TW201040149A - Inhibitors of glucosylceramide synthase - Google Patents

Inhibitors of glucosylceramide synthase Download PDF

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TW201040149A
TW201040149A TW099103666A TW99103666A TW201040149A TW 201040149 A TW201040149 A TW 201040149A TW 099103666 A TW099103666 A TW 099103666A TW 99103666 A TW99103666 A TW 99103666A TW 201040149 A TW201040149 A TW 201040149A
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Naing Aay
Ron G Aoyama
Arlyn Arcalas
Wai Ki Vicky Chan
Hong-Wang Du
Patrick Kearney
Elena S Koltun
Jason August Nachtigall
Michael Pack
Steven James Richards
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Exelixis Inc
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Abstract

The present invention comprises glucosylceramide synthase (GCS) modulators of structural formula (I), wherein R1, A, L, R2, R3, and m are defined herein, as well as N oxides of them and pharmaceutically acceptable salts thereof, and methods of making said compounds. The invention further comprises compositions comprising the compounds, N-oxides, and/or pharmaceutically acceptable salts thereof. The invention also comprises use of the compounds and compositions for treating diseases in which GCS is a mediator or is implicated. The invention also comprises use of the compounds in and for the manufacture of medicaments, particularly for treating diseases in which GCS is a mediator or is implicated.

Description

201040149 六、發明說明： 【發明所屬之技術領域】 本發明涉及用於癌症和代謝性疾病的治療的葡萄糖苷基 腦醯胺合成酶（GCS)的抑制劑。 【先前技術】 葡萄糖苷基腦醯胺合成酶（0<：8)是催化葡萄糖苷基腦醯 胺為基礎的糖鞘脂（GSL)的生物合成的初始糖基化步驟也 就是經由來自葡萄糖從UDP_葡萄糖（UDp_Glc)向腦醯胺的 關鍵轉移以形成葡萄糖苷基腦醯胺中關鍵的酶。Gcs是定 位于高基氏體順面膜囊/中間膜囊（cis/medial G〇lgi)中的穿 透膜的III型整合蛋白。人們相信糖鞘脂（GSL)對於許多細 胞膜事件，包括細胞的相互作用、信號發送和運輸的動力 學來說都是不可或缺的。已經顯示GSL結冑的合成（參見 Yamashita等人，細人々Μ %⑽Μ% ⑽， 9142-9147)對絲胎發育和對於—些組織的分化來說是至 關重要的。㈣胺在神經鞘脂代謝中起到中樞作用並且已 經顯示GCS活性的下調對勒脂模式具有顯著的影響，其導 致糖勒脂的表現減少。神經雜〆c r λ ^ & m稍月曰（SL)在生理狀況以及病理 心血管病況中具有生物調節作 月即作用。尤其地，神經鞘脂和它 們的調節酶看起來在新Φ + ΰ 卿々巧尽你蚵生大乳心臟中對慢性缺氧的適應性 反應中起作用（參見，El Α丨姑， wani # 人，ProWag/aW/ws ά201040149 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to an inhibitor of glucosylceramide synthase (GCS) for the treatment of cancer and metabolic diseases. [Prior Art] Glucosylcerebralamine synthase (0<:8) is an initial glycosylation step that catalyzes the biosynthesis of glucosylceramide-based glycosphingolipid (GSL), that is, via glucose from UDP_glucose (UDp_Glc) is a key transfer to ceramide to form a key enzyme in glucosylceramide. Gcs is a type III integrin of the permeation membrane located in the high-base cis-membrane/intermediate capsule (cis/medial G〇lgi). It is believed that glycosphingolipids (GSL) are indispensable for many cell membrane events, including cellular interactions, signaling, and kinetics of transport. It has been shown that the synthesis of GSL scars (see Yamashita et al., Fine Humans % (10) Μ % (10), 9142-9147) is critical for silk development and for the differentiation of some tissues. (d) Amine plays a central role in sphingolipid metabolism and has been shown to have a significant effect on the Leuze pattern, which results in reduced performance of the leucorrhizal. The neurological scorpion c r λ ^ & m slightly sputum (SL) has a biological regulation as a monthly action in physiological conditions and pathological cardiovascular conditions. In particular, sphingolipids and their regulatory enzymes appear to play a role in the adaptive response to chronic hypoxia in the new Φ + 々 々 ( (see, El Α丨姑, wani # People, ProWag/aW/ws ά

Other Lipid Medi咖rs 78(14) 。 已經提s義將GCS抑制劍用^ 則用於各種疾病的治療（參見，例Other Lipid Medi rs 78 (14). It has been suggested that the GCS suppression sword can be used for the treatment of various diseases (see, for example).

如 ’ WO 2005068426)。i言链.Λ 汰 A <種b療包括糖脂貯積病（例如， 146258.doc 201040149 泰:薩克斯病、山多夫氏病' GM1神經節普脂貯積病和法 布裏病）、與糖脂積累相關的疾病（例如，高歇氏病；美格 ή特（Zavesca) ’ 一種（^抑制劑，已經被批准用於1型高 歇氏病患者的治療’參見’ Treiber等人，—二 ' 膽，37⑺，298·314)、導致腎肥大或增生的疾病例如糖尿 #性腎病變、導致高血糖或高騰島素血症的疾病、其中糖 月曰合成不正常的癌症、由使用細胞表面糖脂作為受體的生 料致㈣染性疾病、葡萄料基腦醯胺的合成不可或缺 或重要的感染性疾病、發生過量的糖脂合成的疾病（例如 動脈粥樣硬化，多囊性腎病和腎肥大）、神經元病症、神 經元損傷、與巨噬細胞補充和活化有關的炎性疾病或病症 (例如，風濕性關節炎，克隆氏病，哮喘和膿毒症）以及糖 尿病和肥胖（參見，WO 2006053043)的治療。 尤其是’已經顯示GCS的過量表現涉及多藥耐藥性並且 擾薦L腦醯胺誘導的〉周亡。例如Turzanski等人，(五 ◎ 2005，33"人62-72)已經顯示腦醯胺在急性骨 髓性白ir病（AML)細胞中誘導凋亡並且P-糖蛋白（p_gp)賦 予對腦醯胺誘導的凋亡的抗性，且對腦醯胺-葡萄糖普基 腦酿胺通路的調節對TF-1細胞中的這種抗性產生顯著貢 獻。因此’ GCS抑制劑對於通過在病態的細胞中誘導凋亡 來治療增殖性病症來說可以是有用的。 【發明内容】 根據可受到GCS抑制劑影響的前述疾病，本領域中具有 對於新的抑制劑的需求。爲了這一目的，已經鑒定在抑制 146258.doc 201040149 GCS的催化活性中有用幷且對於癌症和代謝疾病有用的新 的化合物。 本發明包括結構式⑴的葡萄糖芽基腦酿胺合成酶（GCS) 調節劑以及任選地其藥學上可接受的鹽，Such as ' WO 2005068426). i 链 Λ Λ & & & & & & & & & & & & ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Diseases associated with glycolipid accumulation (eg, Gaucher's disease; Zavesca's one (^ inhibitor, has been approved for the treatment of patients with type 1 Gaucher's disease] see ' Treiber et al. , - two 'biliary, 37 (7), 298 · 314), diseases that cause hypertrophy or hyperplasia of the kidney, such as diabetes, renal diseases, diseases that cause hyperglycemia or hypertonic acidemia, cancers in which the synthesis of glycosides is abnormal, The use of cell surface glycolipids as raw materials for receptors (4) infectious diseases, indispensable or important infectious diseases of grape-based ceramide, and diseases in which excessive glycolipid synthesis occurs (eg, atherosclerosis, Polycystic kidney disease and renal hypertrophy), neuronal disorders, neuronal damage, inflammatory diseases or conditions associated with macrophage supplementation and activation (eg, rheumatoid arthritis, Crohn's disease, asthma, and sepsis) and Diabetes and obesity (see, WO 2006053 Treatment of 043) In particular, 'excessive performance of GCS has been shown to involve multidrug resistance and to provoke L-brainamine-induced death. For example, Turzanski et al., (5 ◎ 2005, 33 " 62-72) Ceramide has been shown to induce apoptosis in acute myeloid white ir disease (AML) cells and P-glycoprotein (p_gp) confers resistance to ceramide-induced apoptosis, and to ceramide-glucosyl Modulation of the brain-branched amine pathway contributes significantly to this resistance in TF-1 cells. Thus 'GCS inhibitors may be useful for treating proliferative disorders by inducing apoptosis in pathological cells. Content] There is a need in the art for new inhibitors based on the aforementioned diseases that can be affected by GCS inhibitors. For this purpose, it has been identified that it is useful in inhibiting the catalytic activity of 146258.doc 201040149 GCS and for cancer and metabolism. Novel compounds useful for disease. The present invention includes a glucose bud brain-enamine synthase (GCS) modulator of structural formula (1) and, optionally, a pharmaceutically acceptable salt thereof,

其中R、A、L、R2、R3和w如下文中所定義的。 在另-方面，本發明包括包含本發明的⑽調節劑化合 物和藥學上可接受的載體、稀釋劑或職形劑的組合物。 在另-方面，本發明包括用於治療需要這種治療的受户 療者中㈣症或代謝性疾病的方法，纟包括向受治療朴 樂有效量的本發明的GCS抑制劑或包含有效量的本發明= GCS抑制劑的藥物組合物。 【實施方式】 作為實施方案 在第一個方面，本發明包括Gcs抑制劑 (1) ’本發明包括結構式⑴的Gcs調節劑，Wherein R, A, L, R2, R3 and w are as defined below. In another aspect, the invention includes a composition comprising a (10) modulator compound of the invention and a pharmaceutically acceptable carrier, diluent or topical agent. In another aspect, the invention includes a method for treating a (four) disease or a metabolic disease in a subject in need of such treatment, comprising administering to the treated Pule an effective amount of a GCS inhibitor of the invention or comprising an effective amount The present invention = a pharmaceutical composition of a GCS inhibitor. [Embodiment] As an embodiment, in a first aspect, the present invention includes a Gcs inhibitor (1) 'The present invention includes a Gcs modulator of the formula (1),

(I) ^者其單一的立體異構體或其立體異構體的現合物 氧化物以及另外地任選地其藥學上可接受的鹽，其中八 146258.doc 201040149 A是異丙基、叔丁基、C3-C8環烷基、雜環基、芳基或 雜芳基，其中所述環烷基、雜環基、芳基和雜芳基任 選地由一個、兩個或三個RA基團取代，其中 每個尺八獨立地為RA2、Ci-Ce烷基、CVC4鹵代烷基、 • 芳基、芳基（Ci-C4)院基或-C^-C^炫基-RA2，其中芳 - 基（C1-C4)烧基基團的芳基任選地由一個、兩個或三 個RA2基團取代，其中 每個RA2獨立地為鹵素、氰基、硝基、_0RA1、_srai、 〇 -N(RA1)2、-C(0)RA1、-S(〇)RA1、-s(o)2ra1、 -s(o)n(ra1)2、-s(o)2n(ra1)2、-c(o)ora1、 -c(o)n(ra1)2、-n(ra1)c(o)ra1、-N(RA1)C(0)ORA1、 -N(RA1)C(〇)N(RA1)2、-N(RA1)S(0)2RA1、-N(RA1) C(=NRA1)N(RA1)2、-P(〇)(〇ra1)2 或 _〇p(〇)(〇ra1)2， 其中每個RA1獨立地為氫、Ci-C4烷基或Ci-C4鹵 代烷基， ❹ 或者與相鄰的碳原子連接的兩個RA—起形成-0-(G)y-0-， 其中’每個G獨立地為-CH2-、-C(H)(F)-或-CF2-， 並且是1、2或3 ; ' L 是-，其中 是 1、2 或 3 ; 分是選自0至（3-p)的整數； L1是鍵或者-0-;並且 每個RL獨立地為氫、甲基或鹵甲基； R1是-NCR^XR11)或式（3)的部分， 146258.doc 201040149 R2〇(I) a single stereoisomer or a stereoisomer of a stereoisomer thereof, and additionally optionally a pharmaceutically acceptable salt thereof, wherein eight 146258.doc 201040149 A is isopropyl, a tert-butyl group, a C3-C8 cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally one, two or three Substituted by a RA group, wherein each of the rulers is independently RA2, Ci-Ce alkyl, CVC4 haloalkyl, • aryl, aryl (Ci-C4) or -C^-C^ s-RA2, Wherein the aryl group of the aryl-based (C1-C4)alkyl group is optionally substituted by one, two or three RA2 groups, wherein each RA2 is independently halogen, cyano, nitro, _0RA1, _srai , 〇-N(RA1)2, -C(0)RA1, -S(〇)RA1, -s(o)2ra1, -s(o)n(ra1)2, -s(o)2n(ra1) 2, -c(o)ora1, -c(o)n(ra1)2, -n(ra1)c(o)ra1, -N(RA1)C(0)ORA1, -N(RA1)C(〇 N(RA1)2, -N(RA1)S(0)2RA1, -N(RA1) C(=NRA1)N(RA1)2, -P(〇)(〇ra1)2 or _〇p(〇 (〇ra1)2, wherein each RA1 is independently hydrogen, Ci-C4 alkyl or Ci-C4 haloalkyl, ❹ or adjacent The two RAs of the atomic linkage form -0-(G)y-0-, where 'each G is independently -CH2-, -C(H)(F)- or -CF2-, and is 1, 2 or 3; 'L is -, where is 1, 2 or 3; the fraction is an integer selected from 0 to (3-p); L1 is a bond or -0-; and each RL is independently hydrogen, methyl Or halomethyl; R1 is -NCR^XR11) or part of formula (3), 146258.doc 201040149 R2〇

(R21)w (a) 其中 R1Q是氫或CVC4烷基；(R21)w (a) wherein R1Q is hydrogen or CVC4 alkyl;

Rn 是-R13、-C3-C6 環垸基·Ν(κΐ2)2、«6 環院基 _Rl3、 _Cl_C6烷基-N(R12)2或-CVC6烷基-R13 ,其中 每個R12獨立地為氫或Cl_c4烷基；並且 R13是（a) 4-10元單環、4_1〇元稠合雙環、5_1〇元橋連 雙環或5-10元螺雙環雜環基環，其中所述雜環基環 包含一個、兩個或三個環氮原子並且任選地包含— 個環氧或環硫原子，或者（b) 5或6元單環雜芳基或 8-1〇元稠合雙環雜芳基，其中所述雜芳基環包含一 個、兩個或三個環氮原子並且任選地包含一個環氧 或環硫原子，其中 所述雜環基和雜芳基各自任選地由一個、兩個或三 個R13A*團取代，其中每個RnA基團獨立地為_ 素、氰基、硝基、Cl-C4烷基、Cl-c4li代烷基、 方基（C1-C4)燒基、-〇RB1、-SRB1、_n(RBi)2、 -C(〇)RB1 . -S(〇)RB1 . -s(〇)2RB1 . -s(〇)N(RB1)2 、-s(o)2n(rb1)2、_c(0)orbi、_c(0)n(rB1)2、 -N(RBI)C(0)RB1 . -N(RB1)C(〇)〇RB, ^ -N(RB1)C(〇)N(RB1)2 或-WRBXOhRB!，其中每個RB丨獨立地為氫、 (VC4烷基、Cl-Cj代烷基、芳基或芳基（Ci_c4) 146258.doc 201040149 烷基； W 是ο、1、2或 3 ; R1的定義中的環Β是（a) 4-10元單環、4-10元稠合雙 環、5-10元橋連雙環或5_10元螺雙環雜環基環，其 中所述雜環基環任選地包含一個環氧或環硫原子和 任選地一個、兩個或三個另外的環氮原子，或者 (b) 5或6元單環雜芳基或8-10元稠合雙環雜芳基， 其中所述雜芳基環任選地包含一個環氧或環硫原子 和任選地一個、兩個或三個另外的環氮原子； R疋-R 、氫、C!-C4烧基、C丨-C4鹵代烧基、〇3-(：8環 烷基、芳基（CVC4)烷基、或-CVC4烷基-RB2，其中 每個R獨立地為氰基、石肖基、_〇rB3、_srB3、_n(rB3)2、 -C(0)RB3 . -S(0)RB3 . -S(0)2RB3 , -S(0)N(RB3)2 、-S(0)2N(RB3)2、_c(〇)〇RB3、_c(〇)n(rB3)2、 -N(R )C(0)RB3 . -N(RB3)C(0)0RB3 , -N(RB3)C(0)N(RB3)2 或-n(rB3)s(o)2rB3，其中 每個RB3獨立地為氫、Cl_C4烷基、Ci_C4函代 烷基、芳基或芳基（Ci-C4)烷基； 或者兩個f與它們都與之連接的氮原子一起 形成飽和或不飽和的單環雜環基或雜芳基， 其中所述雜環基和雜芳基各自任選地由各自 獨立地為（(VC3)淀基、顧素或Ci_C4画代院基 的一個、兩個或三個基團取代； 並且每個R21獨立地為鹵素或12〇 · 146258.doc 201040149 一個R疋虱或任選地由一個、兩個或三個鹵素基團取代 的甲基’並且其他的R2是任選地由一個、兩個或三個 鹵素基團取代的曱基，或者兩個R2與它們與之連接的 碳原子一起形成環丙基基團； w是1、2、3、4或5 ;並且 每個R3獨立地為鹵素、氰基、硝基、Cl-C4烷基、Cl_C4 鹵代烷基、C3-C6環烷基 ' -〇Rcl、_N(RC1)2、-C(0)RC1、 -S(〇)Rcl . -S(0)2RC1 > -S(0)N(RC1)2 ' -S(0)2N(RC1)2 、-C(0)0RC1、_C(0)N(RC1)2、-N(Rcl)C(0)Rcl、 -N(RC1)C(0)0RC1、-N(Rcl)C(0)N(Rcl)2 或-N(RC1)S(0)2RC1， 其中每個RC1獨立地為氫、Cl_C4烷基、Cl_c4鹵代烷 基、芳基或芳基（Ci-CO烷基， 或者兩個R3與它們與之連接的環原子一起形成芳基、雜 芳基、單環環烧基或雜環基，所述芳基、雜芳基、單 環環烷基或雜環基各自任選地由各自獨立地為（Ci_c3) 烷基、鹵素或C〗-(：4鹵代烷基的一個、兩個或三個基 團取代。 本發明還包括結構式（IV)的GCS調節劑， (IV)Rn is -R13, -C3-C6 cyclodecyl Ν (κΐ2) 2, «6 ring-based _Rl3, _Cl_C6 alkyl-N(R12)2 or -CVC6 alkyl-R13, wherein each R12 independently Is hydrogen or Cl_c4 alkyl; and R13 is (a) 4-10 membered monocyclic, 4_1〇 fused bicyclic, 5_1 fluorene bridged bicyclic or 5-10 membered spirobicycloheterocyclyl ring, wherein the heterocycle The base ring contains one, two or three ring nitrogen atoms and optionally contains one epoxy or ring sulfur atom, or (b) a 5 or 6 membered monocyclic heteroaryl group or an 8-1 anthracene fused bicyclic ring An aryl group, wherein the heteroaryl ring contains one, two or three ring nitrogen atoms and optionally one epoxy or ring sulfur atom, wherein the heterocyclic group and the heteroaryl group are each optionally one Substituted by two or three R13A* groups, wherein each RnA group is independently _, cyano, nitro, Cl-C4 alkyl, Cl-c4li alkyl, aryl (C1-C4) Base, -〇RB1, -SRB1, _n(RBi)2, -C(〇)RB1 . -S(〇)RB1 . -s(〇)2RB1 . -s(〇)N(RB1)2 , -s( o) 2n(rb1)2, _c(0)orbi, _c(0)n(rB1)2, -N(RBI)C(0)RB1 . -N(RB1)C(〇)〇RB, ^ -N (RB1)C(〇)N(RB1)2 or -WRBXOhRB!, Each RB 中 is independently hydrogen, (VC4 alkyl, Cl-Cj alkyl, aryl or aryl (Ci_c4) 146258.doc 201040149 alkyl; W is ο, 1, 2 or 3; definition of R1 The cyclic oxime is (a) a 4-10 membered monocyclic ring, a 4-10 membered fused bicyclic ring, a 5-10 membered bridged bicyclic ring or a 5-10 membered spirobicycloheterocyclyl ring, wherein the heterocyclyl ring is optionally Containing an epoxy or epicyclic sulfur atom and optionally one, two or three additional ring nitrogen atoms, or (b) a 5 or 6 membered monocyclic heteroaryl group or an 8-10 membered fused bicyclic heteroaryl group, Wherein said heteroaryl ring optionally comprises an epoxy or epicyclic sulfur atom and optionally one, two or three additional ring nitrogen atoms; R疋-R, hydrogen, C!-C4 alkyl, C丨-C4 haloalkyl, 〇3-(:8-cycloalkyl, aryl(CVC4)alkyl, or -CVC4alkyl-RB2, wherein each R is independently cyano, schwitz, _〇rB3, _srB3, _n(rB3)2, -C(0)RB3 . -S(0)RB3 . -S(0)2RB3 , -S(0)N(RB3)2 , -S(0)2N(RB3)2 , _c(〇)〇RB3, _c(〇)n(rB3)2, -N(R)C(0)RB3 . -N(RB3)C(0)0RB3 , -N(RB3)C(0)N (RB3)2 or -n(rB3)s(o)2rB3, wherein each RB3 is independently hydrogen, Cl_C4 Alkyl, Ci_C4 functional alkyl, aryl or aryl (Ci-C4) alkyl; or two f together with the nitrogen atom to which they are attached form a saturated or unsaturated monocyclic heterocyclic or heteroaryl a group, wherein the heterocyclic group and the heteroaryl group are each optionally substituted by one, two or three groups each independently ((VC3) decyl, gudin or Ci_C4); and each R21 is independently halogen or 12〇·146258.doc 201040149 A R疋虱 or a methyl group optionally substituted by one, two or three halogen groups and the other R2 is optionally one or two One or three halo group-substituted indenyl groups, or two R2 together with the carbon atom to which they are attached form a cyclopropyl group; w is 1, 2, 3, 4 or 5; and each R3 independently Is halogen, cyano, nitro, Cl-C4 alkyl, Cl_C4 haloalkyl, C3-C6 cycloalkyl '-〇Rcl, _N(RC1)2, -C(0)RC1, -S(〇)Rcl. -S(0)2RC1 > -S(0)N(RC1)2 ' -S(0)2N(RC1)2 , -C(0)0RC1, _C(0)N(RC1)2, -N( Rcl)C(0)Rcl, -N(RC1)C(0)0RC1, -N(Rcl)C(0)N(Rcl)2 or -N(RC1)S(0)2RC1, where each RC1 is independent Ground Is hydrogen, Cl_C4 alkyl, Cl_c4 haloalkyl, aryl or aryl (Ci-CO alkyl, or two R3 together with the ring atom to which they are attached form an aryl, heteroaryl, monocyclic cycloalkyl or a heterocyclic group, each of which is optionally independently a (Ci_c3) alkyl group, a halogen or a C--: 4-haloalkyl group, each of which is independently an alkyl group, a heteroaryl group, a monocyclic cycloalkyl group or a heterocyclic group. Two or three groups are substituted. The invention also includes a GCS modulator of structural formula (IV), (IV)

或者其單一的立體異構體或其立體異構體的混合物、其… 氧化物以及另外地任選地其藥學上可接受的鹽其中E 146258.doc -10- 201040149 疋 _C(0)- ; R是 如本文所定義Or a single stereoisomer thereof or a mixture of its stereoisomers, an oxide thereof and, optionally, a pharmaceutically acceptable salt thereof, wherein E 146258.doc -10- 201040149 疋_C(0)- ; R is as defined in this article

並且R1、A、 L、R2、R3以及彷 本文的化合物或它們的藥學上可接受的鹽在它們的結構 中可具有不對稱的碳原子或季銨化的氮原子，並且可作為 早-的立體異構體、外消旋物和立體異構體的混合物存 在。本發明的化合物或它們的藥學上可接受的鹽，作為單 〇And R1, A, L, R2, R3 and the compounds herein or pharmaceutically acceptable salts thereof may have an asymmetric carbon atom or a quaternized nitrogen atom in their structure, and may be used as early- A mixture of stereoisomers, racemates and stereoisomers is present. a compound of the invention or a pharmaceutically acceptable salt thereof, as a monoterpenes

-的立體異構體、外消旋物和立體異構體的混合物都意圖 在本發明的範圍内。 本發明還包括下列實施方案中的每—個： 實施方案(2):在另一個實施方案中，式⑴的化合物為 其中每個R2獨立地為任選地由一個、兩個或三個函素基團 取代的f基或者兩個R2與它們與之連接的碳原子一起形成 環丙基基團，並且所有其他基團如實施方案（1)中所定義 的。在亞實施方案（subemb〇diment)(2-a)中，每個R2是甲 基，或兩個R2與它們與之連接的碳原子一起形成環丙:基 團’並且所有其他基團如實施方案⑴中所定義的。在亞實 施方案（2.b)中’每㈣是甲基，並且所有其他基團如實施 方案（1)中所定義的。 實施方案（3) ··在另—個實施方案中，式⑴的化合物為 其中兩個作它們與之連接的碳原子—起形成環丙基基 團，並且所有其他基團如實施方案（2)中所定義的。 實施方案（4):在另-個實施方案中，式⑴的化合物為 其中A是異丙基、叔丁基、C3_Cs環炫基、雜環基、芳基或 146258.doc 201040149 雜芳基，其尹所述環炫基、雜環基、芳基和雜芳基任選地 由-個、兩個或三個ra基圓取代；並且所有其他基團如實 施方案任一個實施方案尹所定義的。在亞實施方 案（4-a)中，式⑴的化合物為其中八是^<8環烷基、芳基或 雜芳基，其中所述環烷基、芳基和雜芳基任選地由一個、 兩個或三個RA基團取代，·並且所有其他基團如實施方案 (1)-(3)中任一個實施方案中所定義的。在亞實施方案（4_b') 中，A是任選地由一個、兩個或三個rA基團取代的CrG環 烷基；並且所有其他基團如實施方案（1)_(3)中任一個實施 方案中所定義的。在亞實施方案（4_c)中，A是C3_C8環烷基 或芳基，其中所述環烷基和芳基任選地由一個、兩個或2 個尺八基團取代；並且所有其他基團如實施方案（1)_(3)中任 一個實施方案中所定義的。在亞實施方案（4_d)中，A是 CyC8環烷基或雜芳基，其中所述環烷基和雜芳基任選地 由一個、兩個或三個Ra基團取代；並且所有其他基團如實 *方案（1)(3)中任一個實施方案中所定義的。在亞實施方 案（4-e)中，A是芳基或雜芳基，其中所述芳基和雜芳基任 選地由一個、兩個或三個ra基團取代；並且所有其他基團 如實施方案（1)_(3)中任一個實施方案中所定義的。在亞實 施方案（4-f)中，八是任選地由一個、兩個或三個rA基團取 代的雜芳基；並且所有其他基團如實施方案（1)-(3)中任一 個實施方案中所定義的，例如A是任選地由一個、兩個或 三個RA基團取代的吲哚基。 一 實施方案(5):在另一個實施方案中，式⑴的化合物為 146258.doc -12· 201040149 其中A是任選地由一個、兩個或三個rA基團取代的苯基； 並且所有其他基團如實施方案（〖）_(4)中任一個實施方案中 所疋義的。在亞實施方案（5-a)中，a是由與相鄰的碳原子 連接的兩個RA基團取代的苯基，並且所述兩個尺八基團在— 起形成-〇-(G)y-0-;其中每個⑽立地為_CH2_、_c(h)(f)_ 或-CF2- ’並且是1、2、或3 ;例如，諸如A是2,3_二 氫-1，4-苯並二噁烷-6-基或2,2_二氟_丨，3_苯並二噁唑_5_基。 實施方案（6):在另一個實施方案中，式⑴的化合物為 〇 其中當rA存在時，每個RA獨立地為rA2、CVC6烷基、 CVC4鹵代烷基、芳基、芳基（Ci_C4)烷基、或_C1_C6烷 基-RA2，其中所述芳基（Cl_C4)烷基基團任選地由一個、兩 個或三個RA2基團取代，其中每個RA2獨立地為函素、氰 基、硝基、-ORA1、-SRA1、-N(RA1)2、、_s(〇)rAI、 -s(〇)2RA1 . -S(0)N(RA1)2 > -S(〇)2N(RA1)2 . -C(〇)〇Rai . -C(0)N(RA1)2 . -N(RA1)C(0)RA1 . -N(RA1)C(〇)〇RAi , Q _N(RA1)C(〇)N(rA1)2、-N(RA1)S(0)2RA1、-N(RA1)C(=NRA1)N(RA1)2、 -P(〇K〇Ra1)2或-〇P(〇)(〇rA1)2，其中每個rai獨立地為氫、 CrC4烷基或c^C：4鹵代烷基，或者與相鄰的碳原子連接的 兩個RA—起形成_0_(G)y_0_，其中每個G獨立地為_Ch2_、 -C(H)(F)-或-CF2·，並且少是1、2或3 ;並且所有其他基團 如實施方案（1)-(5)中任一個實施方案中所定義的。在亞實 施方案（6-a)中’式（1)的化合物為其中當ra存在時，每個 RA獨立地為鹵素、氰基、Cl_C4烷基、Ci_C4鹵代烷基、笨 基、苄基、-ORa丨、-N(RA1)2或-C(0)RA丨，其中每個獨 146258.doc -13- 201040149 立地為氫、Q-c：4烷基或Cl_C4鹵代烷基；或者與相鄰的碳 原子連接的兩個RA —起形成_〇_(G)y_〇_ ;其中每個G獨立 地為-CH2·、-CmOF)-或-Civ，並且少是卜2或3 ;並且所 有其他基團如實施方案⑴_(5)中任一個實施方案中所定義 的。 實施例（7) ♦·在另一個實施方案中，式⑴的化合物為其 中R20是-RB2、氫、C广a,烷基、Cl_C4鹵代烷基、C3_C8環烷 基、芳基（C丨-C4)烷基或_C]_C4烷基_RB2，其中每個^2獨立 地為氰基、硝基、-〇RB3、_SRB3、_n(rB3)2、⑴>rB3、 -s(〇)RB3 . -S(0)2rB3 . -S(〇)N(RB3)2 . -s(〇)2N(RB3)2 . _c(o)orB3、-c(o)n(rB3)2、_N(RB3)c(〇)rB3、n(rB3)c(〇)〇rB3、 ，其中每個RB3獨立 地為氫、CVC4烷基、Cl_C4鹵代烷基、芳基或芳基（C1_C4) 烷基，·或者兩個RB3與它們都與之連接的氮原子一起形成 飽和的或不飽和的單環的雜環基或雜芳基’其中所述雜環 基和雜芳基各自任選地由各自獨立地為（Ci_C3)烷基、鹵素 或C丨-C4鹵代烷基的一個、兩個或三個基團取代；並且卷 R21存在時，每一個Rh獨立地為鹵素或_R2〇 ;並且所有其 他基團如實施方案（1)_(6)中任一個實施方案中所定義的。 在亞實施方案（7-a)中，式（1)的化合物為其中尺2〇是氫、 orB3、-N(RB3)2、Cl_c4烷基、Ci-C4鹵代烷基、環烷 基、芳基（C丨-C4)院基或-C丨-C4統基-RB2 ;其中rB2是_〇rB3 或-N(RB3)2;並且當R”存在時，每個ru獨立地為齒素 或-R20 ;並且所有其他基團如實施方案（1)_(6)中任—個實 146258.doc 14- 201040149 施方案中所定義的。在亞實施方案（7-b)中，式（I)的化合物 為其中R 〇是氫、C1-C4烷基、-ORB3或-N(RB3)2，其中每個 RB3獨立地為氣、C广C4烧基、Cl-C4_代烧基、芳基或芳基 (C!-C4)烷基，並且當rS1存在時，每個rZ1獨立地為鹵素 或-R ，並且所有其他基團如實施方案（1)_(6)中任一個實 施方案中所定義的。A mixture of stereoisomers, racemates and stereoisomers is intended to be within the scope of the invention. The invention also includes each of the following embodiments: Embodiment (2): In another embodiment, the compound of formula (1) is wherein each R2 is independently, optionally one, two or three The f group substituted by the group or the two R2 together with the carbon atom to which they are attached form a cyclopropyl group, and all other groups are as defined in embodiment (1). In a subemb〇diment (2-a), each R2 is a methyl group, or two R2 together with the carbon atom to which they are attached form a cyclopropane group: a group 'and all other groups as implemented Defined in scheme (1). In the sub-implementation scheme (2.b), each (four) is a methyl group, and all other groups are as defined in the embodiment (1). Embodiment (3) In another embodiment, the compound of the formula (1) is one in which two of the carbon atoms to which they are bonded together form a cyclopropyl group, and all other groups are as in the embodiment (2) Defined in ). Embodiment (4): In another embodiment, the compound of formula (1) is wherein A is isopropyl, tert-butyl, C3_Cscyclo, heterocyclyl, aryl or 146258.doc 201040149 heteroaryl, The cyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one, two or three ra-based circles; and all other groups are as defined in any embodiment of the embodiment of. In sub-embodiment (4-a), the compound of formula (1) is wherein VIII is a cycloalkyl, aryl or heteroaryl group, wherein the cycloalkyl, aryl and heteroaryl are optionally Substituted by one, two or three RA groups, and all other groups are as defined in any one of embodiments (1) to (3). In sub-embodiment (4_b'), A is a CrG cycloalkyl optionally substituted with one, two or three rA groups; and all other groups are as in embodiments (1) to (3) Defined in one embodiment. In sub-embodiment (4-c), A is a C3_C8 cycloalkyl or aryl group, wherein the cycloalkyl and aryl are optionally substituted by one, two or two ampute groups; and all other groups As defined in any one of embodiments (1) to (3). In sub-embodiment (4_d), A is a CyC8 cycloalkyl or heteroaryl group, wherein the cycloalkyl and heteroaryl are optionally substituted by one, two or three Ra groups; and all other groups The group is as defined in any of the embodiments (1) and (3). In sub-embodiment (4-e), A is aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one, two or three ra groups; and all other groups As defined in any one of embodiments (1) to (3). In sub-embodiment (4-f), VIII is a heteroaryl optionally substituted with one, two or three rA groups; and all other groups are as in embodiments (1)-(3) As defined in one embodiment, for example, A is a fluorenyl group optionally substituted with one, two or three RA groups. One embodiment (5): In another embodiment, the compound of formula (1) is 146258.doc -12. 201040149 wherein A is a phenyl group optionally substituted with one, two or three rA groups; Other groups are as defined in any of the embodiments (〖)_(4). In the subembodiment (5-a), a is a phenyl group substituted with two RA groups bonded to an adjacent carbon atom, and the two dentate groups form - 〇-(G) Y-0-; wherein each (10) is _CH2_, _c(h)(f)_ or -CF2-' and is 1, 2, or 3; for example, such as A is 2,3_dihydro-1 , 4-benzodioxan-6-yl or 2,2-difluoro-indole, 3-benzoxazole-5-yl. Embodiment (6): In another embodiment, the compound of formula (1) is hydrazine wherein when RA is present, each RA is independently rA2, CVC6 alkyl, CVC4 haloalkyl, aryl, aryl (Ci_C4) alkane a group, or _C1_C6 alkyl-RA2, wherein the aryl (Cl_C4) alkyl group is optionally substituted by one, two or three RA2 groups, wherein each RA2 is independently a pectin, a cyano group , nitro, -ORA1, -SRA1, -N(RA1)2, _s(〇)rAI, -s(〇)2RA1 . -S(0)N(RA1)2 > -S(〇)2N( RA1)2 . -C(〇)〇Rai . -C(0)N(RA1)2 . -N(RA1)C(0)RA1 . -N(RA1)C(〇)〇RAi , Q _N(RA1 C(〇)N(rA1)2, -N(RA1)S(0)2RA1, -N(RA1)C(=NRA1)N(RA1)2, -P(〇K〇Ra1)2 or -〇 P(〇)(〇rA1)2, wherein each rai is independently hydrogen, CrC4 alkyl or c^C:4 haloalkyl, or two RAs attached to adjacent carbon atoms form a _0_(G Y_0_, wherein each G is independently _Ch2_, -C(H)(F)- or -CF2·, and is less than 1, 2 or 3; and all other groups are as in embodiments (1)-(5 As defined in any of the embodiments. In the sub-embodiment (6-a), the compound of the formula (1) is wherein, when ra is present, each RA is independently halogen, cyano, Cl_C4 alkyl, Ci_C4 haloalkyl, strepyl, benzyl, - ORa丨, -N(RA1)2 or -C(0)RA丨, each of which is 146258.doc -13- 201040149 is a hydrogen, Qc:4 alkyl or Cl_C4 haloalkyl group; or with adjacent carbon atoms The two connected RAs form _〇_(G)y_〇_; where each G is independently -CH2·, -CmOF)- or -Civ, and less is 2 or 3; and all other bases The group is as defined in any one of embodiments (1) to (5). Embodiment (7) ♦ In another embodiment, the compound of formula (1) is wherein R20 is -RB2, hydrogen, C-a, alkyl, Cl-C4 haloalkyl, C3_C8 cycloalkyl, aryl (C丨-C4) An alkyl group or _C]_C4 alkyl group _RB2, wherein each ^2 is independently cyano, nitro, -〇RB3, _SRB3, _n(rB3)2, (1)>rB3, -s(〇)RB3. -S(0)2rB3 . -S(〇)N(RB3)2 . -s(〇)2N(RB3)2 . _c(o)orB3, -c(o)n(rB3)2, _N(RB3) c(〇)rB3, n(rB3)c(〇)〇rB3, wherein each RB3 is independently hydrogen, CVC4 alkyl, Cl_C4 haloalkyl, aryl or aryl (C1_C4) alkyl, or both RB3 together with the nitrogen atom to which they are attached form a saturated or unsaturated monocyclic heterocyclic or heteroaryl group wherein each of said heterocyclyl and heteroaryl is optionally independently (Ci_C3) Alkyla, halogen or one, two or three groups of a C丨-C4 haloalkyl group; and when R1 is present, each Rh is independently halo or _R2〇; and all other groups are as in the embodiment (1) _(6) is defined in any one of the embodiments. In sub-embodiment (7-a), the compound of formula (1) is wherein the caliper is hydrogen, orB3, -N(RB3)2, Cl_c4 alkyl, Ci-C4 haloalkyl, cycloalkyl, aryl (C丨-C4) or the -C丨-C4 system-RB2; wherein rB2 is _〇rB3 or -N(RB3)2; and when R" is present, each ru is independently dentate or - R20; and all other groups are as defined in the embodiment (1)-(6) - 146258.doc 14- 201040149. In the sub-embodiment (7-b), formula (I) The compound is wherein R 〇 is hydrogen, C1-C4 alkyl, -ORB3 or -N(RB3)2, wherein each RB3 is independently a gas, a C-C4 alkyl group, a Cl-C4_alkylene group, an aryl group. Or an aryl (C!-C4) alkyl group, and when rS1 is present, each rZ1 is independently halogen or -R, and all other groups are as in any of embodiments (1)-(6) Defined.

實施方案(8):在另一個實施方案中，式⑴的化合物為 其中R疋.（1)-N(R10)(R"),其中Rio是氫或_C1_C4烷基； 並且 R 疋 _Rl3、-C3-c6 環烷基-N(R12)2、-C3-C6 環烷 基/ 、_Cl-C6烧基-N(Rl2)2或-Cj-Q烷基-R13，其中每個 R獨立地為氫或Cl_C4烷基；並且R13是（a) 4-10元單環、 4-IOtl稠合雙核、5_1()元橋連雙環或卜⑺元螺雙環雜環基 環，其中所述雜環基環包含一個、兩個或三個環氮原子並 且任選地包含一個環氧或環硫原子，或者（b) 5或6元單環 雜芳基或8_心稠合雙環雜芳基，其巾所述雜芳基環包j 一個、兩個或三個環氮原子並且任選地包含一個環氧或環 硫原子’ |中所述雜環基和雜芳基各自任選地由一個、兩 個或三個R13^®取代；或者r>(h)式⑷的部分Embodiment (8): In another embodiment, the compound of formula (1) is wherein R疋.(1)-N(R10)(R"), wherein Rio is hydrogen or _C1_C4 alkyl; and R 疋_Rl3 , -C3-c6 cycloalkyl-N(R12)2, -C3-C6 cycloalkyl/, _Cl-C6 alkyl-N(Rl2)2 or -Cj-Qalkyl-R13, wherein each R is independent Is hydrogen or Cl_C4 alkyl; and R13 is (a) 4-10 membered monocyclic, 4-IOtl fused dinuclear, 5_1()-membered bridged bicyclic or bis(7)-membered spiro bicyclic heterocyclyl ring, wherein said hetero The ring-based ring contains one, two or three ring nitrogen atoms and optionally contains an epoxy or ring sulfur atom, or (b) a 5 or 6 membered monocyclic heteroaryl group or an 8-core fused bicyclic heteroaryl group. , wherein the heteroaryl ring comprises one, two or three ring nitrogen atoms and optionally an epoxy or ring sulfur atom, wherein the heterocyclic group and the heteroaryl group are each optionally One, two or three R13^® substitutions; or r>(h) part of equation (4)

(a); 並且所有其他基團如貫施方案⑴-⑺中任一個實施方案中 所定義的。在亞實施方案㈣中，式⑴的化合物為其中^ 是：（i)-N(Rl〇)(RU)，其中R10是氫或々㈣基，並且R" 146258.doc 201040149 是-Ri3、-c3-c6環烷基-N(R32、-CVC6環烷基_r13、_Ci-c6 貌基-N(R%或_Cl_C6烧基_Ru ’其中每個r12獨立地為氮 或CVCj基；並且…是㈣元單環、5元橋連雙環或 5-H)元螺雙環雜環基環，其中所述雜環基環包含__個、兩 個或三個環氮原子並且任選地包含—個環氧或環硫原子， 其中所述雜環基任選地由-個、兩個或三個r13a基團取 代，其中每個R-基團獨立地為幽素、CA烧基、Μ i代烷基、芳基（Cl-C4)烷基、_〇RBl、或_n(rB1)2,其中每 個RB1獨立地為氫、C1 -Cj惊其、r p上 風丨U烷基Ci-C4鹵代烷基、芳基或芳 基（C】-C4)烷基；或者Ri是（ii)式（a)的部分(a); and all other groups are as defined in any of the embodiments (1)-(7). In sub-embodiment (IV), the compound of formula (1) is wherein (i)-N(Rl) (RU), wherein R10 is hydrogen or deuterium (tetra), and R"146258.doc 201040149 is -Ri3,- C3-c6 cycloalkyl-N (R32, -CVC6 cycloalkyl-r13, _Ci-c6 pheno-N (R% or _Cl_C6 alkyl _Ru' wherein each r12 is independently nitrogen or CVCj; Is a (tetra)membered monocyclic, 5-membered bridged bicyclic or 5-H) snail bicyclic heterocyclyl ring, wherein the heterocyclyl ring contains __, two or three ring nitrogen atoms and optionally comprises An epoxy or epicyclic sulfur atom, wherein said heterocyclic group is optionally substituted by one, two or three r13a groups, wherein each R-group is independently spectrin, CA alkyl, hydrazine I-alkyl, aryl (Cl-C4) alkyl, 〇 RB1, or _n(rB1) 2, wherein each RB1 is independently hydrogen, C1 - Cj, rp, 丨 U alkyl Ci -C4 haloalkyl, aryl or aryl (C)-C4)alkyl; or Ri is part of (ii) formula (a)

(R2\ (a); 氯、-〇RB3、-n(rB3)^_m 基、c 代烧基、 心〇8我基、芳基（Cl_c狀基或_Ci_C4mB2;其中 RB2 是-ORB3 或-N(RB3)2 ;並且 r21 a I且R疋Cl_C4烷基或Ci_C4鹵代 烧基；並且所有其他基團如實 貫轭方案〇)·(7)中任一個實施 方案中所疋義的。在亞實祐古安^、丄 隹让霣轭方案(“)中，式(I)的化合物為 亞實施方案（8)的式⑴的化八你 ..θ 、σ物，其中州是〇、1或2 ;並且 所有其他基團如實施方案⑴·⑺中任一個實施方案中所定 義的。在亞實施方案(“)中’式⑴的化合物為亞實施方案 (8-a)的式（I)的化合物，其 关肀冰疋〇、1或2;並且所有其他 基團如實施方案（丨卜门）中权 、 杀⑴⑺中任一個實施方案中所定義的。 實施方案（9) ··在另—伽香 個實施方案中，式⑴的化合物為 146258.doc * 16 - 201040149 其中R1是： 其中Rl〇是氫或 甲基，或者R1是 (i)-N(R10)(Ru)， (Π)式⑷的部分(R2\ (a); Chlorine, -〇RB3, -n(rB3)^_m, c-alkyl, 〇8, aryl (Cl_c-like or _Ci_C4mB2; where RB2 is -ORB3 or - N(RB3)2; and r21 a I and R疋Cl_C4 alkyl or Ci_C4 haloalkyl; and all other groups are as defined in any of the embodiments of the real conjugate scheme 〇) (7). Ya Shiyou Gu'an ^, 丄隹 霣 霣 霣 方案 ( ( ( ( ( ( ( ( ( ( ( 霣 霣 霣 霣 霣 霣 霣 霣 霣 霣 霣 霣 霣 霣 霣 霣 霣 霣 霣 霣 霣 化合物 化合物 化合物 化合物 化合物 化合物 、 、 、 、 、 1 or 2; and all other groups are as defined in any one of embodiments (1) to (7). In the sub-embodiment ("), the compound of formula (1) is a formula of sub-embodiment (8-a) ( a compound of I) which is related to hail, 1 or 2; and all other groups are as defined in any one of the embodiments (abbreviation), killing (1) (7). Embodiment (9) ·· In another embodiment, the compound of formula (1) is 146258.doc * 16 - 201040149 wherein R1 is: wherein R1〇 is hydrogen or methyl, or R1 is (i)-N(R10)(Ru), ( Π) part of formula (4)

R2〇 其中所述式（a)的部分中 _ M ^ m 长^疋5-10兀橋連雙環或5-10 几螺雙雜％基環，盆中 ^R2〇 wherein the moiety of the formula (a) is _M^m long^疋5-10兀 bridged bicyclic or 5-10 snail double heterozygous cyclyl, in the pot ^

〇 ί52 ϋ ^ « 、 處雜％基環任選地包含一個 衣氧或環硫原子，以及任搜& 以及任選地—個、兩個 環氮原子·，或者 /㈣^卜的 所述式（a)的部分是〇ί52 ϋ ^ « , the heterozygous base ring optionally comprises an oxygen or ring sulfur atom, and any of the search & and optionally one, two ring nitrogen atoms, or / (four) Part of formula (a) is

(β\ Ψ 荦2二3 ’並且、1、2或3;並且所有其他基團 貫包方案（1)_(8)中任—個實施方案中所定義的。 另一個實施方案中，式⑴的化合物為 八中R疋-N(R )(Ru)或式⑷的部分(β\ Ψ 二 2 2 3 ' and 1, 2 or 3; and all other groups are defined in any of the embodiments (1) to (8). In another embodiment, The compound of (1) is an octagonal R疋-N(R)(Ru) or a part of the formula (4)

其中 (二)所述式⑷的部分中的環B是5·1〇元橋連雙環雜環臭 環，其中所述雜環基環任選地包含—個環氧或環硫= 146258.doc -17- 201040149 以及任選地一個、兩個或三個另外的環氮原子’其中 R20是氫、-ORB3、-n(rB3)2、cvc4焼•基、c!-c4 自代烷 基、C3-C8環烷基、芳基（Ci-Cd烷基或-C「C4烧基-rB2 ; 其中RB2是-ORB3或-N(RB3)2，並且R21是C1-C4烷基或 CJ-C4鹵代烷基； (R21)w (b)所述式（a)的部分是 ，其中ί是1、2或3，R20 是氫、CVC4烷基、（VC4鹵代烷基、C3-C8環烷基、芳基 (CVCO烷基或-C丨-C4烷基-RB2，其中RB2是-〇rB3 或-n(rB3)2，並且r2>Ci_c4烷基或Cl_c4由代烷基；或者Wherein the ring B in the moiety of the formula (4) is a 5·1〇 bridged bicyclic heterocyclic ring, wherein the heterocyclic ring optionally contains an epoxy or an epoxide = 146258.doc -17- 201040149 and optionally one, two or three additional ring nitrogen atoms 'wherein R20 is hydrogen, -ORB3, -n(rB3)2, cvc4焼•yl, c!-c4 self-substituted alkyl, C3-C8 cycloalkyl, aryl (Ci-Cd alkyl or -C "C4 alkyl-rB2; wherein RB2 is -ORB3 or -N(RB3)2, and R21 is C1-C4 alkyl or CJ-C4 Haloalkyl; (R21)w (b) The moiety of formula (a) is wherein ί is 1, 2 or 3, R20 is hydrogen, CVC4 alkyl, (VC4 haloalkyl, C3-C8 cycloalkyl, aryl a group (CVCO alkyl or -C丨-C4 alkyl-RB2, wherein RB2 is -〇rB3 or -n(rB3)2, and r2>Ci_c4 alkyl or Cl_c4 is alkyl; or

(c)所述式（a)的部分是 r ，其中r是〇、1、2或3, R20是-n(rB3)24-Ci-c4烧基-n(rB3)2 ;並且R2丨是Ci_C4^ 基或C1-C4鹵代烧基； 並且所有其他基團如實施方案（1)_(9)中任一個實施方案 中所定義的。 ^ 實施方案（η):在另-個實施方案中，式⑴的化 其中R1是-N(R10)(Rn)或式⑷的部分 兩(c) the moiety of the formula (a) is r, wherein r is 〇, 1, 2 or 3, R20 is -n(rB3)24-Ci-c4 alkyl-n(rB3)2; and R2丨 is Ci_C4^ or C1-C4 haloalkyl; and all other groups are as defined in any one of embodiments (1) to (9). ^ Embodiment (η): In another embodiment, the formula (1) wherein R1 is -N(R10)(Rn) or a moiety of formula (4)

(a)， 其中環B是5-10元橋連雙環雜環基環；並且 " R 、R以及所有其他基團如實施方案（ ^ 施方案中所定義的。在亞實施（）中任一個實 4 案 Ul-a)中，R1 146258.doc -18- 201040149 是-寧1。，）或式⑷的部分，其中環8是8_氮雜雙環 [3.2J]辛基、3,8•二氮雜雙環[3 2辛基、以·二氮雜雙環 [2.2.1]庚基或1_氮雜雙環[2 2 2]辛基，並且^(a), wherein ring B is a 5-10 membered bridged bicyclic heterocyclyl ring; and " R , R and all other groups are as defined in the embodiment (wherein the sub-implementation) In a real case of Ul-a), R1 146258.doc -18- 201040149 is -Ning 1. , or a moiety of formula (4), wherein ring 8 is 8-azabicyclo[3.2J]octyl, 3,8-diazabicyclo[3 2 octyl, diazabicyclo[2.2.1]g Or 1_azabicyclo[2 2 2]octyl, and ^

w ' R R21以及所有其他基團如實施方案（1)_(i〇)中任— 個實施方案中所定義的。 (R21)w 實施方案（12广在另一個實施方案中，式⑴的化合物為 其中％产，或式⑷的部分，其中所柳^ ❹ 刀疋 t R ，其中ί是1、2或3;並且Rio、Rll、r20、 R21、w以及所有其他基團如實施方案（ι)_(ι〇)中任一個實 施方案中所定義的。在亞實施方案〇2…中^ 是-N(R10)(Rh)或式⑷的部分，其中_是口瓜嗓小基或^· 二氮雜環庚烷-1-基；並且R1G、R"、R2G 21 八、R 、冰以及所有 其他基團如實施方案⑴-⑽中任—個實施方案中所定義 的。在亞實施方案（12_b)中，R4_n(r10)(r11)或^甲基呢 嗓-1-基、3-甲基狐m、4-曱基十4_二氮雜環庚 基、基、4-(1-甲基乙基P瓜嗪小基、4_(2_氣乙基） 呱嗪-1-基或4-乙基呱嗪小基；並且Ri〇、rU以及所有其二 基團如實施方案（1)-(9)中任一個實施方案中所定義的。 實施方案（13):在另一個實施方案中，式⑴的化合物為 其中R1是^(尺10)^11)或式（a)的部分，w ' R R21 and all other groups are as defined in any of the embodiments (1) - (i). (R21)w Embodiment (12) In another embodiment, the compound of formula (1) is a part thereof, or a part of formula (4), wherein 柳 ^ knife 疋t R , where ί is 1, 2 or 3; And Rio, R11, r20, R21, w and all other groups are as defined in any one of the embodiments (I)_(ι〇). In the sub-embodiment 〇2..., ^ is -N(R10) (Rh) or a moiety of formula (4), wherein _ is a guanoin or a diazepan-1-yl; and R1G, R", R2G 21 VIII, R, ice, and all other groups As defined in any of the embodiments (1) to (10), in the subembodiment (12-b), R4_n(r10)(r11) or ^methylthene-1-yl, 3-methyl fox m , 4-mercapto-deca-4-diazepanyl, phenyl, 4-(1-methylethyl-P-Palaline), 4-(2-hydroxyethyl)pyridazin-1-yl or 4-B a pyridazine small group; and Ri 〇, rU and all its two groups are as defined in any one of embodiments (1) to (9). Embodiment (13): In another embodiment, The compound of the formula (1) is a moiety wherein R1 is ^(foot 10)^11) or formula (a),

(R21)w (a), 146258.doc -19· 201040149 (R厂)w 其中所〇述式⑷的部分是知?"其中…、卜…； :且R、R 1、r2。、r2、从以及所有其他基團如實施方案 ⑴-⑽）中任-個實施方案中所定義的。在亞實施方案 (13-a)中，Rj_N(Rl〇)(Rll)或式⑷的部分，其中環 < 元_ _基、吡咯啶-1-基或呱啶-卜基並且R1G、Rll R20、R21 Λ ' 一 、W以及所有其他基團如實施方案（1Η10)中任一 只施方案中所定義的。在亞實施方案（13-b)中，R! 疋N(R )(r )或3_(二甲基胺基）氮雜環丁炫小基、3_(二甲 基胺基）°比哈唆小基、3-胺基氮雜環丁烧-1-基、3-胺基吡 咯啶-1-基、4-胺基冬曱基狐啶小基、3_胺基狐咬卜基' 4胺基呱。疋小基、3_(甲基胺基）π比咯啶小基、心（甲基胺 基）°瓜、疋1-基、（1_甲基乙基）胺基·呢啶基或4_羥基呱啶小 土並且R 、R以及所有其他基團如實施方案（丨）_(9)中 任一個實施方案中所定義的。 實施方案(14).在另一個實施方案中’式⑴的化合物為 -中 L疋[C(R )2]p_L _[c(RL)2]q_，其中、2 或 3，分是 k自0至（3-p)的整數，Li是鍵或_〇_ ;並且每個#獨立地為 H、甲基或i曱基；並且所有其他基團如實施方案⑴-⑽ 中任-個實施方案中所定義的。在亞實施方案〇“)中，式 ⑴的化合物為其中L是_[C(RL)2]P-Li_[C(RL)2]q_，其中厂是i 或^是選自⑻…的整數：广是鍵或办丨並且每個# 獨立地為氫或甲基；並且所有其他基團如實施方案 (1)-(13)中任一個實施方案中所定義的。 146258.doc •20· 201040149 實施方案（15):在另一個實施方案中，式⑴的化合物為 ΐβ +(^2。 其中R1是式⑷的部分’⑷；並且環b、 R20、R21、州以及所有其他基團如實施方案（1)_(14)中任— 個實施方案中所定義的。 實施方案⑽：在另一個實施方案中，式⑴的化合物為 其中R1是-N(R10)(rii)或式（a)的部分，其中Rll*Rn，其中 Ο ❹ R13是4-1G元單環雜環基環，其巾所述雜環基環包含一個、 兩個或三個環氮料並絲選地包含—個環氧或環硫原 子，其中所述雜環基環任選地由一個、兩個或三個心八基 團取代；並且所有其他基團如實施方案⑴例中任一二 實施方案中所定義的。在亞實施方案〇“)中，式⑴的化 =物為其中Ri是-N(Rl〇)(Rn)或式⑷的部分’其中rU是 R，其中R13是氮雜環丁烷基、吡咯啶基或呱啶基，其中 所述氮雜環丁烧基"叫咬基和㈣基任選地由_個、、兩 個或三個汉-基團取代；並且所有其他基團如實施方案 (1)-(14)中任一個實施方案中所定義的。 實施方案（17):在另一個實施方案中，式⑴的化合物為 其3中R1是或式⑷的部分，其中Rll*Rn，其中 R13是5-H)元橋連雙環雜環基環，其巾所述雜環基環包^ 一 2兩個或三個環氮原子並且任選地包含_個環氧或環硫 '、，其中所述雜環基環任選地由—個、兩個或三個rUa 基團取代；並且所有其他基團如實施方案⑴·⑽中任— 個實施方案中所定義的。在亞實施方案(17⑷中 146258.doc •21 - 201040149 化合物為其中或式（a)的部分，其中Rn* R ，其中R13是8-氮雜雙環[3.2.1]辛_3-基、8-氮雜雙環 [3.2.1]辛-8-基、1_氮雜雙環[2 2 2]辛_3_基、1_氮雜雙環 [2_2.2]辛-4-基、3,8_二氮雜雙環[3.21]辛_3_基或2,5_二氮 雜雙環[2.2.1]庚-2-基，其中8_氮雜雙環[32 1；(辛_3_基、 氮雜雙ί衣[3.2.1]辛-8-基、1-氮雜雙環[2.2_2]辛-3-基、1_氮 雜雙環[2.2.2]辛-4-基、3,8-二氮雜雙環[3.2.1]辛_3_基和 2,5_二氮雜雙環[2.2.1]庚-2-基任選地由一個、兩個或三個 r13A基團取代；並且所有其他基團如實施方案（1)_(14)中任 一個實施方案中所定義的。 實施方案（18):在另一個實施方案中，式⑴的化合物為 其中當R13A存在時，每個ri3A獨立地為齒素、氰基、硝 基、Q-C4烷基、Cl_C4_代烷基、芳基（Ci_C4)烷基、_〇rB1、 SR _N(R )2、_c(〇)rB1、-S(0)RB1、-S(〇)2RB1、_s(〇)N(RB1)2、 -S(0)2N(R )2、-c(〇)〇RB1、_c(0)n(rbi)2、_n(rB1)c(〇)rB1、 、_n(rB1)c(〇)n(rBi)^_n(rB1)s(〇)2rBi， 其中每個rb1獨立地為氫' Cl_C4烧基、Ci_c^代烧基、芳 基或芳基(C丨-c4)烷基；i且所有其他基團如實施方案 ⑴-⑽和⑼中任—個實施方案中所定義的。在亞 實施方案（18-a)中，式⑴的化合物為其中當^存在時， 每個R13A獨立地為鹵素、Ci_C4烷基、㈣函代烷基、芳 基（Cl-C4)烧基、_orB1、hn(rB1)2，其中每個rB1 獨 立地為氫、CVC：4院基、Cl-C4鹵代烷基、芳基或芳基 (C! C4)烧基’並且所有其他基團如實施方案⑴-(H)、（丄6: 146258.doc •22- 201040149 和（17)中任一個實施方案中所定義的。 實施方案(19):在另一個實施方案中，式⑴的化合物為 其中R1是娜1。)^)或式⑷的部分，其中Rlj_Ci_C6烧 基-N(R，2或_C3_C6環烷基_N(Rl2)2 ;並且所有其他基團如 實施方案(1)-(14)中任一個實施方案中所定義#。在亞實 施方案（19-a)中，式（I)的化合物為其中或 式（a)的部分，其中！^是-Cl-C3烷基_N(Rl2)2或_C3_C6環烷 基-N(Rl2)2;每個R12獨立地為氫或-C]-C3烷基；並且所有 ° 其他基團如實施方案0)-(14)中任一個實施方案中所定義 的。在亞實施方案（19-b)中，式⑴的化合物為其中… 疋-N(R 0)(Rn)或式（a)的部分，其中Rll是2_胺基乙基、 (曱基胺基）乙基、2-(二甲基胺基）乙基、2_ (二甲基胺基）_^ 甲基乙基、2-(乙基胺基）乙基、2-(二乙基胺基）乙基、2_ (二乙基胺基）-1-甲基乙基、3-胺基丙基、3_(曱基胺基）丙 基、3-(二甲基胺基）丙基、3-(乙基胺基）丙基、3_(二乙基 ◎ 胺基）丙基、2-胺基-2-甲基丙基、3-(二曱基胺基）_2 2_二甲 基丙基、3-(二乙基胺基）-2,2-二甲基丙基、2_胺基環己 基、3 -胺基琢己基或4-胺基環己基；並且所有其他基團如 實施方案（1)-(14)中任一個實施方案中所定義的。 實施方案（20):在另一個實施方案中，式⑴的化合物為 其中R1是-NCR^XR11);並且R10、R】i以及所有其他基團如 實施方案（1)-(6)、（9)、（14)和（16)-(19)中任一個實施方案 中所定義的。 實施方案（21):在另一個實施方案中，式⑴的化合物為 146258.doc •23- 201040149 其中每個R3獨立地為鹵素、氰基、硝基、C丨-C4烷基、（：丨-(：4 鹵代烷基、（：3-(：6環烷基、-0RC1、-N(RC1)2、-C(0)RC1、 -S(0)RC1、-S(0)2RC1、-S(0)N(RC1)2、-S(0)2N(RC1)2、-C(0)0Rcl、 -C(0)N(RC1)2、-N(Rcl)C(0)Rcl、-N(Rcl)C(0)0Rcl、 ，其中每個 RC1 獨立 地為氫、CVC4烷基、CVC4鹵代烷基、芳基或芳基（cvq) 烧基；或者兩個R3與它們與之連接的環原子一起形成芳 基、雜芳基、單環環烷基或雜環基，所述芳基、雜芳基、 單環環烧基或雜環基各自任選地由各自獨立地為（Ci_c3)烷 0 基、鹵素或匚！-^鹵代烧基的一個、兩個或三個基團取 代；並且所有其他基團如實施方案（1)_(20)中任一個實施 方案中所定義的。在亞實施方案（2丨_a)中，式⑴的化合物 為其中每個R3是鹵素、Ci_C4烷基、Cl_c4鹵代烷基 或-〇Rci ’其中每個Rc】獨立地為氫、Ci_C4烷基或Ci_C4由 代烷基；並且所有其他基團如實施方案（1)_(2〇)中任一個 實施方案中所定義的。在亞實施方案（21_b)中式⑴的化 合物為其中m是i、2或3 ;並且R3是齒素、Ci_C4烷基、〇 CVC4齒代烷基或_0Rci，其中每個RC1獨立地為氫、 烷基或CVQ幽代烷基；並且所有其他基團如實施方案 (1)-(20)中任一個實施方案中所定義的。 實施方案(22):在另—個實施方案中，式⑴的化合物為 其中你是零或i，並且r21，當存在時，是Μ烧基或Μ 函代烧基；並且所有直仙其 v、他基團如實允方案（1)-(15)和（21)中 任一個實施方案中所定義的。 146258.doc -24- 201040149 實施方案（23):在另一個實施方案中，式⑴的化合物為 其中 L疋-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH(CH3)-、 -CHrO-、-CH2CH2-0-或-CHrO-CH2·;並且所有其他基團 如實施方案（1)-(22)中任一個實施方案中所定義的。 實施方案（24):在另一個實施方案中，式⑴的化合物為 其中LSCrC3亞烷基；並且所有其他基團如實施方案 (1)-(23)中任一個實施方案中所定義的。 Ο ❹ 實施方案（25):^在η另;個實施方案中，式⑴的化合物為 式（la)的化合物〆δ η π 士斗 (la)，亚且所有其他基團 如實施方案（1)-(24)中任一個實施方案中所定義的。 實施方案(26匕在另：個實施方案中’式⑴的化合物為(R21)w (a), 146258.doc -19· 201040149 (R factory)w The part of the formula (4) is described as "(), ..., and ..., and R, R1, r2. , r2, from, and all other groups as defined in any one of embodiments (1)-(10)). In sub-embodiment (13-a), Rj_N(Rl〇)(Rll) or a moiety of formula (4), wherein ring < _ _ yl, pyrrolidin-1-yl or acridine-buyl and R1G, Rll R20, R21 Λ 'I, W and all other groups are as defined in any of the embodiments (1Η10). In sub-embodiment (13-b), R! 疋N(R)(r) or 3-(dimethylamino)azetidinyl, 3-(dimethylamino)°H. Small group, 3-aminoazetidin-1-yl, 3-aminopyrrolidin-1-yl, 4-aminoindoleyl sulfainyl group, 3-amino-based fox base Amine oxime. Indole small group, 3_(methylamino)π-pyrrolidinyl group, heart (methylamino) ° melon, 疋1-yl, (1-methylethyl)amino-n-pyridyl or 4_ Hydroxyacridine small earth and R, R and all other groups are as defined in any of the embodiments (丨)_(9). Embodiment (14). In another embodiment, the compound of formula (1) is - in the group L疋[C(R)2]p_L_[c(RL)2]q_, wherein 2 or 3, the fraction is k from An integer from 0 to (3-p), Li is a bond or _〇_; and each # is independently H, methyl or i曱; and all other groups are implemented as in embodiments (1)-(10) As defined in the program. In the sub-embodiment 〇"), the compound of the formula (1) is wherein L is _[C(RL)2]P-Li_[C(RL)2]q_, wherein the plant is i or ^ is an integer selected from (8)... : 广是键或丨 and each # is independently hydrogen or methyl; and all other groups are as defined in any of embodiments (1)-(13). 146258.doc •20· 201040149 Embodiment (15): In another embodiment, the compound of formula (1) is ΐβ + (^2. wherein R1 is a moiety of formula (4) '(4); and ring b, R20, R21, state, and all other groups are as Embodiment (1)-(14) is defined in any one embodiment. Embodiment (10): In another embodiment, the compound of formula (1) is wherein R1 is -N(R10)(rii) or formula ( a moiety of a), wherein R11*Rn, wherein Ο ❹ R13 is a 4-1G-membered monocyclic heterocyclyl ring, the heterocyclyl ring comprising one, two or three ring nitrogen materials and optionally comprising An epoxy or epicyclic sulfur atom, wherein the heterocyclyl ring is optionally substituted by one, two or three octagonal groups; and all other groups are as in any of the embodiments (1) Defined. In the sub-embodiment 〇"), the chemical of formula (1) is where R is -N(Rl) (Rn) or the moiety of formula (4) wherein rU is R, wherein R13 is azetidin An alkyl, pyrrolidinyl or acridinyl group, wherein said azetidinyl group is called a thiol group and a (tetra) group, optionally substituted by _, two or three han-groups; and all others The group is as defined in any one of embodiments (1) to (14). Embodiment (17): In another embodiment, the compound of formula (1) is a moiety wherein R1 is or a formula (4), wherein R11*Rn, wherein R13 is a 5-H)-membered bridged bicyclic heterocyclyl ring, The heterocyclyl ring of the towel comprises one or two or three ring nitrogen atoms and optionally contains an epoxy or an episulfide ring, wherein the heterocyclyl ring is optionally one or two One or three rUa groups are substituted; and all other groups are as defined in any of the embodiments (1).(10). In the sub-embodiment (17(4) 146258.doc •21 - 201040149 the compound is part of or the formula (a), wherein Rn* R , wherein R13 is 8-azabicyclo[3.2.1]oct-3-yl, 8 -azabicyclo[3.2.1]oct-8-yl, 1-azabicyclo[2 2 2]oct-3-yl, 1-azabicyclo[2-2.2]oct-4-yl, 3,8 _Diazabicyclo[3.21]oct-3-yl or 2,5-diazabicyclo[2.2.1]hept-2-yl, wherein 8-azabicyclo[32 1;(xin_3_yl, Aza-bi-[3.2.1]oct-8-yl, 1-azabicyclo[2.2_2]oct-3-yl, 1-azabicyclo[2.2.2]oct-4-yl, 3,8 - diazabicyclo[3.2.1]oct-3-yl and 2,5-diazabicyclo[2.2.1]hept-2-yl are optionally substituted by one, two or three r13A groups; And all other groups are as defined in any one of embodiments (1) to (14). Embodiment (18): In another embodiment, the compound of formula (1) is wherein, when R13A is present, each ri3A is independently dentate, cyano, nitro, Q-C4 alkyl, Cl_C4_alkyl, aryl (Ci_C4) alkyl, _〇rB1, SR _N(R)2, _c(〇)rB1 , -S(0)RB1, -S(〇)2RB1, _s(〇)N(RB1)2, -S(0)2N(R)2, -c( 〇 RB1, _c(0)n(rbi)2, _n(rB1)c(〇)rB1, _n(rB1)c(〇)n(rBi)^_n(rB1)s(〇)2rBi, where each Rb1 is independently hydrogen 'Cl_C4 alkyl, Ci_c^alkyl, aryl or aryl (C丨-c4) alkyl; i and all other groups are as described in embodiments (1)-(10) and (9) Defined in the scheme. In the sub-embodiment (18-a), the compound of the formula (1) is wherein, when present, each R13A is independently halogen, Ci_C4 alkyl, (tetra)-functional alkyl, aryl (Cl) -C4) alkyl, _orB1, hn(rB1)2, wherein each rB1 is independently hydrogen, CVC: 4 fen, Cl-C4 haloalkyl, aryl or aryl (C! C4) alkyl and all Other groups are as defined in any one of embodiments (1)-(H), (丄6: 146258.doc • 22-201040149 and (17). Embodiment (19): In another embodiment, The compound of the formula (1) is a moiety wherein R1 is Na..) or a formula (4), wherein Rlj_Ci_C6 alkyl-N(R, 2 or _C3_C6 cycloalkyl-N(Rl2)2; and all other groups are as # defined in any one of the schemes (1) to (14). In the sub-implementation scheme (19-a), the compound of the formula (I) is a part of or a formula (a), wherein! ^ is -Cl-C3 alkyl-N(Rl2)2 or _C3_C6 cycloalkyl-N(Rl2)2; each R12 is independently hydrogen or -C]-C3 alkyl; and all other groups such as The embodiments 0)-(14) are as defined in any one of the embodiments. In sub-embodiment (19-b), the compound of formula (1) is wherein 疋-N(R 0)(Rn) or a moiety of formula (a), wherein R11 is 2-aminoethyl, (decylamine) Ethyl, 2-(dimethylamino)ethyl, 2-(dimethylamino)-methylethyl, 2-(ethylamino)ethyl, 2-(diethylamine Ethyl, 2-(diethylamino)-1-methylethyl, 3-aminopropyl, 3-(decylamino)propyl, 3-(dimethylamino)propyl, 3-(ethylamino)propyl, 3-(diethyl-2-amino)propyl, 2-amino-2-methylpropyl, 3-(didecylamino)_2 2-dimethyl Propyl, 3-(diethylamino)-2,2-dimethylpropyl, 2-aminocyclohexyl, 3-aminohexyl or 4-aminocyclohexyl; and all other groups such as Defined in any one of embodiments (1)-(14). Embodiment (20): In another embodiment, the compound of formula (1) is wherein R1 is -NCR^XR11); and R10, R]i and all other groups are as in embodiments (1)-(6), 9), (14) and (16)-(19) are defined in any one of the embodiments. Embodiment (21): In another embodiment, the compound of formula (1) is 146258.doc • 23- 201040149 wherein each R3 is independently halogen, cyano, nitro, C丨-C4 alkyl, (:丨-(: 4 haloalkyl, (: 3-(: 6 cycloalkyl, -0RC1, -N(RC1)2, -C(0)RC1, -S(0)RC1, -S(0)2RC1, - S(0)N(RC1)2, -S(0)2N(RC1)2, -C(0)0Rcl, -C(0)N(RC1)2, -N(Rcl)C(0)Rcl, -N(Rcl)C(0)0Rcl, wherein each RC1 is independently hydrogen, CVC4 alkyl, CVC4 haloalkyl, aryl or aryl (cvq) alkyl; or two R3 are attached to them The ring atoms together form an aryl group, a heteroaryl group, a monocyclic cycloalkyl group or a heterocyclic group, each of which is optionally independently (Ci_c3) Alkyla, halogen or one, two or three groups of a halogenated group; and all other groups are as defined in any one of embodiments (1) to (20) In the sub-embodiment (2丨_a), the compound of formula (1) is wherein each R3 is halogen, Ci_C4 alkyl, Cl_c4 haloalkyl or -〇Rci' each Rc] independently of hydrogen, Ci_C4 alkyl or Ci_C4 by alkyl; and all other groups are as defined in any of embodiments (1) to (2). In a sub-embodiment (21_b) a compound of formula (1) wherein m is i, 2 or 3; and R3 is dentate, Ci_C4 alkyl, 〇CVC4 dentate alkyl or _0Rci, wherein each RC1 is independently hydrogen, alkyl or CVQ An alkyl group; and all other groups are as defined in any one of embodiments (1) to (20). Embodiment (22): In another embodiment, the compound of formula (1) is where Zero or i, and r21, when present, is an alkyl group or a fluorenyl group; and all of the groups are implemented as any one of the practical schemes (1)-(15) and (21) Defined in the scheme. 146258.doc -24- 201040149 Embodiment (23): In another embodiment, the compound of formula (1) is wherein L疋-CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3 -, -CHrO-, -CH2CH2-0- or -CHrO-CH2.; and all other groups are as defined in any one of embodiments (1) - (22). (24): In another embodiment, the compound of formula (1) is wherein LSCrC3 alkylene; and all other groups are as defined in any one of embodiments (1)-(23). Ο 实施 Embodiment (25): In another embodiment, the compound of formula (1) is a compound of formula (la) 〆δ η π 士 斗 (la), and all other groups are as in the embodiment (1) - (24) as defined in any one of the embodiments. Embodiment (26 in another embodiment) the compound of formula (1) is

(R\ (lb);並且所有其他基團 如實施方案（1)-(24)中任一個實施方案中所定義的。 實施方案（27):在另一個實施方案中，式⑴的化合物為 表1中所列的化合物。(R\(lb); and all other groups are as defined in any one of embodiments (1) to (24). Embodiment (27): In another embodiment, the compound of formula (1) is The compounds listed in Table 1.

式（lb)的化合物a/L 實施方案（28):在另一個實施方案中，式⑴的化合物為 其中A為任選地由一個、兩個或三個rA基團取代的環 烷基；並且所有其他基團如實施方案⑴_(3)和⑹·⑼中= 一個實施方案中所定義的。 實施方案（29):在另一個實施方案中，式⑴的化合物為 其中所是1、2或3 ;並且所有其他基團如實施方案（1)_(28) 中任一個實施方案中所定義的。 146258.doc -25- 201040149 式⑴的化合物為 施方案（1)-(29)中 實施方案（30):在另一個實施方案中， 其中L是-CHa-;並且所有其他基團如實 任一個實施方案中所定義的。 當R1是式（a)的部分時 ,R20 (a) 二1的：義中的環B」是⑴雜環基環，其任選地包含— 個裱氧或環硫原子以及任選地— 、兩個或三個另外的環 =原「子.，^ 元單環㈣基或㈣元稠合雙環雜芳 基環的環原子。因此…二原起形成雜環基或雜芳 .r2〇, ,d2. 田年^疋，例如，呱嗪基時’ R1是 定義二 的呢嗪基環，其中r2°、r21和-如本文所 疋義的。相似地，當環B是任人 斤 子以及任選地一個、 ：3-固環氧或環硫原 單環雜環基環時，另外㈣U子的4-10元 基、呱啶基、嗎啉美π P如’氮雜環丁烷基、吡咯啶 其中所述㈣元嗪基、硫代嗎録以及類似物， R20 . R2w〇 土衣由R和（尺2丨）w取代，其中 R和从如本文所定義的。 實施方案（31):在另— 其中當Ri”… 個實施方案中，式⑴的化合物為 中田R疋式⑷的部分時巧 基，定基、狐嗪基、二氮雜二氮雜％ 丁烧基、坏定 雜雙環[3 2 11辛美 ”衣庚烷基（diazepanyl)、8-氮 .土、K氮雜雙環[2.2.2]辛_3·基、3,8_二氮 146258.doc -26- 201040149 *雙印.2·辟基、2,5二氫雜雙環[2 2庚基、[氮雜雙 = .2.2]辛基、2,6_二氮雜螺[3,3]庚基、认二氮雜螺[4 ” 六土、2’7-一鼠雜螺[44J壬基或u-二氮雜螺[ο】壬基； 並且所有其他基團如實施方案⑴-(19)和叫(3〇)t任一個 •實施方案中所定義的。在亞實施方案⑴增，環叹7_1〇 .^合雙環雜環基環，其在所述雜環基環1M壬選地包含一 個、兩個或三個另外的氮原子；並且所有其他基團如實施 方案⑴侧和叫(30)中任一個實施方案中所定義的。在 亞實施方案⑴4)巾，環B是7_1()元橋連雙環雜環基環其 在所述雜環基環中任選地包含一個或兩個另外的氮原子；、 並且所有其他基團如實施方案⑴-09)和叫(30)中任一個 實施方案中所定義的。在亞實施方案(31-0中，環B是7_1〇 兀螺雙環雜環基環，其在所述雜環基環中任選地包含—個 另外的氮原子；並且所有其他基團如實施方案⑴训和 叫⑽中任一個實施方案中所定義的。在亞實 〇 (31-d)中，環3是5或6元雜芳基；並且所有其他基團如實施 方糾H19)和（21H30)中任一個實施方案中所定義的。在 亞實施方案（31_e)中，環妓8铜合雙環雜芳基；並且 所有其他基團如實施方案（1H19)和叫⑽中任—個實施 方案中所定義的。在亞實施方案（31_f)中，環b是氮雜= 烷基"比洛咬基、料基"瓜嗓基或二氮雜環庚烧基^並 且所有其他基團如實施方案⑴-⑽和（21)-(30)中任 施方案中所定義的。 貫 實施方案（32):在另—個實施方案中，式⑴的化合物為 146258.doc •27· 201040149 其中L是-((：Η2)ρ-ΐΛ((：Η2ν ’其中p是1或2，q是選自〇至 (3-Ρ)的整數；L1是鍵或·〇·;並且所有其他基團如實施方 案（1)-(22)和（24)-(31)中任一個實施方案中所定義的。在亞 實施方案（32-a)中，L是-CH2〇(CH2)q-。在亞實施方案 (32-b)中，L是-CH2-、-CH2CH2-、-CH2CH2CH2- ' _CIl2_〇 、-CH2CH2-0-或-CHfO-CH2·;並且所有其他基團如實施 方案（1)-(22)和（24)-(3 1)中任一個實施方案中所定義的。 實施方案（33):在另一個實施方案中，式⑴的化合物為 其中A是Compound a/L of formula (lb) Embodiment (28): In another embodiment, the compound of formula (1) is a cycloalkyl group wherein A is optionally substituted with one, two or three rA groups; And all other groups are as defined in one embodiment (1) to (3) and (6) (9). Embodiment (29): In another embodiment, the compound of formula (1) is 1, 2 or 3 thereof; and all other groups are as defined in any one of embodiments (1) to (28) of. 146258.doc -25- 201040149 The compound of formula (1) is in embodiment (1)-(29) in embodiment (30): in another embodiment, wherein L is -CHa-; and all other groups are as As defined in the implementation. When R1 is a moiety of formula (a), R20(a) bis: ring B" in the sense is a (1)heterocyclyl ring optionally containing - an oxo or ring sulphur atom and optionally - , two or three additional rings = the original "sub., ^ elementary monocyclic (tetra) or (tetra) fused bicyclic heteroaryl ring ring atom. Therefore ... the two origins form a heterocyclic group or heteroaryl. r2 〇 , , d2. 田年^疋, for example, when pyridazinyl, 'R1 is a oxazinyl ring of defined definition, wherein r2°, r21 and - are as defined herein. Similarly, when ring B is any And optionally a :3-solid epoxy or episulfide monocyclic heterocyclyl ring, another (iv) 4 to 10 membered U group, acridine group, morpholine π P such as 'azetidine a pyrrolidine wherein the (tetra)oxazinyl, thiophene, and the like, R20. R2w, are substituted by R and (radio 2)w, wherein R and are as defined herein. 31): In another embodiment, wherein, in the embodiment of Ri", the compound of formula (1) is a partial chrono group of the formula R4 (4), a given group, a sulfazinyl group, a diazadiazepine, a butyl group, a bad Ding double ring [3 2 11 Xinmei" Diazepanyl, 8-nitrogen, K azabicyclo[2.2.2]oct-3-yl, 3,8-diaza 146258.doc -26- 201040149 *Double.2. , 2,5 dihydroheterobicyclo[2 2 heptyl, [aza double = .2.2] octyl, 2,6-diazaspiro[3,3]heptyl, diazoxide snail [4 ” Soil, 2'7-one rat snail [44J fluorenyl or u-diazaspiro[o] fluorenyl; and all other groups such as embodiments (1)-(19) and (3〇)t As defined in the implementation. In sub-embodiment (1), the ring is singularly conjugated to a bicyclic heterocyclyl ring which optionally contains one, two or three additional nitrogen atoms in the heterocyclyl ring 1M; and all other groups As defined in any of the embodiments (1) side and (30). In sub-embodiment (1) 4), Ring B is a 7_1()-bridged bicyclic heterocyclyl ring which optionally contains one or two additional nitrogen atoms in the heterocyclyl ring; and all other groups As defined in any one of embodiments (1)-09) and (30). In a sub-embodiment (31-0, ring B is a 7-1 spirobicycloheterocyclyl ring, which optionally contains an additional nitrogen atom in the heterocyclyl ring; and all other groups are as implemented The scheme (1) is defined in any one of the embodiments (10). In the substan oxime (31-d), the ring 3 is a 5- or 6-membered heteroaryl; and all other groups are as defined by the implementing party H19) and (21H30) is defined in any one of the embodiments. In sub-embodiment (31_e), a cyclic fluorene-8 copper bicycloheteroaryl; and all other groups are as defined in any of the embodiments (1H19) and (10). In sub-embodiment (31_f), ring b is aza = alkyl " piroxime, a base" guaryl or diazepine and all other groups are as in embodiment (1)- (10) and (21)-(30) are defined in any of the embodiments. Embodiment (32): In another embodiment, the compound of formula (1) is 146258.doc •27· 201040149 wherein L is -((:Η2)ρ-ΐΛ((:Η2ν ' where p is 1 or 2 , q is an integer selected from 〇 to (3-Ρ); L1 is a bond or 〇·; and all other groups are as described in any one of embodiments (1) to (22) and (24) to (31) Defined in the scheme. In sub-embodiment (32-a), L is -CH2〇(CH2)q-. In sub-embodiment (32-b), L is -CH2-, -CH2CH2-, - CH2CH2CH2-'_CIl2_〇, -CH2CH2-0- or -CHfO-CH2·; and all other groups are as in any one of embodiments (1)-(22) and (24)-(3 1) Embodiment (33): In another embodiment, the compound of formula (1) is wherein A is

並且每個RA獨立地為鹵素、Ci-G烷基、鹵代烷基 或-ORA1，其中每個RA1獨立地為氫、CVC4烷基或鹵 代烷基’或者與相鄰的碳原子連接的兩個RA —起形成_〇_ (G)y-0-;其中每個 G獨立地為-CH2-、-C(H)(F)-或-CF2-， 並且y是1、2或3 ;並且所有其他基團如實施方案 (1)-(3)，、（5)-(27)和（29)-(32)中任一個實施方案中所定義 146258.doc -28- 201040149 的。 作為另外的實施方案，本發㈣包括藥物組合物，其含 :根據刖述實施方案中的任—個的GCS調節劑化合物和藥 學上可接受的賦形劑、稀釋劑或載體。這種組合物基本^ 不含非樂學上可接受的成分，即含有小於提交本巾請時美 國法規要求所允許的量的非藥學上可接受的成分。在這二 Ο 〇 的—實旋* S案中，如果將化合物溶解或懸浮于水 中’所述組合物還任選地含有另外的藥學上可接 體、稀釋劑或賦形劑。 為另外的實施方案，本發明還包括治療在需要這種户 療的受治療者中由⑽介導的疾病或病症或者其中涉: GCS的疾病或病症的方法，所述方法包括向受治療者投藥 有效量的根據前述實施方案中的任—個的化合物或本發明 的组合物（如上）。 由GCS介導或者涉及GCS的疾病和病症包括但不限於癌 症和代謝性病症（metab〇lic dis〇rder)。可由本發明的化人 物或組合物調節的癌症的實例包括但不限於其中糖脂合： 不正常的癌症’例如，乳癌、腎腺癌、腦癌、神經胚細胞 廇肺癌腸癌、騰腺和前列腺（Prostrate)癌。因此，作 為另外的實施方案’本發明還包括治療癌症的方法，其包 括向受治療者投藥有效量的根據前述實施方案中的任—個 的化合物或本發明的組合物。 由GCS介導或者涉及⑽的代謝性疾病和病症的實例包 括但不限於泰-隨克斯病、顯神經節苦脂貯積病、動脈 146258.doc -29- 201040149 粥樣硬化、多量H跃、卜 月病、腎肥大、類風濕性關節炎 '克隆 氏病、哮喘、贈主 、毋症、糖尿病和肥胖症；以及溶酶體貯存 病’例如，諸如、兵古 帝晨病和高歇氏病。因此作為另外的實 Γ、.Λ、' ’本發明還包括治療代謝性病症的方法，其包括向 又口療者技藥有效量的根據前述實施方案中的任一個的化 合物或本發明的組合物。 作為另外的㈣方案’本發明還包括體外誘導細胞中降 二⑽催化活性的方法’其包括將所述細胞與有效量的 根據前述實施方案令的任-個的化合物接觸。 —作為另外的貧施方案，本發明還包括根據本發明的前述 貫施方案中的任一個的々 、一 的Gc_即劑用於製備藥物的用途， 所述藥物用於治療需要這種治瘆 、裡，口潦的梵治療者中由GCS介導 的疾病或病症或者其中涉及Gcs的疾病或病症。 藥物製劑和劑型 本公開内容的化合物或它們的藥風^ 门旳樂學上可接受的鹽（以純 化的形式或以適當的藥物組合物 切的形式）的投藥可經由任 何已接受的投藥方式或用於提供相 焚供相似功用的劑來實現。因 此投藥可以是例如口服地、經鼻 丄异地、胃腸外地（靜脈内、 肌肉内或皮下）、局部地、經皮妯 、陰道内地、膀胱内 地、腦池内地或經直腸地，以固體 U體、+固體、凍乾的粉末And each RA is independently halogen, Ci-G alkyl, haloalkyl or -ORA1, wherein each RA1 is independently hydrogen, CVC4 alkyl or haloalkyl' or two RAs attached to adjacent carbon atoms. Forming _〇_ (G)y-0-; wherein each G is independently -CH2-, -C(H)(F)- or -CF2-, and y is 1, 2 or 3; and all others The group is as defined in any one of embodiments (1)-(3), (5)-(27) and (29)-(32) 146258.doc -28- 201040149. In a further embodiment, the present invention (4) comprises a pharmaceutical composition comprising: a GCS modulator compound according to any of the embodiments described, and a pharmaceutically acceptable excipient, diluent or carrier. Such compositions are substantially free of non-acceptable ingredients, i.e., contain less than the amount of non-pharmaceutically acceptable ingredients permitted by the requirements of the U.S. regulations. In the case of the two-in-one, if the compound is dissolved or suspended in water, the composition optionally further contains an additional pharmaceutically acceptable linker, diluent or excipient. For additional embodiments, the invention also encompasses a method of treating a disease or condition mediated by (10) or a disease or condition involving: GCS in a subject in need of such a household treatment, the method comprising administering to the subject An effective amount of a compound according to any of the preceding embodiments or a composition of the invention (as above) is administered. Diseases and conditions mediated by or involved in GCS include, but are not limited to, cancer and metabolic disorders (metab〇lic dis〇rder). Examples of cancers that can be modulated by a subject or composition of the invention include, but are not limited to, glycolipids: abnormal cancers 'e.g., breast cancer, renal adenocarcinoma, brain cancer, neuroblasts, lung cancer, intestinal cancer, gonads, and Prostrate cancer. Thus, as a further embodiment, the invention also encompasses a method of treating cancer comprising administering to a subject an effective amount of a compound according to any of the preceding embodiments or a composition of the invention. Examples of metabolic diseases and conditions mediated by or involved in GCS include, but are not limited to, Tay-Sykes disease, scrotal fat storage disease, arteries 146258.doc -29- 201040149 atherosclerosis, multiple H hops , buck disease, renal hypertrophy, rheumatoid arthritis 'Clone's disease, asthma, donor, snoring, diabetes and obesity; and lysosomal storage disease', for example, such as Bing Gu Di Chen disease and high rest Disease. Thus, as a further embodiment, the invention also includes a method of treating a metabolic disorder comprising a therapeutically effective amount of a compound according to any one of the preceding embodiments or a combination of the invention Things. As a further (four) scheme, the invention also encompasses a method of inducing a reduced (10) catalytic activity in a cell in vitro' which comprises contacting the cell with an effective amount of a compound according to any of the preceding embodiments. - as an additional embodiment, the invention further comprises the use of a sputum, a Gc- ing agent according to any of the preceding embodiments of the invention for the preparation of a medicament for the treatment of such a treatment A GCS-mediated disease or condition, or a disease or condition in which Gcs is involved, in a sputum, a sputum, or a sputum. Pharmaceutical Formulations and Dosage Forms The compounds of the present disclosure or their pharmaceutically acceptable salts (in purified form or in the form of a suitable pharmaceutical composition) can be administered by any of the accepted modes of administration. Or used to provide phase burning for similar functions to achieve. Thus, the administration can be, for example, orally, nasally, parenterally (intravenously, intramuscularly or subcutaneously), locally, percutaneously, intravaginally, intravesically, intracisternally or rectally, as a solid U body. , + solid, lyophilized powder

的形式’或以液體劑型，例如諸如H 兩如片劑、栓劑、丸劑、軟 彈性膠囊和硬明膠膠囊、粉末、溶 夜、懸浮液或氣溶膠或 類似劑型，較佳地以適用於精確畚，丨 月％齊〗ΐ的簡單投藥的單位劑 型。 146258.doc •30· 201040149 組合物將包括常規的藥學載體、賦形劑和/或稀釋劑以 及作為活性劑的本公開内容的化合物，並且另外可包括載 體和佐劑等。 佐劑包括防腐劑、增濕劑、懸浮劑、甜味劑、增味劑、 香味劑、乳化劑和分散劑。可通過各種抗細菌劑和抗真菌 劑例如對經基苯甲酸醋、氯丁醇、苯盼、山梨酸以及類似 物來確保防止微生物的作用。還可期望的是包括等渗劑， 爿如糖、氣化鈉以及類似物。可注射的藥物形式的延長吸 收可通過使用延遲吸收的劑例如單硬脂酸鋁和明膠來實 現。 如果期望，本公開内容中的化合物的藥物組合物還可含 有少量的辅助物質例如增濕劑或乳化劑、pH緩衝劑、抗氧 化劑以及類似物，例如諸如，檸檬酸、脫水山梨醇單月桂 魷酯、二乙醇胺油酸酯、丁基化苯甲醇等。Form 'either in liquid form, such as, for example, H such as tablets, suppositories, pills, soft elastic capsules and hard gelatin capsules, powders, lysates, suspensions or aerosols or the like, preferably for precise 畚, 丨月% Qi ΐ ΐ simple unit dosage form of administration. 146258.doc • 30· 201040149 The compositions will include conventional pharmaceutical carriers, excipients and/or diluents, and the compounds of the present disclosure as active agents, and may additionally include carriers and adjuvants and the like. Adjuvants include preservatives, moisturizers, suspending agents, sweeteners, flavor enhancers, flavoring agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents such as p-benzoic acid vinegar, chlorobutanol, benzophenone, sorbic acid and the like. It may also be desirable to include isotonic agents, such as sugars, sodium vaporates, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents which delay absorption, such as aluminum monostearate and gelatin. If desired, the pharmaceutical compositions of the compounds of the present disclosure may also contain minor amounts of auxiliary substances such as moisturizers or emulsifiers, pH buffers, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurin Ester, diethanolamine oleate, butylated benzyl alcohol, and the like.

製劑的選擇取決於不同的因素例如藥物投藥的方式（例 如對於口服投藥來說’片劑、丸劑或膠囊形式的製劑是較 佳的)以及藥物物質的生物利用纟，近來，已經在可通過 增加表面積即減小顆粒尺寸來增加生物利用度的原理的基 礎上開發了藥物製劑，特別是用於表現出差的生物利用度 的藥物的藥物製劑。例如，美國專利第卿88號描述了 八有從10至1,000 nm的尺寸範圍内的顆粒的藥物製劑，直 中活性原料被支援在大分子的交聯基質上。美國專利第 5’145,684號描述了藥物製劑的生產，叾中藥物物質在表面 改質劑存在下被粉碎為奈米顆粒（彻nm的平均顆粒尺寸） 146258.doc 31 201040149 並且之後分散在液體介質中以提供表現出非常高的生物利 用度的藥物製劑。 適用於胃腸外注射的組合物可包含生理學上可接受的無 菌含水或不含水的溶液、分散體、懸浮液或乳液，以及用 於重新構成無菌可注射溶液或分散體的無菌粉末。適合的 含水和不含水載體、稀釋劑、溶劑或介質的實例包括水、 乙醇、多元醇（丙二醇、聚乙二醇、甘油以及類似物）、其 適合的混合物、植物油（例如橄欖油）以及可注射的有機醋 例如油酸乙酯。可保留適當的流動性，例如，通過使用包 衣諸如卵鱗脂’通過保持所需要的顆粒尺寸（在分散體的 情況下）以及通過使用表面活性劑。 —個較佳的投藥路線是口服，使用可根據有待被治療的 疾病狀態的嚴重度來調整的方便的每日給藥方案。 用於口服投藥的固體劑型包括膠囊、片劑、丸劑、粉末 和粒劑。在這些固體劑型中，活性化合物與至少一種惰性 苇規賦开> 劑（或载體）混合，所述惰性常規賦形劑（或載體） 例如檸檬酸鈉或磷酸二鈣或（a)填充劑或補充劑，如例如澱 粉、乳糖、蔗糖、葡萄糖、甘露醇和矽酸，（b)結合劑，如 例如，纖維素衍生物、澱粉、藻酸鹽（alignate)、明膠、聚 乙烯吡咯啶酮、蔗糖和阿拉伯膠，（c)保濕劑，如例如甘 油，（d)崩解劑，如例如，緩脂_緩脂、碳酸約、馬鈴薯或 =薯殿粉、褐藻酸、交魏甲基纖維素納、複合料鹽和 碳醆納，⑷溶液緩凝劑，如例如石蟻，⑴吸收加速劑， 如例如季銨化合物，（g)加濕劑，如例如十六醇和單硬脂酸 146258.d〇c •32- 201040149 甘油酯'硬脂酸鎂以及類似物⑻吸附劑，如例如，高嶺土 和膨潤土，以及⑴潤滑劑’如例如，滑石、硬脂酸妈、硬 脂酸鎮、固態聚乙二醇、月桂基硫酸鈉或其混合物。在膠 囊、片劑和丸劑的實例中，劑型還可包含緩衝劑。 如上文所描述的，可使用包衣和殼例如腸溶衣和本領域 熟知的其他包衣製備固體齊丨型。它們可含有乳濁劑 (pacifying agent)並且還可具有以延遲的方式在腸道的特定 Ο 部分釋放一種或多種活性化合物的組合物。可使用的包埋 的組合物的實例是多聚物質和蠟。如果適合，活性化合物 還可與上文提到的賦形财的一種或多帛一起為微膠囊化 的形式。 用於口服投藥的液體劑型包括藥學上可接受的乳液、溶 液、懸浮液、糖漿以及酏劑。這種劑型通過例如將本公開 内容的化合物或其藥學上可接受的鹽以及任選的藥物佐劑 溶解、分散等在載體，例如諸如水、鹽水、葡萄糖水溶 液、甘油、乙醇以及類似物；增溶劑以及乳化劑，如例如 乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯曱醇、笨曱酸苯 子酯、丙二醇、1，3-丁二醇、二甲基甲醯胺；油，尤其是 棉籽油、花生油、玉米胚芽油、橄欖油' 蓖麻油和芝麻 油、甘油、四氫糠醇、聚乙二醇和山梨聚糖的脂肪酸酯或 這些物質的混合物，以及類似物中，以由此形成溶液或懸 浮液來製備。 除了活性化合物，懸浮液可包括懸浮劑，如例如，乙氧 基化的異硬脂醇、聚氧乙烯山梨醇和脫水山梨糖醇酯、微 146258.doc •33- 201040149 晶纖維素、偏氫氧化紹（aluminum metahydr〇xide)、膨潤 土、瓊脂-瓊脂和黃蓍膠或這些物質的混合物以及類似 物。 直腸投藥的組合物是，如例如，栓劑，其可通過將本公 開内容的化合物與例如適當的非刺激性賦形劑或載體諸如 可哥油、聚乙二醇或栓_混合來製備，栓劑在常溫下為 固體但是在體溫下為液體’並且因此當在適當的體腔内時 熔化並釋放其中的活性成分。 用於本公開内容的化合物的局部投藥的劑型包括軟膏、 粉末、噴霧和吸人劑。在無菌條件下將活性成分與生理上 可接受的載體以及可能需要的任何防腐劑、緩衝劑或推進 劑混合。眼用製劑、眼f'粉末和溶液也被考慮用於在本 公開内容中的化合物。 壓縮氣體可被用於以氣溶膠形式分散本公開内容的化合 物。適用於這一目的的惰性氣體為氮氣、二氧化碳等。 通常，取決於想要的投藥方丨，藥學上可接受的組合物 將含有按重量計約1%至約99%的本公開内容的化合物或其 藥學上可接受的鹽，以及按重量計99%至1%的適合的藥物 賦形劑。在一個實例中，組合物將為按重量計約5%和約 75%之間的本公開内容的化合物或其藥學上可接受的鹽， 其餘的為適當的藥物賦形劑。 製備這些劑型的實際方法對本領域技術人員來說是已知 的或明顯的’例如參見Remingt〇n，s pharmaceutical Sciences(雷明頓藥物科學），第 18 版，（Mack pubHshing 146258.doc -34- 201040149The choice of formulation depends on different factors such as the manner in which the drug is administered (for example, in the form of tablets, pills or capsules for oral administration) and the bioavailability of the drug substance, which has recently been A pharmaceutical preparation, particularly a pharmaceutical preparation for a drug exhibiting poor bioavailability, has been developed on the basis of the principle that the surface area is reduced in particle size to increase bioavailability. For example, U.S. Patent No. 88 describes a pharmaceutical preparation having eight particles ranging in size from 10 to 1,000 nm, and the direct active material is supported on a crosslinked matrix of macromolecules. U.S. Patent No. 5,145,684 describes the production of pharmaceutical preparations in which the drug substance is pulverized into nanoparticle in the presence of a surface modifying agent (average particle size throughout the nm) 146258.doc 31 201040149 and thereafter dispersed in a liquid medium To provide a pharmaceutical preparation that exhibits very high bioavailability. Compositions suitable for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and sterile powder for reconstituting a sterile injectable solution or dispersion. Examples of suitable aqueous and non-aqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and Injection of organic vinegar such as ethyl oleate. Appropriate fluidity can be retained, for example, by the use of a coating such as egg yolk lipids by maintaining the desired particle size (in the case of dispersions) and by the use of surfactants. A preferred route of administration is oral, using a convenient daily dosing regimen that can be adjusted depending on the severity of the condition being treated. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one inert oxime-inducing agent (or carrier) such as sodium citrate or dicalcium phosphate or (a) Or a supplement such as, for example, starch, lactose, sucrose, glucose, mannitol, and citric acid, (b) a binding agent such as, for example, a cellulose derivative, starch, alignate, gelatin, polyvinylpyrrolidone , sucrose and gum arabic, (c) humectants such as, for example, glycerin, (d) disintegrants such as, for example, slow fat _ slow fat, carbonic acid, potato or = potato powder, alginic acid, weiwei methyl cellulose , a composite salt and a carbon can, (4) a solution retarder such as, for example, a stone ant, (1) an absorption accelerator such as, for example, a quaternary ammonium compound, (g) a humidifying agent such as, for example, cetyl alcohol and monostearic acid 146258.d. 〇c •32- 201040149 glycerides 'magnesium stearate and analogues (8) adsorbents such as, for example, kaolin and bentonite, and (1) lubricants such as, for example, talc, stearic acid, stearic acid, solid polyethylene Glycol, sodium lauryl sulfate or a mixture thereofIn the case of capsules, tablets and pills, the dosage form may also comprise a buffer. As described above, solid coatings can be prepared using coatings and shells such as enteric coatings and other coatings well known in the art. They may contain a pacifying agent and may also have a composition that releases one or more active compounds in a particular sputum portion of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric materials and waxes. If appropriate, the active compound may also be in microencapsulated form together with one or more of the above-mentioned formulas. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutical adjuvant, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like; a solvent and an emulsifier such as, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzofuran, phenyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide; oil , especially cottonseed oil, peanut oil, corn germ oil, olive oil 'castor oil and sesame oil, glycerin, tetrahydrofurfuryl alcohol, fatty acid esters of polyethylene glycol and sorbitan or mixtures of these substances, and the like, This is prepared as a solution or suspension. In addition to the active compound, suspensions may include suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, micro 146258.doc • 33- 201040149 crystalline cellulose, partial oxidation Aluminum metahydr〇xide, bentonite, agar-agar and tragacanth or a mixture of these and the like. Compositions for rectal administration are, for example, suppositories, which can be prepared by mixing a compound of the present disclosure with, for example, a suitable non- irritating excipient or carrier such as cocoa butter, polyethylene glycol or peg. It is solid at normal temperature but liquid at body temperature' and thus melts and releases the active ingredient therein when it is in a suitable body cavity. Dosage forms for topical administration of the compounds of the present disclosure include ointments, powders, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservative, buffer or propellant which may be required. Ophthalmic formulations, eye f' powders and solutions are also contemplated for use in the compounds of the present disclosure. Compressed gas can be used to disperse the compounds of the present disclosure in aerosol form. The inert gas suitable for this purpose is nitrogen, carbon dioxide or the like. Generally, a pharmaceutically acceptable composition will contain from about 1% to about 99% by weight of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and 99 by weight, depending on the intended dosage. Suitable pharmaceutical excipients from % to 1%. In one example, the composition will be between about 5% and about 75% by weight of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, with the balance being a suitable pharmaceutical excipient. The actual methods of preparing these dosage forms are known or apparent to those skilled in the art'' see, for example, Remingt〇n, s Pharmaceutical Sciences, 18th ed., (Mack pubHshing 146258.doc -34- 201040149

Company，Easton，Pa.，199〇)。在任何情況下，有待被投藥 的組合物將含有治療有效量的本公開内容的化合物或其藥 學上可接受的鹽以便根據本公開内容的教導治療疾病狀 態。 ' ' 以治療有效量投藥本公開内容的化合物或其藥學上可接 受的鹽，治療有效量取決於各種因素而變化，所述因素包 括所使用的特定化合物的活性、化合物的代謝穩定性和作 Ο 用長度、年齡、體重、一般健康、性別、飲食、投藥的方 式和時間、排泄速率、筚人 # + 臬物、·且&、特疋的疾病狀態的嚴重 度以及經歷治療的宿主。可以約至約⑽ =:對患者投藥本公開内容的化合物。對於具有： 千克體重的正常成年人來說，一個實例為在約 ⑽聯千克體重每天的範圍内的劑量。但是，所使用的 要、有…Γ 劑量可取決於包括患者的需 學活性的許多因素。對於使用的化合物的藥 本領域普通技術人貝熟知的。“佳的I的確定是 組合物將包括常規 公開内容的化合物1 劑和作為活性劑的本 (medicinal agent)和藥且：：可包括其他的醫用劑 合物可與通常對有待 纟開内容中的化合物的組 他劑，例如手術、玫:。、癌症的患者投藥的抗癌和/或其 於在治療癌症中與式16^/或化學治療劑组合使用。可用 括院化劑、含始的劑。^合物組合投藥的化學治療劑包 146258.doc •35· 201040149 如果被配製為固定劑量，這些組合產品使用上文描述的 劑量範圍内的本公開内容的化合物以及在其批准的劑量範 圍内的其他藥學活性劑。當組合製劑不適合時，本公開内 容的組合物可以可選擇地與已知的藥學上可接受的劑順序 使用。 定義 本文所使用的術語可前綴或後綴單橫線Γ _」或雙橫線 「=」以指示指定的取代基與其母體部分之間的鍵的鍵 級，單橫線指示單鍵而雙橫線指示雙鍵。當單橫線或雙橫 0 線不存在時’應當理解為在取代基和其母體部分之間形成 單鍵；進一步的，除非橫線指示另外的方式，取代基意在 從左至右」閱讀。例如Cl_C0烷氧基羰基氧基 和-0C(0)0C】-C6烷基指示同樣的官能度。 如果基團「R」被描緣為「漂浮」於環系統上，如例如 在式：Company, Easton, Pa., 199 〇). In any event, the composition to be administered will contain a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating a disease state in accordance with the teachings of the present disclosure. ' ' The administration of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount, the therapeutically effective amount varies depending on various factors including the activity of the particular compound employed, the metabolic stability of the compound, and长度 Length, age, weight, general health, gender, diet, manner and timing of administration, excretion rate, sputum # + sputum, and & severities of the disease state and the host undergoing treatment. The compound of the present disclosure can be administered to a patient up to about (10) =:. For a normal adult having: kilogram body weight, one example is a dose in the range of about (10) kilograms of body weight per day. However, the dosage to be used may be varied depending on a number of factors including the patient's desired activity. Drugs for the compounds used are well known to those of ordinary skill in the art. "The determination of the preferred I is that the composition will include the compound 1 agent of the conventional disclosure and the medicinal agent and the drug as the active agent and:: other medical medicinal compounds may be included with the usual content to be opened A compound of a compound, for example, an anti-cancer administered by a patient in surgery, a cancer, and/or a combination thereof with a chemotherapeutic agent in the treatment of cancer. a combination of agents that administer a combination of chemotherapeutic agents 146258.doc • 35· 201040149 If formulated as a fixed dose, these combination products use the compounds of the present disclosure within the dosage range described above and approved in their Other pharmaceutically active agents within the dosage range. When the combination formulation is unsuitable, the compositions of the present disclosure may alternatively be used sequentially with known pharmaceutically acceptable agents. Definitions The terms used herein may be prefixed or suffixed. Line _ _ or double line "=" to indicate the bond level of the bond between the specified substituent and its parent part, a single horizontal line indicates a single bond and a double horizontal line indicates a double bond. When a single horizontal line or double horizontal 0 line does not exist, 'should be understood to form a single bond between the substituent and its parent moiety; further, unless the horizontal line indicates another way, the substituent is intended to be read from left to right" . For example, Cl_C0 alkoxycarbonyloxy and -0C(0)0C]-C6 alkyl indicate the same functionality. If the group "R" is drawn as "floating" on the ring system, as in the formula:

中，那麼除非以另外的方式定義，取代基「R」可在環系 ,的任何原子上，假^取代來自—個環原子的㈣的、、 指的或明確定義的氫，只要形成穩定的結構。 如果基團「R」被描緣為「漂浮」於雜環的環系统上， 如例如在式： ’ (R)Wherein, unless otherwise defined, the substituent "R" may, at any atom of the ring system, be substituted for (4), refers to or clearly defined hydrogen from a ring atom, as long as it forms a stable structure. If the group "R" is depicted as "floating" on the heterocyclic ring system, as for example in the formula: ’ (R)

(R)(R)

或or

146258.doc -36- 201040149 中’那麼除非以另外的方式定義，取代基「r 的環系統的任何原子上，假定取代來自一個環稍： 的氫（例如上文式中& 1 的描繪 又式中的-NH-)、暗指的氫（例如上文式 & 沒有被顯示但應理解為是存 氧 確疋義的氫(例如上 」等於=叫，只要形成穩定的結構。在 繪的實例中，「R 1 仗尸田 R」基團可位於稠合環系統的5元或6元環146258.doc -36- 201040149 in 'then unless otherwise defined, substituent "R on any atom of the ring system, assuming substitution of hydrogen from a ring: (for example, the depiction of & 1 in the above formula -NH-) in the formula, implied hydrogen (for example, the above formula & is not shown but should be understood as hydrogen that is depleted in oxygen (for example, upper) is equal to = as long as a stable structure is formed. In the example, the "R 1 仗 仗 R R" group can be located in the 5- or 6-membered ring of the fused ring system.

。 描綠的式中，例如當y是2時，那麼兩個「R Ο 可位於環系統的任何兩個原子上，同樣假定每―」 取=環上的描料、暗指的或明確定義的氫。 」 田基團r」m為存在於含有飽和碳 時，如例如在式： 于死上. In the green formula, for example, when y is 2, then the two "R Ο can be located on any two atoms of the ring system, and it is also assumed that each ― 取 = the trace, implied or well-defined on the ring hydrogen. " 田基团r"m is present in the presence of saturated carbon, as for example in the formula: on death

中’其中在這一實你丨由 「 1 . 、|例中’「y」可以大於-，假定每一個 〇 」取代％上目刖描繪的、暗指的或明確定義的氫；那 麼除非以另外的方式定義，#所得的結構穩定時，兩個 」可位於相同的碳上。一個簡單的實例是當r是甲基 土團夺纟所描繪的環的碳（「環」碳）上可存在成對的二 甲基。 b本文所用的某些變量被指示為二價連接部分，例如，[ 疋將A連接至母體結構的二價部分。對於這種二價變量來 說，可以例如—χ·γ —、 -或-Υ-Χ-的形式書寫定義L的特定的成 員。在這一實仓|| τ Φ ’如所寫的，這種成員意在取代被定 義的術語，以蚀Α 吏在則的（左）鍵與母體部分連接而結尾的 146258.doc -37- 201040149 (右）鍵與A連接。例如，如果L具有·χ_γ_的形式，χ被結合 於母體部分而Υ被結合於Α。 與本發明的化合物有關的「投藥」和其變體（例如「投 藥」化合物）意指將本發明的化合物引入需要治療的動物 的系統中。當本發明的化合物或其前藥與一種或多種其他 的活性劑（例如手術、放射、化學治療以及類似活性劑）組 合提供時，「投藥」及其變體都應被理解為包括同時或順 序地引入化合物或其前藥以及其他劑。 「院氧基」意指基團.OR«，其中&。是如本文所定義的烧 基。代表性實例包括甲氧基、乙氧基、丙氧基、丁氧基、 戊氧基、己氧基、4_甲基己氧基、4_甲基庚氧基、4,7_二 甲基辛氧基以及類似烷氧基。 除非以其他方式定義，「烷基」意指具有1至1〇個碳原二 的直鏈或支鏈烴基團。烷基基團的代表性實例包括甲基 乙基、丙基、丁基、戊基、己基、4_甲基己基、4_甲基/ 基、4,7_二曱基辛基以及類似烷基。（Ci_C4)烧基意指選f 甲基、乙基、丙基、異丙基、丁基、仲丁基、異丁基和4 丁基的基團。 芳基」意指具有6至14個環碳原子的單價的、單環的 或多環的基I單環芳基㈣是料族的但是多環的芳基 基團可以是部分飽和的’其中構成多環基團的環中的至二 -個環是芳香族的。多環的芳基基團包括稠合的、橋連二 和螺旋的（s_)環系統。組成多環的芳基基團的任何非芳 香族環的任何1個或2個環碳原子可由_c(〇)_、(卟 146258.doc -38- 201040149 或-C(=NH)-基團代替。除非另外說明，化合價規則允許 時，化合價可位於芳基基團的任何環的任何原子上。代表 性的實例包括苯基、萘基、二氫節基、苯並二鳴唾基、苯 並二嚼烷基、苯並呱喃基、2,3_二氫例嗓基(包括例如 2.3- 二氫]师朵_2_基、2，m"_5·基以及類似 Ο 〇 2.3- 二氫心令朵基）、異叫卜朵基、四氫異啥琳基（包括例 如四氫異喹啉-4-基、四氫異喹啉·6_基以及類似四氫異喹 琳基）、鄰苯二甲醯亞胺基以及類似芳基。 「芳基（cvc4成基」意、指與經由—至四碳亞烧基基團與 母體結構連接的芳基部分。實例包括节基、苯乙基以及類 似芳基（CVC4)烧基。 「橋連雙環雜環基環」是指其中價鍵、原子或―系列原 子連接雜環基環系統的兩個或更多個非相鄰位置的雜環芙 環系統。這㈣統可在其心結構巾含有分離的或共㈣ 不飽和，但;^是芳錢或雜芳香族環（但其上可具有芳香In the 'in this case, you can use "1. , | in the case of 'y' can be greater than -, assuming that each 〇" replaces the % of the depicted, implied or well-defined hydrogen; then unless In another way, when the structure obtained is stable, the two "" can be located on the same carbon. A simple example is the presence of a pair of dimethyl groups on the carbon ("ring" carbon) of the ring depicted by r. b Some of the variables used herein are indicated as bivalent linking moieties, for example, [疋 connects A to the divalent portion of the parent structure. For such a bivalent variable, a particular member defining L can be written in the form of, for example, χ·γ —, — or —Υ-Χ. In this real position || τ Φ ' As written, this member is intended to replace the defined term, ending with 146258.doc -37- at the end of the (left) bond with the parent part. The 201040149 (right) button is connected to A. For example, if L has the form of ·χ_γ_, χ is bonded to the parent moiety and Υ is bound to Α. "Administration" and variants thereof (e.g., "administering" a compound) in connection with a compound of the present invention means introducing a compound of the present invention into a system of an animal in need of treatment. When a compound of the invention or a prodrug thereof is provided in combination with one or more other active agents (eg, surgery, radiation, chemotherapeutic, and similar active agents), "administering" and variations thereof are understood to include simultaneous or sequential The compound or its prodrug and other agents are introduced. "Hospital oxy" means the group .OR«, where &. Is a burn group as defined herein. Representative examples include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, 4-methylhexyloxy, 4-methylheptyloxy, 4,7-dimethyl Alkoxy groups and similar alkoxy groups. Unless otherwise defined, "alkyl" means a straight or branched hydrocarbon group having from 1 to 1 carbonogen. Representative examples of alkyl groups include methylethyl, propyl, butyl, pentyl, hexyl, 4-methylhexyl, 4-methyl/yl, 4,7-didecyloctyl and the like. base. (Ci_C4) alkyl group means a group selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl and tetrabutyl. "Aryl" means a monovalent, monocyclic or polycyclic group I monocyclic aryl group having from 6 to 14 ring carbon atoms. (IV) is a steroid group but a polycyclic aryl group may be partially saturated. The two to one rings in the ring constituting the polycyclic group are aromatic. Polycyclic aryl groups include fused, bridged di- and helical (s_) ring systems. Any one or two ring carbon atoms of any non-aromatic ring constituting the polycyclic aryl group may be _c(〇)_, (卟146258.doc -38- 201040149 or -C(=NH)- group The group is substituted. Unless otherwise stated, the valence of the valence may be at any atom of any ring of the aryl group, and representative examples include phenyl, naphthyl, dihydrogenated, benzodiazepine, Benzo-p-alkyl, benzofuranyl, 2,3-dihydroindenyl (including, for example, 2.3-dihydro), 2, m, and/or Ο 〇 2.3- Dihydromanganin, phenoyl, tetrahydroisoindolyl (including, for example, tetrahydroisoquinolin-4-yl, tetrahydroisoquinoline-6-yl, and similar tetrahydroisoquinolinyl) And phthalic acid and similar aryl groups. "Aryl (cvc4 alkyl) means an aryl moiety attached to the parent structure via a to-tetracarbon alkylene group. Examples include a benzyl group , phenethyl and similar aryl (CVC4) alkyl. "Bridged bicyclic heterocyclyl" refers to two or more non-bonded heterocyclic ring systems in which a valence bond, atom or series of atoms is attached The heterocyclic ring system Fu iv ortho position system which may contain in its core structure (iv) co-towel isolated or unsaturated, but; ^ is an aromatic or heteroaromatic ring money (but which may have an aromatic

(y^ 族取代），例如(y^ family replaced), for example

\ 其中X 是⑴的整數；並且⑷至3的整數。5_1〇元橋連雙環雜 環基環的實例包括8_氮雜雙環[321]辛_3_基、8_氮雜雙環 [3.2.UH基、卜氮雜雙環[2.22]辛_3_基、丨_氮雜= [2.2.2]辛·4·基、3,8_二氮雜雙環[3 2料」·基和π二氮 雜雙環[2.2.1]庚·2_基以及類似5_1()元橋連雙環雜環基。 「環烧基（eyel〇alkyl)」意指具有3至丨3個碳環原子的單 146258.doc -39- 201040149 環或多環的烴基團。 θ 衣坑基基團可以疋飽和或部分不飽和 的但是不能含有芳吞炊ro Λ 方香私裱。環烷基基團包括稠合雙環、橋 連雙環和螺旋的環系站、丄 s 糸統。種基團的實例包括環丙基、環 ^戊基裱己基、雙環[2.2.1]庚烷基、雙環 [2.2.1]庚縣以及雙環[2 2 q辛院基。 稠口 X %」疋指其中兩個環在它們的環結構中具有不 止-個共用原子的雙環環系統，其中每個鍵是環的一部 7其中母個環是與另一個環鄰稠合的，並且其中沒有鍵 =兩個=上的環共用的。螺環系統不是這—定義的稠合雙 裒彳疋本心B月的稍合雙環環系統自身可具有經由桐合多 環的單個環原子與其連接的螺環。在-些實例中，如本領 域普通技術人員所理解的，料族系統上兩個相鄰的基團 可稠合在一起形成環結構。稠合的環結構可含有雜原子。 「画代」和「自素」意指氟代、氣代、漠代或峨代基 團。 鹵代烷基」意指由一個或多個齒代原子取代的如本文 所定義的烷基基團。例如，鹵代取代的4)烷基包括三 氟甲基、2,2-二氯乙基、2,2,2_三氟乙基、全氣乙基 (perchloroethyl)、2-溴丙基以及類似鹵代取代的（Ci 烷 基。i代烷基包括例如齒甲基，其意指由一個、兩個或三 個鹵素原子取代的甲基基團，其中每個齒素是獨立地選擇 的。鹵甲基包括例如三氟甲基、二氟曱基、氟曱基、氣曱 基、氯氟曱基以及類似齒曱基。 「雜芳基」意指具有5至14個環原子的單價的單環或多 146258.doc -40- 201040149 %基團’其環原子中的一個或多個，例如 個或四個環原子是獨立地選自氧、 個、兩個、三 餘的摸甩工氮的雜原子，並且 "餘的¥原子是碳原子。單環雜芳 而多環函疋方香族的，然 而夕衣雜方基基團可以是部分飽和的 中的至少—個是芳香族的， =夕喊團的環 .女 T所述方香族環含有至少一 们雜原子。彡環的雜彡 的瑷U匕祜稠合的、橋連的和螺旋 的％系統。除非另外說明，構成多 婪乐故详ΛΑ , 雜方基基團的任何非 Ο 方香族衣的任们個或2個環碳原子可由_c⑼· 诗NH)-基團代替。除非另外說明，化合價規則允許 化合價可位於雜芳基基團的任何環的任何原子上。更 特別地，術語雜芳基包括但不限於1，2,4-三唑基、丨3 5_三 嗤基"比。定基、鱗基、咪。坐基、嗟吩基、Μ基’、，; 基、異吲哚基、苯並咪唑基、苯並呋喃基、噌啉基、中氮 印基、蔡唆 _3_ 基（naphthyridin_3_yl)、酞嗪 基 (Phthalazin-3-yl)、酞嗪_4_基、蝶啶基（叫咖响、嗓呤 基、喹唑啉基、喹喔啉基、四唑基（tetraz〇yl)、吡唑基7 吡嗪基、嘧啶基、噠嗪基、噁唑基、異噁唑基、噁二唑 基、苯並噁唑基、喹啉基、異喹啉基、吼咯並[3,2_c]吡啶 基（包括，例如吡咯並[3,2-c]吡啶-2-基、吡咯並[3,2-^吡 啶-7-基以及類似吡咯並[3，2_c]吡啶基）、噻唑基、異噻唑 基、噻二唑基、苯並噻唑基、苯並噻吩基及其氧化物衍 生物。 「雜環基」意指具有3至13個環原子的單價的單環或多 環基團，其環原子中的一個或多個，例如1、2、3或4個環 146258.doc -41 - 201040149 原子是獨立地選自氧、访4友 1和鼠的雜原子’並且其餘的環原 t是碳原子。雜環基基團可以是飽和㈣部分不飽和的但 疋不此含有方香族環。雜環基基團包括單環、_合雙環、 橋連雙環㈣雙環m除料外說明，雜《可在任 何環的或橋連的碳或雜科錢接料致敎結構的產 生°更具體地’術語雜環基包括但不限於氮雜環丁烧基、 吼嘻咬基、2,5·:氫·1/f十各基、錢基、嗎琳基"瓜嘻 四虱瓜南基石瓜代嗎琳基（thiomorpholinyl)、硫雜嗎 啉基（thi_rpholinyl)、全氫 〇丫 庚因基（perhydr〇azepi圳、 吼。坐烧基、哺唾琳基、咪錢基、二氫。比唆基、四氮吼。定 基、噁唑啉基、噁唑烷基、異噁唑烷基、噻唑啉基、噻唑 烧基、奎寧環基、異嗟錢基m朵基、人氫異啊 基、十氫異喧琳基n夫喃基、M_二氧_8_氮雜螺[4 5、] 癸烧-8-基、2,3,3a，7a_四氫_17/_異叫卜朵基和四氫呢喃基及 其氧化物衍生物。 術語「任選地取代的」《指取代可以發生或可以不發 生，並且包括其中所述取代發生的情況和其中所述取代不 發生的情況。本領域普通技術人員應當理解的是對於描述 為包含一個或多個取代基的任何分子而言，意圖僅包括空 間上實際的和/或合成上可行的化合物。 「螺環」是指源自另一環的特定環碳的環。例如，如下 所描綠的：\ where X is an integer of (1); and an integer from (4) to 3. Examples of the 5_1 anthracene bridged bicyclic heterocyclic ring include 8-azabicyclo[321]octyl-3-yl, 8-azabicyclo[3.2.UH-based, azabicyclo[2.22]oct-3-yl , 丨 _ aza = [2.2.2] 辛·4·yl, 3,8-diazabicyclo[3 2]·yl and πdiazabicyclo[2.2.1]heptan-2-yl and the like 5_1() is a bridged bicyclic heterocyclic group. "eyel 〇 alkyl" means a single 146258.doc -39- 201040149 ring or polycyclic hydrocarbon group having 3 to 3 carbon ring atoms. The θ pit-based group may be saturated or partially unsaturated but may not contain the aromatic scorpion ro Λ 香 裱. Cycloalkyl groups include fused bicyclic, bridged bicyclic and helical ring system, 丄 s 糸. Examples of such groups include cyclopropyl, cyclopentyl hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.1] geng, and bicyclo [2 2 q xin. "Thick mouth X %" refers to a bicyclic ring system in which two rings have more than one shared atom in their ring structure, wherein each bond is a part of the ring 7 wherein the parent ring is fused to another ring And there is no key = two = on the ring shared. The spiro ring system is not a fused bismuth of this definition. The slightly bicyclic ring system of the B-month may itself have a spiro ring to which it is attached via a single ring atom of the ligated polycyclic ring. In some examples, as understood by one of ordinary skill in the art, two adjacent groups on the family system can be fused together to form a ring structure. The fused ring structure may contain a hetero atom. "Drawing generation" and "self-representation" mean fluoro, gas, desert or deuterated groups. Haloalkyl" means an alkyl group, as defined herein, substituted by one or more dentate atoms. For example, halo substituted 4) alkyl includes trifluoromethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, perchloroethyl, 2-bromopropyl, and Similar to halo substituted (Ci alkyl. i-alkyl includes, for example, dentate methyl, which means a methyl group substituted by one, two or three halogen atoms, wherein each dentate is independently selected The halomethyl group includes, for example, a trifluoromethyl group, a difluorodecyl group, a fluoroindenyl group, a gas fluorenyl group, a chlorofluoroindenyl group, and the like dentate group. "Heteroaryl group" means a unit price having 5 to 14 ring atoms. Single ring or more 146258.doc -40- 201040149 % group 'one or more of its ring atoms, such as one or four ring atoms are independently selected from oxygen, one, two, three A hetero atom of nitrogen, and the remainder of the atom is a carbon atom. The monocyclic heteroaromatic and polycyclic functional group is aromatic, but the oxime heteroaryl group may be at least one of partial saturation. Aromatic, the ring of the screaming group. The female scented ring of the female T contains at least one hetero atom. The 彡 匕祜 匕祜 匕祜 匕祜 匕祜 匕祜 匕祜 桥 桥 桥 桥 桥 匕祜 匕祜 匕祜 匕祜 匕祜% system. Unless otherwise stated, any one or two ring carbon atoms of any non-steroidal clothing of the heterocyclic group may be replaced by a _c(9)·Poet NH)- group. Unless otherwise stated, the valence rules allow the valency to be at any atom of any ring of the heteroaryl group. More particularly, the term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 丨3 5 -trimethylthio" ratio. Base, scale base, microphone. Sodium, anthracenyl, fluorenyl ',,; yl, isodecyl, benzimidazolyl, benzofuranyl, porphyrinyl, nitro-indan, cyanosine_3_yl (naphthyridin_3_yl), pyridazine Phthalazin-3-yl, pyridazine _4_yl, pteridinyl (called caffeine, fluorenyl, quinazolinyl, quinoxalinyl, tetraz〇yl, pyrazolyl) 7 pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, fluoren[3,2_c]pyridine Base (including, for example, pyrrolo[3,2-c]pyridin-2-yl, pyrrolo[3,2-pyridin-7-yl and pyrrolo[3,2-c]pyridyl), thiazolyl, iso Thiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl and oxide derivatives thereof. "Heterocyclyl" means a monovalent monocyclic or polycyclic group having 3 to 13 ring atoms. One or more of the ring atoms, for example 1, 2, 3 or 4 rings 146258.doc -41 - 201040149 The atoms are independently selected from oxygen, the heteroatom of the friend 4 and the mouse' and the remaining ring atoms Is a carbon atom. The heterocyclic group can be saturated (four) part not And 疋 疋 疋 含有 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. The production of the ruthenium structure by the coin is more specifically the term 'heterocyclic group' includes, but is not limited to, azetidinyl, acenaphthyl, 2,5:: hydrogen · 1 / f, each, Qianji , 琳琳基" 嘻 嘻 虱 thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio thio哺 琳 、, immiquid, dihydrogen, fluorenyl, tetrazinium, thiol, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidine, quinuclidinyl , 嗟 嗟 基 m m 、 、 、 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人 人3,3a,7a_tetrahydro-17/_ acenadol and tetrahydropyranyl and its oxide derivatives. The term "optionally substituted" means that the substitution may or may not occur, and includes The occurrence of the substitution and its Where the substitution does not occur, it will be understood by one of ordinary skill in the art that for any molecule described as comprising one or more substituents, it is intended to include only sterically practical and/or synthetically feasible compounds. "Spiro" refers to a ring of a specific ring carbon originating from another ring. For example, as described below:

146258.doc •42- 201040149 飽和的橋環系統（環c和環c，）的環原子，但不是橋頭原子， 可以疋在所述飽和的橋環系統和連接於其上的螺環（環D) 之間共S的原？。螺環系統的代表性的實例是2,3_二氧_8_ 氮雜螺[4.5]癸烷-8-基。 「立體異構體」是指含有以同一方式彼此互相結合的相 同的原子但是彼此在肩子或原子的基團的空間排列上不同 的兩種或多種異構體。「立體異構體」包括例如對映異構 Ο ❹ 體、幾何異構體、非對映異構體、旋轉異構體、順式異構 體、反式異構體以及構象異構體。除非以另外的方式指 本申請中所用的描述本發明的化合物的名稱和說明音 所有可能的立體異構體以及其任何混合物（外消旋 物或其他）。 本發明還包括本發明化合物⑽氧化物衍生物。^氧化 物衍生物是指本發明务人 (即，— 列如，二二生物’其中氮是氧化態 所期望的藥理學活性乳化物，並且所述氧化物具有 其ΐΐί發明目的的「患者」和「受治療者」包括人類和 ==是哺乳動物，以及其他有機體。因此本發 方宰中串:於人類的治療和獸醫應用。在另一個實施 是:類是哺乳動物’而在另-個實施方案中，患者 且=2:上可接受的鹽」是指藥學上可接受的並 藥學上可接受二?：:望的藥理學活性的鹽。應當理解 的鹽疋無毒性的。對於合適的藥學上可接受 146258.doc •43· 201040149 的鹽的其他育訊可在Remington，s pharmaceutical Sciences(雷明頓藥物科學），第丨7版，Mack puMishing Company，Easton，PA，1985中找到，其通過引用併入本 文，或 S. M. Berge，專人，「pharmaceutical Salts(藥物 鹽），」J. Pharm. Sci.，1977; 66:1-19中找到，其均通過引用 併入本文。還應當理解，化合物可具有與其相關的一種或 多種藥學上可接受的鹽。 藥學上可接受的酸加成鹽的實例包括與無機酸和有機酸 形成的酸加成鹽，無機酸諸如鹽酸、氫溴酸、硫酸、硝 酉文、鱗酸及類似無機酸，有機酸諸如乙酸、三氟乙酸、丙 酸、己酸、環戊烷丙酸、乙醇酸、丙酮酸、乳酸、草酸、 馬來酸、丙二酸、琥珀酸、富馬酸、酒石酸、擰檬酸、苯 曱酸、肉桂酸、3-(4-羥基苯曱醯）苯曱酸、扁桃酸、曱磺 酸、乙項酸、1，2-乙二確酸、2-經基乙續酸、苯績酸、4-氣苯磺酸、2-萘磺酸、4-甲苯磺酸、樟腦磺酸、葡庚糖 酸、4,4’-亞曱基雙_(3_經基-2-烯-1-缓酸）、3-苯基丙酸、三 甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨 酸、經萘曱酸、水楊酸、硬脂酸、粘康酸、對甲苯績酸、 水揚酸及類似有機酸。 藥學上可接受的驗加成鹽的實例包括當存在於母體化合 物中的酸性質子被金屬離子替換時形成的鹼加成鹽，例如 鈉、鉀、鋰、銨、鈣、鎂、鐵、辞、銅、錳、鋁鹽及類似 驗加成鹽。較佳的鹽是銨、鉀、鈉、鈣和鎂鹽。衍生自藥 學上可接受的有機無毒鹼的鹽包括，但不限於伯胺、仲胺 I46258.doc -44· 201040149 ❹ Ο 和叔胺、取代的胺（包括天然存在的取代的胺）、環胺和鹼 性離子交換樹月曰的鹽。有機驗的實例包括異丙胺、三曱 胺、一乙胺、二乙胺、二丙胺、乙醇胺、2_二甲基胺基乙 醇、2-二乙基胺基乙醇、二環己基胺、賴氨酸、精胺酸、 組胺酸、咖啡因、普魯卡因、海巴明（hydrabamine)、膽 鹼、甜莱鹼、乙二胺、葡糖胺、甲基葡糖胺、可哥鹼、嘌 呤、呱嗪、呱疋、N-乙基呱啶、氨丁三醇、曱基葡糖 胺、聚胺樹脂及類似有機驗。典型的有機驗為異丙胺、二 乙胺、乙醇胺、三甲胺、二環己基胺、膽鹼和咖啡因。 有效1」π當投藥于患者時有交文治療疾病的本發明化 合物的量。構成「有效量」的本發明化合物的量將根據包 括以下的多種因素而變化：活性、代謝穩定性、化合物的 排液速率和作用㈣時m的年齡、體重、一般健 康、性別、飲食和物種、化合物投藥的方式和時間、佐劑 或另外的治療的共同投藥和尋求治療作用的疾病的嚴重 性。可確定給定條件的有效量而無需過多試驗。 如本文所用的，「治療」（Treating)或「治療」 (treatment)疾病、病症或症候群包括⑴防止疾病、病症或 類中出現…使得疾病、病症或症候群的臨 ==暴露于或易患該疾病、病症或症候群但仍 不出該疾病、病症或症候群的症狀的動物中發 、’⑴Ρ制疾病、病症或症候群， ㈣減輕疾病、病症或症候群，即，使得疾病、：展，和 候癱洁π , 丨便付疾病、病症或症 …。本領域中所知，針對全身遞送和局部遞送， 146258.doc •45· 201040149 患者的年齡、體重、一般健康、性別、飲食和物種，化合 物投藥的方式和時間，佐劑或另外的治療活性成分的共同 投藥和尋求治療作用的疾病的嚴重性進行調整可能是必要 的，並是通過常規試驗可確定的。 合成 本文使用了下列縮寫和首字母縮略詞，146258.doc •42- 201040149 The ring atoms of the saturated bridged ring system (ring c and ring c,), but not the bridgehead atoms, can lie on the saturated bridged ring system and the spiro ring attached to it (ring D ) What is the original between S? . A representative example of a spiro ring system is 2,3-dioxo-8-azaspiro[4.5]decane-8-yl. "Stereoisomer" means two or more isomers which contain the same atoms bonded to each other in the same manner but differ from each other in the spatial arrangement of the shoulder or atomic group. "Stereoisomers" include, for example, enantiomers, enantiomers, geometric isomers, diastereomers, rotamers, cis isomers, trans isomers, and conformational isomers. Unless otherwise indicated, the names and descriptions of the compounds of the invention are used in this application to describe all possible stereoisomers and any mixtures thereof (racemates or others). The present invention also includes the oxide derivative of the compound (10) of the present invention. ^Oxide derivative means the pharmacologically active emulsion of the present invention (i.e., -, for example, the second organism) wherein nitrogen is the desired oxidation state of the oxidation state, and the oxide has its "patient" for the purpose of the invention And "subjects" include humans and == are mammals, as well as other organisms. Therefore, the present invention is in the treatment of humans and veterinary applications. In another implementation: the class is a mammal and in another In one embodiment, the patient and = 2: an acceptable salt" refers to a pharmaceutically acceptable and pharmaceutically acceptable salt of the pharmacologically active salt. It is understood that the salt is non-toxic. Other auxiliaries of pharmaceutically acceptable salts of 146258.doc • 43· 201040149 can be found in Remington, s Pharmaceutical Sciences, vol. 7, Mack puMishing Company, Easton, PA, 1985. It is incorporated herein by reference, or by SM Berge, in particular, "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, which is incorporated herein by reference. And The substance may have one or more pharmaceutically acceptable salts associated therewith. Examples of pharmaceutically acceptable acid addition salts include acid addition salts with inorganic and organic acids, mineral acids such as hydrochloric acid, hydrobromic acid, Sulfuric acid, nitronium, squaric acid and similar inorganic acids, organic acids such as acetic acid, trifluoroacetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, and propylene Acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxyphenylhydrazine) benzoic acid, mandelic acid, sulfonic acid, ethyl acid, 1, 2 - oxadicarboxylic acid, 2-carbyl-supplying acid, benzoic acid, 4-gasbenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4' - fluorenyl bis(3-cyano-2-ene-1-acid acid), 3-phenylpropionic acid, trimethylacetic acid, t-butyl acetic acid, lauryl sulfate, gluconic acid, valley Acid, naphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluene acid, salicylic acid and similar organic acids. Examples of pharmaceutically acceptable test addition salts include when present in the parent compoundA base addition salt formed when an acid proton is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, copper, manganese, aluminum salts, and the like. Salts are ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, primary amines, secondary amines I46258.doc-44· 201040149 ❹ Ο and tertiary amines, substituted Amines (including naturally occurring substituted amines), cyclic amines, and salts of basic ion exchange tree guanidine. Examples of organic tests include isopropylamine, tridecylamine, monoethylamine, diethylamine, dipropylamine, ethanolamine, 2 _Dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, gallbladder Alkali, sweet base, ethylenediamine, glucosamine, methylglucamine, cogandine, hydrazine, pyridazine, anthracene, N-ethyl acridine, tromethamine, decyl glucosamine, Polyamine resin and similar organic tests. Typical organic tests are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. Effective 1" π The amount of the compound of the invention that is administered to treat a disease when administered to a patient. The amount of the compound of the present invention constituting the "effective amount" will vary depending on various factors including activity, metabolic stability, rate of discharge of the compound, and effect (4) age, body weight, general health, sex, diet, and species of m. The manner and time of administration of the compound, the co-administration of the adjuvant or additional treatment, and the severity of the disease seeking therapeutic effect. The effective amount of a given condition can be determined without undue experimentation. As used herein, "treating" or "treatment" a disease, disorder, or syndrome includes (1) preventing the appearance of a disease, disorder, or disorder... causing the disease, disorder, or syndrome to be exposed to or susceptible to the disease. A disease, disorder, or syndrome in which an animal does not develop symptoms of the disease, disorder, or syndrome, '(1) a disease, disorder, or syndrome, (4) a disease, disorder, or syndrome, ie, a disease, an exhibition, and a candidate Clean π, 丨 will pay for diseases, illnesses or illnesses... As known in the art, for systemic delivery and local delivery, 146258.doc •45· 201040149 patient age, weight, general health, sex, diet and species, manner and timing of administration of the compound, adjuvant or additional therapeutically active ingredient Adjustments to the severity of the co-administration and treatment-seeking diseases may be necessary and may be determined by routine experimentation. Synthesis The following abbreviations and acronyms are used in this article.

BnNH2 苄胺 BOC 叔丁氧羰基 BOC-酐二碳酸二叔丁酯 Bzl 节基 CHAPS 3-[(3-膽胺丙基）二甲基胺基]-1-丙磺酸 DCE 1,2-二氣乙烷 DCM 二氣曱烷 DIEA 二異丙基（乙基）胺 DMA Ν,Ν-二甲基乙醯胺 DMF Ν，Ν-二甲基甲醯胺 DMSO 二甲基亞砜 DOPC 二油醯填脂醯膽驗 EDC 1-[3-(二曱基胺基）丙基]-3-乙基碳二亞胺甲 峨鹽BnNH2 benzylamine BOC tert-butoxycarbonyl BOC-anhydride di-tert-butyl dicarbonate Bzl radical CHAPS 3-[(3-cholinylpropyl)dimethylamino]-1-propanesulfonic acid DCE 1,2-two Ethane ethane DCM Dioxane DIEA Diisopropyl (ethyl) amine DMA Ν, Ν-dimethylacetamide DMF Ν, Ν-dimethylformamide DMSO dimethyl sulfoxide DOPC Fat-filled sputum test EDC 1-[3-(didecylamino)propyl]-3-ethylcarbodiimide formazan salt

Et3N 三乙胺Et3N triethylamine

Et2〇 二乙醚Et2〇 diethyl ether

EtOH 乙醇EtOH ethanol

EtOAc 乙酸乙酯 146258.doc •46- 201040149EtOAc ethyl acetate 146258.doc •46- 201040149

HATU HEPES HOBt MeBnBr MeCN MeOH MsCl NADH NMM THF 四曱基-〇-(7 -偶氮笨並三。坐_ι_ 基）脲六氟磷酸酯 4-(2-輕乙基）-l-p瓜嗓乙績酸 1 -羥基苯並三唑 3 ·甲基苄基溴化物 乙腈 曱醇 曱磺醯氯HATU HEPES HOBt MeBnBr MeCN MeOH MsCl NADH NMM THF Tetrakilyl-indole-(7-azo benzo-three. Sit_ι_yl) urea hexafluorophosphate 4-(2-light ethyl)-lp 嗓 嗓Acid 1-hydroxybenzotriazole 3 ·methylbenzyl bromide acetonitrile sterol sulfonium chloride

煙醯胺腺嘌吟二核苷酸 N-曱基嗎啉 四氫呋喃 UDP-葡萄糖尿苷二磷酸葡萄糖 化合物合成： 下列實施例用於提供本發明的進一步的理解，但不意味 著以任何方式限制本發明的有效範圍。 本發明的化合物可通過在方案1中概述的合成路線合 成’由商業上可獲得的穩定的功能化B〇c胺基酸衍生物 或其他Boc保護的胺基酸起始。因此，將B〇c保護的胺基酸 (1)與合適地功能化的胺偶合。偶合反應通常在1_[3_(二曱 基胺基）丙基]-3-乙基碳二亞胺甲碘鹽（EDC，N〇vabi〇chem) 和1-經基本並二坐（HOBt ’ Novabiochem)存在下進行以產 生醯胺（2)。之後通過在酸性條件下進行的去保護反應將所 传的酿胺（2)轉化為相應的2-胺基-酿胺（3)。隨後將2_胺基_ 醯胺（3)與適當地功能化的1-苯基環丙羧酸或卜苯基“，丨—二 146258.doc -47- 201040149 曱基缓酸偶合。偶合反應通常在EDC和HOBt存在下進行以 產生2-(2-芳基曱醯胺）-3-芳基丙基醯胺（4); 一種式（1)的化 合物。 方案1Nicotinamide adenine dinucleotide N-mercaptomorpholine tetrahydrofuran UDP-glucosuridine diphosphate glucose compound synthesis: The following examples are provided to provide a further understanding of the invention, but are not meant to limit the invention in any way The effective range of the invention. The compounds of the present invention can be synthesized by the synthetic route outlined in Scheme 1 'from commercially available stable functionalized B〇c amino acid derivatives or other Boc-protected amino acids. Thus, the B〇c protected amino acid (1) is coupled to a suitably functionalized amine. The coupling reaction is usually carried out in 1-[3_(didecylamino)propyl]-3-ethylcarbodiimide methyl iodide (EDC, N〇vabi〇chem) and 1-based basic and two-seat (HOBt ' Novabiochem The reaction is carried out in the presence of a guanamine (2). The resulting brewing amine (2) is then converted to the corresponding 2-amino-bristamine (3) by deprotection under acidic conditions. Subsequently, the 2-amino-decanamine (3) is coupled with a suitably functionalized 1-phenylcyclopropanecarboxylic acid or a phenyl phenyl group, 146 146258.doc -47- 201040149 hydrazine. It is usually carried out in the presence of EDC and HOBt to give 2-(2-arylguanamine)-3-arylpropyl decylamine (4); a compound of formula (1).

其中L、A、R2、R3以及m是本文所定義的，*指示相鄰碳 原子的任選的（R)或（S)手性，並且_n(Rx)(Ry)是R1，其中 Rx和RY中的一個是R10並且rx和中的另一個是Rii，或Rx 和RY以及它們與之連接的氮原子形成式（3)的部分，Wherein L, A, R2, R3 and m are as defined herein, * indicates an optional (R) or (S) chirality of an adjacent carbon atom, and _n(Rx)(Ry) is R1, wherein Rx One of and RY is R10 and the other of rx and Rix, or Rx and RY and the nitrogen atom to which they are attached form part of formula (3),

其中R20、尺21和从如本文所定義的。 可選擇地，合成可如方案2所概述的來進行。通過在酸 陡條件下進行的去保護-酯化反應將適合地功能化的Boc保 -蒦的月女基酸何生物⑴轉化為相應的胺基酯鹽酸鹽(5)。 146258.doc -48· 201040149 方案2Wherein R20, ruler 21 and as defined herein. Alternatively, the synthesis can be carried out as outlined in Scheme 2. The suitably functionalized Boc-protected Montanolic acid (1) is converted to the corresponding aminoester hydrochloride (5) by deprotection-esterification under acidic conditions. 146258.doc -48· 201040149 Option 2

其中L、A、R2、尺3和所是本文所定義 1疋我的 私不相鄰碳原 子的任選的（R)或（S)手性，並且_n(rX)(rY：^r1，其中rX 和1^中的一個是Ri〇並且rx*ry中的卩一個是r11，或rX和 R以及它們與之連接的氮原子一起形成式（a)的部分，Wherein L, A, R2, Ruler 3 and the optional (R) or (S) chirality of 1 private my non-adjacent carbon atom as defined herein, and _n(rX)(rY:^r1 , wherein one of rX and 1^ is Ri〇 and one of rx*ry is r11, or rX and R together with the nitrogen atom to which they are attached form part of formula (a),

(a), 〇 其中r20、R21和w如本文所定義的。 與適當地功能化的1-苯基環丙羧酸或丨_苯基_u_二曱基 羧酸的隨後的偶合反應通常在2-(1Η-7-偶氮苯並三唑_1_ 基）-1，1，3,3-四甲基脲六氟磷酸甲胺（HATU，Applied Biosystems)存在下進行以產生中間體（6)。酯（6)水解通常 在鹼性條件下進行。之後將所得的羧酸（7)在2-(1Η-7-偶氮 苯並三唑-1-基）-1,1,3,3-四甲基脲六氟磷酸曱胺（11八丁1；， Applied Biosystems)存在下與適當地功能化的胺偶合以產 146258.doc •49- 201040149 生2-(2-芳基甲醯胺）_3•芳基_丙基酿胺（8); 一種式⑴的化 合物。在-些實施例中，其後在酸性條件下進行去保護反 應。 可選擇地通過方案3中概述的合成路線合㈣ 口物因此冑商業上可獲得的羥基琥⑵酿亞胺醋（9)與適 當地功能化的胺偶合’之後在酸性條件下進行去保護反應 以產生胺（11)。 方案3(a), 〇 where r20, R21 and w are as defined herein. Subsequent coupling reaction with suitably functionalized 1-phenylcyclopropanecarboxylic acid or hydrazine-phenyl-u-dimercaptocarboxylic acid is usually carried out at 2-(1Η-7-azobenzotriazole-1-yl) The reaction was carried out in the presence of -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, Applied Biosystems) to give intermediate (6). The hydrolysis of the ester (6) is usually carried out under basic conditions. The resulting carboxylic acid (7) is then 2-(1Η-7-azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate decylamine (11 octadine 1) ;, Applied Biosystems) Coupling with a suitably functionalized amine to produce 146258.doc •49- 201040149 raw 2-(2-arylcarbendazim)_3•aryl-propyl urethane (8); a compound of formula (1). In some embodiments, the deprotection reaction is followed by acidic conditions. Alternatively, the deprotection reaction under acidic conditions is followed by the synthetic route outlined in Scheme 3, whereby the commercially available hydroxysuccinate (2) is made of the imine vinegar (9) coupled with a suitably functionalized amine. To produce an amine (11). Option 3

其中L、A、R2、R3和所是本文所定義的，n是〇、i、2或 3，*指示相鄰碳原子的任選的（R)或⑻手性，並 且-N(RX)(RY)是Ri，其中Rx和ry中的一個是r1〇並且rX* RY中的另一個是RU，或Rx和Ry以及它們與之連接的氮原 子形成式（a)的部分，Wherein L, A, R2, R3 and as defined herein, n is 〇, i, 2 or 3, * indicates an optional (R) or (8) chirality of an adjacent carbon atom, and -N(RX) (RY) is Ri, wherein one of Rx and ry is r1〇 and the other of rX* RY is RU, or Rx and Ry and the nitrogen atom to which they are attached form part of formula (a),

-|-n/T^)R ^^(r21)w (a), 其中R 、R和11；如本文所定義的。 隨後’將胺（11)與適當地功能化的苯基環丙羧酸或^ 苯基-1，1-二曱基羧酸偶合。偶合反應通常在〇_(7_偶氮苯 並三嗤-1-基）-Ν,Ν,Ν’Ν1-四甲基脲六氟磷酸酯（HATU， 146258.doc • 50- 201040149-|-n/T^)R ^^(r21)w (a), wherein R, R and 11; as defined herein. The amine (11) is then coupled with a suitably functionalized phenylcyclopropanecarboxylic acid or phenyl-1,1-dimercaptocarboxylic acid. The coupling reaction is usually carried out in 〇_(7_azobenzotriazin-1-yl)-oxime, oxime, Ν'Ν1-tetramethyluron hexafluorophosphate (HATU, 146258.doc • 50- 201040149

Applied Bi〇Systems)存在下進行以產生2_(2、芳基甲酿胺） 3-芳基·芳基-丙基醯胺（12)，一種式（1)的化合物。 因此，本發明還包括製備式（I)的化合物的方法，所述方 法包括： ⑴偶合式（13)的化合物與式〇4)的化合物以提供式⑴的 化合物或者其單一的立體異構體或其立體異構體的混合 物，Applied Bi〇Systems) is carried out in the presence of a compound of formula (1) which produces 2_(2, arylmethanoamine) 3-aryl-aryl-propyl decylamine (12). Accordingly, the present invention also includes a process for the preparation of a compound of formula (I), which process comprises: (1) coupling a compound of formula (13) with a compound of formula )4) to provide a compound of formula (1) or a single stereoisomer thereof Or a mixture of stereoisomers thereof,

式（）中’A和L是如本文所定義&，*表示相鄰碳原 子的任選的（R)或（S)手性，並且_n(rx)(rY：^r1，其中r> 和RY中的一個是f並且R>RY中的另一個是R11，或 RY以及它們與之連接的氮原子形成式（a)的部分In the formula (), 'A and L are as defined herein, and * represents an optional (R) or (S) chirality of an adjacent carbon atom, and _n(rx)(rY:^r1, where r&gt One of and RY is f and the other of R>RY is R11, or RY and the nitrogen atom to which they are attached form part of formula (a)

〇 其中R2°、R21h如本文所定義的，在式（14)中，r2、尺3和 是如本文所定義的；並且任選地分離單獨的異構體；並 且任選地修飾R2>R2I基團中的任―個以提供式⑴的化合 物；並且任選地形成其藥學上可接受的鹽；或者 ⑴)偶合式(15)的化合物與式(16)的化合物以提供式⑴的 化合物， 146258.doc -51 - 201040149Wherein R 2 °, R 21 h are as defined herein, in formula (14), r 2 , 3 and 3 are as defined herein; and optionally separate individual isomers; and optionally R 2 > R 2 I Any one of the groups to provide a compound of formula (1); and optionally form a pharmaceutically acceptable salt thereof; or (1) a coupling compound of formula (15) with a compound of formula (16) to provide a compound of formula (1) , 146258.doc -51 - 201040149

1^、一是如本文所定義的，並且 在式（15)中，/ 表示相鄰碳原…選的⑻或並且* 中，_N(rX)(R>r1，，在式（16) t ^ . Rll "Υα 原子形成式U)的部分3 匕們與之連接的氮1^, one is as defined herein, and in the formula (15), / represents the adjacent carbon source ... selected (8) or and *, _N (rX) (R > r1, in the formula (16) t ^ . Rll "Υα Atom Formation U) Part 3 The nitrogen to which we are attached

(a) 其中R 、尺丨和诈如本文所定義的.# 又所疋義的，並且任選地分離單獨 的異構體；並且任選地修心。和R21基團中的任—個以提 供式⑴的化合物或者其單一的立體異構體或其立體異構體 的混合物；並且任選地分離單獨的異構體；並且任選地修 飾R2◦和R21基團中的任—個以提供式⑴的化合物；並且任 選地形成其藥學上可接受的鹽。 實施例1 -吲哚-3-基）-1-(4-甲基呱 1_(2,4_二氣苯基）_n_[(2S)_3_(1h 嗪-1-基）-1-氧代丙-2-基】環丙醢胺(a) wherein R, a ruthenium, and a scam are as defined herein, and are also meant to be separated, and optionally separate individual isomers; and optionally modified. And any one of the R21 groups to provide a compound of formula (1) or a single stereoisomer thereof or a mixture of its stereoisomers; and optionally separate the individual isomers; and optionally modify R2◦ And any of the R21 groups to provide a compound of formula (1); and optionally form a pharmaceutically acceptable salt thereof. Example 1 - Indole-3-yl)-1-(4-methylindole 1_(2,4_diphenyl)_n_[(2S)_3_(1h azine-1-yl)-1-oxo Propan-2-yl]cyclopropanamide

146258.doc •52· 201040149 步驟1 : (S)-2-胺基-3-(1Η-吲哚-3-基）-1-(4-甲基呱嗪-i_ 基）丙-l-_ :將（S)-2·(叔丁氧羰基胺基）-3-(1Η-吲哚-3-基） 丙酸2,5-二氧代吼洛咬-1-基酯（入(^&amp;11〇6〇1€；1^11116〇11，803 mg，2 mmol)溶于無水乙腈（10 mL)中。加入N-甲基&quot;瓜嗪 (23 3 μί，2.1 mmol)並且將溶液擾拌兩小時。由LCMS分析 指示完全反應。加入溶於二11 惡烧（2 mL)的4N鹽酸溶液並且 將溶液攪拌隔夜。形成沉澱，將沉澱濾出並且用乙腈清 洗。固體的LCMS分析顯示其為（S)-2-胺基-3-(1Η-吲哚-3-基）-1 -(4-甲基呱嗪-1 -基）丙-1 -酮，推測為二鹽酸鹽。真空 乾燥後，獲得690 mg的標題化合物（1.92mmol的單鹽酸 鹽）。這一材料被用於下一步驟而無需進一步純化。 步驟 2 : (1-(2,4-二氣苯基）-N-【(2S)-3-(lH-吲哚-3-基）-1-(4-甲基11瓜嗓-1-基）-1-氧代丙-2-基]環丙酿胺：向溶于無水 乙腈（10 mL)的（S)-2-胺基-3-(1Η-吲哚-3-基）-1-(4-曱基呱 〇秦-1-基）丙-1-酮二鹽酸鹽（690 mg，1.92 mmol)和 Hunig 驗 (1.64 mL，9.6 mmol)的溶液中加入1-(2,4-二氯苯基）環丙 羧酸（Acros，443 mg’ 1.92 mmol)。加入HATU(Applied Biosystems ’ 802 mg ’ 2.11 mmol)並且將反應溶液授拌隔 夜。通過反相製備級HPLC(含水乙酸銨緩衝液，PH〜4-5， 乙腈；20-70%沖提梯度）分離產物.將含有的純化產物的 部分收集’混合、濃縮並冷凍乾燥以獲得（1-(2,4-二氯苯 基）-N-[(2S)-3-(lH-吲哚-3-基）-1-(4-甲基呱嗪-1-基）-1-氧代 丙-2-基]環丙醯胺（466 mg)。NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 7.61 (d, 1H), 7.41(d, 1H), 7.35 (m, 2H), 7.31 146258.doc -53- 201040149 (d, 1H), 7.04 (t, 1H), 7.01 (d, 1H), 6.85 (t5 1H), 6.68 (d, 1H), 5.93 (dd, 1H), 3.25 (bs, 3H), 3.08 (b, 1H), 2.95 (m, 2H), 2.17 (b, 1H), 2.09 (b, 1H), 2.05 (s, 3H), 1.94 (b, 1H), 1.70 (b, 1H)，1.45 (b，2H), 0.97 (m，2H); C26H28C12N402的 MS (El)，實測值499.〇〇(MH+)。 以類似於實施例1的方式製備下列化合物。 1-(2,4-二氣苯基）_N-[(lS)-2-[3-(二甲基胺基）氮雜環丁 烷-1-基】-1-(1Η-吲哚-3-基甲基）-2-氧代乙基】環丙醢胺：1H NMR (400 MHz, DMSO-d6)： δ 10.87 (d, 1Η), 7.60 (dd, 1H), 7.46 (dd, 1H), 7.42-7.36 (m, 2H), 7.33 (dd, 1H), 7.03 (m, 3H), 6.60 (dd, 1H), 4.57-4.39 (m, 1H), 3.96 (t, 1H), 3.80 (m, 1H), 3.69-3.51 (m, 2H), 3.38 (m, 1H), 2.98-2.91 (m, 2H), 1.98 (s, 3H), 1.90 (s, 3H), 1.48 (m, 2H), 1.12-0.85 (m, 2H). C26H28C12N402的 MS (El)，實測值 500.4 (MH+)。 Να-{[1-(2,4-二氣苯基）環丙基】羰基}-N-【2-(二甲基胺基）-乙基]-L-色胺醢胺：4 NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 7.72 (t, 1H), 7.58 (d, 1H), 7.43 (d, 1H), 7.36 (dd, 1H), 7.31 (d, 2H), 7.10-7.01 (m, 1H), 7.01-6.90 (m, 2H), 6.40 (d, 1H), 4.45 (dd, 1H), 3.20-2.84 (m, 4H), 2.18 (t, 2H), 2.11 (s，6H), 1.43 (d, 2H)，0.99 (d，2H). C25H28C12N402的 MS (El)，實測值488.4 (MH+)。 1-(2,4-二氣苯基）-N-[(lS)-l-(lH_吲哚-3-基曱基）-2-(4-甲 基-1,4-二氮雜環庚烷-1-基）-2-氧代乙基]環丙釀胺：4 NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 7.62 (d, 1H), 146258.doc -54- 201040149 7.44 (dd, 1H), 7.39 (d, 2H), 7.32 (d, 1H), 7.07-6.93 (m, 3H), 6.70 (dd, 1H), 4.94 (dt, 1H), 3.32-3.27 (m, 2H), 3.19 (dd, 1H), 3.07-2.82 (m, 2H), 2.41-2.15 (m, 3H), 2.09 (d, 4H), 2.03-1.92 (m, 1H), 1.61 (s, 1H), 1.47 (s, 3H), 1.00 (d, - 2H). C27H30Cl2N4O2 的 MS (El)，實測值 514.5 (MH+)。 1-(2,4-二氣苯基）-N-[(1S)-1-(1H-吲哚-3-基甲基）-2-氧代-2-呱嗪-1-基乙基]環丙醯胺：1HNMR(400 MHz,DMSO-d6): δ 10.86 (s, 1H)，8.24 (s，1H), 7.63 (d, 1H)，7.44 (d， 〇 1H), 7.41-7.34 (m, 2H), 7.32 (d, 1H), 7.05 (dd, 1H), 7.02 (d, 1H), 6.97 (dd, 1H), 6.72 (d, 1H), 4.94 (dd, 1H), 3.27 (d, J=3.9Hz, 3H), 3.11 (s, 1H), 3.02-2.87 (m, 2H), 2.67-2.52 (m, 1H), 2.46 (s, 1H), 2.23 (s, 1H), 1.55-1.40 (m, 2H), 1.07-0.93 (111，2^1).(：25只26(：121&lt;[4〇2的]^8(丑1)，實測值486.4 (MH+)。 l-(2,4-二氣苯基）-N-[(1S)-1-(1H-吲哚-3-基甲基）-2-嗎啉-4-基-2-氧代乙基]環丙醯胺：4 NMR (400 MHz, DMSO- ❹ d6)： δ 10.87 (s, 1H), 7.66-7.62 (m, 1H), 7.44 (d, 1H), 7.39 (d, 2H), 7.33 (d, 1H), 7.11-7.02 (m, 2H), 7.02-6.93 (m, 1H), • 6.74 (d, 1H), 5.03-4.81 (m, 1H), 3.33-3.20 (m, 5H), 3.12 - (m, 2H), 3.02-2.92 (m, 2H), 2.90-2.78 (m, 1H), 1.57-1.39 (m，2H)，1_01 (m，2H). C25H25C12N303 的 MS (El)，實測值 487.4 (MH+)。 1-(2,4-二氣苯基）-N-[(lS)-2-{4-[3-(二甲基胺基）丙基】呱 嗪-1-基}-1-(111-吲哚-3-基甲基）-2-氧代乙基】環丙醢胺：4 146258.doc -55- 201040149 NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 7.65-7.60 (m, 1H), 7.42 (dd，1H)，7.39-7.37 (m, 2H)，7_32 (d，1H)，7.05 (dd，1H), 7.01 (d，1H)，6.99-6.94 (m，1H)，6.68 (d，1H)， 4.94 (q, 1H), 3.26 (s, 4H), 2.95 (qd, 2H), 2.23 (dd5 2H), 2.16 (s5 2H), 2.15 (s, 6H), 2.10 (d, 2H), 1.96 (d, 1H), 1.70 (d，1H)，1.53-1.41 (m, 4H)，1.01 (d, 2H)· C30H37 (：12乂02的 1^8斤1)，實測值571.6(]^^1+)。 Να-{[1-(2,4-二氣苯基）環丙基]羰基}-N-(l-曱基呱啶-4-基）-L-色胺醯胺：NMR (400 MHz，DMSO-d6): δ 10.75 (s, 1Η), 7.55-7.51 (m, 1H), 7.40 (dd5 1H), 7.33-7.36 (m, 2H), 7.32 (d, 1H), 7.05 (dd, 1H), 7.01 (d, 1H), 6.99-6.94 (m, 1H), 6.68 (d, 1H), 4.94 (q, 1H), 3.60 (m, 1H), 3.11 (m, 2H), 2.48 (m, 4H), 2.23 (s, 3H), 2.19 (m, 2H), 2.26 (m, 2H), Ul (m, 2H)，1.18 (m, 2H). C27H30Cl2N4O2的 MS (El)，實 測值 514.5 (MH+)。 Να-{[1-(2,4-二氣苯基）環丙基】羰基}-N-【3-(二甲基胺基）-丙基]-L-色胺醢胺：NMR (400 MHz，DMSO-d6): δ 10.79 (d&gt; 1Η), 7.88-7.80 (m, 1H), 7.55 (t, 1H), 7.42 (d, 1H), 7.35 (dd, 1H), 7.33-7.27 (m, 2H), 7.03 (ddd, 1H), 6.94 (ddd, 1H), 6.89 (d, 1H), 6.34 (t, J=13.1 Hz, 1H), 4.48-4.33 (m, 1H), 2.99-2.88 (m, 4H), 2.20 (t, 2H), 2.14 (s, 6H), 1.49 -136 (m，4H), 1.02-0.90 (m，2H). C26H30Cl2N4O2 的 MS (EI) ’ 實測值 502.5 (MH+)。 N_[(3S)-1-氮雜雙環【2.2.2】辛-3-基]-Not-{[l-(2,4-二氣苯 146258.doc •56- 201040149 基）-環丙基]羰基}_L-色胺醯胺：4 NMR (400 MHz， DMSO-d6)： δ 10.83 (s, 1Η), 7.88 (d5 1H), 7.57 (s, 1H), 7.42 (d, 1H), 7.32 (m, 3H), 7.02 (t, 1H), 6.94 (m, 2H), 6.38 (d, 1H), 4.50 (m, 1H), 3.55 (m, 1H), 2.93 (m, 3H), 2.63 (m, 4H), 2.21 (m, 1H), 1.68-1.41 (m, 6H), 1.26 (m, 1H), 0.97 (m，2H). C28H30Cl2N4O2的 MS (El)，實測值 526(MH+)。 1-(4-氣苯基）-N-【（lS)-l-(lH-吲哚-3-基甲基）-2-(4-甲基 呱嗪-1-基）-2-氧代乙基】環丙醢胺：NMR (400 MHz, DMSO-d6)： δ 10.86 (s, 1H), 7.38 (d, 1H), 7.32 (m, 3H), 7.20 (m，2H)，7.04 (t, 1H), 6.96 (m，2H)，6.58 (d，1H)，4.91 (m， 1H), 3.26 (s, 2H), 3.18 (m, 2H), 2.95 (m, 2H), 2.10-1.69 (m，4H), 2.02 (s, 3H), 1.32 (m, 2H), 0.95 (m, 2H). C26H29C1N402的MS (El)，實測值466(MH+)。 N-[(1S)-1-(1H-吲哚-3-基曱基）-2-(4-甲基呱嗪-1-基）-2-氧 代乙基]-1-[4-(甲氧基）苯基]環丙醯胺：4 NMR (400 MHz, DMSO-d6): δ 10.88 (s，1H)，7,38 (d，1H)，7.31 (d，1H)，7.14 (d, 2H), 7.04 (t, 1H), 6.96 (m, 2H), 6.83 (d, 2H), 6.40 (d, 1H), 4.93 (m, 1H), 3.73 (s, 3H), 3.23 (s, 2H), 3.13 (m, 2H), 2.93 (m, 2H), 2.11-1.61 (m, 4H), 2.00 (s, 3H), 1.31 (m, 2H), 0.89 (m，2H). C27H32N403 的 MS (El)，實測值 461(MH+)。 實施例2 N-[(lS)-l-[(2,4-二氣苯基）甲基]-2_(4-甲基呱嗪-1-基）-2-氧代乙基】-1-[4-(三氟甲基）苯基】環丙醢胺 H6258.doc -57- 201040149146258.doc •52· 201040149 Step 1: (S)-2-Amino-3-(1Η-indol-3-yl)-1-(4-methylpyridazine-i-yl)propan-l-_ :(S)-2·(tert-Butoxycarbonylamino)-3-(1Η-indol-3-yl)propionic acid 2,5-dioxoindole-1-yl ester (into (^) &amp;11〇6〇1€;1^11116〇11,803 mg, 2 mmol) dissolved in anhydrous acetonitrile (10 mL). Add N-methyl &lt; guarazine (23 3 μί, 2.1 mmol) and The solution was scrambled for two hours. A complete reaction was indicated by LCMS analysis. A 4N hydrochloric acid solution dissolved in dioxone (2 mL) was added and the solution was stirred overnight. A precipitate formed and the precipitate was filtered and washed with acetonitrile. LCMS analysis of solids It is shown to be (S)-2-amino-3-(1Η-indol-3-yl)-1 -(4-methylpyridazin-1-yl)propan-1-one, presumed to be dihydrochloric acid. The title compound (1.92 mmol of monohydrochloride) was obtained after vacuum drying. This material was used in the next step without further purification. Step 2: (1-(2,4-dibenzene) -N-[(2S)-3-(lH-indol-3-yl)-1-(4-methyl 11 guanidin-1-yl)-1-oxopropan-2-yl] ring Acrylic amine: (S)- dissolved in anhydrous acetonitrile (10 mL) 2-amino-3-(1Η-indol-3-yl)-1-(4-indolylindole-1-yl)propan-1-one dihydrochloride (690 mg, 1.92 mmol) and Add 1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Acros, 443 mg ' 1.92 mmol) to a solution of Hunig (1.64 mL, 9.6 mmol). Add HATU (Applied Biosystems ' 802 mg ' 2.11 mmol And the reaction solution was stirred overnight. The product was isolated by reverse phase preparative HPLC (aqueous ammonium acetate buffer, pH~4-5, acetonitrile; 20-70% elution gradient). Part of the purified product was collected. Mix, concentrate and freeze-dry to obtain (1-(2,4-dichlorophenyl)-N-[(2S)-3-(lH-indol-3-yl)-1-(4-methylindole) Pyrazin-1-yl)-1-oxopropan-2-yl]cyclopropanamide (466 mg) NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 7.61 (d, 1H) , 7.41(d, 1H), 7.35 (m, 2H), 7.31 146258.doc -53- 201040149 (d, 1H), 7.04 (t, 1H), 7.01 (d, 1H), 6.85 (t5 1H), 6.68 (d, 1H), 5.93 (dd, 1H), 3.25 (bs, 3H), 3.08 (b, 1H), 2.95 (m, 2H), 2.17 (b, 1H), 2.09 (b, 1H), 2.05 ( s, 3H), 1.94 (b, 1H), 1.70 (b, 1H), 1.45 (b, 2H), 0.97 (m, 2H); MS (El) of C26H28C12N402 Found 499.〇〇 (MH +). The following compounds were prepared in a similar manner to Example 1. 1-(2,4-diphenyl)-N-[(lS)-2-[3-(dimethylamino)azetidin-1-yl]-1-(1Η-吲哚- 3-ylmethyl)-2-oxoethyl]cyclopropanamide: 1H NMR (400 MHz, DMSO-d6): δ 10.87 (d, 1 Η), 7.60 (dd, 1H), 7.46 (dd, 1H) ), 7.42-7.36 (m, 2H), 7.33 (dd, 1H), 7.03 (m, 3H), 6.60 (dd, 1H), 4.57-4.39 (m, 1H), 3.96 (t, 1H), 3.80 ( m, 1H), 3.69-3.51 (m, 2H), 3.38 (m, 1H), 2.98-2.91 (m, 2H), 1.98 (s, 3H), 1.90 (s, 3H), 1.48 (m, 2H) MS (El), found for C26H28C12N402, found 500.4 (MH+). Να-{[1-(2,4-Diphenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)-ethyl]-L-tryptamine: 4 NMR ( 400 MHz, DMSO-d6): δ 10.81 (s, 1H), 7.72 (t, 1H), 7.58 (d, 1H), 7.43 (d, 1H), 7.36 (dd, 1H), 7.31 (d, 2H) , 7.10-7.01 (m, 1H), 7.01-6.90 (m, 2H), 6.40 (d, 1H), 4.45 (dd, 1H), 3.20-2.84 (m, 4H), 2.18 (t, 2H), 2.11 (s, 6H), 1.43 (d, 2H), 0.99 (d, 2H). MS (El) of C25H28C12N402, found 488.4 (MH+). 1-(2,4-diphenyl)-N-[(lS)-l-(lH_indol-3-ylindenyl)-2-(4-methyl-1,4-diaza Cycloheptan-1-yl)-2-oxoethyl]cyclopropanol: 4 NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 7.62 (d, 1H), 146258.doc -54- 201040149 7.44 (dd, 1H), 7.39 (d, 2H), 7.32 (d, 1H), 7.07-6.93 (m, 3H), 6.70 (dd, 1H), 4.94 (dt, 1H), 3.32- 3.27 (m, 2H), 3.19 (dd, 1H), 3.07-2.82 (m, 2H), 2.41-2.15 (m, 3H), 2.09 (d, 4H), 2.03-1.92 (m, 1H), 1.61 ( s, 1H), 1.47 (s, 3H), 1.00 (d, - 2H). MS (El) of C27H30Cl2N4O2, found 514.5 (MH+). 1-(2,4-diphenyl)-N-[(1S)-1-(1H-indol-3-ylmethyl)-2-oxo-2-pyridazin-1-ylethyl Cyclopropanol: 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 8.24 (s, 1H), 7.63 (d, 1H), 7.44 (d, 〇1H), 7.41-7.34 ( m, 2H), 7.32 (d, 1H), 7.05 (dd, 1H), 7.02 (d, 1H), 6.97 (dd, 1H), 6.72 (d, 1H), 4.94 (dd, 1H), 3.27 (d , J=3.9Hz, 3H), 3.11 (s, 1H), 3.02-2.87 (m, 2H), 2.67-2.52 (m, 1H), 2.46 (s, 1H), 2.23 (s, 1H), 1.55- 1.40 (m, 2H), 1.07-0.93 (111, 2^1). (: 25 26 (: 121 &lt; [4〇2]^8 (ugly 1), measured value 486.4 (MH+). l-( 2,4-diphenylphenyl)-N-[(1S)-1-(1H-indol-3-ylmethyl)-2-morpholin-4-yl-2-oxoethyl]cyclopropane Indoleamine: 4 NMR (400 MHz, DMSO- ❹ d6): δ 10.87 (s, 1H), 7.66-7.62 (m, 1H), 7.44 (d, 1H), 7.39 (d, 2H), 7.33 (d, 1H), 7.11-7.02 (m, 2H), 7.02-6.93 (m, 1H), • 6.74 (d, 1H), 5.03-4.81 (m, 1H), 3.33-3.20 (m, 5H), 3.12 - ( m, 2H), 3.02-2.92 (m, 2H), 2.90-2.78 (m, 1H), 1.57-1.39 (m, 2H), 1_01 (m, 2H). MS (El) for C25H25C12N303, found 487.4 ( MH+) 1-(2,4-diphenyl)-N-[(lS)-2- {4-[3-(Dimethylamino)propyl]pyridazin-1-yl}-1-(111-indol-3-ylmethyl)-2-oxoethyl]cyclopropanamide :4 146258.doc -55- 201040149 NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 7.65-7.60 (m, 1H), 7.42 (dd, 1H), 7.39-7.37 (m, 2H ), 7_32 (d, 1H), 7.05 (dd, 1H), 7.01 (d, 1H), 6.99-6.94 (m, 1H), 6.68 (d, 1H), 4.94 (q, 1H), 3.26 (s, 4H), 2.95 (qd, 2H), 2.23 (dd5 2H), 2.16 (s5 2H), 2.15 (s, 6H), 2.10 (d, 2H), 1.96 (d, 1H), 1.70 (d, 1H), 1.53-1.41 (m, 4H), 1.01 (d, 2H)· C30H37 (1^8 kg 1 of 12乂02), measured value 571.6 (]^^1+). Να-{[1-(2,4-Diphenyl)cyclopropyl]carbonyl}-N-(l-decylacridin-4-yl)-L-tryptamine: NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1Η), 7.55-7.51 (m, 1H), 7.40 (dd5 1H), 7.33-7.36 (m, 2H), 7.32 (d, 1H), 7.05 (dd, 1H) , 7.01 (d, 1H), 6.99-6.94 (m, 1H), 6.68 (d, 1H), 4.94 (q, 1H), 3.60 (m, 1H), 3.11 (m, 2H), 2.48 (m, 4H) ), 2.23 (s, 3H), 2.19 (m, 2H), 2.26 (m, 2H), Ul (m, 2H), 1.18 (m, 2H). MS (El) of C27H30Cl2N4O2, found 514.5 (MH+) . Να-{[1-(2,4-Diphenyl)cyclopropyl]carbonyl}-N-[3-(dimethylamino)-propyl]-L-tryptamine: NMR (400 MHz, DMSO-d6): δ 10.79 (d&gt; 1Η), 7.88-7.80 (m, 1H), 7.55 (t, 1H), 7.42 (d, 1H), 7.35 (dd, 1H), 7.33-7.27 (m , 2H), 7.03 (ddd, 1H), 6.94 (ddd, 1H), 6.89 (d, 1H), 6.34 (t, J=13.1 Hz, 1H), 4.48-4.33 (m, 1H), 2.99-2.88 ( m, 4H), 2.20 (t, 2H), 2.14 (s, 6H), 1.49 -136 (m, 4H), 1.02-0.90 (m, 2H). MS (EI) of C26H30Cl2N4O2 '5050 (MH+) . N_[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-Not-{[l-(2,4-diphenylbenzene 146258.doc •56- 201040149 base)-cyclopropyl ]carbonyl}_L-tryptophanamine: 4 NMR (400 MHz, DMSO-d6): δ 10.83 (s, 1 Η), 7.88 (d5 1H), 7.57 (s, 1H), 7.42 (d, 1H), 7.32 (m, 3H), 7.02 (t, 1H), 6.94 (m, 2H), 6.38 (d, 1H), 4.50 (m, 1H), 3.55 (m, 1H), 2.93 (m, 3H), 2.63 ( m, 4H), 2.21 (m, 1H), 1.68-1.41 (m, 6H), 1.26 (m, 1H), 0.97 (m, 2H). MS (El) of C28H30Cl2N4O2, found 526 (MH+). 1-(4-Phenylphenyl)-N-[(lS)-l-(lH-indol-3-ylmethyl)-2-(4-methylpyridazin-1-yl)-2-oxo </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; t, 1H), 6.96 (m, 2H), 6.58 (d, 1H), 4.91 (m, 1H), 3.26 (s, 2H), 3.18 (m, 2H), 2.95 (m, 2H), 2.10-1.69 (m, 4H), 2.02 (s, 3H), 1.32 (m, 2H), 0.95 (m, 2H). MS (El) of C26H29C1N402, found 466 (MH+). N-[(1S)-1-(1H-indol-3-ylindenyl)-2-(4-methylpyridazin-1-yl)-2-oxoethyl]-1-[4- (Methoxy)phenyl]cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 7, 38 (d, 1H), 7.31 (d, 1H), 7.14 ( d, 2H), 7.04 (t, 1H), 6.96 (m, 2H), 6.83 (d, 2H), 6.40 (d, 1H), 4.93 (m, 1H), 3.73 (s, 3H), 3.23 (s , 2H), 3.13 (m, 2H), 2.93 (m, 2H), 2.11-1.61 (m, 4H), 2.00 (s, 3H), 1.31 (m, 2H), 0.89 (m, 2H). C27H32N403 MS (El), found 461 (MH+). Example 2 N-[(lS)-l-[(2,4-Diphenyl)methyl]-2-(4-methylpyridazin-1-yl)-2-oxoethyl]-1 -[4-(trifluoromethyl)phenyl]cyclopropanamide H6258.doc -57- 201040149

NaOHNaOH

ΗΗ

四 步琢1 1-(4-(二氟甲基）苯基）環丙基腈：於向溶於 氫吱鳴(〜)的2-(4_(三氟甲基)苯基)乙腈(l g，54 mmol ’ AK Scientific)溶液加入氫化鈉（〇 4 g，16 6 mmol)。於〇°C將反應混合物攪拌5分鐘，之後加入溶於四 氫呋喃（1 mL)的U2-二漠乙烷（2.6 g，141 _〇1)。將反應 物於〇°C攪拌2小時並於室溫攪拌16小時’之後加入i mL的 水，並且在減壓下濃縮’將所得的漿液溶於丨〇〇 mL乙酸乙 酯，並且用10 mL水萃取。用硫酸鎂乾燥有機層。減壓下 過濾並濃縮得到600 mg(52.6%)的1-(4_(三氟曱基）苯基）環 丙基腈’其用於下一步驟而無需進一步純化。CuHsFgN的 MS (EI)，實測值212 (MH+)。Four-step 琢1 1-(4-(difluoromethyl)phenyl)cyclopropylcarbonitrile: 2-(4-(trifluoromethyl)phenyl)acetonitrile (lg) dissolved in hydrogen (~) , 54 mmol 'AK Scientific) solution was added to sodium hydride (〇4 g, 16 6 mmol). The reaction mixture was stirred at rt for 5 min then added EtOAc &lt The reaction was stirred at 0&lt;0&gt;C for 2 h and at rt for 16 h then added 1 mL water and concentrated under reduced pressure. &lt;&gt; Water extraction. The organic layer was dried over magnesium sulfate. Filtration and concentration under reduced pressure afforded &lt;RTI ID=0.0&gt;&gt;&gt; MS (EI) for CuHs.

步驟2 : 1-(4-(三氟甲基）苯基）環丙羧酸：向^(4-(三氟甲 基）苯基）環丙基腈（600 mg，2_8 mmol)加入20 mL的3 NStep 2: 1-(4-(Trifluoromethyl)phenyl)cyclopropanecarboxylic acid: 20 mL to ^(4-(trifluoromethyl)phenyl)cyclopropylcarbonitrile (600 mg, 2-8 mmol) 3 N

NaOH溶液並且將反應混合物加熱至回流1 8小時，之後冷 卻至室溫。將所得的溶液用1 N HC1酸化至pH3並且用50 mL的EtOAc萃取。用硫酸鎂乾燥有機層。減壓下過濾並濃 縮得到400 mg(62%)的1-(4-(三氟曱基）苯基）-環丙羧酸， 146258.doc •58· 201040149 其用於下一步驟而無需進一步純化。CnH9F302的MS (EI)，實測值 231 (MH+)。 步驟3 : (S)_2-胺基-3-(2,4-二氣苯基）-1-(4-甲基呱嗪-1_ 基）丙-1-酮：向溶於二氯甲烷（100 mL)的（S)-2-(叔丁氧羰 基胺基）-3-(2,4-二氣苯基）丙酸（1〇 g，29 mmol，Aldrich)溶 液加入N-甲基呱嗪（i〇 g，loo mm〇l)、1·羥基苯並三唑（5 g，33 mmol)、Ν-曱基嗎啉（20 mL，182 mmol)、1-[3-(二 甲基胺基）丙基]-3-乙基碳二亞胺鹽酸鹽（7.3g，38 mmol)。 將反應物於室溫攪拌1 8小時。用水（2 X 250 mL)和飽和碳 酸氫鈉溶液（2 X 250 mL)萃取所得的溶液，用硫酸鎂乾 燥，真空過濾並濃縮。將所得的油溶於曱醇（1 〇〇 mL)，之 後加入溶於二噁烷（1〇〇 mL，Aldrich)的4 N HC1。將反應 物於室溫攪拌1 8小時。真空濃縮反應混合物以產生 11-5以100%)的（3)-2-胺基-3-(2,4-二氣苯基）-1-(4-甲基呱嗪_ 1-基）丙-1-酮，其用於下一步驟而無需進一步純化。 C14H19Cl2N3〇的MS (EI)，實測值316.3 (MH+)。 步琢4 : N-[(lS)-l-[(2,4·二氣苯基）甲基】-2-(4-甲基呱嗪· 1-基）-2-氧代乙基]444-(三氟甲基）苯基]環丙醯胺：向溶 於二氣甲烷（5 mL)的（S)-2-胺基-3-(2,4-二氯苯基）-1-(4-甲 基D瓜嗓-1-基）丙-1-酮（200 mg ’ 0.63 mmol)溶液加入1_(4_ (二氟甲基）本基）環丙叛酸（200 mg，0·86 mmol)、1 -經基苯 並三唑（250 mg，1.85 mmol)、N-甲基嗎啉（1 ，9.1 mmol)、1-[3-(二甲基胺基）丙基]_3 -乙基碳二亞胺鹽酸鹽 (3 00 mg，1.56 mmol)。將反應物於室溫攪拌18小時。用水 146258.doc •59- 201040149 (2 X 250 mL)和飽和碳酸氫鈉溶液（2 X 250 mL)萃取有機溶 液，用硫酸鎂乾燥，真空過濾並濃縮。之後通過製備級 HPLC(反相，乙腈/含水的10 mM甲酸緩衝液）純化產物以 產生 24mg的標題化合物。1H NMR (400 MHz，CDC13): δ 7.65 (d, 2Η), 7.50 (d, 2H), 7.36 (d, 1H), 7.15 (dd, 1H), 7.95 (d, 1 H), 6.09 (d, 1 H), 5.22 (dd, 1H), 3.57 (m, 1H), 3.48 (m, 2H), 3.30 (m, 1H), 2.96 (m, 1H),2.87 (m, 1H), 2.34 (m, 3H), 2.24 (s, 3H), 2.06 (m, 1H), 1.52 (m, 2H), 1.04 (m, 2H); C25H26C12F3N302 的 MS (El)，實測值529.2 (MH+)。 以類似於實施例2的方式製備下列化合物。 以與實施例2相似的方式合成N-[(lS)-l-[(2-氣苯基）甲 基]-2-(4-甲基呱嗪-1-基）-2-氧代乙基】_ι_(2,4-二氣苯基）環 丙醯胺’其中（S)-2-(叔丁氧羰基胺基氯苯基）丙酸 (PepTech Corp)替代（S)-2-(叔 丁氧羰基胺基）-3-(2,4-二氯苯 基）丙酸，並且1-(2,4-二氣苯基）環丙羧酸（Aldrich)替代^ (4-(三氟甲基）苯基）環丙羧酸。lHNMR(400 MHz，DMSO-d6)： δ 7.60 (d, 1H), 7.43-7.33 (m, 3H), 7.24-7.17 (m, 3H), 6.87 (d, 1H), 5.02 (m, 1H), 3.44-3.27 (m, 4H), 2.96-2.84 (m, 2H), 2.23-2.10 (m, 7H), I.37 (m? iH), 1.23 (m, 1H), 0.92(111，211);(：241126(：13&gt;13〇2的]^8(丑1)，實測值 495.85 (MH+)。 以與實施例2相似的方式合成i_(2,4-二氣苯基）-N-[(1S)-甲氧基）苯基]甲基}-2·(4-甲基呱嗪-1-基）-2-氧代乙 基】環丙酸胺，其中（S)-2-(叔丁氧羰基胺基）_3_(4_甲氧苯 146258.doc 60· 201040149 基）丙酸（Fluka)替代（S)-2-(叔丁氧羰基胺基）_3_(2,4_二氯苯 基）丙酸’並且1-(2,4-二氣苯基）環丙羧酸（Aldrich)替代 1-(4-(三氟甲基）苯基）環丙羧酸。iH NMR (400 MHz, DMSO-d6): δ 8.15, (s, 1Η), 7.65 (s, 1H), 7.43 (s, 1H), 6.96 (d, 2H), 6.78 (d, 2H), 6.66 (d, 1H), 4.85 (m, 1H), 3.72, (s, 3H), 3.32 (m, 4H), 2.76 (m, 2H), 2.20 (m, 2H), 2.13 (s, 3H), 2.05 (m，2H)，1.42 (m，2H)，l.oi (m，2H). c25h29C12N303的 MS (El) : 491.3 (MH+)。 〇 以與實施例2相似的方式合氣苯基 甲基呱嗪-1-基）-1-氧代丙_2·基卜^^心二氣苯基）環丙醯 胺’其中（S)-2-(叔丁氧羰基胺基）_3_(3_氣苯基）丙酸 (PepTech Corp)替代（S)-2-(叔 丁氧羰基胺基）_3·(2,4_二氯苯 基）丙酸，並且1-(2,4-二氯苯基）環丙羧酸（Aldrich)替代卜 (4-(二氟曱基）苯基）環丙綾酸。iH NMR (4〇〇 MHz，DMS〇_ d6)： δ 7.59 (d, 1H), 7.39(m, 2H), 7.27 (m, 2H), 7.14 (bs, Q IH), 7.06 (m, 1H), 6.89 (d, 1H), 4.88 (m, 1H), 3.41 (m, 2H), 3.35 (m, 2H), 2.80 (m, 2H), 2.17 (m, 4H), 2.12 (s, 3H), 1.35 (m, 2H)，0.95 (m, 2H); C24H26C13N302的 MS (El)，實 測值495.04 (MH+)。 以與實施例2相似的方式合成2_(2,4_二氣苯基）_N_[(is)_ 1- [(2,4-二氣苯基）甲基】·2_(4_甲基呱嗓小基）2氧代乙基】_ 2- 甲基丙醯胺，其中碘甲烷替代丨，2_二溴乙烷，並且2_ (2,4-二氣苯基）乙腈（Aldrich)替代2_(4_(三氟曱基）苯基）乙 腈。H NMR (400 MHz，CDC13): δ 7.26 (m，3H)，7.26 (d， 146258.doc -61 - 201040149 1H)，7.10 (m，1H)，6.96 (d，1H)，5.98 (d, 1H)，5.19 (m, 1H), 3.62 (m，1H)，3·48 (m，1H)，3 38 (m，m)，3 17 ㈤， 3·01 (m，1H)，2.83 (m，1H)，2.30 (m，2H), 2.20 (s，3H)， 2.01(m，2H)，1.46 (d，6H). c24H27C4N302的 MS (El) : 532.5 (MH+)。 以與實施例2相似的方式合成1(2,4二氣苯基）n [(is)_ l-【(3,4-二氣苯基）甲基】_2_(4_甲基呱嗓小基）2氧代乙基】 環丙醯胺，其中（S)-2-(叔了氧幾基胺基）3(3,4二氣苯基） 丙酸（SyntheTech)替代（8)·2_(叔丁氧羰基胺基）_3 (2,4_二氣 苯基）丙酸，並且1-(2,4-二氯苯基）環丙羧酸（Aldrich)替代 1-(4-(二氟甲基）苯基）環丙羧酸。iH NMR (4〇〇 MHz， DMSO-d6): δ 7.61 (d，1H)，7.50 (m，1H)，7.45-7.39 (m, 2H)， 7.37 (d，1H)，7.12 (dd，1H), 6.97 (d, 1H), 4.93-4.87 (m, 1H), 3.46-3.38 (m, 4H), 2.88-2.76 (m, 2H), 2.26-2.15 (m, 7H), 1.41 (m, 1H), 1.28 (m, 1H), 0.97 (m, 2H); C24H25Cl4N3〇2的 MS (El) ’ 實測值 530 3 ][ (MH+)。 以與實施例2相似的方式合成1_(2,4_二氣苯基）_N_[(1S)_ l-[(4-氟苯基）甲基】-2-(4-甲基呱嗪_ι_基）_2_氧代乙基]環丙 酸胺’其中（S)-2-(叔丁氧羰基胺基）·3_(4-氟苯基）丙酸 (Fluka)替代（S)-2-(叔丁氧羰基胺基）_3_(2,4_二氯苯基）丙 酸，並且卜(2,4-二氯苯基）環丙羧酸（Aldrich)替代1-(4-(三 氟曱基）苯基）環丙羧酸。1H NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1Η), 7.63 (s, 1H), 7.43 (s, 1H), 7.08 (m, 4H), 6.81 (d, 1H), 4.59 (m, 1H), 3.34 (m, 4H), 2.81 (m, 2H), 2.19 (m, 146258.doc •62- 201040149 2H), 2.14 (s, 3H), 2.09 (m, 2H), 1.38 (m, 2H), 0.97 (m, 2H); C24H26Cl2FN3〇2的 MS (El)，實測值479.2 (MH+)。 以與實施例2相似的方式合成二氣苯基） l-[(2,4-二氣苯基）甲基】甲基呱嗪“基）2氧代乙基】 環丙酸胺’其中1-(2,4_二氯苯基）環丙羧酸（Aldrich)替代 1-(4-(二氟甲基）苯基）環丙羧酸。lHNMR(400 MHz，D4-MeOD): δ 7.51 (d, 1H), 7.48-7.35 (m, 3H), 7.35 (dd, 1H), 7.15 (d, 1H), 5.18 (t, 1H), 3.78-3.63 (m, 2H), 3.58-3.44 (m, 2H), 3.05 (dd, 1H), 2.96 (dd, 1H), 2.78-2.55 (m, 4H), 1.58-1.43 (m，2H)，1.13-1.10 (m，2H) C24H25Cl4N3〇jMS (El)，實測值 530 (MH+)。 以與實施例2相似的方式合成4_溴二氣苯 基）環丙基】擬基卜N-[2-(二甲基_胺基）乙基】苯丙胺醯 胺’其中（S)-2-(叔丁氧羰基胺基）_3_(4_溴苯基）丙酸 (SyntheTech)替代（S)-2-(叔丁氧羰基胺基）·3_(2,4_二氯笨 ❹ 基）丙酸，ΝΑ二甲基乙-1，2-二胺（Aldrich)替代Ν-曱基呱 嗪，並且1-(2,4-二氯苯基）環丙羧酸（Aldrich)替代丨_(4_(三 氟曱基）苯基）環丙羧酸。1H NMR (4〇〇 MHz，DMSO-d6；): δ 8.19(s, 1Η), 7.81 (t, 1H), 7.59 (s, 1H), 7.39 (m, 4H), 7.〇i (d, 2H), 4.42 (m, 2H), 3.11 (m? 2H), 2.80 (m, 2H), 2.24 2H), 2.14 (s, 6H), 1.37 (m, 2H), 0.95 (m, 2H)； C23H26BrC12N3〇2的 MS (El)，實測值 528 6 (MH+)。 以與實施例2相似的方式合成^(夂‘二氣苯基）_N_[(1S)_ 乙氧基）笨基]甲基}_2_(4•甲基_呱嗪基）_2_氧代乙 146258.doc -63- 201040149 基】環丙醯胺，其中（S)-2-(叔丁氧羰基胺基）-3-(4-乙氧苯 基）丙酸（SyntheTech)替代（S)-2-(叔丁氧羰基胺基）-3-(2,4-二氯苯基）丙酸’並且1-(2,4-二氯苯基）環丙羧酸（Aldrich) 替代1-(4-(三氟曱基）苯基）環丙羧酸。1H NMR (400 MHz， DMSO-d6): δ 8.24 (s，1H)，7.70 (s，1H), 7.17 (m，4H)，6.92 (m, 2H), 4.91 (m, 1H), 4.09 (m, 2H), 3.51 (m, 4H), 2.86 (m, 2H), 2.32 (m, 7H), 1.52 (t, 3H), 0.93 (m, 2H), 0.63 (m, 2H); C26H31C12N303 的 MS (El)，實測值 504.5 (MH+)。 以與實施例2相似的方式合成l-(2,4-二氣苯基）-N-[(1S)_ 1- 【(2,4-二甲基苯基）甲基】-2-(4-甲基-呱嗪-1-基）-2-氧代乙 基]環丙醢胺，其中（S)-2-(叔丁氧羰基胺基）-3-(2,4-二曱基 苯基）丙酸（PepTech)替代（S)-2-(叔丁氧羰基胺基）-3-(2,4-二 氯苯基）-丙酸，並且-(2,4-二氯苯基）環丙羧酸（Aldrich)替 代1-(4-(三氟甲基）苯基）環丙羧酸。1H NMR (400 MHz, DMSO-d6): δ 8.24 (s，1H)，7.73 (s, 1H)，7.20 (m，3H)，7.04 (m, 3H), 4.91 (m, 1H), 4.09 (m, 2H), 3.51 (m, 4H), 2.86 (m, 2H), 2.32 (m, 8H), 1.52 (t, 3H), 0.93 (m, 2H), 0.63 (m, 2H). C26H31C12N302的 MS (El)，實測值 488.5 (MH+)。 以與實施例2相似的方式合成1-(2,4-二氣苯基）_N_[(1S)_ 2- (4-甲基11瓜嗓-1-基）-1-(萘-2-基甲基）-2 -氧代乙基]環丙酸 胺，其中（S)-2-(叔丁氧羰基胺基）-3-(萘·2-基）丙酸 (Aldrich)替代（S)-2-(叔丁氧羰基胺基）-3-(2,4-二氯苯基）丙 酸’並且1-(2,4-二氣笨基）環丙羧酸（Aldrich)替代丨_(4_(三 氟曱基）苯基）環丙羧酸。1H NMR (400 MHz, DMSO-d6): δ 146258.doc • 64 - 201040149 7.84-7.78 (m, 3H), 7.58-7.43 (m, 3H), 7.39-7.25 (m, 4H), 5.19-5.10 (m, 1H), 3.62-3.37 (m, 4H), 3.05 (m, 2H), 2.57-2.40 (m, 2H), 2.35-2.23 (m, 1H), 2.18 (s, 3H), 1.83-1.77 (m, 1H), 1.60-1.50 (m, 2H), 1.16 (m, 1H), l.〇〇 (m&gt; 1H); ' C28H29C12N302 的 MS (El) ’ 實測值 511 (MH+)。 以與實施例2相似的方式合成1(2 +二氣苯基）_沁丨(18)_ 1-[(4-甲基苯基）甲基]-2-(4-甲基-呱嗪-1-基）-2-氧代乙基】環 丙醢胺，其中（S)-2-(叔丁氧羰基胺基）_3_(4-甲基笨基）丙酸 ◎ (Fluka)替代（S)-2-(叔丁氧羰基胺基）-3-(2,4-二氣笨基）丙 酸，並且1-(2,4-二氯苯基）環丙羧酸（Aldrich)替代1-(4-(三 氟甲基）苯基）環丙羧酸。1H NMR (400 MHz，DMSO-d6): δ 7.64 (t, 1Η), 7.42 (d, 2H), 7.03 (d, 2H), 6.94 (d, 2H), 6.69 (d, 1H), 4.87 (m, 1H), 3.42-3.25 (m, 4H), 2.82-2.70 (m, 2H), 2.25 (s, 3H), 2.20-2.13 (m, 7H), 1.42 (m, 2H), 0.97 〇,211);(：251129(：12&gt;1302的]^8(£1)，實測值475.44 (]\411+)。 以與實施例2相似的方式合成N-[(lS)-l-【(4-溴苯基 &gt; 甲 ❹ 基卜2-(4-甲基呱嗪-1-基）-2-氧代乙基]-1-(2,4-二氣苯基）環 丙醢胺，其中（S)-2-(叔丁氧羰基胺基）-3-(4-溴苯基）丙酸 (SyntheTech)替代（S)-2-(叔 丁氧羰基胺基）-3-(2,4-二氯苯 -基）丙酸，並且1-(2,4-二氯苯基）環丙羧酸（Aldrich)替代1-(4-(三氟甲基）苯基）環丙羧酸。1HNMR(400 MHz，DMSO-d6)： δ 7.63 (s, 1H), 7.43 (m, 4H), 7.05 (d, 2H), 6.86 (d, 1H), 4.90 (m, 1H), 3.46-3.33 (m, 4H), 2.86-2.73 (m, 2H), 2.24-2.10 (m, 7H), 1.44-1.34 (m, 2H), 1.01-0.96 (m, 2H); 146258.doc 65- 201040149 (：24112681'(：12]^3〇2的]\/18即），實測值 540.31 (]^+)。 以與實施例2相似的方式合成卜^扣二氣苯基）_N_[(1S)-l-[(2,4-二氣苯基）甲基]-2-(4-甲基呱嗪_ι_基）_2_氧代乙基】 環丙酿胺其中1-(3,4-一氣苯基）環丙缓酸（Aldrich)替代 1-(4-(三氟甲基）苯基）環丙羧酸。iH nmR (400 MHz， DMSO-de)： δ 7.60 (d, 1Η), 7.55 (d, 1H), 7.48 (d, 2H), 7.36 (m，1H)，7.23 (d，2H)，7.19 (d，1H), 4.98 (m，1H)，3.45 (m, 2H), 2.94 (m, 2H), 2.1h (m, 7H), 1.22 (m, 1H), 1.10 (m, 1H)，0·97 (m，2H); C24H25C14N302 的 MS (El)，實測值 529.80 (MH+)。 以與實施例2相似的方式合成n_丨氣苯基）甲 基]-2-(4-曱基呱嗪-1-基）_2_氧代乙基]氣苯基）環 丙醢胺，其中（S)-2-(叔丁氧羰基胺基）_3_(4_氯苯基）丙酸 (Fluka)替代（S)-2-(叔丁氧羰基胺基）_3_(2 4_二氯苯基）丙 酸，並且1-(2,4-一氣笨基）環丙叛酸（Aldrich)替代1-(4-(三 氟曱基）苯基）環丙羧酸。1H NMR (400 MHz，DMSO_d6h δ 7.63 (s, 1Η), 7.40 (s, 2H), 7.26 (d, 2H), 7.09 (d, 2H), 6.83 (d, 1H), 4.87 (m, 1H), 3.46-3.25 (m, 4H), 2.86-2.73 (m, 2H), 2.19-2.02 (m, 7H), 1.42-1.29 (m, 2H), 0.98-0.89 (m, 2H); C24H26C13N302的 MS (El)，實測值 495.84 (MH+)。 以與實施例2相似的方式合成1_(2,4_二氣笨基）_N_丨（1S)_ 1_[(2 -氣苯基）甲基]-2-(4-甲基略嗓_ι_基）_2-氧代乙基]環丙 雄胺，其中（S)-2-(叔丁氧羰基胺基）_3_(2_氟苯基）丙酸 (Synthetech)替代（S)-2-(叔丁氧羰基胺基）_3_(2,4_二氣苯基） 146258.doc -66 - 201040149 丙酸，並且1_(2,4·二氯苯基）環丙羧酸（Aldrich)替代1-(4-(二氟曱基）苯基）環丙羧酸。1H NMR (400 MHz，DMSO-d6): δ 8.14 (s, 1Η), 7.60 (d, 1H), 7.39 (m, 2H), 7.24 (m, 1H), 7.06 (m, 2H), 6.78 (d, 1H), 4.94 (m, 1H), 3.56 (m, 4H), 2.86 (m, 2H), 2.22 (m, 3H), 2.12 (m, 4H), 1.30 (m, 2H), 〇-93〇，211);(：241126(：12卩]^302 的]^8斤1)，實測值 478.4 (MH+)。 以與實施例2相似的方式合成^(2,4-二氣苯基）-N-[(1S)-2-(4-甲基狐嗪-i_基）_2_氧代“—（丨心（三氟甲基）苯基】甲基} 乙基】環丙醯胺，其中（S)-2-(叔丁氧羰基胺基）-3-(4-(三氟 曱基）苯基）丙酸（Fluka)替代（S)-2-(叔丁氧羰基胺基）-3-(2,4-二氣苯基）丙酸，並且ι_(2,4-二氯苯基）環丙羧酸 (Aldrich)替代1-(4-(三氟曱基）苯基）-環丙羧酸。1H NMR (400 MHz, DMSO-d6): δ 8.18 (s, 1Η), 7.61 (d, 3H), 7.41 (s, 1H), 7.33 (d, 2H), 6.95 (d, 2H), 4.96( m, 1H), 3.40 (m, 4H), 2.93 (m, 2H), 2.17 (m, 2H), 2.13 (s, 1H), 2.06 (m, 2H), 1.41 (m，2H), 1.29 (m，2H); C25H26C12F3N302的MS (El)，實測值 529.5 (MH+)。 1-(2,4-二氣苯基）-N-[2-(4-曱基呱嗪-1-基）-2-氧代-1-(苯 基甲基）乙基】環丙醯胺：4 NMR (400 MHz，DMSO-d6): δ 7.51 (d, 1H), 7.48-7.35 (m, 3H), 7.35 (dd, 1H), 7.15 (d, 1H), 5.18 (t, 1H), 3.78-3.63 (m, 2H), 3.58-3.44 (m5 2H), 3.05 (dd, 1H), 2.96 (dd, 1H), 2.78-2.55 (m, 4H), 1.58-1.43 (m, 2H)，1.13-1.10 (m，2H). C24H27C12N302 的 MS (El)，實 146258.doc -67- 201040149 測值 460.402 (MH+)。 1-(2,6-二氣苯基）-N-[(lS)-l-[(2,4-二氯苯基）甲基]-2-(4-甲基呱嗪-1-基）-2-氧代乙基】環丙醢胺：4 NMR (400 MHz, DMSO-d6)： δ 7.52 (d, 1H), 7.48 (m, 2H), 7.39-7.25 (m, 3H), 7.05 (d, 1H), 5.04 (m, 1H), ), 3.47 (m, 4H), 2.93 (3, 2H), 2.27-2.21 (m, 4H), 2.15 (s, 3H), 1.59 (m, 2H), 1.06 (111，211);(：241125(：141\[302的]\48(£1)，實測值529.23 (1^11+)。 1-(2,4-二氣苯基）-N-{(lS)-2-(4-甲基呱嗪基）-2_氧代_ l-[(3,4,5-三氟苯基）甲基]乙基}環丙醢胺：士 NMR (400 MHz，DMSO-d6): δ 7.57 (d，1H)，7.39 (m，1H), 7.26 (m， 1H), 6.88 (m, 2H), 4.89 (q, 1H), 3.33-3.38 (m, 4H), 2.81 (m, 2H), 2.18 (s, 3H), 2.16 (m, 2H) 1.32 (m, 2H), 0.95 (m, 2H). C24H24C12F3N302 的 MS (El)，實測值 515.4 (MH+)。 1-(2,4-二氣苯基）-N-【(lS)-l-[(3,4-二氟苯基）甲基】-2-(4-甲基呱嗪-1-基）-2-氧代乙基]環丙醢胺：NMR (400 MHz, DMSO-d6): δ 8.17 (s，1Η), 7·60 (d，1Η)，7.42 (dt， 2Η), 7.30 (dt, 1H), 7.17 (ddd, 1H), 6.94 (d, J=8.2Hz, 2H), 4.94-4.80 (m, 1H), 3.40 (dd, 4H), 2.81 (qd, 2H), 2.55-2.47 (m, 1H), 2.20 (t, 4H), 1.51-1.21 (m, 2H), 1.02-0.90 (m, 2H). C24H25C12F2N302的 MS (El)，實測值497.4 (MH+)。 1_(2,4-二氣苯基）-N-[(lS)-l-[(4-羥基苯基）甲基]-2-(4-甲 基呱嗪-1-基）-2-氧代乙基】環丙醢胺：4 NMR (400 MHz， DMSO-d6)： δ 9.23 (s, 1H), 7.64 (dd, 1H), 7.50-7.36 (m, 2H), 6.84 (d, 2H), 6.76-6.53 (m, 3H), 4.83 (q, 1H), 3.31 (m, 146258.doc •68- 201040149 4H)，2.69 (m，2H)，2.16 (m，3H)，2.13 (s，3H)，2.09-1.98 (m，1H)，1.53-1.29 (m，2H)，1.00 (m，2H). C24H27C12N303的 MS (El)，實測值477.4 (MH+)。 N-[(lS)-l-[(2,4-二氣苯基）曱基】-2-(4-甲基呱嗪-1-基）-2-氧代乙基】-1-[3-(三氟甲基）苯基]環丙醯胺：NMR (400 MHz, CDC13)： δ 7.51 (m, 4H), 7.35 (s, 1H), 7.16 (d, 1H), 6.92 (d, 1H), 7.03 (d, 1H), 6.04 (d5 1H), 5.22 (d, 1H), 3.46 (m, 4H), 2.99 (dd, 1H), 2.84 (dd, 1H), 2.37 (m, 2H), 2.31 (s，3H), 2.14 (m, 2H), 1.52 (m, 2H), 1.05 (m, 2H). C25H26Cl2F3N3〇A MS (El)，實測值 528.4 (MH+)。 1-(2-氣苯基）-N-[(lS)-l-[(2,4-二氣苯基）甲基]-2-(4-甲基-»瓜嗪-1-基）-2-氧代乙基】環丙醯胺：NMR (400 MHz, DMSO-d6)： δ 7.54 (m, 1Η), 7.48-7.41 (m, 2H), 7.39-7.34 (m, 3H), 7.21 (d, 1H), 6.65 (d, 1H), 5.03 (q, 1H), 3.47-3.43 (m, 2H), 3.37 (m, 2H), 2.95-2.84 (m, 2H), 2.27-2.15 (m, 2H), 2.13 (s, 3H), 2.07-2.03 (m, 1H), 1.86 (s, 1H), 1.42-1.38 (m，1H), 1.26-1.22 (m, 1H), 0.99-0.91 (m, 2H); 匸241126(：131^3〇2的^8(£1)，實測值495.92 (]^11+)。 1^-【(18)-1-[(2,4-二氣苯基）甲基]_2-(4-甲基呱嗪-1-基）-2-氧代乙基]-l-(4-氟苯基）環丙醢胺：4 NMR (400 MHz, DMS〇-d6): δ 7.54 (d，1H)，7.39-7.36 (m, 1H)，7.34-7.30 (m, 2H), 7.20-7.16 (m, 3H), 6.74 (d, 1H), 5.03-4.97 (m, 1H), 3-48-3.30 (m, 4H), 2.98-2.93 (m, 1H), 2.88-2.83 (m, 1H), 2.22-2.17 (m, 3H), 2.13 (s, 4H), 1.24-1.21 (m, 1H), 1.12- 146258.doc -69- 201040149 1.09 (m，1H), 0.91 (d，2H); C24H26C12FN302的 MS (EI)，實 測值 478.03 (MH+)。 N-[(lS)-l-[(2,4 -二氣苯基）甲基]-2-(4-甲基狐嗓-1 基）-2 氧代乙基]三氟甲基）苯基】環丙醯胺：4 NMR (400 MHz, DMSO-de)： δ 7.74-7.68 (m, 2H), 7.59-7.53 (m5 3H), 7.35-7.34 (m, 1H), 7.20 (d, 1H), 6.51 (d, 1H), 5.04-4.99 (m, 1H), 3.44-3.34 (m, 4H), 2.92-2.82 (m, 2H), 2.25-2.17 (m, 2H), 2.12 (s, 4H), 2.08-2.03 (m, 1H), 1.88 (s, 1H), 1.40- 1-38 (m, 1H), 1.04 (s, 2H); C25H26C12F3N302的 MS (EI)，實 O 測值 528.17 (MH+)。 ]^-[(18)-1_【(2,4-二氣苯基）曱基】-2-(4-甲基呱嗪-1-基）-2-氧代乙基]-1-(2,4-二氟苯基）環丙醯胺：4 NMR (400 MHz， DMSO-d6)： δ 7.54 (d, 1Η), 7.42-7.35 (m, 2H), 7.28-7.20 (m, 2H), 7.11-7.06 (m, 1H), 7.00 (d, 1H), 5.02-4.96 (m, 1H), 3.47-3.33 (m, 4H), 2.98-2.84 (m, 2H), 2.25-2.17 (m, 3H), 2.14 (s, 4H), 1.32-1.28 (m, 1H), 1.16-1.13 (m, 1H), 0.93 (d, oThe NaOH solution was heated to reflux for 18 hours and then cooled to room temperature. The resulting solution was acidified to pH 3 with 1N EtOAc and extracted with 50 mL EtOAc. The organic layer was dried over magnesium sulfate. Filtration under reduced pressure and concentration gave 400 mg (62%) of 1-(4-(trifluoromethyl)phenyl)-cyclopropanecarboxylic acid, 146258.doc: 58· 201040149 which was used in the next step without further purification. MS (EI) for CnH9F302, found 231 (MH+). Step 3: (S)_2-Amino-3-(2,4-diphenyl)-1-(4-methylpyridazin-1-yl)propan-1-one: dissolved in dichloromethane ( 100 mL) of (S)-2-(tert-butoxycarbonylamino)-3-(2,4-diphenyl)propanoic acid (1 〇g, 29 mmol, Aldrich) solution was added to N-methyl hydrazine Iridium (i〇g, loo mm〇l), 1·hydroxybenzotriazole (5 g, 33 mmol), Ν-mercaptomorpholine (20 mL, 182 mmol), 1-[3-(dimethyl Amino)propyl]-3-ethylcarbodiimide hydrochloride (7.3 g, 38 mmol). The reaction was stirred at room temperature for 18 hours. The resulting solution was extracted with EtOAc (EtOAc)EtOAc. The resulting oil was dissolved in decyl alcohol (1 〇〇 mL), followed by 4 N HCl dissolved in dioxane (1 〇〇 mL, Aldrich). The reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to give 11-5 to 100% of (3)-2-amino-3-(2,4-diphenyl)-1-(4-methylpyridazin-1-yl) Propan-1-one was used in the next step without further purification. MS (EI) for C14H19CI2N3, found 316.3 (MH+). Step 4: N-[(lS)-l-[(2,4·diphenyl)methyl]-2-(4-methylpyridazin-1-yl)-2-oxoethyl] 444-(Trifluoromethyl)phenyl]cyclopropanamide: (S)-2-amino-3-(2,4-dichlorophenyl)-1 dissolved in di-methane (5 mL) -(4-Methyl D-guanidin-1-yl)propan-1-one (200 mg '0.63 mmol) solution was added to 1_(4_(difluoromethyl)benyl)cyclopropionic acid (200 mg, 0·) 86 mmol), 1-Phenylbenzotriazole (250 mg, 1.85 mmol), N-methylmorpholine (1,9.1 mmol), 1-[3-(dimethylamino)propyl]_3 - Ethylcarbodiimide hydrochloride (300 mg, 1.56 mmol). The reaction was stirred at room temperature for 18 hours. The organic solution was extracted with EtOAc EtOAc EtOAc EtOAc (EtOAc) The product was then purified by preparative HPLC (EtOAc, EtOAc/EtOAc EtOAc) 1H NMR (400 MHz, CDC13): δ 7.65 (d, 2 Η), 7.50 (d, 2H), 7.36 (d, 1H), 7.15 (dd, 1H), 7.95 (d, 1 H), 6.09 (d, 1 H), 5.22 (dd, 1H), 3.57 (m, 1H), 3.48 (m, 2H), 3.30 (m, 1H), 2.96 (m, 1H), 2.87 (m, 1H), 2.34 (m, 3H), 2.24 (s, 3H), 2.06 (m, 1H), 1.52 (m, 2H), 1.04 (m, 2H); MS (El) of C25H26C12F3N302, found 529.2 (MH+). The following compounds were prepared in a similar manner to Example 2. Synthesis of N-[(lS)-l-[(2-phenylphenyl)methyl]-2-(4-methylpyridazin-1-yl)-2-oxoB in a similar manner to Example 2. Base]_ι_(2,4-diphenyl)cyclopropanamide' wherein (S)-2-(tert-butoxycarbonylaminophenyl)propionic acid (PepTech Corp) replaces (S)-2-( tert-Butoxycarbonylamino)-3-(2,4-dichlorophenyl)propionic acid, and 1-(2,4-diphenyl)cyclopropanecarboxylic acid (Aldrich) instead of ^(4-(three Fluoromethyl)phenyl)cyclopropanecarboxylic acid. lHNMR (400 MHz, DMSO-d6): δ 7.60 (d, 1H), 7.43-7.33 (m, 3H), 7.24-7.17 (m, 3H), 6.87 (d, 1H), 5.02 (m, 1H), 3.44-3.27 (m, 4H), 2.96-2.84 (m, 2H), 2.23-2.10 (m, 7H), I.37 (m? iH), 1.23 (m, 1H), 0.92 (111,211); (: 241126 (: 13 &gt; 13 〇 2) ^ 8 (ugly 1), found 495.85 (MH+). Synthesize i_(2,4-diphenyl)-N-[ in a similar manner to Example 2. (1S)-methoxy)phenyl]methyl}-2·(4-methylpyrazin-1-yl)-2-oxoethyl]cyclopropionic acid amine, wherein (S)-2-( Tert-Butoxycarbonylamino)_3_(4-methoxybenzene 146258.doc 60· 201040149) Propionic acid (Fluka) instead of (S)-2-(tert-butoxycarbonylamino)_3_(2,4-dichloro Phenyl)propionic acid' and 1-(2,4-diphenyl)cyclopropanecarboxylic acid (Aldrich) in place of 1-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid. iH NMR (400 MHz, DMSO-d6): δ 8.15, (s, 1Η), 7.65 (s, 1H), 7.43 (s, 1H), 6.96 (d, 2H), 6.78 (d, 2H), 6.66 (d, 1H) , 4.85 (m, 1H), 3.72, (s, 3H), 3.32 (m, 4H), 2.76 (m, 2H), 2.20 (m, 2H), 2.13 (s, 3H), 2.05 (m, 2H) , 1.42 (m, 2H), l.oi (m, 2H). MS (El) of c25h29C12N303 : 491.3 (MH+)合In a similar manner to Example 2, a gas phenylmethylpyridazin-1-yl)-1-oxopropan-2-diyl^^^^^^^^^^^^^^ -2-(tert-Butoxycarbonylamino)_3_(3-p-phenyl)propionic acid (PepTech Corp) instead of (S)-2-(tert-butoxycarbonylamino)_3·(2,4-dichlorobenzene Propionate, and 1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) is substituted for bu (4-(difluoroindolyl)phenyl)cyclopropanoic acid. iH NMR (4〇〇MHz, DMS〇_d6): δ 7.59 (d, 1H), 7.39(m, 2H), 7.27 (m, 2H), 7.14 (bs, Q IH), 7.06 (m, 1H) , 6.89 (d, 1H), 4.88 (m, 1H), 3.41 (m, 2H), 3.35 (m, 2H), 2.80 (m, 2H), 2.17 (m, 4H), 2.12 (s, 3H), 1.35 (m, 2H), 0.95 (m, 2H); MS (El) for C24H26C13N302, found 495.04 (MH+). Synthesis of 2_(2,4_diphenyl)_N_[(is)_ 1-[(2,4-diphenyl)methyl]·2_(4_methylindole) in a similar manner to Example 2.嗓小基)2Oxoethyl]_ 2-methylpropanamide, in which iodomethane replaces hydrazine, 2_dibromoethane, and 2_(2,4-diphenyl)acetonitrile (Aldrich) replaces 2_ (4_(Trifluoromethyl)phenyl)acetonitrile. H NMR (400 MHz, CDC13): δ 7.26 (m, 3H), 7.26 (d, 146258.doc -61 - 201040149 1H), 7.10 (m, 1H), 6.96 (d, 1H), 5.98 (d, 1H) ), 5.19 (m, 1H), 3.62 (m, 1H), 3·48 (m, 1H), 3 38 (m, m), 3 17 (five), 3·01 (m, 1H), 2.83 (m, 1H), 2.30 (m, 2H), 2.20 (s, 3H), 2.01 (m, 2H), 1.46 (d, 6H). MS (El) of c24H27C4N302: 532.5 (MH+). Synthesis of 1(2,4 di-phenylphenyl)n [(is)_ l-[(3,4-diphenyl)methyl]_2_(4_methylhydrazine small) in a similar manner to Example 2. (2) oxoethyl] cyclopropanamide, wherein (S)-2-(tert-oxyaminoamino) 3 (3,4 diphenyl) propionic acid (SyntheTech) replaces (8)·2_ (tert-Butoxycarbonylamino)_3 (2,4-diphenyl)propionic acid, and 1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) instead of 1-(4-(two) Fluoromethyl)phenyl)cyclopropanecarboxylic acid. iH NMR (4〇〇MHz, DMSO-d6): δ 7.61 (d, 1H), 7.50 (m, 1H), 7.45-7.39 (m, 2H), 7.37 (d, 1H), 7.12 (dd, 1H) , 6.97 (d, 1H), 4.93-4.87 (m, 1H), 3.46-3.38 (m, 4H), 2.88-2.76 (m, 2H), 2.26-2.15 (m, 7H), 1.41 (m, 1H) , 1.28 (m, 1H), 0.97 (m, 2H); MS (El) of C24H25Cl4N3 〇 2 Measured value 530 3 ] [ (MH+). Synthesis of 1-(2,4-dioxyphenyl)_N_[(1S)_l-[(4-fluorophenyl)methyl]-2-(4-methylpyridazine) in a similar manner to Example 2. Io_yl)_2_oxoethyl]cyclopropionate' wherein (S)-2-(tert-butoxycarbonylamino)·3_(4-fluorophenyl)propionic acid (Fluka) is substituted (S)- 2-(tert-Butoxycarbonylamino)_3_(2,4-dichlorophenyl)propionic acid, and bis(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) instead of 1-(4-( Trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1 Η), 7.63 (s, 1H), 7.43 (s, 1H), 7.08 (m, 4H), 6.81 (d, 1H), 4.59 (m , 1H), 3.34 (m, 4H), 2.81 (m, 2H), 2.19 (m, 146258.doc •62- 201040149 2H), 2.14 (s, 3H), 2.09 (m, 2H), 1.38 (m, MS (El), calcd. (495) (MH+). Synthesis of diphenyl phenyl) in a similar manner to Example 2) l-[(2,4-diphenyl)methyl]methylpyridazine "yl" 2 oxoethyl] Cyclopropionic acid '1 -(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) in place of 1-(4-(difluoromethyl)phenyl)cyclopropanecarboxylic acid. lHNMR (400 MHz, D4-MeOD): δ 7.51 (d, 1H), 7.48-7.35 (m, 3H), 7.35 (dd, 1H), 7.15 (d, 1H), 5.18 (t, 1H), 3.78-3.63 (m, 2H), 3.58-3.44 (m , 2H), 3.05 (dd, 1H), 2.96 (dd, 1H), 2.78-2.55 (m, 4H), 1.58-1.43 (m, 2H), 1.13-1.10 (m, 2H) C24H25Cl4N3〇jMS (El) Found 530 (MH+). Synthesis of 4-bromodiphenyl)cyclopropyl]p-propyl N-[2-(dimethyl-amino)ethyl] amphetamine oxime in a similar manner to Example 2. Amine 'wherein (S)-2-(tert-butoxycarbonylamino)_3_(4-bromophenyl)propionic acid (SyntheTech) replaces (S)-2-(tert-butoxycarbonylamino)·3_(2, 4_Dichloro cuminyl)propionic acid, dimethyl dimethyl- 1,2-diamine (Aldrich) instead of fluorenyl-hydrazinazine, and 1-(2,4-dichlorophenyl)cyclopropanecarboxylate Acid (Aldrich) instead of 丨_(4_(trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (4〇〇MHz, DM SO-d6;): δ 8.19(s, 1Η), 7.81 (t, 1H), 7.59 (s, 1H), 7.39 (m, 4H), 7.〇i (d, 2H), 4.42 (m, 2H ), 3.11 (m? 2H), 2.80 (m, 2H), 2.24 2H), 2.14 (s, 6H), 1.37 (m, 2H), 0.95 (m, 2H); MS (El) of C23H26BrC12N3〇2, Found 528 6 (MH+). [(夂'di-phenyl)-N-[(1S)_ethoxy)phenyl]methyl}_2_(4•methyl_呱) was synthesized in a similar manner as in Example 2. Benzyl)_2_oxoethyl 146258.doc -63- 201040149 base] Cyclopropylamine, wherein (S)-2-(tert-butoxycarbonylamino)-3-(4-ethoxyphenyl)propanoic acid (SyntheTech) replaces (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid' and 1-(2,4-dichlorophenyl)cyclopropanecarboxylate Acid (Aldrich) replaces 1-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H), 7.70 (s, 1H), 7.17 (m, 4H), 6.92 (m, 2H), 4.91 (m, 1H), 4.09 (m , 2H), 3.51 (m, 4H), 2.86 (m, 2H), 2.32 (m, 7H), 1.52 (t, 3H), 0.93 (m, 2H), 0.63 (m, 2H); MS of C26H31C12N303 ( El), found at 504.5 (MH+). Synthesis of 1-(2,4-diphenyl)-N-[(1S)_ 1-[(2,4-dimethylphenyl)methyl]-2-(in a similar manner as in Example 2) 4-methyl-pyridazin-1-yl)-2-oxoethyl]cyclopropanamide, wherein (S)-2-(tert-butoxycarbonylamino)-3-(2,4-diindole Phenyl)propionic acid (PepTech) replaces (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)-propionic acid, and -(2,4-dichloro Phenyl)cyclopropanecarboxylic acid (Aldrich) replaces 1-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H), 7.73 (s, 1H), 7.20 (m, 3H), 7.04 (m, 3H), 4.91 (m, 1H), 4.09 (m , 2H), 3.51 (m, 4H), 2.86 (m, 2H), 2.32 (m, 8H), 1.52 (t, 3H), 0.93 (m, 2H), 0.63 (m, 2H). MS of C26H31C12N302 ( El), found 488.5 (MH+). Synthesis of 1-(2,4-diphenyl)_N_[(1S)_ 2-(4-methyl 11 guanidin-1-yl)-1-(naphthalene-2-) in a similar manner to Example 2. Methyl)-2-oxoethyl]cyclopropionic acid amine, wherein (S)-2-(tert-butoxycarbonylamino)-3-(naphthalene-2-yl)propionic acid (Aldrich) is substituted (S )-2-(tert-Butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid' and 1-(2,4-dioxaphenyl)cyclopropanecarboxylic acid (Aldrich) instead of hydrazine _(4_(Trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400 MHz, DMSO-d6): δ 146258.doc • 64 - 201040149 7.84-7.78 (m, 3H), 7.58-7.43 (m, 3H), 7.39-7.25 (m, 4H), 5.19-5.10 ( m, 1H), 3.62-3.37 (m, 4H), 3.05 (m, 2H), 2.57-2.40 (m, 2H), 2.35-2.23 (m, 1H), 2.18 (s, 3H), 1.83-1.77 ( m, 1H), 1.60-1.50 (m, 2H), 1.16 (m, 1H), l.〇〇(m&gt;1H); 'MS (El) of C28H29C12N302 'Measured value 511 (MH+). Synthesis of 1(2 + diphenyl)-indole (18) 1- 1-[(4-methylphenyl)methyl]-2-(4-methyl-pyridazine) in a similar manner to Example 2. -1-yl)-2-oxoethyl]cyclopropanamide, wherein (S)-2-(tert-butoxycarbonylamino)_3_(4-methylphenyl)propanoic acid ◎ (Fluka) is substituted ( S)-2-(tert-Butoxycarbonylamino)-3-(2,4-dioxaphenyl)propionic acid, and 1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) is substituted 1-(4-(Trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400 MHz, DMSO-d6): δ 7.64 (t, 1 Η), 7.42 (d, 2H), 7.03 (d, 2H), 6.94 (d, 2H), 6.69 (d, 1H), 4.87 (m , 1H), 3.42-3.25 (m, 4H), 2.82-2.70 (m, 2H), 2.25 (s, 3H), 2.20-2.13 (m, 7H), 1.42 (m, 2H), 0.97 〇, 211) ;(:251129(:12&gt;1302]^8(£1), measured value 475.44 (]\411+). Synthesis of N-[(lS)-l-[(4-) in a similar manner to Example 2. Bromophenyl>methyl hydrazide 2-(4-methylpyridazin-1-yl)-2-oxoethyl]-1-(2,4-diphenyl)cyclopropanamide, of which (S)-2-(tert-Butoxycarbonylamino)-3-(4-bromophenyl)propionic acid (SyntheTech) replaces (S)-2-(tert-butoxycarbonylamino)-3-(2, 4-dichlorophenyl-yl)propionic acid and 1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) in place of 1-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid 1H NMR (400 MHz, DMSO-d6): δ 7.63 (s, 1H), 7.43 (m, 4H), 7.05 (d, 2H), 6.86 (d, 1H), 4.90 (m, 1H), 3.46-3.33 (m, 4H), 2.86-2.73 (m, 2H), 2.24-2.10 (m, 7H), 1.44-1.34 (m, 2H), 1.01-0.96 (m, 2H); 146258.doc 65- 201040149 (: 24112681'(:12]^3〇2]\/18 ie), measured value 540.31 (]^+). 2Synthesis of a similar method to the formation of diphenyl phenyl) _N_[(1S)-l-[(2,4-diphenyl)methyl]-2-(4-methylpyridazine_ι_yl) _2_Oxoethyl] Cyclopropylamine wherein 1-(3,4-monophenyl)cyclopropionic acid (Aldrich) replaces 1-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid. iH nmR (400 MHz, DMSO-de): δ 7.60 (d, 1Η), 7.55 (d, 1H), 7.48 (d, 2H), 7.36 (m, 1H), 7.23 (d, 2H), 7.19 (d ,1H), 4.98 (m,1H), 3.45 (m, 2H), 2.94 (m, 2H), 2.1h (m, 7H), 1.22 (m, 1H), 1.10 (m, 1H), 0·97 (m, 2H); MS (El) for C24H25C14N302, found 529.80 (MH+). Synthesis of n_helium phenyl)methyl]-2-(4-mercaptopyridin-1-yl)_2-oxoethyl] phenyl)cyclopropanamide in a similar manner to Example 2, Wherein (S)-2-(tert-butoxycarbonylamino)_3_(4-chlorophenyl)propionic acid (Fluka) is substituted for (S)-2-(tert-butoxycarbonylamino)_3_(2 4_dichloro Phenyl)propionic acid, and 1-(2,4-azepine)cyclopropionic acid (Aldrich) replaces 1-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400 MHz, DMSO_d6h δ 7.63 (s, 1 Η), 7.40 (s, 2H), 7.26 (d, 2H), 7.09 (d, 2H), 6.83 (d, 1H), 4.87 (m, 1H), 3.46-3.25 (m, 4H), 2.86-2.73 (m, 2H), 2.19-2.02 (m, 7H), 1.42-1.29 (m, 2H), 0.98-0.89 (m, 2H); MS of C24H26C13N302 (El The measured value is 495.84 (MH+). In a similar manner to Example 2, 1_(2,4_dioxaphenyl)_N_丨(1S)_ 1_[(2-phenylphenyl)methyl]-2 was synthesized. -(4-methyl oxime_ι_yl)_2-oxoethyl]cyclopropanol, wherein (S)-2-(tert-butoxycarbonylamino)_3_(2-fluorophenyl)propionic acid (Synthetech) Substituting (S)-2-(tert-Butoxycarbonylamino)_3_(2,4_diphenyl) 146258.doc -66 - 201040149 Propionic acid and 1_(2,4·dichlorophenyl) Cyclopropanecarboxylic acid (Aldrich) in place of 1-(4-(difluoroindolyl)phenyl)cyclopropanecarboxylic acid. 1H NMR (400 MHz, DMSO-d6): δ 8.14 (s, 1 Η), 7.60 (d , 1H), 7.39 (m, 2H), 7.24 (m, 1H), 7.06 (m, 2H), 6.78 (d, 1H), 4.94 (m, 1H), 3.56 (m, 4H), 2.86 (m, 2H), 2.22 (m, 3H), 2.12 (m, 4H), 1.30 (m, 2H), 〇-93〇, 211); (:241126(:12卩]^302]^8 kg 1), Found 474.7 (MH+). In contrast to Example 2 Synthesis of ^(2,4-diphenyl)-N-[(1S)-2-(4-methylfoxazin-i-yl)_2_oxo"-(丨心(Trifluoromethyl) (phenyl)methyl}ethyl}cyclopropanamide, (S)-2-(tert-butoxycarbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid (Fluka) Substituting (S)-2-(tert-butoxycarbonylamino)-3-(2,4-diphenyl)propionic acid, and i-(2,4-dichlorophenyl)cyclopropanecarboxylic acid (Aldrich) Instead of 1-(4-(trifluoromethyl)phenyl)-cyclopropanecarboxylic acid. 1H NMR (400 MHz, DMSO-d6): δ 8.18 (s, 1 Η), 7.61 (d, 3H), 7.41 ( s, 1H), 7.33 (d, 2H), 6.95 (d, 2H), 4.96( m, 1H), 3.40 (m, 4H), 2.93 (m, 2H), 2.17 (m, 2H), 2.13 (s , 1H), 2.06 (m, 2H), 1.41 (m, 2H), 1.29 (m, 2H); MS (El) of C25H26C12F3N302, found 529.5 (MH+). 1-(2,4-diphenyl)-N-[2-(4-mercaptopyridin-1-yl)-2-oxo-1-(phenylmethyl)ethyl]cyclopropene Amine: 4 NMR (400 MHz, DMSO-d6): δ 7.51 (d, 1H), 7.48-7.35 (m, 3H), 7.35 (dd, 1H), 7.15 (d, 1H), 5.18 (t, 1H) , 3.78-3.63 (m, 2H), 3.58-3.44 (m5 2H), 3.05 (dd, 1H), 2.96 (dd, 1H), 2.78-2.55 (m, 4H), 1.58-1.43 (m, 2H), 1.13-1.10 (m, 2H). MS (El) for C24H27C12N302, 146258.doc -67- 201040149 460.402 (MH+). 1-(2,6-diphenyl)-N-[(lS)-l-[(2,4-dichlorophenyl)methyl]-2-(4-methylpyridazin-1-yl) )-2-oxoethyl]cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.52 (d, 1H), 7.48 (m, 2H), 7.39-7.25 (m, 3H), 7.05 (d, 1H), 5.04 (m, 1H), ), 3.47 (m, 4H), 2.93 (3, 2H), 2.27-2.21 (m, 4H), 2.15 (s, 3H), 1.59 (m, 2H) ), 1.06 (111,211); (:241125(:141\[302]\48(£1), found 529.23 (1^11+). 1-(2,4-diphenyl)- N-{(lS)-2-(4-methylpyridazinyl)-2-oxo- l-[(3,4,5-trifluorophenyl)methyl]ethyl}cyclopropanamide: NMR (400 MHz, DMSO-d6): δ 7.57 (d, 1H), 7.39 (m, 1H), 7.26 (m, 1H), 6.88 (m, 2H), 4.89 (q, 1H), 3.33-3.38 (m, 4H), 2.81 (m, 2H), 2.18 (s, 3H), 2.16 (m, 2H) 1.32 (m, 2H), 0.95 (m, 2H). MS (El) for C24H24C12F3N302, found 515.4 (MH+) 1-(2,4-diphenyl)-N-[(lS)-l-[(3,4-difluorophenyl)methyl]-2-(4-methylpyridazine -1-yl)-2-oxoethyl]cyclopropanamide: NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1 Η), 7·60 (d, 1 Η), 7.42 (dt, 2 Η) ), 7.30 (dt, 1H), 7.17 (ddd, 1H), 6.94 (d, J=8 .2Hz, 2H), 4.94-4.80 (m, 1H), 3.40 (dd, 4H), 2.81 (qd, 2H), 2.55-2.47 (m, 1H), 2.20 (t, 4H), 1.51-1.21 (m , 2H), 1.02-0.90 (m, 2H). MS (El) for C24H25C12F2N302, found 497.4 (MH+). 1_(2,4-diphenyl)-N-[(lS)-l-[( 4-hydroxyphenyl)methyl]-2-(4-methylpyridazin-1-yl)-2-oxoethyl]cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 9.23 (s, 1H), 7.64 (dd, 1H), 7.50-7.36 (m, 2H), 6.84 (d, 2H), 6.76-6.53 (m, 3H), 4.83 (q, 1H), 3.31 (m, 146258) .doc •68- 201040149 4H), 2.69 (m, 2H), 2.16 (m, 3H), 2.13 (s, 3H), 2.09-1.98 (m, 1H), 1.53-1.29 (m, 2H), 1.00 ( m, 2H). MS (El) for C24H27C12N303, found 474.7 (MH+). N-[(lS)-l-[(2,4-diphenyl)indenyl]-2-(4-methylpyridazin-1-yl)-2-oxoethyl]-1-[ 3-(Trifluoromethyl)phenyl]cyclopropanamide: NMR (400 MHz, CDC13): δ 7.51 (m, 4H), 7.35 (s, 1H), 7.16 (d, 1H), 6.92 (d, 1H), 7.03 (d, 1H), 6.04 (d5 1H), 5.22 (d, 1H), 3.46 (m, 4H), 2.99 (dd, 1H), 2.84 (dd, 1H), 2.37 (m, 2H) , 2.31 (s, 3H), 2.14 (m, 2H), 1.52 (m, 2H), 1.05 (m, 2H). C25H26Cl2F3N3 〇A MS (El), found 528.4 (MH+). 1-(2-Phenylphenyl)-N-[(lS)-l-[(2,4-diphenyl)methyl]-2-(4-methyl-» guazin-1-yl) -2-oxoethyl]cyclopropanamide: NMR (400 MHz, DMSO-d6): δ 7.54 (m, 1 Η), 7.48-7.41 (m, 2H), 7.39-7.34 (m, 3H), 7.21. (d, 1H), 6.65 (d, 1H), 5.03 (q, 1H), 3.47-3.43 (m, 2H), 3.37 (m, 2H), 2.95-2.84 (m, 2H), 2.27-2.15 (m , 2H), 2.13 (s, 3H), 2.07-2.03 (m, 1H), 1.86 (s, 1H), 1.42-1.38 (m,1H), 1.26-1.22 (m, 1H), 0.99-0.91 (m , 2H); 匸241126(: 131^3〇2^8(£1), measured value 495.92 (]^11+). 1^-[(18)-1-[(2,4-dibenzene) Methyl]_2-(4-methylpyridazin-1-yl)-2-oxoethyl]-l-(4-fluorophenyl)cyclopropanamide: 4 NMR (400 MHz, DMS〇 -d6): δ 7.54 (d,1H), 7.39-7.36 (m, 1H), 7.34-7.30 (m, 2H), 7.20-7.16 (m, 3H), 6.74 (d, 1H), 5.03-4.97 ( m, 1H), 3-48-3.30 (m, 4H), 2.98-2.93 (m, 1H), 2.88-2.83 (m, 1H), 2.22-2.17 (m, 3H), 2.13 (s, 4H), 1.24-1.21 (m, 1H), 1.12- 146258.doc -69- 201040149 1.09 (m,1H), 0.91 (d,2H); MS (EI) for C24H26C12FN302, found 478.03 (MH+). N-[( lS)-l-[(2,4-diphenyl)methyl ]-2-(4-Methylfoxin-1yl)-2 oxoethyl]trifluoromethyl)phenyl]cyclopropanamide: 4 NMR (400 MHz, DMSO-de): δ 7.74-7.68 (m, 2H), 7.59-7.53 (m5 3H), 7.35-7.34 (m, 1H), 7.20 (d, 1H), 6.51 (d, 1H), 5.04-4.99 (m, 1H), 3.44-3.34 ( m, 4H), 2.92-2.82 (m, 2H), 2.25-2.17 (m, 2H), 2.12 (s, 4H), 2.08-2.03 (m, 1H), 1.88 (s, 1H), 1.40- 1- 38 (m, 1H), 1.04 (s, 2H); MS (EI) for C25H26C12F3N302, real O measured 528.17 (MH+). ]^-[(18)-1_[(2,4-diphenyl)indenyl]-2-(4-methylpyridazin-1-yl)-2-oxoethyl]-1-( 2,4-Difluorophenyl)cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.54 (d, 1 Η), 7.42-7.35 (m, 2H), 7.28-7.20 (m, 2H) , 7.11-7.06 (m, 1H), 7.00 (d, 1H), 5.02-4.96 (m, 1H), 3.47-3.33 (m, 4H), 2.98-2.84 (m, 2H), 2.25-2.17 (m, 3H), 2.14 (s, 4H), 1.32-1.28 (m, 1H), 1.16-1.13 (m, 1H), 0.93 (d, o

2H);C24H25Cl2F2N3O2的MS(EI)，實測值496.04 (MH+)。 V N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-N〜2〜-{[l-(2,4-二氣 苯基）環丙基】-羰基}-5-苯基-L-正纈氨醯胺：4 NMR (400 MHz, CD3OD) ： 7.58 (s, 1H), 7.49 (dd, 1H), 7.40-7.37 (m, 1H), 7.28-7.21 (m, 2H), 7.17-7.10 (m, 3H), 4.40-4.36 (m, 1H), 4.05-4.00 (m, 1H), 3.57-3.54 (m, 1H), 3.22-3.05 (m, 4H), 2.80 (dd, 1H), 2.65-2.52 (m, 2H), 2.05-2.02 (m, 1H), 2.00-1.83 (m, 3H), 1.80-1.64 (m, 3H), 1.60-1.53 (m, 5H), 146258.doc -70- 201040149 1.20-1.14 (m, 1H)，1.08-1.00 (m，1H). C28H33C12N302的 MS (El)，實測值514.18 (MH+)。 4-漠-N-{ [1-(2,4-二氯苯基）環丙基]類基卜L-苯丙胺酿基-N-[2-(二甲基胺基）乙基]-L-戚胺酿胺：4 NMR (400 MHz， CD3OD) ： 8.50 (s, 1H), 7.53-7.38 (m, 4H), 7.08-7.00 (m, 2H), 4.82 (t, 1H), 4.23 (dd, 1H), 3.82-3.78 (m, 1H), 3.76-3.64 (m, 1H), 3.62-3.52 (m, 1H), 3.40-3.30 (m, 1H), 3.20-3.00 (m, 3H), 2.85-2.80 (m, 1H), 2.78 (s, 6H), 2.23-2.09 (m, 2H), 2.00-1.90 (m, 2H), 1.60-1.50 (m, 2H), 1.10-1.03 (m，2H). C28H33BrCl2N4〇2 的 MS (EI)，實測值 624.66 (MH+)。 實施例3 2,4·二氣-Ν-α-{[1-(2,4-二氣苯基）環丙基]羰基}-N-【2-(二 甲基胺基）乙基】-L_苯丙胺醯胺MS (EI) for C24H25Cl2F2N3O2, found 496. V N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N~2~-{[l-(2,4-diphenyl)cyclopropyl]-carbonyl }-5-Phenyl-L-n-decylamine: 4 NMR (400 MHz, CD3OD): 7.58 (s, 1H), 7.49 (dd, 1H), 7.40-7.37 (m, 1H), 7.28-7.21 (m, 2H), 7.17-7.10 (m, 3H), 4.40-4.36 (m, 1H), 4.05-4.00 (m, 1H), 3.57-3.54 (m, 1H), 3.22-3.05 (m, 4H) , 2.80 (dd, 1H), 2.65-2.52 (m, 2H), 2.05-2.02 (m, 1H), 2.00-1.83 (m, 3H), 1.80-1.64 (m, 3H), 1.60-1.53 (m, 5H), 146258.doc -70- 201040149 1.20-1.14 (m, 1H), 1.08-1.00 (m, 1H). MS (El) for C28H33C12N302, found 514.18 (MH+). 4-Mo-N-{ [1-(2,4-dichlorophenyl)cyclopropyl]-based phenyl-L-amphetamine-and-N-[2-(dimethylamino)ethyl]-L - amide amine: 4 NMR (400 MHz, CD3OD): 8.50 (s, 1H), 7.53-7.38 (m, 4H), 7.08-7.00 (m, 2H), 4.82 (t, 1H), 4.23 (dd , 1H), 3.82-3.78 (m, 1H), 3.76-3.64 (m, 1H), 3.62-3.52 (m, 1H), 3.40-3.30 (m, 1H), 3.20-3.00 (m, 3H), 2.85 -2.80 (m, 1H), 2.78 (s, 6H), 2.23-2.09 (m, 2H), 2.00-1.90 (m, 2H), 1.60-1.50 (m, 2H), 1.10-1.03 (m, 2H) MS (EI) for C28H33BrCl2N4 〇2, found 624.66 (MH+). Example 3 2,4·di-gas-Ν-α-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)ethyl] -L_Amphetamine

步驟1 : (S)-2-胺基-3-(2,4-二氣苯基）丙酸乙酯··向溶於 二氯甲烷（1〇〇 mL)的（S)-2_(叔丁氧羰基胺基）-3-(2,4-二氯 苯基）丙酸（5 g，I5 mmol，Fluka)溶液加入1-羥基苯並三唑 146258.doc -71 · 201040149 (3 g，22.5 mmol)、N-曱基嗎啉（16.5 mL，150 mmol)、1_ [3-(二甲基胺基）丙基]-3 -乙基碳二亞胺鹽酸鹽（4.3g，22.8 mmol)以及乙醇（13.8 mL，300 mmol)。將反應物於室溫搜 拌18小時。用水（25 mL)、飽和碳酸氫鈉溶液（25 mL)以及1 N HC1溶液（25 mL)萃取所得溶液。分層並用硫酸鎂乾燥有 機層’真空過濾並濃縮。將所得的油溶於曱醇（25 mL) 中’之後加入溶於二噁烷（25 mL，Aldrich)的4 N HC1。將 反應物於室溫攪拌1 8小時。真空濃縮所得的溶液以得到 3.0g(60°/〇)的標題化合物，其用於下一步驟而無需進一步 純化。（：111113(：121^〇2的]^8口1)，實測值26：3.16(]^11+)。 步驟2:(8)-3-(2,4-二氣苯基）_2-(1-(2,4-二氣苯基）環丙 甲醯胺基）丙酸乙酯：向溶於二氣曱烷（1〇〇 mL)的（s)_2胺 基-3-(2,4-二氣苯基）_丙酸乙酯（3 g，us mmol)溶液加入ι_ 經基笨並三唑（1.8 g ’ 13.7 mmol)、N-曱基嗎啉（12.6 mL， 115 mmol)、1-[3-(二曱基胺基）丙基]_3_乙基碳二亞胺鹽酸 鹽（2.6g，13.7 mmol)以及1-(2,4-二氣苯基）環丙羧酸（2 7 g，11·5 mmol，Acros)。將反應物於室溫攪拌18小時。用 水（25 mL)、飽和碳酸氫鈉溶液（25 mL)以及1 N HC1溶液 (25 mL)萃取所得溶液。分層並用硫酸鎂乾燥有機層。真 空濃縮所得溶液以產生l.5g(50%)的標題化合物，其用於 下一步驟而無需進一步純化。CUH19C14N03的MS (EI)，實 測值 476·5 (MH+)。 步驟3:(8)-3-(2,4-二氣苯基）-2-(1-(2,4-二氣苯基）環丙 甲醮胺基）_丙酸：向溶於1〇 mL的MeOH的（S)-3-(2,4-二氯 146258.doc •72· 201040149 苯基）-2-(1-(2,4-二氯苯基）-環丙曱醯胺基）丙酸乙酯（15 g ’ 3.2 mmol)溶液加入20 mL的2 N NaOH溶液並將反應混 合物於室溫攪拌18小時。將所得的溶液於減壓下濃縮，用 1 N HC1酸化至pH=3 ’並且用1 〇〇 mL的EtOAc萃取。用硫 酸鎂乾燥有機層。減壓下過濾並濃縮得到i.2 g(80%)的標 題化合物，其用於下一步驟而無需進一步純化。 C19H15Cl4N〇3 的MS (EI)，實測值448.5 (MH+)。 步驟4 : 2,4-二氣-Ν-α-{【1-(2,4-二氣苯基）環丙基]叛基卜 Ν-[2-(一甲基胺基）乙基】-L-苯丙胺斑胺：向溶於二氣甲烧 (5 1111〇的（8)-3-(2,4-二氣苯基）-2-(1-(2,4-二氯苯基）環丙甲 醯胺基）丙酸（70 g’ 29 mmol)溶液加入1-經基苯並三唾（25 mg，0.19 mmol)、N-甲基嗎啉（〇_172 mL，1.57 mmol) ' 1-[3-( 一甲基胺基）丙基]-3 -乙基碳二亞胺鹽酸鹽（36 mg，0.19 mmol)以及 Ν ,Ν1-二甲基乙-1，2-二胺（16 mg，0.19 mmol， TCI America)。將反應物於室溫攪拌18小時。用水（25 mL) 和飽和碳酸氫鈉溶液（25 mL)清洗所得溶液。分層並用硫 酸鎂乾燥有機層，真空過濾並濃縮。之後用製備級 HPLC(反相，乙腈/含水的1〇 mM甲酸緩衝液）純化產物以 產生 41 mg 的標題化合物。1H NMR (400 MHz，DMSO-d6): δ 7.59 (m, 1Η), 7.50 (d, 1H), 7.42 (m, 2H), 7.33 (dd, 1H), 7.16 (d, 1H), 6.73 (d, 1H), 4.52 (m, 1H), 3.09 (m, 3H), 2.84 (m, 1H), 2.27 (t, 2H), 2.16 (s, 6H), 1.37 (m, 2H), 0.95 (m, 2H); C23H25C14N302的MS (EI)，實測值517.3 (MH+)。 以類似於實施例3的方式製備下列化合物。 146258.doc -73- 201040149 以與實施例3相似的方式合成2,4-二氣-Να-{【1-(2,4-二氣 苯基）環丙基】羰基}-Ν-[2-(二曱基胺基）乙基]-Ν-甲基-L-苯 丙胺酿胺，其中«Ν2-三曱基乙-1,2-二胺（Aldrich)替代 N，N -一 甲基乙 _ι，2-二胺（Aldrich)。4 NMR (400 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.58 (d, 1H), 7.51 (dd, 1H), 7.42 (m, 2H), 7.33 (m, 1H), 7.23 (m, 1H), 4.99 (m, 1H), 3.40 (m, 1H), 3.23 (m, 1H), 2.95 (s, 3H), 2.86 (m, 2H), 2.27 (m, 2H), 2.13 (s, 6H), 1.37 (m, 1H), 1.14 (m, 1H), 0.96 (m, 1H), 0.89 (m，1H); C24H27 C14N302的MS (El)，實測值532.4 (MH+)。 以與實施例3相似的方式合成2,4_二氣二氣 苯基）環丙基]羰基甲基呱啶-4-基）-L-苯丙胺醢胺， 其中1-曱基呱啶-4-胺（TCI)替代β,Ν1-二曱基乙-1,2-二胺 (Aldrich)。4 NMR (400 MHz, DMSO-d6): δ 8.21 (s，1Η)， 7.61 (s, 1H), 7.50 (d, 1H), 7.45-7.40 (m, 2H), 7.33 (dd, 1H), 7.15 (d, 1H), 6.58 (d, 1H), 4.53-4.47 (m, 1H), 3.45-3.41 (m, 1H), 3.00-2.95 (m, 1H), 2.88-2.82 (m, 1H), 2.67 (m, 2H), 2.15 (s, 3H), 1.97 (m, 2H), 1.62 (m, 2H), 1.41- 1.24 (m，4H)，0_96 (m，2H); C25H27C14N302的 MS (El)，實 測值 544.3 3 (MH+)。 以與實施例3相似的方式合成2,4_二氣二氣 苯基）環丙基】羰基卜N-(2-吼咯啶-1-基乙基）-L-苯丙胺醢 胺’其中2_(吡咯啶-1-基）乙胺（Fluka)替代β,Ν1-二曱基乙-1,2-二胺（Aldrich)。NMR (400 MHz, DMSO-d6): δ 9.18 (s, 1Η), 7.69 (t, 1H), 7.57 (d, 1H), 7.50 (d, 1H), 7.42 (m, 146258.doc • 74 - 201040149 2H), 7.32 (dd, 1H)S 7.16 (d, 1H), 4.53 (m, 1H), 3.15 (m, 2H), 3.03 (m, 1H), 2.85 (m, 1H), 2.48 (m, 6H), 1.69 (m, 4H)，1,36 (m，2H)，0.95 (m，2H); C25H27C14N3〇W MS (El) ’ 實測值544.5 (Mh+)。 以與實施例3相似的方式合成2,4二氣 -Να·{[1-(2,4-二氣 苯基）環丙基】幾基卜Ν_甲基·N (1甲基吼洛咬_3基苯丙 胺 Si 胺，47 1 w ’、 -T 基 °比哈。定-3 -胺（Matrix Scientific)替代 N1 N1-二甲其 7 λStep 1: (S)-2-Amino-3-(2,4-diphenyl)propionic acid ethyl ester··(S)-2_(unclear) dissolved in dichloromethane (1〇〇mL) A solution of butoxycarbonylamino)-3-(2,4-dichlorophenyl)propionic acid (5 g, I5 mmol, Fluka) was added to 1-hydroxybenzotriazole 146258.doc -71 · 201040149 (3 g, 22.5 mmol), N-Mercaptomorpholine (16.5 mL, 150 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.3 g, 22.8 mmol ) and ethanol (13.8 mL, 300 mmol). The reaction was stirred at room temperature for 18 hours. The resulting solution was extracted with water (25 mL), saturated sodium bicarbonate (25 mL) and 1 N EtOAc (25 mL). The layers were separated and dried with magnesium sulfate. Vacuum filtered and concentrated. The resulting oil was dissolved in decyl alcohol (25 mL) and then 4N HCl was dissolved in dioxane (25 mL, Aldrich). The reaction was stirred at room temperature for 18 hours. The resulting solution was concentrated in vacuo to give title titled: md. (:111113(:121^〇2)^8 port 1), measured value 26: 3.16(]^11+) Step 2: (8)-3-(2,4-diphenyl)_2- (1-(2,4-Diphenyl)cyclopropionylamino)propionic acid ethyl ester: (s)_2amino-3-(2) dissolved in dioxane (1 mL) , 4-diphenylphenyl)-propionic acid ethyl ester (3 g, us mmol) solution was added to ι_ basal triazole (1.8 g '13.7 mmol), N-mercaptomorpholine (12.6 mL, 115 mmol) , 1-[3-(Didecylamino)propyl]_3_ethylcarbodiimide hydrochloride (2.6 g, 13.7 mmol) and 1-(2,4-diphenyl)cyclopropanecarboxylate Acid (2 7 g, 1 . 5 mmol, Acros). The reaction was stirred at room temperature for 18 h. extracted with water (25 mL), sat. NaH.sub. The solution was separated and dried with EtOAc EtOAc EtOAcjjjjjjjjj 5 (MH+) Step 3: (8)-3-(2,4-Diphenyl)-2-(1-(2,4-diphenyl)cyclopropamimidino)-propionic acid : (S)-3-(2,4-di) dissolved in 1 mL of MeOH 146258.doc •72· 201040149 A solution of ethyl phenyl)-2-(1-(2,4-dichlorophenyl)-cyclopropionamido)propionate (15 g '3.2 mmol) in 20 mL 2 N NaOH solution and the reaction mixture was stirred at room temperature for 18 hr. EtOAc was evaporated. The layers were filtered under EtOAc EtOAc EtOAc. : 2,4-digas-Ν-α-{[1-(2,4-diphenylphenyl)cyclopropyl] ribyl-[2-(monomethylamino)ethyl]-L - amphetamine octamin: to (8)-3-(2,4-diphenyl)-2-(1-(2,4-dichlorophenyl) ring (5) Propionate (70 g' 29 mmol) solution of 1-propenylbenzotrisole (25 mg, 0.19 mmol), N-methylmorpholine (〇_172 mL, 1.57 mmol) ' 1 -[3-(monomethylamino)propyl]-3-ethylcarbodiimide hydrochloride (36 mg, 0.19 mmol) and hydrazine, hydrazine 1-dimethylethyl-1,2-diamine ( 16 mg, 0.19 mmol, TCI America). The reaction was stirred at room temperature for 18 hours. The resulting solution was washed with water (25 mL) and saturated sodium bicarbonate (25 mL). The layers were separated and dried with MgSO4, filtered and evaporated. The product was then purified using preparative HPLC (reverse phase, acetonitrile / aqueous 1 mM EtOAc EtOAc) to afford 41 mg of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 7.59 (m, 1 Η), 7.50 (d, 1H), 7.42 (m, 2H), 7.33 (dd, 1H), 7.16 (d, 1H), 6.73 (d , 1H), 4.52 (m, 1H), 3.09 (m, 3H), 2.84 (m, 1H), 2.27 (t, 2H), 2.16 (s, 6H), 1.37 (m, 2H), 0.95 (m, MS (EI) calcd for C23 H.sub.2. The following compounds were prepared in a similar manner to Example 3. 146258.doc -73- 201040149 Synthesis of 2,4-dioxa-Να-{[1-(2,4-diphenylphenyl)cyclopropyl]carbonyl}-Ν-[2] in a similar manner to Example 3. -(Dimethylamino)ethyl]-indole-methyl-L-amphetamine-terminated amine, wherein «Ν2-trimercaptoethyl-1,2-diamine (Aldrich) replaces N,N-monomethyl _ι,2-diamine (Aldrich). 4 NMR (400 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.58 (d, 1H), 7.51 (dd, 1H), 7.42 (m, 2H), 7.33 (m, 1H), 7.23 (m) , 1H), 4.99 (m, 1H), 3.40 (m, 1H), 3.23 (m, 1H), 2.95 (s, 3H), 2.86 (m, 2H), 2.27 (m, 2H), 2.13 (s, 6H), 1.37 (m, 1H), 1.14 (m, 1H), 0.96 (m, 1H), 0.89 (m, 1H); MS (El) of C24H27 C14N302, found 532.4 (MH+). Synthesis of 2,4_dioxadiphenyl)cyclopropyl]carbonylmethylacridin-4-yl)-L-phenylpropylamine decylamine in the same manner as in Example 3, wherein 1-indolyl acridine-4 - Amine (TCI) replaces β, Ν1-dimercaptoethyl-1,2-diamine (Aldrich). 4 NMR (400 MHz, DMSO-d6): δ 8.21 (s, 1 Η), 7.61 (s, 1H), 7.50 (d, 1H), 7.45-7.40 (m, 2H), 7.33 (dd, 1H), 7.15 (d, 1H), 6.58 (d, 1H), 4.53-4.47 (m, 1H), 3.45-3.41 (m, 1H), 3.00-2.95 (m, 1H), 2.88-2.82 (m, 1H), 2.67 (m, 2H), 2.15 (s, 3H), 1.97 (m, 2H), 1.62 (m, 2H), 1.41- 1.24 (m, 4H), 0_96 (m, 2H); MS (El) of C25H27C14N302, Found 544.3 3 (MH+). Synthesis of 2,4_dioxadiphenyl)cyclopropyl]carbonyl-N-(2-indolyl-1-ylethyl)-L-phenylpropylamine decylamine in the same manner as in Example 3 (Pyropolidine-1-yl)ethylamine (Fluka) replaces β, Ν1-dimercaptoethyl-1,2-diamine (Aldrich). NMR (400 MHz, DMSO-d6): δ 9.18 (s, 1 Η), 7.69 (t, 1H), 7.57 (d, 1H), 7.50 (d, 1H), 7.42 (m, 146258.doc • 74 - 201040149 2H), 7.32 (dd, 1H)S 7.16 (d, 1H), 4.53 (m, 1H), 3.15 (m, 2H), 3.03 (m, 1H), 2.85 (m, 1H), 2.48 (m, 6H) ), 1.69 (m, 4H), 1, 36 (m, 2H), 0.95 (m, 2H); C25H27C14N3 〇W MS (El) ' Found 544.5 (Mh+). Synthesis of 2,4 digas-Να·{[1-(2,4-diphenylphenyl)cyclopropyl]dithiophene-methyl·N (1methylfluorene) in a similar manner to Example 3. Bite _3 phenylalanine Si amine, 47 1 w ', -T base ° Haha. Ding-3 -amine (Matrix Scientific) instead of N1 N1-dimethyl 7 λ

’ Τ 卷匕-1，2_ 二胺（Aldrich)。4 NMR (400 MHz, DMSO-d6)： δ 9.18 (S, 1H), 7.69 (t, 1H), 7.57 (d, 1H), 7.50 (d, 1H), 7.42 (m, 2H), 7.32 (dd, 1H), 7.16 (d, 1H), 4.53 (m, 1H)，3.15 (m，2H)，3.03 (m, iH)，2,85 (m，1H)，2.48 (m， 6H), 1.69 (m, 4H), i.36 (m, 2H)5 0.95 (m, 2H)； C25H27C14N302的 MS (EI)，實測值 544 5 (MH+)。 以與實施例3相似的方式合成2,4_二氣二氣 苯基）環丙基]幾基卜N_曱基_N_(1_f基呱啶_4基）_L苯丙胺 酸胺其中N，l- _甲基吸咬_4_胺（Matrix Scientific)替代 N，N 一曱基乙-1，2~二胺（Aldrich)。4 NMR (400 MHz， DMSO-d6): δ 7_6G (m，1H)，7 56 ㈣，1H), 7 41 (m, 2H), 7 34 (m，1H)’ 7·21 (m, 1H), 4.95 (m, 1H)，4.07 (m，1H), 2.88 (m, 2H), 2.75 (s, 3H), 4.47 (m, 4H), 2.12 (s, 3H), 1.86 (m，2H)，1.68 (m，2H)，1.26 (m, 2H)，0.92 (m，2H);'Τ 匕 匕 1,2_ diamine (Aldrich). 4 NMR (400 MHz, DMSO-d6): δ 9.18 (S, 1H), 7.69 (t, 1H), 7.57 (d, 1H), 7.50 (d, 1H), 7.42 (m, 2H), 7.32 (dd , 1H), 7.16 (d, 1H), 4.53 (m, 1H), 3.15 (m, 2H), 3.03 (m, iH), 2,85 (m, 1H), 2.48 (m, 6H), 1.69 ( m, 4H), i.36 (m, 2H), calcd. Synthesis of 2,4_dioxadiphenyl)cyclopropyl]methylidene N-fluorenyl_N_(1_f-acridinyl-4-yl)-L-phenylalanine amine N,l in a similar manner to Example 3. - _Methyl _4_amine (Matrix Scientific) instead of N, N-mercaptoethyl-1,2-diamine (Aldrich). 4 NMR (400 MHz, DMSO-d6): δ 7_6G (m, 1H), 7 56 (4), 1H), 7 41 (m, 2H), 7 34 (m, 1H)' 7·21 (m, 1H) , 4.95 (m, 1H), 4.07 (m, 1H), 2.88 (m, 2H), 2.75 (s, 3H), 4.47 (m, 4H), 2.12 (s, 3H), 1.86 (m, 2H), 1.68 (m, 2H), 1.26 (m, 2H), 0.92 (m, 2H);

CmHmCmNsO2的MS (El)，實測值 558 3 (MH+)。 以與實施例3相似的方式合成1_(2,4_二氣苯基）_N_{(1S)_ l-[(2,4-二氣苯基）曱基卜2_[(3R)3 (二曱基胺基）吡咯啶小 146258.doc -75- 201040149 基]-2-氧代乙基}環丙酿胺，其中（R)-N，N-二甲基n比0各咬- 3-胺（Aldrich)替代 Ν^Ν1-二曱基乙-1，2-二胺（Aldrich)。4 NMR (400 MHz, DMSO-d6)： δ 7.59 (s, 1H), 7.52 (t, 1H), 7.41 (m, 2H), 7.36-7.32 (m, 1H), 7.21 (m, 1H), 6.96-6.86 (m, 1H), 4.79-4.72 (m, 1H), 3.54-3.49 (m, 1H), 3.44-3.41 (m, 2H), 3.15-3.10 (m, 1H), 2.98-2.86 (m, 3H), 2.08 (d, 6H), 2.02-1.93 (m, 1H), 1.64-1.49 (m, 1H), 1.39-1.35 (m, 1H), 1.23-1.18 (m, 1H), 0.93 (m, 2H); C25H27Cl4N3〇2的 MS (EI)，實測值544.32 (MH+)。 以與實施例3相似的方式合成1_(2,4-二氣苯基）-〜{(18)-1-【(2,4-二氣苯基）甲基卜2_丨(38)-3-(二甲基胺基）_0比洛咬_1_ 基]-2-氧代乙基}環丙醯胺，其中（s)_n,N-二曱基吡咯啶-3-胺（Aldrich)替代 Ν^Ν1-二曱基乙 _ι，2-二胺（Aldrich)。 NMR (400 MHz, DMSO-d6): δ 7_59 (s，1Η), 7.52 (t，1Η)， 7.41 (m，2H)，7.35-7.32 (m，iH)，7.22-7-19 (m，1H)，6.88 (t， 1H)，4.82-4.74 (m，1H)，3.80-3.69 (m, 1H)，3.48-3.45 (m， 1H), 3.29-3.23 (m, 1H), 3.19-3.12 (m? 1H), 2.98-2.87 (m, 3H)，2.10 (d，6H)，2.04-1.93 (m，1H)，1.68-1.48 (m, 1H)， 1.40-1.36 (m，1H)，i.24_117 (m，1H)，0.93 (m，2H); C25H27Cl4N302的 MS (El)，實測值 544.33 (MH+)。 以與實施例3相似的方式合成2,4-二氣_Na_U1_(2,4_二氯 苯基）環丙基]羰基卜N_[2_(二甲基胺基）-1甲基乙基】_L_苯 丙胺酸胺’其中N1，：^1-二甲基丙_1，2-二胺（Matrix)替代 N^N1-二曱基乙]，2_ 二胺（Aldrich)。iH NMR (400 MHz， 146258.doc 201040149 DMSO-d6): δ 7.60 (s，1H)，7.54 (m，3H)，7.32 (m，1H)，7.19 (m, 1H), 4.51 (m, 1H), 3.74 (m, 1H), 3.06 (m, 1H), 2.87 (m, 1H), 2.10 (m, 8H), 1.39 (m，1H)，1.25 (m，1H)，1.00 (d， 211)，0.94(111，311);(：241^7(：14]^3〇2的1^8(£1)，實測值531.3 (MH+)。 以與實施例3相似的方式合成2,4-二氣-Να-{[1_(2,4-二氣 苯基）環丙基】羰基}-Ν-[1-(苯基甲基）-呱啶-4-基】-L-苯丙胺 醯胺，其中1-苄基呱啶-4-胺（Aldrich)替代N^N1-二甲基乙-〇 1，2-二胺(Aldrich)。'H NMR (400 MHz，DMSO-d6): δ 7.60 (m, 2Η), 7.50 (d, 1H), 7.42 (m, 2H), 7.24 (m, 6H), 7.14 (d, 1H), 4.49 (m, 1H), 3.42 (m5 3H), 2.90 (m, 2H), 2.66 (m, 2H), 1.95 (m, 2H), 1.60 (m, 2H), 1.37 (m, 2H), 1.27 (m, 211)，0.96(111,2印；（：311131(：丨4]^3〇2的]^8(£1)，實測值620.6 (MH+)。 l-(2,4-二氣苯基）-N-[(lS)-l-[(2,4-二氣笨基）甲基卜2-(4-甲基呱嗪-1-基）_2_氧代乙基】環丙醢胺：4 NMR (400 ❹ MHz, CD3OD) ： 7.88-7.75 (m, 3H), 7.57-7.43 (m, 3H), 7.40-7.33 (m, 2H), 7.30-7.24 (m, 1H), 5.18-5.07 (m, 1H), • 3.82-3.40 (m, 2H), 3.08-3.00 (m5 2H), 2.55-2.35 (m, 2H), 2.28-2.20 (m, 1H), 2.17 (s, 3H), 1.80-1.70 (m, 1H), 1.60-1.48 (m, 2H), 1.17-1.09 (m, 1H), 1.06-0.98 (m, 1H). C28H29C12N302 的 MS (El)，實測值 510 (MH+)。 1-(2,4-二氣苯基）-N-[(lR)-l-[(2,4-二氣苯基）甲基]-2-(4-甲基呱嗪-1-基）-2-氧代乙基I環丙醯胺：4 NMR (400 146258.doc -77- 201040149 MHz, CD3OD) ： 7.51 (d, 1H), 7.47-7.41 (m, 2H), 7.39-7.35 (m, 1H), 7.29-7.23 (m, 1H), 7.26 (dd, 1H), 7.17-7.13 (d, 1H), 5.15 (dd, 1H), 3.78-3.60 (m, 2H), 3.60-3.43 (m, 2H), 3.05-2.95 (m, 2H), 2.78-2.60 (m, 3H), 2.58-2.43 (m, 4H), 1.57-1.42 (m, 2H), 1.18-1.01 (m，2H)_ C24H25CI4N3O2的MS (El)，實測值 529.68 (MH+)。 l-(2,4-二氣苯基）-N-[(lS)-2-(4-甲基呱嗪-1-基）-2-氧代-1-(苯基曱基）乙基卜環丙醯胺：1HNMR(400 MHz，DMSO-d6) ： 7.51 (s, 1H), 7.44-7.34 (m5 2H), 7.30-7.20 (m5 3H), 7.13-7.08 (m, 1H), 6.57 (d, 1H), 5.09-5.00 (m, 1H), 3.64- 3.48 (m, 3H), 2.88 (d, 2H), 2.65-2.47 (m, 3H), 2.23-2.15 (m, 1H), 1.63-1.52 (m, 2H), 1.18-1.04 (m, 2H). C24H27C12N302的 MS (El)，實測值 461.90 (MH+)。 l-(2,4-二氣苯基）-N-[(lS)-2-(4-甲基呱嗪-1-基）-1-(萘_ι_ 基甲基）-2-氧代乙基】環丙醢胺·· 4 NMR (400 MHz， CD3OD) ： 8.18 (d, 1H), 7.85 (d, 1H), 7.80 (d, 2H), 7.60-7.45 (m, 3H), 7.43-7.35 (m, 3H), 7.27 (d, 1H), 6.63 (d, 1H), 5.25-5.21 (m, 1H), 3.58-3.38 (m，2H)，3.25-3.05 (m, 3H), 2.78-2.65 (m, 1H), 2.42-2.37 (m, 1H), 2.18-2.01 (m, 4Η), 1.97-1.88 (m, 1H), 1.65-1.55 (m, 2H)，1.24-1.04 (m, 3H). C28H29C12N3〇2的 MS (El)，實測值 509.90 (MH+)。 1-(2,4-二氣苯基）-N-{(lS)-l-[(2,4-二氣苯基）甲基】_2_ [(8aR) -六氮洛並-丨l，2-a】®tt嗓-2(1H)·基]-2-氧代乙基}環 丙醢胺：NMR (400 MHz，CD3OD) : 8.23 (s，1H), 7.53- 146258.doc -78- 201040149 7.38 (m, 4H), 7.28-7.12 (m, 2H), 5.22-5.13 (m, 1H), 4.25 (ddd, 2H), 3.45-3.38 (m, 1H), 3.21-3.05 (m, 2H), 3.03-2.78 (m, 4H), 2.58-2.40 (m, 2H), 2.35-2.08 (m, 1H), 2.00-1.84 (m, 3H), 1.55-1.43 (m, 3H), 1.13-1.00 (m, 2H). (：261127(：14]^3〇2的]^即），實測值 555.88 (]^11+)。 N-l-氮雜雙環[2.2.2]辛-3·基-2,4-二氣-Να-{[1-(2,4-二氣 苯基）環丙基】-羰基}-L-苯丙胺醯胺：4 NMR (400 ΜΗζ， CD3OD) ： 8.55 (s, 1H), 7.50-7.38 (m, 4H), 7.25-7.15 (m, 2H), 4.63-4.59 (m, 1H), 4.08-3.98 (m, 1H), 3.57-3.46 (m, 1H), 3.20-3.00 (m, 6H), 2.85-2.65 (m, 1H), 1.97-1.82 (m, 3H)，1.78-1.44 (m，4H)，1.18-1.00 (m, 2H)· C26H27C14N302 的 MS (El)，實測值 556.13 (MH+)。 2.4- 二氣-Να-{[1-(2,4-二氣苯基）環丙基]羰基}-N-[2-(二 乙基胺基）-乙基]-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6)： δ 8.24-8.02 (m, 1H), 7.58 (dd, 1H), 7.50 (d5 1H)，7.42 (t，1H)，7.40 (s，1H)，7.32 (dd, 1H)，7.16 (d，1H)， 6.72 (d, 1H), 4.52 (td, , 1H), 3.11 (td, 2H), 3.02 (ddd, 3H), 2.85 (dd, 1H), 2.44 (d5 2H), 2.38 (td, 2H), 1.37 (dd, 1H), 1.32-1.23 (m, 1H)，0.94 (dt，8H). C25H29C14N302 的 MS (El)，實測值 546·3 (MH+)。 2.4- 二氣-Να-{[1-(2,4-二氣苯基）環丙基]羰基卜N-[2-(l-甲基吡咯啶-2-基）乙基]-L-苯丙胺醢胺：NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1Η), 7.76 (q, 1H), 7.62-7.54 (m, 1H)，7.50 (d，1H)，7.44-7.41 (m，2H)，7.32 (dd，1H)，7.16 146258.doc •79· 201040149 (d, 1H), 6.64 (dd, 1H), 4.50 (tdd, 1H), 3.09-2.92 (m, 4H), 2.85 (ddd, 1H), 2.19 (d5 , 3H), 2.13-1.96 (m, 2H), 1.93-1.77 (m, 1H), 1.72-1.52 (m, 3H), 1.41-1.20 (m, 4H), 1.00-0.87 (m, 2H)· C26H29C14N302的 MS (El)，實測值 558.3 (MH+)。 2.4- 二氣-Να-{[1-(2,4-二氣苯基）環丙基]羰基}-N-(2_呱 啶-1-基乙基）-L-苯丙胺醯胺：1HNMR(400 MHz,DMSO-d6):5 8.17(s，lH),7.63-7.54 (m，2H)，7.50(d,lH),7.47-7.36 (m, 2H), 7.32 (dd, 1H), 7.16 (d, 1H), 6.72 (d, 1H), 4.52 (td, 1H), 3.20-2.99 (m, 3H), 2.85 (dd, 1H), 2.37-2.21 (m, 6H), 1.52-1.42 (m5 4H), 1.42-1.25 (m, 4H), 1.00-0.90 (m，2H). C26H29C14N302的 MS (El)，實測值 558.3 (MH+)。 2.4- 二氣以(*-{[1-(2,4-二氣苯基）環丙基]羰基}-]\-[3-(二 曱基胺基）-丙基】-L-苯丙胺醯胺：4 NMR (400 MHz， DMSO-d6): δ 8.22 (s, 1Η), 7.76 (t, 1H), 7.61-7.55 (m, 1H), 7.50 (d5 1H), 7.42 (s, 1H), 7.32 (dd, 1H), 7.16 (d, 1H), 6.66 (d, 1H), 4.50 (td, 1H), 3.13-2.93 (m, 3H), 2.86 (dd, 1H), 2.23 (t, 2H), 2.17 (s, 6H), 1.55-1.42 (m, 2H), 1.41-1.25 (m, 211)，0.96(1，211).(：241127(：14化〇2的？48斤1)，實測值 532.3 (MH+)。 2.4- 二氣-Να-{[1-(2,4-二氣苯基）環丙基]羰基}-N-(l-乙基 呱啶-3-基）-L-苯丙胺醢胺：NMR (400 MHz, DMSO-d6): δ 7.60 (dd, 1Η), 7.50 (d, 1H), 7.48-7.42 (m, 2H), 7.40 (dd, 1H), 7.33 (dd, 1H), 7.15 (d, 1H), 6.71 (d, 1H), 4.51 (td, 1H), 3.02 (dd, 1H), 2.90-2.80 (m, 1H), 2.37-2.20 (m, 3H), 146258.doc -80- 201040149 1.56 (d, 2H), 1.38 (dd, 2H), 1.29-1.07 (m5 2H), 1.03-0.87 (m，6H). C26H29Cl4N3〇2的 MS (El)，實測值 558.3 (MH+)。 2,4-二氣-Να-{[1-(2,4-二氣苯基）環丙基]羰基}-N-[l-(苯 基甲基）吡咯啶-3-基]-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d.6): δ 8.16 (s, 1H), 7.79 (t, 1H), 7.60-7.57 (m, 1H), 7.51-7.48 (m, 1H), 7.43 (dddd, 2H), 7.32-7.26 (m, 4H), 7.25-7.20 (m, 1H), 7.12 (dd, 1H), 6.60 (d, 1H), 4.50 (td, 1H), 4.13-4.00 (m, 1H), 3.54 (d, 2H), 3.02-2.78 (m, 2H), 2.64-2.50 (m, 2H), 2.38-2.25 (m, 1H), 2.21-1.99 (m, 2H), 1.55-1.34 (m, 2H), 1.25 (dd, 1H), 1.03-0.89 (m, 2H). C30H29Cl4N3O2的MS (El)，實測值606.4 (MH+)。 N-[(lS)-l-[(4-乙酿苯基）甲基]-2-(4-甲基略嗪-1-基）-2-氧 代乙基卜1-(2,4-二氣苯基）環丙醢胺：NMR (400 MHz, DMSO-d6)： δ 7.83-7.78 (m, 2Η), 7.60 (t, 1H), 7.40 (d, 2H), 7.21 (d, 2H), 6.87 (t, 1H), 4.93 (dd, 1H), 3.47-3.27 (m, 4H), 2.88 (ddd, , 2H), 2.54 (s, 3H), 2.19 (s, 3H), 2.12 (s? 4H),MS (El) for CmHmCmNsO2, found 558 3 (MH+). Synthesis of 1_(2,4_diphenyl)_N_{(1S)_ l-[(2,4-diphenyl)indolyl 2_[(3R)3 (two) in a similar manner to Example 3. Mercaptoamine) pyrrolidine small 146258.doc -75- 201040149 yl]-2-oxoethyl}cyclopropanol, wherein (R)-N,N-dimethyl n is 0 bit each - 3- The amine (Aldrich) replaces Ν^Ν1-dimercaptoethyl-1,2-diamine (Aldrich). 4 NMR (400 MHz, DMSO-d6): δ 7.59 (s, 1H), 7.52 (t, 1H), 7.41 (m, 2H), 7.36-7.32 (m, 1H), 7.21 (m, 1H), 6.96 -6.86 (m, 1H), 4.79-4.72 (m, 1H), 3.54-3.49 (m, 1H), 3.44-3.41 (m, 2H), 3.15-3.10 (m, 1H), 2.98-2.86 (m, 3H), 2.08 (d, 6H), 2.02-1.93 (m, 1H), 1.64-1.49 (m, 1H), 1.39-1.35 (m, 1H), 1.23-1.18 (m, 1H), 0.93 (m, 2H); MS (EI) for C25H27Cl4N3 〇2, found 544.32 (MH+). Synthesis of 1-(2,4-diphenyl)-~{(18)-1-[(2,4-diphenyl)methyl b 2_丨(38)- in a similar manner to Example 3. 3-(Dimethylamino)_0 piroxime_1_yl]-2-oxoethyl}cyclopropanamide, wherein (s)-n,N-dimercapyryrrolidine-3-amine (Aldrich) Instead of Ν^Ν1-dimercaptoethyl_ι,2-diamine (Aldrich). NMR (400 MHz, DMSO-d6): δ 7_59 (s, 1 Η), 7.52 (t, 1 Η), 7.41 (m, 2H), 7.35-7.32 (m, iH), 7.22-7-19 (m, 1H) ), 6.88 (t, 1H), 4.82-4.74 (m, 1H), 3.80-3.69 (m, 1H), 3.48-3.45 (m, 1H), 3.29-3.23 (m, 1H), 3.19-3.12 (m 1H), 2.98-2.87 (m, 3H), 2.10 (d, 6H), 2.04-1.93 (m, 1H), 1.68-1.48 (m, 1H), 1.40-1.36 (m, 1H), i.24_117 (m, 1H), 0.93 (m, 2H); MS (El), C, s, s, s. Synthesis of 2,4-digas_Na_U1_(2,4-dichlorophenyl)cyclopropyl]carbonylb N_[2_(dimethylamino)-1methylethyl] in a similar manner to Example 3. _L_Phenylalanine 'where N1, :1 1-dimethylpropan-1,2-diamine (Matrix) replaces N^N1-dimercaptoethyl], 2-diamine (Aldrich). iH NMR (400 MHz, 146258.doc 201040149 DMSO-d6): δ 7.60 (s, 1H), 7.54 (m, 3H), 7.32 (m, 1H), 7.19 (m, 1H), 4.51 (m, 1H) , 3.74 (m, 1H), 3.06 (m, 1H), 2.87 (m, 1H), 2.10 (m, 8H), 1.39 (m, 1H), 1.25 (m, 1H), 1.00 (d, 211), </ RTI> <RTIgt; Gas-Να-{[1_(2,4-diphenyl)cyclopropyl]carbonyl}-indole-[1-(phenylmethyl)-acridin-4-yl]-L-phenylalanamine decylamine, Wherein 1-benzyl acridine-4-amine (Aldrich) is substituted for N^N1-dimethylethyl-hydrazine 1,2-diamine (Aldrich). 'H NMR (400 MHz, DMSO-d6): δ 7.60 ( m, 2Η), 7.50 (d, 1H), 7.42 (m, 2H), 7.24 (m, 6H), 7.14 (d, 1H), 4.49 (m, 1H), 3.42 (m5 3H), 2.90 (m, 2H), 2.66 (m, 2H), 1.95 (m, 2H), 1.60 (m, 2H), 1.37 (m, 2H), 1.27 (m, 211), 0.96 (111, 2); (:311131(:丨4]^3〇2]^8(£1), found 620.6 (MH+). l-(2,4-diphenyl)-N-[(lS)-l-[(2,4 -2-gas base) methyl 2-(4-methylpyridazin-1-yl)_2-oxoethyl]cyclopropanamide: 4 NMR (400 ❹ MHz, CD3 OD) : 7.88-7.75 (m, 3H), 7.57-7.43 (m, 3H), 7.40-7.33 (m, 2H), 7.30-7.24 (m, 1H), 5.18-5.07 (m, 1H), • 3.82 -3.40 (m, 2H), 3.08-3.00 (m5 2H), 2.55-2.35 (m, 2H), 2.28-2.20 (m, 1H), 2.17 (s, 3H), 1.80-1.70 (m, 1H), 1.60-1.48 (m, 2H), 1.17-1.09 (m, 1H), 1.06-0.98 (m, 1H). MS (El) for C28H29C12N302, found 510 (MH+). 1-(2,4-diphenyl)-N-[(lR)-l-[(2,4-diphenyl)methyl]-2-(4-methylpyridazin-1-yl) )-2-oxoethyl Icyclopropanamide: 4 NMR (400 146258.doc -77- 201040149 MHz, CD3OD): 7.51 (d, 1H), 7.47-7.41 (m, 2H), 7.39-7.35 ( m, 1H), 7.29-7.23 (m, 1H), 7.26 (dd, 1H), 7.17-7.13 (d, 1H), 5.15 (dd, 1H), 3.78-3.60 (m, 2H), 3.60-3.43 ( m, 2H), 3.05-2.95 (m, 2H), 2.78-2.60 (m, 3H), 2.58-2.43 (m, 4H), 1.57-1.42 (m, 2H), 1.18-1.01 (m, 2H)_ MS (El) for C24H25CI4N3O2, found 529.68 (MH+). L-(2,4-Diphenyl)-N-[(lS)-2-(4-methylpyridazin-1-yl)-2-oxo-1-(phenylindenyl)ethyl Propylamine: 1H NMR (400 MHz, DMSO-d6): 7.51 (s, 1H), 7.44-7.34 (m5 2H), 7.30-7.20 (m5 3H), 7.13-7.08 (m, 1H), 6.57 ( d, 1H), 5.09-5.00 (m, 1H), 3.64- 3.48 (m, 3H), 2.88 (d, 2H), 2.65-2.47 (m, 3H), 2.23-2.15 (m, 1H), 1.63- 1.52 (m, 2H), 1.18-1.04 (m, 2H). MS (El) of C24H27C12N302, found 461.90 (MH+). L-(2,4-Diphenyl)-N-[(lS)-2-(4-methylpyridazin-1-yl)-1-(naphthalene~ι_ylmethyl)-2-oxo Ethyl]cyclopropanamide·· 4 NMR (400 MHz, CD3OD): 8.18 (d, 1H), 7.85 (d, 1H), 7.80 (d, 2H), 7.60-7.45 (m, 3H), 7.43- 7.35 (m, 3H), 7.27 (d, 1H), 6.63 (d, 1H), 5.25-5.21 (m, 1H), 3.58-3.38 (m, 2H), 3.25-3.05 (m, 3H), 2.78- 2.65 (m, 1H), 2.42-2.37 (m, 1H), 2.18-2.01 (m, 4Η), 1.97-1.88 (m, 1H), 1.65-1.55 (m, 2H), 1.24-1.04 (m, 3H MS (El) of C28H29C12N3 〇2, found 509.90 (MH+). 1-(2,4-diphenyl)-N-{(lS)-l-[(2,4-diphenyl)methyl]_2_[(8aR)-hexazadro-indole, 2-a]®tt嗓-2(1H)·yl]-2-oxoethyl}cyclopropanamide: NMR (400 MHz, CD3OD): 8.23 (s, 1H), 7.53- 146258.doc -78 - 201040149 7.38 (m, 4H), 7.28-7.12 (m, 2H), 5.22-5.13 (m, 1H), 4.25 (ddd, 2H), 3.45-3.38 (m, 1H), 3.21-3.05 (m, 2H ), 3.03-2.78 (m, 4H), 2.58-2.40 (m, 2H), 2.35-2.08 (m, 1H), 2.00-1.84 (m, 3H), 1.55-1.43 (m, 3H), 1.13-1.00 (m, 2H). (:261127(:14]^3〇2]^), measured value 555.88 (]^11+). Nl-azabicyclo[2.2.2]oct-3-yl-2 ,4-diqi-Να-{[1-(2,4-diphenyl)cyclopropyl]-carbonyl}-L-phenylalanamine decylamine: 4 NMR (400 ΜΗζ, CD3OD) : 8.55 (s, 1H ), 7.50-7.38 (m, 4H), 7.25-7.15 (m, 2H), 4.63-4.59 (m, 1H), 4.08-3.98 (m, 1H), 3.57-3.46 (m, 1H), 3.20-3.00 (m, 6H), 2.85-2.65 (m, 1H), 1.97-1.82 (m, 3H), 1.78-1.44 (m, 4H), 1.18-1.00 (m, 2H) · C26H27C14N302 MS (El), measured Value 556.13 (MH+). 2.4- Digas-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-[2-(diethylamino) -ethyl]-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.24-8.02 (m, 1H), 7.58 (dd, 1H), 7.50 (d5 1H), 7.42 (t, 1H) ), 7.40 (s, 1H), 7.32 (dd, 1H), 7.16 (d, 1H), 6.72 (d, 1H), 4.52 (td, , 1H), 3.11 (td, 2H), 3.02 (ddd, 3H) ), 2.85 (dd, 1H), 2.44 (d5 2H), 2.38 (td, 2H), 1.37 (dd, 1H), 1.32-1.23 (m, 1H), 0.94 (dt, 8H). MS of the C25H29C14N302 (El) ), found 546·3 (MH+). 2.4- Digas-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl b-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-L- Amphetamine: NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1 Η), 7.76 (q, 1H), 7.62-7.54 (m, 1H), 7.50 (d, 1H), 7.44-7.41 (m , 2H), 7.32 (dd, 1H), 7.16 146258.doc • 79· 201040149 (d, 1H), 6.64 (dd, 1H), 4.50 (tdd, 1H), 3.09-2.92 (m, 4H), 2.85 ( Ddd, 1H), 2.19 (d5, 3H), 2.13-1.96 (m, 2H), 1.93-1.77 (m, 1H), 1.72-1.52 (m, 3H), 1.41-1.20 (m, 4H), 1.00- MS (El), calcd., calcd. 2.4- Digas-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-(2-acridin-1-ylethyl)-L-phenylpropylamine decylamine: 1HNMR (400 MHz, DMSO-d6): 5 8.17 (s, lH), 7.63-7.54 (m, 2H), 7.50 (d, lH), 7.47-7.36 (m, 2H), 7.32 (dd, 1H), 7.16 (d, 1H), 6.72 (d, 1H), 4.52 (td, 1H), 3.20-2.99 (m, 3H), 2.85 (dd, 1H), 2.37-2.21 (m, 6H), 1.52-1.42 (m5 4H), 1.42-1.25 (m, 4H), 1.00-0.90 (m, 2H). MS (El) of C26H29C14N302, found 558.3 (MH+). 2.4- Digas to (*-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-]\-[3-(didecylamino)-propyl]-L-amphetamine Indoleamine: 4 NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1 Η), 7.76 (t, 1H), 7.61-7.55 (m, 1H), 7.50 (d5 1H), 7.42 (s, 1H) , 7.32 (dd, 1H), 7.16 (d, 1H), 6.66 (d, 1H), 4.50 (td, 1H), 3.13-2.93 (m, 3H), 2.86 (dd, 1H), 2.23 (t, 2H) ), 2.17 (s, 6H), 1.55-1.42 (m, 2H), 1.41-1.25 (m, 211), 0.96 (1,211). (:241127 (: 14 〇2 of 48 kg 1), Found 532.3 (MH+). 2.4-diox-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-(l-ethylacridin-3-yl)- L-Amphetamine amide: NMR (400 MHz, DMSO-d6): δ 7.60 (dd, 1 Η), 7.50 (d, 1H), 7.48-7.42 (m, 2H), 7.40 (dd, 1H), 7.33 (dd , 1H), 7.15 (d, 1H), 6.71 (d, 1H), 4.51 (td, 1H), 3.02 (dd, 1H), 2.90-2.80 (m, 1H), 2.37-2.20 (m, 3H), 146258.doc -80- 201040149 1.56 (d, 2H), 1.38 (dd, 2H), 1.29-1.07 (m5 2H), 1.03-0.87 (m,6H). MS (El) for C26H29Cl4N3〇2, found 558.3 (MH+) 2,4-digas-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-[l-(phenylmethyl) <RTIgt; </RTI> <RTIgt; </RTI> NMR (400 MHz, DMSO-d.6): δ 8.16 (s, 1H), 7.79 (t, 1H), 7.60-7.57 (m, 1H) , 7.51-7.48 (m, 1H), 7.43 (dddd, 2H), 7.32-7.26 (m, 4H), 7.25-7.20 (m, 1H), 7.12 (dd, 1H), 6.60 (d, 1H), 4.50 (td, 1H), 4.13-4.00 (m, 1H), 3.54 (d, 2H), 3.02-2.78 (m, 2H), 2.64-2.50 (m, 2H), 2.38-2.25 (m, 1H), 2.21 -1.99 (m, 2H), 1.55-1.34 (m, 2H), 1.25 (dd, 1H), 1.03-0.89 (m, 2H). MS (El) of C30H29Cl4N3O2, found 606.4 (MH+). N-[(lS)-l-[(4-Ethylphenyl)methyl]-2-(4-methylrazine-1-yl)-2-oxoethyl bup 1-(2,4 -diphenylphenyl)cyclopropanamide: NMR (400 MHz, DMSO-d6): δ 7.83-7.78 (m, 2 Η), 7.60 (t, 1H), 7.40 (d, 2H), 7.21 (d, 2H ), 6.87 (t, 1H), 4.93 (dd, 1H), 3.47-3.27 (m, 4H), 2.88 (ddd, , 2H), 2.54 (s, 3H), 2.19 (s, 3H), 2.12 (s ? 4H),

1.35 (m，2H), 0.99-0.91 (m, 2H). C26H29C12N303 的 MS (El)，實測值503.4 (MH+)。1.35 (m, 2H), 0.99-0.91 (m, 2H). MS (El), C26H29C12N303.

1-(2,4-二氣苯基）-N-[(lS)-2-(4-甲基呱嗪-1_基）_2-氧代-1-{【1-(苯基-甲基兴1!!-咪唑-5-基]甲基}乙基]環丙醯胺：A NMR (400 MHz, DMSO-d6): δ 8.14 (s, 1Η), 7.60-7.57 (m, 1H), 7.52 (d, 1H), 7.41-7.35 (m, 2H), 7.35-7.28 (m, 2H), 7.23-7.18 (m, 2H), 6.95 (d, 1H), 6.74 (d, 1H), 5.09 (s, 2H), 4.82 (q, 1H), 3.33 (d, 4H), 2.72-2.54 (m, 2H), 2.29-1.91 (m5 146258.doc -81 - 201040149 7H)，1-46-1.28 (m，2H)，1.06-0.83 (m，2H). C28H31C12N502 的]^(£1)，實測值541.5(1^11+)。 1-(2,4-二氣苯基）_N-【(1S)-1-丨(2-甲基苯基）甲基]-2-(4-甲 基呱嗪-1-基）-2-氧代乙基】環丙醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.13 (s, 1H), 7.63 (dd, 1H), 7.44-7.37 (m, 2H), 7.11-7.01 (m, 3H), 6.96 (d, 1H), 6.77 (d, 1H), 4.92 (q 1H), 3.40-3.19 (m, 3H), 3.00-2.88 (m, 1H), 2.82-2.74 (m, 2H), 2.22 (s, 3H), 2.13 (ddd, 3H), 2.07 (s, 3H), 1.82-1.72 (m, 1H)，1.44-1.31 (m，2H), 1.03-0.90 (m，2H). C25H29C12N302 的 MS (El)，實測值475.4 (MH+)。 l-(2,4-二氣苯基）-N-[(lS)-l-[(3-甲基苯基）甲基】-2-(4-甲 基呱嗪-1-基）-2-氧代乙基】環丙醢胺：4 NMR (400 MHz， DMSO-d6): δ 7.61 (dd5 1H), 7.45-7.34 (m, 2H), 7.09 (t, 1H), 6.97 (d, 1H), 6.84 (d, 2H), 6.72 (d, 1H), 4.86 (q, J=6.6 Hz, 1H), 3.45-3.21 (m, 4H), 2.75 (qd, 2H), 2.23 (s, 3H), 2.17 (dd, J=14.6, 5.2 Hz, 2H), 2.12 (s, 3H), 2.06-1.97 (m, 1H), 1.40 (d, J=3.3 Hz, 2H)，1.02-0.91 (m, 2H). C25H29C12N302的 MS (El)，實測值475.4 (MH+)。 1-(2,4-二氣苯基）-N-[(lS)-l-[(3-氟苯基）甲基]-2-(4-甲基 呱嗪-1-基）-2-氧代乙基】環丙醢胺：4 NMR (400 MHz, DMSO-d6): δ 7.57 (d, 1H), 7.39 (m, 2H), 7.26 (m, 1H), 6.91 (m, 1H), 6.88 (m, 2H), 4.89 (q, 1H), 3.33-3.38 (m, 4H), 2.81 (m, 2H), 2.18 (s, 3H), 2.16 (m, 2H) 1.32 (m, 2H), 0.95 (m, 2H). C24H26C12FN302 的 MS (El)，實測值479.4 (MH+)。 146258.doc • 82 - 201040149 N-[(lS)-l-[(4-氰基苯基）甲基]-2-(4-甲基》瓜嗓-1-基）-2-氧 代乙基】-1-(2,4-二氣苯基）環丙醯胺：NMR (400 ΜΗζ， DMSO-d6): δ 7.6 (d, 1Η), 7.37-7.42 (m, 2H), 7.23 (m, 1H), 7.04-7.11 (m, 3H), 6.78 (d, 1H), 4.94 (dd, 1H), 3.31-3.41 (m, 4H), 2.87 (dd, 1H), 2.79 (dds 1H), 2.18 (m, 3H), 2.12 (m, 2H), 1.39 (m, 1H), 1.27 (m, 1H), 0.94 (m, 2H). C25H26Cl2N4〇2 的 MS (El)，實測值486.4 (MH+)。 l-(2,4-二氣苯基）-N-{(lS)-l-[(2,4-二氣苯基）曱基卜2-[4-(1-甲基乙基）-呱嗪-1-基]-2-氧代乙基}環丙醢胺：NMR (400 MHz, DMSO-d6)： δ 7.60 (dd, 1H), 7.52 (d, 1H), 7.48-7.36 (m, 2H), 7.34 (dd, 1H), 7.20 (d, 1H), 6.92 (d5 1H), 5.08-4.93 (m, 1H), 3.31-3.23 (m, 2H), 2.96-2.83 (m, 2H), 2.70-2.54 (m, 1H), 2.33 (d, 2H), 2.22 (dd, 1H), 2.15-2.05 (m, 1H), 1.47-1.33 (m, 1H), 1.20 (dd, 1H), 1.00-0.80 (m, 10H)_ C26H29C14N302的MS (El)，實測值 558.3 (MH+)。 1-(2,4 -二氣苯基）-N-[(lS)-2-(4-甲基狐嗪-1-基）_2 -氧代-三氟甲基）苯基]甲基}乙基1環丙醢胺：4 NMR (400 MHz, DMSO-d6): δ 7.57 (d, 1H), 7.53 (d, 1H), 7.47 (d, 1H), 7.43 (t, 2H), 7.39 (dd, 1H), 7.33 (d, 1H), 6.94 (d, 1H), 4.98-4.86 (m, 1H), 3.36 (d, 4H), 2.97-2.85 (m, 2H), 2.20 (d, 3H), 2.14 (s, 4H), 1.48-1.33 (m, 1H), 1.25 (dd, 1H), 1.00-0.87(1!1,211).(：251126(：12?3沁〇2的]^8(丑1)，實測值 529.4 (MH+)。 l-(2,4-二氣苯基）-N-[(lS)-2-(4-甲基呱嗪-l-基）-2-氧代- 146258.doc -S3- 2010401491-(2,4-diphenyl)-N-[(lS)-2-(4-methylpyridazin-1-yl)_2-oxo-1-{[1-(phenyl-A) Kexing 1!!-Imidazol-5-yl]methyl}ethyl]cyclopropanamide: A NMR (400 MHz, DMSO-d6): δ 8.14 (s, 1 Η), 7.60-7.57 (m, 1H) , 7.52 (d, 1H), 7.41-7.35 (m, 2H), 7.35-7.28 (m, 2H), 7.23-7.18 (m, 2H), 6.95 (d, 1H), 6.74 (d, 1H), 5.09 (s, 2H), 4.82 (q, 1H), 3.33 (d, 4H), 2.72-2.54 (m, 2H), 2.29-1.91 (m5 146258.doc -81 - 201040149 7H), 1-46-1.28 ( m, 2H), 1.06-0.83 (m, 2H). C28H31C12N502]^(£1), found 541.5 (1^11+). 1-(2,4-diphenyl)_N-[(1S )-1-丨(2-methylphenyl)methyl]-2-(4-methylpyridazin-1-yl)-2-oxoethyl]cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 8.13 (s, 1H), 7.63 (dd, 1H), 7.44-7.37 (m, 2H), 7.11-7.01 (m, 3H), 6.96 (d, 1H), 6.77 (d, 1H) ), 4.92 (q 1H), 3.40-3.19 (m, 3H), 3.00-2.88 (m, 1H), 2.82-2.74 (m, 2H), 2.22 (s, 3H), 2.13 (ddd, 3H), 2.07 (s, 3H), 1.82-1.72 (m, 1H), 1.44-1.31 (m, 2H), 1.03-0.90 (m, 2H). MS (El) for C25H29C12N302, found 475.4 (MH+). 2,4-diphenyl)-N- [(lS)-l-[(3-methylphenyl)methyl]-2-(4-methylpyridazin-1-yl)-2-oxoethyl]cyclopropanamide: 4 NMR ( 400 MHz, DMSO-d6): δ 7.61 (dd5 1H), 7.45-7.34 (m, 2H), 7.09 (t, 1H), 6.97 (d, 1H), 6.84 (d, 2H), 6.72 (d, 1H ), 4.86 (q, J=6.6 Hz, 1H), 3.45-3.21 (m, 4H), 2.75 (qd, 2H), 2.23 (s, 3H), 2.17 (dd, J=14.6, 5.2 Hz, 2H) , 2.12 (s, 3H), 2.06-1.97 (m, 1H), 1.40 (d, J=3.3 Hz, 2H), 1.02-0.91 (m, 2H). MS (El) for C25H29C12N302, found 475.4 (MH+ ). 1-(2,4-Diphenyl)-N-[(lS)-l-[(3-fluorophenyl)methyl]-2-(4-methylpyridazin-1-yl)-2 -oxoethyl)cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.57 (d, 1H), 7.39 (m, 2H), 7.26 (m, 1H), 6.91 (m, 1H) , 6.88 (m, 2H), 4.89 (q, 1H), 3.33-3.38 (m, 4H), 2.81 (m, 2H), 2.18 (s, 3H), 2.16 (m, 2H) 1.32 (m, 2H) MS (El) for C24H26C12FN302, found 479.4 (MH+). 146258.doc • 82 - 201040149 N-[(lS)-l-[(4-cyanophenyl)methyl]-2-(4-methyl) guanidin-1-yl)-2-oxo -1-(2,4-diphenyl)cyclopropanamide: NMR (400 ΜΗζ, DMSO-d6): δ 7.6 (d, 1 Η), 7.37-7.42 (m, 2H), 7.23 (m , 1H), 7.04-7.11 (m, 3H), 6.78 (d, 1H), 4.94 (dd, 1H), 3.31-3.41 (m, 4H), 2.87 (dd, 1H), 2.79 (dds 1H), 2.18 (m, 3H), 2.12 (m, 2H), 1.39 (m, 1H), 1.27 (m, 1H), 0.94 (m, 2H). MS (El) of C25H26Cl2N4 〇2, found 486.4 (MH+). L-(2,4-diphenyl)-N-{(lS)-l-[(2,4-diphenyl)indolyl 2-[4-(1-methylethyl)- Pyridazin-1-yl]-2-oxoethyl}cyclopropanamide: NMR (400 MHz, DMSO-d6): δ 7.60 (dd, 1H), 7.52 (d, 1H), 7.48-7.36 (m , 2H), 7.34 (dd, 1H), 7.20 (d, 1H), 6.92 (d5 1H), 5.08-4.93 (m, 1H), 3.31-3.23 (m, 2H), 2.96-2.83 (m, 2H) , 2.70-2.54 (m, 1H), 2.33 (d, 2H), 2.22 (dd, 1H), 2.15-2.05 (m, 1H), 1.47-1.33 (m, 1H), 1.20 (dd, 1H), 1.00 MS (El) for -0.80 (m, 10H) _ C26H29C14N302, found 558.3 (MH+). 1-(2,4-diphenyl)-N-[(lS)-2-(4-methylfoxazin-1-yl)_2-oxo-trifluoromethyl)phenyl]methyl} Ethyl 1-cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.57 (d, 1H), 7.53 (d, 1H), 7.47 (d, 1H), 7.43 (t, 2H), 7.39 ( Dd, 1H), 7.33 (d, 1H), 6.94 (d, 1H), 4.98-4.86 (m, 1H), 3.36 (d, 4H), 2.97-2.85 (m, 2H), 2.20 (d, 3H) , 2.14 (s, 4H), 1.48-1.33 (m, 1H), 1.25 (dd, 1H), 1.00-0.87 (1!1,211). (:251126 (:12?3沁〇2)^8 (ugly 1), found 529.4 (MH+). l-(2,4-diphenyl)-N-[(lS)-2-(4-methylpyridazin-l-yl)-2-oxo- 146258.doc -S3- 201040149

1-{[2-(三氟甲基）-苯基】甲基}乙基】環丙醢胺：NMR (400 MHz, DMSO-d6): δ 7.63 (d, 1H), 7.61-7.54 (m, 2H), 7.45-7.39 (m, 3H), 7.39-7.33 (m, 1H), 7.02 (d5 1H), 4.99-4.94 (m, 1H), 3.38 (dd, 3H), 3.20 (dd, 1H), 3.05-2.79 (m, 2H), 2.29-2.17 (m, 3H), 2.13 (s, 3H), 2.00 (dd, 1H), 1.45-1.25 (m, 1H), 1.22-1.06 (m, 1H), 0.99-0.82 (m, 2H). C25H26Cl2F3N3〇2的 MS (El)，實測值 529.4 (MH+)。 1-(2,4-二氣苯基）-N-[(1 S)-2-(4_ 甲基狐嗓-l-基）-2-氧代-1-(吡啶-2-基甲基）乙基】環丙醯胺：4 NMR (400 MHz， DMSO-d6): δ 8.32 (m，1H)，8.15 (s，1H), 7.70-7.54 (m, 1H)， 7.49-7.36 (m, 2H), 7.22-7.07 (m, 3H), 5.07 (dd, 1H), 3.55-3.24 (m, 4H), 2.96 (dd, 1H), 2.85 (dd, 1H), 2.30-2.16 (m, 4H), 2.14 (s, 3H), 1.48-1.26 (m, 2H), 1.07-0.82 (m, 2H). C23H26Cl2N4〇2 的 MS (El)，實測值462.4 (MH+)。 N-[(lS)-l-(環己基甲基）-2-(4-甲基ι»瓜嗓-1-基）_2 -氧代乙 基】-l-(2,4-二 氣-苯基）環丙醢胺：4 NMR (400 MHz, DMSO-d6)： δ 7.70-7.57 (m, 1H), 7.51-7.30 (m, 2H), 6.73 (d, 1H), 4.74 (dd, 1H), 3.49-3.24 (m, 4H), 2.34-2.17 (m, 4H), 2.16 (s, 3H), 1.72 (d, 1H), 1.65-1.34 (m, 6H), 1.31 (t, 2H), 1.24-1.01 (m, 5H), 0.97-0.87 (m, 1H), 0.87-0.63 (m, 2H). C24H33Cl2N3〇2 的 MS (El)，實測值 467.4 (MH+)。 3,4-二氣·Να-{[1-(2,4-二氣苯基）環丙基]羰基卜ν-[2·(二 甲基胺基）乙基卜L-苯丙胺醯胺：4 NMR (400 ΜΗζ， DMSO-d6): δ 7.86 (t, J=5.5Hz, 1H), 7.58-7.55 (m, 1H), 146258.doc -84- 201040149 7.49-7.45 (m, 1H), 7.44-7.38 (m, 2H), 7.31 (d, 1H), 7.08 (dd, 1H), 6.65 (d, 1H), 4.45 (td, 1H), 3.22-3.01 (m, 2H), 2.83 (ddd, J=22.5, 13.5, 6.9Hz，2H)，2.48 (dt, 2H)，2.27 (q， 2H), 2.16 (s, 6H), 1.40-1.31 (m, 2H), 1.04-0.87 (m, 2H). 0231125(：141^302的1^(£1)，實測值518.3(]\«1+)。 Να-{[1-(2,4-二氣苯基）環丙基】羰基}-N-[2-(二甲基胺基）-乙基]-4-(三氟甲基）-L·苯丙胺醯胺：4 NMR (400 MHz， DMSO-d6): δ 7.86 (t, 1H), 7.60-7.53 (m, 3H), 7.44-7.36 (m, 2H), 7.28 (d, 2H), 6.61 (d, 1H), 4.50 (td, 1H), 3.22-3.01 (m, 2H), 2.92 (ddd, 2H), 2.48 (dt, 2H), 2.28 (dd, 2H), 2.17 (s, 6H), 1.40-1.28 (m，2H)，1.01-0.88 (m, 2H). C24H26C12F3N302 的 MS (El)，實測值517.4 (MH+)。 2.4- 二氣-Να-{[1-(2,4-二氣苯基）環丙基]羰基}-N-[3-(二 甲基胺基）-丙基]甲基-L-苯丙胺醯胺：1H NMR (400 MHz, DMSO-d6): δ 7.61-7.56 (m, 1H), 7.51 (d, 1H), 7.42-7.40 (m, 2H), 7.33 (dt, , 1H), 7.22 (dd5 1H), 6.81 (dd, 1H), 5.03 (dtd, 1H), 3.46-3.29 (m, 2H), 3.25-3.14 (m, 2H), 2.99-2.89 (m, 3H), 2.89-2.79 (m, 1H), 2.74 (s, 1H), 2.10 (t, 1H), 2.07 (d, 6H), 1.59 (s, 1H), 1.53-1.44 (m5 1H), 1.37 (d, 1H), 1.23-1.10 (m，1H), 1.00-0.84 (m，2H). C25H29C14N302的 MS (El)，實測值546.3 (MH+)。 2.4- 二氣-Να·{[1-(2,4-二氣苯基）環丙基】羰基}-N_[3-(二 甲基胺基）-2,2_二甲基丙基】-L-苯丙胺醢胺：4 NMR (400 MHz, DMSO-d6): δ 7.60-7.54 (m, 2H), 7.51 (d, 1H), 7.44 146258.doc -85 - 201040149 (dd, 1H), 7.40-7.31 (m, 2H), 7.18 (d, 1H), 6.74 (d, 1H), 4.57 (td, 1H), 3.04-2.92 (m, 2H), 2.91-2.80 (m, 2H), 2.18 (s, 6H), 2.01 (s, 2H), 1.33 (tt, 2H), 1.04-0.88 (m, 2H), 0.74 ((1，611)_匸261131(：14&gt;^〇的]\^(£1)2的^18(£1)，實測值560.4 (MH+)。 2.4- 二氣 _]\〇1-{[1-(2,4-二氣苯基）環丙基]羰基}-?4-[(1-甲 基呱啶-2-基）甲基卜L-苯丙胺醢胺：4 NMR (400 MHz, DMSO-d6)： δ 7.58 (dd, 1Η), 7.52-7.49 (m, 1H), 7.44 (ddd, 1H), 7.39 (dd, 2H), 7.33 (dd, 1H), 7.20-7.08 (m, 1H), 6.78 (dd, 1H), 4.54 (dd, 1H), 3.11-2.82 (m, 3H), 2.75 (d, 1H), 2.14 (d, 3H), 1.98 (t, 1H), 1.87 (s, 1H), 1.62 (s, 1H), 1.49 (s, 1H), 1.39 (d, 3H), 1.27 (d, 1H), 1.13 (dt, 2H), 0.95 (s, 2H). C26H29C14N302 的 MS (El)，實測值 558.3 (MH+)。 2.4- 二氣·Να-{[ΐ-(2,4·二氯苯基）環丙基】羰基比咯 啶-1-基丙基）-L-苯丙胺酿胺：1HNMR(400 MHz,DMSO-d6): δ 7.61 (dd，1H)，7.53 (d, 1H)，7.51-7.46 (m，1H), 7.45 (dd, 1H), 7.41 (d, 1H), 7.35 (dd, 1H), 7.19 (dd, 1H), 6.78 (dd, 1H), 4.56 (dd, 1H), 3.29-3.13 (m, 2H), 3.11-2.98 (m, 2H), 2.97-2.85 (m, 2H), 2.38 (td, 2H), 1.68 (d, 4H), 1.34 (dd，2H)，0.95 (d, 2H)，0.91 (d，2H). C26H29C14N302的 MS (El)，實測值 558·3 (MH+)。 1-(2,4-二氣苯基）-N_[(lS)-l-【(3,5-二氣苯基）甲基]-2-(4-乙基呱嗪-1-基）-2-氧代乙基]環丙醯胺：4 NMR (400 MHz, DMSO-d6): δ 7.62 (d, 1H), 7.54 (d, 1H), 7.43 (m, 146258.doc -86- 201040149 2H), 7.36 (dd, 1H), 7.23 (d, 1H), 6.95 (d, 1H), 5.05-4.99 (m, 1H), 3.53-3.40 (m, 4H), 2.97-2.85 (m, 2H), 2.31-2.26 (m, 4H), 2.20 (m, 1H), 2.12 (m, 1H), 1.40 (m, 1H), 1.21 (m, 1H)，0.99-0.91 (m，5H). C25H27C14N302的MS (El)，實測值 544.3 (MH+)。1-{[2-(Trifluoromethyl)-phenyl]methyl}ethyl]cyclopropanamide: NMR (400 MHz, DMSO-d6): δ 7.63 (d, 1H), 7.61-7.54 (m , 2H), 7.45-7.39 (m, 3H), 7.39-7.33 (m, 1H), 7.02 (d5 1H), 4.99-4.94 (m, 1H), 3.38 (dd, 3H), 3.20 (dd, 1H) , 3.05-2.79 (m, 2H), 2.29-2.17 (m, 3H), 2.13 (s, 3H), 2.00 (dd, 1H), 1.45-1.25 (m, 1H), 1.22-1.06 (m, 1H) MS (El) 552-0.82 (m, 2H). 1-(2,4-diphenyl)-N-[(1 S)-2-(4-methylfox 嗓-l-yl)-2-oxo-1-(pyridin-2-ylmethyl) Ethyl]cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 8.32 (m, 1H), 8.15 (s, 1H), 7.70-7.54 (m, 1H), 7.49-7.36 (m, 2H), 7.22-7.07 (m, 3H), 5.07 (dd, 1H), 3.55-3.24 (m, 4H), 2.96 (dd, 1H), 2.85 (dd, 1H), 2.30-2.16 (m, 4H) MS (El), calcd., calcd, m, m, m,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, N-[(lS)-l-(cyclohexylmethyl)-2-(4-methylι»瓜嗓-1-yl)_2-oxoethyl]-l-(2,4-digas- Phenyl) Cyclopropanol: 4 NMR (400 MHz, DMSO-d6): δ 7.70-7.57 (m, 1H), 7.51-7.30 (m, 2H), 6.73 (d, 1H), 4.74 (dd, 1H ), 3.49-3.24 (m, 4H), 2.34-2.17 (m, 4H), 2.16 (s, 3H), 1.72 (d, 1H), 1.65-1.34 (m, 6H), 1.31 (t, 2H), 1.24-1.01 (m, 5H), 0.97-0.87 (m, 1H), 0.87-0.63 (m, 2H). MS (El) of C24H33Cl2N3 〇2, found 464.6 (MH+). 3,4-diqi·Να-{[1-(2,4-diphenylphenyl)cyclopropyl]carbonyl bv-[2·(dimethylamino)ethyl b--phenylpropylamine decylamine: 4 NMR (400 ΜΗζ, DMSO-d6): δ 7.86 (t, J = 5.5 Hz, 1H), 7.58-7.55 (m, 1H), 146258.doc -84- 201040149 7.49-7.45 (m, 1H), 7.44 -7.38 (m, 2H), 7.31 (d, 1H), 7.08 (dd, 1H), 6.65 (d, 1H), 4.45 (td, 1H), 3.22-3.01 (m, 2H), 2.83 (ddd, J =22.5, 13.5, 6.9Hz, 2H), 2.48 (dt, 2H), 2.27 (q, 2H), 2.16 (s, 6H), 1.40-1.31 (m, 2H), 1.04-0.87 (m, 2H). 0231125(:1^(£1) of 141^302, found 518.3(]\«1+). Να-{[1-(2,4-diphenylphenyl)cyclopropyl]carbonyl}-N- [2-(Dimethylamino)-ethyl]-4-(trifluoromethyl)-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 7.86 (t, 1H), 7.60 -7.53 (m, 3H), 7.44-7.36 (m, 2H), 7.28 (d, 2H), 6.61 (d, 1H), 4.50 (td, 1H), 3.22-3.01 (m, 2H), 2.92 (ddd , 2H), 2.48 (dt, 2H), 2.28 (dd, 2H), 2.17 (s, 6H), 1.40-1.28 (m, 2H), 1.01-0.88 (m, 2H). MS (El) of C24H26C12F3N302, Found 517.4 (MH+). 2.4-diqi-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-[3-( Methylamino)-propyl]methyl-L-phenylalanamine decylamine: 1H NMR (400 MHz, DMSO-d6): δ 7.61-7.56 (m, 1H), 7.51 (d, 1H), 7.42-7.40 ( m, 2H), 7.33 (dt, , 1H), 7.22 (dd5 1H), 6.81 (dd, 1H), 5.03 (dtd, 1H), 3.46-3.29 (m, 2H), 3.25-3.14 (m, 2H) , 2.99-2.89 (m, 3H), 2.89-2.79 (m, 1H), 2.74 (s, 1H), 2.10 (t, 1H), 2.07 (d, 6H), 1.59 (s, 1H), 1.53-1.44 (m5 1H), 1.37 (d, 1H), 1.23-1.10 (m, 1H), 1.00-0.84 (m, 2H). MS (El) of C25H29C14N302, found 546.3 (MH+). 2.4- Digas-Να·{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N_[3-(dimethylamino)-2,2-dimethylpropyl] -L-Amphetamine: 4 NMR (400 MHz, DMSO-d6): δ 7.60-7.54 (m, 2H), 7.51 (d, 1H), 7.44 146258.doc -85 - 201040149 (dd, 1H), 7.40 -7.31 (m, 2H), 7.18 (d, 1H), 6.74 (d, 1H), 4.57 (td, 1H), 3.04-2.92 (m, 2H), 2.91-2.80 (m, 2H), 2.18 (s , 6H), 2.01 (s, 2H), 1.33 (tt, 2H), 1.04-0.88 (m, 2H), 0.74 ((1,611)_匸261131(:14&gt;^〇]\^(£1 ^18(£1) of 2, found value 560.4 (MH+). 2.4- 二气_]\〇1-{[1-(2,4-diphenylphenyl)cyclopropyl]carbonyl}-?4 -[(1-methylacridin-2-yl)methyl b-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 7.58 (dd, 1 Η), 7.52-7.49 (m, 1H) , 7.44 (ddd, 1H), 7.39 (dd, 2H), 7.33 (dd, 1H), 7.20-7.08 (m, 1H), 6.78 (dd, 1H), 4.54 (dd, 1H), 3.11-2.82 (m , 3H), 2.75 (d, 1H), 2.14 (d, 3H), 1.98 (t, 1H), 1.87 (s, 1H), 1.62 (s, 1H), 1.49 (s, 1H), 1.39 (d, (H), 1.27 (d, 1H), 1. Ϊ́-(2,4·Dichlorophenyl)cyclopropyl]carbonylpyrrolidin-1-ylpropyl)-L-amphetamine-tanning amine: 1H NMR (400 MHz, DMSO-d6): δ 7.61 (dd, 1H) ), 7.53 (d, 1H), 7.51-7.46 (m, 1H), 7.45 (dd, 1H), 7.41 (d, 1H), 7.35 (dd, 1H), 7.19 (dd, 1H), 6.78 (dd, 1H), 4.56 (dd, 1H), 3.29-3.13 (m, 2H), 3.11-2.98 (m, 2H), 2.97-2.85 (m, 2H), 2.38 (td, 2H), 1.68 (d, 4H) , 1.34 (dd, 2H), 0.95 (d, 2H), 0.91 (d, 2H). MS (El) of C26H29C14N302, found 558·3 (MH+). 1-(2,4-diphenyl)-N-[(lS)-l-[(3,5-diphenyl)methyl]-2-(4-ethylpyridazin-1-yl) -2-oxoethyl]cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.62 (d, 1H), 7.54 (d, 1H), 7.43 (m, 146258.doc -86- 201040149 2H), 7.36 (dd, 1H), 7.23 (d, 1H), 6.95 (d, 1H), 5.05-4.99 (m, 1H), 3.53-3.40 (m, 4H), 2.97-2.85 (m, 2H) , 2.31-2.26 (m, 4H), 2.20 (m, 1H), 2.12 (m, 1H), 1.40 (m, 1H), 1.21 (m, 1H), 0.99-0.91 (m, 5H). MS of C25H27C14N302 (El), found 544.3 (MH+).

1-(2,4-二氣苯基）-]\-{(18)-1-[(3,5-二氣苯基）甲基】-2-[4-(2-羥乙基）-呱嗪-1-基1-2-氧代乙基}環丙醯胺：4 NMR (400 MHz, DMSO-d6): δ 7.60 (d, 1Η), 7.52 (d, 1H), 7.47- 7.37 (m, 2H), 7.34 (dd, 1H), 7.21 (d, 1H), 6.93 (d, 1H), 4.99 (m, 1H), 3.46 (t, 2H), 3.44-3.24 (m, 4H), 3.01-2.78 (m, 2H), 2.43-2.11 (m, 6H), 1.49-1.29 (m, 1H), 1.30-1.04 (m, 1H)，1.04-0.81 (m, 2H)_ C25H27C14N303 的MS (El)，實測值 560.3 (MH+)。1-(2,4-diphenyl)-]\-{(18)-1-[(3,5-diphenyl)methyl]-2-[4-(2-hydroxyethyl) -pyridazin-1-yl1-2-oxoethyl}cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.60 (d, 1 Η), 7.52 (d, 1H), 7.47- 7.37 (m, 2H), 7.34 (dd, 1H), 7.21 (d, 1H), 6.93 (d, 1H), 4.99 (m, 1H), 3.46 (t, 2H), 3.44-3.24 (m, 4H), 3.01-2.78 (m, 2H), 2.43-2.11 (m, 6H), 1.49-1.29 (m, 1H), 1.30-1.04 (m, 1H), 1.04-0.81 (m, 2H)_ C25H27C14N303 of MS (El ), found at 560.3 (MH+).

1-(2,4-二氣苯基）-N-{(lS)-l-[(3,5-二氣苯基）曱基]-2-[4-(2-氟乙基）呱嗪-1-基】-2-氧代乙基}環丙醯胺：4 NMR (400 MHz, DMSO-d6): δ 7.55 (d, 1H), 7.47 (d, 1H), 7.36 (dd, 2H), 7.29 (dt, 1H), 7.20-7.12 (m, 1H), 6.89 (t, 1H), 4.95 (td, 1H), 4.52 (t, 1H), 4.40 (t, 1H), 3.32 (t, 4H), 2.85 (ddd, 2H), 2.56 (t, 1H), 2.49 (t, 1H), 2.41-2.11 (m, 4H), 1.38-1.29 (m, 1H), 1.18-1.07 (m, 1H), 0.94-0.80 (m, 2H). C25H26Cl4FN3〇2 的 MS (El)，實測值562·3 (MH+)。 4-溴-N(x-{、[l-(2,4-二氣苯基）環丙基】羰基}-N-[2-(二甲基 胺基）-乙基]-N-甲基-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6)： δ 8.16 (s, 1H), 7.60 (dt, 1H), 7.46-7.34 (m, 4H), 146258.doc -87- 201040149 7.08-6.98 (m, 2H), 4.84 (dd, 1H), 3.45 (dt, 1H), 3.25-3.08 (m, 1H), 2.93 (s, 2H), 2.85-2.70 (m, 3H), 2.37-2.20 (m, 2H), 2.21-2.08 (m, 6H), 1.43-1.29 (m, 2H), 1.03-0.88 (m, 2H)_ C24H28BrCl2N302的MS (El)，實測值 542.3 (MH+)。 Να-{[1-(2,4-二氣苯基）環丙基]羰基}-N-[2-(二甲基胺基）-乙基]-N-甲基-4-(三氟甲基）-L_苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.16 (s, 1H), 7.57 (d, 2H), 7.46 (d, 1H), 7.34 (d, 1H), 7.08-6.98 (m, 2H), 4.86 (dd, 1H), 3.40 (dt, 1H), 3.25-3.08 (m, 1H), 2.93 (s, 2H), 2.85-2.70 (m, 3H), 2.37-2.20 (m, 2H), 2.21-2.08 (m, 6H), 1.43-1.29 (m, 2H), 1.03-0.88 (m，2H). C25H28C12F3N302 的 MS (El)，實測值 531.4 (MH+)的 MS (El)。 !\’2’-{[1-(2,4-二氣苯基）環丙基]羰基}-^[2-(二甲基胺 基）乙基]-N-甲基-L-白胺醯胺：1HNMR(400 MHz，DMSO-d6): δ 7.44 (m5 1Η), 7.36 (m, 1H), 7.28 (m, 1H), 5.96-5.85 (m, 1H), 4.94 (m, 1H), ), 3.58-3.42 (m, 2H), 3.28 (m, 1H), 3.06-2.90 (m, 4H), 2.50-2.41 (m, 2H), 2.29-2.25 (m, 6H), 1.79 (m, 1H), 1.31 (m, 2H), 1.09 (m, 1H), 0.96 (m 4H), 0.87 (&lt;1，3印；（：211131(：12：^302的]^8(£1)，實測值428.14 (]^11+)。 2,4-二氣-Να-{【1-(2,4-二氣苯基）環丙基】羰基}-N-甲基-N-[(3R)-1-甲基吡咯啶-3-基】-L-苯丙胺醢胺：4 NMR (400 MHz, CD3OD) ： 7.48-7.38 (m, 4H), 7.22 (d, 1H), 7.17 (d, 1H), 4.57-4.55 (m, 1H), 3.35 (s, 3H), 3.20-3.02 (m, 5H), 2.98 (dd, 1H), 2.97 (s, 3H), 2.57-2.45 (m, 1H), 2.14-2.01 146258.doc -88 · 201040149 (m, 1H), 1.77-1.63 (m, 1H), 1.58-1.43 (m, 2H), 1.19-1.14 (m，1H), 1.05-0.98 (m，1H). C25H27C14N302 的 MS (El)，實 測值 544.1〇(]\411+)。 2,4-二氣-Να-{[1-(2,4-二氣苯基）環丙基]羰基}-N-甲基-N-[l-(苯基甲基）呱啶-4-基】-L-苯丙胺醯胺：4 NMR (400 MHz, CD3OD) ： 7.50-7.29 (m, 9H), 7.24-7.21 (m, 1H), 7.17- 7.12 (m, 1H), 5.20-5.18 (m, 1H), 3.80-3.70 (m, 2H), 3.18- 2.95 (m, 4H), 2.82 (d, 3H), 2.39-2.08 (m, 2H), 1.95-1.65 (m, 2H)，1.60-1.40 (m，2H), 1.13-1.00 (m, 2H). C32H33C14N302 的 MS (El)，實測值63 4.17 (MH+)。 Να-{[1-(2,4-二氣苯基）環丙基】羰基}-N-甲基-N-[l-(苯基 甲基）-呱啶-4-基]-4-(三氟甲基）-L-苯丙胺醯胺：4 NMR (400 MHz, CD3OD) ： 7.60-7.44 (m, 2H), 7.41-7.25 (m, 10H), 5.16-5.07 (m, 1H), 4.25-4.20 (m, 1H), 3.80-3.73 (m, 3H), 3.25-2.92 (m, 4H), 2.52 (d, 3H), 2.44-2.22 (m, 2H), 1.88-1.50 (m, 5H)，1.12-1.00 (m, 2H). C33H34C12F3N302的 ]^18(£1)，實測值63 2.28 (]^11+)。 1-(2,4-二氣苯基）-N-[(lS)-2-[3-(二甲基胺基）氮雜環丁 烷-1-基】-2-氧代-1-{[4-(三氟甲基）苯基】甲基}乙基】環丙醯 胺：4 NMR (400 MHz, CDC13): δ 7.22-7.53 (m, 7H)，5.88 (m, 1H), 4.07 (q, 1H), 3.63-4.11 (m, 3H), 2.73-3.29 (m, 3H), 2.01-2.07 (m, 6H), 1.62 (m, 2H), 1.07 (m, 2H). 〇25出6(：12?3：^302的]^8(£1)，實測值 528.17 (]^11+)。 Να-{[1-(2,4-二氣苯基）環丙基]羰基}-N-[2-(二甲基胺基） 146258.doc -89- 201040149 乙基】-N-乙基-4_(三氟甲基）-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 7.58 (m, 3Η), 7.40 (s5 2H), 7.32 (d, 2H), 6.95-6.77 (m, 1H), 4.88 (s5 1H), 3.29 (m, 2H), 3.14 (m, 2H), 2.89 (m, 2H), 2.20 (m, 2H), 2.10 (s, 6H), 1.33 (m, 2H), 0.97 (m, 5H)_ C26H30C12F3 N302 的 MS (El)，實測值545 (MH+)。1-(2,4-diphenyl)-N-{(lS)-l-[(3,5-diphenyl)indenyl]-2-[4-(2-fluoroethyl)indole Iridazin-1-yl]-2-oxoethyl}cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.55 (d, 1H), 7.47 (d, 1H), 7.36 (dd, 2H ), 7.29 (dt, 1H), 7.20-7.12 (m, 1H), 6.89 (t, 1H), 4.95 (td, 1H), 4.52 (t, 1H), 4.40 (t, 1H), 3.32 (t, 4H), 2.85 (ddd, 2H), 2.56 (t, 1H), 2.49 (t, 1H), 2.41-2.11 (m, 4H), 1.38-1.29 (m, 1H), 1.18-1.07 (m, 1H) MS (El), found for C25H26Cl4FN3 〇2, found 562·3 (MH+). 4-bromo-N(x-{,[l-(2,4-diphenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)-ethyl]-N- --L-Amphetamine amide: 4 NMR (400 MHz, DMSO-d6): δ 8.16 (s, 1H), 7.60 (dt, 1H), 7.46-7.34 (m, 4H), 146258.doc -87- 201040149 7.08-6.98 (m, 2H), 4.84 (dd, 1H), 3.45 (dt, 1H), 3.25-3.08 (m, 1H), 2.93 (s, 2H), 2.85-2.70 (m, 3H), 2.37- 2.20 (m, 2H), 2.21-2.08 (m, 6H), 1.43-1.29 (m, 2H), 1.03-0.88 (m, 2H) _ C24H28BrCl2N302 MS (El), found 542.3 (MH+). {[1-(2,4-Diphenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)-ethyl]-N-methyl-4-(trifluoromethyl) )-L-Amphetamine: 4 NMR (400 MHz, DMSO-d6): δ 8.16 (s, 1H), 7.57 (d, 2H), 7.46 (d, 1H), 7.34 (d, 1H), 7.08- 6.98 (m, 2H), 4.86 (dd, 1H), 3.40 (dt, 1H), 3.25-3.08 (m, 1H), 2.93 (s, 2H), 2.85-2.70 (m, 3H), 2.37-2.20 ( m, 2H), 2.21-2.08 (m, 6H), 1.43-1.29 (m, 2H), 1.03-0.88 (m, 2H). MS (El) for C25H28C12F3N302, MS (El) of 531.4 (MH+) !\'2'-{[1-(2,4-Diphenyl)cyclopropyl]carbonyl}-^[2-(dimethylamino)ethyl]-N- --L-Acetamine amide: 1H NMR (400 MHz, DMSO-d6): δ 7.44 (m5 1 Η), 7.36 (m, 1H), 7.28 (m, 1H), 5.96-5.85 (m, 1H), 4.94 (m, 1H), ), 3.58-3.42 (m, 2H), 3.28 (m, 1H), 3.06-2.90 (m, 4H), 2.50-2.41 (m, 2H), 2.29-2.25 (m, 6H) , 1.79 (m, 1H), 1.31 (m, 2H), 1.09 (m, 1H), 0.96 (m 4H), 0.87 (&lt;1,3 printed; (:211131(:12:^302)]^8 (£1), measured value 428.14 (]^11+). 2,4-digas-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-methyl-N-[(3R)-1-methylpyrrolidine-3 -yl]-L-amphetamine amide: 4 NMR (400 MHz, CD3OD): 7.48-7.38 (m, 4H), 7.22 (d, 1H), 7.17 (d, 1H), 4.57-4.55 (m, 1H) , 3.35 (s, 3H), 3.20-3.02 (m, 5H), 2.98 (dd, 1H), 2.97 (s, 3H), 2.57-2.45 (m, 1H), 2.14-2.01 146258.doc -88 · 201040149 (m, 1H), 1.77-1.63 (m, 1H), 1.58-1.43 (m, 2H), 1.19-1.14 (m,1H), 1.05-0.98 (m,1H). MS (El) of C25H27C14N302, measured The value is 544.1〇(]\411+). 2,4-digas-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-methyl-N-[l-(phenylmethyl)acridine-4 -yl]-L-amphetamine amide: 4 NMR (400 MHz, CD3OD): 7.50-7.29 (m, 9H), 7.24-7.21 (m, 1H), 7.17- 7.12 (m, 1H), 5.20-5.18 ( m, 1H), 3.80-3.70 (m, 2H), 3.18- 2.95 (m, 4H), 2.82 (d, 3H), 2.39-2.08 (m, 2H), 1.95-1.65 (m, 2H), 1.60- 1.40 (m, 2H), 1.13-1.00 (m, 2H). MS (El) for C32H33C14N302, found 63 4.17 (MH+). Να-{[1-(2,4-Diphenyl)cyclopropyl]carbonyl}-N-methyl-N-[l-(phenylmethyl)-acridin-4-yl]-4- (Trifluoromethyl)-L-Amphetamine amide: 4 NMR (400 MHz, CD3OD): 7.60-7.44 (m, 2H), 7.41-7.25 (m, 10H), 5.16-5.07 (m, 1H), 4.25 -4.20 (m, 1H), 3.80-3.73 (m, 3H), 3.25-2.92 (m, 4H), 2.52 (d, 3H), 2.44-2.22 (m, 2H), 1.88-1.50 (m, 5H) , 1.12 - 1.00 (m, 2H). C33H34C12F3N302 of ^ 18 (£1), measured value 63 2.28 (] ^ 11 +). 1-(2,4-diphenyl)-N-[(lS)-2-[3-(dimethylamino)azetidin-1-yl]-2-oxo-1- {[4-(Trifluoromethyl)phenyl]methyl}ethyl]cyclopropanamide: 4 NMR (400 MHz, CDC13): δ 7.22-7.53 (m, 7H), 5.88 (m, 1H), 4.07 (q, 1H), 3.63-4.11 (m, 3H), 2.73-3.29 (m, 3H), 2.01-2.07 (m, 6H), 1.62 (m, 2H), 1.07 (m, 2H). 〇25 6(:12?3:^302]^8(£1), found 528.17 (]^11+). Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl }-N-[2-(Dimethylamino) 146258.doc -89- 201040149 Ethyl]-N-ethyl-4-(trifluoromethyl)-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 7.58 (m, 3Η), 7.40 (s5 2H), 7.32 (d, 2H), 6.95-6.77 (m, 1H), 4.88 (s5 1H), 3.29 (m, 2H), 3.14 ( m, 2H), 2.89 (m, 2H), 2.20 (m, 2H), 2.10 (s, 6H), 1.33 (m, 2H), 0.97 (m, 5H)_ C26H30C12F3 N302 MS (El), measured value 545 (MH+).

Να-{[1-(2,4-二氣苯基）環丙基]羰基}-N-甲基-N-[(3R)-1-甲基-吡咯啶-3-基】-4-(三氟甲基）-L-苯丙胺醯胺·· 4 NMR (400 MHz, DMSO-d6): δ 7.95 (s, 1H), 7.57 (d, 3H), 7.41 (s, 2H), 7.27 (d, 2H), 6.58 (d, 1H), 4.48 (m, 1H), 3.00 (m, 1H), 2.88 (m5 3H), 2.36 (m, 4H), 2.18 (s, 3H), 2.09 (m, 2H), 1.74 (m, 1H)，1.28 (m, 3H)，0.94 (m, 2H). C26H28C12F3N302的 MS (El)，實測值 543 (MH+)。 Να-{[1-(2,4-二氣苯基）環丙基]羰基卜N-(2-&quot;比咯啶-1-基 乙基）-4-(三氟甲基）-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 7.89 (t, 1H), 7.57 (d, 3H), 7.41 (s, 2H), 7.27 (d, 2H), 6.60 (d, 1H), 4.50 (m, 1H), 3.14 (m, 2H), 2.97 (m5 1H), 2.87 (m, 1H), 2.44 (m, 6H), 1.68 (m, 4H), 1.34 (m, 2H), 0.94 (m，2H). C26H28C12F3N302的 MS (El)，實測值543 (MH+)。 實施例4 N-[(lS)-l-({[(4-氣苯基）曱基]氧}甲基）-2-(4-甲基呱嗪-1-基）-2·氧代乙基】-1-(2,4-二氣苯基）環丙醯胺 146258.doc •90· 201040149Να-{[1-(2,4-Diphenyl)cyclopropyl]carbonyl}-N-methyl-N-[(3R)-1-methyl-pyrrolidin-3-yl]-4- (trifluoromethyl)-L-phenylalanamine decylamine·· 4 NMR (400 MHz, DMSO-d6): δ 7.95 (s, 1H), 7.57 (d, 3H), 7.41 (s, 2H), 7.27 (d , 2H), 6.58 (d, 1H), 4.48 (m, 1H), 3.00 (m, 1H), 2.88 (m5 3H), 2.36 (m, 4H), 2.18 (s, 3H), 2.09 (m, 2H ), 1.74 (m, 1H), 1.28 (m, 3H), 0.94 (m, 2H). MS (El) of C26H28C12F3N302, found 543 (MH+). Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl b-N-(2-&quot;pyrrolidin-1-ylethyl)-4-(trifluoromethyl)-L - amphetamine amide: 4 NMR (400 MHz, DMSO-d6): δ 7.89 (t, 1H), 7.57 (d, 3H), 7.41 (s, 2H), 7.27 (d, 2H), 6.60 (d, 1H ), 4.50 (m, 1H), 3.14 (m, 2H), 2.97 (m5 1H), 2.87 (m, 1H), 2.44 (m, 6H), 1.68 (m, 4H), 1.34 (m, 2H), MS (El) for C26H28C12F3N302, found 543 (MH+). Example 4 N-[(lS)-l-({[(4-Phenylphenyl)indolyl]oxy)methyl)-2-(4-methylpyridazin-1-yl)-2.oxo Ethyl]-1-(2,4-diphenyl)cyclopropanamide 146258.doc •90· 201040149

〇 步驟1 : (s)_3_經基-1-(4 -甲基&quot;瓜°秦-1-基）-1-氧代丙-2-基 胺基甲睃叔丁酯：向溶於二氯曱烷（50mL)的（S)-2-(叔丁氧 幾基胺基）-3-經基丙酸（3.0 g，14.62 mmol)溶液加入N-甲 基嗎嚇· (16 mL，146.2 mmol)、1-甲基 〇瓜嗓（1.78 mL， 16_08 mmol)、1-[3-(二甲基胺基）丙基]_3-乙基碳二亞胺甲 峨鹽（EDC)(3.0 g，16 mmol)和 1-羥基笨並三唑（H〇Bt)(2.l g ’ 16 mmol)。將反應混合物於室溫攪拌丨6小時，真空濃 縮之後在· ~~氣甲烧和飽和破酸氣納之間分配。用無水硫酸 〇 鎂乾燥合併的有機層，真空過濾並濃縮以產生3.5 g (83%) 的標題化合物，其用於下一步驟而無需進一步純化。 步驟2 : (S)-2-胺基-3-(4-氣苄基氧）_ι_(4_甲基p瓜噪_1基） 丙-1-酮鹽酸鹽：于0°C向溶於四氫呋喃（4 mL)的（S)-3-經 基-1 -(4-甲基0瓜嗓-1 -基）-1 -氧代丙-2-基胺基甲酸叔丁 g旨 (200 mg，0.7 mmol)加入氫化鈉（18 mg，0.77 mmol)。將反 應混合物於〇°C攪拌5分鐘’之後加入溶於四氫呋。南（i mL)4-溴化氯苄（157 mg ’ 0.77 mmol)。將反應物於〇°c攪拌 146258.doc •91- 201040149 2小時。用5滴水泮滅反應並在真空濃縮。將濃縮的反應混 合物溶於甲醇（5 mL) ’之後加入溶於二噁烷（3 11^)的4 N HC1 ’並將反應混合物加熱至65°C保持1小時。當冷卻時， 將混合物真空？辰縮以產生標題化合物，其用於下一步驟而 無需進一步純化。 步驟3 : N-[(lS)-l-({[(4-氣苯基）甲基]氧}甲基）_2_(4甲 基11 瓜唤-1-基）-2-氧代乙基】-1-(2,4-二氣苯基）環丙酸胺：向 溶於二氣甲烷（4 mL)的（S)-2-胺基-3-(4-氯苄基氧）_ι_(4-甲 基0瓜嗪-1-基）丙-1-W鹽酸鹽（0.7 mmol)溶液加入N-甲基嗎 啉（0.77 mL ’ 7 mmol)、1-(2,4-二氣苯基）環丙羧酸 〇 77 mg’ 0.77mmol)、1-[3-(二曱基胺基）丙基]_3_乙基碳二亞胺 甲埃鹽（EDC)(48 mg ’ 0.77 mmol)以及1-羥基苯並三唑 (HOBt)( 104 mg，0.77 mmol)。將反應混合物於室溫攪拌16 小時，真空濃縮並溶於甲醇。用製備級HPLC(反相，乙腈/ 含0.1%曱酸的水）純化產物以產生43 mg(12%)的標題化合 物。1H NMR (400 MHz, DMSO-d6): δ 7.63 (dd，1H)，7.44 (dd, 2H), 7.39 (d, 1H), 7.38-7.36 (m, 1H), 7.23 (dd, 2H), 6.83 (d, 1H), 4.88 (dt, 1H), 4.38 (d, 2H), 3.53-3.43 (m, 2H), 3.36 (s, 4H), 2.15 (d, 4H), 2.11 (s, 3H), 1.54-1.36 (m, 2H), 1.02 (m, 2H). C25H28C13N303 的 MS (El)，實測值 525.9 (MH+)。 以類似於實施例4的方式製備下列化合物：〇Step 1: (s)_3_Phenyl-1-(4-methyl &quot; melon-methyl-1-yl)-1-oxopropan-2-ylaminocarboxamidine tert-butyl ester: soluble (S)-2-(tert-Butoxyamino)-3-transpropionic acid (3.0 g, 14.62 mmol) solution of dichloromethane (50 mL) was added N-methyl sin (16 mL, 146.2 mmol), 1-methylindole (1.78 mL, 16_08 mmol), 1-[3-(dimethylamino)propyl]_3-ethylcarbodiimide formazan (EDC) (3.0 g, 16 mmol) and 1-hydroxy benzotriazole (H〇Bt) (2. lg '16 mmol). The reaction mixture was stirred at room temperature for 6 hours, concentrated under vacuum, and then partitioned between methane and saturated acid. The combined organic layers were dried with EtOAc EtOAc m. Step 2: (S)-2-Amino-3-(4-carbobenzyloxy)_ι_(4_methylp guar _1 yl) Propan-1-one hydrochloride: dissolved at 0 ° C (S)-3-Phenyl-1 -(4-methyl0 嗓嗓-1 -yl)-1-oxopropan-2-ylcarbamic acid tert-butyl g in tetrahydrofuran (4 mL) (200) Mg, 0.7 mmol) was added sodium hydride (18 mg, 0.77 mmol). The reaction mixture was stirred at 〇 ° C for 5 minutes' and then dissolved in tetrahydrofuran. Southern (i mL) 4-benzyl bromide (157 mg '0.77 mmol). The reaction was stirred at 〇 cc 146258.doc •91- 201040149 for 2 hours. The reaction was quenched with 5 drops of water and concentrated in vacuo. The concentrated reaction mixture was dissolved in MeOH (5 mL) and then 4N &lt;RTI ID=0.0&gt;&gt; When cooling, vacuum the mixture? The title compound was triturated to give the next step without further purification. Step 3: N-[(lS)-l-({[(4-Phenylphenyl)methyl)oxy)methyl)_2_(4methyl11-carbazin-1-yl)-2-oxoethyl -1-(2,4-diphenyl)cyclopropionic acid amine: (S)-2-amino-3-(4-chlorobenzyloxy)_ι_ dissolved in di-methane (4 mL) (4-Methyl 0 guazin-1-yl)propan-1-W hydrochloride (0.7 mmol) solution was added N-methylmorpholine (0.77 mL '7 mmol), 1-(2,4-diox Phenyl) cyanopropanoate 〇 77 mg ' 0.77 mmol), 1-[3-(didecylamino)propyl]_3_ethylcarbodiimide methyl ketone (EDC) (48 mg ' 0.77 mmol) And 1-hydroxybenzotriazole (HOBt) (104 mg, 0.77 mmol). The reaction mixture was stirred at room temperature for 16 h then concentrated in vacuo andEtOAc. The product was purified by preparative HPLC (EtOAc, EtOAc/EtOAc:EtOAc) 1H NMR (400 MHz, DMSO-d6): δ 7.63 (dd, 1H), 7.44 (dd, 2H), 7.39 (d, 1H), 7.38-7.36 (m, 1H), 7.23 (dd, 2H), 6.83 (d, 1H), 4.88 (dt, 1H), 4.38 (d, 2H), 3.53-3.43 (m, 2H), 3.36 (s, 4H), 2.15 (d, 4H), 2.11 (s, 3H), 1.54-1.36 (m, 2H), 1.02 (m, 2H). MS (El) of C25H28C13N303, found 525.9 (MH+). The following compounds were prepared in a similar manner to Example 4:

N-【(lS)-l-({【(3-氣苯基）甲基】氧}甲基）-2-(4-甲基呱嗪-1-基）-2·氧代乙基]-1-(2,4-二氯苯基）環丙醢胺：WNMRGOO 146258.doc •92- 201040149 MHz, DMSO-d6): 8 7.68-7.53 (m, 1H), 7.48-7.40 (m, 2H), 7.39-7.30 (m, 2H), 7.28 (s, 1H), 7.20-7.06 (m, 1H), 6.87 (d, 1H), 4.89 (dd, 1H), 4.50-4.30 (m, 2H), 3.56-3.44 (m, 6H), 2.17 (d, 4H), 2.11 (s, 3H), 1.58-1.32 (m, 2H), 1.07-0.95 (m, 2H). C25H28C13N303的 MS (El)，實測值 525.9 (MH+)。 N-[(lS)-l-({[(2-氣苯基）甲基】氧}甲基）-2-(4-甲基呱嗪-1-基）-2-氧代乙基】-1-(3,5-二氣苯基）環丙醢胺：iHNMRyOO MHz, DMSO-d6): δ 7.61 (d, 1Η), 7.45-7.41 (m, 3H), 7.37-7.31 (m, 3H), 6.86 (d, 1H), 4.93-4.88 (m, 1H), 4.48 (s, 2H), 3.60-3.52 (m, 2H), 3.83 (m, 4H), 2.71 (m, 4H), 2.10 (s, 3H)，1.51-1.40 (m，2H)，1.09-0.96 (m，2H). C25H28C13N303 的 MS (El)，實測值 525.9 (MH+)。 1-(3,5-二氣苯基）-N-[(lS)-l-({[(4-氟苯基）甲基】氧}甲 基）-2-(4-甲基呱嗪-1-基）-2-氧代乙基】環丙醯胺：4 NMR (400 MHz, DMSO-d6): δ 7.64 (d5 1H), 7.44 (m, 2H), 7.25 (dd, 2H), 7.18-7.13 (m, 2H), 6.82 (d, 1H), 4.90-4.85 (m, 1H), 4.36 (d, 2H), 3.51-3.42 (m, 4H), 3.35 (m, 2H), 2.71 (m, 4H), 2.10 (s, 3H), 1.51-1.40 (m, 2H), 1.09-0.96 (m, 2H). C28H28C12FN303 的 MS (El)，實測值 509.4 (MH+)。 l-(3,5-二氣苯基）-N-[(lS)-l-[({[2·(曱氧基）苯基]甲基} 氧）甲基】-2-(4-甲基呱嗪-1-基）-2-氧代乙基]環丙醢胺：ijj NMR (400 MHz, DMSO-d6)： δ 7.63 (s, 1Η), 7.44 (m, 2H), 7.23 (t, 1H), 6.83-6.76 (m, 4H), 4.90-4.85 (m, 1H), 4.36 (d, 2H), 3.72 (s, 3H), 3.51-3.42 (m, 6H), 2.16 (m, 4H), 2.11 (s, 146258.doc -93- 201040149 3H), 1.52-1.40 (m5 2H), 1.08-0.95 (m, 2H). C26H3iC12N3〇4 的 MS (EI) ’ 實測值 521.5 (MH+)。 l-(2,4-二氣苯基）_^丨（111)_2_(4_甲基呱嗪小基^·氧代-1-{[(苯基甲基）氧】-甲基}乙基]環丙醯胺：iH NMR (400 MHz, DMSO-d6)： δ 7.65 (d, 1Η), 7.46 (m, 2H), 7.35 (m, 2H), 7.28 (m, 1H), 7.22 (d, 2H), 6.83 (d, 1H), 4.92 (m, 1H), 4.40 (m, 2H), 3.49 (m, 6H), 2.25 (m, 4H), 2.17 (s, 3H), 1.48 (m，2H)，1.03 (m，2H). C25H29C12N303 的 MS (El),實測值 491(MH+)。 1-(2,4-二氣苯基）_n-[(is)-2-(4-甲基呱嗪-1-基）-2-氧代-1-{[(苯基甲基）氧卜甲基}乙基】環丙醢胺：iH NMR (400 MHz, DMSO-d6)： δ 7.66 (d, 1Η), 7.47 (m, 2H), 7.34 (m, 2H), 7.29 (m, 1H), 7.23 (d, 2H), 6.85 (d, 1H), 4.92 (m, 1H), 4.41 (m, 2H), 3.49 (m, 6H), 2.43 (m, 4H), 2.29 (s, 3H), 1.49 (m，2H), 1.04 (m, 2H). C25H29C12N303 的 MS (EI)，實測值 491(MH+)。 實施例5 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基】·Ν，2·-{[1-(2,4-二氣苯 基）-環丙基]-羰基}-3-(2,3-二氫_1，4-苯並二噁烷_6_基）_L-丙 胺醢胺 J. Med. Chem, 1994, 37, 2090.N-[(lS)-l-({[(3-Phenylphenyl)methyl]oxy}methyl)-2-(4-methylpyridazin-1-yl)-2.oxoethyl] -1-(2,4-dichlorophenyl)cyclopropanamide: WNMRGOO 146258.doc •92- 201040149 MHz, DMSO-d6): 8 7.68-7.53 (m, 1H), 7.48-7.40 (m, 2H ), 7.39-7.30 (m, 2H), 7.28 (s, 1H), 7.20-7.06 (m, 1H), 6.87 (d, 1H), 4.89 (dd, 1H), 4.50-4.30 (m, 2H), 3.56-3.44 (m, 6H), 2.17 (d, 4H), 2.11 (s, 3H), 1.58-1.32 (m, 2H), 1.07-0.95 (m, 2H). MS (El) of C25H28C13N303, measured value 525.9 (MH+). N-[(lS)-l-({[(2-Phenylphenyl)methyl)oxy}methyl)-2-(4-methylpyridazin-1-yl)-2-oxoethyl] -1-(3,5-diphenyl)cyclopropanamide: iHNMRyOO MHz, DMSO-d6): δ 7.61 (d, 1Η), 7.45-7.41 (m, 3H), 7.37-7.31 (m, 3H ), 6.86 (d, 1H), 4.93-4.88 (m, 1H), 4.48 (s, 2H), 3.60-3.52 (m, 2H), 3.83 (m, 4H), 2.71 (m, 4H), 2.10 ( s, 3H), 1.51-1.40 (m, 2H), 1.09-0.96 (m, 2H). MS (El) of C25H28C13N303, found 525.9 (MH+). 1-(3,5-diphenyl)-N-[(lS)-l-({[(4-fluorophenyl)methyl]oxy}methyl)-2-(4-methylpyridazine) -1-yl)-2-oxoethyl]cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.64 (d5 1H), 7.44 (m, 2H), 7.25 (dd, 2H), 7.18-7.13 (m, 2H), 6.82 (d, 1H), 4.90-4.85 (m, 1H), 4.36 (d, 2H), 3.51-3.42 (m, 4H), 3.35 (m, 2H), 2.71 ( MS (El), m.p. L-(3,5-diphenyl)-N-[(lS)-l-[({[2.(decyloxy)phenyl]methyl}oxy)methyl]-2-(4- Methyloxazin-1-yl)-2-oxoethyl]cyclopropanamide: ijj NMR (400 MHz, DMSO-d6): δ 7.63 (s, 1 Η), 7.44 (m, 2H), 7.23 ( t, 1H), 6.83-6.76 (m, 4H), 4.90-4.85 (m, 1H), 4.36 (d, 2H), 3.72 (s, 3H), 3.51-3.42 (m, 6H), 2.16 (m, 4H), 2.11 (s, 146258.doc -93- 201040149 3H), 1.52-1.40 (m5 2H), 1.08-0.95 (m, 2H). MS (EI) of C26H3iC12N3 〇4 </ RTI> 521.5 (MH+). L-(2,4-diphenyl)_^丨(111)_2_(4_methylpyridazine small group ^.oxo-1-{[(phenylmethyl)oxy]-methyl}B Cyclopropanol: iH NMR (400 MHz, DMSO-d6): δ 7.65 (d, 1 Η), 7.46 (m, 2H), 7.35 (m, 2H), 7.28 (m, 1H), 7.22 (d , 2H), 6.83 (d, 1H), 4.92 (m, 1H), 4.40 (m, 2H), 3.49 (m, 6H), 2.25 (m, 4H), 2.17 (s, 3H), 1.48 (m, 2H), 1.03 (m, 2H). MS (El) for C25H29C12N303, found 491 (MH+). 1-(2,4-diphenyl)_n-[(is)-2-(4-methyl Pyridazin-1-yl)-2-oxo-1-{[(phenylmethyl)oxymethyl}ethyl]cyclopropanamide: iH NMR (400 MHz, DMSO-d6): δ 7.66 (d, 1Η), 7.47 (m, 2H), 7.34 (m, 2H), 7.29 (m, 1H), 7.23 (d, 2H), 6.85 (d, 1H), 4.92 (m, 1H), 4.41 (m, 2H) ), 3.49 (m, 6H), 2.43 (m, 4H), 2.29 (s, 3H), 1.49 (m, 2H), 1.04 (m, 2H). MS (EI) of C25H29C12N303, found 491 (MH+) Example 5 N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]·Ν,2·-{[1-(2,4-diphenyl)-cyclopropane ]]-carbonyl}-3-(2,3-dihydro-1,4-benzodioxan-6-yl)-L-alanamine amide J. Med. Chem, 1994, 37, 2090.

AmanoQ D D 0 D 146258.doc 94· 201040149AmanoQ D D 0 D 146258.doc 94· 201040149

步驟1 : 2-乙醯胺基^-((之^-二氫苯並丨…丨^丨二噁烷-心 基）甲基）-丙二酸二乙酯：于室溫向新鮮配製的乙醇鈉（鈉 0.6 g，26 mmol，乙醇50 mL )溶液加入6_(溴甲基）_2 3_二 〇 氫苯並[1)][1，4]二噁烷（2§，8.7,3 111111〇1)和2-乙醯胺-丙二 酸二乙酯（1.9 g，8.75 mmol)。將反應混合物於室溫攪拌2 小時，並真空濃縮以產生標題化合物，其用於下一步驟而 無需進一步純化。 步驟2 : 2-乙醯胺基-3-(2,3-二氫苯並μ] [1，4】二噁烷·6_ 基）丙酸：將溶于水（35 mL)和乙醇（35 mL)的2-乙醯胺基-2- ((2,3-二氫苯並|&gt;][1，4]二噁烷-6-基）甲基）丙二酸二乙酯 (3.17 g，8.7 mmol)和氫氧化鉀（Ml g，27.7 mmol)溶液加 〇 ^ 熱至回流2小時。將反應混合物真空濃縮並且將產物用於 下一步驟而無需進一步純化。 步驟3 : (S)-2-胺基-3-(2,3-二氫苯並[b】[l，4]二噁烷-6·基） 丙酸：於37°C (39°C浴溫）將2-乙醯胺基-3-(2,3-二氫苯並 [b][l，4]二噁烷-6-基）丙酸（8.7 mmol)溶於氫氧化鈉溶液 (0.42g 的 NaOH，50 mL H20)，並加入2 N HC1 將pH調節至 7.5。向所得的溶液加入六水合氣化钴（Aldrich，10m_)以 及Amano醯基轉移酶（Aldrich，200mg)。將反應混合物於 146258.doc -95. 201040149 37°C (39°C浴溫）和ρΗ7·5攪拌16小時。減壓下濃縮得到標題 化合物（以與（尺)-2-乙醯胺基-3-(2,3-二氫苯並[15][1，4]二嗔 烷-6-基）丙酸的混合物的形式），其被用於下一步驟而無需 進一步純化。 步驟4 : (S)-2-胺基-3-(2,3-二氫苯並[b] [1,4】二噁烷_6_基） 丙酸乙酯：向溶於乙醇（25 mL)的（S)-2-胺基-3-(2,3-二氫苯 並[b] [1，4]二°惡烧-6-基）丙酸（8.7 mmol)溶液加入亞硫酿氯 (2.0 mL ’ 27.4 mmol)。將反應混合物於回流條件下（9〇t 浴溫）攪拌2小時。真空濃縮所得的溶液並將產物用於下一 步驟而無需進一步純化。 步驟5 : (S)-2-胺基-3-(2,3-二氫苯並[b】丨1，4]二噪烧基） 丙酸乙酯：向溶於乙腈（15.0 mL)的（S)-2-胺基-3-(2,3-二 虱苯並[b][l，4]二。惡烧-6-基）丙酸乙醋（3〇〇 mg，1.3 mmol) 加入 1-(2,4-二氣苯基）環丙叛酸（250 mg，1.1 mmol)、ν,Ν- 二異丙基乙胺（1.5 mL，9·12 mmol)和 HATU(400 mg，ι. ι mmol)。將反應混合物於室溫攪拌i小時。將所得的溶液真 空濃縮’溶於二氣曱烷（35 mL)，並用水（1〇 mL)萃取兩 次。分層並且真空濃縮有機層。通過管柱層析（石夕膠， EtOAc，己烧）純化產物，得到350 mg (68.8%)的標題化合 物。 步驟6 : (S)-2-(l-(2,4-二氣苯基）環丙甲酿胺基）_3_(2,3_ 二氫-苯並【b][l，4】二鳴烧-6-基）丙酸：向溶於15 mL的Step 1: 2-Ethylaminol^-((^-dihydrobenzopyrene(丨^丨dioxane-cardyl)methyl)-diethyl malonate: freshly prepared at room temperature Add sodium 6-(bromomethyl)_2 3 -dihydrohydrobenzo[1)][1,4]dioxane to a solution of sodium ethoxide (sodium 0.6 g, 26 mmol, ethanol 50 mL) (2§, 8.7, 3 111111 〇1) and 2-acetamide-diethyl malonate (1.9 g, 8.75 mmol). The reaction mixture was stirred with EtOAc EtOAc m. Step 2: 2-Ethylamino-3-(2,3-dihydrobenzo^) [1,4]dioxan-6-yl)propionic acid: will dissolve in water (35 mL) and ethanol (35 mL) 2-Ethylamino-2-((2,3-dihydrobenzo[&gt;][1,4]dioxane-6-yl)methyl)malonate diethyl ester (3.17 The solution of g, 8.7 mmol) and potassium hydroxide (Ml g, 27.7 mmol) was heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo and the product was applied to the next step without further purification. Step 3: (S)-2-Amino-3-(2,3-dihydrobenzo[b][l,4]dioxan-6-yl)propionic acid: at 37 ° C (39 ° C Bath temperature) 2-Ethylamino-3-(2,3-dihydrobenzo[b][l,4]dioxan-6-yl)propionic acid (8.7 mmol) dissolved in sodium hydroxide solution (0.42 g NaOH, 50 mL H20) and the pH was adjusted to 7.5 by the addition of 2 N HCl. To the resulting solution were added cobalt hexahydrate (Aldrich, 10 m_) and Amano thiol transferase (Aldrich, 200 mg). The reaction mixture was stirred at 146258.doc -95.201040149 37 ° C (39 ° C bath temperature) and ρΗ7·5 for 16 hours. Concentration under reduced pressure gave the title compound (m.). In the form of a mixture) which was used in the next step without further purification. Step 4: (S)-2-Amino-3-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)ethyl propionate: soluble in ethanol (25 (S)-2-Amino-3-(2,3-dihydrobenzo[b][1,4]dioxazol-6-yl)propionic acid (8.7 mmol) solution added to the sulfur Brewed with chlorine (2.0 mL ' 27.4 mmol). The reaction mixture was stirred under reflux (9 Torr bath temperature) for 2 hr. The resulting solution was concentrated in vacuo and the product was used in the next step without further purification. Step 5: (S)-2-Amino-3-(2,3-dihydrobenzo[b]fluorene 1,4] dioxin) Ethyl propionate: dissolved in acetonitrile (15.0 mL) (S)-2-Amino-3-(2,3-dioxabenzo[b][l,4]di.Ethylene-6-yl)propionic acid ethyl acetate (3 mg, 1.3 mmol) Add 1-(2,4-diphenyl)cyclopropionic acid (250 mg, 1.1 mmol), ν, Ν-diisopropylethylamine (1.5 mL, 9·12 mmol) and HATU (400 mg, ι. ι mmol). The reaction mixture was stirred at room temperature for 1 hour. The resulting solution was concentrated in vacuo to dissolve in dioxane (35 mL) and extracted twice with water (1 mL). The layers were separated and the organic layer was concentrated in vacuo. The product was purified by column chromatography (EtOAc) eluting Step 6: (S)-2-(l-(2,4-diphenyl)cyclopropanylamino)_3_(2,3_dihydro-benzo[b][l,4] dioxin -6-yl)propionic acid: soluble in 15 mL

MeOH的（S)-2-胺基-3-(2,3-二氫苯並[b][l，4]二噁烷_6_基） 丙酸乙酯（350 mg，0.75 mmol)溶液加入15 mL的2 N NaOH 146258.doc -96· 201040149 溶液並且將反應混合物於室溫攪拌1 8小時。將所得的溶液 在減壓下濃縮，用濃HC1酸化至PH=3，並用300 mL的 EtOAc萃取。用硫酸鎂乾燥有機層。真空濃縮所得的溶液 以產生320 mg(97.5〇/〇)的標題化合物，其用於下一步驟而 無需進一步純化。 步驟 7 : N-[(3S)-1-氮雜雙環[2.2.2】辛-3-基]-Ν，2，-{[1-(2,4 - 一氣苯基）-環丙基]-幾基}-3-(2,3-二氮-1,4 -苯並二嘆 烷-6-基）-L-丙胺醯胺：向溶於乙腈（15.0 mL)的（S)-2-(l-(2,4-二氯苯基）環丙曱醯胺基）_3-(2,3-二氫苯並[13][1，4]二 °惡烧-6-基）-丙酸（320 mg’ 0_73 mmol)溶液加入（S)-奎寧-3-胺（250 mg，1·9 mmol)、N，N-二異丙基乙胺（i.〇mL，6.0 mmol)以及HATU(400 mg ’ 1.1 mmol)。將反應混合物於室 溫攪拌16小時。真空濃縮所得溶液並且用製備級HPLC(反 相’乙腈/含0.1%甲酸的水）純化產物以產生133 mg的標題 化合物。1H NMR (400 MHz, DMSO-d6): δ 8.19 (s，1H), 7.84 (br s, 1H), 7.56 (s, 1H), 7.37 (s, 2H), 6.61 (s, 1H), 6.43 (m, 2H), 6.25 (d, 1H), 4.38 (m, 1H), 4.18 (m, 4H), 2.95-3.57 (m, 7H), 2.65 (m, 4H), 1.16-1.38 (m, 5H), 0.93 (m，2H)· C28H31C12N304的 MS (El)，實測值 544.35 (MH+)。 以類似實施例5的方式製備下列化合物： N-[(3R)-1-氮雜雙環[2.2.2]辛-3-基]-Ν，2，-{[1-(2,4-二氯苯 基）環丙基]-羰基卜3-(2,3-二氫-1,4-苯並二噁烷-6-基）-L-丙 胺酿胺：NMR (4〇〇 MHz，DMSO-d6): δ 8.19 (s, 1H)， 7.84 (br s，1Η)，7.56 (s，1Η)，7.37 (s，2Η), 6.61 (s, 1Η)， 146258.doc -97- 201040149 6.43 (m, 2H), 6.25 (d, 1H), 4.37 (m, 1H), 4.12 (m, 4H), 2.95-3.57 (m, 7H), 2.61 (m, 4H), 1.16-1.38 (m, 5H), 0.93 (m，2H). C28H31C12N304的 MS (El) ’ 實測值 544.28 (MH+)。 N，2，-{[l-(2,4-二氣苯基）環丙基]羰基}-3-(2,3-二氫-1，4-苯並二嚙烷-6-基）-N-[2-(二甲基胺基）乙基]-N-甲基-L-丙胺 醯胺：NMR (400 MHz，CDC13): δ 7.25-7.43 (m，3H)， 5.51-6.72 (m, 3H), 5.96 (d, 1H), 4.97 (q, 1H), 4.23 (s, 4H), 3.66 (m, 1H), 3.41 (m, 1H), 2.75 (m, 10H), 2.52 (m, 3H), 1.61-1.74 (m，2H), 1.00-1.08 (m，2H). C26H31C12N304的 MS (El)，實測值 520.23 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-4-氣-Να-{【1-(2,4-二 氣苯基）-環丙基]-羰基}-3-(三氟甲基）-L-苯丙胺醢胺：4 NMR (400 MHz, DMSO-d6): δ 8.25 (m, 1H), 8.03 (m, 1H), 7.57 (m, 3H), 7.40 (m, 3H), 6.65 (m, 1H), 4.56 (m, 1H), 3.07 (m, 1H), 2.93 (m, 2H), 2.70 (m, 4H), 2.30 (m, 1H), 1.68 (m, 2H), 1.53 (m, 3H), 1.33 (m, 3H), 0.96 (m, 2H). C27H27C13F3N302 的 MS (El)，實測值 589 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基】-Να-{[1-(2,4-二氣苯 基）-環丙基】羰基}-〇-甲基-3-(甲氧基）-L-酪胺醯胺： NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1H), 7.92 (m, 1H), 7.60 (s, 1H), 7.41 (m, 2H), 6.65 (m, 1H), 4.47 (m, 1H), 3.67 (m, 6H), 3.06 (m, 10H), 2.69 (m, 4H), 2.18 (m, 1H), 1.40-1.56 (m, 4H), 0.97 (m，2H)· C28H33C12N304的 MS (El) ’ 實 測值 546.6 (MH+)。 146258.doc -98- 201040149 ]\-[(38)-1-氮雜雙環[2.2.2】辛-3-基卜4-氣_^〇1-{[1-(2,4_二 氣苯基）-環丙基】羰基卜2-氟-L-苯丙胺醢胺：4 NMR (400 MHz, DMSO-d6)： δ 8.24 (s, 1Η), 7.92 (m, 1H), 7.64 (s, 1H), 7.45 (s，2H)，7.30 (d, 1H)，7.16 (m，2H)，6.49 (m，1H)，4.54 (m，1H)，2.33-3.59 (m，12H)，1.32-1.67 (m，4H)，0.97 (m， 2H). C26H27Cl3FN3〇2的MS (El) ’ 實測值 538.5 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2】辛-3-基卜4-氣-Να-{【1-(2,4-二 氣苯基）-環丙基】羰基卜2-氟-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.21 (s，1Η)，8.09 (m，1Η)，7.76 (d，1Η)， 7.58 (d, 1H), 7.45 (m, 3H), 7.29 (t, 1H), 6.69 (m, 1H), 4.58 (m, 1H), 2.69-3.69 (m, 12H), 1.12-1.76 (m, 4H), 0.97 (m, 2H). C27H27C13F3N302的 MS (El)，實測值 588.5 (MH+)。 ]\-[(18)_2-(3-胺基-8-氮雜雙環[3.2.1】辛-8-基）-1-(2,3-二 氫-1，4-苯並二噁烷-6-基甲基）-2-氧代乙基】_i_{4-【（三氟甲 基）氧】苯基}環丙醢胺：WNMR (400 MHz，DMSO-d6): δ 8.24 (m, 1Η), 7.37 (m, 2H), 7.28 (m, 2H), 6.78 (m, 1H), 6.68 (m, 1H), 6.50 (m, 2H), 4.60 (m, 1H), 4.40-4.05 (m, 6H), 3.11 (m, 2H), 2.64 (m, 2H), 1.86 (m, 3H), 1.49 (m, 4H), 1.27 (m，2H)，0.97 (m，2H). C29H32F3N305 的 MS (El)， 實測值560 (MH+)。 3-(2,3-二氫-1，4-苯並二噁烷-6-基）-N-丨2-(二甲基胺基）乙 基]-N-甲基-N〜2〜-[(1-{4-[(三氟甲基）氧】苯基}環丙基）羰 基]-L-丙胺醯胺：NMR (400 MHz，DMSO-d6): δ 8.15 (s， 1Η), 7.33 (m, 4H), 7.65 (m, 4H), 4.76 (m, 1H), 4.18 (s, 4H), 146258.doc •99- 201040149 3.44 (m, 1H), 3.13 (m, 1H), 2.91 (s, 2H), 2.75 (s, 1H), 2.68 (m, 2H), 2.31 (m, 2H), 2.16 (d, 6H), 1.26 (m, 2H), 0.98 (m, 2H). C27H32F3N305 的 MS (El)，實測值 536 (MH+)。 ]^-[(18)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基）-1-(2,3-二 氮-1，4 -苯並二嚼烧-6-基甲基）-2 -氧代乙基]-l-[2 -氟- 4- (二 氟甲基）苯基]環丙醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.30 (s, 1H), 7.62 (d, 1H), 7.55 (m, 2H), 7.03 (m, 1H), 6.67 (m, 1H), 6.52 (m, 2H), 4.60 (m, 1H), 4.40-4.05 (m, 6H), 3.02 (m, 2H), 2.67 (m, 2H), 2.02 (m, 2H), 1.68 (m, 3H), 1.39 (m, 4H), 1.03 (m，2H). C29H31F4N304 的 MS (El)，實測 值 562 (MH+)。 實施例6 N-(氮雜環丁烷-3-基甲基）-4-溴-Να-[(1-{4-[(三氟甲基） 氧]苯基}環丙基）-羰基】_L-苯丙胺醯胺(S)-2-Amino-3-(2,3-dihydrobenzo[b][l,4]dioxane-6-yl)propionic acid ethyl ester (350 mg, 0.75 mmol) in MeOH 15 mL of 2 N NaOH 146258.doc -96·201040149 solution was added and the reaction mixture was stirred at room temperature for 18 hours. The resulting solution was concentrated under reduced pressure and evaporated with EtOAc EtOAc. The organic layer was dried over magnesium sulfate. The resulting solution was concentrated in vacuo to give title titled <RTI ID=0.0> Step 7: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-anthracene, 2,-{[1-(2,4-monophenyl)-cyclopropyl] -Methyl}-3-(2,3-diaza-1,4-benzodioxan-6-yl)-L-propylamine amide: (S)-2 dissolved in acetonitrile (15.0 mL) -(l-(2,4-dichlorophenyl)cyclopropanylamino)_3-(2,3-dihydrobenzo[13][1,4]dioxacarb-6-yl)- Propionic acid (320 mg '0_73 mmol) solution was added (S)-quinuclidin-3-amine (250 mg, 1. 9 mmol), N,N-diisopropylethylamine (i. 〇mL, 6.0 mmol) And HATU (400 mg '1.1 mmol). The reaction mixture was stirred at room temperature for 16 hours. The resulting solution was concentrated in vacuo and purified title title title title title title 1H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.84 (br s, 1H), 7.56 (s, 1H), 7.37 (s, 2H), 6.61 (s, 1H), 6.43 ( m, 2H), 6.25 (d, 1H), 4.38 (m, 1H), 4.18 (m, 4H), 2.95-3.57 (m, 7H), 2.65 (m, 4H), 1.16-1.38 (m, 5H) MS (El), 552.35 (MH+). The following compounds were prepared in a similar manner to Example 5: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-oxime, 2,-{[1-(2,4-di Chlorophenyl)cyclopropyl]-carbonylbu 3-(2,3-dihydro-1,4-benzodioxan-6-yl)-L-propylamine-branched amine: NMR (4〇〇MHz, DMSO -d6): δ 8.19 (s, 1H), 7.84 (br s, 1Η), 7.56 (s, 1Η), 7.37 (s, 2Η), 6.61 (s, 1Η), 146258.doc -97- 201040149 6.43 ( m, 2H), 6.25 (d, 1H), 4.37 (m, 1H), 4.12 (m, 4H), 2.95-3.57 (m, 7H), 2.61 (m, 4H), 1.16-1.38 (m, 5H) , MS3 (m) of C28H31C12N304, found 544.28 (MH+). N,2,-{[l-(2,4-diphenyl)cyclopropyl]carbonyl}-3-(2,3-dihydro-1,4-benzodioxan-6-yl) -N-[2-(Dimethylamino)ethyl]-N-methyl-L-propylamine decylamine: NMR (400 MHz, CDC13): δ 7.25-7.43 (m, 3H), 5.51-6.72 ( m, 3H), 5.96 (d, 1H), 4.97 (q, 1H), 4.23 (s, 4H), 3.66 (m, 1H), 3.41 (m, 1H), 2.75 (m, 10H), 2.52 (m , 3H), 1.61-1.74 (m, 2H), 1.00-1.08 (m, 2H). MS (El) for C26H31C12N304, found 520.23 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-gas-Να-{[1-(2,4-diphenyl)-cyclopropyl]- Carbonyl}-3-(trifluoromethyl)-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.25 (m, 1H), 8.03 (m, 1H), 7.57 (m, 3H) , 7.40 (m, 3H), 6.65 (m, 1H), 4.56 (m, 1H), 3.07 (m, 1H), 2.93 (m, 2H), 2.70 (m, 4H), 2.30 (m, 1H), 1.68 (m, 2H), 1.53 (m, 3H), 1.33 (m, 3H), 0.96 (m, 2H). MS (El) of C27H27C13F3N302, found 589 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-Να-{[1-(2,4-diphenyl)-cyclopropyl]carbonyl}-〇- Methyl-3-(methoxy)-L-tyramine amide: NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1H), 7.92 (m, 1H), 7.60 (s, 1H), 7.41 (m, 2H), 6.65 (m, 1H), 4.47 (m, 1H), 3.67 (m, 6H), 3.06 (m, 10H), 2.69 (m, 4H), 2.18 (m, 1H), 1.40 -1.56 (m, 4H), 0.97 (m, 2H). MS (El) of C28H33C12N304. Found: 546.6 (MH+). 146258.doc -98- 201040149 ]\-[(38)-1-Azabicyclo[2.2.2]oct-3-ylbu 4-gas_^〇1-{[1-(2,4_二气Phenyl)-cyclopropyl]carbonyl carbonyl 2-fluoro-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1 Η), 7.92 (m, 1H), 7.64 (s, 1H), 7.45 (s, 2H), 7.30 (d, 1H), 7.16 (m, 2H), 6.49 (m, 1H), 4.54 (m, 1H), 2.33-3.59 (m, 12H), 1.32-1.67 (m, 4H), 0.97 (m, 2H). MS (El) of C26H27Cl3FN3 〇2, found 538.5 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-ylbu 4-gas-Να-{[1-(2,4-diphenyl)-cyclopropyl]carbonyl 2-fluoro-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.21 (s, 1 Η), 8.09 (m, 1 Η), 7.76 (d, 1 Η), 7.58 (d, 1H), 7.45 (m, 3H), 7.29 (t, 1H), 6.69 (m, 1H), 4.58 (m, 1H), 2.69-3.69 (m, 12H), 1.12-1.76 (m, 4H), 0.97 (m, MS (El) for C27H27C13F3N302, found 588.5 (MH+). ]\-[(18)_2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-1-(2,3-dihydro-1,4-benzodioxin Alkyl-6-ylmethyl)-2-oxoethyl]_i_{4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide: WNMR (400 MHz, DMSO-d6): δ 8.24 ( m, 1Η), 7.37 (m, 2H), 7.28 (m, 2H), 6.78 (m, 1H), 6.68 (m, 1H), 6.50 (m, 2H), 4.60 (m, 1H), 4.40-4.05 (m, 6H), 3.11 (m, 2H), 2.64 (m, 2H), 1.86 (m, 3H), 1.49 (m, 4H), 1.27 (m, 2H), 0.97 (m, 2H). C29H32F3N305 MS (El), found 560 (MH+). 3-(2,3-Dihydro-1,4-benzodioxan-6-yl)-N-indole 2-(dimethylamino)ethyl]-N-methyl-N~2~ -[(1-{4-[(Trifluoromethyl)oxy)phenyl}cyclopropyl)carbonyl]-L-propylamine amide: NMR (400 MHz, DMSO-d6): δ 8.15 (s, 1 Η) , 7.33 (m, 4H), 7.65 (m, 4H), 4.76 (m, 1H), 4.18 (s, 4H), 146258.doc •99- 201040149 3.44 (m, 1H), 3.13 (m, 1H), 2.91 (s, 2H), 2.75 (s, 1H), 2.68 (m, 2H), 2.31 (m, 2H), 2.16 (d, 6H), 1.26 (m, 2H), 0.98 (m, 2H). C27H32F3N305 MS (El), found 536 (MH+). ]^-[(18)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-1-(2,3-diaza-1,4-benzoic acid Chew 6-ylmethyl)-2-oxoethyl]-l-[2-fluoro-4-(difluoromethyl)phenyl]cyclopropanamide: 4 NMR (400 MHz, DMSO-d6) ): δ 8.30 (s, 1H), 7.62 (d, 1H), 7.55 (m, 2H), 7.03 (m, 1H), 6.67 (m, 1H), 6.52 (m, 2H), 4.60 (m, 1H) ), 4.40-4.05 (m, 6H), 3.02 (m, 2H), 2.67 (m, 2H), 2.02 (m, 2H), 1.68 (m, 3H), 1.39 (m, 4H), 1.03 (m, 2H). MS (El) for C29H31F4N304, found 562 (MH+). Example 6 N-(azetidin-3-ylmethyl)-4-bromo-indole α-[(1-{4-[(trifluoromethyl)oxy]phenyl}cyclopropyl)-carbonyl 】_L-Amphetamine

146258.doc -100 201040149 步驟1 . 1-(4-(二氟甲氧基）苯基）環丙基腈：于〇向溶 於™F(450 mL)的2-(4-(三氣甲氧基）苯基）乙腈（lSg, 74.6 mm〇1)加入NaH (100%，9〇 g，375咖〇1)。將反應物於室 溫攪拌30分鐘並加入15 mL的二溴乙烷（i5 mL，174 mmol^將反應物於室温攪拌48小時並通過加入1〇〇 ^^的 水淬滅。將所得的溶液真空濃縮，重溶sEt〇Ac(5〇〇 mL) 中並用100 mL的水清洗。通過炭和矽藻土的塞（a phig 〇f146258.doc -100 201040149 Step 1. 1-(4-(Difluoromethoxy)phenyl)cyclopropylcarbonitrile: 2-(4-(three gas) in TMF (450 mL) Oxy)phenyl)acetonitrile (1Sg, 74.6 mm 〇1) was added to NaH (100%, 9 〇g, 375 Curry 1). The reaction was stirred at room temperature for 30 min and 15 mL of dibromohexane (i.sub.5 mL, &lt;RTI ID=0.0&gt;&gt; Concentrate in vacuo, re-dissolve sEt〇Ac (5〇〇mL) and wash with 100 mL of water. Plug through charcoal and diatomaceous earth (a phig 〇f

CharC〇al and Celite)過濾有機層。將所得的溶液真空濃縮 〇 以產生為灰白色油的14·9 g(88.7。/。）的標題化合物，其用於 下一步驟而無需進一步純化。CliH8F3NC^MS (EI),實測 值 228.14 (MH+)。 步驟2 : 1_(4-(三氟甲氧基）苯基）環丙羧酸：向溶于4〇〇 mL水的NaOH(35 g，795 mmol)溶液加三氟曱氧 基）-苯基）環丙基腈（14_9 g，65·0 mmol)。將反應混合物加 熱至120 C保持48小時》將所得的溶液冷卻至〇。〇並經由加 〇 入》辰HC1酸化至pH3。將所得的沉殿過渡，用水清洗並乾 燥。將乾燥的殘留物重溶於二乙醚（5〇〇 mL)，過濾以與鹽 分開，出來並且在減壓下濃縮。將得到的灰白色固體用於 下一步驟而無需進一步純化（15.6 g，97.5%)。c&quot;H9F3〇3的 ]\48(£1)，實測值247.17 (1^111+)。 步驟3 : (S)-2-胺基-3·(4-溴苯基）丙酸乙酯：向溶於乙醇 (450 mL )的 Boc-L-4-溴苯丙胺酸（30.0g, 87.16 mmol, Chem-Impex)溶液加入亞硫醯氣（8.0 mL，109.67 mmol)。 將反應物於90°C回流18小時。真空濃縮所得的溶液以產生 146258.doc -101- 201040149 27.0 g(90%)標題化合物的HC1鹽，其用於下一步驟而無需 進一步純化。CnHuBrNCh的MS (EI)，實測值273.14 (MH+)。 步驟4 : (S)-3-(4-溴苯基）-2-(1-(4-(三氟甲氧基）苯基）-環 丙甲醯胺基）丙酸乙酯：向溶於乙腈（150.0 mL)的（S)-2-胺 基-3-(4-溴本基）丙酸乙g旨（11.5 g，42.26 mmol)溶液加入1-(4_(二氟曱氧基）苯基）環丙羧酸（10.4 g，42.26 mmol)、 N，N-二異丙基乙胺（13.9 mL，84.52 mmol)以及 HATU(19.3 g ’ 50.71 mmol)。將反應物於室溫攪拌1小時。將所得的溶 液真空濃縮並溶解於一氧甲烧（350 mL)中，用水（350 mL) 萃取兩次。分層並且用硫酸鎂乾燥有機層。真空濃縮所得 的溶液並且在矽膠上層析’用溶於己烷的丨5% EtOAc沖提 以產生17.4 g (82%)的標題化合物。c22H21BrF3N04的MS (EI)，實測值501·3 1 (MH+)。 步驟5 : (S)-3-(4-溴苯基）-2-(1-(4-(三氟甲氧基）苯基）環 丙曱醯胺基）丙酸：向溶於300 mL的MeOH的（S)-3-(4-溴苯 基）-2-(1-(4-(三氟甲氧基）苯基）環丙曱醯胺基）丙酸乙酯 (17.4 g，34.8 mmol)溶液加入 1〇〇 2 N NaC)t^ 液並且 於室溫攪拌反應混合物18小時。將所得的溶液在減壓下濃 縮’用濃HC1酸化至pH=3並用300 mL的EtOAc萃取。將有 機層用硫酸鎂乾燥、過濾並真空濃縮以產生14 5 g(88%)的 標題化合物，其用於下一步驟而無需進一步純化。 (：201117；8斤3&gt;1〇4的1^(£1)’實測值473.25 (]^11+)。 步驟6 : N-(氮雜環丁烷_3_基甲基）_4_溴[(三 146258.doc -102· 201040149 氟甲基）氧]-苯基}環丙基）羰基】_L_苯丙胺醢胺：向溶於乙 腈（5.0 mL)的（S)-3-(4-溴苯基）-2-(1-(4-(三氟甲氧基）苯基） 環丙甲醯胺基）丙酸（1〇〇 mg，〇·2 mni〇l)溶液加入3_(胺基甲 基）氮雜環丁烧-1-叛酸叔丁醋（〇akw〇〇d，40.0 mg，〇 2 mm〇1)、N，N-二異丙基-乙胺（1.1 mL，6.1 mm〇i)以及 HATU(76 mg，0.2 mmol)。將反應物於室溫攪拌丨小時。將 所得的溶液真空濃縮、溶於二氣甲烷（3〇〇 mL)，用水（10 mL)、飽和碳酸氫鈉溶液（1〇 mL)和飽和氣化鈉溶液（ι〇 mL)萃取。分層並將有機層用硫酸鎂乾燥，過濾並且真空 濃縮。將所得的油溶於甲醇（丨〇 mL)之後加入溶於二噁烷（5 mL，Aldrich)的4 N HC1。將反應物加熱至45°C保持2小 時。真空濃縮所得的溶液。用製備級HPLC(反相，乙腈/含 0.1%曱酸的水）純化產物以產生2〇 mg的標題化合物。ιΗ NMR (400 MHz, CDC13): δ 8.54 (s, 1Η), 8.45 (s, 1H), 7.32 (d, 2H), 7.27 (d, 2H), 7.17 (d, 2H), 6.84 (d, 2H), 5.79 (d, 1H), 4.62-4.57 (m, 1H), 4.05 (s, 2H), 3.93 (s, 1H), 3.82 (s, 1H), 3.61-3.58 (m, 1H), 3.27-3.23 (m, 1H), 3.02-2.98 (m, 2H), 2.74-2.68 (m, 1H), 1.47-1.31 (m, 2H), 1.08-0.94 (m, 2H); C24H25BrF3N303的MS (El)，實測值542.15 (MH+)。 以相似於實施例6的方式合成N-[(lS)-2-(3-胺基-8-氮雜 雙環[3.2.1】辛-8-基）_1-[(4-溴苯基）甲基】_2_氧代乙基】·ι_μ- [(三氟甲基）氧】苯基]環丙醢胺’其中8_氮雜雙環[3 2丨]辛- 3-基胺基甲酸叔丁酯替代3-(胺基曱基）氮雜環丁烷_ι_羧酸 叔丁酯（Oakwood)。4 NMR (400 MHz，DMSO-d6): δ 7.42 146258.doc •103· 201040149 (m，2H)，7·31 (m，4H)，7.03(m，3H)，4.67 (m，1H)，4.27 (m， 2H), 3.10 (m, 1H), 2.78 (m5 2H), 1.81 (m, 8H), 1.22 (m, 2H)，0.98 (m，2H). c27H29BrF3N303 的 MS (El)，實測值 581.44 (MH+)。 以類似於實施例6的方式製備下列化合物。 N-[(lS)-2-(2,6-二氮雜螺[3·3]庚 _2_基）_2_ 氧代-(三 氟甲基）苯基]-甲基}乙基】-l-(2,4-二氣苯基）環丙醢胺： NMR (400 MHz, CDC13): δ 7.55 (d，2H)，7.42 (s，1H)， 7.26(m, 4H), 5.80 (d, 1H), 4.50 (dd, 1H), 4.24 (d, 1H), 4.05 (d, 1H), 3.90 (m, 3H), 3.61 (d, 1H), 3.27 (d, 1H), 2.98 (dd, 2H), 2.83 (dd, 2H), 1.73 (m, 1H), 1.62 (m, 1H), 1.12 (m, 1H), 1.05 (m, 1H)· C25H24C12F3N302 的 MS (El)，實測值 526.09 (MH+)。 4-溴-Να-{[1·(2,4-二氣苯基）環丙基】羰基}-N-[2-(甲基胺 基）乙基】-L-苯丙胺醯胺：NMR (400 MHz，DMSO-d6): δ 8.28 (s, 1Η), 8.18 (br s, 1H), 7.59 (s, 1H), 7.41 (m, 3H), 7.01(d, 2H), 6.59 (d, 1H), 4.43 (m, 1H), 3.6 (br s, 1H), 3.17 (m, 2H), 2.89 (m, 1H), 2.76 (m, 1H), 2.63 (m, 2H), 2.34 (s, 3H)，1.37 (s，2H)，0.97 (dd, 2H). C22H24BrCl2N302 的 MS (EI)，實測值514.06(MH+)。 1-(2,4-二氣苯基）_^{(18)-1-[(2,4-二氣苯基）甲基]-2-氧 代-2-呱嗪-1-基乙基}環丙醯胺：4 NMR (400 MHz， DMSO-d6): δ 8.24 (s, 1Η), 7.62 (d, 1H), 7.53 (d, 1H), 7.45-7.40 (m, 1H), 7.37-7.35 (dd, 1H), 7.23 (d, 1H), 6.94 (d, 146258.doc -104- 201040149 1H), 5.04-4.98 (m, 1H), 3.43-3.29 (m, 5H), 2.97-2.84 (m, 2H), 2.67-2.51 (m, 4H), 1.41-1.36 (m, 1H), 1.21-1.18 (m, 1H)，0.97-0.90 (m, 2H); C23H23Cl4N302 的 MS (El)，實測值 516.07 (MH+)。 2,4-二氣-Να-{[1-(2,4-二氣苯基）環丙基】羰基}-N-甲基-N-[2-(甲基胺基）乙基]-L-苯丙胺醢胺：NMR (400 MHz, CD3OD) ： 7.50-7.37 (m, 4H), 7.25 (d, 1H), 7.18 (d, 1H),CharC〇al and Celite) filter the organic layer. The resulting solution was concentrated in vacuo to give EtOAc (EtOAc): CliH8F3NC^MS (EI), found 228.14 (MH+). Step 2: 1_(4-(Trifluoromethoxy)phenyl)cyclopropanecarboxylic acid: to a solution of NaOH (35 g, 795 mmol) dissolved in 4 mL of water (trifluoromethoxy)-phenyl Cyclopropyl nitrile (14_9 g, 65·0 mmol). The reaction mixture was heated to 120 C for 48 hours. The resulting solution was cooled to hydrazine. The hydrazine was acidified to pH 3 by the addition of HCl. The resulting sinking hall was transitioned, washed with water and dried. The dried residue was redissolved in diethyl ether (5 mL), filtered and evaporated and evaporated. The resulting off-white solid was used in the next step without further purification (15.6 g, 97.5%). c&quot;H9F3〇3]\48(£1), measured value 247.17 (1^111+). Step 3: (S)-2-Amino-3-(4-bromophenyl)propanoic acid ethyl ester: Boc-L-4-bromophenylalanine (30.0 g, 87.16 mmol) dissolved in ethanol (450 mL) , Chem-Impex) solution was added with sulfoxide (8.0 mL, 109.67 mmol). The reaction was refluxed at 90 ° C for 18 hours. The resulting solution was concentrated in vacuo to give EtOAc EtOAc EtOAc. MS (EI) for Cn.sub. Step 4: (S)-3-(4-Bromophenyl)-2-(1-(4-(trifluoromethoxy)phenyl)-cyclopropamimidino)propionic acid ethyl ester: dissolved Add 1-(4-(difluorodecyloxy) solution to (S)-2-amino-3-(4-bromobenzyl)propanoic acid (11.5 g, 42.26 mmol) in acetonitrile (150.0 mL) Phenyl)cyclopropanecarboxylic acid (10.4 g, 42.26 mmol), N,N-diisopropylethylamine (13.9 mL, 84.52 mmol) and HATU (19.3 g ' 50.71 mmol). The reaction was stirred at room temperature for 1 hour. The resulting solution was concentrated in vacuo and dissolved in EtOAc (EtOAc)EtOAc. The layers were separated and the organic layer was dried over magnesium sulfate. The resulting solution was concentrated in vacuo and purified eluting with EtOAc EtOAc EtOAc MS (EI) for c22H21BrF3N04, found 501·3 1 (MH+). Step 5: (S)-3-(4-Bromophenyl)-2-(1-(4-(trifluoromethoxy)phenyl)cyclopropanyl)propionic acid: dissolved in 300 mL Ethyl (S)-3-(4-bromophenyl)-2-(1-(4-(trifluoromethoxy)phenyl)cyclopropenyl)propionic acid ethyl ester (17.4 g, 34.8 mmol) solution was added to 1 〇〇 2 N NaC) solution and the reaction mixture was stirred at room temperature for 18 hr. The resulting solution was concentrated under reduced pressure and then acidified to pH = 3 with concentrated HCl and extracted with EtOAc EtOAc. The organic layer was dried with EtOAc EtOAc (EtOAc)EtOAc. (:201117; 8 kg 3 &gt; 1〇4 of 1^(£1)' measured value 473.25 (]^11+). Step 6: N-(azetidinyl-3-ylmethyl)_4_bromo [(三146258.doc -102· 201040149 fluoromethyl)oxy]-phenyl}cyclopropyl)carbonyl]_L_Amphetamine amide: (S)-3-(4- dissolved in acetonitrile (5.0 mL) Addition of 3_(amine) to a solution of bromophenyl)-2-(1-(4-(trifluoromethoxy)phenyl)cyclopropamidino)propionic acid (1 〇〇mg, 〇·2 mni〇l) Methyl)azetidin-1-related tartrate (〇akw〇〇d, 40.0 mg, 〇2 mm〇1), N,N-diisopropyl-ethylamine (1.1 mL, 6.1 Mm〇i) and HATU (76 mg, 0.2 mmol). The reaction was stirred at room temperature for a few hours. The resulting solution was concentrated in vacuo, dissolved in di-methane (3 mL), and extracted with water (10 mL), saturated sodium bicarbonate (1 mL) and sat. The layers were separated and dried with MgSO4. After the obtained oil was dissolved in methanol (丨〇 mL), 4 N HCl dissolved in dioxane (5 mL, Aldrich) was added. The reaction was heated to 45 ° C for 2 hours. The resulting solution was concentrated in vacuo. The product was purified by preparative HPLC (EtOAc, EtOAc/EtOAc) Η NMR (400 MHz, CDC13): δ 8.54 (s, 1Η), 8.45 (s, 1H), 7.32 (d, 2H), 7.27 (d, 2H), 7.17 (d, 2H), 6.84 (d, 2H ), 5.79 (d, 1H), 4.62-4.57 (m, 1H), 4.05 (s, 2H), 3.93 (s, 1H), 3.82 (s, 1H), 3.61-3.58 (m, 1H), 3.27- 3.23 (m, 1H), 3.02-2.98 (m, 2H), 2.74-2.68 (m, 1H), 1.47-1.31 (m, 2H), 1.08-0.94 (m, 2H); MS (El) of C24H25BrF3N303, Found 542.15 (MH+). Synthesis of N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)_1-[(4-bromophenyl) in a similar manner to Example 6. Methyl]_2_oxoethyl]·ι_μ-[(trifluoromethyl)oxy]phenyl]cyclopropanamide' wherein 8_azabicyclo[3 2丨]oct-3-ylaminocarbamic acid Butyl ester replaces 3-(aminomercapto)azetidinyl-tert-butyl carboxylic acid tert-butyl ester (Oakwood). 4 NMR (400 MHz, DMSO-d6): δ 7.42 146258.doc •103· 201040149 (m,2H),7·31 (m,4H), 7.03 (m,3H), 4.67 (m,1H), 4.27 (m, 2H), 3.10 (m, 1H), 2.78 (m5 2H), 1.81 (m, 8H), 1.22 (m, 2H), 0.98 (m, 2H). MS (El) of c27H29BrF3N303, found 581.44 (MH+). The following compounds were prepared in a similar manner to Example 6. N-[(lS)-2-(2,6-diazaspiro[3·3]hept-2-yl)_2-oxo-(trifluoromethyl)phenyl]-methyl}ethyl]- L-(2,4-diphenyl)cyclopropanamide: NMR (400 MHz, CDC13): δ 7.55 (d, 2H), 7.42 (s, 1H), 7.26 (m, 4H), 5.80 (d , 1H), 4.50 (dd, 1H), 4.24 (d, 1H), 4.05 (d, 1H), 3.90 (m, 3H), 3.61 (d, 1H), 3.27 (d, 1H), 2.98 (dd, 2H), 2.83 (dd, 2H), 1.73 (m, 1H), 1.62 (m, 1H), 1.12 (m, 1H), 1.05 (m, 1H)· C25H24C12F3N302 MS (El), found 526.09 (MH+ ). 4-bromo-Να-{[1·(2,4-diphenyl)cyclopropyl]carbonyl}-N-[2-(methylamino)ethyl]-L-phenylalanamine decylamine: NMR ( 400 MHz, DMSO-d6): δ 8.28 (s, 1Η), 8.18 (br s, 1H), 7.59 (s, 1H), 7.41 (m, 3H), 7.01(d, 2H), 6.59 (d, 1H ), 4.43 (m, 1H), 3.6 (br s, 1H), 3.17 (m, 2H), 2.89 (m, 1H), 2.76 (m, 1H), 2.63 (m, 2H), 2.34 (s, 3H) ), 1.37 (s, 2H), 0.97 (dd, 2H). MS (EI) of C22H24BrCl2N302, found 514.06 (MH+). 1-(2,4-diphenyl)-^{(18)-1-[(2,4-diphenyl)methyl]-2-oxo-2-pyridazin-1-ylethyl Cyclopropanol: 4 NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1 Η), 7.62 (d, 1H), 7.53 (d, 1H), 7.45-7.40 (m, 1H), 7.37 -7.35 (dd, 1H), 7.23 (d, 1H), 6.94 (d, 146258.doc -104- 201040149 1H), 5.04-4.98 (m, 1H), 3.43-3.29 (m, 5H), 2.97-2.84 (m, 2H), 2.67-2.51 (m, 4H), 1.41-1.36 (m, 1H), 1.21-1.18 (m, 1H), 0.97-0.90 (m, 2H); MS (El) of C23H23Cl4N302, measured The value is 516.07 (MH+). 2,4-digas-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-methyl-N-[2-(methylamino)ethyl]- L-Amphetamine amide: NMR (400 MHz, CD3OD): 7.50-7.37 (m, 4H), 7.25 (d, 1H), 7.18 (d, 1H),

5.02-4.97 (m, 1H), 3.88-3.80 (m, 1H), 3.42-3.37 (m, 1H), 3.17-3.07 (m, 6H), 3.00-2.90 (m, 1H), 2.64 (s, 3H), 1.58-1.46 (m, 2H), 1.20-1 .〇〇 (m，2H). C23H25CI4N3O2 的 MS (丑1)，實測值518.03(^111+)。 2-(2,4-二氣苯基）-N-[(lS)-l-【(2,4-二氣苯基）甲基】-2-(4_ 甲基-呱嗪-1-基）-2-氧代乙基】丙醯胺：4 NMR (400 MHz， CD3OD) ： 7.46-7.00 (m, 6H), 5.22 (dd, 1H), 4.08-4.02 (m, 1H), 3.65-3.35 (m, 4H), 3.18-2.97 (m, 2H), 2.47-2.30 (m, 3H), 2.23 (s, 3H), 2.13-2.07 (m5 1H), 1.35 (dd, 3H). 〇231^25(：14]^302的]^8(£1)，實測值518.15(]^1&quot;1+)。 Να-{[1-(2,4-二氣苯基）環丙基】羰基}-N-(扯咯啶-2-基甲 基）-4-(三氟甲基）_L苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.65 (d, 1H), 8.31 (s, 1H), 7.56 (m, 3H), 7.40 (s, 2H), 7.30 (d, 2H), 6.73 (m, 1H), 4.51 (m, 1H), 3.31 (m, 1H), 3.20 (m, 2H), 3.00 (m, 3H), 2.87 (m, 1H), 1.74 (m, 3H)，1.37 (m，3H)，0.94 (m，2H). C25H26C12F3N302 的 MS (El)，實測值529 (MH+)。 146258.doc -105- 201040149 N-[(lS)-2-(3-胺基氮雜環丁烷-1-基）-2-氧代-l-{[4-(三氟 甲基）苯基]甲基}-乙基]-1-(2,4-二氣苯基）環丙醯胺： NMR (400 MHz, CDC13): δ 7.22-7.57 (m, 7H)，5.95 (m，1H), 4.58 (q, 1H), 3.38-4.30 (m, 4H), 2.77-3.01 (m, 5H), 1.73 (m，2H)，1.07 (m，2H). C23H22C12F3N302 的 MS (El)，實測值 500.17 (MH+)。 4-溴-Να-{[1-(2,4-二氣苯基）環丙基]羰基}-N-(l-甲基呱 啶-3-基）-L-苯丙胺醯胺：4 NMR (400 MHz, CD3OD): 7.50-7.36 (m, 6H), 7.02-6.98 (m, 2H), 4.53-4.42 (m, 1H), 3.84-3.79 (m, 1H), 3.05-2.79 (m, 4H), 2.57 (s, 3H), 2.43-???2. ), 1.58-1.46 (m, 2H), 1.20-1 .〇〇(m,2H). MS (ug. 1) of C23H25CI4N3O2, found 518.03 (^111+). 2-(2,4-diphenyl)-N-[(lS)-l-[(2,4-diphenyl)methyl]-2-(4-methyl-pyridazin-1-yl) )-2-oxoethyl]propanamine: 4 NMR (400 MHz, CD3OD): 7.46-7.00 (m, 6H), 5.22 (dd, 1H), 4.08-4.02 (m, 1H), 3.65-3.35 (m, 4H), 3.18-2.97 (m, 2H), 2.47-2.30 (m, 3H), 2.23 (s, 3H), 2.13-2.07 (m5 1H), 1.35 (dd, 3H). 〇231^25 (:14]^302]^8(£1), found 518.15(]^1&quot;1+). Να-{[1-(2,4-diphenylphenyl)cyclopropyl]carbonyl}- N-(r-bromo-2-ylmethyl)-4-(trifluoromethyl)-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.65 (d, 1H), 8.31 (s, 1H), 7.56 (m, 3H), 7.40 (s, 2H), 7.30 (d, 2H), 6.73 (m, 1H), 4.51 (m, 1H), 3.31 (m, 1H), 3.20 (m, 2H) ), 3.00 (m, 3H), 2.87 (m, 1H), 1.74 (m, 3H), 1.37 (m, 3H), 0.94 (m, 2H). MS (El) for C25H26C12F3N302, found 529 (MH+) 146258.doc -105- 201040149 N-[(lS)-2-(3-Aminoazetidin-1-yl)-2-oxo-l-{[4-(trifluoromethyl) Phenyl]methyl}-ethyl]-1-(2,4-diphenyl)cyclopropanamide: NMR (400 MHz, CDC13): δ 7.22-7.57 (m, 7H), 5.95 (m, 1H), 4. 58 (q, 1H), 3.38-4.30 (m, 4H), 2.77-3.01 (m, 5H), 1.73 (m, 2H), 1.07 (m, 2H). MS (El) for C23H22C12F3N302, found 500.17 ( MH+) 4-bromo-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-(l-methylacridin-3-yl)-L-phenylpropylamine decylamine :4 NMR (400 MHz, CD3OD): 7.50-7.36 (m, 6H), 7.02-6.98 (m, 2H), 4.53-4.42 (m, 1H), 3.84-3.79 (m, 1H), 3.05-2.79 ( m, 4H), 2.57 (s, 3H), 2.43-

2.36 (m, 1H), 1.85-1.80 (m, 2H), 1.77-1.45 (m, 4H), 1.39-1.24 (m, 1H), 1-18-1.00 (m, 2H). C25H28C12N302 的 MS (El)，實測值 554.05 (MH+)。 N-l-氮雜雙環[2·2·2]辛-3-基-4-溴-Να-{[1-(2,4-二氣苯 基）環丙基】-羰基卜L-苯丙胺醯胺：NMR (400 MHz, CD3OD) ： 8.44 (s, 1H), 7.50-7.37 (m, 5H), 7.04-6.98 (m, 2H), 4.57 (dd, 1H), 4.13-3.98 (m, 1H), 3.63-3.58 (m, 1H), 3.30-3.02 (m, 5H), 2.98-2.80 (m, 3H), 2.00-1.85 (m, 3H), 1-75-1.50 (m, 3H)，1.20-1.00 (m, 2H). C26H28BrCl2N302的 MS (El)，實測值 567.09 (MH+)。 N-[(3R)-1-氮雜雙環[2.2.2]辛-3-基]-4-溴-Να-{[1-(2,4-二 氣苯基）-環丙基]羰基}-L-苯丙胺醯胺：4 NMR (400 MHz, CD3OD) ： 7.52-7.38 (m, 5H), 7.04-6.99 (m, 2H), 4.57 (dd, 1H), 4.07-3.96 (m, 1H), 3.58-3.45 (m, 1H), 3.20-3.05 (m, 146258.doc -106- 201040149 3H), 2.96-2.80 (m, 3H), 1.95-1.80 (m, 3H), 1.65-1.50 (m, 4H)，1.19-1.02 (m，2H). C26H28BrCl2N302 的 MS (El)，實測 值 566.09 (MH+)° 1-(2,4-二氣苯基）-N-{(lS)-l-[(2,4-二氣苯基）甲基】_2-[(8aS)-六氫峨咯並[l，2-a]»lt嗪-2(1H)-基]-2-氧代乙基}環丙 • 醯胺：4 NMR (400 MHz, CD3OD) : 7.57-7.38 (m，4H)， 7.28-7.10 (m, 2H), 5.20 (dd, 1H), 4.40 (dd, 1H), 4.01 (dd, 1H), 3.23-2.93 (m5 6H), 2.64-2.20 (m, 3H), 2.00-1.80 (m, 〇 3H)，1.58-1.40 (m，3H)，1.15-1.00 (m, 2H)· C26H27C14N302 的]^8斤1)，實測值 55 5.75 (1^11+)。 N-[(lS)-2-[(3R)-3-胺基峨咯啶-1-基】-2-氧代-l-{【4-(三氟 甲基）苯基]-甲基}乙基]-1-(2,4-二氣苯基）環丙醢胺：4 NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1H), 7.56 (m，3H)， 7.40 (s, 2H), 7.30 (m, 2H), 6.80 (m, 1H), 4.69 (m, 1H), 3.20 (m, 2H), 2.91 (m, 4H), 1.86 (m, 1H), 1.60 (m, 1H), 1.32 (m, 3H)，0.94 (m，2H)· C24H24Cl2F3N302 的 MS (El)，實測值 515 〇 (MH+)。 ]^_1-氮雜雙環[2.2.2]辛-3-基以〇1-{[1-(2,4-二氣苯基）環丙 • 基]-羰基}-4-(三氟甲基）-L-苯丙胺醢胺：4 NMR (4〇0 • MHz, DMSO-d6): δ 8.20 (s, 1H), 7.92 (m, 1H), 7.54 (m, 3H), 7.37 (s, 2H), 7.23 (m, 2H), 6.49 (m, 1H), 4.51 (m, 1H), 2.99 (m, 1H), 2.86 (m, 2H), 2.59 (m5 4H), 2.25 (m, 1H), 1.63-1.13 (m, 8H), 0.93 (m，2H). C27H28Cl2F3N3〇2 的 MS (El)，實測值 555 (MH+)。 146258.doc -107- 201040149 Να-{[1-(2,4-二氣苯基）環丙基]羰基}-N-(吼咯啶-3-基甲 基）_4-(三氟甲基）-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.38 (d, 1H), 8.13 (s, 1H), 7.57 (m, 3H), 7.41 (s, 2H), 7.28 (d, 2H), 6.70 (t, 1H), 4.48 (m, 1H), 3.12-2.83 (m, 8H), 2.64 (m, 1H), 2.24 (m, 1H), 1.81 (m, 1H), 1.37 (m, 3H)，0.94 (m, 2H). C25H26C12F3N302 的 MS (El)，實測值529 (MH+)。2.36 (m, 1H), 1.85-1.80 (m, 2H), 1.77-1.45 (m, 4H), 1.39-1.24 (m, 1H), 1-18-1.00 (m, 2H). MS of C25H28C12N302 (El ), found 554.05 (MH+). Nl-azabicyclo[2·2·2]oct-3-yl-4-bromo-indole α-{[1-(2,4-diphenyl)cyclopropyl]-carbonyl b-phenylalanamine : NMR (400 MHz, CD3OD): 8.44 (s, 1H), 7.50-7.37 (m, 5H), 7.04-6.98 (m, 2H), 4.57 (dd, 1H), 4.13-3.98 (m, 1H), 3.63-3.58 (m, 1H), 3.30-3.02 (m, 5H), 2.98-2.80 (m, 3H), 2.00-1.85 (m, 3H), 1-75-1.50 (m, 3H), 1.20-1.00 (m, 2H). MS (El) for C26H28BrCl2N302, found 567.09 (MH+). N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Να-{[1-(2,4-diphenyl)-cyclopropyl]carbonyl }-L-Amphetamine amide: 4 NMR (400 MHz, CD3OD): 7.52-7.38 (m, 5H), 7.04-6.99 (m, 2H), 4.57 (dd, 1H), 4.07-3.96 (m, 1H) , 3.58-3.45 (m, 1H), 3.20-3.05 (m, 146258.doc -106- 201040149 3H), 2.96-2.80 (m, 3H), 1.95-1.80 (m, 3H), 1.65-1.50 (m, 4H), 1.19-1.02 (m, 2H). MS (El) for C26H28BrCl2N302, found 566.09 (MH+) ° 1-(2,4-diphenyl)-N-{(lS)-l-[( 2,4-diphenyl)methyl]_2-[(8aS)-hexahydroindolo[l,2-a]»ltazine-2(1H)-yl]-2-oxoethyl} Cyclopropanol: decylamine: 4 NMR (400 MHz, CD3OD): 7.57-7.38 (m, 4H), 7.28-7.10 (m, 2H), 5.20 (dd, 1H), 4.40 (dd, 1H), 4.01 (dd , 1H), 3.23-2.93 (m5 6H), 2.64-2.20 (m, 3H), 2.00-1.80 (m, 〇3H), 1.58-1.40 (m,3H), 1.15.10.00 (m, 2H)· C26H27C14N302 ^^8 kg 1), measured value 55 5.75 (1^11+). N-[(lS)-2-[(3R)-3-Aminopyrrolidin-1-yl]-2-oxo-l-{[4-(trifluoromethyl)phenyl]-methyl Ethyl]-1-(2,4-diphenyl)cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1H), 7.56 (m, 3H), 7.40 ( s, 2H), 7.30 (m, 2H), 6.80 (m, 1H), 4.69 (m, 1H), 3.20 (m, 2H), 2.91 (m, 4H), 1.86 (m, 1H), 1.60 (m , 1H), 1.32 (m, 3H), 0.94 (m, 2H) · MS (El) of C24H24Cl2F3N302, found 515 〇 (MH+). ]^_1-azabicyclo[2.2.2]oct-3-yl to 〇1-{[1-(2,4-diphenyl)cyclopropanyl]-carbonyl}-4-(trifluoromethyl) ))-L-Amphetamine amide: 4 NMR (4 〇 0 • MHz, DMSO-d6): δ 8.20 (s, 1H), 7.92 (m, 1H), 7.54 (m, 3H), 7.37 (s, 2H ), 7.23 (m, 2H), 6.49 (m, 1H), 4.51 (m, 1H), 2.99 (m, 1H), 2.86 (m, 2H), 2.59 (m5 4H), 2.25 (m, 1H), 1.63-1.13 (m, 8H), 0.93 (m, 2H). MS (El) for C27H28Cl2F3N3 〇2, 555 (MH+). 146258.doc -107- 201040149 Να-{[1-(2,4-Diphenyl)cyclopropyl]carbonyl}-N-(indolyl-3-ylmethyl)_4-(trifluoromethyl -L-Amphetamine: 4 NMR (400 MHz, DMSO-d6): δ 8.38 (d, 1H), 8.13 (s, 1H), 7.57 (m, 3H), 7.41 (s, 2H), 7.28 ( d, 2H), 6.70 (t, 1H), 4.48 (m, 1H), 3.12-2.83 (m, 8H), 2.64 (m, 1H), 2.24 (m, 1H), 1.81 (m, 1H), 1.37 (m, 3H), 0.94 (m, 2H). MS (El) of C25H26C12F3N302, found 529 (MH+).

N-[(3R)-1-氮雜雙環[2.2.2]辛-3-基]-Nα-{[l(2,4-二氣苯 基）-環丙基】羰基}-4-(三氟甲基）-L-苯丙胺醯胺：NMR (400 MHz, DMSO-d6): δ 7.94 (m, 1H)，7.54 (m，3H)，7.37 (s, 2H)} 7.23 (t, 2H)S 6.49 (m, 1H), 4.51 (m, 1H), 3.02 (m, 1H), 2.86 (m, 2H), 2.62 (m, 4H), 2.31 (m, 1H), 1.63-1.13 (m，8H)，0.93 (m, 2H). C27H28C12F3N302的MS (El)，實測值 555 (MH+) 〇 N-[(3R)-1-氮雜雙環[2.2.2】辛-3-基】-2,4-二氣-Na-{[1-(2,4-二氣苯基）環丙基]羰基卜l-苯丙胺醯胺：iNMROOO MHz, CD3OD) ： 7.47-7.39 (m, 4H), 7.25-7.15 (m, 2H), 4.60 (dd, 1H), 4.18-4.07 (m, 1H), 3.68-3.60 (m, 1H), 3.33-3.18 (m, 5H), 3.08-2.97 (m, 3H), 2.01-1.95 (m, 3H), 1.80-1.76 (m，1H), 1.60-1.45 (m, 2H)，1.20-1.00 (m, 2H). C26H27C14N302 的]^8(£1)，實測值 555.75 (1^^1+)。N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-Nα-{[l(2,4-diphenyl)-cyclopropyl]carbonyl}-4-( Trifluoromethyl)-L-phenylalanamine decylamine: NMR (400 MHz, DMSO-d6): δ 7.94 (m, 1H), 7.54 (m, 3H), 7.37 (s, 2H)} 7.23 (t, 2H) S 6.49 (m, 1H), 4.51 (m, 1H), 3.02 (m, 1H), 2.86 (m, 2H), 2.62 (m, 4H), 2.31 (m, 1H), 1.63-1.13 (m, 8H) ), 0.93 (m, 2H). MS (El) for C27H28C12F3N302, found 555 (MH+) 〇N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2,4 - di-gas-Na-{[1-(2,4-diphenyl)cyclopropyl]carbonyl b-phenylalanamine decylamine: iNMROOO MHz, CD3OD): 7.47-7.39 (m, 4H), 7.25-7.15 (m, 2H), 4.60 (dd, 1H), 4.18-4.07 (m, 1H), 3.68-3.60 (m, 1H), 3.33-3.18 (m, 5H), 3.08-2.97 (m, 3H), 2.01 -1.95 (m, 3H), 1.80-1.76 (m,1H), 1.60-1.45 (m, 2H), 1.20-1.00 (m, 2H). C26H27C14N302 of ^^8 (£1), found 555.75 (1 ^^1+).

Na-{【l-(2,4-二氣苯基）環丙基】羰基}-N-[2-(二甲基胺基）-乙基]-L-苯丙胺醢胺：4 NMR (400 MHz, DMSO-d6): δ 7.93 (t, 1H), 7.60 (d, 1H), 7.44-7.39 (m, 2H), 7.24-7.15 (m, 146258.doc -108- 201040149 3H), 7.06-7.04 (m, 2H), 6.51 (d, 1H), 4.47-4.42 (m, 1H), 3.23-3.12 (m, 2H), 2.92-2.88 (m, 1H), 2.83-2.78 (m, 1H), 2.44 (t, 2H), 2.29 (s, 6H), 1.42-1.36 (m, 2H), 1.01-0.93 (m, 211);(：231127(：12&gt;^02的1^3斤1)，實測值448.11 (]^11+)。 Να-{[1-(2,4-二氣苯基）環丙基】羰基}-N-【2-(二甲基胺基）-乙基】-N-甲基-L-苯丙胺醯胺：1HNMR(400 MHz，DMSO-d6): δ 7.63-7.61 (m, 1H), 7.42-7.41 (m, 2H), 7.26-7.16 (m, 3H), 7.10-7.07 (m, 2H), 6.85-6.68 (dd, 1H), 4.88-4.83 (m, 1H), 3.50-3.37 (m, 1H), 3.23-3.17 (m, 1H), 2.90 (s, 2H), 2.87-2.78 (m, 2H), 2.75 (s, 1H), 2.42-2.28 (m, 2H), 2.25 (s, 4H), 2.16 (s, 2H), 1.44-1.37 (m, 2H), 0.99-0.98 (m, 2H); C24H29C12N302的 MS (El)，實測值 462.22 (MH+)。 Να-{[1-(2,4-二氣苯基）環丙基】羰基卜N-[2-(甲基胺基）-乙 基】_4_(三氟甲基）-L-苯丙胺醢胺：4 NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1H), 8.19 (t, 1H), 7.56 (m, 3H), 7.40 (s, 2H), 7.28 (d, 2H), 6.67 (d, 1H), 4.49 (m, 1H), 3.18 (m, 2H), 2.98 (m, 1H), 2.87 (m, 1H), 2.64 (m, 2H), 2.35 (s, 3H), 1.34 (m, 2H)，0.93 (m，2H). C23H24C12F3N302的 MS (El)，實 測值 502.4 (MH+)。 Να-{[1-(2,4-二氣苯基）環丙基】羰基}-N-[2-(甲基胺基）-乙 基]-4-(三氟甲基）-L-苯丙胺醯胺：4 NMR (400 MHz， DMSO-d6): δ 8.25 (s, 1H), 7.96 (br s, 1H), 7.58 (s, 1H), 7.50 (s, 1H), 7.42 (s, 2H), 7.33 (d, 1H), 7.18 (d, 1H), 6.79 (d, 1H), 4.54 (m, 1H), 3.19 (m, 2H), 3.06 (m, 1H), 2.87 (m, 146258.doc -109- 201040149 1H), 2.65 (m, 2H), 2.35 (s, 3H), 1.37 (m, 2H), 0.94 (m, 2H). (：221123(：141^3〇2的]^即），實測值 503.25 (]^+)。 N-(2-胺基乙基）-2,4-二氣-Να-{[1-(2,4-二氣苯基）環丙 基]-羰基}-L-苯丙胺醢胺：4 NMR (400 MHz，DMSO-d6): δ 7.69 (m, 1H), 7.59 (m, 1H), 7.50 (m, 1H), 7.43 (m, 2H), 7.32 (m, 1H), 7.16 (d, 1H), 6.67 (m, 1H), 4.51 (m, 1H), 2.99 (m, 4H), 2.86 (m, 1H), 2.50 (m, 2H), 1.33 (m, 2H), 0.95(111,211);€21^21匸14&gt;^3〇2的]^8(£1)’實測值 489.68 (MH+)。 N-{(lS)-2-(3-胺基-8-氮雜雙環丨3.2.1]辛-8_基）_1_[(2,4_二 氣苯基）甲基】-2-氣代乙基}二氣苯基）環丙酿胺：1h NMR (400 MHz, CD3OD) · 7.50-7.39 (m, 4H), 7.28-7.12 (m, 2H), 4.80-4.60 (m&gt; 1H), 4.44-4.27 (m, 1H), 3.25-3.08 (m, 1H), 3.02-2.95 (m? 2H), 2.63-2.58 (m, 1H), 2.23-2.00 (m, 1H), 1.83-1.72 (m，3H), 1.62-1.40 (m，4H)，1.20-1.00 〇11，2印.0261127(：14沁〇2的1^即）’實測值 555.94 (]^11+)。 4-漠-Να-{[1-(2,4-二氣苯基）環丙基]幾·基卜N-(2 -甲基-1-氮雜雙環【2.2.2]辛-3_基）_1&quot;*-苯丙胺酿胺· NMR (400 MHz, CD3OD) ： 8.57 (s, 1H), 7.50-7.38 (m, 5H), 7.06-7.00 (m, 2H), 4.62-4.55 (ηι, 1H), 3.60 (dd, 1H), 3.22-2.97 (m, 7H), 2.93-2.80 (n1? 2H), 2.00-1.78 (m, 2H), 1.63-1.46 (m, 3H) 1 3〇 (dd，3H)，1 ·2〇_ 1 ·〇〇 (m，2H). C2 7H3〇BrCl2N3〇2的 MS (El)，實測值 580.07 (MH+)。 2，4-二氯-Να-{[1-(2，心二氣苯基）環丙基】叛基}_N-(8-甲 146258.doc -110- 201040149Na-{[l-(2,4-diphenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)-ethyl]-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 7.93 (t, 1H), 7.60 (d, 1H), 7.44-7.39 (m, 2H), 7.24-7.15 (m, 146258.doc -108- 201040149 3H), 7.06-7.04 (m, 2H), 6.51 (d, 1H), 4.47-4.42 (m, 1H), 3.23-3.12 (m, 2H), 2.92-2.88 (m, 1H), 2.83-2.78 (m, 1H), 2.44 (t, 2H), 2.29 (s, 6H), 1.42-1.36 (m, 2H), 1.01-0.93 (m, 211); (: 231127 (:12&gt;^02 of 1^3 kg 1), measured value 448.11 (]^11+). Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)-ethyl]-N- Methyl-L-phenylalanamine decylamine: 1H NMR (400 MHz, DMSO-d6): δ 7.63-7.61 (m, 1H), 7.42-7.41 (m, 2H), 7.26-7.16 (m, 3H), 7.10-7.07 (m, 2H), 6.85-6.68 (dd, 1H), 4.88-4.83 (m, 1H), 3.50-3.37 (m, 1H), 3.23-3.17 (m, 1H), 2.90 (s, 2H), 2.87 -2.78 (m, 2H), 2.75 (s, 1H), 2.42-2.28 (m, 2H), 2.25 (s, 4H), 2.16 (s, 2H), 1.44-1.37 (m, 2H), 0.99-0.98 (m, 2H); MS (El) for C24H29C12N302, found 462.22 (MH+). Να-{[1-(2,4-diphenylphenyl)cyclopropyl]carbonyl-N-[2- (Methylamino)-ethyl]_4_(trifluoromethyl)-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1H), 8.19 (t, 1H), 7.56 (m, 3H), 7.40 (s, 2H), 7.28 (d, 2H), 6.67 (d, 1H), 4.49 (m, 1H), 3.18 (m, 2H), 2.98 (m, 1H), 2.87 (m, 1H), 2.64 (m, 2H), 2.35 (s, 3H), 1.34 (m, 2H), 0.93 (m, 2H). MS (El) of C23H24C12F3N302, found 502.4 (MH+). Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-[2-(methylamino)-ethyl]-4-(trifluoromethyl)-L- Amphetamine: 4 NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.96 (br s, 1H), 7.58 (s, 1H), 7.50 (s, 1H), 7.42 (s, 2H) ), 7.33 (d, 1H), 7.18 (d, 1H), 6.79 (d, 1H), 4.54 (m, 1H), 3.19 (m, 2H), 3.06 (m, 1H), 2.87 (m, 146258. Doc -109- 201040149 1H), 2.65 (m, 2H), 2.35 (s, 3H), 1.37 (m, 2H), 0.94 (m, 2H). (:221123(:141^3〇2)^ ), found 503.25 (]^+). N-(2-Aminoethyl)-2,4-dioxa-Να-{[1-(2,4-diphenyl)cyclopropyl]- Carbonyl}-L-amphetamine: 4 NMR (400 MHz, DMSO-d6): δ 7.69 (m, 1H), 7.59 (m, 1H), 7.50 (m, 1H), 7.43 (m, 2H), 7.32 (m, 1H), 7.16 (d, 1H), 6.67 (m, 1H), 4.51 (m, 1H), 2.99 (m, 4H), 2.86 (m, 1H), 2.50 (m, 2H), 1.33 ( m, 2H), 0.95 (111,211); €21^21匸14&gt;^3〇2]^8(£1)' measured value 489.68 (MH+). N-{(lS)-2-(3-amine Alkyl-8-azabicycloindole 3.2.1]oct-8-yl)_1_[(2,4-diphenyl)methyl]-2-epoxyethyl}diphenyl)cyclopropanol :1h NMR (400 MHz, CD3OD ) 7.50-7.39 (m, 4H), 7.28-7.12 (m, 2H), 4.80-4.60 (m&gt; 1H), 4.44-4.27 (m, 1H), 3.25-3.08 (m, 1H), 3.02-2.95 (m? 2H), 2.63-2.58 (m, 1H), 2.23-2.00 (m, 1H), 1.83-1.72 (m, 3H), 1.62-1.40 (m, 4H), 1.20-1.00 〇11, 2 .0261127(:1^ of 14沁〇2)' measured value 555.94 (]^11+). 4-Mo-Να-{[1-(2,4-di-phenylphenyl)cyclopropyl]heptyl N-(2-methyl-1-azabicyclo[2.2.2]oct-3_ Base)_1&quot;*-Amphetamine-amine NMR (400 MHz, CD3OD): 8.57 (s, 1H), 7.50-7.38 (m, 5H), 7.06-7.00 (m, 2H), 4.62-4.55 (ηι, 1H ), 3.60 (dd, 1H), 3.22-2.97 (m, 7H), 2.93-2.80 (n1? 2H), 2.00-1.78 (m, 2H), 1.63-1.46 (m, 3H) 1 3〇 (dd, MS (El), found 580.07 (MH+). 2,4-Dichloro-Να-{[1-(2, bisphenol phenyl)cyclopropyl] 叛基}_N-(8-甲 146258.doc -110- 201040149

基-8-氮雜雙環[3.2.1】辛-3_基）-L-苯丙胺醯胺：1HNMR (400 MHz, CD3OD) ： 7.45-7.38 (m, 4H), 7.24 (d, 1H), 7.18 (d, 1H), 4.63-4.60 (m, 1H), 3.85-3.82 (t, 1H), 3.68-3.59 (m, 1H), 3.19-2.99 (m, 2H), 2.63 (s, 3H), 2.30-2.10 (m, 6H), 2.05- 1.88 (m, 3H), 1.61-1.45 (m, 2H), 1.20-1.13 (m, 1H), 1.05- 1.00 (m，1H). C27H29C14N302 的 MS (El)，實測值 572.13 (MH+)〇 1^_1-氮雜雙環[2.2.2】辛-3-基-2,4-二氣-]\〇1-{[1-(2,4-二氣 苯基）-環丙基]羰基}-N-甲基-L-苯丙胺醯胺：/H NMR (400 MHz, CD3OD) ： 8.41 (s, 1H), 7.52-7.37 (m, 4H), 7.29-7.18 (m, 1H), 5.20-4.07 (m, 1H), 4.40-4.30 (m, 1H), 3.73-3.60 (m, 2H), 3.50-3.40 (m, 2H), 3.28-2.85 (m, 6H), 2.43-2.25 (m, 1H), 2.18-1.80 (m, 5H), 1.55-1.40 (m, 2H), 1.10-1.05 (m，2H). C27H29C14N302 的 MS (El)，實測值 570.18 (MH+)。 Να-{[1-(2,4-二氣苯基）環丙基】羰基}-N-[2-(二甲基胺基）-乙基】-β-曱基苯丙胺醯胺·· NMR (400 MHz, DMSO-d6): δ 8.10-8.07 (m, 1Η), 7.60 (m, 1H), 7.39-7.29 (m, 2H), 7.22-7.19 (m, 3H), 6.97-6.95 (m, 2H), 6.67 (s, 1H), 3.48 (d, 1H), 3.20-3.03 (m, 2H), 2.98 (d, 1H), 2.35-2.24 (m, 2H), 1.55-1.44 (m, 2H), 1.51 (s, 3H), 1.08 (m, 1H), 0.90 (m, 1H); 匸241129。12&gt;1302的1^8(£1)，實測值462.22(]^11+)。 N-l-氮雜雙環[2.2.2]辛·3·基-Να-{[1-(2,4-二氣苯基）環丙 基】-羰基}-2,4·二（三氟甲基）-L-苯丙胺醢胺：NMR (400 MHz, DMSO-d6): δ 8.20 (s, 1Η), 7.99 (t, 1H), 7.88 (s, 1H), 146258.doc -Ill - 201040149 7.73 (m, 1H), 7.54 (m, 2H), 7.41 (s, 2H), 6.63 (t, 1H), 4.58 (m, 1H), 3.08 (m, 2H), 2.91 (m, 1H), 2.66 (m, 4H), 2.28 (m, 1H), 1.55 (m, 4H), 1.31 (m, 2H), 1.14 (m, 2H), 0.91 (m, 2H). C28H27C12F6N302 的 MS (El)，實測值 623 (MH+)。 N-[(3R)-1-氮雜雙環[2.2.2]辛-3-基]-Να-{[1-(2,4-二氣苯 基）-環丙基]羰基}_L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.04-7.97 (m, 1H), 7.63-7.62 (m, 1H), 7.43-7.42 (m, 2H), 7.27-7.16 (m, 3H), 7.10-7.03 (m, 2H), 6.47- 6.41 (m, 1H), 4.55-4.48 (m, 1H), 3.72-3.63 (m, 1H), 3.38- 3.31 (m, 1H), 3.14-3.05 (m, 1H), 2.90-2.64 (m, 6H), 2.46- 2.29 (m, 1H), 1.73-1.51 (m, 3H), 1.41-1.39 (m, 2H), 1.36- 1.28 (m, 1H), 1.00-0.98 (m, 2H); C26H29C12N302 的 MS (El)，實測值486.22 (MH+)。 (PS)-N-[(3R)-1-氮雜雙環[2.2.2]辛-3-基】-Να-{[1-(2,4-二 氣苯基）-環丙基]羰基}-Ρ-曱基-L-苯丙胺醯胺：1H NMR (400 MHz, CDC13)： δ 7.36-7.35 (m, 1Η), 7.28-7.25 (m, 1H), 7.23-7.18 (m, 4H), 6.93-6.91 (m, 2H), 6.50-6.49 (m, 1H), 5.48-5.46 (m, 1H), 4.38-4.35 (m, 1H), 4.00-4.01 (m, 1H), 3.44-3.32 (m, 2H), 2.95-2.86 (m, 4H), 2.52-2.48 (m, 1H), 1.98-1.97 (m, 1H), 1.78-1.68 (m, 3H), 1.63-1.57 (m, 3H), 1.23 (d, 3H), 1.09-0.99 (m，2H); C27H31C12N302 的 MS (El)，實測值500.14 (MH+)。 N-[(3S)-1-氮雜雙環丨2.2.2]辛-3-基]-Να-{[1-(2,4-二氣苯 基）-環丙基]羰基}-L-苯丙胺醯胺：4 NMR (400 MHz, 146258.doc -112- 201040149 DMSO-d6): δ 8.01-7.94 (m, 1H), 7.64-7.62 (m, 1H), 7.46-7.41 (m, 2H), 7.25-7.16 (m, 3H), 7.08-7.02 (m, 2H), 6.46-6.40 (m, 1H), 4.51 (q, 1H), 3.71-3.61 (m, 1H), 3.11-3.03 ， (m, 1H), 2.84-2.79 (m, 2H), 2.78-2.66 (m, 4H), 2.48-2.27 ： (m, 1H), 1.71-1.49 (m, 4H), 1.41-1.39 (m, 2H), 1.36-1.25 . (m, 1H)，1.02-0.98 (m，2H); C26H29C12N302的 MS (El)，實 測值 486.09 (MH+)。 N-l-氮雜雙環[2.2.2]辛-3-基-、(*-{[1-(2,4-二氣苯基）環丙 〇 基】-羰基}-N-甲基-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 7.63 (s, 1H), 7.43 (s, 2H), 7.26-7.18 (m, 3H), 7.11-7.09 (m, 2H), 6.78 (d, 1H), 4.91-4.85 (m, 1H), 4.35-4.24 (m, 1H), 3.39-3.35 (m, 2H), 3.26-3.15 (m, 2H), 3.09 (m, 3H), 2.94-2.84 (m, 5H), 2.07-1.94 (m, 1H), 1.83-1.64 (m, 3H)，1.41-1.39 (m，2H), 1.00 (s, 2H); C27H31C12N302的 ]^8斤1)，實測值500.26 (]\411+)。 N-l-氮雜雙環[2.2.2】辛-3-基-Να-({1-[4-(甲氧基）苯基]環 ❹ 丙基}-羰基）-4-(三氟曱基）-L-苯丙胺醯胺·· 4 NMR (400 MHz, DMSO-d6): δ 8.29-8.24 (m, 1H), 7.63-7.60 (m, 2H), _ 7.26-7.18 (m, 4H), 6.89-6.86 (m, 2H), 6.28-6.23 (m, 1H), - 4.58 (q, 1H), 3.75 (s, 4H), 3.15 (t, 1H), 2.99-2.88 (m, 2H), 2.85-2.70 (m, 4H), 2.55-2.40 (m, 1H), 1.75-1.49 (m, 4H), 1.41-1.28 (m, 1H), 1.25-1.23 (m, 2H), 0.95-0.86 (m, 2H); (：281132?3^[302的]^8(£1)，實測值516.26(]^^1+)。 N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1】辛-8-基）-1-[(4-溴苯 146258.doc -113- 201040149-8-Azabicyclo[3.2.1]oct-3-yl)-L-phenylalanamine decylamine: 1H NMR (400 MHz, CD3OD): 7.45-7.38 (m, 4H), 7.24 (d, 1H), 7.18 (d, 1H), 4.63-4.60 (m, 1H), 3.85-3.82 (t, 1H), 3.68-3.59 (m, 1H), 3.19-2.99 (m, 2H), 2.63 (s, 3H), 2.30 -2.10 (m, 6H), 2.05- 1.88 (m, 3H), 1.61-1.45 (m, 2H), 1.20-1.13 (m, 1H), 1.05- 1.00 (m,1H). MS (El) of C27H29C14N302 , 552.13 (MH+) 〇1^_1-azabicyclo[2.2.2]oct-3-yl-2,4-diqi-]\〇1-{[1-(2,4-dibenzene ))-cyclopropyl]carbonyl}-N-methyl-L-phenylalanamine decylamine: /H NMR (400 MHz, CD3OD): 8.41 (s, 1H), 7.52-7.37 (m, 4H), 7.29-7.18 (m, 1H), 5.20-4.07 (m, 1H), 4.40-4.30 (m, 1H), 3.73-3.60 (m, 2H), 3.50-3.40 (m, 2H), 3.28-2.85 (m, 6H) , 2.43-2.25 (m, 1H), 2.18-1.80 (m, 5H), 1.55-1.40 (m, 2H), 1.10-1.05 (m, 2H). MS (El) for C27H29C14N302, found 570.18 (MH+) . Να-{[1-(2,4-Diphenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)-ethyl]-β-mercaptophenylamine decylamine·· NMR (400 MHz, DMSO-d6): δ 8.10-8.07 (m, 1Η), 7.60 (m, 1H), 7.39-7.29 (m, 2H), 7.22-7.19 (m, 3H), 6.97-6.95 (m, 2H), 6.67 (s, 1H), 3.48 (d, 1H), 3.20-3.03 (m, 2H), 2.98 (d, 1H), 2.35-2.24 (m, 2H), 1.55-1.44 (m, 2H) , 1.51 (s, 3H), 1.08 (m, 1H), 0.90 (m, 1H); 匸 241129.12 &gt; 1302 of 1^8 (£1), measured value 462.22 (]^11+). Nl-azabicyclo[2.2.2]octyl-3-yl-Να-{[1-(2,4-diphenylphenyl)cyclopropyl]-carbonyl}-2,4·bis(trifluoromethyl) -L-Amphetamine amide: NMR (400 MHz, DMSO-d6): δ 8.20 (s, 1 Η), 7.99 (t, 1H), 7.88 (s, 1H), 146258.doc -Ill - 201040149 7.73 (m , 1H), 7.54 (m, 2H), 7.41 (s, 2H), 6.63 (t, 1H), 4.58 (m, 1H), 3.08 (m, 2H), 2.91 (m, 1H), 2.66 (m, 4H), 2.28 (m, 1H), 1.55 (m, 4H), 1.31 (m, 2H), 1.14 (m, 2H), 0.91 (m, 2H). MS (El) for C28H27C12F6N302, found 623 (MH+ ). N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-Να-{[1-(2,4-diphenyl)-cyclopropyl]carbonyl}_L-amphetamine Indoleamine: 4 NMR (400 MHz, DMSO-d6): δ 8.04-7.97 (m, 1H), 7.63-7.62 (m, 1H), 7.43-7.42 (m, 2H), 7.27-7.16 (m, 3H) , 7.10-7.03 (m, 2H), 6.47- 6.41 (m, 1H), 4.55-4.48 (m, 1H), 3.72-3.63 (m, 1H), 3.38- 3.31 (m, 1H), 3.14-3.05 ( m, 1H), 2.90-2.64 (m, 6H), 2.46- 2.29 (m, 1H), 1.73-1.51 (m, 3H), 1.41-1.39 (m, 2H), 1.36- 1.28 (m, 1H), 1.00-0.98 (m, 2H); MS (El) for C26H29C12N302, found 486.22 (MH+). (PS)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-Να-{[1-(2,4-diphenyl)-cyclopropyl]carbonyl }-Ρ-mercapto-L-amphetamine amide: 1H NMR (400 MHz, CDC13): δ 7.36-7.35 (m, 1 Η), 7.28-7.25 (m, 1H), 7.23-7.18 (m, 4H), 6.93-6.91 (m, 2H), 6.50-6.49 (m, 1H), 5.48-5.46 (m, 1H), 4.38-4.35 (m, 1H), 4.00-4.01 (m, 1H), 3.44-3.32 (m , 2H), 2.95-2.86 (m, 4H), 2.52-2.48 (m, 1H), 1.98-1.97 (m, 1H), 1.78-1.68 (m, 3H), 1.63-1.57 (m, 3H), 1.23 (d, 3H), 1.09-0.99 (m, 2H); MS (El) for C27H31C12N302, found 500.14 (MH+). N-[(3S)-1-azabicycloindole 2.2.2]oct-3-yl]-Να-{[1-(2,4-diphenylphenyl)-cyclopropyl]carbonyl}-L- Amphetamine: 4 NMR (400 MHz, 146258.doc -112-201040149 DMSO-d6): δ 8.01-7.94 (m, 1H), 7.64-7.62 (m, 1H), 7.46-7.41 (m, 2H), 7.25-7.16 (m, 3H), 7.08-7.02 (m, 2H), 6.46-6.40 (m, 1H), 4.51 (q, 1H), 3.71-3.61 (m, 1H), 3.11-3.03, (m, (1), 2.84-2. - 1.25 . (m, 1H), 1.02-0.98 (m, 2H); MS (El) of C26H29C12N302, found 486.09 (MH+). Nl-azabicyclo[2.2.2]oct-3-yl-, (*-{[1-(2,4-diphenyl)cyclopropenyl]-carbonyl}-N-methyl-L- Amphetamine: 4 NMR (400 MHz, DMSO-d6): δ 7.63 (s, 1H), 7.43 (s, 2H), 7.26-7.18 (m, 3H), 7.11-7.09 (m, 2H), 6.78 ( d, 1H), 4.91-4.85 (m, 1H), 4.35-4.24 (m, 1H), 3.39-3.35 (m, 2H), 3.26-3.15 (m, 2H), 3.09 (m, 3H), 2.94- 2.84 (m, 5H), 2.07-1.94 (m, 1H), 1.83-1.64 (m, 3H), 1.41-1.39 (m, 2H), 1.00 (s, 2H); C27H31C12N302]^8 kg 1), The measured value is 500.26 (]\411+). Nl-azabicyclo[2.2.2]oct-3-yl-Να-({1-[4-(methoxy)phenyl]cyclodecylpropyl}-carbonyl)-4-(trifluoromethyl) -L-Amphetamine 醯amine·· 4 NMR (400 MHz, DMSO-d6): δ 8.29-8.24 (m, 1H), 7.63-7.60 (m, 2H), _ 7.26-7.18 (m, 4H), 6.89- 6.86 (m, 2H), 6.28-6.23 (m, 1H), - 4.58 (q, 1H), 3.75 (s, 4H), 3.15 (t, 1H), 2.99-2.88 (m, 2H), 2.85-2.70 (m, 4H), 2.55-2.40 (m, 1H), 1.75-1.49 (m, 4H), 1.41-1.28 (m, 1H), 1.25-1.23 (m, 2H), 0.95-0.86 (m, 2H) ; (:281132?3^[302]^8(£1), found 516.26(]^^1+). N-{(lS)-2-(3-Amino-8-azabicyclo[ 3.2.1] oct-8-yl)-1-[(4-bromobenzene 146258.doc -113- 201040149

基）曱基]_2_氧代乙基}-l-(2,4-二氯苯基）環丙醯胺：iH NMR (400 MHz, CD3OD) ： 8.57 (s, 1H), 7.50-7.38 (m, 3H), 7.15-7.00 (m, 3H), 4.84-4.80 (m, 1H), 3.63-3.43 (m, 2H), 4.18 (t, 1H), 3.23-3.18 (m, 1H), 3.19-2.99 (m, 2H), 2.83- 2.78 (m, 3H), 2.58-2.50 (m, 1H), 2.39-2.30 (m, 1H), 2.16- 2.03 (m, 1H), 1.98-1.80 (m, 1H), 1.60-1.40 (m, 5H), 1.20- 1.05 (m, 2H). C26H28BrCl2N302 的 MS (El)，實測值 565-03 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-Να-{[1-(2,4-二氣苯 基）-環丙基]羰基}-2,4-二（三氟甲基）-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6)： δ 8.20 (s, 1H), 8.00 (d, 1H), 7.87 (s, 1H), 7.68 (m, 1H), 7.54 (m, 2H), 7.41 (s, 2H), 6.63 (t, 1H), 4.58 (m, 1H), 3.12 (m, 2H), 2.93 (m, 3H), 2.61 (m, 4H), 2.24 (m, 1H), 1.64 (m, 1H), 1.50 (m, 3H), 1.27 (m, 2H), 1.12 (m, 1H), 0.91 (m, 2H)· C28H27C12F6N302 的 MS (El)，實測值 623 (MH+)。 ]\-[(38)-1-氮雜雙環[2.2.2]辛-3-基]-4-氣-、〇1-{[1-(2,4-二 氣苯基）-環丙基]羰基}-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1Η), 8.01 (d, 1H), 7.62 (s, 1H), 7.43 (s, 2H), 7.27 (d, 2H), 7.05 (d, 2H), 6.47 (d, 1H), 4.49 (m, 1H), 3.08 (m, 1H), 2.81 (m, 2H), 2.72 (m, 4H), 2.42 (m, 2H), 1.57 (m, 2H), 1.48 (m, 2H), 1.38 (m, 2H), 1.26 (m, 1H)，0.98 (m，2H). C26H28C13N302 的 MS (El)，實測值 521 (MH+)。 146258.doc -114- 201040149 N-[(1S)-1-{[(3S)-1-氮雜雙環[2.2.2】辛-3-基胺基】羰基}-3-苯基丙基】-1-(2,4-二氣苯基）環丙醯胺：4 NMR (400 MHz, CD3OD) ： 7.59 (s, 1H), 7.50 (d, 1H), 7.40 (d, 1H), 7.26-7.10 (m, 5H), 4.40 (dd, 1H), 4.02-3.98 (m, 1H), 3.55- 3.44 (m, 1H), 3.20-3.03 (m, 3H), 2.80-2.75 (m, 1H), 2.60- 2.45 (m, 2H), 2.05-1.93 (m, 7H), 1.78-1.58 (m, 3H), 1.22-1.09 (m, 2H). C27H31C12N302 的 MS (El)，實測值 589.07 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基】_4-氣-Να-{[1-(2,4-二 氣苯基）-環丙基]羰基}-2-(三氟甲基）-L-苯丙胺醯胺：咕 NMR (400 MHz, CD3OD) ： 7.70-7.58 (m, 2H), 7.43-7.38 (m, 4H), 4.65-4.60 (m, 1H), 4.09-3.99 (m, 1H), 3.59-3.48 (m, 1H), 3.20-3.05 (m, 5H), 3.02-2.95 (m, 1H), 2.78-2.73 (m, 1H), 2.10-2.04 (m, 1H), 1.99-1.83 (m, 3H), 1.80-1.68 (m, 1H), 1.57-1.44 (m, 2H), 1.17-1.10 (m, 1H), 1.05-0.98 (m，1H). C27H31C12N302的 MS (El)，實測值 500.20 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基】-Να-{[1-(2,4-二氯苯 基）-環丙基]羰基}-1-(苯基甲基）-L-組胺醯胺：4 NMR (400 MHz, CD3OD) ： 8.35 (s, 1H), 7.72 (s, 1H), 7.43-7.22 (m, 9H), 6.80 (s, 1H), 5.18 (s, 2H), 4.44 (t, 1H), 4.09-4.03 (m, 1H), 3.60 (t, 1H), 3.30-3.20 (m, 3H), 3.02-2.80 (m, 3H), 2.15-1.80 (m, 4H), 1.60-1.50 (m, 2H), 1.13-0.97 (m, 3H)_ C30H33Cl2N5O2 的 MS (El)，實測值566.21 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-N~2—{[1-(2,4-二氣 146258.doc -115- 201040149 苯基）環丙基】-羰基}-3-(2,2-二氟-1，3-苯並二噁唑-5-基）-L- 丙胺醢胺：4 NMR (400 MHz, CD3OD) : 8.45 (s，1H), 7.45-7.37 (m, 3H), 7.09 (d, 1H), 6.96 (s, 1H), 6.88 (d, 1H), 4.57 (dd, 1H), 4.09-4.03 (m, 1H), 3.65-3.60 (m, 1H), 3.32-3.13 (m, 4H), 3.03-2.80 (m, 3H), 2.17-2.15 (m, 1H), 2.02-1.95 (m, 3H), 1.90-1.77 (m, 1H), 1.62-1.47 (m, 2H), 1.20-1-02 (m，2H). C27H27C12F2N302 的 MS (El)，實測值 567.15 (MH+)。 4-溴-Να-{[1-(2,4-二氣苯基）環丙基]羰基卜N-[3-(lH-咪 唑-1-基）丙基】-L-苯丙胺醯胺：NMR (400 MHz, CD3OD) ： 8.84 (s, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.44-7.38 (m, 5H), 7.00 (d, 2H), 4.40 (dd, 1H), 4.19 (t, 2H), 3.22-3.05 (m, 2H), 3.00-2.95 (m, 1H), 2.81-2.77 (dd, 1H), 2.05-1.98 (m, 2H), 1.65-1.60 (m, 1H), 1.57-1.44 (m, 1H), 1.22-1.17 (m，1H)，1.05-0.98 (m，1H). C25H25BrCl2N402 的 MS (El)， 實測值 566.08 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-Να-{[1-(2,4-二氣苯 基）-環丙基】羰基}-2-氟-4-(三氟甲基）-L-苯丙胺醯胺：1Η NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1Η), 8.06 (d, 1H), 7.62 (m, 1H), 7.58 (d, 1H), 7.49 (t, 1H), 7.44 (s, 2H), 7.35 (m, 1H), 6.53 (m, 1H), 4.58 (m, 1H), 3.13 (m, 1H), 2.93 (m, 2H), 2.75 (m, 4H), 2.37 (m, 1H), 1.65 (m, 4H), 1.42 (m, 2H)，1_29 (m，2H), 0_99 (m，2H). C27H27C12F4N302 的 MS (El) ’ 實測值 573 (mh+)。 146258.doc 116- 201040149 4-溴-Να-{[1-(2,4-二氣苯基）環丙基]羰基卜N_ [(1S，3S，4S)-1-環氧-1-氣雜雙環【2.2.2]辛-3-基]-L-苯丙胺酿 胺：N_[(3S)-l-氮雜雙環[2.2.2]辛3-基]-4-溴-Nα-{[l-(2,4-二氣苯基）環丙基]-羰基}-L-苯丙胺酿胺（5〇 mg，0.088 mmol)溶於 CH2C12(0.9 mL)中。向溶液加入mcpBA(65.4 mg，0.265 mmol)。將反應混合物於室溫攪拌3〇分鐘。真 空除去溶劑。將殘留物溶於MeOH並使用製備級 HPLC (30-45% MeCN溶於具有0.1%曱酸的水）純化。將純化的材 料凍乾以產生為白色粉末的23 mg(45%)的所期望的產物。 !H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1Η), 7.48-7.37 (m, 5H), 7.02 (m, 2H), 6.33 (m, 1H), 4.52 (m, 1H), 4.17 (m, 1H), 3.72 (m, 1H), 4.51 (m, 1H), 3.38 (m, 4H), 2.88 (m, 3H)，2.01 (m, 5H)，1.55 (m，2H)，1.09 (m, 2H); C26H28BrCl2N303 的 MS (El)，實測值 489.68 (MH+)。 ]&gt;^[(38)-1_氮雜雙環[2.2.2】辛-3-基】-4-氣-Na-{【l-(2,4-二 氣苯基）-環丙基]羰基卜2-氟苯丙胺醯胺：4 NMR (400 MHz，DMSO-d6): δ 8.18 (s, 1H)，7.60 (m，2H)，7.37 (m， 5H), 6.97 (m, 1H), 4.87 (m, 1H), 3.04-3.87 (m, 4H), 2.90 (m, 2H), 2.68 (m, 2H), 2.11 (s, 3H), 1.79 (m, 2H), 1.17-1.48 (m, 4H)，0.93 (m，2H). C27H28Cl2F3N3〇2的MS (El)，實測值 554.35 (MH+)。 1-(2,4-二氯苯基）-N-[(lS)-2-(6•甲基-2,6-二氮雜螺[3.3] 庚-2-基）_2_氧代-l-{[4-(三氟甲基）苯基I甲基}乙基]環丙醢 胺：NMR (400 MHz, DMSO-d6): δ 8.19 (s，1H)，7.58 146258.doc -117- 201040149 (m, 3H), 7.56 (s, 2H), 7.31 (d, 2H), 6.90 (d, 1H), 4.44 (m, 1H), 4.14 (m, 1H), 3.85 (m, 3H), 3.27 (m, 4H), 2.85 (m, 2H), 2.27 (s, 3H)，1.35 (m, 2H), 0.93 (m，2H). C26H26C12F3N302的 厘8卩1)，實測值 540.38 (1^11+)。 N-[(3S)-1-氮雜雙環[2·2·2】辛-3-基]-Να-({1-[4-(甲氧基） 苯基]-環丙基}羰基）-4-(三氟甲基）-L-苯丙胺醯胺：iH NMR (400 MHz, DMSO-d6)： δ 8.29-8.24 (m, 1Η), 7.63-7.60 (m, 2H), 7.26-7.24 (m, 2H), 7.21-7.18 (m, 2H), 6.89-6.86 (m, 2H), 6.28-6.23 (m, 1H), 4.61-4.56 (m, 1H), 3.75 (s, 3H), 3.72-3.65 (m, 1H), 3.18-3.13 (m, 1H), 2.99-2.89 (m, 2H), 2.85-2.79 (m, 4H), 2.54-2.42 (m, 1H), 1.75-1.45 (m, 4H), 1.40-1.28 (m, 1H), 1.25-1.20 (m, 2H), 0.95-0.86 (m, 2H); C28H32F3N303 的 MS (El)，實測值 516.26 (MH+)。 1\-[(31〇-1-氮雜雙環[2.2.2]辛-3-基]-1\〇1-({1-[4-(甲氧基） 苯基]-環丙基}羰基）-4-(三氟甲基）-L-苯丙胺醯胺：4 NMR (400 MHz，DMSO-d6): δ 8.29-8.27 (m, 1H), 7.63-7.60 (m, 2H), 7.27-7.24 (m, 2H), 7.21-7.18 (m, 2H), 6.89-6.86 (m, 2H), 6.28-6.23 (m, 1H), 4.62-4.56 (m, 1H), 3.75 (s, 3H), 3.68 (m, 1H), 3.19-3.13 (m, 1H), 2.99-2.86 (m, 2H), 2.81-2.69 (m, 4H), 2.55-2.41 (m, 1H), 1.75-1.31 (m, 5H), 1.28-1.20 (m，2H)，0.95-0.86 (m，2H); C28H32F3N303 的 MS (El)，實測值516.26 (MH+)。 N-[(3R)-1-氮雜雙環[2.2.2】辛-3-基]-4-溴-Να-({1-[4-(甲 氧基）苯基]-環丙基}羰基）-L-苯丙胺醯胺：4 NMR (400 146258.doc -118· 201040149 MHz, DMSO-d6): δ 8.26 (d, 1H), 7.45-7.41 (m, 2H), 7.22- 7.19 (m, 2H), 6.99-6.95 (m, 2H), 6.91-6.89 (m, 2H), 6.26- 6.21 (m, 1H), 4.55-4.50 (m, 1H), 3.76 (s, 3H), 3.73-3.71 (m, 1H), 3.16-3.10 (m, 1H), 2.86-2.67 (m, 6H), 2.54-2.38 (m, 1H), 1.74-1.33 (m, 5H), 1.30-1.21 (m, 2H), 0.96-0.87 (m, 2H); C27H32BrN303 的MS (El)，實測值 528.17 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-4-溴-Να-({1-[4-(甲 氧基）苯基】-環丙基}羰基）-L-苯丙胺醯胺1H NMR (400 MHz, DMSO-d6): δ 8.21 (d, 1Η), 7.45-7.41 (m, 2H), 7.22- 7.20 (m, 2H), 6.99-6.94 (m, 2H), 6.91-6.89 (m, 2H), 6.25- 6.20 (m, 1H), 4.55-4.50 (m, 1H), 3.76 (s, 3H), 3.72-3.62 (m, 1H), 3.14-3.08 (m, 1H), 2.84-2.67 (m, 6H), 2.52-2.50 (m, 1H), 1.72-1.51 (m, 4H), 1.34-1.28 (m, 1H), 1.27-1.21 (m，2H)，0.96-0.87 (m，2H); C27H32BrN303 的 MS (El)，實測 值 528.17 (MH+)。 4-溴-Να-{[1-(2,4-二氣苯基）環丙基]羰基卜N-&quot;比啶-4-基- L-苯丙胺醯胺· 4 NMR (400 MHz, CD3OD) : 8.42 (s，1Η), 7.70 (s, 2H), 7.50-7.38 (m, 6H), 6.98 (d, 2H), 4.63 (dd, 1H), 3.09 (dd, 1H), 2.90 (dd, 1H), 1.63-1.50 (m, 2H), 1.06-1.00 (m，1H). C24H20BrCl2N3O2 的 MS (El)，實測值 533.83 (MH+)。 N-[(3S)-1-氮雜雙環【2.2.2】辛-3_基】-4-苯基-Να_({1-(2,4-二氣苯基）-環丙基】羰基）-L-苯丙胺醯胺：4 NMR (400 MHz, CD3OD) ： 7.63-7.30 (m, 10H), 7.20-7.15 (m, 2H), 146258.doc -119- 201040149 4.60 (t, 1H), 3.88-3.82 (m, 1H), 3.02-2.78 (m, 7H), 2.47- 2.40 (m, 1H), 1.97-1.93 (m, 1H), 1.82-1.68 (m, 3H), 1.64-曱 曱 ] ] ] ] ] ] ] ] ] ] ] : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : m, 3H), 7.15-7.00 (m, 3H), 4.84-4.80 (m, 1H), 3.63-3.43 (m, 2H), 4.18 (t, 1H), 3.23-3.18 (m, 1H), 3.19- 2.99 (m, 2H), 2.83- 2.78 (m, 3H), 2.58-2.50 (m, 1H), 2.39-2.30 (m, 1H), 2.16- 2.03 (m, 1H), 1.98-1.80 (m, 1H) ), 1.60-1.40 (m, 5H), 1.20-1.05 (m, 2H). MS (El) of C26H28BrCl2N302, found 565-03 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-Να-{[1-(2,4-diphenyl)-cyclopropyl]carbonyl}-2, 4- bis(trifluoromethyl)-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.20 (s, 1H), 8.00 (d, 1H), 7.87 (s, 1H), 7.68 (m, 1H), 7.54 (m, 2H), 7.41 (s, 2H), 6.63 (t, 1H), 4.58 (m, 1H), 3.12 (m, 2H), 2.93 (m, 3H), 2.61 ( m, 4H), 2.24 (m, 1H), 1.64 (m, 1H), 1.50 (m, 3H), 1.27 (m, 2H), 1.12 (m, 1H), 0.91 (m, 2H) · C28H27C12F6N302 MS (El), found 623 (MH+). ]\-[(38)-1-Azabicyclo[2.2.2]oct-3-yl]-4-a-, 〇1-{[1-(2,4-diphenyl)-cyclopropane Carbonyl]-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1 Η), 8.01 (d, 1H), 7.62 (s, 1H), 7.43 (s, 2H) , 7.27 (d, 2H), 7.05 (d, 2H), 6.47 (d, 1H), 4.49 (m, 1H), 3.08 (m, 1H), 2.81 (m, 2H), 2.72 (m, 4H), 2.42 (m, 2H), 1.57 (m, 2H), 1.48 (m, 2H), 1.38 (m, 2H), 1.26 (m, 1H), 0.98 (m, 2H). MS (El) of C26H28C13N302, measured The value is 521 (MH+). 146258.doc -114- 201040149 N-[(1S)-1-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-3-phenylpropyl] -1-(2,4-diphenyl)cyclopropanamide: 4 NMR (400 MHz, CD3OD): 7.59 (s, 1H), 7.50 (d, 1H), 7.40 (d, 1H), 7.26- 7.10 (m, 5H), 4.40 (dd, 1H), 4.02-3.98 (m, 1H), 3.55- 3.44 (m, 1H), 3.20-3.03 (m, 3H), 2.80-2.75 (m, 1H), 2.60- 2.45 (m, 2H), 2.05-1.93 (m, 7H), 1.78-1.58 (m, 3H), 1.22-1.09 (m, 2H). MS (El) for C27H31C12N302, found 589.07 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]_4-qi-Να-{[1-(2,4-diphenylphenyl)-cyclopropyl]carbonyl} -2-(Trifluoromethyl)-L-phenylalanamine decylamine: NMR (400 MHz, CD3OD): 7.70-7.58 (m, 2H), 7.43-7.38 (m, 4H), 4.65-4.60 (m, 1H ), 4.09-3.99 (m, 1H), 3.59-3.48 (m, 1H), 3.20-3.05 (m, 5H), 3.02-2.95 (m, 1H), 2.78-2.73 (m, 1H), 2.10-2.04 (m, 1H), 1.99-1.83 (m, 3H), 1.80-1.68 (m, 1H), 1.57-1.44 (m, 2H), 1.17-1.10 (m, 1H), 1.05-0.98 (m, 1H) MS (El) for C27H31C12N302, found 500.20 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-Να-{[1-(2,4-dichlorophenyl)-cyclopropyl]carbonyl}-1- (phenylmethyl)-L-histamine decylamine: 4 NMR (400 MHz, CD3OD): 8.35 (s, 1H), 7.72 (s, 1H), 7.43-7.22 (m, 9H), 6.80 (s, (H, 3H) MS (El), </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N~2—{[1-(2,4-digas 146258.doc -115- 201040149 phenyl) ring Propyl]-carbonyl}-3-(2,2-difluoro-1,3-benzobisoxazol-5-yl)-L-alanamine: 4 NMR (400 MHz, CD3OD): 8.45 (s ,1H), 7.45-7.37 (m, 3H), 7.09 (d, 1H), 6.96 (s, 1H), 6.88 (d, 1H), 4.57 (dd, 1H), 4.09-4.03 (m, 1H), 3.65-3.60 (m, 1H), 3.32-3.13 (m, 4H), 3.03-2.80 (m, 3H), 2.17-2.15 (m, 1H), 2.02-1.95 (m, 3H), 1.90-1.77 (m , 1H), 1.62-1.47 (m, 2H), 1.20-1-02 (m, 2H). MS (El) for C27H27C12F2N302, found 567.15 (MH+). 4-bromo-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl b-N-[3-(lH-imidazol-1-yl)propyl]-L-phenylalanamine decylamine: NMR (400 MHz, CD3OD): 8.84 (s, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.44-7.38 (m, 5H), 7.00 (d, 2H), 4.40 (dd, 1H ), 4.19 (t, 2H), 3.22-3.05 (m, 2H), 3.00-2.95 (m, 1H), 2.81-2.77 (dd, 1H), 2.05-1.98 (m, 2H), 1.65-1.60 (m , 1H), 1.57-1.44 (m, 1H), 1.22-1.17 (m, 1H), 1.05-0.98 (m, 1H). MS (El) of C25H25BrCl2N402, found 566.08 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-Να-{[1-(2,4-diphenylphenyl)-cyclopropyl]carbonyl}-2- Fluoro-4-(trifluoromethyl)-L-phenylalanamine decylamine: 1 NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1 Η), 8.06 (d, 1H), 7.62 (m, 1H), 7.58 (d, 1H), 7.49 (t, 1H), 7.44 (s, 2H), 7.35 (m, 1H), 6.53 (m, 1H), 4.58 (m, 1H), 3.13 (m, 1H), 2.93 (m, 2H), 2.75 (m, 4H), 2.37 (m, 1H), 1.65 (m, 4H), 1.42 (m, 2H), 1_29 (m, 2H), 0_99 (m, 2H). C27H27C12F4N302 MS (El) 'Found 573 (mh+). 146258.doc 116- 201040149 4-Bromo-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl b. N_ [(1S,3S,4S)-1-epoxy-1- gas Heterobicyclo[2.2.2]oct-3-yl]-L-amphetamine-terminated amine: N_[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Nα-{[ L-(2,4-Diphenyl)cyclopropyl]-carbonyl}-L-phenylpropylamine octaamine (5 mg, 0.088 mmol) was dissolved in CH2C12 (0.9 mL). mcpBA (65.4 mg, 0.265 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 3 min. Remove solvent from the vacuum. The residue was dissolved in MeOH and purified using preparative HPLC (30-45% MeCN in water with 0.1% EtOAc). The purified material was lyophilized to give 23 mg (45%) of desired product as a white powder. !H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1 Η), 7.48-7.37 (m, 5H), 7.02 (m, 2H), 6.33 (m, 1H), 4.52 (m, 1H), 4.17 (m, 1H), 3.72 (m, 1H), 4.51 (m, 1H), 3.38 (m, 4H), 2.88 (m, 3H), 2.01 (m, 5H), 1.55 (m, 2H), 1.09 (m, 2H); MS (El) for C26H28BrCl2N303, found 489.68 (MH+). ]&gt;^[(38)-1_Azabicyclo[2.2.2]oct-3-yl]-4-gas-Na-{[l-(2,4-diphenyl)-cyclopropyl Carbonyl keto 2-fluorophenylpropylamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.60 (m, 2H), 7.37 (m, 5H), 6.97 (m, 1H), 4.87 (m, 1H), 3.04-3.87 (m, 4H), 2.90 (m, 2H), 2.68 (m, 2H), 2.11 (s, 3H), 1.79 (m, 2H), 1.17-1.48 (m, MS (El), 552.35 (MH+). 1-(2,4-Dichlorophenyl)-N-[(lS)-2-(6•methyl-2,6-diazaspiro[3.3]hept-2-yl)_2_oxo- L-{[4-(Trifluoromethyl)phenyl Imethyl}ethyl]cyclopropanamide: NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.58 146258.doc -117 - 201040149 (m, 3H), 7.56 (s, 2H), 7.31 (d, 2H), 6.90 (d, 1H), 4.44 (m, 1H), 4.14 (m, 1H), 3.85 (m, 3H), 3.27 (m, 4H), 2.85 (m, 2H), 2.27 (s, 3H), 1.35 (m, 2H), 0.93 (m, 2H). PCT 8卩1) of C26H26C12F3N302, found 540.38 (1^11 +). N-[(3S)-1-azabicyclo[2·2·2]oct-3-yl]-Να-({1-[4-(methoxy)phenyl]-cyclopropyl}carbonyl) -4-(Trifluoromethyl)-L-phenylalanamine decylamine: iH NMR (400 MHz, DMSO-d6): δ 8.29-8.24 (m, 1 Η), 7.63-7.60 (m, 2H), 7.26-7.24 ( m, 2H), 7.21-7.18 (m, 2H), 6.89-6.86 (m, 2H), 6.28-6.23 (m, 1H), 4.61-4.56 (m, 1H), 3.75 (s, 3H), 3.72- 3.65 (m, 1H), 3.18-3.13 (m, 1H), 2.99-2.89 (m, 2H), 2.85-2.79 (m, 4H), 2.54-2.42 (m, 1H), 1.75-1.45 (m, 4H ), 1.40-1.28 (m, 1H), 1.25-1.20 (m, 2H), 0.95-0.86 (m, 2H); MS (El) of C28H32F3N303, found 516.26 (MH+). 1\-[(31〇-1-azabicyclo[2.2.2]oct-3-yl]-1\〇1-({1-[4-(methoxy)phenyl]-cyclopropyl} Carbonyl)-4-(trifluoromethyl)-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.29-8.27 (m, 1H), 7.63-7.60 (m, 2H), 7.27- 7.24 (m, 2H), 7.21-7.18 (m, 2H), 6.89-6.86 (m, 2H), 6.28-6.23 (m, 1H), 4.62-4.56 (m, 1H), 3.75 (s, 3H), 3.68 (m, 1H), 3.19-3.13 (m, 1H), 2.99-2.86 (m, 2H), 2.81-2.69 (m, 4H), 2.55-2.41 (m, 1H), 1.75-1.31 (m, 5H) ), 1.28-1.20 (m, 2H), 0.95-0.86 (m, 2H); MS (El) of C28H32F3N303, found 516.26 (MH+). N-[(3R)-1-azabicyclo[2.2.2 Oct-3-yl]-4-bromo-indole α-({1-[4-(methoxy)phenyl]-cyclopropyl}carbonyl)-L-phenylalanamine decylamine: 4 NMR (400 146258.doc -118· 201040149 MHz, DMSO-d6): δ 8.26 (d, 1H), 7.45-7.41 (m, 2H), 7.22- 7.19 (m, 2H), 6.99-6.95 (m, 2H), 6.91-6.89 ( m, 2H), 6.26- 6.21 (m, 1H), 4.55-4.50 (m, 1H), 3.76 (s, 3H), 3.73-3.71 (m, 1H), 3.16-3.10 (m, 1H), 2.86- 2.67 (m, 6H), 2.54-2.38 (m, 1H), 1.74-1.33 (m, 5H), 1.30-1.21 (m, 2H), 0.96-0.87 (m, 2H); MS (El) of C27H32BrN303, 528.17 (MH+). N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-bromo-indole α-({1-[4-(methoxy)benzene) 1H NMR (400 MHz, DMSO-d6): δ 8.21 (d, 1 Η), 7.45-7.41 (m, 2H), 7.22- 7.20 (m, 2H) ), 6.99-6.94 (m, 2H), 6.91-6.89 (m, 2H), 6.25- 6.20 (m, 1H), 4.55-4.50 (m, 1H), 3.76 (s, 3H), 3.72-3.62 (m , 1H), 3.14-3.08 (m, 1H), 2.84-2.67 (m, 6H), 2.52-2.50 (m, 1H), 1.72-1.51 (m, 4H), 1.34-1.28 (m, 1H), 1.27 -1.21 (m, 2H), 0.96-0.87 (m, 2H); MS (El), C27H32BrN303, found 528.17 (MH+). 4-bromo-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl b N-&quot;bipyridin-4-yl-L-phenylalanamine decylamine· 4 NMR (400 MHz, CD3OD ) : 8.42 (s, 1Η), 7.70 (s, 2H), 7.50-7.38 (m, 6H), 6.98 (d, 2H), 4.63 (dd, 1H), 3.09 (dd, 1H), 2.90 (dd, 1H), 1.63-1.50 (m, 2H), 1.06-1.00 (m, 1H). MS (El) of C24H20BrCl2N3O2, found 533.83 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-phenyl-Να_({1-(2,4-diphenyl)-cyclopropyl]carbonyl )-L-Amphetamine amide: 4 NMR (400 MHz, CD3OD): 7.63-7.30 (m, 10H), 7.20-7.15 (m, 2H), 146258.doc -119- 201040149 4.60 (t, 1H), 3.88 -3.82 (m, 1H), 3.02-2.78 (m, 7H), 2.47- 2.40 (m, 1H), 1.97-1.93 (m, 1H), 1.82-1.68 (m, 3H), 1.64-

1.50 (m, 3H), 1.18-1.03 (m，2H). C32H33C12N302 的 MS (丑1)，實測值 563.19 (]^11+)。 N-l-氮雜雙環[2.2.2]辛-4-基-4_ 溴-Να-{[1_(2,4-二氣苯 基）-環丙基]羰基}-L-苯丙胺醯胺：4 NMR (400 ΜΗζ， CD3OD) ： 8.55 (s, 1H), 7.50-7.37 (m, 5H), 6.99 (d, 2H), 4.45 (t, 1H), 3.40-3.30 (m, 5H), 2.96 (dd, 1H), 2.89 (dd, 1H), 2.19-2.08 (m, 7H), 1.60-1.48 (m, 2H), 1.17-1.02 (m, 2H)· C26H28BrCl2N302 的 MS (El)，實測值 566.15 (MH+)。 心[(38)-1-氮雜雙環[2.2.2]辛-3-基】-3-環己基-1\〜2〜-{[1-(2,4-二氣苯基）-環丙基]羰基}-L-丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 7.87 (d, 1Η), 7.62 (m, 1H), 7.44 (m, 2H), 6.48 (d, 1H), 4.36 (m, 1H), 3.63 (m, 1H), 3.05 (t, 1H), 2.66 (m, 4H), 2.34 (d, 1H), 1.72-1.23 (m, 14H), 1.03 (m, 6H)，0_78 (m, 2H). C26H35C12N302 的 MS (El)，實測值 493 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-Να-({1-[2-氟-4-(三 氟甲基）-苯基】環丙基}羰基）-4-(三氟甲基）-L-苯丙胺醯胺： !H NMR (400 MHz, DMSO-d6): δ 8.18 (d, 1Η), 7.63-7.55 (m, 5H), 7.32-7.28 (m, 2H), 6.86-6.82 (m, 1H), 4.59-4.54 (m, 1H), 3.74-3.73 (m, 1H), 3.23-3.18 (m, 1H), 2.98-2.91 (m, 2H), 2.86-2.78 (m, 4H), 2.58-2.45 (m, 1H), 1.80-1.60 (m, 4H), 1.44-1.28 (m, 3H), 1.11-0.96 (m, 2H); 146258.doc -120- 201040149 C28H28F7N3O2 的 MS (EI) ’ 實測值 572.26 (MH+)。 1-(2,4-二氯苯基）-N-{(lS)-l-[(2,4-二氣苯基）甲基]_2-[3_ (二甲基-胺基）-8-氮雜雙環【3.2.1】辛-8-基】-2-氧代乙基}環 丙醯胺：4 NMR (400 MHz，CD3OD) : 7.52-7.38 (m，4H)， 7.24-7.10 (m, 2H), 4.82-4.78 (m, 1H), 4.58 (t, 1H), 4.37 (t, • 1H), 3.18-3.00 (m, 3H), 2.90 (s, 6H), 2.62-2.57 (m, 2H), 1.80-1.65 (m, 4H), 1.58-1.47 (m, 4H), 1.28-1.21 (m, 1H), 1.03-.097 (m, 1H). C28H31C14N302 的 MS (El)，實測值 ❸ 583.50 (MH+)。1.50 (m, 3H), 1.18-1.03 (m, 2H). MS (ug. 1) of C32H33C12N302, found 563.19 (]^11+). Nl-azabicyclo[2.2.2]oct-4-yl-4_bromo-indole α-{[1_(2,4-diphenyl)-cyclopropyl]carbonyl}-L-phenylalanamine decylamine: 4 NMR (400 ΜΗζ, CD3OD): 8.55 (s, 1H), 7.50-7.37 (m, 5H), 6.99 (d, 2H), 4.45 (t, 1H), 3.40-3.30 (m, 5H), 2.96 (dd, 1H), 2.89 (dd, 1H), 2.19-2.08 (m, 7H), 1.60-1.48 (m, 2H), 1.17-1.02 (m, 2H)· MS (El) of C26H28BrCl2N302, found 566.15 (MH+) . Heart [(38)-1-azabicyclo[2.2.2]oct-3-yl]-3-cyclohexyl-1\~2~-{[1-(2,4-diphenyl)-cyclo Propyl]carbonyl}-L-alanamine: 4 NMR (400 MHz, DMSO-d6): δ 7.87 (d, 1 Η), 7.62 (m, 1H), 7.44 (m, 2H), 6.48 (d, 1H) ), 4.36 (m, 1H), 3.63 (m, 1H), 3.05 (t, 1H), 2.66 (m, 4H), 2.34 (d, 1H), 1.72-1.23 (m, 14H), 1.03 (m, 6H), 0_78 (m, 2H). MS (El) for C26H35C12N302, found 493 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-Να-({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl }carbonyl)-4-(trifluoromethyl)-L-phenylalanamine decylamine: !H NMR (400 MHz, DMSO-d6): δ 8.18 (d, 1 Η), 7.63-7.55 (m, 5H), 7.32- 7.28 (m, 2H), 6.86-6.82 (m, 1H), 4.59-4.54 (m, 1H), 3.74-3.73 (m, 1H), 3.23-3.18 (m, 1H), 2.98-2.91 (m, 2H) ), 2.86-2.78 (m, 4H), 2.58-2.45 (m, 1H), 1.80-1.60 (m, 4H), 1.44-1.28 (m, 3H), 1.11-0.96 (m, 2H); 146258.doc -120- 201040149 MS (EI) of C28H28F7N3O2 'Measured value 572.26 (MH+). 1-(2,4-Dichlorophenyl)-N-{(lS)-l-[(2,4-diphenyl)methyl]_2-[3_(dimethyl-amino)-8 -azabicyclo[3.2.1]oct-8-yl]-2-oxoethyl}cyclopropanamide: 4 NMR (400 MHz, CD3OD): 7.52-7.38 (m, 4H), 7.24-7.10 ( m, 2H), 4.82-4.78 (m, 1H), 4.58 (t, 1H), 4.37 (t, • 1H), 3.18-3.00 (m, 3H), 2.90 (s, 6H), 2.62-2.57 (m , 2H), 1.80-1.65 (m, 4H), 1.58-1.47 (m, 4H), 1.28-1.21 (m, 1H), 1.03-.097 (m, 1H). MS (El) of C28H31C14N302, measured value ❸ 583.50 (MH+).

N-{(lS)-2-(4-胺基-4-甲基呱啶-1-基）-l-【(2,4-二氣苯基） 甲基】-2-氧代乙基}-1-(2,4-二氣苯基）環丙醢胺：NMR (400 MHz, CD3OD) ： 8.50 (s, 1H), 7.50-7.38 (m, 3H), 7.28- 7.23 (m, 1H), 7.17-7.08 (m, 1H), 5.20-5.10 (m, 1H), 4.10- 3.80 (m, 2H), 4.60-3.45 (m, 1H), 3.18-3.02 (m, 2H), 2.98- 2.83 (s, 1H), 1.85-1.60 (m, 4H), 1.55-1.37 (m, 5H), 1.13- O1.00 (m，2H)_ C28H31C14N302 的 MS (El)，實測值 543.50 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基】-]^，2，-{[1-(2,4-二氣苯 基）環丙基卜羰基}-N，2，-甲基-5-苯基-L-正纈氨醯胺：咕 NMR (400 MHz, CD3OD) ： 8.45 (s, 1H), 7.45-7.35 (m, 3H), 7.25-7.05 (m, 5H), 4.73-4.69 (m, 1H), 4.15-4.08 (m, 1H), 3.65-3.58 (m, 1H), 3.21-3.13 (m, 2H), 3.00-2.95 (m, 1H), 2.68-2.45 (m, 5H), 2.10-1.90 (m, 4H), 1.88-1.65 (m, 4H), 1.65-1.43 (m, 4H), 1.40-1.20 (m, 3H), 0.87-0.80 (m, 1H). 146258.doc -121 - 201040149 C29H35C12N302的 MS (EI)，實測值 528.23 (MH+)。 1^’2’-{[1-(2,4-二氣苯基）環丙基]羰基}_]^-[2-(二曱基胺 基）乙基】-Ν-甲基·5-苯基-L-正纈氨醯胺：】H NMR (400 MHz, CD3OD) ： 8.41 (s, 1H), 7.56 (s, 1H), 7.43 (d, 1H), 7.39 (d, 1H), 7.27-7.14 (m, 5H), 4.68 (dd, 1H), 3.85-3.80 (m, 1H), 3.45-3.38 (m, 1H), 3.17-3.11 (m, 1H), 3.05 (s, 3H)，2.78 (s，6H)，2.63-2.55 (m, 3H)，1.75-1.43 (m，6H)， 1.22-1.05 (m，2H)_ C26H33C12N302 的 MS (EI)，實測值 491.76 (MH+)。 1-(2,4-二氣苯基）-N-{(lS)-l-[(4-甲基呱嗪-1-基）羰基】-4- 苯基丁 基}環丙醯胺：4 NMR (400 MHz，CD3OD) : 8.30 (s, 1H), 7.59 (s, 1H), 7.46 (d, 1H), 7.40 (d, 1H), 7.28-7.12 (m, 5H), 4.82-4.79 (m, 1H), 3.60-3.40 (m, 4H), 2.70-3.42 (m, 6H), 2.40 (s, 3H), 1.73-1.40 (m, 6H), 1.21-1.18 (m, 1H)，1.08-1.03 (m, 1H)_ C26H31C12N302的MS (EI)，實測值 489.93 (MH+)。 1-(2,4-二氣苯基）-N-{(lS)-l-[(2,4-二氣苯基）甲基]-2-[(3R)-3-甲基呱嗪-1-基]-2-氧代乙基}環丙醯胺：b NMR (400 MHz, CD3OD) ： 8.43 (s, 1H), 7.50-7.38 (m, 4H), 7.25-7.15 (m, 2H), 7.20-7.15 (m, 1H), 4.35 (dd, 1H)S 4.00 (dd, 1H), 3.25-2.80 (m, 7H), 1.57-1.43 (m, 2H), 1.20-1.05 (m, 211).(：24?125(：14&gt;^〇2的]^(£1)，實測值529.99 (]^11+)。N-{(lS)-2-(4-Amino-4-methylacridin-1-yl)-l-[(2,4-diphenyl)methyl]-2-oxoethyl }-1-(2,4-diphenyl)cyclopropanamide: NMR (400 MHz, CD3OD): 8.50 (s, 1H), 7.50-7.38 (m, 3H), 7.28- 7.23 (m, 1H ), 7.17-7.08 (m, 1H), 5.20-5.10 (m, 1H), 4.10- 3.80 (m, 2H), 4.60-3.45 (m, 1H), 3.18-3.02 (m, 2H), 2.98- 2.83 (s, 1H), 1.85-1.60 (m, 4H), 1.55-1.37 (m, 5H), 1.13- O1.00 (m, 2H) _ C28H31C14N302 MS (El), found 543.50 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-]^,2,-{[1-(2,4-diphenylphenyl)cyclopropylbucarbonyl] -N,2,-Methyl-5-phenyl-L-n-decylamine: NMR (400 MHz, CD3OD): 8.45 (s, 1H), 7.45-7.35 (m, 3H), 7.25-7.05 (m, 5H), 4.73-4.69 (m, 1H), 4.15-4.08 (m, 1H), 3.65-3.58 (m, 1H), 3.21-3.13 (m, 2H), 3.00-2.95 (m, 1H) , 2.68-2.45 (m, 5H), 2.10-1.90 (m, 4H), 1.88-1.65 (m, 4H), 1.65-1.43 (m, 4H), 1.40-1.20 (m, 3H), 0.87-0.80 ( m, 1H). 146258.doc -121 - 201040149 MS (EI) for C29H35C12N302, found 528.23 (MH+). 1^'2'-{[1-(2,4-Diphenyl)cyclopropyl]carbonyl}_]^-[2-(didecylamino)ethyl]-Ν-methyl·5 -Phenyl-L-n-decylamine: H NMR (400 MHz, CD3OD): 8.41 (s, 1H), 7.56 (s, 1H), 7.43 (d, 1H), 7.39 (d, 1H), 7.27-7.14 (m, 5H), 4.68 (dd, 1H), 3.85-3.80 (m, 1H), 3.45-3.38 (m, 1H), 3.17-3.11 (m, 1H), 3.05 (s, 3H), 2.78 (s,6H), 2.63-2.55 (m, 3H), 1.75-1.43 (m, 6H), 1.22-1.05 (m, 2H) _ C26H33C12N302 MS (EI), found 491.76 (MH+). 1-(2,4-Diphenyl)-N-{(lS)-l-[(4-methylpyridazin-1-yl)carbonyl]-4-phenylbutyl}cyclopropanamide: 4 NMR (400 MHz, CD3OD): 8.30 (s, 1H), 7.59 (s, 1H), 7.46 (d, 1H), 7.40 (d, 1H), 7.28-7.12 (m, 5H), 4.82-4.79 ( m, 1H), 3.60-3.40 (m, 4H), 2.70-3.42 (m, 6H), 2.40 (s, 3H), 1.73-1.40 (m, 6H), 1.21-1.18 (m, 1H), 1.08- MS (EI) for 1.03 (m, 1H) ??? C26H31C12N302, found 489.93 (MH+). 1-(2,4-diphenyl)-N-{(lS)-l-[(2,4-diphenyl)methyl]-2-[(3R)-3-methylpyridazine -1-yl]-2-oxoethyl}cyclopropanamide: b NMR (400 MHz, CD3OD): 8.43 (s, 1H), 7.50-7.38 (m, 4H), 7.25-7.15 (m, 2H ), 7.20-7.15 (m, 1H), 4.35 (dd, 1H)S 4.00 (dd, 1H), 3.25-2.80 (m, 7H), 1.57-1.43 (m, 2H), 1.20-1.05 (m, 211 ).(:24?125(:14&gt;^〇2]^(£1), measured value 529.99 (]^11+).

N-[(3S)_1_ 氮雜雙環[2.2.2]辛-3-基]-4-溴-Να-【（1-{4-[(三 氟甲基）-氧】苯基}環丙基）羰基]-L-苯丙胺酿胺：4 NMR 146258.doc •122- 201040149 (400 MHz, DMSO-d6): δ 8.18 (d, 1H), 7.44 (d, 2H), 7.37 (d, 2H), 7.31 (d, 2H), 7.03 (d, 2H), 6.63 (d, 1H), 4.52 (q, 1H), 3.70 (s, 1H), 3.16 (t, 1H), 2.88-2.78 (m, 6H), 2.45-2.43 (m, 1H), 1.76-1.56 (m, 4H), 1.40 (s, 1H), 1.29-1.22 (m, 2H), 1.04-0.97 (m, 2H); C27H29BrF3N303 的 MS (El)，實測值 580.13 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2]辛3-基】-4-溴-Nα-({l-[2-氟-4_ (三氟甲基）苯基]環丙基}羰基）-L-苯丙胺醯胺：1HNMR 〇 (400 MHz, DMSO-dg): δ 8.18 (d, 1H), 7.65 (d, 1H), 7.59 (d, 2H), 7.32 (d, 2H), 7.04 (d, 2H), 6.83 (d, 1H), 4.49 (q, 1H), 3.73 (s, 1H), 3.20 (t, 1H), 2.84-2.82 (m, 6H), 2.46 (s, 1H), 1.80-1.60 (m, 4H), 1.44-1.30 (m, 3H), 1.11-0.94 (m, 2H); (：27112#斤41^302的^18斤1)，實測值 584.16 (]\411+)。 (PS)-N-[(3S)-1-氮雜雙環[2.2.2】辛-3-基]-4-溴-Να-{[1-(2,4-二氣苯基）-環丙基]羰基}-ρ-甲基苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.31-7.94 (m, 1H), 7.68-7.65 〇 (m, 1H), 7.53-7.31 (m, 4H), 7.13-7.11 (m, 1H), 6.97-6.94 (m, 1H), 6.46-5.95 (m, 1H), 4.54-4.45 (m, 1H), 3.71-3.43 (m, 1H), 3.23-3.01 (m, 1H), 2.96-2.62 (m, 5H), 2.55-2.42 (m, 1H), 1.86-1.71 (m, 1H), 1.65-1.23 (m, 6H), 1.13-1.09 (m, 3H), 1.06-0.96 (m, 2H), 0.93-0.84 (m, 1H); C27H30BrCl2N3O2的MS (El)，實測值 580.07 (MH+)。N-[(3S)_1_ azabicyclo[2.2.2]oct-3-yl]-4-bromo-Να-[(1-{4-[(trifluoromethyl)-oxy]phenyl}cyclopropane Carbonyl)-L-amphetamine octaamine: 4 NMR 146258.doc • 122- 201040149 (400 MHz, DMSO-d6): δ 8.18 (d, 1H), 7.44 (d, 2H), 7.37 (d, 2H) , 7.31 (d, 2H), 7.03 (d, 2H), 6.63 (d, 1H), 4.52 (q, 1H), 3.70 (s, 1H), 3.16 (t, 1H), 2.88-2.78 (m, 6H) ), 2.45-2.43 (m, 1H), 1.76-1.56 (m, 4H), 1.40 (s, 1H), 1.29-1.22 (m, 2H), 1.04-0.97 (m, 2H); MS of C27H29BrF3N303 (El) ), found 580.13 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Nα-({l-[2-fluoro-4_(trifluoromethyl)phenyl]cyclopropane } carbonyl)-L-amphetamine amide: 1H NMR 400 (400 MHz, DMSO-dg): δ 8.18 (d, 1H), 7.65 (d, 1H), 7.59 (d, 2H), 7.32 (d, 2H) , 7.04 (d, 2H), 6.83 (d, 1H), 4.49 (q, 1H), 3.73 (s, 1H), 3.20 (t, 1H), 2.84-2.82 (m, 6H), 2.46 (s, 1H ), 1.80-1.60 (m, 4H), 1.44-1.30 (m, 3H), 1.11-0.94 (m, 2H); (:27112# kg 41^302^18 kg 1), measured value 584.16 (]\ 411+). (PS)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Να-{[1-(2,4-diphenyl)-cyclo Propyl]carbonyl}-ρ-methamphetamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.31-7.94 (m, 1H), 7.68-7.65 〇(m, 1H), 7.53-7.31 (m , 4H), 7.13-7.11 (m, 1H), 6.97-6.94 (m, 1H), 6.46-5.95 (m, 1H), 4.54-4.45 (m, 1H), 3.71-3.43 (m, 1H), 3.23 -3.01 (m, 1H), 2.96-2.62 (m, 5H), 2.55-2.42 (m, 1H), 1.86-1.71 (m, 1H), 1.65-1.23 (m, 6H), 1.13-1.09 (m, 3H), 1.06-0.96 (m, 2H), 0.93 - 0.84 (m, 1H); MS (El) of C27H30BrCl2N3O2, found 580.07 (MH+).

(PR)-N-[(3S)-1-氮雜雙環[2.2.2】辛-3-基]-4-溴-Να-{[1-(2,4-二氣苯基）環丙基]羰基}-ρ-甲基苯丙胺醯胺：NMR 146258.doc -123- 201040149 (400 MHz，DMSO-d6): δ 8.36-7.98 (m，1H)，7.68-7.64 (m, 1H), 7.52-7.36 (m, 4H), 7.13-7.10 (m, 1H), 6.97-6.95 (m, 1H)，6.49-5.97 (m，1H), 4.53-4.45 (m, 1H)，3.74-3.47 (m, 1H), 3.26-3.02 (m, 1H), 2.99-2.67 (m, 5H), 2.57-2.49 (m, 1H)，1.90-1.80 (m, 1H), 1.67-1.23 (m, 6H), 1.13-1.09 (m, 3H)，1.06-1.00 (m, 2H)，0.93-0.88 (m, 1H); C27H3〇BrCl2N302 的 MS (El)，實測值 580.13 (MH+)。 Να-{[1-(2,4·二氣苯基）環丙基】羰基卜n_【反式-4-苯基啦 咯咬_3_基】-4-(三氟甲基）_L_苯丙胺醢胺：c30H28C12F3N3O2 的 MS (EI)，實測值 590.5 (MH+)。 N-1-氮雜雙環[2.2.2]辛-3-基-4-溴-Να-{[1-(2,4-二氣苯 基）-環丙基]羰基}-D-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.22 (s，1H)，8.06 (m，1H), 7.61 (s，1H)，7.41 (m, 4H), 7.00 (m, 2H), 6.49 (m, 1H), 4.50 (m, 1H), 3.14 (m, 1H), 2.77 (m, 6H), 2.37 (m, 1H), 1.63 (m, 4H), 1.35 (m, 3H)，0.97 (m，2H). C26H28BrCl2N302的MS (EI)，實測值566 (MH+)。 N-{(lS)-2-(3-胺基-8-氮雜雙環丨3.2.1]辛-8-基）-l-[(4-溴苯 基）甲基]-2-氧代乙基}-1-{4-[(三氟甲基）氧]苯基}環丙醢 胺：4 NMR (400 MHz，DMSO-d6): δ 8.29 (s, 1H)，7.41 (d， 2H), 7.33 (m, 4H), 6.98 (m5 3H), 4.68 (m, 1H), 4.24 (m, 3H), 3.08 (m, 1H), 2.82 (m, 2H), 2.30-1.51 (m, 8H), 1.23 (m, 2H)，0.97 (m, 2H). C27H29BrF3N303 的 MS (EI)，實測值 581 (MH+)。 146258.doc -124- 201040149 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基卜5-(4-氣苯基）-N〜2~-{[l-(2,4-二氣苯基）-環丙基】羰基}-L-正纈氨酿胺：巾 NMR (400 MHz, CD3〇D): δ 8.40 (s, 1H), 7.57 (s, 1H), 7.44 ' (d, 1H), 7.38 (d, 1H), 7.28-7.23 (m, 2H), 7.17-7.10 (m, 2H), ： 4.40-4.37 (m, 1H), 4.14-4.09 (m, 1H), 3.68-3.60 (m, 1H), . 3.30-3.20 (m, 3H), 2.98-2.85 (m, 1H), 2.63-2.49 (m, 2H), 2.16-1.80 (m, 6H), 1.78-1.62 (m, 2H), 1.58-1.48 (m, 4H), 1.21-1.06 (m, 2H). C28H32C13N3〇2 的 MS (El)，實測值 O 550.21 (MH+)。(PR)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Να-{[1-(2,4-diphenyl)cyclopropane Carbonyl]-ρ-methamphetamine amide: NMR 146258.doc -123- 201040149 (400 MHz, DMSO-d6): δ 8.36-7.98 (m, 1H), 7.68-7.64 (m, 1H), 7.52 -7.36 (m, 4H), 7.13-7.10 (m, 1H), 6.97-6.95 (m, 1H), 6.49-5.97 (m,1H), 4.53-4.45 (m, 1H), 3.74-3.47 (m, 1H), 3.26-3.02 (m, 1H), 2.99-2.67 (m, 5H), 2.57-2.49 (m, 1H), 1.90- 1.80 (m, 1H), 1.67-1.23 (m, 6H), 1.13- 1.09 (m, 3H), 1.06-1.00 (m, 2H), 0.93-0.88 (m, 1H); MS (El) of C27H3 〇BrCl2N302, found 580.13 (MH+). Να-{[1-(2,4·di-phenylphenyl)cyclopropyl]carbonyl bn_[trans-4-phenyl-pole biting_3_yl]-4-(trifluoromethyl)_L_ MS (EI), m.p. </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; N-1-azabicyclo[2.2.2]oct-3-yl-4-bromo-indole α-{[1-(2,4-diphenyl)-cyclopropyl]carbonyl}-D-amphetamine Amine: 4 NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1H), 8.06 (m, 1H), 7.61 (s, 1H), 7.41 (m, 4H), 7.00 (m, 2H), 6.49 (m, 1H), 4.50 (m, 1H), 3.14 (m, 1H), 2.77 (m, 6H), 2.37 (m, 1H), 1.63 (m, 4H), 1.35 (m, 3H), 0.97 ( MS (EI) </RTI> </RTI> (MH+). N-{(lS)-2-(3-Amino-8-azabicycloindole 3.2.1]oct-8-yl)-l-[(4-bromophenyl)methyl]-2-oxo Ethyl}-1-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1H), 7.41 (d, 2H) ), 7.33 (m, 4H), 6.98 (m5 3H), 4.68 (m, 1H), 4.24 (m, 3H), 3.08 (m, 1H), 2.82 (m, 2H), 2.30-1.51 (m, 8H) MS (EI), 1.23 (m, 2H), 0.97 (m, 2H), C27H29BrF3N303, found 581 (MH+). 146258.doc -124- 201040149 N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl b-5-(4-phenylphenyl)-N~2~-{[l-( 2,4-diphenylphenyl)-cyclopropyl]carbonyl}-L-n-decylamine: NMR (400 MHz, CD3〇D): δ 8.40 (s, 1H), 7.57 (s, 1H) , 7.44 ' (d, 1H), 7.38 (d, 1H), 7.28-7.23 (m, 2H), 7.17-7.10 (m, 2H), : 4.40-4.37 (m, 1H), 4.14-4.09 (m, 1H), 3.68-3.60 (m, 1H), . 3.30-3.20 (m, 3H), 2.98-2.85 (m, 1H), 2.63-2.49 (m, 2H), 2.16-1.80 (m, 6H), 1.78 -1.62 (m, 2H), 1.58-1.48 (m, 4H), 1.21-1.06 (m, 2H). MS (El) of C28H32C13N3 〇2, found O 550.21 (MH+).

N-{(lS)-2_[(3R)-3-胺基呱啶-1-基]-l-[(2,4-二氣苯基）曱 基1-2-氧代乙基}-1-(2,4-二氣苯基）環丙醯胺：4 NMR (400 MHz, CD3OD): δ 8.57 (s, 1H), 7.50-7.38 (m, 4H), 7.29-7.13 (m, 2H), 5.20-5.10 (m, 1H), 4.50 (dd, 1H), 3.79- 3.60 (m, 1H), 3.16-2.94 (m, 6H), 2.90-2.80 (m, 1H), 2.18- 2.20 (m, 1H), 1.82-1.40 (m, 5H), 1.18-1.00 (m, 2H). C24H25C14N3〇2的 MS (El)，實測值 530_12 (MH+)。N-{(lS)-2_[(3R)-3-Aminopyridin-1-yl]-l-[(2,4-diphenyl)indenyl1-2-oxoethyl}- 1-(2,4-diphenyl)cyclopropanamide: 4 NMR (400 MHz, CD3OD): δ 8.57 (s, 1H), 7.50-7.38 (m, 4H), 7.29-7.13 (m, 2H ), 5.20-5.10 (m, 1H), 4.50 (dd, 1H), 3.79- 3.60 (m, 1H), 3.16-2.94 (m, 6H), 2.90-2.80 (m, 1H), 2.18- 2.20 (m , 1H), 1.82-1.40 (m, 5H), 1.18-1.00 (m, 2H). MS (El) for C24H25C14N3 〇2, found 530_12 (MH+).

QQ

N-{(lS)-2-(4-胺基-4-甲基呱啶-1-基）-l-[(4-溴苯基）甲 基】-2-氧代乙基}-1-(2,4-二氣苯基）環丙醯胺：4 NMR (400 MHz, CD3OD) ： 8.38 (s, 1H), 7.61 (s, 4H), 7.45-7.39 - (m, 3H), 7.04 (d, 2H), 6.78 (d, 1H), 4.96-4.87 (m, 1H), 3.80-3.42 (m, 2H), 3.40-3.25 (m, 2H), 2.83-2.65 (m, 2H), 1.78-1.30 (m, 4H), 1.19-1.09 (d, 3H), 1.00-0.95 (m, 2H). (：25112881'(：12：^3〇2的]^8(£1)，實測值 554.05 (]^11+)。 ]&gt;[-{(18)-2-(4-胺基呱啶-1-基）-1-丨(2,4-二氯苯基）甲基]-2- 146258.doc •125· 201040149 氧代乙基}-1-(2,4-二氣苯基）環丙醯胺：iHNMRMOOMHz, CD3OD) ： 8.38 (s, 1H), 7.60-7.50 (m, 2H), 7.43-7.30 (m, 2H), 7.24-7.20 (m, 1H), 6.97 (t, 1H), 5.03-4.98 (m, 1H), 4.21-4.18 (m, 1H), 3.95 (t, 2H), 3.35-2.90 (m, 4H), 2.67-2.57 (m, 1H), 1.88-1.78 (m, 2H), 1.40-1.10 (m, 3H), 1.00-0.90 (m，2H). C24H25C14N302 的 MS (El)，實測值 529.99 (MH+)。N-{(lS)-2-(4-Amino-4-methylacridin-1-yl)-l-[(4-bromophenyl)methyl]-2-oxoethyl}-1 -(2,4-diphenyl)cyclopropanamide: 4 NMR (400 MHz, CD3OD): 8.38 (s, 1H), 7.61 (s, 4H), 7.45-7.39 - (m, 3H), 7.04 (d, 2H), 6.78 (d, 1H), 4.96-4.87 (m, 1H), 3.80-3.42 (m, 2H), 3.40-3.25 (m, 2H), 2.83-2.65 (m, 2H), 1.78 -1.30 (m, 4H), 1.19-1.09 (d, 3H), 1.00-0.95 (m, 2H). (:25112881'(:12:^3〇2)^8(£1), measured value 554.05 (]^11+). ]&gt;[-{(18)-2-(4-Aminoacridin-1-yl)-1-anthracene (2,4-dichlorophenyl)methyl]-2 - 146258.doc •125· 201040149 Oxoethyl}-1-(2,4-diphenyl)cyclopropanamide: iHNMRMOOMHz, CD3OD): 8.38 (s, 1H), 7.60-7.50 (m, 2H ), 7.43-7.30 (m, 2H), 7.24-7.20 (m, 1H), 6.97 (t, 1H), 5.03-4.98 (m, 1H), 4.21-4.18 (m, 1H), 3.95 (t, 2H) ), 3.35-2.90 (m, 4H), 2.67-2.57 (m, 1H), 1.88-1.78 (m, 2H), 1.40-1.10 (m, 3H), 1.00-0.90 (m, 2H). MS of C24H25C14N302 (El), found at 529.99 (MH+).

1-(2,4-二氣苯基）-]\-{(18)-1-[(2,4-二氣苯基）甲基]-2-[(3S)-3-甲基呱嗪-1-基]-2-氧代乙基}環丙醯胺：4 NMR (400 MHz, CD3OD) ： 8.42 (s, 1H), 7.53-7.39 (m, 4H), 7.33-7.13 (m, 2H), 5.20-5.15 (m, 1H), 4.40 (dd, 1H), 4.02 (dd, 1H), 3.25-2.84 (m, 6H), 2.80-2.58 (m, 1H), 1.55-1.40 (m, 2H), 1.23-1.00 (m，5H). C24H25C14N302 的 MS (El)，實測值 530.12 (MH+)。 2.4- 二氣-Να-{[1-(2,4-二氣苯基）環丙基]羰基}-N-[(2S)- 吡咯啶-2-基甲基]-L-苯丙胺醯胺：4 NMR (400 MHz, CD3OD) ： 8.40 (br, s, 1H), 7.43-7.37 (m, 4H), 7.22 (d, 1H), 7.18 (d, 1H), 4.58-4.55 (m, 1H), 3.68-3.45 (m, 2H), 3.22- 3.15 (m, 2H), 3.19-3.13 (m, 1H), 3.05-2.97 (m, 1H), 2.17- 1.96 (m, 4H), 1.80-1.68 (m, 1H), 1.80-1.44 (m, 2H), 1.20-1-(2,4-diphenyl)-]\-{(18)-1-[(2,4-diphenyl)methyl]-2-[(3S)-3-methylindole Pyrazin-1-yl]-2-oxoethyl}cyclopropanamide: 4 NMR (400 MHz, CD3OD): 8.42 (s, 1H), 7.53-7.39 (m, 4H), 7.33-7.13 (m, 2H), 5.20-5.15 (m, 1H), 4.40 (dd, 1H), 4.02 (dd, 1H), 3.25-2.84 (m, 6H), 2.80-2.58 (m, 1H), 1.55-1.40 (m, 2H), 1.23-1.00 (m, 5H). MS (El) for C24H25C14N302, found 530.12 (MH+). 2.4- Digas-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-[(2S)-pyrrolidin-2-ylmethyl]-L-phenylalanamine decylamine :4 NMR (400 MHz, CD3OD): 8.40 (br, s, 1H), 7.43-7.37 (m, 4H), 7.22 (d, 1H), 7.18 (d, 1H), 4.58-4.55 (m, 1H) , 3.68-3.45 (m, 2H), 3.22- 3.15 (m, 2H), 3.19-3.13 (m, 1H), 3.05-2.97 (m, 1H), 2.17- 1.96 (m, 4H), 1.80-1.68 ( m, 1H), 1.80-1.44 (m, 2H), 1.20-

1.16 (m, 1H), 1.05-0.97 (m, 1H). C24H25C14N302 的 MS (El)，實測值 531.94 (MH+2)· 2.4- 二氣-Να-{[1-(2,4-二氣苯基）環丙基]羰基}-N-[(2R)-吡咯啶-2-基甲基]-L-苯丙胺醯胺：4 NMR (400 MHz, 146258.doc -126- 201040149 DMSO-d6) : 8 28 (s，1H)，7 58 (s，ih)，7 52 (s，ih) 7 4〇_1.16 (m, 1H), 1.05-0.97 (m, 1H). MS (El) for C24H25C14N302, found 531.94 (MH+2)· 2.4- 二气-Να-{[1-(2,4-二气Phenyl)cyclopropyl]carbonyl}-N-[(2R)-pyrrolidin-2-ylmethyl]-L-phenylalanamine decylamine: 4 NMR (400 MHz, 146258.doc -126- 201040149 DMSO-d6) : 8 28 (s,1H),7 58 (s,ih),7 52 (s,ih) 7 4〇_

7 25 (m，3ΪΪ)，7.19 (d，1H)，6.91 (d，1H)，4.58-4.55 (m，1H)， 3·38·3.10 (m，2H)，3.05-2.90 (m，4H)，1.82-1.58 (m，3H)， i·42 m (rn, 3H)，1.00-0.85 (m，3H). C24H25C14N302的 MS (El)，貫剛值 53〇 12 (MH+)。 一氣_Να_{[1(2 4二氣苯基）環丙基】羰基卜N [(3R)_ w比洛咬-3-复 好 分 备甲基】-L-苯丙胺醯胺：NMR (400 MHz, ❹ DMS〇_d6) : 8.35 (s，1H)，8.03 (dt, 1H)，7.59 (s，1H)，7.54 (S’ 1H)’ 7.42 (s，1H)，7.33 (d，1H)，7.18 (d，1H)，6.80 (dd， 1H), 4.55-4 45 1H)j 3.18-2.97 (m, 6H), 2.93-2.70 (m, 2H), 2.35-2.25 (m, 1H), 1.95-1.88 (m, 1H), 1.52-1.25 (m, 3H)’ 〇·99、0.90 (m，2H). C24H25C14N302的 MS (El)，實測值 529.99 (MH+)。 2’4 一氣、Να{[1(24·二氣苯基）環丙基]羰基卜N丨(3s)_ 比洛咬3'基甲基]-L-苯丙胺醢胺：NMR (400 MHz, Q CD3〇D) · 8.48 (s&gt; 1H)j 7.48-7.38 (m, 4H), 7.24 (d, 1H), 7.16 (d, 4.58-4.52 (m, 1H), 3.18-2.97 (m, 4H), 3.02- 2.88 (m, 2H)5 2.55-2.45 (m, 1H), 2.15-2.00 (m, 1H), 1.75- 1-45 3li)» 1.24-1.10 (m, 2H), 1.03-0.97 (m, 1H). c24h25ci4k3〇wMS (EI)，實測值529 8〇 (MH+)。7 25 (m, 3ΪΪ), 7.19 (d, 1H), 6.91 (d, 1H), 4.58-4.55 (m, 1H), 3·38·3.10 (m, 2H), 3.05-2.90 (m, 4H) , 1.82-1.58 (m, 3H), i·42 m (rn, 3H), 1.00-0.85 (m, 3H). MS (El) of C24H25C14N302, with a value of 53〇12 (MH+).一气_Να_{[1(2 4 diphenyl)cyclopropyl]carbonyl b. [(3R)_ w 洛 咬 -3- 复 复 甲基 甲基 】 】 】 : : : : : : 400 400 400 MHz, ❹ DMS〇_d6) : 8.35 (s,1H),8.03 (dt, 1H),7.59 (s,1H),7.54 (S' 1H)' 7.42 (s,1H),7.33 (d,1H) , 7.18 (d, 1H), 6.80 (dd, 1H), 4.55-4 45 1H)j 3.18-2.97 (m, 6H), 2.93-2.70 (m, 2H), 2.35-2.25 (m, 1H), 1.95 -1.88 (m, 1H), 1.52-1.25 (m, 3H)' 〇·99, 0.90 (m, 2H). MS (El) for C24H25C14N302, found 529.99 (MH+). 2'4 qi, Να{[1(24·diphenyl)cyclopropyl]carbonyl b 丨N丨(3s)_ Bilo bite 3'-ylmethyl]-L-phenylalanamine decylamine: NMR (400 MHz, Q CD3〇D) · 8.48 (s&gt; 1H)j 7.48-7.38 (m, 4H), 7.24 (d, 1H), 7.16 (d, 4.58-4.52 (m, 1H), 3.18-2.97 (m, 4H) , 3.02- 2.88 (m, 2H)5 2.55-2.45 (m, 1H), 2.15-2.00 (m, 1H), 1.75- 1-45 3li)» 1.24-1.10 (m, 2H), 1.03-0.97 (m , 1H). c24h25ci4k3 〇 wMS (EI), found 529 8 〇 (MH+).

N_{(1S)-2_[(3S)-3-胺基吡咯啶-1-基]-l-[(2,4-二氣苯基） 甲基l·2-氡代乙基卜1·(2,4_二氣苯基）環丙醯胺：NMR (400 MHz, CD3OD) ： 8.23 (s, 1H), 7.62-7.52 (m, 2H), 7.44-7.30 (m, 3H), 7.20 (t, 1H), 6.84 (dd, 1H), 4.82-4.76 (m, 146258.doc -127- 201040149 1Η), 3.85-3.65 (m, 2H), 3.40-3.25 (m, 2H), 3.20-3.03 (m, 1H), 3.00-2.90 (m, 1H), 2.85-2.80 (m, 1H), 2.00-1.87 (m, 1H), 1.75-1.57 (m, 1H), 1.40-1.35 (m, 1H), 1.21-1.10 (m, 1H)，0.97-0.85 (m，2H). C23H23C14N302 的 MS (El)，實測值 516.07 (MH+)。N_{(1S)-2_[(3S)-3-Aminopyrrolidin-1-yl]-l-[(2,4-diphenyl)methyl l·2-decylethyl b 1· (2,4_di-phenyl)cyclopropanamide: NMR (400 MHz, CD3OD): 8.23 (s, 1H), 7.62-7.52 (m, 2H), 7.44-7.30 (m, 3H), 7.20 ( t, 1H), 6.84 (dd, 1H), 4.82-4.76 (m, 146258.doc -127- 201040149 1Η), 3.85-3.65 (m, 2H), 3.40-3.25 (m, 2H), 3.20-3.03 ( m, 1H), 3.00-2.90 (m, 1H), 2.85-2.80 (m, 1H), 2.00-1.87 (m, 1H), 1.75-1.57 (m, 1H), 1.40-1.35 (m, 1H), 1.21-1.10 (m, 1H), 0.97-0.85 (m, 2H). MS (El) for C23H23C14N302, found 516.07 (MH+).

N-{(lS)-2-[(3R)-3-胺基《比咯啶-1-基]-l-[(2,4-二氣苯基） 甲基]-2-氧代乙基}-1-(2,4-二氣苯基）環丙醯胺：4 NMR (400 MHz, DMSO-d6) ： 8.28 (s, 1H), 7.62-7.52 (m, 2H), 7.48-7.30 (m, 3H), 7.25-7.20 (m, 1H), 6.83 (dd, 1H), 4.86-4.77 (m, 1H), 3.68-3.57 (m, 3H), 3.45-3.37 (m, 1H), 3.34-3.17 (m, 2H), 3.80-2.90 (m, 2H), 2.05-1.90 (m, 2H), 1.85-1.65 (m, 2H), 1.40-1.33 (m, 1H), 1.27-1.1.10 (m, 1H), 1.03-0.90(m,2H)C23H23Cl4N302 的MS(EI)，實測值516.07 (MH+)。 2,4-二氣-Να-{[1-(2,4-二氣苯基）環丙基】羰基}-N-[(3R)-呱啶-3-基]-L-苯丙胺醯胺：1HNMR(400 MHz,DMSO-d6) ： 8.25 (s, 1H), 7.88 (d, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.43-7.30 (m, 3H), 7.35 (d, 1H), 7.18 (d, 1H), 6.77 (d, 1H), 4.57-4.45 (m, 1H), 3.73-3.65 (m, 1H), 3.00-2.80 (m, 4H), 2.65-2.60 (m, 1H), 1.70-1.60 (m, 2H), 1.50-1.20 (m, 4H), 1.00-0.90 (m, 2H). C24H25C14N302 的 MS (El)，實測值 530.05 (MH+)。N-{(lS)-2-[(3R)-3-Amino"pyrrolidin-1-yl]-l-[(2,4-diphenyl)methyl]-2-oxo }}-1-(2,4-diphenyl)cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): 8.28 (s, 1H), 7.62-7.52 (m, 2H), 7.48-7.30 (m, 3H), 7.25-7.20 (m, 1H), 6.83 (dd, 1H), 4.86-4.77 (m, 1H), 3.68-3.57 (m, 3H), 3.45-3.37 (m, 1H), 3.34 -3.17 (m, 2H), 3.80-2.90 (m, 2H), 2.05-1.90 (m, 2H), 1.85-1.65 (m, 2H), 1.40-1.33 (m, 1H), 1.27-1.1.10 ( MS (EI) </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> 2,4-digas-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-[(3R)-acridin-3-yl]-L-phenylpropylamine decylamine :1HNMR (400 MHz, DMSO-d6): 8.25 (s, 1H), 7.88 (d, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.43-7.30 (m, 3H), 7.35 ( d, 1H), 7.18 (d, 1H), 6.77 (d, 1H), 4.57-4.45 (m, 1H), 3.73-3.65 (m, 1H), 3.00-2.80 (m, 4H), 2.65-2.60 ( m, 1H), 1.70-1.60 (m, 2H), 1.50-1.20 (m, 4H), 1.00-0.90 (m, 2H). MS (El) of C24H25C14N302, found 530.05 (MH+).

N-{(lS)-2-[(3S)-3-胺基呱啶-1-基]-l-[(2,4-二氣苯基）甲 基]-2-氧代乙基}-1-(2,4-二氣苯基）環丙醢胺：h NMR 146258.doc -128- 201040149 (400 MHz, CD3OD) ： 8.56 (s, 1H), 7.50-7.38 (m, 3H), 7-28-7.22 (m, 1H), 7.18-7.13 (m, 1H), 5.20-5.08 (m, 1H), 4.10 (ddd, 1H), 3.64-3.58 (m, 1H), 3.45-3.38 (m, 1H), 3.18-2.80 (m, 4H), 2.10-1.95 (m, 1H), 1.89-1.78 (m, 1H), 1.68-1.57 (m, 1H), 1.50-1.45 (m, 3H), 1.15-1.00 (m, 2H). C24H25CI4N3O2 的 MS (El)，實測值 530.05 (MH+)。 4-溴-Να-{[1-(2,4_;氣苯基）環丙基】羰基}-N-[(3S)-&quot;比咯 啶-3-基]-L-苯丙胺醢胺：NMR (400 MHz，DMSO-d6): δ 8.94 (d, 1Η), 7.58 (s, 1H), 7.39 (m, 4H), 7.01 (d, 2H), 6.61 (d, 1H), 4.38 (m, 1H), 4.11 (m, 1H), 2.94 (m, 3H), 2.73 (m, 3H), 1.90 (m, 1H), 1.60 (m, 1H), 1.37 (m, 2H), 0.95 (m, 2H). C23H24BrCl2N302的 MS (El)，實測值 526 (MH+)。 4-溴-Να-{[1-(2,4-二氣苯基）環丙基】羰基}-N-[(3R)-咕咯 啶-3-基]-L-苯丙胺醯胺：NMR (400 MHz, DMSO-d6): δ 8.80 (d, 1Η), 7.59 (s, 1H), 7.40 (m, 4H), 7.01 (d, 2H), 6.61 (d, 1H), 4.40 (m, 1H), 4.12 (m, 1H), 2.93 (m, 3H), 2.74 (m, 3H), 1.86 (m, 1H), 1.48 (m, 1H), 1.36 (m, 2H), 0.96 (m, 2H)_ C23H24BrCl2N302 的 MS (El) ’ 實測值526 (MH+)。 N-(3-胺基環己基）-2,4-二氣-Να-{[1-(2,4-二氣苯基）-環丙 基】羰基}-L-苯丙胺醯胺：4 NMR (400 MHz, CD3OD): 8.52 (s, 1H), 7.50-7.38 (m, 4H), 7.23-7.15 (m, 2H), 4.82-4.75 (m, 1H), 3.67-3.58 (m, 1H), 2.20-2.13 (m, 1H), 2.02-1.83 (m, 3H), 1.77-1.40 (m, 5H)，1.25-1.00 (m, 3H). (：241127(：14]^3〇2的厘8口1)’實測值544.16 (]\^+)。 146258.doc .129- 201040149 N-[(lS)-l-(聯苯-4-基甲基）-2-(4-曱基呱嗪-1-基）-2-氧代 乙基]-1-(2,4-二氣苯基）環丙醯胺：4 NMR (400 MHz， CD3〇D) ： 7.60 (d, 1H), 7.55-7.50 (m, 3H), 7.45-7.39 (m, 3H), 7.38-7.33 (m, 2H), 7.20-7.15 (m, 2H), 5.07 (t, 1H), 3.60-3.40 (m, 4H), 2.96 (d, 2H), 2.53-2.40 (m, 2H), 2.38-2.30 (m, 1H), 2.24 (s, 3H), 2.05-1.97 (m, 1H), 1.65-1.55 (m, 2H), 1.18-1.06 (m, 2H). C30H31Cl2N3O2的 MS (El)，實 測值 537.99 (MH+)。 N-[(lS)-2-(4-胺基-4-曱基呱啶-1-基）-1-(聯苯-4-基甲基）-2-氧代乙基]-1-(2,4-二氣苯基）環丙醯胺：4 NMR (400 MHz, CD3OD) ： 8.57 (s, 1H), 7.64-7.60 (m, 2H), 7.55-7.50 (m, 2H), 7.45-7.40 (m, 4H), 7.38-7.30 (m, 2H), 7.18-7.14 (m, 2H), 5.03 (dd, 1H), 3.90-3.65 (m, 2H), 3.55-3.43 (m, 1H), 3.30-3.20 (m, 1H), 3.00-2.83 (m, 2H), 1.79-1.50 (m, 6H)，1.30 (dd，3H)，1.20-1.03 (m, 2H). C31H33C12N302的 MS (El)，實測值 550_21 (MH+)。 N-[(lS)-l-(聯苯-4-基甲基）-N-[2-(二甲基胺基）乙基】-2-氧代乙基]-1-(2,4-二氣苯基）環丙醯胺：b NMR (400 MHz, CD3OD) ： 7.60 (d, 2H), 7.56-7.43 (m, 5H), 7.40-7.35 (m, 2H), 7.20-7.16 (m, 2H), 3.80-3.75 (m, 1H), 3.47-3.41 (m,N-{(lS)-2-[(3S)-3-Aminopyridin-1-yl]-l-[(2,4-diphenyl)methyl]-2-oxoethyl} -1-(2,4-diphenyl)cyclopropanamide: h NMR 146258.doc -128- 201040149 (400 MHz, CD3OD): 8.56 (s, 1H), 7.50-7.38 (m, 3H), 7-28-7.22 (m, 1H), 7.18-7.13 (m, 1H), 5.20-5.08 (m, 1H), 4.10 (ddd, 1H), 3.64-3.58 (m, 1H), 3.45-3.38 (m , 1H), 3.18-2.80 (m, 4H), 2.10-1.95 (m, 1H), 1.89-1.78 (m, 1H), 1.68-1.57 (m, 1H), 1.50-1.45 (m, 3H), 1.15 MS (El) for C24H25CI4N3O2, found 530.05 (MH+). 4-bromo-Να-{[1-(2,4_; gas phenyl)cyclopropyl]carbonyl}-N-[(3S)-&quot;pyrrolidin-3-yl]-L-phenylalanamine decylamine: NMR (400 MHz, DMSO-d6): δ 8.94 (d, 1 Η), 7.58 (s, 1H), 7.39 (m, 4H), 7.01 (d, 2H), 6.61 (d, 1H), 4.38 (m, 1H), 4.11 (m, 1H), 2.94 (m, 3H), 2.73 (m, 3H), 1.90 (m, 1H), 1.60 (m, 1H), 1.37 (m, 2H), 0.95 (m, 2H) MS (El) for C23H24BrCl2N302, found 526 (MH+). 4-bromo-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-[(3R)-indolyl-3-yl]-L-phenylpropylamine decylamine: NMR (400 MHz, DMSO-d6): δ 8.80 (d, 1Η), 7.59 (s, 1H), 7.40 (m, 4H), 7.01 (d, 2H), 6.61 (d, 1H), 4.40 (m, 1H) ), 4.12 (m, 1H), 2.93 (m, 3H), 2.74 (m, 3H), 1.86 (m, 1H), 1.48 (m, 1H), 1.36 (m, 2H), 0.96 (m, 2H) _ C23H24BrCl2N302 MS (El) 'Found 526 (MH+). N-(3-Aminocyclohexyl)-2,4-dioxa-Να-{[1-(2,4-diphenyl)-cyclopropyl]carbonyl}-L-phenylalanamine decylamine: 4 NMR (400 MHz, CD3OD): 8.52 (s, 1H), 7.50-7.38 (m, 4H), 7.23-7.15 (m, 2H), 4.82-4.75 (m, 1H), 3.67-3.58 (m, 1H), 2.20-2.13 (m, 1H), 2.02-1.83 (m, 3H), 1.77-1.40 (m, 5H), 1.25-1.00 (m, 3H). (:241127(:14)^3〇2 of PCT口1)'Measured value 544.16 (]\^+). 146258.doc .129- 201040149 N-[(lS)-l-(biphenyl-4-ylmethyl)-2-(4-mercaptopyridazine -1-yl)-2-oxoethyl]-1-(2,4-diphenyl)cyclopropanamide: 4 NMR (400 MHz, CD3〇D): 7.60 (d, 1H), 7.55 -7.50 (m, 3H), 7.45-7.39 (m, 3H), 7.38-7.33 (m, 2H), 7.20-7.15 (m, 2H), 5.07 (t, 1H), 3.60-3.40 (m, 4H) , 2.96 (d, 2H), 2.53-2.40 (m, 2H), 2.38-2.30 (m, 1H), 2.24 (s, 3H), 2.05-1.97 (m, 1H), 1.65-1.55 (m, 2H) MS (El), </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> <RTIgt; -1-(biphenyl-4-ylmethyl)-2-oxoethyl]-1-(2,4-diphenyl)cyclopropanamide: 4 NMR (400 MHz, CD3OD): 8.57 ( s, 1H), 7.64 -7.60 (m, 2H), 7.55-7.50 (m, 2H), 7.45-7.40 (m, 4H), 7.38-7.30 (m, 2H), 7.18-7.14 (m, 2H), 5.03 (dd, 1H) , 3.90-3.65 (m, 2H), 3.55-3.43 (m, 1H), 3.30-3.20 (m, 1H), 3.00-2.83 (m, 2H), 1.79-1.50 (m, 6H), 1.30 (dd, 3H), 1.20-1.03 (m, 2H). MS (El) for C31H33C12N302, found 550_21 (MH+). N-[(lS)-l-(biphenyl-4-ylmethyl)-N-[2-(dimethylamino)ethyl]-2-oxoethyl]-1-(2,4 -diphenylphenyl)cyclopropanamide: b NMR (400 MHz, CD3OD): 7.60 (d, 2H), 7.56-7.43 (m, 5H), 7.40-7.35 (m, 2H), 7.20-7.16 (m , 2H), 3.80-3.75 (m, 1H), 3.47-3.41 (m,

2H), 3.00 (s, 3H), 2.97-2.80 (m, 4H), 2.63 (s, 6H), 1.64-1.55 (m, 2H), 1.18-1.05 (m, 2H). C3〇H33C12N302 的 MS (El)，實測值 538.24 (MH+)。 N-(2-胺基環己基）-2,4-二氣-Να-{[1-(2,4-二氣苯基）-環丙 146258.doc •130· 201040149 基]羰基}-L-苯丙胺醯胺：4 NMR (400 MHz，CD3OD): 8.53 (s, 1H), 7.45-7.37 (m, 4H), 7.30-7.26 (m, 1H), 7.18-7.14 (m, 1H), 4.75-4.60 (m, 1H), 4.30-4.25 (m, 1H), 3.40-3.35 (m, 1H), 3.12-3.06 (m, 2H), 1.80-1.40 (m, 10H), 1.28-1.00 (m，3H)· C25H27C14N302 的 MS (El)，實測值 544.16 (MH+)。 N-[(lR，2R)-2·胺基環己基】-2,4-二氣-Να-{[1-(2,4-二氣苯 基）-環丙基]羰基}-L-苯丙胺醯胺：4 NMR (400 ΜΗζ， CD3OD) ： 7.44-7.37 (m, 4H), 7.26-7.22 (m, 1H), 7.18-7.14 (m, 1H), 4.62 (s, 1H), 4.28 (t, 1H), 3.78 (ddd, 1H), 3.07 (d, 2H), 2.93-2.84 (ddd, 1H), 2.08-2.00 (m5 1H), 1.84-1.62 (m, 4H), 1.52-1.20 (m, 7H)，1.02-0.97 (m，1H). C25H27C14N302 的]\^(丑1)，實測值544.10 (]^11+)。 N-[(lS，2S)-2-胺基環己基】-2,4-二氣-Να-{[1-(2,4-二氣苯 基）-環丙基]羰基}-L-苯丙胺醢胺：4 NMR (400 MHz, CD3OD) ： 8.57 (s, 1H), 7.45-7.38 (m, 4H), 7.28 (d, 1H), 7.17 (d, 1H), 4.63 (s, 1H), 4.58 (dd, 1H), 3.73 (ddd, 1H), 3.25-3.20 (m, 2H), 3.02-2.95 (m, 2H), 2.05-2.00 (m, 1H), 1.90-1.86 (m, 2H), 1.50-1.30 (m, 5H), 1.20-1.90 (m, 1H), 1.03-0.98 (m, 1H). C25H27C14N302 的 MS (El)，實測值 544.04 (MH+) 0 2,4-二氣-Να-{[1-(2,4_二氣苯基）環丙基】羰基}-N-[(3S)-呱啶-3-基】-L-苯丙胺醸胺··1111'^1^400 1^112，01^00)·· 8.57 (s, 1H), 7.48-7.38 (m, 4H), 7.23 (d, 1H), 7.16 (d, 1H), 146258.doc -131 - 201040149 4.63-4.60 (m, 1H), 3.97-3.93 (m, 1H), 3.30-3.27 (m, 1H), 3.18-3.06 (m, 1H), 3.02-2.83 (m, 2H), 2.64-2.57 (m, 1H), 2.00- 1.95 (m, 2H)? 1.82-1.76 (m, 1H), 1.60-1.43 (m, 4H), 1.17-1.00 (m，2H). C24H25C14N302 的 MS (El)，實測值 530.12 (MH+)。 N-{(lS)-2-(4-胺基呱啶-1-基）-l-【(4-溴苯基）甲基]-2·氧代 乙基}-1-(2,4-二氣苯基）環丙醢胺：4 NMR (400 ΜΗζ， CD3〇D) ： 8.37 (s, 1H), 7.58 (d, 1H), 7.40-7.35 (m, 3H), 7.00- 6.90 (m, 2H), 4.85-4.80 (m, 1H), 4.18-4.05 (m, 2H), 3.86-3.78 (m, 2H), 3.05-2.85 (m, 2H), 2.80-2.68 (m, 3H), 1.80-1.73 (m, 2H), 1.37-1.00 (m, 3H), 0.95-0.86 (m, 2H). (：2411241*(：12&gt;13〇2的1^8斤1)，實測值540.07 (]^11+)。 4 -漠-N(*-{[l-(2,4-·一氣苯基）環丙基】幾基} - N- [(3R) -略咬_ 3·基]_L-苯丙胺醢胺：NMR (400 MHz, CD3OD) : 8.37 (s, 1H), 8.40 (d, 1H), 7.60 (s, 1H), 7.48-7.37 (m, 3H), 7.03 (d, 2H), 6.60 (d, 1H), 4.45-4.39 (m, 1H), 3.75-3.65 (m, 1H), 3.06-2.88 (m, 2H), 2.83-2.65 (m, 3H), 2.56-2.48 (m, 2H), 1.76-1.60 (m, 2H), 1.56-1.25 (m, 3H), 1.00-0.94 (m, 2H). C24H26BrCl2N3O2的MS(EI)，實測值 540.01 (MH+)。 N-{(lS)-l-【(4-溴苯基）甲基】-2-[4-(甲基胺基）呱啶-I*]· 2-氧代乙基}-1-(2,4-二氣苯基）環丙醢胺：1h NMR (400 MHz，CD3OD) : 8·50 (s，1H)，7.60-7.40 (m，1H)，7.10-7.00 (m, 2H), 5.10-5.00 (m, 1H), 4.40 (t, 1H), 4.00 (t, 1H), 3.75-3.65 (m, 1H), 3.20-2.08 (m, 1H), 2.80-2.260 (m, 2H), 2.55- 146258.doc -132- 201040149 2.45 (m, 5H), 2.00-1.90 (m, 2H), 1.80-1.63 (m, 3H), 1.55-1.40 (m, 1H), 1.20-1.09 (m，2H)_ C25H28BrCl2N302 的 MS (丑1)，實測值554.12 (]^11+)。 N-(2-胺基-2-甲基丙基）-Να-{【1-(2,4-二氣苯基）環丙基]-羰基}-4·(三氟甲基）-L-苯丙胺醯胺：NMR (400 MHz, DMSO-d6): δ 8.47-8.44 (m, 1Η), 8.37 (s, 2H), 7.59 (d, 2H), 7.54 (s, 1H), 7.41 (s, 2H), 7.32 (d, 2H), 6.82 (d, 1H), 4.59-4.53 (m, 1H), 3.12 (d, 2H), 3.07-3.02 (m, 1H), 2.93-2.87 (m, 1H), 1.34-1.31 (m, 2H), 1.05 (s, 6H), 1.01-0.89 (m, 2印；（：241126(：12?3：^3〇2的]^8(£1)，實測值516.20(^111+)。 N-[(lS)-2-[(3R)-3-(甲基胺基）吼咯啶-1-基】-2-氧代-1_ {[4-(三氟甲基）-苯基】-甲基}乙基】-l-{4-[(三氟甲基）氧】苯 基}-環丙醢胺：4 NMR (400 MHz，CDC13): δ 7.52-7.48 (m, 2H), 7.36-7.28 (m, 2H), 7.24-7.17 (m5 4H), 6.01-5.84 (m, 1H), 4.85-4.74 (m, 1H), 3.73-3.65 (m, 1H), 3.62-3.25 (m, 3H), 3.17-2.74 (m, 4H), 2.51-2.46 (m, 3H), 2.17-1.87 (m, 2H), 1.53-1.47 (m, 2H), 1.06-0.99 (m, 2H); C26H27F6N303的 MS (El)，實測值 544.23 (MH+)。 N-{(lS)_l-[(4-溴苯基）甲基]_2-[(3R)-3·(甲基胺基广比咯 啶-1-基】-2-氧代乙基}-1-{4-[(三氟甲基）氧】苯基}環丙斑 胺··1HNMR(400 MHz，CDCl3)·δ 7.38-7.28 (m，4H)，7·20-7.17 (m, 2H), 7.00-6.90 (m, 2H), 6.00-5.82 (m, 1H), 4.81-4.74 (m, 1H), 3.74-3.71 (m, 1H), 3.67-3.28 (m, 3H), 3.12-2.71 (m, 3H), 2.52-2.47 (m, 3H), 2.23-2.01 (m, 2H), 1.53- 146258.doc -133- 201040149 1.46 (m, 2H), 1.05-0.95 (m，2H); C25H27BrF3N303 的 MS (丑1)，實測值 554.18 (1^11+)。 N-(2-胺基-2-甲基丙基）-4-溴-Να-{[1-(2,4-二氣苯基）-環 丙基】羰基}-L-苯丙胺醢胺：iHNMRHOOMHz, DMSO-d6): δ 8.35 (s, 3H), 7.57 (s, 1H), 7.42 (d, 4H), 7.05 (d, 2H), 6.73 (d, 1H), 4.49 (q, 1H), 3.12 (d, 2H), 2.95-2.79 (m, 2H), 1.37-1.35 (m, 2H), 1.07 (s，6H), 1.03-0.91 (m, 2H); C23H26BrCl2N302 的 MS (El)，實測值 528_10 (MH+)。 N-[(lS)-2-[(3S)-3-(甲基胺基）》比咯啶-1-基]-2-氧代-1-{[4-(三氟甲基）-苯基】甲基}乙基】-l-{4-[(三氟甲基）氧]苯 基}環丙醢胺：NMR (400 MHz，CDC13): δ 7.50 (d，2H)， 7.35-7.28 (m, 2H), 7.22-7.17 (m, 4H), 6.02-5.85 (m, 1H), 5.41 (s, 1H), 4.85-4.79 (m, 1H), 3.69-3.68 (m, 1H), 3.51-3.37 (m, 3H), 3.08-1.352.83 (m, 3H), 2.43 (d, 3H), 2.14-1.95 (m, 2H), 1.53-1.51 (m, 2H), 1.05-0.96 (m, 2H); C26H27F6N3〇3 的 MS (El)，實測值544.23 (MH+)。 N-{(lS)-l-[(4-溴苯基）甲基】-2-[(3S)-3-(甲基胺基）e比咯 啶-1-基】-2-氧代已基}-1-{4-[(三氟甲基）氧丨苯基}環丙醢 胺：4^[^111(400]^1^，〇厘8〇-(16):3 8.25(3，111),7.44- 7.41 (m, 2H), 7.38-7.29 (m, 4H), 7.07-7.03 (m? 2H), 6.86-6.78 (m, 1H), 4.69-4.60 (m, 1H), 3.70-3.58 (m? ih), 3.40-3.23 (m, 4H), 2.89-2.75 (m, 2H), 2.36 (s, 3H), 2.03-1.74 (m, 2H), 1.30-1.23 (m, 2H), 1.04-0.93 (m, 2H); C25H27BrF3N3〇3的 ]^8(£1)，實測值 556.13 (]\411+)。 146258.doc -134· 201040149 N-[(lS)-2-(2,7-二氮雜螺[4.4]壬 _2-基）-2-氧代-l-{[4-(三 氟甲基）苯基]-甲基}乙基]-l-(2,4-二氣苯基）環丙醯胺：ιΗ NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1Η), 7.58 (m, 3H), ' 7.40 (s, 2H), 7.32 (m, 2H), 6.88 (m, iH), 4.67 (m, 1H), 3.61-2.78 (m, 10H), 1.66 (m, 4H), 1.29 (m, 2H), 0.94 (m, • 2H). C27H28C12F3N302的 MS (El)，實測值 555 (MH+)。 N-[(lS)-2-(2,8-二氮雜螺[4.S]癸·8_基）_2·氧代 •(三 氟甲基）苯基】-甲基}乙基]-1-(2,4-二氣苯基）環丙酿胺：ιΗ 〇 NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.58 (m, 3H), 7.40 (s5 2H), 7.30 (d, 2H), 6.91 (m, iH), 4.94 (m, 1H), 3.34-2.76 (m, 10H), 1.64 (m, 2H), 1.28 (m, 6H), 0.96 (m, 2H). C28H3〇C12F3N302 的 MS (El)，實測值 569 (MH+)。 ]\-[(18)-2-(1，7-二氮雜螺[4.4]壬-7-基）-2-氧代-1-{[4-(三 氟曱基）苯基】-甲基}乙基]-1-(2,4-二氣苯基）環丙醢胺：如 WO 2004/005293; Med C/zew，1990, 33, 2270 中描述的製 ❹ 備1，7-二氮雜螺[4.4]壬烷。1HNMR(400 MHz，DMSO-d6): δ 8.21 (s, 1H), 7.57 (m, 3H), 7.39 (s, 2H), 7.30 (m, 2H), 6.81 (m, 1H), 4.67 (m, 1H), 3.62-3.08 (m, 5H), 2.90 (m, 4H), i·73 (m，5H), 1·30 (m，2H)，0.94 (m, 2H). C27H28C12F3N302 • 的 MS (EI)，實測值 555 (MH+)。 N_[(3S)-1-氮雜雙環[2 2 2]辛·3_基卜4_溴·如-⑴·…氟苯 基）-環丙基I羰基}_L_苯丙胺醮胺：iH NMR (400 MHz, DMSO-d6)： δ 8.10 (d, 1H), 7.43-7.35 (m, 4H), 7.23-7.18 (m, 2H), 6.99 (d, 2H), 6.40 (d, 1H), 4.51 (q, 1H), 3.62-3.60 (m, 146258.doc •135- 201040149 1H), 3.11-3.06 (m, 1H), 2.82-2.67 (m, 6H), 2.35-2.30 (m, 1H), 1.72-1.50 (m, 4H), 1.39-1.30 (m, 3H), 1.03-0.95 (m, 2H); C26H29BrFN302的 MS (El)，實測值516.2 (MH+)。 4-溴-Να-{[1-(2,4-二氣苯基）環丙基】羰基}-N-【(3S)-呱啶-3-基】-L-苯丙胺醢胺：4 NMR (400 MHz, CD3OD) : 8.50 (s, 1H), 7.48-7.37 (m, 5H), 7.00 (d, 2H), 4.52 (t, 1H), 3.95-3.88 (m, 1H)? 3.28-3.20 (m, 1H), 2.96-2.77 (m, 4H), 2.58 (t, 2H), 2.00-1.90 (m, 2H), 1.80-1.74 (m, 1H), 1.60-1.45 (m, 3H), 1.18-1.04 (m, 2H). C24H26BrCl2N302 的 MS (El)，實測 值 539.94 (MH+) ° 4-溴-Να-{[1-(2,4-二氣苯基）環丙基】羰基}-N-呱啶-3-基-L-苯丙胺醢胺：1H NMR (400 MHz, CD3OD) : 8.54 (s，1H)， 7.47-7.38 (m, 5H), 6.98 (d, 2H), 4.53-4.44 (m, 1H), 3.90-3.80 (m, 1H), 3.25-3.17 (m, 2H), 2.96-2.73 (m, 4H), 2.58 (t, 2H), 2.00-1.65 (m, 4H), 1.60-1.40 (m, 3H), 1.20-1.02 (m, 2H). C24H26BrCl2N302的MS (El)，實測值539.94 (MH+)。 l-[2-氟-4-(三氟甲基）苯基】-N-[(lS)-2-[(3S)-3-(甲基胺 基）-&quot;比咯啶-1-基]-2·氧代-l-{[4-(三氟甲基）苯基]甲基}乙 基]環丙醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.26 (s， 1Η), 7.64-7.54 (m, 5H), 7.33 (t, 3H), 7.15-7.05 (m, 1Ή), 4.74-4.66 (m, 1H), 3.74-3.63 (m, 1H), 3.47-3.25 (m, 4H), 3.00-2.88 (m, 2H), 2.39 (s, 3H), 2.09-1.80 (m, 2H), 1.34-1.31 (m, 2H)，1.08-0.95 (m，2H); C26H26F7N302的 MS (El)， 實測值546.24 (MH+)。 146258.doc •136- 201040149 N-{(lS)-l-[(4·溴苯基）甲基】-2-[(3S)-3-(甲基胺基）《比洛 咬-1-基】-2-氧代乙基}_1_[2_氟-4-(三氟甲基）苯基】環丙醢 胺：咕 NMR (400 MHz，DMSO-d6): δ 8.24 (s, 1H), 7.66 (d, 1H), 7.59-7.57 (m, 2H), 7.42 (d, 2H), 7.10-7.01 (m, 3H), 4.65- 4.59 (m, 1H), 3.70-3.61 (m, 1H), 3.41-3.19 (m, 4H), 2.86-2.76 (m, 2H), 2.35 (d, 2H), 2.02-1.73 (m, 2H), 1.39-(H, 2H) El), found 538.24 (MH+). N-(2-Aminocyclohexyl)-2,4-dioxa-Να-{[1-(2,4-diphenyl)-cyclopropene 146258.doc •130· 201040149 】]carbonyl}-L - amphetamine amide: 4 NMR (400 MHz, CD3OD): 8.53 (s, 1H), 7.45-7.37 (m, 4H), 7.30-7.26 (m, 1H), 7.18-7.14 (m, 1H), 4.75- 4.60 (m, 1H), 4.30-4.25 (m, 1H), 3.40-3.35 (m, 1H), 3.12-3.06 (m, 2H), 1.80-1.40 (m, 10H), 1.28-1.00 (m, 3H MS) (C) of C25H27C14N302, found 544.16 (MH+). N-[(lR,2R)-2.Aminocyclohexyl]-2,4-dioxa-Να-{[1-(2,4-diphenyl)-cyclopropyl]carbonyl}-L- Amphetamine: 4 NMR (400 ΜΗζ, CD3OD): 7.44-7.37 (m, 4H), 7.26-7.22 (m, 1H), 7.18-7.14 (m, 1H), 4.62 (s, 1H), 4.28 (t , 1H), 3.78 (ddd, 1H), 3.07 (d, 2H), 2.93-2.84 (ddd, 1H), 2.08-2.00 (m5 1H), 1.84-1.62 (m, 4H), 1.52-1.20 (m, 7H), 1.02-0.97 (m, 1H). C25H27C14N302]\^(Ugly 1), found 544.10 (]^11+). N-[(lS,2S)-2-aminocyclohexyl]-2,4-dioxa-Να-{[1-(2,4-diphenylphenyl)-cyclopropyl]carbonyl}-L- Amphetamine: 4 NMR (400 MHz, CD3OD): 8.57 (s, 1H), 7.45-7.38 (m, 4H), 7.28 (d, 1H), 7.17 (d, 1H), 4.63 (s, 1H), 4.58 (dd, 1H), 3.73 (ddd, 1H), 3.25-3.20 (m, 2H), 3.02-2.95 (m, 2H), 2.05-2.00 (m, 1H), 1.90-1.86 (m, 2H), 1.50-1.30 (m, 5H), 1.20-1.90 (m, 1H), 1.03-0.98 (m, 1H). MS (El) for C25H27C14N302, found 544.04 (MH+) 0 2,4-digas-Να- {[1-(2,4_Diphenyl)cyclopropyl]carbonyl}-N-[(3S)-acridin-3-yl]-L-phenylpropylamine decylamine··1111'^1^400 1 ^112,01^00)··· 8.57 (s, 1H), 7.48-7.38 (m, 4H), 7.23 (d, 1H), 7.16 (d, 1H), 146258.doc -131 - 201040149 4.63-4.60 ( m, 1H), 3.97-3.93 (m, 1H), 3.30-3.27 (m, 1H), 3.18-3.06 (m, 1H), 3.02-2.83 (m, 2H), 2.64-2.57 (m, 1H), 2.00- 1.95 (m, 2H)? 1.82-1.76 (m, 1H), 1.60-1.43 (m, 4H), 1.17-1.00 (m, 2H). MS (El) for C24H25C14N302, found 530.12 (MH+). N-{(lS)-2-(4-Aminopyridin-1-yl)-l-[(4-bromophenyl)methyl]-2.oxoethyl}-1-(2,4 -diphenylphenyl)cyclopropanamide: 4 NMR (400 ΜΗζ, CD3〇D): 8.37 (s, 1H), 7.58 (d, 1H), 7.40-7.35 (m, 3H), 7.00- 6.90 (m , 2H), 4.85-4.80 (m, 1H), 4.18-4.05 (m, 2H), 3.86-3.78 (m, 2H), 3.05-2.85 (m, 2H), 2.80-2.68 (m, 3H), 1.80 -1.73 (m, 2H), 1.37-1.00 (m, 3H), 0.95-0.86 (m, 2H). (:2411241*(:12&gt;13〇2 of 1^8 kg1), measured value 540.07 (] ^11+). 4 -Moist-N(*-{[l-(2,4-·一气phenyl)cyclopropyl)-)- N- [(3R) - Slightly bite _ 3·yl]_L - amphetamine amide: NMR (400 MHz, CD3OD): 8.37 (s, 1H), 8.40 (d, 1H), 7.60 (s, 1H), 7.48-7.37 (m, 3H), 7.03 (d, 2H), 6.60 (d, 1H), 4.45-4.39 (m, 1H), 3.75-3.65 (m, 1H), 3.06-2.88 (m, 2H), 2.83-2.65 (m, 3H), 2.56-2.48 (m, 2H) ), 1.76-1.60 (m, 2H), 1.56-1.25 (m, 3H), 1.00-0.94 (m, 2H). MS (EI) of C24H26BrCl2N3O2, found 540.01 (MH+). N-{(lS)- L-[(4-Bromophenyl)methyl]-2-[4-(methylamino)acridine-I*]·2-oxoethyl}-1-(2,4-dibenzene Cyclopropanamide: 1h NMR (400 M Hz, CD3OD): 8·50 (s, 1H), 7.60-7.40 (m, 1H), 7.10-7.00 (m, 2H), 5.10-5.00 (m, 1H), 4.40 (t, 1H), 4.00 ( t, 1H), 3.75-3.65 (m, 1H), 3.20-2.08 (m, 1H), 2.80-2.260 (m, 2H), 2.55- 146258.doc -132- 201040149 2.45 (m, 5H), 2.00- 1.90 (m, 2H), 1.80-1.63 (m, 3H), 1.55-1.40 (m, 1H), 1.20-1.09 (m, 2H)_ C25H28BrCl2N302 MS (ugly 1), found 554.12 (]^11+ ). N-(2-Amino-2-methylpropyl)-Να-{[1-(2,4-diphenyl)cyclopropyl]-carbonyl}-4·(trifluoromethyl)-L - amphetamine amide: NMR (400 MHz, DMSO-d6): δ 8.47-8.44 (m, 1 Η), 8.37 (s, 2H), 7.59 (d, 2H), 7.54 (s, 1H), 7.41 (s, 2H), 7.32 (d, 2H), 6.82 (d, 1H), 4.59-4.53 (m, 1H), 3.12 (d, 2H), 3.07-3.02 (m, 1H), 2.93-2.87 (m, 1H) , 1.34-1.31 (m, 2H), 1.05 (s, 6H), 1.01-0.89 (m, 2 impressions; (:241126(:12?3:^3〇2)^8(£1), measured value 516.20(^111+). N-[(lS)-2-[(3R)-3-(Methylamino)oxaridin-1-yl]-2-oxo-1_ {[4-(three Fluoromethyl)-phenyl]-methyl}ethyl]-l-{4-[(trifluoromethyl)oxy]phenyl}-cyclopropanamide: 4 NMR (400 MHz, CDC13): δ 7.52 -7.48 (m, 2H), 7.36-7.28 (m, 2H), 7.24-7.17 (m5 4H), 6.01-5.84 (m, 1H), 4.85-4.74 (m, 1H), 3.73-3.65 (m, 1H ), 3.62-3.25 (m, 3H), 3.17-2.74 (m, 4H), 2.51-2.46 (m, 3H), 2.17-1.87 (m, 2H), 1.53-1.47 (m, 2H), 1.06-0.99 (m, 2H); MS (El) for C26H27F6N303, found 544.23 (MH+). N-{(lS)_l-[(4-bromophenyl)methyl]_2-[(3R)-3·(A Alkylaminopyrrolidin-1-yl]-2 -oxoethyl}-1-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanol··1H NMR (400 MHz, CDCl3)·δ 7.38-7.28 (m, 4H), 7· 20-7.17 (m, 2H), 7.00-6.90 (m, 2H), 6.00-5.82 (m, 1H), 4.81-4.74 (m, 1H), 3.74-3.71 (m, 1H), 3.67-3.28 (m , 3H), 3.12-2.71 (m, 3H), 2.52-2.47 (m, 3H), 2.23-2.01 (m, 2H), 1.53- 146258.doc -133- 201040149 1.46 (m, 2H), 1.05-0.95 (m, 2H); MS (ug. 1) of C25H27BrF3N303, found 554.18 (1^11+). N-(2-Amino-2-methylpropyl)-4-bromo-indole α-{[1-(2,4-diphenyl)-cyclopropyl]carbonyl}-L-phenylalanamine decylamine: iHNMRHOOMHz, DMSO-d6): δ 8.35 (s, 3H), 7.57 (s, 1H), 7.42 (d, 4H), 7.05 (d, 2H), 6.73 (d, 1H), 4.49 (q, 1H), 3.12 (d, 2H), 2.95-2.79 (m, 2H), 1.37-1.35 (m, 2H), 1.07 (s, 6H), 1.03-0.91 (m, 2H); MS (El) of C23H26BrCl2N302, measured value 528_10 (MH+). N-[(lS)-2-[(3S)-3-(methylamino)"pyrrolidin-1-yl]-2-oxo-1-{[4-(trifluoromethyl)- Phenyl]methyl}ethyl]-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide: NMR (400 MHz, CDC13): δ 7.50 (d, 2H), 7.35- 7.28 (m, 2H), 7.22-7.17 (m, 4H), 6.02-5.85 (m, 1H), 5.41 (s, 1H), 4.85-4.79 (m, 1H), 3.69-3.68 (m, 1H), 3.51-3.37 (m, 3H), 3.08-1.352.83 (m, 3H), 2.43 (d, 3H), 2.14-1.95 (m, 2H), 1.53-1.51 (m, 2H), 1.05-0.96 (m , 2H); MS (El) for C26H27F6N3 〇3, found 544.23 (MH+). N-{(lS)-l-[(4-bromophenyl)methyl]-2-[(3S)-3-(methylamino)e-pyrrolidin-1-yl]-2-oxo Alkenyl}-1-{4-[(trifluoromethyl)oxyindolephenyl}cyclopropanamide: 4^[^111(400]^1^, 〇8〇-(16):3 8.25( 3,111),7.44- 7.41 (m, 2H), 7.38-7.29 (m, 4H), 7.07-7.03 (m? 2H), 6.86-6.78 (m, 1H), 4.69-4.60 (m, 1H), 3.70-3.58 (m? ih), 3.40-3.23 (m, 4H), 2.89-2.75 (m, 2H), 2.36 (s, 3H), 2.03-1.74 (m, 2H), 1.30-1.23 (m, 2H) ), 1.04-0.93 (m, 2H); C25H27BrF3N3〇3]^8(£1), found 556.13 (]\411+). 146258.doc -134· 201040149 N-[(lS)-2-( 2,7-diazaspiro[4.4]壬_2-yl)-2-oxo-l-{[4-(trifluoromethyl)phenyl]-methyl}ethyl]-l-(2 , 4-diphenyl)cyclopropanamide: ιΗ NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1 Η), 7.58 (m, 3H), ' 7.40 (s, 2H), 7.32 (m , 2H), 6.88 (m, iH), 4.67 (m, 1H), 3.61-2.78 (m, 10H), 1.66 (m, 4H), 1.29 (m, 2H), 0.94 (m, • 2H). C27H28C12F3N302 MS (El), found 555 (MH+). N-[(lS)-2-(2,8-diazaspiro[4.S]癸·8_yl)_2.oxo•(trifluoro) Methyl)phenyl]-methyl}ethyl]-1-(2,4-di Phenyl) Cyclopropylamine: ιΗ NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.58 (m, 3H), 7.40 (s5 2H), 7.30 (d, 2H), 6.91 ( m, iH), 4.94 (m, 1H), 3.34-2.76 (m, 10H), 1.64 (m, 2H), 1.28 (m, 6H), 0.96 (m, 2H). MS (El) of C28H3〇C12F3N302 , found 569 (MH+). ]\-[(18)-2-(1,7-diazaspiro[4.4]壬-7-yl)-2-oxo-1-{[4-(trifluoromethyl)phenyl]- Methyl}ethyl]-1-(2,4-diphenyl)cyclopropanamide: as described in WO 2004/005293; Med C/zew, 1990, 33, 2270. Diazaspiro[4.4]decane. </ RTI> <RTIgt; 1H), 3.62-3.08 (m, 5H), 2.90 (m, 4H), i·73 (m, 5H), 1·30 (m, 2H), 0.94 (m, 2H). C27H28C12F3N302 • MS (EI ), measured value 555 (MH+). N_[(3S)-1-azabicyclo[2 2 2]octyl-3_yl b 4_bromo·as-(1)·...fluorophenyl)-cyclopropyl Icarbonyl}_L_phenylalanamine decylamine: iH NMR (400 MHz, DMSO-d6): δ 8.10 (d, 1H), 7.43-7.35 (m, 4H), 7.23-7.18 (m, 2H), 6.99 (d, 2H), 6.40 (d, 1H), 4.51 (q, 1H), 3.62-3.60 (m, 146258.doc • 135- 201040149 1H), 3.11-3.06 (m, 1H), 2.82-2.67 (m, 6H), 2.35-2.30 (m, 1H), 1.72 - 1.50 (m, 4H), 1.39-1.30 (m, 3H), mp. 4-bromo-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-[(3S)-acridin-3-yl]-L-phenylalanamine decylamine: 4 NMR (400 MHz, CD3OD): 8.50 (s, 1H), 7.48-7.37 (m, 5H), 7.00 (d, 2H), 4.52 (t, 1H), 3.95-3.88 (m, 1H)? 3.28-3.20 ( m, 1H), 2.96-2.77 (m, 4H), 2.58 (t, 2H), 2.00-1.90 (m, 2H), 1.80-1.74 (m, 1H), 1.60-1.45 (m, 3H), 1.18- MS (El), m.p. Acridine-3-yl-L-phenylalanamine amide: 1H NMR (400 MHz, CD3OD): 8.54 (s, 1H), 7.47-7.38 (m, 5H), 6.98 (d, 2H), 4.53-4.44 (m , 1H), 3.90-3.80 (m, 1H), 3.25-3.17 (m, 2H), 2.96-2.73 (m, 4H), 2.58 (t, 2H), 2.00-1.65 (m, 4H), 1.60-1.40 (m, 3H), 1.20-1.02 (m, 2H). MS (El) for C24H26BrCl2N302, found 539.94 (MH+). 1-[2-Fluoro-4-(trifluoromethyl)phenyl]-N-[(lS)-2-[(3S)-3-(methylamino)-&quot;bibrididine-1- Base]-2-oxo-l-{[4-(trifluoromethyl)phenyl]methyl}ethyl]cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 8.26 (s, 1Η), 7.64-7.54 (m, 5H), 7.33 (t, 3H), 7.15-7.05 (m, 1Ή), 4.74-4.66 (m, 1H), 3.74-3.63 (m, 1H), 3.47-3.25 ( m, 4H), 3.00-2.88 (m, 2H), 2.39 (s, 3H), 2.09-1.80 (m, 2H), 1.34-1.31 (m, 2H), 1.08-0.95 (m, 2H); C26H26F7N302 MS (El), found 546.24 (MH+). 146258.doc •136- 201040149 N-{(lS)-l-[(4.bromophenyl)methyl]-2-[(3S)-3-(methylamino)"Bilo bite-1- 2-oxoethyl}_1_[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropanamide: 咕NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H) , 7.66 (d, 1H), 7.59-7.57 (m, 2H), 7.42 (d, 2H), 7.10-7.01 (m, 3H), 4.65- 4.59 (m, 1H), 3.70-3.61 (m, 1H) , 3.41-3.19 (m, 4H), 2.86-2.76 (m, 2H), 2.35 (d, 2H), 2.02-1.73 (m, 2H), 1.39-

1.33 (m, 2H), 1.08-0.97 (m, 2H); C25H26BrF4N302 的 MS (£1)，實測值 558.15 (河11+)。 N-{(lS)_l-[(4-溴苯基）甲基】-2-[(3R)-3-(甲基胺基咯 咬-1-基】-2-氧代乙基}-1-[2-氟-4-(三氟甲基）苯基】環丙醯 胺：111丽11(400]^1^，〇]^〇-(16):3 8.25(3，111),7.68-7.64 (m, 1H), 7.59-7.57 (m, 2H), 7.43-7.40 (m, 2H), 7.08-7.03 (m, 3H), 4.65-4.60 (m, 1H), 3.57-3.18 (m, 5H), 2.90-2.77 (m, 2H), 2.35 (d, 2H), 2.07-1.71 (m, 2H), 1.40-1.32 (m, 2H)，1.09-0.97 (m, 2H); C25H26BrF4N302的 MS (El)，實 測值 558.15 (MH+)。 N_[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-4-溴-Να-【(1-{4-[(二 氟甲基）-氧】苯基}環丙基）羰基]-L-苯丙胺醢胺：4 NMR (400 MHz, DMSO-d6): δ 8.20 (d, 1H), 7.43 (d, 2H), 7.08 (d, 2H), 6.97 (d, 2H), 6.71 (d, 2H), 6.21 (d, 1H), 4.51 (q, 1H), 3.66- 3.65 (m, 1H), 3.18-3.12 (m, 1H), 2.86-2.74 (m, 6H), 2.42-2.37 (m, 1H), 1.75-1.54 (m, 4H), 1.41-1.38 (m5 1H), 1.24-1.22 (m，2H)，0.93-0.84 (m，2H); C27H30BrF2N3O3 的 MS (El)，實測值 514.18 (MH+)。 146258.doc •137- 201040149 l-[2-氟-4-(三氟甲基）苯基】-N-[(lS)-2-[(3R)-3-(甲基胺 基）-»比咯啶-1-基]-2-氧代-1-{[4-(三氟甲基）苯基]甲基}乙 基 1環丙醢胺：4 NMR (400 MHz，DMSO-d6): δ 7.65-7.54 (m, 5H), 7.35-7.31 (m, 2H), 7.13-7.07 (m, 1H), 4.72-4.67 (m, 1H), 3.60-3.54 (m, 2H), 3.49-3.19 (m, 4H), 3.03-2.88 (m, 2H), 2.37 (d, 3H), 2.10-1.72 (m, 2H), 1.37-1.28 (m, 2H), 1.10-0.96 (m, 2H); C26H26F7N302 的 MS (El)，實測值 546.24 (MH+) ° N-[(3S)-1-氮雜雙環【2.2.2】辛-3-基]-Να·[(1-{4-[(二氟甲 基）氧】-苯基}環丙基）羰基】-4-(三氟甲基）-L-苯丙胺醢胺： *H NMR (400 MHz, DMSO-d6): δ 8.24-8.24 (m, 2Η), 7.63-7.61 (m, 2H), 7.26-7.21 (m, 2H), 7.08-7.05 (m, 2H), 6.71-6.68 (m, 2H), 6.24-6.22 (m, 1H), 4.57 (q, 1H), 3.71-3.68 (m, 1H), 3.22-3.16 (m, 1H), 2.99-2.74 (m, 6H), 2.46-2.42 (m, 1H), 1.78-1.54 (m, 4H), 1.45-1.38 (m, 1H), 1.24-1.17 (m, 2H)，0.92-0.83 (m，2H); C28H30F5N3O3 的 MS (El)，實測 值 551.28 (MH+)。 4-溴-Να-{[1-(2,4-二氣苯基）環丙基]羰基卜N-呱啶-4-基- L-苯丙胺酿胺：NMR (400 MHz，CD3〇D) : 8.46 (s，1H), 7.48-7.37 (m, 5H), 6.99 (d, 2H), 4.50 (t, 1H), 3.84-3.79 (m, 1H), 3.40-3.34 (m5 2H), 3.08-3.00 (m, 2H), 2.85 (ddd, 2H), 2.06-1.93 (m, 2H), 1.65-1.48 (m, 4H), 1.08-1.04 (m, 2H). C24H26BrCl2N302 的 MS (El)，實測值 540.01 (MH+)。 4-溴-N-[(3R)-呱啶-3-基】-Να-[(1-{4-【（三氟甲基）氧】-苯 146258.doc -138· 201040149 基}環丙基）羰基】-L-苯丙胺醯胺：4 NMR (400 MHz, CD3OD) ： 8.48 (s, 1H), 7.42-7.39 (m, 4H), 7.24 (d, 2H), 6.98 (d, 2H), 4.45 (t, 1H), 3.84-3.79 (m, 1H), 3.25-3.20 (m, 1H), 2.95-2.75 (m, 4H), 2.00-1.68 (m, 3H), 1.52-1.38 (m, 4H), 1.18-1.02 (m, 2H)· C25H27BrF3N302 的 MS (El)，實測 值 556.19 (MH+)。 N-(2-胺基乙基）-4-溴-Να-{[1-(2,4-二氣苯基）環丙基】-羰 基}-1^-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.53 (m, 1H), 8.36 (m, 1H), 7.58 (s, 1H), 7.40 (m, 4H), 7.00 (d, 2H), 6.63 (d, 2H), 4.42 (m, 1H), 3.14 (m, 2H), 2.91-2.68 (m, 4H), 1.38 (m, 2H), 0.96 (m, 2H); C21H22BrCl2N302的 MS (El)，實測值 499.95 (MH+)。 4-溴-Να-{[1-(2,4-二氣苯基）環丙基]羰基}-N-曱基-N-[2-(甲基胺基）乙基】-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1H), 7.63-7.60 (m, 1H), 7.43-7.41 (m, 4H), 7.05 (d, 2H), 6.82 (t, 1H), 4.88-4.82 (m, 1H), 3.44-3.26 (m, 3H), 2.95 (s, 2H), 2.88-2.73 (m, 3H), 2.66 (t, 1H), 2.32 (d, 3H), 1.43-1.31 (m, 2H), 0.98-0.94 (m, 2H); C23H26BrCl2N302, 527.98 (MH+)。 N-(2-胺基乙基）-4-溴-Να-{[1-(2,4-二氣苯基）環丙基]-羰 基}-]\-甲基-L-苯丙胺醯胺：1HNMR(400 MHz,DMSO-d6): δ 8.39 (t, 1H), 8.31 (s, 1H), 7.62-7.60 (m, 1H), 7.45-7.39 (m, 4H), 7.02 (d, 2H), 6.63 (d, 1H), 4.47-4.42 (m, 1H), 3.23 (q, 2H), 2.95-2.88 (m, 1H), 2.80-2.70 (m, 3H), 2.42 (s, 146258.doc 139- 201040149 3H), 1.41-1.38 (m，2H)，1.02-0.94 (m，2H); C22H24BrCl2N302, 513.87 (MH+)。 4 -溪-Να-({1-[2 -氟-4-(三氟甲基）苯基】環丙基}-叛基）-N-曱基-N-[2-(曱基胺基）乙基]-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6)： δ 8.25 (s, 1H), 7.64 (t, 1H), 7.56 (d, 2H), 7.41 (dd, 2H), 7.13 (d, 1H), 7.05 (t, 2H), 4.86-4.73 (m, 1H), 3.39 (ddd, 2H), 2.94 (s, 2H), 2.89-2.65 (m, 5H), 2.38 (d, 3H)，1.41-1.26 (m, 2H), 1.13-0.90 (m, 2H). C24H26BrF4N302的 MS (El)，實測值 545.4 (MH+)。 4-溴-N-[2-(二甲基胺基）乙基】氟苯基）環丙 基】-羰基}-Ν-甲基-L-苯丙胺醢胺：4 NMR (400 MHz, DMSO-d6): δ 7.44-7.34 (m, 4H), 7.22-7.17 (m, 2H), 7.05-7.01 (m, 2H), 6.70 (d, 1H), 4.84-4.79 (m, 1H), 6.65-3.58 (m, 1H), 3.50-3.43 (m, 1H), 3.36-3.11 (m, 3H), 2.97 (s, 2H), 2.90-2.84 (m, 1H), 2.80-2.77 (m, 7H), 1.34-1.32 (m, 2H)，1.01-0.96 (m，2H); C24H29BrFN302 的 MS (El)，實測值 492.14 (MH+)。1.33 (m, 2H), 1.08-0.97 (m, 2H); MS (£1) for C25H26BrF4N302, found 558.15 (River 11+). N-{(lS)_l-[(4-bromophenyl)methyl]-2-[(3R)-3-(methylamino)-1-yl]-2-oxoethyl}- 1-[2-Fluoro-4-(trifluoromethyl)phenyl]cyclopropanamide: 111 Li 11(400]^1^,〇]^〇-(16):3 8.25(3,111), 7.68-7.64 (m, 1H), 7.59-7.57 (m, 2H), 7.43-7.40 (m, 2H), 7.08-7.03 (m, 3H), 4.65-4.60 (m, 1H), 3.57-3.18 (m , 5H), 2.90-2.77 (m, 2H), 2.35 (d, 2H), 2.07-1.71 (m, 2H), 1.40-1.32 (m, 2H), 1.09-0.97 (m, 2H); MS of C25H26BrF4N302 (El), found 558.15 (MH+). N_[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Να-[(1-{4-[(2) Fluoromethyl)-oxophenyl}cyclopropyl)carbonyl]-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.20 (d, 1H), 7.43 (d, 2H), 7.08 (d, 2H), 6.97 (d, 2H), 6.71 (d, 2H), 6.21 (d, 1H), 4.51 (q, 1H), 3.66- 3.65 (m, 1H), 3.18-3.12 (m, 1H) ), 2.86-2.74 (m, 6H), 2.42-2.37 (m, 1H), 1.75-1.54 (m, 4H), 1.41-1.38 (m5 1H), 1.24-1.22 (m, 2H), 0.93-0.84 ( m,2H); MS (El) for C27H30BrF2N3O3, found 514.18 (MH+). 146258.doc •137- 201040149 l-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(lS )-2-[ (3R)-3-(Methylamino)-»byrrolidin-1-yl]-2-oxo-1-{[4-(trifluoromethyl)phenyl]methyl}ethyl 1 ring Propylamine: 4 NMR (400 MHz, DMSO-d6): δ 7.65-7.54 (m, 5H), 7.35-7.31 (m, 2H), 7.13-7.07 (m, 1H), 4.72-4.67 (m, 1H ), 3.60-3.54 (m, 2H), 3.49-3.19 (m, 4H), 3.03-2.88 (m, 2H), 2.37 (d, 3H), 2.10-1.72 (m, 2H), 1.37-1.28 (m , 2H), 1.10-0.96 (m, 2H); MS (El) for C26H26F7N302, found 546.24 (MH+) ° N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl] -Να·[(1-{4-[(difluoromethyl)oxy]-phenyl}cyclopropyl)carbonyl]-4-(trifluoromethyl)-L-phenylalanamine decylamine: *H NMR (400 MHz, DMSO-d6): δ 8.24-8.24 (m, 2Η), 7.63-7.61 (m, 2H), 7.26-7.21 (m, 2H), 7.08-7.05 (m, 2H), 6.71-6.68 (m, 2H), 6.24-6.22 (m, 1H), 4.57 (q, 1H), 3.71-3.68 (m, 1H), 3.22-3.16 (m, 1H), 2.99-2.74 (m, 6H), 2.46-2.42 ( m, 1H), 1.78-1.54 (m, 4H), 1.45-1.38 (m, 1H), 1.24-1.17 (m, 2H), 0.92-0.83 (m, 2H); MS (El) of C28H30F5N3O3, measured value 551.28 (MH+). 4-Bromo-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl b-N-acridin-4-yl-L-phenylpropylamine amide: NMR (400 MHz, CD3〇D) : 8.46 (s,1H), 7.48-7.37 (m, 5H), 6.99 (d, 2H), 4.50 (t, 1H), 3.84-3.79 (m, 1H), 3.40-3.34 (m5 2H), 3.08- 3.00 (m, 2H), 2.85 (ddd, 2H), 2.06-1.93 (m, 2H), 1.65-1.48 (m, 4H), 1.08-1.04 (m, 2H). MS (El) of C24H26BrCl2N302, measured value 540.01 (MH+). 4-bromo-N-[(3R)-acridin-3-yl]-Να-[(1-{4-[(trifluoromethyl)oxy]-benzene 146258.doc -138· 201040149 base} Cyclopropyl Carbonyl]-L-amphetamine amide: 4 NMR (400 MHz, CD3OD): 8.48 (s, 1H), 7.42-7.39 (m, 4H), 7.24 (d, 2H), 6.98 (d, 2H), 4.45 (t, 1H), 3.84-3.79 (m, 1H), 3.25-3.20 (m, 1H), 2.95-2.75 (m, 4H), 2.00-1.68 (m, 3H), 1.52-1.38 (m, 4H MS (El) of 1.18-1.02 (m, 2H)· C25H27BrF3N302, found 556.19 (MH+). N-(2-Aminoethyl)-4-bromo-indole α-{[1-(2,4-diphenyl)cyclopropyl]-carbonyl}-1^-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.53 (m, 1H), 8.36 (m, 1H), 7.58 (s, 1H), 7.40 (m, 4H), 7.00 (d, 2H), 6.63 (d, 2H), 4.42 (m, 1H), 3.14 (m, 2H), 2.91-2.68 (m, 4H), 1.38 (m, 2H), 0.96 (m, 2H); MS (El) for C21H22BrCl2N302, found 499.95 (MH+) . 4-bromo-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-indenyl-N-[2-(methylamino)ethyl]-L-amphetamine Indoleamine: 4 NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1H), 7.63-7.60 (m, 1H), 7.43-7.41 (m, 4H), 7.05 (d, 2H), 6.82 (t , 1H), 4.88-4.82 (m, 1H), 3.44-3.26 (m, 3H), 2.95 (s, 2H), 2.88-2.73 (m, 3H), 2.66 (t, 1H), 2.32 (d, 3H ), 1.43-1.31 (m, 2H), 0.98-0.94 (m, 2H); C23H26BrCl2N302, 527.98 (MH+). N-(2-Aminoethyl)-4-bromo-indole α-{[1-(2,4-diphenyl)cyclopropyl]-carbonyl}-]\-methyl-L-phenylalanamine decylamine :1HNMR (400 MHz, DMSO-d6): δ 8.39 (t, 1H), 8.31 (s, 1H), 7.62-7.60 (m, 1H), 7.45-7.39 (m, 4H), 7.02 (d, 2H) , 6.63 (d, 1H), 4.47-4.42 (m, 1H), 3.23 (q, 2H), 2.95-2.88 (m, 1H), 2.80-2.70 (m, 3H), 2.42 (s, 146258.doc 139 - 201040149 3H), 1.41-1.38 (m, 2H), 1.02-0.94 (m, 2H); C22H24BrCl2N302, 513.87 (MH+). 4--溪-Να-({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}-reactive)-N-indenyl-N-[2-(decylamino) Ethyl]-L-amphetamine amide: 4 NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.64 (t, 1H), 7.56 (d, 2H), 7.41 (dd, 2H) , 7.13 (d, 1H), 7.05 (t, 2H), 4.86-4.73 (m, 1H), 3.39 (ddd, 2H), 2.94 (s, 2H), 2.89-2.65 (m, 5H), 2.38 (d , 3H), 1.41-1.26 (m, 2H), 1.13-0.90 (m, 2H). MS (El) of C24H26BrF4N302, found 545.4 (MH+). 4-bromo-N-[2-(dimethylamino)ethyl]fluorophenyl)cyclopropyl]-carbonyl}-indole-methyl-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO- D6): δ 7.44-7.34 (m, 4H), 7.22-7.17 (m, 2H), 7.05-7.01 (m, 2H), 6.70 (d, 1H), 4.84-4.79 (m, 1H), 6.65-3.58 (m, 1H), 3.50-3.43 (m, 1H), 3.36-3.11 (m, 3H), 2.97 (s, 2H), 2.90-2.84 (m, 1H), 2.80-2.77 (m, 7H), 1.34 -1.32 (m, 2H), 1.01 - 0.96 (m, 2H); MS (El) of C24H29BrFN302, found 492.14 (MH+).

4-溴-N-曱基_N-[2-(曱基胺基）乙基卜Να-[(1-{4-[(三氟甲 基）氧]苯基}-環丙基）羰基】-L-苯丙胺醢胺：NMR (400 MHz, DMSO-d6): δ 8.32 (s, 1Η), 7.44-7.41 (m, 2H), 7.38-7-34 (m, 2H), 7.32-7.30 (m, 2H), 7.09-7.03 (m, 2H), 6.93 (d, 1H), 4.86-4.81 (m, 1H), 3.48-3.45 (m, 2H), 2.98 (s, 2H), 2.93-2.84 (m, 3H), 2.81-2.72 (m, 2H), 2.44 (d, 3H), 1.29-1-24 (m, 2H), 1.02-0.94 (m, 2H); C24H27BrF3N303 的 MS 146258.doc -140. 201040149 (丑1)，實測值542.15 (厘11+)。 4-溴-N-[2-(二甲基胺基）乙基】-N-甲基-Να-【（1-{4-[(三氟 甲基）氧】-苯基}環丙基）羰基】-L-苯丙胺酿胺：iHNMRGOO MHz, DMSO-d6): δ 8.20 (s, 1Η), 7.45-7.41 (m, 2H), 7.38-7.30 (m, 4H), 7.07-7.03 (m, 2H), 6.81 (d, 2H), 4.88-4.85 (m, 1H), 3.51-3.32 (m, 2H), 2.98 (s, 2H), 2.90-2.74 (m, 3H), 2.62 (t, 1H), 2.39 (s, 4H), 2.27 (s, 2H), 1.28-1.25 (m, 2H)，1.02-0.97 (m, 2H); C25H29BrF3N303 的 MS (El)，實測 值 558.15 (MH+)。 N-{(lS)-2_(4-胺基-4-甲基呱啶-1-基）-l-[(4-溴苯基）甲 基氧代乙基卜1-{4-[(三氟曱基）氧】苯基}環丙醯胺：4 NMR (400 MHz, CD3OD) ： 8.40 (s, 1H), 7.42-7.38 (m, 4H), 7.27-7.22 (m, 2H), 7.01-6.99 (d, 2H), 5.05-5.01 (t, 1H), 4.05-4.00 (m, 1H), 3.90-3.70 (m, 2H), 3.55-3.45 (m, 1H), 3.30-3.15 (m, 1H), 3.00-2.86 (m, 1H), 2.82-2.75 (m, 1H), 1.84-1.68 (m, 4H), 1.57-1.38 (m, 6H), 1.18-1.04 (m, 2H). (：27^13。；^?31^2〇3的]^8(£1)，實測值 570.18 (]^11+)。 ]^’2’-{[1-(2,4-二氣苯基）環丙基】羰基}-5-苯基-]\-[(311)-呱啶-3·基]-L-正纈氨醯胺：4 NMR (400 MHz, CD3OD): 8.45 (s, 1H), 7.55-7.38 (m5 3H), 7.28-7.20 (m, 2H), 7.17- 7.08 (m, 3H), 4.37-4.32 (t, 1H), 3.93-3.84 (m, 1H), 3.30- 3.25 (m, 1H), 2.97-2.93 (m, 1H), 2.78-2.73 (m, 1H), 2.62- 2.47 (m, 2H), 2.02-1.85 (m, 2H), 1.80-1.62 (m, 3H), 1.58-4-bromo-N-fluorenyl_N-[2-(decylamino)ethylidene α-[(1-{4-[(trifluoromethyl)oxy]phenyl}-cyclopropyl)carbonyl 】-L-Amphetamine amide: NMR (400 MHz, DMSO-d6): δ 8.32 (s, 1 Η), 7.44-7.41 (m, 2H), 7.38-7-34 (m, 2H), 7.32-7.30 ( m, 2H), 7.09-7.03 (m, 2H), 6.93 (d, 1H), 4.86-4.81 (m, 1H), 3.48-3.45 (m, 2H), 2.98 (s, 2H), 2.93-2.84 ( m, 3H), 2.81-2.72 (m, 2H), 2.44 (d, 3H), 1.29-1-24 (m, 2H), 1.02-0.94 (m, 2H); MS 146258.doc -140 for C24H27BrF3N303. 201040149 (ugly 1), measured value 542.15 (PCT 11+). 4-bromo-N-[2-(dimethylamino)ethyl]-N-methyl-Να-[(1-{4-[(trifluoromethyl)oxy]-phenyl}cyclopropyl )carbonyl]-L-amphetamine amine: iHNMRGOO MHz, DMSO-d6): δ 8.20 (s, 1Η), 7.45-7.41 (m, 2H), 7.38-7.30 (m, 4H), 7.07-7.03 (m, 2H), 6.81 (d, 2H), 4.88-4.85 (m, 1H), 3.51-3.32 (m, 2H), 2.98 (s, 2H), 2.90-2.74 (m, 3H), 2.62 (t, 1H) 2.39 (s, 4H), 2.27 (s, 2H), 1.28-1.25 (m, 2H), 1.02-0.97 (m, 2H); MS (El) of C25H29BrF3N303, found 558.15 (MH+). N-{(lS)-2_(4-Amino-4-methylacridin-1-yl)-l-[(4-bromophenyl)methyloxyethylethyl 1-{4-[( Trifluoromethyl)oxy]phenyl}cyclopropanamide: 4 NMR (400 MHz, CD3OD): 8.40 (s, 1H), 7.42-7.38 (m, 4H), 7.27-7.22 (m, 2H), 7.01 -6.99 (d, 2H), 5.05-5.01 (t, 1H), 4.05-4.00 (m, 1H), 3.90-3.70 (m, 2H), 3.55-3.45 (m, 1H), 3.30-3.15 (m, 1H), 3.00-2.86 (m, 1H), 2.82-2.75 (m, 1H), 1.84-1.68 (m, 4H), 1.57-1.38 (m, 6H), 1.18-1.04 (m, 2H). (: 27^13.;^?31^2〇3]^8(£1), measured value 570.18 (]^11+).]^'2'-{[1-(2,4-diphenyl) Cyclopropyl]carbonyl}-5-phenyl-]\-[(311)-acridin-3-yl]-L-n-decylamine: 4 NMR (400 MHz, CD3OD): 8.45 (s, 1H), 7.55-7.38 (m5 3H), 7.28-7.20 (m, 2H), 7.17- 7.08 (m, 3H), 4.37-4.32 (t, 1H), 3.93-3.84 (m, 1H), 3.30- 3.25 (m, 1H), 2.97-2.93 (m, 1H), 2.78-2.73 (m, 1H), 2.62- 2.47 (m, 2H), 2.02-1.85 (m, 2H), 1.80-1.62 (m, 3H) , 1.58-

1.42 (m, 6H), 1.19-1.04 (m，2H). C26H31C12N303 的 MS 146258.doc -141 201040149 ([1)，實測值490.06 (1；111+)。 1_(2’4· 一氣苯基）-N-[(lS)-2-氧代_2_{3·[(苯基甲基）胺 基]-8-氮雜雙環[3.2.1】辛-8-基}-1-{[4_(三氟甲基）苯基】甲 基}乙基]環丙醯胺：向溶於二氯曱烷（3 (3-胺基-8-氮雜雙環[3,2,^-8_基）_2_氧代小{[4_(三氣甲 基）苯基]曱基}乙基]_1_(2,4-二氯苯基）環丙醯胺（〇 18 mmol)^ 液加入苯曱醛（18 μί, 〇 18 ，Aidrich)和冰醋 酸（30 μι)。將反應混合物於室溫攪拌3〇分鐘，之後加入溶 於THF(0_361 mL，0.3 6 mmol)的1Μ氰基硼氫化鈉，將所 得溶液於室溫攪拌90分鐘’真空濃縮並溶於甲醇。用製備 級HPLC(反相，乙腈/含01%曱酸的水）純化產物以產生39 mg(33°/。）的標題化合物。ij_j NMR (400 MHz, DMSO-d6): δ 7.57 (m, 3Η), 7.39 (m, 2H), 7.29 (m, 7H), 7.20 (m, 1H), 6-94 (m, 1H), 4.77 (m, 1H), 4.23 (m, 2H), 3.63 (d, 2H), 3.05-2.63 (m, 3H), 2.10 (m, 2H), 1.84-1.25 (m, 8H), 0.96 (m，2H). C34H34C12F3N302 的 MS (El)，實測值 645.0 (MH+)。 以與實施例6相似的方式合成N-[(lS)_2-(3-胺基-8-氮雜 雙環[3.2.1】辛_8-基）-2-氧代-1-{[4-(三氟甲基）-苯基]甲基} 乙基]-1-(2,4-二氣苯基）環丙醯胺，其中Boc-L-4-三氟曱基 苯丙胺酸替代Boc-L-4-溴苯丙胺酸，1-(2,4-二氣苯基）環丙 緩酸替代1-(4-(三氟甲氧基）苯基）環丙羧酸，並且8-氮雜雙 環[3.2.1]辛-3-基胺基曱酸叔丁酯替代卜Boc-3-(胺基曱基） 氮雜環丁烷。 146258.doc • 142- 201040149 1-(2,4-二氣苯基）-N-[(lS)-2-{3-[(2-甲基丙基）胺基】-8-氮 雜雙環-[3.2.1】辛-8-基}-2-氧代_1-{【4-(三氟甲基）苯基】甲 基}-乙基]-環丙醯胺：4 NMR (400 MHz，DMSO-d6): δ 7.58 (m, 3H), 7.39 (d, 2H), 7.33 (m, 2H), 6.98 (m, 1H), 4.77 (m, 1H), 4.15 (m, 2H), 3.05-2.53 (m, 3H), 2.25 (m, 2H), 2.04-1.25 (m, 11H), 0.98 (m, 2H), 0.85 (m, 6H). C31H36C12F3N302 的 MS (El)，實測值611.0 (MH+)。 1-(2,4-二氣苯基）-N-[(lS)-2-氧代-2-(3-吼咯啶-1-基-8-氮 雜雙環[3.2.1]辛-8-基）-1-{[4-(三氟甲基）苯基]甲基}乙基】環 丙醯胺：向溶於乙腈（3 mL)的N-[(lS)-2-(3-胺基-8-氮雜雙 環[3_2_1]辛-8-基）-2-氧代-1-{[4-(三氟甲基）苯基]-甲基}乙 基]-1-(2，4-二氣苯基）環丙醯胺（0·18 mmol)溶液加入碳酸卸 (27 mg ’ 0.20 mmol以及 1,4-二溴丁烧（26 μί，0.22 mmol， Aldrich)。將反應混合物加熱至100°C保持4小時，冷卻至 室溫，真空濃縮並溶於甲醇。用製備級HPLC(反相，乙腈/ 含0.1%曱酸的水）純化產物以產生31 mg(28%的標題化合 物。1H NMR (400 MHz，DMSO-d6): δ 8.16 (s, 1H)，7.58 (m, 3Η), 7.35 (m, 4H), 6.97 (m, 1H), 4.77 (m, 1H), 4.20 (m, 3H), 2.91 (m, 3H), 2.42 (m, 3H), 2.10 (m5 1H), 1.96-1.20 (m，13 H)，0.95 (m, 2H). C31H34C12F3N302 的 MS (El)，實測 值 609 (MH+)。 以與實施例6相似的方式合成N-[(lS)_2-(3-胺基-8-氮雜 雙環丨3.2.1】辛-8-基）-2-氧代-1-{[4-(三氟甲基）-苯基】甲基} 乙基]-l-(2,4 -二氣苯基）環丙酿胺’其中Boc-L-4 -二氣曱基 146258.doc •143· 201040149 苯丙胺酸替代Boc-L-4-溴苯丙胺酸，l-(2,4-二氯苯基）環丙 羧酸替代1-(4-(三氟曱氧基）苯基）環丙羧酸，並且8-氮雜雙 環[3.2.1]辛-3-基胺基甲酸叔丁酯替代l-Boc-3-(胺基曱基） 氮雜環丁烷。 4-溴-N-丨2-(二曱基胺基）乙基】-Να-({1-[2-氟-4-(三氟甲 基）·苯基]環丙基}羰基）-Ν-甲基-L-苯丙胺醯胺：NMR (400 MHz, DMSO-d6): δ 7.63 (m, 1H), 7.56 (d, 2H), 7.41 (m, 2H), 7.15-6.98 (m, 3H), 4.79 (ra, 1H), 3.58 (m, 1H), 3.52-3.43 (m, 1H), 2.88 (dd, 1H), 2.85-2.72 (m, 2H), 2.63 (s, 6H), 2.51 (m, 1H), 2.48 (dt, 3H), 1.41-1.24 (m, 2H), 1.02 (m, 2H). C25H28BrF4N3〇2 的 MS (El)，實測值 559.4 (MH+)。 N-8·氮雜雙環【3.2.1】辛-3-基-Να-{【1-(2,4-二氣苯基）環丙 基】-羰基}-4-(三氟甲基）-L-苯丙胺醢胺：NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1Η), 7.79 (s, 1H), 7.59 (d, 2H), 7.53 (s, 1H), 7.39 (m, 2), 7.30 (d, 2H), 6.74 (d, 1H), 4.56 (m, 1H), 3.69 (m, 3H), 2.89 (m, 2H), 2.04 (m, 3H), 1.76 (m, 5H), 1.33 (m, 2H)，0.93 (m, 2H)· C27H28C12F3N302 的 MS (El)，實測值 555 (MH+)。 4-溴-Να-{[1·(3-氟苯基）環丙基]羰基卜N-呱啶-4-基-L-苯 丙胺醢胺：NMR (400 MHz, DMSO_d6): δ 8.34 (s，1H)， 8.12 (s, 1Η), 7.40 (d, 2H), 7.34 (m, 1H), 7.07 (m, 3H), 6.98 (d, 2H), 6.56 (d, 1H), 4.42 (m, 1H), 3.05 (m, 2H), 2.75 (m, 2H), 1.70 (m, 2H), 1.37 (m, 2H), 1.23 (m, 2H), 0.97 (m, 146258.doc •144- 201040149 2H). C24H27BrFN302的 MS (EI)，實測值 489 (MH+)。 4-溴-N-呱啶-4-基·Να-{[1-(2,4,5-三氟苯基）環丙基】-羰 基}-1^·苯丙胺醯胺：NMR (400 MHz, DMSO-d6): δ 8.28 (s, 1Η), 8.06 (s, 1H), 7.50 (m, 2H), 7.41 (d, 2H), 7.02 (d, 2H), 6.80 (d, 1H), 4.38 (m, 1H), 3.08 (m, 2H), 2.75 (m, . 2H), 1.73 (m, 2H), 1.41 (m, 2H), 1.27 (m, 2H), 0.98 (m, 2H). C24H25BrF3N302的MS (EI)，實測值 525 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2】辛-3-基】-2-氣-]^-{[1-(2,4-二 〇 氣苯基）-環丙基】-羰基卜4-氟-L-苯丙胺醢胺：咕NMR (400 MHz, DMSO-de)： δ 8.20 (s, 1Η), 7.81 (m, 1H), Ί.62 (m, 1H)，7.43 (m, 2H)，7.34 (m，1H)，7.16 (m，2H)，6.57 (m， 1H), 4.55 (m, 1H), 3.08 (m, 1H), 2.91 (m, 3H), 2.69 (m, 4H), 2.33 (m, 1H), 1.56 (m, 4H), 1.39 (m, 1H), 1.29 (m, 2H)，0.98 (m，2H). C26H27C13FN302的MS (EI)，實測值539 (MH+)。 N-[(lS)-2-(3-胺基-8-氮雜雙環 P.2.1]辛-8-基）-2-氧代-Ι Ο {[4-(三氟甲基）_苯基]甲基}乙基】[(三氟甲基）氧】苯 基}環丙醯胺：bNMR (400 MHz，DMSO_d6): δ 7.59 (m, 2Η), 7.29 (m, 7H), 7.00 (m, 1H), 4.73 (m, 1H), 4.26 (m, • 1H), 3.08 (m, 2H), 2.88 (m, 2H), 1.92 (m, 4H), 1.62 (m, 2H)，1.45 (m，2H), 1.20 (m，2H)，0.94 (m, 2H). C28H29F6N3〇3的 MS (EI)，實測值 570 (MH+)。 N-[(lS)-2-(3-胺基-8-氮雜雙環[3.2.1】辛-8·基）-2-氧代-i_ {[4-(三氟甲基）-苯基】T基}乙基]-l-[2-氟-4-(三氟甲基）苯 146258.doc -145- 201040149 基 I環丙醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.23 (m, 1Η), 7.57 (m, 5H), 7.32 (m, 2H), 7.18 (d, 1H), 4.72 (m, 1H), 4.27 (m, 2H), 3.02 (m, 2H), 2.87 (m, 2H), 2.18-1.421.42 (m, 6H), 1.19-1.04 (m, 2H). MS 146258.doc - 141 201040149 for C26H31C12N303 ([1), found 490.06 (1; 111+). 1_(2'4·monophenyl)-N-[(lS)-2-oxo-2_{3·[(phenylmethyl)amino]-8-azabicyclo[3.2.1] 辛- 8-yl}-1-{[4_(trifluoromethyl)phenyl]methyl}ethyl]cyclopropanamide: soluble in dichloromethane (3 (3-amino-8-azabicyclo) [3,2,^-8_yl)_2_oxo small {[4_(trimethylmethyl)phenyl]fluorenyl}ethyl]_1_(2,4-dichlorophenyl)cyclopropanamide ( 〇18 mmol)^ was added to phenylfurfural (18 μί, 〇18, Aidrich) and glacial acetic acid (30 μιη). The reaction mixture was stirred at room temperature for 3 min, then added to THF (0-361 mL, 0.36 mmol) 1 Μ sodium cyanoborohydride, the resulting solution was stirred at room temperature for 90 minutes. 'Concentrated in vacuo and dissolved in methanol. The product was purified by preparative HPLC ( reverse phase, acetonitrile / water containing 01% decanoic acid) to yield 39 mg. (33°/.) of the title compound. ij_j NMR (400 MHz, DMSO-d6): δ 7.57 (m, 3 Η), 7.39 (m, 2H), 7.29 (m, 7H), 7.20 (m, 1H), 6-94 (m, 1H), 4.77 (m, 1H), 4.23 (m, 2H), 3.63 (d, 2H), 3.05-2.63 (m, 3H), 2.10 (m, 2H), 1.84-1.25 ( m, 8H), 0.96 (m, 2H). MS (El) for C34H34C12F3N302, found 645.0 (MH+). Example 6 Synthesis of N-[(lS)_2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-2-oxo-1-{[4-(three) Fluoromethyl)-phenyl]methyl}ethyl]-1-(2,4-diphenyl)cyclopropanamide, in which Boc-L-4-trifluoromethylphenylalanine replaces Boc-L- 4-bromophenylalanine, 1-(2,4-diphenyl)cyclopropanoic acid instead of 1-(4-(trifluoromethoxy)phenyl)cyclopropanecarboxylic acid, and 8-azabicyclo[ 3.2.1] tert-butyl oct-3-ylamino decanoate in place of Boc-3-(aminomercapto) azetidine. 146258.doc • 142- 201040149 1-(2,4-two gas Phenyl)-N-[(lS)-2-{3-[(2-methylpropyl)amino]-8-azabicyclo-[3.2.1]oct-8-yl}-2-oxo Generation _1-{[4-(trifluoromethyl)phenyl]methyl}-ethyl]-cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.58 (m, 3H), 7.39 (d, 2H), 7.33 (m, 2H), 6.98 (m, 1H), 4.77 (m, 1H), 4.15 (m, 2H), 3.05-2.53 (m, 3H), 2.25 (m, 2H), MS (El), calcd. (m.p.) (m.). 1-(2,4-diphenyl)-N-[(lS)-2-oxo-2-(3-indolyl-1-yl-8-azabicyclo[3.2.1] octane- 8-yl)-1-{[4-(trifluoromethyl)phenyl]methyl}ethyl]cyclopropanamide: N-[(lS)-2-() dissolved in acetonitrile (3 mL) 3-Amino-8-azabicyclo[3_2_1]oct-8-yl)-2-oxo-1-{[4-(trifluoromethyl)phenyl]-methyl}ethyl]-1- A solution of (2,4-diphenyl)cyclopropanamide (0·18 mmol) was added to the carbonic acid (27 mg '0.20 mmol and 1,4-dibromobutane (26 μί, 0.22 mmol, Aldrich). The reaction mixture was heated to 100 ° C for 4 hours, cooled to room temperature, concentrated in vacuo and taken up in methanol. The product was purified by preparative HPLC ( reverse phase, acetonitrile / water containing 0.1% decanoic acid) to yield 31 mg (28%) The title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.16 (s, 1H), 7.58 (m, 3 Η), 7.35 (m, 4H), 6.97 (m, 1H), 4.77 (m, 1H) , 4.20 (m, 3H), 2.91 (m, 3H), 2.42 (m, 3H), 2.10 (m5 1H), 1.96-1.20 (m, 13 H), 0.95 (m, 2H). MS of the C31H34C12F3N302 (El Found 609 (MH+). N-[(lS)_2-(3-Amino-8-azabicycloindole 3.2.1] oct-8-yl)-2 was synthesized in a similar manner to Example 6. - Generation-1-{[4-(trifluoromethyl)-phenyl]methyl}ethyl]-l-(2,4-diphenyl)cyclopropanol' wherein Boc-L-4 - II Gas 曱 146258.doc • 143· 201040149 phenylalanine replaces Boc-L-4-bromophenylalanine, 1-(4-(dichlorophenyl)cyclopropanecarboxylic acid instead of 1-(4-(trifluoroantimony) Phenyl)cyclopropanecarboxylic acid, and 8-azabicyclo[3.2.1]oct-3-ylaminocarboxylic acid tert-butyl ester in place of l-Boc-3-(aminoindenyl)azetidine 4-bromo-N-丨2-(didecylamino)ethyl]-Να-({1-[2-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl}carbonyl) - Ν-methyl-L-amphetamine amide: NMR (400 MHz, DMSO-d6): δ 7.63 (m, 1H), 7.56 (d, 2H), 7.41 (m, 2H), 7.15-6.98 (m, 3H), 4.79 (ra, 1H), 3.58 (m, 1H), 3.52-3.43 (m, 1H), 2.88 (dd, 1H), 2.85-2.72 (m, 2H), 2.63 (s, 6H), 2.51 (m, 1H), 2.48 (dt, 3H), 1.41-1.24 (m, 2H), 1.02 (m, 2H). MS (El) of C25H28BrF4N3 〇2, found 559.4 (MH+). N-8·azabicyclo[3.2.1]oct-3-yl-Να-{[1-(2,4-diphenyl)cyclopropyl]-carbonyl}-4-(trifluoromethyl) -L-Amphetamine: NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1 Η), 7.79 (s, 1H), 7.59 (d, 2H), 7.53 (s, 1H), 7.39 (m, 2), 7.30 (d, 2H), 6.74 (d, 1H), 4.56 (m, 1H), 3.69 (m, 3H), 2.89 (m, 2H), 2.04 (m, 3H), 1.76 (m, 5H) ), 1.33 (m, 2H), 0.93 (m, 2H) · C27H28C12F3N302 MS (El), found 555 (MH+). 4-bromo-Να-{[1·(3-fluorophenyl)cyclopropyl]carbonylb N-acridin-4-yl-L-phenylalanamine decylamine: NMR (400 MHz, DMSO_d6): δ 8.34 (s ,1H), 8.12 (s, 1Η), 7.40 (d, 2H), 7.34 (m, 1H), 7.07 (m, 3H), 6.98 (d, 2H), 6.56 (d, 1H), 4.42 (m, 1H), 3.05 (m, 2H), 2.75 (m, 2H), 1.70 (m, 2H), 1.37 (m, 2H), 1.23 (m, 2H), 0.97 (m, 146258.doc •144- 201040149 2H MS (EI) for C24H27BrFN302, found 489 (MH+). 4-bromo-N-acridin-4-yl·Να-{[1-(2,4,5-trifluorophenyl)cyclopropyl]-carbonyl}-1^· amphetamine amide: NMR (400 MHz , DMSO-d6): δ 8.28 (s, 1Η), 8.06 (s, 1H), 7.50 (m, 2H), 7.41 (d, 2H), 7.02 (d, 2H), 6.80 (d, 1H), 4.38 (m, 1H), 3.08 (m, 2H), 2.75 (m, . 2H), 1.73 (m, 2H), 1.41 (m, 2H), 1.27 (m, 2H), 0.98 (m, 2H). C24H25BrF3N302 MS (EI), found 525 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2-气-]^-{[1-(2,4-dioxanylphenyl)-cyclopropyl 】-Carbyl 4-fluoro-L-phenylalanamine decylamine: NMR (400 MHz, DMSO-de): δ 8.20 (s, 1 Η), 7.81 (m, 1H), Ί.62 (m, 1H), 7.43 (m, 2H), 7.34 (m, 1H), 7.16 (m, 2H), 6.57 (m, 1H), 4.55 (m, 1H), 3.08 (m, 1H), 2.91 (m, 3H), 2.69 ( m, 4H), 2.33 (m, 1H), 1.56 (m, 4H), 1.39 (m, 1H), 1.29 (m, 2H), 0.98 (m, 2H). MS (EI) of C26H27C13FN302, found 539 (MH+). N-[(lS)-2-(3-Amino-8-azabicycloP.2.1]oct-8-yl)-2-oxo-indole Ο {[4-(trifluoromethyl)-benzene Methyl}ethyl][(trifluoromethyl)oxy]phenyl}cyclopropanamide: bNMR (400 MHz, DMSO_d6): δ 7.59 (m, 2 Η), 7.29 (m, 7H), 7.00 ( m, 1H), 4.73 (m, 1H), 4.26 (m, • 1H), 3.08 (m, 2H), 2.88 (m, 2H), 1.92 (m, 4H), 1.62 (m, 2H), 1.45 ( m, 2H), 1.20 (m, 2H), 0.94 (m, 2H). MS (EI) of C28H29F6N3 〇3, found 570 (MH+). N-[(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8.yl)-2-oxo-i_ {[4-(trifluoromethyl)-benzene T-ethyl}-l-[2-fluoro-4-(trifluoromethyl)benzene 146258.doc -145- 201040149 base I cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 8.23 (m, 1Η), 7.57 (m, 5H), 7.32 (m, 2H), 7.18 (d, 1H), 4.72 (m, 1H), 4.27 (m, 2H), 3.02 (m, 2H), 2.87 (m, 2H), 2.18-1.42

(m，7H), 1.25 (m，2H), 0.99 (m, 2H). C28H28F7N302的 MS (El)，實測值572 (MH+)。 1&gt;1-[(18)-2-(3-胺基-8-氮雜雙環[3.2.1】辛-8-基）-2-氧代-1-{[4-(三氟甲基）-苯基]甲基}乙基】-1-(2,4-二氣苯基）環丙醢 胺：4 NMR (400 MHz，DMSO-d6): δ 8.29 (s，1H)，7.57 (m, 3H), 7.36 (m, 4H), 7.01 (m, 1H), 4.76 (m, 1H), 4.27 (m, 2H), 2.96 (m, 3H), 2.18-1.26 (m, 8H), 1.12 (m, 2H), 0.91 (m，2H). C27H28C12F3N302的 MS (El)，實測值 555 (MH+)。 4-溴_Να-{[1-(2,4_二氣苯基）環丙基】羰基甲基-N-[(3R)-呱啶-3-基]-L-苯丙胺醯胺：NMR (400 MHz, CD3OD) ： 7.57-7.38 (m, 5H), 7.10-7.00 (m, 2H), 4.43-4.37 (m, 1H), 3.10-2.80 (m, 9H), 2.05-1.55 (m, 6H), 1.12-1.06 (m，2H). C25H28BrCl2N303 的 MS (El)，實測值 554.12 (MH+)。 ]&gt;^{(18)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基）-1-[(4-溴苯 基）甲基]-2-氧代乙基}-1-(2,4-二氣苯基）環丙醢胺： NMR (400 MHz, CD3OD) ： 8.55 (s, 1H), 7.52-7.38 (m, 5H), 7.12-7.00 (m, 2H), 4.82-4.77 (m, 1H), 4.63-4.45 (m, 1H), 4.23-4.18 (m, 1H), 2.85-2.75 (m, 2H), 2.66-2.58 (m, 1H), 2.44-2.36 (m, 1H), 2.20-2.10 (m, 1H), 1.95-1.40 (m, 9H), 1.20-1.05 (m, 2H). C26H28BrCl2N303 的 MS (El)，實測值 U6258.doc 146- 201040149 566.02 (MH+) 〇 4_漠-Να-Ηΐρ，4·二氣苯基）環丙基]羰基}_Ν_甲基·Ν•呱 咬-4-基-L-苯丙胺醯胺：iH NMR (400 MHz，CD3OD): 8.40 (s，1H)，7.50-7.37 (m，5H)，7.02-6.97 (m，2H)，4.45 (t， 1H), 3.40-3.35 (m, 1H), 3.10-2.80 (m, 6H), 1.78-1.50 (m, 6H)，1.27-1.04 (ηι, 5H). C25H28BrCl2N303 的 MS (El)，實測 值 555.00 (MH+)。 N-[(3R)-呱啶-3_基】(聯苯·4_基甲基）_2_氧代乙基】 (2,4-二氣苯基卜環丙醯胺：NMR (400 MHz，CD3OD): 8.56 (s, 1H), 7.61 (d, 2H), 7.55-7.34 (m, 7H), 7.38-7.30 (m, 2H), 7.14 (d, 2H), 4.57-4.48 (m, 1H), 3.90-3.80 (m, 1H), 3.22-3.18 (m, 1H), 3.05-2.75 (m, 6H), 2.00-1.80 (m, 2H), 1.78-1.60 (m, 2H), 1.57-1.40 (m, 2H), 1.20-1.00 (m, 2H). (：301131(：12：^3〇3的河8(£1)，實測值53 6.23(1^11+)。 N-呱啶-4-基-1-(聯苯-4·基甲基）-2-氧代乙基]-1-(2,4-二 氣苯基）-環丙醯胺：4 NMR (400 MHz, CD3OD) : 8.57 (s， 1H), 7.60 (d, 2H), 7.52 (d, 2H), 7.45-7.35 (m, 7H), 7.16 (d, 2H), 4.56 (d, 1H), 3.83-3.77 (m, 1H), 3.08-2.85 (m, 5H), 2.03-1.90 (m, 2H), 1.68-1.50 (m, 5H), 1.17-1.03 (m, 2H). C30H31Cl2N3O3的MS(EI)，實測值 53 8.23 (MH+)。 2,4-二氣-Να-{[1-(2,4_二氣苯基）環丙基】羰基卜N-呱啶-4-基-L-苯丙胺醯胺：士 NMR (400 MHz，CD3OD) : 8.57 (s， 1H), 7.47-7.36 (m5 4H), 7.24 (d, 1H), 7.17 (d, 1H), 4.59 (t, 1H), 3.84-3.79 (m, 1H), 3.10-2.95 (m, 5H), 2.02-1.90 (m, 146258.doc -147· 201040149 2H)，1.68-1.48 (m，5H)，1.17-1.03 (m, 2H). C24H25C14N303 的]\48作1)，實測值 530.12 (]^1^)。 2,4-二氣-Να-{[1-(2,4-二氣苯基）環丙基]羰基}-N-呱啶-4-基-L-苯丙胺醢胺：4 NMR (400 MHz，CD3OD) : 8.40 (s， 1H), 7.40 (dd, 4H), 7.25 (d, 2H), 7.10 (d, 2H), 4.55 (t, 1H), 3.40- 3.37 (m, 1H), 3.10-2.80 (m, 7H), 1.77-1.67 (m, 3H), 1.50-1.37 (m, 2H), 1.36-1.20 (m, 2H), 1.16-1.10 (m, 2H). C26H29BrCl4N303 的MS (El)，實測值 570.18 (MH+)。 N-(順式-4-胺基環己基）-4-溴-Να-{[1-(2,4-二氣苯基）-環 丙基】羰基}-L-苯丙胺醢胺：4 NMR (400 MHz，CD3OD): 8.43 (s, 1H), 7.50-7.37 (m, 5H), 7.00 (d, 2H), 4.57 (t, 1H), 3.40- 3.30 (m, 1H), 3.20-3.15 (m, 1H), 2.98-2.80 (m, 2H), 1.83-1.75 (m, 3H), 1.70-1.50 (m, 8H), 1.16-1.05 (m, 2H). (：25112831：(：12仏〇2的1^3(£1)，實測值554.12 (]^^1+)。 N-(反式-4-胺基環己基）-4-溴-Να-{[1-(2,4-二氣苯基）-環 丙基]羰基}-L-苯丙胺醢胺：4 NMR (400 MHz, CD3OD): 8.45 (s, 1H), 7.50-7.37 (m, 5H), 6.98 (d, 2H), 4.45 (t, 1H), 3.57-3.47 (m, 1H), 3.09-3.00 (m, 1H), 2.95-2.77 (m, 2H), 2.07-1.80 (m, 4H), 1.60-1.38 (m, 4H), 1.35-1.05 (m, 4H). (：25112861*(：12：^302的]^8(£1)，實測值 554.12 (]^11+)。 4-溴-Να-{[1-(2,4-二氣苯基）環丙基】羰基}-N-(2_甲基呱 啶-4-基）-L-苯丙胺醯胺：4 NMR (400 MHz, CD3OD): 8.47 (s, 1H), 7.47-7.36 (m, 5H), 7.02-6.97 (m, 2H), 4.45 (t, 1H), 3.82-3.75 (m, 1H), 3.20-3.16 (m, 1H), 3.03-2.79 (m, 146258.doc •148- 201040149 3H), 2.07-1.84 (m, 2H), 1.60-1.38 (m, 2H), 1.30-1.23 (m, 3H)，1.17-1.03 (m, 2H). C25H28BrCl2N302 的 MS (El)，實測 值 554.12 (MH+)。 1^-[(38)-1_氮雜雙環[2.2.2】辛-3-基】-4-溪-]'^-€1-{[1_(2,3-二 氟苯基）-環丙基】羰基卜L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-de)： δ 8.34 (d, 1Η), 7.42 (d, 2H), 7.23-7.14 (m, 3H), 7.05 (d, 2H), 7.76 (d, 1H), 4.51-4.46 (m, 1H), 3.97-3.93 (m, 1H), 3.59-3.53 (m, 1H), 3.24-3.10 (m, 4H), 2.88-2.80 (m, 2H), 2.75-2.71 (m, 1H), 2.01-2.98 (m, 1H), 1.95-1.81 (m, 3H) 1.72-1.66 (m, 1H) 1.42-1.30 (m, 2H), 1.09-0.98 (m, 2H); C26H28BrF2N302, 532.20 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2】辛-3-基】-4-漠-Ν-α-{【1-(2,6-二 氟苯基）-環丙基】羰基}-L-苯丙胺醯胺：C26H28BrF2N3〇2, 534.15 (MH+)。 2,4-二氣-N-[(3R)-孤咬-3-基]-Να-[(1-{4-[(三氟甲基）氧]-苯基}環丙基）羰基】-L-苯丙胺醯胺：4 NMR (400 ΜΗζ， DMSO-d6): δ 7.97 (d, 1H), 7.51 (d, 1H), 7.42-7.35 (m, 2H), 7.35-7.28 (m, 3H), 7.16 (d, 1H), 6.67 (d, 1H), 4.52 (m, 1H), 3.60 (m, 1H), 3.00 (dd, 1H), 2.94-2.75 (m, 3H), 2.56 (t, 1H), 2.42 (dd, 1H), 1.60 (m, 2H), 1.40 (m, 1H), 1.34-1.21 (m，2H)，1.17 (m，1H), 0.97 (m，2H). C25H26C12F3N303 的 MS (El)，實測值545.4 (mH+)。 N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1】辛-8-基）·1-[(2,4·二 氣苯基）甲基】-2-氧代乙基}-1-{4-[(三氟甲基）氧]苯基}環丙 146258.doc -149· 201040149 醯胺：4 NMR (400 MHz，DMSO-d6): δ 7·54 (d，1H)，7.35 (m, 5H), 7.23 (t, 1H), 7.04 (dd, 1H), 4.79 (dd, 1H), 4.28 (m, 2H), 3.12-2.94 (m, 1H), 2.87 (m, 2H), 2.12-1.87 (m, 3H), 1.88-1.70 (m, 1H), 1.60 (m, 2H), 1.47 (t, 2H), 1.30-1.09 (m, 2H)，0.94 (m，2H). C27H28C12F3N303 的 MS (El)，實測值 571.4 (MH+)。 2,4-二氣-N-[(3S)-吼咯啶-3-基]·Να-[(1-{4-[(三氟曱基） 氧卜苯基}環丙基）羰基]-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1Η), 7.51 (d, 1H), 7.41-7.36 (m, 2H), 7.33 (m, 3H), 7.17 (d, 1H), 6.66 (d, 1H), 4.52 (td, 1H), 4.16 (m, 1H), 3.13-2.92 (m, 4H), 2.85 (dd, 1H), 2.69 (m, 1H), 1.96 (m, 1H), 1.72-1.53 (m, 1H), 1.33-1.20 (m, 1H),(m, 7H), 1.25 (m, 2H), 0.99 (m, 2H). MS (El) of C28H28F7N302, found 572 (MH+). 1&gt;1-[(18)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-2-oxo-1-{[4-(trifluoromethyl) )-Phenyl]methyl}ethyl]-1-(2,4-diphenyl)cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1H), 7.57 ( m, 3H), 7.36 (m, 4H), 7.01 (m, 1H), 4.76 (m, 1H), 4.27 (m, 2H), 2.96 (m, 3H), 2.18-1.26 (m, 8H), 1.12 (m, 2H), 0.91 (m, 2H). MS (El) for C27H28C12F3N302, found 555 (MH+). 4-bromo-Να-{[1-(2,4_di-phenylphenyl)cyclopropyl]carbonylmethyl-N-[(3R)-acridin-3-yl]-L-phenylalanamine decylamine: NMR (400 MHz, CD3OD): 7.57-7.38 (m, 5H), 7.10-7.00 (m, 2H), 4.43-4.37 (m, 1H), 3.10-2.80 (m, 9H), 2.05-1.55 (m, 6H ), 1.12-1.06 (m, 2H). MS (El) for C25H28BrCl2N303, found 554.12 (MH+). ]&gt;^{(18)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-1-[(4-bromophenyl)methyl]-2- Oxoethyl}-1-(2,4-diphenyl)cyclopropanamide: NMR (400 MHz, CD3OD): 8.55 (s, 1H), 7.52-7.38 (m, 5H), 7.12-7.00 (m, 2H), 4.82-4.77 (m, 1H), 4.63-4.45 (m, 1H), 4.23-4.18 (m, 1H), 2.85-2.75 (m, 2H), 2.66-2.58 (m, 1H) , 2.44-2.36 (m, 1H), 2.20-2.10 (m, 1H), 1.95-1.40 (m, 9H), 1.20-1.05 (m, 2H). MS (El) of C26H28BrCl2N303, measured value U6258.doc 146 - 201040149 566.02 (MH+) 〇4_ desert-Να-Ηΐρ,4·diphenyl)cyclopropyl]carbonyl}_Ν_methyl·Ν•呱 Bit-4-yl-L-phenylalanamine decylamine: iH NMR (400 MHz, CD3OD): 8.40 (s, 1H), 7.50-7.37 (m, 5H), 7.02-6.97 (m, 2H), 4.45 (t, 1H), 3.40-3.35 (m, 1H), 3.10- 2.80 (m, 6H), 1.78-1.50 (m, 6H), 1.27-1.04 ( ηι, 5H). MS (El) of C25H28BrCl2N303, found 555.00 (MH+). N-[(3R)-acridin-3-yl](biphenyl-4-ylmethyl)_2_oxoethyl] (2,4-diphenylphenylcyclopropanamide: NMR (400 MHz , CD3OD): 8.56 (s, 1H), 7.61 (d, 2H), 7.55-7.34 (m, 7H), 7.38-7.30 (m, 2H), 7.14 (d, 2H), 4.57-4.48 (m, 1H) ), 3.90-3.80 (m, 1H), 3.22-3.18 (m, 1H), 3.05-2.75 (m, 6H), 2.00-1.80 (m, 2H), 1.78-1.60 (m, 2H), 1.57-1.40 (m, 2H), 1.20-1.00 (m, 2H). (: 301131 (:12:^3〇3 of the river 8 (£1), measured value 53 6.23 (1^11+). N-acridine- 4-yl-1-(biphenyl-4-ylmethyl)-2-oxoethyl]-1-(2,4-diphenyl)-cyclopropanamide: 4 NMR (400 MHz, CD3OD ) : 8.57 (s, 1H), 7.60 (d, 2H), 7.52 (d, 2H), 7.45-7.35 (m, 7H), 7.16 (d, 2H), 4.56 (d, 1H), 3.83-3.77 ( m, 1H), 3.08-2.85 (m, 5H), 2.03-1.90 (m, 2H), 1.68-1.50 (m, 5H), 1.17-1.03 (m, 2H). MS (EI) of C30H31Cl2N3O3, measured value 53 8.23 (MH+) 2,4-diqi-Να-{[1-(2,4_di-phenylphenyl)cyclopropyl]carbonyl-N-acridin-4-yl-L-phenylalanamine decylamine: NMR (400 MHz, CD3OD): 8.57 (s, 1H), 7.47-7.36 (m5 4H), 7.24 (d, 1H), 7.17 (d, 1H), 4.59 (t, 1H), 3.84-3.79 (m , 1H), 3.10-2.95 (m, 5H), 2.02-1.90 (m, 146258.doc -147· 201040149 2H), 1.68-1.48 (m, 5H), 1.7-1.03 (m, 2H). C24H25C14N303]\48 for 1 ), found 530.12 (]^1^). 2,4-digas-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-acridin-4-yl -L-Amphetamine: 4 NMR (400 MHz, CD3OD): 8.40 (s, 1H), 7.40 (dd, 4H), 7.25 (d, 2H), 7.10 (d, 2H), 4.55 (t, 1H) , 3.40- 3.37 (m, 1H), 3.10-2.80 (m, 7H), 1.77-1.67 (m, 3H), 1.50-1.37 (m, 2H), 1.36-1.20 (m, 2H), 1.16-1.10 ( m, 2H). MS (El) for C26H29BrCl4N303, found 570.18 (MH+). N-(cis-4-Aminocyclohexyl)-4-bromo-indole α-{[1-(2,4-diphenyl)-cyclopropyl]carbonyl}-L-phenylalanamine decylamine: 4 NMR (400 MHz, CD3OD): 8.43 (s, 1H), 7.50-7.37 (m, 5H), 7.00 (d, 2H), 4.57 (t, 1H), 3.40- 3.30 (m, 1H), 3.20-3.15 ( m, 1H), 2.98-2.80 (m, 2H), 1.83-1.75 (m, 3H), 1.70-1.50 (m, 8H), 1.16-1.05 (m, 2H). (:25112831:(:12仏〇) 1^3(£1) of 2, found 554.12 (]^^1+). N-(trans-4-aminocyclohexyl)-4-bromo-Να-{[1-(2,4- Dioxophenyl)-cyclopropyl]carbonyl}-L-phenylalanamine decylamine: 4 NMR (400 MHz, CD3OD): 8.45 (s, 1H), 7.50-7.37 (m, 5H), 6.98 (d, 2H) , 4.45 (t, 1H), 3.57-3.47 (m, 1H), 3.09-3.00 (m, 1H), 2.95-2.77 (m, 2H), 2.07-1.80 (m, 4H), 1.60-1.38 (m, 4H), 1.35-1.05 (m, 4H). (:25112861*(:12:^302)^8(£1), measured value 554.12 (]^11+). 4-bromo-Να-{[1 -(2,4-diphenyl)cyclopropyl]carbonyl}-N-(2-methylacridin-4-yl)-L-phenylalanamine decylamine: 4 NMR (400 MHz, CD3OD): 8.47 ( s, 1H), 7.47-7.36 (m, 5H), 7.02-6.97 (m, 2H), 4.45 (t, 1H), 3.82-3.75 (m, 1H), 3.20-3.16 (m, 1H), 3.03- 2.79 (m, 1462 58.doc •148- 201040149 3H), 2.07-1.84 (m, 2H), 1.60-1.38 (m, 2H), 1.30-1.23 (m, 3H), 1.7-1.03 (m, 2H). MS of C25H28BrCl2N302 ( El), found 554.12 (MH+). 1^-[(38)-1_Azabicyclo[2.2.2]oct-3-yl]-4-溪-]'^-€1-{[1_( 2,3-Difluorophenyl)-cyclopropyl]carbonyl phenyl L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-de): δ 8.34 (d, 1 Η), 7.42 (d, 2H), 7.23- 7.14 (m, 3H), 7.05 (d, 2H), 7.76 (d, 1H), 4.51-4.46 (m, 1H), 3.97-3.93 (m, 1H), 3.59-3.53 (m, 1H), 3.24- 3.10 (m, 4H), 2.88-2.80 (m, 2H), 2.75-2.71 (m, 1H), 2.01-2.98 (m, 1H), 1.95-1.81 (m, 3H) 1.72-1.66 (m, 1H) 1.42-1.30 (m, 2H), 1.09-0.98 (m, 2H); C26H28BrF2N302, 532.20 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-indi-Ν-α-{[1-(2,6-difluorophenyl)-cyclopropyl 】carbonyl}-L-amphetamine amide: C26H28BrF2N3〇2, 534.15 (MH+). 2,4-di-gas-N-[(3R)- ingo-3-yl]-Να-[(1-{4-[(trifluoromethyl)oxy]-phenyl}cyclopropyl)carbonyl] -L-Amphetamine: 4 NMR (400 ΜΗζ, DMSO-d6): δ 7.97 (d, 1H), 7.51 (d, 1H), 7.42-7.35 (m, 2H), 7.35-7.28 (m, 3H) , 7.16 (d, 1H), 6.67 (d, 1H), 4.52 (m, 1H), 3.60 (m, 1H), 3.00 (dd, 1H), 2.94-2.75 (m, 3H), 2.56 (t, 1H ), 2.42 (dd, 1H), 1.60 (m, 2H), 1.40 (m, 1H), 1.34-1.21 (m, 2H), 1.17 (m, 1H), 0.97 (m, 2H). MS of C25H26C12F3N303 ( El), found 545.4 (mH+). N-{(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)·1-[(2,4·di-phenyl)methyl]-2 -oxoethyl}-1-{4-[(trifluoromethyl)oxy]phenyl}cyclopropene 146258.doc -149· 201040149 decylamine: 4 NMR (400 MHz, DMSO-d6): δ 7· 54 (d,1H), 7.35 (m, 5H), 7.23 (t, 1H), 7.04 (dd, 1H), 4.79 (dd, 1H), 4.28 (m, 2H), 3.12-2.94 (m, 1H) , 2.87 (m, 2H), 2.12-1.87 (m, 3H), 1.88-1.70 (m, 1H), 1.60 (m, 2H), 1.47 (t, 2H), 1.30-1.09 (m, 2H), 0.94 (m, 2H). MS (El) for C27H28C12F3N303, found 571.4 (MH+). 2,4-digas-N-[(3S)-indolyl-3-yl]·Να-[(1-{4-[(trifluoromethyl)oxyphenyl)cyclopropyl)carbonyl] -L-Amphetamine amide: 4 NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1 Η), 7.51 (d, 1H), 7.41-7.36 (m, 2H), 7.33 (m, 3H), 7.17 (d, 1H), 6.66 (d, 1H), 4.52 (td, 1H), 4.16 (m, 1H), 3.13-2.92 (m, 4H), 2.85 (dd, 1H), 2.69 (m, 1H), 1.96 (m, 1H), 1.72-1.53 (m, 1H), 1.33-1.20 (m, 1H),

1.15 (dd，1H)，1.(Η-0·86 (m，2H). C24H24C12F3N303 的 MS 作1)，實測值531.4(]^1^1+)。 N-[(3R)-呱啶-3-基]-4-(三氟甲基）-Να-【（ΐ_{4-【（三氟甲 基）-氧]苯基}環丙基）羰基]-L-苯丙胺醯胺：NMR (400 MHz，DMSO-d6): δ 8.26 (s, 1H)，8.09 (t, 1H)，7.58 (d，2H)， 7.39-7.30 (m, 2H), 7.26 (d, 4H), 6.65 (d, 1H), 4.61-4.37 (m, 1H), 3.58 (s, 1H), 3.04-2.71 (m, 4H), 2.55 (t, 1H), 2.45- 2.25 (m, 1H), 1.61 (d, 2H), 1.47-1.14 (m, 4H), 1.06-0.81 (m，2H). C26H27F6N303的MS (El) ’ 實測值544 5 (MiI+)。 N-[(lS)-2-【(3R)-3-胺基呱啶-1-基]-2-氧代-+ (三氣甲 基）苯基]-甲基}乙基】-l-{4-[(三氟甲基）氧】苯基丨環丙醢 胺：NMR (400 MHz, D6-DMSO，1〇〇 δ 7 54 (m， 146258.doc • 150- 201040149 2H), 7.38-7.20 (m, 6H), 6.56 (bs, 1H), 4.99 (bs, 1H), 3.74 (bs, 1H), ), 3.05-2.82 (m, 3H), 2.56 (bs, 1H), 1.8 (bs, 1H), 1.62 (bs, 1H)，1.28 (m，4H)，0.96 (m, 2H); C26H27F6N303的 MS (El)，實測值 544.30 (MH+)。 N-[(3S)-呱啶-3-基】-4-(三氟甲基）-Να·[(1-{4-[(三氟甲基） 氧]-苯基}環丙基）羰基]-L-苯丙胺醯胺：4 NMR (400 MHz, D6-DMSO): δ 8.49 (d5 1H), 7.58 (d, 2H), 7.34 (d, 2H), 7.30-7.25 (m, 4H), 6.74 (d, 1H), 4.57-4.52 (m, 1H), 3.78 (br s, 1H), 3.05-2.88 (m, 4H), 2.70-2.75 (m, 1H), 2.54-2.59 (m, 1H), 1.73-1.78 (m, 2H), 1.52-1.58 (m, 1H), 1.38-1.45 (m, 1H), 1.20-1.28 (m, 2H), 0.91-1.04 (m, 2H); C26H27F6N303 的 MS (El)，實測值 544.30 (MH+)。 N-[(lS)-2-(4-胺基-4-甲基狐咬-1-基）-2-氧代-l-{[4-(三氣 甲基）-苯基]甲基}乙基】-l-{4-[(三氟甲基）氧]苯基}環丙醯 胺：NMR (400 MHz, DMSO-d6): δ 7.64-7.49 (m，2H), 7.39-7.30 (m, 2H), 7.28 (m, 4H), 6.82 (d, 1H), 4.97 (d, 1H), 3.61-3.26 (m, 6H), 3.03-2.75 (m, 2H), 1.42 (m, 3H), 1.22 (m, 3H), 1.12 (d, 3H), 0.97 (d，2H). C27H29F6N303 的 MS (El)，實測值 558.5 (MH+)。 N-[(3S)-«比咯啶-3-基]-4-(三氟甲基）-Να-[(1-{4-[(三氟甲 基）-氧】苯基}環丙基）羰基]-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.61 (d, 1H), 7.58 (d, 2H), 7.40-7.31 (m, 2H), 7.26 (d, 4H), 6.66 (d, 1H), 4.49 (m, 1H), 4.13 (m, 1H), 3.11-2.92 (m, 4H), 2.87 (dd, 1H), 2.69 (dd, 1H), 1.97 146258.doc •151 - 201040149 (m，1H)，1.65 (m, 1H)，1.29-1.13 (m, 2H), 1.05-0.81 (m， 2H). C25H25F6N3〇3的MS (El)，實測值53〇 5 (MH+)。 4-溴-N_[(3S)-ff比咯咬_3-基】-Να-[(1-{4-[(三氟甲基）氧】苯 基}-環丙基）羰基】-L-苯丙胺醯胺·· 4 NMR (400 MHz, DMSO-de)： δ 8.63 (d, 1H), 7.41 (d, 2H), 7.38-7.32 (m, 2H), 7.29 (d, 2H), 7.00 (d, 2H), 6.63 (d, 1H), 4.48-4.34 (m, 1H), 4.12 (m5 1H), 3.13-2.90 (m, 3H), 2.86 (dd, 1H), 2.82-2.62 (m, 2H), 2.02-1.87 (m, 1H), 1.63 (m, 1H), 1.34-1.13 (m, 2H)，1.08-0.81 (m, 2H). C24H25BrF3N303 的 MS (El)，實測 值 541.4 (MH+)。 N-[(3R)· 口瓜咬-3-基]-Να-[(1-{4-[(三氣甲基）氧]苯基}-環 丙基）羰基]-L-苯丙胺醯胺：^ΝΜΙΙΜΟΟΜΗζ,ΟΜΒΟ-Ι): δ 8.00 (d, 1H), 7.37-7.31 (m, 2H), 7.29 (m, 2H), 7.24-7.14 (m, 3H), 7.09-6.90 (m, 2H), 6.53 (d, 1H), 4.50-4.39 (m, 1H), 3.58 (m, 1H), 2.95-2.71 (m, 4H), 2.55 (t, 1H), 2.40 (dd, 1H), 1.60 (m, 2H), 1.39 (m, 1H), 1.33-1.12 (m, 3H), 1.07-0.81 (m，2H). C25H28F3N303 的 MS (El)，實測值 476.5 (MH+)。1.15 (dd, 1H), 1. (Η-0·86 (m, 2H). MS of C24H24C12F3N303 is 1), measured value 531.4 (]^1^1+). N-[(3R)-Acridine-3-yl]-4-(trifluoromethyl)-Να-[(ΐ_{4-[(trifluoromethyl)-oxy]phenyl}cyclopropyl)carbonyl ]-L-Amphetamine amide: NMR (400 MHz, DMSO-d6): δ 8.26 (s, 1H), 8.09 (t, 1H), 7.58 (d, 2H), 7.39-7.30 (m, 2H), 7.26 (d, 4H), 6.65 (d, 1H), 4.61-4.37 (m, 1H), 3.58 (s, 1H), 3.04-2.71 (m, 4H), 2.55 (t, 1H), 2.45- 2.25 (m , 1H), 1.61 (d, 2H), 1.47-1.14 (m, 4H), 1.06-0.81 (m, 2H). MS (El) of C26H27F6N303 'Measured value 544 5 (MiI+). N-[(lS)-2-[(3R)-3-Aminopyridin-1-yl]-2-oxo-+(trimethylmethyl)phenyl]-methyl}ethyl]-l -{4-[(Trifluoromethyl)oxy]phenylindole propylamine: NMR (400 MHz, D6-DMSO, 1 〇〇 δ 7 54 (m, 146258.doc • 150- 201040149 2H), 7.38 -7.20 (m, 6H), 6.56 (bs, 1H), 4.99 (bs, 1H), 3.74 (bs, 1H), ), 3.05-2.82 (m, 3H), 2.56 (bs, 1H), 1.8 (bs , 1H), 1.62 (bs, 1H), 1.28 (m, 4H), 0.96 (m, 2H); MS (El) of C26H27F6N303, found 544.30 (MH+). N-[(3S)-Acridine-3-yl]-4-(trifluoromethyl)-Να·[(1-{4-[(trifluoromethyl)oxy]-phenyl}cyclopropyl) Carbonyl]-L-amphetamine: 4 NMR (400 MHz, D6-DMSO): δ 8.49 (d5 1H), 7.58 (d, 2H), 7.34 (d, 2H), 7.30-7.25 (m, 4H), 6.74 (d, 1H), 4.57-4.52 (m, 1H), 3.78 (br s, 1H), 3.05-2.88 (m, 4H), 2.70-2.75 (m, 1H), 2.54-2.59 (m, 1H) , 1.73-1.78 (m, 2H), 1.52-1.58 (m, 1H), 1.38-1.45 (m, 1H), 1.20-1.28 (m, 2H), 0.91-1.04 (m, 2H); MS of C26H27F6N303 ( El), found 544.30 (MH+). N-[(lS)-2-(4-Amino-4-methylfoxbit-1-yl)-2-oxo-l-{[4-(trimethylmethyl)-phenyl]methyl Ethyl]-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide: NMR (400 MHz, DMSO-d6): δ 7.64-7.49 (m, 2H), 7.39-7.30 (m, 2H), 7.28 (m, 4H), 6.82 (d, 1H), 4.97 (d, 1H), 3.61-3.26 (m, 6H), 3.03-2.75 (m, 2H), 1.42 (m, 3H) ), 1.22 (m, 3H), 1.12 (d, 3H), 0.97 (d, 2H). MS (El) of C27H29F6N303, found 558.5 (MH+). N-[(3S)-«Byrrolidin-3-yl]-4-(trifluoromethyl)-Να-[(1-{4-[(trifluoromethyl)-oxy]phenyl}cyclopropane Carbonyl)-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.61 (d, 1H), 7.58 (d, 2H), 7.40-7.31 (m, 2H), 7.26 (d, 4H), 6.66 (d, 1H), 4.49 (m, 1H), 4.13 (m, 1H), 3.11-2.92 (m, 4H), 2.87 (dd, 1H), 2.69 (dd, 1H), 1.97 146258. Doc •151 - 201040149 (m,1H),1.65 (m, 1H), 1.29-1.13 (m, 2H), 1.05-0.81 (m, 2H). MS (El) of C25H25F6N3〇3, found 53〇5 (MH+). 4-bromo-N_[(3S)-ff ratio _3-yl]-Να-[(1-{4-[(trifluoromethyl)oxy]phenyl}-cyclopropyl)carbonyl]-L - amphetamine amide · 4 NMR (400 MHz, DMSO-de): δ 8.63 (d, 1H), 7.41 (d, 2H), 7.38-7.32 (m, 2H), 7.29 (d, 2H), 7.00 ( d, 2H), 6.63 (d, 1H), 4.48-4.34 (m, 1H), 4.12 (m5 1H), 3.13-2.90 (m, 3H), 2.86 (dd, 1H), 2.82-2.62 (m, 2H) ), 2.02-1.87 (m, 1H), 1.63 (m, 1H), 1.34-1.13 (m, 2H), 1.08-0.81 (m, 2H). MS (El) of C24H25BrF3N303, found 541.4 (MH+). N-[(3R)· 口瓜咬-3-yl]-Να-[(1-{4-[(trimethyl)oxy]phenyl}-cyclopropyl)carbonyl]-L-phenylpropylamine decylamine :^ΝΜΙΙΜΟΟΜΗζ,ΟΜΒΟ-Ι): δ 8.00 (d, 1H), 7.37-7.31 (m, 2H), 7.29 (m, 2H), 7.24-7.14 (m, 3H), 7.09-6.90 (m, 2H) , 6.53 (d, 1H), 4.50-4.39 (m, 1H), 3.58 (m, 1H), 2.95-2.71 (m, 4H), 2.55 (t, 1H), 2.40 (dd, 1H), 1.60 (m , 2H), 1.39 (m, 1H), 1.33-1.12 (m, 3H), 1.07-0.81 (m, 2H). MS (El) of C25H28F3N303, found 476.5 (MH+).

N-[(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基）-2-氧代-1-(苯基甲基）乙基]-l-{4-[(三氟甲基）氧]苯基}環丙醯胺：1H NMR (400 MHz, DMSO-d6): δ 7.40-7.33 (m, 2Η), 7.33-7.25 (m, 2H), 7.25-7.14 (m, 3H), 7.11-7.00 (m, 2H), 6.87 (dd, 1H), 4.67 (m, 1H), 4.46-3.99 (m, 2H), 2.93 (dd, 1H), 2.84-2.63 (m, 2H), 2.13-1.83 (m, 3H), 1.64 (m, 2H), 1.46 (d, 146258.doc -152- 201040149 3H)，1.34-1.18 (m, 2H)，1,11-0.85 (m，2H), C27H30F3N3O3的 MS (El)，實測值502.5 (MH+)。 N-[(3S)-吼咯啶·3-基】_Να·[(1·{4_[(三氟甲基）氧]苯基}_ 環丙基）羰基】-L-苯丙胺醯胺：1HNMR(400 MHz，DMSO-d6): δ 8.55 (d, 1H), 7.40-7.25 (m, 4H), 7.25-7.10 (m, 3H), 7.08-6.89 (m, 2H), 6.55 (d, 1H), 4.43 (m, 1H), 4.13 (m, 1H), 3.14-2.93 (m, 3H), 2.94-2.82 (m, 1H), 2.76 (dd, 1H), 2.68 (dd, 1H), 1.96 (m, 1H), 1.64 (m, 1H), 1.24 (m, 2H), 0.96 (m，2H). C24H26F3N303 的 MS (El)，實測值 462.5 (MH+)。 3-環己基-N-[(3R)-呱啶-3-基]-N〜2〜-[(l-{4-【（三氟甲基） 氧】苯基}_環丙基）羰基】-L-丙胺醢胺：4 NMR (400 MHz， DMSO-d6)： δ 7.92 (d, 1H), 7.51-7.40 (m, 2H), 7.33 (d, 2H), 6.70 (d, 1H), 4.25 (q, 1H), 3.69-3.57 (m, 1H), 2.91 (dd, 1H), 2.83 (d, 1H), 2.56 (m, 1H), 2.41 (dd, 1H), 1.61 (m, 7H), 1.44-1.22 (m, 6H), 1.12-0.94 (m, 6H), 0.78 (m, 2H). C25H34F3N3〇3 的 MS (El)，實測值 482.6 (MH+)。 N-[(lS)-2-(3-胺基-8-氮雜雙環[3.2.1】辛-8-基）-1-(環己基 甲基）-2-氧代乙基][(三氟甲基）氧】苯基}環丙醢胺： !H NMR (400 MHz, DMSO-d6): δ 7.52-7.39 (m, 2Η), 7.38-7.28 (m, 2H), 6.89 (dd, 1H), 4.54 (dd, 1H), 4.46-4.02 (m, 2H), 3.17 (m, 2H), 2.2K1.95 (m, 3H), 1.95-1.77 (m, 2H), 1.61 (m, 5H), 1.51-1.41 (m, 2H), 1.41-1.20 (m, 4H), 1.16-0.93 (m, 6H)，0.76 (m, 2H). C27H36F3N303 的 MS (El)，實測 146258.doc -153· 201040149 值 508.6 (MH+)。 3-環己基-N-[(3S)-^b咯啶_3_基】_n〜2…丨（1 +【（三氟甲 基）氧】苯基}環丙基）羰基]-L-丙胺醢胺：NMR (400 MHz, DMSO-d6)： δ 8.46 (dd, 1Η), 7.51-7.39 (m, 2H), 7.33 (d, 2H), 6.70 (dd, 1H), 4.24 (dd, 1H), 4.16 (d, 1H), 3.19-2.90 (m, 3H), 2.74 (m, 1H), 1.96 (m, 1H), 1.70-1.45 (m, 6H), 1.42-1.23 (m, 4H), 1.15-0.92 (m, 6H), 0.78 (m, 2H). C24H32F3N303的MS (El)，實測值 468.5 (MH+)。 N-呱啶-4-基-Να-[(1-{4-[(三氟甲基）氧]苯基}環丙基）-羰 基]-L-苯丙胺醢胺：NMR (400 MHz，DMSO-d6): δ 8.07 (d, 1Η), 7.41-7.25 (m, 4H), 7.25-7.12 (m, 3H), 7.02 (d, 2H), 6.49 (d, 1H), 4.44 (dd, 1H), 3.61 (m, 1H), 3.12-3.02 (m, 2H), 2.85 (dd, 1H), 2.76 (m, 3H), 1.69 (m, 2H), 1.52-1.14 (m，4H)，1.07-0.86 (m，2H). C25H28F3N303 的 MS (El)，實測 值 476.5 (MH+)。 N-呱啶-4-基-4-(三氟甲基）-Να-[(1-{4-[(三氟甲基）氧]-苯 基}環丙基）羰基】-L-苯丙胺醯胺：NMR (400 MHz, DMSO-d6)： δ 8.13 (d, 1Η), 7.58 (d, 2H), 7.32 (dd, 2H), 7-29-7.18 (m, 4H), 6.60 (d, 1H), 4.50 (d, 1H), 3.61 (m, 1H), 3-°6 (m, 2H), 2.98-2.81 (m, 2H), 2.70 (t, 2H), 1.71 (m, 2H), [48-1.13 (m, 4H)，0.97 (d，2H). C26H27F6N303 的 MS (El)， 實測值 544.5 (MH+)。 3-環己基-N-呱啶-4-基-N，2’-[(l-{4-[(三氟甲基）氧]苯基}- 環丙基）羰基]-L-丙胺醯胺：4 NMR (400 MHz，DMSO-d6): 146258.doc -154- 201040149 δ 7.95 (d, 1Η), 7.51-7.41 (m, 2H), 7.34 (d, 2H), 6.61 (d, 1H), 4.26 (d, 1H), 3.61 (m, 2H), 3.04 (t, 2H), 2.68 (t, 2H), 1.69 (m, 2H), 1.58 (m, 5H), 1.38-1.28 (m, 5H), 1.15-0.94 (m，6H), 0.77 (m, 2H). C25H34F3N3〇3 的 MS (El)，實測值 482.6 (MH+)。 2,4-二氣-]\-'1瓜咬-4-基_1^€1-[(1-{4-【（三氟甲基）氧]苯基}-環丙基）羰基]-L-苯丙胺醯胺：1111'11^1^4001^1^，1^80-d6)： δ 8.07 (d, 1H), 7.51 (d, 1H), 7.42-7.35 (m, 2H), 7.32 〇 (m, 3H), 7.16 (d, 1H), 6.59 (d, 1H), 4.58-4.46 (m, 1H), 3.63 (d, 1H), 3.06 (m, 2H), 2.97 (dd, 1H), 2.87 (dd, 1H), 2.71 (t, 2H), 1.70 (m, 2H), 1.51-1.29 (m, 2H), 1.30-1.10 (m, 2H), 1.02-0.89 (m，2H). C25H26C12F3N303 的 MS (El)，實測值 545.4 (MH+)。 N-{(lS)-l-[(2,4-二氣苯基）曱基]-2-[4-(甲基胺基）呱啶 基】-2-氧代乙基}-1-{4-【（二氟甲基）氧]苯基}環丙酿胺：ijj NMR (400 MHz, DMSO-d6): δ 7.58-7.47 (m, 1Η), 7.39-7.30 (m，5H)，7.20 (dd，1H)，6_89 (dd，1H)，5.01 (m，1H)，4.12 (dd，1H)，3.86 (t，1H)，2.96 (m, 2H)，2.89-2.81 (m，1H)， 2.68 (m, 2H), 2.34 (d, 3H), 1.83 (m, 2H), 1.30-1.03 (mj . 4H)，0.93 (d，2H). C26H28C12F3N303 的MS (El)，實測值 559.4 (MH+)。 N-{(lS)-2-(4-胺基狐咬-1_基）-l-[(2,4_二氣苯基）甲基]_2_ 氧代乙基}-1-{4-[(三氟甲基）氧]苯基}環丙醯胺：iH nmr (400 MHz, DMSO-d6): δ 7.57 (dd, 2H), 7.33 (dd, 2H), 7.26 146258.doc -155- 201040149 (d, 3H), 6.82 (dd, 1H), 4.96 (dd, 1H), 4.15 (dd, 1H), 3.90 (s, 1H), 3.08-2.90 (m, 3H), 2.90-2.77 (m, 1H), 2.66 (dd, 1H)， 1.81 (t， 2H), 1.37-1.04 (m, 4H), 0.96 (q, 2H). C25H26C12F3N303的 MS (El)，實測值 545.4 (MH+)。 N-[(lS)-2-[4-(曱基胺基）呱咬-1-基]·2-氧代-1-{丨4-(三氟 甲基）苯基]-曱基}乙基]-1-{4-[(三氟甲基）氧]苯基}環丙醯 胺：1HNMR(400 MHz，DMSO-d6):δ7·57(d,2H)，7.35-7.25 (m, 6H), 6.84 (dd, 1H), 4.96 (dd5 1H), 4.12 (dd, 1H), 3.88 (t, 1H), 3.00 (dd, 3H), 2.89-2.67 (m, 3H), 2.35 (d, 3H), 1.84 (m，2H)，1.21 (d，4H)，0.97 (dd，2H)· C27H29F6N303 的 MS (El)，實測值 558.5 (MH+)。 N-[(lS)-2-(4胺基呱啶-1-基）-2-氧代-l-{[4-(三氟甲基）苯 基]甲基}-乙基[(三氟甲基）氧】苯基}環丙醢胺： NMR (400 MHz, DMSO-d6)： δ 7.57 (dd, 2Η), 7.34-7.24 (m, 6H), 6.82 (dd, 1H), 4.96 (dd, 1H), 4.15 (dd, 1H), 3.90 (t, 1H), 3.08-2.94 (m, 3H), 2.90-2.75 (m, 1H), 2.66 (dd, 1H), 1.81 (t, 2H), 1.38-1.06 (m, 4H)，0_96 (q，2H). C26H27F6N303的 MS (El)，實測值 544.5 (MH+)。 N-{(lS)-l-[(4-溴苯基）甲基]-2-[4-(甲基胺基）呱啶-1-基】_ 2-氧代乙基}-1-{4-[(三氟甲基）氧]苯基}環丙醯胺：4 NMR (400 MHz, DMSO-d6): δ 7.40 (dd, 2H), 7.35-7.27 (m, 4H), 7.00 (d, 2H), 6.86 (dd, 1H), 4.90 (dd, 1H), 4.21-4.03 (m, 1H), 3.87 (t, 1H), 3.08-2.92 (m, 2H), 2.83 (t, 2H), 2.74-2.61 (m, 2H), 2.37 (d, 3H), 1.83 (m, 2H), 1.24 (m, 4H), 0.97 (d, 146258.doc -156- 201040149 2H)- C26H29BrF3N3〇3 的MS (EI) ’ 實測值 569.4 (MH+)。 N-{(lS)-2-(4-胺基呱啶·j-基溴苯基）甲基】·2氧代 乙基}-1-{4-[(二氟甲基）氧]苯基}環丙酿胺：NMR (400 MHz, DMSO-d6): δ 7.35 (dd, 2Η), 7.27 (dd, 4H), 6.95 (dd, 2H), 6.73 (dd, 1H), 4.92-4.78 (m, 1H), 4.09 (dd, 1H), 3.83 (t, 1H), 3.03-2.91 (m, 2H), 2.85-2.73 (m, 1H), 2.70-2.53 (m, 2H), 1.74 (m, 2H), 1.28-1.07 (m, 4H), 0.98-0.85 (m, 2H). C25H27BrF3N303 的 MS (El)，實測值 555 4 (MH+)。 N-【（lS)-2-[4-(甲基胺基）《!瓜咬_i_基]_2_氧代(苯基甲基） 乙基】-1-{4-[(三氟甲基）氧]苯基}環丙醢胺· NMR (400 MHz, DMSO-d6): δ 7.34 (dd，2H)，7.28 (d, 3H)，7.22-7.19 (m, 2H), 7.03 (d, 2H), 6.84 (dd, 1H), 4.91 (dd, 1H), 4.09 (dd, 1H), 3.83 (t, 1H), 3.10-2.98 (m, 1H), 2.98-2.81 (m, 2H), 2.79-2.65 (m, 3H), 2.33 (d, 3H), 1.78 (m, 2H), 1.28- 1.19 (m, 2H)，1.14-0.87 (m, 4H)· C26H30F3N3O3的 MS (El)， 實測值490.5 (MH+)。N-[(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-2-oxo-1-(phenylmethyl)ethyl]-l -{4-[(Trifluoromethyl)oxy]phenyl}cyclopropanamide: 1H NMR (400 MHz, DMSO-d6): δ 7.40-7.33 (m, 2 Η), 7.33-7.25 (m, 2H) , 7.25-7.14 (m, 3H), 7.11-7.00 (m, 2H), 6.87 (dd, 1H), 4.67 (m, 1H), 4.46-3.99 (m, 2H), 2.93 (dd, 1H), 2.84 -2.63 (m, 2H), 2.13-1.83 (m, 3H), 1.64 (m, 2H), 1.46 (d, 146258.doc -152- 201040149 3H), 1.34-1.18 (m, 2H), 1,11 MS (El) for C.sub.3, (m.sup.2H), C27H30F3N3O3, found 502.5 (MH+). N-[(3S)-Pyrrolidinyl-3-yl]_Να·[(1·{4_[(Trifluoromethyl)oxy]phenyl}_cyclopropyl)carbonyl]-L-phenylalanamine decylamine: 1HNMR (400 MHz, DMSO-d6): δ 8.55 (d, 1H), 7.40-7.25 (m, 4H), 7.25-7.10 (m, 3H), 7.08-6.89 (m, 2H), 6.55 (d, 1H) , 4.43 (m, 1H), 4.13 (m, 1H), 3.14-2.93 (m, 3H), 2.94-2.82 (m, 1H), 2.76 (dd, 1H), 2.68 (dd, 1H), 1.96 (m , 1H), 1.64 (m, 1H), 1.24 (m, 2H), 0.96 (m, 2H). MS (El) of C24H26F3N303, found 462.5 (MH+). 3-cyclohexyl-N-[(3R)-acridin-3-yl]-N~2~-[(l-{4-[(trifluoromethyl)oxy]phenyl}-cyclopropyl)carbonyl -L-alanamine: 4 NMR (400 MHz, DMSO-d6): δ 7.92 (d, 1H), 7.51-7.40 (m, 2H), 7.33 (d, 2H), 6.70 (d, 1H), 4.25 (q, 1H), 3.69-3.57 (m, 1H), 2.91 (dd, 1H), 2.83 (d, 1H), 2.56 (m, 1H), 2.41 (dd, 1H), 1.61 (m, 7H) MS 1.4 (m, 6H), 1.12-0.94 (m, 6H), 0.78 (m, 2H). MS (El) of C25H34F3N3 〇3, found 482.6 (MH+). N-[(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-1-(cyclohexylmethyl)-2-oxoethyl][( Trifluoromethyl)oxy]phenyl}cyclopropanamide: !H NMR (400 MHz, DMSO-d6): δ 7.52-7.39 (m, 2 Η), 7.38-7.28 (m, 2H), 6.89 (dd, 1H), 4.54 (dd, 1H), 4.46-4.02 (m, 2H), 3.17 (m, 2H), 2.2K1.95 (m, 3H), 1.95-1.77 (m, 2H), 1.61 (m, 5H) ), 1.51-1.41 (m, 2H), 1.41-1.20 (m, 4H), 1.16-0.93 (m, 6H), 0.76 (m, 2H). MS (El) of C27H36F3N303, measured 146258.doc -153· 201040149 The value is 508.6 (MH+). 3-cyclohexyl-N-[(3S)-^b-bromopyridine_3_yl]_n~2...丨(1 +[(trifluoromethyl)oxy]phenyl}cyclopropyl)carbonyl]-L- Alanine: NMR (400 MHz, DMSO-d6): δ 8.46 (dd, 1 Η), 7.51-7.39 (m, 2H), 7.33 (d, 2H), 6.70 (dd, 1H), 4.24 (dd, 1H ), 4.16 (d, 1H), 3.19-2.90 (m, 3H), 2.74 (m, 1H), 1.96 (m, 1H), 1.70-1.45 (m, 6H), 1.42-1.23 (m, 4H), MS (El) for C24H32F3N303, found 468.5 (MH+). N-Acridine-4-yl-Να-[(1-{4-[(trifluoromethyl)oxy]phenyl}cyclopropyl)-carbonyl]-L-phenylpropylamine decylamine: NMR (400 MHz, DMSO -d6): δ 8.07 (d, 1Η), 7.41-7.25 (m, 4H), 7.25-7.12 (m, 3H), 7.02 (d, 2H), 6.49 (d, 1H), 4.44 (dd, 1H) , 3.61 (m, 1H), 3.12-3.02 (m, 2H), 2.85 (dd, 1H), 2.76 (m, 3H), 1.69 (m, 2H), 1.52-1.14 (m, 4H), 1.07-0.86 (m, 2H). MS (El) for C25H28F3N303, found 476.5 (MH+). N-Acridine-4-yl-4-(trifluoromethyl)-Να-[(1-{4-[(trifluoromethyl)oxy]-phenyl}cyclopropyl)carbonyl]-L-amphetamine Indoleamine: NMR (400 MHz, DMSO-d6): δ 8.13 (d, 1 Η), 7.58 (d, 2H), 7.32 (dd, 2H), 7-29-7.18 (m, 4H), 6.60 (d, 1H), 4.50 (d, 1H), 3.61 (m, 1H), 3-°6 (m, 2H), 2.98-2.81 (m, 2H), 2.70 (t, 2H), 1.71 (m, 2H), [48-1.13 (m, 4H), 0.97 (d, 2H). MS (El), C26H27F6N303, found 544.5 (MH+). 3-cyclohexyl-N-acridin-4-yl-N,2'-[(l-{4-[(trifluoromethyl)oxy]phenyl}-cyclopropyl)carbonyl]-L-alanamine Amine: 4 NMR (400 MHz, DMSO-d6): 146258.doc -154- 201040149 δ 7.95 (d, 1 Η), 7.51-7.41 (m, 2H), 7.34 (d, 2H), 6.61 (d, 1H) , 4.26 (d, 1H), 3.61 (m, 2H), 3.04 (t, 2H), 2.68 (t, 2H), 1.69 (m, 2H), 1.58 (m, 5H), 1.38-1.28 (m, 5H MS (El), 1.15-0.94 (m, 6H), 0.77 (m, 2H), C25H34F3N3 〇3, found 482.6 (MH+). 2,4-digas-]\-'1 melon bit-4-yl_1^€1-[(1-{4-[(trifluoromethyl)oxy]phenyl}-cyclopropyl)carbonyl] -L-Amphetamine amide: 1111'11^1^4001^1^,1^80-d6): δ 8.07 (d, 1H), 7.51 (d, 1H), 7.42-7.35 (m, 2H), 7.32 〇(m, 3H), 7.16 (d, 1H), 6.59 (d, 1H), 4.58-4.46 (m, 1H), 3.63 (d, 1H), 3.06 (m, 2H), 2.97 (dd, 1H) , 2.87 (dd, 1H), 2.71 (t, 2H), 1.70 (m, 2H), 1.51-1.29 (m, 2H), 1.30-1.10 (m, 2H), 1.02-0.89 (m, 2H). C25H26C12F3N303 MS (El), found 545.4 (MH+). N-{(lS)-l-[(2,4-diphenyl)indolyl]-2-[4-(methylamino)acridinyl]-2-oxoethyl}-1- {4-[(Difluoromethyl)oxy]phenyl}cyclopropanol: ijj NMR (400 MHz, DMSO-d6): δ 7.58-7.47 (m, 1 Η), 7.39-7.30 (m, 5H), 7.20 (dd, 1H), 6_89 (dd, 1H), 5.01 (m, 1H), 4.12 (dd, 1H), 3.86 (t, 1H), 2.96 (m, 2H), 2.89-2.81 (m, 1H) , 2.68 (m, 2H), 2.34 (d, 3H), 1.83 (m, 2H), 1.30-1.03 (mj . 4H), 0.93 (d, 2H). MS (El) for C26H28C12F3N303, found 559.4 (MH+ ). N-{(lS)-2-(4-Amino-based fox-l-yl)-l-[(2,4-diphenyl)methyl]_2_ oxoethyl}-1-{4- [(Trifluoromethyl)oxy]phenyl}cyclopropanamide: iH nmr (400 MHz, DMSO-d6): δ 7.57 (dd, 2H), 7.33 (dd, 2H), 7.26 146258.doc -155- 201040149 (d, 3H), 6.82 (dd, 1H), 4.96 (dd, 1H), 4.15 (dd, 1H), 3.90 (s, 1H), 3.08-2.90 (m, 3H), 2.90-2.77 (m, 1H), 2.66 (dd, 1H), 1.81 (t, 2H), 1.37-1.04 (m, 4H), 0.96 (q, 2H). MS (El) of C25H26C12F3N303, found 545.4 (MH+). N-[(lS)-2-[4-(indenylamino)indan-1-yl]2-oxo-1-{丨4-(trifluoromethyl)phenyl]-indenyl} Ethyl]-1-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide: 1H NMR (400 MHz, DMSO-d6): δ 7.57 (d, 2H), 7.35-7.25 (m , 6H), 6.84 (dd, 1H), 4.96 (dd5 1H), 4.12 (dd, 1H), 3.88 (t, 1H), 3.00 (dd, 3H), 2.89-2.67 (m, 3H), 2.35 (d MS (El), calcd. (m.p. N-[(lS)-2-(4Aminoacridin-1-yl)-2-oxo-l-{[4-(trifluoromethyl)phenyl]methyl}-ethyl[(3 Fluoromethyl)oxy]phenyl}cyclopropanamide: NMR (400 MHz, DMSO-d6): δ 7.57 (dd, 2 Η), 7.34-7.24 (m, 6H), 6.82 (dd, 1H), 4.96 ( Dd, 1H), 4.15 (dd, 1H), 3.90 (t, 1H), 3.08-2.94 (m, 3H), 2.90-2.75 (m, 1H), 2.66 (dd, 1H), 1.81 (t, 2H) MS (El), calcd., calcd. (m,j,j,j,j, N-{(lS)-l-[(4-bromophenyl)methyl]-2-[4-(methylamino)acridin-1-yl]-2-oxoethyl}-1- {4-[(Trifluoromethyl)oxy]phenyl}cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.40 (dd, 2H), 7.35-7.27 (m, 4H), 7.00 ( d, 2H), 6.86 (dd, 1H), 4.90 (dd, 1H), 4.21-4.03 (m, 1H), 3.87 (t, 1H), 3.08-2.92 (m, 2H), 2.83 (t, 2H) , 2.74-2.61 (m, 2H), 2.37 (d, 3H), 1.83 (m, 2H), 1.24 (m, 4H), 0.97 (d, 146258.doc -156- 201040149 2H)- MS of C26H29BrF3N3〇3 (EI) 'Measured value 569.4 (MH+). N-{(lS)-2-(4-Aminylcridine·j-ylbromophenyl)methyl]·2-oxoethyl}-1-{4-[(difluoromethyl)oxy]benzene } 环 酿 :: NMR (400 MHz, DMSO-d6): δ 7.35 (dd, 2Η), 7.27 (dd, 4H), 6.95 (dd, 2H), 6.73 (dd, 1H), 4.92-4.78 ( m, 1H), 4.09 (dd, 1H), 3.83 (t, 1H), 3.03-2.91 (m, 2H), 2.85-2.73 (m, 1H), 2.70-2.53 (m, 2H), 1.74 (m, 2H), 1.28-1.07 (m, 4H), 0.98-0.85 (m, 2H). MS (El) of C25H27BrF3N303, found 555 4 (MH+). N-[(lS)-2-[4-(methylamino)"! melon bite _i_yl]_2_oxo (phenylmethyl) ethyl]-1-{4-[(trifluoro Methyl)oxy]phenyl}cyclopropanamide · NMR (400 MHz, DMSO-d6): δ 7.34 (dd, 2H), 7.28 (d, 3H), 7.22-7.19 (m, 2H), 7.03 (d , 2H), 6.84 (dd, 1H), 4.91 (dd, 1H), 4.09 (dd, 1H), 3.83 (t, 1H), 3.10-2.98 (m, 1H), 2.98-2.81 (m, 2H), 2.79-2.65 (m, 3H), 2.33 (d, 3H), 1.78 (m, 2H), 1.28- 1.19 (m, 2H), 1.14-0.87 (m, 4H)· MS (El) of C26H30F3N3O3, measured value 490.5 (MH+).

N-【（lS)-2-(4-胺基呱啶-1-基）-2-氧代-l_(苯基甲基）乙基]_ 1-{4-[(三氟甲基）氧】苯基}環丙醯胺：ijj NMR (400 MHz， DMSO-d6): δ 7.31 (dd, 4Η), 7.25-7.16 (m, 3H), 7.08-6.96 (m, 2H), 6.70 (dd, 1H), 4.91 (dd, 1H), 4.26-4.04 (m, 1H), 3.88 (t, 1H), 3.09-2.81 (m, 3H), 2.79-2.56 (m, 2H), 1.78 (d, 2H)，1.24 (m，4H)，1.06-0.83 (m，2H)· C25H28F3N303 的 MS (El)，實測值476.5 (MH+)。 N-{(lS)-l-(環己基甲基）-2-[4-(甲基胺基）呱啶·i•基】_2_ 146258.doc •157· 201040149N-[(lS)-2-(4-Aminoacridin-1-yl)-2-oxo-l-(phenylmethyl)ethyl]_ 1-{4-[(trifluoromethyl) Oxygen]phenyl}cyclopropanamide: ijj NMR (400 MHz, DMSO-d6): δ 7.31 (dd, 4Η), 7.25-7.16 (m, 3H), 7.08-6.96 (m, 2H), 6.70 (dd , 1H), 4.91 (dd, 1H), 4.26-4.04 (m, 1H), 3.88 (t, 1H), 3.09-2.81 (m, 3H), 2.79-2.56 (m, 2H), 1.78 (d, 2H MS (El), 1.24 (m, 4H), 1.06 - 0.83 (m, 2H), C25H28F3N303, found 476.5 (MH+). N-{(lS)-l-(cyclohexylmethyl)-2-[4-(methylamino)acridine·i•yl]_2_ 146258.doc •157· 201040149

氧代乙基}-1-{4-丨（三氟甲基）氧]苯基}環丙醯胺：iH NMR (400 MHz, DMSO-d6): δ 7.40 (d, 2H), 7.34-7.21 (m, 2H), 6.86 (dd, 1H), 4.74-4.64 (m, 1H), 4.28 (t, 1H), 3.83 (t, 1H), 3.04 (d, 2H), 2.49 (s, 3H), 1-93 (m, 2H), 1.63 (m, 1H), 1.53 (m, 3H), 1.41 (m, 2H), 1-27 (d, 5H), 1.16 (m, 1H), 1.08-0.94 (m，6H)，0.73 (m, 2H). C26H36F3N303 的 MS (El)，實測 值 496_6 (MH+)。 N-[(lS)-2-(4-胺基呱啶-1-基）-1-(環己基甲基）-2-氧代乙 基】-l-{4-[(三氟甲基）氧]苯基}環丙醢胺：4 NMR (400 MHz, DMSO-d6): δ 7.45 (dd, 2H), 7.34 (d, 2H), 6.85 (dd, 1H), 4.74 (d, 1H), 4.21 (t, 1H), 3.78 (t, 1H), 3.06 (d, 2H), 2.70-2.54 (m, 1H), 1.83 (dd, 2H), 1.67 (m, 1H), 1.62-1.44 (m, 4H), 1.29 (m, 5H), 1.18-0.93 (m, 7H), 0.80 (m, 2H). C25H34F3N303 的 MS (El)，實測值482.6 (MH+)。 4-溴-N-呱啶-4-基-Να-【（1-{4-[(三氟甲基）氧】苯基卜環丙 基）-羰基]-L_苯丙胺醯胺：NMR (400 MHz，DMSO-D: δ 8.11 (d, 1H), 7.41 (d, 2H), 7.37-7.32 (m, 2H), 7.29 (d, 2H), 6.99 (d, 2H), 6.58 (d, 1H), 4.44 (dd, 1H), 3.62 (m, 1H), 3.08 (t, 2H), 2.83-2.69 (m, 4H), 1.72 (t, 2H), 1.38 (dd,Oxoethyl}-1-{4-indole (trifluoromethyl)oxy]phenyl}cyclopropanamide: iH NMR (400 MHz, DMSO-d6): δ 7.40 (d, 2H), 7.34-7.21 (m, 2H), 6.86 (dd, 1H), 4.74-4.64 (m, 1H), 4.28 (t, 1H), 3.83 (t, 1H), 3.04 (d, 2H), 2.49 (s, 3H), 1-93 (m, 2H), 1.63 (m, 1H), 1.53 (m, 3H), 1.41 (m, 2H), 1-27 (d, 5H), 1.16 (m, 1H), 1.08-0.94 ( m, 6H), 0.73 (m, 2H). MS (El) for C26H36F3N303, found 496_6 (MH+). N-[(lS)-2-(4-Aminoacridin-1-yl)-1-(cyclohexylmethyl)-2-oxoethyl]-l-{4-[(trifluoromethyl) Oxy]phenyl}cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.45 (dd, 2H), 7.34 (d, 2H), 6.85 (dd, 1H), 4.74 (d, 1H) , 4.21 (t, 1H), 3.78 (t, 1H), 3.06 (d, 2H), 2.70-2.54 (m, 1H), 1.83 (dd, 2H), 1.67 (m, 1H), 1.62-1.44 (m , 4H), 1.29 (m, 5H), 1.18-0.93 (m, 7H), 0.80 (m, 2H). MS (El) of C25H34F3N303, found 482.6 (MH+). 4-bromo-N-acridin-4-yl-Να-[(1-{4-[(trifluoromethyl)oxy]phenyl)cyclopropyl)-carbonyl]-L-phenylalanamine decylamine: NMR ( 400 MHz, DMSO-D: δ 8.11 (d, 1H), 7.41 (d, 2H), 7.37-7.32 (m, 2H), 7.29 (d, 2H), 6.99 (d, 2H), 6.58 (d, 1H ), 4.44 (dd, 1H), 3.62 (m, 1H), 3.08 (t, 2H), 2.83-2.69 (m, 4H), 1.72 (t, 2H), 1.38 (dd,

2H)，1.24 (m，2H), 1.06-0.86 (m，2H)· C25H27BrF3N303 的 MS (El)，實測值 555·4 (MH+)。2H), 1.24 (m, 2H), 1.06-0.86 (m, 2H). MS (El) of C25H27BrF3N303, found 555·4 (MH+).

N-{(lS)-2-(4·胺基-4-甲基狐咬-1-基）-l-[(4_溴苯基）甲 基】-2-氧代乙基}-1-(2,3,4-三氟苯基）環丙隨胺：NMR (400 MHz, DMSO-d6): δ 7.40 (dd, 2Η), 7.29 (dd, 1H), 7.18 146258.doc -158- 201040149 (m, 1H), 7.10 (d, 1H), 7.04 (dd, 2H), 4.86 (d, 1H), 3.58-3.31 (m, 4H), 2.90-2.76 (m, 1H), 2.76-2.67 (m, 1H), 1.47 (m, 3H), 1.39-1.22 (m, 3H), 1.15 (d, 3H), 0.98 (m, 2H). C25H27BrF3N302的MS (El)，實測值539.4 (MH+)。 4_溴-N-[(3R)-呱啶-3-基】-Να·{[1-(2,3,4-三氟苯基）-環丙 基 I 羰基}-L-苯丙胺醢胺：4 NMR (400 MHz, DMSO-d6): δ 8.16 (d, 1H), 7.39 (d, 2H), 7.29 (dd, 1H), 7.23-7.11 (m, 1H), 7.03 (d, 2H), 6.91 (d, 1H), 4.47-4.33 (m, 1H), 3.66 (m, 1H), 3.06-2.91 (m, 1H), 2.92-2.69 (m, 4H), 2.62 (t, 1H), 1.66 (m, 2H), 1.45 (m, 1H), 1.37-1.21 (m, 3H), 1.11-0.84 (m, 2H). C24H25BrF3N302 的 MS (El)，實測值 525.4 (MH+)。N-{(lS)-2-(4.Amino-4-methylfoxbit-1-yl)-l-[(4-bromophenyl)methyl]-2-oxoethyl}-1 -(2,3,4-Trifluorophenyl)cyclopropanamide: NMR (400 MHz, DMSO-d6): δ 7.40 (dd, 2 Η), 7.29 (dd, 1H), 7.18 146258.doc -158- 201040149 (m, 1H), 7.10 (d, 1H), 7.04 (dd, 2H), 4.86 (d, 1H), 3.58-3.31 (m, 4H), 2.90-2.76 (m, 1H), 2.76-2.67 ( m, 1H), 1.47 (m, 3H), 1.39-1.22 (m, 3H), 1.15 (d, 3H), 0.98 (m, 2H). MS (El) of C25H27BrF3N302, found 539.4 (MH+). 4-bromo-N-[(3R)-acridin-3-yl]-Να·{[1-(2,3,4-trifluorophenyl)-cyclopropyl I carbonyl}-L-phenylpropylamine decylamine :4 NMR (400 MHz, DMSO-d6): δ 8.16 (d, 1H), 7.39 (d, 2H), 7.29 (dd, 1H), 7.23-7.11 (m, 1H), 7.03 (d, 2H), 6.91 (d, 1H), 4.47-4.33 (m, 1H), 3.66 (m, 1H), 3.06-2.91 (m, 1H), 2.92-2.69 (m, 4H), 2.62 (t, 1H), 1.66 ( M, 2H), 1.45 (m, 1H), 1.37-1.21 (m, 3H), 1.11-0.84 (m, 2H). MS (El) of C24H25BrF3N302, found 525.4 (MH+).

N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基）-l-[(4-溴苯 基）甲基卜2-氧代乙基}-1-(2,3,4-三氟苯基）環丙醢胺： iH NMR (400 MHz, DMSO-d6)： δ 7.43-7.35 (m, 2Η), 7.29 (m, 1H), 7.18 (m, 2H), 7.07 (m, 2H), 4.64 (dd, 1H), 4.34 (d, 2H), 4.11 (m, 1H), 3.19-2.83 (m, 2H), 2.75 (m, 2H), 1.98 (m, 3H), 1.85-1.39 (m, 5H), 1.29 (d, 2H), 1.12-0.84 (m, 2H). C26H27BrF3N302 的 MS (El) ’ 實測值551.4 (MH+)。 N-{(lS)-2-(4-胺基-4-甲基呱啶-1-基）-l-[(4-溴苯基）甲 基】-2-氧代乙基}-1-(2,3-二氟苯基）環丙醢胺：4 NMR (400 MHz, DMSO-d6)： δ 7.41 (dd, 3H), 7.19 (m, 2H), 7.03 (dd, 2H), 6.92 (dd, 1H), 4.90 (m, 1H), 3.52 (m, 2H), 2.87 (m, 2H), 2.80-2.64 (m, 2H), 1.55-1.31 (m, 6H), 1.15 (d, 146258.doc -159· 201040149 3H), 1.02 (m，2H). C25H28BrF2N3〇2 的 MS (EI) ’ 實測值 521.4 (MH+)。 4-溴-Να-{【1-(2,3-二氟苯基）環丙基1羰基}-N-[(3R)-呱咬_ 3-基】-L-苯丙胺醢胺：4 NMR (400 MHz，DMSO-d6): δ 8.20 (d, 1H), 7.32 (d, 3H), 7.22-7.04 (m, 2H), 6.95 (d, 2H), 6.66 (d，1H)，4.36 (dd，1H), 3.62 (m, 1H)，2.93 (d，1H)， 2.81 (m, 2H), 2.80-2.68 (m, 2H), 2.60 (t, 1H), 1.62 (d, 2H), 1.42 (d, 1H)，1.28 (dd，3H)，0.94 (m，2H). C24H26BrF2N3〇2 的 MS (El)，實測值 507.4 (MH+)。 N-{(lS)-2-(3-胺基-8-氮雜雙環【3.2.1】辛-8-基）-l-【(4-溴苯 基）甲基1-2-氧代乙基}-1-(2,3-二氟苯基）環丙醢胺：4 NMR (400 MHz, DMSO-d6): δ 7.35 (m, 3H), 7.09 (m, 2H), 7.05-6.83 (m, 3H), 4.62 (d, 1H), 4.28 (m, 2H), 4.07 (m, 1H), 3.05 (d, 1H), 2.70 (d, 1H), 2.10-1.68 (m, 4H), 1.57 (m, 2H)，1.35 (dd, 4H)，0.97 (d，2H). C26H28BrF2N302 的 MS (El)，實測值 533·4 (MH+)。 N-{(lS)-2-(4-胺基-4-甲基呱啶-1-基）-l-[(4-溴苯基）曱 基】-2-氧代乙基}-1-(4-氟苯基）環丙醯胺：4 NMR (400 MHz, DMSO-d6)： δ 7.46-7.39 (m, 2H), 7.26 (d, 2H), 7.13 (d, 2H), 6.99 (d5 2H), 6.67-6.48 (m, 1H), 4.91 (m, 1H), 3.79 (d, 2H)S 3.08 (d, 2H), 2.91-2.66 (m, 2H), 1.54 (m, 4H), 1.28 (s，3H)，1.23 (m, 2H)，0.87 (d，2H). C25H29BrFN302的 MS (El)，實測值503.4 (MH+)。 4-溴-Να-{[1-(4-氟苯基）環丙基】羰基}-N-[(3R)-呱啶-3- 146258.doc -160· 201040149 基】-L-苯丙胺醯胺：4 NMR (400 MHz，DMSO-d6): δ 8.16 (d, 1Η), 7.44-7.41 (m, 2H), 7.34-7.22 (m, 2H), 7.17-7.13 (m, 2H), 6.98 (d, 2H), 6.42 (d, 1H), 4.47-4.31 (m, 1H), 3.73 (d, 1H), 3.15 (dd, 3H), 2.80 (m, 3H), 1.86-1.64 (m, 2H), 1.57 (d, 1H), 1.35 (dd, 1H), 1.30-1.15 (m, 2H), 1.04-0.81 (m，2H). C24H27BrFN302的 MS (El)，實測值 489.4 (MH+)。 N-{(lS)-2-(3-胺基-8-氮雜雙環 ρ·2·1]辛-8-基）-l-[(4-溴苯 基）甲基]-2-氧代乙基}-1-(4-氟苯基）環丙醯胺：4 NMR 〇 (400 MHz, DMSO-d6): δ 7.39 (dd, 2H), 7.27-7.17 (m, 2H), 7.09 (dd5 2H), 6.99 (m, 2H), 6.77 (dd, 1H), 4.60 (q, 1H), 4.28 (m, 2H), 3.07 (m, 1H), 2.78-2.62 (m, 2H), 2.21 (m, 1H), 1.81-1.34 (m, 6H), 1.20 (m, 3H), 1.04-0.75 (m, 2H). C26H29BrFN302的 MS (El)，實測值 515.4 (MH+)。 2,4-二氣-Να-({l-[2-氟-4-(三氟甲基）苯基】環丙基卜幾 基）-N-[(3R)·呱啶-3-基】-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H)} 7.90 (d, 1H), 7.64 (d, 1H), o 7.58 (d, 2H), 7.51 (d, 1H), 7.32 (dd, 1H), 7.17 (d, 1H), 6.93 (d, 1H), 4.51 (td, 1H), 3.71-3.58 (m, 1H), 3.04-2.80 (m, 4H), 2.60 (dd, 1H), 2.45-2.39 (m, 1H), 1.62 (t, 2H), 1.49-1.19 (m，4H)，1.07-0.94 (m，2H). C25H25C12F4N302 的 MS (El)，實測值 547.4 (MH+)。 N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基）-1-[(2,4_二 氣苯基）甲基]-2-氧代乙基}-1-[2 -氣-4-(三氟甲基）苯基]環丙 醯胺：4 NMR (400 MHz，DMSO-d6): δ 8.23 (s, 1H)，7.61 146258.doc -161 - 201040149 (t, 1H), 7.58-7.51 (m, 3H), 7.34 (ddd, 1H), 7.24 (dd, 2H), 4.80 (d, 1H), 4.28 (t, 2H), 3.15 (s, 1H), 3.09-2.83 (m, 3H), 2.16-1.88 (m, 3H), 1.67 (dd, 3H), 1.49 (d, 2H), 1.38-1.10 (m, 2H)，1.01 (d，2H). C27H27Cl2F4N302的MS (El)，實測值 573.4 (MH+)。 2,4-二氣-Να-({1-[2-氟-4-(三氟甲基）苯基]環丙基}-羰 基）-N-[(3S)-吡咯啶-3-基】-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6)： δ 8.44 (d5 1H), 8.25 (s, 1H), 7.63 (d, 1H), 7.59-7.54 (m, 2H), 7.50 (d, 1H), 7.32 (dd, 1H), 7.17 (d, 1H), 6.92 (d, 1H), 4.51 (td, 1H), 4.17 (d, 1H), 3.10 (dd, 1H), 3.01 (qd, 3H), 2.86 (dd, 1H), 2.71 (dd, 1H), 1.97 (dq, 1H), 1.65 (td, 1H), 1.40-1.20 (m, 2H), 1.09-0.92 (m, 2H). (：24出3(：12?4仏02的 MS (El)，實測值 533.4 (MH+)。 N-[(lS)-2-(4-胺基-4-甲基呱啶-1-基）_2-氧代-l-{[4-(三氟 甲基）-苯基]甲基}乙基】-l-[2-氟-4-(三氟甲基）苯基】環丙醯 胺：NMR (400 MHz, DMSO-d6): δ 8.33 (s，1H)，7.63 (d, 1Η), 7.60-7.50 (m, 4H), 7.29 (d, 2H), 7.06 (dd, 1H), 4.94 (d, 1H), 3.57-3.31 (m, 5H), 2.98-2.80 (m5 2H), 1.51-1.19 (m，6H)，1.13 (d，3H), 1.00 (t，2H). C27H28F7N302 的 MS (El)，實測值 560.5 (MH+)。 Να-({1-[2-氟-4-(三氟甲基）苯基】環丙基}羰基）-N-[(3R)-呱啶-3-基】-4-(三氟甲基）-L-苯丙胺醢胺：4 NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 8.03 (d, 1H), 7.68-7.49 (m, 5H), 7.27 (d5 2H), 6.81 (d, 1H), 4.49 (td, 1H), 3.58 (s, 1H), 146258.doc •162· 201040149 2.88 (ddd, 4H), 2.40 (dd, 1H), 1.60 (d, 2H), 1.46-1.20 (m, 4H)，1.12-1.01 (m，1H)，1.00-0.90 (m, 1H). C26H26F7N302的 MS (El)，實測值 546.5 (MH+)。 Να-({1-[2_氟-4-(三氣甲基）苯基】環丙基}叛基七3S)_ 吡咯啶-3-基】-4-(三氟甲基）-L-苯丙胺醯胺：NMR (400 MHz，DMSO-d6): δ 8.57 (d, 1H)，8.29 (s，1H)，7.64-7.48 (m， 5H)，7.28 (d，2H)，6.83 (d, 1H), 4.47 (td, 1H)，4.14 (d，1H)， 3.10-2.84 (m，5H)，2·69 (dd，1H)，1.97 (dq, 1H), 1.64 (dt， 1H), 1.42-1.22 (m, 2H), 1.12-1.02 (m, 1H), 1.00-0.89 (m, 1H). C25H24F7N302的 MS (El)，實測值 532.5 (MH+)。 4-溴-Να·({1_【2-氟-4-(三氟甲基）苯基]環丙基}羰基）_N-[(3R)-呱啶-3-基】-L-苯丙胺酿胺：4 NMR (400 MHz, DMSO-d6)： δ 8.26 (s, 1H), 8.02 (d, 1H), 7.64 (d, 1H), 7.58-7.53 (m, 2H), 7.46-7.35 (m, 2H), 7.05-6.96 (m, 2H), 6.78 (d, 1H), 4.54-4.35 (m, 1H), 3.58 (d, 1H), 2.91 (dd, 1H), 2.85-2.72 (m, 3H), 2.61-2.50 (m, 1H), 2.40 (dd, 1H), 1.60 (d, 2H), 1.44-1.20 (m, 4H), 1.11-1.02 (m, 1H), 1.01-0.91 (m, 1H). C25H26BrF4N302 的 MS (El)，實測值 557.4 (MH+)。 N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1】辛-8-基）-1-[(4-溴苯 基）曱基]-2-氧代乙基}-1-[2-氟-4-(三氟甲基）苯基】環丙醢 胺：4 NMR (400 MHz，DMSO-d6): δ 8.29 (s，1H)，7.63 (d， 1H), 7.57-7.52 (m, 2H), 7.41 (dd, 2H), 7.11-7.01 (m, 3H), 4.67 (dt, 1H), 4.25 (t, 2H), 3.20-2.86 (m, 2H), 2.79-2.65 146258.doc -163- 201040149 (m, 2H), 2.04 (dt, 3H), 1.91-1.69 (m, 2H), 1.60 (s, 2H), 1.43 (dd, 3H), 1.33 (dt, 2H), 1.12-0.90 (m, 2H). C27H28BrF4N302的 MS (El)，實測值 583.4 (MH+)。 4-溴-Να-({1-[2-氟-4-(三氟甲基）苯基】環丙基}羰基卜N_ [(3S)-吡咯啶-3-基]-L-苯丙胺醯胺：NMR (400 MHz， DMSO-d6)： δ 8.52 (d, 1Η), 8.29 (s, 1H), 7.64 (d, 1H), 7.57 (d, 2H), 7.40 (d, 2H), 7.01 (d, 2H), 6.79 (d, 1H), 4.41 (td, 1H), 4.12 (s, 1H), 3.09-2.90 (m, 3H), 2.79 (qd, 2H), 2.69- 2.59 (m, 1H), 1.95 (td, 1H), 1.61 (d, 1H), 1.36 (dd, 1H), 1.33-1.25 (m, 1H), 1.12-1.00 (m, 1H), 0.99-0.90 (m, 1H). C24H24BrF4N302的 MS (El)，實測值 543.4 (MH+)。 Να-({1-[2-氟-4-(三氟甲基）苯基】環丙基}羰基）-N-[(3R)-呱啶-3-基】-L-笨丙胺醢胺：NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1Η), 7.99 (d, 1H), 7.63 (d, 1H), 7.59-7.47 (m, 2H), 7.32-7.12 (m, 3H), 7.03 (dd, 1H), 4.54-4.32 (m, 1H), 3.59 (d, 2H), 2.97-2.75 (m, 4H), 2.61-2.52 (m, 1H), 2.41 (dd, 1H), 1.61 (d, 2H), 1.39 (ddd, 2H), 1.34-1.21 (m, 2H), 1_10-1_02 (m, 1H), 1.01-0.93 (m, 1H). C25H27F4N302的MS (El)，實測值478.5 (MH+)。 N-[(lS)-2-(3-胺基-8-氮雜雙環[3.2.1】辛-8-基）-2-氧代-1-(苯基甲基）乙基】-1-丨2-氟-4-(三氟甲基）苯基]環丙釀胺：4 NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1H), 7.63 (d, 1H), 7.55 (dd, 2H), 7.25-7.13 (m, 4H), 7.13-7.05 (m, 3H), 4.66 (dq, 1H), 4.43-4.24 (m, 2H), 4.07 (s, 1H), 3.19-3.09 (m, 146258.doc -164· 201040149 1H), 2.94 (dd, 1H), 2.76 (t, 1H), 2.20-2.08 (m, 1H), 1.96 (dd, 1H), 1.86-1.73 (m, 2H), 1.69-1.52 (m, 1H), 1.51-1.29 (m，5H)，1.14-0.89 (m, 2H). C27H29F4N302 的 MS (El)，實測 值 504·5 (MH+)。 Να-({1-【2-氟-4-(三氟甲基）苯基]環丙基}羰基）-N-[(3S)-吡咯啶-3-基】-L-苯丙胺醯胺：111\]^11(40〇]^1^，0^180-d6): δ 8.61 (d, 1H), 8.29 (s, 1H), 7.62 (d, 1H), 7.58-7.50 (m, 2H), 7.24-7.12 (m, 3H), 7.04 (dd, 2H), 6.74 (d, 1H), 4.48-4.35 (m, 1H), 4.15 (dt, 1H), 3.14-2.96 (m, 3H), 2.82 (qd, 2H), 2.73-2.65 (m, 1H), 2.03-1.88 (m, 1H), 1.66 (td, 1H)，1.45-1.25 (m，2H)，1.11-0.89 (m, 2H). C24H25F4N302的 MS (El)，實測值464.5 (MH+)。 3-環己基-N，2，-({l-[2-氟-4-(三氟甲基）苯基】環丙基}-羰 基）-N_[(3R)-呱啶_3_基]-L-丙胺醯胺：4 NMR (400 MHz， DMSO-d6): δ 8.25 (s, 1H), 7.92 (d, 1H), 7.68-7.53 (m, 3H), 6.85 (d, 1H), 4.27 (dt, 1H), 3.72-3.58 (m, 1H)} 2.95 (dd, 1H), 2.86 (d, 1H), 2.60 (t, 1H), 2.46-2.40 (m, 1H), 1.59 (dd, 7H), 1.50-1.24 (m, 6H), 1.17-0.97 (m, 6H), 0.79 (dd, 2H). C25H33F4N302 的 MS (El)，實測值484.5 (MH+)。 N-[(lS)-2-(3-胺基-8-氮雜雙環[3.2.1】辛-8-基）-1-(環己基 甲基）-2-氧代乙基]-1·[2-氟-4-(三氟甲基）苯基】環丙醯胺： lU NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1Η), 7.59 (dt, 3H), 7.12-7.04 (m, 1H), 4.56 (dd, 1H), 4.35 (d, 1H), 4.12 (s, 1H), 3.22-3.13 (m, 1H), 2.16-1.80 (m, 5H), 1.69-1.53 146258.doc -165- 201040149 (m, 5H), 1.52-1.43 (m, 4H), 1.39 (d, 2H), 1.29-1.20 (m, 1H)，1.17-0.98 (m, 7H)，0.79 (dd, 2H). C27H35F4N302的 MS (El)，實測值510.6 (MH+)。 3-環己基-N，2，-({l-[2-氟-4-(三氟甲基）苯基]環丙基}-羰 基）-N-[(3S)-吡咯啶-3-基]-L-丙胺醢胺：NMR (400 MHz, DMSO-d6)： δ 8.30 (d, 1Η), 8.25 (s, 1H), 7.63 (dd, 2H), 7.56 (d, 1H), 6.84 (d, 1H), 4.27 (dt, 1H), 4.13 (d, 1H), 3.08 (dd, 1H), 3.02-2.92 (m, 2H), 2.66 (dd, 1H), 1.95 (dq, 1H), 1.66-1.52 (m, 6H), 1.51-1.44 (m, 1H), 1.42-1.30 (m, 3H), 1.18-0.97 (m，6H), 0.78 (dd, 2H). C24H31F4N302的 MS (El)，實測值470.5 (MH+)。 2,4-二氣-Να-({ΐ-[2_氟-4-(三氟甲基）苯基】環丙基}-羰 基）_N-呱啶-4-基-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.30 (s, 1H), 7.98 (d, 1H), 7.65 (d, 1H), 7.58 (s, 2H), 7.51 (d, 1H), 7.32 (dd, 1H), 7.17 (d, 1H), 6.85 (d, 1H), 4.58-4.42 (m, 1H), 3.66 (s, 1H), 3.11 (dd, 2H), 2.92 (ddd, 2H), 2.78 (t, 2H), 1.73 (t, 2H), 1.38 (ddd, 4H), 1.02 (s, 2H). C25H25C12F4N302 的 MS (El)，實測值 547.4 (MH+)。 Να-({1-[2-氟-4-(三氟甲基）苯基】環丙基}羰基）-N-呱啶- 4-基-4-(三氟甲基）_L-苯丙胺醯胺：4 NMR (400 MHz， DMSO-de)： δ 8.32 (s, 1H), 8.09 (d, J 1H), 7.61-7.55 (m9 4H), 7.27 (d, 2H), 6.78 (d, 1H), 4.48 (dd, 1H), 3.62 (s, 2H), 3.06 (t, 2H), 2.95-2.83 (m, 2H), 2.72 (d, 2H), 1.81-1.64 (m, 146258.doc -166· 201040149 2Η), 1.49-1.24 (m, 4Η), 1.12-1.02 (m, 1H), 0.97 (dd, 1H). C26H26F7N302的 MS (El)，實測值 546.5 (MH+)。 4_漠-Να-({1-[2 -氣-4-(三氟甲基）苯基】環丙基}-数基）-N-呱啶-4-基-L-苯丙胺酿胺：b NMR (400 MHz，DMSO-d6): δ 8.31 (s, 1Η), 8.05 (d, 1H), 7.65 (d, 1H), 7.56 (s, 2H), 7.40 (d, 2H), 7.00 (d, 2H), 6.75 (d, 1H), 4.42 (dd, 1H), 3.61 (s, 2H), 3.06 (t, 2H), 2.84-2.62 (m, 4H), 1.69 (d, 2H), 1.45-1.22 (m, 4H), 1.10-1.03 (m, 1H), 0.98 (dd, 1H). ΟN-{(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-l-[(4-bromophenyl)methyl b 2-oxo B }}-1-(2,3,4-trifluorophenyl)cyclopropanamide: iH NMR (400 MHz, DMSO-d6): δ 7.43-7.35 (m, 2 Η), 7.29 (m, 1H), 7.18 (m, 2H), 7.07 (m, 2H), 4.64 (dd, 1H), 4.34 (d, 2H), 4.11 (m, 1H), 3.19-2.83 (m, 2H), 2.75 (m, 2H) , 1.98 (m, 3H), 1.85-1.39 (m, 5H), 1.29 (d, 2H), 1.12-0.84 (m, 2H). MS (El) of C26H27BrF3N302's found 551.4 (MH+). N-{(lS)-2-(4-Amino-4-methylacridin-1-yl)-l-[(4-bromophenyl)methyl]-2-oxoethyl}-1 -(2,3-difluorophenyl)cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.41 (dd, 3H), 7.19 (m, 2H), 7.03 (dd, 2H), 6.92 (dd, 1H), 4.90 (m, 1H), 3.52 (m, 2H), 2.87 (m, 2H), 2.80-2.64 (m, 2H), 1.55-1.31 (m, 6H), 1.15 (d, 146258 .doc -159· 201040149 3H), 1.02 (m,2H). MS (EI) of C25H28BrF2N3 〇2 </ RTI> </ RTI> 4-bromo-Να-{[1-(2,3-difluorophenyl)cyclopropyl 1carbonyl}-N-[(3R)-呱 _ 3-yl]-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.20 (d, 1H), 7.32 (d, 3H), 7.22-7.04 (m, 2H), 6.95 (d, 2H), 6.66 (d, 1H), 4.36 (dd ,1H), 3.62 (m, 1H), 2.93 (d,1H), 2.81 (m, 2H), 2.80-2.68 (m, 2H), 2.60 (t, 1H), 1.62 (d, 2H), 1.42 ( d, 1H), 1.28 (dd, 3H), 0.94 (m, 2H). MS (El) of C24H26BrF2N3 〇2, found 507.4 (MH+). N-{(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-l-[(4-bromophenyl)methyl1-2-oxo Ethyl}-1-(2,3-difluorophenyl)cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.35 (m, 3H), 7.09 (m, 2H), 7.05-6.83 (m, 3H), 4.62 (d, 1H), 4.28 (m, 2H), 4.07 (m, 1H), 3.05 (d, 1H), 2.70 (d, 1H), 2.10-1.68 (m, 4H), 1.57 (m, 2H), 1.35 (dd, 4H), 0.97 (d, 2H). MS (El) of C26H28BrF2N302, found 533·4 (MH+). N-{(lS)-2-(4-Amino-4-methylacridin-1-yl)-l-[(4-bromophenyl)indolyl]-2-oxoethyl}-1 -(4-fluorophenyl)cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.46-7.39 (m, 2H), 7.26 (d, 2H), 7.13 (d, 2H), 6.99 ( D5 2H), 6.67-6.48 (m, 1H), 4.91 (m, 1H), 3.79 (d, 2H)S 3.08 (d, 2H), 2.91-2.66 (m, 2H), 1.54 (m, 4H), 1.28 (s,3H), 1.23 (m, 2H), 0.87 (d, 2H). MS (El) of C25H29BrFN302, found 50. 4-bromo-Να-{[1-(4-fluorophenyl)cyclopropyl]carbonyl}-N-[(3R)-acridin-3- 146258.doc -160· 201040149 base]-L-amphetamine Amine: 4 NMR (400 MHz, DMSO-d6): δ 8.16 (d, 1 Η), 7.44-7.41 (m, 2H), 7.34-7.22 (m, 2H), 7.17-7.13 (m, 2H), 6.98 ( d, 2H), 6.42 (d, 1H), 4.47-4.31 (m, 1H), 3.73 (d, 1H), 3.15 (dd, 3H), 2.80 (m, 3H), 1.86-1.64 (m, 2H) , 1.57 (d, 1H), 1.35 (dd, 1H), 1.30-1.15 (m, 2H), 1.04-0.81 (m, 2H). MS (El) of C24H27BrFN302, found 489.4 (MH+). N-{(lS)-2-(3-Amino-8-azabicyclo ρ·2·1]oct-8-yl)-l-[(4-bromophenyl)methyl]-2-oxo Ethylethyl}-1-(4-fluorophenyl)cyclopropanamide: 4 NMR 400 (400 MHz, DMSO-d6): δ 7.39 (dd, 2H), 7.27-7.17 (m, 2H), 7.09 ( Dd5 2H), 6.99 (m, 2H), 6.77 (dd, 1H), 4.60 (q, 1H), 4.28 (m, 2H), 3.07 (m, 1H), 2.78-2.62 (m, 2H), 2.21 ( m, 1H), 1.81-1.34 (m, 6H), 1.20 (m, 3H), 1.04-0.75 (m, 2H). MS (El) of C26H29BrFN302, found 515.4 (MH+). 2,4-digas-Να-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropylbuxo)-N-[(3R)·acridin-3-yl 】-L-Amphetamine amide: 4 NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H)} 7.90 (d, 1H), 7.64 (d, 1H), o 7.58 (d, 2H), 7.51 (d, 1H), 7.32 (dd, 1H), 7.17 (d, 1H), 6.93 (d, 1H), 4.51 (td, 1H), 3.71-3.58 (m, 1H), 3.04-2.80 (m, 4H) ), 2.60 (dd, 1H), 2.45-2.39 (m, 1H), 1.62 (t, 2H), 1.49-1.19 (m, 4H), 1.07-0.94 (m, 2H). MS (El) of C25H25C12F4N302, Found 547.4 (MH+). N-{(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-1-[(2,4-diphenyl)methyl]-2 -Oxoethyl}-1-[2- gas-4-(trifluoromethyl)phenyl]cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 8.23 (s, 1H), 7.61 146258.doc -161 - 201040149 (t, 1H), 7.58-7.51 (m, 3H), 7.34 (ddd, 1H), 7.24 (dd, 2H), 4.80 (d, 1H), 4.28 (t, 2H), 3.15 (s, 1H), 3.09-2.83 (m, 3H), 2.16-1.88 (m, 3H), 1.67 (dd, 3H), 1.49 (d, 2H), 1.38-1.10 (m, 2H), 1.01 ( MS (El), calcd. 57 (MH+). 2,4-digas-Να-({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}-carbonyl)-N-[(3S)-pyrrolidin-3-yl 】-L-Amphetamine amide: 4 NMR (400 MHz, DMSO-d6): δ 8.44 (d5 1H), 8.25 (s, 1H), 7.63 (d, 1H), 7.59-7.54 (m, 2H), 7.50 (d, 1H), 7.32 (dd, 1H), 7.17 (d, 1H), 6.92 (d, 1H), 4.51 (td, 1H), 4.17 (d, 1H), 3.10 (dd, 1H), 3.01 ( Qd, 3H), 2.86 (dd, 1H), 2.71 (dd, 1H), 1.97 (dq, 1H), 1.65 (td, 1H), 1.40-1.20 (m, 2H), 1.09-0.92 (m, 2H) (:24 out of 3 (:12?4仏02 of MS (El), found 533.4 (MH+). N-[(lS)-2-(4-Amino-4-methyl acridine-1- )-oxo-l-{[4-(trifluoromethyl)-phenyl]methyl}ethyl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropene Indoleamine: NMR (400 MHz, DMSO-d6): δ 8.33 (s, 1H), 7.63 (d, 1 Η), 7.60-7.50 (m, 4H), 7.29 (d, 2H), 7.06 (dd, 1H) , 4.94 (d, 1H), 3.57-3.31 (m, 5H), 2.98-2.80 (m5 2H), 1.51-1.19 (m, 6H), 1.13 (d, 3H), 1.00 (t, 2H). C27H28F7N302 MS (El), found: 560.5 (MH+). Να-({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-N-[(3R)-acridine -3-yl]-4-(trifluoro ))-L-Amphetamine amide: 4 NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 8.03 (d, 1H), 7.68-7.49 (m, 5H), 7.27 (d5 2H), 6.81 (d, 1H), 4.49 (td, 1H), 3.58 (s, 1H), 146258.doc •162· 201040149 2.88 (ddd, 4H), 2.40 (dd, 1H), 1.60 (d, 2H), 1.46 -1.20 (m, 4H), 1.12-1.01 (m, 1H), 1.00-0.90 (m, 1H). MS (El) of C26H26F7N302, found 546.5 (MH+). Να-({1-[2_Fluoro-4-(trimethyl)phenyl)cyclopropyl}refenyl 7 3)-pyrrolidin-3-yl]-4-(trifluoromethyl)-L - amphetamine amide: NMR (400 MHz, DMSO-d6): δ 8.57 (d, 1H), 8.29 (s, 1H), 7.64-7.48 (m, 5H), 7.28 (d, 2H), 6.83 (d, (H), 4.14 (d, 1H) -1.22 (m, 2H), 1.12-1.02 (m, 1H), 1.00-0.89 (m, 1H). MS (El) of C25H24F7N302, found 532.5 (MH+). 4-bromo-Να·({1_[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)_N-[(3R)-acridin-3-yl]-L- amphetamine Amine: 4 NMR (400 MHz, DMSO-d6): δ 8.26 (s, 1H), 8.02 (d, 1H), 7.64 (d, 1H), 7.58-7.53 (m, 2H), 7.46-7.35 (m, 2H), 7.05-6.96 (m, 2H), 6.78 (d, 1H), 4.54-4.35 (m, 1H), 3.58 (d, 1H), 2.91 (dd, 1H), 2.85-2.72 (m, 3H) , 2.61-2.50 (m, 1H), 2.40 (dd, 1H), 1.60 (d, 2H), 1.44-1.20 (m, 4H), 1.11-1.02 (m, 1H), 1.01-0.91 (m, 1H) MS (El) for C25H26BrF4N302, found 557.4 (MH+). N-{(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-1-[(4-bromophenyl)indolyl]-2-oxo Ethyl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1H), 7.63 (d, 1H), 7.57-7.52 (m, 2H), 7.41 (dd, 2H), 7.11-7.01 (m, 3H), 4.67 (dt, 1H), 4.25 (t, 2H), 3.20-2.86 (m, 2H) , 2.79-2.65 146258.doc -163- 201040149 (m, 2H), 2.04 (dt, 3H), 1.91-1.69 (m, 2H), 1.60 (s, 2H), 1.43 (dd, 3H), 1.33 (dt MS (El), found: 583.4 (MH+). 4-bromo-Να-({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl b N_[(3S)-pyrrolidin-3-yl]-L-amphetamine Amine: NMR (400 MHz, DMSO-d6): δ 8.52 (d, 1 Η), 8.29 (s, 1H), 7.64 (d, 1H), 7.57 (d, 2H), 7.40 (d, 2H), 7.01 ( d, 2H), 6.79 (d, 1H), 4.41 (td, 1H), 4.12 (s, 1H), 3.09-2.90 (m, 3H), 2.79 (qd, 2H), 2.69- 2.59 (m, 1H) , 1.95 (td, 1H), 1.61 (d, 1H), 1.36 (dd, 1H), 1.33-1.25 (m, 1H), 1.12-1.00 (m, 1H), 0.99-0.90 (m, 1H). C24H24BrF4N302 MS (El), found 543.4 (MH+). Να-({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-N-[(3R)-呱啶-3-yl]-L-stupylamine amide: NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1 Η), 7.99 (d, 1H), 7.63 (d, 1H), 7.59-7.47 ( m, 2H), 7.32-7.12 (m, 3H), 7.03 (dd, 1H), 4.54-4.32 (m, 1H), 3.59 (d, 2H), 2.97-2.75 (m, 4H), 2.61-2.52 ( m, 1H), 2.41 (dd, 1H), 1.61 (d, 2H), 1.39 (ddd, 2H), 1.34-1.21 (m, 2H), 1_10-1_02 (m, 1H), 1.01-0.93 (m, MS (El) for C25H27F4N302, found 478.5 (MH+). N-[(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-2 -oxo-1- (phenylmethyl)ethyl]-1-indol-2-fluoro-4-(trifluoromethyl)phenyl]cyclopropanol: 4 NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1H ), 7.63 (d, 1H), 7.55 (dd, 2H), 7.25-7.13 (m, 4H), 7.13-7.05 (m, 3H), 4.66 (dq, 1H), 4.43-4.24 (m, 2H), 4.07 (s, 1H), 3.19-3.09 (m, 146258.doc -164· 201040149 1H), 2.94 (dd, 1H), 2.76 (t, 1H), 2.20-2.08 (m, 1H), 1.96 (dd, 1H), 1.86-1.73 (m, 2H), 1.69-1.52 (m, 1H), 1.51-1.29 (m, 5H), 1.14-0.89 (m, 2H). MS (El) of C27H29F4N302, found 504· 5 (MH+). Να-({1-[2-Fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-N-[(3S)-pyrrolidin-3-yl]-L-phenylalanamine decylamine: 111\]^11(40〇]^1^,0^180-d6): δ 8.61 (d, 1H), 8.29 (s, 1H), 7.62 (d, 1H), 7.58-7.50 (m, 2H) , 7.24-7.12 (m, 3H), 7.04 (dd, 2H), 6.74 (d, 1H), 4.48-4.35 (m, 1H), 4.15 (dt, 1H), 3.14-2.96 (m, 3H), 2.82 (qd, 2H), 2.73-2.65 (m, 1H), 2.03-1.88 (m, 1H), 1.66 (td, 1H), 1.45-1.25 (m, 2H), 1.11-0.89 (m, 2H). C24H25F4N302 MS (El), found 464.5 (MH+). 3-cyclohexyl-N,2,-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}-carbonyl)-N_[(3R)-acridine_3_yl ]-L-Alanine: 4 NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.92 (d, 1H), 7.68-7.53 (m, 3H), 6.85 (d, 1H), 4.27 (dt, 1H), 3.72-3.58 (m, 1H)} 2.95 (dd, 1H), 2.86 (d, 1H), 2.60 (t, 1H), 2.46-2.40 (m, 1H), 1.59 (dd, 7H), 1.50-1.24 (m, 6H), 1.17-0.97 (m, 6H), 0.79 (dd, 2H). MS (El) of C25H33F4N302, found 484.5 (MH+). N-[(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-1-(cyclohexylmethyl)-2-oxoethyl]-1 [2-Fluoro-4-(trifluoromethyl)phenyl]cyclopropanamide: lU NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1 Η), 7.59 (dt, 3H), 7.12- 7.04 (m, 1H), 4.56 (dd, 1H), 4.35 (d, 1H), 4.12 (s, 1H), 3.22-3.13 (m, 1H), 2.16-1.80 (m, 5H), 1.69-1.53 146258 .doc -165- 201040149 (m, 5H), 1.52-1.43 (m, 4H), 1.39 (d, 2H), 1.29-1.20 (m, 1H), 1.17-0.98 (m, 7H), 0.79 (dd, 2H). MS (El) for C27H35F4N302, found 510.6 (MH+). 3-cyclohexyl-N,2,-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}-carbonyl)-N-[(3S)-pyrrolidin-3- ]]-L-alanamine: NMR (400 MHz, DMSO-d6): δ 8.30 (d, 1 Η), 8.25 (s, 1H), 7.63 (dd, 2H), 7.56 (d, 1H), 6.84 ( d, 1H), 4.27 (dt, 1H), 4.13 (d, 1H), 3.08 (dd, 1H), 3.02-2.92 (m, 2H), 2.66 (dd, 1H), 1.95 (dq, 1H), 1.66 -1.52 (m, 6H), 1.51-1.44 (m, 1H), 1.42-1.30 (m, 3H), 1.18-0.97 (m,6H), 0.78 (dd, 2H). MS (El) of C24H31F4N302, measured The value is 470.5 (MH+). 2,4-digas-Να-({ΐ-[2_fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}-carbonyl)_N-acridin-4-yl-L-phenylpropylamine decylamine :4 NMR (400 MHz, DMSO-d6): δ 8.30 (s, 1H), 7.98 (d, 1H), 7.65 (d, 1H), 7.58 (s, 2H), 7.51 (d, 1H), 7.32 ( Dd, 1H), 7.17 (d, 1H), 6.85 (d, 1H), 4.58-4.42 (m, 1H), 3.66 (s, 1H), 3.11 (dd, 2H), 2.92 (ddd, 2H), 2.78 (t, 2H), 1.73 (t, 2H), 1.38 (ddd, 4H), 1.02 (s, 2H). MS (El) of C25H25C12F4N302, found 547.4 (MH+). Να-({1-[2-Fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-N-acridin-4-yl-4-(trifluoromethyl)-L-phenylalanine Amine: 4 NMR (400 MHz, DMSO-de): δ 8.32 (s, 1H), 8.09 (d, J 1H), 7.61-7.55 (m9 4H), 7.27 (d, 2H), 6.78 (d, 1H) , 4.48 (dd, 1H), 3.62 (s, 2H), 3.06 (t, 2H), 2.95-2.83 (m, 2H), 2.72 (d, 2H), 1.81-1.64 (m, 146258.doc -166· 201040149 2Η), 1.49-1.24 (m, 4Η), 1.12-1.02 (m, 1H), 0.97 (dd, 1H). MS (El) for C26H26F7N302, found 546.5 (MH+). 4_ desert-Να-({1-[2- gas-4-(trifluoromethyl)phenyl]cyclopropyl}-numberyl)-N-acridin-4-yl-L-amphetamine amine: b NMR (400 MHz, DMSO-d6): δ 8.31 (s, 1 Η), 8.05 (d, 1H), 7.65 (d, 1H), 7.56 (s, 2H), 7.40 (d, 2H), 7.00 (d , 2H), 6.75 (d, 1H), 4.42 (dd, 1H), 3.61 (s, 2H), 3.06 (t, 2H), 2.84-2.62 (m, 4H), 1.69 (d, 2H), 1.45- 1.22 (m, 4H), 1.10-1.03 (m, 1H), 0.98 (dd, 1H). Ο

C25H26BrF4N302 的 MS (El)，實測值 557.4 (MH+)。 Να-({1-[2-氟-4-(三氟甲基）苯基】環丙基}羰基）-N-呱啶-4-基-L-苯丙胺酿胺：NMR (400 MHz，DMSO-d6): δ 8.32 (s, 1Η), 8.02 (d, 1H), 7.64 (d, 1H), 7.55 (d, 2H), 7.23-7.12 (m, 3H), 7.05-6.98 (m, 2H), 6.66 (d, J=8.1Hz, 1H), 4.46-4.38 (m, 1H), 3.62 (s, 1H), 3.06 (dd, 2H), 2.85-2.78 (m, 2H), 2.71 (t, 2H), 1.70 (dd, 2H), 1.47-1.26 (m, 4H), 1.09-0.92 (m, 2H). C25H27F4N302 的 MS (El)，實測值 478.5 (MH+)。 3-環己基-Ν，2，·({1-[2-氟-4-(三氟甲基）苯基】環丙基}-羰 基）-Ν-呱啶-4-基-L-丙胺醢胺：111&gt;1]^11(400]^1^,〇]^3〇-d6)： δ 8.31 (s, 1H), 7.88 (d, 1H), 7.66 (d, 1H), 7.59 (dd, 2H), 6.76 (d, 1H), 4.27 (dd, 1H), 3.63 (s, 1H), 3.08 (dd, 2H), 2.74 (t, 2H), 1.72 (t, 2H), 1.59 (d, 5H), 1.48-1.28 (m, 6H)，1.16-0.98 (m，6H), 0.84-0.71 (m，2H). C25H33F4N302的 MS (El)，實測值484.5 (MH+)。 146258.doc • 167- 201040149 l-[2-氟-4-(三氟甲基）苯基】-N-[(lS)-2-[4-(甲基胺基）呱 咬-1-基]-2-氧代-1-{【4-(三氟甲基）苯基]甲基}乙基]環丙酿 胺：】H NMR (400 MHz, DMSO-d6): δ 8.30 (s, 1H)，7.62 (dd, 1Η), 7.59-7.51 (m, 4H), 7.29 (d, 2H), 7.13 (dd, 1H), 4.93 (dd, 1H), 4.14 (dd, 1H), 3.86 (t, 1H), 3.13-2.58 (m, 5H), 2.34 (t, 3H), 1.84 (s, 2H), 1.37-1.09 (m, 4H), 1.06-0.92 (m, 2H). C27H28F7N302 的 MS (El)，實測值 560.5 (MH+)。 N-[(lS)-2-(4-胺基呱啶-1-基）-2-氧代-l-{[4-(三氟甲基）苯 基]甲基}•乙基】氟-4-(三氟甲基）苯基]環丙雄胺： NMR (400 MHz, DMSO-d6): δ 8.35 (s, 1Η), 7.66-7.59 (m, 1H), 7.56 (dd, 4H), 7.29 (d, 2H), 7.05 (dd, 1H), 4.93 (dd, 1H), 4.17 (dd, 1H), 3.88 (s, 1H), 3.12-2.80 (m, 4H), 2.65 (dt, 1H), 1.78 (d, 2H), 1.26 (dd, 4H), 1.01 (dt, 2H). C26H26F7N3〇2的 MS (El)，實測值 546.5 (MH+)。 N-{(lS)-l-[(2,4-二氣苯基）曱基]-2-[4-(甲基胺基）呱啶-1-基】-2-氧代乙基}-1-[2-氟-4-(三氟甲基）苯基】環丙醯胺：ιΗ NMR (400 MHz, DMSO-d6): δ 8.29 (s，1H)，7_64 (d，1H)， 7.59-7.54 (m, 2H), 7.54-7.50 (m, 1H), 7.34 (ddd, 1H), 7.25-7.12 (m, 2H), 4.99 (dd, 1H), 4.18 (dd, 1H), 3.87 (d, 1H), 3.13-2.90 (m, 2H), 2.89-2.76 (m, 2H), 2.75-2.52 (m, 1H), 2.37 (d, 3H), 1.86 (d, 2H), 1.35-1.06 (m, 4H), 0.99 (d, 2H). C26H27C12F4N302的 MS (El)，實測值 561.4 (MH+)。 N-{(lS)-2-(4-胺基呱啶_1·基）·1-[(2,4-二氣苯基）甲基】-2- 146258.doc -168- 201040149MS (El) for C25H26Br. Να-({1-[2-Fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-N-acridin-4-yl-L-amphetamine amide: NMR (400 MHz, DMSO -d6): δ 8.32 (s, 1Η), 8.02 (d, 1H), 7.64 (d, 1H), 7.55 (d, 2H), 7.23-7.12 (m, 3H), 7.05-6.98 (m, 2H) , 6.66 (d, J=8.1Hz, 1H), 4.46-4.38 (m, 1H), 3.62 (s, 1H), 3.06 (dd, 2H), 2.85-2.78 (m, 2H), 2.71 (t, 2H ), 1.70 (dd, 2H), 1.47-1.26 (m, 4H), 1.09-0.92 (m, 2H). MS (El) of C25H27F4N302, found 478.5 (MH+). 3-cyclohexyl-indole, 2,·({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}-carbonyl)-indole-acridin-4-yl-L-propylamine Guanamine: 111&gt;1]^11(400]^1^,〇]^3〇-d6): δ 8.31 (s, 1H), 7.88 (d, 1H), 7.66 (d, 1H), 7.59 (dd , 2H), 6.76 (d, 1H), 4.27 (dd, 1H), 3.63 (s, 1H), 3.08 (dd, 2H), 2.74 (t, 2H), 1.72 (t, 2H), 1.59 (d, 5H), 1.48-1.28 (m, 6H), 1.16-0.98 (m, 6H), 0.84-0.71 (m, 2H). MS (El) of C25H33F4N302, found 484.5 (MH+). 146258.doc • 167- 201040149 l-[2-Fluoro-4-(trifluoromethyl)phenyl]-N-[(lS)-2-[4-(methylamino)indan-1-yl ]-2-oxo-1-{[4-(trifluoromethyl)phenyl]methyl}ethyl]cyclopropanol:]H NMR (400 MHz, DMSO-d6): δ 8.30 (s, 1H), 7.62 (dd, 1Η), 7.59-7.51 (m, 4H), 7.29 (d, 2H), 7.13 (dd, 1H), 4.93 (dd, 1H), 4.14 (dd, 1H), 3.86 (t , 1H), 3.13-2.58 (m, 5H), 2.34 (t, 3H), 1.84 (s, 2H), 1.37-1.09 (m, 4H), 1.06-0.92 (m, 2H). MS (El, C27H28F7N302) ), found at 560.5 (MH+). N-[(lS)-2-(4-Aminoacridin-1-yl)-2-oxo-l-{[4-(trifluoromethyl)phenyl]methyl}•ethyl]fluoride -4-(Trifluoromethyl)phenyl]cyclopropanol: NMR (400 MHz, DMSO-d6): δ 8.35 (s, 1 Η), 7.66-7.59 (m, 1H), 7.56 (dd, 4H) , 7.29 (d, 2H), 7.05 (dd, 1H), 4.93 (dd, 1H), 4.17 (dd, 1H), 3.88 (s, 1H), 3.12-2.80 (m, 4H), 2.65 (dt, 1H) ), 1.78 (d, 2H), 1.26 (dd, 4H), 1.01 (dt, 2H). MS (El) of C26H26F7N3 〇2, found 546.5 (MH+). N-{(lS)-l-[(2,4-diphenylphenyl)indolyl]-2-[4-(methylamino)acridin-1-yl]-2-oxoethyl} -1-[2-Fluoro-4-(trifluoromethyl)phenyl]cyclopropanamide: ιΗ NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1H), 7_64 (d, 1H), 7.59-7.54 (m, 2H), 7.54-7.50 (m, 1H), 7.34 (ddd, 1H), 7.25-7.12 (m, 2H), 4.99 (dd, 1H), 4.18 (dd, 1H), 3.87 ( d, 1H), 3.13-2.90 (m, 2H), 2.89-2.76 (m, 2H), 2.75-2.52 (m, 1H), 2.37 (d, 3H), 1.86 (d, 2H), 1.35-1.06 ( m, 4H), 0.99 (d, 2H). MS (El), C26H27C12F4N302. N-{(lS)-2-(4-Aminopyridin-1-yl)·1-[(2,4-diphenyl)methyl]-2- 146258.doc -168- 201040149

氧代乙基}-1-[2-氟-4-(三氟甲基）苯基】環丙酸胺：NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.64 (d, 1H), 7.55 (d, 2H), 7.52 (dd, 1H), 7.34 (td, 1H), 7.26-7.13 (m, 2H), 5.00 (d, 1H), 4.30-4.11 (m, 1H), 3.88 (d, 1H), 3.12-2.81 (m, 5H), 2.75-2.56 (m, 1H), 1.78 (s, 2H), 1.37-1.09 (m, 4H), 0.99 (t, 2H)· C25H25C12F4N302的MS (El)，實測值547.4 (MH+)。 N-{(lS)-l-[(4-溴苯基）甲基】-2-[4-(甲基胺基）呱啶基】· 2-氧代乙基}-1-[2-氟-4-(三氟甲基）苯基】環丙醯胺·· ιΗ NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1Η), 7.60 (dd, 1H), 7.50 (s, 2H), 7.35 (dd, 2H), 6.97 (d, 2H), 4.83 (dd, 1H), 4.08 (dd, 1H), 3.80 (t, 1H), 3.01-2.85 (m, 1H), 2.82-2.49 (m, 5H), 2.31 (d, 3H), 1.77 (s, 2H), 1.28 (s, 2H), 1.11 (dd, 211)，0.98(1，211).(：26出8；8斤41^3〇2的1^斤1)，實測值571.4 (MH+)。 N-{(lS)-2-(4-胺基呱啶-1-基）-l-【(4-溴苯基）甲基】-2-氧代 乙基氟-4-(三氟甲基）苯基】環丙醢胺：4 NMR (400 MHz, DMSO-d6)： δ 8.33 (s, 1H), 7.65 (dd, 1H), 7.56 (s, 2H); 7.39 (dd, 2H), 7.09-6.98 (m, 3H), 4.87 (dd, 1H), 4.16 (dd, 1H), 3.87 (s, 1H), 2.99 (dd, 3H), 2.72 (ddt, 3H), 1.78 (d, 2H), 1.39-1.28 (m, 2H), 1.17 (s, 2H), 1.09-0.94 (m, 2H). C25H26BrF4N302的MS (El)，實測值 557.4 (MH+)。 l-[2-氟-4-(三氟甲基）苯基】-N-[(lS)-2-[4-(甲基胺基）呱 啶-1-基】-2-氧代-1-(苯基甲基）乙基]環丙醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.64 (dd, 1H), 7.55 146258.doc •169- 201040149 (d, 2H), 7.25-7.15 (m, 3H), 7.09-7.03 (m, 2H), 6.90 (d, 1H), 4.89 (s, 1H), 4.30-4.14 (m, 1H), 3.90 (s, 1H), 3.07-2.91 (m, 2H), 2.89-2.70 (m, 2H), 2.69-2.50 (m, 1H), 2.45 (d, 3H), 1.89 (s, 2H), 1.35 (dt, 2H), 1.21-0.95 (m, 4H). C26H29F4N302 的 MS (El)，實測值492.5 (MH+)。 N -丨（lS)-2-(4-胺基狐咬-1-基）-2 -氧代-1-(苯基甲基）乙基]-1_[2_氟-4-(三氟甲基）苯基]環丙醢胺·· 4 NMR (400 MHz， DMSO-d6)： δ 8.33 (d, 1H), 7.64 (d, 1H), 7.54 (d, 2H), 7.29-7.15 (m, 3H), 7.08-7.03 (m, 2H), 6.93 (dd, 1H), 4.88 (dd, 1H), 4.26-4.10 (m, 1H), 3.88 (s, 1H), 3.03 (m, 2H), 2.96-2.56 (m, 4H), 1.77 (d, 2H), 1.41-1.30 (m, 2H), 1.28-1.09 (m，2H), 1.02 (dd，2H)_ C25H27F4N302 的 MS (El)’ 實測值 478.5 (MH+)。 N-{(lS)-l-(環己基甲基）-2-[4-(曱基胺基）呱啶-1-基]-2-氧代乙基}-1-[2-氟-4-(三氟甲基）苯基】環丙醯胺：1H NMR (400 MHz, DMSO-d6) ： δ 8.23 (s, 1H), 7.65 (d, 1H), 7.58 (dd, 2H), 7.02 (dd, 1H), 4.75 (d, 1H), 4.21 (d, 1H), 3.79 (s, 1H), 3.02 (d, 1H), 2.84 (s, 1H), 2.72-2.54 (m, 1H), 2.39 (d, 3H), 1.98-1.81 (m, 2H), 1.61 (dd, 6H), 1.31 (ddd, 4H), 1.10 (d, 6H)，0.79 (d，2H). C26H35F4N302 的 MS (El) ’ 實測值 498.6 (MH+) ° N-[(lS)-2-(4·胺基呱啶-1-基）-1-(環己基曱基）-2-氧代乙 基】-1-丨2-氟_4-(三氟甲基）苯基]環丙醢胺：4 NMR (400 MHz, DMSO-de)： δ 8.34 (s, 1H), 7.60 (dt, 3H), 7.00 (dd, 146258.doc • 170· 201040149 1H), 4.76 (s, 1H), 4.18 (t, 1H), 3.76 (s, 1H), 3.02 (d, 2H), 2.69-2.54 (m, 2H), 1.89-1.65 (m, 3H), 1.65-1.43 (m, 5H), 1.43-1.24 (m, 3H), 1.07 (dd, 6H), 0.82 (s, 2H). C25H33F4N302 的 MS (El)，實測值 484.5 (MH+)。 N-{(lS)_2-(4-胺基-4-甲基呱啶_i_基）44(4-溴苯基）甲 基】-2-氧代乙基}-1-[2-氟-4-三氟甲基）苯基】環丙醢胺：ιΗ NMR (400 MHz, DMSO-d6)： δ 7.65 (d, 1Η), 7.57 (d, 2H), 7.40 (dd, 2H), 7.03 (dd, 3H), 4.88 (d, 1H), 3.56-3.30 (m, 6H), 2.87-2.63 (m, 2H), 1.47-1.25 (m, 6H), 1.11 (d, 3H), 1.07-0.96 (m, 2H). C26H28BrF4N3〇2 的 MS (El)，實測值 571.4 (MH+)。Oxoethyl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropanoic acid amine: NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.64 (d , 1H), 7.55 (d, 2H), 7.52 (dd, 1H), 7.34 (td, 1H), 7.26-7.13 (m, 2H), 5.00 (d, 1H), 4.30-4.11 (m, 1H), 3.88 (d, 1H), 3.12-2.81 (m, 5H), 2.75-2.56 (m, 1H), 1.78 (s, 2H), 1.37-1.09 (m, 4H), 0.99 (t, 2H)· C25H25C12F4N302 MS (El), found 547.4 (MH+). N-{(lS)-l-[(4-bromophenyl)methyl]-2-[4-(methylamino)acridinyl]·2-oxoethyl}-1-[2- Fluoro-4-(trifluoromethyl)phenyl]cyclopropanamide·· ιΗ NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1 Η), 7.60 (dd, 1H), 7.50 (s, 2H ), 7.35 (dd, 2H), 6.97 (d, 2H), 4.83 (dd, 1H), 4.08 (dd, 1H), 3.80 (t, 1H), 3.01-2.85 (m, 1H), 2.82-2.49 ( m, 5H), 2.31 (d, 3H), 1.77 (s, 2H), 1.28 (s, 2H), 1.11 (dd, 211), 0.98 (1,211). (:26 out of 8; 8 kg 41^ 3^2 of 1^ kg 1), measured value 571.4 (MH+). N-{(lS)-2-(4-Aminoacridin-1-yl)-l-[(4-bromophenyl)methyl]-2-oxoethylfluoro-4-(trifluoromethyl) Benzyl) Cyclopropanol: 4 NMR (400 MHz, DMSO-d6): δ 8.33 (s, 1H), 7.65 (dd, 1H), 7.56 (s, 2H); 7.39 (dd, 2H), 7.09-6.98 (m, 3H), 4.87 (dd, 1H), 4.16 (dd, 1H), 3.87 (s, 1H), 2.99 (dd, 3H), 2.72 (ddt, 3H), 1.78 (d, 2H) MS (El), m.p. 1-[2-Fluoro-4-(trifluoromethyl)phenyl]-N-[(lS)-2-[4-(methylamino)acridin-1-yl]-2-oxo- 1-(Phenylmethyl)ethyl]cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.64 (dd, 1H), 7.55 146258.doc • 169- 201040149 (d, 2H), 7.25-7.15 (m, 3H), 7.09-7.03 (m, 2H), 6.90 (d, 1H), 4.89 (s, 1H), 4.30-4.14 (m, 1H), 3.90 (s , 1H), 3.07-2.91 (m, 2H), 2.89-2.70 (m, 2H), 2.69-2.50 (m, 1H), 2.45 (d, 3H), 1.89 (s, 2H), 1.35 (dt, 2H ), 1.21-0.95 (m, 4H). MS (El) for C26H29F4N302, found 492.5 (MH+). N-indole (lS)-2-(4-aminofoxbitone-1-yl)-2-oxo-1-(phenylmethyl)ethyl]-1_[2-fluoro-4-(trifluoro) Methyl)phenyl]cyclopropanamide·· 4 NMR (400 MHz, DMSO-d6): δ 8.33 (d, 1H), 7.64 (d, 1H), 7.54 (d, 2H), 7.29-7.15 (m , 3H), 7.08-7.03 (m, 2H), 6.93 (dd, 1H), 4.88 (dd, 1H), 4.26-4.10 (m, 1H), 3.88 (s, 1H), 3.03 (m, 2H), 2.96-2.56 (m, 4H), 1.77 (d, 2H), 1.41-1.30 (m, 2H), 1.28-1.09 (m, 2H), 1.02 (dd, 2H)_ C25H27F4N302 MS (El)' measured value 478.5 (MH+). N-{(lS)-l-(cyclohexylmethyl)-2-[4-(decylamino)acridin-1-yl]-2-oxoethyl}-1-[2-fluoro- 4-(Trifluoromethyl)phenyl]cyclopropanamide: 1H NMR (400 MHz, DMSO-d6): δ 8.23 (s, 1H), 7.65 (d, 1H), 7.58 (dd, 2H), 7.02 (dd, 1H), 4.75 (d, 1H), 4.21 (d, 1H), 3.79 (s, 1H), 3.02 (d, 1H), 2.84 (s, 1H), 2.72-2.54 (m, 1H), 2.39 (d, 3H), 1.98-1.81 (m, 2H), 1.61 (dd, 6H), 1.31 (ddd, 4H), 1.10 (d, 6H), 0.79 (d, 2H). MS (El) of C26H35F4N302 'Measured value 498.6 (MH+) ° N-[(lS)-2-(4·Aminopyridin-1-yl)-1-(cyclohexylfluorenyl)-2-oxoethyl]-1-丨2-Fluoro-4-(trifluoromethyl)phenyl]cyclopropanamide: 4 NMR (400 MHz, DMSO-de): δ 8.34 (s, 1H), 7.60 (dt, 3H), 7.00 (dd, 146258.doc • 170· 201040149 1H), 4.76 (s, 1H), 4.18 (t, 1H), 3.76 (s, 1H), 3.02 (d, 2H), 2.69-2.54 (m, 2H), 1.89-1.65 (m, 3H), 1.65-1.43 (m, 5H), 1.43-1.24 (m, 3H), 1.07 (dd, 6H), 0.82 (s, 2H). MS (El) for C25H33F4N302, found 484.5 (MH+ ). N-{(lS)_2-(4-Amino-4-methylacridine_i-yl)44(4-bromophenyl)methyl]-2-oxoethyl}-1-[2- Fluoro-4-trifluoromethyl)phenyl]cyclopropanamide: ιΗ NMR (400 MHz, DMSO-d6): δ 7.65 (d, 1 Η), 7.57 (d, 2H), 7.40 (dd, 2H), 7.03 (dd, 3H), 4.88 (d, 1H), 3.56-3.30 (m, 6H), 2.87-2.63 (m, 2H), 1.47-1.25 (m, 6H), 1.11 (d, 3H), 1.07- MS (El) for C26H28BrF4N3 〇2, found: 571.4 (MH+).

N-{(lS)-2-(4-胺基-4-甲基呱啶-l-基）_i_[(4-溴苯基）甲 基】-2-氧代乙基}-1-(2,4·二氟苯基）環丙醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.40 (dd, 3H), 7.27-7.20 (m, 1H), 7.05 (td, 1H), 7.01 (d, 1H), 6.99 (d, 1H), 6.79 (dd, 1H), 4.88 (d, 1H), 3.59-3.24 (m, 6H), 2.77 (tdd, 2H), 1.55-1.37 (m, 3H), 1.36-1.26 (m, 2H), 1.15 (d, 3H), 1.01-0.89 (m，2H). C25H28BrF2N302 的 MS (El)，實測值 521.4 (MH+)。 4-溴-Να-{[1-(2,4-二氟苯基）環丙基I羰基}-N-[(3R)-呱啶-3-基】-L-苯丙胺醢胺：4 NMR (400 MHz, DMSO-d6): δ 8.33 (s, 1Η), 8.29 (d, 1H), 7.43-7.35 (m, 3H), 7.23 (td, 1H), 7.06 (td, 1H), 6.99 (d, 2H), 6.61 (d5 1H), 4.46-4.37 (m, 1H), 3.67 (s, 1H), 2.98 (d, 1H), 2.86 (dd, 1H), 2.83-2.74 (m, 146258.doc -171 - 201040149 2H), 2.71-2.61 (m5 1H), 2.52 (d, 1H), 1.66 (d, 2H), 1.47 (d, 1H), 1.37-1.23 (m, 3H), 1.03-0.86 (m, 2H). C24H26BrF2N3〇2 的MS (El)，實測值 507.4 (MH+)。 N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基）-l-[(4-溴苯 基）曱基]-2-氧代乙基}-1-(2,4-二氟苯基）環丙醯胺： NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.36 (dt5 3H), 7.32-7.27 (m, 1H), 7.17 (tdd, 1H), 6.98 (dd, 3H), 6.83 (d, 1H), 4.68-4.54 (m5 1H), 4.35-4.17 (m, 2H), 4.07 (s, 1H), 3.15-2.96 (m, 1H), 2.84 (dd, 1H), 2.73-2.63 (m, 2H), 2.05-1.92 (m, 1H), 1.92-1.68 (m, 3H), 1.57 (s, 2H), 1.42 (t, 2H), 1.24 (dt, 2H), 0.99-0.83 (m，2H). C26H28BrF2N302 的 MS (El)，實測值 533·4 (MH+)。 4-溴-Να-({1-[4-氟-3-(三氟甲基）苯基】環丙基}羰基）-N-【（3R)-呱啶-3-基】-L-苯丙胺醯胺：4 NMR (400 MHz， DMSO-d6): δ 8.34 (s，1H)，8.31 (d, 1H)，7.58 (dd, 2H)， 7.49-7.41 (m, 1H), 7.39 (d, 2H), 7.02 (d, 2H), 6.93 (d, 1H), 4.42 (td, 1H), 3.79-3.63 (m, 1H), 2.98 (dd, 1H), 2.93-2.81 (m, 2H), 2.76 (dd, 1H), 2.71-2.61 (m, 1H), 2.53 (dd, 1H), 1.68 (d, 2H), 1.54-1.30 (m, 2H), 1.27-1.22 (m, 2H), 1.09-0.90 (m，2H). C25H26BrF4N302 的MS (El)，實測值 557.4 (MH+)。 N-{(lS)_2-(3-胺基-8-氮雜雙環【3.2.1】辛-8-基）·1-[(4-溴苯 基）甲基】-2-氧代乙基}-1-丨4-氟-3-(三氟甲基）苯基】環丙醯 胺：NMR (400 MHz，DMSO-d6): δ 8.30 (s, 1Η), 7.56 146258.doc -172- 201040149 (ddd, 2H), 7.48-7.42 (m, 1H), 7.42-7.38 (m, 2H), 7.22 (dd, 1H), 7.05 (t, 2H), 4.71-4.58 (m, 1H), 4.35 (d, 2H), 4.13 (m, 1H), 3.17-3.01 (m, 1H), 2.74 (dd, 2H), 2.10 (tdlH), 2.02-1.78 (m, 3H), 1.68 (dd, 2H), 1.48 (s, 2H), 1.30-1.18 (m, 2H)，1.09-0.94 (m，2H). C27H28BrF4N302 的 MS (El)，實測 值 583.4 (MH+)。 N-{(lS)-2-(4-胺基-4-甲基呱啶-1-基）-l_[(4-溴苯基）甲 基】-2-氧代乙基}-1-[4-氟-3-(三氟甲基）苯基]環丙醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.58 (s，2H), 7.51-7.41 (m, 1Η)，7.41-7.36 (m，2Η), 7.07-6.99 (m, 3Η)， 4.87 (d, 1H), 3.63-3.27 (m5 6H), 2.78 (dd, 2H), 1.43 (m, 3H), 1.25 (d, 2H), 1.14 (s5 3H), 1.08-0.93 (m, 2H). C2 6H28BrF4N3〇2的 MS (El) ’ 實測值 571.4 (MH+)。 N-{(lS)-2-(4-胺基-4-甲基呱啶-1-基）-l-[(4-溴苯基）甲 基】-2-氧代乙基}-1-(2-氟苯基）環丙醢胺：4 NMR (400 MHz, DMSO-d6) ： δ 8.37 (s, 1H), 7.44-7.30 (m, 5H), 7.18 (t, 2H), 6.97 (d, 2H), 6.60 (dd, 1H), 4.99-4.77 (m, 1H), 3.55 (s, 2H), 3.32 (dd, 2H), 2.79 (ddd, 2H), 1.51 (d, 2H), I.43 (d, 2H), 1.33 (dd, 3H), 1.17 (d, 3H), 0.97 (m, 2H). C25H29BrFN302的 MS (El)，實測值 503.4 (MH+)。 4-溴-Να-{[1-(2-氟苯基）環丙基]羰基}-N-[(3R)-呱唆-3一 基】-L_苯丙胺醢胺：NMR (400 MHz，DMSO-d6): δ 8,32 (s, 1H)，8.27 (d，1H), 7.46-7.29 (m，4H)，7.24-7.12 (m， 7.00-6.88 (m, 2H), 6.43 (d, 1H), 4.43 (d, 1H), 3.62 (d, iH) 146258.doc -173- 201040149 3.07-2.87 (m, 2H), 2.86-2.71 (m, 2H), 2.71-2.51 (m, 2H), 1.65 (s, 2H), 1.46 (m, 1H), 1.40-1.20 (m, 3H), 1.05-0.89 (m，2H)_ C24H27BrFN302的MS (El)，實測值489.4 (MH+)。N-{(lS)-2-(4-Amino-4-methylacridin-l-yl)_i_[(4-bromophenyl)methyl]-2-oxoethyl}-1-( 2,4·difluorophenyl)cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.40 (dd, 3H), 7.27-7.20 (m, 1H), 7.05 (td, 1H), 7.01 (d, 1H), 6.99 (d, 1H), 6.79 (dd, 1H), 4.88 (d, 1H), 3.59-3.24 (m, 6H), 2.77 (tdd, 2H), 1.55-1.37 (m, 3H), 1.36-1.26 (m, 2H), 1.15 (d, 3H), 1.01-0.89 (m, 2H). MS (El) of C25H28BrF2N302, found 521.4 (MH+). 4-bromo-Να-{[1-(2,4-difluorophenyl)cyclopropyl Icarbonyl}-N-[(3R)-acridin-3-yl]-L-phenylpropylamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.33 (s, 1Η), 8.29 (d, 1H), 7.43-7.35 (m, 3H), 7.23 (td, 1H), 7.06 (td, 1H), 6.99 (d , 2H), 6.61 (d5 1H), 4.46-4.37 (m, 1H), 3.67 (s, 1H), 2.98 (d, 1H), 2.86 (dd, 1H), 2.83-2.74 (m, 146258.doc - 171 - 201040149 2H), 2.71-2.61 (m5 1H), 2.52 (d, 1H), 1.66 (d, 2H), 1.47 (d, 1H), 1.37-1.23 (m, 3H), 1.03-0.86 (m, MS (El) for C24H26BrF2N3 〇2, found 507.4 (MH+). N-{(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-l-[(4-bromophenyl)indolyl]-2-oxo Ethyl}-1-(2,4-difluorophenyl)cyclopropanamide: NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.36 (dt5 3H), 7.32-7.27 (m , 1H), 7.17 (tdd, 1H), 6.98 (dd, 3H), 6.83 (d, 1H), 4.68-4.54 (m5 1H), 4.35-4.17 (m, 2H), 4.07 (s, 1H), 3.15 -2.96 (m, 1H), 2.84 (dd, 1H), 2.73-2.63 (m, 2H), 2.05-1.92 (m, 1H), 1.92-1.68 (m, 3H), 1.57 (s, 2H), 1.42 (t, 2H), 1.24 (dt, 2H), 0.99-0.83 (m, 2H). MS (El) of C26H28BrF2N302, found 533·4 (MH+). 4-bromo-Να-({1-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-N-[(3R)-acridin-3-yl]-L- Amphetamine: 4 NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 8.31 (d, 1H), 7.58 (dd, 2H), 7.49-7.41 (m, 1H), 7.39 (d, 2H), 7.02 (d, 2H), 6.93 (d, 1H), 4.42 (td, 1H), 3.79-3.63 (m, 1H), 2.98 (dd, 1H), 2.93-2.81 (m, 2H), 2.76 (dd, 1H), 2.71-2.61 (m, 1H), 2.53 (dd, 1H), 1.68 (d, 2H), 1.54-1.30 (m, 2H), 1.27-1.22 (m, 2H), 1.09-0.90 (m, 2H). MS (El) for C25H26BrF4N302, found 557.4 (MH+). N-{(lS)_2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)·1-[(4-bromophenyl)methyl]-2-oxo }}-1-丨4-fluoro-3-(trifluoromethyl)phenyl]cyclopropanamide: NMR (400 MHz, DMSO-d6): δ 8.30 (s, 1 Η), 7.56 146258.doc -172 - 201040149 (ddd, 2H), 7.48-7.42 (m, 1H), 7.42-7.38 (m, 2H), 7.22 (dd, 1H), 7.05 (t, 2H), 4.71-4.58 (m, 1H), 4.35 (d, 2H), 4.13 (m, 1H), 3.17-3.01 (m, 1H), 2.74 (dd, 2H), 2.10 (tdlH), 2.02-1.78 (m, 3H), 1.68 (dd, 2H), 1.48 (s, 2H), 1.30-1.18 (m, 2H), 1.09-0.94 (m, 2H). MS (El) of C27H28BrF4N302, found: 583.4 (MH+). N-{(lS)-2-(4-Amino-4-methylacridin-1-yl)-l-[(4-bromophenyl)methyl]-2-oxoethyl}-1- [4-Fluoro-3-(trifluoromethyl)phenyl]cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.58 (s, 2H), 7.51-7.41 (m, 1Η), 7.41-7.36 (m, 2Η), 7.07-6.99 (m, 3Η), 4.87 (d, 1H), 3.63-3.27 (m5 6H), 2.78 (dd, 2H), 1.43 (m, 3H), 1.25 (d, 2H), 1.14 (s5 3H), 1.08-0.93 (m, 2H). MS (El) of C2 6H28BrF4N3 〇2, found 571.4 (MH+). N-{(lS)-2-(4-Amino-4-methylacridin-1-yl)-l-[(4-bromophenyl)methyl]-2-oxoethyl}-1 -(2-fluorophenyl)cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 8.37 (s, 1H), 7.44-7.30 (m, 5H), 7.18 (t, 2H), 6.97 ( d, 2H), 6.60 (dd, 1H), 4.99-4.77 (m, 1H), 3.55 (s, 2H), 3.32 (dd, 2H), 2.79 (ddd, 2H), 1.51 (d, 2H), I .43 (d, 2H), 1.33 (dd, 3H), 1.17 (d, 3H), 0.97 (m, 2H). MS (El) of C25H29BrFN302, found 503.4 (MH+). 4-bromo-Να-{[1-(2-fluorophenyl)cyclopropyl]carbonyl}-N-[(3R)-呱唆-3-yl]-L-phenylalanamine decylamine: NMR (400 MHz, DMSO-d6): δ 8,32 (s, 1H), 8.27 (d,1H), 7.46-7.29 (m,4H), 7.24-7.12 (m, 7.00-6.88 (m, 2H), 6.43 (d, (H, 2H), 2.86-2.71 (m, 2H), MS (El), m.p., (m,j,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1】辛-8-基）-l-【(4-溴苯 基）甲基】_2·氧代乙基}-1-(2-氟苯基）環丙醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.26 (s, 1H), 7.41-7.24 (m, 4H), 7.12 (m, 2H), 6.96 (dd, 2H), 6.67 (dd, 1H), 4.63 (dd, 1H), 4.35-4.17 (m, 2H), 4.08 (s, 1H), 3.05 (d, 1H), 2.76-2.59 (m, 2H), 2.09-1.71 (m, 4H), 1.59 (dd, 2H), 1.44 (t, 2H), 1.32- 1.19 (m, 2H), 1.00-0.84 (m, 2H). C26H29BrFN302 的 MS (El)，實測值515.4 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-4-溴-Να-{[1-(2,4,5-三氟苯基）-環丙基]羰基}_L-苯丙胺醢胺：NMR (400 MHz, DMSO-d6): δ 8.20 (s, 1H), 8.10 (d, 1H), 7.50 (m, 2H), 7.42 (d, 2H), 7.04 (d, 2H), 6.84 (d, 1H), 4.36 (m, 1H), 3.69 (m, 1H), 3.16 (m, 1H), 2.78 (m, 6H), 2.42 (m, 1H), 1.60 (m, 4H), 1.40 (m, 1H), 1.27 (m, 2H), 0.98 (m, 2H). C26H27BrF3N302的 MS (El)，實測值 55 i (mh+)。 N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基）-l-[(4-溴苯 基）甲基]-2 -氧代乙基}-1-(2,4,5 -三氟苯基）環丙酿胺：4 NMR (400 MHz, DMSO-d6): δ 8.28 (s, 1Η), 7.45 (m, 4H), 7.20 (m, 1H)，7,06 (t，2H), 4.65 (m，1H), 4.25 (m，2H), 2.88 (m, 3H), 2.13-1.44 (m, 8H), 1.25 (m, 2H), 0.96 (m, 2H). C26H27BrF3N303 的 MS (El)，實測值 55 i (MH+)。 146258.doc -174- 201040149 4-溴-N-[(3R)-呱啶-3-基]-Να-{[1-(2,4,5-三氟苯基）-環丙 基】羰基}-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.31 (s, 1H), 8.11 (d, 1H), 7.50 (m, 2H), 7.41 (d, 2H), 7.03 (d, 1H), 6.87 (d, 2H), 4.38 (m, 1H), 3.64 (m, 1H), 2.94 (m, 1H), 2.79 (m, 3H), 2.59 (m, 1H), 2.43 (m, 1H), 1.64 (m, 2H), 1.43 (m, 1H), 1.27 (m, 3H)，0.98 (m, 2H). C47H25BrF3N302的 MS (El)，實測值 525 (MH+)。 N-{(lR)-2-(3-胺基，8-氮雜雙環[3.2.1】辛-8-基）-l-[(4-溴 苯基）甲基〗-2-氧代己基}-1-{4-[(三氟甲基）氧】苯基}環丙醢 胺：4 NMR (400 MHz, DMSO-d6): δ 7.58 (d，1H)，7.49 (m, 2H), 7.35 (m, 2H), 7.12 (m, 1H), 6.98 (m, 3H), 4.62 (m, 1H), 4.19 (m, 2H), 2.75 (m, 3H), 2.05-1.37 (m, 8H), 1.28 (m, 2H), 0.97 (m，2H). C27H29BrF3N303 的MS (El)，實測值 581 (MH+)。 N-(氮雜環丁烷-3-基甲基）-4-溴-N-甲基-Να-[(l-{4-[(三 氟甲基）-氧]苯基}環丙基）羰基]-L-苯丙胺醯胺：iH NMR (400 MHz, DMSO-d6): δ 7-45-7.41 (m，2H)，7.38-7.29 (m, 4H), 7.08-7.02 (m, 2H), 6.87-6.81 (m, 1H), 4.83-4.78 (m, 1H), 3.92-3.79 (m, 2H), 3.75-3.59 (m, 2H), 3.57-3.52 (m, 1H), 3.40-3.34 (m, ih), 2.93 (s, 3H), 2.90-2.72 (m, 4H), 1·29·1.21 (m，2H)，1.04-0.96 (m，2H); C25H27BrF3N303 的 MS(EI)，實測值 554.18 (MH+)。 N-[(lS)-l-[(4-溴苯基）甲基】-2·(2,5-二氮雜雙環[2.2.1]庚-2-基）-2-氧代乙基]_ι_{4-[(三氟曱基）氧]苯基}環丙醢胺： 146258.doc -175- 201040149 1H NMR (400 MHz，DMSO-d6): δ 8.28 (s, 1H), 7.44-7.39 (m, 2H), 7.35-7.27 (m, 4H), 7.10-7.02 (m, 2H), 7.00 (d, 1H), 4.71-4.39 (m, 2H), 4.05 (d, 1H), 3.65-3.51 (m, 1H), 3.30- 3.15 (m, 1H), 3.05-3.00 (m, 2H), 2.95-2.74 (m, 2H), 1.70-1.69 (m, 1H), 1.59 (d, 1H), 1.27-1.18 (m, 2H), 1.02- 0·90(m,2H);C25H25BrF3N3O3的MS(EI)，實測值 554.18 (MH+)。N-{(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-l-[(4-bromophenyl)methyl]_2·oxo B }--1-(2-fluorophenyl)cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 8.26 (s, 1H), 7.41-7.24 (m, 4H), 7.12 (m, 2H ), 6.96 (dd, 2H), 6.67 (dd, 1H), 4.63 (dd, 1H), 4.35-4.17 (m, 2H), 4.08 (s, 1H), 3.05 (d, 1H), 2.76-2.59 ( m, 2H), 2.09-1.71 (m, 4H), 1.59 (dd, 2H), 1.44 (t, 2H), 1.32- 1.19 (m, 2H), 1.00-0.84 (m, 2H). MS of C26H29BrFN302 ( El), found 514.6 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-indole α-{[1-(2,4,5-trifluorophenyl)-cyclopropyl ]carbonyl}_L-amphetamine amide: NMR (400 MHz, DMSO-d6): δ 8.20 (s, 1H), 8.10 (d, 1H), 7.50 (m, 2H), 7.42 (d, 2H), 7.04 ( d, 2H), 6.84 (d, 1H), 4.36 (m, 1H), 3.69 (m, 1H), 3.16 (m, 1H), 2.78 (m, 6H), 2.42 (m, 1H), 1.60 (m , 4H), 1.40 (m, 1H), 1.27 (m, 2H), 0.98 (m, 2H). MS (El) of C26H27BrF3N302, found 55 i (mh+). N-{(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-l-[(4-bromophenyl)methyl]-2-oxo Ethyl}-1-(2,4,5-trifluorophenyl)cyclopropanol: 4 NMR (400 MHz, DMSO-d6): δ 8.28 (s, 1 Η), 7.45 (m, 4H), 7.20 (m, 1H),7,06 (t,2H), 4.65 (m,1H), 4.25 (m,2H), 2.88 (m, 3H), 2.13-1.44 (m, 8H), 1.25 (m, 2H) ), 0.96 (m, 2H). MS (El) for C26H27BrF3N303, found 55 i (MH+). 146258.doc -174- 201040149 4-Bromo-N-[(3R)-acridin-3-yl]-Να-{[1-(2,4,5-trifluorophenyl)-cyclopropyl]carbonyl }-L-Amphetamine amide: 4 NMR (400 MHz, DMSO-d6): δ 8.31 (s, 1H), 8.11 (d, 1H), 7.50 (m, 2H), 7.41 (d, 2H), 7.03 ( d, 1H), 6.87 (d, 2H), 4.38 (m, 1H), 3.64 (m, 1H), 2.94 (m, 1H), 2.79 (m, 3H), 2.59 (m, 1H), 2.43 (m , 1H), 1.64 (m, 2H), 1.43 (m, 1H), 1.27 (m, 3H), 0.98 (m, 2H). MS (El) of C47H25BrF3N302, found 525 (MH+). N-{(lR)-2-(3-Amino, 8-azabicyclo[3.2.1]oct-8-yl)-l-[(4-bromophenyl)methyl]-2-oxo Hexyl}-1-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.58 (d, 1H), 7.49 (m, 2H) , 7.35 (m, 2H), 7.12 (m, 1H), 6.98 (m, 3H), 4.62 (m, 1H), 4.19 (m, 2H), 2.75 (m, 3H), 2.05-1.37 (m, 8H) ), 1.28 (m, 2H), 0.97 (m, 2H). MS (El) of C27H29BrF3N303, found 581 (MH+). N-(azetidin-3-ylmethyl)-4-bromo-N-methyl-Να-[(l-{4-[(trifluoromethyl)-oxy]phenyl}cyclopropyl) Carbonyl]-L-amphetamine amide: iH NMR (400 MHz, DMSO-d6): δ 7-45-7.41 (m, 2H), 7.38-7.29 (m, 4H), 7.08-7.02 (m, 2H) , 6.87-6.81 (m, 1H), 4.83-4.78 (m, 1H), 3.92-3.79 (m, 2H), 3.75-3.59 (m, 2H), 3.57-3.52 (m, 1H), 3.40-3.34 ( m, ih), 2.93 (s, 3H), 2.90-2.72 (m, 4H), 1·29·1.21 (m, 2H), 1.04-0.96 (m, 2H); MS (EI) of C25H27BrF3N303, measured value 554.18 (MH+). N-[(lS)-l-[(4-bromophenyl)methyl]-2·(2,5-diazabicyclo[2.2.1]hept-2-yl)-2-oxoethyl ]_ι_{4-[(Trifluoromethyl)oxy]phenyl}cyclopropanamide: 146258.doc -175- 201040149 1H NMR (400 MHz, DMSO-d6): δ 8.28 (s, 1H), 7.44- 7.39 (m, 2H), 7.35-7.27 (m, 4H), 7.10-7.02 (m, 2H), 7.00 (d, 1H), 4.71-4.39 (m, 2H), 4.05 (d, 1H), 3.65- 3.51 (m, 1H), 3.30- 3.15 (m, 1H), 3.05-3.00 (m, 2H), 2.95-2.74 (m, 2H), 1.70-1.69 (m, 1H), 1.59 (d, 1H), MS (EI) </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt;

N-[(lS)-l-[(4-溴苯基）甲基]-2-(2,5-二氮雜雙環[2.2.1]庚-2-基）-2-氧代乙基]-1-(2,4-二氣苯基）環丙醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1Η), 7.56-7.54 (m, 1H), 7.37-7.34 (m, 4H), 7.01-6.97 (m, 2H), 6.76 (d, 1H), 4.76-4.71 (m, 1H), 3.72-3.63 (m, 2H), 3.55-3.47 (m, 2H), 3.45-3.30 (m, 2H), 2.84-2.67 (m, 4H), 1.36-1.24 (m, 2H), 0.96-0.87 (m, 2H); C24H24BrCl2N302 的 MS (El)，實測值 540.13 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-4-溴-Να-{[1-(4-氟苯 基）-環丙基]羰基}-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.20 (d, 1Η), 7.46-7.44 (m, 2H), 7.33-7.28 (m, 2H), 7.19-7.14 (m, 2H), 7.02-6.98 (m, 2H), 6.42 (d, 1H), 4.54.4.49 (m, 1H), 3.69-3.68 (m, 1H), 2.88-2.72 (m, 6H), 2.45-2.41 (m, 1H), 1.76-1.54 (m, 4H), 1.44-1.40 (m, 1H), 1.30- 1.22 (m, 2H), 1.00-0.91 (m, 2H); C26H29BrFN302的 MS (丑1)，實測值514.18(]^11+)。 N-[(lS)-l-[(4-溴苯基）甲基】-2-{4-[(l-甲基乙基）胺基]呱 146258.doc -176- 201040149 啶-1-基}-2-氧代乙基]-l-(2,4-二氣苯基）環丙醯胺：咕 NMR (400 MHz, DMSO-d6): δ 7.60 (d, 1H), 7.40 (m, 4H), 7.01 (m, 2H), 6.75 (m, 1H), 4.88 (m, 1H), 3.86 (m, 1H), ' 3.08-2.88 (m, 4H), 2.85-2.54 (m, 3H), 1.80 (m, 2H), 1.38 . (m, 2H), 1.03 (m，8H); C27H32BrCl2N303 的 MS (El)，實測值 „ 581.89 (MH+)。 N-(氮雜環丁烷-3-基甲基）-4-溴-Να-{[1-(2,4-二氣苯基） 環丙基】-羰基}-Ν-甲基-L-苯丙胺醯胺：4 NMR (400 MHz, 〇 DMSO-d6): δ 7.56-7.54 (m, 1H), 7.37-7.34 (m, 4H), 7.01-6.97 (m, 2H), 6.77-6.71 (m, 1H), 4.76-4.71 (m, 1H), 3.72-3.65 (m, 2H), 3.55-3.48 (m, 2H), 3.47-3.30 (m, 2H), 2.84 (s, 3H), 2.81-2.66 (m, 3H), 2.64 (s, 1H), 1.36-1.24 (m, 2H), 0.96-0.87 (m, 2H); C24H26BrCl2N302 的 MS (El)，實測值 540.13 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-4-溴-Να-{[1-(2,3,4-三氟苯基）-環丙基]羰基}-L-苯丙胺醯胺：4 NMR (400 ❹ MHz, DMSO-d6): δ 8.14 (d，1H)，7.42 (d，2H)，7.35-7.28 (m, 1H), 7.22-7.17 (m, 1H), 7.07 (d, 2H), 6.90 (d, 1H), ' 4.51-4.45 (m, 1H), 3.74-3.73 (m, 1H), 3.22-3.17 (m, 1H), 2.86-2.78 (m, 6H), 2.45-2.44 (m, 1H), 1.80-1.73 (m, 2H), 1.71-1.59 (m, 2H), 1.46-1.42 (m, 1H), 1.37-1.27 (m, 2H), 1.09-1.04 (m, 1H)，0.98-0.93 (m，1H); C26H27BrF3N302的 ]^8斤1)，實測值 540.13 (]^^1+)。 N-[(3S)-1-氮雜雙環[2,2.2]辛-3-基]-4-溴-Να-({1-[4-氟-3- 146258.doc 177· 201040149 (三氟甲基）-苯基】環丙基}羰基）-L-苯丙胺醯胺：1H NMR (400 MHz, DMSO-d6)： δ 8.20 (d, 1H), 7.61-7.59 (m, 2H), 7.50-7.41 (m, 3H), 7.06 (d, 2H), 6.90 (d, 1H), 4.53-4.47 (m, 1H), 3.78-3.76 (m, 1H), 3.26-3.21 (m, 1H), 2.90-2.78 (m, 6H), 2.56-2.55 (m, 1H), 1.81-1.80 (m, 1H), 1.78-1.71 (m, 1H), 1.70-1.59 (m, 2H), 1.45 (m, 1H), 1.30-1.23 (m, 2H), 1.08-1.05 (m, 1H)，1.01-0.97 (m，1H); C27H28BrF4N302 的 MS(EI)，實測值 584·16(MH+)。 N-(順式-4-胺基環己基）-4-溴-Να-({1-[2-氟-4-(三氟甲 基）-苯基]環丙基}羰基）-L-苯丙胺醯胺：4 NMR (400 MHz，DMSO-d6): δ 8.30 (s，2H), 8.11 (s, 1H), 7.62 (d，1H)， 7.56 (s, 2H), 7.41 (d, 2H), 7.07-7.02 (m, 3H), 4.56-4.51 (m, 1H), 3.72 (m, 1H), 3.02-2.98 (m, 1H), 2.88-2.77 (m, 2H), 1.76-1.58 (m, 6H), 1.51-1.47 (m, 2H), 1.40-1.28 (m, 2H), 1.10-1.05 (m, 1H), 1.00-0.95 (m, 1H); C26H28BrF4N302 的 ]^8(£1)，實測值 572.19 (1^11+)。 N-(順式-4-胺基環己基）-4 -漠-Να-[(1-{4-[(二氣曱基）氧]-苯基}環丙基）羰基]-L-苯丙胺醯胺：4 NMR (400 ΜΗζ， DMSO-d6): δ 8.39 (s, 2H), 8.16 (d, 1H), 7.42 (d, 1H), 7.35-7.29 (m, 4H), 7.02 (d, 2H), 6.82 (d, 1H), 4.60-4.54 (m, 1H), 3.70 (m, 1H), 3.00-2.98 (m, 1H), 2.91-2.86 (m, 1H), 2.81-2.75 (m, 1H), 1.74-1.55 (m, 6H), 1.51-1.45 (m, 2H), 1.30-1.19 (m, 2H), 1.05-0.90 (m, 2H); C26H29BrF3N303 的 MS (EI)，實測值 570.1 8 (MH+)。 146258.doc -178- 201040149 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基】-4-溴-Να-({1-[4-氟-2-(三氟甲基）苯基】環丙基}羰基）-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.00 (d, 1H), 7.65-7.55 (m, 3H), 7.42 (d, 2H), 7.01 (d, 2H), 6.33 (d, 1H), 4.46 (q, 1H), 3.64-3.63 (m, 1H), 3.12-3.07 (m, 1H), 2.79-2.68 (m, 6H), 2.34-2.30 (m, 1H), 1.72-1.70 (m, 1H), 1.67-1.51 (m, 4H), 1.37-1.34 (m，2H)，1.06 (s, 2H); C27H28BrF4N302的 MS (El)，實 測值 584.22 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2】辛-3-基]-4-溴-Να-{[1-(2,4-二 氟苯基）-環丙基】羰基}-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-dg)： δ 8.10 (d, 1H), 7.43-7.36 (m, 3H), 7.27-7.21 (m, 1H), 7.09-7.04 (m, 1H), 7.00 (d, 2H), 6.55 (d, 1H), 4.50- 4.45 (q, 1H), 3.64 (m, 1H), 3.15-3.09 (m, 1H), 2.81-2.70 (m, 6H), 2.39-2.35 (m, 1H), 1.73-1.53 (m, 4H), 1.38-1.25 (m, 3H), 1.02-0.90 (m，2H); C26H28BrF2N302的 MS (El)，實 測值 53 2.20 (MH+)。 N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基）-l-[(4-氟苯 基）甲基】-2-氧代乙基}-1-{4-[(三氟甲基）氧1苯基}環丙醯 胺：4 NMR (400 MHz, DMSO-d6): δ 7.39-7.29 (m, 4H)， 7.15-7.04 (m, 4H), 6.98-6.88 (m, 1H), 4.72-4.65 (m, 1H), 4.41-4.36 (m5 1H), 4.31-4.30 (m, 1H), 4.15 (m, 1H), 3.17-3.15 (m, 1H), 3.05-2.90 (m, 1H), 2.79-2.75 (m, 2H), 2.14- 1.91 (m, 3H), 1.89-1.76 (m, 1H), 1.68-1.59 (m, 2H), 1.53- 1.46 (m, 2H), 1.31-1.21 (m, 2H), 1.01-0.94 (m, 2H); 146258.doc -179- 201040149 C27H29F4N303的 MS (EI)，實測值 520.30 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2】辛-3-基]-4-溴-Να-({1-【2-(三 氟甲基）-苯基】環丙基}羰基）-L-苯丙胺醯胺：屯NMR (400 MHz, DMSO-d6): δ 8.05 (d, 1H), 7.74 (d, 1H), 7.69 (t, 1H), 7.58 (t, 2H), 7.40 (d5 2H), 6.97 (d, 2H), 6.14 (d, 1H), 4.48 (q, 1H), 3.63-3.61 (m, 1H), 3.12-3.06 (m, 1H), 2.78-2.66 (m, 6H), 2.34-2.29 (m, 1H), 1.71-1.50 (m, 5H), 1.39-1.35 (m, 2H), 1.07 (s, 2H); C27H29BrF3N302 的 MS (EI)，實測值 566.21 (MH+)。 4-氟-N-[(3R)-呱啶-3-基]-Να-[(1-{4-[(三氟曱基）氧】苯 基}-環丙基）羰基]-L-苯丙胺醢胺：4 NMR (400 MHz, DMSO-d6): δ 8.39 (d, 1H), 8.34 (s, 1H), 7.37 (d, 2H), 7.31 (d, 2H), 7.10-7.03 (m, 4H), 6.65 (d, 1H), 4.48-4.42 (m, 1H), 3.77-3.75 (m, 1H), 3.06-3.03 (m, 1H), 2.98-2.95 (m, 1H), 2.91-2.87 (m, 1H), 2.83-2.79 (m, 1H), 2.77-2.70 (m, 1H), 2.62-2.56 (m, 1H), 1.72-1.69 (m, 2H), 1.55-1.50 (m, 1H), 1.40-1.34 (m, 1H), 1.31-1.21 (m, 2H), 1.04-0.92 (m, 2H); (：251127?4^[303的河8(£1)，實測值494.28 (]^11+)。 N-{(lS)-2-(4-胺基呱啶-1-基）-l-[(4_氟苯基）甲基]氧代 乙基[(三氟甲基）氧]苯基}環丙醢胺：NMR (400 MHz，DMSO-d6):S8.40(s，2H)，7.38-7.30(m,4H)，7.11-7.02 (m, 4H), 6.84-6.66 (m, 1H), 4.94-4.89 (m, 1H), 4.24-4.14 (m, 1H), 3.94-3.91 (m, 1H), 3.10-2.96 (m, 2H), 2.90-2.82 (m, 1H), 2.78-2.70 (m, 1H), 2.67-2.59 (m, 1H), 1.90- 146258.doc -180- 201040149 1.81 (m, 2H), 1.35-1.17 (m5 4H), 1.02-0.94 (m, 2H); (：251127?41^303的]^8斤1)，實測值494.28(]^11+)。 N-[(lS)-l-[(4_溴苯基）甲基】-2-(4-羥基呱啶-1-基）-2-氧代 乙基]-1-(2,4-二氣苯基）環丙醢胺：4 NMR (400 MHz, DMSO-d6): δ 7.61 (m, 1H), 7.40 (m, 4H), 7.01 (m, 2H), - 6.75 (m, 1H), 4.88 (m, 1H), 4.74 (m, 1H), 3.86 (m, 1H), 3.84-3.56 (m, 4H), 3.19-2.63 (m, 2H), 1.60 (m, 2H), 1.40-1.11 (m, 7H), 0.96 (m，2H); C24H25BrCl2N203的 MS (El)， 〇 實測值541.01(141'1+)。 4-氟-Να-({1-[2-氟-4-(三氟甲基）苯基】環丙基}羰基）-N-[(3R)-呱啶-3-基]-L-苯丙胺醯胺：4 NMR (400 MHz， DMSO-d6): δ 8_17 (d，1H)，7·64 (d，1H)，7.55 (m，2H), 7.04 (m, 4H), 6.78 (m, 1H), 4.40 (m, 1H), 3.67 (m, 1H), 3.01- 3.64 (m, 5H), 1.65 (m, 2H), 1.51-1.22 (m, 4H), 1.00 (m, 2H); C25H26F5N302的 MS (El)，實測值496.17 (MH+)。 N-{(lS)-2-(3-胺基-8-氮雜雙環0.2.1】辛-8-基）-1-[(4-氟苯 ❹ 基）甲基]-2 -氧代乙基}-1-丨2 -氟-4-(三氟甲基）苯基]環丙斑 胺：NMR (400 MHz，DMSO-d6): δ 7.64-7.51 (m，3H)， 7.24-7.00 (m, 5H), 4.67 (m, 1H), 4.37 (m, 1H), 4.32-4.10 (m, 1H), 3.15-2.70 (m, 2H), 2.21-1.46 (m, 8H), 1.32 (m, 211)，1.01(111，211);(：271128?5&gt;13〇2的]^8(£1)，實測值522.31 (MH+)。 N-{(lS)-2-(4-胺基呱啶-1-基）-l-[(4-氟苯基）甲基卜2-氧代 乙基}-1-[2-氟-4-(三氟甲基）苯基】環丙醢胺：4 NMR (400 146258.doc -181 - 201040149 MHz, DMSO-de)： δ 7.64 (m, 1H), 7.55 (m, 2H), 7.05 (m, 4H), 6.90 (d, 1H), 4.86 (m, 1H), 4.14 (m, 1H), 3.85 (m, 1H), 3.06-2.55 (m, 4H), 1.76 (m, 2H), 1.36-1.08 (m, 4H), 1.00 (m，2H); C25H26F5N302 的 MS (El)，實測值 496.30 (MH+)。 N-{(lS)-2-(4-胺基呱啶-1-基）-l-[(4-氟苯基）甲基]-2-氧代 乙基[(三氟甲基）氧]苯基}環丙醯胺：4 NMR (400 MHz, DMSO-d6): δ 8.40 (s, 2H), 7.38-7.30 (m, 4H), 7.11- 7.01 (m, 4H), 6.84-6.66 (dd, 1H), 4.94-4.89 (m, 1H), 4.24- 4.14 (m, 1H), 3.94-3.91 (m, 1H), 3.10-2.96 (m, 2H), 2.90- 2.82 (m, 1H), 2.78-2.70 (m, 1H), 2.67-2.59 (m, 1H), 1.90- 1.81 (m, 2H), 1.35-1.17 (m, 4H), 1.02-0.94 (m, 2H); C25H27F4N303 的 MS (El)，實測值 494.28 (MH+)。 N-{(lS)-2-[(3S)-3-胺基&quot;比咯啶基]-l-[(4-溴苯基）甲 基]-2-氧代乙基}-1-[2-氟-4-(三氟甲基）苯基]環丙醯胺：iH NMR (400 MHz, DMSO-d6): δ 7.68-7.64 (m, 1Η), 7.61-7.57 (m, 2H), 7.44-7.40 (m, 2H), 7.09-7.04 (m, 2H), 7.13-6.96 (dd, 1H), 5.67 (br s, 2H), 4.67-4.56 (m, 1H), 3.67-3.49 (m, 2H), 3.40-3.33 (m, 2H), 3.32-3.11 (m, 1H), 2.87-2.76 (m, 2H), 2.07-1.90 (m, 1H), 1.81-1.63 (m, 1H), 1.42-1.30 (m, 2H)，1.10-0.97 (m, 2H); C24H24BrF4N302 的 MS (El)，實測 值 542.16 (MH+)。 N-{(lS)-2-[(3S)-3-胺基&quot;比咯啶-1-基】-l-[(4-氟苯基）甲 基]-2-氧代乙基}-1-[2-氟-4-(三氟甲基）苯基]環丙醯胺：屯 146258.doc -182- 201040149 NMR (400 MHz, DMSO-d6): δ 7.69-7.64 (m, 1H), 7.61-7.56 (m, 2H), 7.15-7.10 (m, 2H), 7.08-7.03 (m, 2H), 7.17-6.94 (dd, 1H), 6.25 (br s, 2H), 4.66-4.54 (m, 1H), 3.70-3.50 (m, 2H), 3.41-3.32 (m, 2H), 3.31-3.15 (m, 1H), 2.89-2.77 (m, 2H), 2.04-1.93 (m, 1H), 1.84-1.66 (m, 1H), 1.42-1.30 (m, 2H)，1.10-0.97 (m，2H); C24H24F5N302 的 MS (El)，實測值 482.25 (MH+)。 N-{(lS)-2-[(3S)-3-胺基&quot;比咯啶-1-基]-l-[(4-氟苯基）曱 基]-2-氧代乙基}-1-{4-[(三氟甲基）氧]苯基}環丙醯胺：咕 NMR (400 MHz, DMSO-d6): δ 7.89 (br s，1H)，7.41-7.29 (m, 4H), 7.16-7.03 (m, 4H), 6.90-6.69 (dd, 1H), 4.69-4.56 (m, 1H), 3.75-3.59 (m, 2H), 3.47-3.26 (m, 3H), 2.92-2.76 (m, 2H), 2.10-1.98 (m, 1H), 1.94-1.77 (m, 1H), 1.34-1.20 (m，2H)，1.05-0.91 (m, 2H); C24H25F4N303 的 MS (El)，實測 值 480.29 (MH+)。 N-{(lS)-2-[(3S)-3-胺基 〇比咯啶-1-基]-l-[(4-溴苯基）甲 基]-2-氧代乙基}-1-{4-[(三氟甲基）氧]苯基}環丙醯胺：咕 NMR (400 MHz, DMSO-d6): δ 7.45-7.42 (m, 2H), 7.40-7.29 (m, 4H), 7.08-7.00 (m, 2H), 6.98 (br s, 1H), 6.93-6.73 (dd, 1H), 4.69-4.57 (m, 1H), 3.71-3.58 (m, 2H), 3.45-3.22 (m, 3H), 2.91-2.75 (m, 2H), 2.09-1.98 (m, 1H), 1.89-1.73 (m, 1H), 1.33-1.20 (m，2H)，1.05-0.93 (m, 2H); C24H25BrF3N303 的 MS (El)，實測值 542.09 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2】辛-3-基]-4-(三氟甲基）-Να- 146258.doc -183- 201040149 [(l-{4-[(三氟甲基）-氧]苯基}環丙基）羰基】-L-苯丙胺醯胺： lH NMR (400 MHz, DMSO-d6)： δ 8.26-8.21 (m, 1Η), 7.62- 7.60 (m, 2H), 7.39-7.34 (m, 2H), 7.29-7.26 (m, 4H), 6.67- 6.61 (m, 1H), 4.62-4.57 (m, 1H), 3.74-3.68 (m, 1H), 3.16- 3.11 (m, 1H), 2.97-2.90 (m, 2H), 2.88-2.68 (m, 4H), 2.50- 2.42 (m, 1H), 1.75-1.50 (m, 4H), 1.37-1.33 (m, 1H), 1.30- 1.20 (m，2H), 1.03-0.94 (m，2H); C28H29F6N303的 MS (El)， 實測值570.24 (]^11+)。N-[(lS)-l-[(4-bromophenyl)methyl]-2-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2-oxoethyl ]-1-(2,4-diphenyl)cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1 Η), 7.56-7.54 (m, 1H), 7.37-7.34 (m, 4H), 7.01-6.97 (m, 2H), 6.76 (d, 1H), 4.76-4.71 (m, 1H), 3.72-3.63 (m, 2H), 3.55-3.47 (m, 2H), 3.45 -3.30 (m, 2H), 2.84-2.67 (m, 4H), 1.36-1.24 (m, 2H), 0.96-0.87 (m, 2H); MS (El) of C24H24BrCl2N302, found 540.13 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-indole α-{[1-(4-fluorophenyl)-cyclopropyl]carbonyl}-L - amphetamine amide: 4 NMR (400 MHz, DMSO-d6): δ 8.20 (d, 1 Η), 7.46-7.44 (m, 2H), 7.33-7.28 (m, 2H), 7.19-7.14 (m, 2H) , 7.02-6.98 (m, 2H), 6.42 (d, 1H), 4.54.4.49 (m, 1H), 3.69-3.68 (m, 1H), 2.88-2.72 (m, 6H), 2.45-2.41 (m, 1H), 1.76-1.54 (m, 4H), 1.44-1.40 (m, 1H), 1.30- 1.22 (m, 2H), 1.00-0.91 (m, 2H); MS (ug. 1) of C26H29BrFN302, found 514.18 (]^11+). N-[(lS)-l-[(4-bromophenyl)methyl]-2-{4-[(l-methylethyl)amino] 呱 146258.doc -176- 201040149 pyridine-1- }}-2-oxoethyl]-l-(2,4-diphenyl)cyclopropanamide: 咕NMR (400 MHz, DMSO-d6): δ 7.60 (d, 1H), 7.40 (m , 4H), 7.01 (m, 2H), 6.75 (m, 1H), 4.88 (m, 1H), 3.86 (m, 1H), ' 3.08-2.88 (m, 4H), 2.85-2.54 (m, 3H) , 1.80 (m, 2H), 1.38 . (m, 2H), 1.03 (m,8H); MS (El) of C27H32BrCl2N303, found „ 581.89 (MH+). N-(azetidin-3-yl) Methyl)-4-bromo-indole α-{[1-(2,4-diphenyl)cyclopropyl]-carbonyl}-indole-methyl-L-phenylalanamine decylamine: 4 NMR (400 MHz, 〇 DMSO-d6): δ 7.56-7.54 (m, 1H), 7.37-7.34 (m, 4H), 7.01-6.97 (m, 2H), 6.77-6.71 (m, 1H), 4.76-4.71 (m, 1H) , 3.72-3.65 (m, 2H), 3.55-3.48 (m, 2H), 3.47-3.30 (m, 2H), 2.84 (s, 3H), 2.81-2.66 (m, 3H), 2.64 (s, 1H) , MS6-1 (C, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, Oct-3-yl]-4-bromo-indole α-{[1-(2,3,4-trifluorophenyl)-cyclopropyl]carbonyl}-L-phenylalanamine decylamine: 4 NMR (400 ❹ (M, 1H), 7.42 (d, 2H) , 1H), ' 4.51-4.45 (m, 1H), 3.74-3.73 (m, 1H), 3.22-3.17 (m, 1H), 2.86-2.78 (m, 6H), 2.45-2.44 (m, 1H), 1.80-1.73 (m, 2H), 1.71-1.59 (m, 2H), 1.46-1.42 (m, 1H), 1.37-1.27 (m, 2H), 1.09-1.04 (m, 1H), 0.98-0.93 (m , 1H); C26H27BrF3N302] ^ 8 kg 1), measured value 540.13 (] ^ ^ 1 +). N-[(3S)-1-azabicyclo[2,2.2]oct-3-yl]-4-bromo-Να-({1-[4-fluoro-3- 146258.doc 177· 201040149 (trifluoro Methyl)-phenyl]cyclopropyl}carbonyl)-L-phenylalanamine decylamine: 1H NMR (400 MHz, DMSO-d6): δ 8.20 (d, 1H), 7.61-7.59 (m, 2H), 7.50- 7.41 (m, 3H), 7.06 (d, 2H), 6.90 (d, 1H), 4.53-4.47 (m, 1H), 3.78-3.76 (m, 1H), 3.26-3.21 (m, 1H), 2.90- 2.78 (m, 6H), 2.56-2.55 (m, 1H), 1.81-1.80 (m, 1H), 1.78-1.71 (m, 1H), 1.70-1.59 (m, 2H), 1.45 (m, 1H), MS (EI), found 584.16 (MH+), calcd. (m.m.). N-(cis-4-Aminocyclohexyl)-4-bromo-indole α-({1-[2-fluoro-4-(trifluoromethyl)-phenyl]cyclopropyl}carbonyl)-L- Amphetamine: 4 NMR (400 MHz, DMSO-d6): δ 8.30 (s, 2H), 8.11 (s, 1H), 7.62 (d, 1H), 7.56 (s, 2H), 7.41 (d, 2H) , 7.07-7.02 (m, 3H), 4.56-4.51 (m, 1H), 3.72 (m, 1H), 3.02-2.98 (m, 1H), 2.88-2.77 (m, 2H), 1.76-1.58 (m, 6H), 1.51-1.47 (m, 2H), 1.40-1.28 (m, 2H), 1.10-1.05 (m, 1H), 1.00-0.95 (m, 1H); C26H28BrF4N302 of ^^8(£1), measured The value is 572.19 (1^11+). N-(cis-4-Aminocyclohexyl)-4-indi-Να-[(1-{4-[(dioxamethyl)oxy]-phenyl}cyclopropyl)carbonyl]-L-amphetamine Indoleamine: 4 NMR (400 ΜΗζ, DMSO-d6): δ 8.39 (s, 2H), 8.16 (d, 1H), 7.42 (d, 1H), 7.35-7.29 (m, 4H), 7.02 (d, 2H) ), 6.82 (d, 1H), 4.60-4.54 (m, 1H), 3.70 (m, 1H), 3.00-2.98 (m, 1H), 2.91-2.86 (m, 1H), 2.81-2.75 (m, 1H) ), 1.74-1.55 (m, 6H), 1.51-1.45 (m, 2H), 1.30-1.19 (m, 2H), 1.05-0.90 (m, 2H); MS (EI) of C26H29BrF3N303, found 570.1 8 ( MH+). 146258.doc -178- 201040149 N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Να-({1-[4-fluoro-2-(III) Fluoromethyl)phenyl]cyclopropyl}carbonyl)-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8.00 (d, 1H), 7.65-7.55 (m, 3H), 7.42 ( d, 2H), 7.01 (d, 2H), 6.33 (d, 1H), 4.46 (q, 1H), 3.64-3.63 (m, 1H), 3.12-3.07 (m, 1H), 2.79-2.68 (m, 6H), 2.34-2.30 (m, 1H), 1.72-1.70 (m, 1H), 1.67-1.51 (m, 4H), 1.37-1.34 (m, 2H), 1.06 (s, 2H); MS of C27H28BrF4N302 ( El), found 584.22 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Να-{[1-(2,4-difluorophenyl)-cyclopropyl]carbonyl }-L-Amphetamine: 4 NMR (400 MHz, DMSO-dg): δ 8.10 (d, 1H), 7.43-7.36 (m, 3H), 7.27-7.21 (m, 1H), 7.09-7.04 (m , 1H), 7.00 (d, 2H), 6.55 (d, 1H), 4.50- 4.45 (q, 1H), 3.64 (m, 1H), 3.15-3.09 (m, 1H), 2.81-2.70 (m, 6H ), 2.39-2.35 (m, 1H), 1.73-1.53 (m, 4H), 1.38-1.25 (m, 3H), 1.02-0.90 (m, 2H); MS (El) of C26H28BrF2N302, found 53 2.20 ( MH+). N-{(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-l-[(4-fluorophenyl)methyl]-2-oxo Ethyl}-1-{4-[(trifluoromethyl)oxy-1phenyl}cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.39-7.29 (m, 4H), 7.15-7.04 (m, 4H), 6.98-6.88 (m, 1H), 4.72-4.65 (m, 1H), 4.41-4.36 (m5 1H), 4.31-4.30 (m, 1H), 4.15 (m, 1H), 3.17- 3.15 (m, 1H), 3.05-2.90 (m, 1H), 2.79-2.75 (m, 2H), 2.14- 1.91 (m, 3H), 1.89-1.76 (m, 1H), 1.68-1.59 (m, 2H) ), 1.53 - 1.46 (m, 2H), 1.31-1.21 (m, 2H), 1.01-0.94 (m, 2H); 146258.doc -179 - 201040149 MS (EI) of C27H29F4N303, 520.30 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-indole α-({1-[2-(trifluoromethyl)-phenyl]cyclopropyl }carbonyl)-L-phenylalanamine decylamine: NMR (400 MHz, DMSO-d6): δ 8.05 (d, 1H), 7.74 (d, 1H), 7.69 (t, 1H), 7.58 (t, 2H), 7.40 (d5 2H), 6.97 (d, 2H), 6.14 (d, 1H), 4.48 (q, 1H), 3.63-3.61 (m, 1H), 3.12-3.06 (m, 1H), 2.78-2.66 (m , 6H), 2.34-2.29 (m, 1H), 1.71-1.50 (m, 5H), 1.39-1.35 (m, 2H), 1.07 (s, 2H); MS (EI) of C27H29BrF3N302, found 566.21 (MH+ ). 4-fluoro-N-[(3R)-acridin-3-yl]-Να-[(1-{4-[(trifluoromethyl)oxy]phenyl}-cyclopropyl)carbonyl]-L- Amphetamine: 4 NMR (400 MHz, DMSO-d6): δ 8.39 (d, 1H), 8.34 (s, 1H), 7.37 (d, 2H), 7.31 (d, 2H), 7.10-7.03 (m, 4H), 6.65 (d, 1H), 4.48-4.42 (m, 1H), 3.77-3.75 (m, 1H), 3.06-3.03 (m, 1H), 2.98-2.95 (m, 1H), 2.91-2.87 ( m, 1H), 2.83-2.79 (m, 1H), 2.77-2.70 (m, 1H), 2.62-2.56 (m, 1H), 1.72-1.69 (m, 2H), 1.55-1.50 (m, 1H), 1.40-1.34 (m, 1H), 1.31-1.21 (m, 2H), 1.04-0.92 (m, 2H); (:251127?4^[303 of the river 8 (£1), measured value 494.28 (]^11 +) N-{(lS)-2-(4-Aminoacridin-1-yl)-l-[(4-fluorophenyl)methyl]oxoethyl[(trifluoromethyl)oxy Phenyl}cyclopropanamide: NMR (400 MHz, DMSO-d6): S8.40 (s, 2H), 7.38-7.30 (m, 4H), 7.11-7.02 (m, 4H), 6.84-6.66 ( m, 1H), 4.94-4.89 (m, 1H), 4.24-4.14 (m, 1H), 3.94-3.91 (m, 1H), 3.10-2.96 (m, 2H), 2.90-2.82 (m, 1H), 2.78-2.70 (m, 1H), 2.67-2.59 (m, 1H), 1.90- 146258.doc -180- 201040149 1.81 (m, 2H), 1.35-1.17 (m5 4H), 1.02-0.94 (m, 2H) ; (: 251127? 41^303] ^ 8 kg 1), real 494.28(]^11+). N-[(lS)-l-[(4-bromophenyl)methyl]-2-(4-hydroxyacridin-1-yl)-2-oxo -1(2,4-diphenyl)cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 7.61 (m, 1H), 7.40 (m, 4H), 7.01 (m, 2H), - 6.75 (m, 1H), 4.88 (m, 1H), 4.74 (m, 1H), 3.86 (m, 1H), 3.84-3.56 (m, 4H), 3.19-2.63 (m, 2H), 1.60 (m, 2H), 1.40-1.11 (m, 7H), 0.96 (m, 2H); MS (El) of C24H25BrCl2N203, 〇 found 541.01 (141'1+). 4-fluoro-Να-({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-N-[(3R)-acridin-3-yl]-L- Amphetamine: 4 NMR (400 MHz, DMSO-d6): δ 8_17 (d, 1H), 7·64 (d, 1H), 7.55 (m, 2H), 7.04 (m, 4H), 6.78 (m, 1H), 4.40 (m, 1H), 3.67 (m, 1H), 3.01- 3.64 (m, 5H), 1.65 (m, 2H), 1.51-1.22 (m, 4H), 1.00 (m, 2H); C25H26F5N302 MS (El), found 496.17 (MH+). N-{(lS)-2-(3-Amino-8-azabicyclo 0.2.1]oct-8-yl)-1-[(4-fluorophenylindenyl)methyl]-2-oxo Ethyl}-1-丨2-fluoro-4-(trifluoromethyl)phenyl]cyclopropanol: NMR (400 MHz, DMSO-d6): δ 7.64-7.51 (m, 3H), 7.24-7.00 (m, 5H), 4.67 (m, 1H), 4.37 (m, 1H), 4.32-4.10 (m, 1H), 3.15-2.70 (m, 2H), 2.21-1.46 (m, 8H), 1.32 (m , 211), 1.01 (111, 211); (: 271128? 5 &gt; 13 〇 2) ^ 8 (£1), found 522.31 (MH+). N-{(lS)-2-(4-Amino Acridine-1-yl)-l-[(4-fluorophenyl)methyl-2-oxoethyl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropene Amine: 4 NMR (400 146258.doc -181 - 201040149 MHz, DMSO-de): δ 7.64 (m, 1H), 7.55 (m, 2H), 7.05 (m, 4H), 6.90 (d, 1H), 4.86 (m, 1H), 4.14 (m, 1H), 3.85 (m, 1H), 3.06-2.55 (m, 4H), 1.76 (m, 2H), 1.36-1.08 (m, 4H), 1.00 (m, 2H) MS; El, C25H26F5N302, found 496.30 (MH+). N-{(lS)-2-(4-Aminopyridin-1-yl)-l-[(4-fluorophenyl)methyl ]-2-Oxoethyl[(trifluoromethyl)oxy]phenyl}cyclopropanamide: 4 NMR (400 MHz, DMSO-d6): δ 8.40 (s, 2H), 7.38-7.30 (m, 4H), 7.11- 7.0 1 (m, 4H), 6.84-6.66 (dd, 1H), 4.94-4.89 (m, 1H), 4.24- 4.14 (m, 1H), 3.94-3.91 (m, 1H), 3.10-2.96 (m, 2H ), 2.90- 2.82 (m, 1H), 2.78-2.70 (m, 1H), 2.67-2.59 (m, 1H), 1.90-1.81 (m, 2H), 1.35-1.17 (m, 4H), 1.02-0.94 (m, 2H); MS (El) for C25H27F4N303, found 494.28 (MH+). N-{(lS)-2-[(3S)-3-Amino&quot;pyrrolidinyl]-l-[(4-bromophenyl)methyl]-2-oxoethyl}-1- [2-Fluoro-4-(trifluoromethyl)phenyl]cyclopropanamide: iH NMR (400 MHz, DMSO-d6): δ 7.68-7.64 (m, 1 Η), 7.61-7.57 (m, 2H) , 7.44-7.40 (m, 2H), 7.09-7.04 (m, 2H), 7.13-6.96 (dd, 1H), 5.67 (br s, 2H), 4.67-4.56 (m, 1H), 3.67-3.49 (m , 2H), 3.40-3.33 (m, 2H), 3.32-3.11 (m, 1H), 2.87-2.76 (m, 2H), 2.07-1.90 (m, 1H), 1.81-1.63 (m, 1H), 1.42 -1.30 (m, 2H), 1.10-0.97 (m, 2H); MS (El) of C24H24BrF4N302, found 542.16 (MH+). N-{(lS)-2-[(3S)-3-Amino&quot;pyrrolidin-1-yl]-l-[(4-fluorophenyl)methyl]-2-oxoethyl} -1-[2-Fluoro-4-(trifluoromethyl)phenyl]cyclopropanamide: 屯146258.doc -182- 201040149 NMR (400 MHz, DMSO-d6): δ 7.69-7.64 (m, 1H ), 7.61-7.56 (m, 2H), 7.15-7.10 (m, 2H), 7.08-7.03 (m, 2H), 7.17-6.94 (dd, 1H), 6.25 (br s, 2H), 4.66-4.54 ( m, 1H), 3.70-3.50 (m, 2H), 3.41-3.32 (m, 2H), 3.31-3.15 (m, 1H), 2.89-2.77 (m, 2H), 2.04-1.93 (m, 1H), 1.84-1.66 (m, 1H), 1.42-1.30 (m, 2H), 1.10-0.97 (m, 2H); MS (El) of C24H24F5N302, found 482.25 (MH+). N-{(lS)-2-[(3S)-3-Amino&quot;pyrrolidin-1-yl]-l-[(4-fluorophenyl)indolyl]-2-oxoethyl} 1-{4-[(Trifluoromethyl)oxy]phenyl}cyclopropanamide: 咕NMR (400 MHz, DMSO-d6): δ 7.89 (br s, 1H), 7.41-7.29 (m, 4H ), 7.16-7.03 (m, 4H), 6.90-6.69 (dd, 1H), 4.69-4.56 (m, 1H), 3.75-3.59 (m, 2H), 3.47-3.26 (m, 3H), 2.92-2.76 (m, 2H), 2.10-1.98 (m, 1H), 1.94-1.77 (m, 1H), 1.34-1.20 (m, 2H), 1.05-0.91 (m, 2H); MS (El) of C24H25F4N303, measured The value is 480.29 (MH+). N-{(lS)-2-[(3S)-3-Aminopyridinium-1-yl]-l-[(4-bromophenyl)methyl]-2-oxoethyl}- 1-{4-[(Trifluoromethyl)oxy]phenyl}cyclopropanamide: 咕NMR (400 MHz, DMSO-d6): δ 7.45-7.42 (m, 2H), 7.40-7.29 (m, 4H ), 7.08-7.00 (m, 2H), 6.98 (br s, 1H), 6.93-6.73 (dd, 1H), 4.69-4.57 (m, 1H), 3.71-3.58 (m, 2H), 3.45-3.22 ( m, 3H), 2.91-2.75 (m, 2H), 2.09-1.98 (m, 1H), 1.89-1.73 (m, 1H), 1.33-1.20 (m, 2H), 1.05-0.93 (m, 2H); MS (El) for C24H25BrF3N303, found 542.09 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-(trifluoromethyl)-Να- 146258.doc -183- 201040149 [(l-{4-[ (trifluoromethyl)-oxy]phenyl}cyclopropyl)carbonyl]-L-phenylalanamine decylamine: lH NMR (400 MHz, DMSO-d6): δ 8.26-8.21 (m, 1 Η), 7.62- 7.60 ( m, 2H), 7.39-7.34 (m, 2H), 7.29-7.26 (m, 4H), 6.67- 6.61 (m, 1H), 4.62-4.57 (m, 1H), 3.74-3.68 (m, 1H), 3.16- 3.11 (m, 1H), 2.97-2.90 (m, 2H), 2.88-2.68 (m, 4H), 2.50- 2.42 (m, 1H), 1.75-1.50 (m, 4H), 1.37-1.33 (m , 1H), 1.30- 1.20 (m, 2H), 1.03-0.94 (m, 2H); MS (El) for C28H29F6N303, found 570.24 (]^11+).

N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-2,4·二氣-Ν-α-{[1-(2,4-二氣苯基）-環丙基】羰基}-L-苯丙胺醢胺：4 NMR (400 MHz, CD3OD) ： δ 7.52-7.38 (m, 4H), 7.23 (d, 1H), 7.17 (d, 1H), 4.60 (m, 1H), 4.08 (m, 1H), 3.62 (m, 1H), 3.34-3.13 (m, 3H), 3.08-3.02 (m, 1H), 2.83 (ddd, 1H), 2.17 (m, 1H), 2.02-1.90 (m, 3H), 1.84-1.75 (m, 1H), 1.60-1.43 (m, 2H), 1.20-1.13 (m, 1H), 1.05-1.00 (m, 1H); C26H27Cl4N3〇2的 MS (El)，實測值 557.01 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2】辛-3-基】-4-溴-1\-〇1-{[1-(2,4-二 氣苯基）-環丙基]羰基}-L-苯丙胺醢胺：4 NMR (400 MHz, CD3OD) ： δ 7.52-7.38 (m, 5H), 7.02 (d, 2H), 4.58 (t, 1H), 4.00 (m, 1H), 3.58 (t, 1H), 3.28-3.03 (m, 4H), 2.95-2.80 (m, 2H), 2.65 (m, 1H), 2.08 (m, 1H), 2.00-1.65 (m, 4H), 1.62- 1.43 (m, 2H), 1.20-1.13 (m, 1H), 1.09-1.02 (m, 1H); C26H28BrCl2N302的 MS (El)，實測值 566.78 (MH+)。 N-[(3S)-1-氮雜雙環[2.2.2】辛-3-基]-沁〇[-{【1-(2,4-二氣苯 146258.doc -184- 201040149 基）-環丙基】-羰基}-4-(三氟甲基）-L-苯丙胺醯胺：1H NMR (400 MHz, DMSO-d6) ： δ 8.10 (dd, 1H), 7.58 (m, 3H), 7.41 (s, 2H), 7.28 (t, 2H), 6.56 (dd, 1H), 4.55 (t, 1H), 3.71 (m, 1H), 3.15 (m, 1H), 2.92 (m, 2H), 2.77 (m, 4H), 2.39 (m, 1H), 1.70 (m, 1H), 1.55 (m, 3H), 1.36 (m, 3H), 0.96 (m, 2印；（：271128(：12?3]^302的]^8(£1)，實測值555.43(厘1€+)。 4-溴-Να-[2-(2,4-二氣苯基）-2-甲基丙醯基】-N-[(3R)-呱 啶-3-基】-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6) : δ 〇 8.28 (s, 1H), 8.02 (d, 1H), 7.44 (d, 1H), 7.41 (d, 1H), 7.39 (d, 1H), 7.37 (d, 2H), 7.23 (d, 1H), 7.10 (d, 2H), 4.51-4.35 (m, 1H), 3.72 (s, 1H), 3.01 (dd, 1H), 2.92 (d, 1H), 2.80 (qd, 2H), 2.66 (dd, 1H), 1.68 (d, 2H), 1.49 (d, 1H), 1.34 (d, 6H). C24H28BrCl2N302 的 MS (El)，實測值542.3 (MH+)。 4 -漠-Να-(2-甲基-2-{4-[(三氟甲基）氧】苯基}丙雄基）_N-[(3R)-*»瓜咬-3-基】-L-苯丙胺醯胺：4 NMR (400 MHz, DMSO-d6) : δ 8_33 (s，1H)，8.28 (d，1H)，7.54 (d 1H) 7 38 〇 (d, 2H), 7.20 (s, 4H), 7.10 (d, 2H), 4.47 (tt, 1H), 3.81 (t, 1H), 3.04 (dd, 2H), 2.91-2.70 (m, 3H), 2.67-2.53 (m, 1H), 1.71 (d，2H), 1.60-1.46 (m，1H)，1.34 (s, 6H). C25H29BrF3N3〇3 、 的MS (El)，實測值 557.4 (MH+) N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1】辛基）44(4-溴苯 基）甲基】-2-氧代乙基}-2 -甲基-2-{4-[(三象甲基）氧】苯基}丙 醯胺：4 NMR (400 MHz，DMSO-d6) : δ 8.26 (s, 1H), 7.72 (dd, 1H), 7.39 (m, 2H), 7.24 (dd, 4H), 7.13 (dd, 2H), 4.72 146258.doc -185- 201040149 (m, 1H), 4.35 (m, 2H), 4.15 (m, 1H), 3.17 (m, 1H), 3.01 (m, 1H), 2.98-2.66 (m, 2H), 2.08-1.78 (m, 3H), 1.74-1.44 (m, 4H), 1.36 (m, 6H). C27H31BrF3N303 的 MS (El)，實測值 583.5 (MH+)。 N-{(lS)-2-(4-胺基-4-甲基呱啶-1-基）-l-[(4-溴苯基）甲 基]-2-氧代乙基}-2-(2,4-二氣苯基）-2-甲基丙醯胺：咕 NMR (400 MHz, DMSO-d6) ： δ 7.50-7.30 (m, 6H), 7.14 (t, 2H), 4.91 (m, 1H), 3.77-3.51 (m, 2H), 3.36 (m, 2H), 2.89-2.68 (m, 2H), 1.54 (m, 3H), 1.39 (m, 7H), 1.21 (d, 3H). C25H30BrCl2N3O2的MS (El)，實測值 556.3 (MH+)。 實施例7. 1-(2,4-二氣苯基）-N-[(1S)-1-({[(1-甲基環丙基）甲基】氧} 甲基）-2-(4 -曱基狐n秦-1 -基）-2-氧代乙基】壤丙酿胺N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2,4·diqi-Ν-α-{[1-(2,4-diphenyl)- Cyclopropyl]carbonyl}-L-phenylalanamine decylamine: 4 NMR (400 MHz, CD3OD): δ 7.52-7.38 (m, 4H), 7.23 (d, 1H), 7.17 (d, 1H), 4.60 (m, 1H), 4.08 (m, 1H), 3.62 (m, 1H), 3.34-3.13 (m, 3H), 3.08-3.02 (m, 1H), 2.83 (ddd, 1H), 2.17 (m, 1H), 2.02 -1.90 (m, 3H), 1.84-1.75 (m, 1H), 1.60-1.43 (m, 2H), 1.20-1.13 (m, 1H), 1.05-1.00 (m, 1H); MS of C26H27Cl4N3〇2 ( El), found 557.01 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-1\-〇1-{[1-(2,4-diphenyl)-cyclo Propyl]carbonyl}-L-phenylalanamine decylamine: 4 NMR (400 MHz, CD3OD): δ 7.52-7.38 (m, 5H), 7.02 (d, 2H), 4.58 (t, 1H), 4.00 (m, 1H) ), 3.58 (t, 1H), 3.28-3.03 (m, 4H), 2.95-2.80 (m, 2H), 2.65 (m, 1H), 2.08 (m, 1H), 2.00-1.65 (m, 4H), 1.62- 1.43 (m, 2H), 1.20-1.13 (m, 1H), 1.09-1.02 (m, 1H); MS (El) of C26H28BrCl2N302, found 566.78 (MH+). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-indole[-{[1-(2,4-diphenylbenzene 146258.doc -184- 201040149 base)- Cyclopropyl]-carbonyl}-4-(trifluoromethyl)-L-phenylalanamine decylamine: 1H NMR (400 MHz, DMSO-d6): δ 8.10 (dd, 1H), 7.58 (m, 3H), 7.41 (s, 2H), 7.28 (t, 2H), 6.56 (dd, 1H), 4.55 (t, 1H), 3.71 (m, 1H), 3.15 (m, 1H), 2.92 (m, 2H), 2.77 ( m, 4H), 2.39 (m, 1H), 1.70 (m, 1H), 1.55 (m, 3H), 1.36 (m, 3H), 0.96 (m, 2 printed; (:271128(:12?3]^ 302^^8(£1), found 555.43 (PCT 1 €+). 4-bromo-Να-[2-(2,4-diphenyl)-2-methylpropanyl]-N -[(3R)-Azeridin-3-yl]-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 〇 8.28 (s, 1H), 8.02 (d, 1H), 7.44 (d , 1H), 7.41 (d, 1H), 7.39 (d, 1H), 7.37 (d, 2H), 7.23 (d, 1H), 7.10 (d, 2H), 4.51-4.35 (m, 1H), 3.72 ( s, 1H), 3.01 (dd, 1H), 2.92 (d, 1H), 2.80 (qd, 2H), 2.66 (dd, 1H), 1.68 (d, 2H), 1.49 (d, 1H), 1.34 (d , 6H). MS (El) for C24H28BrCl2N302, found 542.3 (MH+). 4 - Mo-Να-(2-methyl-2-{4-[(trifluoromethyl)oxy]phenyl}propylh-yl) _N-[(3R)-*» melon -3-yl]-L-phenylalanamine decylamine: 4 NMR (400 MHz, DMSO-d6): δ 8_33 (s, 1H), 8.28 (d, 1H), 7.54 (d 1H) 7 38 〇 (d, 2H ), 7.20 (s, 4H), 7.10 (d, 2H), 4.47 (tt, 1H), 3.81 (t, 1H), 3.04 (dd, 2H), 2.91-2.70 (m, 3H), 2.67-2.53 ( m, 1H), 1.71 (d, 2H), 1.60-1.46 (m, 1H), 1.34 (s, 6H). MS (El) for C25H29BrF3N3〇3, found 557.4 (MH+) N-{(lS) -2-(3-Amino-8-azabicyclo[3.2.1]octyl)44(4-bromophenyl)methyl]-2-oxoethyl}-2-methyl-2-{ 4-[(Tri-methyl)oxy]phenyl}propanamine: 4 NMR (400 MHz, DMSO-d6): δ 8.26 (s, 1H), 7.72 (dd, 1H), 7.39 (m, 2H) , 7.24 (dd, 4H), 7.13 (dd, 2H), 4.72 146258.doc -185- 201040149 (m, 1H), 4.35 (m, 2H), 4.15 (m, 1H), 3.17 (m, 1H), 3.01 (m, 1H), 2.98-2.66 (m, 2H), 2.08-1.78 (m, 3H), 1.74-1.44 (m, 4H), 1.36 (m, 6H). MS (El) of C27H31BrF3N303, measured value 583.5 (MH+). N-{(lS)-2-(4-Amino-4-methylacridin-1-yl)-l-[(4-bromophenyl)methyl]-2-oxoethyl}-2 -(2,4-diphenyl)-2-methylpropanamide: NMR (400 MHz, DMSO-d6): δ 7.50-7.30 (m, 6H), 7.14 (t, 2H), 4.91 ( m, 1H), 3.77-3.51 (m, 2H), 3.36 (m, 2H), 2.89-2.68 (m, 2H), 1.54 (m, 3H), 1.39 (m, 7H), 1.21 (d, 3H) MS (El) for C25H30BrCl2N3O2, found 556.3 (MH+). Example 7. 1-(2,4-Diphenyl)-N-[(1S)-1-({[(1-methylcyclopropyl)methyl]oxy}methyl)-2-( 4 - mercapto fox n-methyl-1 -yl)-2-oxoethyl

步驟1. (S)-2-甲基氮丙啶-1,2-二羧酸1-叔丁酯：向溶於 146258.doc -186- 201040149 乙猜（20 mL)的（S)-氦丙β定_2-致酸曱醋（根據 Asymmetry, 2002，Η(ϋ)，1129-1134 製備）（1 .〇 g，9.89 mmol)溶液加入boc-酐（2.37 g，10.88 mmol)。將反應混合 物於室溫攪拌2小時，之後減壓除去溶劑，產生1.86 g的 標題化合物，其用於下一步驟而無需進一步純化。ιΗ NMR (400 MHz, DMSO-d6): δ 3.70 (s, 3Η), 3.14 (q, 1H), 2.46 (m, 1H), 2.39 (m，1H)，1.38 (s，9H)。 步驟2. (S)-2-(叔丁氧羰基胺基）-3-((1-甲基環丙基）-甲氧 基）丙酸甲醋：將（S)-氮丙咬-1，2-二羧酸1-叔丁 2-甲酯（1.0 g，5.0 mmol)溶于無水氯仿（16 mL)，之後加入（1-甲基環 丙基）曱醇（1.2，14.9 mmol )和 0.04 mL(0.25 mmol)的 7 Μ三 氟化硼二乙醚（Aldrich)。將反應混合物於室溫攪拌24小時 並且用幾滴甲醇淬滅。通過管柱層析（EtOAc，己烧，石夕 膠）純化產物以產生為透明油的（S)-2-(叔丁氧羰基胺基）_3_ ((1-甲基環丙基）曱氧基）丙酸甲酯（800 mg )。4 NMR (400 MHz, DMSO-d6) ： 7.13 (d, 1H), 4.23 (m, 1H), 3.63 (s, 3H), 3.59 (m, 2H), 3.17 (m, 2H), 1.38 (s, 9H), 1.01 (s, 3H), 0.33 (m, 2H), 0.24 (m, 2H). 步驟3. (S)-2-(叔丁氧羰基胺基）-3-((1-甲基-環丙基）_甲 氧基）丙酸甲酷.將（S)-2-(叙丁氧幾基胺基）-3-((1-曱基_環 丙基）-曱氧基）丙酸甲醋（800 mg , 2.8 mmol)溶于無水二乙 醚（6 mL)並加入 4 M HC1/二噁烷（14 mL，55.7 mmol， Aldrich) ’將反應混合物於室溫攪拌4小時並且真空除去溶 劑。所得的600 mg的（S)-2-(叔丁氧羰基胺基）-3-((1-甲基環 146258.doc -187- 201040149 丙基）甲氧基）丙酸甲酯被用於下一步驟而無需純化。 C9Hi7N03的 MS (EI) ’ 實測值 188.10 (MH+)。 步驟4· (S)-2-(l-(2,4-二氣苯基）環丙甲醯胺基）3 (0甲 基環丙基）甲氧基）丙酸甲酯：向溶于無水乙腈（1〇瓜卩的 (S)-2-(叔丁氧羰基-胺基）_3_((ι_甲基環丙基）甲氧基）丙酸甲 酯（600 mg，5.7 mmol)和 N，N-二異丙基乙胺（0,9 mL，6.5 mmol)溶液加入ι_(2,4-二氯苯基）環丙叛酸（Acr〇s，500 mg，2.2 mmol)，之後加入 HATU(ApPlied Biosystems，905 mg，2_4 mmol)，並且將反應混合物於室溫擾拌丨8小時。 將所得的溶液真空濃縮’溶於二氣甲烷（3〇〇 m)，用水（2〇 mL)、飽和碳酸氫鈉溶液（2〇 mL)和飽和氣化鈉溶液（2〇 mL)萃取。分層並用硫酸鎂乾燥有機層。減壓下過濾並濃 縮得到（S)-2-(l-(2,4-二氯苯基）環丙曱醯胺基甲基 環丙基）-甲氧基）丙酸甲酯（85〇 mg)，其用於下一步驟而無 需進一步純化。C19H23C12N04的MS (EI)，實測值400.09 (MH+)。 步称5. (S)·甲基2-(1-(2,4-二氣苯基）環丙甲醢胺基）_3_ 甲基-環丙基）甲氧基）丙酸：向溶於10 mL的THF的（S)-2-(1-(2,4-二氣笨基）環丙曱醯胺基曱基環丙基）曱氧 基）丙酸甲醋（8 50 mg，2.1 mmol)溶液加入8.5 mL的1 ν LiOH溶液（8.5 mmol)，並且將反應混合物於室溫攪拌2小 時。將所得的溶液在減壓下濃縮，用濃HC1酸化至pH=3， 並且用100 mL的乙酸乙酯萃取。將有機層用硫酸鈉乾燥、 過滤並真空濃縮以產生700rng的標題化合物，其用於下一 146258.doc 201040149 步驟而無需進一步純化。Cl8H2iCl2N〇4&amp;MS (EI)，實測值 386.05 (MH+) ° 步驟6· 1-(2,4-二氣苯基）曱基環丙基）甲 基】-氧}甲基）-2-(4-甲基呱嗪基）_2_氧代乙基】環丙醯胺： 向溶於乙腈（1.5 mL)的（S)-甲基2-(1-(2,4-二氯苯基）環丙 甲醯胺基）-3-((1-甲基-環丙基）甲氧基）丙酸（1〇〇 mg，〇 2 mmol)溶液加入 N-甲基口瓜唤（sigma_Aldrich，30 mg，0.3 mmol)、N，N-二異丙基乙胺（〇 〇7 mL，0.5 mmol)和 HATU (Applied Biosystems，115 mg，0_3 mmol)。將反應物於室 溫攪拌16小時。將所得溶液真空濃縮，之後通過製備級 HPLC(反相，乙腈/含水的1 〇 mM甲酸緩衝液）純化產物以 產生 12 mg的標題化合*〇1HNMR(400 MHz，DMSO-d6) ： δ 7.66 (d, 1H), 7.48-7.43 (m, 2H), 6.72 (d, 1H), 4.87-4.82 (m, 1H), 3.43 (d, 4H), 3.10 (q, 2H), 2.33-2.18 (m, 4H), 2.15 (s, 3H), 1.90 (s, 2H), 1.54-1.41 (m, 2H), 1.11-0.98 (m, 2H), 0.96 (s, 3H), 0.30-0.26 (m, 2H), 0.24-0.20 (m, 2H); C23H31C12N302 的 MS (El)，實測值468.27 (MH+)。 實施例8 1^-1-氮雜雙環[2.2.2】辛-3-基-]^2’-{[1-(2,4-二氣苯基）環 丙基】羰基甲基環丙基）-L-丙胺醢胺Step 1. (S)-2-Methylaziridine-1,2-dicarboxylic acid 1-tert-butyl ester: soluble in 146258.doc -186- 201040149 B (20 mL) of (S)-氦A solution of propofol-2-acidified vinegar (according to Asymmetry, 2002, Η(ϋ), 1129-1134) (1. 〇g, 9.89 mmol) was added to boc-anhydride (2.37 g, 10.88 mmol). The reaction mixture was stirred at rt EtOAc EtOAc (EtOAc). Η NMR (400 MHz, DMSO-d6): δ 3.70 (s, 3 Η), 3.14 (q, 1H), 2.46 (m, 1H), 2.39 (m, 1H), 1.38 (s, 9H). Step 2. (S)-2-(tert-Butoxycarbonylamino)-3-((1-methylcyclopropyl)-methoxy)propionic acid methyl vinegar: (S)-Azide-Bite-1 , 2-dicarboxylic acid 1-tert-but-2-methyl ester (1.0 g, 5.0 mmol) was dissolved in anhydrous chloroform (16 mL), then (1-methylcyclopropyl) decyl alcohol (1.2, 14.9 mmol) and 0.04 mL (0.25 mmol) of 7 Torr boron trifluoride diethyl ether (Aldrich). The reaction mixture was stirred at room temperature for 24 h and quenched with a few drops of methanol. The product was purified by column chromatography (EtOAc, hexanes, EtOAc) to yield (S)-2-(tert-butoxycarbonylamino)-3 ((1-methylcyclopropyl) oxime as a clear oil. Base) methyl propionate (800 mg). 4 NMR (400 MHz, DMSO-d6): 7.13 (d, 1H), 4.23 (m, 1H), 3.63 (s, 3H), 3.59 (m, 2H), 3.17 (m, 2H), 1.38 (s, 9H), 1.01 (s, 3H), 0.33 (m, 2H), 0.24 (m, 2H). Step 3. (S)-2-(tert-Butoxycarbonylamino)-3-((1-methyl) -cyclopropyl)-methoxy)propionic acid methyl.. (S)-2-(S-butoxymethylamino)-3-((1-indolyl-cyclopropyl)-decyloxy) Methyl propyl citrate (800 mg, 2.8 mmol) was dissolved in anhydrous diethyl ether (6 mL) and 4 M EtOAc / dioxane (14 mL, 55.7 mmol, Aldrich). The mixture was stirred at room temperature for 4 hours and vacuum Remove the solvent. The obtained 600 mg of (S)-2-(tert-butoxycarbonylamino)-3-((1-methylcyclo 146258.doc -187- 201040149 propyl)methoxy)propanoic acid methyl ester was used. The next step without purification. MS (EI) of C9Hi7N03 found 188.10 (MH+). Step 4· (S)-2-(l-(2,4-Diphenyl)cyclopropynylamino)3 (0-methylcyclopropyl)methoxy)propionic acid methyl ester: soluble in Anhydrous acetonitrile ((S)-2-(tert-butoxycarbonyl-amino)_3_((ι-methylcyclopropyl)methoxy)propanoate methyl ester (600 mg, 5.7 mmol) and N,N-diisopropylethylamine (0,9 mL, 6.5 mmol) was added to ι_(2,4-dichlorophenyl)cyclopropionic acid (Acr〇s, 500 mg, 2.2 mmol), followed by HATU (ApPlied Biosystems, 905 mg, 2_4 mmol), and the reaction mixture was stirred at room temperature for 8 hours. The resulting solution was concentrated in vacuo to dissolve in di- methane (3 〇〇m), water (2 〇mL) The mixture was extracted with saturated sodium bicarbonate solution (2 mL) and saturated aqueous sodium chloride (2 mL), and the organic layer was dried over magnesium sulfate, filtered and concentrated to give (S)-2-(l-( Methyl 2,4-dichlorophenyl)cyclopropylaminomethylcyclopropyl)-methoxy)propanoate (85 mg) was used in the next step without further purification. MS (EI) for C19H23C12N04, found 400.09 (MH+). Step 5. 5. (S)·Methyl 2-(1-(2,4-diphenyl)cyclopropynylamino)_3_methyl-cyclopropyl)methoxy)propionic acid: soluble 10 mL of (S)-2-(1-(2,4-dioxa)cyclopropamimidinodecylcyclopropyl)decyloxy)propionic acid methyl vinegar (8 50 mg, 2.1 in THF) The solution was added 8.5 mL of 1 ν LiOH solution (8.5 mmol), and the mixture was stirred at room temperature for 2 hr. The resulting solution was concentrated under reduced pressure, acidified to pH 3 with concentrated EtOAc, and ethyl acetate. The organic layer was dried with EtOAc EtOAc EtOAc EtOAc. Cl8H2iCl2N〇4 &amp; MS (EI), found 386.05 (MH+) ° Step 6· 1-(2,4-diphenylphenyl)nonylcyclopropyl)methyl]-oxo}methyl)-2-( 4-methylpyridazinyl)-2-oxoethyl]cyclopropanamide: (S)-methyl 2-(1-(2,4-dichlorophenyl) dissolved in acetonitrile (1.5 mL) A solution of cyclopropylamido)-3-((1-methyl-cyclopropyl)methoxy)propionic acid (1 〇〇 mg, 〇 2 mmol) was added to the N-methyl squash (sigma_Aldrich, 30 Mg, 0.3 mmol), N,N-diisopropylethylamine (〇〇7 mL, 0.5 mmol) and HATU (Applied Biosystems, 115 mg, 0-3 mmol). The reaction was stirred at room temperature for 16 hours. The resulting solution was concentrated in vacuo then purified by preparative HPLC (EtOAc, EtOAc/EtOAc EtOAc EtOAc EtOAc EtOAc d, 1H), 7.48-7.43 (m, 2H), 6.72 (d, 1H), 4.87-4.82 (m, 1H), 3.43 (d, 4H), 3.10 (q, 2H), 2.33-2.18 (m, 4H), 2.15 (s, 3H), 1.90 (s, 2H), 1.54-1.41 (m, 2H), 1.11-0.98 (m, 2H), 0.96 (s, 3H), 0.30-0.26 (m, 2H) MS (El), found 468.27 (MH+). Example 8 1^-1-Azabicyclo[2.2.2]oct-3-yl-]^2'-{[1-(2,4-diphenylphenyl)cyclopropyl]carbonylmethylcyclopropane -L-alanamine

146258.doc -189- 201040149146258.doc -189- 201040149

步驟1 : (S)-2-(叔丁氧羰基胺基）_4_甲基戊_4_稀酸甲酯： 向溶于無水乙腈（20 mL)的（S)-2-(叔丁氧羰基胺基）_4_甲基 戊-4-稀酸（Alfa Aesar，1.0 g ’ 4.4 mmol)加入碳酸钟（1.8 g ’ 13.1 mmol)和碘甲烷（0.81 mL，13.1 mmol)。將所得的 溶液攪拌隔夜，真空濃縮，重溶於EtOAc(100 mL)，用 1 00ml的1 M NaOH清洗，並且之後用無水硫酸鈉乾燥。減 壓下過濾並濃縮產生300 mg的（S)-2-(叔丁氧羰基胺基）-4-曱基戊-4-烯酸曱酯，其用於下一步驟而無需進一步純化。 (：121121&gt;104的1^8(£1)，實測值244.15 (]^11+)。 步驟2 : (S)-2-胺基-3-(1-甲基環丙基）丙酸甲酯：在氮氣 氣氛下向溶于無水二氯曱烷（12 mL)的（S)-2-(叔丁氧羰基胺 基）-4-曱基戊-4-烯酸曱酯（3〇〇 mg，i_2 mmol)溶液加入二 曱基鋅（3 mL的2 Μ曱苯溶液，6.2 mmol)，之後加入二碘曱 烷（0.5 mL ’ 6.2 mmol)。將反應混合物於室溫攪拌隔夜。 將所得的溶液用飽和氣化銨（3〇 mL)和水（10 mL)萃取。分 層並用硫酸納乾燥有機層。減壓下過濾並濃縮產生19〇 mg 的標題化合物，其用於下一步驟而無需進一步純化。 C8H15N02的 MS (EI)，實測值 158 1〇 (MH+)。 步驟3 : (S)-2-(l-(2,4-二氣苯基）環丙甲醯胺基）-3-(1-甲 基-環丙基）丙陵甲酯：向溶于無水乙腈（5 mL)的胺 基-3-(1-甲基環丙基）丙酸甲酯（187 mg，12 ^ιηί^βοΝ,Ν- 146258.doc •190· 201040149 二異丙基乙胺（0.5 mL，5.5 mmol)溶液加入1-(2，4-二氯苯 基）環丙叛酸（Acros, 250 mg，1.1 mmol)，之後加入 HATU(Applied Biosystems，450 mg，1.2 mmol)。將反應混 合物於室溫攪拌18小時。將所得的溶液真空濃縮，溶解於 二氯甲烧（100 mL) ’用水（20 mL)、飽和碳酸氫鈉溶液（2〇 mL)和飽和氯化納溶液（20 mL)萃取。分層並用硫酸鎂乾燥 有機層。減壓下過濾並濃縮得到350 mg的（S)-2-(l-(2,4-二氣苯基）環丙甲醯胺基）-3-(1-甲基環丙基）丙酸甲酯，其 用於下一步驟而無需進一步純化。Cl8H2lCl2N〇3的Ms 斤1)，實測值370.07 (]^^+)。 步驟4 : (S)-2-(l-(2,4-二氣苯基）環丙甲醯胺基）_3_(1_甲 基環丙基）丙酸：向溶於5 mL的THF的（S)-2-(l-(2,4-二氣苯 基）環丙甲醯胺基）-3-(1-甲基環丙基）丙酸甲酯（350 mg，0.9 mmol)溶液加入1.9 mL的1 N LiOH溶液（1.9 mmol)，並將反 應混合物於室溫擾拌2小時。將所得的溶液在減壓下濃 縮，用濃HC1酸化至pH=2並且用50 mL的乙酸乙醋萃取。 將有機層用硫酸鈉乾燥，過濾並真空濃縮以產生3 1 〇 mg的 標題化合物，其用於下一步驟而無需進一步純化。 (3171119(：12]^〇3的^48(£1)，實測值356.06 (1^11+)。 步驟 5 : N-1-氮雜雙環[2.2.2]辛_3-基-]^，2，-{[1-(2,4-二氣 苯基）環丙基】-羰基卜3-(1-甲基環丙基）_l_丙胺醢胺：向溶 於乙腈（4 mL)的（S)-2-(l-(2,4-二氯笨基）_環丙甲醯胺基）_3_ (1-曱基環丙基）丙酸（300 mg，0.8 mmol)和N，N-二異丙基乙 胺（00.4 mL，2.6 mmol)的溶液加入奎寧_3_胺（sigma- 146258.doc • 191 - 201040149Step 1: (S)-2-(tert-Butoxycarbonylamino)_4_methylpenta-4-dilute methyl ester: (S)-2-(tert-butoxy) dissolved in anhydrous acetonitrile (20 mL) Carbonylamino)_4_methylpent-4-diacid (Alfa Aesar, 1.0 g '4.4 mmol) was added to a carbonic acid clock (1.8 g ' 13.1 mmol) and methyl iodide (0.81 mL, 13.1 mmol). The resulting solution was stirred with EtOAc (EtOAc)EtOAc. Filtration under reduced pressure and concentration gave 300 mg of (S)-2-(tert-butoxycarbonylamino)-4-decylpent-4-enoate, which was used in the next step without further purification. (: 121121 &gt; 104 of 1^8 (£1), measured value 244.15 (]^11+). Step 2: (S)-2-Amino-3-(1-methylcyclopropyl)propanoic acid Ester: (S)-2-(tert-Butoxycarbonylamino)-4-decylpent-4-enoate (3〇〇) dissolved in anhydrous dichloromethane (12 mL) under nitrogen atmosphere Mg, i_2 mmol) solution was added with dimercapto zinc (3 mL of 2 benzene solution, 6.2 mmol) followed by diiododecane (0.5 mL ' 6.2 mmol). The mixture was stirred overnight at room temperature. The solution was extracted with aq. EtOAc (3 mL) (EtOAc)EtOAc. MS (EI) for C8H15N02, found 158 1 〇 (MH+). Step 3: (S)-2-(l-(2,4-diphenylphenyl)cyclopropynylamino)- 3-(1-Methyl-cyclopropyl)methylidene methyl ester: methyl amino-3-(1-methylcyclopropyl)propanoate (187 mg, 12) dissolved in anhydrous acetonitrile (5 mL) ^ιηί^βοΝ,Ν- 146258.doc •190· 201040149 Diisopropylethylamine (0.5 mL, 5.5 mmol) solution added to 1-(2,4-dichloro Base) Cyclopropionic acid (Acros, 250 mg, 1.1 mmol), followed by HATU (Applied Biosystems, 450 mg, 1.2 mmol). The reaction mixture was stirred at room temperature for 18 h. The obtained solution was concentrated in vacuo and dissolved in The chloroform (100 mL) was extracted with water (20 mL), EtOAc (EtOAc) Concentration to give 350 mg of methyl (S)-2-(l-(2,4-diphenyl)cyclopropamimidino)-3-(1-methylcyclopropyl)propanoate for use In the next step without further purification. Ms of Cl8H2lCl2N〇3 1), found 370.07 (]^^+). Step 4: (S)-2-(l-(2,4-diphenyl) Cyclopropyrylamino)_3_(1-methylcyclopropyl)propionic acid: (S)-2-(l-(2,4-diphenyl)cyclopropane in THF dissolved in 5 mL A solution of methyl hydrazino)-3-(1-methylcyclopropyl)propanoate (350 mg, 0.9 mmol) was added to 1.9 mL of 1 N LiOH solution (1.9 mmol) and the mixture was stirred at room temperature 2 hours. The resulting solution was concentrated under reduced pressure, acidified to pH = 2 with concentrated HCl and 50 mL of Ethyl acetate extraction. The organic layer was dried with EtOAc EtOAc m. (3171119(:12)^〇3^48(£1), found 356.06 (1^11+). Step 5: N-1-Azabicyclo[2.2.2] 辛_3-基-]^ ,2,-{[1-(2,4-diphenyl)cyclopropyl]-carbonyl-(3-methylcyclopropyl)-l-propylamine amide: soluble in acetonitrile (4 mL) (S)-2-(l-(2,4-dichlorophenyl)-cyclopropanoylamino)_3_(1-indolylcyclopropyl)propionic acid (300 mg, 0.8 mmol) and N, A solution of N-diisopropylethylamine (00.4 mL, 2.6 mmol) was added to quinine _3_amine (sigma- 146258.doc • 191 - 201040149

Aldrich，117 mg，0.9 mmol)，之後加入 HATU(Applied Biosystems ’ 350 mg ’ 0.9 mmol)。將反應混合物於室溫授 拌1 8小時。將所得的溶液真空濃縮，並且通過製備級 HPLC(反相，乙腈/含水的l〇mM甲酸緩衝液）純化產物以產 生 7.8 mg的標題化合物。1HNMR (400 MHz，CD3OD): δ 8.55-8.47 (m, 1H), 7.57 (s, 1H), 7.54-7.51 (m, 1H), 7.43-7.41 (m, 1H), 6.33-6.31 (m, 1H), 4.42-4.41 (m, 1H), 4.16 (s，1H)，3.75-3.70 (m，1H)，3.14-3.01 (m，2H), 2.22-1.79 (m, 9H), 1.72 (m, 1H), 1.53 (m, 1H), 1.23-1.15 (m, 2H), 1.09-1.08 (m, 1H), 1.01 (s, 3H), 0.21-0.15 (m, 2H), 〇.〇7 (m，lH),-0.04 (m，1H); C24H31C12N302的MS (El)，實測值 465.17 (MH+) 〇 實施例9. GCS癸光脫氫酶_心肌黃酶偶合的酶測定 葡萄糖芽基腦醯胺合成酶（GCS)活性被測量為合成酶催 化的反應過程中消耗的UDP-葡萄糖的量，該反應使用酶 UDP-葡萄糖脫氫酶以從udP·葡萄糖產生nadh，並且之 後用。肌汽轉以及由脫氫酶形成的NADH將低熒光刃天青 疋3：轉化鬲熒光試函靈。合成酶催化的反應將葡萄糖從 UDP -葡萄糖轉移至C6_腦醯胺以產生作為產物的uDp和葡 萄糖苷基腦醯胺；測定測量了 UDp_葡萄糖底物的消失。 反應在384孔黑色、中等結合力微量滴定板（Greiner)上進 行通過首先向板加入溶於i〇〇y。DMSC^〇 〇〇〇5 mL的化 &quot;&quot; 來衣備合成酶反應混合物（25 mM HEPES (pH=7.4)、 146258.doc -192- 201040149 5 0 mM KC1 和 5 mM MgCl2)。向孔加入體積 ν=0·010 mL 的 溶於 25 mM HEPES (ρΗ=7.4)的總濃度=〇.3mM 的 30 mol0/〇 C6-腦蕴胺（Avanti Polar Lipids，Inc)和 70 mol %二油醯填 脂醯膽驗（DOPC，Avanti Polar Lipids)。 將C6-腦醯胺和DOPC製備為溶於95%乙醇的20 mg/mL貯 存液並且貯存於-20°C。將適當體積轉移至具有螺旋帽隔 膜（screw-cap septum)的40 mL的玻璃小瓶中並用氬氣流乾 燥。將脂質重懸於1 mL的dH20中，冷凍並凍乾隔夜。通 過首先加入足夠的25 mM HEPES (pH=7.4)水化脂質以產生 4x的加入板中的所需濃度，渦旋以懸浮凍乾脂質並且靜置 1小時或更久。之後將溶液冷凍，放置在水浴超聲器中並 用超聲處理解凍，將這一過程重複另外三次以產生四個冷 凍-解凍的超聲處理循環。將所得的溶液用25 mM HEPES (ρΗ=7·4)稀釋四倍以產生將被加至板的脂質的溶液。 完全活性的對照（100%活性）僅含有DMSO。無活性對照 反應（0%對照）僅含有0.010〇11^的10〇111〇1%00?(：(0.31111^) 和DMSO。通過向板的所有孔加入V=〇.〇20 mL的溶於25 mM HEPES (ρΗ=7·4)、75 mM KC1 和 7.5 mM MgCl2的 0.020 mM UDP-葡萄糖、1·5 mg/mL CHAPS、0.17 mg/mL GCS起 始反應。將板於26°C保持3小時。通過加入0.015 mL的溶 於 25 mM HEPES (ρΗ=7·4)、50 mM KC1 和 5 mM MgCl2的 0.30 mM NAD+、0.30 mM刃天青、0.11 mg/mL UDP-葡萄 糖脫氫酶和0.030 mg/mL心肌黃酶測量剩餘的UDP-葡萄 糖。將板於26°C保持30分鐘或更久，並且用Envision 1平 146258.doc •193- 201040149 板讀數儀（Perkin Elmer)測量具有激發=530 nm並且發射 = 560的熒光的增加。測定中1]£)1)_葡萄糖的消耗被限制於 40-60%的總UDP-葡萄糖。通過使用四參數方程式[γ=最大 值-(最大值-最小值）/(1 + (χ/Κπ)，]的非線性回歸分析計 算ICw值’其中γ是觀察到的熒光，χ是抑制劑的濃度，最 大值是C6-腦醯胺不存在時（〇%對照）的熒光，最小值是抑 制劑不存在時（1〇〇%對照）的熒光，是產生熒光的5〇增 加的抑制劑的濃度，並且N是經驗性的「Hill」斜率。；^應 當接近1 °使用商業可獲得的軟件（idbs ActivityBase 乂幻進 行曲線擬合。 GCS測定結果 表1中呈現的ICsq數據是通過實施例9的測試方法產生 的並且被編碼如下：A &lt; 200 nm，B=200-1000 nm，C &gt; 1000 nm。如果本發明的化合物的IC5〇值為$ 4〇〇〇 nM，那 麼匕們被認為是活性的。在這一測定中，具有較小的IC5〇 值’例如10 nM的IC5Q，的化合物，被認為比具有較大的 ICsq值’例如1〇〇〇nM的值，的化合物更有效。 146258.doc 194- 201040149Aldrich, 117 mg, 0.9 mmol), followed by HATU (Applied Biosystems '350 mg '0.9 mmol). The reaction mixture was stirred at room temperature for 18 hours. The resulting solution was concentrated in vacuo and the product was purified by preparative HPLC (EtOAc, EtOAc/EtOAc) 1HNMR (400 MHz, CD3OD): δ 8.55-8.47 (m, 1H), 7.57 (s, 1H), 7.54-7.51 (m, 1H), 7.43-7.41 (m, 1H), 6.33-6.31 (m, 1H) ), 4.42-4.41 (m, 1H), 4.16 (s, 1H), 3.75-3.70 (m, 1H), 3.14-3.01 (m, 2H), 2.22-1.79 (m, 9H), 1.72 (m, 1H) ), 1.53 (m, 1H), 1.23-1.15 (m, 2H), 1.09-1.08 (m, 1H), 1.01 (s, 3H), 0.21-0.15 (m, 2H), 〇.〇7 (m, lH), -0.04 (m, 1H); MS (El) of C24H31C12N302, found 465.17 (MH+) 〇 Example 9. GCS phosphorylation dehydrogenase_xinase coupling enzyme assay for glucose bud ceramide synthesis The enzyme (GCS) activity was measured as the amount of UDP-glucose consumed during the reaction catalyzed by the synthetase using the enzyme UDP-glucose dehydrogenase to produce nadh from udP·glucose and used thereafter. Muscle vapor turnover and NADH formed by dehydrogenase will be low-fluorescence resazurin 疋3: transformation 鬲 fluorescence test function. The synthetase-catalyzed reaction transfers glucose from UDP-glucose to C6_ceramide to produce uDp and glucosylceramide as products; the measurement measures the disappearance of the UDp-glucose substrate. The reaction was carried out on a 384-well black, medium binding microtiter plate (Greiner) by first adding to the plate in i〇〇y. DMSC^〇 〇〇〇 5 mL of the &quot;&quot; preparation of synthetase reaction mixture (25 mM HEPES (pH = 7.4), 146258.doc -192 - 201040149 5 0 mM KC1 and 5 mM MgCl2). Add a volume of ν=0·010 mL to the total concentration of 25 mM HEPES (ρΗ=7.4) = 30 mM 30/0 C-cerebral amine (Avanti Polar Lipids, Inc) and 70 mol % DOPC, Avanti Polar Lipids. C6-ceramide and DOPC were prepared as a 20 mg/mL stock solution dissolved in 95% ethanol and stored at -20 °C. The appropriate volume was transferred to a 40 mL glass vial with a screw-cap septum and dried with a stream of argon. The lipids were resuspended in 1 mL of dH20, frozen and lyophilized overnight. The lipid was hydrated by first adding enough 25 mM HEPES (pH = 7.4) to produce the desired concentration in the 4x plate, vortexed to suspend the lyophilized lipid and allowed to stand for 1 hour or longer. The solution was then frozen, placed in a water bath sonicator and thawed by sonication, and this process was repeated three more times to produce four freeze-thaw sonication cycles. The resulting solution was diluted four times with 25 mM HEPES (ρΗ = 7.4) to produce a solution of the lipid to be added to the plate. The fully active control (100% active) contained only DMSO. The inactive control reaction (0% control) contained only 0.010〇11^ of 10〇111〇1%00?(:(0.31111^) and DMSO. By adding V=〇.〇20 mL to all wells of the plate The reaction was initiated with 25 mM HEPES (ρΗ=7·4), 75 mM KC1 and 7.5 mM MgCl2 with 0.020 mM UDP-glucose, 1.5 mg/mL CHAPS, 0.17 mg/mL GCS. The plate was kept at 26 °C. By adding 0.015 mL of 0.30 mM NAD+, 0.30 mM resazurin, 0.11 mg/mL UDP-glucose dehydrogenase and 0.030 in 25 mM HEPES (ρΗ=7·4), 50 mM KC1 and 5 mM MgCl2. The remaining UDP-glucose was measured by mg/mL diaphorase. The plate was kept at 26 ° C for 30 minutes or longer and measured with Envision 1 flat 146258.doc • 193-201040149 plate reader (Perkin Elmer) with excitation = 530 The increase in fluorescence at nm and emission = 560. In the assay, 1) £) 1) The consumption of glucose is limited to 40-60% of total UDP-glucose. Calculate the ICw value by nonlinear regression analysis using the four-parameter equation [γ = maximum - (maximum - minimum) / (1 + (χ / Κ π),]] where γ is the observed fluorescence and χ is the inhibitor Concentration, the maximum is the fluorescence of C6-ceramide in the absence of (〇% control), the minimum is the fluorescence in the absence of inhibitor (1% control), is the inhibitor of 5〇 increase in fluorescence Concentration, and N is the empirical "Hill" slope. ; ^ should be close to 1 ° using commercially available software (idbs ActivityBase 乂 magic curve fitting. GCS measurement results Table 1 presents ICsq data by example The test method of 9 is produced and encoded as follows: A &lt; 200 nm, B = 200-1000 nm, C &gt; 1000 nm. If the IC5 enthalpy of the compound of the invention is $ 4 〇〇〇 nM, then It is considered to be active. In this assay, a compound with a smaller IC5 〇 value, such as 10 nM of IC5Q, is considered to be a compound with a larger ICsq value, such as a value of 1 〇〇〇 nM. More effective. 146258.doc 194- 201040149

表1 # 結構 名稱 IC50 1 \ 1-(2,4-二氯苯基)-Ν-[2-(4-甲基呱嗪-1-基)-2-氧代-1-(苯基曱基)乙基]環丙醯胺 B 2 1-(2,4-二氯苯基)-N-[(lR)-2-(4-曱基呱 嗪-1-基)-2-氧代-1-{[(苯基甲基)氧]甲 基}-乙基]環丙醯胺 C 3 σΗ 1-(2,4-二氯苯基)-N-[(1S)-1-(1H-吲哚-3-基曱基)-2-(4-甲基°瓜唤_1-基)·2-氧代乙 基]環丙醯胺 A 4 Xr狐, 1-(2,4-二氯苯基)-N-[(lS)-2-(4-甲基呱 嗪-1-基)-2-氧代-1-{[(苯基甲基)氧]甲 基}-乙基]環丙醯胺 A 5 1-(4-氯苯基)-N-[(lS)-l-(lH-吲哚-3-基曱 基)-2-(4•曱基狐唤-1-基)-2-乳代乙基]壤 丙醢胺 A 6 N-[(1S)-1-(1H-吲哚-3-基曱基)-2-(4-甲基 狐嗓-1-基)-2-乳代乙基]-1-[4-(甲乳基)苯 基]環丙醯胺 B 7 1-(2,4-二氯苯基)-N-[( 1 S)-2-(4-甲基呱 °秦-1-基)-1-(奈-2-基曱基)-2-乳代乙基]J辰 丙藏胺 A 146258.doc -195- 201040149Table 1 # Structure name IC50 1 \ 1-(2,4-dichlorophenyl)-indole-[2-(4-methylpyridazin-1-yl)-2-oxo-1-(phenylhydrazine) Ethyl]cyclopropanamide B 2 1-(2,4-dichlorophenyl)-N-[(lR)-2-(4-mercaptopyridin-1-yl)-2-oxo -1-{[(phenylmethyl)oxy]methyl}-ethyl]cyclopropanamide C 3 σΗ 1-(2,4-dichlorophenyl)-N-[(1S)-1-( 1H-indol-3-ylindenyl)-2-(4-methyl-pyrano-_1-yl)-2-oxoethyl]cyclopropanamide A 4 Xr fox, 1-(2,4 -dichlorophenyl)-N-[(lS)-2-(4-methylpyridazin-1-yl)-2-oxo-1-{[(phenylmethyl)oxy]methyl}- Ethyl]cyclopropanamide A 5 1-(4-chlorophenyl)-N-[(lS)-l-(lH-indol-3-ylindenyl)-2-(4•indolyl fox -1-yl)-2-miloethyl]profenamide A 6 N-[(1S)-1-(1H-indol-3-ylindenyl)-2-(4-methylfox -1-yl)-2-miloethyl]-1-[4-(methyllacyl)phenyl]cyclopropanamide B 7 1-(2,4-dichlorophenyl)-N-[( 1 S)-2-(4-methyloxime-heptyl-1-yl)-1-(n-2-ylindenyl)-2-lactylethyl]J-campamine A 146258.doc -195 - 201040149

表1 # 結構 名稱 IC50 8 /Nj -\〇 1-(2,4-二氯苯基)-&gt;^[(111)-2-(4-曱基狐 嗓-l-基)-1-(奈-2-基曱基)-2-氧代乙基]J哀 丙酷胺 C 9 /〇ψάα Cl 1-(2,4-二氯苯基)-N-[(lR)-l-[(2,4-二氯苯 基)甲基]-2-(4-甲基呱嗪-1-基)_2_氧代乙 基]環丙醯胺 B 10 0 u Cl ,0^0LCI Cl 1-(2,4-二氯苯基)-N-[(lS)-l-[(2,4-二氯苯 基)曱基]-2-(4-甲基狐嘻-1-基)-2-氧代乙 基]環丙醯胺 A 11 0 u Cl 1-(2,4-二氯苯基)-：^-[(18)-2-(4-曱基呱 嗓-l-基)-2氧代-1-(苯基曱基)乙基]·ί哀 丙醯胺 A 12 〇 Cl 1-(2,4-二氯苯基)-N-[(lS)-2-(4-甲基呱 唤-1-基)_1-(奈-1-基曱基)-2_氧代乙基]ί哀 丙酸胺 B 13 Cl N-[(lS)-l-[(3-氯苯基)曱基]-2-(4-曱基孤 D秦-1 -基)-2-氧代乙基] 1 -(2,4_二鼠苯基） 環丙醯胺 A 14 ^nXJh^Lci N-[(lS)-l-[(4-氯苯基)曱基]-2-(4-甲基狐 °秦-1-基)-2-乳代乙基]-1 -(2,4-二氣苯基) 環丙醯胺 A 15 0 u v-7 Cl 5nh 1 -(2,4-二氯苯基)-N-[( 1 S)-2-[3-(二曱基 胺基)氮雜環丁烷-1-基吲哚-3-基 甲基)-2-氧代乙基]環丙醯胺 C 146258.doc -196- 201040149Table 1 # Structure name IC50 8 /Nj -\〇1-(2,4-dichlorophenyl)-&gt;^[(111)-2-(4-mercaptofox-l-yl)-1- (na-2-ylindenyl)-2-oxoethyl]J acesulfame C 9 /〇ψάα Cl 1-(2,4-dichlorophenyl)-N-[(lR)-l- [(2,4-Dichlorophenyl)methyl]-2-(4-methylpyridazin-1-yl)_2-oxoethyl]cyclopropanamide B 10 0 u Cl ,0^0LCI Cl 1-(2,4-Dichlorophenyl)-N-[(lS)-l-[(2,4-dichlorophenyl)indolyl]-2-(4-methylfoxin-1-yl) )-2-oxoethyl]cyclopropanamide A 11 0 u Cl 1-(2,4-dichlorophenyl)-:^-[(18)-2-(4-mercaptopurine-l -yl)-2-oxo-1-(phenylindenyl)ethyl]· 哀 醯 醯 A A 12 〇Cl 1-(2,4-dichlorophenyl)-N-[(lS)-2 -(4-methylindol-1-yl)_1-(na-1-ylindenyl)-2_oxoethyl] 哀 丙 丙 B B 13 Cl N-[(lS)-l-[ (3-chlorophenyl)indenyl]-2-(4-indolyl D-methyl-1-yl)-2-oxoethyl] 1-(2,4-di-diphenyl) ciprofloxacin A 14 ^nXJh^Lci N-[(lS)-l-[(4-chlorophenyl)indolyl]-2-(4-methylfox-hom-1-yl)-2-lactoethyl] -1 -(2,4-diphenyl)cyclopropanamide A 15 0 u v-7 Cl 5nh 1 -(2,4-dichlorophenyl)-N-[( 1 S)-2-[ 3-(didecylamino)azetidin-1-吲哚-3-ylmethyl)-2-oxoethyl]cyclopropanamide C 146258.doc -196- 201040149

表1 # 結構 名稱 IC5〇 16 σΗ N-ct- {[ 1 -(2,4-二氣苯基)¾ 丙基]戴基} -N_ [2_(二甲基胺基)乙基]_L·色胺醯胺 A 17 ^0 1 -(2,4_ 二氯苯基)-N-[( 1S)-1 - {[4-(甲氧基) 苯基]曱基}-2-(4-曱基狐°秦-1-基)-2-氧代 乙基]環丙醯胺 A 18 0 u v-7 CI α 1-(2,4-二氣苯基)-N-[(1S)-1-(1H-吲哚-3-基甲基)-2-(4-甲基-1,4-二氮雜環庚烷-1-基)-2-氧代乙基]環丙醯胺 A 19 0 u r-7 Cl 5nh 1-(2,4-二氯苯基)-N-[(1S)-1-(1H-吲哚-3-基甲基)-2-乳代-2-u瓜嗓-1-基乙基]環丙 醯胺 A 20 0 u r—7 Cl 〇〇Yf&amp;cl i NH a 1-(2,4-二氣苯基)-N-[(1S)-1-(1H-吲哚-3-基曱基)-2-嗎琳-4-基-2-氧代乙基]ί辰丙 醯胺 C 21 -^oVf^ci $nh 1-(2,4-二氣苯基)-N-[(lS)-2-{4-[3-(二曱 基胺基)丙基]狐唤-1-基}-1-(111-11弓卜朵-3-基曱基)-2-氧代乙基]環丙醯胺 C 22 0 u π Cl 5nh N-a- {[ 1 -(2,4_二亂苯基)¾丙基]綠基} -N-(1-曱基呱啶冰基)-L-色胺醯胺 A 146258.doc -197- 201040149Table 1 # Structure name IC5〇16 σΗ N-ct- {[ 1 -(2,4-diphenylphenyl) 3⁄4 propyl] Daihide} -N_ [2_(dimethylamino)ethyl]_L· Tryptophan amide A 17 ^0 1 -(2,4-dichlorophenyl)-N-[( 1S)-1 - {[4-(methoxy)phenyl]indolyl}-2-(4-曱基狐°秦-1-yl)-2-oxoethyl]cyclopropanamide A 18 0 u v-7 CI α 1-(2,4-diphenyl)-N-[(1S) 1-(1H-indol-3-ylmethyl)-2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl]cyclopropene Amine A 19 0 u r-7 Cl 5nh 1-(2,4-dichlorophenyl)-N-[(1S)-1-(1H-indol-3-ylmethyl)-2-milo- 2-u 嗓 嗓-1-ylethyl]cyclopropanamide A 20 0 ur—7 Cl 〇〇Yf&amp;cl i NH a 1-(2,4-diphenyl)-N-[(1S) -1-(1H-indol-3-ylindenyl)-2-morphin-4-yl-2-oxoethyl] butyl benzoate C 21 -^oVf^ci $nh 1-(2 ,4-diphenylphenyl)-N-[(lS)-2-{4-[3-(didecylamino)propyl]fox-l-yl}-1-(111-11) -3-ylindenyl)-2-oxoethyl]cyclopropanamide C 22 0 u π Cl 5nh Na- {[ 1 -(2,4_disorderylphenyl) 3⁄4 propyl]green} -N-(1-mercaptoacryllyl)-L-tryptophanamine A 146258.doc -197- 201040149

表1 # 結構 名稱 ic5〇 23 1 -(3，4-二氣苯基)-N-[( 1S)-1 - [(2,4-二氯苯 基)甲基]-2-(4-曱基。瓜唤-1-基)-2-氧代乙 基]環丙醯胺 A 24 1-(2,6-二氣苯基)-N-[(lS)-l-[(2,4-二氯苯 基)曱基]-2-(4-曱基11 瓜嗓-1-基)-2-氧代乙 基]環丙醯胺 B 25 1-(2,4-二氯苯基)-乂[(18)-1-[(2,4_二甲基 苯基)曱基]-2-(4-曱基呱嗪-1-基)-2-氧代 乙基]環丙醯胺 A 26 .〇Vf0Lcl F F 1 -(2,4-二氯苯基)-N- {(1 S)-2-(4-曱基呱 嗪-1 -基)_2_氧代-1 -[(3,4,5 -三氟苯基)曱 基]乙基}環丙醯胺 B 27 ο 1-(2,4-二氯苯基)-：^-[(18)-1-{[4-(乙氧基) 苯基]甲基}-2-(4-甲基呱嗪-1-基)_2_氧代 乙基]環丙醯胺 A 28 5νη Ν-α-{[1-(2,4-二氯苯基)環丙基]羰基}-N-[3-(二曱基胺基)丙基]-L-色胺醯胺 B 29 .oVfdc, ci 2-(2,4-二氯苯基)-N-[( 1S)-1 -[(2,4-二氯苯 基)曱基]-2-(4-甲基呱嗪-1-基)-2-氧代乙 基]-2-甲基丙醢胺 A 201040149Table 1 # Structure name ic5〇23 1 -(3,4-diphenyl)-N-[( 1S)-1 - [(2,4-dichlorophenyl)methyl]-2-(4-曱基.瓜瓜-1-yl)-2-oxoethyl]cyclopropanamide A 24 1-(2,6-diphenyl)-N-[(lS)-l-[(2, 4-dichlorophenyl)indenyl]-2-(4-indolyl 11 guanidin-1-yl)-2-oxoethyl]cyclopropanamide B 25 1-(2,4-dichlorobenzene )[(18)-1-[(2,4-dimethylphenyl)indolyl]-2-(4-indolylpyridazin-1-yl)-2-oxoethyl]cyclo Propylamine A 26 .〇Vf0Lcl FF 1 -(2,4-dichlorophenyl)-N- {(1 S)-2-(4-mercaptopyridin-1-yl)_2-oxo-1 -[(3,4,5-trifluorophenyl)indolyl]ethyl}cyclopropanamide B 27 ο 1-(2,4-dichlorophenyl)-:^-[(18)-1- {[4-(ethoxy)phenyl]methyl}-2-(4-methylpyrazin-1-yl)_2-oxoethyl]cyclopropanamide A 28 5νη Ν-α-{[ 1-(2,4-Dichlorophenyl)cyclopropyl]carbonyl}-N-[3-(didecylamino)propyl]-L-tryptamine amide B 29 .oVfdc, ci 2-( 2,4-Dichlorophenyl)-N-[(1S)-1 -[(2,4-dichlorophenyl)indolyl]-2-(4-methylpyridazin-1-yl)-2 -oxoethyl]-2-methylpropanamide A 201040149

表1 # 結構 名稱 IC5〇 30 .〇n1^6lci F l-(2,4-二氯苯基)-N-[(lS)-l-[(4-氟苯基) 甲基]-2-(4-甲基呱嗪-卜基)-2-氧代乙基] 環丙醯胺 A 31 .〇Yfdcl F 1 _(2,4·二氯苯基)-N-[( 1 S)-l - [(3,4-二氟苯 基)曱基]-2-(4-曱基σ瓜σ秦-1-基)-2-氧代乙 基]環丙醯胺 A 32 F F 1-(2,4-二氯苯基)-N-[(lS)-2-(4-甲基呱 嗪-1-基)-2-氧代-1-{[4-(三氟甲基)苯基] 甲基}乙基]環丙醯胺 A 33 .oVf6cl Cl 1-(2,4-二氯苯基)-N-[( 1S)-1-[(3,4-二氣苯 基)曱基]-2·(4-曱基11瓜嗓-1-基)-2-氧代乙 基]環丙醯胺 A 34 Br N-[(l S)-l-[(4-漠苯基)甲基]-2-(4-甲基略 17秦小基)_2-氧代乙基]-1·(2,4-二氯苯基） 環丙醯胺 A 35 .〇^6cl 1-(2,4-二氯苯基)-N-[(lS)-l-[(4-曱基苯 基)甲基]-2-(4-甲基狐11 秦·1·基)-2·乳代乙 基]環丙醯胺 A 36 /〇Νΐ^άα OH 1-(2,4_ 二氯苯基)-N-[(lS)-l-[(4-羥基苯 基)甲基]-2-(4-曱基呱嗪-1-基)-2-氧代乙 基]環丙醯胺 B 146258.doc -199- 201040149Table 1 # Structure name IC5〇30 .〇n1^6lci F l-(2,4-Dichlorophenyl)-N-[(lS)-l-[(4-fluorophenyl)methyl]-2- (4-methylpyridazine-buyl)-2-oxoethyl]cyclopropanamide A 31 .〇Yfdcl F 1 _(2,4·dichlorophenyl)-N-[( 1 S)- l - [(3,4-Difluorophenyl)indolyl]-2-(4-indolyl sulcata σ -9-yl)-2-oxoethyl]cyclopropanamide A 32 FF 1- (2,4-dichlorophenyl)-N-[(lS)-2-(4-methylpyridazin-1-yl)-2-oxo-1-{[4-(trifluoromethyl) Phenyl]methyl}ethyl]cyclopropanamide A 33 .oVf6cl Cl 1-(2,4-dichlorophenyl)-N-[( 1S)-1-[(3,4-diphenyl) )]]]]-(4-indolyl 11-guanidin-1-yl)-2-oxoethyl]cyclopropanamide A 34 Br N-[(l S)-l-[(4- Phenyl)methyl]-2-(4-methyl-l-17-methyl)-(2-oxoethyl)-1·(2,4-dichlorophenyl)cyclopropanamide A 35 .〇^6cl 1- (2,4-dichlorophenyl)-N-[(lS)-l-[(4-mercaptophenyl)methyl]-2-(4-methylfox 11 秦·1·yl)-2 ·Milk-ethyl]cyclopropanamide A 36 /〇Νΐ^άα OH 1-(2,4-dichlorophenyl)-N-[(lS)-l-[(4-hydroxyphenyl)methyl] -2-(4-mercaptopyridin-1-yl)-2-oxoethyl]cyclopropanamide B 146258.doc -199- 201040149

表1 # 結構 名稱 IC5〇 37 .oV/aCF3 Cl N-[(lS)-l-[(2,4·二氯苯基)曱基]-2_(4_ 甲 基0瓜嘻-1-基)-2-氧代乙基]-l-[3-(二氣曱 基)苯基]環丙醯胺 B 38 功 VUF3 Cl N-[(lS)-l-[(2,4-二氣苯基)曱基]-2-(4-曱 基呱嗪-1-基)-2-氧代乙基]-1-[4-(三氟曱 基)苯基]環丙醯胺 A 39 Cl 1-(2-氯苯基)-N-[(lS)-l-[(2,4-二氣苯基) 甲基]-2-(4-曱基呱嗪-1-基)-2-氧代乙基] 環丙醯胺 B 40 Cl N-[(lS)-l-[(2,4-二氯苯基)曱基]-2-(4-甲 基口瓜唤-1·基)-2_氧代乙基]-1-(4_氟苯基) 環丙醯胺 C 41 Cl N-[( 1S)-1 -[(2,4-二氯苯基)曱基]_2-(4_ 曱 基呱嗪-1 -基)-2-氧代乙基]-1 -(2,4-二氟 苯基)環丙醯胺 C 42 部F Cl N-[( 1S)-1 -[(2,4-二氣苯基)曱基]_2_(4-曱 基°瓜嘻-1-基)-2-氧代乙基]-1-[2-(二氣曱 基)苯基]環丙醯胺 C 43 cJOc, 2,4-二氯-Ν-α- {[ 1 -(2,4-二氯苯基)環丙基] 夢炭基}-N-[2-(二乙基胺基)乙基]-L-苯丙 胺醯胺 B 44 c,XX, 2,4-二氣-Ν-α-{[1-(2,4-二氣苯基)¾丙基 _ 羰基}-Ν-[2-(二曱基胺基)乙基]-Ν-曱基-L-苯丙胺醯胺 A 146258.doc -200- 201040149Table 1 # Structure name IC5〇37 .oV/aCF3 Cl N-[(lS)-l-[(2,4·dichlorophenyl)indolyl]-2_(4_methyl 0 嘻 嘻-1-yl) -2-oxoethyl]-l-[3-(dioxamethyl)phenyl]cyclopropanamide B 38 work VUF3 Cl N-[(lS)-l-[(2,4-dibenzene) Alkyl]-2-(4-mercaptopyridin-1-yl)-2-oxoethyl]-1-[4-(trifluoromethyl)phenyl]cyclopropanamide A 39 Cl 1-(2-Chlorophenyl)-N-[(lS)-l-[(2,4-diphenyl)methyl]-2-(4-indolylpyridazin-1-yl)-2 -oxoethyl]cyclopropanamide B 40 Cl N-[(lS)-l-[(2,4-dichlorophenyl)indolyl]-2-(4-methyl guacamole-1 -2_oxoethyl]-1-(4-fluorophenyl)cyclopropanamide C 41 Cl N-[( 1S)-1 -[(2,4-dichlorophenyl)indolyl] _2-(4_Indolylpyridin-1-yl)-2-oxoethyl]-1 -(2,4-difluorophenyl)cyclopropanamide C 42 Part F Cl N-[( 1S)- 1-[(2,4-diphenylphenyl)indolyl]_2_(4-indolyl guar-1-yl)-2-oxoethyl]-1-[2-(dioxyl) Phenyl]cyclopropanamide C 43 cJOc, 2,4-dichloro-indole-α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl] 梦炭基}-N-[2- (Diethylamino)ethyl]-L-phenylpropylamine decylamine B 44 c, XX, 2,4-digas-Ν-α-{[1-(2,4-diphenyl) 3⁄4 propyl _ carbonyl} -Ν-[2-(Didecylamino)ethyl]-fluorenyl-mercapto-L-phenylalanamine decylamine A 146258.doc -200- 201040149

表1 # 結構 名稱 IC50 45 Λ 2,4-二氯_Ν-α- {[ 1 -(2,4_二氯苯基)環丙基] 羰基}-Ν-[2-(1-甲基吼咯啶-2-基)乙基]-L-苯丙胺醯胺 B 46 Λ 2,4-二氯-Ν-α- {[ 1 -(2,4-二氯苯基)環丙基] 罗炭基}-N-(2-atb^^-l-基乙基)-L-苯丙胺 醯胺 A 47 CI^^^CI 2,冬二氣-Ν-α-{[1-(2,4-二氯苯基)環丙基] 羰基丨-N-曱基-N-(l-曱基呱啶-4-基)-L- 苯丙胺醯胺 A 48 CI^^CI Cl 2,4-二鼠-Ν-α- {[ 1 -(2,4-二氣苯基)¾ 丙基] 羰基}-Ν-[1-(苯基甲基)呱啶-4-基]-L-苯 丙胺醯胺 A 49 〇方通 ClCl 2,4-二氣-Ν-α- {[ 1 -(2,4-二氯苯基)環丙基] 癸炭基} &quot;N~(2-p瓜°定-1 -基乙基)_L-苯丙胺龜 胺 B 50 CIA^^CI 2,4-二氣-N-a-{ [1-(2,4-二氣苯基)¾ 丙基] 羰基}-N_[2-(二甲基胺基)乙基]-L-苯丙 胺醯胺 A 51 CI-^s^CI 2,4-二氯-Ν-α- {[ 1 -(2,4-二氯苯基)環丙基] 魏基}·Ν-[3·(二曱基胺基)丙基]-L-苯丙 胺醯胺 B 52 y甩 2,4-二氯-Ν-α-{[1-(2,4-二氯苯基)環丙基] 徵基}·Ν-[2-(二曱基胺基)-1-曱基乙基]-L-苯丙胺醯胺 A 53 CI-^^CI 2,4-二氯-Ν-α-{[1-(2,4-二氯苯基)環丙基] 歹炭基} -Ν-( 1 -乙基狐。定-3 -基)-L-苯丙胺酿 胺 B 146258.doc -201 201040149Table 1 # Structure name IC50 45 Λ 2,4-Dichloro-Ν-α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl}-Ν-[2-(1-methyl吼rrolidine-2-yl)ethyl]-L-phenylalanamine amide B 46 Λ 2,4-dichloro-indole-α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl] Carbonyl}-N-(2-atb^^-l-ylethyl)-L-phenylpropylamine decylamine A 47 CI^^^CI 2, winter two gas-Ν-α-{[1-(2,4 -dichlorophenyl)cyclopropyl]carbonylindole-N-indenyl-N-(l-decylacridin-4-yl)-L-phenylalanamine decylamine A 48 CI^^CI Cl 2,4-II Murine-Ν-α- {[ 1 -(2,4-diphenyl)-3⁄4 propyl]carbonyl}-Ν-[1-(phenylmethyl)acridin-4-yl]-L-phenylalanine Amine A 49 〇方通 ClCl 2,4-digas-Ν-α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl] fluorene base} &quot;N~(2-p 瓜° D--1 -ylethyl)_L-phenylalanamine tocamine B 50 CIA^^CI 2,4-digas-Na-{ [1-(2,4-diphenylphenyl) 3⁄4 propyl]carbonyl}-N_ [2-(Dimethylamino)ethyl]-L-phenylpropylamine decylamine A 51 CI-^s^CI 2,4-Dichloro-indole-α- {[ 1 -(2,4-dichlorobenzene) Cyclo)propyl]]]]]-[3·(didecylamino)propyl]-L-phenylalanamine amide B 52 y甩2,4-dichloro-indole-α-{[1- (2,4-dichlorophenyl)cyclopropyl] levy}·Ν-[2-(dimercapto) ))-1-mercaptoethyl]-L-phenylpropylamine decylamine A 53 CI-^^CI 2,4-dichloro-indole-α-{[1-(2,4-dichlorophenyl)cyclopropane ] 歹 基 ( ( ( ( ( ( ( ( ( ( ( ( 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146

表1 # 結構 名稱 IC5〇 54 0 N-[(lS)-l-[(4-乙醯苯基)曱基]-2-(4-曱基 口瓜嗓-1 -基)-2-氧代乙基]-1 -(2,4-二氣苯 基)環丙醯胺 A 55 CI^^CI 2,4_ 二氣-Ν-α- {[ 1 -(2,4·二氯苯基)環丙基] 羊炭基}-Ν-[1-(苯基曱基)σ比洛°定-3-基]-L-苯丙胺醯胺 B 56 1-(2,4-二氯苯基)-Ν-[( 1 S)-2-(4-曱基呱 嗓-1-基)-2-氧代-1-{[1-(苯基甲基)-111-11 米 唑-5-基]曱基}乙基]環丙醯胺 C 57 2,4-二氯-Ν-α- {[ 1 -(2,4-二氯苯基)環丙基] 羰基}-Ν-曱基-N-(l-曱基。比咯啶-3-基)-L-苯丙胺醯胺 A 58 1 -(2,4-二氣苯基)-Ν-[( 1S)-1 - [(2-甲基苯 基)甲基]-2-(4-甲基狐°秦-1-基)-2-乳代乙 基]環丙醯胺 A 59 /〇f 1-(2,4-二氯苯基)-N-[(lS)-l-[(3-曱基苯 基)曱基]-2-(4-甲基ϋ瓜嗓-1·基)-2-乳代乙 基]環丙醯胺 B 60 F 1 -(2,4-二氯苯基)-Ν-[( 1S)-1 -[(3-氟苯基) 曱基]-2-(4-甲基呱嗪-1-基)-2-氧代乙基] 環丙醯胺 B 61 譬 1-(2,4-二氯苯基)-N-[(lS)-l-[(2-氟苯基) 甲基]-2-(4-曱基呱嗪-1-基)-2-氧代乙基] 環丙醯胺 A 146258.doc -202- 201040149Table 1 # Structure name IC5〇54 0 N-[(lS)-l-[(4-Ethylphenyl)indenyl]-2-(4-indolyl guanyl-1 -yl)-2-oxo Ethylethyl]-1 -(2,4-diphenyl)cyclopropanamide A 55 CI^^CI 2,4_ 二气-Ν-α- {[ 1 -(2,4·dichlorophenyl) Cyclopropyl] 羊炭基}-Ν-[1-(phenylindenyl) σpirol 定-3-yl]-L-phenylalanamine decylamine B 56 1-(2,4-dichlorophenyl) )-Ν-[( 1 S)-2-(4-indolyl-1-yl)-2-oxo-1-{[1-(phenylmethyl)-111-11-mazole-5 -yl]decyl}ethyl]cyclopropanamide C 57 2,4-dichloro-indole-α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl}-Ν-曱--N-(l-fluorenyl.pyrrolidin-3-yl)-L-phenylalanamine decylamine A 58 1 -(2,4-diphenyl)-indole-[( 1S)-1 - [( 2-methylphenyl)methyl]-2-(4-methylfox-hom-1-yl)-2-lactoethyl]cyclopropanamide A 59 /〇f 1-(2,4- Dichlorophenyl)-N-[(lS)-l-[(3-indolylphenyl)indolyl]-2-(4-methylindole-l-yl)-2-miloethyl Cyclopropanamide B 60 F 1 -(2,4-dichlorophenyl)-indole-[( 1S)-1 -[(3-fluorophenyl)indolyl]-2-(4-methylindole Pyrazin-1-yl)-2-oxoethyl]cyclopropanamide B 61 譬1-(2,4-dichlorophenyl)-N-[(lS)-l-[(2-fluorophenyl) ) methyl]-2-(4- Yl piperazine-1-yl) -2-oxoethyl] cyclopropylamino Amides A 146258.doc -202- 201040149

表1 # 結構 名稱 IC5〇 62 N-[(lS)-l-[(4-氰基苯基)曱基]-2-(4-曱基 °瓜°秦 1 -基)-2-乳代乙基]· 1 -(2,4-二氣苯 基)環丙醯胺 C 63 CI^^Cl 1-(2,4_ 二氣苯基)-N-{(lS)-l-[(2,4-二氣 苯基)甲基]-2-[4-(l -甲基乙基)狐唤-1-基]·2_氧代乙基}環丙醯胺 B 64 - 4 1-(2,4-二氣苯基)-Ν-{(1S)-1-[(2,4-二氯 苯基)曱基]_2-[(31〇-3-(二曱基胺基)吼咯 啶-1-基]-2-氧代乙基}環丙醯胺 A 65 -N CI^V^CI 1-(2,4-二氯苯基)-&gt;^-{(18)-1-[(2,4-二氯 苯基)甲基]-2_[(3S)_3-(二甲基胺基比咯 啶-1-基]-2-氧代乙基}環丙醯胺 A 66 Cl-^^CI 2,4-二氯-Ν-α- {[ 1 -(2,4-二氯苯基)環丙基] 美炭基}-Ν-(1-曱基狐°定-4-基)-L-苯丙胺酿 胺 A 67 1-(2,4-二氯苯基)-N-[(lS)-2-(4-甲基呱 °秦-1-基)-2-氧代-1-{[3-(二氟曱基)苯基] 甲基}乙基]環丙醯胺 B 68 F 1-(2,4-二氯苯基)-N-[(lS)-2-(4-甲基呱 °秦-1-基)_2·氧代-1-{[2_(三氟曱基)苯基] 甲基}己基]環丙醯胺 B 146258.doc -203 - 201040149Table 1 # Structure name IC5〇62 N-[(lS)-l-[(4-cyanophenyl)indolyl]-2-(4-indolyl ° melon ° Qin 1 -yl)-2-milk Ethyl]·1 -(2,4-diphenyl)cyclopropanamide C 63 CI^^Cl 1-(2,4_diphenyl)-N-{(lS)-l-[(2 ,4-diphenylphenyl)methyl]-2-[4-(l-methylethyl)foxen-1-yl]·2_oxoethyl}cyclopropanamide B 64 - 4 1- (2,4-diphenyl)-Ν-{(1S)-1-[(2,4-dichlorophenyl)indolyl]_2-[(31〇-3-(didecylamino))吼rrolidine-1-yl]-2-oxoethyl}cyclopropanamide A 65 -N CI^V^CI 1-(2,4-dichlorophenyl)-&gt;^-{(18) 1-[(2,4-dichlorophenyl)methyl]-2_[(3S)_3-(dimethylaminopyrrolidin-1-yl)-2-oxoethyl}cyclopropene Amine A 66 Cl-^^CI 2,4-Dichloro-indole-α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl]cobalt}-Ν-(1-mercapto fox定-4-yl)-L-amphetamine A 67 1-(2,4-dichlorophenyl)-N-[(lS)-2-(4-methyl呱° Qin-1-yl) -2-oxo-1-{[3-(difluoroindolyl)phenyl]methyl}ethyl]cyclopropanamide B 68 F 1-(2,4-dichlorophenyl)-N-[ (lS)-2-(4-methyloxime-methyl-1-yl)_2.oxo-1-{[2_(trifluoromethyl)phenyl]methyl}hexyl]cyclopropanamide B 146258. Doc -203 - 201040149

表1 # 結構 名稱 IC5〇 69 X警 Ν-[( 1 S)-l-[(2-氣苯基)曱基]-2-(4-甲基狐 嗓-1 -基)-2-乳代乙基]-1 -(2,4-二氣苯基） 環丙醯胺 A 70 1-(2,4-二氯苯基)-N-[( 1 S)-2-(4-曱基呱 °秦-1-基)-2-乳代-1_(°比°定-2_基曱基)乙基] 環丙醯胺 B 71 Cl 3,4-二氣-&gt;1-〇1-{[1-(2,4-二氯苯基)環丙基] 羰基}-N-[2-(二甲基胺基)乙基]-L-苯丙 胺醯胺 A 72 N-[(lS)-l-(環己基甲基)-2-(4-甲基呱嗪-1-基)-2-氧代乙基]-1-(2,4-二氣苯基)5哀 丙龜胺 C 73 Ν-α-{[1-(2,4-二氯苯基)環丙基]羰基}-N-[2-(二甲基胺基)乙基]斗(三氟甲基)-L-苯丙胺醯胺 A 74 4-漠-Ν-α-{[1-(2,4-二氯苯基)環丙基]羰 基}-Ν-[2-(二曱基胺基)乙基]-L-苯丙胺 醯胺 A 75 〇,χχ, 2,4-二氣-Ν-α- {[ 1 -(2,4-二氣苯基)環丙基] 羰基}-Ν-Ρ-(二甲基胺基)丙基]-Ν-曱基-L-苯丙胺醯胺 A 76 cJOc, 2,4-二氣-乂〇1-{[1-(2,4-二氯苯基)環丙基] 羰基}-Ν-[3-(二甲基胺基)-2,2-二甲基丙 基]-L-苯丙胺醯胺 B 77 cir々仇 〇,χχ, 2,4-二氯-：^-〇1-{[1-(2,4-二氯苯基)環丙基: 羰基}-Ν-[(1-曱基狐啶-2-基)曱基]-L-苯 丙胺酸胺 A 146258.doc •204- 201040149Table 1 # Structure name IC5〇69 X vigilant-[( 1 S)-l-[(2-phenylphenyl)indolyl]-2-(4-methylfox 嗓-1 -yl)-2-milk Ethylethyl]-1 -(2,4-diphenyl)cyclopropanamide A 70 1-(2,4-dichlorophenyl)-N-[( 1 S)-2-(4-曱呱 秦 秦 -1- -1- -1- -2- -2- -1- -1- -1- -1- -1- -1- -1- -2- -2- -2- -2- -2- 乳 乳 乳 乳 乳 乳 乳 乳 乳 乳 乳 乳 乳 乳 71 71 71 71 71 71 71 71 71 71 1-{[1-(2,4-Dichlorophenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)ethyl]-L-phenylalanamine decylamine A 72 N-[( lS)-l-(cyclohexylmethyl)-2-(4-methylpyridazin-1-yl)-2-oxoethyl]-1-(2,4-diphenyl)5 丙Tortoise C 73 Ν-α-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)ethyl] bucket (trifluoromethyl) )-L-Amphetamine amide A 74 4- Desert-Ν-α-{[1-(2,4-Dichlorophenyl)cyclopropyl]carbonyl}-indole-[2-(didecylamino) Ethyl]-L-phenylpropylamine decylamine A 75 〇, χχ, 2,4-digas-Ν-α- {[ 1 -(2,4-diphenyl)cyclopropyl]carbonyl}-Ν-Ρ -(dimethylamino)propyl]-fluorenyl-fluorenyl-L-phenylalanamine decylamine A 76 cJOc, 2,4-digas-乂〇1-{[1-(2,4-dichlorophenyl) Cyclopropyl]carbonyl}-indole-[3-(dimethylamino)-2,2-dimethylpropyl]-L-amphetamine Indoleamine B 77 cir々, χχ, 2,4-dichloro-:^-〇1-{[1-(2,4-dichlorophenyl)cyclopropyl: carbonyl}-Ν-[(1 -mercaptofoxidin-2-yl)indolyl]-L-phenylalanine A 146258.doc •204- 201040149

表1 # 結構 名稱 IC50 78 〇Ντ^//όια Λ 2,4-二氣-Ν-α- {[ 1 -(2,4-二氯苯基)環丙基] 夢炭基}_^~(2-°比洛0定-1-基丙基)-L-苯丙胺 醯胺 B 79 N-[(lS)-l-({[(4-氯苯基)曱基]氧}曱基)-2-(4·甲基孤。秦-1-基)-2-氧代乙基]-1-(2,4-二氯苯基)環丙醯胺 A 80 V 1 -(2,4-二氣苯基)-N-[( 1S)-1 -({[(1 -曱基環 丙基)甲基]氧}甲基)-2-(4-甲基呱嗪-1 -基)-2-氧代乙基]環丙醯胺 C 81 成务, α!α N-[(lS)-l-({[(2-氯苯基)曱基]氧}甲基)-2-(4-甲基σ瓜嘻-1-基)-2-乳代乙基]-1-(3,5·二氯苯基)環丙醯胺 A 82 c· 1-(3,5-二氯苯基)-N-[(lS)-l-({[(4-氟苯 基)甲基]氧}曱基)-2-(4-曱基°瓜17秦-1-基)-2-氧代乙基]環丙醯胺 A 83 〇；/ 1-(3,5-二氯苯基)-N-[(lS)-l-[({[2-(甲氧 基)苯基]曱基}氧)甲基]_2-(4_曱基呱嗪-1-基)-2-氧代乙基]環丙醯胺 B 84 Cl N-[(lS)-l-({[(3-氣苯基)曱基]氧}甲基)-2-(4-曱基孤嗓-1-基)-2_乳代乙基]-1-(2,4-二氯苯基)環丙醯胺 A 85 rC^rfccl H。〉 /=^. Cl 1-(2,4-二氯苯基)-N-{(lS)-l-[(3,5-二氯 苯基)甲基]-2-[4-(2-經乙基)p瓜σ秦-1-基]- 2-氧代乙基}環丙醯胺 B 146258.doc -205 - 201040149Table 1 # Structure name IC50 78 〇Ντ^//όια Λ 2,4-digas-Ν-α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl] Meng carbon base}_^~ (2-°Bilo 0--1-ylpropyl)-L-phenylpropylamine decylamine B 79 N-[(lS)-l-({[(4-chlorophenyl)indolyl]oxy} fluorenyl) -2-(4.methyliso.qin-1-yl)-2-oxoethyl]-1-(2,4-dichlorophenyl)cyclopropanamide A 80 V 1 -(2,4 -diphenylphenyl)-N-[( 1S)-1 -({[(1 - fluorenylcyclopropyl)methyl)oxy)methyl)-2-(4-methylpyridazin-1-yl) )-2-oxoethyl]cyclopropanamide C 81, α!α N-[(lS)-l-({[(2-chlorophenyl)indolyl]oxy}methyl)-2 -(4-methyl σ 嘻 嘻-1-yl)-2-miloethyl]-1-(3,5·dichlorophenyl)cyclopropanamide A 82 c· 1-(3,5- Dichlorophenyl)-N-[(lS)-l-({[(4-fluorophenyl)methyl)oxy)indolyl)-2-(4-indolyl~ melon 17-methyl-1-yl) -2-oxoethyl]cyclopropanamide A 83 〇; / 1-(3,5-dichlorophenyl)-N-[(lS)-l-[({[2-(methoxy)) Phenyl]fluorenyl}oxy)methyl]_2-(4-mercaptopyridin-1-yl)-2-oxoethyl]cyclopropanamide B 84 Cl N-[(lS)-l-( {[(3-Phenylphenyl)indolyl]oxy}methyl)-2-(4-decylisoin-1-yl)-2_miloethyl]-1-(2,4-dichloro Phenyl) Cyclopropylamine A 85 rC^rfccl H. 〉 /=^. Cl 1-(2,4-Dichlorophenyl)-N-{(lS)-l-[(3,5-dichlorophenyl)methyl]-2-[4-(2 -ethyl)p-guanidinium-1-yl]- 2-oxoethyl}cyclopropanamide B 146258.doc -205 - 201040149

表1 # 結構 名稱 IC5〇 86 γ0^γΗν&amp;〇, Cl 1-(2,4-二氯苯基)-：^-{(13)-1-[(3,5-二氯 苯基)曱基]-2-[4-(2-氣乙基)°瓜嗓-1-基]-2-氧代乙基}環丙醯胺 C 87 Cl 1-(2,4-二氣苯基)-N-[(lS)-l-[(3,5-二氯苯 基)甲基]-2-(4-乙基狐嘻-1-基)-2-乳代乙 基]環丙醯胺 A 88 ^NXJ^0-CI 3a〇, 1-(2,4-二氯苯基)-N-{(lS)-l-[(2,4-二氯 苯基)曱基]-2-氧代-2-呱嗪-1-基乙基}環 丙醯胺 A 89 1:叙 Cl 2,4-二氣-Ν-α- {[ 1 -(2,4-二氯苯基)環丙基] 羰基}-Ν-曱基-Ν-[2-(曱基胺基)乙基]-L-苯丙胺醯胺 A 90 Br 4-演-Ν-α-{[1-(2,4-二氯苯基)環丙基]羰 *}-Ν-[2-(二曱基胺基)乙基]-Ν-甲基-L- 苯丙胺醯胺 A 91 | 0 u V&quot;7 91 Ν-α- {[ 1 -(2,4-二氯苯基)環丙基]羰基} -Ν-[2-(二甲基胺基)乙基]-Ν-甲基冰(三氟甲 基)-L-苯丙胺酿胺 A 92 Cl-^CI 2,4·二鼠-Ν-α-{[1-(2,4-二氣苯基)¾ 丙基 羰基}-Ν-曱基-N-[(3R)-1-曱基吡咯啶-3-基]-L-苯丙胺驢胺 A 93 ▽ Cl 'V Ν2-{[1-(2,4-二氣苯基)環丙基]羰基}-N-[2-(二甲基胺基)乙基]-N-甲基-L-白胺酿 胺 C 146258.doc -206- 201040149Table 1 # Structure name IC5〇86 γ0^γΗν&amp;〇, Cl 1-(2,4-dichlorophenyl)-:^-{(13)-1-[(3,5-dichlorophenyl)fluorene ][4-(2-ethylethyl)°Guar-1-yl]-2-oxoethyl}cyclopropanamide C 87 Cl 1-(2,4-diphenyl) -N-[(lS)-l-[(3,5-dichlorophenyl)methyl]-2-(4-ethylfoxin-1-yl)-2-miloethyl]cyclopropene Amine A 88 ^NXJ^0-CI 3a〇, 1-(2,4-dichlorophenyl)-N-{(lS)-l-[(2,4-dichlorophenyl)indolyl]-2 -oxo-2-pyridazin-1-ylethyl}cyclopropanamide A 89 1: Cl 2,4-digas-Ν-α- {[ 1 -(2,4-dichlorophenyl) Cyclopropyl]carbonyl}-indole-indolyl-indole-[2-(decylamino)ethyl]-L-phenylalanamine decylamine A 90 Br 4-deacting-Ν-α-{[1-(2, 4-Dichlorophenyl)cyclopropyl]carbonyl*}-indole-[2-(didecylamino)ethyl]-indole-methyl-L-phenylalanamine decylamine A 91 | 0 u V&quot;7 91 Ν-α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl} -indole-[2-(dimethylamino)ethyl]-indole-methyl ice (trifluoromethyl) ))-L-amphetamine sulphamine A 92 Cl-^CI 2,4·di- 鼠-Ν-α-{[1-(2,4-diphenyl)3⁄4 propylcarbonyl}- fluorenyl-fluorenyl- N-[(3R)-1-indolylpyrrolidin-3-yl]-L-phenylpropylamine decylamine A 93 ▽ Cl 'V Ν2-{[1-(2,4-two gas Yl) cyclopropyl] carbonyl} -N- [2- (dimethylamino) ethyl] -N- methyl-amine -L- white wine amine C 146258.doc -206- 201040149

表1 # 結構 名稱 IC5〇 94 2,4-二氯-Ν-α- {[ 1 -(2,4-二氯苯基)環丙基] 羰基}-N-甲基-N-[l-(苯基甲基)呱啶-4-基]-L-苯丙胺醯胺 A 95 Crr\ F F Ν-α- {[ 1 -(2,4-二氯苯基)環丙基]羰基} -N-甲基-N-[l-(苯基甲基)呱啶-4-基]-4-(三 氟甲基)-L-苯丙胺醯胺 B 96 O u ^-7 Cl 梦敬 1-(2,4-二氯苯基)-N-[(lS)-2-[3-(二甲基 胺基)氮雜環丁烷小基]-2-氧代-l-{[4-(三氟曱基)苯基]甲基}乙基]環丙醯胺 C 97 Cl 1-(2,4-二氯苯基)以-{(18)-1-[(2,4-二氯 苯基)甲基]-2-[(8aR)-六氫吼咯並[l，2-a] °比嗪-2(1均-基]-2-氧代乙基}環丙醯胺 A 98 CI^^CI N-1-氮雜雙環[2.2.2]辛-3-基-2,4-二氯-N-α-{[1-(2,4-二氯苯基)環丙基]羰基}-L-苯 丙胺醯胺 A 99 CF厂 Ν-α-{[1-(2,4_二氯苯基)環丙基]羰基}-N-[2-(二甲基胺基)乙基]-N-乙基_4_(三氟曱 基)-L-苯丙胺醯胺 B 100 cf3厂 Ν-α-{[1-(2,4_ 二氣苯基)¾ 丙基]幾基]•-Ν-甲基-N-[(3R)-1-甲基。比咯啶-3-基]-4-(三 氟甲基)-L-苯丙胺醯胺 B 101 〇^f0lcl CF厂 Ν-α-{[1-(2,4·-二氣苯基)¾ 丙基]幾基}·_Ν_ (2-。比咯啶-1-基乙基)-4-(三氟甲基)-L-苯 丙胺醯胺 C 146258.doc •207· 201040149Table 1 #Structure name IC5〇94 2,4-Dichloro-indole-α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-methyl-N-[l- (phenylmethyl) acridin-4-yl]-L-phenylpropylamine decylamine A 95 Crr\ FF Ν-α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl} -N -Methyl-N-[l-(phenylmethyl)acridin-4-yl]-4-(trifluoromethyl)-L-phenylalanamine decylamine B 96 O u ^-7 Cl Meng Jing 1-( 2,4-Dichlorophenyl)-N-[(lS)-2-[3-(dimethylamino)azetidinyl]-2-oxo-l-{[4-( Trifluoromethyl)phenyl]methyl}ethyl]cyclopropanamide C 97 Cl 1-(2,4-dichlorophenyl)-{(18)-1-[(2,4-dichloro) Phenyl)methyl]-2-[(8aR)-hexahydroindolo[l,2-a] °pyrazine-2(1-h-yl)-2-oxoethyl}cyclopropanamide A 98 CI^^CI N-1-azabicyclo[2.2.2]oct-3-yl-2,4-dichloro-N-α-{[1-(2,4-dichlorophenyl)cyclopropane ]]carbonyl}-L-amphetamine amide A 99 CF plant Ν-α-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino) Ethyl]-N-ethyl_4_(trifluoromethyl)-L-phenylalanamine decylamine B 100 cf3 plant Ν-α-{[1-(2,4_diphenyl)3⁄4 propyl] ]•-Ν-Methyl-N-[(3R)-1-methyl.Byrrolidin-3-yl]-4-(trifluoromethyl)-L-benzene Amine oxime B 101 〇^f0lcl CF plant Ν-α-{[1-(2,4·-diphenyl)3⁄4 propyl]yl}}_Ν_ (2-.pyrrolidin-1-yl Base)-4-(trifluoromethyl)-L-phenylalanamine decylamine C 146258.doc •207· 201040149

表1 # 結構 名稱 IC5〇 102 CF厂 Ν-α-{[1-(2,4-二氣苯基)環丙基]羰基}-N-(吡咯啶-2-基甲基)-4-(三氟曱基)-L-苯丙 胺醯胺 A 103 Cl 2-(2,4-二氣苯基)-N-[( 1S)-1 -[(2,4-二氯苯 基)曱基]-2-(4-曱基。瓜嗓·!-基)-2-氧代乙 基]丙醯胺 C 104 多疏 N-[(lS)-2-(3-胺基氮雜環丁烷-1-基)_2_ 氧代-1-{[4-(三氟甲基)苯基]甲基}乙基]-1-(2,4-二氯苯基)環丙醯胺 B 105 °Cf N2- {[ 1 -(2,4-二氣苯基)環丙基]羰基} -3-(2,3-二氫-1,4-苯並二噁烷-6-基)-N-P-(二甲基胺基)乙基]-N-曱基-L-丙胺醯胺 A 106 Br 4-溴-Ν-α-{[1-(2,4-二氯苯基)環丙基]羰 基} -Ν-( 1 -甲基呱啶-3 -基)-L-苯丙胺醯胺 A 107 Br-^^ Ν-1-氮雜雙環Ρ.2.2]辛-3-基-4-溴-Ν-α-{[ 1 -(2,4-二氯苯基)環丙基]羰基} -L-苯丙 胺醯胺 A 108 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-2,4-二氣-N-cx- {[ 1 -(2,4-二氣苯基)環丙基]羰 基}丄-苯丙胺醯胺 A 109 Br人^ N-[(3S)-1-氮雜雙環[2.2·2]辛 _3_ 基]_4_ 漠-Ν-α-{[1-(2,4-二氯苯基)環丙基]羰基}-L-苯丙胺醯胺 A 201040149Table 1 # Structure name IC5〇102 CF plant Ν-α-{[1-(2,4-diphenyl)cyclopropyl]carbonyl}-N-(pyrrolidin-2-ylmethyl)-4- (trifluoromethyl)-L-phenylalanamine decylamine A 103 Cl 2-(2,4-diphenyl)-N-[( 1S)-1 -[(2,4-dichlorophenyl)fluorenyl ]-2-(4-indolyl. guano!-yl)-2-oxoethyl]propanamide C 104 poly-N-[(lS)-2-(3-aminoazetidine Alkyl-1-yl)_2_oxo-1-{[4-(trifluoromethyl)phenyl]methyl}ethyl]-1-(2,4-dichlorophenyl)cyclopropanamide B 105 °Cf N2- {[ 1 -(2,4-diphenyl)cyclopropyl]carbonyl}-3-(2,3-dihydro-1,4-benzodioxan-6-yl)- NP-(Dimethylamino)ethyl]-N-mercapto-L-alanamine amide A 106 Br 4-bromo-indole-α-{[1-(2,4-dichlorophenyl)cyclopropane ]]carbonyl}-Ν-(1-methylacridin-3-yl)-L-phenylalanamine decylamine A 107 Br-^^ Ν-1-azabicycloindole.2.2]oct-3-yl-4- Bromo-indole-α-{[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl}-L-phenylalanamine decylamine A 108 N-[(3S)-1-azabicyclo[2.2.2 ]oct-3-yl]-2,4-digas-N-cx- {[ 1 -(2,4-diphenyl)cyclopropyl]carbonyl}oxime-phenylalanamine decylamine A 109 Br human^ N -[(3S)-1-azabicyclo[2.2.2]octyl_3_yl]_4_ desert-Ν-α-{[1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl}-L-phenylalanamine decylamine A 201040149

表1 # 結構 名稱 ic5〇 110 參, N-[(3R)-1-氮雜雙環[2.2.2]辛-3-基]-4-漠-Ν-α-{[1-(2,4-二氣苯基)環丙基]羰基}-L-苯丙胺醯胺 A 111 c〇V^icl Cl 1-(2,4-二氯苯基)-N-{(lS)-l-[(2,4-二氯 苯基)甲基]-2-[(8aS)-六氫吼咯並[1,2-a] 吼嗪-2(1H)-基]-2-氧代乙基}環丙醯胺 B 112 N-[(lS)-2-[(3R)-3-胺基吼咯啶-1-基]-2-氧代-1 - {[4-(三氟甲基)苯基]甲基}乙基]-1-(2,4-二氣苯基)壤丙酿胺 A 113 CF厂 N-1-氮雜雙環[2.2.2]辛-3-基-Ν-α-{[1-(2,4-二氯苯基)環丙基]羰基}-4-(三氟甲 基)-L-苯丙胺酿胺 A 114 CF广 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-*]-Ν-α-{[ 1 -(2,4_二氯苯基)環丙基]羰基} ·4-(三 氟甲基)-L-苯丙胺醯胺 A 115 1^-〇1-{[1-(2,4-二氣苯基)壤丙基]幾基}-]^-(吡咯啶-3-基甲基)-4-(三氟曱基)-L-苯丙 胺醯胺 A 116 CF厂 N-[(3R)-1 -氮雜雙環[2.2.2]辛-3-基]-Ν-α-{[ 1 -(2,4-二氣苯基)環丙基]羰基} _4_(三 氟曱基)-L-苯丙胺醯胺 A 117 CI^^CI N-[(3R)-1-氮雜雙環[2.2.2]辛-3-基]-2,4-二氯-Ν-α- {[ 1 -(2,4-二氯苯基)環丙基]羰 基}丄-苯丙胺醯胺 A 146258.doc -209- 201040149Table 1 # Structure name ic5〇110 参, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-indi-Ν-α-{[1-(2,4 -diphenylphenyl)cyclopropyl]carbonyl}-L-phenylalanamine decylamine A 111 c〇V^icl Cl 1-(2,4-dichlorophenyl)-N-{(lS)-l-[( 2,4-Dichlorophenyl)methyl]-2-[(8aS)-hexahydroindolo[1,2-a]pyridazine-2(1H)-yl]-2-oxoethyl} Cyclopropylamine B 112 N-[(lS)-2-[(3R)-3-Aminopyrrolidin-1-yl]-2-oxo-1 - {[4-(trifluoromethyl) Phenyl]methyl}ethyl]-1-(2,4-diphenyl) acrylamine A 113 CF plant N-1-azabicyclo[2.2.2]oct-3-yl-indole- --{[1-(2,4-Dichlorophenyl)cyclopropyl]carbonyl}-4-(trifluoromethyl)-L-amphetamine Amine A 114 CF N-[(3S)-1- Azabicyclo[2.2.2]octyl-3-*]-Ν-α-{[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl} ·4-(trifluoromethyl)-L -Amphetamine-amine A 115 1^-〇1-{[1-(2,4-diphenylphenyl)-leafyl]-yl}-]^-(pyrrolidin-3-ylmethyl)-4- (Trifluoromethyl)-L-phenylalanamine decylamine A 116 CF plant N-[(3R)-1 -azabicyclo[2.2.2]oct-3-yl]-Ν-α-{[ 1 -(2 ,4-diphenylphenyl)cyclopropyl]carbonyl} _4_(trifluoromethyl)-L-phenylalanamine decylamine A 117 CI^^CI N-[(3R)-1-azabicyclo [2.2.2] Oct-3-yl]-2,4-dichloro-indole-α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl}indole-phenylalanamine amide A 146258 .doc -209- 201040149

表1 # 結構 名稱 IC50 118 Ν-α-{[1-(2,4-二氯苯基)環丙基]羰基}-N-[2-(二甲基胺基)乙基]-L-苯丙胺醯胺 A 119 V7 Cl 1 Sd Ν-α-{[1-(2,4-二氣苯基)環丙基]羰基卜N-[2-(二甲基胺基)乙基]-Ν-曱基-L-苯丙胺 醯胺 A 120 Ν-α-{[1-(2,4-二氣苯基)ί哀丙基]_炭基}-Ν_ [2-(甲基胺基)乙基]-4-(三氟曱基)-L-苯 丙胺酷胺 B 121 4-演-Ν-α-{[1-(2,4-二氯苯基)環丙基]羰 基}-Ν-[2-(曱基胺基)乙基]~L-苯丙胺酸 胺 A 122 2,4-二氣-Ν-α- {[ 1 -(2,4-二氣苯基)環丙基] 羰基}-Ν-[2-(曱基胺基)乙基]-L-苯丙胺 醯胺 A 123 kJ N-[(3R)-1-氮雜雙環[2.2.2]辛-3-基]-Ν2-{[1-(2,4-二氯苯基)環丙基]羰基}-3-(2,3-二氮-1，4-苯並二ϋ惡烧-6-基)-L-丙胺S&amp;胺 A 124 Y7 c, h2n^Xv0ici Ν-(2-胺基乙基)-2,4-二氣-Ν-α-{[1-(2,4-二氯苯基)環丙基]羰基}-L-苯丙胺醯胺 B 125 k^o N-[(3S)-1-氮雜雙環[2.2·2]辛-3-基]-N2-{[1-(2,4-二氯苯基)環丙基機基}-3-(2,3-二氮-1，4-苯並二σ惡烧-6-基)-L-丙胺酿胺 A 146258.doc -210- 201040149Table 1 # Structure name IC50 118 Ν-α-{[1-(2,4-Dichlorophenyl)cyclopropyl]carbonyl}-N-[2-(dimethylamino)ethyl]-L- Amphetamine amide A 119 V7 Cl 1 Sd Ν-α-{[1-(2,4-diphenyl)cyclopropyl]carbonyl b N-[2-(dimethylamino)ethyl]-anthracene - mercapto-L-amphetamine amide A 120 Ν-α-{[1-(2,4-diphenyl) lysyl]-carbon-}-[2-(methylamino) 4-(trifluoromethyl)-L-amphetamine B 121 4-de-Ν-α-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-Ν- [2-(decylamino)ethyl]~L-phenylalanine A 122 2,4-digas-Ν-α- {[ 1 -(2,4-diphenyl)cyclopropyl]carbonyl }-Ν-[2-(decylamino)ethyl]-L-phenylalanamine decylamine A 123 kJ N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-Ν2 -{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-3-(2,3-diaza-1,4-benzobisindole-6-yl)-L- Propylamine S &amp;amine A 124 Y7 c, h2n^Xv0ici Ν-(2-aminoethyl)-2,4-dioxa-indole-α-{[1-(2,4-dichlorophenyl)cyclopropane Carbonyl]-L-phenylalanine decylamine B 125 k^o N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N2-{[1-(2,4- Dichlorophenyl)cyclopropyllocene}-3-(2,3-diaza-1,4-benzobis-sigma Burn-6-yl) -L- stuffed propylamine amine A 146258.doc -210- 201040149

表1 # 結構 名稱 ic5〇 126 nh2 N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-l-[(2,4-二氯苯基)曱基]-2-氧代乙 基}-1-(2,4-二氯苯基)環丙醯胺 A 127 4-漠-Ν-α- {[ 1 -(2,4·二氯苯基)環丙基]羰 *}-Ν-(2-曱基-1-氮雜雙環[2.2.2]辛-3-基)-L-苯丙胺醯胺 A 128 Cl /n^n^T^U.ci Ν-α- {[ 1 -(2,4-二氣苯基)ί哀丙基]_炭基} -Ν_ [2-(二甲基胺基)乙基]-β-甲基苯丙胺醯 胺 A 129 ^mcl CF厂 Ν-1-氮雜雙環[2.2.2]辛-3-基-Ν-α-{[1-(2,4-二氯苯基)環丙基]羰基}-2,4-二(三 氟甲基)-L-苯丙胺醯胺 A 130 H cX&gt;〇, 2,4-二氯-N-cx-{[l-(2/l· 二氯苯基)環丙基] 羰基}-Ν-(8-甲基-8-氮雜雙環[3.2.1]辛-3-基)-L-苯丙胺酿胺 A 131 〇°^A OI-^^CI Ν-1-氮雜雙環[2.2.2]辛-3-基-2,4-二氯-Ν-α- {[ 1 -(2,4_ 二氯 苯基) 環 丙基] 幾基} -Ν- 曱 基-L-苯丙胺醯胺 A 132 N-[(3R)-1-氮雜雙環 Ρ.2.2]辛-3-基]-Ν-α-{[1-(2,4-二氯苯基)環丙基]羰基}-L-苯丙 胺醯胺 A 146258.doc -211 201040149Table 1 # Structure name ic5〇126 nh2 N-{(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-l-[(2,4-di Chlorophenyl)indenyl]-2-oxoethyl}-1-(2,4-dichlorophenyl)cyclopropanamide A 127 4-di-Ν-α- {[ 1 -(2,4 Dichlorophenyl)cyclopropyl]carbonyl*}-indole-(2-mercapto-1-azabicyclo[2.2.2]oct-3-yl)-L-phenylalanamine decylamine A 128 Cl /n^ n^T^U.ci Ν-α- {[ 1 -(2,4-diphenyl) lysyl]-carbyl} -Ν_ [2-(dimethylamino)ethyl]- β-Methylphenylalanine decylamine A 129 ^mcl CF plant Ν-1-azabicyclo[2.2.2]oct-3-yl-Ν-α-{[1-(2,4-dichlorophenyl) ring Propyl]carbonyl}-2,4-bis(trifluoromethyl)-L-phenylalanamine decylamine A 130 H cX&gt;〇, 2,4-dichloro-N-cx-{[l-(2/l· Dichlorophenyl)cyclopropyl]carbonyl}-indole-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-L-amphetamine Amine A 131 〇°^A OI- ^^CI Ν-1-Azabicyclo[2.2.2]oct-3-yl-2,4-dichloro-indole-α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl] }-Ν- fluorenyl-L-amphetamine amide A 132 N-[(3R)-1-azabicycloindole.2.2]oct-3-yl]-Ν-α-{[1-(2,4 -dichlorophenyl)cyclopropyl]carbonyl}-L-phenylalanamine decylamine A 146258.doc -211 201040 149

表1 # 結構 名稱 IC5〇 133 Η &quot;Ό (PS)-N-[(3R)-1-氮雜雙環[2.2.2]辛-3-基]-Ν-α-{[1-(2,4-二氯苯基)環丙基]羰基}-β-甲基-L-苯丙胺醯胺 A 134 Η So N-[(3S)-1-氮雜雙環 Ρ.2.2]辛-3-基]-Ν-α-{[1-(2,4-二氯苯基)環丙基]羰基}-L-苯丙 胺醯胺 A 135 N-1-氮雜雙環 |：2·2·2]辛-3-基-Ν-α-{[1-(2,4-二氯苯基)環丙基]羰基}-Ν-曱基-L-苯丙胺醯胺 A 136 nh2 N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-1-[(4-&gt;臭苯基)曱基]_2·氧代乙基}-1-(2,4-二氯苯基)環丙醯胺 A 137 N-1-氮雜雙環[2·2·2]辛-3-基-Ν-α-({1-[4-(曱氧基)苯基]環丙基}羰基)-4-(三氟甲 基)-L-本丙胺酸胺 A 138 N-1-氮雜雙環[2.2.2]辛-3-基-Ν2-{[1-(2,4-二氯苯基)環丙基]羰基}-3-(l-甲基環丙 基)-L-丙胺醯胺 A 139 ^mcl CF厂 N-[(3S)-1-氮雜雙環[2·2.2]辛-3-基]-Ν-α-{[1-(2,4-二氯苯基)環丙基]羰基}-2,4-二 (三氟曱基)-L-苯丙胺醯胺 A 146258.doc -212- 201040149Table 1 # Structure name IC5〇133 Η &quot;Ό(PS)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-Ν-α-{[1-(2 ,4-dichlorophenyl)cyclopropyl]carbonyl}-β-methyl-L-phenylalanamine decylamine A 134 Η So N-[(3S)-1-azabicycloindole.2.2]oct-3-yl ]-Ν-α-{[1-(2,4-Dichlorophenyl)cyclopropyl]carbonyl}-L-phenylalanamine decylamine A 135 N-1-azabicyclo]|2·2·2] 辛-3-yl-Ν-α-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-indole-indenyl-L-phenylalanamine decylamine A 136 nh2 N-{(lS)- 2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-1-[(4-&gt;odorophenyl)indolyl]_2.oxoethyl}-1- (2,4-dichlorophenyl)cyclopropanamide A 137 N-1-azabicyclo[2·2·2]oct-3-yl-Ν-α-({1-[4-(曱氧Phenyl]cyclopropyl}carbonyl)-4-(trifluoromethyl)-L-benzamide A 138 N-1-azabicyclo[2.2.2]oct-3-yl-Ν2-{ [1-(2,4-Dichlorophenyl)cyclopropyl]carbonyl}-3-(l-methylcyclopropyl)-L-alanamine amide A 139 ^mcl CF plant N-[(3S)- 1-Azabicyclo[2·2.2]oct-3-yl]-Ν-α-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-2,4-di(trifluoro)曱-)-L-amphetamine amide A 146258.doc -212- 201040149

表1 # 結構 名稱 IC50 140 Cl N-[(3S)-1-氮雜雙環[12.2]辛-3-基]-4-氯-Ν-α· {[ 1 -(2,4-二氯苯基)¾丙基]截基} -L-苯丙胺醯胺 C 141 N-[(1S)-1-{[(3S)-1-氮雜雙環[2.2.2]辛-3- 基胺基]徵基}-3-苯基丙基]-1-(2,4-二氣 苯基)環丙醯胺 A 142 Cl N-[(3S)-1-氮雜雙環[2·2·2]辛 _3_ 基]_4_ 氯-Ν-α-{[1-(2,4-二氯苯基)環丙基]羰基}-2-(三氟曱基)-L-苯丙胺醯胺 A 143 0 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-Ν-α-{[ 1 -(2,4-二氯苯基)環丙基]羰基} -1 -(苯 基曱基)-L-組胺臨胺 A 144 HV 4-演-Ν-α-{[1-(2,4_二氯苯基)環丙基]羰 *}-N-[(lS,3S,4S)-l-環氧-1-氮雜雙環 [2.2.2]辛-3-基]-L-苯丙胺醯胺 A 145 〇-F cf/ N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-Ν-α-{[1-(2,4-二氯苯基)$哀丙基]幾基}-2-氟-4-(三氟甲基)-L-苯丙胺醯胺 A 146 F午0 F N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-N2-{[1-(2,4-二氯苯基)環丙基]羰基}-3-(2,2-二亂-1，3-苯並二°惡。坐-5-基)-L-丙胺龜胺 A 147 N-[(lS)-2-(2,6-二氮雜螺[3.3]庚-2-基)-2-氧代-1-{[4-(三敗曱基)苯基]曱基}乙基]-1 -(2,4-二氯苯基)環丙醯胺 A 146258.doc •213 - 201040149Table 1 # Structure name IC50 140 Cl N-[(3S)-1-azabicyclo[12.2]oct-3-yl]-4-chloro-indole-α· {[ 1 -(2,4-dichlorobenzene) ))3⁄4propyl] cleavage} -L-phenylalanine decylamine C 141 N-[(1S)-1-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino] -3-}}-3-phenylpropyl]-1-(2,4-diphenyl)cyclopropanamide A 142 Cl N-[(3S)-1-azabicyclo[2·2·2]辛_3_基]_4_ chloro-indole-α-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-2-(trifluoromethyl)-L-phenylalanamine amide A 143 0 N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-indole-α-{[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl} -1 -(phenylindenyl)-L-histamine amine A 144 HV 4-deacting-Ν-α-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl*}-N-[ (lS,3S,4S)-l-epoxy-1-azabicyclo[2.2.2]oct-3-yl]-L-phenylalanamine amide A 145 〇-F cf/ N-[(3S)-1 -azabicyclo[2.2.2]oct-3-yl]-anthracene-α-{[1-(2,4-dichlorophenyl)$ 丙基 propyl] aryl}-2-fluoro-4-( Trifluoromethyl)-L-amphetamine amide A 146 F noon 0 F N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N2-{[1-(2, 4-Dichlorophenyl)cyclopropyl]carbonyl}-3-(2,2-disorder-1,3-benzodioxanthine.sodium-5-yl)-L-propylamine toxin A 147 N- [(lS)- 2-(2,6-diazaspiro[3.3]heptan-2-yl)-2-oxo-1-{[4-(disindolyl)phenyl]indolyl}ethyl]-1 - (2,4-dichlorophenyl)cyclopropanamide A 146258.doc •213 - 201040149

表1 # 結構 名稱 IC5〇 148 Br *}-Ν-[3-(1Η-咪唑-1-基)丙基]-L-苯丙胺 醢胺 A 149 N-[(3S)-1-氮雜雙環[2·2·2]辛-3-基]-N2-{[1-(2,4-二氯苯基)環丙基]羰基卜5_苯 基正顯氣酸胺 A 150 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-Ν-α-{[1-(2,4_二氣苯基)環丙基]羰基}-2,4-二 (三氟甲基)-L-苯丙胺醯胺 A 151 Br 4-漠-N- {[ 1 -(2,4-二氣苯基)環丙基]羰 基}丄-苯丙胺醯基-N-[2-(二甲基胺基)乙 基]-L-脯胺醯胺 C 152 ci^cf3 N-[(3S)-1-氮雜雙環[2.2.2]辛_3_基]冰氯-Ν-α-{[1-(2,4-二氯苯基)環丙基]羰基}-3-(三氟曱基)-L-苯丙胺醯胺 A 153 f左格。, N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-4-氯-]^-〇1-{[1-(2,4-二氣苯基)5哀丙基]徵基}-2-氟苯丙胺醯胺 A 154 1-(2,4-二氣苯基)-&gt;^-[(18)-2-(8-曱基-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-氧代-1-{[4-(三氟曱基)苯基]曱基}乙基]環丙醯 胺 A 155 -:梦職, 1-(2,4-二氯苯基)-N-[(lS)-2-(6-甲基-2,6-二氮雜螺[3.3]庚_2_基)-2-氧代-1-{[4-(三 氟甲基)苯基]甲基}乙基]環丙醯胺 C 146258.doc -214- 201040149Table 1 # Structure name IC5〇148 Br *}-Ν-[3-(1Η-imidazol-1-yl)propyl]-L-phenylalanamine decylamine A 149 N-[(3S)-1-azabicyclo[ 2·2·2]oct-3-yl]-N2-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl b-5-phenyl-naphthoic acid amine A 150 N-[( 3S)-1-azabicyclo[2.2.2]oct-3-yl]-Ν-α-{[1-(2,4_diphenyl)cyclopropyl]carbonyl}-2,4-di (trifluoromethyl)-L-phenylalanamine decylamine A 151 Br 4-Mo-N- {[ 1 -(2,4-diphenyl)cyclopropyl]carbonyl}oxime-phenylpropylamine fluorenyl-N-[ 2-(Dimethylamino)ethyl]-L-nonylamine decylamine C 152 ci^cf3 N-[(3S)-1-azabicyclo[2.2.2] octyl-3-yl] chlorochloride- Ν-α-{[1-(2,4-Dichlorophenyl)cyclopropyl]carbonyl}-3-(trifluoromethyl)-L-phenylalanamine decyl A 153 f left. , N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-chloro-]^-〇1-{[1-(2,4-diphenyl)5哀propyl] levy}-2-fluorophenylpropylamine amide A 154 1-(2,4-diphenyl)-&gt;^-[(18)-2-(8-fluorenyl-3,8- Diazabicyclo[3.2.1]oct-3-yl)-2-oxo-1-{[4-(trifluoromethyl)phenyl]indolyl}ethyl]cyclopropanamide A 155 -: Dream job, 1-(2,4-dichlorophenyl)-N-[(lS)-2-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)-2 -oxo-1-{[4-(trifluoromethyl)phenyl]methyl}ethyl]cyclopropanamide C 146258.doc -214- 201040149

表1 # 結構 名稱 IC5〇 156 OMe N-[(3S)-1-氮雜雙環[2.2.2]辛-3-*]-Ν-α-{[ 1 -(2,4-二氯苯基)環丙基]羰基} -0-曱 基-3-(甲氧基)-L-酷胺酿胺 A 157 % N-[(3S)-1-氮雜雙環[2·2·2]辛-3-基]-Ν-α-({1-[4_(甲氧基)苯基]環丙基Η炭基)-4-(三氟甲基)-L-苯丙胺醯胺 A 158 νΦ&gt;νλ1^〇.0- % N-[(3R)-1-氮雜雙環[2.2·2]辛-3-基]-Ν-α-({1-[4-(曱氧基)苯基]環丙基}羰基)-4-(三氟曱基)-L-苯丙胺醯胺 A 159 N-[(3R)-1-氮雜雙環[2.2.2]辛-3-基]-4-漠-Ν-α-({ 1-[4-(甲氧基)苯基]環丙基}羰基)-L-苯丙胺醯胺 A 160 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-4-漠-Ν-α-({ 1 -[4_(甲氧基)苯基]環丙基}羰基)-L-苯丙胺醯胺 A 161 αχΛ, Η Vx 4-漠-Ν-α- {[ 1 -(2,4-二氯苯基)環丙基]羰 基}-^~。比°定-4-基-1^-苯丙胺酸胺 C 162 f N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-Ν-α-{[1-(2,4-二氯苯基)環丙基]幾基}-4-苯 基-L-苯丙胺醯胺 A 146258.doc -215- 201040149Table 1 # Structure name IC5〇156 OMe N-[(3S)-1-azabicyclo[2.2.2]oct-3-*]-Ν-α-{[ 1 -(2,4-dichlorophenyl) Cyclopropyl]carbonyl} -0-fluorenyl-3-(methoxy)-L-hydrocarbyl amine A 157 % N-[(3S)-1-azabicyclo[2·2·2] octane -3-yl]-Ν-α-({1-[4_(methoxy)phenyl]cyclopropylphosphonium)-4-(trifluoromethyl)-L-phenylalanamine amide A 158 νΦ&gt; Νλ1^〇.0- % N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-Ν-α-({1-[4-(decyloxy)phenyl] Cyclopropyl}carbonyl)-4-(trifluoromethyl)-L-phenylalanamine amide A 159 N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4- -Ν-α-({ 1-[4-(Methoxy)phenyl]cyclopropyl}carbonyl)-L-phenylpropylamine decylamine A 160 N-[(3S)-1-azabicyclo[2.2.2 ]oct-3-yl]-4-indi-Ν-α-({ 1 -[4_(methoxy)phenyl]cyclopropyl}carbonyl)-L-phenylalanamine decylamine A 161 αχΛ, Η Vx 4- Mo-Ν-α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl}-^~. °定-4-yl-1^-phenylalaninamine C 162 f N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-Ν-α-{[1-( 2,4-Dichlorophenyl)cyclopropyl]alkyl}-4-phenyl-L-phenylalanamine decylamine A 146258.doc -215- 201040149

表1 # 結構 名稱 ic5〇 163 N-1-氮雜雙環[2.2.2]辛-4-基-4-溴-Ν-α-{[1-(2,4-二氣苯基)環丙基]羰基}-L-苯丙 胺醯胺 A 164 N-[(3S)-1-氮雜雙環 P.2.2]辛-3-基]-Ν-α-{[ 1 -(2,4-二氯苯基)環丙基]幾基} -L-色胺 醯胺 A 165 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-3-環 己基-N〜2〜-{[ 1 -(2,4-二氯苯基)環丙基] 羰基}-L-丙胺醯胺 A 166 C,A^f N-[(3S)-1-氮雜雙環[2·2·2]辛-3-基]_4-氯-Ν(χ-{[1-(2,4-二氯苯基)環丙基]羰基}-2-氟-L-苯丙胺醯胺 A 167 Φ,χία0.〇, N-[(3S)-1-氮雜雙環[2·2.2]辛-3-基]_4-(三 氟甲基)-Να-[(1-{4-[(三氟甲基)氧]苯基} 環丙基)羰基]-L-苯丙胺醯胺 A 168 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-Να-({1-[2-氟-4-(三氟曱基)苯基]環丙基}羰 基)-4-(三氟甲基)-L-苯丙胺醯胺 A 169 1-(2,4-二氯苯基)-N-{(lS)-l-[(2,4-二氯 苯基)甲基]_2-[3-(二甲基胺基)-8-氮雜雙 環[3.2.1]辛-8-基]-2-氧代乙基}環丙醯胺 A 170 C 丨 ^~{(18)-2-(4-胺基-4-曱基略咬-1-基)-1-[(2,4-二氯苯基)曱基]-2-氧代乙基}-1-(2,4-二氣苯基)環丙醯胺 A 146258.doc -216- 201040149Table 1 # Structure name ic5〇163 N-1-azabicyclo[2.2.2]oct-4-yl-4-bromo-indole-α-{[1-(2,4-diphenyl)cyclopropane Alkyl}carbonyl}-L-amphetamine amide N 164 N-[(3S)-1-azabicyclo P.2.2]oct-3-yl]-Ν-α-{[ 1 -(2,4-dichloro Phenyl)cyclopropyl]yl}}-L-tryptamine amide N 165 N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3-cyclohexyl-N~ 2~-{[ 1 -(2,4-Dichlorophenyl)cyclopropyl]carbonyl}-L-propylamine amide A 166 C, A^f N-[(3S)-1-azabicyclo[2 ·2·2]oct-3-yl]_4-chloro-indole (χ-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-2-fluoro-L-phenylpropylamine decylamine A 167 Φ,χία0.〇, N-[(3S)-1-azabicyclo[2·2.2]oct-3-yl]_4-(trifluoromethyl)-Να-[(1-{4-[( Trifluoromethyl)oxy]phenyl}cyclopropyl)carbonyl]-L-phenylpropylamine decylamine A 168 N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-Να- ({1-[2-Fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-4-(trifluoromethyl)-L-phenylalanamine decylamine A 169 1-(2,4- Dichlorophenyl)-N-{(lS)-l-[(2,4-dichlorophenyl)methyl]_2-[3-(dimethylamino)-8-azabicyclo[3.2. 1]oct-8-yl]-2-oxoethyl}cyclopropanamide A 170 C 丨^~{(18)-2-(4-amino-4-indole Slightly keto-1-yl)-1-[(2,4-dichlorophenyl)indolyl]-2-oxoethyl}-1-(2,4-diphenyl)cyclopropanamide A 146258.doc -216- 201040149

表1 # 結構 名稱 ic5〇 171 Ur3 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-3-氯-Να-{[1-(2,4-二氯苯基)環丙基]-羰基}-4-(三氟甲基)-苯丙胺醢胺 A 172 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-N〜2〜-{[1-(2,4·二氯苯基)環丙基]羰基}-N〜2〜-甲基-5-苯基-L-正纈氨醯胺 B 173 N'r-{[i-(2,4-二氣苯基)環丙基Η炭基}-Ν-[2-(二甲基胺基)乙基]-Ν-甲基-5-苯 基-L-正纈氨醯胺 B 174 1-(2,4-二氯苯基)以-{(18)-1-[(4-甲基呱 嗪-1-基)羰基]-4-苯基丁基}環丙醯胺 B 175 CIA^CI 1 -(2,4-二氯苯基)-Ν- {(1S)-1-[(2,4-二氯 笨基)曱基]_2-[(3R)-3-甲基狐°秦-1-基]-2- 氧代乙基}環丙醯胺 A 176 N-[(3S)-1-氮雜雙環[2·2.2]辛-3-基]-4-溴-Να-[(Η4-[(三氟曱基)氧]苯基Η裒丙基) 羰基]-L-苯丙胺醯胺 A 177 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-4-漠-Να-({ Ι-p-氟_4_(三氟曱基)苯基]環丙基} 羰基)-L-苯丙胺醯胺 A 178 ^ 'V (pS)-N-[(3S)-l-氮雜雙環[2.2.2]辛-3-基]-4-漠-Να- {[ 1 -(2,4-二氯苯基)環丙基]羰 基}七-曱基苯丙胺醯胺 A 146258.doc -217- 201040149Table 1 # Structure name ic5〇171 Ur3 N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3-chloro-Να-{[1-(2,4-dichloro Phenyl)cyclopropyl]-carbonyl}-4-(trifluoromethyl)-phenylpropylamine decylamine A 172 N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N 〜2~-{[1-(2,4·Dichlorophenyl)cyclopropyl]carbonyl}-N~2~-methyl-5-phenyl-L-n-decylamine B 173 N'r -{[i-(2,4-diphenyl)cyclopropylphosphonium}-indole-[2-(dimethylamino)ethyl]-indole-methyl-5-phenyl-L - n-Protonamine B 174 1-(2,4-dichlorophenyl)-{(18)-1-[(4-methylpyridazin-1-yl)carbonyl]-4-phenyl Cyclopropanol B 175 CIA^CI 1 -(2,4-dichlorophenyl)-indole-{(1S)-1-[(2,4-dichlorophenyl)indenyl]_2-[ (3R)-3-methylfox 秦qin-1-yl]-2-oxoethyl}cyclopropanamide A 176 N-[(3S)-1-azabicyclo[2·2.2]oct-3 -yl]-4-bromo-Να-[(Η4-[(trifluoromethyl)oxy]phenyl hydrazinopropyl)carbonyl]-L-phenylpropylamine decylamine A 177 N-[(3S)-1-nitrogen Heterobicyclo[2.2.2]oct-3-yl]-4-indi-Να-({ Ι-p-fluoro_4_(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-L-phenylpropylamine decylamine A 178 ^ 'V (pS)-N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-4-indi-Να- {[ 1 -( 2,4-Dichlorophenyl)cyclopropyl]carbonyl}heptaphenylphenamidamine A 146258.doc -217- 201040149

表1 # 結構 名稱 IC5〇 179 (PR)-N-[(3S)-1-氮雜雙環[2·2·2]辛-3-基]-4-臭-Να- {[ 1 -(2,4-二氯苯基)環丙基]羰 基}4-甲基苯丙胺醯胺 A 180 P Br N-1-氮雜雙環[2.2.2]辛-3_基-4-溴-Να-{[ 1-(2,4-二氯苯基)環丙基]羰基} -D-苯 丙胺醯胺 A 181 ◎擎 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-5-(4-氯苯基)-N〜2〜-{[ 1 -(2,4-二氯苯基)環丙 基]羰基}-L-正纈氨醯胺 A 182 Cl N-{(lS)-2-[(3R)-3-胺基呱啶-1-基]-1-[(2,4-二氯苯基)曱基]-2-氧代乙基} -1 -(2,4-二氯苯基)環丙醯胺 A 183 cf3 Να-{[1-(2,4-二氯苯基)環丙基]-羰基}-N-[(3S,4R)-4-苯基。比咯啶-3-基]-4-(三氟甲 基)-L-苯丙胺醯胺 C 184 N-[(3S)-1-氮雜雙環[2.2·2]辛各基]_2_氯-Να-{[1-(2,4-二氣苯基)環丙基]-羰基}-4-氟-L-苯丙胺醯胺 A 185 nX1?〇.0CF3 今Vx nh2 Dr N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-1-[(4-漠苯基)曱基]_2_氧代乙基}-1-{4-[(三氟甲基)氧]苯基}-環丙醯胺 A 146258.doc -218- 201040149Table 1 # Structure name IC5〇179 (PR)-N-[(3S)-1-azabicyclo[2·2·2]oct-3-yl]-4-odor-Να- {[ 1 -(2 ,4-dichlorophenyl)cyclopropyl]carbonyl}4-methylphenylpropylamine decylamine A 180 P Br N-1-azabicyclo[2.2.2]oct-3-yl-4-bromo-Να-{ [1-(2,4-Dichlorophenyl)cyclopropyl]carbonyl}-D-phenylalanamine decylamine A 181 ◎ 擎 N-[(3S)-1-azabicyclo[2.2.2]oct-3- 5-(4-chlorophenyl)-N~2~-{[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl}-L-n-decylamine A 182 Cl N -{(lS)-2-[(3R)-3-Aminopyridin-1-yl]-1-[(2,4-dichlorophenyl)indolyl]-2-oxoethyl} 1-(2,4-dichlorophenyl)cyclopropanamide A 183 cf3 Να-{[1-(2,4-dichlorophenyl)cyclopropyl]-carbonyl}-N-[(3S,4R )-4-phenyl. Bilpyridin-3-yl]-4-(trifluoromethyl)-L-phenylpropylamine decylamine C 184 N-[(3S)-1-azabicyclo[2.2.2]octyl]_2_chloro- Να-{[1-(2,4-Diphenyl)cyclopropyl]-carbonyl}-4-fluoro-L-phenylalanamine decylamine A 185 nX1?〇.0CF3 Present Vx nh2 Dr N-{(lS) -2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-1-[(4-oxaphenyl)indolyl]_2-oxoethyl}-1-{ 4-[(Trifluoromethyl)oxy]phenyl}-cyclopropanamide A 146258.doc -218- 201040149

表1 # 結構 名稱 IC50 186 Br N-{(lS)-2-(4-胺基-4-甲基狐唆-1-基)-l_ [(4-溴苯基)曱基]-2-氧代乙基}-l-(2,4-二 氯苯基)環丙醯胺 A 187 Cl N-{(lS)_2-(4-胺基呱啶-1-基)-1-[(2,4_ 二 氯苯基)甲基]-2-氧代乙基}-1-(2,4-二氯 苯基)環丙醯胺 A 188 破敬 1 -(2,4-二氯苯基)-N- {(1S)-1 -[(2,4-二氣 苯基)曱基]-2-[(3S)-3-曱基孤σ秦-1·基]-2- 氧代乙基}環丙醯胺 A 189 Cl 2,4-二氯-Να- {[ 1 -(2,4-二氯苯基)環丙基] 羰基}-N-[(2S)-吡咯啶-2-基甲基]-L-苯丙 胺醯胺 A 190 Q.擎 Cl 2,4-二氯-Να- {[ 1 -(2,4-二氯苯基)環丙基] 羰基}-N-[(2R)-。比咯啶-2-基曱基]-L-苯 丙胺醯胺 A 191 Cl 2,4-二氯-Να- {[ 1 -(2,4-二氯苯基)環丙基] 羰基}-N-[(3R)-吡咯啶-3-基甲基]-L-苯 丙胺醯胺 A 192 0¾¾ Cl 2,4-二氯-Να- {[ 1 -(2,4-二氯苯基)環丙基] 羰基}-N-[(3S)-吼咯啶-3-基甲基]-L-苯丙 胺醯胺 A 193 Cl N-{(lS)-2-[(3S)-3-胺基。比咯啶-1-基]-1-[(2,4-二氣苯基)甲基]-2-氧代乙基}小 (2,4-二氯苯基)環丙醯胺 A 146258.doc 219. 201040149Table 1 #Structure name IC50 186 Br N-{(lS)-2-(4-Amino-4-methylfoxin-1-yl)-l_ [(4-bromophenyl)indolyl]-2- Oxoethyl}-l-(2,4-dichlorophenyl)cyclopropanamide A 187 Cl N-{(lS)_2-(4-Aminopyridin-1-yl)-1-[( 2,4_Dichlorophenyl)methyl]-2-oxoethyl}-1-(2,4-dichlorophenyl)cyclopropanamide A 188 Broken 1 -(2,4-dichlorobenzene -N- {(1S)-1 -[(2,4-diphenylphenyl)indolyl]-2-[(3S)-3-indolyl sigma-1 -yl]-2-oxo Alkenyl}cyclopropanamide A 189 Cl 2,4-dichloro-indole α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-[(2S)-pyrrolidine -2-ylmethyl]-L-amphetamine amide A 190 Q. qing Cl 2,4-dichloro-Να- {[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N -[(2R)-. Birhridin-2-ylindenyl]-L-phenylalanamine decylamine A 191 Cl 2,4-dichloro-indole α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N -[(3R)-pyrrolidin-3-ylmethyl]-L-phenylalanamine decylamine A 192 03⁄43⁄4 Cl 2,4-Dichloro-Να- {[ 1 -(2,4-dichlorophenyl)cyclopropane Carbonyl]-N-[(3S)-indolyl-3-ylmethyl]-L-phenylpropylamine decylamine A 193 Cl N-{(lS)-2-[(3S)-3-Amino. Bilobidine-1-yl]-1-[(2,4-diphenyl)methyl]-2-oxoethyl}small (2,4-dichlorophenyl)cyclopropanamide A 146258 .doc 219. 201040149

表1 # 結構 名稱 ic5〇 194 Cl N-{(lS)-2-[(3R)-3-胺基 α 比咯啶-1-基]-1-[(2,4-二氣苯基)曱基]-2-氧代乙基}-1-(2,4-二氣苯基)環丙醯胺 A 195 Cl 2,4-二氯^〇1-{[1-(2,4-二氯苯基)環丙基] 羰基}-N-[(3R)-呱啶-3-基]-L-苯丙胺醯 胺 A 196 nh2 ~cf3 N-[(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-2-氧代-1 - {[4-(三氟曱基)苯基]曱 基}乙基]-1-{4-[(三氟曱基)氧]苯基}環 丙醯胺 A 197 h〇v,1^^Lc1 4-漠-Να-{[ 1-(2,4-二氣苯基)環丙基Η炭 *}-N-[(3S)-吡咯啶-3-基]-L-苯丙胺醯胺 A 198 我故 NH2 CF3 N-[(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-2-氧代-1-{[4-(三氟曱基)苯基]曱 基}乙基]-1-[2-氟-4-(二氣甲基)苯基]-環 丙酿胺 A 199 hnCX,I^^c1 4-、;臭-Να-{[1-(2,4-二氣苯基)環丙基]羰 *}-N-[(3R)-吡咯啶-3-基]-L-苯丙胺醯 胺 A 200 Cl N-{(lS)-2-[(3S)-3-胺基呱啶-1-基]-1-[(2,4-二氯苯基)甲基]-2-氧代乙基}-1-(2,4-二氯苯基)環丙醯胺 A 201 ct N-(3-胺基環己基)-2,4-二氯-Να- {[ 1 -(2,4-二氣苯基)環丙基]羰基}-L-苯丙胺醯胺 A 146258.doc •220· 201040149Table 1 # Structure name ic5〇194 Cl N-{(lS)-2-[(3R)-3-aminol-pyrrolidin-1-yl]-1-[(2,4-diphenyl) Mercapto]-2-oxoethyl}-1-(2,4-diphenyl)cyclopropanamide A 195 Cl 2,4-dichloro-hydrazine 1-{[1-(2,4- Dichlorophenyl)cyclopropyl]carbonyl}-N-[(3R)-acridin-3-yl]-L-phenylalanamine decylamine A 196 nh2 ~cf3 N-[(lS)-2-(3-amine -8-Azabicyclo[3.2.1]oct-8-yl)-2-oxo-1 - {[4-(trifluoromethyl)phenyl]indolyl}ethyl]-1-{4 -[(Trifluoromethyl)oxy]phenyl}cyclopropanamide A 197 h〇v,1^^Lc1 4-Moist-Να-{[ 1-(2,4-diphenyl)cyclopropyl Η charcoal*}-N-[(3S)-pyrrolidin-3-yl]-L-phenylalanamine amide A 198 I am NH2 CF3 N-[(lS)-2-(3-amino-8-aza Bicyclo[3.2.1]oct-8-yl)-2-oxo-1-{[4-(trifluoromethyl)phenyl]indolyl}ethyl]-1-[2-fluoro-4-( Dimethylmethyl)phenyl]-cyclopropanol A 199 hnCX, I^^c1 4-,; odor-Να-{[1-(2,4-diphenyl)cyclopropyl]carbonyl*} -N-[(3R)-pyrrolidin-3-yl]-L-phenylalanamine decylamine A 200 Cl N-{(lS)-2-[(3S)-3-Aminopyridin-1-yl]- 1-[(2,4-dichlorophenyl)methyl]-2-oxoethyl}-1-(2,4-dichlorophenyl)cyclopropanamide A 201 ct N-(3-amine Base cyclohexyl)-2,4 -Dichloro-Να- {[ 1 -(2,4-diphenyl)cyclopropyl]carbonyl}-L-phenylalanamine amide A 146258.doc •220· 201040149

表1 # 結構 名稱 IC50 202 .〇^cl N-[(l S)-l-(聯苯-4-基甲基)-2-(4-甲基呱 °秦小基)-2-氧代乙基]-1-(2,4-二氯苯基） 環丙醯胺 A 203 Η2Ν η N-[(lS)-2-(4-胺基-4-曱基呱啶-1-基)-1-(聯苯-4·-基甲基)-2-氧代乙基]-1 -(2,4-二 氯苯基)環丙醯胺 B 204 N-[(lS)-l-(聯苯-4-基甲基)-2-((2-(二曱 基胺基)乙基)(曱基)胺基)-2-氧代乙基]-1 -(2,4-二氣苯基)環丙醯胺 A 205 Cl N-(2-胺基環己基)-2,4-二氯-Να- {[ 1 -(2,4-二氯苯基)環丙基]羰基}-L-苯丙胺醯胺 A 206 N-(2-胺基-2-甲基丙基)-Να-{[1-(2,4-二 氣苯基)環丙基]羰基}-4-(三氟甲基)-L-苯丙胺醯胺 B 207 敎 H Olb Br N-(2-胺基-2-甲基丙基)-4-&gt;臭-Να-{[1-(2,4-二氣苯基)環丙基]羰基}-L-苯丙胺 醯胺 A 208 N-[(lS)-2-[(3R)-3-(曱基胺基户比咯啶-1-基]_2-氧代-1-{[4-(三|L曱基)苯基]曱基} 乙基]-l-{4-[(三氟甲基)氧]苯基}環丙醯 胺 C U6258.doc -221 - 201040149Table 1 # Structure name IC50 202 .〇^cl N-[(l S)-l-(biphenyl-4-ylmethyl)-2-(4-methyloxime-Qin Xiaoji)-2-oxoethyl ]-1-(2,4-dichlorophenyl)cyclopropanamide A 203 Η2Ν η N-[(lS)-2-(4-Amino-4-mercaptoacridin-1-yl)-1 -(biphenyl-4-ylmethyl)-2-oxoethyl]-1 -(2,4-dichlorophenyl)cyclopropanamide B 204 N-[(lS)-l-(linked Benz-4-ylmethyl)-2-((2-(didecylamino)ethyl)(indenyl)amino)-2-oxoethyl]-1 -(2,4-digas Phenyl) Cyclopropylamine A 205 Cl N-(2-Aminocyclohexyl)-2,4-dichloro-indole α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl} -L-Amphetamine guanamine A 206 N-(2-Amino-2-methylpropyl)-Να-{[1-(2,4-diphenylphenyl)cyclopropyl]carbonyl}-4-( Trifluoromethyl)-L-phenylalanamine decylamine B 207 敎H Olb Br N-(2-amino-2-methylpropyl)-4-&gt; odor-Να-{[1-(2,4- Dioxophenyl)cyclopropyl]carbonyl}-L-phenylalanamine decylamine A 208 N-[(lS)-2-[(3R)-3-(decylamine carbaryl-pyridin-1-yl)_2 -oxo-1-{[4-(Tri-L-yl)phenyl]indolyl}ethyl]-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide C U6258 .doc -221 - 201040149

表1 # 結構 名稱 IC50 209 α 砵[(1民211)-2-胺基環己基]-2,4-二氯^〇1-{[1-(2,4-二氯苯基)環丙基]羰基}-L-苯丙 胺醢胺 A 210 N-[(l S)-2-[(3S)-3-(甲基胺基)吡咯啶-1-基]-2-氧代-1-{[4-(三氣曱基)苯基]曱基} 乙基]小{4-[(三氟曱基)氧]苯基}環丙醯 胺 A 211 N-{(lS)-l-[(4-溴苯基)曱基]-2-[(3R)-3- (甲基胺基)°比°各°定小基]-2-氧代乙基}-1-{4-[(三氟曱基)氧]苯基}環丙醯胺 B 212 α N-[(lS，2S)-2-胺基環己基]-2,4-二氯-Να-{[ 1 -(2,4-二氯苯基)環丙基]羰基} -L-苯丙 胺醯胺 B 213 &gt;〇货X夂 N-{(lS)-l-[(4-漠苯基)曱基]-2-[(3S)-3- (曱基胺基)°比哈°定小基]·2-氧代乙基}小 {4-[(三氟曱基)氧]苯基}環丙醯胺 A 214 Cl 2,4-二氯-Να- {[ 1 -(2,4-二氯苯基)環丙基]-羰基}-N-[(3S)-呱啶-3-基]-L-苯丙胺醯胺 A 215 B「 N-{(1 S)-2_(4-胺基p瓜α定-1-基)-1-[(4-&gt;臭苯 基)曱基]-2-氧代乙基} -1 -(2,4-二氯苯基) 環丙醯胺 A 216 Br 4-、/臭-Να·{[1-(2,4-二鼠苯基)¾丙基]-徵 *}-N-[(3R)-呱啶-3·基]-L-苯丙胺醯胺 A 146258.doc 222· 201040149Table 1 # Structure name IC50 209 α 砵[(1min211)-2-aminocyclohexyl]-2,4-dichloro-hydrazine 1-{[1-(2,4-dichlorophenyl)cyclopropene Alkyl}carbonyl}-L-amphetamine amide A 210 N-[(l S)-2-[(3S)-3-(methylamino)pyrrolidin-1-yl]-2-oxo-1- {[4-(trimethylhydrazinyl)phenyl]indolyl}ethyl]small {4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide A 211 N-{(lS)-l- [(4-Bromophenyl)indenyl]-2-[(3R)-3-(methylamino)°°°°°小小基]-2-oxoethyl}-1-{4- [(Trifluoromethyl)oxy]phenyl}cyclopropanamide B 212 α N-[(lS,2S)-2-aminocyclohexyl]-2,4-dichloro-Να-{[ 1 -( 2,4-dichlorophenyl)cyclopropyl]carbonyl}-L-phenylalanamine amide 213 &gt; 〇X夂N-{(lS)-l-[(4-Molyphenyl) fluorenyl]- 2-[(3S)-3-(fluorenylamino)°~哈哈定小基]·2-oxoethyl}small {4-[(trifluoromethyl)oxy]phenyl}cyclopropene Amine A 214 Cl 2,4-Dichloro-indole α- {[ 1 -(2,4-dichlorophenyl)cyclopropyl]-carbonyl}-N-[(3S)-acridin-3-yl]- L-Amphetamine amide A 215 B" N-{(1 S)-2_(4-Aminop-guana-1,3-yl)-1-[(4-&gt;odorophenyl)indolyl]-2 -oxoethyl} -1 -(2,4-dichlorophenyl)cyclopropanamide A 216 Br 4-, /odor-Να·{[1-(2 , 4-dimurphenyl) 3⁄4 propyl]-signal *}-N-[(3R)-acridin-3-yl]-L-phenylalanamine amide A 146258.doc 222· 201040149

表1 # 結構 名稱 ICso 217 Br N-{(lS)-l-[(4-溴苯基)曱基]-2-[4-(甲基 胺基户瓜唆基]-2-乳代乙基}-1-(2,4-二 氯苯基)環丙醯胺 A 218 cf3 N-[(lS)-2-(2,7-二氮雜螺[4.4]壬-2-基)-2-氧代-1-{[4-(三氣甲基)苯基]甲基}乙基]-1 -(2,4-二氯苯基)環丙醯胺 A 219 CF( N-[(lS)-2-(2,8-二氮雜螺[4.5]癸-8-基)-2-氧代小{[4-(三氟曱基)苯基]曱基}乙基]-1 -(2,4-二氯苯基)環丙醯胺 A 220 HV N-[(3S)-1-氮雜雙環[2·2·2]辛-3-基]-4-溴-Να-{[1-(2-氟苯基)環丙基]羰基}-L-苯丙 胺醯胺 A 221 cp cf3 N-[(lS)-2-(l,7-二氮雜螺[4.4]壬-7-基)-2-氧代-1-{[4-(三氟甲基)苯基]甲基}乙基]-1-(2,4-二氣苯基)環丙醯胺 A 222 Br 4-漠-Να- {[ 1 -(2,4-二氯苯基)環丙基]羰 基基]-L-苯丙胺酿胺 A 223 Br 4-漠-Να- {[ 1 -(2,4-二氯苯基)環丙基]羰 基定-3-基-L·苯丙胺酿胺 A 146258.doc -223 - 201040149Table 1 # Structure name ICso 217 Br N-{(lS)-l-[(4-bromophenyl)indolyl]-2-[4-(methylaminocarbamate]-2-miloethyl -1-}-1-(2,4-dichlorophenyl)cyclopropanamide A 218 cf3 N-[(lS)-2-(2,7-diazaspiro[4.4]indol-2-yl)- 2-oxo-1-{[4-(trimethylmethyl)phenyl]methyl}ethyl]-1 -(2,4-dichlorophenyl)cyclopropanamide A 219 CF( N-[ (lS)-2-(2,8-diazaspiro[4.5]dec-8-yl)-2-oxo small {[4-(trifluoromethyl)phenyl]indolyl}ethyl]- 1-(2,4-dichlorophenyl)cyclopropanamide A 220 HV N-[(3S)-1-azabicyclo[2·2·2]oct-3-yl]-4-bromo-Να -{[1-(2-fluorophenyl)cyclopropyl]carbonyl}-L-phenylalanamine decylamine A 221 cp cf3 N-[(lS)-2-(l,7-diazaspiro[4.4]壬-7-yl)-2-oxo-1-{[4-(trifluoromethyl)phenyl]methyl}ethyl]-1-(2,4-diphenyl)cyclopropanamide A 222 Br 4-Mo-Να- {[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl]-L-amphetamine A A 223 Br 4-Mo-Να- {[ 1 -(2 ,4-dichlorophenyl)cyclopropyl]carbonyl-3-yl-L·amphetamine Amine 146258.doc -223 - 201040149

表1 # 結構 名稱 ic5〇 224 1-[2-敦-4-(三氟曱基)苯基]-N-[(l S)-2-[(3R)-3-(曱基胺基)°比咯啶-1-基]-2-氧代-1-{[4-(三氟甲基)苯基]曱基}-乙基]環丙 醯胺 B 225 1-[2-氟-4-(三氟曱基)苯基]-N-[(1S)-2-[(3S)-3-(曱基胺基)吼咯啶-1-基]-2-氧代-1-{[4-(三氟甲基)苯基]甲基}-乙基]環丙 醯胺 A 226 N-{(lS)-l-[(4-漠苯基)曱基]-2_[(3S)-3-(曱基胺基)°比0各^定-1-基]-2·氧代乙基}小 [2_氟冰(三氟曱基)苯基]環丙醯胺 A 227 N-{(lS)-l-[(4-、;臭苯基)甲基]-2-[(3R)-3-(曱基胺基)σ比洛σ定-1-基]-2-乳代乙基}-1-[2·氟-4-(三氟甲基)苯基]環丙醯胺 B 228 νΦ，Χ^〇.0αη N-[(3S)-1-氮雜雙環[2.2_2]辛-3-基]-Να-[(1-{4-[(二氟曱基)氧]苯基}環丙基)羰 基]-4-(二鼠甲基)-L-苯丙胺酸胺 C 229 νΦ.χτ5〇.ολη Η V. N-[(3S)-1-氮雜雙環[2.2_2]辛-3-基]-4-溴-Να-[(1-{4-[(二氟曱基)氧]苯基Η裒丙基) 羰基]-L-苯丙胺醯胺 A 146258.doc -224- 201040149Table 1 # Structure name ic5〇224 1-[2-Den-4-(trifluoromethyl)phenyl]-N-[(l S)-2-[(3R)-3-(decylamino) °Byrridin-1-yl]-2-oxo-1-{[4-(trifluoromethyl)phenyl]decyl}-ethyl]cyclopropanamide B 225 1-[2-Fluoro- 4-(Trifluoromethyl)phenyl]-N-[(1S)-2-[(3S)-3-(decylamino)oxaridin-1-yl]-2-oxo-1- {[4-(Trifluoromethyl)phenyl]methyl}-ethyl]cyclopropanamide A 226 N-{(lS)-l-[(4-oxaphenyl)indolyl]-2_[( 3S)-3-(decylamino)° ratio 0 1,4- -1-yl]-2 oxoethyl} small [2-fluoroe(trifluoromethyl)phenyl]cyclopropanamide A 227 N-{(lS)-l-[(4-,;odorophenyl)methyl]-2-[(3R)-3-(decylamino)σ pyrrolidine-1-yl]- 2-miloethyl}-1-[2·fluoro-4-(trifluoromethyl)phenyl]cyclopropanamide B 228 νΦ,Χ^〇.0αη N-[(3S)-1-aza Bicyclo[2.2_2]oct-3-yl]-Να-[(1-{4-[(difluoroindolyl)oxy]phenyl}cyclopropyl)carbonyl]-4-(dimurmethyl)-L - phenylalanine amine C 229 νΦ.χτ5〇.ολη Η V. N-[(3S)-1-azabicyclo[2.2_2]oct-3-yl]-4-bromo-Να-[(1-{4 -[(difluoroindolyl)oxy]phenyl hydrazinopropyl)carbonyl]-L-phenylpropylamine decylamine A 146258.doc -224- 201040149

表1 # 結構 名稱 ic5〇 230 H^mci Br 4-漠-Να- {[ 1 -(2,4-二氯苯基)-環丙基]羰 基} 基~L-苯丙胺驢胺 A 231 Br 4-溴-N-[(3R)-呱啶-3-基]-Να-[(1-{4-[(三 氟甲基)氧]苯基}-環丙基)獄基]-L-苯丙 胺醯胺 A 232 H2N^Nl^lS-cl HV Ν-(2·胺基乙基)-4- &gt;臭-Να- {[ 1 -(2,4-二氣 苯基)環丙基]羰基}-L-苯丙胺醯胺 B 233 \7 Cl 1、 4-溴-Να- {[ 1 -(2,4-二氯苯基)環丙基]羰 基}-队甲基-Ν-[2-(曱基胺基)乙基]-L-苯 丙胺酸胺 A 234 h2n^Xt?0lci 'V Ν-(2-胺基乙基)-4- &gt;臭-Να- {[ 1 -(2,4-二氣 苯基)環丙基]羰基}-Ν-甲基-L-苯丙胺醯 胺 A 235 Ν-(氮雜環丁烷-3-基甲基)-4-溴-Να-[(1-{4-[(三氟曱基)氧]苯基}環丙基)羰基]-L-苯丙胺醯胺 A 236 4_溴-Να-({1-[2-氟冰(三氟甲基)苯基]環 丙基}羰基)-Ν-曱基-Ν-[2-(曱基胺基)乙 基]-L-苯丙胺醯胺 B 146258.doc -225 - 201040149Table 1 # Structure name ic5〇230 H^mci Br 4-Mo-Να- {[ 1 -(2,4-dichlorophenyl)-cyclopropyl]carbonyl} group ~L-Amphetamine amide A 231 Br 4 -Bromo-N-[(3R)-acridin-3-yl]-Να-[(1-{4-[(trifluoromethyl)oxy]phenyl}-cyclopropyl)]-L- Amphetamine amide H 232 H2N^Nl^lS-cl HV Ν-(2·Aminoethyl)-4- &gt; odor-Να- {[ 1 -(2,4-diphenyl)cyclopropyl] Carbonyl}-L-phenylalanamine amide C 233 \7 Cl 1, 4-bromo-Να- {[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl}-team methyl-Ν-[2 -(decylamino)ethyl]-L-phenylalanine A 234 h2n^Xt?0lci 'V Ν-(2-aminoethyl)-4- &gt; odor-Να- {[ 1 -(2 ,4-diphenylphenyl)cyclopropyl]carbonyl}-indole-methyl-L-phenylalanamine decylamine A 235 Ν-(azetidin-3-ylmethyl)-4-bromo-Να-[ (1-{4-[(Trifluoromethyl)oxy]phenyl}cyclopropyl)carbonyl]-L-phenylpropylamine decylamine A 236 4_Bromo-Να-({1-[2-Fluoride (Trifluoro) Methyl)phenyl]cyclopropyl}carbonyl)-fluorenyl-fluorenyl-indole-[2-(decylamino)ethyl]-L-phenylalanamine decylamine B 146258.doc -225 - 201040149

表1 # 結構 名稱 IC50 237 4-、/臭-N-[2-(二曱基胺基)乙基]-N(X-{[1-(2-氟苯基)環丙基]羰基}-N-甲基-L-苯丙 胺醯胺 B 238 4-溴-N-甲基-N-[2-(甲基胺基)乙基]-Να-[(1-{4-[(三氟曱基)氧]苯基}環丙基)羰 基]-L-苯丙胺醯胺 A 239 4-漠-Ν-[2-(二曱基胺基)乙基]-Ν-曱基-Να-[(1-{4-[(三氟曱基)氧]苯基}環丙基) 羰基]-L-苯丙胺醯胺 A 240 Br Ν- {(1 S)-2-(4-胺基-4-甲基呱啶-1 -基)-1 -[(4-溴苯基)曱基]-2-氧代乙基}-1-{4-[(三 氟曱基)氧]苯基}環丙醯胺 A 241 ς^ι N〜2〜-{[1-(2,4-二氣苯基)環丙基滕基}-5-苯基-N-[(3R)-呱啶-3-基]-L-正纈氨醯 胺 A 242 .ΝΗ CFs 0 1-(2,4-二乱苯基)-N-[(l S)-2-乳代-2-{3-[(苯基曱基)胺基]-8-氮雜雙環[3.2.1]辛-8-基}-1-{[4-(三氟曱基)苯基]曱基}-乙 基]環丙醯胺 A 243 .NH CFa 1 -(2,4-二氯苯基)-Ν-[( 1 S)-2- {3-[(2-曱基 丙基)胺基]-8-氮雜雙環[3.2.1]辛-8-基}-2-氛代-1-{[4-(三氟甲基)苯基]甲基}乙 基]環丙醯胺 A 146258.doc -226- 201040149Table 1 # Structure name IC50 237 4-, / odor-N-[2-(didecylamino)ethyl]-N (X-{[1-(2-fluorophenyl)cyclopropyl]carbonyl} -N-methyl-L-phenylalanamine decylamine B 238 4-bromo-N-methyl-N-[2-(methylamino)ethyl]-Να-[(1-{4-[(trifluoro) Mercapto)oxy]phenyl}cyclopropyl)carbonyl]-L-phenylpropylamine decylamine A 239 4-di-indole-[2-(didecylamino)ethyl]-fluorenyl-fluorenyl-Να-[ (1-{4-[(Trifluoromethyl)oxy]phenyl}cyclopropyl)carbonyl]-L-phenylalanamine decylamine A 240 Br Ν- {(1 S)-2-(4-Amino-4 -methyl acridine-1 -yl)-1 -[(4-bromophenyl)indolyl]-2-oxoethyl}-1-{4-[(trifluoromethyl)oxy]phenyl} Cyclopropylamine A 241 ς^ι N~2~-{[1-(2,4-diphenyl)cyclopropyltenyl}-5-phenyl-N-[(3R)-acridine- 3-yl]-L-n-decylamine A 242 .ΝΗ CFs 0 1-(2,4-disorder phenyl)-N-[(l S)-2-milo-2-{3-[ (phenylphenyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}-1-{[4-(trifluoromethyl)phenyl]indolyl}-ethyl] ring Propylamine A 243 .NH CFa 1 -(2,4-dichlorophenyl)-indole-[( 1 S)-2- {3-[(2-mercaptopropyl)amino]-8-nitrogen Heterobicyclo[3.2.1]oct-8-yl}-2-indolyl-1-{[4-(trifluoromethyl)phenyl]methyl}ethyl]cyclopropanamide A 146258.doc -226- 201040149

表1 # 結構 名稱 IC5〇 244 1 Vx 4-漠-N-[2-(二甲基胺基)乙基]-Να-({1_ [2_氟_4_(三氟曱基)苯基]環丙基}羰基)-Ν-曱基-L-苯丙胺醯胺 A 245 H2N^ N-[(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-1 -(2,3-二氮-1,4-苯亚二β惡烧-6-基 甲基)-2-氧代乙基]-1-{4-[(三氟甲基)氧] 苯基}環丙醯胺 A 246 q」 3-(2,3-二氫-1，4-苯並二噁院-6-基)-Ν-[2-(二曱基胺基)乙基]-Ν-甲基-Ν〜2〜-[(1-{4-[(三氟甲基)氧]苯基}環丙基)戴基]-L-丙胺酿胺 A 247 N-[(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-2-氧代-1-{[4-(三氟甲基)苯基]甲 基}乙基]-1-(2,4-二氣苯基)¾丙酿胺 A 248 (!) 1-(2,4-二氯苯基)-N-[(lS)-2-氧代-2-(3·。比 咯啶-1-基-8-氮雜雙環[3.2.1]辛-8-基)-1-{[4-(三氟甲基)苯基]甲基}-乙基]環丙醯 胺 A 249 4-漠-Να- {[ 1 -(2,4-二氯苯基)環丙基]羰 基}-队曱基-N-[(3R)-呱啶-3-基]-L-苯丙 胺醯胺 A 250 jX^^Xa N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-1-[(4-&gt;臭苯基)曱基]-2_氧代乙基}-1-(2,4-二氯苯基)環丙醯胺 A 146258.doc -227- 201040149Table 1 # Structure name IC5〇244 1 Vx 4-Moist-N-[2-(dimethylamino)ethyl]-Να-({1_[2_Fluoro_4_(trifluoromethyl)phenyl] Cyclopropyl}carbonyl)-indole-indenyl-L-phenylalanamine decylamine A 245 H2N^ N-[(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8- -1 -(2,3-diaza-1,4-phenylenedi-?-oxa-6-ylmethyl)-2-oxoethyl]-1-{4-[(trifluoromethyl) Oxy]phenyl}cyclopropanamide A 246 q" 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-indole-[2-(didecylamino) Ethyl]-indole-methyl-oxime~2~-[(1-{4-[(trifluoromethyl)oxy]phenyl}cyclopropyl)-yl]-L-propylamine A 247 N -[(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-2-oxo-1-{[4-(trifluoromethyl)phenyl ]methyl}ethyl]-1-(2,4-diphenyl)3⁄4 propylamine A 248 (!) 1-(2,4-dichlorophenyl)-N-[(lS)-2 -oxo-2-(3.pyrrolidin-1-yl-8-azabicyclo[3.2.1]oct-8-yl)-1-{[4-(trifluoromethyl)phenyl] Methyl}-ethyl]cyclopropanamide A 249 4-Moist-Να- {[ 1 -(2,4-dichlorophenyl)cyclopropyl]carbonyl}- sulphonyl-N-[(3R) -Acridine-3-yl]-L-phenylalanamine decylamine A 250 jX^^Xa N-{(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl )-1-[( 4-&gt;odor phenyl)indenyl]-2_oxoethyl}-1-(2,4-dichlorophenyl)cyclopropanamide A 146258.doc -227- 201040149

表1 # 結構 名稱 IC50 251 cf3 N-8-氮雜雙環[3.2.1]辛-3-基-Να-{[1-(2,4-二氯苯基)環丙基]羰基} -4-(三氟曱 基)-L-苯丙胺醯胺 A 252 Hz〆 N-[(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-1-(2,3-二氫-1,4-苯並二噁烷-6-基 甲基)-2-氧代乙基]-1-P-氟-4-(三氟甲基) 苯基]環丙醯胺 A 253 Br 4-漠-Να- {[ 1 -(2,4-二氣苯基)環丙基]羰 基}-Ν-甲基基-L-苯丙胺驢胺 A 254 ΗαχΛα N-[(l S)-l-(聯苯-4-基曱基)-2-N-[(3R)-呱 17定-3-基]-2·氧代乙基]-1 ~*(2,4-二氣苯基） 環丙醯胺 A 255 N-[(3S)-1-氮雜雙環[2·2·2]辛-3-基]-4-漠-Να- {[ 1 _(2,3 -二氟苯基)環丙基]羰基} -L-苯丙胺醯胺 A 256 Ν0.Ν£ί0 HV N-[(3S)-1-氮雜雙環 Ρ.2.2]辛-3-基]_4_ 溴-Nα-{[l-(2,6-二氟苯基)環丙基]羰基}-L· 苯丙胺醯胺 A 257 ΗαΝΛ?άα N-[(l S)-l-(聯苯-4-基甲基)-2-(呱啶-4-基 胺基)丙-2-基)-2-乳代乙基]-1 -(2,4_二氣 苯基)環丙醯胺 A 201040149Table 1 # Structure name IC50 251 cf3 N-8-azabicyclo[3.2.1]oct-3-yl-Να-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl} -4 -(Trifluoromethyl)-L-phenylalanamine decylamine A 252 Hz〆N-[(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-1 -(2,3-dihydro-1,4-benzodioxan-6-ylmethyl)-2-oxoethyl]-1-P-fluoro-4-(trifluoromethyl)phenyl Cyclopropylamine A 253 Br 4-Mo-Να- {[ 1 -(2,4-diphenyl)cyclopropyl]carbonyl}-indole-methyl-L-phenylalanamine decylamine A 254 ΗαχΛα N -[(l S)-l-(biphenyl-4-ylindenyl)-2-N-[(3R)-呱17-1,3-yl]-2.oxoethyl]-1 ~*( 2,4-diphenylphenyl) Cyclopropylamine A 255 N-[(3S)-1-azabicyclo[2·2·2]oct-3-yl]-4-indi-Να- {[ 1 _(2,3-difluorophenyl)cyclopropyl]carbonyl}-L-phenylalanamine decylamine A 256 Ν0.Ν£ί0 HV N-[(3S)-1-azabicycloindole.2.2]oct-3 -yl]_4_bromo-Nα-{[l-(2,6-difluorophenyl)cyclopropyl]carbonyl}-L· amphetamine amide A 257 ΗαΝΛ?άα N-[(l S)-l-( Biphenyl-4-ylmethyl)-2-(acridin-4-ylamino)propan-2-yl)-2-miloethyl]-1 -(2,4-diphenyl) ring Propylamine A 201040149

表1 # 結構 名稱 ic5〇 258 ΗαχΛ. Λ 2,4-二氯-Να- {[ 1 -(2,4-二氯苯基)環丙基] 参炭基} &quot;N-狐°定-4-基-L-本丙胺驢胺 A 259 Hcr^^0&gt;F Br 4_ 溴-N-(呱啶-4-基曱基)-Na-[(l-{4-[(三 氟甲基)氧]苯基Η裒丙基)裁基]-L-苯丙 胺醯胺 B 260 2,4-二氯-N-[(3R)-呱啶-3-基]-Να-[(1-{4-[(三氟曱基)氧]苯基}環丙基)羰基]-L-苯 丙胺醯胺 A 261 nh2 u N-{(lS)-2-(3-胺基-8-氮雜雙環[3·2·1]辛· 8_基)-1-[(2,4-二氯苯基)甲基]-2-氧代乙 基}-1-{4-[(三氟甲基)氧]苯基}環丙醯胺 A 262 2,4-二氣-N-[(3S&gt; 吡咯啶-3-基]-Να-[(1-{4-[(三氟甲基)氧]苯基}環丙基)羰基]-L-苯丙胺醯胺 A 263 »2^Ί^ F+F 以cf3 N-[(l S)-2-(4-胺基-4-甲基狐σ定小基)-2_ 氧代-1-{[4-(三氟甲基)苯基]曱基}乙基]-Η4-[(三氟甲基)氧]苯基}環丙醯胺 A 264 HaNj〇?a9 HV;f N-[(3R)-呱啶-3-基]-4-(三氟甲基)-Να-[(1-{4-[(三氟曱基)氧]苯基}環丙基)-幾 基]-L-苯丙胺醯胺 A 265 hO,/n(T?〇L9 HV;f N-[(3S)-吼咯啶-3-基]-4-(三氟甲基)-Να-[(Η4-[(三氣甲基)氧]苯基}環丙基Η炭 基]-L-苯丙胺醯胺 A 266 hOv/na1T?0-? H VB+ 4-溴-N-[(3S)-吡咯啶-3-基]-Να-[(1-{4-[(三氟甲基)氧]苯基}環丙基)羰基]-L-苯 丙胺感胺 A 146258.doc -229- 201040149Table 1 # Structure name ic5〇258 ΗαχΛ. Λ 2,4-Dichloro-Να- {[ 1 -(2,4-dichlorophenyl)cyclopropyl] ginsyl} &quot;N-狐°定定- 4-yl-L-benzamine amide A 259 Hcr^^0&gt;F Br 4_ bromo-N-(acridin-4-ylindenyl)-Na-[(l-{4-[(trifluoromethyl) Oxy]phenyl propyl propyl) benzyl]-L-phenylpropylamine guanamine B 260 2,4-dichloro-N-[(3R)-acridin-3-yl]-Να-[(1-{ 4-[(Trifluoromethyl)oxy]phenyl}cyclopropyl)carbonyl]-L-phenylalanamine decylamine A 261 nh2 u N-{(lS)-2-(3-Amino-8-azabicyclo) [3·2·1] 辛·8_yl)-1-[(2,4-dichlorophenyl)methyl]-2-oxoethyl}-1-{4-[(trifluoromethyl) Oxy]phenyl}cyclopropanamide A 262 2,4-digas-N-[(3S&gt; pyrrolidin-3-yl]-Να-[(1-{4-[(trifluoromethyl)oxy) ]phenyl}cyclopropyl)carbonyl]-L-phenylalanamine decylamine A 263 »2^Ί^ F+F with cf3 N-[(l S)-2-(4-amino-4-methylfox σ定小基)-2_ Oxo-1-{[4-(Trifluoromethyl)phenyl]indolyl}ethyl]-indole 4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide A 264 HaNj〇?a9 HV;f N-[(3R)-Acridine-3-yl]-4-(trifluoromethyl)-Να-[(1-{4-[(trifluoromethyl)oxy] Phenyl}cyclopropyl)-yl]-L-phenylalanamine decylamine A 265 hO, /n(T?〇L9 H V;f N-[(3S)-indolyl-3-yl]-4-(trifluoromethyl)-Να-[(Η4-[(trimethyl)oxy]phenyl}cyclopropyl hydrazine Carbon-based]-L-amphetamine amide A 266 hOv/na1T?0-? H VB+ 4-bromo-N-[(3S)-pyrrolidin-3-yl]-Να-[(1-{4-[( Trifluoromethyl)oxy]phenyl}cyclopropyl)carbonyl]-L-amphetamine Amine A 146258.doc -229- 201040149

表1 # 結構 名稱 IC5〇 267 N-[(3R)-呱啶-3-基]-Να-[(1-{4-[(三氟甲 基)氧]苯基}環丙基)羰基]-L-苯丙胺醯 胺 A 268 Χ^ο νη2 N-[(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-2&quot;氧代-1-(苯基曱基)乙基]-l-{4-[(三氟曱基)氧]苯基}環丙醯胺 A 269 N-[(3S)-«比咯啶-3-基]-Να-[(1-{4-[(三氟 甲基)氧]苯基}環丙基)羰基]-L-苯丙胺 醯胺 A 270 Ηαχι?αν 3-¾ 己基基]_Ν〜2[(1-{4-[(三氟曱基)氧]苯基}環丙基)羰基]-L-丙胺S&amp;胺 A 271 nh2 N-[(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-1-(ί哀己基曱基)-2~氧代乙基]-1 - {4-[(三氟曱基)氧]苯基}環丙醯胺 A 272 h〇v人 H b十 3-王展己基-N-[(3S)-°比嗜定-3-基]-Ν~2— [(1-{4-[(三氟曱基)氧]苯基}環丙基)羰 基]-L-丙胺醯胺 A 273 hn^n^?0lcF3 ΗΛ 2,4-二氯-Να-( {1 -[2-亂-4-(三氟甲基)苯 基]環丙基}羰基&gt;N-[(3R)-呱啶-3-基]-L-苯丙胺醯胺 A 274 i^0lCF3 4ίχχ νη2 N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-1-[(2,4-二氯苯基)甲基]_2-氧代乙 基}-1-[2-氣-4-(三氟甲基)苯基]環丙醯胺 A 146258.doc -230 - 201040149 Ο ΟTable 1 #Structure name IC5〇267 N-[(3R)-Acridine-3-yl]-Να-[(1-{4-[(trifluoromethyl)oxy]phenyl}cyclopropyl)carbonyl] -L-Amphetamine amide A 268 Χ^ο νη2 N-[(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-2&quot;Oxo-1 -(phenylindenyl)ethyl]-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide A 269 N-[(3S)-«byridine-3-yl] -Να-[(1-{4-[(Trifluoromethyl)oxy]phenyl}cyclopropyl)carbonyl]-L-phenylpropylamine decylamine A 270 Ηαχι?αν 3-3⁄4 hexyl]]Ν~2[( 1-{4-[(Trifluoromethyl)oxy]phenyl}cyclopropyl)carbonyl]-L-propylamine S&amp;amine A 271 nh2 N-[(lS)-2-(3-Amino-8- Azabicyclo[3.2.1]oct-8-yl)-1-()-oxoethyl]-1 - {4-[(trifluoromethyl)oxy]phenyl} Cyclopropylamine A 272 h〇v human H b 十3-王展己基-N-[(3S)-° than dodyl-3-yl]-Ν~2—[(1-{4-[(3 Fluorinyl)oxy]phenyl}cyclopropyl)carbonyl]-L-propylamine amide A 273 hn^n^?0lcF3 ΗΛ 2,4-dichloro-Να-( {1 -[2-chaos -4- (trifluoromethyl)phenyl]cyclopropyl}carbonyl&gt;N-[(3R)-acridin-3-yl]-L-phenylpropylamine decylamine A 274 i^0lCF3 4ίχχ νη2 N-{(lS)- 2-(3-Amino-8-azabicyclo[3.2 .1]oct-8-yl)-1-[(2,4-dichlorophenyl)methyl]_2-oxoethyl}-1-[2- gas-4-(trifluoromethyl)benzene ] 环 醯 A 146 146258.doc -230 - 201040149 Ο Ο

表1 # 結構 名稱 ic5〇 275 —---- 2,4-二氯-Na-({l-[2-氟-4-(三氟曱基)苯 基]環丙基}幾基)-N_[(3 S)』比咯啶_3-基]_ L-苯丙胺酿胺 A 276 + \χ3 N-[(lS)-2-(4-胺基斗甲基呱啶-1-基)-2-氧代-1-{ [4-(三氟曱基)苯基]曱基}乙基]-1 -[2-氟-4-(三氟甲基)苯基]環丙醯胺 A 277 —,—..... hOt 1^0-cf3 V Να-({1-[2_氟_4_(二氟甲基)苯基]-環丙 基}羰基)-N-[(3R)-呱啶-3-基]-4-(三氟甲 基)-L-苯丙胺醯胺 A 278 HOvn\^^CF3 h\x3 Na-( {1 _[2·氣冬(三氟甲基)苯基]-環丙 基}幾基)-N-[(3S)-e比略咬-3-基]-4-(三氟 甲基)-L-苯丙胺酿胺 A 279 Ηαχ^- 4-溴-Na-({ Ι-p-氟_4_(三氟曱基)苯基]環 丙基}徵基)-N-[(3R)-n瓜咬-3-基]-L-苯丙 胺醯胺 A 280 Νι??ά〇, NH2 ---- N-{(lS)-2-(3-胺基各氮雜雙環[3·2.1]辛-8_基溴笨基)曱基]-2-氧代乙基}-1-[2·氟-4-(三氟曱基)苯基]環丙醢胺 A 281 h〇vnA&gt;ih^0-cF3 H 4·演-Να-({ 1-[2-氟冰(三敦甲基)苯基]環 丙基}羰基)-N-[(3S)-n比咯咬_3_基]-L-苯 丙胺醯胺 A 146258.doc -231 · 201040149 表1 # 結構 名稱 ~~ __ ic5〇 282 HN〇rH1^^0LCF3 Να-({ 1-[2-氟冰(三氟曱基)苯基]-環丙 基}羰基)-N-[(m)-呱啶-3_基]-L-苯丙胺 醯胺 A 283 ^Vo nh2 N-[( 1 S)-2-(3-胺基-8-氮雜雙環[3 _2.1]辛-8_基)_2_氧代-1-(苯基甲基)乙基]-l-[2-氟-4-(三氟甲基)苯基]環丙醯胺 A 284 HOvnJv^^^CF3 Να-({ 1-[2-氟-4-(三1甲基)苯基]-環丙 基}羰基)-N-[(3S)-吡咯啶_3_基]-L_苯丙 胺醯胺 A 285 Ηακχ^〇, 3-ί哀己基-N~2~-({ 1-[2-氟-4-(三氟甲基） 苯基]環丙基}羰基)-N-[(m)-呱啶_3_基]_ L-丙胺醯胺 A 286 XfdCF3 nh2 N-[(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-1-(環己基曱基)_2_氧代乙基]-l-[2-氟-4-(三氟曱基)苯基]環丙醯胺 A 287 ---------- 1 HN〇v Hnco 3-環己基-N〜2〜-({1 -[2-氟-4-(三氟曱基) 苯基]環丙基}羰基)-N-[(3S)』比咯啶-3-基]-L-丙胺酿胺 A 288 Η2ΝΌ^孤 Br —-一-一^ N-(順式-4-胺基環己基)-4-演-Να-{[1-(2,4-二氣苯基)環丙基]羰基} -L-苯丙胺 醯胺 A _ -232· 146258.doc 201040149Table 1 # Structure name ic5〇275 —---- 2,4-Dichloro-Na-({l-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}yl)- N_[(3 S)"pyrrolidin-3-yl]_ L-amphetamine Amineral A 276 + \χ3 N-[(lS)-2-(4-Aminopiperidin-1-yl) -2-oxo-1-{[4-(trifluoromethyl)phenyl]indolyl}ethyl]-1 -[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropanamide A 277 —, —..... hOt 1^0-cf3 V Να-({1-[2_Fluoro_4_(difluoromethyl)phenyl]-cyclopropyl}carbonyl)-N-[( 3R)-Acridine-3-yl]-4-(trifluoromethyl)-L-phenylalanamine decylamine A 278 HOvn\^^CF3 h\x3 Na-( {1 _[2·气冬(Trifluoromethyl) Phenyl]-cyclopropyl}alkyl)-N-[(3S)-e than succinyl-3-yl]-4-(trifluoromethyl)-L-amphetamine A A 279 Ηαχ^- 4-bromo-Na-({ Ι-p-fluoro_4_(trifluoromethyl)phenyl]cyclopropyl} ketone)-N-[(3R)-n guate-3-yl]-L- Amphetamine A 280 Νι??ά〇, NH2 ---- N-{(lS)-2-(3-Amino-azabicyclo[3·2.1]oct-8-ylbromophenyl) fluorenyl ]-2-oxoethyl}-1-[2·fluoro-4-(trifluoromethyl)phenyl]cyclopropanamide A 281 h〇vnA&gt;ih^0-cF3 H 4·演-Να- ({ 1-[2-Fluoride (Tritonyl)phenyl]cyclopropyl}carbonyl)-N-[(3S)-n ratio bite _3_基]-L-Amphetamine amide A 146258.doc -231 · 201040149 Table 1 # Structure name~~ __ ic5〇282 HN〇rH1^^0LCF3 Να-({ 1-[2-Fluoride (trifluoromethane) Phenyl]-cyclopropyl}carbonyl)-N-[(m)-acridin-3-yl]-L-phenylalanamine decylamine A 283 ^Vo nh2 N-[( 1 S)-2-(3 -amino-8-azabicyclo[3 _2.1]oct-8-yl)_2-oxo-1-(phenylmethyl)ethyl]-l-[2-fluoro-4-(trifluoro Methyl)phenyl]cyclopropanamide A 284 HOvnJv^^^CF3 Να-({ 1-[2-fluoro-4-(trimethyl)phenyl]-cyclopropyl}carbonyl)-N-[ (3S)-pyrrolidine_3_yl]-L_phenylalanine decylamine A 285 Ηακχ^〇, 3-ί哀己基-N~2~-({ 1-[2-fluoro-4-(trifluoromethyl) Phenyl]cyclopropyl}carbonyl)-N-[(m)-acridine_3_yl]_ L-propylamine amide A 286 XfdCF3 nh2 N-[(lS)-2-(3-Amino- 8-Azabicyclo[3.2.1]oct-8-yl)-1-(cyclohexylfluorenyl)_2-oxoethyl]-l-[2-fluoro-4-(trifluoromethyl)phenyl ]cyclopropanamide A 287 ---------- 1 HN〇v Hnco 3-cyclohexyl-N~2~-({1 -[2-fluoro-4-(trifluoromethyl)benzene) ]]cyclopropyl}carbonyl)-N-[(3S)"pyrrolidin-3-yl]-L-propylamine uranyl A 288 Η2ΝΌ^ 孤 Br —-一-一^ N-(cis-4- Aminocyclohexyl)-4-deacting-Να-{[1-(2, 4-diphenylphenyl)cyclopropyl]carbonyl}-L-amphetamine decylamine A _ -232· 146258.doc 201040149

表1 # 結構 名稱 ic5〇 289 N-(反式-4-胺基環己基)-4-溴-Na-{[1-(2,4-二氣苯基)J展丙基]^炭基}-L-苯丙胺 醯胺 B 290 waxACF3 Hiac, 2,4-二氯-Ν〇Κ{ 1-[2_氣冰(三氟甲基)苯 基]環丙基}羰基)-Ν-呱啶-4-基-L-苯丙胺 醯胺 A 291 叫氣 Να-({ 1 -[2-氟-4-(三氟甲基)苯基]環丙基} 夢炭基定-4-基-4-(二亂曱基)-L-苯丙 胺醯胺 A 292 Hax^CF3 4_溴-Na-({ 1-[2-氟_4_(三氟曱基)苯基]環 丙基}羰基)-N-呱啶-4-基-L-苯丙胺醯胺 A 293 Hai^&amp;CF3 Na-({ 1-P-氟冬(三氟甲基)苯基]環丙基} 罗炭基)&quot;^-狐。定-4-基苯丙胺酿胺 A 294 h〇/^F3 3-環己基-N〜2~-({ 1 -[2-氟-4-(三氟曱基） 苯基]壤丙基}幾基)-N-狐p定-4-基-L-丙胺 醯胺 A 295 Br N_[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-4-漠-Να-{[1-(2,4,5-三氟苯基)環丙基]羰基}-L-苯丙胺醯胺 A 296 N-(氮雜環丁烷-3-基甲基)-4-漠-N-甲基-Να-[(Η4-[(三氧曱基)氧]苯基}環丙基) 羰基]-L-苯丙胺醯胺 B 146258.doc •233 - 201040149Table 1 # Structure name ic5〇289 N-(trans-4-aminocyclohexyl)-4-bromo-Na-{[1-(2,4-diphenyl)J-propyl]^ carbon-based }-L-Amphetamine Bamine B 290 waxACF3 Hiac, 2,4-Dichloro-indole { 1-[2_glycol (trifluoromethyl)phenyl]cyclopropyl}carbonyl)-indole-acridine 4-yl-L-phenylalanine decylamine A 291 is called gas Να-({ 1 -[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl} 梦炭基定-4-基-4 -(二曱曱基)-L-Amphetamine amide A 292 Hax^CF3 4_Bromo-Na-({ 1-[2-fluoro_4_(trifluoromethyl)phenyl]cyclopropyl}carbonyl)- N-Acridine-4-yl-L-phenylalanamine decylamine A 293 Hai^&amp;CF3 Na-({ 1-P-Fluoro(trifluoromethyl)phenyl]cyclopropyl} Rotamyl)&quot; ^-狐.定-4-基苯丙胺胺胺 A 294 h〇/^F3 3-cyclohexyl-N~2~-({ 1 -[2-fluoro-4-(trifluoromethyl)phenyl] Propyl}alkyl)-N-fox p-1,4-yl-L-alanamine A 295 Br N_[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4- Ν-Να-{[1-(2,4,5-trifluorophenyl)cyclopropyl]carbonyl}-L-phenylpropylamine decylamine A 296 N-(azetidin-3-ylmethyl)- 4-Mo-N-methyl-Να-[(Η4-[(trioxinyl)oxy]phenyl}cyclopropyl)carbonyl]-L-amphetamine amide B 146258.doc • 233 - 201040149

表1 # 結構 名稱 IC50 297 N-[(lS)-l-[(4-漠苯基)曱基]-2_(2,5-二氮 雜雙環[2·2.1]庚_2_基)_2_氧代乙基]-1-{4-[(三氟曱基)氧]苯基}環丙醯胺 A 298 Ηαχ*&gt;〇 HV:tF Ν-呱啶-4-基-4-(三氟曱基)-Να-[(1-{4_ [(三氟曱基)氧]苯基}環丙基)羰基]心苯 丙胺醯胺 A 299 hCXhX^^f N-呱啶_4_基-Να-[(1-{4-[(三氟曱基)氧] 苯基}環丙基)羰基]-L-苯丙胺醯胺 A 300 3-環己基-Ν-呱啶-4-基-Ν〜2〜-[(1 - {4-[(三 氟曱基)氧]苯基}環丙基)幾基]-L-丙胺 醯胺 A 301 N-(氮雜環丁烷-3-基曱基)-4-漠-Να-{[1-(2,4-二氯苯基)環丙基]羰基}-乂甲基心 苯丙胺醯胺 B 302 OLBr Ν-[( 1S)-1-[(4-溴苯基)甲基]-2-(2,5-二氮 雜雙環[2.2.1]庚-2-基)-2-氧代乙基]-1-(2,4-二氯苯基)環丙醯胺 A 303 N-[(lS)-l-[(4-溴苯基)曱基]-2_{4_[(1-甲 基乙基)胺基]狐^定-1-基}-2-氧代乙基]-1_ (2,4-二氯苯基)環丙醯胺 A 304 Ηα,ι^α+ρ 2,4-二氣-&gt;1-呱啶-4-基-1^-[(1-{4-[(三氟 曱基)氧]苯基}環丙基)羰基]-L-苯丙胺 醯胺 A 146258.doc -234 - 201040149Table 1 # Structure name IC50 297 N-[(lS)-l-[(4-Molyphenyl)indolyl]-2_(2,5-diazabicyclo[2·2.1]hept-2-yl)_2 _Oxoethyl]-1-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide A 298 Ηαχ*&gt;〇HV:tF Ν-acridin-4-yl-4-( Trifluoromethyl)-Να-[(1-{4_[(trifluoromethyl)oxy]phenyl}cyclopropyl)carbonyl]pecylamine amide A 299 hCXhX^^f N-acridine_4_yl -Να-[(1-{4-[(Trifluoromethyl)oxy]phenyl}cyclopropyl)carbonyl]-L-phenylalanamine decylamine A 300 3-cyclohexyl-indole-acridin-4-yl- Ν~2~-[(1 - {4-[(Trifluoromethyl)oxy]phenyl}cyclopropyl) benzyl]-L-propylamine amide A 301 N-(azetidin-3-曱基)-4-Mo-Να-{[1-(2,4-Dichlorophenyl)cyclopropyl]carbonyl}-indole methyl amphetamine amide B 302 OLBr Ν-[( 1S)-1 -[(4-bromophenyl)methyl]-2-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2-oxoethyl]-1-(2,4 -dichlorophenyl)cyclopropanamide A 303 N-[(lS)-l-[(4-bromophenyl)indolyl]-2_{4_[(1-methylethyl)amino]fox^ Ding-1-yl}-2-oxoethyl]-1_(2,4-dichlorophenyl)cyclopropanamide A 304 Ηα, ι^α+ρ 2,4-digas-&gt;1- Acridine-4-yl-1^-[(1-{4-[(trifluoromethyl)oxy] Yl} cyclopropyl) carbonyl] -L- amphetamine Amides A 146258.doc -234 - 201040149

表1 # 結構 名稱 IC5〇 305 N-{(lS)-l-[(2+二氣苯基)曱基]-2-[4-(甲 基胺基)狐咬-l-基]-2-乳代乙基}-l-{4-[(三氟曱基)氧]苯基}環丙醯胺 A 306 H2N cMc, F N-{(1 S)-2-(4-胺基狐 π定-1-基)-1-[(2,4-二 氣苯基)甲基]-2-氧代乙基}-1-{4-[(三氟 甲基)氧]苯基}環丙醯胺 A 307 F N-[(l S)-2-[4-(甲基胺基)狐α定-1-基]-2-乳 代-1-{[4-(三氟曱基)苯基]甲基}乙基]-1-{4-[(三氟曱基)氧]苯基}環丙醯胺 A 308 H2N \A^ff F Ν-[( 1 S)-2-(4-胺基11 瓜σ定-1 -基1 _ {[4-(三氟甲基)苯基]甲基}乙基]-H4· [(三氟甲基)氧]苯基}環丙醯胺 A 309 、疮 N-{(1 S)-l-[(4-溴苯基)甲基]-244-(甲基 胺基)孤变-1-基]-2-氧代乙基}-1-{4-[(二 氟甲基)氧]苯基}環丙醯胺 A 310 N- { (1 S)-2-(4-胺基 °瓜咬-1 -基)-1 - [(4- &gt;臭苯 基)甲基]_2_氧代乙基}-H4-[(三氟甲基) 氡]苯基}環丙醯胺 A 311 N-[(lS)-2-[4-(甲基胺基)呱啶-1-基]-2-氧 代-1-(苯基甲基)乙基Η-{4_ [(三氟甲基) 氧]苯基}環丙醯胺 A 312 Ν- [(1 S)-2-(4-胺基呱啶-1 -基)-2-氧代-1 -(苯基甲基)乙基]-H4-[(三氟曱基)氧]苯 基}環丙醯胺 A 146258.doc -235 - 201040149Table 1 #Structure name IC5〇305 N-{(lS)-l-[(2+Diphenyl)indenyl]-2-[4-(methylamino)fox bite-l-yl]-2 -miloethyl}-l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide A 306 H2N cMc, F N-{(1 S)-2-(4-amino fox π定-1-yl)-1-[(2,4-diphenyl)methyl]-2-oxoethyl}-1-{4-[(trifluoromethyl)oxy]phenyl} Cyclopropylamine A 307 F N-[(l S)-2-[4-(methylamino)fox alpha-1,4-yl]-2-milo-1-{[4-(trifluoroanthracene) Phenyl]methyl}ethyl]-1-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide A 308 H2N \A^ff F Ν-[( 1 S)-2 -(4-Amino 11 melon sigma-1 -yl 1 _ {[4-(trifluoromethyl)phenyl]methyl}ethyl]-H4. [(trifluoromethyl)oxy]phenyl} Cyclopropylamine A 309, sore N-{(1 S)-l-[(4-bromophenyl)methyl]-244-(methylamino) orphan-1-yl]-2-oxo Ethyl}-1-{4-[(difluoromethyl)oxy]phenyl}cyclopropanamide A 310 N- { (1 S)-2-(4-Amino- guanate-1 -yl) -1 - [(4- &gt;odorophenyl)methyl]_2_oxoethyl}-H4-[(trifluoromethyl)phosphonium]phenyl}cyclopropanamide A 311 N-[(lS) -2-[4-(methylamino)acridin-1-yl]-2-oxo-1-(phenylmethyl)ethyl hydrazine-{4_[(trifluoromethyl)oxy]phenyl }cyclopropanamide A 312 Ν-[(1 S)-2-(4-Aminopyridin-1-yl)-2-oxo-1 -(phenylmethyl)ethyl]-H4-[ (trifluoromethyl)oxy]phenyl}cyclopropanamide A 146258.doc -235 - 201040149

表1 # 結構 名稱 IC5〇 313 N-{(lS)-l-(環己基曱基)-2-[4-(曱基胺 基基]-2-乳代乙基}-1_{4-[(二亂 曱基)氧]苯基}環丙醯胺 B 314 N-[( 1 S)-2-(4-胺基呱啶小基)-1-(環己基 曱基)-2-氧代乙基]-1-{4-[(三氟甲基)氧] 苯基}環丙醯胺 A 315 、K cA^C, N-{(lS)-l-[(2,4-二氯苯基)曱基]-2-[4-(甲 基胺基户瓜17定-1-基]-2-乳代乙基}-1-[2-氣-4-(三氟曱基)苯基]環丙醯胺 A 316 H2N ci^c, N-{(lS)-2-(4-胺基呱啶-1-基)-l-[(2,4-二 氯苯基)曱基]_2_氧代乙基}-1-[2_氟_4_ (三氟甲基)苯基]環丙醯胺 A 317 Ι-p-氟-4-(三氟甲基)苯基]-N-[(1S)_2_[4-(曱基胺基)狐。定-1-基]·2-氧代-1-{[4-(二 氟甲基)苯基]曱基}乙基]環丙醯胺 C 318 H2N F F N-[(lS)-2-(4-胺基呱啶-1-基)-2-氧代-1-{[4-(三氟甲基)苯基]甲基}乙基]-1-P-1-4-(三氟曱基)苯基]環丙醯胺 A 319 N-{(lS)-l-[(4-漠苯基)曱基]-2-[4-(曱基 胺基)狐ϋ定 I-基]_2_乳代乙基} -1-[2-鼠-4-(三氟曱基)苯基]環丙醯胺 A 146258.doc -236 - 201040149Table 1 # Structure name IC5〇313 N-{(lS)-l-(cyclohexyldecyl)-2-[4-(decylamino)-2-miloethyl}-1_{4-[ (二曱曱基)oxy]phenyl}cyclopropanamide B 314 N-[( 1 S)-2-(4-aminoacridinyl)-1-(cyclohexylfluorenyl)-2-oxo Alkenyl]-1-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide A 315 , K cA^C, N-{(lS)-l-[(2,4-di Chlorophenyl)indenyl]-2-[4-(methylaminobutyric 17-decyl-1-yl]-2-miloethyl}-1-[2- gas-4-(trifluoromethyl) Phenyl]cyclopropanamide A 316 H2N ci^c, N-{(lS)-2-(4-aminoacridin-1-yl)-l-[(2,4-dichlorophenyl) Indenyl]_2_oxoethyl}-1-[2_fluoro_4_(trifluoromethyl)phenyl]cyclopropanamide A 317 Ι-p-fluoro-4-(trifluoromethyl)phenyl ]-N-[(1S)_2_[4-(decylamino)fox.dent-1-yl]2-oxo-1-{[4-(difluoromethyl)phenyl]fluorenyl} Ethyl]cyclopropanamide C 318 H2N FF N-[(lS)-2-(4-Aminoacridin-1-yl)-2-oxo-1-{[4-(trifluoromethyl) Phenyl]methyl}ethyl]-1-P-1-4-(trifluoromethyl)phenyl]cyclopropanamide A 319 N-{(lS)-l-[(4-Molyphenyl) Mercapto]-2-[4-(decylamino)foxidine I-yl]_2_miloethyl}-1-[2-mur-4-(trifluoromethyl)phenyl]cyclopropene Guanamine A 146258.doc -236 - 201040149

表1 # 結構 名稱 IC5〇 320 .ΡΛχβγ F N-{(lS)-2-(4-胺基呱啶-1-基)-l-[(4-溴苯 基)曱基]-2-氧代乙基}-1-[2-氟冬(三氟 甲基)苯基]環丙醯胺 A 321 1 -[2_ 氟_4_(三氟甲基)苯基]-N-[(l S)-2_[4_ (甲基胺基)狐17定-1-基]-2-氧代-1-(苯基曱 基)乙基]環丙醯胺 B 322 (革基甲基)乙基]-l-[2_氟_4_(三氟甲基） 苯基]環丙醯胺 A 323 N-{(1 S)-l-(環己基甲基)-2-[4-(甲基胺 基)狐。定-1-基]-2-乳代乙基}-1-[2-鼠-4_ (三氟曱基)苯基]環丙醯胺 B 324 H2N N-[(lS)-2-(4-胺基呱啶-1-基)-1-(環己基 曱基)_2_氧代乙基]-1-[2_氣冬(三氟甲基) 苯基]環丙醯胺 A 325 Ηώ^^〇, 4-漠-Να- {[ 1 -(2,4-二氯苯基)環丙基]羰 基}-Ν-(2-曱基狐。定-4-基)-L·苯丙胺酸胺 A 326 H V N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-4-漠-術-{[1-(2,3,4-三氟苯基)環丙基]羰基}-L-苯丙胺醯胺 A 327 H V N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-4-溴-Να-({ 1-[4-氟-H三氟甲基)苯基]環丙基} 羰基)-L-苯丙胺醯胺 A 146258.doc -237- 201040149Table 1 #Structure name IC5〇320 .ΡΛχβγ F N-{(lS)-2-(4-Aminopyridin-1-yl)-l-[(4-bromophenyl)indolyl]-2-oxo Ethylethyl}-1-[2-fluorodong(trifluoromethyl)phenyl]cyclopropanamide A 321 1 -[2_fluoro_4_(trifluoromethyl)phenyl]-N-[(l S -2_[4_(Methylamino)fox 17-den-1-yl]-2-oxo-1-(phenylindenyl)ethyl]cyclopropanamide B 322 (Gentylmethyl)ethyl ]-l-[2_Fluoro_4_(trifluoromethyl)phenyl]cyclopropanamide A 323 N-{(1 S)-l-(cyclohexylmethyl)-2-[4-(methyl Amino) fox. Di-1-yl]-2-miloethyl}-1-[2-rat-4_(trifluoromethyl)phenyl]cyclopropanamide B 324 H2N N-[(lS)-2-(4 -aminopyridin-1-yl)-1-(cyclohexylfluorenyl)_2-oxoethyl]-1-[2-glycol(trifluoromethyl)phenyl]cyclopropanamide A 325 Ηώ ^^〇, 4-Mo-Να- {[ 1 -(2,4-Dichlorophenyl)cyclopropyl]carbonyl}-indole-(2-indolyl fox.din-4-yl)-L-amphetamine Acid amine A 326 HV N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-di-surgery-{[1-(2,3,4-trifluorophenyl) Cyclopropyl]carbonyl}-L-amphetamine amide A 327 HV N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-Να-({ 1- [4-Fluoro-H-trifluoromethyl)phenyl]cyclopropyl}carbonyl)-L-amphetamine amide A 146258.doc -237- 201040149

表1 # 結構 名稱 IC5〇 328 以Br Ν-(順式-4-胺基環己基)-4-溴-Να-({ 1-[2-氟-4-(三氟甲基)苯基]環丙基Η炭基)-L-苯丙胺醯胺 A 329 N-(順式-4-胺基ί衷己基)-4-&gt;臭-Ntx-[(l-{4-[(三氟曱基)氧]苯基}環丙基)数基]-L-苯 丙胺醯胺 A 330 rx^3 H2N^ Vr N-{(lS)-2-(4-胺基-4-曱基呱啶-1-基)-1-[(4-&gt;臭苯基)曱基]-2-氧代乙基}-1-[2-氟-4-(三氟甲基)苯基]環丙醯胺 A 331 4-溴-N-呱啶-4-基-Na-[(l-{4-[(三氟甲 基)氧]苯基}環丙基)羰基]-L-苯丙胺醯 胺 A 332 4-漠-Να-{[1-(3-氟苯基)環丙基]羰基}-1^-狐。定-4-基-L·苯丙胺驢胺 B 333 ?料 4-溴-N-呱啶-4-基-Να-{[1-(2,4,5-三氟苯 基)環丙基]羰基}-L-苯丙胺醯胺 A 334 N-[(lS)-l-[(4-溴苯基)曱基]-2-(4-羥基呱 0定-1-基)-2-氧代乙基]-1-(2,4_二氯苯基) 環丙醯胺 B 335 νη2 N-{(lS)-2-(3-胺基-8-氮雜雙環[3·2·1]辛-8-基)-1-[(4-&gt;臭苯基)甲基]-2-乳代乙基}-1-(2,4,5-三氟苯基)環丙醯胺 A 146258.doc -238 - 201040149Table 1 #Structure name IC5〇328 with Br Ν-(cis-4-aminocyclohexyl)-4-bromo-Να-({ 1-[2-fluoro-4-(trifluoromethyl)phenyl] Cyclopropylhydrazine-based-L-phenylalanamine decylamine A 329 N-(cis-4-aminopyranyl)-4-&gt;odor-Ntx-[(l-{4-[(trifluorofluorene) Oxy]phenyl}cyclopropyl)lamyl]-L-phenylalanamine decylamine A 330 rx^3 H2N^ Vr N-{(lS)-2-(4-Amino-4-mercaptoacridine- 1-yl)-1-[(4-&gt;odorophenyl)indolyl]-2-oxoethyl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropene Amine A 331 4-bromo-N-acridin-4-yl-Na-[(l-{4-[(trifluoromethyl)oxy]phenyl}cyclopropyl)carbonyl]-L-phenylpropylamine decylamine A 332 4- Desert-Να-{[1-(3-Fluorophenyl)cyclopropyl]carbonyl}-1^-fox. 4-K-L-Amphetamine Benzamine B 333® 4-Bromo-N-Acridine-4-yl-Να-{[1-(2,4,5-trifluorophenyl)cyclopropyl] Carbonyl}-L-phenylalanine decylamine A 334 N-[(lS)-l-[(4-bromophenyl)indolyl]-2-(4-hydroxyindole-1-decyl)-2-oxo Ethyl]-1-(2,4-dichlorophenyl) Cyclopropylamine B 335 νη2 N-{(lS)-2-(3-Amino-8-azabicyclo[3·2·1] Oct-8-yl)-1-[(4-&gt;odorophenyl)methyl]-2-miloethyl}-1-(2,4,5-trifluorophenyl)cyclopropanamide A 146258.doc -238 - 201040149

表1 # 結構 名稱 ic5〇 336 。又IF N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-4-漠-Na-({ 1 -[2-(三氟甲基)苯基]環丙基}羰 基)-L-苯丙胺醯胺 B 337 N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]斗演-Na-({ 1 -[4-氟-2-(三氟甲基)苯基]環丙基} 羰基)-L-苯丙胺醯胺 A 338 H VBr N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-4-、;臭-Να-{[1-(2,4-二氟苯基)環丙基]羰基}-L-苯丙胺醯胺 A 339 Ηα,ιξφιΡ 4-溴-N-[(3R)-呱啶-3-基]-Να-{[1-(2,4,5-三氟苯基)環丙基]羰基}-L-苯丙胺醯胺 A 340 ^•XiJaF ^ VBr N-[(3S)-1-氮雜雙環[2.2.2]辛-3-基]-4-溴-1^〇1-{[1-(4-鼠苯基)環丙基]隸基}-1^-苯丙 胺醯胺 A 341 ^i^XX0CFs nh2 Br N-{(lR)-2-(3-胺基-8-氮雜雙環[3.2·1]辛-8-基)-1-[(4-溴苯基)曱基]-2-氧代乙基}-1-{4-[(三氟甲基)氧]苯基}環丙醯胺 A 342 ^X^Ci0CF3 N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)小[(4-氟苯基)甲基]-2-氧代乙基}-1-{4-[(三氟曱基)氧]苯基}環丙醯胺 A 146258.doc -239- 201040149Table 1 # Structure Name ic5〇 336. Further IF N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-di-Na-({ 1 -[2-(trifluoromethyl)phenyl]cyclopropane }}carbonyl)-L-phenylalanine decylamine B 337 N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl] bucket-Na-({ 1 -[4-fluoro-2 -(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-L-phenylalanamine decylamine A 338 H VBr N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]- 4-,; odor-Να-{[1-(2,4-difluorophenyl)cyclopropyl]carbonyl}-L-phenylalanamine decylamine A 339 Ηα, ιξφιΡ 4-bromo-N-[(3R)- Acridine-3-yl]-Να-{[1-(2,4,5-trifluorophenyl)cyclopropyl]carbonyl}-L-phenylalanamine decyl A 340 ^•XiJaF ^ VBr N-[(3S --1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-1^〇1-{[1-(4-murinephenyl)cyclopropyl]-yl}-1^- Amphetamine amide A 341 ^i^XX0CFs nh2 Br N-{(lR)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-1-[(4-bromo) Phenyl) indenyl]-2-oxoethyl}-1-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide A 342 ^X^Ci0CF3 N-{(lS)-2 -(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)small [(4-fluorophenyl)methyl]-2-oxoethyl}-1-{4-[ (trifluoromethyl)oxy]phenyl}cyclopropanamide A 146258.doc -239- 201040149

表1 # 結構 名稱 IC50 343 _ ^Br N-{(lS)-2-(4-胺基-4-曱基呱啶-1-基)-1-[(4-漠苯基)甲基]_2_氧代乙基}-1-(2,4-二 氟苯基)環丙醯胺 B 344 4-溴-Να- {[ 1 -(2,4-二氟苯基)環丙基]羰 *}-N-[(3R)-呱啶-3-基]-L-苯丙胺醯胺 A 345 Η2Ν Βγ N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-1 -[(4-溴苯基)甲基]-2-氧代乙基}-1-(2,4-二氟苯基)環丙醯胺 A 346 _ U-Br N- {(1 S)-2-(4-胺基-4-甲基呱啶-1 -基)-1 -[(4-溴苯基)甲基]-2-氧代乙基}-1-(2,3,4-三氟苯基)環丙醯胺 B 347 Ηα,χξ^; 4-溴-N- [(3R)-呱啶-3-基]-Να- {[ 1 -(2,3,4-三氟苯基)環丙基]羰基}-L-苯丙胺醯胺 A 348 擦 Η2〆 Br N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-1-[(4_漠苯基)甲基]_2-氧代乙基}-1-(2,3,4-三氟苯基)環丙醯胺 A 349 hCxx^o^ HV 4-漠-Να-({1-[4-氟-3-(三氟甲基)苯基]環 丙基}搂基)*N~[(3R)-狐咬-3-基]-L-苯丙 胺醯胺 A 350 H2〆 Br N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2·1]辛-8_基)-1-[(4_&gt;臭苯基)曱基]~2·氧代乙基}-1-[4-氟-3-(三氟甲基)苯基]環丙醯胺 A 146258.doc -240- 201040149Table 1 # Structure name IC50 343 _ ^Br N-{(lS)-2-(4-Amino-4-mercaptoacridin-1-yl)-1-[(4-oxaphenyl)methyl] _2_oxoethyl}-1-(2,4-difluorophenyl)cyclopropanamide B 344 4-bromo-Να- {[ 1 -(2,4-difluorophenyl)cyclopropyl] Carbonyl}}-N-[(3R)-acridin-3-yl]-L-phenylalanamine decylamine A 345 Η2Ν Βγ N-{(lS)-2-(3-Amino-8-azabicyclo[3.2 .1]oct-8-yl)-1 -[(4-bromophenyl)methyl]-2-oxoethyl}-1-(2,4-difluorophenyl)cyclopropanamide A 346 _ U-Br N- {(1 S)-2-(4-Amino-4-methylacridin-1-yl)-1 -[(4-bromophenyl)methyl]-2-oxo Ethyl}-1-(2,3,4-trifluorophenyl)cyclopropanamide B 347 Ηα,χξ^; 4-bromo-N-[(3R)-acridin-3-yl]-Να- {[ 1 -(2,3,4-Trifluorophenyl)cyclopropyl]carbonyl}-L-phenylpropylamine decylamine A 348 Η 2〆Br N-{(lS)-2-(3-Amino-8 -azabicyclo[3.2.1]oct-8-yl)-1-[(4_ desertyl)methyl]_2-oxoethyl}-1-(2,3,4-trifluorophenyl) Cyclopropylamine A 349 hCxx^o^ HV 4- Desert-Να-({1-[4-Fluoro-3-(trifluoromethyl)phenyl]cyclopropyl}fluorenyl)*N~[( 3R)-fox bit-3-yl]-L-phenylalanamine decylamine A 350 H2〆Br N-{(lS)-2-(3-amino-8-azabicyclo[3.2.1]oct-8_ Base)-1-[(4_&gt; Odor phenyl) fluorenyl]~2. oxoethyl}-1-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropanamide A 146258.doc -240- 201040149

表1 # 結構 名稱 ic5〇 351 H2N uBr N-{(lS)-2-(4-胺基-4-甲基狐 a定-1-基)-1· [(4-溴苯基)甲基]-2-氧代乙基}-1-(2,3-二 氟苯基)環丙醯胺 C 352 4-漠-Να-{[1-(2,3-二氟苯基)環丙基]羰 基卜N-[(3R)·狐°定-3-基]-L·苯丙胺酸胺 A 353 H2〆 Br N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)_1-[(4_&gt;臭苯基)曱基]-2-氧代乙基}-1 -(2,3 -二氟苯基)環丙醯胺 A 354 N-{(lS)-2-(4-胺基-4-甲基狐 基)-1_ [(4-漠苯基)甲基]-2-氧代乙基}-1-[4-氟-3-(三氟曱基)苯基]環丙醯胺 A 355 h2n X^Br N-{(lS)-2-(4-胺基-4-曱基呱啶-1-基)-1-[(4-溴苯基)甲基]-2-氧代乙基}-1-(2-氟 苯基)環丙醯胺 C 356 Hax^ HV 4-漠' -Να- {[ 1 -(2-氣苯基)環丙基]親基} _ N-[(3R)-呱啶-3-基]苯丙胺醯胺 B 357 费 n2〆 Br N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-1-[(4-&gt;臭苯基)甲基]-2-氧代乙基}-1-(2-氟苯基)環丙醯胺 A 358 4_氟-Na-({ 1-[2_氟_4_(三氟曱基)苯基]環 丙基}羰基)-N-[(3R)-呱啶-3-基]-L-苯丙 胺醯胺 A 146258.doc •241 - 201040149Table 1 # Structure name ic5〇351 H2N uBr N-{(lS)-2-(4-Amino-4-methylfox aden-1-yl)-1· [(4-bromophenyl)methyl ]-2-oxoethyl}-1-(2,3-difluorophenyl)cyclopropanamide C 352 4-Moist-Να-{[1-(2,3-difluorophenyl)cyclopropane Alkyl carbonyl N-[(3R)·狐°-3-yl]-L·phenylalanine A 353 H2〆Br N-{(lS)-2-(3-Amino-8-azabicyclo [3.2.1] Oct-8-yl)_1-[(4_&gt;odorophenyl)indolyl]-2-oxoethyl}-1 -(2,3-difluorophenyl)cyclopropanamide A 354 N-{(lS)-2-(4-Amino-4-methylfoxyl)-1_[(4-oxaphenyl)methyl]-2-oxoethyl}-1-[4- Fluoro-3-(trifluoromethyl)phenyl]cyclopropanamide A 355 h2n X^Br N-{(lS)-2-(4-amino-4-mercaptoacridin-1-yl)- 1-[(4-bromophenyl)methyl]-2-oxoethyl}-1-(2-fluorophenyl)cyclopropanamide C 356 Hax^ HV 4- Desert' -Να- {[ 1 -(2-Phenylphenyl)cyclopropyl]-carbyl} _ N-[(3R)-Acridine-3-yl]-phenylalanamine amide B 357 费n2〆Br N-{(lS)-2-(3 -amino-8-azabicyclo[3.2.1]oct-8-yl)-1-[(4-&gt;odorophenyl)methyl]-2-oxoethyl}-1-(2- Fluorophenyl)cyclopropanamide A 358 4_fluoro-Na-({ 1-[2_fluoro_4_(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-N-[(3R)- Acridine-3-yl]-L-phenylpropylamine amide A 146258.doc •241 - 201040149

表1 # 結構 名稱 IC50 359 N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8_基)-1 -[(4_氟苯基)曱基]-2_氧代乙基}-1 -[2-氟-4-(三氟曱基)苯基]環丙醯胺 A 360 _ UBr N-{(lS)-2-(4-胺基-4-曱基呱啶-1-基)-1-[(4-溴苯基)曱基]-2-氧代乙基} -1 -(4-氟 苯基)環丙醯胺 C 361 Ηαχτ?αΡ HV 4-演-Να-{[1-(4-氟苯基)環丙基]羰基}-N-[(3R)-呱啶-3-基]-L-苯丙胺醯胺 B 362 Η2〆 Βγ N-{(lS)-2-(3_胺基各氮雜雙環[3.2.1]辛-8-基)-1-[(4-&gt;臭苯基)曱基]-2-氧代乙基}-1-(4-氟苯基)環丙醯胺 A 363 Ηηχία0Λ： Η A 4-氟-N-[(3R)-呱啶-3-基]-Να-[(1-{4-[(三 氟曱基)氧]苯基}環丙基)羰基]-L-苯丙 胺醯胺 A 364 rX^3 !''1-{(18)-2-(4-胺基13瓜'1定-1-基)-1-[(4-鼠苯 基)曱基]-2-氧代乙基氟-4-(三氟 曱基)苯基]環丙醯胺 A 365 广 n^^X，cf N-{(1 S)-2-(4-胺基0瓜0定-1-基)-1-[(4-氣苯 基)曱基]-2-氧代乙基}-1-{4-[(三氟曱基) 氧]苯基}環丙醯胺 A 146258.doc -242- 201040149Table 1 # Structure name IC50 359 N-{(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-1 -[(4-fluorophenyl)fluorene 2-[2-oxoethyl}-1 -[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropanamide A 360 _ UBr N-{(lS)-2-(4-amine 4--4-(indolyl-1-yl)-1-[(4-bromophenyl)indolyl]-2-oxoethyl}-1(4-fluorophenyl)cyclopropanamide C 361 Ηαχτ?αΡ HV 4-Derivative-Να-{[1-(4-Fluorophenyl)cyclopropyl]carbonyl}-N-[(3R)-acridin-3-yl]-L-phenylalaninamide B 362 Η2〆Βγ N-{(lS)-2-(3_Amino-azabicyclo[3.2.1]oct-8-yl)-1-[(4-&gt;odorophenyl)indolyl]- 2-oxoethyl}-1-(4-fluorophenyl)cyclopropanamide A 363 Ηηχία0Λ: Η A 4-fluoro-N-[(3R)-acridin-3-yl]-Να-[( 1-{4-[(Trifluoromethyl)oxy]phenyl}cyclopropyl)carbonyl]-L-phenylalanamine decylamine A 364 rX^3 !''1-{(18)-2-(4-amine 13-Melon '1-1-yl)-1-[(4-murophenyl)indolyl]-2-oxoethylfluoro-4-(trifluoromethyl)phenyl]cyclopropanamide A 365 广广 n^^X, cf N-{(1 S)-2-(4-Amino 0 guan0-den-1-yl)-1-[(4-phenylphenyl)indolyl]-2-oxo Alkenyl}-1-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide A 146258.doc -242- 201040149

表1 # 結構 名稱 IC5〇 366 nh2 N-{(lS)-2-(3-胺基-8-氮雜雙環[3.2.1]辛-8-基)-l-[(4-漠苯基)甲基]-2-氧代乙基}-2-曱基_2-{4·[(三氟曱基)氧]苯基}丙醯 胺 A 367 hnCiX^CLo^； 4-溴-&gt;^-(2-曱基-2-{4-[(三氟曱基)氧]苯 基}丙醯基)-N-[(3R)-呱啶-3-基]-L-苯丙 胺醯胺 A 368 N-{(lS)-2-[(3S)-3-胺基。比咯啶-1-基]-1-[(4_氟苯基)甲基]_2_氧代乙基}-1-{4-[(三 氟曱基)氧]苯基}環丙醯胺 A 369 VTCI h2n l^Br N-{(lS)-2-(4-胺基-4-甲基呱啶-1-基)-1-[(4-溴苯基)甲基]-2-氧代乙基}-2-(2,4-二 氯苯基)-2-曱基丙醢胺 A 370 hCVO^&amp;c HV 4-溴-Na-[2-(2,4-二氯苯基)-2-甲基丙醯 基]-N-[(3R)-狐17定-3-基]-L-苯丙胺酿胺 A 371 H2N,0^^^cf N-{(lS)-2-[(3S)-3-胺基吡咯啶-1-基]-1-[(4-溴苯基)甲基]-2-氧代乙基氟-4-(三氟甲基)苯基]環丙醯胺 A 146258.doc -243 - 201040149Table 1 # Structure name IC5〇366 nh2 N-{(lS)-2-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)-l-[(4-Molyphenyl) )methyl]-2-oxoethyl}-2-indenyl-2-{4·[(trifluoromethyl)oxy]phenyl}propanamine A 367 hnCiX^CLo^; 4-bromo-&gt ;^-(2-mercapto-2-{4-[(trifluoromethyl)oxy]phenyl}propenyl)-N-[(3R)-acridin-3-yl]-L-phenylalanine Amine A 368 N-{(lS)-2-[(3S)-3-Amino. Pyrrolidine-1-yl]-1-[(4-fluorophenyl)methyl]_2-oxoethyl}-1-{4-[(trifluoromethyl)oxy]phenyl}cyclopropene Amine A 369 VTCI h2n l^Br N-{(lS)-2-(4-Amino-4-methylacridin-1-yl)-1-[(4-bromophenyl)methyl]-2 -oxoethyl}-2-(2,4-dichlorophenyl)-2-mercaptopropanamide A 370 hCVO^&amp;c HV 4-bromo-Na-[2-(2,4-di Chlorophenyl)-2-methylpropanyl]-N-[(3R)-fox 17-but-3-yl]-L-amphetamine A A 371 H2N,0^^^cf N-{(lS) -2-[(3S)-3-Aminopyrrolidin-1-yl]-1-[(4-bromophenyl)methyl]-2-oxoethylfluoro-4-(trifluoromethyl) Phenyl]cyclopropanamide A 146258.doc -243 - 201040149

表1 # 結構 名稱 IC5〇 372 N-{(lS)-2-[(3S)-3-胺基。比咯咬-1-基]-1-[(4-溴苯基)甲基]-2-氧代乙基[(三 氟曱基)氧]苯基}環丙醯胺 A 373 〇°^A N-{(lS)-2-[(3S)-3-胺基。比咯啶-1-基]-1-[(4_氟苯基)甲基]_2_氧代乙基} - 1-Ρ-1 4-(三氟曱基)苯基]環丙醯胺 B 374 Ηαχία9 HV:子1 N-[(3R)-呱啶-3-基]-4-(三氟甲基)-Να-[(1-{4-[(三氟曱基)氧]苯基}環丙基)-裁 基]-L-苯丙胺醯胺 A 375 cf3 N-[(lS)-2-[(3R)-3-胺基呱啶-1-基]-2-氧 代小{[4-(三氟曱基)苯基]曱基}乙基H-{4-[(三氟甲基)氧]苯基}環丙醯胺 B 376 N-[(3S)-呱啶-3-基]-4-(三氟甲基)-Nct-[(1-{4-[(三敗曱基)氧]苯基}環丙基Η炭 基]-L-苯丙胺疏胺 A 為了清楚和理解目的，已經通過示例性說明和實施例的 方法，比較詳細地描述了前文的發明。還參考各種特定的 實施方案和技術而描述了本發明。然而應當理解的是可進 行許多變化和改進而仍保持在本發明的精神和範圍内。對 於本領域的技術人員來說明顯的是這些變化和改進可在所 146258.doc -244- 201040149 附的申請專利範_„ ......—〜./AS治迎解的是上 文描述意圖為示例性說明的而不是限制性的。 口此’本發明的範圍不應當根據上文說明書來確定，而是應 附申請專利範圍及等同中請專利範圍的全部範n :-申請中引用的所有專利、專利申請和都= 有目的以全文引用的方. 甘2，田众六 丨為了所 &gt;加宙 ^ ，/、引用程度就如同# _ # 每一個專利、專利申社 丨j知不將 甲叫或出版物以全文引用的方式併入 ❹Table 1 # Structure Name IC5〇 372 N-{(lS)-2-[(3S)-3-Amino. Tetidine-1-yl]-1-[(4-bromophenyl)methyl]-2-oxoethyl[(trifluoromethyl)oxy]phenyl}cyclopropanamide A 373 〇°^ A N-{(lS)-2-[(3S)-3-amino group. Bilpyridin-1-yl]-1-[(4-fluorophenyl)methyl]_2-oxoethyl}-1-pyrene-1 4-(trifluoromethyl)phenyl]cyclopropanamide B 374 Ηαχία9 HV: Sub 1 N-[(3R)-acridin-3-yl]-4-(trifluoromethyl)-Να-[(1-{4-[(trifluoromethyl)oxy]benzene } 环 ))))-L-phenylalanine decylamine A 375 cf3 N-[(lS)-2-[(3R)-3-Aminopyridin-1-yl]-2-oxo small {[4-(Trifluoromethyl)phenyl]indolyl}ethyl H-{4-[(trifluoromethyl)oxy]phenyl}cyclopropanamide B 376 N-[(3S)-acridine -3-yl]-4-(trifluoromethyl)-Nct-[(1-{4-[(trisinyl)oxy]phenyl}cyclopropylphosphonium]-L-amphetamine The foregoing invention has been described in some detail by way of the exemplary embodiments and the embodiments of the embodiments of the embodiments of the embodiments of the embodiments of the present invention. The invention has been described with reference to various specific embodiments and techniques. However, it should be understood that many changes can be made. And improvements are still within the spirit and scope of the present invention. It will be apparent to those skilled in the art that these variations and improvements can be found in the patent application 146258.doc-244-201040149. ..-~./AS governance is the above description is intended as an example The scope of the present invention should not be determined in accordance with the above description, but should be attached to the scope of the patent application and the scope of the patent application in the equivalent: - all patents cited in the application , patent application and both = the purpose of the full reference of the party. Gan 2, Tianzhong Liuyi for the purpose of > plus Zhou ^, /, the degree of reference is like # _ # Every patent, patent application society knows not to A name or publication is incorporated by reference in full text❹

146258.doc -245-146258.doc -245-

Claims (1)

201040149 七、申請專利範圍： 1. 一種下式的化合物201040149 VII. Patent application scope: 1. A compound of the following formula (I) 或者其單-的立體異構體或其立體異構體的混合物、其 N-氧化物以及另外地任選地為其藥學上可接受的鹽，其中 〇 A是異丙基、叔丁基、C3_Cs環烧基、雜環基、芳基或雜 芳基，其中所述環烷基、雜環基、芳基和雜芳基任選 地由一個、兩個或三個尺八基團取代，其中 每個RA獨立地為、Ci_C6烷基、c丨&amp;鹵代烷基、芳 基、芳基（Ci-C4)烷基或-CVC6烷基-RA2 ,其中所述 芳基（C^-C4)烷基基團的芳基任選地由一個、兩個或 三個RA2基團取代，其中 每個RA2獨立地為鹵素、氰基、硝基、_〇rai、_srA1、 〇 -N(rA〗)2、-C(0)RA1、_S(0)RA1、-S(0)2RA1、 -S(0)N(RA1)2、-S(〇)2N(RA1)2、-c(o)ora丨、 -C(0)N(RA1)2、-N(RA1)C(0)RA丨、-n(ra1)c(o)ora1 ' N(RA1)C(0)N(RA1)2、-N(RA1)S(0)2RA1、-N(RA1) C(=NRa1)N(Ra1)2、-P(〇)(〇ra1)2 或 _〇p(〇)(〇ra1)2， 其中每個RAI獨立地為氫、c]-c4烷基或Ci-C^鹵代 烷基， 或者與相鄰的碳原子連接的兩個ra —起形成-〇_(G)y.O-， 146258.doc 201040149 其中，每個G獨立地為-CH2-、-C(H)(F)-或-CF2-，並 且7是1、2或3 ; L 是-[QRLWp-LMCHRLWq-，其中 P是1、2或3 ; 分是選自0至（3-p)的整數； L1是鍵或者;並且 每個RL獨立地為氫、甲基或鹵甲基； R1是-Νπ,π11)或式⑷的部分，(I) or a mono- stereoisomer thereof or a mixture of its stereoisomers, an N-oxide thereof, and additionally optionally a pharmaceutically acceptable salt thereof, wherein 〇A is isopropyl, unterminated a butyl group, a C3_Cs cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally one, two or three Substituted, wherein each RA is independently, Ci_C6 alkyl, c丨 &amp; haloalkyl, aryl, aryl (Ci-C4) alkyl or -CVC6 alkyl-RA2, wherein the aryl group (C^ The -C4) aryl group of the alkyl group is optionally substituted by one, two or three RA2 groups, wherein each RA2 is independently halogen, cyano, nitro, _〇rai, _srA1, 〇-N (rA)) 2, -C(0)RA1, _S(0)RA1, -S(0)2RA1, -S(0)N(RA1)2, -S(〇)2N(RA1)2, -c (o)ora丨, -C(0)N(RA1)2, -N(RA1)C(0)RA丨, -n(ra1)c(o)ora1 ' N(RA1)C(0)N( RA1)2, -N(RA1)S(0)2RA1, -N(RA1) C(=NRa1)N(Ra1)2, -P(〇)(〇ra1)2 or _〇p(〇)(〇 Ra1)2, wherein each RAI is independently hydrogen, c]-c4 alkyl or Ci-C^haloalkyl, or with adjacent carbon The two ras of the sub-connections form -〇_(G)yO-, 146258.doc 201040149 where each G is independently -CH2-, -C(H)(F)- or -CF2-, and 7 Is 1, 2 or 3; L is -[QRLWp-LMCHRLWq-, where P is 1, 2 or 3; the fraction is an integer selected from 0 to (3-p); L1 is a bond or; and each RL is independently Is hydrogen, methyl or halomethyl; R1 is -Νπ, π11) or part of formula (4), (a) ’ 其中 R1G是氫或CrQ烷基； 13 Rn 是-R13、-C3-C6 環烷基 _N(Ri2)2、_C3_C6 環烷基 _Rl _Cl—C6 烷基 _N(Rl2)2 或-CVC6 烷基-Rn，其中 每個R12獨立地為氫或Crq烷基；並且 R疋（a) 4-10兀單環、4_1〇元稠合雙環、51〇元橋 連雙環或5_1〇元螺雙環料基環，其巾所述雜環 基環包含一個、兩個或三個環氮原子並且任選地 包含-個環氧或環硫原子，或者(b) 5或6元單環 :!::8·10元稠合雙環雜芳基，其令所述雜芳 基％包έ 一個、兩個或三個 , 彳固椒虱原子並且任選地 包含個核氧或環硫原子，其中 所述雜環基和雜芳基各自住 4地由一個' 兩個或 146258.doc 201040149(a) ' wherein R1G is hydrogen or CrQ alkyl; 13 Rn is -R13, -C3-C6 cycloalkyl-N(Ri2)2, _C3_C6 cycloalkyl_Rl_Cl-C6 alkyl_N(Rl2)2 Or -CVC6 alkyl-Rn, wherein each R12 is independently hydrogen or Crq alkyl; and R疋(a) 4-10兀monocyclic, 4_1〇 fused bicyclic, 51〇 bridged bicyclic or 5_1〇 A snail bicyclic base ring having a heterocyclic ring containing one, two or three ring nitrogen atoms and optionally containing an epoxy or ring sulfur atom, or (b) a 5 or 6 membered monocyclic ring :!:: 8·10-membered fused bicyclic heteroaryl group which encloses one, two or three of the heteroaryl groups, smashes the samarium atom and optionally contains a nucleus or ring sulphur atom Wherein said heterocyclyl and heteroaryl each reside 4 places by a 'two or 146258.doc 201040149 二個尺13八基團取代，其中每個RHA基團獨立地 為鹵素、氰基、硝基、（VC4烷基、Cl_c4鹵代 烷基、芳基(CrC4)烧基、-〇RB1、-SRB1、_N(Rm)2、 -C(0)RB1、-S(〇)RB1、_s(0)2RB1、-S(〇)N(RB1)2 、-s(o)2N(RB1)2、_c(o)orb1、-c(〇)n(rb1)2、 -N(RB1)C(0)RB1 . -N(RB,)C(0)0RB1 . -N(Rbi)C(0)N(Rb,)2 或-N(RB1)S(0)2RB1 ’其中每個RBI獨立地為 氫、c丨-C4烷基、C丨-C4鹵代烷基、芳基或芳基 (CVC4)烷基； R的定義中的環B是（a) 4_10元單環、4_1〇元稠合雙 %、5-ΙΟτο橋連雙環或5_1〇元螺雙環雜環基環，其 中所述雜環基環任選地包含—個環氧或環硫原子和 任選地一個、兩個或三個另外的環氮原子，或者 5或6元單環雜芳基或8·1〇元稠合雙環雜芳基，其中Substituted by two aryl groups, wherein each RHA group is independently halogen, cyano, nitro, (VC4 alkyl, Cl_c4 haloalkyl, aryl (CrC4) alkyl, -〇RB1, -SRB1 _N(Rm)2, -C(0)RB1, -S(〇)RB1, _s(0)2RB1, -S(〇)N(RB1)2, -s(o)2N(RB1)2, _c( o) orb1, -c(〇)n(rb1)2, -N(RB1)C(0)RB1 . -N(RB,)C(0)0RB1 . -N(Rbi)C(0)N(Rb , or 2 or -N(RB1)S(0)2RB1 'wherein each RBI is independently hydrogen, c丨-C4 alkyl, C丨-C4 haloalkyl, aryl or aryl (CVC4) alkyl; R Ring B in the definition of (a) a 4-10 membered monocyclic ring, a 4_1 aglyzed fused bi-%, a 5-oxazol bridged bicyclic ring or a 5 1 indole spiro bicyclic heterocyclyl ring, wherein the heterocyclyl ring is optionally Included as an epoxy or epicyclic sulfur atom and optionally one, two or three additional ring nitrogen atoms, or a 5 or 6 membered monocyclic heteroaryl or 8.1 fluorene fused bicyclic heteroaryl group, wherein 所述雜芳基環任選地包含—個環氧或環硫原子和任 選地一個、兩個或三個另外的環氮原子； R疋-R 、氫、C丨_C4燒基、Ci_C4_代院基、 烷基、芳基（eve*)炫基、或_Ci_C4烧基_rB2，其中 每個R獨立地為氰基、碑基、_〇rB3、_srB3、_n(rB3)2、 -C(0)RB3、_S(0)RB3 -s(〇)2RB3、-s(o)n(rB3)2、 -S(〇)2N(RB3)2, .C(〇)〇rB3, .C(〇)N(rb3)2^ -N(R-)C(0)RB3 , -N(RB3)C(〇)〇rB3 ^ .N(RB3)C(〇)N(RB3)2 或-N(RB3)S(〇)2RB3 ,其中 146258.doc 201040149 每個rB3獨立地為氫、烷基、（VC4鹵代烷 基、芳基或芳基（CrCd烷基； 或者兩個RB3和它們都與之連接的氮原子一起形 成飽和或不飽和的單環雜環基或雜芳基，其中所 述雜環基和雜芳基各自任選地由各自獨立地為 (C1-C3)院基、鹵素或Cl_c4鹵代烷基的一個、兩 個或三個基團取代； 並且每個R21獨立地為鹵素或汛2。； R疋任選地由一個、兩個或三個函素基團取代的甲 基’或者兩個R2與它們與之連接的碳原子一起形成 環丙基基團； w是1'2、3、4或5;並且 每個R3獨立地為鹵素、氰基、硝基、Ci_C4烷基、 Q-C4 _ 代烷基、（^(^環烷基、_〇rC1、_n(rC1)2、 -C(〇)Rcl . -S(0)RC1 . -S(0)2RC1 &gt; -S(0)N(RC1)2 &gt; -S(0)2N(RC1)2 &gt; ~C(0)〇Rcl , -C(0)N(Rc1)2 ^ -N(Rcl)C(0)Rcl ^ -n(Rc1)CW〇rC1、_n(rC1)c(〇)n(rC1)2 或 _n(rC1)s(〇)2rC1， 其中每個以1獨立地為氫、Ci_C4烷基、Ci_c4鹵代烷 基、芳基或芳基（c丨-c4)烷基， 或者兩個R3與它們與之連接的環原子一起形成芳基、 雜芳基、單環環烷基或雜環基，所述芳基、雜芳 基、單環環燒基或雜環基各自任選地由各自獨立地 為（Ci-c：3)烷基、鹵素或Ci_C4鹵代烷基的—個、兩 個或三個基團取代。 146258.doc 201040149 2. 如請求項丨之化合物，或者其單一的立體異構體或其立 體異構體的混合物以及另外地任選地為其藥學上可接成 的鹽’其中R2是甲基或者兩個…與它們與之連接的碳= 子一起形成環丙基基團。 ' 3. 如請求項丨之化合物，或者其單一的立體異構體或其立 體異構體的混合物以及另外地任選地為其藥學上可接受 的鹽，其中兩個R2與它們與之連接的碳原子一起形成^ 丙基基團。 〇 4. *請求項⑴中^壬一項之化Μ勿，或者其單一的立體異 構體或其立體異構體的混合物以及另外地任選地為其藥 學上可接受的鹽，其中Α是C^C：8環烷基、芳基或雜芳 基，其中所述環烷基、芳基和雜芳基任選地由一個、兩 個或三個ra基團取代。 5_如請求項丨至；^中任一項之化合物，或者其單一的立體異 構體或其立體異構體的混合物以及另外地任選地為其藥 Q 學上可接受的鹽，其中八是任選地由-個、兩個或三個 ra基團取代的苯基。 6.如請求項1至5中任一項之化合物，或者其單一的立體異 構體或其立體異構體的混合物以及另外地任選地為其藥 學上可接受的鹽，其中當ra存在時，每個ra獨立地為鹵 素、氰基、CVC4烷基、CVC4鹵代烷基、苯基、节 基、-ORA1、-N(RA1)2或-C(0)RA1，其中每個！^1獨立地 為氫、C^-C4烷基或CrC4鹵代烷基；或者與相鄰的碳原 子連接的兩個RA —起形成_0_(G)y_〇-，每個g獨立地 146258.doc 201040149 為-CH2_、-C(H)(F)_ 或 _Cf2_，並且 y是 1、2或 3。 7_如請求項1至6中任一項之化合物，或者其單一的立體異 構體或其立體異構體的混合物以及另外地任選地為其藥 學上可接受的鹽’其中R20是氫、-〇rB3、_n(rB3)2、 c「c4烧基、Cl_C4鹵代烷基、C3_C8環烷基、芳基（Ci_q) 烷基或-C丨-C4烷基-RB2,其中RB2是-ORB3或_Ν(ΚΒ、·，並 且當r21存在時，每個R21獨立地為鹵素或-r2〇。 8.如請求項1至7中任一項之化合物，或者其單—的立體異 構體或其立體異構體的混合物以及另外地任選地為其藥 學上可接受的鹽，其中尺1是 ⑴-N(R10)(R&quot;)，其中 R疋氣或- C1-C4烧基；並且 R11 是-R13、-C3-C6環烷基-N(R12)2、_c3_c6環烷基_Rl3、 -Ci-C6 烷基-N(R12)2 或-CVC6 烷基-R13，其中 每個R12獨立地為氫或Cl_c4烷基；並且 R13是4-10元單環、5_1〇元橋連雙環或5_1〇元螺 雙環雜環基環，其中所述雜環基環包含一個、 兩個或三個環氮原子並且任選地包含一個環氧 或％•硫原子，其中 所述雜環基任選地由一個 '兩個或三個r1 3 A 基團取代，其中每個RnA基團獨立地為鹵 素、（VC4烷基、CrC4鹵代烷基、芳基（Ci_c4) 烷基、-〇RB1、或-N(rbi)2，其中每個rB1獨立 地為氫、Ci-C4烷基、Cl_C4鹵代烷基、芳基或 146258.doc -6 - 201040149 芳基（CrCd烷基；或R1是 (ii)式（a)的部分，The heteroaryl ring optionally contains an epoxy or epicyclic sulfur atom and optionally one, two or three additional ring nitrogen atoms; R疋-R, hydrogen, C丨_C4 alkyl, Ci_C4 _ Derivative, alkyl, aryl (eve*) leumino, or _Ci_C4 alkyl _rB2, wherein each R is independently a cyano group, a thiol group, _〇rB3, _srB3, _n(rB3)2 -C(0)RB3, _S(0)RB3 -s(〇)2RB3, -s(o)n(rB3)2, -S(〇)2N(RB3)2, .C(〇)〇rB3, . C(〇)N(rb3)2^ -N(R-)C(0)RB3 , -N(RB3)C(〇)〇rB3 ^ .N(RB3)C(〇)N(RB3)2 or- N(RB3)S(〇)2RB3, where 146258.doc 201040149 Each rB3 is independently hydrogen, alkyl, (VC4 haloalkyl, aryl or aryl (CrCd alkyl; or both RB3 and they are associated with The linked nitrogen atoms together form a saturated or unsaturated monocyclic heterocyclic or heteroaryl group, wherein each of the heterocyclic group and the heteroaryl group is optionally independently (C1-C3), halogen or One, two or three groups of a Cl_c4 haloalkyl group are substituted; and each R21 is independently halo or fluorene 2; R 甲基 a methyl group optionally substituted by one, two or three functional groups The two R2 together with the carbon atom to which they are attached form a cyclopropyl group; w is 1'2, 3, 4 or 5; and each R3 is independently halo, cyano, nitro, Ci_C4 alkyl , Q-C4 _ alkyl, (^(^cycloalkyl, _〇rC1, _n(rC1)2, -C(〇)Rcl . -S(0)RC1 . -S(0)2RC1 &gt; - S(0)N(RC1)2 &gt; -S(0)2N(RC1)2 &gt; ~C(0)〇Rcl , -C(0)N(Rc1)2 ^ -N(Rcl)C(0 Rcl ^ -n(Rc1)CW〇rC1, _n(rC1)c(〇)n(rC1)2 or _n(rC1)s(〇)2rC1, wherein each of them is independently hydrogen, Ci_C4 alkyl , Ci_c4 haloalkyl, aryl or aryl (c丨-c4) alkyl, or two R3 together with the ring atom to which they are attached form an aryl, heteroaryl, monocyclic cycloalkyl or heterocyclyl group, The aryl, heteroaryl, monocyclic cycloalkyl or heterocyclic group are each optionally one, two or three independently of (Ci-c:3)alkyl, halo or Ci_C4 haloalkyl. Substituting a group. 146258.doc 201040149 2. A compound as claimed, or a single stereoisomer thereof or a mixture of its stereoisomers, and additionally optionally a pharmaceutically acceptable salt thereof' Wherein R 2 is methyl or both ... together with the carbon = to which they are attached form a cyclopropyl group. 3. A compound as claimed, or a single stereoisomer or a mixture of its stereoisomers and additionally optionally a pharmaceutically acceptable salt thereof, wherein two R2 are attached to them The carbon atoms together form a propyl group. 〇4. * Requested item (1), or a single stereoisomer or a mixture of its stereoisomers, and additionally optionally a pharmaceutically acceptable salt thereof, wherein Is C^C: 8 cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl and heteroaryl are optionally substituted by one, two or three ra groups. 5) A compound according to any one of the preceding claims, or a single stereoisomer thereof or a mixture of its stereoisomers, and additionally optionally a Q-acceptable salt thereof, wherein Eight is a phenyl group optionally substituted with one, two or three ra groups. 6. The compound of any one of claims 1 to 5, or a single stereoisomer thereof or a mixture of its stereoisomers, and additionally optionally a pharmaceutically acceptable salt thereof, wherein ra is present Each ra is independently halogen, cyano, CVC4 alkyl, CVC4 haloalkyl, phenyl, benzyl, -ORA1, -N(RA1)2 or -C(0)RA1, each of which! ^1 is independently hydrogen, C^-C4 alkyl or CrC4 haloalkyl; or two RAs attached to adjacent carbon atoms together form _0_(G)y_〇-, each g is independently 146258. Doc 201040149 is -CH2_, -C(H)(F)_ or _Cf2_, and y is 1, 2 or 3. The compound of any one of claims 1 to 6, or a single stereoisomer thereof or a mixture of its stereoisomers, and additionally optionally a pharmaceutically acceptable salt thereof, wherein R20 is hydrogen , -〇rB3, _n(rB3)2, c"c4 alkyl, Cl_C4 haloalkyl, C3_C8 cycloalkyl, aryl (Ci_q) alkyl or -C丨-C4 alkyl-RB2, wherein RB2 is -ORB3 or _Ν(ΚΒ,·, and, when r21 is present, each R21 is independently halogen or -r2〇. 8. A compound according to any one of claims 1 to 7, or a mono-isomer thereof or a mixture of stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, wherein Rule 1 is (1)-N(R10)(R&quot;), wherein R is helium or -C1-C4 alkyl; R11 is -R13, -C3-C6 cycloalkyl-N(R12)2, _c3_c6 cycloalkyl-Rl3, -Ci-C6 alkyl-N(R12)2 or -CVC6 alkyl-R13, wherein each R12 Independently hydrogen or Cl_c4 alkyl; and R13 is a 4-10 membered monocyclic, 5_1 fluorene bridged bicyclic or 5_1 fluorene spiro bicycloheterocyclyl ring, wherein the heterocyclyl ring comprises one, two or three Ring nitrogen atom and optionally a ring Or a % sulfur atom, wherein the heterocyclic group is optionally substituted by one 'two or three r1 3 A groups, wherein each RnA group is independently halogen, (VC4 alkyl, CrC4 haloalkyl, Aryl (Ci_c4) alkyl, -〇RB1, or -N(rbi)2, wherein each rB1 is independently hydrogen, Ci-C4 alkyl, Cl_C4 haloalkyl, aryl or 146258.doc -6 - 201040149 a group (CrCd alkyl; or R1 is a part of (ii) formula (a), ⑷ 其中w是〇、1或2 〇 9.如請求項1至8中任一項之化合物，或者其單一的立體異 構體或其立體異構體的混合物以及另外地任選地為其藥 © 學上可接受的鹽，其中尺1是 ⑴-N(Rl°)(R11)，其中C是氫或甲基；或R】是 (ii)式（a)的部分，(4) Wherein w is 〇, 1 or 2 〇9. A compound according to any one of claims 1 to 8, or a single stereoisomer thereof or a mixture of stereoisomers thereof, and additionally optionally a drug thereof A permissible salt, wherein the rule 1 is (1)-N (Rl°) (R11), wherein C is hydrogen or methyl; or R is (ii) part of formula (a), (a)， 其中所述式⑷的部分中的環W5_iq元橋(a), wherein the ring W5_iq element bridge in the portion of the formula (4) :螺雙環雜環基環，其中所—環基隸 環氧或環硫原子以及任選地_ 匕含一個 氮原子；或 所述式（a)的部分是： 的環 固、兩個或三個另外 、R20a spirobicycloheterocyclyl ring, wherein the ring group is an epoxy or a ring sulfur atom and, optionally, a nitrogen atom; or the moiety of the formula (a) is: a ring, two or three Another, R20 )w 異 146258.doc 201040149 構體或其立體異構體的混合物以及另外地任選地為其藥 學上可接受的鹽，其中R^_N(RlG)(Rll)或式（a)的部分，'a different mixture of the stereoisomers thereof, and optionally a pharmaceutically acceptable salt thereof, wherein R^_N(RlG)(Rll) or a moiety of formula (a), ' 其中 ⑷所述式⑷的部分中的環8是5，元橋連雙環雜環基 % ’其中所述雜環基環任選地包含—個環氧或環硫原子 以及任選地一個、兩個或三個另外的環氮原子；rZ〇是 氫、-orB3、-n(rB3)2、c】_c4烷基、Ci_c4 函代烷基、 C3-C8環烷基、芳基（Ci_c4)烷基或_Ci-c4烷基_rB2 ; RB2 疋-orB3或-n(rB3)2 ;並且R2丨是Ci_C4烷基或Ci_c一代烷 基；Wherein (4) the ring 8 in the moiety of the formula (4) is 5, a bridged bicyclic heterocyclic group % ' wherein the heterocyclic ring optionally contains an epoxy or an episulfide atom and optionally one or two Or three additional ring nitrogen atoms; rZ〇 is hydrogen, -orB3, -n(rB3)2, c]_c4 alkyl, Ci_c4 functional alkyl, C3-C8 cycloalkyl, aryl (Ci_c4) alkane Or _Ci-c4 alkyl _rB2; RB2 疋-orB3 or -n(rB3)2; and R2丨 is a Ci_C4 alkyl group or a Ci_c first generation alkyl group; (b)所述式⑷的部分是，其中、2或3，r2( 疋氫、CVC4烷基、Cl_C4鹵代烷基、C3_C8環烷基、芳基 (Cl_C4)烷基或 _Ci-C4 烷基-RB2，其中 是 _〇rB3 或-n(rB3)2 ’並且r2丨是Ci_C4烷基或Ci_C4_代烷基；或 (R^1)w / —!—p2〇 (e)所述式（a)的部分是Y ，其中r是〇、1、2或3， R k-N(RB3)24_Ci_C4 烷基 _ν(κΒ3)2，並且 r2 丨是 c 丨 &lt;4 燒 基或Crq鹵代烷基。 11.如4求項1至10中任—項之化合物，或者其單一的立體 、構體或其立體異構體的混合物以及另外地任選地為其 146258.doc 201040149 ❹ 藥學上可接受的鹽， 分， 其中R1 是-n(rI0)(ru)或式⑷的部 -I-N(b) the moiety of the formula (4) is, wherein 2, 3, r2 (hydrogen, CVC4 alkyl, Cl_C4 haloalkyl, C3_C8 cycloalkyl, aryl (Cl_C4) alkyl or _Ci-C4 alkyl- RB2, wherein _〇rB3 or -n(rB3)2' and r2丨 is Ci_C4 alkyl or Ci_C4_alkyl; or (R^1)w / —!-p2〇(e) The moiety is Y, wherein r is 〇, 1, 2 or 3, R kN(RB3)24_Ci_C4 alkyl_ν(κΒ3)2, and r2 丨 is c 丨&lt;4 alkyl or Crq haloalkyl. A compound according to any one of items 1 to 10, or a single stereoisomer, a mixture thereof or a mixture thereof, and additionally optionally 146258.doc 201040149 pharmaceutically acceptable salt thereof, Fraction, where R1 is -n(rI0)(ru) or the part-IN of equation (4) (R21&gt;w (a) 其中％ B疋5-1 0元橋連雙環雜環基環。 12.如請求項1至10中任一 哨^化η物，或者其單沾也體 異構體或其立體里構俨的、尽人此 ，、早一的立體 筚…^ 合物以及另外地往選地為其 分， ，其中R是娜、11)或式⑷的部(R21&gt;w (a) wherein % B 疋 5-1 0 bridges a bicyclic heterocyclyl ring. 12. As claimed in any one of claims 1 to 10, or a single dimeric isomer thereof Or a three-dimensional structure of the human body, the first one, and the other ones, and the other ones, where R is Na, 11) or (4) (R2\ (a)(R2\ (a) 其中所述式（a)的部分是 _ 13.如請求項 〇 、 中任一項之化合物，或者其單—的立見 或’、立體異構體的混合物以及另外地住選地為$ 藥干上可接受的鹽，其中R1是-N(R1G)(RU)或式⑷的！ 分， 其中ί是1、2或3Wherein the moiety of the formula (a) is _ 13. The compound of claim 〇, any of the compounds, or the singular or ', a mixture of stereoisomers and additionally optionally a drug dry An acceptable salt, wherein R1 is -N(R1G)(RU) or formula (4)! Points, where ί is 1, 2 or 3 (R21)w (a)， 其中所述式(，部分是令' 其中广是0、 2或 146258.doc 201040149 14. 如請求項1至13中任一項之化合物’或者其單一的立體 異構體或其立體異構體的混合物以及另外地任選地為其 藥學上可接受的鹽，其中L* _[C(RL)2]p_Ll_[c(RLWq_， 其中户是1或2，分是選自〇至（3_p)的整數，Ll是鍵或七… 並且每個RL獨立地為氫或曱基。 15. 如請求項丨至14中任一項之化合物，或者其單一的立體 異構體或其立體異構體的混合物以及另外地任選地為其 藥學上可接受的鹽，其中R1是式（a)的部分，(R21)w (a), wherein the formula (, is a part of ', which is 0, 2 or 146258.doc 201040149 14. The compound of any one of claims 1 to 13' or its single stereoscopic a mixture of a conformation or a stereoisomer thereof, and additionally optionally a pharmaceutically acceptable salt thereof, wherein L* _[C(RL)2]p_Ll_[c(RLWq_, wherein the household is 1 or 2, Is an integer selected from 〇 to (3_p), L1 is a bond or seven... and each RL is independently hydrogen or fluorenyl. 15. A compound according to any one of claims 14 to 14, or a single stereo a mixture of a conformation or a stereoisomer thereof, and additionally optionally a pharmaceutically acceptable salt thereof, wherein R1 is a moiety of formula (a), 16·:請求項1至14中任-項之化合物，或者其單一的立體 二=體或其立體異構體的混合物以及另外地任選地為其 /樂學上可接受的鹽’其中R1是-專、，或式⑷的部 其中R疋汉3 ’其中R13是4-1〇元單環雜環基環，i :述雜環基環包含一個、兩個或三個環氮原子並且： 選地包含_徊一 %氣或環硫原子，其中所述雜環基環任選 個、兩個或三個RnA基團取代。 17·如請求項1至14中 異構體或盆立體：―項之化合物，或者其單一的立體 藥學上^ 、遐異構體的混合物以及另外地任選地為其 ^其，其中Rl是谭、11)或式⑷的部 環，其中 ，其中Rl3是5_10元橋連雙環雜環基 述雜％基環包含一個、兩個或三個環氮原子 146258.doc -10· 201040149 ί = ?地包含—個環氧或環硫原子，其中所述雜環基 18 :二土由一個、兩個或三個Rl3A基團取代。 18.如印求項1至14、16 和17中任一項之化合物，或者其單 一的立體異構體或 _ , —立體異構體的混合物以及另外地任 二：其樂學上可接受的鹽，其中當R13A存在時，每個 土團獨立地為鹵素、烷基、Ci_c4鹵代烷基、 芳土（Cj-C^)烧基、_〇rbi B1 r 〇R 、-SRB1 或-N(RB1)2 ’ 其中每個 ^•獨立地為氫、e Ο 1-C4燒基、Ci_c4_代烷基、芳基或芳 基（Ci-C4)烧基。 9.如π求項ul4中任一項之化合物，或者其單一的立體 ♦I體或其立體異構體的混合物以及另外地任選地為其 藥予上可接爻的鹽，其中Rl是-N(R1Q)(Rn)或式（a)的部 分，φ ·ρ 11 e 疋 1-匚6烧基-N(Rl2)2或-C3-C6環烧 基-n(r12)2。 々叫求項1至6、9、14和16至19中任一項之化合物，或 者其單的立體異構體或其立體異構體的混合物以及另外 地任選地為其藥學上可接受的鹽，其中r1*_n(r1Q)(r1i)。 21. 如請求項1至20中任一項之化合物，或者其單一的立體 異構體或其立體異構體的混合物以及另外地任選地為其 藥學上可接受的鹽，其中R3是鹵素、c「c4烷基、Cl_C4 鹵代烷基或-0RC1，其中每個^^1獨立地為氫、C〗_C4烷基 或C1-C4鹵代烧基0 22. 如請求項1至15和21中任一項之化合物，或者其單一的 立體異構體或其立體異構體的混合物以及另外地任選地 146258.doc 201040149 23. 24. 25. 為其藥學上可接受的鹽，其中w是零或i，並且rZi，當 存在時，是（VC4烷基或Ci-C4!!代烷基。 田 如請求項1至22中任一項之化合物，或者其單一的立體 異構體或其立體異才冓體的⑥合物以及另外地任選地為其 藥學上可接受㈣’其是偶…CH2CKH2Ch2(^ ' -CH(CH3)-. -ch2-o- ^ -CH2CH2-〇_4-CH2-〇-CH2- ο 如請求们至23中任一項之化合物，或者其單一的立體 異構體或其立體異構體的混合物以及另外地任選地為其 藥學上可接受的鹽’其中L是(VC3亞烷基。 八 如請求項124中任-項之化合物，或者其單—的立體 異構體或其立體異構體的混合物以及另外地任選地為其 藥學上可接受的鹽，所述化合物為式（Ia)的化合物 八16. The compound of any one of claims 1 to 14, or a single stereoisomer thereof or a mixture of its stereoisomers, and additionally optionally a/acceptable salt thereof, wherein R1 Is a -, or, a moiety of the formula (4) wherein R 疋 3 3 'wherein R 13 is a 4-1 〇 monocyclic heterocyclic ring, i: the heterocyclyl ring contains one, two or three ring nitrogen atoms and : optionally comprising a mono- or a ring sulfur atom wherein the heterocyclyl ring is substituted with one, two or three RnA groups. 17. The isomer or pellucid stereoisomer of claim 1 to 14: a compound of the formula, or a mixture of its single stereopharmaceutical, oxime isomers and, optionally, optionally, wherein R1 is Tan, 11) or a partial ring of formula (4), wherein R1 is a 5-10 membered bicyclic heterocyclic ring. The heterocyclic ring contains one, two or three ring nitrogen atoms. 146258.doc -10· 201040149 ί = ? Included is an epoxy or epicyclic sulfur atom wherein the heterocyclic group 18: the two earths are substituted by one, two or three Rl3A groups. 18. The compound of any one of items 1 to 14, 16 and 17, or a single stereoisomer or a mixture of _, - stereoisomers, and additionally any two: it is musically acceptable a salt wherein, when R13A is present, each earth mass is independently halogen, alkyl, Ci_c4 haloalkyl, aryl (Cj-C^) alkyl, _〇rbi B1 r 〇R, -SRB1 or -N ( RB1)2' wherein each of them is independently hydrogen, e Ο 1-C4 alkyl, Ci_c4_alkyl, aryl or aryl (Ci-C4) alkyl. 9. A compound according to any one of π, or a mixture of its stereoisomers or a stereoisomer thereof, optionally additionally a pharmaceutically acceptable salt thereof, wherein R1 is -N(R1Q)(Rn) or a moiety of formula (a), φ ·ρ 11 e 疋1-匚6 alkyl-N(Rl2)2 or -C3-C6 cycloalkyl-n(r12)2. The compound of any one of claims 1 to 6, 9, 14 and 16 to 19, or a single stereoisomer thereof or a mixture of stereoisomers thereof, and additionally optionally pharmaceutically acceptable thereof Salt, where r1*_n(r1Q)(r1i). The compound of any one of claims 1 to 20, or a single stereoisomer thereof or a mixture of its stereoisomers, and additionally optionally a pharmaceutically acceptable salt thereof, wherein R3 is halogen And c "c4 alkyl, Cl_C4 haloalkyl or -0RC1, wherein each ^^1 is independently hydrogen, C"_C4 alkyl or C1-C4 haloalkyl. 22. As claimed in claims 1 to 15 and a compound of any one, or a single stereoisomer thereof or a mixture of its stereoisomers, and additionally optionally 146258.doc 201040149 23. 24. 25. is a pharmaceutically acceptable salt thereof, wherein w is Zero or i, and rZi, when present, is (VC4 alkyl or Ci-C4!! alkyl). The compound of any one of claims 1 to 22, or a single stereoisomer thereof or a stereoisomer of a 6-membered genus and optionally pharmaceutically acceptable (d)' which is an even...CH2CKH2Ch2(^ ' -CH(CH3)-. -ch2-o-^-CH2CH2-〇_4- CH2-〇-CH2- ο The compound of any one of the claims 23, or a single stereoisomer thereof or a mixture of its stereoisomers and additionally optionally Is a pharmaceutically acceptable salt thereof, wherein L is (VC3 alkylene. 8. A compound according to any one of the claims 124, or a stereoisomer thereof, or a mixture thereof, and additionally Optionally a pharmaceutically acceptable salt thereof, the compound being a compound of formula (Ia) (la)。 26. 如請求項1至24中任一項之化合物’或者其單一的立體 異構體或其立體異構體的混合物以及另外地任選地為其 藥學上可接受的鹽，所述化合物為式（Ib)的化合物(la). 26. The compound of claim 1 or any single stereoisomer thereof or a mixture of its stereoisomers, and additionally optionally a pharmaceutically acceptable salt thereof, is a compound of formula (Ib) 27. 一種表1中所列的化合物，或者其單一的立體異構體或 其立體異構體的混合物以及另外地任選地為其藥學上可 接受的鹽。 146258.doc -12- 201040149 28 f 29. 30. Ο 31.32. 33. 〇 .-種藥物組合物，其包含如請求項α27中 合物，任選地為該化合物的藥學上可接受的鹽二: 上可接受的賦形劑、稀釋劑或載體。 ”予 一種如請求項1至27中任-項之化合物或如請求項28之 組合物的用途，其偏在製造治療受治療者之由葡萄糖 普基腦醯胺合成酶（Gcs)介導的疾病或病症或者 及GCS的疾病或病症的藥劑。 v 如請求項29之用途’其中所述疾病或病症是癌症。 如請求項29之料，其中所述疾錢病症是代謝病症。 -種體外誘導細胞中降低的葡萄糖苦基腦醯 化活性的方法’其包括將所H^ 士 珉酶催 、栝將所述細胞與有效量的如請长項 1至27中任一項之化合物接觸。 、 一種製備如請求項1之化合物的方法，所述方法包括. ⑴偶合式（13)的化合物與式（14)的化合物以提供式 ⑴的化合物或者其單一的立體異構體或其立體異構體的 混合物，27. A compound as listed in Table 1, or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof. 146258.doc -12- 201040149 28 f 29. 30. Ο 31.32. 33. A pharmaceutical composition comprising a compound as claimed in claim 27, optionally a pharmaceutically acceptable salt of the compound : An acceptable excipient, diluent or carrier. The use of a compound according to any one of claims 1 to 27, or a composition according to claim 28, for the treatment of a disease mediated by glucosinamine synthase (Gcs) in a therapeutic subject. Or a condition or an agent for a disease or condition of a GCS. v. The use of claim 29, wherein the disease or condition is cancer. The material of claim 29, wherein the disease condition is a metabolic condition. A method of reducing glucosyl-brain cerebral activity in a cell, which comprises contacting the cell with an effective amount of a compound of any one of items 1 to 27, by enzymatically stimulating the sputum. A process for the preparation of a compound of claim 1, which comprises: (1) coupling a compound of formula (13) with a compound of formula (14) to provide a compound of formula (1) or a single stereoisomer thereof or a stereoisomer thereof Mixture of bodies, 在式⑼中表示相鄰碳原子的任選的（R)或⑻手性， 並且-N(Rx)(RYR 其中RY中的一個是Ri。並且r&gt; 和Ry中的另一個是R&quot;，㈣和…以及它們與之連接的 氮原子形成式（a)的部分 146258.doc 201040149 R20In the formula (9), an optional (R) or (8) chirality of an adjacent carbon atom is represented, and -N(Rx) (wherein RYR is one of RY, and r&gt; and the other of Ry is R&quot;, (d) and ... and the nitrogen atom to which they are attached form part of formula (a) 146258.doc 201040149 R20 (r21)w (a)； 並且任選地分離單獨的異構體；並且任選地修飾R2〇和 R21基團中的任一個以提供式⑴的化合物；並且任選地 形成其藥學上可接受的鹽；或者 (Π)偶合式（15)的化合物與式（16)的化合物，以提供式 (I)的化合物或者其單一的立體異構體或其立體異構體的 混合物，(r21)w (a); and optionally isolating the individual isomers; and optionally modifying any of the R2 and R21 groups to provide a compound of formula (1); and optionally forming pharmaceutically acceptable Accepting a salt; or (Π) coupling a compound of formula (15) with a compound of formula (16) to provide a compound of formula (I) or a single stereoisomer thereof or a mixture of stereoisomers thereof, 在式（15)中，*表不相鄰碳原子的任選的（R)或（s)手性， 在式(16)中’ -N(R»k，其中r、rY中的一個是 Rl0並且R&gt;RY中的另-個是R&quot;，或Rx和RY以及它們病 之連接的氮原子形成式（a)的部分In formula (15), * represents an optional (R) or (s) chirality of an adjacent carbon atom, in the formula (16) '-N(R»k, where one of r, rY is The other one of Rl0 and R&gt;RY is R&quot;, or Rx and RY and their diseased nitrogen atoms form part of formula (a) (a)； 並且任選地分離單獨的显椹 21 』叼兵構體，並且任選地修飾R20和 R基團中的任一個以描征4 ϋ 杈供式⑴的化合物；並且任選地 形成其藥學上可接受的鹽。 146258.doc -14- 201040149 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：(a); and optionally separating a separate 椹 21 叼 构 , and optionally modifying any of the R 20 and R groups to characterize 4 ϋ 杈 for the compound of formula (1); and optionally A pharmaceutically acceptable salt thereof is formed. 146258.doc -14- 201040149 IV. Designation of representative drawings: (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 display. Chemical formula of the inventive feature: 146258.doc146258.doc
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