TW200831517A - Chemical compounds - Google Patents

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TW200831517A
TW200831517A TW096147437A TW96147437A TW200831517A TW 200831517 A TW200831517 A TW 200831517A TW 096147437 A TW096147437 A TW 096147437A TW 96147437 A TW96147437 A TW 96147437A TW 200831517 A TW200831517 A TW 200831517A
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mmol
ethyl
compound
formula
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TW096147437A
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Chinese (zh)
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Janelle Comita-Prevoir
Mark Cronin
Bolin Geng
Folkert Reck
Andrew Aydon Godfrey
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Astrazeneca Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Abstract

The present invention relates to compounds of Formula (I): Formula (I) or pharmaceutically acceptable salts thereof, to their use in the treatment of bacterial infections, and to their methods of preparation.

Description

200831517 九、發明說明： 【發明所屬之技術領域】 本發明係關於新穎六氫吡啶類，其醫藥組合物，及使用 方法。此外，本發明係關於治療細菌感染之療法。 【先前技術】 “ 國際保健團體持續表達嚴重關切，抗細菌劑抗藥性之發 展會造成目前可取用之抗細菌劑將無法有效抵抗之菌種。 例如革蘭陽性病原之抗藥性菌種，譬如二曱氧基苯青黴素 抗藥性金資㈣㈣到mrSA)、二甲氧基苯青黴素抗藥性 凝聚酶陰性㈣球菌屬（MRCNS)、青黴素抗藥性W超球磨 及多重抗藥性屑廣硪磨，均為難以治療且難以根除。因此， 為克服廣範圍多抗藥性生物體之威脅，有現行需要以發展 新穎抗生素，特別是具有無論是新穎作用機制及/或含有新 矛員樂效基團者。 【發明内容】 根據本發明，申請人謹此已發現一些化合物，其具有充 作抗微生物劑之能力。因此，本發明係關於展現抗細菌活 性之化合物，其製備方法，含有彼等作為活性成份之醫藥 組合物，其作為藥劑之用途，及其在藥劑製造上之用途， 名藥劑係在溫血動物譬如人類中用於治療細菌感染。 因此，本發明係提供式⑴化合物： 127286 200831517200831517 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to novel hexahydropyridines, pharmaceutical compositions thereof, and methods of use. Furthermore, the invention relates to the treatment of bacterial infections. [Prior Art] “The international health care community continues to express serious concerns that the development of antibiotic resistance will result in strains that are currently not available for antibacterial agents. For example, Gram-positive pathogens are resistant to bacteria, such as Cyclooxyphenylpenicillin resistance to gold (4) (four) to mrSA), methicillin-resistant clotting enzyme-negative (four) genus (MRCNS), penicillin-resistant W-super-ball mill and multi-drug resistant granules are difficult It is difficult to eradicate. Therefore, in order to overcome the threat of a wide range of multi-drug resistant organisms, there is a need to develop novel antibiotics, especially those with novel mechanisms of action and/or containing new lances. In accordance with the present invention, Applicants have hereby discovered certain compounds which have the ability to act as antimicrobial agents. Accordingly, the present invention relates to compounds which exhibit antibacterial activity, processes for their preparation, and pharmaceuticals containing them as active ingredients. a composition, its use as a medicament, and its use in the manufacture of a medicament, the name of which is in a warm-blooded animal such as a human For the treatment of bacterial infections Accordingly, the invention provides a compound of formula ⑴: 127,286,200,831,517

或其藥學上可接受之鹽，其中式(I)化合物係實質 對掌異構物之順式(±)混合物，且其巾 、、 上不含其 A係選自CH與N;Or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) is a cis (±) mixture of the palmo isomers, and the towels thereof are not contained, and the A group is selected from the group consisting of CH and N;

D係選自C-R7與n ; 其中A與D之至少一個為碳； E係選自〇、nh及s， 其中： i) 若R8與R9—起形成=0，則E為NH;且 ϋ) 若R8與R9各為Η，則E為Ο或S ; G係選自〇與s ; J係選自C_R4與Ν ; R1係選自Η、鹵基、氰基、c!-6烷基、C2_6烯基與c2_6炔基、 ORla及《N(Rh)2，其中該Cl_6烷基、c^6烯基及c26炔基係視 情況被一或多個R1 0取代；D is selected from the group consisting of C-R7 and n; wherein at least one of A and D is carbon; E is selected from the group consisting of 〇, nh and s, wherein: i) if R8 and R9 together form =0, then E is NH; ϋ) If R8 and R9 are each Η, then E is Ο or S; G is selected from 〇 and s; J is selected from C_R4 and Ν; R1 is selected from Η, halo, cyano, c!-6 a C2_6 alkenyl group and a c2_6 alkynyl group, ORla and "N(Rh)2, wherein the Cl_6 alkyl group, the c^6 alkenyl group and the c26 alkynyl group are optionally substituted by one or more R1 0;

Rla，於各存在處，係獨立選自11與（：1-6烷基，其中該Cl 6 烷基係視情況被一或多個R2G取代； R2係選自Η、鹵基、氰基、C卜6烷基、C2-6烯基、C2-6炔基、 -OR2a&-N(R2a)2，其中該Cu烷基、C：2-6烯基及(：2-6炔基係視 情況被一或多個R2 0取代； 127286 200831517 R2a，於各存在處，係獨立選自Η與Cu烷基，其中該Cu 燒基係視情況被一或多個R2 0取代， R3係選自Η、鹵基、氰基、Cu烷基、c2-6烯基與c2_6炔基、 •0R3a及-N(R3a)2，其中該Ci6烷基、c2_6烯基及C2_6炔基係視 情況被一或多個r3〇取代； R3a ’於各存在處，係獨立選自11與(：1-6烷基，其中該 烷基係視情況被一或多個R3 〇取代； _ r4係選自Η、鹵基、·〇)2Η、氰基、Ch烷基、c2_6烯基及 C2-6炔基，其中該Ci-6烷基、C2-6烯基及c2-6炔基係視情況 被一或多個R40取代； R係選自氟基、C! _6烧基、C2-6烯基、C2-6快基、_〇R6a，其 中該Ci-6燒基、C：2-6烯基及C2_6炔基係視情況被一或多個r6〇 取代； R6a，於各存在處，係獨立選自11與（：16烷基，其中該 烧基係視情況被一或多個R6 0取代； _ R7係選自H、鹵基、氰基、烷基、c26烯基及Ch炔基， 其中該Ch院基、c2_6稀基及Ch炔基係視情況被一或多個 R70取代； R8與R9各為氫，或圮與圮一起形成=〇;且 發明詳述 ^乂’^^’㈣及^’於各存在處’各獨立選自齒 基、搜基、氛基、_C〇2H、烧基、C2.6烯基及c2_6炔基。 ，當使用於術語譬如Cx_y 係指示存在於該基團中之 在本專利說明書中，字首Q 烷基等（其中X與y為整數）中時 127286 200831517 碳原子數字範圍；例如，C1-4烷基包括Ci烷基（甲基）、c2 烧基（乙基）、C3烷基（丙基與異丙基）及c4烷基（丁基、μ甲 基丙基、厶甲基丙基及第三·丁基）。 於本文中使用之”烧基"一詞係指直鏈與分枝鏈飽和烴基 兩者，具有所指定之碳原子數。對個別烷基譬如”丙基，，之 指稱，係僅專指直鏈變型，而對個別分枝鏈烷基譬如”異丙 基’’之指稱’係僅專指分枝鏈變型。 ”烯基”一詞係指直鏈與分枝鏈烴基兩者，具有所指定之 碳原子數，且含有至少一個碳_碳雙鍵。例如，，，C2_8烯基，， 包括但不限於-些基團，譬如c2 6稀基、c2 4稀基、乙稀基、 2-丙烯基、2-甲基_2·丙烯基、3·丁烯基、4_戊烯基、5•己烯基、 2-庚烯基及2-甲基小庚烯基。 炔基一詞係指直鏈與分枝鏈烴基兩者，具有所指定之 火原子數且3有至少一個碳·碳參鍵。例如，"Cm炔基” 包括但不限於一歧基團，疑‘ r 一丞图詧如C2·6炔基、c2-4炔基、乙炔基、Rla, in each presence, is independently selected from the group consisting of 11 and (: 1-6 alkyl, wherein the Cl 6 alkyl group is optionally substituted by one or more R 2 G; R 2 is selected from the group consisting of hydrazine, halo, cyano, C 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 2a & -N(R 2a) 2 wherein the Cu alkyl group, C: 2-6 alkenyl group and (: 2-6 alkynyl group) Optionally substituted by one or more R20; 127286 200831517 R2a, in each presence, independently selected from the group consisting of hydrazine and Cu alkyl, wherein the Cu alkyl group is optionally substituted by one or more R20, R3 is selected From hydrazine, halo, cyano, Cu alkyl, c2-6 alkenyl and c2_6 alkynyl, • 0R3a and -N(R3a)2, wherein the Ci6 alkyl, c2_6 alkenyl and C2_6 alkynyl are optionally One or more r3〇 substituted; R3a' is independently selected from the group consisting of 11 and (: 1-6 alkyl, wherein the alkyl group is optionally substituted by one or more R3 ;; _r4 is selected from Η, halo, 〇) 2Η, cyano, Ch alkyl, c 2_6 alkenyl and C 2-6 alkynyl, wherein the Ci-6 alkyl, C 2-6 alkenyl and c 2-6 alkynyl are optionally One or more R40 substitutions; R is selected from the group consisting of a fluorine group, a C!-6 alkyl group, a C2-6 alkenyl group, a C2-6 fast group, and a 〇R6a, wherein the Ci-6 is burned. , C: 2-6 alkenyl and C 2_6 alkynyl are optionally substituted by one or more r 6 ;; R 6a, in each presence, is independently selected from 11 and (: 16 alkyl, wherein the alkyl group is optionally Substituted by one or more R6 0; _ R7 is selected from the group consisting of H, halo, cyano, alkyl, c26 alkenyl and Ch alkynyl, wherein the Ch, the c2-6, and the Ch alkynyl are optionally One or more R70 substitutions; R8 and R9 are each hydrogen, or 圮 and 圮 together form =〇; and the invention details ^乂'^^' (four) and ^' in each of the places 'each independently selected from the tooth base, search a base, an aryl group, a _C〇2H, a decyl group, a C2.6 alkenyl group, and a c2_6 alkynyl group. When used in a term such as Cx_y, it is indicated in the group, in the present specification, the prefix Q alkyl group, etc. (where X and y are integers) when 127286 200831517 carbon number range; for example, C1-4 alkyl includes Ci alkyl (methyl), c2 alkyl (ethyl), C3 alkyl (propyl and isopropyl) And c4 alkyl (butyl, μmethylpropyl, fluorenylmethylpropyl and tert-butyl). As used herein, the term "alkyl" refers to the saturation of linear and branched chains. Both hydrocarbon groups, with The number of carbon atoms specified. For individual alkyl groups such as "propyl", the reference is only for straight-chain variants, and for individual branched-chain alkyl groups such as "isopropyl", the term "only" refers to Branch chain modification. The term "alkenyl" refers to both straight-chain and branched-chain hydrocarbon groups having the specified number of carbon atoms and containing at least one carbon-carbon double bond. For example, C2_8 alkenyl, including but not limited to - some groups, such as c2 6 dilute, c2 4 dilute, ethyl, 2-propenyl, 2-methyl-2-propenyl, 3· Butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl and 2-methylstetonyl. The term alkynyl refers to both straight-chain and branched-chain hydrocarbon radicals having the specified number of fire atoms and 3 having at least one carbon-carbon bond. For example, "Cm alkynyl" includes, but is not limited to, a cleavage group, suspected ‘r 丞 丞 such as C2·6 alkynyl, c2-4 alkynyl, ethynyl,

2-丙炔基、2-甲基_2-丙故其、1 丁 κ甘 , 、土 3-丁炔基、4-戊炔基、5-己炔基、 2-庚炔基及4-甲基-5-庚炔基。 H鹵基"一詞係指氟基、翕其 肌签亂基及溴基。於一方面，”.基” 可指氟基。 ^用取代基係選自"_或多種"基團之情況下，應明瞭 此定義係包括所有取代基均選自所指定基團之一， 或取代基係選自所指定基團中之兩種或多種。 ”碳環基"一詞係指飽和、 狀碳環，其含有化個環原子和或不飽和，單或雙環 ，、子其中一或多個-CH2_基團可 127286 200831517 視1¾況被相應數目之·c(〇)4團置換。於一方面，"碳環基" 4可扣含有3或6個環原子之單環狀環或含有9或1〇個原 子之雙％狀環。於另-方面，”碳環基，’-詞可指含有5或6 個原子^單環狀環。”碳環基之說明例包括但不限於金剛 燒基％丙基、環丁基、環戊基、環戊烯基、環己基、環 稀基1酉同基％戊基、苯基、蕃基、四氫蓁基、氫雜基 或1·酮基氫雖基。，，# # # ·, & ^ p丞 妷裱基之特定實例為苯基。2-propynyl, 2-methyl-2-propane, 1, butyl gamma, 3-butynyl, 4-pentynyl, 5-hexynyl, 2-heptynyl and 4- Methyl-5-heptynyl. The term "H halo" refers to a fluoro group, a sputum, and a bromo group. In one aspect, "." can mean a fluoro group. ^ Where the substituent is selected from a "_ or a plurality of " groups, it should be understood that this definition includes all substituents selected from one of the specified groups, or the substituents are selected from the specified groups. Two or more. The term "carbocyclyl" refers to a saturated, carbocyclic ring containing a ring atom and or an unsaturated, mono- or bicyclic ring, one or more of the -CH2_ groups may be 127286 200831517 A corresponding number of c(〇) 4 group substitutions. In one aspect, "carbocyclyl" 4 may be a one-ring ring containing 3 or 6 ring atoms or a double-shaped ring containing 9 or 1 atom.环. In another aspect, "carbocyclyl," can refer to a ring containing 5 or 6 atoms. Examples of carbocyclic groups include, but are not limited to, adamantyl group, propyl group, cyclobutyl group, cyclopentyl group, cyclopentenyl group, cyclohexyl group, cycloazinyl group, fluorenyl group, phenyl group, phenyl group. A tetrahydroindenyl group, a hydrohalyl group or a 1 keto group is a phenyl group, a specific example of a ###, &

襄土 屑係指飽和、部份飽和或不飽和，單或雙環 ，環:含有‘12個環原子，其中至少一個環原子編氮： 硫及乳’且除非另有指日月，否則其可經碳或氮連接，其中 CH2基團可視情況被《(〇)_置換。環硫原子可視情況被氧 化以形成8_氧化物。環氮原子可視情況被氧化以形成轉化 物雜&基—詞之說明ί列，包括但不限於苯并二氧伍 圜稀基基六氫封基、㈣基”㈣基、異如林 酮異峰嗤基L坐基、嗎福琳基、2 •酉同&四氯峨嘻基、 2酮基汰3’塞唑啶基、六氫吡畊基、六氫吡啶基、哌喃基、 峨嗤基”比咬基、㈣基、四氫料基、二氫㈣基、口密 : 比井基、吡唑基、嗒畊基、4-吡啶_、喹啉基、四 辽哌南基、噻唑基”塞二唑基”塞唑啶基、噻吩基、硫代 嗎福《、硫苯基”㈣·叫化物及__n•氧化物。於本 發明之一方面， — ’、衣土 5司可才日稱飽和、部份飽和或不 飽和：單環狀環，含有5或6個原子，其中至少一個原子係 k k或氧，且除非另有指明，否則可經碳或氮連結， 而％氮原子可視情況被氧化以形成N-氧化物。 127286 -10- 200831517 ㈣”(±)”係意欲表示外消旋混合物；意即所指示化合物 等里（+)與（-)對阜異構物之光學上不活性混合物。 當化合物或混合物被稱為”順式（土)"或，，反式（±)”時，應明 瞭的是，於其中所㈣之順式或反式關係，係關於礙％"上 基團與碳”b”上-NH-基團間之關係。 在特定R基團係於式（I)化合物中存在超過一次之情況 下，所意欲的是，對該R基團之各選擇在每一存在處係為 獨立。 • ^ 示非特別地敘述，否則_個基團之結合原子可為該基團 之任何適當原子；例如，丙基包括丙小基與丙絲。 。貝貝上不含’’ 一詞係意欲表示所指定之實體係以低於 ίο%，更特別是低於5%，特別是低於2%，更特別是低於μ， 特別是低於0.5%，特別是低於〇·2%之量存在。 於本文中使用之”視情況經取代” 一詞係表示取代為選 用，因此對於所指定之基團可為無論是經取代或未經取代。 _在需要取代之情況中，於所指定基團上之任何數目之氫可 破選自所指示之取代基置換，其條件是不得超過特定取代 基上之原子之正常價鍵，且此取代會造成顯示抗細菌作用 之安定化合物。 於本文中使用之”藥學上可接受"一詞，係指此等化合 物、物質、組合物及/或劑型係在安全可靠醫學判斷之範圍 内，適用於與人類及動物之組織接觸，而無過度毒性、刺 激性、過敏性回應或其他問題或併發症，伴隨著合理利益/ 風險比。 127286 200831517 於本文中使用之》有效量"扭 旦甘p、 日辭係忍謂化合物或組合物之 里，，、足以顯著且正面地改變 又i奴被治療之病徵及/或症狀 (例如獒供正臨床回應）。供 之有效量將合产&… 〜梁組合物之活性成份 /將曰^者被治療之特定症狀、症狀之嚴重性、治 療之延續時間、同時療法之性質 ^ ^ 貝破知用之特定活性成份、 所使用之特定華學γ# 、 梁予上了接文之賦形劑/载劑及在負責醫師 之知識與專門技術内之類似因素而改變。 、襄 屑 refers to saturated, partially saturated or unsaturated, mono- or bicyclic, ring: contains '12 ring atoms, at least one ring atom nitrogen: sulfur and milk' and unless otherwise indicated Linked by carbon or nitrogen, wherein the CH2 group may be replaced by "(〇)_ as appropriate. The ring sulfur atom may optionally be oxidized to form an 8-oxide. The ring nitrogen atom may be oxidized as appropriate to form a conversion impurity & base word description, including but not limited to benzodioxanthene hexahydrohexyl, (tetra)yl (tetra), iso-linone Iso-indolyl L-based group, phoranyl, 2 • bismuth & tetrachloroindolyl, 2-keto-based 3'-oxazolidinyl, hexahydropyridinyl, hexahydropyridyl, piperidyl , 峨嗤基" than bite base, (tetra) base, tetrahydrogen base, dihydro (tetra) base, mouth: specific well, pyrazolyl, hydrazine, 4-pyridine, quinolinyl, tetragoniper , thiazolyl "sedadiazolyl" oxazolidinyl, thienyl, thiofolf ", thiophenyl" (tetra), called __n oxidant. In one aspect of the invention, - ', clothing It is said that it is saturated, partially saturated or unsaturated: a single ring containing 5 or 6 atoms, at least one of which is kk or oxygen, and may be linked by carbon or nitrogen unless otherwise specified. And the % nitrogen atom may be oxidized as appropriate to form an N-oxide. 127286 -10- 200831517 (4) "(±)" is intended to mean a racemic mixture; that is, the indicated compound (etc.) (-) an optically inactive mixture of oxime isomers. When a compound or mixture is referred to as "cis (soil) " or, trans (±)", it should be understood that (4) The cis or trans relationship is related to the relationship between the upper group and the -NH- group on the carbon "b". The presence of a particular R group in the compound of formula (I) occurs more than once. In the following, it is intended that each choice of the R group is independent at each occurrence. • ^ is not specifically described, otherwise the bonding atom of the _ group may be any suitable atom of the group; For example, the propyl group includes a propyl group and a propyl group. The word "be on the babe" is intended to mean that the specified system is less than ίο%, more specifically less than 5%, especially less than 2%. , more particularly below μ, especially below 0.5%, especially below 〇·2%. The term "optionally substituted" as used herein means substitution is optional and therefore specified The group may be either substituted or unsubstituted. _in the case of a substitution, any of the specified groups Hydrogen can be broken from the indicated substituent substitutions, provided that the normal valence bond of the atom on the particular substituent is not exceeded, and the substitution results in a stability compound that exhibits an antibacterial effect. The term "acceptable" means that such compounds, substances, compositions and/or dosage forms are within the scope of safe and reliable medical judgment and are suitable for use in contact with human and animal tissues without excessive toxicity or irritation. An allergic response or other problem or complication is accompanied by a reasonable benefit/risk ratio. 127286 200831517 As used herein, "effective amount" is used to significantly and positively alter the signs and/or symptoms of i slave treatment (for example, in a compound or composition).獒 For positive clinical response). The effective amount will be combined with the active ingredients of the beam composition / the specific symptoms of the treatment, the severity of the symptoms, the duration of the treatment, the nature of the simultaneous treatment ^ ^ The active ingredients, the particular Chinese gamma used, and the excipients/carriers of the above-mentioned texts, and similar factors in the knowledge and expertise of the physician are changed. ,

本發明之化合物與取代基定義 疋義已猎助於稱為ACD/Labs®之 ACD/Name進行命名。 ㈣化合物可形成安^藥學上可接受之酸或驗鹽，而在 此種情況中，化合物以鹽之投率 杀』為適當的，且藥學上可 接受之鹽可藉此項技藝中所習知之習用方法製成1 本發明化合物之適當藥學上可: ..^ ^ 丧之鹽係為例如足夠鹼 性之本鲞明化合物之酸加成鹽 1〗如興例如無機或有機酸 之I加成鹽，該酸類例如鹽酸、 4 /兴0夂、硫酸、石粦酸、二 氟醋酸、檸檬酸或順丁烯二酸。 一 &人仏 此外，足夠酸性之本發明 化合物之適當藥學上可接受鹽， ^ 1屬鹽，例如鈉或 鉀凰，鹼土金屬鹽，例如鈣或鎂 Μ μ ^ ^ ^ ^ ^ 敢孤或與提供生理 予可接X%離子之有機驗之鹽，例如與甲胺、二甲胺、 三甲胺、六氫^定、嗎福啦或參做乙基)胺之睡。 式（I)化合物在中心六氫吡啶環 此外，化合物可具有有= 幾何異構中心（Ε-與Ζ-異構物）。應明 及或 的疋，本發明儀涵芸 所有此種光學非對映異構物與幾何 、^ 一稱物，其具抗細菌活 127286 -12- 200831517 14。本發明係進一步關於具有抗細菌活性之式（i)化合物之 任何及所有互變異構形式。 亦應明瞭的是，某些式（I)化合物可以已溶劑化合以及未 溶劑化合形式存在，例如水合形式。應明瞭的是，本發明 係涵蓋具有抗細菌活性之所有此種溶劑化合形式。 本發明之其他具體實施例如下。此等其他具體實施例係 關於式（I)化合物及其藥學上可接受之鹽。此特定取代基與 _立體化學關係可在適當情況下，與前文或後文所界定之任 何定義、請求項或具體實施例一起使用。 碳”a”與碳”b” 於一方面，在碳”a”上之r6基團與在碳” b"上之基團可 對彼此呈順式（+)關係，其中式①化合物係實質上不含其對 掌異構物之順式（±)混合物； 於另一方面，在碳"a”上之r6基團與在碳”b”上之-ΝΗ•基團 可對彼此呈順式㈠關係，式（I)化合物係實質上不含其對掌 φ 異構物之順式（±)混合物； 於又另一方面，在碳"a"上之R6基團與在碳"b"上之-ΝΑ 基團可對彼此呈反式（+)關係。 於又再另一方面，在碳，，a”上之R6基團與在碳"b,,上之_丽_ 基團可對彼此呈反式㈠關係。The definitions of the compounds and substituents of the present invention have been naming the ACD/Name called ACD/Labs® for naming. (d) The compound may form a pharmaceutically acceptable acid or salt, and in this case, the compound is suitably salted, and the pharmaceutically acceptable salt may be used in the art. Knowing the method of preparation 1 The compound of the present invention is suitably pharmaceutically acceptable: .. ^ ^ The salt of the fungus is, for example, an acid addition salt of a compound of the present invention which is sufficiently basic, such as an inorganic or organic acid. Salt formation, the acid such as hydrochloric acid, 4, sulphuric acid, sulphuric acid, difluoroacetic acid, citric acid or maleic acid. In addition, a suitably pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic, a salt of the formula 1, such as sodium or potassium phos, an alkaline earth metal salt such as calcium or magnesium Μ μ ^ ^ ^ ^ ^ It is asleep with an organic test salt that provides physiologically acceptable X% ions, for example, with methylamine, dimethylamine, trimethylamine, hexahydrodithiomethane, chlorhexidine or ethylamine. The compound of formula (I) is in the central hexahydropyridine ring. Furthermore, the compound may have a geometric center of isomerism (Ε-and Ζ-isomer). The present invention encompasses all such optical diastereoisomers and geometries, which have antibacterial activity 127286 -12-200831517 14 . The invention further relates to any and all tautomeric forms of the compounds of formula (i) having antibacterial activity. It should also be understood that certain compounds of formula (I) may exist in solvated as well as unsolvated forms, such as in hydrated form. It should be understood that the present invention encompasses all such solvated forms having antibacterial activity. Other embodiments of the invention are as follows. These other specific embodiments relate to the compound of formula (I) and pharmaceutically acceptable salts thereof. This particular substituent may be used in conjunction with any definition, claim or embodiment as defined above or below. Carbon "a" and carbon "b" In one aspect, the r6 group on carbon "a" and the group on carbon "b" can be in a cis (+) relationship with each other, wherein the compound of formula 1 is substantially Containing no cis (±) mixture of its palmomers; on the other hand, the r6 group on carbon "a" and the ΝΗ• group on carbon"b" In the cis (a) relationship, the compound of formula (I) is substantially free of its cis (±) mixture of the φ isomers; and on the other hand, the R6 group on carbon "a""b"上上-ΝΑ Groups can be in a trans (+) relationship with each other. In still another aspect, the R6 group on carbon, a" and the _ group on the carbon "b, can be in a trans (a) relationship with each other.

A 於一方面，A可為N。 於另一方面，A可為CH。 於又另一方面，A可選自N與CH。 127286 -13· 200831517A On the one hand, A can be N. On the other hand, A can be CH. In yet another aspect, A can be selected from the group consisting of N and CH. 127286 -13· 200831517

D 於一方面，D可為N。 於另一方面，D可為CH。 於又另一方面，D可選自N與CH。D On the one hand, D can be N. In another aspect, D can be CH. In yet another aspect, D can be selected from the group consisting of N and CH.

A與D 於一方面，A可為N; 且D可為CH。 於另一方面，A可為CH;且 ⑩D可為N。 E，Q R8 及 R9 於一方面，E與G可各為0;且 R8與R9可各為Η。 於另一方面，Ε可為NH; G可選自Ο與S;且 R8與R9可一起形成=0 ; 於又另一方面，Ε可為NH; G可為S;且 R8與R9可一起形成=0。 於又再另一方面，Ε可為ΝΗ ; G可為Ο ;且 R8與R9可一起形成=0。A and D are in one aspect, A can be N; and D can be CH. In another aspect, A can be CH; and 10D can be N. E, Q R8 and R9 In one aspect, E and G can each be 0; and R8 and R9 can each be Η. In another aspect, Ε can be NH; G can be selected from Ο and S; and R8 and R9 can together form =0; on the other hand, Ε can be NH; G can be S; and R8 and R9 can be together Form = 0. On the other hand, Ε can be ΝΗ; G can be Ο; and R8 and R9 can form =0 together.

J 於一方面，J可為Ν。 於另一方面，J可為CH。 於另一方面，J可選自Ν與CH。 於又另一方面，J可選自Ν與C-R4 ;且 R4可選自Η與烷基。 -14- 127286 200831517 於又再另一方面，j w 了選自N與C-R4 ;且 R4可選自Η與甲基。 A，D，G，E，R8 及 R9J On the one hand, J can be awkward. On the other hand, J can be CH. In another aspect, J can be selected from the group consisting of hydrazine and CH. In yet another aspect, J can be selected from the group consisting of ruthenium and C-R4; and R4 can be selected from the group consisting of ruthenium and alkyl. Further, in another aspect, j w is selected from the group consisting of N and C-R 4 ; and R 4 may be selected from the group consisting of hydrazine and methyl. A, D, G, E, R8 and R9

於一方面，A，D，G飞RS ，K及R和彼等所連接 形成基團，選自： 條< %原子一起In one aspect, A, D, G fly RS, K and R and they are joined to form a group selected from: strip < % atom together

於一方面，R1可為Η。 R2 於一方面，R2可選自氰基與_OR2a ;且 R2a可為Cb6烷基。 於另一方面，R2可選自氰基與甲氧基。 於又另一方面，R2可為氰基。 於又再另一方面，R2可為-〇R2a ;且 R2a可為烷基。 R3 於一方面，R3可為Η。 R6 於—方面，R6可選自氟基與_〇R6a ;且 R6a可選自11與（：1_6烷基。In one aspect, R1 can be Η. R2 In one aspect, R2 may be selected from cyano and _OR2a; and R2a may be Cb6 alkyl. In another aspect, R2 can be selected from the group consisting of cyano and methoxy. In yet another aspect, R2 can be a cyano group. In still another aspect, R2 can be -〇R2a; and R2a can be an alkyl group. R3 On the one hand, R3 can be Η. R6 In the aspect, R6 may be selected from a fluoro group and 〇R6a; and R6a may be selected from the group consisting of 11 and (:1_6 alkyl).

於另一方面，R6可選自氟基、羥基及甲氧基。 Rl’ R2, R3, R6, R8, R9, A，D，E，G 及 J 127286 -15- 200831517 於一方面，式⑴化合物可為式（Ia)化合物：In another aspect, R6 can be selected from the group consisting of a fluoro group, a hydroxy group, and a methoxy group. Rl' R2, R3, R6, R8, R9, A, D, E, G and J 127286 -15- 200831517 In one aspect, the compound of formula (1) can be a compound of formula (Ia):

或其藥學上可接受之鹽，其中^，^，^，^，丄及於句如上文 =混且合其:。式_ 於式（la)化合物之一方面， G可選自〇與s ; J可選自N與CH ; R1可為Η ; R2可選自氰基與-ORh ; R2a可為Ci-6烷基； R3可為Η ; R6可選自氤基與_〇R6a ;且 R6a可選自Η與Cu烷基。 於式（la)化合物之另一方面， G可選自〇與s ; J可選自N與CH ; R1可為Η ; R2可選自氰基與甲氧基； 127286 -16 * 200831517 R3可為Η ;且 妒可選自氟基、羥基及甲氧基。 於式（la)化合物或其藥學上可接受鹽之 入另一方面， G可選自〇與S ; J可選自N與C-R4 ; R1可為Η ; R2可選自氰基與-〇R2a ; _ 於a可為Cle6烷基； 於可為Η ; ¥可選自11與(：1-6烷基； R6可選自氟基與-OR6a ;且 R6a可選自11與(：1-6烷基。 於式（la)化合物或其藥學上可接受鹽之又再另一方面 G可選自Ο與S ; J可選自N與C-R4 ; % 权1可為Η ; 阳可選自氰基與-〇R2a ; R2a可為曱基； $可為H; 狄4可選自Η與甲基； 政6可選自氟基與-OR6a ;且 R6 a可選自Η與甲基。 於另一方面，式（I)化合物可為式（Ib)化合物·· -17· 200831517Or a pharmaceutically acceptable salt thereof, wherein ^, ^, ^, ^, 丄 and the sentence are as above = mixed and combined:. In one aspect of the compound of formula (la), G may be selected from ruthenium and s; J may be selected from N and CH; R1 may be ruthenium; R2 may be selected from cyano and -ORh; and R2a may be Ci-6 alkane R3 may be hydrazine; R6 may be selected from fluorenyl and 〇R6a; and R6a may be selected from hydrazine and Cu alkyl. In another aspect of the compound of formula (la), G may be selected from the group consisting of ruthenium and s; J may be selected from N and CH; R1 may be ruthenium; R2 may be selected from cyano and methoxy; 127286 -16 * 200831517 R3 It is Η; and 妒 can be selected from a fluorine group, a hydroxyl group, and a methoxy group. In another aspect of the compound of formula (la) or a pharmaceutically acceptable salt thereof, G may be selected from the group consisting of ruthenium and S; J may be selected from N and C-R4; R1 may be ruthenium; R2 may be selected from cyano and - 〇R2a; _ can be Cle6 alkyl; a can be Η; ¥ can be selected from 11 and (: 1-6 alkyl; R6 can be selected from fluoro and -OR6a; and R6a can be selected from 11 and (: 1-6 alkyl. In the compound of the formula (la) or a pharmaceutically acceptable salt thereof, G may be selected from the group consisting of ruthenium and S; J may be selected from N and C-R4; The cation may be selected from the group consisting of cyano and -R2a; R2a may be a fluorenyl group; $ may be H; Di 4 may be selected from fluorenyl and methyl; chemistry 6 may be selected from fluoro and -OR6a; and R6 a may be selected from hydrazine; And the methyl group. On the other hand, the compound of the formula (I) can be a compound of the formula (Ib)·· -17· 200831517

八 ，，尺，玟及J均如上文定Eight, , ruler, 玟 and J are as above

義’其中式⑽化合物係實質上不含其對掌異構物 (±)混合物。 ' < 於式（lb)化合物之一方面， J可選自N與CH ; R1可為Η ; R2可選自氰基與-OR2a ; R2a可為Cu烷基； R3可為Η ; R6可選自氟基與-OR6a ;且 R6a可選自Η與（V6烷基。 於式（lb)化合物之另一方面， J可選自N與CH ; 可為Η ; R2可選自氰基與甲氧基； R3可為Η;且 H6可選自氟基、羥基及曱氧基。 於式（lb)化合物或其藥學上可接受鹽之又另一方面， J可選自N與CH ; 1勿86 -18· 200831517 R1可為Η ; R2可選自氰基與-〇R2a ; R2a可為（V6烷基； R3可為Η ; R6可選自氟基與-〇R6a ;且 R6a可選自Η與（ν6烷基。 於式（lb)化合物或其藥學上可接受鹽之又再另一方面， J可選自N與CH ; R1可為Η ; R2可選自氰基與曱氧基； R3可為Η ;且 R6可選自氟基、羥基及甲氧基。 於又另一方面，式（I)化合物可為（Ic)化合物：The compound of formula (10) is substantially free of its mixture of palmier isomers (±). < In one aspect of the compound of formula (lb), J may be selected from N and CH; R1 may be Η; R2 may be selected from cyano and -OR2a; R2a may be Cu alkyl; R3 may be ruthenium; And R6a may be selected from the group consisting of ruthenium and (V6 alkyl. In another aspect of the compound of formula (lb), J may be selected from N and CH; may be ruthenium; R2 may be selected from cyano and And methoxy; 1Be 86 -18· 200831517 R1 may be Η; R2 may be selected from cyano and -R2a; R2a may be (V6 alkyl; R3 may be Η; R6 may be selected from fluoro and -R6a; and R6a may In another aspect, J is selected from the group consisting of a compound of formula (lb) or a pharmaceutically acceptable salt thereof, J may be selected from N and CH; R1 may be hydrazine; and R2 may be selected from cyano and hydrazine. Alkyl; R3 may be hydrazine; and R6 may be selected from fluoro, hydroxy and methoxy. In yet another aspect, the compound of formula (I) may be a compound of (Ic):

式（Ic)Formula (Ic)

或其藥學上可接受之鹽，其中R1，R2, R3, R6, R8, R9, A，D，E，G 及J均如上文定義，其中式（Ic)化合物係實質上不含其對掌 異構物之順式（±)混合物。 於式（Ic)化合物或其藥學上可接受鹽之一方面， 一起形成基團， A，D，G，E，R8及R9和彼等所連接之環原子 選自： 127286 -19- 200831517Or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R6, R8, R9, A, D, E, G and J are as defined above, wherein the compound of formula (Ic) is substantially free of its palm A cis (±) mixture of isomers. Forming a group together with one of the compounds of the formula (Ic) or a pharmaceutically acceptable salt thereof, A, D, G, E, R8 and R9 and the ring atom to which they are attached are selected from the group consisting of: 127286 -19- 200831517

J可選自N與CR4 ; R1可為Η ; R2可選自氰基與-OR2"; R2a可為Cu烷基； R3可為Η ; _ R4可選自Η與Cu烷基； R6可選自氟基與-〇R6a ;且 R6a可選自Η與Cu烷基。 於式（Ic)化合物或其藥學上可接受鹽之另一方面， A，D，G，E，R8及R9和彼等所連接之環原子一起形成基團， 選自：J may be selected from N and CR4; R1 may be hydrazine; R2 may be selected from cyano and -OR2"; R2a may be Cu alkyl; R3 may be hydrazine; _ R4 may be selected from hydrazine and Cu alkyl; From the fluorine group to -〇R6a; and R6a may be selected from the group consisting of ruthenium and Cu alkyl. In another aspect of the compound of formula (Ic), or a pharmaceutically acceptable salt thereof, A, D, G, E, R8 and R9, together with the ring atoms to which they are attached, form a group selected from the group consisting of:

J可選自N與CR4 ; R1可為Η ; R2可選自氰基與-〇R2a ; R2a可為曱基； R3可為Η ; R4可選自Η與甲基； R6可選自氟基與-〇R6a ;且 127286 -20- 200831517 R6a可選自Η與甲基。 於又再另―方面’式(1)化合物可為式⑽化合物J may be selected from N and CR4; R1 may be Η; R2 may be selected from cyano and -R2a; R2a may be fluorenyl; R3 may be Η; R4 may be selected from fluorenyl and methyl; R6 may be selected from fluoro And -R6a; and 127286 -20-200831517 R6a may be selected from hydrazine and methyl. Further, the compound of the formula (1) may be a compound of the formula (10)

或其藥學上可接受之鹽，其中r1，r2，r3，r6，r8，r9，a，d，eg 均如上文定義’且其中式⑽化合物係實質上不含對 旱異構物之順式（±)混合物。 丁 於式（Id)化合物或其藥學上可接受鹽之一方面， A, D，G，E，R8及R9和彼等所遠接 子所連接之％原子一起形成基團， 選自：Or a pharmaceutically acceptable salt thereof, wherein r1, r2, r3, r6, r8, r9, a, d, eg are as defined above and wherein the compound of formula (10) is substantially free of cis to isomers (±) mixture. In one aspect of the compound of the formula (Id) or a pharmaceutically acceptable salt thereof, A, D, G, E, R8 and R9 together with the % atom to which the distal link is attached form a group selected from the group consisting of:

J可選自N與CR4J can be selected from N and CR4

可為Η ; 1(2可選自氰基與-OR2a ; R2a可為烷基； R3可為Η ; R4可選自Η與Cu烷基； 可選自氟基與-OR6a ;且 R6a可選自Η與CV6烷基。 127286 200831517 於式（id)化合物或其藥學上可接受鹽之另一方面， A，D，G，E，R8及R9和彼等所連接之環原子—起形成基團 選自：It may be Η; 1 (2 may be selected from cyano and -OR2a; R2a may be alkyl; R3 may be oxime; R4 may be selected from oxime and Cu alkyl; may be selected from fluoro and -OR6a; and R6a is optional From oxime to CV6 alkyl. 127286 200831517 In another aspect of the compound of formula (id) or a pharmaceutically acceptable salt thereof, A, D, G, E, R8 and R9 and the ring atom to which they are attached form a radical The group is selected from:

J可選自Ν與CR4 ; R1可為Η ; R2可選自氰基與-OR2a ; R2a可為曱基； R3可為Η ; R4可選自Η與曱基； R6可選自氟基與-OR6a ;且 R6a可選自Η與甲基。 於進一步方面’式（I)化合物可為式（Ie)化合物：J may be selected from fluorene and CR4; R1 may be hydrazine; R2 may be selected from cyano and -OR2a; R2a may be fluorenyl; R3 may be hydrazine; R4 may be selected from fluorenyl and fluorenyl; -OR6a; and R6a may be selected from the group consisting of hydrazine and methyl. In a further aspect the compound of formula (I) may be a compound of formula (Ie):

或其藥學上可接受之鹽，其中Rl，R2，R3，R6，R8，R9，A，D，E，G 均如上文定義，且其中式（le)化合物係實質上不含其對 掌異構物之順式（±)混合物。 127286 -22· 200831517 於式（Ie)化合物或其藥學上可接受鹽之—方面， A，D，QE，R8及R9和彼等所連接之環原子一起形成基團 選自：Or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R6, R8, R9, A, D, E, G are as defined above, and wherein the compound of formula (le) is substantially free of its A cis (±) mixture of constructs. 127286 -22· 200831517 In the aspect of the compound of the formula (Ie) or a pharmaceutically acceptable salt thereof, A, D, QE, R8 and R9 together with the ring atom to which they are attached form a group selected from the group consisting of:

J可選自N與CR4 ; R1可為Η ; 胪可選自氰基與-OR2a ; R2a可為cv6烷基； 鲈可為Η ;且 R4可選自11與(：1-6烷基。 於式（Ie)化合物之另*方面， A，D，G，E，R4R>彼等所連接之環原子—起形成基團 選自：J may be selected from N and CR4; R1 may be Η; 胪 may be selected from cyano and -OR2a; R2a may be cv6 alkyl; 鲈 may be Η; and R4 may be selected from 11 and (: 1-6 alkyl). In another aspect of the compound of formula (Ie), A, D, G, E, R4R> the ring atom to which they are attached - the forming group is selected from the group consisting of:

J可選自N與CR4 ; &1可為Η ; ^可選自氰基與甲氡基； 把可為Η;且 故4可選自Η與甲基。 於又進一步方面，式⑴化合物可為式⑽化合物： 127286 200831517J may be selected from N and CR4; & 1 may be Η; ^ may be selected from cyano and formamidine; may be oxime; and 4 may be selected from ruthenium and methyl. In still a further aspect, the compound of formula (1) can be a compound of formula (10): 127286 200831517

或其藥學上可接受之鹽，其中Rl，R2，R3，R8，R9，A，D，E，Gj J均如上文定義，其中在碳"a”上之氟基與在碳” b"上之 基團係對彼此呈順式關係，且其中式（If)化合物係實質上不 含其對掌異構物之順式（±)混合物。 於式（If)化合物或其藥學上可接受鹽之一方面， 鳥认〇，£，妒及妒和彼等所連接之環原子一起形成基團， 選自： 〇Or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R8, R9, A, D, E, Gj J are as defined above, wherein the fluoro group and the carbon in the carbon "a" The groups above are in cis relationship to each other, and wherein the compound of formula (If) is substantially free of its cis (±) mixture of palmier isomers. In one aspect of the compound of the formula (If) or a pharmaceutically acceptable salt thereof, the bird, £, 妒 and 妒 together with the ring atom to which they are attached form a group selected from the group consisting of: 〇

J可選自N與CR4 ; 狄1可為Η ; R2可選自氰基與-OR2a ; R2a可為Ci_6烷基； 狄3可為Η;且 政4可選自Η與CV6烷基。 於式（If)化合物之另一方面， 之環原子一起形成基團 A, D, G，E，R8及R9和彼等所連接 127286 -24- 200831517 選自J may be selected from N and CR4; Di1 may be hydrazine; R2 may be selected from cyano and -OR2a; R2a may be Ci_6 alkyl; Di3 may be hydrazine; and Pol. 4 may be selected from hydrazine and CV6 alkyl. In another aspect of the compound of the formula (If), the ring atoms together form a group A, D, G, E, R8 and R9 and are attached thereto. 127286 -24- 200831517

R1可為Η ; r2可選自氰基與甲氧基； R3可為H;且 R4可選自Η與曱基。 於又再進一步方面’式①化合物可為式_匕合物 R8R1 may be Η; r2 may be selected from cyano and methoxy; R3 may be H; and R4 may be selected from fluorenyl and fluorenyl. In still further aspects, the compound of formula 1 can be a formula _ chelate R8

或其藥學上可接受之鹽，其中軋驮心以㈣及 J均如上文定義，#中式(Ig)化合物係實質上不含其對掌異 構物之順式（±)混合物。 於式（Ig)化合物或其藥學上可接受鹽之—方面， A，D，G，E，R8及R9和彼等所連接之擇盾 心衣原子一起形成基團， 選自： 127286 -25- 200831517Or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (Ig) is substantially free of its cis (±) mixture of palmitic isomers as defined above. In the aspect of the compound of the formula (Ig) or a pharmaceutically acceptable salt thereof, A, D, G, E, R8 and R9 form a group together with the selected core of the sheath, selected from the group consisting of: 127286 -25 - 200831517

J可選自N與CR4 ; R1可為Η ; R2可選自氰基與-〇R2a ; R2a可為Cu烷基； R3可為Η ;且 _ R4可選自Η與Cu烷基。 於式（Ig)化合物之另一方面， A, D，G，E，R8及R9和彼等所連接之環原子一起形成基團， 選自：J may be selected from N and CR4; R1 may be Η; R2 may be selected from cyano and -R2a; R2a may be Cu alkyl; R3 may be ruthenium; and _R4 may be selected from ruthenium and Cu alkyl. In another aspect of the compound of formula (Ig), A, D, G, E, R8 and R9, together with the ring atoms to which they are attached, form a group selected from the group consisting of:

J可選自N與CR4 ; R1可為Η ; R2可選自氰基與甲氧基； R3可為Η ;且 R4可選自Η與甲基。 於一方面，式（I)化合物可為式（Ih)化合物： 127286 -26- 200831517J may be selected from N and CR4; R1 may be hydrazine; R2 may be selected from cyano and methoxy; R3 may be hydrazine; and R4 may be selected from hydrazine and methyl. In one aspect, the compound of formula (I) can be a compound of formula (Ih): 127286 -26- 200831517

J均如上文定義，其中式（Ih)化合物係實質上不含其對掌異 構物之順式（±)混合物。 八 或其藥學上可接受之鹽’其中Ri，R2，R3，R8，R9, A，D，E g及 於式（Ih)化合物或其藥學上可接受鹽之一方面， 卑认^:^妒及妒和彼等所連接之環原子一起形成基團， 選自：J is as defined above, wherein the compound of formula (Ih) is substantially free of its cis (±) mixture of palmitic isomers. Or a pharmaceutically acceptable salt thereof, wherein Ri, R2, R3, R8, R9, A, D, Eg and one of the compounds of the formula (Ih) or a pharmaceutically acceptable salt thereof, are happed ^:^妒 and 妒 together with the ring atoms to which they are attached form a group selected from:

J可選自N與CR4 ; 可為Η ; 仅2可選自氰基與-OR2a ; R2a可為(^_6烷基； R3可為Η ;且 把可選自11與0：1_6烷基。 於式（Ih)化合物之另一方面， A，D，G，E，R4R9和料料接之環科—㈣成基團 選自： 12^286 200831517J may be selected from N and CR4; may be oxime; only 2 may be selected from cyano and -OR2a; R2a may be (^_6 alkyl; R3 may be oxime; and may be selected from 11 and 0:1_6 alkyl. In another aspect of the compound of formula (Ih), A, D, G, E, R4R9 and the enthalpy of the compound - (iv) are selected from the group consisting of: 12^286 200831517

J可選自N與CR4 ; R1可為Η; R2可選自氰基與甲氧基； R3可為H;且 R4可選自Η與甲基。 於另一方面，本發明係提供式（ΪΙ)化合物：J may be selected from N and CR4; R1 may be hydrazine; R2 may be selected from cyano and methoxy; R3 may be H; and R4 may be selected from hydrazine and methyl. In another aspect, the invention provides a compound of formula (ΪΙ):

式（II) 或其藥學上可接受之鹽，其中在碳”a”上之R6與在碳，，^，上 -NH-基團係對彼此呈反式關係，且其中 A係選自CH與N ; D係選自C-R7與N; 其中A與D之至少一個為碳； E係選自〇、nh及s， 其中： 1) 若R8與R9 —起形成=〇，則E為NH ;且 ϋ) 若R8與R9各為Η，則E為〇或S ; G係選自〇與s ; 127286 -28- 200831517 J係選自C-R4與N; R1係選自Η、鹵基、氰基、c〗_6烷基、C2-6烯基與c26炔基、 〇Rla及-N(Rla)2，其中該C〗_6烷基、C2·6烯基及C2-6炔基係視 情況被一或多個R10取代；Or a pharmaceutically acceptable salt thereof, wherein R6 on carbon "a" is in trans relationship with each other on a carbon, -, and -NH- group, and wherein A is selected from CH And N; D is selected from C-R7 and N; wherein at least one of A and D is carbon; E is selected from 〇, nh and s, wherein: 1) if R8 and R9 together form = 〇, then E is NH; and ϋ) If R8 and R9 are each Η, then E is 〇 or S; G is selected from 〇 and s; 127286 -28- 200831517 J is selected from C-R4 and N; R1 is selected from lanthanum and halogen a cyano group, a cyano group, a c -6 alkyl group, a C 2-6 alkenyl group and a c26 alkynyl group, 〇Rla and -N(Rla) 2, wherein the C -6 alkyl group, the C 2 ·6 alkenyl group and the C 2 -6 alkynyl group Replaced by one or more R10 as appropriate;

Rla，於各存在處，係獨立選自Η與烷基，其中該〇16 烷基係視情況被一或多個R2〇取代； R係選自Η、鹵基、氰基、C〗· 6烧基、C2 - 6浠基' c2 - 6炔基、 -〇R2a及-N(R2a)2，其中該Cl_6烷基、C2_6烯基及C2-6炔基係視 情況被一或多個R20取代； R2a，於各存在處，係獨立選自Η與烷基，其中該Cl-6 烷基係視情況被一或多個R20取代； R係選自Η、鹵基、氰基、-6烧基、C2 - 6稀基與c2 - 6快基、 •OR3a&-N(R3a)2，其中該Ci_6烷基、C2-6烯基及(：2-6炔基係視 情況被一或多個R3 0取代； R3a ’於各存在處，係獨立選自Η與C!_6烷基，其中該 烧基係視情況被一或多個R3 0取代； R4係選自Η、鹵基、-C02H、氰基、CV6烷基、C2-6烯基及 C2-6炔基，其中該(^_6烷基、C2-6烯基及C2-6炔基係視情況 被一或多個R40取代； R6係選自氟基、Ch烷基、C2-6烯基、c2_6炔基、-〇R6a，其 中該Ci_6烷基、C2_6烯基及C2_6炔基係視情況被一或多個R60 取代； R6a ’於各存在處，係獨立選自Η與C!_6烷基，其中該 烧基係視情況被一或多個R6 〇取代； 127286 -29- 200831517 R7係選自、_基、氡其、「 虱基Cl_6烷基、C2-6烯基及c2_6炔基， 其中該Ch縣、C2.6縣叫·6炔基係視情職—或多個 R7G取代； 记與R9各為氫，或R8與R9 一起形成=〇;且 R3〇,R-,R6〇aR7〇 ’於各存在處，各獨立選自函 基L基、氰基、-C02H ' Ch燒基、c2 6烯基及CH块基。 於式（II)化合物或其藥學上可接受鹽之一方面，Rla, in each presence, is independently selected from the group consisting of hydrazine and alkyl, wherein the 〇16 alkyl group is optionally substituted by one or more R 2 ;; R is selected from the group consisting of hydrazine, halo, cyano, C 〗 6 An alkyl group, a C2-6 fluorenyl 'c2-6 alkynyl group, a -R2a and -N(R2a)2, wherein the Cl_6 alkyl group, the C2_6 alkenyl group and the C2-6 alkynyl group are optionally one or more R20 Substituting; R2a, in each presence, independently selected from the group consisting of hydrazine and alkyl, wherein the Cl-6 alkyl group is optionally substituted with one or more R20; R is selected from the group consisting of hydrazine, halo, cyano, -6 An alkyl group, a C2-6 thin group and a c2-6 fast group, • OR3a&-N(R3a)2, wherein the Ci_6 alkyl group, the C2-6 alkenyl group, and the (2-6 alkynyl group) are optionally treated as one or a plurality of R 3 0 substituted; R 3a ' is independently selected from the group consisting of hydrazine and C! 6 alkyl, wherein the alkyl group is optionally substituted by one or more R 3 0 ; R 4 is selected from the group consisting of hydrazine, a halogen group, -C02H, cyano, CV6 alkyl, C2-6 alkenyl and C2-6 alkynyl, wherein the (^-6 alkyl, C2-6 alkenyl and C2-6 alkynyl groups are optionally one or more R40 Substituted; R6 is selected from the group consisting of a fluoro group, a Ch alkyl group, a C2-6 alkenyl group, a c2_6 alkynyl group, a -R6a group, wherein the Ci_6 alkyl group, the C2_6 alkenyl group and the C2_6 alkynyl group Optionally substituted by one or more R60; R6a' is independently selected from the group consisting of hydrazine and C!-6 alkyl, wherein the alkyl group is optionally substituted by one or more R6 ;; 127286 -29- 200831517 R7 is selected from the group consisting of _ 氡, 氡, 虱, 虱 Cl Cl_6 alkyl, C 2-6 alkenyl and c 2 _ alkynyl, wherein the Ch county, C 2.6 county is 6 acetylene based on the situation - or more R7G is substituted; R9 is each hydrogen, or R8 and R9 together form =〇; and R3〇, R-, R6〇aR7〇' are in each of the respective positions, each independently selected from the group L group, cyano group, -C02H 'Ch alkyl, c2 6 alkenyl and CH block. In one of the compounds of formula (II) or a pharmaceutically acceptable salt thereof,

八，》，〇，£，妒及妒和彼等所連接之環原子一起形成基團， 選自：Eight, ", 〇, £, 妒 and 妒 together with the ring atoms to which they are attached form a group, selected from:

J可選自N與CR4 ; 可為Η ; R2可選自氰基與-〇R2a ; R2a可為Cu烷基； R3可為Η ; R4可選自11與（：1-6烷基； 可選自氟基與-〇R6a ;且 R6a可選自只與心―烷基。 於式（II)化合物或其藥學上可接受鹽之另一方面， 人，认〇，£，妒及^和彼等所連接之環原子一起形成基團， 選自： -30- 127之86 200831517J may be selected from N and CR4; may be Η; R2 may be selected from cyano and -R2a; R2a may be Cu alkyl; R3 may be Η; R4 may be selected from 11 and (: 1-6 alkyl; It is selected from the group consisting of a fluoro group and a hydrazine R6a; and R6a may be selected from only a heart-alkyl group. On the other hand, a compound of the formula (II) or a pharmaceutically acceptable salt thereof, human, 〇, £, 妒 and ^ and The ring atoms to which they are attached together form a group, selected from: -30- 127 of 86 200831517

J可選自N與CR4 ; R1可為Η ; R2可選自氰基與-〇R2a ; R2a可為甲基； R3可為Η ; Φ R4可選自Η與甲基； R6可選自氟基與-〇R6a ;且 R6a可選自Η與曱基。 於一方面，式（II)化合物可為式（Ila)化合物：J may be selected from N and CR4; R1 may be Η; R2 may be selected from cyano and -R2a; R2a may be methyl; R3 may be Η; Φ R4 may be selected from ruthenium and methyl; R6 may be selected from fluorene And -R6a; and R6a may be selected from fluorenyl and fluorenyl. In one aspect, the compound of formula (II) can be a compound of formula (Ila):

式（Ila)Formula (Ila)

或其藥學上可接受之鹽，其中圮，妒，圮，妒，妒，尺9, A，D，E，G 及J均如上文定義。 於式（Ila)化合物或其藥學上可接受鹽之一方面， A，D，G，E，R8及R9和彼等所連接之環原子一起形成基團， 選自： 127286 -31 - 200831517Or a pharmaceutically acceptable salt thereof, wherein 圮, 妒, 圮, 妒, 妒, 尺 9, A, D, E, G and J are as defined above. In one aspect of the compound of the formula (Ila) or a pharmaceutically acceptable salt thereof, A, D, G, E, R8 and R9 together with the ring atom to which they are attached form a group selected from the group consisting of: 127286 -31 - 200831517

J可選自N與CR4 ; R1可為Η ; R2可選自氰基與-〇R2a ; R2a可為Cu烷基； R3可為Η ; _ R4可選自Η與CV6烷基； R6可選自氟基與-〇R6a ;且 R6a可選自Η與（ν6烷基。 於式（Ila)化合物或其藥學上可接受鹽之另一方面， A，D，G，E，R8及R9和彼等所連接之環原子一起形成基團， 選自：J may be selected from N and CR4; R1 may be Η; R2 may be selected from cyano and -R2a; R2a may be Cu alkyl; R3 may be Η; _R4 may be selected from fluorene and CV6 alkyl; From the fluorine group and -〇R6a; and R6a may be selected from the group consisting of ruthenium and (ν6 alkyl group. On the other hand, a compound of the formula (Ila) or a pharmaceutically acceptable salt thereof, A, D, G, E, R8 and R9 and The ring atoms to which they are attached together form a group selected from:

J可選自N與CR4 ; R1可為Η ; R2可選自氰基與-〇R2a ; R2a可為甲基； R3可為Η ; R4可選.Η與甲基； R6可選自氟基與-〇R6a ;且 127286 -32- 200831517 R6a可選自Η與甲基。 於另一方面，式（π)化合物可為式（IIb)化合物： R8J may be selected from N and CR4; R1 may be Η; R2 may be selected from cyano and -R2a; R2a may be methyl; R3 may be Η; R4 may be selected. Η and methyl; R6 may be selected from fluoro And - R6a; and 127286 - 32 - 200831517 R6a may be selected from the group consisting of hydrazine and methyl. In another aspect, the compound of formula (π) can be a compound of formula (IIb): R8

其中R1，R2, R3, R6, R8, R9, A，D，E，G及J均如上文定義。 於式（lib)化合物或其藥學上可接受鹽之一方面， 怠1>，（^1：，舻及妒和彼等所連接之環原子一起形成基團Wherein R1, R2, R3, R6, R8, R9, A, D, E, G and J are as defined above. In one aspect of the compound of formula (lib) or a pharmaceutically acceptable salt thereof, 怠1>, (^1: 舻 and 妒 together with the ring atom to which they are attached form a group

選自： J可選自N與CR4 ;Selected from: J can be selected from N and CR4;

狄1可為Η ; 可選自氰基與-OR2a ; R2a可為C卜6烷基； 妒可為Η ; 把可選自Η與Ch烷基； R6可選自氟基與-ORh ;且 把3可選自11與(^6烷基。 一方面， 起形成基團 於式（lib)化合物或其藥學上可接受鹽之另 A, D，G，E，R8及R9和彼等所連接之環原子一 12乃86 -33- 200831517 選自：Di 1 may be oxime; may be selected from cyano and -OR2a; R2a may be C 6 alkyl; 妒 may be Η; may be selected from Η and Ch alkyl; R 6 may be selected from fluoro and -ORh; 3 may be selected from the group consisting of 11 and (6) alkyl. In one aspect, the group is formed from a compound of formula (lib) or a pharmaceutically acceptable salt thereof, A, D, G, E, R8 and R9 and the same The ring atom to be connected is 12 is 86 -33- 200831517 From:

J可選自N與CR4 ; R1可為Η ; R2可選自氰基與-OR2a ; R2a可為甲基； R3可為Η ; R4可選自Η與甲基； R6可選自氟基與-OR6a ;且 R6a可選自Η與甲基。 於又另一方面，式（II)化合物可為式（IIc)化合物J may be selected from N and CR4; R1 may be Η; R2 may be selected from cyano and -OR2a; R2a may be methyl; R3 may be Η; R4 may be selected from fluorenyl and methyl; R6 may be selected from fluoro and -OR6a; and R6a may be selected from the group consisting of hydrazine and methyl. In yet another aspect, the compound of formula (II) can be a compound of formula (IIc)

或其藥學上可接受之鹽’其tRl，R2，R3，R8，R9，A，D，E，G& J均如上文定義，且其中在碳”a”上之敗基與在碳” b"上之 _NH-基團係對彼此呈反式關係。 於式（lie)化合物或其藥學上可接受鹽之一方面， ^，（^，:^及心彼等所連接之環原子一起形成基團， 127286 -34- 200831517 選自：Or a pharmaceutically acceptable salt thereof, wherein tR1, R2, R3, R8, R9, A, D, E, G& J are as defined above, and wherein the carbon group "a" is in the carbon "b" The upper _NH-groups are in a trans relationship with each other. In one aspect of the compound of the formula (lie) or a pharmaceutically acceptable salt thereof, ^, (^,:^ and the ring atoms to which they are attached are together Forming group, 127286 -34- 200831517 From:

J可選自N與CR4 ; R1可為Η ; R2可選自氰基與-〇R2a ; R2a可為Cb6烷基； R3可為Η;且 R4可選自Η與〇ν6烷基。 於式（lie)化合物之另一方面 原子一起形成基團 A，D，G，E，R8及R9和彼等所連接之環 選自：J may be selected from N and CR4; R1 may be hydrazine; R2 may be selected from cyano and -R2a; R2a may be Cb6 alkyl; R3 may be hydrazine; and R4 may be selected from fluorene and 〇ν6 alkyl. In another aspect of the compound of the formula (lie), the atoms together form a group A, D, G, E, R8 and R9 and the ring to which they are attached are selected from:

J可選自N與CR4 ; R1可為Η ; R2可選自氰基與甲氧基； R3可為Η;且 R4可選自Η與甲基。 於又再另一方面，式（II)化合物可為式（nd)化合物·· 127286 -35- 200831517J may be selected from N and CR4; R1 may be hydrazine; R2 may be selected from cyano and methoxy; R3 may be hydrazine; and R4 may be selected from hydrazine and methyl. In yet another aspect, the compound of formula (II) can be a compound of formula (nd) · 127286 -35- 200831517

或其藥學上可接受之鹽，其中R1，r2,R3，R8，R9，a，d，e，G& J均如上文定義。Or a pharmaceutically acceptable salt thereof, wherein R1, r2, R3, R8, R9, a, d, e, G&J are as defined above.

於式（lid)化合物或其藥學上可接受鹽之一方面 '认〇，£，妒及#和彼等所連接之環原子一起，可選In the case of a compound of formula (lid) or one of its pharmaceutically acceptable salts, 'puppets, £, 妒 and # together with the ring atoms to which they are attached are optional

J可選自N與CR4 ; 狄1可為Η ;J may be selected from N and CR4; Di 1 may be Η;

W可選自氰基與-OR2a ; R2a可為CV6烷基； 把可為Η;且 及4可選自Η與CV6烷基。 於式（lid)化合物之另一方面， 起形成基團 A，D，G，E，R8及於和彼等所連接之環原子 選自： 12乃86 -36 - 200831517W may be selected from cyano and -OR2a; R2a may be CV6 alkyl; 把 may be Η; and 4 may be selected from Η and CV6 alkyl. In another aspect of the compound of formula (lid), the groups A, D, G, E, R8 and the ring atom to which they are attached are selected from the group consisting of: 12:86 -36 - 200831517

N—y 與 y-/ κΡ. J可選自N與CR4 ; R1可為H ; R2可選自氰基與曱氧基； 可為Η;且 R4可選自Η與甲基。 於進一步方面，式（Π)化合物可為式（ne)化合物 R°N-y and y-/ κΡ. J may be selected from N and CR4; R1 may be H; R2 may be selected from cyano and decyloxy; may be hydrazine; and R4 may be selected from hydrazine and methyl. In a further aspect, the compound of formula (Π) can be a compound of formula (ne) R°

或其藥學上可接受之鹽，其中r1，r2，r3，r8，r9，a，d，e，q J岣如上文定義。 選 於式（lie)化合物或其藥學上可接受鹽之一方面 ^(^，妒及於和彼等所連接之環原子—起形成基團， r\Or a pharmaceutically acceptable salt thereof, wherein r1, r2, r3, r8, r9, a, d, e, q J are as defined above. Selecting one of the compounds of the formula (lie) or a pharmaceutically acceptable salt thereof ^(^, and forming a group with the ring atom to which they are attached, r\

J可選自N與CR4 ; 12?286 200831517 R1可為Η ; R2可選自氰基與-〇R2a ; R2a可為CV6烷基； R3可為Η;且 R4可選自Η與CV6烷基。 於式（lie)化合物之另一方面， ^(^，:^及纪和彼等所連接之環原子—㈣成基團J may be selected from N and CR4; 12?286 200831517 R1 may be Η; R2 may be selected from cyano and -R2a; R2a may be CV6 alkyl; R3 may be hydrazine; and R4 may be selected from fluorene and CV6 alkyl . In another aspect of the compound of the formula (lie), ^(^,:^ and the ring atoms to which they are attached - (iv) a group

選自： J可選自N與CR4 ; R1可為Η ; R2可選自氰基與甲氧基； R3可為Η ;且Selected from: J may be selected from N and CR4; R1 may be Η; R2 may be selected from cyano and methoxy; R3 may be Η;

R4可選自Η與甲基。 於又進-步方面’式(Π)化合物可為式㈣化合物： ΟR4 may be selected from hydrazine and methyl. In the case of further steps, the compound of the formula (IV) can be a compound of the formula (IV): Ο

或其藥學上可接受之鹽，直中Rl 又I八甲K，R，妒及J均如上文定義， 基團係對彼此Or a pharmaceutically acceptable salt thereof, wherein R 1 and I 八 K, R, 妒 and J are as defined above, the groups are to each other

且其中在碳”a”上之氟基與在碳”b”上之A ^7286 -38· 200831517 呈反式關係。 於式（Ilf)化合物或其藥學上可接受鹽之一方面， J可選自N與CR4 ; 可為Η ; R2可選自氰基與-OR2a ; R2a可為（V6烷基； R3可為Η ;且 _ R4可選自Η與Cu烷基。 於式（Ilf)化合物之另一方面， J可選自N與CR4 ; R1可為Η ; R2可選自氰基與甲氧基； R3可為Η ;且 R4可選自Η與曱基。 於又再進一步方面，式（II)化合物可為式（IIg)化合物：And wherein the fluorine group on carbon "a" has a trans relationship with A ^ 7286 - 38 · 200831517 on carbon "b". In one aspect of the compound of Formula (Ilf) or a pharmaceutically acceptable salt thereof, J may be selected from N and CR4; may be hydrazine; R2 may be selected from cyano and -OR2a; R2a may be (V6 alkyl; R3 may be And _ R4 may be selected from the group consisting of hydrazine and Cu alkyl. In another aspect of the compound of formula (Ilf), J may be selected from N and CR4; R1 may be hydrazine; R2 may be selected from cyano and methoxy; It may be Η; and R4 may be selected from fluorenyl and fluorenyl. In yet a further aspect, the compound of formula (II) may be a compound of formula (IIg):

R3 式（¾) 或其藥學上可接受之鹽’其中R^R'r3及j均如上文定義， 且其中在碳"a"上之氟基與在碳”b”上之基團係對彼此 呈反式關係。 於式（IIg)化合物或其藥學上可接受鹽之一方面， ^7286 -39 - 200831517 J可選自N與CR4 ; R1可為Η; R2可選自氰基與-OR2a ; R2a可為C^6烷基； R3可為H·，且 R4可選自：^與心^烷基。 於式（Ilg)化合物之另一方面 • J可選自N與CR4 ; R1可為Η ; R2可選自氰基與甲氧基； R3可為H;且 R4可選自Η與曱基。 -去甘— , ’、 物，如藉由實例所 不者’其母一項係提供本發明之進一步 ^ ^ ^ 獨立方面。 生物學活性R3 Formula (3⁄4) or a pharmaceutically acceptable salt thereof, wherein R^R'r3 and j are as defined above, and wherein the fluoro group on carbon "a" and the group on carbon "b" They are in a trans relationship with each other. In one aspect of the compound of the formula (IIg) or a pharmaceutically acceptable salt thereof, ^7286 -39 - 200831517 J may be selected from N and CR4; R1 may be hydrazine; R2 may be selected from cyano and -OR2a; R2a may be C ^6 alkyl; R3 may be H., and R4 may be selected from: ^ and heart. In another aspect of the compound of formula (Ilg): J may be selected from N and CR4; R1 may be hydrazine; R2 may be selected from cyano and methoxy; R3 may be H; and R4 may be selected from fluorenyl and fluorenyl. - Going to Gan-, ', and, by way of example, the parental line provides a further ^ ^ ^ independent aspect of the invention. Biological activity

於本文 可藉由 式(I)化合物係由於其抗㈣作用而令人感興趣 中所揭示之本發明化合物達成抗細菌作用之能力 下述試驗註實。 細菌易感染性測試方法1 Ν π /代骚螺質中，以96井；Ν 式，測試關於抗微生物活性。 、， 了使化合物溶於二甲亞颯中 並以10種加倍稀釋液，在易减 4木性檢測中測試。於檢測兮 使用之生物體可在適當瓊脂 曰^養基中生長過夜，然後懸诗 於適合生物體生長之液體媒質 貝中。可將此懸浮液調整至| 127286 200831517 於0.5 McFarland ’並在相同液體媒質中施行進一步1比1〇稀 釋’以製備最後生物體懸浮液於100微升中。在讀取之前， 可將板在適當條件下，於3Tc下培養24小時。最低抑制濃 度（MIC)係以能夠降低生長達8〇%或更多之最低藥物濃度測 定。 化合物係針對革蘭陽性物種之試驗名單進行評估，包括 金黃色葡萄球菌、肺炎鏈球菌、釀膿鏈球菌I屎腸球菌。 _ 此外’化合物係針對革蘭陰性物種之試驗名單進行評估， 括流感嗜企菌、大腸桿菌反黏膜莫拉氏菌。本發碾之也 合物係具有對一或多種上文所指稱生物體之MJC低於或等 於8微克/毫升。 實例2之化合物針對金黃慈濛奢硪磨具有為0.25 (毫 克/升），而針對乂麖痒磨之MIC為0.5 (毫克/升）。 細菌易感染性測試方法2 化合物係藉由易感染性測試，使用由CSLI所建議之微培 鲁養基稀釋方法’測試關於抗微生物活性。可使化合物溶於 二甲亞颯中，並以1〇種加倍稀釋液，在易感染性檢測中測 試’以致在檢測中之最後二甲亞颯濃度為2〇/〇 (v/v)。於檢測 中所使用之金旁慈磨奢球磨(San) 516細胞，可在適當瓊脂培 養基上生長過夜，然後懸浮於NCCLS所建議之液體易感染 性測試媒質中。可將各懸浮液之混濁度調整至等於0.5 McFarland標準物，並在相同液體媒質中施行進一步i比2〇〇 稀釋’以製備最後生物體懸浮液，且將100微升此懸浮液添 加至含有已溶於2微升二甲亞砜中之化合物之微滴定板各 127286 •41- 200831517 井中。在讀取之前，可將士 ^ 將板在大氧壓與溫度之適當條件下 培養，且歷經減Ncm# π <崎間。當於下矣1中徒 用時，"抑制”一詞係指藉由 ^ τ 才日不貝例編號之化合物所抑 制金#芑##硪磨516細胞生具夕石八L / t 肥生長之百分比（與未經處理之試 樣作比較）。 當在上文活體外檢測中測試時，下文所列示實例編號之 化合物係於所指示之濃度下測試，提供所顯示之抑制。於 大部份情況中，在其下測試化合物之最高濃度為8微克/毫 升。但是’於一些情況中，化合物係在高於8微克/亳升之 濃度下測試，典型上為當濃度係首先以//M度量，接著轉化 成微克/毫升時。於其中化合物係在超過一種高於8微克/ 毫升之濃度下測試之情況中，最接近8微克/毫升之濃度係 提供於下文。 表1 實例 編號 所測試之濃度 (微克/毫升） 抑制（％) 1 8 100 2 8 100 3 8 99 4 8 100 5 1 8 100 6 8 99 7 8 100 8 8 99 9 8 100 10— -----------* 100 127286 -42- 200831517The ability of the compounds of formula (I) to achieve antibacterial action by the compounds of formula (I) which are of interest in the art by virtue of their anti-(iv) action is described herein. Bacterial Infectivity Test Method 1 Ν π / generation snails, 96 wells; Ν, test for antimicrobial activity. The compound was dissolved in dimethyl hydrazine and tested in 10 doubling dilutions in an easy-to-reduced wood assay. The organism used for the test can be grown overnight in a suitable agar medium and then hanged in a liquid medium suitable for growth of the organism. This suspension can be adjusted to | 127286 200831517 at 0.5 McFarland ' and further 1 to 1 〇 dilution in the same liquid medium to prepare the final biological suspension in 100 μl. The plates can be incubated for 24 hours at 3 Tc under appropriate conditions prior to reading. The minimum inhibitory concentration (MIC) is determined by the lowest drug concentration that can reduce growth by up to 8% or more. The compounds were evaluated against a list of tests for Gram-positive species, including Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes. _ In addition, 'compounds' were evaluated against a list of trials for Gram-negative species, including influenza bacterium, E. coli, M. catarrhalis. The present hair milling composition has an MJC of less than or equal to 8 micrograms per milliliter for one or more of the organisms referred to above. The compound of Example 2 had a 0.25 (milligram/liter) for Golden Charcoal and a MIC of 0.5 (mg/L) for the itching mill. Bacterial Infectivity Test Method 2 Compounds were tested for antimicrobial activity by a susceptibility test using the micro-culture dilution method recommended by CSLI. The compound can be dissolved in dimethyl sulfoxide and tested in a susceptibility test with a 1 doubling double dilution so that the final concentration of dimethyl hydrazine in the assay is 2 〇/〇 (v/v). The Jinbian Cijiao Ball Mill (San) 516 cells used in the assay can be grown overnight on a suitable agar medium and then suspended in the liquid susceptibility test medium recommended by NCCLS. The turbidity of each suspension can be adjusted to equal 0.5 McFarland standard and a further i to 2 〇〇 dilution can be performed in the same liquid medium to prepare the final biological suspension, and 100 microliters of this suspension is added to the containing The microtiter plates of the compound dissolved in 2 μl of dimethyl sulfoxide were each 127286 • 41- 200831517 well. Before reading, the plate can be cultured under the conditions of high oxygen pressure and temperature, and reduced by Ncm# π < When used in 矣1, the word "suppression" refers to the inhibition of gold by the compound of ^ τ, which is not the case number. #芑##硪磨516 cells 生夕石八 L / t肥Percentage of growth (compared to untreated samples). When tested in the above in vitro assay, the compounds of the example numbers listed below are tested at the indicated concentrations to provide the indicated inhibition. In most cases, the highest concentration of the test compound is 8 μg/ml. However, in some cases, the compound is tested at a concentration higher than 8 μg/μl, typically when the concentration is first //M metric, then converted to micrograms/ml. In the case where the compound is tested at a concentration greater than 8 μg/ml, the concentration closest to 8 μg/ml is provided below. Table 1 Examples No. Tested concentration (μg/ml) Inhibition (%) 1 8 100 2 8 100 3 8 99 4 8 100 5 1 8 100 6 8 99 7 8 100 8 8 99 9 8 100 10— ------ -----* 100 127286 -42- 200831517

實例11至20 11 8 100 12 8 100 13 8 100 14 8 100 15 8 97 16 8 97 17 8 99 18 8 95 19 8 100 20 8 100 實例21至30 21 8 100 22 8 100 23 8 100 24 8 100 25 8 98 26 8 98 27 8 87 28 8 98 29 8 84 30 8 98 實例31至40 31 8 87 32 8 98 33 13 96 34 12 91 35 14 100 36 12 90 37 13 100 127286 -43- 200831517 38 12 100 39 14 100 40 12 100 實例41-47及50 41 8 100 42 8 100 43 4 100* 44 8 100 45 8 97 46 8 100 47 8 100 50 14 100 51 9 100 52 13 100Examples 11 to 20 11 8 100 12 8 100 13 8 100 14 8 100 15 8 97 16 8 97 17 8 99 18 8 95 19 8 100 20 8 100 Examples 21 to 30 21 8 100 22 8 100 23 8 100 24 8 100 25 8 98 26 8 98 27 8 87 28 8 98 29 8 84 30 8 98 Examples 31 to 40 31 8 87 32 8 98 33 13 96 34 12 91 35 14 100 36 12 90 37 13 100 127286 -43- 200831517 38 12 100 39 14 100 40 12 100 Examples 41-47 and 50 41 8 100 42 8 100 43 4 100* 44 8 100 45 8 97 46 8 100 47 8 100 50 14 100 51 9 100 52 13 100

*關於實例43之化合物在8微克/毫升濃度下之抑制係為 12%，惟一般認為12%數字為錯誤的。 因此，於一方面，係提供式（I)化合物或其藥學上可接受 之鹽，作為藥劑使用。 於又另一方面，係提供式（I)化合物或其藥學上可接受之 鹽於藥劑製造上之用途，該藥劑係在溫血動物譬如人類中 用於治療細菌感染。 於又另一方面，係提供式（I)化合物或其藥學上可接受之 鹽於藥劑製造上之用途，該藥劑係在溫血動物譬如人類中 用於治療因一或多種致病生物體所造成之細菌感染，該生 物馥警如玻曼尼不動桿菌、親水性需氣菌、炭疽芽孢桿菌、 脆弱擬桿菌、百日咳博德特氏菌、Burkholderia cepacia、肺炎 衣原體、弗氏擰檬酸桿菌、Μ難梭菌、陰溝腸桿菌、糞腸 127286 -44- 200831517 球菌、屎腸球菌、產氣腸桿菌、大腸桿菌、壞死梭桿菌、 流感嗜血菌、副流感嗜血菌、梭門嗜血桿菌、oxytoca克雷 伯氏菌、肺炎克雷伯氏菌、肺列吉内拉菌、單核細胞增生 利斯特氏菌、黏膜莫拉氏菌、摩氏摩根氏菌、肺炎枝原體、 淋病奈瑟氏球菌、腦膜炎奈瑟氏球菌、多殺巴斯德氏菌、 奇異變形菌、普通變形菌、銅綠假單胞菌、傷寒沙門氏菌、 鼠傷寒沙門氏桿菌、黏質沙雷氏菌、弗氏志贺氏菌、痢疾 志贺氏菌、金黃色葡萄球菌、表皮葡萄球菌、溶血葡萄球 菌、間型葡萄球菌、腐生葡萄球菌、Stenotrophomonas maltophila、無乳鏈球菌、突變型鏈球菌、肺炎鏈球菌Sl熱 原鏈球菌。 於進一步方面，係提供式（I)化合物或其藥學上可接受之 鹽於藥劑製造上之用途，該藥劑係在溫血動物譬如人類中 用於治療感染，譬如枝氣管炎、齦難梭菌結腸炎、子宮頸 炎、心内膜炎、淋菌尿道炎、吸入炭疽、腹内感染、腦膜 炎、骨髓炎、中耳炎、咽炎、肺炎、***炎、敗血病、 竇炎、皮膚與柔軟組織感染及尿道感染。 於又進一步方面，係提供式（I)化合物或其藥學上可接受 之鹽於藥劑製造上之用途，該藥劑係在溫血動物譬如人類 中用於治療細菌感染，其中細菌為一種屬，選自產農革虑 菌屬、不動桿菌屬、芽孢桿菌屬、擬桿菌屬、博德特氏菌 屬、Burkholderia、衣原體屬、檸檬酸細桿屬、梭菌屬、腸桿 菌屬、腸球菌屬、埃希氏菌屬、黃桿菌屬、梭桿菌屬、嗜 皇桿菌屬、克雷伯氏菌屬、列吉内拉菌屬、利斯特氏菌屬、 127286 -45- 200831517 摩根氏菌屬、莫拉氏菌屬、枝原體屬、奈瑟氏球菌屬、巴 斯德菌屬、消化球菌屬、消化鏈球菌屬、普弗提拉菌屬、 變形菌屬、沙門桿菌屬、假單胞菌屬、沙雷氏菌屬、志賀 氏菌屬、Stenotrophomonas、鏈球菌屬反葡萄球菌屬。 於另一方面，係提供一種在溫血動物譬如人類中治療細 菌感染之方法，該方法包括對該動物投予有效量之式（I)化 合物或其藥學上可接受之鹽。 於又另一方面，係提供一種在溫血動物譬如人類中治療 因一或多種致病生物體所造成之細菌感染之方法，該生物 鲁％如玻曼尼不動桿菌、親水性需氣菌、炭疽芽孢桿菌、 脆弱擬桿菌、百日咳博德特氏菌、Burkholderia cepacia、肺炎 衣原體、弗氏檸檬酸桿菌、艱難梭菌、陰溝腸桿菌、糞腸 球菌、屎腸球菌、產氣腸桿菌、大腸桿菌、壞死梭桿菌、 流感嗜血菌、副流感嗜血菌、梭門嗜企桿菌、o^ytoca克雷 伯氏菌、肺炎克雷伯氏菌、肺列吉内拉菌、單核細胞增生 利斯特氏菌、黏膜莫拉氏菌、摩氏摩根氏菌、肺炎枝原體、 淋病奈瑟氏球菌、腦膜炎奈瑟氏球菌、多殺巴斯德氏菌、 奇異變形菌、普通變形菌、銅綠假單胞菌、傷寒沙門氏菌、 鼠傷寒沙門氏桿菌、黏質沙雷氏菌、弗氏志贺氏菌、痢疾 志賀氏菌、金黃色葡萄球菌、表皮葡萄球菌、溶企葡萄球 菌、間型葡萄球菌、腐生葡萄球菌、Stenotrophomonas maltophila、無乳鍵球菌、突變型鏈球菌、肺炎鍵球菌I熱 及鏈硪磨，該方法包括對該動物投予有效量之式（I)化合物 或其藥學上可接受之鹽。 127286 -46- 200831517 丙另 方面，係提供一種在溫金動物譬如人類中治 療細菌感染t古、+ 、 法，譬如枝氣管炎、艱難梭菌結腸炎、子 呂頸炎、心内胺火 、九、淋囷尿道炎、吸入炭疽、腹内感染、 腦膜炎、骨驗、養、士 1 > 尺中耳炎、咽炎、肺炎、***炎、敗血 病、宮彡 、* ^ 貝、、反膚與柔軟組織感染及尿道感染，該方法包括 對該動物投予古^胃 仪丁有效1之式⑴化合物或其藥學上可接受之 鹽。* The inhibition of the compound of Example 43 at a concentration of 8 μg/ml was 12%, but the 12% number was generally considered to be erroneous. Thus, in one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for use as a medicament. In yet another aspect, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a bacterial infection in a warm-blooded animal such as a human is provided. In yet another aspect, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of one or more pathogenic organisms in a warm-blooded animal such as a human Caused by bacterial infections such as Acinetobacter bovis, hydrophilic gas-demanding bacteria, Bacillus anthracis, Bacteroides fragilis, B. pertussis, Burkholderia cepacia, Chlamydia pneumoniae, Citricus faecalis, Clostridium difficile, Enterobacter cloacae, fecal intestine 127286 -44- 200831517 cocci, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusarium oxysporum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus serovar , oxytoca Klebsiella, Klebsiella pneumoniae, G. jejuni, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, gonorrhea Neisseria, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Common Proteobacteria, Pseudomonas aeruginosa, Salmonella typhimurium, Salmonella typhimurium, Serratia marcescens, Fushishi Shiga Bacteria, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus aureus, Staphylococcus aureus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae S. Cocci. In a further aspect, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an infection, such as bronchitis, Clostridium difficile, in a warm-blooded animal such as a human. Colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation of anthrax, intra-abdominal infection, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections And urinary tract infections. In still a further aspect, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a bacterial infection in a warm-blooded animal such as a human, wherein the bacterium is a genus, selected Self-produced Agrobacterium, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydia, Citric Acid, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Pseudomonas, Klebsiella, Legianella, Listeria, 127286 -45- 200831517, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Digestococcus, Peptostococcus, Pftilida, Proteus, Salmonella, Pseudomonas Genus, Serratia, Shigella, Stenotrophomonas, Streptococcus anti-Staphylococcus. In another aspect, a method of treating a bacterial infection in a warm-blooded animal, such as a human, is provided, the method comprising administering to the animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, the invention provides a method for treating a bacterial infection caused by one or more pathogenic organisms in a warm-blooded animal such as a human, such as Acinetobacter baumannii, hydrophilic gas-demanding bacteria, Bacillus anthracis, Bacteroides fragilis, Bordetella pertussis, Burkholderia cepacia, Chlamydia pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli , Neisseria gonorrhoeae, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus sphaeroides, O. ytoca Klebsiella, Klebsiella pneumoniae, G. elegans, Monocyte proliferation Streptomyces, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Common proteobacteria , Pseudomonas aeruginosa, Salmonella typhimurium, Salmonella typhimurium, Serratia marcescens, Shigella flexneri, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus aureus, type Staphylococcus, Staphylococcus aureus, Stenotrophomonas maltophila, Noococcus lactis, Streptococcus mutans, Pneumococcal I heat and chain honing, the method comprising administering to the animal an effective amount of a compound of formula (I) or pharmaceutically thereof Acceptable salt. 127286 -46- 200831517 In another aspect, the invention provides a method for treating bacterial infections in Wenjin animals such as humans, such as t, +, method, such as bronchitis, C. difficile colitis, sub-cerebral inflammation, intracardiac fire, Nine, dripping urethritis, inhalation of anthrax, intra-abdominal infection, meningitis, bone test, raising, 1 > ulnar otitis, pharyngitis, pneumonia, prostatitis, septicemia, palace sputum, * ^ shell, and anti-skin In combination with a soft tissue infection and a urinary tract infection, the method comprises administering to the animal a compound of the formula (1) or a pharmaceutically acceptable salt thereof.

^ 面’係提供一種在溫血動物譬如人類中治療 、田菌感木之方法，其中細菌為一種屬，選自產崖皐虑磨屬、 不動桿圆屬、芽抱桿菌屬、擬桿菌屬、博德特氏菌屬、 Bi^khcMena、衣原體屬、擰檬酸細桿屬、梭菌屬、腸桿菌屬、 备戎磨屬埃希氏菌屬、黃桿菌屬、梭桿菌屬、嗜血桿菌 屬、免雷伯氏菌屬、列吉内拉菌屬、利斯特氏菌屬、摩根^ 氏囷屬、莫杈氏菌屬、枝原體屬、奈瑟氏球菌屬、巴斯德 菌屬、消化球菌屬 '消化鏈球菌屬、普弗提拉菌屬、變形 菌屬、沙門桿菌屬、假單胞菌屬、沙雷氏菌屬、志贺氏菌 Μ ' StenotwphGmmas、鏈球菌屬反葡萄球菌屬，議方法匕括 對該動物投予有效量之式（I)化合物或其藥學上可接受之 鹽〇 於又進一步方面，係提供式（I)化合物或其藥學上可接受 之鹽，以在溫血動物譬如人類中用於治療細菌感染。 於另一方面，係提供式（I)化合物或其藥學上可接受之 鹽’以在溫血動物譬如人類中用於治療因一或多種致病生 物體所造成之細菌感染，該生物體譬如滅f名不翁岸磨、 127286 -47- 200831517 親水性需氣菌、炭疽芽孢桿菌、脆弱擬桿菌、百曰咳博德 特氏菌、Burkholderia cepacia、肺炎衣原體、弗氏檸檬酸桿菌、 難難梭菌、陰溝腸桿菌、糞腸球菌、屎腸球菌、產氣腸桿 菌、大腸桿菌、壞死梭桿菌、流感嗜企菌、副流感嗜金菌、 梭門嗜血桿菌、oxytoca克雷伯氏菌、肺炎克雷伯氏菌、肺 列吉内拉菌、單核細胞增生利斯特氏菌、黏膜莫拉氏菌、 摩氏摩根氏菌、肺炎枝原體、淋病奈瑟氏球菌、腦膜炎奈 瑟氏球菌、多殺巴斯德氏菌、奇異變形菌、普通變形菌、 銅綠假單胞菌、傷寒沙門氏菌、鼠傷寒沙門氏桿菌、黏質 沙雷氏菌、弗氏志贺氏菌、痢疾志贺氏菌、金黃色葡萄球 菌、表皮葡萄球菌、溶企葡萄球菌、間型葡萄球菌、腐生 葡萄球菌、Stenotrophomonas maltophila、無乳鏈球菌、突變型 鏈球菌、肺炎鏈球菌反熱原鏈球菌。 於又另一方面，係提供式（I)化合物或其藥學上可接受之 鹽，以在溫血·動物譬如人類中用於治療感染，譬如枝氣管 炎、艱難梭菌結腸炎、子宮頸炎、心内膜炎、淋菌尿道炎、 吸入炭疽、腹内感染、腦膜炎、骨髓炎、中耳炎、咽炎、 肺炎、***炎、敗血病、竇炎、皮膚與柔軟組織感染及 尿道感染。 於又再另一方面，係提供式（I)化合物或其藥學上可接受 之鹽，以在温血動物譬如人類中用於治療細菌感染，其中 U亀為一綠亀，亀為產氣單胞菌屬、不動桿菌屬、芽孢桿 菌屬、擬桿菌屬、博德特氏菌屬、Burkholderia、衣原體屬、 檸檬酸細桿屬、梭菌屬、腸桿菌屬、腸球菌屬、埃希氏菌 127286 -48- 200831517 屬、黃桿菌屬、梭桿菌屬、嗜叙桿菌屬、克雷伯氏菌屬、 列吉内拉菌屬、利斯特氏菌屬、摩根氏菌屬、莫拉氏菌屬、 枝原體屬、奈瑟氏球菌屬、巴斯德菌屬、消化球菌屬、消 化鏈球菌屬、普弗提拉菌屬、變形菌屬、沙門桿菌屬、假 單胞菌屬、沙雷氏菌屬、志贺氏菌屬、Stenotrophomonas、鏈 硪苈屬與##球磨廣及門黑米亞菌屬。 於一方面，感染”與”細菌感染"術語可指因竑f yg不鳶 #磨所造成之細菌感染。於另一方面，’’感染”與’’細菌感染” 術語可指因/親恭炫君扇磨所造成之細菌感染。於又另一方 面，π感染π與”細菌感染”術語可指因羞痘穿疱#磨所造成 之細菌感染。於又再另一方面，”感染”與”細菌感染”術語 可指因應凝#磨所造成之細菌感染。於進一步方面， π感染’’與”細菌感染”術語可指因，0贫濘##武磨所造 成之細菌感染。於又進一步方面，"感染π與”細菌感染π術 語可指因所造成之細菌感染。於又再進一 步方面，”感染”與"細菌感染”術語可指因厣爻衣摩邀所造 成之細菌感染。於一方面，ft感染’’與"細菌感染”術語可指 因弟戌##鑀#磨所造成之細菌感染。於另一方面，’’感染” 與"細菌感染”術語可指因蔡#禮磨所造成之細菌感染。於 又另一方面，π感染”與”細菌感染”術語可指因麿#靡#磨 所造成之細菌感染。於又再另一方面，”感染”與”細菌感染 "術語可指因球磨所造成之細菌感染。於進一步方面， ”感染”與’’細菌感染’’術語可指因廣廣球磨所造成之細菌 感染。於又進一步方面，”感染”與’’細菌感染”術語可指因 127286 -49- 200831517 產農廣#磨所造成之細菌感染。於又再進一步方面，”感染” 與”細菌感染"術語可指因乂廣禅磨所造成之細菌感染。於 一方面，’1感染”與”細菌感染”術語可指因禳死禮#磨所造 成之細菌感染。於另一方面，”感染”與”細菌感染”術語可 指因滿滅营盖磨所造成之細菌感染。於又另一方面，”感染” 與”細菌感染”術語可指因歡流滅营益磨所造成之細菌感 染。於又再另一方面，”感染”與π細菌感染”術語可指因禮 π营讼#磨所造成之細菌感染。於進一步方面，”感染”與 "細菌感染”術語可指因—toca尤蒙伯成磨所造成之細菌感 染。於又進一步方面，”感染"與"細菌感染”術語可指因厣 爻义,伯武磨所造成之細菌感染。於又再進一步方面， ”感染”與π細菌感染’’術語可指因摩歹/ #冷拉磨所造成之 細菌感染。於一方面，"感染”與"細菌感染"術語可指因革 孩細應增义矜教#武磨所造成之細菌感染。於另一方面， ”感染”與”細菌感染’’術語可指因#廯：#拉成磨所造成之 細菌感染。於又另一方面，"感染”與"細菌感染”術語可指 因#沃#廣戌磨所造成之細菌感染。於又再另一方面， "感染”與”細菌感染’’術語可指因厣爻授#藶所造成之細 菌感染。於進一步方面，"感染"與”細菌感染”術語可指因 满病奈遂武球磨所造成之細菌感染。於又進一步方面， ”感染11與”細菌感染”術語可指因腐廯爻奈瑟茂球磨所造 成之細菌感染。於又再進一步方面，’1感染”與’’細菌感染” 術語可指因多歲S新德戌磨所造成之細菌感染。於一方 面，n感染”與”細菌感染π術語可指因奇異變形磨所造成之 127286 -50- 200831517 細菌感染。於另一方面，”感染”與，，細菌感染，，術語可指因 普道變形#所造成之細菌感染。於又另-方面，”感染”盘 ”細菌感染”術語可指因游雜㈣#所造成之細菌感染。^面's method provides a method for treating and mulching wood in warm-blooded animals such as humans, wherein the bacterium is a genus, selected from the group consisting of the genus, the genus, the genus Bacillus, and the genus Bacteroides. , Bordetella, Bi^khcMena, Chlamydia, citric acid, Clostridium, Enterobacter, Escherichia, Flavobacterium, Fusobacterium, bloodthirsty Bacillus, Lactobacillus, Legianella, Listeria, Morgan, Moss, Mycoplasma, Neisseria, Pasteur Genus, Digestive genus 'Digestive Streptococcus, Pftilida, Proteobacter, Salmonella, Pseudomonas, Serratia, Shigella Ste ' Stenotwph Gmmas, Streptococcus A method of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the formula (I) or a pharmaceutically acceptable salt thereof Salt for the treatment of bacterial infections in warm-blooded animals such as humans. In another aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for use in treating a bacterial infection caused by one or more pathogenic organisms in a warm-blooded animal such as a human, such as灭 149 179 127286 -47- 200831517 Hydrophilic gas, Bacillus anthracis, Bacteroides fragilis Clostridium, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusarium oxysporum, Influenza bacterium, Parainfluenzae, Haemophilus haemophilus, Klebsiella oxytoca Klebsiella pneumoniae, G. elegans, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, meningitis Neisseria, Pasteurella, Proteus, Common Proteobacteria, Pseudomonas aeruginosa, Salmonella typhimurium, Salmonella typhimurium, Serratia marcescens, Shigella flexneri, Shigella dysenteriae, golden yellow Portuguese Staphylococcus, Staphylococcus epidermidis, Staphylococcus aureus, Staphylococcus aureus, Staphylococcus aureus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, Streptococcus pyogenes. In yet another aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of infections in warm blood, animals, such as humans, such as bronchitis, C. difficile colitis, cervicitis Endocarditis, gonococcal urethritis, inhalation of anthrax, intra-abdominal infection, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections and urinary tract infections. In still another aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a bacterial infection in a warm-blooded animal such as a human, wherein U is a green scorpion and the sputum is a gas production list. Cyanobacteria, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydia, Citric Acid, Clostridium, Enterobacter, Enterococcus, Escherichia 127286 -48- 200831517 Genus, Flavobacterium, Fusobacterium, Pedibacterium, Klebsiella, Legianella, Listeria, Morganella, Moraxella Genus, Mycoplasma, Neisseria, Pasteurella, Digestive, Digestive Streptococcus, Pftilida, Proteus, Salmonella, Pseudomonas, Sand Helicobacter, Shigella, Stenotrophomonas, Streptomyces and ##球磨广和门黑米亚属. In one aspect, the term "infection" and "bacterial infection" can refer to a bacterial infection caused by 竑f yg 不磨#磨. On the other hand, the terms 'infection' and ''bacterial infection'' may refer to a bacterial infection caused by a fan. In yet another aspect, the term π-infected with π and "bacterial infection" may refer to a bacterial infection caused by blistering. On the other hand, the term "infection" and "bacterial infection" may refer to a bacterial infection caused by a cure. In a further aspect, the terms π-infected with 'bacterial infection' may refer to a bacterial infection caused by 0 泞##武磨. In a further aspect, the term "infected π" and "bacterial infection" may refer to the bacterial infection caused by it. In yet further, the term "infection" and "bacterial infection" may refer to the cause of the injury. Bacterial infection. On the one hand, the term "fever" and "bacterial infection" may refer to bacterial infections caused by the 戌##鑀# grinding. On the other hand, the terms 'infection' and 'bacterial infection' may refer to The bacterial infection caused by Cai #礼磨. On the other hand, the term “π infection” and “bacterial infection” may refer to bacterial infection caused by 麿#靡# grinding. On the other hand, "infection" and "bacterial infection" terms may refer to bacterial infections caused by ball milling. In further aspects, the terms "infection" and "bacterial infection" may refer to a wide-body ball mill. Bacterial infection. In a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by 127286 -49-200831517. In a further aspect, the term "infection" and "bacterial infection" can refer to bacterial infections caused by 乂 禅 禅 。. On the one hand, the term '1 infection' and 'bacterial infection' can refer to 禳 礼 礼# Bacterial infection caused by grinding. On the other hand, the terms "infection" and "bacterial infection" may refer to bacterial infections caused by full-scale tamping. On the other hand, the terms "infection" and "bacterial infection" may refer to bacterial infections caused by the annihilation of the camp. On the other hand, the term "infection" and "bacterial infection of π" may refer to a bacterial infection caused by a rug. In a further aspect, the term "infection" and "bacterial infection" may refer to -toca. A bacterial infection caused by Yumenbo. In a further aspect, the term "infection" and "bacterial infection" may refer to a bacterial infection caused by the sputum. In yet a further aspect, the term "infection" and π bacterial infection '' can refer to a bacterial infection caused by Capricorn / #冷拉磨. On the one hand, "infection" and "bacterial infection" terminology may refer to bacterial infections caused by meditation and martial arts. On the other hand, "infection" and "bacterial infection" The term may refer to a bacterial infection caused by #廯:# pulling into a mill. On the other hand, the terms "infection" and "bacterial infection" may refer to bacterial infections caused by #沃#广戌磨. On the other hand, "infection" and "bacterial infection'' may refer to bacterial infections caused by 厣爻. In a further aspect, the term "infection" and "bacterial infection" may refer to a bacterial infection caused by a full-body rifle. In a further aspect, the term "infection 11" and "bacterial infection" may refer to a bacterial infection caused by the rot of Neisser. In yet further aspects, the terms '1 infection' and ''bacterial infection' may refer to On the one hand, the term "n infection" and "bacterial infection" π term can refer to 127286 -50-200831517 bacterial infection caused by singular deformation grinding. On the other hand, "infection "And, bacterial infection, the term can refer to bacterial infection caused by Pu Dao Deformation #. In another aspect, the term "infected" disk "bacterial infection" can refer to a bacterial infection caused by a miscellaneous (four) #.

； 另方面，感染，’與"細菌感染，，術語可指因殤荩汐 賴所造成之細菌感染，進一步方面，"感染”與"細菌 感染”術語可指因㈣料W㈣所造成之細菌感染。於 又進一步方面，”感染”與，，細菌感染”術語可指因淼質汐, 代磨所造成之細菌感染。於又再進—步方面，，,感染，，與 ”細菌感染”術語可指因以所造成之細菌感染。 於方面，感染"與"細菌感染"術語可指因痨疾，志f戌磨 所以成之細菌感染。於另一方面，，，感染"與"細菌感染"術 語可指因金資β磨身硪磨所造成之細菌感染。於又另一方 面，’’感染”與”細菌感染”術語可指因表犮球磨所造成 之細囷感染。於又再另一方面，，，感染，，與，，細菌感染，，術語 可指因溶▲衮奢球磨所造成之細菌感染。於進一步方面， ’’感染’’與”細菌感染”術語可指因激堃昜身破磨所造成之 細菌感染。於又進一步方面，”感染"與”細菌感染，，術語可 指因房立磨#球磨所造成之細菌感染。於又再進一步方面， 感&與細ii感染術語可指因及所 造成之細菌感染。於一方面，”感染”與"細菌感染，，術語可 才曰因無爲趙破琢所造成之細菌感染。於另一方面，π感染” 與"細菌感染”術語可指因芡變麥鏈硪磨所造成之細菌感 染。於又另一方面，”感染，，與，，細菌感染，，術語可指因厣芡 鏈破磨所造成之細菌感染。於又再另一方面，，，感染，，與 127286 -51 - 200831517 ’，細菌感染”術語可指因癬眾鐽磺磨所造成之細菌感染。 於一方面’"感染”與"細菌感染，，術語可指因產農專虑磨 邊之細菌所造成之細菌感染。於另一方面，”感染，，與”細菌 感染π術語可指因不鳶禅磨肩之細菌所造成之細菌感染。於 又另一方面，”感染"與"細菌感染"術語可指因穿疱斧磨簷 之細®所造成之細菌感染。於又再另一方面，”感染”與 ’’細菌感染”術語可指因凝##肩之細菌所造成之細菌感 _ 杂。於進一步方面，”感染”與"細菌感染"術語可指因濘# #戌爾邊之細菌所造成之細菌感染。於又進一步方面， 感^與細囷感染術语可指因万办η·α之細菌所造成 之細菌感染。於又再進一步方面，”感染”與”細菌感染，，術 語可指因衣及藶邊之細菌所造成之細菌感染。於一方面， "感染’’與’’細菌感染，，術語可指因#濛鑀細#屬之細菌所 造成之細菌感染。於另一方面，"感染”與"細菌感染"術語 可才曰因禮戽屬之細麵所造成之細菌感染。於又另一方面， _ ’’感染"與"細菌感染"術語可指因廣斧磨詹之細菌所造成 之細菌感染。於又再另一方面，”感染，，與，，細菌感染，，術語 可才曰因I球磨邊之細菌所造成之細菌感染。於進一步方 面’感染’’與’’細鼬感染"術語可指因赛;產屬之細菌所 造成之細菌感染。於又進一步方面，，，感染”與，，細菌感染” 術浯可指因斧#磨肩之細菌所造成之細菌感染。於又再進 一步方面，"感染”與”細菌感染”術語可指因禮#磨屬之細 菌所造成之細菌感染。於一方面，"感染"與”細菌感染”術 语可指因营血#磨肩之細菌所造成之細菌感染。於一方面， 127286 -52· 200831517 感木/、細菌感染"術語可指因克#伯戌磨肩之細菌所 二成=細囷感染。於另一方面，"感染"與"細菌感染，，術語 可扣口歹冷拉磨屬之細菌所造成之細菌感染。於又另一 方面感木與”細菌感染，，術語玎指因抑寿得戌磨屬之細 =斤l成之細菌感染。於又再另一方面，"感染”與，，細菌感 木術阳可扣因摩猶代磨屬之細菌所造成之細菌感染。於進 乂方面，感染"與"細菌感染"術語可指因莫拉武磨屬之 細：所造成之細菌感染。於又進一步方面，"感染"與"細菌 感染”術語可指因丧居禮屬之細菌所造成之細菌感染。於又 再進V方面，感染，，與”細菌感染”術語可指因奈瑟戌硪 囷屬、菌所這成之細菌感染。於一方面，，，感染"與"細菌 感染”術語可指gj叙細菌所造成之細菌感染。於 另方面，感染”與"細菌感染”術語可指因漭允硪磨肩之 、、、田菌所k成之細菌感染。於又另〆方面，”感染"與"細菌感 染’’術語可指m趣㈣叙細菌所造成之細菌感染。於 又再另一方面，”感染"與"細菌感染"術語可指因奢弟提拉 磨之細菌所造成之細菌感染。於進一步方面，”感染，，與 ’’細菌感染”術語可指因變彤磨簷之細菌所造成之細菌减 染。於又進一步方面，”感染"與"細菌感染”術語可指=銨 辠虑苈肩之細菌所造成之細菌感染。於又另_方面二感^ f’與’’細菌感染"術語可指因汐尸7#磨肩之細菌所造成1細 菌感染。於又再進一步方面，"感染”與”細菌感染"術語可 指因汐蒙式磨屬之細菌所造成之細菌感染。於一方面二 ”感染”與”細菌感染”術語可指因志貪武磨屬之細菌所造 127286 •53- 200831517 成之細菌感染。於又另一方面，” n n Q木興細_感染”術語 可'因_•象細菌所造成之細菌感染。於另一方 面’感染•’與"細菌感染”術語可指因咖__之細菌 細菌感染。於又另—方面，"感染"與,，細菌感染" 知-可指因_•❹之細菌所造成之細菌感染。On the other hand, infection, 'and' bacterial infection, the term can refer to bacterial infection caused by blasphemy, further aspects, "infection" and "bacterial infection" can refer to the cause of (four) material W (four) Bacterial infection. In a further aspect, the term "infection" and "bacterial infection" may refer to a bacterial infection caused by sputum sputum, which may be caused by sputum sputum. In terms of further steps, infection, and "bacterial infection" may be used. Refers to the bacterial infection caused by the cause. In terms of infection, "and"bacterial infection" term can refer to bacterial infection caused by dysentery, and on the other hand, infection ""Bacterialinfection" terminology may refer to a bacterial infection caused by the thorns of the gold stalk. On the other hand, the terms 'infection' and 'bacterial infection' may refer to the fineness caused by the smashing of the ball. infection. In yet another aspect, the infection, and, bacterial infection, the term may refer to a bacterial infection caused by a sputum. In a further aspect, the terms 'infected' and "bacterial infection" may refer to a bacterial infection caused by a sharpening of the body. In a further aspect, "infection" and "bacterial infection," the term can refer to a bacterial infection caused by Fangli Mill # ball mill. In still further aspects, the term & and the term ii infection may refer to the bacterial infection caused by it. On the one hand, "infection" and "bacterial infection," the term can be caused by a bacterial infection caused by Zhao. On the other hand, the terms π infection and "bacterial infection" may refer to bacterial infections caused by tampering of the wheat chain. On the other hand, "infection, and,, bacterial infection, the term can refer to bacterial infection caused by smashing of the scorpion chain. On the other hand,,, infection, with 127286 -51 - 200831517 The term 'bacterial infection' can refer to a bacterial infection caused by sputum sulphur. On the one hand '"infection" and "bacterial infection, the term may refer to a bacterial infection caused by bacteria that are edging by the peasant. On the other hand, the term "infection," and "bacterial infection" may refer to Bacterial infection caused by bacteria that do not smash the shoulders. On the other hand, the term "infection" and "bacterial infection" can refer to a bacterial infection caused by the use of a fine ape. On the other hand, the terms "infection" and "bacterial infection" may refer to the bacterial sensation caused by the bacteria of the ## shoulder. In a further aspect, the "infection" and "bacterial infection" terms may Refers to the bacterial infection caused by the bacteria of ##戌尔边. In a further aspect, the terminology and the infection of the fine sputum may refer to the bacterial infection caused by the bacteria of η·α. "Infection" and "bacterial infection," the term can refer to a bacterial infection caused by bacteria in the clothing and the rim. In one aspect, "infect' and ' bacterial infection, the term may refer to a bacterial infection caused by a bacterium of the genus. On the other hand, "infection" and "bacterial infection" can only cause bacterial infections caused by fine-grained rituals. On the other hand, _ ''infection" and "bacterial infections "The term can refer to the bacterial infection caused by the bacteria of the wide axillary mill. On the other hand, "infection,, and,, bacterial infection, the term can be caused by the bacteria caused by the bacteria of the I ball." infection. Further in the 'infected' and ''inferior infections" terms may refer to the bacterial infection caused by the bacteria of the genus. In a further aspect, the infection "and, bacterial infection" can refer to a bacterial infection caused by the bacteria of the axe. In a further aspect, the terms "infection" and "bacterial infection" may refer to bacterial infections caused by bacteria of the genus. In one aspect, the term "infection" and "bacterial infection" may refer to营血# The bacterial infection caused by the bacteria of the shoulder. On the one hand, 127286 -52· 200831517 sensible wood / bacterial infections " terminology can refer to the bacteria of the gram 戌 戌 戌 = = = = = = = = = = = = = = = = =. On the other hand, "infection" and "bacterial infection, the term can be used to buckle the bacteria caused by the cold-grinding bacteria. On the other hand, the sense of wood and "bacterial infection," the term refers to Because of the suppression of life, it is the fineness of the genus. On the other hand, "infection" and, bacterial sensation can be deducted by the bacterial infection caused by the bacteria of the genus Jurassic. In the case of 乂, infection " &"bacterialinfection" The term may refer to the bacterial infection caused by the genus Moura mulberry. In a further aspect, the term "infection" and "bacterial infection" may refer to a bacterial infection caused by bacteria of the genus Fungus. In terms of re-entering V, infection, and the term "bacterial infection" may refer to bacterial infections caused by Neisseria genus and bacteria. In one aspect, the term "infection" and "bacterial infection" may refer to a bacterial infection caused by bacteria. In other respects, the term "infection" and "bacterial infection" may refer to In addition, the "infection" & "bacterial infection" term can refer to the bacterial infection caused by bacteria. On the other hand, the term "infection" and "bacterial infection" can refer to a bacterial infection caused by a bacterium of the genus Tira Mill. In a further aspect, the term "infection," and "bacterial infection" It can refer to the bacterial infection caused by the bacteria that have been honed. In a further aspect, the term "infection" and "bacterial infection" can refer to the bacterial infection caused by the bacteria of the ammonium. Another _ aspect of the second sense ^ f 'and ''bacterial infections' term can refer to a bacterial infection caused by the bacteria of the body 7# grinding shoulder. In a further aspect, "infection" and "bacterial infection" terms It may refer to a bacterial infection caused by a genus of the genus Mongolian genus. On the one hand, the term "infection" and "bacterial infection" may refer to bacterial infections caused by bacteria belonging to the genus genus genus 127286 • 53- 200831517 On the other hand, the term "nn Q 木兴细_感染" can be caused by bacterial infections caused by bacteria. On the other hand, the term 'infection•' and "bacterial infections can refer to _ bacterial bacterial infection. In another aspect, "infection" and, bacterial infections " know- may refer to bacterial infections caused by bacteria.

於方面，"感染"與"細菌感染"術語可指婦科感染。於 另方面，"感染"與，，細菌感染"術語可指呼吸道感染师）。 :又另方面，感染"與"細菌感染"術語可指性傳染疾 病。於又再另一方面，"感染"與"細菌感染"術語可指尿道 感染。於進-步方面’"感染"與"細菌感染”術語可指慢性 枝氣管炎之急性惡化(ACEB)。於又再進一步方面，"感染" 與細菌感染”術語可指急性中耳炎。於一方面，"感染"與 ”細菌感染"術語可指急性竇炎。於另-方面，"感染"盥、 "細菌感染"術語可指因抗藥性細菌所造成之感染。於又另 一方面感染"與"細g感染"術語可指導尿管相關敗叙 病於又再另方面，”感染"與”細菌感染"術語可指軟下 舟。於進-步方面’"感染”與"細菌感染”術語可指衣原體 屬於又進步方面，”感染"與”細菌感染"術語可指團體 後天肺炎(CAP)。於又再進一步方面，”感染"與"細菌感染" 術語可指併發性皮膚與皮膚結構感染。於-方面，”感半” 與"細菌感染”術語可指非併發性皮膚與皮膚結構感染。於 另方面感*與"細菌感染"術語可指心、内膜炎。於又 感木與細菌感染"術語可指發熱嗜中性白血 球減少症。於又再另—方面’"感染"與"細菌感染"術語可 127286 -54- 200831517 指淋菌子宮頸炎。於；隹 ^ 貝人於進-步方面，，，感染”與，，細菌感染”術 語可指淋菌尿道炎。於又進，面，”感染"與"細菌感染 "術語可指醫院後天肺炎（HAP)。於又另一方面，"感染，，與 "細菌感染"術語可指骨髓炎。於進一步方面，，，感染"； "細菌感染”術語可指敗血病。於又進一步方面，”感染Γ與 ”細菌感染”術語可指梅毒。 於進步方面，係提供一種醫藥組合物，其包含式①化 合物或其藥學上可接受之鹽，及至少一種藥學上可接受之 載劑、稀釋劑或賦形劑。 於又進一步方面，係提供一種醫藥組合物，其包含式（lc) 化合物或其藥學上可接受之鹽，及至少一種藥學上可接受 之載劑、稀釋劑或賦形劑。 於又再進一步方面，係提供一種醫藥組合物，其包含式 (Id)化合物或其藥學上可接受之鹽，及至少一種藥學上可接 受之載劑、稀釋劑或賦形劑。 於一方面’係提供一種醫藥組合物，其包含式（Ie)化合物 或其藥學上可接受之鹽，及至少一種藥學上可接受之載 劑、稀釋劑或賦形劑。 本發明之組合物可呈適合口服使用（例如作成片劑、錠 劑、硬或軟膠囊、水性或油性懸浮液、乳化液、可分散粉 末或顆粒、糖漿或酏劑）、局部使用（例如作成乳膏、軟膏、 凝膠或水性或油性溶液或懸浮液）、藉吸入投藥（例如作成 細分粉末或液體氣溶膠）、藉吹入投藥（例如作成細分粉末） 或非經腸投藥（例如作成無菌水性或油性溶液供靜脈内、皮 127286 -55- 200831517 下、肌内或肌内服藥，或作成栓劑供直腸服藥）形式。 本發明之組合物可藉由習用程序，使用此項技藝中所習 知之習用醫藥賦形劑獲得。因此，欲供口服使用之組合物 可含有例如一或多種著色、增甜、矯味及/或防腐劑。 供片劑配方用之適當藥學上可接受之賦形劑，包括例如 惰性稀釋劑，譬如乳糖、碳酸鈉、磷酸鈣或碳酸鈣，粒化 與崩解劑，譬如玉米澱粉或海藻酸；黏合劑，譬如澱粉； 潤滑劑，譬如硬脂酸鎂、硬脂酸或滑石；防腐劑，譬如對_ 羥基苯甲酸乙酯或丙酯；及抗氧化劑，譬如抗壞血酸。片 劑配方可未經塗覆或經塗覆，無論是為改變其崩解作用， 及活性成份在胃腸道中之隨後吸收，或為改良其安定性及/ 或外觀，在任一情況中，係使用此項技藝中所習知之習用 塗覆劑與程序。 供口服使用之組合物可呈硬明膠膠囊形式，其中活性成 份係與惰性固體稀釋劑混合，例如碳酸鈣、磷酸鈣或高嶺 土，或作成軟明膠膠囊，其中活性成份係與水或油譬如花 生油、液態石蠟或橄欖油混合。 含水懸淨液通常含有呈微細粉末形式或呈毫微或微粉化 粒子形式之活性成份，伴隨著一或多種懸浮劑，譬如羧甲 基纖維素鈉、甲基纖維素、羥丙甲基纖維素、海藻酸鈉、 聚乙烯基四氫t各酉同、西黃蓍樹膠及***膠；分散或潤 濕劑，譬如卵磷脂，或氧化烯與脂肪酸類之縮合產物（例如 聚氧化乙烯硬脂酸酯），或環氧乙燒與長鍵脂族醇之縮合產 物，例如十七氧化乙烯鯨蠟醇，或環氧乙烷與衍生自脂肪 127286 -56· 200831517 酸類與己糖醇之部份酯類之縮合產物，譬如聚氧化乙烯單 油酸花楸醇酯，或環氧乙烷與長鏈脂族醇之縮合產物，例 如十七氧化乙烯鯨蠟醇，或環氧乙烷與衍生自脂肪酸類與 己糖醇之部份酯類之縮合產物，譬如聚氧化乙烯單油酸花 楸醇S曰或環氧乙烧與衍生自脂肪酸類與己糖醇酐類之部 份酯類之縮合產物，例如聚乙烯單油酸花楸聚糖酯。此含 水懸浮液亦可含有一或多種防腐劑，譬如對-羥基苯甲酸乙 酯或丙酯；抗氧化劑，譬如抗壞血酸；著色劑；矯味劑； 及/或增甜劑，譬如蔗糖、糖精或天冬醯***酸甲酯。 油性懸浮液可經由使活性成份懸浮在植物油，譬如花生 油、橄欖油、芝麻油或椰子油，或在礦油譬如液態石蠟中 進行調配。油性懸浮液亦可含有增稠劑，譬如蜂蠟、硬石 蠟或鯨蠟醇。可添加增甜劑，譬如上文所陳述者，與矯味 劑，以提供美味口服製劑。此等組合物可藉由添加抗氧化 劑譬如抗壞血酸保存著。 適用於藉由添加水以製備含水懸浮液之可分散粉末與顆 粒通吊含有活性成份，伴隨著分散或潤濕劑、懸浮劑及 一或多種防腐劑。適當分散或潤濕劑及懸浮劑之實例為已 於上文提及者。其他賦形劑，譬如增肖、續味及著色劑， 亦可存在。 本發明之醫藥組合物亦可呈油在水中型乳化液之形式。 油相^為植物油’譬如橄揽油或花生油，或礦油，例如液 態石壤，或任何此等之混合物。適當乳化劑可為例如天然 成之膠貝，譬如***膠或西黃蓍樹膠，天然生成之磷 127286 -57- 200831517 月曰，譬如大丑、卵磷脂、衍生自脂肪酸類與己糖醇酐類之 曰頟或邛伤類（例如單油酸花楸聚糖酯）及該部份酯類與 %乳乙烷之縮合產物，譬如聚氧化乙烯單油酸花楸聚糖 酯。乳化液亦可含有增甜、矯味及防腐劑。 糖水/、醜劑可以增甜劑調配，譬如甘油、丙二醇、花楸 醇天；I本丙胺酸甲酯或蔗糖，且亦可含有和潤劑、防 腐劑、矯味及/或著色劑。 _ 面為、且δ物亦可呈無囷可注射水性或油性懸浮液形式， 其可根據已知程序，使用一或多種已於上文提及之適當分 散或潤濕劑與懸浮劑調配。無菌可注射製劑亦可為無菌可 注射溶液或懸浮液，在無毒性非經腸上可接受之稀釋劑或 溶劑中，例如在1，3-丁二醇中之溶液。 供吸入投藥用之組合物可呈習用加壓氣溶膠形式，經安 排以分配活性成份，無論是作成含有細分固體或液滴之氣 溶膠。可使用習用氣溶膠推進劑，譬如揮發性氟化烴類或 _烴類，且氣溶膠裝置可合宜地經安排，以分配經計量之活 性成份量。 / 關於配方之進一步資訊，讀者可參閱綜合醫藥化學第》 卷第25·2章（Corwin Hansch;編委會***），Perg_n出版社携〇。 與一或多種賦形劑合併以產生單一劑型之活性成份量， 將必須依待治療之宿主及特定投藥途徑而改變。例如，欲 供口服投予人類之配方，通常將含有例如〇·5毫克至4克活 性劑，與適當且合宜量之賦形劑摻配，該賦形劑可從全部 組合物重量之約5改變至約98%。劑量單位形式通常含有約 127286 •58- 200831517 1宅克至約500毫克活性成份。關於投藥途徑與劑量服用法 之進一步資訊，讀者可參閱綜合醫藥化學第5卷第25.3章 (Corwin Hansch ;編委會***），Pergam〇n 出版社 199〇。 除了本發明化合物之外，本發明之醫藥組合物亦可含有 或共同投予（同時、相繼或個別地）一或多種已知藥物，選 自之’、他床上可用種類之抗細菌劑（例如大環内酯類、4 啉酮類、尽内醯胺類或胺基糠苷類）及/或其他抗傳染劑（例 籲如抗真菌三哇或兩性黴素）。此等可包括竣罕青徽素類 (carbapenems) ’例如美若苄青黴素（mer〇penem)或衣米苄青黴素 (imipenem)，以加寬治療有效性。本發明化合物亦可含有或 共同投予殺細g /增加滲透性蛋白f (Βρι)產物或射流泵送 抑制劑，以改良抵抗革蘭陰性細菌及對於抗微生物劑具抗 藥性之細菌之活性。 ” 如上述，治療或預防治療特定疾病狀態所需要之劑量大 小’係必須依待治療之宿主、投藥途徑及被治療疾病之嚴 鲁重性而改變。較佳係採用㈣毫克/公斤r色圍内之日服劑量。 因此，最適宜劑量可由正在治療任何特定病患之執業醫師 決定。 式(I)化合物及其藥學上可接受之鹽，除了其在治療醫藥 =之用途以外，亦可在活體外與活體内試驗系統之發展與 ‘準化中作為藥理學工具使用，以評估在實驗室動物中之 抗細菌作用，譬如猶、狗、兔子、猴子、大白鼠及老鼠， 作為搜尋新穎治療劑之一部份。 在本發明之任何上文所提及之醫藥組合物、製程、方法、 127286 -59- 200831517 用途、藥劑及製造特徵中，本文中所述本發明化合物之任 何替代具體實施例亦適用。， 方法 若不能市購取得，則供此等程序用之必須起始物質，譬 如本文中所述者，可藉由一些程序製成，其係選自標準有 機化學技術，類似合成已知而於結構上類似化合物之技術， 或類似所述程序或實例中所述程序之技術。In contrast, "infection" and "bacterial infection" terms can refer to gynecological infections. In another aspect, "infection" and, bacterial infection" terminology can refer to a respiratory infectionist. In yet another aspect, the infection "and"bacterial infection" term can refer to a sexually transmitted disease. On the other hand, "infection" and "bacterial infection" terms may refer to urinary tract infections. In terms of 'steps', 'infections' and 'bacterial infections' can refer to acute exacerbations of chronic bronchitis (ACEB). In yet further, the term "infection" and "bacterial infection" can refer to acute Otitis media. On the one hand, "infection" and "bacterial infection" terms may refer to acute sinusitis. In another aspect, "infection"盥, "bacterial infection" terminology may be caused by drug-resistant bacteria Infection, on the other hand, infection "and"fine g infection" terminology can guide urinary catheter-related failures in another aspect, "infection" and "bacterial infection" can refer to soft boating. In terms of 'steps' and 'infections' and 'bacterial infections', it is meant that Chlamydia is a progressive aspect, and "infections" and "bacterial infections" can refer to group acquired pneumonia (CAP). "Infection" and "bacterial infection" terms may refer to concomitant skin and skin structure infections. On the -, "sense half" and "bacterial infection" terms can refer to non-concurrent skin and skin structure infections. In other senses * and "bacterial infections" terms can refer to heart, endometritis. The term "wood and bacterial infection" can refer to fever neutropenia. In addition, the '"infection" and "bacterial infection" term can be 127286 -54- 200831517 refers to gonococcal cervicitis. ;隹^Bei people in the step-by-step,,, infection, and, bacterial infections, the term can refer to gonococcal urethritis. In addition, face, "infection" and "bacterial infection" terms can refer to hospitals Pneumonia (HAP). On the other hand, "infection,, and "bacterial infection" terms can refer to osteomyelitis. In a further aspect, the term "infection" can refer to septicemia. In still further aspects, the term "infected sputum" and "bacterial infection" may refer to syphilis. In an advanced aspect, a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient is provided. In still a further aspect, there is provided a pharmaceutical composition comprising a compound of formula (lc), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient. In still a further aspect, there is provided a pharmaceutical composition comprising a compound of formula (Id), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient. In one aspect, the invention provides a pharmaceutical composition comprising a compound of formula (Ie), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient. The compositions of the present invention may be suitably used orally (for example, as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example, Creams, ointments, gels or aqueous or oily solutions or suspensions), by inhalation (for example as a finely divided powder or liquid aerosol), by insufflation (for example as a finely divided powder) or parenterally (for example as sterile) The aqueous or oily solution is administered intravenously, 127286-55-200831517, intramuscularly or intramuscularly, or as a suppository for rectal administration. The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients as are known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservatives. Suitable pharmaceutically acceptable excipients for tablet formulation, including, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulation and disintegrating agents, such as corn starch or alginic acid; binders For example, starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl p-hydroxybenzoate; and antioxidants such as ascorbic acid. The tablet formulation may be uncoated or coated, whether to alter its disintegration, and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve its stability and/or appearance, in either case, Conventional coating agents and procedures are known in the art. The composition for oral use can be in the form of a hard gelatin capsule, wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as a soft gelatin capsule, wherein the active ingredient is water or oil such as peanut oil, Mix with liquid paraffin or olive oil. The aqueous suspension usually contains the active ingredient in the form of a fine powder or in the form of nano or micronized particles, accompanied by one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose. , sodium alginate, polyvinyl tetrahydrogen t, the gums and gum arabic; dispersing or wetting agents, such as lecithin, or condensation products of alkylene oxides with fatty acids (such as polyethylene oxide stearic acid) Ester), or a condensation product of ethylene bromide with a long-bond aliphatic alcohol, such as cetyl vinyl ether cetyl alcohol, or an ester of ethylene oxide with a derivative derived from fat 127286 -56·200831517 acid and hexitol a condensation product of the class, such as a polyoxyethylene monooleate, or a condensation product of ethylene oxide with a long-chain aliphatic alcohol, such as cetyl vinyl ether cetyl alcohol, or an ethylene oxide derived from a fatty acid a condensation product of a partial ester with a hexitol such as polyoxyethylene monooleate S- or a mixture of Ethylene Ethylene and a partial ester derived from a fatty acid and a hexitol anhydride For example, polyethylene monooleate ester. The aqueous suspension may also contain one or more preservatives, for example ethyl or propyl p-hydroxybenzoate; an antioxidant such as ascorbic acid; a coloring agent; a flavoring agent; and/or a sweetening agent such as sucrose, saccharin or day. Methyl phenylalanine. The oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may also contain a thickening agent, such as beeswax, hard wax or cetyl alcohol. Sweetening agents, such as those set forth above, with flavoring agents may be added to provide a savoury oral preparation. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for use in the preparation of aqueous suspensions by the addition of water contain the active ingredient with dispersion or wetting agents, suspending agents and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those already mentioned above. Other excipients, such as scent, scent and coloring agents, may also be present. The pharmaceutical composition of the present invention may also be in the form of an oil in the form of an aqueous emulsion. The oil phase is a vegetable oil such as olive oil or peanut oil, or mineral oil, such as liquid stone soil, or a mixture of any of these. Suitable emulsifiers may be, for example, natural gelatin such as gum arabic or scutellaria gum, naturally occurring phosphorus 127286 -57 - 200831517 曰, such as ugly, lecithin, derived from fatty acids and hexitols The product of a sputum or a sputum (for example, a monoolein monooleate) and a condensation product of the partial ester with the % lactobion, such as a polyoxyethylene monooleate. The emulsion may also contain sweetening, flavoring and preservatives. The syrup/widiness agent may be formulated with a sweetener such as glycerin, propylene glycol or saponin; I methyl propylamine or sucrose, and may also contain a emollient, a preservative, a flavor and/or a coloring agent. The surface may be in the form of a sputum-injectable aqueous or oily suspension which may be formulated according to known procedures using one or more suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. The compositions for administration by inhalation may be in the form of conventional pressurized aerosols which are arranged to dispense the active ingredient, either as an aerosol containing finely divided solids or liquid droplets. Conventional aerosol propellants, such as volatile fluorinated hydrocarbons or hydrocarbons, may be used, and the aerosol device may conveniently be arranged to dispense the metered amount of active ingredient. / For further information on the formula, the reader can refer to Chapter 25 of the Comprehensive Medical Chemistry (Corwin Hansch; Chairman of the Editorial Board), and Perg_n Press. The amount of active ingredient combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host to be treated and the particular route of administration. For example, a formulation intended for oral administration to humans will typically contain, for example, from 5 mg to 4 g of active agent, in admixture with suitable and suitable amounts of excipients, which may be from about 5 parts by weight of the total composition. Change to about 98%. Dosage unit forms will generally contain from about 127286 • 58 to 200831517 1 gram to about 500 mg of active ingredient. For further information on the route of administration and dosage regimen, the reader is referred to Chapter 25.3 of the Journal of Integrated Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergam〇n Press 199〇. In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may also contain or co-administer (simultaneously, sequentially or individually) one or more known drugs, selected from the group's available antibacterial agents (eg, Macrolides, 4-linoleones, linoleamides or aminoglycosides) and/or other anti-infective agents (such as antifungal tri-wound or amphotericin). These may include carbapenems such as mer〇penem or imipenem to broaden the therapeutic effectiveness. The compounds of the present invention may also contain or co-administer a finely divided g/increased permeability protein f (Βρι) product or a jet pumping inhibitor to improve the activity against Gram-negative bacteria and bacteria resistant to antimicrobial agents. As described above, the dose size required to treat or prevent a particular disease state must be changed depending on the host to be treated, the route of administration, and the severity of the disease being treated. Preferably, (four) mg/kg r color is used. The daily dosage will therefore be determined by the practitioner who is treating any particular patient. The compound of formula (I) and its pharmaceutically acceptable salts, in addition to its use in therapeutic medicine, may also Development of in vitro and in vivo test systems and use as a pharmacological tool in quasi-chemotherapy to assess antibacterial effects in laboratory animals such as Jewish, Dog, Rabbit, Monkey, Rat and Mouse, as a novel treatment for search Any of the alternative embodiments of the compounds of the invention described herein in any of the above-mentioned pharmaceutical compositions, processes, methods, 127286-59-200831517 uses, agents and manufacturing characteristics of the invention The example also applies. If the method is not commercially available, the necessary starting materials for such procedures, such as those described herein, may be Is made, which is selected from standard organic chemical techniques, techniques similar to the synthesis of known similarly to the structure of the compound, or a similar technique or the application instance of the program.

應注意的是，關於如本文中所述合成方法之許多起始物 質係為市購可得及/或廣泛地報告於科學文獻中，或可使用 科學文獻中所報告方法之修改，t自市購可得化合物。讀 乂 ί考而荨有機化學弟5版，由March與Michael Smith著’由j〇hn Wiley & Sons於2〇〇1年出版，關於反應條件 與試劑之一般指引。 亦應明瞭的是，在—些本文中所提及之反應中，可能必 須/想要保護化合物中之任何敏感性基團。其中保護係為必 須或想要之情況，係為熟諳此藝者所已知，其係為此種保 羞之適田方法。習用保護基可根據標準實務使用（關於說 明，可參閱T.W.如此，有機合成之保護基，由John Wiley & Sons 出版，1991)。 關於經基之適當保護基眚 貝例係為例如酸基，例如烧隨It should be noted that many of the starting materials for the synthetic methods as described herein are commercially available and/or widely reported in the scientific literature, or may be modified using methods reported in the scientific literature, t. Available compounds are available. Read 乂 ί 考 荨 Organic Chemistry 5th Edition, by March and Michael Smith' by J〇hn Wiley & Sons, published in 2002, general guidelines on reaction conditions and reagents. It should also be understood that in some of the reactions mentioned herein, it may be necessary/want to protect any sensitive groups in the compound. Where the protection is necessary or desirable, it is known to those skilled in the art and is a method of such shame. Conventional protecting groups can be used according to standard practice (for a description, see T.W. Thus, Protective Groups for Organic Synthesis, published by John Wiley & Sons, 1991). With regard to the appropriate protecting group of the thiol group, for example, an acid group, such as burning

基’譬如乙醢基，芳其，A 一 基例如本甲醯基，矽烷基，譬如 三甲基矽烷基，或芳 甲基’例如苄基。關於上文保護基 之去除保護條件，將必須隨 通考保瘦基之選擇而改變。因此， 例如醯基，譬如烷醯基或芳 尺方I基，可例如以適當鹼，譬如 127286 200831517 驗金屬氫氧化物，例如氫氧化鐘或納，藉由水解作用而被 移除。，者，石夕烧基，譬如三甲基石夕燒基，可例如藉由氣 化物或藉由含水酸而被移除，·或芳基基，链 例如於觸媒存在下，譬一藉由氮化作：移下除基。 關於胺基之適當保護基係為例如醯基，例如院醯基，譬 如乙^基，院氧羰基，例如甲氧幾基、乙氧幾基或第三_ 丁，幾基，芳基甲氧幾基，例如爷氧羰基，或芳醯基，例 鲁如苯甲ι基。關於上文保護基之去除保護條件必須隨著保 f基之選擇而改變。因此，例如醯基，譬如㈣基或烧氧 μ基或芳醯基，可例如以適當驗，譬如驗金屬氯氧化物， 例如虱氧化鋰或鈉，藉由水解作用移除。或者，醯基，譬 如第二-丁氧羰基，可例如經由以適當酸譬如鹽酸、硫酸、 磷酸或三氟醋酸處理而被移除，及彡基甲氧幾基，譬如芊 氧幾基’可例如於觸料如Ιε/碳上，藉由氫化作用，或經 由以路易士酸例如參(三氟醋酸)硼處理而被移除。關於一級 _胺基之適當替代保護基係為例如酉太酿基，其可經由以烧基 胺’例如二甲胺基丙胺或2•經乙胺，或以月井處理而被移除。 關於胺之另-種適當保護基係為例如環狀謎，譬如四氮咬 南八可、纟工由以適當酸譬如三氟醋酸處理而被移除。 保-蔓基可在合成中之任何合宜階段下使用化學技藝上 習知之習用技術移除，或其可在稍後反應步驟或處理期間 被移除。 於方面，本發明係提供一種製備式（I)或式化合物或 其樂學上可接受趟夕士 又夏之方法，該方法包括使式（ΑΑ)化合物： 127286 -61 - 200831517The base ', for example, an ethyl group, an a, a group thereof, for example, a benzyl group, a decyl group, for example, a trimethyl decyl group, or an arylmethyl group such as a benzyl group. With regard to the removal protection conditions of the above protecting groups, it will have to be changed with the choice of the test basis. Thus, for example, a fluorenyl group, such as an alkanoyl group or an aryl group I group, can be removed by hydrolysis, for example, with a suitable base such as 127286 200831517, a metal hydroxide such as a hydroxide clock or sodium. , such as trimethyl sulphide, such as trimethyl sulphide, may be removed, for example, by vaporization or by aqueous acid, or aryl groups, such as in the presence of a catalyst, by nitrogen Turn into: remove the base. Suitable protecting groups for the amine group are, for example, anthracenyl groups, such as, for example, a fluorenyl group, such as an ethyl group, a oxycarbonyl group, such as a methoxy group, an ethoxy group or a third group, a aryl group, an aryl group. A few groups, such as an oxycarbonyl group, or an aryl fluorenyl group, such as a benzyl group. The removal protection conditions for the above protecting groups must be changed with the choice of the protecting group. Thus, for example, a sulfhydryl group, such as a (iv) group or a oxy-oxygen group or an aryl group, can be removed, for example, by hydrolysis, such as a metal oxychloride, such as lithium ruthenate or sodium. Alternatively, a mercapto group, such as a second-butoxycarbonyl group, can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid, and a mercaptomethoxy group, such as an anthracene group. For example, on a contact such as Ιε/carbon, it is removed by hydrogenation or by treatment with a Lewis acid such as fluoro(trifluoroacetate) boron. A suitable alternative protecting group for the primary amide group is, for example, anthraquinone, which can be removed via treatment with an alkylamine such as dimethylaminopropylamine or 2. ethylamine or with a monthly well. Another suitable protecting group for the amine is, for example, a cyclical mystery, such as a four-nitrogen bite, which is removed by treatment with a suitable acid such as trifluoroacetic acid. The sulphate can be removed at any convenient stage in the synthesis using conventional techniques known in the art, or it can be removed at a later reaction step or treatment. In one aspect, the present invention provides a process for the preparation of a compound of formula (I) or a formula or a method thereof which is acceptable for the day and summer, comprising the compound of formula (ΑΑ): 127286 -61 - 200831517

ReRe

與式（AB)化合物： 式(AB)Compound with formula (AB): formula (AB)

於適當還原劑存在下反應， 然後，若必要則： 0使式（1)化合物轉化成另一種式（I)化合物； 移除任何保護基；及/或 m)形成藥學上可接受之鹽。 式（AA)化合物可與式（AB)化合物於典型還原胺化條件下 反應。此反應之第一個步驟，亞胺形成，典型上係於脫水 劑譬如分子_S3A)存在下進行，惟反應—般係未使用脫 進行適當浴劑為曱醇或甲醇/氯仿混合物。亞胺中間 物典型上未每單離；反而是，還原劑通常係於亞胺形成後 被添=反應混合物中。關於此方法之第二個（還原）步驟 k田還原刈包括硼還原劑，譬如NaB(〇AchH或n沾玛〇 於另6、方面，本發明係提供一種製備式（I)或（II)化合物， 其中R為F ’或其藥學上可接受鹽之方法，該方法包括使 式（AC)化合物： 127286 -62· 200831517The reaction is carried out in the presence of a suitable reducing agent, and then, if necessary: 0 to convert a compound of formula (1) to another compound of formula (I); remove any protecting groups; and/or m) form a pharmaceutically acceptable salt. The compound of formula (AA) can be reacted with a compound of formula (AB) under typical reductive amination conditions. The first step of the reaction, the formation of the imine, typically in the presence of a dehydrating agent such as the molecule _S3A, is carried out, except that the reaction is generally carried out without a suitable bath as a mixture of methanol or methanol/chloroform. The imine intermediate is typically not per detached; rather, the reducing agent is typically added to the reaction mixture after the imine is formed. Regarding the second (reduction) step of the method, the reduction of the ruthenium includes a boron reducing agent, such as NaB (〇AchH or n 〇玛〇 in another aspect, the invention provides a preparation of the formula (I) or (II) A compound, wherein R is F' or a pharmaceutically acceptable salt thereof, the process comprising the compound of formula (AC): 127286 - 62 · 200831517

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

式(AB) φ 於適當還原劑存在下反應， 然後，若必要則： 0 使式（I)或（II)化合物轉化成另一種式①或（II)化合 物； U) 移除任何保護基；及/或 Hi) 形成藥學上可接受之鹽。 關於式（AC)化合物與式（AB)化合物反應之反應條件，係 如上文關於式（AA)化合物與式（AB)化合物之反應所述。 • 於又另一方面，本發明係提供-種製備式(I)或(II)化合物 或其藥學上可接受鹽之方 万法，該方法包括使式（BI)化合物： R8Formula (AB) φ is reacted in the presence of a suitable reducing agent, and then, if necessary: 0 to convert a compound of formula (I) or (II) to another compound of formula 1 or (II); U) removing any protecting groups; And/or Hi) form a pharmaceutically acceptable salt. The reaction conditions for the reaction of the compound of the formula (AC) with the compound of the formula (AB) are as described above for the reaction of the compound of the formula (AA) with the compound of the formula (AB). • In yet another aspect, the invention provides a process for the preparation of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula (BI): R8

與適當還原劑反應， 然後，若必要則： 127286 200831517 i)使式（I)或⑼化合物轉化成另一種式（ι)或⑼化人 物； 〇 ϋ) 移除任何保護基；及/或 &) 形成藥學上可接受之鹽。 關於式（BI)化合物之還原作用之適當還原劑包括爛還原 劑，譬如NaB(OAc)3H或NaB^CN。適當溶劑A帀龄斗讲’、 ⑴匈Τ醇或甲醇/ 氣仿混合物。 式（ΑΑ)化合物可按圖式1中所示製成。 囷式1Reacting with a suitable reducing agent, then, if necessary: 127286 200831517 i) converting a compound of formula (I) or (9) to another formula (1) or (9) character; 〇ϋ) removing any protecting groups; and/or &;) Form a pharmaceutically acceptable salt. Suitable reducing agents for the reduction of the compound of formula (BI) include rotten reducing agents such as NaB(OAc)3H or NaB^CN. Appropriate solvent A 帀 斗 斗 ', (1) Hungarian alcohol or methanol / gas imitation mixture. The compound of the formula (ΑΑ) can be produced as shown in Scheme 1.囷式1

去除保護 R6Removal protection R6

式(Μ) 式（AD)化合物與式（ΑΕ)化合物於鹼譬如氫化鈉存在下之 反應，可用以獲得式（AF)化合物。去除保護係提供式（ΑΑ) 化合物。適當脫離基包括譬如甲烷磺酸鹽、氯基、溴基及 碘基之脫離基。適當保護基包括烷氧羰基，譬如第三·丁氧 羰基，其可使用酸類譬如HC1去除保護。 127286 -64- 200831517 可用以製備式（AA)化合物之另一種方法係示於圖式2中。 圖式2A reaction of a compound of the formula (AD) with a compound of the formula (ΑΕ) in the presence of a base such as sodium hydride can be used to obtain a compound of the formula (AF). Removal of the protection system provides a compound of the formula (ΑΑ). Suitable exfoliating groups include exfoliating groups such as methanesulfonate, chloro, bromo and iodo. Suitable protecting groups include alkoxycarbonyl groups, such as a third butoxycarbonyl group, which can be removed using an acid such as HCl. Another method which can be used to prepare the compound of formula (AA) is shown in Scheme 2. Figure 2

ReRe

^ (AG) 去除保護^ (AG) removal protection

If R6If R6

式（AD)化合物與式（AG)化合物於Mitsunobu條件下之反應， 可用以獲得式（AF)化合物。去除保護係提供式（AA)化合物。 適當保護基包括烷氧羰基，譬如第三-丁氧羰基，其可使用 酸類譬如HC1移除。 圖式3係描繪關於製備式（AA)化合物之另一種方法。 127286 65- 200831517 圖式3The reaction of a compound of the formula (AD) with a compound of the formula (AG) under Mitsunobu conditions can be used to obtain a compound of the formula (AF). Removal of the protecting system provides a compound of formula (AA). Suitable protecting groups include alkoxycarbonyl groups, such as a third-butoxycarbonyl group, which can be removed using an acid such as HCl. Scheme 3 depicts another method for preparing a compound of formula (AA). 127286 65- 200831517 Figure 3

PG 式（Al) 還原劑PG type (Al) reducing agent

ReRe

去除保護Removal protection

ReRe

式（AF) 式（AD)化合物可與鹼譬如NaH反應，接著與溴·或氯乙醇 或 >臭-或氣乙路’或與其經保護之衍生物反應（在醇衍生物 之情況下，接著去除保護與氧化作用），提供式（AH)化合物。 式（AH)化合物可與式（AI)化合物於典型還原胺化條件下反 φ 應。如上文關於式（AA)化合物與式（AB)化合物之反應所述， 亞胺形成典型上係於脫水劑譬如分子篩（MS 3人）存在下進 行，惟反應一般還是未使用脫水劑進行。適當溶劑為四氫 呋喃、二氣甲烷或氣仿/甲醇混合物。亞胺中間物典型上未 經單離；反而是，還原劑通常係於亞胺形成後被添加至反 應混合物中。關於反應之第二個步驟（還原作用）之適當還 原劑包括硼還原劑，譬如NaB(OAc)3H或NaBH3CN。式（AF)化 合物之去除保護係提供式（AA)化合物。關於在式（AI)化合物 之六氫吡啶環上胺基取代基之適當保護基，包括烷氧羰 127286 -66- 200831517 基，譬如第三-丁氧羰基，其可使用酸類譬如HC1移除；與 疊氮化物，其可無論是使用三苯膦（Staudinger反應）或藉由氫 化作用，以還原方式轉化成胺。 式（AL)化合物，其為其中脫離基為甲烷磺酸酯脫離基之 式（AE)化合物，可根據圖式4製成。 圖式4The compound of the formula (AF) can be reacted with a base such as NaH, followed by reaction with bromine or chlorohydrin or > odor or gas path or with a protected derivative thereof (in the case of an alcohol derivative, Subsequent removal of protection and oxidation) provides a compound of formula (AH). The compound of formula (AH) can be reacted with a compound of formula (AI) under typical reductive amination conditions. As described above with respect to the reaction of the compound of the formula (AA) with the compound of the formula (AB), the imine formation is typically carried out in the presence of a dehydrating agent such as a molecular sieve (MS 3 person), but the reaction is generally carried out without using a dehydrating agent. A suitable solvent is tetrahydrofuran, di-methane or a gas/methanol mixture. The imine intermediate is typically not isolated; instead, the reducing agent is typically added to the reaction mixture after the imine is formed. Suitable reducing agents for the second step of the reaction (reduction) include boron reducing agents such as NaB(OAc)3H or NaBH3CN. The removal protection of the compound of formula (AF) provides a compound of formula (AA). With respect to suitable protecting groups for the amine substituents on the hexahydropyridine ring of the compound of formula (AI), including alkoxycarbonyl 127286-66-200831517 groups, such as a third-butoxycarbonyl group, which may be removed using an acid such as HCl; With an azide, it can be converted to an amine in a reducing manner, whether using triphenylphosphine (Staudinger reaction) or by hydrogenation. A compound of the formula (AL) which is a compound of the formula (AE) wherein the leaving group is a methanesulfonate cleavage group can be produced according to the formula 4. Figure 4

式(AG) 式(AL) 式（AL)化合物可經由式（AI)化合物與溴基乙醇或其衍生 物，於鹼譬如三乙胺存在下之反應而製成，提供式（AG)化 合物。式（AG)化合物可與氣化曱烷磺醯，於鹼譬如三烷基 胺或其在樹脂上之經固定化變型存在下反應，提供式（AL) φ 化合物。式（AL)化合物係潛在不安定，且可以具有相應氯 化物（源自於氯化物在甲烷磺醯基上之攻擊）之混合物之一 部份存在，故必須在小心控制之條件下製備新的。 式（AO)化合物，其為式（AD)化合物，其中J為CH，可根 據圖式5製成。 127286 -67- 200831517Formula (AG) Formula (AG) Compounds of formula (AG) can be prepared by reacting a compound of formula (AI) with bromoethanol or a derivative thereof in the presence of a base such as triethylamine to provide a compound of formula (AG). The compound of the formula (AG) can be reacted with a gasified decanesulfonium sulfonate in the presence of an alkali hydrazine such as a trialkylamine or an immobilized modification thereof on a resin to provide a compound of the formula (AL) φ. The compound of formula (AL) is potentially unstable and may be present in part of a mixture of the corresponding chloride (derived from the attack of chloride on methanesulfonyl), so new conditions must be prepared under carefully controlled conditions. . A compound of the formula (AO) which is a compound of the formula (AD) wherein J is CH can be prepared according to Scheme 5. 127286 -67- 200831517

式(AM) 圖式5Formula (AM) Figure 5

式(AN) 綱 化：：式5中所示’式_化合物可製自市構可得之綱Formula (AN) Outline: The formula of the formula (Formula 5) can be obtained from the municipality.

° 其方式是與氯化桂皮醯，於適當鹼譬如2 6_二甲基 匕疋存在下反應，接著以三氯化銘進行環化作用。 以類似方式，氯化桂皮醯可被Ε_乙氧基氯化丙稀酿置換， 且：間物Ε-乙氧基丙烯醯基醯胺類之環化作用係以硫酸代 替二氯化鋁達成（Ε. Baston等人，歐洲醫藥化學期刊％ (2〇〇〇) 931)。經不對稱取代之苯胺通常會導致區域異構性喹啉 -2(1H)-酮衍生物，其可能難以藉層析分離，此係由於有限溶 解度所致。此種混合物可無論是藉由結晶化作用分離，或 可被轉化成其相應之2-氯峻琳衍生物（例如以***， 其可藉層析或經由結晶化作用分離，然後可以回流氫氯化 物酸水解回復成式（AO)化合物之單一區域異構物。 式（AO)化合物亦可根據圖式6製成。 127286 68· 200831517° The reaction is carried out with chlorinated cinnabarin in the presence of a suitable base such as 2 6-dimethyl hydrazine, followed by cyclization with trichlorin. In a similar manner, chlorinated cinnabarin can be replaced by Ε ethoxylated propylene chloride, and the cyclization of the hydrazine-ethoxy propylene decyl amide is achieved by replacing the aluminum chloride with sulfuric acid. (Ε. Baston et al., European Journal of Medicinal Chemistry (2〇〇〇) 931). Asymmetrically substituted anilines generally result in regioisomeric quinoline-2(1H)-one derivatives which may be difficult to separate by chromatography due to limited solubility. Such a mixture may be isolated by crystallization or may be converted to its corresponding 2-chlorojunlin derivative (for example, phosphorus oxychloride, which may be separated by chromatography or via crystallization, and then The reflux hydrochloride acid hydrolyzes back to a single regioisomer of the compound of formula (AO). The compound of formula (AO) can also be prepared according to Scheme 6. 127286 68· 200831517

丙烯酸曱酯 Ρ(3·觸媒 圖式6Ethyl acrylate Ρ (3·catalyst)

0、 Me 2. uv 光 ΙΖη0, Me 2. uv light ΙΖη

ΟΟ

式（AO)化合物可製自式（ΑΡ)化合物，其方式是形成碳-碳 鍵結，接著為適當地安裝之順式不飽和系統之分子内醯胺 鍵結形成。反式雙鍵之異構化作用可在UV光下以以熱方式 或光化學方式進行。或者，碳-碳鍵結形成可如Sonogashira 偶合至炔烴中間物進行，此中間物可在Lindlar條件下部份氫 化成順式雙鍵。 式（AO)化合物亦可根據圖式7製成。 127286 69- 200831517 圖式7The compound of formula (AO) can be prepared from a compound of the formula ( ΑΡ) by forming a carbon-carbon bond followed by intermolecular guanamine linkage formation of a suitably installed cis-unsaturated system. The isomerization of the trans double bond can be carried out thermally or photochemically under UV light. Alternatively, carbon-carbon bond formation can be carried out as a coupling of Sonogashira to an alkyne intermediate which can be partially hydrogenated to a cis double bond under Lindlar conditions. The compound of the formula (AO) can also be produced according to the formula 7. 127286 69- 200831517 Figure 7

式（AO)化合物可製自式（BE)化合物，其方式是以鹼譬如 乙醇鈉之去質子化作用，接著與草酸二乙酯反應，以形成 式（BF)化合物。然後，此中間物可以適當還原劑譬如硼氫 化鈉進行還原，提供式（BG)化合物。於硝基以適當還原劑 譬如醋酸中之鐵或二氯化錫之還原作用後，式（BG)化合物 可接著被環化成式（BH)化合物。最後，以鹼譬如DBU之脫 除，係提供式（AO)化合物。 式（AU)化合物，其係為其中J為N之式（AD)化合物，可根 據圖式8製成。 圖式8The compound of formula (AO) can be prepared from a compound of formula (BE) by protonation with an alkali such as sodium ethoxide followed by reaction with diethyl oxalate to form a compound of formula (BF). This intermediate can then be reduced with a suitable reducing agent such as sodium borohydride to provide a compound of formula (BG). After reduction of the nitro group with a suitable reducing agent such as iron in acetic acid or tin dichloride, the compound of formula (BG) can be subsequently cyclized to a compound of formula (BH). Finally, the removal of a base such as DBU provides the compound of formula (AO). A compound of the formula (AU) which is a compound of the formula (AD) wherein J is N, can be prepared according to Scheme 8. Figure 8

乙醛酸乙酯 式(ΑΤ> 式（AU)化合物之區域異構性混合物可藉由上文關於圖式 5所述之方法分離。 127286 -70- 200831517 圖式9係描繪關於製備式(AU)化合物之另 乃一種方法The regioisomeric mixture of the ethyl glyoxylate (ΑΤ) formula (AU) can be isolated by the method described above with respect to Scheme 5. 127286 -70- 200831517 Figure 9 is a depiction of the preparation formula (AU) Another method of compound

Ri 圖式9 rTVn〇2 式(AW)Ri Figure 9 rTVn〇2 (AW)

式(AY)Formula (AY)

>式_化合物可藉由式(ΑΧ)化合物以氧化劑譬如過氧化 气氧化作用獲#。式⑽)化合物可經由使式（AV)化合物 與漠醋酸8旨類’或與乙㈣乙S旨反應，接著為硝基之還原 乍乂、自％丨生環化作用而獲得。適當還原劑包括Pd/c與 H2、於醋酸中之鐵及氯化錫。 式（AZ)化合物，其係為其中保護基為第三_ 丁氧羰基之式 (AG)化合物，可根據圖式1〇製成。 127286 •71 - 200831517> The compound of the formula can be obtained by oxidation of a compound of the formula (ΑΧ) with an oxidizing agent such as peroxidation. The compound of the formula (10)) can be obtained by reacting a compound of the formula (AV) with methylene acetate 8 or with B (IV) B, followed by reduction of nitro group, and cyclization from %. Suitable reducing agents include Pd/c and H2, iron in acetic acid, and tin chloride. A compound of the formula (AZ) which is a compound of the formula (AG) wherein the protecting group is a third-butoxycarbonyl group can be produced according to the formula 1 . 127286 •71 - 200831517

圖式ίοSchematic

式(BC)Formula (BC)

1) H2, Pd(OH)2 2) 二碳酸二-第三-丁酯 去除保護1) H2, Pd(OH)2 2) Di-tertiary-butyl phthalate removal protection

式(BD) 式（BA)化合物可與式（BB)化合物於鹼存在下反應，提供 式（BC)化合物。鹼之實例為CS2 C〇3、NaH、& c〇3或Ν&2 c〇3。 關於此反應之適當脫離基包括甲烷磺酸鹽與鹵基，譬如氯 基與溴基。關於此反應之適當保護基包括矽烷基保護基， 譬如第三·丁基-二甲基矽烷基。式（BC)化合物之保護基可使The compound of formula (BD) can be reacted with a compound of formula (BB) in the presence of a base to provide a compound of formula (BC). Examples of bases are CS2 C〇3, NaH, & c〇3 or Ν&2 c〇3. Suitable leaving groups for this reaction include methane sulfonates and halo groups such as chloro and bromo groups. Suitable protecting groups for this reaction include a decyl protecting group such as a third butyl-dimethyl decyl group. The protecting group of the compound of formula (BC) can

用第三-丁基氟化銨移除，提供式（BD)化合物。式（bd)化合 物可藉由氫化作用去除保護。關於此種反應之適#觸媒之 實例包括Pd(OH)2、鉑黑及Pt〇2 ’接著為與碳酸二第三丁醋 之反應，提供式（AZ)化合物。 當需要本發明化合物之光學活性形式時，其可藉由進行 上述程序之―，使用純對掌異構物作為起始物質f或使用 標準程序，藉由最後產物或對掌性中間物之對掌異構物或 非對映異構物混合物之解析而獲得。對掌異構物之解析可 於對掌固定相上藉層析達成，譬如Chiralpak处管柱。必須 127286 -72· 200831517 :量：解度以及解析度。或者，解析可藉由對掌性中間物 或對旱性產物與對掌性酸譬如樟腦磺酸之非對映異構鹽之 製備與選擇性結晶化作 1匕TF用而獲侍。或者，可採用立體選擇 f…口成之方法’例如在適當情況下，於反應順序中，利用 保:蔓基之對莩性變型、對掌性觸媒或對掌性試劑。 •一素技術亦可用於製備光學活性化合物及/或中間物。 一同樣地’當需要本發明化合物之純區域異構物時，其可 :由進行上述程序之―，使用純區域異構物作為起始物 或使用‘準序’藉由區域異構物或中間物之混合物 之解析而獲得。 冰有機化學師將能夠㈣與修改上述參考資㈣所包 合與論及之資訊，且伴隨著 現者其中之實例，以及本文之實例， 獲侍必須之起始物質與產物。 【實施方式】 實例Removal with tri-butylammonium fluoride provides the compound of formula (BD). The compound of the formula (bd) can be removed by hydrogenation. Examples of suitable catalysts for such reactions include Pd(OH)2, platinum black and Pt〇2' followed by reaction with dibutyl succinic acid to provide a compound of formula (AZ). When an optically active form of a compound of the invention is desired, it can be carried out by using the above procedure, using the pure palmomerate as the starting material f or using standard procedures, by the final product or the pair of palmitic intermediates. Obtained by analysis of a palmomer or a mixture of diastereomers. The analysis of the palm isomer can be achieved by chromatography on the palm stationary phase, such as the Chiralpak column. Must be 127286 -72· 200831517 : Quantity: resolution and resolution. Alternatively, the resolution can be obtained by the preparation and selective crystallization of a palmitic intermediate or a diastereomeric salt of a palmitic acid such as camphorsulfonic acid as a 1 TF. Alternatively, a stereoselective method can be employed. For example, where appropriate, in the reaction sequence, a parasitic variant, a palmitic catalyst or a palmitic reagent can be utilized. • A single technique can also be used to prepare optically active compounds and/or intermediates. Similarly, when a pure regioisomer of a compound of the invention is desired, it may be: by performing the above procedure, using a pure regioisomer as a starting material or using 'sequence' by a regioisomer or Obtained by analysis of a mixture of intermediates. The Ice Organic Chemist will be able to (4) revise the information contained in the reference (4) above, along with examples of the present, as well as examples of this article, to obtain the necessary starting materials and products. [Embodiment] Example

現在藉由下述實例說明本發明 非另有述及，否則： 但不受其所限，其中除 而處理程序係在 (〇蒸發係藉迴轉式蒸發在真空中進行 藉過濾移除殘留固體後進行； ⑻溫度係以。C引用· p 〆 在·… 室溫τ進行，其典型上係 在-26C之粑圍内，而未排除空氣，除 非熟練人員以其他方式在惰性大氣下工作；1 :)使用，層析(藉急驟式程序)以純化化合物， 他♦哟（品物5)上進行，除非另有述及； 127286 -73- 200831517 (iv) 一般而言，反應過程係藉TLC、HPLC或LC/MS追蹤，且 給予反應時間僅為說明；給予產率僅為說明，未必是可達 到之最大值； (v) 本發明最終產物之結構，係一般性地藉由NMR與質譜 技術確認。質子磁共振光譜一般係在DMSO-d6中測定，除非 另有述及，使用Brnker DRX-300光譜儀或31111^010^400光譜 儀，個別在場強度為300 MHz或400 MHz下操作。在NMR光 譜為複雜之情況中，僅報告診斷信號。化學位移係以距作 為内標準之四甲基矽烷低磁場之每百萬份之份數作報告 ((5尺度），而吸收峰多重性係被顯示為：s，單峰；d，二 重♦ ; dd，二重峰之二重峰；dt，三重峰之二重峰；dm， 多重峰之二重峰；t，三重峰；m，多重峰；br，寬廣。快 速原子撞擊（FAB)質譜數據一般係使用平台光譜儀（由 Micromass提供）獲得，以電喷霧操作，並於適當情況下，收 集無論是正離子數據或負離子數據，或使用Agilent 1100系列 LC/MSD，裝有Sedex 75ELSD，並於適當情況下，收集無論是 正離子數據或負離子數據。最低質量主要離子係針對其中 同位素***會造成多重質譜吸收峰之分子報告（例如當氯 存在時）。逆相HPLC係使用YMC組件ODS-AQ (100x20毫米内 徑，S-5//粒子大小，12毫微米孔隙大小）於Agilent儀器上進 行； (vi) 各中間物係被純化至後續階段所需要之標準，並以足 夠細節表現其特徵，以確認所指定之結構係為正確的；純 度係藉HPLC、TLC或NMR評估，而其身分係藉紅外線光譜 127286 -74- 200831517 學（IR)、質量光譜學或NMR光譜學按適當方式測定；及 (vii)可使用下列縮寫： TLC為薄層層析法；HPLC為高壓液相層析法；MPLC為中 壓液相層析法；NMR為核磁共振光譜學；DMSO為二甲亞 颯；CDC13為氘化氯仿；MeOD為氘化甲醇，意即D3 COD ; MS為質量光譜學；ESP (或ES)為電喷霧；El為電子碰撞； APCI為大氣壓力化學電離；THF為四氳呋喃；DCM為二氯 甲烷；MeOH為甲醇；DMF為二甲基甲醯胺；EtOAc為醋酸 乙酯；LC/MS為液相層析法/質量光譜法；h為小時；min為 分鐘；d為天；MTBD為N-甲基-1，5,7-三氮雙環并[4.4.0]癸-5-烯； TFA為三氟醋酸；v/v為體積/體積之比例；Boc表示第三-丁 氧羰基；Cbz表示苄氧羰基；Bz表示苯甲醯基；atm表示大 氣壓力，rt表不室溫，mg表不宅克，g表不克，//L表不微 升；mL表示毫升；L表示升；//M表示微莫耳濃度；mM表 示毫莫耳濃度；Μ表示莫耳濃度；N表示當量濃度；nm表 示毫微米。 中間物1 1-{2-【(3ΙΙ，48)·4·胺基-3-羥基六氮吡啶-1-基】乙基}-2-酮基·1，2-二 氫ρ奎琳-7-甲腈 與 中間物2 l-{2-[(3S，4R)-4-胺基-3-羥基六氩吡啶-1-基]乙基}_2·酮基_1，2_二 氮峻p林-7-甲赌 將1-[2-順式（± )(4-疊氮基-3-輕基六氫p比淀-1·基）乙基]-2-酮基 127286 -75- 200831517 -1，2-二氫喹啉-7-甲腈（中間物3) (〇·545克，L61毫莫耳)與三苯 膦（0.507克，1.93毫莫耳）在乙腈/水(9 :丨，5〇毫升）中之混合 物於室溫下攪拌6天。使反應混合物在減壓下濃縮至乾涸。 於矽膠上，以二氯甲烷/甲醇（6 : !，含有〇·2%氫氧化銨）層 析，獲得中間物1與2之外消旋混合物，為無色硬質泡沫物， 〇·452 克（90%)。 MS (ESP) ： 313 (MH+)f^c17H20N4〇2 'H-NMR (DMSO-d6) δ ： 1.48 (m, 2H) ； 2.20-2.40 (m? 2H) ； 2.45-2.61 (m，4H)，2·72 (m，1H) ; 3·44 (m，1H) ; 4·35 (dd，2H) ; 6.78 (d，1H); 7·64 (d，1H) ; 7.90 (d，1H) ; 8·00 (d，1H) ; 8·08 (d，1H)· (OH 和 NH2 質 子係與甲醇交換）. 將外消旋混合物於Chiralpak AD管柱（250 x 20毫米，i〇微 米）上，以含有0.1%二乙胺之6〇%己烷與4〇%乙醇/曱醇（1 : 1)分離。中間物2係首先溶離出，[a]D= +45·5，接著為中間 物 1，[Q]d= -45.9 (在曱醇 / 氯仿中，1: i，〇=1)。 中間物3 順式（±)(4·疊氮基-3-羥基六氫P比m )乙基】_2_酮基·1，2_ 二氫喹啉-7-曱腈 將1-[2-順式（4-疊氮基-3-{[第三_丁基（二甲基）石夕烷基]氧基} 六氫吡啶·1·基）乙基]-2-酮基-1，2-二氫Ρ奎淋·7-甲腈（中間物4) (0.724克’ 1·6耄莫耳）在THF (5毫升）中之溶液，於室溫下， 以氟化四丁基銨在THF中之溶液(1Μ，2.2毫升）逐滴處理。 一小時後，添加飽合碳酸氫鈉水溶液（1〇毫升），並在減壓 下移除THF。將其以二氯甲烷/醚（1: 1，〜2〇〇毫升）萃取。 127286 -76- 200831517 分離含有一些不溶性產物之有機相，验& 4 ^ 啊和，將水相以二氣曱烷The invention will now be described by way of example only, but not limited thereto, wherein the treatment procedure is followed by (the evaporation is carried out by vacuum evaporation in a vacuum to remove residual solids. (8) The temperature is measured by C. · p 〆 at room temperature τ, which is typically within the range of -26C, without excluding air, unless the skilled person otherwise works in an inert atmosphere; :) use, chromatography (by a flash procedure) to purify the compound, which is carried out on 哟 (Item 5), unless otherwise stated; 127286 -73- 200831517 (iv) In general, the reaction process is by TLC, HPLC or LC/MS tracking, and the reaction time is only a description; the yield is only an indication, not necessarily the maximum achievable; (v) The structure of the final product of the invention is generally by NMR and mass spectrometry confirm. Proton magnetic resonance spectroscopy is generally measured in DMSO-d6, unless otherwise stated, using a Brnker DRX-300 spectrometer or a 31111^010^400 spectrometer with individual field strengths of 300 MHz or 400 MHz. In the case where the NMR spectrum is complicated, only the diagnostic signal is reported. The chemical shift is reported in parts per million of the low magnetic field of tetramethyl decane as the internal standard ((5 scale), and the absorption peak multiplicity is shown as: s, single peak; d, double ♦ ; dd, the doublet of the doublet; dt, the doublet of the triplet; dm, the doublet of the multiplet; t, the triplet; m, the multiplet; br, broad. Fast atomic impact (FAB) mass spectrometry data Obtained using a platform spectrometer (provided by Micromass), operated by electrospray, and, where appropriate, collected either positive ion data or negative ion data, or using an Agilent 1100 Series LC/MSD, equipped with Sedex 75ELSD, and where appropriate Underneath, collect either positive ion data or negative ion data. The lowest mass primary ion is reported for molecules where isotopic splitting causes multiple mass spectral absorption peaks (eg when chlorine is present). Reverse phase HPLC uses YMC component ODS-AQ (within 100x20 mm) Diameter, S-5//particle size, 12 nm pore size) was performed on an Agilent instrument; (vi) each intermediate was purified to the required standard for subsequent stages, with sufficient detail It is characterized by the fact that the specified structure is correct; the purity is evaluated by HPLC, TLC or NMR, and its identity is determined by infrared spectroscopy 127286 -74 - 200831517 (IR), mass spectroscopy or NMR spectroscopy The following abbreviations can be used; and (vii) the following abbreviations can be used: TLC is thin layer chromatography; HPLC is high pressure liquid chromatography; MPLC is medium pressure liquid chromatography; NMR is nuclear magnetic resonance spectroscopy; AZ; CDC13 is deuterated chloroform; MeOD is deuterated methanol, meaning D3 COD; MS is mass spectrometry; ESP (or ES) is electrospray; El is electron collision; APCI is atmospheric pressure chemical ionization; Is tetrafurfuran; DCM is dichloromethane; MeOH is methanol; DMF is dimethylformamide; EtOAc is ethyl acetate; LC/MS is liquid chromatography/mass spectrometry; h is hour; Min; d is day; MTBD is N-methyl-1,5,7-triazabicyclo[4.4.0]non-5-ene; TFA is trifluoroacetic acid; v/v is volume/volume ratio; Boc represents a third-butoxycarbonyl group; Cbz represents a benzyloxycarbonyl group; Bz represents a benzamidine group; atm represents atmospheric pressure, rt is not room temperature, and mg is not a house gram, g Table is not gram, / L table does not rise slightly; mL means milliliter; L means liter; / / M means micromolar concentration; mM means millimolar concentration; Μ means molar concentration; N means equivalent concentration; Intermediate 1. Intermediate 1 1-{2-[(3ΙΙ,48)·4·amino-3-hydroxyhexaazin-1-yl]ethyl}-2-keto·1,2-dihydroquinoquinone Lin-7-carbonitrile and intermediate 2 l-{2-[(3S,4R)-4-amino-3-hydroxyhexafluoropyridin-1-yl]ethyl}_2·keto-1,2_ Nitrogen sulphate -7-A gambling 1-[2-cis(±)(4-azido-3-light hexahydrop-p-pred-l-yl)ethyl]-2-keto 127286 -75- 200831517 -1,2-dihydroquinolin-7-carbonitrile (Intermediate 3) (〇·545 g, L61 mmol) and triphenylphosphine (0.507 g, 1.93 mmol) in acetonitrile The mixture in /water (9: hydrazine, 5 mL) was stirred at room temperature for 6 days. The reaction mixture was concentrated to dryness under reduced pressure. Chromatography on dichloromethane/methanol (6::, containing 〇·2% ammonium hydroxide) afforded the racemic mixture of intermediates 1 and 2 as colorless rigid foam, 452·452 g ( 90%). MS (ESP): 313 (MH+),,,,,,,,,,, 2·72 (m, 1H); 3·44 (m, 1H); 4·35 (dd, 2H); 6.78 (d, 1H); 7·64 (d, 1H); 7.90 (d, 1H); 8·00 (d,1H) ; 8·08 (d,1H)· (OH and NH2 protons exchanged with methanol). The racemic mixture was applied to a Chiralpak AD column (250 x 20 mm, i〇 micron) Separated with 6% hexane containing 0.1% diethylamine and 4% ethanol/decyl alcohol (1:1). Intermediate 2 was first eluted, [a] D = +45·5, followed by intermediate 1, [Q]d = -45.9 (in sterol / chloroform, 1: i, 〇 = 1). Intermediate 3 cis (±) (4·azido-3-hydroxyhexahydroP to m)ethyl]_2-keto·1,2_dihydroquinolin-7-indolecarbonitrile 1-[2- Cis (4-azido-3-{[tert-butyl(dimethyl)oxalyl]oxy}hexahydropyridine·1·yl)ethyl]-2-keto-1, a solution of 2-dihydroquinone-7-carbonitrile (Intermediate 4) (0.724 g '1.66 mol) in THF (5 mL) at room temperature with tetrabutylammonium fluoride The solution in THF (1 Torr, 2.2 mL) was applied dropwise. After one hour, a saturated aqueous solution of sodium hydrogencarbonate (1 mL) was added and the THF was removed under reduced pressure. It was extracted with dichloromethane/ether (1:1 to 2 mL). 127286 -76- 200831517 Separate the organic phase containing some insoluble products, test & 4 ^ ah and, the aqueous phase is dioxane

(100毫升）逆萃取，並使合併之有機、#广 A ’機相在減壓下濃縮至乾(100 ml) reverse extraction, and the combined organic, #广A' machine phase was concentrated to dryness under reduced pressure

涸，及在高真空下乾燥，獲得產物，ΛI 苟無色固體，0.545克（定 量）。 4-NMR _购6) d : L56 (m，1H) ; U1 (m，1Η) ; 2 25 2说（m， 6H) ； 3.67 (m, 2H) ； 4.35 (dd, 2H) ； 5.06 (m, 1H) ； 6&gt;78 (d&gt; m); ? 64 ⑽， 1H) ； 7.90 (d, 1H) ； 8.00 (d, 1H) ； 8.08 (brs, 1H). 中間物4 参吵順式⑴(4-養氮基_3_{[第三-丁基(二甲基〉魏基】氧基}六 氫吡啶-1-基)乙基】_2·酮基·1，2·二氫峻琳甲赌 將2-酮基-1，2-二氫喹啉-7-甲腈（中間物5) (〇·51克，3 〇毫莫 耳）在DMF (15毫升）中之懸浮液，於下，以氫化鈉（在油 中，60%，132毫克）處理。將其攪拌2小時，接著經由注射 1§添加曱烷磺酸2-順式（4-疊氮基·3][第三_丁基（二甲基）石夕烷 基]氧基}/、虱ρ比咬-1-基）乙1旨（中間物6) (3毫莫耳）在DMp (7 φ 毫升）中之溶液。移除冷卻，並將其在室溫下攪拌過夜。在 減壓下移除DMF，使殘留物溶於二氯甲烷(〜2〇〇毫升）與飽和 碳酸氫納水溶液(20毫升，以iMNaOH溶液將ΡΗ調整至pHIO) 中。將水相以二氯甲烷(2x 1〇〇毫升）逆萃取兩次，並使合併 之有機相以硫酸鈉脫水乾燥。於矽膠上，以己烷/丙酮（4 : 1)層析’獲得產物，為硬質泡沫物，〇·724克（53%)。 MS (ESP) : 453 (ΜΗ+)對 C23H32N602Si 'H-NMR (DMSO-d6) ： 0.00 ^ 0.03 (2xs, 6H) ； 0.80 (s, 9H) ； 1.59 (m, _ ; 1.70 (m，m) ; 2.30-2.65 (m，6H) ; 3.69 (m，1H) ; 3.80 (m，1H); 127286 -77· 200831517 4.29 (m，1H) ; 4·42 (m，1H) ; 6·77 (d，1H) ; 7·63 (d，1H) ; 7·90 (d，1H); 7.99 (d5 1H) ； 8.08 (s, 1H). 中間物5 2-酮基-1，2-二氫p奎n林_7_甲腈 將7·溴基喹啉々(IK)-酮（中間物46) (9·21克，41毫莫耳）與氰 化銅（I) (4.05克）在N-甲基四氫p比嘻酮（5〇毫升）中，於下 加熱16小時。使其冷卻至室温，添加乙二胺四醋酸鹽水溶 液（2M，pH 8.3，1〇〇毫升）’並將混合物於室溫下檀拌，及 開放至空氣，歷經5天。經過〇·45微米薄膜，藉過濾收集沉 屬又物，以水與醋酸乙醋洗務，並自DMF/水再結晶，獲得產 物，為褐色固體，90%純度，4·72克（60%)，使用之而無需進 一步純化。Dry, and dry under high vacuum to give the product, </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 4-NMR _6) d : L56 (m,1H) ; U1 (m,1Η) ; 2 25 2 says (m, 6H) ; 3.67 (m, 2H) ; 4.35 (dd, 2H) ; 5.06 (m , 1H); 6&gt;78 (d&gt;m); 64 (10), 1H); 7.90 (d, 1H); 8.00 (d, 1H); 8.08 (brs, 1H). Intermediate 4 arguing (1) ( 4-N-nitrogen group_3_{[Third-butyl(dimethyl>weiki)oxy}hexahydropyridin-1-yl)ethyl]_2·keto group·1,2·dihydrojun A A suspension of 2-keto-1,2-dihydroquinolin-7-carbonitrile (Intermediate 5) (〇·51 g, 3 〇 mmol) in DMF (15 mL) Treated with sodium hydride (60% in oil, 132 mg). Stir it for 2 hours, then add cis-sulfonate 2-cis (4-azido-3) via injection 1 § [third_ Butyl (dimethyl) oxalate]oxy}/, 虱ρ ratio -1-yl) B1 (Intermediate 6) (3 mM) solution in DMp (7 φ mL) The cooling was removed, and it was stirred at room temperature overnight. DMF was removed under reduced pressure and the residue was dissolved in dichloromethane (~~~~~~~~~~~~~~~~~~~~ The solution will adjust ΡΗ to pHIO). The aqueous phase was back-extracted twice with dichloromethane (2×1 mL), and the combined organic phases were dried with sodium sulfate and evaporated to hexane/acetone (4:1). For rigid foam, 724·724 g (53%) MS (ESP): 453 (ΜΗ+) vs. C23H32N602Si 'H-NMR (DMSO-d6): 0.00 ^ 0.03 (2xs, 6H); 0.80 (s, 9H) 1.59 (m, _ ; 1.70 (m, m); 2.30-2.65 (m, 6H); 3.69 (m, 1H); 3.80 (m, 1H); 127286-77· 200831517 4.29 (m, 1H); 4·42 (m,1H) ; 6·77 (d,1H) ; 7·63 (d,1H) ; 7·90 (d,1H); 7.99 (d5 1H) ; 8.08 (s, 1H). 5 2-keto-1,2-dihydrop-quino-n-lin_7-carbonitrile 7·bromoquinolinium (IK)-ketone (intermediate 46) (9·21 g, 41 mmol) With copper (I) cyanide (4.05 g) in N-methyltetrahydropyrhenone (5 mL), heated under 16 hours, allowed to cool to room temperature, and added aqueous solution of ethylenediaminetetraacetate (2M, pH 8.3, 1 mL) and mix the mixture at room temperature and open to air for 5 days. After 〇·45 micron film, the genus was collected by filtration, washed with water and ethyl acetate, and recrystallized from DMF/water to obtain the product as a brown solid, 90% purity, 4.72 g (60%) ), used without further purification.

MS (ESP) : 171 (ΜΗ+)對 C10H6N2O 'H-NMR (DMSO-d6) ά ： 6.66 (d5 1Η) ； 7.55 (d5 1H) ； 7.61 (s5 1H)； 7·85 (d，1H) ; 7·99 (d，1H) ; 12.01 (s，1H)· 關於合成中間物5之替代程序 將3-經基-2-酮基-1，2,3,4·四氫喹啉；甲腈（中間物66，15 51 克，82.42毫莫耳）與W-工氮雙環并[5A〇]十一·7_烯(DBu)在乙 腈（155毫升）中之混合物，於751下加熱2 5小時。使反應混 合物冷卻至室溫，並藉過濾收集沉澱物，以水（77毫升）及 以甲醇（77毫升）洗滌，且於減壓下乾燥，獲得產物，為灰 白色固體，9.71克（68%)。 熔點 &gt;25(Τ(：MS (ESP): 171 (ΜΗ+) vs. C10H6N2O 'H-NMR (DMSO-d6) ά : 6.66 (d5 1Η); 7.55 (d5 1H); 7.61 (s5 1H); 7·85 (d, 1H); 7.99 (d,1H); 12.01 (s,1H)· An alternative procedure for the synthesis of intermediate 5 is 3-methyl-2-keto-1,2,3,4·tetrahydroquinoline; carbonitrile (Intermediate 66, 15 51 g, 82.42 mmol) and a mixture of W-azabicyclo[5A〇]11·7-ene (DBu) in acetonitrile (155 ml), heated at 751 2 5 hour. The reaction mixture was cooled to EtOAc EtOAc (EtOAc m. . Melting point &gt;25(Τ(:

MS (ESP) : 171 (MHLC10H6N2O 127286 -78- 200831517 iH-NMR (DMSO-d6) 5 : ppm 6.67 (d，1H); 7.48-7.68 (m，2H); 7.85 (d， 1H) ; 7_98 (d，1H) ; 12.01 (s，1H)· 中間物6 甲燒項酸2-(順式（土 ))-(4-疊氮基-3·{【第三-丁基(二甲基)發燒基】 氧基}六氫吡啶-1-基）乙酯 將2-(順式）-(4-疊氮基-3-{[第三丁基（二甲基）石夕燒基]氧基} 六氫吡啶4·基）乙醇（中間物7，1,8克，6毫莫耳）在無水二氯 曱烷（20毫升）與三乙胺（1.18毫升，8.4毫莫耳）中之混合物， 於〇°C下，以氣化甲烷磺醯（0.556毫升，7·2毫莫耳）處理。9〇 分鐘後’藉TLC (氯仿/甲醇6 : 1，rf〜〇·9)，反應已完成。添 加磷酸鉀緩衝劑（pH 7，1Μ，15毫升），在減壓下移除二氯 甲烧’並將其以冰冷醚（100宅升）萃取。將水相以鱗（5〇毫升） 逆萃取一次’並使合併之有機相以硫酸鈉脫水乾燥。於減 壓下移除溶劑，並使殘留物溶於DMF (1〇毫升）中。將此甲 烷磺酸酯之粗製物使用於下一步驟，而未延遲。 MS (ESP) : 379 (MH+)對 C! 4 H3 6 N4 04 SSi 中間物7 2-(順式（±))-(4_養氮基各{[第三-丁基（二甲基）矽烷基】氧基}六 氫吡啶-1·基）乙醇 將（順式）-4-疊氮基-3-{[第三-丁基（二甲基）石夕烷基]氧基}六 氫峨咬（中間物8) (1.625克，6.34毫莫耳）、n，N_二異丙基乙胺 (1.65宅升’ 9.5宅莫耳）及2-漠基乙醇（〇·584毫升，8.25毫莫耳） 在無水乙腈（17毫升）中之混合物，於微波中，在7〇〇c下加熱 兩小時。於減壓下移除溶劑，使殘留物溶於醋酸乙酯（〜15〇 127286 -79- 200831517 毫升）中，並以飽和碳酸氫鈉水溶液（〜25毫升）洗滌。將水 相以酸乙酯（100毫升）逆萃取一次，並使合併之有機相以 硫酸鈉脫水乾燥。於矽膠上，以二氯甲烷/甲醇（2〇:丨）層析， 獲得1.80克（95%)產物，為無色油。 MS(ESP): 301(MH+MiC13H28N4O2Si !Η-ΝΜΚ (DMSO-d6) δ · 0.08 (s5 6H) ； 0.87 (s5 9H) ； 1.65 (m, 2H)； 2.18 (m? 1H) ； 2.25-2.60 (m? 5H) ； 3.44 (m? 2H) ； 3.73 (m5 1H) ； 3.91 (m3 1H) ； 4.35 (m, 1H). ®中間物8 (順式（±))-4·疊氮基-3-{【第三-丁基（二甲基)發烷基】氧基}六氫 將（順式）冰疊氮基-3-{[第三-丁基（二甲基）石夕烷基]氧基}六 氫p比啶-1-羧酸第三-丁酯（中間物9) (2.3克，6.45毫莫耳）在二 氣甲烷（50毫升）中之溶液，於〇。〇下，以三氟醋酸（5毫升） 處理。3小時後，在減壓下濃縮混合物，並使殘留物與二氯 φ 甲烷一起共蒸餾兩次。使殘留物溶於二氯甲烷（1〇〇毫升） 中’並以飽和碳酸鼠鈉水溶液（3〇毫升）洗滌。將水相以二 氯曱燒（100毫升）逆萃取一次，並使合併之有機相以硫酸納 脫水乾煉’獲得產物，為稍微黃色油，1625克（98%)。 iH-NMR (DMSO-d6) (5 : 〇·〇7 與 0.09 (2xs，6H); 0.88 (s5 9H); 1.49-1.73 (m，2H) ; 2·45 (m，1Η) ; 2.56-2.69 (m5 3H) ; 3·65 (m，1H) ; 3·79 (m，1H)· 中間物9 (順式（±))-4-曼氮基·3-{[第三-丁基（二甲基)發烷基】氧基}六氫 吡啶小羧酸第三-丁酯 127286 -80 - 200831517MS (ESP): 171 (MHLC10H6N2O 127286 -78 - 200831517 iH-NMR (DMSO-d6) 5 : ppm 6.67 (d,1H); 7.48-7.68 (m,2H); 7.85 (d, 1H); 7_98 (d ,1H) ; 12.01 (s,1H)· Intermediate 6 combidic acid 2-(cis (soil))-(4-azido-3·{[T-butyl (dimethyl)) fever 2-(cis)-(4-azido-3-{[t-butyl(dimethyl)-stone)-oxyl a mixture of hexahydropyridine 4·yl)ethanol (intermediate 7,1,8 g, 6 mmol) in anhydrous dichloromethane (20 mL) and triethylamine (1.18 mL, 8.4 mmol) , at 〇 ° C, treated with gasified methane sulfonate (0.556 ml, 7.2 mmol). After 9 minutes, 'by TLC (chloroform / methanol 6 : 1, rf ~ 〇 · 9), the reaction has Complete. Add potassium phosphate buffer (pH 7, 1 Μ, 15 ml), remove the methylene chloride under reduced pressure and extract it with ice-cold ether (100 liters). The water phase is scaled (5 〇 ml) The mixture was back-extracted once and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue dissolved in DMF (1 mL) The crude methanesulfonate was used in the next step without delay. MS (ESP): 379 (MH+) to C! 4 H3 6 N4 04 SSi Intermediate 7 2-(cis (±)) -(4_N-nitrogen group {[T-butyl(dimethyl)decyl)oxy}hexahydropyridin-1yl)ethanol (cis)-4-azido-3-{ [Third-butyl (dimethyl) oxalate]oxy} hexahydropurine (Intermediate 8) (1.625 g, 6.34 mmol), n,N-diisopropylethylamine (1.65 Zhaisheng '9.5 house Moh) and 2-glycolethanol (〇·584 ml, 8.25 mmol) were mixed in anhydrous acetonitrile (17 ml) and heated in a microwave at 7 ° C for two hours. The solvent was removed under reduced pressure and the residue was purified ethyljjjjjjjjjjjjjjjjjjjjj (100 ml) was back-extracted once, and the combined organic phases were dried with sodium sulfate, and then purified eluting with methylene chloride/methanol (2 〇: 丨) to give 1.80 g (95%) of product as colorless. Oil. MS (ESP): 301 (MH+MiC13H28N4O2Si !Η- ΜΚ (DMSO-d6) δ · 0.08 (s5 6H) ; 0.87 (s5 9H); 1.65 (m, 2H); 2.18 (m? 1H); 2.25-2.60 (m? 5H); 3.44 (m? 2H); 3.73 (m5 1H) ; 3.91 (m3 1H) ; 4.35 (m, 1H). ® Intermediate 8 (cis (±))-4·azido-3-{[T-butyl (dimethyl)发 】 】 氧基 氧基 六 六 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺A solution of the third-butyl carboxylic acid (Intermediate 9) (2.3 g, 6.45 mmol) in di-methane (50 mL). Underarm, treated with trifluoroacetic acid (5 mL). After 3 hours, the mixture was concentrated under reduced pressure and the residue was twice distilled twice with dichloro </ br> methane. The residue was dissolved in dichloromethane (1 mL) and washed with saturated aqueous sodium hydrogen carbonate (3 mL). The aqueous phase was back-extracted once with chlorohydrin (100 mL) and the combined organic phases were dried <RTI ID=0.0></RTI> to <RTI ID=0.0> iH-NMR (DMSO-d6) (5: 〇·〇7 and 0.09 (2xs, 6H); 0.88 (s5 9H); 1.49-1.73 (m, 2H); 2·45 (m, 1Η); 2.56-2.69 (m5 3H) ; 3·65 (m,1H) ; 3·79 (m,1H)· Intermediate 9 (cis (±))-4-manazyl·3-{[Third-butyl ( Dimethyl)alkyl]oxy}hexahydropyridine small carboxylic acid tert-butyl ester 127286 -80 - 200831517

將（順式）-4-疊氮基-3·羥基六氫吡啶-1·羧酸第三-丁酯（中間 物10) (1.76克，7_25毫莫耳）與咪唑(0.74克，ΐ〇·9毫莫耳）在DMF (7毫升）中之混合物，於下，以氯化第三·丁基二甲基矽 统（1.3克’ 8.7耄莫耳）處理。移除冷卻，並將混合物於室溫 下擾拌過仪。使其冷卻至〇°C，並以麟酸鹽緩衝劑（iM，pH 7 ’ 20毫升）使反應淬滅。15分鐘後，以醋酸乙酯（1〇〇毫升） 稀釋混合物，以水(2χ 50毫升）洗滌有機相，並以硫酸鈉脫 _ 水乾燥。於矽膠上以己烷/醋酸乙酯（9 : 1)層析，獲得產物， 為無色油，2.3克（89%)。 'H-NMR (DMSO-d6) 5 ： 0.10 (s? 6H) ； 0.87 (s? 9H) ； 1.37 (s? 9H)； 1.56^1.80 (m? 2H) ； 3.09-3.30 (m, 2H) ； 3.46 (m5 2H) ； 3.62 (m, 1H) ； 3.88 (m, 1H). 中間物10 (順式（±))-4·疊氮基-3-羥基六氫吡啶-i_羧酸第三-丁酯 於（順式）_4-@氮基六氫p比贫_3_醇（按照2005/066176中關 φ 於對掌性物質所述之程序製成）（2.1克，14.8毫莫耳）與氫氧 化鉀（2.5克，44毫莫耳）在異丙醇（2〇毫升）與二氯甲烷卬毫 升）中之混合物内，於〇°C下，添加二碳酸二_第三_丁酯（3·9 克，17·7毫莫耳）在二氯甲烷（10毫升）中之溶液。移除冷卻， 亚將其在室溫下攪拌2小時。以水（5〇毫升）使反應淬滅，並 在減壓下移除異丙醇與二氯甲烷。以磷酸鉀緩衝劑（1Μ， 7，100毫升）中和，以醋酸乙酯（2χ 3〇〇毫升）萃取兩次，並 使合併之有機相以硫酸鈉脫水乾燥。於減壓下移除溶劑， 並將殘留物自己烷（〜20毫升）研製，獲得〇 %6克產物，為無 127286 -81 - 200831517 色固體。母液以己烷/醋酸乙酯（5 : 1)之層析，提供〇 353克 產物（35%)。 MS (ESP) : 265·2 (MNa+)對 q οΗ! 8N403 ^-NMRODMSO-d^ 5 ： 1.39 (s,9H)； 1.58 (m5 1H) ； L74 (m, 1H)； 3.20-3.40 (m，4H) ; 3·69 (m，2H) ; 5·40 (d，1H)· 中間物11 l-{2-[(3R，4S)-4·胺基-3-羥基六氫吡啶-1·基】乙基}-7-甲氧基喹喏 啉 _2(1H)_酮 與 中間物12 l-{2_[(3S，4R)-4·胺基-3-羥基六氫吡啶-1·基]乙基}-7_曱氧基喹喏 啉酮 將1-[2-{(順式）-(4-璺氮基-3-經基六氯p比咬-1-基）}乙基]-7-甲 氧基喳喏啉-2(1H)-酮（中間物13) (0.507克，1.47毫莫耳）與三 苯膦（0.463克，1.77毫莫耳）在乙腈/水(9: 1，20毫升）中之混 合物於室溫下攪拌5天。使反應混合物在減壓下濃縮至乾 涸。使殘留物溶於二氣甲烷（5毫升）中，並於矽膠上以二氯 曱烷/甲醇（6: 1，含有0.2%氫氧化銨）層析，獲得外消旋混 合物中間物11與12，為無色硬質泡沫物（0.422克，90%)。 MS(ESP): 319(MH+)對 C16H22N403 iH-NMR (DMSO-d6) (5 ·· 1.48 (m，2H) ; 1·89 (m，1H) ; 2·28 (m，1H); 2.37 (dd5 1H) ； 2.54-2.62 (m5 3H) ； 2.71 (m, 1H) ； 3.45 (m5 1H) ； 3.91 (s5 3H); 4.30 (dd，2H) ; 6.96-7.00 (m，2H) ; 7.73 (d，1H) ; 8.03 (s，1H)· (OH 和NH2質子係與甲醇交換）. 127286 -82 - 200831517 將外消旋混合物於Chiralpak AD管柱（250 x 20毫米，10微 米）上，以含有0.1%二乙胺之乙醇/甲醇: U分離。中間物 12係首先溶離出，[a]D= +45.5，接著為中間物u，[a]D= ·44.7 (在甲醇/氯仿1: 1，c=l)。 中間物13 順式（±))-(4-疊氮基各羥基六氫吡啶-1·基）}乙基】-7·甲氧 基喹喏啉-2(1H)-酮 _ 將1-[2-(順式）冰疊氮基-3-{[第三丁基（二曱基）石夕烷基]氧 基}六氫外b咬-1-基）乙基]-7-甲氧基p奎喏琳-2(1H)-酮（中間物 14，0.721克，1·57毫莫耳）在THF(5毫升）中之溶液，於室溫 下，以氟化四丁基銨在THF中之溶液（1M，2.2毫升）逐滴處 理。一小時後，添加飽和碳酸氫鈉水溶液（1〇毫升），並在 減壓下移除THF。將其以二氯甲烷/醚（1 : 1，〜2〇〇毫升）萃 取。將水相以二氯曱烷（1〇〇毫升）逆萃取，並使合併之有機 相以硫酸鈉脫水乾燥。於矽膠上，以己烷/丙酮（1 : 1)層析， φ 獲得產物，為無色硬質泡沫物，0.507克（94%)。 MS (ESP) : 345 (MH+)對 Ci6h2gN603 ^-NMR (DMSO-d6) 5 ： 1.58 (m? 1H) ； 1.70 (m5 1H) ； 2.25-2.65 (m? 6H); 3.67 (m，2H) ; 3.90 (s，3H); 4.31 (dd，2H) ; 5.11 (m，1H) ; 6.97-7.00 (m，2H) ; 7.73 (d，1H) ; 8.03 (s，1H). 中間物14 1-12-(順式（±))-4-疊氮基-3-{[第三-丁基（二甲基)珍烷基]氧基}六 氫吡啶-1-基）乙基】-7-甲氧基喹喏啉-2(1H)-酮 使用類似關於合成中間物4所述之程序，將7-甲氧基喳喏 127286 -83 - 200831517 淋-2(m)-酮（中間物15，0.528克，3·0毫莫耳）以氫化鈉（於油 中，60%，132毫克）與甲烷磺酸2-順式（4_疊氮基_3_{[第三_丁 基C一甲基)碎烧基]氧基}六氯p比唆-1-基）乙醋（中間物6，3毫 莫耳）處理’獲得產物，為硬質泡沫物，〇·721克（52%)。 MS (ESP) : 459 (MH+)對 C2 2 H3 4 N6 03 Si 1H-NMR (DMSO-d6) 5 : 0.03 與 0·05 (2xs，6H) ; 0.82 (s，9H) ; 1.65 (m， 2H) ; 2.25-2.70 (m，6H) ; 3·70 (m，1H) ; 3·90 (s，3H) ; 3·83 (m，1H); 4.24 (m，1H) ; 4.39 (m，1H) ; 6.96-7.00 (m，2H) ; 7.73 (m，1H) ; 8.02 (s， 1H). 中間物15 7·甲氧基喳喏啉-2(1H)-酮 於8%氫氧化鈉水溶液（1·32升）中，添加7_甲氧基_3,4_二氫 喳喏啉-2(1H)-酮（中間物16，100克），接著為3重量％過氧化 氫在水中之溶液（L17升）。將反應混合物慢慢加熱至8〇它， 並在此溫度下保持4小時。接著移除加熱源，並逐滴添加醋 φ 酸（150毫升）。將此懸浮液於室溫下攪拌過夜，並藉過濾收 集已沉澱之固體，而得產物，為黃褐色固體（9〇克）。 MS (ESP) : 177 (MH+)對 C9H8N202 ^-NMR (DMSO-d6) δ ： 3.83 (s? 3Η) ； 6.76 (d, 1H) ； 6.90 (dd, 1H)； 7.67 (d, 1H) ； 7.97 (s? 1H) ； 12.32 (brs, 1H). 中間物16 7-甲氧基-3,4-二氫喹喏啉-2(1H&gt;酮 於18升帕爾裝置中，使[(4-甲氧基_2_硝基苯基）亞胺基]醋 酸乙酯（中間物17)之懸浮液在55 psi下，於20重量❶/〇 Pd/C (100 127286 •84- 200831517 克，含有〜50重量％水）存在下氫化，直到沒有任何氫被消 耗為止（註··反應係為強放熱，且溫度應藉由調整再充填氫 之速率，及經由冷卻系統，被控制在約6〇。〇下）。排放反應 混合物，於矽藻土餅上過濾，及在減壓下蒸發，獲得粗製 固體，將其以MTBE (6升）研製，獲得產物，為黃褐色固體 (400 克）。 MS (ESP) : 179 (MH+)對 C9Hl gN2〇2 'H-NMR (DMSO-d6) ά ： 3.61 (m? 5H) ； 5.57 (m5 1H) ； 6.35-6.40 (m? 2H) ; 6.60 (m，1H) ; 10.13 (brs，1H)· 關於中間物16之替代程序 使N-(4-曱氧基-2-硝基苯基)甘胺酸乙酯（中間物18，ι5·8克 粗製物）溶於200毫升1:丨甲醇/醋酸中，以1〇%鈀/碳(之克） 處理，並在氫大氣下攪拌過夜。經過矽藻土過濾反應混合 物，並使濾液濃縮至乾涸，獲得10.6克粗產物，為黃褐色固 體。將其使用，無需進一步純化。 MS (ESP) : Π9 (ΜΗ+)對 C9Hl 〇Ν2〇2 中間物17 【(4-甲氧基-2-硝基苯基）亞胺基】醋酸乙酉旨 使4-甲氧基-2_硝基苯胺（1公斤，5 95莫耳）與乙醛酸乙醋 _毫升’ 50重量％ ’在甲苯中，595莫耳）在甲苯（1〇升） 中之溶液，於Dean-Stark裝置中回流8小時，及在減壓下蒸發， 獲得粗產物，為深褐色油，使用之而無需進一步純化。 中間物18 Ν-(4·甲氧基-2-硝基苯基）甘胺酸乙酯 127286 -85- 200831517 將4-甲氧基-2-硝基苯胺（25·0克，0·15莫耳）、溴醋酸乙酯 (200毫升，1.8莫耳）及碳酸鉀（3U克，〇·23莫耳）之混合物在 150°C下加熱4.5小時。於冷卻至室溫後，添加氫氧化鈉水溶 液（1M，600毫升）。以醋酸乙酯（2X500毫升）萃取此混合物。 使合併之有機相以硫酸鎂脫水乾燥，及濃縮至乾涸。於石夕 膠上，以己烷中之25-50%丙酮層析，獲得22·1克粗產物，為 紅色固體。1H NMR顯示〜20%二烷基化產物存在。使用此物 質而無需進一步純化。 XH NMR (DMSO-d6) δ ： 1.18-1.23 (t5 3H) ； 3.74 (s5 3H) ； 4.12-4.18 (q5 2H)，4.23-4.25 (d，2H)，6.90-6.93 (d, 1H) ; 7.25-7.29 (dd，1H); 7·51-7.52 (d5 1H) ； 8.23-8.27 (t? 1H). 中間物19 順式（±)1_[2-(4_胺基-3-氟基六氫吡啶小基）乙基】嗣基4,2-二 氫喹啉_7_甲腈 將順式（±){1-[2-(7-氰基-2-酮基喳啉-；ι(2Η)-基）乙基]-3-氟基六 φ 氫吡啶4_基}胺基甲酸第三·丁酯（中間物20，397毫克，0.95 «莫耳）在氯仿（8毫升）中之溶液，於0。〇下，以氯仿中之3〇% 三氟醋酸（5毫升）處理。於室溫下5小時後，在減壓下移除 溶劑’獲得產物之三氟醋酸鹽，將其帶至下一步驟，無需 進一步純化。 MS(ESP): 315(MH+)對 C17H19FN4〇 中間物20 順式（±){1-丨2-(7_氰基·2-酮基喹啉基）乙基】各氟基六氫吡 啶-4-基}胺基甲酸第三-丁酯 127286 -86 - 200831517 按關於中間物4所述，將2-酮基·ι，2-二氫喹啉_7_曱腈（中間 物5，0·3克，L7晕莫耳）在DMF (1〇毫升）中之懸浮液，於室 溫下，以氫化鈉與甲烷磺酸順式[(第三_丁氧羰基）胺 基]-3-氟基六氫吡啶-l-基}乙酯（中間物21，〜17毫莫耳）處理。 於矽膠上，以己烷/醋酸乙酯（2: 3)層析，獲得產物，為固 體，397 毫克（73%)。 MS (ESP) : 415 (ΜΗ+)對 C22H27FN4〇3 ^-NMR (DMSO-d6) δ ： 1.37 (s, 9Η) ； 1.48 (m, 1H) ； 1.67 (m5 1H)； 2.27 (m，2H); 2.56 (m，2H); 2.96 (m，1H); 3.15 (m，1H); 3.46 (m，1H); 4.34 (m，2H); 4·60 (m，1H); 6.77 (m，1H); 6.91 (m，1H); 7·64 (m，1H); 7·90 (m，1H) ; 7.99 (m，1H) ; 8.07 (s，1H)· 中間物21 甲烧績酸順式（±)2-{4_[(第三-丁氧羰基）胺基]-3·氟基六氮吡啶 -1_基}乙酿 使用類似關於合成中間物6所述之程序，在三乙胺存在 φ 下’使順式（±)[3_氟基小(2-羥乙基）六氫吡啶-4-基]胺基甲酸第 三-丁酯（中間物22，314毫克，1·2毫莫耳）與氯化甲烷磺醯 反應。將粗製甲烧磺酸酯使用於下一步驟，而未延遲。 中間物22 順式（±)[3-氟基小(2·羥乙基）六氫吡啶冬基】胺基甲酸第三丁酯 於順式（±)[1-(2-{[第三-丁基（二甲基）石夕烷基]氧基}乙基）各 氣基六氫吡啶·4·基]胺基甲酸第三_丁酯（中間物23，530毫 克’ 1.4毫莫耳）在四氫呋喃（1〇毫升）中之溶液内，於〇。〇下， 添加氟化四丁基銨（1Μ，在THF中，2.8毫升）。30分鐘後， 127286 -87- 200831517 以飽和碳酸氫納使反應淬滅，並以醋酸乙酯萃取兩次，以 硫酸鎂脫水乾燥’及濃縮。以醋酸乙酯中之2 5%甲醇矽膠 層析’獲得產物，為無色固體，314毫克（85%)。 ^-NMR (CDCI3-d) ά ： 1.43 (s3 9H) ； 1.81 (m? 2H) ； 2.30 (m5 1H)； 2.36 (m，1H); 2.59 (m5 2H); 2·75 (m，1H); 2·95 (m，1H); 3·24 (m，1H); 3.61 (m，2H) ; 3·71 (m，1H) ; 4·68 (m，1H) ; 4·85 (m，1H)· 中間物23 _順式(MHM【第三丁基（二甲基)發烷基]氧基}乙基)-3-氟基六 氫峨咬冰基】胺基曱酸第三-丁酯 於室溫下，將順式⑴1-(2][第三·丁基（二甲基）石夕烷基]氧 基}乙基）-3-氟基六氫吡啶_4·胺（中間物24，2.8克，10.4毫莫 耳）與二碳酸二-第三-丁酯（3.4克，15.6毫莫耳）在四氫呋喃 (50毫升）中合併。90分鐘後，在減壓下濃縮反應混合物。 以己烧/醋酸乙酯（3: 2)矽膠層析，獲得產物，為無色油， 3_2 克（82%)。 _ ^-NMR (CDCl3-d) δ ： 0.03 (s5 6H) ； 0.86 (s5 9H) ； 1.43 (s5 9H) ； 1.77 (m5 2H) ; 2·25 (m，1H) ; 2·37 (m，1H) ; 2.58 (m，2H) ; 2.95 (m，1H); 3.26 (m，1H) ; 3·62 (m，1H) ; 3.74 (m，2H) ; 4·65 (m，1H) ; 4.83 (m，1H). 中間物24 順式（±)l-(2-{【第三·丁基（二甲基)發烷基]氧基}乙基)各氟基六 氫吡咬-4_胺 使順式（±)节基[1-(2-{[第三-丁基（二甲基）石夕烷基]氧基}乙 基)-3-氟基六氫吡啶-4-基]胺基甲酸苄酯（中間物25，5.2克， 1〇·4毫莫耳）在無水甲醇（15毫升）中，於氫氧化鈀20重量％/ 127286 -88 - 200831517 碳（31毫克）上氫化24小時，然後經過矽藻土過濾，及在減 壓下濃縮，而得產物，為無色油，2·8克。 中間物25 將順式（±)爷基【1_(2·{丨第三-丁基(二甲基)砍烷基】氧基丨乙基)各 氟基六氫吡啶-4-基】胺基甲酸苄酯 將順式（±)爷基（3-貌基六氫吡啶_4_基）胺基甲酸芊_鹽酸 鹽（中間物26 ’ 4·3克，6·1毫莫耳)、（2-溴基乙氧基）_第三·丁 φ基二甲基石夕烧（9·8毫升，45.7毫莫耳）及碳酸铯（9.9克，30.4 毫莫耳）在乙腈（150毫升）中之混合物於60°c下加熱過夜。過 濾、反應混合物’及在減壓下濃縮。以己烧/醋酸乙酯（3 : 2) 石夕膠層析，獲得產物，為無色油，5.2克（91%)。 MS (ESP) : 501 (MH+)對 C28H41FN2〇3Si 中間物26 順式（±)苄基(3_氟基六氫吡啶-4-基）胺基甲酸芊酯 於順式（±)4_{苄基[(苄氧基）羰基]胺基}_3_氟基六氫吡啶-1-φ 羧酸第三·丁酯（中間物27，6克，13·5毫莫耳）在二氣甲烷（50 耄升）中之溶液内’於〇°C下，添加二氧陸圜中之HCi (6 8 宅升）。將反應混合物於室溫下攪拌過夜。藉過濾收集沉澱 物’而得產物，為無色固體，4.4克（86%)。 MS (ESP) : 343 (ΜΗ+ )對 c2 0H2 3 FN2 02 中間物27 順式（±)4_{爷基丨(节氧基機基]胺基卜3_氟基六氫吡啶士羧酸 第二·丁 S旨 於順式（±)4-(;胺基）_3·敗基六氫ττ比唆-1-叛酸第三_丁酯（中 127286 -89- 200831517 間物28，1·1克，3.6毫莫耳）在二氧陸圜（20毫升）與飽和碳酸 鈉（10毫升）中之混合物内，於〇。〇下，逐滴添加氯甲酸字（〇.76 毫升，5.4毫莫耳），並將反應混合物於〇°c下攪拌〗小時。 添加醋酸乙酯（〜20毫升）與鹽水(〜20毫升），並分離液層。將 水相以醋酸乙酯萃取一次，並使合併之有機相以硫酸鎂脫 水乾燥，及在減壓下濃縮，獲得產物，為無色固體，1·4克 (89%) 〇 MS (ESP) : 343 (-BOC，ΜΗ+)對 C2 5 H3! FN2 04 ^-NMR (CDCl3-d) δ ： IA6 (s, 9H) ； L46 (m? 1H) ； 2.00 (m, IH)； 2.91 (m5 2H) ； 4.33 (m5 4H) ； 4.86 (m5 2H) ； 5.16 (m? 2H) ； 7.28 (m5 10H). 中間物28 順式（±) 4-(苄胺基）-3-氟基六氫吡啶小羧酸第三-丁酯 將3-氟基-4-酮基六氫吡啶-1-羧酸第三-丁酯（中間物29，8.1 克，37.3毫莫耳）、苄胺(4.5毫升，41毫莫耳）及3A分子篩在 二氯甲烷（150毫升）中之混合物，於〇°C下，以三乙醯氧基硼 • 氫化鈉（11.8克，56毫莫耳）分次處理。將反應混合物於室溫 下授拌30分鐘，然後過濾。添加飽和碳酸氫鈉水溶液，並 分離液層。將水層以二氯甲烷萃取一次。使合併之有機相 以硫酸鎭脫水乾燥，及在減壓下濃縮。以己烧/醋酸乙酯（3 : 2)矽膠層析，獲得產物，為灰白色固體，6.9克（60%)。 MS(ESP): 309 (MH+)對 C17H25FN202 中間物29 氟基-4-酮基六氫峨啶·1-叛酸第三-丁酯 將4-[(三甲基矽烷基）氧基]-3,6_二氫毗啶·1(2Η)-羧酸第三·丁 127286 -90- 200831517 酯（中間物30，14克’ 51毫莫耳）在乙腈（2〇〇毫升）中之溶液， 於Ot：下’以SELECTFLUORTMqo克，57毫莫耳）分次處理。 將反應混合物於0 C下檀拌30分鐘，接著以酷酸乙酯稀釋， 以飽和氯化鈉洗滌，以硫酸鎂脫水乾燥，及濃縮。以己烷/ 醋酸乙酯（3 · 2)石夕膠層析’獲得產物，為無色油，81克（72%)。 !Η-ΝΜΚ (CDCI3-d) 5-1.48 (s, 9H) ； 2.56 (m? 2H) ； 3.22 (m5 2H)； 4·18 (m，1H) ; 4-45 (m5 1H) ; 4·72 (m5 1H)· 中間物30 4_[(三甲基矽烷基）氧基]_3,6_二氫吡咬-叩办叛酸第三丁酯 將4-酮基·1_六氫吡啶羧酸第三_丁酯（n克，55毫莫耳）與三 乙胺（18.5毫升，132毫莫耳）在DMF(40毫升）中之混合物，於 0 C下，以氯基二甲基石夕烧（8·4毫升，66毫莫耳）逐滴處理。 將反應混合物在80°C下加熱過夜，然後冷卻至室溫。添加 飽和碳酸氫鈉，並將產物以己烷萃取兩次。使合併之有機 萃液以硫酸鎂脫水乾燥，及濃縮，而得14克（93%)產物，為 黃色油。 ^-NMR (CDC13) δ ： 0.18 (s5 9H) ； 1.45 (s, 9H) ； 2.09 (m5 2H) ； 3.51 (m，2H) ; 3·86 (m，2H) ; 4·78 (m，1H)· 中間物31 l-{2-[(3S，4R)-4-胺基甲氧基六氫吡啶小基】乙基卜7•曱氧基喹 喏啉-2(1H)-酮 將{(3S，4R)_3_甲氧基-!·[2_(7_甲氧基·2_酮基p奎喏琳心阳)·基） 乙基]六氫吡啶斗基}胺基甲酸第三·丁酯（中間物32，42〇毫 克，〇·97毫莫耳）在二氯甲烷（5〇毫升）中之溶液以三氟醋酸 127286 -91 - 200831517 (1〇笔升）處理。1小時後，使反應物濃縮至乾涸。使殘留物 溶於氯仿中之15%甲醇(3G毫升）内’並以飽和碳酸氫納溶液 洗務。將水層以15%甲醇/氣仿（4χ3〇毫升）再萃取。使合併 之有機相以硫酸鎂脫水乾燥，及濃縮至乾涸，獲得3ι〇毫克 (97%)粗產物，為油狀物。 MS (ESP) : 333 (MH+)ff C17H24N403 中間物32 ⑩{(3S,4R) 3甲氧基甲氧基士酮基，奎嘆淋_ι(2冠)_基）乙基】 六氫峨咬义基}胺基甲酸第三-丁酯 使7-甲氧基喳喏啉-2(1H)-酮（中間物15，320毫克，ι·79毫莫 耳）在無水DMF(10毫升）中之溶液，於氮氣下，在冰浴中冷 卻，並以氫化鈉（60%，於油中，86毫克，215毫莫耳）處理。 將反應物於室溫下攪拌〜9〇分鐘。使反應物於冰浴中再一次 冷卻，並以甲烷磺酸2-{(3S，4R)-4-[(第三-丁氧羰基）胺基甲 氧基六氫吡咬-l-基}乙酯在無水DMF中之溶液（中間物33， _ 耄莫耳/宅升，1.97晕莫耳）處理。將反應物於室溫下攪 拌過仪’然後在減壓下濃縮至乾涸。使殘留物於醋酸乙酯 與水之間作分液處理。將水相以醋酸乙酯再萃取2χ。使合 併之有機層以硫酸鎂脫水乾燥。於石夕膠上，以15-25%丙酮 在己烷中之梯度液層析，獲得420毫克（55%)產物，為無色固 體。 MS (ESP) : 433 (ΜΗ+)對 C22H32N4〇5 WNMR (DMSO-d6 ) 5 : 1.38(s，9H); 1.43-1.51(m，lH); 1.57-1.72 (m， 1H); 2.20-2.40 (m，2H); 2.55-2.66 (m，2H); 2·67-2·78(ηι，1H); 2.80-2.93 127286 •92· 200831517 (m，1H) ; 3·18 (s，3H) ; 3.29 (s，1H) ; 3.51-3.65 (m，1H) ; 3.92 (s，3H); 4.24-4.43 (m5 2H) ； 6.40 (d5 1H) ； 6.96-7.05 (m9 2H) ； 7.75 (d5 1H) ； 8.04 (s5 1H). 中間物33 甲烷磺酸2_{(3S，4R)-4-[(第三-丁氧羰基）胺基】各甲氧基六氫吡 啶小基}乙酯 將[(3S，4R)-l-(2-羥乙基）各甲氧基六氫吡啶-4-基]胺基曱酸第 三·丁酯（中間物34，540毫克，1.97毫莫耳）在無水二氯甲烷 (20毫升）中之溶液，於〇°C下，以三乙胺（〇·38毫升，2.76毫莫 耳），接著以氯化甲烧績醢（0·18毫升，2.36毫莫耳）處理。15 分鐘後，TLC顯示起始物質完全被消失。以磷酸卸緩衝劑 (1Μ，pH 7)使反應淬滅。將水相以二氯甲燒再萃取（1χ)。將 醋酸乙酯添加至合併之有機相中。在減壓下移除二氯甲烧， 留下產物在醋酸乙酯溶液中。以水洗滌此有機相，以移除 任何殘留之鹽。將水相以醋酸乙酯再萃取（1Χ)。使合併之有 機相以硫酸鈉脫水乾燥，及過濾。將無水DMp (1〇毫升）添 加至濾液中。在減壓下移除醋酸乙酯，留下DMF中之產物， 將其直接使用於下一步驟，無需進一步純化。 中間物34 [(3S，4R)-l-(2-經乙基）_3·甲氧基六氫p比咬_4_基】胺基甲酸第三_ 丁酯 使2-[(3S，4R)-4·(二苄基胺基）-3-甲氧基六氫吡咬+基]乙醇 (中間物35，940毫克，2.66毫莫耳）與二碳酸二_第三_丁酯 (〇·67毫升，2.92毫莫耳）在曱醇（1〇〇毫升）中之溶液於2〇0/〇氫 127286 -93- 200831517 氧化鈀/碳（240耄克）上氫化過夜。經過矽藻土過濾反應混合 物，及在減壓下濃縮至乾涸。於矽膠上，以氯仿中之2_1〇% 甲醇層析，獲得540毫克（74%)產物，為無色油。 4 NMR(DMSO-d6) 6 : 1.38(s，9H); L43-1.50 (m，lH); 1.58-1.73 (m， 1H) ’ 2.15 (d，2H)，2.37 (t，2H) ; 2·54·2·64 (m，1H); 2·75-2·88 (m，1H); 3.22 (s5 3H) , 3.27-3.32 (m5 1H) ； 3.41-3.59 (m, 3H) ； 4.37 (t? 1H) ； 6.35 (d，1H)· 中間物35 2-[(3S，4R)-4-(二苄基胺基)各甲氧基六氫吡啶+基】乙醇 與 中間物36 2-[(3R，4S)_4-(二苄基胺基)·3_甲氧基六氫吡啶小基】乙醇 類似關於中間物7所述，使順式（土)ν，Ν-二苄基各甲氧基六 氫吡啶-4-胺（1.7克，5.5毫莫耳）（WO 2005/068461)、溴基乙醇 (〇·5耄升’ 7·1宅莫耳）及Ν，Ν·二異丙基乙胺（1.4毫升，8.3毫莫 _ 耳）之丨匕合物反應’但在70 C下加熱一小時。於碎膠上，以 S有0·25 鼠氧化叙之一氣甲烧中之5%甲醇層析，獲得1 3 克（68%)順式-外消旋產物，為無色固體。 MS (ESP) ·· 355 (ΜΗ+)對 C22H3()N202 'H NMR (DMSO-d6) ： 1.44-1.58 (m, 1H)； 1.64 (d5 1H)； 1.79-2.08 (m? 2H) ； 2.32 (t? 2H) ； 2.36-2.45 (m? 1H) ； 2.88 (d5 1H) ； 3.13 (d? 1H) ； 3.30 (s, 3H)； 3.40-3.49 (m, 2H)； 3.56 (s, 1H)； 3.59-3.87 (m5 4H); 4.34 (s? m)； 7.11-7.24 (m，2H) ; 7.24-7.40 (m，8H). ，10微 對掌異構物係於對掌性元件OJ管柱（250 x 20毫米 127286 -94- 200831517 米）上，藉由對掌性層析分離，以1: j甲醇/乙醇與〇1%二 乙胺，在ίο毫升/分鐘流率下溶離。(·)異構物(中間物36)係 首先溶離出，接著為⑴異構物（中間物35) ^ 中間物37 1- {2-【(3R，4S)冰胺基各甲氧基六氫吡啶基】乙基甲氧基喹 喏啉-2(1H)-酮 使用類似關於合成中間物所述之程序，使{(3R 4S)_3_甲 φ氧基小[2-(7-曱氧基冬酮基喹喏啉-1(2H)-基）乙基]六氫吡啶斗 基}胺基甲酸第三-丁酯（中間物38，1〇〇毫克，〇·23毫莫耳） 與三氟醋酸反應，獲得70毫克（91%)粗產物，為油狀物。 MS (ESP)： 333 (MH+)fiC17H24N403 中間物38 {(3R，4S)-3·曱氧基-i_[2_(7_甲氧基_2_酮基p奎喏琳^基）乙基] 六氫竹1：咬-4-基}胺基甲酸第三-丁酯 使用類似關於合成中間物32所述之程序，使7-甲氧基p奎 _ u若琳_2(1H)__ (中間物15,530毫克，3.00毫莫耳）、曱烷磺酸 2- {(3R，4S)-4-[(第三-丁氧羰基）胺基]_3_甲氧基六氫吡啶小基}乙 醋（中間物39，〜〇·33毫莫耳/毫升，3·30毫莫耳）及氫化鈉 (60%，於油中，140毫克，3·60毫莫耳）反應。將粗產物藉急 驟式層析純化，以己烷中之25%丙酮溶離，獲得540毫克 (42%)產物，為灰白色固體。 MS (ESP) : 433 (ΜΗ+)對（：221132风〇5 1HNMR(DMSO-d6) (5 : 1.38 (s59H)； 1.42-1.50 (m5 1H)； 1.57-1.72 (m, 1H) ； 2.20-2.38 (m5 2H) ； 2.60 (t, 2H) ； 2.68-2.78 (m5 1H) ； 2.79-2.93 (m5 127286 -95· 200831517 1H) ； 3.18 (s? 3H) ； 3.25-3.31 (m3 1H) ； 3.50-3.67 (m, 1H) ； 3.92 (s? 3H)； 4.23-4.42 (m，2H) ; 6.41 (d，1H) ; 6.96-7.07 (m，2H) ; 7·75 (d，1H) ; 8.04 (s，1H). 中間物39 甲燒磺酸2-{(3R，4S)-4-丨(第三-丁氧羰基）胺基】-3-甲氧基六氫吡 咬-1-基}乙g旨 按關於中間物33所述，使[(3R，4S)4-(2-羥乙基&gt;3-甲氧基六 _ 氫吡啶-4-基]胺基甲酸第三-丁酯（中間物4〇，0.91克，3.3毫 莫耳）、三乙胺（0.64毫升，4.62毫莫耳）及氯化曱烷磺醯（0.31 毫升’ 3.99晕莫耳）反應。將此粗產物直接使用於下一步驟 中，無需進一步純化。 中間物40 [(3R，4S)-l-(2_經乙基）-3-甲氧基六氫峨咬-4-基】胺基甲酸第三-丁酯 使用類似關於合成中間物34所述之程序，使2-[(3R，4S)-4-肇（一爷基胺基）-3-甲氧基六氫峨咬-1-基]乙醇（中間物36，3·2 克’ 9.0宅莫耳）反應’獲得ι·7克（68%)產物，為無色油。 ^ NMR (DMSO-d6) 5 ： 1.38 (s, 9H)； 1.42-1.50 (m, 1H)； 1.58-1.73 (m? 1H)，2·11-2.21 (m，2H) ; 2.38 (t，2H) ; 2.55-2.66 (m，1H) ; 2.77-2.89 (m， 1H), 3.23 (s, 3H) ； 3.28-3.33 (m5 1H) ； 3.41-3.59 (m5 3H) ； 4.38 (s, 1H)； 6.36 (d，1H)· 中間物41 l_{2_[(3S，4R)-4-胺基-3-甲氧基六氫!i比咬-i-基j乙基卜2·酮基-ΐ，2· 二氫喳啉_7-甲腈 127286 -96- 200831517 使用類似關於合成中間物31所述之程序，使{(3s，4R)婚 (7-氰基-2·酮基如林·_·基）乙基]_3•甲氧基六氣峨咬_4_基飧 基甲酸第三-丁酯（中間物42，37〇亳克，〇87毫莫耳）與三氟 醋酸在二氯甲烧中反應，獲得3〇〇毫克（定量）粗產物，為油 狀物。 MS (ESP) : 327 (MH+)對 q 8Η22Ν402 中間物42 {(3S，4R)-l-【2-(7-氰基-2-酮基峻淋-1(2H)-基）乙基]-3-甲氧基六氫 吡啶_4-基}胺基甲酸第三-丁酯 使用類似關於合成中間物32所述之程序，使2-酮基-i，2-二 氫喹啉尽甲腈（中間物5，370毫克，2.20毫莫耳）、甲烷磺酸 2-{(3S，4R)-4-[(弟二-丁氧幾基）胺基]_3·甲氧基六氫?比σ定小基}乙 酯（中間物33，〜〇·24毫莫耳/毫升，2.40毫莫耳）及氫化鈉 (60% ’於油中，11〇毫克，2.60毫莫耳）反應。於石夕膠上，以 己烷中之25-35%丙酮層析，獲得370毫克（39%)產物，為灰白 色固體。 MS (ESP) : 427 (ΜΗ+)對 C23H3GN404 1H NMR(DMSO-d6) 5 : 1.38 (s，9H); 1.42-1.51 (m，1H); 1.57-1.71 (m， 1H) ； 2.18-2.40 (m, 2H) ； 2.56 (t, 2H) ； 2.65-2.76 (m, 1H) ； 2.78-2.90 (m5 1H)； 3.18 (s53H)； 3.27 (s51H)； 3.58 (s5 1H) ； 4.30-4.46 (m? 2H) ； 6.37 (d，1H) ; 6.78 (d，1H) ; 7.66 (dd，1H) ; 7·91 (d，1H) ; 8·01 (d，1H) ; 8.09 (s，1H)_ 中間物43 l-{2-[(3R，4S)-4·胺基各甲氧基六氫吡啶-1-基】乙基卜2-酮基-1，2- 127286 -97- 200831517 二氫喹啉-7-甲腈 使用類似關於合成中間物31所述之程序，使{(3R，4S)-l-[2-(7-氰基-2-酮基喳啉-1(2H&gt;基）乙基]-3-甲氧基六氫吡啶_4-基}胺 基甲酸第三-丁酯（中間物44，320毫克，〇·75毫莫耳）與三氟 醋酸反應，獲得250毫克（定量）粗產物，為油狀物。 MS(ESP): 327 (MH+)對 C18H22N4〇2 中間物44 {(3R，4S)-l-[2-(7-氰基-2-酮基喹啉·1(2Η)_基）乙基】各甲氧基六氫 吡啶_4_基}胺基甲酸第三丁酯 使{(3R，4S)-l-[2-(7-演基-2-酮基ρ奎琳-1(2Η)-基）乙基]-3-甲氧基 六氫吡啶-4-基}胺基甲酸第三-丁酯（中間物45，46〇毫克，〇·98 毫莫耳）與氰化鉀（96毫克，1.5毫莫耳）在乙腈（1〇毫升）中之 混合物脫氣，並以氮滌氣（3次）。添加氣化三丁基錫（14微升 /毫升，在庚烷中，0·90微升，0.003毫莫耳)、4,5-雙（二苯基 膦基)-9,9-二甲基二苯并哌喃（3毫克，0.005毫莫耳）及參（二苯 _ 亞甲基丙酮）二鈀（〇) (5毫克，〇·〇〇5毫莫耳）之溶液。使混合 物脫氣3χ，並於室溫下攪拌30分鐘。使混合物再一次脫氣， 接著加熱至80°C過夜。LC/MS顯示不完全轉化成產物。添加 更多氯化三丁基錫（14微升/毫升，在庚烧中，0.90微升，〇.〇〇3 毫莫耳）、4,5-雙（二苯基膦基)-9,9-二曱基二苯并哌喃（3毫克， 0.005毫莫耳）及參（二苯亞甲基丙酮）二把⑼（5毫克，〇 〇〇5毫 莫耳）。將反應物再一次攪拌過夜，而造成完全轉化成產物。 以二氯曱烷稀釋反應物。以水洗滌有機相。將水相以二氯 甲烷再萃取4x。使合併之有機相以硫酸鈉脫水乾燥，及濃 127286 -98 - 200831517 縮。於矽膠上’以己烷中之25-35%丙酮層析，獲得320毫克 (76%)產物，為黃色固體。 MS (ESP) : 427 (MH+)iC23H3()N404 1H NMR(DMSO-d6) 5 : L33-1.41 (m，9H); 1.42-L50 (m，1H); 1.56-1.73 (m, 1H) ； 2.17-2.41 (m? 2H) ； 2.57 (t? 2H) ； 2.64-2.76 (m? 1H) ； 2.78-2.91 (m，1H) ; 3.13-3.22 (m，3H) ; 3.25-3.30 (m，1H) ; 3.52-3.66 (m，1H); 4,29-4.44 (m5 2H) ； 6.38 (d? 1H) ； 6,79 (d5 1H) ； 7,65 (dd? 1H) ； 7.92 (d5 1H) ; 8.01 (d，1H) ; 8.09 (d，1H). 中間物45 {(3R，4S)-l-[2_(7-演基：酮基，奎淋-1(2h)-基）乙基]-3-甲氧基六氩 吡啶-4-基}胺基甲酸第三-丁酯 使用類似關於合成中間物32所述之程序，使7-溴基喳啉 -2(1H)-酮（中間物46，450毫克，2.00毫莫耳）、甲烷磺酸 2-{(3R，4SH-[(第三·丁氧羰基）胺基]_3_甲氧基六氫吡啶小基}乙 酯（中間物39，〜0.23毫莫耳/毫升，2.30毫莫耳）及氫化鈉 (60%，於油中，100毫克，2·61毫莫耳）反應。將粗產物藉急 驟式層析純化，以15-30%丙酮在己烷中之梯度液溶離，獲 得460毫克（48%)產物，為灰白色固體。 MS (ESP) : 480/482 (ΜΗ+)對 C2 2 Η3 〇 BrN3 〇4 1H NMR (DMSO-d6) 5 : 1.36-1.41 (m，9H); 1.43-1.52 (m，1H); 1·59-1·75 (m? 1H) ； 2.20-2.38 (m5 2H) ； 2.54 (t5 2H) ； 2.63-2.75 (m5 1H) ； 2.77-2.89 (m，1H) ; 3.16-3.23 (m，3H) ; 3·26-3·32 (m，1H) ; 3.52-3.68 (m，1H) ; 4·33 (t，2H); 6·40 (d，1H); 6·64 (d，1H); 7.44 (dd，1H); 7.68 (d，1H); 7.73-7.78 (m，1H) ; 7.91 (d，1H). 127286 -99- 200831517 中間物46 7·溴基喹啉·2(1Η&gt;酮 將（2Ε)-Ν_(3^、苯基)_3_苯基丙烯醯胺（中間物47，16克，53 笔莫耳）與三氯化鋁（31.8克，238毫莫耳）在氯苯（1〇〇毫升） 中’於90 C浴溫下加熱一小時。使反應混合物冷卻至室溫， 並傾倒在冰上。將其攪拌，直到冰已完全熔化為止，過濾 混合物，並以水與醋酸乙酯洗滌，獲得粗產物，為稍微褐 0 色固體，在具有較少產物5-溴基喳啉々(111)-酮（〜3 : 2)之混合 物中’ 8.8克（70%)。此混合物不能被分離。將混合物在氣化 磷酿（50毫升）中，於65°C下加熱一小時。使反應混合物冷卻 至室溫，並傾倒在冰上。使其在〇°C下，以碳酸鈉小心中和， 於醋酸乙酯（300毫升）中萃取，以鹽水洗滌，以硫酸鈉脫水 乾燥’及?辰縮’而得7-漠基-2·氣p套琳與5-溪基-2-氯p奎琳之粗 製混合物。使混合物溶於二氯甲烷（1〇〇毫升）中，以矽膠（〜2〇 克）處理’過濾，並以二氯甲烷洗滌濾餅。將濾液與洗液合 _ 併，及濃縮。使殘留物自甲苯/己烷（〜70毫升，1 : 1)結晶， 提供純7-溴基-2·氣喳啉，3.74克，為無色固體，熔點ii3°c。 ^-NMR (DMSO-d6 ) δ ： 7.63 (d? J 8.4 Hz? 1H) ； 7.81 (dd, J 8.4, 1.6 Hz5 1H)； 8,03 (d5 J 8.4 Hz5 1H)； 8.18 (d5 J 1.6 Hz5 1H)； 8.48 (d, J 8.4 Hz? 1H).(cis)-4-azido-3-hydroxyhexahydropyridine-1.carboxylic acid tert-butyl ester (Intermediate 10) (1.76 g, 7-25 mmol) and imidazole (0.74 g, hydrazine) A mixture of 9 mmoles in DMF (7 mL) was treated with tributyl butyl chloride (1.3 g, 8.7 Torr). The cooling was removed and the mixture was scrambled at room temperature. It was allowed to cool to 〇 ° C and the reaction was quenched with sulphate buffer (iM, pH 7 &lt After 15 minutes, the mixture was diluted with ethyl acetate (1 mL) and brine and evaporated. Chromatography on EtOAc/EtOAc (EtOAc:EtOAc) 'H-NMR (DMSO-d6) 5 : 0.10 (s? 6H); 0.87 (s? 9H); 1.37 (s? 9H); 1.56^1.80 (m? 2H); 3.09-3.30 (m, 2H); 3.46 (m5 2H) ; 3.62 (m, 1H) ; 3.88 (m, 1H). Intermediate 10 (cis (±))-4·azido-3-hydroxyhexahydropyridine-i-carboxylic acid third - butyl ester in (cis)_4-@nitrogen hexahydrop ratio lean _3_alcohol (made according to the procedure described in 2005/066176 for yttrium) (2.1 g, 14.8 mmol) And a mixture of potassium hydroxide (2.5 g, 44 mmol) in isopropanol (2 ml) and dichloromethane (ml), at 〇 ° C, adding di-dicarbonate A solution of the ester (3·9 g, 17.7 mmol) in dichloromethane (10 mL). The cooling was removed and it was stirred at room temperature for 2 hours. The reaction was quenched with water (5 mL) and isopropyl alcohol and dichloromethane were removed under reduced pressure. It was neutralized with potassium phosphate buffer (1 Torr, 7, 100 ml), extracted twice with ethyl acetate (2 χ 3 mL), and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified from methylene chloride (~ 20 ml) to afford -6 % of product as 127286 - 81 - 200831517. The mother liquor was chromatographed with hexane / ethyl acetate (5:1) to afford 353 g of product (35%). MS (ESP): 265·2 (MNa+) vs q οΗ! 8N403 ^-NMRODMSO-d^ 5 : 1.39 (s,9H); 1.58 (m5 1H) ; L74 (m, 1H); 3.20-3.40 (m, 4H) ; 3·69 (m, 2H) ; 5·40 (d, 1H)· Intermediate 11 l-{2-[(3R,4S)-4·Amino-3-hydroxyhexahydropyridine-1· Ethyl}-7-methoxyquinoxaline-2(1H)-one and intermediate 12 l-{2_[(3S,4R)-4·amino-3-hydroxyhexahydropyridine-1· Ethyl]ethyl}-7_decyloxyquinoxalinone 1-[2-{(cis-)-(4-indole-nitro-3-ylhexachloro-p-but-1-yl)}B Benzyl-7-methoxyporphyrin-2(1H)-one (Intermediate 13) (0.507 g, 1.47 mmol) with triphenylphosphine (0.463 g, 1.77 mmol) in acetonitrile/water ( The mixture in 9: 1, 20 ml) was stirred at room temperature for 5 days. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in di-methane (5 mL) and chromatographed eluted eluted eluted eluted It is a colorless rigid foam (0.422 g, 90%). MS (ESP): 319 (MH+) vs. C16H22N403, iH-NMR (DMSO-d6) (5 ·· 1.48 (m, 2H); 1·89 (m, 1H); 2·28 (m, 1H); 2.37 ( Dd5 1H) ; 2.54-2.62 (m5 3H) ; 2.71 (m, 1H) ; 3.45 (m5 1H) ; 3.91 (s5 3H); 4.30 (dd, 2H) ; 6.96-7.00 (m, 2H) ; 7.73 (d , 1H); 8.03 (s, 1H)· (OH and NH2 protons exchanged with methanol). 127286 -82 - 200831517 The racemic mixture was applied to a Chiralpak AD column (250 x 20 mm, 10 μm) to contain 0.1% diethylamine in ethanol/methanol: U separated. Intermediate 12 was first dissolved out, [a] D = +45.5, followed by intermediate u, [a] D = · 44.7 (in methanol/chloroform 1:1) , c = l). Intermediate 13 cis (±))-(4-azido-hydroxypyrohydropyridin-1yl)}ethyl-7-methoxyquinoxaline-2 (1H) -ketone _ 1-[2-(cis) ice azide-3-{[t-butyl(diindenyl) oxalate]oxy}hexahydro b--1-yl) a solution of 7-methoxy-p-quineline-2(1H)-one (intermediate 14, 0.721 g, 1.57 mmol) in THF (5 mL) at room temperature A solution of tetrabutylammonium fluoride in THF (1 M, 2.2 mL) was applied dropwise. After one hour, a saturated aqueous solution of sodium hydrogencarbonate (1 mL) was added, and THF was removed under reduced pressure. It was extracted with dichloromethane/ether (1:1 to 2 mL). The aqueous phase was back-extracted with dichloromethane (1 mL) and the combined organic phases dried over sodium sulfate. Chromatography on hexane/acetone (1:1) afforded the product as a colorless ss. foam, 0.507 g (94%). MS (ESP): 345 (MH+) vs. Ci6h2gN603^-NMR (DMSO-d6) 5: 1.58 (m? 1H); 1.70 (m5 1H); 2.25-2.65 (m? 6H); 3.67 (m, 2H); 3.90 (s,3H); 4.31 (dd,2H) ; 5.11 (m,1H) ; 6.97-7.00 (m,2H) ; 7.73 (d,1H) ; 8.03 (s,1H). Intermediate 14 1-12 -(cis(±))-4-azido-3-{[tert-butyl(dimethyl)]alkyl]oxy}hexahydropyridin-1-yl)ethyl]-7- Methoxyquinoxaline-2(1H)-one using a procedure similar to that described for the synthesis of intermediate 4, 7-methoxyindole 127286 -83 - 200831517 -2(m)-one (intermediate 15 , 0.528 g, 3.00 mmol) with sodium hydride (60% in oil, 132 mg) and 2-cis of methanesulfonate (4-azido_3_{[Third-butyl C- Methyl)cracking]oxy}hexachlorop-pyridin-1-yl)acetic acid (intermediate 6,3 mmol) treatment to obtain the product as a rigid foam, 〇·721 g (52%) . MS (ESP): 459 (MH+) vs. C2 2 H3 4 N6 03 Si 1H-NMR (DMSO-d6) 5 : 0.03 and 0·05 (2xs, 6H); 0.82 (s, 9H); 1.65 (m, 2H) ; 2.25-2.70 (m,6H) ; 3·70 (m,1H) ; 3·90 (s,3H) ; 3·83 (m,1H); 4.24 (m,1H) ; 4.39 (m,1H ; 6.96-7.00 (m, 2H); 7.73 (m, 1H); 8.02 (s, 1H). Intermediate 15 7 · methoxy porphyrin-2 (1H)-one in 8% aqueous sodium hydroxide solution (1·32 liters), 7-methoxy_3,4-dihydroporphyrin-2(1H)-one (intermediate 16,100 g) was added, followed by 3 wt% hydrogen peroxide in water Solution (L17 liters). The reaction mixture was slowly heated to 8 Torr and maintained at this temperature for 4 hours. The heat source was then removed and vinegar acid (150 mL) was added dropwise. The suspension was stirred at room temperature overnight, and the solid which crystallised was collected by filtration to give the product as a tan solid (9 g). MS (ESP): 177 (MH+) vs. C9H8N202^-NMR (DMSO-d6) δ: 3.83 (s? 3Η); 6.76 (d, 1H); 6.90 (dd, 1H); 7.67 (d, 1H); (s? 1H); 12.32 (brs, 1H). Intermediate 16 7-Methoxy-3,4-dihydroquinoxaline-2 (1H&gt; ketone in 18 liter Parr apparatus, [[4- a suspension of methoxy-2-nitrophenyl)imido]acetate (intermediate 17) at 55 psi at 20 weights ❶/〇Pd/C (100 127286 •84-200831517 grams, containing Hydrogenation in the presence of ~50% by weight of water) until no hydrogen is consumed (Note) The reaction is strongly exothermic and the temperature should be controlled by a cooling system to be controlled at about 6 Torr. The reaction mixture was discharged, filtered over EtOAc EtOAc (EtOAc)EtOAc. MS (ESP): 179 (MH+) vs. C9H1 gN2 〇 2 'H-NMR (DMSO-d6) ά : 3.61 (m? 5H); 5.57 (m5 1H); 6.35-6.40 (m? 2H); 6.60 (m , 1H); 10.13 (brs, 1H) · An alternative procedure for intermediate 16 to make N-(4-decyloxy- Ethyl 2-nitrophenyl)glycine (intermediate 18, ι 5 · 8 g of crude material) was dissolved in 200 ml of 1: methanol/acetic acid, treated with 1% palladium on carbon (g) After stirring overnight under a hydrogen atmosphere, the reaction mixture was filtered over EtOAc EtOAc (EtOAc m.). ) for C9Hl 〇Ν2〇2 Intermediate 17 [(4-Methoxy-2-nitrophenyl)imido]Acetylacetate for 4-methoxy-2-nitroaniline (1 kg, 5 95 Mohr) with glyoxylic acid vinegar _ml '50% by weight in toluene, 595 mol) in toluene (1 liter), refluxed in a Dean-Stark apparatus for 8 hours, and under reduced pressure Evaporation gave the crude product as a dark brown oil which was used without further purification. Intermediate 18 Ν-(4·methoxy-2-nitrophenyl)glycolic acid ethyl ester 127286 -85- 200831517 4-methoxy-2-nitroaniline (25·0 g, 0·15 A mixture of ethyl bromoacetate (200 ml, 1.8 mol) and potassium carbonate (3 U g, 〇 23 mol) was heated at 150 ° C for 4.5 hours. After cooling to room temperature, an aqueous sodium hydroxide solution (1M, 600 mL) was added. The mixture was extracted with ethyl acetate (2 x 500 mL). The combined organic phases were dried over magnesium sulfate and concentrated to dryness. Chromatography on 25-30% acetone in hexane gave a crude product of 22.1 g as a red solid. 1H NMR showed the presence of ~20% dialkylation product. This material was used without further purification. XH NMR (DMSO-d6) δ : 1.18-1.23 (t5 3H) ; 3.74 (s5 3H) ; 4.12-4.18 (q5 2H), 4.23-4.25 (d, 2H), 6.90-6.93 (d, 1H); 7.25 -7.29 (dd,1H); 7·51-7.52 (d5 1H) ; 8.23-8.27 (t? 1H). Intermediate 19 cis (±)1_[2-(4_Amino-3-fluoroyl-6 Hydropyridine small) ethyl] fluorenyl 4,2-dihydroquinoline-7-carbonitrile cis (±) {1-[2-(7-cyano-2-ketoporphyrin-; (2Η)-yl)ethyl]-3-fluorohexafluoropyridin-4-yl}amino carboxylic acid tert-butyl ester (intermediate 20,397 mg, 0.95 «m) in chloroform (8 ml) The solution is at 0. Underarm, treated with 3 % trifluoroacetic acid (5 mL) in chloroform. After 5 hours at room temperature, the solvent was removed under reduced pressure to give the product trifluoroacetate which was taken to the next step without further purification. MS (ESP): 315 (MH+) vs. C17H19FN4 〇 intermediate 20 cis (±) {1-丨2-(7-cyano-2-ylquinolinyl)ethyl]fluorohexahydropyridine- 3-Hydryl}aminocarbamic acid tert-butyl ester 127286 -86 - 200831517 2-keto·ι,2-dihydroquinoline-7-indenecarbonitrile (intermediate 5,0) as described for intermediate 4 · 3 g, L7 Halo) suspension in DMF (1 mL) at room temperature with sodium hydride and methanesulfonate cis [(t-butoxycarbonyl)amino]-3- Treatment with fluoropiperidine-l-yl}ethyl ester (intermediate 21, ~17 mmol). Chromatography on hexane/ethyl acetate (2:3) gave the product as a solid, 397 mg (73%). MS (ESP): 415 (ΜΗ+) vs. C22H27FN4 〇3^-NMR (DMSO-d6) δ: 1.37 (s, 9Η); 1.48 (m, 1H); 1.67 (m5 1H); 2.27 (m, 2H) ; 2.56 (m, 2H); 2.96 (m, 1H); 3.15 (m, 1H); 3.46 (m, 1H); 4.34 (m, 2H); 4·60 (m, 1H); 6.77 (m, 1H) 6.91 (m,1H); 7·64 (m,1H); 7·90 (m,1H); 7.99 (m,1H) ; 8.07 (s,1H)· Intermediate 21 A burnt acid cis (±) 2-{4_[(Thr-Butoxycarbonyl)amino]-3·fluoropyridinium-1-yl}ethyl was synthesized using a procedure similar to that described for the synthesis of intermediate 6, in triethylamine The presence of φ under '' cis (±) [3_fluoro-small (2-hydroxyethyl) hexahydropyridin-4-yl]carbamic acid tert-butyl ester (intermediate 22,314 mg, 1.2 Millol) reacts with methane chloride. The crude methanesulfonate was used in the next step without delay. Intermediate 22 cis (±) [3-fluoro-based small (2. hydroxyethyl) hexahydropyridinyl] tert-butyl carbazate in cis (±) [1-(2-{[third -butyl (dimethyl) oxalyl]oxy}ethyl) each gas hexahydropyridine · 4 yl] carbamic acid tert-butyl ester (intermediate 23, 530 mg ' 1.4 millimoles ) in a solution of tetrahydrofuran (1 mL) in hydrazine. Under the armpit, tetrabutylammonium fluoride (1 Torr in THF, 2.8 mL) was added. After 30 minutes, 127286 - 87 - 200831517 was quenched with saturated NaHCO3 and EtOAc (EtOAc) The product was obtained as a colorless solid, 314 mg (85%). ^-NMR (CDCI3-d) ά : 1.43 (s3 9H) ; 1.81 (m? 2H) ; 2.30 (m5 1H); 2.36 (m, 1H); 2.59 (m5 2H); 2·75 (m, 1H) ; 2·95 (m,1H); 3·24 (m,1H); 3.61 (m,2H) ; 3·71 (m,1H) ; 4·68 (m,1H) ; 4·85 (m, 1H)· Intermediate 23 _cis (MHM [t-butyl(dimethyl)-alkyl)oxy}ethyl)-3-fluoro hexahydroindole biting ice base] amino decanoic acid third - Butyl ester cis(1) 1-(2][t-butyl(dimethyl)oxalyl]oxy}ethyl)-3-fluoropyrohydropyridine-4-amine Intermediate 24, 2.8 g, 10.4 mmoles, combined with di-tert-butyl dicarbonate (3.4 g, 15.6 mmol) in tetrahydrofuran (50 mL). After 90 minutes, the reaction mixture was concentrated under reduced pressure. Chromatography with hexane/ethyl acetate (3:2) gave the product as a colorless oil, 3-2 g (82%). _ ^-NMR (CDCl3-d) δ : 0.03 (s5 6H) ; 0.86 (s5 9H) ; 1.43 (s5 9H) ; 1.77 (m5 2H) ; 2·25 (m, 1H) ; 2·37 (m, 1H); 2.58 (m, 2H); 2.95 (m, 1H); 3.26 (m, 1H); 3·62 (m, 1H); 3.74 (m, 2H); 4·65 (m, 1H); 4.83 (m, 1H). Intermediate 24 cis (±) l-(2-{[T-butyl(dimethyl)alkyl)oxy}ethyl)fluorohexahydropyridyl-4 _Amine makes cis (±) benzyl [1-(2-{[tri-butyl(dimethyl))-yl)oxy}ethyl)-3-fluorohexahydropyridine-4- Benzyl carbamic acid ester (intermediate 25, 5.2 g, 1 〇 4 mmol) in anhydrous methanol (15 ml) in palladium hydroxide 20% by weight / 127286 -88 - 200831517 carbon (31 mg) The mixture was hydrogenated for 24 hours, then filtered over Celite, and concentrated under reduced pressure to give the product as a colorless oil, 2.8 g. Intermediate 25 will be cis (±) aryl [1_(2·{丨T-butyl(dimethyl)c-alkyl]oxyanthracene))fluorohexahydropyridin-4-yl]amine Benzyl carbamate will be cis (±) y (3-formyl hexahydropyridin-4-yl) guanidine carboxylic acid hydrazine hydrochloride (intermediate 26 '4.3 g, 6.1 mmol) , (2-bromoethoxy)-tris-butyl dimethyl ketone (9·8 ml, 45.7 mmol) and cesium carbonate (9.9 g, 30.4 mmol) in acetonitrile (150 The mixture in ml) was heated at 60 ° C overnight. Filtration, reaction mixture' and concentration under reduced pressure. The product was obtained as a colorless oil, 5.2 g (yield: 91%). MS (ESP): 501 (MH+) on C28H41FN2〇3Si intermediate 26 cis (±) benzyl (3-fluorohexahydropyridin-4-yl) carbazate in cis (±) 4 _ benzyl Base [(benzyloxy)carbonyl]amino}_3_fluoropyrohydropyridin-1-φcarboxylic acid tert-butyl ester (intermediate 27, 6 g, 13.5 mmol) in di-methane ( In the solution of 50 liters, add HCi (6 8 house liters) in dioxane in the solution at 〇 °C. The reaction mixture was stirred at room temperature overnight. The product was obtained as a colourless solid, 4.4 g (86%). MS (ESP) : 343 (ΜΗ+ ) to c2 0H2 3 FN2 02 Intermediate 27 cis (±) 4_{爷基丨(Ethylene oxy-based) Aminodi 3_Fluorohexahydropyridinecarboxylic acid Di-S-S are intended for cis(±)4-(;amino)_3· yl hexahydro ττ than 唆-1-teric acid third butyl ester (in 127286 -89- 200831517) 28,1· 1 g, 3.6 mmol.) In a mixture of dioxane (20 ml) and saturated sodium carbonate (10 ml), add chloroformic acid (〇.76 ml, 5.4 m) dropwise. Mohr), and the reaction mixture was stirred at 〇 °c for an hour. Add ethyl acetate (~20 ml) and brine (~20 ml), and separate the liquid layer. The aqueous phase was extracted once with ethyl acetate. The combined organic phases were dried over MgSO4 and evaporated and evaporated tolulujjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj H3! FN2 04 ^-NMR (CDCl3-d) δ : IA6 (s, 9H) ; L46 (m? 1H) ; 2.00 (m, IH); 2.91 (m5 2H) ; 4.33 (m5 4H) ; 4.86 (m5 2H) ; 5.16 (m? 2H) ; 7.28 (m5 10H). Intermediate 28 cis (±) 4-(benzylamino)-3- Fluorylhexahydropyridine small carboxylic acid tert-butyl ester 3-fluoro-4-ketohexahydropyridine-1-carboxylic acid tert-butyl ester (intermediate 29, 8.1 g, 37.3 mmol), a mixture of benzylamine (4.5 ml, 41 mmol) and 3A molecular sieves in dichloromethane (150 mL) at 〇 ° C with triethyl ethoxy hydride • sodium hydride (11.8 g, 56 mmol) The reaction mixture was stirred at room temperature for 30 minutes, then filtered. A saturated aqueous solution of sodium hydrogencarbonate was added and the layers were separated. The aqueous layer was extracted once with dichloromethane. Dehydration and drying, and concentrating under reduced pressure. EtOAc/EtOAc (EtOAc (EtOAc) C17H25FN202 Intermediate 29 Fluoro-4-ketohexahydroacridine·1-Resinic acid tert-butyl ester 4-[(Trimethyldecyl)oxy]-3,6-dihydroabipyridine·1 (2Η)-carboxylic acid third · Ding 127286 -90- 200831517 ester (intermediate 30, 14 g '51 mmol) solution in acetonitrile (2 ml), under Ot: 'with SELECTFLUORTM qo grams, 57 millimoles) deal with. The reaction mixture was triturated at 0 C for 30 min then diluted with EtOAc EtOAc. The product was obtained as a colorless oil (yield: hexane/ethyl acetate (3·2). !Η-ΝΜΚ (CDCI3-d) 5-1.48 (s, 9H) ; 2.56 (m? 2H) ; 3.22 (m5 2H); 4·18 (m, 1H) ; 4-45 (m5 1H) ; 72 (m5 1H)· Intermediate 30 4_[(Trimethyldecyl)oxy]_3,6-dihydropyridinyl-叩T-butyl tartrate 4-keto·1_hexahydropyridinium carboxylate a mixture of acid tert-butyl ester (ng, 55 mmol) and triethylamine (18.5 ml, 132 mmol) in DMF (40 mL), chloro dimethyl sulphate at 0 C Xishou (8.4 ml, 66 mmol) was treated dropwise. The reaction mixture was heated at 80 ° C overnight and then cooled to room temperature. Saturated sodium bicarbonate was added and the product was extracted twice with hexane. The combined organic extracts were dried with EtOAc EtOAc (EtOAc) ^-NMR (CDC13) δ : 0.18 (s5 9H) ; 1.45 (s, 9H) ; 2.09 (m5 2H) ; 3.51 (m, 2H) ; 3·86 (m, 2H) ; 4·78 (m, 1H) ·· Intermediate 31 l-{2-[(3S,4R)-4-Aminomethoxyhexahydropyridine small group] ethyl b 7• methoxy quinoxaline-2(1H)-one will be { (3S,4R)_3_methoxy-!·[2_(7_methoxy·2_keto-p-quinonin-cardioin)·yl) ethyl]hexahydropyridyl]aminocarbamic acid • A solution of butyl ester (intermediate 32, 42 mg, 〇·97 mmol) in dichloromethane (5 mL) was treated with trifluoroacetic acid 127286-91 - 200831517 (1 liters). After 1 hour, the reaction was concentrated to dryness. The residue was dissolved in 15% methanol (3 g mL) in chloroform and washed with saturated sodium hydrogen carbonate. The aqueous layer was re-extracted with 15% methanol / EtOAc (4 EtOAc). The combined organic phases were dried with EtOAc EtOAc (EtOAc) MS (ESP) : 333 (MH+)ff C17H24N403 Intermediate 32 10{(3S,4R) 3 methoxymethoxy ketone, 奎 淋 _ ιιιιιιιιιιι Amino-based carboxylic acid tert-butyl ester gives 7-methoxyporphyrin-2(1H)-one (intermediate 15,320 mg, ι·79 mmol) in anhydrous DMF (10 mL) The solution was cooled in an ice bath under nitrogen and treated with sodium hydride (60%, EtOAc, EtOAc. The reaction was stirred at room temperature for ~9 min. The reaction was cooled once more in an ice bath and methanesulfonic acid 2-{(3S,4R)-4-[(T-butoxycarbonyl)aminomethoxyhexahydropyridyl-l-yl} Ethyl ester was treated in anhydrous DMF (intermediate 33, _ 耄mole / house liter, 1.97 faint). The reaction was stirred at room temperature and then concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate. Chromatography on 15-30% acetone in hexanes afforded 420 mg (55%) of product as colorless solid. MS (ESP): 433 (ΜΗ+) vs. C22H32N4 〇5 W NMR (DMSO-d6) 5 : 1.38 (s, 9H); 1.43-1.51 (m, lH); 1.57-1.72 (m, 1H); 2.20-2.40 (m,2H); 2.55-2.66 (m,2H); 2·67-2·78(ηι,1H); 2.80-2.93 127286 •92· 200831517 (m,1H) ; 3·18 (s,3H) 3.29 (s,1H) ; 3.51-3.65 (m,1H) ; 3.92 (s,3H); 4.24-4.43 (m5 2H) ; 6.40 (d5 1H) ; 6.96-7.05 (m9 2H) ; 7.75 (d5 1H ; 8.04 (s5 1H). Intermediate 33 methanesulfonic acid 2_{(3S,4R)-4-[(tris-butoxycarbonyl)amino] methoxy hexahydropyridine small ethyl ester ethyl ester [ (3S,4R)-l-(2-hydroxyethyl) methoxy hexahydropyridin-4-yl]amino decanoic acid tert-butyl ester (intermediate 34,540 mg, 1.97 mmol) A solution of anhydrous methylene chloride (20 mL) was obtained from triethylamine (yield: 38 ml, 2.76 mmol) at 〇 ° C, followed by chlorobenzene (0·18 ml, 2.36 m). Moore) processing. After 15 minutes, TLC showed that the starting material was completely disappeared. The reaction was quenched with a phosphate buffer (1 Torr, pH 7). The aqueous phase was re-extracted with methylene chloride (1 Torr). Ethyl acetate was added to the combined organic phase. The methylene chloride was removed under reduced pressure, leaving the product in ethyl acetate. This organic phase is washed with water to remove any residual salts. The aqueous phase was re-extracted with ethyl acetate (1 Torr). The combined organic phases were dried over sodium sulfate and filtered. Anhydrous DMp (1 mL) was added to the filtrate. The ethyl acetate was removed under reduced pressure to leave the product in DMF which was used directly in the next step without further purification. Intermediate 34 [(3S,4R)-l-(2-ethyl)_3·methoxyhexahydropyp ratio bite_4_yl]carbamic acid tert-butyl ester makes 2-[(3S,4R) -4·(dibenzylamino)-3-methoxyhexahydropyridinium+yl]ethanol (intermediate 35,940 mg, 2.66 mmol) and di-tert-butyl ester dicarbonate • 67 ml, 2.92 mmol) solution in decyl alcohol (1 mL) was hydrogenated over 2 〇 0 / 〇 hydrogen 127286 - 93 - 200831517 palladium oxide / carbon (240 gram) overnight. The reaction mixture was filtered through celite and concentrated to dryness under reduced pressure. Chromatography on 2% hydrazine in chloroform to give 540 mg (yield: 74%) of product as colorless oil. 4 NMR (DMSO-d6) 6 : 1.38 (s, 9H); L43-1.50 (m, lH); 1.58-1.73 (m, 1H) ' 2.15 (d, 2H), 2.37 (t, 2H); 5.4·2·64 (m,1H) 1H); 6.35 (d,1H)· Intermediate 35 2-[(3S,4R)-4-(dibenzylamino)methoxymethoxypyroquinone+yl]ethanol and intermediate 36 2-[ (3R,4S)_4-(dibenzylamino)·3_methoxyhexahydropyridine small group] Ethanol similar to the intermediate 7 described, cis (soil) ν, Ν-dibenzyl each Oxy hexahydropyridin-4-amine (1.7 g, 5.5 mmol) (WO 2005/068461), bromoethanol (〇·5 耄 '7·1 house Moule) and Ν, Ν·diisopropyl The reaction of the ethylamine (1.4 ml, 8.3 mmol) was heated for one hour at 70 C. On a crushed gel, 5% methanol in a gas chromatograph of S. 0.25 was used to obtain 13 g (68%) of the cis-racemic product as a colorless solid. MS (ESP) ··355 (ΜΗ+) vs. C22H3()N202 'H NMR (DMSO-d6): 1.44-1.58 (m, 1H); 1.64 (d5 1H); 1.79-2.08 (m? 2H); (t? 2H); 2.36-2.45 (m? 1H); 2.88 (d5 1H); 3.13 (d? 1H); 3.30 (s, 3H); 3.40-3.49 (m, 2H); 3.56 (s, 1H) ; 3.59-3.87 (m5 4H); 4.34 (s? m); 7.11-7.24 (m, 2H); 7.24-7.40 (m, 8H). , 10 micro-palm isomers in the palm of the OJ tube Columns (250 x 20 mm 127286 - 94 - 200831517 m) were separated by palm chromatography, eluted with 1:j methanol/ethanol and hydrazine 1% diethylamine at a flow rate of ίο ml/min. (·) The isomer (intermediate 36) is first eluted, followed by (1) isomer (intermediate 35) ^ intermediate 37 1- {2-[(3R, 4S) amylamine methoxy six Hydropyridyl]ethylmethoxyquinoxaline-2(1H)-one is similar to the procedure described for the synthesis of intermediates, such that {(3R 4S)_3_methyl oxime is small [2-(7-曱) Oxybutanyl quinoxaline-1(2H)-yl)ethyl]hexahydropyridine hydrazino} methic acid tert-butyl ester (intermediate 38, 1 mg, 〇 23 mmol) Reaction with trifluoroacetic acid gave 70 mg (91%) of crude material. MS (ESP): 333 (MH+)fiC17H24N403 Intermediate 38 {(3R,4S)-3·decyloxy-i_[2_(7-methoxy-2-keto-p-quinone)-ethyl] Hexahydrogen 1: Digestive-4-yl}aminocarbamic acid tert-butyl ester using a procedure similar to that described for the synthesis of intermediate 32 to give 7-methoxy p-quino-u Ruolin_2(1H)__ ( Intermediate 15,530 mg, 3.00 mmol, decanesulfonic acid 2-{(3R,4S)-4-[(T-butoxycarbonyl)amino]_3_methoxyhexahydropyridine small group}B Vinegar (intermediate 39, ~〇·33 mmol/ml, 3·30 mmol) and sodium hydride (60% in oil, 140 mg, 3.60 mmol). The crude product was purified by flash chromatography eluting with EtOAc EtOAc MS (ESP): 433 (ΜΗ+) pair (:221132 pneumatic 〇5 1H NMR (DMSO-d6) (5: 1.38 (s59H); 1.42-1.50 (m5 1H); 1.57-1.72 (m, 1H); 2.20- 2.38 (m5 2H) ; 2.60 (t, 2H) ; 2.68-2.78 (m5 1H) ; 2.79-2.93 (m5 127286 -95· 200831517 1H) ; 3.18 (s? 3H) ; 3.25-3.31 (m3 1H) ; 3.50 -3.67 (m, 1H); 3.92 (s? 3H); 4.23-4.42 (m, 2H); 6.41 (d, 1H); 6.96-7.07 (m, 2H); 7·75 (d, 1H); 8.04 (s, 1H). Intermediate 39 methanesulfonic acid 2-{(3R,4S)-4-indole (t-butoxycarbonyl)amino]-3-methoxyhexahydropyridin-1-yl } 乙为为[(3R,4S)4-(2-Hydroxyethyl]3-methoxyhexahydropyridin-4-yl]carbamic acid tri-butyl as described for intermediate 33 The ester (intermediate 4 〇, 0.91 g, 3.3 mmol), triethylamine (0.64 mL, 4.62 mmol) and decanesulfonium chloride (0.31 mL ' 3.99 </ br> Used directly in the next step without further purification. Intermediate 40 [(3R,4S)-l-(2_ethyl)-3-methoxyhexamidine-4-yl]carbamic acid Tri-butyl ester is used analogously to the synthesis intermediate 34 Order, 2-[(3R,4S)-4-肇(---ylamino)-3-methoxyhexahydroindole-1-yl]ethanol (intermediate 36,3·2 g' 9.0 house The reaction was obtained as a colorless oil. NMR (DMSO-d6) 5: 1.38 (s, 9H); 1.42-1.50 (m, 1H); 1.58-1.73 (m) 1H), 2·11-2.21 (m, 2H); 2.38 (t, 2H); 2.55-2.66 (m, 1H); 2.77-2.89 (m, 1H), 3.23 (s, 3H); 3.28-3.33 (m5 1H) ; 3.41-3.59 (m5 3H) ; 4.38 (s, 1H); 6.36 (d,1H)· Intermediate 41 l_{2_[(3S,4R)-4-Amino-3-methoxy Hexahydro!i ratio bite-i-based j ethyl b 2 keto-oxime, 2 · dihydroporphyrin_7-carbonitrile 127286 -96- 200831517 using a procedure similar to that described for the synthesis of intermediate 31, {(3s,4R) marriage (7-cyano-2.keto group such as linyl) ethyl]_3•methoxy hexazone bite _4_ carbazyl formate third-butyl ester (middle The product was reacted with trifluoroacetic acid in methylene chloride to give 3 mg (yield) of crude product as an oil. MS (ESP): 327 (MH+) vs. q 8 Η 22 Ν 402 Intermediate 42 {(3S,4R)-l-[2-(7-Cyano-2-keto)-1(2H)-yl)ethyl] 3-methoxy hexahydropyridine _4-yl} carbamic acid tert-butyl ester using a procedure similar to that described for the synthesis of intermediate 32 to give 2-keto-i,2-dihydroquinoline Nitrile (intermediate 5,370 mg, 2.20 mmol), methanesulfonic acid 2-{(3S,4R)-4-[(dioxa-butoxy)amino]-3·methoxyhexahydro? Ethyl ester (intermediate 33, ~ 〇 24 mmol/ml, 2.40 mmol) and sodium hydride (60% 'in oil, 11 〇 mg, 2.60 mmol) were reacted. Chromatography on 25-30% acetone in hexane afforded 370 mg (39%) of product as a white solid. MS (ESP): 427 (ΜΗ+) vs. C23H3GN404 1H NMR (DMSO-d6) 5 : 1.38 (s, 9H); 1.42-1.51 (m,1H); 1.57-1.71 (m, 1H); 2.18-2.40 ( m, 2H); 2.56 (t, 2H); 2.65-2.76 (m, 1H); 2.78-2.90 (m5 1H); 3.18 (s53H); 3.27 (s51H); 3.58 (s5 1H); 4.30-4.46 (m 2H) ; 6.37 (d,1H) ; 6.78 (d,1H) ; 7.66 (dd,1H) ; 7·91 (d,1H) ; 8·01 (d,1H) ; 8.09 (s,1H)_ Intermediate 43 l-{2-[(3R,4S)-4.Aminomethylmethoxyhexahydropyridin-1-yl]ethylid-2-keto-1,2-127286-97- 200831517 Dihydrogen Quinoline-7-carbonitrile The procedure described for the synthesis of intermediate 31 was used to give {(3R,4S)-l-[2-(7-cyano-2-ketoporphyrin-1 (2H&gt; Ethyl]-3-methoxyhexahydropyridine 4-yl}aminocarboxylic acid tert-butyl ester (intermediate 44, 320 mg, 〇·75 mmol) was reacted with trifluoroacetic acid to obtain 250 mg (Quantitative) crude product as an oil. MS (ESP): 327 (MH+) to C18H22N4 〇2 Intermediate 44 {(3R,4S)-l-[2-(7-Cyano-2-ketoquinequine Porphyrin·1(2Η)-yl)ethyl] each methoxy hexahydropyridine _4_yl} carbamic acid tert-butyl ester makes {(3R,4S)-l-[2-(7- Tert-butanyl ketolin-1(2Η)-yl)ethyl]-3-methoxyhexahydropyridin-4-yl}carbamic acid tert-butyl ester (intermediate 45, 46 〇 mg , 〇·98 mM) degassed with a mixture of potassium cyanide (96 mg, 1.5 mmol) in acetonitrile (1 mL) and purged with nitrogen (3 times). Add vaporized tributyltin ( 14 μl/ml in heptane, 0. 90 μl, 0.003 mmol, 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (3 Mg (0.005 mmol) and a solution of bis(diphenyl-methyleneacetone)dipalladium (〇) (5 mg, 〇·〇〇 5 mmol). The mixture was degassed for 3 Torr and allowed to stand at room temperature. Stir for 30 minutes. The mixture was again degassed and then heated to 80 ° C overnight. LC/MS showed incomplete conversion to product. Add more tributyltin chloride (14 μL/ml, in hexane, 0.90 s.升,〇.〇〇3 mM), 4,5-bis(diphenylphosphino)-9,9-dimercaptodibenzopyran (3 mg, 0.005 mmol) and ginseng Benzomethyleneacetone) two (9) (5 mg, 〇〇〇 5 mmol). The reaction was stirred once more overnight, resulting in complete conversion to the product. The reaction was diluted with dichloromethane. The organic phase is washed with water. The aqueous phase was re-extracted 4x with methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated 127286 - 98 - 200831517. Chromatography on 25-55% acetone in hexane afforded 320 mg (76%) of product as a yellow solid. MS (ESP): 427 (MH+), i.sup..sup..sup..sup..sup..sup..sup..sup.. -2.41 (m? 2H) ; 2.57 (t? 2H) ; 2.64-2.76 (m? 1H) ; 2.78-2.91 (m,1H) ; 3.13-3.22 (m,3H) ; 3.25-3.30 (m,1H) ; 3.52-3.66 (m, 1H); 4,29-4.44 (m5 2H); 6.38 (d? 1H); 6,79 (d5 1H); 7,65 (dd? 1H); 7.92 (d5 1H); 8.01 (d,1H) ; 8.09 (d,1H). Intermediate 45 {(3R,4S)-l-[2_(7-Alkyl: keto, quinolate-1(2h)-yl)ethyl] 3-methoxyhexafluoropyridin-4-yl}carbamic acid tert-butyl ester using a procedure similar to that described for the synthesis of intermediate 32 to give 7-bromoporphyrin-2(1H)-one (middle 46,450 mg, 2.00 mmol, methanesulfonic acid 2-{(3R,4SH-[(t-butoxycarbonyl)amino]_3_methoxyhexahydropyridyl) ethyl ester 39, ~0.23 mmol/ml, 2.30 mmol, and sodium hydride (60% in oil, 100 mg, 2.61 mmol). The crude product was purified by flash chromatography. 15-30% acetone was dissolved in a gradient of hexane to obtain 460 mg (48%) of product as a white solid. MS (ESP): 480/482 (ΜΗ+) vs. C2 2 Η3 〇BrN3 〇4 1H NMR (DMSO-d6) 5 : 1.36-1.41 (m,9H); 1.43-1.52 (m,1H); 59-1·75 (m? 1H) ; 2.20-2.38 (m5 2H) ; 2.54 (t5 2H) ; 2.63-2.75 (m5 1H) ; 2.77-2.89 (m,1H) ; 3.16-3.23 (m,3H) ; 3·26-3·32 (m,1H) ; 3.52-3.68 (m,1H) ; 4·33 (t,2H); 6·40 (d,1H); 6·64 (d,1H); 7.44 (dd,1H); 7.68 (d,1H); 7.73-7.78 (m,1H); 7.91 (d,1H). 127286 -99- 200831517 Intermediate 46 7 ·Bromoquinoline·2(1Η&gt; ketone (2Ε)-Ν_(3^,phenyl)_3_phenylpropenylamine (intermediate 47, 16 g, 53 moles) with aluminum trichloride (31.8 g, 238 mmol) in chlorobenzene (1 〇〇 ml) Medium 'heat at 90 ° bath temperature for one hour. The reaction mixture was allowed to cool to room temperature and poured on ice. Stir it until the ice has completely melted, and the mixture is filtered and washed with water and ethyl acetate to give a crude product as a slightly brown solid, with less product 5-bromopyridinium (111)- '8.8 g (70%) in a mixture of ketones (~3:2). This mixture cannot be separated. The mixture was heated in a gasified phosphorus (50 ml) at 65 ° C for one hour. The reaction mixture was allowed to cool to room temperature and poured on ice. It was carefully neutralized with sodium carbonate at 〇 ° C, extracted with ethyl acetate (300 ml), washed with brine, dehydrated with sodium sulfate and dried, and obtained 7-methanol-2. A crude mixture of gas p-lin and 5-xiyl-2-chlorop-quine. The mixture was dissolved in dichloromethane (1 mL), filtered with EtOAc (~2 g) and filtered. The filtrate was combined with the washing solution and concentrated. The residue was crystallized from toluene / hexanes (~ 70 mL, 1:1) to afford purified crystals. ^-NMR (DMSO-d6) δ : 7.63 (d? J 8.4 Hz? 1H); 7.81 (dd, J 8.4, 1.6 Hz5 1H); 8,03 (d5 J 8.4 Hz5 1H); 8.18 (d5 J 1.6 Hz5 1H); 8.48 (d, J 8.4 Hz? 1H).

MS (ESP) : 242/244/246 (MH+)對 C9H5BrClN 將此氯化物在5M HC1 (100毫升）與二氧陸圜（i〇毫升）中， 於回流下加熱1小時。使其冷卻，過濾，並以水洗滌，而得 標題化合物2·89克，為無色固體，熔點295。〇。MS (ESP): 242/244/246 (MH+), C.sub.2H.sub.2BrClN. It was cooled, filtered, and washed with EtOAcjjjjjjjj Hey.

MS(ESP): 224.13/226.13 (MH+e+C9H6Bi*NO 127286 -100- 200831517 ^-NMR (DMSO-d6) &lt;5 : 6.51 (d, J 9.6 Hz, 1H) ； 7.32 (dd, J 8.6, 1.6 Hz, 1H) ； 7.46 (d, J 1.6 Hz, 1H) ； 7.61 (d, J 8.6 Hz, 1H) ； 7.88 (d, J 9.6 Hz, 1H) ； 11.80 (brs, 1H). 中間物47 (2Ε)·Ν-(3·溴苯基)·3·苯基丙浠酿胺 於3-溴基苯胺（13.1毫升，120毫莫耳）在二氯甲烷（1〇〇毫升） 與2,6-二甲基吡啶（21毫升，180毫莫耳）中之溶液内，於叱 _ 下，逐滴添加氯化桂皮醯(20克，120毫莫耳）在二氯甲烷（5〇 毫升）中之溶液。使反應混合物達到室溫，並攪拌2小時。 以碌酸鉀緩衝劑（100毫升，1M，pH 7)使反應淬滅，並擾拌 15刀鐘。在減壓下移除二氣甲燒，並將其以醋酸乙_萃取。 以磷酸鹽緩衝劑（類似上述，200毫升）洗滌有機相，以硫酸 鈉脫水乾燥，及濃縮至乾涸。使殘留物自甲苯/己烷結晶， 獲得產物，為無色固體（33.4克，92%)。 MS (ESP) : 302/304 (MH+ )對 q 5 氏 2 BrNO _ H-NMR (DMSO-d6) δ · 6.79 (d? 1H)； 7.23-7.70 (m5 9H)； 8.07 (s? 1H)； 10.38 (s, 1H). 中間物48 l-{2-[(3S，4S)-4-胺基-3-甲氧基六氫吡啶·1_基]乙基卜7_甲氧基，奎 喏啉_2(1H)-酮 按關於中間物31所述，使{(3S，4S)-3-甲氧基-μ[2-(7-甲氧基-2- 酉同基ρ奎嗟淋_1(2Η)·基）乙基]六氯p比咬-4-基}胺基甲酸第三·丁 酯，〇反式對掌異構物（中間物49，190毫克，〇.44毫莫耳） 與三氟醋酸反應，獲得140毫克（93%)粗產物，為油狀物。 127286 -101 - 200831517 MS(ESP): 333(MH+)對 C17H24N403 中間物49 {(3S，4S)-3·甲氧基-1·【2-(7-甲氧基-2-酮基喹喏啉-1(2H)-基）乙基] 六氫吡啶-4-基}胺基甲酸第三-丁酯，㈠反式對掌異構物 與 中間物50 {(3R，4R)-3-甲氧基-1-丨2-(7-甲氧基-2-酮基喳喏啉_1(2H)-基）乙基】 六氫吡啶冬基}胺基甲酸第三-丁酯，⑺反式對掌異構物 使用類似關於合成中間物32所述之程序，使7-甲氧基4 喏琳-2(1H)-酮（中間物15，430毫克，2.45毫莫耳）、甲燒石黃酸 2-{反式（±)-4_[(弟二-丁氧戴基）胺基]·3_甲氧基六氮p比咬_1_基} 乙酉旨（中間物51 ’〜0.27毫莫耳/毫升，2.70毫莫耳）及氫化鈉 (60%，於油中，11〇毫克，2.70毫莫耳）反應。將粗產物藉急 驟式層析純化，以15-35%丙酮/己烷之梯度液溶離，獲得49〇 毫克（45%)產物之外消旋混合物，為灰白色固體。 MS (ESP) : 433 (ΜΗ+)對 C22H32N405 4 NMR(DMSO-d6) δ : 1.21-1.33 (m，lH); L37(s，9H); 1.63-1.74 (m， 1H)； 1.78 (t5 1H)； 2.01 (t? 1H)； 2.62 (t5 2H)； 2.80-2.90 (m? 1H)； 2.96-3.06 (m，1H) ; 3.07-3.18 (m，1H) ; 3·22-3·29 (m，4H) ; 3·93 (s，3H) ; 4·27-4·43 (m，2H) ; 6·78 (d，1H) ; 6·96·7·06 (m，2H) ; 7·75 (d，1H) ; 8·05 (s，1H). 將對掌異構物之混合物於Chiralpak AD_H管柱（250 x 21毫 米’ 5微米）上藉超臨界流體層析分離，以2〇%異丙醇/〇1% 二甲基乙胺之恒定組成梯度液，在60毫升/分鐘之流率下溶 離。這獲得190毫克{(3S，4S)-3-甲氧基小[2-(7-曱氧基冬_基喳 127286 -102- 200831517 喏啉基）乙基]六氫吡啶斗基}胺基甲酸第三-丁酯（中間 物49)(第一個溶離之化合物㈠反式對掌異構物）與携毫克 {(3R,4R) 3甲氧基_1·[2·(7-甲氧基-2,基4 ,若u(2H)_基）乙基] 六氫吡啶斗基}胺基甲酸第三_丁酯（中間物洲）（第二個溶離 之化合物（+)反式對掌異構物）。 中間物51 甲烷磺酸2-{反式（±)·4_【(第三·丁氧羰基）胺基】净甲氧基六氫 外b咬-l-基}乙酿 使用類似關於合成中間物33所述之程序，使[反式（土)小(2_ 羥乙基）各甲氧基六氫吡啶斗基]胺基甲酸第三_丁酯（中間 物52，0.74克’ 2.7耄莫耳）、三乙胺（〇幻毫升，3·78毫莫耳） 及氯化曱烷磺醯（0·25毫升，3·24毫莫耳）反應。將此粗產物 直接使用於下一步驟中，無需進一步純化。 中間物52 【反式（±)_1_(2_羥乙基)_3·甲氧基六氫吡啶冰基】胺基甲酸第三_ 丁酯 使用類似關於合成中間物7所述之程序，使[反式（土)各甲 氧基六氫吡啶斗基]胺基曱酸第三·丁酯（中間物幻，u克， 4.8毫莫耳）、2-溴基乙醇(0·44毫升，6·2毫莫耳）及乙基（二異 丙基）胺（1.25毫升，7.2毫莫耳）反應，獲得〇74克（57%)產物， 為無色油。 ^HNMRiDMSO.d,) 5 ： 1.24-1.34 (m? 1H)； 1.38 (s,9H)； 1.62-1.77 (m5 2H) ； 1.82-1.97 (m? 1H) ； 2.38 (t5 2H) ； 2.73 (d3 1H) ； 2.98-3.18 (m5 3H)； 3·27 (s，3H) ; 3.46 (q，2H) ; 4.39 (t，1H) ; 6·78 (d，1H) 127286 -103 - 200831517 中間物53 【反式（±)各甲氧基六氫吡啶-4·基】胺基甲酸第三-丁酯 使反式（±)-4-[(第三-丁氧讓基）胺基]·3-甲氧基六氫ρ比淀-1-羧酸苄酯（中間物54，0.98克，2.69毫莫耳）在甲醇（50毫升） 中，於10% Pd/C (400毫克)上，在常壓下氫化。1小時後，經 過矽藻土過濾反應混合物。使濾液濃縮至乾涸，獲得0.61 克（98%)產物，為無色油。 1H NMR(DMSO-d6) 5 : 1.14-1.29 (m，lH); L34-L42(m，9H); 1·68 (d5 1Η) ； 2.11 (dd5 1H) ； 2.26-2.38 (m5 1H) ； 2.71-2.82 (m? 1H) ； 2.86-2.98 (m，1H) ; 3.14-3.21 (m，3H) ; 3.26 (s，3H) ; 6·75-6·86 (m，1H)· 中間物54 反式（±&gt;4_[(第三·丁氧羰基）胺基】各甲氧基六氫吡啶小羧酸 苄酯 使反式（±&gt;4·[(第三-丁氧羰基）胺基]_3·經基六氫吡啶小羧 酸爷(中間物55，L0克，2.86毫莫耳）懸浮於1〇毫升甲苯 _ 中，並以氫氧化鈉水溶液之50重量％溶液（6毫升），接著以 硫酸二甲酿（0.33毫升，3.43毫莫耳）與苄基三乙基氣化銨（催 化K )處理。將反應物激烈攪拌一小時。以冰使反應淬滅。 分離液相。將水相以醋酸乙酯再萃取。使合併之有機相以 硫酸鈉脫水乾燥，及濃縮至乾涸。於矽膠·上，以己烷中之 25-50%丙酮層析，獲得〇·78克（78%)產物，為無色油。 MS (ESP)： 365 (MH+)f^c19H28N205 NMR (DMS〇-d6) δ ： 0.55-0.68 (m5 10H) ； 1.04-1.19 (m5 1H)； 2.17-2.46 (m5 2H) ； 2.55-2.64 (m5 2H) ； 2.67-2.80 (m5 1H) ； 2.85-3.07 (m5 127286 •104- 200831517 1H) ; 3·1〇‘3·31 (m，1H) ; 4.09 (s，3H) ; 4.32 (s5 2H) ; 6.45-6.61 (m, 5H)· 中間物55 反式（±)-4-【(第三-丁氧羰基)胺基】各經基六氫吡啶小羧酸苄酯 將反式（±)冬胺基-3-羥基六氫吡啶-1-羧酸苄酯（WO 2005/ 066176，3.0克，12.0毫莫耳）、二碳酸二-第三-丁酯（2_9克， 13.2耄莫耳）及碳酸氫鈉（3.〇克，36.0毫莫耳）在醋酸乙酯/水 (1 : 1 ’ 100毫升）中之混合物激烈攪拌過夜。分離兩相混合 • 物。將水相以醋酸乙酯再萃取lx。使合併之有機相以硫酸 鈉脫水乾燥，及濃縮至乾涸，獲得4.2克產物，為無色固體。 使用此物質而無需進一步純化。 XH NMR (DMSO-d6) δ ： 1.15-1.32 (m, 1H)； 1.35-1.42 (m5 9H)； 1.71-1.83 (m，1H) ; 2.60-2.79 (m，1H) ; 2.82-2.98 (m，1H) ; 3.15-3.29 (m5 2H); 3.74-3.86 (m，1H) ; 3.88-3.98 (m，1H); 5.00 (d，1H); 5.04-5.08 (m，2H); 6.73 (d，1H) ; 7.25-7.42 (m，5H). 中間物56 φ W2·^31^，4%4·胺基_3·甲氧基六氫吡啶·1-基】乙基卜7-甲氧基喹 喏啉·2(1Η)-酮 使用類似關於合成中間物31所述之程序，使{(3r，4r)_3_曱 氧基-l-[2-(7-甲氧基-2-酮基峻喏p林-ι(2Η)-基）乙基]六氫吡啶_4· 基}胺基甲酸第三-丁酯，㈩反式對掌異構物（中間物5〇，19〇 毛克，〇·44毫莫耳）與三氟醋酸反應，獲得15〇毫克（定量） 粗產物，為油狀物。 MS (ESP) : 333 (ΜΗ+)對 C17H24N403 中間物57 127286 -105- 200831517 1·{2-丨(4-胺基·3·經基六氮〃比咬-1-基]乙基}^7·甲氧基p奎1*若p林 -2(m)-酮，反式對掌異構物a 按關於中間物31所述，使{(3-經基小[2-(7-甲氧基-2-酮基峻 喏啉-1(2H)-基）乙基]六氫吡啶4-基}胺基甲酸第三-丁酯，反 式對掌異構物A (中間物58，130毫克，0.31毫莫耳）與三氟 酸反應，獲得78毫克（79%)粗產物，為油狀物。 MS(ESP): 319(MH+)對 C16H22N403 中間物58 {3-經基_1-[2-(7·甲氧基-2-酮基喹喏啉·ι(2Η)-基）乙基]六氫吡啶 冰基}胺基甲酸第三-丁酯，反式對掌異構物a 與· 中間物59MS (ESP): 224.13/226.13 (MH+e+C9H6Bi*NO 127286-100-200831517^-NMR (DMSO-d6) &lt;5: 6.51 (d, J 9.6 Hz, 1H); 7.32 (dd, J 8.6 , 1.6 Hz, 1H); 7.46 (d, J 1.6 Hz, 1H); 7.61 (d, J 8.6 Hz, 1H); 7.88 (d, J 9.6 Hz, 1H); 11.80 (brs, 1H). Intermediate 47 (2Ε)·Ν-(3·Bromophenyl)·3·Phenylpropionylamine in 3-bromoaniline (13.1 ml, 120 mmol) in dichloromethane (1 mL) with 2 In a solution of 6-lutidine (21 ml, 180 mmol), chlorinated cinnabarin (20 g, 120 mmol) in dichloromethane (5 mL) was added dropwise under 叱_ The reaction mixture was allowed to reach room temperature and stirred for 2 hours. The reaction was quenched with potassium sulphate buffer (100 mL, 1 M, pH 7) and spoiled for 15 kn. The gas was burned and extracted with ethyl acetate. The organic phase was washed with a phosphate buffer (similar to the above, 200 ml), dried over sodium sulfate, and concentrated to dryness. The product was obtained as a colorless solid (33.4 g, 92%) MS (ESP): 302/304 (M H+) vs q 5 2 BrNO _ H-NMR (DMSO-d6) δ · 6.79 (d? 1H); 7.23-7.70 (m5 9H); 8.07 (s? 1H); 10.38 (s, 1H). 48 l-{2-[(3S,4S)-4-Amino-3-methoxyhexahydropyridine·1-yl]ethyl b-7-methoxy, quinoxaline-2(1H)-one According to the intermediate 31, {(3S,4S)-3-methoxy-μ[2-(7-methoxy-2-indenyl)-quinoquinone-1(2Η)·yl) Ethyl]hexachloropyptotridyl-4-yl}aminocarbamic acid tert-butyl ester, ruthenium trans-isomer (intermediate 49,190 mg, 〇.44 mmol) reacted with trifluoroacetic acid Obtained 140 mg (93%) of crude material as oil. 127286 - 101 - 200831517 MS (ESP): 333 (MH+) to C17H24N403 Intermediate 49 {(3S,4S)-3·methoxy-1· [2-(7-methoxy-2-ketoquinoxalin-1(2H)-yl)ethyl]hexahydropyridin-4-yl}carbamic acid tert-butyl ester, (a) trans-pair Isomers and intermediates 50 {(3R,4R)-3-methoxy-1-indol-2-(7-methoxy-2-ketoporphyrin-1(2H)-yl)ethyl] Hexa-butyl hexahydrocarbylaminocarbamic acid, (7) trans-palphasomer isomers using a procedure similar to that described for the synthesis of intermediate 32 to make 7-methoxy 4 喏琳-2(1H)-ketone (intermediate 15,430 mg, 2.45 mmol), carbofuric acid 2-{trans (±)-4_[(di-butoxy-yl)amine Base]·3_methoxyhexanitrogen p is more than bite_1_base} Intermediate (51'~0.27 millimoles/ml, 2.70 millimoles) and sodium hydride (60% in oil, 11 〇mg, 2.70 mmol) reaction. The crude product was purified by flash chromatography eluting eluting elut elut MS (ESP): 433 (ΜΗ+) vs. C22H32N405 4 NMR (DMSO-d6) δ: 1.21-1.33 (m, lH); L37 (s, 9H); 1.63-1.74 (m, 1H); 1.78 (t5 1H ); 2.01 (t? 1H); 2.62 (t5 2H); 2.80-2.90 (m? 1H); 2.96-3.06 (m, 1H); 3.07-3.18 (m, 1H); 3·22-3·29 ( m,4H) ; 3·93 (s,3H) ; 4·27-4·43 (m,2H) ; 6·78 (d,1H) ; 6·96·7·06 (m,2H) ; ·75 (d,1H) ; 8·05 (s,1H). Separate the mixture of palmomerisomers on a Chiralpak AD_H column (250 x 21 mm '5 μm) by supercritical fluid chromatography to 2 A constant composition gradient of 〇% isopropanol/〇1% dimethylethylamine was dissolved at a flow rate of 60 ml/min. This gave 190 mg of {(3S,4S)-3-methoxyl[2-(7-fluorenyloxy-ylhydrazone 127286-102-200831517 porphyrinyl)ethyl]hexahydropyridinyl}amino group Formic acid tert-butyl ester (intermediate 49) (first dissolved compound (a) trans-palomerisomer) and carrying milligram {(3R,4R) 3 methoxy_1·[2·(7-A) Oxy-2,yl 4,if u(2H)-yl)ethyl]hexahydropyridyl}aminoglycolic acid tert-butyl ester (intermediate continent) (second dissolved compound (+) trans For palm isomers). Intermediate 51 methanesulfonic acid 2-{trans (±)·4_[(t-butoxycarbonyl)amino] net methoxy hexahydro-external b-l-yl} ethyl brewing similar to synthetic intermediates The procedure described in 33 gives [trans (earth) small (2-hydroxyethyl) methoxy hexahydropyridyl] methic acid tert-butyl ester (intermediate 52, 0.74 g '2.7 耄 mol ), triethylamine (〇 毫升 ml, 3.78 mmol) and decane sulfonium chloride (0·25 ml, 3·24 mmol). This crude product was used directly in the next step without further purification. Intermediate 52 [trans (±)_1_(2_hydroxyethyl)_3·methoxyhexahydropyridyl) Amino carboxylic acid tert-butyl ester was prepared using a procedure similar to that described for the synthesis of intermediate 7 Trans (soil) methoxy hexahydropyridine sulfhydryl] amino decanoic acid tert-butyl ester (intermediate phantom, u grams, 4.8 millimoles), 2-bromoethanol (0.44 ml, 6 • 2 mM) and ethyl (diisopropyl)amine (1.25 mL, 7.2 mmol) were obtained as a colourless oil. ^HNMRiDMSO.d,) 5 : 1.24-1.34 (m? 1H); 1.38 (s, 9H); 1.62-1.77 (m5 2H); 1.82-1.97 (m? 1H); 2.38 (t5 2H); 2.73 (d3 1H) ; 2.98-3.18 (m5 3H); 3·27 (s,3H) ; 3.46 (q,2H) ; 4.39 (t,1H) ; 6·78 (d,1H) 127286 -103 - 200831517 Intermediate 53 [trans (±) each methoxy hexahydropyridin-4 yl] methamic acid tert-butyl ester to give trans (±) -4-[(third-butoxy)amino]·3 -methoxy hexahydro ρ than benzyl-1-carboxylate (intermediate 54, 0.98 g, 2.69 mmol) in methanol (50 mL) over 10% Pd / C (400 mg) Hydrogenation under normal pressure. After 1 hour, the reaction mixture was filtered through celite. The filtrate was concentrated to dryness to give 0.61 g (98%). 1H NMR (DMSO-d6) 5 : 1.14-1.29 (m, lH); L34-L42 (m, 9H); 1.68 (d5 1Η); 2.11 (dd5 1H); 2.26-2.38 (m5 1H); -2.82 (m? 1H) ; 2.86-2.98 (m,1H) ; 3.14-3.21 (m,3H) ; 3.26 (s,3H) ; 6·75-6·86 (m,1H)· Intermediate 54 Formula (±&gt;4_[(t-butoxycarbonyl)amino) benzyl hexahydropyridine small carboxylic acid cis ester (±&gt;4·[(T-butoxycarbonyl)amino group) ]_3·Sodium hexahydropyridine small carboxylic acid (intermediate 55, L0 g, 2.86 mmol) was suspended in 1 mL of toluene _, and a 50% by weight solution (6 mL) of aqueous sodium hydroxide solution, It was then treated with dimethyl sulfate (0.33 mL, 3.43 mmol) and benzyltriethylammonium hydride (catalyzed K). The reaction was stirred vigorously for one hour. The reaction was quenched with ice. The aqueous phase was re-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to dryness. EtOAc EtOAc EtOAc The product is a colorless oil. MS (ESP): 365 (MH+)f^c19H28N205 NMR (DMS〇-d6) δ: 0.55-0. 68 (m5 10H) ; 1.04-1.19 (m5 1H); 2.17-2.46 (m5 2H) ; 2.55-2.64 (m5 2H) ; 2.67-2.80 (m5 1H) ; 2.85-3.07 (m5 127286 •104- 200831517 1H) ; 3·1〇'3·31 (m,1H) ; 4.09 (s,3H) ; 4.32 (s5 2H) ; 6.45-6.61 (m, 5H)· Intermediate 55 Trans (±)-4-[( Third-butoxycarbonyl)amino]benzyl perhexyl hexahydropyridine carboxylic acid benzyl trans-(±)-glyamyl-3-hydroxyhexahydropyridine-1-carboxylate (WO 2005/066176, 3.0 g, 12.0 mmol, di-tert-butyl dicarbonate (2-9 g, 13.2 mol) and sodium bicarbonate (3 g, 36.0 mmol) in ethyl acetate/water (1 The mixture of 1 '100 ml) was stirred vigorously overnight. The two phases were separated and the aqueous phase was re-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to dryness to yield 4.2 g. The product was obtained as a colorless solid. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -2.79 (m, 1H); 2.82-2.98 (m, 1H); 3.15-3.29 (m5 2H); 3.74-3.86 (m, 1H); 3.88-3.98 (m,1H); 5.00 (d,1H); 5.04-5.08 (m,2H); 6.73 (d,1H); 7.25-7.42 (m,5H). Intermediate 56 φ W2·^31^ , 4% 4 · Amino-3 methoxy hexahydropyridine · 1-yl] ethyl b 7-methoxyquinoxaline · 2 (1 fluorene) ketone using a procedure similar to that described for the synthesis of intermediate 31 ,{(3r,4r)_3_decyloxy-l-[2-(7-methoxy-2-keto 喏 喏 林 - - -1(Η)-yl)ethyl]hexahydropyridine _4 · } 胺 胺 胺 第三 , , , , , 胺 胺 胺 胺 胺 胺 胺 胺 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( The crude product is an oil. MS (ESP): 333 (ΜΗ+) vs. C17H24N403 Intermediate 57 127286 -105- 200831517 1·{2-丨(4-Amino·3·Pyridinylhexazinium-1-yl]ethyl}^ 7. methoxy p-quinone 1 * if p-lin-2 (m)-ketone, trans-palphasomer isomer a as described in relation to intermediate 31, such that {(3-pyrase is small [2-(7-) Methoxy-2-ketopyl porphyrin-1(2H)-yl)ethyl]hexahydropyridin-4-yl}carbamic acid tert-butyl ester, trans-p-isomer A (intermediate 58 , 130 mg (0.31 mmol) were reacted with trifluoro acid to give 78 mg (yield: 79%) of crude product as an oil. MS (ESP): 319 (MH+) to C16H22N403 Intermediate 58 {3- 1-[2-(7.Methoxy-2-ketoquinoxalinium·ι(2Η)-yl)ethyl]hexahydropyridylsyl)-amino carbamic acid tert-butyl ester, trans-pair Structure a and · Intermediate 59

{3邊基·Η2-(7-甲氧基-2-酮基喹喏啉-1(2H)-基）乙基]六氫吡啶 4基}胺基甲酸第三_ 丁酯，反式對掌異構物B 將{反式（±)-3-{[第三-丁基（二甲基）石夕烷基]氧基}小[2_(7_甲 • ^基1酮基喹喏啉，況)-基）乙基]六氫吡啶斗基}胺基甲酸 第一-丁知（中間物60，0·60克，1·13毫莫耳）在THF (20毫升） 中之办液，於〇 C下，以氟化四丁基銨在THF中之溶液（1Μ， 2·2,升）處理。將反應物於室溫下攪拌2小時，然後在減壓 下濃縮至乾涸。使粗製殘留物溶於醋酸乙酯中。以水洗滌 t機相。將水相以㈣乙酯再萃取3次。使合併之有機相以 1酉夂納脫水乾燥，及濃縮。於石夕膠上，以二氣甲烧中之 曱予層析，獲得0·27克所要之產物與0.12克Ο-乙醯化副產 物。使此副產物溶於甲醇中，並以催化量之碳酸鉀處理。 127286 -106- 200831517 將其在室溫下擾拌一小時，而造成完全轉化成醇。使反應 混合物濃縮至乾涸。使殘留物於磷酸鉀水溶液緩衝劑（pH =7)與醋酸乙酯之間作分液處理。以醋酸乙酯再萃取2χ水 相。使合併之有機相以硫酸鈉脫水乾燥，過濾，及濃縮至 乾涸，獲得另外100毫克所要之（總計79%)產物。 MS (ESP)： 419 (MH+)^C21H3〇N405 ^NMRiDMSO-d^ (5 ： 1.18-133 (m5 1H)； L38(s59H)； 1.63-1.77 (m5 ⑩ 1H) ； 1.86 (t? 1H) ； 1.97 (t5 1H) ； 2.54-2.64 (m? 2H) ； 2.80-2.93 (m5 1H)； 2.96-3.09 (m，2H); 3.23 (dd，1H); 3·92 (s，3H); 4.32 (t，2H); 4.67 (d，1H); 6.62 (d，1H) ; 6·94-7·06 (m，2H) ; 7.69-7.79 (m，1H) ; 8.04 (s，1H)· 將對掌異構物之混合物於Chimlpak AD-H管柱（250 x 21毫 米’ 5微米）上藉超臨界流體層析分離，以25%異丙醇/〇1% 一甲基乙胺之恒定組成梯度液，在60毫升/分鐘之流率下溶 離。這獲得130毫克{3-羥基-1-[2-(7-甲氧基冬酮基喹喏啉 -1(2Η)-基）乙基]六氫吡啶4-基}胺基甲酸第三-丁酯，反式對 籲掌異構物A (中間物58，第一個溶離之對掌異構物）與130毫 克{(3-經基-1·[2·(7-甲氧基-2-酮基喳喏啉-1(2H)-基)乙基]六氫吡 咬-4-基}胺基曱酸第三·丁酯，反式對掌異構物b (中間物 59，第二個溶離之對掌異構物）。 中間物60 {反式(±)-3-{丨第三-丁基（二甲基)發烷基】氧基卜甲氧基： 酮基喹喏啉基）乙基】六氫吡啶-4-基}胺基甲酸第三-丁酯 使用類似關於合成中間物32所述之程序，使7-曱氧基喳 嗜啉·2(1Η)-酮（中間物15，430毫克，2.43毫莫耳）、甲烷磺酸 127286 -107- 200831517 2-(反式（±)-4·[(第三-丁氧羰基）胺基]-3-{[第三-丁基（二甲基）石夕 烷基]氧基}六氫吡啶-1-基）乙酯（中間物61，〜0·27毫莫耳/毫 升，2·70毫莫耳）及氫化鈉（60%，於油中，110毫克，2.70毫 莫耳）反應。將粗產物藉急驟式層析純化，以10-25%丙酮/ 己烷之梯度液溶離，獲得600毫克(46%)產物，為灰白色固體。 MS (ESP) : 533 (ΜΗ+)對 C27H44N405Si 1H NMR (DMSO-d6) δ ： 0.00 (s? 6H) ； 0.79 (s, 9H) ； L33 (s? 9H)； 1.37-L47 (m, 1H) ； 1.49-1.59 (m9 1H) ； 1.87 (t5 1H) ； 1.95-2.07 (m5 1H)； 2.55-2.66 (m5 2H) ； 2.77-2.89 (m5 1H) ； 2.92-3.02 (m5 1H) ； 3.11 (s5 1H)； 3.30-3.40 (m，1H); 3.89 (s，3H); 4.17-4.41 (m，2H); 6.57 (d，1H); 6.91-7.04 (m，2H) ; 7.72 (d，1H) ; 8·01 (s，1H). 中間物61 甲烷磺酸2·(反式（±)·4_[(第三-丁氧羰基）胺基]各{[第三-丁基 (二甲基)梦烧基】氧基}六氫p比咬小基）乙醋 使用類似關於合成中間物33所述之程序，使[反式（土)各 • {[第三·丁基（二曱基）矽烷基]氧基Η·(2·羥乙基）六氫吡啶-4- 基]胺基曱酸第三-丁酯（中間物62，1〇克，27毫莫耳）、三 乙胺（0.52毫升’ 3.74毫莫耳）及氯化甲烷磺醯（〇25毫升，321 毫莫耳）反應。將此粗產物直接使用於下一步驟中，無需進 一步純化。 中間物62 【反式（±)各{[第三·丁基（二甲 氫吡啶-4-基]胺基甲酸第三 基)發燒基]氧基羥乙基）六 -丁酯 使用類似關於合成中 間物7所述之程序，使（反式（±)-3-{[第 127286 -108- 200831517 一 &quot;丁基（一甲基）碎烧基]氧基}六氯？比〇定-4-基）胺基甲酸第三· 丁酯（中間物63，1·3克，3.9毫莫耳）、2-溴基乙醇（0.36毫升， 5·1宅莫耳）及乙基（二異丙基）胺（1.〇毫升，5.9毫莫耳）反應， 獲得1.0克（67%)所要之產物。 ^ NMR (DMSO-d6) δ ： 0.00 (s5 6H) ； 0.79 (s3 9H) ； 1.33 (s? 9H)； 1·39 (dd，1H); 1.46-1.58 (m，1H); 1.71-L82 (m，1H); 1.82-1.93 (m，1H); 2·33 (t，2H); 2J2 (d，1H); 2.80-2.90 (m，1H); 2,99-3-16 (m，1H); 3.32-3.47 (m，3H) ; 4.36 (t，1H) ; 6.56 (d，1H). 中間物63 (反式（:t)-3-{[第三-丁基（二甲基）矽烷基]氧基}六氫吡啶-4-基） 胺基甲酸第三-丁酯 使反式（±)-4-[(第三-丁氧羰基）胺基]-3-{[第三-丁基（二曱基） 矽烷基]氧基}六氫吡啶小羧酸苄酯（中間物64，1.8克，3.9 毫莫耳）在甲醇（50毫升）中，於10%鈀/碳（〜400毫克）上，在 常壓下氫化一小時。經過矽藻土過濾反應混合物。在減壓 下濃縮濾液，獲得1.3克（定量）產物，為無色固體。 1H NMR (DMSO-d6) (5 : 0·00 (s，6H); 0.80 (s，9H); L20-1.30 (m，1H); 1.33 (s，9H) ; 1.53 (d，1Η) ; 2.15 (dd，1H) ; 2·23-2·39 (m，1H) ; 2.74 (d 1H) ; 2.88 (dd5 1H) ; 3.20-3.30 (m，2H) ; 4.08 (s，1H) ; 6·58 (d，1H)· 中間物64 反式（±)-4-[(第三-丁氧羰基）胺基]-3-{【第三-丁基（二甲基）矽燒 基]氧基}六氫吡啶-1_羧酸苄酯 將反式（±)-4-[(第三-丁氧羰基)胺基&gt;3-羥基六氫吡啶|缓 酸苄酯（中間物55，2·0克，5.7毫莫耳）、咪唑（0·58克，8.6毫 127286 -109- 200831517 莫耳）及第三-丁基（氯基）二甲基矽烷（1·〇克，6.9毫莫耳）在 DMF (15毫升）中之混合物於室溫及氮氣下攪拌過夜。將水 (50毫升）添加至反應物中，並以醚萃取2χ混合物。使合併 之有機相以硫酸鈉脫水乾燥，及濃縮至乾涸。於矽膠上， 以己烷中之10-25%丙酮層析，獲得1.8克（69%)產物，為無色 固體。 ln NMR (DMSO-d6) δ ： 0.00 (Sj 6H) ； 0.80 (s? 9H) ； 1.27-1.41 (m5 _ l〇H); 1.61-1.72 (m，1H); 2.59-3.05 (m，2H); 3.30-3.40 (m，2H); 3.69-3.95 (m，2H) ; 4.92-5.14 (m，2H) ; 6.68 (d5 1H) ; 7.24-7.40 (m，5H). 中間物65{3 aryl Η 2-(7-methoxy-2-ketoquinoxaline-1(2H)-yl)ethyl]hexahydropyridine 4 yl} carbamic acid tert-butyl ester, trans-pair Palmeromer B will be {trans (±)-3-{[Third-butyl(dimethyl)-indolyl]oxy} small [2_(7-methyl•yl 1 ketoquinazoline) Phenanthroline, ethyl)ethyl]hexahydropyridinyl}aminocarbamic acid first-butan (intermediate 60,0·60 g, 1.9 mmol) in THF (20 ml) The solution was treated with a solution of tetrabutylammonium fluoride in THF (1 Μ, 2·2, liter) under EtOAc. The reaction was stirred at room temperature for 2 hr then concentrated to dryness under reduced pressure. The crude residue was dissolved in ethyl acetate. Wash the t phase with water. The aqueous phase was re-extracted 3 times with (tetra)ethyl ester. The combined organic phases were dried over 1 min, and concentrated. On the Shixi gum, the mixture was chromatographed in a gas-fired gas to obtain 0. 27 g of the desired product and 0.12 g of the hydrazine-acetamidine by-product. This by-product was dissolved in methanol and treated with a catalytic amount of potassium carbonate. 127286 -106- 200831517 It was disturbed at room temperature for one hour, resulting in complete conversion to alcohol. The reaction mixture was concentrated to dryness. The residue was partitioned between potassium phosphate aqueous solution buffer (pH = 7) and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness eluting MS (ESP): 419 (MH+)^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 1.97 (t5 1H) ; 2.54-2.64 (m? 2H); 2.80-2.93 (m5 1H); 2.96-3.09 (m, 2H); 3.23 (dd, 1H); 3.92 (s, 3H); 4.32 ( t,2H); 4.67 (d,1H); 6.62 (d,1H) ; 6·94-7·06 (m,2H) ; 7.69-7.79 (m,1H) ; 8.04 (s,1H)· A mixture of palmomers was separated by supercritical fluid chromatography on a Chimlpak AD-H column (250 x 21 mm '5 μm) with a constant composition gradient of 25% isopropanol/〇1% monoethylethylamine. The solution was dissolved at a flow rate of 60 ml/min. This gave 130 mg of {3-hydroxy-1-[2-(7-methoxybutanylquinoxalin-1(2Η)-yl)ethyl] Hexa-butyl hexahydropyridine 4-yl}aminocarbamate, trans-p-isomer A (intermediate 58, the first dissolving para-isomer) with 130 mg {(3-carbyl) -1·[2·(7-methoxy-2-ketoporphyrin-1(2H)-yl)ethyl]hexahydropyridin-4-yl}amino decanoic acid tert-butyl ester, Trans-palphasomer b (intermediate 59, second dissolving para-isomer). Intermediate 60 {trans (±)-3-{丨T-butyl(dimethyl)alkyl]oxybumethoxy: ketoquinoxalinyl)ethyl]hexahydropyridin-4-yl} The third-butyl carbamic acid ester was used in a procedure similar to that described for the synthesis of intermediate 32 to give 7-decyloxyguanidine-2(1Η)-one (intermediate 15,430 mg, 2.43 mmol), Methanesulfonic acid 127286 -107- 200831517 2-(trans (±)-4·[(T-butoxycarbonyl)amino]-3-{[T-butyl(dimethyl)-toluene ]oxy}hexahydropyridin-1-yl)ethyl ester (intermediate 61, ~0·27 mmol/ml, 2.70 mmol) and sodium hydride (60% in oil, 110 mg, 2.70 mmol. The crude product was purified by flash chromatography eluting elut elut elut elut elut elut elut elut (ΜΗ+) vs. C27H44N405Si 1H NMR (DMSO-d6) δ : 0.00 (s? 6H); 0.79 (s, 9H); L33 (s? 9H); 1.37-L47 (m, 1H); 1.49-1.59 (m9 1H) ; 1.87 (t5 1H) ; 1.95-2.07 (m5 1H); 2.55-2.66 (m5 2H) ; 2.77-2.89 (m5 1H) ; 2.92-3.02 (m5 1H) ; 3.11 (s5 1H); 3.30-3.40 (m,1H); 3.89 (s,3H); 4.17-4.41 (m,2H); 6.57 (d,1H); 6.91-7.04 (m,2H); 7.72 (d,1H) ; 01 (s, 1H). Intermediate 61 methanesulfonic acid 2 · (trans (±) · 4 _ [(t-butoxycarbonyl) amine group] {[T-butyl (dimethyl)) Ethyl oxy] hexahydro p is a small base. Ethyl vinegar is similar to the procedure described for the synthesis of intermediate 33, so that [trans (soil) each • {[T. butyl (didecyl) decyl) ]oxy Η·(2·hydroxyethyl)hexahydropyridin-4-yl]amino decanoic acid tert-butyl ester (intermediate 62, 1 gram, 27 mmol), triethylamine (0.52 ml) ' 3.74 mmoles and chloromethanesulfonate (〇 25 ml, 321 mmol). This crude product was used directly in the next step without further purification. Intermediate 62 [trans (±) each {[Third butyl (dimethylhydropyridin-4-yl) carbamic acid tertyl) calcinyl] oxy hydroxyethyl) hexa-butyl ester The procedure described for the synthesis of intermediate 7 is such that (trans (±)-3-{[12728-108-200831517 a &quot;butyl (monomethyl) decyl] oxy} hexachloropyrene -4-yl) carbamic acid tert. butyl ester (intermediate 63, 1.3 g, 3.9 mmol), 2-bromoethanol (0.36 ml, 5.2 m mole) and ethyl (two Reaction of isopropyl)amine (1. mM, 5.9 mmol) gave 1.0 g (67%) of desired product. ^ NMR (DMSO-d6) δ : 0.00 (s5 6H) ; 0.79 (s3 9H) ; 1.33 (s? 9H); 1·39 (dd, 1H); 1.46-1.58 (m, 1H); 1.71-L82 ( m,1H); 1.82-1.93 (m,1H); 2·33 (t,2H); 2J2 (d,1H); 2.80-2.90 (m,1H); 2,99-3-16 (m,1H) 3.32-3.47 (m,3H) ; 4.36 (t,1H) ; 6.56 (d,1H). Intermediate 63 (trans (:t)-3-{[T-butyl(dimethyl))矽alkyl]oxy}hexahydropyridin-4-yl) methamic acid tert-butyl ester to trans(±)-4-[(tris-butoxycarbonyl)amino]-3-{[third - butyl (diindenyl) decyl]oxy} hexahydropyridine carboxylic acid benzyl ester (intermediate 64, 1.8 g, 3.9 mmol) in methanol (50 mL) at 10% palladium on carbon ( ~400 mg), hydrogenated at atmospheric pressure for one hour. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give &lt 1H NMR (DMSO-d6) (5: 0·00 (s, 6H); 0.80 (s, 9H); L20-1.30 (m, 1H); 1.33 (s, 9H); 1.53 (d, 1Η); (dd,1H) ; 2·23-2·39 (m,1H) ; 2.74 (d 1H) ; 2.88 (dd5 1H) ; 3.20-3.30 (m,2H) ; 4.08 (s,1H) ; 6·58 (d,1H)· Intermediate 64 trans (±)-4-[(Thr-Butoxycarbonyl)amino]-3-{[T-butyl(dimethyl)oxime]oxy } Benzylpyridin-1_carboxylic acid benzyl ester trans (±)-4-[(tris-butoxycarbonyl)amino group &gt; 3-hydroxy hexahydropyridine | benzylic acid benzyl ester (intermediate 55, 2 · 0 g, 5.7 mmol, imidazole (0 · 58 g, 8.6 127 286 - 109 - 200831517 Mo) and third - butyl (chloro) dimethyl decane (1 · gram, 6.9 mmol) The mixture was stirred at room temperature under nitrogen overnight. Water (50 mL) was added to the mixture and the mixture was extracted with ether. And concentrating to dryness. Chromatography on 10% toluene in hexanes eluted EtOAc (EtOAc: EtOAc: 0.80 (s? 9H); 1.27-1.41 (m5 _ l〇H); 1.61-1.72 (m,1H); 2.59-3.05 (m,2H); 3.30-3.40 (m,2H); 3.69-3.95 (m,2H) ; 4.92-5.14 (m, 2H); 6.68 (d5 1H) ; 7.24-7.40 (m, 5H). Intermediate 65

胺基各羥基六氫吡啶-1-基]乙基卜7-曱氧基喹喏啉 -2(1H)-酮，反式對掌異構物B 使用類似關於合成中間物31所述之程序，使{3-經基 甲氧基-2-酮基喹喏啉-1(211)_基）乙基]六氫吡啶冰基}胺 基甲酸第三-丁酯，反式對掌異構物B (中間物59，13〇毫克， _ 〇·31毫莫耳）與三說醋酸反應，獲得84毫克（85%)粗產物，為 灰白色泡沫物。 MS(ESP): 319(ΜΗ+)對 C16H22N403 中間物66 3-經基-2·酮基-1，2,3,4·四氫4淋_7-甲腈 將3-(4-氣基-2-硝基苯基）-2-酮基丙酸乙酯（6·5公斤，24.8莫 耳）與乙腈（21升）在22°C下攪拌。分次添加硼氫化鈉（〇·3〇公 斤，7.9莫耳），然後，將混合物於24〇c下攪拌1小時。將醋 酸（65升）添加至溶液中，並使内部溫度升高至仍它。將鐵（3 3 127286 •110- 200831517 公斤）分次添加至溶液（6 χ 0.5公斤）中，歷經1小時。再1小 時後，藉過濾分離產物，以水(3 X 25升）與乙醇（29升）相繼 洗滌，並於減壓下乾燥，獲得產物，為米黃色固體，3 〇7 公斤（66%)。Amino-hydroxy hexahydropyridin-1-yl]ethyl 7-decyloxyquinoxaline-2(1H)-one, trans-p-isomer B using procedures similar to those described for the synthesis of intermediate 31 To make {3-carbyloxy-2-ketoquinoxaline-1(211)-yl)ethyl]hexahydropyridylsyl-aminocarbamic acid tert-butyl ester, trans-pair Compound B (intermediate 59, 13 〇 mg, _ 〇 · 31 mmol) was reacted with three of acetic acid to give 84 mg (85%) of crude material as pale white foam. MS (ESP): 319 (ΜΗ+) on C16H22N403 Intermediate 66 3-Terino-2·keto-1,2,3,4·tetrahydro 4 _7-carbonitrile 3-(4-Galy Ethyl 2-nitrophenyl)-2-ketopropanoate (6.5 kg, 24.8 mol) was stirred with acetonitrile (21 L) at 22 °C. Sodium borohydride (〇·3 〇 kg, 7.9 mol) was added in portions, and then the mixture was stirred at 24 ° C for 1 hour. Acetic acid (65 liters) was added to the solution and the internal temperature was raised to still it. Iron (3 3 127286 • 110 - 200831517 kg) was added to the solution (6 χ 0.5 kg) in portions for 1 hour. After an additional 1 hour, the product was isolated by filtration, washed sequentially with water (3.times.25 liters) and ethanol (29 liters) and dried under reduced pressure to give the product as a beige solid, 3 〇 7 kg (66%) .

熔點&gt;250°C MS (ESP) : 189 (MH+ )對 C〗〇 H8 N2 02 ^-NMR (DMSO-d6) δ ppm ： 2.90-3.20 (m5 2H) ； 4.10-4.20 (m, 1H)； 5·65 (d，1H) 7.15 (s，1H) 7.35-7.45 (m，2H) ; 1〇·38 (s，1H). 中間物67Melting point &gt; 250 ° C MS (ESP): 189 (MH+) vs. C 〇H8 N2 02 ^-NMR (DMSO-d6) δ ppm : 2.90-3.20 (m5 2H); 4.10-4.20 (m, 1H); 5·65 (d,1H) 7.15 (s,1H) 7.35-7.45 (m,2H) ; 1〇·38 (s,1H). Intermediate 67

1_{2·[·4-胺基-3-氣基六氩峨咬-1_基]乙基卜2-嗣基-1，2-二氫p奎琳 -7-甲腈，反式對掌異構物A 於{l-[2_(7-氰基_2-酮基喹啉-1(2H)-基）乙基]-3_氟基六氫吡咬 斗基}胺基甲酸第三-丁酯，反式對掌異構物a (中間物68， 0.30克’ 0.72毫莫耳）在二氯曱烧(20毫升）中之溶液内，添加 三氟醋酸（4毫升），並在冰浴中冷卻。使反應混合物溫熱至 室溫。TLC係在〜30分鐘後顯不純淨，但不完全轉化（含有 0.5%氫氧化銨之15%甲醇/二氣甲烷作為溶離劑）。添加另 外4毫升三氟醋酸。30分鐘後，使反應物濃縮至乾涸。使粗 製殘留物於15%甲醇/二氣甲烷與飽和碳酸氫鈉之間作分液 處理。將水相以飽和碳酸鈉溶液調整至pH〜10。分離液層。 將水相以15%甲醇/二氣甲烷再萃取2x。使合併之有機相以 硫酸納脫水乾燥，過遽’及濃縮至乾涸，獲得030克粗產物， 為油狀物。 MS(ESP): 315(MH+)對 C17H19FN4〇5 127286 -111- 200831517 中間物681_{2·[·4-Amino-3-carbylhexafluoroindole-1_yl]ethyl b-indenyl-1,2-dihydrop-quinion-7-carbonitrile, trans-pair Palmomerium A in {l-[2_(7-cyano-2-ketoquinolin-1(2H)-yl)ethyl]-3-fluorohexahydropyridyl)aminocarbamic acid Tri-butyl ester, trans-p-isomer a ( intermediate 68, 0.30 g '0.72 mmol) in dichlorohydrin (20 mL), trifluoroacetic acid (4 mL) Cool in an ice bath. The reaction mixture was allowed to warm to room temperature. The TLC system was not pure after ~30 minutes but was not completely converted (15% methanol/di-methane containing 0.5% ammonium hydroxide as the eliminator). An additional 4 ml of trifluoroacetic acid was added. After 30 minutes, the reaction was concentrated to dryness. The crude residue was partitioned between 15% methanol/diqi methane and saturated sodium bicarbonate. The aqueous phase was adjusted to a pH of ~10 with a saturated sodium carbonate solution. Separate the liquid layer. The aqueous phase was re-extracted 2x with 15% methanol / di-methane. The combined organic phases were dried over sodium sulfate, dried and evaporated to dryness. MS (ESP): 315 (MH+) vs. C17H19FN4〇5 127286 -111- 200831517 Intermediate 68

{1-丨2-(7-氰基-2-酮基喳啉-1(2H)-基）乙基】·3·氟基六氫吡啶冬基} 胺基甲酸第三-丁酯，反式對掌異構物A 將2-酮基-1，2-二氫喹啉-7-甲腈（中間物5，500毫克，2·94毫 莫耳）在無水DMF (10毫升）中之溶液，於〇°C下，以氫化鈉 (60%，於油中，153毫克，3.82毫莫耳）處理。移除冷卻，並 將反應物於室溫下攪拌90分鐘。使反應物於冰浴中再一次 0 冷卻，且以甲烷磺酸2-{(3R，4R)斗[(第三-丁氧羰基）胺基]_3_氟 基六氫吡啶-l-基}乙酯，反式對掌異構物A (中間物69，〜0.38 毫莫耳/毫升，3.82毫莫耳）在無水DMF中之溶液處理，將反 應物於室溫下攪拌過夜。以水（1〇〇毫升）使反應淬滅，並以 醋酸乙酯（200毫升）萃取。以鹽水洗滌有機層，以硫酸鈉脫 水乾燥，過濾，及在真空中濃縮。於矽膠上，以.10_50〇/〇丙 酮在己烷中之梯度液層析，獲得680毫克（56%)產物，為灰白 色固體。 φ ^ NMR (DMS〇-d6) δ ppm ： 1.25-1.43 (m5 11H) ； 1.67-1.78 (m, 1H)； 2.04-2.17 (m? 2H) ； 2.57-2.68 (m5 2H) ； 2.80-2.89 (m5 1H) ； 3.25-332 (m5 1H) ; 4.27-4.47 (m，2H) ; 4·30 (m，1H) ; 6.78 (d，1H) ; 6.99 (d，1H); 7.66 (dd，1H) ; 7.91 (d，1H) ; 8·01 (d，1H) ; 8.09 (s，1H)· MS (ESP) : 415 (MH+)對 C22H27FN403 中間物69{1-丨2-(7-Cyano-2-ketoporphyrin-1(2H)-yl)ethyl]·3·fluoropyrohydropyridinyl}-tert-butyl carbamic acid Formulation of 2-keto-1,2-dihydroquinolin-7-carbonitrile (intermediate 5,500 mg, 2.94 mmol) in anhydrous DMF (10 mL) The solution was treated with sodium hydride (60% in oil, 153 mg, 3.82 mmol) at EtOAc. Cooling was removed and the reaction was stirred at room temperature for 90 min. The reaction was allowed to cool once again in an ice bath, and methanesulfonic acid 2-{(3R,4R) s[(tris-butoxycarbonyl)amino]_3_fluorohexahydropyridine-l-yl} Ethyl ester, trans-p-isomer A (intermediate 69, ~0.38 mmol/ml, 3.82 mmol) was treated in dry DMF and the reaction was stirred at room temperature overnight. The reaction was quenched with water (1 mL) andEtOAc. The organic layer was washed with brine, dried over sodium sulfate sulfate Chromatography on a silica gel eluting EtOAc EtOAc (EtOAc) φ ^ NMR (DMS〇-d6) δ ppm : 1.25-1.43 (m5 11H) ; 1.67-1.78 (m, 1H); 2.04-2.17 (m? 2H); 2.57-2.68 (m5 2H) ; 2.80-2.89 ( M5 1H) ; 3.25-332 (m5 1H) ; 4.27-4.47 (m, 2H) ; 4·30 (m, 1H) ; 6.78 (d, 1H); 6.99 (d, 1H); 7.66 (dd, 1H) 7.91 (d,1H) ; 8·01 (d,1H) ; 8.09 (s,1H)· MS (ESP) : 415 (MH+) vs. C22H27FN403 Intermediate 69

甲燒續酸2-{4_[(第三-丁氧羰基）胺基]·3_氟基六氫吡啶小基} 乙酯，反式對掌異構物A 於〇 C下’將[3-氟基-1-(2·經乙基）六氮p比咬-4-基]胺基甲酸 127286 -112- 200831517 第二-丁酯，反式對掌異構物A (中間物70，2.0克，7_62毫莫 耳）在無水二氯甲烷（5〇毫升）中之溶液以三乙胺（15毫升， 10.7毫莫耳），接著以氯化甲烷磺醯（〇·71毫升，915毫莫耳） 處理。15分鐘後，以磷酸鉀緩衝劑（1Μ，ρΗ 7)使反應淬滅。 以一氯甲烷萃取水相一次。將醋酸乙酯添加至合併之有機 相中。在減壓下移除二氯甲烷，留下醋酸乙酯溶液中之產 物。以水洗滌此有機相，以移除任何殘留之鹽。將水相以 _醋酸乙酯再萃取（lx)。使合併之有機相以硫酸鈉脫水乾燥， 及過濾。將無水DMF (20毫升）添加至濾液中。在減壓下移 除醋酸乙酯，留下DMF中之產物，其係未延遲而被使用於 下一步驟中，無需進一步純化。 中間物70Methyl benzoate 2-{4_[(T-butoxycarbonyl)amino]·3_fluoropyrohydropyridyl} ethyl ester, trans-p-isomer A under 〇C will [3 -fluoro-1-(2·ethyl)hexanitrogen p butyl-4-yl]carbamic acid 127286 -112- 200831517 second-butyl ester, trans-p-isomer A (intermediate 70, 2.0 g, 7_62 mmol, in anhydrous dichloromethane (5 mL), triethylamine (15 mL, 10.7 mmol), followed by chloromethanesulfonate (〇·71 mL, 915 mM Mohr) processing. After 15 minutes, the reaction was quenched with potassium phosphate buffer (1 Μ, ρ Η 7). The aqueous phase was extracted once with methyl chloride. Ethyl acetate was added to the combined organic phases. The dichloromethane was removed under reduced pressure to leave the product in ethyl acetate. This organic phase is washed with water to remove any residual salts. The aqueous phase was re-extracted (1x) with ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered. Anhydrous DMF (20 mL) was added to the filtrate. The ethyl acetate was removed under reduced pressure to leave a product in DMF which was used in the next step without further purification without further purification. Intermediate 70

[3-氟基-1·(2-羥乙基）六氫吡啶斗基】胺基甲酸第三_丁酯，反 式對掌異構物A 於卞基[3-氟基小(2-羥乙基）六氫吡啶_4_基]胺基曱酸芊酯， φ反式對掌異構物A (中間物71，5·6克，14.5毫莫耳）在乙醇 (1〇〇耄升）中之溶液内，添加20%氫氧化鈀/碳（1·5克）。將反 應物於氫大氣下攪拌過夜。TLC顯示起始物質完全消失（含 有0.5%氫氧化銨之15%甲醇/二氯甲烷作為溶離劑）。然後， 將反應混合物以二碳酸二第三_ 丁酯（4〇毫升，17·4毫莫耳） 處理，並於氮氣下攪拌i小時。TLC顯示起始物質完全消失。 經過矽藻土過濾反應混合物。使濾液濃縮至乾涸，並使其 在矽膠上接受層析，以〇_5%甲醇/二氯甲烷之梯度液，接著 以含有0.25%氫氧化銨之5%甲醇/二氣曱烷之恒定組成梯度 127286 •113- 200831517 液 &gt;谷離’獲得2.86克（75%)產物，為黃色油。 ^ NMR (DMSO-d6) δ ppm ： 1.29-1.45 (m5 11H) ； 1.65-1.79 (m? 1H)； 1.93-2.08 (m，2H) ; 2.38-2.46 (m，2H) ; 2.69-2.79 (m，1H) ; 3.10-3.21 (m， 1H) ； 3.47 (q5 2H) ； 4.26 (m? 1H) 4.44 (t5 1H) ； 6.99 (d, 1H). 中間物71[3-Fluoro-1(2-hydroxyethyl)hexahydropyridyl] Aminobutyric acid tert-butyl ester, trans-p-isomer A in thiol [3-fluoro-based small (2- Hydroxyethyl) hexahydropyridine _4_yl] amino decanoate, φ trans-palphasomer A (intermediate 71, 5.6 g, 14.5 mmol) in ethanol (1 〇〇耄In the solution of liter), 20% palladium hydroxide/carbon (1.5 g) was added. The reaction was stirred overnight under a hydrogen atmosphere. TLC showed complete disappearance of starting material (15% methanol/dichloromethane containing 0.5% ammonium hydroxide as solvent). Then, the reaction mixture was treated with di-tert-butyl dicarbonate (4 mL, 14.7 mmol) and stirred for 1 hour under nitrogen. TLC showed the starting material completely disappeared. The reaction mixture was filtered through celite. The filtrate was concentrated to dryness and subjected to chromatography on silica gel eluting with a gradient of 5% hexanes / methylene chloride, followed by a constant composition of 5% methanol / dioxane containing 0.25% ammonium hydroxide. Gradient 127286 • 113- 200831517 Liquid &gt; Valley Separation' obtained 2.86 g (75%) of product as a yellow oil. ^ NMR (DMSO-d6) δ ppm : 1.29-1.45 (m5 11H) ; 1.65-1.79 (m? 1H); 1.93-2.08 (m, 2H); 2.38-2.46 (m, 2H); 2.69-2.79 (m ,1H) ; 3.10-3.21 (m, 1H) ; 3.47 (q5 2H) ; 4.26 (m? 1H) 4.44 (t5 1H) ; 6.99 (d, 1H). Intermediate 71

苄基-[3-氟基-1-(2-羥乙基）六氫吡啶-4-基]胺基甲酸芊酯，反 式對掌異構物A 與 中間物72Benzyl-[3-fluoro-1-(2-hydroxyethyl)hexahydropyridin-4-yl]carbamic acid decyl ester, trans-p-isomer A and intermediate 72

苄基-丨3-氟基-1-(2-羥乙基）六氫吡啶-4-基]胺基甲酸苄酯，反 式對掌異構物B 將氟化四丁基銨在四氫呋喃中之溶液（1M，21·3毫升，21.3 毫莫耳）於0°C下添加至四氫呋喃（20毫升）中之反式（±)节基 [1-(2_{[弟二-丁基（二甲基）石夕烧基]氧基}乙基）·3_氣基六氫吨 啶斗基]胺基甲酸苄酯（中間物73，8·9克，17.8毫莫耳)内。 _ 使溶液溫熱至室溫，並攪拌一小時。然後，使混合物冷卿 至〇 °C，並以水使反應淬滅。以醋酸乙酯萃取混合物，且以 鹽水洗滌。使有機相以硫酸鈉脫水乾燥，及在減壓下濃縮。 於矽膠上，以己烷中之40%丙酮層析，獲得產物，為油狀 物（5.1 克，74%)。 XH NMR (DMSO-d6) δ ppm ： 1.55 (m5 1H) ； 1.67 (m? 1H) ； 2.〇2 (m 2H) ; 2.40 (m，2H) ; 2.74 (m，1H) ; 3.14-3.28 (m，2H) ; 3·43 (m，2H); 3.93 (m，1H) ; 4·40 (t，2H) ; 4.50 (m，1H) ; 5.06 (m，2H); 7.15 (m，ljj) · 7.20-7.31 (m，8H) ; 7.36 (m，1H)· 127286 -114· 200831517 MS (ESP)： 387.25 (MH+)fiC22H27FN2〇3 外消旋混合物係KChiralpak仙管柱(5〇〇 x 2〇毫米，職 米）上以3有0 J /° —乙胺之乙醇/甲醇（1 :丨）分離。反式對 掌異構物A(中間物71)係首先溶離出，接著為反式對掌異構 物B (中間物72)。關於兩種對掌異構物，對掌性純度（使用 相田於上述製備方法之分析方法）係被測定為&gt;98% a.。 中間物73 φ反式(±)苄基士(2喟第三-丁基(二甲基)發烷基]氧基}乙基)各氟 基六風p比唆_4_基]胺基甲酸爷西旨 將反式（±)爷基（3-氟基六氫吡啶冬基）胺基甲酸芊酯鹽酸 鹽（中間物74，7.98克，2U毫莫耳）、（2-溴基乙氧基）_第三· 丁基一曱基矽烷（6.85克，27.5毫莫耳）及碳酸鉋（17·9克，55.0 宅莫耳）在乙腈（60毫升）中之混合物加熱至6〇〇c，歷經十二 小日t。使反應混合物冷卻至室溫，及在減壓下濃縮至接近 乾涸。以醋酸乙酯稀釋殘留物，並以水及鹽水洗滌。使有 φ 機相以硫酸鈉脫水乾燥，及在減壓下濃縮。於矽膠上，以 己烧中之10%丙酮層析，獲得產物，為油（8·9克，84%)。 1H NMR (氣仿-d3) ά ppm : 0.04-0.07 (s，6Η) ; 0.77-0.88 (s，9Η); 1.58-L74(m，2H); 2.05-2.20 (m，2H); 2.44-2.58 (m，2H); 2.69-2.84 (m， 1H); 3·24 (m，1H); 3·65 (s，2H); 4.44-4.59 (m，3H); 5.11 (s，2H); 7.13-7.28 (m，9H) ; 7.34 (m，2H). MS(ESP): 501·28(ΜΗ+)對 C28H41FN203Si 中間物74 反式（±)芊基(3-氟基六氫吡啶_4_基）胺基甲酸苄酯鹽酸鹽 127286 -115- 200831517 於反式（±)4-{爷基[(爷氧基）幾基]胺基卜3_氟基六氫吡啶小 羧酸第三-丁酯（中間物75，12·05克，28·2毫莫耳）在二氯甲 燒（50毫升）中之溶液内，於下，添加氯化氲（1Μ，在乙 醚中，56.5毫升，56.5毫莫耳）。將溶液攪拌一小時。過濾 固體’並以乙謎洗滌濾餅，獲得產物之單鹽酸鹽（1〇1克， 95%) 〇 NMR (DMS〇.d6) 6 ppm ： 1.68 (m? 1H) ； 2.00-2J5 (m5 1H) ； 3.08 (m，1H); 3.18 (m，1H); 3·34 (m，2H); 3·50 (m，1H); 4·34-4·49 (m，2H); 4.65 (m，1H) ; 5.02 (s，1H) ; 5.14 (d，J = 19.40 Hz，2H) ; 7·15-7·30 (m， 8H) ; 7·32 (m，2H)· MS (ESP) : 343.19 (MH+)對 C2gH23FN202 中間物75 反式（±)冰{爷基[(;氧基）幾基]胺基}各氟基六氫吡啶小羧酸 第三-丁酯 於反式（±)(4-爷胺基）-3-氣基六氫吡啶·!·羧酸第三_丁酯（中 間物76，1〇_3克，33.4毫莫耳）在ι，4-二氧陸圜〇〇〇毫升）中， 與碳酸鈉（5.31克，5(U毫莫耳）在水（2〇毫升）中之溶液内， 於0 C下’逐滴添加氯甲酸苄酯（5.89毫升，41.8毫莫耳）。使 /%合物1熱至室溫’並攪拌兩小時。然後，使反應混合物 濃縮至接近乾涸，並以醋酸乙酯稀釋。以水及鹽水洗滌有 機相’接著以硫酸鈉脫水乾燥。於矽膠上，以己烷中之2〇% 醋酸乙酯層析，獲得產物，為固體（12.5克，94%)。 MS (ESP) : MW (MH+ _B〇c)對 C2 $ Η” 〇4 1H NMR (氣仿-d3) 5 ppm ·· ι·45 (s，9Η) ; 1.67 (d，J = 8·67 Ηζ，2Η); 127286 •116- 200831517 1.84 (m，1H) ; 2.59-2.75 (m，2H) ; 3·91-4·07 (m，2H) ; 4·48 (d，J = 16 Hz， 2H) ; 4.63 (d，J = 16 Hz，1H) ; 5.18 (s，2H) ; 7·20-7·34 (m，10H)· 中間物76 反式（± )(4-爷胺基)各氟基六氫吡啶-1·羧酸第三-丁酯 標題化合物係按藉由Monique B. van Neil等人，J. Med. Chem.， 1999, 42, 2〇87_21〇4與其中之參考資料所述製成。 !H NMR (DMSO-d6) δ ppm ： 132 (m5 1H) ； 1.39 (s5 9H) ； 1.79 (m5 1H); 2.38 (m，1H); 2.73 (m，1H); 3·18 (m，1H); 3.31 (m，1H); 3.46 (m， 1H) ； 3.60-3.80 (m5 3H) ； 4.39 (m, 1H) ； 7.20-7.38 (m5 5H). 中間物77Benzyl-indole-3-fluoro-1-(2-hydroxyethyl)hexahydropyridin-4-yl]carbamic acid benzyl ester, trans-p-isomer B. tetrabutylammonium fluoride in tetrahydrofuran The solution (1M, 21.3 ml, 21.3 mmol) was added to the trans (±) base in tetrahydrofuran (20 mL) at 0 ° C [1-(2_{[di-butyl] Methyl) 石 烧 ] 氧基 氧基 氧基 氧基 氧基 氧基 。 。 。 。 。 ] ] ] ] ] ] 。 。 。 中间 中间 。 。 中间 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 _ Warm the solution to room temperature and stir for one hour. Then, the mixture was cooled to 〇 ° C, and the reaction was quenched with water. The mixture was extracted with ethyl acetate and washed with brine. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. Chromatography on 40% acetone in hexanes eluted elute δ ppm : 1.55 (m5 1H) ; m,2H) ; 3·43 (m,2H); 3.93 (m,1H) ; 4·40 (t,2H) ; 4.50 (m,1H) ; 5.06 (m,2H); 7.15 (m,ljj) · 7.20-7.31 (m,8H); 7.36 (m,1H)· 127286 -114· 200831517 MS (ESP): 387.25 (MH+)fiC22H27FN2〇3 racemic mixture KChiralpak (5〇〇x 2〇) Millimeter, job m) separated by 3 with 0 J / ° - ethylamine ethanol / methanol (1: 丨). The trans-p-isomer A (intermediate 71) is first eluted, followed by the trans-p-isomer B (intermediate 72). Regarding the two palmar isomers, the palm purity (analytical method using the above-mentioned preparation method) was determined to be &gt;98% a. Intermediate 73 φ trans (±) benzyl (2 喟 tri-butyl (dimethyl) carbonyl) oxy} ethyl) each fluorohexaphos p 唆 _ 4 _ group] amine Formic acid is a trans-(±)-based (3-fluorohexahydropyridyl) carbazate hydrochloride (intermediate 74, 7.78 g, 2 U mmol), (2-bromo) A mixture of ethoxy)-t-butyl decyl decane (6.85 g, 27.5 mmol) and carbonated (17. 9 g, 55.0 house Mo) in acetonitrile (60 mL) was heated to 6 〇. 〇c, after twelve days t. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to dryness. The residue was diluted with ethyl acetate and washed with water and brine. The φ machine phase was dehydrated and dried over sodium sulfate, and concentrated under reduced pressure. The product was obtained as an oil (8·9 g, 84%). 1H NMR (gas-d3) ά ppm : 0.04-0.07 (s,6Η); 0.77-0.88 (s,9Η); 1.58-L74(m,2H); 2.05-2.20 (m,2H); 2.44-2.58 (m, 2H); 2.69-2.84 (m, 1H); 3·24 (m, 1H); 3·65 (s, 2H); 4.44-4.59 (m, 3H); 5.11 (s, 2H); 7.13 -7.28 (m,9H) ; 7.34 (m,2H). MS(ESP): 501·28(ΜΗ+) for C28H41FN203Si intermediate 74 trans(±) mercapto (3-fluorohexahydropyridine_4_ Benzyl carbamic acid benzyl ester hydrochloride 127286 -115- 200831517 in trans (±) 4-{ aryl [(yloxy) benzyl] aminyl 3 fluoro hexahydropyridine small carboxylic acid third - Butyl ester (intermediate 75, 12·5 g, 28.2 mmol) in a solution of methylene chloride (50 ml), then added cesium chloride (1 Μ in diethyl ether, 56.5 ml) , 56.5 millimoles). The solution was stirred for one hour. The solid was filtered and the filter cake was washed with a riddle to give the monohydrochloride salt of the product (1 〇 1 g, 95%) NMR (DMS 〇.d6) 6 ppm : 1.68 (m? 1H); 2.00-2J5 (m5 1H) ; 3.08 (m,1H); 3.18 (m,1H); 3·34 (m,2H); 3·50 (m,1H); 4·34-4·49 (m,2H); 4.65 ( m,1H) ; 5.02 (s,1H) ; 5.14 (d,J = 19.40 Hz, 2H) ; 7·15-7·30 (m, 8H) ; 7·32 (m, 2H)· MS (ESP) : 343.19 (MH+) to C2gH23FN202 Intermediate 75 trans (±) ice {Yuyl [(;oxy) aryl] amine} each fluorohexahydropyridine small carboxylic acid tert-butyl ester in trans (± (4-Y-Amino)-3-ylhexahydropyridine···carboxylic acid tert-butyl ester (intermediate 76, 1〇_3 g, 33.4 mmol) in ι,4-diox In 圜〇〇〇ml), add benzyl chloroformate (5.89 ml, dropwise) at 0 °C with sodium carbonate (5.31 g, 5 (U mmol) in water (2 mL). 41.8 mmol). / / Compound 1 was allowed to warm to room temperature ' and stirred for two hours. Then, the reaction mixture was concentrated to near dryness and diluted with ethyl acetate. The organic phase was washed with water and brine. Sodium dehydration The product was obtained as a solid (12.5 g, 94%) eluting with EtOAc EtOAc EtOAc (EtOAc: EtOAc) 〇4 1H NMR (gas-d3) 5 ppm ·· ι·45 (s,9Η); 1.67 (d, J = 8·67 Ηζ, 2Η); 127286 •116- 200831517 1.84 (m,1H); 2.59 -2.75 (m, 2H) ; 3·91-4·07 (m, 2H) ; 4·48 (d, J = 16 Hz, 2H); 4.63 (d, J = 16 Hz, 1H); 5.18 (s , 2H) ; 7·20-7·34 (m, 10H) · Intermediate 76 trans (± ) (4- arylamino) each fluoro hexahydropyridine-1 carboxylic acid tert-butyl ester title compound Made by Monique B. van Neil et al., J. Med. Chem., 1999, 42, 2〇87_21〇4, and references therein. !H NMR (DMSO-d6) δ ppm : 132 (m5 1H) ; 1.39 (s5 9H) ; 1.79 (m5 1H); 2.38 (m, 1H); 2.73 (m, 1H); 3·18 (m, 1H); 3.31 (m, 1H); 3.46 (m , 1H) ; 3.60-3.80 (m5 3H) ; 4.39 (m, 1H) ; 7.20-7.38 (m5 5H). Intermediate 77

l-{2-[4-胺基_3·氟基六氫吡啶_1-基]乙基卜7·甲氧基邊喏淋 -2(1H)-酮，反式對掌異構物A 使用類似關於合成中間物67所述之程序，使{3-氟基 -1·[2·(7-甲氧基-2-酮基喳喏啉-1(2H)-基）乙基]六氫吡啶斗基}胺 基曱酸第三·丁酯，反式對掌異構物A (中間物78，0.30克， φ 0·71毫莫耳）與三氟醋酸反應，獲得〇·25克粗產物，為油狀 物。 MS (ESP) ·· 321 (ΜΗ+)對 C16H21FN402 中間物78 {3-氣基-1·[2·(7-甲氧基-2-酮基喹喏啉-i(2H&gt;基）乙基】六氫吡啶 冬基}胺基甲酸第三-丁酯，反式對掌異構物a 使用類似關於合成中間物68所述之程序，使甲氧基口奎 嗜啉-2(1H)-酮（中間物15，0.52克，2.95毫莫耳）、甲烧碏酸 2-{4-[(第三-丁氧羰基）胺基]-3-氟基六氫吡啶·基}乙自旨，反式 127286 •117- 200831517 對軍異構物A (中間物69，〜0.38毫莫耳/毫升，3 82毫莫耳） 及氫化鈉（60%，於油中，153毫克，3.82毫莫耳）反應。於矽 膠上’以10-50%丙酮在己烧中之梯度液層析，獲得〇幻克 (67%)產物，為灰白色固體。 ^ NMR (DMSO-d6 ) δ ppm ： 1.23-1.45 (m5 11H) ； 1.64-1.80 (m? 1H)； 2.04-2.19 (m，2H) ; 2.61-2.71 (m，2H); 2.84 (d，1H) ; 3.25-3.33 (m，1H); 3.92 (s, 3H) ； 4.27-4.43 (m5 2H) ； 4.28 (m? 1H) ； 16,94-7.05 (m5 3H)； 7.75 (d，1H) ; 8.04 (s，1H)· MS (ESP) : 421 (MH+ )對 C2 〗H2 9 FN4 04 中間物79L-{2-[4-Amino-3·fluorohexahydropyridin-1-yl]ethyl b 7·methoxylated guanidine--2(1H)-one, trans-p-isomer A Using a procedure similar to that described for the synthesis of intermediate 67, {3-fluoroyl-1·[2·(7-methoxy-2-ketoporphyrin-1(2H)-yl)ethyl]hexa Hydrogen pyridinyl}amino decanoic acid, third butyl ester, trans-p-isomer A (intermediate 78, 0.30 g, φ 0·71 mmol) was reacted with trifluoroacetic acid to obtain 〇·25 g. The crude product was an oil. MS (ESP) ·· 321 (ΜΗ+) to C16H21FN402 Intermediate 78 {3-Alkyl-1·[2·(7-Methoxy-2-ketoquinoxaline-i(2H&gt;yl)ethyl </RTI> hexahydropyridinyl}-amino carbamic acid tert-butyl ester, trans-p-isomer a, using a procedure similar to that described for the synthesis of intermediate 68, to give methoxy quinoxaline-2(1H)- Ketone (intermediate 15, 0.52 g, 2.95 mmol), 2-{4-[(T-butoxycarbonyl)amino]-3-fluoropyridinyl} , trans 127286 •117- 200831517 to the isomer A (intermediate 69, ~0.38 mmol/ml, 3 82 mmol) and sodium hydride (60% in oil, 153 mg, 3.82 mmol) The reaction was carried out on a silica gel eluting with a gradient of 10-50% acetone in hexane to give the product (67%) as an off-white solid. NMR (DMSO-d6) δ ppm : 1.23- 1.45 (m5 11H) ; 1.64-1.80 (m? 1H); 2.04-2.19 (m, 2H) ; 2.61-2.71 (m, 2H); 2.84 (d, 1H); 3.25-3.33 (m, 1H); 3.92 (s, 3H); 4.27-4.43 (m5 2H); 4.28 (m? 1H); 16,94-7.05 (m5 3H); 7.75 (d,1H); 8.04 (s,1H)· MS (ESP): 421 (MH+) to C2 H2 9 FN4 04 Intermediate 79

1- {2-[4-胺基-3-氟基六氫吡啶小基]乙基}_2，基^•二氫喹啉 -7-甲腈，反式對掌異構物B 使用類似關於合成中間物67所述之程序，使{i_[2_(7_氰基 _2_酮基喹淋-1(2H&gt;基）乙基]-3-氟基六氫吡啶冬基}胺基甲酸 弟二-丁 S曰，反式對萃異構物B (中間物8〇，〇 %克，ο·%毫莫 φ耳）與三氟醋酸反應，獲得〇·25克粗產物，為油狀物。 MS(ESP): 315(ΜΗ+)對 C17H19FN40 中間物801-{2-[4-Amino-3-fluorohexahydropyridinyl]ethyl}_2,yl^•dihydroquinolin-7-carbonitrile, trans-p-isomer B The procedure described in the synthesis of intermediate 67 is such that {i_[2_(7-cyano-2-oxoquinolin-1(2H&gt;yl)ethyl]-3-fluoropyrohydropyridyl)aminocarbamic acid Di-Di-S-, trans-extracted isomer B (intermediate 8 〇, 〇% gram, ο·% mM) and trifluoroacetic acid to obtain 〇·25 g of crude product as oil MS (ESP): 315 (ΜΗ+) vs. C17H19FN40 Intermediate 80

{1-【2-(7-氰基-2-嗣基，奎琳-1(2H)-基）乙基卜3_氟基六氫吡啶‘基} 胺基甲酸第三-丁酯，反式對掌異構物B 使用類似關於合成中間物68所述之程序，使2_酮基-；1，2_二 氫4淋-7-甲腈（中間物5，0·50克，2.94毫莫耳）、甲烷續酸 2- {4-[(第二-丁氧羰基）胺基]-3-氟基六氫吡啶小基丨乙酯，反式 對掌異構物Β (中間物81，〜〇·38毫莫耳/毫升，3·82毫莫耳） 127286 •118- 200831517 及氫化鈉（60%，於油中，153毫克，3.82毫莫耳）反應。於矽 膠上，以10_50%丙酮在己烷中之梯度液層析，獲得0.64克 (53%)產物，為灰白色固體。 MS(ESP): 415(MH+)對 C22H27FN403 ^ NMR (DMSO-d6) δ ppm ： 1.25-1.43 (m5 11H) ； 1.67-1.78 (m? 1H)； 2.04-2.17 (m，2H) ; 2.57-2.68 (m，2H) ; 2·80-2·89 (m，1H) ; 3.25-3.32 (m， 1H) ； 4.27-4,47 (m? 2H) ； 430 (m3 1H) ； 6.78 (d? 1H) ； 6.99 (d5 1H)； 7.66 (dd，1H) ; 7.91 (d，1H) ; 8.01 (d，1H) ; 8·09 (s，1H). *中間物81{1-[2-(7-Cyano-2-indenyl, quinolin-1(2H)-yl)ethyl b-3-fluorohexahydropyridinyl}-amino carboxylic acid tert-butyl ester, anti The formula for the palmomeromer B was similar to that described for the synthesis of intermediate 68 to give 2-keto-; 1,2-dihydrotetralin-7-carbonitrile (intermediate 5,0.50 g, 2.94). Mol), methane-reductive acid 2-{4-[(second-butoxycarbonyl)amino]-3-fluoropyrohydropyridinyl ethyl ester, trans-palomerisomer Β (intermediate 81, ~〇·38 mmol/ml, 3.82 mmol) 127286 •118- 200831517 and sodium hydride (60% in oil, 153 mg, 3.82 mmol). Chromatograph on 10% to 50% of EtOAc in EtOAc (EtOAc) MS (ESP): 415 (MH+) vs. C22H27FN403 NMR (DMSO-d6) δ ppm : 1.25-1.43 (m5 11H); 1.67-1.78 (m? 1H); 2.04-2.17 (m, 2H); 2.57-2.68 (m, 2H); 2·80-2·89 (m, 1H); 3.25-3.32 (m, 1H); 4.27-4, 47 (m? 2H); 430 (m3 1H); 6.78 (d? 1H 6.99 (d5 1H); 7.66 (dd,1H) ; 7.91 (d,1H) ; 8.01 (d,1H) ; 8·09 (s,1H). *Intermediate 81

甲烷磺酸2-{4-[(第三·丁氧羰基）胺基]-3-氟基六氫吡啶小基} 乙酯，反式對掌異構物B 使用類似關於合成中間物69所述之程序，使[3-1基 罗莖乙基）六氣p比tr定-4-基]胺基甲酸第三-丁醋，反式對掌異構 物B (中間物82，2.0克，7.62毫莫耳）、三乙胺（1·5毫升，1〇 7 宅莫耳）及氯化甲烧續醯(0·71毫升，9.15毫莫耳）反應。將此 _ 粗產物直接使用於下一步驟中，無需進一步純化。 中間物82 [3-氟基小(2-羥乙基）六氫吡啶-4-基]胺基甲酸第三·丁酯，反 式對掌異構物Β 使用類似關於合成中間物70所述之程序，使爷基氣基 小(2-¾乙基）六氫ρ比咬_4_基]胺基甲酸爷g旨，反式對掌異構 物B(中間物72，5·6克，！4.4毫莫耳）、20%氫氧化鈀/碳（〇5 克）及二碳酸二-第三-丁酯（3.5克，15.8毫莫耳）反應。於矽膠 上層析，以醋酸乙酯中之10%甲醇（0.1%氫氧化銨）溶離，獲 127286 -119- 200831517 得2.9克（76%)產物，為油狀物。 XH NMR (CDCI3) δ ppm 1.36-L55 (m, 1〇Η) ； 2.02-2.31 (m, 3H)； 2.52-2.64 (m5 2H) ； 2.72-2.82 (m, 2H) ； 3.09-3.20 (m5 1H) ； 3.60 (t, 3H)； 4.31 (m，1H) ; 4.80 (d，1H) 中間物832-{4-[(Thrs. Butoxycarbonyl)amino]-3-fluorohexahydropyridyl) ethyl ester, trans-p-isomer B is similar to that used in the synthesis of intermediates 69 The procedure described is such that [3-1 ketone stem ethyl) hexaqip is more than ter-4-yl] carbamic acid tert-butyl vinegar, trans-palphaliomer B (intermediate 82, 2.0 g) , 7.62 millimolar), triethylamine (1.5 ml, 1〇7 house Moule) and a continuous reaction of methylamine (0.71 ml, 9.15 mmol). This crude product was used directly in the next step without further purification. Intermediate 82 [3-Fluorosuccinyl (2-hydroxyethyl)hexahydropyridin-4-yl]carbamic acid tert-butyl ester, trans-p-isomer hydrazine using similar to synthetic intermediate 70 The procedure is to make the base gas base small (2-3⁄4 ethyl) hexahydro ρ than the bite _4_ yl] carbamic acid for the purpose of the trans, the palm to the isomer B (intermediate 72, 5. 6 grams , 4.4 mmol, 20% palladium hydroxide/carbon (〇5 g) and di-tert-butyl dicarbonate (3.5 g, 15.8 mmol). Chromatography on silica gel, eluting with 10% methanol (0.1% ammonium hydroxide) in ethyl acetate afforded y. XH NMR (CDCI3) δ ppm 1.36-L55 (m, 1〇Η); 2.02-2.31 (m, 3H); 2.52-2.64 (m5 2H); 2.72-2.82 (m, 2H) ; 3.09-3.20 (m5 1H ; 3.60 (t, 3H); 4.31 (m, 1H); 4.80 (d, 1H) Intermediate 83

l-{2-【4-胺基-3-氟基六氫吡啶·1_基】乙基曱氧基喹喏琳 -2(1H)-酮，反式對掌異構物B 使用類似關於合成中間物67所述之程序，使{3-氟基 -Η2·(7-甲氧基-2-酮基喹喏啉·1(2Η)·基）乙基]六氫吡啶斗基}胺 基甲酸第三-丁酯，反式對掌異構物Β (中間物84，0·33克， 〇·78毫莫耳）與三氟醋酸反應，獲得〇·27克粗產物，為油狀 物0 MS (ESP) : 321 (ΜΗ+)對 C! 6Η2! FN402 中間物84 {3-氟基-l-[2-(7-甲氧基-2-酮基4喏淋_1(211)_基）乙基]六氫吡咬 冬基}胺基甲酸第三-丁酯，反式對掌異構物β 使用類似關於合成中間物68所述之程序，使7_甲氧基峻 α若淋·2(1Η)-酮（中間物15，0.52克，2.95毫莫耳）、甲燒石黃酸 [(弟二-丁氧魏基）胺基]_3·散基六氫μ比咬_1_基}乙酉旨，反式 對莩異構物Β (中間物81，〜0.38毫莫耳/毫升，3.82毫莫耳） 及氫化鈉（60%，在油中，153毫克，3.82毫莫耳）反應。於矽 膠上’以10-50%丙酮在己烷中之梯度液層析，獲得〇 93克 (78%)產物，為灰白色固體。 MS (ESP) : 421 (ΜΗ+)對 C21H29FN4〇4 127286 •120- 200831517 XH NMR (DMSO-d6) δ ppm ： L23-1.45 (m5 11H) ； L64-1.80 (m, 1H)； 2.04-2.19 (m? 2H) ； 2.61.2.71 (m5 2H) ； 2.84 (d5 1H) ； 3.25-3.33 (m? 1H)； 3.92 (s，3H) ; 4.27-4.43 (m，2H) ; 4.28 (m，1H) ; 16·94-7·05 (m，3H); 7.75 (d，1H) ; 8.04 (s，1H). 中間物85 l-{2-【(3R，4R)-4-胺基·3·甲氧基六氫吡啶基]乙基卜2-酮基-1，2-二氫喳啉-7-甲腈 將{(3R，4R)-H2-(7-氰基-2-酮基喳啉-l(2H)-基）乙基]-3-曱氧基 六氫吡啶-4-基}胺基甲酸第三-丁酯（中間物86，280毫克，0.66 毫莫耳）在二氯甲烷（30毫升）中之溶液以三氟醋酸（10毫升） 處理。1小時後，使反應物濃縮至乾涸。使殘留物溶於氯仿 中之15%甲醇（30毫升）内，並以飽和碳酸氫鈉溶液洗滌。將 水層以餘和碳酸鈉溶液調整至pH〜1〇，並以15%甲醇/氯仿（3 X 30毫升）再萃取。使合併之有機相以硫酸鈉脫水乾燥，及 濃縮至乾涸’獲得240毫克粗產物，為油狀物。 MS(ESP): 327 (MH+)對 C18H22N402 中間物86 {(3R，4R)-l-[2-(7-氰基_2·酮基喹啉_i(2H)_基）乙基】-3·甲氧基六氫 吡啶-各基}胺基甲酸第三-丁酯 與 中間物87 {(3S，4S)-l-【2-(7-氰基-2-酮基喹啉_1(211)_基）乙基】-3·甲氧基六氫 吡啶冰基}胺基甲酸第三丁酯 將[反式（±)-3-甲氧基六氫p比咬-4-基]胺基甲酸第三-丁酯 127286 -121- 200831517 (中間物_克’ 2·7毫莫耳）與2·酮基啡酮基乙基似 二氫喹啉丨甲腈（中間物88，〇·57克，2·7毫莫耳）在ι: ι無 水甲醇/氯仿（30毫升）中之混合物加熱至耽，歷經2小時。 使反應物冷卻至室溫，以三乙醯氧基硼氫化鈉（U克，Μ 毫莫耳）處理’並於室溫下授拌2小時。經過石夕藻土過滤反 應物，並在真空中濃縮濾液。使粗製殘留物於醋酸乙酯與 飽和碳酸氫鈉水溶液之間作分液處理。分離液層，並將水 _相以醋酸乙酯再萃取一次。使合併之有機相以硫酸鈉脫水 乾知，過濾、’及在真空中濃縮。於矽膠上，以己烷中之25-5〇% 丙酮層析，獲得〇·74克（62%)產物之外消旋混合物。 MS (ESP) : 427 (ΜΗ+)對 C23H3GN4〇4 H NMR (DMSO-d6) δ ppm： 1.19-133 (m, 1H)； 1.37 (s,9H)； 1.64-1.73 (m，1H)，1.77 (m，1H); 1.99 (m，1H); 2.59 (m5 2H); 2.79-2.87 (m，1H); 2.93-3.04 (m5 1H) ； 3.05-3.15 (m5 1H) ； 3.23-3.30 (m5 1H) ； 3.28 (s? 3H)； 4.30-4.47 (m，2H) ; 6.79 (d，2H) ; 7.66 (dd，1H) ; 7.91 (d，1H) ; 8.01 (d， _ 1H) ; 8·09 (s，1H)· 對掌異構物之混合物係於Chiralpak AD管柱（20 x 250毫米， 10微米）上，藉HPLC，以80%己烷、20% 1 : 1乙醇/甲醇、〇·ι〇/0 一乙胺之恒定組成梯度液，在20毫升/分鐘之流率下分離。 這獲得0·28克{(3R，4R)小[2-(7_氰基-2-酮基喹啉-1(2Η&gt;基）乙 基&gt;3-甲氧基六氫吡啶-4-基}胺基曱酸第三-丁酯（中間物86， 第二個溶離峰㈩異構物）與0.32克{(3S，4S&gt;l-[2-(7•氰基-2-酮基 喳啉-1(2H)-基）乙基]-3-甲氧基六氫吡啶-4-基}胺基甲酸第三-丁酯（中間物87，第一個溶離峰㈠異構物）。 127286 -122- 200831517 中間物88 2-酮基-1-(2-酮基乙基)_1，2_二氫喳啉·7·甲腈 於1-(2,2- 一乙氧基乙基）-2-晒基·1，2·二氯ρ奎淋_7·甲腈（中間 物89，21·5克，75.1毫莫耳）在乙腈（230毫升）中之溶液内， 添加濃鹽酸(2當量，12·5毫升）。1小時後，藉過濾收集所形 成之沉澱物。於乾燥後，這獲得16克（100%)產物，為無色固 體，使用之而無需進一步純化。 MS (ESP) : 213 (ΜΗ+)對 C12H8N202 ^ NMR (DMSO-d6) δ ppm ： 5.25-5.38 (m? 2H) ； 6.82 (d5 1H) ； 7.67 (d? 1H) ; 7.95 (d，1H) ; 8.02-8.14 (m，2H) ; 9.64-9.74 (m，1H)· 中間物89 l-(2,2·一乙氧基乙基)_2嗣基_1，2_二氮峻琳_7_甲腈 將2-酮基-1，2-二氫喹啉-7-甲腈（中間物5，35·〇克，2〇1毫莫 耳）、2-漠基-1，1-一乙氧基乙烧（44.1笔升，281毫莫耳）及碳酸 铯（78.5克’ 241毫莫耳）在無水ΝΜΡ (2⑻毫升）中之混合物於 _ 70 C下攪拌過夜。以水（350毫升）稀釋反應混合物，並以醋L-{2-[4-Amino-3-fluorohexahydropyridine·1_yl]ethyl decyloxyquinoxaline-2(1H)-one, trans-p-isomer B The procedure described in the synthesis of intermediate 67 is such that {3-fluoro-indenyl 2 (7-methoxy-2-ketoquinoxaline·1(2Η)·yl)ethyl]hexahydropyridine The third-butyl carboxylic acid, trans-palladium isomer Β (intermediate 84, 0. 33 g, 〇 · 78 mmol) was reacted with trifluoroacetic acid to obtain 〇·27 g of crude product as an oil. MS 0 (ESP): 321 (ΜΗ+) to C! 6Η2! FN402 Intermediate 84 {3-Fluoro-l-[2-(7-methoxy-2-keto 4 喏 _1 _1 (211 _ yl) ethyl] hexahydropyridinyl carbyl} methic acid tert-butyl ester, trans-palphaliomer β using a procedure similar to that described in the synthesis of intermediate 68 to make 7-methoxy若若淋·2(1Η)-ketone (intermediate 15, 0.52 g, 2.95 mmol), formazanic acid [(di-butoxy-yl)amino]_3·san hexahydropy ratio Bite _1_ base} B, the trans-isomer isomer Β (intermediate 81, ~0.38 mmol/ml, 3.82 mmol) and sodium hydride (60% in oil, 153 mg, 3.82) Millions of reactions. Chromatography on 10-5% acetone in hexane afforded EtOAc (EtOAc) MS (ESP): 421 (ΜΗ+) vs. C21H29FN4〇4 127286 • 120- 200831517 XH NMR (DMSO-d6) δ ppm : L23-1.45 (m5 11H) ; L64-1.80 (m, 1H); 2.04-2.19 ( m? 2H) ; 2.61.2.71 (m5 2H) ; 2.84 (d5 1H) ; 3.25-3.33 (m? 1H); 3.92 (s, 3H) ; 4.27-4.43 (m, 2H) ; 4.28 (m, 1H) ; 16·94-7·05 (m,3H); 7.75 (d,1H) ; 8.04 (s,1H). Intermediate 85 l-{2-[(3R,4R)-4-Amino·3· Methoxy hexahydropyridyl]ethyl b 2-keto-1,2-dihydroporphyrin-7-carbonitrile will be {(3R,4R)-H2-(7-cyano-2-ketoindole) L-(2H)-yl)ethyl]-3-decyloxyhexahydropyridin-4-yl}carbamic acid tert-butyl ester (intermediate 86, 280 mg, 0.66 mmol) in dichloro The solution in methane (30 mL) was taken in trifluoroacetic acid (10 mL). After 1 hour, the reaction was concentrated to dryness. The residue was dissolved in 15% MeOH (30 mL)EtOAc. The aqueous layer was adjusted to pH ~1 EtOAc and then extracted with 15% methanol / chloroform (3 X 30 mL). The combined organic phases were dried with sodium sulfate <RTI ID=0.0> MS (ESP): 327 (MH+) to C18H22N402 Intermediate 86 {(3R,4R)-l-[2-(7-Cyano-2. ketoquinoline_i(2H)-yl)ethyl]- 3. Methoxyhexahydropyridine-each yl}-amino carboxylic acid tri-butyl ester and intermediate 87 {(3S,4S)-l-[2-(7-cyano-2-ketoquinoline_1 (211)-yl)ethyl]-3-methoxyhexahydropyridine ice-based} tert-butyl carbazate [trans (±)-3-methoxyhexahydrop to butyl-4-yl Amino carboxylic acid tert-butyl ester 127286 -121 - 200831517 (intermediate - gram '2.7 mM) and 2 keto phenone ketoethyl like dihydroquinolinium carbonitrile (intermediate 88, 〇·57 g, 2·7 mmoles) A mixture of ι: ι anhydrous methanol/chloroform (30 ml) was heated to hydrazine over 2 hours. The reaction was allowed to cool to rt and was taken &lt;RTI ID=0.0&gt;&gt; The reaction was filtered through celite, and the filtrate was concentrated in vacuo. The crude residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The liquid layer was separated and the water phase was extracted once more with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on 25-50% hexane in hexane afforded a racemic mixture of y 74 g (62%). MS (ESP): 427 (ΜΗ+) vs. C23H3GN4 〇4H NMR (DMSO-d6) δ ppm: 1.19-133 (m, 1H); 1.37 (s, 9H); 1.64-1.73 (m,1H), 1.77 (m,1H); 1.99 (m,1H); 2.59 (m5 2H); 2.79-2.87 (m,1H); 2.93-3.04 (m5 1H); 3.05-3.15 (m5 1H) ; 3.23-3.30 (m5 1H ; 3.28 (s? 3H); 4.30-4.47 (m, 2H); 6.79 (d, 2H); 7.66 (dd, 1H); 7.91 (d, 1H); 8.01 (d, _ 1H); 8·09 (s, 1H)· The mixture of palmomers is attached to a Chiralpak AD column (20 x 250 mm, 10 μm) by HPLC with 80% hexane, 20% 1:1 ethanol/methanol, hydrazine A constant gradient of ι〇/0 monoethylamine was separated at a flow rate of 20 ml/min. This gave 0·28 g of {(3R,4R) small [2-(7-cyano-2-ketoquinoline-1(2Η&gt;yl)ethyl]&gt;3-methoxyhexahydropyridine-4- Aminobutyric acid tri-butyl ester (intermediate 86, second dissolved peak (ten) isomer) and 0.32 g {(3S,4S&gt;l-[2-(7•cyano-2-one) Porphyrin-1(2H)-yl)ethyl]-3-methoxyhexahydropyridin-4-yl}carbamic acid tert-butyl ester (Intermediate 87, first dissolving peak (I) isomer) 127286 -122- 200831517 Intermediate 88 2-keto-1-(2-ketoethyl)_1,2-dihydroporphyrin·7·carbonitrile in 1-(2,2-ethoxylated Base)-2-Tenyl·1,2·Dichloro ρ 淋 _7·carbonitrile (intermediate 89, 21·5 g, 75.1 mmol) in acetonitrile (230 ml), add concentrated Hydrochloric acid (2 eq., 12.5 mL). After 1 hr, the formed precipitate was collected by filtration. After drying, this afforded 16 g (100%) of product as a colourless solid. (ESP): 213 (ΜΗ+) vs. C12H8N202^ NMR (DMSO-d6) δ ppm: 5.25-5.38 (m? 2H); 6.82 (d5 1H); 7.67 (d? 1H); 7.95 (d, 1H); 8.02-8.14 (m, 2H) ; 9.64-9.74 (m, 1H) · Intermediate 89 l-(2,2·Ethoxyethyl) 2 fluorenyl-1,2_diazo ____carbonitrile 2-keto-1,2-dihydroquinoline- 7-carbonitrile (intermediate 5,35·〇g, 2〇1 mmol), 2-Mo,-1,1-ethoxy bethane (44.1 liters, 281 mmol) and cesium carbonate (78.5 g of '241 mmol) mixture in anhydrous hydrazine (2 (8) mL) was stirred at _ 70 C overnight. The reaction mixture was diluted with water (350 mL) and vinegar

酸丁醋（2x 350毫升）萃取。經過矽藻土過濾合併之有機相， 且以水（lx 175毫升）洗滌。使醋酸丁酯溶液濃縮至14〇毫升， 並以異己烷525毫升稀釋。藉過濾單離沉殿物，及以異己烷 70宅升洗滌。於乾燥後，這獲得34克（6〇%)產物，為無色固 體’使用之而無需進一步純化D MS (ESP) : 309 (MNa+)對 q 6¾ 8N2 03 ^-NMR (DMSO-d6) δ ppm： 0.96 (t5 6H)； 334-3.47 (m? 2H)； 3.56-3.73 (m，2H) ; 4.39 (d，2H) ; 4.72 (t，1H) ; 6.80 (d，1H) ; 7·62 (d，1H) ; 7·89 127286 -123 - 200831517 (d5 1H) ； 8.02 (d, 1H) ； 8.13-8.22 (m, 1H). 中間物90 、 l-{2-【(3S，4S)-4_胺基-3-甲氧基六氫吡啶-i-基】乙基酮基_l，2_ 二氫喹啉-7_甲腈 使用類似關於合成中間物85所述之程序，使{(3S，4S)4-|&gt; (7-氰基-2·酮基喹啉-i(2H)·基）乙基]-3-曱氧基六氫吡啶冰基}胺 基甲酸第二·丁酯（中間物87，（U2克，0.75毫莫耳）與三氟醋 酉文反應’獲得0.24克粗產物，為油狀物。 MS (ESP) : 327 (MH+)對 q 8Η22Ν402 中間物91 順式（±)1·[2-(4·胺基·3_氟基六氫吡啶小基）乙基】甲氧基p奎嘆 啉-2(111)_酮，三氟醋酸鹽 於順式（±){3·氟基小[2-(7-甲氧基-2-酮基p奎喏琳-似印-基）乙 基]六氫吡啶斗基}胺基甲酸第三-丁酯（中間物92,222毫克， 0·53毫莫耳）在氯仿（1〇毫升）中之溶液内，於下，添加氯 仿中之30%三氟醋酸（6毫升）。於室溫下3小時後，在減壓下 移除溶劑，提供標題化合物，將其使用於下一步驟中，無 需純化。標題化合物可以雙-三氟醋酸鹽形式存在。 MS (ESP) ·· 321 (ΜΗ+)對 q 6Η21FN4〇 中間物92 ㈣_H2_(7_甲氧基_2，基〇味q㈣基）乙基】六 氫吡啶-4-基}胺基甲酸第三-丁酯 使用類似關於合成中間物20所述之程序，使7_甲氧基4 喏啉-2(1Η)-酮（中間物15，181毫克，！古贫7 毛兄莫耳）與甲烷磺酸順 127286 -124- 200831517 式（±)2-{4-[(第三-丁氧羰基）胺基]-3-氟基六氫吡啶小基}乙酯 (中間物21，〜1毫莫耳）反應。於矽膠上，以己烷/醋酸乙酯 (2 : 3)層析，獲得222毫克（51%)產物，為固體。 MS (ESP) : 421 (MH+)對 C21H29FN404 ^-NMR (CDCI3-d) 5 ： 1.44 (s, 9H) ； 1.86 (m? 2H) ； 2.40 (m? 2H)； 2·80 (m，2H) ; 3.15 (m，1H); 3·41 (m，1H) ; 3.70 (m，1H) ; 3.94 (s，3H); 4.42 (m5 2H) ； 4.70 (m5 2H) ； 6.93 (m? 2H) ； 7.77 (m5 1H) ； 8.11 (s? 1H). 中間物93 l-{2-[(3R，4S)-4-胺基·3-甲氧基六氫吡咬小基]乙基η-曱基_2-酮 基-1，2-二氫，奎琳-7-甲腈，三氟醋酸鹽 使用類似關於合成中間物91所述之程序，使{(3r，4S)-1-[2-(7-氰基-4-甲基-2-酮基喳啉-l(2H)·基）乙基]_3_甲氧基六氫吡啶 斗基}胺基甲酸第三-丁酯（中間物94，36〇毫克，〇81毫莫耳） 與二氟醋酸反應，提供標題化合物。標題化合物可以雙三 氟醋酸鹽形式存在。 MS (ESP)： 341 (MH+)ff C19H24N4〇2 中間物94 {(3R，4S)-l-【2-(7-氰基-4-甲基-2-酮基喳啉4(2H)•基)乙基]_3•甲氧 基六氫p比咬_4_基}胺基甲酸第三_ 丁輯 於4-甲基-2-酮基-1，2-二氫喹啉_7_甲腈（ν· N.㈤取s b. KuMmi 及 B.D. Tilak，衫允學射y，现，勝773 (i977))⑽毫 克，2毫莫耳）在無水DMF (2〇冑升）中之溶液内，添加氯化 納020毫克，· ’於油中，3毫莫耳）。將混合物於室溫下 攪拌1小時。接著，於吖下添加甲烷磺酸2_{(3R，4s&gt;4_[(第三· 127286 -125- 200831517 丁氧羰基）胺基]-3-甲氧基六氫吡啶小基}乙酯（中間物39，〜2 毫莫耳）在DMF中之溶液。將反應混合物於室溫下授拌過 夜，然後以水稀釋，並以二氯甲烷萃取三次。使有機萃液 以硫酸鎂脫水乾燥，及濃縮。以己烷/醋酸乙酯（3 : 2)矽膠 層析，獲得360毫克標題化合物與〇-烷基化作用產物之3 : 1 混合物。 MS (ESP) : 441 (MH+)對 C24H32N404 中間物95 順式（±)1-【2-(4-胺基-3-氟基六氫p比唆基）乙基】-4-甲基-2-嗣基 -1，2-二氫喳啉-7-甲腈，三氟醋酸鹽 使用類似關於合成中間物91所述之程序，使順式 (±){1-[2-(7-氰基-4-甲基-2-酮基喳啉-i(2H)-基）乙基]-3-敦基六氫 峨咬-4-基}胺基甲酸第三-丁酯（中間物％，269毫克，〇幻毫 莫耳）與三氟醋酸反應，獲得粗產物（2〇〇毫克）。標題化合物 可以雙-三氟醋酸鹽形式存在。 φ MS (ESP)： 329 (MH+)#C18H21FN4〇 中間物96 順式（±){1-丨2-(7-氰基-4-甲基-2·酮基喹啉基）乙基]各氟基 六氫吡啶4基}胺基甲酸第三_丁 _ 於4_甲基酮基_1，2_二氫喹啉甲腈（ν· N· G〇gte，Μ. Kulkami 及 B.D· Tilak，命度允學翁办，15Β，769·773 (1977)) (35〇 毫 克，1_9耄莫耳）在無水dmf (2〇亳升）中之混合物内，添加氫 化鈉⑼毫克，60%，於油中，2·2毫莫耳）。將混合物於室溫 下擾拌1 λΙΊ接著於叱下添加甲烧磺酸順式⑴2分[(第三 127286 •126· 200831517 -丁氧羰基）胺基]·3-氟基六氫吡啶小基}乙酯（中間物21，〜】9 毫莫耳）在DMF中之溶液。將反應混合物於室溫下授掉過 夜，然後以水稀釋，並以二氯甲烷萃取三次。使有機萃液 以硫酸鎂脫水乾燥，及濃縮。以己烷/醋酸乙酯（1 : 矽膠 層析，獲得269毫克（33%)產物，為黃褐色固體。 MS (ESP) : 428 (MH+)對 C23H29FN403 中間物97 l-(2-((3S，4R)-4_胺基_3·氟基六氫p比咬-1-基）乙基）·2__基七2·二 氫喳啉甲腈，三氟醋酸鹽 使用類似關於合成中間物91所述之程序，使（3S，4R)-l-(2-C7-氰基-2·酮基P奎琳-l(2H)-基）乙基）-3-氣基六氫μ比咬_4_基胺基甲 酸第三-丁酯（中間物98，0.5克，1.21毫莫耳）與三氟醋酸反 應’以定量產率獲得粗產物，將其直接使用於下一步驟。 標題化合物可以雙_三氟醋酸鹽形式存在。 MS(ESP): 315(ΜΗ+)對 C17H19FN40 中間物98 (3S，4R)-1-(2-(7-氰基·2-酮基喹啉基）乙基）各氟基六氫吡 啶-4-基胺基甲酸第三-丁酯 將2-酮基-i，2-二氫喹啉·7-曱腈（中間物5，〇_5克，2.94毫莫 耳）與礦油中之60重量％氫化鈉（0.176克，4.41毫莫耳）在DMF (5〇毫升）中之混合物於室溫及氮氣下攪拌1小時。使溶液冷 卻至0°C，並添加甲烷磺酸2-((3S，4R)-4-(第三-丁氧羰基胺基)-3-氟基六氫吡啶小基）乙酯（中間物99，1克，2.94毫莫耳）在DMF (1〇毫升）中之溶液。將反應混合物於室溫下攪拌過夜。以 127286 -127- 200831517 水稀釋反應混合物，並以二氯甲烷萃取兩次。使合併之有 機萃液以硫酸鎮脫水乾燥’過濾，及蒸發。石夕膠層析（在己 烧中之0%-75%醋酸乙S旨）’獲得標題化合物，為黃褐色固體 0.55 *(45%p[a]D=+0.063 (c = 0.25DMSO)· MS(ESP): 415(1^)對 C22H27FN4〇3 中間物99 甲烧績酸2-((3S，4R)-4_(第三-丁氧羰基胺基)各氟基六氮吡咬小 基）乙酯 標題化合物係使用類似關於中間物21自中間物24合成所 述之程序，製自（3S，4RH-(2-(第三-丁基二甲基矽烷基氧基）乙 基）-3-氟基六氫吡啶-4-胺（中間物100)。 MS (ESP) : 341 (MH+)對 q 3 H2 5 FN2 05 S 中間物100 (3S，4R)-l-(2-第三·丁基二甲基矽烷基氧基）乙基）-3-氟基六氫 比咬-4-胺 使（3S，4R)-：K2-(第三-丁基二甲基矽烷基氧基）乙基）各氟基 六氫吡啶-4-基胺基甲酸芊酯（中間物101，8克，19.48毫莫耳） 在乙醇（100毫升）中之溶液於鈀/碳（10%，經活化，1.037克） 上，在常壓及室溫下氫化過夜。經過0.45微米薄膜過濾反應 混合物，並於減壓下蒸發溶劑，而得標題化合物，為油狀 物（5 克，93%)。 MS (ESP) : 277 (MH+)對 C13H29FN2OSi ^-NMR (CDCl3-d) δ ： 0.04 (s, 6Η) ； 0.87 (s? 9H) ； L75 (m5 4H)； 2.35 (m5 2H) ； 2.56 (m5 2H) ； 2.81 (m? 2H) ； 3.15 (m, 1H) ； 3.74 (m, 2H)； 127286 -128- 200831517 4.57 (m, 1H). 中間物101 陶扣雖第三-丁基二甲基發燒基氧基）乙基)_3氟基六氣 吡啶-4·基胺基甲酸芊醋 於（3 S，4R)-3-氟基六氫吡啶斗基胺基甲酸芊酯鹽酸鹽（中間 物102，5·9克，20.43毫莫耳）與碳酸鉋（33·3克，1〇217毫莫耳） 在乙腈（300毫升）中之經攪拌混合物内，於室溫下，添加（2_ 溴基乙氧基）(第三-丁基）二甲基矽烷（21·92毫升，1〇217毫莫 耳)。將反應物於60°C下攪拌過夜。經過燒結漏斗過濾反應 混合物’及濃縮。矽膠層析（在己烷中之〇%_5〇0/〇醋酸乙酯）， 獲得標題化合物，為黃色油，8克（95❻/〇)。 MS (ESP)： 411 (MH+)^c21H35FN203Si 中間物102 (3S，4R)-3-氟基六氫吡啶-4-基胺基甲酸苄酯，鹽酸鹽 於（3S，4R)-4-(辛氧魏基胺基）-3-氟基六氫P比唆小羧酸第三· 丁酯（中間物103，8克，22.7毫莫耳）在二氯甲烷（200毫升） 中之溶液内，於(TC下，添加二氧陸圜中之4M氯化氫（11.35 毫升，45·4毫莫耳）。使反應混合物溫熱至室溫，並攪拌過 仪。添加另一當量之二氧陸圜中之4Μ氯化氫，並將反應物 再攪拌4小時。藉過濾收集所形成之白色沉澱物，並於減壓 下乾燥，而得標題化合物（5·9克，90%)。 MS (ESP) : 253 (ΜΗ+ )對 q 3呒 7FN202 中間物103 (3S，4R)-4-(辛氧羰基胺基)-3·氟基六氫吡啶小羧酸第三-丁酯 127286 -129- 200831517 於（3S，4R)-4·胺基各氟基六氫吡啶小羧酸第三-丁酯（使用 PCT公報案號WO 2006087543與WO 2007071965中所述之程序 製成)(5_1克，23.37毫莫耳）在二氧陸圜（150毫升）與飽和碳 酸鈉（50毫升）中之混合物内，於〇°c下，添加氯甲酸芊酯（5 〇〇 毫升，35.05毫莫耳）。15分鐘後，以醋酸乙酯與飽和氯化鈉 稀釋反應混合物。分離液層，並使有機萃液以硫酸鎂脫水 乾燥，過濾，及蒸發。矽膠層析（在己烷中之〇〇/❾_5〇%醋酸乙 酯），獲得標題化合物，為灰白色固體，8克（97%)。 MS (ESP) : 353 (MH+)對 C〗8 H2 5 FN2 04 XH-NMR (CDCl3-d) 5 ： 1.44 (m5 9H) ； L73 (m5 2H) ； 2.80 (m5 2H)； 3.60 (m，1H); 4.30 (m，2H); 4.65 (m，1H); 5.06 (m，1H) ; 5.09 (s，2H); 7·34 (m，5H)· 中間物104 l-{2-【(3S，4R)-4-胺基_3_甲氧基六氫吡啶小基]乙基}冬甲基綱 基-1，2-二氫〃奎淋-7_甲赌，三氣酷酸鹽 使用類似關於合成中間物91所述之程序，使{(3j§，4r)_；^[2 (7-氰基-4-甲基-2-酮基喹啉-1(2H)·基）乙基甲氧基六氫峨咬 -4-基}胺基曱酸第二-丁醋（中間物1〇5，191毫克，〇.43毫莫耳） 與三氟醋酸反應，以定量產率獲得粗製標題化合物，將其 直接使用於下一步驟。標題化合物可以雙-三氟醋酸鹽形式 存在。 MS (ESP) : 341 中間物105 {(3S，4R)-l-【2-(7-氰基·4·甲基-2-酮基喹琳-i(2H)-基）乙基μ3_甲氧 127286 -130- 200831517 基六氫吡啶冬基}胺基甲酸第三丁酯 於4-甲基-2-酮基4,2-二氫喹啉_7-甲腈（v. N· G〇gte，s.B.Extraction of butyl vinegar (2 x 350 ml). The combined organic phases were filtered through celite and washed with water (1× 175 mL). The butyl acetate solution was concentrated to 14 mL and diluted with 525 mL of isohexane. Use the filter to separate the Shen Temple and wash it with 70 liters of isohexane. After drying, this gave 34 g (6 %) of product as a colorless solids. &lt;EMI ID=9.1&&&&&&&&&&&&&&&&&&&&&& : 0.96 (t5 6H); 334-3.47 (m? 2H); 3.56-3.73 (m, 2H); 4.39 (d, 2H); 4.72 (t, 1H); 6.80 (d, 1H); 7·62 ( d,1H) ; 7·89 127286 -123 - 200831517 (d5 1H) ; 8.02 (d, 1H) ; 8.13-8.22 (m, 1H). Intermediate 90, l-{2-[(3S,4S)- 4_Amino-3-methoxyhexahydropyridine-i-yl]ethyl keto-l,2-dihydroquinoline-7-carbonitrile was prepared using a procedure similar to that described for the synthesis of intermediate 85. 3S,4S)4-|&gt; (7-Cyano-2·ketoquinoline-i(2H)·yl)ethyl]-3-decyloxyhexahydropyridyl yl) Butyl ester (intermediate 87, (U2 g, 0.75 mmol) was reacted with trifluoroacetic acid to give 0.24 g of crude product as an oil. MS (ESP): 327 (MH+) vs. q 8 Η 22 Ν 402 Intermediate 91 Cis (±) 1·[2-(4·amino·3_fluorohexahydropyridyl) ethyl]methoxy p-quephetine-2(111)-one, trifluoroacetate in cis Formula (±){3·Fluoro group small [2-(7-methoxy-2-keto) - Illustrated - yl) ethyl] hexahydropyridine hydrazino} carbamic acid tert-butyl ester (intermediate 92, 222 mg, 0·53 mmol) in chloroform (1 mL), under The title compound was obtained in the next step without purification. The form of bis-trifluoroacetate is present. MS (ESP) ·· 321 (ΜΗ+) vs. q 6Η21FN4〇 intermediate 92 (IV) _H2_(7-methoxy-2, oxime q(tetra)yl)ethyl]hexahydropyridine- 4-Base} Amino Butyrate Tri-Butyl Ester Using a procedure similar to that described for the synthesis of Intermediate 20, 7-methoxy-4-carboline-2(1Η)-one (intermediate 15,181 mg,! Lean 7 Maosi Moer) and methanesulfonic acid cis 127286 -124- 200831517 Formula (±) 2-{4-[(T-Butoxycarbonyl)amino]-3-fluoropyrazine small base} B The ester (intermediate 21, 〜1 mmol) was purified by chromatography eluting EtOAc EtOAc EtOAc MS (ESP): 421 (MH+) vs. C21H29FN404^-NMR (CDCI3-d) 5: 1.44 (s, 9H); 1.86 (m? 2H); 2.40 (m? 2H); 2·80 (m, 2H) 3.15 (m, 1H); 3·41 (m, 1H); 3.70 (m, 1H); 3.94 (s, 3H); 4.42 (m5 2H); 4.70 (m5 2H); 6.93 (m? 2H); 7.77 (m5 1H) ; 8.11 (s? 1H). Intermediate 93 l-{2-[(3R,4S)-4-Amino-3-methoxyhexahydropyridinyl]ethyl η-曱Base 2-keto-1,2-dihydro, quinolin-7-carbonitrile, trifluoroacetate using a procedure similar to that described for the synthesis of intermediate 91 to give {(3r,4S)-1-[2 -(7-Cyano-4-methyl-2-keto porphyrin-l(2H).yl)ethyl]_3_methoxyhexahydropyridyl]-amino carboxylic acid tert-butyl ester (middle Reaction 94, 36 mg, 〇 81 mmol (m. The title compound can exist as a ditrifluoroacetate salt. MS (ESP): 341 (MH+)ff C19H24N4〇2 Intermediate 94 {(3R,4S)-l-[2-(7-Cyano-4-methyl-2-ketoporphyrin 4(2H)• Ethyl]ethyl]_3•methoxy hexahydropp ratio bite_4_yl}amino carboxylic acid third _ butyl in 4-methyl-2-keto-1,2-dihydroquinoline _7_ Nitrile (ν· N. (5) takes s b. KuMmi and BD Tilak, shirts are allowed to shoot y, now, win 773 (i977)) (10) mg, 2 millimoles) in anhydrous DMF (2 liters) In the solution, add 020 mg of sodium chloride, · 'in oil, 3 mmol. The mixture was stirred at room temperature for 1 hour. Next, methanesulfonic acid 2_{(3R,4s&gt;4_[(Third 127286-125-200831517 Butoxycarbonyl)amino]-3-methoxyhexahydropyridine small ethyl ester) was added under the armpit. a solution of 39, 〜2 mmol of the mixture in DMF. The reaction mixture was stirred at room temperature overnight, then diluted with water and extracted with dichloromethane three times. Concentration. Chromatography with hexane/ethyl acetate (3:2) afforded 360 mg of the title compound as a 3:1 mixture of the hydrazine-alkylation product MS (ESP): 441 (MH+) to C24H32N404 Intermediate 95 cis (±) 1-[2-(4-Amino-3-fluorohexahydrop-indenyl)ethyl]-4-methyl-2-indolyl-1,2-dihydroporphyrin -7-carbonitrile, trifluoroacetate using a procedure similar to that described for the synthesis of intermediate 91 to give cis(±){1-[2-(7-cyano-4-methyl-2-ketohydrazide) Porphyrin-i(2H)-yl)ethyl]-3-dylhexahydroindole-4-yl}amino-carbamic acid tert-butyl ester (intermediate %, 269 mg, 〇 毫 莫) and trifluoro The acetic acid is reacted to give the crude product (2 mg). φ MS (ESP): 329 (MH+)#C18H21FN4〇Intermediate 96 cis (±){1-丨2-(7-cyano-4-methyl-2.ketoquinolinyl)ethyl Each of the fluoro-piperidine 4 yl} carbamic acid _ _ _ _ 4-methyl keto group 1, 2 - dihydroquinoline carbonitrile (ν · N · G〇gte, Μ. Kulkami and BD · Tilak, Life Degree, Yunwen, 15Β, 769·773 (1977)) (35〇 mg, 1_9耄莫耳) Add sodium hydride (9) mg, 60% in a mixture of anhydrous dmf (2 liters) %, in oil, 2 · 2 millimoles). The mixture was stirred at room temperature for 1 λ ΙΊ followed by the addition of methanesulfonic acid cis (1) 2 points [(third 127286 • 126·200831517 -butoxycarbonyl)amino] 3-fluorohexahydropyridine small group } Ethyl ester (intermediate 21, ~) 9 millimolar) solution in DMF. The reaction mixture was allowed to stand overnight at room temperature, then diluted with water and extracted thrice with dichloromethane. The organic extract was dried over magnesium sulfate and concentrated. Chromatography with hexanes / ethyl acetate (1: EtOAc, 269 mg (33%) ield: s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s , 4R)-4_Amino_3·Fluorohexahydrop-biti-1-yl)ethyl)·2__yl-7-2-dihydroporphyrin carbonitrile, trifluoroacetate is similar to synthetic intermediates The procedure described in 91 is such that (3S,4R)-l-(2-C7-cyano-2.keto-P-quinion-1(2H)-yl)ethyl)-3-ylhexahydropyrene Bite _4_ carbamic acid tert-butyl ester (intermediate 98, 0.5 g, 1.21 mmol) was reacted with trifluoroacetic acid. The crude product was obtained in quantitative yield and used directly in the next step. The title compound can exist as a bis-trifluoroacetate salt. MS (ESP): 315 (ΜΗ+) vs. C17H19FN40 Intermediate 98 (3S,4R)-1-(2-(7-Cyano- 2-ketoquinolinyl)ethyl)-fluorohexahydropyridine- 4-tert-aminocarbamic acid tert-butyl ester 2-keto-i,2-dihydroquinoline-7-indolecarbonitrile (intermediate 5, 〇_5 g, 2.94 mmol) and mineral oil A mixture of 60% by weight of sodium hydride (0.176 g, 4.41 mmol) in DMF (5 mL) was stirred at room temperature under nitrogen for 1 hour. The solution was cooled to 0 ° C and 2-((3S,4R)-4-(tris-butoxycarbonylamino)-3-fluorohexahydropyridinyl)ethyl methanesulfonate was added (intermediate) 99, 1 g, 2.94 mmol) solution in DMF (1 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water 127286 - 127 - 200831517 and extracted twice with dichloromethane. The combined organic extracts were dehydrated and dried with sulfuric acid, filtered, and evaporated. The title compound was obtained as a yellow-brown solid 0.55* (45% p[a]D=+0.063 (c = 0.25 DMSO)··················· MS(ESP): 415(1^) for C22H27FN4〇3 Intermediate 99 A calcination acid 2-((3S,4R)-4_(tris-butoxycarbonylamino)fluorohexanitropyridine The ethyl ester title compound was prepared using a procedure similar to that described for the synthesis of intermediate 21 from intermediate 24 from (3S,4RH-(2-(T-butyl-dimethyl decyloxy)ethyl)- 3-fluorohexahydropyridin-4-amine (Intermediate 100) MS (ESP): 341 (MH+) vs. q 3 H2 5 FN2 05 S Intermediate 100 (3S,4R)-l-(2-third · Butyl dimethyl decyloxy) ethyl)-3-fluoro hexahydro butyl-4-amine to give (3S,4R)-:K2-(tris-butyldimethyl decyloxy Ethyl) fluorinated hexahydropyridin-4-ylaminocarbazide (intermediate 101, 8 g, 19.48 mmol) solution in ethanol (100 ml) in palladium on carbon (10%) Activated, 1.037 g), hydrogenated overnight at ambient pressure and room temperature. The reaction mixture was filtered through EtOAc EtOAc (EtOAc) MS (ESP): 277 (MH+) vs. C13H29FN2OSi^-NMR (CDCl3-d) δ: 0.04 (s, 6 Η); 0.87 (s? 9H); L75 (m5 4H); 2.35 (m5 2H); 2.56 (m5) 2H) ; 2.81 (m? 2H) ; 3.15 (m, 1H) ; 3.74 (m, 2H); 127286 -128- 200831517 4.57 (m, 1H). Intermediate 101 ceramic buckle although third-butyl dimethyl Fenyloxy)ethyl)_3fluorohexafluoropyridin-4-ylaminocarbamic acid hydrazine vinegar in (3 S,4R)-3-fluorohexahydropyridinyl guanidinoate oxime hydrochloride (102, 5·9 g, 20.43 mmol) and carbonated planer (33·3 g, 1〇217 mmol) in a stirred mixture of acetonitrile (300 ml) at room temperature (2_ Bromoethoxy) (t-butyl) dimethyl decane (21.92 ml, 1 〇 217 mmol). The reaction was stirred at 60 ° C overnight. The reaction mixture was filtered through a sintered funnel and concentrated. The title compound was obtained as a yellow oil (yield: EtOAc/EtOAc). MS (ESP): 411 (MH+)^c21H35FN203Si Intermediate 102 (3S,4R)-3-fluorohexahydropyridin-4-ylaminocarbamate, hydrochloride (3S,4R)-4-( Octyl oxy-amino)-3-fluoro hexahydro-P is a solution of hydrazine carboxylic acid tert-butyl ester (intermediate 103, 8 g, 22.7 mmol) in dichloromethane (200 mL) , (TC, add 4M hydrogen chloride in dioxane (11.35 ml, 45·4 mmol). Allow the reaction mixture to warm to room temperature and stir the instrument. Add another equivalent of dioxane. The title compound (5·9 g, 90%) was obtained from the title compound (5·9 g, 90%). 253 (ΜΗ+) to q 3呒7FN202 intermediate 103 (3S,4R)-4-(octyloxycarbonylamino)-3·fluoropyrohydropyridine small carboxylic acid tert-butyl ester 127286 -129- 200831517 (3S,4R)-4.Amino-fluoro-hexahydropyridine small carboxylic acid tert-butyl ester (made using the procedure described in PCT Publication No. WO 2006087543 and WO 2007071965) (5_1 g, 23.37 mmol) Ear) in dioxane (150 ml) and saturated In a mixture of sodium (50 ml), decyl chloroformate (5 〇〇 ml, 35.05 mmol) was added at 〇 ° C. After 15 minutes, the reaction mixture was diluted with ethyl acetate and saturated sodium chloride. The layers were separated and dried (MgSO4) eluted eluted elut elut elut elut elut克(97%) MS (ESP): 353 (MH+) to C 8 H2 5 FN2 04 XH-NMR (CDCl3-d) 5 : 1.44 (m5 9H) ; L73 (m5 2H) ; 2.80 (m5 2H) 3.60 (m,1H); 4.30 (m,2H); 4.65 (m,1H); 5.06 (m,1H); 5.09 (s,2H); 7·34 (m,5H)· Intermediate 104 l- {2-[(3S,4R)-4-Amino-3_methoxyhexahydropyridyl)-ethyl}methylenemethyl-1,2-dihydroquinone-7- Tris-carbamate uses a procedure similar to that described for the synthesis of intermediate 91 to give {(3j§,4r)_;^[2(7-cyano-4-methyl-2-ketoquinolin-1) 2H)·yl)ethylmethoxyhexahydroindole-4-yl}amino decanoic acid second-butyl vinegar (intermediate 1〇5,191 mg, 〇43 mmol) with trifluoroacetic acid Should, obtained in quantitative yield crude title compound which was used directly in the next step. The title compound can exist as a bis-trifluoroacetate salt. MS (ESP): 341 Intermediate 105 {(3S,4R)-l-[2-(7-Cyano-4·methyl-2-ketoquineline-i(2H)-yl)ethyl μ3_ Methoxy 127286 -130- 200831517 hexahydropyridinyl-based methic acid tert-butyl ester in 4-methyl-2-keto 4,2-dihydroquinoline-7-carbonitrile (v. N·G 〇gte, sB

Kulkami 及 B.D· Tilak，令彦光學截 ，15B，769-773 (1977)) (435 毫 克，2·36毫莫耳）在無水DMF (2〇毫升）中之溶液内，添加氫 化鈉（142毫克，60%，於油中，3·54毫莫耳）。將混合物於室 溫下攪拌1小時。接著於〇。〇下添加甲烷磺酸2-{(3S，4R)-4-[(第 二-丁氧羰基）胺基]-3-甲氧基六氫p比唆小基}乙酯（中間物33， 〜2·8毫莫耳）在DMF中之溶液。將反應混合物於室溫下攪拌 過仪’然後以水稀釋，並以二氯甲烧萃取三次。使有機萃 液以硫酸鎂脫水乾燥，及濃縮。以乙腈/水/醋酸銨逆相層 析，於涞乾後，獲得標題化合物，為淡黃色固體（191毫克， 18%) 〇 MS (ESP) : 441 (ΜΗ+)對 C24H32N404 中間物106 l-(2-((3R，4S)_4-胺基-3·氣基六氫峨啶小基）乙基）士酮基二 氫喹啉-7-曱腈三氟醋酸鹽 標題化合物係藉由類似關於外消旋物質（中間物19)所述 順序之方法，製自（3R，4S&gt;4-(;胺基）_3_氟基六氫吡啶小羧酸 第三-丁酯（WO2007071965與W02006087543)，惟關於最後步驟 中之下述修改除外：使標題化合物之粗製三氟醋酸鹽溶於 一氯甲烷（100耄升）中，並以飽和碳酸氫鈉（2〇毫升）洗滌一 次。將含水洗液以20%氫氧化鈉調整至阳=1〇，並以二氯 甲烷（100毫升）萃取三次。使合併之有機萃液以硫酸鎂脫水 乾燥，過濾，及濃縮至乾涸，而得標題化合物，為灰白色 127286 •131- 200831517 固體，352毫克（81%)。 MS (ESP)： 315 (MH+)^C17H19FN4〇 實例1 H2-{(m，4s)-4-[(2,3·^氫μ，4】：氧陸圓烯并ρ，3·φ比啶-7_基甲基） 胺基】各經基六氫吡啶+基）乙基酮基4,2_二氫喳啉甲 腈，雙鹽酸鹽 將l-{2-[(3R，4S)-4-胺基-3-羥基六氫吡啶-1-基]乙基}·2-酮基 -1，2-二氫喳啉尽曱腈（中間物i，74毫克，0.24毫莫耳)與2,3_ 二氫[1，4]二氧陸圜烯并[2,3-φ比啶孚羧甲醛（WO 2〇〇4/〇58144) (39毫克，0·24毫莫耳）之混合物，於剛經活化之3A分子篩上， 在70°C下加熱3小時。使反應混合物冷卻至室溫，並添加三 乙醯氧基硼氫化鈉（15〇毫克，0.75毫莫耳）。將所形成之反 應混合物於室溫下攪拌30分鐘，然後經過〇·45微米薄膜過 濾’及在減壓下濃縮至乾涸。於石夕膠上，以二氯甲烧/甲醇 (8: 1至4: 1)層析。匯集含有產物之溶離份，及濃縮至乾涸。 _ 使殘留物溶於二氯甲烷/***（1 : 2，10毫升）中，並添加乙 醚中之HC1 (2Μ，〜〇·15毫升）。使混合物在減壓下濃縮至乾 酒’與一氯甲烧(2 X 15耄升）一起共蒸餾兩次，並自_研製， 獲得組合物，為無色固體，91毫克（72%)，熔點&gt;21〇。〇。 MS (ESP) : 462 (MH+)對 C2 5 H27N5 〇4 ^H-NMR (DMSO-d6) 5 ： 2.18 (m, 2H) ； 3.15 (m5 1H) ； 3.25-3.36 (m5 4H) ; 3.69 (m，2H) ; 4.10-4.49 (m，7H) ; 4.61 (dd，2H) ; 6·64 (bi*s，1H); 6.83 (d, 1H) ； 7.30 (s, 1H) ； 7.72 (d5 1H) ； 7.97 (d5 1H) ； 8.08 (d3 1H)； 8.22 (m，2H) ; 9.45 (brs，2H) ; 10.00 (brs，1H)· 127286 -132· 200831517 實例2 H2-((3R，4S)-3-羥基-4-{【(3_酮基_3,4_二氫如_吡啶并丨3,2顿14】噚 畊-6-基）甲基】胺基}六氫吡啶小基）乙基]_2_酮基二氫喹啉 -7-甲腈，雙鹽酸鹽 使用類似關於合成實例1所述之程序，使3-酮基_3,4_二氫 -2H-吡啶并[3,2-b][l，4]嘮啡-6-羧甲醛（w〇 2〇〇4/〇58144)與中間物 1反應，提供標題組合物。 4 NMR (D20) 5 : (D20) 2.28 (m，2H); 3.15 (ddd，1H); 3.26 (m，1H); 3.40- 3.72 (m，4H) ; 3·91 (m，1H) ; 4·28 (s，2H) ; 4·52 (m，1H) ; 4.61 (m， 1H) ; 4.71 (s，2H) ; 4.80 (m，1H) ; 6.65 (d，1H) ; 7.08 (d，1H) ; 7.35 (d， 1H) ; 7.66 (d，1H) ; 7·87 (d，1H) ; 7.96 (s，1H) ; 8.02 (d，1H)· ES (MH)+ ： 475 實例3 1-【2_((3R，4S)_3-經基-4-{【(3-酮基-3,4-二氫-2H_p比咬并 |3,2-b][l，4]^ 畊-6-基）甲基】胺基}六氫吡啶_1_基）乙基】-2-酮基-1，2-二氫喹琳 -7-甲腈，雙-鹽酸鹽 使用類似關於合成實例1所述之程序，使3-酮基-3,4-二氫 -2H-吡啶并[3,2-b][l，4]噻畊-6-羧甲醛（WO 2004/058144)與中間物 1反應，提供標題組合物。 NMR (D20) δ ： (D2 0)2.31 (m, 2H)； 3.20 (ddd5 1H)； 3.31 (m? 1H)； 3.40- 3.80 (m? 4H) ； 3.55 (s? 2H) ； 3.95 (m? 1H) ； 4.34 (s5 2H) ； 4.55-4.70 (m，2H) ; 4.82 (m，1H) ; 6.84 (d，1H) ; 7.11 (d，1H) ; 7.66 (d，1H) ; 7.80 (d，1H) ; 7·87 (d，1H) ; 7.96 (s5 1H) ; 8·03 (d，1H)· ES (MH)+ ： 491 127286 -133- 200831517 實例4 1-(2-{(38，卿4-【处一氩【1，4】二氧陸圓烯并【2 3_小比冬^ 胺基]各羥基六氫吡啶小基丨乙基）·2_鲷基山2_二氫喳啉_7甲 腈，雙鹽酸鹽 使用類似關於合成實例1所述之程序，使2,3-二氫[丨⑷二氧 陸圜烯并[2,3-c]吡啶-7-羧曱醛與中間物2反應，提供標題組 合物。 NMR (DMSO-d6) δ ： 2.17 (m? 2H) ； 3.14 (m5 1H) ； 3.25-3.38 (m? 4H) ; 3.69 (m，2H) ; 4.00-4.49 (m，7H);《61 (dd，2H) ; 6 62 (brs，m); 6.83 (d，1H) ; 7.25 (s，1H) ; 7·72 (d，1H) ; 7.97 (d，ih) ; 8.06 (d，1H); 8.20 (m，2H) ; 9.39 (brs，2H) ; 9.93 (brs，1H) ES (MH)+ ： 462 實例5 l-【2-((3S，4R)-3-經基 _4-{[(3·酮基 _3,4-二氫比啶并[3,2邮 畊-6-基）甲基]胺基}六氫吡啶小基）乙基卜2_酮基二氫喹啉 -7-甲腈，雙鹽酸鹽 使用類似關於合成實例1所述之程序，使3-酮基-3,4-二氫 -2H-p比咬并[3,2-b][l，4]今畊-6·鲅曱酸與中間物2反應，提供標 題組合物。 XH NMR (DMSO-d6) δ ： 2.20 (m? 2Η) ； 3.19 (m? IH) ； 3,25-3.48 (m? 4H) ; 3.71 (m，2H) ; 4.19 (m，2H) ; 4.55-4.65 (m，3H) ; 4.69 (s，2H); 6.63 (brs，IH) ; 6·83 (d，IH) ; 7.26 (d，IH); 7·44 (d，IH) ; 7·73 (d，IH); 7.97 (d, IH) ； 8.07 (d, IH) ； 8.24 (brs5 IH) ； 9.28 (m5 IH) ； 9.58 (m5 IH)； 10.07 (m，IH) ; 11.40 (m，IH). 127286 -134- 200831517 ES (MH)+ ： 475 實例6 l-[2-((3S，4聯-經基-4·{[(3-酮基_3,4c氫班吡啶并【3 2_叫關 畊-6·基）甲基】胺基}六氫吡啶+基）乙基】_2_酮基^义二氫喹啉 _7_甲腈，雙鹽酸鹽 使用類似關於合成實例1所述之程序，使3_酮基_3,4_二氫 -2H-吡啶并[3,2-b][l，4]嘧畊各羧甲醛與中間物2反應，提供標 題組合物。 NMR (DMSO-d6) δ ： 2.21 (m5 2H) ； 3.20 (m? 1H) ； 3.30-3.76 (m? 6H) ; 3.60 (s，2H) ; 4.24 (m，2H) ; 4.57-4.67 (m5 3H) ; 6.62 (d，1H); 6.83 (d，1H) ; 7.27 (d，1H) ; 7.73 (d，1H) ; 7.89 (d，1H) ; 7.98 (d，1H); 8_07 (d，1H); 8.24 (m，1H); 9·34 (m，1H); 9.61 (m，1H); 10.04 (m，1H); 11.08 (s，1H). ES (MH)+ ： 491 實例7 φ 1_(2-{(3民48)-4-【(2,3-二氫[1，4]二氧陸圜烯并[2,3_十比啶-7-基曱基） 胺基]-3·羥基六氫吡啶-l-基}乙基）-7-甲氧基喹喏啉-2(1H)-酮， 雙鹽酸鹽 使用類似關於合成實例1所述之程序，使2,3-二氫[1，4]二氧 陸圜烯并[2,3-c]吡啶-7-羧甲醛與中間物11反應，提供標題組 合物。 XH NMR (ρ20) δ ： 2.28 (m, 2Η) ； 3.20 (ddd? 1H) ； 3.31 (m, 1H)； 3.45-3.76 (m? 4H) ； 3.92 (s? 3H) ； 3.99 (m? 1H) ； 4.29-4.62 (m? 8H) ； 4.83 (m，1H) ; 6.93 (m，1H) ; 7·12 (m，1H) ; 7·22 (d，1H) ; 7.81 (dd，1H); 127286 -135- 200831517 8.06 (d，1H) ; 8.19 (d，1H). ES (MH)+ ： 468 實例8 6-【({(3R，4S)_3·經基-l-[2-(7_甲氧基·2·酮基喹喏啉-1(2H^基）乙基】 六氫峨咬-4-基}胺基）甲基卜211-吡啶并[3,2-13][1，4]噚畊-3(411)-酮， 雙鹽酸鹽 使用類似關於合成實例1所述之程序，使3-酮基_3,4_二氫 2H·峨啶并[3,2-b][l，4]号啡-6-羧甲醛與中間物u反應，提供標 •題組合物。 ^ NMR (DMSO-d6) δ ： 2.19 (m? 2H) ； 3.19 (m? 1H) ； 3.30-3.48 (m? 4H); 3.62-3.83 (m，2H): 3.96 (s，3H); 4.18 (m，2H) ; 4.54-4.76 (m，3H); 4.69 (s，2H) ; 6.54 (m，1H) ; 7.04 (dd，1H) ; 7.21 (d，1H) ; 7.26 (d，1H); 7·44 (d，1H) ; 7_79 (d，1H) ; 8.09 (s，1H) ; 9.28 (m，1H) ; 9·61 (m，1H); 10.26 (m，1H) ; 11.41 (s，1H). ES (MH)+ ： 481 $ 實例9 6-[({(3R，4S)_3_經基-1·[2·(7·甲氧基酮基喳喏啉_i(2H)_基）乙基】 六氫吡啶-4-基}胺基）甲基】_211_吡啶并丨3,2-1&gt;]【1，4】嘧__3(411)-酮， 雙鹽酸鹽 使用類似關於合成實例1所述之程序，使3_酮基_3,4_二氫 -2H-吡啶并[3,2-b][l，4]噻畊-6-羧甲醛與中間物u反應，提供標 題組合物。 XH NMR (DMSO-d6) δ ： 2.19 (m5 2Η) ； 3.17 (m5 1H) ； 3.25-3.70 (m? 6H); 3·59 (s，2H); 3.96 (s，3H) ; 4.23 (m，2H) ; 4.55-4.67 (m，3H) ; 6.53 127286 -136- 200831517 (d，1H) ; 7.04 (dd，1H) ; 7.20 (d，1HV 7 n) ^ /-27 (d5 1H) ； 7.79 (d5 1H) ； 7.90 (d, 1H) ; 8.09 (s，1H) ; 9.30 (m lm · 0 心 / 、，iH)，9·60 (m，1H) ; 10.21 (m，1H); 11·08 (s，1H)· ES (MH)+ ： 497 實例10 吵’㈣斗似二氫⑽二氧陸園烯并即啦 胺基】-3-經基六氫峨咬小基}乙&amp; K_甲氧基峻嗔淋__•嗣， 雙鹽酸鹽 使用類似關於合成實m所述之程序，使2,3_二氫[Μ]二氧 陸圜稀并[2,3_e]M•續f酸財間物12反應，提供標題組 合物。 lH NMR (DMS〇'd6) &quot; ： 2·18 2H) ； 3.16 (m5 1H) ； 3.26-3.40 (m, 4H)，3·65_3·74 (m，2H)，3.96 (s，3H); 4·26·4·43 (m，7H); 4·62 (dd，2H); 6.55 (m，1H) ’ 7.04 (dd，1H)，7.19 (d，1H) ; 7.36 (s，1H) ; 7·79 (d，1H); 8.08 (s，1H)，8.26 (s，1H)，9.51 (m，2H) ; 10.18 (m，1H)· ES (MH)+ : 468 實例11 6-【({(38,41〇各經基-1-【2_(7-甲氧基劣酮基喹喏啉1(211)基）乙基】 六氫吡啶-4-基}胺基）甲基]-211-吡啶并[3,2七】[1，4]噚畊-3(411)-酮， 雙鹽酸鹽 使用類似關於合成實例1所述之程序，使酮基_3,4_二氫 -2H·峨咬并[3,2-b][l，4]$畊-6-羧甲醛與中間物12反應，提供標 題組合物。 XH NMR (D20) δ ： 2.28 (m5 2Η) ； 3.17 (ddd5 1H) ； 3.27 (m5 1H)； 127286 -137- 200831517 3.51-3.75 (m? 4H) ； 3.91 (s5 3H) ； 3.99 (m5 1H) ； 4.28 (m? 2H) ； 4.50-4.62 (m，2H) ; 4.71 (s5 2H) ; 4.80 (m，1H) ; 6·90 (d，1H) ; 7.08 (d，1H) ; 7·11 (dd，1H) ; 7·34 (d，1H) ; 7·79 (d，1H) ; 8.05 (s，1H). ES (MH)+ ： 481 實例12 1-(2-{(38,4叫-4-【(2,3-二氫[1，4]二氧陸困烯并[2,3-〇】吡啶-7-基甲基） 胺基]-3-貌基六風峨淀-l-基}乙基）-2-嗣基·1，2·二氮p奎琳-7-甲 腈，單醋酸鹽 與 實例13 l-(2-{(3R，4S)-4-[(2,3-二氫[1，4]二氧陸圜烯并[2,3-c】峨啶-7-基甲基) 胺基】-3-氟基六風咐咬小基}乙基）_2-酮基4,2-二氫p奎淋_7-甲 腈，單醋酸鹽Kulkami and BD·Tilak, Yan Yan Optics, 15B, 769-773 (1977)) (435 mg, 2.36 mmol) in a solution of anhydrous DMF (2 mL), sodium hydride (142 mg, 60% in oil, 3.54 millimoles). The mixture was stirred at room temperature for 1 hour. Then Yu Yu. Adding methanesulfonic acid 2-{(3S,4R)-4-[(second-butoxycarbonyl)amino]-3-methoxyhexahydrop to hydrazinyl}ethyl ester (intermediate 33, ~2·8 millimoles) solution in DMF. The reaction mixture was stirred at room temperature and then diluted with water and extracted three times with dichloromethane. The organic extract was dried over magnesium sulfate and concentrated. The title compound was obtained as a pale yellow solid (191 mg, 18%) EtOAc (ESP): 441 (ΜΗ+) vs. C24H32N404 Intermediate 106 l- After EtOAc/EtOAc/EtOAc. (2-((3R,4S)4-Amino-3.sodium hexahydroacridinyl)ethyl)n-ketonedihydroquinolin-7-indolenitriletrifluoroacetate The title compound is similar The procedure for the sequence of the racemic material (intermediate 19) is prepared from (3R,4S&gt;4-(;amino)_3_fluorohexahydropyridine small carboxylic acid tert-butyl ester (WO2007071965 and WO2006087543) Except for the following modifications in the final step: the crude trifluoroacetate salt of the title compound was dissolved in chloroform (100 liters) and washed once with saturated sodium bicarbonate (2 mL). The mixture was adjusted to EtOAc = EtOAc (EtOAc (EtOAc) Grayish white 127286 •131- 200831517 solid, 352 mg (81%). MS (ESP): 315 (MH+)^C17H19FN4〇Example 1 H2-{(m,4s )-4-[(2,3·^ Hydrogen μ,4]: Oxalo-ene ρ,3·φ-pyridin-7-ylmethyl) Amino] each hexahydropyridinium+yl)ethyl Keto group 4,2-dihydroporphyrin carbonitrile, dihydrochloride salt 1-{2-[(3R,4S)-4-amino-3-hydroxyhexahydropyridin-1-yl]ethyl}· 2-keto-1,2-dihydroporphyrin as a nitrile (intermediate i, 74 mg, 0.24 mmol) and 2,3-dihydro[1,4]dioxolene [2,3 A mixture of -φ pyridine carboxaldehyde (WO 2〇〇4/〇58144) (39 mg, 0·24 mmol) was heated on a just-activated 3A molecular sieve at 70 ° C for 3 hours. The reaction mixture was allowed to cool to room temperature and sodium triacetoxyborohydride (15 mg, 0.75 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes, then filtered through a 〇·45 μm film and concentrated to dryness under reduced pressure. Chromatography on dichloromethane/methanol (8:1 to 4:1). The fractions containing the product were pooled and concentrated to dryness. The residue was dissolved in dichloromethane/diethyl ether (1:2, 10 mL), and EtOAc (2 EtOAc, EtOAc) The mixture was concentrated to dryness under reduced pressure to dryness &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&&&gt;21〇. Hey. MS (ESP): 462 (MH+) vs. C2 5 H27N5 〇4^H-NMR (DMSO-d6) 5 : 2.18 (m, 2H); 3.15 (m5 1H); 3.25-3.36 (m5 4H) ; 3.69 (m , 2H) ; 4.10-4.49 (m,7H) ; 4.61 (dd,2H) ; 6·64 (bi*s,1H); 6.83 (d, 1H); 7.30 (s, 1H) ; 7.72 (d5 1H) ; 7.97 (d5 1H) ; 8.08 (d3 1H); 8.22 (m, 2H) ; 9.45 (brs, 2H) ; 10.00 (brs, 1H)· 127286 -132· 200831517 Example 2 H2-((3R,4S)- 3-hydroxy-4-{[(3-keto-3,4-dihydrogen such as _pyridinopyrene 3,2 ton 14] 噚 -6-6-yl)methyl]amino}}hexahydropyridine small group) Ethyl]_2-ketodihydroquinoline-7-carbonitrile, dihydrochloride salt was used in a procedure similar to that described in Synthesis Example 1, to give 3-keto-3,4-dihydro-2H-pyridinium [ 3,2-b][l,4] morphine-6-carboxaldehyde (w〇2〇〇4/〇58144) was reacted with Intermediate 1 to provide the title composition. 4 NMR (D20) 5 : (D20) 2.28 (m, 2H); 3.15 (ddd, 1H); 3.26 (m, 1H); 3.40- 3.72 (m, 4H); 3·91 (m, 1H); ·28 (s,2H) ; 4·52 (m,1H) ; 4.61 (m, 1H) ; 4.71 (s,2H) ; 4.80 (m,1H) ; 6.65 (d,1H) ; 7.08 (d,1H 7.35 (d, 1H); 7.66 (d, 1H); 7·87 (d, 1H); 7.96 (s, 1H); 8.02 (d, 1H)· ES (MH)+ : 475 Example 3 1- [2_((3R,4S)_3-radio-4-{[(3-keto-3,4-dihydro-2H_p ratio bite|3,2-b][l,4]^ 耕-6 -yl)methyl]amino}hexahydropyridin-1-yl)ethyl]-2-keto-1,2-dihydroquinolin-7-carbonitrile, bis-hydrochloride using similar synthetic examples The procedure described for the 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]thratic-6-carboxaldehyde (WO 2004/058144) and intermediate Reagent 1 was reacted to provide the title composition. NMR (D20) δ : (D2 0) 2.31 (m, 2H); 3.20 (ddd5 1H); 3.31 (m? 1H); 3.40- 3.80 (m? 4H); 3.55 (s? 2H); 3.95 (m? 1H) ; 4.34 (s5 2H) ; 4.55-4.70 (m, 2H) ; 4.82 (m, 1H) ; 6.84 (d, 1H); 7.11 (d, 1H); 7.66 (d, 1H); 7.80 (d, 1H) ; 7·87 (d,1H) ; 7.96 (s5 1H) ; 8·03 (d,1H)· ES (MH)+ : 491 127286 -133- 200831517 Example 4 1-(2-{(38,卿4-[1] argon [1,4] dioxo-alkenes and [2 3_small than winter ^ amine] hydroxy hexahydropyridine small oxime ethyl) · 2_ 鲷基山 2_ dihydroanthracene Porphyrin_7 carbonitrile, dihydrochloride salt was used in a procedure similar to that described in Synthesis Example 1, to give 2,3-dihydro[indenyl(4)dioxoamphet[2,3-c]pyridine-7-carboxyindole The aldehyde is reacted with the intermediate 2 to provide the title compound. NMR (DMSO-d6) δ: 2.17 (m? 2H); 3.14 (m5 1H); 3.25-3.38 (m? 4H); 3.69 (m, 2H); -4.49 (m, 7H); "61 (dd, 2H); 6 62 (brs, m); 6.83 (d, 1H); 7.25 (s, 1H); 7·72 (d, 1H); 7.97 (d ,ih) ; 8.06 (d,1H); 8.20 (m,2H) ; 9.39 (brs,2H) ; 9.93 (brs,1H) ES (MH)+ : 462 Example 5 l-[2-((3S,4R )-3- Base_4-{[(3·keto-3,4-dihydropyridinium[3,2 mailing-6-yl)methyl]amino}hexahydropyridine small) ethyl b-2-one Dihydroquinoline-7-carbonitrile, dihydrochloride salt was used to make 3-keto-3,4-dihydro-2H-p ratio bite [3,2- using a procedure similar to that described in Synthesis Example 1. b][l,4]Recombinant -6-decanoic acid was reacted with Intermediate 2 to provide the title composition. XH NMR (DMSO-d6) δ: 2.20 (m? 2Η); 3.19 (m? IH); , 25-3.48 (m? 4H); 3.71 (m, 2H); 4.19 (m, 2H); 4.55-4.65 (m, 3H); 4.69 (s, 2H); 6.63 (brs, IH); (d, IH); 7.26 (d, IH); 7·44 (d, IH); 7.73 (d, IH); 7.97 (d, IH); 8.07 (d, IH); 8.24 (brs5 IH) 9.28 (m5 IH); 9.58 (m5 IH); 10.07 (m, IH); 11.40 (m, IH). 127286 -134- 200831517 ES (MH)+ : 475 Example 6 l-[2-((3S, 4-linked-radio--4·{[(3-keto-3,4chydro-piperidine[3 2_called Guan Geng-6·yl)methyl]amino}hexahydropyridine+yl)ethyl] _2-keto-l-dihydroquinoline-7-carbonitrile, dihydrochloride salt was similarly used in the procedure described in Synthesis Example 1 to give 3-keto-3,4-dihydro-2H-pyrido[3 ,2-b][l,4]pyrimidine Each carbaldehyde and Intermediate 2 response, providing the title composition. NMR (DMSO-d6) δ : 2.21 (m5 2H) ; 3.20 (m? 1H) ; 3.30-3.76 (m? 6H) ; 3.60 (s, 2H) ; 4.24 (m, 2H) ; 4.57-4.67 (m5 3H 6.62 (d,1H); 6.83 (d,1H); 7.27 (d,1H); 7.73 (d,1H); 7.89 (d,1H); 7.98 (d,1H); 8_07 (d,1H) ; 8.24 (m,1H); 9·34 (m,1H); 9.61 (m,1H); 10.04 (m,1H); 11.08 (s,1H). ES (MH)+ : 491 Example 7 φ 1_( 2-{(3民48)-4-[(2,3-Dihydro[1,4]dioxolynene[2,3_decapyridin-7-ylfluorenyl)amino]-3 Hydroxyhexahydropyridine-l-yl}ethyl)-7-methoxyquinoxaline-2(1H)-one, dihydrochloride salt using a procedure similar to that described in Synthesis Example 1, 2,3- Dihydro[1,4]dioxantim[2,3-c]pyridine-7-carboxaldehyde was reacted with Intermediate 11 to provide the title composition. XH NMR (ρ20) δ : 2.28 (m, 2Η); 3.20 (ddd? 1H); 3.31 (m, 1H); 3.45-3.76 (m? 4H); 3.92 (s? 3H) ; 3.99 (m? 1H) 4.29-4.62 (m? 8H); 4.83 (m, 1H); 6.93 (m, 1H); 7·12 (m, 1H); 7·22 (d, 1H); 7.81 (dd, 1H); 127286 -135- 200831517 8.06 (d,1H) ; 8.19 (d,1H). ES (MH)+ : 468 Example 8 6-[({(3R,4S)_3·经基-l-[2-(7_ Methoxy·2·ketoquinoxaline-1(2H^yl)ethyl] hexahydroindole-4-yl}amino)methyl b 211-pyrido[3,2-13][1, 4] 噚耕-3(411)-ketone, dihydrochloride using a procedure similar to that described in Synthesis Example 1, to give 3-keto-3,4-dihydro 2H·acridine [3,2-b [[,4] No.6-carboxaldehyde is reacted with the intermediate u to provide the target composition. ^ NMR (DMSO-d6) δ: 2.19 (m? 2H); 3.19 (m? 1H); 3.30 -3.48 (m? 4H); 3.62-3.83 (m, 2H): 3.96 (s, 3H); 4.18 (m, 2H); 4.54-4.76 (m, 3H); 4.69 (s, 2H); 6.54 (m ,1H) ; 7.04 (dd,1H) ; 7.21 (d,1H) ; 7.26 (d,1H); 7·44 (d,1H) ; 7_79 (d,1H) ; 8.09 (s,1H) ; 9.28 ( m,1H) ; 9·61 (m,1H); 10.26 (m,1H) ; 11.41 (s 1H). ES (MH)+ : 481 $ Example 9 6-[({(3R,4S)_3_ 经基-1·[2·(7·methoxy keto porphyrin _i(2H)_ Ethyl)ethyl hexahydropyridin-4-yl}amino)methyl]_211_pyridine hydrazine 3,2-1&gt;][1,4]pyrimyl-_3(411)-one, use of dihydrochloride Similar to the procedure described in Synthesis Example 1, 3-keto- 3,4-dihydro-2H-pyrido[3,2-b][l,4]thratic-6-carboxaldehyde and intermediate u Reaction, providing the title composition. XH NMR (DMSO-d6) δ: 2.19 (m5 2Η); 3.17 (m5 1H); 3.25-3.70 (m? 6H); 3·59 (s, 2H); 3.96 (s, 3H) ; 4.23 (m, 2H) ; 4.55-4.67 (m, 3H) ; 6.53 127286 -136- 200831517 (d,1H) ; 7.04 (dd,1H) ; 7.20 (d,1HV 7 n) ^ /-27 (d5 1H) ; 7.79 (d5 1H) ; 7.90 (d, 1H) ; 8.09 (s, 1H) ; 9.30 (m lm · 0 heart / , , iH ) , 9 · 60 (m, 1H) ; 10.21 (m , 1H); 11·08 (s, 1H)· ES (MH)+ : 497 Example 10 Noisy (4) Duo-like dihydro (10) dioxerem and then amine-based 3--3-yl hexamidine Small base} B &amp; K_methoxy 嗔 _ __• 嗣, bis-hydrochloride using a procedure similar to that described for the synthesis of m, 2,3_ dihydro[Μ]diox Won dilute and [2,3_e] f between M • continued fiscal acid 12 was reacted to provide the title composition. lH NMR (DMS〇'd6) &quot; : 2·18 2H) ; 3.16 (m5 1H) ; 3.26-3.40 (m, 4H), 3·65_3·74 (m, 2H), 3.96 (s, 3H); 4·26·4·43 (m,7H); 4·62 (dd,2H); 6.55 (m,1H) ' 7.04 (dd,1H), 7.19 (d,1H); 7.36 (s,1H) ; 7.79 (d,1H); 8.08 (s,1H), 8.26 (s,1H),9.51 (m,2H); 10.18 (m,1H)· ES (MH)+ : 468 Example 11 6-[( {(38,41〇 Each ketone-1-[2_(7-methoxyl-ketoquinoquinoxaline 1(211)))ethyl]hexahydropyridin-4-yl}amino)methyl]- 211-pyrido[3,2-7][1,4]indole-3(411)-one, dihydrochloride salt was used in a procedure similar to that described in Synthesis Example 1, to give keto-3,4-dihydrogen -2H·bite and [3,2-b][l,4]$ till -6-carboxaldehyde was reacted with intermediate 12 to provide the title composition. XH NMR (D20) δ: 2.28 (m5 2 Η); (ddd5 1H) ; 3.27 (m5 1H); 127286 -137- 200831517 3.51-3.75 (m? 4H) ; 3.91 (s5 3H) ; 3.99 (m5 1H) ; 4.28 (m? 2H) ; 4.50-4.62 (m, 2H); 4.71 (s5 2H); 4.80 (m, 1H); 6·90 (d, 1H); 7.08 (d, 1H); 7·11 (dd, 1H); 7·34 (d, 1H); 7.79 (d, 1H); 8.05 (s, 1H). ES (MH)+: 481 Example 12 1-(2-{(38,4)-4-[(2,3-Dihydro[1,4]dioxo-area[2,3-indole]pyridine -7-ylmethyl)amino]-3-formyl hexafluorene-l-yl}ethyl)-2-indenyl-1,2.diazop-quineline-7-carbonitrile, monoacetic acid Salts and Examples 13 l-(2-{(3R,4S)-4-[(2,3-Dihydro[1,4]dioxolynene[2,3-c]acridin-7-yl) Methyl)amino]-3-fluorohexafluoropterin small base}ethyl)_2-keto 4,2-dihydrop-quinone_7-carbonitrile, monoacetate

使順式（±)1-[2-(4-胺基-3-氟基六氫吡啶+基）乙基]_2_酮基 -U·二氫喳啉-7·甲腈（中間物19，〇95毫莫耳）懸浮於氯仿/ 甲醇（1: 1，20毫升）中，並藉由逐滴添加N，N_二異丙基乙胺 自由鹼化’直到全部物質溶解為止。接著，使用類似關於 合成實例1所述之程序，使其接受以2,3_二氫[M]二氧陸園稀 并[2,3-〇比咬-7-緩甲藤⑽冑克，〇95毫莫耳）與三乙酿氧基 硼氫化納（_毫克，2.8毫莫耳）之還原性胺化作用。使過滤 後所得之殘留物溶於二氯甲烧與飽和碳酸氫納中。以脱氯 氧化鈉溶液將水相tpH值調整至阳♦將水相以二氯甲烧 逆萃取’亚使合併之有機相以硫酸納脫水乾燥，及濃縮。 以水/乙腈/醋酸錢之逆相層析’獲得產物，為黃褐色泡珠 127286 -138- 200831517 物，276 毫克（62%)。 ^-NMR (CDCl3-d) δ ： 1.86 (m, 2H) ； 2.34 (m5 3H) ； 2.71 (m5 2H)； 2.82 (m, 1H) ； 3.03 (m? 1H) ； 3.30 (m5 1H) ； 3.93 (m5 2H) ； 4.30 (m5 4H)； 4·42 (m，2H) ; 4·90 (m，1H) ; 6.80 (d，1H) ; 6.90 (s5 1H) ; 7·45 (d，1H); 7.65 (m，2H) ; 7.78 (s，1H) ; 8.09 (s，1H). MS (ESP) : 464 (MH+ )對 C2 5 H2 6 FN5 03 外消旋混合物係於Chiralpak _AD，250 x 20毫米，10 μ管柱 (50%甲醇、50%乙醇、〇·1%二乙胺）上分離。實例12係首先 ⑩溶離出，[a]D=+14.3 (c = 0.3，甲醇）（89毫克），接著為實例 13，[a]D=-11.6 (c = 〇·328，甲醇）（80 毫克）。 實例14 1-(2-{(38,411)-4-【(2,3-二氫[1，4】二氧陸圜烯并丨2,3^】吡啶-7-基甲基） 胺基】-3-甲氧基六氫吡啶-i-基}乙基)_7_甲氧基喹喏啉_2(1Η)_ 酮，雙_鹽酸鹽 將l_{2_[(3S，4R)-4-胺基-3-甲氧基六氫峨咬-1·基]乙基曱氧 _ 基p奎嗜琳-2(1H)-酮（中間物31，160毫克粗製物，〇·48毫莫耳） 與2,3-二氫[I，4]二氧陸圜烯并[2,3-c]吡啶；羧甲醛（8〇毫克， 〇·48毫莫耳）在無水甲醇/氯仿（i :〗，1〇毫升）中之混合物， 於氮氣下，在3A分子篩上，於7(rc下加熱一小時。使反應 物冷卻至室溫，並添加三乙醯氧基硼氫化鈉（31〇毫克，144 耄莫耳）。30分鐘後，經過矽藻土過濾反應物。使濾液濃縮 至乾涸，溶於氣仿中之15%甲醇内，並以飽和碳酸氫鈉溶 液洗滌。將水相以15%甲醇/氯仿再萃取兩次。使合併之有 機相以硫酸鎂脫水乾燥，及在減壓下濃縮。於矽膠上，以 127286 • 139 - 200831517 含有0.25%氫氧化銨之2-5%甲醇在二氣甲烷中之梯度液層 析，獲得160毫克（70%)標題組合物之自由態鹼，為油狀物。 使其溶於二氣甲烷/***（1 : 1，5毫升）中，並以醚中之2 〇M HC1 (〜2當量）處理。藉過濾收集所形成之沉澱物，在水中重 配，並凍乾，獲得148毫克標題組合物，為固體。 XH NMR φ2〇) δ ： 2.04-2.33 (m5 2H)； 3.05-3.25 (m? 2H)； 3.44 (s, 3H)； 3,50-3,71 (m5 3H) ; 3-87 (s5 3H) ; 4.04 (s5 1H) ; 4.21 (d5 3H) ; 4.26-4.32 (m，3H) ; 4.33-4.40 (m，2H) ; 4.45-4.58 (m，1H) ; 4.74-4.87 (m，1H); 6·82-6·92 (m，1H) ; 7 02-7.12 (m，2H) ; 7.75 (d，1H) ; 8.01 (s，1H) ; 8.09 (s，lH)· MS (ESP) : 482 (MH+ )對 C2 5 H3 i N5 05 實例15 6-[({(3S，4R)-3-甲氧基-l-[2_(7_甲氧基-2-酮基喹喏啉_1(2H)_基）乙 基]六氫吡啶_4_基}胺基）甲基]-2H-吡啶并[3,2_b][l，4】噚畊·3(4Η)_ 酮 按關於實例14所述（惟其鹽酸鹽製備除外），使 l-{2-[(3S，4R)-4-胺基-3-曱氧基六氫ρ比咬-1-基]乙基}-7-甲氧基ρ奎 喏啉-2(1H)-酮（中間物31，160毫克粗製物，0.48毫莫耳）、3-酮基-3,4-二氫-2H·吡啶并[3,2-b][l，4]噚畊-6-羧甲醛（WO 2004/ 058144) (85毫克，0·48毫莫耳）及三乙醯氧基硼氫化鈉（310毫 克，1.44毫莫耳）反應，獲得139毫克（58%)標題組合物。 ^NMRCDMSO-de) δ ： 1364.53 (m? 1H)； 1.59-1.77 (m, 1H)； 2.24-2.37 (m，1H) ; 2.40-2.46 (m，1H) ; 2.60 (t，2H) ; 2.65-2.84 (m，2H) ; 3.14-3.21 (m，3H) ; 3.30-3.34 (m，2H) ; 3·67 (q，2H) ; 3·92 (s，3H) ; 4·22-4·45 (m， 127286 -140- 200831517 2H) ; 4.61 (s，2H) ; 6.92-7.10 (m，3H) ; 7.30 (d，1H) ; 7.75 (d，1H) ; 8.04 (s, 1H) ； 11.15-11.27 (m? 1H). MS (ESP) : 495 (MH+)對 C2 5 H3 〇 N6 05 實例16 l-(2-{(3R，4S)_4-[(2,3-二氫[1，4]二氧陸圜烯并P，3-c】吡啶冬基甲基） 胺基]-3-曱氧基六氫吡啶-l-基}乙基）-7-甲氧基喳喏啉·2(1Η)_ 酮，雙-鹽酸鹽 按根據實例14所述，使l-{2-[(3R，4S)-4-胺基-3-甲氧基六氫吡 啶-1-基]乙基}-7-甲氧基喹喏啉-2(1Η)-酮（中間物37，37毫克， 0·11毫莫耳）、2,3-二氫[1，4]二氧陸圜烯并[2,3-c]吡啶-7-羧甲醛 (WO 2004/058144) (18毫克，0·11毫莫耳）及三乙醯氧基硼氫化 鈉（70毫克，0.33毫莫耳)反應，獲得29毫克標題組合物，為 無色固體。 ^ NMR (〇2〇) δ ： 2.17-2.30 (m? 2H)； 3.12-3.24 (m5 2H)； 3.49 (s, 3H)； 3·56-3·75 (m，3H) ; 3.92 (s，3H) ; 4·09 (s，1H) ; 4.25 (d5 2H) ; 4.34 (dd， 2H)； 4.41 (dd? 2H)； 4.52-4.70 (m5 2H)； 4.79-4.93 (m5 2H)； 6.93 (d5 1H)； 7.08-7.16 (m? 2H) ； 7.82 (d5 1H) ； 8.07 (s, 1H) ； 8.13 (s, 1H). MS (ESP) ·· 482 (MH+)對 C2 5 H3 i N5 05 實例17 6_[({(3R，4S)-3-甲氧基-1·[2·(7-甲氧基-2_酮基p奎嗔淋_i(2H)_基）乙 基】六氫吡啶_4-基}胺基）甲基]_2Η-峨啶并[3,2-b] [1，4]噚畊-3(4H)-酮 按關於實例14所述（惟其鹽酸鹽製備除外），使 l-{2-[(3R，4S)-4-胺基-3-甲氧基六氫吡咬小基]乙基卜7-甲氧基喳 喏啉-2(1H)-酮（中間物37，37毫克粗製物，ail毫莫耳）、3_ 127286 -141 - 200831517 酮基-3,4-二氫-2H-吡啶并[3,2-b][l，4]嘮畊-6-羧甲醛（WO 2004/ 058144) (20毫克，〇·11毫莫耳）及三乙醯氧基硼氫化鈉（7〇毫 克，0.33毫莫耳）反應，獲得34毫克（63%)標題組合物。 ^NMRCDMSO-^) (5 ： 1.39-1.53 (m? 1H) ； 1.59-1.77 (m5 1H) ； 2.29 (d，1Η) ; 2.38-2.47 (m，1Η) ; 2.60 (t，2H) ; 2.65-2.85 (m，3H) ; 3.13-3.22 (m5 3H) ； 3.30-3.34 (m5 2H) ； 3.58-3.78 (m5 2H) ； 3.92 (s5 3H) ； 4.24-4.44 (m5 2H) ； 4.61 (s? 2H) ； 6.93-7.07 (m5 3H) ； 7.30 (d5 1H) ； 7.75 (d, 1H)； 8.04 (s，1H) ; 11.20 (s，1H). MS (ESP) : 495 (MH+)對 C2 5 H3 〇 N6 05 實例18 6-【({(3R，4S)-3·曱氧基·1-【2·(7-甲氧基-2-酮基喹喏啉-1(2H)-基）乙 基]六氫吡啶冰基}胺基）甲基】-2H-吡啶并[3,2-b][l，4】^_-3(4H)-酮，雙-鹽酸鹽 使用類似關於合成實例14所述之程序，使l-{2-[(3R，4S)-4-胺基-3-甲氧基六氫吡啶-1-基]乙基}_7_甲氧基喹喏啉-2(1H)-酮 (中間物37，70毫克粗製物，〇·21毫莫耳）、3-酮基-3,4-二氫-2H-吡啶并[3,2-b][l，4]嘧畊-6·羧甲醛（WO 2004/058144) (40 毫克，0.21 毫莫耳）及三乙醯氧基硼氫化鈉（130毫克，0.63毫莫耳）反 應，獲得73毫克標題組合物，為灰白色固體。 ~ XH NMR φ20) δ ： 2.13-2.28 (m5 2H)； 3.03-3.21 (m5 2H)； 3.41-3.46 (m, 3H)； 3.50 (s5 2H)； 3.52-3.72 (m, 4H)； 3.86 (s5 3H)； 4.08 (s5 1H)； 4.19-4.35 (m，3H); 4.44-4.59 (m，1H) ; 4.74-4.88 (m，1H) ; 6.86 (d，1H); 7.01-7.10 (m，2H) ; 7.70-7.79 (m，2H) ; 8.01 (s，1H).Cis (±) 1-[2-(4-Amino-3-fluorohexahydropyridine+yl)ethyl]_2-keto-U-dihydroporphyrin-7·carbonitrile (Intermediate 19 , 〇95 mmol, suspended in chloroform / methanol (1:1, 20 mL), and free alkalized by dropwise addition of N,N-diisopropylethylamine until all the material was dissolved. Next, using a procedure similar to that described in Synthesis Example 1, it was accepted to accept 2,3-dihydro[M]dioxanthine and [2,3-indole ratio -7-staple (10) gram, 〇 Reductive amination of 95 mmoles with triethyloxyborohydride (_mg, 2.8 mmol). The residue obtained after filtration was dissolved in methylene chloride and saturated sodium hydrogencarbonate. The aqueous phase tpH was adjusted to a positive value by dechlorination of sodium oxide solution. The aqueous phase was reversely extracted with methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated. The product was obtained by reverse phase chromatography of water / acetonitrile / acetic acid to afford a yellow brown bead 127286 -138 - 200831517, 276 mg (62%). ^-NMR (CDCl3-d) δ: 1.86 (m, 2H); 2.34 (m5 3H); 2.71 (m5 2H); 2.82 (m, 1H); 3.03 (m? 1H); 3.30 (m5 1H); (m5 2H) ; 4.30 (m5 4H); 4·42 (m, 2H) ; 4·90 (m, 1H); 6.80 (d, 1H); 6.90 (s5 1H) ; 7·45 (d, 1H) 7.65 (m,2H) ; 7.78 (s,1H) ; 8.09 (s,1H). MS (ESP): 464 (MH+) to C2 5 H2 6 FN5 03 The racemic mixture is attached to Chiralpak _AD, 250 x 20 Millimeter, 10 μ column (50% methanol, 50% ethanol, 〇·1% diethylamine) was separated. Example 12 was first dissolved in 10, [a] D = +14.3 (c = 0.3, methanol) (89 mg), followed by Example 13, [a] D = -11.6 (c = 〇·328, methanol) (80) Mg). Example 14 1-(2-{(38,411)-4-[(2,3-Dihydro[1,4]dioxolynene oxime 2,3^]pyridin-7-ylmethyl)amino] -3-methoxyhexahydropyridine-i-yl}ethyl)-7-methoxyquinoxaline-2(1Η)_one, bis-hydrochloride salt l_{2_[(3S,4R)-4 -amino-3-methoxyhexahydropurine -1 -yl]ethyl oxime _ ke p Kui Lin -2 (1H)-ketone (intermediate 31, 160 mg crude, 〇 · 48 mmol Ear) with 2,3-dihydro[I,4]dioxantemene[2,3-c]pyridine; carboxaldehyde (8 mg, 〇·48 mmol) in anhydrous methanol/chloroform (i : 〗 〖, 1 〇 ml), under nitrogen, on a 3A molecular sieve, heated at 7 (rc) for one hour. The reaction was cooled to room temperature and sodium triethyl sulfonate hydride (31 〇) was added. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 15% methanol / chloroform was extracted twice more. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. On the silica gel, 127286 • 139 - 200831517 Chromatography of 0.25% ammonium hydroxide in 2-5% methanol in di-methane to afford 160 mg (yield: 70%) of the title compound as free oil as an oil. Treated with diethyl ether (1:1,5 mL) and treated with 2 〇M HCl (~2 eq.) in ether. The precipitate formed was collected by filtration, reconstituted in water, and lyophilized to give 148 mg of title combination. XH NMR φ2〇) δ : 2.04-2.33 (m5 2H); 3.05-3.25 (m? 2H); 3.44 (s, 3H); 3,50-3,71 (m5 3H) ; 3- 87 (s5 3H) ; 4.04 (s5 1H) ; 4.21 (d5 3H) ; 4.26-4.32 (m,3H) ; 4.33-4.40 (m,2H) ; 4.45-4.58 (m,1H) ; 4.74-4.87 (m ,1H); 6·82-6·92 (m,1H) ; 7 02-7.12 (m,2H) ; 7.75 (d,1H) ; 8.01 (s,1H) ; 8.09 (s,lH)· MS ( ESP): 482 (MH+) to C2 5 H3 i N5 05 Example 15 6-[({(3S,4R)-3-methoxy-l-[2_(7-methoxy-2-ketoquinazoquinone) Oleone_1(2H)-yl)ethyl]hexahydropyridine_4_yl}amino)methyl]-2H-pyrido[3,2_b][l,4]噚耕·3(4Η)_ ketone According to Example 14 (except for the preparation of the hydrochloride salt), l-{2-[(3S,4R)-4-amino-3-oxo Hexahydro-p-buty-1 -yl]ethyl}-7-methoxy ρ quinoxaline-2(1H)-one (intermediate 31, 160 mg crude, 0.48 mmol), 3-keto -3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-carboxaldehyde (WO 2004/ 058144) (85 mg, 0·48 mmol) and three Reaction with sodium acetoxyborohydride (310 mg, 1.44 mmol) afforded 139 mg (58%) of the title compound. ^NMRCDMSO-de) δ : 1364.53 (m? 1H); 1.59-1.77 (m, 1H); 2.24-2.37 (m, 1H); 2.40-2.46 (m, 1H); 2.60 (t, 2H); 2.65- 2.84 (m, 2H) ; 3.14-3.21 (m, 3H) ; 3.30-3.34 (m, 2H) ; 3·67 (q, 2H) ; 3·92 (s, 3H) ; 4·22-4·45 (m, 127286 -140- 200831517 2H); 4.61 (s, 2H); 6.92-7.10 (m, 3H); 7.30 (d, 1H); 7.75 (d, 1H); 8.04 (s, 1H); 11.15- 11.27 (m? 1H). MS (ESP): 495 (MH+) vs. C2 5 H3 〇N6 05 Example 16 l-(2-{(3R,4S)_4-[(2,3-Dihydro[1,4 Dioxanedecene and P,3-c]pyridinylmethyl)amino]-3-decyloxyhexahydropyridine-l-yl}ethyl)-7-methoxyporphyrin·2 (1Η) ketone, bis-hydrochloride salt as described in Example 14, l-{2-[(3R,4S)-4-amino-3-methoxyhexahydropyridin-1-yl] -7-7-methoxyquinoxaline-2(1Η)-one (intermediate 37, 37 mg, 0·11 mmol), 2,3-dihydro[1,4]dioxene terpene And [2,3-c]pyridine-7-carboxaldehyde (WO 2004/058144) (18 mg, 0·11 mmol) and sodium triethoxysulfonate (70 mg, 0.33 mmol) , obtained 29 mg of the title composition, which is colorless and solid . ^ NMR (〇2〇) δ : 2.17-2.30 (m? 2H); 3.12-3.24 (m5 2H); 3.49 (s, 3H); 3·56-3·75 (m, 3H) ; 3.92 (s, 3H) ; 4·09 (s, 1H) ; 4.25 (d5 2H) ; 4.34 (dd, 2H); 4.41 (dd? 2H); 4.52-4.70 (m5 2H); 4.79-4.93 (m5 2H); 6.93 ( D5 1H); 7.08-7.16 (m? 2H) ; 7.82 (d5 1H) ; 8.07 (s, 1H) ; 8.13 (s, 1H). MS (ESP) ·· 482 (MH+) vs C2 5 H3 i N5 05 Example 17 6_[({(3R,4S)-3-methoxy-1·[2·(7-methoxy-2-keto-p-p-quinone- _i(2H)-yl)ethyl) Hydropyridine-4-yl}amino)methyl]_2Η-acridino[3,2-b][1,4]indole-3(4H)-one as described in Example 14 (but its hydrochloride) Except for the preparation), l-{2-[(3R,4S)-4-amino-3-methoxyhexahydropyridinyl]ethyl b 7-methoxyporphyrin-2 (1H) -ketone (intermediate 37, 37 mg crude, ail millimolar), 3_127286-141 - 200831517 keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]唠耕-6-carboxaldehyde (WO 2004/ 058144) (20 mg, 〇·11 mmol) and sodium triethoxy borohydride (7 〇 mg, 0.33 mmol) to obtain 34 mg (63 %) title composition^NMRCDMSO-^) (5: 1.39-1.53 (m? 1H); 1.59-1.77 (m5 1H); 2.29 (d, 1Η); 2.38-2.47 (m, 1Η); 2.60 (t, 2H); 2.65- 2.85 (m,3H) ; 3.13-3.22 (m5 3H) ; 3.30-3.34 (m5 2H) ; 3.58-3.78 (m5 2H) ; 3.92 (s5 3H) ; 4.24-4.44 (m5 2H) ; 4.61 (s? 2H ;;93.30 (d5 1H) 〇N6 05 Example 18 6-[({(3R,4S)-3·曱oxy·1-[2·(7-methoxy-2-ketoquinoxalin-1(2H)-yl)) Hexylpyridylsylamino}amino)methyl]-2H-pyrido[3,2-b][l,4]^_-3(4H)-one, bis-hydrochloride The procedure described in Example 14 gave 1-{2-[(3R,4S)-4-amino-3-methoxyhexahydropyridin-1-yl]ethyl}_7-methoxyquinoxaline- 2(1H)-ketone (intermediate 37, 70 mg crude, 〇·21 mmol), 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l, 4] Pyridine-6·carboxyformaldehyde (WO 2004/058144) (40 mg, 0.21 mmol) and sodium triethoxysulfonate (130 mg, 0.63 mmol) to obtain 73 mg of the title combination , XH NMR φ20) δ : 2.13-2.28 (m5 2H); 3.03-3.21 (m5 2H); 3.41-3.46 (m, 3H); 3.50 (s5 2H); 3.52-3.72 (m, 4H); 3.86 (s5 3H); 4.08 (s5 1H); 4.19-4.35 (m, 3H); 4.44-4.59 (m, 1H); 4.74-4.88 (m, 1H); 6.86 (d, 1H); 7.01 -7.10 (m, 2H); 7.70-7.79 (m, 2H); 8.01 (s, 1H).

MS(ESP): 511(MH+)對 C25H30N6O4S 127286 -142- 200831517 實例19 l-(2-{(3S，4R)-4_[(2,3-二氫[1，4】二氧陸園烯并【2,3-c]吡啶-7·基甲基） lie基]-3-甲氧基六乳峨咬-i-基}乙基）_2_嗣基-i，2_二氮T?奎p林 甲腈，雙-鹽酸鹽 使用類似關於合成實例14所述之程序，使1-{2-[(3S，4R)-4-胺基-3-曱氧基六氫p比唆·1_基]乙基}_2-酮基-1，2-二氫P奎琳-7-甲 腈（中間物41，93毫克，0.29毫莫耳）、2,3-二氫[1，4]二氧陸圜 烯并P，3-c]吡啶-7-羧甲醛（WO 2004/058144) (47毫克，0.29毫莫 耳）及三乙醯氧基硼氫化鈉（180毫克，0.86毫莫耳）反應，獲 得95毫克標題組合物，為無色固體。 NMR (D20) δ ： 2.14-2.33 (m5 2H)； 3.12-3.27 (m, 2H)； 3.42-3.49 (m? 3H); 3.54-3.62 (m，2H); 3.63-3.76 (m，2H); 4.09 (s，1H) ; 4.25 (d，1H); 4.32-4.39 (m, 4H) ； 4.43-4.50 (m5 2H) ； 4.50-4.65 (m5 1H) ； 4.83 (d? 1H)； 6.80 (d，1H) ; 7.29 (s，1H) ; 7.61 (dd，1H) ; 7.82 (d，1H) ; 7.91 (s，1H); 7.97 (d, 1H) ； 8.22 (s5 1H). MS (ESP) : 476 (MH+)對 C26H29N5 04 實例20 l-【2-((3S，4R)-3-甲氧基·4-{[(3·酮基-3,4-二氫-2H_吡啶并[3,2-b]丨 1，4J 噚畊-6-基）甲基]胺基}六氫吡啶-1-基）乙基]·2·酮基-1，2-二氫4 啉-7-甲腈 使用類似關於合成實例14所述之程序（惟其鹽酸鹽製備 除外），使l-{2-[(3S，4R)-4·胺基斗曱氧基六氫吡啶小基]乙基 酮基-1，2-二氫喹啉-7-甲腈（中間物41，93毫克，0.29毫莫耳）、 3-酮基-3,4-二氫-2H-吡啶并[3,2-b][l，4]噚畊-6-羧甲醛 127286 -143- 200831517 2004/058144) (51毫克，0.29毫莫耳）及三乙醯氧基硼氫化鈉 (180毫克，0.86毫莫耳）反應，獲得80毫克（57%)標題化合物， 為灰白色固體。 4 NMR(DMSO-d6) 6 : 1.36-1.51 (m，1H); L59-1.75 (m，1H); 2.23-2.37 (m? 1Η) ； 2.56 (t? 2H) ； 2.60-2.80 (m? 3H) ； 3.17 (s? 3H) ； 3.26-3.32 (m? 2H) ; 3.68 (q，2H) ; 4·25-4·45 (m，2H) ; 4.61 (s，2H) ; 6.78 (d，1H) ; 6.99 (d，1H) ; 7·29 (d，1H) ; 7·65 (dd，1H) ; 7,91 (d5 1H) ; 8.00 (d5 1H) ; 8.10 (s，1H) ; 11.20 (s，1H). MS (ESP) : 489 (MH+)對 C26H28N604 實例21 1-[2_((3S，4R)_3-甲氧基-4-{[(3-酮基-3,4·二氫 _2H-p比咬并[3,2-b]【l，4】 嘍畊-6-基）甲基]胺基}六氫吡啶-1-基）乙基】-2-酮基·1，2_二氫喹 啉-7-甲腈，雙·鹽酸鹽 使用類似關於合成實例14所述之程序，使l-{2-[(3S，4R)-4-胺基-3-甲氧基六氫吡啶小基]乙基}-2-酮基-1，2-二氫喹啉-7·甲 腈（中間物41，93毫克，0.29毫莫耳）、3-酮基-3,4-二氫-2H-吡啶并[3,2_b][l，4]嘧嗜-6-羧甲醛（WO 2004/058144) (55 毫克，0.29 毫莫耳）及三乙醯氧基硼氫化鈉（180毫克，0.86毫莫耳）反 應，獲得68毫克標題組合物，為黃色固體。 NMR (D20) (5 ： 2.14-2.27 (m5 2H)； 3.00-3.15 (m? 2H)； 3.44 (s5 3H)； 3.47-3.53 (m? 4H) ； 3.57-3.70 (m5 2H) ； 4.05 (s5 1H) ； 4.12-4.21 (m3 1H)； 4·27 (d，2H) ; 4.47-4.64 (m，1H) ; 4.72-4.86 (m，1H) ; 6.80 (d，1H) ; 7·05 (d，1H) ; 7·61 (dd，1H) ; 7.75 (d，1H) ; 7·82 (d，1H) ; 7·91 (s，1H) ; 7.97 (d，1H). 127286 -144- 200831517MS (ESP): 511 (MH+) vs. C25H30N6O4S 127286 - 142 - 200831517 Example 19 l-(2-{(3S,4R)-4_[(2,3-Dihydro[1,4]dioxene) [2,3-c]pyridin-7-ylmethyl) lie-based]-3-methoxy hexaploid-i-yl}ethyl)_2_mercapto-i,2_diaza T? p-Linonitrile, bis-hydrochloride using a procedure similar to that described in Synthesis Example 14 to give 1-{2-[(3S,4R)-4-amino-3-yloxyhexahydrop-pyrene 1_yl]ethyl}_2-keto-1,2-dihydro-p-quinolin-7-carbonitrile (intermediate 41,93 mg, 0.29 mmol), 2,3-dihydro[1,4 Dioxordecene and P,3-c]pyridine-7-carboxaldehyde (WO 2004/058144) (47 mg, 0.29 mmol) and sodium triethoxysulfonate (180 mg, 0.86 mmol) Reaction of the ear gave 95 mg of the title compound as a colourless solid. NMR (D20) δ : 2.14-2.33 (m5 2H); 3.12-3.27 (m, 2H); 3.42-3.49 (m? 3H); 3.54-3.62 (m, 2H); 3.63-3.76 (m, 2H); 4.09 (s,1H) ; 4.25 (d,1H); 4.32-4.39 (m, 4H) ; 4.43-4.50 (m5 2H) ; 4.50-4.65 (m5 1H) ; 4.83 (d? 1H); 6.80 (d, 1H) ; 7.29 (s,1H) ; 7.61 (dd,1H) ; 7.82 (d,1H) ; 7.91 (s,1H); 7.97 (d, 1H) ; 8.22 (s5 1H). MS (ESP) : 476 (MH+) vs. C26H29N5 04 Example 20 l-[2-((3S,4R)-3-Methoxy·4-{[(3·keto-3,4-dihydro-2H-pyrido[3, 2-b]丨1,4J 噚耕-6-yl)methyl]amino}hexahydropyridin-1-yl)ethyl]·2·keto-1,2-dihydrotetralin-7- The nitrile was used in a procedure similar to that described in the synthesis of Example 14 (except for the preparation of the hydrochloride salt) to give l-{2-[(3S,4R)-4.amino-indoleoxyhexahydropyridinyl]ethyl ketone Base-1,2-dihydroquinolin-7-carbonitrile (intermediate 41,93 mg, 0.29 mmol), 3-keto-3,4-dihydro-2H-pyrido[3,2- b][l,4]噚耕-6-carboxaldehyde 127286 -143- 200831517 2004/058144) (51 mg, 0.29 mmol) and sodium triethoxysulfonate (180 mg, 0.86 mmol) reaction, 80 mg (57%) of the title compound was obtained as a white solid. 4 NMR (DMSO-d6) 6 : 1.36-1.51 (m, 1H); L59-1.75 (m, 1H); 2.23-2.37 (m? 1Η); 2.56 (t? 2H); 2.60-2.80 (m? 3H) 3.17 (s? 3H); 3.26-3.32 (m? 2H); 3.68 (q, 2H); 4·25-4·45 (m, 2H); 4.61 (s, 2H); 6.78 (d, 1H) 6.99 (d,1H) ; 7·29 (d,1H) ; 7·65 (dd,1H) ; 7,91 (d5 1H) ; 8.00 (d5 1H) ; 8.10 (s,1H) ; 11.20 ( s,1H). MS (ESP): 489 (MH+) to C26H28N604 Example 21 1-[2_((3S,4R)_3-methoxy-4-{[(3-keto-3,4·dihydro) _2H-p ratio bite [3,2-b][l,4] 喽耕-6-yl)methyl]amino}hexahydropyridin-1-yl)ethyl]-2-keto- 1 , 2_dihydroquinoline-7-carbonitrile, bis-hydrochloride using a procedure similar to that described in Synthesis Example 14, l-{2-[(3S,4R)-4-amino-3-methyl Oxy hexahydropyridine small group] ethyl}-2-keto-1,2-dihydroquinolin-7·carbonitrile (intermediate 41,93 mg, 0.29 mmol), 3-keto-3 ,4-dihydro-2H-pyrido[3,2_b][l,4]pyrazine-6-carboxycarboxaldehyde (WO 2004/058144) (55 mg, 0.29 mmol) and triethoxyhydroxyborohydride Sodium (180 mg, 0.86 mmol) was reacted to obtain a 68 mg heading combination As a yellow solid. NMR (D20) (5: 2.14-2.27 (m5 2H); 3.00-3.15 (m? 2H); 3.44 (s5 3H); 3.47-3.53 (m? 4H); 3.57-3.70 (m5 2H); 4.05 (s5 1H) ; 4.12-4.21 (m3 1H); 4·27 (d, 2H); 4.47-4.64 (m, 1H); 4.72-4.86 (m, 1H); 6.80 (d, 1H) ; 7·05 (d , 1H); 7·61 (dd, 1H); 7.75 (d, 1H); 7·82 (d, 1H); 7·91 (s, 1H); 7.97 (d, 1H). 127286 -144- 200831517

MS(ESP): 505 (MH+：^C26H28N6〇3S 實例22 1-(2-{(311，48)-4-【(2,3-二氫[1，4】二氧陸園烯并【2,3却比咬-7-基甲基） 胺基]·3-甲氧基六風峨咬小基}乙基）_2_酮基-口-二氫？奎淋_7_ 甲腈，雙-鹽酸鹽 使用類似關於合成實例14所述之程序，使i-{2-[(3R，4S)-4-胺基-3·甲氧基六氫吡啶_1·基]乙基卜2-g同基_i，2_二氫喹琳-7-甲 •腈（中間物43，80毫克，0.25毫莫耳）、2&gt;二氫[1，4]二氧陸圜 細并[2,3-c]口比咬-7-魏甲酸（WO 2004/058144) (41 毫克，〇·25 毫莫 耳）及三乙醯氧基獨氫化鈉（160毫克，〇·74毫莫耳）反應，獲 得69毫克標題組合物，為灰白色固體。 ^ NMR (D20) δ ： 2.14-2.30 (m5 2H)； 3.12-3.25 (m, 2H)； 3.41-3.48 (m5 3H) ； 3.54-3.62 (m? 2H) ； 3.63-3.74 (m? 2H) ； 4.08 (s5 1H) ； 4.26 (s5 1H)； 4.30-4.38 (m, 4H) ； 4.40-4.47 (m? 2H) ； 4.53-4.66 (m5 1H) ； 4.75-4.90 (m5 1H) ; 6.80 (d，1H) ; 7.24 (s，1H) ; 7.62 (dd，1H) ; 7.83 (d，1H) ; 7.92 (s， 1H) ; 7.98 (d，1H) ; 8·19 (s，1H)·MS (ESP): 505 (MH+:^C26H28N6〇3S Example 22 1-(2-{(311,48)-4-[(2,3-Dihydro[1,4] Dioxererene and [2] , 3 is better than biting 7-ylmethyl) Amino]·3-methoxy hexazone bite small base} ethyl)_2-keto-mouth-dihydro-quinoline_7_carbonitrile, double- The hydrochloride salt was similar to that described in Synthesis Example 14 to give i-{2-[(3R,4S)-4-amino-3-methoxyhexahydropyridin-1-yl]ethyl b-2- g with the same base _i, 2_ dihydroquinolin-7-methyl nitrile (intermediate 43, 80 mg, 0.25 mmol), 2 &gt; dihydro[1,4]dioxane hydrazin [2, 3-c] mouth ratio bite-7-weilic acid (WO 2004/058144) (41 mg, 〇·25 mmol) and triethyl decyloxydisodium (160 mg, 〇·74 mmol) Obtained 69 mg of the title compound as an off-white solid. NMR (D20) δ: 2.14-2.30 (m5 2H); 3.12-3.25 (m, 2H); 3.41-3.48 (m5 3H); 3.54-3.62 (m? 2H); 3.63-3.74 (m? 2H); 4.08 (s5 1H); 4.26 (s5 1H); 4.30-4.38 (m, 4H); 4.40-4.47 (m? 2H); 4.53-4.66 (m5 1H); 4.75-4.90 (m5 1H) ; 6.80 (d,1H) ; 7.24 (s,1H) ; 7.62 (dd,1H) ; 7.83 (d,1H) ; 7.92 (s, 1H) ; 7.98 (d, 1H) ; 8·19 (s, 1H)·

W MS (ESP) : 476 (MH+)對 C2 6 H2 9 N5 04 實例23 l-[2-((3R，4S)-3·曱氧基·4_{[(3_酮基·3,4·二氫-：2H_吡啶并【3,2-b]【l，4] 3 p井-6-基）甲基]胺基}六風〃比咬-1-基）乙基】-2·嗣基-1，2-二氮邊 淋-7-甲月青 使用類似關於合成實例14所述之程序（惟其鹽酸鹽製備 除外），使l-{2-[(3R，4S)-4-胺基-3-曱氧基六氫吡啶小基]乙基}_2_ 酮基·1，2-二氫喳啉-7-曱腈（中間物43，80毫克，0.25毫莫耳）、 127286 -145- 200831517 3-酮基-3,4-二氫-2H-p比唆并[3,2-b][l，4]p号p井-6-羧甲駿（w〇 2004/058144) (45毫克，0.25毫莫耳）及三乙醯氧基硼氫化鈉 (160毫克，0·74毫莫耳）反應，獲得62毫克(55%產率）標題化 合物，為灰白色固體。 !H NMR (DMSO-d6) (5 ： 1.36-1.51 (m5 1H)； 1.6M.74 (m? 1H)； 2.23-2.36 (m9 1H) ； 2.58 (t5 2H) ； 2.61-2.85 (m5 3H) ； 3.13-3.21 (m? 3H) ； 3.26-3.32 (m5 2H) ； 3,58-3.78 (m5 2H) ； 4.30-4.45 (m5 2H) ； 4.61 (s? 2H) ； 6.78 (d? 1H) ; 7 00 (d，1H) ; 7.30 (d，1H) ; 7.65 (dd，1H) ; 7.91 (d，1H) ; 8.00 (d， 1H) ; 8·07·8·13 (m，1H) ; 1L21 (s，1H). MS (ESP) : 489 (MH+ )對 C2 6 H2 8 N6 04 實例24 H2-((3R，4S)-3·曱氧基-4-{[(3-酮基-3,4-二氫·2Η·吡啶并【3,2-b】丨 1，4] 嘍畊-6-基）曱基]胺基}六氫吡啶小基）乙基]·2-酮基-1，2-二氫喹 啉-7_曱腈，雙·鹽酸鹽 按關於實例14所述，使l-{2-[(3R，4S)-4-胺基-3-甲氧基六氫吡 啶-1_基]乙基}-2-酮基-1，2-二氫喹啉-7·甲腈（中間物43，80毫 克，0.25毫莫耳）、3-酮基-3,4·二氫_2Η·吡啶并[3,2-b][l，4]嘧畊-6-羧甲醛（WO 2004/058144) (48毫克，0·25毫莫耳）及三乙醯氧基 硼氫化鈉（160毫克，0.74毫莫耳）反應，獲得56毫克標題組 合物，為灰白色固體。 NMR (D20) δ ： 2.10-2.24 (m, 2H)； 2.89-3.13 (m? 2H)； 3.38-3.46 (m, 5H); 3.48-3.52 (m，2H); 3.53-3.68 (m，2H) ; 4·04 (s5 1H) ; 4.11 (d，1H); 4.27 (d? 2H) ； 4.49-4.62 (m5 1H) ； 4.73-4.84 (m5 1H) ； 6.79 (d? 1H) ； 7.05 (d，1H) ; 7.61 (dd，1H) ; 7.75 (d，1H) ; 7.82 (d，1H) ; 7_91 (s，1H) ; 7.97 127286 -146· 200831517 (d，1H). MS (ESP) : 505 (MH+)對 C26H28N6〇3S 實例25 l_(2-{(3S，4S)-4-[(2,3·二氳【1，4】二氧陸圃烯并【2,3_φ比咬i基甲基） 胺基]-3-甲氧基六氫吡啶-l-基}乙基）-7-甲氧基喹喏啉-2(1H^ 酮，雙-鹽酸鹽 使用類似關於合成實例14所述之程序，使i_{2_[(3s,4S)-4-胺基-3-曱氧基六氫p比唆-1-基]乙基卜7-甲氧基p奎喏淋·2(ιη)·酮 _ (中間物48，70毫克，〇·21毫莫耳）、2,3_二氫[Μ]二氧陸圜烯 并[2,3-c]p比唆-7-魏曱酿（WO 2004/058144) (35 毫克，0.21 毫莫耳） 及三乙醯氧基硼氫化鈉（130毫克，〇·63毫莫耳）反應，獲得 61毫克標題組合物，為黃色固體。 ^NMR^O) δ ： 1.83-2.02 (m5 1H)； 2.37-2.50 (m5 1H)； 2.90-3.06 (m? 1H)； 3.08-3.23 (m5 1H)； 3.33-3.48 (m5 4H) ； 3.55-3.70 (m5 3H) ； 3.73-3.81 (m，1H) ; 3.87 (s，3H) ; 4.16-4.26 (m，1H) ; 4.32-4.39 (m，4H) ; 4.43-4.51 馨（m，2H); 4.60-4.80 (m，2H) ; 6.87 (d，1H) ; 7·07 (dd，1H) ; 7·27 (s，1H); 7.76 (d，1H) ; 8·01 (s，1H) ; 8.20 (s，1H)· MS (ESP) : 482 (MH+)對 C25H3 &quot;505 實例26 6-[({(3S，4S)-3_甲氧基_1-【2_(7·甲氧基-2_酮基喹喏啉-1(2H)-基）乙基] 六氫吡啶冰基}胺基）甲基]_2H_吡啶并[3,2-b]【1，4】噚畊-3(4H)-酮 按關於實例14所述（惟其鹽酸鹽製備除外），使 l-{2-[(3S，4S)-4-胺基各甲氧基六氫吡啶小基]乙基}-7-甲氧基喹 喏啉-2(1H)-酮（中間物48，70毫克，0·21毫莫耳）、3-酮基-3,4- 127286 -147- 200831517 二氫-2H-吡啶并 p，2-b][l，4]嘮畊-6-羧甲醛（WO 2⑽4/058144) (37 毫 克，0.21毫莫耳）及三乙醯氧基硼氫化鈉（13〇毫克，0.63毫莫 耳）反應。使粗產物接受急驟式層析，以〇_1〇〇/0甲醇/二氯甲 烷之梯度液溶離，獲得62毫克（62%)標題化合物，[a]D= -19.5 (甲醇，c = 0.58)。 ^NMRCDMSO-^) δ ： 1.04-1.23 (m? 1H)； 1.76 (t, 1H)； L81-L9I (m5 1H) ； 1.93-2.07 (m3 1H) ； 2,18-242 (m5 1H) ； 2.61 (t5 2H) ； 2.79-2.99 (m? 2H) ； 3.20-3.30 (m, 4H) ； 3.54-3.75 (m, 2H) ； 3.91 (s? 3H) ； 4.25-4.43 (m? 2H); 4·59 (s，2H); 6.90-7.06 (m，3H); 7.27 (d，1H); 7·74 (d，1H); 8.02-8.06 (m，1H) ; 1L18 (s，1H). MS (ESP) : 495 (MH+ )對 C2 5 H3 0N6 05 實例27 l-(2_{(3R，4R)-4-[(2,3-二氫[1，4】二氧陸圜烯并[2,3-c】吡啶-7-基甲 基）胺基】-3·甲氧基六氫吡啶小基}乙基）-7-甲氧基喳喏啉 -2(111)_酮，雙-鹽酸鹽 按關於實例14所述，使l-{2-[(3R，4R)-4-胺基-3-甲氧基六氫吡 啶-1-基]乙基}-7-甲氧基喳喏啉-2(1Η)-酮（中間物56，75毫克， 〇·23毫莫耳）、2,3-二氫[1，4]二氧陸圜烯并[2,3-c]吡啶-7·羧甲醛 (WO 2004/058144) (37毫克，0.23毫莫耳）及三乙醯氧基硼氫化 鈉（150毫克，0·69毫莫耳）反應，獲得標題組合物（63毫克）， 為黃色固體。 1H NMR (D20) 5 : 1·81-2·02 (m，1H); 2.34-2.52 (m，1H); 2.92-3.05 (m， 1H)； 3.10-3.23 (m, 1H)； 337-3.49 (m5 4H) ； 3.54-3.72 (m, 3H) ； 3.73&lt;3.82 (m，1H) ; 3.85-3.90 (m，3H) ; 4.22 (d，1H) ; 4.29-4.41 (m，4H) ; 4.43-4.51 127286 -148· 200831517 (m，2H); 4.60-4.80 (m，2H) ; 6.83-6.91 (m，1H); 7.07 (dd，1H) ; 7·26-7·31 (m，1H) ; 7·74 (d，1H) ; 7.97-8.03 (m，1H) ; 8·17_8·26 (m，1H). MS (ESP) : 482 (MH+)對 C25H3 實例28 6-[({(3R，4R)-3-甲氧基-l-[2-(7-甲氧基-2-酮基喹喏啉_1(2H)_基）乙 基]六氫吡啶-4-基}胺基）甲基】-2H-吡啶并[3,2-b] [1，4]，号，井-3(4H&gt;酮 按關於實例14所述（惟其鹽酸鹽製備除外），使 l-{2-[(3R，4R)-4-胺基-3-甲氧基六氫吡啶小基]乙基}·7-甲氧基喳 喏啉-2(1Η)-酮（中間物56，75毫克，0.23毫莫耳）、3-酮基-3,4-二氫-2Η-吡啶并 p，2-b][l，4]噚畊-6-羧甲醛（WO 2004/058144) (40 毫 克，0.23毫莫耳）及三乙醯氧基硼氫化鈉（150毫克，〇·69毫莫 耳）反應，獲得73毫克（66%)標題化合物，[a]D= +17.5 (曱醇， c = 0.56) 〇 1H NMR(DMSO-d6) 5 : 1.04-1.22 (m，lH); 1.78 (t，lH); 1.834.93 (m， 1H) ； 2.00 (m? 1H) ； 2.22-2.35 (m5 1H) ； 2.62 (t? 2H) ； 2.81-3.00 (m5 2H)； 3.20-3.30 (m, 4H) ； 3.56-3.78 (m5 2H) ； 3.92 (s? 3H) ； 4.26-4.44 (m, 2H)； 4.61 (s，2H); 6.92-7.08 (m，3H); 7.29 (d，1H); 7.75 (d，1H); 8·05 (s，1H); 11.21 (s5 1H). MS (ESP) : 495 (MH+)對 C25H3〇N605 實例29 l-(2-{4-丨(2,3-二氫[1，4]二氧陸圜烯并[2,3-c]吡啶-7-基甲基)胺基】-3-經基六氮〃比咬-l-基}乙基）-7-甲氧基p奎嘆淋晒，反式 對掌異構物A，雙鹽酸鹽 按關於實例14所述，使1-{2-[4-胺基-3-羥基六氫吡啶-1-基] 127286 -149- 200831517 乙基}-7-甲氧基喳喏啉-2(1H)-酮，反式對掌異構物a (中間物 57，39宅克，〇_12毫莫耳）、2,3-二氫[1，4]二氧陸圜烯并[2,3-c] 吡啶-7-羧甲醛（WO 2004/058144) (20毫克，0J2毫莫耳）及三乙 醯氧基硼氫化鈉（76毫克，0.36毫莫耳）反應，獲得標題組合 物，為黃色固體（39毫克）。 NMR (D20) (5 : 1.82-2.00 (m? 1H) ； 2.48 (dd5 1H) ； 3.01 (t5 1H)； 3.08-3.21 (m5 1H) ； 3.30-3.44 (m? 1H) ； 3.58 (t? 2H) ； 3.79-3.95 (m? 5H)； 3·97·4·09 (m，1H) ; 4.30-4.50 (m，6H) ; 4.65 (t，2H) ; 6.87 (d，1H) ; 7.07 (dd，1H) ; 7·28 (s，1H) ; 7.76 (d，1H) ; 8.01 (s，1H) ; 8.20 (s，1H). MS (ESP) : 468 (MH+)對 C24H29N505 實例30W MS (ESP): 476 (MH+) vs. C2 6 H2 9 N5 04 Example 23 l-[2-((3R,4S)-3·曱oxy·4_{[(3_keto·3,4· Dihydro-: 2H-pyridine and [3,2-b][l,4] 3 p-well-6-yl)methyl]amino}hexazone quinone-1-yl)ethyl]-2· Mercapto-1,2-diazepine-7-methasin was used similarly to the procedure described in Synthesis Example 14 except for the preparation of the hydrochloride salt, such that l-{2-[(3R,4S)-4 -amino-3-indolyl hexahydropyridine small group] ethyl}_2_ keto·1,2-dihydroporphyrin-7-indoleonitrile (intermediate 43, 80 mg, 0.25 mmol), 127286 -145- 200831517 3-keto-3,4-dihydro-2H-p is more than [3,2-b][l,4]p p well-6-carboxymethyl (w〇2004/058144 (45 mg, 0.25 mmol) and sodium triethoxysulfonyl borohydride (160 mg, 0. 74 mmol) gave 62 mg (55% yield) of !H NMR (DMSO-d6) (5: 1.36-1.51 (m5 1H); 1.6M.74 (m? 1H); 2.23-2.36 (m9 1H); 2.58 (t5 2H); 2.61-2.85 (m5 3H) 3.13-3.21 (m? 3H); 3.26-3.32 (m5 2H); 3,58-3.78 (m5 2H); 4.30-4.45 (m5 2H); 4.61 (s? 2H); 6.78 (d? 1H); 7 00 (d,1H) ; 7.30 (d,1H) ; 7.65 (dd,1H) ; 7.91 (d,1H) ; 8.00 (d, 1H) ; 8·07·8·13 (m,1H) ; 1L21 (s,1H). MS (ESP): 489 (MH+) vs. C2 6 H2 8 N6 04 Example 24 H2-((3R,4S)-3·曱oxy-4-{[(3-keto-3) ,4-dihydro·2Η·pyrido[3,2-b]丨1,4] 喽耕-6-yl) fluorenyl]amino}hexahydropyridine small) ethyl]·2-keto- 1,2-dihydroquinoline-7-indoleonitrile, bis-hydrochloride as described in Example 14, l-{2-[(3R,4S)-4-amino-3-methoxy-6 Hydropyridine-1_yl]ethyl}-2-keto-1,2-dihydroquinolin-7·carbonitrile (intermediate 43, 80 mg, 0.25 mmol), 3-keto-3, 4·Dihydro 2Η·pyrido[3,2-b][l,4]pyrazine-6-carboxaldehyde (WO 2004/058144) (48 mg, 0·25 mmol) and triethylene oxide Sodium borohydride (160 mg, 0.74 mmol) was reacted to obtain 56 mg The composition is an off-white solid. NMR (D20) δ: 2.10-2.24 (m, 2H); 2.89-3.13 (m? 2H); 3.38-3.46 (m, 5H); 3.48-3.52 (m, 2H); 3.53-3.68 (m, 2H); 4·04 (s5 1H); 4.11 (d, 1H); 4.27 (d? 2H); 4.49-4.62 (m5 1H); 4.73-4.84 (m5 1H); 6.79 (d 1H) ; 7.05 (d,1H) ; 7.61 (dd,1H) ; 7.75 (d,1H) ; 7.82 (d,1H) ; 7_91 (s,1H) ; 7.97 127286 -146· 200831517 (d,1H) MS (ESP): 505 (MH+) vs. C26H28N6〇3S Example 25 l_(2-{(3S,4S)-4-[(2,3·二氲[1,4] Dioxetene] [2 , 3_φ ratio bit i methyl) Amino]-3-methoxyhexahydropyridine-1-yl}ethyl)-7-methoxyquinoxaline-2 (1H^one, bis-hydrochloride Using a procedure similar to that described in Synthesis Example 14, i_{2_[(3s,4S)-4-amino-3-indolylhexahydrop-pyridin-1-yl]ethyl b-7-methoxy p奎喏淋·2(ιη)·ketone _ (intermediate 48, 70 mg, 〇·21 mmol), 2,3-dihydro[Μ]dioxolene [2,3-c] p is more than 唆-7-Wei ( (WO 2004/058144) (35 mg, 0.21 mmol) and sodium triethoxy borohydride (130 mg, 〇 · 63 mmol) 61 mg of the title composition is obtained, as yellow solid. ^NMR^O) δ : 1.83-2.02 (m5 1H); 2.37-2.50 (m5 1H); 2.90-3.06 (m? 1H); 3.08-3.23 (m5 1H); 3.33-3.48 (m5 4H) ; 3.55- 3.70 (m5 3H) ; 3.73-3.81 (m,1H) ; 3.87 (s,3H) ; 4.16-4.26 (m,1H) ; 4.32-4.39 (m,4H) ; 4.43-4.51 馨 (m,2H); 4.60-4.80 (m, 2H); 6.87 (d, 1H); 7·07 (dd, 1H); 7·27 (s, 1H); 7.76 (d, 1H); 8·01 (s, 1H); 8.20 (s,1H)· MS (ESP): 482 (MH+) vs. C25H3 &quot;505 Example 26 6-[({(3S,4S)-3_methoxy_1-[2_(7·methoxy) -2_ketoquinoxaline-1(2H)-yl)ethyl]hexahydropyridine ice-based}amino)methyl]_2H_pyrido[3,2-b][1,4] 3(4H)-one as described in Example 14 (except for the preparation of the hydrochloride salt), l-{2-[(3S,4S)-4-amino group methoxy hexahydropyridine small group] ethyl }-7-methoxyquinoxaline-2(1H)-one (intermediate 48, 70 mg, 0·21 mmol), 3-keto-3,4-127286-147-200831517 Dihydro- 2H-pyrido-p,2-b][l,4]indole-6-carboxaldehyde (WO 2(10)4/058144) (37 mg, 0.21 mmol) and sodium triethoxysulfonate (13 mg) , 0.63 millimoles) reaction . The crude product was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut elut ). ^NMRCDMSO-^) δ : 1.04-1.23 (m? 1H); 1.76 (t, 1H); L81-L9I (m5 1H); 1.93-2.07 (m3 1H); 2,18-242 (m5 1H); (t5 2H); 2.79-2.99 (m? 2H); 3.20-3.30 (m, 4H); 3.54-3.75 (m, 2H); 3.91 (s? 3H); 4.25-4.43 (m? 2H); 59 (s, 2H); 6.90-7.06 (m, 3H); 7.27 (d, 1H); 7·74 (d, 1H); 8.02-8.06 (m, 1H); 1L18 (s, 1H). MS ( ESP): 495 (MH+) vs. C2 5 H3 0N6 05 Example 27 l-(2_{(3R,4R)-4-[(2,3-Dihydro[1,4] Dioxetidene[2, 3-c]pyridin-7-ylmethyl)amino]-3·methoxyhexahydropyridine small group}ethyl)-7-methoxyindoline-2(111)-one, double-salt Acid salt as described in Example 14 to give 1-{2-[(3R,4R)-4-amino-3-methoxyhexahydropyridin-1-yl]ethyl}-7-methoxyanthracene Porphyrin-2(1Η)-one (intermediate 56, 75 mg, 〇·23 mmol), 2,3-dihydro[1,4]dioxolynene[2,3-c]pyridine -7. Carboxaldehyde (WO 2004/058144) (37 mg, 0.23 mmol) and sodium triethoxysulfonium borohydride (150 mg, 0·69 mmol) gave the title compound (63 mg) , a yellow solid. 1H NMR (D20) 5 : 1·81-2·02 (m,1H); 2.34-2.52 (m,1H); 2.92-3.05 (m, 1H); 3.10-3.23 (m, 1H); 337-3.49 (m5 4H) ; 3.54-3.72 (m, 3H) ; 3.73 &lt;3.82 (m,1H) ; 3.85-3.90 (m,3H) ; 4.22 (d,1H) ; 4.29-4.41 (m,4H) ; 4.43 -4.51 127286 -148· 200831517 (m,2H); 4.60-4.80 (m,2H) ; 6.83-6.91 (m,1H); 7.07 (dd,1H) ; 7·26-7·31 (m,1H) 7·74 (d,1H) ; 7.97-8.03 (m,1H) ; 8·17_8·26 (m,1H). MS (ESP) : 482 (MH+) vs. C25H3 Example 28 6-[({(3R) , 4R)-3-methoxy-l-[2-(7-methoxy-2-ketoquinoxalin-1(2H)-yl)ethyl]hexahydropyridin-4-yl}amino )methyl]-2H-pyrido[3,2-b][1,4],#, well-3 (4H&gt; ketone as described in Example 14 (except for the preparation of the hydrochloride), l-{ 2-[(3R,4R)-4-amino-3-methoxyhexahydropyridine small group]ethyl}·7-methoxyindoline-2(1Η)-one (intermediate 56,75 Mg, 0.23 mmol, 3-keto-3,4-dihydro-2Η-pyrido p,2-b][l,4]indole-6-carboxaldehyde (WO 2004/058144) (40 Mg, 0.23 mM) and sodium triethoxy borohydride (150 mg, 〇·69 The reaction was carried out to give the title compound (d,j,j,j,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (t,lH); 1.834.93 (m, 1H); 2.00 (m? 1H); 2.22-2.35 (m5 1H); 2.62 (t? 2H); 2.81-3.00 (m5 2H); 3.20-3.30 (m , 4H) ; 3.56-3.78 (m5 2H) ; 3.92 (s? 3H) ; 4.26-4.44 (m, 2H); 4.61 (s, 2H); 6.92-7.08 (m, 3H); 7.29 (d, 1H) 7.75 (d,1H); 8·05 (s,1H); 11.21 (s5 1H). MS (ESP): 495 (MH+) vs. C25H3〇N605 Example 29 l-(2-{4-丨(2, 3-Dihydro[1,4]dioxolynene[2,3-c]pyridin-7-ylmethyl)amino]-3-peryl hexanitropurine than bite-l-yl}ethyl - 7-methoxy p-couver, trans-p-isomer A, dihydrochloride as described in Example 14, 1-{2-[4-amino-3-hydroxyhexahydro Pyridin-1-yl] 127286 -149- 200831517 ethyl}-7-methoxyporphyrin-2(1H)-one, trans-palomeris a (intermediate 57, 39 house, 〇_ 12 millimolar), 2,3-dihydro[1,4]dioxolynene[2,3-c]pyridine-7-carboxaldehyde (WO 2004/058144) (20 mg, 0 J 2 mmol) And triethyl decyloxy Sodium hydride (76 mg, 0.36 mmol) to give the title composition as a yellow solid (39 mg). NMR (D20) (5: 1.82-2.00 (m? 1H); 2.48 (dd5 1H); 3.01 (t5 1H); 3.08-3.21 (m5 1H); 3.30-3.44 (m? 1H); 3.58 (t? 2H) ;79.95 (d,2H); ,1H) ; 7·28 (s,1H) ; 7.76 (d,1H) ; 8.01 (s,1H) ; 8.20 (s,1H). MS (ESP) : 468 (MH+) vs. C24H29N505 Example 30

H({3-羥基-l-[2-(7-甲氧基-2_酮基喳喏啉-1(2H)_基）乙基]六氫吡 啶-4-基}胺基）甲基】-；2H-吡啶并【3,2_b】【l，4】哼畊_3(4H)·酮，反式 對掌異構物A 按關於實例14所述（惟其鹽酸鹽製備除外），使i-{2-[4-胺 基-3·!^基六氫p比咬-1-基]乙基}_7_曱氧基p奎嗜p林_2(1H)_酮，反 式對掌異構物A (中間物57，39毫克，0.12毫莫耳）、3-酮基 -3,4-二氫-2H-吡啶并[3,2-b][l，4]崎畊冬羧甲醛（WO 2004/058144) (21毫克，0.12毫莫耳）及三乙醯氧基硼氫化鈉（76毫克，0.36 毫莫耳）反應，獲得49毫克（84%)標題化合物。 XH NMR (DMSO-d6) δ ： 1.09-1.26 (m, 1H)； 1.94 (t, 2H)； 2.04 (t? 1H)； 2.20-2.35 (m，1H); 2.64 (t，2H); 2·88·3·10 (m，2H) ; 3.18-3.32 (m，1H); 3.63-3.87 (m，2H); 3.98 (s，3H); 4·39 (t，2H); 4.67 (s，2H); 4.90 (d，1H); 6.99-7.11 (m，3H); 7·36 (d，1H); 7.81 (d，1H); 8.10 (s，1H); 11.27 (s，lH). 127286 •150- 200831517 MS (ESP) : 481 (MH+)對 c24H28N605 實例31 l-(2-{4-[(2,3-二氫丨1，4】二氧陸園烯并p，3-c】吡啶-7-基甲基）胺 基]_3·羥基六氫吡啶小基}乙基)-7-甲氧基喳喏啉酮，反 式對掌異構物B，雙-鹽酸鹽 按關於實例14所述，使1-{2-[4-胺基-3-羥基六氫吡啶小基] 乙基}-7-甲氧基喹喏啉_2(m)_酮，反式對掌異構物（中間物 65，42毫克，0.13毫莫耳）、2,3-二氫[1，4]二氧陸圜烯并[2,3-c] 吡啶-7-羧曱醛（WO 2004/058144) (22毫克，0·13毫莫耳）及三乙 醯氧基硼氫化鈉（83毫克，0.39毫莫耳）反應，獲得45毫克標 題組合物，為黃色固體。 1HNMR(D20) 5 ： L82-1.99 (m, 1H)； 2.42-2.53 (m5 1H)； 3.01 (t5 1H)； 3·08·3·20 (m，1H) ; 3.32-3.44 (m5 1H) ; 3.58 (t，2H) ; 3.80-3.95 (m，5H); 3.96-4.09 (m5 1H) ； 4.32-4.50 (m, 6H) ； 4.65 (t5 2H) ； 6.87 (d5 1H) ； 7.07 (dd，1H) ; 7.29 (s，1H) ; 7·76 (d，1H) ; 8.00 (s，1H) ; 8·21 (s，1H)· MS (ESP) : 467 (MH+)對 C24H29N505 實例32H({3-hydroxy-l-[2-(7-methoxy-2-keto porphyrin-1(2H)-yl)ethyl]hexahydropyridin-4-yl}amino)methyl 】-; 2H-pyrido[3,2_b][l,4] 哼3_4(4H)·one, trans-palphasomer A as described in Example 14 (except for the preparation of the hydrochloride), I-{2-[4-Amino-3·!^-ylhexahydro-p-diyl-1-yl]ethyl}_7_fluorenyl p-quino-p-lin-2(1H)-one, trans Pair of palm isomer A (intermediate 57, 39 mg, 0.12 mmol), 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4] Carboxycarboxaldehyde (WO 2004/058144) (21 mg, 0.12 mmol) and sodium triethoxysulfonylborohydride (76 mg, 0.36 mmol) afforded 49 mg (84%) XH NMR (DMSO-d6) δ: 1.09-1.26 (m, 1H); 1.94 (t, 2H); 2.04 (t? 1H); 2.20-2.35 (m, 1H); 2.64 (t, 2H); 88·3·10 (m,2H) ; 3.18-3.32 (m,1H); 3.63-3.87 (m,2H); 3.98 (s,3H); 4·39 (t,2H); 4.67 (s,2H 4.90 (d,1H); 6.99-7.11 (m,3H); 7·36 (d,1H); 7.81 (d,1H); 8.10 (s,1H); 11.27 (s,lH). 127286 • 150-200831517 MS (ESP): 481 (MH+) vs. c24H28N605 Example 31 l-(2-{4-[(2,3-Dihydroindole-1,4)dioxanthene and p,3-c]pyridine -7-ylmethyl)amino]-3·hydroxyhexahydropyridine small group}ethyl)-7-methoxy porphyrinone, trans-p-isomer B, bis-hydrochloride according to examples 14, let 1-{2-[4-amino-3-hydroxyhexahydropyridinyl]ethyl}-7-methoxyquinoxaline_2(m)-one, trans-pair Structure (intermediate 65, 42 mg, 0.13 mmol), 2,3-dihydro[1,4]dioxantho[2,3-c]pyridin-7-carboxaldehyde (WO 2004) </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; 1H NMR (D20) 5 : L82-1.99 (m, 1H); 2.42-2.53 (m5 1H); 3.01 (t5 1H); 3·08·3·20 (m, 1H); 3.32-3.44 (m5 1H); 3.58 (t, 2H); 3.80-3.95 (m, 5H); 3.96-4.09 (m5 1H); 4.32-4.50 (m, 6H); 4.65 (t5 2H); 6.87 (d5 1H) ; 7.07 (dd, 1H) ; 7.29 (s,1H) ; 7·76 (d,1H) ; 8.00 (s,1H) ; 8·21 (s,1H)· MS (ESP) : 467 (MH+) vs C24H29N505 Example 32

6-[({3_經基·1_[2_(7_甲氧基-2-酮基喳喏啉-1(2H)_基）乙基】六氫吡 咬乂基}胺基）甲基】_2H-吡啶并[3,2-|&gt;】【1，4]噚_ -3(4H)-酮，反式 對掌異構物B 按關於實例14所述（惟其鹽酸鹽製備除外），使丨_{2-[4-胺 基-3-羥基六氫吡啶小基;j乙基}_7_曱氧基喳喏啉-2(m)_酮，反 式對掌異構物（中間物65，42毫克，0·13毫莫耳）、3·酮基-3,4-二氫-2H-吡啶并[3,2-b][l，4]嘮畊-6-羧甲醛（W02004/058144) (24 毫 127286 -151 - 200831517 克，0.13毫莫耳）及三乙醯氧基硼氫化鈉（83毫克，〇_39毫莫 耳）反應，獲得42毫克（68%產率）標題化合物。 1H NMR (DMSO-d6) 5 : 1.02-1.21 (m，1H); 1.88 (t，2H); 1.98 (t，1H); 2·15-2·31 (m，1H) ; 2.59 (t，2H) ; 2.84-3.03 (m，2H) ; 3.13-3.25 (m，1H); 3.58-3.80 (m，2H); 3·92 (s，3H); 4·32 (t，2H); 4.61 (s5 2H); 4·84 (d，1H); 6.94-7.05 (m，3H) ; 7·30 (d，1H) ; 7.68-7.79 (m，1H) ; 8.04 (s，1H); 11.16-1L29 (m5 1H). MS (ESP) : 481 (MH+)對 C24H28N605 β實例33 H2-{4_[(2,3-二氫【1，4】二氧陸圜浠并[2,3_e]吡啶·7_基甲基）胺 基]-3-氟基六氫吡啶小基}乙基）_2·酮基二氫p奎淋_7_甲腈， 反式對掌異構物A，雙·鹽酸鹽 將1-{2-[4-胺基-3-氟基六氫吡啶-μ基]乙基卜2,基_丨，2_二氫 4淋-7_甲腈，反式對掌異構物a (中間物67，粗製物，15〇 笔克’ 0.48毫莫耳）與2,3-二氫[1，4]二氧陸圜烯并[2,3-c]吡啶-7-φ 羧甲駿（W〇 2004/058144) (80毫克，0.48毫莫耳）在無水甲醇/ 氯仿（1 : 1，20毫升）中之混合物，在氮氣下，於3A分子篩 上’在70 C下加熱一小時。使反應物冷卻至室溫，並添加 一乙酿氧基硼氫化鈉（3〇〇毫克，1·43毫莫耳）。將反應物於 至/凰下攪拌過夜。經過矽藻土過濾反應混合物。使濾液濃 縮至乾/固。使粗產物溶於15〇/〇甲醇/氣仿中，並以飽和碳酸 氯納溶液洗滌。將水相以15%甲醇/氯仿再萃取一次。使合 併之有機相以硫酸鈉脫水乾燥，過濾，及在減壓下濃縮。 於石夕膠上’以0-5%甲醇在二氯甲烷中之梯度液層析，獲得 127286 -152- 200831517 66毫克（26%)標題組合物之自由態驗，為油狀物。使其溶於 1 · 1二氯甲烧/***（5毫升）中，並以醚中之10M HC1 (〜2當 量）處理，而造成沉澱物。使此混合物濃縮至乾涸。將所形 成之固體在水中重配，並凍乾，獲得66毫克標題組合物。 ^NMR^O) δ ppm： 1.81-1.94 (m, 1H)； 2.30-2.43 (m? 1H)； 3.13-3.26 (m? 1H) ； 3.32-3.42 (m5 1H) ； 3.42-3.50 (m5 1H) ； 3.53 (t? 2H) ； 3.57-3.66 (m5 1H) ； 3,79-3,93 (m? 1H) ； 4.11-4.27 (m5 2H) ； 4.38-4.43 (m5 2H)； 4.50-4.56 (m，2H) ; 4·62_4·75 (m，1H) ; 4.80-4.88 (m，1H) ; 4.85 (m，1H) 6.85 (d，1H) ; 7·25 (s，1H) ; 7.68 (dd，1H) ; 7.89 (d，1H) ; 7.98 (s，1H); 8.03 (d, 1H) ； 8.20 (s5 1H). MS (ESP) ·· 464 (MH+)對 C25H26FN503 實例346-[({3_经基·1_[2_(7_methoxy-2-keto)porphyrin-1(2H)-yl)ethyl]hexahydropyridinyl}amino)methyl 】 _2H-pyrido[3,2-|&gt;][1,4]噚_-3(4H)-one, trans-palphasomer B as described in Example 14 (except for the preparation of the hydrochloride salt) ,{{2-[4-Amino-3-hydroxyhexahydropyridine small group; jethyl}_7_decyloxyporphyrin-2(m)-one, trans-palphaliomer (Intermediate 65, 42 mg, 0·13 mmol), 3·keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]唠耕-6-carboxyl Formaldehyde (W02004/058144) (24 127286 -151 - 200831517 g, 0.13 mmol) and sodium triethoxy borohydride (83 mg, 〇 _ 39 mmol) to obtain 42 mg (68% yield) Rate) Title compound. 1H NMR (DMSO-d6) 5 : 1.02-1.21 (m, 1H); 1.88 (t, 2H); 1.98 (t, 1H); 2·15-2·31 (m, 1H); 2.59 (t, 2H) ; 2.84-3.03 (m, 2H); 3.13-3.25 (m, 1H); 3.58-3.80 (m, 2H); 3·92 (s, 3H); 4·32 (t, 2H); 4.61 (s5 2H); 4·84 (d,1H); 6.94-7.05 (m,3H); 7·30 (d,1H); 7.68-7.79 (m,1H); 8.04 (s,1H); 11.16-1L29 ( M5 1H). MS (ESP): 481 (MH+) vs. C24H28N605 β Example 33 H2-{4_[(2,3-Dihydro[1,4] Dioxetan[2,3_e]pyridine·7_ Methyl)amino]-3-fluoropyrohydropyristyl}ethyl)_2·ketodihydropyrazine_7-carbonitrile, trans-p-isomer A, bis-hydrochloride 1-{2-[4-Amino-3-fluorohexahydropyridine-μ-yl]ethyl b 2,yl-indole, 2-dihydrotetralin-7-carbonitrile, trans-pair A (intermediate 67, crude, 15 〇 gram '0.48 mmol) and 2,3-dihydro[1,4]dioxene deceno[2,3-c]pyridine-7-φ A mixture of carboxymethyl jun (W 〇 2004/058144) (80 mg, 0.48 mmol) in anhydrous methanol / chloroform (1:1, 20 mL), heated at 70 C on a 3A molecular sieve under nitrogen. One hour. The reaction was allowed to cool to room temperature and a solution of sodium succinate (3 mg, 1.43 mmol) was added. The reaction was stirred overnight to / pho. The reaction mixture was filtered through celite. The filtrate was concentrated to dry/solid. The crude product was dissolved in 15 mL / methanol / pets and washed with saturated aqueous sodium chloride. The aqueous phase was extracted once more with 15% methanol / chloroform. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Chromatography on a mixture of 0-5% methanol in dichloromethane afforded 127286 - 152 - </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; This was dissolved in 1 · 1 methylene chloride / diethyl ether (5 ml) and treated with 10M EtOAc (~2 eq. This mixture was concentrated to dryness. The resulting solid was reconstituted in water and lyophilized to give 66 mg of the title compound. ^NMR^O) δ ppm: 1.81-1.94 (m, 1H); 2.30-2.43 (m? 1H); 3.13-3.26 (m? 1H); 3.32-3.42 (m5 1H); 3.42-3.50 (m5 1H) 3.53 (t? 2H) ; 3.57-3.66 (m5 1H) ; 3,79-3,93 (m? 1H) ; 4.11-4.27 (m5 2H) ; 4.38-4.43 (m5 2H); 4.50-4.56 (m , 2H); 4·62_4·75 (m, 1H); 4.80-4.88 (m, 1H); 4.85 (m, 1H) 6.85 (d, 1H); 7·25 (s, 1H); 7.68 (dd, 1H); 7.89 (d,1H); 7.98 (s,1H); 8.03 (d, 1H); 8.20 (s5 1H). MS (ESP) ·· 464 (MH+) vs. C25H26FN503 Example 34

l-[2-((3-氟基-4_{[(3_酮基-3,4-二氫-2H-吡啶并[3,2七][1，4】噚畊-6-基）甲基1胺基}六氫吡啶-1-基)乙基]-2-酮基-1，2-二氫喹啉-7-甲 腈，反式對掌異構物A 按關於實例33所述（惟其鹽酸鹽製備除外），l-{2-[4-胺基-3-氟基六氫吡啶小基]乙基}-2-酮基-1，2-二氫喹啉-7-甲腈，反式 對掌異構物A (中間物67，150毫克，0.48毫莫耳）、3-酮基·3,4-二氫-2Η-吡啶并[3,2-b][l，4]嘮畊-6·羧甲醛（WO 2004/058144) (85 毫 克，0·48毫莫耳）及三乙醯氧基硼氫化鈉（300毫克，1.43毫莫 耳）反應，獲得70毫克（30%)標題組合物。[a]D= -12.4 (曱醇， c = 0.5). XH NMR (DMSO-d6) δ ppm： 1.21 (m5 1H)； L84-L95 (m, 1H)； 2.04-2.21 (m，2H) ; 2.30-2.41 (m，1H) ; 2.57-2.67 (m，2H) ; 2.78-2.87 (m，1H); 127286 -153- 200831517 3.18-3.29 (m, 1H) ； 3.73 (s3 2H) ； 4.29 (m5 1H) ； 4.29-4.46 (m? 2H) ； 4.61 (s，2H) ; 6.78 (d，1H) ; 7·01 (d，1H) ; 7.30 (d，1H) ; 7·66 (dd，1H) ; 7.91 (d，1H) ; 8.01 (d，1H) ; 8.11 (s，1H) ; 1U9 (s，1H)· MS (ESP) : 477 (MH+)對 C2 5 H2 5 FN6 03 使實例3S至4〇於Waters XBridge C-18管柱上藉逆相HPLC純 化，以具有醋酸銨緩衝劑（pH == 8)之5-50%水/乙腈溶離。 實例35 1_(2-{4-【(2,3-二氫[Μ]二氧陸圜烯并p，3-c]吡啶-7-基甲基）胺 基]-3-1基六氫吡啶小基}乙基)-7-甲氧基喹喏啉-2(1H)-酮，反 式對掌異構物，雙鹽酸鹽 使用類似關於合成實例33所述之程序，使2,3-二氫[1，4]二 氧陸圜烯并[2,3-c]吡啶-7-羧甲醛與1-{2-[4-胺基-3-氟基六氫吡 咬-1-基]乙基}_7_甲氧基峻嗜琳-2(1H)-酮，反式對掌異構物A (中間物77)反應，提供標題組合物。 1HNMR(D20) δ ppm： 1.81-1.97 (m5 1H)； 2.32-2.45 (m? 1H)； 3.20-3.32 (m，1H) ; 3.35-3.44 (m，1H) ; 3.52-3.72 (m，4H) ; 3.91 (s，3H) ; 3.85-3.95 (m，1H) ; 4·13·4·28 (m，2H) ; 4.37-4.43 (m，2H) ; 4.51-4.56 (m，2H); 4.57-4.73 (m，2H) ; 4·94 (m，1H) ; 6.90 (d，1H) ; 7.10 (dd，1H) ; 7.30 (s， 1H) ; 7·78 (d，1H) ; 8.03 (s，1H) ; 8.22 (s，1H)· ES (MH)+ 470 實例36L-[2-((3-fluoro)-4_{[(3-keto-3,4-dihydro-2H-pyrido[3,2-7][1,4]噚耕-6-yl) Methyl 1 amino}}hexahydropyridin-1-yl)ethyl]-2-keto-1,2-dihydroquinolin-7-carbonitrile, trans-p-isomer A (except for the preparation of hydrochloride), l-{2-[4-amino-3-fluorohexahydropyridinyl]ethyl}-2-keto-1,2-dihydroquinoline-7 -carbonitrile, trans-p-isomer A (intermediate 67, 150 mg, 0.48 mmol), 3-keto-3,4-dihydro-2Η-pyrido[3,2-b][ l,4] 唠耕-6·carboxycarboxaldehyde (WO 2004/058144) (85 mg, 0·48 mmol) and sodium triethoxy borohydride (300 mg, 1.43 mmol) to obtain 70 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 2.04-2.21 (m, 2H); 2.30-2.41 (m, 1H); 2.57-2.67 (m, 2H); 2.78-2.87 (m, 1H); 127286-153-200831517 3.18-3.29 (m, 1H); 3.73 (s3 2H) ; 4.29 (m5 1H) ; 4.29-4.46 (m? 2H) ; 4.61 (s, 2H) ; 6.78 (d, 1H) ; 7·01 (d, 1H) ; 7.30 (d, 1H) ; 7·66 (dd, 1H); 7.91 (d,1H) ; 8.01 (d,1H) ; 8.11 (s,1H) ; 1U9 (s,1H)· MS (ESP) : 477 (MH+) vs. C2 5 H2 5 FN6 03 Let Examples 3S to 4 Waters XBridge C-18 column was purified by reverse phase HPLC and eluted with 5-50% water/acetonitrile with ammonium acetate buffer (pH == 8). Example 35 1_(2-{4-[(2,3) -Dihydro[indenyl]dioxanthene and p,3-c]pyridin-7-ylmethyl)amino]-3-1ylhexahydropyridine small group}ethyl)-7-methoxyquin Porphyrin-2(1H)-one, trans-palladium isomer, dihydrochloride using 2,3-dihydro[1,4]dioxene terpene using procedures similar to those described in Synthesis Example 33 And [2,3-c]pyridine-7-carboxaldehyde and 1-{2-[4-amino-3-fluorohexahydropyridin-1-yl]ethyl}_7_methoxy -2(1H)-one, trans-reaction to palmoisomer A (intermediate 77) provides the title composition. 1H NMR (D20) δ ppm: 1.81-1.97 (m5 1H); 2.32-2.45 (m? 1H); 3.20-3.32 (m, 1H); 3.35-3.44 (m, 1H); 3.52-3.72 (m, 4H) 3.91 (s,3H) ; 3.85-3.95 (m,1H) ; 4·13·4·28 (m,2H) ; 4.37-4.43 (m,2H) ; 4.51-4.56 (m,2H); 4.57- 4.73 (m,2H) ; 4·94 (m,1H) ; 6.90 (d,1H) ; 7.10 (dd,1H) ; 7.30 (s, 1H) ; 7·78 (d,1H) ; 8.03 (s, 1H) ; 8.22 (s,1H)· ES (MH)+ 470 Example 36

6-[({3·氟基-l-[2-(7-甲氧基-2-嗣基峻嗔琳-1(2H)-基）乙基]六氫，比 啶-4-基}胺基）甲基]-2H·吡啶并[3,2-b]丨1，4]，号畊-3(4H)-酮，反式 對掌異構物A 127286 -154- 200831517 使用類似關於合成實例33所述之程序（惟其鹽酸鹽製備 除外），使3-酮基-3,4-二氫-2H-吡啶并[3,2-b][l，4]嘮畊-6-羧甲醛 與1-{2-[4-胺基-3-氣基六鼠ρ比咬-1-基]乙基]-7-甲氧基峻嗜p林 -2(1H)-酮，反式對掌異構物A (中間物77)反應，提供標題化 合物。 NMR (DMSO-d6) δ ppm ： 1.14-1.29 (m? 1H) ； 1.82-1.95 (m5 1H)； 2,04-2,20 (m5 2H) ； 2.52-2.61 (m5 1H) ； 2.60-2.70 (m5 2H) ； 2.78-2.89 (m? 1H)； 3.16-3.27 (m? 1H) ； 3.67-3.80 (m? 2H) ； 3.88-3.96 (m, 3H) ； 4.29-4.43 (m，2H) ; 4.30 (m，1H) ; 4·61 (s，2H) ; 6.96-7.06 (m，3H) ; 7.30 (d，1H); 7.75 (d，1H) ; 8.00-8.09 (m，1H) ; 11.19 (s，1H)· ES (MH)+483 實例37 l_(2-{4-[(2,3-二氫[1，4]二氧陸圜烯并【2,3-c]吡啶-7-基甲基）胺 基]-3·氟基六氫〃比咬-l-基}乙基)-2·酮基-1，2·二氫ττ奎琳-7-甲腈， 反式對掌異構物Β，雙-鹽酸鹽 使用類似關於合成實例33所述之程序，使2,3-二氫[1，4]二 氧陸圜烯并[2,3-c]吡啶-7-羧甲醛與1-{2-[4-胺基-3-氟基六氫吡 啶-1-基]乙基}-2-酮基-1，2-二氫喹啉-7-甲腈，反式對掌異構物 B (中間物79)反應，提供標題組合物。 ΐΗΝΜΚ(°2〇) δ ppm： 1.81-1.94 (m, 1H)； 2.30-2.43 (m5 1H)； 3.13-3.26 (m? 1H) ； 3.32-3.42 (m5 1H) ； 3.42-3.50 (m5 1H) ； 3.53 (t, 2H) ； 3.57-3.66 (m? 1H) ； 3.79-3.93 (m5 1H) ； 4.11-4.27 (m, 2H) ； 438-4.43 (m? 2H)； 4.50-4.56 (m，2H) ; 4·62_4·75 (m，1H) ; 4.80_4,88 (m，1H) ; 4.85 (m，1H) 6.85 (d，1H) ; 7·25 (s，1H) ; 7.68 (dd，1H) ; 7.89 (d，1H) ; 7·98 (s，1H); 127286 -155- 200831517 8.03 (d5 1H) ； 8.20 (s5 1H) ES (MH)+464 實例386-[({3·Fluoro-l-[2-(7-methoxy-2-indenyl)- quinone-1(2H)-yl)ethyl]hexahydro,pyridin-4-yl} Amino)methyl]-2H·pyrido[3,2-b]indole 1,4], cultivating-3(4H)-one, trans-palphasomer isomer A 127286 -154- 200831517 The procedure described in Synthesis Example 33 (except for the preparation of the hydrochloride salt) was such that 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6- Carboxaldehyde and 1-{2-[4-amino-3-yl-based squirrel ρ-diyl-1-yl]ethyl]-7-methoxy-suppressed p-lin-2(1H)-one The reaction is carried out on the palm of the isomer A (Intermediate 77) to afford the title compound. NMR (DMSO-d6) δ ppm : 1.14-1.29 (m? 1H) ; 1.82-1.95 (m5 1H); 2,04-2,20 (m5 2H) ; 2.52-2.61 (m5 1H) ; 2.60-2.70 ( M5 2H) ; 2.78-2.89 (m? 1H); 3.16-3.27 (m? 1H); 3.67-3.80 (m? 2H); 3.88-3.96 (m, 3H); 4.29-4.43 (m, 2H); 4.30 (m,1H) ; 4·61 (s,2H) ; 6.96-7.06 (m,3H) ; 7.30 (d,1H); 7.75 (d,1H) ; 8.00-8.09 (m,1H) ; 11.19 (s , 1H)·ES (MH)+483 Example 37 l_(2-{4-[(2,3-Dihydro[1,4]dioxolynene[2,3-c]pyridin-7-yl) Methyl)amino]-3·fluorohexahydroindole than biting-l-yl}ethyl)-2·keto-1,2·dihydroττ quinine-7-carbonitrile, trans-pair The construct, bis-hydrochloride, was similar to the procedure described in Synthesis Example 33 to give 2,3-dihydro[1,4]dioxantim[2,3-c]pyridine-7-carboxylate. Formaldehyde with 1-{2-[4-amino-3-fluorohexahydropyridin-1-yl]ethyl}-2-keto-1,2-dihydroquinolin-7-carbonitrile, trans Reaction of palmate isomer B (Intermediate 79) provides the title composition. ΐΗΝΜΚ(°2〇) δ ppm: 1.81-1.94 (m, 1H); 2.30-2.43 (m5 1H); 3.13-3.26 (m? 1H); 3.32-3.42 (m5 1H) ; 3.42-3.50 (m5 1H) 3.53 (t, 2H) ; 3.57-3.66 (m? 1H) ; 3.79-3.93 (m5 1H) ; 4.11-4.27 (m, 2H) ; 438-4.43 (m? 2H); 4.50-4.56 (m, 2H) ; 4·62_4·75 (m,1H) ; 4.80_4,88 (m,1H) ; 4.85 (m,1H) 6.85 (d,1H) ; 7·25 (s,1H) ; 7.68 (dd,1H 7.89 (d,1H) ; 7·98 (s,1H); 127286 -155- 200831517 8.03 (d5 1H) ; 8.20 (s5 1H) ES (MH)+464 Example 38

•氟基_4·{[(3-酮基_3,4·二氫_2H-峨咬并【3,2-b】丨l，4]兮唯i基） 甲基】胺基}六氫p比咬_1·基）乙基酮基-1，2·二氫峻琳_7_甲月青， 反式對掌異構物B 使用類似關於合成實例33所述之程序（惟其鹽酸鹽製備 除外），使3-酮基-3,4-二氫-2H·吡啶并[3,2七][1，4]噚畊各鲮甲駿 與1-{2-[4-胺基-3-氣基六氫p比咬-1-基]乙基}-2-S同基-1，2-二氫口奎 啉-7-甲腈，反式對掌異構物B (中間物79)反應，提供標題化 合物。 1HNMR(DMSO-d6) 5 ppm: 1.21 (m，1H) 1.84-1.95 (m，1H); 2.04-2.21 (m5 2H) ; 2.30-2.41 (m，1H) ; 2·57·2·67 (m, 2H) ; 2.78-2.87 (m，1H); 318-3.29 (m，1H) ; 3.73 (s，2H); 4.29 (m，1H) 4·29_4·46 (m，2H) ; 4.61 (s， 2H) ; 6.78 (d，1H) ; 7.01 (d，1H) ; 7.30 (d，1H) ; 7.66 (dd，1H) ; 7.91 (d， 1H) ; 8·01 (d，1H) ; 8.11 (s，1H) ; 11.19 (s，1H) ES (MH)+477 [a]D= +19.8 (甲醇，c = 0.46) 實例39 l-(2-{4-[(2,3-二氫【1，4]二氧陸圓烯并【2,3-c】吡啶-7-基甲基）胺 基]-3-敗基六氫吡啶-l-基}乙基)_7·甲氧基喹喏啉·2(1Η)·酮，反 式對掌異構物Β，雙-鹽酸鹽 使用類似關於合成實例33所述之程序，使2,3-二氫[1，4]二 氧陸圜烯并[2,3-c]吡啶-7-綾甲醛與μ{2_[4·胺基-3-氟基六氫吡 啶-1-基]乙基}-7-甲氧基喳喏啉_2(m)_酮，反式對掌異構物Β 127286 -156- 200831517 (中間物83)反應，提供標題組合物。 !H NMR (D20) δ ppm： 1.81-1.97 (m? 1H)； 2.32-2.45 (m? IH)； 3.20-3.32 (m，1H) ; 3.35-3.44 (m，1H) ; 3.52-3.72 (m，4H) ; 3_91 (s，3H) ; 3.85-3.95 (m，1Ή) ; 4.13-4.28 (m，2H) ; 4.37-4.43 (m，2H) ; 4.51-4.56 (m，2H); 4.57-4.73 (m，2H) ; 4_94 (m，1H) ; 6.90 (d，1H) ; 7·10 (dd，1H) ; 7.30 (s， IH) ; 7·78 (d，IH) ; 8·03 (s，IH) ; 8·22 (s，1H). ES (MH)+470 實例40• Fluoro group _4·{[(3-keto- 3,4·dihydro-2H-峨 bite and [3,2-b]丨l,4] 兮i i base) methyl]amino}6 Hydrogen p is more specific than the salt described in the synthesis of Example 33 (only the salt thereof). Except for the preparation of acid salt, 3-keto-3,4-dihydro-2H·pyrido[3,2-7][1,4] 噚 鲮 鲮 与 与 与 and 1-{2-[4-amine Benzyl-3-ylhexahydrop-p-but-1-yl]ethyl}-2-S synthyl-1,2-dihydro-hydroxyquinoline-7-carbonitrile, trans-p-isomer B ( Intermediate 79) was reacted to provide the title compound. 1H NMR (DMSO-d6) 5 ppm: 1.21 (m, 1H) 1.84-1.95 (m, 1H); 2.04-2.21 (m5 2H); 2.30-2.41 (m, 1H); 2·57·2·67 (m , 2H) ; 2.78-2.87 (m,1H); 318-3.29 (m,1H) ; 3.73 (s,2H); 4.29 (m,1H) 4·29_4·46 (m,2H) ; 4.61 (s, 2H) ; 6.78 (d,1H) ; 7.01 (d,1H) ; 7.30 (d,1H) ; 7.66 (dd,1H) ; 7.91 (d, 1H) ; 8·01 (d,1H) ; 8.11 (s ,1H); 11.19 (s,1H) ES (MH)+477 [a]D= +19.8 (methanol, c = 0.46) Example 39 l-(2-{4-[(2,3-dihydro[1] , 4] dioxo-encyclo[6,3-c]pyridin-7-ylmethyl)amino]-3-decylhexahydropyridine-1-yl}ethyl)-7-methoxyquinidine Porphyrin·2(1Η)·one, trans-p-isomer, bis-hydrochloride, using a procedure similar to that described in Synthesis Example 33, to 2,3-dihydro[1,4]dioxane Alkeno[2,3-c]pyridine-7-indolecarboxaldehyde and μ{2_[4.amino-3-fluorohexahydropyridin-1-yl]ethyl}-7-methoxy porphyrin_ 2(m)-ketone, trans-p-isomer Β 127286 - 156 - 200831517 (Intermediate 83) was reacted to provide the title composition. !H NMR (D20) δ ppm: 1.81-1.97 (m? 1H); 2.32-2.45 (m? IH); 3.20-3.32 (m,1H); 3.35-3.44 (m,1H) ; 3.52-3.72 (m , 4H); 3_91 (s, 3H); 3.85-3.95 (m, 1Ή); 4.13-4.28 (m, 2H); 4.37-4.43 (m, 2H); 4.51-4.56 (m, 2H); 4.57-4.73 (m,2H) ; 4_94 (m,1H) ; 6.90 (d,1H) ; 7·10 (dd,1H) ; 7.30 (s, IH) ; 7·78 (d,IH) ; 8·03 (s , IH) ; 8·22 (s, 1H). ES (MH)+470 Example 40

6-[({3-氟基-l-[2-(7_甲氧基·2·酮基p奎嗔琳-1(2H)-基）乙基】六氫p比 啶-4-基}胺基）甲基]-2H-吡啶并[3,2-b][l，4]噚畊-3(4H)-酮，反式 對掌異構物B 使用類似關於合成實例33所述之程序（惟其鹽酸鹽製備 除外），使3-酮基-3,4-二氫-2H-吡啶并[3,2-b][l，4]哼畊-6-羧甲醛 與1-{2-[4-胺基-3-氟基六氫峨°定-1-基]乙基卜7-甲氧基ρ奎ϋ若琳 -2(1Η)-酮，反式對掌異構物Β (中間物83)反應，提供標題化 合物。 NMR (DMSO-d6) δ ppm ： L14-L29 (m5 IH) ； 1.82-1.95 (m, IH)； 2.04-2.20 (m，2H) ; 2.52-2.61 (m，IH) ; 2.60-2.70 (m，2H) ; 2.78-2.89 (m， IH)； 3.16-3.27 (m5 IH) ； 3.67-3.80 (m5 2H)； 3.88-3.96 (m? 3H)； 4.29-4.43 (m，2H) ; 4.30 (m，IH) ; 4.61 (s，2H) ; 6.96-7.06 (m，3H) ; 7.30 (d，IH); 7.75 (d5 IH) ； 8.00-8.09 (m? IH) ； 11.19 (s, IH) ES (MH)+483 實例41 l-(2-{(3R，4R)-4-[(2,3-二氫【1，4]二氧陸困烯并 p，3-c]吡啶-7-基甲 127286 -157- 200831517 基)胺基Η·甲氧基六氫_小基}乙基)_2，基·w.二氨峻琳 •7-甲腈，雙鹽酸鹽 ^ 1-{2.[(3R,4R&gt;4^ ^ -3.f ^ ^ ^ ^ ,k ^ ^ ^ ^ -U-二氫峻#-7-甲月奮（中間物85，1〇5毫克粗製物，〇·32毫莫 耳m 2,3-二氫二氧陸圜烯并[2场比以幾甲駿_聊 隱叫⑸毫克’㈣毫莫恥在無水甲醇/氯仿⑴卜⑺毫 升）中之混合物，在氮大氣下，於认分子篩上，在7〇它下加 _熱三小時。使反應物冷卻至室溫，並添加三乙耗基爛氯 化鈉（205毫克，〇·97耄莫耳）。將反應物於室溫下攪拌過夜， 然後經過矽藻土過濾。使濾液濃縮至乾涸，溶於氯仿中之 15%曱醇内，並以飽和碳酸氫鈉溶液洗滌。將水相以15%甲 醇/氯仿再萃取兩次。使合併之有機相以硫酸鎂脫水乾燥， 及在減壓下濃縮。於矽膠上，以含有〇25%氫氧化銨之2_1〇% 曱醇在二氯甲烷中之梯度液層析，獲得61毫克（4〇%)標題組 合物之自由態驗，為油狀物。使其溶於1:〗二氯甲烧/乙_ _ (5毫升）中，並以醚中之1·〇Μ HC1 (〜2當量）處理。藉過濾收 集所形成之沉澱物’在水中重配，並滚乾，獲得63毫克標 題組合物，為固體。 MS (ESP) : 476 (ΜΗ+)對 C26H29N504 rH NMR (D20) δ ppm： 1.84-2.00 (m? 1H)； 2.37-2.49 (m? 1H)； 2.93-3.06 (m5 1H) ； 3.10-3,23 (m? 1H) ； 3.33-3.44 (m5 4H) ； 3,53-3.80 (m5 4H) ； 4.19 (d，1H) ; 4.27-4.40 (m，4H) ; 4.40-4.48 (m，2H) ; 4.62-4.76 (m，2H); 6.79 (d，1H) ; 7·22 (s，1H) ; 7.62 (dd，1H) ; 7·83 (d，1H) ; 7.91 (s，1H) ; 7.97 (4 1H) ; 8·14-8·20 (m，1H). 127286 -158- 200831517 實例42 1- [2_((3R，4R)_3_ 甲氧基 _4_{丨(3-酮基 _3,4·二氫-2H-吡啶并[3,2-b】[l，4】 噚畊-6·基）甲基】胺基}六氫吡啶-1·基）乙基】-2-酮基-1，2-二氫喹 啉-7-甲腈 使用類似關於合成實例41所述之程序（惟其鹽酸鹽製備 除外），使l-{2-[(3R，4R)-4-胺基-3-甲氧基六氫P比。定-1-基]乙基 酮基二氫峻琳-7-甲赌（中間物85，105毫克，0.32毫莫耳)、 3-酮基-3,4-二氳-2Η-峨唆并[3,2-b][l，4]4 ρ井-6-魏甲酸（WO 2004/ 058144) (57毫克，0.32毫莫耳）及三乙醯氧基硼氫化鈉（2〇5毫 克，0.97毫莫耳）反應。於矽膠上，以含有〇·25%氫氧化銨之 2- 10%甲醇在二氯甲烷中之梯度液層析，獲得88毫克（56%) 標題化合物，為灰白色固體。 MS (ESP) : 489 (MH+)對 C2 6 H2 8 N6 04 lH NMR (DMSO-d6) δ ppm · 1.00-1.15 (m5 1H) ； 1.76 (m5 1H) ； 1.87 (d，1H) ; 1.99 (m，1H) ; 2·22-2·34 (m，1H) ; 2·59 (m，2H) ; 2.78-2.96 (m， 2H) ； 3.25-3.33 (m5 2H) ； 3.30 (s? 3H) ； 3.55-3.77 (m? 2H) ； 4.30-4.50 (m, 2H) ; 4·61 (s，2H) ; 6·79 (d，1H) ; 6.97 (d，1H) ; 7.28 (d，1H) ; 7,66 (dd， 1H) ; 7·91 (d，1H) ; 8.01 (d，1H) ; 8.12 (s，1H) ; 11.21 (s，1H). 實例43 l-(2-{(3S，4S)-4-【(2,3-二氫【1，4]二氧陸圜烯并【2,3-c]p比咬-7·基甲基） 胺基]甲氧基六風p比咬-l-基}乙基）_2_嗣基·1，2-二氮p奎u林-7_ 甲腈，雙鹽酸鹽 使用類似關於合成實例41所述之程序，使i_{2-[(3S，4S)-4-胺基-3·甲氧基六氮峨淀_1-基]乙基}-2-綱基-1，2-二氯峻淋-7-甲 127286 -159- 200831517 腈（中間物90，120毫克，〇·37毫莫耳）、2,3-二氫[1，4]二氧陸 圜烯并[2,3·φ比啶·7_羧甲醛（WO 2004/058144) (61毫克，〇·37毫 莫耳）及三乙醯氧基硼氫化鈉（234毫克，1·1〇毫莫耳）反應， 提供標題組合物（54毫克）。 MS (ESP) : 476 (ΜΗ+)對 C26H29N504 1H NMR (D20) 5 ppm 1.84-2.00 (m，1H); 2.37-2.49 (m，1H); 2.93-3.06 (m? 1H) ； 3.10-3.23 (m5 1H) ； 3.33-3.44 (m? 4H) ； 3.53-3.80 (m? 4H) ； 4.19 (d? 1H) ； 4.27-4.40 (m? 4H) ； 4.40-4.48 (m5 2H) ； 4.62-4.76 (m5 2H) ； 6.79 (d，1H) ; 7·22 (s，1H) ; 7·62 (dd，1H) ; 7.83 (d，1H) ; 7.91 (s，1H) ; 7.97 (d5 1H) ； 8.14-8.20 (m5 1H). 實例44 l-【2-((3S，4S)-3_ 曱氧基-4_{[(3·酮基-3,4-二氫-2H·吡咬并[3,2-b][l，4] 噚畊_6_基）甲基]胺基}六氫峨啶·1_基）乙基】·2-酮基-1，2-二氫喹 啉-7-甲腈 使用類似關於實例41所述之程序（惟其鹽酸鹽製備除 外），使H2-[(3S，4SH-胺基-3·曱氧基六氫吡啶小基;]乙基}-2_ 酮基-1,2-二氫喹啉-7-曱腈（中間物90，Π0毫克，0.37毫莫耳）、 3-酮基-3,4-二氫-2H-P比唆弁[3,2-b][l，4]p号 井-6·緩甲酸（WO 2004/ 058144) (61毫克，0·37毫莫耳）及三乙醯氧基硼氫化鈉（234毫 克，L10毫莫耳）反應，提供標題化合物。 MS (ESP) : 489 (ΜΗ+)對 C26H28N604 1H NMR (DMSO-d6) 5 ppm 1.00-1.15 (m，1H) ; 1.76 (m5 1H) ; 1.87 (d， 1H); 1·99 (m5 1H); 2.22-2.34 (m，1H); 2.59 (m，2H); 2.78-2.96 (m5 2H); 3.25-3.33 (m5 2H) ； 3.30 (s5 3H) ； 3.55-3.77 (m, 2H) ； 4.30-4.50 (m, 2H)； 127286 -160- 200831517 4.61 (s，2H) ; 6·79 (d，1H) ; 6·97 (d，1H) ; 7.28 (d，1H) ; 7·66 (dd，1H); 7·91 (d，1H) ; 8.01 (d，1H) ; 8·12 (s，1H) ; 11.21 (s，1H)· 實例45 6-【({(3S，4R)-3-氟基·1-【2_(7-甲氧基-2-酮基喳喏啉基）乙基] 六氫吡啶斗基}胺基）甲基]-2Η-吡啶并丨3,2七py]噚畊-3(4H)·酮， 雙鹽酸鹽 與 實例46 6-[({(3R，4S)-3-氟基小【2-(7-甲氧基-2·酮基喹喏啉-1(2H)-基）乙基】 六氫吡啶-4-基}胺基）甲基】·2Η_吡啶并【3,2_b][1，4]噚喷〜3(4H)-酮， 雙鹽酸鹽 使順式（:!:)1-[2-(4-胺基-3-氟基六氫吡啶-1-基）乙基]甲氧基 喹喏啉-2(1Η)-酮，三氟醋酸鹽（中間物91，〜〇·53毫莫耳）在二 氣乙烷/甲醇（1 ·· 1，20毫升）中之溶液以ν，Ν-二異丙基乙胺 中和。添加3-酮基·3,4-二氫-2Η-吡啶并[3,2-b][l，4]噚啡冬羧甲醛 (WO 2004/058144) (113毫克，〇·63毫莫耳），並將反應物在回流 下，於3人分子篩上攪拌過夜。使反應混合物冷卻至〇c&gt;c，並 添加氰基硼氫化鈉（40毫克，〇·63毫莫耳）。將反應混合物於 室溫下攪拌2小時，然後經過燒結漏斗過濾，及濃縮。使殘 留物溶於醋酸乙酯中，且以飽和碳酸氫鈉，接著以飽和氯 化鈉洗滌。使有機萃液以硫酸鎂脫水乾燥，及濃縮。以水/ 甲醇/二氟醋酸逆相層析，產生產物，為三氟醋酸鹽。使此 鹽溶於水與氯仿中，並以飽和碳酸鈉鹼化。分離液層，且 以氯仿萃取水溶液。使有機萃液以硫酸鎂脫水乾燥，及濃 127286 -161 - 200831517 縮，而得標題組合物之自由態鹼之外消旋混合物，為固體， 26 毫克（10%)。 MS (ESP) : 483 (MH+)對 C24H27FN604 ^-NMR (CDC!3-d) δ ： 1.70 (m5 4Η) ； 2.35 (m5 2H) ； 2.64 (m? IH)； 2.73 (m? 2H) ； 3.04 (m? 1H) ； 3.31 (m5 1H) ； 3.86 (s5 2H) ； 3.92 (s5 3H)； 4.35 (m，2H) ; 4.63 (s，2H) ; 4.83 (m，1H) ; 6.86 (m，1H); 6·92 (m，IH); 6.98 (m5 1H) ； 7.21 (m5 1H) ； 7.77 (m5 IH) ； 8.11 (s5 1H). 外消旋混合物係藉對掌性層析（HPLC，Chimlcel OJ，250 x 20 毫米，10 //流動相：50%己烷、25%乙醇、25%曱醇、0·1% 二乙胺）分離。實例45之自由態鹼係首先溶離出，接著為實 例46之自由態鹼。其鹽酸鹽係經由使自由態鹼溶於二氯曱 烷（2毫升）中，並添加2.2當量之二氧陸圜中之4Ν HC1而製 成。藉過濾收集所形成之無色沉澱物，個別產生48毫克與 46毫克之實例45與46。 實例47 l-[2-((3R，4S)-3-曱氧基-4-{【(3-酮基-3,4_二氫-2Η·ρ比咬并[3,2_b]【l，4] 噚畊-6-基）甲基]胺基}六氫吡啶-1_基）乙基Η-甲基-2-酮基-1，2-二氫喹啉_7_甲腈，雙-鹽酸鹽 使l-{2-[(3R，4S)-4-胺基·3-曱氧基六氫p比咬-1-基]乙基甲基 -2-酮基-1，2-二氫ρ奎淋-7-甲腈（中間物93，〜0·81毫莫耳）懸浮於 氯仿/甲醇（1 : 1，20毫升）中，並逐滴添加Ν，Ν-二異丙基乙 胺，直到固體溶解為止。添加3-酮基_3,4_二氫-2Η_ρ比咬并 P，2-b][l，4]哼呼-6-羧甲醛（WO 2004/058144) (210 毫克，1.2 毫莫 耳），並使反應物於3A分子篩上回流5小時。於〇它下添加三 127286 -162- 200831517 乙醯氧基硼氫化鈉（340毫克，16毫莫耳）。將反應混合物於 室溫下攪拌2小時，然後經過〇·45微米薄膜過濾，及濃縮。 使殘留物溶於二氯甲烷與飽和碳酸氫鈉中。將水相之ρΗ值 以1Μ氫氧化鈉溶液調整至pH〜10。以二氯甲烷逆萃取水相， 並使合併之有機相以硫酸鈉脫水乾燥，及濃縮。以水/乙腈 /醋酸銨逆相層析，獲得標題組合物之自由態鹼，為黃褐色 泡沫物’ 144毫克（36%)。其雙·鹽酸鹽係使用類似關於合成 實例45所述之程序製成。 MS (ESP) ： 503 (MH+) tj- C27H3〇N604 ^-NMR (DMSO-d6) δ ： 1.41 (m, 1H) ； 1.75 (m? 2H) ； 2.28 (m5 1H)； 2_44 (s，3H) ; 2·53 (m，2H) ; 2.70 (m，2H); 3.16 (s，3H) ; 3.31 (m，2H); 3.64 (m5 2H) ; 4.35 (m，2H) ; 4·59 (s，2H) ; 6·68 (s，1H) ; 6·97 (d，1H); 7.27 (d，1H) ; 7·66 (d，1H) ; 7.92 (d，1H) ; 8.08 (s，1H) ; 8.31 (s，1H); 11.19 (s? 1H). 實例48 l-[2_((3S，4R)-3_氟基-4-{【(3_酮基-3,4·二氫 _2H-吡啶并[3,2-b][l，4]哼 嗜-6·基）甲基】胺基}六氫吡啶-1-基）乙基]_4-甲基-2-酮基-1，2-二 氫喹啉-7-甲腈，雙鹽酸鹽 與 實例49 l-[2_((3R，4S)-3-氟基-4-{[(3-酮基-3,4-二氫-2H-吡啶并丨3,2七]【1，4】哼 啼-6·基）甲基】胺基}六氫吡啶-1-基）己基]冬甲基-2-酮基-1，2-二 氫喳啉-7-甲腈，雙鹽酸鹽 使用類似關於合成實例47所述之程序，使順式（±)1-[2-(4- 127286 -163- 200831517 胺基-3-氟基六氫吡啶-1·基）乙基]-4-甲基-2-酮基-1，2-二氫啥琳 -7-甲腈（中間物95，200毫克，0.63毫莫耳）、3·酮基-3,4-二氫 -m-吡啶并[3,2-b][l，4]噚 _ 冬羧甲醛（WO 2004/058144) (170 毫克， 〇·94毫莫耳）及三乙醯氧基硼氫化鈉（26〇毫克，126毫莫耳） 反應，以水/乙腈/TFA逆相層析，提供標題化合物之外消旋 混合物，為乾膜，80毫克。 外消旋混合物係藉對掌性層析（SFC，Chiralpak AD-H，250 X 21毫米，5 ; 5〇%甲醇、〇.ι〇/0二曱基乙胺）分離。實例48 之自由態鹼係首先溶離出，接著為實例49之自由態鹼。其 雙-鹽酸鹽係使用類似關於合成實例45所述之程序製成，提 供標題化合物，為無色固體(個別為6毫克與4毫克）。 MS (ESP) : 491 (MH+)對 C26H27FN6〇3 ^-NMR (DMSO-d6) δ ： 1.60 (m, 2Η) ； 2.12 (m? 4H) ； 2.44 (s? 3H)； 2.54 (m，2H); 2.91 (m，1H); 3.12 (m，1H); 3.71 (m，2H); 4.34 (m，2H); 4·59 (s，2H) ; 4.70 (m，1H) ; 6.68 (s，1H) ; 7.01 (d，1H) ; 7.28 (d，1H); 7.66 (m，1H) ; 7.92 (d，1H) ; 8.07 (s，1H) ; iL18 (s，1H). 實例50 H2-((3s，4r)-3-氟基_4_{[(3·嗣基·3,4_二氫抓吡啶并丨3，叫 哜_6_基）甲基】胺基}六氫吡啶小基）乙基卜2•酮基氫喹啉 '甲腈，雙鹽酸鹽 使l-{2-[(3S，4R&gt;4_胺基-3-氟基六氫吡啶q•基]乙基}_2-酮基 1,2-一氫喳啉-7-曱恥二氟醋酸鹽（中間物97，毫莫耳）懸浮 於氯仿/甲醇（1: 2，30毫升）中，並藉由逐滴添加Ν，Ν·Ι異 丙基乙胺進行中和。添加3-_基_3,4_二氫-2Η_吡啶并[3&gt;b][1，4] 127286 -164- 200831517 噚畊-6·羧曱醛（WO 2004/058144) (258毫克，1.45毫莫耳），並使 反應物於3A分子篩上回流5小時。於〇〇c下添加三乙醯氧基 硼氫化鈉（512毫克，2·42毫莫耳）。將反應混合物於室溫下 攪拌30分鐘，然後經過燒結漏斗過濾，及濃縮。使殘留物 溶於二氣曱烧中，並以飽和碳酸氫鈉與飽和氯化鈉洗滌。 使有機相以硫酸鎂脫水乾燥，及濃縮。以水/乙腈/醋酸銨 逆相層析’於耒乾後’獲得產物，為灰白色固體。其鹽酸 鹽係經由使經凍乾之產物溶於二氯甲烷（5毫升）中，並添加 2·2當量之二氧陸圜中之4Ν HC1製成，而得標題組合物，為 無色固體，154毫克（26%)。 MS (ESP) : 477 (ΜΗ+)對 C25H25FN603 ^-NMR (DMSO-d6) 5 ： 1.61 (m, 2H) ； 2.20 (m5 2H) ； 2.52 (m? 4H)； 3.04 (m，2H) ; 3.72 (s，2H) ; 4·34 (m，2H) ; 4.59 (s，2H) ; 4.82 (m，1H); 6.67 (d，1H) ; 7·01 (d，1H) ; 7.28 (d，1H) ; 7.64 (d，1H) ; 7.89 (d，1H); 8.00 (d，1H) ; 8.09 (s，1H) ; 11.19 (s，1H)· 實例51 1-[2_((3S，4R)·3-甲氧基 _4_{[(3_酮基 _3,4_二氫 _2h_p比咬并[3,2-b】[l，4] 嘮哜-6-基）甲基]胺基}六氫吡啶-1-基）乙基]-4-甲基_2_酮基j，2_ 二氫喹啉-7-甲腈，雙-三氟醋酸鹽 使l-{2-[(3S，4R)斗胺基·3·曱氧基六氫吡啶-μ基]乙基甲基 -2·酮基-1，2-二氫ρ奎琳-7·曱腈，三氟酷酸鹽（中間物1〇4，〜0.52 毫莫耳）懸浮於氯仿/甲醇（1: 2，15毫升）中，並藉由逐滴 添加Ν，Ν-二異丙基乙胺進行中和。添加3-酮基-3,4-二氫-2Η-吡啶并 P，2-b][l，4]噚啼-6-羧甲醛（WO 2004/058144) (93 毫克，0.52 127286 -165 - 200831517 毫莫耳），並使反應物於3A分子篩上回流過夜。於(TC下添 加三乙醯氡基硼氫化鈉（138毫克，0.65毫莫耳）。將反應混 合物於室溫下攪拌5小時，然後經過燒結漏斗過濾，及濃縮。 使殘留物溶於二氯曱烷中，並以飽和碳酸氫鈉與飽和氣化 鈉洗滌。使有機相以硫酸鎂脫水乾燥，及濃縮。於凍乾後， 以水/乙腈/三氟醋酸逆相層析，獲得標題組合物，為白色 固體，108毫克（34%)。 MS(ESP): 503(MH+)對 c27H3GN604 ^-NMR (D20-d2) δ ： 2.26 (m5 2H) ； 2.49 (s, 3H) ； 3.20 (m5 2H)； 3.48 (s，3H) ; 3.64 (m，4H) ; 4.18 (m，4H); 4·70 (m，6H) ; 6·75 (s，1H); 7·06 (d，1H) ; 7.35 (d，1H) ; 7.69 (m，1H) ; 7.94 (s，1H) ; 8.01 (d，1H). 實例52 1-P-((3R，4S)_3-氟基酮基_3,4_二氫-2H•吡啶并[3,2七】队化号 畊-6-基）甲基】胺基}六氫吡啶+基）乙基】_2-酮基二氳喹啉 -7-甲腈，雙鹽酸鹽 使l-{2-[(3R，4SH-胺基各氟基六氫吡啶小基]乙基}_2_酮基 -1，2-二氫喳啉-7·甲腈（中間物106，352毫克，1.12毫莫耳)懸 浮於氯仿/甲醇（1 : 1，30毫升）中。添加3·酮基-3,4-二氫-2H· 吡啶并[3,2-b][l，4]噚畊-6-羧甲醛（WO 2004/058144) (299 毫克，1.68 毫莫耳），並使反應物於3A分子篩上回流過夜。於〇°C下添 加三乙醯氧基硼氫化鈉（356毫克，L68毫莫耳）。將反應混 合物於至溫下擾拌5小時’然後經過燒結漏斗過濾，及濃縮。 使殘留物溶於二氣甲烷中，並以飽和碳酸氫鈉與鹽水洗 滌。使有機相以硫酸鎂脫水乾燥，及濃縮。於凍乾後，以 127286 •166- 200831517 水/乙腈/醋酸銨逆相層析，獲得標題化合物之醋酸鹽，為 灰白色固體。其雙-HC1鹽係藉由添加2.2當量之二氧陸圜中 之4ΝΗα，製自醋酸鹽在二氯甲烷中之溶液（5毫升）。過濾， 及在真空下乾燦’獲付所要之化合物，為無色固體，154毫 克（26%) 〇 MS (ESP) : 477 (ΜΗ+)對 C2 5 H2 5 FN6 036-[({3-Fluoro-l-[2-(7-methoxy-2-keto)p-quineline-1(2H)-yl)ethyl]hexahydrop-pyridin-4-yl }Amino)methyl]-2H-pyrido[3,2-b][l,4]indole-3(4H)-one, trans-p-isomer B was used as described in Synthesis Example 33. Procedure (except for the preparation of hydrochloride), 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-carboxaldehyde and 1- {2-[4-Amino-3-fluorohexahydroindole-1-yl]ethyl b-7-methoxy ρ ϋ ϋ 琳 -2-2(1Η)-one, trans-pair The title compound (Intermediate 83) was reacted to provide the title compound. NMR (DMSO-d6) δ ppm : L14-L29 (m5 IH) ; 1.82-1.95 (m, IH); 2.04-2.20 (m, 2H); 2.52-2.61 (m, IH); 2.60-2.70 (m, 2H) ; 2.78-2.89 (m, IH); 3.16-3.27 (m5 IH); 3.67-3.80 (m5 2H); 3.88-3.96 (m? 3H); 4.29-4.43 (m, 2H); 4.30 (m, 4.H (3,3H); )) +483 Example 41 l-(2-{(3R,4R)-4-[(2,3-Dihydro[1,4]dioxoalthene and p,3-c]pyridine-7-yl) 127286 -157- 200831517 yl) hydrazinyl methoxy hexahydro _ small group} ethyl) 2, yl · w. diammonium • 7-carbonitrile, dihydrochloride ^ 1-{2. (3R,4R&gt;4^^ -3.f ^ ^ ^ ^ ,k ^ ^ ^ ^ -U-Dihydrojun #-7-甲月奋 (Intermediate 85,1〇5mg crude, 〇·32 Milliole m 2,3-dihydrodioxyterpenem and a mixture of 2 fields compared to a few jun Talk (5) milligrams (4) in a dry methanol/chloroform (1) (7) ml Under nitrogen atmosphere, add _ heat for 3 hours on the molecular sieve. Allow the reaction to cool to room temperature and add triethyl sulphate sodium chloride (205 mil. , 〇·97耄莫耳). The reaction was stirred at room temperature overnight, then filtered through celite. The filtrate was concentrated to dryness, dissolved in 15% methanol in chloroform, and saturated sodium bicarbonate solution The aqueous phase was extracted twice with 15% methanol/chloroform. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. Chromatography of the sterol in dichloromethane gave 61 mg (4%) of the title compound as free oil as an oil, which was dissolved in 1: chloroform / _ _ ( The mixture was treated with 1% hydrazine HC1 (~2 eq.) in ether. The precipitate formed by filtration was collected and reconstituted in water, and dried to give 63 mg of the title compound as a solid. MS (ESP): 476 (ΜΗ+) vs. C26H29N504 rH NMR (D20) δ ppm: 1.84-2.00 (m? 1H); 2.37-2.49 (m? 1H); 2.93-3.06 (m5 1H); 3.10-3, 23 (m? 1H); 3.33-3.44 (m5 4H); 3, 53-3.80 (m5 4H); 4.19 (d, 1H); 4.27-4.40 (m, 4H); 4.40-4.48 (m, 2H); 4.62-4.76 (m, 2H); 6.79 (d, 1H) ; 7·22 (s 1H) ; 7.62 (dd,1H) ; 7·83 (d,1H) ; 7.91 (s,1H) ; 7.97 (4 1H) ; 8·14-8·20 (m,1H). 127286 -158- 200831517 Example 42 1- [2_((3R,4R)_3_methoxy_4_{丨(3-keto-3,4·dihydro-2H-pyrido[3,2-b][l,4] 噚Plung-6-yl)methyl]amino}hexahydropyridine-1·yl)ethyl]-2-keto-1,2-dihydroquinolin-7-carbonitrile was used in a similar manner as described in Synthesis Example 41. The procedure (except for the preparation of the hydrochloride salt) is such that the ratio of 1-{2-[(3R,4R)-4-amino-3-methoxyhexahydro-P. Ding-1-yl]ethyl ketone dihydrogen -7- gambling (intermediate 85,105 mg, 0.32 mmol), 3-keto-3,4-diindole-2Η-峨唆[3,2-b][l,4]4 ρ Well-6-Weicarboxylic acid (WO 2004/ 058144) (57 mg, 0.32 mmol) and sodium triethoxy borohydride (2 〇 5 mg, 0.97 millimoles) reaction. Chromatography on EtOAc (EtOAc) elute MS (ESP): 489 (MH+) vs. C2 6 H2 8 N6 04 lH NMR (DMSO-d6) δ ppm · 1.00-1.15 (m5 1H) ; 1.76 (m5 1H) ; 1.87 (d,1H) ; 1.99 (m , 1H); 2·22-2·34 (m, 1H); 2·59 (m, 2H); 2.78-2.96 (m, 2H); 3.25-3.33 (m5 2H); 3.30 (s? 3H); 3.55-3.77 (m? 2H); 4.30-4.50 (m, 2H); 4·61 (s, 2H); 6·79 (d, 1H); 6.97 (d, 1H); 7.28 (d, 1H); 7,66 (dd, 1H) ; 7·91 (d,1H) ; 8.01 (d,1H) ; 8.12 (s,1H) ; 11.21 (s,1H). Example 43 l-(2-{(3S, 4S)-4-[(2,3-Dihydro[1,4]dioxolysine and [2,3-c]p ratio -7-ylmethyl)amino]methoxy hexazone p Than-l-yl}ethyl)_2_fluorenyl-1,2-diazap-kulin-7-carbonitrile, dihydrochloride using a procedure similar to that described in Synthesis Example 41, i_{2- [(3S,4S)-4-amino-3-methoxyhexaazepine-_1-yl]ethyl}-2-yl-1,2-dichloro-Jun--7-A 127286-159 - 200831517 Nitrile (intermediate 90, 120 mg, 〇 · 37 mmol), 2,3-dihydro[1,4]dioxanthene [2,3·φ than pyridine·7-carboxaldehyde ( WO 2004/058144) (61 mg, 〇·37 mmol) and triethoxynitride boron Sodium (234 mg, 1.1 mmol 1〇) to provide the title composition (54 mg). MS (ESP): 476 (ΜΗ+) vs. C26H29N504 1H NMR (D20) 5 ppm 1.84-2.00 (m,1H); 2.37-2.49 (m,1H); 2.93-3.06 (m? 1H); 3.10-3.23 ( M5 1H) ; 3.33-3.44 (m? 4H) ; 3.53-3.80 (m? 4H) ; 4.19 (d? 1H) ; 4.27-4.40 (m? 4H) ; 4.40-4.48 (m5 2H) ; 4.62-4.76 ( M5 2H) ; 6.79 (d,1H) ; 7·22 (s,1H) ; 7·62 (dd,1H) ; 7.83 (d,1H) ; 7.91 (s,1H) ; 7.97 (d5 1H) ; 8.14 -8.20 (m5 1H). Example 44 l-[2-((3S,4S)-3_ 曱oxy-4_{[(3·keto-3,4-dihydro-2H·pyro[3, 2-b][l,4] 噚 _6_yl)methyl]amino}hexahydroacridine·1_yl)ethyl]·2-keto-1,2-dihydroquinoline-7 -carbonitrile using a procedure similar to that described in Example 41 (except for the preparation of the hydrochloride salt) to give H2-[(3S,4SH-amino-3.nonyloxyhexahydropyridine small group;]ethyl}-2_ Ketopropyl-1,2-dihydroquinolin-7-indenecarbonitrile (intermediate 90, Π0 mg, 0.37 mmol), 3-keto-3,4-dihydro-2H-P 唆弁[3 , 2-b][l,4]p well-6·retarded formic acid (WO 2004/ 058144) (61 mg, 0·37 mmol) and sodium triethoxy borohydride (234 mg, L10 mil Moore) reaction MS (ESP): 489 (ΜΗ+) vs. C26H28N604 1H NMR (DMSO-d6) 5 ppm 1.00-1.15 (m, 1H); 1.76 (m5 1H); 1.87 (d, 1H); M5 1H); 2.22-2.34 (m,1H); 2.59 (m,2H); 2.78-2.96 (m5 2H); 3.25-3.33 (m5 2H) ; 3.30 (s5 3H) ; 3.55-3.77 (m, 2H) 4.30-4.50 (m, 2H); 127286 -160- 200831517 4.61 (s, 2H) ; 6·79 (d, 1H); 6·97 (d, 1H); 7.28 (d, 1H); 7·66 (dd,1H); 7·91 (d,1H) ; 8.01 (d,1H) ; 8·12 (s,1H) ; 11.21 (s,1H)· Example 45 6-[({(3S,4R) 3-fluoroyl·1-[2_(7-methoxy-2-ketophenyl)ethyl]hexahydropyridyl]amino)methyl]-2Η-pyridoindole 3,2 Seven py] 噚耕-3(4H)·one, bis-hydrochloride and Example 46 6-[({(3R,4S)-3-fluoroyl[2-(7-methoxy-2.keto) Quinoxaline-1(2H)-yl)ethyl]hexahydropyridin-4-yl}amino)methyl]·2Η_pyridine[3,2_b][1,4]噚 〜~3(4H) - Ketone, dihydrochloride salt cis (:!:) 1-[2-(4-Amino-3-fluorohexahydropyridin-1-yl)ethyl]methoxyquinoxaline-2 ( 1Η)-ketone, trifluoroacetate (intermediate 91, ~〇·53 mmol) in two In the ethane / methanol (1 mL, 20 ··) solution ν, Ν- diisopropylethylamine neutralization. Add 3-keto-3,4-dihydro-2-indole-[3,2-b][l,4]indolylcarboxaldehyde (WO 2004/058144) (113 mg, 〇·63 mmol) The reaction was stirred overnight on a 3 person molecular sieve under reflux. The reaction mixture was cooled to 〇c &lt;c, and sodium cyanoborohydride (40 mg, EtOAc &lt; The reaction mixture was stirred at room temperature for 2 hr then filtered over EtOAc EtOAc. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate then brine. The organic extract was dried over magnesium sulfate and concentrated. Reverse phase chromatography with water/methanol/difluoroacetic acid gave the product as trifluoroacetate. This salt was dissolved in water and chloroform and basified with saturated sodium carbonate. The liquid layer was separated, and the aqueous solution was extracted with chloroform. The organic extract was dehydrated to dryness with MgSO.sub.sub.sub.sub.sub.sub. MS (ESP): 483 (MH+) vs. C24H27FN604^-NMR (CDC!3-d) δ: 1.70 (m5 4 Η); 2.35 (m5 2H); 2.64 (m? IH); 2.73 (m? 2H); (m? 1H) ; 3.31 (m5 1H) ; 3.86 (s5 2H) ; 3.92 (s5 3H); 4.35 (m, 2H) ; 4.63 (s, 2H) ; 4.83 (m, 1H) ; 6.86 (m, 1H 6·92 (m, IH); 6.98 (m5 1H); 7.21 (m5 1H); 7.77 (m5 IH); 8.11 (s5 1H). The racemic mixture is by palm chromatography (HPLC, Chimlcel) OJ, 250 x 20 mm, 10 // mobile phase: 50% hexane, 25% ethanol, 25% decyl alcohol, 0.1% diethylamine). The free base of Example 45 was first eluted, followed by the free base of Example 46. The hydrochloride salt was prepared by dissolving a free base in dichloromethane (2 ml) and adding 2.2 equivalents of 4 HCl in dioxane. The colorless precipitate formed was collected by filtration, and 48 and 46 mg of Examples 45 and 46 were separately produced. Example 47 l-[2-((3R,4S)-3-曱-oxy-4-{[(3-keto-3,4-dihydro-2Η·ρ ratio bite [3,2_b][l , 4] 噚耕-6-yl)methyl]amino}hexahydropyridine-1_yl)ethyl hydrazine-methyl-2-keto-1,2-dihydroquinoline _7-carbonitrile, Bis-hydrochloride salt l-{2-[(3R,4S)-4-amino-3-pyridyloxyhexahydrop to butyl-1-yl]ethylmethyl-2-keto-1, 2-Dihydro-p-quinoline-7-carbonitrile (intermediate 93, ~0·81 mmol) was suspended in chloroform/methanol (1:1, 20 ml), and hydrazine, hydrazine-diiso was added dropwise. Propylethylamine until the solid dissolves. Add 3-keto-3,4-dihydro-2Η_ρ to bite P,2-b][l,4]哼h-6-carboxaldehyde (WO 2004/058144) (210 mg, 1.2 mmol) The reaction was refluxed on a 3A molecular sieve for 5 hours. Under it, add three 127286 -162- 200831517 sodium acetoxyborohydride (340 mg, 16 mmol). The reaction mixture was stirred at room temperature for 2 hours, then filtered through a EtOAc EtOAc EtOAc. The residue was dissolved in dichloromethane and saturated sodium bicarbonate. The pH value of the aqueous phase was adjusted to pH 〜10 with 1 NaOH solution. The aqueous phase was back-extracted with dichloromethane and the combined organic phases dried over sodium sulfate and concentrated. The free-form base of the title composition was obtained as a tan-yellow foam of 144 mg (36%). Its bis-hydrochloride salt was prepared using a procedure similar to that described in Synthesis Example 45. MS (ESP): 503 (MH+) tj- C27H3 〇N604^-NMR (DMSO-d6) δ: 1.41 (m, 1H); 1.75 (m? 2H); 2.28 (m5 1H); 2_44 (s, 3H) ; 2·53 (m, 2H) ; 2.70 (m, 2H); 3.16 (s, 3H); 3.31 (m, 2H); 3.64 (m5 2H); 4.35 (m, 2H); 4·59 (s, 2H) ; 6·68 (s,1H) ; 6·97 (d,1H); 7.27 (d,1H) ; 7·66 (d,1H) ; 7.92 (d,1H) ; 8.08 (s,1H) ; 8.31 (s, 1H); 11.19 (s? 1H). Example 48 l-[2_((3S,4R)-3_Fluoro-4-{[(3-keto-3,4·dihydro) 2H-pyrido[3,2-b][l,4]indole-6-yl)methyl]amino}hexahydropyridin-1-yl)ethyl]-4-methyl-2-keto- 1,2-Dihydroquinoline-7-carbonitrile, dihydrochloride and Example 49 l-[2_((3R,4S)-3-fluoro-4-{[(3-keto-3,4) -Dihydro-2H-pyridoindole 3,2-7][1,4]哼啼-6·yl)methyl]amino}hexahydropyridin-1-yl)hexyl]methanol-2-keto -1,2-dihydroporphyrin-7-carbonitrile, dihydrochloride using a procedure similar to that described in Synthesis Example 47 to give cis (±) 1-[2-(4-127286-163-200831517 amine 3-fluorohexahydropyridin-1yl)ethyl]-4-methyl-2-keto-1,2-dihydroinden-7-carbonitrile 95,200 mg, 0.63 mmol, 3·keto-3,4-dihydro-m-pyrido[3,2-b][l,4]噚_carboxaldehyde (WO 2004/058144) (170 mg, 〇·94 mmol) and sodium triethoxysulfonate hydride (26 mg, 126 mmol), eluted with water / acetonitrile / TFA to afford the title compound The mixture was a dry film, 80 mg. The racemic mixture was isolated by palm chromatography (SFC, Chiralpak AD-H, 250 X 21 mm, 5; 5 % methanol, 〇.ι〇/0 dimercaptoethylamine). The free base of Example 48 was first eluted, followed by the free base of Example 49. The bis-hydrochloride salt was prepared using a procedure similar to that described for the synthesis of Example 45 to afford the title compound as a colorless solid (6 mg and 4 mg each). MS (ESP): 491 (MH+) vs. C26H27FN6 〇3^-NMR (DMSO-d6) δ: 1.60 (m, 2 Η); 2.12 (m? 4H); 2.44 (s? 3H); 2.54 (m, 2H) 2.91 (m,1H); 3.12 (m,1H); 3.71 (m,2H); 4.34 (m,2H); 4·59 (s,2H) ; 4.70 (m,1H) ; 6.68 (s,1H ; 7.01 (d,1H) ; 7.28 (d,1H); 7.66 (m,1H) ; 7.92 (d,1H) ; 8.07 (s,1H) ; iL18 (s,1H). Example 50 H2-(( 3s, 4r)-3-fluoroyl_4_{[(3·嗣基·3,4-dihydropyridinium hydrazide 3, 哜6_yl)methyl]amino}hexahydropyridine small group) Ethyl 2 ketohydroquinoline 'carbonitrile, dihydrochloride salt l-{2-[(3S,4R&gt;4_amino-3-fluorohexahydropyridine q•yl]ethyl}_2 - Ketopropyl 1,2-monohydroporphyrin-7-oxime difluoroacetate (intermediate 97, millimolar) suspended in chloroform / methanol (1: 2, 30 mL) and added dropwise Ν,Ν·Ιisopropylethylamine was neutralized. Add 3-_yl_3,4_dihydro-2Η_pyridine and [3&gt;b][1,4] 127286 -164- 200831517 噚耕-6 Carboxyfurfural (WO 2004/058144) (258 mg, 1.45 mmol), and refluxing the reaction on a 3A molecular sieve for 5 hours. Add triethoxycarbonyl under 〇〇c Sodium hydride (512 mg, 2.42 mmol). The reaction mixture was stirred at room temperature for 30 min then filtered over a sifting funnel and concentrated. The sodium and the saturated sodium chloride were washed. The organic phase was dried over magnesium sulfate and concentrated, and then purified with water/acetonitrile / ammonium acetate reverse phase chromatography 'after drying' to obtain the product as an off-white solid. The lyophilized product was dissolved in dichloromethane (5 mL) and EtOAc (EtOAc m. MS (ESP): 477 (ΜΗ+) vs. C25H25FN603 ^-NMR (DMSO-d6) 5 : 1.61 (m, 2H); 2.20 (m5 2H); 2.52 (m? 4H); 3.04 (m, 2H) 3.72 (s,2H) ; 4·34 (m,2H) ; 4.59 (s,2H) ; 4.82 (m,1H); 6.67 (d,1H) ; 7·01 (d,1H) ; 7.28 (d ,1H) ; 7.64 (d,1H) ; 7.89 (d,1H); 8.00 (d,1H) ; 8.09 (s,1H) ; 11.19 (s,1H)· Example 51 1-[2_((3S,4R )·3-methoxy_4_{[(3_keto_3,4_dihydro-2h_p ratio bite [3,2-b][l,4] 唠哜-6-yl) Amino]hexahydropyridin-1-yl)ethyl]-4-methyl-2-keto-j,2-dihydroquinoline-7-carbonitrile, bis-trifluoroacetate makes l-{2 -[(3S,4R) piperidinyl·3·decyloxyhexahydropyridine-μ-yl]ethylmethyl-2·keto-1,2-dihydroρ-quinion-7-indene nitrile, trifluoro The succinate (intermediate 1〇4, ~0.52 mmol) was suspended in chloroform/methanol (1:2, 15 mL) and neutralized by dropwise addition of hydrazine, hydrazine-diisopropylethylamine. . Add 3-keto-3,4-dihydro-2-indole-pyrido P,2-b][l,4]indole-6-carboxaldehyde (WO 2004/058144) (93 mg, 0.52 127286 -165 - 200831517 millimolar) and the reaction was refluxed over 3A molecular sieves overnight. Add sodium triethylsulfonylborohydride (138 mg, 0.65 mmol) to TC. The reaction mixture was stirred at room temperature for 5 hr then filtered over a fritted funnel and concentrated. The mixture was washed with saturated sodium hydrogencarbonate and saturated sodium sulfate. The organic phase was dried over magnesium sulfate and concentrated. After lyophilization, the mixture was subjected to water/acetonitrile/trifluoroacetic acid reverse phase chromatography to obtain the title combination. , as a white solid, 108 mg (34%). MS (ESI): 503 (MH+), s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, 2H); 3.48 (s,3H) ; 3.64 (m,4H) ; 4.18 (m,4H); 4·70 (m,6H) ; 6·75 (s,1H); 7·06 (d,1H) 7.35 (d,1H); 7.69 (m,1H); 7.94 (s,1H); 8.01 (d,1H). Example 52 1-P-((3R,4S)_3-fluoroketone-based, 4_Dihydro-2H•pyridyl[3,2-7]Craft No.5-yl)methyl]amino}hexahydropyridinium+yl)ethyl]_2-ketoquinonequinoline-7- The carbonitrile and the dihydrochloride salt l-{2-[(3R,4SH-amino-fluorohexahydropyridinyl)ethyl}_2-keto-1,2-dihydroporphyrin-7·A Nitrile (intermediate 106, 352 Mg, 1.12 mmol, suspended in chloroform/methanol (1:1,30 mL). Add 3·keto-3,4-dihydro-2H·pyrido[3,2-b][l,4 ] 噚 -6-6-carboxaldehyde (WO 2004/058144) (299 mg, 1.68 mmol), and the reaction was refluxed overnight on 3A molecular sieves. Sodium triethoxy borohydride was added at 〇 ° C ( The residue was dissolved in dioxethane and washed with saturated sodium bicarbonate and brine. The organic phase was dried over MgSO4, EtOAc (EtOAc m.) A solution of the acetate in dichloromethane (5 ml) was prepared by adding 2.2 eq. of 4 ΝΗα in dioxane, filtered, and dried under vacuum to give the desired compound as a colorless solid. 154 mg (26%) 〇MS (ESP): 477 (ΜΗ+) vs C2 5 H2 5 FN6 03

^-NMR (DMSO-d6) δ ： 1.57 (m5 2Η) ； 2.37 (m5 2H) ； 2.58 (m? 4H)； 2.91 (m5 2H) ； 3.71 (s? 2H) ； 4.34 (m5 2H) ； 4.59 (s? 2H) ； 4.70 (m5 1H)； 6.76 (d，1H) ; 7·00 (d，1H) ; 7·28 (d，1H) ; 7.63 (d，1H) ; 7·89 (d，1H); 7.98 (d，1H) ; 8.08 (s，1H).^-NMR (DMSO-d6) δ: 1.57 (m5 2Η); 2.37 (m5 2H); 2.58 (m? 4H); 2.91 (m5 2H); 3.71 (s? 2H); 4.34 (m5 2H); 4.59 ( s? 2H) ; 4.70 (m5 1H); 6.76 (d, 1H) ; 7·00 (d, 1H); 7·28 (d, 1H); 7.63 (d, 1H); 7·89 (d, 1H) ); 7.98 (d, 1H); 8.08 (s, 1H).

127286 -167·127286 -167·

Claims (1)

200831517 十、申請專利範圍： h —種式（I)化合物：200831517 X. Patent application scope: h - compound of formula (I): 或其藥學上可接受之鹽，其中碳&quot;a&quot;與碳”b&quot;係對彼此呈 順式㈩關係、順式㈠關係、反式㈩或反式（_)關係，其 中式（I)化合物係實質上不含其對掌異構物之順式（±)混 合物，且其中 A係選自CH與N ; D係選自C-R7與N ; 其中A與D之至少一個為碳·， E係選自〇、NH及s， 其中： 1) 若R8與R9 —起形成=〇，則E為NH ;且 U)若R8與R9各為Η，則E為Ο或S ; G係選自〇與S ; J係選自C-R4與Ν; R1係選自Η、鹵基、氰基、Ci_6烷基、c26烯基與C2_6 炔基、OR1 &amp;及-N(Ri %，其中該Ci —烷基、C2 6烯基及c2_6 炔基係視情況被一或多個Rl 〇取代； Rla，於各存在處，係獨立選自Η與（^_6烷基，其中該 127286 200831517 娱:基係視情況被一或多個R2 0取代； R2係選自鹵基、氰基、Cu烷基、C2-6烯基、C2_6炔基、 -OR2a及-N(R2a)2，其中該Cp6烷基、C2_6烯基及C2_6炔基 係視情況被一或多個R2 0取代； R2a，於各存在處，係獨立選自只與心^烷基，其中該C!-6 烷基係視情況被一或多個R2 0取代； R3係選自Η、鹵基、氰基、Cb6烷基、C2-6烯基及C2-6 炔基、-OR3a以及-N(R3a)2，其中該C卜6烷基、C2_6烯基及 • C2-6炔基係視情況被一或多個R30取代； R3a，於各存在處，係獨立選自11與&lt;21-6烷基，其中該Cle6 烷基係視情況被一或多個R30取代； R4係選自Η、鹵基、氰基、-C02H、CV6烷基、C2_6烯基 及C2-6炔基，其中該(^-6烷基、C2-6烯基及C2_6炔基係視 情況被一或多個R40取代； R6係選自氟基、C!_6烷基、C2_6烯基、（：2-6炔基、-〇R6a， ^ 其中該q-6烷基、C2_6烯基及C2_6炔基係視情況被一或 多個R60取代； R6a，於各存在處，係獨立選自Η與Cu烷基，其中該C^6 烷基係視情況被一或多個R60取代； R7係選自Η、鹵基、氰基、Cl_6烷基、C2_6烯基及C2-6 炔基，其中該心·6烷基、C2_6烯基及C2_6炔基係視情況 被一或多個R7 0取代； R8與R9各為氫，或R8與R9 —起形成=〇;且 Rl〇，R2❹，妒〇，圮0，妒〇及炉〇，於各存在處，各獨立選自 127286 • 2 - 200831517 鹵基、羥基、氰基、-C02H、（V6烷基、c2_6烯基及c2_ 炔基。Or a pharmaceutically acceptable salt thereof, wherein the carbon &quot;a&quot; and carbon"b&quot; are in a cis (ten) relationship, a cis (a) relationship, a trans (ten) or a trans (_) relationship with each other, wherein the formula (I) The compound is substantially free of its cis (±) mixture of palmar isomers, and wherein the A is selected from the group consisting of CH and N; the D is selected from the group consisting of C-R7 and N; wherein at least one of A and D is carbon. , E is selected from 〇, NH and s, wherein: 1) If R8 and R9 together form =〇, then E is NH; and U) If R8 and R9 are each Η, then E is Ο or S; G system It is selected from the group consisting of hydrazine and S; the J series is selected from the group consisting of C-R4 and hydrazine; and the R1 is selected from the group consisting of anthracene, halo, cyano, Ci-6 alkyl, c26 alkenyl and C2_6 alkynyl, OR1 & and -N (Ri %, Wherein the Ci-alkyl, C2 6 alkenyl and c2_6 alkynyl groups are optionally substituted by one or more R1 ;; Rla, in each presence, is independently selected from hydrazine and (^_6 alkyl, wherein the 127286 200831517 Entertainment: The base is optionally substituted by one or more R20; R2 is selected from the group consisting of halo, cyano, Cu alkyl, C2-6 alkenyl, C2_6 alkynyl, -OR2a and -N(R2a)2, wherein The Cp6 alkyl group, the C2_6 alkenyl group and the C2_6 alkynyl group are optionally substituted by one or more R2 0 R2a, in each presence, is independently selected from the group consisting of only the alkyl group, wherein the C!-6 alkyl group is optionally substituted with one or more R20; R3 is selected from the group consisting of hydrazine, halo, cyano, Cb6 alkyl, C2-6 alkenyl and C2-6 alkynyl, -OR3a and -N(R3a)2, wherein the C 6 alkyl group, the C 2_6 alkenyl group and the C 2-6 alkynyl group are optionally treated as one or a plurality of R30 substituted; R3a, in each presence, independently selected from 11 and <21-6 alkyl, wherein the Cle6 alkyl is optionally substituted with one or more R30; R4 is selected from the group consisting of hydrazine and halo a cyano group, a -C02H, a CV6 alkyl group, a C2_6 alkenyl group, and a C2-6 alkynyl group, wherein the (^-6 alkyl group, the C2-6 alkenyl group, and the C2_6 alkynyl group are optionally substituted by one or more R40; R6 is selected from the group consisting of a fluorine group, a C!-6 alkyl group, a C2_6 alkenyl group, (: 2-6 alkynyl group, -〇R6a, ^ wherein the q-6 alkyl group, the C2_6 alkenyl group and the C2_6 alkynyl group are optionally Or a plurality of R60 substitutions; R6a, in each presence, independently selected from the group consisting of hydrazine and Cu alkyl, wherein the C1-6 alkyl group is optionally substituted with one or more R60; R7 is selected from the group consisting of hydrazine, halo, a cyano group, a Cl 6 alkyl group, a C 2_6 alkenyl group, and a C 2-6 alkynyl group, wherein the heart 6 alkyl group, the C 2_6 alkenyl group, and the C 2_6 alkyne group Depending on the situation, it is replaced by one or more R7 0; R8 and R9 are each hydrogen, or R8 and R9 together form =〇; and Rl〇, R2❹, 妒〇, 圮0, 妒〇 and furnace exist in each Each is independently selected from the group consisting of 127286 • 2 - 200831517 halo, hydroxy, cyano, -C02H, (V6 alkyl, c2_6 alkenyl and c2_alkynyl). 127286 200831517 七、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: 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：127286 200831517 VII. 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: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 127286127286
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WO2008071961A8 (en) 2009-10-22
AU2007331247A1 (en) 2008-06-19
RU2009126731A (en) 2011-01-20
PE20081511A1 (en) 2008-12-12
BRPI0720236A2 (en) 2013-12-24
NO20092655L (en) 2009-09-02
MX2009006325A (en) 2009-07-24
CO6190619A2 (en) 2010-08-19
AR064369A1 (en) 2009-04-01
ECSP099506A (en) 2009-08-28
UY30788A1 (en) 2008-07-31
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KR20090090385A (en) 2009-08-25
CA2671485A1 (en) 2008-06-19

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