TW201121961A - Aminothiazole derivatives - Google Patents

Aminothiazole derivatives Download PDF

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TW201121961A
TW201121961A TW099136784A TW99136784A TW201121961A TW 201121961 A TW201121961 A TW 201121961A TW 099136784 A TW099136784 A TW 099136784A TW 99136784 A TW99136784 A TW 99136784A TW 201121961 A TW201121961 A TW 201121961A
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Taiwan
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amino
ethyl
thiazol
phenyl
ylmethyl
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TW099136784A
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Chinese (zh)
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David Michael Evans
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Vantia Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides compounds of formula (I): compositions comprising such compounds; the use of such compounds in therapy (such as asthma or COPD); and methods of treating patients wich such compounds; wherein R1 to R17 and A1 are as defined herein.

Description

201121961 六、發明說明： 【發明所屬之技術領域】 本發明係關於胺基噻唑衍生物及製備該等衍生物之方 法、製備該等衍生物所用之中間物、含有該等衍生物之組 合物及該等衍生物之用途β 【先前技術】 本發明之胺基噻唑衍生物為組織激肽釋放酶之抑制劑， 且具有多種治療應用’尤其應用於治療發炎性疾病，諸如 哮喘及慢性阻塞性肺病（COPD)。 本發明化合物為人類組織激肽釋放酶（KLK丨）之選擇性抑 制劑。特定而言，其抑制KLK1之能力大於其抑制其他類P 胰蛋白酶絲胺酸蛋白酶之能力。 人類組織激肽釋放酶KLK1(EC.3·4.21.35，亦稱作hKl、 腺體激肽釋放酶及尿激肽釋放酶）為一種類胰蛋白酶絲胺 酸蛋白酶，其屬於激肽釋放酶基因家族，該激肽釋放酶基 因家族中存在另外14個成員（包括***特異性抗原 M. Y〇usef等人，五⑻朐v 2〇〇1，22, 18句。其他密切 相關之類胰蛋白酶絲胺酸蛋白酶包括血衆激狀釋放酶、凝 血酶、胰蛋白酶及纖維蛋白溶酶。活性KLK1為膜結合型 酶且廣泛表現。在胰臟、唾液腺、結腸、腎、淋巴結、前 列腺、小腸、胃、甲狀腺及***中觀測到最強表現。 KLK1中度表現於肺中’以及表現於唾液中且在慢性肺 損傷後之患者痰液中亦已偵測到其活性增強。 KLK1可藉由限制性蛋白質水解自激肽原釋放激肽，自 I5l651.doc 201121961 低分子量激肽原釋放胰激肽，而自高分子量激肽原釋放緩 激肽（K· D. Bhoola 等人，P/iarmaco/ogica/ i?ev·，1992 44 1)。諸如胰激肽（Lys-緩激肽）及缓激肽之激肽為強有力的 炎症介體。激肽之作用係藉由活化兩種主要緩激肽受體亞 型B1及B2來介導，所述兩種亞型皆為七次跨膜〇蛋白偶合 受體（seven trans-membrane G protein-coupled receptor)家 族之成員。B 1受體牽涉於慢性反應中且以基礎含量低表 現’但其在組織損傷及/或炎症後上調，而B 2受體牽涉於 急性反應中且組成性表現。KLK1亦活化基質金屬蛋白酶 (MMP)、膠原蛋白酶原及明膠酶原，且裂解胰島素樣生長 因子結合蛋白-3(J. A. Clements等人，[μ. &/·，2004，41，265-312)。亦有報導表明KLK1可直接活化 緩激狀受體（C. Hecquet專人，Λ/ο/· P/ziirwaco/., 2000，39, 508-515)。 激肽已經展示為過敏性炎症（諸如哮喘及枯草熱）中之重 要，丨體(S. C· Chrstiansen專人，《/. /«veii.，1987，79, 188-197)且在哮喘個體之氣管中主要負責釋放激肽之酶為 KLK1(S. C. Chrstiansen等人，Jm. 及以户卜· Dz.5·, 1992, 145, 900-905)。亦已表明炎性細胞釋放KLK1(I. Τ. Lauredo 等尺，Am. J. Physiol. Lung Cell Mol. Physiol., 2004, 286, 734)。抑制KLK1可為治療哮喘之新穎途徑。 另外，KLK1牽涉於多種其他疾病病況中，包括急性胰 臟炎（T. Griesbacher, Pharmacology^ 2000, 60, 1 13! Τ201121961 VI. Description of the Invention: [Technical Field] The present invention relates to aminothiazole derivatives and methods for preparing the same, intermediates for preparing the derivatives, compositions containing the derivatives, and Use of such derivatives β [Prior Art] The aminothiazole derivatives of the present invention are inhibitors of tissue kallikrein and have various therapeutic applications' especially useful for treating inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD). The compounds of the invention are selective inhibitors of human tissue kallikrein (KLK(R)). In particular, its ability to inhibit KLK1 is greater than its ability to inhibit other P-like trypsin serine proteases. Human tissue kallikrein KLK1 (EC.3·4.21.35, also known as hKl, glandular kallikrein and urinary kallikrein) is a tryptase serine protease, which belongs to kallikrein Gene family, there are 14 other members in the kallikrein gene family (including prostate specific antigen M. Y〇usef et al, five (8) 朐 v 2〇〇 1, 22, 18 sentences. Other closely related pancreas Proteatin serine proteases include blood stimulator, thrombin, trypsin and plasmin. Active KLK1 is a membrane-bound enzyme and is widely expressed in the pancreas, salivary glands, colon, kidney, lymph nodes, prostate, small intestine. The strongest performance was observed in the stomach, thyroid, and vagina. KLK1 was moderately expressed in the lungs and was expressed in saliva and its activity was also detected in the sputum of patients after chronic lung injury. KLK1 can be restricted by Sexual proteolysis releases kinin from kininogen, releasing mitokinin from low molecular weight kininogen from I5l651.doc 201121961 and bradykinin from high molecular weight kininogen (K·D. Bhoola et al., P/iarmaco/ Ogica/ i?ev·,199 2 44 1). Kinins such as pancreatic kinin (Lys-bradykinin) and bradykinin are potent inflammatory mediators. The action of kinins is by activating the two major bradykinin receptor subtypes B1. And B2 to mediate that both subtypes are members of the seven trans-membrane G protein-coupled receptor family. The B 1 receptor is involved in a chronic response and is based on Low content 'but it is up-regulated after tissue damage and/or inflammation, and B 2 receptor is involved in acute reaction and constitutively. KLK1 also activates matrix metalloproteinase (MMP), collagenase and gelatinase, and Insulin-like growth factor binding protein-3 is cleaved (JA Clements et al., [μ. &/·, 2004, 41, 265-312). It has also been reported that KLK1 directly activates the slow-acting receptor (C. Hecquet) , Λ / ο / · P / ziirwaco /., 2000, 39, 508-515). Kinin has been shown to be important in allergic inflammation (such as asthma and hay fever), corpus callosum (S. C · Chrstiansen, "/. /«veii., 1987, 79, 188-197) and the enzyme responsible for releasing kinins in the trachea of asthmatic individuals KLK1 (SC Chrstiansen et al., Jm. and Eb. Dz. 5, 1992, 145, 900-905). It has also been shown that inflammatory cells release KLK1 (I. Τ. Lauredo et al., Am. J. Physiol Lung Cell Mol. Physiol., 2004, 286, 734). Inhibition of KLK1 can be a novel approach to the treatment of asthma. In addition, KLK1 is implicated in a variety of other disease conditions, including acute pancreatitis (T. Griesbacher, Pharmacology^ 2000, 60, 1 13! Τ

Griesbacher等人，Br. */. P/zarmaco/.，2003，139，299)、發炎 15165I.doc 201121961 性腸病（A. Stadnicki，Dz'gejhve απί/ Z/ver D/iease，2005, 37，648 ; A. Stadnicki等人，Digesi/ve Scz.ewce， 2003，48，615)、關節炎（R. W. Colman， 1999, 43, 103 ； R. J. Williams, Brit. J. Rheumatology, 1997, 36, 420) 〇 高含量之循環KLK1會誘發慢性低血壓，非選擇性KLK1 抑制劑抑肽酶已經展示可抑制此情況（J. N. Sharma等人， Pharmacology, Ί995, 50, 363 .，Q· Song等人，Immunopharmacology, 1996, 32, 105)。 激肽之拮抗劑（諸如緩激肽受體拮抗劑）先前已作為用於 治療多種發炎性病症之潛在治療劑加以研究（F. Marceau及 D. Regoli, Nature Rev., Drug Discovery, 2004, 3, 845-852)。特定而言，緩激肽B2受體拮抗劑已作為用於氣管疾 病之潛在治療加以研究（W. M. Abraham等人，五《/\乂 尸/^隱，2006, 533, 215) ° 亦有證據表明KLK1在癌症中起作用（K. D. Bhoola等人， Cwrr. /«veji. Z)rM^y，2007，8，462)。KLK1起以下作 用：經由活化基質金屬蛋白酶、膠原蛋白酶原及明膠酶原 增強腫瘤侵襲性（K. D. Bhoola等人，价〇/. CTie/w·，2001， 382，77 ; H. Tschesche等人，Ji/v. Exp. Med. Biol., 1969, 247A，545)。另外，KLK1間接牽涉於經由釋放促有絲*** 激肽來促進增殖中（R. A. Roberts等人，·/. Ce//. ,1989, 94, 527)。 KLK1亦牽涉於生長因子調節中，且牽涉於各種生長因 151651.doc 201121961 子（例如EGF、NGF)之前驅物的加工中。 内源性KLK1抑制劑包括絲胺酸蛋白酶抑制劑（serpin)、 激肽釋放酶抑素（kallistatin)、抗蛋白C、αι-抗胰蛋白酶及 〇h -抗胰凝乳酶。抑肽酶亦為有效之非選擇性KLK1抑制 劑。低分子量之KLK1抑制劑先前已有報導（M· szelke等 人，WO 199204371 ; M. Szelke 等人，WO 199507291 ; C. Olivier等人，2000，705 ; Μ. M. Staveski等人， WO 2003101941 ; Μ. Tokumasu等人，WO 2005095327 ; J.Griesbacher et al., Br. */. P/zarmaco/., 2003, 139, 299), Inflammation 15165I.doc 201121961 Enteropathy (A. Stadnicki, Dz'gejhve απί/ Z/ver D/iease, 2005, 37 , 648 ; A. Stadnicki et al., Digesi/ve Scz.ewce, 2003, 48, 615), Arthritis (RW Colman, 1999, 43, 103; RJ Williams, Brit. J. Rheumatology, 1997, 36, 420) High levels of circulating KLK1 induce chronic hypotension, and the non-selective KLK1 inhibitor aprotinin has been shown to inhibit this (JN Sharma et al, Pharmacology, Ί995, 50, 363., Q· Song et al, Immunopharmacology, 1996, 32, 105). Antagonists of kinins, such as bradykinin receptor antagonists, have previously been studied as potential therapeutic agents for the treatment of a variety of inflammatory conditions (F. Marceau and D. Regoli, Nature Rev., Drug Discovery, 2004, 3). , 845-852). In particular, bradykinin B2 receptor antagonists have been investigated as potential treatments for airway diseases (WM Abraham et al., V./\乂尸/^隐, 2006, 533, 215) ° There is also evidence KLK1 plays a role in cancer (KD Bhoola et al., Cwrr. / «veji. Z) rM^y, 2007, 8, 462). KLK1 plays a role in enhancing tumor invasiveness via activation of matrix metalloproteinase, collagenase and gelatinase (KD Bhoola et al., 〇/. CTie/w·, 2001, 382, 77; H. Tschesche et al, Ji /v. Exp. Med. Biol., 1969, 247A, 545). In addition, KLK1 is indirectly involved in promoting proliferation via release of mitogenic kinin (R. A. Roberts et al., /. Ce//., 1989, 94, 527). KLK1 is also involved in the regulation of growth factors and is involved in the processing of precursors of various growth factors (e.g., EGF, NGF). Endogenous KLK1 inhibitors include serpin, kallistatin, anti-protein C, alpha-antitrypsin, and 〇h-antichymotrypsin. Aprotinin is also a potent non-selective KLK1 inhibitor. Low molecular weight KLK1 inhibitors have previously been reported (M. Szelke et al, WO 199204371; M. Szelke et al, WO 199507291; C. Olivier et al, 2000, 705; Μ. M. Staveski et al, WO 2003101941; To. Tokumasu et al, WO 2005095327; J.

Burton等人，US 5464820)。KLK1抑制劑已經報導在以下 動物模型中呈現活性：過敏性炎症（M. Szelke等人，Braz. J. Med. 5ζ.ο/· Λα., 1994，27，1943 ; D. Μ· Evans等人，Burton et al., US 5464820). KLK1 inhibitors have been reported to exhibit activity in the following animal models: allergic inflammation (M. Szelke et al., Braz. J. Med. 5ζ.ο/· Λα., 1994, 27, 1943; D. Μ· Evans et al. ,

Immunopharmacology, 1 996，32，11 7)、捧檬酸誘發之咳漱 (R. L. Featherstone等人，1996, 174, 269)及急性胰臟 炎（T. Griesbacher 等人，心· J. Pharmacol., 2002, 137, 692)。KLK1抑制劑亦已經展示在癌症模型中具有活性（在 基質膠（matrigel)侵襲檢定中KLK1抑制劑以劑量依賴性方 式抑制腫瘤細胞遷移）(W. C. Wolf等人，dw. J. 2001，159，1797)。以奈莫耳效能抑制KLK1之人類KLK1抗 體已經展示在過敏性綿羊哮喘模型中具有活性。該抗體抑 制晚期支氣管收縮且完全阻斷氣管過度反應（D. J. Sexton 專人，WO 2006017538 ; D. J. Sexton等人，州.《/〇wrw<3/， 2009, 422, 383)〇 活體外結合KLK1且使KLK1失活之玻尿酸已經展示可阻 斷綿羊由豬胰臟彈性蛋白酶誘發之支氣管收縮（M. Scuri等 151651.doc 201121961 人，«/. Crz7. Care Med.，2001，164，1855)。 激肽釋放酶結合蛋白（KBP)為一種絲胺酸蛋白酶抑制劑 (serpin)，其特異性結合至組織激肽釋放酶且抑制激肽釋 放酶活性》KBP已經展示可藉由下調血管内皮生長因子 (VEGF)來抑制視網膜新血管生成且減少血管滲漏（G. Gao 等人，Ζ)ζ·α 6 eio/ogia，2003，46，689)，且藉由減少 VEGF 產生 來抑制胃癌瘤生長（L. Lu 等人，Mo/· Cimcer. 2007，6, 3297)。VEGF亦與血液-視網膜障壁破壞有關，血液-視網 膜障壁破壞為糖尿病性視網膜病之標諸（D. A. Antonettie 等人，1998, 47, 1953)。VEGF亦牵涉於慢性炎症 中之氣管血管結構重塑中（D. M. McDonald, Jw. J. CW/. Care Med.，2001，164, S39) 〇Immunopharmacology, 1 996, 32, 11 7), citrate-induced cough (RL Featherstone et al., 1996, 174, 269) and acute pancreatitis (T. Griesbacher et al., J. Pharmacol., 2002). , 137, 692). KLK1 inhibitors have also been shown to be active in cancer models (KLK1 inhibitors inhibit tumor cell migration in a dose-dependent manner in matrigel invasion assays) (WC Wolf et al., dw. J. 2001, 159, 1797) ). Human KLK1 antibodies that inhibit KLK1 with naim efficacy have been shown to be active in the allergic sheep asthma model. This antibody inhibits late bronchoconstriction and completely blocks tracheal overreaction (DJ Sexton, WO 2006017538; DJ Sexton et al., ed./〇wrw <3/, 2009, 422, 383) 〇 in vitro binding to KLK1 and makes KLK1 Inactivated hyaluronic acid has been shown to block bronchoconstriction induced by porcine pancreatic elastase in sheep (M. Scuri et al. 151651.doc 201121961, «/. Crz7. Care Med., 2001, 164, 1855). Kallikrein-binding protein (KBP) is a serine protease inhibitor (serpin) that specifically binds to tissue kallikrein and inhibits kallikrein activity. KBP has been shown to downregulate vascular endothelial growth factor (VEGF) to inhibit retinal neovascularization and reduce vascular leakage (G. Gao et al., Ζ) ζ·α 6 eio/ogia, 2003, 46, 689), and inhibit gastric cancer growth by reducing VEGF production ( L. Lu et al., Mo/·Cimcer. 2007, 6, 3297). VEGF is also associated with blood-retinal barrier destruction, and blood-retinal barrier destruction is the hallmark of diabetic retinopathy (D. A. Antonettie et al., 1998, 47, 1953). VEGF is also implicated in the remodeling of tracheal vascular structures in chronic inflammation (D. M. McDonald, Jw. J. CW/. Care Med., 2001, 164, S39) 〇

對於類胰蛋白酶絲胺酸蛋白酶家族之其他成員（尤其對 於血漿激肽釋放酶）之選擇性為一個重要問題。呈現弱血 漿激肽釋放酶活性之組織激肽釋放酶抑制劑先前已有報導 (M. Szelke^ A, Brazilian J. Med. Biol. Res. 1994, 27, 1935 及 D. M. Evans 等人，Immunopharmacology, 1996，32, 11 7)，但仍需要選擇性抑制組織激肽釋放酶之其他化合 物。若干團體已揭示合成性血漿激肽釋放酶抑制劑。此等 抑制劑包括精胺酸酮亞甲基衍生物（WO 92/04371及D. M. Evans^A, Immunopharmacology, 1996， 32, 115-116)、降 鯡精胺（noragmatine)及鯡精胺衍生物（WO 95/07291、WO 94/29335)、苯曱脒衍生物（J.Sturzbecher等人，*/. Med. Biol. Res., 1994, 27, 1929-1934)、晒酸衍生物（US 151651.doc 201121961 5，187，157)及胺甲基環己醯基衍生物（N Ten〇等人The selectivity of other members of the tryptase-like serine protease family, especially for plasma kallikrein, is an important issue. Tissue kallikrein inhibitors exhibiting weak plasma kallikrein activity have previously been reported (M. Szelke^ A, Brazilian J. Med. Biol. Res. 1994, 27, 1935 and DM Evans et al, Immunopharmacology, 1996 , 32, 11 7), but still require other compounds that selectively inhibit tissue kallikrein. Synthetic plasma kallikrein inhibitors have been revealed in several groups. Such inhibitors include ketamine ketamine derivatives (WO 92/04371 and DM Evans^A, Immunopharmacology, 1996, 32, 115-116), norragmatine and stilbenamine derivatives ( WO 95/07291, WO 94/29335), benzoquinone derivatives (J. Sturzbecher et al., */. Med. Biol. Res., 1994, 27, 1929-1934), sun-acid derivatives (US 151651. Doc 201121961 5,187,157) and amine methylcyclohexyl derivatives (N Ten〇 et al.

其為選擇性KLK1抑制劑（且因此其副作用有可能降低）。另 外，其相較於先前技術之化合物而言可能更為有效，作用 時間可能更長，生物可用性可能更大或可能具有其他更多 所需特性。 【發明内容】 在一態樣中’本發明提供式⑴化合物：It is a selective KLK1 inhibitor (and therefore its side effects are likely to decrease). In addition, it may be more effective than prior art compounds, may have a longer duration of action, may have greater bioavailability or may have other more desirable properties. SUMMARY OF THE INVENTION In one aspect, the invention provides a compound of formula (1):

其中： R及R2係獨立地選自Η 基、（C，-CU 祕裳、/r 、羥基、（CVCw)烷基、（CVC6)烷氧 、（c2-c6)烯基、（C2_C6)炔基、（c3_CiQ)環烷基、雜環烷 基、方基、雜芳基、芳基（Ci_C4)烷基_及雜芳基（Ci_C4)烷 基; R3係選自Η、（Cl_cIG)烷基及（CVC6)烯基； R4及R5係獨立地選自H及（c广c6)烷基； A1係選自CR6及S(〇)r7 ; 151651.doc 201121961 R6係選自R7及以下式II、III及IV之基團：Wherein: R and R2 are independently selected from the group consisting of fluorenyl, (C, -CU cleavage, /r, hydroxy, (CVCw) alkyl, (CVC6) alkoxy, (c2-c6)alkenyl, (C2_C6) alkyne , (c3_CiQ)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(Ci_C4)alkyl- and heteroaryl(Ci_C4)alkyl; R3 is selected from fluorene, (Cl_cIG) alkyl And (CVC6) alkenyl; R4 and R5 are independently selected from H and (c-c6) alkyl; A1 is selected from CR6 and S(〇)r7; 151651.doc 201121961 R6 is selected from R7 and Formula II below Groups of III, III and IV:

R7係選自(Ci-c6)烷基、(c2_c6)烯基、(C3_C1。)環烷基、芳 基及芳基（CVC4)烷基-; R8及R9係獨立地選自H、（C1_C1G)烷基、（C2_C^烯基、 C10)環烷基、雜環烷基、芳基、雜芳基、芳基烷基' 及雜芳基（C丨-c4)烷基-; R10及R11係獨立地選自H、（c丨烷基、（C2_C6)烯基、 (C3-C10)環烷基、雜環烷基、芳基、雜芳基、芳基 烷基-、芳基（C2-C4)烯基-、雜芳基（Ci_c4)烷基…_s〇2(Ci_ c6)烷基、-so2芳基及_s〇2芳基（Ci_c4)烷基； 或R1G與R11可連同其所連接之氮原子一起形成4員至7員 含N環，該含!^環視情況含有另一選自N、〇及8之雜原 子，且視情況經i或2個獨立地選自（Ci_C6)烷基、（c^ CO烷氧基、_基、CN及羥基之取代基取代，該含^^環 亦可視情況稠合至芳基； 或R8與R1G可連同其所連接之原子一起形成飽和或部分 不飽和4員至7員含n環，該含!^環視情況含有另一選自 N、Ο及S之雜原子，且視情況在碳上經丨或2個獨立地選 自（Cl_C6)烧基、（Ci-C6)烷氧基、鹵基、CN及羥基之取 151651.doc •10· 201121961R7 is selected from the group consisting of (Ci-c6)alkyl, (c2_c6)alkenyl, (C3_C1.)cycloalkyl, aryl and aryl (CVC4)alkyl-; R8 and R9 are independently selected from H, (C1_C1G) Alkyl, (C2_C^alkenyl, C10)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl' and heteroaryl (C丨-c4)alkyl-; R10 and R11 Is independently selected from H, (c丨alkyl, (C2_C6)alkenyl, (C3-C10)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl-, aryl (C2 -C4) alkenyl-, heteroaryl (Ci_c4)alkyl..._s〇2(Ci_c6)alkyl, -so2aryl and _s〇2 aryl(Ci_c4)alkyl; or R1G and R11 together with The nitrogen atoms to be joined together form a 4-member to 7-membered N-containing ring, which contains another hetero atom selected from N, fluorene and 8 as the case may be, and optionally, i or 2 independently selected from (Ci_C6) Substituting a substituent of an alkyl group, (c^CO alkoxy group, _ group, CN and a hydroxyl group, the ring containing the ring may be optionally fused to an aryl group; or R8 and R1G may be formed together with the atom to which they are attached Saturated or partially unsaturated 4 to 7 members containing n-rings, which contain !^ depending on the situation, contain another hetero atom selected from N, Ο and S, and as appropriate On carbon, by hydrazine or two independently selected from (Cl_C6) alkyl, (Ci-C6) alkoxy, halo, CN and hydroxyl. 151651.doc •10· 201121961

代基取代； 驭κ不存在且R8與R j連问其所連接之原子— 員、6員' 9員或10員單環或雙環含N芳環，該含N芳環 2 =含有另-選自心〇及5之雜原子，且視情況在碳 /美2㈣獨立地選自（以）烧基、（μ)烧氧 土 ▲ CN、方基、C00Rl5及羥基之取代基取代； 或R8與R丨。可-起形成式V或式VI之基團：Substituent substitution; 驭κ does not exist and R8 and R j are connected to the atom to which they are attached - 6 members, 9 members or 10 members of the monocyclic or bicyclic N-containing ring, the N-containing ring 2 = contains another - a hetero atom selected from the group consisting of ruthenium and 5, and optionally substituted with a substituent of carbon/beautiful 2 (d) independently selected from the group consisting of (or) an alkyl group, (μ) an aerobic earth ▲ CN, a aryl group, a C00Rl5 group, and a hydroxyl group; or R8 With R丨. It can form a group of formula V or formula VI:

Rl\r~(CH2)hRl\r~(CH2)h

(ch2)9 (CH2)f 、/ (V) (VI)。 R】2及R,3係獨立地選自H、（c】_Ci。）烧基、（C2_c6)稀基、 (C3_c1G)環烷基、雜環烷基、芳基、雜芳基、芳基（Ci C4) 烷基-、芳基（c2-c4)烯基…雜芳基（Ci_c4)烷基_、_s〇2(c]_ C6)烷基、-so2芳基及_s〇2芳基（Ci_c4)烷基； mb係獨立地選自H、（Ci_CiQ)烧基、（C2_C6)稀基、（C3_ C10)環烷基、雜環烷基、芳基、雜芳基、芳基（Ci C4)烷基_ 、芳基（c2-c4)稀基-、雜芳基（Ci_c4)烧基…_s〇2(Ci_c6)烧 基、-so2芳基及_s〇2芳基（Ci_c4)烷基； 或Ra與Rb可連同其所連接之原子一起形成飽和或部分 不飽和4員至7員含N環，該含N環視情況含有另一選自 N、0及S之雜原子，且視情況在碳上經1或2個獨立地選 自（C丨-C6)烧基、（Cl_C6)烷氧基、鹵基、cn及羥基之取 151651.doc 201121961 代基取代；該含1^環亦可視情況稠合至芳基； 或Ra與Rb可連同其所連接之原子一起形成5員、6員、9 員或10員單環或雙環含N芳環，該含N芳環視情況含有 另選自Ν、Ο及S之雜原子，且視情況在碳上經丨、2或 3個獨立地選自（Cl_C6)烷基、（C〗_C0)烷氧基、鹵基、 CN、芳基、COOR15及羥基之取代基取代； R14係選自 Η、（CVC6)烧基、（Cl-C6)炫氧基、〇H、CN、 CF3、COOR〗5、鹵基及抓丨5Ri6 ; R15及R16係獨立地選自H及（CrCj烷基； R17係選自Η、羥基、齒基、CN、（Ci_Ci〇)烷基及（Ci_C6)烷 氧基； f及g係獨立地選自〇、1、2及3，以使f+g=l、2或3 ; h係選自1及2 ; 其中： 烷基可視情況經1或2個獨立地選自（C3_C1Q)環院基、 (CVC6)烷氧基、〇H、CN、CF3、COORJ5、氣及 NR15R16之取代基取代； 烯基可視情況經1或2個獨立地選自（C3_C1Q)環院其、 (CVC6)烷氧基、OH、CN、CF3、COOH丨5、敗及 NR15R16之取代基取代； 炔基可視情況經1或2個獨立地選自（C3-ClQ；)if产Λ、 (Ci-Ce)烷氧基、OH、CN、CF3、COOR11 匕 β 、氟及 NRnR12之取代基取代； 烷氧基可視情況經1或2個獨立地選自（C3-C1Q)學产某、 151651.doc •12· 201121961 OH、CN、CF3、COOR15、氟及 NRi5Ri6 之取代基取代； 環烷基為視情況稠合至芳基之非芳族單環或雙環烴 %，其_該環烷基環可能時視情況含有至多2個雙鍵； 且其中，除非另外說明，否則該環烷基可視情況經1或 2個獨立地選自（Cl_C6)烷基、（c丨·C6)烷氧基、、 CN、CF3、COOR15、氟及NRi5Ri6之取代基取代： 雜環烷基為C鍵聯或N鍵聯之3員至10員㈣族單環或雙 環，其中該雜環炫基環可能時含有i、2或3個獨立地選 自N NR、S(0)q&〇之雜原子；且該雜環燒基環可能 時視情況含有1或2個雙鍵’且視情況在碳上經!或2個 獨立地選自（cvc6)燒基、（CVC6)院氧基、〇h、cn、 eF3 mQRl5' nr15r16及芳基之取代基取代； 芳基為含有6或1〇個碳原子之單芳環或稠合芳環系統； 其中’除非另外說明’否則芳基在每次出現時可視情 況經至多5個獨立地選自（C c (1 烷基、（Cl_c6)烷氧基、 、鹵基、CN、COOR15、cf » 心15 CF3及NR 5r〗6之取代基取 代； 雜芳基為可能時含有卜2或3個獨立地選自N、NRi5、s 及0之環成員的5員' 6員、9員i . ^ 員或10員單環或雙環芳 级，其中，除非另外說明，否 ,〇 + 否則邊雜芳基可視情況經 2或3個獨立地選自（c c ) OM ^ ^ 烷基' (C,-C6)烷氧基、 、_ 基、CN、c〇〇r】5 代； h及NR15R,6之取代基取 q為0、1或2 ; 15165I.doc 201121961 及其互變異構體、立體異構體、醫藥學上可接受之鹽及溶 劑合物。 在另〜、樣中，本發明提供如本文所定義之式（!）化合物 之前藥或其醫藥學上可接受之鹽。 在另〜、樣中，本發明提供如本文所定義之式（I)化合物 之N-氧化物’或其前藥或醫藥學上可接受之鹽。 應瞭解，某些本發明化合物可以溶劑合物（例如水合物） 形式以及非溶劑合物形式存在。應瞭解本發明涵蓋所有該 等溶劑合物形式。 在式（I)化合物之一子集中： R1係選自（Ci-C：6)烷基、（C3_CiQ)環烷基、雜環烷基、芳基 及雜芳基； R2係選自Η、羥基、（Cl_C6)烷基、（Ci_c6)烷氧基、π〗· C10)環烷基及芳基； R3、R4及R5係獨立地選自H及（Ci_C6)烷基； A1係選自CR6及S(0)R7 ; R6係選自R7及以下式II、⑴及IV之基團：(ch2)9 (CH2)f, / (V) (VI). R] 2 and R, 3 are independently selected from H, (c) - Ci.) alkyl, (C2_c6), (C3_c1G) cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl (Ci C4) alkyl-, aryl (c2-c4) alkenyl...heteroaryl (Ci_c4)alkyl-, _s〇2(c]-C6)alkyl, -so2aryl and _s〇2 (Ci_c4)alkyl; mb is independently selected from H, (Ci_CiQ)alkyl, (C2_C6), (C3_C10)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl ( Ci C4)alkyl-, aryl (c2-c4) dilute-, heteroaryl (Ci_c4) alkyl... _s〇2(Ci_c6) alkyl, -so2 aryl and _s〇2 aryl (Ci_c4) An alkyl group; or Ra and Rb may form, together with the atom to which they are attached, a saturated or partially unsaturated 4 to 7 membered N ring, the N ring optionally containing another hetero atom selected from N, 0 and S, and Optionally substituted on the carbon by 1 or 2 independently selected from (C丨-C6) alkyl, (Cl_C6) alkoxy, halo, cn and hydroxy; 151651.doc 201121961 alkenyl; The ring may also be fused to an aryl group as appropriate; or Ra and Rb may form a 5-, 6-, 9- or 10-membered monocyclic or bicyclic N-containing group together with the atoms to which they are attached Ring, the N-containing aromatic ring optionally contains a hetero atom selected from the group consisting of ruthenium, osmium and S, and optionally, on the carbon, 2 or 3 independently selected from the group consisting of (Cl_C6)alkyl, (C _C0) alkane Substituents of oxy, halo, CN, aryl, COOR15 and hydroxy; R14 is selected from fluorene, (CVC6) alkyl, (Cl-C6) methoxy, hydrazine H, CN, CF3, COOR , halo and grab 5Ri6; R15 and R16 are independently selected from H and (CrCj alkyl; R17 is selected from the group consisting of anthracene, hydroxy, dentate, CN, (Ci_Ci) alkyl and (Ci_C6) alkoxy; f and g are independently selected from 〇, 1, 2 and 3 such that f+g = 1, 2 or 3; h is selected from 1 and 2; wherein: the alkyl group may be independently selected by 1 or 2 Substituted from (C3_C1Q) ring, (CVC6) alkoxy, hydrazine H, CN, CF3, COORJ5, gas and NR15R16 substituent; alkenyl group may be independently selected from (C3_C1Q) ring by 1 or 2 It is substituted with a substituent of (CVC6) alkoxy group, OH, CN, CF3, COOH丨5, NR15R16; the alkynyl group may be independently selected from (C3-ClQ;)if by one or two, (Ci-Ce) alkoxy, OH, CN, CF3, COOR11 匕β, fluorine and NRnR12 substituents The alkoxy group may be optionally substituted with one or two substituents independently selected from (C3-C1Q), 151651.doc •12·201121961 OH, CN, CF3, COOR15, fluorine and NRi5Ri6; The base is optionally a non-aromatic monocyclic or bicyclic hydrocarbon fused to the aryl group, which ring may optionally contain up to 2 double bonds; and wherein, unless otherwise stated, the cycloalkyl group Optionally, substituted by 1 or 2 substituents independently selected from the group consisting of (Cl_C6)alkyl, (c丨·C6)alkoxy, CN, CF3, COOR15, fluorine, and NRi5Ri6: heterocycloalkyl is C-bonded Or N-bonded 3 to 10 member(s) of a monocyclic or bicyclic ring, wherein the heterocyclic ring may contain i, 2 or 3 heteroatoms independently selected from N NR, S(0)q& And the heterocycloalkyl ring may optionally contain 1 or 2 double bonds 'and optionally on carbon! or 2 independently selected from (cvc6) alkyl, (CVC6) alkoxy, 〇h , cn, eF3 mQRl5' nr15r16 and a substituent of an aryl group; the aryl group is a single aromatic ring or a fused aromatic ring system containing 6 or 1 carbon atoms; wherein 'unless otherwise stated', the aryl group is in each When present, may be substituted with up to 5 substituents independently selected from (C c (1 alkyl, (Cl_c6) alkoxy, halo, CN, COOR15, cf » core 15 CF3 and NR 5r 6; A heteroaryl group is a 5-membered, 6-membered, 9-membered, or 10-membered monocyclic or bicyclic aromatic grade of a 2 or 3 ring members independently selected from N, NRi5, s, and 0, where possible. Unless otherwise stated, no, 〇+ Otherwise, the heteroaryl group may be independently selected from (cc) OM ^ ^ alkyl '(C, -C6) alkoxy, _ group, CN, by 2 or 3 independently. C〇〇r]5 generation; h and NR15R, 6 substituents take q as 0, 1 or 2; 15165I.doc 201121961 and its tautomers, stereoisomers, pharmaceutically acceptable salts and solvents Compound. In another example, the invention provides a prodrug of a compound of formula (!), as defined herein, or a pharmaceutically acceptable salt thereof. In another example, the invention provides an N-oxide' of a compound of formula (I) as defined herein, or a prodrug or pharmaceutically acceptable salt thereof. It will be appreciated that certain of the compounds of the invention may exist in the form of solvates (e.g., hydrates) as well as unsolvated forms. It will be understood that the invention encompasses all such solvate forms. In a subset of the compounds of formula (I): R1 is selected from (Ci-C: 6) alkyl, (C3_CiQ) cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R2 is selected from hydrazine, Hydroxy, (Cl_C6)alkyl, (Ci_c6)alkoxy, π"·C10)cycloalkyl and aryl; R3, R4 and R5 are independently selected from H and (Ci_C6)alkyl; A1 is selected from CR6 And S(0)R7; R6 is selected from the group consisting of R7 and the following formula II, (1) and IV:

(II) (III) (IV)； R7係選自（Ci-CO烷基、芳基及芳基（Cl-C4)烷基-; R係選自Η、（¢^-(^6)烧基、（C3-C1())環烧基及芳基 烧基； 15l651.doc -14· 201121961 R9係選自Η及（CVC6)烧基； R10係選自Η、（CVC6)烷基、（C3-Ci〇)環烷基及芳基（Ci_C4) 烧基； R11係選自Η及（CVC6)烷基； 或R10與R11可連同其所連接之氮原子一起形成5員至6員 含N環，該含N環視情況經1或2個（Ci_C6)烷基取代基取 代； 或R8與…^可連同其所連接之原子一起形成飽和或部分 不飽和5員至6員含N環，該含N環視情況在碳上經丨或2 個（(^-(：6)烷基取代基取代； 或R9不存在且R8與R1G可連同其所連接之原子一起形成5 員、6員、9員或10員單環或雙環含^^芳環，該含N芳環 視情況在碳上經1或2個（Ci-C6)烷基取代基取代； R12係選自Η及（CVC6)烷基； R13係選自H、（Cl-C6)烷基、芳基及芳基（Ci_C4)烷基(II) (III) (IV); R7 is selected from (Ci-CO alkyl, aryl and aryl (Cl-C4) alkyl-; R is selected from Η, (¢^-(^6)) Base, (C3-C1()) cycloalkyl and arylalkyl; 15l651.doc -14· 201121961 R9 is selected from fluorene and (CVC6) alkyl; R10 is selected from fluorene, (CVC6) alkyl, ( C3-Ci〇)cycloalkyl and aryl (Ci_C4) alkyl; R11 is selected from fluorene and (CVC6) alkyl; or R10 and R11 together with the nitrogen atom to which they are attached form 5 to 6 members containing N Ring, the N-containing ring is optionally substituted with 1 or 2 (Ci_C6) alkyl substituents; or R8 and ... may together with the atoms to which they are attached form a saturated or partially unsaturated 5 to 6 membered N ring, which The N-containing ring is substituted on the carbon by hydrazine or 2 ((^-(:6)) alkyl substituents; or R9 is absent and R8 and R1G may form 5, 6 and 9 together with the atoms to which they are attached Or 10 members of a monocyclic or bicyclic ring containing an aromatic ring, the N-containing ring optionally substituted with 1 or 2 (Ci-C6) alkyl substituents on carbon; R12 is selected from fluorene and (CVC6) alkyl ; R13 is selected from H, (Cl-C6) alkyl, aryl and aryl (Ci_C4) alkyl

Ra及Rb係獨立地選自H、（CVC6)烷基、（cvc：6)環烷基、雜 環烷基、芳基、雜芳基； 或Ra與Rb可連同其所連接之原子一起形成飽和或部分 不飽和5員至6員含N環，該含N環視情況在碳上經丨或2 個（C!-C6)烷基取代基取代； 或1^與1^可連同其所連接之原子一起形成5員、6員、9 員或10員單環或雙環含^^芳環，該含環視情況在碳 上經1或2個（C^C：6)烷基取代基取代； R17係選自Η及（CVC6)烷基； 151651.doc -15- 201121961 其中烷基、烷氧基、環烷基、雜環烷基、芳基及雜芳基係 如上文所定義； 及其互變異構體、立體異構體、醫藥學上可接受之鹽及溶 劑合物® 在式（I)化合物之另一子集中： R1係選自（C3_C10)環烷基及芳基； R2係選自Η及（C3_ClG)環烷基； R3、R4 及 R5 為 Η ; Α丨為CR6 ; R6係選自R7及以下式II及III之基團：Ra and Rb are independently selected from H, (CVC6)alkyl, (cvc:6)cycloalkyl, heterocycloalkyl, aryl, heteroaryl; or Ra and Rb may be taken together with the atom to which they are attached Saturated or partially unsaturated 5 to 6 members containing an N ring, which may be substituted on the carbon by hydrazine or 2 (C!-C6) alkyl substituents; or 1^ and 1^ may be attached thereto The atoms together form a 5-, 6-, 9- or 10-membered monocyclic or bicyclic ring containing an aromatic ring which is optionally substituted on the carbon with 1 or 2 (C^C:6)alkyl substituents; R17 is selected from the group consisting of fluorene and (CVC6) alkyl; 151651.doc -15- 201121961 wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are as defined above; Tautomers, stereoisomers, pharmaceutically acceptable salts and solvates® In another subset of the compounds of formula (I): R1 is selected from (C3_C10)cycloalkyl and aryl; R2 It is selected from the group consisting of hydrazine and (C3_ClG) cycloalkyl; R3, R4 and R5 are Η; Α丨 is CR6; R6 is selected from the group consisting of R7 and the following formulae II and III:

(11) (III)； R7為芳基（CVC4)烷基-; R8係選自Η及（CVC6)烷基； R9 為 Η ; R1Q係選自Η及（CVCe)烷基； R"係選自Η及（CVC6)烷基； 或R1G與R11可連同其所連接之氮原子一起形成5員至6員含 N環’該含N環視情況經1或2個（CrC6)烷基取代基取代； 或R與R可連同其所連接之原子一起形成飽和或部分 不飽和5員至6員含N環，該含N環視情況在碳上經1或2 個（C!-C6)烷基取代基取代； I5I651.doc -16· 201121961 員、6員、9員或10員單環或雙環含N芳環，該含n芳環 視情況在碳上經】或2個（Cl_C6)烷基取代基取代； & R12為 Η ; R13為芳基（(^ο烷基-; R17為 Η ; 其中烷基、烷氧基、環烷基、雜環烷基、芳基及雜芳基係 如上文所定義； 及其互變異構體、立體異構體、醫藥學上可接受之鹽及溶 劑合物。 本發明亦包含下列態樣及其組合： 在一態樣中，本發明提供如下式⑴化合物，其中r〗係選 自（cvcw烷基、（C3_Ci())環烷基、芳基、雜芳基及芳基 (C1-C4)烧基-。 在另一態樣中，本發明提供如下式⑴化合物，其中…係 選自（Cl-C6)烷基、（C5-CIQ)環烷基、芳基及雜芳基。 在另一態樣中，本發明提供如下式⑴化合物，其中…係 選自（Cs-Cw)環烷基、芳基及雜芳基。 在另一態樣中，本發明提供如下式⑴化合物，其中尺〗為 視情況經取代之笨基。視情況存在之取代基係選自上文對 於「芳基」所定義之取代基。 在樣中本發明提供如下式⑴化合物，其中R2係選 自Η、（CA)院基、0H、（Ci_C6)烧氧基、（C3_Ci。）環烷基 及芳基。 ι 151651.doc 17- 201121961 在另一態樣中，本發明提供如下式⑴化合物，其中R2係 選自Η、（C3-C10)環烷基及芳基。 在另一態樣中，本發明提供如下式⑴化合物，其中R2係 選自Η、（CVCd烷基、0H、（Ci_c6)烷氧基及（c3_c…環烷 基。 在另一態樣中，本發明提供如下式⑴化合物，其中R2係 選自Η、OH及（C4-C6)環烷基。 在另一態樣中，本發明提供如下式⑴化合物，其中R2為 Η。 在一態樣中，本發明提供如下式⑴化合物，其中R3係選 自Η及（CVCO烷基。 在另一態樣中，本發明提供如下式⑴化合物，其中R3為 Η。 在一態樣中，本發明提供如下式⑴化合物，其中R3為Η 且R所連接之碳原子具對掌性且具有〇構型。 在另一態樣中’本發明提供如下式⑴化合物，其中…為 Η且R3所連接之碳原子具對掌性且具有構型。 在一態樣中，本發明提供如下式⑴化合物，其中R4係選 自Η或（CVC6)烷基。 在另一態樣中，本發明提供如下式（I)化合物，其中R4為 Η。 在態樣中’本發明提供如下式⑴化合物’其中R5係選 自Η或（CVC6)烷基。 在另一態樣中’本發明提供如下式⑴化合物，其中R5為 151651.doc 201121961 Η。 在一態樣中’本發明提供如下式⑴化合物，其中Α1為 CR6。 在另一態樣中’本發明提供如下式⑴化合物，其中八】為 S(0)R7。 在一態樣中，本發明提供如下式⑴化合物，其中R6係選 自以下式（11)、（111)及（1¥)之基團：(11) (III); R7 is aryl (CVC4) alkyl-; R8 is selected from fluorene and (CVC6) alkyl; R9 is hydrazine; R1Q is selected from fluorene and (CVCe) alkyl; R" Η and (CVC6)alkyl; or R1G and R11 together with the nitrogen atom to which they are attached form a 5- to 6-membered N-containing ring. The N-containing ring is optionally substituted with 1 or 2 (CrC6) alkyl substituents. Or R and R together with the atom to which they are attached form a saturated or partially unsaturated 5- to 6-membered N-containing ring which is optionally substituted with 1 or 2 (C!-C6) alkyl groups on the carbon. Substituent; I5I651.doc -16· 201121961 Member, 6 member, 9 member or 10 member monocyclic or bicyclic N-containing ring, the n-aryl ring optionally on carbon or 2 (Cl_C6) alkyl substituents Substituting; & R12 is hydrazine; R13 is aryl ((^οalkyl-; R17 is Η; wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are as above) And the tautomers, stereoisomers, pharmaceutically acceptable salts and solvates thereof. The present invention also encompasses the following aspects and combinations thereof: In one aspect, the present invention provides the following formula (1) Compound, where r is selected (cvcw alkyl, (C3_Ci())cycloalkyl, aryl, heteroaryl and aryl (C1-C4)alkyl-. In another aspect, the invention provides a compound of formula (1), wherein Selected from (Cl-C6)alkyl, (C5-CIQ)cycloalkyl, aryl and heteroaryl. In another aspect, the invention provides a compound of formula (1), wherein ... is selected from (Cs-Cw A cycloalkyl group, an aryl group and a heteroaryl group. In another aspect, the invention provides a compound of the formula (1), wherein the ruthenium is an optionally substituted stupid group. The substituents optionally present are selected from the group consisting of The substituents defined for "aryl". In the present invention, the invention provides a compound of the formula (1) wherein R2 is selected from the group consisting of ruthenium, (CA), OH, (Ci_C6) alkoxy, (C3_Ci.) naphthenic In another aspect, the invention provides a compound of formula (1) wherein R 2 is selected from the group consisting of hydrazine, (C 3 -C 10 )cycloalkyl, and aryl. In the present invention, the present invention provides a compound of the formula (1) wherein R2 is selected from the group consisting of hydrazine, (CVCd alkyl, 0H, (Ci_c6) alkoxy and (c3_c...cycloalkyl. In another aspect) The present invention provides a compound of the formula (1) wherein R2 is selected from the group consisting of hydrazine, OH and (C4-C6)cycloalkyl. In another aspect, the invention provides a compound of the formula (1) wherein R2 is fluorene. In one embodiment, the invention provides a compound of formula (1) wherein R3 is selected from the group consisting of hydrazine and (CVCO alkyl). In another aspect, the invention provides a compound of formula (1) wherein R3 is hydrazine. In one aspect, the invention provides a compound of formula (1) wherein R3 is Η and the carbon atom to which R is attached is palmarous and has an oxime configuration. In another aspect, the present invention provides a compound of the following formula (1) wherein ... is Η and the carbon atom to which R3 is attached is palmar and has a configuration. In one aspect, the invention provides a compound of formula (1) wherein R4 is selected from the group consisting of hydrazine or (CVC6) alkyl. In another aspect, the invention provides a compound of formula (I) wherein R4 is hydrazine. In the aspect, the present invention provides a compound of the following formula (1) wherein R5 is selected from hydrazine or (CVC6) alkyl. In another aspect, the invention provides a compound of formula (1) wherein R5 is 151651.doc 201121961 Η. In one aspect, the invention provides a compound of formula (1) wherein Α1 is CR6. In another aspect, the invention provides a compound of formula (1) wherein VIII is S(0)R7. In one aspect, the invention provides a compound of formula (1) wherein R6 is selected from the group consisting of the following formulae (11), (111) and (1):

(11) (III) (IV)。 在另一態樣中’本發明提供如下式（I)化合物，其中R6係 選自以下式（II)及（III)之基團：(11) (III) (IV). In another aspect, the invention provides a compound of formula (I) wherein R6 is selected from the group consisting of the following formulae (II) and (III):

(II) (III)。 在另一態樣中，本發明提供如下式⑴化合物，其中R6為 以下式（II)基團：(II) (III). In another aspect, the invention provides a compound of formula (1), wherein R6 is a group of formula (II):

R10 \R11 (Π) 〇 在另一態樣中，本發明提供如下式⑴化合物，其中R6為 15l65l.doc -19. 201121961 以下式（III)基團：R10 \R11 (Π) 〇 In another aspect, the present invention provides a compound of the following formula (1) wherein R6 is 15l65l.doc -19. 201121961 Group of the following formula (III):

OH (III)。 在另一態樣中’本發明提供如下式⑴化合物，其中尺6為 以下式（IV)基團：OH (III). In another aspect, the invention provides a compound of formula (1) wherein uldent 6 is a group of formula (IV):

Ra\ /\Ra\ /\

II

Rb (IV)。 在另一態樣中，本發明提供如下式⑴化合物，其中R6為 R7。 在態樣中，本發明提供如下式（I)化合物，其中R7係選 自（C,_C6)烷基、（C3-C1())環烷基、芳基及芳基（Cl_c4)烷 基·。 在另一態樣中’本發明提供如下式⑴化合物，其中R7係 選自（c〗-c6)烷基、芳基及芳基（Ci_c4)烷基·。 在另一態樣中，本發明提供如下式（I)化合物，其中厌7係 選自（Ci-C6)烷基及經（CrC：6)烷基取代之芳基（C丨-c4)烷基-。 在另一態樣中，本發明提供如下式⑴化合物，其中R7係 選自正丙基或經甲基取代之苯甲基。 在一態樣中，本發明提供如下式（I)化合物，其中R8係選 自Η、（Ci-Ce)烷基、（c3-c1())環烷基及芳基（CVC4)烷基。 在另一態樣中，本發明提供如下式（I)化合物，其中尺8係 選自Η、（CVC6)烷基。 151651.doc •20· 201121961 在另一態樣中’本發明提供如下式⑴化合物，其中…為 (Ci-C6)烧基。 在一態樣中’本發明提供如下式⑴化合物，其中R9係選 自Η、（CVC6)烷基。 在另一態樣中，本發明提供如下式⑴化合物，其中尺9為 Η。 在一態樣中’本發明提供如下式⑴化合物，其中“與汉9 中之一者為Η且R8與R9中之另一者不為Η，且…及尺9所連 接之碳原子具對掌性且具有π)構型。 在一態樣中’本發明提供如下式⑴化合物，其中…與尺9 中之一者為Η且R8與R9中之另一者不為Η，且R8及R9所連 接之故原子具對掌性且具有「幻構型。 在一態樣中’本發明提供如下式⑴化合物，其中R3為Η 且R3所連接之碳原子具對掌性且具有構型，且其中Μ 與R中之一者為H&amp;R8與R9中之另一者不為Η，且r8&amp;r9 所連接之碳原子具對掌性且具有「幻構型。 在另一態樣中，本發明提供如下式⑴化合物’其中R3為 Η且R3所連接之碳原子具對掌性且具有〇構型，且其中Μ 與R中之一者為^1且尺8與R9中之另一者不為H ,且R8及R9 所連接之碳原子具對掌性且具有構型。 在 心樣中，本發明提供如下式（I)化合物，其中ri〇係 '、 ⑷1 Cio)燒基、（c3-Ci〇)環烧基、雜環院基、芳 ”芳基务基（C1-C4)烧基-、芳基（CrC4)稀基-及雜芳 基（C 1-〇4)恢基&gt;。 151651.doc •21 · 201121961 在另一態樣中，本發明提供如下式⑴化合物，其中r10 係選自Η、（CVCJ烷基、（c3_Ci〇)環烷基及芳基（Ci_C4)烷 基。 在另一態樣中，本發明提供如下式⑴化合物，其中Rl0 係選自Η、（CVC6)烷基及（c4_c6)環烷基。 在另一態樣中，本發明提供如下式⑴化合物，其中Rl0 係選自Η及（CVC6)烷基。 在另一態樣中’本發明提供如下式⑴化合物’其中r10 為（CVC6)烷基。 在一態樣中，本發明提供如下式⑴化合物，其中Rn係 選自Η及（Ci-Ciq)烧基。 在另一態樣中，本發明提供如下式⑴化合物，其中Rn 係選自Η及（CVC6)烷基。 在另一態樣中，本發明提供如下式⑴化合物，其中r1 1 為（C^Cd烷基。 在一態樣中，本發明提供如下式⑴化合物，其中R〗〇與 R11可連同其所連接之氮原子一起形成5員至6員含N環，該 含N環視情況含有另一選自n、〇及s之雜原子，且視情況 經1或2個獨立地選自（C丨_C6)烷基、（Ci_c6)烷氧基、鹵基、 CN及羥基之取代基取代，該含n環亦可視情況稠合至芳 基。 在另一態樣中，本發明提供如下式（I)化合物，其中R〗0 與R11可連同其所連接之氮原子一起形成5員至6員含N環， 該含N環視情況經丨或2個（Ci_c6)烷基取代基取代。 151651.doc •22· 201121961 在一態樣中，本發明提供如下式（I)化合物，其中R8與 R可連同其所連接之原子一起形成飽和或部分不飽和$員 至6員含N環，該含N環視情況含有另一選自N、〇及§之雜 原子且視情況在碳上經i或2個獨立地選自烷基、 (c丨-Co烷氧基、鹵基、CN及羥基之取代基取代。 在另一態樣中，本發明提供如下式⑴化合物，其中尺8與 Κ可連同其所連接之原子一起形成飽和5員至ό員含N環， 该含Ν環視情況在碳上經丨或2個（Ci_C6)烷基取代基取代。 在一態樣中，本發明提供如下式⑴化合物，其中R9不存 在且118與11]()可連同其所連接之原子一起形成5員、6員、9 員或10員單環或雙環含N芳環，該含N芳環視情況含有另 一選自N、〇及s之雜原子，且視情況在碳上經丨、2或3個 獨立地選自（C〗-C6)烷基、（c丨-C6)烷氧基、鹵基、CN、芳 基、COOR15及羥基之取代基取代。 在另一態樣中，本發明提供如下式⑴化合物，其中R9不 存在且R與R1G可連同其所連接之原子一起形成5員、6 員、9員或1〇員單環或雙環含]^芳環，該含N芳環視情況在 碳上經1、2或3個獨立地選自（C丨-c：6)烷基、（C]_C6)烷氧 基、II基、CN、芳基、C00Ri5及羥基之取代基取代。 在另一態樣中’本發明提供如下式（1)化合物，其中尺9不 存在且R8與R1G可連同其所連接之原子一起形成5員、6 員、9員或1〇員單環或雙環芳環，該含N芳環視情況在 碳上經1或2個（CrCd烷基取代基取代。 在一態樣中，本發明提供如下式（I)化合物.，其中尺!2係 151651.doc •23· 201121961 選自Η及（(^(：6)烷基。 在另一態樣中’本發明提供如下式⑴化合物，其中rU 為Η。 在一態樣中，本發明提供如下式⑴化合物，其中rU係 選自Η、（C〗-C6)烷基、芳基、雜芳基、芳基（Ci_C4)烷基_及 雜芳基（CVC4)烷基_。 在另一態樣中，本發明提供如下式⑴化合物，其中R〗3 係選自Η、（C^Ce)烷基、芳基及芳基（Ci_c4)烷基_。 在另一態樣中，本發明提供如下式⑴化合物，其中rH 為芳烧基-。 在另一態樣中’本發明提供如下式⑴化合物，其中 為笨曱基。 在一態樣中，本發明提供如下式⑴化合物，其中R,2與 R中之一者為η且R12與R丨3中之另一者不為H，且尺12及r13 所連接之碳原子具對掌性且具有構型。 在一態樣中’本發明提供如下式⑴化合物，其中與 R中之一者為Η且R丨2與Rn中之另一者不，且r12&amp;rU 所連接之碳原子具對掌性且具有〈幻構型。 在一態樣中，本發明提供如下式（I)化合物，其中R3為H 且R3所連接之碳原子具對掌性且具有構型，且其中尺〗2 與Rl3中之一者為1^且尺丨2與Ru中之另一者不為Η，且R12及 R所連接之碳原子具對掌性且具有〈①構型。 在另一態樣中’本發明提供如下式⑴化合物，其中“為 Η且R3所連接之碳原子具對掌性且具有⑻構型，且其中 151651.doc •24· 201121961 R與R中之一者為HaRl2與Rn中之另一者不為H，且R12 及R所連接之碳原子具對掌性且具有「及〉構型。 在一態樣中，本發明提供如下式⑴化合物，其中Ra及Rb 係獨立地選自H、（Ci-Cig)烷基、（c2-c6)烯基、（c3-c丨〇)環 烷基、雜環烷基、芳基、雜芳基、芳基（Ci_C4)烷基、芳 基（CVC4)烯基-、雜芳基（CVC4)烷基_、-S〇2(Cl-C6)烷 基、-s〇2芳基及-so2芳基（Cl_c4)烷基。 在另—態樣中’本發明提供如下式⑴化合物，其中尺3及 R係獨立地選自Η、（C丨-C6)烷基、（C3-C6)環烷基、雜環烷 基、芳基、雜芳基。 在另—態樣中，本發明提供如下式（I)化合物，其中113與 R可連同其所連接之原子一起形成飽和或部分不飽和4員 至7員含，該含N環視情況含有另一選自N、〇及§之雜 原子，且視情況在碳上經個獨立地選自烷基、 (1 6)烷氧基、齒基、CN及羥基之取代基取代；該含n環 亦可視情況稠合至芳基。 匕在另態樣中，本發明提供如下式（I)化合物，其中…與 σ連同/、所連接之原子一起形成餘和或部分不飽和5員 員，该含Ν環視情況在碳上經丄或】個（c「c6)烷基 取代基取代。 匕在另態樣中，本發明提供如下式⑴化合物，其中尺3與 t可連同其所連接之原子-起形成5員、6員、9員或1〇員 早壤或雙環含Ns 3 N方i衣，該含n芳環視情況含有另一選自N、 Θ及S之雜原早 ’、丁 ’且視情況在碳上經1、2或3個獨立地選自 151651.doc -25- 201121961 (Cl_C6)炫基、（C1_C6)院氧基、 及羥基之取代基取代。 鹵基、CN、芳基、COOR15 在另樣中，本發明提供如下式（I)化合物，其中Ra與 R可連同其所連接之原子一起形成5員、6員、9員或1〇員 早環或雙環含N芳環，該含N芳環視情況在碳上經個 (Ci-C6)炫基取代基取代。 在一態樣中’本發明提供如下式⑴化合物，其中r!4為 Η。 在一態樣中，本發明提供如下式⑴化合物，其中Rl5為 Η。 在一態樣中，本發明提供如下式⑴化合物，其中R】6為 Η。 在一態樣中，本發明提供如下式（I)化合物，其中R17係 選自Η、鹵基及（CVC6)烷基。 在另一態樣中，本發明提供如下式（I)化合物，其中R] 7 係選自Η及（CVCO烷基。 在另一態樣中，本發明提供如下式（I)化合物，其中Rl7 為Η。 在一態樣中，本發明提供選自以下之式（I)化合物： (R)-2-胺基-3-甲基-戊酸{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺 甲醯基]-2-萘-1-基-乙基}-醢胺； (R) -l-甲基-吡咯啶-2-甲酸[(S)-l_[(2-胺基-噻°坐_5_基甲基）-胺甲醯基]-2-(3,4-二氟-苯基）_乙基]-酿胺； (S) -N-[(S)-l-[(2-胺基-噻唑-5-基甲基）_胺甲醯基]·2·(4_氟- 151651.doc -26 - 201121961 苯基）-乙基]-2-(異丙基-甲基-胺基）·丙醯胺； 3-甲基-1H-吡咯-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺 甲醯基]-2-(3,4-二氯·苯基乙基]_醯胺； (R) -N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2-(3,4-二 氣-苯基）-乙基]-2-羥基-3-苯基-丙醯胺； (S) -N-(2-胺基-噻唑-5-基曱基）-3-萘-1-基-2-(丙烷-1-磺醯胺 基）-丙醯胺； (S)-l-甲基比咯啶-2-甲酸{(R)-l-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]-2,2-二環己基·乙基}_醯胺； (R)-吡咯啶-2-曱酸[(S)-l-[(2-胺基·噻唑-5-基曱基）-胺甲醢 基]-2·(3,4-二氟-笨基）-乙基]-醯胺； (R)-2-胺基-3-甲基-戊酸[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺 曱醯基]-2-(3,4-二氟-苯基）_乙基]•醯胺； (R) -3-甲基-2-曱胺基-戊酸[(S)-l-[(2-胺基-噻唑-5-基甲基）_ 胺甲醯基]-2-(3,4-二氟-苯基）-乙基]-醯胺； (S) -N-[(S)-M(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2-(3,4_二 氟-苯基）-乙基]-2-二丙胺基-丙醯胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]·2_(3,4-二 氟-苯基）-乙基]-2-(異丙基-甲基-胺基）-丙醯胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2-(3,4_二 氟-苯基）-乙基]-2-二乙胺基-丙醯胺； (S)-N-[(S)-W(2-胺基-嚷唑-5-基曱基）-胺甲醯基]·2-(3,4。 氟-苯基）-乙基]-2-二曱胺基-丙醯胺； (R)-N-[(S)-l-[(2-胺基-噻唑·5-基曱基）-胺甲醯基]-2-(3,4-二 151651.doc -27- 201121961 氟^ -苯基）-乙基]-2 -二曱胺基-丙酿胺， (S)-1 -曱基-°比洛。定-2-曱酸[(S)-l-[(2-胺基-°塞。坐-5-基甲基）_ 胺曱酿基]-2-(3,4-二氣-苯基）-乙基]-酿胺， (R)-l-乙基比咯啶·2-曱酸[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺曱酿基]-2-(3，4·二氣-苯基）·乙基]-酿胺， (R)-l-異丙基-吡咯啶-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基曱 基）-胺甲酿基]-2-(3,4-二敗-苯基）-乙基]-酿胺， (R)-l-異丙基-旅ϋ定-2-曱酸[(S)-l-[(2-胺基-。塞。坐-5 -基甲基）_ 胺曱酿基]-2-(3，4-二氣-苯基）·乙基]-酿胺； (R) -1 -甲基-旅。定-2-曱酸[(S)-l-[(2-胺基-σ塞ϋ坐-5-基甲基）-胺 曱醯基]-2-(3,4-二氟-苯基）-乙基]•醯胺； (S) -1 -曱基-旅。定-2-甲酸[(S)-l-[(2-胺基-售。坐-5-基甲基）-胺 曱酿基]-2-(3,4-二氣-苯基）-乙基]-酿胺， (11)-^[-[(8)-1-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]-2-(3,4-二 亂-苯基）-乙基]-2-二甲胺基·3-苯基-丙酿胺， (8)-^[-[(8)-1-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]-2-(3,4-二 氣-苯基）-乙基]-2 -二甲胺基-3 -苯基-丙酿胺， (S)-N-[(S)-l-[(2 -胺基-°塞 σ坐-5-基甲基）-胺曱酿基]-2-(3,4 -二 狀-本基）·乙基]-2 -略咬· 1 -基-丙酿胺， (R) -N-[(S)-l-[(2-胺基-°塞。坐-5-基甲基）-胺甲酿基]·2-(3,4 -二 敗-本基）·乙基]· 2 -略。定_ 1 -基-丙酿胺， (S) -N-(2 -胺基-°塞°坐-5-基甲基）-3·(3,4-二氣-苯基）-2-(2-二 異丙胺基-乙醯胺基）-丙醯胺； (S)-N-(2·胺基-0塞 σ坐-5-基甲基）-3-(3,4 -二敗-本基）-2-[2_ 151651.doc -28 - 201121961 (2,6-二甲基-哌啶-1-基）-乙醯胺基]-丙醯胺； (R) -l-曱基比咯啶-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲酿基]-2-(4 -亂-苯基）-乙基]-酿胺， (S) -N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-(4-氟-苯基）-乙基]-2-二曱胺基-丙醯胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2-(4-氟-苯基）-乙基]-2-二乙胺基-丙醯胺； (S)-N-[(S)-l-[(2-胺基-α塞唾-5-基甲基）-胺曱酿基]-2-(4-氣_ 苯基）-乙基]-2 -旅咬-1 ·基-丙隨胺， (11)-：^-[(8)-1-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]-2-(4-氟-笨基）-乙基]-2 - ^底。定-1 -基-丙酿胺， (S)-N-(2 -胺基-°塞。坐-5-基曱基）-2-[2-(2,6 -二曱基-旅咬-_ 基）-乙酿胺基]-3-(4-亂-苯基）-丙酿胺， (R) -l-曱基-吡咯啶-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲酿基]-2-(3 -亂-苯基）-乙基]-酿胺， (S) -N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2·(3-氟-笨基）-乙基]-2-(異丙基-曱基-胺基）-丙酿胺， (S)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2-(3-氟-苯基）-乙基]-2-二曱胺基-丙醯胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺曱醯基]-2-(3-氟-苯基）-乙基]-2-二乙胺基-丙醯胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]-2-(3-氟-苯基）-乙基]-2 -派咬-1 -基-丙酿胺， (R)-N-[(S)-l-[(2-胺基·噻唑-5-基甲基）-胺甲醯基]-2-(3-氟- 151651.doc -29- 201121961 苯基）-乙基]-2-哌啶-1-基-丙醯胺； (R) -l-甲基-0比咯啶-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基甲基）_ 胺曱酿基]-2-(2-氟-苯基）·乙基]-酿胺， (S) -N-[(S)-l-[(2-胺基-嗟唑-5-基甲基）-胺甲醯基]-2-(2-氟_ 苯基）-乙基]_2-(異丙基-甲基-胺基）-丙酿fer ’ (R) -l-曱基-吡咯啶-2-曱酸{(S)-l-[(2_胺基-噻唑-5-基甲基）_ 胺曱酿基]-2 -秦一I-基-乙基]-酿胺； (S) -N-{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]-2-萘-1-基-乙基}-2-(異丙基-曱基-胺基）-丙醯胺； (S)-N-{(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2-萘-1-基-乙基}-2·二乙胺基-丙醯胺； (3)-：^-{(3)-1-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-萘-1-基-乙基}-2-哌啶-1-基-丙醯胺； (R) -N-{(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2-萘-1-基-乙基}-2-哌啶-1-基-丙醯胺； (S) -N-{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]-2-萘-1-基-乙基}-2-二曱胺基-3-笨基-丙醯胺； (R) -l-曱基-吡咯啶-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基甲基）· 胺甲醯基]-2-(4-氯-苯基）-乙基]-醯胺； (S) -N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺曱醯基]-2-(4-氯-苯基）-乙基]-2-(異丙基·曱基-胺基）-丙醯胺； (R) -l-甲基-吡咯啶-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基甲基）_ 胺甲醯基]-2-(3-氣·苯基）·乙基]-醯胺； (S) -N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2-(3-氣· 151651.doc •30- 201121961 苯基）-乙基]-2_(異丙基-甲基-胺基）-丙醯胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-(3-氯_ 苯基）-乙基]-2-二曱胺基-丙醯胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲酿基]-2-(3-氯― 苯基）-乙基]-2-二乙胺基-丙醯胺； (S)-N-[(S)小[(2-胺基塞唑-5-基甲基）-胺甲醯基]-2_(3-氣-苯基）-乙基]-2-哌啶-1-基-丙醯胺； (R)-N-[(S)-l-[(2-胺基塞唑-5-基曱基）-胺甲醯基]Κ3-氯-笨基）-乙基]-2-哌啶-1-基-丙醯胺； (R) -l-甲基-0比咯啶-2-曱酸[(S)-l-[(2-胺基-噻唑_5-基甲基）_ 胺曱醯基]-2-(3,4-二氣-苯基）-乙基]-醯胺； (S) -N-[(S)-l-[(2-胺基-嗟唑-5-基甲基）·胺甲醯基]-2-(3,4-二 氣-苯基）-乙基]_2-(異丙基-曱基-胺基）-丙醯胺’ (S)-N-[(S)-卜[(2-胺基·。塞唑-5-基甲基）·胺甲醯基]_2-(3,4-二 氣-苯基）-乙基]-2-二曱胺基-丙醯胺； (S)-N-[(S)-l-[(2-胺基-養唑-5-基曱基）-胺甲醯基]-2-(3,4_二 氣-苯基）-乙基]-2-二乙胺基-丙醯胺； (S)-N-[(S)-l-[(2-胺基-嘆唑-5-基曱基）_胺甲醯基卜2-(3,4-二 氣-苯基）-乙基]-2-哌啶-1-基-丙醯胺； (R) -N-[(S)-l-[(2-胺基-嗟唑-5-基甲基）_胺甲醯基]_2_(3,4·二 氣-苯基）-乙基]-2-α底咬_1_基_丙醯胺， (S) -N-{(S)-l-[(2-胺基-噻唑-5-基甲基）·胺曱醯基]_2·對曱苯 基-乙基}-2-(異丙基-甲基·胺基）-丙醯胺； (R)-l-曱基-吡咯啶-2-曱酸{(S)-l-[(2-胺基-噻唑_5_基甲基） 151651.doc •31 - 201121961 胺曱醯基]-2-對曱苯基-乙基}_醯胺； (R)-l-甲基-吡咯啶-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-間甲苯基-乙基}_醯胺； (3)-1^-{(5)-1-[(2-胺基-噻唑-5-基甲基）-胺甲醢基]-2-間曱苯 基-乙基}-2-(異丙基-曱基-胺基）-丙醯胺； (R) -l-甲基-吡咯啶-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基曱基）_ 胺曱醯基]-2-鄰甲苯基-乙基}-醯胺； (S) -N-{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]-2·鄰甲苯 基-乙基}-2-(異丙基-甲基-胺基）-丙醯胺； (R)-吡咯啶-2-曱酸{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯 基]-2-環己基-乙基}-醯胺； (R) -卜甲基比咯啶-2-甲酸{(S)-l-[(2-胺基-嘆。坐_5-基甲基）_ 胺甲醯基]-2-環己基·乙基}-醯胺； (S) -l-甲基比咯啶-2-甲酸{(S)-l-[(2-胺基塞。坐_5-基甲基）-胺曱醯基]-2-環己基-乙基}-醯胺； (S)-N-{(S)-l-[(2-胺基-噻唑-5-基甲基）_胺甲醢基]_2-ί衣己 基-乙基}-2-(異丙基-甲基-胺基）·丙醢胺； (S)-N-{(S)-l-[(2-胺基-噻唑-5-基曱基）_胺甲醯基卜2_%己 基-乙基}-2-二甲胺基-丙醯胺； (S)-N-{(S)-l-[(2-胺基-噻唑-5-基甲基）_胺甲醢基卜2-%己 基-乙基二乙胺基-丙酿胺’ (R)-l-乙基比咯咬-2-甲酸{(S)-l-[(2-胺基_°塞°坐-5-基甲基）_ 胺甲醯基]-2-環己基-乙基卜醯胺； (R)-l-異丙基-0比0各口定_2-甲酸{(S)-l-[(2-胺基-塞坐5 土 151651.doc • 32· 201121961 基）-胺甲醯基]-2-環己基-乙基醯胺； (R) -l-甲基-哌啶-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺 甲醯基]-2-環己基-乙基}-醯胺； (S) -N-{(S)-l-[(2-胺基-噻唑-5-基曱基）-胺曱醯基]-2-環己 基-乙基}- 2 -娘咬-1 ·基-丙酿胺， (R) -N-{(S)-l-[(2·胺基-。塞°坐-5-基甲基）-胺曱酿基]-2-環己 基-乙基} - 2 -略。定-1 -基-丙酿胺， 3 -曱基-1Η - 0比嘻-2 -甲酸{(S)-l-[(2 -胺基-。塞ϋ坐-5 -基曱基）-胺 甲酿基]-2 -奈-1-基-乙基}-酿胺， 1H-吲哚-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯 基]-2 -奈-1-基-乙基}-酿胺， (S) -N-(2-胺基-噻唑-5-基曱基）-3-萘-1-基-2-(2-間曱苯基-乙 醯胺基）-丙醯胺； 3,5-二甲基-111-吡咯-2-甲酸[(8)-1-[(2-胺基-噻唑-5-基甲 基）&quot;胺曱酿基]-2-(3,4-二氣-苯基）-乙基]-酿胺， 3·曱基-1H·吡咯-2-甲酸[(S)-l-[(2·胺基-噻唑-5-基甲基）-胺 甲酿基]-2-(3，4·二氣-苯基）-乙基]-酿胺， 1H-吲哚-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯 基]-2-(3,4-二默-苯基）-乙基]-酿胺， 3-甲基-1H-吡咯-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺 甲酿基]-2-(4 -氟-苯基）-乙基]-酿胺， 3-曱基-1H-吡咯·2-曱酸[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺 甲酿基]-2-(3 -氣·苯基）-乙基]•酿胺， 3-曱基-1H-吼咯-2·曱酸[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺 I51651.doc -33· 201121961 甲酿基]-2-(2 -氣-苯基）-乙基]-酿胺， 3-甲基-1H-。比咯-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺 甲醯基]-2-(4-氣-苯基）-乙基]-醯胺； 3-曱基-1H-吡咯-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺 甲醯基]-2-(3-氣-苯基）-乙基]-醯胺； 3-甲基-1H-吡咯-2-曱酸{(S)-l-[(2-胺基-噻唑-5-基曱基）-胺 甲醯基]-2-對甲苯基-乙基}-醯胺； 3-曱基-1H-吡咯-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基曱基）-胺 甲醯基]-2-間甲苯基-乙基}-醯胺； 3-曱基-1H-吡咯-2-曱酸{(S)-l-[(2-胺基-噻唑-5-基曱基）-胺 甲醯基]-2-鄰甲苯基-乙基}-醯胺； 3-甲基-1H-吡咯-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基曱基）-胺 曱醯基]-2-環己基-乙基}-醯胺； (R)-N-{(S)-l-[(2-胺基-。塞。坐-5-基甲基）-胺甲醒基]-2 -奈-1_ 基-乙基}_ 2 -經基-3 -苯基-丙酿胺， (11)-^[-[(8)-1-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]-2-(3,4-二 氟-苯基）-乙基]-2-羥基-3-苯基-丙醯胺； (R)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]-2-(4-氟-苯基）-乙基]-2 -經基-3 -苯基-丙酿胺， (R)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2-(3-氟-苯基）-乙基]-2-羥基-3-苯基-丙醯胺； (R)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2-(2-氟-苯基）-乙基]-2-羥基-3-苯基-丙醯胺； (R)-N-[(S)-l-[(2-胺基-α塞0坐-5-基甲基）-胺曱酿基]-2-(4-氣_ 151651.doc -34- 201121961 苯基）-乙基]-2-經基-3-苯基-丙醯胺； (R)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基;|_2_(3_氣_ 苯基）-乙基]-2-經基-3-笨基-丙醯胺； (11)-：^-{(8)-1-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]_2_對曱 苯基-乙基}-2-經基-3-苯基-丙醯胺； (R)-N-{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]_2_間甲 苯基-乙基}-2_經基-3-苯基-丙醯胺； (R)-N-{(S)-M(2-胺基-噻唑-5-基甲基）-胺甲醯基]_2_鄰甲 苯基-乙基}-2_經基苯基-丙酿胺； (R)-N-{(S)-卜[(2-胺基-噻唑-5-基甲基）-胺甲醯基]_2_環己 基-乙基}-2-經基苯基-丙酿胺； (R)-N-{(S)-卜[(2-胺基-噻唑-5-基甲基）·胺甲醯基]·2_蔡小 基-乙基}-2-羥基-丁醯胺； (R) -N-{(S)-l-[(2-胺基-°塞°坐-5-基曱基）-胺曱酿基]―之-蔡心 基-乙基}-2-羥基-3-曱基-丁醯胺； (S) -N-{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]_2_萘·^ 基-乙基}-2-羥基-3-曱基-丁醯胺； (R) -N-[(S)-l-[(2-胺基塞唑-5-基甲基）-胺甲醯基]_2_(34_二 氟-苯基）-乙基]-2-羥基-3-甲基-丁醯胺； (S) _N-[(S)-l-[(2-胺基-嘆唑-5-基曱基）-胺曱醯基]_2_(3,4_二 氟-苯基）-乙基]-2-羥基-3-曱基-丁醯胺； 及其互變異構體、立體異構體、醫藥學上可接受之鹽及溶 劑合物。 在另一態樣中，本發明提供選自以下之式⑴化合物： 151651.doc -35- 201121961 (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2_(4_氟-苯基）-乙基]-2-(異丙基-甲基-胺基）-丙醯胺； (R)-3-甲基-2-甲胺基-戊酸[(S)-l-[(2-胺基-噻唑-5_基甲基）-胺曱醯基]-2-(3,4-二氟-苯基乙基μ醯胺； (8)-1^-[(8)-1-[(2-胺基-嘆唑_5-基甲基）-胺甲醯基]-2-(3,4_二 氟-苯基）-乙基]-2-(異丙基-曱基-胺基）-丙醯胺； (R)-l -乙基-0比咯啶-2-曱酸[(s)-l-[(2-胺基-噻唑·5-基甲基）_ 胺曱醯基]-2-(3,4-二氟-苯基;)—乙基]_醯胺； (R)-l-異丙基-吡咯啶-2-甲酸[(S)-l-[(2-胺基-噻唑_5-基甲 基）-胺曱醯基]-2-(3,4-二氟-苯基）-乙基]-醯胺； (R)-l-甲基-哌啶-2-曱酸[(S)-l-[(2-胺基-噻唑-5·基甲基）_胺 曱醯基]-2-(3,4-二氟-笨基）_乙基]_醯胺； (R) -l-甲基-0比咯啶-2-曱酸[(S)-l-[(2-胺基-噻唑_5-基甲基）_ 胺甲醯基]-2-(4-氟-笨基）_乙基]_醯胺； (S) -N-{(S)-l-[(2-胺基-噻唑-5-基曱基）-胺曱醯基]-2-萘-1· 基-乙基}-2-(異丙基-甲基·胺基）-丙醯胺； (R) -l-曱基比咯啶-2-曱酸[(S)-l-[(2-胺基-噻唑_5_基甲基）_ 胺甲醯基]-2-(4-氯-苯基乙基]-醯胺； (S) -N-[(S)-l-[(2-胺基-嚷唑-5-基曱基）_胺曱醯基]-2-(4-氣-笨基）-乙基]-2-(異丙基-曱基-胺基）-丙醢胺； (R) -l-曱基-吡咯啶-2-曱酸[(S)-l-[(2-胺基-噻唑_5_基甲基 胺甲醯基1-2-(3-氣-苯基乙基]-醯胺； (S) -N-[(S)-l-[(2-胺基-噻唑基甲基）·胺曱醯基]-2-(3_氯-苯基）-乙基]-2-(異丙基-曱基-胺基）-丙醯胺； 151651.doc -36- 201121961 (R) -l-曱基-吡咯啶-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基甲基） 胺甲醯基]-2_(3,4-二氯-苯基）·乙基]_醯胺； (S) -N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-(3,4、二 氣_苯基）·乙基]-2-(異丙基-甲基-胺基）-丙醯胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺曱醢基]-2-(3,4_ 一 氯-苯基）-乙基]·2·二乙胺基-丙醯胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-(3/- ~ 氣-苯基）-乙基]-2-哌啶-1·基-丙醯胺； (8)-&gt;1-{(8)-1-[(2-胺基-噻唑-5-基曱基）-胺曱醯基]-2-董十甲笨 基-乙基}-2-(異丙基-曱基-胺基）-丙醯胺； (S)-N-{(S)-l-[(2-胺基·噻唑-5-基曱基）-胺甲醯基]_2_間甲芽 基-乙基}-2-(異丙基-甲基-胺基）-丙酿胺； (S)-N-{(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]環己 基-乙基}-2-(異丙基-甲基-胺基）_丙醯胺； (R)-l-曱基-哌啶-2-曱酸{(S)-l-[(2-胺基-噻唑·5_基曱基）_胺 曱醯基]-2-環己基-乙基}-醯胺； 及其互變異構體、立體異構體 '醫藥學上可接受之鹽及溶 劑合物。 熟習此項技術者將瞭解上文所鑑別或下文提供之實例中 所鑑別之各化合物以單獨或與其他所鑑別化合物之任何組 合形式表示本發明之一獨立態樣。 治療應用 如先前所提及， 具有多種治療應用 本發明化合物由於其能夠抑财⑴而 ’尤其用於治療發炎性疾病，諸如哮喘 151651.doc -37- 201121961 及COPD。 特定而言’本發明化合物可用於治療涉及氣管炎症之啤 吸道病症’例如哮喘（過敏性及非過敏性），包括由哮喘及 慢性阻塞性肺病（COPD)引起之惡化。該等化合物亦可用 於治療其他形式之過敏性炎症，包括過敏性鼻炎（枯草 熱）、鼻結膜炎、鼻漏、蓴麻療、過量產生肺黏液、形成 腹水、慢性支氣管炎、慢性呼吸道阻塞、肺纖維化及肺氣 腫。 可以本發明化合物治療之其他發炎性病症包括多發性項 化症、關節炎、類風濕性關節炎、骨病性關節炎 (osteopathic arthritis)、骨關節炎、鼻炎、竇炎、發炎性腸 病（諸如克羅恩氏病（Crohn's disease)及潰瘍性結腸炎）、免 疫介導之糖尿病、急性胰臟炎及間質性膀胱炎、熱損傷、 壓傷、結膜炎、牙周病、慢性***炎、慢性復發性腮腺 炎、發炎性皮膚病症（例如牛皮癬、濕疹）、肝硬化、脊趙 創傷及SIRS(全身性發炎反應症候群）；平滑肌痙攣（例如哮 喘、心絞痛）、RDS(呼吸窘迫症候群）；低血壓（例如由出 血、敗血症或全身性過敏反應所致之休克、類癌症候群、 胃傾倒症侯群水腫（例如燒傷、腦創傷、血管神經性水 腫（無論是否由以血管收縮素轉化酶抑制劑治療所引起））. 疼痛及刺激（例如燒傷、傷口、士刀口、皮療、刺傷、昆蟲 咬傷）、偏頭痛；由抑制***激肽釋放酶所產生之男性 避孕劑；防止手術裎序期間失血過量。 本發明化合物亦可用於治療可為對發炎介體釋放作出之 151651.doc •38· 201121961 反應的病症（例如咳嗷）。 本發明化合物亦可用於治療涉及生長因子（例如血管内 皮生長因子（VEGF))調節之病症，該等病症可能涉及增加 血管滲透性（例如糖尿病性視網膜病及敗血性休克）。 本發明化合物可用於治療贅生性病症（例如轉移性胰臟 腺癌、腫瘤血管生成）’特定而言，其可用於減少與贅瘤 (例如癌症及腫瘤生長）相關之血管生成，且調控血管生成 及與瘤形成及腫瘤生長相關之其他過程，且特定而言可用 於阻斷腫瘤血管生成及/或癌細胞侵襲及轉移。 哮喘 哮喘為一種慢性肺病狀，其可分類為過敏性（内源性）或 非過敏性（外源性）。罹患哮喘之患者由於氣管狹窄或阻 塞，使得較難吸入及呼出空氣而經歷呼吸困難。此狹窄可 由氣管炎症及支氣管收縮引起。哮喘之症狀包括例如喘 鳴、呼吸急促、支氣管收縮、氣管過度反應、肺活量降 低、纖維化、氣管炎症及產生黏液。哮喘之另一症狀為由 初始哮喘發病引起之惡化，其在該疾病中所佔之罹病率顯 著。KLK1抑制劑可用於改善或預防至少一種哮喘症狀。 KLK1抑制劑亦可聯合另一治療哮喘之藥劑（例如吸入型類 固醇、口服類固醇、長效β·促效劑、白三烯調節劑、色甘 酸鈉（cromolyn s〇dium)及奈多羅米（ned〇cr〇mil)、茶鹼 (theophylline)及抗igE抗體）（參見下文）一起投與。 過敏性鼻炎 過敏性鼻炎或「枯草熱」涉及對來自草、樹木及雜草之 151651.doc -39· 201121961 花粉的過敏反應。當罹患過敏性鼻炎之個體吸入花粉時， 觸發抗體產生及組織胺釋放。過敏性鼻炎之症狀包括（但 不限於）咳嗽；頭痛；眼睛、口腔、咽喉或鼻發癢；打喷 嗓’鼻充血；喘鳴；咽喉痛；及流淚。不同人之間與枯草 熱相關之症狀顯著不同，且過敏性鼻炎可與其他諸如哮喘 之病狀相關。 慢性阻塞性肺病（COPD) 慢性阻塞性肺病（COPD)為一種涉及氣管炎症之疾病。 肺氣腫以及慢性支氣管炎屬於C〇Pd。其為一種嚴重肺病 且呈進行性’通常出現於老年患者中。COPD引起肺中稱 作肺/包或氣囊之結構過度充氣。肺泡壁破裂引起肺呼吸能 力降低。罹患此疾病之患者可首先經歷呼吸急促及咳嗽。 KLK1抑制劑可用於改善至少一種c〇pD症狀。KLK1抑制 劑亦可聯合另一治療COPD之藥劑（例如吸入型類固醇、口 服類固醇、長效β-促效劑、白三烯調節劑、色甘酸鈉及奈 多羅米、茶驗及抗IgE抗體）（參見下文）一起投與。 咳嗽 咳嗽可由病毒感染所致之上呼吸道（咽喉及氣管）炎症引 起。病毒感染包括普通感冒、流行性感冒、喉炎及支氣管 炎。此等病毒感染亦可波及下呼吸道（支氣管）引發咳嗷。 咳漱為包括哮喘、支氣管炎、流行性感冒及百曰咳 (whooping cough/pertussis)之多種疾病及病狀的症狀，且 亦可作為使用某些諸如ACE抑制劑之藥物的副作用產生。 吸菸之個體常有吸菸者咳嗽，即常引起痰液呼出之大聲頻 151651.doc •40· 201121961 咳。KLK1抑制劑可用於改善或預防至少一種咳漱症狀。 由哮喘及慢性阻塞性肺病（COPD)引起之惡化 罹患哮喘及C Ο P D之個體在其肺及氣管開始對某些觸發 此等發病之物質過度反應時有惡化之風險。在惡化期間， 氣管内襯層突然腫脹且發炎。此等氣管之肌肉將變緊張且 黏液之產生將增加。 此組合使得開口更為狹窄，且可能幾乎使其完全閉合， 使得呼吸困難。惡化之罹病率顯著且造成不成比例量的哮 喘管理成本，在惡化後症狀常持續至少一個月。當前用於 哮喘急性惡化之治療策略很大程度上依賴於支氣管擴張劑 及吸入型或全身性皮質類固醇。KLK1抑制劑可用於改善 或預防至少一種惡化症狀。KLK1抑制劑亦可聯合另一治 療由哮喘及COPD引起之惡化的藥劑（例如吸入型類固醇、 口服類固醇、長效β-促效劑、白三烯調節劑、色甘酸鈉及 奈多羅米、茶鹼及抗IgE抗體）（參見下文）—起投與。 胰臟炎 急性胰臟炎-炎症在數小時内快速發展，且通常會治癒 而不留下永久性損傷，但以現併發症，則其可能為致命 的（5%病例）。 慢性胰臟炎-此病狀通常以急性胰臟炎多次發作開始， 且最終變為永久性病狀。胰臟持續發炎。 KLK1抑制劑可用於改善或預防至少一 只防主乂 種胰臟炎症狀。 類風濕性關節炎（RA) 151651.doc -41 - 201121961 此病症特徵在於關節及/或其他内臟之内襯層炎症。其 通常為慢性的，但可包括突發。症狀包括關節炎症、腫 脹、移動困難、疼痛及發熱。KLK1抑制劑可用於改善或 預防至少一種類風濕性關節炎症狀。 KLK1抑制劑可與另一治療類風濕性關節炎之藥劑（諸如 NSAID及阿司匹靈（aspirin)、鎮痛劑及皮質類固醇卜起投 與，s亥另一藥劑有助於減輕關節疼痛、僵硬及腫脹。 骨關節炎 骨關節炎為一種退化性關節病。其特徵在於關節軟骨破 裂，從而引起骨質彼此摩擦’造成疼痛及運動能力喪失。 KLK1抑制劑可用於改善或預防至少一種骨關節炎症狀。 KLK1抑制劑可與另一治療類風濕性關節炎之藥劑（諸如皮 質類固醇或NSAID)—起投與。 血管生成相關性及贅生性病症 在一實施例中，KLK1抑制劑可投與個體以調控血管生 成或與瘤形成及腫瘤生長相關之其他過程。 舉例而言，KLK1抑制劑可用於減少血管生成（例如失控 或不期望之血管生成），諸如與以下病症相關之血管生 成：血管畸形及心血管病症（例如動脈粥樣硬化、再狹窄 及動靜脈畸形）、慢性發炎性疾病（例如糖尿病、發炎性腸 病、牛皮癬及類風濕性關節炎）、皮膚病症（例如動脈潰 瘍、全身性血管炎及硬皮病）或眼部病症（例如由新生血管 性疾病所致之失明、新生血管性青光眼、角膜新血管生 成、沙眼、糖尿病性視網膜病及近視性退化症）。 151651.doc -42- 201121961 特定而言’ KLK1抑制劑可用於減少與瘤形成（例如癌症 及腫瘤生長，例如良性、惡性或轉移性腫瘤生長）相關之 灰管生成。 癌性病症之貫例包括（但不限於）實艘戚瘤、軟組織腫瘤 及轉移性病變。實例包括各種器官系統之肉瘤、腺癌及癌 瘤，諸如侵襲肺、***、淋巴、胃腸（例如結腸）及泌尿生 殖道（例如腎尿道上皮細胞）、咽、***、卵巢之肉瘤' 腺癌及癌瘤，以及包括諸如大部分結腸癌、直腸癌、腎細 胞癌、肝癌、非小細胞肺癌、咽癌、小腸癌、食道癌及其 他癌症之惡性病的腺癌。 可治療之例示性實體腫瘤包括：纖維肉瘤、黏液肉瘤、 脂肉瘤、軟骨肉瘤 '骨原性肉瘤、脊索瘤、淋巴血管内皮 肉瘤（lymphanangioendotheliosarcoma)、滑膜瘤、間皮瘤、 尤文氏腫瘤（Ewing’s tumour)、平滑肌肉瘤、橫紋肌肉瘤、 結腸癌、胰臟癌、乳癌、卵巢癌、***癌、鱗狀細胞 癌、基底細胞癌、_腺癌、汗腺癌、皮脂腺癌、乳頭狀癌、 乳頭狀腺癌、囊腺癌、髓性癌、支氣管癌、腎細胞癌、肝 癌、膽管癌、絨膜癌、精原細胞瘤、胚胎性癌、子宮頸 癌、睾丸腫瘤、肺癌、小細胞肺癌 '非小細胞肺癌、膀胱 癌、上皮癌、神經膠質瘤、星形細胞瘤、神經管胚細胞 瘤、顱咽管瘤、室管膜瘤、松果腺瘤、血管母細胞瘤、聽 神經瘤、少突神經膠質瘤、腦膜瘤、黑素瘤、神經母細胞 瘤及視網膜母細胞瘤。 KLK1抑制劑亦可用於治療癌瘤，例如上皮或内分泌組 151651.doc -43- 201121961 織之惡性病’包括呼吸系統癌瘤、胃腸系統癌瘤、生殖泌 尿系統癌瘤及黑素瘤。例示性癌瘤包括子宮頸、肺、前列 腺、***、頭頸、結腸及卵巢組織之腺癌、癌瘤。 KLK1抑制劑亦可用於治療肉瘤，例如間質源性惡性腫 瘤。 KLK1抑制劑可組合另一治療贅生性及/或轉移性病症之 藥劑一起投與。該等其他藥劑之實例包括： ⑴其他抗血管生成劑（例如三羧胺基喹啉（lin〇mide)、血管 抑制素（angiostatin)、丙亞胺（razoxane)); (11)細胞生長抑制劑，諸如抗***劑（例如他莫昔芬 (tamoxifan)、托瑞米芬（toremifene)、雷洛昔芬（raloxifene))、 孕激素（例如醋酸甲地孕_ (megestr〇l acetate))、芳香酶抑 制劑（例如女美達鍵（anastroz〇ie)、來曲。坐（ietroz〇ie))、抗 孕激素劑、抗雄激素劑（例如氟他胺（flutarnide)、尼魯米特 (nilutamide)、比卡魯胺（bicalutamide))、抗侵襲劑（例如金 屬蛋白抑制劑（諸如馬立馬司他（marimastat))及尿激酶纖 維蛋白溶酶原活化劑受體功能抑制劑）。 (iii)如醫藥腫瘤學中所用之抗增殖/抗贅生性藥物及其組 合’諸如抗代謝物（例如氟嘧啶，如5-氟尿嘧啶（5_ fluorouracil)、嘌吟及腺苷類似物、胞嘴咬***糖苷 (cytosine arabinoside));嵌入抗腫瘤抗生素（例如蒽環黴素 (anthracycline)，如小紅每（doxorubicin)、柔紅黴素 (daunomycin)、表柔比星（epirubicin));鉑衍生物（例如順 鉑（cisplatin)、卡鉑（carboplatin));烷基化劑（例如苯丁酸 151651.doc -44· 201121961 氮芬（chlorambucil)、環填醢胺（cyclophosphamide));抗有 絲***劑（例如長春花生物驗（vinca alkaloid)，諸如長春新 驗（vincristine);及紫杉烧（taxoid)，如TAXOL®(太平洋紫 杉醇（paclitaxel))、TAXOTERE®(多烯紫杉醇（docetaxel))); 拓撲異構酶抑制劑（例如表鬼臼毒素（epipodophyllotoxin)， 諸如依託泊苷（etoposide)及替尼泊甙（teniposide));及蛋白 酶體抑制劑，諸如VELCADE®(波普單抗（bortezomib))。 因此’本發明提供用於治療之式（I)化合物。 本發明亦提供式（I)化合物之用途，其係用於製造供治療 或預防涉及KLK1活性之疾病或病狀用的藥物。涉及KLK1 活性之疾病或病狀包括炎症、呼吸道病症、涉及生長因子 調節之病症及贅生性病症。該等疾病及病狀之特定實例包 括上文所列者。 本發明亦提供用於治療或預防涉及KLK1活性之疾病或 病狀的式（I)化合物。涉及KLK1活性之疾病或病狀包括炎 症、呼吸道病症、涉及生長因子調節之病症及贅生性病 症。該等疾病及病狀之特定實例包括上文所列者。 本發明亦提供治療涉及KLK1活性之疾病或病狀的方 法’其包含為有需要之個體投與治療有效量之式（1)化合 物。涉及KLK1活性之疾病或病狀包括炎症、呼吸道病 症、涉及生長因子調節之病症及贅生性病症。該等疾病及 病狀之特定實例包括上文所列者。 在一態樣中，涉及KLK1活性之疾病或病狀係選自發炎 性或呼吸道病症或病狀，其係選自哮喘（過敏性及非過敏 151651.doc -45- 201121961 性）、慢性阻塞性肺病（COPD)、過敏性鼻炎（枯草熱）、咳 嗽、由哮喘及慢性阻塞性肺病（C0PD)引起之惡化 '多發 性硬化症、關節炎、類風濕性關節炎、骨病性關節炎、骨 關節炎I &amp;竇义、發炎性腸病(諸如克羅恩氏病及潰 瘍I·生，，腸炎）免疫介導之糖尿病、急性騰臟炎及間質性 膀胱炎、結膜炎、牙周冑、慢性***炎、慢性復發性腮 腺炎、發炎性皮膚病症（例如牛皮癬、濕疹）&amp;SIRs(全身性 發炎反應症候群）；平滑肌痙攣（例如哮喘、心絞痛）、 RDS(呼吸窘迫症候群）、鼻結膜炎、鼻漏、蓴麻疹、贅生 性病症、慢性支氣管炎、慢性呼吸道阻塞、肺纖維化及肺 氣腫。 在另一態樣中，涉及KLK1活性之疾病或病狀為選自哮 喘（過敏性及非過敏性）、慢性阻塞性肺病（c〇pD)、過敏性 鼻炎（枯草熱）、咳嗽、由哮喘及慢性阻塞性肺病（c〇pD)引 起之惡化的呼吸道病症。 在另態樣中，涉及KLK1活性之疾病或病狀係選自哮 喘（過敏性及非過敏性）及由哮喘及慢性阻塞性肺病（c〇pD) 引起之惡化。 在另態樣中，涉及KLK1活性之疾病或病狀為選自哮 喘（過敏性及非過敏性）及咳漱之啤吸道病症。 在另一態樣中，涉及KLK1活性之疾病或病狀為由哮喘 及慢性阻塞性肺病（COPD)引起之惡化。 組合療法 本治療法對呼吸道疾病可產生重要之效益，然而此等藥 151651.doc • 46 · 201121961 =之某些藥劑之功效常不盡人意，尤其治紅_及與 二S疾病相關之惡化的功效不盡人意。此外，鑒於諸如哮 而PD之呼吸道疾病的複雜性，有可能任何一種介體 ::治療該疾病可能不會令人滿意，而治療劑之組合卻可 犯也月有i 0特定而言，雖然使用類固醇可產生治療作 用，但需要能夠以低劑量使用類固醇以使可能與常規投藥 相關之不合需要之料料出現率及嚴重度降至最低，且 與諸如KLK1抑制劑之另—藥劑的組合可使類固酵劑量顯 著降低，且因此使潛在副作用減至最少。 因此其他化合物可與本發明化合物組合用於預防及治 療發炎性肺病。因&amp; ’本發明亦關於用於預防及治療諸如 以下呼吸道病症之醫藥組合物：哮喘（過敏性及非過敏 性）（包括由哮喘引起之惡化）、過敏性鼻炎及慢性阻塞性肺 病（COPD),該等醫藥組合物包含治療有效量之本發明化 合物及一或多種其他治療劑。該等組合物亦可用於治療其 他形式之過敏性炎症，包括過敏性鼻炎（枯草熱）、鼻結膜 炎、鼻漏 '蓴麻疹、過量產生肺黏液、形成腹水、慢性支 氣管炎、慢性呼吸道阻塞、肺纖維化及肺氣腫。 因此’本發明包括如上文所述之本發明化合物與一或多 種消炎藥、支氣管擴張劑、抗組織胺劑、解充血劑或止咳 劑之組合，該等本發明化合物及該等組合劑存在於同—或 不同醫藥組合物中，單獨、連續或同時投與。組合可包含 兩種或三種不同醫藥組合物。可與本發明化合物組合使用 之適合治療劑包括： 151651.doc •47- 201121961 (i) 類固醇糖皮質激素促效劑。可用於此實施例中之 類固醇糖皮質激素促效劑之實例包括布*** (budesonide)、氟替卡松（fluticasone)(例如呈丙酸 醋形式）、莫美他松（mometasone)(例如呈吱β南甲酸 酉旨形式）、倍氣米松（beclomethasone)(例如呈17 -丙 酸醋或17,21-二丙酸醋形式）、環索奈德（(^165011丨(}6)、 氣替潑諾（loteprednol)(例如呈依碳酸酯（etabonate) 形式）、艾潑諾（etipednol)(呈例如二氯乙酸酯 (dicloacetate)形式）、曲安西龍（triamcinolone)(例 如呈縮丙鋼化物形式）、敗尼縮松（flunisolide)、左 替卡松（zoticaasone)、氟曱氧縮松（flumoxonide)、 羅氣奈德（roofleponide)、布替可特（butixocort)(例 如呈丙酸醋形式）、強的松龍（prednisolone)、強的 松（prednisone)、替潑尼旦（tipredane)、類固醇 酯，例如6α，9α-二氟-17α-[2-呋喃基羰基）氧基]· 11β-經基-16α-曱基-3-側氧基-雄固- ΐ，4-二稀- Ι7β-硫代甲酸S-氟甲酯、6α，9α-二氟-11 β-羥基_ΐ6α-甲 基-3-側氧基-17α-丙醯氧基-雄固- ΐ，4-二烯- Ι7β-硫 代甲酸S-(2-側氧基-四氫-呋喃_3S-基）酯及6α，9α-二 氟-11β-羥基-16α-甲基-17α·[(4-甲基-1，3-嗟。坐-5-幾 基）氧基]-3-側氧基-雄固-1，4 -二稀-Ι7β-硫代甲酸S-氟甲酯、DE 4129535之類固醇酯、WO 2002/00679、 WO 2005/041980之類固醇，或類固醇GSK 870086、 GSK 685698及 GSK 799943 ; I51651.doc • 48- 201121961 (ii) 非類固醇糖皮質激素受體促效劑；Rb (IV). In another aspect, the invention provides a compound of formula (1) wherein R6 is R7. In one aspect, the invention provides a compound of formula (I) wherein R7 is selected from the group consisting of (C,_C6)alkyl, (C3-C1())cycloalkyl, aryl and aryl(Cl_c4)alkyl. . In another aspect, the invention provides a compound of formula (1) wherein R7 is selected from the group consisting of (c)-c6)alkyl, aryl and aryl(Ci_c4)alkyl. In another aspect, the invention provides a compound of formula (I) wherein anaphylly 7 is selected from the group consisting of (Ci-C6)alkyl and (CrC:6)alkyl substituted aryl (C丨-c4) alkane base-. In another aspect, the invention provides a compound of formula (1) wherein R7 is selected from n-propyl or methyl substituted benzyl. In one aspect, the invention provides a compound of formula (I) wherein R8 is selected from the group consisting of hydrazine, (Ci-Ce)alkyl, (c3-c1())cycloalkyl, and aryl(CVC4)alkyl. In another aspect, the invention provides a compound of formula (I) wherein the uldent 8 is selected from the group consisting of hydrazine, (CVC6) alkyl. 151651. Doc • 20· 201121961 In another aspect, the present invention provides a compound of the following formula (1), wherein ... is a (Ci-C6) alkyl group. In one aspect, the invention provides a compound of formula (1) wherein R9 is selected from the group consisting of hydrazine, (CVC6) alkyl. In another aspect, the invention provides a compound of formula (1) wherein the rule 9 is hydrazine. In one aspect, the present invention provides a compound of the following formula (1), wherein "one of the metals 9 is ruthenium and the other of R8 and R9 is not ruthenium, and the carbon atoms to which the ruthenium 9 and the ruthenium 9 are attached are Palm-like and having a π) configuration. In one aspect, the invention provides a compound of the following formula (1), wherein one of the ... and the ruler 9 is ruthenium and the other of R8 and R9 is not ruthenium, and R8 and The atom to which R9 is attached has a palmarity and has a "phantom configuration. In one aspect, the present invention provides a compound of the following formula (1) wherein R3 is Η and the carbon atom to which R3 is attached is palmar and has a configuration. And wherein one of Μ and R is H&amp;R8 and R9 are not Η, and the carbon atom to which r8&r9 is attached is palmar and has a "phantom". In another aspect The present invention provides a compound of the formula (1) wherein R3 is fluorene and the carbon atom to which R3 is attached has a palmarity and an oxime configuration, and wherein one of Μ and R is ^1 and the ruthenium 8 and R9 are The other is not H, and the carbon atom to which R8 and R9 are attached has a palmarity and a configuration. In the heart, the present invention provides a compound of the following formula (I), wherein the ri〇 system (4) 1 Cio) alkyl, (c3-Ci〇)cycloalkyl, heterocyclic, aryl(aryl)-(aryl)-, aryl(CrC4)- and heteroaryl (C) 1-〇4) Recovery base&gt;. 151651. Doc • 21 · 201121961 In another aspect, the invention provides a compound of formula (1) wherein r10 is selected from the group consisting of hydrazine, (CVCJ alkyl, (c3_Ci〇)cycloalkyl, and aryl (Ci_C4) alkyl. In one aspect, the invention provides a compound of formula (1) wherein R10 is selected from the group consisting of hydrazine, (CVC6) alkyl, and (c4_c6) cycloalkyl. In another aspect, the invention provides a compound of formula (1), wherein R10 In another aspect, the invention provides a compound of the formula (1) wherein r10 is (CVC6)alkyl. In one aspect, the invention provides a compound of formula (1), wherein Rn is selected from the group consisting of ruthenium and (Ci-Ciq) alkyl. In another aspect, the invention provides a compound of formula (1) wherein Rn is selected from the group consisting of ruthenium and (CVC6) alkyl. In another aspect, The invention provides a compound of the formula (1), wherein r1 1 is (C^Cd alkyl. In one aspect, the invention provides a compound of the formula (1) wherein R 〇 and R11 together with the nitrogen atom to which they are attached form 5 members Up to 6 members containing N rings, the N ring containing optionally containing another hetero atom selected from n, 〇 and s, and optionally Substituted by 1 or 2 substituents independently selected from the group consisting of (C丨_C6)alkyl, (Ci_c6)alkoxy, halo, CN and hydroxy, the n-containing ring may also be fused to the aryl group as appropriate. In another aspect, the invention provides a compound of formula (I), wherein R 0 and R 11 together with the nitrogen atom to which they are attached form a 5- to 6-membered N-containing ring, the N-containing ring optionally being oxime or 2 Substituted (Ci_c6) alkyl substituents. 151651. Doc • 22· 201121961 In one aspect, the invention provides a compound of formula (I) wherein R8 and R together with the atom to which they are attached form a saturated or partially unsaturated member to 6 members containing an N ring, the inclusion The N ring optionally contains another hetero atom selected from N, oxime and § and optionally, on the carbon, i or 2 independently selected from alkyl, (c丨-Co alkoxy, halo, CN and hydroxy) In another aspect, the present invention provides a compound of the formula (1) wherein the uldent 8 and hydrazine together with the atom to which they are attached form a saturated 5 member to the oxime containing N ring, which is optionally in the carbon The above is substituted with hydrazine or 2 (Ci_C6) alkyl substituents. In one aspect, the invention provides a compound of formula (1) wherein R9 is absent and 118 and 11]() together with the atoms to which they are attached form 5 Member, 6 member, 9 member or 10 member of a monocyclic or bicyclic ring containing an N-aryl ring, the N-containing ring optionally containing another hetero atom selected from N, hydrazine and s, and optionally on the carbon, 2 or Substituent substitutions of three substituents independently selected from (C-C6)alkyl, (c丨-C6)alkoxy, halo, CN, aryl, COOR15 and hydroxy. In another aspect, the invention provides a compound of formula (1) wherein R9 is absent and R and R1G, together with the atom to which they are attached, form a 5-, 6-, 9- or 1-membered monocyclic or bicyclic ring. The aromatic ring, the N-containing ring optionally, on the carbon, is independently selected from (C丨-c:6)alkyl, (C]-C6)alkoxy, II-based, CN, aryl through 1, 2 or 3 Substituting C00Ri5 and a substituent of a hydroxyl group. In another aspect, the invention provides a compound of the following formula (1), wherein the ruler 9 is absent and R8 and R1G may form a 5-member, a 6-member, together with the atom to which they are attached, 9 or 1 member of a monocyclic or bicyclic aromatic ring, the N-containing ring optionally substituted on the carbon by 1 or 2 (CrCd alkyl substituents. In one aspect, the invention provides a compound of formula (I) below . , where the ruler! 2 series 151651. Doc • 23· 201121961 is selected from the group consisting of hydrazine and ((^(:6)alkyl). In another aspect, the invention provides a compound of the following formula (1), wherein rU is Η. In one aspect, the invention provides the following formula (1) A compound wherein rU is selected from the group consisting of hydrazine, (C-C6)alkyl, aryl, heteroaryl, aryl(Ci_C4)alkyl-, and heteroaryl(CVC4)alkyl-. In another aspect The present invention provides a compound of the formula (1) wherein R 3 is selected from the group consisting of anthracene, (C^Ce)alkyl, aryl and aryl (Ci_c4)alkyl-. In another aspect, the invention provides the following A compound of the formula (1), wherein rH is arylalkyl-. In another aspect, the invention provides a compound of the following formula (1), wherein is a ruthenium group. In one aspect, the invention provides a compound of the formula (1), wherein R, One of 2 and R is η and the other of R12 and R丨3 is not H, and the carbon atoms to which the dents 12 and r13 are attached are palmar and have a configuration. In one aspect, 'this The invention provides a compound of the following formula (1), wherein one of R is ruthenium and the other of R丨2 and Rn is not, and the carbon atom to which r12&amp;rU is attached is palm-like and has a phantom configuration. In one aspect, the invention provides a compound of formula (I) wherein R3 is H and the carbon atom to which R3 is attached is palmar and has a configuration, and wherein one of the scales 2 and Rl3 is 1^ The other of the ruthenium 2 and Ru is not ruthenium, and the carbon atom to which R12 and R are attached has a palmarity and has a <1 configuration. In another aspect, the present invention provides a compound of the following formula (1), wherein "For the Η and the carbon atom to which R3 is attached is palmar and has the (8) configuration, and 151651. Doc •24· 201121961 One of R and R is that the other of HaRl2 and Rn is not H, and the carbon atoms to which R12 and R are attached are palmar and have a “and” configuration. The present invention provides a compound of the formula (1) wherein Ra and Rb are independently selected from H, (Ci-Cig)alkyl, (c2-c6)alkenyl, (c3-c丨〇)cycloalkyl, heterocyclic Alkyl, aryl, heteroaryl, aryl (Ci_C4) alkyl, aryl (CVC4) alkenyl-, heteroaryl (CVC4) alkyl-, -S〇2(Cl-C6)alkyl, - S〇2 aryl and -so2 aryl(Cl_c4)alkyl. In another aspect, the invention provides a compound of the following formula (1), wherein the sizing 3 and the R are independently selected from the group consisting of hydrazine, (C丨-C6) alkane (C3-C6)cycloalkyl, heterocycloalkyl, aryl, heteroaryl. In another aspect, the invention provides a compound of formula (I) wherein 113 and R may be attached thereto The atoms together form a saturated or partially unsaturated 4 to 7 member, and the N ring optionally contains another heteroatom selected from the group consisting of N, hydrazine and §, and optionally, independently selected from the group consisting of alkyl groups on the carbon, 1 6) substitution of alkoxy, dentate, CN and hydroxy substituents; The n-containing ring may also be fused to the aryl group as appropriate. In another aspect, the invention provides a compound of formula (I) wherein ... together with σ, together with the attached atom, form a residual or partially unsaturated 5 member The guanidine ring is optionally substituted on the carbon by hydrazine or a (c "c6) alkyl substituent. In another aspect, the invention provides a compound of the following formula (1), wherein the sizing 3 and t are together with The atom of the connection - forming 5 members, 6 members, 9 members or 1 member of the early soil or bicyclic ring containing Ns 3 N square i, the n-containing ring containing another impurity selected from N, Θ and S as early as possible ', D' and depending on the situation on the carbon 1, 2 or 3 independently selected from 151651. Doc -25- 201121961 (Cl_C6) Substituted for the base group, (C1_C6), and the substituent of the hydroxyl group. Halogen, CN, aryl, COOR15 In another embodiment, the present invention provides a compound of formula (I) wherein Ra and R, together with the atom to which they are attached, form a 5 member, 6 member, 9 member or 1 member. The ring or bicyclic ring contains an N-aryl ring which is optionally substituted on the carbon via a (Ci-C6) leukoyl substituent. In one aspect, the invention provides a compound of formula (1) wherein r!4 is hydrazine. In one aspect, the invention provides a compound of formula (1) wherein R15 is deuterium. In one aspect, the invention provides a compound of formula (1) wherein R 6 is hydrazine. In one aspect, the invention provides a compound of formula (I) wherein R17 is selected from the group consisting of an anthracene, a halo group, and a (CVC6) alkyl group. In another aspect, the invention provides a compound of formula (I), wherein R] 7 is selected from the group consisting of hydrazine and (CVCO alkyl. In another aspect, the invention provides a compound of formula (I), wherein Rl7 In one aspect, the invention provides a compound of formula (I) selected from the group consisting of: (R)-2-amino-3-methyl-pentanoic acid {(S)-l-[(2-amine) (R)-l-methyl-pyrrolidine-2-carboxylic acid [(S)-(thiazol-5-ylmethyl)-amine-mercapto]-2-naphthalen-1-yl-ethyl}-decylamine -l_[(2-Amino-thiazolidine-5-ylmethyl)-amine-methylmethyl]-2-(3,4-difluoro-phenyl)-ethyl]-bristamine; (S -N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminecarbamyl]·2·(4_Fluoro- 151651. Doc -26 - 201121961 Phenyl)-ethyl]-2-(isopropyl-methyl-amino)·propanamine; 3-methyl-1H-pyrrole-2-carboxylic acid [(S)-l- [(2-Amino-thiazol-5-ylindenyl)-aminemethylmercapto]-2-(3,4-dichlorophenylethyl]-decylamine; (R) -N-[(S )-l-[(2-Amino-thiazol-5-ylindenyl)-amine-mercapto]-2-(3,4-dioxa-phenyl)-ethyl]-2-hydroxy-3- Phenyl-propionamide; (S)-N-(2-amino-thiazol-5-ylindenyl)-3-naphthalen-1-yl-2-(propane-1-sulfonylamino)-propane Indoleamine; (S)-l-methylpyrrolidine-2-carboxylic acid {(R)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]-2,2 -dicyclohexylethyl}-decylamine; (R)-pyrrolidine-2-furic acid [(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminecarboxamide ]-2·(3,4-difluoro-styl)-ethyl]-decylamine; (R)-2-amino-3-methyl-pentanoic acid [(S)-l-[(2- Amino-thiazol-5-ylindenyl)-aminoindenyl]-2-(3,4-difluoro-phenyl)-ethyl]•decylamine; (R)-3-methyl-2- Amidino-pentanoic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine-methylmethyl]-2-(3,4-difluoro-phenyl)-B (S)-N-[(S)-M(2-amino-thiazol-5-ylindenyl)-aminecarboxylidene]-2-(3,4-difluoro-benzene base -ethyl]-2-dipropylamino-propionamide; (S)-N-[(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminecarbamyl] 2-(3,4-difluoro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propanin; (S)-N-[(S)-l-[( 2-amino-thiazol-5-ylmercapto)-amine-mercapto]-2-(3,4-difluoro-phenyl)-ethyl]-2-diethylamino-propionamide; S)-N-[(S)-W(2-Amino-carbazol-5-ylindenyl)-aminecarbamyl]·2-(3,4.fluoro-phenyl)-ethyl]- 2-diaminoamine-propanin; (R)-N-[(S)-l-[(2-amino-thiazole·5-ylindenyl)-aminecarbamyl]-2-(3 , 4-two 151651. Doc -27- 201121961 Fluorine-(phenyl)-ethyl]-2-diamino-propylamine, (S)-1 -fluorenyl-pyrrol.曱-2-decanoic acid [(S)-l-[(2-amino-°C. sit-5-ylmethyl)_amine aryl]-2-(3,4-di-phenyl-phenyl )-ethyl]-bristamine, (R)-l-ethylpyrrolidine·2-decanoic acid [(S)-l-[(2-amino-thiazol-5-ylindenyl)-amine oxime] Styrene]-2-(3,4·di-phenyl)ethyl]-bristamine, (R)-l-isopropyl-pyrrolidine-2-carboxylic acid [(S)-l-[( 2-Amino-thiazol-5-ylmercapto)-amine-mercapto]-2-(3,4-di-phenyl)-ethyl]-bristamine, (R)-l-isopropyl - ϋ ϋ 曱 曱 曱 曱 [ [ ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( -Phenyl)ethyl]-bristamine; (R) -1 -methyl-brigade.曱-2-decanoic acid [(S)-l-[(2-amino- σ ϋ ϋ -5-5-ylmethyl)-amine fluorenyl]-2-(3,4-difluoro-phenyl )-ethyl]•decalamine; (S) -1 - thiol-bred. Benzene-2-carboxylic acid [(S)-l-[(2-amino-sale.sodium-5-ylmethyl)-amine oxime]-2-(3,4-di-phenyl)- Ethyl]-bristamine, (11)-^[-[(8)-1-[(2-amino-thiazol-5-ylmethyl)-amineindolyl]-2-(3,4- Di-(phenyl)-ethyl]-2-dimethylamino-3-phenyl-acrylamide, (8)-^[-[(8)-1-[(2-amino-thiazole- 5-ylmethyl)-aminoindenyl]-2-(3,4-dioxa-phenyl)-ethyl]-2-dimethylamino-3-phenyl-propanol, (S) -N-[(S)-l-[(2-Amino-° 塞 坐-5-ylmethyl)-amine aryl]-2-(3,4-di-subunit)·B Base]-2 - slightly bite · 1-yl-propanol, (R) -N-[(S)-l-[(2-amino-°-sodium.sodium-5-ylmethyl)-amine A Brewed base]·2-(3,4-di-f-yl)-ethyl]· 2 - slightly. _ 1 -yl-propylamine, (S) -N-(2-amino-°°°-5-ylmethyl)-3·(3,4-di-phenyl)-2- (2-diisopropylamino-acetamido)-propionamine; (S)-N-(2.Amino-0-Syttrium-5-ylmethyl)-3-(3,4-di Defeat - Benki)-2-[2_ 151651. Doc -28 - 201121961 (2,6-Dimethyl-piperidin-1-yl)-acetamido]-propanamide; (R) -l-nonylpyrrolidine-2-carboxylic acid [(S )-l-[(2-Amino-thiazol-5-ylmethyl)-amine-mercapto]-2-(4-disorgano-phenyl)-ethyl]-bristamine, (S)-N- [(S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminemethylmercapto]-2-(4-fluoro-phenyl)-ethyl]-2-didecylamino -propanolamine; (S)-N-[(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminemethylmercapto]-2-(4-fluoro-phenyl) -ethyl]-2-diethylamino-propionamide; (S)-N-[(S)-l-[(2-Amino-α-supept-5-ylmethyl)-amine ]]-2-(4-carbo-phenyl)-ethyl]-2 - brigade-1 ·yl-propanoid amine, (11)-:^-[(8)-1-[(2-amine Base-thiazole-5-ylmethyl)-aminoindenyl]-2-(4-fluoro-styl)-ethyl]-2 -^. Ding-1 -yl-propanol, (S)-N-(2-amino-° plug. sit-5-ylindenyl)-2-[2-(2,6-dimercapto-branches bite -_基)-Ethylamino]-3-(4-dis-phenyl)-propanol, (R)-l-decyl-pyrrolidine-2-decanoic acid [(S)-l-[ (2-Amino-thiazol-5-ylmethyl)-amine-mercapto]-2-(3-disorgano-phenyl)-ethyl]-bristamine, (S)-N-[(S)- L-[(2-Amino-thiazol-5-ylmethyl)-aminecarbamimidyl]-2·(3-fluoro-phenyl)-ethyl]-2-(isopropyl-indenyl-amine ())-Acetylamine, (S)-N-[(S)-l-[(2-amino-thiazol-5-ylindenyl)-amine-methylmethyl]-2-(3-fluoro-benzene ()-N-[(S)-l-[(2-amino-thiazol-5-ylindenyl)-amine oxime] 2-(3-fluoro-phenyl)-ethyl]-2-diethylamino-propionamide; (S)-N-[(S)-l-[(2-amino-thiazole) -5-ylmethyl)-aminoindenyl]-2-(3-fluoro-phenyl)-ethyl]-2-pyro-l-yl-propylamine, (R)-N-[( S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminecarboxylidene]-2-(3-fluoro-151651. Doc -29- 201121961 Phenyl)-ethyl]-2-piperidin-1-yl-propionamide; (R) -l-methyl-0-pyridin-2-indole [(S)-l -[(2-Amino-thiazol-5-ylmethyl)-amine aryl]-2-(2-fluoro-phenyl)-ethyl]-bristamine, (S) -N-[(S )-l-[(2-Amino-oxazol-5-ylmethyl)-amine-mercapto]-2-(2-fluoro-phenyl)-ethyl]_2-(isopropyl-methyl -amino)-propanol fer ' (R) -l-fluorenyl-pyrrolidine-2-furic acid {(S)-l-[(2_amino-thiazol-5-ylmethyl)-amine oxime (2-)-N-{(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine oxime Indenyl]-2-naphthalen-1-yl-ethyl}-2-(isopropyl-indolyl-amino)-propanin; (S)-N-{(S)-l-[(2 -amino-thiazol-5-ylindenyl)-amine-mercapto]-2-naphthalen-1-yl-ethyl}-2.diethylamino-propionamide; (3)-:^-{ (3)-1-[(2-Amino-thiazol-5-ylmethyl)-amine-methylmethyl]-2-naphthalen-1-yl-ethyl}-2-piperidin-1-yl-propane Indoleamine; (R) -N-{(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminecarbamyl]-2-naphthalen-1-yl-ethyl}- 2-piperidin-1-yl-propanamide; (S) -N-{(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]-2- Naphthalen-1-yl-ethyl}-2-didecylamino-3- stupid -propanolamine; (R) -l-decyl-pyrrolidine-2-decanoic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminocarboxylidene]- 2-(4-Chloro-phenyl)-ethyl]-decylamine; (S) -N-[(S)-l-[(2-Amino-thiazol-5-ylindenyl)-amine oxime 2-(4-chloro-phenyl)-ethyl]-2-(isopropyl-indolyl-amino)-propanamine; (R)-l-methyl-pyrrolidin-2- Formic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine-mercapto]-2-(3-a-phenyl)ethyl]-decylamine; (S -N-[(S)-l-[(2-Amino-thiazol-5-ylindenyl)-aminecarbamyl]-2-(3-gas·151651. Doc •30- 201121961 Phenyl)-ethyl]-2_(isopropyl-methyl-amino)-propanamide; (S)-N-[(S)-l-[(2-Amino- Thiazol-5-ylmethyl)-aminecarbamido]-2-(3-chloro-phenyl)-ethyl]-2-didecylamino-propionamide; (S)-N-[(S )-l-[(2-Amino-thiazol-5-ylindenyl)-amine-mercapto]-2-(3-chloro-phenyl)-ethyl]-2-diethylamino-propionium Amine; (S)-N-[(S) small [(2-aminopyrazole-5-ylmethyl)-aminecarbamyl]-2_(3-a-phenyl)-ethyl]-2 -piperidin-1-yl-propanamide; (R)-N-[(S)-l-[(2-aminostazole-5-ylindenyl)-amine-methylmethyl] fluorene 3-chloro- Stable base)-ethyl]-2-piperidin-1-yl-propanamide; (R)-l-methyl-0-pyridin-2-indole [(S)-l-[(2- Amino-thiazole-5-ylmethyl)-aminoindenyl]-2-(3,4-di-phenyl)-ethyl]-decylamine; (S)-N-[(S)- L-[(2-Amino-oxazol-5-ylmethyl)-amine-mercapto]-2-(3,4-dioxa-phenyl)-ethyl]_2-(isopropyl-oxime -Amino)-propionamine '(S)-N-[(S)-Bu[(2-amino].-propazol-5-ylmethyl)-aminomethylindenyl]_2-(3, 4-dioxa-phenyl)-ethyl]-2-diguanylamino-propanamine; (S)-N-[(S)-l-[(2-amino-azol-5-yl) Mercapto)-aminomercapto]-2-( 3,4_di-phenyl)-ethyl]-2-diethylamino-propionamide; (S)-N-[(S)-l-[(2-amino------- -(indenyl)-amine-methylmercapto 2-(3,4-di-phenyl)-ethyl]-2-piperidin-1-yl-propanamide; (R) -N-[( S)-l-[(2-Amino-oxazol-5-ylmethyl)-amine-methylmethyl]_2_(3,4·di-phenyl)-ethyl]-2-α bottom bite_ 1_yl-propionamide, (S)-N-{(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminoindenyl]_2·p-phenylene-B }}-2-(isopropyl-methyl-amino)-propanin; (R)-l-decyl-pyrrolidine-2-furic acid {(S)-l-[(2-amino group) -thiazole_5_ylmethyl) 151651. Doc •31 - 201121961 Aminomethyl]-2-p-phenylene-ethyl}-decylamine; (R)-l-methyl-pyrrolidine-2-carboxylic acid {(S)-l-[(2 -amino-thiazol-5-ylmethyl)-amine-mercapto]-2-m-tolyl-ethyl}-decylamine; (3)-1^-{(5)-1-[(2- Amino-thiazol-5-ylmethyl)-amine-carbamoyl]-2-m-phenylphenyl-ethyl}-2-(isopropyl-indolyl-amino)-propanin; (R) -l-methyl-pyrrolidine-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminoindolyl]-2-o-tolyl-ethyl} - guanamine; (S) -N-{(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]-2-o-tolyl-ethyl}-2 -(isopropyl-methyl-amino)-propanin; (R)-pyrrolidine-2-furic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl) -(amino)-cyclohexyl-ethyl}-decylamine; (R)-methyl-pyrrolidine-2-carboxylic acid {(S)-l-[(2-amino-sigh. sitting_5 -ylmethyl)-aminocarbamido]-2-cyclohexylethyl}-guanamine; (S)-l-methylpyrrolidine-2-carboxylic acid {(S)-l-[(2- Amino-based. Sodium 5-ylmethyl)-aminoindenyl]-2-cyclohexyl-ethyl}-decylamine; (S)-N-{(S)-l-[(2-Amino) -thiazol-5-ylmethyl)-amine-methyl hydrazino]_2- tributyl-ethyl}-2-(iso (M)-Amino-amino)·propanamine; (S)-N-{(S)-l-[(2-Amino-thiazol-5-ylindenyl)-amine-methylpyridyl 2_%-hexyl -ethyl}-2-dimethylamino-propionamide; (S)-N-{(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine-methyl sulfonyl 2-% hexyl-ethyldiethylamino-propanol' (R)-l-ethyl than singly-carboxylic acid {(S)-l-[(2-Amino-°°°°- 5-ylmethyl)-aminocarbamimido]-2-cyclohexyl-ethyldoximine; (R)-l-isopropyl-0- 0 each _2-formic acid {(S)-l -[(2-Amino-plug sitting 5 soil 151651. Doc • 32· 201121961 base)-amine-mercapto]-2-cyclohexyl-ethyl decylamine; (R) -l-methyl-piperidine-2-carboxylic acid {(S)-l-[(2- Amino-thiazol-5-ylmethyl)-aminecarbamido]-2-cyclohexyl-ethyl}-decylamine; (S)-N-{(S)-l-[(2-amino- Thiazol-5-ylindenyl)-aminoindenyl]-2-cyclohexyl-ethyl}- 2 - Nichinin-1 · yl-propylamine, (R) -N-{(S)-l- [(2. Amino-.sup.su-5-ylmethyl)-amine oxime]-2-cyclohexyl-ethyl} - 2 - slightly. Des- 1 -yl-propenolamine, 3-mercapto-1 - 0 - 嘻-2 - formic acid {(S)-l-[(2-amino-. seloxime-5-ylindenyl)- Aminomethyl]-2-n-yl-ethyl}-bristamine, 1H-indole-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl) )-Aminomethylindenyl]-2 -na-1-yl-ethyl}-bristamine, (S)-N-(2-amino-thiazol-5-ylindenyl)-3-naphthalene-1- 2-(2-m-phenylphenyl-acetamido)-propanamine; 3,5-dimethyl-111-pyrrole-2-carboxylic acid [(8)-1-[(2-amino) -thiazol-5-ylmethyl)&quot;amine aryl]-2-(3,4-di-phenyl)-ethyl]-bristamine, 3·mercapto-1H·pyrrole-2-carboxylic acid [(S)-l-[(2.Amino-thiazol-5-ylmethyl)-amine methyl]-2-(3,4·di-phenyl)-ethyl]-bristamine, 1H-indole-2-decanoic acid [(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminecarboxyl]-2-(3,4-dimer-phenyl) )-ethyl]-bristamine, 3-methyl-1H-pyrrole-2-decanoic acid [(S)-l-[(2-amino-thiazol-5-ylindenyl)-amine] -2-(4-fluoro-phenyl)-ethyl]-chiral amine, 3-mercapto-1H-pyrrole-2-indoleic acid [(S)-l-[(2-amino-thiazole-5- Methyl)-amine-mercapto]-2-(3- gas phenyl)-ethyl]•-bristamine, 3-mercapto-1H-pyrrole-2· Acid [(S) -l - [(2- amino - thiazol-5-yl Yue-yl) - amine I51651. Doc -33· 201121961 甲基基]-2-(2- gas-phenyl)-ethyl]-bristamine, 3-methyl-1H-. Bile-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminecarboxy]-2-(4-a-phenyl)-ethyl]- Indoleamine; 3-mercapto-1H-pyrrole-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylindenyl)-amine-mercapto]-2-(3- gas -phenyl)-ethyl]-guanamine; 3-methyl-1H-pyrrole-2-furic acid {(S)-l-[(2-amino-thiazol-5-ylindenyl)-amine A Mercapto]-2-p-tolyl-ethyl}-decylamine; 3-mercapto-1H-pyrrole-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylfluorenyl) )-aminomercapto]-2-m-tolyl-ethyl}-decylamine; 3-mercapto-1H-pyrrole-2-decanoic acid {(S)-l-[(2-amino-thiazole- 5-(indenyl)-aminomethylindenyl]-2-o-tolyl-ethyl}-decylamine; 3-methyl-1H-pyrrole-2-carboxylic acid {(S)-l-[(2-amine) (R)-N-{(S)-l-[(2-Amino-.-)-(yl)-yl]-cyclohexyl-ethyl}-decylamine;塞.Sodium-5-ylmethyl)-amine ketone]-2-n-l-yl-ethyl}_ 2-trans--3-phenyl-propanol, (11)-^[-[ (8)-1-[(2-Amino-thiazol-5-ylmethyl)-amineindolyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-hydroxy- 3-phenyl-propionamide; (R)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]-2-(4-fluoro - Phenyl)-ethyl]-2-yl-amino-3-phenyl-propanol, (R)-N-[(S)-l-[(2-amino-thiazol-5-ylindenyl) -aminomercapto]-2-(3-fluoro-phenyl)-ethyl]-2-hydroxy-3-phenyl-propanamine; (R)-N-[(S)-l-[( 2-amino-thiazol-5-ylindenyl)-amine-methylcarbonyl]-2-(2-fluoro-phenyl)-ethyl]-2-hydroxy-3-phenyl-propanamine; )-N-[(S)-l-[(2-Amino-α-e-sodium-5-ylmethyl)-amine oxime]-2-(4-gas _ 151651. Doc -34- 201121961 Phenyl)-ethyl]-2-yl-3-phenyl-propionamide; (R)-N-[(S)-l-[(2-amino-thiazole-5) -ylmethyl)-aminemethanyl;|_2_(3_qi_phenyl)-ethyl]-2-yl-3-phenyl-propanamine; (11)-:^-{(8 1-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]_2-p-phenyl-ethyl}-2-yl-3-phenyl-propionamide; (R)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-amine fluorenyl]_2-m-tolyl-ethyl}-2_ylamino-3 -phenyl-propanamide; (R)-N-{(S)-M(2-amino-thiazol-5-ylmethyl)-aminecarbamyl]_2-o-tolyl-ethyl}- 2_Phenylphenyl-propanol; (R)-N-{(S)-Bu[(2-Amino-thiazol-5-ylmethyl)-aminecarbamyl]_2_cyclohexyl-B (R)-N-{(S)-Bu[(2-amino-thiazol-5-ylmethyl)-aminecarboxylidene]·2_ Cai Xiaoji-ethyl}-2-hydroxy-butanamine; (R)-N-{(S)-l-[(2-Amino-°°°-5-ylindenyl)-amine broth ]―之-蔡心基-ethyl}-2-hydroxy-3-indolyl-butanamine; (S) -N-{(S)-l-[(2-amino-thiazol-5-ylmethyl) )-Aminomercapto]_2_naphthalene·^-ethyl}-2-hydroxy-3-indolyl-butanamine; (R) -N-[(S)-l-[(2- Aminopyrazole-5-ylmethyl)-amine-mercapto]_2_(34-difluoro-phenyl)-ethyl]-2-hydroxy-3-methyl-butanamine; (S) _N- [(S)-l-[(2-Amino-indolazole-5-ylindenyl)-aminoindenyl]_2_(3,4-difluoro-phenyl)-ethyl]-2-hydroxy- 3-mercapto-butylamine; and its tautomers, stereoisomers, pharmaceutically acceptable salts and solvates. In another aspect, the invention provides a compound of formula (1) selected from the group consisting of: 151651. Doc -35- 201121961 (S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminecarbamyl]-2_(4-fluoro-phenyl)- Ethyl]-2-(isopropyl-methyl-amino)-propanin; (R)-3-methyl-2-methylamino-pentanoic acid [(S)-l-[(2- Amino-thiazol-5-ylmethyl)-amine hydrazino]-2-(3,4-difluoro-phenylethyl sulfonamide; (8)-1^-[(8)-1- [(2-Amino- oxazole-5-ylmethyl)-amine-mercapto]-2-(3,4-difluoro-phenyl)-ethyl]-2-(isopropyl-fluorenyl) -amino)-propionamine; (R)-l-ethyl-0-pyridin-2-carboxylic acid [(s)-l-[(2-amino-thiazole·5-ylmethyl)_ Amidino]-2-(3,4-difluoro-phenyl;)-ethyl]-decylamine; (R)-l-isopropyl-pyrrolidine-2-carboxylic acid [(S)-l -[(2-Amino-thiazole-5-ylmethyl)-aminoindenyl]-2-(3,4-difluoro-phenyl)-ethyl]-decylamine; (R)-l- Methyl-piperidine-2-furoic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]-2-(3,4-difluoro-stupid (R) -l-methyl-0pyrrolidine-2-decanoic acid [(S)-l-[(2-amino-thiazole-5-ylmethyl) _ Aminomethyl hydrazino]-2-(4-fluoro-styl)-ethyl] decylamine; (S) -N-{(S)-l-[(2-Amino-thiazol-5-yl) Indenyl)-aminoindenyl]-2-naphthalen-1·yl- }}-2-(isopropyl-methyl-amino)-propanin; (R)-l-nonylpyrrolidine-2-decanoic acid [(S)-l-[(2-amino) -thiazol-5-ylmethyl)-aminocarboxylidene-2-(4-chloro-phenylethyl)-guanamine; (S)-N-[(S)-l-[(2-amine -oxazol-5-ylindenyl)-aminoindenyl]-2-(4-a-phenyl)-ethyl]-2-(isopropyl-indolyl-amino)-propanamide (R) -l-decyl-pyrrolidine-2-decanoic acid [(S)-l-[(2-amino-thiazole-5-methylmethylcarbamyl 1-2-(3- gas -phenylethyl]-nonylamine; (S) -N-[(S)-l-[(2-amino-thiazolylmethyl)-aminoindenyl]-2-(3-chloro-benzene Base)-ethyl]-2-(isopropyl-indolyl-amino)-propanamide; 151651. Doc -36- 201121961 (R) -l-Mercapto-pyrrolidine-2-furic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)aminemethanyl]-2_ (3,4-dichloro-phenyl)·ethyl]-decylamine; (S)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine A Mercapto]-2-(3,4,diox-phenyl)ethyl]-2-(isopropyl-methyl-amino)-propanamine; (S)-N-[(S) -l-[(2-Amino-thiazol-5-ylmethyl)-amine fluorenyl]-2-(3,4-monochloro-phenyl)-ethyl]·2·diethylamino-propyl Indoleamine; (S)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarboxylidene]-2-(3/- ~ gas-phenyl) -ethyl]-2-piperidine-1·yl-propionamide; (8)-&gt;1-{(8)-1-[(2-amino-thiazol-5-ylindenyl)-amine曱醯基]-2-东十甲基基-ethyl}-2-(isopropyl-indolyl-amino)-propanamine; (S)-N-{(S)-l-[(2- Amino-thiazol-5-ylindenyl)-amine-mercapto]_2-m-m-mentyl-ethyl}-2-(isopropyl-methyl-amino)-propanol; (S)- N-{(S)-l-[(2-Amino-thiazol-5-ylindenyl)-aminecarbenyl]cyclohexyl-ethyl}-2-(isopropyl-methyl-amino) _ propylamine; (R)-l-decyl-piperidine-2- decanoic acid {(S)-l-[(2-amino-thiazole·5-ylindenyl)-amine fluorenyl]- 2 -cyclohexyl-ethyl}-decylamine; and tautomers, stereoisomers thereof - pharmaceutically acceptable salts and solvates. Those skilled in the art will recognize that each of the compounds identified in the examples identified above or hereinafter provided, in any combination, alone or in combination with other identified compounds, represent an independent aspect of the invention. Therapeutic Applications As mentioned previously, there are a variety of therapeutic applications. The compounds of the present invention are particularly useful for the treatment of inflammatory diseases such as asthma 151651 because of their ability to suppress (1). Doc -37- 201121961 and COPD. In particular, the compounds of the present invention are useful in the treatment of avian respiratory conditions involving airway inflammation such as asthma (allergic and non-allergic), including exacerbations caused by asthma and chronic obstructive pulmonary disease (COPD). These compounds can also be used to treat other forms of allergic inflammation, including allergic rhinitis (hay fever), nasal conjunctivitis, rhinorrhea, urticaria, excessive production of pulmonary mucus, formation of ascites, chronic bronchitis, chronic airway obstruction, and lungs. Fibrosis and emphysema. Other inflammatory conditions which may be treated by the compounds of the invention include polymorphism, arthritis, rheumatoid arthritis, osteopathic arthritis, osteoarthritis, rhinitis, sinusitis, inflammatory bowel disease ( Such as Crohn's disease and ulcerative colitis, immune-mediated diabetes, acute pancreatitis and interstitial cystitis, thermal injury, crush, conjunctivitis, periodontal disease, chronic prostatitis, Chronic recurrent mumps, inflammatory skin conditions (eg psoriasis, eczema), cirrhosis, spinal trauma and SIRS (systemic inflammatory response syndrome); smooth muscle spasms (eg asthma, angina), RDS (respiratory distress syndrome); Hypotension (eg shock caused by hemorrhage, sepsis or systemic allergic reactions, cancer-like episodes, edema of gastric dumpings (eg burns, brain trauma, angioedema (whether or not inhibited by angiotensin converting enzyme) Caused by treatment)).  Pain and irritation (eg burns, wounds, scalpels, skin treatments, stab wounds, insect bites), migraine; male contraceptives produced by inhibition of prostate kallikrein; prevention of excessive blood loss during surgical procedures. The compounds of the invention may also be used to treat 151651 which may be for the release of inflamed mediators. Doc •38· 201121961 Reaction to illness (eg cough). The compounds of the invention are also useful in the treatment of conditions involving modulation of growth factors, such as vascular endothelial growth factor (VEGF), which may involve increased vascular permeability (e.g., diabetic retinopathy and septic shock). The compounds of the invention are useful in the treatment of neoplastic conditions (e.g., metastatic pancreatic adenocarcinoma, tumor angiogenesis). In particular, they can be used to reduce angiogenesis associated with neoplasms (e.g., cancer and tumor growth) and to modulate angiogenesis. And other processes associated with neoplasia and tumor growth, and in particular, can be used to block tumor angiogenesis and/or cancer cell invasion and metastasis. Asthma Asthma is a chronic lung condition that can be classified as allergic (endogenous) or non-allergic (exogenous). Patients with asthma suffer from difficulty breathing due to stenosis or obstruction of the trachea, making it difficult to inhale and exhale air. This stenosis can be caused by tracheal inflammation and bronchoconstriction. Symptoms of asthma include, for example, wheezing, shortness of breath, bronchoconstriction, tracheal overreaction, decreased lung capacity, fibrosis, tracheal inflammation, and mucus production. Another symptom of asthma is the deterioration caused by the onset of initial asthma, which has a significant incidence of rickets in the disease. KLK1 inhibitors can be used to ameliorate or prevent at least one symptom of asthma. KLK1 inhibitors may also be combined with another agent for the treatment of asthma (eg, inhaled steroids, oral steroids, long-acting beta agonists, leukotriene modifiers, cromolyn s〇dium, and nedocromil (ned 〇cr〇mil), theophylline and anti-igE antibody (see below) were administered together. Allergic rhinitis Allergic rhinitis or "wild grass fever" involves 151651 from grass, trees and weeds. Doc -39· 201121961 Allergic reaction to pollen. When an individual suffering from allergic rhinitis inhales pollen, it triggers antibody production and histamine release. Symptoms of allergic rhinitis include (but are not limited to) coughing; headache; itching of the eyes, mouth, throat or nose; sneezing 嗓 'nasal congestion; wheezing; sore throat; and tearing. Symptoms associated with hay fever are significantly different between different people, and allergic rhinitis can be associated with other conditions such as asthma. Chronic Obstructive Pulmonary Disease (COPD) Chronic Obstructive Pulmonary Disease (COPD) is a disease involving airway inflammation. Emphysema and chronic bronchitis belong to C〇Pd. It is a severe lung disease and is progressive&apos; usually present in elderly patients. COPD causes excessive inflation of the structure called lung/bag or balloon in the lung. A ruptured alveolar wall causes a decrease in lung respiration. Patients with this disease can first experience shortness of breath and cough. KLK1 inhibitors can be used to ameliorate at least one symptom of c〇pD. KLK1 inhibitors may also be combined with another agent for the treatment of COPD (eg, inhaled steroids, oral steroids, long-acting beta-agonists, leukotriene modifiers, sodium cromoglycate and nedocromil, tea and anti-IgE antibodies) (see below) to vote together. Coughing Cough can be caused by inflammation of the upper respiratory tract (throat and trachea) caused by viral infection. Viral infections include the common cold, influenza, laryngitis and bronchitis. These viral infections can also cause coughing in the lower respiratory tract (bronchial tubes). Cough is a symptom of various diseases and conditions including asthma, bronchitis, influenza, and whooping cough/pertussis, and can also be produced as a side effect of using certain drugs such as ACE inhibitors. Smoking individuals often have a cough in a smoker, which often causes a loud sputum exhalation 151651. Doc •40· 201121961 Cough. KLK1 inhibitors can be used to ameliorate or prevent at least one coughing symptom. Deterioration Caused by Asthma and Chronic Obstructive Pulmonary Disease (COPD) Individuals with asthma and C Ο P D are at risk of exacerbation when their lungs and trachea begin to overreact to certain substances that trigger these morbidities. During the deterioration, the tracheal inner liner suddenly swells and becomes inflamed. The muscles of these trachea will become tense and the production of mucus will increase. This combination makes the opening narrower and may almost completely close it, making breathing difficult. The worsening rickets rate is significant and causes a disproportionate amount of asthma management costs, which often persist for at least a month after progression. Current treatment strategies for acute exacerbation of asthma are largely dependent on bronchodilators and inhaled or systemic corticosteroids. KLK1 inhibitors can be used to ameliorate or prevent at least one of the worsening symptoms. KLK1 inhibitors may also be combined with another agent that treats exacerbations caused by asthma and COPD (eg, inhaled steroids, oral steroids, long-acting beta-agonists, leukotriene modifiers, sodium cromoglycate and nedocromil, tea) Base and anti-IgE antibodies) (see below) - from the cast. Pancreatitis Acute pancreatitis - inflammation develops rapidly within a few hours and usually heals without leaving permanent damage, but with current complications, it can be fatal (5% of cases). Chronic pancreatitis - This condition usually begins with multiple episodes of acute pancreatitis and eventually becomes a permanent condition. The pancreas continues to be inflamed. KLK1 inhibitors can be used to ameliorate or prevent at least one pancreatic inflammation. Rheumatoid arthritis (RA) 151651. Doc -41 - 201121961 This condition is characterized by inflammation of the inner lining of joints and/or other internal organs. It is usually chronic but can include bursts. Symptoms include joint inflammation, swelling, difficulty moving, pain, and fever. KLK1 inhibitors can be used to ameliorate or prevent at least one symptom of rheumatoid arthritis. KLK1 inhibitors can be combined with another agent for the treatment of rheumatoid arthritis (such as NSAID and aspirin, analgesics and corticosteroids). Another agent helps to relieve joint pain and stiffness. Osteoarthritis Osteoarthritis is a degenerative joint disease characterized by rupture of articular cartilage, which causes bones to rub against each other', causing pain and loss of exercise capacity. KLK1 inhibitors can be used to ameliorate or prevent at least one symptom of osteoarthritis The KLK1 inhibitor can be administered in combination with another agent for treating rheumatoid arthritis, such as a corticosteroid or an NSAID. Angiogenesis-related and neoplastic disorders In one embodiment, a KLK1 inhibitor can be administered to an individual. Other processes that regulate angiogenesis or are associated with neoplasia and tumor growth. For example, KLK1 inhibitors can be used to reduce angiogenesis (eg, uncontrolled or undesirable angiogenesis), such as angiogenesis associated with: vascular malformations and Cardiovascular disorders (such as atherosclerosis, restenosis, and arteriovenous malformations), chronic inflammatory diseases (such as sugar) Urine, inflammatory bowel disease, psoriasis and rheumatoid arthritis), skin disorders (such as arterial ulcers, systemic vasculitis and scleroderma) or ocular disorders (eg blindness, neonatal due to neovascular diseases) Vascular glaucoma, corneal neovascularization, trachoma, diabetic retinopathy, and myopia degeneration. 151651. Doc-42- 201121961 In particular, KLK1 inhibitors can be used to reduce ash tube formation associated with neoplasia, such as cancer and tumor growth, such as benign, malignant or metastatic tumor growth. Examples of cancerous conditions include, but are not limited to, solid tumors, soft tissue tumors, and metastatic lesions. Examples include sarcoma, adenocarcinoma, and carcinoma of various organ systems, such as invasive lung, breast, lymph, gastrointestinal (eg, colon) and genitourinary tract (eg, renal urinary tract epithelial cells), pharyngeal, prostate, ovarian sarcoma, adenocarcinoma and Cancer, and adenocarcinoma including malignant diseases such as most colon cancer, rectal cancer, renal cell carcinoma, liver cancer, non-small cell lung cancer, pharyngeal cancer, small intestine cancer, esophageal cancer, and other cancers. Exemplary solid tumors that can be treated include: fibrosarcoma, mucinous sarcoma, liposarcoma, chondrosarcoma 'osteogenic sarcoma, chordoma, lymphatic angioendotheliosarcoma, synovial tumor, mesothelioma, Ewing's tumor (Ewing's) Tumour), leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, papillary gland Cancer, cystadenocarcinoma, myeloid carcinoma, bronchial carcinoma, renal cell carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, cervical cancer, testicular tumor, lung cancer, small cell lung cancer Cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, neural tube blastoma, craniopharyngioma, ependymoma, pineal adenoma, hemangioblastoma, acoustic neuroma, oligodendrocyte Glioma, meningioma, melanoma, neuroblastoma, and retinoblastoma. KLK1 inhibitors can also be used to treat cancers, such as the epithelial or endocrine group 151651. Doc -43- 201121961 The malignant disease of the woven disease includes respiratory cancer, gastrointestinal cancer, genitourinary cancer and melanoma. Exemplary cancers include adenocarcinomas and carcinomas of the cervix, lung, prostate, breast, head and neck, colon and ovarian tissue. KLK1 inhibitors can also be used to treat sarcomas, such as mesenchymal malignancies. The KLK1 inhibitor can be administered in combination with another agent for treating a neoplastic and/or metastatic disorder. Examples of such other agents include: (1) other anti-angiogenic agents (e.g., lin〇mide, angiostatin, razoxane); (11) cytostatic agents , such as anti-estrogen agents (such as tamoxifan, toremifene, raloxifene), progesterone (such as megestr〇l acetate), Aromatase inhibitors (eg, anastroz〇ie, lysine, sittroz〇ie), antiprogestin, antiandrogen (eg flurtanide, nilutamide) Nilutamide), bicalutamide, anti-invasive agents (eg metalloproteinase inhibitors (such as marimastat) and urokinase plasminogen activator receptor function inhibitors). (iii) anti-proliferative/anti-neoplastic drugs and combinations thereof used in medical oncology such as antimetabolites (eg, fluoropyrimidines such as 5-fluorouracil, purine and adenosine analogs, and cytotoxins) Cytosine arabinoside; embedded anti-tumor antibiotics (eg anthracycline, such as doxorubicin, daunomycin, epirubicin); platinum derivatives (eg cisplatin, carboplatin); alkylating agents (eg phenylbutyric acid 151651. Doc -44· 201121961 chlorambucil, cyclophosphamide; anti-mitotic agents (eg vinca alkaloid, such as vincristine; and taxoid) Such as TAXOL® (paclitaxel), TAXOTERE® (docetaxel); topoisomerase inhibitors (eg epipodophyllotoxin, such as etoposide and teniposide) Teniposide; and proteasome inhibitors such as VELCADE® (bortezomib). Thus the invention provides a compound of formula (I) for use in therapy. The invention also provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention of a disease or condition involving KLK1 activity. Diseases or conditions involving KLK1 activity include inflammation, respiratory disorders, conditions involving the regulation of growth factors, and neoplastic disorders. Specific examples of such diseases and conditions include those listed above. The invention also provides a compound of formula (I) for use in the treatment or prevention of a disease or condition involving KLK1 activity. Diseases or conditions involving KLK1 activity include inflammatory diseases, respiratory conditions, conditions involving the regulation of growth factors, and neoplastic diseases. Specific examples of such diseases and conditions include those listed above. The invention also provides a method of treating a disease or condition involving KLK1 activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (1). Diseases or conditions involving KLK1 activity include inflammation, respiratory diseases, conditions involving the regulation of growth factors, and neoplastic disorders. Specific examples of such diseases and conditions include those listed above. In one aspect, the disease or condition involving KLK1 activity is selected from an inflammatory or respiratory condition or condition selected from asthma (allergic and non-allergic 151651. Doc -45- 201121961), chronic obstructive pulmonary disease (COPD), allergic rhinitis (hay fever), cough, deterioration caused by asthma and chronic obstructive pulmonary disease (C0PD) 'multiple sclerosis, arthritis, rheumatoid Arthritis, osteoarthritis, osteoarthritis I &amp; sinus, inflammatory bowel disease (such as Crohn's disease and ulcer I, raw, enteritis) immune-mediated diabetes, acute otitis and Interstitial cystitis, conjunctivitis, periodontal palsy, chronic prostatitis, chronic recurrent mumps, inflammatory skin conditions (eg psoriasis, eczema) &amp; SIRs (systemic inflammatory response syndrome); smooth muscle spasms (eg asthma, Angina), RDS (respiratory distress syndrome), rhinoconjunctivitis, rhinorrhea, urticaria, neoplastics, chronic bronchitis, chronic airway obstruction, pulmonary fibrosis, and emphysema. In another aspect, the disease or condition involving KLK1 activity is selected from the group consisting of asthma (allergic and non-allergic), chronic obstructive pulmonary disease (c〇pD), allergic rhinitis (hay fever), cough, by asthma And respiratory diseases caused by chronic obstructive pulmonary disease (c〇pD). In other aspects, the disease or condition involving KLK1 activity is selected from asthma (allergic and non-allergic) and exacerbations caused by asthma and chronic obstructive pulmonary disease (c〇pD). In another aspect, the disease or condition involving KLK1 activity is a beer aspiration condition selected from the group consisting of asthma (allergic and non-allergic) and cough. In another aspect, the disease or condition involving KLK1 activity is aggravation caused by asthma and chronic obstructive pulmonary disease (COPD). Combination therapy This treatment can have important benefits for respiratory diseases, however these drugs 151651. Doc • 46 · 201121961 = The efficacy of certain remedies is often unsatisfactory, especially for the treatment of redness _ and the deterioration associated with the second S disease is not satisfactory. In addition, in view of the complexity of respiratory diseases such as sputum and PD, it is possible that any mediator: the treatment of the disease may not be satisfactory, and the combination of therapeutic agents may be guilty, although The use of steroids can produce a therapeutic effect, but requires the ability to use steroids at low doses to minimize the incidence and severity of undesirable materials that may be associated with conventional administration, and in combination with other agents such as KLK1 inhibitors. The leaven dosage is significantly reduced and thus minimizes potential side effects. Therefore, other compounds can be used in combination with the compounds of the present invention for the prevention and treatment of inflammatory lung diseases. &amp; 'The present invention also relates to pharmaceutical compositions for the prevention and treatment of respiratory diseases such as asthma (allergic and non-allergic) (including deterioration caused by asthma), allergic rhinitis and chronic obstructive pulmonary disease (COPD). The pharmaceutical compositions comprise a therapeutically effective amount of a compound of the invention and one or more additional therapeutic agents. The compositions may also be used to treat other forms of allergic inflammation, including allergic rhinitis (hay fever), nasal conjunctivitis, rhinorrhea 'urticaria, excessive production of pulmonary mucus, formation of ascites, chronic bronchitis, chronic airway obstruction, lungs Fibrosis and emphysema. Thus, the invention includes a combination of a compound of the invention as described above and one or more anti-inflammatory agents, bronchodilators, antihistamines, decongestants or antitussives, the compounds of the invention and such combinations present in In the same or different pharmaceutical compositions, administered separately, continuously or simultaneously. Combinations can include two or three different pharmaceutical compositions. Suitable therapeutic agents for use in combination with the compounds of the invention include: 151651. Doc •47- 201121961 (i) Steroid glucocorticoid agonist. Examples of steroid glucocorticoid agonists that can be used in this embodiment include budesonide, fluticasone (e.g., in the form of vinegar propionate), and mometasone (e.g., 吱β南). Form of formic acid), beclomethasone (for example in the form of 17-propionic acid vinegar or 17,21-dipropionic acid vinegar), ciclesonide ((^165011丨(}6), gasteprine) (loteprednol) (for example in the form of etabonate), etipednol (in the form of, for example, dicloacetate), triamcinolone (for example in the form of a propylene sulfide) , flunisolide, zoticaasone, flomoxonide, roofleponide, butixocort (eg in the form of propionic acid vinegar), Prednisolone, prednisone, tipredane, steroid esters such as 6α, 9α-difluoro-17α-[2-furylcarbonyl)oxy]· 11β- -16-αα-mercapto-3-yloxy-androstactin-ΐ,4-di-salt-Ι7β-thiocarbamate S-fluoro , 6α, 9α-difluoro-11 β-hydroxy-ΐ6α-methyl-3-oxooxy-17α-propoxycarbonyl-androstidine-ΐ,4-diene-Ι7β-thiocarboxylic acid S-(2 -Sideoxy-tetrahydro-furan-3S-yl)ester and 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α·[(4-methyl-1,3-嗟.sitting-5 -Alkyloxy]-3-oxo-androst-1,4-di-saliper- 7β-thiocarboxylic acid S-fluoromethyl ester, steroid ester of DE 4129535, WO 2002/00679, WO 2005/041980 Steroids, or steroids GSK 870086, GSK 685698 and GSK 799943; I51651. Doc • 48- 201121961 (ii) Non-steroidal glucocorticoid receptor agonists;

(iii) β2腎上腺素受體促效劑，例如舒喘寧（albuterol) (沙 丁胺醇（salbutamol))、沙美特羅（salmeterol)、 間經異丙腎上腺素（metaproterenol)、特布他林 (terbutaline) '非諾特羅（fenoterol)、異丙喧喘寧 (procaterol)、卡莫特羅（carmoterol)、茚達特羅 (indacaterol)、福莫特羅（formoterol)、阿福特羅 (arformoterol)、°比庫特羅（picumeterol)、GSK-159797、 GSK-597901、GSK-159802、GSK-64244、GSK-678007、TA-2005以及以下專利之化合物：EP 1440966、JP 05025045、WO 93/18007、WO 99/64035 、 US 2002/0055651 、 US 2005/0133417 、 US 2005/5159448、WO 00/0751 14、WO 01/42193、 WO 01/83462、WO 02/66422、WO 02/70490、WO(iii) β2 adrenergic receptor agonists, such as albuterol (salbutamol), salmeterol, metaproterenol, terbutaline 'fenoterol, procaterol, carmoterol, indacaterol, formoterol, arformoterol, ° Compounds of picumeterol, GSK-159797, GSK-597901, GSK-159802, GSK-64244, GSK-678007, TA-2005 and the following patents: EP 1440966, JP 05025045, WO 93/18007, WO 99 /64035, US 2002/0055651, US 2005/0133417, US 2005/5159448, WO 00/0751 14, WO 01/42193, WO 01/83462, WO 02/66422, WO 02/70490, WO

02/76933、WO 03/42164、WO 03/99764 ' WO 04/22547 ' WO 04/37768 、WO02/76933, WO 03/42164, WO 03/99764 'WO 04/22547 'WO 04/37768, WO

03/24439、WO 03/72539、WO 04/16578、WO 04/32921 ' WO 04/37773 、WO03/24439, WO 03/72539, WO 04/16578, WO 04/32921 'WO 04/37773, WO

03/42160 ' WO 03/91204、WO 04/016601、WO 04/33412、WO 04/37807 、WO 0439762、WO 04/39766、WO 04/45618、WO 04/46083 ' WO 04/71388、WO 04/80964、EP 1460064 ' WO 04/087142 &gt; WO 04/89892 ' EP 01477167 ' US 2004/0242622 、 US 2004/0229904 ' WO 04/108675、WO 04/108676、WO 05/033121、 151651.doc -49- 201121961 WO 05/040103、WO 05/044787、WO 04/071388、 WO 05/058299 ' WO 05/058867 ' WO 05/065650 &gt; WO 05/066140 ' WO 05/070908、WO 05/092840、 WO 05/092841 、WO 05/092860、WO 05/092887、 WO 05/092861 ' WO 05/090288 ' WO 05/092087 ' WO 05/080324、WO 05/080313、US 20050182091、 US 20050171147、WO 05/092870、WO 05/077361、 DE10258695、WO 05/1 1 1002、WO 05/1 1 1005、 WO 05/110990、US 2005/0272769、WO 05/110359、 WO 05/121065、US 2006/0019991、WO 06/016245、 WO 06/014704、WO 06/031556、WO 06/032627、 US 2006/0106075、US 2006/0106213、WO 06/051373、 WO 06/056471 ； (iv) 白三稀調節劑，例如孟魯司特（montelukast)、紮魯 司特（zafirlukast)或普侖司特（pranlukast);蛋白酶 抑制劑，諸如基質金屬蛋白酶（例如MMP12)之抑 制劑及TACE抑制劑，諸如馬立馬司他、0卩(：-333 ' GW- 3333 ；03/42160 'WO 03/91204, WO 04/016601, WO 04/33412, WO 04/37807, WO 0439762, WO 04/39766, WO 04/45618, WO 04/46083 'WO 04/71388, WO 04/ 80964, EP 1460064 'WO 04/087142 &gt; WO 04/89892 'EP 01477167 ' US 2004/0242622 , US 2004/0229904 ' WO 04/108675, WO 04/108676, WO 05/033121, 151651.doc -49- 2011-05961 WO 05/040103, WO 05/044787, WO 04/071388, WO 05/058299 'WO 05/058867 'WO 05/065650 &gt; WO 05/066140 'WO 05/070908, WO 05/092840, WO 05/ 092841, WO 05/092860, WO 05/092887, WO 05/092861 'WO 05/090288 'WO 05/092087 'WO 05/080324, WO 05/080313, US 20050182091, US 20050171147, WO 05/092870, WO 05 /077361, DE10258695, WO 05/1 1 1002, WO 05/1 1 1005, WO 05/110990, US 2005/0272769, WO 05/110359, WO 05/121065, US 2006/0019991, WO 06/016245, WO 06/014704, WO 06/031556, WO 06/032627, US 2006/0106075, US 2006/0106213, WO 06/051373, WO 06/056471; (iv) white tristimulators, such as montelukast ), zafirlukast Or pranlukast; a protease inhibitor, such as a matrix metalloproteinase (e.g., MMP12) inhibitor, and a TACE inhibitor, such as marimastat, 0卩 (:-333 ' GW-3333;

(v) 人類嗜中性白血球彈性蛋白酶抑制劑，諸如西維 來司（sivelestat)及以下專利中所述之化合物：WO 04/043942、WO 05/021509、WO 05/021512、WO 05/026123 ' WO 05/026124、WO 04/024700、WO 04/024701 ' WO 04/020410、WO 04/020412、WO 05/080372 ' WO 05/082863 ' WO 05/082864、WO 151651.doc -50- 201121961 03/053930 ； (vi) 磷酸二酯酶-4(PDE4)抑制劑，例如羅氟司特 (roflumilast)、阿羅茶鹼（ar〇fylline)、西洛司特 (cimomilast)、異 丁司特（Ibudilast)、利米司特 (Lirimilast)、美沙普安（Mesopram)、0NO6126 或 1C-485 ； (vii) 鱗酸二醋酶-7抑制劑； (viii) 激酶抑制劑’尤其P3 8有絲***原活化蛋白激酶 (MAP Kinase)抑制劑； (ix) 蕈毒鹼受體拮抗劑； (X)趨化因子受體功能調節劑，例如CCR1、CCR2、 CCR3、CXCR2、CXCR3、CX3CR1 及 CCR8之拮抗 劑’諸如 SB-332235 、 SB-656933 、 SB-265610 、 SB-225002 ' MC P-l(9-76) ' RS-504393 ' MLN-1202、INCB-3284 ;及 (xi) CRTH2受體促效劑。 定義 術語「烷基」包括飽和烴殘基，其包括： -具有至多10個原子（Ci-Cio)，或具有至多6個原子（Ci_c6) 或具有至多4個原子（CrC4)之直鏈基團。該等烷基之實 例包括（但不限於）Cl甲基、c：2乙基、C3丙基及C4正丁 基。 •具有3至10個原子（(VCl〇)，或具有至多7個原子π” C7)，或具有至多4個原子（Cs-C：4)之分支鏈基團。該等烷 151651.doc -51- 201121961 基之實例包括（但不限於）c：3異丙基、C4第二丁基、（：4異 丁基、C4第三丁基及(：5新戊基。 各者視情況如上文所述經取代。 術語「烯基」包括單不飽和烴殘基，其包括： -具有2至6個原子（CyC：6)之直鏈基團。該等烯基之實例包 括（但不限於）C2乙歸基、C3_l-丙稀基、C3埽丙基、c4_2_ 丁烯基。 -具有3至8個原子（C3_C：8)之分支鍵基團。該等稀基之實例 包括（但不限於）C4_2-甲基-2-丙稀基及C：6-2,3-二甲基αχ烯基。 各者視情況如上文所述經取代β 術語「炔基」包括具有碳碳參鍵之單不飽和烴殘基，其 包括： -具有2至6個原子（c^-c：6)之直鏈基團。該等炔基之實例包 括（但不限於）C2乙炔基、（^-丨-丙炔基、C4_2 丁炔基。 -具有3至8個原子（(：3_(：8)之分支鏈基團。該等炔基之實例 包括（但不限於）C4-3-甲基-1-丙炔基。 術語「烷氧基」包括〇鍵聯之烴殘基，其包括： _具有1至6個原子（C»_C6)，或具有1個至4個原子（Cl_C4)之 直鏈基團。該等烷氧基之實例包括（但不限於）c〗甲氧 基、C2乙氧基、C3正丙氧基及C4正丁氧基。 -具有3至6個原子（(VC6)，或具有3個至4個原子（C3_⑸之 分支鏈基團。該等烷氧基之實例包括(但不限於心異丙 氧基及C4第二丁氧基及第三丁氧基。 151651.doc •52· 201121961 各者視情況如上文所述經取代。 除非另外說明，否則齒基係選自a、F、Bf及卜 環烧基係如上文駭義。環烧基宜含w個碳原子 或至1G個碳原Wm子。適合單環㈣基之實 例包括環丙基、環丁基、環戊基'環己基、環庚基、環戍 稀、環戊-U3-二稀、環己婦及環己十4_二稀（視情況如上 文所述經取代）。適合雙環環垸基之實例包括十氫萘、八 氫L情況如上文所述經取代)。在與芳基稠合時， 適合環烧基之實例包括二氫節基及…士四氫萘基㈠見情 況如上文所述經取代）。 雜環烧基係如上文所定義。適合雜環絲之實例包括環 氧乙基、氮丙啶基、氮雜環丁基、四氫呋喃基、吡咯啶 基、四氫哌喃基、哌啶基、N•甲基哌啶基、嗎啉基、ν·甲 基嗎嘴基、硫代嗎琳基、硫代嗎琳基小氧化物硫代嗎嚇 基-l，l-二氧化物、哌嗪基' Ν_甲基哌嗪基、氮呼基、氧氮 呼基、二氮呼基及12,3,4-四氫吡啶基（視情況如上文所述 經取代）。 芳基係如上文所定義。通常，芳基視情況經丨、2或3個 取代基取代。視情況存在之取代基係選自上述者。適合芳 基之貫例包括本基及秦基（各者視情況如上文所述經取 代）。 雜芳基係如上文所定義。適合雜芳基之實例包括噻吩 基、呋喃基、吡咯基、吡唑基、咪唑基、噁唑基、異嗯。坐 基、噻唑基、異噻唑基、***基、噁二唑基、噻二峻基、 151651.doc •53· 201121961 四唑基、吡啶基、噠嗪基、嘧啶基、吡嗪基、吲哚基、笨 并咪唑基、苯并***基、喹啉基及異喹啉基（視情況如上 文所述經取代）。 諸如「c鍵聯之雜環烷基」中之術語「c鍵聯」意謂雜 環烧基經由環碳原子連接至分子其餘部分。 諸如「N鍵聯之雜環烷基」中之術語「N鍵聯」意謂雜 環烷基經由環氮原子連接至分子其餘部分。 諸如「Ο鍵聯之烴殘基」中之術語「〇鍵聯」意謂烴殘 基經由氧原子連接至分子其餘部分。 在諸如芳基（C〗-C4)烷基-及-SOJC^Cd烷基之基團中， 「-」表示基團與分子其餘部分之連接點。 「醫藥學上可接受之鹽」意謂生理學上或毒理學上可耐 受之鹽’且適當時包括醫藥學上可接受之驗加成鹽及醫藥 學上可接受之酸加成鹽。舉例而言⑴若本發明化合物含有 一或多個酸性基團（例如羧基），則可形成之醫藥學上可接 受之鹼加成鹽包括鈉鹽、鉀鹽、鈣鹽、鎂鹽及銨鹽，或與 有機胺形成之鹽，該等有機胺諸如二乙胺、TV-曱基-葡糖 胺、二乙醇胺或胺基酸（例如離胺酸）及其類似者；（ii)若本 發明化合物含有驗性基團（諸如胺基），則可形成之醫藥學 上可接受之酸加成鹽包括鹽酸鹽、氫溴酸鹽、疏酸鹽、填 酸鹽、乙酸鹽、檸檬酸鹽、乳酸鹽、酒石酸鹽、甲確酸 鹽、丁二酸鹽 '草酸鹽、填酸鹽、乙項酸鹽、甲笨項酸 鹽、苯磺酸鹽、萘二磺酸鹽、順丁烯二酸鹽、反丁稀二酸 鹽、馬尿酸鹽、羥萘曱酸鹽、對乙醯胺基苯甲酸鹽、二經 151651.doc -54- 201121961 基笨曱酸鹽、羥基萘曱酸鹽、丁二酸鹽、抗壞血酸鹽、油 酸鹽、硫酸氫鹽及其類似者。 亦可形成酸及驗之半鹽，例如半硫酸鹽及半鈣鹽。 關於適合鹽之評述，參見「Handbook of pharmaceutical(v) Human neutrophil elastase inhibitors, such as sivelestat and the compounds described in the following patents: WO 04/043942, WO 05/021509, WO 05/021512, WO 05/026123 ' WO 05/026124, WO 04/024700, WO 04/024701 'WO 04/020410, WO 04/020412, WO 05/080372 'WO 05/082863 ' WO 05/082864, WO 151651.doc -50- 201121961 03/ 053930; (vi) Phosphodiesterase-4 (PDE4) inhibitors, such as roflumilast, ar〇fylline, cimomilast, ibudilast (Ibudilast) ), Lirimilast, Mesopram, 0NO6126 or 1C-485; (vii) bisulphate diacetase-7 inhibitor; (viii) kinase inhibitor 'especially P3 8 mitogen-activated protein a kinase (MAP Kinase) inhibitor; (ix) a muscarinic receptor antagonist; (X) a chemokine receptor function modulator, such as an antagonist of CCR1, CCR2, CCR3, CXCR2, CXCR3, CX3CR1, and CCR8, such as SB-332235, SB-656933, SB-265610, SB-225002 'MC Pl(9-76) 'RS-504393 ' MLN-1202, INCB-3284; and (xi) CRTH2 receptor Agonist. Definitions The term "alkyl" includes saturated hydrocarbon residues including: - a linear group having up to 10 atoms (Ci-Cio), or having up to 6 atoms (Ci_c6) or having up to 4 atoms (CrC4) . Examples of such alkyl groups include, but are not limited to, Cl methyl, c: 2 ethyl, C3 propyl, and C4 n-butyl. • a branching group having 3 to 10 atoms ((VCl〇), or having up to 7 atoms π” C7), or having up to 4 atoms (Cs-C: 4). The alkane 151651.doc - 51-201121961 Examples include, but are not limited to, c: 3 isopropyl, C4 second butyl, (: 4 isobutyl, C4 tert-butyl, and (: 5 neopentyl). Substituted as described herein. The term "alkenyl" includes monounsaturated hydrocarbon residues which include: - a linear group having from 2 to 6 atoms (CyC: 6). Examples of such alkenyl groups include (but not Limited to) C2 ethyl group, C3_l-propyl group, C3 propyl group, c4_2_butenyl group. - Branching group having 3 to 8 atoms (C3_C: 8). Examples of such a group include (but Not limited to) C4_2-methyl-2-propylidene and C:6-2,3-dimethyla-decenyl. Each case is substituted as described above. The term "alkynyl" includes carbon and carbon. a monounsaturated hydrocarbon residue of a bond comprising: - a linear group having 2 to 6 atoms (c^-c: 6). Examples of such alkynyl groups include, but are not limited to, C2 ethynyl, ^-丨-propynyl, C4_2 butynyl. - with 3 Up to 8 atoms ((: 3_(:8)) branched chain groups. Examples of such alkynyl groups include, but are not limited to, C4-3-methyl-1-propynyl. The term "alkoxy" includes a hydrazine-bonded hydrocarbon residue comprising: _ having from 1 to 6 atoms (C»_C6), or a linear group having from 1 to 4 atoms (Cl_C4). Examples of such alkoxy groups include But not limited to) c methoxy, C2 ethoxy, C3 n-propoxy and C4 n-butoxy. - has 3 to 6 atoms ((VC6), or has 3 to 4 atoms (C3_(5)) Branched chain groups. Examples of such alkoxy groups include, but are not limited to, heso-isopropoxy group and C4 second butoxy group and third butoxy group. 151651.doc • 52· 201121961 Each case is as above Unless otherwise stated, the dentate base is selected from the group consisting of a, F, Bf, and a cycloalkyl group as defined above. The cycloalkyl group preferably contains w carbon atoms or up to 1 G carbon atoms Wm. Examples of the ring (tetra) group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl 'cyclohexyl group, a cycloheptyl group, a cyclopentene group, a cyclopenta-U3-dicarbea, a cyclohexanyl group, and a cyclohexayl group. The situation is replaced as described above.) Suitable for double Examples of the cycloalkyl group include decalin and octahydro L as described above. When condensed with an aryl group, examples of suitable cycloalkyl groups include dihydrogenated groups and ... tetrahydronaphthyl groups (I) The case is substituted as described above.) The heterocyclic alkyl group is as defined above. Examples of suitable heterocyclic filaments include epoxyethyl, aziridine, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetra Hydropyranyl, piperidinyl, N•methylpiperidinyl, morpholinyl, ν·methyl-methyl, thio-allinyl, thio-allinyl-based small oxide thio-shock-l , l-dioxide, piperazinyl' Ν-methylpiperazinyl, aziryl, oxazolidinyl, diazephyl and 12,3,4-tetrahydropyridyl (as appropriate) Replaced). The aryl group is as defined above. Typically, the aryl group is optionally substituted with hydrazine, 2 or 3 substituents. Substituents which are optionally present are selected from the above. Examples of suitable aryl groups include the base and the dimethyl group (each of which is replaced as described above). Heteroaryl is as defined above. Examples of suitable heteroaryl groups include thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, iso. Sodium, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadicarbyl, 151651.doc •53· 201121961 tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, anthracene Mercapto, stupid imidazolyl, benzotriazolyl, quinolyl and isoquinolyl (substituted as described above). The term "c linkage" as in "c-bonded heterocycloalkyl" means that a heterocycloalkyl group is attached to the remainder of the molecule via a ring carbon atom. The term "N-bonding" as used in "N-linked heterocycloalkyl" means that a heterocycloalkyl group is attached to the remainder of the molecule via a ring nitrogen atom. The term "ruthenium linkage" as used in "hydrocarbon residues of hydrazine linkage" means that a hydrocarbon residue is attached to the remainder of the molecule via an oxygen atom. In a group such as an aryl (C-C4)alkyl- and -SOJC^Cd alkyl group, "-" represents the point of attachment of the group to the rest of the molecule. "Pharmaceutically acceptable salt" means a physiologically or toxicologically tolerable salt' and, where appropriate, a pharmaceutically acceptable test addition salt and a pharmaceutically acceptable acid addition salt . For example, (1) if the compound of the present invention contains one or more acidic groups (for example, a carboxyl group), the pharmaceutically acceptable base addition salts which may be formed include sodium salts, potassium salts, calcium salts, magnesium salts and ammonium salts. Or a salt formed with an organic amine such as diethylamine, TV-mercapto-glucosamine, diethanolamine or an amino acid (for example, an amine acid) and the like; (ii) if the present invention The compound may contain an identifiable group (such as an amine group), and the pharmaceutically acceptable acid addition salts which may be formed include hydrochloride, hydrobromide, acid salt, acid salt, acetate, citrate. , lactate, tartrate, formate, succinate 'oxalate, sulphate, ethyl sulphate, methyl sulphate, benzene sulphonate, naphthalene disulfonate, butene Diacid salt, anti-succinic acid salt, horse urate, hydroxynaphthyl citrate, p-acetamidobenzoate, 153651.doc -54- 201121961 base citrate, hydroxynaphthoic acid Salts, succinates, ascorbates, oleates, hydrogen sulphates and the like. Acids and semi-salts such as hemisulfate and hemi-calcium salts can also be formed. For a review of suitable salts, see "Handbook of pharmaceutical

Salts: Properties，Selecti〇n an(J 心」，Stahl&amp;Wermuth (Wiley-VCH，Weinheim，Germany，2002)。 「前藥」係指可在活體内由代謝方式（例如藉由水解、 還原或氧化）轉化為本發明化合物的化合物。適用於形成 前藥之基團描述於「The Practice 〇f Medicinal Chemistry」， 第 2 版，第 561-585 頁（2003)及 F. J. Leinweber，Drwg 1987，18，379 中。 本發明化合物可以非溶劑合物及溶劑合物形式存在。術 語『溶劑合物』在本文中用於描述包含本發明化合物及化 學計算量之一或多種醫藥學上可接受之溶劑分子（例如乙 醇）的分子複合物。術語『水合物』在溶劑為水時使用。 若本發明化合物呈一或多種幾何、光學、對映異構、非 對映異構及互變異構形式存在時，其包括（但不限於）順式 及反式、五型及Z型、«、㈣及内消旋型、酮式及烯醇 式。除非另外說明，否則提及特定化合物包括所有該等異 構形式，包括其外消旋混合物及其他混合物。適當時，該 等異構體可藉由應用或修改已知方法（例如層析技術及再 結晶技術）自其混合物中分離。適當時，該等異構體可藉 由應用或修改已知方法（例如不對稱合成）來製備。 式（I)化合物之典型構型包括： I5I651.doc •55· 201121961Salts: Properties, Selecti〇n an (J Heart), Stahl &amp; Wermuth (Wiley-VCH, Weinheim, Germany, 2002). "Prodrugs" means those that can be metabolized in vivo (for example by hydrolysis, reduction or oxidation). a compound which is converted into a compound of the present invention. A group suitable for forming a prodrug is described in "The Practice 〇f Medicinal Chemistry", 2nd edition, pp. 561-585 (2003) and FJ Leinweber, Drwg 1987, 18, 379. The compounds of the invention may exist in the form of unsolvates and solvates. The term "solvate" is used herein to describe a compound comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules ( a molecular complex such as ethanol. The term "hydrate" is used when the solvent is water. If the compound of the invention is present in one or more geometric, optical, enantiomeric, diastereomeric and tautomeric forms, These include, but are not limited to, cis and trans, penta and z, «, (iv) and meso, keto and enol. Unless otherwise stated, reference to a particular compound includes Such isomeric forms include racemic mixtures thereof and other mixtures. Where appropriate, such isomers may be separated from the mixture by the application or modification of known methods, such as chromatography techniques and recrystallization techniques. The isomers can be prepared by applying or modifying known methods, such as asymmetric synthesis. Typical configurations of the compounds of formula (I) include: I5I651.doc • 55· 201121961

包括提及洽愈 在本發明上下文中，本文中提及「治療 性、緩解性及預防性治療。 通用方法 愿评疋式⑴化合物之生物醫藥特性，諸如溶解性及溶 穩定性（不同PH值之間）、穿透性等以選擇最適用於治療 提出徵候之劑型及投藥途徑。 意欲用於醫藥用途之本發明化合物 物形式投與。其可藉由諸如沈殿、結日、…日或非晶形 乾燥、蒸發乾燥、熔融;東凝及擠屬之:、冷滚乾燥、喷 物、粉末或薄膜形式獲得。包:法例如以固體塞 赞態/動態烘箱、紅 151651.doc •56· 201121961 助形成上述 線、微波或射頻乾燥之習知乾 礼冻方法可用於協 結日日及非晶形產物。 /可單獨或與一或多種其他本發明化合物組合或與—戍 夕種其他藥物（或以其任何纟人 ▲饮、17，、且口形式）組合投與。_般而 :，其以與一或多種醫藥學上可接受之賦形劑締合之調配 物形式投與。術語『賦形劑』在本文中用於描述除本發明 化合物以外之可賦㈣配物以功能性（亦即藥物釋放速率 控制)及/或非功能性(亦即加工助劑或稀釋劑)特徵的任何 成分。賦形劑之選擇在很大程度上取決於諸如特定投華模 式、賦形劑對溶解性及穩定性之影響及劑型性質之因素。 適合於傳遞本發明化合物之醫藥組合物及其製備方法對 熟習此項技術者而言為顯而易見的。該等組合物及其製備 方法可見於例如 Remingt〇nis pharmaceuticai Sciences，第 19版（Mack Publishing Company，1995)中。 因此’本發明提供一種醫藥組合物’其包含式⑴化合物 及醫藥學上可接受之載劑、稀釋劑或賦形劑。 本發明化合物可經口投與ϋ與可涉及吞咽以使化 合物進入胃腸道；及/或經頰、經舌或舌下投與藉以使化 合物直接自口腔進入血流。 適用於經口投與之調配物包括固體塞狀物、固體微粒、 半固體及液體（包括多相或分散系統），諸如錠劑；含有多 微粒或奈米微粒、液體、乳液或粉末之軟或硬膠囊；*** 錠（包括液體填充型）；口嚼劑；凝膠劑；快速分散劑型； 薄膜；卵形栓劑；喷霧劑；及頰/黏膜黏附性貼片。 151651.doc -57- 201121961 適用於經口投與之調配物亦可經設計以便以立即釋放方 式或以速率持續方式傳遞式（I)化合物，其中釋放概況可經 延遲、呈脈衝式、控制、持續或延遲且持續或以使該等化 合物之治療功效最佳化的方式改良。以速率持續方式傳遞 化合物之方式在此項技術中為已知的且包括可與該等化合 物一起調配以控制該等化合物釋放的緩慢釋放聚合物。 速率持續聚合物之實例包括可用於藉由擴散或擴散與聚 合物侵蝕之組合釋放該等化合物的可降解及不可降解聚合 物。速率持續聚合物之實例包括羥丙基甲基纖維素、羥丙 基纖維素、甲基纖維素、乙基纖維素、羧甲基纖維素鈉、 聚乙烯醇、聚乙烯吡咯啶酮、三仙膠、聚甲基丙烯酸酯、 聚氧化乙烯及聚乙二醇。 液體（包括多相及分散系統）調配物包括乳液、懸浮液、 溶液、糖漿及酏劑。該等調配物可作為軟或硬膠囊（例如 由明膠或羥丙基甲基纖維素製成）中之填充物存在，且通 常包含載劑，例如水、乙醇、聚乙二醇、丙二醇、甲基纖 維素或適合油；以及一或多種乳化劑及/或懸浮劑。液體 調配物亦可藉由使例如藥囊中之固體復原來製備。 本發明化合物亦可以快速溶解、快速崩解劑型使用，諸 如 Liang 及 Chen, Expert Opinion in Therapeutic Patents， 2001，11 (6)，981-986中所述之劑型。 鍵劑之調配論述於 Pharmaceutical Dosage Forms: Tablets,第 1 卷，H. Lieberman 及 L. Lachman (Marcel Dekker, New York, 1980) 〇 151651.doc •58- 201121961 本發明化合物亦可直接投與至血流中、投與至皮下組織 中、投與至肌肉中或投與至内臟中。適用於非經腸投藥之 方式包括靜脈内、動脈内、腹膜内、鞘内、心室内、尿道 内、胸骨内、顱内、肌肉内、滑膜内及皮下投藥。適用於 非經腸投藥之裝置包括針（包括微針）注射器、無針注射器 及輸注技術。 非經腸調配物通常為水性溶液或油性溶液。若溶液為水 性溶液，則可使用諸如糖（包括（但不限於）葡萄糖、甘露糖 醇、山梨糖醇等）、鹽、碳水化合物及緩衝劑（較佳達到3至 9之pH值）之賦形劑，但對於一些應用，其可能更適於調配 成無菌非水性溶液或調配成需要聯合諸如無菌無熱原質水 之適合媒劑使用之乾物形式。 非經腸調配物可包括源自可降解聚合物之植入物，該等 可降解聚合物諸如聚酯（亦即聚乳酸、聚乳酸交酯、聚乳 酸交醋·共-乙交酿、聚己内0旨、聚經基丁酸醋）、聚原酸醋 及聚酸酐。此等調配物可經由手術切口投與至皮下組織' 肌肉組織中或直接投與至特定器官甲。 例如藉由冷凍乾燥在無菌條件下製備非經腸調配物可易 於使用熟習此項技術者所熟知之標準醫藥技術來達成。 用於製備非經腸溶液之式（I)化合物之溶解性可藉由使用 諸如以下適當調配技術來增加：併入共溶劑及/或溶解增 強劑’諸如界面活性劑、微胞結構及環糊精。 本發明化合物亦可鼻内投與或藉由吸入投與，通常以乾 粉形式（單獨、呈混合物形式（例如呈與乳糖之乾燥摻合^ 151651.doc •59· 201121961 形式）或呈例如與磷脂（諸如磷脂醯膽鹼）混合的混合組分粒 子形式）自乾粉吸入器投與，在使用或不使用適合推進劑 (諸如1，1，1，2-四氟乙烷或ΐ，ΐ，ι，2,3,3,3-七氟丙烷）下呈氣溶 膠喷霧形式自加壓容器、泵、喷灑器、霧化器（較佳為使 用電流體動力學產生細霧的霧化器）或喷霧器投與，或呈 滴鼻劑形式投與。對於鼻内使用，粉末可包含生物黏附 劑’例如聚葡萄胺糖（chitosan)或環糊精。 加壓容器、泵、噴灑器、霧化器或喷霧器容納本發明化 合物之溶液或懸浮液，該溶液或懸浮液包含例如乙醇、乙 醇水溶液或用於分散、溶解或延長釋放活性劑之適合替代 性試劑、推進劑作為溶劑，以及視情況選用之界面活性 劑諸如脫水山梨糖醇三油酸酯、油酸或寡聚乳酸 (oligolactic acid)。 於乾粉或懸浮液調配物中使用之前，將藥物產物微米尺 寸化至適於藉由吸入傳遞之尺寸（通常小於5微米）。此可藉 由諸如螺旋喷射研磨、流化床喷射研磨、超臨界流體加: 形成奈米粒子、高壓均質化或錢乾狀任何適當粉碎方 膠囊（例如由日月3¾ + _ 於吸入器或吹入:Λ基甲基纖維素製成)、發泡藥及 人物、°使用之樂筒可經調配成含有本發明化 “胺：:：露乳糖或澱粉)及效能調節劑(諸如 醇或硬脂酸鎂）之粉末混合物。乳糖 劑勺杯形式或呈單水合物形式，後者較佳。其他適人賦形 劑包括聚*萄糖、葡萄*、麥芽糖'山梨糖醇、 151651.doc 201121961 果糖、蔗糖及海藻糖。 用於吸入/鼻内投與之調配物可使用例如PGLA調配成立 即釋放及/或修倚釋放調配物。修飾釋放調配物包括延遲 釋放、持續釋放、脈衝式釋放、控制釋放' Jfe向釋放及程 控釋放調配物。 由於例如出於治療特定疾病或病狀之目的可能需要投與 活性化合物之組合，所以在本發明範疇内，兩種或兩種以 上醫藥組合物（其中至少一者含有式⑴化合物）宜以適用於 共同投與該等組合物之套組形式組合。 因此，本發明之套組包含兩種或兩種以上各別醫藥組合 物，其中至少一者含有本發明之式⑴化合物；以及用於分 別盛裝該等組合物之構件，諸如容器、分隔式瓶或分隔式 箔包裝。該套組之實例為用於封裝錠劑、膠囊及其類似物 之常用發泡包裝。 本發明之套組尤其適用於投與不同劑型（例如經口及非 經腸），適用於以不同給藥時間間隔投與各別組合物，或 適用於針對彼此調定各別組合物。為了輔助順應性，套組 通常包含投藥說明書且可具備所謂之記憶輔助物。 為了向人類患者投藥，本發明化合物之總日劑量通常處 於 0_01 mg至 1000 mg ’ 或 0.1 mg至 25〇 mg，或 i mg至 5〇 mg 之範圍内’當然’視投藥模式而定。總曰劑量可以單次給 藥或分次給藥投與’且可由醫師決定處於本文既定之典型 範圍以外。此等劑量係基於體重為約6〇公斤至7〇公斤之平 均人類個體。醫師應能夠容易地確定用於體重處於此範圍 151651.doc 61 201121961 以外之個體（諸如嬰兒及老年人）的劑量。 合成方法 本發明化合物可根據下列流程及實例之程序，使用適合 物質來製備，且進一步由下文提供之特定實例來例示。此 外，藉由利用本文所述之程序，一般技術者可易於製備處 於本文所主張之本發明範疇内的其他化合物。然而，實例 中所說明之化合物不應視作構成可視作本發明之唯—類 別。實例進一步說明製備本發明化合物之細節。熟習此項 技術者將易於瞭解，可使用下列製備程序之條件及製程的 已知改變形式來製備此等化合物。 本發明化合物可呈其醫藥學上可接受之鹽（諸如先前上 文所述之鹽）形式分離。 可能需要保護用於製備本發明化合物之中間物中之反應 性官能基（例如羥基、胺基、硫基或羧基）以避免其不必要 地參與形成該等化合物之反應中。可使用習知保護基，例 如由 Τ. W· Greene及 P. G. M. Wuts在「ρ崎gr〇ups in 〇rganiCChemistry」JohnWileyands〇nsj^，2〇〇0 所述之保護基1例而言，適用於本文巾之常見胺基保護 基為第三丁氧羰基（Boc)，其易於藉由以諸如三氟乙酸或 氯化氫之酸’在諸如三氯甲烧之有機溶劑中處㈣移除。 或者，胺基保護基可為苯甲氧羰基（z)基團，其可藉由以 鈀催化劑在氫氣氛圍下氫化來移除；或9_第基甲氧羰基 (Fmoc)基團，其可利用含二級有機胺（諸如二乙胺或哌啶） 之有機溶劑溶液移除。羧基通常保護為酯，諸如甲酯、乙 I51651.doc -62- 201121961 醋、本甲酿或第三丁醋，其皆可藉由在諸如氣氧化鐘或氣 氧化納之驗存在下進行水解來移除。苯f基保護基亦可藉 由以鈀催化劑在氫氣氛圍下氫化來移除，而第三丁基亦可 由三氟乙酸移除。或者’三氣乙酯保護基係用肖，在乙酸 中移除。適用於本文中之常見經基㈣基為甲冑，脫除保 護基之條件包括在48%HBr水溶液中回流^^小時或與 三溴化曱硼烷-起在二氯甲烷中攪拌】至24小日夺。或者， 若經基係、保護成笨甲_，則脫除保護基之條件包括以把倍 化劑在氫氣氛圍下氫化。 在下列流程中： R -R 、R/及Rb係如先前對於式⑴化合物所定義； PG!、PG2或PG3為適合保護基； R3()為Η、（CVCM烧基、_素、經基或（CVC6)院氧基； R31及R32係獨立地選自Η、(Ci_c丨。)烷基、(C2_C6)烯基、 (C3-cIQ)環烷基、雜環烷基、芳基、雜芳基、芳基（c】_C4) 烷基-、芳基（c2-c4)烯基_、雜芳基（CVC4)烷基_、_s〇2(c,_ C6)烧基、-S02芳基及-S02芳基（Ci_c4)烧基。 通式I化合物可使用習知合成方法來製備。在典型第一 步驟中，使用標準肽偶合條件將胺甲胺基㈣⑴偶合至胺 基經諸如第三丁氧羰基（B〇c)、苯曱氧羰基（2)或9_第基曱 氧羰基（Fmoc)之標準保護基適當保護之α胺基酸（2)。該等 基團之使用在此項技術中為熟知的。若Rl*R2具有諸如胺 或羧酸之反應性官能基，則亦對此基團加以保護。標準肽 偶合方法包括使酸與胺在羥基笨并***及碳化二亞胺（諸 15165I.doc • 63 · 201121961 如水溶性碳化二亞胺）或六氟磷酸2_(1h_笨并三唾i某） 1，1，3,3-四甲基銨或六氟磷酸笨并***_丨_基_氧基-參吡 咯啶基）-鎸或六氟磷酸溴-參（N-吡咯啶基）_鱗存在下，在諸 如三乙胺、二異丙基乙胺或Ν-應。 甲基嗎琳之有機驗存在下反Included in the context of the present invention is the reference to "therapeutic, palliative and prophylactic treatments. The general method is intended to evaluate the biomedical properties of the compounds of formula (1), such as solubility and solubility stability (different pH values) Between), penetrability, etc. to select the dosage form and route of administration that is most suitable for the treatment of the proposed condition. The form of the compound of the present invention intended for medical use may be administered by means of, for example, a medlar, a knot, a day, or a Crystal form drying, evaporative drying, melting; East coagulation and extrusion: cold roll drying, spray, powder or film form. Package: method for example, solid state or dynamic oven, red 151651.doc • 56· 201121961 A conventional dry freeze method for assisting in the formation of the above-described line, microwave or radio frequency drying can be used to cope with daytime and amorphous products. / can be used alone or in combination with one or more other compounds of the invention or with other drugs (or Any combination of sputum, drink, 17, and oral form. _ Generally: it is administered in the form of a formulation associated with one or more pharmaceutically acceptable excipients. Agents are used herein to describe any component of a compound other than a compound of the invention that is characterized by functionality (ie, drug release rate control) and/or non-functionality (ie, processing aid or diluent). The choice of excipients depends to a large extent on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for delivery of the compounds of the invention and methods for their preparation It will be apparent to those skilled in the art that such compositions and methods for their preparation can be found, for example, in Remingt〇nis pharmaceuticai Sciences, 19th edition (Mack Publishing Company, 1995). Thus the present invention provides a pharmaceutical composition. 'It comprises a compound of formula (1) and a pharmaceutically acceptable carrier, diluent or excipient. The compounds of the invention may be administered orally and may involve swallowing to allow the compound to enter the gastrointestinal tract; and/or buccal, menstrual The tongue or sublingual administration allows the compound to enter the bloodstream directly from the oral cavity. Formulations suitable for oral administration include solid plugs, solid particles, semi-solids, and Body (including multiphase or dispersion systems), such as tablets; soft or hard capsules containing multiparticulate or nanoparticulates, liquids, emulsions or powders; buccal ingots (including liquid filled); chewables; gels Rapid dispersible dosage form; film; ovate suppository; spray; and buccal/mucosal adhesive patch. 151651.doc -57- 201121961 Formulations suitable for oral administration can also be designed for immediate release or The compound of formula (I) is delivered in a rate-continuous manner, wherein the release profile can be modified in a delayed, pulsed, controlled, sustained or delayed and sustained manner or in a manner that optimizes the therapeutic efficacy of the compounds. The manner of the compounds is known in the art and includes slow release polymers that can be formulated with the compounds to control the release of such compounds. Examples of rate-sustaining polymers include degradable and non-degradable polymers that can be used to release such compounds by diffusion or diffusion in combination with polymer attack. Examples of rate-sustaining polymers include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and three cents. Glue, polymethacrylate, polyethylene oxide and polyethylene glycol. Liquid (including multiphase and dispersion systems) formulations include emulsions, suspensions, solutions, syrups and elixirs. The formulations may be present as a filler in a soft or hard capsule (for example made of gelatin or hydroxypropyl methylcellulose) and usually comprise a carrier such as water, ethanol, polyethylene glycol, propylene glycol, A A cellulose or suitable oil; and one or more emulsifiers and/or suspending agents. Liquid formulations can also be prepared by reconstituting, for example, a solid in a sachet. The compounds of the invention may also be used in rapidly dissolving, rapidly disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 2001, 11 (6), 981-986. The formulation of the agents is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980) 〇 151651.doc • 58- 201121961 The compounds of the invention may also be administered directly to blood. Flow, into the subcutaneous tissue, into the muscle or into the internal organs. Suitable methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration. Devices suitable for parenteral administration include needle (including microneedle) syringes, needle-free injectors, and infusion techniques. Parenteral formulations are typically aqueous or oily solutions. If the solution is an aqueous solution, such as sugar (including but not limited to glucose, mannitol, sorbitol, etc.), salts, carbohydrates and buffers (preferably having a pH of 3 to 9) can be used. Shape agents, but for some applications, they may be more suitable for formulation into a sterile non-aqueous solution or formulation into a dry form for use in combination with a suitable vehicle such as sterile pyrogen-free water. Parenteral formulations may include implants derived from degradable polymers such as polyester (ie, polylactic acid, polylactide, polylactic acid, vinegar, co-b, brewing, poly) It has been used in the past, polyacetic acid vinegar and polyanhydride. Such formulations can be administered to the subcutaneous tissue 'muscle tissue via a surgical incision or directly to a specific organ. Preparation of parenteral formulations under sterile conditions, for example by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of the compound of formula (I) for the preparation of parenteral solutions can be increased by the use of suitable formulation techniques such as incorporation of cosolvents and/or dissolution enhancers such as surfactants, cell structures and cyclods. fine. The compounds of the invention may also be administered intranasally or by inhalation, usually in the form of a dry powder (either alone, in a mixture (for example in the form of a dry blend with lactose^151651.doc • 59·201121961) or as a phospholipid, for example (in the form of a mixed component particle such as phospholipid choline) mixed with a dry powder inhaler, with or without a suitable propellant (such as 1,1,1,2-tetrafluoroethane or hydrazine, hydrazine, ι , 2,3,3,3-heptafluoropropane) in the form of an aerosol spray from a pressurized container, pump, sprinkler, atomizer (preferably a nebulizer using electrohydrodynamics to produce a fine mist) or The nebulizer is administered or administered as a nasal drop. For intranasal use, the powder may comprise a bioadhesive&apos; such as chitosan or cyclodextrin. A pressurized container, pump, sprinkler, nebulizer or nebulizer containing a solution or suspension of a compound of the invention, which solution, for example, comprises ethanol, an aqueous solution of ethanol or suitable for dispersing, dissolving or prolonging the release of the active agent Alternative agents, propellants as solvents, and optionally surfactants such as sorbitan trioleate, oleic acid or oligolactic acid. Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be done by, for example, spiral jet milling, fluidized bed jet milling, supercritical fluid addition: formation of nanoparticles, high pressure homogenization or money dryness of any suitable comminuted square capsule (eg by sun and rain 33⁄4 + _ inhaler or blown) Into: mercaptomethylcellulose), foaming agents and figures, ° used can be formulated to contain the invention "amine::: lactose or starch" and performance regulators (such as alcohol or hard A powder mixture of magnesium sulphate. The dosage of the lactose is in the form of a cup or in the form of a monohydrate, the latter being preferred. Other suitable excipients include polydextrose, grape*, maltose sorbitol, 151651.doc 201121961 fructose , Sucrose and Trehalose. Formulations for inhaled/intranasal administration may be formulated as immediate release and/or repair release formulations using, for example, PGLA. Modified release formulations include delayed release, sustained release, pulsed release, control Release of 'Jfe to release and programmed release of the formulation. Two or more of the above are within the scope of the present invention, as a combination of active compounds may be required, for example for the purpose of treating a particular disease or condition. The compositions, at least one of which contains a compound of formula (1), are preferably combined in a kit format suitable for co-administration of such compositions. Thus, the kit of the invention comprises two or more separate pharmaceutical compositions, wherein At least one of the compounds of formula (1) of the present invention; and a member for holding the compositions, such as a container, a divided bottle or a divided foil package, respectively. Examples of the kit are for encapsulating tablets, capsules and the like Commonly used blister packs for analogs. The kits of the present invention are particularly useful for administering different dosage forms (e.g., oral and parenteral), for administering individual compositions at different dosing intervals, or for targeting each other. The individual compositions are set. To aid compliance, the kit typically contains instructions for administration and may have so-called memory aids. For administration to human patients, the total daily dose of the compound of the invention is typically between 0_01 mg to 1000 mg' or 0.1. From mg to 25 〇 mg, or from i mg to 5 〇 mg, of course, depending on the mode of administration. The total sputum dose can be administered in a single dose or in divided doses. The division is determined to be outside the typical range as defined herein. These doses are based on an average human subject weighing approximately 6 to 7 kg. Physicians should be able to easily identify individuals for weights outside this range 151651.doc 61 201121961 Dosages (such as infants and the elderly). Methods of Synthesis The compounds of the present invention can be prepared according to the procedures of the following schemes and examples, using suitable materials, and further exemplified by the specific examples provided below. Other compounds which are within the scope of the invention as claimed herein can be readily prepared by a person skilled in the art. However, the compounds illustrated in the examples should not be construed as forming the only class that can be considered as the invention. The examples further illustrate the preparation of the compounds of the invention. The details. Those skilled in the art will readily appreciate that such compounds can be prepared using known modifications of the conditions and procedures of the following preparation procedures. The compounds of the invention may be isolated in the form of their pharmaceutically acceptable salts, such as the salts previously described. It may be desirable to protect the reactive functional groups (e.g., hydroxyl, amine, thio or carboxy groups) used in the preparation of the compounds of the present invention to avoid unnecessarily participating in the reaction to form such compounds. A conventional protecting group can be used, for example, by Τ. W. Greene and PGM Wuts in the case of "protective group" described in "Kakisaki gr〇ups in 〇rganiCChemistry" John Wileyands〇nsj^, 2〇〇0 A common amine protecting group for towels is the third butoxycarbonyl (Boc) which is readily removed by the use of an acid such as trifluoroacetic acid or hydrogen chloride in an organic solvent such as trichloromethane. Alternatively, the amine protecting group can be a benzyloxycarbonyl (z) group which can be removed by hydrogenation with a palladium catalyst under a hydrogen atmosphere; or a 9-methoxycarbonyl (Fmoc) group, which Removal is carried out using an organic solvent solution containing a secondary organic amine such as diethylamine or piperidine. The carboxyl group is usually protected as an ester, such as methyl ester, ethyl I51651.doc-62-201121961 vinegar, the present brewery or the third butan vinegar, all of which can be hydrolyzed by the presence of a gas oxidation clock or a gas oxidized nanometer. Remove. The benzene-f-protecting group can also be removed by hydrogenation with a palladium catalyst under a hydrogen atmosphere, and the third butyl group can also be removed by trifluoroacetic acid. Alternatively, the tri-ethane ethyl ester protecting group is removed in acetic acid with a dip. The common transyl group used in this paper is formazan. The conditions for removing the protecting group include refluxing in 48% HBr aqueous solution or stirring with lanthanum tribromide-methane in dichloromethane to 24 hours. Day capture. Alternatively, if the substrate is protected by a substrate, the conditions for removing the protecting group include hydrogenating the doubling agent under a hydrogen atmosphere. In the following schemes: R -R , R / and Rb are as previously defined for the compound of formula (1); PG!, PG2 or PG3 are suitable protecting groups; R3 () is hydrazine, (CVCM alkyl, _, rhyme Or (CVC6) alkoxy; R31 and R32 are independently selected from the group consisting of hydrazine, (Ci_c丨.)alkyl, (C2_C6)alkenyl, (C3-cIQ)cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, aryl (c)-C4) alkyl-, aryl (c2-c4) alkenyl, heteroaryl (CVC4) alkyl, _s〇2 (c, _C6) alkyl, -S02 aromatic And -S02 aryl (Ci_c4) alkyl. The compound of formula I can be prepared using conventional synthetic methods. In a typical first step, the amine methylamino (4) (1) is coupled to an amine group using standard peptide coupling conditions such as The alpha-amino acid (2) suitably protected by a standard protecting group of a tributyloxycarbonyl group (B〇c), a benzoquinoneoxycarbonyl group (2) or a 9-yloxycarbonylcarbonyl group (Fmoc). The use of such groups is It is well known in the art. If Rl*R2 has a reactive functional group such as an amine or a carboxylic acid, the group is also protected. Standard peptide coupling methods include the acid and amine in the hydroxy benzotriazole and carbonization. Diimine (15165I.doc • 63 · 20 1121961 such as water-soluble carbodiimide) or hexafluorophosphate 2_(1h_stupidin), 1,1,3,3-tetramethylammonium or hexatrifluorophosphate benzotriazole_丨_yl_oxy - in the presence of pyridine pyridinyl)-hydrazine or bromine-hexafluorophosphate- cis (N-pyrrolidinyl)-scale, such as triethylamine, diisopropylethylamine or hydrazine-. Methyllin's organic test exists in the opposite

使用先前所述之標準方法移除（3)之保護基，得到胺Removal of the protecting group of (3) using standard methods previously described to yield an amine

使用先前所述之標準肽偶合條件將胺（4)偶合至胺基經 諸如第三丁氧幾基（B〇c)、笨曱氧幾基（z)或9_第基甲氧幾 土（ moc)之適合保護基適當保護之^胺基酸（5)。若汉丨或r2 ^有諸如胺或羧酸之反應性官能基，則亦對此基團加以保 護。使用先前所述之標準方法移除所得之經保護二肽衍生 物（6)之保護基，得到胺（7)。 151651 .doc -64- 201121961 R1Coupling of the amine (4) to an amine group using a standard peptide coupling condition as described above via, for example, a third butoxy group (B〇c), an alumoxyl group (z) or a 9-methoxy methoxy group ( The amino acid (5) of moc) suitable for the protection of the protecting group. If the ruthenium or r2^ has a reactive functional group such as an amine or a carboxylic acid, the group is also protected. Removal of the protecting group of the resulting protected dipeptide derivative (6) using the standard method previously described provides the amine (7). 151651 .doc -64- 201121961 R1

胺⑺藉由以適合酸或_進行還原性烧基化而進一步衍 生化’得到烧基化胺（8)°通常，在室溫下，使胺⑺與盤 _在諸如1基删氫化鈉或乙酿氧基棚氫化鈉之適合還原 劑存在下，於諸如甲醇之適合溶劑中反應。The amine (7) is further derivatized by reductive alkylation with a suitable acid or hydration to give an alkylated amine (8). Typically, at room temperature, the amine (7) is combined with a disk such as sodium hydride or The ethyl oxy hydride sodium hydride is reacted in a suitable solvent such as methanol in the presence of a suitable reducing agent.

亦可使用先前所述之標準肽偶合條件使烷基化α胺基酸 (9)與胺（4)偶合來製備化合物1〇。 151651.doc -65- 201121961Compound 1 can also be prepared by coupling an alkylated alpha amino acid (9) with an amine (4) using standard peptide coupling conditions as previously described. 151651.doc -65- 201121961

可藉由使母體α胺基酸谁γ α夂進仃還原性烷基化來製備烷基化α 胺基酸（12)，其中羧基夫絲^地 土禾經保護（11)或其中羧基經諸如甲 si、第三tsi或三氣乙s旨之標準保護基保護成醋（14)，在 烧基化後’使用先前所述之標準方法移除此保護基。進行 還原性烷基化之典型條件描述於上文中。The alkylated α-amino acid (12) can be prepared by reductive alkylation of the parent α-amino acid, γ α, into the oxime, wherein the carboxyl group is protected (11) or the carboxyl group thereof A standard protecting group such as a Si, a third tsi or a tris, is protected as vinegar (14), which is removed after the alkylation using standard methods previously described. Typical conditions for carrying out reductive alkylation are described above.

或者，α胺基酸（9)可藉由使羧基經諸如曱酯、第三丁 酯、三氣乙酯之標準保護基適當保護之相應溴乙酸衍生物 06)與所需胺反應，繼而使用標準方法脫除保護基來製 151651.doc -66 - 201121961 備。通常，在室溫下，使溴乙酸衍生物（15)與胺在諸如二 異丙基乙胺或碳酸鉀或碳酸鈉之驗存在下，於諸如乙猜或 四氫呋喃之適合溶劑中反應。Alternatively, the alpha amino acid (9) can be reacted with the desired amine by reacting the carboxyl group with a corresponding bromine acetic acid derivative 06) suitably protected by a standard protecting group such as decyl ester, tert-butyl ester or tri-ethane ethyl ester, and then used. Standard method to remove the protective base to make 151651.doc -66 - 201121961. Usually, the bromoacetic acid derivative (15) is reacted with an amine in a suitable solvent such as dipyridylamine or tetrahydrofuran in the presence of an amine such as diisopropylethylamine or potassium carbonate or sodium carbonate at room temperature.

9 化合物（11)亦可自胺基經諸如第三丁氧羰基（B〇c)、苯甲 氧羰基（Z)或9-苐基甲氧羰基（Fm〇c)之標準保護基適當保護 之二肽（18)合成。該二肽可自兩個α胺基酸製備，其中一 者之胺基經諸如第二丁氧幾基（Β。。）、苯甲氧幾基（Ζ)或卜 第基甲氧羰基（Fm〇c)之標準保護基保護，而另一者之羧基 經諸如醋(諸如甲酯、第三丁醋、三氣乙醋)之標準保護： 保護°在偶合反應後’藉由先前所述之標準方法移除（17) 之緩基保護基。可錢上文料之標準肽偶合條件進行酿 胺鍵形成反應。 151651.doc •67· 2011219619 Compound (11) may also be suitably protected from an amine group via a standard protecting group such as a third butoxycarbonyl group (B〇c), a benzyloxycarbonyl group (Z) or a 9-fluorenylmethoxycarbonyl group (Fm〇c). Dipeptide (18) synthesis. The dipeptide can be prepared from two alpha amino acids, one of which is via, for example, a second butoxy group (Β), a benzyloxy group (Ζ) or a bromomethoxycarbonyl group (Fm). The standard protecting group of 〇c) is protected, while the carboxyl group of the other is protected by a standard such as vinegar (such as methyl ester, third butyl vinegar, triethyl vinegar): protection ° after the coupling reaction 'by the previously described The standard method removes the slow-acting protecting group of (17). The amine bond formation reaction can be carried out by standard peptide coupling conditions of the above materials. 151651.doc •67· 201121961

55

6 186 18

使用先前所述之標準肽偶合條件使胺（4)偶合至吡咯衍 生物（19)。若R1或R2具有諸如胺或羧酸之反應性官能基， 則亦對此基團加以保護。The amine (4) is coupled to the pyrrole derivative (19) using standard peptide coupling conditions as previously described. If R1 or R2 has a reactive functional group such as an amine or a carboxylic acid, the group is also protected.

OHOH

化合物（20)亦可自λ 目化合物（22)合成。該化合物可自 酸及吡咯衍生物（19彳制1 )製備，其中羧酸官能基經諸如酯（諸 151651.doc •68· 201121961 甲酯、第三丁醋、_知 ^ ^ 二氣乙酯）之標準保護基保護。在偶合 反應後’藉由办5 所所述之標準方法移除（21)之羧基保護 所述之標準肽偶合條件進行醯胺鍵形成反 R1Compound (20) can also be synthesized from λ compound (22). The compound can be prepared from an acid and a pyrrole derivative (manufactured by 19:1), wherein the carboxylic acid functional group is subjected to, for example, an ester (the 151651.doc •68·201121961 methyl ester, the third butyl vinegar, the _ knowing ^ ^ digas ethyl ester) ) Standard protection base protection. After the coupling reaction, the standard peptide coupling condition of (21) is removed by the standard method described in 5 to carry out the standard peptide coupling conditions for the indole bond formation to form an anti-R1

0 j吏用卜V 應。 使用先前所述之標準肽偶合條件使胺（4)偶合至乳酸衍 生物（23) °若Rl或R2具有諸如胺或羧酸之反應性官能基， 則亦對此基團加以保護。 R10 j吏 Use Bu V should. The amine (4) is coupled to the lactic acid derivative (23) using standard peptide coupling conditions as previously described. If Rl or R2 has a reactive functional group such as an amine or a carboxylic acid, the group is also protected. R1

R12 151651.doc •69· 23 201121961 化合物（24)亦可自化合物（26)合成。該化合物可自^胺基 酸及乳酸衍生物（23)製備，其中羧酸官能基經諸如酯（諸如 曱醋、第三丁酯、三氣乙酯）之標準保護基保護。在偶合 反應後’藉由先前所述之標準方法移除（25)之羧基保護 基。可使用上文所述之標準肽偶合條件進行醯胺鍵形成反 應。R12 151651.doc •69· 23 201121961 Compound (24) can also be synthesized from compound (26). The compound can be prepared from the amine acid and the lactic acid derivative (23) wherein the carboxylic acid functional group is protected by a standard protecting group such as an ester such as acenaphthene, tert-butyl ester or tri-ethyl ester. After the coupling reaction, the carboxyl protecting group of (25) is removed by standard methods previously described. The indole bond formation reaction can be carried out using the standard peptide coupling conditions described above.

胺（4)可藉由與磺醯氯化物（27)反應而衍生化，得到磺醯 胺衍生物（28)。若R1或R2具有諸如胺或羧酸之反應性官能 基，則亦對此基團加以保護。 151651.doc .70· 201121961 R1The amine (4) can be derivatized by reaction with sulfonium chloride (27) to give a sulfonamide derivative (28). If R1 or R2 has a reactive functional group such as an amine or a carboxylic acid, the group is also protected. 151651.doc .70· 201121961 R1

+ o^Vci R7 27 化合物（28)亦可自化合物（30)合成。該化合物可自α胺基 酸及讀醯氯化物（27)製備，其中缓酸官能基經諸如醋（諸如 甲酯、第三丁酯、三氯乙酯）之標準保護基保護。在偶合 反應後’藉由先前所述之標準方法移除（29)之羧基保護 基。可使用上文所述之標準肽偶合條件進行醯胺鍵形成反 應0 R1+ o^Vci R7 27 Compound (28) can also be synthesized from compound (30). The compound can be prepared from alpha amino acid and hydrazine chloride (27) wherein the acid retarding functional group is protected by a standard protecting group such as acetonide such as methyl ester, tert-butyl ester, trichloroethyl ester. After the coupling reaction, the carboxyl protecting group of (29) is removed by standard methods previously described. The indole bond formation reaction can be carried out using the standard peptide coupling conditions described above.

151651.doc -71- 201121961 胺（4)可藉由與酸氣化物或羧酸（31)反應而衍生化，得到 at胺衍生物（32)。若使用羧酸，則可使用上文所述之標準 肽偶合條件進行醯胺鍵形成反應。若R1或R2具有諸如胺或 羧酸之反應性官能基，則亦對此基團加以保護。151651.doc -71- 201121961 The amine (4) can be derivatized by reaction with an acid gasification or a carboxylic acid (31) to give an at amine derivative (32). If a carboxylic acid is used, the indole bond formation reaction can be carried out using the standard peptide coupling conditions described above. If R1 or R2 has a reactive functional group such as an amine or a carboxylic acid, the group is also protected.

化合物（32)亦可自1，1-幾基二咪唾化合物（34)合成。該化 合物可自α胺基酸及酸氯化物或羧酸（31)製備，其中額外 羧酸官能基經諸如酯（諸如甲酯、第三丁酯、三氯乙醋）之 標準保護基保護。在偶合反應後’藉由先前所述之標準方 法移除（33)之羧基保護基。可使用上文所述之標準肽偶合 條件進行醯胺鍵形成反應。 151651.doc 72· 201121961Compound (32) can also be synthesized from 1,1-diyldimethine compound (34). The compound can be prepared from an alpha amino acid and an acid chloride or a carboxylic acid (31) wherein the additional carboxylic acid functional group is protected by a standard protecting group such as an ester such as methyl ester, tert-butyl ester or trichloroacetic acid. After the coupling reaction, the carboxyl protecting group of (33) is removed by the standard method previously described. The indole bond formation reaction can be carried out using the standard peptide coupling conditions described above. 151651.doc 72· 201121961

胺（4)可藉由與胺（35)在諸如Μ-羰基二咪唑之適合試劑 存在下反應而衍生化，得到脲衍生物（36)。若R1或R2具有 諸如胺或羧酸之反應性官能基’則亦對此基團加以保護。The amine (4) can be derivatized by reaction with an amine (35) in the presence of a suitable reagent such as fluorene-carbonyldiimidazole to give a urea derivative (36). This group is also protected if R1 or R2 has a reactive functional group such as an amine or a carboxylic acid.

+ Ra+ Ra

36 R1736 R17

NHNH

Rb 35 化合物（3 6)亦可自化合物（38)合成。該化合物可自^胺基 酸及胺（35)製傷，其中羧酸官能基經諸如酯（諸如曱酯、第 三丁酿、三氣乙酯）之標準保護基保護。在偶合反應後， 藉由先前所述之標準方法移除（37)之羧基保護基。可使用 151651.doc •73· 201121961 上文所述之標準肽偶合條件進行酿胺鍵形成反應The Rb 35 compound (36) can also be synthesized from the compound (38). The compound can be modified from the amine acid and the amine (35) wherein the carboxylic acid functional group is protected by a standard protecting group such as an ester such as oxime ester, third butyl alcohol, or tri-ethane ethyl ester. After the coupling reaction, the carboxy protecting group of (37) is removed by standard methods as previously described. The amine bond formation reaction can be carried out using the standard peptide coupling conditions described above 151651.doc •73· 201121961

本發明亦涵蓋可用於合成式（I)化合物之中間化合物。因 此，本發明之一態樣提供選自包括以下之群的中間化合 物： {(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-萘-^基—乙 基}-胺基曱酸第三丁酯； (S)-2-胺基-N-(2-胺基-嗟&lt;»圭-5-基曱基）-3-秦-1 -基-丙酿胺. ((R)-l-{(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]蔡 基-乙基胺甲醯基}-2-甲基-丁基）-胺基甲酸第三丁隨； [(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-(3,4-二氣_笨 基）-乙基]-胺基甲酸第三丁酯； (S)-2-胺基-Ν-(2·胺基-噻唑-5-基曱基）-3-(3,4-二氟_笨基） 丙酿胺； [(S)-l-[(2-胺基·噻唑-5-基甲基）-胺甲醯基]-2-(4-氟-苯基） 乙基]-胺基甲酸第三丁酯； (S)-2-胺基-N-(2-胺基-〇塞吐-5-基甲基）-3-(4-氟-笨基）_兩酿 151651.doc • 74· 201121961 胺； (S)-N-[(S)-l-[(2-胺基-°塞°坐-5-基曱基）-胺曱酿基]-2_(4_氣_ 苯基）-乙基]-2-(異丙基-甲基-胺基）·丙酿胺； [(S)-l-[(2-胺基塞0坐-5-基甲基）-胺甲酿基]-2_(3,4_二氣-苯 基）-乙基]-胺基曱酸第三丁酯； (3)-2-胺基-&gt;^-(2-胺基_噻唑-5-基甲基）-3-(3,4-二氣-苯基）-丙醯胺； 3-甲基-1H-吡咯-2-曱酸[(S)-l-[(2-胺基-噻坐_5-基甲基）·胺 曱醯基]-2-(3,4-二氯-苯基）-乙基]-醯胺； (R) -N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醢基卜2_(3,4 一 氣-苯基）-乙基]-2-羥基-3-苯基-丙醯胺； (S) -2-胺基-3-萘-1-基-丙酸甲酯； (S)-3 -蔡-1-基- 2- (丙烧-1-績酿胺基）-丙酸甲西曰 (S)-3-萘-1-基-2-(丙炫-1-橫酿胺基）-丙酸， 1石黃酿胺 (S)-N-(2-胺基-噻唑-5-基甲基）-3-萘-1-基_2-(丙炫-^ 基）-丙醯胺； (R)-2-第三丁氧羰基胺基—3,3-二環己基-丙酸’ ^ 2 2-二環己&gt; {(R)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基卜’ 乙基}-胺基曱酸第三丁酯； 〆f己基-丙酸 (R) -2-胺基-N_(2-胺基-嗟〇坐-5-基曱基衣 胺； 、 基甲基）- (S) -1 -甲基比&lt;»各„定甲酸{(R)-l-[(2_胺基-癌 胺甲醯基]-2,2-二環己基-乙基}·醯胺； 及其醫藥學上可接受之鹽及溶劑合物。 151651.doc -75- 201121961 在一態樣中，本發明提供製備式（i)化合物之方法The invention also encompasses intermediate compounds which can be used in the synthesis of compounds of formula (I). Accordingly, one aspect of the present invention provides an intermediate compound selected from the group consisting of: {(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarbamyl]-2- (3)-2-Amino-N-(2-amino-indole&lt;&gt; Qin-1 -yl-propanolamine. ((R)-l-{(S)-l-[(2-Amino-thiazol-5-ylindenyl)-aminecarbamyl]Cetyl-ethyl [(S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminecarboxamidine] ]-2-(3,4-diqi_styl)-ethyl]-aminocarboxylic acid tert-butyl ester; (S)-2-amino-indole-(2.amino-thiazol-5-yl) Mercapto)-3-(3,4-difluoro-stupyl) propylamine; [(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarbamyl]- T-butyl 2-(4-fluoro-phenyl)ethyl]-carbamic acid; (S)-2-amino-N-(2-amino-decet-5-ylmethyl)- 3-(4-Fluoro-stupyl)_ two-flavored 151651.doc • 74· 201121961 Amine; (S)-N-[(S)-l-[(2-Amino-°°°°-5-yl曱-)-amine aryl group]-2_(4_gas_phenyl)-ethyl]-2-(isopropyl-methyl-amino)·propanol; [(S)-l-[ (2-Amino-based 0--5-ylmethyl)- Aminomethyl]-2_(3,4-di-phenyl)-ethyl]-amino decanoic acid tert-butyl ester; (3)-2-amino group-&gt;^-(2-amino group _thiazole-5-ylmethyl)-3-(3,4-di-phenyl)-propanamine; 3-methyl-1H-pyrrole-2-decanoic acid [(S)-l-[( 2-Amino-thiadosin-5-ylmethyl)-aminoindenyl]-2-(3,4-dichloro-phenyl)-ethyl]-decylamine; (R) -N-[( S)-l-[(2-Amino-thiazol-5-ylindenyl)-amine-mercaptopurin 2-(3,4-mono-phenyl)-ethyl]-2-hydroxy-3-phenyl- Propylamine; (S)-2-amino-3-naphthalen-1-yl-propionic acid methyl ester; (S)-3 -cain-1-yl- 2- (propyl ketone-1) )-Metoxime propionate (S)-3-naphthalen-1-yl-2-(propan-1-lanine)-propionic acid, 1 schistosamine (S)-N-(2-amine (R)-2-tert-butoxycarbonylamino-3,3, thiazol-5-ylmethyl)-3-naphthalen-1-yl-2-(propanyl-yl)-propanamine -dicyclohexyl-propionic acid '^ 2 2-bicyclohexanide&gt; {(R)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarboxamido'ethyl}- Tert-butyl amide decanoate; 〆f-hexyl-propionic acid (R)-2-amino-N-(2-amino-indolyl-5-yl decylamine; benzyl group)- S) -1 -methyl ratio &lt;» each _ carboxylic acid {(R)-l-[(2_amino-carcinoma) Acyl methyl] -2,2-dicyclohexyl -ethyl} - · Amides; and the pharmaceutically acceptable salts and solvates. 151651.doc -75- 201121961 In one aspect, the invention provides a method of preparing a compound of formula (i)

其包含使式（VI)化合物：It comprises a compound of formula (VI):

與式（VII)化合物：With the compound of formula (VII):

在標準肽偶合條件下反應；其中Rl_R5、R〗7及^係如先前 對於式⑴化合物所定義。 標準狀偶合條件包括使酸與胺在羥基苯并***及碳化二 亞胺（諸如水溶性碳化二亞胺）或六氟磷酸2_(1H•苯并***_ 卜基）-1’1，3,3-四甲基銨或六氟磷酸苯并***-基-氧基-參_ (Ν·°比咯啶基鱗或六氟磷酸溴-參（N-。比咯啶基）-鱗存在 下，在諸如三乙胺、二異丙基乙胺或N_甲基嗎啉之有機鹼 存在下反應。此等反應通常在諸如二氯甲烷及二曱基曱醯 胺之溶劑中進行。 【實施方式】 實例 I5165l.doc •76· 201121961 本發明係藉由下列非限制性實例來說明，其中使用下列 縮寫及定義： DMF N,N-二曱基曱醯胺 EtOAc 乙酸乙酯 hrs 小時 HBTU 六氟磷酸2-(1Η-苯并***-1-基）-1,1,3,3-四甲 基錁 HOBt 羥基苯并*** lie 異白胺酸 LCMS 液相層析質譜 Me 曱基 MeCN 乙腈 MeOH 曱醇 Min 分鐘 MS 質譜 Nal 萘丙胺酸 NMR 除非另外指示，否則核磁共振譜-NMR譜係在 400 MHz之頻率下記錄 Pet_ 醚 沸點為60°C -80°C之石油醚餾分 Phe ***酸 Pro 脯胺酸 THF 四氫呋喃 TFA 三氟乙酸 除非另外指定，否則所有反應皆在氮氣氛圍下進行。 1H NMR譜係在 Brucker Avance 111(400 MHz)光譜儀上參 照氘溶劑且在室溫下記錄。 分子態離子係使用LCMS獲得，LCMS係使用Chromolith Speedrod RP-1 8e 管柱（5〇χ4.6 mm)，經 11 分鐘以含 1 0% 至 151651.doc -77- 201121961 90% 0.1% HC02H/MeCN之0.1% HC02H/H20的線性梯度及 1.5毫升/分鐘之流速進行》使用具有電喷霧電離之 Thermofinnigan Surveyor MSQ 質譜儀聯合 Thermofinnigan Surveyor LC系統收集數據。 使用來自MDL Information Systems之作為ISIS繪圖套件 之一部分提供的Autonom軟體產生化學名稱。 若藉由急驟層析純化產物，則「二氧化矽」係指0.035 至0.070 mm(220至440篩目）之層析用矽膠（例如Merck矽膠 60)，且所施加之氮氣壓力至多10 p.s.i以加速管柱溶離。 逆相製備型HPLC純化係使用Waters 2525二元梯度抽汲系 統，以通常為20毫升/分鐘之流動速率且使用Waters 2996 光電二極體陣列偵測器進行。 所有溶劑及市售試劑皆原樣使用》 實例1 (R)-2-胺基-3 -甲基-戍酸{(S)-l-[(2-胺基-嗟吃-5-基甲基）-胺 甲酿基]_2-蔡_1-基-乙基}-酿胺The reaction is carried out under standard peptide coupling conditions; wherein R1_R5, R7 and ^ are as previously defined for the compound of formula (1). Standard coupling conditions include the acid and amine in hydroxybenzotriazole and carbodiimide (such as water-soluble carbodiimide) or hexafluorophosphate 2_(1H•benzotriazole-bu)-1'1, 3,3-Tetramethylammonium or benzotriazole-yl-oxy- hexafluorophosphate (Ν·°pyrrolidyl scale or hexafluorophosphate-paraben (N-.pyridinyl)- In the presence of scales, it is reacted in the presence of an organic base such as triethylamine, diisopropylethylamine or N-methylmorpholine. These reactions are usually carried out in a solvent such as dichloromethane and decylguanamine. [Embodiment] Example I5165l.doc • 76· 201121961 The present invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used: DMF N,N-dimercaptoamine EtOAc Ethyl acetate hrs hour HBTU 2-(1Η-benzotriazol-1-yl)-1,1,3,3-tetramethylhydrazine HOBt hydroxybenzotriazole lie isoleucine LCMS liquid chromatography mass spectrometry Me 曱MeCN acetonitrile MeOH sterol Min min MS mass spectrum Nal naphthyl NMR NMR spectra were recorded at a frequency of 400 MHz unless otherwise indicated. Petroleum ether fraction Phe Amphetamine Pro phthalic acid THF Tetrahydrofuran TFA Trifluoroacetic acid Unless otherwise specified, all reactions were carried out under a nitrogen atmosphere. 1H NMR spectrum at Brucker Avance 111 (400 MHz) The spectrometer was referenced to the solvent and recorded at room temperature. The molecular state ion was obtained by LCMS, and the LCMS system was Chromolith Speedrod RP-1 8e column (5〇χ4.6 mm), containing 10% to 11% 151651.doc -77- 201121961 90% 0.1% 0.1% of HC02H/MeCN Linear gradient of HC02H/H20 and flow rate of 1.5 ml/min" was collected using a Thermofinnigan Surveyor MSQ mass spectrometer with electrospray ionization in conjunction with a Thermofinnigan Surveyor LC system Data. Use the Autonom software from MDL Information Systems as part of the ISIS plotting kit to generate chemical names. If the product is purified by flash chromatography, "cerium oxide" means 0.035 to 0.070 mm (220 to 440 mesh). Chromatography with tannin (eg, Merck Silicone 60) and applying a nitrogen pressure of up to 10 psi to accelerate column leaching. Reverse phase preparative HPLC purification Using Waters 2525 binary gradient pumping system to a flow rate typically 20 ml / minute and using Waters 2996 photodiode array detector for. All solvents and commercially available reagents are used as such. Example 1 (R)-2-Amino-3-methyl-decanoic acid {(S)-l-[(2-Amino-indole-5-ylmethyl) )-Aminomethyl]_2-cai-1-yl-ethyl}-bristamine

A.【5-(第三丁氧羰基胺基-甲基）-噻唑-2-基】-胺基甲酸第三 丁酯 將2-胺基售唾-5-甲腈（5.0 g，39.95 mmol)溶解於甲醇 151651.doc -78- 201121961 (250 ml)中。將此溶液冷卻至〇乞。添加六水合氯化鎳 (11)(0.95 g，4.0 mmol)及二碳酸二第三丁酯（17 44 g，8〇 mmol) ’繼而逐份添加硼氫化鈉（1〇 6 g，mo mm〇1)。在 〇°C至室溫下攪拌反應混合物丨8小時。藉由蒸發移除 MeOH。將殘餘物溶解於Et〇Ac(200 mi)中，用飽和 NaHC03(lx5〇 ml)、水（ΐχ50 ml)、鹽水（lx5〇 ml)洗滌，乾 燥（NadCU)且經由PS紙過濾，且在真空中蒸發，得到棕色 油狀物。藉由急驟層析（二氧化矽），溶離劑3% Me〇H、 97% CHCI3純化殘餘物，得到鑑別為標題化合物之橙色油 狀物。 產量=4,30 g，13.05 mmol，33%。 B. 5·胺基甲基-噻唑-2-基胺二鹽酸鹽 用4 M HC1/二噁烷（100 ml)處理[5-(第三丁氧羰美胺基_ 甲基）-喧嗤-2-基]-胺基甲酸第三丁醋（K1 g，3&lt;34 在室溫下1小時後，移除溶劑’得到鑑別為標題化合物之 黃色固體。 產量=630 mg，3.12 mmol，93%。 [M+H]+ = 130.15。 C. {(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]_2萘^基― 乙基卜胺基甲酸第三丁酯 將5-胺基曱基-噻唑-2-基胺二鹽酸鹽（90 mg，〇 45 溶解於ml)及DMF(2爪1)中。將此溶液冷卻至 。添加 B〇C-lNal-OH(154 mg ’ 〇.49 軸〇1)，繼而添加 HOBt(120 mg，0.89 mmol)及水溶性碳化二亞胺（i〇2 ， 151651.doc •79- 201121961 0.53 mmol)。15分鐘後，添加三乙胺（135 mg，j 34 在〇 c至室溫下18小時後，在真空中移除溶劑且將 殘餘物溶解於EtOAc(70 ml)中，用NaHCO3(lx20 ml)、水 (1χ20 ml)、鹽水（1x20 ml)洗滌此溶液，乾燥（Na2S〇4)且在 真空中蒸發。藉由急驟層析（二氧化矽），溶離劑3〇/〇 MeOH、97% CHCI3純化殘餘物，合併溶離份且在真空中 蒸發，得到鑑別為標題化合物之泡洙狀白色固體。 產量=68 mg，0.16 mmol，36%。 [M+H]+ = 470.27。 D· (S)-2-胺基-N-(2-胺基-噻唑-5-基甲基）_3_萘-1-基·丙醯胺 二-三氟乙酸鹽 將{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]_2_萘基-乙基}-胺基甲酸第二丁醋（68 mg ’〇· 16 mmol)溶解於 TFA(20 ml)中。在室溫下丨小時後，在真空中移除溶劑， 付到鑑別為標題化合物之黃色油狀物。 產量=88 mg ’ 0.16 mmol，100%。 [M+H]+ = 327.07。 H NMR (CD3OD) 3.52-3.61 (2H, m), 3.98 (1H, d, 1=15.5 Hz), 4.12-4.28 (2H, m), 4.92 (4H, s), 6.85 (1H, s), 7.37. 7-39 (2H, m), 7.51-7.57 (3H, m), 7.81-7.91 (2H, m), 8.07 (1H，d，J=8.1 Hz)。 Ε· ((R)-i_{(s)-l-[(2-胺基-嘆唑_5_基甲基）胺甲醯基卜2萘_ 1-基-乙基胺甲醯基}-2-甲基-丁基）-胺基甲酸第三丁酯 將（S)-2-胺基-N-(2-胺基-噻唑-5-基曱基）-3-萘-1-基-丙酿 151651.doc -80- 201121961 胺一-二氟乙酸鹽（7〇 mg，0.13 mmol)溶解於 CH2C12(20 ml) 及DMF(2 ml)中。將此溶液冷卻至〇〇c。添加B〇c_DI】e_ OH(32 mg ’ 0.14 mmol) ’ 繼而添加H〇Bt(34 mg，0_25 mmol)及水溶性碳化二亞胺（29 mg，〇 15 mm〇i)。15分鐘 後，添加二乙胺（3 8 mg，0_38 mmol)。在〇°C至室溫下1 8小 時後’在真空中移除溶劑且將殘餘物溶解於Et〇AC(70 mi) 中，用NaHCO3(lx20 ml)、水（1x20 ml)、鹽水（1x20 ml)洗 滌此溶液’乾燥（NasSCU)且在真空中蒸發，得到黃色油狀 物。藉由急驟層析（二氧化矽），溶離劑3% Me〇H、97% CHCI3純化殘餘物’合併溶離份且在真空中蒸發，得到鑑 別為標題化合物之無色油狀物。 產量=26 mg，0.048 mmol，38%。 [M+H]+ = 540.36。 F· (R)-2-胺基·3-甲基-戊酸{(s)-l-[(2-胺基-噻唑-5-基甲 基）.-胺甲醯基】-2-萘-1-基-乙基}-醯胺二氟乙酸鹽 將（(R)-l-{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]-2-萘-1-基-乙基胺曱醯基}-2-甲基·丁基）-胺基甲酸第三丁酯 (26 mg，0.048 mmol)溶解於TFA(20 ml)中。在室溫下1小 時後，在真空中移除溶劑，得到橙色油狀物。藉由製備型 HPLC(Sunfire 製備型 C18 OBD 管柱，19x250 mm，10 μ)， 以20毫升/分鐘經35分鐘含10%至90% 0.1% TFA/MeCN之 0· 1 % TFA/H2〇純化殘餘物。合併溶離份且冷凍乾燥，得到 鑑別為標題化合物之白色固體。 產量=6 mg，0.009 mmol，19%。 151651.doc • 81 - 201121961 [M+H]+ = 440.24。 NMR: (CD3〇D) 0.70-0.76 (6Η, m) 1.15-1.30 (1H, m) 1.60-1.80 (1H, m) 3.29-3.32 (1H, m) 3.63-3.69 (2H, m) 4.25 (1H, d, J=33 Hz) 4.86 (1H, d, J=9.1 Hz), 4.93-4.95 (8H, m) 6.95 (1H, s) 7.36-7.38 (2H, m) 7.50-7.56 (2H, m) 7.70-7.80 (1H，m) 7·87 (1H，d，J=8,2 Hz) 8.17 (1H，d，J=8.4 Hz)。 實例2 (R)-l-甲基比洛咬_2_甲酸[(s)-l-[(2-胺基-噻唑-5-基甲基）-胺甲酿基】-2-(3,4-二氣-苯基）_乙基]-酿胺A. [5-(Tertidinoxycarbonylamino-methyl)-thiazol-2-yl]-aminocarboxylic acid tert-butyl ester 2-Amine-based saliva-5-carbonitrile (5.0 g, 39.95 mmol ) dissolved in methanol 151651.doc -78- 201121961 (250 ml). This solution was cooled to hydrazine. Add nickel (6) hexahydrate (0.95 g, 4.0 mmol) and dibutyl succinate (17 44 g, 8 〇 mmol) ' and then add sodium borohydride (1 〇 6 g, mo mm 逐) 1). The reaction mixture was stirred at 〇 ° C to room temperature for 8 hours. The MeOH was removed by evaporation. The residue was dissolved in EtOAc (EtOAc) (EtOAc) (EtOAc) Evaporation gave a brown oil. The residue was purified by EtOAc EtOAc (EtOAc) Yield = 4,30 g, 13.05 mmol, 33%. B. 5 · Aminomethyl-thiazol-2-ylamine dihydrochloride salt treated with 4 M HC 1 /dioxane (100 ml) [5-(T-butoxycarbonylamido-methyl)-oxime嗤-2-yl]-carbamic acid terpene vinegar (K1 g, 3 &lt; 34 after 1 h at room temperature, solvent removed) gave the title compound as a yellow solid. Yield = 630 mg, 3.12 mmol, 93%. [M+H]+ = 130.15. C. {(S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminecarboxylidene]-2-naphthalenyl-ethyl bromide The third butyl carbamic acid ester 5-aminomercapto-thiazol-2-ylamine dihydrochloride (90 mg, hydrazine 45 dissolved in ml) and DMF (2 claw 1). The solution was cooled to. Add B〇C-lNal-OH (154 mg '〇.49 Axis 〇1), followed by HOBt (120 mg, 0.89 mmol) and water-soluble carbodiimide (i〇2, 151651.doc •79- 201121961 0.53 After 15 minutes, triethylamine (135 mg, EtOAc EtOAc (EtOAc) (EtOAc) Wash the solution with lx20 ml), water (1 χ 20 ml), brine (1×20 ml), dry (Na2S 〇 4) and evaporate in vacuo. The ruthenium oxide), the eluent 3 〇 / 〇 MeOH, 97% CHCI3 purified residue, mp EtOAc (EtOAc) [M+H]+ = 470.27. D·(S)-2-Amino-N-(2-amino-thiazol-5-ylmethyl)_3_naphthalen-1-ylpropanamide II- Trifluoroacetate salt {(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine-carbamoyl]-2-naphthyl-ethyl}-carbamic acid second butyl vinegar ( 68 mg '〇· 16 mmol) was dissolved in TFA (20 mL). After EtOAc EtOAc (EtOAc) M, NMR (CD3OD) 3.52-3.61 (2H, m), 3.98 (1H, d, 1 = 15.5 Hz), 4.12-4.28 (2H, m), 4.92 (4H, s), 6.85 (1H, s), 7.37. 7-39 (2H, m), 7.51-7.57 (3H, m), 7.81-7.91 (2H, m), 8.07 (1H,d,J= 8.1 Hz). Ε·((R)-i_{(s)-l-[(2-Amino- oxazole-5-ylmethyl)amine-methylpyridyl 2naphthalene-1-yl-ethylamine-methyl hydrazino} Benzyl-2-methyl-butyl)-carbamic acid tert-butyl (S)-2-amino-N-(2-amino-thiazol-5-ylindenyl)-3-naphthalene-1- Base-propyl 151651.doc -80- 201121961 Amine-difluoroacetate (7 mg, 0.13 mmol) was dissolved in CH2C12 (20 ml) and DMF (2 ml). This solution was cooled to 〇〇c. Add B〇c_DI]e_OH (32 mg '0.14 mmol)' followed by H〇Bt (34 mg, 0-25 mmol) and water-soluble carbodiimide (29 mg, 〇 15 mm〇i). After 15 minutes, diethylamine (3 8 mg, 0-38 mmol) was added. After 18 hours at room temperature to room temperature, 'solvent was removed in vacuo and the residue was dissolved in Et EtOAc (70 mi), NaHCO3 (1×20 ml), water (1×20 ml), brine (1×20 This solution was washed with dryness (NasSCU) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography (EtOAc) eluting elute Yield = 26 mg, 0.048 mmol, 38%. [M+H]+ = 540.36. F·(R)-2-Amino-3-methyl-pentanoic acid {(s)-l-[(2-Amino-thiazol-5-ylmethyl).-Aminomethyl]-2- Naphthyl-1-yl-ethyl}-nonylamine difluoroacetate will be ((R)-l-{(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine oxime Tert-butyl 4-naphthalen-1-yl-ethylamine decyl}-2-methyl-butyl)-carbamic acid tert-butyl ester (26 mg, 0.048 mmol) dissolved in TFA (20 ml) . After 1 hour at room temperature, the solvent was removed in vacuo to give an orange oil. Purified by preparative HPLC (Sunfire preparative C18 OBD column, 19 x 250 mm, 10 μ) at 20 mL/min for 10 min with 10% to 90% 0.1% TFA/MeCN 0.1% TFA/H2 The residue. The fractions were combined and lyophilized to give a white solid that was identified as the title compound. Yield = 6 mg, 0.009 mmol, 19%. 151651.doc • 81 - 201121961 [M+H]+ = 440.24. NMR: (CD3〇D) 0.70-0.76 (6Η, m) 1.15-1.30 (1H, m) 1.60-1.80 (1H, m) 3.29-3.32 (1H, m) 3.63-3.69 (2H, m) 4.25 (1H , d, J=33 Hz) 4.86 (1H, d, J=9.1 Hz), 4.93-4.95 (8H, m) 6.95 (1H, s) 7.36-7.38 (2H, m) 7.50-7.56 (2H, m) 7.70-7.80 (1H,m) 7·87 (1H,d,J=8,2 Hz) 8.17 (1H,d,J=8.4 Hz). Example 2 (R)-l-methyl piroxime _2_carboxylic acid [(s)-l-[(2-amino-thiazol-5-ylmethyl)-amineyl]-2-(3 ,4-diqi-phenyl)-ethyl]-bristamine

A· (R)-l-甲基-吡咯啶 _2_ 甲酸（N_Me_DPro-OH) 將 H-DPro-OH(10.〇 g，86.9 mmol)溶解於甲醇（200 ml) 中，添加曱酸（37重量％溶液，7 ml)，繼而添加i〇〇/0 Pd/C (5 g)。在15 psi下震盪反應混合物18小時。此時段後，經 由矽藻土濾出催化劑且用Me〇H(1〇〇 ml)洗滌殘餘物。在真 二中蒸發合併之遽液，得到白色固體，使其自Me〇H/*** 中再…曰曰付到鐘別為標題化合物之白色結晶固體。 產里—10.72 g，83 mmol，96%。 [M+H]+ = 130.17。 Β· [(S)-l-【(2-胺基·嗟唑丄基甲基卜胺甲醯基卜2_(3,4二氣· 151651.doc -82- 201121961 苯基）-乙基】-胺基甲酸第三丁酯 將 Boc-(3,4-二氟）Phe-OH(270 mg，〇·9〇 mm〇l)溶解於 CH2C12(100 ml)及DMF(10 ml)中’將此溶液冷卻至〇。〇。添 加5-胺基曱基-&quot;塞唑-2-基胺二鹽酸鹽（199 mg，0.99 mmol) ’繼而添加HOBt( 145 mg，1.08 mmol)及二異丙基乙 胺（347 mg，2.69 mmol)。接著添加水溶性碳化二亞胺（189 mg，0.99 mmol)。在〇°C至室溫下5小時後，固體溶解，用 CHC13(150 ml)稀釋反應混合物，用飽和NaHC03( 1 χ50 ml)、水（1x50 ml)、鹽水（1x50 ml)洗滌此溶液，乾燥 (NaJO4)且在真空中蒸發。藉由急驟層析（二氧化矽），溶 離劑3% MeOH、97% CHC13純化殘餘物，合併溶離份且在 真空中蒸發’得到鑑別為標題化合物之白色固體。 產量=82 mg，〇·2〇 mmol，73%。 [M+H]+ = 413.49。 C. (S)-2-胺基_N_(2_胺基噻唑_5•基甲基）3(3,4二氟笨 基）-丙醯胺二鹽酸鹽 用4 M HC1/二噁院（50 ml)處理[(S)-l-[(2-胺基“塞。坐-5-基 甲基）-胺甲酿基]_2-(34_二I·苯基）乙基]_胺基曱酸第三丁 Μ80 mg ’ 〇·ΐ9 mm〇丨）。在室溫下i小時後，在真空中移除 /合劑’仔到鑑別為標題化合物之白色固體。 產量=75mg, 〇,19_q1，_%。 [M+H]+ = 313.37。 D. (R)_1_甲基比咯啶·2·曱酸[(S)-l-[(2-胺基-噻唑-5-基甲 基）胺曱酿基卜2·(3,4_二氟-苯基)_乙基]醯胺二_三氟乙酸鹽 151651.doc -83- 201121961 將（S)-2-胺基-N-(2-胺基塞唑-5-基甲基）-3-(3,4-二氟·苯 基）-丙酿胺二鹽酸鹽（79 mg’ 0.21 mmc^)溶解於CH2Cl2(20 ml)及DMF(2 ml)中。將此溶液冷卻至ot。添加NMe_ DPro-OH(29 mg，0.23 mmol)，繼而添加HOBt(33 mg， 0.25 mmol)及三乙胺（62 mg，0.62 mmol)。接著添加水溶 性碳化二亞胺（43 mg ’ 0.22 mmol)。在Ot：至室溫下is小時 後’用氣仿（100 ml)稀釋反應混合物且用NaHC〇3(lx；2〇 ml)、水（1x20 Μ)、鹽水（lx70 ml)洗滌，乾燥（Na2S〇4)且 在真空中蒸發，得到黃色油狀物。藉由製備型 HPLC(Sunfire 製備型 C18 OBD 管柱，19x250 mm，1〇 μ)， 以20毫升/分鐘經35分鐘含10%至90% 0.1% TFA/MeCN之 0· 1 °/〇 TFA/H2〇純化殘餘物。合併溶離份且冷;東乾燥，得到 鑑別為標題化合物之白色固體。 產量=46 mg，0.19 mmol，34%。 [M+H]+ = 424.48。 】H NMR: (CD3OD) 1.77-1.79 (1H，m)，1.92-1.97 (1H，m) 2.17-2.28 (2H, m), 2.47-2.56 (1H, m), 2.95 (3H} s), 3.06 (1H, s), 3.14-3.28 (2H, m), 3.68-3.83 (1H, m), 4.1〇-4.15 (1H, m), 4.30-4.46 (2H, m), 4.63-4.75 (1H, m), 4.91 (3H s), 7.06-7.25 (3H, m), 8.82-8.90 (1H, m) » 實例3 (S)-N-【(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基卜2-(4·^_ 笨基）·乙基】-2-(異丙基-甲基-胺基）-丙酿胺 151651.doc -84· 201121961A·(R)-l-methyl-pyrrolidine_2_carboxylic acid (N_Me_DPro-OH) H-DPro-OH (10. g, 86.9 mmol) was dissolved in methanol (200 ml), and citric acid (37) was added. % by weight solution, 7 ml), followed by addition of i〇〇/0 Pd/C (5 g). The reaction mixture was shaken at 15 psi for 18 hours. After this time, the catalyst was filtered off through celite and the residue was washed with &lt;RTI ID=0.0&gt; The combined mash was evaporated in EtOAc to give a white solid. Production - 10.72 g, 83 mmol, 96%. [M+H]+ = 130.17. Β·[(S)-l-[(2-Amino-oxazolylmethylammonium carbazyl 2_(3,4二气·151651.doc -82- 201121961 phenyl)-ethyl] -T-butyl carbamic acid ester, Boc-(3,4-difluoro)Phe-OH (270 mg, 〇·9〇mm〇l) was dissolved in CH2C12 (100 ml) and DMF (10 ml). This solution was cooled to 〇.〇. Add 5-aminomercapto-&quot;- oxazol-2-ylamine dihydrochloride (199 mg, 0.99 mmol)' followed by HOBt (145 mg, 1.08 mmol) and diiso Propylethylamine (347 mg, 2.69 mmol) followed by the addition of water-soluble carbodiimide (189 mg, 0.99 mmol). After 5 hours at 〇 °C to room temperature, the solid was dissolved and diluted with CHC13 (150 ml) The reaction mixture was washed with saturated NaHC03 (1 50 50 ml), water (1×50 ml), brine (1×50 ml), dried (NaJO4) and evaporated in vacuo. by flash chromatography (c. 3% MeOH, 97% CH.sub.3, EtOAc. 413.49 C. (S)-2-Amino-N-(2-aminothiazole_5•ylmethyl)3 ( 3,4 difluorophenyl)-propanamide dihydrochloride was treated with 4 M HC1/dioxin (50 ml) [(S)-l-[(2-Amino" plug. sit-5-yl Methyl)-amine methyl-based] 2 - (34-di-I-phenyl)ethyl]-amino decanoic acid tributyl hydrazine 80 mg ' 〇 · ΐ 9 mm 〇丨). After i hours at room temperature, The mixture was removed in vacuo to a white solid identified as the title compound. Yield = 75 mg, 〇, 19_q1, _%. [M+H]+ = 313.37. D. (R)_1_methylpyrrolidine ·2·Citrate [(S)-l-[(2-Amino-thiazol-5-ylmethyl)amine oxime 2·(3,4-difluoro-phenyl)-ethyl]醯Amine di-trifluoroacetate 151651.doc -83- 201121961 (S)-2-Amino-N-(2-aminoserrazol-5-ylmethyl)-3-(3,4-difluoro · Phenyl)-propanolamine dihydrochloride (79 mg '0.21 mmc^) was dissolved in CH2Cl2 (20 ml) and DMF (2 ml). This solution was cooled to ot. NMe_DPro-OH (29 mg) was added. , 0.23 mmol), followed by addition of HOBt (33 mg, 0.25 mmol) and triethylamine (62 mg, 0.62 mmol). Water-soluble carbodiimide (43 mg '0.22 mmol) was then added. After Os: to room temperature, after an hour, the reaction mixture was diluted with a gas imitation (100 ml) and washed with NaHC 3 (1×2 mL), water (1×20 Μ), brine (1×70 ml), and dried (Na2S) 〇 4) and evaporated in vacuo to give a yellow oil. Prepared by HPLC (Sunfire preparative C18 OBD column, 19x250 mm, 1 μμ), 20%/90% 0.1% TFA/MeCN 0·1 °/〇TFA at 20 ml/min over 35 minutes The residue was purified by H2. The combined fractions were combined and cooled to dryness to give a white solid. Yield = 46 mg, 0.19 mmol, 34%. [M+H]+ = 424.48. H NMR: (CD3OD) 1.77-1.79 (1H, m), 1.92-1.97 (1H, m) 2.17-2.28 (2H, m), 2.47-2.56 (1H, m), 2.95 (3H} s), 3.06 (1H, s), 3.14-3.28 (2H, m), 3.68-3.83 (1H, m), 4.1〇-4.15 (1H, m), 4.30-4.46 (2H, m), 4.63-4.75 (1H, m ), 4.91 (3H s), 7.06-7.25 (3H, m), 8.82-8.90 (1H, m) » Example 3 (S)-N-[(S)-l-[(2-Amino-thiazole- 5-ylmethyl)-amine-mercaptopurine 2-(4·^_ stupyl)·ethyl]-2-(isopropyl-methyl-amino)-propanol 151651.doc -84· 201121961

A· (S)-2-(異丙基甲基-胺基）_丙酸 將 N-Me-Ala-OH(2.0 g，15.5 mmol)溶解於曱醇（200 ml) 中’添加丙酮（1·3 g，23.2 mmol)，繼而添加 10% Pd/C(1.5 g)。在15 psi下震盪反應混合物1 8小時。此時段後，經由 矽藻土濾出催化劑且用MeOH( 100 ml)洗滌殘餘物。在真空 中蒸發合併之濾液，得到白色固體，使其自MeOH/***中 再結晶’得到鑑別為標題化合物之白色結晶固體。 產量=2.48 g ’ 17.1 mmol，88%。 [M+H]+ = 146.36。 Β·【(S)-l-[(2-胺基·噻唑-5-基甲基）-胺甲醯基】-2-(4-氟-苯 基）-乙基】-胺基甲酸第三丁酯 將 Boc-4-氟-Phe-OH(2.0 g，7·06 mmol)溶解於 CH2C12 (100 ml)中。向此溶液中添加HBTU(2.95 g，7.77 mmol)及 三乙胺（2.14 g，21.18 mmol)。20分鐘後，添加2-胺基-5-嗟°坐甲胺鹽酸鹽（1.29 g，7.77 mmol)。再於室溫下20分鐘 後，用CHC13(150 ml)稀釋反應混合物，用飽和NaHC03 (1x50 ml)、水（1x50 ml)、鹽水（1x50 ml)洗滌此溶液，乾 燥（NaaSO4)且在真空中蒸發。藉由急驟層析（二氧化矽）， 溶離劑3% MeOH、7% CHC13純化殘餘物，合併溶離份且 151651.doc •85- 201121961 在真空中蒸發，得到鑑別為標題化合物之白色固體β 產量=1.575 g ’ 3·99 mmol，57%。 [M+H]+ = 413,11。 C. (S)-2-胺基·Ν-(2-胺基-噻唑_5_基甲基）_3_(4·氟-苯基）·丙 醯胺二鹽酸鹽 用4 M HC1之二噁烷溶液〇〇〇 ml)處理基-噻 唑-5-基曱基）-胺甲醯基]_2(4氟_苯基乙基]_胺基曱酸第 二丁 Sa (1.575 g ’ 3.99 mm〇i)。在室溫下1小時後’在真空 中移除溶劑’得到鑑別為標題化合物之白色固體。 產量=1.03 g，2.67 mmol，ι〇〇〇/β。 [Μ+Η]+ = 313.13 〇 D· (S)-N-【(S)-l-【(2-胺基-嗔唾_5_基甲基）_胺甲酿基]·2_(4_ 氟-苯基）-乙基】·2-(異丙基_甲基-胺基）_丙醯胺二_三氟乙 酸鹽 將（S)-2-(異丙基-甲基_胺基）_丙酸（5〇 mg，0.34 mmol)溶 解於 CH2Cl2(30 ml)中。添加 HBTU(144 mg，0.38 mmol)及 三乙胺（105 mg，1.03 mmol)。在室溫下20分鐘後，添加 (S)-2-胺基-N-(2-胺基·噻唑_5_基甲基）-3-(4-氟-苯基）-丙醯 胺二鹽酸鹽（139 mg，〇·38 mmol)。在室溫下20分鐘後，用 CHC13(50 ml)稀釋反應混合物，用飽和NaHC〇3(lx3〇 ml)、水（1x30 ml)、鹽水（1x30 ml)洗滌此溶液，乾燥 (Naj 〇4)且在真空中蒸發。藉由急驟層析（二氧化石夕），溶 離劑7。/。MeOH、93% CHCh純化殘餘物，合併溶離份且在 真空中蒸發，得到白色固體。藉由製備型HPLC(Sunfire製 151651.doc • 86· 201121961 備型C18 OBD管柱，19x250 mm，1〇 μ)，以2〇毫升/分鐘 經 35 分鐘含 1〇% 至 90% 0.1% TFA/MeCN 之 0.1% TFA/H2〇 進 一步純化殘餘物。合併溶離份且冷凍乾燥，得到鑑別為標 題化合物之白色固體。 產量=31 mg，0.047 mmol，14%。 [Μ+Η]+ = 422·12。A·(S)-2-(isopropylmethyl-amino)-propionic acid N-Me-Ala-OH (2.0 g, 15.5 mmol) was dissolved in decyl alcohol (200 ml). • 3 g, 23.2 mmol), followed by 10% Pd/C (1.5 g). The reaction mixture was shaken at 15 psi for 18 hours. After this time the catalyst was filtered through EtOAc (EtOAc) (EtOAc) The combined filtrate was evaporated in vacuo to give crystals crystals crystals crystals Yield = 2.48 g ' 17.1 mmol, 88%. [M+H]+ = 146.36. Β·[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminecarbamyl]-2-(4-fluoro-phenyl)-ethyl]-carbamic acid Tributyl ester Boc-4-fluoro-Phe-OH (2.0 g, 7.06 mmol) was dissolved in CH2C12 (100 ml). To this solution were added HBTU (2.95 g, 7.77 mmol) and triethylamine (2.14 g, 21.18 mmol). After 20 minutes, 2-amino-5-oxime methylamine hydrochloride (1.29 g, 7.77 mmol) was added. After 20 minutes at room temperature, the reaction mixture was diluted with CH.sub.3 (150 mL). EtOAc (EtOAc) evaporation. The residue was purified by flash chromatography (EtOAc) eluting with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc =1.575 g '3·99 mmol, 57%. [M+H]+ = 413,11. C. (S)-2-Amino-indole-(2-amino-thiazole-5-ylmethyl)_3_(4·fluoro-phenyl)·propanamine dihydrochloride 4 M HC1 Oxane solution 〇〇〇ml) Treatment group - thiazol-5-ylindenyl)-amine carbaryl]_2 (4 fluoro-phenylethyl)-amino decanoic acid second butyl Sa (1.575 g ' 3.99 mm 〇i). After 1 hour at room temperature, 'solvent was removed in vacuo' to give a white solid identified as the title compound. Yield = 1.03 g, 2.67 mmol, ι〇〇〇/β. [Μ+Η]+ = 313.13 〇D· (S)-N-[(S)-l-[(2-Amino-嗔 __5_ ylmethyl)-amine aryl]] 2_(4_ fluoro-phenyl)-B (S)-2-(isopropyl-methyl-amino)-propionic acid (5〇) Mg, 0.34 mmol) dissolved in CH 2 Cl 2 (30 ml). Add HBTU (144 mg, 0.38 mmol) and triethylamine (105 mg, 1.03 mmol). After 20 min at room temperature, add (S)-2- Amino-N-(2-amino-thiazole-5-ylmethyl)-3-(4-fluoro-phenyl)-propanamide dihydrochloride (139 mg, 〇·38 mmol). After 20 minutes at room temperature, dilute the reaction mixture with CHC13 (50 ml) using sat. NaHC 〇3 (1×3 〇ml) Wash the solution with water (1 x 30 ml), brine (1 x 30 ml), dry (Naj 〇 4) and evaporate in vacuo. by flash chromatography (salt dioxide), lysing agent 7. MeOH, 93% The residue was purified by CHCHjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Mg, 0.047 mmol, 14% [Μ+Η]+ = 422·12.

*H NMR: (CD3〇D) 1.12 (3H, d, J=5.44 Hz), 1.26 (6U J=6.53 Hz), 1.32-1.39 (1H，m)，1_55 (3H，d，J=6.52 如） 2.52 (1H，s，br)，2.68 (3H，s)，2.83 (1H，s，br), 2.91、2 旳 (1H，m)，3.18-3.23 (1H，m), 3.95 (1H，q，J=6.85 Hz)，4 3】 4·44 (2H，m)，7.05-7.13 (3H，m)，7.31-7.35 (2H，m)。 實例4 3-曱基-1H-吡咯-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基甲基）、膝 甲醯基]-2-(3,4-二氣-苯基）-乙基】-醯胺*H NMR: (CD3〇D) 1.12 (3H, d, J=5.44 Hz), 1.26 (6U J=6.53 Hz), 1.32-1.39 (1H,m),1_55 (3H,d,J=6.52) 2.52 (1H, s, br), 2.68 (3H, s), 2.83 (1H, s, br), 2.91, 2 旳 (1H, m), 3.18-3.23 (1H, m), 3.95 (1H, q, J = 6.85 Hz), 4 3] 4·44 (2H, m), 7.05-7.13 (3H, m), 7.31-7.35 (2H, m). Example 4 3-Mercapto-1H-pyrrole-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl), Ketylmercapto]-2-(3,4- Dioxo-phenyl)-ethyl]-decylamine

A. [(S)-l-[(2-胺基-嗟唾_5-基甲基）-胺甲醯基】_2-(3,4-二氣 笨基）-乙基l·胺基甲酸第三丁醋 將 Boc-3,4-二氯-Phe-OH(1.〇 g ’ 2.99 mmol)溶解於 CH2C12(30 ml)中。向此溶液中添加 HBTU(1.13 g，2 % 151651.doc -87 - 201121961 mmol)及二乙胺（1.26 g’ 8.98 mmol)。20分鐘後，添力口 2-胺 基-5-噻唑曱胺鹽酸鹽（545 mg，3.29 mm〇l)。在室溫下2小 時後，用CHC13(50 ml)稀釋反應混合物，用飽和NaHC〇3 (1x3 0 ml)、水（1x30 ml)、鹽水（ix3〇 ml)洗滌此溶液，乾 燥（NazSO4)且在真空中蒸發。藉由急驟層析（二氧化矽）， 溶離劑6% MeOH、94% CHsCh純化殘餘物，合併溶離份且 在真工中蒸發’付到鑑別為標題化合物之白色固體。 產量=1.05 g，2.36 mmol，79%。 [Μ+Η]+ = 445.00 ° 8.(8)-2-胺基-]\-(2-胺基-噻唑-5-基甲基）-3-(3,4-二氣-苯 基）-丙醯胺二鹽酸鹽 用4 M HC1之二噁烷溶液（20 ml)處理[(S)-l-[(2-胺基-噻 唑-5-基甲基）-胺曱醯基]-2-(3,4-二氯·苯基）-乙基]-胺基甲 酸第三丁酯（1.05 g ’ 2.36 mmol)。在室溫下1小時後，在真 空中移除溶劑，得到鑑別為標題化合物之淺棕色固體。 產量=980 mg，2.34 mmol，99%。 [M+H]+ = 344.96 〇 C. 3-甲基-1H-吡咯-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基甲基）_ 胺甲醢基】-2-(3,4-二氯-苯基）-乙基]-酿胺 將3-甲基-1H-吡咯-2-曱酸（25 mg，0_20 mmol)溶解於 CH2C12(30 ml)中。添加HBTU(76 mg，0.20 mmol)及三乙 胺（84 mg，603 mmol)。在室溫下1小時後，添加（S)-2-胺 基-N-(2-胺基-噻唑-5-基甲基）-3-(3,4-二氣-苯基）-丙醯胺二 鹽酸鹽（92 mg，0.22 mmol)。在室溫下20分鐘後，用 151651.doc -88 - 201121961 CHC13(50 ml)稀釋反應混合物，用飽和NaHCO3(lx30 ml)、 水（1x3 0 ml)、鹽水（1x3 0 ml)洗滌此溶液，乾燥（Na2S04)且 在真空中蒸發。藉由急驟層析（二氧化石夕），溶離劑8 % MeOH、92% CHKh純化殘餘物，合併溶離份且在真空中 蒸發，得到鑑別為標題化合物之灰白色固體。 產量=36 mg，0.08 mmol，40%。 [M+H]+ = 452.02&amp;454.01 ° ]H NMR (d6-DMSO) 2.17 (3H, s), 2.84-2.90 (1H, m), 3.〇〇. 3.05 (1H，m), 4.18-4.28 (2H, m)，4.62-4.68 (1H, m), 5 91 (1H，t, J=2.3 Hz), 6.76-6.78 (4H，m)，7.23 (ih，dd J=8.3,2.0 Hz)，7.40 (1H，d，J=8.4 Hz)，7.47-7.51 (ih, m) 7.53 (1H，d，J=1.9 Hz)，8.57 (1H，t，J=5.7 Hz)。 實例5 (1〇-〜[(8)-1-[(2-胺基-嘆唑-5-基甲基）_胺甲醯基】_2_(34 一氣-苯基）-己基】-2-經基-3-苯基-丙醯胺A. [(S)-l-[(2-Amino-indenyl-5-ylmethyl)-amine-methylcarbonyl]_2-(3,4-dioxaphenyl)-ethyll-amine Toluene formic acid citrate Boc-3,4-dichloro-Phe-OH (1. 〇g ' 2.99 mmol) was dissolved in CH 2 C 12 (30 ml). To this solution were added HBTU (1.13 g, 2% 151651.doc -87 - 201121961 mmol) and diethylamine (1.26 g' 8.98 mmol). After 20 minutes, add 2-amino-5-thiazolylamine hydrochloride (545 mg, 3.29 mm 〇l). The reaction mixture was diluted with CHC13 (50 ml Evaporate in a vacuum. The residue was purified by flash chromatography (EtOAc) elut elut elut elut elut elut elut elut Yield = 1.05 g, 2.36 mmol, 79%. [Μ+Η]+ = 445.00 ° 8. (8)-2-Amino-]\-(2-amino-thiazol-5-ylmethyl)-3-(3,4-di-phenyl-phenyl) - propylamine dihydrochloride was treated with 4 M HCl in dioxane (20 ml) [(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl) ]-2-(3,4-Dichlorophenyl)-ethyl]-carbamic acid tert-butyl ester (1.05 g ' 2.36 mmol). After 1 hour at room temperature, the solvent was removed in vacuo to afford a pale brown solid that was identified as the title compound. Yield = 980 mg, 2.34 mmol, 99%. [M+H]+ = 344.96 〇C. 3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminocarboxamidine 2-(3,4-Dichloro-phenyl)-ethyl]-chiral amine 3-methyl-1H-pyrrole-2-furic acid (25 mg, 0-20 mmol) dissolved in CH2C12 (30 ml) in. HBTU (76 mg, 0.20 mmol) and triethylamine (84 mg, 603 mmol) were added. After 1 hour at room temperature, (S)-2-amino-N-(2-amino-thiazol-5-ylmethyl)-3-(3,4-di-phenyl)-propane was added. Indoleamine dihydrochloride (92 mg, 0.22 mmol). After 20 minutes at room temperature, the reaction mixture was diluted with 151651.doc -88 - 201121961 CHC13 (50 ml), and the solution was washed with saturated NaHCO3 (1×30 ml), water (1×30 ml), brine (1×30 ml). Dry (Na2S04) and evaporate in vacuo. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut Yield = 36 mg, 0.08 mmol, 40%. [M+H]+ = 452.02 &amp;454.01 ° ]H NMR (d6-DMSO) 2.17 (3H, s), 2.84-2.90 (1H, m), 3.〇〇. 3.05 (1H,m), 4.18- 4.28 (2H, m), 4.62-4.68 (1H, m), 5 91 (1H, t, J = 2.3 Hz), 6.76-6.78 (4H, m), 7.23 (ih, dd J=8.3, 2.0 Hz) , 7.40 (1H, d, J = 8.4 Hz), 7.47-7.51 (ih, m) 7.53 (1H, d, J = 1.9 Hz), 8.57 (1H, t, J = 5.7 Hz). Example 5 (1〇-~[(8)-1-[(2-Amino- oxazol-5-ylmethyl)-amine-carbamoyl]_2_(34-a-phenyl)-hexyl]-2- Benzyl-3-phenyl-propanamide

A. (R)-N-[(S)-l-[(2-胺基-噻唑_5_基甲基）_胺曱酿基】^ (3,4-二氣-苯基）·乙基】-2-羥基_3_苯基_丙醯胺三氟乙酸鹽 將（S)-2-胺基-Ν-(2·胺基-噻唑_5•基甲基）_3_(3 4-二氯-笨 151651.doc •89- 201121961 基）-丙醯胺二鹽酸鹽（101 mg，0.24 mmol)溶解於CH2C12(10 ml)中。將此溶液冷卻至〇〇c。添加D_3_苯基乳酸（4〇 mg， 0.24 mmol) ’ 繼而添加 H〇Bt(39 mg，0.29 mmol)及水溶性 碳化二亞胺（65 mg ’ 0.34 mmol)。15分鐘後，添加三乙胺 (135 mg，0.96 mmol)。在〇°C至室溫下18小時後，用 CHCIWO ml)稀釋反應混合物，用飽和NaHC〇3(lx2〇 ml)、水（1x20 ml)、鹽水（lx2〇 ml)洗滌此溶液，乾燥 (NaaSO4)且在真空中蒸發。藉由急驟層析（二氧化矽），溶 離劑8% MeOH、92。/。純化殘餘物。藉由製備型 HPLC(Sunfire製備型 C18 OBD管柱，19χ25〇 mm，ι〇 幻， 以20毫升/分鐘經35分鐘含1〇%至9〇。/。〇 1% TFA/MeCN之 〇·1% TFA/H2〇進一步純化殘餘物。合併溶離份且冷凍乾 無，得到鑑別為標題化合物之白色固體。 產量=10 mg，0.02 mmol，70/。。 [M+H]+ = 493.04&amp;495.04。 H NMR (CD3OD) 2.83-2.90 (1H，m)，2.95-3.00 (1H，m)， 3.05-3.11 (2H’ m)，4.22-4.36 (3H，m)，4.56-4.62 (1H，m)， 7.12 (1H, s), 7.17 (1H, dds 1=8.2,2.0 Hz), 7.20-7.31 (5H, m), 7.39 (1H, d, J=2.0 Hz), 7.44 (1H, d, J=8.2 Ηζ), 8.〇〇 (1H，d，J=8.0 Hz), 8.56 (1H, t，J=5.7 Hz)。 實例6 ⑻-ν·(2-胺基_嗔唾_5_基甲基^蔡+基^丙^^胺 基）-丙酿胺 151651.doc •90- 201121961A. (R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-amine oxime] ^ (3,4-di-phenyl)·B (2-)-3-hydroxy-3-phenyl-propionamine trifluoroacetate (S)-2-amino-indole-(2.amino-thiazole-5(yl)methyl)_3_(3 4- Dichloro- stupid 151651.doc •89- 201121961 base)-propanamide dihydrochloride (101 mg, 0.24 mmol) was dissolved in CH2C12 (10 ml). This solution was cooled to 〇〇c. D_3_phenyl lactic acid (4 mg, 0.24 mmol) was added followed by H〇Bt (39 mg, 0.29 mmol) and water-soluble carbodiimide (65 mg '0.34 mmol). After 15 minutes, triethylamine (135 mg, 0.96 mmol) was added. After 18 hours at 〇 ° C to room temperature, the reaction mixture was diluted with CHCIWO ml), washed with saturated NaHC 〇 3 (1×2 〇ml), water (1×20 ml), brine (1×2 〇ml), and dried (NaaSO4) And evaporate in a vacuum. By flash chromatography (ceria), the solvent was 8% MeOH, 92. /. The residue was purified. Prepared by HPLC (Sunfire preparative C18 OBD column, 19χ25〇mm, ι〇幻, containing 1〇% to 9〇 at 20ml/min for 35 minutes. 〇1% TFA/MeCN〇·1 The residue was further purified by EtOAc (EtOAc): EtOAc (EtOAc). H NMR (CD3OD) 2.83-2.90 (1H, m), 2.95-3.00 (1H, m), 3.05-3.11 (2H' m), 4.22-4.36 (3H, m), 4.56-4.62 (1H, m) , 7.12 (1H, s), 7.17 (1H, dds 1=8.2, 2.0 Hz), 7.20-7.31 (5H, m), 7.39 (1H, d, J=2.0 Hz), 7.44 (1H, d, J= 8.2 Ηζ), 8.〇〇(1H,d,J=8.0 Hz), 8.56 (1H, t, J=5.7 Hz). Example 6 (8)-ν·(2-Amino-嗔______基基甲基^蔡+基^丙^^Amino)-propanol 151651.doc •90- 201121961

HNHN

A· (S)_2-胺基-3·萘-1_基_丙酸曱酯鹽酸鹽 將H-lNal-OH(5.〇 g’ 23 2 mm〇1)溶解於曱醇（2〇〇 如) 中。將此溶液冷卻至代，缓慢添加亞硫醯氣（5 9 ml，8ι mmol)。在〇 c至室溫下3小時後，在真空中移除溶劑。使 殘餘物自MeOH/***中再結晶，得到鑑別為標題化合物之 白色固體。 產量=6.10 g ’ 22.96 mmol，99%。 [M+H]+ = 230.10。 Β· (S)-3-萘-1-基-2·(丙烷磺醯胺基）·丙酸曱酯 將（S)-2-胺基-3-萘基-丙酸曱酯鹽酸鹽（2 〇 g , 7 535 mmol)溶解於二氯曱烷（1〇〇 ml)中。添加卜丙烷磺醯氣〇 g，9_03 繼而添加三乙胺〇 68 g，166 mm〇i)。在 室溫下攪拌反應混合物5小時，且用CHCl3(15〇 ml)稀釋， 用 0.3 M KHSO4(lx50 ml)、飽和 NaHCO3(lx50 ml)、水 (1 50 ml)、鹽水（lx5〇 mi)洗務此溶液，乾燥且經 由PS紙過濾，且在真空中蒸發。藉由急驟層析（二氧化 矽），溶離劑2¼ MeOH、98¼ CHCl3純化殘餘物，合併溶 離份且在真空中蒸發，得到鑑別為標題化合物之白 151651.doc -91 - 201121961 體。 產量=2.162 g ’ 6.45 mmol，86%。 [M+H]+ = 336.13。 C. (S)-3-蔡-1-基-2-(丙炫》-1-續酿胺基）-丙酸 將（S)-3-萘-1-基-2-(丙烷-1-磺醯胺基）-丙酸曱酯（2.16 g’ 6.64 mmol)溶解於 THF(100 ml)及水（10 ml)中。添加單 水合氫氧化鋰（297 mg，7.1 mmol)。在室溫下攪拌反應混 合物18小時。用EtOAc( 150 ml)稀釋反應混合物。用1 Μ鹽 酸（1χ50 ml)、水（1x50 ml)、鹽水（1x50 ml)洗滌此溶液， 乾燥（Na2S04)且在真空中蒸發，得到鑑別為標題化合物之 白色固體。 產量=1.85 g，5.76 mmol，89%。 [M+H]+ = 321.91。 D. (S)-N-(2-胺基-噻唑-5-基甲基）-3-萘-1-基-2-(丙烷-1-續 醯胺基）-丙醯胺三氟乙酸鹽 將（S)-3 -萘-1-基-2-(丙烷-1-磺醯胺基）_丙酸（218 mg， 0.68 mmol)溶解於 CH2C12(30 ml)中，添加 HBTU(283 mg， 0.75 mmol)及三乙胺（206 mg，2·03 mmol)。在室溫下 20分 鐘後，添加2-胺基-5-噻唑曱胺鹽酸鹽（124 mg，0.75 mmol)。在室溫下20分鐘後’用CHC13(50 ml)稀釋反應混 合物，用飽和 NaHC03(l x30 ml)、水（1x30 mi)、鹽水（1 χ3〇 ml)洗蘇此溶液’乾燥（NajO4)且在真空中蒸發。藉由急驟 層析（二氧化矽）’溶離劑3°/d MeOH，97% CHC13純化殘餘 物，合併溶離份且在真空中蒸發，得到白色固體。藉由製 151651.doc •92. 201121961 備型 HPLC(SUnfire 製備型 C18 〇BD 管柱，19χ25〇 爪爪，ι〇 μ)，以20毫升/分鐘經35分鐘含1〇%至9〇% 〇 1% 之0.1% TFA/H2〇進一步純化殘餘物。合併溶離份且冷凍乾 燥，得到鑑別為標題化合物之白色固體。 產量=491 mg，〇.〇9 mmol，13%。 [M+H]+ = 43 3.00 ° H NMR: (CD3OD), 0.69 (3H，t, J=7.4 Hz), 1.23-1.30 (1H, m), 1.32-1.44 (1H, m), 2.32-2.41 (2H, m), 3.14-3.26 (1H, m), 3.64-3.69 (1H, m), 4.19-4.32 (3H, m), 4.90 (3H, s), 6.99 (1H, s), 7.38-7.43 (2H, m), 7.51-7.62 (2H, m), 7.81-7.83 (1H, m), 7.90-7.91 (1H, d, J=7.72 Hz), 8.18 (1H, d, J=8.49 Hz), 8.58-8.62 (1H，m)。 實例7 (S)-l-甲基-吡咯啶_2_曱酸{(R)-i_[(2-胺基-噻唑_5_基甲基）_ 胺甲醯基】-2,2-二環己基-乙基}-醯胺A·(S)_2-Amino-3·naphthalen-1-yl-propionate hydrochloride The H-lNal-OH (5.〇g' 23 2 mm〇1) was dissolved in decyl alcohol (2〇) For example, in the middle. The solution was cooled to completion and sulfite gas (5 9 ml, 8 ι mmol) was slowly added. After 〇 c to room temperature for 3 hours, the solvent was removed in vacuo. The residue was recrystallized from MeOH /EtOAc toield Yield = 6.10 g ' 22.96 mmol, 99%. [M+H]+ = 230.10. Β·(S)-3-naphthalen-1-yl-2·(propanesulfonylamino)·decyl propionate (S)-2-Amino-3-naphthyl-propionic acid decyl ester hydrochloride (2 〇g, 7 535 mmol) was dissolved in dichloromethane (1 mL). Add propane sulfonium gas 〇 g, 9_03 followed by triethylamine 〇 68 g, 166 mm 〇i). The reaction mixture was stirred at room temperature for 5 hours and diluted with CHCl 3 (15 mL), washed with 0.3 M KHSO 4 (1×50 ml), saturated NaHCO3 (1×50 ml), water (1 50 ml), brine (1×5 〇mi) The solution was dried, filtered through PS paper, and evaporated in vacuo. The residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut Yield = 2.162 g ' 6.45 mmol, 86%. [M+H]+ = 336.13. C. (S)-3-Cai-1-yl-2-(Prohanced Ethyl)-1-Continuous Amino)-propionic acid (S)-3-naphthalen-1-yl-2-(propane-1) - sulfonylamino)- decanoyl propionate (2.16 g ' 6.64 mmol) was dissolved in THF (100 ml) and water (10 ml). Lithium hydroxide monohydrate (297 mg, 7.1 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (150 mL). This solution was washed with EtOAc (1 EtOAc) (EtOAc) Yield = 1.85 g, 5.76 mmol, 89%. [M+H]+ = 321.91. D. (S)-N-(2-Amino-thiazol-5-ylmethyl)-3-naphthalen-1-yl-2-(propane-1-continuous amino)-propanamide trifluoroacetic acid Salt (S)-3-naphthalen-1-yl-2-(propan-1-sulfonylamino)-propionic acid (218 mg, 0.68 mmol) was dissolved in CH2C12 (30 ml), and HBTU (283 mg) was added. , 0.75 mmol) and triethylamine (206 mg, 2.03 mmol). After 20 minutes at room temperature, 2-amino-5-thiazolylamine hydrochloride (124 mg, 0.75 mmol) was added. After 20 minutes at room temperature, the reaction mixture was diluted with CHC13 (50 ml), and the solution was dried (NajO4) with saturated NaHC03 (1 x 30 ml), water (1×30 mi), brine (1 30 3 〇ml) and Evaporate in a vacuum. The residue was purified by EtOAc EtOAc (EtOAc) By 151651.doc •92.201121961 Prepared HPLC (SUnfire preparative C18 〇BD column, 19χ25〇 claw, ι〇μ), containing 20%/min for 1 minute to 9〇% at 35 ml/min The residue was further purified by 1% of 0.1% TFA/H2. The combined fractions were combined and dried to give a white solid. Yield = 491 mg, 〇.〇 9 mmol, 13%. [M+H]+ = 43 3.00 ° H NMR: (CD3OD), 0.69 (3H, t, J = 7.4 Hz), 1.23-1.30 (1H, m), 1.32-1.44 (1H, m), 2.32-2.41 (2H, m), 3.14-3.26 (1H, m), 3.64-3.69 (1H, m), 4.19-4.32 (3H, m), 4.90 (3H, s), 6.99 (1H, s), 7.38-7.43 (2H, m), 7.51-7.62 (2H, m), 7.81-7.83 (1H, m), 7.90-7.91 (1H, d, J=7.72 Hz), 8.18 (1H, d, J=8.49 Hz), 8.58-8.62 (1H, m). Example 7 (S)-l-Methyl-pyrrolidine_2_decanoic acid {(R)-i_[(2-amino-thiazole-5-ylmethyl)-aminocarboxylidene-2,2- Dicyclohexyl-ethyl}-decylamine

A· (R)-2-第三丁氧羰基胺基·3,3-二環己基-丙酸 將 Boc-D-3,3-二***酸（4.86 g，14.06 mmol)溶解於甲 酵（200 ml)中。在60 psi及室溫下，經5% Rh/碳（500 mg)氫 化此溶液。在室溫下2天後，再添加5°/。Rh/碳（500 mg)且 151651.doc -93- 201121961 再在60 psi及室溫下繼續氫化3天。此時段後，經由矽藻土 濾出催化劑且用MeOH(l 〇〇 ml)洗滌殘餘物。在真空中蒸發 合併之濾液，得到鑑別為標題化合物之泡沫狀白色固體。 產量=4.95 g，14 mmol，1〇〇〇/0。 [M+H]+ = 354.28 〇 B. {(R)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2,2-二環已 基-乙基}-胺基甲酸第三丁醋 將（R)-2·第三丁氧羰基胺基-3,3-二環己基-丙酸（1.0 g， 2·83 mmol)溶解於CH2C12(100 ml)中。添加三乙胺（859 mg ’ 8.490 mmol)及 HBTU( 1.18 g，3.114 mmol)，繼而添加 2-胺基-5-0塞哇甲胺鹽酸鹽（515 mg，3.11 mmol)。在室溫下 20分鐘後，用CHC13(150 ml)稀釋反應混合物，用飽和A·(R)-2-Tertidinoxycarbonylamino-3,3-dicyclohexyl-propionic acid Boc-D-3,3-diphenylalanine (4.86 g, 14.06 mmol) was dissolved in the yeast ( 200 ml). This solution was hydrogenated at 5% Rh/carbon (500 mg) at 60 psi and room temperature. After 2 days at room temperature, add another 5 ° /. Rh/carbon (500 mg) and 151651.doc -93- 201121961 were further hydrogenated at 60 psi and room temperature for 3 days. After this time, the catalyst was filtered through celite and washed with MeOH (1 EtOAc). The combined filtrate was evaporated in vacuo to give a white solid. Yield = 4.95 g, 14 mmol, 1 〇〇〇 / 0. [M+H]+ = 354.28 〇B. {(R)-l-[(2-Amino-thiazol-5-ylindenyl)-aminecarbamyl]-2,2-dicyclohexyl-B (R)-2·t-butoxycarbonylamino-3,3-dicyclohexyl-propionic acid (1.0 g, 2.83 mmol) was dissolved in CH2C12 (100 ml) )in. Triethylamine (859 mg ' 8.490 mmol) and HBTU ( 1.18 g, 3.114 mmol) were added followed by 2-amino-5-0 swamethane hydrochloride (515 mg, 3.11 mmol). After 20 minutes at room temperature, dilute the reaction mixture with CHC13 (150 ml) and saturate

NaHCO3(lx20 ml)、水（1x50 ml)、鹽水（1x50 ml)洗滌此溶 液’乾燥（NazSO4)且在真空中蒸發》藉由急驟層析（二氧化 矽）’溶離劑3%甲醇、970% CHC13純化殘餘物，合併溶離 份且在真空中蒸發，得到鑑別為標題化合物之無色油狀 物。 產量=700 mg ’ 1.51 mmol，53% 〇 [M+H]+ = 465.08 ° C. (R)-2-胺基-N-(2-胺基-噻唑_5·基甲基）_3,3·二環己基_丙 醯胺二-三氟6酸鹽 用三氟乙酸（5〇 ml)處理{(R)-i_[(2-胺基-噻唑·5_基甲基）_ 胺甲酿基]-2，2-二環己基-乙基}-胺基曱酸第三丁醋（7〇〇 mg，1.5 1 mmol)。在室溫下1小時後，移除溶劑，得到鐘 151651.doc •94· 201121961 別為標題化合物之無色油狀物。 產量=890 mg，1.5 mmol，100%。 [M+H]+ = 365.21。 ]H NMR: (CD3OD), 1.09-1.40 (10H, m), 1.52-1.91 (12H, m), 4.07 (1H, d, J=4.28 Hz), 4.29-4.36 (1H, m), 4.54-4.61 (1H，m)，4.91 (6H, s), 7.21 (1H, s)。 D· (S)-l-甲基-吡咯啶-2-曱酸{(R)-l-[(2-胺基-噻唑-5-基甲 基）-胺曱醯基]-2,2-二環己基-乙基}-醯胺二·三氟乙酸鹽 將 N-Me-Pro-OH(60 mg，0.46 mmol)溶解於 CH2Cl2(30 ml)中。添加三乙胺（141 mg，1.392 mmol)及 HBTU(194 mg，0.51 mmol)，繼而添加（R)-2-胺基-N-(2-胺基-«塞°坐-5· 基甲基）-3,3-二環己基-丙醯胺二-三氟乙酸鹽（303 mg， 〇_51 mmol)。在室溫下20分鐘後，用CHC13(50 ml)稀釋反 應混合物，用飽和NaHC〇3(lx20 ml)、水（1x20 ml)、鹽水 (1 x20 ml)洗蘇此溶液’乾燥（NadO4)且在真空中蒸發。藉 由急驟層析（二氧化矽），溶離劑7%甲醇、93% CHC13純化 殘餘物’合併溶離份且在真空中蒸發。藉由製備型 HPLC(19x250 mm Simfire C-18 管柱）’以 2〇 毫升 / 分鐘經35 分鐘含 10% 至 90°/。0.1% TFA/MeCN 之 0.1% TFA/H2〇 進一步 純化殘餘物。合併溶離份且冷凍乾燥’得到鑑別為標題化 合物之白色固體。 產量=32 mg，0.045 mmol，10〇/〇 [M+H]+ = 476.27。 ]H NMR: (CD3OD) 1.04-1.38 (12H, m), 1.50-1.82 (HH, m), 151651.doc -95- 201121961 2.05-2.15 (2H, m), 2.25-2.31 (1H, m), 2.62-2.68 (1H, m), 2.98 (3H, s), 3.25-3.32 (1H, m), 3.76-3.81 (1H, m), 4.20-4.24 (1H, m), 4.29-4.34 (1H, m), 4.44-4.49 (1H, m), 4.70 (1H，d，J=7.48 Hz)，4.91 (4H，s), 7.17 (1H，s)。 表1 如對於實例1至7所述來合成化合物。This solution was washed with NaHCO3 (1×20 ml), water (1×50 ml), brine (1×50 ml), dried (NazSO4) and evaporated in vacuo. by flash chromatography (cerium dioxide), solvant 3% methanol, 970% The residue was purified by EtOAc (EtOAc): Yield = 700 mg ' 1.51 mmol, 53% 〇[M+H]+ = 465.08 ° C. (R)-2-Amino-N-(2-amino-thiazole-5-ylmethyl)_3,3 · Dicyclohexyl-propionamine di-trifluoro 6 acid salt treated with trifluoroacetic acid (5 〇 ml) {(R)-i_[(2-amino-thiazole·5-ylmethyl)-amine 2,2-dicyclohexyl-ethyl}-amino decanoic acid terpene vinegar (7 mg, 1.5 1 mmol). After 1 hour at room temperature, the solvent was removed to give the title compound 151651.doc. Yield = 890 mg, 1.5 mmol, 100%. [M+H]+ = 365.21. ]H NMR: (CD3OD), 1.09-1.40 (10H, m), 1.52-1.91 (12H, m), 4.07 (1H, d, J=4.28 Hz), 4.29-4.36 (1H, m), 4.54-4.61 (1H, m), 4.91 (6H, s), 7.21 (1H, s). D·(S)-l-methyl-pyrrolidine-2-furic acid {(R)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]-2,2 -Dicyclohexyl-ethyl}-nonylamine di-trifluoroacetate N-Me-Pro-OH (60 mg, 0.46 mmol) was dissolved in CH2Cl2 (30 ml). Add triethylamine (141 mg, 1.392 mmol) and HBTU (194 mg, 0.51 mmol), followed by the addition of (R)-2-amino-N-(2-amino-«塞°坐-5·ylmethyl -3,3-Dicyclohexyl-propionamide di-trifluoroacetate (303 mg, 〇_51 mmol). After 20 minutes at room temperature, the reaction mixture was diluted with CHC13 (50 ml) and washed with saturated NaHC 3 (1×20 ml), water (1×20 ml), brine (1×20 ml) and dried (NadO4) Evaporate in a vacuum. The residue was purified by flash chromatography (c.c.), solv. Prepare HPLC (19 x 250 mm Simfire C-18 column) at 10% to 90°/ at 35 mL for 2 minutes. 0.1% TFA/H2 of 0.1% TFA/MeCN The residue was further purified. The fractions were combined and lyophilized to give a white solid identified as the title compound. Yield = 32 mg, 0.045 mmol, 10 〇 / 〇 [M+H] + = 476.27. ]H NMR: (CD3OD) 1.04-1.38 (12H, m), 1.50-1.82 (HH, m), 151651.doc -95- 201121961 2.05-2.15 (2H, m), 2.25-2.31 (1H, m), 2.62-2.68 (1H, m), 2.98 (3H, s), 3.25-3.32 (1H, m), 3.76-3.81 (1H, m), 4.20-4.24 (1H, m), 4.29-4.34 (1H, m ), 4.44-4.49 (1H, m), 4.70 (1H, d, J = 7.48 Hz), 4.91 (4H, s), 7.17 (1H, s). Table 1 Compounds were synthesized as described for Examples 1 to 7.

實例編號 γ Y之立體化學Example number γ Y stereochemistry

R1R1

12 S 13 产1S12 S 13 Production 1S

分子量 409.14 425.17 439.19 467.59 439.19 439.19 [M+H]+ 410.08 426.10 440.10 468.21 440.14 440.11 151651.doc -96·Molecular weight 409.14 425.17 439.19 467.59 439.19 439.19 [M+H]+ 410.08 426.10 440.10 468.21 440.14 440.11 151651.doc -96·

SS

RR

SS

RR

RR

RR

RR

SS

RR

SS

SS

RR

411.15 412.11 411.15 423.15 437.17 451.19 465.20 437.17 437.17 487.19 487.19 451.19 451.19 412.11 424.07 438.10 452.10 465.89 438.09 438.19 488.09 488.16 452.10 452.10 -97-411.15 412.11 411.15 423.15 437.17 451.19 465.20 437.17 437.17 487.19 487.19 451.19 451.19 412.11 424.07 438.10 452.10 465.89 438.09 438.19 488.09 488.16 452.10 452.10 -97-

SS

SS

ss

453.20 465.20 405.16 393.16 421.19 433.19 433.19 447.21 405.16 421.19 393.16 421.19 433.19 454.11 465.89 406.2 394.09 422.13 433.90 433.90 448.2 406.14 422.16 394.13 422.17 433.95 -98-453.20 465.20 405.16 393.16 421.19 433.19 433.19 447.21 405.16 421.19 393.16 421.19 433.19 454.11 465.89 406.2 394.09 422.13 433.90 433.90 448.2 406.14 422.16 394.13 422.17 433.95 -98-

R R S R S R S R S R S R S SR R S R S R S R S R S R S S

433.19 405.16 421.19 437.19 453.22 453.22 465.22 465.22 501.22 421.13 437.17 421.13 437.17 409.13 433.95 406.13 422.17 438.14 454.18 454.19 465.98 465.98 502.20 422.10 438.13 422.10 438.14 410.16 -99-433.19 405.16 421.19 437.19 453.22 453.22 465.22 465.22 501.22 421.13 437.17 421.13 437.17 409.13 433.95 406.13 422.17 438.14 454.18 454.19 465.98 465.98 502.20 422.10 438.13 422.10 438.14 410.16 -99-

S R S R S Sss R RS R S R S Sss R R

437.17 438.18 449.17 449.93 449.17 450.18 456.03, 455.09 458.07 471.13 443.09 471.13 483.13 483.13 417.22 472.03, 474.07 444.11， 446.1 472.07, 474.11 484.10, 486.10 484.11, 486.12 418.01 401.19 401.95 401.19 401.96 417.22 418.00 100 201121961 66 R - -γ 401.19 67 R 〆 417.22 68 R 379.20 69 R 393.22 70 S ^ 393.22 71 S ^ 409.25 72 s 381.22 73 产（y s 409.25 74 R 407.24 75 R 421.25 76 ο, R 407.24 77 S Q 421.25 78 οΛ R ^ 421.25 表2 402.21 418.24 380.23 394.17 394.25 410.18 382.27 410.28 408.23 422.27 408.23 422.28 422.22 如對於實例1至3所述來合成化合物。 151651.doc -101 - 201121961437.17 438.18 449.17 449.93 449.17 450.18 456.03, 455.09 458.07 471.13 443.09 471.13 483.13 483.13 417.22 472.03, 474.07 444.11, 446.1 472.07, 474.11 484.10, 486.10 484.11, 486.12 418.01 401.19 401.95 401.19 401.96 417.22 418.00 100 201121961 66 R - -γ 401.19 67 R 〆417.22 68 R 379.20 69 R 393.22 70 S ^ 393.22 71 S ^ 409.25 72 s 381.22 73 Production (ys 409.25 74 R 407.24 75 R 421.25 76 ο, R 407.24 77 SQ 421.25 78 οΛ R ^ 421.25 Table 2 402.21 418.24 380.23 394.17 394.25 410.18 382.27 410.28 408.23 422.27 408.23 422.28 422.22 The compound was synthesized as described for Examples 1 to 3. 151651.doc -101 - 201121961

83 8483 84

85 86 87 8885 86 87 88

8989

R1R1

分子量 433.16 469.16 458.18 433.14 419.12 455.12 401.13 401.13 401.13 417.10 417.10 [M+H]+ 433.91 470.14 459.18 433.86 420.06 456.03 402.15 401.90 401.91 418.08 418.08 151651.doc -102- 201121961 90 91 92 93Molecular weight 433.16 469.16 458.18 433.14 419.12 455.12 401.13 401.13 401.13 417.10 417.10 [M+H]+ 433.91 470.14 459.18 433.86 420.06 456.03 402.15 401.90 401.91 418.08 418.08 151651.doc -102- 201121961 90 91 92 93

397.16 397.16 397.16 389.19 398.14 398.12 398.18 390.13 表3如對於實例5所述來合成化合物。397.16 397.16 397.16 389.19 398.14 398.12 398.18 390.13 Table 3 The compounds were synthesized as described for Example 5.

實例編號 94 95 96Instance number 94 95 96

X之立體化學 R1X Stereochemistry R1

RR

RR

RR

分子量 474.17 460.14 442.15 97Molecular weight 474.17 460.14 442.15 97

RR

401.13 [M+H]+ 475.16 461.04 443.16 443.12 151651.doc -103 - 201121961 98 99 100 101 102 103 104 105401.13 [M+H]+ 475.16 461.04 443.16 443.12 151651.doc -103 - 201121961 98 99 100 101 102 103 104 105

106 107106 107

108108

109109

442.15 458.12 458.12 438.17 438.17 438.17 430.20 412.16 426.17 426.17 412.14 412.14 443.11 459.09 459.09 439.13 439.13 439.13 431.19 413.14 427.13 427.12 413.12 413.11 表4實例之^ NMR數據： 151651.doc -104 201121961 實例 編號 溶劑化學位移 8 9 10 1.70-1.78 (1H, m), 1.88-1.93 (1H, m), 1.99-2.09 (2H, m), 2.32-2.41 (1H, m), 2.92-2.98 (2H, m), 3.20 (1H, dd, J=6.24, 13.88 Hz), 3.28-CD3OD 3.33 (2H, m), 4.27-4.32 (2H, m), 4.72 (1H, dd, J=6.29, 9.25 Hz), 4.91 (3H, s), 5.55 (1H, s), 7.07-7.11 (1H, m), 7.13 (1H, s), 7.17-7.26 (2H, m)。 0.86-0.89 (6H, m), 0.94-0.99 (1H, m), 1.24-1.31 (1H, m), 1.76-1.81 (1H, m), 2.93 (1H, dd, J=10.28, 14.08 Hz), 3.22 (1H, dd, J=5.48, CD3OD 14.0 Hz), 3.75 (1H, d, J=5.28 Hz), 4.38 (2H, dd, J=15.49, 43.57 Hz), 4.73 (1H, dd, J=5.57, 10.21 Hz), 4.91 (5H, s), 5.54 (1H, s), 7.11 (1H, s)，7.12-7.13 (1H, m)，7.21-7.27 (2H, m)。 0.87 (3H, d, J=6.92 Hz), 0.90 (3H, d, J=4.0 Hz), 1.34-1.37 (1H, m), 1.816-1.85 (1H, m), 2.68 (3H, s), 2.95 (1H, dd, J=10.33, 14.05 Hz), CD3OD 3.18 (1H, dd, J=5.72, 14.09 Hz), 3.68 (1H, d, J=4.96 Hz), 4.32-4.45 (2H, m), 4.71 (1H, dd, J=5.68, 10.16 Hz), 4.91 (6H, s), 7.11 (1H, s), 7.12-7.13 (1H, m), 7.21-7.27 (2H，m)。 11 0.88-0.95 (6H, m), 1.17 (3H, d, J=7.00 Hz), 1.36-1.52 (4H, m), 2.35-2.43 (4H, m), 2.93-2.99 (1H, m), 3.07-3.15 (1H, m), 4.28-4.32 (1H, m), 4.39-4.43 (1H, m), 4.601-4.64 (1H, m), 4.91 (5H, s), 6.84 (1H, s)，6.99-7.03 (1H, m)，7.11-7.21 (2H, m)。 12 1.00-1.07 (6H, m), 1.22-1.32 (4H, m), 2.20 (3H, s), 2.84-2.91 (3H, m), 3.05-3.10 (1H, m), 3.31(lH,s,br), 4.31 (2H, q, J=15.41 Hz), 4.60 (1H, q, J=6.12 Hz), 4.90 (2H, s), 6.79 (1H, s), 6.99-7.11 (1H, m), 7.12-7.17 (2H，m)。 13 1.01-1.08 (6H, m), 1.17 (4H, q, J=5.65 Hz), 2.45-2.51 (4H, m), 2.54-2.59 (1H, m), 2.93-2.99 (1H, m), 3.07-3.16 (1H, m), 4.30-4.43 (2H, m), 4.61-4.66 (1H, m), 4.91 (4H, s), 6.85 (1H, s), 7.00-7.03 (1H, m), 7.14-7.21 (lH，m)。 14 1.59 (3H, d, J=7.0 Hz), 2.83 (6H,s, br), 2.96-3.02 (1H, m), 3.13-3.18 (1H, m), 3.91 (1H, q, J=6.92 Hz), 4.348 (2H, dd, J=15.0, 50.1 Hz), 4.69 (1H, dd, J=7.0, 8.56 Hz), 4.91 (3H, s), 5.54 (1H, s), 7.09 (1H, s), 7.10-7.11 (1H, m)，7.18-7.25 (2H，m)。 15 1.44 (3H, d, J-6.96 Hz), 2.90 (6H, s), 2.98-3.03 (1H, m), 3.12-3.17 (1H, m), 3.88 (1H, q, J=6.89 Hz), 4.35 (2H, dd, J=15.05, 48.14 Hz), 4.66 (1H, dd, J=6.84, 8.76 Hz), 4.91 (3H, s), 7.09 (1H, s), 7.07-7.10 (2H，m)，7.18-7.25 (2H，m)。 151651.doc -105- 201121961 16 17 18 19 20 21 22 2.05-2.09 (2H, m), 2.21-2.27 (1H, m), 2.56-2.65 (1H, m), 2.86 (3H, s), 2.99-3.16 (2H, m), 3.22-3.25 (1H, m), 3.71-3.76 (1H, m), 4.06-CD3OD 4.10 (1H, m), 4.24-4.30 (1H, m), 4.34-4.44 (1H, m), 4.65-4.73 (1H, m), 4.91 (4H, s), 7.06 (1H, s), 7.08-7.12 (1H, m), 7.18-7.25 (2H, m) 〇 1.18- 1.34 (3H, m), 1.75-1.82 (1H, m), 1.90-2.08 (3H, m), 2.13-2.22 (1H, m), 2.43-2.51 (2H, m), 2.94-3.03 (1H, m), 3.11-3.31 (4H, m), CD3OD 3.71-3.76 (1H, m), 4.10-4.18 (1H, m), 4.28-4.42 (2H, m), 4.69-4.73 (1H, m), 4.92 (1H, s), 7.07-7.13 (2H, m), 7.21-7.25 (2H, m), 8.82-8.89 (1H，m)。 1.19- 1.39 (6H, m), 1.79-1.90 (2H, m), 2.09-2.18 (2H, m), 2.41-2.51 (1H, m), 2.95-3.02 (1H, m), 3.14-3.20 (1H, m), 3.26-3.33 (1H, m), CD3OD 3.57- 3.69 (2H, m), 4.18-4.42 (3H, m), 4.68-4.74 (1H, m)5 4.92 (2H, s), 7.07-7.12 (2H, m), 7.18-7.26 (2H, m), 8.84-8.86 (1H, m)« 1.33 (3H, d, J=6.76 Hz), 1.40 (3H, d, J=6.68 Hz), 1.57-1.63 (1H, m), 1.75-2.05 (5H, m), 2.95-3.00 (4H, m), 3.11-3.16 (1H, m), 3.41-3.47 CD3OD (1H, m), 3.62 (1H, q, 6.68 Hz), 3.92 (1H, dd, J=2.68, 11.76 Hz), 4.35 (2H, dd, J=6.71, 8.65 Hz), 4.63 (1H, dd, J=2.68, 11.76 Hz), 4.91 (2H，s), 7.07 (2H，s)，7.19-7.23 (2H, m)。 1.58- 1.63 (2H, m), 1.77-1.80 (1H, m), 1.95-1.99 (4H, m), 2.84 (3H, s), 2.97-3.00 (1H, m), 3.12-3.17 (2H, m), 3.52 (1H, d, J=12.44 Hz), CD3OD 3.73 (1H, d, J=8.69 Hz), 4.35 (2H, dd, J=15.73,46.78 Hz), 4.66 (1H, dd, J=6.84, 8.68 Hz), 4.91 (3H, s), 7.06-7.09 (2H, m), 7.17-7.25 (2H, m)-&gt; 1.60-1.64 (1H, m), 1.65-1.81 (3H, m), 1.96-2.05 (2H, m), 2.09-2.24 (1H, m), 2.65 (3H, s), 2.97-3.02 (1H, m), 3.07-3.17 (2H, m), 3.40-CD3OD 3.53 (1H, m), 3.69-3.72 (1H, m), 4.34 (2H, dd, J=15.6, 44.73 Hz), 4.70 (1H, dd, J=6.07, 8.64 Hz), 4.91 (3H, s), 7.11 (2H, s), 7.19-7.25 (m, m)。 2.54-2.60 (1H, m), 2.75-2.80 (1H, m), 3.05 (6H, s), 3.07-3.09 (1H, m), 3.39-3.42 (1H, m), 4.06 (1H, q, J=4.68 Hz), 4.24-4.37 (3H, m), CD3OD 4.92 (4H, s), 6.77-6.80 (1H, m), 6.87-6.93 (1H, m), 7.07-7.12 (2H, m)，7.19-7.22 (2H，m)，7.28-7.33 (3H，m)。 23 2.86 (6H, s), 2.88-2.92 (1H, m), 3.00-3.03 (1H, m), 3.09-3.15 (1H, m), 4.04-4.08 (2H, m), 4.13 (1H, d, J=15.61 Hz), 4.25 (1H, d, J=15.69 Hz), 4.58-4.62 (1H, m), 4.92 (4H, s), 7.02-7.05 (1H, m), 7.11 (1H，s)，7.13-7.15 (2H，m)，7.30-7.36 (5H，m)。 151651.doc -106- 201121961 24 25 26 27 28 29 30 31 32 1.41 (3H, d, J=6.89 Hz), 1.69-1.89 (6H, m), 2.79-2.85 (4H, m), 2.99-3.04 (2H, m), 3.52-3.55 (1H, m), 3.68-3.77 (1H, m), 4.20 (2H, q, CD3OD J=15.48 Hz), 4.58 (lH,t, J=2.92 Hz), 4.76 (3H, s), 6.95 (2H, s), 7.06-7.10 (2H，m)。 1.41 (3H, d, J=6.93 Hz), 1.63-1.73 (1H, m), 1.90-2.05 (6H, m), 2.93-2.99 (4H, m), 3.13-3.26 (2H, m), 3.85 (1H, q, J=6.92 Hz), 4.35 (2H, CD3OD q, J=15.40 Hz), 4.63-4.67 (1H, m), 4.91 (3H, s), 6.93 (1H, s), 7.06-7.09 (1H, m)，7.18-7.25 (2H，m)。 1.03 (12H，d, J=6.49 Hz)，2·90-3·14(6Η，m)，4.36 (2H，q，15.0 Hz), CD3OD 4.64 (1H, q, J-7.01 Hz), 4.75 (4H, s), 6.85 (1H, s), 6.98-7.01 (1H, m)，7.11-7.20(2H,m)。 0.80 (3H，d，J=6.24 Hz), 0.86 (3H，d, J=5.55 Hz), 1.17-1.38 (4H，m), 1.47-1.31 (2H, m), 1.47-1.60 (1H, m), 2.37 (2H,s,br), 2.79-2.84 (1H, CD3OD m), 2.93-2.99 (3H, m), 4.19 (2H,q, 15.32 Hz), 4.50 (lH,t, J=7.44 Hz), 4.75 (3H, s), 6.69 (1H, s), 6.85-6.88 (1H, m), 7.00-7.04 (2H, m)。 1.67-1.76 (1H, m), 1.89-1.96 (1H, m), 2.09-2.23 (2H, m), 2.43-2.53 (1H, m), 2.94 (3H, s), 2.95-2.99 (1H, m), 3.19-3.25 (3H, m), 3.67-CD3OD 3.72 (1H, m), 4.10 (lH,t, J=8.49 Hz), 4.37 (2H, q, J=15.61 Hz), 4.71-4.75 (1H, m), 4.91 (2H, s), 7.03-7.07 (2H, m), 7.11 (1H, s), 7.28-7.31 (2H，m)。 0.97-1.08 (6H, m), 1.14-1.19 (4H, m), 2.45-2.51 (4H, m), 2.98-3.00 CD3OD (1H, m), 3.09-3.16 (1H, m), 4.29-4.42 (2H, m), 4.61-4.65 (1H, m), 4.91 (4H, s), 6.84 (1H，s)，7.00-7.04 (2H，m)，7.22-7.25 (2H，m)。 0.97-1.08 (6H, m), 1.14-1.19 (4H, m), 2.45-2.51 (4H, m), 2.98-3.00 CD3OD (1H, m), 3.09-3.16 (1H, m), 4.29-4.42 (2H, m), 4.61-4.65 (1H, m), 4.91 (4H，s)，6.84 (1H, s)，7.00-7.04 (2H, m)，7.22-7.25 (2H，m)。 1.56 (3H, d, J=6.88 Hz), 1.60-1.68 (1H, m), 1.73-1.93 (6H, m), 2.73-2.84 (2H, m), 2.92-3.01 (4H, m), 3.17-3.22 (1H, m), 3.47-3.56 (1H, 3 m), 3.80 (1H, q, 6.68 Hz), 4.65 (1H, q, J=15.49 Hz), 4.77 (lH,t, J=6.12 Hz)，4.91 (2H, s), 7.03-7.12 (3H, m)，7.29-7.34 (2H，m)。 1.41 (3H, d, J=6.93 Hz), 1.56-1.58 (1H, m), 1.86-2.05 (6H, m), 2.96-3.01 (4H, m), 3.15-3.19 (1H, m), 3.41-3.42 (1H, m), 3.54-3.58 (1H, 3 m), 3.58 (1H, q, 6.96 Hz), 4.27-4.42 (2H, m), 4.65 (lH,t, J-6.76 Hz), 4.91 (2H, s), 7.03-7.11 (3H, m), 7.28-7.31 (2H, m) 〇 151651.doc -107- 201121961 33 34 35 36 37 38 39 0.93 (3H, d, J=6.20 Hz), 1.00 (3H, d, J=6.24 Hz), 1.24-1.47 (4H, m), 1.60-1.64 (2H, m), 1.70-1.75 (1H, m), 2.49 (2H,s,br), 2.95-3.00 (1H, CD3OD m), 3.09-3.14 (3H, m), 4.35 (2H,q, 15.08 Hz), 4.63 (lH,t, J=7.25 Hz), 4.91 (3H, s), 6.84 (1H, s), 6.99-7.05 (2H, m), 7.22-7.26 (2H，m)。 1.57-1.74 (1H, m), 1.88-1.95 (1H, m), 2.15-2.20 (1H, m), 2.43-2.50 (1H, m), 2.94 (3H, s), 2.95-3.00 (1H, m), 3.17-3.26 (3H, m), 3.67-CD3OD 3.72 (1H, m), 4.10 (lH,t, J=8.44 Hz), 4.36 (2H, q, J=15.01 Hz), 4.75-4.79 (1H, m), 4.91 (3H, s), 6.99-7.02 (2H, m), 7.10 (1H, s), 7.31-7.37 (2H，m) » 1.13(3H,s, br), 1.26(6H, d, J=6.56 Hz), 1.32-1.40 (1H, m), 1.55 (3H, d, J=6.68 Hz), 2.54 (lH,s, br), 2.68 (3H, s), 2.87 (lH,s, br), 2.94- CD3OD 3.00 (1H, m), 3.19-3.25 (1H, m), 3.95 (1H, q, J=6.88 Hz), 4.32-4.45 (2H, m), 7_02-7_ 15 (3H，m)，7.34-7.39 (2H，m)。 1.58 (3H, d, J=6.97 Hz), 2.78 (6H, s), 2.99-3.05 (1H, m), 3.17-3.22 (1H, m),3.86 (1H, q, J=6.93 Hz), 4.27-4.31 (1H, m), 4.38-4.42 (1H, CD3OD m), 4.70-4.76 (1H, m), 4.91 (4H, s), 6.96-7.14 (4H, m), 7.31-7.37 (lH，m)» 0.99-1.07 (6H, m), 1.16 (3H,q, J =2.28 Hz), 2.44-2.49 (3H, m), 2.51-2.61 (1H, m), 2.96-3.03 (1H, m), 3.11-3.20 (1H, m), 4.34-4.38 (2H, CD3OD m)，4 66 (1H，q, 1.88 Hz), 4.91 (5H, s), 6.84 (1H, s), 6.99-7.06 (2H，m)，7.28-7.34 (2H，m)。 1.41 (3H, d, 3=6.92 Hz), 1.50-1.58 (1H, m), 1.85-2.05 (6H, m), 2.99-3.05 (4H, m), 3.17-3.22 (1H, m), 3.41-3.42 (1H, m), 3.54-3.58 (1H, CD3OD m), 3.58 (1H, q, 6.96 Hz), 4.27-4.31 (1H, m), 4.38-4.43 (1H, m), 4.68 (lH,t, J=6.60 Hz), 4.92 (1H, s), 7.02-7.05 (2H, m), 7.11 (2H, t, J=4_45 Hz)，7.32-7.35 (1H, m), 8.84-8.87 (1H，m)。 1.56 (3H, d, J=6.84 Hz), 1.61-1.72 (1H, m), 1.74-1.93 (6H, m), 2.75-2.86 (2H, m), 2.96-3.02 (4H, m), 3.19-3.24 (1H, m), 3.56 (1H, s, br), CD3OD 3.82 (1H, q, 6.92 Hz), 4.31-4.44 (2H, m), 4.79 (lH,t, J=6.13 Hz), 7.00-7.09 (2H, m), 7.11-7.15 (2H, m), 7.32-7.38 (1H, m), 8.85-8.88 (1H，m)。 40 1.69-1.78 (1H, m), 1.84-1.96 (1H, m), 2.12-2.22 (1H, m), 2.51-2.53 (1H, m), 2.93 (3H, s), 3.01-3.07 (1H, m), 3.19-3.31 (2H, m), 3.66-3.71 (1H, m), 4.11 (lH,t, J=8.45 Hz), 4.31-4.43 (2H, m), 4.81-4.85 (1H, m), 4.91 (2H, s)，7.08-7.15 (3H, m)，7.31-7.357 (2H，m)。 15l651.doc • 108 · 201121961 41 42 43 44 47 48 49 1.16(3H,s, br), 1.26(6H, d, J=6.44 Hz), 1.29-1.40 (1H, m), 1.54 (3H, d, J=6.68 Hz), 2.67(1 H,s, br), 2.72 (3H, s), 2.93-2.95 (1H, m), 3.00-CE&gt;3〇D 3.11 (1H, m), 3.94-3.99 (1H, m), 4.29-4.44 (2H, m), 4.71-4.77 (1H, m)，7.05-7.17 (3H，m)，7.29-7.36 (2H，m)。 2.06-2.36 (4H, br m) 2.72-2.75 (1H, m) 2.90 (3H, s) 3.06 (3H, s) 3.60 (1H, s) 3.75-3.85 (2H, m) 4.09 (1H, t, J=8.0 Hz) 4.42 (1H, t, CD3〇D J=8.0 Hz) 4.52 (2H, s) 4.94 (1H, m) 7.33 (1H, s) 7.37-7.46 (2H, m) 7.48-7.64 (2H, m) 7.74-7.84 (2H, m) 7.90 (1H, d, J=8.0 Hz) 8.23 (lH，d，J=8.0Hz)。 0.84 (3H, d, J=4.0 Hz) 0.88 (3H, d, J=4.0 Hz) 1.07 (3H, d, J=4.0 Hz) 1.39 (1H, d, J=4.0 Hz) 1.98 (3H, s) 2.53 -2.59 (1H, br m) 2.88 (1H, CD3OD s) 3.44-3.49 (1H, m) 4.22 (2H, d, J=8.0 Hz) 4.75 (5H, s) 6.65 (1H, t,J=4.0 Hz) 7.19-7.29 (2H, m) 7.37-7.47 (2H, m) 7.67 (1H, dd, J=8.0,4.0 Hz) 7.78 (1H，d，J=8_0 Hz) 8.11 (1H，d，J=8.0 Hz)。 1.01 (2H ,t ,J=8.0 Hz) 1.16 (2H, t, J=8.0 Hz) 1.52 (2H, d, J=8.0 Hz) 1.77 (2H, d, J=8.0 Hz) 2.38-2.43 (1H, m) 2.73-2.87 (1H, m) 3.10-3.15 (1H, m) 3.22-3.37 (3H, m) 3.44-3.53 (2H, m) 3.64-3.69 (1H, CD3OD m) 3.85-3.90 (1H, m) 4.30-4.35 (1H, m) 4.43-4.48 (1H, m) 4.55-4.59 (1H, m) 4.87-5.02 (1H, br m) 7.33 (1H, s) 7.38-7.44 (2H, m) 7.51-7.67 (2H, br m) 7.81 (1H, dd, J=8.0, 4.0 Hz) 7.91-7.95 (1H, m) 8.27 (1H，d, J=8_0 Hz) 8.83 (1H, t，J=8.0 Hz)。 1.91-1.96 (6H, m) 2.71-2.77 (2H, m) 3.04-3.14 (2H, m) 3.41-3.49 (1H, m) 4.04 (2H, s) 4.57-4.61 (1H, m) 6.60 (1H, s) 6.94-7.00 (2H, CD3OD m) 7.03-7.17 (3H, m) 7.19-7.25 (2H, m) 7.34-7.45 (2H, m) 7.57-7_64 (1H，m) 7.74 (1H, d，J=8_0 Hz) 8.07 (1H，d，J=8.0 Hz)。 1.62-1.71 (3H, m), 2.07-2.11 (1H, m), 2.13 (3H, s), 2.24-2.33 (1H, m), 2.75-2.79 (1H, m), 2.93-2.98 (1H, m), 3.02-3.06 (1H, m), 3.11-CDCI3 3.16 (1H, m), 4.23-4.36 (2H, m), 4.62-4.68 (1H, m), 5.47 (2H, s), 6.67 (1H, s), 7.11 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 7.41 (1H，t，J=5.4 Hz), 7.81 (1H，d，J=8.6 Hz)。 0.84(6H, d, J=6.5 Hz), 0.98 (3H, d, J=7.0 Hz), 1.83 (3H, s), 2.59- 2.68 (1H, m), 2.83-2.90 (1H, m), 2.94-3.00 (1H, m), 3.10(1H, q, CDCI3 J=7.0 Hz), 4.11-4.22 PH, m)，4.49(1H, q，J=7.7 Hz), 5.12 (2H，s)， 6.53 (1H, s), 6.98-7.02 (3H, m), 7.09 (2H, d, J=8.3 Hz), 7.80 (1H, d, J=8.4 Hz)。 151651.doc -109- 201121961 50 51 52 53 54 55 56 57 1.67-1.79 (3H, m), 2.15 (3H, s), 2.27-2.34 (1H, m), 2.78-2.83 (2H, m), 2.95-3.01 (1H, m), 3.05-3.08 (1H, m), 3.14-3.19 (1H, m), 4.24- CDCI3 4.40 (2H, m), 4.61-4.67 (1H, m), 5.46 (2H, s), 6.72 (1H, s), 7.08-7.38 (4H, m)，7.86 (1H，d, J=8.2 Hz)。 1.28(6H, d, 3=6.6 Hz), 1.37-1.44 (1H, m), 1.55 (3H, d, J=6.8 Hz), 2.67 (3H, s), 2.86-2.99 (2H, m), 3.20-3.25 (1H, m), 3.96(1H, q, CD3OD J=6.8 Hz), 4.32-4.46 (2H, m), 7.13 (1H, s), 7.26-7.36 (4H, m), 8.89 (lH，t，J=5.0Hz)。 1.06 (3H, d, J=7.0 Hz), 2.10(6H, s)9 2.93-3.00 (2H, m), 3.12-3.17 (1H, m), 4.25-4.37 (2H, m), 4.68(1H, q, J=7.8 Hz), 5.25 (2H, s), 6.68 (1H, s), 7.07-7.11 (1H, m), 7.16-7.20 (4H, m), 7.75 (1H, d, J=8.4 Hz)。 0.95(6H, t, J=7.1 Hz), 1.08 (3H, d, J=7.0 Hz), 2.30-2.48 (4H, m), 2.94-2.99 (1H, m), 3.11-3.16 (1H, m), 3.29(1H, q, J=6.9 Hz), 4.22-CDCI3 4.36 (2H, m), 4.78(1H, q, J=7.8 Hz), 5.53 (2H, s), 6.60 (1H, s), 7.06-7.09 (1H, m), 7.15-7.19 (3H, m), 7.49 (1H, t, J=5.1 Hz), 7.98 (1H, d, J=8.5 Hz)。 1.41-1.51 (1H, m), 1.56 (3H, d, J=6.90 Hz), 1.67-1.93 (5H, m), 2.76-2.84 (2H, m), 2.94-3.00 (2H, m), 3.18-3.24 (1H, m), 3.55-3.57 (1H, CD3OD m)s 3.84(ih, q, J=6.9 Hz), 4.31-4.44 (2H, m), 4.78-4.82 (1H, m), 7.14 (1H，s)，7.25-7.38 (4H，m)，8.89 (1H，t, J=5.7 Hz)。 1.42 (3H, d, J=7.0 Hz), 1.53-1.59 (1H, m)5 1.87-1.99 (5H, m), 2.97-3.03 (3H, m), 3.17-3.22 (1H, m), 3.42(lH,br s), 3.58(lH,br s), CD3〇D 3.92(1H, q, J=6.9 Hz), 4.29-4.42 (2H, m), 4.66-4.70 (1H, m), 7.12 (1H, s)，7.23-7.36 (4H，m)。 1.61-1.77 (4H, m), 2.19 (3H, s), 2.28-2.35 (1H, m), 2.81-2.84 (1H, m), 2.96-3.01 (1H, m), 3.05-3.08 (1H, m), 3.14-3.19 (1H, m), 4.28-CDCI3 4.42 (2H, m), 4.55-4.61 (1H, m), 5.02 (2H, s), 6.80 (1H, s), 6.99-7.01 (1H, m), 7.06 (1H, dd, J=8.2,2.0 Hz), 7.32-7.36 (2H, m), 7.81 (1H, d，J=8.5 Hz)。 0.99(6H，d，J=6.5Hz)，1.16(3H，d，J=7.0Hz)，2.01(3H，s)，2_72-2.81 (1H, m), 2.98-3.04 (1H, m), 3.10-3.15 (1H, m), 3.27(1H, q, CDCU J=7.0 Hz), 4.35 (2H, ds J=5.5 Hz), 4.54-4.59 (1H, m), 5.00 (2H, s), 6.80 (1H, s), 6.84 (1HS t, J=5.3 Hz), 7.06 (1H, dd, J=8.2,2.0 Hz), 7·31 (1H，d，J=2.0 Hz), 7.34-7.39 (1H，m)，7.81 (1H，d，J=7.5 Hz)。 151651.doc •110· 201121961 58 59 60 61 62 1.59 (3H, d, J=7.0 Hz), 2.82(6H, s), 3.00-3.05 (1H, m), 3.14-3.19 (1H, m), 3.93(1H, q, J=7.0 Hz), 4.27-4.42 (2H, m), 4.68-4.72 (1H, CD3OD m), 7.13 (1H, s), 7.25 (1H, dd, J=8.3,2.0 Hz), 7.46-7.48 (2H, m), 8.87(lH，t，J=5.7Hz)。 0.96(6H, t, J=7.1 Hz), 1.10 (3H, d, J=7.0 Hz), 2.31-2.47 (4H, m), 2.92-2.98 (1H, m), 3.09-3.14 (1H, m), 3.29(1H, q, J=7.0 Hz), 4.30 CDCI3 (2H, d, J=5.5 Hz), 4.74(1H, q, J=7.8 Hz), 5.34 (2H, s), 6.64 (1H, s), 7.04 (1H, dd, J=8.2,2.0 Hz), 7.27-7.36 (3H, m), 7.97 (1H, d, J=8.6 Hz)。 1.56 (3H, d, J=6.9 Hz), 1.61-1.93(6H, m), 2.94-3.00 (4H, m), 3.18-3.23 (1H, m), 3.56(lH,br s), 3.85 (1H, q, 3=6.9 Hz), 4.31-4.44 (2H, CD3OD m)，4.77-4.81 (1H，m)，7.14 (1H, s)，7.27 (1H, dd, J=8.3,2.0 Hz), 7.48-7.50 (2H, m), 8.88 (1H，t，J=5.7 Hz)。 1.45 (3H, d, J=7.0 Hz), 1.54-1.62 (1H, m), 1.86-1.99 (5H, m), 2.97-3.03 (3H, m), 3.15-3.20 (1H, m), 3.42(lH,br s), 3.59(lH,br s), CD3OD 3.93(1H, q, J=6.9 Hz), 4.28-4.42 (2H, m), 4.65-4.69 (1H, m), 7.13 (1H, s), 7.24 (1H, dd, J=8.3,2.0 Hz), 7.46 (1H, d, J=2.0 Hz), 7.47-7.49 (1H, m)。 1.07 (3H, s), 1.22 (3H, d, J=6.4 Hz), 1.54 (3H, d, J=6.8 Hz), 2.35 (3H, s), 2.64 (3H, s), 2.86-2.92 (1H, m), 3.17-3.21 (1H, m), CD3OD 3.94(1H, q, J=6.8 Hz), 4.33-4.44 (2H, m), 4.84-4.88 (1H, m), 7.13-7·21 (5H，m), 8_86 (1H，s)。 63 1.63-1.72 (1H, m), 1.82-1.93 (1H, m), 2.09-2.19 (1H, m), 2.33 (3H, s), 2.40-2.49 (1H, m), 2.88-2.91 (1H, m), 2.93 (3H, s), 3.17-3.23442.15 458.12 458.12 438.17 438.17 438.17 430.20 412.16 426.17 426.17 412.14 412.14 443.11 459.09 459.09 439.13 439.13 439.13 431.19 413.14 427.13 427.12 413.12 413.11 Table 4 Example NMR data: 151651.doc -104 201121961 Example number Solvent chemical shift 8 9 10 1.70-1.78 ( 1H, m), 1.88-1.93 (1H, m), 1.99-2.09 (2H, m), 2.32-2.41 (1H, m), 2.92-2.98 (2H, m), 3.20 (1H, dd, J=6.24 , 13.88 Hz), 3.28-CD3OD 3.33 (2H, m), 4.27-4.32 (2H, m), 4.72 (1H, dd, J=6.29, 9.25 Hz), 4.91 (3H, s), 5.55 (1H, s ), 7.07-7.11 (1H, m), 7.13 (1H, s), 7.17-7.26 (2H, m). 0.86-0.89 (6H, m), 0.94-0.99 (1H, m), 1.24-1.31 (1H, m), 1.76-1.81 (1H, m), 2.93 (1H, dd, J=10.28, 14.08 Hz), 3.22 (1H, dd, J=5.48, CD3OD 14.0 Hz), 3.75 (1H, d, J=5.28 Hz), 4.38 (2H, dd, J=15.4, 43.57 Hz), 4.73 (1H, dd, J=5.57 , 10.21 Hz), 4.91 (5H, s), 5.54 (1H, s), 7.11 (1H, s), 7.12-7.13 (1H, m), 7.21-7.27 (2H, m). 0.87 (3H, d, J=6.92 Hz), 0.90 (3H, d, J=4.0 Hz), 1.34-1.37 (1H, m), 1.816-1.85 (1H, m), 2.68 (3H, s), 2.95 (1H, dd, J=10.33, 14.05 Hz), CD3OD 3.18 (1H, dd, J=5.72, 14.09 Hz), 3.68 (1H, d, J=4.96 Hz), 4.32-4.45 (2H, m), 4.71 (1H, dd, J=5.68, 10.16 Hz), 4.91 (6H, s), 7.11 (1H, s), 7.12-7.13 (1H, m), 7.21-7.27 (2H, m). 11 0.88-0.95 (6H, m), 1.17 (3H, d, J=7.00 Hz), 1.36-1.52 (4H, m), 2.35-2.43 (4H, m), 2.93-2.99 (1H, m), 3.07 -3.15 (1H, m), 4.28-4.32 (1H, m), 4.39-4.43 (1H, m), 4.601-4.64 (1H, m), 4.91 (5H, s), 6.84 (1H, s), 6.99 -7.03 (1H, m), 7.11 - 7.21 (2H, m). 12 1.00-1.07 (6H, m), 1.22-1.32 (4H, m), 2.20 (3H, s), 2.84-2.91 (3H, m), 3.05-3.10 (1H, m), 3.31 (lH, s, Br), 4.31 (2H, q, J=15.41 Hz), 4.60 (1H, q, J=6.12 Hz), 4.90 (2H, s), 6.79 (1H, s), 6.99-7.11 (1H, m), 7.12-7.17 (2H, m). 13 1.01-1.08 (6H, m), 1.17 (4H, q, J=5.65 Hz), 2.45-2.51 (4H, m), 2.54-2.59 (1H, m), 2.93-2.99 (1H, m), 3.07 -3.16 (1H, m), 4.30-4.43 (2H, m), 4.61-4.66 (1H, m), 4.91 (4H, s), 6.85 (1H, s), 7.00-7.03 (1H, m), 7.14 -7.21 (lH,m). 14 1.59 (3H, d, J=7.0 Hz), 2.83 (6H, s, br), 2.96-3.02 (1H, m), 3.13-3.18 (1H, m), 3.91 (1H, q, J=6.92 Hz ), 4.348 (2H, dd, J=15.0, 50.1 Hz), 4.69 (1H, dd, J=7.0, 8.56 Hz), 4.91 (3H, s), 5.54 (1H, s), 7.09 (1H, s) , 7.10-7.11 (1H, m), 7.18-7.25 (2H, m). 15 1.44 (3H, d, J-6.96 Hz), 2.90 (6H, s), 2.98-3.03 (1H, m), 3.12-3.17 (1H, m), 3.88 (1H, q, J=6.89 Hz), 4.35 (2H, dd, J=15.05, 48.14 Hz), 4.66 (1H, dd, J=6.84, 8.76 Hz), 4.91 (3H, s), 7.09 (1H, s), 7.07-7.10 (2H, m) , 7.18-7.25 (2H, m). 151651.doc -105- 201121961 16 17 18 19 20 21 22 2.05-2.09 (2H, m), 2.21-2.27 (1H, m), 2.56-2.65 (1H, m), 2.86 (3H, s), 2.99- 3.16 (2H, m), 3.22-3.25 (1H, m), 3.71-3.76 (1H, m), 4.06-CD3OD 4.10 (1H, m), 4.24-4.30 (1H, m), 4.34-4.44 (1H, m), 4.65-4.73 (1H, m), 4.91 (4H, s), 7.06 (1H, s), 7.08-7.12 (1H, m), 7.18-7.25 (2H, m) 〇1.18- 1.34 (3H, m), 1.75-1.82 (1H, m), 1.90-2.08 (3H, m), 2.13-2.22 (1H, m), 2.43-2.51 (2H, m), 2.94-3.03 (1H, m), 3.11- 3.31 (4H, m), CD3OD 3.71-3.76 (1H, m), 4.10-4.18 (1H, m), 4.28-4.42 (2H, m), 4.69-4.73 (1H, m), 4.92 (1H, s) , 7.07-7.13 (2H, m), 7.21-7.25 (2H, m), 8.82-8.89 (1H, m). 1.19- 1.39 (6H, m), 1.79-1.90 (2H, m), 2.09-2.18 (2H, m), 2.41-2.51 (1H, m), 2.95-3.02 (1H, m), 3.14-3.20 (1H , m), 3.26-3.33 (1H, m), CD3OD 3.57- 3.69 (2H, m), 4.18-4.42 (3H, m), 4.68-4.74 (1H, m)5 4.92 (2H, s), 7.07- 7.12 (2H, m), 7.18-7.26 (2H, m), 8.84-8.86 (1H, m)« 1.33 (3H, d, J=6.76 Hz), 1.40 (3H, d, J=6.68 Hz), 1.57 -1.63 (1H, m), 1.75-2.05 (5H, m), 2.95-3.00 (4H, m), 3.11-3.16 (1H, m), 3.41-3.47 CD3OD (1H, m), 3.62 (1H, q (6H, dd, J=2.68, 11.76 Hz) , s), 7.07 (2H, s), 7.19-7.23 (2H, m). 1.58- 1.63 (2H, m), 1.77-1.80 (1H, m), 1.95-1.99 (4H, m), 2.84 (3H, s), 2.97-3.00 (1H, m), 3.12-3.17 (2H, m ), 3.52 (1H, d, J=12.44 Hz), CD3OD 3.73 (1H, d, J=8.69 Hz), 4.35 (2H, dd, J=15.73, 46.78 Hz), 4.66 (1H, dd, J=6.84) , 8.68 Hz), 4.91 (3H, s), 7.06-7.09 (2H, m), 7.17-7.25 (2H, m)-&gt; 1.60-1.64 (1H, m), 1.65-1.81 (3H, m), 1.96-2.05 (2H, m), 2.09-2.24 (1H, m), 2.65 (3H, s), 2.97-3.02 (1H, m), 3.07-3.17 (2H, m), 3.40-CD3OD 3.53 (1H, (m), 3.69 (3H, dd, J = 15.6, 44.73 Hz) , s), 7.19-7.25 (m, m). 2.54-2.60 (1H, m), 2.75-2.80 (1H, m), 3.05 (6H, s), 3.07-3.09 (1H, m), 3.39-3.42 (1H, m), 4.06 (1H, q, J =4.68 Hz), 4.24-4.37 (3H, m), CD3OD 4.92 (4H, s), 6.77-6.80 (1H, m), 6.87-6.93 (1H, m), 7.07-7.12 (2H, m), 7.19 -7.22 (2H, m), 7.28-7.33 (3H, m). 23 2.86 (6H, s), 2.88-2.92 (1H, m), 3.00-3.03 (1H, m), 3.09-3.15 (1H, m), 4.04-4.08 (2H, m), 4.13 (1H, d, J=15.61 Hz), 4.25 (1H, d, J=15.69 Hz), 4.58-4.62 (1H, m), 4.92 (4H, s), 7.02-7.05 (1H, m), 7.11 (1H, s), 7.13-7.15 (2H, m), 7.30-7.36 (5H, m). 151651.doc -106- 201121961 24 25 26 27 28 29 30 31 32 1.41 (3H, d, J=6.89 Hz), 1.69-1.89 (6H, m), 2.79-2.85 (4H, m), 2.99-3.04 ( 2H, m), 3.52-3.55 (1H, m), 3.68-3.77 (1H, m), 4.20 (2H, q, CD3OD J=15.48 Hz), 4.58 (lH,t, J=2.92 Hz), 4.76 ( 3H, s), 6.95 (2H, s), 7.06-7.10 (2H, m). 1.41 (3H, d, J=6.93 Hz), 1.63-1.73 (1H, m), 1.90-2.05 (6H, m), 2.93-2.99 (4H, m), 3.13-3.26 (2H, m), 3.85 ( 1H, q, J=6.92 Hz), 4.35 (2H, CD3OD q, J=15.40 Hz), 4.63-4.67 (1H, m), 4.91 (3H, s), 6.93 (1H, s), 7.06-7.09 ( 1H, m), 7.18-7.25 (2H, m). 1.03 (12H,d, J=6.49 Hz), 2·90-3·14(6Η,m), 4.36 (2H,q,15.0 Hz), CD3OD 4.64 (1H, q, J-7.01 Hz), 4.75 ( 4H, s), 6.85 (1H, s), 6.98-7.01 (1H, m), 7.11-7.20 (2H, m). 0.80 (3H,d,J=6.24 Hz), 0.86 (3H,d, J=5.55 Hz), 1.17-1.38 (4H,m), 1.47-1.31 (2H, m), 1.47-1.60 (1H, m) , 2.37 (2H, s, br), 2.79-2.84 (1H, CD3OD m), 2.93-2.99 (3H, m), 4.19 (2H, q, 15.32 Hz), 4.50 (lH,t, J=7.44 Hz) , 4.75 (3H, s), 6.69 (1H, s), 6.85-6.88 (1H, m), 7.00-7.04 (2H, m). 1.67-1.76 (1H, m), 1.89-1.96 (1H, m), 2.09-2.23 (2H, m), 2.43-2.53 (1H, m), 2.94 (3H, s), 2.95-2.99 (1H, m ), 3.19-3.25 (3H, m), 3.67-CD3OD 3.72 (1H, m), 4.10 (lH,t, J=8.49 Hz), 4.37 (2H, q, J=15.61 Hz), 4.71-4.75 (1H , m), 4.91 (2H, s), 7.03-7.07 (2H, m), 7.11 (1H, s), 7.28-7.31 (2H, m). 0.97-1.08 (6H, m), 1.14-1.19 (4H, m), 2.45-2.51 (4H, m), 2.98-3.00 CD3OD (1H, m), 3.09-3.16 (1H, m), 4.29-4.42 ( 2H, m), 4.61-4.65 (1H, m), 4.91 (4H, s), 6.84 (1H, s), 7.00-7.04 (2H, m), 7.22-7.25 (2H, m). 0.97-1.08 (6H, m), 1.14-1.19 (4H, m), 2.45-2.51 (4H, m), 2.98-3.00 CD3OD (1H, m), 3.09-3.16 (1H, m), 4.29-4.42 ( 2H, m), 4.61-4.65 (1H, m), 4.91 (4H, s), 6.84 (1H, s), 7.00-7.04 (2H, m), 7.22-7.25 (2H, m). 1.56 (3H, d, J=6.88 Hz), 1.60-1.68 (1H, m), 1.73-1.93 (6H, m), 2.73-2.84 (2H, m), 2.92-3.01 (4H, m), 3.17- 3.22 (1H, m), 3.47-3.56 (1H, 3 m), 3.80 (1H, q, 6.68 Hz), 4.65 (1H, q, J=15.49 Hz), 4.77 (lH,t, J=6.12 Hz) , 4.91 (2H, s), 7.03-7.12 (3H, m), 7.29-7.34 (2H, m). 1.41 (3H, d, J=6.93 Hz), 1.56-1.58 (1H, m), 1.86-2.05 (6H, m), 2.96-3.01 (4H, m), 3.15-3.19 (1H, m), 3.41- 3.42 (1H, m), 3.54-3.58 (1H, 3 m), 3.58 (1H, q, 6.96 Hz), 4.27-4.42 (2H, m), 4.65 (lH,t, J-6.76 Hz), 4.91 ( 2H, s), 7.03-7.11 (3H, m), 7.28-7.31 (2H, m) 〇151651.doc -107- 201121961 33 34 35 36 37 38 39 0.93 (3H, d, J=6.20 Hz), 1.00 (3H, d, J=6.24 Hz), 1.24-1.47 (4H, m), 1.60-1.64 (2H, m), 1.70-1.75 (1H, m), 2.49 (2H, s, br), 2.95-3.00 (1H, CD3OD m), 3.09-3.14 (3H, m), 4.35 (2H, q, 15.08 Hz), 4.63 (lH,t, J=7.25 Hz), 4.91 (3H, s), 6.84 (1H, s ), 6.99-7.05 (2H, m), 7.22-7.26 (2H, m). 1.57-1.74 (1H, m), 1.88-1.95 (1H, m), 2.15-2.20 (1H, m), 2.43-2.50 (1H, m), 2.94 (3H, s), 2.95-3.00 (1H, m ), 3.17-3.26 (3H, m), 3.67-CD3OD 3.72 (1H, m), 4.10 (lH,t, J=8.44 Hz), 4.36 (2H, q, J=15.01 Hz), 4.75-4.79 (1H , m), 4.91 (3H, s), 6.99-7.02 (2H, m), 7.10 (1H, s), 7.31-7.37 (2H,m) » 1.13(3H,s, br), 1.26(6H, d , J=6.56 Hz), 1.32-1.40 (1H, m), 1.55 (3H, d, J=6.68 Hz), 2.54 (lH, s, br), 2.68 (3H, s), 2.87 (lH, s, Br), 2.94- CD3OD 3.00 (1H, m), 3.19-3.25 (1H, m), 3.95 (1H, q, J=6.88 Hz), 4.32-4.45 (2H, m), 7_02-7_ 15 (3H, m), 7.34 - 7.39 (2H, m). 1.58 (3H, d, J=6.97 Hz), 2.78 (6H, s), 2.99-3.05 (1H, m), 3.17-3.22 (1H, m), 3.86 (1H, q, J=6.93 Hz), 4.27 -4.31 (1H, m), 4.38-4.42 (1H, CD3OD m), 4.70-4.76 (1H, m), 4.91 (4H, s), 6.96-7.14 (4H, m), 7.31-7.37 (lH,m )» 0.99-1.07 (6H, m), 1.16 (3H,q, J =2.28 Hz), 2.44-2.49 (3H, m), 2.51-2.61 (1H, m), 2.96-3.03 (1H, m), 3.11-3.20 (1H, m), 4.34-4.38 (2H, CD3OD m), 4 66 (1H, q, 1.88 Hz), 4.91 (5H, s), 6.84 (1H, s), 6.99-7.06 (2H, m), 7.28-7.34 (2H, m). 1.41 (3H, d, 3=6.92 Hz), 1.50-1.58 (1H, m), 1.85-2.05 (6H, m), 2.99-3.05 (4H, m), 3.17-3.22 (1H, m), 3.41- 3.42 (1H, m), 3.54-3.58 (1H, CD3OD m), 3.58 (1H, q, 6.96 Hz), 4.27-4.31 (1H, m), 4.38-4.43 (1H, m), 4.68 (lH,t , J=6.60 Hz), 4.92 (1H, s), 7.02-7.05 (2H, m), 7.11 (2H, t, J=4_45 Hz), 7.32-7.35 (1H, m), 8.84-8.87 (1H, m). 1.56 (3H, d, J=6.84 Hz), 1.61-1.72 (1H, m), 1.74-1.93 (6H, m), 2.75-2.86 (2H, m), 2.96-3.02 (4H, m), 3.19- 3.24 (1H, m), 3.56 (1H, s, br), CD3OD 3.82 (1H, q, 6.92 Hz), 4.31-4.44 (2H, m), 4.79 (lH,t, J=6.13 Hz), 7.00- 7.09 (2H, m), 7.11-7.15 (2H, m), 7.32-7.38 (1H, m), 8.85-8.88 (1H, m). 40 1.69-1.78 (1H, m), 1.84-1.96 (1H, m), 2.12-2.22 (1H, m), 2.51-2.53 (1H, m), 2.93 (3H, s), 3.01-3.07 (1H, m), 3.19-3.31 (2H, m), 3.66-3.71 (1H, m), 4.11 (lH,t, J=8.45 Hz), 4.31-4.43 (2H, m), 4.81-4.85 (1H, m) , 4.91 (2H, s), 7.08-7.15 (3H, m), 7.31-7.357 (2H, m). 15l651.doc • 108 · 201121961 41 42 43 44 47 48 49 1.16(3H,s, br), 1.26(6H, d, J=6.44 Hz), 1.29-1.40 (1H, m), 1.54 (3H, d, J=6.68 Hz), 2.67(1 H,s, br), 2.72 (3H, s), 2.93-2.95 (1H, m), 3.00-CE>3〇D 3.11 (1H, m), 3.94-3.99 ( 1H, m), 4.29-4.44 (2H, m), 4.71-4.77 (1H, m), 7.05-7.17 (3H, m), 7.29-7.36 (2H, m). 2.06-2.36 (4H, br m) 2.72-2.75 (1H, m) 2.90 (3H, s) 3.06 (3H, s) 3.60 (1H, s) 3.75-3.85 (2H, m) 4.09 (1H, t, J =8.0 Hz) 4.42 (1H, t, CD3〇DJ=8.0 Hz) 4.52 (2H, s) 4.94 (1H, m) 7.33 (1H, s) 7.37-7.46 (2H, m) 7.48-7.64 (2H, m 7.74-7.84 (2H, m) 7.90 (1H, d, J=8.0 Hz) 8.23 (lH,d,J=8.0Hz). 0.84 (3H, d, J=4.0 Hz) 0.88 (3H, d, J=4.0 Hz) 1.07 (3H, d, J=4.0 Hz) 1.39 (1H, d, J=4.0 Hz) 1.98 (3H, s) 2.53 -2.59 (1H, br m) 2.88 (1H, CD3OD s) 3.44-3.49 (1H, m) 4.22 (2H, d, J=8.0 Hz) 4.75 (5H, s) 6.65 (1H, t, J=4.0 Hz) 7.19-7.29 (2H, m) 7.37-7.47 (2H, m) 7.67 (1H, dd, J=8.0, 4.0 Hz) 7.78 (1H,d,J=8_0 Hz) 8.11 (1H,d,J= 8.0 Hz). 1.01 (2H, t, J=8.0 Hz) 1.16 (2H, t, J=8.0 Hz) 1.52 (2H, d, J=8.0 Hz) 1.77 (2H, d, J=8.0 Hz) 2.38-2.43 (1H, m) 2.73-2.87 (1H, m) 3.10-3.15 (1H, m) 3.22-3.37 (3H, m) 3.44-3.53 (2H, m) 3.64-3.69 (1H, CD3OD m) 3.85-3.90 (1H, m ) 4.30-4.35 (1H, m) 4.43-4.48 (1H, m) 4.55-4.59 (1H, m) 4.87-5.02 (1H, br m) 7.33 (1H, s) 7.38-7.44 (2H, m) 7.51- 7.67 (2H, br m) 7.81 (1H, dd, J=8.0, 4.0 Hz) 7.91-7.95 (1H, m) 8.27 (1H,d, J=8_0 Hz) 8.83 (1H, t, J=8.0 Hz) . 1.91-1.96 (6H, m) 2.71-2.77 (2H, m) 3.04-3.14 (2H, m) 3.41-3.49 (1H, m) 4.04 (2H, s) 4.57-4.61 (1H, m) 6.60 (1H, s) 6.94-7.00 (2H, CD3OD m) 7.03-7.17 (3H, m) 7.19-7.25 (2H, m) 7.34-7.45 (2H, m) 7.57-7_64 (1H, m) 7.74 (1H, d, J =8_0 Hz) 8.07 (1H,d,J=8.0 Hz). 1.62-1.71 (3H, m), 2.07-2.11 (1H, m), 2.13 (3H, s), 2.24-2.33 (1H, m), 2.75-2.79 (1H, m), 2.93-2.98 (1H, m ), 3.02-3.06 (1H, m), 3.11-CDCI3 3.16 (1H, m), 4.23-4.36 (2H, m), 4.62-4.68 (1H, m), 5.47 (2H, s), 6.67 (1H, s), 7.11 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 7.41 (1H, t, J=5.4 Hz), 7.81 (1H, d, J=8.6 Hz) . 0.84(6H, d, J=6.5 Hz), 0.98 (3H, d, J=7.0 Hz), 1.83 (3H, s), 2.59- 2.68 (1H, m), 2.83-2.90 (1H, m), 2.94 -3.00 (1H, m), 3.10 (1H, q, CDCI3 J=7.0 Hz), 4.11-4.22 PH, m), 4.49 (1H, q, J=7.7 Hz), 5.12 (2H, s), 6.53 ( 1H, s), 6.98-7.02 (3H, m), 7.09 (2H, d, J=8.3 Hz), 7.80 (1H, d, J=8.4 Hz). 151651.doc -109- 201121961 50 51 52 53 54 55 56 57 1.67-1.79 (3H, m), 2.15 (3H, s), 2.27-2.34 (1H, m), 2.78-2.83 (2H, m), 2.95 -3.01 (1H, m), 3.05-3.08 (1H, m), 3.14-3.19 (1H, m), 4.24- CDCI3 4.40 (2H, m), 4.61-4.67 (1H, m), 5.46 (2H, s ), 6.72 (1H, s), 7.08-7.38 (4H, m), 7.86 (1H, d, J = 8.2 Hz). 1.28(6H, d, 3=6.6 Hz), 1.37-1.44 (1H, m), 1.55 (3H, d, J=6.8 Hz), 2.67 (3H, s), 2.86-2.99 (2H, m), 3.20 -3.25 (1H, m), 3.96 (1H, q, CD3OD J=6.8 Hz), 4.32-4.46 (2H, m), 7.13 (1H, s), 7.26-7.36 (4H, m), 8.89 (lH, t, J = 5.0 Hz). 1.06 (3H, d, J=7.0 Hz), 2.10(6H, s)9 2.93-3.00 (2H, m), 3.12-3.17 (1H, m), 4.25-4.37 (2H, m), 4.68 (1H, q, J=7.8 Hz), 5.25 (2H, s), 6.68 (1H, s), 7.07-7.11 (1H, m), 7.16-7.20 (4H, m), 7.75 (1H, d, J=8.4 Hz ). 0.95(6H, t, J=7.1 Hz), 1.08 (3H, d, J=7.0 Hz), 2.30-2.48 (4H, m), 2.94-2.99 (1H, m), 3.11-3.16 (1H, m) , 3.29 (1H, q, J=6.9 Hz), 4.22-CDCI3 4.36 (2H, m), 4.78 (1H, q, J=7.8 Hz), 5.53 (2H, s), 6.60 (1H, s), 7.06 -7.09 (1H, m), 7.15-7.19 (3H, m), 7.49 (1H, t, J=5.1 Hz), 7.98 (1H, d, J=8.5 Hz). 1.41-1.51 (1H, m), 1.56 (3H, d, J=6.90 Hz), 1.67-1.93 (5H, m), 2.76-2.84 (2H, m), 2.94-3.00 (2H, m), 3.18- 3.24 (1H, m), 3.55-3.57 (1H, CD3OD m)s 3.84(ih, q, J=6.9 Hz), 4.31-4.44 (2H, m), 4.78-4.82 (1H, m), 7.14 (1H , s), 7.25-7.38 (4H, m), 8.89 (1H, t, J = 5.7 Hz). 1.42 (3H, d, J=7.0 Hz), 1.53-1.59 (1H, m)5 1.87-1.99 (5H, m), 2.97-3.03 (3H, m), 3.17-3.22 (1H, m), 3.42 ( lH,br s), 3.58(lH,br s), CD3〇D 3.92(1H, q, J=6.9 Hz), 4.29-4.42 (2H, m), 4.66-4.70 (1H, m), 7.12 (1H , s), 7.23-7.36 (4H, m). 1.61-1.77 (4H, m), 2.19 (3H, s), 2.28-2.35 (1H, m), 2.81-2.84 (1H, m), 2.96-3.01 (1H, m), 3.05-3.08 (1H, m ), 3.14-3.19 (1H, m), 4.28-CDCI3 4.42 (2H, m), 4.55-4.61 (1H, m), 5.02 (2H, s), 6.80 (1H, s), 6.99-7.01 (1H, m), 7.06 (1H, dd, J=8.2, 2.0 Hz), 7.32-7.36 (2H, m), 7.81 (1H, d, J=8.5 Hz). 0.99 (6H, d, J = 6.5 Hz), 1.16 (3H, d, J = 7.0 Hz), 2.01 (3H, s), 2_72-2.81 (1H, m), 2.98-3.04 (1H, m), 3.10 -3.15 (1H, m), 3.27(1H, q, CDCU J=7.0 Hz), 4.35 (2H, ds J=5.5 Hz), 4.54-4.59 (1H, m), 5.00 (2H, s), 6.80 ( 1H, s), 6.84 (1HS t, J=5.3 Hz), 7.06 (1H, dd, J=8.2, 2.0 Hz), 7·31 (1H, d, J=2.0 Hz), 7.34-7.39 (1H, m), 7.81 (1H, d, J = 7.5 Hz). 151651.doc •110· 201121961 58 59 60 61 62 1.59 (3H, d, J=7.0 Hz), 2.82(6H, s), 3.00-3.05 (1H, m), 3.14-3.19 (1H, m), 3.93 (1H, q, J=7.0 Hz), 4.27-4.42 (2H, m), 4.68-4.72 (1H, CD3OD m), 7.13 (1H, s), 7.25 (1H, dd, J=8.3, 2.0 Hz) , 7.46-7.48 (2H, m), 8.87 (lH, t, J = 5.7 Hz). 0.96(6H, t, J=7.1 Hz), 1.10 (3H, d, J=7.0 Hz), 2.31-2.47 (4H, m), 2.92-2.98 (1H, m), 3.09-3.14 (1H, m) , 3.29 (1H, q, J=7.0 Hz), 4.30 CDCI3 (2H, d, J=5.5 Hz), 4.74 (1H, q, J=7.8 Hz), 5.34 (2H, s), 6.64 (1H, s ), 7.04 (1H, dd, J=8.2, 2.0 Hz), 7.27-7.36 (3H, m), 7.97 (1H, d, J=8.6 Hz). 1.56 (3H, d, J=6.9 Hz), 1.61-1.93 (6H, m), 2.94-3.00 (4H, m), 3.18-3.23 (1H, m), 3.56(lH,br s), 3.85 (1H , q, 3=6.9 Hz), 4.31-4.44 (2H, CD3OD m), 4.77-4.81 (1H, m), 7.14 (1H, s), 7.27 (1H, dd, J=8.3, 2.0 Hz), 7.48 -7.50 (2H, m), 8.88 (1H, t, J = 5.7 Hz). 1.45 (3H, d, J=7.0 Hz), 1.54-1.62 (1H, m), 1.86-1.99 (5H, m), 2.97-3.03 (3H, m), 3.15-3.20 (1H, m), 3.42 ( lH, br s), 3.59 (lH, br s), CD3OD 3.93 (1H, q, J=6.9 Hz), 4.28-4.42 (2H, m), 4.65-4.69 (1H, m), 7.13 (1H, s ), 7.24 (1H, dd, J=8.3, 2.0 Hz), 7.46 (1H, d, J=2.0 Hz), 7.47-7.49 (1H, m). 1.07 (3H, s), 1.22 (3H, d, J=6.4 Hz), 1.54 (3H, d, J=6.8 Hz), 2.35 (3H, s), 2.64 (3H, s), 2.86-2.92 (1H , m), 3.17-3.21 (1H, m), CD3OD 3.94 (1H, q, J=6.8 Hz), 4.33-4.44 (2H, m), 4.84-4.88 (1H, m), 7.13-7·21 ( 5H, m), 8_86 (1H, s). 63 1.63-1.72 (1H, m), 1.82-1.93 (1H, m), 2.09-2.19 (1H, m), 2.33 (3H, s), 2.40-2.49 (1H, m), 2.88-2.91 (1H, m), 2.93 (3H, s), 3.17-3.23

CD3OD 64 (2H, m), 3.66-3.71 (1H, m), 4.12 (1H, t, J=8.3 Hz), 4.31-4.42 (2H, m), 4.71-4.74 (1H，m)，7.11-7.17 (5H，m), 8.87 (1H，t, J=5.7 Hz) » 1.60-1.69 (1H, m), 1.81-1.92 (1H, m), 2.09-2.19 (1H, m), 2.34 (3H, s), 2.39-2.48 (1H, m), 2.87-2.91 (1H, m), 2.93 (3H, s), 3.16-3.25 CD3OD (2H, m), 3.65-3.71 (1H, m), 4.13 (1H, t, J=8.3 Hz), 4.32-4.43 (2H, m), 4.73-4.77 (1H, m), 7.06-7.10 (4H, m), 7.19 (1H, t, J=7.5 Hz), 8.89 (1H, t，J=5_7 Hz)。 65 1.05 (3H, s), 1.23 (3H, d, J=6.5 Hz), 1.54 (3H, d, J=6.8 Hz), 2.35 (3H, s), 2.65 (3H, s), 2.87-2.93 (1H, m), 3.18-3.23 (1H, m), 3.95CD3OD 64 (2H, m), 3.66-3.71 (1H, m), 4.12 (1H, t, J=8.3 Hz), 4.31-4.42 (2H, m), 4.71-4.74 (1H, m), 7.11-7.17 (5H,m), 8.87 (1H,t, J=5.7 Hz) » 1.60-1.69 (1H, m), 1.81-1.92 (1H, m), 2.09-2.19 (1H, m), 2.34 (3H, s ), 2.39-2.48 (1H, m), 2.87-2.91 (1H, m), 2.93 (3H, s), 3.16-3.25 CD3OD (2H, m), 3.65-3.71 (1H, m), 4.13 (1H, t, J=8.3 Hz), 4.32-4.43 (2H, m), 4.73-4.77 (1H, m), 7.06-7.10 (4H, m), 7.19 (1H, t, J=7.5 Hz), 8.89 (1H , t, J=5_7 Hz). 65 1.05 (3H, s), 1.23 (3H, d, J=6.5 Hz), 1.54 (3H, d, J=6.8 Hz), 2.35 (3H, s), 2.65 (3H, s), 2.87-2.93 ( 1H, m), 3.18-3.23 (1H, m), 3.95

CD3OD (1H, q, J=6.8 Hz), 4.33-4.453 (2H5 m)3 4.87-4.91 (1H? m), 7.09-7.15 (4H，m)，7.21 (1H，t，J=7.5 Hz)，8·86 (1H，t5 J=5.2 Hz)。 151651.doc -Ill - 201121961 66 1.66-1.75 (1H, m), 1.82-1.93 (1H, m), 2.09-2.19 (1H, m), 2.41 (3H, s), 2.44-2.51 (1H, m), 2.93 (3H, s), 2.94-3.00 (1H, m), 3.17-3.24 (1H, m), 3.27-3.32 (1H, m), 3.65-3.71 (1H, m), 4.14 (1H, t, J=8.3 Hz), 4.29-4.41 (2H, m), 4.77-4.81 (1H, m), 7.08 (1H, s), 7.09-7.14 (1H, m), 7.16-7.17 (3H, m), 8.84 (1H, t, J=5.7 Hz), 8.93 (1H, d, J=8.0 Hz)。 67 1.14 (3H, s), 1.22 (3H, d, J=6.5 Hz), 1.54 (3H, d, J=6.8 Hz), 2.45 (3H, s), 2.63 (3H, s), 2.97-3.02 (1H, m), 3.21-3.29 (1H, m), CE&gt;3〇D 3.96(1H, q, J=6.8 Hz), 4.31-4.43 (2H, m), 7.09 (1H, s), 7.11-7.22 (4H, m)，8.86(1 H，s)。 68 0.94-1.10 (2H, m), 1.19-1.42 (4H, m), 1.60-1.80 (7H, m), 1.99-2.19 (3H, m), 2.47-2.56 (1H, m), 3.38-3.49 (2H, m), 4.34-4.41 (3H, m), 4.43-4.50 (1H, m), 7.17 (1H, s), 8.78 (1H, d, J=7.6 Hz), 8.91 (1H, t, J=5.8 Hz)。 69 70 71 0.94-1.09 (2H, m), 1.22-1.42 (4H, m), 1.61-1.79 (7H, m), 2.02-2.14 (2H, m), 2.21-2.31 (1H, m), 2.61-2.69 (1H, m), 2.98 (3H, s), 3.25- CD3OD 3.32 (1H, m), 3.74-3.80 (1H, m), 4.18 (1H, t, J=8.2 Hz), 4.36-4.42 (2H，m)，4.45-4.49 (1H, m), 7.17 (1H, s)，8.93 (1H，t，J=5.8 Hz)。 0.96-1.08 (2H, m), 1.19-1.44 (4H, m), 1.65 (2H, t, J=7.3 Hz), 1.74-1.84 (5H, m), 2.01-2.30 (3H, m), 2.60-2.69 (1H, m), 2.97 (3H, s), CE&gt;3〇D 3.23-3.30 (1H, m), 3.73-3.79 (1H, m), 4.15-4.19 (1H, m), 4.33-4.41 (2H，m)，4.43-4.48 (1H，m), 7.16 (1H，s)，8.92 (1H，t，J=5.8 Hz)。 0.96-1.09 (2H, m), 1.21-1.42(10H, m), 1.61-1.73 (7H, m), 1.79 (3H, d, J=9.8 Hz), 2.79 (3H, s), 3.58 (1H, br s), 4.11 (1H, q, J=6.8 Hz), CD3OD 4.34-4.45 (2H, m), 4.54-4.59 (1H, t, J=7.7 Hz), 7.17 (1H, s), 8.89 (lH，t，J=5.7Hz)» 72 73 0.95-1.08 (2H, m), 1.19-1.43 (4H, m), 1.62 (3H, d, J=7.0 Hz), 1.64-CD3OD 1.80 (7H, m), 2.94(6H, s), 3.99 (1H, q, J=7.0 Hz), 4.34-4.49 (3H, m)，7.17 (1H，s), 8.89 (1H，t，J=5.7 Hz)。 0.85-1.01 (2H, m), 1.04 (6H, t, J=7.1 Hz), 1.10-1.28 (7H, m), 1.51-1.79 (7H, m), 2.37-2.55 (4H, m), 3.35 (1H, q, J=7.0 Hz), 4.32-4.47 (3H, m), 5.09 (2H, s), 6.82 (1H, s), 7.09 (1H, t, J=5.4 Hz), 7.74 (1H, d，J=8.3 Hz)。 lS16Sl.doc -112- 201121961 74 75 76 77 78 79 80 81 0.94-1.08 (2H, m), 1.22-1.30 (4H, m), 1.34 (3H, t, J=7.3 Hz), 1.63-1.79 (7H, m), 2.02-2.14 (2H, m), 2.21-2.30 (1H, m), 2.60-2.68 (1H, CD3OD m), 3.22-3.35 (3H, m), 3.76-3.80 (1H, m), 4.21 (1H, t, J=8.0 Hz), 4.34-4.41 (2H, m), 4.44-4.48 (1H, m), 7.17 (1H, s), 8.95 (1H, t, J=5.7 Hz)。 1.00-1.14 (2H, m), 1.25-1.36 (4H, m), 1.40 (3H, d, J=6.6 Hz), 1.43 (3H, d, J=6.6 Hz), 1.72 (2H, t, J=7.4 Hz), 1.78-1.85 (5H, m), 2.02- 2.18 (2H, m), 2.21-2.31 (1H, m), 2.61-2.69 (1H, m), 3.36-3.41 (1H, CD3OD 3.63-3.70 (1H, m), 3.75-3.79 (1H, m), 4.35-4.39 (1H, m), 4.44 (2H, d, J=5.2 Hz), 4.50 (1H, t, J=7.7 Hz), 7.24 (1H, s), 9.01 (1H, t, J=5.8 Hz)。 0.94-1.08 (2H, m), 1.22-1.40 (4H, m), 1.65 (2H, t, J=7.3 Hz), 1.71-1.88 (8H, m), 1.97-2.00 (2H, m), 2.17-2.20 (1H, m), 2.86 (3H, s), CD3OD 3.12-3.18 (1H, m), 3.53-3.57 (1H, m), 3.78-3.82 (1H, m), 4.35-4.45 (3H, m), 7.18 (1H, s), 8.85 (1H, d, J=6.9 Hz), 8.96 (1H, t, J=5.8 Hz)。 0.96-1.08 (2H, m), 1.21-1.43 (4H, m), 1.60-1.98( 16H, m), 3.02-3.09 CD3OD (2H, m), 3.46(lH,br s), 3.67(lH,br s), 3.95 (1H, q, J=6.9 Hz), 4.34- 4.50 (3H，m), 7.16 (1H，s), 8.88 (1H，t，J=5.8 Hz)。 0.98-1.08 (2H, m), 1.25-1.41 (4H, m), 1.60-1.98(16H, m), 3.02-3.09 CD3OD (2H, m), 3.47(lH,br s), 3.66(lH,br s), 3.96(1H, q, J=6.9 Hz), 4.34-4.49 (3H，m)，7.17 (1H, s), 8.93 (1H, t, J=5.8 Hz)。 2.12 (3H, s) 3.43-3.56 (2H, m) 3.93 (1H, s) 3.98 (1H, s) 4.02 (1H, s) 4.12 (1H, s) 5.89 (1H, s) 6.69 (1H, d, J=4.0 Hz) 6.82 (1H, s) 7.21-CD3OD 7 31 (2h, m) 7.38-7.48 (2H, m) 7.66 (1H, dd, J=8.0, 4.0 Hz) 7.76 (1H，dd，J=8.0,4.0 Hz) 8.11 (1H, d，J=8.0 Hz) 10.58 (1H, br s)。 3.41-3.57 (2H, m) 3.62-3.78 (2H, m) 4.07 (1H, d, J=4.0 Hz) 4.17 (1H, d, J=4.0 Hz) 4.80-4.86 (4H, br m) 6.81 (1H, s) 6.97 (1H, td, J-4.0 Hz) 7.03 (1H, s) 7.12 (1H, td, J=4.0 Hz) 7.23 (1H, t, J=8.0 Hz) CD3OD 7 3〇_7 34 (2H, m) 7.39 (1H, td, J=4.0 Hz) 7.44 (1H, td, J=4.0 Hz) 7.51 (1H, d, J=8.0 Hz) 7.65 (1H, d, J=8.0 Hz) 7.85 (1H, d, J=4.0 Hz) 8.40-8.44 (1H, m)。 2.18 (3H, s) 3.20-3.22 (1H, m) 3.25-3.42 (3H, m) 3.98-4.03 (1H, m) 4.10-4.15 (1H, m) 4.56-4.63 (1H, m) 4.75-4.85 (3H, m) 6.81-6.87 CD3OD (3H, m) 6.95 (1H, d, J=8.0 Hz) 7.01-7.10 (1H, m) 7.14-7.20 (2H, m) 7.39-7.44 (2H, m) 7.64 (1H, d, J=8.0 Hz) 7.75 (1H, d, J=8.0 Hz) 8-03 (1H, d, J=8.0 Hz) 8.36 (1H，t, J=8.0 Hz)。 151651.doc • 113· 201121961 82 83 84 85 2.11 (3H, s), 2.13 (3H, s), 2.82-2.88 (1H, m), 2.99-3.03 (1H, m), d6 DMSO 3.31 (1H，s)，4.16-4.27 (2H，m)，4.61-4.67 (1H, m)，5.63 (1H，d， &quot; J=1.96 Hz), 6.73 (1H, s), 6.77 (2H, s), 7.03-7.07 (1H, m), 7.19-7.32 (3H，m)，8.53 (1H，t，J=5.60 Hz)。 2.16 (3H, s), 2.83-2.89 (1H, m), 3.00-3.05 (1H, m), 4.21-4.24 (2H, d6 DMSO m)，4.62_4·66 (1H，m)，5 90 (1H，L J=2·28 Hz), 6·74-6·77 (4H，m)， ' 7.05-7.08 (1H, m), 7.25-7.31 (3H, m), 7.39 (1H, d, J=8.44 Hz), 8.55 (1H, t, J=5.68 Hz)。 CD3OD 3.13-3.17 (1H, m), 3.25-3.30 (1H, m), 4.33-4.37 (2H, m), 4.78-4.83 (1H, m), 4.96-5.01 (1H, m), 7.10-7.30(9H, m), 7.47-7.49 (1H, m), 7.67 (1H, d, J=8.04 Hz), 8.52 (1H, d, J=7.84 Hz), 8.77 (1H, t, J=5.89 Hz)。 CD3OD 2.28 (3H, s), 3.05-3.10 (2H, m), 3.18-3.23 (2H, m), 4.30 (1H, d, J=15.0 Hz), 4.42 (1H, d, J=15.09 Hz), 4.77 (1H, t, J=6.88 Hz), 4.91 (3H, s), 6.05 (1H, d, J=2.44 Hz), 6.84 (2H, t, J=0.84 Hz), 6.99-7.03 (2H，m), 7.23-7.26 (2H，m)。 86 2.31 (3H, s), 3.12-3.17 (1H, m), 3.19-3.26 (1H, m), 4.27-4.31 (1H, m)s 4.37-4.41 (1H, m), 4.76-4.81 (1H, m), 4.91 (4H, s), 6.06 (1H, d, J=3.21 Hz), 6.84 (2H, t, J=2.32 Hz), 6.99-7.03 (2H, m), 7.08-7.11 (2H, m), 7.30-7.35 (1H，m)，8.75-8.78 (1H，m)。 87 2.29 (3H, s), 3.13-3.18 (1H, m), 3.23-3.28 (1H, m), 4.30-4.34 (1H, m), 4.39-4.42 (1H, m), 4.83-4.86 (1H, m), 4.91 (4H, s), 6.04 (1H, d, CD3OD J=2.45 Hz), 6.83 (2H, t, J=2.68 Hz), 7.06-7.12 (2H, m), 7.26-7.32 (2H，m)。 88 2.15 (3H, s), 2.83-2.88 (1H, m), 3.00-3.05 (1H, m), 4.17-4.27 (2H, d6 DMSO m)，4.61·4·67 (1H，m)，5·90 (1H，J=2.3 Hz)，6·75·6·78 (4H，m)， ' 7.24-7.30 (4H, m), 7.35 (1H, d, J=8.4 Hz), 8.57 (1H, t, J=5.7 Hz), 11.10 (1H，s)。 89 90 2.16 (3H，s)，2.84-2.90 (1H，m)，3.01-3.06 (1H, m)，4.18-4.28 (2H， d6 DMSO m)，4·62-4.67 (1H, m)，5.90 (1H，L J=2·2 Hz)，6.75_6·77 (4H，m)， ' 7.19-7.28 (3H，m)，7.35 (1H，s)，7.38 (1H, d，J=8.4 Hz)，8.57 (1H，t， J=5.7Hz)，11.10 (lH,s)。 2.29 (3H, s), 2.34 (3HS s), 3.06-3.11 (1H, m), 3.15-3.20 (1H, m), 4.27-4.40 (2H, m), 4.75 (1H, t, J=7.2 Hz), 6.05 (1H, t, J=2.3 Hz), CD3〇D 6.84 (1H, t, J=2.7 Hz), 7.09-7.16 (5H, m), 8.73 (1H, t, J=5.7 Hz), 10.72 (1H，s)。 151651.doc • 114· 201121961 91 92 93 94 95 96 97 98 99 100 2.21 (3H, s), 2.23 (3H, s), 3.04-3.14 (2H, m), 4.20-4.30 (2H, m), 4.86(1H, q, J=7.1 Hz), 5.51(2H,br s), 6.00 (1H, s), 6.58 (1H, d, J=7.2 Hz), 6.66 (1H, s), 6.73-6.74 (1H, m), 6.96-7.03 (3H, m), 7.12 (1H, t, J=7.4 Hz), 7.24-7.26 (1H，m), 9.90(1H，s)。 CD3OD 2.14 (3H, s), 2.24 (3H, s), 2.92-2.97 (1H, m), 3.04-3.10 (1H, m), 4.09-4.26 (2H, m), 4.64 (1H, t, J=7.4 Hz), 5.88 (1H, d, &gt;2.4 Hz), 6.62 (1H, s)，6.67 (1H, d, J=2.5 Hz), 6.91-7.07 (4H, m)。 d6-DMSO 0.80-0.93 (2H, m), 1.07-1.33 (4H, m), 1.45-1.73 (7H, m), 2.25 (3H, s), 4.12-4.25 (2H, m), 4.42-4.48 (1H, m), 5.93 (1H, t, J=2.2 Hz), 6.73-6.79 (4H, m), 7.31 (1H, d, J=8.2 Hz), 8.45 (1H, t, J=5.8 Hz), 11.16 (1H, s)。 CD3OD 2.62-2.68 (1H, m) 2.73 (2H, s) 3.24-3.43 (2H, m) 4.02 (1H, s) 4.07-4.13 (2H, m) 4.60 (1H, t, J=8.0 Hz) 6.57 (1H, s) 6.95-7.21 (7H, m) 7.39-7.47 (2H, m) 7.63 (1H, d, J=8.0 Hz) 7.74 (1H, d, J=8.0 Hz) 8.11 (lH,d, J=8.0Hz)。 CD3OD 2.82-2.88 (1H, m), 2.94-2.99 (1H, m), 3.05-3.10 (2H, m), 4.23-4.30 (3H, m), 4.56-4.60 (1H, m), 4.91 (4H, s), 7.00-7.04 (1H, m), 7.10 (1H, s), 7.13-7.31 (6H, m), 8.00 (1H, d, J=8.04 Hz), 8.51 (1H; t, J=5.64 Hz) » CD3OD 2.80-2.86 (1H, m), 2.91-2.97 (1H, m), 3.04-3.10 (2H, m), 4.23-4.31 (3H, m), 4.57 J=7.09 Hz), 4.9 (5H, s), 6.82 (1H, s), 6.97-7.02 (2H，m), 7.18-7.30 (7H，m)» CD3OD 2.80-2.87 (1H, m), 2.94-3.13 (3H, m), 4.23-4.31 (3H, m), 4.61 (lH,t, J=7.16 Hz), 4.9 (5H, s), 6.81 (1H, s), 6.98-7.03 (3H, m), 7.24-7.32 (6H, m)。 CD3OD 2.80-2.85 (1H, m), 3.04-3.09 (2H, m), 3.15-3.20 (1H, m), 4.23-4.29 (3H, m), 4.62-4.67 (1H, m), 4.91 (5H, s), 7.09-7.13 (2H, m), 7.22-7.31 (6H, m)，8.00 (1H, d，J=8.0 Hz), 8_55 (1H, t, J=5.8 Hz)。 CD3OD 2.82-2.89 (1H, m), 2.95-3.00 (1H, m), 3.04-3.11 (2H, m), 4.23-4.34 (3H, m), 4.57-4.63 (1H, m), 7.10 (1H, s), 7.20-7.30(9H, m), 7.98 (1H，d，J=8.0 Hz), 8.54 (1H, t，J=5.8 Hz)。 CD3OD 2.82-2.B7 (1H, m), 2.97-3.02 (1H, m), 3.04-3.12 (2H, m), 4.21-4.35 (3H, m), 4.57-4.63 (1H, m), 7.09 (1H, s), 7.14-7.31(9H, m), 7.98 (1H，d，J=8.0 Hz), 8.55 (1H, t, J=5.8 Hz) » 151651.doc -115- 201121961 101 102 103 104 105 106 107 108 CD3OD 2.19 (3H, s), 2.67-2.72 (1H, m), 2.79-2.84 (1H, m), 2.88-2.94 (2H, m), 4.07-4.19 (3H, m), 4.40-4.46 (1H, m), 6.94-6.99 (5H, m), 7.06-7.18 (5H，m)，7.76 (1H，d，J=7.9 Hz)，8·33 (1H，t, J=5_8 Hz)» CD3OD 2.33 (3H, s), 2.81-2.86 (1H, m), 2.94-2.99 (1H, m), 3.02-3.08 (2H, m), 4.22-4.34 (3H, m), 4.56-4.61 (1H, m), 7.02 (1H, d, J=7.6 Hz), 7.05-7.08 (3H, m), 7.16-7.31 (6H, m), 7.92 (1H, d, J=7.9 Hz), 8.49 (1H, t，J=5.8 Hz)。 CDC13 (CDC13) 2.28 (3H, s), 2.73-2.78 (1H, m), 2.91-2.96 (1H, m), 3.03-3.10 (2H, m), 4.01-4.06 (1H, m), 4.20-4.25 (2H, m), 4.67(1H, q, J=7.8 Hz), 5.48 (2H, s), 6.44 (1H, s), 7.01-7.26(9H, m), 7.52 (1H, d, J=8.2 Hz)。 CD3OD 0.90-1.04 (2H, m), 1.17-1.32 (4H, m), 1.54-1.81 (7H, m), 2.88-2.93 (1H, m), 3.09-3.13 (1H, m), 4.32-4.36 (3H, m), 4.40-4.46 (1H, m), 7.16 (1H, s), 7.22-7.36 (5H, m), 7.92 (1H, d, J=7.9 Hz), 8.58 (1H, t, J=5_8 Hz)。 CD3OD 0.93 (3H, t, J=8.0 Hz) 1.56-1.67 (1H, m) 1.73-1.83 (1H, m) 3.52-3.67 (2H, m) 4.01 (1H, q, J=4.0 Hz) 4.12-4.15 (1H, m) 4.25-4.29 (1H, m) 4.77-4.82 (1H, m) 6.95 (1H ,s) 7.35-7.43 (2H, m) 7.51-7.64 (2H, m) 7.71-7.83 (1H, m) 7.91 (lh, d, J=8.0 Hz) 8.27 (lh, d, J=8.0 Hz)» CD3OD 0.66 (3H, d, J=4.0 Hz) 0.84 (3H, d, J=4.0 Hz) 1.84-1.95 (1H, m) 3.20-3.22 (1H, m) 3.35-3.46 (2H, m) 3.74 (1H, d, J=4.0 Hz) 3.97-4.02 (1H, m) 4.08-4.13 (1H, m) 4.63-4.68 (1H, m) 4.72-4.81 (4H, br m) 6.81 (1H, s) 7.20-7.28 (2H, m) 7.35-7.47 (2H, m) 7.64-7.70 (1H, m) 7.76 (1H，d，J=8.0 Hz) 8.10 (1H, d，J=8.0 Hz)。 CD3OD 0.66 (3H, d, J=4.0 Hz) 0.92 (3H, d, J=4.0 Hz) 1.94-2.09 (1H, m) 3.08 (1H, s) 3.49-3.54 (1H, m) 3.59-3.64 (1H, m) 3.86-3.89 (1H, m) 4.14-4.18 (1H, m) 4.28-4.32 (1H, m) 4.79-4.86 (1H, m) 4.93-5.03 (4H, br m) 6.98 (1H, s) 7.36-7.46 (2H, m) 7.54-7.64 (2H, m) 7.75-7.82 (1H，m) 7.96 (1H，d, J=8.0 Hz) 8.23 (1H，d, J=8.0 Hz)。 CD3OD 0.81 (3H, d, J=6.84 Hz), 0.99 (3H, d, J=6.96 Hz), 2.01-2.09 (1H, m), 2.99-3.04 (1H, m), 3.10-3.15 (1H, m), 3.87 (1H, d, J=3.64 Hz), 4.31-4.38 (2H, m), 4.63-4.66 (1H, m), 4.91 (3H, s), 7.05-7.08 (1H, m), 7.16 (1H, s), 7.18-7.21 (2H, m), 8.03 (1H, d, J=8.05 Hz), 8.74 (1H, t，J=5.68 Hz)。 151651.doc -116- 201121961 0.71 (3H, d, J=6.88 Hz), 0.96 (3H, d, J=6.93 Hz), 1.99-2.07 (1H, m), 2.99-3.05 (1H, m), 3.11-3.16 (1H, m), 3.86 (1H, d, J=3.68 Hz), 4.27-4.28 (1H, m), 4.31-4.37 (1H, m), 4.63-4.69 (1H, m), 4.91 (3H, s), 7.07-7.10 (1H, m), 7.13 (1H, s), 7.16-7.23 (2H, m), 8.03 (1H, d, J=8.13 Hz)，8.74 (1H，t, J=5.80 Hz)。 cd3od 109 表5 實例名稱 實例 名稱 編號 8 9 10 11 12 13 14 15 16 17 18 (R)-吡咯啶-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺甲醯基]-2-(3,4-二氟-苯基)-乙基]-醯胺 (R)-2-胺基-3-曱基-戊酸[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-(3,4-二氟-苯基)-乙基]-酿胺 (R) -3-甲基-2-甲胺基·戊酸[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-.2-(3,4-二氟-苯基)-乙基]-醯胺 (S) -N-[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺曱醯基]-2-(3,4-二氟-苯基)-乙基]-2-二丙胺基-丙酿胺 (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醢基]-2-(3,4-二氟-笨基)-乙基]-2-(異丙基-甲基-胺基)-丙醯胺 (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-(3,4-二氟-苯基)-乙基]-2-二乙胺基-丙醯胺 (S)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺曱醯基]-2-(3,4-二氟-苯基)-乙基]-2-二甲胺基-丙醯胺 (R) -N-[(S)-l-[(2-胺基塞α坐-5-基曱基)-胺甲酿基]-2-(3,4-二氣-苯基)-乙基]-2-二甲胺基-丙醯胺 (S) -l-甲基比咯啶-2-曱酸[(S)-l-[(2-胺基噻唑-5-基曱基)-胺曱醯基]-2-(3,4-二氟-苯基)-乙基]-醯胺 (R)-l-乙基-吡咯啶-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-(3,4-二氣-苯基)-乙基]-醯胺 (R)-l-異丙基-吡咯啶-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-(3,4-二氟-苯基)-乙基]-酿胺 151651.doc -117- (R)-l-異丙基-哌啶-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醢基]-2-(3,4-二氟-苯基)-乙基]-酿胺 (R) -l-曱基-哌啶-2-甲酸[巧)-卜[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-(3,4-二氣-苯基)_乙基]••酿胺 (S) -l-曱基-哌啶-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-(3,4-二氟-苯基)-乙基]-酿胺 (R) -N-[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺甲醯基]-2-(3,4-二氟-苯基)-乙基]-2-二甲胺基-3-苯基-丙醯胺 (S) -N-[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺甲醯基]-2-(3,4-二氟-苯基)-乙基]-2-二甲胺基-3-苯基-丙醯胺 (S)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺曱醯基]-2-(3,4-二氟·苯基)-乙基]-2-π底咬-1-基-丙酿胺 (R) -N-[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-(3,4-二氟-苯基)-乙基]-2-旅咬-1 -基-丙酿胺 (S) -N-(2-胺基-售〇坐-5-基甲基)-3-(3,4-二氣-苯基)-2-(2-二異丙胺基-乙酿胺 基)-丙醯胺 (S)-N-(2-胺基-噻唑-5-基甲基)·3-(3,4-二氣-苯基)-2-[2-(2,6-二曱基-哌啶-1-基)-乙醯胺基]-丙醯胺 (R) -l-曱基-吡咯啶-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺曱醯基]-2-(4-氣-苯基)-乙基]-酿胺 (S) -N-[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-(4-氟-苯基)-乙基]-2-二 甲胺基-丙醯胺 (S)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺曱醯基]-2-(4-氟-苯基)-乙基]-2-二 乙胺基-丙醯胺 (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-(4-氟-苯基)-乙基]-2-哌 β定-1-基-丙酿胺 (R) -N-[(S)-l-[(2-胺基-噻唑-5·基甲基)-胺甲醯基]-2-(4-氟-苯基)-乙基]-2-哌 咬-1-基-丙酿胺 (S) -N-(2-胺基-噻唑-5-基甲基)-2-[2-(2,6-二曱基-哌啶-1-基)-乙醯胺基]-3-(4-氟-苯基)-丙醯胺 (R)-l-甲基-吡咯啶-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺曱醯基]-2-(3-氟-苯基)-乙基]-酿胺 -118- 201121961 (S)-N-[(S)-l-[(2-胺基-噻唑·5-基甲基)-胺甲醯基]-2-(3_氟-苯基)-乙基]-2- 35 (異丙基-甲基-胺基)-丙醯胺 (S)-N-[(S)-l-[(2-胺基-噻唑_5_基甲基)-胺甲醯基]-2_(3-氟-苯基)-乙基]-2-二 36 甲胺基-丙醯胺 (S)-N-[(S)-l-[(2-胺基-噻唑-5_基曱基)-胺曱醯基]-2-(3·氟-苯基)-乙基]-2-二 37 乙胺基_丙酿胺 (S)-N-[(S)-l-[(2-胺基塞0坐-5-基曱基)-胺曱酿基]-2-(3-氣-苯基)-乙基]-2-0底 38 啶-1-基-丙醯胺 (R)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺曱醢基]-2-(3-乳-苯基)-乙基]-2.·哌 39 啶-1-基-丙醯胺 (R) -l-曱基-吡咯啶-2-曱酸[(S)-l-[(2-胺基-噻唑-5·基曱基)-胺甲醯基]-2-(2- 40 鼠-苯基)-乙基]-酿胺 (S) -N-[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-(2-氟-苯基)·乙基]-2- 41 (異丙基-曱基-胺基)-丙醯胺 (R) -l-甲基-吡咯啶-2-曱酸{(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2- 42 秦-1-基-乙基}-酿胺 (S) -N-{(S)-l-[(2-胺基-噻唑-5-基曱基)-胺曱醢基]-2-萘-1-基-乙基}-2-(異丙 43 基-曱基-胺基)-丙醯胺 (S)-N-{(S)-l-[(2-胺基-噻唑-5-基曱基)-胺曱醯基]-2-萘-1-基-乙基}-2-二乙 44 胺基-丙酿胺 (S)-N-{(S)-l-[(2-胺基-°塞°坐-5-基甲基)-胺曱酿基]基-乙基}-2-0底咬· 45 1-基-丙酿胺 (R) -N-{(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-萘-1-基-乙基}-2-哌啶- 46 1-基-丙醯胺 (S) -N-{(S)-l-[(2-胺基-噻唑-5-基曱基)-胺曱醯基]-2-萘-1-基-乙基}-2-二甲 47 胺基-3-苯基-丙醯胺 (R) -l-曱基-吡咯啶-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺曱醯基]-2-(4- 48 氣-苯基)-乙基]-酿胺 (S) -N-[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺甲醯基]-2-(4-氣-苯基)-乙基]-2- 49 (異丙基-甲基-胺基)-丙醯胺 (R)-l-甲基-吡咯啶-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-(3- 50 氣-苯基)-乙基]-酿胺 151651.doc - 119- (S)-N-[(S)-l-[(2-胺基-嘆〇坐-5-基甲基)-胺曱酿基]-2-(3-氣-苯基)-乙基]-2-(異丙基-甲基-胺基)-丙醯胺 (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-(3-氯-苯基)-乙基]-2-二 甲胺基-丙醢胺 (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-(3-氯-苯基)-乙基]-2-二 乙胺基-丙酿胺 (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-(3-氣-苯基)-乙基]-2-哌 咬-1-基-丙酿胺 (R)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基)·胺甲醯基]-2-(3-氯-苯基)-乙基]-2-哌 咬-1 _基-丙酿胺 (R) -l-曱基-吡咯啶-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺曱醯基]-2-(3,4-二氣-苯基)-乙基]-酿胺 (S) -N-[(S)-l-[(2·胺基-噻嗤-5-基曱基)-胺甲醯基]-2-(3,4-二氣-苯基)-乙基]-2-(異丙基-曱基-胺基)-丙醯胺 (S)-N-[(S)-1 -[(2-胺基-噻唑-5-基曱基)-胺曱醯基]-2-(3,4-二氣-苯基)-乙基]-2-二甲胺基-丙醯胺 (S)-N-[(S)-1 -[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-(3,4-二氣-苯基)-乙基]-2-二乙胺基-丙酿胺 (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-(3,4-二氣-苯基)-乙基]-2-〇底°定-1-基-丙酿胺 (R) -N-[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-(3,4-二氣-苯基)-乙基]-2-派咬-1-基-丙酿胺 (S) -N-{(S)-l-[(2-胺基-噻唑-5-基曱基)-胺曱醯基]-2-對甲苯基-乙基}-2-(異 丙基-曱基-胺基)-丙醯胺 (R)-l-甲基-吡咯啶-2-曱酸{(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-對 甲笨基-乙基}-醯胺 (R) -l-曱基-吡咯啶-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-間 曱苯基-乙基}-醯胺 (S) -N-{(S)-l-[(2-胺基-噻唑-5-基曱基)-胺甲醯基]-2-間曱苯基-乙基}-2-(異 丙基-甲基-胺基)-丙醯胺 (R)-l-甲基-吡咯啶-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基曱基)-胺曱醯基]-2-鄰 甲苯基-乙基}-醯胺 -120- (S)-N-{(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-鄰曱苯基-乙基}-2-(異 丙基-甲基-胺基)-丙醯胺 (R)-吡咯啶-2-甲酸{(S)-l-[(2-胺基-噻唑·5-基甲基)-胺甲醯基]-2-環己基-乙 基}-醯胺 (R) -：!-曱基-吡咯啶-2-曱酸{(S)-l-[(2-胺基-噻唑-5-基曱基)-胺曱醢基]-2-環 己基-乙基}-醯胺 (S) -l-甲基-吡咯啶-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2··環 己基-乙基}-醯胺 (S)-N-{(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-環己基-乙基}-2-(異丙 基-甲基-胺基)-丙醯胺 (S)-N-{(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-環己基-乙基}-2-二甲 胺基-丙酿胺 (S)-N-{(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-環己基-乙基}-2-二乙 胺基-丙酿胺 (R)-l-乙基-吡咯啶-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基曱基)-胺甲醯基]-2-環 己基-乙基}-醯胺 (R)-l-異丙基-吡咯啶-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-環己基-乙基}-醯胺 (R) -l-甲基-略啶-2-曱酸{(S)-l-[(2-胺基-噻唑-5-基曱基)-胺甲醯基]-2-環己 基-乙基}-酿胺 (S) -N-{(S)-l-[(2-胺基-σ塞°坐-5-基甲基)-胺曱酿基]-2-環己基-乙基}-2-。底咬· 1-基-丙酿胺 (R) -N-{(S)-l-[(2-胺基塞σ坐-5-基甲基)-胺曱酿基]-2-環己基-乙基}-2-。底唆· 1-基-丙酿胺 3·曱基-1Η-吡咯-2-甲酸{(S)-l-[(2·胺基-噻唑-5-基甲基)-胺甲醯基]-2-萘-1-基-乙基}-醯胺 1H-叫h朵-2-甲酸{(S)-l-[(2-胺基塞。坐-5-基甲基)-胺曱醯基]-2-萘-1-基-乙 基}-醯胺 (S) -N-(2-胺基-嘆。坐-5-基甲基)-3-蔡-1-基-2-(2-間曱苯基-乙酿胺基)-丙酿胺 3,5-二甲基-1H-吡咯-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-(3,4-二敗-苯基)-乙基]-酿胺 -121 - 3-曱基-1H-吼咯-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺甲醯基]-2-(3,4-二氣苯基)·乙基]-酿胺 114-叫丨《朵-2-曱酸[(5)-1-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-(3,4-二氟-苯 基)-乙基]-酿胺 3-甲基-1H-。比咯-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-(4-敗-苯基)-乙基]-酿胺 3-甲基-1H-。比咯-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-(3-敦-苯基)-乙基]-醯胺 3-甲基-1H-。比咯-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺甲醯基]-2-(2-氟-苯基)-乙基]-醯胺 3-曱基-1H-吡嘻-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺甲醯基]-2-(4-氣-苯基)-乙基]-醯胺 3-曱基-1H-吡咯-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-(3-氣-苯基)-乙基]-醯胺 3-曱基-1H-吡咯-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基曱基)-胺曱醯基]-2-對甲 苯基-乙基}-醯胺 3-曱基-1H-吡咯-2-曱酸{(S)-l-[(2-胺基-噻唑-5·基甲基)-胺曱醯基]-2-間曱 苯基-乙基}-醯胺 3-曱基-1H-吡咯-2-曱酸{(S)-l-[(2-胺基-噻唑-5-基曱基)-胺甲醯基]-2-鄰曱 苯基-乙基}-醯胺 3-甲基-1H-吡咯-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-環己 基-乙基}-酿胺 (R)-N-{(S)-l-[(2-胺基-噻唑-5·基曱基)-胺曱醯基]-2-萘-1-基-乙基}-2-羥基-3-苯基-丙醯胺 (R)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醢基]-2-(3,4-二敗-苯基)-乙基]-2-羥基-3-苯基-丙醯胺 (R)-N-[(S)-l-[(2-胺基-嗟。坐-5-基甲基)-胺曱酿基]-2-(4-氟!-苯基)-乙基]-2-經 基-3-苯基-丙醯胺 (R)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-(3-氟-苯基)-乙基]-2-羥 基-3-苯基·丙醯胺 (R)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-(2-氟-苯基)-乙基]-2-羥 基-3-苯基-丙醯胺 -122- 201121961 99 100 101 102 103 104 105 106 107 108 109 (R)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基)-胺甲醯基]-2-(4-氯-苯基)-乙基]-2-羥 基-3-苯基-丙醯胺 (R)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-(3-氣-苯基)-乙基]-2-羥 基-3-苯基-丙醯胺 (R)-N-{(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-對曱苯基-乙基}-2-羥 基-3-苯基-丙醯胺 (R)-N-{(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-間甲苯基-乙基}-2-羥 基-3-苯基-丙醯胺 (R)-N-{(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-鄰甲苯基-乙基}-2·•羥 基-3-本基-丙酿胺 (R)-N-{(S)-l-[(2-胺基塞。坐-5-基曱基)-胺曱酿基]-2-環己基-乙基}-2-經基_ 3-苯基-丙醯胺 (R)-N-{(S)-l-[(2-胺基-嘆°坐-5-基甲基)-胺甲酿基]-2-秦-1-基-乙基}-2-經基· 丁醯胺 (R) -N-{(S)-l-[(2-胺基-噻唑-5-基甲基)-胺曱醯基]-2-萘-1-基-乙基}-2-羥基-3-甲基-丁醯胺 (S) -N-{(S)-l-[(2-胺基-噻唑-5-基甲基)-胺甲醯基]-2-萘-1-基-乙基}-2-羥基-3-甲基-丁醯胺 (R) -N-[(S)-l-[(2-胺基-噻唑-5-基曱基)·胺曱醯基]-2-(3,4-二氟-苯基)-乙基]-2·羥基-3-曱基-丁醯胺 (S) -N-[(S)-l-[(2-胺基-°S°坐-5-基曱基)-胺曱酿基]-2-(3,4-二敦-苯基)-乙基]_ 2-羥基-3-甲基-丁醯胺 生物方法 可使用下列生物檢定測定式（I)化合物抑制KLK1之能 力： 測定針對KLK1之ICS0 使用公開之標準方法（參見例如Johansen等人，Int. J. Tiss. Reac. 1986, 8, 185 ; Shori 等人，Biochem. Pharmacol,, 1992, 43, 1209 ; Stiirzebecher 等人，Biol. Chem.Hoppe- 151651.doc -123 - 201121961CD3OD (1H, q, J=6.8 Hz), 4.33-4.453 (2H5 m)3 4.87-4.91 (1H? m), 7.09-7.15 (4H,m), 7.21 (1H,t,J=7.5 Hz), 8·86 (1H, t5 J=5.2 Hz). 151651.doc -Ill - 201121961 66 1.66-1.75 (1H, m), 1.82-1.93 (1H, m), 2.09-2.19 (1H, m), 2.41 (3H, s), 2.44-2.51 (1H, m) , 2.93 (3H, s), 2.94-3.00 (1H, m), 3.17-3.24 (1H, m), 3.27-3.32 (1H, m), 3.65-3.71 (1H, m), 4.14 (1H, t, J=8.3 Hz), 4.29-4.41 (2H, m), 4.77-4.81 (1H, m), 7.08 (1H, s), 7.09-7.14 (1H, m), 7.16-7.17 (3H, m), 8.84 (1H, t, J=5.7 Hz), 8.93 (1H, d, J=8.0 Hz). 67 1.14 (3H, s), 1.22 (3H, d, J=6.5 Hz), 1.54 (3H, d, J=6.8 Hz), 2.45 (3H, s), 2.63 (3H, s), 2.97-3.02 ( 1H, m), 3.21-3.29 (1H, m), CE>3〇D 3.96(1H, q, J=6.8 Hz), 4.31-4.43 (2H, m), 7.09 (1H, s), 7.11-7.22 (4H, m), 8.86 (1 H, s). 68 0.94-1.10 (2H, m), 1.19-1.42 (4H, m), 1.60-1.80 (7H, m), 1.99-2.19 (3H, m), 2.47-2.56 (1H, m), 3.38-3.49 ( 2H, m), 4.34-4.41 (3H, m), 4.43-4.50 (1H, m), 7.17 (1H, s), 8.78 (1H, d, J=7.6 Hz), 8.91 (1H, t, J= 5.8 Hz). 69 70 71 0.94-1.09 (2H, m), 1.22-1.42 (4H, m), 1.61-1.79 (7H, m), 2.02-2.14 (2H, m), 2.21-2.31 (1H, m), 2.61- 2.69 (1H, m), 2.98 (3H, s), 3.25- CD3OD 3.32 (1H, m), 3.74-3.80 (1H, m), 4.18 (1H, t, J=8.2 Hz), 4.36-4.42 (2H , m), 4.45-4.49 (1H, m), 7.17 (1H, s), 8.93 (1H, t, J = 5.8 Hz). 0.96-1.08 (2H, m), 1.19-1.44 (4H, m), 1.65 (2H, t, J=7.3 Hz), 1.74-1.84 (5H, m), 2.01-2.30 (3H, m), 2.60- 2.69 (1H, m), 2.97 (3H, s), CE>3〇D 3.23-3.30 (1H, m), 3.73-3.79 (1H, m), 4.15-4.19 (1H, m), 4.33-4.41 ( 2H, m), 4.43-4.48 (1H, m), 7.16 (1H, s), 8.92 (1H, t, J = 5.8 Hz). 0.96-1.09 (2H, m), 1.21-1.42 (10H, m), 1.61-1.73 (7H, m), 1.79 (3H, d, J=9.8 Hz), 2.79 (3H, s), 3.58 (1H, Br s), 4.11 (1H, q, J=6.8 Hz), CD3OD 4.34-4.45 (2H, m), 4.54-4.59 (1H, t, J=7.7 Hz), 7.17 (1H, s), 8.89 (lH ,t,J=5.7Hz)» 72 73 0.95-1.08 (2H, m), 1.19-1.43 (4H, m), 1.62 (3H, d, J=7.0 Hz), 1.64-CD3OD 1.80 (7H, m) , 2.94(6H, s), 3.99 (1H, q, J=7.0 Hz), 4.34-4.49 (3H, m), 7.17 (1H, s), 8.89 (1H, t, J = 5.7 Hz). 0.85-1.01 (2H, m), 1.04 (6H, t, J=7.1 Hz), 1.10-1.28 (7H, m), 1.51-1.79 (7H, m), 2.37-2.55 (4H, m), 3.35 ( 1H, q, J=7.0 Hz), 4.32-4.47 (3H, m), 5.09 (2H, s), 6.82 (1H, s), 7.09 (1H, t, J=5.4 Hz), 7.74 (1H, d , J = 8.3 Hz). lS16Sl.doc -112- 201121961 74 75 76 77 78 79 80 81 0.94-1.08 (2H, m), 1.22-1.30 (4H, m), 1.34 (3H, t, J=7.3 Hz), 1.63-1.79 (7H , m), 2.02-2.14 (2H, m), 2.21-2.30 (1H, m), 2.60-2.68 (1H, CD3OD m), 3.22-3.35 (3H, m), 3.76-3.80 (1H, m), 4.21 (1H, t, J=8.0 Hz), 4.34-4.41 (2H, m), 4.44-4.48 (1H, m), 7.17 (1H, s), 8.95 (1H, t, J=5.7 Hz). 1.00-1.14 (2H, m), 1.25-1.36 (4H, m), 1.40 (3H, d, J=6.6 Hz), 1.43 (3H, d, J=6.6 Hz), 1.72 (2H, t, J= 7.4 Hz), 1.78-1.85 (5H, m), 2.02- 2.18 (2H, m), 2.21-2.31 (1H, m), 2.61-2.69 (1H, m), 3.36-3.41 (1H, CD3OD 3.63-3.70 (1H, m), 3.75-3.79 (1H, m), 4.35-4.39 (1H, m), 4.44 (2H, d, J=5.2 Hz), 4.50 (1H, t, J=7.7 Hz), 7.24 ( 1H, s), 9.01 (1H, t, J=5.8 Hz) 0.94-1.08 (2H, m), 1.22-1.40 (4H, m), 1.65 (2H, t, J=7.3 Hz), 1.71-1.88 (8H, m), 1.97-2.00 (2H, m), 2.17-2.20 (1H, m), 2.86 (3H, s), CD3OD 3.12-3.18 (1H, m), 3.53-3.57 (1H, m), 3.78-3.82 (1H, m), 4.35-4.45 (3H, m), 7.18 (1H, s), 8.85 (1H, d, J=6.9 Hz), 8.96 (1H, t, J=5.8 Hz). -1.08 (2H, m), 1.21-1.43 (4H, m), 1.60-1.98 ( 16H, m), 3.02-3.09 CD3OD (2H, m), 3.46(lH,br s), 3.67(lH,br s ), 3.95 (1H, q, J=6.9 Hz), 4.34- 4.50 (3H,m), 7.16 (1H,s), 8.88 (1H,t,J=5.8 Hz). 0.98-1.08 (2H, m) , 1.25-1.41 (4H, m), 1.60-1.98(16H, m), 3.02-3.09 CD3OD (2H, m), 3.47(lH,br s), 3.66(lH,br s), 3.96(1H, q , J=6.9 Hz), 4.34-4.49 (3H,m), 7.17 (1H, s ), 8.93 (1H, t, J = 5.8 Hz). 2.12 (3H, s) 3.43-3.56 (2H, m) 3.93 (1H, s) 3.98 (1H, s) 4.02 (1H, s) 4.12 (1H, s) 5.89 (1H, s) 6.69 (1H, d, J=4.0 Hz) 6.82 (1H, s) 7.21-CD3OD 7 31 (2h, m) 7.38-7.48 (2H, m) 7.66 (1H, dd, J=8.0, 4.0 Hz) 7.76 (1H,dd,J= 8.0, 4.0 Hz) 8.11 (1H, d, J=8.0 Hz) 10.58 (1H, br s). 3.41-3.57 (2H, m) 3.62-3.78 (2H, m) 4.07 (1H, d, J=4.0 Hz) 4.17 (1H, d, J=4.0 Hz) 4.80-4.86 (4H, br m) 6.81 (1H , s) 6.97 (1H, td, J-4.0 Hz) 7.03 (1H, s) 7.12 (1H, td, J=4.0 Hz) 7.23 (1H, t, J=8.0 Hz) CD3OD 7 3〇_7 34 ( (2H, td, J = 4.0 Hz) 7.44 1H, d, J=4.0 Hz) 8.40-8.44 (1H, m). 2.18 (3H, s) 3.20-3.22 (1H, m) 3.25-3.42 (3H, m) 3.98-4.03 (1H, m) 4.10-4.15 (1H, m) 4.56-4.63 (1H, m) 4.75-4.85 ( 3H, m) 6.81-6.87 CD3OD (3H, m) 6.95 (1H, d, J=8.0 Hz) 7.01-7.10 (1H, m) 7.14-7.20 (2H, m) 7.39-7.44 (2H, m) 7.64 ( 1H, d, J=8.0 Hz) 7.75 (1H, d, J=8.0 Hz) 8-03 (1H, d, J=8.0 Hz) 8.36 (1H, t, J=8.0 Hz). 151651.doc • 113· 201121961 82 83 84 85 2.11 (3H, s), 2.13 (3H, s), 2.82-2.88 (1H, m), 2.99-3.03 (1H, m), d6 DMSO 3.31 (1H, s ), 4.16-4.27 (2H, m), 4.61-4.67 (1H, m), 5.63 (1H, d, &quot; J=1.96 Hz), 6.73 (1H, s), 6.77 (2H, s), 7.03- 7.07 (1H, m), 7.19-7.32 (3H, m), 8.53 (1H, t, J = 5.60 Hz). 2.16 (3H, s), 2.83-2.89 (1H, m), 3.00-3.05 (1H, m), 4.21-4.24 (2H, d6 DMSO m), 4.62_4·66 (1H, m), 5 90 (1H , LJ=2·28 Hz), 6·74-6·77 (4H,m), '7.05-7.08 (1H, m), 7.25-7.31 (3H, m), 7.39 (1H, d, J=8.44 Hz), 8.55 (1H, t, J=5.68 Hz). CD3OD 3.13-3.17 (1H, m), 3.25-3.30 (1H, m), 4.33-4.37 (2H, m), 4.78-4.83 (1H, m), 4.96-5.01 (1H, m), 7.10-7.30 ( 9H, m), 7.47-7.49 (1H, m), 7.67 (1H, d, J = 8.04 Hz), 8.52 (1H, d, J = 7.84 Hz), 8.77 (1H, t, J = 5.89 Hz). CD3OD 2.28 (3H, s), 3.05-3.10 (2H, m), 3.18-3.23 (2H, m), 4.30 (1H, d, J=15.0 Hz), 4.42 (1H, d, J=15.09 Hz), 4.77 (1H, t, J=6.88 Hz), 4.91 (3H, s), 6.05 (1H, d, J=2.44 Hz), 6.84 (2H, t, J=0.84 Hz), 6.99-7.03 (2H,m ), 7.23-7.26 (2H, m). 86 2.31 (3H, s), 3.12-3.17 (1H, m), 3.19-3.26 (1H, m), 4.27-4.31 (1H, m)s 4.37-4.41 (1H, m), 4.76-4.81 (1H, m), 4.91 (4H, s), 6.06 (1H, d, J=3.21 Hz), 6.84 (2H, t, J=2.32 Hz), 6.99-7.03 (2H, m), 7.08-7.11 (2H, m ), 7.30-7.35 (1H, m), 8.75-8.78 (1H, m). 87 2.29 (3H, s), 3.13-3.18 (1H, m), 3.23-3.28 (1H, m), 4.30-4.34 (1H, m), 4.39-4.42 (1H, m), 4.83-4.86 (1H, m), 4.91 (4H, s), 6.04 (1H, d, CD3OD J=2.45 Hz), 6.83 (2H, t, J=2.68 Hz), 7.06-7.12 (2H, m), 7.26-7.32 (2H, m). 88 2.15 (3H, s), 2.83-2.88 (1H, m), 3.00-3.05 (1H, m), 4.17-4.27 (2H, d6 DMSO m), 4.61·4·67 (1H, m), 5· 90 (1H, J=2.3 Hz), 6.75·6·78 (4H, m), ' 7.24-7.30 (4H, m), 7.35 (1H, d, J=8.4 Hz), 8.57 (1H, t , J=5.7 Hz), 11.10 (1H, s). 89 90 2.16 (3H, s), 2.84-2.90 (1H, m), 3.01-3.06 (1H, m), 4.18-4.28 (2H, d6 DMSO m), 4·62-4.67 (1H, m), 5.90 (1H, LJ=2·2 Hz), 6.75_6·77 (4H, m), ' 7.19-7.28 (3H, m), 7.35 (1H, s), 7.38 (1H, d, J=8.4 Hz), 8.57 (1H, t, J = 5.7 Hz), 11.10 (lH, s). 2.29 (3H, s), 2.34 (3HS s), 3.06-3.11 (1H, m), 3.15-3.20 (1H, m), 4.27-4.40 (2H, m), 4.75 (1H, t, J=7.2 Hz ), 6.05 (1H, t, J=2.3 Hz), CD3〇D 6.84 (1H, t, J=2.7 Hz), 7.09-7.16 (5H, m), 8.73 (1H, t, J=5.7 Hz), 10.72 (1H, s). 151651.doc • 114· 201121961 91 92 93 94 95 96 97 98 99 100 2.21 (3H, s), 2.23 (3H, s), 3.04-3.14 (2H, m), 4.20-4.30 (2H, m), 4.86 (1H, q, J=7.1 Hz), 5.51(2H, br s), 6.00 (1H, s), 6.58 (1H, d, J=7.2 Hz), 6.66 (1H, s), 6.73-6.74 (1H , m), 6.96-7.03 (3H, m), 7.12 (1H, t, J = 7.4 Hz), 7.24-7.26 (1H, m), 9.90 (1H, s). CD3OD 2.14 (3H, s), 2.24 (3H, s), 2.92-2.97 (1H, m), 3.04-3.10 (1H, m), 4.09-4.26 (2H, m), 4.64 (1H, t, J= 7.4 Hz), 5.88 (1H, d, &gt; 2.4 Hz), 6.62 (1H, s), 6.67 (1H, d, J=2.5 Hz), 6.91-7.07 (4H, m). D6-DMSO 0.80-0.93 (2H, m), 1.07-1.33 (4H, m), 1.45-1.73 (7H, m), 2.25 (3H, s), 4.12-4.25 (2H, m), 4.42-4.48 ( 1H, m), 5.93 (1H, t, J=2.2 Hz), 6.73-6.79 (4H, m), 7.31 (1H, d, J=8.2 Hz), 8.45 (1H, t, J=5.8 Hz), 11.16 (1H, s). CD3OD 2.62-2.68 (1H, m) 2.73 (2H, s) 3.24-3.43 (2H, m) 4.02 (1H, s) 4.07-4.13 (2H, m) 4.60 (1H, t, J=8.0 Hz) 6.57 ( 1H, s) 6.95-7.21 (7H, m) 7.39-7.47 (2H, m) 7.63 (1H, d, J=8.0 Hz) 7.74 (1H, d, J=8.0 Hz) 8.11 (lH,d, J= 8.0Hz). CD3OD 2.82-2.88 (1H, m), 2.94-2.99 (1H, m), 3.05-3.10 (2H, m), 4.23-4.30 (3H, m), 4.56-4.60 (1H, m), 4.91 (4H, s), 7.00-7.04 (1H, m), 7.10 (1H, s), 7.13-7.31 (6H, m), 8.00 (1H, d, J=8.04 Hz), 8.51 (1H; t, J=5.64 Hz » CD3OD 2.80-2.86 (1H, m), 2.91-2.97 (1H, m), 3.04-3.10 (2H, m), 4.23-4.31 (3H, m), 4.57 J=7.09 Hz), 4.9 (5H, s), 6.82 (1H, s), 6.97-7.02 (2H, m), 7.18-7.30 (7H,m)» CD3OD 2.80-2.87 (1H, m), 2.94-3.13 (3H, m), 4.23-4.31 (3H, m), 4.61 (lH, t, J = 7.16 Hz), 4.9 (5H, s), 6.81 (1H, s), 6.98-7.03 (3H, m), 7.24-7.32 (6H, m). CD3OD 2.80-2.85 (1H, m), 3.04-3.09 (2H, m), 3.15-3.20 (1H, m), 4.23-4.29 (3H, m), 4.62-4.67 (1H, m), 4.91 (5H, s), 7.09-7.13 (2H, m), 7.22-7.31 (6H, m), 8.00 (1H, d, J = 8.0 Hz), 8_55 (1H, t, J = 5.8 Hz). CD3OD 2.82-2.89 (1H, m), 2.95-3.00 (1H, m), 3.04-3.11 (2H, m), 4.23-4.34 (3H, m), 4.57-4.63 (1H, m), 7.10 (1H, s), 7.20-7.30 (9H, m), 7.98 (1H, d, J = 8.0 Hz), 8.54 (1H, t, J = 5.8 Hz). CD3OD 2.82-2.B7 (1H, m), 2.97-3.02 (1H, m), 3.04-3.12 (2H, m), 4.21-4.35 (3H, m), 4.57-4.63 (1H, m), 7.09 ( 1H, s), 7.14-7.31(9H, m), 7.98 (1H,d,J=8.0 Hz), 8.55 (1H, t, J=5.8 Hz) » 151651.doc -115- 201121961 101 102 103 104 105 106 107 108 CD3OD 2.19 (3H, s), 2.67-2.72 (1H, m), 2.79-2.84 (1H, m), 2.88-2.94 (2H, m), 4.07-4.19 (3H, m), 4.40-4.46 (1H, m), 6.94-6.99 (5H, m), 7.06-7.18 (5H,m), 7.76 (1H,d,J=7.9 Hz),8·33 (1H,t, J=5_8 Hz)» CD3OD 2.33 (3H, s), 2.81-2.86 (1H, m), 2.94-2.99 (1H, m), 3.02-3.08 (2H, m), 4.22-4.34 (3H, m), 4.56-4.61 (1H, m), 7.02 (1H, d, J=7.6 Hz), 7.05-7.08 (3H, m), 7.16-7.31 (6H, m), 7.92 (1H, d, J=7.9 Hz), 8.49 (1H, t , J = 5.8 Hz). CDC13 (CDC13) 2.28 (3H, s), 2.73-2.78 (1H, m), 2.91-2.96 (1H, m), 3.03-3.10 (2H, m), 4.01-4.06 (1H, m), 4.20-4.25 (2H, m), 4.67 (1H, q, J=7.8 Hz), 5.48 (2H, s), 6.44 (1H, s), 7.01-7.26(9H, m), 7.52 (1H, d, J=8.2 Hz). CD3OD 0.90-1.04 (2H, m), 1.17-1.32 (4H, m), 1.54-1.81 (7H, m), 2.88-2.93 (1H, m), 3.09-3.13 (1H, m), 4.32-4.36 ( 3H, m), 4.40-4.46 (1H, m), 7.16 (1H, s), 7.22-7.36 (5H, m), 7.92 (1H, d, J=7.9 Hz), 8.58 (1H, t, J= 5_8 Hz). CD3OD 0.93 (3H, t, J=8.0 Hz) 1.56-1.67 (1H, m) 1.73-1.83 (1H, m) 3.52-3.67 (2H, m) 4.01 (1H, q, J=4.0 Hz) 4.12-4.15 (1H, m) 4.25-4.29 (1H, m) 4.77-4.82 (1H, m) 6.95 (1H, s) 7.35-7.43 (2H, m) 7.51-7.64 (2H, m) 7.71-7.83 (1H, m 7.91 (lh, d, J=8.0 Hz) 8.27 (lh, d, J=8.0 Hz) » CD3OD 0.66 (3H, d, J=4.0 Hz) 0.84 (3H, d, J=4.0 Hz) 1.84-1.95 (1H, m) 3.20-3.22 (1H, m) 3.35-3.46 (2H, m) 3.74 (1H, d, J=4.0 Hz) 3.97-4.02 (1H, m) 4.08-4.13 (1H, m) 4.63- 4.68 (1H, m) 4.72-4.81 (4H, br m) 6.81 (1H, s) 7.20-7.28 (2H, m) 7.35-7.47 (2H, m) 7.64-7.70 (1H, m) 7.76 (1H,d , J = 8.0 Hz) 8.10 (1H, d, J = 8.0 Hz). CD3OD 0.66 (3H, d, J=4.0 Hz) 0.92 (3H, d, J=4.0 Hz) 1.94-2.09 (1H, m) 3.08 (1H, s) 3.49-3.54 (1H, m) 3.59-3.64 (1H , m) 3.86-3.89 (1H, m) 4.14-4.18 (1H, m) 4.28-4.32 (1H, m) 4.79-4.86 (1H, m) 4.93-5.03 (4H, br m) 6.98 (1H, s) 7.36-7.46 (2H, m) 7.54-7.64 (2H, m) 7.75-7.82 (1H, m) 7.96 (1H, d, J = 8.0 Hz) 8.23 (1H, d, J = 8.0 Hz). CD3OD 0.81 (3H, d, J=6.84 Hz), 0.99 (3H, d, J=6.96 Hz), 2.01-2.09 (1H, m), 2.99-3.04 (1H, m), 3.10-3.15 (1H, m ), 3.87 (1H, d, J=3.64 Hz), 4.31-4.38 (2H, m), 4.63-4.66 (1H, m), 4.91 (3H, s), 7.05-7.08 (1H, m), 7.16 ( 1H, s), 7.18-7.21 (2H, m), 8.03 (1H, d, J = 8.05 Hz), 8.74 (1H, t, J = 5.68 Hz). 151651.doc -116- 201121961 0.71 (3H, d, J=6.88 Hz), 0.96 (3H, d, J=6.93 Hz), 1.99-2.07 (1H, m), 2.99-3.05 (1H, m), 3.11 -3.16 (1H, m), 3.86 (1H, d, J=3.68 Hz), 4.27-4.28 (1H, m), 4.31-4.37 (1H, m), 4.63-4.69 (1H, m), 4.91 (3H , s), 7.07-7.10 (1H, m), 7.13 (1H, s), 7.16-7.23 (2H, m), 8.03 (1H, d, J=8.13 Hz), 8.74 (1H, t, J=5.80 Hz). Cd3od 109 Table 5 Instance Name Instance Name No. 8 9 10 11 12 13 14 15 16 17 18 (R)-Pyrrolidin-2-carboxylic acid [(S)-l-[(2-Amino-thiazol-5-ylindole) ()-aminomethyl hydrazino]-2-(3,4-difluoro-phenyl)-ethyl]-nonylamine (R)-2-amino-3-indolyl-pentanoic acid [(S)- L-[(2-Amino-thiazol-5-ylmethyl)-amine-mercapto]-2-(3,4-difluoro-phenyl)-ethyl]-bristamine (R) -3- Methyl-2-methylamino valeric acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarbamyl]-.2-(3,4-difluoro -phenyl)-ethyl]-nonylamine (S)-N-[(S)-l-[(2-amino-thiazol-5-ylindenyl)-amine fluorenyl]-2-(3 ,4-difluoro-phenyl)-ethyl]-2-dipropylamino-propylamine (S)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl) )-Aminomethylindenyl]-2-(3,4-difluoro-indolyl)-ethyl]-2-(isopropyl-methyl-amino)-propanamide (S)-N-[ (S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminemethylmercapto]-2-(3,4-difluoro-phenyl)-ethyl]-2-diethyl Amino-propionamine (S)-N-[(S)-l-[(2-amino-thiazol-5-ylindenyl)-amine fluorenyl]-2-(3,4-difluoro -Phenyl)-ethyl]-2-dimethylamino-propanamide (R)-N-[(S)-l-[(2-Amino-Sodium-5-ylindenyl)-amine酿-kilo]-2-(3,4-di-phenyl)-ethyl]-2-dimethylamine -propionamide (S) -l-methylpyrrolidine-2-decanoic acid [(S)-l-[(2-aminothiazolyl-5-ylindenyl)-amineindolyl]-2- (3,4-difluoro-phenyl)-ethyl]-nonylamine (R)-l-ethyl-pyrrolidine-2-carboxylic acid [(S)-l-[(2-amino-thiazole-5) -ylmethyl)-aminoindenyl]-2-(3,4-dioxa-phenyl)-ethyl]-nonylamine (R)-l-isopropyl-pyrrolidine-2-carboxylic acid [( S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminoindenyl]-2-(3,4-difluoro-phenyl)-ethyl]-bristamine 151651.doc -117-(R)-l-isopropyl-piperidine-2-furic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarbamyl]-2 -(3,4-difluoro-phenyl)-ethyl]-bristamine (R)-l-decyl-piperidine-2-carboxylic acid [巧]-卜[(2-amino-thiazole-5- Methyl)-amine-mercapto]-2-(3,4-dioxa-phenyl)-ethyl]••••······················ S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminoindenyl]-2-(3,4-difluoro-phenyl)-ethyl]-bristamine (R) -N-[(S)-l-[(2-Amino-thiazol-5-ylindenyl)-aminemethylmercapto]-2-(3,4-difluoro-phenyl)-ethyl]- 2-Dimethylamino-3-phenyl-propanamide (S)-N-[(S)-l-[(2-Amino-thiazol-5-ylindenyl)-aminecarbamyl]- 2-(3,4-difluoro-phenyl)-ethyl]-2-dimethylamino-3-phenyl-propanamide (S)-N-[(S)-l-[(2-Amino-thiazol-5-ylindenyl)-aminoindenyl]-2-(3,4-difluoro-phenyl)-B Base]-2-π bottom bit-1-yl-propylamine (R)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarbamyl] -2-(3,4-Difluoro-phenyl)-ethyl]-2-Big bite-1 -yl-propanolamine (S)-N-(2-Amino-Sodium -5--5-yl Methyl)-3-(3,4-dioxa-phenyl)-2-(2-diisopropylamino-ethanoylamino)-propanin (S)-N-(2-amino-thiazole -5-ylmethyl)·3-(3,4-dioxa-phenyl)-2-[2-(2,6-dimercapto-piperidin-1-yl)-acetamido]- Propionamide (R) -l-decyl-pyrrolidine-2-decanoic acid [(S)-l-[(2-amino-thiazol-5-ylindenyl)-amine fluorenyl]-2- (4-Gas-phenyl)-ethyl]-bristamine (S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminecarbamyl]- 2-(4-Fluoro-phenyl)-ethyl]-2-dimethylamino-propanamide (S)-N-[(S)-l-[(2-amino-thiazol-5-yl) Indenyl)-aminoindenyl]-2-(4-fluoro-phenyl)-ethyl]-2-diethylamino-propanylamine (S)-N-[(S)-l-[( 2-Amino-thiazol-5-ylmethyl)-amine-mercapto]-2-(4-fluoro-phenyl)-ethyl]-2-piperidin-1-yl-propanol (R -N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminecarbamido]-2-(4-fluoro-phenyl)-ethyl]-2- Pipette bite-1- -Acetylamine (S)-N-(2-Amino-thiazol-5-ylmethyl)-2-[2-(2,6-diamidino-piperidin-1-yl)-acetamide 3-(4-fluoro-phenyl)-propionamide (R)-l-methyl-pyrrolidine-2-furic acid [(S)-l-[(2-amino-thiazole-5) -indolyl)-aminoindenyl]-2-(3-fluoro-phenyl)-ethyl]-bristamine-118- 201121961 (S)-N-[(S)-l-[(2- Amino-thiazole·5-ylmethyl)-amine-mercapto]-2-(3-fluoro-phenyl)-ethyl]-2-35 (isopropyl-methyl-amino)-propionate Amine (S)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarbamimidyl]-2_(3-fluoro-phenyl)-ethyl]- 2-Di 36-Methylamino-propionamide (S)-N-[(S)-l-[(2-Amino-thiazol-5-ylindenyl)-amineindolyl]-2-(3 ·Fluoro-phenyl)-ethyl]-2-di37ethylamino-propanolamine (S)-N-[(S)-l-[(2-amino-based-spin-5-yl fluorenyl) )-amine aryl]-2-(3-a-phenyl)-ethyl]-2-0 bottom 38 pyridine-1-yl-propanamide (R)-N-[(S)-l- [(2-Amino-thiazol-5-ylindenyl)-aminoindenyl]-2-(3-lacto-phenyl)-ethyl]-2.·P.39-pyridin-1-yl-propionium Amine (R) -l-decyl-pyrrolidine-2-decanoic acid [(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminecarboxylidene]-2-(2 - 40 murine-phenyl)-ethyl]-bristamine (S)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)- Aminomethyl]-2-(2-fluoro-phenyl)ethyl]-2- 41 (isopropyl-indolyl-amino)-propanamide (R)-l-methyl-pyrrolidine -2-decanoic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]-2-42-methyl-1-yl-ethyl}-bristamine S) -N-{(S)-l-[(2-Amino-thiazol-5-ylindenyl)-amineindolyl]-2-naphthalen-1-yl-ethyl}-2-(iso Propane 43-mercapto-amino)-propanamine (S)-N-{(S)-l-[(2-amino-thiazol-5-ylindenyl)-amine fluorenyl]-2 -naphthalen-1-yl-ethyl}-2-diethyl 44 Amino-propylamine (S)-N-{(S)-l-[(2-Amino-°°°°-5-yl Methyl)-amine aryl]yl-ethyl}-2-0 bottom bite 45 1-yl-propylamine (R)-N-{(S)-l-[(2-amino-thiazole -5-ylmethyl)-aminoindenyl]-2-naphthalen-1-yl-ethyl}-2-piperidine- 46 1-yl-propionamide (S) -N-{(S)- L-[(2-Amino-thiazol-5-ylindenyl)-aminoindenyl]-2-naphthalen-1-yl-ethyl}-2-dimethyl47amino-3-phenyl-propane Indoleamine (R)-l-decyl-pyrrolidine-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylindenyl)-amine fluorenyl]-2-(4 - 48 gas-phenyl)-ethyl]-bristamine (S)-N-[(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminecarbamyl]-2 -(4-gas-phenyl)-ethyl]-2-49 (isopropyl-methyl-amino)-propanamide (R)-l-methyl-pyrrolidine-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarbamyl]-2-(3- 50 Gas-phenyl)-ethyl]-bristamine 151651.doc - 119- (S)-N-[(S)-l-[(2-amino-sindol-5-ylmethyl)-amine Brewing base]-2-(3-a-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propanamide (S)-N-[(S)-l- [(2-Amino-thiazol-5-ylmethyl)-aminoindenyl]-2-(3-chloro-phenyl)-ethyl]-2-dimethylamino-propanamide (S) -N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]-2-(3-chloro-phenyl)-ethyl]-2-di Ethylamino-propylamine (S)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarboxylidene]-2-(3-gas-benzene ()-ethyl]-2-piperidin-1-yl-propylamine (R)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine A Mercapto]-2-(3-chloro-phenyl)-ethyl]-2-piperidin-1 _yl-propylamine (R)-l-mercapto-pyrrolidine-2-decanoic acid [(S )-l-[(2-Amino-thiazol-5-ylindenyl)-aminoindenyl]-2-(3,4-dioxa-phenyl)-ethyl]-bristamine (S) - N-[(S)-l-[(2.Amino-thiazol-5-ylindenyl)-amine-carbamoyl]-2-(3,4-di-phenyl)-ethyl]- 2-(isopropyl-indolyl-amino)-propanamide (S)-N-[(S)-1 -[(2-amino-thiazol-5-ylindenyl)-amine oxime 2-(3,4-dioxa-phenyl)-ethyl]-2-dimethylamino-propanamide (S)-N-[(S)-1 -[(2-amino) -thiazol-5-ylmethyl)-aminoindenyl]-2-(3,4-dioxa-phenyl)-ethyl]-2-diethylamino-propylamine (S)-N- [(S)-l-[(2-Amino-thiazol-5-ylmethyl)-amine-mercapto]-2-(3,4-di-phenyl)-ethyl]-2-indole Desin-1-yl-propylamine (R)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarboxylidene]-2-(3 ,4-diqi-phenyl)-ethyl]-2-pyran-1-yl-propylamine (S)-N-{(S)-l-[(2-amino-thiazole-5- (曱))-aminoindenyl]-2-p-tolyl-ethyl}-2-(isopropyl-indolyl-amino)-propanin (R)-l-methyl-pyrrolidine- 2-decanoic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]-2-p-methylphenyl-ethyl}-decylamine (R) - L-Mercapto-pyrrolidine-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]-2-m-phenylene-ethyl} - decylamine (S) -N-{(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminecarbamyl]-2-m-phenylene-ethyl}-2 -(isopropyl-methyl-amino)-propionamide (R)-l-methyl-pyrrolidine-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-yl) Indenyl)-aminoindenyl]-2-o-tolyl-ethyl}-decylamine-120- ( S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-amine fluorenyl]-2-o-phenylene-ethyl}-2-(isopropyl --methyl-amino)-propanamide (R)-pyrrolidine-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine-methyl) -2-cyclohexyl-ethyl}-decylamine (R)-:!-mercapto-pyrrolidine-2-furic acid {(S)-l-[(2-amino-thiazol-5-ylfluorenyl) )-Amidino]-2-cyclohexyl-ethyl}-decylamine (S)-l-methyl-pyrrolidine-2-carboxylic acid {(S)-l-[(2-amino-thiazole- 5-ylmethyl)-aminoindenyl]-2··cyclohexyl-ethyl}-decylamine (S)-N-{(S)-l-[(2-amino-thiazol-5-yl) Methyl)-aminoindenyl]-2-cyclohexyl-ethyl}-2-(isopropyl-methyl-amino)-propanamide (S)-N-{(S)-l-[ (2-Amino-thiazol-5-ylmethyl)-aminoindenyl]-2-cyclohexyl-ethyl}-2-dimethylamino-propanolamine (S)-N-{(S) -l-[(2-Amino-thiazol-5-ylmethyl)-aminemethylmercapto]-2-cyclohexyl-ethyl}-2-diethylamino-propylamine (R)-l- Ethyl-pyrrolidine-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminecarbamimidyl]-2-cyclohexyl-ethyl}-decylamine ( R)-l-isopropyl-pyrrolidine-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)-amineindolyl]-2-cyclohexyl-B Ketone (R) -l-methyl-slight acridine-2-decanoic acid {(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminemethylmercapto]-2-cyclohexyl- Ethyl}-bristamine (S)-N-{(S)-l-[(2-amino-σ-[sodium]-5-ylmethyl)-amine aryl]-2-cyclohexyl-B Base}-2-. Bottom bite 1-yl-propanolamine (R)-N-{(S)-l-[(2-aminopyrazine-5-ylmethyl)-amine oxime]-2-cyclohexyl -Ethyl}-2-.唆··1-yl-propanol 3·mercapto-1Η-pyrrole-2-carboxylic acid {(S)-l-[(2·amino-thiazol-5-ylmethyl)-aminecarbamyl] -2-naphthalen-1-yl-ethyl}-decylamine 1H-called h-butylic acid {(S)-l-[(2-aminopyran.sodium-5-ylmethyl)-amine oxime Indenyl]-2-naphthalen-1-yl-ethyl}-decylamine (S)-N-(2-Amino-story. Sodium-5-ylmethyl)-3-cain-1-yl-2 -(2-m-phenylphenyl-ethenylamino)-propanol 3,5-dimethyl-1H-pyrrole-2-decanoic acid [(S)-l-[(2-amino-thiazole- 5-ylmethyl)-amine-mercapto]-2-(3,4-dioxo-phenyl)-ethyl]-bristamine-121 - 3-mercapto-1H-pyrrole-2-decanoic acid [(S)-l-[(2-Amino-thiazol-5-ylindenyl)-aminemethylmercapto]-2-(3,4-diphenyl)ethyl]-bristamine 114-丨 朵 朵 朵 曱 曱 曱 ( [(5)-1-[(2-amino-thiazol-5-ylmethyl)-amine-mercapto]-2-(3,4-difluoro-phenyl )-Ethyl]-bristamine 3-methyl-1H-. Bis-2-nonanoic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]-2-(4-f-phenyl)-ethyl] - Stearamine 3-methyl-1H-.咯r--2-decanoic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarbamyl]-2-(3-d-phenyl)-ethyl] - guanamine 3-methyl-1H-. Bile-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminecarboxy]-2-(2-fluoro-phenyl)-ethyl]- Indole 3-mercapto-1H-pyridin-2-indole [[S)-l-[(2-amino-thiazol-5-ylindolyl)-aminecarboxylidene]-2-(4- Gas-phenyl)-ethyl]-nonylamine 3-mercapto-1H-pyrrole-2-decanoic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine A Mercapto]-2-(3-a-phenyl)-ethyl]-nonylamine 3-mercapto-1H-pyrrole-2-carboxylic acid {(S)-l-[(2-amino-thiazole-5) -ylindenyl)-aminoindenyl]-2-p-tolyl-ethyl}-nonylamine 3-mercapto-1H-pyrrole-2-furic acid {(S)-l-[(2-amino group) -thiazol-5-ylmethyl)-aminoindenyl]-2-m-decylphenyl-ethyl}-nonylamine 3-mercapto-1H-pyrrole-2-indole {{S)-l-[ (2-Amino-thiazol-5-ylindenyl)-amine-mercapto]-2-o-indolephenyl-ethyl}-nonylamine 3-methyl-1H-pyrrole-2-carboxylic acid {(S) -l-[(2-Amino-thiazol-5-ylmethyl)-aminecarbamimidyl]-2-cyclohexyl-ethyl}-bristamine (R)-N-{(S)-l-[ (2-Amino-thiazol-5-ylindenyl)-aminoindenyl]-2-naphthalen-1-yl-ethyl}-2-hydroxy-3-phenyl-propanamide (R)-N -[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminemethylmercapto]-2-(3,4-di-phenyl)-ethyl]-2- Hydroxy-3-phenyl-propionamide (R)-N-[(S)-l-[(2-嗟-嗟. sit-5-ylmethyl)-amine aryl]-2-(4-fluoro!-phenyl)-ethyl]-2-yl-3-phenyl-propanamide (R )-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-amineindolyl]-2-(3-fluoro-phenyl)-ethyl]-2- Hydroxy-3-phenylpropanamide (R)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]-2-(2- Fluoro-phenyl)-ethyl]-2-hydroxy-3-phenyl-propanamine-122- 201121961 99 100 101 102 103 104 105 106 107 108 109 (R)-N-[(S)-l- [(2-Amino-thiazol-5-ylindenyl)-amine-mercapto]-2-(4-chloro-phenyl)-ethyl]-2-hydroxy-3-phenyl-propanamide ( R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminecarboxylidene]-2-(3-a-phenyl)-ethyl]-2 -hydroxy-3-phenyl-propionamide (R)-N-{(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]-2-p-quinone Phenyl-ethyl}-2-hydroxy-3-phenyl-propanamide (R)-N-{(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine oxime Mercapto]-2-m-tolyl-ethyl}-2-hydroxy-3-phenyl-propanamide (R)-N-{(S)-l-[(2-amino-thiazole-5- Methyl)-amine-mercapto]-2-o-tolyl-ethyl}-2·•hydroxy-3-benyl-propanamine (R)-N-{(S)-l-[(2 - Amine plug. -5-ylindenyl)-amine aryl]-2-cyclohexyl-ethyl}-2-yl-yl-3-phenyl-propanamide (R)-N-{(S)-l- [(2-Amino-Spirulina-5-ylmethyl)-Amineyl]-2-Chin-1-yl-ethyl}-2-yl-butanylamine (R)-N- {(S)-l-[(2-Amino-thiazol-5-ylmethyl)-amineindolyl]-2-naphthalen-1-yl-ethyl}-2-hydroxy-3-methyl- Butylamine (S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminecarbamyl]-2-naphthalen-1-yl-ethyl}- 2-hydroxy-3-methyl-butanamine (R)-N-[(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminoindenyl]-2-( 3,4-difluoro-phenyl)-ethyl]-2.hydroxy-3-indolyl-butanamine (S) -N-[(S)-l-[(2-amino-°S° The biological method of 5-(3,4-di-phenyl)-ethyl]- 2-hydroxy-3-methyl-butanamine can be used as follows. Bioassay to determine the ability of a compound of formula (I) to inhibit KLK1: The standard method disclosed for the determination of ICS0 for KLK1 is used (see, for example, Johansen et al, Int. J. Tiss. Reac. 1986, 8, 185; Shori et al, Biochem. Pharmacol,, 1992, 43, 1209; Stiirzebecher et al, Biol. Chem.Hoppe- 151651.doc -123 - 201121961

Seyler，1992, 373, 1025)測定活體外對KLK1之抑制活性。 在37°C下將人類KLKl(Callbiochem)與螢光受質η DVal Leu-Arg-AFC及各種濃度之測試化合物—起培育。藉由量 測410 nm下之吸光度的變化來測定殘餘酶活性（初始反應 率），且測定測試化合物之IC5G值。 測定酶選擇性 使用適合酶及產色受質（Chromogenix AB)進一步針對所 選化合物針對其他類胰蛋白酶絲胺酸蛋白酶之抑制活性來 篩選該等化合物。測試針對下列人類酶之活性（括號中為 受質）：血漿激肽釋放酶（S-2302)、凝血酶（S-223 8)、纖維 蛋白溶酶（S-2390)及胰蛋白酶（S-2222)。在37°C下將酶與 產色受質一起培育。藉由量測405 nm下之吸光度的變化來 測定殘餘酶活性（初始反應率）》 由此等檢定獲得之數據展示於下表6及7中： 表6 針對KLK1之活體外活性 實例編號 IC5Q(nM)(KLKl) 1 10.2 2 3.5 3 2.01 4 10.54 5 13.18 6 117.1 7 283.0 8 6.66 9 15.36 151651.doc •124- 201121961 10 4.22 11 111.66 12 1.70 13 7.30 14 27.03 15 265.7 16 18.28 17 3.69 18 4.56 19 15.21 20 0.87 21 92.32 22 128.98 23 85.05 24 56.32 25 289.93 26 7.26 27 5.71 28 4.86 29 42.79 30 9.27 31 18.80 32 96.58 33 10.29 34 14.28 35 5.73 36 139.02 37 30.70 38 289.93 39 7.33 40 37.72 41 15.51 151651.doc -125 201121961 42 224.61 43 0.90 44 365.82 45 27.69 46 7.33 47 37.23 48 1.28 49 0.35 50 2.95 51 1.64 52 40.36 53 7.79 54 17.60 55 57.19 56 1.15 57 0.25 58 7.58 59 1.64 60 3.04 61 19.43 62 1.82 63 9.05 64 7.52 65 2.57 66 30.45 67 9.50 68 20.02 69 23.86 70 87.69 71 1.77 72 71.59 73 5.71 151651.doc -126- 201121961 74 21.52 75 37.67 76 4.43 77 21.65 78 110.44 79 17.03 80 83.11 81 412.08 82 19.21 83 33.19 84 131.02 85 50.29 86 5.73 87 368.73 88 25.39 89 17.58 90 81.43 91 28.52 92 102.33 93 &gt;1000 94 39.19 95 49.81 96 76.76 97 114.42 98 1060.4 99 82.55 100 33.56 101 763.25 102 42.48 103 750.49 104 392.62 105 80.10 151651.doc -127- 201121961 106 40.05 107 216.19 108 167.8 109 412.9 表7(選擇性數據） 實例編號 IC5〇(nM) 血漿激肽釋放酶 凝血酶 胰蛋白酶 纖維蛋白溶酶 1 &gt;10000 &gt;10000 &gt;10000 &gt;10000 2 &gt;10000 &gt;10000 &gt;10000 &gt;10000 另外，實例3至109經測試且針對血漿激肽釋放酶呈現 &gt;1000 nM之 IC5。值。 151651.doc 128-Seyler, 1992, 373, 1025) Determines the inhibitory activity of KLK1 in vitro. Human KLK1 (Callbiochem) was incubated with fluorescent receptor η DVal Leu-Arg-AFC and various concentrations of test compound at 37 °C. The residual enzyme activity (initial reaction rate) was determined by measuring the change in absorbance at 410 nm, and the IC5G value of the test compound was determined. Determination of Enzyme Selectivity These compounds were screened for further inhibition of the activity of the selected compounds against other tryptase serine proteases using suitable enzymes and chromogenic substrates (Chromogenix AB). The test was performed on the following human enzyme activities (supply in brackets): plasma kallikrein (S-2302), thrombin (S-223 8), plasmin (S-2390), and trypsin (S- 2222). The enzyme was incubated with the chromogenic substrate at 37 °C. Residual enzyme activity (initial reaction rate) was determined by measuring the change in absorbance at 405 nm. The data obtained from these assays are shown in Tables 6 and 7 below: Table 6 In Vitro Activity Example No. IC5Q for KLK1 ( nM)(KLKl) 1 10.2 2 3.5 3 2.01 4 10.54 5 13.18 6 117.1 7 283.0 8 6.66 9 15.36 151651.doc •124- 201121961 10 4.22 11 111.66 12 1.70 13 7.30 14 27.03 15 265.7 16 18.28 17 3.69 18 4.56 19 15.21 20 0.87 21 92.32 22 128.98 23 85.05 24 56.32 25 289.93 26 7.26 27 5.71 28 4.86 29 42.79 30 9.27 31 18.80 32 96.58 33 10.29 34 14.28 35 5.73 36 139.02 37 30.70 38 289.93 39 7.33 40 37.72 41 15.51 151651.doc -125 201121961 42 224.61 43 0.90 44 365.82 45 27.69 46 7.33 47 37.23 48 1.28 49 0.35 50 2.95 51 1.64 52 40.36 53 7.79 54 17.60 55 57.19 56 1.15 57 0.25 58 7.58 59 1.64 60 3.04 61 19.43 62 1.82 63 9.05 64 7.52 65 2.57 66 30.45 67 9.50 68 20.02 69 23.86 70 87.69 71 1.77 72 71.59 73 5.71 151651.doc -126- 201121961 74 21.52 75 37.67 76 4.4 3 77 21.65 78 110.44 79 17.03 80 83.11 81 412.08 82 19.21 83 33.19 84 131.02 85 50.29 86 5.73 87 368.73 88 25.39 89 17.58 90 81.43 91 28.52 92 102.33 93 &gt;1000 94 39.19 95 49.81 96 76.76 97 114.42 98 1060.4 99 82.55 100 33.56 101 763.25 102 42.48 103 750.49 104 392.62 105 80.10 151651.doc -127- 201121961 106 40.05 107 216.19 108 167.8 109 412.9 Table 7 (Selective data) Example number IC5〇(nM) Plasma kallikrein thrombin trypsin fiber Plasmin 1 &gt; 10000 &gt; 10000 &gt; 10000 &gt; 10000 &gt; 10000 &gt; 10000 &gt; 10000 &gt; 10000 In addition, Examples 3 to 109 were tested and presented for plasma kallikrein &gt; 1000 nM IC5. value. 151651.doc 128-

Claims (1)

201121961 七、申請專利範圍： 1· 一種式（I)化合物：201121961 VII. Patent application scope: 1. A compound of formula (I): 2 Η Ν ⑴， 其中 R及R2係獨立地選自H、羥基、（Ci_CiQ)烷棊 ^ 基、（C2-C6)稀基、（c2_c6)炔基、（C3_Ci〇)iRHC6= 環烷基、芳基、雜芳基、芳基（Ci_C4)烷基_及雜芳基 C4)烧基-; R3係選自Η、（CVCw)烷基及（c2-c6)烯基； R4及R5係獨立地選自Η及（Ci-C6)烷基； A1係選自CR6及S(0)R7 ; R6係選自R7及以下式Π、III及IV之基團：2 Η Ν (1), wherein R and R2 are independently selected from H, hydroxy, (Ci_CiQ) alkanoyl, (C2-C6), (c2_c6) alkynyl, (C3_Ci〇)iRHC6=cycloalkyl, Aryl, heteroaryl, aryl (Ci_C4)alkyl- and heteroaryl C4)alkyl-; R3 is selected from the group consisting of ruthenium, (CVCw) alkyl and (c2-c6) alkenyl; R4 and R5 are independent It is selected from the group consisting of ruthenium and (Ci-C6) alkyl; A1 is selected from CR6 and S(0)R7; and R6 is selected from the group consisting of R7 and the following formulas: III, IV: N- OH I (II) (III) (IV); R7係選自（CVC6)院基、（c2_c6)稀基、（C3_Ci〇)環燒某、 芳基及芳基（Ci-CO烷基·； 土 R8及R9係獨立地選自η、（Cl_CiQ)烷基、（C2_C6)烯基、 (C3-C1Q)環烷基、雜環烷基、芳基、雜芳基' 方基（C 1， 151651.doc 201121961 C4)烧基及雜芳基（cvc4)烧基_; R10及R11係獨立地選自 丨。）烧基、（C2-C6)烯基、 (C3-C1G)環烷基、雜瑷 雜環烷基、方基、雜芳基、芳基（CV C4)烧基-、芳基r、## 基（C2_C4)烯基·、雜芳基（Ci-C4)烷基- 、-s〇2|^c6)絲、_叫芳基及娜芳基（Cl·基； 或R與11&quot;可連同其所連接之氮原子-起形成4員至7 員3陶，該含崎視情況含有另-選自Ν、Ο及S之 ，、原子且視情况經1或2個獨立地選自（Ci_c6)烷基、 (CIO烧氧基、_基、CN及經基之取代基取代，該 含N環亦可視情況稠合至芳基； 或R與R彳連同其所連接之原子—起形成飽和或部 分不飽和4員至7員含轉，該含N環視情況含有另一 選自N、〇及S之雜原子且視情況在碳上經丨或]個獨立 地選自（c】-c6)烷基、（C〗_C6)烷氧基、函基、CN及羥 基之取代基取代； 或R9不存在且R8與R1G可連同其所連接之原子一起形 成5員、6員、9員或10員單環或雙環含N芳環，該含N 芳環視情況含有另一選自N、〇及s之雜原子，且視情 況在碳上經1、2或3個獨立地選自（c丨_C6)烷基、（c丨· C6)烧氧基、鹵基、CN、芳基、COOR】5及經基之取代 基取代； 或R8與R10可一起形成式V或式VI之基團： 151651.doc 201121961 b (CH2)g Rl\C~{CvH2)h (CH2)f — 、/ L 、/ (V) (VI) R及R13係獨立地選自η、（Cl_Ci〇)烧基、（C2_C6)稀基、 (C3_C1())環烷基、雜環烷基、芳基、雜芳基、芳基（Ci_ C4)烷基·、芳基（CVC4)烯基…雜芳基（Ci_c4)烷基-、-scmcvq)烷基、·δ〇2芳基及-S〇2芳基（C]_C4)烷基， RaUb係獨立地選自H、（Cl_Ci〇)烧基、（CVC6)稀基、 (CVC一環烷基、雜環烷基、芳基、雜芳基芳基（Ci_ C4)烷基-、芳基（C2_C4)烯基·、雜芳基（CVC4)烷基·、1 -SOdCVCd烷基、_s〇2芳基及_s〇2芳基（CiC4)烷基； 或Ra與Rb可連同其所連接之原子一起形成飽和或部分 不飽和4員至7員含N環，該含N環視情況含有另一選 自N、〇及S之雜原子，且視情況在碳上經丨或2個獨立 地選自（C】-C6)烷基、（C]_C6)烷氧基、南基、cn及羥 基之取代基取代；該含N環亦可視情況稠合至芳基； 或Ra與Rb可連同其所連接之原子一起形成5員、6員、 9員或10員單ί衣或雙環含n芳環，該含N芳環視情況含 有另一選自N、〇及S之雜原子，且視情況在碳上經 1、2或3個獨立地選自（c丨-C6)烷基、（c】_c6)烷氧基、 鹵基、CN、芳基、c〇〇R15及羥基之取代基取代； R14係選自 Η、（CVC6)烧基、（Cl-C6)烧氧基、〇H、CN、 CF3、COOR15、鹵基及NR15R16 ; 151651.doc 201121961 R15及R16係獨立地選自Η及（C丨-C6)烷基； Rl7係選自H、羥基、鹵基、CN、（CVCw)烷基及（Cl_c6) 烷氧基； f及g係獨立地選自〇、1、2及3，以使f+g=l、2或3 ; h係選自1及2 ; 其中： 烷基可視情況經1或2個獨立地選自（C3-C1G)環烷基、 (Cj-Ce)垸氧基、〇H、CN、CF3、COOR15、龠；5 NR15R16之取代基取代； 烯基可視情況經1或2個獨立地選自（C3-Ci〇)環烷基、 (c!-c6)烷氧基、〇H、CN、Cf3、c〇〇r15、 nr15r16之取代基取代； 炔基可視情況經1或2個獨立地選自（C3-CiQ)環烷基、 (CVC6)烷氧基、〇H、CN、CF〗、c〇〇Rll、氟及 NRnR12之取代基取代； 烷氧基可視情況經！或2個獨立地選自（C3_c一環烷 基OH (：1^、〇?3、（：0〇尺15、氟及似151^16之取代基 取代； ㈣基為視情況稍合至芳基之非芳族單環或雙環煙 %，其中該環烷基環可能時視情況含有至多2個雙 鍵且其中，除非另外說明，否則該環烷基可視情況 經1或2個獨立地選自（ci-c6)燒基、（C】-C6)烧氧基、 H CN CF3、COOR15、氟及nr15r16之取代基取 代； 151651.doc 201121961 雜環烷基為C鍵聯或N鍵聯之3員至〗〇員非芳族單環戍 雙環，其中該雜環烧基環可能時含有卜2或3^立 地選自心，、8(叫及〇之雜原子；且該雜環烧基 環可能時視情況含有鴻2個雙鍵’且視情況在碳上經 1或2個獨立地選自（C丨·C6)烷基、^丨/^烷氧基、 OH、CN、CF3 鹵基、COOR15 NR R16及芳基之取 代基取代； 芳基為含有6或1 〇個碳原子之單芳環或稠合芳環系 統；其中，除非另外說明’否則芳基在每次出現時可 視情況經至多5個獨立地選自（Ci_C6)烷基、烷 氧基、OH、i 基、CN、COOR15、CFjNRl5Rl6 之取 代基取代； 雜芳基為可能時含有1、2或3個獨立地選自N、 NR15、S及Ο之環成員的5員、6員、9員或1〇員單環或 雙環芳環；其中，除非另外說明，否則該雜芳基可視 情況經1、2或3個獨立地選自（Ci_C6)烷基、（c】_cj烷 氧基、0H、鹵基、CN、COOR15、CF3及NR15r14之取 代基取代； q為〇、1或2 ; 及其互變異構體、立體異構體、醫藥學上可接受之鹽及 溶劑合物。 2.如請求項1之化合物，或其互變異構體、立體異構體、 醫藥學上可接受之鹽或溶劑合物，其中： R係選自（Ci_c6)烧基、（c3-c1G)環烧基、雜環统基、 I51651.doc 201121961 芳基及雜芳基； R2係選自Η、羥基、（C〗-C6)烷基、（C〗-C6)烷氧基、 (C3_Ci〇)環统基及芳基； R3、R4及R5係獨立地選自Η及（CVCe)烷基； Α1係選自CR6及S(0)R7 ; R6係選自R7及以下式II、III及IV之基團：N- OH I (II) (III) (IV); R7 is selected from (CVC6), (c2_c6), (C3_Ci), aryl and aryl (Ci-CO alkyl) The soils R8 and R9 are independently selected from the group consisting of η, (Cl_CiQ)alkyl, (C2_C6)alkenyl, (C3-C1Q)cycloalkyl, heterocycloalkyl, aryl, heteroaryl 'aryl (C 1 , 151651.doc 201121961 C4) alkyl and heteroaryl (cvc4) alkyl group; R10 and R11 are independently selected from the group consisting of hydrazine, (C2-C6) alkenyl, (C3-C1G) cycloalkyl , heterocycloalkylene, aryl, heteroaryl, aryl (CV C4) alkyl-, aryl r, ## base (C2_C4) alkenyl, heteroaryl (Ci-C4) alkyl- , -s〇2|^c6) silk, _ aryl and aryl (Cl· group; or R and 11&quot; can be combined with the nitrogen atom to which they are connected to form 4 to 7 members 3, including The situation may include another - selected from the group consisting of ruthenium, osmium and S, an atom and optionally 1 or 2 independently selected from the group consisting of (Ci_c6)alkyl, (CIO alkoxy, _ group, CN and thiol) Substituted, the N-containing ring may also be fused to an aryl group as appropriate; or R and R彳 together with the atom to which they are attached form a saturated or partially unsaturated 4 member to 7 members contain a rotation, and the N-containing ring optionally contains another hetero atom selected from N, hydrazine, and S, and optionally, on the carbon, or independently selected from (c)-c6) alkyl, (C) _C6) alkoxy, a functional group, a substitution of a substituent of CN and a hydroxyl group; or R9 is absent and R8 and R1G may form a 5-, 6-, 9- or 10-membered monocyclic or bicyclic ring together with the atom to which they are attached The N aromatic ring, the N-containing aromatic ring optionally contains another hetero atom selected from N, hydrazine and s, and optionally, on the carbon, 1, 2 or 3 independently selected from (c丨_C6)alkyl, (c丨·C6) alkoxy, halo, CN, aryl, COOR 5 and substituted by a substituent; or R8 and R10 may together form a group of formula V or formula VI: 151651.doc 201121961 b (CH2)g Rl\C~{CvH2)h (CH2)f — , / L , / (V) (VI) R and R13 are independently selected from η, (Cl_Ci〇) alkyl, (C2_C6) dilute (C3_C1())cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(Ci_C4)alkyl, aryl(CVC4)alkenyl...heteroaryl(Ci_c4)alkyl-, -scmcvq)alkyl, ·δ〇2 aryl and -S〇2 aryl(C]_C4)alkyl, RaUb is independently selected from H, (Cl_Ci〇 a calcinyl group, a (CVC6) dilute group, (CVC-cycloalkyl, heterocycloalkyl, aryl, heteroarylaryl (Ci_C4)alkyl-, aryl(C2_C4)alkenyl, heteroaryl ( CVC4) alkyl, 1-SOdCVCd alkyl, _s〇2 aryl and _s〇2 aryl (CiC4) alkyl; or Ra and Rb together with the atom to which they are attached form a saturated or partially unsaturated 4 member To 7 members containing an N ring, the N ring optionally containing another hetero atom selected from N, hydrazine and S, and optionally, on the carbon, or 2 independently selected from (C)-C6) alkyl, (C)_C6) Substituent substitution of alkoxy, south, cn and hydroxy; the N-containing ring may also be fused to an aryl group as appropriate; or Ra and Rb may form a 5 member, 6 together with the atom to which they are attached , 9 or 10 members of a single or double ring containing an n-aryl ring, the N-containing ring optionally containing another hetero atom selected from N, hydrazine and S, and optionally 1, 2 or 3 on carbon Substituent independently selected from (c丨-C6)alkyl, (c)-c6)alkoxy, halo, CN, aryl, c〇〇R15 and hydroxy; R14 is selected from fluorene, (CVC6) Burning base, (Cl-C6) alkoxy group, hydrazine H, CN, CF3, COOR15, halogen group and NR15 R16; 151651.doc 201121961 R15 and R16 are independently selected from the group consisting of hydrazine and (C丨-C6) alkyl; Rl7 is selected from the group consisting of H, hydroxy, halo, CN, (CVCw) alkyl and (Cl_c6) alkoxy f and g are independently selected from 〇, 1, 2 and 3 such that f+g = 1, 2 or 3; h is selected from 1 and 2; wherein: the alkyl group may be independently 1 or 2 independently Substituted from (C3-C1G)cycloalkyl, (Cj-Ce)nonyloxy, hydrazine H, CN, CF3, COOR15, hydrazine; 5 NR15R16 substituent; alkenyl may be independently selected by 1 or 2 Substituted from a substituent of (C3-Ci〇)cycloalkyl, (c!-c6)alkoxy, hydrazine H, CN, Cf3, c〇〇r15, nr15r16; the alkynyl group may be independently 1 or 2 independently Substituted from a substituent of (C3-CiQ)cycloalkyl, (CVC6)alkoxy, hydrazine H, CN, CF, c〇〇Rll, fluorine and NRnR12; alkoxy can be used as it is! Or 2 independently selected from (C3_c-cycloalkyl OH (:1^, 〇?3, (:0〇15, fluorine, and 151^16-substituted substituents; (d)) is optionally taken to the aryl group Non-aromatic monocyclic or bicyclic nicotin%, wherein the cycloalkyl ring may optionally contain up to 2 double bonds and wherein, unless otherwise stated, the cycloalkyl group may optionally be independently selected from 1 or 2 Substituting (ci-c6) alkyl, (C)-C6) alkoxy, H CN CF3, COOR15, fluorine and nr15r16; 151651.doc 201121961 Heterocycloalkyl is a C-bond or N-bond 3 To a member of the non-aromatic monocyclic indole bicyclic ring, wherein the heterocyclic ring of the ring may contain a di or a ring selected from the group, a hetero atom of 8 (called and deuterium); and the heterocyclic ring Where possible, containing 2 double bonds' and optionally 1 or 2 independently selected from (C丨·C6)alkyl, ^丨/^ alkoxy, OH, CN, CF3 halo on carbon , COOR15 NR R16 and a substituent of an aryl group; the aryl group is a single aromatic ring or a fused aromatic ring system containing 6 or 1 carbon atoms; wherein, unless otherwise stated, the aryl group may be present at each occurrence. Optionally substituted with up to 5 substituents independently selected from (Ci_C6)alkyl, alkoxy, OH, i groups, CN, COOR15, CFjNRl5Rl6; heteroaryl groups if possible contain 1, 2 or 3 independently a 5-membered, 6-membered, 9-membered or 1-membered monocyclic or bicyclic aromatic ring selected from the group consisting of N, NR15, S and oxime ring members; wherein, unless otherwise stated, the heteroaryl group may be subjected to 1, 2 or 3 substituents independently selected from (Ci_C6)alkyl, (c)-cj alkoxy, 0H, halo, CN, COOR15, CF3 and NR15r14; q is deuterium, 1 or 2; and tautomerism thereof a compound, a pharmaceutically acceptable salt or a solvate. 2. A compound according to claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof And wherein: R is selected from the group consisting of (Ci_c6) alkyl, (c3-c1G) cycloalkyl, heterocyclo, I51651.doc 201121961 aryl and heteroaryl; R2 is selected from hydrazine, hydroxy, (C) -C6)alkyl, (C-C6)alkoxy, (C3_Ci〇)cycloalkyl and aryl; R3, R4 and R5 are independently selected from fluorene and (CVCe)alkyl; Α1 is selected from CR6 And S(0)R7; R6 is selected from the group consisting of R7 and the following formulae II, III and IV: (II) (HI) (IV)； R7係選自（(VC6)烷基、芳基及芳基（Cl_c4)烷基_ ; R8係選自Η、（C丨-C6)烷基、（c3-c丨〇)環烷基及芳基（Ci_ c4)烷基； R9係選自Η及（CVC6)烷基； R丨0係選自Η、（C丨-C6)烷基、（C3-C10)環烷基及芳基（Ci_ c4)烷基； R11係選自Η及（CVC6)烷基； 或R1Q與Rn可連同其所連接之氮原子一起形成5員 至6員含N環，該含N環視情況經1或2個（CpCJ院基 取代基取代； 或R8與R1G可連同其所連接之原子一起形成飽和或 部分不飽和5員至6員含N環’該含n環視情況在碳 上經1或2個（CrC6)烷基取代基取代； 或R9不存在且R8與R1Q可連同其所連接之原子一起 151651.doc -6 - 201121961 形成5員、6員、9員或1〇員單環或雙環含n芳環， 該3 N芳ί衣視情況在碳上經丨或2個（Ci_C6)烷基取代 基取代； Rl2係選自Η及（Cl_C6)烧基； \係選自Η、（CVC6)烧基、芳基及芳基（Ci_C4)烧基·； Ra及Rb係獨立地選自H、(Ci_C6)烷基、(C3_C6)環烷 基、雜環烷基、芳基、雜芳基； 仪與Rb可連同其所連接之原子—起形成飽和或部 刀不飽和5員至6員含N環，該含N環視情況在碳上 經1或2個（Ci-C：6)烷基取代基取代； 或Ra與Rb可連同其所連接之原子一起形成$員、6 員、9員或1〇員單環或雙環含1^芳環，該含n芳環視 情況在碳上經1或2個（CrC6)烷基取代基取代； R”係選自Η及（cvc6)烧基。 3. 如明求項1或請求項2之化合物，或其互變異構體、立體 異構體、醫藥學上可接受之鹽或溶劑合物，其中…為 CR6。 ’、 4. 如請求項3之化合物，或其互變異構體、立體異構體、 醫藥學上可接受之鹽或溶劑合物，其中r6為以下式（1】） 之基團： R9 R8^ /N\ R10 (ii)。 151651.doc 201121961 5.如2求項4之化合物，或其互變異_、立體異構體、 醫藥學上可接受之鹽或溶劑合物，其中R8係選自H、（Cl. C6)烷基、（C3-ClQ)環烷基及芳基（CVC4)烷基。 月长項4或。月求項5之化合物，或其互變異構體、立體 異構體、醫藥學上可接受之鹽或溶劑合物，其中R9係選 自Η及（C〗-C6)院基。 奢长項4至6中任一項之化合物，或其互變異構體、立 體異構體、醫藥學上可接受之鹽或溶劑合物，其中…。係 選自H、（c〗-c6)院基、（C3_C|〇)環院基及芳基（Ci Q)烧 基。 月长項4至7中任一項之化合物，或其互變異構體、立 體異構體、醫藥學上可接受之鹽或溶劑合物’其中r11係 選自Η及（CVQ)院基。 9. ^ :求項4之化合物，或其互變異構體、立體異構體、 馐藥予上可接爻之鹽或溶劑合物其中R8與r1〇可連同其 斤連接之原子一起形成飽和或部分不飽和5員至6員含N 裒該3 Νί衣視情況在碳上經1或2個（〇】-(：6)烷基取代基 取代》 如明求項1至.9中任一項之化合物，或其互變異構體、立 體異構體、醫藥學上可接受之鹽或溶劑合物，其中^係 選自（C5-C1())環烷基、芳基及雜芳基。 如-月求項1至10中任一項之化合物，或其互變異構體、 立體異構體、醫藥學上可接受之鹽或溶劑合物，其中r2 係選自H、（C3-C1())環烷基及芳基。 151651.doc 201121961 1 2 女Ϊ言奢來τΕ 1 ' f項1至11中任一項之化合物，或其互變異構體、 立體異構體、醫藥學上可接受之鹽或溶劑合物，其中R3 至R及11丨7係獨立地選自H或（Ci-C6)烷基。 13.如請求項丨之化合物，其係選自： (R)-2-胺基-3- f基-戊酸{(S)-l-[(2-胺基-噻唑-5-基甲 基）-胺甲醯基]-2-萘-1-基-乙基}-醯胺； (R) -l -曱基-吡咯啶-2-甲酸[(S)-l-[(2_胺基-噻唑-5-基甲 基）-胺甲醯基]-2-(3,4·二氟-苯基）-乙基]-醯胺； (S) -N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]-2-(4-氟·苯基）-乙基]-2-(異丙基-甲基-胺基）-丙醯胺； 3-甲基-1H-吡咯-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基甲 基）-胺曱醯基]-2-(3,4-二氯-苯基）-乙基]-醯胺； (尺)-1^-[(8)-1-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2-(3,4 -二氣-苯基）-乙基]-2 -經基-3 -本基-丙酿私’ (S)-N-(2-胺基-噻唑_5_基曱基）-3-萘-1·基-2_(丙烧_1_續 醯胺基）-丙醯胺； (S)-l·曱基-吡咯啶-2-甲酸{(R)-l-[(2-胺基-噻唑-5-基曱 基）-胺曱醯基]-2,2-二環己基-乙基}•醯胺； (R)-«比咯啶-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基曱基）_胺 甲醯基]-2-(3,4-二氟-苯基）-乙基]-醯胺； (R)-2-胺基-3-甲基-戊酸[(S)-l-[(2-胺基-噻唑-5-基甲 基）-胺曱醯基]-2-(3,4-二氟-苯基）-乙基]-醯胺； (R)-3-曱基-2-甲胺基-戊酸[(S)-l-[(2-胺基-噻唑-5-基甲 基）-胺曱醯基]-2-(3,4-二氟-苯基）-乙基]-酿胺； I51651.doc 201121961 (S)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2-(3,4-二敗-苯基）-乙基]-2 -二丙胺基-丙酿胺， (8)-&gt;^-[(8)-1-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-(3,4-二氣-笨基）-乙基]-2-(異丙基-甲基-胺基）-丙酿 胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2-(3,4-二氣-苯基）-乙基]-2-二乙胺基-丙酿胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-(3,4-二氣-苯基）-乙基]-2-二曱胺基-丙酿胺； (R) -N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-(3,4-二氟-苯基）-乙基]-2-二甲胺基-丙酿胺； (S) -l-甲基-吡咯啶-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基曱 基）-胺甲醯基]-2-(3,4-二氟-苯基）-乙基]-醯胺； (R)-l-乙基-吡咯啶-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基甲 基）-胺甲醯基]-2-(3,4-二氟-苯基）-乙基]-醯胺； (R)-l-異丙基-吡咯啶-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基 曱基）-胺曱醯基]-2-(3,4-二氟-苯基）-乙基]-醯胺； (R)-1-異丙基-哌啶-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基甲 基）-胺甲醯基]-2-(3,4-二氟-苯基）-乙基]-醯胺； (R) -l-曱基-哌啶-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基甲 基）-胺甲醯基]-2-(3,4-二氟-苯基）-乙基]-醯胺； (S) -l-曱基-哌啶-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基曱 基）-胺曱醯基]-2-(3,4-二氟-苯基）-乙基]-醯胺； (R)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2- 151651.doc -10- 201121961 (3,4-二氣-笨基）_乙基]-2-·—甲胺基-3-笨基-丙酿胺， (S)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2-(3,4-二氟-笨基）_乙基]-2-二甲胺基-3-笨基-丙醯胺； (8)-义[(8)-1-[(2-胺基-噻唑-5-基甲基）-胺甲酿基]_2-(3,4·二氟·苯基）-乙基]-2-哌啶-1-基-丙醯胺； (11)-义[(8)-1-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-(3,4-二氟-苯基）·乙基]-2-哌啶-1-基-丙醢胺； (S)-N-(2-胺基-噻唑-5-基曱基）-3-(3,4-二氟-笨基）-2-(2-二異丙胺基-乙醯胺基）-丙醯胺； (S)-N-(2-胺基-噻唑-5·基甲基）-3-(3,4-二氟-苯基）_2-[2-(2,6-二甲基-哌啶-1-基）-乙醯胺基]-丙醯胺； (R) -l·曱基-吡咯啶-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基甲 基）-胺甲酿基]-2-(4-氟-苯基）-乙基]-酿胺； (S) -N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺曱醯基 敗-苯基）-乙基]-2-二曱胺基-丙酿胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]_2-(4_ 氟··苯基）-乙基]-2-二乙胺基-丙醯胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]-2_(4-氟-苯基）-乙基]-2-哌啶-1-基-丙醯胺； (11)-：^-[(3)-1-[(2-胺基-噻唑-5-基曱基）-胺曱醯基]-2-(4-氟-苯基）-乙基]定-1-基-丙醢胺， (S)-N-(2-胺基-噻唑-5-基甲基）-2-[2·(2,6-二曱基-哌啶_ 1-基）-乙醯胺基]-3-(4-氟-苯基）-丙醯胺； (R)-l·甲基-吡咯啶-2-甲酸[(S)-l-[(2-胺基-噻唑_5_基甲 151651.doc • 11 - 201121961 基）-胺曱醯基]-2-(3-氟-苯基）-乙基]-醯胺； (S)-N-[(S)-l-[(2-胺基·噻唑-5-基甲基）-胺曱醯基]-2-(3-氟-苯基）-乙基]-2-(異丙基-甲基-胺基）-丙醯胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-(3-氟-苯基）-乙基]-2-二甲胺基-丙醯胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]-2-(3-氟-笨基）-乙基]-2-二乙胺基-丙醯胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-(3-氣-笨基）-乙基]-2 -派σ定-1-基-丙酿胺’ (R)-N-[(S)-l-[(2-胺基-嘆唑-5-基甲基）_胺甲醯基]_2_(3_ 氟-苯基）-乙基]-2-哌啶-1-基-丙醯胺； (R) -l-甲基-吡咯啶-2-甲酸[(S)-l_[(2-胺基-嗔°坐_5-基甲 基）-胺甲醯基]-2-(2-氟-苯基）_乙基]-醯胺； (S) -N-[(S)-l-[(2-胺基-噻唑-5-基甲基）_胺甲醯基]_2-(2_ 氟-苯基）-乙基]-2-(異丙基-甲基-胺基）_丙醯胺； (R) -i-甲基-吡咯啶-2-甲酸{(s)-1-^2-胺基-噻唑基甲 基）-胺甲醯基]-2-萘-1-基-乙基}•醢胺； (8)-&gt;^-{(8)-1-[(2-胺基_噻唑-5-基甲基）_胺甲醯基]_2_ 萘-1-基-乙基卜2-(異丙基-甲基-胺基）·丙醯胺； (8)-^[-{(8)-1-[(2-胺基-噻唑-5_基甲基）_胺甲醯基]-2_ 萘-1-基-乙基}-2-二乙胺基-兩酿胺， (S) -N-{(S)-l-[(2·胺基-嗔唑基甲基）·胺甲醯基]-2· 萘-1-基-乙基}-2-哌啶-1-基-丙酿胺； (R)-N-{(S)-l-[(2-胺基-嘆咬基甲基）·胺曱醯基]_2 151651.doc -12- 201121961 秦-1-基-乙基}-2_旅咬-1-基-丙酿胺； (8)-：^-{(8)-：1-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2· 萘-1-基-乙基}-2-二甲胺基_3_苯基-丙醯胺； (R) -l-甲基-吡咯啶-2-甲酸[(s)-l-[(2-胺基-噻唑-5-基甲 基）-胺甲醯基]-2-(4-氣-苯基乙基]_醯胺； (S) -N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺曱醯基]-2-(4-氣-苯基）-乙基]-2-(異丙基-曱基-胺基）-丙醯胺； (R) -l-曱基-吡咯啶-2-曱酸[(s)-l-[(2-胺基-噻唑-5-基甲 基）-胺甲醯基]-2-(3-氯-苯基）·乙基]-醯胺； (S) -N-[(S)-M(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-(3-氣-苯基）-乙基]-2-(異丙基-曱基-胺基）-丙醯胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺曱醯基]-2-(3-氣-苯基）-乙基]-2-二甲胺基-丙醯胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲酿基]-2-(3-氣-苯基）-乙基]-2-二乙胺基-丙醯胺； (S)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-(3-氣-苯基）-乙基]-2-°辰咬-1-基-丙酿胺； (R)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-(3-氣-苯基）-乙基]-2-哌啶-1-基-丙醯胺； (R) -l-甲基-吡咯啶-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基甲 基）-胺甲醯基]-2-(3,4-二氣·苯基）-乙基]-醯胺； (S) -N-[(S)-l-[(2·胺基-噻唑-5-基曱基）-胺曱醯基]-2-(3,4-二氣-苯基）-乙基]_2-(異丙基·甲基-胺基）-丙醯 胺； 151651.doc •13· 201121961 (S)-N_[(S)-l-[(2-胺基-噻唑·5-基甲基）-胺甲酿基]_2_ (3,4-二氯-苯基）-乙基]-2-二甲胺基-丙醯胺； (s)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）_胺甲醯基]_2_ (3,4-二氯-苯基）-乙基]-2·二乙胺基-丙醯胺； (s)-N-[(S)-l-[(2-胺基_噻唑_5-基甲基）_胺甲醯基]_2_ (3,4-二氯-苯基）-乙基]-2-哌啶-1-基-丙醯胺； (汉)-1^-[(8)-1-[(2-胺基-噻唑-5-基甲基）_胺甲醯基]_2-(3,4-二氣-苯基）-乙基]-2-哌啶-1-基-丙醢胺； (s)-N-{(S)-l-[(2-胺基-噻唑-5-基甲基）_胺甲醯基]-2_對 甲笨基-乙基}-2-(異丙基-甲基-胺基）·丙醯胺； (R)-l-甲基-吡略啶-2-曱酸{(S)-l-[(2-胺基-噻唑_5-基甲 基）-胺甲醯基]-2-對甲苯基-乙基卜酿胺； (R) -l-甲基比咯啶-2-甲酸{(S)-l_[(2-胺基-噻唑_5_基甲 基）-胺曱醯基]-2-間曱苯基-乙基卜醯胺； (S) -N-{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]間 曱苯基-乙基}-2-(異丙基-甲基·胺基）_丙醢胺； (R) -l-甲基-吡咯啶-2-曱酸{(S)-l_[(2-胺基塞唑-5_基曱 基）-胺甲醯基]-2_鄰曱苯基-乙基卜醯胺； (S) -N-{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2_鄰 甲苯基-乙基}-2-(異丙基-甲基··胺基）_丙醯胺； (R)-吡咯啶-2-甲酸{(S)-M(2-胺基-噻唑_5_基甲基胺 曱醯基]-2-環己基-乙基}-醯胺； (R)-l-曱基-吡咯啶-2-曱酸{(SV1-[(2-胺基-噻唑基甲 基）-胺甲醯基]-2-環己基-乙基}-醯胺； 151651.doc -14- 201121961 (S)-l-甲基-吡咯啶-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基曱 基）-胺甲醯基]-2-環己基-乙基}-醯胺； (S)-N-{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺曱醯基]-2-環 己基-乙基}-2-(異丙基-甲基-胺基）-丙醯胺； (S)-N-{(S)-；l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-環 己基-乙基}-2-二甲胺基-丙醯胺； (S)-N-{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]環 己基-乙基}-2-二乙胺基-丙醯胺； (R)-l-乙基比咯啶-2-曱酸{(S)-l-[(2-胺基-嘆0坐-5-基甲 基）-胺甲酿基]_2-壞己基-乙基}•酿胺， (R)-l-異丙基-〇t匕咯啶-2-甲酸{(S)-l-[(2-胺基-嘆嗤-5-基 曱基）_胺曱醯基]-2-環己基-乙基}-酿胺； (R) -l-甲基·哌啶-2-甲酸{(S)-l-[(2-胺基-噻唑_5_基甲 基）-胺甲醯基]-2-環己基-乙基}-醯胺； (S) -N-{(S)-l-[(2-胺基-噻唑-5-基甲基）_胺甲酿基]-2_環 己基·乙基}-2-娘咬-1-基-丙酿胺； (R) -N-{(S)-l-[(2-胺基-噻唑-5·基曱基）_胺甲醯基]-2-環 己基-乙基}-2-略°定-1_基-丙酿胺， 3-甲基-1H-吡咯-2-曱酸{(S)-l-[(2-胺基·噻0坐_5_基甲 基）-胺甲酿基]-2 -秦-1-基-乙基}-酿胺’ 1H-吲哚-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基甲基）_胺甲 酿基]-2 -萘-1-基-乙基}•酿胺， (S) -N-(2-胺基-噻唑-5-基甲基）-3-萘-1-基-2-(2-間曱苯 基-乙醯胺基）-丙醯胺； 151651.doc •15· 201121961 3，5 -二曱基-1Η -0比洛-2 -甲酸[(S) -1 - [(2 -胺基-0塞0坐-5 -基 甲基）-胺甲酿基]-2-(3，4-二氣-苯基）-乙基]-酿胺， 3-曱基-1H-吡咯-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基曱 基）-胺甲醯基]-2-(3,4-二氟-苯基）-乙基]-醯胺； 1H-吲哚-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲 酿基]-2-(3，4 -二氣-苯基）-乙基]-酿胺， 3-甲基-1H-吡咯-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基甲 基）-胺甲酿基]-2-(4-^-苯基）-乙基]-酿胺； 3-甲基-1H-吡咯-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基甲 基）-胺曱酿基]-2-(3-氣-苯基）-乙基]-酿胺； 3-甲基-1H-吡咯-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基甲 基）-胺甲醯基]-2-(2-氟-苯基）-乙基]-醯胺； 3-曱基-1H-吡咯-2-曱酸[(S)-l-[(2-胺基-噻唑-5-基甲 基）-胺甲醯基]-2-(4-氯-苯基）-乙基]-醯胺； 3-曱基-1H-吡咯-2-甲酸[(S)-l-[(2-胺基-噻唑-5-基曱 基）-胺曱醯基]-2-(3-氣-苯基）-乙基]-醯胺； 3-甲基-1H-吡咯-2-曱酸{(S)-l-[(2-胺基·噻唑-5-基甲 基）-胺甲醯基]-2-對曱苯基-乙基}-醯胺； 3-甲基-1H-吡咯-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基曱 基）-胺甲醯基]-2-間甲苯基-乙基}-醯胺； 3-曱基-1H-吡咯-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基甲 基）-胺曱醯基]-2-鄰甲苯基-乙基}-醯胺； 3-曱基-1H-吡咯-2-甲酸{(S)-l-[(2-胺基-噻唑-5-基甲 基）-.胺甲醯基]-2-環己基-乙基卜醯胺； 151651.doc -16- 201121961 (R)-N-{(S)-l-[(2-胺基-噻唑-5-基曱基）·胺曱醢基]-2_ 蔡-1-基-乙基}-2 -經基-3 -苯基-丙酿胺， (R)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]_2_ (3,4-二氟-苯基）-乙基]-2-羥基-3-苯基-丙醢胺； (R)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醯基]-2-(4_ 氟-苯基）-乙基]-2-羥基-3-苯基-丙醯胺； (R)-N-[(S)-l-[(2-胺基-噻唑-5-基曱基）-胺甲醯基]-2_(3_ 氟-苯基）-乙基]-2-羥基-3-苯基-丙醯胺； (R)-N-[(S)-l-[(2-胺基-噻唑-5-基甲基）·胺甲醯基] 氟-苯基）-乙基]-2-羥基-3-苯基-丙醯胺； (R)-N-[(S)-l-[(2-胺基塞唑-5-基甲基）-胺甲醯基]_2_(4-氣·苯基）-乙基]-2-羥基-3-苯基-丙醯胺； (R)-N-[(S)-l-[(2-胺基噻唑-5-基甲基）_胺甲醯基]-2-(3_ 氣-苯基）-乙基]-2-羥基-3-苯基-丙醯胺； (R)-N-{(S)-l-[(2-胺基-嘆唑-5-基甲基）-胺甲醢基]_2_對 甲苯基-乙基} - 2-沒基-3-苯基-丙酿胺’ (R)-N-{(S)-l-[(2-胺基-嗔唑-5·基甲基）_胺甲醯基]_2_間 甲苯基-乙基} - 2-經基-3-苯基-丙酿胺’ (R)-N-{(S)-l-[(2-胺基-噻唑-5-基甲基）-胺甲醢基]鄰 曱苯基-乙基}-2-羥基-3-苯基-丙醯胺； (R)-N-{(S)-l-[(2-胺基-噻唑-5-基甲基）_胺甲醯基]-2-環 己基-乙基}-2-羥基-3-苯基-丙醯胺； (11)-：^-{(8)-1-[(2-胺基_噻唑-5-基甲基）-胺甲醯基]_2-萘-1-基-乙基}-2-羥基-丁醯胺； I51651.doc • 17- 201121961 W-N](S)-W(2-胺基-嗟唾_5-基甲基）_胺甲酿基k 萘-1-基-乙基}-2-羥基-3-甲基-丁醯胺； - ⑻-&gt;h⑻小[(2_胺基n5·基甲基）_胺甲醢基]_2 萘基·乙基}-2-羥基-3-甲基-丁醯胺； - [⑻小[(2-胺基-嗟嗤_5·基甲基）_胺甲醯基]I (3,4~二氟-苯基）-乙基]-2-羥基_3-曱基_ 丁醯胺. ⑻—(2-胺基-…基甲基)·：甲酿基]·2· (3,4-二氟-苯基）-乙基]-2_經基_3_甲基-丁醯胺； 及其互變異構體、立體異構體、醫藥學上可接 及溶劑合物。 歲 14 至13中任一項之化合物，或其互變異構體、 於2構體、醫藥學上可接受之鹽或溶劑合物，其係用 15. —種如請求項〗至13中任一項之化八 體、立舻s姐地^ 0物或其互變異構 途異構體、醫藥學上可接受之鹽或溶劑合物的用 …用於製造供治療或預防涉及klk 或病狀用的藥物。 展届 16. —種治療涉及KLK 為有需要…&quot; 病狀的方法，其包含 -項之化：： 有效量之如請求項1至13中任 :之化.物或其互變異構體、立體異構體、上 可接跫之鹽或溶劑合物。 、 17·==Γ用途或如請求項16之方法，其中該涉及 病狀？： 病狀係選自發炎性或啤吸道病症或 Μ選自哮喘（秘性^㈣性） 151651.doc •18· 201121961 肺病（COPD)、過敏性鼻炎（枯草熱）、咳嗽、由哮喘及斤 性阻塞性肺病（COPD)引起之惡化、多發性硬化症、^ 炎、類風濕性關節炎、骨病性關節炎、骨關節炎、^ 炎、竇炎、發炎性腸病（諸如克羅恩氏病^ok disease)及潰瘍性結腸炎）、免疫介導之糖尿病、急性膦 臟炎及間質性膀胱炎、結膜炎、牙周，病、慢性*** 炎、慢性復發性腮腺炎、發炎性皮膚病症(例如牛皮癬、 濕療）及SIRS(全身性發炎反應症候群）；平滑肌癌擎（例 如哮喘、心絞痛）、RDS(呼吸奢迫症候群）、I結膜炎、 鼻漏、蓴麻疹、贅生性病症、慢性支氣管炎、慢性呼吸 道阻塞、肺纖維化及肺氣腫。 18. 19. 20. 如晴求項15之用途或如請求項16之方法，其中該涉及 K L K1活性之疾病或病狀係選自哮喘（過敏性及非過敏 性）、慢性阻塞性肺病（C〇PD)、過敏性鼻炎（枯草熱）、咳 嗽、由哮喘及慢性阻塞性肺病（c〇pD)引起之惡化。 如請求項15之用途或如請求項16之方法，其中該涉及 KLK1活性之疾病或病狀係選自哮喘（過敏性及非過敏性） 及由孝喘及慢性阻塞性肺病（c〇PD)引起之惡化。 種邊藥組合物，其包含如請求項i至13中任一項之化 口物或其互變異構體、立體異構體、醫藥學上可接受之 鹽或溶劑合物’以及醫藥學上可接受之載劑、稀釋劑或 賦形劑。 151651.doc 201121961 四、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：(II) (HI) (IV); R7 is selected from ((VC6)alkyl, aryl and aryl (Cl_c4)alkyl]; R8 is selected from fluorene, (C丨-C6) alkyl, (c3 -c丨〇)cycloalkyl and aryl(Ci_ c4)alkyl; R9 is selected from fluorene and (CVC6)alkyl; R丨0 is selected from fluorene, (C丨-C6)alkyl, (C3- C10) cycloalkyl and aryl (Ci_ c4) alkyl; R11 is selected from fluorene and (CVC6) alkyl; or R1Q and Rn together with the nitrogen atom to which they are attached form a 5- to 6-membered N-ring, The N-containing ring is optionally substituted by 1 or 2 (CpCJ-based substituents; or R8 and R1G may form a saturated or partially unsaturated 5-member to 6-membered N-ring together with the atoms to which they are attached. Substituted by 1 or 2 (CrC6) alkyl substituents on carbon; or R9 is absent and R8 and R1Q may together with the atoms to which they are attached 151651.doc -6 - 201121961 form 5, 6 or 9 members or 1 单 member monocyclic or bicyclic ring containing n aromatic ring, the 3 N fang clothing is optionally substituted on carbon by hydrazine or 2 (Ci_C6) alkyl substituent; Rl2 is selected from hydrazine and (Cl_C6) alkyl; Selected from lanthanum, (CVC6) alkyl, aryl and aryl (Ci_C4) alkyl; Ra and Rb Sitely selected from H, (Ci_C6)alkyl, (C3_C6)cycloalkyl, heterocycloalkyl, aryl, heteroaryl; the instrument and Rb may form a saturated or scalloped unsaturated ring together with the atom to which they are attached Members to 6 members containing an N ring, which is optionally substituted on the carbon by 1 or 2 (Ci-C: 6) alkyl substituents; or Ra and Rb may form a $member along with the atoms to which they are attached, 6 members, 9 members or 1 member of a single or bicyclic ring containing 1 ^ aromatic ring, the n-containing ring is optionally substituted on the carbon by 1 or 2 (CrC6) alkyl substituents; R" is selected from the group consisting of Cvc6) A compound according to claim 1 or claim 2, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein ... is CR6. 4. The compound of claim 3, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein r6 is a group of the following formula (1): R9 R8^ / N. R10 (ii) 151651.doc 201121961 5. The compound of claim 4, or a tautomeric, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from the group consisting of H , Cl. C6) alkyl, (C3-ClQ)cycloalkyl and aryl (CVC4) alkyl. Moon length term 4 or a compound of the formula 5, or its tautomers, stereoisomers, pharmaceuticals A pharmaceutically acceptable salt or solvate wherein R9 is selected from the group consisting of hydrazine and (C-C6). A compound according to any one of items 4 to 6, or a tautomer, a stereoisomer, a pharmaceutically acceptable salt or solvate thereof, wherein. It is selected from the group consisting of H, (c)-c6), (C3_C|〇) ring and aryl (Ci Q). A compound according to any one of items 4 to 7, or a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a solvate thereof, wherein r11 is selected from the group consisting of hydrazine and (CVQ). 9. ^: a compound of claim 4, or a tautomer, a stereoisomer thereof, a pharmaceutically acceptable salt or a solvate thereof, wherein R8 and r1〇 together with the atoms to which they are attached form a saturation Or partially unsaturated, 5 to 6 members containing N 裒, 3 Ν ί, depending on the case, substituted by 1 or 2 (〇)-(:6) alkyl substituents on carbon, as described in any of items 1 to 9. A compound, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of (C5-C1()) cycloalkyl, aryl and heteroaryl The compound of any one of clauses 1 to 10, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein r2 is selected from H, (C3- C1())cycloalkyl and aryl. 151651.doc 201121961 1 2 A rumor of a compound, or a tautomer, stereoisomer, or pharmaceutical thereof A pharmaceutically acceptable salt or solvate wherein R3 to R and 11丨7 are independently selected from H or (Ci-C6)alkyl. 13. A compound according to claim ,, which is selected from the group consisting of: )-2-amino-3- f group -Pentanoic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine-carbamoyl]-2-naphthalen-1-yl-ethyl}-decylamine; (R) -l-decyl-pyrrolidine-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarbamyl]-2-(3,4·difluoro -phenyl)-ethyl]-guanamine; (S)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]-2-( 4-fluoro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propanamine; 3-methyl-1H-pyrrole-2-decanoic acid [(S)-l- [(2-Amino-thiazol-5-ylmethyl)-aminoindenyl]-2-(3,4-dichloro-phenyl)-ethyl]-indolyl; (foot)-1^- [(8)-1-[(2-Amino-thiazol-5-ylindenyl)-aminemethanyl]-2-(3,4-di-phenyl)-ethyl]-2 - -3-3-Benyl-propanol private '(S)-N-(2-Amino-thiazole-5-ylindenyl)-3-naphthalen-1-yl-2-(propane _1_ decylamine ())-propanolamine; (S)-l-decyl-pyrrolidine-2-carboxylic acid {(R)-l-[(2-amino-thiazol-5-ylindenyl)-amine fluorenyl] -2,2-dicyclohexyl-ethyl}• decylamine; (R)-«Byrrolidine-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylindenyl) _amine-mercapto]-2-(3,4-difluoro-phenyl)-ethyl]-indolyl; (R)-2-amino-3-methyl-pentanoic acid [(S)-l -[(2-Amino- (oxazol-5-ylmethyl)-aminoindenyl]-2-(3,4-difluoro-phenyl)-ethyl]-decylamine; (R)-3-mercapto-2-methylamino - Valeric acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]-2-(3,4-difluoro-phenyl)-ethyl]- Amine; I51651.doc 201121961 (S)-N-[(S)-l-[(2-Amino-thiazol-5-ylindenyl)-amine-methylmethyl]-2-(3,4-di Phenyl-phenyl)-ethyl]-2-dipropylamino-propanol, (8)-&gt;^-[(8)-1-[(2-amino-thiazol-5-ylmethyl) -aminomercapto]-2-(3,4-dioxa-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propanol; (S)-N-[ (S)-l-[(2-Amino-thiazol-5-ylindenyl)-aminemethylmercapto]-2-(3,4-di-phenyl)-ethyl]-2-diethyl Amino-propanol; (S)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine-mercapto]-2-(3,4-di Gas-phenyl)-ethyl]-2-didecylamino-propanol; (R)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)- Aminomethyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-dimethylamino-propanol; (S)-l-methyl-pyrrolidine-2-carboxylic acid [(S)-l-[(2-Amino-thiazol-5-ylindenyl)-amine-mercapto]-2-(3,4-difluoro-phenyl)-ethyl]-decylamine; (R)-l-ethyl-咯 曱 曱 曱 曱 [(S)-l-[(2-Amino-thiazol-5-ylmethyl)-amine-mercapto]-2-(3,4-difluoro-phenyl)- Ethyl]-guanamine; (R)-l-isopropyl-pyrrolidine-2-furic acid [(S)-l-[(2-amino-thiazol-5-ylindenyl)-amine oxime (2-(3,4-difluoro-phenyl)-ethyl]-decylamine; (R)-1-isopropyl-piperidine-2-carboxylic acid [(S)-l-[(2 -amino-thiazol-5-ylmethyl)-amine-mercapto]-2-(3,4-difluoro-phenyl)-ethyl]-decylamine; (R)-l-fluorenyl-piperidin Pyridine-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarbamido]-2-(3,4-difluoro-phenyl)-ethyl [-] guanamine; (S) -l-fluorenyl-piperidin-2-furic acid [(S)-l-[(2-amino-thiazol-5-ylindenyl)-amine fluorenyl]- 2-(3,4-difluoro-phenyl)-ethyl]-decylamine; (R)-N-[(S)-l-[(2-amino-thiazol-5-ylindenyl)- Aminomethyl hydrazino]-2- 151651.doc -10- 201121961 (3,4-diqi-stupyl)-ethyl]-2-yl-methylamino-3-styl-propanol, (S )-N-[(S)-l-[(2-Amino-thiazol-5-ylindenyl)-amine-methylcarbonyl]-2-(3,4-difluoro-phenyl)ethyl] -2-dimethylamino-3-phenyl-propionamine; (8)-yi[(8)-1-[(2-amino-thiazol-5-ylmethyl)-amine] _2-(3,4·difluoro-benzene )-ethyl]-2-piperidin-1-yl-propionamide; (11)-yi[(8)-1-[(2-amino-thiazol-5-ylmethyl)-amine-carboxamidine (2-)-(2-Amino-thiazole-5- (3-)-(3-diisopropylamino-acetamido)-propanin; (S)-N-(2-amino) -thiazol-5-ylmethyl)-3-(3,4-difluoro-phenyl)_2-[2-(2,6-dimethyl-piperidin-1-yl)-acetamido] -propanolamine; (R) -l-decyl-pyrrolidine-2-decanoic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine-branthyl]- 2-(4-Fluoro-phenyl)-ethyl]-bristamine; (S) -N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-amine oxime (S)-N-[(S)-l-[(2-Amino-thiazol-5-ylindenyl) -Aminomethylindenyl]_2-(4-fluorophenyl)-ethyl]-2-diethylamino-propionamide; (S)-N-[(S)-l-[(2-amine (yl)-thiazol-5-ylmethyl)-aminoindenyl]-2-(4-fluoro-phenyl)-ethyl]-2-piperidin-1-yl-propanamide; (11)-:^ -[(3)-1-[(2-amino-thiazol-5-ylindenyl)-amineindolyl]-2-(4-fluoro-phenyl)-ethyl]-1-yl- Propylamine, (S)-N-(2- Amino-thiazol-5-ylmethyl)-2-[2·(2,6-diamidino-piperidin-1-yl)-acetamido]-3-(4-fluoro-phenyl) -propanolamine; (R)-l.methyl-pyrrolidine-2-carboxylic acid [(S)-l-[(2-amino-thiazole_5_ylmethyl 151651.doc • 11 - 201121961 base)- Amidino]-2-(3-fluoro-phenyl)-ethyl]-indolyl; (S)-N-[(S)-l-[(2-amino-thiazol-5-yl) (-)-amino-yl]-2-(3-fluoro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propanin; (S)-N-[( S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminemethylmercapto]-2-(3-fluoro-phenyl)-ethyl]-2-dimethylamino-propyl Indoleamine; (S)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine fluorenyl]-2-(3-fluoro-phenyl)-B (2-)-diethylamino-propionamide; (S)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarbamyl]-2 -(3-gas-stupyl)-ethyl]-2-pyrazine-1-yl-propanolamine '(R)-N-[(S)-l-[(2-amino------- -5-ylmethyl)-amine-mercapto]_2_(3-fluoro-phenyl)-ethyl]-2-piperidin-1-yl-propanamide; (R)-l-methyl-pyrrolidine -2-carboxylic acid [(S)-l_[(2-amino-hydrazone-5-ylmethyl)-amine-methylcarbonyl]-2-(2-fluoro-phenyl)-ethyl]-oxime Amine; (S) -N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine-methylcarbonyl]_2-(2-fluoro-phenyl)-ethyl]-2-(isopropyl (-)-i-methyl-pyrrolidine-2-carboxylic acid {(s)-1-^2-amino-thiazolylmethyl)-amine formazan (2-naphthalen-1-yl-ethyl}• decylamine; (8)-&gt;^-{(8)-1-[(2-amino-thiazol-5-ylmethyl)-amine Mercapto]_2_naphthalen-1-yl-ethyl-2-(isopropyl-methyl-amino)·propanamine; (8)-^[-{(8)-1-[(2- Amino-thiazol-5-ylmethyl)-amine-methyl hydrazino]-2-naphthalen-1-yl-ethyl}-2-diethylamino-di-amine, (S) -N-{(S) -l-[(2.Amino-carbazolylmethyl)-amine-carbamoyl]-2.naphthalen-1-yl-ethyl}-2-piperidin-1-yl-propanol; (R )-N-{(S)-l-[(2-Amino-snotic methyl)-aminoindenyl]_2 151651.doc -12- 201121961 Qin-1-yl-ethyl}-2_ Traveling bite-1-yl-propanol; (8)-:^-{(8)-:1-[(2-amino-thiazol-5-ylmethyl)-aminecarbamyl]-2· Naphthalen-1-yl-ethyl}-2-dimethylamino-3-phenyl-propionamide; (R)-l-methyl-pyrrolidine-2-carboxylic acid [(s)-l-[( 2-amino-thiazol-5-ylmethyl)-amine-methylcarbonyl]-2-(4-carbo-phenylethyl)-decylamine; (S)-N-[(S)-l-[ (2- -thiazol-5-ylindenyl)-aminoindenyl]-2-(4-a-phenyl)-ethyl]-2-(isopropyl-indolyl-amino)-propanin; (R) -l-decyl-pyrrolidine-2-decanoic acid [(s)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarboxylidene]-2-(3- (S)-N-[(S)-M(2-amino-thiazol-5-ylmethyl)-aminecarboxylidene]-2-(3) - gas-phenyl)-ethyl]-2-(isopropyl-indolyl-amino)-propanin; (S)-N-[(S)-l-[(2-amino-thiazole) -5-ylindenyl)-aminoindenyl]-2-(3-a-phenyl)-ethyl]-2-dimethylamino-propionamide; (S)-N-[(S) -l-[(2-Amino-thiazol-5-ylmethyl)-amine-mercapto]-2-(3-a-phenyl)-ethyl]-2-diethylamino-propionamide (S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminecarbamyl]-2-(3-a-phenyl)-ethyl] -2-°Chen-1-yl-propanol; (R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-aminecarbamyl]- 2-(3-Gas-phenyl)-ethyl]-2-piperidin-1-yl-propanamide; (R)-l-methyl-pyrrolidine-2-carboxylic acid [(S)-l- [(2-Amino-thiazol-5-ylmethyl)-amine-mercapto]-2-(3,4-dioxaphenyl)-ethyl]-decylamine; (S) -N-[ (S)-l-[(2. Amino-thiazole-5- Mercapto)-aminoindenyl]-2-(3,4-dioxa-phenyl)-ethyl]_2-(isopropyl-methyl-amino)-propanamide; 151651.doc •13 · 201121961 (S)-N_[(S)-l-[(2-Amino-thiazole·5-ylmethyl)-amineyl]2-(3,4-dichloro-phenyl)-ethyl ]-2-dimethylamino-propionamide; (s)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarbamyl]_2_ (3 , 4-dichloro-phenyl)-ethyl]-2·diethylamino-propionamide; (s)-N-[(S)-l-[(2-amino-thiazole-5-yl) Methyl)-aminocarbazino]_2_(3,4-dichloro-phenyl)-ethyl]-2-piperidin-1-yl-propanamide; (Han)-1^-[(8) 1-[(2-amino-thiazol-5-ylmethyl)-amine-methylmethyl]_2-(3,4-di-phenyl)-ethyl]-2-piperidin-1-yl -propanolamine; (s)-N-{(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarbamyl]-2_p-methyl-ethyl} -2-(isopropyl-methyl-amino)·propanamine; (R)-l-methyl-pyrrolidine-2-decanoic acid {(S)-l-[(2-amino- Thiazole _5-ylmethyl)-amine carbaryl]-2-p-tolyl-ethyl broth; (R) -l-methylpyrrolidine-2-carboxylic acid {(S)-l_[( 2-amino-thiazolyl-5-ylmethyl)-aminoindenyl]-2-m-phenylene-ethyldoxime; (S) -N-{(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarboxylidene]-p-phenylene-ethyl}-2-(isopropyl-methyl· Amino)-propanamine; (R)-l-methyl-pyrrolidine-2-furic acid {(S)-l_[(2-aminostazole-5-ylindenyl)-aminecarboxylidene -2_ o-phenyl phenyl-ethyl hydrazide; (S) -N-{(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarbamyl]- 2_o-tolyl-ethyl}-2-(isopropyl-methyl-amino)-propanamine; (R)-pyrrolidine-2-carboxylic acid {(S)-M(2-amino group -thiazole-5-methylaminoindenyl]-2-cyclohexyl-ethyl}-decylamine; (R)-l-fluorenyl-pyrrolidine-2-indole {{SV1-[(2- Amino-thiazolylmethyl)-amine-mercapto]-2-cyclohexyl-ethyl}-decylamine; 151651.doc -14- 201121961 (S)-l-methyl-pyrrolidine-2-carboxylic acid { (S)-l-[(2-Amino-thiazol-5-ylindenyl)-aminecarbamimidyl]-2-cyclohexyl-ethyl}-decylamine; (S)-N-{(S) -l-[(2-Amino-thiazol-5-ylmethyl)-amine fluorenyl]-2-cyclohexyl-ethyl}-2-(isopropyl-methyl-amino)-propanoid Amine; (S)-N-{(S)-; l-[(2-amino-thiazol-5-ylmethyl)-aminecarboxylidene]-2-cyclohexyl-ethyl}-2-di Methylamino-propionamide; (S)-N-{(S)-l-[(2-amino group) -thiazol-5-ylmethyl)-amine-mercapto]cyclohexyl-ethyl}-2-diethylamino-propionamide; (R)-l-ethylpyrrolidine-2-decanoic acid { (S)-l-[(2-Amino-single-spin-5-ylmethyl)-amine-branthyl]_2-d-hexyl-ethyl}• octaamine, (R)-l-isopropyl -〇t匕rrolidine-2-carboxylic acid {(S)-l-[(2-amino- sin-5-ylindenyl)-amine fluorenyl]-2-cyclohexyl-ethyl}- Amine; (R) -l-methylpiperidine-2-carboxylic acid {(S)-l-[(2-amino-thiazole-5-ylmethyl)-amine-mercapto]-2-cyclohexyl -ethyl}-decylamine; (S) -N-{(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine-branthyl]-2-cyclohexylethyl }-2-娘 bit-1-yl-propanol; (R) -N-{(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminecarbamyl]- 2-cyclohexyl-ethyl}-2-succinyl-1-yl-propylamine, 3-methyl-1H-pyrrole-2-decanoic acid {(S)-l-[(2-amino) Thioquinones _5_ylmethyl)-amine-mercapto]-2-hendyl-1-yl-ethyl}-bristamine' 1H-indole-2-carboxylic acid {(S)-l-[(2 -amino-thiazol-5-ylmethyl)-amine-aryl]-2-naphthyl-1-yl-ethyl}•-enamine, (S)-N-(2-amino-thiazole-5- Methyl)-3-naphthalen-1-yl-2-(2-m-decylphenyl-acetamido)-propanamine; 1516 51.doc •15· 201121961 3,5-dimercapto-1Η-0 piro-2-formic acid [(S) -1 - [(2 -amino--0-oxo-5-ylmethyl)- Aminomethyl]-2-(3,4-dioxa-phenyl)-ethyl]-bristamine, 3-mercapto-1H-pyrrole-2-decanoic acid [(S)-l-[(2 -amino-thiazol-5-ylindenyl)-amine-mercapto]-2-(3,4-difluoro-phenyl)-ethyl]-decylamine; 1H-indole-2-carboxylic acid [( S)-l-[(2-Amino-thiazol-5-ylindenyl)-amineyl]-2-(3,4-di-phenyl)-ethyl]-bristamine, 3- Methyl-1H-pyrrole-2-decanoic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine-methyl]-2-(4-^-phenyl) -ethyl]-bristamine; 3-methyl-1H-pyrrole-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine oxime]-2 -(3- gas-phenyl)-ethyl]-bristamine; 3-methyl-1H-pyrrole-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl) )-Aminomethyl hydrazino]-2-(2-fluoro-phenyl)-ethyl]-decylamine; 3-mercapto-1H-pyrrole-2-decanoic acid [(S)-l-[(2- Amino-thiazol-5-ylmethyl)-amine-mercapto]-2-(4-chloro-phenyl)-ethyl]-decylamine; 3-mercapto-1H-pyrrole-2-carboxylic acid [( S)-l-[(2-Amino-thiazol-5-ylindenyl)-aminoindenyl]-2-(3-a-phenyl)-B ]-decylamine; 3-methyl-1H-pyrrole-2-furic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)-amine-methylmethyl]-2-pair曱Phenyl-ethyl}-decylamine; 3-methyl-1H-pyrrole-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminecarbamyl ]-2-m-tolyl-ethyl}-decylamine; 3-mercapto-1H-pyrrole-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)- Amidino]-2-o-tolyl-ethyl}-decylamine; 3-mercapto-1H-pyrrole-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-yl) Methyl)-.Aminomethyl]-2-cyclohexyl-ethyldoxime; 151651.doc -16- 201121961 (R)-N-{(S)-l-[(2-Amino-thiazole -5-ylindenyl)-aminoindenyl]-2_cai-1-yl-ethyl}-2-trans-yl-3-phenyl-propanol, (R)-N-[(S)- L-[(2-Amino-thiazol-5-ylmethyl)-amine-mercapto]_2_(3,4-difluoro-phenyl)-ethyl]-2-hydroxy-3-phenyl-propyl Indoleamine; (R)-N-[(S)-l-[(2-amino-thiazol-5-ylmethyl)-aminecarboxylidene]-2-(4-fluoro-phenyl)-ethyl ]-2-hydroxy-3-phenyl-propionamide; (R)-N-[(S)-l-[(2-amino-thiazol-5-ylindenyl)-aminecarbamyl]- 2_(3_fluoro-phenyl)-ethyl]-2-hydroxy-3-phenyl-propanamide; (R)-N-[(S)-l-[( 2-amino-thiazol-5-ylmethyl)-aminocarboxylidene]fluoro-phenyl)-ethyl]-2-hydroxy-3-phenyl-propionamide; (R)-N-[( S)-l-[(2-Aminopyrazol-5-ylmethyl)-aminemethylmercapto]_2_(4-Gasylphenyl)-ethyl]-2-hydroxy-3-phenyl-propane Indoleamine; (R)-N-[(S)-l-[(2-aminothiazol-5-ylmethyl)-aminecarboxylidene]-2-(3-a-phenyl)-ethyl] -2-hydroxy-3-phenyl-propionamide; (R)-N-{(S)-l-[(2-amino-tresor-5-ylmethyl)-aminecarbamyl]_2 _p-Tolyl-ethyl}-2-nonyl-3-phenyl-propanol' (R)-N-{(S)-l-[(2-amino-carbazole-5-yl) ()-aminomethyl hydrazino]_2-m-tolyl-ethyl}-2-yl-yl-3-phenyl-propanol' (R)-N-{(S)-l-[(2-amine (-)-N-{(S)-l -[(2-Amino-thiazol-5-ylmethyl)-amine-methylmethyl]-2-cyclohexyl-ethyl}-2-hydroxy-3-phenyl-propanamine; (11)-: ^-{(8)-1-[(2-Amino-thiazol-5-ylmethyl)-aminemethanyl]-2-naphthalen-1-yl-ethyl}-2-hydroxy-butanamine; I51651.doc • 17- 201121961 WN](S)-W(2-Amino-嗟 __5-ylmethyl)_amine-branth k-naphthalene-1- -Ethyl}-2-hydroxy-3-methyl-butanamine; - (8)-&gt;h(8) small [(2-aminon5.ylmethyl)-amine-methylmethyl]- 2-naphthyl-ethyl }-2-hydroxy-3-methyl-butanamine; - [(8) small [(2-amino-indole-5)methyl)-aminomethyl]I (3,4~difluoro- Phenyl)-ethyl]-2-hydroxy-3-pyrimidinyl-butanamine. (8)-(2-Amino-...ylmethyl)·:cartosan]·2· (3,4-difluoro -Phenyl)-ethyl]-2-trans-yl-3-methyl-butanamine; and tautomers, stereoisomers, pharmaceutically acceptable solvates thereof. A compound according to any one of the items 14 to 13, or a tautomer thereof, a 2-constituent, a pharmaceutically acceptable salt or a solvate thereof, which is used in the above-mentioned claims. Any of various substances, or tautomeric isomers, pharmaceutically acceptable salts or solvates thereof used in the manufacture of a therapeutic or prophylactic substance involving klk or disease. The drug used. Exhibition 16. A treatment involving KLK is needed...&quot; The method of the disease, which contains the term:: The effective amount is as claimed in claims 1 to 13: the substance or its tautomer , a stereoisomer, an upper salt or a solvate. , 17·==Γ Use or as in the method of claim 16, where the condition is involved? : The condition is selected from an inflammatory or beer-sucking condition or sputum is selected from asthma (secret^(4)) 151651.doc •18· 201121961 Pulmonary disease (COPD), allergic rhinitis (hay fever), cough, asthma and Deterioration caused by catatonic obstructive pulmonary disease (COPD), multiple sclerosis, inflammatory disease, rheumatoid arthritis, osteoarthritis, osteoarthritis, inflammatory disease, sinusitis, inflammatory bowel disease (such as Crowe Enke disease ^ok disease and ulcerative colitis), immune-mediated diabetes, acute phosphatidylitis and interstitial cystitis, conjunctivitis, periodontal disease, chronic prostatitis, chronic recurrent mumps, inflammatory Skin conditions (eg psoriasis, moist treatment) and SIRS (systemic inflammatory response syndrome); smooth muscle cancer (eg asthma, angina), RDS (breathing syndrome), conjunctivitis, rhinorrhea, urticaria, neonatal disorders, Chronic bronchitis, chronic airway obstruction, pulmonary fibrosis, and emphysema. 18. 19. 20. The use of the claim 15 or the method of claim 16, wherein the disease or condition involving KL K1 activity is selected from the group consisting of asthma (allergic and non-allergic), chronic obstructive pulmonary disease ( C〇PD), allergic rhinitis (hay fever), cough, deterioration caused by asthma and chronic obstructive pulmonary disease (c〇pD). The use of claim 15 or the method of claim 16, wherein the disease or condition involving KLK1 activity is selected from the group consisting of asthma (allergic and non-allergic) and by Xiaochuan and chronic obstructive pulmonary disease (c〇PD) Caused deterioration. A pharmaceutical composition comprising the pharmaceutically acceptable substance or a tautomer thereof, a stereoisomer, a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 13 and a medicinal An acceptable carrier, diluent or excipient. 151651.doc 201121961 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 2 Η Ν \«7 I /IV 151651.doc2 Η Ν \«7 I /IV 151651.doc
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