TWI299039B - Pyrrolindine compounds - Google Patents
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1299039 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種醫藥組成物，尤指一種適用於抑制 雙肽酶IV之方法與醫藥組成物。 5 【先前技術】 類升醣素胜肽（Glucagon-like peptide_l，GLP-1)是一種 I 小腸贺爾蒙，由腸内腺L細胞（intestinal endocrine L- cell) 在消化營養素後所製造出，GLP-1抑制升醣素的分泌，並刺 10 激依賴升_素之胰島素自膜臟的分泌。研究觀察到提供 GLP-1於第二型糖尿病病患時，可明顯的降低血糖值 (Zander M，et al. Lancet 2002)。 然而，不管内生性或外源性提供的GLP-1，都會因為 快速的降解而縮短其生命期（Kieffer T.J·，et al· 15 Endocrinology 136:3585-3596，1995 ; &MentleinR，etal.1299039 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD The present invention relates to a pharmaceutical composition, and more particularly to a method and a pharmaceutical composition suitable for inhibiting dipeptidase IV. 5 [Prior Art] Glucagon-like peptide (GLP-1) is a small intestinal hormone, which is produced by intestinal endocrine L-cell after digesting nutrients. GLP-1 inhibits the secretion of glycoside, and the stimulating 10 is dependent on the secretion of insulin from the membrane. Studies have shown that providing GLP-1 in patients with type 2 diabetes can significantly reduce blood glucose levels (Zander M, et al. Lancet 2002). However, regardless of endogenous or exogenously provided GLP-1, its lifespan is shortened by rapid degradation (Kieffer T.J., et al. 15 Endocrinology 136: 3585-3596, 1995; & Mentlein R, etal.
Eur. J. Biochem. 214:829-839, 1993)，而此降解起因於雙肽 > peptidase IV，DPP-IV)的催化，一種脯胺醯 基胜肽酶（prolyl peptidase)。近來臨床數據顯示抑制DPP-IV 可提升胰島素之分泌，降低血漿葡萄糖濃度並增進胰臟β-2〇 細胞之功能（Pederson R.A·，et al. Diabetes 47:1253-1258, 1998; and Ahren B，et al· Diabetes Care 25:869-875, 2002)， 因此以DPP-IV抑制因子作為第二型糖尿病之藥物將具有其 潛力。 1299039 雙肽酶VIII (Dipeptidyl peptidase VIII，DPP-VIII)為另 一脯胺醯基胜肽酶，與DPP-IV具有最高之同源性，目前研 究顯示，在多種DPP-IV之功效中，有一部份是衍生自 DPP-VIII之活性（Rosenblum J.S·，et al. Current Opinion in 5 Chemical Biology，7:496-504, 2003)。 【發明内容】 本發明發現一新的吡咯啉啶化合物群組可抑制 DPP-IV，其態樣之一係有關於一如下結構式之化合物：Eur. J. Biochem. 214: 829-839, 1993), and this degradation results from the catalysis of dipeptide > peptidase IV, DPP-IV), a prolyl peptidase. Recent clinical data show that inhibition of DPP-IV increases insulin secretion, lowers plasma glucose concentrations, and enhances the function of pancreatic β-2〇 cells (Pederson RA·, et al. Diabetes 47:1253-1258, 1998; and Ahren B, Et al Diabetes Care 25: 869-875, 2002), therefore, DPP-IV inhibitors as potential drugs for type 2 diabetes will have their potential. 1299039 Dipeptidyl peptidase VIII (DPP-VIII) is another amidoxime-based peptide, which has the highest homology with DPP-IV. Current studies have shown that among the effects of various DPP-IV, there is one Part is the activity derived from DPP-VIII (Rosenblum JS, et al. Current Opinion in 5 Chemical Biology, 7: 496-504, 2003). SUMMARY OF THE INVENTION The present inventors have discovered that a novel group of pyrrolopridinium compounds can inhibit DPP-IV, one of which is related to a compound of the formula:
在上式中，R1為氫或氰基；每一 “，“，^，以以及以分別 為氫，_素，硝基，氰基，胺基，氫，烷基，鹵化烷基， 烷氧基，烷氧基，芳烷基，環基，雜環基，芳基或雜芳基； m為〇, 1，2,3,4或5 ;每一η以及p分別為〇, U2,3或4; χ為 CR R，NR，〇或S ;其中Ra以及Ra分別為氫，鹵素，烷基， 或芳基；Y為 NRb，0，S 或 CRb(NRb’Rb，，）；其中Rb，Rb，以及 Rb分別為氫，烷基或芳基；A為 〇In the above formula, R1 is hydrogen or cyano; each ",", ^, and to each are hydrogen, _, nitro, cyano, amine, hydrogen, alkyl, alkyl halide, alkoxy Alkyl, alkoxy, aralkyl, cyclic, heterocyclic, aryl or heteroaryl; m is 〇, 1, 2, 3, 4 or 5; each η and p are 〇, U2, 3, respectively Or 4; χ is CR R,NR,〇 or S; wherein Ra and Ra are respectively hydrogen, halogen, alkyl, or aryl; Y is NRb, 0, S or CRb (NRb'Rb,,); wherein Rb , Rb, and Rb are each hydrogen, alkyl or aryl; A is 〇
II RCN，S\ , /S\，RC|STS、II RCN, S\ , /S\, RC|STS,
1299039 烷基，環基，雜環基，芳基，芳烷基或雜芳基；且z為NR7R8， 其中每一 R7以及R8分別為氫，烷基，烷氧基烷基，鹵化烷 基，環基，雜環基，芳基，芳烷基或雜芳基，或NR7R8為 一具有1或2個雜原子之3-8元環，其係選擇性的以鹵素， 5 CN，N02，-ORe，烷基，芳基，雜芳基，鹵化烷基，-ORe， -C(0)Rc，-SRC，_S(0)Rc，_S(0)2Rc，-NRCRC’，_C(0)0Rc， -C(0)NRcRc，，-0C(0)Rc，-NRcC(0)Rc’，-NRcC(0)0Rc 或 -NReC(0)NRe’Re’’所取代，或選擇性的與環基，雜環基，芳 1 基以及雜芳基其中之一融合；其中每一 Re，Re’以及Re’’分別 10 為氫，院基或芳基。 如上結構式，另一次群組化合物之特徵在R1為CN且X 為CH2;在此之一部分化合物中，每一 R5以及R6可以為氫， Y可以為CRb(NRb’Rb’’）且Z可以為NR7R8，其中R7為氫且R8 為烷基，芳烷基，環基，雜環基，芳基或雜芳基，或NR7R8 15 為一具有1或2個雜原子之3-8元環。而其他化合物中，每一 R5以及R6可以為氫，Y可以為NH且Z可以為NR7R8，其中R7 丨為氫或烷基，且R8為烷基，芳烷基，環基，雜環基，芳基 或雜芳基，或NR7R8為一具有1或2個雜原子之3-8元環。 另一化合物之次群組特徵在Z為NR7R8，其中R7為氫 20 或烷基，且R8為烷基，芳烷基，環基，雜環基，芳基或雜 芳基；在這些化合物中，Y可以是CH(NH2)或NH。 另一化合物之次群組特徵在Z為NR7R8，其中NR7R8為 一具有1或2個雜原子之3-8元環；在這些化合物中，Y可以 是 CH(NH2)或 NH。 1299039 下列各結構式為化合物範例：1299039 alkyl, cyclo, heterocyclyl, aryl, aralkyl or heteroaryl; and z is NR7R8, wherein each R7 and R8 are independently hydrogen, alkyl, alkoxyalkyl, haloalkyl, A cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl group, or NR7R8 is a 3-8 membered ring having 1 or 2 heteroatoms, optionally halogen, 5 CN, N02,- ORe, alkyl, aryl, heteroaryl, alkyl halide, -ORe, -C(0)Rc, -SRC, _S(0)Rc, _S(0)2Rc, -NRCRC',_C(0)0Rc , -C(0)NRcRc,, -0C(0)Rc, -NRcC(0)Rc', -NRcC(0)0Rc or -NReC(0)NRe'Re'', or a selective ring One of a group, a heterocyclic group, an aryl group and a heteroaryl group is fused; wherein each of Re, Re' and Re'' is 10, hydrogen, a group or an aryl group. In the above structural formula, another group of compounds is characterized in that R1 is CN and X is CH2; in one of the compounds, each R5 and R6 may be hydrogen, Y may be CRb(NRb'Rb'') and Z may Is NR7R8 wherein R7 is hydrogen and R8 is alkyl, aralkyl, cyclo, heterocyclyl, aryl or heteroaryl, or NR7R8 15 is a 3-8 membered ring having 1 or 2 heteroatoms. In other compounds, each of R5 and R6 may be hydrogen, Y may be NH and Z may be NR7R8, wherein R7 is hydrogen or alkyl, and R8 is alkyl, aralkyl, cyclic, heterocyclic, An aryl or heteroaryl group, or NR7R8 is a 3-8 membered ring having 1 or 2 heteroatoms. The subgroup of the other compound is characterized in that Z is NR7R8, wherein R7 is hydrogen 20 or alkyl, and R8 is alkyl, aralkyl, cyclo, heterocyclyl, aryl or heteroaryl; among these compounds , Y can be CH(NH2) or NH. The subgroup of the other compound is characterized by Z being NR7R8 wherein NR7R8 is a 3-8 membered ring having 1 or 2 heteroatoms; in these compounds, Y can be CH(NH2) or NH. 1299039 The following structural formulas are examples of compounds:
化合物1Compound 1
OMeOMe
OMeOMe
化合物 10Compound 10
CNCN
OMeOMe
OMeOMe
化合物 11 OMeCompound 11 OMe
化合物 3Compound 3
化合物 6 OMeCompound 6 OMe
12990391299039
化合物 16 化合物 17 化合物 18Compound 16 compound 17 compound 18
化合物 21 化合物 23 化合物 24 1299039Compound 21 compound 23 compound 24 1299039
化合物 25Compound 25
化合物 26Compound 26
化合物 27Compound 27
化合物 28Compound 28
化合物 30Compound 30
化合物 34 化合物 35 化合物 36 10 1299039Compound 34 compound 35 compound 36 10 1299039
trN? H O CNtrN? H O CN
化合物 38Compound 38
化合物 37Compound 37
化合物 40 化合物 41 化合物 42Compound 40 compound 41 compound 42
化合物 46 化合物 47 化合物 48 11 1299039 基；「芳烷基」一詞係指一被芳基取代之烷基。 「環基」一詞係指一飽和與部分不飽和含3_12個碳 之環狀碳氫鏈，環基的範例包括但不侷限於：環丙基， 環丁基，環戊基，環戊烯基，環己基，環己烯基，環庚 5 基以及環辛基。 「雜芳基」一詞係指含一個或多個雜原子（如N、〇 或S)之5至8元單環、8至12元雙環，或11至14元三環；雜 芳基範例包括°比啶基（pyridyl)、呋喃基（furyl)、咪唑基 ’ （imidazolyl)、苯並咪唑基（benzimidaz〇lyl)、嘧啶基 10 、苯硫基（thiophenyl)或塞吩（thienyl)、奎 啉基（quinolinyl)、吲哚基（吲哚yl),以及噻唑基 (thiazolyl)。「雜芳烷基」一詞係指一取代有一雜芳基之 ^ 烷基。 「雜環基」一詞係指含一個或多個雜原子（如N、〇 15 或S)之5至8元單環、8至12元雙環，或1丨至14元三環；雜 環基之範例包括但不限於派嗪基（piperazinyl)，°比嘻烧 | 基（pyrrolidinyl)，二氧陸圜基（di〇xanyi)，嗎啉基 (morpholinyl)以及四羥基呋喃基（tetrahydrofuranyl)。 上述之烷基，環基，雜環基，芳基，雜芳基，芳烷 2〇 基’雜方烧基’烧氧基以及方氧基包括飽和與不飽和基 團；取代基範例包括但不限於函素，羥基，胺基，氰基， 硝基，硫醇基（mercapto) ’ 烧氧幾基（alkoxycarbonyl)， 醯胺基（amido)， 叛基（carboxy)，績胺烧 (alkanesulfonyl)，烧毅基（alkylcarbonyl)，氨基甲醢胺基 13 1299039 (carbamido)，胺甲醯基（carbamyl)，缓基（carboxyl)，硫 脲基（thioureido)，硫氰基（thiocyanato)，績醢胺基 (sulfonamido)，烧基，浠基（alkenyl)，炔基（alkynyl)， 烷氧基，芳基，雜芳基，環基，雜環基；其中烷基，烯 5 基’炔基，烧氧基，芳基，雜芳基，環基以及雜環基係 選擇性的更以烷基，芳基，雜芳基，自素，羥基，胺基， 硫醇基，氰基或硝基所取代之。 上述化合物包括其醫藥可接受的鹽類以及可應用的 鲁 前驅藥。此類鹽類可形成於吡咯啉啶化合物帶負電之離 10 子基團（如碳酸基）與帶正電之相反離子（counter ion)(如 鈉、鉀、鈣或鎂離子）之間。同樣地，吡咯啉啶化合物帶 正電之離子基團（如銨基）亦可與帶負電之相反離子（如 氯、溴或碘離子）形成鹽類。其前驅藥物之範例包括酯類 • 以及其他醫藥可接受之化合物，包括可提供上述吡咯啉 15 啶化合物之鹽類，端視主體投藥方式。 本發明化合物可用抑制DPP-iv ;因此，本發明化合 # 物之另一態樣係將上述吡咯啉啶化合物作為DPP-IV之 抑制劑；一種抑制DPP-IV之方法，即投予一受體所需有 效劑量之吡咯啉啶化合物之方法；以及一利用吡咯啉啶 20化合物製造可抑制DPP_IV藥劑之方法；由於抑制DPP-IV 可使血中葡萄糖濃度下降並提升胰島素的分泌，因此本 發明之化合物亦可用於治療第二型糖尿病’於是，本發 月化合物之另一態樣係將上述吡咯啉啶化合物作為治 療第二型糖尿病藥劑之方法；—種治療第二型糖尿病之 1299039 方法’即投予一受體所需有效劑量之π比洛琳咬化合物之 方法；以及一使用σ比洛琳11定化合物以製造可治療第二型 糖尿病藥劑之方法。 本發明化合物可用抑制雙肽酶vih(dpp-viii);因 5 此’本發明化合物之另一態樣係將上述吼咯啉啶化合物 作為DPP-VIII之抑制劑；一種抑制Dpp-VIII之方法，即 投予一受體所需有效劑量之吡咯啉啶化合物之方法；以 及一利用吡咯啉啶化合物製造可抑制DPP-VIII藥劑之 ® 方法。 10 本發明亦相關於一種包含上述吼咯啉啶化合物，及 一醫藥上可接受之載體之組成物。 本發明之諸多實施例細節將於下揭示。本發明之其 他特徵、目的與優點將由各說明與專利申請範圍中闡 • 明。 15 【實施方式】 # 本發明吡咯啉啶化合物可依照下列二種方法擇一製 備。 一製備°比咯琳唆化合物之方法係如同流程圖i所 20 示。本合成路徑中之起使化合物為胺基取代之二羧酸 (I) ’其中胺基以及酸基之一係被保護住，將此化合物與 2-取代 η比略琳 σ定鹽酸鹽（2-substituted pyrrolidine hydoixhloride salt) (II)—起反應，以形成一中間產物—單 胺化合物（monoamide)(III);而2-取代吼洛琳咬鹽酸鹽（Π)Compound 46 Compound 47 Compound 48 11 1299039 The term "aralkyl" means an alkyl group substituted by an aryl group. The term "ring group" refers to a saturated and partially unsaturated cyclic hydrocarbon chain containing 3 to 12 carbons. Examples of ring groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentene. Base, cyclohexyl, cyclohexenyl, cycloheptyl 5 and cyclooctyl. The term "heteroaryl" means a 5- to 8-membered monocyclic ring, an 8- to 12-membered bicyclic ring, or an 11- to 14-membered tricyclic ring containing one or more heteroatoms (such as N, hydrazine or S); heteroaryl examples Including pyridyl, furyl, imidazolyl, benzimidaz〇lyl, pyrimidinyl 10, thiophenyl or thienyl, quinine Quinolinyl, 吲哚yl, and thiazolyl. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group. The term "heterocyclyl" means a 5- to 8-membered monocyclic ring, an 8- to 12-membered bicyclic ring, or a 1 to 14-membered tricyclic ring containing one or more heteroatoms (such as N, 〇15 or S); Examples of bases include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanan, morpholinyl, and tetrahydrofuranyl. The above alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl 2 decyl 'heteroalkyl" alkoxy and aryloxy groups include saturated and unsaturated groups; examples of substituents include Not limited to the element, hydroxyl, amine, cyano, nitro, mercapto 'alkoxycarbonyl, amido, carboxy, alkanesulfonyl , alkylcarbonyl, carbamate 13 1299039 (carbamido), carbamel, carboxyl, thioureido, thiocyanato, decylamine Sulfonamido, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aryl group, a heteroaryl group, a cyclic group, a heterocyclic group; wherein an alkyl group, an alkene group, an alkynyl group, The oxy, aryl, heteroaryl, cyclo and heterocyclic groups are more optionally alkyl, aryl, heteroaryl, arginyl, hydroxy, amine, thiol, cyano or nitro Replace it. The above compounds include pharmaceutically acceptable salts thereof and applicable Lu precursors. Such salts can be formed between a negatively charged 10 subgroup (e.g., a carbonate group) of a pyrroline pyridine compound and a positively charged counter ion (e.g., sodium, potassium, calcium or magnesium ions). Similarly, a positively charged ionic group (e.g., an ammonium group) of a pyrroline pyridine compound can also form a salt with a negatively charged opposite ion (e.g., chlorine, bromine or iodide). Examples of prodrugs include esters and other pharmaceutically acceptable compounds, including those which provide the above pyrroline 15 pyridine compounds, depending on the mode of administration. The compound of the present invention can inhibit DPP-iv; therefore, another aspect of the compound of the present invention is to use the above pyrroline pyridine compound as an inhibitor of DPP-IV; a method for inhibiting DPP-IV, that is, to administer a receptor a method for obtaining an effective dose of a pyrroline pyridine compound; and a method for producing a DPP_IV inhibitor by using a pyrroline pyridine 20 compound; since the inhibition of DPP-IV can lower the blood glucose concentration and increase insulin secretion, the present invention The compound can also be used for the treatment of type 2 diabetes. Thus, another aspect of the compound of the present invention is the above-mentioned pyrroline pyridine compound as a method for treating a second type diabetes drug; a method for treating type 2 diabetes of 1299039 A method of administering an effective dose of π to a dose of a compound to a receptor; and a method of using a quinololidine compound to produce a medicament for treating a second type of diabetes. The compound of the present invention can be used to inhibit the diaplase vih (dpp-viii); another aspect of the compound of the present invention is the above-mentioned porphyrin pyridine compound as an inhibitor of DPP-VIII; a method for inhibiting Dpp-VIII , a method of administering an effective dose of a pyrroline pyridine compound to a receptor; and a method of producing a DPP-VIII-inhibiting agent using a pyrroline pyridine compound. The invention is also related to a composition comprising the above porphyrin pyridine compound, and a pharmaceutically acceptable carrier. Details of various embodiments of the invention are disclosed below. Other features, objects, and advantages of the invention will be apparent from the description and appended claims. [Embodiment] # The pyrrolopridinium compound of the present invention can be prepared by the following two methods. A method of preparing a compound is shown in Scheme i. In the present synthetic route, the compound is an amine-substituted dicarboxylic acid (I) 'where one of the amine group and the acid group is protected, and the compound is substituted with 2-substituted η bicin sedative hydrochloride ( 2-substituted pyrrolidine hydoixhloride salt) (II) - reacts to form an intermediate product - monoamide (III); and 2-substituted indolylate hydrochloride (Π)
15 1299039 可以本領域中習知方法製備得；例如，可參考Bi〇〇rg Med· Chem· Lett· 1996, 6, 1163中之敘述製備2取代吡咯 啉啶鹽酸鹽（II)，移除中間產物（ΠΙ)酸基上之保護基，以 形成單胺化合物（IV)，接著以胺基鍵結形成一雙胺化合 物（diamide)(V)，在雙胺化合物（ν)去保護之後可形成所 需之胺基取代之雙胺化合物（VI)。 流程圖115 1299039 can be prepared by methods known in the art; for example, the 2-substituted pyrroline pyridinium hydrochloride (II) can be prepared by reference to the description of Bi〇〇rg Med·Chem. Lett. 1996, 6, 1163, and the middle is removed. a protecting group on the acid group of the product to form a monoamine compound (IV), followed by bonding with an amine group to form a diamine compound (V), which can be formed after deprotection of the bisamine compound (ν) The desired amine substituted bisamine compound (VI). Flow chart 1
IIII
10 第二種製備吡咯啉啶化合物之方法係如同流程圖 2所示。本合成路徑中之起使化合物為緩酸（VII)，其係 被保護性胺基所取代，此化合物（VII)係與胺基（VIII)鍵 結以形成一醯胺化合物（IX)，將醯胺化合物（IX)去保護 15 之後可形成一胺基化合物（X)，接著與1-(2-溴-乙醯基） 1299039 吡咯啉啶化合物（XI)反應，形成所需之化合物（XII); 1-(2-溴-乙醯基）吡咯啉啶化合物（XI)可以本領域中習知 方法製備得；例如，可參考J· Med· Chem. 2003, 46, 2774. 中之敘述製備1-(2_溴-乙醯）吡咯啉啶-2-曱腈（IX)。 5 流程圖210 The second method for preparing a pyrroline pyridine compound is as shown in Scheme 2. In the present synthetic route, the compound is a slow acid (VII) which is substituted by a protective amine group which is bonded to an amine group (VIII) to form a guanamine compound (IX). The indoleamine compound (IX) is deprotected to form an amine compound (X), which is then reacted with 1-(2-bromo-ethenyl) 1299039 pyrrolopridinium compound (XI) to form the desired compound (XII). The 1-(2-bromo-ethinyl)pyrroline pyridine compound (XI) can be produced by a method known in the art; for example, it can be prepared as described in J. Med. Chem. 2003, 46, 2774. 1-(2-bromo-acetamidine)pyrrolidinium-2-indolecarbonitrile (IX). 5 Flowchart 2
XII XI 於上述合成路徑中所使用之化學品，可包括如溶劑， 藥劑、催化劑以及保護基與去保護基之藥劑；上述方法可 更包括額外之步驟，可於所述之特定步驟前或後，加入或 •10 移除適當的保護基，以合成吡咯啉啶化合物。此外，可以 不同合成步驟之方法以合成所需之化合物，可用以合成吡 咯啉啶化合物之合成化學轉形與保護基方法論（保護與去 保護）係該領域中之習知，請見：R. Larock，⑼hve Organic Transformations^ VCH Publishers (1989); T.W. 15 Greene and P.G.M. Wuts5 Protective Groups in Organic Synthesis, 3rd Ed.5 John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., 17 1299039XII XI The chemical used in the above synthetic route may include, for example, a solvent, a drug, a catalyst, and a protecting group and a deprotecting agent; the above method may further include an additional step before or after the specific step , Add or • 10 Remove the appropriate protecting group to synthesize the pyrroline pyridine compound. In addition, the synthesis of the desired compounds can be carried out in different synthetic steps. The synthetic chemical transformation and protecting group methodology (protection and deprotection) which can be used to synthesize pyrroline pyridine compounds is well known in the art. See: R. Larock, (9) hve Organic Transformations^ VCH Publishers (1989); TW 15 Greene and PGM Wuts5 Protective Groups in Organic Synthesis, 3rd Ed.5 John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., 17 1299039
Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995)與其後續版本。 另一合成本發明°比n各琳咬化合物之方法可採用本領域 習知之方法，請參考流程圖3至6所示之4種主要吼11各琳咬 5 化合物之合成路徑。 流程圖3Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent versions. Another method for synthesizing the present invention is to use a method known in the art. Please refer to the synthetic routes of the four main compounds shown in Schemes 3 to 6. Flow chart 3
於上流程圖中’起使化合物Ν·保護之2-胺基-2-甲基-丙烧續酸（N-protected 2-amino-2-methyl-propane-sulfanoic 10 acid)(l)先與氯化硫醯（sulfuryl chloride)進行反應，再與2,3· 二經基異,ϋ朵（2,3-dihydroisoindole)反應以合成績胺 (sulfonyl amide)(4)，接著再去保護以得胺基化合物（5);將 此胺基化合物與β-氨化漠（β-bromo amide)(6)鍵結以形成所 需之本發明化合物（7)。 15 流程圖4In the above flow chart, the N-protected 2-amino-2-methyl-propane-sulfanoic 10 acid (l) is first Sulfuryl chloride is reacted and reacted with 2,3-dihydroisoindole to form sulfonyl amide (4), followed by deprotection. Amine compound (5); this amine compound is bonded to β-bromo amide (6) to form the desired compound (7) of the present invention. 15 Flowchart 4
18 1299039 CCNH \Λα + H2N^V0^^ o 3 818 1299039 CCNH \Λα + H2N^V0^^ o 3 8
9 6 10 參考流程圖4，亞硫醯氯（thionyl chloride)連續與2,3- f 二羥基異吲哚（3)以及（2-胺基-1，1二甲基-乙基）_氨基甲酸 苄酯（8)進行反應，將其產物--被保護住之胺基化合物 5 (圖未示）去保護，以形成一游離之胺基化合物（9)，其再與 β-氨化溴（6)耦合形成吡咯啉啶化合物（1〇)，為本發明另一 .化合物。 同樣的，本發明之另外二種化合物，即化合物（14)與 ()可藉由類似於上述流程圖3與4之流程完成合成。 10 流程圖59 6 10 Referring to Scheme 4, thionyl chloride is continuously and 2,3-f dihydroxyisoindole (3) and (2-amino-1,1 dimethyl-ethyl)-amino The benzyl formate (8) is reacted, and the product-protected amine compound 5 (not shown) is deprotected to form a free amine compound (9), which is further reacted with β-ammonium bromide. (6) Coupling to form a pyrroline pyridine compound (1〇), which is another compound of the present invention. Similarly, the other two compounds of the present invention, Compounds (14) and (), can be synthesized by a procedure similar to the above Schemes 3 and 4. 10 Flowchart 5
15 流程圖6 19 129903915 Flowchart 6 19 1299039
丨上述合成途徑中所使用之化學品均可以於市面上購得 (如化合物1)’或是已經於先前公開過合成方法（如化合物 5 12與16);於合成途徑中之多個步驟可以不同次序進行以 合成出所需之化合物。應用化學轉形與保護基理論（保護與 去保護）合成吡咯啉啶化合物係為本領域中之習知’可參考 下列文獻：R. Larock， Comprehensive OrganicThe chemicals used in the above synthetic routes are commercially available (eg, Compound 1)' or have been previously disclosed in synthetic methods (eg, Compounds 5 12 and 16); multiple steps in the synthetic pathway may The different sequences are carried out to synthesize the desired compound. The use of chemical transformation and protecting group theory (protection and deprotection) to synthesize pyrroline pyridine compounds is well known in the art. References to the following documents: R. Larock, Comprehensive Organic
Transformations, VCH Publishers (1989); T.W. Greene and 10 P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser ^ and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.5 Encyclopedia of Reagents /br Oga/n’c 办John Wiley and Sons (1995)與其後續 15 出版輯。 上述製備出之σ比洛琳咬化合物更可藉由管柱層析法、 高效液相層析法或結晶法進行純化。 本發明吼洛啦咬化合物可包括一非芳香雙鍵與一個或 多個非對稱中心。所以，此化合物可以外消旋酸鹽、單一 20 1299039 鏡像異構物、個別非鏡像異構物、非鏡像體混合物、以及 順_/反-或E-/Z-雙鍵形式之異構物形式存在。所有類似形式 之異構物均被考慮在内。 本發明之範圍包括一抑制DPP_IV之方法，此方法包括 5投予一需要抑制DPIMV之主體一有效劑量之本發明上述 0比略琳σ定化合物。 本發明更包括一治療第二型糖尿病之方法，此方法包 括投予一有需要之主體一有效劑量之本發明上述吡咯啉啶 1 化合物及其醫藥可接受之載體。「治療」一詞係指將包括吡 10 咯琳σ疋化合物在内的一組合物應用或提供給一患有第二型 糖尿病，有第二型糖尿病症狀，或是具有罹患第二型糖尿 病傾向之本體，可能達成之治癒，痊癒，減輕，緩和，改 變，醫治，改善，增進，或是第二型糖尿病，第二型糖尿 病之感染症狀，以及具有罹患第二型糖尿病之傾向有影響 15 之效果。「一有效劑量」指吡咯啉啶化合物劑量可以對投 藥個體有治療的效果；如熟習此項技藝者之所知，有效劑 t Ϊ亦可能依治療之疾病種類，投藥的路徑，受試者的利用 率與其他治療合併使用之活性物質而改變。此促，於本發 明範圍中更包括一抑制DPP-VIII之方法，此方法包括投予 20 一有需要抑制DpP-VIII之受體一有效劑量之上述吡咯啉啶 化合物。 本發明更包括一含至少一有效劑量之上述η比咯啉啶化 合物之醫藥組成物及一醫藥可接受之載體。 為實行本發明所述之方法，包含一種或數種上述之t!比 21 1299039 洛琳唆化合物之組合物，可經由靜脈，口服，經鼻，經直 腸局邛或疋舌下等方式投藥。「靜脈投藥」在此指的是 皮下腹腔，靜脈注射，肌肉注射，關節腔内注射，主動 脈注射，關即液内注射，胸腔注射，脊髓内注射，疾病部 5位内’主射’顧内注射，或其他適合的投藥技術。 無菌可注射的組成物可為一溶液或是懸浮於無毒的靜 脈注射稀釋液或溶劑中，此類溶劑如丨，3_丁二醇。可接受的 鲁 載，或是溶劑可以為甘露醇（mannitol)或是水。除此之外， 固疋油則為一般習用於溶劑或是懸浮介質（例如··合成單或 1〇雙甘油酉旨）。脂肪酸，如油酸（Oleic Acid)與其甘油醋衍生物 白可作為製備可注射並為自然醫藥可接受之用乂由，如撤揽 ：油或繁麻油等，特別是其多氧乙基化之型態。這些油類溶 液或懸、牙液可包含長鏈酒精稀釋液或分散劑、叛甲基纖維 素或類似的分散劑。其他一般使用的介面活性劑如 15或是SpanS或其他相似的乳化劑或是一般醫藥製造業所使 用於4藥可接受之固態、液態或其他可用於劑型開發目的 • 之劑量型式。 用於口服投藥之組合物是任何一種口服可接受的劑 型，型式包括膠囊、錠片、乳化劑與液狀懸浮液、分散劑 20與溶劑。以錠片為例，一般所使用的載體為乳糖或是玉米 ，粉；潤滑劑，如硬脂酸鎂為基本添加物。以口服膠囊投 藥型式，有效的稀釋液包括乳糖與乾燥玉米澱粉。當以液 狀懸浮液或乳化劑經π投藥時，活性物質可以懸浮或是溶 解於結合乳化劑或懸浮劑的油狀介面中。如果需要，可添 22 1299039 加適度的甜味劑，風味劑或是色素。 鼻用氣化喷霧劑或吸入劑組成物可根據已知的醫藥劑 型技術進行製備。例如，此組成物可製備於生理食鹽水中， 應用笨曱醇或其他適合的防腐劑，促吸收劑以增強生物可 5利用性，碳氟化合物與或其他已知良好利用的可溶解分散 劑。包含一種或多種活性吡咯啉啶化合物之組合物亦可以 栓劑方式進行直腸投藥。 在醫藥級組合物中載體必須為「可接受性」，即其必 1須與組合物中活性主成分相容（更佳的是，具有穩定活性主 1〇 j分的功能），並且不能對受體造成傷害。一種或多種溶解 7可作為傳送吡咯啉啶化合物活性主成分的醫藥性賦形 、刮其他的載體例如包括氧化矽膠、硬脂酸鎂、纖維素、 硫酸月桂酸鈉與D&C Yellow # 10。 15 本發明所述之吡咯啉啶化合物可初步針對其抑制 =ρΡ-ιν以及DPP_VIII之活性，經由體外抑制分析進行篩 〉、、&過初步篩選之高活性之化合物可進一步以活體試驗 人 刀析其、;口療第一型糖尿病之效果。如，一測試用化 合物可投予一患有第二型糖尿病之動物（如以一老鼠模式 ；0 ψ吁）並接著评估其治療效果。根據這些結果，可以評估 一適當劑量之範圍與投藥途徑。 下列特定具體實施例僅解釋為說明性，無論以任何方 ^限制本揭示之其餘者。對本發明中配方的形式與細 略、修飾、減損、與改變，在不背離本發明之精神 色可下，均可由熟習本項技藝者加以進行。將本文所引Transformations, VCH Publishers (1989); TW Greene and 10 PGM Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser ^ and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.5 Encyclopedia of Reagents /br Oga/n'c Do John Wiley and Sons (1995) and its follow-up 15 publications. The above prepared σ piroxime biting compound can be purified by column chromatography, high performance liquid chromatography or crystallization. The indole compound of the present invention may comprise a non-aromatic double bond and one or more asymmetric centers. Therefore, this compound can be a racemic acid salt, a single 20 1299039 mirror image isomer, an individual non-image isomer, a non-image mixture, and an isomer of the cis/trans- or E-/Z-double bond form. Form exists. All similar forms of isomers are taken into account. The scope of the present invention includes a method of inhibiting DPP_IV, which comprises administering 5 of the above-mentioned 0-bilelin sigma compound of the present invention in an amount effective to inhibit the body of DPIMV. The invention further comprises a method of treating a second type of diabetes which comprises administering to a subject in need thereof an effective amount of the above pyrroline pyridine 1 compound of the invention and a pharmaceutically acceptable carrier therefor. The term "treatment" refers to the application or supply of a composition comprising a pyridoxine 疋 compound to a type 2 diabetes, a second type of diabetes, or a predisposition to type 2 diabetes. The ontology, the possible cure, healing, alleviation, alleviation, change, healing, improvement, enhancement, or type 2 diabetes, the symptoms of type 2 diabetes, and the tendency to have type 2 diabetes affect 15 effect. "An effective dose" means that the dose of the pyrroline pyridine compound can have a therapeutic effect on the individual to be administered; as is known to those skilled in the art, the effective agent t Ϊ may also depend on the type of disease to be treated, the route of administration, the subject's The utilization rate is changed with the active substance used in combination with other treatments. Further, in the scope of the present invention, a method of inhibiting DPP-VIII is further included, which comprises administering an effective amount of the above pyrrolopridinium compound to a receptor which is required to inhibit DpP-VIII. The invention further comprises a pharmaceutical composition comprising at least one effective amount of the above η-pyrroline pyridine compound and a pharmaceutically acceptable carrier. For carrying out the method of the present invention, a composition comprising one or more of the above-mentioned t! ratio 21 1299039 lindane compounds can be administered intravenously, orally, nasally, orally or sublingually. "Intravenous administration" refers to subcutaneous abdominal cavity, intravenous injection, intramuscular injection, intra-articular injection, aortic injection, intra-liquid injection, intrathoracic injection, intraspinal injection, and the main part of the disease department. Intra-injection, or other suitable drug delivery techniques. The sterile injectable composition can be a solution or suspended in a non-toxic intravenous diluent or solvent such as hydrazine, 3-butanediol. Acceptable Lu load, or the solvent can be mannitol or water. In addition, solid oils are generally used in solvents or suspension media (for example, synthetic single or one-dimensional diglycerin). Fatty acids, such as Oleic Acid and its glycerol vinegar derivative, can be used as an injectable and acceptable pharmaceutical for natural medicine, such as withdrawal: oil or sesame oil, especially its polyoxyethylation. Type. These oil solutions or suspensions may contain long-chain alcohol diluents or dispersants, cytotoxic or similar dispersants. Other commonly used surfactants, such as 15 or SpanS or other similar emulsifiers, are used in the pharmaceutical industry for solid, liquid or other dosage forms that are acceptable for formulation purposes. The composition for oral administration is any orally acceptable dosage form comprising a capsule, a tablet, an emulsifier and a liquid suspension, a dispersing agent 20 and a solvent. In the case of tablets, the carrier generally used is lactose or corn, powder; a lubricant such as magnesium stearate is a basic additive. In the form of oral capsule administration, effective diluents include lactose and dried corn starch. When the liquid suspension or emulsifier is administered by π, the active substance may be suspended or dissolved in an oily interface in combination with an emulsifier or a suspending agent. If necessary, add 22 1299039 with a mild amount of sweetener, flavor or color. Nasal gasifying sprays or inhalant compositions can be prepared according to known pharmaceutical dosage form techniques. For example, the composition can be prepared in physiological saline using stupid alcohol or other suitable preservatives to enhance bioavailability, fluorocarbons or other known well-utilizable dissolvable dispersants. Compositions comprising one or more active pyrrolopridinium compounds can also be administered in the form of a suppository for rectal administration. The carrier must be "acceptable" in the pharmaceutical grade composition, i.e., it must be compatible with the active principal component of the composition (more preferably, it has the function of stabilizing the active primary component) and cannot be The receptor causes damage. One or more of the dissolutions 7 can be used as a pharmaceutical ingredient for delivering the active ingredient of the pyrroline pyridine compound, and other carriers include, for example, cerium oxide gum, magnesium stearate, cellulose, sodium laurate sulfate, and D&C Yellow #10. 15 The pyrrolopridinium compound of the present invention can be preliminarily tested for its activity of inhibition = ρΡ-ιν and DPP_VIII by in vitro inhibition analysis, and the compound having high activity after preliminary screening can be further tested by a living body. Analyze it; the effect of oral therapy type 1 diabetes. For example, a test compound can be administered to an animal having type 2 diabetes (e.g., in a mouse mode; 0 ψ ) ) and then evaluated for its therapeutic effect. Based on these results, the range of appropriate doses and route of administration can be assessed. The following specific examples are merely illustrative, and the remainder of the disclosure is limited by any means. The form, details, modifications, derogations, and modifications of the formulations of the present invention can be carried out by those skilled in the art without departing from the spirit of the invention. Will be cited in this article
23 1299039 述之所有發表文獻全部併入本文以供參考。 化學合成 實施例1、合成1-[2-胺基-4·(3,4-雙經-1氮-異唉1淋-2-基）-4-氧 5 基-丁基]-吡咯啉啶-2-甲腈三氟醋酸（化合物1) 流程圖3顯示出化合物1之合成路徑。 (1) 製備3-叔丁氧幾基胺基-4-(2-氰基-吼11各琳咬-l-基）-4-氧 基-丁酸苄基酯（C) • 將一含叔丁氧羰基（BOC)-L-麩胺酸5-苄基酯（A) (0.65g， 10 2 mmol)以及N-經基·丁二酸亞醯胺（HOSu，0.23g，2mmol)的 6ml二氣甲烷/1，4-環氧己烷（2/1)於一冰浴槽下冷卻，接著邊 攪拌邊加入二環己基二亞醢銨（dicyclohexylcarbodimide， - DCC，0.45g，2.2 mmol)。將反應混合液於室溫下攪拌一小 . 時，並加入11比洛琳咬-2-甲腈氫氯酸鹽（B) (0.27g，2mmol)以 15 及三乙胺（Et3N，0.22g，2.2mmol);於室溫處理4小時後，以 過濾方式移除DCC並以二氣曱烷清洗；將過濾液與清洗液 ^ 結合，並以10%擰檬酸溶液與飽和碳酸氫鈉溶液清洗，以硫 酸鎂乾燥，並於真空下濃縮，以快速管柱層析法（以正己烷 /二氯甲烷/乙酸乙酯=5 / 4 /1萃取）純化，形成一泡沫狀化合物 20 (C) (80%) 〇 (2) 製備N-t-BOC保護1-[2-胺基-4-(3,4-雙羥-1氫-異喹啉-2-基）-4 -氧基·丁基]·ϋ比洛淋ϋ定-2-甲猜 將化合物（C) (0.40g，lmmol)以及5% Pd/C (20mg)溶於 乙酸乙酯（6mL)與曱醇（250μΙ〇中，並於氫氣氛圍下攪拌7 25 小時並過濾，將過濾液於真空下濃縮以形成一白色固態化All of the published documents are hereby incorporated by reference. Chemical Synthesis Example 1. Synthesis of 1-[2-amino-4(3,4-bis-l-nitro-isoindole-1-yl)-4-oxo-5-butyl]-pyrroline Pyridine-2-carbonitrile trifluoroacetic acid (Compound 1) Scheme 3 shows the synthetic route of Compound 1. (1) Preparation of 3-tert-butoxymethylamino-4-(2-cyano-indole 11-lin-l-yl)-4-oxo-butyric acid benzyl ester (C) • tert-Butoxycarbonyl (BOC)-L-glutamic acid 5-benzyl ester (A) (0.65 g, 10 2 mmol) and N-carbamic acid succinic acid succinimide (HOSu, 0.23 g, 2 mmol) 6 ml of di-methane/1,4-epoxyhexane (2/1) was cooled in an ice bath, followed by the addition of dicyclohexylcarbodimide (DCC, 0.45 g, 2.2 mmol) with stirring. The reaction mixture was stirred at room temperature for one hour. Then, 11 pirolin-2-meronitrile hydrochloride (B) (0.27 g, 2 mmol) was added to 15 and triethylamine (Et3N, 0.22 g). , 2.2mmol); after treatment at room temperature for 4 hours, remove DCC by filtration and wash with dioxane; combine the filtrate with the cleaning solution, and use 10% citric acid solution and saturated sodium bicarbonate solution Washed, dried over MgSO.sub.sub.sub.subsubsubsubsubsubsubsubsubsubsubsubsubsubsubsubsubsub (80%) 〇(2) Preparation of Nt-BOC protected 1-[2-amino-4-(3,4-bishydroxy-1 hydrogen-isoquinolin-2-yl)-4-oxy·butyl The compound (C) (0.40 g, 1 mmol) and 5% Pd/C (20 mg) were dissolved in ethyl acetate (6 mL) and decyl alcohol (250 μM, And stirred under a hydrogen atmosphere for 7 25 hours and filtered, and the filtrate was concentrated under vacuum to form a white solidified
24 1299039 合物（D)，此化合物（D)可直接使用無須經過更進一步之純 化。將化合物（D)與HOSu(0.12g，lmmol)溶於3ml二氯曱烷 /1，4-環氧己烷（2/1)之溶液中，並於一冰浴槽中冷卻。攪拌 加入DCC(0.23g，1.1 mmol)l小時後，加入1，2,3,4-四氫異喹 5 啉（0.20g，1.5mmol)，於室溫下攪拌反應液4小時。接著， 以過濾方式移除DCC並以二氯曱烷清洗；將過濾液與清洗 液結合，並以10%擰檬酸溶液與飽和碳酸氫鈉溶液清洗，以 硫酸鎂乾燥，並於真空下濃縮，以快速管柱層析法（以正己 ® 烷/二氯甲烷/乙酸乙酯=3/6/1萃取）純化，獲得一泡沫狀之 10 Ν-ί-BOC保護之1-[2-胺基·4-(3,4-雙羥-1氫-異喹啉-2-基）_4- 氧基-丁基]-吼咯啉啶-2_曱腈(85%)。 (3)製備1-[2-胺基-4-(3,4-雙羥-1氫·異喹啉-2-基）-4-氧基-丁 • 基]-吡咯啉啶-2-曱腈三氟醋酸 - 將Ν-ί-BOC保護之1-[2-胺基-4-(3,4-雙羥-1氫-異喹啉 15 -2-基）-4-氧基·丁基]-吡咯啉啶-2-曱腈(0.43g，lmmol)溶於冷 卻之TFA (2mL)，所形成之溶液於室溫下攪拌10分鐘，並 φ 濃縮成標題化合物（E)，為一淡黃色半固體。 MS (ES+) m/z. 327.1 (M+H)+? 349.1 (M+Na)+. 20 流程圖324 1299039 Compound (D), this compound (D) can be used directly without further purification. Compound (D) and HOSu (0.12 g, 1 mmol) were dissolved in a solution of 3 ml of dichloromethane / 1,4-hexanehexane (2/1) and cooled in an ice bath. After stirring, DCC (0.23 g, 1.1 mmol) was added for 1 hour, then 1,2,3,4-tetrahydroisoquinoline (0.20 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Next, DCC was removed by filtration and washed with dichloromethane; the filtrate was combined with the washing solution, washed with 10% citric acid solution and saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated under vacuum. Purified by flash column chromatography (extracted with n-hexane/dichloromethane/ethyl acetate = 3/6/1) to give a foamy 10-[2-amine 4-(3,4-bishydroxy-1 hydrogen-isoquinolin-2-yl)-4-yloxy-butyl]-nonporphyrin pyridine-2-indene nitrile (85%). (3) Preparation of 1-[2-amino-4-(3,4-bishydroxy-1 hydrogen·isoquinolin-2-yl)-4-oxy-butanyl]-pyrroline pyridine-2- Indole trifluoroacetic acid - 1-[2-amino-4-(3,4-bishydroxy-1 hydrogen-isoquinoline 15 -2-yl)-4-oxy group protected by Ν-ί-BOC Butyl]-pyrroline pyridine-2-indenecarbonitrile (0.43 g, 1 mmol) was dissolved in EtOAc (EtOAc) A pale yellow semi-solid. MS (ES+) m/z. 327.1 (M+H)+? 349.1 (M+Na)+. 20 Flowchart 3
25 129903925 1299039
實施例2-18Example 2-18
CC
OH COH C
D 每一化合物2-18之製備方法係以類似實施例1所述之方式 5 完成。 實施例2 6-{4_[3 -胺基_4-(2 -亂基π比洛琳咬-1 -基）-4-丁乳基]-旅 嗪-1-基卜菸鹼腈基，三氟醋酸（化合物2) MS (ES+) m/z. 382.1 (M+H)+, 404.1 (M+Na)+. 10 實施例3 : l-[2-胺基-4-(6,7-二曱氧基-3,4-雙羥-1氫-異喹啉-2-基）-4-丁 氧基]-2-氰基-〇S)-吼咯啉啶，三氟醋酸（化合物3) MS (ES+) m/z. 387.1 (M+H)+, 409.1 (M+Na)+. 實施例4: 15 1-[2-胺基_4·(4·苯曱酿旅嘻-1 -基）-4-氧基-丁基]-2-亂基-($)- 26 1299039D The preparation of each of the compounds 2-18 was carried out in a manner similar to that described in Example 1. Example 2 6-{4_[3-Amino-4-(2-disyl-based pi-Lolinine-1 -yl)-4-butyryl]-benzin-1-yl-nicotinyl nitrile group, (3) -dimethoxy-3,4-bishydroxy-1hydro-isoquinolin-2-yl)-4-butoxy]-2-cyano-oxime S)-indolopyridinium, trifluoroacetic acid ( Compound 3) MS (ES+) m/z. 387.1 (M+H)+, 409.1 (M+Na)+. Example 4: 15 1-[2-Amino- 4·(4·Benzene 曱 嘻-1 -yl)-4-oxy-butyl]-2-ranyl-($)- 26 1299039
10 1510 15
20 σ比洛淋咬，三氟醋酸（化合物4) MS (ES+) m/z. 384.1 (M+H)+, 406.1 (M+Na)+. 實施例5 : l-{2-胺基-4·[1-(2-羥乙基）-6,7-二甲氧基·3,4-雙羥-1氫、異嗜 淋-2-基]-4·丁氧酿基]-2-氰基比嘻琳ϋ定’二鼠酷峻（彳匕八 物5) MS (ES+) m/z. 453.5 (M+Na)+? 469.4(M+K)+. 實施例6 : 化合物6之製備方法係以類似實施例1所述之方式完成。 1_[2_胺基-4-(3,4-雙羥-1氫-異喹啉-2·基）-4· 丁氧基卜％哈 啉啶-2-甲腈三氟醋酸（化合物6) MS (ES+) m/z. 313.4 (M+H)+ 實施例7 : l-[2-胺基-4-(1-異丙基·6,7-二甲氧基-3,4-雙羥-1氫-異喹琳 -2-基）-4-丁氧醯基]-2-氰基-〇S)-处咯啉啶，三氟醋酸（化合物 7) MS (ES+) m/z.429.5 (M+H)+, 451.5 (M+Na)+. 實施例8 : l-[2-胺基-4-(1-苯甲基-6,7-二甲氧基-3,4-雙羥-1氫-異喹啉 -2-基）-4-丁氧基]-2·氰基-〇S>吼咯啉啶，三氟醋酸（化合物 8) MS (ES+) m/z.477.5 (M+H)+? 499.5 (M+Na)+. 實施例9 : l-[2-胺基-4-(1·第三丁基-6,7-二甲氧基-3,4_雙羥-1氫-異喹 25 啉-2-基）_4·丁氧基]-2_氰基-(5>吡咯啉啶，三氟醋酸（化合物 27 1299039 9) MS (ES+) m/z.443.2(M+H)+5 465.2 (M+Na)+. 實施例10:3-胺基-4-(2-氰基-(aS)-11比洛琳咬-1·基）_N-[2-(3,4_二曱氧基- 苯基）-乙基]-4-氧丁醯胺，三氟醋酸（化合物10) lR NMR (CD3OD) δ 2.09-2.31 (m, 4H5)5 2.69-2.8820 σ piroxime bite, trifluoroacetic acid (compound 4) MS (ES+) m/z. 384.1 (M+H)+, 406.1 (M+Na)+. Example 5: l-{2-Amino- 4.·[1-(2-Hydroxyethyl)-6,7-dimethoxy-3,4-bishydroxy-1 hydrogen, iso-p-yl-2-yl]-4·butoxycarbonyl]-2 - cyanopyrene ϋ ϋ ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' The preparation process was carried out in a manner similar to that described in Example 1. 1_[2_Amino-4-(3,4-bishydroxy-1hydro-isoquinolin-2-yl)-4. Butoxyb%Halolinidine-2-carbonitrile trifluoroacetic acid (Compound 6 MS (ES+) m/z. 313.4 (M+H) + Example 7: l-[2-amino-4-(1-isopropyl-6,7-dimethoxy-3,4- Dihydroxy-1 hydrogen-isoquinolin-2-yl)-4-butoxyindolyl]-2-cyano-indenyl S)-per porphyrin pyridine, trifluoroacetic acid (compound 7) MS (ES+) m/ Z.429.5 (M+H)+, 451.5 (M+Na)+. Example 8: l-[2-amino-4-(1-phenylmethyl-6,7-dimethoxy-3, 4-bishydroxy-1 hydrogen-isoquinolin-2-yl)-4-butoxy]-2.cyano-indole S> porphyrin pyridine, trifluoroacetic acid (compound 8) MS (ES+) m/ Z.477.5 (M+H)+? 499.5 (M+Na)+. Example 9: l-[2-Amino-4-(1·t-butyl-6,7-dimethoxy-3 , 4_bishydroxy-1 hydrogen-isoquine 25 oxalin-2-yl)_4.butoxy]-2-cyano-(5>pyrrolidine,trifluoroacetic acid (compound 27 1299039 9) MS (ES+) m/z. 443.2 (M+H)+5 465.2 (M+Na)+. Example 10: 3-amino-4-(2-cyano-(aS)-11 pirolene-1. )_N-[2-(3,4-dioxalyl-phenyl)-ethyl]-4-oxetamine, trifluoroacetic acid (Compound 10) lR NMR (CD3OD) δ 2.09-2.31 (m, 4H5)5 2.69-2.88
(m，4H，)，3.29-3.43 (m，2H，)，3.60-3.73 (m，2H，)，3.78 (s，3H， OCH3)，3·81 (s，3H，OCH3)，4.47-4.52 (dd，= 7.7, 4.5 Hz， 1H，)，4.78-4.82 (dd，/= 7.8, 5.4 Hz，1H，C//CN)，6.73-6.86(m，3H，）； MS (ES+) m/z.375.4(M+H)+，397.4 (M+Na)+· 實施例11 : 化合物11之製備方法係以類似實施例 1所述之方式完成 15 1-P-胺基-4-(3-羥甲基-3,4-雙羥-1氫-異喹啉-2-基）-4、氣< 丁醯]比哈琳咬-2-甲腈(化合物11) MS (ES+) m/z.357.4 (M+H)+ 實施例12:(m,4H,), 3.29-3.43 (m, 2H,), 3.60-3.73 (m, 2H,), 3.78 (s, 3H, OCH3), 3·81 (s, 3H, OCH3), 4.47-4.52 (dd, = 7.7, 4.5 Hz, 1H,), 4.78-4.82 (dd, /= 7.8, 5.4 Hz, 1H, C//CN), 6.73-6.86 (m, 3H,); MS (ES+) m/ Z.375.4(M+H)+, 397.4 (M+Na)+· Example 11: Preparation of Compound 11 was carried out in a manner similar to that described in Example 1 15 1-P-Amino-4-(3) -hydroxymethyl-3,4-bishydroxy-1hydro-isoquinolin-2-yl)-4, gas <butane]Biharine bite-2-carbonitrile (Compound 11) MS (ES+) m /z.357.4 (M+H)+ Example 12:
3-胺基苯甲基_4_(2-氰基-(5>吡咯啉啶_1-基丁 基，三氟醋酸（化合物12) 20 MS (ES+) m/z.301.4(M+H)+, 323.4 (M+Na)+. 實施例13: 3-胺基-4-(2 -乳基- 比洛琳咬-1_基）-4-氧基-笨為^ 基）丁醯基；三氟醋酸（化合物13) MS (ES+) m/z.329.2(M+H)+5 35 1.2 (M+Na)+. 實施例14: 25 3-胺基-4-(2·乳基-(夕)-11比洛琳〇定-1 _基1 -曱基-1 ·笨 基乂 28 1299039 基）-4-丁氧醯基，三氟醋酸（化合物14) ]H NMR (CD3OD) (3 to 1 mixture of trans/cis amide rotomers)(5 1.60〜1.75(m，3H，CH3)，2.05〜2.38(m，4H)， 2.40〜2.65 (m，2H)，3.40 (m，1/4H)，3.46〜3.65 (m，lH)， 5 3.65〜3.78(m，3/4H)，3.96〜4.05(m，lH).3.65〜3.78(m， 3/4H)，5.05 (d，/ = 7.5，1.8Hz，1/4H)，7.08〜7.40 (m，5H， ArH); MS (ES+) m/z.329.2(M+H)+，351.2 (M+Na)+· 實施例15: 化合物15之製備方法係以類似實施例1所述之方式完成。3-aminobenzylmethyl_4_(2-cyano-(5>pyrrolidine-1-ylbutyl,trifluoroacetic acid (compound 12) 20 MS (ES+) m/z.301.4 (M+H) +, 323.4 (M+Na)+. Example 13: 3-amino-4-(2-lacyl-bilorinine-1 -yl)-4-oxo-stupylyl)butanyl; Fluoroacetic acid (Compound 13) MS (ES+) m/z. 329.2 (M+H) + 5 35 1.2 (M+Na)+. Example 14: 25 3-amino-4-(2·milyl-(夕)-11 piroxicam -1-1 _yl 1 -mercapto-1 笨 乂 乂 28 1299039 ))-4-butoxycarbonyl, trifluoroacetic acid (compound 14) ]H NMR (CD3OD) (3 To 1 mixture of trans/cis amide rotomers) (5 1.60 to 1.75 (m, 3H, CH3), 2.05 to 2.38 (m, 4H), 2.40 to 2.65 (m, 2H), 3.40 (m, 1/4H), 3.46~3.65 (m,lH), 5 3.65~3.78(m,3/4H), 3.96~4.05(m,lH).3.65~3.78(m, 3/4H),5.05 (d, / = 7.5,1.8 Hz, 1/4H), 7.08~7.40 (m, 5H, ArH); MS (ES+) m/z.329.2 (M+H)+, 351.2 (M+Na) + · Example 15: Preparation of Compound 15 The method was completed in a manner similar to that described in Example 1.
I 10 實施例16: 3-胺基-4-(2-亂基比嘻琳唆-1-基）_7V»(2·甲基-1-苯基丙 基）·4·丁醯基，三氟醋酸（化合物16) MS (ES+) m/z.343.2(M+H)+5 365.1 (M+Na)+. 實施例17: 15 3-胺基_4_(2·氰基-(5)-°比洛琳咬-1_基）-尽（1_甲氧基甲基-2- 苯基乙基）-4-丁醯基，三氟醋酸（化合物17) lH NMR (CD3OD) 5 2.09-2.31 (m, 4H5)5 2.62-2.90 _ (m，4H，），3.25-3.39 (m，5H，overlapped with single at 3.32, 0CH3 and others)，3.56-3.69 (m，2H，），4.18-4.23 (m，2H，）， 2〇 4.34-4.48 (dd5 J = 7.8, 5.4 Hz, 1H)5 4.78-4.82 (dd, J = 7.85 4·5 Hz，1H，C//CN)，7.15-7,29 (m，5H，ArH)); MS (ES+) m/z.349.1(M+H)+, 381.1 (M+Na)+. 實施例18: 3-胺基-4·(2_氰基比略淋σ定-1-基）_义(2,2-二甲基-1-苯 25 基丙基）-4-丁氧醯基，三氟醋酸（化合物18) MS (ES+) m/z.357.2 (M+H)+, 379.2 (M+Na)+. 29 1299039 實施例19: 合成1-{2-[3-(3,4·雙經-1氫-異喧琳-2·基）-3-氧基-丙基胺基]-乙醯}-吡咯啉啶-2-曱腈(化合物19) 流程圖4說明化合物19之合成步驟。 5 (1)製備[3-(3,4-雙羥-1氫-異喹啉-2-基）-3-氧基-丙基]-氨基 甲酸叔丁酯（G) 將 BOC-β-丙胺酸（1.89g，lOmmol)以及 HOSu(1.15g， lOmmol)溶於20mL二氯曱烷/1，4_環氧己烷（2/1)中，並置於 > 冰浴槽中冷卻，攪拌加入DCC(2.3g，11 mmol)，於室溫下攪 10 拌一小時，再加入1，2,3,4-四氫·異者淋(2.0g，15mmol)，於室 溫下反應4小時後，以過濾方式移除DCC並以二氯甲烷清 洗；將過濾液與清洗液結合，並以10%擰檬酸溶液與飽和碳 ~ 酸氫鈉溶液清洗，以硫酸鎂乾燥，並於真空下濃縮，以快 速管柱層析法（以二氯甲烧/乙酸乙酯=9/1)純化，產出一泡 15 沫狀之化合物（G) (88%)。 (2)製備標題之化合物 | 將化合物（G) (0.30g，lmmol)溶於冷卻之TFA(2mL) 中於室溫下攪拌10分鐘，並於真空下濃縮3小時，將所產生 之黃色油狀物溶於二氯甲烷並於冰浴槽中冷卻。加入Et3N 20 (0.3g，3mmol)於溶液中，並逐滴加入含溴化合物（I)之二氯 甲烧溶液（O.llg，〇.5mmol)，所產生之混合物於室溫下授拌 隔夜。以二氯甲烷稀釋此混合物，並以飽和之碳酸氫鈉溶 液清洗，再以硫酸鎂乾燥，並於真空下濃縮，以快速管柱 層析法進行純化（以二氯甲烷/曱醇=96/4提取），產出一淡黃 30 1299039 色油狀化合物（19, 45%)。 4 NMR (CD3OD) δ 2.16-2.28 (m，4H)，2.87 (t，1H， /=6.0 Hz)，2.94-2.98 (m，3H)，3·41 (t，2H，j = 5.9 Hz)， 3.46-3.51 (m，2H)，3.63-3.68 (m，1H)，3.73 (t，lh，6·〇 Hz)， 5 3.81 (t，1H，J = 6.0 Hz)，4.11·4·13 (m，2H)，4.70 (d，2H，= 9.9 Hz，ArC//2N)，4.81 (dd，1H，9.9 and 5.1 Hz，Ci/CN)， 7.18-7.19 (m，4H); HRMS (El) m/z calcd f〇r c19H24N4〇2 340.1899, found 340.1899.I 10 Example 16: 3-Amino-4-(2-ranyl-pylinyl-1-yl)_7V»(2·methyl-1-phenylpropyl)·4·butanyl, trifluoroacetic acid (Compound 16) MS (ES+) m/z. 343.2 (M+H) + 5 365.1 (M+Na)+. Example 17: 15 3-amino _4_(2· cyano-(5)-° Bilolin biting -1_yl)-(1_methoxymethyl-2-phenylethyl)-4-butenyl, trifluoroacetic acid (compound 17) lH NMR (CD3OD) 5 2.09-2.31 (m , 4H5)5 2.62-2.90 _ (m,4H,), 3.25-3.39 (m,5H, overlapped with single at 3.32, 0CH3 and others), 3.56-3.69 (m,2H,), 4.18-4.23 (m, 2H,), 2〇4.34-4.48 (dd5 J = 7.8, 5.4 Hz, 1H)5 4.78-4.82 (dd, J = 7.85 4·5 Hz, 1H, C//CN), 7.15-7, 29 (m , 5H,ArH)); MS (ES+) m/z. 349.1 (M+H)+, 381.1 (M+Na)+. Example 18: 3-amino-4. σ定-1-yl)_(2,2-dimethyl-1-phenyl-25-propyl)-4-butoxycarbonyl, trifluoroacetic acid (compound 18) MS (ES+) m/z.357.2 (M+H)+, 379.2 (M+Na)+. 29 1299039 Example 19: Synthesis of 1-{2-[3-(3,4·bis-l-hydrogen-isoindolene-2)- 3-oxy-propylamino]-acetamidine}-pyrroline pyridine-2-indole (compound) 19) Scheme 4 illustrates the synthetic steps of compound 19. 5 (1) Preparation of [3-(3,4-bishydroxy-1hydro-isoquinolin-2-yl)-3-oxy-propyl]-carbamic acid tert-butyl ester (G) BOC-β- Alanine (1.89 g, 10 mmol) and HOSu (1.15 g, 10 mmol) were dissolved in 20 mL of dichloromethane/1,4-epoxyhexane (2/1), placed in an ice bath, cooled, and stirred. DCC (2.3 g, 11 mmol), stirred at room temperature for 10 hours, and then added 1,2,3,4-tetrahydro-isoform (2.0 g, 15 mmol), and reacted at room temperature for 4 hours. The DCC was removed by filtration and washed with dichloromethane; the filtrate was combined with the washing solution, washed with 10% citric acid solution and saturated sodium hydrogencarbonate solution, dried over magnesium sulfate, and concentrated under vacuum. Purification by flash column chromatography (dichloromethane / ethyl acetate = 9 / 1) yielded a foamy compound (G) (88%). (2) Preparation of the title compound. The compound (G) (0.30 g, 1 mmol) was dissolved in EtOAc. The material was dissolved in dichloromethane and cooled in an ice bath. Et3N 20 (0.3 g, 3 mmol) was added to the solution, and a solution of the bromine-containing compound (I) in methylene chloride (O.llg, 〇. 5 mmol) was added dropwise, and the resulting mixture was stirred overnight at room temperature. . The mixture was diluted with methylene chloride and washed with EtOAc EtOAc EtOAc EtOAc. 4 extraction), yielding a pale yellow 30 1299039 color oily compound (19, 45%). 4 NMR (CD3OD) δ 2.16-2.28 (m,4H), 2.87 (t,1H, /=6.0 Hz), 2.94-2.98 (m,3H),3·41 (t,2H,j = 5.9 Hz), 3.46-3.51 (m, 2H), 3.63-3.68 (m, 1H), 3.73 (t, lh, 6·〇Hz), 5 3.81 (t, 1H, J = 6.0 Hz), 4.11·4·13 (m , 2H), 4.70 (d, 2H, = 9.9 Hz, ArC//2N), 4.81 (dd, 1H, 9.9 and 5.1 Hz, Ci/CN), 7.18-7.19 (m, 4H); HRMS (El) m /z calcd f〇r c19H24N4〇2 340.1899, found 340.1899.
實施例20-48: 每一化合物20·48係以類似於實施例18所述之方式製備 實施例20 15 1-[3_[2-[2_氰基_(幻-°比咯啉啶·1β基乙氧基胺基]-1、氧基 丙基]-4-[二-(4-氟苯基）曱基]哌嗪（化合物2〇) ^ 31 1299039 NMR (CDC13)5;2.62〜2·18 (m，10H)，2.91 (m，2H)， 3.20〜3·80 (m，8H)，4.22 (s，1H)，4·75 (br d，6·0Ηζ, 3/4H)， 4.82 (br d，/= 6·3Ηζ，1/4H)，6.95 (d，8·4Ηζ，2H)，6·98 (d， J = 8.4Hz5 2H)5 7.31 (d5 J = 8.4Hz, 2H), 7.34 (d5 J = 8.4Hz5 5 2H); MS (ES+) m/z. 496.3 (M+H)+. 實施例21 1- [3-[2-氰基-(幻/比咯啉啶-1-基]-2-乙氧基胺基]-1-氧基丙 基]-4-[2-甲氧基苯基]哌嗪（化合物21) ^ MS (ES+) m/z. 400.2 (M+H)+5 422.2 (M+Na)+. W10 實施例22 2- [3-[2-[2-氰基-〇S)·吼咯啉啶-1-基]-2-乙氧基胺基]-1-氧基 丙基]-1-(2_羥乙基）-6,7-二甲氧基-1，2,3,4-雙羥異喹啉(化合 ； 物 22) MS (ES+) m/z. 445.2 (M+H)+，467.3 (M+Na)+_ '15 實施例23 2-[3-[2-[2 -亂基·($) - °比洛琳咬-1-基]-2 -氧基乙基胺基]·1-氧 基丙基]·6,7-二甲氧基-1，2,3,4-四氫異喹琳(化合物23) • lH NMR (CDC13) (9 to 1 mixture of trans/cis amide fotomers) δ 2.16-2.28 (m5 4H)，2.68 (t，2H，/=6.0 Hz)，2.77 (t， 20 1H, /= 6.0 Hz), 2.83 (t, 1H5 7 = 6.0 Hz), 3.04 (t5 2H? J= 6.3Examples 20-48: Example 20 15 was prepared in a manner similar to that described in Example 18 for each compound 20-48. 1-[3_[2-[2-cyano-[ 1β-ethoxyethoxyamino]-1,oxypropyl]-4-[bis-(4-fluorophenyl)indolyl]piperazine (Compound 2〇) ^ 31 1299039 NMR (CDC13) 5; 2.62~ 2·18 (m,10H), 2.91 (m,2H), 3.20~3·80 (m,8H), 4.22 (s,1H),4·75 (br d,6·0Ηζ, 3/4H), 4.82 (br d, /= 6·3Ηζ, 1/4H), 6.95 (d,8·4Ηζ,2H),6·98 (d, J = 8.4Hz5 2H)5 7.31 (d5 J = 8.4Hz, 2H) , 7.34 (d5 J = 8.4 Hz 5 5 2H); MS (ES+) m/z. 496.3 (M+H)+. Example 21 1- [3-[2-cyano-(phantom/pyrroline pyridine)- 1-yl]-2-ethoxyamino]-1-oxypropyl]-4-[2-methoxyphenyl]piperazine (Compound 21) ^ MS (ES+) m/z. 400.2 ( M+H)+5 422.2 (M+Na)+. W10 Example 22 2- [3-[2-[2-Cyano-〇S)·吼- oxalin-1-yl]-2-ethoxy Amino]-1-oxypropyl]-1-(2-hydroxyethyl)-6,7-dimethoxy-1,2,3,4-bishydroxyisoquinoline (combination; 22 MS (ES+) m/z. 445.2 (M+H)+, 467.3 (M+Na) + _ '15 Example 23 2-[3-[2-[2 - 乱基·($) - ° ratio Lorraine biting -1-yl]-2-ethoxyethylamino]·1-oxypropyl]·6,7-dimethoxy-1,2,3,4-tetrahydroisoquineline (Compound 23) • lH NMR (CDC13) (9 to 1 mixture of trans/cis amide fotomers) δ 2.16-2.28 (m5 4H), 2.68 (t, 2H, /=6.0 Hz), 2.77 (t, 20 1H, /= 6.0 Hz) ), 2.83 (t, 1H5 7 = 6.0 Hz), 3.04 (t5 2H? J= 6.3
Hz), 3.41-3.62 (m, 4H, overlapped singlet at 3.51), 3.67 (t3 1H，/=6.0 Hz)，3.79-3.87 (m，7H，overlapped singlet OC//3 at 3.87)，4.56 (s，0.9H，ArCi/2N)，4.65 (s，1·1Η，ArCi/2N)， 4.73-4.74 (m，0.9H，Ci/CN)，4·83 (d，0·1Η，= 6.0 Hz， 25 Ci/CN)，6.60-6.63 (m, 2H); HRMS (El) m/z calcd for C21H28N404 400.2111，found 400.2112Hz), 3.41-3.62 (m, 4H, overlapped singlet at 3.51), 3.67 (t3 1H, /=6.0 Hz), 3.79-3.87 (m, 7H, overlapped singlet OC//3 at 3.87), 4.56 (s, 0.9H, ArCi/2N), 4.65 (s, 1·1Η, ArCi/2N), 4.73-4.74 (m, 0.9H, Ci/CN), 4·83 (d, 0·1Η, = 6.0 Hz, 25 Ci/CN), 6.60-6.63 (m, 2H); HRMS (El) m/z calcd for C21H28N404 400.2111, found 400.2112
32 1299039 實施例24 1-[3-[2-[2-氰基-(5>)-°比11各琳11定-1-基]-2-氧基乙基胺基]-1-氧 基丙基]-4-[3-氣苯基]哌嗪（化合物24) lH NMR (CDCI3) (4 to 1 mixture of trans/cis amide 5 rotomers) δ 2.05-2.33 (m, 4H), 2.61 (t? 2H? J = 6.6 Hz)? 2.92-3.03 (m，2H)，3.14-3.21 (m，4H)，3.38-3.46 (m，3H， overlapped singlet at 3.46), 3.55-3.65 (m5 3H), 3.77 (t5 2H, J =5.4 Hz)，3.74-3.78 (m，4/5H，Ci/CN)，4·83 (dd，1/5H，J = 7.5 and 1.8 Hz，Ci/CN)，6.77-6.89 (m，3H)，7.19 (t，1H，J = ^10 7.8 Hz); MS (ESI) m/z 404.2 (M+H)+. 實施例25 l-[3-[2-[2-氰基-〇S)-吼咯啉啶-1-基]-2·氧基乙基胺基]-1-氧 基丙基]-4-苯甲醯哌嗪（化合物25) MS (ES+) m/z. 398.3 (M+H)+5 420.2 (M+Na)+. 15 實施例26 1-[3-[2-[2-氣基-(*9)-11比洛琳咬-1-基]-2-氧基乙基胺基]-1-氧 基丙基]-4-[3,5·二氣苯甲醯]哌嗪（化合物26) | !H NMR (CDCI3) δ 2.10-2.20 (m, 2H), 2.21-2.30 (m, 2H)，2.60 (bs，2H)，2.85-2.95 (bm，2H)，3.36-3.55 (m，3H)， 20 3.56-3.88 (m，9H)，4.77-4.80 (m，1H，CifCN)，6.88-6.96 (m， 3H); HRMS (El) m/z calcd for C21H25F2N503 433.1925, found 433.1922. 實施例27 2·[3-[2_[2-氰基-〇S)-吼咯啉啶-1-基]-2-氧基乙基胺基]-1_氧 25 基丙基]_ 1，3-二羥基異吲哚（化合物27). lU NMR (CDCI3) δ 2.05-2.31 (m5 4H)5 2.62-2.66 (m5 33 1299039 2H)，3.04-3.08 (m，2H)，3.43-3.50 (m，3H，overlapped singlet at 3.50, ArCi/2NCi/2, CifCN)，3.59-3.65 (m，1H)，4.75-4.83 (m，5H，two overlapped singlet at 4.79 and 4.83)，7.28-7.30 (m，4H); HRMS (El) m/z calcd for C18H22N402 326-1743， 5 found 326.1744. 實施例28 1-[3-[2·[2 -亂基- ϋ比洛琳σ定-1 _基]-2 -氧基乙基胺基]-1 -氧 基丙基]-4-[4-[1-氧基乙基胺基]苯基磺醯基]哌嗪（化合物 28) 10 !H NMR (CD3OD) δ 2.11-2.23 (m? 7H5 overlapped singlet -NHC(0)C//3 at 2.13), 2.57 (t, 2H, /= 6.6 Hz)5 2.88 (t5 2H, J = 6.6 Hz), 2.96 (bt5 2H, J = 4.8 Hz), 3.01 (bt? 2H, J = 4.8 Hz)，3.41-3.67 (m，8H，overlapped doublet at 3.49，/ = 6.0 Hz)，4.71 (t，1H，/ = 5.4 Hz)，7.69-7.73 (m，2H)， 15 7.79-7.83 (m，2H); MS (ES+) m/z. 491.4 (M+H)+，513.3 (M+Na)+. 實施例29 l-[3-[2-[2-氰基-〇S)·吼咯啉啶-1_基]-2·氧基乙基胺基]-1-氧 > 基丙基]_4-[5-氰基-2-吼啶]哌嗪（化合物29) 20 MS (ES+) m/z. 396.3 (M+H)+. 實施例30 3_[2-(2-氣基-($)- n比洛嚇^ σ定-1_基）-2_氧基乙基胺 基]-A/~indan- 2-基-丙酿胺（化合物30) 1HNMR(CDCl3)32.50〜1.80(m，6H)，3.00〜2.60(m， 25 4H)，3.70〜3·10 (m，6H)，4.63 (br s，2H)，7.25〜6.88 (m，5H)， 7.58 (br s5 1H); MS (ES+) m/z. 341.1 (M+H)+.32 1299039 Example 24 1-[3-[2-[2-Cyano-(5>)-° ratio 11 lin 11 -1-yl]-2-oxoethylamino]-1-oxo Propyl]-4-[3-phenylphenyl]piperazine (Compound 24) lH NMR (CDCI3) (4 to 1 mixture of trans/cis amide 5 rotomers) δ 2.05-2.33 (m, 4H), 2.61 ( t? 2H? J = 6.6 Hz)? 2.92-3.03 (m, 2H), 3.14 - 3.21 (m, 4H), 3.38-3.46 (m, 3H, overlapped singlet at 3.46), 3.55-3.65 (m5 3H), 3.77 (t5 2H, J = 5.4 Hz), 3.74 - 3.78 (m, 4/5H, Ci/CN), 4·83 (dd, 1/5H, J = 7.5 and 1.8 Hz, Ci/CN), 6.77- 6.89 (m, 3H), 7.19 (t, 1H, J = ^10 7.8 Hz); MS (ESI) m/z 404.2 (M+H)+. Example 25 l-[3-[2-[2- Cyano-hydrazine S)-nonyl-pyridin-1-yl]-2-oxyethylamino]-1-oxypropyl]-4-benzopyridazine (Compound 25) MS (ES+) m/z. 398.3 (M+H)+5 420.2 (M+Na)+. 15 Example 26 1-[3-[2-[2-carbyl-(*9)-11 pirole bite-1 -yloxy-2-aminoethylamino]-1-oxypropyl]-4-[3,5·dioxabenzhydrazide]piperazine (Compound 26) | !H NMR (CDCI3) δ 2.10 -2.20 (m, 2H), 2.21-2.30 (m, 2H), 2.60 (bs, 2H), 2.85-2.95 (bm, 2H), 3.36-3.55 (m, 3H), 20 3. 56-3.88 (m, 9H), 4.77-4.80 (m, 1H, CifCN), 6.88-6.96 (m, 3H); HRMS (El) m/z calcd for C21H25F2N503 433.1925, found 433.1922. Example 27 2·[ 3-[2_[2-cyano-indenyl)-indoloxalin-1-yl]-2-oxoethylamino]-1_oxy-25-propyl]-1,3-dihydroxyiso吲哚 (Compound 27). lU NMR (CDCI3) δ 2.05-2.31 (m5 4H)5 2.62-2.66 (m5 33 1299039 2H), 3.04-3.08 (m, 2H), 3.43-3.50 (m, 3H, overlapped singlet At 3.50, ArCi/2NCi/2, CifCN), 3.59-3.65 (m, 1H), 4.75-4.83 (m, 5H, two overlapped singlet at 4.79 and 4.83), 7.28-7.30 (m, 4H); HRMS (El m/z calcd for C18H22N402 326-1743, 5 found 326.1744. Example 28 1-[3-[2·[2-乱基-ϋ比洛琳σ定-1 _基]-2-ethoxyethyl Amino]-1 -oxypropyl]-4-[4-[1-oxyethylamino]phenylsulfonyl]piperazine (Compound 28) 10 !H NMR (CD3OD) δ 2.11-2.23 (m? 7H5 overlapped singlet -NHC(0)C//3 at 2.13), 2.57 (t, 2H, /= 6.6 Hz)5 2.88 (t5 2H, J = 6.6 Hz), 2.96 (bt5 2H, J = 4.8 Hz), 3.01 (bt? 2H, J = 4.8 Hz), 3.41-3.67 (m, 8H, overlapped doublet at 3.49 / = 6.0 Hz), 4.71 (t, 1H, / = 5.4 Hz), 7.69-7.73 (m, 2H), 15 7.79-7.83 (m, 2H); MS (ES+) m/z. 491.4 (M+H +, 513.3 (M+Na)+. Example 29 l-[3-[2-[2-Cyano-oxime S)·吼 啉 啉 -1-1-yl]-2-ethoxyethylamino ]-1-Oxygen> propyl] 4-[5-cyano-2-acridine]piperazine (Compound 29) 20 MS (ES+) m/z. 396.3 (M+H)+. Example 30 3_[2-(2-Alkyl-($)-n-Biro--------------------------------------- Compound 30) 1H NMR (CDCl3) 32.50~1.80 (m, 6H), 3.00~2.60 (m, 25 4H), 3.70~3·10 (m, 6H), 4.63 (br s, 2H), 7.25~6.88 (m , 5H), 7.58 (br s5 1H); MS (ES+) m/z. 341.1 (M+H)+.
34 1299039 實施例31 1-[3·[2-[2-氰基-〇S)-吼咯啉啶-1-基]-2-氧基乙基胺基]-1-氧 基丙基]-4·(3,5-二甲氧基-苯甲醯基）哌嗪（化合物SUMS (ES+) m/z. 458.3 (M+H)+， 480.1 (M+Na)+· 5 實施例32 l-{2-[3-(3,4-雙羥-1氫-異喹啉-2_基）-1-(1氫-吲哚-3-基甲 基）-3-氧基-丙基胺基]乙醯基卜2-氰基-(5>吼咯啉啶化合物 (化合物32)· _ MS (ES+) m/z· 470.2 (M+H)+，492.1 (M+Na)+. 10 實施例33 2-[3-[2-[2-氰基吼咯啉啶-1-基]-2-氧基乙基胺基]-4-甲 基-1-氧基戊基]-1，2,3,4-四羥基異喹啉（化合物33) lU NMR (CDC13) δ 0.93-0.99 (m, 5H)? 1.90-2.00 (m5 1H)，2.01-2.27 (m，4H)，2.40-2.52 (m，2H)，2.86-3.07 (m，3H， 15 three overlapped multiplets), 3.25-3.89 (m5 6H)5 4.49-4.86 (m，3H)，7.14-7.18 (m，4H); HRMS (El) m/z calcd for C22H30N4O2 382.2369, found 382.2369. > 實施例34 化合物34之製備方法係類似於實施例18中所述。 20 1-{2-[3-(3-苯甲醯-咪唑啉啶-1-基）·3-氧基-丙基胺基]-乙醯 基}-吡咯啉啶-2-甲腈（化合物34) MS (ES+) m/z. 384.4 (M+H)+ 實施例35 苯甲基-3-[2-(2-氰基-〇S)-吼咯啉啶-1-基）-2-氧基乙基胺 25 基]-丙醯胺（化合物35) 35 1299039 lU NMR (CDCI3) (4 to 1 mixture of trans/cis amide rotomers) δ 2.05-2.32 (m, 4H), 2.45 (t, 2H, J= 6.0 Hz)? 2.95 (t，2H，《/= 6.0 Hz)，3.31-3.57 (m，4H，overlapped doublet at 3.38, 3.3 Hz)，4.45 (d，2H，5.7 Hz)，4.64 (dd，1/5H，J= 5 7.5 and 1.5 Hz, C//CN)，4.70-4.73 (m，4/5H，C//CN)， 7.22-7.36 (m，5H)，7.56 (br s，1/5H，ArCH2N/〇，7.74 (bs， 4/5H，ArCH2Ni/); HRMS (El) m/z calcd for C17H22N402 314.1743, found 314.1741. 實施例36 ®10 ，苯甲基-3-[2-(2-氰基-〇S>吼咯啉啶-1-基）-2-氧基乙基胺 基]-TV-甲基丙醯胺（化合物36) MS (ES+) m/z. 329.1 (M+H)+. 實施例37 」 1-[3-[2-[2·氰基-〇S)-吼咯啉啶-1-基]-2-氧基乙基胺基] -15 -1_氧基丙基]-4-[苯並噻唑-2-基]哌嗪（化合物37) !H NMR (CDCI3) δ 2.09-2.36 (m5 4H), 2.62 (t? 2H, J = 6·3 Hz)，2·97·3·04 (m，2H)，3.37-3.52 (m，3H，overlapped 贏 singlet at 3.47)，3.53-3.81 (m，9H)，4.74-4.78 (m，1H)， 7.09-7.14 (m，1H)，7.29-7.35 (m，1H)，7.56-7.64 (m，2H); 20 HRMS (El) m/z calcd for C21H26N602S 426.1838，found 426.1841. 實施例38 3-[>(2-氰基-〇S>呢咯啉啶-ΐ·基）-2-氧基乙基胺 基]-7V-[2-(4-硝基苯基）乙基]丙醯胺（化合物38) 25 lU NMR (CDCI3) 52.55^1.85 (m5 6H), 2.83 (m5 2H)? 2.97 (m5 2H)，3.75〜3.10 (m，6H)，4.65 (d，7.6 Hz，1/4H)，4.72 (m， 36 1299039 3/4 H)，7.39 (d，·/= 8.4 Hz，2H)，7·86 (m，1Η)，8·12 (d，J = 8.1 Hz, 2H); MS (ES+) m/z.374.2 (M+H)+. 實施例39 3-[2-(2-氰基吼咯啉啶-1-基）-2-氧基乙基胺基]-尽(4-硝 5 基苯甲基）丙醯胺（4匕合物39) ]H NMR (CDC13) (4 to 1 mixture of trans/cis amide rotomers) δ 2.05-2.35 (m，4H)，2.50 (t，2H，·/= 6.0 Hz)，3.00 (t, 2H? J = 6.0 Hz), 3.30-3.70 (m5 4H, overlapped doublet at 3.44, J = 7.5 Hz)，4.44-4.60 (m，2H+1/5H，overlapped 10 doublet at 4.54, J = 7.5 Hz, 2H ArC/f2N and 1/5H C/iCN), 4.68-4.76 (m，4/5H，C//CN)，7.50 (d，2H，《/= 12.0 Hz)，8.16 (d，2H，/ = 12.0 Hz)，8.28 (bt，1/5H，ArCH2N/i)，8.40 (bt， 4/5H，ArCH2N//); HRMS (El) m/z calcd for C17H21N504 359.1594, found 359.1594· 15 實施例40 3-[2-(2•乳基- (iS)-11比洛琳咬-l-基）-2 -氧基乙基胺基]苯乙 基丙醯胺（化合物40) !H NMR (CDCI3) (4 to 1 mixture of trans/cis amide rotomers) δ 2.05-2.35 (m, 6H5 overlapped triplet at 2.31, J = 6.0 Hz), 20 2.75-2.83 (m5 4H), 3.17-3.35 (m, 3H, overlapped doublet at 3.23, J = 3.0 Hz), 3.42-3.51 (m, 3H), 4.60 (dd, 1/5H, J = 7.5 and 1.8 Hz，Ci/CN)，4.69-4.73 (m，4/5H，Ci/CN)，7.16-7.27 (m，5H)，7.29 (bs，1/5H，ArCH2CH2N//)，7.52 (bs，4/5H， ArCH2CH2N/〇; HRMS (El) m/z calcd for C18H24N402 25 328.1899, found 328.1904. 實施例41 2-[3-[2-[2-氰基吼咯啉啶-1-基]-2-氧基乙基胺 37 1299039 基]-1-氧基丙基]-l-異丙基-1，2,3,4-雙羥異喹啉（化合物41). MS (ES+) m/z. 383.3 (M+H)+, 405.2 (M+Na)+ 實施例42 3-[2-(2 -乳基-(aS) - ntb 洛琳1^ -1 -基）-2-氧基乙基胺基]1 _ 5 苯丙基）丙醯胺（化合物42) ιΐί NMR (CDC13) (9 to 1 mixture of trans/cis amide rotomers) δ 0.88 (t，3H，= 7·5 Hz)，1·74_1·90 (m，2H)， 2.02-2.31 (bm，4H)，2.37-2.49 (m，2H)，2.86-3.01 (m，2H)， I 3.32-3.62 (m? 4H), 4.62 (d3 1/10H, J = 7.5 Hz, C//CN) 10 4.73-4.77 (m，9/10H，Ci/CN)，4.89 (q，1H，= 7.5 Hz)， 7.22-7.40 (m，5H)，7.81 (bt，1H); HRMS (El) m/z calcd for C19H26N4O2 342.2056, found 342.2060. 實施例43 2-[3-[2-[2-氣基_(*S)-σ比嘻琳咬-1-基]-2-氧基乙基胺基]-1 -氧 15 基丙基]-1-異丙基-7-氟-1，2,3,4-雙羥異喹啉（化合物43)· MS (ES+) m/z. 401.2 (M+H)+ 實施例44 j 2-[3·[2-[2-氰基比洛琳唆-1-基]-2 -氧基乙基胺基]_1-氧 基丙基]_1_氫曱基-1，2,3,4-雙羥異喹啉（化合物44). 20 MS (ES+) m/z. 371.2 (M+H)+, 393.1 (M+Na)+. 實施例45 2-[3-[2_[(2 -氮基- ntt洛琳°定-1-基）-2-氧基乙基胺 基]-1-氧基丙基]-Μ-丁基-7-氟-1，2,3,4-四羥基異喹啉（化合 物 45). 25 MS (ES+) m/z. 415.3 (M+H)+5 438.3 (M+Na)+. 實施例46 38 1299039 3 -[2-(2 -鼠基- (aS)·11比洛琳β定-1-基）-2·氧基乙基胺基]-iV"( 1 -甲 基-1-苯丙乙基）丙醯胺（化合物46) !H NMR (CDCI3) (9 to 1 mixture of trans/cis amide rotomers) δ 1.68 (s，6H)，2.05-2.31 (m，4H)，2.38-2.46 (m， 5 2H)，2.92-2.98 (m，2H)，3.31-3.44 (m，1H)，3.45-3.65 (m，3H， overlapped singlet at 3.48), 4.67 (dd, 1/10H, J = 7.5 Hz and 2·1，Ci/CN) 4.73-4.75 (m，9/10H，Ci/CN)，7.17-7.45 (m，6H); HRMS (El) m/z calcd for C19H26N402 342.2056，found 342.2057. •10實施例47 2·[3·[[2·[2-氰基-〇S)-吼咯啉啶_1·基]-2-氧基乙基]胺基]·1· 氧基丁基]-1，2,3,4·四羥基異喹啉（化合物47)34 1299039 Example 31 1-[3·[2-[2-Cyano-indoleS)-indolyl-1-yl]-2-oxoethylamino]-1-oxypropyl] -4·(3,5-Dimethoxy-benzimidyl)piperazine (Compound SUMS (ES+) m/z. 458.3 (M+H)+, 480.1 (M+Na)+· 5 Example 32 L-{2-[3-(3,4-Dihydroxy-1hydro-isoquinolin-2-yl)-1-(1hydro-indol-3-ylmethyl)-3-oxy-propyl胺 ] 醯 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 10 Example 33 2-[3-[2-[2-Cyanoindolopyridin-1-yl]-2-oxoethylamino]-4-methyl-1-oxypentyl] -1,2,3,4-tetrahydroxyisoquinoline (Compound 33) lU NMR (CDC13) δ 0.93-0.99 (m, 5H)? 1.90-2.00 (m5 1H), 2.01-2.27 (m, 4H), 2.40-2.52 (m, 2H), 2.86-3.07 (m, 3H, 15 three overlapped multiplets), 3.25-3.89 (m5 6H)5 4.49-4.86 (m, 3H), 7.14-7.18 (m, 4H); HRMS (El) m/z calcd for C22H30N4O2 382.2369, found 382.2369. > Example 34 The procedure for the preparation of compound 34 is similar to that described in Example 18. 20 1-{2-[3-(3-benzamide- Imidazolin-1-yl)·3-oxy-propylamino]-醯-}-pyrroline pyridine-2-carbonitrile (Compound 34) MS (ES+) m/z. 384.4 (M+H)+ Example 35 benzyl-3-[2-(2-cyano-indole) S)-Indolylpyridin-1-yl)-2-oxoethylamine 25-yl]-propanamide (Compound 35) 35 1299039 lU NMR (CDCI3) (4 to 1 mixture of trans/cis amide rotomers) δ 2.05-2.32 (m, 4H), 2.45 (t, 2H, J= 6.0 Hz)? 2.95 (t, 2H, "/= 6.0 Hz), 3.31-3.57 (m, 4H, overlapped doublet at 3.38, 3.3 Hz ), 4.45 (d, 2H, 5.7 Hz), 4.64 (dd, 1/5H, J = 5 7.5 and 1.5 Hz, C//CN), 4.70-4.73 (m, 4/5H, C//CN), 7.22-7.36 (m,5H), 7.56 (br s, 1/5H, ArCH2N/〇, 7.74 (bs, 4/5H, ArCH2Ni/); HRMS (El) m/z calcd for C17H22N402 314.1743, found 314.1741. Example 36 ® 10 , Benzyl-3-[2-(2-cyano-indole S> oxalyl-1-yl)-2-oxoethylamino]-TV-methylpropanamide (Compound 36) MS (ES+) m/z. 329.1 (M+H) +. Example 37 " 1-[3-[2-[2.Cyano-indole-S)-- ]-2-oxyethylamino] -15 -1 -oxypropyl]-4-[benzothiazol-2-yl]piperazine (Compound 37) !H NMR (CDCI3) δ 2.09-2.36 ( M5 4H), 2.62 (t 2H, J = 6·3 Hz), 2·97·3·04 (m, 2H), 3.37-3.52 (m, 3H, overlapped win singlet at 3.47), 3.53-3.81 (m, 9H), 4.74 4.78 (m,1H), 7.09-7.14 (m,1H), 7.29-7.35 (m,1H),7.56-7.64 (m,2H); 20 HRMS (El) m/z calcd for C21H26N602S 426.1838,found 426.1841. Example 38 3-[>(2-Cyano-indole S> oxopiperidinium-fluorenyl)-2-oxoethylamino]-7V-[2-(4-nitrophenyl) Ethyl]propanamide (Compound 38) 25 lU NMR (CDCI3) 52.55^1.85 (m5 6H), 2.83 (m5 2H)? 2.97 (m5 2H), 3.75~3.10 (m, 6H), 4.65 (d, 7.6 Hz, 1/4H), 4.72 (m, 36 1299039 3/4 H), 7.39 (d, ·== 8.4 Hz, 2H), 7·86 (m, 1Η), 8·12 (d, J = 8.1 Hz, 2H); MS (ES+) m/z. 374.2 (M+H)+. Example 39 3-[2-(2-cyanoindolinoxadin-1-yl)-2-oxyethyl Amino]-(4-nitro-5-benzylmethyl)propanamide (4 chelate 39) ]H NMR (CDC13) (4 to 1 mixture of trans/cis amide rotomers) δ 2.05-2.35 (m, 4H), 2.50 (t, 2H, ·/= 6.0 Hz), 3.00 (t, 2H? J = 6.0 Hz), 3.30-3.70 (m5 4H, overlapped doublet at 3.44, J = 7.5 Hz), 4.44 - 4.60 ( m, 2 H+1/5H, overlapped 10 doublet at 4.54, J = 7.5 Hz, 2H ArC/f2N and 1/5H C/iCN), 4.68-4.76 (m, 4/5H, C//CN), 7.50 (d, 2H, "/= 12.0 Hz), 8.16 (d, 2H, / = 12.0 Hz), 8.28 (bt, 1/5H, ArCH2N/i), 8.40 (bt, 4/5H, ArCH2N//); HRMS (El) m/z calcd for C17H21N504 359.1594, found 359.1594· 15 Example 40 3-[2-(2•lacyl-(iS)-11-pirolene-l-yl)-2-ethoxyethylamino Benzylpropionamide (Compound 40) !H NMR (CDCI3) (4 to 1 mixture of trans/cis amide rotomers) δ 2.05-2.35 (m, 6H5 overlapped triplet at 2.31, J = 6.0 Hz), 20 2.75 -2.83 (m5 4H), 3.17-3.35 (m, 3H, overlapped doublet at 3.23, J = 3.0 Hz), 3.42-3.51 (m, 3H), 4.60 (dd, 1/5H, J = 7.5 and 1.8 Hz, Ci/CN), 4.69-4.73 (m, 4/5H, Ci/CN), 7.16-7.27 (m, 5H), 7.29 (bs, 1/5H, ArCH2CH2N//), 7.52 (bs, 4/5H, ArCH2CH2N/〇; HRMS (El) m/z calcd for C18H24N402 25 328.1899, found 328.1904. Example 41 2-[3-[2-[2-Cyanoindolopyridin-1-yl]-2-oxyl Ethylamine 37 1299039 yl]-1-oxypropyl]-l-isopropyl-1,2,3,4-dihydroxyisoquine (Compound 41). MS (ES+) m/z. 383.3 (M+H)+, 405.2 (M+Na)+ Example 42 3-[2-(2---------) ^ -1 -yl)-2-oxoethylamino]1 _ 5 phenylpropyl)propanamide (Compound 42) ιΐί NMR (CDC13) (9 to 1 mixture of trans/cis amide rotomers) δ 0.88 ( t,3H,= 7·5 Hz),1·74_1·90 (m,2H), 2.02-2.31 (bm,4H), 2.37-2.49 (m,2H),2.86-3.01 (m,2H), I 3.32-3.62 (m? 4H), 4.62 (d3 1/10H, J = 7.5 Hz, C//CN) 10 4.73-4.77 (m, 9/10H, Ci/CN), 4.89 (q, 1H, = 7.5) Hz), 7.22-7.40 (m, 5H), 7.81 (bt, 1H); HRMS (El) m/z calcd for C19H26N4O2 342.2056, found 342.2060. Example 43 2-[3-[2-[2-] _(*S)-σ 嘻 嘻 -1--1-yl]-2-oxoethylamino]-1 -oxy-15 propyl]-1-isopropyl-7-fluoro-1,2, 3,4-Dihydroxyisoquinoline (Compound 43)· MS (ES+) m/z. 401.2 (M+H)+ Example 44 j 2-[3·[2-[2-Cyanobilorin唆-1-yl]-2-ethoxyethylamino]_1-oxypropyl]_1-hydroindolyl-1,2,3,4-bishydroxyisoquinoline (Compound 44). 20 MS (ES+ m/z. 371.2 (M+H)+, 393.1 (M+Na)+. Example 45 2-[3-[2_[(2-N-yl-nt) t洛琳°-1-yl)-2-oxoethylamino]-1-oxypropyl]-indole-butyl-7-fluoro-1,2,3,4-tetrahydroxyisoquine Phenanthine (Compound 45). 25 MS (ES+) m/z. 415.3 (M+H)+5 438.3 (M+Na)+. Example 46 38 1299039 3 -[2-(2 -Nymyl-(aS) · 11 Bilene beta-1,4-yl)-2-oxyethylamino]-iV"(1-methyl-1-phenylpropylethyl)propanamide (Compound 46) !H NMR (CDCI3 (9 to 1 mixture of trans/cis amide rotomers) δ 1.68 (s, 6H), 2.05-2.31 (m, 4H), 2.38-2.46 (m, 5 2H), 2.92-2.98 (m, 2H), 3.31 -3.44 (m,1H), 3.45-3.65 (m,3H, overlapped singlet at 3.48), 4.67 (dd, 1/10H, J = 7.5 Hz and 2.·1, Ci/CN) 4.73-4.75 (m,9 /10H, Ci/CN), 7.17-7.45 (m, 6H); HRMS (El) m/z calcd for C19H26N402 342.2056, found 342.2057. • 10 Example 47 2·[3·[[2·[2-Cyanide 〇-〇S)-吼 吼 啶 啶 · · · · · · -2- 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物47)
lU NMR (CDCI3) δ 1.20 (d5 3H, / = 8.4 Hz), 2.07-2.32 ^ (m，4H)，2.41-2.49 (m，1H)，2.59-2.68 (m，1H)，2.85 (t，1H，J 15 = 6.0 Hz)5 2.92 (t, 1H? J = 6.0 Hz), 3.24-3.31 (m5 1H), 3.36-3.58 (m，4H)，3.61-3.73 (m，1H)，3.75-3.86 (m，1H)， 4.65-4.77 (m5 3H, overlapped doublet at 4.65, J = 3.9 Hz and a singlet at 4.74，ArC//2N and C//CN)，7·10·7·23 (m，4H); ® HRMS (El) m/z calcd for C20H26N4O2 354.2056，found 20 354.2057. 實施例48 2_[3·[[2_[2 -氰基- ($)-11比洛琳咬_1·基]-2-氧基乙基]胺基]-3-甲基-1-氧基丁基]-1，2,3,4-四羥基異喹啉（化合物48) !H NMR (CDCI3) (4 to 1 mixture of trans/cis amide 25 rotomers) δ 1.23 (s，3H)，1.25 (s，3H)，2·05_2·33 (m，4H), 2.53 (s，2H)，2.85 (t，lH，/= 6.0 Hz)，2.91 (t，1H，/= 6.0 Hz), 39 1299039 3.38-3.48 (m5 3H, overlapped doublet at 3.39, J = 7.5 Hz), 3.53-3.64 (m3 1H) 3.73 (t, 1H5 J = 6.0 Hz), 3.83 (t5 1H5 J = 6.0 Hz)，4.66-4.76 (m，2.8H，two overlapped singlets at 4.67 and 4.73, 2H ArC7/2N and 0.8H C/iCN)，5.10 (d，0.2H，= 5 7.5 Hz5 Ci/CN), 7.09-7.22 (m, 4H); HRMS (El) m/z calcd for C21H28N4O2 368.2212, found 368.2215. 實施例49 苯甲基- 3- [2-(2 -氣基-(aS)·ϋ比洛琳咬· 1 -基）-2-氧基乙基胺 基]·3_甲基丁醯胺（化合物49) •10 MS (ES+) m/z. 343.4(M+H)+. 實施例50 3_[2·(2-氰基-〇S)-吼咯啉啶-1-基）-2-氧基-乙基胺基]-3-甲基 沁苯基丁醯胺（化合物50) MS (ES+) m/z. 329.4(M+H)+. -15 實施例51 342-(2-氰基吼咯啉啶-1-基）-2-氧基乙基胺基]-3-甲基 -N-(2_吡啶-2-基·乙基）丁醯胺（化合物51) φ !H NMR (CDC13)5 1.08(s5 6H)5 2.31-2.2.15(m? 7H), 2.98(t，2H，J=6.6Hz)，3.27(s，2H)，3.55-3.36(m，2H)，3.64(dd， 20 2H，6.0, 6·6Ηζ)，4.76-4.73(m，1H)，7.11(dd，1H，《/= 7.5, 7·8Ηζ)，7.17( d，1H，7.8Hz)，7.58(dd，1H，7.5, 7.8Hz)， 8.41(s5 1H)? 8.47( d, 1H, J = 7.5Hz). MS (ES+) m/z. 358.4(M+H)+，480.4 (M+Na)+. 實施例52 25 l-{2-[3-(3,4-雙經_1氯·異喧琳-2-基）-l，l-二曱基-3-硫代-丙 基胺基]-乙醯基}-吡咯啉啶-2·甲腈（化合物52)係依據下述lU NMR (CDCI3) δ 1.20 (d5 3H, / = 8.4 Hz), 2.07-2.32 ^ (m, 4H), 2.41-2.49 (m, 1H), 2.59-2.68 (m, 1H), 2.85 (t, 1H) , J 15 = 6.0 Hz) 5 2.92 (t, 1H? J = 6.0 Hz), 3.24-3.31 (m5 1H), 3.36-3.58 (m, 4H), 3.61-3.73 (m, 1H), 3.75-3.86 ( m,1H), 4.65-4.77 (m5 3H, overlapped doublet at 4.65, J = 3.9 Hz and a singlet at 4.74, ArC//2N and C//CN), 7·10·7·23 (m, 4H) ® HRMS (El) m/z calcd for C20H26N4O2 354.2056, found 20 354.2057. Example 48 2_[3·[[2_[2 -Cyano-($)-11 Bilene bite_1·yl]-2 -oxyethyl]amino]-3-methyl-1-oxybutyl]-1,2,3,4-tetrahydroxyisoquinoline (Compound 48) !H NMR (CDCI3) (4 to 1 Mixture of trans/cis amide 25 rotomers) δ 1.23 (s, 3H), 1.25 (s, 3H), 2·05_2·33 (m, 4H), 2.53 (s, 2H), 2.85 (t, lH, /= 6.0 Hz), 2.91 (t, 1H, /= 6.0 Hz), 39 1299039 3.38-3.48 (m5 3H, overlapped doublet at 3.39, J = 7.5 Hz), 3.53-3.64 (m3 1H) 3.73 (t, 1H5 J = 6.0 Hz), 3.83 (t5 1H5 J = 6.0 Hz), 4.66-4.76 (m, 2.8H, two overlapped singlets at 4.67 and 4.73, 2H ArC7/2 N and 0.8HC/iCN), 5.10 (d, 0.2H, = 5 7.5 Hz5 Ci/CN), 7.09-7.22 (m, 4H); HRMS (El) m/z calcd for C21H28N4O2 368.2212, found 368.2215. 49 Benzyl-3-(2-(2-carbo-(aS)·ϋ 洛 洛 琳 琳 · 1 -yl)-2-oxyethylamino]·3_methylbutanamine (compound) 49) • 10 MS (ES+) m/z. 343.4 (M+H)+. Example 50 3_[2·(2-Cyano-indolyl)-indoloxalin-1-yl)-2-oxo Benzyl-ethylamino]-3-methylindole phenylbutaamine (Compound 50) MS (ES+) m/z. 329.4 (M+H)+.吼 ! ! 基 基 基 基 基 基 基 基 ( ( ( ( ( ( ( ( ( H H H (CDC13)5 1.08(s5 6H)5 2.31-2.2.15(m? 7H), 2.98(t,2H,J=6.6Hz), 3.27(s,2H),3.55-3.36(m,2H),3.64 (dd, 20 2H, 6.0, 6·6Ηζ), 4.76-4.73 (m, 1H), 7.11 (dd, 1H, "/= 7.5, 7.8 Ηζ), 7.17 (d, 1H, 7.8 Hz), 7.58 ( Dd,1H,7.5, 7.8Hz), 8.41(s5 1H)? 8.47( d, 1H, J = 7.5Hz). MS (ES+) m/z. 358.4(M+H)+,480.4 (M+Na) +. Example 52 25 l-{2-[3-(3,4-Bis-l-Chloro-isoindol-2-yl)-l,l-di 3-thioxo - propan-ylamino] - acetyl yl} - pyrroline -2-piperidine-carbonitrile (Compound 52) according to the following system
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