氯一2 Η — D 奎卩坐琳一3 — 基）一哌啶一 1 _羧酸〔2 -（ 1，4 /〕聯哌啶—1 / 一基 —1— (7 —氯—1Η — D引Π坐—5 —基甲基）一2 —酬基一乙 基〕一醯胺 ΗΝ 一 ΝExample 4 3 (Earth)-4-(2-Cyclo-1,4 -Cloyl-2, hydrazone -D quinoxaline -3 -yl) -piperidine- 1-carboxylic acid [2-(1, 4 /] Bipiperidin-1 / 1-1-1-(7-chloro-1 Η-D Π π-5-yl methyl)-2-methoxy 1-ethyl]-amine 醯 Ν-Ν

—2— { 〔4— (2 —酮基一1，4一二氫一2Η — 〇奎唑啉—3 一基）一哌啶一 1 一羰基〕一胺基} 一丙酸甲酯（1 5 mg， 0.029毫莫耳）之1:1四氫呋喃/甲醇（1 ml )懸浮液與 L i Ο Η ( 3 m g，2 · 5當量）之水（0 · 2 5 m 1 )溶液反應，並攪 拌所生成之溶液1 .5小時。冷卻該溶液至0°C，隨後與1IV[硫 酸氫鉀水溶液（60 " 1，2.0當量）反應，經濃縮後生成粗 -162- (158) (158)200529835 酸，其係未經純化立即使用。令該粗酸溶解於二甲基甲醯 胺（0.3 ml )中，隨後與二氯甲烷（0.1 5 ml ) 、4 —哌啶 基一丨派卩定（1 〇 · 1 m g，2當量）、二異丙基乙胺（1 0 // 1，2 當量）及PyBOP® (16.5 mg，1.1當量）反應。攪拌該溶 液3 0分鐘，隨後進行濃縮。藉由管柱層析純化產物生成 14.7mg(77%，2步驟）。 】H-NMR: ( CDC13，500MHz) (5 1.30-1.60( 8H)—2— {[4- (2-keto-1,4-dihydro-2H- —quinazoline-3 mono) -piperidine-1 monocarbonyl] monoamino} methyl propionate (1 5 mg, 0.029 mmol) of a 1: 1 tetrahydrofuran / methanol (1 ml) suspension and a solution of Li i Η (3 mg, 2 · 5 equivalents) in water (0 · 2 5 m 1), and stirred The resulting solution was 1.5 hours. The solution was cooled to 0 ° C, and then reacted with 1IV [aqueous solution of potassium hydrogen sulfate (60 " 1,2.0 equivalents), and concentrated to form a crude -162- (158) (158) 200529835 acid, which was immediately purified without purification. use. The crude acid was dissolved in dimethylformamide (0.3 ml), followed by dichloromethane (0.1 5 ml), 4-piperidinyl-pyridine (10.1 mg, 2 equivalents), Diisopropylethylamine (1 0 // 1, 2 equivalents) and PyBOP® (16.5 mg, 1.1 equivalents) were reacted. The solution was stirred for 30 minutes and then concentrated. The product was purified by column chromatography to yield 14.7 mg (77%, 2 steps). ] H-NMR: (CDC13, 500MHz) (5 1.30-1.60 (8H)

，1.65— 1.88 (m，5H) ，2.14(m，1H) ，2.23(m，1H )，2·30— 2.70 (m，7H) ，2·80— 3.20 (m，5H) ^ 3.94 (d，J=13.4，13.1，1H) ，4.10-4.30(m，4H) ，4.55 (m，lH) ，4.62(dd，J=13.1，12.8，lH) ，5.19(m ，1 H ) ，5.91 (dd，J=30.2，22.3，1 H ) ，6.70(d，J =, 1.65— 1.88 (m, 5H), 2.14 (m, 1H), 2.23 (m, 1H), 2.30— 2.70 (m, 7H), 2.80— 3.20 (m, 5H) ^ 3.94 (d, J = 13.4, 13.1, 1H), 4.10-4.30 (m, 4H), 4.55 (m, lH), 4.62 (dd, J = 13.1, 12.8, lH), 5.19 (m, 1 H), 5.91 (dd, J = 30.2, 22.3, 1 H), 6.70 (d, J =

7.6，1H) ，6.92(dd，J=7.6，7.3，lH) ，7.01(dd，J = 7.9，7.6，1H) ，7.13(s，0.4H) ，7.15(dd，J=7.9 ，，7.6，1H) ，7.24 ( s，0.6H ) ，7 · 3 3 ( s，0 · 4 H )， 7.43 ( s，0.6H) ，7.49 ( bs，1H) ，7 · 91 ( s，0.4 H )， 7.95 (s，0.6H) ，：11.25 (bd，J=50.7，1H)。質譜： 64 7.3 7 ( ΜΗ ) +。 4 一溴一2 —乙基一 6 —甲基一苯胺7.6, 1H), 6.92 (dd, J = 7.6, 7.3, 1H), 7.01 (dd, J = 7.9, 7.6, 1H), 7.13 (s, 0.4H), 7.15 (dd, J = 7.9 ,, 7.6, 1H), 7.24 (s, 0.6H), 7.33 (s, 0.4H), 7.43 (s, 0.6H), 7.49 (bs, 1H), 7.91 (s, 0.4H), 7.95 (s, 0.6H), 11.25 (bd, J = 50.7, 1H). Mass spectrum: 64 7.3 7 (ΜΗ) +. 4-bromo- 2 -ethyl- 6 -methyl-aniline

令2 —乙基一 6 —甲基—苯胺（]4 ml，100毫莫耳）溶 -163- 200529835 解濃H C ] ( 3 0 // 1 )和3 ( 2 2 0 m 1 )之溶液中，並冷卻至〇 °C 。隨後逐滴地加入溴（5」ml，1當量）。迅速生成白色 沈澱物。過該沈澱物並利用二乙醚進行冲洗。令該沈澱物 懸浮於水中並加入K2C03水溶液進行中和。利用二乙醚萃 取所生成之油狀物。將該醚液置於K2C03上乾燥’經過濾 和濃縮後生成紫色油狀物（7.0 g，3 3 % )，其係未經純 化而直接使用。質譜：214.01 ( MH) +。 4一溴一 2—乙基一 6-甲基苯基重氮基一特丁基硫化物Let 2-ethyl-6-methyl-aniline (] 4 ml, 100 millimoles) be dissolved in a solution of -163- 200529835 deconcentrated HC] (3 0 // 1) and 3 (2 2 0 m 1) And cooled to 0 ° C. Bromine (5 "ml, 1 equivalent) was then added dropwise. A white precipitate formed rapidly. Pass the precipitate and rinse with diethyl ether. The precipitate was suspended in water and neutralized by adding K2C03 aqueous solution. The resulting oil was extracted with diethyl ether. This ether solution was dried on K2C03 ', filtered and concentrated to give a purple oil (7.0 g, 33%), which was used directly without purification. Mass spectrum: 214.01 (MH) +. 4-bromo- 2-ethyl- 6-methylphenyldiazo-tert-butyl sulfide

令4 —溴一 2—乙基一 6—甲基苯胺（7.0 g，33毫莫耳 )懸浮於7.8M HC1 ( 30 ml )中。冷卻該攪拌混合物至一 2 〇 °C，隨後與以超過1 0分鐘之時間逐滴加入亞硝酸鈉（ 2 ·27 g，1.05當量）之水（5 ml )溶液反應，同時維持溫 度低於—5 °C。於一 5 °C至一 2 0 °C之溫度下經3 0分鐘後，利 用乙酸鈉固體緩衝該混合物至約p Η 5。於0 °C下以超過約 1 〇分鐘之時間，將該混合物（維持於約- 1 〇 °C下）分數份 地加入至特丁基硫赶（3.7 ml，1當量）之乙醇（50 ml) 攪拌溶液中。隨後，於〇 °C下攪拌該混合物3 0分鐘，並加 入碎冰（約5 0 m ])。於冰箱中貯存該混合物2小時。藉由 過濾以收集所生成之淡棕色固體，經水冲洗並於高真空下 -164- (160) (160)200529835 乾燥數小時（9.47 g，92% )。質譜：3 1 5·05 ( ΜΗ ) 5 —溴一 7 —乙基一1 Η —吲唑4-Bromo-2-ethyl-6-methylaniline (7.0 g, 33 mmol) was suspended in 7.8M HC1 (30 ml). Cool the stirred mixture to -20 ° C, and then react with a solution of sodium nitrite (2.27 g, 1.05 equivalents) in water (5 ml) added dropwise over 10 minutes, while maintaining the temperature below- 5 ° C. After 30 minutes at a temperature between -5 ° C and -20 ° C, the mixture was buffered with sodium acetate solids to about pΗ5. This mixture (maintained at about -100 ° C) was added in portions to t-butylthiosulfate (3.7 ml, 1 equivalent) of ethanol (50 ml) at 0 ° C for more than about 10 minutes. ) Stir the solution. Subsequently, the mixture was stirred at 0 ° C for 30 minutes, and crushed ice (about 50 m] was added. The mixture was stored in the refrigerator for 2 hours. The resulting light brown solid was collected by filtration, rinsed with water and dried under high vacuum -164- (160) (160) 200529835 for several hours (9.47 g, 92%). Mass spectrum: 3 1 5 · 05 (ΜΗ) 5 -bromo- 7 -ethyl- 1 fluorene-indazole

藉由套管將4一溴一 2—乙基一 6 —甲基苯基重氮基一 特丁基硫化物（9.4 g，30毫莫耳）之DMSO( 100 ml)溶 液加入至特丁氧化鉀（33.6 g，10當量）之DMSO(200 ml )攪拌溶液中。劇烈攪拌該混合物1小時。將該反慜混 合物小心地倒入至碎冰（5 00 ml )、濃HC1 ( 25 ml )及水 (1 00 ml )之混合物中。過濾所生成之沈澱物，經水冲洗 並溶解於甲醇中，經濃縮後生成黃褐色固體（5.7 g，8 5 % )。 】H-NMR ( CDC13，5 0 0MHz ) 5 1 · 3 9 ( t，J = 7 · 6，3 Η ) ，2.92(q，J=7.6，2H) ，7.30(s，2H) ，7·7 5(δ，1Η )，8.04(s，lH)。質譜：225.00(MH)+。 7—乙基一1H—吲唑一5 —醛A solution of 4-bromo-2-ethyl-6-methylphenyldiazo-tert-butyl sulfide (9.4 g, 30 mmol) in DMSO (100 ml) was added to the tert-butyl oxide through a cannula. Potassium (33.6 g, 10 eq.) In DMSO (200 ml) was stirred in a solution. The mixture was stirred vigorously for 1 hour. The reaction mixture was carefully poured into a mixture of crushed ice (500 ml), concentrated HC1 (25 ml) and water (100 ml). The resulting precipitate was filtered, washed with water and dissolved in methanol. After concentration, a yellow-brown solid (5.7 g, 85%) was obtained. ] H-NMR (CDC13, 500 MHz) 5 1 · 3 9 (t, J = 7 · 6, 3 Η), 2.92 (q, J = 7.6, 2H), 7.30 (s, 2H), 7.7 5 (δ, 1Η), 8.04 (s, 1H). Mass spectrum: 225.00 (MH) +. 7-ethyl-1H-indazole-5

將5—溴—7 —乙基一 1H-吲唑（2.0 g，8.9毫莫耳） 和NaH ( 2 2 6 mg，1.1當量）載入含有磁石攪拌棒之經火焰 -165- 200529835 (161) 乾燥的圓底燒瓶中。於室溫和氮氣下，加入乾四氫呋喃（ 60 ml)。室溫下攪拌該混合物15分鐘。冷卻該攪拌混合 物至-7 8 °C，並以數分鐘之時間加入特丁基鋰之戊烷溶液 (1.7M，10.5 ml，2·0當量）。於一7 8 °C 下經 1 5 分鐘後， 令該反應混合物逐漸地回溫至- 5 0 °C，並再冷卻至-7 8 °C 。緩慢地加入二甲基甲醯胺（2 · 8 ml )並令該混合物回溫 至一 50 °C。將該溶液迅速地轉移至1M硫酸氫鉀（25 ml ) 和水（3 00 ml )之攪拌溶液中。利用二乙醚萃取所生成之 懸浮液，經水和鹽水冲洗且置於MgS04上乾燥，並進行濃 縮。管柱層析生成白色固體（160mg，10%)。 】H-NMR(CD3OD，500MHz) 5 1.38 (t，J二 7.6，3H)Load 5-bromo-7-ethyl-1H-indazole (2.0 g, 8.9 mmol) and NaH (226 mg, 1.1 equivalent) into a flame-165-200529835 (161) containing a magnetic stir bar Dry round bottom flask. At room temperature under nitrogen, dry tetrahydrofuran (60 ml) was added. The mixture was stirred at room temperature for 15 minutes. The stirred mixture was cooled to -7 ° C, and a solution of t-butyllithium in pentane (1.7M, 10.5 ml, 2.0 equivalents) was added over several minutes. After 15 minutes at -78 ° C, the reaction mixture was gradually warmed to -50 ° C, and then cooled to -78 ° C. Slowly add dimethylformamide (2.8 ml) and allow the mixture to warm to -50 ° C. The solution was quickly transferred to a stirred solution of 1M potassium bisulfate (25 ml) and water (300 ml). The resulting suspension was extracted with diethyl ether, washed with water and brine, dried over MgS04, and concentrated. Column chromatography gave a white solid (160 mg, 10%). ] H-NMR (CD3OD, 500MHz) 5 1.38 (t, J 2 7.6, 3H)

，2.98(q，J=7.6，2H) ，7.71(s，lH) ，8.22(s，lH )，8.24(s，lH) ，9.96(s，lH)。質譜：175.08 (Μ H ) H 。, 2.98 (q, J = 7.6, 2H), 7.71 (s, 1H), 8.22 (s, 1H), 8.24 (s, 1H), 9.96 (s, 1H). Mass spectrum: 175.08 (MH) H.

2 -苄氧羰基胺基—3 - （7 —乙基—1H —吲唑一 5 —基） 一丙烯酸甲酯2-benzyloxycarbonylamino-3-(7-ethyl-1H-indazol-5-yl) monoacrylate

於0°C下將四甲基胍（0.22 ml，1.9當量）加入至N-苄氧羰基一 ^ 一亞磷羧基甘胺酸三甲酯（〇 . 6 1 g，2.0當量 )和7 —乙基—]Η -吲唑一 5 —醛（1 6 0 m g，0 · 9 2毫莫耳） -166- (162) 200529835 之四氫呋喃（5 m 1 )攪拌溶液中。令該反應混合物隔夜緩 慢地回溫至室溫。濃縮該反應混合物，令其溶解於二乙醚 中，經水和鹽水冲洗，隨後乾燥（MgS〇4 )並濃縮。藉由 管柱層析以純化殘餘物，生成油狀物（3 3 3 mg，95% )。 】H-NMR ( CDC13，5 00MHz ) 5 1 · 3 3 ( t，J 二 7 · 6，3 Η )Tetramethylguanidine (0.22 ml, 1.9 equivalents) was added to N-benzyloxycarbonyl mono ^ -phosphorous carboxyglycine trimethyl ester (0.61 g, 2.0 equivalents) and 7-B at 0 ° C. The base —] fluorene-indazole-5 —aldehyde (160 mg, 0.92 mmol) —166- (162) 200529835 in a stirred solution of tetrahydrofuran (5 m 1). The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was concentrated, dissolved in diethyl ether, washed with water and brine, then dried (MgS04) and concentrated. The residue was purified by column chromatography to give an oil (3 3 3 mg, 95%). ] H-NMR (CDC13, 5 00MHz) 5 1 · 3 3 (t, J 2 7 · 6, 3 Η)

，2.86(q，J=7.3，2H) ，3.83(s，3H) ，5.11(S，2H )，6.39(bs，lH) ，7.29(bs，5H) ，7.43(s，1H) ，7.50(s，lH) ，7.78(s，lH) ，8.04(s，lH) 〇 質 譜：380·17(ΜΗ) +。 (±) — 2—胺基一3— （7 -乙基一 1H —吲唑一 5—基）— 丙酸甲酯, 2.86 (q, J = 7.3, 2H), 3.83 (s, 3H), 5.11 (S, 2H), 6.39 (bs, lH), 7.29 (bs, 5H), 7.43 (s, 1H), 7.50 (s 1H), 7.78 (s, 1H), 8.04 (s, 1H) Mass spectrum: 380 · 17 (ΜΗ) +. (±) — 2-Amino-3— (7-ethyl-1H—indazol-5-yl) —methyl propionate

HN 一 NHN a N

於氮氣下將Pd/C( 10%，33 mg)加入至2 —苄氧羰 基胺基一 3— (7—乙基一1H - D引卩坐—5 —基）一丙嫌酸甲 酯（3 3 0 mg，0.78毫莫耳）之甲醇（5 ml )溶液中。利用 氫氣冲洗該燒瓶，並於氫氣下隔夜攪拌。利用氮氣冲洗該 反應混合物，通過寅氏鹽過濾，經濃縮後生成產物（2 1 0 mg，98% )，其係未經純化而直接使用。 W-NMR ( CDC13，5 00MHz ) ά 1 · 3 4 ( t，J = 7.6，3 Η ) ，2.85 ( q ^ J 二 7.6，2H) ，2.96 (dd，J=]3.7，7.6， )，3.19(dd，J=13.7，8.6，lH) ，3.48(s，2H)， -167- (163) 200529835 3.73(s，3H) ，3.80(dd，J=7.6，5.2，lH) ，6.99(s ，1H) ，7.38(s，lH) ，7.97(s，lH)。質譜：248.15 (Μ H ) +。 實施例4 4 (±) — 3— (7 —乙基一1H —吲唑一5 —基）一2— { 〔4 —(2 —酮基一1，4 —二氫一 2H — D奎唑啉一3 —基）—哌 啶一 1 一羰基〕一胺基} 一丙酸甲酯Under nitrogen, Pd / C (10%, 33 mg) was added to 2-benzyloxycarbonylamino-3- (7-ethyl-1H-D indio-5-yl) -propionic acid methyl ester ( 3 3 0 mg, 0.78 mmol) in methanol (5 ml). The flask was flushed with hydrogen and stirred overnight under hydrogen. The reaction mixture was flushed with nitrogen, filtered through Yin's salt, and concentrated to give the product (210 mg, 98%), which was used directly without purification. W-NMR (CDC13, 5 00MHz) ά 1 · 3 4 (t, J = 7.6, 3 Η), 2.85 (q ^ J 7.6, 2H), 2.96 (dd, J =) 3.7, 7.6,), 3.19 (dd, J = 13.7, 8.6, lH), 3.48 (s, 2H), -167- (163) 200529835 3.73 (s, 3H), 3.80 (dd, J = 7.6, 5.2, lH), 6.99 (s, 1H), 7.38 (s, 1H), 7.97 (s, 1H). Mass spectrum: 248.15 (MH) +. Example 4 4 (±) — 3— (7-ethyl-1H—indazol-5-yl)-2— {[4 — (2-keto-1,4-dihydro-2H—Dquinazole Phenyl-3-yl) -piperidine-1 monocarbonyl] monoamino} methyl propionate

H3CO \〇 於Ot：下令（±) — 2 —胺基一3— (7 —乙基一 1H —吲 唑一 5 —基）—丙酸甲酯（100 mg，0.41毫莫耳）之四氫 呋喃（2 m 1 )攪拌溶液與羰基二咪唑（6 6 m g，〗當量）反 應。攪拌該反應混合物5分鐘，令其回溫至室溫，再攪拌 15分鐘，隨後與3 — 定一 4 —基—3，4 —二氯—1H — D奎 唑啉—2 —酮（103 mg，1.1當量）反應。室溫下隔夜攪拌 該混合物。蒸溶劑並藉由管柱層析以純化殘餘物，生成白 色固體（1 88 mg，92% )。 1H-NMR ( CDC13，5 0 0MHz ) ο 1.36 ( t，J= 7.6，3H ) ，1.69(m，4H) ，2.86(m，2H) ，2.90 (q，J = 7.6, 2H ) ，3.22(dd，J=5.5，4.9，2H) ，3.75(s，3H)， 4.03 (dd，J 二 44.0，13.7，2H) ，4.26 ( s ^ 2H ) ，4.5 1 -168- 200529835 (164) (m，1H) ，4·84 ( m，1H) ，5.02 ( m，1H) ，6.70 ( d ，J=7.9，1H) ，6.90—7.05 (m，4H) ，7.16(dd，J = 7.6，7.6，1H) ，7.34(s，lH) ，8.03(s，lH)。質譜 ：502.29 ( ΜΗ ) + 〇 實施例4 5 (土） 一 4 — (2 一 嗣基一1,4 一 一 氯 一 2 Η — D 奎 口坐琳一3 — 基）—暖啶一1 —羧酸〔2 — ( 1，4 >〕聯哌一 1 / 一基— (7 —乙基一1Η —吲唑一5 —基甲基）一2—酮基一乙基〕 一醯胺H3CO in Ot: Order (±) -2-amino-3- (7-ethyl-1H-indazole-5-yl) -methyl propionate (100 mg, 0.41 mmol) tetrahydrofuran ( 2 m 1) The stirred solution was reacted with carbonyldiimidazole (66 mg, equivalent). The reaction mixture was stirred for 5 minutes, allowed to warm to room temperature, and stirred for another 15 minutes, and then with 3-butyl-4-yl-3,4-dichloro-1H-D-quinazolin-2-one (103 mg , 1.1 equivalent) reaction. The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by column chromatography to give a white solid (188 mg, 92%). 1H-NMR (CDC13, 500 MHz) ο 1.36 (t, J = 7.6, 3H), 1.69 (m, 4H), 2.86 (m, 2H), 2.90 (q, J = 7.6, 2H), 3.22 (dd , J = 5.5, 4.9, 2H), 3.75 (s, 3H), 4.03 (dd, J 2 44.0, 13.7, 2H), 4.26 (s ^ 2H), 4.5 1 -168- 200529835 (164) (m, 1H ), 4.84 (m, 1H), 5.02 (m, 1H), 6.70 (d, J = 7.9, 1H), 6.90-7.05 (m, 4H), 7.16 (dd, J = 7.6, 7.6, 1H) , 7.34 (s, 1H), 8.03 (s, 1H). Mass spectrum: 502.29 (ΜΗ) + 〇 Example 4 5 (soil) a 4 — (2 amidino-1, 4 a 1 chloro a 2 Η — D Kuikouzalin a 3 — yl) — unionidine a 1 — Carboxylic acid [2 — (1,4 >] dipiperazine 1/1 radical — (7 —ethyl 1 1 —indazole 5 —ylmethyl) 2 —keto 1 ethyl] monoamine

將1^〇11單水合物（3.011^，2.5當量）之水（0.11111) 溶液加入至（± ) — 3 — （ 7 —乙基一 1 Η —吲唑一5 —基） 一 2—丨〔4— (2 —酮基一1，4 —二氫一2Η—喧唑啉一3 一基）一 _ Π定一 1 一鑛基〕一胺基} 一丙酸甲醋（1 5 m g， 0.03毫莫耳）之甲醇（0· 6 ml )溶液中，並攪拌所生成之 溶液6小時。冷卻該溶液至0 °C，令其與1 Μ硫酸氫鉀水溶 液（60 μ 1，2.0當量）反應，經濃縮後生成粗酸，其係未 經純化而立即使用。令該粗酸溶解於二甲基甲醯胺（〇 . 4 m 1 )中，冷卻至01，隨後令其與二氯甲烷（0.2 m 1 ) 、4 -169- (165) (165)200529835 —哌啶基—_啶（1 1 m g，2 · 2當量）、二異丙基乙胺（1 2 //1，2.3 當量）及 PyBOP® (19 mg，1.2 當量）反應。於 0 °C下攪拌該溶液1 5分鐘，令其回溫至室溫，再攪拌1 . 5小 時，並進行濃縮。藉由管柱層析以純化產物，生成14.5 mg， （76%，2步驟）。 1 H-NMR ( CDC13，5 00MHz ) 5 1 · 2 8 — 1 · 4 8 ( m，1 0 Η ) ，1.52(m，2Η) ，1.60-1.82 (m，6Η) ，1.95( m， 1·4Η) ，2.06(m，1.6H) ，2.20-2.50 (m，5H) ^ 2.77 一 2.93(m，5H) ，2.96—3.71 (m，2H) ，3.76(d，J = 13.4，0.4H) ，3.86(d，J=13.7，0.6H) ，4.10— 4.20( m，2H) ，4.26(s，2H) ，4.57(m，2H) ，5.10—5.24 (m，lH) ，5.67(d，J=8.2，0.6H) ，5.74(d，J=7.9 ，0.4H) ，6.67(d，J=7.9，lH) ，5.67(d，J=8.2， 0.6H ) ，5.7 4(d，J=7.9，0.4H) ，6.67(d，J=7.9， 1 H ) ，6.93 (dd，J = 7.6，7.3，1H) ，6.96(s，0.4H) ，7.03(dd， ，J=7.0，6.7，1H) ，7.09( ni，1.6H)， 7.15(dd，J=7.0，6.7，lH) ，7.31(s，0.4H) ^ 7.38 (s，0.6H) ，7.94(s，0.4H) ，7.95(s，0.6H)。質譜 ：64 1.5 0 ( ΜΗ ) + 。 (3，4 一二硝基—苯基）一甲醇A solution of 1 ^ 〇11 monohydrate (3.011 ^, 2.5 equivalents) in water (0.11111) was added to (±) — 3 — (7 —ethyl — 1 Η — indazole — 5 —yl) — 2 — 丨 [ 4- (2-keto-1,4-dihydro-1, 2-fluorene-oxazoline-3, 1-yl) -_ Π 定 -1, 1-mine] monoamine} monopropionate (1 5 mg, 0.03 Millimoles) in methanol (0.6 ml), and the resulting solution was stirred for 6 hours. The solution was cooled to 0 ° C, and allowed to react with a 1 M aqueous potassium hydrogen sulfate solution (60 μ1, 2.0 equivalents). After concentration, a crude acid was formed, which was used immediately without purification. The crude acid was dissolved in dimethylformamide (0.4 m 1), cooled to 01, and then mixed with dichloromethane (0.2 m 1), 4 -169- (165) (165) 200529835 — Piperidinyl-pyridine (1 1 mg, 2.2 equivalents), diisopropylethylamine (1 2 // 1, 2.3 equivalents), and PyBOP® (19 mg, 1.2 equivalents) were reacted. The solution was stirred at 0 ° C for 15 minutes, allowed to warm to room temperature, stirred for another 1.5 hours, and concentrated. The product was purified by column chromatography to yield 14.5 mg, (76%, 2 steps). 1 H-NMR (CDC13, 5000 MHz) 5 1 · 2 8 — 1 · 4 8 (m, 1 0 Η), 1.52 (m, 2 Η), 1.60-1.82 (m, 6 Η), 1.95 (m, 1 · 4Η), 2.06 (m, 1.6H), 2.20-2.50 (m, 5H) ^ 2.77-2.93 (m, 5H), 2.96-3.71 (m, 2H), 3.76 (d, J = 13.4, 0.4H), 3.86 (d, J = 13.7, 0.6H), 4.10-4.20 (m, 2H), 4.26 (s, 2H), 4.57 (m, 2H), 5.10-5.24 (m, lH), 5.67 (d, J = 8.2, 0.6H), 5.74 (d, J = 7.9, 0.4H), 6.67 (d, J = 7.9, 1H), 5.67 (d, J = 8.2, 0.6H), 5.74 (d, J = 7.9, 0.4H), 6.67 (d, J = 7.9, 1H), 6.93 (dd, J = 7.6, 7.3, 1H), 6.96 (s, 0.4H), 7.03 (dd ,, J = 7.0, 6.7, 1H) , 7.09 (ni, 1.6H), 7.15 (dd, J = 7.0, 6.7, 1H), 7.31 (s, 0.4H) ^ 7.38 (s, 0.6H), 7.94 (s, 0.4H), 7.95 (s, 0.6H). Mass spectrum: 64 1.50 (ΜΗ) +. (3,4-dinitro-phenyl) -methanol

於-20°C下以超過45分鐘之時間，將硼烷一四氫呋喃 複合物（1 Μ四氫呋喃溶液，8 0 0 m 1，8 0 0毫莫耳）加入至 -170- (166) 200529835Boron-tetrahydrofuran complex (1 M tetrahydrofuran solution, 800 m 1,800 mmol) was added to -170- (166) 200529835 at -20 ° C for more than 45 minutes.

3，4 —二硝基苯甲酸（93.5 g，441毫莫耳）之四氫呋喃 (3 0 0 ml )溶液中。於—2CTC下攪拌所生成之混合物1小 時，隨後回溫至室溫，並隔夜攪拌。藉由添加1 : 1乙酸 /水（3 2 ml )以中止反應。真空下除去溶劑並於劇烈攪 拌下以超過1 5分鐘之時間將殘餘物倒入至冰冷飽和 NaHC03水溶液（1000 ml)中。利用乙酸乙酯（ 3x500 ml )萃取該混合物。利用飽和NaHC03水溶液和鹽水冲洗結 合之有機層，並將其置於Na2S04上乾燥。經過濾後，除去 溶劑以生成淡黃色固體之標的化合物（1 〇〇% )。 】H-NMR ( CDC13，5 00MHz ) δ 7.91 ( d，J= 8.0Hz，1H )，7.89(s，lH) ，7.71(dd，J=8.5，1.0Hz，lH)， 4.87(s，2H) ，2.30(s，lH)。 3，4 一二硝基一苯醛3,4-Dinitrobenzoic acid (93.5 g, 441 mmol) in tetrahydrofuran (300 ml). The resulting mixture was stirred at -2CTC for 1 hour, then warmed to room temperature and stirred overnight. The reaction was stopped by adding 1: 1 acetic acid / water (32 ml). The solvent was removed under vacuum and the residue was poured into ice-cold saturated NaHC03 aqueous solution (1000 ml) over 15 minutes with vigorous stirring. The mixture was extracted with ethyl acetate (3x500 ml). The combined organic layer was washed with a saturated aqueous solution of NaHC03 and brine, and dried over Na2S04. After filtration, the solvent was removed to give the title compound (100%) as a pale yellow solid. ] H-NMR (CDC13, 500 MHz) δ 7.91 (d, J = 8.0 Hz, 1H), 7.89 (s, lH), 7.71 (dd, J = 8.5, 1.0 Hz, lH), 4.87 (s, 2H) , 2.30 (s, lH). 3,4 dinitro-benzoaldehyde

將（3，4 —二硝基一苯基）—甲醇（95.3 g，481毫 莫耳）之CH2C1 2 ( 5 0 0 ml )溶液全部一次加入至吡啶鑰氯 鉻酸鹽（156 g，722毫莫耳）之CH2C】2 (900 ml)懸浮液 中。室溫下攪拌該混合物1.5小時，隨後加入乙醚（1500 ml )。自所生成之黑色膠狀物傾析上淸液，並利用CH2C12 ( 3 x 2 5 0 ηι 1 )完全地冲洗不溶之殘餘物。經由通過i夕酸 鎂（Florisil )墊過濾結合之有機溶液，生成淡亮黃色澄 淸溶液。真空下除去溶劑並藉由矽膠層析且利用C H 2 C 12爲 -171 - (167) (167)200529835 流洗液以純化殘餘物，生成黃色固體之標的化合物（7 l % )° j-NMR ( CDC13，3 00MHz ) 5 8.4 5 ( d，J = 1 · 5 Η z，1 Η )，8·28 (dd，J=8.1，1·5Ηζ，1H) ，8.07(d，J = 8 · 1 Hz，H)。 13C NMR ( CD3OD，1 25MHz ) ά 1 8 7.7，1 3 9 · 2，1 3 4 · 2， 126.2， 125.7 ° 2 —节氧鑛基胺基一 3— (3，4 一二硝基一苯基）一丙嫌酸 甲酯(3,4-Dinitromonophenyl) -methanol (95.3 g, 481 mmol) in CH2C1 2 (500 ml) was added all at once to pyridinium chlorochromate (156 g, 722 mmol) Mol) of CH2C] 2 (900 ml) suspension. The mixture was stirred at room temperature for 1.5 hours, and then ether (1500 ml) was added. The supernatant was decanted from the resulting black gum and the insoluble residue was completely rinsed with CH2C12 (3 x 2 50 nm). The combined organic solution was filtered through a pad of magnesium (Florisil) to produce a light yellow clear solution. The solvent was removed under vacuum and the residue was purified by silica gel chromatography using a CH 2 C 12 -171-(167) (167) 200529835 stream to purify the residue to give the title compound as a yellow solid (7 l%) ° j-NMR (CDC13, 3 00MHz) 5 8.4 5 (d, J = 1 · 5 Η z, 1 Η), 8 · 28 (dd, J = 8.1, 1 · 5Ηζ, 1H), 8.07 (d, J = 8 · 1 Hz, H). 13C NMR (CD3OD, 1 25MHz) ά 1 8 7.7, 1 3 9 · 2, 1 3 4 · 2, 126.2, 125.7 ° 2 —Bentoxanylamino — 3 — (3,4 dinitronitrobenzene Methyl) monopropionate

於室溫下將1，1，3，3 —四甲基胍（42.1 ml，329毫 莫耳）加入至N- （苄氧羰基）- α -亞磷羧基甘胺酸三 甲酯（114.1 g，344毫莫耳）之四氫呋喃（800 ml)溶液 中。室溫下攪拌該混合物1 5分鐘，隨後冷卻至—7 8 °C。藉 由套管緩慢地加入3，4 一二硝基一苯醛（6丨.4 g，3 1 3毫 莫耳）之四氫呋喃（2〇〇 ml )溶液。於一 78 °C下攪拌所生 成之混合物2小時，隨後令其隔夜回溫至室溫。真空下除 去溶劑，並令黃色殘餘物溶解於乙酸乙酯（4 · 5 L )中。 利用1 N硫酸（1 · 5 L )、水（2 x )及鹽水冲洗該溶液，並置 於N a S 0 4上乾燥。經過濾後，真空下除去溶劑並自乙酸乙 酯中結晶出殘餘物（2 0 g粗產物/ 1 0 〇 ml乙酸乙酯）。收 集黃色結晶並經矽膠層析（流洗液：CH2C12 )進一步純化 。得到黃色結晶之標的化合物（7 7 % )。 -172- (168) (168)200529835 】H-NMR ( CDC13，5 00MHz ) 5 7 · 8 5 ( d，J = 1 · 5 H z，1 H )，7,74 ( d，J = 8·0Ηζ，1 H ) ，7 · 6 2 ( d d，J 二 8 · 5， 1·5Ηζ，1H) ，7.35— 7·34 ( m，3H ) ，7.34 ( brs，2H ) ，7.23 ( s，1H ) ，6.95 ( brs，1 H ) ，5.07 ( s，2H )， 3.90 ( s，3H )。 類似之方法製備： 2—苄氧羰基胺基一 3 -（3 -羥基一 4 —硝基—苯基）一丙 烯酸甲酯Add 1,1,3,3-tetramethylguanidine (42.1 ml, 329 mmol) to N- (benzyloxycarbonyl) -α-phosphorous carboxyglycine trimethyl ester (114.1 g at room temperature) , 344 mmol) in tetrahydrofuran (800 ml). The mixture was stirred at room temperature for 15 minutes and then cooled to -7 8 ° C. A solution of 3,4-dinitromonobenzaldehyde (6.1.4 g, 3 1 3 mmol) in tetrahydrofuran (200 ml) was slowly added through the cannula. The resulting mixture was stirred at -78 ° C for 2 hours, and then allowed to warm to room temperature overnight. The solvent was removed in vacuo and the yellow residue was dissolved in ethyl acetate (4.5 L). The solution was washed with 1 N sulfuric acid (1.5 L), water (2 x), and brine, and dried over Na S 0 4. After filtration, the solvent was removed in vacuo and the residue crystallized from ethyl acetate (20 g of crude product / 100 ml of ethyl acetate). The yellow crystals were collected and further purified by silica gel chromatography (flow washing solution: CH2C12). The target compound (77%) was obtained as yellow crystals. -172- (168) (168) 200529835】 H-NMR (CDC13, 5000 MHz) 5 7 · 8 5 (d, J = 1 · 5 H z, 1 H), 7, 74 (d, J = 8 · 0Ηζ, 1 H), 7 · 6 2 (dd, J 2 8 · 5, 1 · 5Ηζ, 1H), 7.35-7 · 34 (m, 3H), 7.34 (brs, 2H), 7.23 (s, 1H) , 6.95 (brs, 1 H), 5.07 (s, 2H), 3.90 (s, 3H). Prepared in a similar way: 2-benzyloxycarbonylamino- 3-(3-hydroxy- 4 -nitro-phenyl) monopropenoic acid methyl ester

】H-NMR ( CDC13，5 00MHz ) 5 7 · 9 3 ( d，J = 9 · 0 Η z，1 Η )，7.32(brs，sH) ，7.28(brs，2H) ，7.17(s，lH) ，7.16 (d，J二 2·0Ηζ，1H) ，7.01 (dd，J=9.0，2.0Hz ，1 H ) ，6.74 ( brs，1 H ) ，5.06 ( s，2H ) ，3.86 ( s， 3H ) 〇 (R) - 2 —苄氧羰胺基一 3— (3，4 一二硝基一苯基）— 丙酸甲醋] H-NMR (CDC13, 500 MHz) 5 7 · 9 3 (d, J = 9 · 0 Η z, 1 Η), 7.32 (brs, sH), 7.28 (brs, 2H), 7.17 (s, 1H) , 7.16 (d, J = 2.00Ηζ, 1H), 7.01 (dd, J = 9.0, 2.0Hz, 1H), 6.74 (brs, 1H), 5.06 (s, 2H), 3.86 (s, 3H) 〇 (R)-2 -benzyloxycarbonylamino 3-(3,4 -dinitro-phenyl)-methyl propionate

將經烤箱乾燥之5 0 0 m 1 S h 1 e n c k燒瓶置入充滿氮氣之 手套袋中。經將該手套袋抽真空並塡充氮氣（3x)後，密 封該燒瓶，自該手套袋中取出並稱重。再將該燒瓶置回該 -173- (169) (169)200529835 手套袋中，抽宜並塡充氮氣（3x)，隨後載入（一）一 1 ，2—雙（（211，5尺）一2，5—二乙基磷烷並）苯（環辛 二烯）铑（I )三氟甲烷磺酸酯。密封該燒瓶，自該手套 袋中取出並稱重（784 mg，1.08毫莫耳）。將2 -苄氧羰 基胺基一 3 — （3，4 一二硝基一苯基）一丙烯酸甲酯（ 8.72 g，21.7¾莫耳）加入至另一個500 ml，Shlenck燒瓶 中，隨後抽真空並塡充氮氣（3x)。加入CH2C12 (350 ml ，利用氮氣脫氣2小時），將所生成之溶液由套管轉移至 該觸媒燒瓶中。對該燒瓶噴灑且塡充氫氣（4x )，並於室 溫下攪拌該混合物4小時。真空下除去溶劑，並藉由矽膠 層析且利用乙酸乙酯/己烷（1 : 1 )爲流洗液以純化殘餘 物，生成淡黃褐色膠狀固體之標的化合物（99 %產率且 9 9.2%對映體過量，其測定係藉由HPLC分析且利用下述 之條件：Chiralpak AD管柱（ 4.6x250 mm，10// m; A = 乙醇，B=己烷；40% Β@1·0 ml/分達14分鐘·，滯留時間 :對R對映異構物爲1 〇 . 9分鐘，且對S對映異構物爲6.9分 鐘）。 】H-NMR ( CDC13，5 00MHz ) 5 7 · 8 0 ( d，J 二 8.0 Η z，1 Η )，7.63(s，lH) ，7.45(d，J=8.0Hz，lH) ，7·38 — 7.31(m，5H) ，5.37(d，J=6.0Hz，lH) ，5.13 - 5.05 (m，2H ) ，4.68 (d，J = 6.0Hz ^ 1H ) ，3.71 (s，3H ) ，3.36(dd，J=13.5，5.0Hz，lH) ，3.17(dd，J二 13.5 ，6.0Hz，1 H )。 -174- (170) 200529835 類似之方法製備： (R) - 2 -苄氧羰胺基一 3 - （3 -羥基一 4一硝基—苯基 )一丙酸甲酯An oven-dried 5000 m 1 S h 1 e n c k flask was placed in a nitrogen-filled glove bag. After the glove bag was evacuated and flushed with nitrogen (3x), the flask was sealed, removed from the glove bag and weighed. The flask was placed back in the -173- (169) (169) 200529835 glove bag, pumped and filled with nitrogen (3x), and then loaded into (a) 1,2-double ((211, 5 feet) A 2,5-diethylphosphorano) benzene (cyclooctadiene) rhodium (I) trifluoromethanesulfonate. The flask was sealed, removed from the glove bag and weighed (784 mg, 1.08 mmol). Add 2-benzyloxycarbonylamino-3- (3,4-dinitromonophenyl) monoacrylate (8.72 g, 21.7¾ mole) to another 500 ml, Shlenck flask, and then evacuate Fill with nitrogen (3x). CH2C12 (350 ml, degassed with nitrogen for 2 hours) was added, and the resulting solution was transferred from the cannula to the catalyst flask. The flask was sprayed and flushed with hydrogen (4x), and the mixture was stirred at room temperature for 4 hours. The solvent was removed under vacuum, and the residue was purified by silica gel chromatography using ethyl acetate / hexane (1: 1) as the eluent to give the title compound as a pale yellow-brown gelatinous solid (99% yield and 9%). 9.2% enantiomeric excess was determined by HPLC analysis using the following conditions: Chiralpak AD column (4.6x250 mm, 10 // m; A = ethanol, B = hexane; 40% Β @ 1 · 0 ml / minute up to 14 minutes, retention time: 10.9 minutes for the R enantiomer and 6.9 minutes for the S enantiomer.] H-NMR (CDC13, 5 00MHz) 5 7 · 8 0 (d, J 8.0 Η z, 1 Η), 7.63 (s, lH), 7.45 (d, J = 8.0 Hz, lH), 7.38 — 7.31 (m, 5H), 5.37 (d , J = 6.0Hz, lH), 5.13-5.05 (m, 2H), 4.68 (d, J = 6.0Hz ^ 1H), 3.71 (s, 3H), 3.36 (dd, J = 13.5, 5.0Hz, lH) , 3.17 (dd, J 2 13.5, 6.0 Hz, 1 H). -174- (170) 200529835 Prepared in a similar manner: (R)-2 -benzyloxycarbonylamino-3-(3-hydroxyl-4 mononitrate) -Phenyl) methyl propionate

1UC02Me NHCbz j-NMR ( CDC13，5 00MHz) 5 7.97 ( d，J= 9·0Ηζ，1H )，7·36— 7.30(m，5H) ，6.90(s，lH) ，6.71(d，J = 8·5Ηζ，1Η) ，5.29(d，J=7.0Hz，lH) ，5.11(d，J φ =12.5Hz » 1 H ) ，5.07(d，J=12.0Hz，1 H ) ，4.68(dd1UC02Me NHCbz j-NMR (CDC13, 500 MHz) 5 7.97 (d, J = 9 · 0Ηζ, 1H), 7.36— 7.30 (m, 5H), 6.90 (s, 1H), 6.71 (d, J = 8 5Ηζ, 1Η), 5.29 (d, J = 7.0Hz, 1H), 5.11 (d, J φ = 12.5Hz »1H), 5.07 (d, J = 12.0Hz, 1H), 4.68 (dd

，J=13.0’ 6.0Hz，1H) ，3.74(s，3H) ，3.20(dd，J = 13.5，5·0Ηζ，1H) ，3.05 (dd，J二 13.5，6.0Hz，1H) (R) _2-苄氧羰基胺基—3 -（3，4 —二胺基一苯基） 一丙酸甲酯, J = 13.0 '6.0Hz, 1H), 3.74 (s, 3H), 3.20 (dd, J = 13.5, 5.0 · ΗΗ, 1H), 3.05 (dd, J2 13.5, 6.0Hz, 1H) (R) _2 -Benzyloxycarbonylamino-3-(3,4-diaminomonophenyl) methyl propionate

於0 °C下將甲酸銨固體（2 · 2 7 g，3 6毫莫耳）分小部 份地加入至（R ) - 2 -苄氧羰基胺基一 3 -（ 3，4 —二硝 基一苯基）一丙酸甲酯（1.45 g，3.6毫莫耳）和鋅粉（ 1.41 g，21.6毫莫耳）之甲醇（50 ml，經氮氣脫氣2小時 )懸浮液中。室溫下隔夜攪拌所生成之混合物。真空下除 去溶劑，隨後加入甲苯（3 0 m 1，脫氣）、乙酸乙醋（3 〇 ml，脫氣）及乙酸（3 ml )。進一步稀釋該混合物，直到 - 175- (171) 200529835 所有有機固體皆溶解，隨後利用水和鹽水進行沖洗’ i置 於Na2S04上乾燥。經過濾後，真空下除去溶劑以生成含有 1當量乙酸之標的化合物（帶紅色之膠狀固體，8 5 % ) ° 質譜：344·18(ΜΗ)+。 (R) — 2 —苄氧羰基胺基一 3 — （2—甲基一1Η —苯並咪 唑一 5—基）一丙酸甲酯Add ammonium formate solid (2.27 g, 36 mmol) to (R)-2 -benzyloxycarbonylamino- 3-(3,4- dinitrate) in small portions at 0 ° C Methylphenyl) monopropionate (1.45 g, 3.6 mmol) and zinc powder (1.41 g, 21.6 mmol) in methanol (50 ml, degassed with nitrogen for 2 hours). The resulting mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and toluene (30 ml, degassed), ethyl acetate (30 ml, degassed), and acetic acid (3 ml) were added. The mixture was further diluted until-175- (171) 200529835 all organic solids were dissolved, followed by rinsing with water and brine ' i and drying on Na2S04. After filtration, the solvent was removed in vacuo to produce the target compound containing 1 equivalent of acetic acid (reddish gelatinous solid, 85%). Mass spectrum: 344 · 18 (ΜΗ) +. (R) — 2 —benzyloxycarbonylamino — 3 — (2-methyl-1,1-benzimidazole- 5-yl) monopropionate

ΝΝ

Me—( N Η 於130 °C下加熱（R) — 2—苄氧羰基胺基一 3 -（3，4 —二胺基一苯基）—丙酸甲酯—乙酸（640 mg )之乙酸（ 8 ml )溶液4小時。將該混合物倒入至水中並冷卻至0°C。 藉由逐漸地加入NaHC03固體調整其pH 至8。利用乙酸乙 酯（3 X 1 0 0 ml )萃取該混合物，利用水和鹽水冲洗結合 之有機層，隨後置於Na2S04上乾燥。經過濾後，除去溶劑 以生成帶棕色之泡沬狀固體的標的化合物（95 % )。 j-NMR ( CDCI3，5 00MHz ) 5 7 · 3 9 ( d，J = 8 · 5 Η z，1 ΗMe— (N Η) heated at 130 ° C (R) — 2-benzyloxycarbonylamino — 3 — (3,4-diaminomonophenyl) — methyl propionate — acetic acid (640 mg) in acetic acid (8 ml) solution for 4 hours. Pour the mixture into water and cool to 0 ° C. Adjust its pH to 8 by gradually adding NaHC03 solids. Extract the mixture with ethyl acetate (3 × 100 ml) The combined organic layer was washed with water and brine, and then dried over Na2S04. After filtration, the solvent was removed to give the title compound (95%) as a brown foamy solid. J-NMR (CDCI3, 500 MHz) 5 7 · 3 9 (d, J = 8 · 5 Η z, 1 Η

)，7.35(s，lH) ，7·26— 7.22(m，5H) ，7.06(d，J), 7.35 (s, lH), 7.26—7.22 (m, 5H), 7.06 (d, J

8.0Hz， 1H ) ，i 5.03 (d， J 二 1 2, ,5Hz， 1H ) ，4· 49 i 〔d， = 13, .OH z，1 H ) ，4. 51( dd，J =8.5 ，5.5Hz， 1 H )， 70 ( S 5 3H )，： 3.27 (dd ，，J = =13.5 ，5.0Hz， 1 H )， 03 ( dd ^ J - 14.0 丨，9 .0Hz ，1 H ) ，2.55 (s，3H ) O 質譜 3 6 8. 19 (MH ) + O -176- 200529835 (172) (R) — 苄氧羰基胺基—3— 〔2 一甲基一 3一 （三甲基 甲砂院基〜乙烷磺醯基）一 π —苯並咪唑一 5一基〕丙酸 甲酯 和 (R) — 2〜苄氧羰基胺基一3—〔2 —甲基一1 一（2 —三甲 基甲砂院基〜乙烷磺醯基）—1H —苯並咪唑—5 —基〕-丙酸甲酯8.0Hz, 1H), i 5.03 (d, J 22, 5, 5Hz, 1H), 4.49 i [d, = 13, .OH z, 1 H), 4. 51 (dd, J = 8.5, 5.5Hz, 1 H), 70 (S 5 3H), 3.27 (dd ,, J = = 13.5, 5.0 Hz, 1 H), 03 (dd ^ J-14.0, 9.0 Hz, 1 H), 2.55 (s, 3H) O Mass spectrum 3 6 8. 19 (MH) + O -176- 200529835 (172) (R) —benzyloxycarbonylamino—3— [2 monomethyl-1 3- (trimethylformyl sand Ranji ~ ethanesulfonyl) -π-benzimidazole-5-yl] propionic acid methyl ester and (R) -2 ~ benzyloxycarbonylamino-1 3- [2-methyl-1 1- (2 — Trimethylmethanthyl group ~ ethanesulfonyl)-1H-benzimidazole-5 -yl]-methyl propionate

將乾燥之2 -三甲基甲矽烷基-乙烷磺醯氯全部一次 加入至（R) 一 2一节氧鑛基胺基—3— (2-甲基—1H — 苯並咪D坐〜5 —基）—丙酸甲酯（533 mg，1.96毫莫耳） 和Na2C〇3之乙腈（20 ml )懸浮液中。室溫下隔夜攪拌該 混合物。除去溶劑並藉由矽膠層析且利用乙酸乙酯/己烷 (1 : 2 )作爲流洗液以純化殘餘物，生成蠟狀固體之標的 化合物（1 : 1 N】和N3異構物混合物，66% )。 ]H-NMR ( CDC13 5 5 00MHz ) δ 7.68 ( d，J 二 8·5Ηζ， 0·5Η) ，7·55 (d，J=8.5Hz，0.5Η) ，7·53 (s，0·5Η) ，7.41(s，0.5H) ，7.34-7.29 (m，5H) ，7.06 — 7.04 (m，lH) ，5.22(d，J=8.0Hz，0.5H) ，5.17(d，J = 7·5Ηζ，0.5H ) ，5.11-5.07 (m，2H ) ，4.72—4.69 (m ，1H) ，3·75 ( s，] ·5Η ) ，3.72 ( s，1 ·5Η ) ，3.24- 3.17 (m，2H) ，2.79(s，3H) ，〇·92— 0.83 (m，2H) ，-0.02(s，4.5H) ，-0.0 5(s，4.5H)。質譜：532,26( -177- (173) (173)200529835 ΜΗ ) +。 (R) — 2 —胺基一3— 〔2 —甲基一1— (2 —二甲基甲石夕院 基一乙烷磺醯基）一 1H —苯並咪唑—5—基〕丙酸甲酯 (R) — 2_胺基一3— 〔2 —甲基一3— (2 —二甲基甲石夕|完 基—乙烷磺醯基）一 1H —苯並咪唑一 5—基〕一丙酸甲酯Add the dried 2-trimethylsilyl-ethanesulfonyl chloride all at once to (R) -2Amoxylamino-3- (2-methyl-1H—benzimidyl) ~ 5-Base) -methyl propionate (533 mg, 1.96 mmol) and Na2CO3 in acetonitrile (20 ml) suspension. The mixture was stirred overnight at room temperature. The solvent was removed and the residue was purified by silica gel chromatography using ethyl acetate / hexane (1: 2) as the eluent to give the target compound (1: 1 N) and N3 isomer mixture as a waxy solid, 66%). ] H-NMR (CDC13 5 5 00MHz) δ 7.68 (d, J = 8.5Ηζ, 0.5Η), 7.55 (d, J = 8.5Hz, 0.5Η), 7.53 (s, 0.5 ·) ), 7.41 (s, 0.5H), 7.34-7.29 (m, 5H), 7.06-7.04 (m, lH), 5.22 (d, J = 8.0Hz, 0.5H), 5.17 (d, J = 7.5 · 5Ηζ , 0.5H), 5.11-5.07 (m, 2H), 4.72—4.69 (m, 1H), 3.75 (s,] · 5Η), 3.72 (s, 1 · 5Η), 3.24-3.17 (m, 2H ), 2.79 (s, 3H), 0.92-0.83 (m, 2H), -0.02 (s, 4.5H), -0.0 5 (s, 4.5H). Mass spectrum: 532, 26 (-177- (173) (173) 200529835 MW) +. (R) — 2 —Amine — 3 — [2 —Methyl — 1 — (2 —Dimethylmethoxanyl — ethanesulfonyl) — 1H —Benzimidazole — 5 —yl] propanoic acid Methyl Ester (R) — 2-Amino-3— [2-Methyl-3— (2-Dimethylmethazine | Endyl—Ethanesulfonyl) —1H—Benzimidazole-5—yl Methyl propionate

於室溫和40 psi氫氣下，在Parr裝置上，隔夜搖動（R )一 2—平氧鑛基胺基一3— 〔2 —甲基一3— (2 —三甲基 —甲5夕院基一乙院擴酿基）—3H—苯並味卩坐一 5 —基〕— 丙酸甲酯和（R) — 2—苄氧羰基胺基一 3 — 〔2—甲基 一 （2—三甲基甲矽烷基一乙烷磺醯基）一 1H—苯並咪口坐 —5 —基〕一丙酸甲酯（1 : 1混合物，6 0 0 m g )和1 〇 % Pd/C ( 180 mg)之甲醇（50 ml)懸浮液。經以氮氣取代 氫氣後，經由通過寅氏鹽墊過濾該混合物。真空下除去溶 劑以生成黃褐色固體之標的化合物（8 0 % )。 】H-NMR ( CD3〇D，5 00MHz ) ό 7.8 1 ( d，J = 8.5， 〇·5Ηζ，0·5Η) ，7.70(S，0.5H) ，7.58(d，J=8.5Hz， 0.5H) ，7.49 (s，〇.5H) ，7.25 (d，J=9.0Hz, 1H)， 3.89(dd，J =14.0，6.5Hz，1H) ，3.75(s，1.5H)， 3.7 2(s，1.5H) ， 3.55—3.51 (m，2H) ，3.18(d，j> 6.0Hz，1 H ) ，3.22 - 3 · I 8 ( s，4.5H ) ，3 . ] 4 - 3.0 9 ( m， -178- (174) (174)200529835 0.5H ) ，2.81 (s，1.5 H) ，2.80(s，1.5H) ，0.92-0.88 (m，2H) ，0.02(s，4.5H) ，0.01(s，4.5H)。 13C NMR ( CD3OD， 125MHz ) 5 174.3， 174.1 ， 153.5， 153.3 ， 141.7 ， 140.6 ， 133.9 ， 133.82 ， 133.78 ， 132.7 ， 126.5，126.3，119.7，119.0，114.1，113.4，55.6，51.8 ，51.7， 51.6， 40.2， 39.8， 15.83， 15.77， 9.9， -3.07， -3· 1 1。質譜：3 9 8.2 0 ( MH ) +。 (R) — 3 — 〔2—甲基一1— (2 —三甲基甲石夕院基一乙院 礦釀基）—1H -苯並味卩坐—5 —基〕一 2— { 〔4 一 （2 — 酬基一1，4 — 一·氨—2H —喧口坐琳一 3 —基）一口庇口定一 1 — 羰基〕一胺基} 一丙酸甲酯 (R) — 3— 〔2 —甲基一3 — （2 —二甲基甲石夕烷基一乙院 礦酿基）一 3H —苯並味η坐—5 -基〕—2- { 〔4一（2- 酬基一1，4 — 一氯—2 Η — D奎口坐琳—3 —基）一Π定一]— 羰基〕一胺基} 一丙酸甲酯Under room temperature and 40 psi hydrogen on a Parr device, shake (R)-2-oxoaminoamine-3-[2-methyl-3-(2-trimethyl-methyl) Yiyiyuan Group Co., Ltd.) — 3H—Benzo miso group—5-methyl group] —methyl propionate and (R) —2-benzyloxycarbonylamino group—3— [2-methyl-1 (2-3 Methylsilyl monoethanesulfonyl) 1H-benzimidazo-5-yl] monopropionic acid methyl ester (1: 1 mixture, 600 mg) and 10% Pd / C (180 mg) of methanol (50 ml) suspension. After replacing the hydrogen with nitrogen, the mixture was filtered through a pad of Yin's salt. The solvent was removed in vacuo to give the target compound (80%) as a yellow-brown solid. ] H-NMR (CD3OD, 500MHz) 7.8 1 (d, J = 8.5, 0.5Ηζ, 0.5Η), 7.70 (S, 0.5H), 7.58 (d, J = 8.5Hz, 0.5H ), 7.49 (s, 0.5H), 7.25 (d, J = 9.0Hz, 1H), 3.89 (dd, J = 14.0, 6.5Hz, 1H), 3.75 (s, 1.5H), 3.7 2 (s, 1.5H), 3.55-3.51 (m, 2H), 3.18 (d, j > 6.0Hz, 1H), 3.22-3 · I 8 (s, 4.5H), 3.] 4-3.0 9 (m,- 178- (174) (174) 200529835 0.5H), 2.81 (s, 1.5 H), 2.80 (s, 1.5H), 0.92-0.88 (m, 2H), 0.02 (s, 4.5H), 0.01 (s, 4.5H). 13C NMR (CD3OD, 125MHz) 5 174.3, 174.1, 153.5, 153.3, 141.7, 140.6, 133.9, 133.82, 133.78, 132.7, 126.5, 126.3, 119.7, 119.0, 114.1, 113.4, 55.6, 51.8, 51.7, 51.6, 40.2, 39.8, 15.83, 15.77, 9.9, -3.07, -3.11. Mass spectrum: 3 9 8.20 (MH) +. (R) — 3 — [2-Methyl-1— (2-Trimethylmethylate and 1-Yinyuan brewing base) —1H—benzo miso-sat—5—based] —2— {〔〔 4 one (2 — phenyl group 1, 1, 4 — amine — 2H — oxazoline — 3 — group) one mouthpiece — 1 — carbonyl] monoamino} methyl propionate (R) — 3 — [2-Methyl-3 — (2-Dimethylmethoxanyl-Yiyuan Mining Group) — 3H —Benzo η —5 -yl] — 2- {[4 一 (2- Phenyl-1,4-monochloro-2 hydrazone — D quinololine-3 —yl) — Π] —] —carbonyl] monoamino} methyl propionate

如前述製備（R) — 2- { 〔 4一 2 —酮基—1，4一二氫 -179- 200529835 (175) 一 2 Η -哇哗琳—3 —基）一喊Π定—1 一羯基〕一胺基} — 3 一 〔1 一 （2—二甲基甲5夕院基一乙院礦酿基）一 1H—D引 唑一 5 —基〕一丙酸甲酯之方法。藉由矽膠層析且利用含 有1 %三乙胺之乙酸乙酯作爲流洗夜以進行純化，生成灰 白色固體之標的化合物（87% )。 W-NMR ( CD3OD，5 00MHz ) 5 7.82 ( d，J= 8.5Hz， 0.5H) ，7.80(s，0.5H) ，7.59(d，J=8.0Hz，0.5H) ，7.55 (s，0.5 Η) ，7·33— 7.30(s，lH) ，7.16(t，J二 8·0Ηζ，1 Η ) ，7.12 (t，J=7_5Hz，1 H ) ，6.95 ( t ^ J 二 7·5Ηζ，1 Η ) ，6.79(d，J 二 7·5Ηζ，1 Η ) ，4.60 - 4.5 5 ( m，1Η) ，4·45— 4.40 (m，1H) ，4.29— 4.27 (m，2H) ，4.15-4.10 (m，2H) ，3.77(s，1.5H) ，3.74(s， 】.5H) ，3.6— 3.51(m，2H) ，3.35-3.31 (m，2H)， 3.21-3.15 (m^ 1H) ，2·91— 2.80(m，2H) ^ 2.78 ( s ，：1.5H) ，2.77(s，1·5Η) ，：i.76— 1.73 (m，1H)， 1.66-1.61 (m，2H) ，0.92— 0.87( m，2H) ^ 0.009 ( s ，4·5Η) ，-0.00 7 (s，4.5H)。 13C NMR ( CD3OD， 125MHz) ， 1 7 3 . 8， 1 7 3 · 7， 1 5 8 · 2， 158.1，155.6，153.4，153.2，141.6，140.3，137.2， 135.3，135.1，133.7，132.5，128.2，126.4，126.3， 125.7，122.13，122.10，119.6，118.8，118.4，114.0， 113.4，113.2，57.3，56.2，51.9，51.7，51.5，43.8， 43.7，42.9，37.6，37.2，28.4，17.4，15.7，15.6，9.9 ，-3 · 1，- 3 . 2。質譜：6 5 5 . 3 6 ( Μ H ) +。 -180- (176) (176)200529835 (R) — 3— (2—甲基—1H —苯並味哩一 5 —基）—2— { 〔4— (2 —酮基一1，4 —二氫一 2H — D奎唑啉一3 —基）一 哌啶一 1 一羰基〕一胺基} 一丙酸(R) — 2- {〔4—2 —keto—1,4—dihydro-179- 200529835 (175) — 2 Η—wowalin—3 —yl) as described above Fluorenyl] -amino group} — 3- [1 ((2-dimethylformaldehyde, 5-amino-based, 1-based mineral-based)), 1H-D, oxazole, 5-, and 5-methyl] monopropionate. Purification by silica gel chromatography and washing with 1% triethylamine in ethyl acetate as a stream gave the title compound (87%) as an off-white solid. W-NMR (CD3OD, 500 MHz) 5 7.82 (d, J = 8.5 Hz, 0.5H), 7.80 (s, 0.5H), 7.59 (d, J = 8.0 Hz, 0.5H), 7.55 (s, 0.5 Η ), 7.33—7.30 (s, lH), 7.16 (t, J = 8 · 0Ηζ, 1Η), 7.12 (t, J = 7_5Hz, 1H), 6.95 (t ^ J 2: 7.5Ηζ, 1 Η), 6.79 (d, J 7.5 Η Ηζ, 1 Η), 4.60-4.5 5 (m, 1Η), 4.45-4.40 (m, 1H), 4.29-4.27 (m, 2H), 4.15-4.10 (m, 2H), 3.77 (s, 1.5H), 3.74 (s,】 .5H), 3.6—3.51 (m, 2H), 3.35-3.31 (m, 2H), 3.21-3.15 (m ^ 1H), 2.91— 2.80 (m, 2H) ^ 2.78 (s ,: 1.5H), 2.77 (s, 1.5mm) ,: i.76—1.73 (m, 1H), 1.66-1.61 (m, 2H), 0.92—0.87 (m, 2H) ^ 0.009 (s, 4.5mm), -0.007 (s, 4.5H). 13C NMR (CD3OD, 125MHz), 1 7 3. 8, 1 7 3 · 7, 1 5 8 · 2, 158.1, 155.6, 153.4, 153.2, 141.6, 140.3, 137.2, 135.3, 135.1, 133.7, 132.5, 128.2, 126.4, 126.3, 125.7, 122.13, 122.10, 119.6, 118.8, 118.4, 114.0, 113.4, 113.2, 57.3, 56.2, 51.9, 51.7, 51.5, 43.8, 43.7, 42.9, 37.6, 37.2, 28.4, 17.4, 15.7, 15.6, 9.9, -3 · 1,-3.2. Mass spectrum: 6 5 5. 36 (MH) +. -180- (176) (176) 200529835 (R) — 3— (2-methyl-1H —benzobenzoyl-5 —yl) — 2 — {〔4— (2 —keto-1,4 — Dihydro- 2H — D quinazoline- 3-yl) -piperidine-1 monocarbonyl] monoamino} monopropionic acid

如前述對（R) — 2— { 〔4— (2 -酮基一 1，4 —二氫 一 2 Η — D奎唑啉—3 -基）一哌啶—1 —羧基〕一胺基丨一 3 一 〔1 一 （ 2 —三甲基甲矽烷基一乙烷磺醯基）一 1 Η -吲 唑一 5 —基〕一丙酸，處理（R) - 3—〔2 —甲基一1— (2 一三甲基甲矽烷基一乙烷磺醯基）一 1Η—苯並咪唑一 5 — 基〕一2 — { 〔4 — (2 —嗣基 一 1 ’ 4 — 一 氣一2 Η — 〇 奎 口坐琳 —3 —基）一哌啶一 1 一羧基〕一胺基}—丙酸甲酯和（R )一 3— 〔2 —甲基一 3— (2 —三甲基甲矽烷基一乙烷磺醯 基）一3Η —苯並咪唑一 5 —基〕一 2—丨〔4 一 （2 —酮基 —1，4 —二氯一2Η — D奎口坐琳一3 —基）一口JRD定一 1—羯基 〕一胺基} 一丙酸甲酯之】：1混合物。所使用之水解條 件爲L i Ο Η /甲醇—四氫呋喃一水（1 : 1 : 1 )，於—1 5 t： 下隔夜。得到白色固體之標的化合物（2 5 % )。質譜： 47 7.24 ( MH ) +。 -181 - (177) (177)200529835 實施例4 6 (R) — 4— (2 —酮基一；[，4 —二氫 _2H—d奎唑啉一 3-基）—哌啶〜〗一羧酸〔2 — 〔 1，4 /〕聯丨旅啶一 1 / 一基 —1— (2 —甲基_1H 一苯並咪唑一 5一基甲基）一2 -酮As mentioned above, (R) — 2— {[[4 -— (2-keto-1,4-dihydro-2—fluorene—D quinazoline-3—yl) -piperidine-1—carboxyl] -amino group 丨One 3 one [1 one (2-trimethylsilyl monoethanesulfonyl) -one 1 fluorene-indazol 5-yl] monopropionic acid, treatment (R)-3-[2-methyl one 1— (2-trimethylsilyl-ethanesulfonyl) —1Η—benzimidazole—5 —yl] —2 — {[4 — (2 —fluorenyl—1 ′ 4 — one gas—2 Η — 〇 quetiazolin-3 -yl) -piperidine-1 -carboxyl] -amino}-methyl propionate and (R) -3-[2 -methyl -3-(2-trimethylformyl) Silyl-ethanesulfonyl)-3′-benzimidazole-5′-yl] —2— 丨 [4— (2-keto-1,4—dichloro-1—2 ′ — D Kuizilin 3 — Base) a mouthful of JRD 1-fluorenyl] -amino} monomethyl propionate]: 1 mixture. The hydrolysis conditions used were Li i 0Η / methanol-tetrahydrofuran monowater (1: 1: 1), at -15 t: overnight. The title compound was obtained as a white solid (25%). Mass spectrum: 47 7.24 (MH) +. -181-(177) (177) 200529835 Example 4 6 (R) — 4 — (2-keto-one; [, 4-dihydro_2H—d-quinazolin-3-yl) —piperidine ~] Monocarboxylic acid [2 — [1,4 /] biphenyl] 1-1-1-1-(2-methyl_1H-benzimidazole-5-methyl)-2 -one

如前述製備（R) — 4-（2 —酮基—1，4一二氫—2H 一喹唑啉一 3〜基）一哌啶一 1 一羧酸{ 2 — 〔 1，4 /〕聯 哌啶一一基一 2 —酮基一 1— 〔1— (2 —三甲基甲矽烷 基—乙烷磺醯基）—1H —吲唑一 5—基甲基〕一乙基丨一 醯胺之方法。藉由矽膠層析並利用C H 2 C 12 /甲醇/三乙胺 (95 : 5 : 2 )爲流洗液進行純化，生成白色固體。令該產 物溶解於乙酸乙酯（6 0 m 1 )中，並經1 : 1飽和N a H C Ο 3 水溶液和鹽水冲洗2次，隨後置於Na2S04上乾燥。經過濾 後，除去溶劑以生成白色固體之標的化合物（Π %產率） LC/MS: tR=1.59 分，627·34(ΜΗ) (R) — 3 - （4 一胺基—3 -淫基一苯基）一 2 —卡氧^灰基 -182-(R) — 4- (2-keto-1,4-dihydro-2H-quinazoline- 3 ~ yl) -piperidine- 1-carboxylic acid {2 — [1,4 /] Piperidine-one-yl 2-keto-1— [1- (2-trimethylsilyl-ethanesulfonyl) -1H-indazole-5-ylmethyl] -ethyl 丨 a Amine method. Purification was performed by silica gel chromatography using CH 2 C 12 / methanol / triethylamine (95: 5: 2) as a flow-through washing solution to produce a white solid. The product was dissolved in ethyl acetate (60 m 1), washed with a 1: 1 saturated Na H C 0 3 aqueous solution and brine twice, and then dried over Na 2 S 04. After filtration, the solvent was removed to yield the target compound as a white solid (Π% yield) LC / MS: tR = 1.59 minutes, 627 · 34 (ΜΗ) (R) — 3-(4-monoamino — 3 —amino (Monophenyl)-2 -carbooxy ash-182-

HCI 200529835 (178) 胺基-丙酸甲酯氫氯化物 於0 r下將鐵粉（3.7 g，6 6 · 4毫莫耳）和氯 g，111毫莫耳）加入至（R) - 2 —卡氧鑛基胺3 一羥基一 4一硝基一苯基）一丙酸甲酯（2.07 g 耳）之脫氣：1:1甲醇/水（400ml)溶液中 攪拌所生成之混合物4 8小時。加入三氟乙酸（7 該混合物形成镟渦，直到其爲含有未反應之鐵輕 的澄淸暗紅色溶液爲止。過濾該混合物並於真3 液。利用乙酸乙酯（2 X 1 5 0 m 1 )萃取殘餘物， 水冲洗結合之有機層，隨後置於Na2S04上乾燥。 ，加入HC1 ( 4.2 ml，4M二噁烷溶液）。真空下 ，得到黃褐色泡沬狀固體之標的化合物（8 0 % ) ]H-NMR (CD3OD ， 5 0 0MHz ) δ 7.34 - -7.28 ( ，7. 20 ( d， J = 8.0Hz ，1 H ) ，6.88 (s， 1 H )， J = 7 .5Hz， 1 H ) ，5.05— 5.00 (m， 2H ) ，4.42 8.5， 5.0Hz ,，1 H )，： 3.70 ( s，3H )，3 .65 ( s 3.33 (brs， 2H ) ，3· 1 1 ( dd，J = 14.0， 5.0Hz 2.90 (dd， J= 13.5，9 • 0Hz，1 H )。 13 C NMR ( CD3〇D » 125MHz ) 1 7 2.5 ， 157.4 140.2，137.0，128.5，128.0，127.7，123.8 117.0，Π6.9，67.2，55.7，52.0，37.2。質譜： (MH ) +。 化銨（5 · 9 卜 3 -（3 ’ 5·53毫莫 1。室溫下 ml )，令 >之懸浮液 ?下濃縮濾 並利用鹽 經過濾後 除去溶劑 〇 m，5 Η ) 6·78 ( d ， (dd，J = ，1H )， ，1H )， ，1 5 1 .2， ，120.9， 3 45.2 0 - 183- (179) (179)200529835 (R) — 2 —干氧鑛基胺基一 3 — （醒基—2，3 —二氫一苯 並噁唑一 6 -基）丙酸甲酯HCI 200529835 (178) Amino-methyl propionate hydrochloride Add iron powder (3.7 g, 66. 4 mmol) and chlorine g (111 mmol) to (R)-2 at 0 r —Deoxycarbamylamine 3 -hydroxyl-4 -nitro-phenyl) monopropionate (2.07 g ears) degassing: the resulting mixture was stirred in a 1: 1 methanol / water (400ml) solution 4 8 hour. Trifluoroacetic acid (7) was added to the mixture to form a vortex until it was a light, clear, dark red solution containing unreacted iron. The mixture was filtered and filtered into 3 liquids. Ethyl acetate (2 X 1 5 0 m 1 ) Extract the residue, rinse the combined organic layer with water, then dry on Na2S04. Add HC1 (4.2 ml, 4M dioxane solution). Under vacuum, the yellow-brown foamy solid-like compound (80%) is obtained. )] H-NMR (CD3OD, 500MHz) δ 7.34--7.28 (, 7.20 (d, J = 8.0Hz, 1 H), 6.88 (s, 1 H), J = 7.5Hz, 1 H ), 5.05—5.00 (m, 2H), 4.42 8.5, 5.0Hz ,, 1 H), 3.70 (s, 3H), 3.65 (s 3.33 (brs, 2H)), 3.1 · 1 (dd, J = 14.0, 5.0Hz 2.90 (dd, J = 13.5, 9 • 0Hz, 1 H). 13 C NMR (CD3OD »125MHz) 1 7 2.5, 157.4 140.2, 137.0, 128.5, 128.0, 127.7, 123.8 117.0, Π6 .9, 67.2, 55.7, 52.0, 37.2. Mass spectrum: (MH) +. Ammonium (5. 9 b 3-(3 '5.53 mmol 1. ml at room temperature), let > suspension? After concentrated filtration and filtration with salt Solvent 0m, 55) 6.78 (d, (dd, J =, 1H) ,, 1H) ,, 1 5 1.2,, 120.9, 3 45.2 0-183- (179) (179) 200529835 (R) — 2 —anhydroxenylamino — 3 — (pentyl-2,3-dihydro-benzoxazole-6-yl) propionate

於〇°C下將羰基二咪唑（498 mg，3.07毫莫耳） CH2Cl2(15 ml)溶液加入至（R) — 3— (4 —胺基—3 — 羥基一苯基）一 2 —苄氧羰基胺基一丙酸甲酯（1.17 g， 3·〇7毫莫耳）、二異丙基乙胺（1.60 m卜9.21毫莫耳）及 CH2C12 ( 85 ml )之溶液中。於0°c下攪拌該混合物4小時 。真空下除去溶劑並藉由矽膠層析（利用乙酸乙酯/己烷 爲流洗液）純化殘餘物，生成白色固體之標的化合物（5 1 % )。 ]H-NMR ( CDC13 ， 5 00MHz ) 5 9·07 ( s ， 1 Η ) ， 7·37 — 7.29(m，5H) ，6.96(s，lH) ，6.90(d，J=8.0Hz， 1 Η ) ，6.87(d，J=8.0Hz，lH) ，5.36(d，J=8.0Hz， 1 H ) ，5.11 (d，J=12.0Hz，1 H ) ，5.07 (d，J = 1 2.5Hz ，1 H ) ，4.65 ( dd ^ J=13.5，5·5Ηζ，1H) ，3.74 ( s ^ 3H ) ，3.17(dd，J=14.0，5.5Hz，lH) ，3.07(dd，J = 1 4.0，6· 0Hz，1 H )。 】3C NMR ( CDCI3，125MHz ) 5 1 7 1 . 9，1 5 5.7，1 5 5 · 5， 144.1，136.2，130.8，128.6，1 2 8.42，1 2 8.3 8，128.2， 125.1，11].1，109.8，67.2，55.1，52.6，38.3。質譜： 3 71 . ] 8 ( ΜΗ ) + 。 -184 - (180) 200529835 (R) — 2 —胺基—3 -（2-酮基—2，3 —二氫—苯並噁唑 一 6—基）一丙酸甲酯Add a solution of carbonyldiimidazole (498 mg, 3.07 mmol) in CH2Cl2 (15 ml) to (R) — 3 — (4-amino — 3 —hydroxy-phenyl) — 2-benzyloxylate at 0 ° C. A solution of methyl carbonylaminomonopropionate (1.17 g, 3.07 mmol), diisopropylethylamine (1.60 m, 9.21 mmol) and CH2C12 (85 ml). The mixture was stirred at 0 ° C for 4 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (using ethyl acetate / hexane as the eluent) to give the title compound (51%) as a white solid. ] H-NMR (CDC13, 500 MHz) 5 9 · 07 (s, 1 Η), 7.37 — 7.29 (m, 5H), 6.96 (s, 1H), 6.90 (d, J = 8.0 Hz, 1 Η ), 6.87 (d, J = 8.0 Hz, 1H), 5.36 (d, J = 8.0 Hz, 1 H), 5.11 (d, J = 12.0 Hz, 1 H), 5.07 (d, J = 1 2.5 Hz, 1 H), 4.65 (dd ^ J = 13.5, 5 · 5Ηζ, 1H), 3.74 (s ^ 3H), 3.17 (dd, J = 14.0, 5.5 Hz, 1H), 3.07 (dd, J = 1 4.0, 6 0Hz, 1H). ] 3C NMR (CDCI3, 125MHz) 5 1 7 1. 9, 1 5 5.7, 1 5 5 · 5, 144.1, 136.2, 130.8, 128.6, 1 2 8.42, 1 2 8.3 8, 128.2, 125.1, 11] .1 , 109.8, 67.2, 55.1, 52.6, 38.3. Mass spectrum: 3 71.] 8 (ΜΗ) +. -184-(180) 200529835 (R) — 2 —amino — 3 — (2-keto-2,3-dihydro-benzoxazole — 6-yl) monopropionate

〇〇

N Η 藉由套管將（R) - 2 —苄氧羰基胺基—3 一（2 一酮基 一 2，3 —二氫一苯並噁唑一6—基）一丙酸甲酯（310 mg )於4_4%甲酸中之甲醇（20 ml，新製備之脫氣甲醇）溶 春 液加入至10%Pd/C於4.4%甲酸中之甲醇（20 ml，新配 製之脫氣甲醇）懸浮液中。室溫下攪拌所生成混合物4小 時。經過寅氏鹽墊過濾後，真空下除去溶劑以生成黃褐色 固體。令該固體溶解於乙酸乙酯（50 ml)、甲苯（1〇 ml )及乙醇（40 ml )之混合物中，並加入NaHC03固體（3.1 g )。室溫下攪拌該混合物2小時並進行過濾。真空下除去 溶劑以生成標的化合物。 】H-NMR ( CD3OD，500MHz ) 5 8·41 ( brs，2Η ) ，7. 1 7 · (s，lH) ，7.09(brs，2H) ，4.32(s，lH) ^ 3.83 ( s ，1H) ，3.33(s，lH) ，3.30(s，lH) ，3.22(s，ih )。質譜：237·20(ΜΗ)+。 (R) — 3— (2 —酬基一 2，3 —二氫—苯並卩惡卩坐一 6—基） 一 2— { 〔4— (2 —酮基一1，4一 二氫一2H —喹唑啉—3 一基）一哌啶一 1 一羰基〕—胺基丨一丙酸甲酯 -185- (181) 200529835 ΗN Η methyl (R)-2 -benzyloxycarbonylamino-3-(2-keto-2,3-dihydro-benzoxazole-6-yl) monopropionate (310 mg) in 4 ~ 4% formic acid in methanol (20 ml, freshly prepared degassed methanol) dissolved spring solution was added to 10% Pd / C in 4.4% formic acid in methanol (20 ml, freshly prepared degassed methanol) suspension in. The resulting mixture was stirred at room temperature for 4 hours. After filtration through a Yin's salt pad, the solvent was removed under vacuum to yield a tan solid. This solid was dissolved in a mixture of ethyl acetate (50 ml), toluene (10 ml) and ethanol (40 ml), and NaHC03 solid (3.1 g) was added. The mixture was stirred at room temperature for 2 hours and filtered. The solvent was removed under vacuum to produce the target compound. ] H-NMR (CD3OD, 500MHz) 5 8 · 41 (brs, 2Η), 7. 1 7 · (s, lH), 7.09 (brs, 2H), 4.32 (s, lH) ^ 3.83 (s, 1H) , 3.33 (s, lH), 3.30 (s, lH), 3.22 (s, ih). Mass spectrum: 237 · 20 (ΜΗ) +. (R) — 3— (2 —Paxyl-2,3—dihydro-benzopyrazine —6-6-yl) — 2— {[4— (2-keto-1,4-dihydro-1 2H-quinazoline-3 monoyl) -piperidine-1 monocarbonyl] -amino group monomethyl propionate-185- (181) 200529835 Η

如前述製備（R) - 2- { 〔4一（2-酮基—1，4一二 氫一2H —喹唑啉一3 -基）一哌啶—1 一羰基〕—胺基} —3 — 〔1 一 （2—二甲基甲砂院基一乙院礦酿基）一1H — 吲唑一 5 —基〕一丙酸甲酯之方法。藉由矽膠層析並利用 CH2C12/甲醇/三乙胺（93 : 5 : 2 )作爲流洗液以進行純 化，生成白色固體之標的化合物（3 3 % )。 1 H-NMR ( CD3OD，5 00MHz ) 5 7 . 1 7 — 7 · 1 3 ( m，3 Η ) ，7·08 (d，J=7.9Hz，1 Η ) ，7.03 ( d ^ J = 8.0Hz ^ 1 H ) ，6.95 (t，J=7.0Hz，1 H ) ，6.79 (d，J - 8.0Hz ^ 1 H ) ，4.55— 4.51 (m，1 H ) ，4.44— 4.41 (m，1 H ) ，4.33 ( s，2H) ，4.14— 4.10(m，2H) ，3.74(s，3H) ^ 3.33 (brs，2H) ，3.23(dd，J=13.7，5.2Hz，lH) ，3.03( dd，J=14.0，9.7Hz，lH) ，2.92— 2.82( ni，2H)， 1·79 — 1.63 ( m，4H)。 13C NMR ( CD3OD，125MHz ) 1 7 3 · 8，] 5 8.2，1 5 6 · 2， 155.6，144.4，137.1，132.7，129.3，128.2，125.7， 125.0，]22.2，118.4，113.4，110.6，109.6，56.2，52.0 ，5 1.7，43.8，42.9，3 7.3，28.4。質譜：494.30(MH) + o -186- (182) (182)200529835 (R) - 3 —（2 —酬基—2，3 — 一氨一苯並卩惡卩坐一 6-基） —2 — { [ 4 — ( 2 —嗣基一1 ’ 4 — 一氣一2 Η — 〇 奎 口坐琳 一 3 —基）一哌啶一 1 一羰基〕一胺基} 一丙酸(R)-2- {[4-((2-keto-1,4-dihydro-1H-quinazolin-3-yl) -piperidine-1-carbonyl] -amino group} -3 — Method of [1- (2-dimethylformazine-based base-Yinyuan base)-1H-indazole-5-yl] monopropionate. Purification was performed by silica gel chromatography using CH2C12 / methanol / triethylamine (93: 5: 2) as a flow wash solution to produce the target compound (33%) as a white solid. 1 H-NMR (CD3OD, 5000 MHz) 5 7. 1 7 — 7 · 1 3 (m, 3 Η), 7.08 (d, J = 7.9Hz, 1 Η), 7.03 (d ^ J = 8.0Hz ^ 1 H), 6.95 (t, J = 7.0 Hz, 1 H), 6.79 (d, J-8.0 Hz ^ 1 H), 4.55-4.51 (m, 1 H), 4.44- 4.41 (m, 1 H) , 4.33 (s, 2H), 4.14-4.10 (m, 2H), 3.74 (s, 3H) ^ 3.33 (brs, 2H), 3.23 (dd, J = 13.7, 5.2Hz, lH), 3.03 (dd, J = 14.0, 9.7 Hz, lH), 2.92—2.82 (ni, 2H), 1.79—1.63 (m, 4H). 13C NMR (CD3OD, 125MHz) 1 7 3 · 8,] 5 8.2, 1 5 6 · 2, 155.6, 144.4, 137.1, 132.7, 129.3, 128.2, 125.7, 125.0,] 22.2, 118.4, 113.4, 110.6, 109.6, 56.2, 52.0, 5 1.7, 43.8, 42.9, 3 7.3, 28.4. Mass spectrum: 494.30 (MH) + o -186- (182) (182) 200529835 (R)-3 — (2 —Panetyl — 2, 3 — Mono-amino-benzopyrene-pyridine — 6-yl) —2 — {[4 — (2 —Amidino-1 ′ 4 —one gas one 2 Η — 〇 Kuizuline 3 —yl) -piperidine-1 1-carbonyl] monoamine} monopropionic acid

如前述製備（R) — 2- {4〔 （2—酮基一 1，4一二氫 2Η - D奎D坐琳一 3 -基）—I派0定一 1—鑛基〕—胺基} — 3 — 〔1 一 （ 2 —三甲基甲矽烷基一乙烷磺醯基）一 1 Η —吲唑 —5 —基〕一丙酸之方法。所使用之水解條件：Li ΟΗ/甲 醇一四氫呋喃—水（1 : 1 : 1 )於—1 5 °C下隔夜。得到白 色固體之標的化合物（95% )。質譜：4 8 0.3 0 ( MH )+。 實施例4 7 (R) — 4 — (2 —嗣基一1，4 一 一·氣一2 Η — D 奎 口坐琳一3 — 基）一哌啶一 1 —羧酸〔2 -〔 ]，4 /〕聯哌啶—1 ——基 一 2 —酮基一 1 一（2-酮基—2，3 —二氫—苯並噁唑一 6 — 基甲基）一乙基〕一醯胺 -187- 200529835 (183)(R) — 2- {4 [(2-keto-1,4-dihydro 2Η-D-quinone-D-silylin-3-yl) —I group 0-determining 1-mine-based] —amine } — 3 — Method of [1-((2-trimethylsilyl-ethanesulfonyl)-1] -indazol-5-yl] -propionic acid. Hydrolysis conditions used: Li 0Η / methanol-tetrahydrofuran-water (1: 1: 1) overnight at -15 ° C. The target compound was obtained as a white solid (95%). Mass spectrum: 4 8 0.3 0 (MH) +. Example 4 7 (R) — 4 — (2 —fluorenyl-1,4—one · gas—2 fluorene —D quetiazolin—3-yl) —piperidine—1-carboxylic acid [2-[] , 4 /] bipiperidine-1 ——yl-2-keto-1 1- (2-keto-2,3-dihydro-benzoxazole-6-ylmethyl) monoethyl] -fluorene Amine-187- 200529835 (183)

如前述製備（R) — 4-（2 —醒基—1’ 4 — 一氣 —D奎唑啉—3 —基）—哌啶一 1 一羧酸{ 2 -〔 1，4 一 口爪'D定一1 —基一 2 —酮|基一 1— 〔1一 （2—二甲基甲 基一乙烷磺醯基）—1H—吲唑一 5 —基甲基〕一乙基 醯胺之方法。藉由矽膠層析且利用CH2C12/甲醇/三 (9 3 : 5 : 2 )爲流洗液以純化粗產物，生成白色固體 該產物溶解於乙酸乙酯（60 ml )中，經1 : 1(R) — 4- (2 —Axyl — 1 ′ 4 — monogas — D quinazoline — 3 —yl) —piperidine — 1 monocarboxylic acid {2-[1, 4 claw 'D fixed 1- 1- 2 -keto | 1- 1-[1-(2-dimethylmethyl-ethanesulfonyl)-1H-indazole-5-ylmethyl] monoethylamidine . The crude product was purified by silica gel chromatography using CH2C12 / methanol / tri (9 3: 5: 2) as a wash solution to produce a white solid. The product was dissolved in ethyl acetate (60 ml) and subjected to 1: 1

NaHC03水溶液/鹽水冲洗2次，隨後置於Na2S04上乾 經過濾液後，除去溶劑以生成白色固體之標的化合物 % )。 j-NMR ( CD3OD，5 0 0MHz ) (5 7 · 2 0 - 7 · 1 4 ( m， ，7·08 ( d，J = 9·0Ηζ，1 Η ) ，6.9 6 ( t d，J = 7 · 5，] ，1H) ，6.79(d，J=8.0Hz，lH) ? 4.99 - 4.94 ( m )，4.61— 4.58(m，lH) ，4·47— 4.43 (m，lH)， (s，lH) ，4.23— 4.16(m，2H) ，4.08—4.04 (m )，3.06-2.88 (m，5H) ，2.74—2.69 (m，2H)， —2.52(m，2H) ，2.41— 2.33(m，2H) ，1.96—1. m，] H ) ，1 · 8 8 — 1 . 4 7 ( n]，1 6 H )。 -2H 〕聯 矽烷 }-乙胺 。令 飽和 燥。 (70 4H ) [.0Hz ，1 Η 4.39 ，1 Η 2.59 89 ( -188 - (184) (184)200529835 LC/MS: tR=1.86分，630.31 (ΜΗ) + 〇 (R) — 3 — （1Η —苯並三卩坐一 5 —基）—2 —苄氧羯基胺 基一丙酸甲酯NaHC03 aqueous solution / brine was rinsed twice, and then dried on Na2S04. After the filtrate, the solvent was removed to produce the target compound as a white solid (%). j-NMR (CD3OD, 50 MHz) (5 7 · 2 0-7 · 1 4 (m,, 7.08 (d, J = 9 · 0Ηζ, 1 Η)), 6.96 (td, J = 7 · 5,], 1H), 6.79 (d, J = 8.0Hz, lH)? 4.99-4.94 (m), 4.61-4.58 (m, lH), 4.47-4.43 (m, lH), (s, lH ), 4.23— 4.16 (m, 2H), 4.08—4.04 (m), 3.06-2.88 (m, 5H), 2.74—2.69 (m, 2H), —2.52 (m, 2H), 2.41— 2.33 (m, 2H), 1.96—1.m,] H), 1 · 8 8—1.4. 7 (n), 16 H). -2H] bissilane} -ethylamine. Saturate and dry. (70 4H) [ .0Hz, 1 Η 4.39, 1 Η 2.59 89 (-188-(184) (184) 200529835 LC / MS: tR = 1.86 minutes, 630.31 (ΜΗ) + 〇 (R) — 3 — (1Η —benzotrifluorene 5-methyl) -2-benzyloxyfluorenylamino monopropionate

室溫下將亞硝酸鈉（〇 · 4 6 g ’ 6.6 5毫莫耳）之水（8 ml )溶液以超過數分鐘之時間逐滴地加入至（R ) — 2 -苄氧羰基胺基一 3— (3，4 一二胺基一苯基）一丙酸甲酯 單乙酸鹽（2.68 g，6.65毫莫耳）之乙酸（30 ml)和水（ 4 0 m 1 )的溶液中。室溫下攪拌所生成之混合物2 0分鐘， 隨後冷卻至〇°C ，加入濃NH40H溶液調整PH至11。於 NaCl固體之存在下利用乙酸乙酯萃取該混合物2次，令該 有機層於N a2 S 0 4上乾燥。經過濾後，真空下除去溶劑並藉 由矽膠層析且利用乙酸乙酯/己烷（6 : 4 )爲流洗液以純 化殘餘物，生成黃褐色固體之標的化合物（94 %產率）。 】H-NMR ( CD30D，5 0 0MHz ) (5 7 · 7 5 ( d，J = 8 · 5 Η z， 1 H ) ，7.58(s，lH) ，7.31—7.25(m，5H) ，7.18(d ，J=8.5Hz，1 H ) ，5.39 (d，J=8.0Hz，1 H ) ，5 . 1 0 ( d ，J = 12.0Hz ^ 1 H ) ，5.05 (d，J = 1 2.0Hz ^ 1 H ) ，4.74 (dd，J=13.5，6·0Ηζ，1H) ，3.73(s，3H) ^ 3.34 ( dd ,j 二 14.0，5.5Hz，]H) ，3.22 ( dd > J=13.5，6.0Hz, 1 H )。 13CNMR(CD3OD，125 MHz) o 172.]，156.0，136.]， -189- (185) 200529835 128·6，128.3，128.1，67.2，55.2，52.7，38.5。質譜： 355.18 (ΜΗ) +。 (R) — 2 —胺基一 3— (1Η-苯並三唑—5 -基）一丙酸 甲酯A solution of sodium nitrite (0.46 g '6.6 5 millimolar) in water (8 ml) was added dropwise to (R)-2 -benzyloxycarbonylamino-1 at room temperature over several minutes. 3- (3,4-diaminomonophenyl) monopropionate methyl acetate (2.68 g, 6.65 mmol) in a solution of acetic acid (30 ml) and water (40 m 1). The resulting mixture was stirred at room temperature for 20 minutes, then cooled to 0 ° C, and concentrated NH40H solution was added to adjust the pH to 11. The mixture was extracted twice with ethyl acetate in the presence of NaCl solids, and the organic layer was dried over Na 2 S 0 4. After filtration, the solvent was removed in vacuo and the residue was purified by silica gel chromatography using ethyl acetate / hexane (6: 4) as the eluent to yield the title compound as a tan solid (94% yield). ] H-NMR (CD30D, 500 MHz) (5 7 · 7 5 (d, J = 8 · 5 Η z, 1 H), 7.58 (s, 1H), 7.31-7.25 (m, 5H), 7.18 ( d, J = 8.5Hz, 1 H), 5.39 (d, J = 8.0Hz, 1 H), 5. 1 0 (d, J = 12.0Hz ^ 1 H), 5.05 (d, J = 1 2.0Hz ^ 1 H), 4.74 (dd, J = 13.5, 6.0 · ζ, 1H), 3.73 (s, 3H) ^ 3.34 (dd, j 2 14.0, 5.5 Hz,] H), 3.22 (dd > J = 13.5, 6.0 Hz, 1 H). 13CNMR (CD3OD, 125 MHz) o 172.], 156.0, 136.], -189- (185) 200529835 128 · 6, 128.3, 128.1, 67.2, 55.2, 52.7, 38.5. Mass spectrum: 355.18 (ΜΗ) +. (R) — 2-Amino-3- (1Η-benzotriazol-5-yl) monopropionate

N N" \ N ΗN N " \ N Η

如前述製備（R) - 2 -胺基一 3— (2 —酮基一 2，3-二氫一苯並噁唑一 6—基）一丙酸甲酯之方法。 ]H-NMR ( CD3〇D ^ 5 00MHz) 5 8.38 ( brs，2H ) ，7.89 (d，J=7.5Hz，lH) ，7.81(s，lH) ，7.40(d，J = 7·5Ηζ，1 Η ) ，4.44 (s，1 Η ) ，3.81 (s，3H ) ，3.48-A method for preparing (R) -2-amino-3- (2-keto-2,3-dihydro-benzoxazole-6-yl) monopropionate as described above. ] H-NMR (CD30D ^ 500MHz) 5 8.38 (brs, 2H), 7.89 (d, J = 7.5Hz, 1H), 7.81 (s, 1H), 7.40 (d, J = 7.5Ηζ, 1 Η), 4.44 (s, 1 Η), 3.81 (s, 3H), 3.48-

3.45 (m，1 H ) ，3.40-3.37 (m，1 H ) ，3.33(brs，1 H ；0 13CNMR(CD3OD，125MHz) 0 169.8，139.4，138.9,3.45 (m, 1 H), 3.40-3.37 (m, 1 H), 3.33 (brs, 1 H; 0 13CNMR (CD3OD, 125MHz) 0 169.8, 139.4, 138.9,

133.0， 127.6， 115.52， 115.47， 54.3 ^ 52.6， 36.7。質譜 :2 2 1 . 1 5 ( Μ H ) +。 實施例4 8 (R) — 3 — （1H —苯並三唑—5 —基）—2— { (4-(2 一酮基一1，4 —二氫一 2 Η — D奎唑啉一3 —基）一_啶一1 一羰基〕一胺基} 一丙酸甲酯 -190- (186) 200529835 Η133.0, 127.6, 115.52, 115.47, 54.3 ^ 52.6, 36.7. Mass spectrum: 2 2 1. 1 5 (MH) +. Example 4 8 (R) — 3 — (1H —benzotriazol-5-yl) — 2 — {(4- (2 monoketo-1,4-dihydro-1 2 hydrazone — D quinazoline-1 3-yl) -pyridine-1 monocarbonyl] monoamino} methyl propionate-190- (186) 200529835 Η

如前述製備（R) — 2— { 〔4一（2_酮基一 1，4 —二(R) — 2 — {[4 一 (2_keto-1,4—two

氨一 2Η - D奎Π坐啉一 3 —基）一卩底卩定―1 一類基〕一胺基} 一 3 — 〔1 一 （2-三甲基甲矽烷基一乙烷磺醯基）一 1Η — 吲唑一 5 —基〕-丙酸甲酯之方法，唯其利用羰基二咪唑 以替代Ν，Ν -二琥珀醯亞胺碳酸酯（D S C )。 W-NMR ( CD3OD，300MHz) 5 7.82 ( d，J 二 8.4Hz，Ammonia 2Η-D Π 坐 thioline-3 -yl)-卩 卩 卩 一 1 type of group] a amine group}-3-[1-(2-trimethylsilyl-ethanesulfonyl) The method of 1 1-indazole-5 -yl] -propanoic acid methyl ester uses carbonyl diimidazole instead of N, N -disuccinimidyl carbonate (DSC). W-NMR (CD3OD, 300MHz) 5 7.82 (d, J 8.4Hz,

1 H ) ，7.24 ( s ^ 1 H ) ，7.39 (dd， ，J = 8.7 ^ 1.2Hz，1H )，7.15— 7.08(m，2H) ，6.94(td，J=7.5，0.9Hz， 1 H ) ，6.75(d，J二 7.8Hz，1H) ，4.67— 4.60 (m，1H)1 H), 7.24 (s ^ 1 H), 7.39 (dd,, J = 8.7 ^ 1.2Hz, 1H), 7.15—7.08 (m, 2H), 6.94 (td, J = 7.5, 0.9Hz, 1 H) , 6.75 (d, J = 7.8Hz, 1H), 4.67— 4.60 (m, 1H)

，4.39— 4.31 (m，1H) ，4.15 (s，2H) ，4.08-4.03 ( m，2H) ，3.72(s，3H) ，3.38(dd，J=13.9，5.5Hz， 1 H ) ， 3.32— 3.29( m，lH) ，3.17(dd，J=13.9, 10.3Hz，1H) ，2.87— 2.71 (m，2H) ，：1.64— 1.48 (m， 4H )。質譜：478·30(ΜΗ)+。 實施例4 9 (R) — 4— (2 —酮基一]，4 —二氫一 2H — D奎唑啉一3 — 基）一哌啶一 1 一羧酸〔1 一 （】H —苯並三唑一 5 —基甲基 )—2 — 〔 1，4 /〕聯哌啶一 1 / —基一 2 —酮基—乙基〕 -191 - 200529835 (187) 醯胺, 4.39— 4.31 (m, 1H), 4.15 (s, 2H), 4.08-4.03 (m, 2H), 3.72 (s, 3H), 3.38 (dd, J = 13.9, 5.5Hz, 1 H), 3.32— 3.29 (m, lH), 3.17 (dd, J = 13.9, 10.3Hz, 1H), 2.87—2.71 (m, 2H), 1.64—1.48 (m, 4H). Mass spectrum: 478.30 (ΜΗ) +. Example 4 9 (R) — 4 — (2-keto-1], 4-dihydro—2H — D-quinazoline—3-yl) -piperidine—1—carboxylic acid [1 — (] H—benzene Benzotriazol-5-ylmethyl) -2-[[1,4 /] bipiperidinyl-1 / -yl-2-2-keto-ethyl] -191-200529835 (187) pyridoxamine

如前述製備（R) — 4-（2 -酮基一 1，4 —二 一喹唑啉一 3 —基）—哌啶—1 —羧酸{ 2 —〔 1，4 聯哌啶一 1/ —基—2 —酮基一 1—〔一（2_三甲基 基—乙烷磺醯基）一 1 Η —吲哚一5 —基甲基〕一乙 醯胺之方法。藉由矽膠層析且利用CH2C12/甲醇/ (93 : 5 : 2 )爲流洗液進行純化。 ]H-NMR ( CD3〇D » 5 0 0MHz) 5 7 · 8 3 ( d，J 二 8 0.75H ) ，7.79(d，J=8.5Hz，0.25H) ，7.71(s, )，7.69 (s，0.75H ) ，7.33 (d，J=9.2Hz，1 H ) —7.12(m，2H) ，6.96—6.91 (m，lH) ，6.78( 8·0Ηζ，0.75H ) ，6.77 ( d，J = 8·0Ηζ，0.25H )， 5·03 (ηι，1H) ，4.58— 4.55 (m，1H) ，4.45 — 4 ，1 H ) ，4.34 ( s，1.25H) ，4·24 ( s，0.75H )， 4.05 (m，2.25H) ，4.00— 3.96 (m，0.75H)， 3.09( in，2H) ，2.91— 2·78(ηι，4Η) ^ 2.64-2 ，2H) ，2.56-2.42 (m，2H) ，2·]5— 2.]0(m， )，2 · 0 2 — ] . 9 8 ( m，1 . 7 5 H ) ，1 . 9 5 — 1 · 9 0 ( m，] 氨一2 H 甲矽院 基}— 三乙胺 • 2Hz， 0.25H ，7· 1 6 d，J = 5.07 -.40 ( m 4.20 -3.24-.61 ( m 1 .25H :H )， -192- (188) (188)200529835 1.68— 1.60( m，8H) ，1·54— 1.46(m，6H)。 LC/MS: tR 二 1·86 分，614·28(ΜΗ) +。 (R) — 2 —苄氧羰基胺基一 3 —（2-酮基—2，3 —二氫— 2 Η — D引哚一 5 —基）一丙酸甲酯(R) — 4- (2-keto-1,4-di-quinazoline-3-yl) -piperidine-1—carboxylic acid {2 — [1,4 dipiperidine-1 / —Methyl-2—Keto-1— [1- (2-trimethylyl-ethanesulfonyl) —1—pyridine—indole-5—methylmethyl] -ethylamidine. Purified by silica gel chromatography using CH2C12 / methanol / (93: 5: 2) as a flow wash. ] H-NMR (CD3OD »500 MHz) 5 7 · 8 3 (d, J 2 8 0.75H), 7.79 (d, J = 8.5Hz, 0.25H), 7.71 (s,), 7.69 (s , 0.75H), 7.33 (d, J = 9.2Hz, 1 H) —7.12 (m, 2H), 6.96—6.91 (m, 1H), 6.78 (8 · 0Ηζ, 0.75H), 6.77 (d, J = 8 · 0Ηζ, 0.25H), 5.03 (η, 1H), 4.58—4.55 (m, 1H), 4.45—4, 1H), 4.34 (s, 1.25H), 4.24 (s, 0.75H) ), 4.05 (m, 2.25H), 4.00-3.96 (m, 0.75H), 3.09 (in, 2H), 2.91-2.78 (η, 4Η) ^ 2.64-2, 2H), 2.56-2.42 (m , 2H), 2 ·] 5— 2.] 0 (m,), 2 · 0 2 —]. 9 8 (m, 1. 7 5 H), 1. 9 5 — 1 · 9 0 (m,) Ammonia-2H methylsilyl base} —triethylamine • 2Hz, 0.25H, 7.16d, J = 5.07 -.40 (m 4.20 -3.24-.61 (m1.25H: H), -192 -(188) (188) 200529835 1.68— 1.60 (m, 8H), 1.54— 1.46 (m, 6H). LC / MS: tR 2.86 points, 614 · 28 (ΜΗ) +. (R) — 2-benzyloxycarbonylamino-3 — (2-keto-2,3-dihydro-2 2 hydrazone —Dindole-5 —yl) monopropionate

將PyHBr3(1.28 g，4.02毫莫耳）以超過30分鐘之時 且以小部份地加入至（R ) - 2 -苄氧羰基胺基一 3 — ( 1 Η —吲哚一 5 —基）—丙酸甲酯（〇·47 g ’ 1.34毫莫耳）之特 丁醇（1 0 ml )溶液中，同時維持反應溫度介於2 5至3 0 °C 。室溫下攪拌所生成之混合物3 .5小時。真空下除去溶劑 並利用乙酸乙酯（2x )萃取殘餘物。利用鹽水冲洗結合之 有機層並置於Na2 SO4上乾燥。經過濾液後，除去溶劑並利 用無水乙醇共沸乾燥殘餘物。令殘餘物溶解於冰醋酸（1 0 ml )並加入鋅粉（0.88 g，13.4毫莫耳）。室溫下隔夜攪 拌該混合物。經於真空下除去乙酸後，藉由矽膠閃蒸層析 並利用乙酸乙酯/己烷（首先爲1 : 3，隨後爲3 : 2 )爲流 洗液以純化殘餘物，生成白色固體之標的化合物（4 1 %， 2步驟）。 ]H-NMR ( CDC13 5 5 00MHz ) J 8.03 ( s，1H ) ，7·36 - 7.3 1 ( m，5H ) ，6·94 ( s，1H ) ，6.9 1 ( d，J= 8.0Hz， 1H ) ，6.73 (d，J 二 7·5Ηζ，1 Η ) ，5.26(d，J=8.0Hz， 1 H ) ，5.11 (d，J - 12.0Hz ^ 1 H ) ，5.05 (d，J - 1 2.5 H z -193- (189) 200529835 ，1Η ) ，4.61 ( dd，J= 13.5，6·0Ηζ，1 Η ) ，3.72 ( s，PyHBr3 (1.28 g, 4.02 mmol) was added to (R)-2 -benzyloxycarbonylamino-3-(1 Η -indole-5 -yl) in small portions over 30 minutes -Methyl propionate (0.47 g '1.34 mol) in tert-butanol (10 ml) while maintaining the reaction temperature between 25 and 30 ° C. The resulting mixture was stirred at room temperature for 3.5 hours. The solvent was removed in vacuo and the residue was extracted with ethyl acetate (2x). The combined organic layers were washed with brine and dried over Na2SO4. After passing through the filtrate, the solvent was removed and the residue was azeotropically dried with absolute ethanol. The residue was dissolved in glacial acetic acid (10 ml) and zinc powder (0.88 g, 13.4 mmol) was added. The mixture was stirred overnight at room temperature. After removing the acetic acid under vacuum, the residue was purified by flash chromatography on silica gel using ethyl acetate / hexane (first 1: 3, then 3: 2) as a washing solution to produce the target compound as a white solid. Compound (41%, 2 steps). ] H-NMR (CDC13 5 5 00MHz) J 8.03 (s, 1H), 7.36-7.3 1 (m, 5H), 6.94 (s, 1H), 6.9 1 (d, J = 8.0Hz, 1H ), 6.73 (d, J 2 7. 5Ηζ, 1 Η), 5.26 (d, J = 8.0 Hz, 1 H), 5.11 (d, J-12.0 Hz ^ 1 H), 5.05 (d, J-1 2.5 H z -193- (189) 200529835, 1Η), 4.61 (dd, J = 13.5, 6.00Ηζ, 1Η), 3.72 (s,

3Η ) ，3.45(s，2H) ，3.10(dd，J=；1.40，5.5Hz，lH )，3.00 (dd，J =14·0，6·0Ηζ，1Η)。 13C NMR ( CDC13， 125MHz ) ά 1 7 7.7， 1 7 2.2，1 5 5 · 7， 141.7，136.3，129.8，128.9，128.6，128.3，128.2， 125.8， 125.6， 109.8， 67.1 ， 55.1 ， 52.5， 38.0， 36。質 譜：369.20( ΜΗ) +。 (11)—2_胺基—3—(2—酮基一2，3—二氫—111—吲 哚一 5 —基）一丙酸甲酯3Η), 3.45 (s, 2H), 3.10 (dd, J =; 1.40, 5.5Hz, 1H), 3.00 (dd, J = 14 · 0, 6 · 0Ηζ, 1Η). 13C NMR (CDC13, 125MHz) 1 7 7.7, 1 7 2.2, 1 5 5 · 7, 141.7, 136.3, 129.8, 128.9, 128.6, 128.3, 128.2, 125.8, 125.6, 109.8, 67.1, 55.1, 52.5, 38.0, 36. Mass spectrum: 369.20 (ΜΗ) +. (11) -2-Amino-3- (2-keto-2,3-dihydro-111-indole-5-yl) monopropionate

N Η 如則述製備（R) — 2 —胺基—3— (2 —酬基一 2，3 — 二氫一苯並噁唑一 6 —基）一丙酸甲酯之方法。 】H-NMR ( CD3OD，5 00MHz ) 5 8.48 ( brs，2H ) ，7.16 (s，lH) ，7.10(s，lH) ，6.89(s，lH) ，4.21(s， 1 H ) ，3.81(s，3H) ，3.54(s，lH) ，3.33(s，2H) ，3.20(s，lH) ，3.12(s，lH) 〇 13C NMR ( CD3OD，125MHz ) 5 1 7 8.9，170.7，143.3， 129.0 ， 128.6 ， 126.9 ， 125.6 ， 110.0 ， 57.3 ， 54.6 ， 52.3 ，37.0。質譜：235.30(MH) +。 (R) — 3— (2 —酮[基一 2，3 — 一氯—1H — D 引 D朵一 5 —基 )—2— { 〔4— (2 —酮基一1，4 —二氫一2H — 口奎唑啉一 -194 - (190) (190)200529835 3 一基）__啶一 1 一羰基〕一胺基丨一丙酸甲酯N Η As described above, the method for preparing (R) -2-amino-3- (2-amino-2,3-dihydro-benzoxazole-6-yl) monopropionate is described. ] H-NMR (CD3OD, 500 MHz) 5 8.48 (brs, 2H), 7.16 (s, lH), 7.10 (s, lH), 6.89 (s, lH), 4.21 (s, 1 H), 3.81 (s 3H), 3.54 (s, 1H), 3.33 (s, 2H), 3.20 (s, 1H), 3.12 (s, 1H) 〇13C NMR (CD3OD, 125MHz) 5 1 7 8.9, 170.7, 143.3, 129.0, 128.6, 126.9, 125.6, 110.0, 57.3, 54.6, 52.3, 37.0. Mass spectrum: 235.30 (MH) +. (R) — 3— (2 —ketone [Base-2, 3 — Monochloro-1H — D — D — 5 — Group) — 2 — {[4— (2 —Keto-1,4 —dihydro -2H — quinazoline mono-194-(190) (190) 200529835 3 mono) __pyridin-1 monocarbonyl] monoamino 丨 mono propionate

將碳釀氣之甲苯溶液（2M，0.158 ml，0.30毫莫耳） 加入至（r) — 2 -胺基一 3— (2 —酮基一 2，3 - 一 Mi ~ 1H —卩引D朵一 5—基）一丙酸甲酯（7〇 mg’ 0.25¾莫耳）之 二氯甲烷（15 nil )和NaHC03飽和溶液（7.5 ml )的劇烈 攪拌混合物中。經於室溫下攪拌該混合物3 0分鐘後’加入 3 — _ 陡—4 一基一 3，4 —二氫—1 Η —喹唑啉—2 -酮（5 8 mg，0.25毫莫耳）。室溫下攪拌所生成之混合物1.5小時 ，經乙酸乙酯稀釋，並以經NaCl固體飽和之0.25N HC丨冲 洗。於Na2S04上乾燥有機層。經過濾後’除去溶劑以生成 黃褐色黏稠油狀物之標的化合物。 LC/MS: tR=2.01 分，492·10(ΜΗ) + 〇 實施例5 0 (R) — 4— （2 —酬基一]，4 —二氯一2Η — D 室口坐琳一 3 — 基）—哌啶—1 一羧酸〔2 - 〔 1，4 /〕聯哌啶一 1，一基 —2 —酮基—1— (2 —酮基一 2，3 —二氫一 1Η — D引 D朵—5 一基甲基）一乙基〕一醯胺 -195- (191) (191)200529835Carbon toluene gas solution (2M, 0.158 ml, 0.30 mmol) was added to (r) — 2 -amino — 3 — (2 — keto — 2, 3 — — Mi ~ 1H — A 5-yl) methyl propionate (70 mg '0.25¾ mole) in a vigorously stirred mixture of dichloromethane (15 nil) and a saturated solution of NaHC03 (7.5 ml). After stirring the mixture at room temperature for 30 minutes, 3 — _ steep — 4 yl — 3, 4 — dihydro — 1 Η — quinazolin — 2 -one (5 8 mg, 0.25 mmol) . The resulting mixture was stirred at room temperature for 1.5 hours, diluted with ethyl acetate, and washed with 0.25N HC1 saturated with NaCl solids. The organic layer was dried over Na2S04. After filtration ', the solvent was removed to give the target compound as a yellow-brown viscous oil. LC / MS: tR = 2.01 minutes, 492 · 10 (ΜΗ) + 〇 Example 5 0 (R) — 4 — (2 — phenyl group 1], 4 —dichloro 1 — 2 — D chamber mouth sitting Lin 3 — (Yl) -piperidine-1 monocarboxylic acid [2-[1,4 /] bipiperidine-1, 1-yl-2-keto-1-(2 -keto-2,3-dihydro-1 1- D-D-D-5 monomethyl) monoethyl] monomethylamine-195- (191) (191) 200529835

如則述製備（R) — 4— (2—酬基—1，4 — 一氯—2H —喹唑啉一3 —基）一暖啶一 1 —羧酸{ 2 — 〔 1，4 /〕一 聯哌啶一 1/ —基一 2-酮基—1 一 〔1 一 （2—三甲基甲矽 院基一乙院礦酿基）一 1H — D引D坐一 5 —基甲基一〕—乙基 } 一醯胺之方法。藉由矽膠閃蒸層析利用CH2C12/甲醇/ 三乙胺（93 : 5 : 2 )爲流洗液以進行純化。 ]H-NMR(CD3OD，500MHz) 57.20-7.09( m，4H)Prepared as described (R) — 4 — (2—Amino—1,4—monochloro—2H —quinazolin — 3 —yl) —piperidine—1 —carboxylic acid {2 — [1, 4 /] A piperidine 1 / -yl-2 2-keto-1 1 [1 1 (2-trimethylsilyl group 1 ethyl mineral group) 1H — D group D 5 — 5-methyl group A] -Ethyl} Monoamine method. Purification was performed by silica gel flash chromatography using CH2C12 / methanol / triethylamine (93: 5: 2) as a flow wash. ] H-NMR (CD3OD, 500MHz) 57.20-7.09 (m, 4H)

，6·97 (t，J=7.3Hz，1 Η ) ，6.88 (d，J=7.9Hz，0.65H )，6.84(d，J=7.6Hz，0.35H) ，6.80(d，J=7.7Hz， 0.35H ) ，5.51(s，0.65H) ，5.23(s，0.35H) ^ 4.99 - 4.95 (m，0.65H) ，4.92.— 4.88 (m，0.35H) ，4.60- 4·56(ηι，1.65H) ，4·46— 4·41 (m，1.35H) ，4.39(s， 1 . 3 H ) ，4.36(m，0.7H) ，4·24— 4.17(m，2H) ^ 4.05 —4.02 (m，1H ) ，3.65-3.61 (m，2H) ，3.52— 3.47 ( m，lH) ，3.20—3.16 (m，lH) ，3.00—2.88 (m，2H) ，2.70— 2.64 ( m，2H) ，2.53—2.46 (m，2H) ，2.40 — 2 · 3 4 ( m，2 H ) ，：1 . 9 4 - 1 . 4 6 ( m，1 5 H ) ，1 · 3 9 — 1 . 3 6 ( ni ，2H )。 -196- (192) 200529835 LC/MS : tR 二 1·83 分，628.40 ( ΜΗ) + 〇 2— （二一特丁氧羰基胺基）一丙烯酸甲酯 〇 〇, 6.97 (t, J = 7.3Hz, 1 Η), 6.88 (d, J = 7.9Hz, 0.65H), 6.84 (d, J = 7.6Hz, 0.35H), 6.80 (d, J = 7.7Hz , 0.35H), 5.51 (s, 0.65H), 5.23 (s, 0.35H) ^ 4.99-4.95 (m, 0.65H), 4.92.-4.88 (m, 0.35H), 4.60-4.56 (ηι, 1.65H), 4.46-4.41 (m, 1.35H), 4.39 (s, 1.3H), 4.36 (m, 0.7H), 4.24-4.17 (m, 2H) ^ 4.05-4.02 (m, 1H), 3.65-3.61 (m, 2H), 3.52--3.47 (m, lH), 3.20-3.16 (m, lH), 3.00-2.88 (m, 2H), 2.70- 2.64 (m, 2H) , 2.53—2.46 (m, 2H), 2.40 — 2 · 3 4 (m, 2 H), 1. 9 4-1. 4 6 (m, 1 5 H), 1 · 3 9 — 1. 3 6 (ni, 2H). -196- (192) 200529835 LC / MS: tR di 1.83 points, 628.40 (ΜΗ) + 〇 2-(di-tert-butoxycarbonylamino) monomethyl acrylate 〇 〇

室溫下將4 一二甲基胺基吡啶（0 · 4 8 g，0.1當量）加 入至2—特丁氧羰基胺基一 3-羥基一丙酸甲酯（10.0 g ’ 39毫莫耳）和二碳酸二特丁酯（21·8 g，2·6當量）之乙腈 (40 ml )溶液中。隔夜攪拌該溶液並進行濃縮。令殘餘 物溶解於二乙醚中，先後經1M KHS04溶液（2x )、飽和 NaHC03溶液及鹽水冲洗，置於MgS04上乾燥，並經濃縮 以生成油狀物（15.6 g，定量）。】H — NMR分析顯示標的 化合物與2— （二一特丁氧羰基胺基）一 3—特丁氧羰基氣 -丙酸甲酯之混合物。隨後發現該二者皆與二級胺反應以 生成相同之產物，隨後未經分離而使用該混合物。4-Dimethylaminopyridine (0.48 g, 0.1 eq.) Was added to methyl 2-tertoxycarbonylamino-3-hydroxymonopropionate (10.0 g '39 mmol) at room temperature And ditert-butyl dicarbonate (21.8 g, 2.6 equivalents) in acetonitrile (40 ml). The solution was stirred overnight and concentrated. The residue was dissolved in diethyl ether, washed with 1M KHS04 solution (2x), saturated NaHC03 solution, and brine, dried over MgS04, and concentrated to form an oil (15.6 g, quantitative). H-NMR analysis showed a mixture of the target compound and 2- (di-tert-butoxycarbonylamino) -3-tert-butoxycarbonyl-propionic acid methyl ester. Both were subsequently found to react with the secondary amine to produce the same product, and the mixture was subsequently used without isolation.

2 —二一特丁氧羰基胺基）一丙烯酸甲酯：】H-NMR( CDC13)(5 1.45(s，1H) ，3.78(s，3H) ，5.63(s，1H )，6.33(s，lH)。質譜：324.14(M+Na)+。〕—（ 二一特丁氧羰基胺基）一 3-特丁氧羰基氧一丙酸甲酯： 】H-NMR ( CDC13，5 00MHz ) 5 1.46 ( s，9H) ，1.49 ( s，2-Di-tert-butoxycarbonylamino) monoacrylate:] H-NMR (CDC13) (5 1.45 (s, 1H), 3.78 (s, 3H), 5.63 (s, 1H), 6.33 (s, lH). Mass spectrum: 324.14 (M + Na) +.] — (Di-tert-butoxycarbonylamino) -3-tert-butoxycarbonyloxymonopropionate:] H-NMR (CDC13, 500 MHz) 5 1.46 (s, 9H), 1.49 (s,

18H) ，3.72 (s’ 3 H ) ，4.42 ( d d 5 J=11.6，9·2Ηζ，1H )，4.75 (dd，J=】】·3，4.6Hz » 1 H ) ，5_30 (dd，J = 9.2，4.6，1H)。質譜：442.21 (M+Na) +。 -197- (193) (193)200529835 (±) — 3— (4氧基—2 —酮基一 2H—D比 u定一；[―基） 一 2—（二一特丁氧羰基胺基）—丙酸甲酯18H), 3.72 (s' 3 H), 4.42 (dd 5 J = 11.6, 9 · 2Ηζ, 1H), 4.75 (dd, J =]] · 3, 4.6 Hz »1 H), 5_30 (dd, J = 9.2, 4.6, 1H). Mass spectrum: 442.21 (M + Na) +. -197- (193) (193) 200529835 (±) — 3— (4-oxy-2-ketone group-2H—D is more specific than u; [―yl] —2— (di-tert-butoxycarbonylamino group) ) —Methyl propionate

將碳酸鉋（100 mg，0.10當量）加入至2-（二一特 丁氧鑛基）—丙燦酸甲酯（900 mg，3.0毫莫耳）和4一； 氧基一1H—吡啶一 2—酮（630 mg，1.03當量）之乙腈（ 2.5 m 1 )中。藉由微波加熱所生成之懸浮液至8 〇 °C達2小 時。濃縮該反應混合物，令其溶解於水中，並利用CH2C12 (3 X )進行萃取。利用鹽水冲洗結合之有機層，置於 M g S Ο 4上乾燥，並經濃縮以生成1 · 4 7 g ( 9 7 % )，其係未 經純化而使用。質譜：5 0 3 . 5 6 ( Μ Η ) +。 (± ) — 4 —苄氧基一1 一 〔 3 — 〔 1，4 /〕聯哌啶一厂一 基一 2 — （二—特丁氧羰基胺基）—3 -酮基一丙基〕—Carbonic acid shavings (100 mg, 0.10 equivalents) were added to 2- (di-tert-butoxy-based) -methyl propionate (900 mg, 3.0 mmol) and 4-a; oxy-1H-pyridine-2 -Ketone (630 mg, 1.03 equivalents) in acetonitrile (2.5 m 1). The resulting suspension was heated by microwave to 80 ° C for 2 hours. The reaction mixture was concentrated, dissolved in water, and extracted with CH2C12 (3X). The combined organic layers were washed with brine, dried over MgS04, and concentrated to give 1.47 g (97%), which was used without purification. Mass spectrum: 50 3. 5 6 (M Η) +. (±) — 4-benzyloxy-1 1 [3 — [1,4 /] piperidine one plant one base one 2 — (di-tert-butoxycarbonylamino) 3 -ketomonopropyl] —

1 Η —吡啶—2 —酮 將LiOH單水合物（0.50 g，4當量）之水（2.85 ml) 溶液加入至3 — ( 4 -苄氧基—2 —酮基一 2 Η —吡啶—1 一 -198- (194) (194)200529835 基）一 2—(二一特丁氧羰基胺基）一丙酸甲酯（1· 47 g ，2 9毫莫耳）之甲醇（1 7 m 1 )攪拌彳谷液中。室溫下攪拌 該反應混合物3小時’隨後冷卻至0°C ’與濃HC1 ( 0.99 ml )反應並經濃縮後生成粗酸，取其一半量進行下述之步驟 。該該粗酸溶解於CH2C12 ( 6 ml )中，隨後冷卻至〇°C， 並先後與4 —卩尼啶基—哌啶（0 · 2 5 g，1當量）、三乙胺（ 0.31 ml，2·5當量）及雙—2 —酮基—3 -噁唑烷基—亞膦 醯氯（0 · 3 8 g，1當量）反應。令該反應混合物回溫至室 溫並隔夜攪拌。濃縮該反應混合物，經製備性HPLC純化 後生成 489 mg (52%，2步驟）。質譜：639.41 (MH) + 實施例5 1 (土）一 4 一 （2 —酬基一 1，4一 二氨一 2H — 口奎口坐琳一 3 — 基）一哌啶一 1 一羧酸〔1 一 （4 一苄氧基）—2 -酮基— 2 Η — D比Π疋一 1 一基甲基）—2 — 〔 1，4 /〕聯派旋一 基一 2—酮基一乙基〕一醯胺1 Η —pyridine — 2 — ketone A solution of LiOH monohydrate (0.50 g, 4 equivalents) in water (2.85 ml) was added to 3 — (4 -benzyloxy — 2 —keto — 2 —pyridine — 1 — -198- (194) (194) 200529835 group)-2- (di-tert-butoxycarbonylamino) monopropionate methyl ester (1.47 g, 29 mmol) methanol (17 m 1) Stir in the barley solution. The reaction mixture was stirred at room temperature for 3 hours 'and then cooled to 0 ° C' to react with concentrated HC1 (0.99 ml) and concentrated to form a crude acid, and half of it was subjected to the following steps. The crude acid was dissolved in CH2C12 (6 ml), and then cooled to 0 ° C, followed by 4-pyridinyl-piperidine (0.25 g, 1 equivalent), triethylamine (0.31 ml, 2.5 equivalents) and bis-2-keto-3-oxazolidinyl-phosphiniumphosphonium chloride (0.38 g, 1 equivalent) were reacted. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated and purified by preparative HPLC to yield 489 mg (52%, 2 steps). Mass spectrum: 639.41 (MH) + Example 5 1 (soil)-4 ((2-amino-1,4-diamino- 2H-Koukouzilin 3 -yl) -piperidine- 1 -carboxylic acid [1- (4-benzyloxy) -2-keto-2 2 Η — D ratio Π 疋 -1 1-yl methyl) -2 — [1,4 /] allo-one- 2-keto- Ethylamine

-199- (195) (195)200529835 於〇 t：下將三氟乙酸（1 ml )加入至4 —苄氧基—l — 〔3— 〔1，4 〕聯哌卩定一 1 一基—2—(二一特丁氧鑛 基胺基）一3 —酮基—丙基〕一 1H — 〇比啶一 2 —酮之 CH2C12 ( 3 ml )攪拌溶液中。經2小時後，濃縮該反應混 合物以生成粗胺（151 mg，97% ;其三氟乙酸鹽；質譜： 43 9.6 1 ( MH ) +，隨後分爲2部份，利用其中一部份進行 下述之步驟。於〇°C下將羰基二咪唑（29 mg，1.6當量， 分2部份）加入至該粗胺（75 mg，0.11毫莫耳）和二異丙 基乙胺（80 // 1，4當量）之CH2C12 ( 3 ml )溶液中。經攪 拌1 〇分鐘後，令該溶液與3 —哌啶—4 -基—3，4 一二氫一 1H—喹唑啉一2 —乙酸（40 mg，1.15當量）反應。令該反 應混合物回溫至室溫並進行隔夜攪拌。濃縮該反應混合物 並經製備性TLC純化後，生成40.8 mg ( 53% )。 】Η-ΝΜΙΙ ( CD3OD，5 00MHz ) ό 1 · 2 5 - 1 · 5 6 ( m，4 Η ) 1 . 56 — 1 . 84 ( m ， 9H ) ，1 .90-2. 0 8 ( m， 3H ) ，2, .60 - 2. 95 ( m J 8H ) 5.11( dd， J = 24 •1 ， 12.8 ，1 H )， 3.89 ( ddd ，J \ = :22. 0， 13.2， 9.2 ，1 H ) ，4. 1 0 (dd， J = 14.3 1 4 .1 5 2H ) ，4. 27 — 4.54 (m， 5H ) ，4 • 60 ( bd ，J = 11 .9 9 1H ) 9 5.08 (dd ，J = =13.2 ，12.2 ，： 2H ) ，5. 26 ( ddd ，J = 9 .4， 9.4 ，4.8 ，1 H )，6· 05 ( dd ， J = 1 3.7 ，2.7 ， 1H) ， 6 • 16 (m ，1 H ) ，6 • 77 ( d ，J = 8 · 0 ，1 H )， 6.84 ( ddd ，J 7.6 ，7 • 6，2 • 1， 1 H )， 7.04 ( d ，J = 7.6 ，1 H ) 9 7. 12 ( dd， J = 7.6， 7.4 ，1 H ) ，7.28 - 7.43 (m ，5H ) ， 7. 4 8 ( d，. J = 7 .6，1 H) 。質譜 ：696.85 (MH )+ o -200 - (196) 200529835 實施例5 2 (±) — 4— (2 —酮基一1，4 —二氫一2H — D奎唑啉一3 — 基）—哌啶一 1 —羧酸〔2 —〔 1，4 /〕聯哌啶一 1 / 一（ 4 一羥基）一 2 —酮基一 2H—吡啶一 1—基甲基）一 2—酮基 —乙基〕一醯胺-199- (195) (195) 200529835 Add trifluoroacetic acid (1 ml) to 4-benzyloxy-l-[3-[1,4] dipyridinyl-1 1- 2- (Di-tert-butoxyamine-based amine) -3-keto-propyl]-1H-0-pyridine-2-ketone in CH2C12 (3 ml) in a stirred solution. After 2 hours, the reaction mixture was concentrated to form a crude amine (151 mg, 97%; its trifluoroacetate salt; mass spectrum: 43 9.6 1 (MH) +, then divided into 2 parts, using one part for the next step Add the carbonyl diimidazole (29 mg, 1.6 equivalents, 2 parts) to the crude amine (75 mg, 0.11 mmol) and diisopropylethylamine (80 // at 0 ° C) 1,4 equivalents) in a solution of CH2C12 (3 ml). After stirring for 10 minutes, the solution was mixed with 3-piperidine-4-yl-3,4-dihydro-1H-quinazoline-2 2-acetic acid (40 mg, 1.15 equivalents). The reaction mixture was allowed to warm to room temperature and stirred overnight. After concentrating the reaction mixture and purifying by preparative TLC, 40.8 mg (53%) was obtained.] Η-ΝΜΙΙ (CD3OD, 5 00MHz) ό 1 · 2 5-1 · 5 6 (m, 4 Η) 1. 56 — 1. 84 (m, 9H), 1.90-2. 0 8 (m, 3H), 2, .60 -2. 95 (m J 8H) 5.11 (dd, J = 24 • 1, 12.8, 1 H), 3.89 (ddd, J \ =: 22.0, 13.2, 9.2, 1 H), 4. 1 0 ( dd, J = 14.3 1 4 .1 5 2H), 4. 27 — 4.54 (m, 5H), 4 60 (bd, J = 11.9 9 1H) 9 5.08 (dd, J = = 13.2, 12.2,: 2H), 5. 26 (ddd, J = 9.4, 9.4, 4.8, 1 H), 6 · 05 (dd, J = 1 3.7, 2.7, 1H), 6 • 16 (m, 1 H), 6 • 77 (d, J = 8 · 0, 1 H), 6.84 (ddd, J 7.6, 7 • 6 , 2 • 1, 1 H), 7.04 (d, J = 7.6, 1 H) 9 7. 12 (dd, J = 7.6, 7.4, 1 H), 7.28-7.43 (m, 5H), 7. 4 8 (d,. J = 7.6, 1 H). Mass spectrum: 696.85 (MH) + o -200-(196) 200529835 Example 5 2 (±) — 4— (2 —keto-1,4 —2 Hydrogen-2H — D quinazoline-3 —yl) —piperidine — 1 —carboxylic acid [2 — [1, 4 /] bipiperidin — 1/1 (4-hydroxy) — 2 — keto — 2H — Pyridine-l-ylmethyl) -2-keto-ethyl] monomethylamine

HH

將4 — (2 —嗣基一 1，4 — 一氯—2 Η 一 D奎口坐琳一 3 —基 )一哌啶—1 一羧酸〔1 一 （4 —苄氧基—2 —酮基一 2Η -口比旋—1 —基甲基）一2 —〔 1 ’ 4 〕聯呢D定—1 —基—2 —酮基一乙基〕一醯胺（29 mg)和 10%Pd/C(5 mg) 之甲醇（1 ml )攪拌溶液置於氫氣下。於室溫下經1小時 後，利用氮氣冲洗該反應混合物，經通過寅氏鹽進行過濾 ，隨後經濃縮以生成產物。 】H-NMR ( CD3OD，5 0 0MHz ) 5 1 · 4 0 - 1 . 8 5 ( m，1 Η ) ，2.04(dd，J=27.4，17.0，2H) ，2.66(dd，J=21.1 ，11.0，1H) ，2.80-3.19 (m，8H ) ，3.95 (ddd，J = 49.8，12.5，7.9，1H) ，4.07-4.28(m，3H) ，4.34( bs，2H) ，4·36— 4.59(】n，2H) ，4.63(bd，J二]2.8， 1 H ) ，5 · 2 0 ( m，1 H ) ，5 . 7 5 ( d d，J = 7.3，2 . ]，1 H )， -201 - (197) (197)200529835 5.97(dd’J=8.9’7.6，lH) ，6.78(d，J=7.6，lH) ，6.93 (dd，J二 7.6，7·3，1H) ，7.08— 7·18 (m，2H) ，7.33(dd，J=18.3，ll.〇，1H)。質譜：6〇632 (ΜΗ ) +。 (±) — 2— （二一特丁氧羰基胺基）一3一 （4一羥基— 哌啶一 1 —基）一丙酸甲酯Add 4- (2-Amidino-1,4-chloro-1,2,1-D-quinoxaline-3-A) -piperidine-1,1carboxylic acid [1 ((4-benzyloxy-2-one) 2- (2-methyl)-(1- (1-methyl))-2-([1'4] dibenzidine-1- (2-yl) -2-keto-ethyl] -pyridamine (29 mg) and 10% Pd / C (5 mg) in methanol (1 ml) was stirred under hydrogen. After 1 hour at room temperature, the reaction mixture was flushed with nitrogen, filtered through yin salt, and then concentrated to produce the product. ] H-NMR (CD3OD, 500 MHz) 5 1 · 4 0-1. 8 5 (m, 1 Η), 2.04 (dd, J = 27.4, 17.0, 2H), 2.66 (dd, J = 21.1, 11.0 , 1H), 2.80-3.19 (m, 8H), 3.95 (ddd, J = 49.8, 12.5, 7.9, 1H), 4.07-4.28 (m, 3H), 4.34 (bs, 2H), 4.36-4.59 ( ] N, 2H), 4.63 (bd, J2) 2.8, 1H), 5.20 (m, 1H), 5.7.5 (dd, J = 7.3, 2 ...], 1H),- 201-(197) (197) 200529835 5.97 (dd'J = 8.9'7.6, lH), 6.78 (d, J = 7.6, lH), 6.93 (dd, J2 7.6, 7.3, 1H), 7.08-- 7.18 (m, 2H), 7.33 (dd, J = 18.3, 110.0, 1H). Mass spectrum: 6032 (MΗ) +. (±) — 2— (di-tert-butoxycarbonylamino) -3- (4-hydroxy-piperidine- 1-yl) monopropionate

將哌啶一 4 一醇（〇 . 3 3 g，1 · 1當量）加入至2 -（二— 特丁氧羰基胺基）一丙烯酸甲酯（1.0 g，3.0毫莫耳）之 乙腈（1 0 ml )溶液中。隔夜攪拌該反應混合物，同時於 其上方通過氮氣流。令所生成之粗油狀物溶於乙酸乙酯中 ’先後經水和鹽水冲洗，置於Mg S04上乾燥，經濃縮後產 生油狀物（1 .3 8 g，定量），其係未經純化而使用。質譜 :403.42 ( MH ) + 〇 (± ) — 1 一 〔 1，4 /〕聯哌啶一厂—基—2 — （二一特 丁氧羰基胺基）一 3-（4 —羥基一哌啶一 1 一基）一丙一 1Piperidine-4 monool (0.33 g, 1.1 equivalents) was added to 2- (di-tert-butoxycarbonylamino) monoacrylate (1.0 g, 3.0 mmol) in acetonitrile (1 0 ml) solution. The reaction mixture was stirred overnight while passing a stream of nitrogen over it. The resulting crude oil was dissolved in ethyl acetate ', washed with water and brine, dried on Mg S04, and concentrated to give an oil (1.38 g, quantitative), which was not Purified and used. Mass spectrum: 403.42 (MH) + 〇 (±) — 1- [1,4 /] dipiperidine-one plant-radical-2-(di-tert-butoxycarbonylamino)-3- (4-hydroxy-piperidine One one one base) one one 1

將1^〇}^單水合物（40〇1]：^，3.9當量）之水（]1111) 200529835 (198) 溶液加入至2- （二一特丁氧羰基胺基）一 3 -（4一羥基 一哌啶一1 一基）一丙酸甲酯（1.0 g’ 2.5毫莫耳）之甲醇 (6 m 1 )溶液中。攪拌該反應混合物6小時，隨後冷卻至0 。(：，利用濃HC1進行中和，並進行濃縮。使用未經純化之 粗酸。令該粗酸懸浮於CH2C12 ( 25 ml )中，隨後加入數 滴甲醇以增進溶解該酸’並冷卻至0 °C。令所生成之懸浮 液先後與4 一哌啶基—卩底卩定（〇 · 5 3 g，1 · 2 5當量）、三乙胺 (0.70 ml，2當量）及雙一 2-酮基—3一噁唑烷基—亞磷 醯氯（〇·80 g，1·25當量）反應。令該反應混合物隔夜回 溫至室溫。濃縮該反應混合物’隨後藉由製備性HPLC進 行純化以生成3 1 0 ni g ( 2 3 % ’ 2步驟）。質譜·· 5 3 9.4 9 ( MH ) +。A solution of 1 ^ 〇} ^ monohydrate (40〇1]: ^, 3.9 equivalents in water (] 1111) 200529835 (198) was added to 2- (di-tert-butoxycarbonylamino)-3-(4 Monohydroxy-piperidine- 1-yl) monopropionate (1.0 g '2.5 mmol) in methanol (6 m 1). The reaction mixture was stirred for 6 hours and then cooled to 0. (:, Neutralize with concentrated HC1, and concentrate. Use unpurified crude acid. Suspend the crude acid in CH2C12 (25 ml), then add a few drops of methanol to promote dissolution of the acid 'and cool to 0. ° C. Let the resulting suspension be successively mixed with 4-piperidinyl-dipyridine (0.53 g, 1.25 equivalents), triethylamine (0.70 ml, 2 equivalents), and bis-2- Keto-3-oxazolidinyl-phosphonium phosphonium chloride (0. 80 g, 1.25 equivalents) was reacted. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated 'followed by preparative HPLC Purified to yield 3 10 nig (23% '2 steps). Mass spectrum ... 5 3 9.4 9 (MH) +.

於0 °C下將三氟乙酸（2 ml )加入至1 一〔 1 ’ 4 /〕聯 _D定一厂一基一 2-（二一特丁氧羰基胺基）一 3-（4 一 經基一 _啶一 1 一基）一丙—1 一酮（310 mg ’ 0·5 8毫莫耳 } 2 ( 5 ml )溶液中。除去冰浴並攪拌該反應混合 _ 3 鐘。濃縮該反應混合物以生成產物（彼之三氟乙酸 臨，4〇〇 ’定量）’其係未經純化而使用。質譜： -203 - (199) 200529835 3 3 9.46 ( ΜΗ ) (土）一 〔2—〔1’4 〕聯呢11疋一1 —基一1— (4 —經 基一丨派卩定一 1 一基甲基）一 2 —酮基一乙基〕一氯基甲酸特 丁酯Trifluoroacetic acid (2 ml) was added to 1 1 [1 '4 /] Dian_Dingyi Plant one base one 2- (dione special butoxycarbonylamino) one 3- (4 one at 0 ° C 1-pyridine-1 1-yl) -propan-1 monoketone (310 mg '0.58 mmol) 2 (5 ml) solution. Remove the ice bath and stir the reaction for 3 minutes. Concentrate the reaction The mixture was produced as a product (the trifluoroacetic acid pro, 400 'quantitative') which was used without purification. Mass Spectrum: -203-(199) 200529835 3 3 9.46 (ΜΗ) (Earth)-[2-[ 1'4] Nine 11 疋 1 1-1-1-(4-1-methyl 1-1-methyl) 2-keto 1-ethyl] t-butyl chloroformate

將二碳酸二特丁酯（128 mg’ 1當量）加入至2—胺基 一 1 —〔 1，4 '〕聯_卩定一 1 一基—3 — ( 4 —經基一哌π定 —1—基）一丙—1 一酮（三氟乙酸鹽，300 mg’ 0.58毫莫 耳）和二異丙基乙胺（0.3 ml ’ 4當量）之四氫呋喃（5 ml )溶液中。室溫下攪拌所生成之溶液1小時，並進行濃縮 。令殘餘物溶解於乙酸乙酯中，先後經水和鹽水冲洗，置 於MgS04上乾燥，經濃縮後生成248 mg ( 98% ) ’其係未Di-tert-butyl dicarbonate (128 mg '1 eq.) Was added to 2-amino- 1-[1,4'] biphenyl-1,1-yl-3-(4 -yl-piperidine- 1-based) monopropan-1 monoketone (trifluoroacetate, 300 mg '0.58 mmol) and diisopropylethylamine (0.3 ml' 4 equivalents) in a solution of tetrahydrofuran (5 ml). The resulting solution was stirred at room temperature for 1 hour and concentrated. The residue was dissolved in ethyl acetate, washed with water and brine, dried over MgS04, and concentrated to give 248 mg (98%).

經純化而使用。質譜：43 9.65 ( MH ) +。 (± ) — 〔 2 — 〔 1，4 /〕聯哌啶一1 / 一基一 2 —酮基一1 一 （4 一酮基一哌啶一 1 一基甲基）一乙基〕一氨基甲酸特 丁酯Purified and used. Mass spectrum: 43 9.65 (MH) +. (±) — [2 — [1,4 /] bipiperidine-1 / 1-1-2-keto-1-(4-keto-piperidine-1-methyl)-ethyl]-amino Tert-butyl formate

將 D e s s - M a r t i η P e r i 〇 d i n a n e 試劑（3 1 6 m g ’ 2 昌里）力 2部份加入至1 一 〔 1，4 /〕聯哌啶—厂一基一 2一 （二一 - 204 - (200) (200)200529835 特丁氧羰基胺基）一 3 - （4 一羥基一哌啶一 1 一基）一丙 —1—酮（200 mg，0.37 毫莫耳）之 CH2C12(4 ml)溶液 中。經1小時後，藉由加入飽和N a H C Ο 3溶液中止該反應， 並利用CH2C12 ( 3χ )進行萃取。利用鹽水冲洗結合之有機 層，置於M g S Ο 4上乾燥，經濃縮後生成1 8 7 m g ( 9 4 % )， 其係未純化而使用。質譜：4 3 7.6 3 ( ΜΗ ) +。 (± ) — 1 — ( 2 —胺基一 3 — 〔 1，4 /〕聯哌啶一厂—基Add 2 parts of Dess-M arti η Peri 〇 の ane reagent (3 16 mg '2 Changli) to 1 1 [1, 4 /] piperidine-factory one base one 2 one (two one- 204-(200) (200) 200529835 Tetrabutoxycarbonylamino)-3-(4-hydroxy-piperidine-1 1-yl) -propan-1-one (200 mg, 0.37 mmol) CH2C12 (4 ml) solution. After 1 hour, the reaction was stopped by adding a saturated Na H C 0 3 solution, and extraction was performed with CH 2 C 12 (3 ×). The combined organic layer was washed with brine, dried over M g S 0 4, and concentrated to produce 187 mg (94%), which was used without purification. Mass spectrum: 4 3 7.6 3 (ΜΗ) +. (±) — 1 — (2 —amino- 3 — 〔1,4 /] dipiperidine first plant-based

一 3 —酮基一丙基）一呢Π定一 4 一酮 於〇 °C下將三氟乙酸加入〔2 -〔 1，4 <〕聯哌卩定_ 1^ 一基一2 —酮基一1 一 （4 一酮基一_11定一 1 一基甲基） 一乙基〕—氨基甲酸特丁酯（100 mg，0.23毫莫耳）之 C Η 2 C 12 ( 5 m 1 )彳谷液中。移除冰浴，持續攪拌I小時，濃 縮反應產物產生150 mg (96%)，其係彼之三氟乙酸鹽且 未經純化而使用。質譜：3 3 7.6 4 ( Μ Η ) +。 實施例5 3 (±) — 4- (2 —酮基一1，4一二氫一2Η — D 奎口坐啉一 3 — 基）一哌啶—1 一羧酸〔2 -〔 1，4 >〕聯哌啶〜丨-一基 一 1 一 （4 —羥基一哌啶一 1 一基甲基）—2 一酮基—乙基 〕一醯胺 -205 - (201) (201)200529835 Η-3-ketomonopropyl) -n-tinidine-4 monoketone Trifluoroacetic acid was added to [2-[1, 4 <] dipyridinium_ 1 ^ -one 2- 2-ketone at 0 ° C 1- (1-keto--11-di-1-methyl) monoethyl] -tetrabutyl carbamate (100 mg, 0.23 mmol) C Η 2 C 12 (5 m 1) In the barley solution. The ice bath was removed and stirring was continued for 1 hour. The concentrated reaction product produced 150 mg (96%), which was trifluoroacetate and was used without purification. Mass spectrum: 3 3 7.6 4 (ΜΗ) +. Example 5 3 (±) — 4- (2-keto-1,4-dihydro-1, 2Η — D quinololine-3 —yl) -piperidine-1 monocarboxylic acid [2-[1,4 >] piperidine ~ 丨 -one-one-one (4-hydroxy-piperidine-one-ylmethyl) -2 one keto-ethyl] -amidine-205-(201) (201) 200529835 Η

於〇°C下將二異丙基乙胺（0.27 ml，3.9當量）和羰基 二咪唑（63 mg，1當量）加入至4 一（2—酮基—1，4 —二 氫一 2 Η —喹唑啉一 3 —基）一哌啶一 1 一羧酸〔2 —〔 1， 4 /〕聯哌啶一1 / —基一 1 一 （ 4 一羥基一哌啶一1 —基甲 基）一2 —酮基一乙基〕—醯基（三氟乙酸鹽，200 mg， 0.39毫莫耳）之01120：12(51111)溶液中。經攪拌15分鐘後 ，力□入3 — _啶一4 —基一3，4 -二氫一1H — D奎唑啉一2 — 酮（乙酸鹽，142 mg，1.25當量）。令該溶液回溫至室溫 並隔夜攪拌。濃縮反應產物並藉由製備性HPLC進行純化 ，生成130 mg ( 56% )之油狀物。 LC/MS : tR= 1.7 分，5 96.44 ( MH) +。 3 —二甲基胺基亞甲基—4 一酮基一哌啶一 1 一羧酸特丁酯Diisopropylethylamine (0.27 ml, 3.9 equiv.) And carbonyldiimidazole (63 mg, 1 equiv.) Were added to 0- (2-keto-1,4-dihydro-2) at 0 ° C. Quinazoline- 3-yl) -piperidine- 1-carboxylic acid [2- — [1, 4 /] bipiperidin- 1 / -yl- 1-(4 -hydroxy-piperidine- 1 -ylmethyl) -2-ketomonoethyl] -fluorenyl (trifluoroacetate, 200 mg, 0.39 mmol) in a solution of 01120: 12 (51111). After stirring for 15 minutes, 3 -pyridinyl-4-yl-1,3,4-dihydro-1H-D quinazolin-2-2-one (acetate, 142 mg, 1.25 equivalents) was added. The solution was allowed to warm to room temperature and stirred overnight. The reaction product was concentrated and purified by preparative HPLC to give 130 mg (56%) of an oil. LC / MS: tR = 1.7 points, 5 96.44 (MH) +. 3-dimethylaminomethylene-4 monoketo-piperidine-1 monobutyl carboxylate

令4 —酮基一哌啶一 1 —羧酸特丁酯（1 0 g，5 0毫莫耳 )溶解於二甲基甲醯胺二甲基乙縮醛（5 0 ml )中並加熱 至迴流狀態達1 .25小時。冷卻該溶液，進行濃縮，藉由閃 蒸層析純化以生成2 · 5 5 g ( ] 9 % )。質譜：2 5 5 . 1 6 -206- 200529835 (202) (Μ Η ) + 1，4，6，7 —四氫一口比唑並〔4，3 — c〕D比υ定一 5—殘酸特 丁酯Let 4- keto-piperidine-1 -tetrabutyl carboxylate (10 g, 50 mmol) be dissolved in dimethylformamide dimethyl acetal (50 ml) and heated to The reflux state reached 1.25 hours. The solution was cooled, concentrated, and purified by flash chromatography to give 2.55 g (9%). Mass spectrum: 2 5 5. 1 6 -206- 200529835 (202) (Μ Η) + 1,4,6,7-tetrahydro-one-zozozo [4,3 — c] D ratio ν-a 5-residual acid Tert-butyl ester

將聯氨水合物（〇·61 ml，1.25當量）加入至3 —二甲 基胺基亞甲基一 4 一酮基一哌啶一 1 一羧酸特丁酯（2.55 g ，1〇毫莫耳）之甲醇（50 ml )溶液中。加熱該溶液至迴 流狀態，隨後立即地冷卻至室溫，經濃縮後生成1 .4 g ( 6 3%)，其係未經純化而使用。質譜：2 2 4.1 1 ( Μ Η )+。 4，5，6，7 —四氫一 1 Η — D比唑並〔4，3 — c〕D比啶Add hydrazine hydrate (0.61 ml, 1.25 equivalents) to 3-dimethylaminomethylene-4, keto-piperidine-1, tert-butyl carboxylate (2.55 g, 10 mmol) Ear) in methanol (50 ml). The solution was heated to reflux and immediately cooled to room temperature. After concentration, 1.4 g (63%) was obtained, which was used without purification. Mass spectrum: 2 2 4.1 1 (ΜΗ) +. 4,5,6,7 -tetrahydro- 1 fluorene-D-pyrazolo [4,3-c] D-pyridine

於0 °C下令1，4，6，7 —四氫—D比Π坐並〔4，3 - c〕口比 啶—5—羧酸特丁酯（0.70 g，3.1毫莫耳）溶解於三氟乙 酸（1 0 ml )中，隨後攪拌1小時並進行濃縮。令殘餘物溶 解於乙醇中，並經濃HC1 ( 1 ml )處理。該雙氫氯化物鹽 沈澱爲白色固體，其係經過濾以生成5 1 0 mg ( 8 3 % )。製 備所需之自由鹼係藉由溶解該鹽於水中，載入SCX管柱上 ，經甲醇冲洗，隨後藉由2M氨之甲醇溶液流洗。 -207 - (203) 200529835 (土）— 2—(二一特 丁氧羰基胺基）一 3— （1，4，6，7 一四氫—吡唑並〔4 ’ 3 — c〕吡啶一 5 —基）一丙酸甲酯 〇Order 1,4,6,7-tetrahydro-D ratio Π at 0 ° C and dissolve [4,3-c] orbitidine-5-carboxylic acid tert-butyl ester (0.70 g, 3.1 mmol) in Trifluoroacetic acid (10 ml), followed by stirring for 1 hour and concentration. The residue was dissolved in ethanol and treated with concentrated HC1 (1 ml). The dihydrochloride salt precipitated as a white solid, which was filtered to yield 5 10 mg (83%). The required free base was prepared by dissolving the salt in water, loading it on an SCX column, washing with methanol, and then washing with 2M ammonia in methanol. -207-(203) 200529835 (Earth) — 2- (di-tert-butoxycarbonylamino) —3— (1,4,6,7—tetrahydro-pyrazolo [4 ′ 3 —c] pyridine— 5 -yl) methyl propionate

B0C2N 將2— （二—特丁氧鑛基胺基）一丙嫌酸甲酯（400 mg)加入至4，5，6，7—四氫一 1H —吡唑並〔4，3— c〕 吡啶（1 60 mg )之甲醇（2.5 ml )溶液中。藉由施用氮氣 流，濃縮該反應溶液至約1 · 5 ml。室溫下隔夜攪拌該溶液 。濃縮該反應溶液，令其溶解於乙酸乙酯中，經鹽水冲洗 ，置於MgS04上乾燥，隨後進行濃縮。所生成之殘餘物的 純度係足以未經純化而使用。 】H-NMR ( CDC13，5 00MHz ) 5 1.44 ( s，9H ) ，2.73 (B0C2N Add 2- (di-tert-butoxyamino) monopropionic acid methyl ester (400 mg) to 4,5,6,7-tetrahydro-1H-pyrazolo [4,3—c] Pyridine (1 60 mg) in methanol (2.5 ml). The reaction solution was concentrated to about 1.5 ml by applying a nitrogen stream. The solution was stirred overnight at room temperature. The reaction solution was concentrated, dissolved in ethyl acetate, washed with brine, dried over MgS04, and then concentrated. The resulting residue was pure enough to be used without purification. ] H-NMR (CDC13, 500 MHz) 5 1.44 (s, 9H), 2.73 (

m，3H) ，2.91(m，lH) ，3.06(dd，J=13.4，8.6，lH )，3.22(dd，J=13.4，8.2，1H) ，3.54(d，J=13.4 ，1H) ，3.63(d，J=13.4，1H) ’ 3.71 (s，3H) ，5.11 (dd，J=8.5，5.2，lH)7.25(s，lH)。質譜：425.23 (ΜΗ ) +。 (±) — 2—胺基一 3 — （1，4，6，7 —四氫一吡唑並〔4 ，3 — c〕吡Π定一 5 —基）—丙酸甲酯 - 208- (204) (204)200529835m, 3H), 2.91 (m, lH), 3.06 (dd, J = 13.4, 8.6, lH), 3.22 (dd, J = 13.4, 8.2, 1H), 3.54 (d, J = 13.4, 1H), 3.63 (d, J = 13.4, 1H) '3.71 (s, 3H), 5.11 (dd, J = 8.5, 5.2, 1H) 7.25 (s, 1H). Mass spectrum: 425.23 (ΜΗ) +. (±) — 2-amino-3- (1,4,6,7-tetrahydro-pyrazolo [4,3-—c] pyridine—5-yl) —methyl propionate—208- ( 204) (204) 200529835

將三氟乙酸（l·5 ml)加入至2- （二—特丁氧羰基 胺基）一3— (1，4，6，7—四氫—吼卩坐並〔4，3 - c〕吼 啶一5 —基）一丙酸甲酯（0.55 g，1當量）之CH2C12(5 ml，0°C )溶液中。移除冰浴並持續攪拌2小時。濃縮該溶 液，令其再溶解於甲醇中，並通過強陽離子交換樹脂管柱 。經利用甲醇冲洗後，藉由2 Μ氨之甲醇溶液流洗管柱， 以生成自由鹼之產物（275mg，95%)。 j-NMR ( CDC13，5 00MHz ) 5 2.7 1 ( d d，J = 1 2 · 8，8.6 ，1H ) ，2.74—2.91 (m» 6H ) ，3.48 (s，2 H ) ，3.54 ( d，J=13.4，lH) ，3.62(d，J=13.4，lH) ，3.69(dd ，j=8.2，4.9，1H) ，3.73(s，3H) ，7.27(s，1H) 〇 質譜：225·16(ΜΗ) +。 3，3-二甲基—4 一酮基一哌啶一丨一羧酸特丁酯Trifluoroacetic acid (1.5 ml) was added to 2- (di-tert-butoxycarbonylamino) -3- (1,4,6,7-tetrahydro-hydroquinone) and [4,3-c] Amidin-5-yl) monopropionate (0.55 g, 1 equivalent) in CH2C12 (5 ml, 0 ° C). Remove the ice bath and continue stirring for 2 hours. The solution was concentrated, redissolved in methanol, and passed through a column of strong cation exchange resin. After rinsing with methanol, the column was washed with a 2 M ammonia solution in methanol to produce a free base product (275 mg, 95%). j-NMR (CDC13, 500 MHz) 5 2.7 1 (dd, J = 1 2 · 8, 8.6, 1H), 2.74—2.91 (m »6H), 3.48 (s, 2 H), 3.54 (d, J = 13.4, lH), 3.62 (d, J = 13.4, lH), 3.69 (dd, j = 8.2, 4.9, 1H), 3.73 (s, 3H), 7.27 (s, 1H). Mass spectrum: 225 · 16 (ΜΗ ) +. 3,3-dimethyl-4 monoketo-piperidine-tert-butyl carboxylate

於〇°C下將NaH ( 4·1 g ’ 2.；[當量）分4部份加入至4 — 酮基一哌啶一 1 一羧酸特丁酯（1 6 g，8 0毫莫耳）之四氫 呋喃（4〇〇 ml )溶液中。隨後逐滴地加入碘甲烷（12.5 ml ’ 2 · 5當量）。令該反應溶液逐漸地回溫至室溫並隔夜攪 拌。濃細該反應丨谷液’令其溶解於二乙酸中，經由鹽水冲 -209- (205) (205)200529835 洗’置於M g S Ο4上乾燥，並進行濃縮。自熱戊烷（2 x )中 結晶產物，生成5.9 g ( 3 2 % )。 W-NMR ( CDC13，5 00MHz ) 5 1 ·09 ( s，6H ) ，1.47 ( s ，9 Η ) ，2.47 ( dd 5 J=6.4，6.4，2 Η ) ，3.41 (m，2H ) ，3.70(m，2H)。質譜：250.12(M+Na) +。 5 —二甲基胺基亞甲基一 3，3 —二甲基一 4 一酮基一哌啶一 1 一羧酸特丁酯NaH (4.1 g '2 .; [equivalent]) was added to 4-keto-piperidine-l-tetrabutyl monocarboxylate (16 g, 80 mmol) at 4 ° C at 0 ° C. ) In tetrahydrofuran (400 ml). Then methyl iodide (12.5 ml ′ 2 · 5 equivalents) was added dropwise. The reaction solution was gradually warmed to room temperature and stirred overnight. The reaction was concentrated. The valley solution was made to dissolve in diacetic acid, washed with brine -209- (205) (205) 200529835, washed and dried on M g S 0 4, and concentrated. The product crystallized from hot pentane (2 x), yielding 5.9 g (32%). W-NMR (CDC13, 500 MHz) 5 1 · 09 (s, 6H), 1.47 (s, 9 Η), 2.47 (dd 5 J = 6.4, 6.4, 2 Η), 3.41 (m, 2H), 3.70 ( m, 2H). Mass spectrum: 250.12 (M + Na) +. 5-dimethylaminomethylene- 3,3-dimethyl- 4 -keto-piperidine- 1 -tetrabutyl carboxylate

令3，3-二甲基一 4 一酮基—哌啶—1 一羧酸特丁酯（ 5 g ’ 22毫莫耳）溶解於二甲基甲醯胺二甲基乙縮醛（25 ml )中，並於迴流狀態下加熱2小時。藉由微波加熱該反 應混合物至130°C達1小時，經濃縮後生成油狀產物（6.43 g ’定量），其係未經純化而使用。 】H-NMR ( CDC13，5 00MHz ) 5 1·07 ( s，6Η ) ’ 1 .45 ( sLet 3,3-dimethyl-1, 4-keto-piperidine-1, 1-butyl carboxylic acid tert-butyl ester (5 g '22 mmol) be dissolved in dimethylformamide dimethyl acetal (25 ml ) And heated under reflux for 2 hours. The reaction mixture was heated to 130 ° C for 1 hour by microwave. After concentration, an oily product was obtained (6.43 g 'quantitative), which was used without purification. ] H-NMR (CDC13, 500 MHz) 5 1 · 07 (s, 6Η) ′ 1.45 (s

，9H) ，3.06(s，6H) ，3.37( m，2H) ，4.57(m，2H )，7.4 1 ( bs，1 H ) 〇 7’ 7 — ~ 甲基一1，4，6，7 —四氯一 D 比 Π坐並〔4，3— c〕 吡啶一 5 一羧酸特丁酯 -210 - (206) (206)200529835, 9H), 3.06 (s, 6H), 3.37 (m, 2H), 4.57 (m, 2H), 7.4 1 (bs, 1 H) 〇7 '7 — ~ Methyl-1, 4, 6, 7 — Tetrachloro-D ratio π [4,3-c] pyridine-5 tert-butyl monocarboxylate-210-(206) (206) 200529835

將聯氨水合物（1.2 ml，1.1當量）加入至5 —二甲基 胺基亞甲基—3’ 3—二甲基一 4 —酮基一哌啶一 1 一羧酸特 丁酯（6.35 g，22毫莫耳）之甲醇（15 ml)溶液中。室溫 下隔夜攪拌該溶液，並經濃縮後生成5 .3 g ( 94 % )’其 係未經純化而使用。質譜：2 5 2 · 1 9 ( M + Η ) +。 7，7 —二甲基一 4，5，6，7—四氫一1Η — D比唑並〔4，3 一 c〕D比Π定Add hydrazine hydrate (1.2 ml, 1.1 equivalents) to 5-dimethylaminomethylene-3 '3-dimethyl-4, keto-piperidine-1 1-tetrabutyl carboxylate (6.35 g, 22 mmol) in methanol (15 ml). The solution was stirred overnight at room temperature and concentrated to give 5.3 g (94%) ', which was used without purification. Mass spectrum: 2 5 2 · 1 9 (M + Η) +. 7,7 —dimethyl-1, 4,5,6,7-tetrahydro-1, 1Η — D than zolozo [4,3 —c] D ratio

於〇°C下將三氟乙酸（5 ml )加入至7，7—二甲基一 1 ，4，6，7 —四氫一口比唑並〔4，3 — c〕〇比啶一5 —羧酸特 丁酯（5.3 g，21毫莫耳）之CH2C12(10 ml)溶液中。令 該反應溶液回溫至室溫，攪拌1 5分鐘，並加入額外之三氟 乙酸（5 ml )。經1小時後，濃縮該反應溶液，令其溶解 於乙醇（10 ml )中，冷卻至〇°C加入濃HC1 ( 3 ml )，並 進行濃縮。利用乙醇碾製所生成之固體’經過濾後生成彼 之雙氫氯化物鹽（3.02 g，64%)。製備所需之自由鹼係 藉由溶解該鹽水於水中，載入SCX管柱上’經甲醇冲洗， 隨後經2M氨之甲醇溶液流洗。 H- NMR(D20，500MHz) 〇1.49(s，6H) 5 3.46 ( s (207) 200529835 152.14 ，2H) ，4.39(s，2H) ，7.86(s，lH)。質譜： (ΜΗ ) +。 -二甲 5 -基 (±) — 2— （二一特丁氧羰基胺基）一 3 — （7，7 基一1，4，6，7 —四氫一D比口坐並〔4，3— c〕D比卩定-)一丙酸甲酯 0Trifluoroacetic acid (5 ml) was added to 7,7-dimethyl-1,4,6,7-tetrahydrobiprazolo [4,3-c] -pyridine-5 at 0 ° C at 0 ° C. Tert-butyl carboxylate (5.3 g, 21 mmol) in CH2C12 (10 ml). The reaction solution was allowed to warm to room temperature, stirred for 15 minutes, and additional trifluoroacetic acid (5 ml) was added. After 1 hour, the reaction solution was concentrated, dissolved in ethanol (10 ml), cooled to 0 ° C, concentrated HC1 (3 ml) was added, and concentrated. The solid produced by milling with ethanol was filtered to form its dihydrochloride salt (3.02 g, 64%). The required free base was prepared by dissolving the brine in water, loading it on an SCX column ', washing with methanol, and then washing with 2M ammonia in methanol. H-NMR (D20, 500 MHz) 〇 1.49 (s, 6H) 5 3.46 (s (207) 200529835 152.14, 2H), 4.39 (s, 2H), 7.86 (s, 1H). Mass spectrum: (ΜΗ) +. -Dimethyl 5 -yl (±) — 2 — (di-tert-butoxycarbonylamino) — 3 — (7,7 radical —1,4,6,7 —tetrahydro-D ratio and [4, 3— c) D than hydradin-) methyl propionate 0

將2 — （二一特丁氧羰基胺基）一丙烯酸甲酷 mg)力口入至7，7 —二甲基一4，5，6，7 —四氫一： 口坐並〔4，3 — c〕D 比 π定（1 6 0 m g )之甲醇（3 m 1 ) 。施用氮氣流並隔夜攪拌該反應溶液。隔天早上溶 顯著地減少。於高真空下除去最後殘餘之溶劑以5 mg (定量），其係未經純化而使用。 】H-NMR ( CDC13，5 00MHz ) ά 1 .2 4 ( s，3Η ) ，1 ，3Η) ，1.38(s，18H) ，2.33(dd，J=11.3，l 2.57(d，J=11.3，lH) ，3.09(dd，J=13.1，5Put 2- (di-tert-butoxycarbonylamino) -methyl methacrylate into the mouth of 7,7-dimethyl-4,5,6,7-tetrahydro-1: — C] methanol (3 m 1) with a D ratio (160 mg). A nitrogen stream was applied and the reaction solution was stirred overnight. The dissolution was significantly reduced the next morning. The last remaining solvent was removed under high vacuum to 5 mg (quantitative), which was used without purification. 】 H-NMR (CDC13, 5 00MHz) ά 1.2. 4 (s, 3 ，), 1, 3Η), 1.38 (s, 18H), 2.33 (dd, J = 11.3, l 2.57 (d, J = 11.3, lH), 3.09 (dd, J = 13.1, 5

)，3.15(dd，J=13.4，9.5，lH) ，3.35(d，J ，：1H) ，3.57(d，J=12.8，lH) ，3.68(s，3H) (dd，J=9.5，3.7，lH) ，7.16(s，lH) 4 5 3.3 0 ( ΜΗ) +。 (±) — 2 —胺基一3 — （7，7 —二甲基一1，4，6, -212- I ( 331 1 Η -吡 溶液中 液體積 ί 成 490), 3.15 (dd, J = 13.4, 9.5, lH), 3.35 (d, J ,: 1H), 3.57 (d, J = 12.8, lH), 3.68 (s, 3H) (dd, J = 9.5, 3.7 1H), 7.16 (s, 1H) 4 5 3.3 0 (ΜΗ) +. (±) — 2 —amino — 3 — (7,7 —dimethyl-1,4,6, -212- I (331 1 Η-pyridine solution in liquid volume to 490

• 26 ( s Η )， .5，1 Η =12.8 ，5· 1 3 !譜： 7 —四 (208) (208)200529835 氫一吡唑並〔4，3 — c〕吡啶一 5 —基）丙酸甲酯• 26 (s Η), .5,1 Η = 12.8, 5. · 1 3! Spectrum: 7-tetra (208) (208) 200529835 hydrogen-pyrazolo [4,3 — c] pyridine-5-yl) Methyl propionate

將三氟乙酸（1.5 ml )加入至2—(二一特丁氧羰基 胺基）一3— (7，7 —二甲基一 1，4，6，7 —四氫一吡唑 並〔4，3— c〕D比π定一 5—基）—丙酸甲醋（〇·49 g，1當量 )之CH2C12 ( 5 ml，0°C )溶液中。移除冰浴並持續攪拌2 小時。濃縮該溶液，令再溶解於甲醇中，並載入強陽離子 交換樹脂管柱上。經甲醇冲洗後，藉由2 Μ氨之甲醇溶液 流洗該管柱以生成產物（自由鹼，2 5 0 mg，94% )。 】H-NMR(CDC13，500MHz) 5l.27(s，3H) ，1.28(s ，3H) ，2.41(d，J=11.3，lH) ，2.50(d，J=ll.3， 1H) ，2.69 (dd，J=12.5，7.9，1H) ，2.82 (dd，J 二Trifluoroacetic acid (1.5 ml) was added to 2- (di-tert-butoxycarbonylamino) -3- (7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo [4 , 3-c] D ratio π-a 5-yl)-methyl propionate (0.49 g, 1 equivalent) in a solution of CH2C12 (5 ml, 0 ° C). Remove the ice bath and continue stirring for 2 hours. The solution was concentrated, redissolved in methanol, and loaded on a strong cation exchange resin column. After washing with methanol, the column was washed with a 2 M ammonia solution in methanol to produce a product (free base, 250 mg, 94%). ] H-NMR (CDC13, 500MHz) 51.27 (s, 3H), 1.28 (s, 3H), 2.41 (d, J = 11.3, 1H), 2.50 (d, J = 11. 3, 1H), 2.69 (dd, J = 12.5, 7.9, 1H), 2.82 (dd, J 2

12.5，5.2，1H) ’ 3.45 (d，J=12.8，1H) ，3.52(d，J = 12.8，1H) ，3.67 (m，1H) ，3.69 (s，3H) ，7.19( s，1H )。質譜：25 3.1 6 ( MH ) +。 (±) — 2— { 〔4- (2 —酮基一1，4 —二氫一2H — 口奎唑 啉一 3-基）一 I派卩定—1—幾基〕一胺基} — 3一（i，4，6 ，7 —四氫一吡唑並〔4，3 — c〕吡啶一 5 —基）一丙酸甲 酯 -213- (209) 20052983512.5, 5.2, 1H) '3.45 (d, J = 12.8, 1H), 3.52 (d, J = 12.8, 1H), 3.67 (m, 1H), 3.69 (s, 3H), 7.19 (s, 1H). Mass spectrum: 25 3.1 6 (MH) +. (±) — 2— {[4- (2- keto-1,4-dihydro-1H—or quinazolin-3-yl) -I-Pyridin-1-1-yl] -amino group} — 3- (i, 4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-yl) monopropionate-213- (209) 200529835

將羰基二咪唑（188 mg，1當量）加入至 —(1，4，6，7 —四氫一吼唑並〔4，3— c〕I )—丙酸甲酯（260 mg，1當量）之CH2C12(: 溶液中。經1 5分鐘後，一次加入3 - _ Π定一 4 一 二氫一 1H —喹唑啉一2 —酮（295 mg，1.1當量 浴並持續隔夜攪拌。濃縮該反應溶液並藉由管 純化，生成118 mg ( 21% )。 W-NMR ( CDC13，5 00MHz ) 5 1.60 - 1.80 ( 2.70-3.05 (m，8H) ，3.45(s，2H) ，3· 13.4，1H) ，3.62(d，J=13.4，lH) ，3.75 4.02(d，J=13.1，lH) ，4.10(d，J 二 12 4.24(s，2H) ，4.45— 4.57 (m，2H) ，5.79 ，6.68 (d，J=7.94，1H ) ，6.90 (dd，J 二 7. )，7.00(d，J=7.3，lH) ，7.13(dd，J二 1 H ) ，7.25(s，lH) ，7.82(s，lH)。質譜 (Μ H ) + 。 實施例5 4 (±) — 4— (2 —酮基一1，4 —二氫一2H — 2 -胺基—3 批啶一5 —基 2 ml，0〇C ) 基一3，4 — ：)。移除冰 柱層析進行 m，4H )， 56 ( d，J = (s，3H )， .5，1 Η )， (bs，1 Η ) 3，7·3，1Η 7.6 ， 7·3 ， ·· 4 82.27 唑啉一 3 - -214- (210) 200529835 基）—哌啶—1 一羧酸〔2 — 〔 1，4 /〕聯帳啶一 1 / —基 —2_ 酮基一1— (1，4，6，7 —四氫一口比 口坐並〔4，3— c 〕吡啶一 5 —基甲基）一乙基〕一醯胺Add carbonyldiimidazole (188 mg, 1 equivalent) to — (1,4,6,7 —tetrahydromonozolo [4,3-c] I) -propionic acid methyl ester (260 mg, 1 equivalent) CH2C12 (: in solution. After 15 minutes, add 3-_ 定 定 定-4-dihydro-1H-quinazolin-2-ketone (295 mg, 1.1 equivalent bath and continue stirring overnight. The reaction was concentrated The solution was purified through a tube to yield 118 mg (21%). W-NMR (CDC13, 500 MHz) 5 1.60-1.80 (2.70-3.05 (m, 8H), 3.45 (s, 2H), 3.1.3, 1H ), 3.62 (d, J = 13.4, lH), 3.75 4.02 (d, J = 13.1, lH), 4.10 (d, J 2:12 4.24 (s, 2H), 4.45—4.57 (m, 2H), 5.79, 6.68 (d, J = 7.94, 1H), 6.90 (dd, J = 7.), 7.00 (d, J = 7.3, 1H), 7.13 (dd, J = 1 H), 7.25 (s, 1H), 7.82 (s, lH). Mass spectrum (MH) +. Example 5 4 (±) — 4— (2-keto-1,4-dihydro-2H-2 —amino-3 —pyridine-5 —yl 2 ml, 0 ° C) based on 3,4 — :). Remove the icicle chromatography and perform m, 4H), 56 (d, J = (s, 3H), .5, 1 Η), (bs, 1 Η) 3, 7 · 3, 1Η 7.6, 7 · 3 ， ·· 4 82.27 oxazoline-3--214- (210) 200529835 group) -piperidine-1 monocarboxylic acid [2 — [[1,4 /] biazidine-1 / -yl-2_ keto-1 — (1,4,6,7 —tetrahydro sits in one mouth and [4,3 — c] pyridine—5-ylmethyl) monoethyl] monofluorene

HH

將LiOH單水合物（3 mg，2.2當量）之水（0.1 ml) 溶液加入至2— { 〔4— (2 -酮基一 l，4 —二氫—2H—D奎 唑啉一 3 —基）一哌啶—1 一羰基〕—胺基丨—3 — ( 1，4 ，6，7 —四氫一吡唑並〔4，3 — c〕D比啶一 5 —基）一丙酸 甲酯（1 6 mg，1當量）之甲醇（〇· 6 ml )溶液中，並於室 溫下攪拌4小時。冷卻該溶液至〇 °c，加入1 Μ K H S 0 4 ( 6 0 // 1，1 · 8當量0水溶液，並經濃縮後產生粗酸，其係未經 純化而直接使用。將該粗酸溶解於二甲基甲醯胺（〇. 3 m 1 )中’隨後先後加入C Η 2 C 12 ( 〇 . 1 5 m 1 ) 、4 — Pjg π定基—_ D定（11 mg，2當量）、二異丙基乙胺（12//1，2當量）及 PyBOP® (19 mg’ 1·1當量）。攪拌該溶液3〇分鐘，並進 行濃縮。藉由管柱層析純化產物，生成17.6 mg ( 85%，2 步驟）。Add a solution of LiOH monohydrate (3 mg, 2.2 equivalents) in water (0.1 ml) to 2- {[4- (2-keto-l, 4-dihydro-2H-D quinazoline-3-yl ) 1-piperidine-1 monocarbonyl] -amino group 丨 3 — (1,4,6,7-tetrahydro-pyrazolo [4,3-c] D than pyridin-5-yl) monopropionate Ester (16 mg, 1 eq.) In methanol (0.6 ml) and stirred at room temperature for 4 hours. The solution was cooled to 0 ° C, and 1 M KHS 0 4 (6 0 // 1, 1.8 equivalents of 0 aqueous solution was added, and concentrated to produce a crude acid, which was used directly without purification. The crude acid was dissolved In dimethylformamide (0.3 m 1), then C Η 2 C 12 (0.1 5 m 1), 4 — Pjg π amidin — —D (11 mg, 2 equivalents), Diisopropylethylamine (12 // 1, 2 equivalents) and PyBOP® (19 mg '1.1 equivalents). The solution was stirred for 30 minutes and concentrated. The product was purified by column chromatography to yield 17.6 mg (85%, 2 steps).

3.59 ( d，J 】H-NMR ( CDC13，5 00MHz ) (5 1 · 3 0 — l · 6 〇 ( s，9 Η ), 1.62 — 1.78 ( m j 5 H ) ，1.81 (bd，J = 1 1 . 〇 , 2 H ) ，2.23 —2.4 9 ( m，6 H ) ，2 · 5 5 - 3 . I 0 ( m，1 ] H ) -215- (211) 200529835 = 7·3，2Η) ，4.00—4.20 (m，2H) ，4.23(s，2H)， 4.50 (m，lH) ，4.63(m，lH) ，5.03(m，lH) ^ 5.71 (d，J=7.3，1 H ) ，6.67 ( dd ^ J=7.9，1 H ) ，6.9 1 ( dd ，J=7.6，7.3，1H) ，7.02(dd，J=7.9，7.3，lH)， 7.14(dd，J=7.6，7.6，lH) ，7.24(s，lH) ^ 7.39 ( s ，：IH) ，10.76(bs，lH)。質譜：618.34(MH)+。3.59 (d, J) H-NMR (CDC13, 500 MHz) (5 1 · 3 0 — 1 · 6 〇 (s, 9 Η), 1.62 — 1.78 (mj 5 H), 1.81 (bd, J = 1 1 〇, 2 H), 2.23 —2.4 9 (m, 6 H), 2 · 5 5-3. I 0 (m, 1] H) -215- (211) 200529835 = 7.3, 2Η), 4.00 —4.20 (m, 2H), 4.23 (s, 2H), 4.50 (m, lH), 4.63 (m, lH), 5.03 (m, lH) ^ 5.71 (d, J = 7.3, 1 H), 6.67 ( dd ^ J = 7.9, 1 H), 6.9 1 (dd, J = 7.6, 7.3, 1H), 7.02 (dd, J = 7.9, 7.3, 1H), 7.14 (dd, J = 7.6, 7.6, 1H), 7.24 (s, lH) ^ 7.39 (s ,: IH), 10.76 (bs, lH). Mass spectrum: 618.34 (MH) +.

實施例5 5 (±) — 3- (7，7 —二甲基一1，4，6，7 —四氫一D比唑 哄〔4，3— c〕D 比啶一5 —基）一2— { 〔4— (2 —酮基一1 ，4 — _•氯一2H — D奎Π坐琳—3 —基）一喊H定一1 一端基〕一 胺基} 一丙酸甲酯Example 5 5 (±)-3- (7,7-dimethyl-1,4,6,7-tetrahydro-D-pyrazole (4,3-c) D-pyridine-5-yl)- 2— {[4 -— (2-keto-1, 4-—Chlorine-2H—D-quinoneline—3-yl) —H—H1—1 end group] —amino group} methyl propionate

將羰基二咪唑（162 mg，1當量）加入至2 —胺基—3 —(7，7 — 二甲基一1，4，6，7 —四氫一吼唑並〔4，3- c〕吼啶一5 —基）一丙酸甲酯（2 5 0 mg，1當量）之四氫 呋喃（4 ml，0 °C )溶液中。經5分鐘後，移除冰浴並於室 溫下攪拌該反應溶液3 0分鐘。一次加入3 —哌啶—4 一基一 3，4 —二氫—1H —喹唑啉—2 —酮（250 nig，1.1 當量）， 並隔夜攪拌該反應溶液。濃縮該反應溶液並藉由管柱層析 進行純化，生成2 2 8 m g ( 4 5 % )。 -216- 200529835 (212) ]H-NMR ( CDC13 ^ 5 00MHz) 5 1 .3 0 ( s，3 H ) ，：1.31 ( sAdd carbonyldiimidazole (162 mg, 1 eq.) To 2-amino-3- (7,7-dimethyl-1,4,6,7-tetrahydro-imidazo [4,3-c] Amidin-5-yl) monopropionate (250 mg, 1 equivalent) in a solution of tetrahydrofuran (4 ml, 0 ° C). After 5 minutes, the ice bath was removed and the reaction solution was stirred at room temperature for 30 minutes. Add 3-piperidine-4, 1-yl-3,4-dihydro-1H-quinazolin-2-one (250 nig, 1.1 equivalents) in one portion, and stir the reaction solution overnight. The reaction solution was concentrated and purified by column chromatography to give 228 mg (45%). -216- 200529835 (212)] H-NMR (CDC13 ^ 5 00MHz) 5 1 .3 0 (s, 3 H): 1.31 (s

，3H) ，1.60— 1.80(m，4H) ，2.43(d，J=11.6，]H )，2.53(d，J=11.3，lH) ，2.80—2.95 (m，4H)， 3.5 1 (dd，J二 20.4，13·1，2H) ，3.74 (s，3H) ，4.00 (d，J=13.7，lH) ，4.10(d，J=12.2，lH) ，4.25(, 3H), 1.60— 1.80 (m, 4H), 2.43 (d, J = 11.6,] H), 2.53 (d, J = 11.3, 1H), 2.80—2.95 (m, 4H), 3.5 1 (dd, J. 20.4, 13.1, 2H), 3.74 (s, 3H), 4.00 (d, J = 13.7, 1H), 4.10 (d, J = 12.2, 1H), 4.25 (

dd，J=16.2，14.2，2H) ，4.86(m，2H) ，6.66(d，J 二 7.6，1H) ，6.92(dd，J=7.6，7.3，lH) ，7.02(d， J=7.3，1H) ，7.14(dd，J=7.6，7.6，1H) ^ 7.24 ( s ，1H)。質譜：510.27( MH ) +。 實施例5 6 (土） 一 4 一 ( 2 —酬基一1 ’ 4 — _ 氣一2 Η 一 D 奎 口坐琳一3 — 基）一哌啶一 1 —羧酸〔2 —〔 1，4 /〕聯哌啶一 1 > 一基 —1— (7，7-二甲基一1，4，6，7 —四氫一口比唑並〔4, 3— c〕吡啶—5 —基甲基）—2 —酮基一乙基〕醯胺dd, J = 16.2, 14.2, 2H), 4.86 (m, 2H), 6.66 (d, J 7.6, 1H), 6.92 (dd, J = 7.6, 7.3, 1H), 7.02 (d, J = 7.3, 1H), 7.14 (dd, J = 7.6, 7.6, 1H) ^ 7.24 (s, 1H). Mass spectrum: 510.27 (MH) +. Example 5 6 (Earth) 1 4 1 (2 -Paid 1-1 '4-_ Qi-2 Η 1 D kuizuline-3 -yl) -piperidine-1 -carboxylic acid [2 — [1, 4 /] Bipiperidin-1 > mono-1- (7,7-dimethyl-1,4,6,7-tetrahydro-bizolop [4, 3-c] pyridin-5- (Methyl) -2-ketomonoethyl] fluorenamine

將LiOH單水合物（4 mg，2.2當量）之水（0· 1 ml ) 溶液加入至3— (7，7 —二甲基一 1，4，6，7 —四氫—吡 唑並〔4，3— c〕口比啶一5 —基）一2— { 〔4— (2 —酮基 —1，4 — 氣一2 Η — D奎口坐琳一3 —基）—呢D定一1 —類基 -217- 200529835 (213) 〕一fl女基丨—丙酸甲酯（20 mg，1.0當量）之甲醇（〇·6 ml )溶液中’並於室溫下攪拌4小時。冷卻該溶液至， 加入1 Μ K H S Ο 4 ( 7 5 # 1，1 . 8當量）水溶液，並經濃縮後 生成粗酸，其係未經純化而立即使用。令該粗酸溶解於二 甲基甲醯胺（0.3 mi)中，隨後先加入ml) 、4 一哌啶基一哌啶（1 3 mg，2當量）、二異丙基乙胺（ 14//1，2 當量）及 pyB0P® (22 MG，1.1 當量）。攪拌該 溶液1 · 5小時並進行濃縮。藉由管柱層析純化產物，生成 污染Η Ο B T之產物。令該產物通過鹼性氨之塞物並經】〇 % 甲醇之CH2C12溶液洗以除去ΗΟΒΤ。經濃縮產生18.3 mg ( 7 2 %，2 步驟）。 】H-NMR ( CDC13，5 00MHz ) 5 1 · 2 5 - 1 · 3 2 ( m，6 Η )， 1.40(m，4H) ，1.54(m，5H) ，1.65(m，4H) ，1.83 (m，2H) ，2.30—2.56 (m，8H) ，2.81 (m，4H)， 3.04 (dt，J=57.1，12.2，1H) ，3.43—3.60 (m，2H) ，4.00— 4.17 (m，2H) ，4.18— 4.26 (m，3H) ，4.49 ( m’lH) ，4.62( m，lH) ，5·03(ηι，1Η) ，5.80(dd， J=16.8，9.8，1H) ，6.69(d，J=7.9，1H) ，6.90(dd ，J=7.3，7.3，1H) ，6.99(dd，J=7.6，7.3，lH)， 7.13 (dd，J=7.6，7·6，1H) ，7.19(s，1H) ，7.66( bd，J=12.8，1H)。質譜：646·43 (MH) +。 2—节氧類基胺基一 3 —（6 —甲氧基—D比π定一 3 -基）一丙 烯酸甲酯 -218- (214) (214)200529835A solution of LiOH monohydrate (4 mg, 2.2 equivalents) in water (0.1 ml) was added to 3- (7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo [4 ， 3— c] oxopyridine-5—yl) —2— {〔4— (2-keto-1,4—qi-1 2 Η — D Kuikouline 1-3-yl) —then D fixed one 1-type group-217- 200529835 (213)] -fl-methylene group-methyl propionate (20 mg, 1.0 equivalent) in a methanol (0.6 ml) solution 'and stirred at room temperature for 4 hours. The solution was cooled to 1 M K H S 0 4 (7 5 # 1, 1.8 equivalents) aqueous solution was added and concentrated to form a crude acid, which was used immediately without purification. The crude acid was dissolved in dimethylformamide (0.3 mi), followed by ml), 4-piperidinyl-piperidine (1 3 mg, 2 equivalents), and diisopropylethylamine (14 / / 1, 2 equivalents) and pyB0P® (22 MG, 1.1 equivalents). The solution was stirred for 1.5 hours and concentrated. The product was purified by column chromatography to yield a product contaminating Η Ο B T. The product was passed through a plug of basic ammonia and washed with 0% methanol in CH2C12 solution to remove ΒΒΤ. Concentrated to produce 18.3 mg (72%, 2 steps). ] H-NMR (CDC13, 5 00MHz) 5 1 · 2 5-1 · 3 2 (m, 6 Η), 1.40 (m, 4H), 1.54 (m, 5H), 1.65 (m, 4H), 1.83 ( m, 2H), 2.30—2.56 (m, 8H), 2.81 (m, 4H), 3.04 (dt, J = 57.1, 12.2, 1H), 3.43—3.60 (m, 2H), 4.00— 4.17 (m, 2H ), 4.18-4.26 (m, 3H), 4.49 (m'lH), 4.62 (m, lH), 5.03 (η, 1Η), 5.80 (dd, J = 16.8, 9.8, 1H), 6.69 (d , J = 7.9, 1H), 6.90 (dd, J = 7.3, 7.3, 1H), 6.99 (dd, J = 7.6, 7.3, 1H), 7.13 (dd, J = 7.6, 7.6, 1H), 7.19 (s, 1H), 7.66 (bd, J = 12.8, 1H). Mass spectrum: 646 · 43 (MH) +. 2-Ethoxybenzylamino- 3-(6-methoxy-D than π-A fixed 3-methyl) -monoacrylate -218- (214) (214) 200529835

將N—苄氧羰基一 α -亞磷羧基甘胺酸三甲酯（3.63 g，1·5當量）之CH2C12 ( 15 ml )溶液加入至特丁氧化鉀 (1.23 g，1 .5當量）之 CH2C12 ( 70 ml，一 20t：)懸浮液 中。攪拌所生成之溶液5分鐘，隨後與6 -甲氧基-吡啶-3 —醛（10.0 g，7.3毫莫耳）之CH2C12(15 ml)溶液反應 。經攪拌1 . 5小時後，令該反應溶液回溫至0 °C，隨後攪拌 1小時。將該反應溶液迅速地倒入至含有乙酸乙酯和水之 分離漏斗中。加入鹽水以幫助相層分離。利用乙酸乙酯（ 3 X )萃取水層，隨後經鹽水冲洗，置於μ g S Ο 4上乾燥，經 濃縮後生成2.63 g (定量），其係未經純化而使用。質譜 :343.08 ( MH )+。 (±) — 2 —胺基一 3— (6 —甲氧基一吡啶一 3 —基）一丙 酸甲酯A solution of N-benzyloxycarbonyl-α-phosphorous carboxyglycine trimethyl ester (3.63 g, 1.5 equivalents) in CH2C12 (15 ml) was added to potassium tetrabutoxide (1.23 g, 1.5 equivalents). CH2C12 (70 ml, 20t :) suspension. The resulting solution was stirred for 5 minutes, and then reacted with a solution of 6-methoxy-pyridine-3-aldehyde (10.0 g, 7.3 mmol) in CH2C12 (15 ml). After stirring for 1.5 hours, the reaction solution was allowed to warm to 0 ° C, followed by stirring for 1 hour. The reaction solution was quickly poured into a separating funnel containing ethyl acetate and water. Brine was added to help separate the layers. The aqueous layer was extracted with ethyl acetate (3X), then washed with brine, dried on μg S 04, and concentrated to give 2.63 g (quantitative), which was used without purification. Mass spectrum: 343.08 (MH) +. (±) — 2-amino-3- (6-methoxy-pyridine-3-yl) monopropionate

在最終連接添加氫氣球形瓶之前，先後利用氮氣和氫 氣冲洗含有2 —干氧羯基胺基—3 -（6 —甲氧基—吼1]定—3 —基）一丙烯酸甲酯（6 2 0 m g ) 、P d / C ( 1 0 %，] 〇 〇 m g -219- (215) 200529835 )、乙酸乙酯（10 )及甲醇（20 mi )之燒瓶。隔夜攪 拌該反應溶液。利用氮氣冲洗該燒瓶，通過寅氏鹽過濾， 經濃縮生成3 9 0 m g (定量），其係未經純化而使用。質譜 :21 1 · 1 1 ( MH) +。 (±) — 3— (6 —甲氧基一 D 比 π定一 3 — 基）一2 — { 〔4 — (2-酮基—1，4 —二氫一 2H — D奎唑啉—3 -基）一哌啶 —1 一羰基〕一胺基} 一丙酸甲酯 ΗBefore the final addition of the hydrogen-filled spherical flask, nitrogen and hydrogen were used to flush the methyl acrylate containing 2-dryoxyfluorenylamino-3- (6-methoxy-l-methyl-1) -3-methyl) (6 2 0 mg), P d / C (10%,] 00 mg -219- (215) 200529835), ethyl acetate (10) and methanol (20 mi) flasks. The reaction solution was stirred overnight. The flask was flushed with nitrogen, filtered through Yin's salt, and concentrated to give 390 mg (quantitative), which was used without purification. Mass spectrum: 21 1 · 1 1 (MH) +. (±) — 3— (6 —methoxy-D ratio to π-a-3 — group) — 2 — {[4 — (2-keto-1,4-dihydro-1H—D quinazoline-3 -Yl) monopiperidine-1 monocarbonyl] monoamino} methyl propionate

將N ’ N /〜二琥珀醯亞胺碳酸酯（1 5 8 mg )加入至2 一胺基一3— (6〜甲氧基—吡啶一 3 —基）一丙酸甲酯（ 130mg)和二異丙基乙胺（〇·3ηιι)之 cH2Cl2(2ml，（TC )溶液中。經3 0分鐘後，藉由套管加入3 一哌啶—4 —基一 3，4一 二氫一1Η〜喹唑啉一 2 —酮（120 mg)之 CH2C12( 1 ml )溶液。令該反應溶液回溫至室溫並隔夜攪拌。濃縮 該反應溶液並經製備性Η P L C純化後，生成1 6 0 m g ( 5 5 % )。質譜：468.19(MH) +。 實施例5 7 (±) — 4— (2 〜酮基—；ι，4 —二氫一 2H —喹唑啉一 3 — 基）一哌啶—1〜羧酸〔2 —〔丨，4 /〕聯哌啶_】-一基 -220 - (216) 200529835 —1— (6 一甲氧基一D比Π定一 3 —基甲基）一 2—嗣基一乙基 〕一醯胺 Η ki r\N'N / ~ disuccinimide imide carbonate (158 mg) was added to 2-monoamino-3- (6-methoxy-pyridine-3-yl) monopropionate (130mg) and Diisopropylethylamine (0.3ml) in a solution of cH2Cl2 (2ml, (TC). After 30 minutes, add 3-piperidin-4-yl-1,3,4-dihydro-1, 1Η through the cannula. ~ Chlorazolin-2-one (120 mg) in CH2C12 (1 ml). Allow the reaction solution to warm to room temperature and stir overnight. Concentrate the reaction solution and purify it with preparative ΗPLC to produce 1 6 0 mg (55%). Mass spectrum: 468.19 (MH) +. Example 5 7 (±) — 4 — (2 ~ keto —; ι, 4 —dihydro — 2H — quinazoline — 3 —yl) — Piperidine-1 ~ carboxylic acid [2 — [丨, 4 /] bipiperidine _]-monoyl-220-(216) 200529835 —1— (6 monomethoxy-D ratio Π fixed 3 -ylmethyl Group)-2-fluorenyl monoethyl]-hydrazine Η ki r \

將Li OH單水合物（29 mg )之水（1 ml )溶液加入至3 —(ό —甲氧基一吼卩定—3 —基）一2— { [ 4 — (2 酬基 —1，4一二氫一 2Η—喹唑啉—3 —基）一_啶一1 一羰基 〕一胺基} 一丙酸甲酯（160 mg)之甲醇（6 ml)溶液中 。室溫下攪拌該反應溶液4小時並隨後冷卻至0 °C。將1 N H CI ( 0.6 ml )加入該反應溶液中並進行濃縮。令所得到 之殘餘物溶解於C Η 2 C 11 2 ( 5 m 1 )中’隨後先後加4 呢'B疋 基一哌啶（75 mg)、三乙胺（〇·14 ml)及雙一 （2-酮 基—3 — Π惡唑烷基）次膦醯氯1 〇4 mg )。隔夜攪拌該反應 溶液，隨後經濃縮及製備HPLC^化後’生成94 mg ( 45% )° LC/MC: tR=1.86分 ’ 604.51 (MH) + 〇 1 -苄氧羰基胺基—3-（2—甲氧基一嘧啶一 5—基）一丙 2 烯酸甲酯 (217) 200529835A solution of Li OH monohydrate (29 mg) in water (1 ml) was added to 3 — (ό —methoxy-monoamidine — 3 —yl) — 2 — {[4 — (2 4-dihydro-2,2-quinazoline-3-yl) -pyridine-1, 1-carbonyl] -amino} monopropionate (160 mg) in methanol (6 ml). The reaction solution was stirred at room temperature for 4 hours and then cooled to 0 ° C. 1 N H CI (0.6 ml) was added to the reaction solution and concentrated. The resulting residue was dissolved in C Η 2 C 11 2 (5 m 1) 'Successively followed by 4' 'B fluorenyl-piperidine (75 mg), triethylamine (0.14 ml) and bis-one (2-keto-3—IIoxazolidinyl) phosphiniumphosphonium chloride (104 mg). The reaction solution was stirred overnight, followed by concentration and preparative HPLC, which yielded 94 mg (45%) ° LC / MC: tR = 1.86 minutes' 604.51 (MH) + 〇1-benzyloxycarbonylamino-3- ( 2-methoxymonopyrimidin-5-yl) monopropenoic acid methyl ester (217) 200529835

CO〇Me CBZHNCO〇Me CBZHN

OMe 將N —苄氧羰基一 α -亞磷羧基甘胺酸三甲酯（3.63 g )之二氯甲烷（1 5 ml )溶液加入至特丁氧化鉀（1.23 g )之CH2C12 ( 70 ml，一 30°C )懸浮液中。攪拌所生成之 溶液5分鐘，隨後加入2 -甲氧基—嚼b定一 5 -醒（1 · 〇 g ) 之CH2C12 ( 1 5 ml )溶液。經攪拌；[·5小時後，令該反應溶 液回溫至〇 °C並攪拌1小時。將該反應溶液迅速地倒入至含 有乙酸乙酯之分離漏斗中。加入鹽水以幫助相層分離。利 用乙酸乙酯（3 X )萃取水層，隨後經鹽水冲洗，置於 MgSCU上乾燥，並進行濃縮。自熱甲醇中再結晶粗產物以 生成純物質（1.4g)。質譜：344·10(ΜΗ) +。OMe Add a solution of N-benzyloxycarbonyl-α-phosphorous carboxyglycine trimethyl ester (3.63 g) in dichloromethane (15 ml) to CH2C12 (70 ml, 1 t-potassium oxide) (1.23 g) 30 ° C) suspension. The resulting solution was stirred for 5 minutes, followed by the addition of a 2-methoxy-b-a solution of 5-awakening (1.0 g) in CH2C12 (15 ml). After stirring; [· 5 hours later, the reaction solution was warmed to 0 ° C and stirred for 1 hour. The reaction solution was quickly poured into a separating funnel containing ethyl acetate. Brine was added to help separate the layers. The aqueous layer was extracted with ethyl acetate (3 ×), then washed with brine, dried over MgSCU, and concentrated. The crude product was recrystallized from hot methanol to give pure material (1.4 g). Mass spectrum: 344 · 10 (ΜΗ) +.

(土）〜2 —胺基一3 — （2 —甲氧基一嘧u定一 5 —基）一丙 酸甲酯(Earth) ~ 2-Amino- 3-(2-methoxy-pyrimidine- 5 -yl) monopropionate

OMe 在最終連接添加氫氣球形瓶之前，先後利用氮氣和氫 氣冲洗含有胺基酯（7 0 0 m g ) 、P d / C ( 1 0 %，1 0 0 m g ) & ¥ _ ( 20 ml)之燒瓶。隔夜攪拌該反應溶液。利用氮 /氣冲洗該燒瓶，通過寅氏鹽過濾，並經濃縮以生成3 7 9 mg -222 - (218) 200529835 (88%) ’其係未經純化而使用。質譜：2 1 2.0 8 ( Μ Η ) + (土）一 3— (2— 甲氧基—嘧啶一 5 一基）一 2— { 〔4一 (2 —酮基一1，4 —二氫一 2H - D奎Π坐啉一 3 —基）一哌D定 一 1 一羰基〕一胺基} 一丙酸甲酯 將Ν，ΝOMe Before the final addition of the hydrogen-filled spherical flask, nitrogen and hydrogen were used to flush the amine ester (700 mg), Pd / C (100%, 100 mg), and ¥ _ (20 ml). Flask. The reaction solution was stirred overnight. The flask was flushed with nitrogen / gas, filtered through Yin's salt, and concentrated to give 397 mg -222-(218) 200529835 (88%) 'which was used without purification. Mass spectrum: 2 1 2.0 8 (Μ Η) + (Earth)-3-(2-methoxy-pyrimidine-5-1)-2-{[4-(2-keto-1, 4-dihydro-1 2H-D quinoline oxoline 3 -yl) 1 piperidine D 1-1 carbonyl] monoamino} methyl propionate will be N, N

ΗΗ

二琥珀醯亞胺碳酸酯（155 mg)加入至2Disuccinimidyl carbonate (155 mg) was added to 2

一胺基一3— (2 —甲氧基嘧啶一 5 —基）一丙酸甲酯（125 mg )和二異丙基乙胺（0.3 ml )之 CH2C12 ( 2 ml，0°C ) 溶液中。經3 0分鐘後，藉由套管加入3 —哌啶—4 —基一 3 ，4 —二氫—1H—D奎 D坐啉—2 —酮（120 mg)之 CH2C】2(2 ml )溶液。令該反應溶液回溫至室溫並隔夜攪拌。濃縮該 反應溶液並經製備性Η P L C純化後，生成9 9 m g ( 3 6 % )。 質譜：469·10(ΜΗ) +。 實施例5 8 (土）一4— (2 —酮基一1，4一二氫一2Η — D奎唑啉一 3 — 基）一哌啶一 1 一羧酸〔2 — 〔 1，4 /〕聯哌啶一 ]/ 一基 —】一（2 —甲氧基—喃D定一 5 —基甲基）一2—酮基—乙基 〕一醯胺 -223 - (219) 200529835 ΗMonoamine-3- (2-methoxypyrimidin-5-yl) monopropionate (125 mg) and diisopropylethylamine (0.3 ml) in a solution of CH2C12 (2 ml, 0 ° C) . After 30 minutes, 3-piperidin-4-yl-3,4-dihydro-1H-D-quinoline-2-ketone (120 mg) of CH2C] 2 (2 ml) was added through a cannula. Solution. The reaction solution was allowed to warm to room temperature and stirred overnight. After concentrating the reaction solution and purifying it with preparative ΗPLC, 9.9 mg (36%) was produced. Mass spectrum: 469 · 10 (ΜΗ) +. Example 5 8 (Earth) -4- (2-keto-1,4-dihydro-1, 2Η-D-quinazoline-3-yl) -piperidine-1 1-carboxylic acid [2-[1, 4 / 〕 Bipiperidinyl]] / monoyl —] mono (2-methoxy-pyranyl-1, 5-methyl) 2-keto-ethyl] monoamidine-223-(219) 200529835 Η

將L i Ο Η單水合物（1 8 m g )之水（1 πι1 )溶液加入至3 一 （2 —甲氧基一嘧啶一 5 —基）一 2- {〔 4一 一酮基 一 1，4一二氫——喹D坐啉一 3 —基）一_卩定一丨―幾基 〕一胺基}—丙酸甲酯（99 mg )之甲醇（6 mI )溶液中 。室溫下攪拌該反應溶液4小時並冷卻至〇°C °將1N HC1 ( 0.4 ml )加入該反應溶液中並進行濃縮。令所生成之殘餘 物溶解於C Η 2 C 1 2 ( 3 m 1 )中，並先後加入4 一 US啶基—哌 U定（50 mg)、三乙胺（88#1)及雙一（2 -酮基一 D惡〇坐 烷基）次膦醯氯（7 1 mg )。隔夜攪拌該反應溶液，並經 濃縮及製備性HPLC純化後，生成103 mg ( 45% )。 LC/MS : tR= 1.23 分，605.54 ( MH) + 〇 2 —卡氧基一 5 -漠—吼D定Add a solution of L i 0 Η monohydrate (18 mg) in water (1 πι1) to 3-(2-methoxy-pyrimidin-5-yl)-2-{[4-one-keto-1, 4-dihydro-quino-daziline-3-yl)-hydrazine-1-several aryl] -amino} -propionic acid methyl ester (99 mg) in methanol (6 ml) solution. The reaction solution was stirred at room temperature for 4 hours and cooled to 0 ° C °. 1N HC1 (0.4 ml) was added to the reaction solution and concentrated. The resulting residue was dissolved in C Η 2 C 1 2 (3 m 1), and 4-US-pyridyl-piperidine (50 mg), triethylamine (88 # 1), and bis- ( 2-keto-Doxoalkyl) phosphiniumphosphonium chloride (71 mg). The reaction solution was stirred overnight and concentrated and purified by preparative HPLC to yield 103 mg (45%). LC / MS: tR = 1.23 points, 605.54 (MH) + 〇 2 -caroxy- 5-Mo-D

於配置有Dean-Stark阱之裝置中，於迴流狀態下加熱 2，5 —二溴吡啶（2.0 g，8.4毫莫耳）、二苯並一 18—冠 —6(0.14 g，0.05 當量）、苄醇（1.1 ml，1.3 當量）及 KOH ( 1 · 1 g，2.4當量）之甲苯（30 ml )懸浮液3小時。 冷卻該懸浮液，經濃縮後懸浮於水中，並經C H 2 C 12萃取。 -224 - (220) 200529835 先後利用水和鹽水冲洗結合之有機層，置於M g S Ο 4上乾燥 ，經濃縮後生成1 . 9 g ( 8 5 % )，其係未經純化而使用。 質譜：264.25 ( MH ) +。In a device equipped with a Dean-Stark trap, heat 2,5-dibromopyridine (2.0 g, 8.4 mmol), dibenzo-18-crown-6 (0.14 g, 0.05 equivalent) under reflux, Suspension of benzyl alcohol (1.1 ml, 1.3 equivalents) and KOH (1.1 g, 2.4 equivalents) in toluene (30 ml) for 3 hours. The suspension was cooled, concentrated, suspended in water, and extracted with CH 2 C 12. -224-(220) 200529835 The combined organic layer was washed with water and brine, dried over M g S 0 4, and concentrated to produce 1.9 g (85%), which was used without purification. Mass spectrum: 264.25 (MH) +.

將正丁基鋰（2.5M己烷溶液，2.61 ml，1.05當量）加 入至2 —苄氧基—5—溴一吡啶（1.64 g，6.2毫莫耳）之四 氫呋喃（2 5 ml，一 7 8 °C )溶液中。於—7 8 °C下經1小時後 ，加入二甲基甲醯胺（0.97 ml，2當量）並攪拌該反應混 合物30分鐘。將該反應溶液迅速地倒入至5% NaHC03之 攪拌水溶液（5 0 ml )中並利用二乙醚（3 X )進行萃取。 利用鹽水冲洗該乙醚液，置於MgS04上乾燥，經濃縮後生 成1 .16 g (定量），其係未經純化而使用。質譜：186.34 (Μ Η ) + 〇 2—苄氧鑛基胺基一 3 —（6—苄氧基一吡啶—3 —基）—丙 烯酸甲酯 - 225 - (221) 200529835Add n-butyllithium (2.5M hexane solution, 2.61 ml, 1.05 equivalents) to 2-benzyloxy-5-bromo-pyridine (1.64 g, 6.2 mmol) tetrahydrofuran (2 5 ml, 7 8 ° C) in solution. After 1 hour at -7 ° C, dimethylformamide (0.97 ml, 2 equivalents) was added and the reaction mixture was stirred for 30 minutes. The reaction solution was quickly poured into a stirred aqueous solution (50 ml) of 5% NaHC03 and extracted with diethyl ether (3 ×). The ether solution was washed with brine, dried on MgS04, and concentrated to produce 1.16 g (quantitative), which was used without purification. Mass spectrum: 186.34 (Μ Η) + 〇2-benzyloxyaminoamino-3- (6-benzyloxy-pyridin-3-yl) -methyl acrylate-225-(221) 200529835

Y°Y °

於一 20 °c下將Ν —苄氧羰基一α -亞磷羧基甘胺酸三 甲酯（1.3 g，1.7當量）之CH2C12(5 ml)溶液加入至特 丁氧化鉀（0.440 g，1.7當量）之CH2C12 ( 25 ml )攪拌懸 浮液中。攪拌所生成之溶液5分鐘，隨後令其與6 -苄氧基 一吡啶—3—醛（0.49 g，2,28 毫莫耳）之 CH2C12(5 ml) 溶液反應。於- 20 °C下攪拌該反應溶液1小時，隨後令其 緩慢地回溫至0 °C，並將其倒入至含有水和二乙醚之分離 漏斗中。利用二乙醚（2 X )萃取該反應溶液，經鹽水冲洗 ’置於MgS04上乾燥，經濃縮後生成0.98 g (定量）之油 狀物，其係未經純化而使用。質譜：4 1 9 · 3 2 ( Μ Η ) 4。 (土）一 2—苄氧锻基胺基一 3 — （6 —苄氧基一口比Π定一 3 -基）一丙酸甲酯A solution of N-benzyloxycarbonyl-α-phosphorous carboxyglycine trimethyl ester (1.3 g, 1.7 equivalents) in CH2C12 (5 ml) was added to potassium tetrabutoxide (0.440 g, 1.7 equivalents) at -20 ° C. ) Of CH2C12 (25 ml) in a stirred suspension. The resulting solution was stirred for 5 minutes, and then reacted with a solution of 6-benzyloxy-pyridine-3-aldehyde (0.49 g, 2,28 mmol) in CH2C12 (5 ml). The reaction solution was stirred at -20 ° C for 1 hour, then slowly allowed to warm to 0 ° C and poured into a separation funnel containing water and diethyl ether. The reaction solution was extracted with diethyl ether (2X), washed with brine, dried over MgS04, and concentrated to give 0.98 g (quantitative) of an oil, which was used without purification. Mass spectrum: 4 1 9 · 3 2 (ΜΗ) 4. (Earth) a 2-benzyloxy forthylamino group 3-(6 -benzyloxy group mouth ratio than a 3 -yl) monopropionate methyl ester

- 226 - (222) 200529835 將2-爷氧羯基胺基一 3-（6 -节氧基一 DttH定一 3-基 )—丙烯酸甲酯（0.50 g，1.2毫莫耳）、Wilkinson氏觸 媒（200 mg，0.2當量）、甲醇（5 ml )及甲苯（3 ml )載 入燒瓶中。先後利用氮氣和氫氣冲洗該燒瓶，隨後加熱至 3 5 °C，並於氫氣下攪拌4天。利用氮氣冲洗該反應溶液， 經甲醇稀釋，並經過濾和濃縮後生成粗產物，其係經管柱 層析純化後生成1 4 5 m g ( 2 9 % )。 (±) — 2—胺基一3— (6—节氧基一口比D定一3 —基）一丙 酸甲酯-226-(222) 200529835 2-Ethyloxyamidoamino-3- (6-benzyloxy-DttH-a-3-yl) -methyl acrylate (0.50 g, 1.2 mmol), Wilkinson's contact Vehicle (200 mg, 0.2 equivalent), methanol (5 ml) and toluene (3 ml) were charged into the flask. The flask was flushed with nitrogen and then hydrogen, then heated to 35 ° C and stirred under hydrogen for 4 days. The reaction solution was flushed with nitrogen, diluted with methanol, and filtered and concentrated to produce a crude product, which was purified by column chromatography to yield 145 mg (29%). (±) — 2-amino-3- (6-benzyloxy) than methyl 3-propanyl monopropionate

& 將三甲基甲矽烷基碘化物（44 // 1，1 · 〇當量）加入至 2—苄氧羰基胺基一 3 - （6 —苄氧基—吡啶一3 —基）一丙 酸甲酯（130 mg，0.31毫莫耳）之 CH2C12 ( 5 ml，0°C ) 之攪拌溶液中。移除冰浴並持續攪拌1小時。將該反應溶 液倒入至飽和NaHC03溶中，經乙酸乙酯（3x )萃取，並 經鹽水冲洗，置於Mg S04上乾燥，且經濃縮後生成81 mg (91 % )，其係未經純化而使用。質譜：2 8 7.3 7 ( ΜΗ ) + (±) — 3— (6 —苄氧基一吡啶一 3 —基）一 2— { 〔4 — (2 -酮基—1，4 —二氫—2 Η —喹唑啉一 3 —基）一丨派啶 - 227- (223) 200529835 一 1—羰基〕一胺基} 一丙酸甲酯& Add trimethylsilyl iodide (44 // 1,1 · 0 equivalents) to 2-benzyloxycarbonylamino-3-(6-benzyloxy-pyridine-3 -yl) monopropionic acid Methyl ester (130 mg, 0.31 mmol) in a stirred solution of CH2C12 (5 ml, 0 ° C). Remove the ice bath and continue stirring for 1 hour. The reaction solution was poured into saturated NaHC03 solution, extracted with ethyl acetate (3x), washed with brine, dried on Mg S04, and concentrated to produce 81 mg (91%), which was not purified. While using. Mass spectrum: 2 8 7.3 7 (ΜΗ) + (±) — 3— (6-benzyloxy-pyridine-3—yl) —2— {[4 — (2-keto-1,4-dihydro-2 Η —quinazoline-3 —yl) -Pyridine- 227- (223) 200529835 1 -carbonyl] monoamino} methyl propionate

將羰基二咪唑（34 mg，1.0當量）加入至2 -胺基一 3 一 （6—节氧基一 D比η定一3 —基）一丙酸甲醋（60 mg’ 0.21毫莫耳）之CH2C12 ( 1 ml，0°C )攪拌溶液中。經15 分鐘後，藉由套管加入3 —哌啶—4 一基一 3，4 —二氫一 1 Η 一 D 奎 Π坐琳—2 —嗣（58 mg，1.2 當量）之 CH2Cl2(〇.5 ml )溶液。移除冰浴並持續隔夜攪拌。濃縮反應溶液並經 管柱層析純化後，生成59 mg ( 52% )。質譜：544.49 (MH) + 。 實施例5 9 (±) — 4— (2 -酮基一1，4一 二氫一 2H -喹唑啉一3 — 基）一哌啶一 1 一羧酸〔1 一 （ 6 —苄氧基—吡啶一 3 —基甲 基）一 2— 〔1，〕聯哌啶一厂—基一 2-酮基一乙基 〕一醯胺 - 228 - (224) (224)200529835 ΗAdd carbonyldiimidazole (34 mg, 1.0 eq.) To 2-amino-3,3- (6-benzyloxy-D ratio η-a-3) -methyl propionate (60 mg '0.21 mmol) CH2C12 (1 ml, 0 ° C) in a stirred solution. After 15 minutes, 3-piperidine-4, 4-dihydro-1, 3,4-dihydro-1, 1-D-quinolinium-2, 2- (1, 5-mg) (58 mg, 1.2 equivalents) of CH2Cl2 (0. 5 ml) solution. Remove the ice bath and continue to stir overnight. The reaction solution was concentrated and purified by column chromatography to yield 59 mg (52%). Mass spectrum: 544.49 (MH) +. Example 5 9 (±) — 4 — (2-keto-1,4-dihydro-2H-quinazoline-3-yl) -piperidine-1 1-carboxylic acid [1 1- (6-benzyloxy) —Pyridine —3-methyl — 2 — [1,] piperidine 1 plant — 2-methyl-2-keto-ethyl] -amidine-228-(224) (224) 200529835 Η

將Li〇H單水合物（9.1 mg，2當量）之水（0.5 ml) 溶液加入至3 — （6 —苄氧基一吡卩定一 3 一基）—2一丨〔4 一 （2 —酮基一 1，4 一二氫一 2H—D奎唑啉—3 —基）—哌 D定一；[一羰基〕一胺基} 一丙酸甲酯（59 mg，0.11毫莫耳 )之甲醇（3 ml )攪拌溶液中。室溫下攪拌該反應溶液2 小時，隨後冷卻至〇 °C，藉由加入1 N H c 1 ( 0 · 1 5 m 1 )以中 止反應，並進行濃縮。該粗產物未經純化而使用。令該粗 酸溶解於dCh ( 2 ml，〇°C )中隨後先後加4 一哌啶基— _啶（34 mg，1.8當量）、三乙胺（35 //】，2.3當量）及 雙一（2 -酮基一 3-噁唑烷基）次膦醯氯（34 mg，1.2當 量）。移除冰浴並隔夜攪拌該反應溶液。濃縮該反應溶、液 並藉由製備性HPLC進行純化，生成30·3 mg ( 41% )。 LC/MS : tR 二 1·49 分，680.29 ( ΜΗ) +。 實施例60 (土） — 4一 （2 —酮基—ι，4 —二氫一2H-D奎唑啉 一3一 基）一哌啶一1 一羧酸〔2 - 〔 1，4 /〕聯哌啶一 1 - 一基 一 2—酮基一 1— (6 —酮基—]，6—二氫—吡啶〜3〜基甲 基）一乙基〕一醯胺 -229 - (225) 200529835 Η Μ Γ\A solution of LiOH monohydrate (9.1 mg, 2 equivalents) in water (0.5 ml) was added to 3-(6-benzyloxy-pyridoxine-3 -yl)-2-[4-(2- Keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine; [monocarbonyl] -amino} methyl propionate (59 mg, 0.11 mmol) Methanol (3 ml) was stirred in the solution. The reaction solution was stirred at room temperature for 2 hours, then cooled to 0 ° C, the reaction was stopped by adding 1 N H c 1 (0 · 15 m 1), and concentrated. This crude product was used without purification. The crude acid was dissolved in dCh (2 ml, 0 ° C), and then 4-piperidinyl-pyridine (34 mg, 1.8 equivalents), triethylamine (35 //), 2.3 equivalents, and dione were added successively. (2-keto-3-oxazolidinyl) phosphiniumphosphonium chloride (34 mg, 1.2 equivalents). The ice bath was removed and the reaction solution was stirred overnight. The reaction solution was concentrated and purified by preparative HPLC to give 30.3 mg (41%). LC / MS: tR 1.49 minutes, 680.29 (ΜΗ) +. Example 60 (Earth)-4- (2-keto-ι, 4-dihydro- 2H-D quinazoline- 3-yl) -piperidine- 1 -carboxylic acid [2-[1, 4 /] Bipiperidine 1-1-1-2-keto 1-(6-keto-], 6-dihydro-pyridine ~ 3 ~ ylmethyl) monoethyl]-amidamine-229-(225) 200529835 Η Μ Γ \

氫一 2H—D奎唑啉一3 —基 氧基一 D比0定一 3 —基甲基 一基—2 —嗣基一乙基〕Hydrogen- 2H-D quinazoline-3-yloxy-D ratio 0 to 1-3-methylmethyl-yl-2 -fluorenyl-ethyl]

Pd/ C ( 1 0%，4 mg )及 利用氮氣和氫氣冲洗該燒 利用氮氣冲洗該燒瓶，經 成 22.1 mg (94%) 〇Pd / C (10%, 4 mg) and flushing the flask with nitrogen and hydrogen. The flask was flushed with nitrogen to produce 22.1 mg (94%).

將 4一（2基一 1,4一二 )一派D定—1 一殘酸〔1 一（6 -)—2 — 〔 1，4，〕聯哌啶—厂 一醯胺（27 mg，〇·〇4毫莫耳）、 甲醇（1 m 1 )載入燒瓶中。先後 瓶，並於氫氣下進行隔夜攪拌。 通過寅氏鹽過濾該反應溶液，生 LC/MS: tR=〇.93 分，590.32 (MH) + 〇 _啶一 1，4 一二羧酸 1 一特丁酯 4 一乙酯Assign 4-a (2-base-1,4-1,2) -D-D-1 to 1-residual acid [1- (6-)-2— [1,4,] bipiperidine-plantaramide (27 mg, 〇 〇4 millimolar), methanol (1 m 1) were loaded into the flask. The bottles were successively stirred overnight under hydrogen. The reaction solution was filtered through yin salt, and LC / MS was obtained: tR = 0.93 min, 590.32 (MH) + 〇-pyridine-1, 4-dicarboxylic acid 1 t-butyl ester 4 monoethyl ester

於〇°C下將二碳酸二特丁酯（7.2 g，0.033莫耳）之 CH2C12 ( 25 ml )溶液緩慢地力口入至異_啶酸乙酯（5·〇〇 g ’ 0.032 吳耳）和二乙胺（4.9 mi，〇·〇35 莫耳）之 ch2C12 (25 ml )溶液中。室溫下隔夜攪拌該反應混合物，隨後 經KHSO4溶液冲洗3次及經鹽水冲洗1次。將有機萃取液置 於無水Na2S〇4上乾燥，經過濾和真空下濃縮後生成無色油 - 230- "、 (226)200529835 狀之所欲產物（ ]H NMR ( C61 )，2·52 ( m，] 9H ) ，0·92 ( t， 4 — ( 2 -硝基一 酯 4 —乙酯 8.23 g，100%)。A solution of dit-butyl dicarbonate (7.2 g, 0.033 mol) in CH2C12 (25 ml) was slowly poured into ethyl isopicolinate (5.0 g '0.032 ul) at 0 ° C and Diethylamine (4.9 mi, 0.035 mole) in ch2C12 (25 ml). The reaction mixture was stirred overnight at room temperature, and then washed 3 times with KHSO4 solution and once with brine. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to produce a colorless oil-230- ", (226) 200529835, the desired product (] H NMR (C61), 2.52 ( m,] 9H), 0.92 (t, 4- (2-nitromonoester 4-ethyl ester 8.23 g, 100%).

，5 0 0MHz ) 5 3.88 ( q，J 二 7.5Hz，2H H) ，1.60—1.48 (m，8H) ，1.42(s， 3H )。質譜：280.44 ( M + Na ) +。 苄基）一哌啶一 1，4 一二羧酸 1 一特丁, 500 MHz) 5 3.88 (q, J 7.5Hz, 2H H), 1.60-1.48 (m, 8H), 1.42 (s, 3H). Mass spectrum: 280.44 (M + Na) +. Benzyl) -piperidine-1,4-dicarboxylic acid 1-tert-butyl

將雙（三甲 耳）溶液緩慢地 4 —乙酯（8 · 2 3 ί 中。經於一 7 8 t： 硝基苄基溴化物 合物回溫至室溫 餘物分佈於水和 置於無水MgS04. 由矽膠管柱層析 雜之反應混合物 (1.61 g ^ 13% ) 4 一 （ 2 —胺基― 基甲矽烷基）醯胺鈉（44 ml，0.044毫莫 加入至哌啶一 1，4 一二羧酸 1 一特丁酯 ;，0.032莫耳）之四氫呋喃（851111)溶液 下攪拌所生成之混合物1小時後，加入2 — (8.21 g，0.038莫耳）溶液。令該反應混 馨 並隔夜攪拌。濃縮該反應混合物，並令殘 乙酸乙酯中。利用鹽水冲洗有機萃取物， 上乾燥，隨後經過濾並於真空下濃縮。藉 (流洗液：己烷/乙酸乙酯 4 : 1 )自複 中純化終產物，生成褐色油狀之所欲產物 。質譜：415.38 ( M+ Na) +。 苄基）一哌啶一]，4 一二羧酸 ]_特丁 >231 - (227) 200529835 酯 4 一乙酯The bis (trimethylol) solution was slowly added to 4-ethyl ester (8.32 liters). After a period of 7 8 t: the nitrobenzyl bromide was warmed to room temperature and the residue was distributed in water and placed in anhydrous MgS04. Hybrid reaction mixture (1.61 g ^ 13%) by silica gel column chromatography 4 (2-amino-silyl) sulfonamide sodium (44 ml, 0.044 mmol) was added to piperidine-1, 4 Mono-dicarboxylic acid, 1 t-butyl ester; 0.032 mol) of tetrahydrofuran (851111) solution was stirred for 1 hour, and then a 2- (8.21 g, 0.038 mol) solution was added. The reaction was mixed and mixed. Stir overnight. Concentrate the reaction mixture and remove the residual ethyl acetate. Rinse the organic extract with brine, dry over, then filter and concentrate under vacuum. (Lluent: hexane / ethyl acetate 4: 1 ) The final product was purified from the compound to give the desired product as a brown oil. Mass spectrum: 415.38 (M + Na) +. Benzyl) -piperidine-1], 4-dicarboxylic acid] _tetin > 231-(227 200529835 Ester 4 Monoethyl Ester

Λ 於50 psi氫氣下隔夜氫化4一（2 —硝基一卡基）—η联 啶一1，4 —二羧酸 1 一 特丁酯 4 —乙酯（1.61 g，4.102 毫莫耳）和10%Pd/C(0.10 g)之乙醇（190 ml)溶液 。經由通過寅氏鹽以過濾所生成之混合物’並於真空下濃 縮濾液以生成無色油狀之所欲產物（1.29 g，99% )。質 譜：3 63.45 ( MH )+。 4 一（ 2 —胺基—苄基）—哌啶一 4 一羧酸乙酯氫氯化物Λ Hydrogenated 4- (2-nitro-carbyl) -n-bipyridine-1,4-dicarboxylic acid-1-tert-butyl ester 4-ethyl ester (1.61 g, 4.102 mmol) under 50 psi hydrogen overnight and 10% Pd / C (0.10 g) in ethanol (190 ml). The resulting mixture 'was filtered through yin salt and the filtrate was concentrated under vacuum to give the desired product as a colorless oil (1.29 g, 99%). Mass spectrum: 3 63.45 (MH) +. 4-mono (2-amino-benzyl) -piperidine- 4-monocarboxylic acid ethyl ester hydrochloride

N H-HCI 將4.0M HC1之二噁烷（5 ml)溶液加入至4— ( 2 —胺 基—苄基）一哌啶一 1，4一二羧酸 1 一特丁酯 4 一乙酯 (1.29 g，4.102 毫莫耳）之 CH2C12(15 ml)溶液中。室 溫下隔夜攪拌所生成之溶液。真空下濃縮該溶液以生成白 色固體之標的化合物（1 · 2 3 g，1 0 0 % )，其係未經純化 而使用於下一個步驟中。質譜：2 63.40 ( MH)—。 3，4 —苯並—2，9一重氮環〔5.5〕——h —烷—1 一酮 -232 - (228) 200529835 Η ΝN H-HCI A solution of 4.0M HC1 in dioxane (5 ml) was added to 4- (2-amino-benzyl) -piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4 monoethyl ester (1.29 g, 4.102 mmol) in CH2C12 (15 ml). The resulting solution was stirred overnight at room temperature. The solution was concentrated in vacuo to give the target compound (1.23 g, 100%) as a white solid, which was used in the next step without purification. Mass spectrum: 2 63.40 (MH) —. 3,4-Benzo-2,9-diazo ring [5.5]-h-alkane-1 monoone -232-(228) 200529835 Η Ν

令4一 （2—胺基一苄基）—哌啶一 4一羧酸乙酯氫氯 化物（1 · 2 3 g，4.1 0 2毫莫耳）溶液溶解於甲醇中，並於室 溫下隔夜攪拌所生成之溶液。該溶液藉由一半量之水進行 稀釋，並令其通過AG®1—X2離子交換樹脂（1〇〇 - 200篩 孔）之氫氧化物型式的短筒，且經5 0 %甲醇水溶液流洗。 蒸發所收集之分級液產生白色固體之所欲產物（〇. 8 9， 100% )。 】H-NMR ( CD3OD，5 0 0MHz ) δ 7.23 ( m，2Η ) ，7.05 (d，J=7.5Hz，1 H ) ，6.89(d，J=8.0Hz，1H) ，3.46 —3.41(m，2H) ，3.34—3.30 (m，2H) ，2.14— 2.09( m，2H) ，：1.73 — 1.67 (m，4H)。質譜：217.46 (MH) (R) — 2 —胺基一 3 —苯並〔b〕噻吩—3-基—1一〔1， 4 /〕聯哌啶一 1 / 一基一丙一 1 一酮，氫氯化物A solution of 4- (2-amino-benzyl) -piperidine-4-carboxylic acid ethyl ester hydrochloride (1.23 g, 4.102 mmol) was dissolved in methanol and the solution was allowed to stand at room temperature. The resulting solution was stirred overnight. The solution was diluted with half the amount of water and passed through a short cartridge of hydroxide type of AG®1-X2 ion exchange resin (100-200 mesh), and washed with a 50% methanol aqueous solution. . The collected fractions were evaporated to give the desired product as a white solid (0.89, 100%). ] H-NMR (CD3OD, 500MHz) δ 7.23 (m, 2Η), 7.05 (d, J = 7.5Hz, 1H), 6.89 (d, J = 8.0Hz, 1H), 3.46-3.41 (m, 2H), 3.34—3.30 (m, 2H), 2.14—2.09 (m, 2H), 1.73—1.67 (m, 4H). Mass spectrum: 217.46 (MH) (R) — 2 —amino—3—benzo [b] thiophen-3-yl—1— [1, 4 /] bipiperidine— 1 / 1-yl-propan-1—one , Hydrochloride

室溫下先後將4 一 _ 0定並喊症（5 7 3 m g，3 · 4毫莫耳） 、三乙胺（1·3 ml，9.3毫莫耳）及3—(二乙氧基磷醯氧 - 233 - (229) (229)200529835 基）一1，2，3 —苯並三嗪—4(3H)—酮（1·〇2 g，3.4 毫莫耳）加入至3 —苯並〔b〕噻吩一 3-基一（2R) — 2-特丁氧羰基胺基—丙酸（1.0 g3.l毫莫耳）之Ch2C12(30 ml )充分攪拌溶液中。經3小時後，先後加NaHC03水溶液 (1 5 ml )和鹽水（20 ml )至該反應混合物中並進行乾燥 (Na2S04 )。藉由閃蒸層析並利用5%甲醇之CH2C12溶液 爲流洗液以純化粗混合物，生成（1 R )-苯並〔b〕噻吩 —3 —基甲基一2—〔1，〕聯哌啶一 1，一基—2 —酮基 —乙基）一氨基甲酸特丁醋（82%產率）。將（1R) — 1 一苯並〔b〕噻吩一 3 —基甲基一 2—〔1，4>〕聯哌啶一 一基一 2—酮基一乙基）一氨基甲酸特丁酯（1.2 g， 2.54毫莫耳）之（：1120：12(5 1111)溶液加入至1^1之二噁烷 (20 ml )飽和溶液中並攪拌2小時。除去溶劑以生成（2R )一 2 —胺基—3 —苯並〔b〕噻吩一 3 —基—1 一〔1，4^ 〕聯哌啶—1 / 一基—丙—1 一酮，氫氯化物（9 8 %產率） 〇 ]H NMR ( 500MHz，CD3OD) : 5 7 · 9 8 - 7 · 8 8 ( ηι，2 Η )，7·55— 7.40 (m，3H) ，4.85-4.83 (m，lH) J 3.66 —2.68(m，9H) ，：1.92 - 1.44 (m，12H)。質譜：372 (ΜΗ ) +。 實施例6 1 (R) — 1 - 酮基一3，4 —苯並一 2，9 —重氮一螺〔5.5〕 十一碳一 3 —烯一 9 一羧酸（1 —苯並〔b〕噻吩一 3 —基甲 -234 - (230) (230)200529835 基一2— 〔1，4 〕聯哌卩定—] —基一 2 —嗣基一乙基） 一醯胺Symptoms of 4-0 were determined at room temperature (5 7 3 mg, 3.4 mmol), triethylamine (1.3 ml, 9.3 mmol), and 3- (diethoxyphosphorus) Phenoxy-233- (229) (229) 200529835 group) -1,2,3-benzobenzotriazine-4 (3H) -one (1.02 g, 3.4 mmol) was added to 3-benzo [B] Thiophene-3-yl- (2R) —2-tert-butoxycarbonylamino-propionic acid (1.0 g3.1 ml) of Ch2C12 (30 ml) was stirred well in the solution. After 3 hours, NaHC03 aqueous solution (15 ml) and brine (20 ml) were added to the reaction mixture and dried (Na2S04). The crude mixture was purified by flash chromatography and using a 5% methanol in CH2C12 solution as the eluent to produce (1 R) -benzo [b] thiophene-3-ylmethyl-2- [1,] bipipe Pyridinyl-1,2-keto-2-ethyl) monobutyl urethane (82% yield). (1R) — 1-benzo [b] thiophene 3-ylmethyl—2- [1,4 >] piperidine-one-yl 2-keto-ethyl) -tetrabutyl carbamate ( 1.2 g, 2.54 mmol) (1120: 12 (5 1111)) solution was added to a saturated solution of 1 ^ 1 dioxane (20 ml) and stirred for 2 hours. The solvent was removed to form (2R)-2 — Amino-3—benzo [b] thiophene-3-yl-1— [1,4 ^] bipiperidin-1 / 1-yl-propan-1 monoketone, hydrochloride (98% yield). ] H NMR (500MHz, CD3OD): 5 7 · 9 8-7 · 8 8 (η, 2 Η), 7.55— 7.40 (m, 3H), 4.85-4.83 (m, 1H) J 3.66 —2.68 ( m, 9H) ,: 1.92-1.44 (m, 12H). Mass spectrum: 372 (ΜΗ) +. Example 6 1 (R) — 1-Keto-3,4-benzo-2,9-diazo- Spiro [5.5] undecyl-3-ene-9-carboxylic acid (1-benzo [b] thiophene 3-methyl-234- (230) (230) 200529835 radical one 2- [1,4] Piperidine —] —yl-2 —fluorenyl monoethyl) monofluorenamine

將N，N / —二琥珀醯亞胺碳酸酯（34.6 mg，0.1 35毫 莫耳）和二異丙基乙胺（0.091 ml，0.500毫莫耳）加入至 2 —胺基—3 —苯並〔b〕噻吩一 3 —基一 1 一〔1，〕聯 哌啶一厂—基—丙—1 一酮（50·0 mg，0.135毫莫耳）之 1，2 —二氯乙烷（1 .5 ml )溶液中。攪拌所生成之溶液1 小時，隨後加3，4 —苯並—2，9 —重氮螺〔5 · 5〕一十一 碳烷一1 一酮（30.4 mg，0.140毫莫耳）。室溫下隔夜攪 拌該反應混合物並進行濃縮。藉由逆相製備性HPLC完成 純化以生成褐色油狀之所欲產物（7 5 . 5 mg，7 7 % )。 NMR(CD3OD，500MHz) ά 7.92-7.85 (m^ 2Η) ，7·44— 7.34 (m，3H) ，7·21— 7.16(m，2H) ，7.00( t，J=7.0Hz，1 H ) ，6.86(t，J=8.5Hz，1H) ，5.15 — 5.02 (m，1H) ，4.72-4.45 (m，1H) ^ 3.9 5 - 3.2 0 ( m ，8H) ，3·18— 2.92(m，4H) ，2.92—2.75 (m，2H) ，2.75—2.63 (m，lH)，2.40—2.30 (m，lH)，2.08 — 1.64(ni，8H) ，：1.58— 1.20 (m，6H)。質譜：614.3 7 (ΜΗ ) -235 - (231) (231)200529835 實施例62 N〔 （1R) — 1—(苯並〔b〕噻嗯一 3 —基甲基）—2—〔 1，4一聯 定〕—1 一基一 2 —酮基乙基〕—3 / ，4·" —二 氯一 2 —嗣基螺一〔呢D定一4’ 4 ( 1 Η ) — 〇奎琳〕一 1 — 羧醯胺Add N, N / -bissuccinimide carbonate (34.6 mg, 0.1 35 mmol) and diisopropylethylamine (0.091 ml, 0.500 mmol) to 2-amino-3-benzo [B] Thiophene-3-yl-1 1- [1,] piperidine-one plant-yl-propan-1 monoketone (50 · 0 mg, 0.135 mmol) 1,2 dichloroethane (1 .5 ml) solution. The resulting solution was stirred for 1 hour, followed by the addition of 3,4-benzo-2,9-diazospiro [5 · 5] -11-carbane- 1-one (30.4 mg, 0.140 mmol). The reaction mixture was stirred overnight at room temperature and concentrated. Purification was accomplished by reverse-phase preparative HPLC to yield the desired product as a brown oil (75. 5 mg, 77%). NMR (CD3OD, 500MHz) ά 7.92-7.85 (m ^ 2Η), 7.44— 7.34 (m, 3H), 7.21— 7.16 (m, 2H), 7.00 (t, J = 7.0Hz, 1 H) , 6.86 (t, J = 8.5Hz, 1H), 5.15 — 5.02 (m, 1H), 4.72-4.45 (m, 1H) ^ 3.9 5-3.2 0 (m, 8H), 3.18— 2.92 (m, 4H), 2.92—2.75 (m, 2H), 2.75—2.63 (m, 1H), 2.40—2.30 (m, 1H), 2.08—1.64 (ni, 8H), 1.58—1.20 (m, 6H). Mass spectrum: 614.3 7 (ΜΗ) -235-(231) (231) 200529835 Example 62 N [(1R) — 1— (benzo [b] thien—3-methylmethyl) —2— [1,4 A joint]-1-1-2-ketoethyl]-3 /, 4 · " —dichloro — 2 — fluorenyl spiro 1 [? D fixed a 4 '4 (1 Η) — 〇 琳琳1-Carboxamide

如前述製備（R) — 1—酮基一 3，4 —苯並—2，9一重 氮一螺〔5.5〕一十一烯—3 —烯—9 一羧酸（1 一苯並〔b 〕嘻吩—3 —基甲基一 2-〔1，4 〕聯喊1?定一 1 一基一 2 —酮基一乙基）一酿胺之方法，自3 ，4 —二氫一 2 — 酮基螺—哌啶—4，4 / ( 1 Η ) — D奎啉（M . S . C h a m b e r s， et al. J. Med. Chem，1 992，3 5, 2 03 3 -203 9 ； WO 94/ 1 3 6 9 6 )進行製備。 NMR ( CDCh ? 5 0 0MHz ) ： 5-0.35 (lH，m)， 0.79(lH，m) ，：l.2-2.1(12H，m) ，2.22(5H，m) ，2.38(2H，m) ，2.74(2H，ABq) ，3.19(3H，m)， 3.33(2H，m) ，3.65(lH，d) ，3.80(lH，m) ^ 3.93 (lH，t) ，4.49(lH，d) ，5.31(lH，t) ，5·96(1Η ，t) ，6.89(lH，d) ，7.05(lH，t) ，7.18(lH，d) ，7 · 2 6 ( 1 H，m ) ，7 · 3 3 ( 1 H，m ) ，7.4 0 ( 1 H，m )， - 236 - (232) (232)200529835 7.78(lH，m) ，7.96(lH，Abq) ，9.01(lH，brs)， 9.17( 1H，brs)。質譜：614.36(MH) +。 實施例6 3 N- [ (1R) — （苯並〔b〕噻嗯一3 —基甲基）—2—〔1 ，4 —聯哌啶〕—1 —基一 2 —酮基乙基〕—2 /，3 / —二 氫一 1 一酮基螺一〔哌啶一 4，4 /( 1 Η ) -異D奎啉〕一 1 -羧醯胺(R) —1-keto-3,4-benzo-2,9-diazo-spiro [5.5] undecene-3-ene-9-carboxylic acid (1—benzo [b]) Hexene—3-methyl-2— [1,4], a method of fixing 1—1—2—keto—ethyl—monomethylamine, from 3,4-dihydro-2— Ketospiro-piperidine-4,4 / (1 Η)-D quinoline (M.S.C hambers, et al. J. Med. Chem, 1 992, 3 5, 2 03 3 -203 9; WO 94/1 3 6 9 6). NMR (CDCh? 500 MHz): 5-0.35 (lH, m), 0.79 (lH, m), 1.2-2.1 (12H, m), 2.22 (5H, m), 2.38 (2H, m) , 2.74 (2H, ABq), 3.19 (3H, m), 3.33 (2H, m), 3.65 (lH, d), 3.80 (lH, m) ^ 3.93 (lH, t), 4.49 (lH, d), 5.31 (lH, t), 5.96 (1Η, t), 6.89 (lH, d), 7.05 (lH, t), 7.18 (lH, d), 7 · 2 6 (1 H, m), 7 · 3 3 (1 H, m), 7.40 (1 H, m),-236-(232) (232) 200529835 7.78 (lH, m), 7.96 (lH, Abq), 9.01 (lH, brs), 9.17 (1H, brs). Mass spectrum: 614.36 (MH) +. Example 6 3 N- [(1R) — (Benzo [b] thien-3-ylmethyl) -2- [1,4-bipiperidine] -1-yl-2—ketoethyl] —2 /, 3 / —dihydro-1, 1-ketospiro-1 [piperidine-4, 4 / (1 Η) -isoD-quinoline] -1-carboxamide

如前述製備（R) - 1—酮基一 3，4 —苯並一 2，9一重 氮—螺〔5.5〕十一碳—3 -烯—9 一羧酸（1—苯並〔b〕 噻吩一3 —基甲基一2—〔1，4，〕聯哌啶—1/ —基—2 -酮基一乙基）醯胺之方法自2 / ，3 / —二氫一 1—酮基螺 —〔派陡一4，4' (1H)—異 D奎啉（M.S. Chambers，et al” J. Med. Chem” 1 992，35，2 03 3 -2 03 9; WO- 94/ 1 3 6 96 ) 進行製備。 ]H NMR ( CDCI3 ^ 5 00MHz ) : 50.01 (lH，m) ，0.78 (1 H，111 ) ，：1 . 1 一 2.0 ( 1 2 H，m ) ，2 · 1 5 — 2 · 3 0 ( 5 H，m )，2.74(lH，t) ，3.0— 3·6(9Η) ，3·89(2Η，ηι)， 4.46( lH，d) ，5.29(lH，m) ，5.62(lH，d) ，6.47 (】H，b 1· s ) ，7 · 3 8 ( 5 H，m ) ，7.5 ] ( ] H，m ) ，7.7 7 ( -237 - (233) (233)200529835 lH，m) ，7.85(lH，m) ，8.11(lH，d)。質譜： 6 1 4.42 ( ΜΗ ) +。 實施例6 4 N— 〔 （1R) - （苯並〔b〕噻嗯—3 —基甲基）—2—〔1 ，4/ —聯哌啶〕一 1〃一基一2 —酮基乙基〕一1，2 —二 氯一2 —嗣基螺—〔4H— 3，1—苯並卩惡秦—4，4 —哌D定 〕一 1 / 一羧醯胺(R)-1-keto-3,4-benzo-2,9-diazo-spiro [5.5] undec-3-ene-9 monocarboxylic acid (1-benzo [b] thiophene A method of 3-methylmethyl-2- [1,4,] bipiperidin-1-1 / yl-2-ketomonoethyl) fluorenamine from 2/3, 3-dihydro-1-1-keto Spiro— [Piaso-4,4 '(1H) -isoD-quinoline (MS Chambers, et al "J. Med. Chem" 1 992, 35, 2 03 3-2 03 9; WO- 94/1 3 6 96). ] H NMR (CDCI3 ^ 5 00MHz): 50.01 (lH, m), 0.78 (1 H, 111): 1.1-2.0 (1 2 H, m), 2 · 1 5-2 · 3 0 (5 H, m), 2.74 (lH, t), 3.0-3.6 (9Η), 3.89 (2Η, η), 4.46 (lH, d), 5.29 (lH, m), 5.62 (lH, d) , 6.47 (] H, b 1 · s), 7 · 3 8 (5 H, m), 7.5] (] H, m), 7.77 (-237-(233) (233) 200529835 lH, m), 7.85 (lH, m), 8.11 (lH, d). Mass spectrum: 6 1 4.42 (ΜΗ) +. Example 6 4 N — [(1R) — (Benzo [b] thien-3-ylmethyl) -2- [1,4 / —bipiperidine] —1—one—2—ketoethyl Yl] -1,2-dichloro-2-pyridylspiro- [4H-3,1-benzobenzoxine-4,4-piperidine]] 1/1 carboxamide

如前述製備（R) - 1 一酮基—3，4一苯並—2，9 —重 氮—螺〔5.5〕--碳一 3 -燃一 9 —竣酸（1 一苯並〔b〕 嚷吩一 3 —基甲基一2 —〔 1，4 〕聯呢Π定—1 —基一2 — 酮基一乙基）醯胺之方法自1，2-二氫一 2—酮基螺一〔 〔4 Η — 3，1 —苯並Π惡嗪—4，4 一暖D定（其製備係描述 於 Takai，et al., Chem. Pharm. Bull. 1 9 8 5, 3 3, 1 1 2 9 - 1 1 3 9 )進行製備以生成標的化合物（76 % )。質譜：61 6 (MH ) +。Rf = 1 .42。 琥珀酸酯中間產物及實施例 3—苯並〔b〕噻吩一 3-基—丙烯酸 -238 - (234) (234)200529835(R)-1 monoketo-3,4-benzo-2,9-diazo-spiro [5.5] -carbon-3-flame-9-complete acid (1-benzo [b] The method of stilbene-1, 3-methyl-2, [1,4] bisidine-1, 1--2, keto-ethyl) fluorenamine is from 1,2-dihydro-2, 2-ketospiro 1 [〔4 pyrene — 3,1 —benzo Πoxazine —4,4 — warm D (the preparation is described in Takai, et al., Chem. Pharm. Bull. 1 9 8 5, 3 3, 1 1 2 9-1 1 3 9) was prepared to produce the target compound (76%). Mass spectrum: 61 6 (MH) +. Rf = 1.42. Succinate Intermediate and Example 3-Benzo [b] thiophene 3-yl-acrylic acid -238-(234) (234) 200529835

於110 °C下隔夜加熱1—苯並噻吩一 3 —醛（4.9 g， 〇·〇3莫耳）、丙二酸（6.6 g，0.06莫耳）及哌啶（1 mi) 之無水吡啶（1 〇 〇 m 1)懸浮液。冷卻該反應混合物至室溫 ，並於真空下除去溶劑。將殘餘物置於水（100 ml )中並 加入IN HC1調整其pH至約3。過濾該懸浮液並收集黃色 固體，經水（3 X 5 0 ml )冲洗及真空下濃縮後，生成所欲 春 之產物（95% 純度 ’ 5.65 g，91%)。 3—苯並〔b〕噻吩—3—基一丙酸1-benzothiophene-3-aldehyde (4.9 g, 0.003 mole), malonic acid (6.6 g, 0.06 mole), and piperidine (1 mi) of anhydrous pyridine (1 mi) were heated overnight at 110 ° C. 100m 1) suspension. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. Place the residue in water (100 ml) and adjust its pH to about 3 by adding IN HC1. The suspension was filtered and a yellow solid was collected, washed with water (3 × 50 ml) and concentrated under vacuum to produce the desired spring product (95% purity '5.65 g, 91%). 3-benzo [b] thiophene-3-yl-propionic acid

於Parr裝置中在50 psi氫氣下，隔夜氫化3 一苯並〔b 〕噻吩—3 —基—丙烯酸（5·6 g，0.027莫耳）和l〇%Pd/ C ( 600 mg )之1 : 1甲醇/乙酸乙酯（50 ml )懸浮液。 過濾該混合物，經濃縮後（但未經進一步純化）生成粗產 物（約1 0 0 %轉化）。質譜：2 0 5 ( Μ Η ) 一。 3 -（3—苯並〔b〕噻吩一 3—基一丙醒基）一 4(R) -爷 基一 B惡D坐院一 2 -嗣Hydrogenated 1-benzo [b] thiophene-3-yl-acrylic acid (5.6 g, 0.027 mol) and 10% Pd / C (600 mg) in a Parr unit overnight at 50 psi hydrogen: 1 Methanol / ethyl acetate (50 ml) suspension. The mixture was filtered and concentrated (but without further purification) to yield a crude product (about 100% conversion). Mass spectrum: 2 0 5 (ΜΗ). 3-(3-Benzo [b] thiophene- 3-yl-propionyl)-4 (R) -Yeyl-B

- 239 - (235) (235)200529835 於〇°C下將特戊醯氯（1.38 ml，0.01 1莫耳）加入至3 —苯並〔b〕噻吩一 3 -基一丙酸（2.1 g，〇·〇1〇莫耳）和 三乙胺（4.12 g，〇·〇40莫耳）之無水四氫呋喃（1〇〇 ml) 溶液中。經於〇°C下攪拌1·5小時後，加入LiCl ( 0.475 g， 0.011莫耳）和（R) 一 4 —苄基一 2 —噁唑烷Μ·988 g， 0.0 1 1莫耳）。令該反應混合物回溫至室溫並進行隔夜攪 拌。利用水（3 X 1 5 0 ml )冲洗該混合物。分離有機層， 經乾燥和蒸發後生成粗產物。藉由矽膠閃蒸層析並利用 100% CH2C12爲流洗液，得到褐色油狀之標的產物（90 % )。立即使用該化合物於下述之步驟中。 3(S) —本並〔b} π塞吩一 3 —基甲基一 4 一 （4 一卡基—2 一酮基一噁唑烷一 3 —基）一 4一酮基一丁酸特丁酯-239-(235) (235) 200529835 Tvalprosium chloride (1.38 ml, 0.01 1 mole) was added to 3-benzo [b] thiophene-3-yl-propionic acid (2.1 g, Mol) and triethylamine (4.12 g, 040 molar) in anhydrous tetrahydrofuran (100 ml). After stirring at 0 ° C. for 1.5 hours, LiCl (0.475 g, 0.011 mole) and (R) 4-benzyl-2 2-oxazolidine M · 988 g, 0.0 1 1 mole) were added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was rinsed with water (3 X 150 ml). The organic layer was separated and the crude product was formed after drying and evaporation. By silica gel flash chromatography and using 100% CH2C12 as a flow washing solution, the target product (90%) was obtained as a brown oil. The compound was used immediately in the steps described below. 3 (S) —benzyl [b] π phenphenone 3-ylmethyl-4 4 (4 4-carbyl-2 keto-oxazolidine-3-yl) 4 4-keto-butyrate Butyl ester

於—7 8 °C下將二異丙基氨化鋰之四氫呋喃（6.1 ml， 1 1 · 0 1毫莫耳）溶液加入至3 一 （ 3 一苯並〔b〕噻吩—3 一 基一丙醯基）—4 —苄基—噁唑烷—2-酮（3.35 g，9.18 毫旲耳）之無水四氫呋喃（1〇〇 ml)溶液中，並攪拌該反 應、?比合物3 0分鐘。經於—7 8 °C下加入溴乙酸特丁醋（1 · 6 2 ml，Π · 0 1毫莫耳）後，隔夜攪拌該混合物，同時令其回 溫至室溫。蒸發溶劑並利用乙酸乙酯稀釋殘餘物。利用（ 3 X 1 〇〇 ml )冲洗有機層，經乾燥、過濾及濃縮後生成粗 -240- (236) (236)200529835 產物。經由通過二氧化矽墊過濾並經CH2C12流洗後，得到 標的產物（4 9 % )。 2(S) —苯並〔b〕噻吩一 3 —基甲基一琥珀酸 4 一特丁 酯Add a solution of lithium diisopropylamide tetrahydrofuran (6.1 ml, 1 · 1.0 1 mmol) to 3-(3 -benzo [b] thiophene-3 -yl-propyl) at -7 ° C. Amidino) 4-benzyl-oxazolidine-2-one (3.35 g, 9.18 millitorles) in a solution of anhydrous tetrahydrofuran (100 ml), and the reaction was stirred for 30 minutes. After adding tert-butyl bromoacetate (1.62 ml, Π · 01 mmol) at -7 ° C, the mixture was stirred overnight while it was allowed to warm to room temperature. The solvent was evaporated and the residue was diluted with ethyl acetate. The organic layer was washed with (3 × 100 ml), dried, filtered, and concentrated to give the crude -240- (236) (236) 200529835 product. After filtering through a pad of silica and washing with a stream of CH2C12, the target product (49%) was obtained. 2 (S) -benzo [b] thiophene 3- 3-methylmethyl monosuccinate 4-tert-butyl ester

於〇°C下將30%過氧化氫水溶液（1 ml )和LiOH ( 〇·2155 g’ 8·98毫莫耳）先後加入至3 一苯並〔b〕噻吩—3 一基甲基—4— (4 一苄基_2 —酮基一噁唑烷一 3一基）一 4 一酮基丁酸特丁酯（2.15 g，4.49毫莫耳）之四氫呋喃（ 5 0 ml )和水（30 ml )之攪拌溶液中。隔夜攪拌該反應混 合物。真空下除去四氫呋喃並利用；[〇 %檸檬酸酸化所生成 之溶液，隨後利用乙酸乙酯（3 X 5 0 ml )進行萃取。利用30% aqueous hydrogen peroxide solution (1 ml) and LiOH (0.2155 g '8.98 mmol) were added to 3-benzo [b] thiophene-3-ylmethyl-4 successively at 0 ° C. — (4-monobenzyl_2 —keto-oxazolidine-3 3-yl) — 4-tetrabutyl ketobutyrate (2.15 g, 4.49 mmol) tetrahydrofuran (50 ml) and water (30 ml) in a stirred solution. The reaction mixture was stirred overnight. The tetrahydrofuran was removed under vacuum and the solution was acidified with [0% citric acid, followed by extraction with ethyl acetate (3 × 50 ml). use

NaHSCh溶液冲洗有機層，經乾燥和濃縮後生成標的產物 〇 3(S)—苯並〔b〕噻吩一3—基甲基一 4一 〔 1，4，〕聯 _ π定—1 / 一基一 4 一酮基一丁酸特丁酯The organic layer was rinsed with NaHSCh solution, and the target product was formed after drying and concentration. 0 (S) —benzo [b] thiophene—3-methyl—4— [1,4,] biphenyl — 1/1 radical 4-tetrabutyl butyl monobutyrate

-241 - (237) (237)200529835 令2—苯並〔b〕噻吩—3 —基甲基一琥珀酸 4 一特丁 酯（1 · 8 4 2 0 g，5 · 7 6毫莫耳）、哌啶基哌啶（1 . 2 2 4 0 g， 7.28毫莫耳）及三乙胺（ 0.7353 g，7.28毫莫耳）之 CH2C12(100 ml)溶液與3一（二乙氧基磷醯氧基）— 2，3 —苯並三嗪—4(3H)—酮（DEPBT，1.8953 g，6.34 毫莫耳）反應。隔夜攪拌該混合物並隨後經水（3 X 4 0 ml )冲洗。乾燥有機層，經過濾和真空下濃縮後生成粗產物 。藉由矽膠閥蒸層析並經〇至10% 2M氨之甲醇/ CH2C12 流洗以進行進一步純化，生成所欲之產物。未經進一步之 純化而使用該產物。 3(S)—苯並〔b〕噻吩一 3 —基甲基一4— 〔1，4 /〕聯 哌啶一 1 > —基一 4 一酮基一丁酸-241-(237) (237) 200529835 Let 2-benzo [b] thiophene-3-ylmethylmonosuccinic acid 4-tert-butyl ester (1.84 2 0 g, 5.76 millimoles) CH2C12 (100 ml) solution of piperidinylpiperidine (1.22 40 g, 7.28 mmol) and triethylamine (0.7353 g, 7.28 mmol) and 3-mono (diethoxyphosphorane) (Oxy)-2,3-benzotriazine-4 (3H) -one (DEPBT, 1.8953 g, 6.34 mmol). The mixture was stirred overnight and then rinsed with water (3 × 40 ml). The organic layer was dried, filtered and concentrated in vacuo to give a crude product. Chromatography through a silica gel valve and washing with 0 to 10% 2M ammonia in methanol / CH2C12 for further purification to produce the desired product. The product was used without further purification. 3 (S) —benzo [b] thiophene—3-ylmethyl—4 -— [1,4 /] bipiperidine—1 > —yl—4—ketomonobutyric acid

令三氟乙酸（3 ml )與3 —苯並〔b〕噻吩一 3 -基甲 基—4 一 〔 1，4 /〕聯哌啶一 1 / —基一 4 —酮基—丁酸特 丁酯之CH2C】2 ( 15 ml )溶液反應，並於室溫下隔夜攪伴 該反應混合物。蒸發溶劑以生成標的化合物之對應三氟乙 酸鹽（99% )。 實施例6 5 】—〔1，4 /〕聯 _ D定—1 ——基—2 — ( 3 ( S )—苯並〔b -242 - 200529835 (238) 〕噻吩一 3 —基甲基）一 4 —〔 1 >，2 / —二氫一酮基螺一 〔4 Η — 3 ，1 一苯並卩惡嗦—4，4 —呢卩定基〕一丁 — 1， 4 —二酮Let trifluoroacetic acid (3 ml) and 3-benzo [b] thiophene-3-ylmethyl-4 4- [1,4 /] bipiperidinyl 1 / -yl -4 -keto -butyric acid butan A solution of the ester in CH2C] 2 (15 ml) was reacted and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated to produce the corresponding trifluoroacetic acid salt of the target compound (99%). Example 6 5] — [1,4 /] Bi-D-D—1 —Base—2 — (3 (S) —Benzo [b -242-200529835 (238)] Thienone—3-Methyl) One 4 — [1 >, 2 / —dihydromonoketospiro [4 Η — 3,1 benzopyrene 嗦 4,4 —nepidinyl] monobutane-1, 4-dione

室溫令3 —苯並〔b〕喧吩—3 —基甲基一 4—〔1，4 〕聯哌啶—一基—4 一酮基—丁酸（25.0 mg，0.060毫 莫耳）、1，2—二氫—2-酮基螺一411一3，1一二氫一苯 並噁嗪一4，4 / —哌啶（1 5 · 7 m g，0 · 0 7 2毫莫耳）及三乙 胺（7.3 mg，0.072 毫莫耳）之 CH2C12(5 ml)溶液與 3 — (二乙氧基磷醯氧基）一 1，2，3 -苯並三嗪一4(3H) —酮（DEPBT，21·5 mg，0.072毫莫耳）反應。隔夜攪拌 該溶液，隨後經水（3 X 5 ml )冲洗。乾燥有機層，經濃 縮，並藉由矽膠閃蒸層析且經〇至1 〇 % 2M氨之甲醇/ CH2C12溶液流洗以純化粗產物，生成所欲之產物（60%產 率）。 LC/MS: tR=l.34 分，615.45 (MH) +。 2 — ( 7 —甲基一1 Η —吲唑—5 —基亞甲基）一琥珀酸1 一 甲酯 -243 - (239) 200529835At room temperature, 3-benzo [b] quinone-3-ylmethyl-1,4- [1,4] bipiperidinyl-1,4-monoketo-butyric acid (25.0 mg, 0.060 mmol), 1,2-dihydro-2-ketospiro-411-3,1-dihydro-benzoxazine-4,4 / -piperidine (15.7 mg, 0 0.72 mmol) And triethylamine (7.3 mg, 0.072 mmol) in CH2C12 (5 ml) with 3- (diethoxyphosphoryloxy) -1,2,3-benzotriazine-4 (3H) — Ketone (DEPBT, 21.5 mg, 0.072 mmol). The solution was stirred overnight and then rinsed with water (3 X 5 ml). The organic layer was dried, concentrated, and purified by silica gel flash chromatography and a 0 to 10% 2M ammonia in methanol / CH2C12 solution to purify the crude product to yield the desired product (60% yield). LC / MS: tR = 1.34 points, 615.45 (MH) +. 2- (7-methyl-1,1,1-indazole-5, -methylene) monosuccinic acid, 1-methyl ester -243-(239) 200529835

將特丁氧化鉀（0.4036 g，3·60毫莫耳）加入至7—甲 基吲唑醛（0.2619 g，1.64毫莫耳）和DBE— 4—二價酸醋 (琥珀酸二甲酯；〇·32 ml，2.45毫莫耳）之特丁醇（2〇 ml )溶液中。於50 °C和氮氣下，加熱該反應溶液2小時， 經於室溫下1 6小時後’真空下除去溶劑，將殘餘物置於水 (100 ml)中並利用乙酸乙酯（3x50 ml)進行萃取。利 用IN HC1酸化水層至pH 3至4並經乙酸乙酯（3χ5〇 ml) 萃取。乾燥結合之乙酸乙酯溶液，經真空下濃縮後生成黃 色固體粗產物（99%，.順式/反式異構物約4〇 ·· 6〇)。該 粗混合物未經進一步純化而用於下一個步驟中。質譜： 2 7 5 ( MH ) +。 (±) — 2— (7 —甲基一 1H — D弓[ti坐一 5 —基甲基）一琥j白Potassium terbutoxide (0.4036 g, 3.60 millimoles) was added to 7-methylindazol (0.2619 g, 1.64 millimoles) and DBE-4-divalent acid vinegar (dimethyl succinate; 0.32 ml, 2.45 mmol) in tert-butanol (20 ml). The reaction solution was heated at 50 ° C under nitrogen for 2 hours. After 16 hours at room temperature, the solvent was removed under vacuum. The residue was placed in water (100 ml) and performed with ethyl acetate (3x50 ml). extraction. The aqueous layer was acidified to pH 3 to 4 with IN HC1 and extracted with ethyl acetate (3 x 50 ml). The combined ethyl acetate solution was dried and concentrated in vacuo to give a crude product as a yellow solid (99%, .cis / trans isomer approximately 40 ·· 60). This crude mixture was used in the next step without further purification. Mass spectrum: 2 7 5 (MH) +. (±) — 2— (7—methyl-1H—D-bow

酸 1 一甲酯Acid 1 monomethyl ester

OH 於Parr裝置中且在50 psi氫氣下，隔夜氫化2— (7 — 甲基一 1 Η —吲唑一 5 —基亞甲基）一琥珀酸 1 一甲酯（ 0.4440 g，1.62 毫莫耳）和 i〇%Pd/C(0.04 g )之乙酸乙 酯（1 5 ml )和甲醇（5 ml )的懸浮液。經由通過寅氏鹽 墊以過濾該反應混合物，經蒸發濾液後生成黃色固體之所 欲產物（】〇〇% )。質譜：2 7 7 ( MH ) +。 -244 - (240) (240)200529835 實施例66 (±) — 2— （7 —甲基一1H —吲唑一5 —基甲基）一 4一酮 基一 4—〔厂，2^ —二氫一2，一酮基螺一 〔4H一 3〆， 1 一苯並噁唑一4，4 / 一哌啶基〕一丁酸甲酯OH in a Parr unit under hydrogen at 50 psi, hydrogenated 2- (7-methyl-1, hydrazone-indazole-5-ylmethylene) -monosuccinic acid, 1-methyl ester (0.4440 g, 1.62 mmol) ) And i0% Pd / C (0.04 g) in a suspension of ethyl acetate (15 ml) and methanol (5 ml). The reaction mixture was filtered through a pad of yin's salt, and the desired product was obtained as a yellow solid (100%) after evaporation of the filtrate. Mass spectrum: 2 7 7 (MH) +. -244-(240) (240) 200529835 Example 66 (±) — 2- (7-methyl-1H —indazole- 5-ylmethyl) — 4-one keto — 4 — [plant, 2 ^ — Dihydro-2,1-ketospiro- [4H-3〆, 1-benzoxazole-4,4 / monopiperidinyl] monobutyrate methyl ester

令2— （7 —甲基一1H—吲唑一 5—基甲基）一琥珀酸 1 一甲酯（0.2253 g，0.82 毫莫耳）、1，2 —二氫-2-酮 基螺—4 Η - 3 - ，1 一二氫—苯並噁嗪一 4 / ，4 一哌啶（ 0.1938 g，0.89毫莫耳）及三乙胺（〇〇99 g，098毫莫耳 )之CH2C12 ( 1 5 ml )溶液與3 -（二乙氧基磷醯氧基）一 1，2，3 -苯並三嗪—4(3H) - 酮（DEpBT，〇·2685 g, 0.9 0毫莫耳）反應。隔夜攪拌該混合物，隨後經水（3 χ 5 m 1 )冲洗。乾燥有機層並於真空下濃縮。藉由矽膠閃蒸層 析且經〇至1〇% 2M氨之甲醇/ CH2Cl2溶液流洗以純化殘 餘物，生成所欲產物（5 3 % )。 LC/MS: tR=l.40分，477.28 (MH) +。 類似之方法製備： 實施例6 7 -245- (241) 200529835 (土）一 2 — ( 7 一甲基一1 Η —卩引口坐一 5 —基甲基）一4 一酬 基—4一 〔4— (2 —酮基一 1，4 —二氫一2Η — D奎唑啉—3 一基）一哌啶一 1 一基〕一丁酸甲酯 ΗLet 2- (7-methyl-1H-indazol-5-ylmethyl) -monomethyl succinate (0.2253 g, 0.82 mmol), 1,2-dihydro-2-ketospiro— 4 C-3-, 1 -dihydro-benzoxazine-4 /, 4 -piperidine (0.1938 g, 0.89 mmol) and triethylamine (〇99 g, 098 mmol) CH2C12 ( 1 5 ml) solution with 3-(diethoxyphosphoryloxy) -1,2,3-benzotriazine-4 (3H) -one (DEpBT, 0.2685 g, 0.9 0 mmol) reaction. The mixture was stirred overnight and then rinsed with water (3 x 5 m 1). The organic layer was dried and concentrated under vacuum. The residue was purified by silica gel flash chromatography and washed with 0 to 10% 2M ammonia in methanol / CH2Cl2 to yield the desired product (53%). LC / MS: tR = 1.40 minutes, 477.28 (MH) +. Prepared by a similar method: Example 6 7 -245- (241) 200529835 (Earth)-2-(7 -methyl-1 1 Η-卩 Introduced by a 5-methyl group)-4-1-4-1- [4- (2-keto-1,4-dihydro-1, 2Η-D-quinazoline-3, 1-yl) -piperidine-1, 1-yl] methyl butyrateΗ

〇、Ν W-NMR ( 400MHz，CDC13 ) (5 8·02 ( 1H，s) ，7.98 ( lH，m) ，7.90(lH，m) ，7.35— 6.89(4H，m) » 6.72 (lH，m) ，4.71(lH，m) ，4.57(lH，m) ，4.27( lH，s) ，4.22(lH，m) ，3.85(lH，m) ，3.65(3H， m ) ，3.30(lH，m) ，3.11(2H，m) ，2.83(2H，m) ，2.81— 2.54 (4H，m) ，2.35 ( 1H，m) ^ 1.73 - 1.67 ( 4H，m)。質譜：490·32(ΜΗ)+。 (±) — 2— (7 —甲基一1H —吲唑一 5_基甲基）一4 —酮 基—4一〔厂，2，—二氫—2^ —酮基螺—〔4H - 3'， 1 一苯並噁嗪一 4，4 / 一哌啶基〕一丁酸〇 NMR (400MHz, CDC13) (5 8 · 02 (1H, s), 7.98 (lH, m), 7.90 (lH, m), 7.35-6.89 (4H, m) »6.72 (lH, m ), 4.71 (lH, m), 4.57 (lH, m), 4.27 (lH, s), 4.22 (lH, m), 3.85 (lH, m), 3.65 (3H, m), 3.30 (lH, m) , 3.11 (2H, m), 2.83 (2H, m), 2.81—2.54 (4H, m), 2.35 (1H, m) ^ 1.73-1.67 (4H, m). Mass spectrum: 490 · 32 (ΜΗ) +. (±) — 2 -— (7-methyl-1H—indazole-5-ylmethyl) —4-keto-4— [plant, 2, —dihydro—2 ^ —ketospiro— [4H- 3 ', 1-benzoxazine-4,4 / monopiperidinyl] monobutyric acid

室溫下隔夜攪拌一 2 - （ 7 —甲基一 1 Η — D引D坐一 5 —基 -246 - (242) 200529835 酮基螺 一丁酸 0.80 毫 甲基）—4 —嗣基—4— 〔1 ，2'—二氫—2'— 一 〔4 Η — 3 / ’ 1 一苯並卩惡嗪一 4，4 > —哌啶基〕 甲酯（0.191 1 g，0.40毫莫耳）和 Li〇H ( 19.3 mg，Stir overnight at room temperature-2-(7 -methyl-1 fluorene-1-1-5 -yl-246-(242) 200529835 ketospiromonobutyric acid 0.80 millimethyl)-4-fluorenyl-4 — [1,2, '-dihydro-2'-mono- [4 Η — 3 /' 1 monobenzoxazine-4,4 > —piperidinyl] methyl ester (0.191 1 g, 0.40 mmol ) And LiOH (19.3 mg,

莫耳）之四氫呋喃（10 ml )和水（8 ml )溶液。利用1N H C I酸化該反應混合物至約ρ Η 1，隨後真空下濃縮以除去 四氫咲喃，生成白色固體沈澱物，其係藉由過濾而收集。 利用少量水冲洗該固體2次並於真空下隔夜乾燥（1 〇 〇 % ) 。質譜：477 ( ΜΗ ) +。 實施例6 8 (土）一 1 一 〔1，f〕聯哌啶一厂一基—2— (7—甲基 —1Η—吲U坐一 5 —基甲基）一4—〔厂一二氫一 2^ —酮基螺一 〔4 Η - 3 /，1 一苯並噁嗪—4，4 / —哌啶基 〕一丁 — 1，4 —二酮 0 X Ο ΝΗMol) in tetrahydrofuran (10 ml) and water (8 ml). The reaction mixture was acidified with 1N H C I to about ρ Η 1 and then concentrated under vacuum to remove tetrahydrofuran to form a white solid precipitate, which was collected by filtration. The solid was rinsed twice with a small amount of water and dried overnight (1000%) under vacuum. Mass spectrum: 477 (ΜΗ) +. Example 6 8 (soil) 1 1 [1, f] piperidine one plant one base — 2 — (7-methyl — 1 Η — indole U sitting 5 — methyl group) — 4 — [plant one two Hydrogen-2 ^ -ketospiro- [4 Η-3 /, 1 monobenzoxazine-4,4 / -piperidinyl] monobutyl-1,4-dione 0 X Ο ΝΗ

室溫下令一 2— （7 —甲基—1Η — D引D坐一 5 —基甲基） 一 4 —酮基一 4—〔1^ ，2，一二氫—2，一酮基螺—〔4Η 一 3 — ，1 一苯並噁嗪—4，4 / —哌啶基〕一丁酸（0 · 〇 2 〇 g，0 · 0 4毫莫耳）、哌啶基哌啶（0 . 〇 〇 8 7 g，0 · 0 5毫莫耳） 及三乙胺（0.0 9 g，0 · 0 8毫莫耳）之C Η 2 C12 ( 5 m】）溶液 -247- (243) 200529835 與3—(二乙氧基磷醯氧基）—1，2，3 -苯並三嗪 3H)—酮（DEPBT，0.0155 g，0.05 毫莫耳）反應 攪拌該混合物，隨後經水（3 X 5 0 ml )冲洗。乾燥i 並於真空下除去溶劑。藉由製備性矽膠TLC (流洗ί % 2Μ ΝΗ4ΟΗ/甲醇之CH2C12溶液）純化粗產物， 所欲之產物（3 6 % )。 LC/MS: tR=1.18 分，613.47 (MH) +。 類似之方法製備： 實施例6 9 (± ) — 1 — 〔 1，4，〕聯哌啶一1 〆一基一2 — ( 7 —1H — D引唑一5 —基甲基）一4— 〔4— (2 -酮基- — 氯一2 Η — D奎口坐琳一3 —基）一呢D定一 1 —基〕一 ，4 一二酮 一 4 ( 隔夜 「機層 ί : 10 生成At room temperature, order a 2- (7-methyl-1, 1-, 2-, 4-, 5-methyl), 4-keto, 4- [1, 2, 2, dihydro-2, and one ketospiro— [4Η-1,3,1,1-benzoxazine-4,4 / -piperidinyl] monobutyric acid (0.02 g, 0.4 mmol), piperidinylpiperidine (0. 〇〇7 7g, 0. 05mmol) and triethylamine (0.09g, 0. 08mmol) C Η 2 C12 (5 m)) solution -247- (243) 200529835 and 3- (diethoxyphosphoryloxy) -1,2,3-benzobenzotriazine 3H) -one (DEPBT, 0.0155 g, 0.05 mmol) was stirred and the mixture was subsequently reacted with water (3 X 5 0 ml). Dry i and remove the solvent under vacuum. The crude product was purified by preparative silica gel TLC (flow washed with 2% ΝΗ4ΟΗ / methanol in CH2C12), the desired product (36%). LC / MS: tR = 1.18 points, 613.47 (MH) +. Prepared in a similar manner: Example 6 9 (±) — 1 — [1,4,] bipiperidine-1 1 fluorenyl — 2 — (7 —1H — D-azole- 5 —ylmethyl) — 4 — [4 -— (2-keto-—chloro-1, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 3-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, benzyl, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 2-, 1-, 2-, 2-, 2-, keto,-,-,-,-,-,-). generate

-甲基 -1，4 丁 一 1-Methyl-1,4 butane-1

】H-NMR ( 400MHz，CDC13 ) <5 7.9 9 ( 1 Η，m ) ，7H-NMR (400MHz, CDC13) < 5 7.9 9 (1 Η, m), 7

1 Η，m ) ，7.3 8 ( 1 Η，m ) ，7 · 1 4 ( 1 Η，m ) ，7 · 0 4 - (3H，m) ，6.70(2H，d，J=8.0Hz) ，4.70— ，m ) ，4 · 2 4 ( 2 H，ni ) ，4 · 0 0 ( 2 H，m ) ，3 · 7 0 ( 1 )，3.]8— 2.72(5H，m) ，2.64— 2.22(8H，m): -248 - • 62 ( -6.90 ! ( 3H Η，m 2.18 (244) 200529835 —0·82(17Η，m)。質譜：626·34(ΜΗ) +。 實施例7 0 (±) — 1— (1，4 —二氧雜一8 —氮雜一螺〔4.5〕癸一8 —基）一 2— (7 —甲基一1H—D引唑一5 -基甲基）一4 — 〔4 一 （2 — 嗣基一1 ’ 4 — —•氣一2 Η — D 奎 D坐琳一3 —基）一 口定 一 1—基〕一 丁 — 1,4 — 一 嗣 Η1 Η, m), 7.38 (1 Η, m), 7 · 1 4 (1 Η, m), 7 · 0 4-(3H, m), 6.70 (2H, d, J = 8.0Hz), 4.70 —, M), 4 · 2 4 (2 H, ni), 4 · 0 0 (2 H, m), 3 · 7 0 (1), 3.] 8— 2.72 (5H, m), 2.64— 2.22 (8H, m): -248-• 62 (-6.90! (3H Η, m 2.18 (244) 200529835-0.82 (17Η, m). Mass spectrum: 626 · 34 (ΜΗ) +. Example 7 0 ( ±) — 1— (1,4—dioxa-8—aza-spiro [4.5] decyl-8-yl) —2— (7-methyl-1H—Dimidazole-5-ylmethyl) One 4 — [4 One (2 — 嗣 基 一 1 '4 — — • qi 1 2 Η — D Kui D Zelin 1 3 —）) 口 一 1 —〕] 丁 — 1, 4, — 嗣 Η

JH-NMR ( 400MHz ^ CDC13) δ 8·06 ( 1H，s) ，7.75 ( lH，m) ，7.36(lH，m) ，7·14(1Η，η〇 ，7.01—6.7 9 (3H，m) ，6.70(lH，m) ，4.70— 4.49 (2H，m)，JH-NMR (400MHz ^ CDC13) δ 8.06 (1H, s), 7.75 (lH, m), 7.36 (lH, m), 7.14 (1Η, η, 7.01-6.7 9 (3H, m) , 6.70 (lH, m), 4.70— 4.49 (2H, m),

4.23 (2H，m) ，3.98(lH，m) ，3.87(3H，m) ，3.65 一 3·44(4Η，ηι) ，3.26(lH，m) ，3.10—2.88 (3H，m )，2.75(lH，m) ，2.51(3H，s) ，2.35(lH，m)， 2.00(lH，m) ，：1.70— 1.00(9H，m)。質譜：601.38 (ΜΗ ) +。 實施例7 ] (土）一] - (1，4 —二氧雜一8 —氮雜一螺〔4.5〕癸一8 一基）一2 — ( 7 —甲基一]Η —吲唑一 5 —基甲基）一4 一 - 249 - (245) (245)200529835 [1 ^ ，2 — -二氫一2 / —酮基螺〔4H — 3 / —苯並噁嗪 —4，4 / 一哌啶基〕—丁一 1，4 一二酮4.23 (2H, m), 3.98 (lH, m), 3.87 (3H, m), 3.65-3.44 (4Η, η), 3.26 (lH, m), 3.10-2.88 (3H, m), 2.75 ( lH, m), 2.51 (3H, s), 2.35 (lH, m), 2.00 (lH, m) ,: 1.70-1.00 (9H, m). Mass spectrum: 601.38 (ΜΗ) +. Example 7] (Earth)-]-(1,4-dioxa-8-aza-spiro [4.5] dec-8-yl)-2-(7-methyl-] fluorene-indazole-5 -Methyl) -4-249-(245) (245) 200529835 [1 ^, 2--dihydro-2 / -ketospiro [4H-3 / -benzoxazine -4,4 / one Piperidinyl] -butane-1,4-dione

^H-NMR ( 400MHz，CDC13 ) 5 9.2 7 ( 1Η，m ) ，8.00 ( lH，s) ，7.37(lH，m) ，7.23(lH，m) ，7.10-6.99 (3H，m) ，6.87(lH，m) ，4.54(lH，m) ，3·97 — 3.50(10H，m) ，3.30(lH，m) ，3.16-2.76 (4H，m )，2.53(3H，s) ，2.35(lH，m) ，2.20— 1.00(9H， m )。質譜：588·36(ΜΗ)+。 實施例7 2 (±) — N，N— 二甲基一2— （7 —甲基一1H— D 引唑一5 — 基甲基）一 4 —嗣基—4—〔4一（2-嗣基—1，4 —二氯— 2 Η — D奎唑啉一 3 —基）一哌啶—1 —基〕一 丁醯胺^ H-NMR (400MHz, CDC13) 5 9.2 7 (1Η, m), 8.00 (lH, s), 7.37 (lH, m), 7.23 (lH, m), 7.10-6.99 (3H, m), 6.87 ( lH, m), 4.54 (lH, m), 3.97 — 3.50 (10H, m), 3.30 (lH, m), 3.16-2.76 (4H, m), 2.53 (3H, s), 2.35 (lH, m), 2.20—1.00 (9H, m). Mass spectrum: 588 · 36 (ΜΗ) +. Example 7 2 (±) —N, N—dimethyl—2— (7—methyl—1H—D azole—5-ylmethyl) —4—fluorenyl—4— [4— (2- Fluorenyl-1,4-dichloro-2 fluorenyl-D quinazoline-3-yl) -piperidine-1-yl] monobutylamine

-250- (246) 200529835 實施例7 3 (±) — 1— (2，6 —二甲基一嗎啉一4 —基）一2— (7 — 甲基一1H —吲唑一5 —基甲基）一4一 〔4一 （2 —酮基—1 ，4 —二氫—2 Η — D奎唑啉一 3 —基）一哌啶—1 —基〕—丁 Η-250- (246) 200529835 Example 7 3 (±) — 1 — (2,6 —dimethylmonomorpholine — 4-yl) — 2 — (7 —methyl — 1H — indazole — 5-yl (Methyl) -4-[[4-((2-keto-1, 4-dihydro-2, hydrazone-D-quinazoline-3-yl) -piperidine- 1-yl] -butyridine

LC/MS: tR=1.41 分，573·39(ΜΗ) +。 Ο. 實施例74 (±) — 2— (7 —甲基一1Η — 口 引唑一5 —基甲基）一1—( 4 —甲基一呢11定一1 —基）一4 — 〔4 — (2 — 嗣基一1’4 — 一氯一2 Η — D奎 口坐琳一3 — 基）一Ι|β Π定 一 1 —基〕丁 一 1，4 -二酮 ΗLC / MS: tR = 1.41 points, 573.39 (ΜΗ) +. 〇. Example 74 (±) — 2 — (7 —methyl-1 1 — — oxazol 5 —ylmethyl) — 1 — (4 —methyl — 11 11 — 1 —yl) — 4 — [ 4 — (2 — fluorenyl-1'4 — monochloro — 2 hydrazine — D quinone seroline — 3 —yl) — Ι | β Π 定 一 1 —yl] butan-1,4-dione hydrazone

H-NMR ( 4 0 0MHz CDC]3) 58.06 (]H，b) ，7·60 — -251 - 200529835 (247) 6.73 (7H，m) ，4.71(lH，m) ，4.54(2H，m) ，4.26 (2H，m) ，4·05— 3.89 (2H，m) ，3.65(lH，m)， 3.09-2.81 (4H，m) ，2.61(3H，s) ，2.41(2H，m) ，：1.76— 0.51(15H，m)。質譜：557.38(MH) +。 實施例7 5 (±) — 2— （7—甲基一1H —吲唑一 5 —基甲基）一1—嗎 啉一4 —基-4— 〔4— (2 —酮基—1，4 —二氫—2H —喹 唑啉—3 —基）一哌啶—1 一基〕丁一 1，4 一二酮 ΗH-NMR (400 MHz CDC) 3) 58.06 (] H, b), 7.60 — -251-200529835 (247) 6.73 (7H, m), 4.71 (lH, m), 4.54 (2H, m) , 4.26 (2H, m), 4.05-3.89 (2H, m), 3.65 (lH, m), 3.09-2.81 (4H, m), 2.61 (3H, s), 2.41 (2H, m) ,: 1.76—0.51 (15H, m). Mass spectrum: 557.38 (MH) +. Example 7 5 (±)-2-(7-methyl-1H-indazol 5-ylmethyl)-1-morpholine 4-yl-4-[4-(2-keto-1, 4-dihydro-2H-quinazolin-3-yl) -piperidine-1-yl] butan-1,4-dione

LC/MS : tR= 1.32 分，5 4 5.42 ( ΜΗ) 實施例76 (±) — Ν，Ν —二甲基一2— (7 —甲基一1Η — D引唑一5 — 基甲基）一 4一酮基一〔厂，2> —二氫—2 / -酮基螺— 〔4Η - 3 / ，1 —苯並噁嗪一 4，4 / 一哌啶基〕一丁醯胺LC / MS: tR = 1.32 minutes, 5 4 5.42 (ΜΗ) Example 76 (±) — Ν, Ν —dimethyl—2— (7 —methyl—1Η — dazole—5 —methylmethyl) -4-keto-one [factory, 2> -dihydro-2 / -ketospiro-[4—-3 /, 1 -benzoxazine -4,4 / -piperidinyl] -butyramine

-252 - (248) (248)200529835 LC/MS : tR = 1.27 分，512.30 ( M+Na) 實施例7 7 (土）一 2— (7 —甲基一1H—D引唑一5 —基甲基）一1—( 哌啶—1 —基）—4 — 〔 1 / ，2 / —二氫—2 / —酮基螺— 〔4 Η - 3 ’1 —苯並D惡嗦—4 ’ 4 —喊Β定基〕一 丁 — 1 ’ 4 —二酮-252-(248) (248) 200529835 LC / MS: tR = 1.27 minutes, 512.30 (M + Na) Example 7 7 (Earth) -2 (7-methyl-1H-D-oxazole-1-5-yl (Methyl)-1- (piperidine-1-yl) -4— [1 /, 2 / —dihydro-2 / —ketospiro — [4 Η-3 '1 —benzo Doxa-4 — 4-Hydroxybenzyl] monobutyl-1'4-dione

]H-NMR ( 400MHz » CDC13) 5 9 · 2 6 - 9 · 0 1 ( 1 Η，m )， 8.09(lH，s) ，7·42— 6.89(7H，m) ，4.56(lH，m) ，3·84(1Η，ηι) ，3.65(3H，m) ，3·30(2Η，ηι)， 3.05 (3H，m) ，2.81(lH，m) ，2.60(3H，s) ，2.39 (lH，m) ，2.09(2H，m) ，1.85(lH，m) ，1·43 — 0.79(9H，m)。質譜：530.34(MH)+。 實施例7 8 (±) — 2— (7 —甲基一1H — D 引唑一5 —基甲基）一 4—〔 4— (2—酮基一1，4 —二氫一 2H— D奎唑啉一 3 —基）一哌 啶一 1 一基〕—1 一哌啶—基一丁一 1，4 —二酮 - 253 - (249) 200529835 Η] H-NMR (400MHz »CDC13) 5 9 · 2 6-9 · 0 1 (1 Η, m), 8.09 (lH, s), 7.42— 6.89 (7H, m), 4.56 (lH, m) , 3.84 (1Η, η), 3.65 (3H, m), 3.30 (2Η, η), 3.05 (3H, m), 2.81 (lH, m), 2.60 (3H, s), 2.39 (lH , M), 2.09 (2H, m), 1.85 (lH, m), 1.43-0.79 (9H, m). Mass spectrum: 530.34 (MH) +. Example 7 8 (±) — 2— (7-methyl-1H—D Indazole—5-ylmethyl) —4— [4- (2-keto-1,4-dihydro-2H—D Quinazoline- 3-yl) -piperidine- 1-yl] -1 -piperidine-yl-butane- 1,4-dione-253-(249) 200529835 Η

1H-NMR ( 400MHz，CDC13 ) 5 8.02 ( 1H，s) ，7 lH，m) ，7.14(lH，m) ，7.04-6.90(3H，m)， (lH，d，J=8.0Hz) ，4.69(lH，m) ，4·56(1Η， ，4.24(2H，d，J=7.2Hz) ，4.02(lH，m) ，3.65 ，m) ，3.33(3H，m) ，3·07(3Η，ηι) ，2.78 (1] )，2」5(3H，s) ，2.36(lH，m) ^ 1.8 0 - 1.5 0 ( m ) ，：1.43(4H，b) ，：l.26(2H，b) ，0·81(2Η， 。質譜：543.40(MH) +。 實施例7 9 (土）1— 〔1，4 〕聯呢卩定一 1 —基一2— ( 1Η — —5 —基甲基）一 4—〔〗/ ，2< —二氫—2 — —酮基 4 Η — 3 — ，：1 一苯並噁嗪一4，4 / 一哌啶基〕—丁一 .82 ( 6.73 m) (2H Λ » m 4H， b ) 吲唑 螺〔 1 ， 41H-NMR (400MHz, CDC13) 5 8.02 (1H, s), 7 lH, m), 7.14 (lH, m), 7.04-6.90 (3H, m), (lH, d, J = 8.0Hz), 4.69 (lH, m), 4.56 (1Η,, 4.24 (2H, d, J = 7.2Hz), 4.02 (lH, m), 3.65, m), 3.33 (3H, m), 3.07 (3Η, η), 2.78 (1), 2 "5 (3H, s), 2.36 (lH, m) ^ 1.8 0-1.5 0 (m), 1.43 (4H, b), 1.26 (2H, b ), 0 · 81 (2Η,. Mass spectrum: 543.40 (MH) +. Example 7 9 (Earth) 1— [1, 4] 卩 卩 一 1 1 — radical — 2 — (1Η — — 5 — base A) 4— [〗 /, 2 < —dihydro — 2 — — keto 4 Η — 3 —,: 1 monobenzoxazine 4, 4 / monopiperidinyl] — butyl 1.82 (6.73 m) (2H Λ »m 4H, b) Indoxaspiro [1, 4

-254 - 200529835 (250) 】H-NMR(400MHz，CDC13) 58.86( lH，m) ，7. lH，s) ，7·54— 6.85 (7H，m) ，4·73— 4·48 (3H， ，3.96— 3.80 (3H，m) ，3.73—3.58 (3H，m) ，3. 2.78 (5H，m) ，2.55— 2.24(5H，m) ，2.02—1.79 ，m) ，1.70— 0.79(7H，m)。質譜：599.31 (M + N a ) + 。 實施例8 0 (±) — 1- (1，4 一 二氧雜一8 —氮雜一螺〔4.5〕 —基）一2 — ( 7 —甲基一1 Η — D引口坐一 5 一基甲基） [1 ^ ，2，一二氫—2，一 酮基螺〔4Η— 3，，1 — 嗦一 4，4 —呢Π定基〕—丁一 1，4一 一酬 苯 卜8 -4 -並噁-254-200529835 (250)] H-NMR (400MHz, CDC13) 58.86 (lH, m), 7.lH, s), 7.54-6.85 (7H, m), 4.73-4.48 (3H ,, 3.96— 3.80 (3H, m), 3.73—3.58 (3H, m), 3. 2.78 (5H, m), 2.55— 2.24 (5H, m), 2.02—1.79, m), 1.70—0.79 (7H) , M). Mass spectrum: 599.31 (M + Na) +. Example 8 0 (±) — 1- (1,4 dioxa-8—aza-spiro [4.5] —yl) 2 — (7 —methyl-1 1 Η — D inlet sitting one 5 one Methyl group) [1 ^ 2, 2, dihydro-2, 1 ketospiro [4Η-3 ,, 1-嗦 -4, 4-Π 定 基]-Ding 1,2,4-one benzene 8 -4-and evil

98 ( m ) 1 7 — (6H 人 Ο ΝΗ98 (m) 1 7 — (6H person Ο ΝΗ

LC/MS ; tR= 1.25 分，5 74.25 ( ΜΗ) 實施例8 1 (±)—】一（1，4 —二氧雜一8— 氮雜一螺〔4.5〕^ —基）一2— (1H — 口引唑一5 —基甲基）一4— 〔4—( 酬基一1，4 — —•氯一2 Η — D奎口坐琳一3 —基）—l|R 口定一 基〕一丁 — ]，4 一二酮 —8 2 — 1 - -255 - (251) 200529835LC / MS; tR = 1.25 minutes, 5 74.25 (ΜΗ) Example 8 1 (±) —]-(1,4-dioxa-8-aza-spiro [4.5] ^-yl) -2— ( 1H — oxazolyl-5 —ylmethyl) — 4 — 〔4— (amyl-1,4 — — • chloro-1 2 Η — D quinone azine 3 —yl) —l | R Yl] monobutyl —], 4-dione-8 2 — 1--255-(251) 200529835

LC/MS ·· tR= 1.34 分，5 8 7.3 8 ( ΜΗ) + 〇 實施例82 (±) — 2- (1H-D引唑一5 —基甲基）一Ν，Ν —二甲基 —4— 〔4— (2 —酮基一1，4 一二氫一2H-D奎唑啉一3 — 基）一哌啶一 1 一基〕一 丁醯胺 ΗLC / MS ·· tR = 1.34 minutes, 5 8 7.3 8 (ΜΗ) + 〇 Example 82 (±) — 2- (1H-D azole—5-ylmethyl) —N, N —dimethyl— 4— [4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine-1 1-yl] monobutylamine

LC/MS : tR= 1.28 分，4 8 9.3 3 ( ΜΗ) +。 實施例8 3 (± ) — 5 — { 2 — 〔 1，4 〕聯哌 D定基一1 —幾基）一 4 一酮基一 4— 〔4— (2 —酮基一1，4 —二氫一 2H — D奎唑啉 一 3 —基）一哌啶一 1 一基〕—丁基一吲唑一 1 —羧酸特丁 酯 -256 - (252)200529835LC / MS: tR = 1.28 minutes, 4 8 9.3 3 (ΜΗ) +. Example 8 3 (±) — 5 — {2 — [1,4] piperidine D amidyl — 1 — several bases — 4 —one keto — 4 — [4 — (2 — keto 1, 4 — 2 Hydrogen-2H — D-quinazoline-3 —yl) -piperidine-1 1yl] —butyl-1indazole-1 1-butyl carboxylate -256-(252) 200529835

LC/ MS : 實施例8 4 (± ) - 2 -( 酮基—4 — 〔 4 3 —基）一哌Π定 7Η —甲基一 1Η — D引唑一 5 —基甲基）一4 — —(2—酮基一1,4 —二氫一 2Η — 〇奎唑啉一 —1 一基〕—Ν-丙一 2-’炔基—丁醯胺LC / MS: Example 8 4 (±)-2-(keto-4 — [4 3 —yl) -pididine 7Η —methyl — 1Η — dozozol — 5-ylmethyl) — 4 — — (2-keto-1,4—dihydro-2Η — O quinazoline-1 — 1]] — N-propan-2-'alkynyl-butanamide

L C / M S : 門冬氨酸酯中 (L) — 2—特 基一1，4 —二 〕丁酸苄酯 tR=l.33 分，535.32 (M+Na) + 。 荀產物及實施例 T氧羰基胺基一 4一酮基—4一〔4一 （2-酮 氨一 2 Η — D奎Π坐琳一 3 —基）—I派Π定—1 一基 -257 - (253) (253)200529835L C / M S: (L) — 2-tertyl-1,4-di] benzyl butyrate in aspartic acid ester tR = 1.33 minutes, 535.32 (M + Na) +. Hydrazone products and examples T oxycarbonylamino- 4 -keto-4-[4-(2-ketoamine-2 Η-D quineline-3 -yl) -I pi-1-1- 257-(253) (253) 200529835

對N —特丁氧羰基一 L一門冬氨酸一 α —苄酯（1.4 g ，4.33毫莫耳）和3’ 4 —二氫—3— (4—哌啶基一 2(1H )—[]奎唑啉酮（1.26 g，4.33 毫莫耳）之 CH2C12(12 ml) 攪拌溶液，一次加入3-（二乙氧基磷醯氧基）一 1，2，3 —苯並三嗪—4(3H) — 酮（DEPBT，1.425 g，4.76 毫莫 耳），隨後再逐滴地加入三乙胺（0.724 ml，5.20毫莫耳 )。於攪拌下所生成之懸浮液逐漸轉呈均質並於室溫下隔 夜攪拌（15小時）。利用Ch2C12稀釋該混合物並利用 NaOH ( 0.5N )和水進行冲洗。分離相層，藉由Na2S04乾 燥有機層，並於真空下濃縮後產生淡黃色泡沬。藉由閃蒸 管柱層析（流洗液：10%甲醇之CH2C12溶液）純化該粗產 物，生成無色油狀物。質譜：5 5 9 ( M + Na) +。 (L) 一 2-特丁氧鑛基胺基—4一酮基一 〔4一 （2-酮基 —1，4 —二氫一2 Η — D奎哇啉一 3 —基）一Π定一 1 一基〕 一丁酸 - 258 - (254)200529835For N-tert-butoxycarbonyl-L-aspartic acid-α-benzyl ester (1.4 g, 4.33 mmol) and 3 '4-dihydro-3— (4-piperidinyl-2 (1H) — [ ] Stirring solution of quinazolinone (1.26 g, 4.33 mmol) in CH2C12 (12 ml), add 3- (diethoxyphosphoryloxy) -1,2,3-benzotriazine-4 in one portion (3H) — ketone (DEPBT, 1.425 g, 4.76 mmol), and then triethylamine (0.724 ml, 5.20 mmol) was added dropwise. The resulting suspension was gradually homogeneous with stirring Stir overnight at room temperature (15 hours). Dilute the mixture with Ch2C12 and rinse with NaOH (0.5N) and water. Separate the phases, dry the organic layer with Na2S04, and concentrate under vacuum to produce a pale yellow foam. The crude product was purified by flash column chromatography (flow washing solution: 10% methanol in CH2C12) to give a colorless oil. Mass spectrum: 5 5 9 (M + Na) +. (L)-2-special Butoxyminylamino-4-keto-mono- [4-((2-keto-1,4-dihydro-1, 2 hydrazine-D quinaline-3-yl), 1-dione- 1-yl], 1-butyl Acid-258-(254) 200529835

ο HOο HO

丄 i 將10%Pd/C ( 150 mg) —次加入至Parr瓶中之2 —特 丁氧鑛基胺基—4 —酮基一 4—〔4— (2-酮基—1，4一 一 氫一 2 Η —喹唑啉一 3 —基）一哌啶—1 一基〕一丁酸苄酯 (1.48 g，2.76毫莫耳）之乙酸乙酯/甲醇（16 ml，1: 1 )溶液中。於5 2 p s i氫氣下，利用P a r r裝置進行氫化1小時 。丁LC分析（10%甲醇之CH2C12溶液）顯示定量轉化。過 濾該混合物並於真空下濃縮，生成玻璃狀無色固體（1 . 1 4 g，93% )。 實施例8 5 (L ) 一 { 1 一 〔 1，4 /〕聯哌啶—1 / 一羰基）一 3 -酮基 一 〔4 — (2 —嗣基一1，4 — 一 氯一2 Η — D 奎 π坐琳一3 —基) 一哌啶一 1 —基〕一丙基} 一氨基甲酸特丁酯 Λ丄 i Add 10% Pd / C (150 mg) to the Parr bottle at a time 2-Tetraoxoamino-4-Keto-4-[4-keto-1, 4-one Monohydro-2, hydrazone-quinazoline-3-yl) -piperidine-1-yl] benzyl monobutyrate (1.48 g, 2.76 mmol) in ethyl acetate / methanol (16 ml, 1: 1) In solution. Hydrogenation was performed under a hydrogen of 5 2 p s i using a Parr apparatus for 1 hour. LC analysis (10% methanol in CH2C12) showed quantitative conversion. The mixture was filtered and concentrated under vacuum to give a glassy colorless solid (1.14 g, 93%). Example 8 5 (L)-{1-[1,4 /] bipiperidin-1-one-carbonyl) -3-keto- [4 -— (2-fluorenyl-1,4—monochloro—2] —D-Quinyl-spiline-3-yl) -piperidine-1-yl] -propyl} -butyl carbamate Λ

對2 -特丁氧羰基胺基一 4 一酮基一 4 一 〔 4 一 （ 2 —酮 200529835 (255) 基一1，4 —二氫—2 Η - D奎唑啉一 3 —基）—哌啶—1 -基 〕一丁酸（1 · 1 4 g，2 · 5 5 毫莫耳）和 4 一哌啶（5 2 5 mg， 2·81毫莫耳）之CH2C12 ( 20 ml )攪拌溶水，一次加入3 — (二乙氧基磷醯氧基）—1，2，3 -苯並三嗪一 4(3H) —酮（〇£?8丁，840 1^，2.81毫莫耳），並隨後逐滴地加 入三乙胺（ 0.427 ml，3.06毫莫耳）。室溫下隔夜攪拌所 生成之混合物（1 5小時）。利用C Η 2 C 12稀釋該混合物並利 用NaOH ( 0·5Ν )溶液和水進行冲洗。分離相層，利用 Na2S〇4乾燥有機層，經於真空下濃縮後生成淡黃色泡沫。 藉由閃蒸管柱層析（流洗液：1 0 % ( 1 Μ氨之甲醇溶液） 之CH 2。12 溶 液） 純化粗 .產物 ，生成無 丨色泡沫（ 1 . 08 g， 7 1 % ) 〇 1 Η -NMR ( 400MHz， CDC13 ) 5 8. 8 6 — 8.55 (1 i H ，br ) ，7_05 ( 1Η， b r )，6. 93 ( 1H，br ) ，6.82 ( 1 H ’ br ) j 6.72 (1H， d ，J =7.6 Η z )， 6.10- -5 .68 ( 1H， b r ) ，5. 20 (1Η ，m ) y 54 .70-4 • 40 ( 2 H，b r ) ，4.20 ( 2H 5 br ) ， 4.0 1- -3.82 ( 2H ，br ) ，3 . 10-2. 88 (3H，br ) 5 2.99 ( 3Η， b r )， 2 .53 (6H， br ) ，1 .90 — 1 · 1 0 ( 23H， m )° 質 譜：5 9 7 ( Μ Η ) +。 (L) — 2 —胺基—1—〔1，4'〕聯 定—1-—基一 4 一 〔4一 （2- 酮基—1，4一 二氫一 2Η — D 奎 ti坐啉一 3—基）一 哌陡—1 —基〕一丁 — 1’ 4 —二酮 -260 - (256) (256)200529835P-tert-butoxycarbonylamino-4, keto-4, [4-mono (2-ketone 200529835 (255) yl-1,4-dihydro-2, hydrazone-D quinazoline-3-yl) — Piperidin-1-yl] monobutyric acid (1.14 g, 2.55 mmol) and 4 piperidine (5 2 5 mg, 2.81 mmol) were stirred in CH2C12 (20 ml) Dissolve in water and add 3- (diethoxyphosphoranyloxy) -1,2,3-benzotriazine-4 (3H) -one (0.008? Butyl, 840 1 ^, 2.81 mmol) in one portion. ), And then triethylamine (0.427 ml, 3.06 mmol) was added dropwise. The resulting mixture was stirred overnight at room temperature (15 hours). The mixture was diluted with C Η 2 C 12 and rinsed with NaOH (0.5N) solution and water. The phases were separated and the organic layer was dried over Na2SO4 and concentrated under vacuum to form a pale yellow foam. The crude product was purified by flash column chromatography (flow washing solution: 10% (1 M ammonia in methanol solution) in CH 2.12 solution) to give a colorless foam (1.08 g, 71%). ) 〇1 Η-NMR (400MHz, CDC13) 5 8. 8 6 — 8.55 (1 i H, br), 7_05 (1 Η, br), 6. 93 (1H, br), 6.82 (1 H 'br) j 6.72 (1H, d, J = 7.6 Η z), 6.10- -5 .68 (1H, br), 5. 20 (1Η, m) y 54 .70-4 • 40 (2 H, br), 4.20 ( 2H 5 br), 4.0 1- -3.82 (2H, br), 3. 10-2. 88 (3H, br) 5 2.99 (3Η, br), 2.53 (6H, br), 1.90 — 1 · 1 0 (23H, m) ° Mass spectrum: 5 9 7 (ΜΗ) +. (L) — 2 —Amine—1— [1,4 ′] Binding—1-—A-4— [4— (2-Keto-1,4—Dihydro—2Η) — D quinoline -3 -yl) -piperidin-1 -yl] -butyl-1 '4-dione -260-(256) (256) 200529835

將三氟乙酸（2 m 1 )加入至{ 1 — 〔 1，4 /〕聯哌D定 —1 —羯基）—3 —酮基—3—〔4一（2- 酮基—1，4 — 二氯一2H — D奎哇琳—3 —基）一呢Π定一 1 一基〕一丙基} —氨基甲酸特丁酯（1.05 g，1.76毫莫耳）之CH2C12(12 ml )攪拌溶液中。室溫下攪拌該混合物直至完全轉化爲止 (經由LCMS監測，約1 5小時）。利用水稀釋該混合物並 於攪拌下緩慢地加入NaOH ( 1 .5 g )。分離相層並利用 CH2C12萃取水層。將結合之有機層置於Na2S04上乾燥，經 於真空下濃縮後生成淡黃色泡沬（8 60 mg，98% )。質譜 ：497 ( MH ) +。 實施例8 6 (L ) — 1 一 〔 1，4 〕聯派 D定一 1 一基—2 — ( 1 Η — D引 D朵一 5 —基胺基）一 4— 〔4 一 （2 —酮基一 1，4 —二氫— 2 Η 一 □奎 D坐琳一3 基）一喊 D定 一 1 —基〕一丁 一 1，4 一 一 酮 -261 - (257) (257)200529835Trifluoroacetic acid (2 m 1) is added to {1 — [1, 4 /] piperidine Didine — 1 — fluorenyl — 3 — keto — 3 — [4-one (2- keto — 1, 4 — Dichloro—2H—D quivalin—3—yl) —Nine—1—1—yl] —propyl} —T-butyl carbamate (1.05 g, 1.76 mmol) stirred in CH2C12 (12 ml) In solution. The mixture was stirred at room temperature until complete conversion (monitored by LCMS, approximately 15 hours). The mixture was diluted with water and NaOH (1.5 g) was added slowly with stirring. The phases were separated and the aqueous layer was extracted with CH2C12. The combined organic layer was dried over Na2S04, and concentrated under vacuum to give a pale yellow foam (8 60 mg, 98%). Mass spectrum: 497 (MH) +. Example 8 6 (L) — 1 — [1, 4] assigns D to a 1 1 — 2 — (1 Η — D to D 1 — 5 — aminoamino) — 4 — [4 1 (2 — Keto-1,4-dihydro-2 2 Η □ 奎 D D 坐 坐 一 3 3 基) yell D 一 1 1-〕] butyl -1, 4- ketone-261-(257) (257) 200529835

於氮氣下將2 —二環己基膦基一 2，一 （N，N—二甲 基胺基）一聯苯（4.1 mg，0.0105 毫莫耳）、Pd2(dba) 3 (4·8 mg，0_005毫莫耳）及碳酸絶（54.6 mg，0.168毫莫 耳）加入至5 m 1轉瓶中之2 一胺基一 1 一〔 1，4 /〕聯哌啶 一 1，一基一4一 〔4一 （2 —酮基—1,4 —二氫一 2H —喹 口坐啉—3 —基）一哌卩定一 1 一基〕一丁 — 1，4 —二酮（52 mg，0.105毫莫耳）N-特丁氧羰基—5 —溴—吲哚（31 mg，0.105 毫吴耳）；文獻 Tetrahedon 2000，PP.8473-8482 描述之方法製備）之四氫呋喃（1 ml )溶液中。利用 t e fl 〇 η ®蓋子密封該瓶。於8 0 °C和攪拌下加熱該深澄色反 應混合物。於8(TC下隔夜持續該反應。經1 7小時後’轉化 達約50%。真空下除去溶劑，令殘餘物溶解於CHWh中並 進行過濾。藉由製備性TLC ( 1 0%甲醇之CH/h溶液）純 化所欲之產物，生成經特丁氧羰基保護之產物（1 1 mg ’ 1 5 % )。質譜·· 71 2 ( ΜΗ ) +。令該中間產物（1 1 mg )溶 解於CH2CI2 ( 3 ml )中，並加入三氟乙酸〇·5 ）。該 無色溶液轉變爲黃褐色並於室溫下攪拌1 · 5小時。真空下 濃縮該混合物，經高真空下乾燥後生成黃褐色粉末（1 5 -262 - (258) (258)200529835 mg，100%)。質譜：612(MH)+。 實施例8 7 (L) 一 1一 〔1，4 〕聯呢陡一1 —基—2— (5 —氯—2 —硝基一苯基胺基）—4— 〔4— (2 -醒基一 1，4一二氫 一 2H — D奎唑啉一3 —基）一哌啶一1—基〕一丁 一 1，4 一 二酮Under nitrogen, 2-dicyclohexylphosphino-2,1- (N, N-dimethylamino) -biphenyl (4.1 mg, 0.0105 mmol), Pd2 (dba) 3 (4.8 mg, 0_005 millimoles) and carbonic acid (54.6 mg, 0.168 millimoles) were added to a 5 m 1 rotary flask. 2 Amine 1 1 [1, 4 /] piperidine 1 1, 1 base 4 1 [4-((2-keto-1,4-dihydro-2H-quinoxaline-3-yl) -piperidine-1 1-yl] -butan-1,4-dione (52 mg, 0.105 Mmol) N-tert-butoxycarbonyl-5-bromo-indole (31 mg, 0.105 mmol); Tetrahedon 2000, prepared by the method described in PP.8473-8482) in tetrahydrofuran (1 ml) solution. The bottle was sealed with a t e fl o η ® cap. The dark colored reaction mixture was heated at 80 ° C with stirring. The reaction was continued overnight at 8 ° C. After 17 hours, the conversion reached about 50%. The solvent was removed under vacuum, the residue was dissolved in CHWh and filtered. Preparative TLC (10% methanol in CH / h solution) to purify the desired product to produce a product protected by t-butoxycarbonyl (11 mg '15%). Mass spectrum · 71 2 (ΜΗ) +. The intermediate product (11 mg) was dissolved in CH2CI2 (3 ml), and trifluoroacetic acid (0.5) was added. The colorless solution turned yellow-brown and was stirred at room temperature for 1.5 hours. The mixture was concentrated under vacuum and dried under high vacuum to give a yellow-brown powder (1 5 -262-(258) (258) 200529835 mg, 100%). Mass spectrum: 612 (MH) +. Example 8 7 (L) 1 1 [1, 4] dibenzyl 1 —yl — 2 — (5 —chloro — 2 —nitro-phenylamino) — 4 — [4 — (2- 1-1,2-dihydro-2H-D quinazoline-3-yl) -piperidine-1-yl] -butane-1,4-dione

將飽和NaHC03溶液（4滴）加入至2 —胺基—1 —〔 1 ，4 /〕聯哌啶一 1 / —基一 4 —〔 4 — ( 2 —酮基—1，4 — 一·氣一 2 Η — D奎口坐琳一3 —基）一呢D定一1 —基〕一丁 一 1 ’ 4 —二酮（33.7 mg，0.068 毫莫耳）和 4一氯一1，2 —二硝 基苯（16.8 mg，0.075毫莫耳）之乙醇（0.5 ml)攪拌溶 液中。室溫下攪拌該混合物70小時直至達到約轉化60%。 藉由製備性HPLC純化產物以生成黃色固體（1 7.7 mg，40 % )。質譜：652 ( ΜΗ ) +。 實施例8 8 (L ) — 1 一 〔 1，4 〕聯喊 D定—1 —基一 2 — ( 6 -氯— 嘧啶一 4 —基胺基）一4一 〔4— (2-酮基—1，4 —二氫— -263 - (259) (259)200529835 2H 一 D奎唑啉—3 —基）—哌啶—1 一基〕丁〜1，4 —二嗣Saturated NaHC03 solution (4 drops) was added to 2-amino-1— [1,4 /] bipiperidine-1 / -yl-4— [4 — (2 —keto-1,4 —one gas) 1 2 Η — D Kuikou Lin Lin 3 — Ji) a D D 1 — Ji] 1 butan 1 1 4-dione (33.7 mg, 0.068 mmol) and 4-Chloro-1, 2 — Dinitrobenzene (16.8 mg, 0.075 mmol) in a stirred solution of ethanol (0.5 ml). The mixture was stirred at room temperature for 70 hours until about 60% conversion was reached. The product was purified by preparative HPLC to give a yellow solid (1 7.7 mg, 40%). Mass spectrum: 652 (ΜΗ) +. Example 8 8 (L) — 1 — [1, 4] D-D — 1 — 1 — 2 — (6-chloro — pyrimidine — 4 —amino) — 4 — [2 — (2-keto) —1,4 —dihydro — -263 — (259) (259) 200529835 2H 1-D-quinazolin-3-yl) -piperidine-1 monoyl] butane ~ 1,4-dihydrazone

於1 3 0 °C下藉由微波輻射，加熱置於可受微波之小瓶 中的2 —胺基—1 一〔 1，4 /〕聯哌啶一 1 - 一基—4 一〔 4 —(2 —酮基一 1，4 —二氫一 2H — D奎唑啉〜3_基）一口底 Π定一1—基〕一丁 ―1，4 —二酮（22.3 mg，0.045 毫莫耳 )和4，6 -二氯嚼D定（16 mg，0.095毫莫耳）之2 -丙醇 (0.5 ml)溶液40分鐘。LC/MS顯示90%轉化真空下除 去溶劑並令殘餘物分佈於CH2C12和IN NaOH溶液中。分離 有機層，置於Na2S04上乾燥，並於真空下濃縮。藉由閃蒸 管柱層析（10% 1N氨之甲醇溶液的CH2C12溶液）純化殘 餘物，生成白色固體（23mg，84%)。 】H-NMR ( 400MHz，CDC13 ) 5 8.36 ( 1H，d ’ J = 12.8Hz) ，8.04 - 7.8 1 ( 1 H，2s ) ’ 7.14 ( 1H，t，J = 7·6Ηζ) ，7·10— 6.80 (2H，m) ，6.74 ( 1H’ t，J = 8.2Hz) ，6.52— 6.42 ( lH，m) ，5.90-5.50 (lH’br) ，4·85 — 4.40(3H，m) ，4·40—4·05(3Η，πι) ，4.05 — 3.82 ( 1H，m) ’ 3.20— 3.00 ( 2H ’ m) ’ 3.00— 2.68 ( 2H ，m) ，2·68— 2.30(8 H，ni) ，2.05— 1.90(2H，m)， 1 .90 — 0.7 0 ( 1 2H，m )。質譜：609 ( ΜΗ ) +。 - 264 - (260) 200529835 類似之方法製備： 實施例8 9 (L ) — 1 一 〔 1，4 /〕聯哌啶—1 / —基—2 — ( 2 —氯— 9H —嘿 Π 令—6 —基胺基）—4 一 〔4— (2 —嗣基—1，4一 二氫一2H — D奎唑啉一3 —基）一哌啶一1—基〕一丁一 1，Heated by microwave radiation at 130 ° C 2 -amino-1-[1, 4 /] piperidine-1-1-4-[4 — ( 2-keto-1,4-dihydro-2H-D quinazoline ~ 3-yl) one mouthful of dine-1-yl] -butane-1,4-dione (22.3 mg, 0.045 mmol) And a solution of 4,6-dichlorochlodine (16 mg, 0.095 mmol) in 2-propanol (0.5 ml) for 40 minutes. LC / MS showed 90% conversion. The solvent was removed under vacuum and the residue was distributed in CH2C12 and IN NaOH solutions. The organic layer was separated, dried over Na2S04, and concentrated under vacuum. The residue was purified by flash column chromatography (10% 1N ammonia in methanol in CH2C12) to give a white solid (23 mg, 84%). ] H-NMR (400MHz, CDC13) 5 8.36 (1H, d 'J = 12.8Hz), 8.04-7.8 1 (1 H, 2s)' 7.14 (1H, t, J = 7 · 6Ηζ), 7 · 10— 6.80 (2H, m), 6.74 (1H't, J = 8.2Hz), 6.52—6.42 (lH, m), 5.90-5.50 (lH'br), 4.85 — 4.40 (3H, m), 4. · 40-4 · 05 (3Η, π), 4.05—3.82 (1H, m) '3.20- 3.00 (2H'm)' 3.00- 2.68 (2H, m), 2.68- 2.30 (8 H, ni), 2.05— 1.90 (2H, m), 1.90—0.7 0 (12H, m). Mass spectrum: 609 (ΜΗ) +. -264-(260) 200529835 Prepared by a similar method: Example 8 9 (L) — 1-[1,4 /] bipiperidine — 1 / —yl — 2 — (2 —chloro — 9H —Hey Π — 6-ylamino) -4— [4 -— (2-fluorenyl—1,4—dihydro—2H—D quinazoline—3-yl) —piperidine—1-yl] —butan-1,

實施例9 0 · (L) 一 2- （4 一胺基一 6—甲基一5 —硝基—嘧啶—2-基 胺基）—1 — 〔 1，4 /〕聯哌啶—1 / —基—4 — 〔 4 一（ 2 —酬基一1 ’ 4 一 一氯一 2 Η — D奎口坐琳一3 —基）一卩JR Π定—1 一基〕一丁 — 1，4 —二酮 -265 - (261) (261)200529835Example 9 0 · (L)-2- (4-monoamino-6-methyl-5 -nitro-pyrimidin-2-ylamino)-1-[1,4 /] bipiperidine-1 / —Base—4 — [4 One (2 —Paid 1 — 1 '4 —Chlorine 2 2 — D Kuikou Zaolin 3 —Base) —JR Π 定 —1 1 base] —Ding — 1, 4 --Dione-265-(261) (261) 200529835

LC/MS: tR=1.12 分，649 (MH) 實施例9 1 (L ) — 1 —〔 1，4 /〕聯哌啶—1 / —基—2 — ( 4，5 —二 胺基一 6 —甲基—嘧啶一 2 —基胺基）—4—〔4一 （2-酮 基一1，4 — 一氨一2 Η — D奎口坐琳一 3 —基）一呢Β定一1 —基 〕—丁 — 1，4 —二酮LC / MS: tR = 1.12 minutes, 649 (MH) Example 9 1 (L) — 1 — [1,4 /] bipiperidine — 1 / —yl — 2 — (4,5 —diamino-6 —Methyl—pyrimidin — 2-amino — 4 — [4- (2-keto-1, 4 — —amino — 2 Η — D quinoxaline — 3 — yl) — B 1 — 1 —Yl] —butane-1,4-dione

將10%Pd/C(60 mg)加入至Parr瓶中之2— (4 —胺 基一 6 —甲一基5 -硝基一嘧啶一 2—基胺基）一 1 一〔1， 4 聯哌啶一 1 / 一基—4 —〔 4 一（ 2 —酮基—1，4 —二 氣一 2 Η 一 D奎D坐琳一 3 —基)—卩低D 疋一1 —基〕一丁 一 1 ’ 4 —二酮之2 : 1甲醇/乙酸乙酯（6 m 1 )溶液中。於5 5 -266 - 200529835 (262) psi氫氣下搖動該混合物20小時。經由通過寅氏鹽過濾該 混合物，並於真空下濃縮爲濾液以生成無色固體（4 1 .2 m g，2 步驟 4 9 · 2 % )。 LC/MS: tR=0.86分，619(MH) + 。 實施例92 (L ) — 1 — 〔 1，4 /〕聯哌啶—1 / —基一2 — ( 7 —甲基 —1H— 〔1，2，3〕三唑並〔4，5— d〕嘧啶一 5 —基胺基 )—4— 〔4— (2 —酮基一 1，4 —二氫一2H — D奎唑啉一3 —基）一卩浪D定—1—基〕—丁 — 1，4 —二嗣Add 10% Pd / C (60 mg) to the 2- (4-amino group-6-methyl-yl 5-nitro-pyrimidine-2-ylamino group)-1- [1,2 Piperidine 1/1 -4-[4-(2 -keto -1,4 -digas-2 Η-D quinine D zeolin-3 -yl)-卩 low D 疋 1 -yl] 1 Butan-1'4-dione in a 2: 1 methanol / ethyl acetate (6 ml) solution. The mixture was shaken under 5 5 -266-200529835 (262) psi hydrogen for 20 hours. The mixture was filtered through yin's salt and concentrated to a filtrate under vacuum to give a colorless solid (4 1.2 mg, 2 step 49 · 2%). LC / MS: tR = 0.86 minutes, 619 (MH) +. Example 92 (L) — 1 — [1,4 /] bipiperidine — 1 / —yl — 2 — (7 —methyl — 1H — [1,2,3] triazolo [4,5 — d ] Pyrimidin-5-ylamino) -4— [4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -pyridine-1-yl] — Ding — 1, 4, 2

對 1 — 〔 1，4 /〕聯哌啶—1 / —基—2 - （ 4，5 —二 胺基一 6—甲基—嘧啶一 2 —基胺基）一4— 〔4一 （2—酮 基—1，4 — 一·氯一2H — D奎 口坐琳一3 —基）一 D定一1 —基 〕一丁一 1，4 —二酮（10.6 mg，0.0125 毫莫耳）之乙酸 (1 .5 ml )攪拌溶液加入亞硝酸鈉（25 mg )，隨後加入 數滴水。室溫下攪拌所生成之淡黃色溶液6小時。利用水 和甲醇稀釋該反應混合物，並藉由製備性HP LC進行純化 ，生成無色油/固體（3 · 0 m g，2 8 % )。 -267 - (263) 200529835 LC/MS : tR= 1.07 分，63 0 ( ΜΗ) +。 合成實施例93至95之一般方法 令 2 —胺基—1 一〔1，4 〕聯_0定—1 一基—4一〔 4 一 （2 —酮基—1，4一二氫—2Η —喹唑啉一 3 —基）一哌 啶—1—基〕一丁 一 1，4一二酮（0.014毫莫耳）、一系列 之中的·一個（〇·〇7毫莫耳，5當量）及無水MgS04固體（ 0.031毫莫耳，2.2當量）之1，2 —二氯乙烷（3.0 ml)溶 · 液與催化量之乙酸反應，並隔夜搖動。一次加入氰基氫硼 化鈉（〇·〇7毫莫耳，5當量）並再次隔夜搖動該懸浮液。 藉由通過SCX筒過濾或製備性HPLC以進行純化。 實施例93 (L ) 一 1 一 〔 1，4 '〕聯哌啶—1 ' 一基—2 —（ 2 '— 口比旋基）一甲基—胺基）一 4一 〔4— (2 —酮基一 1，4 —For 1-[1, 4 /] bipiperidin-1 /-radical-2-(4,5-diamino-6-methyl-pyrimidine-2 -ylamino)-4-[4-(2 —Keto—1,4—monochloro-1 2H — D quinoxaline 3 —yl) —D amine 1 —yl] —butan-1,4-dione (10.6 mg, 0.0125 millimoles) To a stirred solution of acetic acid (1.5 ml) was added sodium nitrite (25 mg), followed by a few drops of water. The resulting pale yellow solution was stirred at room temperature for 6 hours. The reaction mixture was diluted with water and methanol and purified by preparative HP LC to give a colorless oil / solid (3.0 mg, 28%). -267-(263) 200529835 LC / MS: tR = 1.07 minutes, 63 0 (ΜΗ) +. General Methods for Synthesis Examples 93 to 95 Let 2 —Amine—1— [1,4] sodium — 1—4—1—4— [4— (2 —Keto—1,4—Dihydro—2Η —Quinazoline- 3-yl) -piperidine-1-yl] -butane-1,4-dione (0.014 mmol), one of a series 1,2) -dichloroethane (3.0 ml) in anhydrous MgS04 solid (0.031 mmol, 2.2 eq) was reacted with a catalytic amount of acetic acid and shaken overnight. Sodium cyanoborohydride (0.07 mmol, 5 eq.) Was added in one portion and the suspension was shaken again overnight. Purification was performed by filtration through a SCX cartridge or preparative HPLC. Example 93 (L)-1-[1,4 '] piperidine-1'-1-2-(2 '-orbital)-methyl-amino)-4-[4-(2 —Keto-1,4 —

二氫一 2H —喹唑啉一 3 —基）—_啶—1 一基〕一丁一 1，Dihydro- 2H -quinazoline- 3 -yl) -_pyridin-1 -yl] -butan-1,

LC/MS: tR=0.87 分，588 (MH) -268 - (264) (264)200529835 實施例94 (L ) — 1 — 〔 1，4 /〕聯哌啶—1 / 一基—2 — ( ( 5 ' D引Π坐基）—甲基一胺基）—4一 〔4— (2 —酬基一 1，4 一氨一2H — D奎Π坐琳一 3 —基）一呢Π定—1 _基〕一 丁 一 1 4 —二酮LC / MS: tR = 0.87 minutes, 588 (MH) -268-(264) (264) 200529835 Example 94 (L) — 1 — [1,4 /] bipiperidine — 1/1 base — 2 — ( (5'D-inducing group) —methyl-amino group) —4— [4 -— (2-indicyl group—1,4—amino—2H—D quinyl group—3—yl group) — —1 _yl] monobutan 1 4 —dione

LC/MS: tR=0.92 分，626 (MH) +。 實施例9 5 (L) 一 1— 〔1，4 〕聯呢11定—1 —基—2— （ （3 甲基一苯基）—甲基—胺基）一 4〔4— (2 —酮基一 1， 一 _•氣一2 Η — 〇奎哇琳一 3 —基）一喊Π定一1 —基〕一 丁 — ，4 —二酮 -269- (265) 200529835LC / MS: tR = 0.92 points, 626 (MH) +. Example 9 5 (L)-1-[1, 4] hydrazine 11-1 -yl-2-((3 methyl-phenyl)-methyl-amino)-4 [4-(2- Keto-1, 1- • Ga-1 2 Η — 〇Quavalene — 3 —yl) yidene — 1 —yl] 1-butyl —, 4-dione-269- (265) 200529835

LC/MS: tR=1.08 分，600(MH)LC / MS: tR = 1.08 points, 600 (MH)

實施例9 6 (L ) — 1 —〔 1，4 /〕聯哌啶一 1 '—基—4 — [ 4 - ( 2 - 酮基一1，4 —二氫一2H-D奎唑啉—3 —基）一哌啶一1 — 基〕—2-（嘧啶—4一基胺基）一丁 — 1，4一二酮Example 9 6 (L) — 1 — [1,4 /] bipiperidin-1′-yl-4 — [4-(2 -keto-1,4-dihydro-2H-D quinazoline — 3 -yl) -piperidine-1 -yl] -2- (pyrimidin-4-ylamino) -butane-1,4-dione

N^NN ^ N

將 10%Pd/C ( 10 mg)加入至 Parr瓶中之 1 — 〔 1， 4 /〕聯哌啶—1 / —基—2 — ( 6 —氯一嘧啶一4 —基胺基 )—4— 〔4— (2 —酮基一1，4 —二氫一2H — 口奎唑啉一 3 —基）一呢 H定—1 一基〕一丁 — 1，4 —二酮I (21 mg)之 1 :1乙酸乙酯/甲醇（4 ml )溶液中。於55 psi氫氣下且 在Parr裝置上進行隔夜氫化。過濾脫氣之混合物並於真空 下濃縮。藉由製備性HPLC純化殘餘物，生成黃色固體（ - 270 - (266) 200529835 12.4 mg，45%)。質譜：575(MH) +。 實施例9 7 (L) 一 1一 〔1，〕聯_11定一 1 —基一 2— (4—經基 4 一 二氫一 2H 4一二酮 —環己基胺基）一 4—〔4一（2 —酮基一 1 一 D奎π坐琳一 3—基）一呢π定一 1 一基〕丁一 110% Pd / C (10 mg) was added to Parr bottle 1-[1, 4 /] bipiperidin-1 /-yl-2-(6-chloro-pyrimidine-4-ylamino)-4 — [4- (2-keto-1,4-dihydro-2H-orthoquinazolin-3-yl) -n-Hidine-1-yl] -butane-1,4-dione I (21 mg ) In a 1: 1 ethyl acetate / methanol (4 ml) solution. Overnight hydrogenation was performed on a Parr unit under 55 psi hydrogen. The degassed mixture was filtered and concentrated under vacuum. The residue was purified by preparative HPLC to give a yellow solid (-270- (266) 200529835 12.4 mg, 45%). Mass spectrum: 575 (MH) +. Example 9 7 (L) 1 1 1 [1,] 2 1 11 1 1-radical 1 2-(4- via radical 4-dihydro-2H 4-dione-cyclohexylamino)-4-[ 4 one (2-keto-1 1-D-quinone sirine 3-3-yl) one π fixed one 1 one group] Ding one 1

對2 -胺基—1 一〔 1，4 /〕聯哌啶一 1 / —基—4 —〔 4 一 （2 —酮基—1，4 —二氫一 2H —喹唑啉一 3 -基）一哌 啶一 1 一基〕—丁 — 1，4一二酮（47.9 mg，0.096 毫莫耳 )和4 一羥基—環己酮（11 mg，0.096毫莫耳；合成方法 記載於文獻 Can· J. Chem· 1 994，72，1 699- 1 704 )之甲醇（ 1.0 ml )攪拌溶液，加入過量之氯化鋅，隨後加入氰基氫 硼化鈉（5當量）。室溫下攪拌該懸浮液6天。真空下除去 甲醇並令殘餘物分佈CH2C12和IN NaOH溶液中。利用 C H 2 C 12 ( 3 X )萃取水層。令結合之c H 2 C12溶液通過寅氏鹽 筒並於真空下濃縮。藉由製備性TLC ( 10 % IN氣之甲醇 溶液的CH2C12溶液）純化白色固體之所欲產物（I5·3 ，2 7% )。質譜：5 9 5 ( ΜΗ ) +。 -271 - (267) 200529835 實施例9 8 (L) — 1— 〔1，4'〕聯_|]定一 1'—基〜 咪U坐—4 一基甲基）胺基〕—4—〔4一（2— _其 —•氣一2 Η 一嗤哗琳一 3 -基）一呢D定一 1〜基〕 4 —二酮P-amino-1-[1,4 /] piperidine-1 /-4-[4-(2-keto-1, 4-dihydro-2H-quinazoline-3-group ) -Piperidine- 1-yl] -butane-1,4-dione (47.9 mg, 0.096 mmol) and 4-hydroxy-cyclohexanone (11 mg, 0.096 mmol); the synthesis method is described in the literature Can J. Chem 1 994, 72, 1 699-1 704) in methanol (1.0 ml), a solution was stirred, an excess of zinc chloride was added, followed by sodium cyanoborohydride (5 equivalents). The suspension was stirred at room temperature for 6 days. The methanol was removed under vacuum and the residue was distributed in CH2C12 and IN NaOH solution. The aqueous layer was extracted with C H 2 C 12 (3 X). The combined c H 2 C 12 solution was passed through a Yin's salt cartridge and concentrated under vacuum. The desired product (I5 · 3, 2 7%) was purified by preparative TLC (CH2C12 solution of 10% IN gas in methanol in CH2C12). Mass spectrum: 5 9 5 (ΜΗ) +. -271-(267) 200529835 Example 9 8 (L) — 1— [1,4 '] Co_ |] Determining a 1′-yl group to a methyl group—4 monomethyl) amine group] —4— 〔4 一 (2— _ 其 — • qi-1 2 Η 嗤 嗤 林林 33- 基) 一 呢 D 定 一 1〜 基〕 4-dione

斗）—次加入 至2 -胺基1 一〔 1，4 /〕聯哌啶—1，—基〜4〜^ 將氰基氫硼化鈉（8.8 mg，0.04 15毫莫；§：、 〔4〜（2 —酮基一 1，4 —二氫一 2Η -喧唑啉一 3 —基）〜哌啶〜 —基〕—丁一 1，4一二酮（20.6 mg，0.0415 毫莫耳）和々 —咪唑羧基醛（4 11^，0.04 15毫莫耳）之（^2(：12(1.〇1111 )攪拌溶液中。室溫下攪拌該懸液2天，隨後分彳布方々 dCl2和IN NaOH溶液中。分離相層並利用CH2C12萃取水 層。將結合之有機層置於NadCU上乾燥並於真空下濃縮。 藉由製備TLC ( 10% 1N氨之甲醇溶液的ChC】2溶液）純 化殘餘物，生成無色油狀之所欲產物，其係靜置固化（ 6 · 1 m g，2 6 % ) 〇 】H - NMR(400MHz，CDCh) 〇7·61 ( 1H，d，J=4.8Hz )，7.16(lH，t，J=7.6Hz) ，7」〇— 6.85(3H，m)， -272 - 200529835 (268) 6.67 (lH，d，J二 8.0Hz) ，4.85— 4·63(2Η，ιη) ，4.63 —4.40( 1H，m) ，4.40—3.63 (7H，m) ，3.25-2.40( 10Η，ηι) ，2·15— 0.70(18H，m)。質譜：577(MH) + 實施例9 9 (L ) 一 1 一〔 1，4 /〕聯哌啶基—1 / —羰基）一 3 -酮基 —3— [ 4 - (2 — 酮基一1，4一二氫一2H—D奎唑啉一3 — 基）一哌啶一基〕丙基} 一 4一甲氧基一苯醯胺Bucket)-added to 2-amino group 1-[1,4 /] dipiperidine -1,-group ~ 4 ~ ^ sodium cyanoborohydride (8.8 mg, 0.04 15 mmol; § :, [ 4 ~ (2-keto-1,4-dihydro-2H-oxazoline-3-yl) ~ piperidine ~ -yl] -butan-1,4-dione (20.6 mg, 0.0415 millimoles) And 々-imidazole carboxylic aldehyde (4 11 ^, 0.04 15 mmol) in a stirred solution (^ 2 (: 12 (1.01111)). The suspension was stirred at room temperature for 2 days, and then divided into df2 And IN NaOH solution. The phases were separated and the aqueous layer was extracted with CH2C12. The combined organic layer was dried on NadCU and concentrated under vacuum. TLC (ChC] 2 solution of 10% 1N ammonia in methanol solution) was prepared The residue was purified to give the desired product as a colorless oil, which was solidified upon standing (6.1 mg, 26%). 〇] H-NMR (400MHz, CDCh) 〇7 · 61 (1H, d, J = 4.8 Hz), 7.16 (lH, t, J = 7.6Hz), 7 "-6.85 (3H, m), -272-200529835 (268) 6.67 (lH, d, J = 8.0Hz), 4.85-4.63 (2Η, ιη), 4.63 — 4.40 (1H, m), 4.40—3.63 (7H, m), 3.25-2.40 (10Η, η), 2.15-0.70 (18H, m). Mass spectrum: 577 (MH) + Example 9 9 (L)-1-[1, 4 /] bipiperidinyl-1 /-carbonyl)-3- Keto-3— [4-(2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine-yl] propyl} -4-methoxy-phenylhydrazone amine

〕聯呢卩定—1 一基—4— 〔4— (2 —嗣基一 1’ 4 — 一氯— 2H — D奎唑啉一3 —基）一哌啶一1—基〕一1，4 —二酮（ 91.5 mg，0.184毫莫耳）和對—茴香醯氯（34.6 mg， 0.203毫莫耳）之CH2C12攪拌溶液中。室溫下攪拌該淡黃 色溶液2.5小時以達成完全轉化。利用IN NaO Η溶液冲洗 該反應混合物，隨後利用CH2C12萃取水層。令結合之有機 層通過寅氏鹽筒，經真空下濃縮後生成玻璃狀固體。藉由 閃蒸管柱層析（]〇%】N氨之甲醇溶液的CH2C12溶液）純 -273- (269) (269)200529835 化粗產物，生成玻璃狀固體（92.8 mg，80% )。 】H-NMR ( 400MHz，CDC13 ) 5 8 · 5 5 — 8.4 7 ( 1 Η，d )， 8.10 - 7.78 ( 3H ^ m ) ，7.09(lH，t，J=7.4Hz) ，6.96 -6.74 (4H，m) ，5.62-5.44 (lH，br) ，4.75-4.40( 3H，m) ，4.40-4.05 (3H，m) ，4.05—3.82 (lH，br) ，3.76(3H，s) ，3.18— 2.88(3H，m) ,2.88-2.70( lH，m) ，2.70— 2.30(8H，m) ，2·05— 1.19(14H，m )。質譜：631 ( MH) +。 實施例1 〇 〇 (L ) — N — { 1 —〔 1，4 /〕聯哌啶基—1 / —羰基）—3 —酬基一3 — [ 4 — ( 2 —嗣基一1 ’ 4 — _氣一2 Η 一 D奎口坐琳 —3-基）一哌啶_1 一基〕一丙基丨一 4一羥基一苯醯胺〕 Binadin-1—1-yl-4— [4 -— (2-methyl-1 ′ 4—monochloro-2H—D quinazoline-3-yl) -piperidine-1—yl] —1, CH2C12 in a solution of 4-dione (91.5 mg, 0.184 mmol) and p-anisyl chloride (34.6 mg, 0.203 mmol). The pale yellow solution was stirred at room temperature for 2.5 hours to achieve complete conversion. The reaction mixture was washed with IN NaO Η solution, and then the aqueous layer was extracted with CH 2 C 12. The combined organic layer was passed through a Yin's salt cartridge and concentrated under vacuum to give a glassy solid. The crude product was purified by flash column chromatography (] 0%] N ammonia in methanol solution of CH2C12), and the crude product was converted to a glassy solid (92.8 mg, 80%). ] H-NMR (400MHz, CDC13) 5 8 · 5 5 — 8.4 7 (1 Η, d), 8.10-7.78 (3H ^ m), 7.09 (lH, t, J = 7.4Hz), 6.96 -6.74 (4H , M), 5.62-5.44 (lH, br), 4.75-4.40 (3H, m), 4.40-4.05 (3H, m), 4.05-3.82 (lH, br), 3.76 (3H, s), 3.18- 2.88 (3H, m), 2.88-2.70 (lH, m), 2.70-2.30 (8H, m), 2.05--1.19 (14H, m). Mass spectrum: 631 (MH) +. Example 1 〇〇 (L) —N — {1 — [1,4 /] bipiperidinyl-1 / —carbonyl) —3 —anal — 3 — [4 — (2 —fluorenyl — 1 ′ 4 — _Qi 2 Η 1 D Kuiziline — 3-yl) a piperidine_1 1 yl] a propyl 丨 a 4 hydroxy monophenylamine

室溫下將三溴化硼（1Μ CH2C12溶液，0.6 ml )逐滴 地加入N -丨1 — 〔 1，4 /〕聯哌啶基—1 / —羰基—3 — 酬基一 3 — 〔4 一 （2 —醒基一1 ’ 4 — 一氣一2 Η — D奎口坐琳一 3 -基）—哌啶一 1 一基〕一丙基} — 4 —甲氧基一苯醯胺 之CH2 CMS拌溶液（69 mg )中以進行反應。室溫下攪拌 - 274 - 200529835 (270) 所生成之懸浮液7小時，隨後先後藉由利用過量之三乙胺 和甲醇以中止該反應。真空下除去溶劑，令殘餘物溶解於 甲醇中並藉由製備性HPLC進行純化。 LC/MS: tR 二 1.03 分，617(MH) +。 實施例1 〇 1 (L ) — 1 Η —吡啶一3 —羧酸{ 1 —〔 1，4 /〕聯哌啶基一 1' 一幾基）一 3 —酮基一 3— 〔4一 （2 —酮（基一1，4 —二 氫一 2Η-喹唑啉一 3 -基）一哌啶一 1—基〕一丙基} 一 醯胺Boron tribromide (1M CH2C12 solution, 0.6 ml) was added dropwise at room temperature to N-丨 -1-[1,4 /] bipiperidinyl-1 / -carbonyl -3-thiol-3-[4 Mono (2-awake 1-4 '-one gas-2 Η-D kui zeolin-3 -yl)-piperidine-1-yl]-propyl}-4-methoxy-benzylamine CH2 The CMS was stirred in a solution (69 mg) for the reaction. The resulting suspension was stirred at room temperature-274-200529835 (270) for 7 hours, and then the reaction was stopped by using an excess of triethylamine and then methanol. The solvent was removed in vacuo, the residue was dissolved in methanol and purified by preparative HPLC. LC / MS: tR 1.03 points, 617 (MH) +. Example 1 〇1 (L) — 1 hydrazone —pyridine — 3-carboxylic acid {1 — [1, 4 /] bipiperidinyl — 1 ′ — several groups — 3 — keto — 3 — [4 ( 2-keto (yl-1,4-dihydro-2'-quinazoline-3-yl) -piperidine-1-yl] monopropyl} monofluorenamine

對吡唑—3 —羧酸（4 mg，0.03 6毫莫耳）和2 —胺基 一 1 一 〔1，4>〕聯_11 定—1 —基—4—〔4— (2- 酮基 一 1，4一二氫—2H —喹唑啉一 3 —基）一哌啶一 1 一基〕 —丁一 1，4 —二酮（13 mg，0.026 毫莫耳）之 CH2C12(1 m 1 )攪拌溶液，一次加入3 —(二乙氧基碟醯氧基）一 1， 2，3 —苯並三嗪一4(3H)—酮（DEPBT，8.6 mg，0.036 毫莫耳），隨後加入1滴三乙胺。室溫下隔夜攪拌所生成 之混合物（〗5小時）。令該混合物分佈於0.5 N N a 0 H溶液 - 275 - (271) (271)200529835 和CH2C12中。分離相層並利用CH2C12 ( 3x )萃取水層。 LC MS分析顯示產物殘留於水層中。藉由製備HPLC純化產 物以生成黃色油狀物（17.2 mg，94% )。質譜：591 (MH) + 。 合成實施例102至134之一般方法P-pyrazole-3-carboxylic acid (4 mg, 0.03 6 millimoles) and 2-amino-1 1- [1,4 >] di-11-1-1-yl-4— [4— (2-one 1,4-dihydro-2H —quinazolin-3 —yl) —piperidine—1 1yl] —butan-1,4-dione (13 mg, 0.026 mmol) CH2C12 (1 m 1) Stir the solution, and add 3- (diethoxydiacetoxy) -1,2,3-benzotriazine-4 (3H) -one (DEPBT, 8.6 mg, 0.036 mmol) in one portion, and then Add 1 drop of triethylamine. The resulting mixture was stirred overnight at room temperature (5 hours). The mixture was distributed in a 0.5 N N a 0 H solution-275-(271) (271) 200529835 and CH2C12. The phases were separated and the aqueous layer was extracted with CH2C12 (3x). LC MS analysis showed that the product remained in the aqueous layer. The product was purified by preparative HPLC to give a yellow oil (17.2 mg, 94%). Mass spectrum: 591 (MH) +. General method for synthesizing Examples 102 to 134

令起始胺2 -胺基一 1 一〔 1，4 /〕聯哌啶—1 / —基 —4 — 〔 4 — (2 —酮| 基一1，4 一 二氯一 2H—D奎卩坐啉一 3 — 基）一哌B定一 1 一基〕一丁 — 1，4 一二酮分散於9 6孔槽反 應鹽（每個約10 mg / 1 ml CH2C12 )中。先後加入個別之 醯基氯（約2當量）和結合樹脂之因相哌啶鹼（4當量）。 隨後進行隔夜搖動。將約4當量之反式胺樹脂加入至每個 孔槽中，並進一步搖動該微反應盤5小時。過濾該反應混 合物，隨後藉由製備性HP LC或通過SCX筒過濾或該二者 以進行純化。每個實施例之HPLC滯留時間和質譜數據係 示於表2。 -276 - (272) 200529835 表2 .醯胺和氨基甲酸酯 實施例 結構 HPLC 以（分） MS (M+) 102 0 旋光性 Up V。〇 ^Vyf 〇 广入 σ 1.84 637.38 103 Vr^i旋光性 ° V 1.39 565.45 104 〇 ，旋光性 \ 1.89 641.46 105 旋光性 1.73 619.42Let the starting amine 2-amino- 1-[1, 4 /] dipiperidin-1- 1--4-[4 — (2-ketone | 1-1, 4-dichloro-2H-D quinidine Isoline-3-yl) -piperidine-B-1 1-yl] -butyl-1,4-dione is dispersed in 96-well reaction salts (approximately 10 mg / 1 ml of CH2C12 each). Separate fluorenyl chloride (approximately 2 equivalents) and in-phase piperidine base (4 equivalents) of the resin were added. It was then shaken overnight. About 4 equivalents of the trans-amine resin was added to each well, and the micro-reaction disk was further shaken for 5 hours. The reaction mixture was filtered and then purified by preparative HP LC or by filtration through an SCX cartridge or both. The HPLC retention time and mass spectrometry data for each example are shown in Table 2. -276-(272) 200529835 Table 2. Amines and carbamates Examples Structure HPLC MS (M +) 102 0 Optical rotation Up V. 〇 ^ Vyf 〇 Wide entry σ 1.84 637.38 103 Vr ^ i optical rotation ° V 1.39 565.45 104 〇, optical rotation \ 1.89 641.46 105 optical rotation 1.73 619.42

-277 - (273)200529835 實施例 結構 HPLC Zr (分） MS _ 106 ΛΛ 旋光性 b 1.62 615.41 107 ^ 旋光性 XV F οςχτ 十 2.25 737.37 108 旋光性 XV 〇 ^Vrc, 又j〇人V HN N (V 2.12 669.3 109 ^ 旋光性 。4。 1.59 675.46-277-(273) 200529835 Example Structural HPLC Zr (min) MS _ 106 ΛΛ Optical rotation b 1.62 615.41 107 ^ Optical rotation XV F οχχ τ 2.25 737.37 108 Optical rotation XV 〇Vrc, and j human V HN N ( V 2.12 669.3 109 ^ Optical rotation. 4. 1.59 675.46

-278 - (274)200529835 實施例 結構 HPLC ，R (分） MS (M+) 110 旋光性 0 r,^ 1.62 601.43 111 旋光性 ^VxCI HN人7M人」 2.09 669.33 112 旋光性 \==/ NH °1 Cl 1.91 665.36 113 °\ /=\ 旋先性 5 。 1.68 646.37-278-(274) 200529835 Example Structural HPLC, R (min) MS (M +) 110 Optical rotation 0 r, ^ 1.62 601.43 111 Optical rotation ^ VxCI HN Human 7M Human "2.09 669.33 112 Optical rotation \ == / NH ° 1 Cl 1.91 665.36 113 ° \ / = \ Convolution. 1.68 646.37

-279 - (275)200529835 實施例 結構 HPLC tR (分) MS (Μ+) 114 旋光性 〇^ΝΗ Ο Qy ο—1 1.66 645.4 115 Q 旋光性 〇 ΗΝ^ο <s〇 2.14 690.45 116 旋光性 Ν^/ 。ο Ρ^οΗί 汾。 1.59 607.39 117 νΛ 旋光性 〇-°Χ ο 1.59 621.4-279-(275) 200529835 Example Structural HPLC tR (minutes) MS (M +) 114 Optical rotation 〇 Ν Ν Ο Qy ο-1.66.5.4 64 Q 115 Optical rotation 〇 Ν ^ ο < s〇2.14 690.45 116 Optical rotation Ν ^ /. ο Ρ ^ οΗί Fen. 1.59 607.39 117 νΛ optical rotation 〇- ° Χ ο 1.59 621.4

- 280 - (276)200529835 實施例 結構 HPLC Zr (分） MS (M+) 118 旋光性 0 η 广 H 丫 Ιγϋ u 〇rA 2.01 735.43 119 旋光性 ° 0 °^Η kAN/\ $ 0 Br 1.92 679.32 120 〇 旋光性 b 1.22 537.4 121 乂3 旋光性 O-O^VO^t^ 2.03 685.4-280-(276) 200529835 Example Structural HPLC Zr (Min) MS (M +) 118 Optical rotation 0 η Wide H γγγ u 〇rA 2.01 735.43 119 Optical rotation ° 0 ° ^ Η kAN / \ $ 0 Br 1.92 679.32 120 〇 Optical rotation b 1.22 537.4 121 乂 3 Optical rotation OO ^ VO ^ t ^ 2.03 685.4

-281 - (277)200529835 實施例 結構 HPLC 以（分） MS (Μ+) 122 旋光性 υΌγ。 〇 r^N^o V 丫 1.79 637.38 123 旋光性 1.84 669.3 124 Kv Jio旋光性 0” 1.53 636.35 125 /^Λ 旋光性 νΡ ΗΝ \ 2.04 691.35-281-(277) 200529835 Example Structural HPLC with (min) MS (M +) 122 Optical rotation υΌγ. 〇 r ^ N ^ o V γ 1.79 637.38 123 optical rotation 1.84 669.3 124 Kv Jio optical rotation 0 ”1.53 636.35 125 / ^ Λ optical rotation νΡ ΗΝ \ 2.04 691.35

- 282 - (278)200529835 實施例 結構 HPLC 办（分） MS (M+) 126 ΑΛ 旋光性 n}=^〇 1.89 657.35 127 cl 丫、 旋光性 r， 「ΝΛ) 〇 car H 1.86 649.39 128 旋光性 ry1? Hrv° 、。承 1.67 691.42 129 Cl-^^ 旋光性 1.84 635.38 - 283 - (279)200529835 實施例 結構 HPLC & (分） MS (M+) 130 旋光性 b 1.69 617.42 131 FN^| 旋光性 以！ Ο 〇·^ΝΗ r， Ι^ΝΛ)。 οςχτ 1.74 635.38 132 旋光性 b 1.84 631.44 133 ΒΓγ^Ι 旋光性 η Ο^^ΝΗ rV^ p人0 oar H 1.94 695.28-282-(278) 200529835 Example Structure HPLC Office (points) MS (M +) 126 ΑΛOptical rotation n} = ^ 〇1.89 657.35 127 cl γ, Optical rotation r, “NΛ) 〇car H 1.86 649.39 128 Optical rotation ry1 ? Hrv °, bearing 1.67 691.42 129 Cl-^^ optical rotation 1.84 635.38-283-(279) 200529835 Example structure HPLC & (MS) MS (M +) 130 optical rotation b 1.69 617.42 131 FN ^ | 〇 〇〇 ^ ΝΗ r, Ι ^ ΝΛ). Οςχτ 1.74 635.38 132 optical rotation b 1.84 631.44 133 ΒΓγ ^ 1 optical rotation η 〇 ^^ ΝΗ rV ^ p person 0 oar H 1.94 695.28

-284 - (280) (280)200529835-284-(280) (280) 200529835

合成實施例135至200之一般方法··General method for synthesizing Examples 135 to 200 ...

令起始胺2 —胺基—1 一〔 1，4 /〕聯哌啶一 1 / 一基 —4— 〔4— (2 —酮基—1，4 —二氫—2H —喹唑啉一 3 — 基）一哌啶一 1 一基〕一丁一 1，4 一二酮分散於9 6孔槽之 微反應盤（每個孔槽約1〇 nig/ 1 ml CH2C12 )中。將個別 之異氰酸酯（約2當量）加入至個別之孔槽中。進行搖動2 天。將4當量之反式胺樹脂加入至每一個孔槽中並進一步 搖動該微反應盤2天。過濾該反應混合物，並藉由製備性 HPLC或通過SCX筒過或該二者以純化個別之產物。每個 實施例之HPLC滯留時間和質譜數據係示於表3。 -285 - (281)200529835 第3 .脈 實施例 結構 HPL C iR (分） MS (MH)+ 135 旋光性 1.43 665.84 136 旋光性 b 〇 b 1.56 707.88 137 旋光性 \ Μ° /-Λ /Tlo 1.39 665.84Let the starting amine 2-amino-1— [1,2,4] piperidine-1 / mono-4— [4 -— (2-keto-1,4-dihydro-2H—quinazoline-1 3-Base) -piperidine- 1-yl] -butane-1,4-dione is dispersed in 96-well microreactors (each well is about 10nig / 1 ml CH2C12). Add individual isocyanates (about 2 equivalents) to individual wells. Shake for 2 days. 4 equivalents of trans-amine resin was added to each well and the micro-reaction disk was further shaken for 2 days. The reaction mixture was filtered and the individual products were purified by preparative HPLC or through a SCX cartridge or both. The HPLC retention time and mass spectrometry data for each example are shown in Table 3. -285-(281) 200529835 3. Structure of the pulse example HPL C iR (min) MS (MH) + 135 optical rotation 1.43 665.84 136 optical rotation b 〇b 1.56 707.88 137 optical rotation \ Μ ° / -Λ / Tlo 1.39 665.84

- 286 - (282)200529835 實施例 結構 HPL C /r (分） MS _)+ 138 /=\ 旋光性 VnG^O Ν—\ Q 。化 1.3 643.83 139 ΛΑ 旋光性 b 1.44 657.86 140 旋光性 以Γ ο 0*^^ΝΗ fiW 〇 CCXo Η 1.42 650.22-286-(282) 200529835 Example Structure HPL C / r (min) MS _) + 138 / = \ Optical rotation VnG ^ O Ν— \ Q. Chemical 1.3 643.83 139 ΛΑ optical rotation b 1.44 657.86 140 optical rotation to Γ ο 0 * ^^ NΗ fiW 〇 CCXo Η 1.42 650.22

-287 - (283)200529835 實施例 結構 HPL CtR (分） MS (MH)+ 141 旋光性 1.26 629.81 142 旋光性 。^)。 1.41 643.83 143 旋光性 b 1.24 615.78-287-(283) 200529835 Example Structure HPL CtR (min) MS (MH) + 141 Optical rotation 1.26 629.81 142 Optical rotation ^). 1.41 643.83 143 optical rotation b 1.24 615.78

-288 - 200529835 (284)-288-200529835 (284)

-289 - 200529835 (285) 實施例 結構 HPL C/R (分） MS (MH)+ 148 旋光性 丫0 HN 大八^ 0 Hf|l 人0 人 NH :力 1.44 684.67 149 旋光性 °\ 1.3 645.81 150 旋光性 b 1.24 645.81-289-200529835 (285) Example structure HPL C / R (minutes) MS (MH) + 148 optical rotation ah 0 HN big eight ^ 0 Hf | l human 0 human NH: force 1.44 684.67 149 optical rotation ° \ 1.3 645.81 150 optical rotation b 1.24 645.81

-290- 200529835 (286) 實施例 結構 HPL C (分） MS (MH)+ 151 旋光性 b 1.33 643.83 152 P C，\ 旋光性 Ftq 。彳： 1.56 718.22 153 VF旋光性 ΗΝγΝ"Τ^Ί 0丫NH ° ^nv^/；vnh 〇 以0 1.55 683.78 -291 - 200529835 (287) 實施例 結構 HPL C fR (分） MS _)+ 154 旋光性 匕》 0 2大人Nq 〇 0人 rjJH 人 NH 1.37 655.84 155 旋光性 b °\ 1.27 675.83 156 0 一 Vh旋光性 CK3 今 HN Ht° V 1.26 651.76-290- 200529835 (286) Example Structure HPL C (min) MS (MH) + 151 optical rotation b 1.33 643.83 152 PC, \ optical rotation Ftq.彳: 1.56 718.22 153 VF optical rotation ΗNγN " T ^ Ί 0 丫 NH ° ^ nv ^ /; vnh 〇 0 1.55 683.78 -291-200529835 (287) Example structure HPL C fR (min) MS _) + 154 optical rotation Sex Dagger 0 2 Adult Nq 〇0 Person rjJH Person NH 1.37 655.84 155 Optical rotation b ° \ 1.27 675.83 156 0 One Vh optical rotation CK3 Today HN Ht ° V 1.26 651.76

-292 - 200529835 (288) 實施例 結構 HPL C (分） MS (MH)+ 157 旋光性 b 1.39 643.83 158 /~λ 旋光性 ^—Ν 谷 1.43 643.83 159 /' 旋光性 c'-Q NH 〇=(nh %_〇 善〇〇 1.57 684.67 -293- 200529835 (289) 實施例 結構 HPL C fR (分） MS (MH)+ 160 F\/f 旋光性 Ο^^ΝΗ ρ人0 οα〇 Η 1.46 683.78 161 η 旋光性 CKD 今» ΗΝ \=/ 。名 Cl 1.48 684.67 162 /~\ 旋光性 b 1.5 657.86 163 〇辦>為臟 ΗΝ \=/ HN F 1.14 651.76 -294 - 200529835 (290) 實施例 結構 HPL C /r (分） MS (MH)+ 164 yC, 旋光性 NH 〇=Knh 1.34 685.66 165 旋光性 b 〇一 1.26 675.83 166 /=\ n 旋光性 ^<>-^0-0 H。 。彳H vH 1.28 701.87 167 F^/F 旋光性 ΗΝγΝνΤ^Ί °ΥΝΗ 0 ^V^ynh 以〇 1.52 718.22-292-200529835 (288) Example structure HPL C (min) MS (MH) + 157 optical rotation b 1.39 643.83 158 / ~ λ optical rotation ^ -N valley 1.43 643.83 159 / 'optical rotation c'-Q NH 〇 = (nh% _〇 善 〇〇〇1.57 684.67 -293- 200529835 (289) Example structure HPL C fR (minutes) MS (MH) + 160 F \ / f optical rotation 0 ^^ NΗ ρ human 0 οα〇Η 1.46 683.78 161 η optically active CKD today »ΗΝ \ = /. Name Cl 1.48 684.67 162 / ~ \ Optically active b 1.5 657.86 163 〇 Office > For dirty ΗN \ = / HN F 1.14 651.76 -294-200529835 (290) Example structure HPL C / r (min) MS (MH) + 164 yC, optical rotation NH 〇 = Knh 1.34 685.66 165 optical rotation b 〇—1.26 675.83 166 / = \ optical rotation ^ < >-^ 0-0 H.彳 H vH 1.28 701.87 167 F ^ / F optical rotation ΗΝγΝνΤ ^ Ί ° ΥNΗ 0 ^ V ^ ynh to 〇1.52 718.22

-295- 200529835 (291)-295- 200529835 (291)

- 296- 200529835 (292) 實施例 結構 HPL C (分） MS (MH)+ 171 Vu 旋光性 HN Η HN 1.31 633.77 172 _ _ 〇 ^ V-R 旋光性 ΟΌ 今 HN 上。 c,-^ 1.34 650.22 173 n Vh 旋光性 〇-〇 卞 >N〇t^ HN^ Cl——Cl 1.47 684.67 174 旋光性 b 為 °\ 1.27 675.83-296- 200529835 (292) Example Structure HPL C (minutes) MS (MH) + 171 Vu optical rotation HN Η HN 1.31 633.77 172 _ _ ^ ^ V-R optical rotation 〇Ό now HN. c,-^ 1.34 650.22 173 n Vh optical rotation 〇-〇 卞 > N〇t ^ HN ^ Cl——Cl 1.47 684.67 174 optical rotation b is ° \ 1.27 675.83

-297 - 200529835 (293) 實施例 結構 HPL C /r (分） MS (MH)+ 175 旋光性 b Μ。π尤 0 ) 1.34 659.83 176 1¾ 9"旋光性 〇丫 L 以〇 1.41 694.68 177 ςτ旋光性 ΗΝνΐΓΝνΤ^ 〇丫NH 0 :人1 以0 1.28 633.77-297-200529835 (293) Example Structure HPL C / r (min) MS (MH) + 175 optical rotation bM. π especially 0) 1.34 659.83 176 1¾ 9 " Optical rotation 〇γ L to 〇 1.41 694.68 177 τ Optical rotation ΗΝνΐΓΝνΤ ^ 〇γNH 0: Person 1 to 0 1.28 633.77

-298 - 200529835 (294) 實施例 結構 HPL CiR (分） MS (ΜΗ)+ 178 ςτ 性 ΗΝγΝ 丫^ 。丫 L 0 以0 1.39 650.22 179 Βγν^Ι 旋光性 以Γ 〇 Ο^^ΝΗ rW |^人0 〇A Η 1.42 694.68 180 ργ^Ι 旋光性 以τ ο Ο^^ΝΗ rW ρ人0 οα〇 Η 1.26 633.77 -299 - 200529835 (295) 實施例 結構 HPL C tR (分） MS (MH)+ 181 ΑΛ 旋光性 b 抑冷普。/ 1.19 645.81 182 旋光性 〇 b〇 1.34 687.84 183 旋光性 °。〇L 以0 1.08 581.76 184 n 〇vM 旋光性 OO 今 }。 各 1.31 651.76-298-200529835 (294) Example Structure HPL CiR (min) MS (ΜΗ) + 178 τ τ γγΝ ^. Γ L 0 with 0 1.39 650.22 179 Βγν ^ Ι optical rotation with Γ 〇〇 ^^ ΝΗ rW | ^ person 0 〇A Η 1.42 694.68 180 ργ ^ Ι optical rotation with τ ο Ο ^^ ΝΗ rW ρ person 0 οα〇Η 1.26 633.77 -299-200529835 (295) Example structure HPL C tR (min) MS (MH) + 181 ΑΛ optical rotation b. / 1.19 645.81 182 optical rotation 〇 b〇 1.34 687.84 183 optical rotation °. 〇L at 0 1.08 581.76 184 n 〇vM optical rotation OO present}. 1.31 651.76 each

-300- 200529835 (296) 實施例 結構 HPL C fR (分） MS (MH)+ 185 <Λ~\) 旋光性 1.39 643.83 186 \ 旋光性 c-Q 。彳： 1.33 664.25 187 (Γ^ι αγ^| 旋光性 VS ΗΝγΝνΤ^Ί °γΝΗ 0 ：λη 以〇 1.41 680.25 188 /X V«旋光性 ΟΌ 卞,广〇-\_^ Hh。 4¾ Cl 1.48 718.22-300- 200529835 (296) Example Structure HPL C fR (min) MS (MH) + 185 < Λ ~ \) Optical rotation 1.39 643.83 186 \ Optical rotation c-Q.彳: 1.33 664.25 187 (Γ ^ ι αγ ^ | optical rotation VS ΗΝγΝνΤ ^ Ί ° γΝΗ 0: λη to 〇 1.41 680.25 188 / X V «optical rotation 〇Ό 广, Guang 〇-\ _ ^ Hh. 4¾ Cl 1.48 718.22

-301 - 200529835 (297) 實施例 結構 HPL C (分） MS (MH)+ 189 旋光性 1.28 659.83 190 Γ\ 旋光性 b 1.41 643.83 191 旋光性 0人 H r， P人0 car H 1.41 664.25 192 9: 性 ΗΝγΝΎ^Ί °Ύ"νη 0 k^N^^NH 以0 1.41 664.25-301-200529835 (297) Example structure HPL C (min) MS (MH) + 189 optical rotation 1.28 659.83 190 Γ \ optical rotation b 1.41 643.83 191 optical rotation 0 human H r, P human 0 car H 1.41 664.25 192 9 : Sex ΗΝγΝΎ ^ Ί ° Ύ " νη 0 k ^ N ^^ NH to 0 1.41 664.25

- 302 - 200529835 (298)-302-200529835 (298)

- 303 - 200529835 (299) 實施例 結構 HPL C (分) MS (MH)+ 196 /-λ 旋光性 b 1.27 673.82 197 旋光性 1.45 691.88 198 〇丫口旋光性 °Y〇 广 hv° m^L· 0 1.26 643.83-303-200529835 (299) Example structure HPL C (min) MS (MH) + 196 / -λ optical rotation b 1.27 673.82 197 optical rotation 1.45 691.88 198 〇 口 口 光度 ° Y〇 广 hv ° m ^ L · 0 1.26 643.83

- 304 - 200529835 (300)-304-200529835 (300)

2 — （ 1 Η -吲唑—5 -基胺基）一琥珀酸—4 一特丁酯一 1 一乙酯2 — (1 fluorene-indazole-5 -ylamino) -succinic acid-4 -tert-butyl ester 1 -ethyl ester

對5 —胺基吲唑（1 . 0 1 g，7 · 6毫莫耳）之四氫呋喃（ 2 0 m )溶液/懸浮液，一次加入乙醛酸乙酯溶液（約5 0 % 甲苯溶液，1.7 m卜1.1當量），隨後加入MgS04 ( 4.6 g ) 。室溫下隔夜攪拌該混合物（23小時），隨後經過濾及真 - 305 - 200529835 (301) 空下濃縮。藉由與無水苯共沸以乾燥所生成之粗亞胺中間 產物（1.3 g，6毫莫耳），並進一步於高真空下乾燥。令 殘餘物再溶解於四氫呋喃（20 ml )中並冷卻至〇°C。緩慢 地加入2—特丁氧基一 2—酮基乙基氯化鋅（〇.5 Μ乙醚溶 液，24 ml，2當量）。經於〇 °C下攪拌1小時後，於4 °C下 隔夜貯存該混合物。利用乙酸乙酯稀釋該混合物，並利用 半飽和NH4C1溶液驟冷該混合物，且利用最少量之〇.5 HC1 溶解沈澱之固體。分離相層並利用乙酸乙酯萃取水層。利 用水和飽和NaHC〇3溶液冲洗結合之有機層。將該有機層 置於Na2S〇4上乾燥並於真空下進行濃縮。藉由矽膠閃蒸管 柱層析（經10%甲醇之CH2C12溶液流洗）純化粗產物，生 成黃褐色油狀之所欲產物（1.3 g，65% )。To a solution / suspension of 5-aminoindazole (1.01 g, 7.6 mmol) in tetrahydrofuran (20 m), add ethyl glyoxylate solution (about 50% toluene solution, 1.7 at a time) m (1.1 equivalent), and then MgS04 (4.6 g) was added. The mixture was stirred overnight at room temperature (23 hours), then filtered and concentrated in vacuo. The resulting crude imine intermediate (1.3 g, 6 mmol) was dried by azeotroping with anhydrous benzene and further dried under high vacuum. The residue was redissolved in tetrahydrofuran (20 ml) and cooled to 0 ° C. Slowly add 2-tertoxy-2-ketoethylzinc chloride (0.5 M ether solution, 24 ml, 2 eq). After stirring at 0 ° C for 1 hour, the mixture was stored overnight at 4 ° C. The mixture was diluted with ethyl acetate, and the mixture was quenched with a half-saturated NH4C1 solution, and the precipitated solid was dissolved with a minimum of 0.5 HC1. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated NaHC03 solution. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel flash column chromatography (flow washed with 10% methanol in CH2C12 solution) to give the desired product (1.3 g, 65%) as a yellow-brown oil.

]H-NMR ( 400MHz ^ CDC13) 5 7.89 ( 1H > s) 7.40-7.27( lH，m) ，6·98— 6.77 (2H，m) > 4.42 - 4.3 5 ( 1 H ，m) ，4.30 - 4.12(3H，m) ，2.80(2H，d，J=4.4Hz )，1.43(9H，s) ，1.27 - l」7(4H，m)。質譜： 3 56.24 ( M + Na ) +，278.23 ( M - lBu ) +，tR=1.287 分 2 —（ 1 H —吲唑—5 -基胺基）—琥珀酸1 一乙酯] H-NMR (400MHz ^ CDC13) 5 7.89 (1H > s) 7.40-7.27 (lH, m), 6.98— 6.77 (2H, m) > 4.42-4.3 5 (1 H, m), 4.30 -4.12 (3H, m), 2.80 (2H, d, J = 4.4Hz), 1.43 (9H, s), 1.27-l "7 (4H, m). Mass spectrum: 3 56.24 (M + Na) +, 278.23 (M-lBu) +, tR = 1.287 points 2 — (1 H —indazole-5 -ylamino) — 1 monoethyl succinate

室溫下隔夜攪拌2 — ( 1 Η -吲唑一 5 一基胺基）一琥 - 306- 200529835 (302) 珀酸4 —特丁酯1 一乙酯（123.6 mg，〇·37毫莫耳）之 C Η 2 C 12 ( 2 m 1 )和三氟乙酸（0 · 5 m 1 )溶液。利用乙酸乙 酯稀釋該反應混合物，並先後利用飽和N Η 4 C 1溶液、水及 鹽水進行冲洗。乾燥有機層並經濃縮後生成暗綠色油狀物 ·· LC/MS: tR=0.643 分，278·19(ΜΗ) +。 2 - （1Η —吲唑—5 —基胺基）—4 一酮基—4 一 〔4一（2Stir overnight at room temperature 2- (1 fluorene-indazole-5 monoylamino) monosuccinate-306-200529835 (302) 4-tert-butyl ester 1 monoethyl ester (123.6 mg, 0.37 mmol) ) Solution of C Η 2 C 12 (2 m 1) and trifluoroacetic acid (0.5 m 1). The reaction mixture was diluted with ethyl acetate and washed with a saturated NN4C1 solution, followed by water and brine. The organic layer was dried and concentrated to give a dark green oil. LC / MS: tR = 0.643 minutes, 278 · 19 (ΜΗ) +. 2-(1Η -indazole-5 -ylamino)-4 -keto-4-[4-(2

—酮基一 1，4 —二氫一 2Η —喹唑啉一 3 —基）_哌啶一 1 一基〕一丁酸乙酯—Keto-1,4-dihydro-1 2Η —quinazoline- 3 —yl) _piperidine-1 1-yl] monobutyrate

對2 - （ 1 Η —吲唑一 5 -基胺基）一琥珀酸1 —乙酯（P- 2-(1 Η-indazole-5 -ylamino) monosuccinic acid 1-ethyl ester (

85 mg，0.215毫莫耳）之CH2C12(1 ml)攪拌溶，加入該 胺（99 mg，0.429毫莫耳，2當量），隨後加入DEPBT( 128 mg’ 0.43毫莫耳，2當量）和三乙胺（70//1，0.47毫 莫耳，2.2當量）。隔夜攪拌該混合物，經乙酸乙酯稀釋 ，並先後經半飽和NH4C1溶液、水及鹽水冲洗。乾燥有機 層並經濃縮後生成黃褐色油狀物。藉由矽膠閃蒸管柱層析 (流洗液：1 〇%甲醇之CH2C12溶液）純化粗產物，生成帶 紅色油狀之所欲產物（3 6 · 2 mg，3 4 · 5 %，2步驟）。 ]H-NMR ( 400MHz » CDC13 ) 5 7 · 9 0 ( 2 Η，d，J = 4 · 4 Η z -307- 200529835 (303) )，7.33(lH，d，J=8.4Hz) ，7.20—7.14(lH，m)， 7·00— 6·80(4Η，m) ，6.70( lH，t，J=6.8Hz) ^ 4.58 -4.48 (lH，m) ，4.65-4.40 (2H，m) ,4.34-4.05 ( 3H，m) ，4·02— 3.82 ( lH，m) ，3.20—2.99 (2H，m) ，2.99-2.84 ( 1H，m) ，2.70-2.52 ( 1H，m) ，1.80-1.50(5H，m) ，1.35-1.12(5H，m)。 LC/MS: tR=1.130分，491·37(ΜΗ) +。85 mg, 0.215 millimoles) of CH2C12 (1 ml) with stirring, add the amine (99 mg, 0.429 millimoles, 2 equivalents), followed by DEPBT (128 mg '0.43 millimoles, 2 equivalents) and three Ethylamine (70 // 1, 0.47 mmol, 2.2 equivalents). The mixture was stirred overnight, diluted with ethyl acetate, and washed with half-saturated NH4C1 solution, water and brine. The organic layer was dried and concentrated to give a yellow-brown oil. The crude product was purified by silica gel flash column chromatography (flow washing solution: 10% methanol in CH2C12 solution) to yield the desired product (3 6 · 2 mg, 3 4 · 5% as a reddish oil, 2 steps) ). ] H-NMR (400MHz »CDC13) 5 7 · 9 0 (2 Η, d, J = 4 · 4 Η z -307- 200529835 (303)), 7.33 (lH, d, J = 8.4 Hz), 7.20— 7.14 (lH, m), 7.00-6.80 (4Η, m), 6.70 (lH, t, J = 6.8Hz) ^ 4.58 -4.48 (lH, m), 4.65-4.40 (2H, m), 4.34-4.05 (3H, m), 4.02—3.82 (lH, m), 3.20—2.99 (2H, m), 2.99-2.84 (1H, m), 2.70-2.52 (1H, m), 1.80-1.50 (5H, m), 1.35-1.12 (5H, m). LC / MS: tR = 1.130 minutes, 491.37 (ΜΗ) +.

2 - (1H —吲唑—5 —基胺基）—4 —酮基—4一 〔4— (2 —醒基一 1，4 — 一^氯一2 Η — D奎Π坐琳—3 —基）一喊Β定一 1 一基〕一丁酸2-(1H -indazole-5 -ylamino) -4 -keto-4-[4-(2 -Xingyl -1,4--^ chloro -2 Η-D quinine seroline -3- Radicals) yelled B fixed 1 1 radical] monobutyric acid

將LiOH水溶液（1Μ，2 80 // 1，4當量）加入至該乙酯 (34 mg，0.069毫莫耳）之四氫呋喃（0.3 ml )溶液中， 並於室溫下攪拌該混合物1 7小時。藉由氮氣流乾燥該溶液 。對殘餘物加入四氫呋喃（0.2 ml )和無水苯（0.2 ml ) ，並利用氮氣流吹乾該懸浮液。LC/ MS : tR= 0.900分， 464.3 0 ( ΜΗ ) H 。 實施例2 0 1 -308- 200529835 (304) (± ) — 1 — 〔 1，4 / 〕聯哌啶一1 / 一基一2 — ( 1Η —吲 唑一 5 —基胺基）一 4— 〔4 一（2 -酮基—1，4 一二氫— 2 Η —咱唑啉一 3 -基）一哌啶—1 —基〕丁一 1，4 —二酮Aqueous LiOH (1M, 2 80 // 1.4 equivalents) was added to a tetrahydrofuran (0.3 ml) solution of the ethyl ester (34 mg, 0.069 mmol), and the mixture was stirred at room temperature for 17 hours. The solution was dried under a stream of nitrogen. To the residue were added tetrahydrofuran (0.2 ml) and anhydrous benzene (0.2 ml), and the suspension was blown dry with a stream of nitrogen. LC / MS: tR = 0.900 minutes, 464.3 0 (ΜΗ) H. Example 2 0 1 -308- 200529835 (304) (±) — 1 — [1,4 /] bipiperidine-1 / 1-based 2 — (1 Η — indazole-5 -ylamino) — 4 — [4-((2-keto-1,4-dihydro-2) pyrene-oxazoline-3-yl) -piperidine-1-yl] butan-1,4-dione

對置於加蓋圓筒瓶中之2 -（ 1 Η —吲唑—5 -基胺基 )—4 —酮基—4— 〔4一（2 —酮基—1，4一二氫—2Η — 喹唑啉一3 —基）一哌啶一 1 —基〕一丁酸乙酯（0.069毫 莫耳）之二甲基甲醯胺（0.5 ml )溶液，加入瞻啶基哌啶 (14.3 mg，0.076 毫莫耳，1.1 當量）、DEPBT(22.8 mg ，：1.1當量）及三乙胺（8滴，約160 // 1 )。室溫下隔夜攪 拌該混合物。藉由製備性HPLC純化終產物以生成黃褐色 固體之所欲產物（15 mg，26%，2步驟）。LC/ MS : tR 二 0.917 分，613.54 ( ΜΗ) +。 其他實施例 (1 一；基一脈Π定一 4 一基）一（2 —硝基一卡基）一胺Opposite to 2-(1 Η -indazole-5 -ylamino) -4 -keto-4-[4-one (2-keto-1,4-dihydro-2) — A solution of quinazoline- 3-yl) -piperidine- 1-yl] monobutyrate (0.069 mmol) in dimethylformamide (0.5 ml), followed by addition of prinidylpiperidine (14.3 mg , 0.076 millimoles, 1.1 equivalents), DEPBT (22.8 mg,: 1.1 equivalents), and triethylamine (8 drops, about 160 // 1). The mixture was stirred overnight at room temperature. The final product was purified by preparative HPLC to give the desired product as a tan solid (15 mg, 26%, 2 steps). LC / MS: tR 0.919 points, 613.54 (ΜΗ) +. Other Examples (1 1; radicals, 4 a radicals, 4 1 radicals)-(2-nitro-carbyl) monoamine

將2 —硝基苯醛（1 g，6 · 6 1毫莫耳）和4 一胺基一 1 — -309- 200529835 (305) 苄基哌啶（1.35 ml，6.61毫莫耳）置於乙醇（2〇 nU)中 。室溫下攪拌所生成之懸浮液20分鐘，隨後以超過1〇分鐘 之時間逐滴地加入氫硼化鈉（0 · 2 5 g，6 · 6 1毫莫耳）之乙 醇（5 ml )溶液。經添加完成後，攪拌該反應溶液1小時 ，隨後冷卻至〇 °C，加入濃氯化銨溶液至該反應混合物中 直至未發現有氣泡產生爲止。真空下蒸發溶劑並令所生成 之粗混合物溶解於水（1 〇 ml )和CH2C12 ( 1 0 ml )中。分 離相層並利用水（2x )和鹽水（2x )冲洗有機層，隨後置 於Na2S04上乾燥，經過濾和濃縮後生成所欲之產物（1.5 g，70%) 。LC/MS: tR=0.7分，326.18 (ΜΗ) +。 (2 — |女基—卞基）一（1—卡基一呢卩定一 4 —基）胺Place 2-nitrobenzaldehyde (1 g, 6.61 mmoles) and 4-monoamino-1 -309-200529835 (305) benzylpiperidine (1.35 ml, 6.61 mmoles) in ethanol (20 nU). The resulting suspension was stirred at room temperature for 20 minutes, and then a solution of sodium borohydride (0.25 g, 6.61 mmol) in ethanol (5 ml) was added dropwise over 10 minutes. . After the addition was completed, the reaction solution was stirred for 1 hour, then cooled to 0 ° C, and a concentrated ammonium chloride solution was added to the reaction mixture until no bubbles were found. The solvent was evaporated under vacuum and the resulting crude mixture was dissolved in water (10 ml) and CH2C12 (10 ml). The phases were separated and the organic layer was washed with water (2x) and brine (2x), then dried over Na2S04, filtered and concentrated to give the desired product (1.5 g, 70%). LC / MS: tR = 0.7 minutes, 326.18 (ΜΗ) +. (2 — | feminine—fluorenyl)-(1—carboxyl-methylenediamine—4-yl) amine

將（1 一卞基一呢D定—4 一基）一 （2 —硝基一卞基） —胺（1.2 g，3.7毫莫耳）和鋅粉（1 g，過量），置於75 %乙酸水溶液（16 ml )中並於60 °C下攪拌2小時。經冷卻 至室溫後，真空下除去溶劑並令所生成之粗產物溶解於水 (10 ml )中，隨後加入nH4〇H直至達到pH 3。利用 CH2C12 ( 3x )萃取該溶液。集中有機層，經水（2x )和鹽 水（2x)冲洗，置於Na2s〇4上乾燥，經過濾和濃縮後生成 所欲產物（〇 · 8 g，7 3 % )。 1H-NMR ( CD3OD ) (5 2.5 0 ( m，2H) ，3·20 ( m，2H) ，3.49(dd’J=7.0，7.3，iH) ，3.62(ni，4H) ^ 4.20 -310- 200529835 (306) (s，2H) ，4.36(s，2H) ，7.〇4(m，2H) ，7.32(dd ，j=7.3，7.6，1H) ，7.41(d，J=7.9，lH) ，7.50( m ，5H )。質譜：296.40 ( MH ) 4 ° 3—(1—苄基一哌啶_4—基）—3，4一二氫—111—苯並 〔1，2，6〕噻二嗪—2，2 -二氧化物Place (1-fluorenyl-hydrazone-4-yl)-(2-nitro- fluorenyl)-amine (1.2 g, 3.7 mmol) and zinc powder (1 g, excess) in 75% Acetic acid (16 ml) and stirred at 60 ° C for 2 hours. After cooling to room temperature, the solvent was removed under vacuum and the resulting crude product was dissolved in water (10 ml), and then nH4OH was added until pH 3 was reached. The solution was extracted with CH2C12 (3x). The organic layer was concentrated, washed with water (2x) and saline (2x), dried over Na2s04, filtered and concentrated to give the desired product (0.88 g, 73%). 1H-NMR (CD3OD) (5 2.5 0 (m, 2H), 3.20 (m, 2H), 3.49 (dd'J = 7.0, 7.3, iH), 3.62 (ni, 4H) ^ 4.20 -310- 200529835 (306) (s, 2H), 4.36 (s, 2H), 7.04 (m, 2H), 7.32 (dd, j = 7.3, 7.6, 1H), 7.41 (d, J = 7.9, 1H), 7.50 (m, 5H). Mass spectrum: 296.40 (MH) 4 ° 3- (1-benzyl-piperidine_4-yl) -3,4-dihydro-111-benzo [1,2,6] thia Diazine-2,2-dioxide

於迴流狀態下加熱（2 -胺基一苄基）一（1 一苄基一 哌啶一 4 一基）—胺（1.0 g，3 ·3 9毫莫耳）和硫醯胺（ 0.64 g，6.7 8毫莫耳）之吡啶溶液1 4小時。經冷卻至室溫 後，蒸發溶劑並令粗產物溶解於水中。經利用6N NaOΗ溶 液調整所生成之混合物至pH 9後’利用CH2C12 ( 2χ )進行 萃取。利用水（2χ )冲洗萃取液，置於Na2S04上乾燥，經 過濾和濃縮後生成油狀殘餘物，隨後令其溶解於乙酸乙酯 (4 ml)中。令該溶液與4N HC1之1，4 —二噁烷（2 ml) 溶液混合，隨後加入二乙醚直至沈澱出產物爲止。藉由過 濃得到所欲之產物（0.7 g，53%) 。LC/MS: tR=〇.96 分，3 5 8. 1 6 ( ΜΗ ) +。 3—(哌啶一 4一基一 3，4 —二氫—1Η —苯並〔1，2，6〕 噻二嗪一 2，2 —二氧化物 -311 - 200529835 (307)Heat (2-amino-benzyl)-(1-benzyl-piperidine-4-yl) -amine (1.0 g, 3.39 mmol) and thiamidine (0.64 g, 6.7 8 mmoles) of pyridine solution for 14 hours. After cooling to room temperature, the solvent was evaporated and the crude product was dissolved in water. After adjusting the resulting mixture to pH 9 with a 6N NaOΗ solution, it was extracted with CH2C12 (2χ). The extract was washed with water (2x), dried over Na2S04, filtered and concentrated to give an oily residue, which was then dissolved in ethyl acetate (4 ml). This solution was mixed with a solution of 4N HC1 in 1,4-dioxane (2 ml) and then diethyl ether was added until the product precipitated. The desired product was obtained by overconcentration (0.7 g, 53%). LC / MS: tR = 0.96 minutes, 3 5 8. 16 (ΜΗ) +. 3- (piperidine-1, 4-yl-1, 3,4-dihydro-1, 1-pyridine, benzo [1,2,6] thiadiazine-1, 2,2-dioxide -311-200529835 (307)

利用氮氣冲洗3 — （ 1 —苄基一哌啶一 4 —基）一 3，4 —二氫_1H-苯並〔1，2，6〕噻二嗪一 2，2 —二氧化物 (0.46 g，1.29毫莫耳）之甲醇（10 ml )溶液，隨後令其 與Pd / C ( 10% ’ 46 mg )反應。利用氫氣冲洗該燒瓶並 於氫氣下進行隔夜攪拌。利用氮氣冲洗該反應溶液，隨後 通過寅氏鹽過濾並進行濃縮。管柱層析產生所欲產物（ 0.26 g，75% )。 iH-NMR ( CD3OD ) (5 1 .53 — 1.61 ( m，2H ) » 1.80 ( m ，2H) ，2.55(m，2H) ，2.95-3.05 (m，2H) » 3.30 (m，2H ) ，3.70 ( m，2H ) ，4.65 ( s，2H ) ，6.70 ( d ，J=7.9，1H) ，7.40(dd，J=8.2，6.7，lH) ，7.10( m，2H)。質譜：268.10(MH)+。Purge 3- (1-benzyl-piperidine-4-yl) -3,4-dihydro_1H-benzo [1,2,6] thiadiazine-2,2-dioxide (0.46 g, 1.29 millimoles) in methanol (10 ml), which was then reacted with Pd / C (10% '46 mg). The flask was flushed with hydrogen and stirred overnight under hydrogen. The reaction solution was flushed with nitrogen, and then filtered through Yin's salt and concentrated. Column chromatography produced the desired product (0.26 g, 75%). iH-NMR (CD3OD) (5 1 .53 — 1.61 (m, 2H) »1.80 (m, 2H), 2.55 (m, 2H), 2.95-3.05 (m, 2H)» 3.30 (m, 2H), 3.70 (m, 2H), 4.65 (s, 2H), 6.70 (d, J = 7.9, 1H), 7.40 (dd, J = 8.2, 6.7, 1H), 7.10 (m, 2H). Mass spectrum: 268.10 (MH) +.

6_漠一 3 —呢卩定—4_基—3’ 4 —二氨—1H —哇嗤琳—2 —酮6_ Mo Yi 3 —Nanthidine—4_yl—3 ’4—Diamino—1H —Wahlin—2 —Ketone

令3 —脈Π定—4 —基—3，4 —二氨一 1 Η — D奎卩坐琳—2 — 酮（0.2 g，0.87毫莫耳）溶解於乙酸（2 ml )中。對該溶 液以超過5分鐘之時間，逐滴地加入溴（1 . 8 m 1，3 5 · 1 4毫 莫耳）之乙酸（0.5 m 1 )溶液。經於室溫下攪拌1小時後 -312- 200529835 (308) ，利用C Η 2 C 12稀釋該反應混合物，經水（2 χ )和鹽（2 x ) 冲洗，置於N a2 S 04上乾燥’經過濾和濃縮後生成〇 .〗6 g ( 59% )，其係未經進一步純化而直接使用。LC/ MS : tR =0.91 分，310.15 ( ΜΗ) +。 2 —酮基一3—卩底卩定一4 一基一1，2，3，4 —四氫—D奎n坐啉 6 —腈Let 3-pulsidine-4-base-3, 4-diammonium-1 Η-D quinoxaline-2-ketone (0.2 g, 0.87 mmol) dissolved in acetic acid (2 ml). To this solution was added dropwise a solution of bromine (1.8 m 1, 3 5 · 14 mmol) in acetic acid (0.5 m 1) over 5 minutes. After stirring for 1 hour at room temperature -312- 200529835 (308), the reaction mixture was diluted with C Η 2 C 12, washed with water (2 x) and salt (2 x), and dried on Na 2 S 04 'After filtration and concentration, 0.06 g (59%) was obtained, which was used directly without further purification. LC / MS: tR = 0.91 minutes, 310.15 (ΜΗ) +. 2-keto-3-dioxotriazine- 4-keto-1,2,3,4-tetrahydro-D-quinoline 6-nitrile

將6 —溴一3 —哌D定—4 一基—3，4 —二氫—1 Η - CI奎口坐 啉一 2 —酮（0.16 g，0.52毫莫耳）、氰化鋅（37 mg， 0.31毫莫耳）及四（三苯膦）銷（〇) (60 mg，0·05毫莫 耳）置入二甲基甲醯胺（4 ml)中。令該反應燒瓶連接高 真空並藉由冷凍乾燥法進行脫氣（3 χ )，隨後於9 0 °C、氮 氣及攪拌下加熱1小時。經冷卻至室溫後，真空下蒸發該 溶液並藉由製備性Η P L C純化該粗混合物，生成所欲之腈 (50 mg，38% )。 1H-NMR ( CD3〇D ) (5 1.99 ( m，2H) ^ 2.0 8 - 2.23 ( m ，2H) ，3.15(m，2H) ，3.50(bs，lH) ，3.55(bs， 1H) ，4.40 ( m，1H) ，4.47 ( s，2H) ，6.93 ( d，J = 8.1，1H) ，4.10(m，2H)。質譜：257.13(MH) +。 N— (1—苄基—哌啶一 4 —基）—2— (2 —硝基一苯基） 一乙醯胺 -313- 200529835 (309)6-bromo-3-piperidine-4-yl-3,4-dihydro-1 hydrazone-CI quinololine-2 -one (0.16 g, 0.52 mmol), zinc cyanide (37 mg (0.31 mmol) and tetrakis (triphenylphosphine) pin (0) (60 mg, 0.05 mmol) were placed in dimethylformamide (4 ml). The reaction flask was connected to a high vacuum and degassed (3 x) by freeze-drying, followed by heating at 90 ° C, nitrogen, and stirring for 1 hour. After cooling to room temperature, the solution was evaporated in vacuo and the crude mixture was purified by preparative ΗPLC to yield the desired nitrile (50 mg, 38%). 1H-NMR (CD3OD) (5 1.99 (m, 2H) ^ 2.0 8-2.23 (m, 2H), 3.15 (m, 2H), 3.50 (bs, 1H), 3.55 (bs, 1H), 4.40 ( m, 1H), 4.47 (s, 2H), 6.93 (d, J = 8.1, 1H), 4.10 (m, 2H). Mass spectrum: 257.13 (MH) +. N-(1-benzyl-piperidine-4 —Base) —2— (2-Nitromonophenyl) monoethylamine-313- 200529835 (309)

將（2 —硝基一苯基）-乙酸（2.0 g，11.04毫莫耳） 、4 —胺基—1—卡基哌卩定（2.25 ml，10.03毫莫耳）、1 — 羥基苯基三唑（1.49 g，11.04毫莫耳）及1- (3〜二甲基 胺基丙基）一 3 -乙基羰二醯亞胺（2.3 g，12·03毫莫耳；） 置入乙酸乙酯（25 ml )中。將三乙胺（4.2 ml，3·〇1毫莫 耳）加入該溶液中，並於4〇°C下攪拌該反應混合物2小時 。經冷卻至室溫後，利用乙酸乙酯稀釋該混合物，先彳戔，經 水（2x、5 % NaHC03溶液及鹽水（2x )冲洗，置於 Na2S04上乾燥，經濃縮後生成所欲之產物（3.5 g，98% )〇 LC/ MS : tR= 1 ·24分，3 54.3 0 ( MH )+。 〔2—（2 —胺基一苯基）一乙基〕一（1 一爷基一呢卩定一 4 一基）一胺(2-Nitro-phenyl) -acetic acid (2.0 g, 11.04 mmol), 4-amino-1-carbazididine (2.25 ml, 10.03 mmol), and 1-hydroxyphenyltris Azole (1.49 g, 11.04 mmol) and 1- (3 ~ dimethylaminopropyl) -3-ethylcarbonyldiamidine (2.3 g, 12.03 mmol); ethyl acetate Ester (25 ml). Triethylamine (4.2 ml, 3.01 mol) was added to the solution, and the reaction mixture was stirred at 40 ° C for 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, rinsed first, washed with water (2x, 5% NaHC03 solution and brine (2x), dried on Na2S04, and concentrated to form the desired product ( 3.5 g, 98%) LC / MS: tR = 1.24 minutes, 3 54.3 0 (MH) +. [2- (2-aminoaminophenyl) -ethyl]-(1-monomethyl-one) Hydrazine-1, 4-yl) monoamine

將Ν-（1—苄基一哌啶—4 —基）一 2-（2-硝基— 苯基）—乙醯胺（3.2 g，9.06毫莫耳）和氫化鋁鋰（1.0 g，1 8 · 1 2毫莫耳）置入經火焰乾燥之燒瓶中。加入1，4 — 二噁烷（1 5 ml )，令該混合物以超過1小時之時間緩慢地 達至迴流狀態，並於迴流狀態下攪拌1 6小時。冷卻該反應 混合物至〇 °C，藉由逐滴地加入甲醇以破壞過量之氫化銘 鋰，隨後小心地加入20 % KOH溶液。過濾該鋁鹽，濃縮 -314- 200529835 (310) 濾液並用於下一個反應中。 3— (1—苄基—哌啶—4 一基）一 1，3，4，5—四氫—苯 基〔d〕 〔1，3〕二吖庚因一 2 —酮Add N- (1-benzyl-piperidine-4-yl) -2- (2-nitro-phenyl) -acetamidamine (3.2 g, 9.06 mmol) and lithium aluminum hydride (1.0 g, 1 8.12 mmol) into a flame-dried flask. 1,4-Dioxane (15 ml) was added, and the mixture was slowly brought to a reflux state over a period of 1 hour, and stirred under reflux for 16 hours. The reaction mixture was cooled to 0 ° C, and excess hydride lithium was destroyed by adding methanol dropwise, followed by careful addition of a 20% KOH solution. The aluminum salt was filtered, and the -314- 200529835 (310) filtrate was concentrated and used in the next reaction. 3- (1-benzyl-piperidine-4 mono) -1,3,4,5-tetrahydro-phenyl [d] [1,3] diazepine-1 2-one

於〇°C下令〔2— (2—胺基一苯基）—乙〕一（1 一苄 基一呢卩定—4 —基）一胺（0.44 g，1.42毫莫耳）之四氯口夫 喃（5 ml)攪拌溶液與羰基二咪唑（0.23 g，1.42毫莫耳 )反應。於〇°C下攪拌該反應溶液30分鐘並於迴流狀態下 攪拌1小時。經冷卻至室溫後，蒸發溶劑並藉由管柱層析 純化殘餘物以生成所欲之產物（1 0 0 m g，2 1 % ) 。L C / MS : tR= 1.29分，3 3 6.34 ( ΜΗ) +。 3 — 定一 4 一基一1，3，4，5 —四氫一苯並〔d〕 〔 1，3 〕二吖庚因一 2 —酮Ordered the tetrachloride of [2- (2-amino-phenyl) -ethyl]-(1-benzyl-metidine-4-yl) -amine (0.44 g, 1.42 mmol) at 0 ° C. The furfuran (5 ml) stirred solution was reacted with carbonyldiimidazole (0.23 g, 1.42 mmol). The reaction solution was stirred at 0 ° C for 30 minutes and under reflux for 1 hour. After cooling to room temperature, the solvent was evaporated and the residue was purified by column chromatography to give the desired product (100 mg, 21%). L C / MS: tR = 1.29 minutes, 3 3 6.34 (ΜΗ) +. 3 — fixed one 4 one base one 1,3,4,5 —tetrahydro-benzo [d] [1,3] diazepine-1 2-one

利用氮氣冲洗3 — ( 1 —苄基一哌π定一 4 —基）一 1，3 ，4，5 —四氫—苯並〔d〕 〔1，3〕二吖庚因一 2 —酮（ 100 mg，0.3毫莫耳）之甲醇（5 ηι1)溶液，並令其與Pd / C ( 1 0 %，i 〇 mg )反應。利用氫氣冲洗該燒瓶並於氫 氣下進行隔夜攪拌。利用氮氣冲洗該反應溶液，經由通過 -315- 200529835 (311) 寅氏鹽過濾，並進行濃縮。管柱層析所欲之產物（5 0 ，68%)。：LC/MS:tR=1.07分，246.26(MH)+。 3 —〔（ 1 一苄基一哌啶一 4一基一胺基）一甲基〕一 4 —硝 基-酚Purge 3- (1-benzyl-piperidine- 4-yl) -1,3,4,5-tetrahydro-benzo [d] [1,3] diazepine- 2-one ( 100 mg, 0.3 mmol) in methanol (5 μm) and allowed to react with Pd / C (10%, 100 mg). The flask was flushed with hydrogen and stirred overnight under hydrogen. The reaction solution was flushed with nitrogen, filtered through -315-200529835 (311) Yin's salt, and concentrated. Desired product by column chromatography (50, 68%). : LC / MS: tR = 1.07 minutes, 246.26 (MH) +. 3-[((1-benzyl-piperidine-4- 4-yl-amino) -methyl]-4-nitro-phenol

將5 -羥基一 2-硝基—苯醛（5 g，29.9毫莫耳）和4 —胺基一 1-苄基哌啶（5.6 ml，29.9毫莫耳）置入乙醇（ 3 0 ml )中。室溫下攪拌所生成之懸浮液20分鐘，隨後以 超過10分鐘之時間逐滴地加入氫硼化鈉（1.13 g，29· 9毫 莫耳）之乙醇（1 〇 ml )溶液。經該加入完成後，室溫下 攪拌該反應溶液1小時，隨後冷卻至〇°C並將濃NH4C1溶液 加該反應混合物中直至無氣泡產生爲止。真空下蒸發溶劑 並令所生成之粗混合物溶解於水（30 ml )和CH2C12 ( 4 ml )中。分離相層，利用水（2x )和鹽水（2x )冲洗有機 層，將其置於Na2S04上乾燥，經過濾和濃縮後，生成所欲 之產物（5.8 g，57%) 。：LC/MS: tR=0.95 分，342.27 (MH) + 。 4_胺基一 3—〔 （1—苄基一哌卩定一 4 一基一胺基）一甲基 〕一酚 -316- 200529835Place 5-hydroxy-2-nitro-benzoaldehyde (5 g, 29.9 mmol) and 4-amino-1-benzylpiperidine (5.6 ml, 29.9 mmol) into ethanol (30 ml) in. The resulting suspension was stirred at room temperature for 20 minutes, and then a solution of sodium borohydride (1.13 g, 29.9 mmol) in ethanol (10 ml) was added dropwise over 10 minutes. After the addition was completed, the reaction solution was stirred at room temperature for 1 hour, then cooled to 0 ° C and a concentrated NH4C1 solution was added to the reaction mixture until no bubbles were generated. The solvent was evaporated under vacuum and the resulting crude mixture was dissolved in water (30 ml) and CH2C12 (4 ml). The phases were separated, and the organic layer was washed with water (2x) and brine (2x), dried over Na2S04, filtered and concentrated to give the desired product (5.8 g, 57%). : LC / MS: tR = 0.95 points, 342.27 (MH) +. 4-Amino-3-((1-benzyl-piperidine-1, 4-mono-amino) -methyl] -phenol -316- 200529835

將（1 —苄基一哌啶一 4 一基）（2 —硝基一苄基） 一胺（0.25 g，0.7毫莫耳）和鋅粉（〇·2 g，過量）置入 75%乙酸水溶液（8 ml )中並於60 °C下攪拌2小時。經冷 卻至室溫後，真空下除去溶劑並令所生成之粗混合物溶解 於水（10 ml)中，隨後加入NH4OH直至該溶液之pH爲3。 利用CH2C12 ( 3x )萃取該溶液。集中有機層，經水（2x ) 和鹽水（2x )冲洗，置於Na2S04上乾燥，經過濾和濃縮後 生成所欲之產物（〇·18 g，79% )。 3— (1—苄基—哌啶—4 —基）—6 —羥基—3，4 —二氫— 1 Η —喹唑啉一 2 —酮Put (1-benzyl-piperidine-4-yl) (2-nitro-benzyl) monoamine (0.25 g, 0.7 mmol) and zinc powder (0.2 g, excess) into 75% acetic acid It was stirred in an aqueous solution (8 ml) at 60 ° C for 2 hours. After cooling to room temperature, the solvent was removed under vacuum and the resulting crude mixture was dissolved in water (10 ml), and then NH4OH was added until the pH of the solution was 3. The solution was extracted with CH2C12 (3x). The organic layer was concentrated, washed with water (2x) and brine (2x), dried on Na2S04, filtered and concentrated to form the desired product (0.18 g, 79%). 3- (1-benzyl-piperidine-4-yl) -6-hydroxy-3,4-dihydro-1 1 hydrazone-quinazolinone 2-one

於0 °C下令4 —胺基一 3 -〔（ 1 一苄基一哌啶_ 4 一基 —胺基）一甲基〕—酉分（0.16 g，0.51毫莫耳）之四氫D夫 喃（3 ml )攪拌溶液與羰基二咪唑（52 mg，0.51毫莫耳 )反應。於〇 t下攪拌該反應溶液3 0分鐘並於迴流狀態下 再攪拌1小時。經冷卻至室溫後，蒸發溶劑並藉由管柱層 析純化殘餘物以生成所欲之產物（1 〇 〇 m g，5 7 % ) 。L C / MS : tR= 1 ,09 分，3 3 8.2 8 ( ΜΗ )—。 200529835 (313) 6 —羰基一3 —哌啶一 4 —基一3，4一二氫一1H — D奎唑啉— 2 —酮Order 4-amino-3-([(1-benzyl-piperidine_4-mono-amino) -methyl)]-tetrahydrofuran (0.16 g, 0.51 mmol) at 0 ° C Ran (3 ml) was stirred with carbonyldiimidazole (52 mg, 0.51 mmol). The reaction solution was stirred for 30 minutes at 0 t and stirred for an additional hour under reflux. After cooling to room temperature, the solvent was evaporated and the residue was purified by column chromatography to give the desired product (1000 mg, 57%). L C / MS: tR = 1.09 minutes, 3 3 8.2 8 (ΜΗ) —. 200529835 (313) 6-carbonyl-3-piperidine-4- 4-yl-3,4-dihydro-1H-D quinazolin-2-one

利用氮氣冲洗3 -（ 1 一苄基一哌啶—4 —基）一 6 -羥 基一3，4 —二氫一 1H — D奎唑啉—2 —酮（100 mg，0.3毫莫 耳）之甲醇（5 ml)溶液，並令其與Pd/C( 10%，10mg )反應。利用氫氣冲洗該燒瓶並令其於氫氣下隔夜攪拌。 利用氮氣冲洗該反應溶液，經由通過寅氏過濾並進行濃縮 。管柱層析生成所欲之產物（60 mg，81%) °LC/MS: tR= 〇·75 分，248.22 ( ΜΗ ) +。 Ν— (Ι—1^基一呢D定一 4 —基）_2—甲氧基一 6—硝基一 苯醯胺Purge nitrogen with 3- (1-benzyl-piperidine-4-yl) -6-hydroxy-3,4-dihydro-1H-D quinazolin-2-one (100 mg, 0.3 mmol) using nitrogen. Methanol (5 ml) solution and react it with Pd / C (10%, 10 mg). The flask was flushed with hydrogen and allowed to stir overnight under hydrogen. The reaction solution was flushed with nitrogen, filtered through Yin and concentrated. Column chromatography produced the desired product (60 mg, 81%) ° LC / MS: tR = 0.75 min, 248.22 (ΜΗ) +. Ν— (Ι-1,1 -yl, 1D, 1 -4 -yl) _2-methoxy- 6-nitro-benzidine

將2 —甲氧基一 6-硝基一苯甲酸（2.0 g’ ίο·〗毫莫耳 )、4 —胺基—1 一苄基哌啶（1.9 ml ’ 10.1毫莫耳）、！〜 羥基苯並三唑（1.43 g，10.5毫莫耳）及1 一 （3 —二甲基 胺基丙基）—3-乙基羰二醯亞胺（1.9 g’ 10·1毫莫耳） 置入乙酸乙酯（25 ml)中。對該溶液加入三乙胺（4 2 _ ，3 〇·3毫莫耳）並於40 °C下攪拌該反應混合物2小時。經 -318- 200529835 (314) 冷卻至室溫後，利用乙酸乙酯稀釋該混合 、5% NaHC03溶液及鹽水（2x)冲洗， 燥，經過濾和濃縮後生成所欲產物（1 ·2 / MS : tR= 1·1〇分，3 70.2 8 ( MH) +。 (2 —胺基—ό 一甲氧基一节基）一（1 一 ： 基）一胺Add 2-methoxy- 6-nitro-benzoic acid (2.0 g ’ίο 〖millimolar), 4-amino-1-benzylpiperidine (1.9 ml ′ 10.1 millimolar) ,! ~ Hydroxybenzotriazole (1.43 g, 10.5 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbonyldiamidine (1.9 g '10.1 mmol) Place in ethyl acetate (25 ml). To this solution was added triethylamine (4 2 _, 30.3 mmol) and the reaction mixture was stirred at 40 ° C for 2 hours. After -318- 200529835 (314) cooled to room temperature, the mixture was diluted with ethyl acetate, rinsed with 5% NaHC03 solution and brine (2x), dried, filtered and concentrated to produce the desired product (1 · 2 / MS : tR = 1.10 minutes, 3 70.2 8 (MH) +. (2-amino group-monomethoxy group)-(1 1: group) monoamine

將Ν — ( 1 —苄基一哌啶一 2 一基）一 硝基一苯醯胺（1.0 g，2·8毫莫耳）和氫 ，8.4 5毫莫耳）置入經火焰乾燥之燒瓶中 —二B惡院（1 5 m 1 )。以超過1小時之時間 地至迴流狀態並於迴流狀態下攪拌1 6小時 物冷卻至0 °C，藉由逐滴地加入甲醇以破 鋰，隨後小心地加入2 0 % Κ Ο Η溶液。過 濾液，其係用於下一個步驟中。 物，經水（2 X ) 置於Na2S04上乾 g，8 6 % ) 〇 LC r 基 一 _ Π定一 4 一 2 —甲氧基一6 — 化鋁鋰（〇 · 3 1 g 。加入無水1，4 令該混合物緩慢 。令該反應混合 壞過量之氫化鋁 濃該鋁鹽，濃縮/ 基一 3，4 — 一氯 -319- 1 — (1 一卞基—丨柩卩疋一 4 —基）一8 —甲氧 2 —1 Η —卩奎唑啉一2 —酮 200529835 (315) ΟPut N— (1-benzyl-piperidine- 2 -yl) -nitro-benzidine (1.0 g, 2.8 mmol) and hydrogen (8.4 5 mmol) into a flame-dried flask Chinese-Second B evil hospital (1 5 m 1). Over 1 hour to reflux and stir for 16 hours under reflux. The contents were cooled to 0 ° C, lithium was added dropwise to break the lithium, and then a 20% KOH solution was carefully added. The filtrate was used in the next step. Material, dried with water (2X) on Na2S04, 86%) 〇LC r radical _ 定 一 4-2 -methoxy-6-lithium aluminum hydride (0.31 g. Add anhydrous 1, 4 makes the mixture slow. The reaction is mixed with an excess of aluminum hydride to concentrate the aluminum salt, and concentrated to a base of 3,4-chloro-319- 1 — (1 amidino — 丨 — 4 — A) 8-methoxy-2- 1 hydrazone-imidazoline-2 2-one 200529835 (315) 〇

於0C下令（2—胺基—6—甲氧基一；基）_ 基一卩联卩疋—4 一基）—胺（0.2 g，0.62毫莫耳） 喃（3 ml )攪拌溶液與羰基二咪唑（99 mg，〇. )反應。於下攪拌該反應溶液30分鐘並於迴 攪拌1小時。經冷卻至室溫後，蒸發溶劑並藉由 純化殘餘物，生成所欲之產物（1 5 0 m g，6 8 % MS: tR=1.4l 分，352·30(ΜΗ) + 〇 8 —甲氧基一3—呢Π定—4 —基一3，4 —二氯一1Η —2 —酮 -（1 一苄 之四氫呋 62毫莫耳 流狀態下 管柱層析 )。LC/ -D奎唑啉 \〇(2-Amino-6-methoxyl; yl) _yl-pyridine-4-yl) -amine (0.2 g, 0.62 mmol) was stirred at 0C and the solution was stirred with carbonyl (3 ml) Diimidazole (99 mg, 0.1) was reacted. The reaction solution was stirred for 30 minutes at the bottom and for 1 hour at the back. After cooling to room temperature, the solvent was evaporated and the residue was purified to yield the desired product (150 mg, 68% MS: tR = 1.4l min, 352 · 30 (ΜΗ) + 〇8 -methoxy Benzyl-3—Nididine-4—yl-1,3,4-Dichloro-1Η-2—ketone- (column chromatography under 1-benzyltetrahydrofuran 62 mM flow state). LC / -D Quinazoline \ 〇

利用氮氣冲洗3 —（ 1 一苄基一哌啶—4 —基） 氧基一 3，4 —二氫一1Η — D奎唑啉—2 —酮（100Purge 3- (1-benzyl-piperidine-4-yl) oxy- 3,4-dihydro-1,1-D-quinazolin-2-one (100

毫莫耳）之甲醇（5 ml)溶液，並令其與Pd/C 1 〇 mg )反應。利用氫氣冲洗該燒瓶，並於氫氣 夜攪拌。利用氮冲洗該反應溶液，經由通過寅氏 並進行濃縮。管柱層析生成所欲之產物（6 8 mg 〇 LC/MS: tR=l.ll 分，262.23 (ΜΗ)'。 -320 - 一 8 -甲 mg» 0.28 (10%， 下進行隔 鹽過濾’ ，93 % ) 200529835 (316) N — (1 —苄基一哌啶—4 一基）Millimoles) in methanol (5 ml) and allowed to react with Pd / C (10 mg). The flask was flushed with hydrogen and stirred overnight under hydrogen. The reaction solution was flushed with nitrogen, passed through Yinshi, and concentrated. Column chromatography yields the desired product (68 mg 〇LC / MS: tR = 1.11 min, 262.23 (ΜΗ) '. -320--8 -methyl mg »0.28 (10%, salt filtration ', 93%) 200529835 (316) N — (1-benzyl-piperidine-4 4-yl)

2一氯一 6-硝基一苯醯 將2—氯一6 —硝基一苯甲酸（i.2g，597毫莫耳）、 4 —胺基一 1 一；基哌Π定（1 · 1 m 1 ’ 5 · 9 7毫莫耳）、1 一 ^基 苯並三哗（0.84 g’ 1.05當量）及1一（3_二甲基胺基丙 基）—3 —基乙基羰基二醯胺亞胺（i」g，1〇5當量）置 入乙酸乙酯（20 ml)中。加入三乙胺（2 5 ml，3〇當量 )並於40°C下攪拌該反應混合物2小時。經冷卻至室溫後 ，利用乙酸乙酯稀釋該混合物，經水（2χ ) 、5 %2-Chloro-6-nitro-phenyl hydrazone 2-Chloro-6-nitro-benzoic acid (i.2g, 597 mmol), 4-Amine-1 1; Gypidine III (1 · 1 m 1 '5 · 97 7 mol), 1-dibenzobenzotriazole (0.84 g' 1.05 equivalents), and 1- (3-dimethylaminopropyl) -3-ylethylcarbonyldifluorene The imine (i "g, 105 equivalents) was placed in ethyl acetate (20 ml). Triethylamine (25 ml, 30 equivalents) was added and the reaction mixture was stirred at 40 ° C for 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, and water (2χ), 5%

NaHC〇3溶液及鹽水（2χ)冲洗，置於心”…上乾燥，經 過濾和濃縮後生成所欲之產物（1 .9 g，8 5 % 。 (2 —胺基一 6—氣一卡基）—（1一；基一哌η定一 4 —基） -胺NaHC〇3 solution and saline (2χ) were rinsed, placed on the heart ", dried, filtered and concentrated to produce the desired product (1.9 g, 85%. (2-amino- 6-gas-card) )-(1-a; yl-pi-n-a-4-yl) -amine

將N -（ 1 一苄基—哌啶一 4 —基）一 2-氯一6—硝基 —苯醯胺（1.67 g’ 4.47毫莫耳）和氫化鋁鋰（〇·51 g， 1 3.4 3毫莫耳）置入經火焰乾燥之燒瓶中。加入無水1，4 一二D惡院（1 5 m 1 )。令該混合物緩慢地至迴流狀態並攪 拌1 6小時。冷卻該反應混合物至〇 °C ’藉由逐滴地加入甲 -321 - 200529835 (317) 醇以破壞過量之氫化鋁鋰，隨後小心地加入2 0 % Κ Ο Η溶 液。過濾該鋁鹽，濃縮濾液，其係用於下一個反應中。 3 — （ 1 一爷基一哌Π定—4 一基）一 8 —氯一 3，4 一二氫一 1 Η — D奎唑啉一 2 —酮Add N-(1 -benzyl-piperidine-4 -yl)-2-chloro-6-nitro-phenylhydrazine (1.67 g '4.47 mmol) and lithium aluminum hydride (0.51 g, 1 3.4 3 millimoles) into a flame-dried flask. Anhydrous 1,4 one and two D hospitals (1 5 m 1) were added. The mixture was slowly brought to reflux and stirred for 16 hours. The reaction mixture was cooled to 0 ° C 'by destroying excess lithium aluminum hydride by adding methyl-321-200529835 (317) alcohol dropwise, followed by careful addition of a 20% KOH solution. The aluminum salt was filtered and the filtrate was concentrated and used in the next reaction. 3 — (1-methyl-pididine-4 -yl)-8 -chloro- 3,4 -dihydro- 1 hydrazone-D quinazoline-2 -one

於〇°C下令（2-胺基一 6-氯一苄基）一（1 一苄基一 哌啶一 4 —基）一胺（0.66 g，2.0毫莫耳）之四氫呋喃（8 ml)攪拌溶液與羰基二咪唑（0.36 g，2.05毫莫耳）反應 。於〇°C下攪拌該反應溶液30分鐘並於迴流下狀態下攪拌1 小時。經冷卻至室溫後，蒸發溶劑並藉由管柱層析純化殘 餘物以生成所欲之產物（0.58 g，82%) 。LC/MS: tR = 1.40 分，356·25(ΜΗ) +。 參 2 —氯一 3 -哌啶—4 —基一 3，4一二氫—1H —喹唑啉一 2Tetrahydrofuran (8 ml) of (2-amino-6-chloro-benzyl)-(1-benzyl-piperidine-4-yl) -amine (0.66 g, 2.0 mmol) was ordered at 0 ° C. The solution was reacted with carbonyldiimidazole (0.36 g, 2.05 mmol). The reaction solution was stirred at 0 ° C for 30 minutes and under reflux for 1 hour. After cooling to room temperature, the solvent was evaporated and the residue was purified by column chromatography to give the desired product (0.58 g, 82%). LC / MS: tR = 1.40 points, 356 · 25 (ΜΗ) +. Reference 2-Chloro- 3 -piperidine-4 -yl- 3,4-dihydro-1H -quinazoline- 2

利用氮氣冲洗3 — ( 1 —苄基—哌卩定—4 一基）一 8 —氯 —3，4 —二氫一 1Η — D奎唑啉 一2 —酮（〇.17 g, 0.48 毫莫 -322 - 200529835 (318) 耳）之甲醇（10 ml )溶液，並令其與Pd / C ( 10%，17 mg )反應。加入三氟乙酸（0.2 ml )，利用氮氣冲洗該混 合物，隨後於氫氣下進行隔夜攪拌。利用氮氣冲洗該反應 溶液，經由通過寅氏過濾，並進行濃縮。管柱層析生成所 欲之產物（1〇〇 mg，79% ) 。LC/MS: tR=0.99 分， 266.08 ( MH ) +。 5 —溴一1 Η —吲哚_ 3 —腈Purge 3- (1-benzyl-piperidine-4-yl) -8-chloro-3,4-dihydro-1H-D-quinazolin-2-one (0.17 g, 0.48 mmol) with nitrogen -322-200529835 (318) ears) in methanol (10 ml) and allowed to react with Pd / C (10%, 17 mg). Trifluoroacetic acid (0.2 ml) was added, and the mixture was flushed with nitrogen, followed by overnight stirring under hydrogen. The reaction solution was flushed with nitrogen, filtered through a filter, and concentrated. Column chromatography produced the desired product (100 mg, 79%). LC / MS: tR = 0.99 points, 266.08 (MH) +. 5 —bromo-1 fluorene —indole_ 3 —nitrile

於迴流狀態下加熱5 —溴一吲哚一 3 —醛（5 g，22· 3 毫莫耳）和磷酸氫二銨（15.6 g，31.8毫莫耳）之1—硝基 丙烷（6 6 m 1 )和乙酸（2 2 m 1 )的混合物1 6小時。經冷卻 至室溫後，減壓下除去溶劑並將水加入至該黑色殘餘物中 。經過短暫之時間，迅速沈澱出5 -溴一 1 Η -吲哚一 3 -腈。過濾該固體，經水冲洗數次，隨後乾燥數小時，生成 所欲之產物（4 · 3 g，8 6 % )。 1H-NMR ( CD3〇D ) ά 7.4 0 ( m » 2 Η ) ，7.77(s，1Η) ，7.97(s，2H)。質譜：222.95( MH ) +。 5 —甲醯基一 1 Η —吲D朵〜3 —腈Heat 5-bromo-indole-3 -aldehyde (5 g, 22.3 mmol) and 1-nitropropane (6 6 m) of diammonium hydrogen phosphate (15.6 g, 31.8 mmol) under reflux. 1) A mixture with acetic acid (2 2 m 1) for 16 hours. After cooling to room temperature, the solvent was removed under reduced pressure and water was added to the black residue. After a short period of time, 5-bromo- 1 fluorene-indole- 3 -nitrile precipitated rapidly. The solid was filtered, washed several times with water, and then dried for several hours to yield the desired product (4.3 g, 86%). 1H-NMR (CD3〇D) 7.4 0 (m »2Η), 7.77 (s, 1Η), 7.97 (s, 2H). Mass spectrum: 222.95 (MH) +. 5-Methanyl- 1 Η-InD ~~ 3-Nitrile

g，1 9.23毫莫耳 將5 —溴—1 Η —吲哚一 3 —腈（4 · 2 5 - 323 - 200529835 (319)g, 1 9.23 millimoles 5-bromo-1 hydrazone-indole-1 3-nitrile (4 · 2 5-323-200529835 (319)

)和氫化鈉（0.51 g，21 ·2毫莫耳）載入至含有磁石攪拌 棒且經火焰乾燥之圓底燒瓶中。於室溫和氮氣下，加入乾 四氫呋喃（24 ml )。室溫下攪拌該混合物15分鐘，期間 該溶液轉呈均質狀。冷卻該攪拌混合物至- 78t，隨後以 超過數分鐘之時間加入另丁基鋰之環己烷溶液（1.4M， 30.2 ml，2.2當量）。於一 7 8 °C下經1小時後，緩慢地加入 二甲基甲醯胺（6.0 ml )並令該混合物隔夜回溫至室溫。 冷卻該溶液至0 °C並令其小心地與1 N H C1 ( 4 5 m 1 )反應。 經數分鐘後，加入NaHC03固體直至pH達至9至10。分離 兩層，利用乙酸乙酯冲洗水層2次。利用水（2 X )和鹽水 (2x)冲洗結合之有機層，置於Na2S04上乾燥，並進行濃 縮。管柱層析生成純產物（2.4 g，72%) 。：LC/MS: tR = 0.99分，171.07( ΜΗ )+。 2 —卡氧鑛基胺基一 3_ (3 -氨基—1Η-卩引D朵一 5 -基） 一丙嫌酸甲酯) And sodium hydride (0.51 g, 21.2 mmol) were loaded into a flame-dried round bottom flask containing a magnetic stir bar. At room temperature under nitrogen, dry tetrahydrofuran (24 ml) was added. The mixture was stirred at room temperature for 15 minutes, during which time the solution turned homogeneous. The stirred mixture was cooled to -78t, and then a solution of another butyllithium in cyclohexane (1.4M, 30.2 ml, 2.2 equivalents) was added over a few minutes. After 1 hour at 78 ° C, dimethylformamide (6.0 ml) was slowly added and the mixture was allowed to warm to room temperature overnight. The solution was cooled to 0 ° C and allowed to react carefully with 1 N H C1 (45 m 1). After a few minutes, NaHC03 solid was added until the pH reached 9 to 10. The two layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were washed with water (2X) and brine (2x), dried over Na2S04, and concentrated. Column chromatography produced pure product (2.4 g, 72%). : LC / MS: tR = 0.99 points, 171.07 (ΜΗ) +. 2 —Carbonylaminoamine 3 — (3-amino-1Η-fluorene-D-do 5- 5-yl) methyl propionate

室溫下令Ν-苄氧羰基- α 一亞磷羧基甘胺酸三甲酯 (1·68 g，5.1毫莫耳）之四氫呋喃（1〇 ml )攪拌溶液與 四甲基胍（0·6 ml，1.1當量）反應。經10分鐘後，加入5 —甲醯基—1H —吲哚—3 -腈（0.72 g，4.24毫莫耳）。 -324- 200529835 (320) 室溫下經攪拌3天後，蒸發溶劑並利用（2x )和鹽水（2x )冲洗殘餘物’置於Na2S〇4上乾燥，並進行濃縮。管柱層 析產生純產物（1.3 g，82%) 。LC/MS: tR=1.43 分， 3 76.22 ( MH ) h。 (土） 2 月女基~~ 3 — (3 —氯基一 1 Η — D引口朵一5 —基）一 丙酸甲酯Tetrahydrofuran (10 ml) was stirred with a solution of N-benzyloxycarbonyl-α-phosphorous carboxyglycine trimethyl ester (1.68 g, 5.1 mmol) and tetramethylguanidine (0.6 ml , 1.1 equivalent) reaction. After 10 minutes, 5-methylamidino-1H-indole-3 -nitrile (0.72 g, 4.24 mmol) was added. -324- 200529835 (320) After stirring at room temperature for 3 days, the solvent was evaporated and the residue was washed with (2x) and brine (2x) ', dried over Na2SO4, and concentrated. The column chromatography gave pure product (1.3 g, 82%). LC / MS: tR = 1.43 minutes, 3 76.22 (MH) h. (Earth) February feminine ~~ 3 — (3 —Chloroyl 1 1 Η — D inlet Duo 5 —yl) a methyl propionate

利用氣氣冲洗2氧幾基胺基一 3— （3—氰基一 1Η 一吲唑一 5—基）一丙烯酸甲酯（〇·5 g，1.3毫莫耳）之甲 醇（8 ml)溶液，並令其與Pd/C( 10%，50 mg)反應。 利用氫氣冲洗該燒瓶並令其於氫氣下隔夜攪拌。利用氮氣 冲洗該反應溶液，經由通過寅氏鹽過濾，並進行濃縮。管 柱層析產生所欲之產物（0.3 g，92%) 。LC/MS: tR = 0.80 分，244.20 ( MH ) 4 。 實施例202 (土）一 3— (3 —氰基一1H — D 引口朵一5 —基）一 2— { 〔4 一 （2 —嗣基〜1，4一 一*氯一 2H—卩奎卩坐琳—3 —基）一丨依 啶一 1一羰基〕一胺基} 一丙酸甲酯 - 325 - 200529835 (321)Rinse a solution of 2-oxoylamino-3- (3-cyano-1,1-indazole-5-yl) -methyl acrylate (0.5 g, 1.3 mmol) in methanol (8 ml) with air. And let it react with Pd / C (10%, 50 mg). The flask was flushed with hydrogen and allowed to stir overnight under hydrogen. The reaction solution was flushed with nitrogen, filtered through yin salt, and concentrated. Column chromatography produced the desired product (0.3 g, 92%). LC / MS: tR = 0.80 minutes, 244.20 (MH) 4. Example 202 (Earth) —3— (3—cyano—1H—D—Introduction——5—based] —2— {[4— (2—fluorenyl ~ 1,4—1 * chlorine 2H— 卩Quinazeline—3-yl)-丨 Epiridine-1-carbonyl] -amino} methyl monopropionate-325-200529835 (321)

於〇 °C下令2 —胺基一 3 — ( 3 —氰基一 1 Η —吲哚—5 — 基）一丙酸甲酯（25 mg，0.11毫莫耳）之四氫呋喃（3 ml )攪拌溶液與羰基二咪唑（17.5 mg，1.1當量）反應。 於〇°C下攪拌該反應混合物5分鐘，令其回溫至室溫再攪拌 10分鐘，隨後與3 —哌啶—4 —基—3，4 —二氫一1H —喹 唑啉一 2—酮（25 mg，1.1當量）反應。室溫下隔夜攪拌 該混合物。蒸發溶劑並藉由管柱層析純化殘餘物，生成白 色粉末（40 mg，75%) 。LC/MS: tR=1.37 分，501.33 (MH )十。 實施例203 (±) — 4— (2 —酮基一1，4 —二氫一 2H — D奎唑啉一3 — 基）一哌啶一 1 一羧酸〔2 —〔 1，4 /〕聯哌啶一 1 / 一基 一 1— (3 —氰基—1H—D引D朵—5 —基甲基）一 2 —酮基一 乙基〕一醯胺 - 326 - 200529835 (322)Tetrahydrofuran (3 ml) was stirred at 0 ° C as a solution of 2-amino-3- (3-cyano-1,1 indole-5-inyl) monopropionate (25 mg, 0.11 mmol). Reacted with carbonyldiimidazole (17.5 mg, 1.1 equivalents). The reaction mixture was stirred at 0 ° C for 5 minutes, allowed to warm to room temperature and stirred for another 10 minutes, and then with 3-piperidine-4-yl-3,4-dihydro-1H-quinazoline-2. Ketones (25 mg, 1.1 equivalents) were reacted. The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by column chromatography to give a white powder (40 mg, 75%). LC / MS: tR = 1.37 points, 501.33 (MH) ten. Example 203 (±) — 4 -— (2-keto-1,4-dihydro-1H—D quinazoline-3-yl) -piperidine-1 monocarboxylic acid [2 — [1, 4 /] Bipiperidine 1/1 radical 1 1-(3-cyano-1H-D-D 5 -ylmethyl)-2 -ketomonoethyl] -amidine-326-200529835 (322)

室溫下令3— (3 —氰基一 1H —吲哚—5 —基）一 2 - { 〔4— (2— 酮基一1，4一 二氫一2H—D奎唑啉一3 —基） 一哌啶一1 —羰基〕—胺基}—丙酸甲酯（15 mg，0.03毫 莫耳）之甲醇（0.6 ml)溶液與LiOH單水合物（3.0 mg， 2 · 5當量）之水（0 . 1 ml )溶液反應。室溫下攪拌該溶液2 小時。冷卻該溶液至〇°C，令其與1M KHS04水溶液（60 # 1，2.0當量）反應，隨後蒸發溶劑以生成粗酸，其係未 經純化而直接使用。令該粗酸溶解於冷卻至〇 °C之二甲基 甲醯胺（0.4 ml)中，隨後先後加入CH2C12(0.2 ml) 、4 一呢卩定基一喊卩定（11 mg’ 2.2當量）、Ν’ N - 一異丙基 乙胺（12//1，2,3 當量）及 PyBOP(19mg，1.2 當量）。 於〇 °C下攪拌該溶液1 5分鐘，令其回溫至室溫，再攪拌1 . 5 小時，隨後進行濃縮。藉由管柱層析純產物，生成1 〇. 1 mg(52%，2步驟）。 ^-NMR ( CD30D ) δ 1.60-2.10 (m，14H) ，2·53 ( d ，J=13.0，1Η) ，2.58(d，J二 12.2，1Η) ，2.65— 3.00 (m，7H) ，3.12(d，J=7.0，lH) ，3.17(d，J二 7.0 ，1H) ，3.84(s，lH) ，3.46(bs，lH) ，4.08-4.86(At room temperature, 3- (3-cyano-1H-indole-5-yl)-2-{[4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl ) Water of a piperidine-l-carbonyl] -amino group} -methyl propionate (15 mg, 0.03 mmol) in methanol (0.6 ml) and LiOH monohydrate (3.0 mg, 2.5 equivalents) (0.1 ml) solution reaction. The solution was stirred at room temperature for 2 hours. The solution was cooled to 0 ° C and allowed to react with a 1M KHS04 aqueous solution (60 # 1, 2.0 equivalents), and then the solvent was evaporated to form a crude acid, which was used without purification. The crude acid was dissolved in dimethylformamide (0.4 ml) cooled to 0 ° C, followed by the addition of CH2C12 (0.2 ml), 4 monomethyl aridinyl group (11 mg '2.2 equivalents), Ν 'N-Monoisopropylethylamine (12 // 1, 2, 3 equivalents) and PyBOP (19 mg, 1.2 equivalents). The solution was stirred at 0 ° C for 15 minutes, allowed to warm to room temperature, stirred for another 1.5 hours, and then concentrated. The pure product was purified by column chromatography to give 0.1 mg (52%, 2 steps). ^ -NMR (CD30D) δ 1.60-2.10 (m, 14H), 2.53 (d, J = 13.0, 1Η), 2.58 (d, J-2 12.2, 1Η), 2.65- 3.00 (m, 7H), 3.12 (d, J = 7.0, lH), 3.17 (d, J = 7.0, 1H), 3.84 (s, lH), 3.46 (bs, lH), 4.08-4.86 (

m，5H) ，4.70( in，1H) ，5.02(dd，J=8.3，6.7，lH -327- 200529835 (323) )，6.79(d，J=7.6，lH) ，6.9(m，lH) ^ 7.10 ( dd ，J=7.3，7.9，1H) ，9.18(s，lH) ，7.15(dd，j = 7.3，7·6，1Η) ，7.30(m，lH) ，7.50( m，lH) ，8·〇〇 (s，1 H )。質譜：6 4 7 · 4 1 ( Μ H ) 1。 3— (4—溴一2 —甲基—苯基胺基）一2 —甲基一丙烯酸乙 酯m, 5H), 4.70 (in, 1H), 5.02 (dd, J = 8.3, 6.7, lH -327- 200529835 (323)), 6.79 (d, J = 7.6, lH), 6.9 (m, lH) ^ 7.10 (dd, J = 7.3, 7.9, 1H), 9.18 (s, lH), 7.15 (dd, j = 7.3, 7.6, 1Η), 7.30 (m, lH), 7.50 (m, lH), 8 〇〇 (s, 1 H). Mass spectrum: 6 4 7 · 4 1 (MH) 1. 3- (4-bromo- 2-methyl-phenylamino)-2-methyl-ethyl acrylate

對4一溴一 2 —甲基—苯胺（7.0 g，37.8毫莫耳）之乙 腈（80 ml )溶液，在冰冷卻下先後加入濃HC1 ( 15 ml ) 、水（40 ml)及亞硝酸鈉（2.74 g，39.7毫莫耳）之水（ 4 0 ml )溶液以生成重氮鹽。於下將該溶液逐滴地轉移 至50% KOH溶液（16 ml)和2 —甲基乙醯乙酸（5.38 ml ，3 8毫莫耳）之乙醇（5 0 ml )溶液中。經加入完成後， 將該反應混合物倒入至冰水（1 5 0 m 1 )中並利用乙酸乙酯 進行萃取。利用鹽水（2x )冲洗有機層，置於Na2S04上乾 燥，經過濾和濃縮後生成標的化合物（7.5 g，66% )， 其係未經純化而直接使用。 ^-NMR ( CD3〇D ) 51.80(t，J二 7·0，3Η) ，2.13(s ，3 Η ) ，2.29 (s，3 Η ) ，4.26(dd，1=5.8» 7·0，1Η ) ，4.30(dd，J— 5·8，7.0，1Η) ，7.26(m，2H) ，7·43 - 328- 200529835 (324) m，1H )。質譜：3 23.07 ( MNa ) 一溴_ 7 —甲基一 1 H —吲哚—2 —羧酸乙酯To a solution of 4-bromo-2-methyl-aniline (7.0 g, 37.8 mmol) in acetonitrile (80 ml), add HC1 (15 ml), water (40 ml), and sodium nitrite successively under ice cooling. (2.74 g, 39.7 mmol) in water (40 ml) to form a diazonium salt. The solution was transferred dropwise to a 50% KOH solution (16 ml) and a solution of 2-methylacetametic acid (5.38 ml, 38 mmol) in ethanol (50 ml) below. After the addition was completed, the reaction mixture was poured into ice water (150 m 1) and extracted with ethyl acetate. The organic layer was washed with brine (2x), dried over Na2S04, filtered and concentrated to give the target compound (7.5 g, 66%), which was used directly without purification. ^ -NMR (CD3〇D) 51.80 (t, J 2 7.0, 3Η), 2.13 (s, 3 Η), 2.29 (s, 3 Η), 4.26 (dd, 1 = 5.8 »7.0, 1Η ), 4.30 (dd, J—5.8, 7.0, 1Η), 7.26 (m, 2H), 7.43-328- 200529835 (324) m, 1H). Mass spectrum: 3 23.07 (MNa) monobromo-7-methyl- 1 H-indole-2-carboxylic acid ethyl ester

於Dean-Stark水分離器中且在迴流條件下，加熱對甲 苯磺酸單水合物（4.26 g，75毫莫耳）之甲苯（80 ml)溶 液1 · 5小時。加入5 —溴一 7 -甲基一 1 Η —吲哚—2 —羧酸乙 酯（7.5 g，25.0毫莫耳）之甲苯（40 ml )溶液並於迴流 .狀態下加熱該反應混合物5小時。經冷卻至室溫後，將該 反應混合物倒入至冰水（1 20 ml )中並利用乙酸乙酯萃取 2次。集中有機層，經NaHC03溶液（2x)和鹽水（2x)冲 洗，置於Na2S04上乾燥，隨後進行過濾和濃縮。矽膠管柱 層析生成標的化合物（5.5 g，78% )。 iH-NMR ( CD3OD ) 5 1 ·35 ( t，J = 7.0，3H ) ，2.52 ( s ，3H) ，4.36(q，J=7.0，2H) ，7.13(s，lH) ，7.14 (s，lH) ，7.70(s，lH) ，：ll.90(s，lH)。質譜： 2 84.09 ( ΜΗ ) + 〇 5 —溴一7 —甲基一 1 H —吲哚A toluene (80 ml) solution of p-toluenesulfonic acid monohydrate (4.26 g, 75 mmol) was heated in a Dean-Stark water separator under reflux for 1.5 hours. A solution of ethyl 5-bromo-7-methyl-1 1-indole-2-carboxylic acid ethyl ester (7.5 g, 25.0 mmol) in toluene (40 ml) was added and the reaction mixture was heated under reflux for 5 hours. . After cooling to room temperature, the reaction mixture was poured into ice water (120 ml) and extracted twice with ethyl acetate. The organic layer was concentrated, washed with NaHC03 solution (2x) and brine (2x), dried over Na2S04, and then filtered and concentrated. Silica gel column chromatography yielded the target compound (5.5 g, 78%). iH-NMR (CD3OD) 5 1 · 35 (t, J = 7.0, 3H), 2.52 (s, 3H), 4.36 (q, J = 7.0, 2H), 7.13 (s, lH), 7.14 (s, lH ), 7.70 (s, lH), ll.90 (s, lH). Mass spectrum: 2 84.09 (ΜΗ) + 〇5 -Bromo-7-methyl-1H-indole

將5 —溴一 7 -甲基一1 Η —吲哚—2 —羧酸乙酯（5 · 3 g ，18.7毫莫耳）加入至]<：01^之1:1之水/乙醇混合物（2〇 -329- 200529835 (325) ml )溶液中並於迴流狀態下加熱1 2小時。經冷卻至室溫後 ，真空下除去溶劑並將所生成之殘餘物轉移至6N H C1溶液 (2 0 m 1 )中。過濾所生成之白色沈澱物，經水冲洗數次 ，並乾燥數小時。令粗固體溶解於喹啉（1 4 ml )中並於 迴流狀態下加熱4小時。經冷卻至室溫後，將粗混合物倒 入至冰水（1〇〇 ml )和濃HC1 ( 16 ml )之混合物中，經乙 酸乙酯（2x )和鹽水（2x )萃取，置於Na2S04上乾燥並進 行濃縮。自異丙醇再結晶所欲之產物係造成顯著之分解。 藉由矽膠閃蒸層析得到標的化合物（1.5 g，38%，2步驟 )。LC/MS: tR=1.72 分，210.05 (MH) +。 5 —溴一7 —甲基一 1 Η —吲哚一3 —醛Ethyl 5-bromo-7-methyl-1, 1 indole-2, carboxylic acid ethyl ester (5.3 g, 18.7 mmol) was added to a water / ethanol mixture of 1: 1 (20-329-200529835 (325) ml) and heated under reflux for 12 hours. After cooling to room temperature, the solvent was removed under vacuum and the resulting residue was transferred to a 6N H C1 solution (20 m 1). The white precipitate formed was filtered, washed several times with water, and dried for several hours. The crude solid was dissolved in quinoline (14 ml) and heated under reflux for 4 hours. After cooling to room temperature, the crude mixture was poured into a mixture of ice water (100 ml) and concentrated HC1 (16 ml), extracted with ethyl acetate (2x) and brine (2x), and placed on Na2S04 Dry and concentrate. The desired product recrystallized from isopropanol causes significant decomposition. The title compound was obtained by silica gel flash chromatography (1.5 g, 38%, 2 steps). LC / MS: tR = 1.72 points, 210.05 (MH) +. 5-Bromo-7-methyl-1 1 fluorene-indole-3-aldehyde

令5 —溴—7 —甲基—1Η — D引D朵（1.2 g，5.71毫莫耳 )溶解於乙腈（6 ml )中並於一 1 0 °C至0 °C下將其緩慢地 轉移至溴亞甲基二甲基溴化銨（1·36 g，6.28毫莫耳）之 乙腈（9 ml )溶液中。於下攪拌該反應溶液2小時，並 於室溫下攪拌3 0分鐘。蒸發溶劑並令粗混合物溶解於水中 且於50 °C下攪拌4小時。經冷卻至室溫後，利用乙酸乙醋 (2x )萃取該粗混合物。集中有機層，經鹽水（2x )冲洗 ，置於M g S Ο4上乾燥，隨後進行過濾和濃縮。藉由矽膠問 蒸層進行純化，生成所欲之化合物（〇 · 7 g，5 2 %，2步驟 - 330 - 200529835 (326) H-NMR ( CD3OD ) 5 2.50 ( s，3H) ，7.24 ( s，1H) ，8.34( m，lH) ，9.93(s，lH)。質譜：238.05 (ΜΗ)1。 5 —溴—7 —甲基一1 H - D引D朵—3 —腈Let 5-bromo-7-methyl-1 hydrazone-D-D (1.2 g, 5.71 mmol) be dissolved in acetonitrile (6 ml) and slowly transferred at a temperature of 10 ° C to 0 ° C. To a solution of bromomethylenedimethylammonium bromide (1.36 g, 6.28 mmol) in acetonitrile (9 ml). The reaction solution was stirred for 2 hours and 30 minutes at room temperature. The solvent was evaporated and the crude mixture was dissolved in water and stirred at 50 ° C for 4 hours. After cooling to room temperature, the crude mixture was extracted with ethyl acetate (2x). The organic layer was concentrated, washed with brine (2x), dried over MgS04, and then filtered and concentrated. Purification by evaporation from a silica gel layer yielded the desired compound (0.7 g, 52%, 2 steps-330-200529835 (326) H-NMR (CD3OD) 5 2.50 (s, 3H), 7.24 (s , 1H), 8.34 (m, 1H), 9.93 (s, 1H). Mass spectrum: 238.05 (ΜΗ) 1. 5-Bromo-7-methyl- 1H-D primer D-3—nitrile

於迴流狀態下加熱5 -溴—吲哚—3 —醛（0.7 g，2.94 毫莫耳）和磷酸氫二銨（2.05 g，15.5毫莫耳）之1 —硝基 丙烷（9 ml )和乙酸（3 ml )混合物1 6小時。經冷卻至室 溫後，減壓下除去溶劑並加水至黑色殘餘物中。經短暫時 間後，5 -溴一 1 Η —吲唑—3 -腈迅速沈澱，經過濾後利 用水冲洗數次，經乾燥小時後，生成所欲之腈（〇 · 6 g， 87% ) 。LC/MS: tR=1.71 分，235.01 (MH) +。 5 —甲醯基一7 —甲基—1H — D引D朵—3 —腈Heat 5-bromo-indole-3-aldehyde (0.7 g, 2.94 mmol) and diammonium hydrogen phosphate (2.05 g, 15.5 mmol) in 1-nitropropane (9 ml) and acetic acid under reflux. (3 ml) of the mixture for 16 hours. After cooling to room temperature, the solvent was removed under reduced pressure and water was added to a black residue. After a short period of time, 5-bromo-1,1-oxazole-indazole-3-nitrile precipitated rapidly. After filtration, it was washed with water several times. After drying for an hour, the desired nitrile (0.66 g, 87%) was formed. LC / MS: tR = 1.71 points, 235.01 (MH) +. 5-methylformyl-7-methyl-1H-D

將5 —溴一7 —甲基—1H — D引D朵一3 —腈（〇·58 g’ 2.46毫莫耳）和NaH (68 mg，2.7毫莫耳）載入含有磁石 攪拌棒之經火焰乾燥的圓底燒瓶中。於室溫和氮氣下，加 入四氫呋喃（9 m 1 )。室溫下攪拌該混合物1 5分鐘’期間 -331 - 200529835 (327) 該混合物轉呈均質狀。令該攪拌混合物冷卻至-7 8 t並以 超過數分鐘之時間加入另丁基鋰之環己烷（1.4M，3.8 ml ，2.2當量）溶液。於一 78 °C下經1小時後，緩慢地加入二 甲基甲醯胺（〇 · 9 ml )並令該混合物隔夜回溫至室溫。冷 卻該溶液至〇°C並小心地加入IN HC1。經數分鐘後，加入 NaHC03固體直至pH達至9 — 10。分離2層並利用乙酸乙 酯冲洗水層2次。利用水（2x )和鹽水（2x )冲洗結合之 有機層，置於Na2S04上乾燥，並進行濃縮。管柱層析生成 所欲之產物（60 mg，14%)和未反應之起始物（0·4 g) 。LC/MS: tR=1.21 分，185·10(ΜΗ) +。 j 2—苄氧羰基胺基一 3— (3 -氰基一 7 —甲基一 1H—吲哚 一 5—基）一丙烯酸甲酯Load 5-bromo-7-methyl-1H-D-D-D3-trinitrile (0.58 g '2.46 mmol) and NaH (68 mg, 2.7 mmol) into a magnetic stirrer bar Flame dried round bottom flask. Tetrahydrofuran (9 m 1) was added at room temperature under nitrogen. The mixture was stirred at room temperature for 15 minutes' period -331-200529835 (327) The mixture turned homogeneous. The stirred mixture was allowed to cool to -78 t and a solution of cyclohexane (1.4M, 3.8 ml, 2.2 equivalents) in butyllithium was added over a few minutes. After 1 hour at -78 ° C, dimethylformamide (0.9 ml) was slowly added and the mixture was allowed to warm to room temperature overnight. Cool the solution to 0 ° C and carefully add IN HC1. After a few minutes, add NaHC03 solids until the pH reaches 9-10. The two layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were washed with water (2x) and brine (2x), dried over Na2S04, and concentrated. Column chromatography produced the desired product (60 mg, 14%) and unreacted starting material (0.4 g). LC / MS: tR = 1.21 minutes, 185 · 10 (ΜΗ) +. j 2-benzyloxycarbonylamino- 3- (3-cyano-7-methyl-1H-indole-5-yl) monoacrylate

室溫下令N-苄氧羰基- α -亞磷羧基甘胺酸三甲酯 (1 80 mg，0.5 4毫莫耳）之四氫呋喃（3 ml )攪拌溶液與 四甲基胍（40 // 1，1 · 1當量）反應。經1 〇分鐘後，加入5 —甲醯基一7 —甲基一1H—吲哚—3 —腈（50 mg，0.27毫 莫耳）。室溫下經攪拌3天後，蒸發溶劑並利用水（2x ) 和鹽水（2x )冲洗殘餘物，置於MgS04上乾燥，隨後進行 -332- 200529835 (328)A solution of N-benzyloxycarbonyl-α-phosphorous carboxyglycine trimethyl ester (1 80 mg, 0.5 4 mmol) in tetrahydrofuran (3 ml) was stirred at room temperature with tetramethylguanidine (40 // 1, 1 · 1 equivalent) reaction. After 10 minutes, 5-methylamidinyl-7-methyl-1H-indole-3-nitrile (50 mg, 0.27 mmol) was added. After stirring for 3 days at room temperature, the solvent was evaporated and the residue was washed with water (2x) and brine (2x), dried on MgS04, and then -332- 200529835 (328)

濃縮。管柱層析生成純產物（100 mg，95% ) ° LC/ MS ：tR=1.59分，390·24(ΜΗ) +。 (±) — 2 —胺基一3— (3 —氰基一7—甲基一 1Η—吲哚一 5 —基）一丙酸甲酯 Οconcentrate. Pure product was obtained by column chromatography (100 mg, 95%) ° LC / MS: tR = 1.59 minutes, 390 · 24 (ΜΗ) +. (±) — 2 —amino — 3 — (3 —cyano — 7 — methyl — 1 — indole — 5 — methyl) monopropionate 〇

利用氮氣冲洗2—苄氧羰基胺基一 3— (3 -氰基一 7一 甲基一1Η—吲哚一 5 —基）一丙烯酸甲酯（0.1 g，0·26毫 莫耳）之甲醇（2.5 ml )溶液，隨後令其與Pd / C ( 10 % ，：I 0 m g )反應。利用氫氣冲洗該燒瓶並於氫氣下進行_ 夜攪拌。利用氮氣冲洗該反應溶液，經由通過寅氏_ @ 並進行濃縮。管柱層析生成所欲之產物（60 mg，Μ% °LC/MS:tR=0.93 分，258·22(ΜΗ)+。 参 實施例204 (±) — 4— （2— 酮基一1，4一 二氫一2Η — D奎唑啉 基）一 _卩定一 1 —竣酸〔1 一〔 1，4 '〕聯哌Π定一 1 一 1 (3 —氰基一 7 —甲基一 1Η — D引D朵—5—基甲基） 酮基一乙基〕一醯胺 - 333- 200529835 (329)Methanol of 2-benzyloxycarbonylamino-3- (3-cyano-7-methyl-1,1-indole-5-yl) monoacrylate (0.1 g, 0.26 mmol) in methanol was purged with nitrogen. (2.5 ml) solution, which was then reacted with Pd / C (10%, 100 mg). The flask was flushed with hydrogen and stirred overnight under hydrogen. The reaction solution was flushed with nitrogen, passed through Yin's @@, and concentrated. Column chromatography yields the desired product (60 mg, M% ° LC / MS: tR = 0.93 minutes, 258 · 22 (ΜΗ) +. See Example 204 (±) — 4 — (2 — Keto-1 , 4-dihydro-2Η-D-quinazolinyl)-卩 卩 -1 卩 -acid [1-[1,4 '] bipipedine 一 1-1 1 (3-cyano-7-methyl One 1Η — D — 5 —ylmethyl) Ketomonoethyl] monofluorenamine-333- 200529835 (329)

Ο 如前述實施例203之方法進行製備：j-NMRCCDsOD )5 1.55— 2.01 (m，16H) ，2.50(s，3H) » 2.80-3.20 (m，9H) ，4.10-4.40(m，7H) ，4.90(m，3H)， 6.72(d，J=7.9，1H) ，6.93(dd，J=8.5，8.5，1H) ，7.40(S，1H) ，7.88(s，lH) ，7.99(s，lH)。質 譜：651·57(ΜΗ) +。 4 —溴一 2—異丙基一 6一甲基—苯基胺〇 Prepared according to the method of the previous Example 203: j-NMRCCDsOD) 5 1.55-2.01 (m, 16H), 2.50 (s, 3H) »2.80-3.20 (m, 9H), 4.10-4.40 (m, 7H), 4.90 (m, 3H), 6.72 (d, J = 7.9, 1H), 6.93 (dd, J = 8.5, 8.5, 1H), 7.40 (S, 1H), 7.88 (s, lH), 7.99 (s, lH) ). Mass spectrum: 651.57 (ΜΗ) +. 4-Bromo-2-isopropyl-6-methyl-phenylamine

令2-異丙基一 6-甲基—苯基胺（5 g，33.5毫莫耳 )溶解於乙酸（20 ml )中。以超過10分鐘之時間，逐滴 地加入溴（1.8 ml，35.14毫莫耳）之乙酸（5 ml )溶液。 室溫下經攪泮1小時後，利用CH2C12稀釋該反應混合物， 隨後經水（2x )、飽和硫代硫酸鈉溶液（2x )、飽和 NaHC〇3溶液（2x )及鹽水冲洗。將有機層置於Na2S04上 乾:k ’隨後進行過濾和濃縮。經矽膠閃蒸層析純化後，生 成所欲之產物（7.6 g，定量）。LC/MS: tR=1.37分， -334- 200529835 (330) 23 0.07 ( ΜΗ ) *。 4一溴一 2-異丙基一 6—苯基重氮基一特丁硫醚2-Isopropyl-6-methyl-phenylamine (5 g, 33.5 mmol) was dissolved in acetic acid (20 ml). Over 10 minutes, a solution of bromine (1.8 ml, 35.14 mmol) in acetic acid (5 ml) was added dropwise. After stirring at room temperature for 1 hour, the reaction mixture was diluted with CH2C12, and then washed with water (2x), saturated sodium thiosulfate solution (2x), saturated NaHC0 solution (2x), and brine. The organic layer was dried over Na2S04: k 'and then filtered and concentrated. After purification by silica gel flash chromatography, the desired product (7.6 g, quantitative) was produced. LC / MS: tR = 1.37 minutes, -334- 200529835 (330) 23 0.07 (ΜΗ) *. 4-bromo- 2-isopropyl- 6-phenyldiazo-tert-butyl sulfide

令4 一溴一 2 -異丙基—6 -甲基一苯基胺（7.6 g， 33.5毫莫耳）懸浮於24% HC1 ( 15 ml )中。冷卻該攪拌 混合物至-20 °C，並令其與以超過30分鐘之時間逐滴加入 之亞硝酸鈉（2.4 g，1 · 0 5當量）之水（5 m 1 )溶液反應， 同時維持溫度低於—5°C。於一 5°C至—20°C下經30分鐘後 ，利用乙酸鈉固體緩衝該混合物至約pH 5。將該混合物（ 維持於約—1 0 °C下）於〇 °C下以超過約3 0分鐘之時間分數 部份地加入至特丁基硫赶（3.77 ml，1 ·0當量）之乙醇（ 2 5 ml )攪拌溶液中。完成添加後，於〇°c下攪拌該混合物 3 0分鐘，隨後加入碎冰（約5 0 m 1 )。經由過濾以收集所 生成之淡褐色固體，經水冲洗並於高真空下乾燥數小時， 生成所欲之產物（7.9 g，72%)。 ^-NMR ( CDC13 ) 5 1.15(t，J=6.7，3H) ，1.58(sSuspend 4-bromo-2-isopropyl-6-methyl-phenylamine (7.6 g, 33.5 mmol) in 24% HC1 (15 ml). Cool the stirred mixture to -20 ° C and allow it to react with a solution of sodium nitrite (2.4 g, 1.05 equivalents) in water (5 m 1) added dropwise over 30 minutes while maintaining the temperature Below -5 ° C. After 30 minutes at a temperature between 5 ° C and -20 ° C, the mixture was buffered to approximately pH 5 with sodium acetate solids. This mixture (maintained at about -10 ° C) was partially added to tert-butylthiophene (3.77 ml, 1.0 equivalent) at 0 ° C over a time fraction of about 30 minutes ( 2 5 ml). After the addition was complete, the mixture was stirred at 0 ° C. for 30 minutes, followed by the addition of crushed ice (about 50 m 1). The resulting light brown solid was collected by filtration, rinsed with water and dried under high vacuum for several hours to yield the desired product (7.9 g, 72%). ^ -NMR (CDC13) 5 1.15 (t, J = 6.7, 3H), 1.58 (s

，9H) ，2.00(s，3H) ，2.54( m，lH) ，7.20(s，lH )，7.28(s，lH) 0 質譜：331.08( MNa )十。 5 -溴一 7 —異丙基一；1 H -吲唑 -335 - 200529835 (331), 9H), 2.00 (s, 3H), 2.54 (m, 1H), 7.20 (s, 1H), 7.28 (s, 1H). Mass spectrum: 331.08 (MNa). 5-bromo-1 7-isopropyl-1; 1 H-indazole-335-200529835 (331)

將4 一溴一2，6 —二乙基苯基重氮基一特丁硫醚（ 7.94 g，24毫莫耳）和特丁氧化鉀（27 g，10當量）載入 經火焰乾燥之圓底燒瓶中。加入攪拌棒並將該混合物置於 氮氣下。加入乾二甲亞硕（7〇 ml )。室溫下隔夜劇烈攪 拌該混合物。將該反應混合物小心地倒入至碎冰（2 50 ml )和10% HC1 ( 120 ml )之混合物中。藉由過濾以收集 所生成之懸浮液並經水冲洗數次。收集固體並經真空下乾 燥，生成所欲之產物（4.2 g，74% ) 。LC/ MS : tR = 1 .73 分，24 1.06 ( ΜΗ ) +。 7—異丙基一 1Η—吲唑一 5 —醛Load 4 monobromo-2,6-diethylphenyldiazo-tert-butyl sulfide (7.94 g, 24 mmol) and tert-butoxide (27 g, 10 equivalents) into a flame-dried circle Bottom flask. A stir bar was added and the mixture was placed under nitrogen. Add dry dimethyl arsenic (70 ml). The mixture was stirred vigorously overnight at room temperature. The reaction mixture was carefully poured into a mixture of crushed ice (2 50 ml) and 10% HC1 (120 ml). The resulting suspension was collected by filtration and rinsed several times with water. The solid was collected and dried under vacuum to yield the desired product (4.2 g, 74%). LC / MS: tR = 1.73 minutes, 24 1.06 (ΜΗ) +. 7-isopropyl-1, 1-indazole, 5-aldehyde

將5 —溴一 7 —異丙基一1Η—吲唑（3.1 g，12.1毫莫 耳）和NaH ( 0.34 g，1.1當量）載入含有磁石攪拌棒之經 火焰乾燥之圓底燒瓶中。於室溫和氮氣下，加入乾四氫呋 喃（18 ml )。室溫下攪拌該混合物15分鐘，期間該混合 物轉呈均質狀。冷卻該攪拌混合物至- 7 8 °C，並以超過數 分鐘之時間加入另丁基鋰之環己烷（1 .4M，20 ml，2.2當 量）溶液。於—7 8 °C下經1小時後，緩慢地加入二甲基甲 醯胺（3.0 ml )並令該混合物隔夜回溫至室溫。冷卻該溶 •336- 200529835 (332) 液至〇 °C並小心地與1 N H C1 ( 3 5 m 1 )反應。經數分鐘後， 加入NaHC03固體直至溶液達到pH 9至10。分離2層並利用 乙酸乙酯冲洗水層2次。利用水（2 X )和鹽水（2 X )冲洗 結合之有機層，置於Na2S04上乾燥並進行濃縮。管柱層析 生成純產物（2.1 g ’ 92% ) 。LC/MS · tR = 1.15 分， 1 8 9 · 1 2 ( Μ Η ) 4 。5-Bromo-7-isopropyl-1H-indazole (3.1 g, 12.1 mmol) and NaH (0.34 g, 1.1 equivalents) were charged into a flame-dried round bottom flask containing a magnetic stir bar. At room temperature under nitrogen, dry tetrahydrofuran (18 ml) was added. The mixture was stirred at room temperature for 15 minutes, during which time the mixture turned homogeneous. The stirred mixture was cooled to -78 ° C and a solution of cyclohexane (1.4M, 20 ml, 2.2 equivalents) in butyllithium was added over several minutes. After 1 hour at -7 ° C, dimethylformamide (3.0 ml) was slowly added and the mixture was allowed to warm to room temperature overnight. Cool the solution • 336- 200529835 (332) to 0 ° C and carefully react with 1 N H C1 (35 m 1). After a few minutes, NaHC03 solid was added until the solution reached pH 9 to 10. The two layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were washed with water (2X) and brine (2X), dried over Na2S04 and concentrated. Column chromatography yielded the pure product (2.1 g ' 92%). LC / MS · tR = 1.15 minutes, 1 8 9 · 1 2 (ΜΗ) 4.

2—苄氧羰基胺基一 3— (7-異丙基一 1Η —吲唑一 5 -基 )丙烯酸甲酯2-benzyloxycarbonylamino-1,3- (7-isopropyl-1,1'-indazol-5-yl) acrylate

室溫下令Ν-苄氧羰基- α -亞磷羧基甘胺酸三甲酯 (0.39 g，1 .2當量）之四氫呋喃（5 ml )攪拌溶液與四甲 基胍（0.16 ml，1.1當量）反應。經10分鐘後，加入7-異 丙基一 1H —吲唑—5 —醛（0.2 g，1.06毫莫耳）。室溫下 經攪拌3天後，蒸發溶劑並藉由矽膠閃蒸層析純化殘餘物 ，生成產物（〇·35 g，84%) 。LC/MS: tR 二 1.61 分， 394.16 ( ΜΗ) +。 (±) — 2 —胺基一 3— (7—異丙基一 1Η—吲唑一 5 —基） 一丙酸甲酯 -337- 200529835 (333)Tetrahydrofuran (5 ml) stirred solution of N-benzyloxycarbonyl-α-phosphorous carboxyglycine trimethyl ester (0.39 g, 1.2 equivalents) was reacted with tetramethylguanidine (0.16 ml, 1.1 equivalents) at room temperature. . After 10 minutes, 7-isopropyl-1H-indazole-5-aldehyde (0.2 g, 1.06 mmol) was added. After stirring for 3 days at room temperature, the solvent was evaporated and the residue was purified by silica gel flash chromatography to give the product (0.35 g, 84%). LC / MS: 1.61 points tR, 394.16 (ΜΗ) +. (±) — 2 —Amine — 3 — (7 —Isopropyl — 1 —Indazole — 5 —yl) Methyl monopropionate -337- 200529835 (333)

HN*^NHN * ^ N

利用氮氣冲洗2—卡氧羯基胺基一 3 — （7-異丙基一 1H—吲唑一5 —基）一丙烯酸甲酯（0.35 g，0.89毫莫耳 )之甲醇（7 ml)溶液，並令其與Pd/C(10%，35 mg) 反應。利用氫氣冲洗該燒瓶並令其於氫氣下隔夜攪拌。利 用氮氣冲洗該反應溶液，經通過寅氏鹽過濾並進行濃縮。 管柱層析生成所欲之產物（0.21 g，90%)。 實施例2 0 5 (土）一 3— (7 — 異丙基一1H—口引 tl坐一 5 —基）一 2— {〔 4— (2 —酮基一 1，4_二氫一 2H—哇唑啉—3—基）一哌 啶一 1 一羰基〕一胺基} 一丙酸甲酯Rinse a solution of 2-carbofluorenylamino-3- (7-isopropyl-1H-indazol-5-yl) -monoacrylate (0.35 g, 0.89 mmol) in methanol (7 ml) with nitrogen. And let it react with Pd / C (10%, 35 mg). The flask was flushed with hydrogen and allowed to stir overnight under hydrogen. The reaction solution was flushed with nitrogen, filtered through Yin salt and concentrated. Column chromatography produced the desired product (0.21 g, 90%). Example 2 0 5 (Earth) —3— (7—Isopropyl—1H—Introduction TL—5—Base) —2 — [[4— (2 —Keto-1,4-dihydro-1H —-Oxazoline —3-yl) monopiperidine-1 monocarbonyl] monoamino} methyl propionate

如則述3— （3 —氰基一 1H—D引H朵一基）一 2— ^ 〔4— (2—酮基—ι，4 —二氫一 2H-喹唑啉一 3 —棊）一 哌啶一 1 一羰基〕一胺基丨—丙酸甲酯之方法製備。L C / MS ·· tR = 1.49分，5 1 9.35 ( MH ) H 〇 - 338- 200529835 (334) 實施例206 (±) — 4— (2 —酮基一1，4一二氫一2H — 口奎唑啉一3 — 基）—哌啶—1 一羧酸〔2 — 〔 1，4 /〕聯哌啶—1 / 一基 一 1(7—異丙基一 1H—吲唑一 5 -基甲基）一 2 —酮基— 乙基〕一醯胺As stated in the following 3- (3-cyano-1H-D-H-do) -2- [4— (2-keto-ι, 4-dihydro-2H-quinazoline 3-3-fluorene) Monopiperidine-l-carbonyl] -amino group --- propionic acid methyl ester. LC / MS ·· tR = 1.49 minutes, 5 1 9.35 (MH) H 〇-338- 200529835 (334) Example 206 (±) — 4— (2 —keto-1,4—dihydro—2H — mouth Quinazoline- 3-yl) -piperidine-1 monocarboxylic acid [2- — [1,4 /] bipiperidine-1 / 1-yl-1 (7-isopropyl-1H-indazole-5-yl (Methyl)-2-keto-ethyl] monofluorenamine

如前述實施例2 03之方法自3-（7—異丙基一 1H—吲 唑—5 - 基）一 2— { 〔4— (2 —酮基—1，4 —二氫一 2H 一喹唑啉一 3 —基）一哌啶一 1 一羰基〕一胺基} 一丙酸甲 酯進行製備·· iH-NMRCCDsOD) 51.45(m，6H) ，1.60The method described in Example 2 03 above is from 3- (7-isopropyl-1H-indazol-5-yl) -2- {[4- (2-keto-1,4-dihydro-2H-quine Preparation of oxazoline 3-yl) -piperidine-1 monocarbonyl] -amino} monopropionate · iH-NMRCCDsOD) 51.45 (m, 6H), 1.60

—2.05 (m，14H) ，2.20-2.50 (m，4H) ，2.73 (d，J—2.05 (m, 14H), 2.20-2.50 (m, 4H), 2.73 (d, J

二 13.7，1H) ，2.90(m，4H) ，4.05(d，J=14.0，lH )，4.20 ( m，2H ) ，4.35 ( s，1 H ) ，4.65 ( dd，J = 12.2，14.3，1H) ，4.95 (m，2H) ，6.79 (d，J二 7.9， 1 H ) ，6.92(dd，J=7.6，6.1，lH) ，7.13(m，lH)， 7.80(s，lH) ，7.45(s，lH) ，8.05(s，lH)。質譜 :6 5 5.40 ( ΜΗ ) + ° 4一溴一 2，6—二乙基苯基重氮基—特丁硫醚 - 339 - 200529835 (335)2 13.7, 1H), 2.90 (m, 4H), 4.05 (d, J = 14.0, 1H), 4.20 (m, 2H), 4.35 (s, 1 H), 4.65 (dd, J = 12.2, 14.3, 1H ), 4.95 (m, 2H), 6.79 (d, J 2 7.9, 1 H), 6.92 (dd, J = 7.6, 6.1, 1H), 7.13 (m, 1H), 7.80 (s, 1H), 7.45 ( s, lH), 8.05 (s, lH). Mass spectrum: 6 5 5.40 (ΜΗ) + ° 4 monobromo-1,6-diethylphenyldiazo-tert-butyl sulfide-339-200529835 (335)

令4 —溴—2，6 —二乙基苯胺（6·3 g，27.6毫莫耳） 懸浮於2 4 % H C1 ( 1 5 m 1 )中。冷卻該攪拌混合物至—2 0 °C，並以超過3 0分鐘之時間令其與逐滴加入之亞硝酸鈉（ 2.0 g，1.05當量）之水（5 ml )溶液反應，同時維持溫度 低於一 5 t：。於—5 °C至—2 0 °C下經3 0分鐘後’利用乙酸鈉 固體緩衝該混合物至約pH 5。於0°C下以超過約30分鐘之 時間，將該混合物（維持於約- 1 〇 °C下）分數部份地加入 至特丁基硫赶（3.15 ml，1.0當量）之乙醇（25 ml)攪拌 溶液中。隨後於〇°C下攪拌該混合物30分鐘並加入碎冰（ 約5 0 ml )。藉由過濾以收集所生成之淡棕色固體，經水 冲洗並於高真空下乾燥數小時後，生成所欲之產物（6 · 0 g 5 6 6%) 〇 ^-NMR ( CDC13 ) (5 1 · 1 5 ( t，J = 7·6，6H ) ，1.50 ( s ，9H) ，2.27(m，4H) ，7.21(s，3H)。質譜：331.08 (Μ H ) +。 5 —漠一 7 —乙基一3—甲基D引D坐Let 4-bromo-2,6-diethylaniline (6.3 g, 27.6 mmol) be suspended in 24% H C1 (15 m 1). Cool the stirred mixture to -20 ° C and allow it to react with a solution of sodium nitrite (2.0 g, 1.05 equivalents) in water (5 ml) added dropwise over 30 minutes while maintaining the temperature below A 5 t :. After 30 minutes at -5 ° C to -20 ° C, the mixture was buffered with sodium acetate solids to about pH 5. Partially add this mixture (maintained at about -10 ° C) to tert-butylthiophene (3.15 ml, 1.0 equivalent) in ethanol (25 ml) at 0 ° C over a period of about 30 minutes ) Stir the solution. The mixture was then stirred at 0 ° C for 30 minutes and crushed ice (about 50 ml) was added. The resulting light brown solid was collected by filtration, washed with water and dried under high vacuum for several hours to yield the desired product (6.0 g 5 6 6%). NMR (CDC13) (5 1 · 1 5 (t, J = 7.6, 6H), 1.50 (s, 9H), 2.27 (m, 4H), 7.21 (s, 3H). Mass spectrum: 331.08 (Μ H) +. 5-Moyi 7 —Ethyl 3-methyl D

-340- 200529835 (336) 將4一溴一 2，6-二乙基苯基重氮基一特丁硫醚（4·0 g，12.1毫莫耳）和特丁氧化鉀（13.2 g，10當量）載入經 火焰乾燥之圓底燒瓶中。加入攪拌棒並將該混合物置於氮 氣下。加入乾二甲亞硕（3 5 ml )。室溫下隔夜劇烈攪拌 該混合物。將該反應混合物小心地倒入至碎冰（1 3 0 ml ) 和1 0 % H C 1 ( 6 0 m 1 )之混合物中。藉由過濾以收集所生 成之懸浮液並利用水冲洗數次。收集固體並於真空下乾燥 ，生成灰色固體（2.85g，98%)。 φ ]H-NMR ( CD3OD ) ά 1 ·32 ( t，J = 7.6，3H ) ，2·50 ( s-340- 200529835 (336) 4-bromo-2,6-diethylphenyldiazo-tert-butyl sulfide (4.0 g, 12.1 mmol) and tert-butyl oxide (13.2 g, 10 (Equivalent) into a flame-dried round bottom flask. A stir bar was added and the mixture was placed under nitrogen. Add dry dimethyl arsenic (3 5 ml). The mixture was stirred vigorously overnight at room temperature. The reaction mixture was carefully poured into a mixture of crushed ice (130 ml) and 10% HC1 (60 m1). The resulting suspension was collected by filtration and rinsed several times with water. The solid was collected and dried under vacuum to give a gray solid (2.85 g, 98%). φ] H-NMR (CD3OD) 1 · 32 (t, J = 7.6, 3H), 2.50 (s

，3H) ，2.88(m，2H) ，7.25(s，lH) ，7.68(s，lH )。質譜：23 9.26 ( MH ) +。 7 —乙基一 3 —甲基吲唑一 5—醛3H), 2.88 (m, 2H), 7.25 (s, 1H), 7.68 (s, 1H). Mass spectrum: 23 9.26 (MH) +. 7-ethyl- 3 -methylindazole- 5-aldehyde

Η 、0 將5 —溴一7—乙基一3 —甲基吲唑（2.85 g，11.9毫莫 耳）和NaH ( 0.31 g，1.1當量）載入含有磁石攪拌棒之經 火焰乾燥的圓底燒瓶中。於室溫和氮氣下，加入乾四氫呋 喃（1 5 ml )。室溫下攪拌該混合物1 5分鐘，期間該混合 物轉呈均質狀。冷卻該攪拌混合物至-7 8 °C，並以超過數 分鐘之時間加入特丁基鋰之戊烷溶液（1.4M，1 8.7 ml， 2.0當量）。於—78°C下經1小時後，緩慢地加入二甲基甲 醯胺（2.8 ml )並令該混合物隔夜回溫至室溫。冷卻該溶 -341 - 200529835 (337) 液至〇 °C並令其小心地與1 N H C 1 ( 3 0 m 1 )反應。經數分鐘 後，加入NaHC03固體直至pH達到9至1〇。分離2層，並 利用乙酸乙酯冲洗水層2次。利用水（2x )和鹽水（2x ) 冲洗結合之有機層，置於Na2S04上乾燥，並進行濃縮。管 柱層析生成純產物（1.5 g，67%) 。LC/MS: tR=1.15 分，1 89· 1 2 ( ΜΗ ) +。Η, 0 Load 5-bromo-7-ethyl-3 methylindazole (2.85 g, 11.9 mmol) and NaH (0.31 g, 1.1 equivalent) into a flame-dried round bottom containing a magnetic stir bar In the flask. At room temperature under nitrogen, dry tetrahydrofuran (15 ml) was added. The mixture was stirred at room temperature for 15 minutes, during which time the mixture turned homogeneous. The stirred mixture was cooled to -7 ° C, and a solution of t-butyllithium in pentane (1.4M, 1 8.7 ml, 2.0 equivalents) was added over several minutes. After 1 hour at -78 ° C, dimethylformamide (2.8 ml) was slowly added and the mixture was allowed to warm to room temperature overnight. The solution -341-200529835 (337) was cooled to 0 ° C and allowed to react carefully with 1 N H C 1 (30 m 1). After a few minutes, NaHC03 solid was added until the pH reached 9 to 10. The two layers were separated, and the aqueous layer was washed twice with ethyl acetate. The combined organic layer was washed with water (2x) and brine (2x), dried over Na2S04, and concentrated. Column chromatography yielded the pure product (1.5 g, 67%). LC / MS: tR = 1.15 minutes, 1 89 · 1 2 (ΜΗ) +.

2 —苄氧羰基胺基—3 — （7 -乙基一 3 —甲基一 1Η—吲唑 一 5—基）一丙酸甲酯2-benzyloxycarbonylamino-3— (7-ethyl-1, 3-methyl-1, 1-indazole, 5-yl) monopropionate

室溫下令Ν-苄氧羰基一 α 一亞磷羧基甘胺酸三甲酯 (3.17 g，9·57毫莫耳，1.2當量）之四氫呋喃（15 ml) 攪拌溶液與四甲基胍（1·1 ml，1,1當量）反應。經10分鐘 後，加入7 —乙基—3 —甲基吲唑—5 —醛（1.5 g，7.98毫 莫耳）。室溫下經攪拌3天後，蒸發溶劑並藉由矽膠閃蒸 層析純化殘餘物，生成產物（2.5 g，8 0 % ) 。L C / M S : tR= L61 分，394.1 6 ( ΜΗ) + 〇 (±) — 2—胺基一 3— (7 —乙基—3—甲基一1H —吲唑一 5—基）一丙酸甲酯 -342 - 200529835 (338)Tetrahydrofuran (15 ml) was stirred with a solution of N-benzyloxycarbonyl-α-phosphorous carboxyglycine trimethyl ester (3.17 g, 9.57 mmol, 1.2 equivalents) at room temperature with tetramethylguanidine (1 · 1 ml, 1,1 equivalent). After 10 minutes, 7-ethyl-3-methylindazol-5-aldehyde (1.5 g, 7.98 mmol) was added. After stirring for 3 days at room temperature, the solvent was evaporated and the residue was purified by silica gel flash chromatography to give the product (2.5 g, 80%). LC / MS: tR = L61, 394.1 6 (ΜΗ) + 〇 (±) — 2-amino-3- (7-ethyl-3-methyl-1H—indazole-5-yl) monopropionic acid Methyl-342-200529835 (338)

利用氮氣冲洗2-卡氧鑛基胺基一 3—（7 —乙基一 3-甲基—1H—吲唑一 5—基）一丙烯酸甲酯（1.0 g，2.54毫 莫耳）之甲醇（15 ml)溶液，並令其與Pd/C(10%，Use nitrogen to flush methyl 2-oxomethylamido-3- (7-ethyl-3-methyl-1H-indazol-5-yl) -methacrylate (1.0 g, 2.54 mmol) 15 ml) solution and mix it with Pd / C (10%,

1 00 mg )反應。利用氫氣冲洗該燒瓶。並於氫氣下進行隔 夜攪拌。利用氮氣冲洗該反應溶液，經通過寅氏鹽過濾並 進行濃縮。管柱層析生成所欲之產物（0.6 g，91% )。 ^-NMR ( CD3〇D ) 5 1.32 ( m，3H) ，2·50 ( s，3H) ，2.88(dd，J=7.3，7.6，lH) ，2.89(dd，J=7.6，7.6 ，1 H ) ，30.2 (dd，J=6.4，7.0，1H ) ，3.11 (dd，J = 7.6，5.8，1H) ，3.35(s，lH) ，3.65(m，3H) ^ 7.00 (s，lH) ，7.33(s，lH)。質譜：262.24(MH)+。100 mg). The flask was flushed with hydrogen. It was stirred overnight under hydrogen. The reaction solution was flushed with nitrogen, filtered through Yin salt, and concentrated. Column chromatography produced the desired product (0.6 g, 91%). ^ -NMR (CD3OD) 5 1.32 (m, 3H), 2.50 (s, 3H), 2.88 (dd, J = 7.3, 7.6, 1H), 2.89 (dd, J = 7.6, 7.6, 1 H ), 30.2 (dd, J = 6.4, 7.0, 1H), 3.11 (dd, J = 7.6, 5.8, 1H), 3.35 (s, lH), 3.65 (m, 3H) ^ 7.00 (s, lH), 7.33 (s, lH). Mass spectrum: 262.24 (MH) +.

實施例207 (土） 一 4 — (2 — 嗣基一1 ’ 4 一 —·氣一2 Η — D 奎 口坐琳一3 — 基）—哌啶—1 —羧酸〔2 -〔 1，4 >〕聯哌啶一1 > 一基 —1(7—乙基一1Η — D引唑一5 —基一甲基）一2 —酮基一 乙基〕一醯胺 - 343- 200529835 (339)Example 207 (Earth)-4-(2-fluorenyl-1 '4--qi-2 hydrazine-D Kuizuline-3-yl)-piperidine-1-carboxylic acid [2-[1, 4 >] piperidine-1 > mono-1 (7-ethyl-1, 1-diazole, 5-yl-methyl), 2-ketomonoethyl] monofluorenamine-343- 200529835 (339)

如前述實施例2 03之方法，自（± ) — 2 —胺基—3 —As in the method of Example 20 03, from (±) — 2 —amino — 3 —

(7 —乙基一3 —甲基一1H—吲唑一 5—基）一丙酸甲酯進 行製備。 ^-NMRCCDCls) ά1.35(πι^3Η) ，：1.85— 2.00(m， 4H ) ，2.50(s，lH) ，2.70(m，2H) ，2.85(s，3H)(7-Ethyl-3-methyl-1H-indazol-5-yl) monopropionate was prepared. ^ -NMRCCDCls) ά 1.35 (πι ^ 3Η), 1.85—2.00 (m, 4H), 2.50 (s, lH), 2.70 (m, 2H), 2.85 (s, 3H)

，2.88— 3.25 (m，7H ) ，3.35 (s，1 H ) ，3.47 (dd，J, 2.88— 3.25 (m, 7H), 3.35 (s, 1 H), 3.47 (dd, J

= 7.3，7.3，1H) ，4·00— 4.40 (m，7H) ，4.70(m，lH )，5.00(m，3H) ，6.79(d，J=7.6，lH) ^ 6.93 ( dd ，J=7.3，7.3，1H) ，7.10(m，lH) ，7.15(dd，J = 7.3，7.6，1H) ，7.45(m，lH)。質譜：655.50= 7.3, 7.3, 1H), 4.00-4.40 (m, 7H), 4.70 (m, lH), 5.00 (m, 3H), 6.79 (d, J = 7.6, lH) ^ 6.93 (dd, J = 7.3, 7.3, 1H), 7.10 (m, 1H), 7.15 (dd, J = 7.3, 7.6, 1H), 7.45 (m, 1H). Mass spectrum: 655.50

(ΜΗ ) + 。 實施例208 (土） 一 4 — (2，2 — __•醒基一1 ’ 4 — __•氣一2 Η — 2λ 6 — 苯並〔1，2，6〕噻二嗪—3 -基）一哌啶一 1 —羧酸〔2 — 〔1，4 /〕聯哌啶一 1 / 一基一1 ( 7 —甲基一1 Η —吲唑— 5 —基一甲基）一 2-酮基一乙基〕一醯胺 -344 - 200529835 (340)(ΜΗ) +. Example 208 (Earth)-4-(2, 2 — __ • Awake 1-1 '4 — __ • Gas 2 2-2λ 6-Benzo [1,2,6] thiadiazine-3 -yl) 1-piperidine- 1-carboxylic acid [2 — [1,4 /] bipiperidine- 1 / 1-yl-1 (7-methyl-1 1 hydrazine-indazole-5 -yl-methyl)-2-one -Ethyl] monomethylamine-344-200529835 (340)

YOYO

如前述實施例2 0 3之方法，自3 -哌啶一 4 —基—3，4 —二氫一 1H—苯並〔1，2，6〕噻二嗪一 2，2 —二氧化物 進行製備··】H-NMR ( CD3OD) 5 1.20— 2.10 ( m，12H) ，2·20— 2.60 (m，6H) ，2.90(m，6H) ，3.78-4.11(According to the method of the previous Example 203, it was carried out from 3-piperidine-4-yl-3,4-dihydro-1H-benzo [1,2,6] thiadiazine-2,2-dioxide. Preparation ··] H-NMR (CD3OD) 5 1.20— 2.10 (m, 12H), 2.20— 2.60 (m, 6H), 2.90 (m, 6H), 3.78-4.11 (

m，4H) ，4.60(s，3H) ，4.90(m，lH) ，6.70(d，J = 8.1，1H) ，6.79 (dd，J=7.67，7·3，1H) ^ 7.44 ( sm, 4H), 4.60 (s, 3H), 4.90 (m, 1H), 6.70 (d, J = 8.1, 1H), 6.79 (dd, J = 7.67, 7. · 3, 1H) ^ 7.44 (s

，1H) ，7.10(m，lH) ，7.13( m，3H) ，8.03(s，lH )。質譜：663.60(MH)+。 實施例209 (土）一 4— (2，2 —二酮基一1，4 —二氫一2H— 2λ6 — 苯並〔1，2，6〕噻二嗪一 3 _基）—暖啶一 1 一羧酸〔2 — 〔1，4 /〕聯哌啶一 1 > —基一 1 ( 7 —乙基一3 —甲基一 1H —吲唑一 5—基一甲基）一 2-酮基一乙基〕一醯胺1H), 7.10 (m, 1H), 7.13 (m, 3H), 8.03 (s, 1H). Mass spectrum: 663.60 (MH) +. Example 209 (Earth) —4- (2,2-dione group—1,4-dihydro—2H—2λ6—benzo [1,2,6] thiadiazine—3 —yl) —warmidine— 1 monocarboxylic acid [2 — [1,4 /] bipiperidine-1] > -yl-1 (7-ethyl-3-methyl-1H-indazole-5-yl-methyl) -1 Keto-ethyl

200529835 (341) 如前述實施例2 0 3之方法，自3 —哌啶—4 —基—3，4 —二氫_1H—苯並〔1，2，6〕噻二嗪—2，2-二氧化物 進行製備：j-NMRCCDgOD) δ1_35(ηι，3H) ，1·42 — 2.05(m，10H) ，2.40(m，3H) ，2.55(s，3H) ，2.67 -3.12 (m，7H) ，3.85(m，lH) ，3.97(s，lH)， 4.03 (m，3H) ，4.65(m，4H) ，4.95(dd，J二 4.9， 5.8，1H) ，6.73 (d，J=7.9，1H) ，6.98(dd，J=7.3 ，6.4，1H) ，7.20(m，2H) ，7.88(s，lH)。質譜： 69 1 ·5 1 ( ΜΗ ) +。 實施例2 1 0 (土）一 2 — 〔4 — (6 — 氯基一2 —醒基一1，4 — —•氣一2 Η 一喹唑啉一 3 -基）一哌啶—1 —羰基〕—胺基〕—3 —（ 7 一甲基一1Η—吲唑一5—基）一丙酸甲酯200529835 (341) According to the method of the previous Example 203, from 3-piperidin-4-yl-3,4-dihydro_1H-benzo [1,2,6] thiadiazine-2,2- Preparation of dioxide: j-NMRCCDgOD) δ1_35 (η, 3H), 1.42-2.05 (m, 10H), 2.40 (m, 3H), 2.55 (s, 3H), 2.67 -3.12 (m, 7H) , 3.85 (m, lH), 3.97 (s, lH), 4.03 (m, 3H), 4.65 (m, 4H), 4.95 (dd, J 4.9, 5.8, 1H), 6.73 (d, J = 7.9, 1H), 6.98 (dd, J = 7.3, 6.4, 1H), 7.20 (m, 2H), 7.88 (s, 1H). Mass spectrum: 69 1 · 5 1 (ΜΗ) +. Example 2 1 0 (Earth)-2-[4-(6-Chloroyl 2-Xingyl 1, 1, 4---Gas-2 Η-Quinazoline-3 -yl)-Piperidine-1- Carbonyl] -amino] -3 — (7-methyl-1,1-indazole-5-yl) monopropionate

如前述一 3— (3 —氰基一 1Η —吲唑—5 —基）一2 - { [ 4 — (2 —嗣基 一 1 ’ 4 — —^氣一2 Η —喧 口坐琳一3 —基) 一哌啶一 1 一羰基〕一胺基} 一丙酸甲酯之方法製備：LC /MS: tR=1.34 分，516·40(ΜΗ) +。 -346- 200529835 (342) 實施例2 1 1 (±) — 4— (6 —氰基一2 -酮基一1，4一 2H —喹唑啉—3 一基）一哌啶一 1 —羧酸丨2 -〔 1，4 —〕聯哌啶—1 / 一 基—1— (7 一甲基—1H—吲唑一 5 —基甲基）一 2 —酮基 一乙基} 一醯胺As mentioned above, a 3- (3-cyano-1Η-indazole-5-yl)-2-{[4 — (2 -fluorenyl-1 '4 —- ^ qi-1 2 Η — 口 口 座 琳 -1 3 —Base) Preparation of monopiperidine-1 monocarbonyl] monoamino} monopropionate: LC / MS: tR = 1.34 points, 516 · 40 (ΜΗ) +. -346- 200529835 (342) Example 2 1 1 (±) — 4— (6-cyano-2-keto-1,4—2H—quinazoline-3 mono) —piperidine-1—carboxy Acid 丨 2-[1,4- —] bipiperidin-1 / 1-1-(7 -methyl-1H-indazole-5-ylmethyl)-2-keto-ethyl} monoamine

如目II述貫施例2 0 3之方法’自2 —酮[基一 3 —喊B定—4 — 基—1，2，3，4 —四氫一 D奎唑啉—6 —腈進行製備·· 1H-NMR ( CD3〇D ) 5 1.80 ( m，12H) ，2.40 ( m，4H)， 2.60(s，3H) ，2.70-3.20(m，10H) ^ 4.00 - 4.3 0 ( m ，6H) ，5.00( m，lH) ，5.50(s，2H) ，6.90(d，J = 7.8，1H) ，7.21(s，lH) ，7.50(m，4H) ，8.05(s， 1 H )。質譜：652.64(MH)+。 實施例2 1 2 (±) — 4— (2 —酮基一1，2，4，5 —四氫一苯並〔d〕 〔1，3〕二吖庚因—3 —基—1 一羧酸{2- 〔1，4 /〕聯 丨IR D疋一 1 —基一1 一 （7 —甲基一 1 Η — D弓丨口坐一 5 —基甲基 )一 2—酮基—乙基丨一醯胺 -347- 200529835 (343)As described in head II, the method of Example 203 is carried out from '2-ketone [group-1-hydrazidine-4-group-1,2,3,4 -tetrahydro-D-quinazoline-6 -nitrile. Preparation · 1H-NMR (CD3OD) 5 1.80 (m, 12H), 2.40 (m, 4H), 2.60 (s, 3H), 2.70-3.20 (m, 10H) ^ 4.00-4.3 0 (m, 6H ), 5.00 (m, 1H), 5.50 (s, 2H), 6.90 (d, J = 7.8, 1H), 7.21 (s, 1H), 7.50 (m, 4H), 8.05 (s, 1H). Mass spectrum: 652.64 (MH) +. Example 2 1 2 (±) — 4 — (2-keto-1,2,4,5-tetrahydro-benzo [d] [1,3] diazepine-3-yl-1 monocarboxy Acid {2- 〔1,4 /〕 linked 丨 IR D 疋 -1 1-yl-1 1- (7-methyl-1 1 Η- D bow 丨 sat-5 5-ylmethyl)-2-keto-B Benzylamine-347- 200529835 (343)

如前述實施例203之方法，自3 -哌啶一 4 一基一 1，3 ，4，5 —四氫一苯並〔d〕 〔 1，3〕二d丫庚因一 2 —酮進行 製備：1H-NMR(CD3OD) 5 1.40— 2.00(m，12H)， 2·30— 2.60( m，8H ) ，2.70 - 3.20 ( m ^ 1 OH ) ，3.70 ( m ，2H) ，3.60(d，J=9.5，lH) ，4·00— 4.30 (m，4H) ，4.70(m，lH) ，5.00(m，lH) ，6.90(m，2H)， 7.10(m，3H) ，7.20(s，lH) ，7.50(s，lH) » 8.05 (s，lH)。質譜：652.64 (\1}1)+。 實施例2 1 3 (土） 一 4 — ( 6 —經基一2 —嗣基一1，4 — 一* 氨一2 Η — D 奎 唑啉一 3 一基）一哌啶—1 一羧酸丨2 一〔 1，4 /〕聯哌啶 —1’ 一基一 1— (7 —甲基一1Η — D引唑一5 —基甲基）一2 一酮基一乙基} 一醯胺 -348- 200529835 (344)According to the method of the foregoing Example 203, it was prepared from 3-piperidine-4, 4-yl-1,3,4,5-tetrahydro-benzo [d] [1,3] di-d-heptane-2-one. : 1H-NMR (CD3OD) 5 1.40—2.00 (m, 12H), 2.30— 2.60 (m, 8H), 2.70-3.20 (m ^ 1 OH), 3.70 (m, 2H), 3.60 (d, J = 9.5, lH), 4.0- 4.30 (m, 4H), 4.70 (m, lH), 5.00 (m, lH), 6.90 (m, 2H), 7.10 (m, 3H), 7.20 (s, lH) ), 7.50 (s, lH) »8.05 (s, lH). Mass spectrum: 652.64 (\ 1} 1) +. Example 2 1 3 (Earth)-4-(6-meridian-2-fluorenyl-1, 4--* ammonia-2 hydrazine-D quinazoline-3-yl)-piperidine-1-carboxylic acid丨 2 [1,4 /] bipiperidin-1'-yl-1— (7-methyl-1Η—D-zolazole-5-ylmethyl) —2—one keto-ethyl} monomethylamine -348- 200529835 (344)

如前述實施例2 0 3之方法，自6 -羥基一 3 -哌啶一 4 — 基—3，4 一二氫—1H —喹唑啉一 2 -酮進行製備：LC/ MS: tR=1.24 分，643.62 (MH) +。 實施例2 1 4 (±) — 4— （8 —甲氧基一2 —酮基一1，4 —二氫一2H — 喹唑啉一 3 -基）一哌啶一 1 —羧酸—{ 2 —〔 1，4 /〕聯 哌啶一—基一1 一 （7 —甲基一1H — D引唑一5 —基甲基 )一 2—酮基一乙基}—醯胺According to the method of the previous Example 203, it was prepared from 6-hydroxy-3-piperidine-4-yl-3,4-dihydro-1H-quinazolin-2-2-one: LC / MS: tR = 1.24 Minutes, 643.62 (MH) +. Example 2 1 4 (±) — 4— (8-methoxy-2, keto-1,4-dihydro-1 2H—quinazoline-3—yl) -piperidine-1—carboxylic acid— { 2- [1,4 /] bipiperidinyl-yl-1 (7-methyl-1H-D-azole-5-ylmethyl) -2-keto-ethyl} -amidamine

如則述實施例2 0 3之方法’自8 —甲氧基—3 —丨派卩定一 4 一基一 3，4 一二氫—1H — D奎唑啉—2 —酮進行製備：】H-NMR ( CD3〇D ) 5 1.40— 2.00 (m，12H) ，2.40(m，2HThe method of Example 203 is described as follows: from 8-methoxy-3, 丨 Pyridine-1, 4-one, 3,4-dihydro-1H, D quinazoline-2, and ketone are prepared:] H-NMR (CD3〇D) 5 1.40—2.00 (m, 12H), 2.40 (m, 2H)

)，2.50(s，3H) ，2.80(m，3H) ，3·00— 3.20(m， 3H ) ，3.50( m，2H) ，4.00— 4.60( m，6H) ，5.00( m -349 - 200529835 (345)), 2.50 (s, 3H), 2.80 (m, 3H), 3.00— 3.20 (m, 3H), 3.50 (m, 2H), 4.00— 4.60 (m, 6H), 5.00 (m -349-200529835 (345)

，2H) ，6.70(dd，J=8.5，10.1，lH) ，6.85( m，2H )，7.10( m，lH) ，7.20(s，lH) ，7.47(s，lH)。 質譜：657.41 (ΜΗ) +。 實施例2 1 5 (±) — 4— (8 —氯一2 —酮基一 1，4 —二氫一2H —喹唑 啉—3 —基）—哌啶—1 一羧酸{ 2 -〔 1，4 /〕聯哌啶一 1 —基一1 — (7 —甲基—1H — D弓丨哇—5 —基甲基）一2 — 酮基一乙基} 一醯胺, 2H), 6.70 (dd, J = 8.5, 10.1, 1H), 6.85 (m, 2H), 7.10 (m, 1H), 7.20 (s, 1H), 7.47 (s, 1H). Mass spectrum: 657.41 (ΜΗ) +. Example 2 1 5 (±) — 4— (8-chloro-2—keto-1,4-dihydro-2H—quinazolin-3-yl) —piperidine-1 monocarboxylic acid {2-[ 1,4 /] piperidine- 1 -yl-1-(7 -methyl-1H-D-bow 丨 wa-5 -ylmethyl)-2 -ketomonoethyl} monofluorenamine

如前述實施例2 0 3之方法，自2 -氯一 3 —哌啶—4 一基 —3，4一二氫—1H -喹唑啉—2 —酮進行製備：iH-NMR ( CD3〇D ) 5 1.40-2.00 (m，14H) ，2·30— 2.60 (m，8H )，2.80( m，4H) ，3.50(m，3H) ，3.98(s，lH)， 4.10(m，lH) ，4.40(m，2H) ，4.60(m，lH) ，4.95 (ηι，1H) ，6.95(dd，J=7.9，7.9，1H) ，7.10(m， 1 H ) ，7.26(dd，J=6.7，7.6，lH) ，7.47( m，lH)， 8.04(s，lH)。質譜：661.27(MH)+。 實施例2 1 6 - 350- 200529835 (346) (±) — N— (3— (7 —乙基一3 —甲基一1H — D 引唑一5 — 基）一 1 —酮基一 1 — ( 4 一 （哌啶—1 —基）—哌啶—1 一 基）一丙—2_基）一 2 / ，3 / 一二氫一 2<一酮基螺—（ 哌啶一 4，4 / 一 D奎唑啉）一 1 一羧醯胺According to the method of the previous Example 203, the preparation was performed from 2-chloro-3-piperidine-4, 4-yl-3,4-dihydro-1H-quinazolin-2-one, iH-NMR (CD3OD ) 5 1.40-2.00 (m, 14H), 2.30— 2.60 (m, 8H), 2.80 (m, 4H), 3.50 (m, 3H), 3.98 (s, lH), 4.10 (m, lH), 4.40 (m, 2H), 4.60 (m, 1H), 4.95 (η, 1H), 6.95 (dd, J = 7.9, 7.9, 1H), 7.10 (m, 1 H), 7.26 (dd, J = 6.7, 7.6, lH), 7.47 (m, lH), 8.04 (s, lH). Mass spectrum: 661.27 (MH) +. Example 2 1 6-350- 200529835 (346) (±) — N — (3 — (7 —ethyl — 3 —methyl — 1H — D) azole — 5 —yl — 1 — keto — 1 — (4-(piperidine-1-yl) -piperidine-1 -yl) -propan-2-yl)-2 /, 3 / -dihydro-2 < -ketospiro- (piperidine-1,4 / -D quinazoline)-1 -carboxamide

如前述實施例203之方法進行製備：LC/ MS : tR二 1.51 分，641.63 (MH) +。 實施例2 1 7 (±) — N— (3— (7 -乙基一3 —甲基一1H — D引唑一5 — 基）一 1 —酮基—1 — ( 4 —(暖啶一 1 —基）一哌啶一 1 — 基）一丙一 2-基）一 2，4一二氫一 2 —醒基螺—（_D定 —4，4 / — 1 Η —苯並〔d〕 〔 1，3〕噁嗪）一 1 一羧醯胺It was prepared according to the method of the foregoing Example 203: LC / MS: tR = 1.51 minutes, 641.63 (MH) +. Example 2 1 7 (±) — N— (3— (7-ethyl—3—methyl—1H—Detazole—5—yl) — 1—keto—1 — (4— (armidine— 1-yl) -piperidine- 1-yl) -propanyl 2-yl) -2,4-dihydro-2-xylylspiro-(_ Dding-4, 4 / — 1 pyrene —benzo [d] 〔1,3〕 oxazine

如前述實施例203之方法進行製備：LC/ MS : tR = 1 .48 分，642.6 1 ( MH ) -351 - 200529835 (347) 2 —氟苯基氨基甲酸特丁酯 NHBocPrepared according to the method of the foregoing Example 203: LC / MS: tR = 1.48 minutes, 642.6 1 (MH) -351-200529835 (347) 2-fluorophenylcarbamic acid tert-butyl ester NHBoc

F 室溫下將2—氟苯胺（20.0 ml，207毫莫耳）加入至 二碳酸二特丁酯（45.2 g，207毫莫耳，1.0當量）之四氫 呋喃（2 1 0 ml )溶液中。加熱該反應溶液至迴流狀態並於 迴流狀態下加熱6小時。冷卻該反應溶液’經濃縮’溶解 於戊烷中，先後經5%檸檬酸、1M KHS04溶液（2x )、水 、20% K0H溶液及鹽水冲洗，置於MgS04上乾燥，經濃 縮後生成琥珀色油狀物（4 8.0 g，定量），其係未經純化 而使用。 j-NMR ( CDC13，5 00MHz ) δ 1.52 ( s，9Η ) ，6.68 ( bs，lH) ，6·85— 7.20 (m，3H) ，8_07(dd，J=8.1， 8·1，1H )。質譜：234.1 8 ( MNa) +。 2— （特丁氧羰基胺基）一 3-氟一苯甲酸 co2hF Add 2-fluoroaniline (20.0 ml, 207 mmol) to a solution of di-tert-butyl dicarbonate (45.2 g, 207 mmol, 1.0 equivalent) in tetrahydrofuran (210 ml) at room temperature. The reaction solution was heated to a reflux state and heated under reflux for 6 hours. The reaction solution was cooled and dissolved in pentane, washed with 5% citric acid, 1M KHS04 solution (2x), water, 20% K0H solution, and brine, dried on MgS04, and concentrated to produce an amber color. Oil (4 8.0 g, quantitative), which was used without purification. j-NMR (CDC13, 500 MHz) δ 1.52 (s, 9Η), 6.68 (bs, lH), 6.85-7.20 (m, 3H), 8_07 (dd, J = 8.1, 8.1, 1H). Mass spectrum: 234.1 8 (MNa) +. 2- (tert-butoxycarbonylamino) -3-fluoro-benzoic acid co2h

0c NHBoc F 於—78 t下將特丁基鋰之戊烷溶液（1.7M，3 06 ml， 2.5當量）逐滴地加入至2-氟苯基氨基甲酸特丁酯（44.0 g，2 0 8毫莫耳）之四氫咲喃（6 6 0 m 1 )溶液中。經加入完 成後，於-78t下攪拌該反應溶液30分鐘。令該溶液緩慢 地回溫至-20 °C，隨後再冷卻至- 78 °C，將該溶液經由套 -352 - 200529835 (348) 管轉移C〇2 (過量）和四氫呋喃（5 00 ml )之漿泥中。令 該溶液緩慢地回溫至室溫。濃縮該反應溶液以除去大部份 之四氫呋喃，隨後將其倒入含有水和二乙醚之分離漏斗中 。分離相層，並利用二乙醚萃取水層超過2次。丟棄醚液 。利用5 %檸檬酸酸化水層，並利用二乙醚（3 X )進行萃 取。將該醚液置於Mg S04上乾燥，經濃縮後生成淡黃色固 體，其係自熱甲苯中再結晶析出以生成暗黃色固體（37」 g，70% )。 1H-NMR ( CDC13，5 00MHz ) δ 1·50 ( s，9H) ，6·25 ( bs，lH) ，7.18(ddd，J=7.9，7.9，4.9，lH) ，7.33( dd，J=9.5，9.2，1Η) ，7.79(d，J=7.9，1H) » 7.94 (s，1H )。質譜·· 278.2 1 ( MNa ) +。 2〜（1—苄基哌啶一 4一基氨基甲醯基）一 6—氟苯基氨基 甲酸特丁酯0c NHBoc F At -78 t dropwise a solution of tert-butyllithium in pentane (1.7M, 3 06 ml, 2.5 equivalents) was added dropwise to tert-butyl 2-fluorophenylcarbamate (44.0 g, 2 0 8 Millimoles) in tetrahydrofuran (660 m 1) solution. After the addition was completed, the reaction solution was stirred at -78t for 30 minutes. Allow the solution to slowly warm to -20 ° C, and then cool to -78 ° C. Transfer the solution between CO2 (excess) and tetrahydrofuran (500 ml) via a jacket -352-200529835 (348) tube. In the mud. The solution was allowed to slowly warm to room temperature. The reaction solution was concentrated to remove most of the tetrahydrofuran, and then poured into a separation funnel containing water and diethyl ether. The phases were separated and the aqueous layer was extracted more than 2 times with diethyl ether. Discard the ether solution. The aqueous layer was acidified with 5% citric acid and extracted with diethyl ether (3X). The ether solution was dried on Mg S04, and concentrated to form a pale yellow solid, which was recrystallized from hot toluene to form a dark yellow solid (37 "g, 70%). 1H-NMR (CDC13, 500 MHz) δ 1.50 (s, 9H), 6.25 (bs, lH), 7.18 (ddd, J = 7.9, 7.9, 4.9, lH), 7.33 (dd, J = 9.5 , 9.2, 1Η), 7.79 (d, J = 7.9, 1H) »7.94 (s, 1H). Mass spectrum 278.2 1 (MNa) +. 2 ~ (1-benzylpiperidine-1, 4-methylcarbamoyl)-6-fluorophenylcarbamic acid tert-butyl ester

將1 一 （3 —二甲基胺基丙基）一 3 —乙基鑛二醯亞氛 氯化物（30.7 g，1.1當量）一次加入至2-（特丁氧羰基 胺基）一3 —氟—苯甲酸（37.1 g，145毫莫耳）、4—胺 基一 1—;基_卩定（35.6 ml，1.20當量）、1—羥基苯並三 唑（21.6 g，1·1當量）及三乙胺（44.1 g，3.0當量）之乙 酸乙酯（4 5 0 m 1 )溶液中。起初所有加入之物質係進入溶 液中，但是極迅速地產生沈澱物。該反應裝置配備迴流冷 -353- 200529835 (349) 凝器，並於迴流狀態下加熱該反應溶液5小時。利用乙酸 乙酯稀釋該反應溶液’先後經水（2 X) 、1 N N a Ο Η溶液（ 2 X )及鹽水冲洗’置於M g s 0 4上乾燥’經濃縮後生成白色 固體（6 7.0 g，定量），其係未經純化而使用。 】Η-ΝΜΙΙ ( CDC13，5 00MHz ) 5 1.48 ( s，9H) » 1.55 ( m，2H) ，1.99(bd，J=11.0，2H) ，2.17(dd，J = 11.0，11.0，2H) ，2.84(bd，J=11.3，3H) ^ 3.51 ( s ，2H) ，3.94(m，lH) ，6.13(bd，J=7.6，lH)， 7·10— 7.28(m，4H) ，7.31(m，4H) ，7.59(s，lH) 。質譜：428.4 1 ( MH ) +。 2 -胺基—N — ( 1 -苄基哌啶一 4 一基）一 3 —氟苯醯胺Add 1- (3-Dimethylaminopropyl) -3-Ethylmine diammonium chloride (30.7 g, 1.1 equivalents) to 2- (tert-butoxycarbonylamino) -3-fluoro —Benzoic acid (37.1 g, 145 millimoles), 4-amino- 1-amino; hydrazidine (35.6 ml, 1.20 equivalents), 1-hydroxybenzotriazole (21.6 g, 1.1 equivalents), and Triethylamine (44.1 g, 3.0 eq.) In a solution of ethyl acetate (450 m 1). At the beginning all the added substances entered the solution, but precipitated very quickly. The reaction device was equipped with a reflux cold-353-200529835 (349) condenser, and the reaction solution was heated under reflux for 5 hours. The reaction solution was diluted with ethyl acetate, washed with water (2 X), 1 NN a 〇Η solution (2 X), and brine, dried on M gs 0 4, and concentrated to form a white solid (6 7.0 g , Quantitative), which was used without purification. Η-NMILI (CDC13, 500 MHz) 5 1.48 (s, 9H) »1.55 (m, 2H), 1.99 (bd, J = 11.0, 2H), 2.17 (dd, J = 11.0, 11.0, 2H), 2.84 (bd, J = 11.3, 3H) ^ 3.51 (s, 2H), 3.94 (m, lH), 6.13 (bd, J = 7.6, lH), 7.10-7.28 (m, 4H), 7.31 (m, 4H), 7.59 (s, 1H). Mass spectrum: 428.4 1 (MH) +. 2 -amino-N-(1 -benzylpiperidine- 4 -yl)-3 -fluorobenzidine

於〇t：下將三氟乙酸（1〇〇 ml)加入至2— （1—苄基 哌啶一 4一基氨基甲醯基）一 6—氟苯基氨基甲酸特丁酯（ 67.0 g，157毫莫耳）之CH2C12 (700 ml)溶液中。移除冰 浴並於室溫下隔夜攪拌該反應溶液。濃縮該反應溶液並令 其分佈於乙酸乙酯和飽和NaHC03溶液中。利用乙酸乙酯 (2x )萃取水層，經水（3x )和鹽水冲洗，置於Mg2S〇4 上乾燥，經濃縮後生成白色固體（47.6 g，93% )，其係 未經純化而使用。質譜：3 2 8.33 ( MH ) +。 N —（2 -胺基一 3—氟苄基）一 1 一苄基哌啶一 4 一胺 -354 - 200529835Add trifluoroacetic acid (100 ml) to 2- (1-benzylpiperidine-4-ylaminocarbamyl) -6-fluorophenylcarbamic acid tert-butyl ester (67.0 g, 157 mmol) in CH2C12 (700 ml). The ice bath was removed and the reaction solution was stirred overnight at room temperature. The reaction solution was concentrated and distributed between ethyl acetate and a saturated NaHC03 solution. The aqueous layer was extracted with ethyl acetate (2x), washed with water (3x) and brine, dried over Mg2SO4, and concentrated to give a white solid (47.6 g, 93%), which was used without purification. Mass spectrum: 3 2 8.33 (MH) +. N — (2-amino-3-fluorobenzyl)-1-benzylpiperidine- 4 -amine -354-200529835

將2 —胺基—n〜（1 一苄基哌啶—4 —基）—3 —氟苯 醯胺（3 9 · 7 g ’ 1 2 1毫莫耳）之二噁烷（2 5 〇 m丨）溶液加入 至氫化銘鋰（16.1 g，424毫莫耳，3·5〇當量）之二噁烷（ 8 00 ml )的迴流懸浮液中，該加入之速率係使得氣體冒出 限於安全之流速。該加入完成後，於迴流狀態下加熱所生 成之懸浮液4小時。冷卻該反應溶液至〇它，並小心地加入 20% Κ0Η溶液以中該反應。生成白色可過濾之沈澱物， 由通過玻璃燒結漏斗以過濾該固體，濃縮流出液以生成淡 黃色油狀物（36.3 g，96% )，其係未經純化而使用。質 譜·· 314·29(ΜΗ) + 〇 3— （1 一苄基哌啶一4一基）—8—氟一 3，4—二氫喹唑啉 —2 ( Η )—酮Add 2-amino-n ~ (1-benzylpiperidine-4-yl) -3-fluorobenzidine (39.7 g '1 2 1 mmol) to dioxane (2 5 0 m丨) The solution was added to a reflux suspension of lithium hydride lithium (16.1 g, 424 millimolars, 3.50 equivalents) in dioxane (800 ml) at a rate such that gas evolution was restricted to safe Flow rate. After the addition was completed, the resulting suspension was heated under reflux for 4 hours. The reaction solution was cooled to zero, and a 20% KOH solution was carefully added to the reaction. A white filterable precipitate was formed, which was filtered through a glass sintering funnel, and the effluent was concentrated to give a pale yellow oil (36.3 g, 96%), which was used without purification. Spectroscopy ·· 314 · 29 (ΜΗ) + 〇 3 -— (1-benzylpiperidine-4-yl) -8-fluoro- 3,4-dihydroquinazoline —2 (fluorene) -one

室溫下將羰基二咪唑（20.7 g，1·1〇當量）一次加入 至Ν—（2 —胺基一 3 一氟苄基）_ι 一苄基哌啶一 4一胺（ 36.3 g，116毫莫耳）之四氫呋喃（600 mi)溶液中。室溫 下攪拌該反應溶液3小時，隨後於迴流狀態下加熱30分鐘 ，並進行濃縮。令所生成之固體溶解於1 : 1二乙醇/乙 酸乙酯中，經水（3x )和鹽水冲洗，置於MgS04上乾燥， - 355- 200529835 (351) 經濃縮後生成濕狀黃色固體之粗產物。利用二乙醚碾製該 固體，經過濾後生成白色粉末（30.0 g，76% )。 ^-NMR ( CDC13 i 5 00MHz) 51.68(m，2H) ，1.86( dddd，J=11.9，11.9，11.9，3.4，2H) ，2.14(dd，j = 11.6，10.1，2H) ，2.98(d，J=11.6，2H) ，3.51(s， 2H ) ，4.34 — 4.44 ( m，3H) ，6.71(bs，lH) ，6·79 — 6.89(m，2H) ，6.94(dd，J=9.2，9.2，lH) ，7.21 — 7.34(m，5H)。質譜：340.30(MH) +。 8—氟一3，4 —二氫一3—(哌啶一4 一基）一喹唑啉〜2( 1H)—酮Add carbonyldiimidazole (20.7 g, 1.10 equivalents) to N- (2-amino-3-fluorofluorobenzyl) -ι-benzylpiperidine-4-monoamine (36.3 g, 116 mmol) in one portion at room temperature. Mol) in tetrahydrofuran (600 mi) solution. The reaction solution was stirred at room temperature for 3 hours, then heated under reflux for 30 minutes, and concentrated. The resulting solid was dissolved in 1: 1 diethanol / ethyl acetate, washed with water (3x) and brine, and dried on MgS04.-355- 200529835 (351) After concentration, a thick yellow wet solid was obtained. product. This solid was triturated with diethyl ether and filtered to give a white powder (30.0 g, 76%). ^ -NMR (CDC13 i 5 00MHz) 51.68 (m, 2H), 1.86 (dddd, J = 11.9, 11.9, 11.9, 3.4, 2H), 2.14 (dd, j = 11.6, 10.1, 2H), 2.98 (d, J = 11.6, 2H), 3.51 (s, 2H), 4.34 — 4.44 (m, 3H), 6.71 (bs, 1H), 6.79 — 6.89 (m, 2H), 6.94 (dd, J = 9.2, 9.2 , LH), 7.21-7.34 (m, 5H). Mass spectrum: 340.30 (MH) +. 8-fluoro-3,4-dihydro-3- (piperidine-4yl) -quinazoline ~ 2 (1H) -one

將 3— (1 - 爷基_11 定—4 —基）一8— — 3，4 —二氫 喹唑啉_2(111)—酮（1.40§，4.12毫莫耳）和甲醇（ 25.0 ml )載入25 0 ml燒瓶中。利用熱槍加熱該懸浮液以幫 助溶解。利用氮氣冲洗該燒瓶，令其與Pd/ C ( 141 mg， 0.03 2當量）反應，先後經氮氣和氫氣冲洗，並於氫氣下 進行隔夜劇烈攪拌。利用氮氣冲洗該反應溶液，經通過寅 氏鹽過濾，經濃縮後生成白色固體（0.99 g，97% )，其 係未經純化而使用。 ]H-NMR ( CDCI3 5 5 00MHz ) 5 1.71 ( m，4H ) ，2.75 ( m，2H) ，3.16( m，2H) ，4.38(s，2H) ，4.46( m， 1 H ) ，6.77(bs，lH) ，6.81 — 6.89( 111，2H) ，6.95(m -356- 200529835 (352) ，：l Η )。質譜：2 5 0 · 2 2 ( Μ Η ) 1。 3 — （ 1 一苄基哌啶—4 一基）一 8 -氟D奎唑啉一 2，4 一（ 1 Η，3H )，二酮Add 3- (1-undecyl_11-determined 4-yl) -8--3,4-dihydroquinazolin_2 (111) -one (1.40§, 4.12 mmol) and methanol (25.0 ml ) Load into a 250 ml flask. The suspension was heated with a heat gun to help dissolve. The flask was flushed with nitrogen, reacted with Pd / C (141 mg, 0.03 2 equivalents), flushed with nitrogen and then with hydrogen, and stirred vigorously overnight under hydrogen. The reaction solution was flushed with nitrogen, filtered through Yin's salt, and concentrated to give a white solid (0.99 g, 97%), which was used without purification. ] H-NMR (CDCI3 5 5 00MHz) 5 1.71 (m, 4H), 2.75 (m, 2H), 3.16 (m, 2H), 4.38 (s, 2H), 4.46 (m, 1 H), 6.77 (bs , LH), 6.81-6.89 (111, 2H), 6.95 (m-356-200529835 (352), ll). Mass spectrum: 2 5 0 · 2 2 (ΜΗ) 1. 3 — (1-benzylpiperidine-4 -yl)-8 -fluoroD quinazoline-2,4-(1 Η, 3H), dione

將三光氣（277 mg，0.33當量）之CH2C12(5 ml)溶 液於〇 °C下加入至2 -胺基一 N -（ 1 —苄基哌啶—4 一基） -3 —氟苯醯胺（750 mg，2.29 毫莫耳）之 CH2C12(30 mi )溶液中。移除冰浴並流狀態下加熱該反應溶液6小時。 濃縮該反應溶液，令其溶解於乙酸乙酯中，先後經飽和 NaHC03溶液、水及鹽水冲洗。置於MgS04上乾燥，經濃 縮後生成白色固體（ 700 mg)。藉由閃蒸層析純化粗產物 ，生成色固體（205 mg，25%)。質譜：354·13(ΜΗ) + 8 —氟—3—(哌啶—4 —基）一喹唑啉—2，4— (1Η，3Η )一二酮Add a solution of triphosgene (277 mg, 0.33 equivalents) in CH2C12 (5 ml) at 0 ° C to 2-amino-N- (1-benzylpiperidine-4-yl) -3-fluorobenzidine (750 mg, 2.29 mmol) in CH2C12 (30 mi). The ice bath was removed and the reaction solution was heated under co-current conditions for 6 hours. The reaction solution was concentrated, dissolved in ethyl acetate, and washed with a saturated NaHC03 solution, water, and brine. It was dried on MgS04 and concentrated to give a white solid (700 mg). The crude product was purified by flash chromatography to give a colored solid (205 mg, 25%). Mass spectrum: 354 · 13 (ΜΗ) + 8-fluoro-3- (piperidin-4-yl) -quinazoline-2,4- (1Η, 3Η) -dione

先後利用氮氣和氫氣冲洗含有3 — （ 1 一苄基哌啶- 4 —基）—8 —氟喹唑啉—2，4(1Η，3Η) — 二酮（75.0 mg，0.21 毫莫耳）和 Pd/C( 8.00 mg，0.035 當量）之甲 200529835 (353) 醇（3 ml )溶液的燒瓶。氫氣下隔夜攪拌該反應溶液。利 用氮氣冲洗該反應溶液，經通過寅氏鹽過濾，經濃縮後生 成白色固體（53 mg，95% )，其係未經純化而使用。質 譜：2 6 4 · 2 5 ( Μ Η ) 4。 8 一氟一 ，3'—二氫—2 -酮基螺一（1—苯基甲 基哌Π定）一 4，4 ' 一 D奎嗤啉Nitrogen and hydrogen were successively flushed containing 3- (1-benzylpiperidin-4-yl) -8-fluoroquinazoline-2,4 (1Η, 3Η) -dione (75.0 mg, 0.21 mmol) and Flask of Pd / C (8.00 mg, 0.035 equivalent) of methyl 200529835 (353) alcohol (3 ml) solution. The reaction solution was stirred overnight under hydrogen. The reaction solution was flushed with nitrogen, filtered through yin salt, and concentrated to give a white solid (53 mg, 95%), which was used without purification. Mass spectrum: 2 6 4 · 2 5 (ΜΗ) 4. 8 monofluoro-1,3'-dihydro-2-ketospiro- (1-phenylmethylpididine) -4,4'-D quinoxaline

將多磷酸（110 ml)載入至配備有頂部攪拌器、氮氣 入口及起泡器之5 00 ml三頸燒瓶中。利用氮氣冲洗該燒瓶 並於油浴中加熱至1 0 5 °C。加入1 一苄基—4 —哌啶酮（ 2 1.0 1 ml，1 15毫莫耳）。隨後以超過2小時之時間分許多 小部份之方試加入N - （ 2-氟苯基）脲（21.3 g，1.2當 量）。於劇烈攪拌下加熱該反應溶液至160 °C。經2小時後 ，藉由倒至碎冰上以驟冷該反應溶液並利用20% KOH溶 液進行中和。利用CH2C12萃取該反應混合物，先後經水和 鹽水冲洗，置於MgS04上乾燥，並進行濃縮。整批產物係 藉由製備性HPLC (約130個注射）純水以生成較爲純化之 產物。藉由閃蒸層析再純化該產物以生成固體，其係經二 乙醚碾製並經過濾後生成白色固（275 mg，0.7% )。 j-NMR ( CDC13，5 00MHz ) (51.91 ( dd，J 二 13·71， 2·1，2H) ，2.10 ( ddd，J = 13·1，13.1，4.3，2Η )， 2.27(ddd，J=12.5，12.5，2.1，2H) ，2.86(m，2H) -358- 200529835 (354) ’ 3.57 (s，2 Η ) ，5.40 (bs，1 Η ) ，6.90 (bs，1 Η ) ’ 6.90— 7.05 (m，3Η) ，7.27(m，1H) ，7.32(m，4H) 。質譜：326.13( MH) +。 8—氟—2/，3/—二氣—2— —_基螺—_11定一4，4/一 D奎D坐啉 ΟPolyphosphoric acid (110 ml) was loaded into a 500 ml three-necked flask equipped with a top stirrer, a nitrogen inlet, and a bubbler. The flask was flushed with nitrogen and heated to 105 ° C in an oil bath. Add 1-benzyl-4-piperidone (2 1.0 1 ml, 1 15 mmol). N- (2-fluorophenyl) urea (21.3 g, 1.2 equivalents) was then added in many small portions over a period of more than 2 hours. The reaction solution was heated to 160 ° C with vigorous stirring. After 2 hours, the reaction solution was quenched by pouring onto crushed ice and neutralized with a 20% KOH solution. The reaction mixture was extracted with CH2C12, washed with water and then brine, dried over MgS04, and concentrated. The entire batch was purified by preparative HPLC (about 130 injections) with pure water to produce a more purified product. The product was repurified by flash chromatography to give a solid, which was triturated with diethyl ether and filtered to give a white solid (275 mg, 0.7%). j-NMR (CDC13, 500 MHz) (51.91 (dd, J 2 13.71, 2.1, 2H), 2.10 (ddd, J = 13.1, 13.1, 4.3, 2Η), 2.27 (ddd, J = 12.5, 12.5, 2.1, 2H), 2.86 (m, 2H) -358- 200529835 (354) '3.57 (s, 2 Η), 5.40 (bs, 1 Η), 6.90 (bs, 1 Η)' 6.90- 7.05 (m, 3Η), 7.27 (m, 1H), 7.32 (m, 4H). Mass spectrum: 326.13 (MH) +. 8-Fluoro-2 ,, 3 / -Digas-2, —_Base Spiro—_11 -4,4 / -D

HN 人 NHHN People NH

將 Pd/C(33.〇mg，0.037 當量）力口入至 —氟一 2 / ，3 〃 一酮基螺一 （1 一苯基甲基哌啶）—4，4 / _ 口奎Pd / C (33.0 mg, 0.037 equivalents) was orally injected into —fluoro- 2 /, 3 〃-ketospiro- (1 -phenylmethylpiperidine) -4,4 / _ Kou Kui

唑啉（250 mg，0.77毫莫耳）之甲醇（4 ml)和CH2C12( 4 ml )溶液中。利用氫氣冲洗該反應溶液，並於氫氣下進 行隔夜攪拌。移除球形瓶，利用氮氣冲洗該反應溶液，經 通過寅氏鹽過濾後，經甲醇冲洗，隨後經濃縮後生成白色 固體（1 5 8 mg，8 7 % )，其係未經純化而使用。 ]H-NMR ( CDCI3/CD3OD » 5 00MHz) 5 1 · 8 7 ( d，J = 12·8，2H) ，2· 1 5 ( ddd，J = 14.0，14.0，5·5，2H )，Oxazoline (250 mg, 0.77 mmol) in methanol (4 ml) and CH2C12 (4 ml). The reaction solution was flushed with hydrogen and stirred overnight under hydrogen. The spherical bottle was removed, and the reaction solution was flushed with nitrogen, filtered through Yin's salt, flushed with methanol, and then concentrated to form a white solid (158 mg, 87%), which was used without purification. ] H-NMR (CDCI3 / CD3OD »5 00MHz) 5 1 · 8 7 (d, J = 12 · 8, 2H), 2 · 1 5 (ddd, J = 14.0, 14.0, 5 · 5, 2H),

3.10 (m，4H) ，6.84(m，2H) ，6.93(d，J=7.0，lH )。質譜·· 23 6· 1 1 ( MH ) +。 實施例2 1 8 (±) — N— (3— (7 —乙基一1H —吲唑一5 —基）一1 — (6，7 —二氫一1 H — 吡唑並〔4，3 — c〕吼啶一5 ( 4 Η ) —基）一 1—酮基丙一 2 —基）一 4— (1，2 — 一氫一 2 —酮 -359- 200529835 (355) 基咱唑啉一 3 ( 4H ) -基）哌啶一 1 一羧醯胺3.10 (m, 4H), 6.84 (m, 2H), 6.93 (d, J = 7.0, 1H). Mass spectrum ... 23 6 1 1 (MH) +. Example 2 1 8 (±) —N— (3— (7-ethyl-1H—indazol-5-yl) -1— (6,7—dihydro-1H—pyrazolo [4,3 — C] aziridin-5 (4Η) —yl) — 1 —ketopropanyl 2 —yl) — 4 — (1, 2 — monohydro-2 — keto-359- 200529835 (355) oxazoline 3 (4H) -yl) piperidine-1 carboxamide

如前述實施例203之方法進行製備：j-NMR ( CD3OD ，5 00MHz ) ά 1.24 (m，2H ) ，1.55-2.07 (m，5H )， 2.57(m，lH) ，2.82(m，4H) ，3.08(m，2H) » 3.30 (m，3H) ，3.35(m，5H) ，3.48(m，3H) ，3.65(m ，1H) ，4.14(m，2H) ，4.27(m，2H) ，4.33— 4.57Prepared according to the method of the foregoing Example 203: j-NMR (CD3OD, 500 MHz), 1.24 (m, 2H), 1.55-2.07 (m, 5H), 2.57 (m, 1H), 2.82 (m, 4H), 3.08 (m, 2H) »3.30 (m, 3H), 3.35 (m, 5H), 3.48 (m, 3H), 3.65 (m, 1H), 4.14 (m, 2H), 4.27 (m, 2H), 4.33 — 4.57

(m，2H) ，5.06(dd，J=6.7，6.7，lH) ，5.22(d，J = 1.8，2H) ，6.78(d，J=7.6，lH) ，6.93(m，lH) ，7·00— 7.18(m，3.5H) ，7.37(d，J=9.8，lH)， 7.46 ( s，0.5H) ，7.9 1 ( dd，J = 1 0· 1，1 .80，1 H )。質 譜：596·43(ΜΗ) +。 實施例2 1 9 (±) - Ν— (3— (7 —乙基一1Η — D 引唑一5 —基）一1 — (6，7 —二氫一7，7 —二甲基一1Η —哦唑並〔4，3— c〕 口比 D定 一 5 ( 4 Η )—基）—1 —醒基丙—2 - 基）—4 — (1， 2 一 _^氣—2 一 嗣基 D 奎 D坐琳 一 3(4Η)—基)—l|K D定 一 1 — 羧醯胺 - 360- 200529835 (356) n-nh(m, 2H), 5.06 (dd, J = 6.7, 6.7, lH), 5.22 (d, J = 1.8, 2H), 6.78 (d, J = 7.6, lH), 6.93 (m, lH), 7. · 00— 7.18 (m, 3.5H), 7.37 (d, J = 9.8, 1H), 7.46 (s, 0.5H), 7.9 1 (dd, J = 1 0 · 1, 1.80, 1 H). Mass spectrum: 596 · 43 (ΜΗ) +. Example 2 1 9 (±)-Ν— (3— (7-ethyl-1Η-D) Indazole-55-yl) -1— (6,7-dihydro-7,7-dimethyl-1Η) —Ohzo [4,3—c] The ratio of D is 5 (4 Η) — radical) — 1 — propyl propyl — 2 — radical) — 4 — (1, 2 — _ — qi — 2 1 嗣Radical D quinine D 3 (4 坐)-radical)-l | KD fixed 1 1-carboxamide-360- 200529835 (356) n-nh

如前述實施例203之方法進行製備：】H-NMR ( CD3OD ，500MHz) 5 1.11(m，3H) ，1.50-1.80 (m，4H)， 2.87(m，4H) ，3.10(m，2H) ，3.32(m，9H) ，3.48Prepared according to the method of the foregoing Example 203:] H-NMR (CD3OD, 500MHz) 5 1.11 (m, 3H), 1.50-1.80 (m, 4H), 2.87 (m, 4H), 3.10 (m, 2H), 3.32 (m, 9H), 3.48

(m，4H) ，4.00— 4.45 (m，6H) ，5.05—5.25 (m，2H )，6.77(d，J=6.1，lH) ，6.93(m，lH) ^ 7.13 ( m ，3H) ，7.30— 7.60 (m，2H) ，7.95(m，lH)。質譜 ：624.49 ( ΜΗ ) + ° 實施例220 (±)—甲基一2 — （4— (8 —氟一 1，2 —二氫一2 — 酮基 D奎唑啉—3 ( 4 Η )—基）一哌啶一 1 —羧醯胺基）一 3 -（ 7 —甲基一 1 Η —吲唑一 5 —基）丙酸酯(m, 4H), 4.00-4.45 (m, 6H), 5.05-5.25 (m, 2H), 6.77 (d, J = 6.1, lH), 6.93 (m, lH) ^ 7.13 (m, 3H), 7.30 — 7.60 (m, 2H), 7.95 (m, lH). Mass spectrum: 624.49 (ΜΗ) + ° Example 220 (±) -methyl-1 2 — (4-—8-fluoro-1, 2 —dihydro-2 — keto D quinazoline-3 (4 Η) — ) -Piperidine- 1-carboxamido)-3-(7-methyl-1 fluorenyl-indazole-5-yl) propionate

如前述3 - （ 3 —氰基—1 Η -吲哚—5 —基）一2 — { 〔4— (2 —酮基一1，4一二氫一2Η—咱唑啉一3 —基）一 哌啶一 1 一羰基〕一胺基} 一丙酸甲酯之方法進行製備： 】H-NMR ( CDC13，500MHz) 5 1·53 - 1.68 ( m，4H)， -361 - 200529835 (357) 2.48(s，3H) ，2.82(m，2H) ，3.05(m，6H) ^ 3.09 (dd，Jab=13.7，6.1，1 H ) ，3.14(dd，JAB=14.0，6.1 ，1H) ，3.35(bs，lH) ，3.68(s，3H) ^ 3.8 8 - 4.02 ( m，2H) ，4.22(d，JAB=15.6，lH) ，4.25(d，JAB 二 15.3，1H) ，4.44(m，1H) ，4.71(dd，J=6.1，6.1， 1H ) ，6.78 (d，J=7.3，1 H ) ，6.84(ddd，J=7.6，7.6 ，4·9，1Η) ，6.88-6.95 (m，2H) ，7.28(s，lH)，As mentioned before, 3-(3-cyano-1 fluorene-indole-5-yl)-2-{[4- (2-keto-1,4-dihydro-2 fluorene-oxazoline-3-yl) Monopiperidine-1 monocarbonyl] monoamino} monopropionate: [H-NMR (CDC13, 500MHz) 5 1.53-1.68 (m, 4H), -361-200529835 (357) 2.48 (s, 3H), 2.82 (m, 2H), 3.05 (m, 6H) ^ 3.09 (dd, Jab = 13.7, 6.1, 1 H), 3.14 (dd, JAB = 14.0, 6.1, 1H), 3.35 ( bs, lH), 3.68 (s, 3H) ^ 3.8 8-4.02 (m, 2H), 4.22 (d, JAB = 15.6, lH), 4.25 (d, JAB two 15.3, 1H), 4.44 (m, 1H) , 4.71 (dd, J = 6.1, 6.1, 1H), 6.78 (d, J = 7.3, 1 H), 6.84 (ddd, J = 7.6, 7.6, 4.9, 1Η), 6.88-6.95 (m, 2H ), 7.28 (s, lH),

7.91 (s，lH)。質譜：509.25(MH)+。 實施例221 (±) — 4— （8 —氟一1，2—二氫一2—酮基喹唑啉一3( 4H )—基）一N— (3— (7 —甲基一1H — D 引唑一5 -基） 一 1 一酮基一 1 — ( 4 一（哌啶一 1 —基）哌啶一 1 一基）丙 一 2 —基）哌啶—1 —羧醯胺7.91 (s, 1H). Mass spectrum: 509.25 (MH) +. Example 221 (±) —4 -— (8-fluoro-1,2-dihydro-2-2-ketoquinazoline-3 (4H) -yl) -N- (3- (7-methyl-1H- D Indazole-1 5-yl) 1 1 keto-1 1-(4-(piperidine-1 -yl) piperidine-1 1 -yl) propan-2-yl) piperidine-1 -carboxamide

如前述實施例203之方法進行製備：W-NMR ( CD3OD ，500MHz) δ-0.25(ιιι，1H) ，0.82(m，1H) ，1.25- 2.10(m，13H) ，2.20—2.63 (m，6H) ，2.68— 2.98 ( m ，4H) ，3.00—3.22 (m，3H) ，3.31(m，2H) » 3.44 (bs，lH) ，4.00— 4.50 (m，6H) ，4.64(m，lH)， -362 - 200529835 (358)Prepared according to the method of the foregoing Example 203: W-NMR (CD3OD, 500MHz) δ-0.25 (ιιι, 1H), 0.82 (m, 1H), 1.25-2.10 (m, 13H), 2.20-2.63 (m, 6H ), 2.68— 2.98 (m, 4H), 3.00—3.22 (m, 3H), 3.31 (m, 2H) »3.44 (bs, 1H), 4.00—4.50 (m, 6H), 4.64 (m, 1H), -362-200529835 (358)

4.96( m，lH) ，6.85-7.05 (m，3H) ，7.08(s，0.4H )，7.20(s，0.6H) ，7.46(d，J=7.0，lH) ，7.99(s ，0.4H) ，8.05(d，J=2.4，0.6H)。質譜：645.58 (Μ H ) f。 實施例222 (±) — 4— (8 —氣一 1，2 — 一氨一2 —嗣基□奎 口坐琳一3( 4H)—基）一N — （3— (7— 甲基一1H — D 引唑一5 —基） 一 1—嗣基—1— (4 —苯基嘛嗪—1—基）—丙—2 —基） 哌啶一 1 一羧醯胺4.96 (m, lH), 6.85-7.05 (m, 3H), 7.08 (s, 0.4H), 7.20 (s, 0.6H), 7.46 (d, J = 7.0, lH), 7.99 (s, 0.4H) , 8.05 (d, J = 2.4, 0.6H). Mass spectrum: 645.58 (MH) f. Example 222 (±) — 4 — (8 —Gas 1, 2, —Ammonia — 2 —Amino group — Kui Keizurin 3 (4H) — Group) — N — (3 — (7 — Methyl 1 1H — D Indazole-5 —yl — 1 —fluorenyl — 1 — (4-phenylmazine — 1 —yl) —propanyl — 2 —piperidine — 1 —carboxamide

如前述實施例203之方法進行製備1H-NMR ( CD3OD， 500MHz ) 5 1 .73 ( m，4H ) ，2·49 ( m，4Η ) ，2.80- 3.26(m，7H) ，3.43(m，2H) ，3.65-3.95 (m，3H) ，4.14(dd，J=21.7，14.3，2H) ，4.32(s，2H)， 4.51 (m，lH) ，5.15(dd，J=7.9，6.4，lH) ，5.90(1H-NMR (CD3OD, 500MHz) 5 1 .73 (m, 4H), 2.49 (m, 4Η), 2.80-3.26 (m, 7H), 3.43 (m, 2H) ), 3.65-3.95 (m, 3H), 4.14 (dd, J = 21.7, 14.3, 2H), 4.32 (s, 2H), 4.51 (m, lH), 5.15 (dd, J = 7.9, 6.4, lH) , 5.90 (

bs，1H ) ，6.80 ( d ^ J 二 7.3，1 H ) ，6.83— 7.01 (m，4H )，7.06 (dd，J=7.6，7.3，1H) ，7.10(s，1H)， 7.26-7.33 (m，2H) ，7.44(s，lH) ，7.87(m，lH) ，8.06(s，1H)。質譜：639·36(ΜΗ) +。 -363- 200529835 (359) 實施例2 2 3 (±) — 4— (8 —氟一1，2 —二氫一2 —酮基喹唑啉一 3( 4 Η )—基）一 Ν— (1— ( 4 — (4一 氣苯基）一喊 Π定一 1 — 基）一3— (7 —甲基一 1Η -吲唑一 5 —基）一 1—酮基丙 一 2 -基）哌啶一 1 一羧醯胺bs, 1H), 6.80 (d ^ J, 7.3, 1H), 6.83-7.01 (m, 4H), 7.06 (dd, J = 7.6, 7.3, 1H), 7.10 (s, 1H), 7.26-7.33 ( m, 2H), 7.44 (s, 1H), 7.87 (m, 1H), 8.06 (s, 1H). Mass spectrum: 639.36 (ΜΗ) +. -363- 200529835 (359) Example 2 2 3 (±) — 4— (8 —fluoro-1, 2 —dihydro — 2 — ketoquinazoline — 3 (4 Η) —yl) — N — ( 1- (4-(4-Gas phenyl)-1-1 -yl)-3-(7 -methyl-1 1-indazole-5-yl)-1-ketopropan-2-yl) piper Pyrimidine-1 carboxamide

如前述實施例203之方法進行製備：i-NMR ( CD3OD ，5 00MHz ) ά 1.73 (m，4Η ) ，1.26(dd，3=7.9, 7.6， 1 Η ) ，2.49(s，3H) ，2·75— 3.05(m，4H) ，3.09(m ，2H) ，3.19— 3.45 (m，3H) ，3.63 (m，1H) ，3.78 (m，2H) ，4.13 ( dd，J — 16.5，15.3，2H ) ，4.32 ( s ，2H) ，4.50(m，lH) ，5.15(dd，JU，6.1，lH) ，5.85 ( bs ^ 1 H ) ，6.70 - 6.84 ( m ^ 3H ) ，6.8 5 - 7.02 (It was prepared according to the method of the foregoing Example 203: i-NMR (CD3OD, 500 MHz), 1.73 (m, 4Η), 1.26 (dd, 3 = 7.9, 7.6, 1Η), 2.49 (s, 3H), 2. · 75— 3.05 (m, 4H), 3.09 (m, 2H), 3.19— 3.45 (m, 3H), 3.63 (m, 1H), 3.78 (m, 2H), 4.13 (dd, J — 16.5, 15.3, 2H ), 4.32 (s, 2H), 4.50 (m, lH), 5.15 (dd, JU, 6.1, lH), 5.85 (bs ^ 1 H), 6.70-6.84 (m ^ 3H), 6.8 5-7.02 (

m，5H) ，7.09(s，lH) ，7.43(s，lH) ，7.78(s，lH )，8.06(s，lH)。質譜：657.35(MH)+。 實施例224 (±) 4— (8— 氟一 1，2—二氫一2— 酮基 D奎唑啉一 3 (4H )—基）一Ν — 1 — ( 4 — ( 2 —氟苯基）哌啶一 1 一基）一 -364 - 200529835 (360) 3 — （7—甲基—1H —吲唑—5-基）—1 一酮基丙—2—基 )一哌啶一 1 一羧醯胺m, 5H), 7.09 (s, 1H), 7.43 (s, 1H), 7.78 (s, 1H), 8.06 (s, 1H). Mass spectrum: 657.35 (MH) +. Example 224 (±) 4- (8-fluoro-1,2-dihydro-2-keto D-quinazoline-3 (4H) -yl) -N — 1 — (4 — (2-fluorophenyl ) Piperidine- 1-yl) -364-200529835 (360) 3 — (7-methyl-1H-indazol-5-yl) -1 -ketopropyl-2-yl) -piperidine-1 1- Carboxamide

如前述實施例203之方法進行製備：iH-NMR ( CDC13 ，500MHz) 5 1.62 — 1.78 (m， 2H) ， 2.24 (dd， J=7.9 ，8.2，1H) ，2.50(s，3H) ，2.70-2.85 (m，2H)，Prepared according to the method of the foregoing Example 203: iH-NMR (CDC13, 500MHz) 5 1.62 — 1.78 (m, 2H), 2.24 (dd, J = 7.9, 8.2, 1H), 2.50 (s, 3H), 2.70- 2.85 (m, 2H),

2.8 5 - 2.96 ( m，2H ) ，2.00 ( m，1 H ) ，3.08 ( dd，JAB =13.1，8.6，1H) ，3.12(m，lH) ，3.30(m，lH)， 3.57(m，lH) ，3.73(m，2H) ，4.13(dd，J=19.8， 15.0，2H) ，4.33(s，2H) ，4.53(m，lH) ^ 5.18 ( dd ，J=8.2，5.8，1H) ，5.82(bs，lH) ，6.58(dd，J = 8.2，8.2，1H) ，6.81 (d，J二 7.6，1H) ，6.85-7.05 (2.8 5-2.96 (m, 2H), 2.00 (m, 1 H), 3.08 (dd, JAB = 13.1, 8.6, 1H), 3.12 (m, lH), 3.30 (m, lH), 3.57 (m, lH) ), 3.73 (m, 2H), 4.13 (dd, J = 19.8, 15.0, 2H), 4.33 (s, 2H), 4.53 (m, lH) ^ 5.18 (dd, J = 8.2, 5.8, 1H), 5.82 (bs, lH), 6.58 (dd, J = 8.2, 8.2, 1H), 6.81 (d, J 7.6, 1H), 6.85-7.05 (

m，5H) ，7.09(s，lH) ，7.44(s，lH) ，7.58(s，lH )，8.05(s，1H)。質譜：657.37(MH) +。 實施例225 (±) —4一 （8 —氟一1，2 —二氫一2_酮基喹唑啉一3( 4 Η )—基）一Ν — (3 — (7 —甲基一1Η — D 引口坐一5 —基） 一 1 —酮基—1 — ( 4 一鄰甲苯基哌嗪一 1 一基）丙一 2 —基 )哌啶一 1 一羧醯胺 - 365- 200529835 (361)m, 5H), 7.09 (s, 1H), 7.44 (s, 1H), 7.58 (s, 1H), 8.05 (s, 1H). Mass spectrum: 657.37 (MH) +. Example 225 (±) —4— (8—fluoro-1, 2—dihydro—2—ketoquinazoline—3 (4 Η) —yl) —N — (3 — (7 —methyl—1Η) — D Introduces a 5-base) — 1 —keto — 1 — (4-o-tolylpiperazine — 1 —yl) propan — 2 —yl) piperidine — 1 —carboxamide — 365- 200529835 ( 361)

如前述實施例2 03之方法進行製備：iH-NMR ，5 00MHz ) (5 1 ·60 — 1 ·79 ( m，4Η ) ，2·03 ( dd， ，8.2，1Η) ，2.22(s，3H) ，2.49(s，3H) ，2 ，J=8.6，8.5，1H) ，2.65(m，lH) ^ 2.81 ( m ，2.85—2.97 (m，2H) ，3.05—3.22 (m，2H)， m，lH) ，3.50-3.65 (m，2H) ，3.83(m，lH) (dd，J=15.9，15.3，2H) ，4.31(s，2H) ，4 ，1 H ) ，5.19(dd，J=7.9，5·8，1H) ^ 5.84 ( bs ，6.54(d，J=7.6，lH) ，6.81(d，J=7.6， 6.89(ddd，J=7.6，7.6，5.2，lH) ，6.96(m， 7.00— 7.23 (m，4H) ，7.39(s，lH) ^ 7.43 ( s ，8.04(s，lH)。質譜：653.38(MH)+。 實施例226 (土）—甲基 一 2— (4— (8 —氯—1，2 — 一•氨—2 哇唑啉一 3 ( 4 Η ) -基）哌啶一 1 一羧醯胺基）一 —乙基—3—甲基一1Η —吲唑一5—基）丙酸酯 (CDC13 J = 8.5 .54 ( dd ，1 Η ) 3.38 ( ，4· 1 5 .53 ( m ，1 Η ) 1 Η )， 2Η )， ，1 Η ) 一酮基 3-(7 -366 - 200529835 (362)Prepared according to the method of the foregoing Example 2 03: iH-NMR, 500 MHz) (5 1 · 60 — 1 · 79 (m, 4Η), 2 · 03 (dd,, 8.2, 1Η), 2.22 (s, 3H ), 2.49 (s, 3H), 2, J = 8.6, 8.5, 1H), 2.65 (m, lH) ^ 2.81 (m, 2.85-2.97 (m, 2H), 3.05-3.22 (m, 2H), m , LH), 3.50-3.65 (m, 2H), 3.83 (m, lH) (dd, J = 15.9, 15.3, 2H), 4.31 (s, 2H), 4, 1 H), 5.19 (dd, J = 7.9, 5.8, 1H) ^ 5.84 (bs, 6.54 (d, J = 7.6, lH), 6.81 (d, J = 7.6, 6.89 (ddd, J = 7.6, 7.6, 5.2, lH), 6.96 (m , 7.00— 7.23 (m, 4H), 7.39 (s, 1H) ^ 7.43 (s, 8.04 (s, 1H). Mass spectrum: 653.38 (MH) +. Example 226 (Earth) —methyl-1— (4 — (8 —Chloro-1,2 —mono • amino — 2 oxazoline — 3 (4 Η) —yl) piperidine — 1 —carboxamido) — 1 —ethyl — 3 —methyl — 1 — —ind Azole- 5-yl) propionate (CDC13 J = 8.5.54 (dd, 1 Η) 3.38 (, 4 · 1 5 .53 (m, 1 Η) 1 Η), 2Η),, 1 Η) monoketone Base 3- (7 -366-200529835 (362)

MeO 'Ο 如前述—3 — （3 —氰基一 1H —吲哚一 5 —基）一 2 — { 〔4— (2 -酮基一 1，4 —二氫一2H—D奎唑啉一3 —基） 一哌啶一 1 一羰基〕一胺基} 一丙酸甲酯之方法進行製備 :W-NMR ( CD30D，5 00MHz ) δ 1·33 ( m，3H) ，1.39MeO '〇 as described above—3— (3-cyano-1H—indole-5—yl) —2 — {[4 -— (2-keto-1,4-dihydro-2H—D quinazoline-1 3-methyl) -piperidine-1 monocarbonyl] monoamino} monopropionate: W-NMR (CD30D, 500 MHz) δ 1 · 33 (m, 3H), 1.39

—1.72(m，4H) ，2.70—2.95 (m，3H) ，3.06(m，lH )，3.25(m，lH) ，3·95— 4.30( m，4H) ，4.38(m， 1 H ) ，4.57(m，lH) ，6·80— 7.05 (m，3H) ^ 7.08 ( s ，1H) ，7.38(s，lH)。質譜：537.47(MH) +。 實施例227 (±) — N— ( 3 - (7 -乙基一3 —甲基一1H — D 引唑一5 — 基）一 1 —酮基—1 — ( 4 一（哌啶—1 —基）哌啶一 1 一基 )丙—2 —基）一 4一（8 —氣—1’2 - 一·氯一 2 —酬基D奎口坐 啉一3 ( 4H ) Π浪啶—1 —羧醯胺—1.72 (m, 4H), 2.70—2.95 (m, 3H), 3.06 (m, 1H), 3.25 (m, 1H), 3.95— 4.30 (m, 4H), 4.38 (m, 1 H), 4.57 (m, lH), 6.80—7.05 (m, 3H) ^ 7.08 (s, 1H), 7.38 (s, lH). Mass spectrum: 537.47 (MH) +. Example 227 (±) — N— (3-(7-ethyl- 3 -methyl- 1H — D indazole-5 —yl) — 1 —keto-1 — (4 — (piperidine-1 — Base) piperidine-1 base) propan-2-yl) -4 (8-gas-1'2-one-chloro-2 2-amino group D quinololine-3 (4H) Π amidin-1 —Carboxamide

如前述實施例203之方法進行製備：h-NMR ( CD30D - 367- 200529835 (363)Prepared by the method of the foregoing Example 203: h-NMR (CD30D-367- 200529835 (363)

5 0 0MHz ) 5 - 0.36 (m， 1H ) ， 0. 70 ( m，1 H ) ， 1 . 2 1 ( bd ，J = 1 1 . 9，1 H ) ，1.28 ：-2. 00 ( m 1 9H )， 2. 3 1 ( dd J = 11.6 ， 1 1 . 3，1 H )， 2.40 ( dd， J : =13.1 » 11 .6 1 H ) ，2.79 - 3.16 (m ，7H ) ，3. 72 ( m 1 H ) ，3_ 8 5 — 4. 03 ( m，1 H ) ，4. 1 0 - 4.48 ( m ， 5H [) 4 .53 ( bd ，J Γ = 1 1 • 0 ， 1 H ) ，5 • 05 ( m ， 1H ) ，6.85 - — 7.03 (m，3H ) 7. 08 ( s，0.2H ) ，7 .18 ( s，0 · 8H ) 7. 37 ( s，1 H ) o 質 譜 673.42 ( ΜΗ ) +。 實施例228 (R) — N— (R) - 3—（2- 酮基 一2，3 — 二氫一苯並噁 唑一 6 —基）—1 —酮基一 1 一（ 4 一（哌啶一 1 —基）哌啶 —1 —基）丙一2 —基）一4 — (8 —氯—1，2 — __* 氯 _ 2 — 酮基喹啉3 — ( 4H ) —基）哌啶一 1 一羧醯胺5 0 0MHz) 5-0.36 (m, 1H), 0.70 (m, 1 H), 1.2 1 (bd, J = 1 1. 9, 1 H), 1.28:-2. 00 (m 1 9H), 2. 3 1 (dd J = 11.6, 1 1.3, 1 H), 2.40 (dd, J: = 13.1 »11.. 6 1 H), 2.79-3.16 (m, 7H), 3. 72 (m 1 H), 3_ 8 5 — 4. 03 (m, 1 H), 4. 1 0-4.48 (m, 5H [) 4 .53 (bd, J Γ = 1 1 • 0, 1 H), 5 • 05 (m, 1H), 6.85-— 7.03 (m, 3H) 7. 08 (s, 0.2H), 7.18 (s, 0 · 8H) 7. 37 (s, 1H) o Mass spectrum 673.42 (ΜΗ) +. Example 228 (R) —N— (R) —3- (2-keto-2,3-dihydromonobenzoxazole-6-yl) -1-keto-1 1- (4- Pyridinyl-l-yl) piperidine-1-yl) propanyl-2-yl) -4- (8-chloro-1,2 — __ * chloro_2-ketoquinoline 3 — (4H) -yl) piperyl Pyrimidine-1 carboxamide

如前述實施例2 03之方法進行製備：h-NMR ( CD3OD ，500MHz) 50.71 (m，1H) ，1·26(ηι，1H) ，1.40 — 2.15(m，13H) ，2.50-3.29 (m，9H) ，3.32— 3.64 ( m ，3H) ，4.14(d，JAB=12.8，lH) ，4.17(d，JAB = 11.6，1H) ，4.32—4.45 (m，3H) ，4.68 (bd，J = 13.4 -368- 200529835 (364) ，1Η) ，4·92(ηι，1Η) ，6.87— 7.22 ( ni，6H)。質譜 :64 8.47 ( ΜΗ )丨 ° 實施例229 (±) - Ν— (3— (7— 甲基一1Η — D引唑一 5 —基）一1 — 酮基一 1 一 （ 4 一 （哌啶—1 —基）哌啶——1基）丙一 2 -基）一 8> —氟—2，，3> -二氫一 2/ —酮基螺—（哌啶 —4，4 / —喹唑啉）—1 一羧醯胺Prepared according to the method of the foregoing Example 2 03: h-NMR (CD3OD, 500MHz) 50.71 (m, 1H), 1.26 (η, 1H), 1.40-2.15 (m, 13H), 2.50-3.29 (m, 9H), 3.32— 3.64 (m, 3H), 4.14 (d, JAB = 12.8, 1H), 4.17 (d, JAB = 11.6, 1H), 4.32—4.45 (m, 3H), 4.68 (bd, J = 13.4 -368- 200529835 (364), 1Η), 4.92 (η, 1Η), 6.87-7.22 (ni, 6H). Mass spectrum: 64 8.47 (ΜΗ) 丨 ° Example 229 (±)-Ν— (3— (7—methyl- 1Η — D azole-5-yl) — 1 — keto — 1 — (4- Pyridin-1-yl) piperidine-l-yl) propan-2-yl) -8 > -fluoro-2,, 3 > -dihydro-2 / -ketospiro- (piperidine-4,4 /- Quinazoline) -1 monocarboxamide

N-NHN-NH

如前述實施例203之方法進行製備：W-NMR ( CD3OD ，500MHz) 5-0.23 (m，1H) ，0.85(m，1H) » 1.20- 2.10(m，22H) ，2.25-2.55 (m，7H) ，2.58(s，3H) ，2.74(d，J=11.3，lH) ，2.94(dd，J=12_5，12.2， 2H ) ，3.00— 3.20 (m，5H) ，：3.40— 3.65 (m，2H)， 3.80— 4.15 (m，4H) ，4.55— 4.73 (m，2H) ，4.96(dd ，J=7.9，7.6，1H) ，5.01 (dd，J=10.4，5.8，1H)， 6.65— 7.15 (m，5H) ，7.21(s，lH) ，7.47(s，lH)Prepared according to the method of the foregoing Example 203: W-NMR (CD3OD, 500MHz) 5-0.23 (m, 1H), 0.85 (m, 1H) »1.20- 2.10 (m, 22H), 2.25-2.55 (m, 7H ), 2.58 (s, 3H), 2.74 (d, J = 11.3, 1H), 2.94 (dd, J = 12_5, 12.2, 2H), 3.00-3.20 (m, 5H), 3.40-3.65 (m, 2H) ), 3.80— 4.15 (m, 4H), 4.55— 4.73 (m, 2H), 4.96 (dd, J = 7.9, 7.6, 1H), 5.01 (dd, J = 10.4, 5.8, 1H), 6.65— 7.15 ( m, 5H), 7.21 (s, lH), 7.47 (s, lH)

，7.96( m，lH) ，8.04(s，lH)。質譜：631.29(MH - 369 - 200529835 (365) 實施例2 3 0 (±) — 4— （8 —氟一1，2 — 一氫一2，4 —二酬基[1 奎 口坐啉 -3 ( 4H )—基）一N— (3— (7 —甲基一1H — D 引唑一5 — 基）一 1 —嗣基一 1 — ( 4 一 （ Π底Π定一 1 —基）_ U定—1 —基 )丙一 2 -基）哌Π定一 1 一殘醯胺, 7.96 (m, 1H), 8.04 (s, 1H). Mass spectrum: 631.29 (MH-369-200529835 (365) Example 2 3 0 (±) — 4 — (8 —fluoro-1,2 — monohydro-2,4 —diphenyl group [1 quetialine-3 (4H) -group) -N- (3— (7-methyl-1H—D azole-5-group)-1-fluorenyl- 1 — (4-group U-Di-1-yl) propan-2-yl) piperidine-1 1-residue amine

如前述實施例203方法進行製備：W-NMR ( CD3OD， 500MHz ) δ -0.26 ( m，1 Η ) ，0·81 ( m，1 Η ) ，1.20- 2.10(m，11Η) ，2·20— 2.80 (m，9Η) ，2.90(m，3Η )，3.10(m，3H) ，3.34(m，lH) ，3.44(m，lH)， 4.06 (bd，J=13.4，1H) ，4.17(d，JAB=15.9，1H)， 4.22(d，JAB=13.1，lH) ，4.64(dd，J=24.4，13.1， 1H ) ，4.91-5.13 (m，2H) ，7.00—7.25 (m，2H)， 7.44 (m，2H) ，7.81 (m，1H) ，7.92— 8.08 (m，1H) 。質譜：65 9.5 9 ( MH ) H。 (R) —甲基一 2 —胺基—3 - （2 —三氟甲基）一 1H —苯 並〔d〕咪唑一 5-基）丙酸酯Prepared according to the method of Example 203: W-NMR (CD3OD, 500MHz) δ -0.26 (m, 1 Η), 0.81 (m, 1 Η), 1.20-2.10 (m, 11Η), 2.20— 2.80 (m, 9Η), 2.90 (m, 3Η), 3.10 (m, 3H), 3.34 (m, lH), 3.44 (m, lH), 4.06 (bd, J = 13.4, 1H), 4.17 (d, JAB = 15.9, 1H), 4.22 (d, JAB = 13.1, 1H), 4.64 (dd, J = 24.4, 13.1, 1H), 4.91-5.13 (m, 2H), 7.00-7.25 (m, 2H), 7.44 (m, 2H), 7.81 (m, 1H), 7.92-8.08 (m, 1H). Mass spectrum: 65 9.5 9 (MH) H. (R) —methyl-1 2-amino-3 — (2-trifluoromethyl) —1H —benzo [d] imidazol-5-yl) propionate

-370 - 200529835 (366) 於80t下加熱（R ) — 2 -苄氧羰基胺基一 3 -（ 3，4 —二胺基—苯基）—丙酸甲酯（5 00 mg，1.20毫莫耳）和 三氟乙酸（6 ml )之混合物1 6小時。將該反應混合物倒入 至冰水（75 ml )中，利用飽和NaHC03水溶液中和至pH 7 ，隨後利用乙酸乙酯（2 X 2 5 0 ml )進行萃取。將有機萃 取液置於N a2 S Ο 4上乾燥，經過濾和蒸發後生成三氟乙酸鹽 之標的化合物（459mg，84%產率）。 j-NMR ( CDC13，3 00MHz ) δ 7.37 ( bs » 1Η) ，7.35 (bs，1H ) ，1.17 (d，J— 8.4Hz，1H ) ，4.70(s，2H ) ，3.85 (dd，J = 8.4 » 4·8Ηζ，1 H ) ，3.77 ( s 5 3H)， 3.30(dd，J=13.9，4.8Hz，1H) ’ 2.97(dd，J=13.5， 8.4Hz，lH)。質譜：288(MH)+。 (R)—甲基一2 - （4— (1，2 —二氫〜2— _基0奎Π坐啉— 3 ( 4H )—基）哌啶—1 一羧醯胺基）〜3 一 （ 2 —三氟甲 基）一 1H-苯並〔d〕咪唑一 5-基）丙酸酯 \〇-370-200529835 (366) heated at 80t (R) — 2-benzyloxycarbonylamino- 3-(3,4-diamino-phenyl) -propionic acid methyl ester (500 mg, 1.20 mmol Ear) and trifluoroacetic acid (6 ml) for 16 hours. The reaction mixture was poured into ice water (75 ml), neutralized to pH 7 with a saturated aqueous solution of NaHC03, and then extracted with ethyl acetate (2 × 2 50 ml). The organic extract was dried over Na 2 S 0 4 and filtered and evaporated to form the target compound (459 mg, 84% yield) of trifluoroacetate. j-NMR (CDC13, 3 00MHz) δ 7.37 (bs »1Η), 7.35 (bs, 1H), 1.17 (d, J—8.4Hz, 1H), 4.70 (s, 2H), 3.85 (dd, J = 8.4 »4 · 8Ηζ, 1 H), 3.77 (s 5 3H), 3.30 (dd, J = 13.9, 4.8 Hz, 1H) '2.97 (dd, J = 13.5, 8.4 Hz, 1H). Mass spectrum: 288 (MH) +. (R) -methyl- 2-(4- (1,2, dihydro ~ 2-_yl group 0 quinololine-3 (4H) -yl) piperidine-1 monocarboxyamido)) ~ 3 a (2-trifluoromethyl) -1H-benzo [d] imidazol-5-yl) propionate \ 〇

室溫下攪拌胺酯（R) — 2 -胺基一 （2 —三氟甲基 —1H —苯並〔d〕咪唑一5 —基）丙酸甲酯（wo mg，0.51 毫莫耳）、二異丙基乙胺（262 mg，2·〇3毫莫耳）及二號 珀醯亞胺碳酸酯（120 mg，0.51毫莫耳）之ch2C12 /二甲 基甲醯胺（15: 1)溶液30分鐘。加入4〜（2 —酮基—1 — 200529835 (367) 苯並咪唑）哌啶，並於室溫下攪拌該反應混合物1 6小時。 過濾該反應混合物以除去任何固體，並藉由閃蒸管柱層析 (95:3:2 CH2C12/甲醇/三乙胺）進行純化，生成黃 褐色固體之標的化合物（2 1 5 m g，7 7 %產率）。Stir amine ester (R) — 2-amino- (2-trifluoromethyl-1H —benzo [d] imidazol-5-yl) propionate (wo mg, 0.51 mmol) at room temperature, Ch2C12 / dimethylformamide (15: 1) of diisopropylethylamine (262 mg, 2.03 mol) and Permimidate carbonate (120 mg, 0.51 mol) Solution for 30 minutes. Add 4 ~ (2-keto-1—200529835 (367) benzimidazole) piperidine, and stir the reaction mixture at room temperature for 16 hours. The reaction mixture was filtered to remove any solids and purified by flash column chromatography (95: 3: 2 CH2C12 / methanol / triethylamine) to give the title compound (2 1 5 mg, 7 7 %Yield).

j-NMR ( CDC13，5 00MHz ) 5 7 · 6 7 ( d，J = 8.4 Η z，1 H )，7.39 (s，1H ) ，7.21-7.16 (m，1H ) ，7.05 - 6.94 (m，3H) ，6.70-6.68 (m，2H) ，5.11(d，J=7.3Hzj-NMR (CDC13, 500 MHz) 5 7 · 6 7 (d, J = 8.4 Η z, 1 H), 7.39 (s, 1H), 7.21-7.16 (m, 1H), 7.05-6.94 (m, 3H) ), 6.70-6.68 (m, 2H), 5.11 (d, J = 7.3Hz

，1H) ，4.78(dd，J=12.1，5.5Hz，lH) ，4.42(d，J = 4·4Ηζ，2H ) ，4.29 (d，J = 12·1Ηζ，1 H ) ，3.82- 3.72 (m，2H) ，3.74 ( s，3H) ，3 · 4 4 ( d d，J = 1 3 · 9，5 · 5 H z ，1H ) ，3.22 ( dd ^ J=13.9，5.5Hz) ，2.95-2.83 (m， 3H ) ，2.18 - 2·03(ηι，2Η) ，1·79 — 1.68 (m，2H)。 質譜：545 ( ΜΗ ) +。 (R) — 2— (4 -（1，2 —二氫—2— 酮基 ti 奎唑啉—3(4Η )一基）哌啶一 1 一羧醯胺基）一 3 — （ 2 —(三氟甲基） 一 1H —苯並〔d〕咪唑一 5-基）一丙酸, 1H), 4.78 (dd, J = 12.1, 5.5Hz, 1H), 4.42 (d, J = 4.4 Ηζ, 2H), 4.29 (d, J = 12 · 1 Ηζ, 1 H), 3.82-3.72 (m , 2H), 3.74 (s, 3H), 3 · 4 4 (dd, J = 1 3 · 9, 5 · 5 H z, 1H), 3.22 (dd ^ J = 13.9, 5.5 Hz), 2.95-2.83 ( m, 3H), 2.18-2.03 (η, 2Η), 1.79-1.68 (m, 2H). Mass spectrum: 545 (ΜΗ) +. (R) — 2— (4-(1,2, dihydro-2) -ketoti quinazoline-3 (4Η) -yl) piperidine-1 1-carboxamido) -3— (2 — ( Trifluoromethyl) 1H-benzo [d] imidazol-5-yl) monopropionic acid

於〇°C下將LiOH(36 mg，1.51毫莫耳）之水（10 ml )溶液加入至酯（R) - 2-（4 一（1，2-二氫一2-酮基 喹唑啉一 3 ( 4H ) -基）I派啶一 1 一羧醯胺基）一 3 - （ 2 一三氟甲基一 1H-苯並〔d〕咪唑—5 —基）一丙酸甲酯 - 372 - 200529835 (368) (220 mg，0.40毫莫耳）之四氫呋喃和甲醇（1 : 1混合 物，2 0 m 1 )的溶液中。於〇 °C下攪拌該混合物2小時，隨 後貯存於一 1 5 °C下1 6小時。蒸發有機溶劑。利用乙酸乙酯 萃取該水溶液，並利用1N HC1 ( 3 ml )調整至PH 4。於 Na2S04上乾燥有機萃取液，經過濾和蒸發後生成標的化合 物（176 mg，82% 產率）。：LC/MS: tR 二 2.01 分，531 (MH) + 。A solution of LiOH (36 mg, 1.51 mmol) in water (10 ml) was added to the ester (R)-2- (4-mono (1,2-dihydro-2-ketoquinazoline) at 0 ° C. 1-3 (4H) -yl) I pyridine-1-carboxyamido)-3-(2-trifluoromethyl-1H-benzo [d] imidazol-5-yl) monopropionate-372 -200529835 (368) (220 mg, 0.40 mmol) in a solution of tetrahydrofuran and methanol (1: 1 mixture, 20 m 1). The mixture was stirred at 0 ° C for 2 hours and then stored at 15 ° C for 16 hours. The organic solvent was evaporated. The aqueous solution was extracted with ethyl acetate and adjusted to pH 4 with 1N HC1 (3 ml). The organic extract was dried over Na2S04, filtered and evaporated to give the target compound (176 mg, 82% yield). : LC / MS: tR 2.01 points, 531 (MH) +.

實施例231 N( (R) — 3— （2—(三氟甲基）一 1H —苯並〔d〕咪唑 —5- 基）—1—酮基一 1— (4— (_Π定一 1 一 基）定一 1 一基）丙_2-基）—4一（1，2-二氫一 2_酮基喹唑啉 —3 ( 4H ) -基）哌啶—1 一羧醯胺Example 231 N ((R) — 3 -— (2- (trifluoromethyl) —1H—benzo [d] imidazol-5-yl) —1-keto-1— (4— (_Π 定 一 1 1 base) fixed 1 1 base) propan-2-yl) -4 4- (1,2-dihydro-2 ketoquinazoline-3 (4H) -yl) piperidine-1 monocarboxamide

將P y Β Ο P ( 3 3 m g，0 · 0 6毫莫耳）和4 一哌啶並哌啶（ 1 2 m g，0.0 7毫莫耳）之C Η 2 C 12 ( 1 m 1 )溶液加入至該酸C Η 2 C 12 (1 m 1) solution of P y Β 0 P (33 mg, 0.06 mmol) and 4 piperidine and piperidine (12 mg, 0.07 mmol) Added to the acid

(R) — 2— (4 —（1，2 - 二氫一 2— 酮基 D奎唑啉一 3(4H - 373- 200529835 (369) )一基）I帳啶一 1 一羧醯胺基）—3 - （ 2 —三氟甲基—1 Η —苯並〔d〕咪唑一 5 —基）丙酸（33 mg，0.06毫莫耳） 和二異丙基乙胺（33 mg，0.25毫莫耳）之CH2C12 ( 2 ml )攪拌溶液中。室溫下攪拌該反應混合物1 6小時，隨後藉 由製備性薄層層析（1 : 10 2M氨之甲醇/ CH2C12溶液）進 行純化，生成標的化合物（4.6 mg，1 2 %產率）。 j-NMR ( CD3OD，5 00MHz ) 5 7.73 - 7.71 ( m，1 Η ) ，7.62(bs，lH) ，7.39—7.36 (m，lH) ，7.19-7.11( m，2H ) ，6.96 ( t，J = 7·2Ηζ，1H ) ，6.81 ( d，J = 7·9Ηζ，1 H ) ，5.06-5.02 (m，1 H ) ，4.67-4.58 (m， 1H ) ，4·49 一 4.40(m，lH) ，4.38(s，lH) ^ 4.33 ( bs ，1H) ，4.25-4.16 (m，2H) ，4.10— 4.03 (m，1H) ，3.22-3.14 (m，3H) ，3.04— 2.87 (m，4H) » 2.79 - 2.71 (m，1H) ，2.58-2.48 (m，1H) » 2.44 - 2.3 3 ( m ，1H) ，2.31— 2.22 (m，1H) ，2.04-1.92 (m，1H) ，1.86 — 1.43 (m，11H) ，1.33 — 1.29 (m，1H) ，0.94 —0.84(m，1H) ，一 0.04— -0.12(m，1H )。 LC/MS: tR=1.97 分，681(MH)十。 實施例232 N — （R) — 1—( 一甲基氨基甲酿基）一 2— (2 —二氟甲 基）一 1H—苯並〔d〕咪唑—5—基）乙基）一 4一 （1，2 一二氫一2 -酮基喹唑啉—3 ( 4 Η )—基）哌啶一 1 一羧醯 胺 374- 200529835 (370)(R) — 2— (4— (1,2-dihydro—2—keto D quinazoline — 3 (4H — 373 — 200529835 (369)) — 1 group) —Acetyl — 1 —Carboxamido ) -3-(2-trifluoromethyl-1 fluorene-benzo [d] imidazol-5-yl) propionic acid (33 mg, 0.06 mmol) and diisopropylethylamine (33 mg, 0.25 mmol) Mol) of CH2C12 (2 ml) in a stirred solution. The reaction mixture was stirred at room temperature for 16 hours, and then purified by preparative thin layer chromatography (1: 10 2M ammonia in methanol / CH2C12 solution) to give the target compound (4.6 mg, 12% yield). j-NMR (CD3OD, 500 MHz) 5 7.73-7.71 (m, 1 Η), 7.62 (bs, lH), 7.39-7.36 (m, lH), 7.19-7.11 (m, 2H), 6.96 (t, J = 7.2Ηζ, 1H), 6.81 (d, J = 7.9Ηζ, 1H), 5.06-5.02 (m, 1H), 4.67-4.58 (m, 1H), 4.49-4.40 (m, lH ), 4.38 (s, lH) ^ 4.33 (bs, 1H), 4.25-4.16 (m, 2H), 4.10—4.03 (m, 1H), 3.22-3.14 (m, 3H), 3.04— 2.87 (m, 4H) ) »2.79-2.71 (m, 1H), 2.58-2.48 (m, 1H)» 2.44-2.3 3 (m, 1H), 2.31—2.22 (m, 1H), 2.04-1.92 (m, 1H), 1.86 — 1.43 (m, 11H), 1.33 — 1.29 (m, 1H), 0.94 — 0.84 (m, 1H), 0.04 — -0.12 (m, 1H). LC / MS: tR = 1.97 points, 681 (MH) ten. Example 232 N — (R) — 1 — (monomethylcarbamoyl) — 2 — (2-difluoromethyl) — 1H —benzo [d] imidazole — 5-yl) ethyl) — 4 Mono (1,2-dihydro-2-ketoquinazoline-3 (4Η) -yl) piperidine-1 monocarboxamide 374-200529835 (370)

如前述實施例231之方法進行製備：h-NMR ( CD3OD ，300MHz) 57.69— 7.56(m，2H) ，7.34(d，J=7.7HzPrepared according to the method of the foregoing Example 231: h-NMR (CD3OD, 300MHz) 57.69-7.56 (m, 2H), 7.34 (d, J = 7.7Hz

，1 H ) ，7.17-7.08 (m，2H ) ，6.92(t，J=7.7Hz，1 H, 1 H), 7.17-7.08 (m, 2H), 6.92 (t, J = 7.7Hz, 1 H

)，6.77 ( d，J = 8.4Hz，1 H ) ，6 · 5 6 ( d，J = 7 · 7 H z，1 H )，5·02— 4.97 (m，lH) ，4.46-4.35 (m，lH) ^ 4.29 (s，2H) ，4.15(d，J=12.8Hz，lH) ，3.26— 3.11 (m ，5H) ，2.87(s，6H) ，1·86— 1.68 (m，2H) » 1.66-), 6.77 (d, J = 8.4 Hz, 1 H), 6 · 5 6 (d, J = 7 · 7 H z, 1 H), 5.02-4.97 (m, lH), 4.46-4.35 (m , LH) ^ 4.29 (s, 2H), 4.15 (d, J = 12.8Hz, lH), 3.26— 3.11 (m, 5H), 2.87 (s, 6H), 1.86— 1.68 (m, 2H) » 1.66-

1 .59 ( m，2H )。 LC/MS: tR=2.37 分，558 (MH) +。 (R) — 1—(甲氧羰基）—2— (2，3 —二氫一 2 —酮基一 1H—苯並〔d〕咪唑一 6—基）乙基氨基甲酸苄酯1.59 (m, 2H). LC / MS: tR = 2.37 points, 558 (MH) +. (R) — 1- (methoxycarbonyl) -2- (2,3-dihydro-1, 2-keto-1H-benzo [d] imidazole-6-yl) ethylcarbamate

- 375- 200529835 (371) 將三乙胺（3 20 mg，3. 17毫莫耳）和i，厂一羰基二 咪唑（2 8 0 mg，1.73毫莫耳）先後加入至（r) _ 2—苄氧 羯基胺基一3，4一二胺基一苯基）〜丙酸甲酯（6〇〇 mg， 1·44毫莫耳）之四氫呋喃（125 ml)稀釋溶液中。室溫下 攪拌該反應混合物1 6小時，隨後經過濾以除去固體。蒸發 濾液並經閃蒸管柱層析（1 : 12甲醇/ ch2C12 )純化， 生成標的化合物（313 mg，59%產率）。 ]H-NMR ( CD3〇D ^ 3 00MHz) 5 7 · 2 8 - 7 · 2 1 ( m，5 Η ) ，6_94— 6.83 (m，3Η) ，5.06— 4.95 (rn，2Η) ，4.46 — 4.41 (m，1H) ，3.68(s，3H) ，3.17—3.11 (m，1H) ，2.95 — 2.88 (m，lH)。 LC/MS: tR=2.11 分，370(MH) + 〇 (R) - 2-胺基—3— (2，3 - 二氫 一2-酮I 基一 1H- 苯 並〔d〕咪唑一 6—基）丙酸甲酯-375- 200529835 (371) Triethylamine (3 20 mg, 3. 17 mmol) and i, factory monocarbonyldiimidazole (280 mg, 1.73 mmol) are added to (r) _ 2 — Benzyloxyfluorenylamino-3,4-diaminomonophenyl) ~ methyl propionate (600 mg, 1.44 mmol) in a tetrahydrofuran (125 ml) diluted solution. The reaction mixture was stirred at room temperature for 16 hours and then filtered to remove solids. The filtrate was evaporated and purified by flash column chromatography (1:12 methanol / ch2C12) to give the target compound (313 mg, 59% yield). ] H-NMR (CD3OD ^ 3 00MHz) 5 7 · 2 8-7 · 2 1 (m, 5 Η), 6_94— 6.83 (m, 3Η), 5.06— 4.95 (rn, 2Η), 4.46 — 4.41 (m, 1H), 3.68 (s, 3H), 3.17 to 3.11 (m, 1H), 2.95 to 2.88 (m, 1H). LC / MS: tR = 2.11 minutes, 370 (MH) + 〇 (R)-2-amino-3- (2,3-dihydro-2 -keto I group -1H-benzo [d] imidazole-6 —Methyl) propionate

利用Parr裝置並於50 psi氫氣下，攪動（R) — 1—( 甲氧羰基）一2— (2，3-二氫—2 —酮基—1H-苯並〔d 〕咪唑一 6 —基）乙基氨基甲酸苄酯（265 mg，〇·72毫莫 耳）和10% Pd / C ( 30 mg)之甲醇（15 ml)溶液1·5小時 。利用3次真空/氮氣淸洗循環淸洗該反應混合物。經通 過寅氏鹽®墊過濾該反應混合物，隨後利用數份甲醇輕洗 該墊。蒸發甲醇濾液以生成標的化合物（1 6 8 m g，定量產 - 376- 200529835 (372) 率）。 1H-NMR ( CD3OD，3 00MHz ) 5 6.97 ( d，J 二 8.1Hz， 1 H ) ，6.87(s，lH) ，6.86(d，J=8.2Hz，lH) ^ 3.71Using a Parr device under 50 psi of hydrogen, agitate (R) — 1 — (methoxycarbonyl) — 2 — (2,3-dihydro — 2 —keto — 1H —benzo [d] imidazole — 6 —yl ) A solution of benzyl ethyl carbamate (265 mg, 0.72 mmol) and 10% Pd / C (30 mg) in methanol (15 ml) for 1.5 hours. The reaction mixture was purged with 3 vacuum / nitrogen purging cycles. The reaction mixture was filtered through a pad of Yin's Salt®, and the pad was then gently washed with several portions of methanol. The methanol filtrate was evaporated to produce the target compound (168 mg, quantitative yield-376-200529835 (372) rate). 1H-NMR (CD3OD, 3 00MHz) 5 6.97 (d, J 2 8.1Hz, 1H), 6.87 (s, 1H), 6.86 (d, J = 8.2Hz, 1H) ^ 3.71

—3.64(m，lH) ，3.67(s，3H) ，3.0 4- 2.89(m，2H )° LC/MS: tR 二 0.87 分，236 (MH) +。 實施例2 3 3—3.64 (m, 1H), 3.67 (s, 3H), 3.0 4- 2.89 (m, 2H) ° LC / MS: tR 0.88 points, 236 (MH) +. Example 2 3 3

(R) — 2— (4— (1，2 —二氫一2 —酮基 口 奎唑啉一3(4H )一基）哌啶—1 一羧醯胺基）一 3 -（2，3 -二氫一 2 — 酮基一 1H—苯並〔d〕咪唑一 6-基）丙酸甲酯(R) — 2— (4 -— (1,2, dihydro-2—ketoquinazoline-3 (4H) -yl) piperidine-1—carboxamido) —3— (2,3 -Dihydro-2-keto-1H-benzo [d] imidazole-6-yl) propionic acid methyl ester

如前述（R) — 2— (4— (1，2 —二氫—2 —酮基D奎唑 啉一 3 ( 4 Η ) —基）哌啶一 1 —羧醯胺基）一 3 — （ 2 —三 氟甲基）一 1Η—苯並〔d〕咪唑一 5 —基）丙酸甲酯之方 法進行製備。 j-NMR ( CD3OD，300MHz) 57.16-7.08 (m^ 2H) ，6.9 8 - 6.9 0 ( m ^ 4H ) ，6.76 (d，J=8.1Hz，1H )， 4.52— 4.47 (m，lH) ，4.39— 4.35 (m，lH) ，4.27(s ，2H) ，4.13-4.05 (m，2H) ，3.70(s，3H) ^ 3.2 1- 3.14( m，1H) ，3.04— 2.96(m，1H) ，2.89— 2.74( m ，2H) ，1.78— 1.59( m，4H)。 -377 - 200529835 (373) LC/ MS : tR = 1 .77 分，493 ( ΜΗ ) 4。As mentioned above (R) — 2 — (4 — (1,2, dihydro-2 —keto D quinazoline — 3 (4 Η) —yl) piperidine — 1 —carboxamido) — 3 — ( 2-Trifluoromethyl) -l-benzo [d] imidazole-5-yl) propionate was prepared by the method. j-NMR (CD3OD, 300MHz) 57.16-7.08 (m ^ 2H), 6.9 8-6.9 0 (m ^ 4H), 6.76 (d, J = 8.1Hz, 1H), 4.52-4.47 (m, 1H), 4.39 — 4.35 (m, lH), 4.27 (s, 2H), 4.13-4.05 (m, 2H), 3.70 (s, 3H) ^ 3.2 1- 3.14 (m, 1H), 3.04- 2.96 (m, 1H), 2.89— 2.74 (m, 2H), 1.78— 1.59 (m, 4H). -377-200529835 (373) LC / MS: tR = 1.77 minutes, 493 (ΜΗ) 4.

(R) — 2— (4— (1，2_ 二氫—2 —酮基喹唑啉—3(4H )一基）定一 1 一殘醯胺基）—3— (2，3-二氫—2- 酮基—1H-苯並〔d〕咪唑一 6-基）丙酸(R) — 2— (4— (1,2-dihydro-2—ketoquinazoline-3 (4H) -one group) fixed-one 1-residual amine group) —3— (2,3-dihydro —2-keto-1H-benzo [d] imidazole-6-yl) propionic acid

如前述（R) —2— (4— (1，2-二氫—2—酮基喹唑 啉一 3 ( 4H )—基）哌啶一 1 —羧醯胺基）一 3 — （ 2 —( 三氟甲基）一 1H-苯並〔d〕咪唑一 5 -基）丙酸之方法 進行製備。 W-NMR ( CD3OD，3 00MHz ) 5 7 · 1 6 - 7 · 0 9 ( m，2 Η ) ，6.99-6.90(m，4H) ，6.76(d，J=7.3Hz，lH)， 4.5 3 - 4.4 8 ( m ^ 1 H ) ，4.28 (s，2H ) ，4.1 3 - 4.03 ( m ，2H) ，3.07— 2.97 (m，lH) ，2.89— 2.77 (m，2H) ，1·79— 1.60 (m，4H) ，：1.28-1.21 (m，lH)。 LC/ MS ： tR=1.83 分，479(MH) +。 實施例2 3 4 N— (R) — 3— (2，3 —二氫—2 —酮基—1H —苯並〔d〕 咪唑一 6 -基）—1 一酮基一 1 ( 4 一哌啶一 1 一基）哌啶—1 —基）丙—2 —基）—4- (1，2 —二氫一 2 -酮基喹唑啉 —3 ( 4 Η ) 一基）I派卩定—1 一殘醯胺 -378 - 200529835 (374)As mentioned before (R) —2— (4 -— (1,2-dihydro-2—ketoquinazoline-3 (4H) -yl) piperidine—1—carboxyamido) —3— (2— (Trifluoromethyl) -1H-benzo [d] imidazole-5-yl) propionic acid is prepared by a method. W-NMR (CD3OD, 3 00MHz) 5 7 · 1 6-7 · 0 9 (m, 2 Η), 6.99-6.90 (m, 4H), 6.76 (d, J = 7.3Hz, 1H), 4.5 3- 4.4 8 (m ^ 1 H), 4.28 (s, 2H), 4.1 3-4.03 (m, 2H), 3.07-2.97 (m, lH), 2.89-2.77 (m, 2H), 1.79-1.60 ( m, 4H), 1.28-1.21 (m, 1H). LC / MS: tR = 1.83 minutes, 479 (MH) +. Example 2 3 4 N— (R) —3— (2,3-dihydro-2—keto-1H—benzo [d] imidazol-6-yl) -1 monoketo-1 (4-piperone Pyridinyl-1yl) piperidine-1-yl) propan-2-yl) -4- (1,2, dihydro-2-ketoquinazoline-3 (4Η) monoyl) piperidine —1 Monoresin-378-200529835 (374)

如前述實施例23 1之方法進行製備。 !H-NMR ( CD3〇D » 3 00MHz) (5 7. 1 7 — 7.1 0 ( m，2H ) ，7.01(s，lH) ，6.95-6.90(m，3H) ，6.78(d，J二 8.1Hz ^ 1H ) ，4.98— 4.93 (m，1 H ) ，4.62 - 4.5 5 ( m > 1 H ) ，4.41-4.33 (m，2H) ，4.20-4.16 (m，2H)， 4.04— 3.96 (m，lH) ，3.05—2.85 (m，7H) ，2·71- 2.57 ( m ^ 1H ) ，2.53— 2.32(m，lH) ^ 1 .8 6 - 1 .76 ( m ，2H) ，1.70-1.61 (m，8H) ，1.50-1.41 (m，2H) ，1·03— 0.89 (m，lH) ，0.10— -0.02(m，lH)。質譜 ：629.22 ( ΜΗ ) + 〇 實施例2 3 5 N— (R) — 1—(二甲基氨基甲醯基）一2— (2，3 —二 氫一2 -酮基一 1H-苯並〔d〕咪唑—6 —基）乙基）一 4 一 （1，2 —二氫一2 —酮基喹唑啉一3 ( 4 Η ) —基）哌啶 一 1 —羧醯胺It was prepared as described in Example 231 above. ! H-NMR (CD3OD »3 00MHz) (5 7. 1 7 — 7.1 0 (m, 2H), 7.01 (s, 1H), 6.95-6.90 (m, 3H), 6.78 (d, J 2 8.1 Hz ^ 1H), 4.98— 4.93 (m, 1 H), 4.62-4.5 5 (m > 1 H), 4.41-4.33 (m, 2H), 4.20-4.16 (m, 2H), 4.04— 3.96 (m , LH), 3.05-2.85 (m, 7H), 2.71- 2.57 (m ^ 1H), 2.53--2.32 (m, lH) ^ 1. 8 6-1. 76 (m, 2H), 1.70-1.61 (m, 8H), 1.50-1.41 (m, 2H), 1.03-0.89 (m, 1H), 0.10--0.02 (m, 1H). Mass spectrum: 629.22 (Μ) + 〇 Example 2 3 5 N — (R) — 1— (dimethylaminomethylamino) —2— (2,3-dihydro-2—keto—1H—benzo [d] imidazole-6—yl) —4 Mono (1,2-dihydro-2 ketoquinazoline-3 (4Η) -yl) piperidine-1 1-carboxamide

- 379 - 200529835 (375) 如前述實施例23 1之方法進行製備。 LC/MS: tR=1.96 分，506(MH) (R)— 2—〔2 ，3 — 一氣一 2 —酬基螺—（丨根D定—4 ，4>—(11〇—[奎唑啉）羰基胺基〕一3-2，3-二氫 一 2 —酮基一 1H—苯並〔d〕咪唑一 6—基）丙酸甲酯-379-200529835 (375) It was prepared according to the method of Example 23 1 described above. LC / MS: tR = 1.96 minutes, 506 (MH) (R) — 2— [2, 3 — one gas one 2 —one-based spiro— (root D fixed—4, 4 >> — (11〇— [quinazole Phenyl) carbonylamino]-3-2,3-dihydro-2 -keto-1H-benzo [d] imidazole-6-yl) propionic acid

如 \ , · 刖 述 (R )- 2—( 4 - -(1，2 —二氫- - 2 -酮 1基 D| 唑 啉 -3 (4Η )- 基） 哌D定 — 1 一羧醯 胺基） -3 - (2 — ( 二 氟甲 基 ) -1 H - 苯並 C d 〕咪唑- - 5 -基 )丙酸 甲 酯 之 方 法進 行 製 ^-NMR (DMSO -d6 5 5 00MHz ) 5 10.54 (s， 1 Η ) 10 • 50 ( S 1H ) ，9 • 22 ( s ， 1 Η )， 7.2 1 ( s ，1 Η ) j 7. 13 — 7.10 ( m ，1H )， 6.96 - -6 • 79 ( m， 7H )， 4.29 - 4. 25 ( m ，1 Η ) j 3.82 —3· 7 8 ( m， 2H )， 3.60 ( s ，3Η ) 3. 3 2 — 3.23 ( m ，1H )， 3.16- -3 • 1 4 ( m， 1 Η )， 3.00- 2. 90 ( m ，2Η ) 2.08 (s， 1H) ， 1 .67 — 1 .5 5 ( m， 4Η ) 〇 LC/MS: tR 二 1.62 分，479 (MH) +。 (R ) — 2 -〔 2 > ，3 / —二氫一 2 — — 酮基螺一（哌啶—4 -380 - 200529835 (376) ，4 / — ( 1 Η ) — D奎唑啉）羰基胺基〕—3 — 2，3 —二氫 一 2 —酮基一 1H —苯並〔d〕咪唑—6 —基）丙酸Such as \, · Describe (R)-2— (4--(1,2-dihydro--2 -one 1-yl D | oxazoline-3 (4Η) -yl) piperidine— 1 monocarboxylic acid Amine group) -3-(2 — (difluoromethyl) -1 H -benzo C d] imidazole--5 -yl) propionic acid methyl ester ^ -NMR (DMSO -d6 5 5 00MHz) 5 10.54 (s, 1 Η) 10 • 50 (S 1H), 9 • 22 (s, 1 Η), 7.2 1 (s, 1 Η) j 7. 13 — 7.10 (m, 1H), 6.96--6 • 79 (m, 7H), 4.29-4.25 (m, 1Η) j 3.82 — 3. 7 8 (m, 2H), 3.60 (s, 3Η) 3. 3 2 — 3.23 (m, 1H), 3.16- -3 • 1 4 (m, 1Η), 3.00- 2.90 (m, 2Η) 2.08 (s, 1H), 1.67 — 1.55 (m, 4Η) 〇LC / MS: tR 1.62 points, 479 (MH) +. (R) — 2-[2 >, 3 / —dihydro — 2 — — ketospiro (piperidine — 4 -380-200529835 (376), 4 / — (1 Η) — D quinazoline) Carbonylamino] -3,2,3-dihydro-2, keto-1H-benzo [d] imidazole-6-yl) propionic acid

如則述（R) — 2—（4一（1’ 2 — 一·氯一 2 —醒基D奎口坐 啉一 3 (4H) -基）哌卩定一 1 一竣醯胺基）一 3 - （2 - （ 三氟甲基）一 1H —苯並〔d〕咪唑一 5 —基）丙酸之方法 進行製備。 ]H-NMR ( CD3〇D ^ 3 00MHz ) (57.19-7.14 (m^ 1H) ，7.05 - 6.95 (m，5H ) ，6.81 (d，J=7.7Hz，1 H )， 5.04-4.90 (m» 1H) ，4.57-4.52 (m，1H) ，3.96- 3.84(m，2H) ，3.24—3.14 (m，2H) ，3.07-2.95 (m ，：1 H ) ，：l ·94 - 1 .73 ( m，4H )。 LC/MS : tR= 1.67 分，465 ( ΜΗ) +。 實施例236 N — ( R ) — 3 — (2，3 - —* 氣—2 —醒基—1 Η _ 苯並〔d〕 咪唑一 6 _基）—酮基—1 ( 4 —哌啶—1 一基）哌啶—1 一 基）丙—2-基）一 4一 （2< ，3/ —二氫—-酮基螺 (哌啶—4，4 > 一（ 1 Η ) — D奎唑啉）羧醯胺 -381 - 200529835 (377) οAs stated (R) — 2— (4— (1 ′ 2 ——Chlorine 2 —Xingyl D Kuiziline — 3 (4H) —yl) piperidine — 1 — amine group) — 3-(2-(trifluoromethyl)-1H-benzo [d] imidazole-5-yl) propionic acid was prepared. ] H-NMR (CD30D ^ 3 00MHz) (57.19-7.14 (m ^ 1H), 7.05-6.95 (m, 5H), 6.81 (d, J = 7.7Hz, 1H), 5.04-4.90 (m » 1H), 4.57-4.52 (m, 1H), 3.96-3.84 (m, 2H), 3.24-3.14 (m, 2H), 3.07-2.95 (m ,: 1 H), l: 94-1.73 ( m, 4H). LC / MS: tR = 1.67 minutes, 465 (ΜΗ) +. Example 236 N — (R) — 3 — (2, 3-— * Gas — 2 — Amino — 1 Η benzo [D] Imidazole-6-yl) -keto-1 (4-piperidine-1-yl) piperidine-1-yl) propan-2-yl) -4- (2 <, 3 / -dihydro- -Ketospiro (piperidine-4,4 > mono (1 Η) —D quinazoline) carboxamide-381-200529835 (377) ο

如前述實施例23 1之方法進行製備。 LC/MS: tR=1.55 分，615 (ΜΗ) + 4 一乙醯胺基一3—甲基苯甲酸 〇It was prepared as described in Example 231 above. LC / MS: tR = 1.55 minutes, 615 (ΜΗ) + 4 ethylamidoamino 3-methylbenzoic acid.

將三乙胺（121 g，1.19莫耳）加入至4一胺基—3 — 甲基苯甲酸（60 g，0.40莫耳）之CH2C12(800 ml)懸浮 液中。該溶液轉呈澄淸。加入乙酸酐（81 g，0.79莫耳） 並於室溫下攪拌該反應混合物60小時。蒸發溶劑。利用（ 4 00 ml )稀釋殘餘物並利用乙酸乙酯（3 x 6 0 0 ml )進行萃 取。於MgS04上乾燥結合之有機萃取液，經過濾和蒸發後 生成黃褐色固體之標的化合物（43 g，56%產率）。 1H-NMR ( d6 — DMSO，3 00MHz ) 5 9·36 ( s，1H)， 7.77 ( s ^ 1 H ) ，7.10(s，2H) ，2.27(s，3H) ，2.10( s，3H )。 - 382- 200529835 (378) LCMS: tR=1.22 分，194(MH) 酸 4 —乙醯胺基—3 —甲基一 5-硝基苯甲 〇Triethylamine (121 g, 1.19 mol) was added to a suspension of 4-monoamino-3-methylbenzoic acid (60 g, 0.40 mol) in CH2C12 (800 ml). The solution turned clear. Acetic anhydride (81 g, 0.79 mol) was added and the reaction mixture was stirred at room temperature for 60 hours. The solvent was evaporated. The residue was diluted with (400 ml) and extracted with ethyl acetate (3 x 600 ml). The combined organic extracts were dried over MgS04, filtered and evaporated to give the target compound as a tan solid (43 g, 56% yield). 1H-NMR (d6 — DMSO, 300 MHz) 5 9 · 36 (s, 1H), 7.77 (s ^ 1 H), 7.10 (s, 2H), 2.27 (s, 3H), 2.10 (s, 3H). -382- 200529835 (378) LCMS: tR = 1.22 minutes, 194 (MH) acid 4-acetamido-3-methyl- 5-nitrobenzyl 〇

以超過4 0分鐘之時間，在同時藉 將4 一乙醯胺基一3—甲基苯甲酸（43 部份地加入至60%硝酸之硫酸（410 : 所有之醯胺酸，於〇°C下攪拌該反應渭 其緩慢地倒入至超過1 5 00 ml之冰中 色固體，經冰冷水冲洗後，生成標的 產率）。 h-NMR ( CD30D，300MHz ) δ 8. (s，1Η ) ，2·39 ( s，3H ) ，2.16 ( s (MH) + 。 4一胺基一 3 —甲基一 5—硝基苯甲酸 由冰浴冷卻之情況， g，0.22莫耳）分小 tn 1 )溶液中。經加入 [合物1小時，隨後將 。藉由過濾以收集黃 化合物（38 g，78% 29 ( s，1H ) ，8.18 ;，3H)。質譜：237At the same time over 40 minutes, at the same time by adding 4-acetamido-3-methylbenzoic acid (43 part to 60% nitric acid sulfuric acid (410: all of the amino acids, at 0 ° C) The reaction was stirred while it was slowly poured into more than 1500 ml of ice-colored solid and washed with ice-cold water to produce the target yield.) H-NMR (CD30D, 300MHz) δ 8. (s, 1Η) , 2.39 (s, 3H), 2.16 (s (MH) +. 4-amino-3-methyl-5-nitrobenzoic acid cooled by ice bath, g, 0.22 mole) divided into small tn 1) in solution. After adding the compound for 1 hour, The yellow compound (38 g, 78% 29 (s, 1H), 8.18 ;, 3H) was collected by filtration. Mass spec: 237

方< 迴丨;IL·狀下加熱4 -乙釀胺基 苯甲酸（38g，0.16莫耳）之3NHC1 3 一甲基一 5 —硝基 8 0 0 m 1 )懸浮液M、 - 383- 200529835 (379) 時，隨後於室溫下攪拌8小時。藉由過濾以收集黃色固體 ，並將其轉移至含有CH2C12和甲醇之混合物的2升燒瓶中 。高真空下蒸發溶劑以生成標的化合物（23 g，74%產率 )° W-NMR ( DMSO - d6，3 00ΜΗζ ) δ 12.79 ( bs ^ 1 H )， 8.46(s，lH) ，7.79(s，lH) ，7.61(s，2H) ，2.34( s，3H )。 13C-NMR ( d6 — DMSO，75MHz ) δ 166.0，147.0， 135.1，130.0，126.4，125.9，116.7，17.9。LC/MS: tR =1.23分，1 95 ( MH ) +。 3 —甲基一 4，5 —二硝基苯甲酸Fang < Back 丨; IL · Heat 4 -Ethylaminobenzoic acid (38g, 0.16 mole) 3NHC1 3 monomethyl-5 -nitro 8 0 0 m 1) suspension M,-383- 200529835 (379) hours, followed by stirring at room temperature for 8 hours. The yellow solid was collected by filtration and transferred to a 2 liter flask containing a mixture of CH2C12 and methanol. The solvent was evaporated under high vacuum to yield the target compound (23 g, 74% yield) ° W-NMR (DMSO-d6, 3 00MΗζ) δ 12.79 (bs ^ 1 H), 8.46 (s, 1H), 7.79 (s, lH), 7.61 (s, 2H), 2.34 (s, 3H). 13C-NMR (d6 — DMSO, 75 MHz) δ 166.0, 147.0, 135.1, 130.0, 126.4, 125.9, 116.7, 17.9. LC / MS: tR = 1.23 minutes, 1 95 (MH) +. 3-methyl-4,5-dinitrobenzoic acid

將過氧化氫（50重量％，15 ml)加入至4 —胺基一 3 —甲基—5 —硝基苯甲酸（5.0 g，25.5毫莫耳）之三氟乙 酸（200 ml )懸浮液中。於50 °C下加熱該反應混合物2小 時，最後該溶液自暗澄色澄淸溶液轉爲灰黃色澄淸溶液。 將該反應混合物緩慢地倒入冰水（8 0 0 m 1 )中。藉由過濾 以收集固體，經於真空下乾燥後，生成灰白色固體之標的 化合物（4.0 g，70%產率）。 1 H-NMR ( CD3OD，3 00MHz ) ό 8 · 5 9 ( s，1 Η ) ，8.40 ( s，lH) ，2.45(s，3H)。 -384- 200529835 (380) ，3C-NMR ( CD3OD，75MHz ) 5 165.8，147.4，142.0， 139.3， 134.8， 134.6， 125.4， 17.2。質譜：225.14 (ΜΗ )—。 (3—甲基一4，5—二硝基苯基）甲醇Hydrogen peroxide (50% by weight, 15 ml) was added to a suspension of 4-amino-3-methyl-5-nitrobenzoic acid (5.0 g, 25.5 mmol) in trifluoroacetic acid (200 ml). . The reaction mixture was heated at 50 ° C for 2 hours, and finally the solution was changed from a dark clear solution to a gray-yellow clear solution. The reaction mixture was slowly poured into ice water (800 m 1). The solid was collected by filtration and dried under vacuum to give the title compound as an off-white solid (4.0 g, 70% yield). 1 H-NMR (CD3OD, 300 MHz) δ 8 · 5 9 (s, 1 Η), 8.40 (s, 1H), 2.45 (s, 3H). -384- 200529835 (380), 3C-NMR (CD3OD, 75MHz) 5 165.8, 147.4, 142.0, 139.3, 134.8, 134.6, 125.4, 17.2. Mass spectrum: 225.14 (ΜΗ) —. (3-methyl-4,5-dinitrophenyl) methanol

利用乾冰/丙酮浴將3 -曱基一 4，5 —二硝基苯甲酸 (4.0 g，17.7毫莫耳）之四氫呋喃（ 200 ml)溶液冷卻至 一 70 °C。加入甲硼烷/四氫呋喃（1 Μ 四氫呋喃溶液， 35·4 ml )。令該反應混合物緩慢地回溫至室溫並攪拌16 小時。該反應未完全，再冷卻該反應混合物至- 5 0 °C，並 加入額外之甲硼烷/四氫呋喃（1 Μ 四氫呋喃溶液，3 5 · 4 ml )。再次令該反應混合物緩慢地隔夜回溫至室溫。於0 °C下冷卻下，藉由乙酸和水（1 : 1，3 0 ml )之混合物驟 冷該反應混合物。經攪拌3 0分鐘後，蒸發所有之有機溶劑 ，並藉由小部份地倒入至冰冷飽和之NaHC03溶液（350 m 1 )以中和水層。利用乙酸乙酯萃取水層。利用鹽水冲洗 萃取液，置MgS04上乾燥，並進行過濾和蒸發。藉由閃蒸 管柱層析（1 : 2己烷/乙酸乙酯）純化殘餘物，生成標 的化合物（3.2 g，86%產率）。 1H-NMR ( CDC13，3 00MHz ) 5 8.00 ( s，1 Η ) ，7.62 ( s ，：1H ) ，4.82 ( s，2H ) ，2·41 ( s，3H )。 - 385- 200529835 (381) 13C-NMR ( CDC13，75MHz ) 5 1 4 4 · 5， 1 4 3 . 3， 1 4 0 · 9 ’ 134.3，132.9，120.8，63.0，17.4 ° 3 —甲基—4，5— 一硝基苯醒A dry ice / acetone bath was used to cool a solution of 3-fluorenyl-4,5-dinitrobenzoic acid (4.0 g, 17.7 mmol) in tetrahydrofuran (200 ml) to 70 ° C. Add borane / tetrahydrofuran (1 M tetrahydrofuran solution, 35.4 ml). The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction was not complete, the reaction mixture was cooled to -50 ° C, and additional borane / tetrahydrofuran (1M tetrahydrofuran solution, 35.4 ml) was added. The reaction mixture was again slowly allowed to warm to room temperature overnight. The reaction mixture was quenched with a mixture of acetic acid and water (1: 1, 30 ml) under cooling at 0 ° C. After stirring for 30 minutes, all the organic solvents were evaporated and poured into a small portion of ice-cold saturated NaHC03 solution (350 m 1) to neutralize the aqueous layer. The aqueous layer was extracted with ethyl acetate. The extract was washed with brine, dried over MgS04, filtered and evaporated. The residue was purified by flash column chromatography (1: 2 hexane / ethyl acetate) to give the title compound (3.2 g, 86% yield). 1H-NMR (CDC13, 3 00MHz) 5 8.00 (s, 1 Η), 7.62 (s ,: 1H), 4.82 (s, 2H), 2.41 (s, 3H). -385- 200529835 (381) 13C-NMR (CDC13, 75MHz) 5 1 4 4 · 5, 1 4 3. 3, 1 4 0 · 9 '134.3, 132.9, 120.8, 63.0, 17.4 ° 3-methyl-4 , 5—mononitrobenzene

N〇2N〇2

於經火焰乾燥之燒瓶中，令二氧化錳（IV ) ( 36.0 g ，414毫莫耳）與甲苯共沸乾燥。隨後將（3 —甲基一 4，5 —二硝基苯基）甲醇（3.2 g，15毫莫耳）之氯仿（100 ml )溶液轉移至該含有二氧化錳之燒瓶中。於5 0 °C和攪拌加 熱該反應混合物3小時。當反應完成後，經過寅氏鹽®墊 過濾該反應混合物以除去二氧化錳，並利用氯仿冲洗該寅 氏鹽墊數次。蒸發濾液以生成標的化合物（1.4 g，44% 產率）。In a flame-dried flask, manganese (IV) dioxide (36.0 g, 414 mmol) was azeotropically dried with toluene. A solution of (3-methyl-1,4-dinitrophenyl) methanol (3.2 g, 15 mmol) in chloroform (100 ml) was then transferred to the flask containing manganese dioxide. The reaction mixture was heated at 50 ° C with stirring for 3 hours. When the reaction was complete, the reaction mixture was filtered through a Yin's salt® pad to remove manganese dioxide, and the Yin's salt pad was rinsed several times with chloroform. The filtrate was evaporated to give the target compound (1.4 g, 44% yield).

j-NMR ( CDC13，3 00MHz ) δ 1 0 · 0 9 ( s，1 Η ) ，8 · 5 1 (s，1Η ) ，8.16 ( s，1H ) ，2.51 ( s，3H )。 (Z) — 1 一（甲氧鑛基）一2— (3 —甲基一4，5— 一硝基 苯基）乙烯基氨基甲酸苄酯j-NMR (CDC13, 3 00MHz) δ 1 0 · 0 9 (s, 1 Η), 8. 5 1 (s, 1 Η), 8.16 (s, 1H), 2.51 (s, 3H). (Z) — 1 mono (methoxide-based) 2- (3-methyl-4,5-mononitrophenyl) vinyl carbamate

- 386- 200529835 (382) 於一78 °C 下將 1，1，3，3 —四甲基胍（729 mg，6.33 毫莫耳）加入至N—（苄氧羰基）一 α 一亞磷羧基甘胺酸 二甲酯（2.4 g，7.3毫旲耳）之四氫卩夫喃（4〇 mi)溶液中 ’並於一 78 °C下攪拌該混合物1小時。加入3〜甲基—4，5 一二硝基苯醛（1.4 g，6.7毫莫耳）之四氫呋喃（15 ml) 溶液。令該反應混合物緩慢地回溫至室溫，並於室溫下攪 拌1 6小時。蒸發溶劑並藉由閃蒸管柱層析（1 : 2至丨：} 乙酸乙酯/己烷之梯度溶液）純化殘餘物。自乙酸乙酯/ 己烷（1 : 1 )再結晶產物以生成標的化合物（1 .7 g，6 2 %產率）。 】H-NMR ( CDC13，3 00MHz ) δ 8.01 ( s ^ 1 Η ) ，7.55 ( s，lH) ，7.33-7.22 (m，6H) ，6.94(bs，iH) , 5>06 (s，2H) ，3.89(s，3H) ，2.29(s，3H) 〇 13C-NMR ( CDC13，75MHz ) 5 164.7 » 152.5 , 143.1 , 140.6，137.7，137.0，135.3，132.5，128.8，；i28.7， 128.6， 127.1 ， 123.5， 123.2， 68.3， 53.5， 17.4。質譜： 4 1 4.20 ( ΜΗ ) 一。 (R) — 1一 （甲氧幾基）一2— (3—甲基一4，5一二硝基 苯基）乙基氨基甲酸苄酯-386- 200529835 (382) Add 1,1,3,3-tetramethylguanidine (729 mg, 6.33 mmol) to N- (benzyloxycarbonyl) -α-phosphorous carboxyl group at -78 ° C A solution of dimethyl glycinate (2.4 g, 7.3 mF) in tetrahydrofuran (40 mi) and the mixture was stirred at -78 ° C for 1 hour. Add a solution of 3 ~ methyl-4,5-dinitrobenzaldehyde (1.4 g, 6.7 mmol) in tetrahydrofuran (15 ml). The reaction mixture was allowed to slowly warm to room temperature and stirred at room temperature for 16 hours. The solvent was evaporated and the residue was purified by flash column chromatography (1: 2 to 1:} gradient solution of ethyl acetate / hexane). The product was recrystallized from ethyl acetate / hexane (1: 1) to give the target compound (1.7 g, 62% yield). ] H-NMR (CDC13, 3 00MHz) δ 8.01 (s ^ 1 Η), 7.55 (s, 1H), 7.33-7.22 (m, 6H), 6.94 (bs, iH), 5 > 06 (s, 2H) , 3.89 (s, 3H), 2.29 (s, 3H) 〇13C-NMR (CDC13, 75MHz) 5 164.7 »152.5, 143.1, 140.6, 137.7, 137.0, 135.3, 132.5, 128.8 ,; i28.7, 128.6, 127.1 , 123.5, 123.2, 68.3, 53.5, 17.4. Mass spectrum: 4 1 4.20 (ΜΗ) One. (R) — 1- (methoxyquinyl) -2- (3-methyl-4,5-dinitrophenyl) ethylcarbamate

- 387 - 200529835 (383) 於經3次真空/氮氣淸洗循環處理之手套袋中，對酉己 備有攪拌棒之AIRFREE ® ( Schlenk )反應燒瓶載入（— )—1，2—雙—（211，511)—2，5-二乙基磷烷並（ phospholano)苯（環辛二烯）铑（I)三氟甲基磺酸酯（ 125 g，0.1 73毫莫耳，4莫耳％ )，經橡膠隔板密封後， 自該手套袋取出該燒瓶。將（Z) - 1 一 （甲氧羰基）一 2 一 （3 —甲基一 4，5 —二硝基苯基）乙烯基氨基甲酸苄酯 (1.64 g，3.97毫莫耳）載入第2個配備有攪拌棒之 AIRFREE ® ( Schlenk )反應燒瓶中，並經橡膠隔板密封 。經3次真空/氮氣淸洗循環後，令其溶解於無水CH2C12 (4 0 m 1 )中。於加入溶劑前，藉由噴佈氮氣至少1小時使 該溶劑去氧。一旦於溶液中，再次令該混合物經3次真空 /氮氣淸洗循環。經由套管將該脫氫胺基酸溶液導入至含 有該觸媒之AIRFREE® (S chi enk)反應燒瓶中。令該反 應混合物經5次真空/氫氣淸洗循環，隨後於1大氣壓氫氣 下打開該燒瓶。經1 6小時後，利用3次真空/氮氣淸洗循 環淸洗該反應混合物。蒸發溶劑並藉由管柱層析（1 : 1 乙酸乙酯/己烷）純化殘餘物，生成標的化合物（1 · 5 8 g ，95% )。 ]H-NMR ( CDC13 » 3 00ΜΗζ) δ 7.75 ( s » 1H) * 7.39- 7.33 (m，6H) ，5.37 (d，J二 7·0Ηζ，1H) ，5.15—5.04 (m，2H) ，4.70 - 4.46 ( m，lH) ，3.77(s，3H) ’ 3.30(dd，J=13.9，5.5Hz，lH) ，3.12(dd，J=13.9’ 6.2Hz，1H ) ，2.33 ( s，3H )。 -388- 200529835 (384) LC/MS: tR 二 2.71 分，418(MH) 1。 (R) — 1 一 （甲氧羰基）一 2—（3，4 一二胺基一 5 —甲基 苯基）乙基氨基甲酸苄酯-387-200529835 (383) Load the AIRFREE ® (Schlenk) reaction flask equipped with a stirring rod into a glove bag treated with 3 vacuum / nitrogen purging cycles (—) —1,2—double— (211,511) -2,5-diethylphosphanobenzene (cyclooctadiene) rhodium (I) trifluoromethanesulfonate (125 g, 0.1 73 millimoles, 4 moles %), After sealing with a rubber septum, remove the flask from the glove bag. Load (Z)-1 mono (methoxycarbonyl) -2 2- (3-methyl-1,4-dinitrophenyl) vinyl carbamate (1.64 g, 3.97 mmol) into the second An AIRFREE® (Schlenk) reaction flask equipped with a stir bar and sealed with a rubber septum. After 3 vacuum / nitrogen purging cycles, it was dissolved in anhydrous CH2C12 (40 m 1). Before adding the solvent, the solvent was deoxygenated by spraying nitrogen for at least 1 hour. Once in solution, the mixture was again subjected to 3 vacuum / nitrogen purge cycles. The dehydroamino acid solution was introduced through a cannula into an AIRFREE® (Schienk) reaction flask containing the catalyst. The reaction mixture was subjected to 5 vacuum / hydrogen purge cycles, and then the flask was opened under 1 atmosphere of hydrogen. After 16 hours, the reaction mixture was washed with 3 vacuum / nitrogen purging cycles. The solvent was evaporated and the residue was purified by column chromatography (1: 1 ethyl acetate / hexane) to give the target compound (1.58 g, 95%). ] H-NMR (CDC13 »3 00ΜΗζ) δ 7.75 (s» 1H) * 7.39- 7.33 (m, 6H), 5.37 (d, J 2 7.0.0Ηζ, 1H), 5.15-5.04 (m, 2H), 4.70 -4.46 (m, lH), 3.77 (s, 3H) '3.30 (dd, J = 13.9, 5.5Hz, lH), 3.12 (dd, J = 13.9' 6.2Hz, 1H), 2.33 (s, 3H). -388- 200529835 (384) LC / MS: tR 2.71 points, 418 (MH) 1. (R) — 1- (methoxycarbonyl) -2- (3,4-diamino-5-methylphenyl) ethylcarbamate

於〇°C下將甲酸銨固體（75 5 mg，1 1.9毫莫耳）分小 部份地加入至（R) -（甲氧鑛基）一 2—（3—甲基一 4，5 —二硝基苯基）乙基氨基甲酸苄酯（500 mg，1.20毫 莫耳）和鋅粉（470 mg，7.19毫莫耳）之甲醇（20 ml， 經氮氣脫氣2小時）懸浮液中。室溫下攪拌所生成之混合 物6 0小時。反應未完全。再次冷卻該反應混合物至〇 °C並 加入額外之鋅粉（470 mg，7.19毫莫耳）。攪拌該反應混 合物4小時，期間反應完全。過濾該反應混合物以除去鋅 。蒸發濾、液。加入甲苯和乙酸乙酯（1 : 1 )混合物’隨後 加入乙酸（2 ml )。稀釋該混合物直至所有之有機固體皆 溶解，隨後經水和鹽水冲洗，置於Na2S〇4上乾燥，並進行 蒸發。令殘餘物再溶解於乙酸乙酯中並加入4N H C 1之二螺 烷溶液（4 m 1 )。蒸發溶劑，產生標的化合物，其爲二氫 氯化物鹽（5 1 5 m g，定量產率）。 1H-NMR ( CD3OD J 3 00MHz ) 5 7.35 - 7.30 (m ’ 5 Η ) ’ 6,94—6_93(ni，2H)’5.03(s’2H)’4.42—4.37 ( -389- 200529835 (385) m，lH) ，3.70(s，3H) ，3.09— 3.03 (m，lH) ，2.87 —2.79 ( m，1 H ) ，2.25 ( s，3H ) LC/MS: tR=1.79分，358 (MH) +。 (R) — 1—(甲氧幾基）一 2— (7 —甲基一 1H —苯並〔d 〕〔1，2，3〕三唑一 5—基）乙基氨基甲酸苄酯Add ammonium formate solid (75 5 mg, 1 1.9 mmol) in small portions at (° C) to (R)-(methoxide-based)-2-(3-methyl-4, 5- A suspension of benzyl dinitrophenyl) ethylcarbamate (500 mg, 1.20 mmol) and zinc powder (470 mg, 7.19 mmol) in methanol (20 ml, degassed with nitrogen for 2 hours). The resulting mixture was stirred at room temperature for 60 hours. The reaction was incomplete. The reaction mixture was cooled again to 0 ° C and additional zinc powder (470 mg, 7.19 mmol) was added. The reaction mixture was stirred for 4 hours, during which the reaction was complete. The reaction mixture was filtered to remove zinc. Evaporate the filter and liquid. A mixture of toluene and ethyl acetate (1: 1) was added 'followed by acetic acid (2 ml). The mixture was diluted until all organic solids were dissolved, then washed with water and brine, dried over Na2SO4, and evaporated. The residue was redissolved in ethyl acetate and a 4N H C 1 bisspirane solution (4 m 1) was added. Evaporation of the solvent gave the target compound as a dihydrochloride salt (5 1 5 mg, quantitative yield). 1H-NMR (CD3OD J 3 00MHz) 5 7.35-7.30 (m '5 Η)' 6,94-6_93 (ni, 2H) '5.03 (s'2H)' 4.42-4.37 (-389- 200529835 (385) m , LH), 3.70 (s, 3H), 3.09—3.03 (m, lH), 2.87—2.79 (m, 1 H), 2.25 (s, 3H) LC / MS: tR = 1.79 points, 358 (MH) + . (R) — 1— (methoxyquinyl) —2— (7—methyl—1H—benzo [d] [1,2,3] triazole—5-yl) ethylcarbamate

室溫下以超過數分鐘之時間，將亞硝酸鈉（40 mg， 0.58毫莫耳）之水（1 ml)溶液逐滴地加入至（R) - 1 — (甲氧羰基）一2—（3，4 一二胺基一 5—甲基苯基）乙基 氨基甲酸苄酯（250 mg，0.58毫莫耳）之乙酸（6 ml)和 水（1 0 ml )的溶液中。室溫下攪拌所生成之混合物3 0分 鐘，隨後冷卻至〇°C。加入NH4OH和水之混合物（1 :；[， 15 ml )以調整pH至1 1。利用乙酸乙酯萃取該混合物2次 。利用鹽水冲洗有機層，並置於NaaSO4上乾燥。經過濾後 ，真空下除去溶劑並藉由矽膠閃蒸管柱（1 : 1乙酸乙酉旨 /己烷）純化殘餘物，生成黃褐色固體之標的化合物（ 1 5 5 ni g，7 2 % 產率）。 】H-NMR ( CDC13，3 00MHz ) 5 7.34 ( s，1H) ，7·32〜 7.28( m，6H) ，6.93(s，lH) ，5.40(d，J=8.1Hz， -390- 200529835 (386) 1 Η ) ，5·13— 5·02(ιώ，2Η) ，4·76 — 4·69(ηι，1Η)， 3.73 (s，3Η ) ，3.28(dd，J=13.9，5·5Ηζ，1Η) ，3.16 (dd，J=13.9，6.2Hz，lH) ，2.64(s，3H)。 LC/MS: tR=2.30分，369 (MH) + 〇 (R) — 2 —胺基一3 — （7 —甲基一1H— 苯並〔d〕 〔1，2 ，3〕三唑—5—基）丙酸甲酯A solution of sodium nitrite (40 mg, 0.58 mmol) in water (1 ml) was added dropwise to (R)-1-(methoxycarbonyl)-2-( A solution of benzyl 3,4-diamino-5-methylphenyl) ethylcarbamate (250 mg, 0.58 mmol) in acetic acid (6 ml) and water (10 ml). The resulting mixture was stirred at room temperature for 30 minutes and then cooled to 0 ° C. Add a mixture of NH4OH and water (1 :; [, 15 ml) to adjust the pH to 11. The mixture was extracted twice with ethyl acetate. The organic layer was washed with brine and dried over NaaSO4. After filtration, the solvent was removed under vacuum and the residue was purified by a silica gel flash column (1: 1 ethyl acetate / hexane) to give the title compound as a tan solid (15 5 nig, 72% yield). ). H-NMR (CDC13, 3 00MHz) 5 7.34 (s, 1H), 7.32 ~ 7.28 (m, 6H), 6.93 (s, 1H), 5.40 (d, J = 8.1Hz, -390- 200529835 ( 386) 1Η), 5.13—5.02 (ιώ, 2Η), 4.76 — 4.69 (η, 1Η), 3.73 (s, 3Η), 3.28 (dd, J = 13.9, 5.5Ηζ , 1Η), 3.16 (dd, J = 13.9, 6.2Hz, 1H), 2.64 (s, 3H). LC / MS: tR = 2.30 minutes, 369 (MH) + 〇 (R) — 2 —amino — 3 — (7 —methyl — 1H — benzo [d] [1,2,3] triazole-5 —Methyl) propionate

令（R) —1—(甲氧羰基）一2— （7—甲基一1H — 苯並〔d〕 〔1，2，3〕三唑一 5—基）乙基氨基甲酸苄酯 (146 mg，0.40毫莫耳）溶液於4.4%甲酸之甲醇溶液（ 1 2 ml )中。令有該溶液之反應燒瓶配備有磁性攪拌棒， 並隨後利用氮氣冲洗數分鐘。加入Pd/C ( 10%，200 mg )並於室溫和氮氣環境下攪拌該反應混合物1 6小時。經通 過寅氏鹽®墊過濾該反應混合物，並利用甲醇冲洗該墊數 次。蒸發濾液以生成標的化合物（定量產率）。 j-NMR ( CDC13，3 00MHz ) 5 8.40 ( bs，1H ) ，7.55 (s，lH) ，7.14(s，lH) ，4.29— 4.24( m，lH)， 3.78 (s，3H) ，3.39-3.19(m，2H) ，2.69(s，3H) LC/MS: tR=1.18 分，235 (MH) +Let (R) —1- (methoxycarbonyl) -2— (7-methyl-1H—benzo [d] [1,2,3] triazol-5-yl) ethylcarbamate (146 mg, 0.40 mmol) in 4.4% formic acid in methanol (12 ml). The reaction flask with the solution was equipped with a magnetic stir bar, and then flushed with nitrogen for several minutes. Pd / C (10%, 200 mg) was added and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was filtered through a Yin's Salt® pad and the pad was rinsed with methanol several times. The filtrate was evaporated to give the target compound (quantitative yield). j-NMR (CDC13, 3 00MHz) 5 8.40 (bs, 1H), 7.55 (s, 1H), 7.14 (s, 1H), 4.29-4.24 (m, 1H), 3.78 (s, 3H), 3.39-3.19 (m, 2H), 2.69 (s, 3H) LC / MS: tR = 1.18 minutes, 235 (MH) +

(R) — 2— (4— (1，2 —二氫—2— 酮基哇唑啉一 3(4H -391 - 200529835 (387) )哌啶一 1 一羧醯胺基）一 3 — ( 7 -甲基一 1 Η -苯並〔d 〕〔1，2，3〕三唑一 5-基）丙酸甲酯(R) — 2— (4— (1,2, dihydro-2—keto oxazoline-3 (4H-391-200529835 (387)) piperidine-1 1-carboxamido) —3 — ( 7-methyl-l-pyrene-benzo [d] [1,2,3] triazol-5-yl) propanoic acid methyl ester

如前述（R) — 2— （4— (1，2 —二氫一2 -酮基口奎唑 啉一 3 ( 4H ) -基）哌啶一 1 —羧醯胺基）一 3 — ( 2 -（ 三氟甲基）一 1H—苯並〔d〕咪唑一 5 —基）丙酸甲酯之 方法製備。 LC/MS: tR=2.17分，492 (MH) +。 (R ) — 2 一 ( 4 一（1，2 — 一·氯 一 2，4 —二嗣基 D 奎 Π坐琳 一 3 (4H ) —基）哌啶一 1 —羧醯胺基）一 3 —（ 7 —甲基—1 Η 一苯並〔d〕 〔1，2，3〕三唑—5 —基）丙酸As mentioned above (R) — 2 — (4 -— (1,2, dihydro-2—ketoquinazoline-3 (4H) -yl) piperidine—1—carboxyamido) —3— (2 -(Trifluoromethyl)-1H-benzo [d] imidazole-5-yl) propionic acid methyl ester. LC / MS: tR = 2.17 points, 492 (MH) +. (R) — 2 1 (4 1 (1, 2 — 1 -chloro-2, 4-difluorenyl D quinolinium 3 (4H) —yl) piperidine 1 1 —carboxamido) — 3 — (7 -Methyl-1 fluorene-benzo [d] [1,2,3] triazol-5-yl) propionic acid

如則述（R) — 2— (4—（1，2—二氫一 2 —酮[基D奎口坐 啉一 3 ( 4 Η )—基）哌D定—1 —竣醣胺基）—3 - （ 2 -二 氟甲基）一 1H -苯並〔d〕咪唑一 5 -基）丙酸之方法加 以製備。 - 392 - 200529835 (388) LC/MS: tR=2.11 分，492 (MH)卜。 實施例2 3 7 4 一 （ 1 ’ 2 — 一·氣一2 ’ 4 — 一·嗣基 D 奎 口坐琳一3 ( 4 Η )—基 )—N— ( (R) — 3— (7 —甲基一1Η —苯並〔d〕 〔1，2 ，3〕三唑—5 —基）—1 —酮基一 1 — ( 4 一（哌啶—1 —基 )哌啶一 1 一基）丙一 2 -基）一哌啶—1 一羧醯胺As stated (R) — 2— (4— (1,2-dihydro-2—one—ketone D quinololine-3 (4 Η) —yl) piperidine — 1 — glycosamino group) —3- (2-difluoromethyl) -1H-benzo [d] imidazole-5-yl) propionic acid is prepared by a method. -392-200529835 (388) LC / MS: tR = 2.11 points, 492 (MH) Bu. Example 2 3 7 4 1 (1 '2 — 1 · qi 1 2' 4 — 1 · 嗣 基 D Kuikou Zaolin 1 3 (4 Η) —Base) —N— ((R) — 3— (7 —Methyl-1,1—Benzo [d] [1,2,3] triazol-5-yl) -1-keto-1— (4-mono (piperidine-1-yl) piperidine-1 1-yl ) Propan-2-yl) monopiperidine-1 monocarboxamide

如前述實施例231之方法進行製備。 h-NMR ( CD3OD，3 00MHz ) 5 8 · 0 1 ( d，J 二 8 · 1 Η z， 1 Η ) ，7.63 (t，J 二 7·5Ηζ，1 Η ) ，7.28-7.11 (m，4Η ) ，5.06-5.00 (m，1 Η ) ，4.70— 4.60 (m，1 Η ) ，4.3 1- 4.17 (m，2H) ，3·50— 3.44 (m，lH) ^ 3.2 0 - 2.8 2 ( m ，7H) ，2·75— 2.47 (m，6H) ，2.12—2.02 (m，2H) ，1.93— 1.67 ( m，11H) ，1.37— 1.28 (m，2H) ，0.97 —0.79(m，2H) ，0.23— 0.09 (m，lH)。質譜：642 (Μ H ) +。 - 393- 200529835 (389) (R) — 2 —苄氧羰基胺基—3 -（4 一氯一 2 —酮基—2，3 一二氫一苯並噁唑一 6—基）一丙酸甲酯It was prepared as described in Example 231 above. h-NMR (CD3OD, 300 MHz) 5 8 · 0 1 (d, J 2 8 · 1 Η z, 1 Η), 7.63 (t, J 2 7. 5 Η ζ, 1 Η), 7.28-7.11 (m, 4Η ), 5.06-5.00 (m, 1 Η), 4.70— 4.60 (m, 1 Η), 4.3 1- 4.17 (m, 2H), 3.50— 3.44 (m, lH) ^ 3.2 0-2.8 2 (m , 7H), 2.75— 2.47 (m, 6H), 2.12—2.02 (m, 2H), 1.93— 1.67 (m, 11H), 1.37— 1.28 (m, 2H), 0.97 —0.79 (m, 2H) , 0.23-0.09 (m, lH). Mass spectrum: 642 (MH) +. -393- 200529835 (389) (R) — 2-Benzyloxycarbonylamino-3 — (4-chloro-2-keto-2,3-dihydro-benzoxazole-6-yl) monopropionic acid Methyl ester

於90 °C下加熱（R) — 2 —卡氧鑛基胺基—3 —（2-酮 基一2，3 —二氫—苯並噁唑—6 —基）一丙酸甲酯（373 mg，1.01毫莫耳）、N —氯琥珀醯亞胺（168 mg’ 1.26毫 莫耳）及矽膠（EM Scientific，230 至 400 篩孑L ’ 3.73 g) 之二氯乙烷（2 0 m 1 )混合物1 6小時。經冷卻至室溫後， 真空下除去溶劑。藉由矽膠層析並利用乙酸乙酯/己烷（ 1 : 2 )爲流洗液以純化殘餘物，生成標的化合物（4 0 m g ，9.8%)及2 —苄氧羰基胺基—3 -（5 —氯一 2—酮基一2 ’ 3 —二氯—苯並B惡Π坐—6 —基）—丙酸甲醋（78 mg’ 19 % )。藉由2D NMR和與2 —苄氧羰基胺基—3 —（5 —氯— 2—酮基_2，3 -二氫一苯並噁唑一 6—基）—丙酸甲酯（ 其製備係示於下述之反應）之2D NMR相比較，證實該結 構。 】H-NMR ( CD3COCD3，5 00MHz ) 5 7 · 3 7 — 7 · 2 7 ( m，5 Η )，7.18(d，J=1.0Hz，lH) ，7.16(s，lH) ，6.76(d ，J=8.5Hz，1 H ) ，5.06(d，J=12.5Hz，1 H ) ，5.02 ( d，J=12.5Hz，lH) ，4.55—4.51 (m，lH) ，3.72(s， 3H ) ，3.26(dd，J=14.0，5.0Hz，1H) ，3.04(dd，J = 14.0，9.5Hz，1 H )；丨3 C - N M R ( C D 3 C O C D 3，1 25MHz ) (5 1 7 2.2， 1 5 6.4， 1 5 4 · 0， 1 4 4.8， 1 3 7 · 6， 1 3 3 · 3 ， 1 2 8 · 7， -394- 200529835 (390) 128.2，128.0，127.9，125.0，66.3，55·9，52.0，37.3 ; 質譜：4 0 5 ( Μ Η ) 1。 (R) — 2氧鑛基胺基—3— (5 -氯—2-酮基一 2，3 一二氫一苯並噁唑一 6-基）一丙酸甲酯Heated at 90 ° C (R) — 2-Carbonylamino — 3 — (2-keto-2,3-dihydro-benzoxazole-6 —yl) monopropionate (373 mg, 1.01 mmoles), N-chlorosuccinimide (168 mg '1.26 mmoles) and silicone (EM Scientific, 230 to 400 sieve L' 3.73 g) of dichloroethane (20 m 1 ) Mixture for 16 hours. After cooling to room temperature, the solvent was removed under vacuum. The residue was purified by silica gel chromatography using ethyl acetate / hexane (1: 2) as the eluent to produce the target compound (40 mg, 9.8%) and 2-benzyloxycarbonylamino-3-( 5-Chloro-2-keto- 2 '3 -dichloro-benzo-B-oxazi-6-yl) -methyl propionate (78 mg' 19%). By 2D NMR and 2-benzyloxycarbonylamino-3- (5-chloro-2-keto_2,3-dihydromonobenzoxazole-6-yl) -methyl propionate (the preparation The structure was confirmed by 2D NMR comparison with the reaction shown below. ] H-NMR (CD3COCD3, 500 MHz) 5 7 · 3 7 — 7 · 2 7 (m, 5 Η), 7.18 (d, J = 1.0 Hz, lH), 7.16 (s, lH), 6.76 (d, J = 8.5Hz, 1 H), 5.06 (d, J = 12.5Hz, 1 H), 5.02 (d, J = 12.5Hz, lH), 4.55-4.51 (m, lH), 3.72 (s, 3H), 3.26 (dd, J = 14.0, 5.0Hz, 1H), 3.04 (dd, J = 14.0, 9.5Hz, 1H); 3 C-NMR (CD 3 COCD 3, 1 25MHz) (5 1 7 2.2, 1 5 6.4, 1 5 4 · 0, 1 4 4.8, 1 3 7 · 6, 1 3 3 · 3, 1 2 8 · 7, -394- 200529835 (390) 128.2, 128.0, 127.9, 125.0, 66.3, 55 · 9,52.0,37.3; Mass spectrum: 4 0 5 (Μ () 1. (R) — 2oxanylamino — 3 — (5 -chloro-2-keto-2,3 -dihydromonobenzox Azole-6-yl) monopropionate

室溫下將N -氯琥珀醯亞胺（315 mg，2.36毫莫耳） 加入至（R) — 2—节氧鑛基胺基—3— (2-酬基_2，3 — 二氫一苯並噁唑—6—基）一丙酸甲酯（ 700 mg，1.89毫 莫耳）之乙酸（50 ml )溶液中。於1〇〇 °C下加熱該混合物 1 6小時。經冷卻至室溫後，真空下除去溶劑。藉由矽膠層 析並先後利用4 : 6和1 : 1之乙酸乙酯/己烷爲流洗液以純 化殘餘物，生成灰黃色固體之標的化合物（242 mg，32% )。藉由2D NMR證實該產物之結構。 j-NMR ( CD3COCD3，5 00MHz ) (5 10.47 ( s，1 Η )， 7.3 6-7.28 (m» 6H ) ，7·20 ( s，1Η ) ，6·80 ( d，J =Add N-chlorosuccinimide (315 mg, 2.36 millimoles) to (R) — 2-oxybenzylamino — 3 — (2-amyl_2,3 —dihydro-1) at room temperature Benzoxazole-6-yl) monopropionate (700 mg, 1.89 mmol) in acetic acid (50 ml). The mixture was heated at 100 ° C for 16 hours. After cooling to room temperature, the solvent was removed under vacuum. The residue was purified by silica gel layer analysis and successively using 4: 6 and 1: 1 ethyl acetate / hexane as the eluent to purify the residue to produce the target compound (242 mg, 32%) as a gray-yellow solid. The structure of the product was confirmed by 2D NMR. j-NMR (CD3COCD3, 500 MHz) (5 10.47 (s, 1 Η), 7.3 6-7.28 (m »6H), 7 · 20 (s, 1Η), 6.80 (d, J =

8·5Ηζ，1H ) ，5·05 ( d，J = 12·5Ηζ，1H ) ，5.00 ( d，J = 12.5Hz，1H) ，4.65— 4.60 (m，1H) ，3.73(s，3H) ，3.43 ( dd，J = 14.0，5.0Hz，1H) ，3.0 8 ( d d，J 二 14.0 ，1〇·5Ηζ， 1H ) ； 13C-NMR ( CD3COCD3， 1 25MHz ) δ 172.2，156.5，154.5，143.1，137.5，130.8，129.0， 128.9，128.7，128.2，128.0，112.8 ’ 110.9，66.3，54.3 ，52· 1，35.8 ;質譜：405 ( ΜΗ ) 1。 - 395- 200529835 (391) (R ) 一 2-卡氧羯基胺基一 3 -（4一漠一 2-醒基一 2，3 一二氫一苯並噁唑一 6—基）一丙酸甲酯8 · 5Ηζ, 1H), 5.05 (d, J = 12 · 5Ηζ, 1H), 5.00 (d, J = 12.5Hz, 1H), 4.65-4.60 (m, 1H), 3.73 (s, 3H), 3.43 (dd, J = 14.0, 5.0 Hz, 1H), 3.0 8 (dd, J 2 14.0, 10.5 · ζ, 1H); 13C-NMR (CD3COCD3, 1 25MHz) δ 172.2, 156.5, 154.5, 143.1, 137.5 , 130.8, 129.0, 128.9, 128.7, 128.2, 128.0, 112.8 ′ 110.9, 66.3, 54.3, 52.1, 35.8; Mass spectrum: 405 (ΜΗ) 1. -395- 200529835 (391) (R)-2-carbofluorenylamino 3-(4-molyl 2- 2-pentyl-2,3 -dihydro-benzoxazole-6-yl) -propane Methyl ester

室溫下攪拌（R) - 2-苄氧羰基胺基一 3 -（2-酮基 一 2，3 —二氫一苯並噁唑—6-基）—丙酸甲酯（418 mg ，1.13毫莫耳））、N —溴琥珀醯亞胺（221 mg，1.24毫 莫耳）、矽膠（EM Scientific，230至 400篩孔，2.51 g) 及CH2C12 ( 70 ml )之混合物16小時。真空下除去溶劑並 藉由矽膠層析且利用乙酸乙酯/己烷（2 : 3 )爲流洗液以 純化殘餘物，生成標的化合物。 j-NMR ( CD3COCD3，5 00MHz ) 5 10.71 (s’ 1 Η )， 7.3 5 — 7.28 (m，6H) ，7.21 (s，1Η ) ，6.75 (d，J =Stir at room temperature (R)-2-benzyloxycarbonylamino-3-(2-keto-2,3-dihydromonobenzoxazole-6-yl) -propionic acid methyl ester (418 mg, 1.13 Millimoles)), N-bromosuccinimide (221 mg, 1.24 millimoles), silicone (EM Scientific, 230 to 400 mesh, 2.51 g) and CH2C12 (70 ml) for 16 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using ethyl acetate / hexane (2: 3) as the eluent to produce the title compound. j-NMR (CD3COCD3, 5000 MHz) 5 10.71 (s' 1 Η), 7.3 5 — 7.28 (m, 6H), 7.21 (s, 1Η), 6.75 (d, J =

7·5Ηζ，1 Η ) ，5·06 ( d，J = 12·5Ηζ，1 Η ) ，5·02 ( d，J =12.5Hz > 1 Η ) ，4·56— 4.51 (m，1H) ，3·73 (s，3Η) ，3·26 ( dd，J 二 14.0，5·0Ηζ，1H) ，3·03 ( dd，J = 14.0 ，10.0Hz，1H) ； 13C-NMR ( CD3COCD3，1 25MHz ) 5 172.2，156.4，153.8，144.4，137.6，133.7，129.8， 128·7，128.2，128.0，127.8，110.1，100.9，66.3，55.9 ，52.0，37.3 ;質譜：44 8.03 ( ΜΗ ) +。 (R) - 2 —苄氧羰基胺基—3 -（5 —溴一 2-酮基—2，3 一二氫一苯並噁唑一 6 -基）一丙酸甲酯 - 396 - 200529835 (392) ο〆7 · 5Ηζ, 1 Η), 5.06 (d, J = 12 · 5Ηζ, 1 Η), 5.02 (d, J = 12.5Hz > 1 Η), 4.56—4.51 (m, 1H) , 3.73 (s, 3Η), 3.26 (dd, J 2 14.0, 5.0 · ζ, 1H), 3.03 (dd, J = 14.0, 10.0 Hz, 1H); 13C-NMR (CD3COCD3, 1 25MHz) 5 172.2, 156.4, 153.8, 144.4, 137.6, 133.7, 129.8, 128 · 7, 128.2, 128.0, 127.8, 110.1, 100.9, 66.3, 55.9, 52.0, 37.3; Mass spectrum: 44 8.03 (ΜΗ) +. (R)-2 -Benzyloxycarbonylamino-3-(5-bromo-2-keto-2,3-dihydro-benzoxazole-6-yl) monopropionate-396-200529835 ( 392) ο〆

於105 °C下加熱（r) - 2 —苄氧羰基胺基—3 -（2 — 酮基一 2，3 —二氫一苯並噁唑—6 —基）一丙酸甲酯（ 1.07 g，2.89毫莫耳）、N —溴號拍醯亞胺（643 mg，3.61 毫莫耳）及乙酸（150 ml )之混合物Μ小時。經冷卻至室 溫後，真空下除去溶劑。藉由矽膠層析並先後利用2 : 3和 1 ·· 1之乙酸乙酯/己烷溶液爲流洗液以純化殘餘物，生成 標的化合物（446 mg , 34% )。藉由2D NMR證實該標的 化合物之結構。 !H-NMR ( CD3COCD3 ? 5 00MHz ) δ 10.46 ( s，1Η)， 7.36 - 7.28 ( m » 7H ) ，6.82(d，J=8.5Hz，1H) ，5.05 (d，J = 12.5Hz » 1 H ) ，5.00(d，J 二 12.5Hz，1 H )， 4.67— 4.62 (m，lH) ，3.73(s，3H) ，3.43(dd，J = 14.0，5·0Ηζ，1H) ，3.10(dd，J=14.0，10·5Ηζ，1H) ；13CNMR ( CD3COCD3，125MHz ) 5 172.2，156.4， 154.2，143.7，137.6，131.1，130.6，128.7，128.2， 128.0，118.2，113.9，112.9，66.2，54.3，52.1，38.3 ; 質譜·· 448.03 ( MH ) +。 (R) - 2—;氧鑛基胺基—3— (4 —碘一 2 —酮基—2，3 一二氫一苯並噁唑一 6—基）—丙酸甲酯Heated at 105 ° C (r)-2 -benzyloxycarbonylamino-3-(2-keto-2,3-dihydro-benzoxazole-6-yl) monopropionate (1.07 g , 2.89 millimoles), a mixture of N-bromopatimine (643 mg, 3.61 millimoles) and acetic acid (150 ml) for 24 hours. After cooling to room temperature, the solvent was removed under vacuum. The residue was purified by silica gel chromatography and successively using an ethyl acetate / hexane solution of 2: 3 and 1 ·· 1 to obtain the target compound (446 mg, 34%). The structure of the target compound was confirmed by 2D NMR. ! H-NMR (CD3COCD3? 500 MHz) δ 10.46 (s, 1 ，), 7.36-7.28 (m »7H), 6.82 (d, J = 8.5Hz, 1H), 5.05 (d, J = 12.5Hz» 1 H ), 5.00 (d, J 2 12.5 Hz, 1 H), 4.67-4.62 (m, 1H), 3.73 (s, 3H), 3.43 (dd, J = 14.0, 5.0 Ηζ, 1H), 3.10 (dd, J = 14.0, 10.5Ηζ, 1H); 13CNMR (CD3COCD3, 125MHz) 5 172.2, 156.4, 154.2, 143.7, 137.6, 131.1, 130.6, 128.7, 128.2, 128.0, 118.2, 113.9, 112.9, 66.2, 54.3, 52.1, 38.3; Mass spectrum 448.03 (MH) +. (R)-2-; Oxylamido-3-(4 -iodo- 2 -keto-2,3 -dihydro-benzoxazole-6 -yl)-methyl propionate

- 397 - 200529835 (393) 於90 °C下加熱（R) — 2 —苄氧羰基胺基一 3— (2-酮 基一 2，3 —二氫—苯並噁唑一6 —基）—丙酸甲酯（324 mg，0.87 毫莫耳）、I(PyH) 2BF4 (409 mg，1.08 毫莫耳 )、矽膠（EM Scientific，230 至 400篩孔，3.24 g )及二 氯乙烷（2 0 m 1 )之混合物6小時。經冷卻至室溫後，真空 下除去溶劑。藉由矽膠層析並利用乙酸乙酯/己烷（1 : 2 )爲流洗液以純化殘餘物，生成標的化合物（175 mg ’ 40 % )。藉由2D NMR證實該標的化合物之結構。 W-NMR ( CD3COCD3，5 00MHz ) δ 10.47 ( s ^ 1Η )， 7.46 (s，1Η ) ，7·37—7·29(πι，5Η) ，7.22(s，1Η ) ’ 6.74 ( d，J 二 8·5Ηζ，1 Η ) ，5 · 0 7 ( d，J = 1 2.5 Η ζ，1 Η )，5.02(d，J=12.5Hz，1Η) ，4.54 - 4.49(m，1Η) ，3.72 ( s，3H ) ，3.23 ( dd，J = 14.0，5.0Hz，1H )， 3.01 ( dd，J= 14.0，9.5Hz，1 H ) ； 13 C-N M R ( C D 3 C 0 C D 3 ，125MHz) 5 172.2，156.4，153.4，143.3，137.6， 134.1 ， 133.64 ， 133.60 ， 128.7 ， 128.2 ， 128.0 ， 110.7 ， 71.1，66.3 > 56.0，52.0 > 37.1 ；質譜：496.01 (MH+)。 (R) — 2 —胺基一 3— (5 —溴一 2 —酮基—2，3—二氫一 苯並噁唑-基）-丙酸甲酯-397-200529835 (393) heated at 90 ° C (R) — 2 —benzyloxycarbonylamino — 3 — (2-keto-2,3-dihydro-benzoxazole-6 —yl) — Methyl propionate (324 mg, 0.87 mmol), I (PyH) 2BF4 (409 mg, 1.08 mmol), silicone (EM Scientific, 230 to 400 mesh, 3.24 g), and dichloroethane (2 0 m 1) of mixture for 6 hours. After cooling to room temperature, the solvent was removed under vacuum. The residue was purified by silica gel chromatography using ethyl acetate / hexane (1: 2) as the eluent to produce the target compound (175 mg '40%). The structure of the target compound was confirmed by 2D NMR. W-NMR (CD3COCD3, 500 MHz) δ 10.47 (s ^ 1Η), 7.46 (s, 1Η), 7.37-7.29 (π, 5Η), 7.22 (s, 1Η) '6.74 (d, J 2 8 · 5Ηζ, 1 Η), 5 · 0 7 (d, J = 1 2.5 Η ζ, 1 Η), 5.02 (d, J = 12.5Hz, 1Η), 4.54-4.49 (m, 1Η), 3.72 (s , 3H), 3.23 (dd, J = 14.0, 5.0Hz, 1H), 3.01 (dd, J = 14.0, 9.5Hz, 1 H); 13 CN MR (CD 3 C 0 CD 3, 125MHz) 5 172.2, 156.4 , 153.4, 143.3, 137.6, 134.1, 133.64, 133.60, 128.7, 128.2, 128.0, 110.7, 71.1, 66.3 > 56.0, 52.0 >37.1; Mass spectrum: 496.01 (MH +). (R) — 2 —Amine — 3 — (5 —Bromo 2 —Keto-2,3-dihydro-benzoxazol-yl) -propionic acid methyl ester

室溫下將三甲基甲矽烷基碘化物（73 ml，0.73毫莫 耳）加入至經共沸乾燥之（R ) — 2 -苄氧羰基胺基一 3 — - 398 - 200529835 (394) (5 —漠一 2 —醒基—2，3 —二氯—苯並卩惡嗤一 6-基）— 丙酸甲酯（146 mg，0.3 3毫莫耳）之乙腈（10 ml )溶液 中，並於室溫下攪拌所生成之混合物2小時。加入三乙胺 (0 · 1 2 ml )並於室溫下攪拌該混合物1 5分鐘。真空下除 去溶劑並利用乙酸乙酯萃取殘餘物。先後利用NaHC03溶 液和鹽水冲洗結合之有機層，置於Na2S04上乾燥，並進行 過濾除去溶劑且該殘餘物直接用於下一個步驟中。質譜：Trimethylsilyl iodide (73 ml, 0.73 mmol) was added to azeotropically dried (R)-2 -benzyloxycarbonylamino-3--398-200529835 (394) ( 5 —Mo-1—2-Axyl—2,3—dichloro—benzopyrazine—6-yl) — methyl propionate (146 mg, 0.3 3 mmol) in acetonitrile (10 ml), The resulting mixture was stirred at room temperature for 2 hours. Triethylamine (0.12 ml) was added and the mixture was stirred at room temperature for 15 minutes. The solvent was removed in vacuo and the residue was extracted with ethyl acetate. The combined organic layer was washed with NaHC03 solution and brine, dried over Na2S04, and filtered to remove the solvent and the residue was used directly in the next step. Mass spec:

(R) — 2 —胺基—3— (4 —溴—2 —酮基一 2，3-二氫— 苯並噁唑一 6—基）丙酸甲酯(R) — 2 —Amino-3 — (4-bromo-2 —keto-1,3-dihydro-benzoxazole-6-yl) propionate

如前述（R) - 2 -胺基一 3— (5-溴一 2-酮基一 2, 3—二氫一苯並噁唑一 6-基）一丙酸甲酯之方法進行製備 。質譜：315·06(ΜΗ) +。It is prepared as described in the aforementioned (R)-2 -amino-3- (5-bromo- 2-keto- 2,3-dihydro-benzoxazole- 6-yl) monopropionate. Mass spectrum: 315.06 (ΜΗ) +.

(R) —2 —胺基—3— (5- 氯一 2 —酮基—2 苯並噁唑一 6 —基）丙酸甲酯 0(R) —2 —Amine —3— (5-Chloro-2-keto-2 benzoxazole-6-yl) methyl propionate 0

如前述（R) - 2 —胺基—3— (5—溴一 酮基一 2, 3 —二氫一苯並噁唑一 6 —基）一丙酸甲酯之方法進行製備 。質譜：2 7 1 . 1 0 ( Μ Η ) Η。 -399 200529835 (395) (R ) 苯並噁 -2—胺基—3— (4 —氯—2—酮基—2，3 - 二氫一 唑一 6 -基）一丙酸甲酯It is prepared by the method of (R)-2 -amino-3- (5-bromo-one-keto-2,3-dihydro-benzoxazole-6-yl) monopropionate. Mass spectrum: 2 7 1. 1 0 (ΜΗ) Η. -399 200529835 (395) (R) Benzoxan-2-amino-3- (4-chloro-2-keto-2,3-dihydromonozole 6-yl) monopropionate

如 -2，3 譜 271 (R ) 2 並嚼哗 前述製備（R) - 2 —胺基一 3 -（5 —溴—2-酮[基Such as -2,3 spectrum 271 (R) 2 and chewing the aforementioned preparation (R)-2 -amino- 3-(5 -bromo-2-one [group

一二氯一苯並B惡π坐一 6—基）丙酸甲酯之方法。質 • 16 ( MH) + 。 一胺基—3— (4 —碘—2 —酮基一 2，3 —二氫—苯 一 6 —基）丙酸甲酯：A method for dichloro-benzo-benzo-oxanyl-6-yl) propionate. Quality • 16 (MH) +. Monoamino-3— (4-iodine-2—keto-1,3-dihydro-benzene-6-yl) methyl propionate:

如 —2，3 譜 3 63 (R)--2- { 1 Η —苯 丙酸甲iSuch as —2,3 spectrum 3 63 (R)-2- {1 Η —phenyl propionate

前述製備（R) — 2-胺基一3-（5 -溴一 2 —酮基 一二氫一苯並噁唑一 6—基）丙酸甲酯之方法。質 .04 ( MH ) +。 3 一（2 -醒[基_ 2’ 3 — —*氣一苯並D惡哗一 6 一基） 〔2，4 一 一氫一 2 -酬基螺一（暖U定一 4 ’ 4 — 並〔d〕 〔 1，3〕噁嗪）一 1 一羰基〕一胺基} 一 -400- 200529835 (396)The aforementioned method for preparing (R) -methyl 2-amino-3- (5-bromo-2-keto-dihydro-benzoxazole-6-yl) propanoate. Quality .04 (MH) +. 3 a (2-awake [base_ 2 '3 — — * qi-benzo D savage 6 6 a base) [2, 4-a hydrogen-2-phenyl spiro 1 (warm U fixed a 4' 4 — And [d] [1,3] oxazine) -1 monocarbonyl] monoamino} mono-400- 200529835 (396)

N Η 如則述製備（R) —甲基 2— （4一 （1，2- 一氯—2 一酮基喹唑啉一 3 ( 4 Η ) -基）哌啶一 1 一羧醯胺基）一 3 一 （2 — （三氟甲基）一 1Η —苯並〔d〕咪唑一 5 —基）丙 酸酯之方法。質譜 48 1.20 ( MH) 1。 (R) - 3—（2 —酮基—2，3 —二氫—苯並噁唑—6 —基） —2— { 〔2，4 —二氫—2 —酮I 基螺—（哌陡—4，4 — 1 Η —喹唑啉）一 1 —羰基〕一胺基} 一丙酸甲酯N Η Prepared as described (R) —Methyl 2 — (4-((1,2-chloro-2 —one ketoquinazolin — 3 (4 Η) -yl) piperidine — 1 —carboxamido ) A method of 3- (2- (trifluoromethyl)-1 fluorene-benzo [d] imidazol-5-yl) propionate. Mass Spectrometry 48 1.20 (MH) 1. (R)-3— (2-keto-2,3-dihydro-benzoxazole-6-yl) —2— {[2,4 —dihydro-2 —one I-spiro— (piperidine —4,4 — 1 hydrazone —quinazoline) 1 —carbonyl] monoamino} methyl propionate

如前述製備（R) —甲基 2 —（4 一（1，2 —二氫一 2 一酮基D奎唑啉一 3 ( 4Η ) -基）哌啶—1 一羧醯胺基）一 3 一 （2 - （三氟甲基）—1Η —苯並〔d〕咪唑一 5 —基）丙 酸酯之方法。質譜 4 80.24 ( MH) +。 6 —基） (R) — 3— (4-氯一 2 —酮基—2，3-二氫—苯並噁唑— 一 2— { 〔4— (2 —酮基—1，4 —二氫一2H — D 奎 -401 - 200529835 (397) 口坐啉一 3 —基）一· D定一 1 一羰基〕一胺基} 一丙酸甲醋 〇=<(R) —methyl 2 — (4— (1,2-dihydro—2—one keto D quinazoline—3 (4Η) —yl) piperidine—1—carboxamido) —3 Method for mono (2- (trifluoromethyl) -1-fluorene-benzo [d] imidazol-5-yl) propionate. Mass spectrum 4 80.24 (MH) +. 6-yl) (R) — 3— (4-chloro-2 —keto-2,3-dihydro-benzoxazole — 1 2 — {[4— (2 —keto-1, 4 —di Hydrogen-2H — D quinol-401-200529835 (397) oxoline-3-yl)-· D-fixed-1 monocarbonyl] monoamino} monopropionate 〇 = <

如前述製備（R)甲基 2— (4 — （1，2 —二氫一 2-酮基喹唑一 3 ( 4H ) -）哌啶一 1 一羧醯胺基）—3 -（ 2 一（三氟甲基）一 1H-苯並〔d〕咪唑—5 -基）丙酸酯 之方法。質譜 5 2 8.1 6 ( MH) +。 (R) — 3—（5 —氯—2-酮|基—2，3-二氯—苯並B惡D坐— 6 —基）—2 — { 〔4 — (2 —醒基—1，4 — 一 氣—2 Η — D 奎 唑啉一 3 —基）一哌啶一 1 一羰基〕一胺基} 一丙酸甲酯(R) methyl 2- (4- (1,2-dihydro-2-ketoquinazole-3 (4H)-) piperidine-1 1-carboxamido)-3-(2- (Trifluoromethyl) -1H-benzo [d] imidazol-5-yl) propionate. Mass spectrum 5 2 8.1 6 (MH) +. (R) — 3— (5-chloro-2-ketone | yl —2,3-dichloro—benzoBoxD — 6 —yl) — 2 — {〔4 — (2 —Xingyl—1, 4 — monogas — 2 Η — D quinazoline — 3-yl) monopiperidine — 1 monocarbonyl] monoamino} methyl propionate

如則述製備（R)甲基 2 — （4— (1，2—二氫—2— 酮基D奎唑啉一 3 ( 4Η )—基）哌啶一 1 一羧醯胺基）一 3 -(2 - （三氟甲基）一 1Η —苯並〔d〕咪唑—5 -基）丙酸 酯之方法。質譜 5 2 8 · 2 0 ( Μ Η ) -402- 200529835 (398) (R) — 3—（4 一溴一2 —酮基一 2，3 —二氫—苯並噁唑— 6— 基）—2— { 〔4— (2 —酮基—1，4 —二氫—2H —喹 口坐啉一 3 -基）一哌D定一 1 一碳基〕一胺基丨一丙酸甲酯Prepare (R) methyl 2- (4- (1,2-dihydro-2--2-keto-D-quinazoline-3 (4Η) -yl) piperidine-1, carboxamido) -3 -(2- (trifluoromethyl) -l-benzo [d] imidazol-5-yl) propionate. Mass spectrum 5 2 8 · 2 0 (Μ Η) -402- 200529835 (398) (R) — 3— (4 monobromo-2—keto-2,3-dihydro-benzoxazole-6-yl) —2— {[4— (2-keto-1,4—dihydro-2H—quinoloxolin-3—yl) —piperidine—1—carbon group] —amino group—monopropionate

如前述製備（R)甲基 2— (4 — （1，2 —二氫一 2-酮基喹唑啉一 3 ( 4H ) -基）哌啶一 1 一羧醯胺基）一 3 - (2—(三氟甲基）一 1H —苯並〔d〕咪唑—5—基）丙酸 酯之方法。質譜 5 72.20 ( MH) +。 (R) — 3-（5 —溴—2 —酮基一 2，3—二氫—苯並噁唑一 6 —基）—2 — { 〔4— (2 —酮基—1，4一 二氫—2H — 口奎 口坐啉一 3 —基）一哌Π定一 1 一羯基〕一胺基} 一丙酸甲酯(R) methyl 2- (4- (1,2-dihydro-2-ketoquinazoline-3 (4H) -yl) piperidine-1 1-carboxamido)-3-( Method for 2- (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) propionate. Mass spectrum 72.20 (MH) +. (R) — 3- (5-bromo-2—keto-2,3-dihydro-benzoxazole-6-yl) —2 — {[4— (2 —keto-1, 4-one Hydrogen — 2H — oxoquinoline — 3-yl) —piridine — 1 —fluorenyl] —amino} methyl propionate

如前述製備（R) —甲基 2 — （4 一 （1，2—二氫—2 -403 - 200529835 (399) 一酮基喹唑啉一 3 ( 4 Η ) -基）哌啶一 1 一羧醯胺基）一 3 —(2—(三氟甲基）—1H —苯並〔d〕咪唑一 5 —基）一 丙酸酯之方法。質譜 5 2 7.1 5 ( MH )—。 (R) — 3— (4 —職—2-嗣基—2’ 3 - —^氯—苯並卩惡哇— 6 — 基）—2— { 〔4— (2 —酮基—1，4 —二氫—2H — D 奎 唑啉一 3 —基）一哌啶一 1 一羰基〕一胺基}丙酸甲酯(R) —Methyl 2 — (4 mono (1,2-dihydro-2 -403-200529835) (399) monoketoquinazoline 3 (4 Η) -yl) piperidine 1 1 Carboxamido) -3- (2- (trifluoromethyl) -1H-benzo [d] imidazole-5-yl) monopropionate. Mass spectrum 5 2 7.1 5 (MH) —. (R) — 3— (4 —Position—2-fluorenyl—2 ′ 3 — — ^ Chloro-benzoxoxa-6—yl) —2— {〔4— (2 —keto—1,4 —Dihydro—2H —D quinazoline-3—yl) -piperidine-1 monocarbonyl] monoamino} methyl propionate

如則述製備（R)—甲基 2— (4 — （1，2—二氫—2 一酮基喹唑一 3 ( 4 Η ) -基）哌啶一 1 一羧醯胺基）一 3 -(2 — （三氟甲基）一 1Η—苯並〔d〕咪唑一 5 —基）丙酸 酯之方法。質譜 620.20 ( MH ) +。 (R) — 3— (2 -酮基一 2，3-二氫一苯並噁唑一 6-基） 一 2— { 〔2，4 —二氫—2> —酮基螺一（哌啶一4，4<一 1H —苯並〔d〕 〔1，3〕D惡嗪）一 1_羰基〕—胺基}— 丙酸 -404- 200529835 (400) 、、、、co2h 〇=(Prepare (R) -methyl 2- (4- (1,2-dihydro-2) -ketoquinazole-3 (4Η) -yl) piperidine-1, 1-carboxamido) -3 as described -(2- (trifluoromethyl) -l-benzo [d] imidazole-5-yl) propionate. Mass spectrum 620.20 (MH) +. (R) — 3— (2-keto-2,3-dihydro-benzoxazol-6-yl) — 2 — {[2,4-dihydro-2—> ketospiro-1 (piperidine -4,4 < -1H-benzo [d] [1,3] Doxazine) -1-carbonyl] -amino group} -propionic acid-404- 200529835 (400) 、,,, co2h 〇 = (

如前述製備（R) - 2— (4— (1，2-二氫一 2-酮共 D奎唑啉一 3 ( 4 Η ) -基）哌啶一 1 一羧醯亞胺）一 3 — ( 2 一（三氟甲基）一 1Η-苯並〔d〕咪唑一 5 -基）丙酸之 方法。質譜 467.1 8 ( MH) +。 (R) — 3— (2 —嗣基—2，3 - —*氣—苯並卩惡哗一6 —基） —2 — { 〔2，4 — —*氯—2 —嗣基螺—（喊卩定—4’ 4 — 1 Η — D奎唑啉）一 1 一羰基〕一胺基}丙酸(R)-2-(4- (1,2-dihydro-2-one co-D quinazoline-3 (4 Η) -yl) piperidine-1 1-carboximide) -3- (2 A method of (trifluoromethyl) -1 fluorene-benzo [d] imidazol-5-yl) propionic acid. Mass spectrum 467.1 8 (MH) +. (R) — 3— (2 —fluorenyl—2,3-— * Gas—benzopyrene—6-yl) —2 — {〔2,4 — — * Chloro-2—fluorenylspiro— (卩 卩-4 '4-1 Η-D quinazoline)-1 monocarbonyl] monoamine} propanoic acid

如前述製備（R) - 2— (4-（1’ 2 — 一氫一 2 —酮基 D奎唑啉一 3 ( 4 Η ) -基）哌啶一 1 一羧醯胺基）一 3 — ( 2 一三氟甲基）一 1Η —苯並〔d〕咪唑一 5 —基）丙酸之方 法。質譜 446.20 ( MH )+。 (R) — 3— (4-氯一 2 —醒基—2，3 - —*氧—苯並卩惡卩坐一 6 —基）—2 — { [ 4 一 ( 2 —酬基—1’4 — __•氨一2 Η — D 奎 -405- 200529835 (401) U坐琳一 3 -基）一哌D定一 1 一類基〕一胺基丨—丙酸 〇=((R)-2-(4- (1 '2-monohydro-2-keto D quinazoline-3 (4 Η) -yl) piperidine-1-carboxyamido)-3- (2-trifluoromethyl) -1,1-benzo [d] imidazol-5-yl) propionic acid. Mass spectrum 446.20 (MH) +. (R) — 3— (4-Chloro-2 —Axyl-2,3 — — * Oxy-benzopyrene, a 6-based group) — 2 — {[4 1 (2 —Amino-1 — 1 ' 4 — __ • Ammonia — 2 Η — D Kui-405- 200529835 (401) U Slimine 3 -yl) 1 piperidine D 1-1 type of group] -amino group 丨-propionic acid 〇 = (

如前述製備（R) - 2-（4一（1，2 —二氫一 2-酮基 D奎哇琳—3(4H)—基）派II定一 1 一竣釀胺基）—3- （2 一（三氟甲基）一 1H—苯並〔d〕咪唑一 5 —基）丙酸之 方法。質譜 5 14.20 ( MH ) +。 (R) —3— (5 —氯—2-酮基—2，3-二氫 — 苯並噁唑一 6—基） —2— { 〔4一 （2 —酮基—1，4一 二氫—2H —喹 唑啉一 3 -基）一哌啶一 1 一羰基〕一胺基} 一丙酸(R)-2- (4-((1,2-dihydro-2-keto D quivalin-3 (4H) -yl) was assigned as described above and amines were prepared as described above) —3- (2 Mono (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) propionic acid. Mass spectrum 14.20 (MH) +. (R) —3— (5-chloro-2-keto-2,3-dihydro-benzoxazole-6-yl) —2— {[4 一 (2 —keto-1,4-one Hydrogen-2H-quinazoline-3-yl) -piperidine-1 monocarbonyl] monoamino} monopropionic acid

如前述製備（R) - 2-（4— (1，2-二氫一 2 —酮基 II奎唑啉一 3 ( 4 Η ) -基）哌啶一 1 一羧醯胺基）—3 - （ 2 —(三氟甲基）一 1Η-苯並〔d〕咪唑一 5 —基）丙酸之 方法。質譜 5 1 4.2 4 ( Μ Η ) -406 - 200529835 (402) (R) — 3— (4 —漠—2 —酮I基一 2，3 — 一^氧—苯並卩惡卩坐— 6 —基）—2— { 〔4— (2 —酮基—1，4 —二氫—2H — D 奎 唑啉一 3 一基）—哌啶一 1 一羰基〕一胺基丨—丙酸(R)-2- (4- (1,2-dihydro-2-ketoII-quinazoline-3 (4Η) -yl) piperidine- 1-carboxamido) -3 as described above -3- (2- (trifluoromethyl) -l-benzo [d] imidazol-5-yl) propionic acid. Mass spectrum 5 1 4.2 4 (Μ Η) -406-200529835 (402) (R) — 3 — (4 — Mo — 2 — keto I group — 2, 3 — 1 —oxy —benzopyrazine — 6 — — 2 — {[4— (2 —keto —1,4 —dihydro — 2H — D quinazoline — 3 —yl) — piperidine — 1 —carbonyl] —amino — —propionic acid

°=K° = K

如目U述製備（R) — 2— (4—（1，2—二氫一 2—酮基 喹唑啉一 3 ( 4H )—基）哌啶一 1 一羧醯胺基）一 3 — ( 2 一（三氟甲基）一 1H—苯並〔d〕咪唑一 5 —基）丙酸之 方法。質譜 5 5 8.3 0 ( MH) +。 (R) - 3— (5-溴—2 —酮基—2，3 —二氫一苯並噁唑一 6 —基）一2— { 〔4— (2 —酮基一1，4 —二氫一2H — D 奎 口坐啉一 3 -基）一哌Π定一 1 一幾基〕一胺基}—丙酸(R) — 2 — (4- (1,2-dihydro-2-ketoquinazoline-3 (4H) -yl) piperidine-1 1-carboxamido) —3— (2 Mono (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) propionic acid. Mass spectrum 5 5 8.30 (MH) +. (R)-3— (5-Bromo-2-keto-2,3-dihydromonobenzoxazole-6-yl)-2— {[4— (2-keto-1,4—di Hydrogen- 2H — D quinololine- 3 -yl) -piperidine-1 1-several amino groups] -amino group} -propionic acid

如前述製備（R) — 2— (4 -（1，2 -二氫一 2 —酮基 -407 - 200529835 (403) 口奎唑啉一 3 ( 4 Η ) 一基）哌啶一 1 一羧醯胺基）一 3 - （ 2 一（二氣甲基）—1H—苯並〔d〕一咪哗—5—基）丙酸 之方法。質譜 5 5 8.25 ( MH ) +。 (R) — 3— (4 —碘—2—酮基一 2，3—二氫一苯並噁唑一 6 —基）—2 - { [ 4 — ( 2 —嗣基—1’ 4 — _-氣—2 Η 一 D 奎 唑一 3 -基）一哌啶一 1 一羰基〕一胺基} 一丙酸(R) — 2- (4- (1,2-dihydro-2-keto-407-200529835) (403) quinazolin-3 (4Η) -yl) piperidine-1 1-carboxy Method of amidino) 3-(2 mono (difluoromethyl)-1H-benzo [d]-imidyl-5-yl) propionic acid. Mass spectrum 5 5 8.25 (MH) +. (R) — 3— (4 —iodine—2—keto—2,3—dihydromonobenzoxazole — 6 —yl) — 2-{[4 — (2 —fluorenyl — 1 ′ 4 — _ -Gas—2 Η-D quinazol-3-yl) -piperidine-1 monocarbonyl] monoamino} monopropionic acid

如前述製備（R) - 2-（4一（1，2 - 一氫一 2 —酮基 喹唑啉一 3 ( 4 Η )—基）哌啶一 1 一羧醯胺基）—3 - （ 2 一（三氟甲基）一 1Η—苯並〔d〕咪唑一 5 —基）丙酸之 方法。質譜 606.1 0 ( MH) +。 實施例238 (R) — 4— (2 —酮基一1，4一 二氫一2H — D奎唑啉一3 — 基）一哌啶—1 一羧酸〔2 -（ 4 一環己基一哌嗪一 1 —基） 一 2 —酮基—1 一（2 —酮基—2，3 —二氫—苯並噁唑—6 — 基甲基）一乙基〕醯胺 -408- 200529835 (404)(R)-2- (4-((1,2-monohydro-2, -ketoquinazoline-3 (4Η) -yl) piperidine-1,1-carboxamido) -3-( 2 A method of mono (trifluoromethyl) -1,1-benzo [d] imidazol-5-yl) propionic acid. Mass spectrum 606.1 0 (MH) +. Example 238 (R) —4- (2-keto-1,4-dihydro-1H—D quinazoline-3-yl) -piperidine-1 monocarboxylic acid [2- (4-cyclohexyl-piper Hydrazine 1-yl) 2 keto-1 1 (2-keto-2,3-dihydro-benzoxazole-6-ylmethyl) monoethyl] amidamine-408- 200529835 (404 )

如前述實施例231之製備方法。LC/MS: tR=1.80分 ，63 0.3 7 ( ΜΗ ) + ° 實施例239 (R ) — 4 一 ( 2 —酬基一1，4 — 一 氯一2 Η — 口奎 口坐琳一3 — 基）一哌啶—1 一羧酸〔2 -（ 4 一異丙基一哌嗪一 1 一基） 一 2 —酮基一 1— (2 —酮基—2，3 —二氫一苯並噁唑—6-基甲基）一乙基〕一醯胺The preparation method is as described in the foregoing Example 231. LC / MS: tR = 1.80 minutes, 63 0.3 7 (ΜΗ) + ° Example 239 (R) — 4 1 (2 —Pacl-1, 4 — 1Chloro-2 2 Η — Kou Koukou Lin 1 — 3 — ) -Piperidine-1 monocarboxylic acid [2-(4-isopropyl-piperazine-1 1-yl)-2-keto-1-(2-keto-2,3-dihydro-benzo Oxazole-6-ylmethyl) monoethyl] monomethylamine

如前述實施例231之製備方法。LC/MS: tR二1.71分 ，5 90.3 4 ( MH ) " ° -409 - 200529835 (405) 實施例240 (R) — N— ( (R) — 3— (2 —酮基一 2，3 —二氫—苯並 口惡ij坐—6 -基）一 1 —嗣基—1 — ( 4 一（喊B定一1 —基）嘛 Π定一 1—基）丙—2 -基）—2，4 — 一氯一 2 —酮I基螺一 (哌啶—4，4 > — 1 Η —苯並〔d〕 〔 1，3〕噁嗪）一 1 — 羧醯胺The preparation method is as described in the foregoing Example 231. LC / MS: tR 2 1.71 minutes, 5 90.3 4 (MH) " ° -409-200529835 (405) Example 240 (R) — N— ((R) — 3— (2 —Keto-2, 3 —Dihydro—benzoxanyl — 6 —yl) — 1 —fluorenyl — 1 — (4 1 (called B 1 — 1) — 2 — 1 — 2) — — 2,4-chloro-2-keto-I-spiro- (piperidine-4,4 > — 1 pyrene-benzo [d] [1,3] oxazine) -1-carboxamide

Η 如前述實施例231之製備方法。LC/MS: tR=1.64分 ，6 1 7.34 ( MH ) + 。Η The preparation method of the foregoing embodiment 231. LC / MS: tR = 1.64 minutes, 6 1 7.34 (MH) +.

實施例2 4 1 (R) — N — ( ( R ) 一 3 一（2 —國基 一 2，3 — —•氯一苯並 噁唑—6 -基）一 1 一酮基一 1 一（ 4 一（環己一 1 一基）哌 嗪一 1 一基）丙—2 —基）—2，4一二氫—2 —酮基螺— (哌啶—4，4 > 一 1 Η —苯並〔d〕 〔 1，3〕噁嗪）—1 一 羧醯胺 -410- 200529835 (406)Example 2 4 1 (R) — N — ((R) —3— (2—National Group—2,3—— • Chloro-benzoxazole-6-yl) —1—Keto—1— ( 4 mono (cyclohexyl-1 mono) piperazine-1 mono-1) propan-2-yl) -2,4-dihydro-2 2-ketospiro- (piperidine-4,4 > a 1 Η — Benzo [d] [1,3] oxazine) -1 monocarboxamide-410- 200529835 (406)

如前述實施例231之製備方法。LC/ MS : tR = 1.69分 ，6 1 7·3 5 ( ΜΗ ) +。 實施例242 (R ) — N — ( ( R ) — 3 — (2 —嗣基—2，3 — 一·氯—苯並 噁唑—6 -基）—1 —酮基—1 — ( 4 —(丙—2 —基）哌嗪 —1—基）丙一 2-基）—2，4一二氫一 2 —酮基螺—（ 哌啶—4，4 / 一 1 Η —苯並〔d〕 〔 1，3〕噁嗪）—1 一羧 醯胺The preparation method is as described in the foregoing Example 231. LC / MS: tR = 1.69 minutes, 6 1 7 · 3 5 (ΜΗ) +. Example 242 (R) — N — ((R) — 3 — (2 —fluorenyl-2,3 —monochloro-benzoxazole-6-yl) —1 —keto —1 — (4 — (Propan-2-yl) piperazin-1-yl) propan-2-yl) -2,4-dihydro-2-2-ketospiro- (piperidine-4,4 / -1 1 pyrene-benzo [d 〕 〔1,3〕 oxazine) -1 monocarboxamide

N Η 如前述實施例23 1之製備方法。LC/ MS : tR = 1 .57分 ，5 7 7.3 2 ( MH ) 4 ° 實施例243 200529835 (407) (R ) — N — ( R ) — 3 — (2 —嗣基—2 ’ 3 — 一> 氣—本並 口惡 唑一 6 —基）—1 —酮基一 1 — ( 4 一 （ I帳啶—1 —基）哌啶 —1—基）丙一 2-基）—2，4一 —^氨一 2 —嗣基螺—（ 哌啶一 4，4 — 一 1 Η -喹唑啉）—1 一羧醯胺N Η was prepared as described in Example 23 1 above. LC / MS: tR = 1.57 minutes, 5 7 7.3 2 (MH) 4 ° > Qi-Benzooxazol-6-yl) -1-Keto-1-(4-(Iconidin-1-yl) piperidine-1 -yl) propanyl-2-yl) -2, 4-ammonia-2-pyridylspiro- (piperidine-4,4-pyridine-quinazoline) -1carboxamide

如前述實施例231之製備方法。LC/ MS : tR= 1.74分 ，616.37 ( MH )+。 實施例244 (1〇—1^一（（11)—3—(2—酮基—2，3-二氫—苯並 噁唑一6 —基）—1 一酮基一 1 一（ 4 一（環己—1 一基）哌 嗪一 1 一基）丙一 2—基）—2，4 —二氫一 2 / —酮基螺— (哌啶一 4，4，一 1 Η - D奎唑啉）—1 一羧醯胺The preparation method is as described in the foregoing Example 231. LC / MS: tR = 1.74 minutes, 616.37 (MH) +. Example 244 (10- 1 ^-((11) -3- (2-keto-2,3-dihydro-benzoxazole-6-yl) -1 keto-1 1- (4- (Cyclohexan-1yl) piperazine-1diyl) propan-2-yl) -2,4-dihydro-2 / 2-ketospiro- (piperidine-4,4,1 1 Η -D Oxazoline) -1 monocarboxamide

Ν '0 Η -412- 200529835 (408) 如前述之製備方法。LC/MS: tR = 1.79分，616.36 (Μ Η ) 1 。 實施例245 (R) — Ν-（ （R) — 3— (2 —酮基一 2，3 —二氫—苯並Ν'0Η -412- 200529835 (408) Prepared as described above. LC / MS: tR = 1.79 minutes, 616.36 (Μ Η) 1. Example 245 (R)-Ν- ((R)-3-(2-keto-2,3-dihydro-benzo

噁唑一 6-基）—1 一酮基一 1 一（4 一 （丙—2 —基）哌嗪 一 1—基）丙一 2 —基）—2，4 —二氫一 2 —嗣基螺一（ 哌啶一 4，4 / 一 1 Η - II奎唑啉）—1 一羧醯胺Oxazole-6-yl) -1 monoketo-1 1- (4-mono (propan-2-yl) piperazine-1-yl) propan-2-yl) -2,4-dihydro-2 2-fluorenyl Spiro- (piperidine-4,4 / 1-1 fluorene-II quinazoline) -1 carboxamide

Η 如前述實施例231之製備方法。LC/MS: tR=1.67分 ，5 76.3 4 ( MH ) 4 ° 實施例2 4 6 (R) — 4— (2 —酮基一1，4 —二氫一2H — D奎唑啉一3 — 基）一哌啶一 1 一羧酸〔2 —〔 1，4 /〕聯哌啶一1 / 一基 —1一（4一氯—2 —醒基—2，3 — 一氨—苯並卩惡卩坐—6-基 甲基）一 2—酮基一乙基〕一醯胺 -413- 200529835 (409)Η The preparation method of the foregoing embodiment 231. LC / MS: tR = 1.67 minutes, 5 76.3 4 (MH) 4 ° Example 2 4 6 (R) — 4— (2 —keto-1,4—dihydro—2H — D quinazoline—3 — A) piperidine-1 monocarboxylic acid [2 — [1,4 /] bipiperidine-1 / 1-yl-1-(4 -chloro-2 -pentyl-2,3 -monoamino-benzopyrene Dioxan-6-ylmethyl) -2-ketomonoethyl] monofluorenamine-413- 200529835 (409)

如前述實施例231之製備方法。LC/MS: tR=1.91分 ，664.3 5 ( ΜΗ )+ 。 實施例247 (R) — 4— (2 —酮基一1，4 —二氫一 2Η — D奎唑啉一3 — 基）一哌啶一 1 —羧酸〔2 -〔 1，4，〕聯哌啶一1 / —基 一 1一（5-氯—2 —酬基—2，3 —二氯一苯並D惡哇—6 —基 甲基）一 2—酮基一乙基〕一醯胺The preparation method is as described in the foregoing Example 231. LC / MS: tR = 1.91 minutes, 664.3 5 (ΜΗ) +. Example 247 (R) — 4 — (2-keto-1,4-dihydro-1, 2Η — D quinazoline — 3-yl) —piperidine — 1 —carboxylic acid [2-[1, 4 ,,] Bipiperidinyl 1 / -yl 1-1 (5-chloro-2-phenyl-2, 3-dichloro-benzo Doxa-6-yl methyl)-2-keto-ethyl]- Amidine

如前述實施例231之製備方法。LC / MS : tR = 1.91分 ，6 64.3 4 ( MH ) 1 ° -414- 200529835 (410) 實施例248 (R) — 4— (2 —酮基一1，4 —二氫一2H-D奎唑啉一3 — 基）一哌啶—1 —羧酸〔2 —〔 1，4 /〕聯哌啶一 1 / 一基 一 1 一 （4 一漠—2 —嗣基一 2，3 - 一氯—苯並卩惡卩坐—6 —基 甲基）一 2—酮基一乙基〕一醯胺The preparation method is as described in the foregoing Example 231. LC / MS: tR = 1.91 minutes, 6 64.3 4 (MH) 1 ° -414- 200529835 (410) Example 248 (R) — 4 — (2 —keto-1,4-dihydro-2H-D Oxazoline-3 -yl) piperidine-1 -carboxylic acid [2 — [1,4 /] bipiperidine-1 / 1 -yl 1 -1 (4 1 -2 -fluorenyl -2,3-1 Chloro-benzoxanthene-6-ylmethyl) -2-ketomonoethyl] monomethylamine

如前述實施例231之製備方法。LC/MS: tR=1.96分 ，7 08.3 1 ( MH ) +。 實施例249 (R) — 4— (2 —酮基一1，4 —二氫一2H — 口奎唑啉一3 — 基）一哌啶一 1 _羧酸〔2 —〔 1，4 /〕聯哌啶—厂一基 —1— (5 —漠一 2—嗣基—2，3 ——.氣—苯並暇哗—6-某 甲基）一 2—酮基一乙基〕一醯胺 -415- 200529835 (411)The preparation method is as described in the foregoing Example 231. LC / MS: tR = 1.96 minutes, 7 08.3 1 (MH) +. Example 249 (R) — 4 — (2-keto-1,4-dihydro-2H — mouth quinazoline-3-yl) -piperidine-1-carboxylic acid [2 — [1, 4 /] Piperidine—Plant-based—1— (5—Molybdenyl—2—Methenyl—2,3 ——. Gas—Benzene—6—Methyl) —2—Keto—Ethyl] —Hexyl Amine-415- 200529835 (411)

如前述實施例231之製備方法。LC/ MS : tR= 1.96分 ，70 8.3 1 ( ΜΗ ) +。 實施例2 5 0 (R) — 4— (2 —酮基一1，4一二氫一2H — D奎唑啉一3- 基）一呢D定一 1 一殘酸〔2 —〔 1，4 〕聯喊卩定一1 一基 —1一（4 —确—2 —酮基—2，3 -二氫—苯並B惡哇—6-基 甲基）一 2—酮基一乙基〕一醯胺The preparation method is as described in the foregoing Example 231. LC / MS: tR = 1.96 minutes, 70 8.3 1 (ΜΗ) +. Example 2 5 0 (R) — 4 — (2-keto-1,4-dihydro-2H—D quinazoline-3-yl) -dane D-1 1-residual acid [2 — [1, 4] Synthesis of 1- 1- 1- 1- (4 -2 -keto-2,3-dihydro-benzo-B-oxa-6-ylmethyl)-2 -keto-ethyl Monoamine

如前述實施例23 1之製備方法。LC/ MS : tR = 1 .97分 ，75 6.3 6 ( MH ) •丨。 -416- 200529835 (412) 實施例2 5 1 (土） 一 N— (1—禾基一2 —經基一乙基）一 2— (7 — 甲 基—1H —吲唑-5—基甲基）—4 —酮基一 4— 〔1〃 ，2, —_^氯—2 —嗣基螺一〔4H — 3 ’1 —苯並卩惡—4’ 4 一哌啶基〕一 丁醯胺The preparation method is as described in Example 23 1 above. LC / MS: tR = 1.97 minutes, 75 6.3 6 (MH) • 丨. -416- 200529835 (412) Example 2 5 1 (Earth) -N— (1-Hydroxy-2—Ethyl-Ethyl) —2- (7—Methyl-1H—Indazole-5—Methylmethyl ) —4 —keto — 4 — [1〃, 2 ,, —_ ^ chloro — 2 —fluorenylspiro [4H — 3 '1 —benzoxoxan — 4' 4 -piperidinyl] monobutyrin amine

Ο X Ο NHΟ X Ο NH

如前述製備（± ) — 1 一 〔 1，4 /〕聯哌啶一 1 / 一基 一 2— （7 —甲基一1H —吲唑一5 —基甲基）一4〔1^ ，(±) — 1-[1, 4 /] bipiperidine-1/1-1-2-(7 -methyl-1H-indazole-5-methyl)-4 [1 ^,

2^ —二氫—2 ——酮基螺一〔4H— 3，，1 一苯並噁唑嗪 一 4，—哌啶基〕一丁一 1，4_二酮之方法。LC/MS :tR= 1 .38 分，596 ( MH ) +。 實施例2 5 2 (±) — N— （1—苄基一2 —羥基一乙基）2— （7 —甲基 一 1H — D引唑一5 —基甲基）一4 —酮基一4一 〔4一 （2 —酮 基一1，4 —二氫一2 Η — D奎唑啉一3 —基）一_啶一1 —基 〕一 丁醯胺 -417 - 200529835 (413) Η2 ^ —dihydro-2 — ketospiro [4H-3,, 1-benzoxazosin-1,4-piperidinyl] -butane-1,4-dione method. LC / MS: tR = 1.38 points, 596 (MH) +. Example 2 5 2 (±) —N— (1-benzyl-1—hydroxy-ethyl) 2— (7-methyl-1H—D-azole-5-ylmethyl) —4-keto-1 4- [4-((2-keto-1,4-dihydro-2) Η —D quinazoline-3-yl) -pyridine- 1-yl] -butanidine-417-200529835 (413) Η

如前述製備（± ) — 1 — 〔 1，4 >〕聯哌啶一厂一基Prepared as above (±) — 1 — [1,4 >] piperidine one plant one base

-2 — （7 —甲基一1H — D 引唑一5 —基甲基）一4— 〔1，， 2^ —二氫一 2，—酮基螺—〔4H— 3，，1—苯並噁嗪—4 ，4 / —哌啶基〕一丁一 1，4 —二酮之方法。LC/ MS : tR =1 .50 分，609 ( ΜΗ ) +。 lU NMR ( 400MHz，CD3OD) 5 7.9 0 ( 1 Η，s ) ，7.64 — 7.84(lH，m) ，6·71-7·42(11Η，ηι) ，4.58(lH，m )，3·82— 4.50 (6H，m) ，2·21— 3.52( 13H，m)， 1 .42 - 1 .87 ( 4H，m )。-2 — (7 —methyl-1H — D indazole-5 —ylmethyl) — 4 — [1 ,, 2 ^ —dihydro-2, —ketospiro — [4H — 3, 1 —benzene And oxazin-4,4 / -piperidinyl] -butane-1,4-dione method. LC / MS: tR = 1.50 minutes, 609 (ΜΗ) +. 1U NMR (400MHz, CD3OD) 5 7.9 0 (1 Η, s), 7.64 — 7.84 (lH, m), 6.71-7.42 (11 Η, η), 4.58 (lH, m), 3.82— 4.50 (6H, m), 2.21—3.52 (13H, m), 1.42-1.87 (4H, m).

實施例2 5 3 (±)—苯基一乙酸一N— — {2 — （7 —甲基一1H — 〇引唑 —5 —基甲基）一 4一酮基—4— 〔4一 （2 —酮基—1，4 — 二氫一 Η —喹唑啉一 3 -基）—哌啶一 1 一基〕—丁醯基} -醯肼 -418- 200529835 (414) ΗExample 2 5 3 (±) -Phenyl monoacetic acid-N— {2— (7-methyl-1H—〇zolo-5—ylmethyl) —4—keto-4— [4— ( 2 —keto—1,4 —dihydromonofluorene —quinazoline — 3-yl) —piperidine — 1 mono] —butanyl} -hydrazine-418- 200529835 (414) Η

如前述製備（± ) - 1 — 〔 1，4 >〕聯哌啶一厂一基(±)-1 — [1,4 >] bipyridine one plant one base

—2— (7 —甲基一1H —吲唑一 5 —基甲基）一4— 〔1^ ， 2 — 一^氯一 2 —嗣基螺一〔4H— 3 ，1—苯並H惡嗦一 4 ，—哌啶基〕—丁 — 1，4 —二酮之方法。LC/MS: tR =1 .43 分，63 0 ( ΜΗ ) +。 實施例2 5 4 (土）一 1 — 〔1’4 〕聯喊 D定 一 1 —基一4 — 〔4 — (8—2— (7—methyl-1H—indazole—5-ylmethyl) —4— [1 ^, 2—one ^ chloro—2—fluorenylspirone— [4H-3, 1—benzoH嗦 A-4, -piperidinyl] -butane-1,4-dione method. LC / MS: tR = 1.43 points, 63 0 (ΜΗ) +. Example 2 5 4 (soil) one 1 — [1’4] yell D Ding one 1 —base one 4 — [4 — (8

一氟一2 —酮基一1，4 —二氫一2Η — D奎唑啉一3 —基）一 哌啶一1 —基〕一 2 — ( 7 —甲基一 1 Η — D引唑一 5 —基甲基 )一丁一 1，4 —二酮Monofluoro- 2 -keto-1,4-dihydro- 2 fluorenyl-D quinazoline-3 -yl) -piperidine-1 -yl]-2-(7 -methyl-1 fluorenyl-1 5-ylmethyl) monobutane-1,4-dione

如前述製備（± ) — 1 一 〔 1，4 〕聯丨帳陡一〗一基 -419- 200529835 (415) —2 — ( 7 — 2 —二氫 ，4〆一哌I =1 . 1 8 分， ]H NMR 7.40 ( 6H， ，3.85- 4. 5H ， m)， 實施例2 5 5 (± ) —1-一 1 Η -吲吗 酮基螺一（ 甲基一1Η — D引唑一5 —基甲基）一4— 〔1^ ， —2 > —酮基螺—〔4 Η — 3 >，1 —苯並噁嗪一 4 淀基〕—丁一 1，4一二酮之方法。LC/MS: tR 644 ( ΜΗ )丨。 (400MHz，CDCI3 ) ό 8.00 ( 1H，s) ，6.82 -m ) ，4.48-4.70 (3H，m) ，4.31(2H，s) ll(2H，m) ，3.65(lH，m) ，2.70-3.16( 2.53 (3H，s) ，0.72— 2.52 (23H，m)。 _〔 1，4 —〕聯哌啶—1 / 一基一2 — （ 7 —甲基 —5 —基甲基）一 4〔2，，3^ —二氫一2一一 哌啶一 4，4 / —喹唑啉〕—丁 — 1，4 —二酮Prepared as described above (±) — 1- [1,4] couplet 丨 steep one-one-419- 200529835 (415) — 2 — (7 — 2 —dihydro, 4 〆 1 pipe I = 1. 1 8 , H NMR 7.40 (6H,, 3.85-4.5H, m), Example 2 5 5 (±) — 1-1 1 Η-indoxone spiro- (methyl-1 Η-D-indolazole- 5-Methyl)) 4- [1 ^, —2 > —ketospiro— [4 Η — 3 >, 1 —benzoxazine — 4yl] —butane-1,4-dione Method: LC / MS: tR 644 (ΜΗ) 丨. (400MHz, CDCI3) 8.00 (1H, s), 6.82-m), 4.48-4.70 (3H, m), 4.31 (2H, s) ll (2H , M), 3.65 (lH, m), 2.70-3.16 (2.53 (3H, s), 0.72-2.52 (23H, m). _ [1,4 —] piperidine-1/1 base-2-( 7-methyl-5-ylmethyl) -4 [2,, 3 ^ -dihydro-2-2-piperidine-4,4 / -quinazoline] -butane-1,4-dione

如前述 —2 — (7 — 2 一 -二氫· ，4 / — Ι|β D 二 1.09 分， 製備（± ) — 1 — 〔 1，4 /〕聯哌啶一厂一基 甲基一 1H —吲唑一5 —基甲基）一4— 〔1，， —酮基螺—〔4H — 3〃 ，1—苯並噁嗪—4As mentioned above, -2 — (7 — 2 mono-dihydro ·, 4 / — Ι | β D, 1.09 minutes, to prepare (±) — 1 — [1, 4 /] dipiperidine, a plant, a methyl group, 1H —Indazole-5 —methylmethyl — 4 — [1 ,, —ketospiro — [4H — 3〃, 1 —benzoxazine — 4

t 基〕一丁 — 1，4 —二酮之方法。LC/MS: tR 612(ΜΗ) -420 - 200529835 (416) 2 —酮基—2，3 —二氫—苯並噁唑—6—酸 〇t group] method of monobutyl-1,4-dione. LC / MS: tR 612 (ΜΗ) -420-200529835 (416) 2-keto-2,3-dihydro-benzoxazole-6-acid

在加入正丁基鋰（2· 5M己烷溶液，3.8 ml ’ 2.2當量前 ，於氮氣下令6 —溴—3H —苯並噁唑一 2-酮（0.9236 g， 4.31毫莫耳）之無水四氫呋喃（25 ml)和二甲基甲醯胺 (3 ml )溶液冷卻至—78 °C。於—78 °C下經攪拌1〇分鐘後 ，加入24 ml之另丁基鋰（1.4M環己烷溶液，8當量）。攪 拌該反應溶液，同時緩慢地令其回溫至- 40 °C。當達到一 4 0°C時，藉由加入甲醇中止該反應。真空下濃縮該反應混 合物並加入水。利用IN HC1 (約pH 5 )酸化水層並利用乙 酸乙酯（3 X 50 ml )進行萃取，置於Na2S04上乾燥，經過 濾和濃縮後生成產物，0.6402 g(91%) 。MS(ESI) 164 (ΜΗ)'。 *Η NMR ( 400MHz，DMSO - d6 ) (5 9 · 9 0 ( 1 H，s )， 7.79(lH，d，J=8.0Hz) ，7.74(lH，s) ，7.28(1H， d，J 二 8 ·0Ηζ )。 3 — （2—酮基—2，3 -二氫一苯並D惡Π坐—6—基亞甲基） 一戊二酸單甲酯 -421 - 200529835 (417)Before adding n-butyllithium (2.5 M hexane solution, 3.8 ml '2.2 equivalents), order 6-bromo-3H-benzoxazol-2-one (0.9236 g, 4.31 mmol) in anhydrous tetrahydrofuran under nitrogen. (25 ml) and dimethylformamide (3 ml) solution was cooled to -78 ° C. After stirring for 10 minutes at -78 ° C, 24 ml of another butyl lithium (1.4M cyclohexane) was added. Solution, 8 equivalents). The reaction solution was stirred while slowly warming it to -40 ° C. When it reached-40 ° C, the reaction was stopped by adding methanol. The reaction mixture was concentrated under vacuum and water was added The aqueous layer was acidified with IN HC1 (about pH 5) and extracted with ethyl acetate (3 X 50 ml), dried on Na2S04, filtered and concentrated to give the product, 0.6402 g (91%). MS (ESI ) 164 (ΜΗ) '. * Η NMR (400MHz, DMSO-d6) (59.90 (1H, s), 7.79 (lH, d, J = 8.0Hz), 7.74 (lH, s), 7.28 (1H, d, J di 8 · 0Ηζ). 3 — (2-keto-2,3-dihydromonobenzoDoxazole-6-ylmethylene) monomethyl glutarate-421 -200529835 (417)

如前述製備2— （7 —甲基一 1H—吲唑一 5 -基亞甲基 )一琥珀酸 1 一甲酯之方法（1.4 g，90%產率）。MS ( ESI ) 3 0 0 ( Μ + N a )'。 (±) — 3— (2 —酮基一2，3 —二氫一苯並噁唑一6 —基 甲基）一戊二酸單甲酯A method for preparing 2- (7-methyl-1H-indazole-5-ylmethylene) -monosuccinic acid 1-methyl ester as described above (1.4 g, 90% yield). MS (ESI) 300 (M + Na) '. (±) — 3— (2-keto-2,3-dihydro-benzoxazole-6-ylmethyl) monoglutarate

如前述製備（±) — 2— （7—甲基一1H —吲唑一 5 — 基甲基）一琥珀酸 1 —甲酯之方法（1.4 g，99%產率） 。MS ( ESI ) 3 02 ( Μ + Na ) 4。 (±) — 4 一酮基一 2— （酮基一2，3 —二氫一苯並噁唑一 6 —基甲基）—4 — 〔4 — (2 —嗣基—1，4 一 一氯—2 Η — _唑啉一 3 —基）一哌啶一 1 一基〕丁酸甲酯 ΗThe method for preparing (±) -2- (7-methyl-1H-indazol-5-ylmethyl) -succinic acid 1-methyl ester as described above (1.4 g, 99% yield). MS (ESI) 3 02 (M + Na) 4. (±) — 4 monoketo-2 — (keto-2,3-dihydromonobenzoxazole-6-ylmethyl) — 4 — [4 — (2 —fluorenyl-1,4 —1 Chloro-2 hydrazone — _oxazoline-3 —yl) -piperidine-1 1 -yl] methyl butyrate Η

-422 - 200529835 (418) 如前述製備（：t ) 2 — （ 7 —甲基一 1 Η —吲唑一 5 —基 甲甲基）—4一酮基一4一 〔1 ，2 —二氫一 2 —酮基 螺一4 Η — 3 ，1 一苯並D惡嗪一 4，4 —喊Π定基〕一丁酸 甲酯之方法。MS(ESI) 493 (ΜΗ)—。 (土）一 4 —嗣基一 2— (2 —嗣基一2，3 —二氨一苯並口惡 唑—6 —基甲基）一4— 〔2< ，3< —二氫一2^ —酮基螺-422-200529835 (418) Prepared as above (: t) 2-(7 -methyl-1 1 fluorene-indazole-5-methylmethyl)-4-keto-4-[1, 2-dihydro A method of 2-ketospiro-4-pyridine-3,1-benzoDoxazine-4,4-ylidene] monobutyrate. MS (ESI) 493 (ΜΗ). (Earth) 4-Amidino-2— (2-Amidino-2,3-diamino-benzoxazole-6-ylmethyl) —4— [2 <, 3 < —dihydro-2 ^-Ketospiro

—(哌啶一 4，4 / 一喹唑啉）〕一丁酸甲酯 〇— (Piperidine-4,4 / monoquinazoline)] methyl monobutyrate

X ΗΝ ΝΗX ΗΝ ΝΗ

Η 如前述製備（±) 2 — （7 —甲基一 1Η—吲唑一 5 -基Η Prepared as above (±) 2-(7-methyl-1 1-indazole- 5 -yl

甲基）一 4一酮基一 4一 〔厂，2< -二氫一 2，一酮基螺 —〔4Η - 3，1 / —苯並噁嗪—4，4 — 一哌啶基〕—丁酸 甲酯之方法。MS (ESI) 479 (ΜΗ) +。 (±) — 4 一酮基一2 — （2 —酮基一 2，3 —二氫一苯並噁 唑—6 —基甲基）一 4〔2< ，3 / —二氫一 2，一酮基螺— (哌啶一 4，4 > 一 D奎唑啉）〕一丁酸(Methyl) -4-keto-1-4- [plant, 2 < -dihydro-2, -ketospiro- [4Η-3, 1 / -benzoxazine-4,4-monopiperidinyl]- Method of methyl butyrate. MS (ESI) 479 (ΜΗ) +. (±) — 4 monoketo-2 — (2-keto-2,3-dihydro-benzoxazole-6-ylmethyl) — 4 [2 <, 3 / —dihydro-2, 1 Ketospiro — (piperidine-4,4 > -D-quinazoline)] monobutyric acid

如前述製備（土）2 — （ 7 —甲基一 1 Η —吲唑一 5 —基 -423- 200529835 (419) 甲基）一 4 —酮基—4— 〔1 ，2 -二氣—2 -酮基螺 —〔4H — 3，1 '—苯並H惡嗪—4，4 / 一哌U定基〕一丁酸 之方法。MS(ESI) 465(MH) 4。 (土）一 4 —嗣基一2 — ( 2 —酬基一2 ’ 3 — 一·氣一苯並II惡 唑一6—基甲基）一4— 〔4一 （2 —酮基—1，4一二氫一 2 Η —喹唑啉—3 -基）一哌啶一 1 一基〕一丁酸 Η(Ethyl) 2- (7-methyl-1, hydrazone-indazole-5-yl-423-200529835 (419) methyl) -4-keto-4— [1,2,2-digas-2] -Ketospiro- [4H-3,1'-benzoHoxazine-4,4 / monopiperidinyl] monobutyric acid method. MS (ESI) 465 (MH) 4. (Earth) 4 —fluorenyl 2 — (2 —vinyl — 2 ′ 3 — mono-benzo-oxazolyl 6-ylmethyl) — 4 — [4— (2-keto-1 , 4-dihydro-2 fluorene-quinazoline-3-yl) -piperidine-1 1-yl] monobutyrate

如前述製備（±) 2 — （7 —甲基一 1Η —吲唑一 5 —基 甲基）一 4 —酮基一4—〔I，，—二氫—2，—酮基螺 —〔4 Η — 3，1 '—苯並H惡嗪一 4，4 ' 一哌卩定基〕—丁酸 之方法。MS ( ESI ) 479 ( ΜΗ ) +。(±) 2- (7-methyl-1,1-indazole-5-ylmethyl) -4-keto-4- [I ,,-dihydro-2, -ketospiro- [4 Pyrene — 3,1′-benzoHoxazine-4,4′-piperidinyl] -butyric acid. MS (ESI) 479 (ΜΗ) +.

實施例2 5 6 (± ) — 1 — ( 4 —環己基一哌嗪一 1 —基）一2 — ( 2 -酮 基一 2，3 — 一‘氨—苯並D惡D坐一 6 —基甲基）—4 — 〔4 一 （2 —嗣基一 1 ’ 4 一 一·氣一2 Η 一 D奎口坐琳一 3 —基）一咖H定一1 一基〕—丁一 1，4一二酮 -424 - 200529835 (420)Example 2 5 6 (±) — 1 — (4-cyclohexyl-piperazine — 1 —yl) — 2 — (2 -keto —2,3 — —'amino-benzo Dox D — 6 — Methyl group) —4— [4— (2—fluorenyl—1 ′ 4—one · qi—2] —D Kuikouline—3—yl) —caffeine H—1—1—] , 4-dione-424-200529835 (420)

如前述製備（土）一 1 — 〔 1，4 〕聯_ D定一 1 —基 —2 — (7 —甲基一1H — D 引 Π坐—5 —基甲基）一4 —〔1 ’ 2 —二氨一 2 -酬基螺—〔4H— 3，1 —苯並卩惡嗦—4 ，4 /一哌啶基〕一丁 — 1，4一 二酮之方法。LC/MS: tR =1 · 1 0分，629 ( ΜΗ ) +。 實施例2 5 7 (± ) — 1 — 〔 1，4 〕聯丨派D定一1 —基一 2 — ( 2 —酮基 一 2，3—二氫一苯並噁唑—6—基甲基）一 4〔4一（2 —酮 基一 1，4 —二氯一 2H—D奎口坐琳_3 —基）一呢Π定一 1—基 〕—丁一 1，4一 二酮 Η(Earth) -1— [1,4] Co-D is fixed as 1-based—2— (7-methyl-1H—D) — (4-methyl-1) —4— [1 ' 2-Diamino-2-stilbyl spiro-[4H-3, 1-benzopyrazine-4, 4 / -piperidinyl] monobutyl-1, 4-dione. LC / MS: tR = 1.10 points, 629 (ΜΗ) +. Example 2 5 7 (±) — 1 — [1,4] Coordination D 1- 1-2-(2-keto-2, 3-dihydro-benzoxazole-6-ylmethyl Radical) a 4 [4-a (2-keto-1,4-dichloro- 2H-D Kuizuline_3 -yl) a Π a fixed 1-yl]-butan-1,4-dione Η

如前述製備（± ) — 1 — 〔 1，4 /〕聯哌啶一1 / 一基 —2— (7—甲基一1Η —吲唑—5 —基甲基）一 4— 〔1^ ， -425- 200529835 (421) —二氫一 2 / —酮基螺—〔4H— 3，1〃 —苯並噁嗪—4 ，4 /一哌啶基〕—丁一 1，4 —二酮之方法。LC/ MS : tR =1 .08 分，629 ( ΜΗ ) +。 ]H NMR ( 400MHz，CDC13 ) 5 9.89 ( 1H，s) ，8.28 ((±) — 1 — [1,4 /] bipiperidinyl 1 / 1-yl-2 — (7-methyl-1 1 —indazole-5 —ylmethyl) — 4 — [1 ^, -425- 200529835 (421) —dihydro-2 / —ketospiro — [4H — 3,1〃 —benzoxazin-4, 4 / monopiperidinyl] —butan-1,4-dione method. LC / MS: tR = 1.08 minutes, 629 (ΜΗ) +. ] H NMR (400MHz, CDC13) 5 9.89 (1H, s), 8.28 (

lH，d，J=11.2Hz) ，6.90—7.25 (5H，m) ，6.75(1H ，d，J二 8·0Ηζ) ，4·40— 4.79(3H，ni) ，4.35(2H，s )，2.27—3.98 ( 19H，m) ，1·46— 2.10(9H，m)，lH, d, J = 11.2Hz), 6.90-7.25 (5H, m), 6.75 (1H, d, J = 8 · 0Ηζ), 4.40-4.79 (3H, ni), 4.35 (2H, s), 2.27—3.98 (19H, m), 1.46— 2.10 (9H, m),

1.36(lH，m) ，1.08(lH，m) ，0.12(lH，m)。 實施例2 5 8 (± ) — 1 — 〔 1，4 /〕聯哌啶一厂一基一2 - ( 2 —酮基 —2，3 —二氫一苯並噁唑一 6—基甲基）一4— 〔2 / ，3〆 一二氫一 2 〃 一酮基螺一（哌啶一 4，4 / —喹唑啉）〕— 丁一 1，4 —二酮1.36 (lH, m), 1.08 (lH, m), 0.12 (lH, m). Example 2 5 8 (±) — 1 — [1,4 /] Bipiperidine No. 1 Plant One Base One 2-(2-keto-2,3-dihydro-benzoxazole 6-ylmethyl ) —4— [2 /, 3〆-dihydro-1, 2〃-ketospiro-1 (piperidine-4, 4 / —quinazoline)] — butan-1, 4-dione

如前述製備（± ) — 1 一 〔 1，4 >〕聯哌啶一 1 / 一基 —2— (7 —甲基一1H —吲唑一5 —基甲基）一4— [ 1 "， 2 / -二氫一2 ——酮基螺—〔4H — 3，1 > —苯並噁嗪—4 ，4 / —哌啶基〕一丁 — 1，4 —二酮之方法。LC/ MS : tR = 1.02 分，615 (ΜΗ) -426 - 200529835 (422) 實施例2 5 9 (±) — 1— (4 —環己基一暖嗪一1—基）一 2— （2 —嗣 基一2，3—二一苯並噁唑—6—基甲基）一 4—〔2< ，3' 一二氫一 2 / —酮基螺一（哌啶一 4，4 / 一喹唑啉）〕一 丁 一 1，4 一二酮Prepared as above (±) — 1- [1,4 >] piperidine-1 / 1-yl-2 — (7-methyl-1H—indazole-5-ylmethyl) —4— [1 ", 2 / -dihydro-2-ketospiro- [4H-3,1 > -benzoxazine-4,4 / -piperidinyl] monobutyl-1,4-dione method. LC / MS: tR = 1.02 points, 615 (ΜΗ) -426-200529835 (422) Example 2 5 9 (±) — 1 — (4 —cyclohexyl-thermazine — 1 —yl) — 2 — (2 — Fluorenyl-2,3-di-benzoxazole-6-ylmethyl) -4- [2 <, 3'-dihydro-2 / 2-ketospiro- (piperidine-4,4 / monoquine Oxazoline)] monobutane-1,4-dione

〇 U HN NH〇 U HN NH

如前述製備（± ) — 1 一 〔 1，4 /〕聯哌啶一 1 / 一基 一 2— (7—甲基一1H —吲唑一5 —基甲基）一4— 〔1^ ， 2 — _•氧一2 —嗣基螺—〔4H— 3，1 —苯並螺嗦一 4(±) — 1- [1,4 /] bipiperidine- 1 / 1-yl-2— (7-methyl-1H—indazole-5-ylmethyl) —4— [1 ^, 2 — _ • Oxygen 2 —Pyrospiro— [4H— 3,1 —Benospiropyrene 4

，4 / 一哌啶基〕一丁一 1，4 一 二酮之方法。LC/ MS : tR =1 .04 分，61 5 ( ΜΗ ) +。 實施例2 6 0 (土） 一 4 — (2 —嗣基一1，4 — 一氨一2Η — 口 奎 口坐琳一3 — 基）一暖Π定一 1 一殘酸〔2 -（ 4 一環己基一哌嗪一1 一基） 一 1— (7 —甲基一1Η —吲唑一5—基甲基）一2 —酮基一 乙基〕一醯胺 -427- 200529835 (423), 4 / -piperidinyl] -butane-1,4-dione method. LC / MS: tR = 1.04 minutes, 61 5 (ΜΗ) +. Example 2 6 0 (soil)-4-(2-fluorenyl-1, 4-amine-2 hydrazine-koukui zoline-3-yl)-warm hydrazine-1-residual acid [2-(4 1-cyclohexyl-piperazine-1 1-yl) 1- (7-methyl-1 1-indazole-5-ylmethyl) -2 2-ketomonoethyl] -amidamine-427- 200529835 (423)

如前述實施例16之製備方法。 W-NMR ( CD3OD，5 00MHz ) 5 0.81 ( 1H，m) ，0.89 (lH，m) ，1.02(lH，m) ，1.1— 2.0(12H，m)， 2.23 (H，d) ，2.47(lH，d) ，2.61(3H，s) ，2.90( 4H，t) ，3.08(4H，m) ，3.2-3.5(4H，m) ，3.82( lH，m) ，4.14(2H，d) ，4.29(2H，s) ，4.40(H，t )，6.80(lH，d) ，6.95(H，t) ，7.12(3H，m)， 7.47( 1H，s) ，8.01 (H，s )。質譜·· 627·47(ΜΗ) + 實施例2 6 1 (±) — 4— (2 —酮基一1，4 —二氫一2H — 口奎唑啉一3 — 基）一哌啶—1 —羧酸 〔2 -〔 4 — ( 4 一氟—苯基）—哌 嗪一 1—基〕一 1 一 （7 —甲基一1Η —吲唑一5 —基甲基） 一 2—酮基—乙基〕一醯胺 -428- 200529835 (424)The preparation method is as described in Example 16. W-NMR (CD3OD, 500 MHz) 5 0.81 (1H, m), 0.89 (lH, m), 1.02 (lH, m), 1.1-2.0 (12H, m), 2.23 (H, d), 2.47 (lH , D), 2.61 (3H, s), 2.90 (4H, t), 3.08 (4H, m), 3.2-3.5 (4H, m), 3.82 (lH, m), 4.14 (2H, d), 4.29 ( 2H, s), 4.40 (H, t), 6.80 (lH, d), 6.95 (H, t), 7.12 (3H, m), 7.47 (1H, s), 8.01 (H, s). Mass spectrometry · 627 · 47 (ΜΗ) + Example 2 6 1 (±) — 4— (2-keto-1,4-dihydro-1 2H — quinazolin-3 —yl) -piperidine-1 —Carboxylic acid [2-[4- (4-fluoro-phenyl) -piperazine-1-yl]-1- (7-methyl-1 1-indazole-5-ylmethyl) 2-keto --Ethyl] monoamine-428- 200529835 (424)

如前述實施例16之製備方法° LC/MS: tR=2·43分 ，62 1.42 ( ΜΗ ) +。LC / MS: tR = 2.43 minutes, 62 1.42 (ΜΗ) +.

實施例262 (±) — 3— (7 —甲基一1H —吲唑一5 —基）一2— { 〔4 —(2 —酮基一1，4一二氫—2H-喹唑啉—3 —基）—哌 啶一 1 一羰基〕一胺基丨一丙酸特丁酯Example 262 (±) — 3 — (7 —methyl-1H —indazole-5 —yl) — 2 — {[4 — (2 —keto-1,4-dihydro-2H-quinazoline — 3 -yl) -piperidine-1 monocarbonyl] -amino group-tert-butyl propionate

N-NHN-NH

基）_2- { 〔4— (2 —酮基—1，4 —二氫一 2H —喹唑- 3 —基）一哌啶一 1 —羰基〕—胺基} 一丙酸（5 0 mg， 0.1 05毫莫耳）和二環己基羰二醯亞胺（25 mg，0· 12毫莫 耳）之二甲基甲醯胺溶液達30分鐘，隨後加入五氟酚（26 mg，1 · 3毫莫耳）。室溫下隔夜持續攪拌，隨後除去溶劑 ’並於高度真空下乾燥殘餘物達4小時。該五氟苯酯粗產 物未經進一步之純化而直接用於下一個步驟中。將1 .4 Μ另 -429- 200529835 (425) 丁基鋰之環己烷溶液（1 0當量）於-7 8 °C和氮氣下加入特 丁醇（1 〇當量）之四氫呋喃溶液中。經1 0至1 5分鐘後，加 入五氟酚酯（1當量）之四氫呋喃溶液。室溫下隔夜攪拌 該反應混合物。真空下除去溶劑，並藉由製備性HPLC純 化殘餘物以生成所欲之化合物。 JH-NMR ( CD3〇D ) 5 1.40 ( s，9H) ，1.56 ( m，4H) ，2.54 ( s，3H ) ，2.85 ( m，2H ) ，3·05 ( m，1H )， 3.19(m，lH) ，4.14(m，4H) ，4.44( m，2H) ^ 6.76 (d，J=7.69Hz，1H) ，6.93(t，J二 7·5Ηζ，1H) » 7.10 (m，3H) ，7.14(s，lH) ，7.97(s，lH)。 LC/MS: tR=2.19分，533·36(ΜΗ) +。 實施例263 (土）一 3 — （7 — 甲基一1H — D引 口坐一 5 —基）一2— { 〔4 一 （2 —酮基—1，4一二氫—2H — D奎唑啉一3_基）一哌 啶一 1 一羰基〕—胺基} 一丙酸1 一甲基環己酯Yl) _2- {[4- (2-keto-1,4-dihydro- 2H-quinazol-3-yl) -piperidine-1-carbonyl] -amino} monopropionic acid (50 mg, 0.1 05 mmol) and dimethylformamide solution of dicyclohexylcarbonyldiimine (25 mg, 0.12 mmol) for 30 minutes, followed by pentafluorophenol (26 mg, 1.3 Mol). Stirring was continued overnight at room temperature, after which the solvent was removed and the residue was dried under high vacuum for 4 hours. This crude pentafluorophenyl ester was used directly in the next step without further purification. A 1.4 M solution of -429- 200529835 (425) butyllithium in cyclohexane (10 equivalents) was added to a tetrahydrofuran solution of t-butanol (10 equivalents) at -78 ° C under nitrogen. After 10 to 15 minutes, add a solution of pentafluorophenol ester (1 equivalent) in tetrahydrofuran. The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was purified by preparative HPLC to yield the desired compound. JH-NMR (CD3OD) 5 1.40 (s, 9H), 1.56 (m, 4H), 2.54 (s, 3H), 2.85 (m, 2H), 3.05 (m, 1H), 3.19 (m, lH), 4.14 (m, 4H), 4.44 (m, 2H) ^ 6.76 (d, J = 7.69Hz, 1H), 6.93 (t, J = 7.5Ηζ, 1H) »7.10 (m, 3H), 7.14 (s, lH), 7.97 (s, lH). LC / MS: tR = 2.19 points, 533.36 (ΜΗ) +. Example 263 (Earth)-3-(7-Methyl 1H-D Introducer-5-Group)-2-{[4 1 (2-Keto-1, 4-Dihydro-2H-D) Oxazoline- 3-yl) -piperidine- 1-carbonyl] -amino} monopropionate 1-methylcyclohexyl ester

如前述製備（±) — 3 — （7 —甲基一 1H—吲唑一5 — 基）一 2— { 〔4— (2 —酮基—1，4一二氫—2H — D 奎 D坐啉 —3 —基）一哌啶一 1 一羰基〕一胺基} 一丙酸特丁酯之方 法。LC/MS: tR=2.47分，574.39 (MH) +。 -430- 200529835 (426) 實施例2 6 4 (土） — 3〜（7 —甲基一1H —吲唑一5 —基）一2〜 —(2 —酮基—^彳―二氫—2H — D奎唑啉—3 —基） 陡_1 一羰基〕—胺基}—丙酸1 一氮雜一雙環〔2.2.2 辛_ 3 -酯(±) — 3 — (7-methyl-1H—indazol-5 —yl) — 2 — {[4— (2 —keto-1,4-dihydro-2H —D) Phenolin-3-yl) -piperidine-1 monocarbonyl] -amino} monobutyl propionate method. LC / MS: tR = 2.47 points, 574.39 (MH) +. -430- 200529835 (426) Example 2 6 4 (Earth)-3 ~ (7-methyl-1H-indazole-5-yl) -2 ~-(2-keto-^-dihydro-2H — D quinazoline-3 —yl] steep_1 monocarbonyl] —amino} —propanoic acid 1 monoazabicyclo [2.2.2 octane 3-ester

將氮雜一雙環〔222〕辛一 3_基醇（〇·525毫莫耳， 5當量）加入至（土）— 3_ (7 —甲基—iH —吲唑〜基 )—2 一丨4 一 （ 2 —酮基一 1，4 —二氫—2Ή —喹唑啉—3 一基）〜哌啶一 1 一羰基〕一胺基} 一丙酸（50 mg， 0·105毫莫耳）、EDCI(100 mg)及4 —二甲基胺基吡啶（ 0 · 2當量）之二甲基甲醯胺溶液中。室溫下隔夜攪拌該混 合物。真空下除去溶劑並令殘餘物溶解於乙酸乙酯中，經 鹽水冲洗，置於MgS04上乾燥且經製備性HPLC純化後， 生成所欲之化合物。 LC/ MS : tR= 1.62分，5 86.4 1 ( MH )丨。 實施例265 (±) — 3 — （7 -甲基一1H —吲唑一5 —基）一2— { [ 4 -431 - 200529835 (427) 一 (2 一嗣基一 1，4 — 一氣—2 Η 一喧卩坐琳—3 -基）一呢 Π定一 1 —羰基〕一胺基} 一丙酸D定一 4 一醋Add aza-bicyclo [222] octyl-3-yl alcohol (0.525 mmol, 5 eq) to (Earth) — 3 — (7 —methyl — iH — indazole ~ yl) — 2 — 4 Mono (2-keto-1,4-dihydro-2Ή-quinazoline-3 mono) ~ piperidine-1 monocarbonyl] monoamino} monopropionic acid (50 mg, 0.105 mmol) EDCI (100 mg) and 4-dimethylaminopyridine (0.2 equivalents) in dimethylformamide solution. The mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate, washed with brine, dried over MgS04 and purified by preparative HPLC to yield the desired compound. LC / MS: tR = 1.62 minutes, 5 86.4 1 (MH). Example 265 (±) — 3 — (7-methyl-1H —indazole-5 —yl) — 2 — {[4 -431-200529835 (427) 1 (2 amidino-1,4 — one gas — 2 Η 卩 琳 琳 琳 — 3-yl) 呢 定 一 1-carbonyl] monoamine} monopropionate D 定 4 vinegar

如前述製備（±) _3— (7 —甲基一1Η—吲唑一5 — 基)—2 — { 〔4 — (2 —酬基一1，4 — —•氯一2 Η — 口奎 〇坐琳 一 3 —基）一哌啶一 1 一羰基〕一胺基丨一丙酸 1 一氮雜 —雙環〔2.2.2〕辛—3 —酯之方法。LC/MS: tR=1.58 分 ，5 60.3 7 ( MH ) " ° 實施例266 (土） 一 3 — ( 7 —甲基一1 Η — 口 引口坐 一 5 —基）一 2 — { 〔4 —(2 —酮基一1，4 —二氫一2Η — D奎唑啉一 3 —基）一哌 啶一 1 一羰基〕一胺基丨一丙醯氧基）一哌啶一 1 一羧酸特 丁酯(±) _3— (7-methyl-1,1-indazole-5—yl) —2 — {[4 — (2 —amino-1,4 — — • chloro-1, 2 — — quinone) Zirin- 3 -yl) -piperidine- 1-carbonyl] -amino group- 1-propionic acid 1-aza-bicyclo [2.2.2] octane-3 -ester method. LC / MS: tR = 1.58 minutes, 5 60.3 7 (MH) " ° Example 266 (soil)-3-(7 -methyl-1 1 Η-mouth inlet sitting 5-base)-2 — {〔[ 4- (2-keto-1,4-dihydro-2H-D-quinazoline-3-yl) -piperidine-1 1-carbonyl] -amino group 丨 -propionyloxy) -piperidine-1 1- Tert-butyl carboxylate

如前述製備（±) — 3— (7 -甲基一 1Η—吲唑一 5 — 基）一2 — { 〔4 — (2 —嗣基一1’ 4 — 一·氣一2 Η — 口奎 口坐琳 一 3 —基）一哌啶一 1 一羰基〕—胺基丨一丙酸 1 一氮雜 雙環〔2.2.2〕辛—3 -酯之方法。LC / MS : tR= 2.3 8分， 200529835 (428) 660.42 ( ΜΗ ) 實施例2 6 7 (土） 一 3— (7 —甲基一1H — D引唑一5 —基）一2— { 〔4 一 (2 —酬基一1 ’ 4 一 —·氣一2 Η — D奎口坐琳一3 —基）一呢 啶一1一羰基〕一胺基}一丙酸3，4，5，6—四氫—211-〔1，4 /〕聯哌D定一 4 一酯 Η(±) — 3— (7-methyl-1′-indazole-5′-yl)-2 — {〔4 — (2 —fluorenyl-1 ′ 4—one · qi-1 2 Η—Kou Kui Izoline 3 -yl) -piperidine-1 -carbonyl]-amino group-monopropionate 1-azabicyclo [2.2.2] octane 3-ester method. LC / MS: tR = 2.3 8 points, 200529835 (428) 660.42 (ΜΗ) Example 2 6 7 (Earth)-3-(7 -methyl-1H-D-azole-5-yl)-2-{〔 4 1 (2-phenyl group 1 '4--qi-2 Η — D kuizuline-3-group) 1 oxidine-1-carbonyl]-amino group} monopropionic acid 3, 4, 5, 6-tetrahydro-211- [1,4 /] piperidine D-di-4 monoester

如前述製備（±) — 3 — （7 —甲基一 1Η —吲唑一 5 — 基）一2— { 〔4— (2—酮基一1，4一二氫一2Η —喹唑啉(±) — 3 — (7-methyl-1, 1-indazole-1, 5-yl), 2— {[4— (2-keto-1,4-dihydro-2,2—quinazoline)

一 3 —基）一哌啶一 1 一羰基〕一胺基丨—丙酸 1 一氮雜 雙環〔2.2.2〕辛—3 —酯之方法。LC/MS: tR=1.67 分， 63 7.43 ( MH ) + 。 實施例2 6 8 (±) — 3— (7 -甲基一1H — D 引唑一5 —基）一2— { 〔4 —(2 —酮基一1，4 —二氫一2H —哇唑啉一 3 —基）一哌 啶一 1 一羰基〕一胺基} 一丙酸 1 一二乙基胺基一1 一甲 基一乙酯 -433 - 200529835 (429)A 3-yl) -piperidine- 1-carbonyl] -amino group --- propionic acid 1-azabicyclo [2.2.2] octane-3-ester method. LC / MS: tR = 1.67 minutes, 63 7.43 (MH) +. Example 2 6 8 (±) — 3— (7-methyl-1H—D azole—5-yl) —2— {[4 — (2 —keto-1,4-dihydro-2H —wow Oxazoline 3-yl) -piperidine-1 monocarbonyl] monoamino} monopropionic acid 1 diethylamino-1 monomethyl monoethyl-433-200529835 (429)

八0 如前述製備（±) — 3— (7_甲基一 1H—吲唑一5 — 基）一 2— { 〔4一（2 —酮基—1，4一 二氫—2H — 口奎唑啉 —3 -基啶—1 一羰基〕一胺基丨一丙酸 1 一氮雜 雙環〔2.2.2〕辛—3 —酯之方法。LC/MS: tR=1.66 分， 5 90.44 ( MH ) +。 實施例269 (±) — 3— (7 —甲基一1H — D引唑一5-基）一2— { 〔4 —(2 —酮基一1，4一二氫一2H — D奎唑啉一3 —基）一哌 啶一 1 一羰基〕—胺基} 一丙酸 1，1 一二甲基—2 —苯基 一乙酯80 Prepared as above (±) — 3— (7_methyl-1H—indazol-5 —yl) — 2 — {[4 一 (2-keto-1,4-dihydro-2H — Kou Kui Method of oxazoline-3 -pyridine-1 monocarbonyl] monoamine 丨 monopropionate 1 azabicyclo [2.2.2] octane-3-ester. LC / MS: tR = 1.66 points, 5 90.44 (MH ) +. Example 269 (±) — 3 — (7 —methyl-1H — D-azole-5-yl) — 2 — {[4 — (2 —keto-1,4-dihydro-2H — D quinazoline- 3-yl) -piperidine- 1-carbonyl] -amino} monopropionate 1,1-dimethyl-2 -phenyl monoethyl ester

如前述製備（±) — 3 — （7—甲基一1H—吲唑一5 — 基）一 2— { 〔4— (2 —酮基—1，4一 二氫—2H—D奎唑啉 一 3 -基）一哌啶一 1 一羰基〕—胺基} 一丙酸特丁酯之方 法。LC/MS: tR=2.52 分，609.46 (MH)(。 實施例2 7 0 -434- 200529835 (430) (±) — 3— (7 —甲基一1H — D 引唑一5 —基）一2— { 〔4 —(2 —酮基一1，4 —二氫一2H — D奎唑啉一 3 —基）一哌 啶一 1 一羰基〕一胺基} 一丙酸 1，1 一二甲基一 3 -苯基 -丙酯(±) — 3 — (7-methyl-1H-indazol-5-yl)-2— {[4— (2-keto-1,4-dihydro-2H-D quinazoline -3-yl) -piperidine- 1-carbonyl] -amino} -t-propionate. LC / MS: tR = 2.52 minutes, 609.46 (MH) (. Example 2 7 0 -434- 200529835 (430) (±) — 3 — (7 —methyl-1H — D indazole — 5-yl) — 2— {[4- (2-keto-1,4-dihydro-2H—D quinazoline-3—yl) -piperidine-1 1-carbonyl] -1amino} 1, propionic acid 1,1,2 Methyl-3-phenyl-propyl ester

如前述製備（±) — 3- (7 —甲基一 1H—吲唑一5 — 基）一 2— { 〔4一 （2 —酮基一 1，4一 二氫一 2H — ti奎唑啉 一 3 —基）—哌啶一 1 一羰基〕一胺基}—丙酸特丁酯之方 法。LC/MS: tR=2.61 分，623.48 (MH) +。 實施例271 (±) — 3- (7 —甲基一1H — D引唑一5 —基）一2— { 〔4 一 （2 —酮基一1，4 —二氫一2 Η — D奎唑啉一3 —基）一哌 D定一 1 一鑛基〕一胺基}—丙酸乙酯(±) — 3- (7-methyl-1H—indazol-5-yl) —2 — {[4-((2-keto-1,4-dihydro-2H—tiquinazoline) A 3-yl) -piperidine-1 monocarbonyl] -amino} -tert-butyl propionate method. LC / MS: tR = 2.61 points, 623.48 (MH) +. Example 271 (±) — 3- (7-methyl-1H — D-azole-5-yl) — 2 — {[4 1 (2-keto-1,4-dihydro-2 hydrazone — D-quinone Oxazoline- 3 -yl) -piperidine D a-1 -mineral] monoamine}-ethyl propionate

如則述製備（ί) 一 3— (7 —甲基一 1Η—口引口坐一 5 — 基）一2— { 〔4一 （2 —酮基一 1，4 —二氫一2Η — D奎唑啉 —3 -基）一哌啶一 1 -羰基〕一胺基丨一丙酸特丁酯之方 -435- 200529835 (431) 法。LC/MS: tR = 1.98 分，505.32 (ΜΗ) 實施例272 (土） 一1— (7 —甲基一1Η — 口引唑一 5 —基）一2— 〔1 — 毗啶一4 一甲基〕一2 —酮基乙基〕一 —二氫一 2 一 —酮基螺—〔哌啶一 4，4 > — ( 1 Η ) -喹唑啉〕—1 -羧醯胺As described in the preparation (ί) a 3— (7—methyl—1Η—mouth mouth sits a 5 — base) — 2 — {[4— (2 —keto—1,4 —dihydro—2Η — D Quinazoline-3-yl) -piperidine-1-carbonyl] -amino group-tert-butyl propionate-435-200529835 (431) method. LC / MS: tR = 1.98 minutes, 505.32 (ΜΗ) Example 272 (Earth)-1-(7 -methyl-1 Η-oxazole-5 -yl)-2-[1-pyrimidine-4-1 []] 2-ketoethyl] 1-dihydro-2 2-ketospiro-[piperidine-4, 4 > — (1 Η) -quinazoline]-1 -carboxamide

如前述製備實施例16之方法。LC/MS: tR=1.49分 ，533.12(MH) f。The method of Example 16 was prepared as previously described. LC / MS: tR = 1.49 minutes, 533.12 (MH) f.

實施例273 (±) — 1- (7 —甲基一1H — D 引唑一5 —基）一2— 〔1 — 吡啶一 4 —基—哌嗪基〕一 2 —酮基乙基〕—2 /，3 / -二 氫一 2 / —酮基螺一〔哌啶一 4，4 / 一 （ 1 Η ) — D奎唑啉〕 一 1 一羧醯胺 -436- 200529835 (432)Example 273 (±) — 1- (7-methyl-1H—D indazole—5-yl) —2- [1-pyridine—4-yl—piperazinyl] —2-ketoethyl] — 2 /, 3 /-dihydro-1 / 2-ketospiro [piperidine-4, 4/1 (1 Η) — D quinazoline]-1-Carboxamide -436- 200529835 (432)

如前述製備實施例16之方法。LC/MS: tR=1.56分 ，60 8. 1 8 ( ΜΗ ) + 。 實施例274 (±) — 1— (7 —甲基一1Η — 口引唑一5 —基）一2— 〔2 — —^甲基胺基一乙基一乙基氛基甲釀基一 2 —酮[基乙基〕一 2' ，3/ —二氫—2> —酮基螺—〔哌啶一 4，4/一 （1Η )一 D奎唑啉〕一 1 一羧醯胺The method of Example 16 was prepared as previously described. LC / MS: tR = 1.56 minutes, 60 8. 1 8 (ΜΗ) +. Example 274 (±) — 1 — (7 —methyl-1, 1 — — oxazole-5 —yl) — 2 — [2 — — ^ methylamino, ethyl, ethyl, ethyl, methyl, 2 —Keto [ylethyl] -2 ′, 3 / —dihydro-2> —ketospiro— [piperidine-4,4 / -1 (1Η) -D-quinazoline] -1carboxamidine

如前述製備實施例16之方法。LC / MS : tR= 1.5 8分 ，5 1 6 · 2 0 ( Μ Η ) +。The method of Example 16 was prepared as previously described. LC / MS: tR = 1.5 8 minutes, 5 1 6 · 2 0 (ΜΗ) +.

實施例275 (±) — 1— (7 —甲基一1H — D 引唑一5 —基）一2— 〔1 一 口比D定一4 一基一哌嗪基〕—2 —嗣基乙基〕一 1 ，2 — 一 -437- 200529835 (433) 氫一2 / —酮基螺一 〔4 Η — 3 > ，1 —苯並噁嗪一 4，4〆一Example 275 (±) — 1— (7-methyl-1H—D indazole—5-yl) —2— [1—one ratio than D—4—one—piperazinyl] —2—fluorenylethyl 〕 -1,2-a-437-200529835 (433) hydrogen-2 / -ketospiro-1 [4 Η — 3 >, 1 -benzoxazine-1,4,4〆-1

如前述製備實施例16之方法。LC/MS: tR=1.56分 ，609· 1 4 ( MH ) +。 哌啶〕一 1 一羧醯胺 實施例2 7 6 (±) — 1— (7 —甲基一1H — D 引唑一5 —基）一2— 〔1 — 吡啶一 2 —基—哌嗪基〕—2 -酮基乙基〕—1 /，2 / —二 氯一2 -酮I基螺一〔4H— 3 ’ 1—苯並卩惡嗦一 4 ’4 一 哌D定〕一 1 一竣醯胺The method of Example 16 was prepared as previously described. LC / MS: tR = 1.56 minutes, 60 · 14 (MH) +. Piperidine]-1-carboxamide Example 2 7 6 (±) — 1— (7-methyl-1H — D Indazole-5 —yl) — 2 — [1 —pyridine — 2 —yl —piperazine Yl] -2 -ketoethyl]-1 /, 2 / -dichloro-2 -keto I ylspiro-[4H-3 '1-benzopyrazine-4' 4-piperidine]-1 Diamidine

如前述製備實施例16之方法。LC/ MS : tR = 1.5 7分 ，609·17(ΜΗ)斗。 -438- 200529835 (434) 實施例2 7 7 (R) — 4— (2 —酮基一 1，4 一二氫一2H — D奎唑啉一3 — 基）一哌啶—1 d —羧酸〔2 -〔 1，4 /〕聯哌啶一厂一基 一 1— (7 —甲基一1H — D引唑一5 —基甲基）一2 —酮基一 乙基〕醯胺The method of Example 16 was prepared as previously described. LC / MS: tR = 1.5 7 minutes, 609 · 17 (ΜΗ) bucket. -438- 200529835 (434) Example 2 7 7 (R) — 4— (2-keto-1,4-dihydro-2H—D quinazoline-3—yl) -piperidine-1 d-carboxy Acid [2-[1,4 /] bipiperidine one plant one base one 1- (7-methyl-1H-D-indazole-5-ylmethyl) one 2-ketomonoethyl] fluorenamine

如前述製備實施例16之方法。 ]H-NMR ( CD3〇D » 5 00MHz) 5 -0.27 ( 1H，m) > 0.75 (lH，m) ，1·1— 2.0(12H，m) ，2.10(2H，m) ，2.4 -2.5(3H，m) ，2.57(3H，s) ，2.68(2H，m) » 2.92 (4H，m) ，3.10(4H，m) ，3.9-5.1 (4H，數 m)， 6.82(lH，d) ，6.96(lH，t) ，7.18(3H，m) ^ 7.50 (1 H，s) ，8.05 ( 1 H，s)。 LC/MS : tR 二 1.68 分，627.42 ( ΜΗ) +。 實施例2 7 8 (±) — 1 — （7 —甲基一 1H —吲唑一5 —基甲基）一2—〔 1，4 一聯哌啶〕一 1 —基一 2 —酮基乙基〕一2 /，3 / —二 氣一 2 —酬基螺一〔喊D定一 4 ’ 4 一 （ 1 Η ) — D奎哇琳〕 一 1 一羧醯胺 -439- 200529835 (435)The method of Example 16 was prepared as previously described. ] H-NMR (CD3OD »5 00MHz) 5 -0.27 (1H, m) > 0.75 (lH, m), 1.1 · 2.0 (12H, m), 2.10 (2H, m), 2.4 -2.5 (3H, m), 2.57 (3H, s), 2.68 (2H, m) »2.92 (4H, m), 3.10 (4H, m), 3.9-5.1 (4H, several m), 6.82 (lH, d) , 6.96 (lH, t), 7.18 (3H, m) ^ 7.50 (1H, s), 8.05 (1H, s). LC / MS: tR 2.68 points, 627.42 (ΜΗ) +. Example 2 7 8 (±) — 1 — (7-methyl-1H—indazol-5-ylmethyl) —2— [1,4-dipiperidine] —1—yl-2—ketoethyl Base]-2 /, 3 /-Digas 1-2-Chiral Spiro 1 [D D 1-4 '4 1 (1 Η)-D quinavaline]-1-Carboxamide -439- 200529835 (435)

如前述製備實施例16之方法。LC/MS: tR=1.63分 ，6 1 3.36 ( ΜΗ ) +。 本發明能想像且能依據本文敘述或熟習此技藝之人士 習知之方法製備之其他化合物包括下述之預言性實施例： 4— (2—酮基—1,4 —二氫一 2Η〜喹唑啉一 3一基）一_ D疋一 1 一殘酸〔2 —〔 1，4 /〕聯呃 D定一 1 - _ 基一 1 一（ 7 —溴一 1H—吲唑一 5 —基甲基）〜2一酮基一乙基〕一醯 胺The method of Example 16 was prepared as previously described. LC / MS: tR = 1.63 minutes, 6 1 3.36 (ΜΗ) +. Other compounds conceivable by the present invention and prepared according to methods known to those skilled in the art described or familiar with this art include the following prophetic examples: 4- (2-keto-1,4-dihydro- 2Η ~ quinazole Porphyrin- 3 -yl)-_ D 疋-1-Residual acid [2 — [1, 4 /] Di er D-1-_ 1-1-(7 -bromo-1H-indazole-5-dimethyl) Group) ~ 2 keto monoethyl] monomethylamine

4 — ( 2 —酮基一 1 , 4 —二氫一 2H〜[I奎唑啉一 3 —基）一哌 η疋一 1 一殘酸〔2-酮基一1一（2〜_基一2，3-二氫一苯 並嚼哗—6 —基甲基）一 2 - （ 4〜吡陡一 4 一基一 I派嗪一 1 一基）一乙基〕一醯胺 -440- 200529835 (436)4- (2-keto-1, 4-dihydro-2H ~ [I quinazoline-3-yl) -piper η 疋 -1 1 residual acid [2-keto-1-1 (2 ~ _yl-1 2,3-dihydro-benzobenzoyl-6-ylmethyl)-2-(4 ~ pyridine-4-yl-I-pyrazine-1-yl) -ethyl] -pyridamine-440- 200529835 (436)

4 一 ( 2 一嗣基一 1，4 — 一氯一2 Η — D奎口坐琳一 3 —基）一喊 啶—1—羧酸〔2-酮基—1 一（2 —酮基一 2，3 —二氫—苯 並噁唑—6 —基甲基）—2 -哌啶—1 —基一乙基〕一醯胺 〇4 a (2 amidino-1,4 — a chloro-2 2 Η — D kuizuline a 3 -yl) a oxidine — 1 —carboxylic acid [2-keto-1 — (2-keto-1 2,3-dihydro-benzoxazole-6-ylmethyl) -2-piperidine-1-yl-ethyl] monofluorenamine.

4 一 （2 -酮基一1，4一二氫一2Η — □奎唑啉一 3 —基）—哌 啶一1—羧酸〔2—（4一甲基一哌—1 一基）一2 —酮基一1 —(2—酮基—2，3 —二氫—苯並噁唑—6 —基甲基）—乙 基〕一醯胺 〇4-((2-keto-1,4-dihydro-2) — □ -quinazoline-3-yl) -piperidine-1-carboxylic acid [2- (4-methyl-piper-1-yl) -1 2-keto-1-(2-keto-2,3-dihydro-benzoxazole-6-ylmethyl) -ethyl] monomethylamine.

4 一 （2 —酮基一 1，4一二氫一 2Η — D奎唑啉一3 —基）一哌 -441 - 200529835 (437) 啶一 1 一羧酸〔 一甲基一 2 —酮 —2 —酮基一乙 2 — 〔 1，4 〕聯丨IR D定一 1 —基—1 — ( 4 基一 2，3 —二氫一苯並噁唑一 6 —基甲基） 基〕一醯胺4 mono (2-keto-1,4-dihydro-2Η-D quinazoline-3-yl) -piperyl-441-200529835 (437) pyridine-1 monocarboxylic acid [monomethyl-2-ketone — 2 —keto-ethyl 2 — [1,4] -IR D 1 — 1 — 1 — (4 2 — 3,2 —dihydromonobenzoxazole 6 —ylmethyl) 1] Amidine

4— ( 2—酮基-啶一 1 一羧酸〔 並噁唑一 6 -基 〕一醯胺 -1，4 —二氫一2 Η — ti奎唑啉一3 —基）一哌 1 — (4 —甲基—2 —嗣基一 2，3 — 一《氨—苯 甲基）一2-酮基一哌啶一 1 一基）一乙基4- (2-keto-pyridinyl-1 monocarboxylic acid [oxazolyl-6-yl] monofluorenamine-1,4-dihydro-2 hydrazone — tiquinazoline 3- 3-yl) -piperidine 1 — (4-methyl-2, fluorenyl-2, 3—-ammonia-benzyl)-2-keto-piperidine- 1-yl) -ethyl

4- ( 2—酮基 啶一 1 一羧酸〔 噁唑一 6 —基甲 -醯胺 -1，4 —二氫一2 Η — D奎唑啉一3 —基）一哌 1 一（4 一氯—2 —酮基一 2，3 —二氫一苯並 基）一 2 -酮基一 2 —哌啶一 1 一基—乙基〕 -442 - 200529835 (438) ο4- (2-ketopyridine-1 monocarboxylic acid [oxazole-6-ylmethyl-fluorenamine-1,4-dihydro-2 hydrazone-D quinazoline-3-yl) -piperidine 1- (4 Monochloro-2-keto-2,3-dihydromonobenzoyl)-2-keto-2-piperidine-1 mono-ethyl] -442-200529835 (438) ο

4— (2—酮基一1，4 —二氫—2Η — D奎唑啉一3 —基）一哌 啶一1—羧酸〔1—二甲基氨基甲醯基一 2— (4 —甲基一 2 —酮基一 2，3 -二氫一苯並噁唑—6—基）一乙基〕—醯 胺4- (2-keto-1,4-dihydro-2—-D quinazoline-3-yl) -piperidine-1-carboxylic acid [1-dimethylaminomethylamido-2— (4 — Methyl 2-keto-2,3-dihydro-benzoxazole-6-yl) monoethyl] -amidamine

4— (2 —酮基一1，4一二氫一2H — D奎唑啉一3 —基）一哌 Π定—1—竣酸〔2(4 —氯—2 —醒基一 2，3 — 一氨一苯並H惡 唑一 6—基）一 1 一二甲基氨基甲醯基一乙基〕一醯胺4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) piperidine-1-dicarboxylic acid [2 (4-chloro-2 -pentyl-2,3 — Monoamino-benzoHoxazole-6-yl)-1-dimethylaminocarbamoyl-ethyl] -pyridamine

4— (2 —酮基—1，4一二氫—2H—D奎唑啉一 3 —基）一I根 -443- 200529835 (439) 啶—1—羧酸〔1 一 （4 —甲基—2 —酮基—2，3 —二氫—苯 並噁唑一 6—基甲基）一2-酮基一 2- （4一吡啶—4一基 一哌嗪一 1 —基）—乙基〕一醯胺4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -I-443- 200529835 (439) pyridin-1-carboxylic acid [1 mono (4-methyl —2 —keto—2,3—dihydro-benzoxazole—6-ylmethyl) —2-keto—2- (4-pyridine-4—yl—piperazine—1-yl) —ethyl Amidamine

4 — (2 —酬I基一 1，4 — 一*氯一2 Η — D奎口坐琳一3 —基）一喊 D定一 1 一竣酸〔1 一（4 —氯—2-酮|基—2，3 —二氫一苯並 噁唑一6 —基甲基）一 2 —酮基一 2 — （4一吡啶一4 一基一 哌嗪—1 —基）一乙基〕—醯胺4 — (2 —Patent I, 1, 4 — 1 * Chloro 2 — D — D Kuikou Lin Lin 3 — Chi), D, D 1 — 1, complete acid [1 1 (4-Chloro-2-one | Yl-2,3-dihydromonobenzoxazole-6-ylmethyl) 2-keto-2-2- (4-pyridyl-4 4-yl-piperazin-1-yl) -ethyl]- Amidine

啶一 1 一羧酸〔2 —〔 1，4 >〕聯哌啶—1 / 一基一（4 —乙 基一 2 —酮基一 2，3 —二氫一苯並咪唑—6 —基甲基）一2 一酮基）一乙基〕一醯胺 -444- 200529835 (440) οPyridin-1 monocarboxylic acid [2 — [1,4 >] Bipiperidin-1 / 1-yl-1 (4-ethyl-2 keto-2,3-dihydro-benzimidazole-6-yl (Methyl)-2 -keto) -ethyl] -amidamine-444- 200529835 (440) ο

4— (2 —酮基—1，4 —二氫—2Η —喹唑啉—3 —基）一 啶一 1 —羧酸〔2 —〔 1，4 /〕聯哌啶一 1，—基—1 — 一甲基一 2 —麵基一 2，3 — 一氯一苯並味哇一 5 —基甲基 一 2—酮基）—乙基〕一醯胺4- (2-keto-1,4-dihydro-2,2-quinazoline-3-yl) -pyridine-1, carboxylic acid [2-[1,2,4]] piperidine-1, -yl- 1 —monomethyl — 2 —yl — 2,3 —chloro-benzobenzoyl — 5 —ylmethyl — 2-keto) —ethyl] monofluorenamine

4— (2 —酮基一1，4一二氫一2Η — D奎唑啉一3 —基）一 Β定一 1 一竣酸〔2 —〔 1，4 〕聯哌H定一 1 一基—1 一 一氮—2 —酮基一 2，3-二氫一苯並咪唑一 5 —基甲基） 2 —酮基一乙基〕一醯胺 -445- 200529835 (441)4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -B-fixed 1-completed acid [2-[1,4] piperidine H-fixed 1-base —1-monoazol-2-one-keto-2,3-dihydro-benzimidazole-5—ylmethyl) 2-ketomonoethyl] monofluorenamine-445- 200529835 (441)

4— (2 —酮基一1，4 —二氫一2H — D奎唑啉一3 —基）一哌 啶一 1 —羧酸〔2 —〔 1，4 /〕聯哌啶—1 / 一基一 1 一（ 7 一乙基一 2 —酬基一 2，3— _•氨一苯並味卩坐一 5—基甲基） 一 2 -酮基一乙基〕一醯胺 〇4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine-1-carboxylic acid [2-[1,2,4]] piperidine-1 / 1 1-1-(7-ethyl-2-phenyl-2, 3-_ -amino-benzo miso benzo-5-yl methyl)-2-keto-ethyl]-amine.

4 — ( 2 —酮基一1，4 —二氫一2 Η — D奎唑啉一3 —基）—哌 D定—1 _殘酸〔2 —〔 1，4 〕聯喊H定—1 一基一 1 一 （ 3 一甲基一2 —酮基一 2，3—二氫一苯並咪唑一 5—基甲基） 一 2 -酮基一乙基〕一醯胺 -446- 200529835 (442)4 — (2 —keto-1,4 —dihydro — 2 Η — D quinazoline — 3-yl) —piperidine — 1 —residual acid [2 — [1, 4,]] 1 radical 1 1 (3-methyl-2 2-keto-2,3-dihydro-benzimidazole-5-ylmethyl) 2-ketomonoethyl] -fluorenamine-446- 200529835 ( 442)

4一 （2 —酮基一1，4 —二氫一2H — D奎唑啉一3 —基）一哌 U定一 1—竣酸〔2—〔1，4 〕聯哌B定一 1 —基—1— (34-((2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine 1-dicarboxylic acid [2-[1,4] dipiperidine B 1- 1- Base—1— (3

，7 —二甲基一 2 —酮基—2，3 -二氫一苯並咪唑一 5 —基 甲基）一 2-酮基一乙基〕一醯胺, 7-dimethyl-1 2-keto-2,3-dihydro-benzimidazole-1 5-ylmethyl)-2-ketomonoethyl] -amidine

4— (2—酮基一1，4 —二氫一2H-D奎唑啉一3 —基）一哌 啶一 1 —羧酸〔2 -〔 1，4 /〕聯哌啶—1 / 一基一 1 — ( 7 —氯—3 —甲基—2 —嗣基—2，3 — _.氣一苯並味哗—5 — 基甲基）一 2—酮基一乙基〕一醯胺 -447- 200529835 (443)4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine-1-carboxylic acid [2-[1,4 /] bipiperidine-1 / a 1- (7-chloro-3 -methyl-2 -fluorenyl-2,3-_.Gas-benzo-methyl- 5 -ylmethyl) -2 -ketomonoethyl] -ammonium -447- 200529835 (443)

4— (2—酮基一1，4一二氫一 2H — D奎唑啉一 3 —基）一哌 啶一 1 一羧酸〔2 —〔 1，4 /〕聯哌啶—1 / —基—1 一（ 7 —乙基一3 —甲基一 2 —酮基一 2，3 —二氫一苯並咪唑一 5 一基甲基）一 2—酮基一乙基〕一醯胺 〇4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine-1 monocarboxylic acid [2- — [1,4 /] bipiperidine-1 / — 1-1- (7-ethyl-1, 3-methyl-2, keto-2, 3-dihydro-benzimidazole-5, ylmethyl), 2-ketomonoethyl] -amine

3 — ( 7 —甲基一1 Η — 口 引口坐一5 —基）一2 — { [ 4 — (2 — 酮基一 1，4 —二氫一 2 Η - D奎唑啉—3 -基）一哌啶—1 一 羰基-胺基} -丙酸異丙酯3 — (7 —methyl-1 1 Η — mouth lead sitting 5 — base) — 2 — {[4 — (2 — keto-1,4 —dihydro — 2 Η-D quinazoline — 3- ) Monopiperidine-1 monocarbonyl-amino} -isopropyl propionate

3 — (7 —氯一1Η — 口 引口坐 一 5 一 基）一 2 — { 〔4 — (2 —醒 基一1，4一二氫一 2Η — □奎唑啉一3 —基）一I哌啶一1 —羰 基-胺基} -丙酸異丙酯 -448- 200529835 (444)3 — (7 —chlorine — 1Η — mouth lead sitting 5 — 1 base) — 2 — {[4 — (2 — awake base 1, 1, 4 — dihydro 1 2 — — □ quinazoline 3 — base) 1 I-Piperidine-1 -carbonyl-amino} -isopropyl propionate-448- 200529835 (444)

3 — ( 7 —乙基 酮基—1，4 一 羰基-胺基} —1H — D 引唑一5 —基）一2— { 〔4— (2 — 一氣一2 Η — D奎D坐琳一 3 一基）一呢Β定一 1 — -丙酸異丙酯3 — (7 —Ethyl keto —1,4 monocarbonyl-amino group — —1H — D Indazole-5 —yl) — 2 — {〔4— (2 — one gas one 2 Η — D quinine One three one base) one? B fixed one 1-isopropyl propionate

3 — ( 7 -氯— 基一1，4 一 二 基一胺基} 一 1Η—吲唑—5 —基）—2— { 〔4— (2 —酮 氫—2 Η -喹唑啉一 3 —基）一哌啶一 1 一羰 号酸特丁酯3 — (7 -Chloro-yl-1,4-diyl-amino group} 1 1 -indazole-5 -yl) -2-{〔4— (2- ketohydro-2 hydrazone-quinazoline-3 -Yl) -piperidine-1 tert-butyl carbonyl acid

3 — ( 7 —乙基 酮基一 1，4 一 羰基-胺基} —1Η — D 引唑一5 -基）一2— { 〔4— ( 2 - 二氫一2 Η — D奎唑啉一 3 —基）一哌啶一 1 一 丙酸特丁酯3 — (7 —ethyl keto-1,4-monocarbonyl-amino} —1Η — D indazole-5 —yl — 2 — {[4— (2-dihydro-1 2 Η — D quinazoline 3 -yl) -piperidine-1 tert-butyl propionate

3 — （ 7 —氯一 1Η — D 引哗—5 —基）—2— { 〔4— (2 —酬 -449 - 200529835 (445) 基一1 ’ 4 — 一^氣一2 Η —哇 口坐琳一3 —基）一nj|X' D定一1 —羯 基一胺基} -丙酸環己酯3 — (7 —Chloro-1Η — D Initiation —5 —Base) — 2 — {〔4— (2 —Pay-449-200529835 (445) Base—1 ′ 4 — One ^ One 2Η —Wow mouth Zirin- 3 -yl) -nj | X 'D fixed 1 1 -fluorenyl-amino} -cyclohexyl propionate

3— (7 —乙基一1H — D 引唑一5 —基）一2— { 〔4— (2 — 酬基一1 ’ 4 — —•氯—2 Η —哇 口坐琳—3 —基）一 D定—1 —3— (7—Ethyl-1H—D Indazole-5—yl) —2— {〔4— (2—Ethyl-1 ′ 4 — — • Chlorine-2 ) One D fixed — 1 —

羰基-胺基} -丙酸環己酯 3— (7 — 氯一1H — D引唑一5 —基）一2— { 〔4— (2 — 酮 基—1’4 — 一>氨一 2H — D奎Π坐琳—3 -基）—呢B定一1 一擬 基一胺基}—丙酸 1 一甲基一哌啶一 4 —酯Carbonyl-amino} -cyclohexyl propionate 3— (7—chloro-1H—D-azole-5-yl) —2— [[4— (2 —keto-1′4—one> ammonia-1 2H — D quinine (3 —yl) —? B fixed 1 1 peptidyl monoamine} — propionic acid 1 methylated piperidine 4 ester

CICI

3— (7 —乙基一1H — D 引唑一5 —基）一2- { 〔4— (2 — 酮基一1，4 —二氫—2 Η — D奎唑啉一 3 —基）一哌啶—1 — 滕基一胺基}—丙酸 1 一甲基一哌D定一 4 一酯 -450- 200529835 (446)3- (7-Ethyl-1H-D Indazole-5-yl) -2- [[4 -— (2-keto-1,4-dihydro-2 hydrazone—D-quinazolin-3-yl) 1-piperidine-1-tentenyl-amino} -propionic acid 1-methyl-piperidine D-di-4-ester-450- 200529835 (446)

3 — (7 —氣一1 Η — D 引口坐一5 —基）一2 — { 〔4 — ( 2 —嗣 基—1’4 — 一氨—2H — D奎哇琳—3 —基）—喊D定一 1 一鑛 基一胺基丨一丙酸 1 一甲基一環己酯3 — (7 — qi — 1 Η — D inlet sits a 5 — base) — 2 — {〔4 — (2 — fluorenyl — 1'4 — ammonia — 2H — D quivalin — 3 — base) —Choose D-1, 1-mineral-amine group, 1-propionic acid, 1-methyl-cyclohexyl ester

3— (7 —乙基一1H — D 引唑一5 —基）一2— { 〔4— (2 — 酮基一1，4 一二氫—2H — D奎唑啉一3 —基）一哌啶一1 — 羰基一胺基丨一丙酸 1 一甲基一環己酯3— (7—ethyl-1H—D indazole—5-yl) —2— [[4 -— (2-keto-1,4—dihydro-2H—D quinazoline—3-yl) — Piperidine-1—carbonyl-amino group 丨 propionic acid 1-methyl-cyclohexyl ester

3— (7 —氯一1H — 口引唑一 5 —基）一2— { 〔4— (2 — 酮3— (7—Chloro-1H—oripizole-5—yl) —2— {〔4— (2- ketone

基一 1，4 —二氫一2 Η — D奎唑啉一3 —基）一哌啶一 1 —羰 基一胺基} 一丙酸 4 一苯基一環己酯 -451 - 200529835 (447)Phenyl-1,4-dihydro-2 fluorene-D quinazoline-3-yl) -piperidine-1 1-carbonylmonoamino} monopropionic acid 4-phenylphenylcyclohexyl ester -451-200529835 (447)

3— (7 —乙基一1H —吲唑—5 —基）一2— { 〔4- (2 — 酮基—1，4 —二氫一 2H—喧D坐啉—3 —基）一_11定一 1一 鑛基一胺基}一丙酸4一苯基-環己酯3- (7-ethyl-1H-indazol-5-yl)-2- [[4- (2- (keto-1,4-dihydro-2H-dioxoline-3-yl)-_ 11Amine-1Amine-monoamino} monopropionate 4-phenyl-cyclohexyl ester

CGRP結合分析 組織培養：於37°C和5% C02下，使SK— N— MC細胞 於培養基（其係由MEM、Earle氏鹽、L 一榖胺醯胺（ Gibco)及10%胎牛血淸（Gibco)所構成）中單層生長。 細胞沈澱物：利用磷酸鹽緩衝鹽水（155 mM NaCl、 3 3 mM Na2HP04、1 · 1 mM KH2P〇4，pH 7.4 )輕洗該細胞 2 次，並於4 °C下在低滲性溶解緩衝液（其係由1 0 mM Tr i s (pH 7 ·4 )和5 mM EDT A所構成）中培育5至10分鐘。將 該細胞自盤轉移至聚丙烯管（1 6 X 1 0 0 mm )中並利用均質 機使該細胞均質化。於3 2，0 0 0 X g下離心該均質物達3 0分 -452- 200529835 (448) 鐘。令沈澱物再懸浮於含有〇 . 1 %哺乳動物蛋白酶抑制劑 混合物（Sigma )之冰冷滲性溶解緩衝液中並分析其蛋白 質濃度。隨後分裝該SK - N - MC細胞均質物並貯存於一 80°C下直到需要使用時。 放射線配合體結合分析：利用100% DMSO溶解本發 明之化合物並進行系列稀釋。一部份該化合物系列稀釋液 藉由分析緩衝液（50 mM Tris— Cl、pH 7.5，5 mM MgCl2 及0.00 5 % Triton X — 100)進一步進行25倍稀釋，並將 其（體積50//1)轉移至96孔槽分析盤中。將〔251〕一 CGRP(Amersham Bioscienes)於分析緩衝液中稀釋爲60 pM並將其體積50//1加入至每一個孔槽中。令SK—N— MC 細胞沈澱物解凍，藉由含有新配製0.1 %哺乳動物蛋白酶 抑制劑混合物（Sigma )之分析緩衝液進行稀釋，並再次 進行均質化。加入體積1〇〇 # 1之SK - N - MC細胞均質物（ 5 // g/孔槽）。隨後於室溫下培養該分析盤2小時。加入 過量冰冷冲洗緩衝液（20 mM Tris — Cl，pH 7.5，0.1 % BSA )以中止該分析反應，隨後立即已先浸沒於0.5% PEI 中之玻璃纖維濾膜（Whatman，GF/ B )進行過濾。利用1 β Μ /3 - CGRP界定非特異性結合。利用r計數器或閃蒸 計數器測定結合蛋白質之放射活性。IC5〇値係定義爲取代 50%放射線配體結合所需之本發明化合物的濃度。 下表中之結果表示如下：AS 10 nM< BS 100 nM ; 100nM<Cgl00nM; D>100nM。 -453 - 200529835 (449)CGRP binding analysis tissue culture: at 37 ° C and 5% C02, SK-N-MC cells were cultured in a medium (which is composed of MEM, Earle's salt, L-bamine (Gibco) and 10% fetal bovine blood (Gibco) single layer growth. Cell pellet: lightly wash the cells twice with phosphate buffered saline (155 mM NaCl, 3 3 mM Na2HP04, 1.1 mM KH2P04, pH 7.4), and dissolve the buffer in hypotonicity at 4 ° C (It is composed of 10 mM Tris (pH 7.4) and 5 mM EDT A) and incubated for 5 to 10 minutes. The cells were transferred from a tray to a polypropylene tube (16 x 100 mm) and the cells were homogenized using a homogenizer. Centrifuge the homogenate at 3,200 x g for 30 minutes -452- 200529835 (448) minutes. The pellet was resuspended in an ice-cold osmotic lysis buffer containing 0.1% mammalian protease inhibitor mixture (Sigma) and analyzed for protein concentration. The SK-N-MC cell homogenate was then aliquoted and stored at 80 ° C until needed. Radiation complex binding analysis: 100% DMSO was used to dissolve the compounds of the invention and serial dilutions were performed. A part of the serial dilution of this compound was further diluted 25-fold by analysis buffer (50 mM Tris-Cl, pH 7.5, 5 mM MgCl2, and 0.00 5% Triton X — 100), and the volume (50 // 1 volume) ) Transfer to a 96-well trough analysis plate. [251] -CGRP (Amersham Bioscienes) was diluted to 60 pM in analysis buffer and added to each well at a volume of 50 // 1. The SK-N-MC cell pellet was thawed, diluted with analysis buffer containing a newly prepared 0.1% mammalian protease inhibitor mixture (Sigma), and homogenized again. Add SK-N-MC cell homogenate (5 // g / well) in a volume of 100%. The analysis dish was then incubated at room temperature for 2 hours. An excessive amount of ice-cold wash buffer (20 mM Tris-Cl, pH 7.5, 0.1% BSA) was added to stop the analysis reaction, and immediately after filtering by a glass fiber filter (Whatman, GF / B) in 0.5% PEI . Non-specific binding was defined using 1 β M / 3 -CGRP. The radioactivity of the bound protein was measured using an r counter or a flash counter. IC50 is defined as the concentration of the compound of the invention required to replace 50% of the radioligand binding. The results in the following table are expressed as follows: AS 10 nM < BS 100 nM; 100 nM < Cgl00 nM; D > 100 nM. -453-200529835 (449)

表4. C GRP結合、cAMP功能及活體外人體大腦動脈數據 實施例# CGRP結合 cAMP功能2 大腦動脈3 IC5〇(nM) IC5〇(nM) IC5〇(nM) 1 C 氺 * 2 A A A 3 B B B 4 B B 氺 5 A A 氺 6 A A A 7 C C 氺 8 C C 氺 9 B B 氺 10 C B * 11 B B * 12 B C * 13 C 氺 氺 14 D * 氺 15 C C * 16 A A A 17 A A A 18 A B A 19 A A A 20 A A A 2 1 A A A 22 A A 氺 23 A A A 24 B B 氺 25 、A A ATable 4. C GRP binding, cAMP function, and in vitro human cerebral arterial data Example # CGRP binds cAMP function 2 Cerebral artery 3 IC50 (nM) IC50 (nM) IC50 (nM) 1 C 氺 * 2 AAA 3 BBB 4 BB 氺 5 AA 氺 6 AAA 7 CC 氺 8 CC 氺 9 BB 氺 10 CB * 11 BB * 12 BC * 13 C 氺 氺 14 D * 氺 15 CC * 16 AAA 17 AAA 18 ABA 19 AAA 20 AAA 2 1 AAA 22 AA 氺 23 AAA 24 BB 氺 25 、 AAA

-454- 200529835 (450) 實施例# CGRP結合 cAMP功能2 大腦動脈3 IC5〇(nM) IC5〇(nM) IC5〇(nM) 26 B B * 27 B C * 8 C 氺 氺 29 A * * 30 B * 氺 3 1 A A * 32 C * 氺 33 C * * 34 A A 氺 35 B B * 36 B B 氺 37 A B 氺 38 B B 氺 39 C C * 40a A A 氺 40b B 氺 * 40c D * * 40d C * 氺 40e D 氺 氺 40f D 氺 氺 4〇g D * * 40h D * * 40i B * * 4〇j D 氺 氺 40k D 氺 * 4 1a B 氺 * 4 1b A 氺 氺 4 1c A 氺 * 4 1 d B 氺 氺 4 1 e A 氺 氺-454- 200529835 (450) Example # CGRP combined with cAMP function 2 Cerebral artery 3 IC50 (nM) IC50 (nM) IC50 (nM) 26 BB * 27 BC * 8 C 氺 氺 29 A * * 30 B *氺 3 1 AA * 32 C * 氺 33 C * * 34 AA 氺 35 BB * 36 BB 氺 37 AB 氺 38 BB 氺 39 CC * 40a AA 氺 40b B 氺 * 40c D * * 40d C * 氺 40e D 氺 氺40f D 氺 氺 4〇g D * * 40h D * * 40i B * * 4〇j D 氺 氺 40k D 氺 * 4 1a B 氺 * 4 1b A 氺 氺 4 1c A 氺 * 4 1 d B 氺 氺 4 1 e A 氺 氺

-455- 200529835 (451)-455- 200529835 (451)

實施例# CGRP結合 IC5〇(nM) cAMP功能2 IC5〇(nM) 大腦動脈3 IC5〇(nM) 41f B * * 42 C 氺 * 43 A A A 44 C 氺 * 45 A * 氺 46 B B 氺 47 A A A 48 D 氺 氺 49 A * 氺 50 A * 氺 5 1 D * * 52 D * 氺 53 D * * 54 B C A 5 5 C 氺 氺 56 A A 氺 57 C * 氺 5 8 D * * 59 C 氺 氺 60 C 氺 * 6 1 C C * 62 B B * 63 C C * 64 B 氺 B 65 AA B B 66 C * 氺 67 B C B 68 A A A 69 A A A 70 A A A -456- 200529835 (452) 實施例# CGRP結合 cAMP功能2 大腦動脈3 IC5〇(nM) IC5〇(nM) IC5〇(nM) 7 1 A A A 72 A A A 73 B B 氺 74 A A A 75 A B 氺 76 B B. A 77 B B * 78 A A 氺 79 B C * 80 C * * 8 1 B c 氺 82 B c 氺 83 B c 氺 84 B B 氺 85 C 氺 氺 86 C B C 87 B B 氺 88 C B 氺 89 C B 氺 90 B * * 91 C 氺 氺 92 B C * 93 C 氺 氺 94 C c 95 C * * 96 D * * 97 D * * 98 D 氺 * 99 D D 氺 100 C * 氺Example # CGRP combined with IC50 (nM) cAMP function 2 IC50 (nM) Cerebral artery 3 IC50 (nM) 41f B * * 42 C 氺 * 43 AAA 44 C 氺 * 45 A * 氺 46 BB 氺 47 AAA 48 D 氺 氺 49 A * 氺 50 A * 氺 5 1 D * * 52 D * 氺 53 D * * 54 BCA 5 5 C 氺 氺 56 AA 氺 57 C * 氺 5 8 D * * 59 C 氺 氺 60 C 氺* 6 1 CC * 62 BB * 63 CC * 64 B 氺 B 65 AA BB 66 C * 氺 67 BCB 68 AAA 69 AAA 70 AAA -456- 200529835 (452) Example # CGRP combined with cAMP function 2 Cerebral artery 3 IC5. (nM) IC50 (nM) IC50 (nM) 7 1 AAA 72 AAA 73 BB BB 74 AAA 75 AB 氺 76 B B. A 77 BB * 78 AA 氺 79 BC * 80 C * * 8 1 B c 氺 82 B c 氺 83 B c 氺 84 BB 氺 85 C 氺 氺 86 CBC 87 BB 氺 88 CB 氺 89 CB 氺 90 B * * 91 C 氺 氺 92 BC * 93 C 氺 氺 94 C c 95 C * * 96 D * * 97 D * * 98 D 氺 * 99 DD 氺 100 C * 氺

-457- 200529835 (453) 實施例# CGRP結合 c A Μ P功倉g 2 大腦動脈3 IC5〇(nM) IC5〇(nM) IC$o(nM) 101 D 氺 氺 1 02 C 氺 * 103 C 氺 氺 1 04 c 氺 氺 105 C 氺 氺 106 C * * 107 c * 氺 108 c 氺 * 109 c 氺 氺 110 c 氺 氺 111 c 氺 氺 1 12 c 氺 氺 113 c * * 114 c * 氺 115 c * 氺 116 c * * 117 c * 氺 118 c * 氺 119 c 氺 * 120 c 氺 * 12 1 c 氺 氺 122 c 氺 * 123 B 氺 * 124 c 氺 * 125 c 氺 氺 126 c 氺 * 127 c 氺 氺 128 c * 氺 129 c 氺 氺 130 c 氺 氺-457- 200529835 (453) Example # CGRP combined with c A Μ P work chamber g 2 cerebral artery 3 IC50 (nM) IC50 (nM) IC $ o (nM) 101 D 氺 氺 1 02 C 氺 * 103 C 041 04 c 氺 氺 105 C 氺 氺 106 C * * 107 c * 氺 108 c 氺 * 109 c 氺 氺 110 c 氺 氺 111 c 氺 氺 1 12 c 氺 氺 113 c * * 114 c * 氺 115 c * 氺 116 c * * 117 c * 氺 118 c * 氺 119 c 氺 * 120 c 氺 * 12 1 c 氺 氺 122 c 氺 * 123 B 氺 * 124 c 氺 * 125 c 氺 氺 126 c 氺 * 127 c 氺氺 128 c * 氺 129 c 氺 氺 130 c 氺 氺

-458- 200529835 (454) 實施例# CGRP結合 IC5〇(nM) cAMP功能2 IC5〇(nM) 大腦動脈3 IC5〇(nM) 13 1 C 氺 * 132 c 氺 氺 133 c 氺 * 134 c * 氺 1 35 c 氺 氺 136 c * 氺 137 c * 氺 138 c 氺 氺 139 c 氺 * 140 B 氺 氺 141 C 氺 * 142 C 氺 氺 143 c 氺 * 144 c * 氺 145 c * 氺 146 B 氺 氺 147 C * * 148 B 氺 氺 149 B 氺 氺 150 B 氺 氺 15 1 C 氺 氺 152 C * * 153 C * 氺 154 C * 氺 155 C 氺 氺 156 C 氺 氺 157 C 氺 * 158 B 氺 氺 159 B * 氺 160 C * 氺-458- 200529835 (454) Example # CGRP combined with IC50 (nM) cAMP function 2 IC50 (nM) cerebral artery 3 IC50 (nM) 13 1 C 氺 * 132 c 氺 氺 133 c c * 134 c * * 1 35 c 氺 氺 136 c * 氺 137 c * 氺 138 c 氺 氺 139 c 氺 * 140 B 氺 氺 141 C 氺 * 142 C 氺 氺 143 c 氺 * 144 c * 氺 145 c * 氺 146 B 氺 氺 147 C * * 148 B 氺 氺 149 B 氺 氺 150 B 氺 氺 15 1 C 氺 氺 152 C * * 153 C * 氺 154 C * 氺 155 C 氺 氺 156 C 氺 氺 157 C 氺 * 158 B 氺 氺 159 B * 氺 160 C * 氺

-459- 200529835 (455) 實施例# CGRP結合 cAMP功能2 大腦動脈3 IC5〇(nM) IC5〇(nM) IC50(nM) 16 1 B * * 1 62 C * 氺 163 C 氺 * 164 C 氺 氺 165 C 氺 * 166 C 氺 氺 167 C * 氺 168 C 氺 氺 169 C 氺 氺 1 70 C 氺 氺 17 1 B 氺 氺 172 B 氺 氺 1 73 C 氺 氺 1 74 C 氺 氺 175 C 氺 * 176 B 氺 氺 1 77 B * 氺 1 78 B 氺 氺 179 C * 氺 1 80 C * 氺 18 1 C 氺 氺 182 C 氺 * 1 83 C * 氺 1 84 B * 氺 1 85 C 氺 氺 1 86 C 氺 * 1 87 C * 氺 1 88 C * 氺 1 89 C 氺 氺 190 C 氺 氺-459- 200529835 (455) Example # CGRP combined with cAMP function 2 Cerebral artery 3 IC50 (nM) IC50 (nM) IC50 (nM) 16 1 B * * 1 62 C * * 163 C 氺 * 164 C 氺 氺165 C 氺 * 166 C 氺 氺 167 C * 氺 168 C 氺 氺 169 C 氺 氺 1 70 C 氺 氺 17 1 B 氺 氺 172 B 氺 氺 1 73 C 氺 氺 1 74 C 氺 氺 175 C 氺 * 176 B 771 77 B * 氺 1 78 B 氺 氺 179 C * 氺 1 80 C * 氺 18 1 C 氺 氺 182 C 氺 * 1 83 C * 氺 1 84 B * 氺 1 85 C 氺 氺 1 86 C 氺 * 1 87 C * 氺 1 88 C * 氺 1 89 C 氺 氺 190 C 氺 氺

-460- 200529835 (456) 實施例# CGRP結合 cAMP功能2 大腦動脈3 IC5〇(nM) IC5〇(nM) IC5〇(nM) 191 C * * 192 c 氺 * 193 B * * 1 94 C * * 195 C 氺 * 196 B * 氺 197 C 氺 * 198 C 氺 氺 199 B 氺 * 200 B * * 201 C * 氺 cAMP分析 功能性拮抗作用：藉由測定內源性表現人類C GRP受 體之SK — N — MC細胞中cAMP (腺苷3 > ，5 / —環單磷酸 )之生成以測定本發明化合物之拮抗作用。C G RP受體複 合物係與Gs蛋白質偶合且CGRP與此複合物結合後經由依 賴Gs腺苷酸環化酶之活化導致CAMP之生成（Juaneda C. et al·，TiPS，2000; 21 : 432-438，其倂入本文作爲參考） 。因此’ CGRP受體拮抗劑係於Sk - N — MC細胞中抑制 CGRP 誘發之 cAMP 之生成（Doods H. et al·，Br· J. -461 - 200529835 (457)-460- 200529835 (456) Example # CGRP combined with cAMP function 2 Cerebral artery 3 IC50 (nM) IC50 (nM) IC50 (nM) 191 C * * 192 c 氺 * 193 B * * 1 94 C * * 195 C 氺 * 196 B * 氺 197 C 氺 * 198 C 氺 氺 199 B 氺 * 200 B * * 201 C * 氺 cAMP analysis of functional antagonism: by measuring SK, which endogenously expresses the human C GRP receptor — The production of cAMP (adenosine 3 >, 5 / -cyclic monophosphate) in N-MC cells was used to determine the antagonism of the compounds of the present invention. The CG RP receptor complex is coupled to the Gs protein, and CGRP binds to this complex, which results in the generation of CAMP via Gs adenylate cyclase-dependent activation (Juaneda C. et al., TiPS, 2000; 21: 432- 438, which is incorporated herein by reference). Therefore, ’CGRP receptor antagonists inhibit CGRP-induced cAMP production in Sk-N — MC cells (Doods H. et al ·, Br · J. -461-200529835 (457)

Pharmacol.，2000 ; 129 ( 3) : 420-423，其倂入本文作爲 參考）。爲測cAMP，於室溫下利用單獨〇·3 nM CGRP或於 不同濃度之本發明化合物的存在下培養S K - N - M C細胞 30分鐘。在添加CGRP之前，令本發明之化合物與SK— Ν —MC細胞先行培育15分鐘以佔據受體（Edvinsson et al.， Eur. J. Pharmacol·，2 00 1，4 14： 39-44，其倂入本文作爲 參考）。利用裂解劑萃取cAMP並藉由放射免疫分析法利 用RPA 5 5 9 cAMP SPA直接篩選分析套組（Amersham Pharmacia Biotech)測定其濃度。利用Excel適合法計算 IC5〇値。當本發明之測試化合物對CGRP誘發之cAMP之生 成具有取決劑量之抑制作用時，決定該測試化合物係拮抗 劑。參閱表3之結果摘要。Pharmacol., 2000; 129 (3): 420-423, which is incorporated herein by reference). To measure cAMP, SK-N-MC cells were cultured for 30 minutes at room temperature with 0.3 nM CGRP alone or in the presence of different concentrations of the compound of the invention. Prior to the addition of CGRP, the compounds of the present invention and SK-N-MC cells were incubated for 15 minutes to occupy the receptor (Edvinsson et al., Eur. J. Pharmacol., 2001, 4 14: 39-44, which (Herein incorporated by reference). The cAMP was extracted with a lysing agent and the concentration was determined by radioimmunoassay using RPA 5 5 9 cAMP SPA directly screening analysis set (Amersham Pharmacia Biotech). The IC50 was calculated using the Excel fit method. When the test compound of the present invention has a dose-dependent inhibitory effect on CGRP-induced cAMP generation, it is determined that the test compound is an antagonist. See Table 3 for a summary of the results.

Schild分析：可利用Schild分析以說明本發明化合物 之拮抗作用的本質。利用單獨之CGRP或於不同濃度之本 發明化合物的存在下’產生C G R P刺激之c A Μ P生成的劑量 反應。圖形上拮抗劑之量係爲Χ軸’而劑量比例（界定存 有化合物之激動劑的ICw値/單獨激動劑之ICy値）減1作 爲Y軸。對乂和γ軸之對數轉形値進行線性迴歸。不會顯著 地不同於1之斜率表不競爭性拮抗作用。K b係拮抗劑之解 離常數。 -462- 200529835 (458) 表5 . S c h i 1 d分析 實施例# Kb(nM) 斜率 2 0.16 0.94 3 55 0.96 5 3 0.93 6 0.36 0.93 16 1.3 17 1.1 0.92 18 1 0.8 2 1 0.018 0.89 43 0.018 1 .2 45 1.4 47 0.1 0.93 69 0.016 1 70 0.71 71 2 0.87Schild analysis: Schild analysis can be used to illustrate the nature of the antagonism of the compounds of the invention. Dose response to C G R P stimulated c A M P production using CGRP alone or in the presence of different concentrations of the compounds of the invention. The amount of antagonist on the graph is the X-axis' and the dose ratio (ICw 値 defining the agonist in which the compound is present / ICy 値 of the agonist alone) is reduced by 1 as the Y-axis. Linear regression was performed on the logarithmic transformations of the 乂 and γ axes. Slopes that do not differ significantly from 1 indicate non-competitive antagonism. K b is the dissociation constant of the antagonist. -462- 200529835 (458) Table 5. S chi 1 d analysis example # Kb (nM) slope 2 0.16 0.94 3 55 0.96 5 3 0.93 6 0.36 0.93 16 1.3 17 1.1 0.92 18 1 0.8 2 1 0.018 0.89 43 0.018 1 .2 45 1.4 47 0.1 0.93 69 0.016 1 70 0.71 71 2 0.87

參閱圖1. Schild分析 活體外人大腦動脈分析 原理和槪觀：爲提供新穎化合物能於人大腦血管逆轉 CGRP誘發之擴張的直接證據，設計活體外分析。簡言之 ，經分離之血管環係封固於組織浴中，其中利用KC1使血 管先行收縮並利用hCERP使該血管充分擴張，隨後藉由累 -463- 200529835 (459) 積性添加C GRP受體拮抗劑以逆轉該鬆弛狀態（其完整細 節係如下所述）。 組織樣品：自供應商（ABS Inc.或NDRI )取得人體動 脈之驗屍樣品。輸送所有血管於冰冷HEP ES緩衝液（組成 (mM ) ： NaCl 1 3 0、KC1 4、ΚΗ2Ρ04 1 · 2、MgS Ο4 1 · 2、See Figure 1. Schild analysis. In vitro human cerebral arterial analysis. Principles and observations: In order to provide direct evidence that novel compounds can reverse CGRP-induced expansion in human cerebral blood vessels, an in vitro analysis was designed. In short, the isolated vascular ring system is sealed in a tissue bath, in which KC1 is used to shrink the blood vessel in advance and hCERP is used to expand the blood vessel, and then C-GRP is added by accumulating -463- 200529835 (459) Body antagonists to reverse this relaxed state (the full details of which are described below). Tissue samples: Autopsy samples of human veins were obtained from suppliers (ABS Inc. or NDRI). Deliver all blood vessels in ice-cold HEP ES buffer (composition (mM): NaCl 1 3 0, KC1 4, ΚΗ2Ρ04 1 · 2, MgS 〇4 1 · 2,

CaCl2 1.8、葡萄糖 6、NaHC03 4、HEPES 10、EDTA 0.025 )中。收到後，將該血管置於以碳氧混合氣（5% C02和95 %氧）飽和之冰Kreb氏緩衝液（組成（mM )： NaCl 1 1 8·4、KC1 4.7、KH2P〇4 1 ·2、MgS04 1 .2、CaCl2 1.8、葡萄糖 10.0、NaHC03 25)中。 經分離之組織浴液··淸除該血管之結締組織並將該血 管切成長度爲4至5 mm之圓柱狀片段。於2個不銹鋼鈎（ 其中1個係經固定，而另一個係與力置換換能器連接）之 間將血管封固於組織浴液中。利用與該換能器連接之數據CaCl2 1.8, glucose 6, NaHC03 4, HEPES 10, EDTA 0.025). Upon receipt, the vessel was placed in ice Kreb's buffer (composition (mM)) saturated with carbon-oxygen mixture (5% CO2 and 95% oxygen): NaCl 1 1 8 · 4, KC1 4.7, KH2P〇4 1 · 2, MgS04 1.2, CaCl2 1.8, glucose 10.0, NaHC03 25). The separated tissue bath removes connective tissue of the blood vessel and cuts the blood vessel into a cylindrical segment having a length of 4 to 5 mm. The vessel was sealed in a tissue bath between two stainless steel hooks (one of which was fixed and the other was connected to a force displacement transducer). Utilizing data connected to the transducer

取得系統（Powerlab AD Instruments，Mountain View，CA )連續記錄血管張力。含有Kreb氏緩衝液和封固血管之組 織浴液維持於溫度3 7 °C下，且利用持續冒出之碳氧混合氣 控制其pH爲7.4。令該動脈片段達到平衡約30至45分鐘 ，直至達到穩定之休息狀態。於進行分析前’對該血管灌 入（調整狀態）1 〇〇 mM KC1並隨後冲洗。利用1 〇 mM KC1 使該血管先前收縮並隨後利用1 nM hCGRP使該血管完全 擴張。藉由於完全擴張之向管中累積添加半對數單位之藥 物，記錄.對CGRP受體拮抗劑之濃度反應曲線。對於每一 個濃度，該藥物之功效係以對每一個血管CGRP誘發之舒 -464- 200529835 (460) 緩的回復％表示。對每一個血管個別進行真正之分析和數 據分析，藉由非線性迴歸分析使該濃度反應數據適合於4 個參數之邏輯函數以評估EC 5G値。其結果摘要示於表3。 Η平估哺乳動物體內小分子C GRP受體拮抗劑之活體內功效 的非終端方法 槪觀：已提出阻斷由降鈣素基因相關肽（CGRP )所 誘發之大腦動脈擴張係治療偏頭痛之方法，然而新穎之小 分子CGRP受體拮抗劑已顯示物種特異性之差異且於齧齒 類動物體內顯現相對差之活性（^^11^61&1.，厂8丨〇1· Chem. 2002，277: 14294)，故需要評估活體內功效之新 穎模式。非人類之靈長類（例如狨）係已知具有似人類 CGRP受體藥理學之僅有動物，其於其raMP 1序列中存有 特定之胺基酸殘基（Trp74)，該RAMP 1序列負責人類受 體之表現型（Mallee et al.，J· Biol. Chem. 2002，277: 1 4294 )。因爲現今之偏頭痛模式主要係使用鼠（Escott el al·，Brain Res· 195，669 : 93 ; Williamson et al·， Cephalalgia 1 997，1 7: 525 )或係使用靈長類動物侵入性 終端處置（Doods et al·，Br· J. Pharmacol. 2000, 149: 420 )，本發明之用於CGRP受體拮抗劑之活體內功效評估 的非人類之露長類的新穎非侵入性且存活之模式係重要之 貢獻。雖然已知三叉神經活化增加大腦血流（G ο 〇 d s b y & Edvinsson，1993)和面部血流（Doods et al·，2000)，但 是未知已證實於相同動中面部血流與大腦動脈擴張間之直 -465 - 200529835 (461) 接關係。因.此，於起始非人類之靈長類硏究前，直接確認 鼠面血流之雷射Doppler測量係測量相同動物之大腦動脈 徑和面部血流改變之終端硏究的大腦動物擴張之替代物（ 參閱圖2.直接確認鼠面部血流爲顱內動脈擴張之替代物 )。於該二者測量中，可比較之增加係由靜脈內注射 CGRP所誘發且由肽拮抗劑h a CGRP ( 8 — 37 )所阻斷。隨 後，利用h a CGRP ( 8 — 37 )之靜脈內注射CGRP誘發之面 剖血流的改變之方法係確認爲經異氟烷麻醉之鼠的恢復模 式。隨後於非人類之靈長類建立此存活方法且完成界定靜 脈內注射之CGRP活性的劑量反應硏究（參閱圖3. h a CGRP於非人類之靈長類的雷射Doppler面部血流之劑 量反應）。利用肽和小分子C GRP受體拮抗劑以確認非人 類之靈長類模式。小分子拮抗劑或h a CGRP ( 8 - 37 )之 先行處理依劑量抑制靜脈內注射C GRP刺激之靈長類面部 血流的增加（參閱圖4.抑制CGRP誘發之非人類之靈長類 之面部血流的改變），但未改變血壓（參閱圖5. CGRP拮 抗劑於非人類之靈長類的血壓上之功效）。拮抗劑之後處 理亦逆轉CGRP誘發之面部血流的增加（數據未顯示）。 此存活模式提供一種新穎非侵入性之恢復處置，其係用於 評估CGRP受體拮抗劑於非人類之靈長類或具有人類化 RAMP 1 ( Trp 74 )之轉殖基因動物（該動物具有相似之 CGRP受體藥理學以作爲大腦血管徑之活性替代物標言己） 之預防疾病或失敗的功效。 動物··自Harlan購得重3 50至5 5 0 g之雄性和雌性普通 -466 - 200529835 (462) 成狨（Callithrix jacchus )作爲標的固體。本發明描述之 方法亦可使用內源性表現含有Trp 74之RAMP 1之其他哺 乳動物或具有含有Trp 74之人類化RAMP 1之轉殖基因哺 乳動物。 麻碎和手術製劑：於導入室中藉由吸入異氟烷以麻碎 動物（4至5%迅速導入，維持1至2.5%，Solomon et al.， 1 9 99 )。經由面罩或藉由插管和通氣以遞送一定供應量之 空氣：氧氣（5 0 : 5 0 )及異氟烷以維持麻醉（同時監視血 液氣體量）。藉由置入直腸探針之自動化溫度控制表面以 維持體溫於3 8 ± 0 . 5 °C。藉由施用脫毛霜及/或刮毛之方 法，自臉面之一側或兩側除去小面積之毛髮（約1 · 5平方 公分）。剪取手術用面積並藉由優碘（betadine )消毒。 將靜脈內注射置入可使用之靜脈內以利於投遞測試化合物 和CGRP受體激動劑，且如有需要可抽取血液樣品（最多 2 · 5 ml，1 0 % )以進行血液中氣體量監測和成份分析。靜 脈內投遞5 %葡萄糖溶液以維持血糖量。分別利用非侵入 性臂套方法和脈博血氧計測量血壓和心跳以監控麻醉深度 。如有需要，可藉由靜脈注射補充5至10 mg/ kg哌乙啶（ guanethidine )(例如5 mg/ kg )以於重覆刺激誘導之血 流改變下穩定面部血流之峰流量（Escott et al.，1 999 ;其 倂入本文作爲參考）。藉由於面皮膚上黏貼自黏性雷射 Doppler流量探針以監控微血管血流。 化合物投遞：投遞測試化合物可藉由靜脈內（〇 . 0 1至 5 ml/kg)、肌肉內（0.01 至 0·5 ml/kg)、皮下（〇.〇1 -467- 200529835 (463) 至 5 ml/kg)或口服（0.1 至 10 ml/kg)之途徑（Diehl et al.，200 1 ;其倂入本文作爲參考）。投遞CGRP受體激動 劑可藉由靜脈內（〇·〇1至5 ml/kg)、皮下（10至100//1 /部位）或皮下（10至100// 1/部位）之途徑。 雷射Doppler流量測量：藉由投遞血管擴張劑（諸如 CGRP ( 0.05至10// g/kg靜脈內注射或2至20 pmol /部部 皮內投遞）或腎上腺髓質素（ADM，0.05至5 mg/kg靜脈 內注射或10至100 pmol/部位皮內投遞））以誘發面部血 流之控制增加。在隨後重覆投遞該血管擴張劑前（治療前 )或之後（治療後），投遞測試化合物或載體以提供評估 其預防疾病或治療功效之能力。持續監控血壓以確保適當 之麻醉深度，並調整麻醉劑量以維持與治療前相同之安定 量。在收集雷射Doppler流量測量數據期間，降低異氟烷 量至0.25至0.75%，因爲於狨之先前電生理硏究結果發現 其記錄數値係對異氟烷濃度敏感（Solomon，1 999 ;其倂 入本文作爲參考）。爲減少使用之動物數目，於單一測試 期間，測試化合物於靜脈注射血管擴張誘發之血流改變上 的功效可重覆高達6次。 復原：令動物返回運輸籠，其係置於控制溫度之表面 上以維持動物溫暖直至該動物完全甦醒並能移動。動物經 7至14天休息後可再度進行試測，且依據該動物之健康狀 態於7至1 4天之間隔可進行重覆測試。 參閱文獻 Diehl KH, Hull R, Morton D，Pfister R， Rabemampianina Y? Smith D，Vidal JM, van de -468- 200529835 (464)The acquisition system (Powerlab AD Instruments, Mountain View, CA) continuously recorded vascular tension. The tissue bath containing Kreb's buffer and the sealed blood vessel was maintained at a temperature of 37 ° C, and its pH was controlled to 7.4 using a continuous carbon-oxygen mixture. Allow the arterial segment to equilibrate for approximately 30 to 45 minutes until a stable resting state is reached. Prior to analysis, the vessel was perfused (adjusted) with 100 mM KC1 and subsequently washed. The blood vessel was previously contracted with 10 mM KC1 and then completely expanded with 1 nM hCGRP. By cumulatively adding semi-logarithmic units of the drug to the tube due to full expansion, the concentration response curve to the CGRP receptor antagonist was recorded. For each concentration, the efficacy of the drug is expressed as a% of slow response to CGRP induced by each vessel -464- 200529835 (460). Real analysis and data analysis are performed on each blood vessel individually, and the concentration response data is adapted to a logical function of 4 parameters by nonlinear regression analysis to evaluate EC 5G 値. The results are summarized in Table 3.非 A non-terminal method to estimate the in vivo efficacy of small molecule C GRP receptor antagonists in mammals. Concept: A method has been proposed to treat migraine by blocking cerebral arterial expansion induced by calcitonin gene-related peptide (CGRP). However, novel small-molecule CGRP receptor antagonists have shown species-specific differences and relatively poor activity in rodents (^^ 11 ^ 61 & 1, Plant 8 丨 〇1 · Chem. 2002, 277 : 14294), so new models of efficacy in vivo need to be evaluated. Non-human primates (eg tadpoles) are the only animals known to have human-like CGRP receptor pharmacology, which have specific amino acid residues (Trp74) in their raMP 1 sequence, the RAMP 1 sequence Responsible for the phenotype of human receptors (Mallee et al., J. Biol. Chem. 2002, 277: 1 4294). Because the current migraine mode is mainly the use of mice (Escott el al., Brain Res. 195, 669: 93; Williamson et al., Cephalalgia 1 997, 17: 525) or the use of primate invasive terminal treatment (Doods et al., Br. J. Pharmacol. 2000, 149: 420), a novel non-invasive, non-human, prolonged model of non-human proboscis for in vivo efficacy evaluation of CGRP receptor antagonists of the present invention Is an important contribution. Although trigeminal activation is known to increase cerebral blood flow (G o dsby & Edvinsson, 1993) and facial blood flow (Doods et al., 2000), it has not been confirmed that facial blood flow and cerebral arterial dilatation have been confirmed during the same movement Zhizhi-465-200529835 (461) Connection. Therefore, before initiating a non-human primate study, a laser Doppler measurement that directly confirms the blood flow on the rat's face is a measurement of the expansion of the brain animals in the same animal as the diameter of the cerebral arteries and facial blood flow. Substitute (see Figure 2. Direct confirmation of rat facial blood flow as a substitute for intracranial arterial dilatation). In both measurements, the comparable increase was induced by intravenous injection of CGRP and blocked by the peptide antagonist ha CGRP (8-37). Subsequently, the method of changing the anatomical blood flow induced by intravenous injection of CGRP using ha CGRP (8-37) was confirmed as the recovery mode of isoflurane-anesthetized rats. This survival method was subsequently established in non-human primates and completed a dose-response study defining CGRP activity for intravenous injection (see Figure 3. ha CGRP in non-human primates' laser Doppler facial blood flow dose response ). Peptides and small molecule C GRP receptor antagonists were used to confirm non-human primate patterns. Pre-treatment of small molecule antagonists or ha CGRP (8-37) inhibits the increase in primate facial blood flow stimulated by intravenous injection of C GRP by dose (see Figure 4. Inhibition of CGRP-induced non-human primate facials) Changes in blood flow) but no change in blood pressure (see Figure 5. Effect of CGRP antagonists on blood pressure in non-human primates). Subsequent treatment with the antagonist also reversed CGRP-induced increase in facial blood flow (data not shown). This survival model provides a novel non-invasive recovery treatment for evaluating CGRP receptor antagonists in non-human primates or transgenic animals with humanized RAMP 1 (Trp 74) (the animal has similar The CGRP receptor pharmacology has been labeled as an active surrogate for the diameter of the cerebral blood vessels to prevent disease or failure. Animals · Males and females weighing 3500 to 550 g were purchased from Harlan. -466-200529835 (462) Callithrix jacchus as the target solid. The method described in this invention can also be used with other mammals that endogenously express RAMP 1 containing Trp 74 or mammals with transgenic genes that have humanized RAMP 1 containing Trp 74. Anesthesia and surgical preparations: Anesthetize animals by inhaling isoflurane in the introduction chamber (4 to 5% for rapid introduction, maintaining 1 to 2.5%, Solomon et al., 1999). Deliver a certain supply of air through a mask or by intubation and ventilation: oxygen (50:50) and isoflurane to maintain anesthesia (while monitoring blood gas volume). The temperature was maintained at 38 ± 0.5 ° C by an automated temperature control surface with a rectal probe. Remove a small area of hair (approximately 1.5 cm²) from one or both sides of the face by applying a depilatory cream and / or shaving. The surgical area was cut out and sterilized with betadine. Intravenous injection is placed into a usable vein to facilitate the delivery of test compounds and CGRP receptor agonists, and blood samples (up to 2.5 ml, 10%) can be drawn if necessary for blood gas monitoring and Ingredient analysis. Intravenous delivery of a 5% glucose solution to maintain blood glucose. Blood pressure and heartbeat were measured using a non-invasive armband method and a pulse oximeter, respectively, to monitor the depth of anesthesia. If needed, 5 to 10 mg / kg guanethidine (for example, 5 mg / kg) can be supplemented by intravenous injection to stabilize peak facial blood flow under repeated stimulation-induced changes in blood flow (Escott et al., 1 999; which is incorporated herein by reference). The self-adhesive laser Doppler flow probe is attached to the facial skin to monitor microvascular blood flow. Compound delivery: Test compounds can be delivered intravenously (0.01 to 5 ml / kg), intramuscularly (0.01 to 0.5 ml / kg), subcutaneously (0.01-467-200529835 (463) to 5 ml / kg) or orally (0.1 to 10 ml / kg) (Diehl et al., 2001; which is incorporated herein by reference). CGRP receptor agonists can be delivered intravenously (0.01 to 5 ml / kg), subcutaneously (10 to 100 // 1 / site) or subcutaneously (10 to 100 // 1 / site). Laser Doppler flow measurement: by delivery of a vasodilator (such as CGRP (0.05 to 10 // g / kg intravenously or 2 to 20 pmol / intradermal delivery) or adrenomedullin (ADM, 0.05 to 5 mg / kg intravenous injection or intradermal delivery of 10 to 100 pmol / site)) to induce a controlled increase in facial blood flow. The test compound or vehicle is delivered to provide the ability to assess its preventive or therapeutic efficacy before or after subsequent repeated delivery of the vasodilator (after treatment). Continuously monitor blood pressure to ensure proper depth of anesthesia, and adjust the dose of anesthesia to maintain the same stable amount as before treatment. During the collection of laser Doppler flow measurement data, the amount of isoflurane was reduced to 0.25 to 0.75%, as Yu's previous electrophysiological study found that the number of records was sensitive to isoflurane concentration (Solomon, 1 999; which (Herein incorporated by reference). To reduce the number of animals used, the efficacy of the test compound on changes in blood flow induced by intravenous vasodilation can be repeated up to 6 times during a single test. Rehabilitation: Return the animal to the transport cage and place it on a temperature controlled surface to keep the animal warm until the animal is fully awake and able to move. After 7 to 14 days of rest, animals can be tested again, and repeated tests can be performed at intervals of 7 to 14 days depending on the animal's health status. See references Diehl KH, Hull R, Morton D, Pfister R, Rabemampianina Y? Smith D, Vidal JM, van de -468- 200529835 (464)

Vorstenbosch C. A good practice guide to the administration of substances and removal of blood, including routes and volumes. J Appp 1 Toxicol. 200 1 Jan-Feb ； 2 1 ( 1 ) ： 15-23 ; Doods H? Hallermayer G, Wu D,Vorstenbosch C. A good practice guide to the administration of substances and removal of blood, including routes and volumes. J Appp 1 Toxicol. 200 1 Jan-Feb; 2 1 (1): 15-23; Doods H? Hallermayer G, Wu D,

Entzeroth M, Rudolf K? Engel W, Eberlein W. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP-receptor antagonist. B r J Pharmacol. 2 0 0 0 Feb ; 1 2 9 ( 3 ) : 4 2 0-3 ； Edvinsson L.Entzeroth M, Rudolf K? Engel W, Eberlein W. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP-receptor antagonist. B r J Pharmacol. 2 0 0 0 Feb; 1 2 9 (3): 4 2 0-3 ; Edvinsson L.

Calcitonin gene-related peptide ( C GRP ) and the pathophysiology of headache : therapeutic implications. CNS Drugs 200 1 ； 15 ( 10) ： 745 -5 3 ; Escott KJ, Beattie DT，Connor HE, Brain SD. Trigeminal ganglon stimulation increases facial skin blood flow in the rat: a major role for calcitonin gene-related peptide. Brain Res. 1 995 Jan 9 ；6 6 9 ( 1 ) : 93 -9 ; Goadsby PJ? Edvinsson L. The trigeminovascular system and migraine : studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1 993 Jan; 33 ( 1) ·· 48-56; Lassen LH，Haderslev PA，Jacobsen VB, Iversen HK，Sperling B，Olsen J. CGRP may play a causative role in migraine. Cep halalgir，2002， 22， 54-61 ; Mallee JJ，Calcitonin gene-related peptide (C GRP) and the pathophysiology of headache: therapeutic implications. CNS Drugs 200 1; 15 (10): 745 -5 3; Escott KJ, Beattie DT, Connor HE, Brain SD. Trigeminal ganglon stimulation increases facial skin blood flow in the rat: a major role for calcitonin gene-related peptide. Brain Res. 1 995 Jan 9; 6 6 9 (1): 93 -9; Goadsby PJ? Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1 993 Jan; 33 (1) · 48-56; Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olsen J. CGRP may play a causative role in migraine. Cep halalgir, 2002, 22, 54-61; Mallee JJ,

Salvatore CA, LeBour delies B，Oliver K R, Long more J， Koblan K S, Kane S A. RAMP 1 determines the species selectivity of non- peptide CGRP receptor antagonists. J - 469- 200529835 (465)Salvatore CA, LeBour delies B, Oliver K R, Long more J, Koblan K S, Kane S A. RAMP 1 determines the species selectivity of non- peptide CGRP receptor antagonists. J-469- 200529835 (465)

Biol Chem. 2002 Feb 14 [ epub ahead of print] ； Solomon SG，White AJ，Martin PR. Temporal contrast sensitivity in the lateral geniculate nucleus of a New World monkey, the marmoset Call ithrix j acchus. J. Physiol. 1999 Jun 15 ： 5 17 ( Pt 3 ) : 90 7- 1 7 ;所有上述文獻係倂入本文作爲參考 〇 背離其他之偏頭痛模式：本發明代表新穎之偏頭痛模 式，其係與其他之偏頭痛模式顯著不同。本發明方法之某 些區別特徵包括：（i )任何物種僅有之偏頭痛模式存活 式；（Π )證實CGRP拮抗劑於血流之活性誘導增加上的失 敗（治療後）功效之僅有模式；（i i i )證實相同動物中面 部血流與顚內動脈擴張間之直接關係的僅有模式；（iv ) 利用非侵入性手術方法之僅有模式，其不需要置入導管、 插管或神經肌肉阻斷；（v )僅有靈長類模式，其使用外 源性CGRP作爲剌激源並證實藉由CGRP拮抗作用之治療前 阻斷作用和藉由CGRP拮抗作用之治療後逆轉作用；及， (vi )於自發性呼吸之動物中，使用異氟烷麻醉之僅有偏 頭痛模式。 文獻 Williamson e t al·，Sumatriptan inhibits neurogenic vasodilation of dural blood vessels in the anaesthetized rat- intr avital microscope studies.Biol Chem. 2002 Feb 14 [epub ahead of print]; Solomon SG, White AJ, Martin PR. Temporal contrast sensitivity in the lateral geniculate nucleus of a New World monkey, the marmoset Call ithrix j acchus. J. Physiol. 1999 Jun 15 : 5 17 (Pt 3): 90 7- 1 7; All the above documents are incorporated herein by reference. Departure from other migraine modes: The present invention represents a novel migraine mode, which is significantly different from other migraine modes. . Some distinguishing features of the method of the invention include: (i) the only migraine mode survival mode of any species; (Π) the only mode that demonstrates the failure (after treatment) of CGRP antagonists in failing to increase the activity-induced increase in blood flow (Iii) the only mode that confirms the direct relationship between facial blood flow and internal iliac artery dilatation in the same animal; (iv) the only mode that uses non-invasive surgical methods that do not require the placement of a catheter, cannula or nerve Muscle block; (v) a primate-only model that uses exogenous CGRP as a stimulus and demonstrates a pre-treatment block effect by CGRP antagonism and a reversal effect after treatment by CGRP antagonism; and (Vi) In animals with spontaneous breathing, the only migraine mode is the anesthesia with isoflurane. Literature Williamson e t al ·, Sumatriptan inhibits neurogenic vasodilation of dural blood vessels in the anaesthetized rat- intr avital microscope studies.

Cephalalgi. 1 997 Jun ； 17 ( 4) ： 5 2 5 - 3 1 ； Williamson DJ?Cephalalgi. 1 997 Jun; 17 (4): 5 2 5-3 1; Williamson DJ?

Hargreave RJ, Hill RG, Shepheard SL. Intravital microscope studies on the effects of neurokinin agonists -470- 200529835 (466) and calcitonin gene-related pepide on dural vessel diameter in the anaesthetized rat. Cephalalgia. 1 997 Jun ;17(4) ·· 518-24 ； Escott K J et al., Trigeminal ganglion stimulation increases facial skin blood flow in the rat ·· a major role for calcitonin gene-related peptide. Brain Res. 1 9 95 Jan 9 ； 6 69 ( 1 ) · 93-9 ； Chu DQ et al.?Hargreave RJ, Hill RG, Shepheard SL. Intravital microscope studies on the effects of neurokinin agonists -470- 200529835 (466) and calcitonin gene-related pepide on dural vessel diameter in the anaesthetized rat. Cephalalgia. 1 997 Jun; 17 (4) 518-24; Escott KJ et al., Trigeminal ganglion stimulation increases facial skin blood flow in the rat · a major role for calcitonin gene-related peptide. Brain Res. 1 9 95 Jan 9; 6 69 (1) · 93-9; Chu DQ et al.?

The calcitonin gene -related peptide ( C GRP ) antagonist CGRP ( 8-37) blocks vasodilatation in inflamed rat skin ·· involvement of adrenomedullin in addition to CGRP. Neurosci Lett. 200 1 Sep 14; 310 ( 2-3) ·_ 1 69-72 ； Escott KJ，Brain S D. Effect of a calcitonin gene-related peptide antagonist ( CGRP 8-37) on skin vasodilatation and oedema induced by stimulation of the rat saphenous nerve. Br Jharmacol. 1 993 Oct ； 110(2) ： 772-6 ; Hall JM，The calcitonin gene -related peptide (C GRP) antagonist CGRP (8-37) blocks vasodilatation in inflamed rat skin ·· involvement of adrenomedullin in addition to CGRP. Neurosci Lett. 200 1 Sep 14; 310 (2-3) · _ 1 69-72; Escott KJ, Brain S D. Effect of a calcitonin gene-related peptide antagonist (CGRP 8-37) on skin vasodilatation and oedema induced by stimulation of the rat saphenous nerve. Br Jharmacol. 1 993 Oct; 110 (2 ): 772-6; Hall JM,

Siney L, L ipp ton H，Hyman A, Kang-Chang J, Brain S D. Interction of human adrenomedullin 13-52 with calcitonin gene-related peptide receptors in the microvasculature of the rat and hamster. Br J Pharmacol. 1 995 Feb ; 114 ( 3) :592-7; Hall JM, Brain SD. Interaction of amylin with calcitoning gene-related peptide receptors in the microvasculature of the hamster cheek pouch in vivo. Br J Pharmacol. 1999 Jan ; 1 2 6 ( 1) : 280-4;及 Doods H，Siney L, L ipp ton H, Hyman A, Kang-Chang J, Brain S D. Interction of human adrenomedullin 13-52 with calcitonin gene-related peptide receptors in the microvasculature of the rat and hamster. Br J Pharmacol. 1 995 Feb ; 114 (3): 592-7; Hall JM, Brain SD. Interaction of amylin with calcitoning gene-related peptide receptors in the microvasculature of the hamster cheek pouch in vivo. Br J Pharmacol. 1999 Jan; 1 2 6 (1) : 280-4; and Doods H,

Hallermayer G, Wu D，Entzeroth M，Rudolf K，Engel W， Eberlein W. Pharmacological profile of BIBN4096BS, the -471 - 200529835 (467) first selective small molecule CGRP-receptor antagonist. Br J Pharmacol. 2000 Feb； 129 ( 3) : 420-3 並未具備本 發明方法之顯著特徵。 於下表中，結果表示如下：W€25% ; 25<XS50% ;50% < Y ^ 15% ； Ζ > 75%。 表6·於非人類之靈長類（例如普通狨）中抑制CGRP誘發 之雪 1射Doppler面部血流之增加 於非人類之靂 kg)誘發之雷！ ΐ長類中經CGRP(靜脈內（iv)注射，1 0 // g/ 寸Doppler面部血流增加之抑制（％) 實施例 0·01 mg/kg， iv 0.03mg/kg? iv 0· lmg/kg， iv 0.3mg/kg, iv lmg/kg， i v 2 j W X X Y Z 6 Z 16 Y 69 Υ ζ h a CGRP (8-37) Z 25% ； 25%< 50% ； 5 0%< 75% ； Z> 75%Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W. Pharmacological profile of BIBN4096BS, the -471-200529835 (467) first selective small molecule CGRP-receptor antagonist. Br J Pharmacol. 2000 Feb; 129 (3 ): 420-3 does not have the significant features of the method of the present invention. In the table below, the results are expressed as follows: W € 25%; 25 <XS50%; 50% < Y ^ 15%; Z > 75%. Table 6: Inhibition of snow induced by CGRP in non-human primates (such as common salamanders) 1 shot Doppler facial blood flow increase in non-human lightning (kg) induced thunder! ΐ Long class via CGRP (intravenous (iv) injection, 1 0 // g / inch Doppler facial blood flow increase inhibition (%) Example 0 · 01 mg / kg, iv 0.03mg / kg? iv 0 · lmg / kg, iv 0.3mg / kg, iv lmg / kg, iv 2 j WXXYZ 6 Z 16 Y 69 ζ ζ ha CGRP (8-37) Z 25%; 25% <50%; 50% <75%; Z > 75%

參閱圖5· CGRP拮抗劑於非人類之靈長類的血壓上之 功效。 【圖式簡單說明】 -472- 200529835 (468) 圖1 . Schild分析 在缺少（實方塊）和存有（所有其他）CGRP拮抗劑 (實施例2 )之增加濃度（由左至右）的情況下，經CGRP 刺激之cAMP產量的劑量反應。插圖係log (劑量比例一 1 )(Y軸）對log (拮抗劑（實施例2 )濃度）（X軸）之 Schild 圖··斜率= 0.94，Kb 二 〇·16ηΜ。。 圖2.直接確認鼠面部血流係顱內動脈擴張之替代物 靜脈內投遞h a CGRP於鼠中間腦膜動脈徑和鼠面部血 流（分別爲左邊和右邊之條紋柱）誘發相當可比較之加％ (基礎値之1〇〇至120% )。利用肽拮抗劑CGRP ( 8 — 37 ) 之失期處理對前揭2者之測量對隨後之靜脈內h a CGRP投 遞產生50%之抑制作用（實體柱）。對每隻動物（n= 5隻 鼠）同時測量顱內動脈徑和面部血流。數據係中間値土標 準差，*ρ<0·05，**ρ<0·01 對對應單獨 haCGRP。 圖3.非人類靈長類之雷射Doppler面部血流之 h a CGRP的劑量反應 對非人類之靈長類（例如普通狨）投遞h a CGRP誘發 取決於劑量之雷射Doppler面部血流的增加。於30分鐘間 隔，對動物（η = 6 )投遞增加劑量之h a CGRP。數據係自 基礎値標準差改變之峰値％，每隻動物作爲其自身之對 照組。 圖4·抑制非人類之靈長類面部血流的經CGRP誘發之 改變 於h a CGRP (條紋柱）之前投遞新穎之CGRP拮抗劑 200529835 (469) (實施例2 )(實體柱）係取決劑量地抑制雷射Doppler面 部血流經CGRP誘發之增加。載體（空白柱）係無作用。 數據係中間値土標準差（η二5至6隻靈長類/組）。*ρ < 0.05相比於單獨之CGRP。 圖5· CGRP拮抗劑對非人類靈長類血壓的效果 相對比於對靈長類面部血流之取決劑量的抑制作用（ 參閱圖4 )，實施例2之CGRP拮抗劑對血壓幾無影響（個 別動物之平行硏究，η = 6 )。於20分鐘間隔，對動物投遞 重覆厘之實施例2的CGRP掊抗劑。ΒΡ數據係藉由臂袖套測 量於超過20分鐘期間得到之中間値±標準差。 -474-See Figure 5. The effect of CGRP antagonists on blood pressure of non-human primates. [Schematic description] -472- 200529835 (468) Figure 1. Schild analysis of increasing concentration (from left to right) in the absence of (solid squares) and the presence of (all other) CGRP antagonists (Example 2) The dose response of cAMP production stimulated by CGRP. The inset is a Schild plot of log (dose ratio 1) (Y-axis) versus log (antagonist (Example 2) concentration) (X-axis). Slope = 0.94, Kb 2.016ηM. . Figure 2. Directly confirming that the rat's facial blood flow is an alternative to intracranial arterial dilatation. Intravenous delivery of ha CGRP induces a fairly comparable addition in the rat's middle meningeal artery diameter and rat facial blood flow (left and right striped bars, respectively) (100% to 120% of the basis). Measurements using the peptide antagonist CGRP (8-37) of the phasic treatment on the former two revealed a 50% inhibitory effect on subsequent intravenous ha CGRP delivery (solid column). The intracranial arterial diameter and facial blood flow were measured simultaneously for each animal (n = 5 mice). The data is the standard deviation of the middle soil. * Ρ < 0 · 05, ** ρ < 0 · 01 pairs correspond to individual haCGRP. Figure 3. Dose response of non-human primate laser Doppler facial blood flow. H a CGRP delivery to non-human primates (such as common tadpoles). Induction of dose-dependent increase in laser Doppler facial blood flow. At 30 minute intervals, animals (n = 6) were delivered with an increased dose of a CGRP. The data is the peak change in% from the base 値 standard deviation, with each animal as its own control group. Figure 4. CGRP-induced changes in non-human primate facial blood flow. Novel CGRP antagonists delivered before ha CGRP (striped column) 200529835 (469) (Example 2) (solid column) are dose-dependent Inhibition of laser Doppler facial blood flow induced increase by CGRP. The carrier (blank column) has no effect. The data are the standard deviation of middle earth soil (η 2 5 to 6 primates / group). * ρ < 0.05 compared to CGRP alone. Figure 5. The effect of CGRP antagonists on non-human primate blood pressure compared to the dose-dependent inhibition of primate facial blood flow (see Figure 4). The CGRP antagonist of Example 2 has little effect on blood pressure ( Parallel studies of individual animals, η = 6). At 20 minute intervals, the CGRP antagonist of Example 2 was repeatedly delivered to the animals. The BP data is the median ± standard deviation obtained by measuring the cuff over a period of more than 20 minutes. -474-

Claims (1)

200529835 (1) 十、申請專利範圍 1. 一種化合物，其係選自 (土）一 3— (3 —氨基一1H — D 引口朵一5 —基）一2— { 〔4— (2 —酮基一1，4 —二氫一2H—喹唑啉一3 —基）一 哌啶一 1 一羰基〕一胺基} 一丙酸甲酯； (±) — 4— （2 —酮基一1，4 —二氫一2H — D奎唑啉一 3 —基）一哌Π定—1 一殘酸〔2-〔1，4 〕聯哌D定—1 — 基一1— (3 —氰基一1H —吲哚一5 —基一甲基）一2-酮 基一乙基〕—醯胺； (土）一 4 — (2 —醒基一1，4 — —•氣一2 Η — 口奎嗤琳一 3 —基）—哌D定—1 一殘酸〔2 —〔 1，4 〕聯哌Π定—1 — 基一1 (3 —氰基一7 —甲基一1Η —吲哚一5 —基一甲基） 一 2 -酮基一乙基〕一醯胺； (±) — 3— (7 —異丙基一1Η — D弓[唑一5 —基）一2 — { 〔4 — (2 —酬基 一 1，4 一 一* 氣一2 Η — D 奎 口坐琳一3 —基） 一哌啶一 1 一羰基〕一胺基} 一丙酸甲酯； (土）一 4 — (2 —嗣基一1，4 — 一一2 Η — D奎哗琳一 3 —基）一哌D定—1 —竣酸〔2 —〔 1，4 〕聯哌Π定—1 — 基一 1(7 —異丙基一1H-D弓丨唑一 5 —基一甲基）一2 —酮 基一乙基〕一酿胺； (土）一 4 — (2 —嗣基一1 ’ 4 — 一> 氣一2 Η — 口奎 口坐琳一 3 —基）一哌啶—1 一羧酸〔2 —〔 1，4 >〕聯哌啶一 1 > — 基一1(7 —乙基一1Η — D弓丨唑一5 —基一甲基）一2 —酮基 一乙基〕一醯胺； -475- 200529835 (2) (土）一 4 — (2’ 2 — _•醒基一1 ’ 4 — 一2 Η — 2Λ6—苯並〔1，2’ 6〕嘻一^嗦一3 —基）一喊Π定一 1—殘 酸〔2 — 〔 1，4 /〕聯哌啶一1 / —基—1 ( 7 —甲基—1 Η 一吲唑一 5—基一甲基）一 2 —酮基一乙基〕一醯胺； (土）一 4— (2，2 —二酮基一1，4一二氫一2Η — 2λ6-苯並〔1，2，6〕噻二嗪一 3 —基）—哌啶一 1 一羧 酸〔2— 〔1，4 〕聯喊11定—1 —基—1(7 —乙基—3 —200529835 (1) 10. Scope of patent application 1. A compound selected from the group consisting of (earth) 3— (3-amino-1H—D inlet—5—base) —2— {〔4— (2 — Keto-1,4-dihydro-2H-quinazoline-3-yl) -piperidine-1 monocarbonyl] -amino} methyl propionate; (±) — 4— (2-keto-1 1,4-dihydro-2H-D quinazoline-3-yl) -piperidine-1-residual acid [2- [1,4] dipiperidine-didine-1-yl- 1- (3-cyanine 1H-indole-5-yl-methyl) -2-ketomonoethyl] -fluorenamine; (Earth) -4— (2—pentyl-1,4—— • gas-2 2— Kuquiline-3-yl) -piperidine-1—Residual acid [2 -— [1,4] bipidinidine-1—1-yl-1 (3-cyano-7-methyl-1fluorene—ind Indole-5-yl-methyl) -2-ketomonoethyl] monofluorenamine; (±) — 3— (7-isopropyl-1Η—D-bow [azole-5 —yl) — 2 — { [4 — (2 —Cyclo-1,4 — 1 * Gas — 2 Η — D Glycoline 3 —yl) Piperidine — 1 —Carbonyl] Monoamino} Monopropionic acid Methyl ester; (Earth) -4— (2—fluorenyl-1,4—one-2 hydrazone—D quinoxaline—3-yl) -piperidine-1—contained acid Dipyridine — 1 —yl — 1 (7 —isopropyl — 1H-D archazole — 5 —yl — methyl) — 2 — keto — ethyl] — amine; (Earth) — 4 — (2-Methenyl-1'4-One > Qi-1 2Mr-Kuokoukoulin-3-Myl) -piperidine-1 monocarboxylic acid [2— [1,4 >] bipiperidin-1 1 > —yl-1 (7-ethyl-1,1′-D-bendazole-5-yl-methyl) -1, 2-ketomonoethyl] -amidine; -475- 200529835 (2) (earth) One 4 — (2 '2 — _ • awake base 1' 4 — one 2 Η — 2Λ6 —benzo [1,2,6] he — ^ 嗦 one 3 —base) [2 — [1,4 /] bipiperidin-1-yl-1 (7-methyl-1 fluorene-indazole-5-yl-methyl) -1 2-ketomonoethyl] -amidine (Earth) —4— (2,2-dione group—1,4—dihydro—2fluorene — 2λ6-benzo [1,2,6] thiadiazine—3—yl) —piperidine—1— Carboxylic acid [2— 〔1,4〕 Syllable 11- 1-1-1 (7-ethyl-3- 甲基—1Η —吲唑一 5 —基—甲基）一2 —酮基—乙基〕一 醯胺； (±) — 2— 〔4一 （6 —氰基一2 —酮基一1，4一二氫 一 2 Η — D奎唑啉—3 -基）—哌啶一 1 —羰基〕—胺基〕一 3 —(7 —甲基一1Η —吲唑—5 —基）一丙酸甲酯； (土）一 4 — (6 _ 氯基一2 —嗣基一1，4 — —•氯一2 Η _喹唑啉—3 —基）一哌啶—1 一羰基{ 2 —〔 1，4 /〕聯 哌啶一1/ —基一 1— (7 —甲基一 1Η — D弓丨唑一5 -基一甲Methyl-1'-indazole-5'-yl-methyl) -2'-keto-ethyl] monofluorenamine; (±) -2 '-[4' (6-cyano-2'-keto-1 ', 4-dihydro-2 hydrazone —D quinazoline-3-yl) —piperidine-1—carbonyl] —amino] —3- (7-methyl-1hydrazone—indazole-5—yl) monopropionic acid Methyl ester; (Earth) 4 — (6 _ chloro — 2 —fluorenyl — 1, 4 — — • chloro — 2 chloro — 2 — quinazoline — 3 —) piperidine — 1 monocarbonyl {2 — [ 1,4 /] bipiperidin-1-/-yl-1- (7-methyl-1 1-D-bendazole-5-yl-1 基）—2-酮基一乙基} 一醯胺； (±) — 4— (2 —酮基一1，2，4，5 —四氫一苯並〔 d〕 〔1，3〕二氮雜箪—3—基一1一羧酸{2-〔1，4/〕 聯哌啶一 1 / —基—1 一 （ 7 —甲基一 1 Η —吲唑一 5 —基一 甲基）一 2—酮基一乙基} 一醯胺； (土）一 4— (6 —羥基一2 —酮基一1，4一 二氫一2Η —□奎卩坐琳一 3 -基）—喊D定一 1 —竣酸{ 2 - 〔 1，4 〕聯 哌啶一1 > —基一1 — ( 7 —甲基一1 Η — D引唑一 5 —基一甲 基）一 2—酮基一乙基}—醯胺； -476- 200529835 (3) (土）一 4 — (8 —甲氧基一2 — 醒基 一 1，4 — 一·氨一 2 Η — D奎唑啉一3 —基）—哌啶—1 —羧酸{ 2 -〔 1，4 —〕 聯哌啶一 1 / —基一 1 — ( 7 -甲基一 1 Η —吲唑一5 -基一 甲基）一 2—酮基一乙基} 一醯胺； (土）一 4 — (8 —氯一2 —嗣基一1，4 — 一^氯一2Η — D奎唑啉一3 -基）一哌啶—1 一羧酸{ 2 —〔 1，4 >〕聯哌 啶一〗/ 一基一 1— (7 —甲基一 1Η — D弓丨唑一5 —基一甲基 )一 2—酮基一乙基}—醯胺； (±) — Ν— (3— (7 —乙基一3 — 甲基一1Η —吲唑 —5 —基）一 1 一酮基—1 — ( 4 —(哌啶—1 一基）哌啶—1 一基）丙—2-基）—2，，3，—二氫—-酮基螺一（ 哌啶一 4，4 — — D奎唑啉）一1 一羧醯胺； (±) — Ν— (3— (7 —乙基一3 —甲基一1Η — D引唑 一 5 —基）—1 一酮基一 1 — ( 4 一（哌啶—1 —基）哌啶一 1 一基）丙一 2—基）—2，4一二氫——酮基螺—（哌啶 —4，— 1Η —苯並〔d〕 〔1，3〕噁嗪）一 1—羧醯胺 j (±) — N- (3— (7 —乙基一1H — D 引唑一5 —基） —1— (6，7 -二氫一1H —吼唑並〔4，3-c〕D 比啶一5( 4H) — 基）—1 一 酮基丙—2 —基）—4— (1，2 - 二氫一 2 —酮基D奎唑啉一 3 ( 4H ) -基）哌啶一 1 一羧醯胺； (±) - N- (3— (7 —乙基一1H-D 引唑一5 —基） —1— (6，7 —二氫一7，7 —二甲基一1H —吼唑並〔4，3 —c〕吼啶一5(4H)—基）一1—酮基丙一2 —基）一 4 — -477- 200529835 (4) (1，2 —二氫一 2 —酮基D奎唑啉—3 ( 4 Η ) —基）哌啶一 1 一羧醯胺； (±)—甲基 2— (4— (8 —氟一1，2 —二氫一2 —酮 基喹唑啉一 3 ( 4H ) -基）哌啶一 1 —羧醯胺基）一 3 - （ 7 —甲基一 1 Η —吲唑一 5 —基）丙酸酯； (±) — 4 — （8 —氟一 1，2—二氫一2 —酮基喹唑啉) -2-ketomonoethyl} monofluorenamine; (±) — 4 -— (2-ketomono1,2,4,5-tetrahydromonobenzo [d] [1,3] diazepine Hexamidine-3-yl-1 monocarboxylic acid {2- [1,4 /] bipiperidinyl-1 / -yl-1 (7-methyl-1 1 fluorene-indazole-5-yl-methyl) A 2-ketomonoethyl} monoammine; (earth) a 4- (6-hydroxy-2 2-keto-1,4-dihydro-2a — □ quinazoline 3 -yl) — shout D fixed 1 1-Junacic acid {2-[1, 4] Bipiperidin-1 1 > — radical 1 — (7 —methyl 1 1 Η — D indole 5 —yl 1 methyl) 1 2 — Ketomonoethyl} -amidamine; -476- 200529835 (3) (Earth) -4— (8-methoxy-2—xylyl-1,4—ammonia-2 hydrazone—D quinazoline -3-yl) -piperidine-1-carboxylic acid {2-[1,4- —] dipiperidine-1 / -yl-1-(7 -methyl-1 1 fluorene -indazole-5 -yl -methyl (Yl) -2-ketomonoethyl} monofluorenylamine; (Earth) 4- (8-chloro-2-2-fluorenyl-1,4—monochloro- 2fluorenyl—D-quinazoline 3- 3-yl) Monopiperidine-1 monocarboxylic acid {2 — [1,4 >] piperidine-1 / 1-yl-1 — (7 —methyl-1 1 — —D-bendazole-5 —yl-methyl) — 2-keto-ethyl} — 醯Amine; (±) — Ν— (3— (7—ethyl—3—methyl—1′—indazole—5—yl) —1—one keto—1— (4— (piperidine— 1—yl) Piperidine-1 monoyl) propan-2-yl) -2,3,3-dihydro-ketospiro-1 (piperidine-4,4—D-quinazoline) -1 carboxamide; ±) — Ν— (3— (7-ethyl-3—methyl-1) — D-azole-5-yl) — 1-keto-1 — (4- (piperidine-1-yl) piperidine 1 1 1 group) propan-2-yl) -2,4-dihydro——ketospiro- (piperidine-4, —1Η —benzo [d] [1,3] oxazine) 1-carboxyl Amine j (±) — N- (3-—7-ethyl-1H—D indazole-5—yl) —1— (6,7-dihydro-1H—imidazo [4,3-c ] D pyridinyl-5 (4H) —yl) -1 monoketopropan-2-yl) —4— (1,2-dihydro-2 —keto D quinazoline-3 (4H) -yl) Piperidine-1 carboxamide; (±)-N- (3- (7-Ethyl-1H-D Indazole-5-yl) —1— (6,7-Dihydro-7,7-Dimethyl-1H-oxazolo [4,3- —c] pyrimidin-1 5 (4H) -yl)-1-ketopropan-2-yl) -4- -477- 200529835 (4) (1,2, dihydro-2 -keto D-quinazoline-3 (4 Η) -Yl) piperidine-l-carboxamidine; (±) -methyl 2- (4- (8-fluoro-1,2, dihydro-2, -ketoquinazoline-3 (4H) -yl) Piperidine-1 -carboxamido)-3-(7 -methyl-1 fluorene -indazole-5 -yl) propionate; (±)-4-(8 -fluoro-1,2-dihydro One 2-ketoquinazoline -3 ( 4Η )—基）一Ν— (3— (7 -甲基一1Η — 口引唑一5 — 基）一 1 一酮基一 1 一（ 4 一（哌啶—1 一基）哌啶一 1 一） 丙一 2 -基）哌D定一 1 一竣醯胺； (±) — 4 一 （8—氟一1，2 —二氫一2—酮基D奎唑啉 -3 ( 4H )—基）一 N— （3 — （7 —甲基一1H — 口 引唑一5 — 基）—1 一酬基—1— (4 一苯基呢嗦—1 一基）丙一 2 —基 )哌啶一 1 一羧醯胺；-3 (4Η) -yl) -N- (3- (7-methyl-1Η-orazol-5-yl)-1-keto-1 1- (4-((piperidine-1-yl) piper) Pyridin-1 a) Propan-2-yl) piperidine D-1 1-permandiamine; (±) — 4— (8-fluoro-1,2-dihydro-2—keto D quinazoline-3 ( 4H) -yl) -N- (3-(7-methyl-1H-methylazol-5-yl) -1 monophenyl-1- (4-phenylphenylfluorene-1yl) propyl-2 -Yl) piperidine-l-carboxamide; (±) — 4 — （8—氟一 1，2 —二氫一 2 —酮基喹唑啉 -3 ( 4Η )—基）一Ν— (1— (4— (4 —氟苯基）哌嗪— 1—基）一 3— (7—甲基一1Η — D弓丨唑一5 —基）一1-酮基 丙一 2 -基）哌啶一 1 一羧醯胺； (±) — 4— (8 —氣一1，2 — —•氯一 2 —酬基D奎口坐琳 -3 ( 4Η )—基）—Ν — ( 1 -（ 4 — ( 2 —氟苯基）哌嗪— 1 —基）一3 — ( 7 一甲基一1 Η — D引口坐一5 —基）一 1 一嗣基 丙一 2 -基）喊Π定一 1 一殘釀胺； (土）一 4 一 （8 —氯一1，2— —^氨一2—嗣基D奎卩坐琳 -3 ( 4Η )—基）一Ν— ( 3 - (7 —甲基一1Η — 口引唑一5 — 基）—1 一酮基—（4 一鄰甲苯基I婚嗪—1 一基）丙一 2 —基 -478- 200529835 (5) )哌啶一 1 一羧醯胺； (土）一甲基 2— ( 4- (8—氟一1，2 — 二氫一2 —酮 基D奎唑啉—3 ( 4 Η ) -基）一哌啶一 1 一羧醯胺基）—3 -(7 —乙基—3 —甲基一 1Η —吲唑一 5 —基）丙酸酯；(±) — 4 — (8-fluoro-1, 2-dihydro-2 — ketoquinazolin-3 (4Η) —yl) — N — (1 — (4 — (4-fluorophenyl) piperazine Azine — 1-yl) — 3 — (7-methyl-1 1 — — D-bendazole — 5-yl) — 1-ketopropyl — 2-yl) piperidine — 1 —carboxamide; 4— (8—Ga-1, 2—— • Chlor-2—Ethyl D-Keikoline-3 (4Η) —yl) —N — (1-(4 — (2 —fluorophenyl) piperazine — 1 —yl) — 3 — (7-methyl-1 1 Η — D inlet sits a 5 —yl) — 1 —methyl propyl — 2 —yl) Π 一 1 — 1 residual amine; (soil) One 4 one (8-chloro-1,2— — ^ ammonia 2 —fluorenyl D quinoxaline-3 (4 Η) —yl) — N — (3-(7 —methyl — 1 Η — orbital azole) -5 -yl)-1 -keto-(4 -o-tolyl I, hydrazine-1 -yl), propanyl 2- -478- 200529835 (5)) piperidine-1 -carboxamide; (Earth) Monomethyl 2- (4- (8-fluoro-1,2-dihydro-2 -keto-D-quinazoline-3 (4 Η) -yl) -piperidine-1 -carboxamido) -3 -(7 -ethyl-3 -methyl-1 1Η —Indazole- 5-yl) propionate; (±) — Ν— (3— (7 —乙基一3 —甲基一1Η — D引唑 —5 -基）—1 —酮基—1 一（ 4 —(哌啶一 1 —基）哌啶—1 —基）丙—2 —基）—4— (8 —氟—1，2 -二氫一2 —嗣基 唑啉—3 ( 4Η ) —哌啶—1 —羧醯胺； (±) — Ν— （R) — 3— (2—嗣基一二氣一苯並Β惡口坐 —6 -基）—1 一酮基—1 — ( 4 —(哌啶—1 一基）哌啶一 1 —基）丙—2 —基）一 4一（8_ 氟—1，2- 二氣一 2— _ 基 D奎唑啉一 3 ( 4 Η ) -基）哌啶一 1 一羧醯胺； (±) — Ν— (3— (7 —甲基一1Η — 口 引唑一5 —基） —1 一酮基一 1 一（ 4 —(哌啶一 1 一基）哌啶一 1 —基）丙 —2-基）一 8 -氟—2 ，3 —二氫一 2 -酮基螺—(±) — Ν— (3— (7-ethyl-3—methyl-1) — D-zol-5 —yl — 1 —keto-1 — 1 (4- (piperidine-1 —yl) piper Pyridin-1-yl) propan-2-yl) -4— (8-fluoro-1,2-dihydro-2-2-fluorenazoline-3 (4Η) —piperidine-1—carboxamide; (± ) — Ν— (R) — 3— (2-fluorenyl-digas-benzobenzoxoxan-6-yl) -1 keto-1— (4— (piperidine-1-yl) piperidine Pyridinyl- 1-yl) propan-2-yl) -1 4- (8_fluoro-1,2-digas-2-2-yl D quinazoline- 3 (4 Η) -yl) piperidine- 1 -carboxamidine Amine; (±) — Ν— (3— (7—methyl-1, 1′—oripazol-5—yl) — 1—one keto—1— (4 — (piperidine—1—yl) piperidine—1 —Yl) propan-2-yl) -8-fluoro-2,3-dihydro-2-2-ketospiro— (哌啶一 4，4 / 一 D奎唑啉）一1 一羧醯胺； (±) — 4— (8 —氟一1，2 -二氫一2，4 -二酮基口奎 唑啉一3(4Η)—基）一Ν— (3— (7 —甲基一1Η — D引唑 —5 —基）一 1 —酮基一 1 一（ 4 一（哌啶一 1 —基）哌啶—1 一基）丙一 2 -基）哌啶—1 一羧醯胺； Ν— （ （R) — 3—（2- （三氟甲基）—1Η—苯並〔d 〕咪唑一 5-基）一 1 一酮基一 1 一（4一（哌啶一 1—基） 口浪口定——1——基）丙一2—基）一4— (1，2——__*氨—— 2——醒基 D奎唑啉一 3 ( 4H ) -基）哌啶一 1 一羧醯胺； -479- -(2 — 200529835 (6) N— （ （R) — 1 — （二甲基氨基甲醯基）一 2- (三氟甲基）一 1H—苯並〔d〕咪唑一 5 —基）乙3 —(1,2 — 一氣一 2 一嗣基D奎D坐琳—3(4H)—基 一 1 一羧醯胺； (R ) 一 甲基 2 — (4 — (1’2 — 一·氯一2 —嗣基 —3 ( 4 Η ) 一基）哌Β定—1—殘醯胺基）一 3— (2, 氫一 2 —酮基一 1Η-苯並〔d〕咪唑一 6-基）丙酸_ N — ( ( R ) 一 3 — (2’ 3 — _^* 氯—2 —嗣基—] 並〔d〕咪唑一 6 —基）—1—酮基一 1(4 —哌啶—1 哌啶—1 一基）丙一 2 —基）一 4— (1，2 —二氫—2 D奎唑啉一 3 ( 4H ) -基）哌啶一 1 一羧醯胺； N— ( (R) — 1 一 （二甲基氨基甲醯基）一 2- 3 — _>氨—2 —酬基一 1H —苯並〔d〕味Π坐—6 —基 )一 4— (1，2 - 二氫一 2 —酮基 D奎唑啉一 3(4H) 哌啶一 1 一羧醯胺； N — ( ( R ) — 3 — (2，3 — 一 氨—2 —酬基—1 並〔d〕咪唑—6-基）—1 一酮基—1(4一哌啶一 1 哌啶—1—基）丙—2 —基）—4— (2^ ，3"—二氫 一酮基螺（哌啶—4，4 > 一（ 1 Η ) -喹唑啉）羧醯f 4一 （1，2-二氫—2，4 —二酮基[I奎唑啉一3 一基）—N — ( ( R ) — 3 — (7 —甲基 一 1 Η —苯並〔 1，2，3〕三唑—5 —基）—1—酮基一1— (4—([派 一基）哌啶一 1 一基）丙一 2 -基）哌啶一 1 一羧醯胺 (R) — 4- (2 —酮基一1，4 —二氫一2 —喧哗 | ) 一 4 )哌Π定 喹唑啉 3 -二 I Η —苯 -基） 一酮基 (2， )乙基 一基） Η —苯 一基） 按； (4H ) d〕〔 :π定—1 y 琳一 3 200529835 (7) 一基）一哌啶一 1 一羧酸〔2 -（ 4 一環己基一哌嗪—1 —基 )一 2-酮基一 1 一（2 —酮基一 2，3 —二氫一苯並噁唑—6 一基甲基）一乙基〕一醯胺； (R ) — 4 — (2 —嗣基一1 ’ 4 — 一·氣一2 — 口奎 口坐琳一3 一基）一呢陡一 1 一殘酸〔2— (4-異丙基—喊嗦一 1 —基 )一 2 —酮基一 1 一（2 -酮基一 2，3-二氫一苯並噁唑—6 一基甲基）一乙基〕一醯胺； (R) — N— ( (R) — 3— (2 —嗣基—2，3 — 一 氯— 苯並噁唑一 6 -基）一 1 一酮基一 1 — ( 4 一哌啶一 1 —基） 酿Π定一 1—基）丙一 2 —基）—2’ 4 — 一氯—2 —酮I基螺 —(哌啶一 4，4 / — ( 1 Η ) —苯並〔d〕 〔 1，3〕噁嗪） 一 1 —羧醯胺； (R) — N— ( (R) — 3— (2 —酮基一2，3—二氫 — 苯並噁唑一6-基）—l—酮基一l—(4一環己一l—基） 呢嗦—1 一基）丙一 2 —基）一 2，4 — _•氯一 2 -酮I基螺 —(哌啶一 4，4 / — ( 1 Η ) —苯並〔d〕 〔 1，3〕噁嗪） 一 1 一羧醯胺； (R) — N-（ （R) — 3— (2 —酮基—2，3 — 二氫— 苯並B惡哩一 6 —基）一 1—嗣基一 1 一（4 一 （丙一 2 —基） —呢嗪—1—基）丙—2-基）—2’ 4 — —«氨一 2 -嗣基 螺一（哌啶—4，4 > 一 （ 1 Η ) -苯並〔d〕 〔 1，3〕噁嗪 )一 1 —羧醯胺； (R ) — N — ( ( R ) — 3 — ( 2 —酬基—2，3 — _^•氣— 苯並噁唑—6 —基）—1 一酮基一 1 一（ 4 一 （哌啶一 1 一基 -481 - 200529835 (8) )π辰啶一 1 一基）丙一 2 —基）—2，4 一二氫一 2 / —酮基 螺一（丨哌D定—4，4 一（ 1 Η ) - 奎哗琳）一 1 一殘釀胺； (R ) — N — ( ( R ) — 3 — (2 —酬基—2,3 — _> 氣— 苯並D惡嗤一 6 —基）—1 一嗣基一 1 一 （4一（環己—1 一基 )哌嗪—1—基）丙—2-基）一 2，4 —二氫一 2 / —酮基 螺一（哌啶一 4，4 > — ( 1 Η )—喹唑啉）—1 一羧醯胺； (R ) 一 Ν — ( ( R ) — 3 — (2 —嗣基—2，3 — __* 氯— 苯並D惡哇一 6 —基）—1 一酮(基一 1 一 （4 一（丙一 2-基） 呢嗦一 1—基）丙一 2-基）一 2’ 4一 一氯一 2 -嗣基螺 一（喊Π定—4 ’ 4 一（ 1 Η ) - D奎卩坐琳）一 1 —殘釀胺； (R) — 4— (2 —酮基一1，4 —二氫一 2Η — D奎唑啉一 3 —基）—脈D定一 1 —殘酸〔2 —〔 1，4 〕聯喊Π定—1 — 基一 1— (4 一氯—2 -酮基一 2，3-二氫—苯並噁唑一 6-基甲基）一 2-酮基一乙基〕一醯胺； (R) — 4 — ( 2 —嗣基一1 ’ 4 — —•氣一2 Η — 口奎 口坐琳一 3 —基）—哌啶一 1 —羧酸〔2 —〔 1，4 /〕聯哌啶一 1 / 一 基一 1 一（5 —氯—2 —嗣基—2，3 - _*氯—苯並卩惡卩坐—6 — 基甲基）一 2-酮基一乙基〕一醯胺； (R ) — 4 — (2 —醒I 基一1 ’ 4 — —•氣一2 Η — D 奎 口坐琳一 3 —基）—哌啶一 1 一羧酸〔2 —〔 1，4，〕聯哌啶—1 / — 基一 1 一（4 —溴一 2 —酮基一 2，3-二氫—苯並噁唑一6-基甲基）一 2-酮基一乙基〕一醯胺； (R) — 4— (2 —酮基一1，4 —二氫一2Η — D奎唑啉一 3 —基）—哌啶—1 一羧酸〔2 —〔 1，4 /〕聯哌啶—1 / 一 -482- 200529835 (9) 基一 1 一（5—溴—2 -酮基一 2，3 —二氫—苯並噁唑—6 — 基甲基）一 2—酮基一乙基〕一醯胺； (R) —4— (2 —酮基一 1，4一 二氫一2H — D奎唑啉一 3 —基）一哌啶—1 一羧酸〔2 -〔 1，4 /〕聯哌啶—1 > 一 基一 1 一（4 一碗—2 —嗣基—2，3 — —*氨—苯並卩惡卩坐—6 一 基甲基）一 2—酮基一乙基〕—醯胺；(Piperidine-4,4 / -D-quinazoline)-1-carboxamidine; (±) — 4 -— (8-fluoro-1,2-dihydro-2,4-diketoquinololine -3 (4Η) -yl) -N- (3- (7-methyl-1Η-D-zolazole-5-yl)-1-keto-1 1- (4-(piperidine-1 -yl) piperyl Pyridin-1 monoyl) propan-2-yl) piperidine-1 monocarboxamide; Ν— ((R) — 3— (2- (trifluoromethyl) -1 fluorene—benzo [d] imidazole-5) -Radical) 1 1 keto 1 1 (4 1 (piperidine 1 1 -yl) glutamine-1-1 -yl) C 2 -yl)-4-(1, 2-__ * Ammonia-2-propyl quinazoline-3 (4H) -yl) piperidine-1 -carboxamide; -479--(2 — 200529835 (6) N — ((R) — 1 — ( Dimethylcarbamoyl) -2- (trifluoromethyl) -1H-benzo [d] imidazol-5-yl) ethyl 3- (1,2- —3 (4H) —yl-1 monocarboxamidine; (R) monomethyl 2 — (4 — (1'2 — mono · chloro — 2 —amidino-3 (4 Η) mono)) piperidine —1—residual amino group) —3— (2, Hydrogen-2-keto-1H-benzo [d] imidazol-6-yl) propanoic acid N — ((R) — 3 — (2 '3 — _ ** chloro-2 —fluorenyl —] and [ d] imidazole-6-yl) -1-keto-1 (4-piperidine-1piperidine-1yl) propan-2-yl) -4 (1,2-dihydro-2 D quinazole Porphyrin-3 (4H) -yl) piperidine-1monocarboxamide; N — ((R) —1— (dimethylaminomethylamidino) —2—3— — &#; amino-2 1H —benzo [d] amidino-6-yl) —4— (1,2-dihydro-2—keto D quinazoline—3 (4H) piperidine—1—carboxamide]; N — ((R) — 3 — (2,3 —monoamino-2 —amyl — 1 and [d] imidazol 6 —yl) — 1 monoketo — 1 (4-piperidine — 1 piperidine — 1 — (Propyl) propan-2-yl) -4— (2 ^, 3 " -dihydromonoketospiro (piperidine-4,4 > mono (1 Η) -quinazoline) carboxy 醯 f 4 （(1 , 2-dihydro-2,4-dione group [I quinazoline-3 mono-yl] —N — ((R) — 3 — (7 —methyl-1 1 pyrene —benzo [1,2,3 ] Triazole-5 -yl)-1 -keto-1-(4-([派(Yl) piperidine-1, 1-yl) propan-2-yl) piperidine-1, 1-carboxamide (R) — 4- (2-keto-1,4 —dihydro — 2 —noisy |) 4) Piperidine quinazoline 3 -diI Η —benzene-yl) monoketone (2,) ethyl mono) hydrazine — phenyl mono) (4H) d] [: π 定 -1 y Linyi 3 200529835 (7) mono-piperidine-1 monocarboxylic acid [2- (4-cyclohexyl-piperazin-1-yl)-2-keto-1 1- (2-keto-2,3-di Hydrogen-benzoxazole-6 monomethyl) monoethyl] monofluorenamine; (R) — 4 — (2 —fluorenyl — 1 ′ 4 — mono · qi — 2 — koukuizurin — 3 1-base) 1-blank-1 1-residual acid [2- (4-isopropyl-methyl- 1-yl)-2-keto-1 1- (2-keto-2,3-dihydro-benzene Benzoxazole-6 monomethyl) monoethyl] monofluorenamine; (R) — N— ((R) — 3— (2 —fluorenyl —2,3 — monochloro—benzoxazole-6) -Yl) -1, 1-keto-1, 1- (4-piperidine-1, 1-yl), 1-Adiyl, 1-yl), 2-2-yl), 2'4, 1-chloro-2, 1-keto I-spiro— (Piperidine-1 4,4 / — (1 Η) —benzo [d] [1,3] oxazine) 1 -carboxamide; (R) — N— ((R) — 3— (2 —keto-2) , 3-dihydro-benzoxazol-6-yl) -l-keto-l- (4-cyclohexyl-l-yl) ne? -1-yl) propan-2-yl) -2,4- _ • Chloro-2-keto I-based spiro— (piperidine-4,4 / — (1 fluorene) —benzo [d] [1,3] oxazine) —1—carboxamide; (R) — N -((R) — 3— (2 —keto—2,3 —dihydro—benzo-B-oxazol-6-yl) —1—fluorenyl—1— (4— (propanyl 2 —yl) — Memazine-1-yl) propan-2-yl) -2 '4 — — «Ammonia 2 -fluorenylspiro-1 (piperidine-4,4 > mono (1 fluorene) -benzo [d] 〔1 , 3] oxazine) 1-carboxamidine; (R) — N — ((R) — 3 — (2 —amyl — 2, 3 — _ ^ • Gas — benzoxazole — 6 —yl) —1 monoketo-1 1- (4-piperidine- 1-yl-481-200529835 (8)) pentanidine-1 1-yl) propan-2-yl) -2,4-dihydro-2 / —Ketospiro-1 (丨 pididine-4,4 a (1 Η)-quetzolin)-1-1 residual amine; (R) — N — ((R) — 3 — (2 —Ethyl —2,3 — _ > —Base) —1—Amidino—1— (4— (Cyclohexan—1—yl) piperazin—1—yl] propan-2-yl) —2,4—Dihydro—2 / —Ketospiro— (Piperidine-4,4 > — (1 Η) -quinazoline) — 1 monocarboxamide; (R) —N — ((R) — 3 — (2 —fluorenyl — 2, 3 — __ * Chloro-benzo-D-oxa-6-yl) -1 ketone (1- 1- (4- 1- (propyl- 2-yl)) 1-yl- 1-yl) 2- 2-yl)-2 '4- 1 1-Chloro-2-pyridylspiro- (Sydidine-4'-4- (1 Η) -D-Quylenoxine)-1-residual amine; (R) — 4— (2 —keto-1, 4 —dihydro-2Η — D quinazoline — 3 —yl) — D D 1 — 1-Residual acid [2 — [1, 4] 喊 Π 1 — 1 — 1 — (4 chloro-2 -Keto-2,3-dihydro-benzoxazole-6-ylmethyl)-2-ketomonoethyl] monofluorenamine; (R) — 4 — (2 —fluorenyl — 1 ′ 4 — — • 气 一 2 Η — Kou Kuikou sits Lin 3 -yl) -piperidine-1 -carboxylic acid [2- — [1,4 /] bipiperidine-1 / 1-yl-1 1- (5-chloro-2 -fluorenyl-2,3-_ * chlorine- Benzo (a) pyrazine-6-ylmethyl)-2-keto-ethyl] -ammonium amine; (R) — 4 — (2 —Xing I group — 1 ′ 4 — — • Gas 2 Η — D Quizilin 3-yl) -piperidine-1 monocarboxylic acid [2- [1,4,] bipiperidine-1 / -yl-1 1-(4-bromo-2 -keto-2, 3-dihydro-benzoxazole-6-ylmethyl) -2-ketomonoethyl] monofluorenamine; (R) — 4 -— (2-keto-1,4-dihydro-2 一 — D quinazoline- 3-yl) -piperidine-1 monocarboxylic acid [2- — [1,4 /] bipiperidine-1 / mono-482- 200529835 (9) radical 1-(5-bromo-2 -Keto-2,3-dihydro-benzoxazole-6-ylmethyl)-2-ketomonoethyl] monomethylamine; (R) —4— (2-keto-1,4 Monodihydro-2H — D quinazoline-3-yl) -piperidine-1 monocarboxylic acid [2-[1, 4 /] bipiperidin-1> > monoradical 1 1 (4 bowl-2 — 嗣 基 —2, 3 — — * Ammonia-benzoxazone-6-6-methylmethyl)-2-ketomonoethyl] -fluorenamine; —N— (1—爷基—2 — 基一乙基）—2 — (7 — 甲基 —1 Η — D引口坐一5 —基甲基）一4 一嗣基一 4 — 〔1 ，2 — 一氯—2 —酮[基螺—〔4Η— 3 ， 1 一苯並卩惡嗦—4，4 一哌啶基〕丁醯胺； (±) — Ν— (1—苄基一2 —羥基一乙基）一 2— (7 —甲基一1Η — D引唑一5 —基甲基）一4 —酮基一4_ 〔4 — (2 —酮基一1，4 —二氫一2Η — D奎唑啉—3 —基）一口尼啶 一 1 一基〕一丁醯胺； (±)—苯基一乙酸Ν> — {2— (7 -甲基一1Η—吲—N— (1—Lee — 2 —yl-ethyl) — 2 — (7 —methyl — 1 — — — — — — — — — — — — — — — — — — — — # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # 2-monochloro-2-ketone [ylspiro— [4Η-3, 1-benzopyrazine-4,4-piperidinyl] butanamide; (±) — Ν— (1-benzyl-2 —Hydroxymonoethyl) —2— (7—Methyl—1Η—D-azole—5-ylmethyl) —4—Keto-4— [4— (2-Keto-1,4—dihydro— 2Η — D quinazoline — 3-yl) mononiridinyl — 1 —yl] monobutyramide; (±) —phenylmonoacetic acid N > 唑—5 —基甲基）一4一酮基一 4一 〔4— (2—酮基一 1，4 一二氫一 2 Η — D奎唑啉一 3 —基）一哌啶—1 —基〕一丁醯 胺} 一醯肼； (± ) — 1 — 〔 1，4 /〕聯哌啶一 1，一基一4 — 〔 4 — (8 —氟—2 —酮基—1，4 —二氫一 2Η-喹唑啉一 3 —基） —哌啶一1 -基〕一2 — ( 7 —甲基一 1 Η — D引唑一5 —基甲 基）—丁 — 1，4一 二酮； (± ) — 1 — 〔 1，4 ^〕聯哌啶一1 一 一基一2 — ( 7 — 甲基一1Η — D引唑一5 —基甲基）一4 一 〔2 — ，3< —二氫 -483- 200529835 (10) 一 2 — -酮基螺—（哌啶—4，4 / — D奎唑啉〕丁一 1，4 — 二酮； (±) — 1— (4 —環己基一哌嗪一 1—基）一2— (2 一酮基一 2，3 —二氫—苯並噁唑—6 -基甲基）—4一〔4 一 (2 一嗣基一 1 ’ 4 一 一·氣一2 Η 一 D奎口坐琳一 3 —基）一 Ρ底 口定—1—基〕一丁 — 1，4 — 一^嗣； (土）一 1— 〔1’4 〕聯派〇定一1 一基一2— (2 —Azole-5 -methylmethyl) -4 -keto-4-[4-(2-keto-1,4 -dihydro -2 Η-D quinazoline -3-yl) -piperidine-1- Phenyl] monobutylammonium amine} monomethylhydrazine; (±) — 1 — [1,4 /] bipiperidine -1, 1 yl 4 — [4 — (8 —fluoro-2 — keto-1, 4 —Dihydro-2′-quinazoline-3 —yl) —piperidine-1 —yl] — 2 — (7 —methyl-1 1 Η — dazole—5-ylmethyl) —but — 1, 4 Monodione; (±) — 1 — [1,4 ^] piperidine — 1 — 1 — 1 — 2 — (7 — methyl — 1 — — Dazole — 5 — methyl — 1 — 2 — ,, 3 < —dihydro-483- 200529835 (10) — 2 — —ketospiro — (piperidine-4, 4 / — D quinazoline] butane 1, 1, 4 — dione; (±) — 1 — (4-cyclohexyl-piperazine-1—yl) —2— (2—one keto—2,3-dihydro—benzoxazole-6—ylmethyl] —4— [4— (2—嗣 基 一 1 '4 一 · 气 一 2 Η One D Kuikou sitting Lin 1 3—base) —P bottom mouth set—1—base] —ding—1, 4—a ^ 嗣; (土) 一 1 — [ 1’4] Alliance 0 fixed one 1 one base one 2 — (2 — 酮基一2，3 —二氫一苯並噁唑一 6 —基甲基）一 4一〔4一 (2 -酮基一1，4一二氫一2Η —哇唑啉一 3 —基）一哌啶 —1— 丁基〕一丁 — 1，4—二酮； (±) — 1— 〔1’4 〕聯脈D定一1 —基一2— (2 — 酮基一2，3 —二氫一苯並噁唑一6 —基甲基）一4— 〔2， ，3 〃 —二氫一2 / —酮基螺—（哌啶—4，4 / —喹唑啉） 〕一丁 一 1，4 -二酮； (±) — 1- (4 —環己基一哌嗪一1—基）一2— (2Keto-2,3-dihydro-benzoxazole-6-ylmethyl) -4 [[4-((2-keto-1,4-dihydro-2) -oxazoline-3-yl) 1-piperidine-1—butyl] 1-butane-1,4-dione; (±) — 1— [1'4] diamidine D 1-yl-2— (2-keto-2,3 —Dihydromonobenzoxazole-6-ylmethyl) —4— [2,, 3 〃 —dihydro-1 2 / —ketospiro — (piperidine-4,4 / —quinazoline)] 1 Butane-1,4-dione; (±) — 1- (4-cyclohexyl-piperazine-1—yl) —2— (2 一嗣基一 2，3 — —^氣一苯並D惡哗—6 一基甲基）一 4 一〔 2 / ，3 — -二氫一 2 / _酮基螺—（哌啶一 4，4 / 一喹唑 啉）〕丁一 1，4 —二酮； (±) — 4— (2 —酮基一1，4一 二氫一 2Η—喹唑啉一 3 —基）一哌啶一 1 一羧酸〔2 - （ 4 —環己基一哌嗪一 1 一 基）一 1 — (7 —甲基一1 Η — β弓丨口坐一5 一基甲基）一 2 —嗣 基一乙基〕一醯胺； (±) — 4— (2 —酮基一1，4 —二氫一2Η — 口奎唑啉一 3 —基）—哌啶一 1 一羧酸〔2 — 〔 4 一 （ 4 —氟一苯基）— -484- 200529835 (11) 哌嗪一〗一基〕一1 一 （7 —甲基一 1H—吲唑—5 —基甲基 )一 2—酮基一乙基〕一醯胺； (±) — 3— (7 -甲基一1H — D引唑一5 —基）一2- { 〔4— (2 —酮基一1，4 —二氫一2H — D奎唑啉一3 —基）一 哌啶一 1 一羰基〕一胺基〕一丙酸特丁酯； (±) — 3— (7 —甲基一1H — D引唑一5-基）一2— { 〔4— (2— 酮基一1，4 —二氫一2H—D奎唑啉一3 —基）一Monomethyl-2,3-^-gas-benzo-D-sulmon-6-ylmethyl) -4- [2 /, 3 --- dihydro-2 / _ketospiro- (piperidine-4, 4 / 1-quinazoline)] butane-1,4-dione; (±) — 4- (2-keto-1,4-dihydro- 2Η-quinazoline-3-yl) -piperidine-1 1 monocarboxylic acid [2-(4-cyclohexyl-piperazine-1 1-yl)-1-(7 -methyl-1 1 Η-β-bend 一 5-yl methyl)-2-fluorenyl-1 Ethyl] monomethylamine; (±) — 4 -— (2-keto-1,4-dihydro-1, 2-pyridine — or quinazoline-3-yl) —piperidine-1 —carboxylic acid [2 — [4 Mono (4-fluoro-phenyl)--484- 200529835 (11) piperazine mono-]] 1- (7-methyl- 1H-indazol-5-yl-methyl)-2-keto- Ethyl] monomethylamine; (±) — 3— (7-methyl-1H—D-azole-5-yl) —2- {[4 -— (2-keto-1,4-dihydro-2H — D quinazoline- 3-yl) -piperidine-1 mono-carbonyl] -amino] mono-butyl propionate; (±) — 3 — (7 —methyl-1H — D-azole-5- ) A {2- [4- (2-keto-one 1,4 - dihydro - 2H-D Kui oxazoline-3 - yl) a 哌啶一 1—羰基〕一胺基〕一丙酸1 一甲基環己酯； (±) — 3— (7 —甲基一1H — D引唑一5 —基）一2— { 〔4一 （2—酮基一1，4一 二氫一2H — D奎唑啉一 3 —基）一 哌啶一 1 一羰基〕一胺基} 一丙酸 1—氮雜—雙環〔2.2.2 〕辛—3 -酯； (±) — 3— (7 —甲基一1H —吲唑一5— 基）一2— { 〔4— (2 —酮基一 1，4 —二氫一2H — D奎唑啉一3 —基）一 哌啶一 1 一羰基〕一胺基} 一丙酸哌啶一 4 一酯；Piperidine-l-carbonyl] -amino] monopropionate 1-methylcyclohexyl ester; (±) — 3 — (7 —methyl — 1H — D-azole — 5-yl) — 2 — {[4 Mono (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine-1 monocarbonyl] monoamino} monopropanoic acid 1-aza-bicyclo [2.2.2 ] Octane-3-ester; (±) — 3— (7-methyl-1H—indazol-5-yl)-2— {[4— (2-ketone-1,4-dihydro-2H— D quinazoline- 3-yl) -piperidine- 1-carbonyl] -amino group} piperidine-propionate- 4 ester; (±) — 4— (3— (7 —甲基一1H — D 引唑一5 —基）一 2 一 { 〔4 — ( 2 —酬基一1，4 — _ 氣一2 Η — D 奎 D坐琳一3 — 基）一哌啶一 1一羰基〕一胺基} 一丙醯氧基）一哌啶一 1 -羧酸特丁酯； (土）一 3— (7 —甲基一1Η —吲唑一5 —基）一2— { 〔4— (2 —酮基一1，4一 二氫一2Η — D奎唑啉一3 —基）一 哌啶一 1 一羰基〕—胺基}—丙酸3，4，5，6 —四氫一 2Η —〔1，4 〕聯吼Π定—4 一酯； (±) — 3— (7 —甲基一1Η — D 引唑一5 —基）一2— { -485- 200529835 (12) 〔4— (2 —酮基一1，4 —二氫一2H — D奎唑啉一3 —基）一 哌啶一 1 一羰基〕一胺基丨一丙酸 1 一二乙基胺基—1 一 甲基一乙酯； (±) — 3— (7 —甲基一1H —吲唑一5 —基）一2— { 〔4— (2 —酮基一1，4 —二氫一 2H — D奎唑啉一3 —基）一 哌啶—1 一羰基〕—胺基} 一丙酸 1，1 —二甲基一 2 -苯 基一乙酯； (±) — 3— (7 -甲基一1H — D引唑一5 —基）一2— { 〔4— (2 —酮基一1，4一 二氫一2H — D奎唑啉一3 —基）一 哌啶—1 一羰基〕—胺基} 一丙酸 1，1—二甲基—3-苯 基一丙酯； (土） 一 3 — (7 —甲基一1 Η — D 引口坐一5 —基）一2 — { 〔4— (2 —酮基一1，4 —二氫一2Η — D奎唑啉一3 — 基）一 哌啶—1 一羰基〕一胺基}—丙酸乙酯 (±) — 1 — （7 -甲基一1Η — D引唑一5 —基甲基）一2 一 〔1 一吡啶一4 —基—甲基〕一 2 —酮基乙基〕一 2 —， 3 _ 二氮一 2 -酮基螺—〔_D定一 4，4 — ( 1 Η )— 口奎唑啉〕一 1 一羧醯胺； (±) — 1— （7—甲基一1Η —吲唑一5 —基甲基）一2 —〔1 一卩比卩定一4 一基一 Ρ很嗪基〕一 2—酮基乙基〕一2 ’ 3 ’ —二氫一 2 / —酮基螺—〔哌啶 一 4，4 / — ( 1Η ) - 喹唑啉〕一 1 一羧醯胺； (±) — 1- (7 —甲基一1Η — 口引唑一 5 —基甲基）一2 一 〔2—二甲基胺基一乙基一乙基一氨基甲醯基〕一2 —酮 -486- 200529835 (13) 基乙基〕一 2 / ，3 > —二氫一 2，—酮基螺一〔哌啶—4， 4 / 一（ 1 Η ) - D奎唑啉〕一 1 —羧醯胺； (±) — 1- (7—甲基一1Η — D引唑一5—基甲基）一2 一 〔1 一吼卩定一 4 一基一甲基〕一 2 —醒基乙基〕—1 ’ —二氫一2〃 一酮基螺—〔4Η— 3，，1—苯並噁嗪—4 ，4 > 一哌啶〕一 1 一羧醯胺； (±) — 1— (7 -甲基一1Η —吲唑一5 —基甲基）一2 一〔1—吡啶一 4一基一甲基〕一 2 —酮基乙基〕一厂， 2 — 一氨—2 —嗣基螺—〔4Η - 3 ，1—苯並D惡嘻一 4 ，4 — — _ U定〕一 1 —竣醯胺； (R) — 4— (2 —酮基一1，4 —二氫一2Η —喹唑啉一 3 —基）一哌D定一 1 d —殘酸〔2 -〔 1，4 〕聯哌Π定一 1 —基一1— (7 —甲基一1H —吲唑一 5 —基甲基）一2 -酮 基一乙基〕—醯胺； 或 (R) — 1 一 ( 7 —甲基一1 Η — D引口坐一5 —基甲基）一2 —〔1，4 /〕聯哌啶—1 / —基—2 —酮基乙基〕一2 / ， 3一 —二氫—2，—酮基螺—〔哌啶一 4，4> — (1Η)— 口奎唑啉〕一 1 一羧醯胺；或 其醫藥上可接受之鹽或溶劑化物。 2. 一種化合物，其係選自 4— (2—酮基一1，4一二氫一 2Η — D奎唑啉一3 —基） —哌啶—1 _羧酸〔2 —〔 1，4，〕聯哌啶一 1 > —基一 1 — (7—溴一1Η—吲唑一 5 —基甲基）—2—酮基一乙基〕一 -487- 200529835 (14) 醯胺； 4— (2 —酮基一1，4 —二氫一2H — □奎唑啉一3 —基） 一 I派卩定—1 一竣酸〔2-酮基—1— (2 —酮基一 2，3-二氫 一苯並卩惡Π坐—6 —基甲基）—2 — ( 4 - □比Π定—4 一基一喊嗦 —1—基）一乙基〕一醯胺； 4一 （2 —酮基一1，4 —二氫一2H—D奎唑啉一3 —基） 一帳Π定—1 一竣酸〔2-酮基—1— (2-酮基一 2，3 —二氫 —苯並噁唑一6 —基甲基）一 2 —哌啶一 1—基一乙基〕一 醯胺； 4一 （2 —酮基一1，4 —二氫一2H —喹唑啉一3 —基） —哌啶一1 一羧酸〔2 — （ 4 一甲基—哌嗪一1 —基）—2 — 酮I基一1— (2 —嗣基一 2，3 —二氣一苯並Π惡哗—6—基甲 基）一乙基〕一醯胺； 4— (2 —酮基一1，4 —二氫一2H — D奎唑啉一3 —基） —哌啶一 1 一羧酸〔2 -〔 1，4 /〕聯哌啶—1 / —基—1 — (4 —甲基一 2 —酮基—2，3 -二氫—苯並噁唑一 6—基甲 基）一 2-酮基—乙基〕一醯胺； 4 — ( 2 —嗣基一1 ’ 4 — —•氣一2 Η 一 口奎 口坐琳一3 —基） 一哌Π定一 1 一殘酸〔1— (4 一甲基一 2 —調基一 2’ 3 — 一氣 —苯並Β惡Π坐—6—基甲基）—2—酮[基—2—派Π定一 1 一基一 乙基〕一醯胺； 4一 （2 —酮基一1，4 —二氫一 2Η — □奎唑啉一3 —基） 一哌啶一1 —羧酸〔1 一（ 4 一氯一 2 -酮基一 2，3 —二氫一 苯並噁唑一 6 —基甲基）一 2 -酮基一 2 —哌啶—1 一基—乙 -488 - 200529835 (15) 基〕一醯胺； 4 — ( 2 一 嗣基一1，4 — 一* 氧一2 Η 一 D 奎 口坐琳一3 — 基） —哌啶一 1 一羧酸〔1 一二甲基氨基甲醯基一 2 —（4 一甲基 一 2 —酮基一2，3—二氫一苯並噁唑—6—基）—乙基〕— 醯胺； 4 一（2 —酮基—1，4一二氫—2H—D奎唑啉—3 —基） 一喊卩定一 1 一殘酸〔2-（4 —氯一 2 —酮|基—2，3 - 一氯— 苯並噁唑一 6—基）—1 一二甲基氨基甲醯基一乙基〕一醯 胺； 4 一 （2 —酮基一1，4 —二氫一2H—D奎唑啉一3 —基） 一哌啶一1 一羧酸〔1 一（4 —甲基—2 —酮基—2，3—二氫 一苯並噁唑一 6—基甲基）一 2—酮基一 2 —（4一吡啶一 4 —基一哌嗪一 1 —基）—乙基〕一醯胺； 4— (2 —酮基一1，4 —二氫一2Η — D奎唑啉一3—基） —哌啶—1—羧酸〔1— (4 —氯—2 —酮基—2，3-二氫— 苯並II惡D坐一 6 —基甲基）一 2 —嗣基一2— （4 一 〇比Π定一4 — 基一哌嗪—1 一基）一乙基〕一醯胺； 4— (2 —酮基一1，4一二氫一2Η — D奎唑啉一3 —基） 一哌啶—1 一羧酸〔2 -〔 1，4 /〕聯哌啶—1 / 一基一 1 — (4 一乙基一2 —酮基一2，3 —二氫—苯並噁唑一6 —基甲 基）一 2—酮基一乙基〕一醯胺； 4— (2 —酮基一1，4 一二氫一2H-D奎唑啉一3 —基） 一哌D定—1 —殘酸〔2 —〔 1，4 /〕聯丨派Π定—1 / —基一 1 一 (7—甲基—2 —酮基一 2，3 —二氫—1Η —苯並咪唑—5 — -489- 200529835 (16) 基甲基）一 2—酮基一乙基〕一醯胺； 4 — (2 — 基一1 ’ 4 — 一氣一2 Η 一 D 奎 口坐琳 一 3 —基） —哌啶一 1 —羧酸〔2 —〔 1，4 /〕聯哌啶—厂—基一 1 — (7-氯—2 -酮基—2，3 —二氫一 1Η —苯並咪唑—5 —基 甲基）一 2—酮基一乙基〕一醯胺； 4 一 （2 —嗣基一 1，4 _ —>氨一 2Η — D奎哗琳一3 —基） —哌啶—1 —羧酸〔2 —〔 1，4 /〕聯哌啶—1 — 一基—1 — (7 —乙基一2 —酮基—2，3—二氫—1Η-苯並咪唑—5 — 基甲基）—2—酮基一乙基〕一醯胺； 4- (2—酮基一1，4一二氫一2Η — D奎唑啉一 3 —基） 一哌啶—1 一羧酸〔2 —〔 1，4 /〕聯哌啶一厂—基—1 一 (3 —甲基一 2 —酮基一2，3 —二氫一 1Η—苯並咪唑一 5 — 基甲基）—2—酮基一乙基〕一醯胺； 4 一（2 —酮基一 1，4 —二氫—2Η —喹唑啉一3 —基） —呢卩定一 1 —竣酸〔2 —〔 1，4 〕聯呢D定—1 一基一 1 — (3 ’ 7 — __•甲基一 2 —嗣基—2 ’ 3 — 一氣—1 Η 一苯並味口坐 —5—基甲基）一 2—酮基一乙基〕一醯胺； 4 — ( 2 一 嗣基一1，4 一 —* 氨 一 2 Η — D 奎 D坐琳一3 —基） 一哌啶—1 一羧酸〔2 -〔 1，4 /〕聯哌啶一 1 / —基一 1 — (7—氯—3 —甲基一 2-嗣基—2，3—二氯—1Η —苯並味 唑一 5—基甲基）一 2 —酮基一乙基〕一醯胺； 4一 （2 —酮基一 1，4一二氫一2Η — D奎唑啉一 3 —基） —1帳卩定—1 —竣酸〔2 —〔 1，4 〕聯脈D定一 1 —基一 1 — (7 —乙基一 3 —甲基一 2 —酮基一 2，3 —二氣一1Η—苯並 -490- 200529835 (17) 咪唑一 5-基甲基）一 2—酮基一乙基〕一醯胺； 3— (7 —甲基一1H — D 引唑一5 —基）一2— { 〔4—( 2 一嗣基一1 ’ 4 — 一^氣一2 Η — D奎口坐琳一3 —基）一爬D疋一1 一羰基〕一胺基} 一丙酸異丙酯； 3— (7 —氯—1Η —吲唑—5 —基）—2— { 〔4— ( 2 —酮基一1，4 —二氫一2Η — D奎唑啉一3 —基）一哌啶一1 一羰基〕一胺基} 一丙酸異丙酯； 3— (7 —乙基一1Η — D 引唑一5 —基）一2— { 〔4—( 2 —酮基一1，4一二氫一2H—D奎唑啉一 3 —基）一哌啶一 1 一羰基〕一胺基丨一丙酸異丙酯； 3 — ( 7 —氣一1 Η — D 引口坐一5 —基）一2 — { [ 4 — (2 —酮基一1，4一二氫一2Η —喹唑啉一3 —基）一哌啶一 1 一羰基〕一胺基} 一丙酸特丁酯； 3— (7 —乙基一1Η — D 引唑一5 —基）一2— { 〔4—( 2 —酮基—1，4 —二氫一 2Η — D奎唑啉—3 -基）一哌啶一 1 一羰基〕一胺基} 一丙酸特丁酯； 3— (7 —氯一1Η — 口引唑一5 -基）一2— { 〔4— ( 2 —嗣基一1 ’ 4 — 一·氣一 2 Η — D奎口坐咐一3 —基）一派Π疋一1 一羰基〕一胺基} 一丙酸環己酯； 3— (7 —乙基一1Η — D 引唑一5 —基）一2— { 〔4—( 2 —酮基一 1，4 —二氫一 2Η —喹唑啉一 3 —基）一哌啶—1 一羰基〕一胺基} 一丙酸環己酯； 3— (7 —氯一1Η — 口引唑一5 —基）一2— { 〔4— ( 2 一酮基一 1，4 —二氫一 2Η —喹唑啉一3 —基）一哌啶一1 -491 - 200529835 (18) 一羰基〕一胺基丨一丙酸 1 一甲基一哌啶一 4 —酯； 3— (7 —乙基一1H — D 引唑一5 —基）一2— { 〔4—( 2 —酮基—1，4 —二氫—2 Η —喹唑啉一 3 —基）一瞻啶一 1 一羰基〕一胺基} 一丙酸 1 一甲基一哌啶一 4一酯； 3— (7 —氯—1Η — D 引卩坐—5 —基）—2— { 〔4— (2 一酮基一1，4一二氫一2Η — D奎唑啉一3 —基）一哌啶一1 一羰基〕一胺基} 一丙酸 1 一甲基一環己酯； 3— (7 —乙基一1Η — 口 引唑一5-基）一2— { 〔4-( 2 —嗣基—1 ’ 4 — 一《氯一 2Η — D奎D坐琳一 3 -基）一派D定一 1 一羰基〕一胺基} 一丙酸 1 一甲基一環己酯； 3— (7 —氯一 1H—D引唑一5 —基）一2 — { 〔4— (2 —嗣基一1 ’ 4 — —•氯一2 Η — D奎口坐琳一3 —基）一喊D定一 1 一羰基〕一胺基} 一丙酸 4 一苯基一環己酯；或 3— (7 —乙基一1Η — D 引唑一5 —基）一2— { 〔4-( 2 —酮基一 1，4 —二氫一 2Η — D奎唑啉一 3 —基）一哌啶一 1 一羰基〕一胺基} 一丙酸 4 一苯基一環己酯；或 其醫藥上可接受之鹽或溶劑化物。 3. 一種醫藥組成物，其包含選自下述之化合物： (土）一 3— （3 —氛基一1Η—口引卩朵一5 —基）一2— { 〔4一 （2 —酮基一 1，4一 二氫一2H—D奎唑啉一3 —基）一 哌啶一 1 一羰基〕一胺基} 一丙酸甲酯； (土）一 4 一 ( 2 —酬基 一 1 ’ 4 — —•氣—2 Η — 口奎 口坐琳一 3 —基）—哌啶—1 —羧酸〔2 —〔 1，4 /〕聯哌啶—1 / — 基一 1— (3 —氰基—1Η—吲哚一 5 —基一甲基）一 2 —酮 -492- 200529835 (19) 基一乙基〕一酸胺； (土）一 4 一 ( 2 —嗣基一1，4 — •氯一2 Η -3 —基）一哌啶一 1 一羧酸〔2 —〔 1，4 /〕聯哌 基一1 (3 —氯基—7 —甲基—1Η — D引D朵一 5— J 一 2 -酮基一乙基〕一醯胺； (±) — 3 — （7 —異丙基一1Η—吲唑一5 — { 〔4— (2 —酮基一1，4 —二氫一2Η — D奎唑啉 一哌啶一 1 一羰基〕一胺基} 一丙酸甲酯； (土）一 4 — ( 2 —嗣基一1，4 — 一 氣一2 Η -3 —基）—哌啶—1 —羧酸〔2 —〔 1，4 —〕聯哌 基一 1 (7 —異丙基一1Η — D引嗤—5 —基一甲基 基一乙基〕—醯胺； (±) — 4— (2 —酮基一1，4 —二氫一2Η- 3 —基）—哌啶一 1 —羧酸〔2 —〔 1，4 /〕聯哌 基一1 (7_乙基—1Η —吲唑一5 —基一甲基） 一乙基〕一醯胺； (土）一 4 — (2，2 — —•嗣基一1 ’ 4 — 一^ 氣一 2λ6 —苯並〔1，2，6〕喧一*嗦一3 —基）一呢 酸〔2 - 〔 1，4 —〕聯哌啶—厂—基—1 ( 7 — 一 D引卩坐一 5—基一甲基）—2—酬基一乙基〕一醒 (土）一 4 — (2，2 — —•酬基一1 ’ 4 — 一^氣一 2 λ 6 —苯並〔1，2，6〕噻二嗪—3 —基）—哌 酸〔2 - 〔 1，4 >〕聯哌啶—1 / 一基—1 ( 7 — 甲基一 1Η — D引哗一 5 —基一甲基）一2 —嗣基一 -口奎唑啉一 啶-厂— ;一甲基） 基）一 2-—3—基） -D奎唑啉一 卩定—1 — )—2 —酮 -D奎唑啉一 Β定—1 — 一 2 —酮基 2Η - D定一 1 一竣 甲基一 1 Η :胺； 2Η - 啶—1 —羧 乙基一3 — 乙基〕一(±) — 4— (3— (7 —methyl-1H — D azole—5-yl) — 2 — {[4 — (2 —amino-1, 4 — — qi-1 2 Η — D Kui D-Zeline- 3 -yl) -piperidine- 1-carbonyl] -amino}}-propionyloxy) -piperidine- 1-tert-butyl carboxylic acid; 1Η —indazole-5 —yl) 2 — {[4 -— (2-keto-1,4-dihydro-2Η—D quinazolin-3-yl) -piperidine-1 1-carbonyl] -amine } —Propionic acid 3,4,5,6—tetrahydro-1 2Η — [1,4] hydrazidine-4 monoester; (±) — 3— (7 —methyl-1 1Η — D 5 -yl)-2-{-485- 200529835 (12) [4- (2- keto-1,4-dihydro-2H-D quinazoline -3-yl) -piperidine-1 -carbonyl] Monoamine 丨 monopropionic acid 1 diethylamino -1 monomethyl monoethyl ester; (±) — 3 — (7 —methyl mono 1H — indazole 5 —yl) — 2 〔[4 — (2-keto-1,4-dihydro-2H—D quinazoline-3—yl) -piperidine-1 monocarbonyl] —amino} monopropionate 1,1-dimethyl-1 2- Phenyl- Esters; (±) — 3— (7-methyl-1H—D-indolizol-5-yl) —2— [[4 -— (2—keto-1,4-dihydro-2H—D quinazoline A 3-yl) -piperidine-1 monocarbonyl] -amino group} 1,1-dimethyl-3-phenyl monopropyl propionate; (earth) a 3- (7-methyl-1 1 Η — D-introducer — 5-yl) — 2 — {[4 -— (2-keto-1,4-dihydro-2 一 —D quinazoline—3-yl) —piperidine—1—carbonyl] — Amine} —Ethyl propionate (±) — 1 — (7-methyl-1, 1 ′ — D-azole- 5-ylmethyl) — 2 — [1 —pyridine — 4-yl —methyl] — 2 — Ketoethyl]-2-, 3 _-diaza-2 -ketospiro — [_ Ddefinitely 4,4 — (1 Η) — quinazolin]-1 -carboxamidine; (±) — 1 — (7-methyl-1,1—indazole-5—ylmethyl) —2— [1, 1—1, 2—1—1—1, 1—1, 1—1, 2—1, 1—1, 1—1, 2—1, 2—1, 2—3, 3—one, 3, 2—one, 3, 1—one, 2—3, 1—one, 2—one, 2—3 '—Dihydro-2 / —ketospiro — [piperidine-4, 4 / — (1Η)-quinazoline]-1 -carboxamide; (±) — 1- (7 —methyl-1Η —Indazole-5-methyl-methyl) -2 2- [2-dimethylamino-ethyl-ethyl-carbamoyl]-2-keto-486- 200529835 (13) ylethyl]-2 / , 3 > —dihydro-2, —ketospiro- [piperidine-4, 4/1 (1 Η)-D quinazoline]-1 -carboxamide; (±) — 1- (7— Methyl-1,1-D, 2-azole, 5-ylmethyl), 2-, [1, 1-methyl, 4-, 4-methyl, 1-methyl], 2-, 2-ethyl], 1'-dihydro-2, 1- Ketospiro— [4Η—3,, 1-benzoxazine-4,4 > monopiperidine] -1 1-carboxamidine; (±) — 1- (7-methyl-1 1-indazole— 5-ylmethyl)-2-[1-pyridine-4-yl-methyl] -2-ketoethyl] -plant, 2 -amino-2 -fluorenylspiro- [4Η-3, 1- Benzo D oxazine 4,4 — — — 定 定] — 1 —Junamine; (R) — 4 — (2 —Keto-1,4 —dihydro — 2Η —quinazolin — 3 —yl ) 1 piperidine D 1 d —residual acid [2-[1, 4] dipiperidine 1 1 -yl 1-(7 -methyl 1H -indazole 5 -ylmethyl)-2- ketone (Monoethyl) -ammonium amine; or (R) — 1 — (7 —methyl — 1 Η — D inlet — 5 —ylmethyl) — 2 — [1, 4 /] dipiperidine — 1 / —Yl — 2 —ketoethyl]-2 /, 3-dihydro-2, — ketospiro — [piperidine-4, 4 > — (1Η) — quinazoline] 1 1 carboxyl Amidine; or a pharmaceutically acceptable salt or solvate thereof. 2. A compound selected from the group consisting of 4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine-1_carboxylic acid [2 — [1,4 ,] Piperidine-1 > -yl-1-(7-bromo-1,1-indazol-5-ylmethyl) -2-ketomonoethyl] -487-200529835 (14) pyridine; 4- (2-keto-1,4-dihydro-2H- □ quinazoline-3-yl) 1-Pyridin-1 monocarboxylic acid [2-keto-1— (2-keto-1 2,3-dihydro-benzobenzoxyl-6-ylmethyl) -2- (4-□ than Ding-4-1 -yl- 1 -yl) -ethyl] -pyramine; 4-((2-keto-1,4-dihydro-2H-D quinazoline-3-yl) , 3-dihydro-benzoxazole-6-ylmethyl)-2-piperidine-1-yl-ethyl] -ammonium amine; 4- (2-keto-1,4-dihydro-2H —Quinazoline-3 —yl) —piperidine-1 monocarboxylic acid [2 — (4-methyl-piperazine-1 —yl) —2 — keto I group — 1 — (2 —fluorenyl — 2, 3 — two gas one Oxin-6-ylmethyl) monoethyl] -amidine; 4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine-1 Monocarboxylic acid [2-[1,4 /] bipiperidin-1 / -yl-1-(4-methyl-1 -keto-2,3-dihydro-benzoxazole-6-ylmethyl A) 2-keto-ethyl] -ammonium amine; 4 — (2 —fluorenyl — 1 ′ 4 — — • gas — 2 Η a mouthful of hydrazine — 3 —yl) a piperidine — 1 — Residual acid [1- (4-methyl-2, humor-2 '3—one gas-benzo-β-oxan-6-ylmethyl) -2-ketone Monoethyl] monomethylamine; 4- (2-keto-1,4-dihydro-1,2Η- □ quinazoline-3-yl) -piperidine-1-carboxylic acid [1- (4-chloro -2-keto-2,3-dihydro-benzoxazole-6-methyl)-2-keto- 2-piperidine-1 -yl-ethyl-488-200529835 (15) yl]- Amidamine; 4 — (2 amidino-1,4 —a * oxygen — 2 Η 1 D quinoxaline — 3 —) —piperidine — 1 — carboxylic acid [1 — 2 Aminocarbamoyl- 2-(4-methyl-2 -keto-2,3-dihydro-benzoxazol-6-yl) -ethyl] -fluorenamine; 4-(2-keto —1,4—dihydro—2H—D quinazoline—3-yl) yelline—1—residual acid [2- (4-chloro-2—one—keto | yl-2,3—monochloro—benzene Oxazolyl-6-yl) -1 dimethylaminocarbamoyl-ethyl] monofluorenamine; 4-mono (2-keto-1,4-dihydro-2H-D quinazoline-3 3- Radical) monopiperidine-1 monocarboxylic acid [1-mono (4-methyl-2-keto-2,3-dihydromonobenzoxazole-6-ylmethyl) 2-keto-2 — (4-pyridyl-4-yl-piperazine-1-yl) -ethyl] monofluorenamine; 4- (2-keto-1,4-dihydro-2fluorene-D-quinazoline-3-yl) —Piperidine-1—carboxylic acid [1— (4-chloro-2 —keto-2,3-dihydro —benzo IIoxD — 6-ylmethyl) — 2 —fluorenyl — 2 — ( 4- (10-)-(4-methyl-piperazine- 1-yl) -ethyl] -ammonium amine; 4-(2-keto-1,4-dihydro-2 hydrazone-D quinazoline- 3- Base) Monopiperidine-1 monocarboxylic acid [2-[1,4 /] bipiperidine-1 / 1 radical-1-(4 monoethyl -2 -keto -2,3 -dihydro -benzoxazole 1- (6-methyl)-(2-keto) -ethyl] -amidine; 4- (2- (keto) -1,2-dihydro-2H-D-quinazoline-3-yl) -piperidine —1 —Residual acid [2 — [1,4 /] biphenylidene-1 / 1 —yl-1 1- (7-methyl-2 —keto-1,2,3-dihydro-1Η —benzimidazole —5 — -489- 200529835 (16) Methyl) 2 -ketomonoethyl] monomethylamine; 4 — (2-methyl-1 ′ 4—one gas one 2 Η one D Kuizuline-1 —Yl) —piperidine-1 —carboxylic acid [2 — [1,4 /] dipiperidine—factory —yl-1 — (7-chloro-2-keto-2,3 —dihydro-1,1 —benzene Benzimidazole-5-ylmethyl) -2-ketomonoethyl] monomethylamine; 4-mono (2-methylamino-1,4 — —> ammonia —2 methyl — D quinoxaline 3 —yl) —Piperidine-1 —carboxylic acid [2 — [1,4 /] bipiperidine-1 — 1 — 1 — 1 — (7 —ethyl — 2 —keto — 2, 3 —dihydro — 1 — benzo —benzo] Imidazole-5 Methyl) -2-ketomonoethyl] monomethylamine; 4- (2-ketomono-1,4-dihydro-2ino-D quinazoline-3-yl) monopiperidine-1 monocarboxy Acid [2 — [1,4 /] dipiperidine one plant —yl — 1 — (3-methyl — 2 —keto — 2, 3 —dihydro — 1 — benzimidazole — 5 — methyl) —2-ketomonoethyl] monofluorenamine; 4-one (2-keto-1,4-dihydro-2hydrazone—quinazolin-3—yl) —noridine-1—complete acid [2 — 〔1,4〕 Dynamic D—1 one base one 1 — (3 '7 — _ •• methyl one 2 —fluorenyl — 2' 3 — one gas — 1 Η one benzoate mouth sitting — 5 — base A) 2 -ketomonoethyl] -ammonium amine; 4-(2 -amidino-1,4--* ammine 2 -a Carboxylic acid [2-[1,4 /] bipiperidine- 1 / -yl-1-(7-chloro-3 -methyl-2-fluorenyl-2,3-dichloro-1 fluorene -benzazole A 5-methyl group) a 2-ketomonoethyl] -ammonium amine; 4-a (2-keto-1,4-dihydro-2a-D-quinazoline-a 3-yl) — 1 account Ding -1-Junic acid [2 — [1, 4,] Dianmai D Ding 1-1-1-1-(7-ethyl-3-methyl-2-keto-2, 3-digas-1Η- Benzo-490- 200529835 (17) Imidazol-5-ylmethyl) -2-ketomonoethyl] monofluorenamine; 3- (7-methyl-1H-D indazole-5-yl) -2 — {〔4— (2 amidino-1 ′ 4 — a ^ qi a 2 Η — D Kuikouzai Lin 3 — a) a climb D 疋 1 1 carbonyl] monoamine} isopropyl propionate Ester; 3- (7-chloro-1—-indazol-5-yl) -2- 2- {[4— (2-keto-1,4-dihydro-1, 2Η-D-quinazolin-3-yl)- Piperidine-1 monocarbonyl] monoamino} isopropyl monopropionate; 3- (7-ethyl-1 一 -D indazole-5-yl)-2 {[4— (2 —keto-1 , 4-dihydro-2H-D quinazoline-3-yl) -piperidine-1 monocarbonyl] -amino group isopropyl propionate; 3 — (7 —gas — 1 Η — D One 5-yl) one 2- {[4- — (2-keto-1,4-dihydro-2 hydrazone-quinazoline-3-yl) -piperidine-1 1-carbonyl] -amino group} one Tert-butyl acid ester; 3- (7-ethyl-1 1- — D indazole-5-yl)-2 [{4-(2 -keto-1,4-dihydro-2 2-D quinazoline- 3 -yl) -piperidine-1 monocarbonyl] monoamino} tert-butyl propionate; 3— (7 —chloro-1Η — oxazole-5 —yl) — 2 — {[4— (2 — Fluorenyl-1 ′ 4 —one · gas 2 2 Η—D Kuikou zuyi a 3—yl) a group Π 疋 -1 1 carbonyl] monoamine} cyclohexyl propionate; 3 — (7 — ethyl 1 1 Η — D indazole — 5 —yl — 2 — {[4- (2 -keto-1,4-dihydro-2 2 —quinolinol —3-yl) -piperidine-1 —carbonyl] — Amine} Cyclohexyl monopropionate; 3- (7-chloro-1Η-orazol-5-yl)-2- [[4— (2 monoketo-1,4-dihydro-2Η-quine Oxazoline- 3-yl) -piperidine- 1 -491-200529835 (18) monocarbonyl] -amino group-propionic acid 1 -methyl-piperidine- 4 -ester; 3-(7 -ethyl-1H — D Indazole—5-yl) —2— [[4 -— (2-keto-1,4-dihydro-2—fluorene—quinazoline—3-yl) —pyridine— 1 monocarbonyl] monoamine} monopropionate 1 methyl monopiperidine 4 monoester; 3— (7 —chloro—1Η — D indio —5 —yl) — 2 — {〔4— (2 1-keto-1,4-dihydro-2Η — D quinazoline — 3-yl) -piperidine-1 1 carbonyl] monoamino} monopropionate 1 monomethyl cyclohexyl ester; 3 — (7 — Ethyl-1Η — orallyzol-5-yl) — 2 — {[4- (2 —fluorenyl — 1 ′ 4 — 1 —chlorine 2Η — Dquinol — 3 —yl) 1 1 monocarbonyl] monoamino} monopropionic acid 1 methyl monocyclohexyl ester; 3— (7—chloro—1H—D azole—5-yl) —2 — {[4— (2 —fluorenyl-1 '4 — — • Chloro-2 Η — D Kuizulin 3 —yl) yell D 1 — 1 carbonyl] monoamino} monopropionate 4 phenyl monocyclohexyl ester; or 3 — (7 — Ethyl-1,1-D, 3-azole, 5-yl), 2-, [[4- (2-keto-1,4-dihydro-2,2-D, quinazoline-3-yl), 1-piperidine, 1- Carbonyl] monoamino} monopropionate 4-phenylphenylcyclohexyl ester; or a pharmaceutically acceptable salt or solvate thereof. 3. A medicinal composition comprising a compound selected from the following: (Earth)-3-(3-aryl group-1 Η-mouth indole-5-group)-2-{〔4 一 (2- ketone -Methyl 1,4-dihydro-2H-D quinazoline-3-yl) -piperidine-1 1-carbonyl] -amino} methyl propionate; 1 '4 — — • qi — 2 Η — Kou Kui Zi Lin-3 —) —piperidine — 1 — carboxylic acid [2 — [1, 4, /] bipiperidin — 1 / — base 1 — ( 3-Cyano-1-fluorene-indole-5-yl-methyl) -2-keto-492- 200529835 (19) yl-ethyl] monoacidamine; (Earth) -4 4- (2-fluorenyl-1 , 4 — • Chloro-2H 3 -yl) -piperidine- 1 monocarboxylic acid [2 — [1,4 /] bipipel-1 (3-Chloro-7-methyl-1H — 1 D-do 5—J—2-keto-ethyl] -ammonium amine; (±) — 3 — (7-isopropyl—1—-indazole—5 — {〔4— (2 —keto-1 , 4-dihydro-2Η-D quinazoline-piperidine-1 1-carbonyl] -amino} methyl propionate; (Earth) 4-(2 -fluorenyl-1 , 4—one gas one 2 Η -3 —yl) —piperidine — 1 —carboxylic acid [2 — [1, 4, —] bipiperidinyl 1 (7 —isopropyl-1 Η — D fluorene — 5 — group Monomethyl-ethyl] -amidamine; (±) — 4 -— (2-keto-1,4-dihydro-2Η-3 —yl) —piperidine-1—carboxylic acid [2 — [1 , 4 /] bipiperidinyl-1 (7-ethyl-1'-indazole-5'-yl-methyl) -ethyl] monofluorenamine; (Earth) -4-(2,2--• fluorenyl 1 1 '4 — 1 ^ gas — 2λ6 — benzo [1,2, 6] benzo [1, 2 — 6] benzoic acid [2-[1, 4 —] dipiperidine-plant-base-1 (7 — 1 D phenyl group — 5 —yl — methyl) — 2 — phenyl — ethyl] — (soil) — 4 — (2, 2 — — • phenyl — 1 '4 — yee -2 λ 6 -benzo [1,2,6] thiadiazine-3-yl) -piperic acid [2-[1, 4 >] bipiperidin-1 / monoyl-1 (7-methyl A 1-fluorenyl-D group, a 5-methyl-methyl group, a 2-fluorenyl group, a quinazoline-pyridine group, a monomethyl group, a 2-methyl group, and a 3-methyl group.卩 定 —1 —) —2 — Keto-D quinazoline-β-determined by 1-1-2 -keto 2 '-D-determined by 1 1-methyl 1 1: amine; 2--pyridine-1-carboxyethyl-3-ethyl]- -493- 200529835 (20) 醯胺； (±) — 2— 〔4— (6 —氰基一2 —酮基一1，4 —二氫 一 2H -喹唑啉一 3 —基）一哌啶一 1 一羰基〕-胺基〕一 3 一 （7 —甲基一1 Η —吲唑一 5 —基）一丙酸甲酯； (土）一 4 一 （6 —氰基一2 —酮基一1，4 —二氫一2Η 一喹唑啉一 3 -基）一哌啶一 1 一羰基{ 2 - 〔 1，4 /〕聯 喊Π定一1 —基一 1 — (7 —甲基—1Η — D引η坐一5 —基—甲-493- 200529835 (20) pyridoxamine; (±) — 2— [4 -— (6-cyano-2—keto-1,4-dihydro-2H-quinazolin-3—yl) -piperidine -1-monocarbonyl] -amino]-3-(7 -methyl-1 fluorene-indazole-5-yl) monopropionate; (Earth)-4-(6-cyano-2-keto) 1,4-dihydro-2, 1-quinazoline-3-yl) -piperidine-1, 1-carbonyl {2-[1,4 /] —1Η — D 引 ηη 一 -5 — 基 — 甲 基）一 2—酮基一乙基} 一醯胺； (土）一 4 一 ( 2 —嗣基一1’2’ 4，5 —四氯一苯並〔 d ] 〔1，3〕二氮雜罩一3—基—1一羧酸{2—〔1，4/〕 聯哌啶一1 / —基一 1 — ( 7 —甲基一 1 Η —吲唑一 5 —基一 甲基）一2—酮基一乙基}一醯胺； (±) — 4— (6 —羥基一2 —酮基一 1，4一 二氫一2Η —D奎哇琳一 3 —基）一哌D定一 1 一殘酸{ 2 -〔 1，4 〕聯 呢陡一1 一基一 1 — (7 —甲基一 1Η — D弓丨口坐一5 —基一甲(Yl) -2-ketomonoethyl} monofluorenamine; (Earth) -4 (2-pyridyl-1'2 '4,5-tetrachloro-benzo [d] [1,3] diazepine Miscellaneous 3-yl-1-monocarboxylic acid {2- [1,4 /] Bipiperidinyl-1 / -yl-1— (7-methyl-1 1 fluorene-indazole-5-yl-methyl) -2-keto-ethyl} -amidine; (±) — 4 -— (6-hydroxy-2—keto—1,4—dihydro—2Η —D quinaline—3-yl) —piperidine D Fixed 1 1 residual acid {2-[1, 4] bien steep 1 1 radical 1 — (7 —methyl 1 1 — — D bow 丨 mouth sitting 5 — base 1 A 基）一2—醒基一乙基}一醯胺； (土）一 4 — (8 —甲氧基一2 —嗣基一1，4 — __•氣一 2 Η —喹唑啉—3 —基）一哌啶—1 —羧酸{ 2 —〔 1，4 /〕 聯哌啶一 1 > 一基一 1 一 （ 7 —甲基一 1 Η —吲唑一5 —基一 甲基）一 2 —酮基一乙基} 一醯胺； (土）一 4 — (8 —氯一2 —嗣基一1，4 — 一 氯一2 Η — 口奎ϋ坐琳一 3 —基）一丨哌卩定一 1 一竣酸{ 2 - 〔 1 ’ 4 〕聯丨 Π定一 1 —基一1 — (7 —甲基—1 Η — D引坐一5 —基一甲基 )一 2-酮基—乙基} 一醯胺； -494- 200529835 (21) (±) — N— (3— (7 —乙基一3 —甲基一1H — D引唑 一 5 —基）一 1 —酮基—1 — ( 4 —(哌啶—1 —基）哌啶一 1 一基）丙一 2-基）—2 / ，3> —二氫一 2，—酮基螺—（ Π辰啶一 4，4 / 一 D奎唑啉）一 1 一羧醯胺； (±) — N— (3— (7 —乙基一3 —甲基一 1H — D引唑 一 5 —基）一 1 一酮基—1 一（ 4 一（哌啶—1 —基）哌啶—1 —基）丙一 2—基）—2，4 —二氫一 2 —酬基螺一（哌Π定 —4，4' 一 1H —苯並〔d〕 〔 1，3〕D惡嗪）—1—竣醯胺 > (±) — N— (3— (7 —乙基一1H — D 引唑一5 — 基） —1— (6，7 —二氫一1H — D比唑並〔4，3— c〕口比啶一5( 4H) - 基）—1 一 酮基丙—2 —基）—4一（1，2 - 二氫一 2 -酮基喹唑啉一 3 ( 4H ) -基）哌啶一 1 一羧醯胺； (±) — N- (3 — （7— 乙基一1H-D 引唑一5 —基） —1— (6，7 —二氫一7，7 —二甲基一1H — D比唑並〔4，3 一 c〕D比啶一 5(4H) — 基）一1—酮基丙一2—基）一4 — (1，2 —二氫一 2 —酮基D奎唑啉一 3 ( 4 Η )—基）哌啶一 1 -羧醯胺； (±)—甲基 2— (4— (8—氟一1，2 —二氫一2 —酮 基喹唑啉一 3 ( 4 Η ) -基）哌啶—1 一羧醯胺基）一 3 - （ 7 —甲基一 1 Η —吲唑一 5 —基）丙酸酯； (±) — 4 — （8 —氣一1，2 — _•氨一2 —醒基口奎口坐琳 -3 ( 4Η )—基）一Ν— (3— (7 —甲基一1Η — D引唑一 5- 基）—1一嗣基—1— (4—([派D定一 1 一基）哌D定—1 一） - 495- 200529835 (22) 丙—2 —基）哌啶一 1 一羧醯胺； (±) — 4 一 （8—氟一 1，2—二氫一 2—酮基喹唑啉 -3 ( 4H ) 一基）一 N— ( 3 - (7 —甲基一1H —吲唑一5 — 基）一 1—酮基—1 一（4 一苯基哌嗪一 1 一基）丙—2 —基 )哌D定一 1 一殘酿胺； (土）一 4 — (8 —氣一1 5 2 — _•氯一 2 —嗣基口奎口坐琳(Yl)-2 -pentyl-ethyl} -amidamine; (Earth)-4-(8 -methoxy- 2 -amidino-1,4-__ • gas-1 2-quinazoline-3- Group) monopiperidine-1-carboxylic acid {2 — [1,4 /] dipiperidine-1 1 > mono-1-1 (7-methyl-1 1 hydrazine-indazole-5-yl-methyl) A 2-ketomonoethyl} monofluorenamine; (earth) a 4 -— (8-chloro-2 2-fluorenyl-1,4—monochloro-2 hydrazone — a quaternary triazine-1 3-yl) a丨 piperidine-1 monocarboxylic acid {2-〔1 '4】 Coupling 丨 π-1—1-methyl-1 — (7-methyl-1 Η — D-adaptive 5-methyl-1methyl) —2 -Keto-ethyl} monofluorenamine; -494- 200529835 (21) (±) — N— (3— (7—ethyl—3—methyl—1H—D-azole—5-yl) —1 —Keto-1 — (4 — (piperidin-1-yl) piperidine-1 1-yl) propan-2-yl) -2 / ， 3 > —dihydro-2, —ketospiro— (Π 辰Pyridinyl-4,4 / -D quinazoline) -1 Carboxamide; (±) — N— (3— (7—Ethyl 3—methyl—1H—D-azole—5-yl) — 1 a 1-1- (4- (piperidine-1-yl) piperidine-1-yl) propan-2-yl) -2,4-dihydro-2 2-pyrrolyl-1 (piperidine-4,4 '1H —benzo [d] 〔1,3〕 D oxazine) —1—endamidine> (±) — N— (3— (7 —ethyl—1H — D) ) —1— (6,7 —dihydro-1H — D-pyrazolo [4,3—c] pyridine-5 (4H) -yl) -1—one ketopropan-2-yl) —4-one (1,2-dihydro-2-ketoquinazoline-3 (4H) -yl) piperidine-1 monocarboxamide; (±) — N- (3 — (7-ethyl-1H-D Indazole-5-yl) —1— (6,7-dihydro-7,7-dimethyl-1H—D-pyrazolo [4,3-c] D-pyridinyl-5 (4H) —yl) -1-ketopropan-2-yl) -4- (1,2, dihydro-2, keto-D-quinazoline-3 (4Η) -yl) piperidine-1-carboxamide; (± ) —Methyl 2— (4- (8-fluoro-1,2-dihydro-2—ketoquinazoline-3 (4Η) -yl) piperidine-1—carboxamido) —3— (7-methyl-1,1,2-indazol-5-yl) propionate; (±) — 4 — (8 — Qi-1, 2 — _Ammonia — 2 — Xingjikou Kuikouline-3 (4Η) —yl) — N — (3 — (7 —methyl — 1Η — Dazole) -5-yl) —1—fluorenyl—1— (4 — ([Paid D 1 — 1 1) piperidine 1 — 1) — 495- 200529835 (22) Propan-2-yl) piperidine 1 1 Monocarboxamide; (±) — 4- (8-fluoro-1,2-dihydro-2-ketoquinazoline-3 (4H) -yl) -N— (3-(7-methyl- 1H —indazole-5 —yl) — 1 —keto — 1 ((4-phenylpiperazine — 1 —yl) propan — 2-yl) piperidine — 1 — residual amine; (earth) — 4 — (8 —qi one 1 5 2 — _ • chloro one 2 —Yan Jikou Kuikou Zuolin —3(4H)—基）—N— (1— (4 - （4 —氟苯基）哌嗪一 1 一基）一3 — （7—甲基一1H — D引唑一 5 —基）一1 一酮基 丙一 2 -基）哌D定一 1 一殘醯胺； (±) — 4 一 （8 —氣一 1，2— 一氯一 2 —嗣基D奎口坐琳 —3 ( 4 Η ) 一基）—Ν-（1— (4 一（2—氟苯基）_ 嗪— 1 一基）一3— (7 —甲基—1Η —吲唑一 5 —基）—1—酮基 丙一 2 -基）哌啶一 1 一羧醯胺； (±) — 4— (8 —氟一1，2—二氫一2 —酮基喹唑啉—3 (4H) —yl) —N— (1— (4- (4-fluorophenyl) piperazine-1 1-yl) —3— (7-methyl-1H—D-azole—5-yl) 1 1 ketopropyl 2- 2-yl) piperidine D 1-1 stilbene amine; (±) — 4 1 (8 —Gas 1, 2 — 1 Chloro 2 — Fluorenyl D Kui Zui Lin 3 — (4 Η) mono-)-N- (1- (4- mono (2-fluorophenyl) _azine-1- 1-yl)-3- (7-methyl-1 Η-indazole- 5-yl) -1 —Ketopropan-2-yl) piperidine-1 monocarboxamide; (±) — 4 -— (8-fluoro-1,2-dihydro-2—ketoquinazoline -3 ( 4Η )—基）一Ν— (3— (7 —甲基一1H-D 引唑一5 — 基）一 1 一酮基一（4 —鄰甲苯基_嗪一 1 一基）丙一 2-基 )哌啶一 1 一羧醯胺； (±)—甲基 2— (4— (8 —氟一1，2 —二氫一2 —酮 基喹唑啉一 3 ( 4Η ) -基）—哌啶一 1 一羧醯胺基）一 3 — (7 —乙基一 3—甲基—1Η—吲唑一 5—基）丙酸酯； (±) — Ν— (3— (7 —乙基一3 —甲基一1Η — D引唑 一 5 —基）一 1 —嗣基—1 — ( 4 —(呢D定—1 一基）嘛Β定一 1 一基）丙一 2-基）—4— (8-氟一 1,2 —二氫一 2-酮基 唑啉一 3 ( 4Η ) —哌啶一 1 一羧醯胺； -496- 200529835 (23) (±) —N— (R) — 3— (2 —酮基一二氫一苯並噁唑 —6 —基）一 1 一嗣基一1 — (4 — ( I紙口定一1 —基）呢U疋一1 —基）丙—2-基）—4_ (8 —氟—1，2 —二氫—2-酮基 喹唑啉—3 ( 4 Η ) 一基）哌啶—1 一羧醯胺； (±) — Ν— ( 3 - (7 -甲基一1Η — 口引唑一5 —基） 一 1 一嗣基一 1 一（4一（Ρ很Π定一 1 一基）脈D定一 1—基）丙 —2 —基）一 8 —氟—2 ，3 -二氫—2 —酮基螺—-3 (4Η) -yl) -N- (3- (7-methyl-1H-D indazole-5-yl) -1 keto- (4-o-tolyl_azine-1 1-yl) propanyl -2-yl) piperidine-1 monocarboxamide; (±) -methyl 2- (4- (8-fluoro-1,2-dihydro-2 2-ketoquinazoline-3 (4Η)- ())-Piperidine-1,1-carboxamido) -3- (7-ethyl-3-methyl-1,1-indazole-5-yl) propionate; (±) — Ν— (3— ( 7-ethyl-1, 3-methyl-1, 1-diazole, 5-yl), 1-fluorenyl, 1- (4 — (? D-1, 1-yl), β-1, 1-yl), C1 2-yl) —4— (8-fluoro-1,2-dihydro-2-ketooxazoline-3 (4Η) —piperidine-1 1-carboxamide; -496- 200529835 (23) (±) —N— (R) — 3— (2 —keto-dihydro-benzoxazole-6-yl) — 1 —fluorenyl — 1 — (4 — (I Hydrazine 1-yl) propan-2-yl) -4_ (8-fluoro-1,2-dihydro-2-ketoquinazoline-3 (4 fluorene) -yl) piperidine-1 monocarboxamide ; (±) — Ν— (3-(7 -methyl-1Η) — mouth lead Azole- 5 -yl)-1-fluorenyl-1-(4-(P = π-1-1)) D-1-1-propyl-2-)-8-fluoro-2, 3- Dihydro-2 —ketospiro — (哌啶—4，4 / — □奎唑啉）一1 —羧醯胺； (±) — 4- (8 —氟一1，2 —二氫一2，4 —二酮基喹 唑啉一3(4Η)—基）一Ν— (3— (7 -甲基一1Η — D引唑 —5 —基）一 1 一酮基一 1 一（ 4 一（哌啶—1 一基啶—1 一基）丙—2 -基）哌啶一 1 一羧醯胺； N— ( (R) — 3— (2—(三氟甲基）—1Η —苯並〔d 〕味哇一 5 —基）一1 —酬基一 1 — (4 —(喊D定一 1 —基）(Piperidine-4,4 / — quinazoline) 1-carboxamide; (±) — 4- (8-fluoro-1,2-dihydro-1,2,4-diketoquinazoline-1 3 (4Η) -yl) -N- (3- (7-methyl-1Η-D-zolazole-5-yl)-1-keto-1 1- (4-(piperidine-1 -ylpyridin-1) 1-yl) propan-2-yl) piperidine- 1-carboxamidine; N- ((R) — 3— (2- (trifluoromethyl) -1′-benzo [d] weiwa-5-yl ) One 1 — Reward Base One 1 — (4 — (Shout D Set One 1 — Base) 脈D定一1—基）丙一 2-基）—4一（1’ 2 - 一氯一 2 —嗣基 喹唑啉一 3 ( 4 Η ) —基）哌啶一 1 一羧醯胺； N— ( (R) — 1 一 （二甲基氨基甲醯基）一2— (2 — (三氟甲基）一 1Η—苯並〔d〕咪唑一 5 —基）乙基）一 4 一 （1，2 -二氫—2 —酮基D奎唑啉—3 ( 4H ) -基）哌啶 一 1 —羧醯胺； (R) —甲基2— (4— (1，2 —二氫一 2—酮基D奎唑啉 —3 ( 4 Η ) —基）I派啶—1 —羧醯胺基）—3 -（ 2，3 -二 氫一 2—酮基-1Η-苯並〔d〕咪唑—6—基）丙酸酯； N— ( (R) — 3— (2，3 —二氫—2 —酮基一 1H —苯 -497 - 200529835 (24) 並〔d〕咪唑—6 -基）一 1 一酮基—1 ( 4 一哌啶一 1 一基） I派陡一1 一基）丙一 2-基）—4— (1’2 - 一*氯—2 —嗣基 口奎唑啉一 3 ( 4 Η ) 一基）哌啶一 1 一羧醯胺； N— ( (R) — 1 一 （二甲基氨基甲醯基）一2— (2, 3 -二氫—2 -酮基一 1Η—苯並〔d〕咪唑一 6 —基）乙基 )—4一（1，2-二氫—2 —酮基 D奎唑啉 _3(4H)—基） 哌陡一 1 一竣醯胺； N — ( ( R ) — 3 — (2’ 3 — _•氣—2 _ 酬基—1 Η —苯 並〔d〕咪唑一 6 —基）一 1 一酮基—1(4 一哌啶—1 一基） 口底 B定 一 1 一 基）丙 一 2 —基）一 4 — ( 2 ’3 — _* 氯 一 2 一酮基螺（哌啶—4，4 > 一（ 1 Η ) — D奎唑啉）羧醯胺； 4 — ( 1 ’ 2 — —•氣一2 ’ 4 一 _ 醒基 口奎 口坐琳一3 ( 4 Η ) —基）—N— ( (R) — 3— （7 —甲基—1Η —苯並〔d〕〔 1，2，3〕三唑—5 —基）一1—酮基—1— (4—(哌啶—1 一基）哌啶—1 —基）丙—2 -基）哌啶一 1 —羧醯胺； (R) — 4— (2 —酮基一1，4一 二氫一2 — D奎唑啉一3 一基）—哌啶一 1 一羧酸〔2 — ( 4 —環己基一哌嗪—1 一基 )—2 —酮基一 1— (2 —酮基—2，3 —二氫—苯並噁唑—6 一基甲基）一乙基〕一醯胺； (R) — 4一 （2 —酮基一1，4 —二氫一2 — D奎唑啉一 3 一基）—哌啶一 1 一羧酸〔2 —（ 4 一異丙基一哌嗪一 1 —基 )一 2-酮[基一 1— (2 —酮[基—2，3 - 一.氣—苯並頓哗—6 一基甲基）一乙基〕一醯胺； (R ) — N — ( (R) — 3 一（2 —醒基 一 2，3 — _^氯— -498- 200529835 (25) 苯並噁唑一 6 —基）一 1 —酮基—1 — ( 4 一哌啶一 1 —基） I哌Π定一 1—基）丙—2-基）一 2’ 4 — 一氨一 2 -酮基螺 一（哌啶—4，4 / 一 （ 1Η )—苯並〔d〕 〔 1，3〕噁嗪） 一 1 —羧醯胺； (R) — N— ( (R) — 3— (2 —酮基 一2，3—二氫— 苯並噁唑一 6 —基）一 1—酮基—1 一（4 一環己一 1 一基） 口质嗪—1 一基）丙—2 —基）—2’ 4 — 一氨—2 -酮基螺 —(哌啶一4，4 / — ( 1Η )—苯並〔d〕 〔 1，3〕噁嗪） 一 1 一羧醯胺； (R) — N— ( (R) — 3— (2 —酮基—2，3 —二氫— 苯並噁唑一 6—基）一 1 一酮基—1一（4 一（丙—2-基） 一卩浪嗪一 1—基）丙一 2-基）—2，4 —二氫—2 -酬基 螺—（哌啶—4，4 / 一 （ 1Η ) —苯並〔d〕 〔 1，3〕噁嗪 )一 1 —羧醯胺； (R) — N— ( (R) — 3— (2 —酮基—2，3 —二氫— 苯並H惡Π坐—6—基）—1_嗣基—1 一（4—(喊D定一 1—基 )呢D定一 1 一基）丙一2 —基）一2，4 — _^氯一2 —酬基 螺一（呢陡—4 ’ 4 一（ 1 Η ) - D奎D坐琳）—1 —殘酿胺； (R) — N— ( (R) — 3— (2 —酮基—2，3 —二氫— 苯並噁唑—6-基）一 1—酮基一 1 一（4一（環己一 1—基 )哌嗪一 1 一基）丙一 2 —基）一 2，4 —二氫一 —酮基 螺—（哌啶一 4，4 / — ( 1 Η )—喹唑啉）-1 —羧醯胺； (R) — N— ( (R) — 3— (2 —酮基—2，3 — 一氧一 苯並噁唑一 6 —基）—1 一酮基一 1 一 （4 一 （丙一 2 —基） -499- 200529835 (26) 呢嗦一 1 一基）丙—2—基）—2，4一 _^氣一 2 -酬基螺 一（哌啶一 4，4 / — ( 1 Η ) — D奎唑啉）一 1 一羧醯胺； (R) — 4 — (2 —醒基 一 1 ’ 4 — 一> 氣—2 Η — D奎哩琳一 3 —基）一哌啶—1 一羧酸〔2 -〔 1，4 /〕聯哌啶一 1 / — 基—1— (4 —氯—2-酮[基—2，3 —二氯一苯並D惡卩坐—6 -基甲基）一 2—酮基一乙基〕一醯胺； (R) — 4— (2 —酮基一1，4_ 二氫一2Η — D奎唑啉一 3 _基）—哌啶—1 —羧酸〔2 -〔 1，4 /〕聯哌啶—1 / 一 基—1— (5-氯—2 —酮基—2，3 —二氫—苯並噁唑—6 — 基甲基）一 2—酮基一乙基〕一醯胺； (R ) — 4 — (2 —調基—1，4 一 一氨一2Η — D奎卩坐琳一 3 —基）—哌D定—1 —竣酸〔2 —〔 1，4 〕聯_ Π定—1 — 基—1— (4一溴一 2 —酮基一 2，3 —二氫—苯並噁唑—6 — 基甲基）—2—酮基一乙基〕一醯胺； (R ) — 4 — (2 —嗣基一1，4 — —^氨一2 Η — 口奎 口坐琳一 3 —基）一哌啶一 1 —羧酸〔2 —〔 1，4 /〕聯哌啶一 1 / 一 基一 1— (5 —溴—2—酮基—2，3 —二氫一苯並噁唑—6 — 基甲基）一 2 —酮基一乙基〕一醯胺； (R ) — 4 — ( 2 —嗣基一1，4 — 一·氣一2 Η — D 奎 口坐琳一 3 -基）一哌啶一 1 —羧酸〔2 -〔 1，4 >〕聯哌啶—厂— 基—1— (4 一碘2 —嗣基—2，3 —二氯一苯並卩惡D坐—6 — 基甲基）一 2—酮基一乙基〕一醯胺； —Ν— (1—卡基一 2 —經基—乙基）_2 — （7 —甲基 一 1Η — D 引唑一5 —基甲基）一4 —酮基一 4一 〔I，，2^ — -500- 200529835 (27) 二氫一 -酮基螺—〔4H— 3，，1—苯並噁嗪一 4， 一 I派π定基〕丁醯胺； (±) — N — （1—苄基一2 —羥基一乙基）一2- (7 一甲基一1 Η — D弓丨口坐一 5 —基甲基）一4 —嗣基一4 一 〔4 一 (2 — 基一 1，4 一 一·氯一2H — D奎口坐琳一3 —基）一脈D定 一 1 一基〕一丁醯胺； (土）一苯基一乙酸N — { 2 — (7 —甲基一1 Η — 口引 口坐一 5 —基甲基）—4 一顕1基—4 一 〔4 — ( 2 —酬基一 1 ’ 4 一 __*氣一 2Η — D奎哗琳—3—基）一呢D定一 1 一基〕—丁釀 胺} 一醯肼； (± ) — 1 — 〔 1，4 '〕聯哌 H定一1 '—基一4 — 〔 4 — (8-氟—2 —嗣基—1，4 —二氫—2H — D奎D坐琳—3 -基） —哌啶一1—基〕一 2— (7 —甲基一1H — D引唑一5 —基甲 基）一丁 — 1，4 —二酮； (±) — 1— 〔1，4 〕聯喊口定一1 —基一2— (7 — 甲基一1H — D引唑一5 —基甲基）一4— 〔2， ，3 — —二氫 —2 —酬基螺—（喊D定一 4，4 一 D奎Π坐琳〕丁 — 1，4 — 二酮； (±) — 1— (4 —環己基一哌嗪一1—基）一2— (2 —酮基一2，3 —二氫—苯並噁唑一 6—基甲基）一4— 〔4 —(2 —酬基一1，4 — 一 氯一2 Η — 口奎 口坐琳一3 —基）~~ Π定—1—基〕—丁 — 1，4 — 一·國； (土）一 1— 〔1，4 〕聯呢口定一1 —基一2— (2 — 酮基一 2，3 —二氫—苯並噁唑一 6-基甲基）一 4— 〔4一 -501 - 200529835 (28) (2 —酮基一1，4一二氫一2H—咱唑啉-—1— 丁基〕—丁 — 1，4 —二酮； (± ) — 1 — 〔 1，4 〕聯喊 D定一1 酮基一 2，3 —二氫—苯並噁唑—6—基甲 ，3 / -二氫—2 — -酮基螺一（哌啶—4 〕一丁 — 1，4 一 二酮； (± ) — 1 — （ 4 —環己基一哌嗪一 1 一酮基一 2，3—二氫一苯並噁唑一 6-基E 2 ，3 — 一*氯—2 —酬基螺—（呢D定 啉）〕丁一 1，4 —二酮； (土）一 4 — (2 —嗣基一1，4 — 一·氨 3 —基）—哌啶—1 一羧酸〔2 -（ 4 一環E 基）一1— (7 —甲基一1H —吲唑一5 — 3 基一乙基〕一醯胺； (土）一 4 — ( 2 —酬基一1，4 — 一 氯 3 —基）—哌啶—1 —羧酸〔2 —〔 4 一（ 4 哌嗪一 1 —基〕一 1 — ( 7 —甲基一1 Η — 口弓 )一 2—酮基一乙基〕一醯胺； (± ) - 3 - ( 7 —甲基一1 Η —吲唑一 〔4— (2 —酮基一1，4 —二氫一2Η — D 奎 Ρ 哌啶一 1 一羰基〕一胺基〕一丙酸特丁酯； (±) — 3— (7 —甲基一1Η — D引唑一 〔4— (2 —酮基一1，4 —二氫一2Η — D奎巧 哌啶一 1 一羰基〕一胺基〕一丙酸1 一甲基 -3 -基）—I哌D定 —基—2 — (2 — 基）—4—〔 2 / ，4 / — D奎唑琳） —基）-2— (2 戸基）—4-〔 —4 ， 4〆 一D奎口坐 —2 Η —喹唑啉一 3基一喊嗦一 1 一 g甲基）一 2 —酮 —2 Η —口奎唑啉一 —氟—苯基）— I丨唑一 5 —基甲基 5 -基）—2 - { |啉一 3 —基）— 5 -基）-2 — { 轻啉—3 —基）一 環己酯； -502 - 200529835 (29) (±) — 3— (7 —甲基一1H — D 引唑一5-基）一2— { 〔4— (2 —酮基一1，4一二氫一2H —哇唑啉一 3 —基）一 哌啶一 1 一羰基〕一胺基} 一丙酸 1 一氮雜一雙環〔2.2.2 〕辛一 3 —酯； (±) — 3 — （7 —甲基一 1H —吲唑一 5 —基）一2— { 〔4— (2 —酮基一 1，4 —二氫一 2H-D奎唑啉一3-基）一 哌D定一 1 —鑛基〕一胺基} 一丙酸_ U定一 4 一酯； (±) — 4— (3— (7 —甲基一1H — 口引唑一5 —基）一 2— { 〔4— (2 —酮基一1，4 —二氫一 2H — II 奎唑啉一3 — 基）一哌啶一 1 一羰基〕一胺基} 一丙醯氧基）一哌啶一 1 -羧酸特丁酯； (±) — 3— (7 —甲基一1H—D引唑一5 —基）一2— { 〔4— (2 —酮基一1，4 —二氫一2H — □奎唑啉一3— 基）一 哌啶一 1 一羰基〕一胺基} 一丙酸3，4，5，6 —四氫一 2H 一〔1，4 /〕聯 D(：t Π定一 4 —酯； (土） 一 3 — (7 —甲基一1 Η — 〇 引口坐一5 —基）一 2 — { [4 — (2 —嗣基一1，4 — 一.氣—2 Η — D 奎 口坐琳一3 —基）一 哌啶一1 一羰基〕一胺基} 一丙酸 1 —二乙基胺基—1 一 甲基一乙酯； (±) — 3— (7 —甲基一1H—D引唑一5 —基）一2— { 〔4— (2 —酮基一1，4一 二氫一2Η — D奎唑啉一3 —基）一 哌啶一1 一羰基〕一胺基} 一丙酸 1，1—二甲基一 2—苯 基一乙酯； (士） 一 3 — (7 —甲基一1 Η — 口引口坐一5 一 基)—2 — { -503- 200529835 (30) 〔4 — ( 2 —嗣基一1 ’ 4 — —•氣 一 2 Η —喧 口坐琳一3 —基）一 哌啶一 1—羰基〕一胺基} 一丙酸 1，1 一二甲基—3-苯 基一丙酯； (±) — 3— (7 —甲基一 1Η — 口引唑一5-基）一2— { 〔4— (2 —酮基一 1，4一二氫一2Η—喹唑啉一 3 —基）一 哌啶一 1 —羰基〕一胺基} 一丙酸乙酯 (土）一 1— (7 —甲基一1Η —卩引口坐一5 —基甲基）一2Vein D a 1-yl) propanyl 2-yl) -4 4- (1 '2 -chloro- 2 -fluorenylquinazoline- 3 (4 Η) -yl) piperidine 1 -carboxamidine; N— ((R) — 1 mono (dimethylaminomethylamino) —2— (2— (trifluoromethyl) —1—benzo [d] imidazole—5-yl) ethyl) —4— (1,2-dihydro-2-keto-D-quinazoline-3 (4H) -yl) piperidine-1-carboxamide; (R) -methyl 2- (4- (1,2-di Hydrogen 2-keto D quinazoline-3 (4 Η) -yl) I pyridine-1 -carboxamido)-3-(2, 3-dihydro-2-keto-1-benzo-benzo [D] imidazole-6-yl) propionate; N — ((R) —3 -— (2,3-dihydro-2—keto-1H—benzene-497—200529835 (24) and [d] imidazole —6 -yl) — 1 monoketo — 1 (4 piperidine — 1 mono) — 1 — 1 — 1 —yl — 2-yl) — 4 — (1'2-1 * chloro — 2 — Fluorenylquinazoline-3 (4 Η) -yl) piperidine-1 -carboxamidine; N-((R) — 1-(dimethylaminocarbamoyl)-2-(2, 3- Dihydro-2 -keto-l-pyrene [d] imide 1- (6-yl) ethyl) -4 ((1,2-dihydro-2) -keto D-quinazoline_3 (4H) -yl) piperidine- 1-monoamine; N — ((R) — 3 — (2 '3 — _ • Gas — 2 _ phenyl group — 1 fluorene —benzo [d] imidazol 6 —yl) — 1 monoketo — 1 (4 piperidine — 1 mono) B-A-1, 1-yl), propan-2-yl), 4— (2 '3 — _ * chloro-2, 2-ketospirospira (piperidine-4, 4 > mono (1 Η) — D quinazoline) Carboxamide; 4 — (1 '2 — — • Ga-1 2' 4 — _ Xingjikou Kuikou Zuolin-3 (4 Η) —Base) —N — ((R) — 3— (7 —A 1-1-pyridobenzo [d] [1,2,3] triazol-5-yl) -1-keto-1- (4- (piperidine-1-yl) piperidine-1-yl) propyl —2 -yl) piperidine-1 —carboxamide; (R) — 4— (2 —keto-1,4—dihydro—2 —D quinazoline—3 1yl) —piperidine-1 1 — Carboxylic acid [2- (4-cyclohexyl-piperazine-1 mono) -2—keto-1— (2-keto-2,3-dihydro-benzoxazole-6 monomethyl) Monoethyl] monoamidine; (R) — 4- (2-keto-1,4-dihydro-2-D quinazoline-3 3-yl) -piperidine-1 monocarboxylic acid [2- (4-isopropyl-piperazine-1-yl )-2-keto [yl-1— (2-ketone [yl-2,3—one.gas-benzotonyl-6-ylmethyl) monoethyl] monofluorenamine; (R) —N— ((R) — 3— (2—Axyl—2,3 — — ^ chloro — -498- 200529835 (25) benzoxazole—6 —yl) — 1 —keto — 1 — (4-piperidine -1 -yl) I piperidine-1 -yl) propan-2-yl)-2 '4--ammonia-2-ketospiro- (piperidine-4, 4/1 (1)-benzo [ d] 〔1,3〕 oxazine) 1-carboxamidine; (R) — N— ((R) — 3— (2-keto-2,3-dihydro—benzoxazole-6— ) 1-keto-1- 1 (4-cyclohexyl-1 1-yl) Moxazine-1 1-yl) propan-2-yl) -2 '4 — monoamino-2-ketospiro- (piperidine -4,4 / — (1Η) -benzo [d] [1,3] oxazine) 1 -carboxamidine; (R) — N— ((R) — 3— (2 —keto-2) , 3-dihydro-benzoxazole-1 6-yl) -1, 1-keto-1, 1- (4-((propan-2-yl)) monoammonazine- 1-yl, propan-2-yl) -2, 4-dihydro-2 — (Piperidine—4,4 / a (1Η) —benzo [d] [1,3] oxazine) —1—carboxamide; (R) — N— ((R) — 3— (2 — Keto-2,3-dihydro-benzo-Hexyl-6-yl) -1_fluorenyl-1-1 (4- (sound D-fixed 1-yl)? D-fixed 1-yl) C -2-base) -2,4-_ ^ chloro-1 2 -stilbyl spiro (then steep-4 '4 1 (1 Η)-D Kui D Zolin)-1-residual amine; (R)- N— ((R) — 3— (2 —keto-2,3-dihydro—benzoxazol-6-yl) —1—keto—1— (4— (cyclohexyl—1-based) Piperazine-1 1-yl) propan-2-yl) -2,4-dihydromono-ketospiro- (piperidine-4, 4 / — (1 Η) -quinazoline) -1 -carboxamide (R) — N— ((R) — 3— (2 —keto—2,3 —dioxo-benzoxazole — 6 —yl) — 1 —keto — 1 — (4 ((1) 2 — base) -499- 200529835 (26) 嗦 1 1 1 base) C 2-yl) -2,4-a- ^ gas-1 2-pyridylspiro-1 (piperidine-4, 4 / — (1 Η) — D quinazoline) — 1 —carboxamide; (R) — 4 — (2 —Wake group 1 ′ 4 —one> Gas — 2 Η — D quetialine 3 —yl) monopiperidine — 1 carboxylic acid [2-[1, 4 /] bipiperidine 1 / —Yl — 1 — (4-chloro-2-ketone [yl-2,3-dichloro-benzoDoxanyl-6-ylmethyl) — 2-ketomonoethyl] -pyridamine; (R) — 4— (2 —keto-1,4_dihydro—2 D — D quinazoline —3 —yl) —piperidine —1 —carboxylic acid [2-[1,4 /] bipiperidine — 1/1-1-(5-chloro-2-keto-2, 3-dihydro-benzoxazole-6-ylmethyl)-2-keto-1-ethyl] monofluorenamine; (R ) — 4 — (2 —Thumb —1,4 — Ammonia — 2Η — D quinazine — 3 —Base) — Pipedine — 1 — Junacic acid [2 — [1,4] Coupling —1 —yl — 1 — (4-bromo-2-keto-2,3-dihydro-benzoxazole-6-ylmethyl) -2-ketomonoethyl] monofluorenamine; (R ) — 4 — (2 —Amidino-1, 4 — — ^ Ammonia-2 Η — Kou Kou Kou Lin 3 —yl) -piperidine 1 1 —carboxylic acid [2 — [1, 4 /] piperidine 1/1 base 1 — (5 —bromo 2 — keto — 2,3-dihydromonobenzoxazole-6-ylmethyl)-2-ketomonoethyl] -pyridamine; (R) — 4 — (2 —pyridyl-1,4 — mono-gas 1 2 Η — D quetiazolin — 3 -yl) 1 piperidine — 1 —carboxylic acid [2-[1, 4 >] dipiperidine — plant — radical — 1 — (4 1 iodine 2 — fluorenyl —2,3 —dichloro-benzoxanthone D — 6 —ylmethyl) — 2 —ketomonoethyl] monomethylamine; —N — (1 —carbyl — 2 — meridyl — ethyl ) — 2 — (7-methyl-1, 1- — D-azole- 5-ylmethyl) — 4-keto-4 — [I ,, 2 ^ — -500- 200529835 (27) dihydro-ketospiro — [4H—3,, 1—Benzoxazine—4, —I group π adenyl] butanamide; (±) — N — (1-benzyl-2—hydroxy-ethyl) —2- (7 One methyl one 1 Η — D bow 丨 mouth sits a 5-methyl group) one 4 — fluorenyl one 4 one [4 one (2 — one one 1, 4 one one • chlorine one 2H — D Kuikou sitting Lin 3-methyl) 1-pulse D 1- 1-yl] -butylammonium; (earth) -phenyl-monoacetic acid N — {2 — (7 —methyl-1 1 hydrazine — mouth 5-methyl ) —4 顕 1 base—4— [4 — (2—reward base—1 ′ 4 —__ qi—2Η — D quebalin—3—base) —do D—1—1 base] —Ding Fermented amines} monohydrazine; (±) — 1 — [1,4 '] piperidine H 1-1'-radical 4 — [4 — (8-fluoro-2 —fluorenyl — 1, 4 —dihydro —2H — D quinine — 3 —yl) —piperidine — 1 —yl] — 2 — (7 —methyl — 1H — Doxazole — 5 —ylmethyl) — butane — 1, 4, 2 Ketone; (±) — 1— [1,4] singly conjugated 1 —yl — 2 — (7 —methyl — 1H — dazole — 5 —ylmethyl) — 4 — [2,, 3 — —Dihydro — 2 —Stilyl Spiro — (Should be D, 4, 4, D, D, 坐, 坐, Seline] Butan — 1, 4, — dione; (±) — 1 — (4 —cyclohexyl—piperazine— 1-yl) -2- (2-keto-2,3-dihydro-benzoxazole-6-ylmethyl) -4- 4- [2- 2 Η — Kou Kui sit Lin Yi 3 — Ji) ~~ ΠDing—1—Ki] —Ding—1, 4 — One country; (Tu) —1— [1, 4] Liankoukou Ding 1—Ki—2— (2 — Keto-2,3-dihydro-benzoxazole-6-ylmethyl) —4— [4-one-501-200529835 (28) (2-keto-1,4-dihydro-2H— Oxazoline--1-butyl] -butane-1,4-dione; (±) — 1- [1,4] yell D-1 keto-2,3-dihydro-benzoxan Azole-6-methylmethyl, 3 / -dihydro-2--ketospiro- (piperidine-4) -butane-1,4-dione; (±) — 1 — (4-cyclohexyl-piperazine One 1 one keto-2,3-dihydromonobenzoxazole 6-yl E 2, 3-one * chloro-2 -amylspiro- (theno-d-morpholine)] butan-1,4 -di Ketone; (Earth) 4- (2-Amidino-1,4-amino · 3-Amino) -piperidine-1 monocarboxylic acid [2-(4-monocyclic E group) 1- (7-methyl -1H-indazole- 5-3 -monoethyl] monofluorenamine; (Earth)-4-(2 -alanyl-1,4-chloro-1 -3-yl) -piperidine-1 -carboxylic acid [2 — [4 Mono (4-piperazine-l-yl] -1- (7-methyl-1, hydrazone-oral bow) -2-keto-ethyl] -methylamine; (±)-3-(7-methyl- 1 gadolinium-indazole- [4- (2-keto-1,4-dihydro-1,2 g—D-Quippiperidine-1 mono-carbonyl] -amino] -t-propionate; (±) — 3 — (7 —Methyl-1,1 ′ —D-azole, [4— (2-Keto-1,4-dihydro—2,2 —D, quinolpiperidine—1—carbonyl] —amino]], propionic acid, 1— Methyl-3 -yl) -I piperidinyl-2-(2 -yl)-4-[2 /, 4 / — D quinazoline) -yl)-2-(2 fluorenyl)-4 -[-4, 4 〆 1-D 奎 口 坐 2-Η 喹-quinazoline 3 3-嗦 嗦 1 1 1 g of methyl)-2-ketone-2 Η 奎 奎 quinazoline-fluoro-phenyl ) — I-azole-5 —ylmethyl 5 —yl) — 2 — {| Phenyl — 3 —yl) — 5 —yl) — 2 — {Light phenyl — 3 —yl) monocyclohexyl ester; -502-200529835 (29) (±) — 3— (7 —methyl-1H — D inzozol-5-yl) — 2 — {[4— (2 —keto-1,4-dihydro-2H — oxazoline One 3-base) 1 piperidine-1 monocarbonyl] monoamino} monopropionate 1 aza-bicyclo [2.2.2] octyl 3-ester; (±) — 3 — (7 —methyl-1H — indazole-5 —Yl) —2— [[4 -— (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine D-1—mineral] monoamino}} Acid _ U-Di-4 monoester; (±) — 4— (3— (7 —Methyl-1H — Metazol-5 —yl) — 2 — {〔4— (2 —Keto-1,4 —Dihydro—2H — II quinazoline—3—yl) -piperidine—1—carbonyl] —amino} —propionyloxy) —piperidine—1-butyl carboxylic acid tert-butyl ester; (±) — 3 — (7 —Methyl-1H—D Indazole-5 —yl) — 2 — {[4— (2 —keto-1,4-dihydro-2H — □ quinazolin-3 —yl) -piper Pyridinyl-1 monocarbonyl] monoamino} 3,4,5,6-propionic acid 3,4,5,6-tetrahydro-2H- [1,4 /] di-D (: t π-determined 4-ester; (earth)-3- (7 —methyl-1 1 Η — 〇 lead sits a 5-base) a 2 — {[4 — (2 — amidyl-1, 4 — a. Qi — 2 Η — D Kuikou sit Lin a 3 — ) -Piperidine 1 monocarbonyl] monoamino} 1-diethylamino-1 monomethyl monoethyl propionate; (±) — 3 — (7-methyl-1H-D-azole-5-yl)- 2— {[4 -— (2-keto-1,4-dihydro-2H—D quinazolin-3—yl) -piperidine-1 1-carbonyl] monoamino} monopropionic acid 1,1,2 Methyl- 2-phenyl-ethyl ester; (Shi) 3 — (7 —Methyl-1 1 Η — mouth 5 — 1-yl) — 2 — {-503- 200529835 (30) [4 — ( 2 —Methyl-1 ′ 4 — — • Ga-1 2 M —Mixyl-Zirin-3—yl) -piperidine-1—carbonyl] monoamino} monopropionic acid 1,1 dimethyl-3— Phenyl monopropyl ester; (±) — 3 — (7 —methyl-1 1 — — oxazole — 5-yl) — 2 — {[4 — (2 —keto-1,4—dihydro—2— Quinazoline- 3-yl) -piperidine- 1-carbonyl] -amino group} ethyl propionate (earth)-1- (7-methyl-1 1 Η-卩 introduction of a 5-methyl group) minus 2 一〔1—吡啶一4 一基一甲基〕—2—酮基乙基〕一2一 ， 3 —二氨一 2 —酮基螺一〔哌 D定一 4，4 — ( 1 Η )— 喹唑啉〕一 1 一羧醯胺； (±) — 1— (7 —甲基一1Η -吲唑一5 —基甲基）一2 —〔1 —吡啶一 4 一基一哌嗪基〕—2 —酮基乙基〕一 2 —， 3 —二氯—2 —嗣基螺—〔哌 D定一 4，4 — ( 1 Η )— 喹唑啉〕一 1 一羧醯胺； (±) — 1— (7 —甲基一1Η—吲唑一5 —基甲基）一 2One [1-pyridine-4 monoylmethyl] -2-ketoethyl] -2,3-diamino-2-ketospiro- [piperidine-4,4 — (1 Η) — Quinazoline] 1-carboxamidine; (±) — 1 — (7-methyl-1 1-indazole-5 —ylmethyl) 2 — [1 —pyridine 4 —yl —piperazinyl] —2 —ketoethyl] —2—, 3—dichloro—2—fluorenylspiro— [piperidine, 4,4 — (1 Η) — quinazoline] —1—carboxamidine; (± ) — 1— (7-methyl-1,1′-indazole-5′-methyl)-2 一 〔2—二甲基胺基一乙基一乙基一氨基甲醯基〕一2-酮 基乙基〕一 ，3/ —二氫一 2> —酮基螺一〔哌啶一 4， 4 / — ( 1 Η ) —喹唑啉〕—1 一羧醯胺； (土）一 1 一 （7 —甲基一1 Η — D引口坐一5 一基甲基）一2 —〔1 一吡啶一4 —基—甲基〕一 2 —酮基乙基〕一厂， 2 一 一氣一 2 —嗣基螺一〔4Η— 3 ，1 一苯並螺嗦一 4 ，4 / 一哌啶〕一 1 一羧醯胺； (土）一 1 一 （7 —甲基一 1Η —吲唑一5 —基甲基）一 2 一 〔1—吼D定一4 一基—甲基〕一 2 —嗣基乙基〕一1 ’ -504 - 200529835 (31) 2 — 一氯一 2 —國基螺一 〔4H— 3 ’ 1 一苯並D惡嗦—4 ，4 一哌卩定〕一 1 一殘酿胺； (R) — 4— (2 —酮基—1，4一二氫—2H —喹唑啉一 3 —基）一哌啶一1 d —羧酸〔2 — 〔 1，4 /〕聯哌啶—1 / —基一1 一 （7 —甲基一1H-D弓丨唑一5 -基甲基）一 2 —酮 基一乙基〕一酿胺； 或 (R) — 1- (7 —甲基一1H — D引唑一5 —基甲基）一2 —〔1，4 —〕聯哌啶—1 / 一基一2 —酮基乙基〕—2 / ， 3 - 一《氨—2 —嗣基螺一〔脈 D定 一4，4 — ( 1 Η )— D奎唑啉〕一 1 一羧醯胺；或 其醫藥上可接受之鹽或溶劑化物。 4. 一種醫藥組成物，其包含選自下述之化合物： 4 一 （2 —酮基一1，4 —二氫一 2H—D奎唑啉一3 —基） 一哌啶一 1 —羧酸〔2 -〔 1，4 /〕聯哌啶—1 / —基—1 — (7—溴一1Η —吲唑一 5 —基甲基）—2—酮基一乙基〕— 醯胺； 4— (2 —酮基一 1，4一二氫一2Η — D奎唑啉一3 —基） 一 I派Π定一 1—殘酸〔2-_基一 1— (2 —酮基一 2，3—二氫 一苯並螺哇一 6-基甲基）—2 —（4 —吼Π定一 4 —基一嘛嚷 一 1一基）一乙基〕—醯胺； 4— (2—酮基一1，4一二氫一2H-D奎唑啉一 3—基） 一哌Π定一 1—殘酸〔2 —酮基—1一（2 -酮基一 2，3—一氫 一苯並噁唑—6 -基甲基）—2 —哌啶一 1—基一乙基〕一 -505- 200529835 (32) 醯胺； 4— (2-酮基一 1，4一二氫一 2H —喧唑啉一 3 —基） 一暖Π定一 1 一竣酸〔2 — （ 4 一甲基—哌嗪一1 —基）一 2 — 酮基一1— (2 —酮基一 2，3 —二氫一苯並噁唑一 6 —基甲 基）一乙基〕一酸胺； 4— (2 —酮基一1，4 —二氫一2H—D奎唑啉一3 —基） 一卩辰D定一 1 —錢酸〔2 _〔 1，4 /〕聯哌U定_ 1 > 一基—1 一 (4 —甲基一2 —陋基一 2，3 — _•氯—苯並D惡哗—6 —基甲 基）一 2—酮基一乙基〕一醯胺； 4— (2 —酮基一1，4 —二氫一2H — D奎唑啉一3 -基） —呢U定—1 一殘酸〔1— (4 一甲基一 2 —酮[基一 2，3 — 一*氨 —苯並卩惡π坐一 6 —基甲基）一 2 —酮基一 2—哌D定—1—基— 乙基〕一醯胺； 4— (2 —酮基一 1，4 —二氫一2H—D奎唑啉一 3 —基） —哌啶一 1—羧酸〔1— (4 —氯—2 —酮基—2，3 —二氫— 苯並噁唑一 6—基甲基）—2 —酮基一 2 —哌啶—1—基一乙 基〕一醯胺； 4一 （2 —酮基一1，4 —二氫一2H — D奎唑啉一3 —基） 一哌啶一 1—羧酸〔1 一二甲基氨基甲醯基一 2 — （4 —甲基 —2 —酮基一 2，3—二氫—苯並噁唑一 6 —基）一乙基〕一 醯胺； 4— (2 —酮基一1，4 —二氫一2H —咱唑啉一3 —基） —哌啶—1 一羧酸〔2-（4 —氯—2 —酮基—2，3 -二氫一 苯並噁唑一 6-基）一 1 一二甲基氨基甲醯基一乙基〕一醯 -506- 200529835 (33)-[2-Dimethylamino-ethyl-ethyl-carbamoyl]-2-ketoethyl]-, 3 / -dihydro-2 > --- ketospiro-1 [piperidine-4, 4 / — (1 Η) —quinazoline]-1 -carboxamide; (Earth)-1-(7 -methyl-1 Η-D inlet seat-5-methyl group)-2-[1 1-pyridine- 4-methyl-methyl]-2-ketoethyl] 1 plant, 2 1-gas 2-fluorenylspiro-1 [4-3-3, 1 benzospirofluorene-4, 4/1 pipe Pyridine]-1-carboxamidine; (earth)-1- (7-methyl-1 1-indazole-5-ylmethyl)-2 1 2 —fluorenylethyl] —1'-504-200529835 (31) 2—chloro-1—2—spirospiro [4H—3'1—benzoxoxan-4, 4—piperidine] — 1 Residual amine; (R) — 4 — (2 —keto —1,4 —dihydro — 2H —quinazolin — 3 —yl) —piperidine — 1 d —carboxylic acid [2 — [1, 4 /] piperidine-1 / -yl 1-(7 -methyl-1H-D archiazole-5-ylmethyl)-2-keto-ethyl] monomethylamine ; Or (R) — 1- (7 —methyl-1H — D-zolazole — 5-ylmethyl) — 2 — [1,4 —] piperidine — 1 / 1-one 2-ketoethyl ]-2 /, 3--"Ammonia-2-fluorenyl spiro- [pulse D fixed a 4,4-(1 Η)-D quinazoline]-1-carboxamide; or a pharmaceutically acceptable Salt or solvate. 4. A pharmaceutical composition comprising a compound selected from the group consisting of: 4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine-1-carboxylic acid [2-[1,4 /] Bipiperidin-1 / -yl-1-(7-bromo-1,1-indazole-5 -ylmethyl) -2-ketomonoethyl]-hydrazine; 4 — (2 —Keto-1,4—dihydro—2Η — D quinazoline —3 —yl) — 1 group, 1 — 1 —residual acid [2- — 1 — (2 — keto-2 , 3-dihydro-benzospiro-6-ylmethyl) —2— (4—cyclopentadienyl—4-methyl—1-methyl-1—1-yl) —ethyl] —fluoramine; 4— (2 —Keto-1,4-dihydro-2H-D quinazoline-3-yl) Piperidine-1 1-residual acid [2-keto-1— (2-keto-2,3-one Hydro-benzoxazole-6-ylmethyl) -2-piperidine-1-yl-ethyl] -505-200529835 (32) fluorenamine; 4- (2-keto-1,4-1,2 Hydrogen-2H — oxazoline-3 —yl) —Honyl — 1 —Acid [2 — (4-methyl-piperazine-1 —yl) — 2 —keto-1 — (2 —keto minus 2 , 3-dihydromonobenzoxazole-6-ylmethyl) monoethyl] monoacid; 4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl ) 1-Chen D-Ding- 1-Canoic acid [2 _ [1,4 /] piperidine U-Ding_ 1 > 1-base-1 1- (4-methyl-1 2-ugly-2, 3 — _ • Chloro-benzo D oxamine-6-ylmethyl) -2-ketomonoethyl] -pyridamine; 4- (2-keto-1,4-dihydro-2H-D quinazoline-3 -Yl) —? Udine —1 a residual acid [1 — (4 -methyl-2-ketone [group -2,3--* amino-benzopyridine π-6 -ylmethyl)-2 —Keto-2-piperidine-1—yl-ethyl] monofluorenamine; 4- (2-keto-1,4-dihydro-2H—D quinazoline-3—yl) —piperidine 1-carboxylic acid [1- (4-chloro-2-keto-2,3-dihydro-benzoxazole-6-ylmethyl) -2-keto-2-piperidine-1-yl Monoethyl] monomethylamine; 4-one (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) piperidine-1carboxylic acid [1-dimethylcarbamate醯 基 一 2 — (4 Methyl-2-keto-2,3-dihydro-benzoxazole-6-yl) monoethyl] monomethylamine; 4- (2-keto-1,4-dihydro-2H-we Oxazoline 3-yl) -piperidine-1 monocarboxylic acid [2- (4-chloro-2-keto-2,3-dihydromonobenzoxazole-6-yl) -1 dimethyl Carbamidyl-ethyl] -fluorene-506- 200529835 (33) 4 — ( 2 —酬基一1 ’ 4 — 一^氣一2 Η — D 奎 口坐琳一3 —基） 一呢Β定一 1 一竣酸〔1— (4 一甲基—2 —嗣基—2，3 — 一·氯 —苯並噁唑—6 —基甲基）—2—酮基一 2— (4—吡啶一 4 一基一哌嗪一 1一基）一乙基〕一醯胺； 4— (2 —酮基一1，4一二氫一2Η — 口奎唑啉一 3—基）4 — (2 —Paid 1 — 4 — 1 气 一 2 Η — D Kuikou Zaolin — 3 — 基 —B 定 1 1 竣 Acid [1— (4 1 methyl-2 — 嗣-2,3—mono-chloro-benzoxazole-6-ylmethyl) —2—keto—2— (4-pyridine—4—yl—piperazine—1—yl] —ethyl] — Amidoamine; 4- (2-keto-1,4-dihydro-2H-quinoxaline-3-yl) —哌Π定一1—殘酸〔1— (4 —氯一 2 —酮(基—2，3-二氫— 苯並Β惡哇—6 —基甲基）一 2 —嗣基—2— (4 —吼11定一 4一 基一卩辰嗪一 1 一基）一乙基〕一釀胺； 4— (2 -酮基一1，4 —二氫一2H—喹唑啉一3 —基） 一哌啶—1 —羧酸〔2 —〔 1，4 /〕聯哌啶—1 / —基一 1 一 (4 一乙基一2 —酮基一 2，3 -二氫一苯並噁唑一 6 —基甲 基）—2-酮基一乙基〕一醯胺； 4 一 （2 —酮基一1，4 —二氫一 2H — D奎唑啉一 3 —基） 一哌啶一 1 一羧酸〔2 -〔 1，4 /〕聯哌啶—1 / 一基—1 ——Piperidine-1—residual acid [1— (4-chloro-2-ketone (yl-2,3-dihydro-benzo-B-oxa-6-ylmethyl) —2—fluorenyl-2— (4- —11-di-4-diyl-1, 2-tetrazine—1-diyl) —ethyl] -vinylamine; 4- (2-keto-1,4-dihydro-2H-quinazoline-3— Radical) monopiperidin-1-carboxylic acid [2 — [1,4 /] bipiperidin-1- 1 -yl-1 (4-ethyl-2 -keto-2,3-dihydro-benzo) Oxazole-6-ylmethyl) -2-ketomonoethyl] monofluorenamine; 4-mono (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperone Pyridin-1 monocarboxylic acid [2-[1,4 /] bipiperidin-1 / 1-yl-1 — (7 —甲基—2—酮基一 2，3 —二氫—1H —苯並咪唑一 5-基甲基）一 2—酮基一乙基〕一醯胺； 4 — ( 2 一 酬| 基 一 1’ 4 — 一·氨 一 2H — D奎 口坐琳 一 3 —基） —1派D定一 1 —竣酸〔2 -〔 1，4 〕聯哌D定—1 一基一 1 — (7 —氯—2 —酮基一 2，3 -二氫一 1H—苯並咪唑一 5 —基 甲基）—2—酮基一乙基〕一醯胺； 4— (2—酮基一1,4 —二氫一 2H-D奎唑啉一3 —基） 一哌啶一 1 —羧酸〔2 -〔 1，4，〕聯哌啶—1 / 一基—1 — (7—乙基—2—酮基—2，3 —二氫—1H —苯並咪唑一 5 — -507- 200529835 (34) 基甲基）一 2—酮基一乙基〕一醯胺； 4 一 （2 —酮基一 1，4 —二氫--2H — D奎唑啉一3 —基） 一哌啶—1 —羧酸〔2 —〔 1，4 /〕聯哌啶一 1 / —基—1 — (3 —甲基一 2 —嗣基—2，3 — —^氯一 1H -苯並味哇一 5 — 基甲基）一 2 —酮基一乙基〕一醯胺； 4— (2 —酮基一 1，4 -二氫一2H — D奎唑啉一3 —基） —呢卩定一 1 一殘酸〔2 -〔 1，4 〕聯脈卩定—1 一基—1 一 (3 ’ 7 — 一^甲基一2 —醒[基—2 ’ 3 — —^氯一 1 Η —苯並咏口坐 一 5—基甲基）一 2—酮基一乙基〕一醯胺； 4— (2—酮基一1，4一二氫一2Η —喹唑啉一3 —基） 一哌卩定一 1 一竣酸〔2 —〔 1，4 〕聯_ D定一 1 一基—1 — (7 —氣一 3 —甲基一2 —酬基一 2 ’ 3 — 一氨—1 Η —苯並味 唑一 5—基甲基）一 2—酮基—乙基〕一醯胺； 4 — (2 —嗣基一1，4 — —氯一2Η — D 奎 口坐琳一3 —基） 一哌啶—1 一羧酸〔2 —〔 1，4 /〕聯喊啶一 1 ——基—1 — (7 —乙基—3 —甲基—2—酮基—2，3-二氫—1Η—苯並 咪唑一 5—基甲基）一 2-酮基一乙基〕—醯胺； 3— (7 —甲基一1Η — D 引唑一5 —基）一2— { 〔4—( 2 —酮基一 1，4一二氫一 2Η — D奎唑啉—3 —基）一哌啶一1 一羰基〕一胺基} 一丙酸異丙酯； 3— (7 —氯一1Η-吲唑—5 —基）—2— { 〔4— (2 —酬基一 1 ’ 4 一 一·氯一2Η — D奎口坐琳一3 —基）一呢D定一1 一羰基〕一胺基} 一丙酸異丙酯； 3— (7 —乙基一1Η — D 引唑一5 —基）一2— { 〔4—( -508 - 200529835 (35) 2 —酮基一 1，4 —二氫一2 Η — D奎唑啉一3 —基）一哌啶一1 一羰基〕一胺基} 一丙酸異丙酯； 3— (7- 氯—1H —吲唑—5 —基）—2— { 〔4— (2 —爾基一〗，4 一 —^氯一 2 Η — D奎Π坐琳—3 —基）一丨旅D疋一1 一羰基〕一胺基} 一丙酸特丁酯； 3— (7 —乙基一1Η — D引唑一 5 —基）一 2— { 〔4—((7-Methyl-2-keto-2,3-dihydro-1H-benzimidazole-5-ylmethyl) -2-ketomonoethyl] monofluorenamine; 4 — (2 Base 1 '4 — 1 · Ammonia 2H — D Kuikouzai Lin 3 — Base) — 1 Group D Ding 1 1 — Juncid [2-[1, 4] Piperidine D 1 — 1 Base 1 1 — (7 —Chloro-2 —keto-2,3-dihydro-1H-benzimidazole-5 —ylmethyl) —2 —ketomonoethyl] monomethylamine; 4- (2-keto -1,4-dihydro-2H-D quinazoline-3-yl) 1-piperidine-1-carboxylic acid [2--[1,4,] bipiperidin-1 / 1-1-1-(7- Ethyl-2-keto-2,3-dihydro-1H-benzimidazole-5—507-200529835 (34) ylmethyl) 2-ketomonoethyl] monofluorenamine; 4 a ( 2-keto-1,4-dihydro-2H-D quinazoline-3-yl) piperidine-1 carboxylic acid [2-[1,4 /] bipiperidin-1 / -yl- 1 — (3 —methyl — 2 —fluorenyl — 2, 3 — — ^ chloro — 1H —benzoyl — 5 —methylmethyl) — 2 —ketomonoethyl] monomethylamine; 4 — ( 2-ketone -1,4 -dihydro-2H-D quinazoline -3 -yl) -Nanidine-1 -Residual acid [2-[1,4] diamidine-1-1-1-(3 ' 7 —one ^ methyl — 2 — wake [yl — 2 ′ 3 — — ^ chloro — 1 Η —benzobenzoyl — 5-methyl — 2 —ketomonoethyl] monofluoramide; 4 — (2-keto-1,4-dihydro-2H-quinazoline-3-yl) 1-piperidine-1 1-monocarboxylic acid [2- — [1,4] di-D fixed 1 1- 1 — (7 —Gas — 3 —Methyl — 2 —Phenyl — 2 ′ 3 —Ammonia — 1 —Benzol — 5 —Methyl — 2 —Keto —Ethyl] amine ; 4 — (2 —Methyl-1,4 — —Chloro-2M —D quinoxaline —3 —Methyl) 1 piperidine — 1carboxylic acid [2 — [1, 4 /] hydrazine 1 ——Methyl-1— (7-ethyl-3—methyl-2-keto-2,3-dihydro-1′-benzimidazole—5-ylmethyl) —2-ketomonoethyl] —Methylamine; 3— (7—Methyl—1— — D Indazole—5 —yl) — 2 — {[4— (2 —Keto-1,4—Dihydro—2— —D quinazoline-3 —Base) one Piperidine-1 monocarbonyl] monoamino} isopropyl monopropionate; 3- (7-chloro-1,1-indazol-5-yl) -2— {[4— (2 —vinyl-1 ′ 4 1 · Chloro-2Η—D-Keikoline- 3—Base) —D-D—1—Carbonyl] —Amine} Isopropyl Propionate; 3— (7—Ethyl—1Η—D Indazole One 5-yl) one 2- {[4— (-508-200529835 (35) 2-keto-1,4-dihydro-1 2 fluorene — D quinazoline one 3-yl) one piperidine one one one Carbonyl] monoamino} isopropyl monopropionate; 3- (7-chloro-1H-indazol-5-yl) -2— {[4— (2- —yl — 1], 4- 1 —chloro-1 2 Η — D Π 坐 琳 — — 3 —)-旅 D 疋 1-1 carbonyl]-amine} monobutyl propionate; 3-(7-ethyl-1 Η-D azole-5- Base) 1: 2— {[4— ( 2 一嗣基一1，4 — 一^氨一 2Η — D奎口坐琳一 3 —基）一呢D疋一1 一羰基〕一胺基} 一丙酸特丁酯； 3 - (7 —氯一1Η — D 引唑一5 —基）一2— { 〔4— (2 —酮基一 1，4一二氫—2Η—喹唑啉—3 —基）一哌啶一 1 一羰基〕一胺基} 一丙酸環己酯； 3— (7 —乙基一1Η — D 引唑一5 —基）一2— { 〔4-( 2 —酮基一1，4一二氫一2Η —喹唑啉一 3 —基）—哌啶—1 一羰基〕一胺基} 一丙酸環己酯； 3— (7 —氯一1Η — D 引唑一5 —基）一2— { 〔4— ( 22 amidino-1,4 — 1 ^ ammonia 2 D — D Kuikou Lin 3 —yl) 1 疋 D 疋 1 1 carbonyl] monoamine} monobutyl propionate; 3-(7 — Chlorine-1Η — D Indazole-5 —yl) 2 — {[4— (2-keto-1,4-dihydro-2Η-quinazolin-3 —yl) -piperidine-1 1-carbonyl] Monoamino} cyclohexyl monopropionate; 3- (7-ethyl-1, 1-diazole, 5-azole, 5-diyl), 2- 2- [[4- (2 -keto-1,4-dihydro-2 —Quinazoline-3-yl) —piperidine-1 monocarbonyl] -amino group} cyclohexyl monopropionate; 3-(7-chloro-1 1-D-azole-5-yl)-2— {[[ 4— (2 —酮基一1，4 —二氫一 2Η —喹唑啉一3 —基）一哌啶一 1 一羰基〕一胺基} 一丙酸 1 一甲基一哌啶一 4 一酯； 3— (7 —乙基一1Η — D 引唑一5 —基）一2— { 〔4—( 2 —酮基一1，4一二氫一 2H—D奎唑啉一3 —基）一哌啶一1 一羰基〕一胺基} 一丙酸 1 一甲基一哌啶—4 —酯； 3— (7 —氯—1Η — 口引唑一5 —基）一2— { 〔4— ( 2 —酮基一 1，4 —二氫一 2 Η — D奎唑啉一3 —基）一哌啶一 1 一羰基〕一胺基} 一丙酸1 一甲基一環己酯； 3— (7 —乙基一1Η — 口引唑一5 —基）一2— { 〔4—( -509- 200529835 (36) 2 —酮基一 1，4 —二氫一2 Η —喹唑啉一 3 —基）一I派啶一 1 一羰基〕一胺基} 一丙酸1 一甲基一環己酯； 3 - (7 —氯一1H — D引唑一 5 —基）一2— { 〔4— (2 一嗣基一 1 ’ 4 — 一^氨一2H — D奎口坐琳一3 —基）一酿d疋一1 一羰基〕一胺基} 一丙酸 4 一苯基一環己酯；或 3 — （7 —乙基一1H—D引唑一5 —基）一2- { 〔4—(—Keto—1,4—dihydro—2Η —quinazoline—3—yl) -piperidine—1—carbonyl] —amino group} —propionic acid—1—methyl—piperidine—4—ester; 3— (7-Ethyl-1H-D Indazole-5-yl) -2- [[4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine 1 1 carbonyl] monoamino} 1 propionate 1 methyl monopiperidin-4-ester; 3 — (7 —chloro — 1 — — triazol 5 —yl) — 2 — {〔4— (2 —Keto-1,4-dihydro-2 hydrazone — D quinazoline-3-yl) -piperidine-1 1-carbonyl] -amino group} 1-propionic acid 1-methyl-cyclohexyl ester; 3— (7 —Ethyl-1, — Orazol-5 —yl — 2 — {〔4— (-509- 200529835 (36) 2 —Keto-1,4-dihydro-1 2 Η —Quazazoline 3 — Group) -I-pyridinyl-1-carbonyl] -amino group} monopropionate 1-methyl-cyclohexyl ester; 3-(7-chloro-1H-D-azole-5-yl)-2-{〔4— (2 amidino-1 ′ 4 —a ^ ammonia 2H —D kuizuline 3 —yl) a brewed d 疋 1 1 carbonyl] monoamine} monopropionic acid 4 monobenzene A cyclohexyl ester; or 3 - (7 - ethyl-1H-D a-indazol-5 -yl) - one 2- {[4- ( 2 —酮基一 1，4一二氫一2H -喹唑啉一3 -基）一哌啶—1 一羰基〕一胺基} 一丙酸 4 一苯基一環己酯；或 其醫藥上可接受之鹽或溶劑化物。 5. —種選自下述之化合物或其醫藥上可接受之鹽或 溶劑化物於製造藥物以治療或預防偏頭痛上之用途； (±) — 3— (3 —氰基一1H —吲哚一5 —基）一2— { 〔4一 （2 —酮基一1，4 —二氫一2H — D奎唑啉一3 —基）一 哌啶一 1 一羰基〕一胺基} 一丙酸甲酯； (土）一 4 — (2 —嗣基一1，4 — 一 氯 一 2H — 口奎 口坐琳一2-keto-1,4-dihydro-2H-quinazoline-3-yl) -piperidine-1 monocarbonyl] -amino group} monopropionate 4-phenylphenylcyclohexyl ester; or pharmaceutically acceptable Accepted salts or solvates. 5. —The use of a compound selected from the following or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prevention of migraine; (±) — 3 — (3 —cyano-1H —indole A 5-yl group-a 2- {[4-a (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine-1 1-carbonyl group] -amino group} Methyl ester; (soil) a 4 — (2 —fluorenyl-1,4 — a chlorine — 2H — Koukou Zuolin 1 3 —基）一 I派卩定—1 一殘酸〔2 —〔 1，4 〕聯哌D定—1 一 基一 1一 （3 —氰基一 1H —吲哚—5 —基一甲基）—2 -酮 基一乙基〕一醯胺； (土）一 4— (2 —酮基一1，4一 二氫一2H — D奎唑啉一 3 —基）一哌啶一 1 —羧酸〔2 —〔 1，4 /〕聯哌啶一厂一 基一 1 (3 —氰基一7 —甲基一 1H —吲哚—5 —基一甲基） 一 2-酮基—乙基〕一醯胺； (土）一 3 — （7 —異丙基一 1H — 口引口坐一5 —基）一2 — { 〔4— (2—酮基一1，4一二氫一2H —咱唑啉一3 —基） -510 - 200529835 (37) 一哌啶一 1 一羰基〕一胺基} 一丙酸甲酯； (±) — 4— (2 —酮基一1，4 —二氫一 2H —喹唑啉一 3 —基）—哌Π定一 1 —殘酸〔2 —〔 1，4 〕聯哌D定—1 一 基一 1(7 —異丙基一 1H—吲唑一 5 —基一甲基）—2 -酮 基一乙基〕一醯胺； (土）一 4 — ( 2 —醒基 一 1，4 — 一.氣—2 Η — 口奎 口坐琳一 3 —基）—哌D定一 1 —竣酸〔2 -〔 1，4 〕聯哌卩定—1 一3 -yl) -I-Pyrididine-1 -Residual acid ) -2-ketomonoethyl] monomethylamine; (Earth) -4— (2-keto-1,4-dihydro-2H—D quinazoline-3-yl) -piperidine-1— Carboxylic acid [2 — [1,4 /] piperidine one plant one group one 1 (3-cyano-7-methyl-1H-indole-5-yl-methyl) 2-keto-ethyl []] Hydrazine; (Earth) 3-(7-isopropyl-1H-mouth mouth seat 5-base)-2-{[4-(2-keto-1, 4-dihydro- 2H —oxazoline-3 —yl) -510-200529835 (37) monopiperidine-1 monocarbonyl] monoamino} methyl propionate; (±) — 4— (2 —keto-1,4 —Dihydro—2H —quinazoline—3-yl) —piperidine-1—residual acid [2 — [1,4] bipiperidine—1—yl-1 (7—isopropyl-1H— Indazole-5 -yl-methyl) -2-ketomonoethyl] monofluorenamine; (earth) 4-(2 -pentyl-1,4-1 Lin take a 3 - yl) - piperidin-1 set D - carboxylic acids [2 - [1,4] bipiperidinyl Jie a predetermined -1 基一1(7 —乙基一 1Η —吲唑—5 —基—甲基）—2—酮基 _乙基〕—醯胺； (土）一 4 — (2，2 — _^嗣基一1 ’ 4 — __* 氯一2Η — 2λ6—苯並〔1，2，6〕噻二嗪—3 -基）—哌啶—1 一羧 酸〔2 — 〔 1，4 /〕聯哌啶一 1 > —基一 1 ( 7 —甲基一1 Η —吲唑—5 —基一甲基）—2_酮基—乙基〕一醯胺； (土）一 4 — (2，2 — 一 酬基一1 ’ 4 — _* 氣一2 Η —1- (1-ethyl-1,1-indazole-5-yl-methyl) -2-keto-ethyl] -fluorenylamine; (Earth)-4— (2,2 — _ ^ fluorenyl-1 1 '4 — __ * chloro-2Η — 2λ6—benzo [1,2,6] thiadiazine-3-yl) -piperidine-1 monocarboxylic acid [2 — [1,4 /] bipiperidine-1 1 > -yl-1 (7-methyl-1 1 fluorene-indazole-5-yl-methyl) -2-keto-ethyl] monofluorenamine; (earth) 4-(2, 2- One pay base one 1 '4 — _ * Qi one 2 Η — 2λ6—苯並〔1，2，6〕噻二嗪—3 —基）一哌啶—1—羧 酸〔2 — 〔 1，4 >〕聯哌啶一 1 / —基一 1 ( 7 —乙基一3 — 甲基一 1Η—吲唑一5 —基一甲基）一.2—酮基一乙基〕一 酿胺； (±) — 2— 〔4— (6 —氰基一2 —酮基一1，4 —二氫 —2 Η —喹唑啉一 3 -基）—哌啶一 1 一羰基〕一胺基〕—3 —(7—甲基—1Η —吲唑一 5 —基）一丙酸甲酯； (±) — 4— (6 —氰基一2 —酮基一1，4一 二氫一 2Η 一 D奎唑啉一 3 -基）一哌啶—1 一羰基{ 2 —〔 1，4 /〕聯 哌啶一1 > —基一 1 — ( 7 —甲基一1 Η — D弓丨唑一5 —基一甲 511 - 200529835 (38) 基）一 2-酮基—乙基} 一醯胺； (土）一 4 — (2 —嗣基一1’ 2’ 4’ 5 —四氣一本並〔 d〕 〔1，3〕二氮雜罩一3-基—1一羧酸{2—〔1，4—〕 聯哌啶一1 / —基一 1 一 （ 7 —甲基一 1 Η —吲唑—5 —基— 甲基）一2—酮基一乙基} 一醯胺； (土）一 4 — (6 —經基一2 —酬基一1，4 — 一·氯一2Η 一 □奎Π坐琳一 3 -基）一派D定—1 一殘酸{ 2 —〔 1，4 〕聯 哌啶一 1 / —基一1 — ( 7 —甲基一 1 Η - D弓丨唑一5 —基一甲 基）—2—醒基一乙基}—酿胺； (±) — 4— (8 —甲氧基一2 —酮基一1，4一 二氫一 2 Η — D奎唑啉一3 —基）一哌啶一 1 —羧酸{ 2 — 〔 1，4 —〕 聯哌啶一1 / 一基一1 — ( 7 —甲基一1 Η — D弓丨唑一5 —基一 甲基）一 2—酮基一乙基}—醯胺； (±) — 4— (8 —氯一2 —酮基一1，4一 二氫一 2Η — 口奎Π坐琳一 3 —基）一脈D定一 1 —殘酸{ 2 —〔 1，4 〕聯呢 啶一—基一 1— (7 —甲基一1Η — D引唑一 5 —基一甲基 )—2 —酬基—乙基}—釀胺； (±) — Ν— (3— (7 —乙基一3 —甲基一1Η — D引唑 一 5 —基）一1 一酬基—1 一（4 —(呢D定—1 一基）呢D定—1 —基）丙一 2-基）—2 ，3 —二氫一 2 -国基螺—（ 哌啶一 4，4 / 一喹唑啉）一 1 —羧醯胺； (土） 一 Ν- (3— (7 —乙基一3 —甲基一1Η — D 引唑 一 5 —基）一1 一酮基—1 一（ 4 —(哌啶一 1 一基）哌啶一 1 一基）丙一 2 —基）一 2，4 —二氫一 2 / -酮基螺—（哌啶 -512 - 200529835 (39) 一 4，— 1H —苯並〔d〕 〔1，3〕B惡嗪）—1—竣醯胺 (±) — N— (3— (7 —乙基一1H — D 引唑一5 —基） 一 1 — ( 6，7 —二氫一1 Η — D比唑並〔4，3 — c〕吼啶一5 ( 4Η) - 基）一 1 一 酮基丙—2- 基）—4— (1,2 —二氫— 2 —酮基喹唑啉一 3 ( 4Η )—基）哌啶—1 —羧醯胺； (±) — Ν— (3— (7— 乙基一1Η — D 引唑一5 —基） 一 1— (6，7 —二氫一7，7 —二甲基一1Η — D比唑並〔4，3 —c〕D比啶一5(4Η)—基）一1—酮基丙一2 —基）一4 — (1，2 —二氫一 2 —酮基喹唑啉一 3(4Η)—基）哌啶一 1 一羧醯胺； (土）—甲基 2— (4— (8 —氣一1，2 — 一^氯一2 —嗣 基喹唑啉一 3 ( 4Η ) -基）哌啶一 1 一羧醯胺基）一 3 -（ 7 —甲基一1 Η —吲唑一 5 —基）丙酸酯； (土）一 4 一 （8 —戴一 1，2 — 一氨一 2—嗣基口奎口坐琳 -3 ( 4Η )—基）一Ν— (3— (7 —甲基一1Η — D 引唑一5 — 基）—1 一酮基一 1 — ( 4 一（哌啶一 1 一基）哌啶—1 一） 丙一 2 —基Π定一 1 一殘醯胺； (±) — 4— (8—氟一 1，2—二氫一 2—酮基喹唑啉 -3 ( 4Η )—基）一Ν— (3— (7 —甲基一1Η — 口引唑一5 — 基）一 1—酮基一 1— (4 —苯基哌嗪一 1—基）丙—2 —基 )哌啶一 1 一羧醯胺； (±) — 4— (8 —氟一1，2—二氫一 2 —酮基口奎唑啉 -3 ( 4Η )—基）一Ν— (1— (4— (4 —氟苯基）哌嗪— -513- 200529835 (40) 1 一基）—3— (7 —甲基—1H —吲唑—5 —基）一 1—酮基 丙一 2 —基）哌啶一 1 一羧醯胺； (±) — 4 — （8—氟一 1，2—二氫一 2—酮基口奎唑啉 -3 ( 4H )—基）一 N— (1— (4— (2 —氟苯基）哌嗪一 1—基）—3 — （7 —甲基一 1H —吲唑一 5 —基）一 1—酮基 丙一 2 —基）哌啶一 1 —羧醯胺； (±) — 4— (8 —氟一1，2—二氫一2 —酮基喹唑啉 —3(4H)-基）一N— (3— (7 —甲基一1H — D引唑一5- 基）一 1 一酮基—（4 一鄰甲苯基哌嗪一 1 一基）丙一 2-基 )哌π定一 1 一竣酿胺； (±)—甲基 2— (4— (8 —氟一1，2 —二氫一2 —酮 基喹唑啉一 3 ( 4H ) -基）一哌啶—1 一羧醯胺基）一 3 - (7—乙基一3 —甲基一 1H —吲唑—5—基）丙酸酯； (士） 一 N — (3 — ( 7 一 乙基一3 —甲基一1 Η — D 引口坐 —5 —基）一 1 一酮基一 1 — ( 4 —(哌啶—1 一基）哌啶一 1 一基）丙一 2 —基）—4— (8 —氧—1’2 — __^氯—2 —酬基 唑啉一3 ( 4 Η ) -哌啶一 1 —羧醯胺； (±) —Ν— （R) — 3— （2—酮基一二氫一苯並噁唑 —6 —基）一1 一酮基—1 — ( 4 —(哌啶一 1 一基）哌啶一 1 —基）丙—2-基）—4一（8-氟一 1，2 —二氫一2 —酮基 □奎唑啉一 3 ( 4Η ) -基）哌啶一 1 一羧醯胺； (±) — Ν— (3— (7 —甲基一1Η — D 引唑一5 —基） 一 1 一酮基—1 一（ 4 —([派啶一 1 —基）哌啶—1 —基）丙 —2 —基）—8^ —氟—2^ ，3^ - 二氫一 2^ —酮基螺— -514- 200529835 (41) (哌啶一 4，4 / 一 D奎唑啉）一1 一羧醯胺； (±) — 4— (8 —氣—1，2 — —^氯—2， 唑啉—3(4H)—基）—N— (3— (7 —甲基 —5 —基）—1 —酮基一 1 — ( 4 一（哌啶—1 — 一基）丙一 2 -基）哌啶一 1 一羧醯胺； N — （（R)— 3— (2—(三氟甲基）一 〕咪唑一 5-基）一1 一酮基一 1 一 （4—(哌 哌啶一 1 一基）丙—2 —基）一4— (1，2- 二 口奎D坐琳一 3 ( 4 Η ) -基）呢Π定一 1 —殘釀胺； Ν— （ （R) — 1 一 （二甲基氨基甲醯基） (三氟甲基）一 1Η—苯並〔d〕咪唑一 5 —基 —(1，2 —二氫一 2 —酮基喹唑啉一3 (4H) 一 1 一羧醯胺； (R )—甲基 2— (4— (1，2 —二氫一2- -3 ( 4H ) 一基）哌啶一 1 一羧醯胺基）—3 — 氫一 2-酮基—1H-苯並〔d〕咪唑—6-基） N— ( ( R ) — 3— (2，3 —二氫—2 —酮 並〔d〕咪唑一 6 -基）一 1 —酮基一 1 ( 4 一哌 哌啶一1—基）丙—2 —基）—4一（1，2 —二 嘻唑啉一 3 ( 4H ) -基）哌啶一 1 一羧醯胺； N— （ （R) - 1一（二甲基氨基甲醯基） 3 -二氫—2 -酮基一 1H —苯並〔d〕咪唑—f )—4一 （1，2-二氫—2—酮基D奎唑啉一 3( 哌啶一 1 —羧醯胺； 4 一二酮基D奎 ;—1 Η -吲唑 基）哌啶一 1 1 Η —苯並〔d 啶一 1 —基） 氫一 2 -酮基 -2 - ( 2 -)乙基）一4 一基）哌啶 -酮基喹唑啉 (2，3 — _ 丙酸酯； 基—1 Η —苯 D定一 1 —基） 氫一2-酮基 —2 — ( 2， ;一基）乙基 4Η )-基） -515- 200529835 (42) N— ( (R) — 3— (2，3 — _^、氯—2 —嗣某—1H- 苯 並〔d〕味哩一 6-基）—1 一調基一 1(4 一喊B定一 1 一基） 哌啶—1—基）丙—2 —基）一4— (2> ，3〃 —二氫—2^ 一酮基螺（哌啶一 4，4 / — ( 1 Η ) -喹唑啉）羧醯胺； 4— ( 1，2-二氫—2，4 —二酮基 口 奎唑啉—3 (4Η) 一基）一 Ν — ( ( R ) — 3 — (7 —甲基—1Η —苯並〔d〕〔2λ6-benzo [1,2,6] thiadiazine-3-yl) piperidine-1-carboxylic acid [2 — [1,4 >] bipiperidine-1 / -yl-1 (7 — Ethyl 3-methyl 1-indazole-5-yl-methyl)-. 2-ketomonoethyl] -vinylamine; (±) — 2-— [4-—6-cyano-2 —Keto-1,4 —dihydro-2 fluorene —quinazoline —3-yl) —piperidine — 1 monocarbonyl] monoamino] —3 — (7-methyl-1 fluorene — indazole-5 — Methyl) monopropionate; (±) — 4 -— (6-cyano-2—keto—1,4-dihydro—2Η—D quinazoline—3-yl) —piperidine—1—carbonyl {2 — [1,4 /] bipiperidin-1 > —yl-1 — (7-methyl-1 1 Η — D-bendazole-5-azole-1methyl 511-200529835 (38) group) -2 -Keto-ethyl} monofluorenamine; (earth)-4-(2-fluorenyl- 1 '2' 4 '5 -tetraki-monobenzyl [d] [1,3] diaza hood-3 -Yl-1 monocarboxylic acid {2- [1,4—] dipiperidine-1 / -yl-1 1 (7-methyl-1 1 fluorene-indazole-5 -yl-methyl)-2-one Yl-ethyl} Hydrazine; (soil) a 4 — (6 — meridian — 2 — mesogen — 1, 4 — —chlorine — 2Η — □ quinidine — 3 —yl) — D — 1 — residual acid {2 — [1,4] Bipiperidinyl 1 / —yl-1 — (7 —methyl-1 1 Η-D archiazole-5 -yl -methyl)-2-methylamine-ethyl (±) — 4 -— (8-methoxy-2-keto-1,4-dihydro-2 Η — D-quinazoline-3-yl) -piperidine-1-carboxylic acid {2 — 〔 1,4- —] piperidine-1 / 1-yl-1 — (7-methyl-1 1 Η — D bow azole-5-yl-methyl)-2-ketomonoethyl}-hydrazine; (±) — 4— (8 —chloro-2 —keto-1,4—dihydro—2Η — Kou Kui • Zaolin−3 —yl) One pulse D fixed one 1 —Residual acid {2 — [1, 4] Binadin 1-yl-1— (7-methyl-1 1- —D-zrazole-5—yl 1-methyl) -2—Ethyl—ethyl} —vinylamine; (±) — Ν— ( 3— (7—ethyl—3—methyl—1Η — D-azole—5 —yl] — 1 — 1 — 1 — (4 — (? D—1 — 1) —D—1 — 1 ) C-2-yl) 2, 3-dihydro-2-national spiro- (piperidine-4, 4 / -quinazoline)-1 -carboxamide; (Earth)-N-(3-(7-ethyl-3- Methyl-1,1-D, 4-azole, 5-yl), 1-keto-1, 1- (4- (piperidine-1, 1-yl) piperidine-1, 1-yl), propan-2-yl), 2, 4-— Dihydro-2 / -ketospiro- (piperidine-512-200529835 (39) -4, 1H -benzo [d] [1,3] B oxazine)-1-endamidine (±)- N— (3 -— (7-ethyl-1H—D) -oxazole-5—yl) —1— (6,7—dihydro—1 fluorene — D-pyrazolo [4,3 — c] pyridine—5 (4Η) -yl) 1 -one ketopropan-2-yl) -4-(1,2 -dihydro-2 -ketoquinazoline -3 (4 Η) -yl) piperidine-1 -carboxamidine Amine; (±) — Ν— (3— (7—ethyl-1Η — D azole—5-yl) — 1 — (6,7 —dihydro-7,7 —dimethyl — 1Η — D ratio Zolo [4,3-c] D than pyridin-5 (4Η) -yl) -1-ketopropan-2-yl) -4- (1,2-dihydro-2-2-ketoquinazoline-1 3 (4Η) -yl) piperidine-1 1 Hydrazine; (earth) -methyl 2- (4- (8-gas-1,2,1-chloro-1, 2-chloroquinazoline-3 (4, fluorene) -yl) piperidine-1, 1-carboxamide Base)-3-(7 -methyl-1 1 Η -indazole -5 -yl) propionate; (Earth)-4-(8 -dai-1,2--ammonia -2-fluorenyl Zirin-3 (4Η) -yl) -N- (3- (7-methyl-1Η-D indazole-5-yl) -1 keto-1 1- (4-piperidine-1 1-yl ) Piperidine-1 a) propan-2-yl hydrazine-1 residual amidine; (±) — 4— (8-fluoro-1,2-dihydro-2-2-ketoquinazoline-3 (4Η ) -Yl) -N- (3- (7-methyl-1,1,1-methylazol-5-yl) -1-keto-1- (4-phenylpiperazine-1-yl) propan-2— ) Piperidine- 1-carboxamidine; (±) — 4 -— (8-fluoro-1,2-dihydro-2 —ketoquinazoline-3 (4 Η) -yl) —N— (1 — (4- (4-fluorophenyl) piperazine — -513- 200529835 (40) 1 mono) — 3- (7 —methyl — 1H — indazole — 5 —yl) — 1 —ketopropyl — 2 -yl) piperidine-1 1 monocarboxamide; (±) — 4 — (8-fluoro-1,2-dihydro-2 2-ketoquinazoline-3 (4H) -yl) -N— (1— (4— ( 2-fluorophenyl) piperazine-1-yl) -3— (7-methyl-1H—indazol-5-yl) -1—ketopropyl-2-yl) piperidine-1—carboxamide (±) — 4— (8—fluoro-1,2, dihydro-2—ketoquinazolin-3 (4H) -yl) —N— (3— (7—methyl-1H—D) Azole-5-yl)-1-keto- (4-o-tolylpiperazine-1 1-yl) propan-2-yl) piperidine-1 1-complete amine; (±) -methyl 2— ( 4- (8-fluoro-1,2-dihydro-2-ketoquinazoline-3 (4H) -yl) -piperidine-1-carboxamido) -3- (7-ethyl-3 —Methyl-1H—indazol-5-yl) propionate; (±) —N— (3— (7-ethyl-3—methyl-1 11—D inlet—5—yl) — 1 monoketo- 1-(4-(piperidine-1 -yl) piperidine-1 -yl) propan-2-yl) -4-(8 -oxo-1'2 — __ ^ chloro-2- Oxazoline-3 (4Η) -piperidine-1 Carboxamidine; (±) —N— (R) — 3— (2-keto-dihydro-benzoxazole-6-yl)-1-keto-1 — (4 — (piperidine-1 1-yl) piperidine- 1-yl) propan-2-yl) -4- (8-fluoro-1,2-dihydro- 2 -keto-quinazoline- 3 (4) -yl) piperidine- 1 1-carboxamidine; (±) — Ν— (3— (7-methyl-1,1—D, oxazole-5—yl), 1—one keto-1, 1 — ([pyridine—1—yl ) Piperidine-1-yl) propan-2-yl) -8 ^ -fluoro-2 ^, 3 ^ -dihydro-2 ^ -ketospiro-514- 200529835 (41) (piperidine-4,4 / -D quinazoline) -1 monocarboxamide; (±) — 4— (8 —gas—1,2, — ^ chloro-2, oxazoline-3 (4H) —yl) —N— (3 — (7 —methyl-5 —yl) — 1 —keto — 1 — (4 (piperidine — 1 —yl) propan 2 —yl) piperidine — 1 —carboxamide; N — (( R) —3 -— (2- (trifluoromethyl)-] imidazole-5-yl) -1, 1-keto-1, 1- (4- (piperidine-1, 1-yl) propan-2-yl), 4 — (1,2, Kui D, Kui D, Zai Lin 3 (4 ))-Group) 定-1-residual amine; Ν-((R)-1 (dimethylaminomethyl) (trifluoromethyl)-1 fluorene-benzo [d] imidazole-5 --Yl- (1,2, dihydro-2, ketoquinazoline-3 (4H) -1 monocarboxamidine; (R) -methyl 2- (4, (1,2, dihydro-2 --3 (4H) 1 -yl) piperidine-1 -carboxamido)-3-hydrogen-2 -keto-1H-benzo [d] imidazol 6 -yl) N — ((R) — 3 — (2,3 —dihydro-2 —keto [d] imidazol-6-yl) — 1 —keto-1 (4-piperidine-1 —yl) propan-2-yl) —4 ( 1,2-dioxazoline-3 (4H) -yl) piperidine-1monocarboxamidine; N-((R)-1- (dimethylaminomethylamidino) 3-dihydro-2- Keto-1H-benzo [d] imidazole-f) -4- (1,2-dihydro-2-ketoD-quinazoline-3 (piperidine-1-carboxamide); 4-dione D-quinone; -1 fluorene-indazolyl) piperidine-1 1 fluorene-benzo [d-pyridinyl- 1-yl) hydrogen- 2 -keto-2-(2-) ethyl)-4 -yl) piperyl Pyridyl-ketoquinazoline (2,3 — _ propionic acid Ester; 1-fluorene-benzene D 1-1-) hydrogen-2-keto-2-(2,; 1 -yl) ethyl 4)--) -515- 200529835 (42) N-((R ) — 3— (2,3 — _ ^, chloro—2—ammonium—1H-benzo [d] weili-6-yl) —1 tune-one 1 (4 yell B-definite 1 1-base ) Piperidin-1-yl) propan-2-yl) -4- (2 >, 3〃-dihydro-2 ^ -one ketospiro (piperidine-4, 4 /-(1Η) -quinazoline ) Carboxamide; 4- (1,2-dihydro-2,4-diketylquinazoline-3 (4Η) -yl) -N-((R) -3-(7-methyl- 1Η —benzo [d] [ 1，2，3〕二哩—5 —基）—1—酮[基一 1 一（4— (P很 D定—1 一基）哌啶一 1 一基）丙一 2 -基）哌啶一 1 一羧醯胺； (R ) — 4 — (2 —酬基一1，4 — 一^氨 一 2 — D 奎 口坐琳一3 一基）—定一 1—竣酸〔2-（4 一環己基—哌嗪—1—基 )一 2-酮基—1— (2 —酮基一 2，3 —二氫一苯並噁唑—6 一基甲基）一乙基〕一醯胺； (R) — 4— (2— 酮基一1，4一二氫一2 — D奎唑啉一 31,2,3] 2-mile-5-yl) -1-one [keto-1 1- (4- (P-D-D-1) -yl) piperidine-1 1-yl) propan-2-yl) piperidine -1 -carboxamidine; (R) — 4 — (2 —amyl-1,4 — —ammonia — 2 — D kuizuline — 3 —yl) — definite 1 — carboxylic acid [2- ( 4 monocyclohexyl-piperazin-1-yl) -2-keto-1- (2-keto-2,3-dihydromonobenzoxazole-6 monomethyl) monoethyl] monofluorenamine (R) — 4— (2—keto-1,4-dihydro-2—D quinazoline-1 3 一基）一哌D定一 1 一竣酸〔2 -（ 4 一異丙基一哌嗪一 1 一基 )一 2 —酮基一 1— (2 —酮基—2，3-二氫—苯並噁唑一 6 一基甲基）一乙基〕一醯胺； (R) — N-（ （R) - 3— (2 —酮基-2，3-二氫一 苯並卩惡哗—6—基）一 1 一酮[基—1 一（4 一喊D定一 1—基） 口底Π定一 1 一基）丙—2—基）一 2’ 4一 一>氮—2 -嗣基螺 一（哌啶一 4，4 > — ( 1 Η )—苯並〔d〕 〔 1，3〕噁嗪） 一 1 一羧醯胺； (R) — N—（ （R) — 3— (2 —酮基—2，3 —二氫― 苯並噁唑—6—基）—1—酮基一 1— (4 一環己一 1 一基） 喊嗦一 1 一基）丙—2-基）—2’ 4一 一^氯一 2 -嗣基螺 -516- 200529835 (43) —(哌啶一 4，4 ——(〗Η )—苯並〔d〕 〔 1，3〕噁嗪） 一 1 一殘醯胺； (R ) — N— ( ( R ) 一 3— (2 —酮基—2，3 —二氫— 苯並噁唑—6 —基）—1—酮基一 1 一 （4—(丙—2-基） 一哌嗪一 1 一基）丙一 2-基）—2，4一二氫一 —酮基 螺一（哌啶—4，4 — — ( 1 Η )—苯並〔d〕 〔 1，3〕噁嗪 )一 1 一羧醯胺； (R) — N — ( (R) — 3 — (2 一 嗣基 一 2 ’ 3 — * 氣— 苯並噁唑一 6-基）一 1 一酮基—1 一（4一 （哌啶一 1 一基 )哌啶一 1 一基）丙一 2—基）—2，4一二氫——酮基 螺—（哌啶一 4，4 / 一（ 1 Η ) -喹唑啉）一 1 一羧醯胺； (R) — Ν — ( ( R ) — 3 — (2 —酬基—2，3 - _•氨— 苯並噁唑—6 —基）—1—酮基—1 一（4—(環己—1—基 )喊嗦—1—基）丙一2 —基）一 2’ 4 — 一^氨一 2 -酬基 螺一（哌啶—4，4 / — ( 1 Η )—喹唑啉）—1 —羧醯胺； (R) — N— ( (R) — 3-（2- 酮基—2，3 —二氫一 苯並噁唑一 6-基）一1 一酮基—1— (4 一 （丙—2-基） 呢D秦—1 一基）丙一 2—基）一 2，4一二氨—2 —酬基螺 一（哌啶一 4，4 / 一（ 1 Η ) -曈唑啉）一 1 一羧醯胺； (R) — 4— (2 —酮基一 1，4 —二氫一2Η — D奎唑啉一 3 —基）—哌啶—1 —羧酸〔2 —〔 1，4 /〕聯哌啶一 1 > — 基—1— (4 —氯—2 —酮基—2，3-二氫—苯並噁唑一 6 — 基甲基）—2-酮基一乙基〕一醯胺； (R) — 4 — (2 —嗣基一1，4 — 一·氣一2 Η — 口 奎 口坐琳一 -517- 200529835 (44) 3 -基）一哌啶一 1 一羧酸〔2 -〔 1，4 /〕聯暖啶一厂一 基—1 一（5-氯—2 —酬基一 2，3 - 一.氯一苯並卩惡哗—6 -基甲基）一 2-酮基一乙基〕一醯胺； (R ) — 4 一 ( 2 —嗣基一1 ’ 4 — —•氣 一 2 Η 一 D 奎 口坐琳一 3 —基）一哌啶一 1 —羧酸〔2 -〔 1，4 >〕聯哌啶—1 / — 基一 1 一（4 —溴一 2 —酮基一 2，3-二氫—苯並噁唑—6 — 基甲基）一 2-酮基一乙基〕—醯胺；(1 group) 1 piperidine D 1 1 1 monocarboxylic acid [2-(4-isopropyl 1 piperazine 1 1 group)-2-keto 1-(2-keto-2, 3-dihydro- Benzoxazole-6 monomethyl) monoethyl] monofluorenamine; (R) — N- ((R)-3— (2-keto-2,3-dihydromonobenzopyridine) —6 —yl) — 1 monoketone [Base — 1 — (4 — D, 1 — 1) Bottom of the mouth — 1 — 1 — 2) — 2 '4 — 1 > Nitrogen — 2 -fluorenyl spiro- (piperidine-4,4 > — (1 —) -benzo [d] [1,3] oxazine)-1 -carboxamide; (R)-N-((R ) — 3— (2-keto—2,3-dihydro-benzoxazole-6-yl) — 1-keto-1 — (4-cyclohexyl — 1 —yl) — # 1 — 1 —yl) Propan-2-yl) -2 '4-chloro ^ 2-fluorenylspiro-516- 200529835 (43) — (piperidine-4,4 —— (〗 Η) —benzo [d] [1, 3] oxazine) 1 1 stilbamine; (R) — N— ((R) 3 — (2 —keto-2, 3 —dihydro — benzoxazole — 6 —yl) — 1 — Keto-1 1- (4- (propan-2-yl) -piperone 1 1 1 radical) propan-2-yl) -2,4-dihydro-ketospiro- (piperidine-4,4 — — (1 Η) —benzo [d] [1,3] oxazine )-1-carboxamidine; (R) — N — ((R) — 3 — (2 amidino-2 ′ 3 — * qi — benzoxazole-6-yl) 1 1 keto-1 One (4- (piperidine-1, 1-yl) piperidine-1, 1-yl) propan-2-yl) -2,4-dihydro-ketospiro- (piperidine-4, 4/1 (1 Η ) -Quinazoline)-1-carboxamidine; (R) — Ν — ((R) — 3 — (2 —amyl — 2,3 — — • ammonia — benzoxazole — 6 —yl) — 1-keto-1— (4- (cyclohex-1-yl) yl—1-yl) propanyl-2—yl) —2 ′ 4—one ^ amino—2-ylaminospiro (piperidine— 4,4 / — (1 Η) -quinazoline) —1 —carboxamide; (R) — N — ((R) — 3- (2-keto-2,3-dihydromonobenzox Azole-6-yl) -1 keto-1— (4-mono (propan-2-yl)? D D-1—1-yl) propan-2-yl) -2,4-diamino-2- Spiro- (piperidine-4,4 / a (1 Η) -oxazoline )-1-carboxamidine; (R) — 4-— (2- keto-1,4-dihydro-2 hydrazone — D quinazoline- 3-yl) —piperidine — 1 —carboxylic acid [2 — [ 1,4 /] piperidine-1 > -yl-1- (4-chloro-2 -keto-2,3-dihydro-benzoxazole-6-ylmethyl) -2-keto (Ethyl) -ammonium amine; (R) — 4 — (2 —fluorenyl-1,4 — mono-gas — 2 hydrazine — Kou Kuizilin-517- 200529835 (44) 3 -yl) -piperidine Pyridine-1 monocarboxylic acid [2--[1,4 /] Liannonidine one plant one base — 1 — (5-chloro-2 —amyl — 2,3-one. Chloro-benzopyrene — 6 -Ylmethyl)-2-keto-ethyl] -ammonium; (R) — 4 — (2 —fluorenyl — 1 ′ 4 — — • gas — 2 Η —D ) A piperidine-1 carboxylic acid [2-[1,4 >] bipiperidin-1 / 1-1-1-(4-bromo-2-keto-2, 3-dihydro-benzoxan Azole-6-ylmethyl) -2-ketomonoethyl] -amidamine; (R) — 4- (2 —酮基一 1，4 —二氫一2Η — D奎唑啉一 3 - 基）一_11 定—1—竣酸〔2-〔1，4 〕聯哌 D定一 1 一 基—1— (5 —溴—2 -酮基一 2，3 —二氫—苯並噁唑—6 — 基甲基）一 2-酮基一乙基〕一醯胺； (R) — 4- (2 —酮基一1，4 —二氫一2Η —喧唑啉一 3 —基）一哌啶一 1 —羧酸〔2 -〔 1，4 /〕聯暖啶一 1 > 一 基一 1 一（4 —碘—2-酮基—2，3 —二氫—苯並噁唑一 6-基甲基）一 2—酮基一乙基〕一醯胺；(R) — 4- (2-keto-1,4-dihydro-1, 2Η — D quinazoline- 3 -yl) 1 —11- 1-carboxylic acid [2- [1,4] dipiperidine D A 1-1-1-(5-bromo-2-keto-2, 3-dihydro-benzoxazole-6-yl methyl)-2-keto-1-ethyl] monoamine; R) — 4- (2 —keto-1,4 —dihydro — 2Η — —oxazoline — 3-yl) —piperidine — 1 —carboxylic acid [2-[1, 4 /] diazepine-1 > mono-1, 1- (4-iodo-2-keto-2,3-dihydro-benzoxazole-6-ylmethyl) 2-ketomonoethyl] -pyridamine; —Ν— (1—苄基一2—羥基一乙基）—2— （7 —甲基 一 1 Η — D引口坐一5 —基甲基）一4 一醒基一 4 一 〔1 ’2 — 二氫——酮基螺—〔4Η— 3 — ，1—苯並噁嗪—4，4, 一哌啶基〕丁醯胺； (±) — Ν— (1 — 节基一 2—經基一乙基）一2— (7 —甲基一1 Η — D弓丨口坐一5 —基甲基）一4 —嗣基一4 — 〔4 一 (2 —嗣基一1，4 — _*氣一 2 Η 一哇口坐琳一 3 —基）一Ρ肢D定 —1 —基〕一丁醯胺； (±) —苯基一乙酸Ν> — {2 — （7 —甲基一 1Η —吲 -518- 200529835 (45) π坐一 5 -基甲基）一4 一嗣基一 4 — 〔4 — (2 -嗣基一 1，4 一二氫—2 Η — D奎唑啉—3 -基）一哌啶—1 一基〕—丁醯 胺} 一醯胼； (土）一 1 一 〔1，4 〕聯脈陡 一 1 —基一4 — 〔4 — (8 —氯一2 —酬基一1’ 4 — 一^氣一 2 Η — D奎口坐琳一 3 —基） 一哌啶一 1—基〕一2— (7 —甲基一 1Η — D弓丨唑一5—基甲 基）—丁 — 1，4一 二酮； (土）一 1 一 〔1’4 〕聯呢 Π定一1 —基一2 — ( 7 — 甲基一1Η — D引唑一5 —基甲基）一4一 〔2，，3，一二氫 一 2 / —酮基螺一（哌啶一4，4 / — D奎唑啉〕丁一 1，4 — 二酮； (±) -1— (4 —環己基一哌嗪一1—基）一2 — （2 —酮基一 2，3 —二氫—苯並噁唑一6—基甲基）一 4一〔4 —(2 —酮基一1，4 —二氫一2Η — α奎唑啉一 3 —基）一哌 D定一1 一基〕—丁一 1，4 —二酬； (土）一 1 — 〔 1，4 〕聯呢 D定一1 —基一2 — (2 — 酮基—2，3 —二氫一苯並Π惡Π坐一 6—基甲基）—4一〔4 — (2 —酮基一1，4 一二氫一 2 Η — D奎唑啉一 3 —基）一哌啶 一 1— 丁基〕一丁一 1，4 —二酮； (± ) — 1 — 〔 1，4 〕聯呢 D定一1 —基一2 — ( 2 — 酮基一 2，3 -二氫—苯並噁唑一 6—基甲基）—4一〔2一 ，3 / —二氫—2 / —酮基螺一（哌啶一 4，4，一 D奎唑啉） 〕一丁 — 1，4—二酮； (± ) — 1 — ( 4 —環己基一哌嗪一1 —基）一 2 — （ 2 -519- 200529835 (46) —醒基一 2’ 3 — 一·氯一苯並11惡哗—6-基甲基）一 4 一〔 2 >，3 — -二氫一 2 / —酮基螺一（哌啶一 4，4 / —喹唑 啉）〕丁一 1，4一一 醒； (±) — 4- (2 —酮基一1，4 —二氫一2H — 口奎唑啉一 3 —基）一哌啶—1 —羧酸〔2 - （ 4 一環己基—哌嗪一 1 — 基）一 1— (7 —甲基一1H-B弓丨唑一5 —基甲基）一 2 —酮 基一乙基〕一醯胺；—N— (1-benzyl-2-hydroxy-ethyl) —2— (7-methyl-1 1 Η—D inlet—5-ylmethyl) —4—pentyl — 4— [1 ' 2 —dihydro—ketospiro— [4Η—3 —, 1—benzoxazine—4,4, monopiperidinyl] butanamide; (±) — Ν— (1 — nodyl-2— Transyl-ethyl)-2- (7-methyl-1 1 Η- D bow 丨 mouth sits a 5--methyl-)-4-fluorenyl- 4-[4 1 (2-fluorenyl- 1, 4 — _ * 气 一 2 Η 一口 口 琳 -1—3-based) —P-D-D-1— 1-] butanamide; (±) —phenylmonoacetic acid N > — {2 — (7 —A Radical 1-indene-ind-518- 200529835 (45) π-a-5-ylmethyl)-4 amidinyl 4 — [4 — (2 -fluorenyl-1,4-dihydro-2 fluorene — D-quinone Oxazoline-3 -yl) -piperidine-1 -yl] -butamidin}-hydrazone; (soil)-1-1 [1, 4] diamidine-1-radical-4-[4 — (8 —Chloro-2 —Cydro-1 ′ 4 —Cyclo-2 —D-Koukou-Zeline-3 —Base) —Piperidine-1—Base] —2— (7—Methyl-1 1—D bow丨 zole-5-methyl) -butane-1,4-dione; (Earth) -1 1- [1'4] bi-nine-1-1-yl-2— (7-methyl-1Η—D Indazole-5-ylmethyl) -4- [2,3, -dihydro- 2 / -ketospiro- (piperidine-4,4 / -D-quinazoline) butan-1,4- -2 Ketones; (±) -1— (4-cyclohexyl-piperazine-1—yl) —2— (2-keto-2,3-dihydro-benzoxazole-6-ylmethyl) —4 One [4- — (2 —keto-1,4-dihydro-1, 2 α — α-quinazoline — 3 —yl) — piperidine D — 1 — 1] — butane 1, 1, 4 — diluent; (earth) One 1-[1, 4] dibenzidine D 1-1-2-(2-keto-2, 3-dihydro-benzobenzoxoxine 6-ylmethyl)-4-[4 — (2-keto-1,4-dihydro-2 hydrazone—D quinazoline-3-yl) -piperidine-1-butyl] -butane-1,4-dione; (±) — 1 — [1,4] Bindine D 1-yl-2 — (2-keto-2,3-dihydro-benzoxazole-6-ylmethyl) —4 1 [2,3 / —Dihydro—2 / — Spiro- (piperidine-4,4, -D-quinazoline)]-butane-1,4-dione; (±) — 1 — (4-cyclohexyl-piperazine-1 —yl) — 2 — (2 -519- 200529835 (46) —Axyl-2 ′ 3 —-Chloro-benzo11-oxo-6-methylmethyl) —4— [2 >, 3 — -dihydro-1 2 / — Ketospiro- (piperidine-4,4 / -quinazoline)] butan-1,4-one wake up; (±) — 4- (2 —keto-1,4-dihydro-2H — Kou Kui Oxazoline- 3-yl) -piperidine- 1-carboxylic acid [2-(4-cyclohexyl-piperazine- 1 -yl)-1-(7 -methyl- 1H-B A) 2-keto-ethyl] -ammonium; (±) — 4— (2 —酮基一 1，4 —二氫一 2H —喹唑啉一 3 —基）一哌啶一 1—羧酸〔2- 〔4— (4 —氟一苯基）一 哌嗪—1 —基〕—1 — ( 7 —甲基一1 Η — D引唑一5 —基甲基 )一 2 —酮基—乙基〕—醯胺； (土） 一 3 — （7 — 甲基 一 1 Η — 口引口坐一5 —基)—2 — { 〔4— (2 —酮基一 1，4一 二氫一2Η — D 奎唑啉一3 —基）一 哌啶一 1 一羰基〕一胺基〕一丙酸特丁酯； (±) — 3— (7 —甲基一1Η —吲唑一5 —基）一2— {(±) — 4 -— (2-keto-1,4-dihydro-2H—quinazoline-3-yl) -piperidine-1—carboxylic acid [2- [4- (4-fluoro-phenyl) ) Monopiperazin-1-yl] -1 — (7-methyl-1 1 hydrazone — D-zolazole 5-ylmethyl) — 2-keto-ethyl] -amidamine; (earth) — 3 — (7 —methyl-1, 1 — — mouth, 5 — base), 2 — {[4— (2-keto-1,4-dihydro-1, 2Η — D quinazoline, 3 —yl), 1 Piperidine-1 monocarbonyl] monoamino] tert-butyl propionate; (±) — 3 — (7 —methyl-1 1 —indazole-5 —yl) — 2 — { 〔4 — ( 2 一 酬基 一 1 ’ 4 — —•氣一2 Η 一 D 奎 口坐琳一3 —基）一 哌啶一 1 一羰基〕一胺基〕一丙酸1 一甲基環己酯； (±) — 3— (7 —甲基一1Η —吲唑一5 —基）一2— { 〔4— (2 —酮基一 1，4一二氫一2Η — D奎唑啉一3 —基）一 哌啶一 1 一羰基〕一胺基} 一丙酸 1 一氮雜一雙環〔2·2·2 〕辛一 3 -酯； (±) — 3— (7 -甲基一1Η —吲唑一5 —基）一2— { 〔4- (2 —酮基一 1,4 —二氫一2Η—喹唑啉一3 —基）一 I紙陡一 1 一鑛基〕—胺基} 一丙酸I帳陡一 4 一醋； -520- 200529835 (47) (±) — 4— (3— (7 —甲基一1H — D引唑一5 —基）一 2 - { 〔4— (2 —酮基一1，4 一 二氫一 2H — D奎唑啉一3 — 基）一哌Π定一 1 一羰基〕一胺基丨一丙醯氧基）一哌B定一 1 -羧酸特丁酯； (±) — 3— (7— 甲基一1H —吲唑一5 —基）一2— {[4 — (2 monophenyl group 1 '4 — — • qi 1 2 Η 1 D Kuizulin 3 —yl) a piperidine 1 1 carbonyl] monoamino] monopropionic acid 1 monomethyl ring Hexyl esters; (±) — 3 — (7 —methyl-1Η — indazole — 5-yl) — 2 — {[4 — (2 —keto-1,4-dihydro-2Η — D-quinazoline -3-yl) -piperidine- 1-carbonyl] -amino}}-propionic acid 1-aza-bicyclo [2 · 2 · 2] octyl 3-ester; (±) — 3— (7-methyl 1 1Η —indazole-5 —yl] 2 — {[4- (2- keto-1,4-dihydro-2 hydrazine—quinazoline — 3-yl) — 1 paper steep 1 1 —mineral] —Amine group] Monopropionate 1—4—Ethyl acetate; -520- 200529835 (47) (±) — 4— (3— (7—Methyl—1H—D-azole—5-Base) —2— {[4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine- 1-carbonyl] -amino group 丨 -propionyloxy) -piperone B 1-tert-butyl carboxylate; (±) — 3— (7—methyl-1H—indazole-5—yl) —2— { (4 — ( 2 一 酬基一1，4 — 一^ 氣一2 Η — D 奎 口坐琳一3 —基）一 哌啶一 1—羰基〕一胺基} 一丙酸3，4，5，6 —四氫一 2Η —〔1，4 /〕聯吡啶一 4 —酯； (土）一 3— (7 —甲基一1Η —吲唑一5 —基）一2— { 〔4— (2 —酮基一1，4一二氫一2Η — D奎唑啉一 3 — 基）一 哌啶一 1 一羰基〕一胺基} 一丙酸 1 一二乙基胺基一 1 一 甲基一乙酯； (±) — 3— (7 —甲基一1Η — 口引唑一5 —基）一2— {(4 — (2 monophenyl-1,4—1 ^ qi-1 2 Η —D quetialine-3-yl) -piperidine-1—carbonyl] monoamino} monopropionate 3,4,5 , 6—tetrahydro-2Η— [1,4 /] bipyridine-4-ester; (earth) —3— (7—methyl—1Η—indazole—5-yl) —2— {[4— ( 2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine-1 monocarbonyl] monoamino} monopropionic acid 1 diethylamino 1 monomethyl Monoethyl ester; (±) — 3— (7 —methyl-1 1Η — oxazole-5 —yl) — 2 — { 〔4一 （2 —酮基一1，4 —二氫一2Η—喹唑啉一 3 —基）一 哌啶一 1—羰基〕一胺基}—丙酸 1，1 一二甲基—2-苯 基一乙酯； (土） 一 3 — (7 —甲基一1 Η — D 引口坐一5 —基）一2 — { 〔4 — (2 —嗣基一1，4 — 一·氣 一 2 Η — 口奎 η坐琳一3 —基)— 哌啶一 1 一羰基〕—胺基}—丙酸 1，1 一二甲基—3—苯 基一丙酯； (±) — 3— (7 —甲基一1Η — D引唑一5 —基）一2— { 〔4— (2 —酮基一1，4一二氫一2Η — D奎唑啉一 3 —基）一 哌啶一 1 一羰基〕一胺基} 一丙酸乙酯 (士） 一 1— (7 —甲基一 1Η — D引唑一5 —基甲基）一2 -521 - 200529835 (48) —〔1 一吡啶一 4 —基一甲基〕一 2—酮基乙基〕—2〃 ， 3 — 一氣—2 —嗣基螺—〔丨紙U疋—4’ 4 — ( 1 Η )— 口奎唑啉〕一 1 一羧醯胺； (±) — 1— (7 —甲基一1Η — 口引唑一5 —基甲基）一2 一〔1 一卩比卩定一 4 —基一呢嗦基〕一 2-醒基乙基〕—2 ’ 3 — 一·氯一 2 —嗣基螺—〔哌 D定—4，4 — ( 1 Η )— 喹唑啉〕—1 一羧醯胺； (土）一 1 — (7 —甲基一1Η — 口弓丨哇一 5 —基甲基）一 2 一〔2—二甲基胺基一乙基一乙基—氨基甲醯基〕一 2—酮 基乙基〕—2 — ，3，_二氫—2，一酮基螺一〔哌啶—4， 4 > — ( 1 Η ) —喹唑啉〕一 1 一羧醯胺； (士）一 1 — (7 —甲基一1 Η — D引口坐一5 —基甲基）一 2 一〔1 一吡啶一 4一基—甲基〕—2—酮基乙基〕一厂， 2 — 一氯一 2 —酬基螺—〔4Η - 3 ，1 一苯並卩惡嗦一 4 ，4 /一哌啶〕一 1 一羧醯胺； (±) — 1— (7 —甲基一1Η — D引唑一5 —基甲基）一2 一〔1 一吡啶—4 一基—甲基〕—2_酮基乙基〕一厂， 2 一 一二氫一 2，—酮基螺—〔4Η — 3 /，1 —苯並噁嗪一 4 ，4 / 一哌啶〕—1 一羧醯胺； (R) — 4 — ( 2 一 酬基一1 ’ 4 ——> 氣一2 Η — D 奎 口坐淋一 3 —基）—哌啶-1 d -羧酸〔2 —〔 1，4，〕聯哌啶—1 > —基一1 一 （7 —甲基一 1H — D弓丨唑一5 —基甲基）一2 —酮 基一乙基〕一醯胺； 或 -522 200529835 (49) (R ) — 1 — ( 7 一甲基一1 Η — D引口坐一 5 —基甲基）一2 —〔1，4 /〕聯哌啶一 1 / —基—2 -酮基乙基〕—2 —， 3 / -二氫—2 / —酮基螺—〔哌啶—4，4 — — ( 1Η )— 喹唑啉〕一 1 一羧醯胺。 6. —種選自下述之化合物或其醫藥上可接受之鹽或 溶劑化物於製造藥物以治療或預防偏頭痛上之用途；[4-((2-keto-1,4-dihydro-2'-quinazoline-3-yl) -piperidine-1-carbonyl] -amino group} -propionic acid 1,1-dimethyl-2 -Phenyl monoethyl ester; (earth) a 3 — (7 —methyl 1 1 Η — D inlet sitting a 5 — base) a 2 — {〔4 — (2 — amidino-1, 4 — a · Qi-2 Η — Kou Kui 坐 琳 3 3 —yl) — piperidine — 1 monocarbonyl] — amino} — propanoic acid 1, 1, dimethyl 3 — phenyl monopropyl ester; (±) — 3- (7-methyl-1,1-diazole- 5-yl)-2- [[4 -— (2-keto-1,4-dihydro-2,2-diquinazoline- 3-yl)- Piperidine-1 monocarbonyl] monoamino} ethyl propionate (±) 1- (7-methyl-1 1-diazole-5-methylmethyl)-2 -521-200529835 (48) — [1-pyridyl-4-yl-methyl] -2-ketoethyl] -2〃, 3—one gas-2—fluorenylspiro— [丨 paper U 疋 -4 '4 — (1 Η) — mouth Quinazoline]-1-carboxamidine; (±) — 1— (7 —methyl-1 1 — — oxazole-5 —ylmethyl) — 2 — [1 — 1 4-Methyl-molyl] -2 2-pentylethyl] -2 '3 —-Chloro-2—fluorenylspiro— [piperidine-4,4 — (1 Η) —quinazoline] — 1 Carboxamidine (Methylamino)-2-ketoethyl] -2 —, 3, _dihydro-2, monoketospiro- [piperidine-4, 4 > — (1 Η) —quinazoline]-1 Monocarboxamidine; (±) 1 — (7 —methyl — 1 Η — D inlet — 5 —ylmethyl) — 2 — [1 —pyridine — 4 —yl —methyl] — 2-one [Ethylethyl] one plant, 2-chloro-2-phenyl spirospira-[4 3-3,1-benzopyrene oxan-4,4 / -piperidine]-1 -carboxamide; (±) — 1- (7-methyl-1, 1-diazole-5-ylmethyl)-2 [1 -pyridin-4 -yl-methyl] -2 -ketoethyl] one plant, two one one two Hydrogen-2, —ketospiro— [4Η — 3 /, 1 —benzoxazine — 4, 4 / monopiperidine] — 1-carboxamide; (R) — 4 — (2 a Phenyl group 1 '4 —— > qi-1 2 Η — D Kuikouxin lysine 3-group) -piperidine-1 d -carboxylic acid [2 — [1,2,4] bipiperidine-1 > —Yl-1 1- (7-methyl-1H—D archylazole-5—ylmethyl) —2-ketomonoethyl] -amidine; or -522 200529835 (49) (R) — 1 — (7 monomethyl-1 Η — D inlet sitting 5-ylmethyl)-2-[1,4 /] piperidine 1 / -yl-2-ketoethyl]-2-, 3 / -Dihydro-2 / -ketospiro-[piperidine-4,4--(1Η)-quinazoline]-1 -carboxamide. 6. —The use of a compound selected from the following or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prevention of migraine; 4— (2 —酮基一1，4 —二氫一2Η — D奎唑啉一3 —基） 一哌啶一 1 一羧酸〔2 —〔 1，4 〃〕聯哌啶—1 < —基—1 — (7—溴一 1Η —吲唑一 5 —基甲基）一2—酮基一乙基〕— 醯胺； 4— (2 —酮基一1，4一二氫一2H—D奎唑啉一3 —基） 一哌啶一 1—羧酸〔2-酮基—1 一（2 —酮基一 2，3—二氫 一苯並Π惡Π坐—6 —基甲基）—2— (4 — D比Β定一 4 —基一哌嗪 一 1 一基）一乙基〕一醯胺；4- (2-keto-1,4-dihydro-2H-D-quinazoline-3-yl) -piperidine-1 monocarboxylic acid [2-[[1,4H]] bipiperidine-1 < —Yl — 1 — (7-bromo-1′-indazol-5-ylmethyl) —2-ketomonoethyl] -fluorenamine; 4- (2-keto-1,4-dihydro-2H —D quinazoline- 3-yl) -piperidine-1-carboxylic acid [2-keto-1— (2-keto-2,3-dihydro-benzo-oxo-2-oxo-6-ylmethyl] Radical) —2— (4-D than bis-a-4-piperazine- 1-yl) -ethyl] -amidine; 4 一 （2—酮基一 1，4 —二氫一2Η — D奎唑啉一3 —基） 一脈D定一 1 一殘酸〔2 —嗣基—1— (2 —酬基一 2，3 —二氯 一苯並噁唑一6 —基甲基）—2—哌啶一 1 一基一乙基〕一 醯胺； 4— (2 —酮基一1，4 —二氫一2Η — D奎唑啉一3 —基） 一哌啶一1 —羧酸〔2 — ( 4 —甲基—哌嗪—1 一基）一 2 — 酮基一1 一 （2 —酮基一 2，3 —二氫一苯並噁唑一 6—基甲 基）一乙基〕一醯胺； 4 — ( 2 —嗣基一 1 ’ 4 — _•氣一2 Η —嗤口坐琳一3 —基） 一 _啶一 1 一羧酸〔2 -〔 1，4 >〕聯哌啶一]/ —基—1 — -523- 200529835 (50) (4 —甲基一 2 —酮基一 2，3 —二氫一苯並噁唑一 6-基甲 基）一 2—酮基一乙基〕一醯胺； 4— (2 —酮基一1，4一二氫一 2H — D奎唑啉一3 —基） —哌啶一1—羧酸〔1 一（4 —甲基—2 —酮基一 2，3 —二氫 一苯並噁唑一 6—基甲基）—2 —酮基一 2 —哌啶—1 一基一 乙基〕一醯胺； 4 一 （2 —酮基一 1，4 —二氫一 2H — D奎唑啉一3 —基） 一哌啶一1—羧酸〔1— (4 —氯—2 —酮基—2，3 —二氫— 苯並噁唑一 6—基甲基）一 2—酮基一 2 —哌啶一 1 一基—乙 基〕一醯胺； 4— (2 —酮基一 1，4 —二氫一 2H—D奎唑啉一3 —基） 一哌啶一 1 一羧酸〔1 一二甲基氨基甲醯基一 2 — （4 一甲基 一 2-酮基—2，3 —二氫—苯並噁唑—6 —基）—乙基〕— 醯胺； 4一 （2 —酮基一1，4一二氫一2H — D奎唑啉一 3 —基） —哌啶一 1 一羧酸〔2-（4 一氯一 2 —酮基—2，3-二氫一 苯並噁唑一 6-基）一 1 一二甲基氨基甲醯基一乙基〕一醯 胺； 4— (2 —酮基一1，4一二氫—2H — D奎唑啉一 3 —基） —哌啶一 1 一羧酸〔1 一（4 一甲基—2 —酮基一 2，3-二氫 一苯並噁唑一 6 —基甲基）一 2 —酮基—2— (4—吡啶—4 一基—喊嗪一 1 一基）一乙基〕—醯胺； 4— (2 —酮基一1，4一二氫一 2H —咱唑啉一3 —基） 一丨iR D定一 1 一殘酸〔1— (4 一氯—2- 酮[基一 2’ 3 - 一氨— - 524- 200529835 (51) 苯並噁唑一6 —基甲基）—2-酮基一 2 — （4 一吡啶—4 一 基一哌嗪一 1 —基）一乙基〕一醯胺； 4 一 （2—酮基一1，4 —二氫一2H — □奎唑啉一3 —基） —哌D定一 1 一殘酸〔2 —〔 1，4 /〕聯哌卩定一 1 / —基—1 — (4 一乙基—2 —酮基—2，3 —二氫一苯並噁唑—6 —基甲 基）一 2 —酮基一乙基〕一醯胺； 4 — (2 — 嗣基 一 1，4 — 一氣一2 Η — D 奎 口坐琳一3 —基） —哌啶一 1 —羧酸〔2 —〔 1，4 /〕聯哌啶一 1 / 一基—1 — (7 —甲基—2 —酮基一 2，3 —二氫一1Η—苯並咪唑—5 — 基甲基）一 2—酮基一乙基〕一醯胺； 4— (2 —酮基一1，4 —二氫一2Η — D奎唑啉一3 —基） —峨卩定—1 —殘酸〔2 —〔 1，4 〕聯_ D定一 1 一基一 1 — (7 —氯一 2 —酮基一 2，3 —二氫—1Η—苯並咪唑—5 —基 甲基）一 2—酮基一乙基〕一醯胺； 4— (2—酮基一1，4一二氫一2Η — D奎唑啉一3 —基） 一脈Π定—1 —竣酸〔2 -〔 1，4 〕聯_ Π定—1 一基一 1 — (7—乙基—2-酮基一 2，3 —二氫一 1Η —苯並咪唑一 5 — 基甲基）一 2—酮基一乙基〕一醯胺； 4一 （2 —酮基一1，4一二氫一2Η — D奎唑啉一3 —基） —哌啶—1 —羧酸〔2 —〔 1，4，〕聯哌啶—厂—基—1 — (3 —甲基—2 —酮基一 2，3 —二氫—1Η-苯並咪唑一 5 — 基甲基）—2-酮基一乙基〕一醯胺； 4— (2 —酮基一1，4一二氫_2H — D奎唑啉一3 —基） 一哌卩定一 1 —羧酸〔2 —〔 1，4 〕聯哌陡—1 —基—1 一 -525- 200529835 (52) (3，7 —二甲基—2 —酮基一 2，3 —二氫一 1H —苯並咪唑 一 5-基甲基）一 2—酮基—乙基〕一醯胺； 4 — (2 —酬基一1，4 — 一氣 一 2 Η — D 奎 口坐琳 一 3 —基） 一喊卩定一 1 一竣酸〔2 —〔 1，4 〕聯喊Π定一 1 —基—1 一 (7 一氣—3 一甲基一 2 —醒基一 2 ’ 3 — 一氣—1 Η —苯並味 唑一 5-基甲基）一 2-酮基一乙基〕一醯胺； 4 一 （2—酮基一1，4一二氫一2Η — D奎唑啉一3 —基） —哌啶一 1 一羧酸〔2 —〔 1，4 /〕聯哌啶—1 / —基一 1 一 (7 —乙基一3 —甲基—2 —酮基一 2，3—二氫—1Η —苯並 咪唑一 5—基甲基）一 2-酮基一乙基〕一醯胺； 3— (7 —甲基一1Η — D 引唑一5 —基）一2— { 〔4—( 2—酮基一1，4 —二氫一2H—D奎唑啉一 3 —基）一哌啶一1 一羰基〕一胺基} 一丙酸異丙酯； 3— (7 —氯一1Η — 口引唑一5 —基）一 2— { 〔4— (2 —酮基一1，4 —二氫—2 Η — D奎唑啉一 3 -基）一丨派啶一1 一羰基〕一胺基} 一丙酸異丙酯； 3— (7 -乙基一1Η — D引唑一5 —基）一2— { 〔4—( 2—嗣基—1’4一 —氮一 2H—D奎哗琳—3 —基）一呢D定一 1 一羰基〕一胺基} 一丙酸異丙酯； 3— (7 —氯一1Η — D 引唑一5 —基）一2— { 〔4— (2 一酮基一1，4 一二氫—2 Η —喹唑啉一3 —基）一哌啶一1 一羰基〕一胺基丨一丙酸特丁酯； 3— (7 —乙基一1Η —吲唑一5— 基）一2— { 〔4—( 2 —酮基一1，4 —二氫一 2 Η —咱唑啉一3 —基）一I派啶一1 -526- 200529835 (53) 一羰基〕一胺基丨一丙酸特丁酯； 3 — ( 7 —氯一1 Η — 〇 引口坐一5 —基）一2 — { [ 4 — ( 2 一醒基一1，4 — —•氨—2 Η — D奎口坐琳一3 —基）一丨派D疋一 1 一羰基〕一胺基} 一丙酸環己酯； 3— (7 —乙基一1Η — D 引唑一5 —基）一2— { 〔4—( 2 —酮基一 1，4 —二氫一 2H-D奎唑啉一 3 —基）一哌啶-1 一羰基〕一胺基）—丙酸環己酯；4 mono (2-keto-1,4-dihydro-2Η-D quinazoline-3-yl) a pulse D fixed 1 1 residual acid [2-fluorenyl-1-(2-phenyl group 2 , 3-dichloro-benzoxazole-6-ylmethyl) -2-piperidine-1 1-yl-ethyl] monofluorenamine; 4- (2-keto-1,4-dihydro-2) — D-quinazoline-3-yl) -piperidine-1-carboxylic acid [2 -— (4-methyl-piperazine-1-yl) —2-keto-1— (2-keto-2, 3-dihydro-benzoxazole-6-ylmethyl) monoethyl] monofluorenamine; 4 — (2 -fluorenyl-1 ′ 4 — —qi-1 2 Η — 嗤 口 坐 琳 -1 — ) 1-pyridine-1 monocarboxylic acid [2-[1,4 >] bipiperidine-1] / -yl-1--523- 200529835 (50) (4-methyl-1 2-keto-2 , 3-dihydromonobenzoxazole-6-ylmethyl) -2-ketomonoethyl] monofluorenamine; 4- (2-keto-1,4-dihydro-2H-D quinazole 1- (4-methyl) -piperidine- 1-carboxylic acid [1- (4-methyl-2-keto-2,3-dihydro-benzoxazole-6-ylmethyl) -2-one base 2-piperidine-1 monoylethyl] monomethylamine; 4 mono (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) monopiperidine-1-carboxylic acid [1- (4-chloro-2—keto-2,3-dihydro-benzoxazole-6-ylmethyl) —2—keto—2—piperidine—1—yl—ethyl] — Amidoamine; 4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) piperidine-1 monocarboxylic acid [1-dimethylcarbamoyl-2 — (4-monomethyl-2-keto-2,3-dihydro-benzoxazole-6-yl) -ethyl] -amidamine; 4-one (2-keto-1,4-dihydro-1 2H —D quinazolinone 3-yl) —piperidine-1 monocarboxylic acid [2- (4-chloro-1-2-keto-2,3-dihydromonobenzoxazole-6-yl) -1 1-dimethylaminocarbamyl-ethyl] -ammonium amine; 4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) -piperidine-1 monocarboxylic acid [1- (4-methyl-2-keto-2,3-dihydro-benzoxazole-6-ylmethyl) 2-keto-2— (4-pyridine-4 a —Hyrazine—1—one group] —ethyl] —fluorenamine; 4— (2—keto—1,4—dihydro—2H—oxazoline—3—yl) —iR D—1—one residue Acid [1— (4-Chloro-2-one— [2- 2 ′ 3 -monoammonium — 524- 200529835 (51) benzoxazole-6-ylmethyl) — 2-keto-2 — (4 1-pyridine-4-yl-piperazine-1-yl) monoethyl] monofluorenamine; 4 1- (2-keto-1,4-dihydro-2H- □ quinazoline-3-yl) -piperidine D fixed 1 1 residual acid [2 — [1, 4 /] biperidine fixed 1 / — 1 — 1 — (4 1 ethyl 2 — keto 2 2, 3 — dihydromonobenzoxazole —6 —ylmethyl) —2—ketomonoethyl] monofluorenamine; 4 — (2—fluorenyl—1,4—one gas—2 hydrazone—D quetiazolin—3-yl) —piperidine 1-carboxylic acid [2 — [1,4 /] bipiperidine-1 / 1-yl-1 — (7 -methyl-2 —keto-1,2,3-dihydro-1 1 -benzimidazole-5 —Ylmethyl) —2-ketomonoethyl] -ammonium amine; 4- (2-keto-1,4-dihydro-2hydrazone—D-quinazoline-3—yl) —E Luddin-1 —Residual acid [2 — [1,4] Co-D-D-1 — 1 radical — 1 — (7 —chloro — 2 —keto —2, 3 —dihydro — 1 hydrazone — benzimidazole — 5 —Ylmethyl) —2-ketomonoethyl] monomethylamine; 4 -— (2-ketomono-1,4-dihydro—2hydrazone—D quinazoline—3-yl) —dine-1 — Junic acid [2-[1, 4] Bi- 定 定 -1 — 1 radical — 1 — (7-ethyl — 2 keto — 2, 3 — dihydro — 1 hydrazone — benzimidazole — 5 — methylmethyl) A) 2-keto-ethyl] -ammonium amine; 4- (2-keto-1,4-dihydro-2a-D quinazoline-3-yl) -piperidine-1 -carboxylic acid [ 2 — [1,4,] piperidine—plant—yl—1— (3-methyl-2—keto-2,3-dihydro-1,1′-benzimidazole-5′-methyl) -2 -Ketomonoethyl] monoamidine; 4- (2-keto-1,4-dihydro-2H-D quinazoline-3-yl) piperidine-1 carboxylic acid [2-[ 1,4] dipiperidin-1-yl-1-1-525- 200529835 (52) (3,7-dimethyl-2-keto-1,2,3-dihydro-1H-benzimidazole-5 Base ) A 2-keto-ethyl] -ammonium amine; 4 — (2-amyl-1, 4 — one gas — 2 hydrazine — D Kuikoulin-3-yl) yell a certain amount of 1-complete acid [2 — [1,4] Synthesis Π 1-1-1-1 (7 1-3-methyl-2-axyl-2 '3-1-1-hydrazone-benzotriazole-5-yl (Methyl) -2-keto-ethyl] monofluorenamine; 4-((2-keto-1,4-dihydro-2) -D quinazoline-3-yl) -piperidine-1 monocarboxylic acid [2 — [1,4 /] bipiperidin-1 / -yl-1 1-(7 -ethyl-3 -methyl -2-keto -2,3 -dihydro -1 fluorene -benzimidazole -5 —Ylmethyl) -2-ketomonoethyl] monofluorenamine; 3- (7—methylmono1Η—D introzol-5-yl) —2— {[4— (2-keto-1 , 4-dihydro-2H-D quinazoline-3-yl) -piperidine-1 monocarbonyl] monoamino} isopropyl propionate; 3- (7-chloro-1 hydrazone-orbitazol-5 —Yl) —2— [[4 -— (2-keto-1,4-dihydro-2—fluorene—D-quinazoline—3-yl) —pyridine—1—carbonyl] —amino group} Isopropyl monopropionate; 3- (7-ethyl-1, 1-, 1-oxazole, 5-, 1-, 2-, 2- {[4— (2-fluorenyl-1'4, 1-nitrogen, 2H-D, quinol Lynn — 3 —yl) 1 D 1 — 1 carbonyl] monoamino} isopropyl monopropionate; 3 — (7 —chloro — 1 — — D indazole — 5 —yl) — 2 — {[4— (2 monoketo-1,4-dihydro-2 fluorene-quinazoline-3-yl) -piperidine-1 monocarbonyl] monoamino group butyl monopropionate; 3- (7-ethyl 1 1-indazole-5 -yl)-2-{[4-(2 -keto-1,4 -dihydro-2 Η -oxazoline -3 -yl) -I pyridine 1 -526- 200529835 (53) monocarbonyl] monoamino tetrabutyl propionate; 3 — (7 —chloro-1 Η — 〇 inlet 5 —yl) — 2 — {[4 — (2 1,4 — — • Ammonia — 2 Η — D Kuikouline-3 -yl)-D 疋 1-1-carbonyl]-amino group} cyclohexyl monopropionate; 3-(7-ethyl-1 1Η — D Indazole-5 —yl) 2 — {[4- (2 -keto-1,4-dihydro-2H-D quinazoline-3 —yl) -piperidine-1 -carbonyl]- amine ) - cyclohexyl propionate; 3 - (7 —氯一1Η — 口引唑一5 —基）一2— { 〔4— (2 —酮基一 1，4 一二氫一 2Η —喹唑啉一3 —基）一哌啶一1 一羰基〕一胺基丨一丙酸 1 一甲基一哌啶一 4一酯； 3— (7 —乙基一 1Η —吲唑一5 —基）一2— { 〔4—( 2 —酮基_1，4 —二氫一 2Η — D奎唑啉一 3 —基）一哌啶一 1 一羰基〕一胺基丨—丙酸 1 一甲基一哌啶一 4一酯； 3 - (7 —氯一 1Η —吲唑—5 —基）2— { 〔4一 （23-(7 -Chloro-l-pyridinium-oxazolyl- 5-yl)-2-{[4 -— (2-keto-1,4-dihydro-2 hydrazine-quinazoline-3-yl) -piperidine 1-1 -carbonyl] -amino group-1-propionic acid-1-methyl-piperidine-4-ester; 3-(7 -ethyl-1 fluorene-indazole-5 -yl)-2-{[4-(2 —Keto_1,4 —dihydro — 2Η — D quinazoline — 3-yl) -piperidine — 1 —carbonyl] —amino group — —propionic acid 1 —methyl — piperidine — 4 ester; 3 -(7 —chloro-1Η —indazole-5 —yl) 2 — {〔4 一 (2 —酬基一1 ’ 4 一 一·氨一2 Η — D奎口坐琳一3 —基）一呢Π疋一1 一羰基〕一胺基}—丙酸 1 一甲基一環己酯； 3 — ( 7 —乙基一1 Η — 口 引口坐一5 —基）一2 — { 〔4 —( 2 一嗣基一1 ’ 4 一 一*氣一2 Η 一 D奎卩坐琳一3 —基）一卩浪D疋一1 一羰基〕一胺基} 一丙酸1—甲基一環己酯； 3— (7 —氯一1Η - 口引唑一5 —基）一2— { 〔4— (2 一酮基一 1，4 —二氫—2 Η — D奎唑啉一 3 —基）一哌啶一1 一羰基〕一胺基}—丙酸 4一苯基一環己酯；或 3 - (7 —乙基一1Η — D 引唑一5 —基）一2— { 〔4—( 2 —酮基一 1，4 —二氫一 2 Η — D奎唑啉一3 —基）一哌啶一 1 -527- 200529835 (54) 一羰基〕一胺基} 一丙酸 4 一苯基一環己酯；或 其醫藥上可接受之鹽或溶劑化物。—Aceto-1 ′ 4—a · Amine 2 Η — D Kuikouzai 3—A)-呢 Π 疋 -1 1-Carbonyl] -Amino} -propionic acid 1-methyl-cyclohexyl ester; 3 — (7 —ethyl-1 1 1 — mouth lead sitting 5 — base) 1 2 — {〔4 — (2 1 base 1 1 4 4 1 * qi 1 2 Η 1 D 卩 卩 1 琳 3 —Yl) monoammonium D 1 — 1 carbonyl] monoamino} 1-methyl monocyclohexyl propionate; 3— (7—chloro-1 1—orazol-5—yl) —2— [〔 4- (2-keto-1,4-dihydro-2 fluorene-D quinazoline-3-yl) -piperidine-1 1-carbonyl] -amino} -propionic acid 4-phenylphenylcyclohexyl ester; Or 3-(7 -ethyl-1,1 -D, azole, 5 -yl), 2-{[4-(2 -keto, 1,4 -dihydro -2 fluorene-D quinazoline -3 -yl ) -Piperidine-1-527-200529835 (54) monocarbonyl] -amino} monopropionate 4-phenylphenylcyclohexyl ester; or a pharmaceutically acceptable salt or solvate thereof. 528 -528-
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