TW200406394A - 1-Phenylalkyl-piperazines - Google Patents

1-Phenylalkyl-piperazines Download PDF

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TW200406394A
TW200406394A TW092116294A TW92116294A TW200406394A TW 200406394 A TW200406394 A TW 200406394A TW 092116294 A TW092116294 A TW 092116294A TW 92116294 A TW92116294 A TW 92116294A TW 200406394 A TW200406394 A TW 200406394A
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crc6
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alkyl
cyclohexyl
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TW092116294A
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Amedeo Leonardi
Gianni Motta
Carlo Riva
Elena Poggessi
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Recordati Chem Pharm
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Urology & Nephrology (AREA)
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  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Compounds of formula I, (R and R1 are a wide range of substituents, Q is CO, CHOH or CHOR2, R2 is alkyl, alkenyl, alkynyl or cycloalkyl group, each of which is optionally substituted, or is alkanoyl, alkanoyoxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminothiocarbonyl, alkylaminothiocarbonyl or dialkylaminothiocarbonyl, R3 is H, alkyl, -alkenyl, alkynyl, cycloalkyl, aryl or heterocyclic group, each of which is optionally substituted, n is 1 or 2, A is a bond or a methylene or ethylene group and R4 is an aryl or heteroaryl group, either of which is optionally substituted) have affinity for serotoninergic receptors. These compounds and their enantiomers, diastereoisomers, N-piperazine oxides; polymorphs, solvates and pharmaceutically acceptable salts are useful in the treatment of patients with neuromuscular dysfunction of the lower urinary tract and diseases related to 5-HT1A receptor activity.

Description

200406394 玖、發明說明： 【明所屬技^^領诚】 發明領域 本發明係有關對於血清素激導性受體（serotoninergic 5 receptors)具有親和性之1-苯烧基·免啡、包含它們之藥學組成物 以及此類化合物與組成物的用途。 【先前老J 發明背景 於哺乳動物，排尿(撒尿）是一複雜的過程，其需要膀胱、 10 其内與外括約肌整合的動作、骨盆底的肌肉組織與神經對這些 肌肉於三個層次的控制（於大腦皮質的控制之下腦幹（橋腦）中 的橋腦排尿中樞（pontine micturition centre，PMC)的階段之膀胱 壁或括約肌本身 '脊髓的自律中樞與中樞神經系統）（De Groat， Neurobiology 〇f Incontinence, Ciba Foundation Symposium 15 •^丄:27，1990)。排尿係由交織的平滑肌纖維所組成的迫肌收縮 所造成，迫肌係在源自薦骨脊髓的副交感自律系統的控制之下 作用。一個簡單的排泄的反射作用係由膀胱通往薦骨脊髓之有 關於痛、溫度及膨脹的感覺神經所引發。然而，由膀胱的感覺 徑亦可到達PMC，以產生神經衝動，其正常地壓抑反射弧的皮 20質抑制作用之薦骨脊柱的抑制，並鬆弛該骨盆底的肌肉與外括 約肌。最後，該迫肌收縮與排泄發生。下泌尿道功能的不正常， 例如排尿困難、失禁與遺尿，係普遍存在於一般大眾之中。排 尿困難包括尿的頻率、夜尿症與急尿，且可能是由膀胱炎（包括 間質性膀胱炎）、前列腺炎或良性前列腺肥大(BpH)(其影響大 200406394 約70%的年長男性）、或由神經性失調所引起。失禁徵候群包 括壓迫性失禁、急迫性失禁、充溢性失禁與混合性失禁。遺尿 係有關在夜間或於睡眠時尿的不隨意排出。 先前’下泌尿道神經肌肉的機能障礙之治療涉及直接作用 5 於膀胱肌肉的化合物之投藥，諸如：一種解痙藥黃銅酯 (flavoxate)(Ruffman，J· Int· Med. Res. M:3175 1988)，其對 PMC 亦為具活性的（Guarneri α/.，¢/7¾也迎:91，1994)，或 抗膽鹼激導性的（anticholinergic)化合物，諸如奥斯必得寧 (oxybutynin)(Andersson? 丛:477，1988)與托特羅定 10 (tolterodine)(Nilvebrant，h/e 5cz··赵(22-23): 2549, 2001)。為治 療BPH而使用αΐ-腎上腺素受體拮抗劑亦為常見，但係基於一 種不同的作用機制（Lepor，C/ro/ogj;，42:483, 1993)。然而，涉及骨 盆肌肉組織（包括迫肌）之直接抑制的治療可能會有不想要的副 15 作用，諸如不完全的排泄或調節癱瘓、心動快速與口乾 (Andersson，ϋ:477, 1988)。因此，較偏好使用的化合物， 其係以一種回復排尿機制之正常功能的方式經由中樞神緩系 統去作用以影響，例如薦骨脊柱反射作用及/或PMC抑制途# EP 0982304揭示合劑可被使用CNS失調的治療 諸如抑鬱。 20 【^-明内容】 發明概要 本發明係提供具有下列化學式I之化合物： 200406394200406394 发明 、 Explanation of the invention: [Technology of the Ming ^ ^ Cheng Cheng] Field of the invention The present invention relates to 1-benzyl-free phloem, free phloem, and pharyngein-free phloem, which contain affinity to serotoninergic 5 receptors. Pharmaceutical compositions and uses of such compounds and compositions. [Previously, the background of the invention of the old J in mammals. Urination (urinating) is a complicated process that requires the bladder, the internal and external sphincter integration, the pelvic floor muscle tissue and nerves to control these muscles at three levels. (The bladder wall or sphincter itself in the pontine micturition centre (PMC) stage of the brain stem (pontine) under the control of the cerebral cortex (the sphincter itself's autonomic center and central nervous system of the spinal cord)) (De Groat, Neurobiology (F Incontinence, Ciba Foundation Symposium 15 • ^ 丄: 27, 1990). The urinary system is caused by the contraction of forced muscles composed of interlaced smooth muscle fibers. The forced muscle system is under the control of the parasympathetic autonomic system derived from the sacral spinal cord. A simple excretory reflex effect is initiated by the bladder leading to the sacral spinal cord about pain, temperature, and dilated sensory nerves. However, the sensory diameter of the bladder can also reach the PMC to generate nerve impulses, which normally suppress the suppression of the sacral spine of the reflex arc, and relax the pelvic floor muscles and external sphincter. Finally, the compression muscle contraction and excretion occur. Abnormalities in the lower urinary tract, such as dysuria, incontinence, and enuresis, are common among the general public. Difficulty urinating includes the frequency of urine, nocturia and urgency, and may be caused by cystitis (including interstitial cystitis), prostatitis, or benign prostatic hypertrophy (BpH) (which affects approximately 40% of older men with 200,406,394), Or caused by neurological disorders. Incontinence syndromes include oppressive incontinence, urge incontinence, overflow incontinence, and mixed incontinence. Enuresis refers to the involuntary discharge of urine at night or during sleep. Previously, the treatment of neuromuscular dysfunction of the lower urinary tract involved the administration of compounds that act directly on the bladder muscle, such as: a spasmolytic agent, flavoxate (Ruffman, J. Int. Med. Res. M: 3175 1988), which is also active against PMC (Guarneri α /., ¢ / 7¾ also welcomes: 91, 1994), or anticholinergic compounds such as oxybutynin ( Andersson? Series: 477, 1988) and tolterodine (Nilvebrant, h / e 5cz · Zhao (22-23): 2549, 2001). The use of α 使用 -adrenergic receptor antagonists for the treatment of BPH is also common, but based on a different mechanism of action (Lepor, C / ro / ogj ;, 42: 483, 1993). However, treatments involving direct inhibition of the pelvic muscle tissue (including the perforator) may have unwanted side effects such as incomplete excretion or regulation of paralysis, rapid heart movement, and dry mouth (Andersson, ϋ: 477, 1988). Therefore, the more preferred compounds are used to affect the central nervous system in a manner that restores the normal function of the urination mechanism, such as sacral spine reflex and / or PMC inhibition # EP 0982304 reveals that the mixture can be used Treatment of CNS disorders such as depression. 20 [^-明 内容] Summary of the Invention The present invention provides compounds having the following chemical formula I: 200406394

RR

其中： R代表氫或一或更多選自於由下列所構成之群組的取代 基：（CrQ)-烷基、（CrC6)-烷氧基、（CrC6)_烷硫基、羥基、^ 5 素、（c2_c6l·烯基、（c2-c6)-炔基、（crc6)-ii 烷基、（crc6>^ 烧氧基、（CrC6)-羥烷基、烷氧烷基、硝基、胺基、（CrC士胺 烧基、（CrC6)-烷胺基-(Crc6)-烷基、（Crc6)_烷胺基、二气 烧胺基、酿胺基、（Crc6)-烷磺醯基胺基、胺磺醯基、（CrC士 烧胺基磺醯基、氰基、胺羰基、烷胺羰基、N，队二 10 -(C「C6)-烧胺羰基、（Crc0)-烷氧羰基、（Crc6)-烷羰基、烷羰 烷基、曱醯基、烷醯基氧基烷基、（CrC6)-烷胺羰基胺基、（Crc6)_ 烧亞石戸'6&基、（CrC6)-烧石黃醯基，以及N-二-(C^-Cg)-烧胺石黃 酿基基團； R!代表一選自於由下列所構成之群組的成員：氫、環烷 15基、芳基、芳氧基、芳烧基、芳烧氧基、雜環狀基、雜環氧基、 雜環烷基以及雜環烷氧基基團，各個基團被選擇性取代以一或 更多如上所定義之取代基R ; Q代表-c(〇)-或-CH(0R2)_，其中R2代表一選自於由下列 所構成之成員：氫、（crC6)-烷基、（cvc^烯基、（C2_C6)_炔基 20以及環烷基基團，其中各個基團被選擇性取代以一或更多選自 200406394 於R5與R6之基團，其中R5係選自於由下列所構成之群組： 鹵素、（CrC6)-烷氧基、（CrC6：l·鹵烷氧基、氰基、（CrC6)-烷氧 羰基、（CrC6)-烷羰基、烷氧烷基、胺羰基、N-(CrC6)-烷胺羰 基、N，N-二-(CrC6)-烷胺羰基基團，而R6係選自於由下列所構 5 成之群組：芳基、雜芳基、芳氧基、雜芳氧基、芳烷氧基，以 及雜芳烷氧基基團（各個基團被選擇性取代以R)，或者R2代表 -C(0)-(Ci_C6)-烧基、-C(0)0_(Ci-C6)-烧基、-C(〇)NR7R8 或 -C(S)NR7R8，其中仏與尺8係分別為氫或(CKC6)-烷基； R3代表氮或一（Ci-C6)-烧基、（C2-C6)-細基、（C2-C6)-快基、 10 環烷基、芳基或雜環基基團，各個基團被選擇性取代以一或更 多如上所定義之取代基R或Ri ; R4代表一芳基或雜環狀基，各個被選擇性取代以一或更多 如上所定義之取代基R; A代表一鍵或（CH2)n ;以及 15 η = 1 或 2， 或該化合物之一鏡像異構物、光學異構物、非鏡像異構 物、Ν-氧化物（例如，Ν-哌讲氧化物）、結晶形式、水合物、溶 劑化物或藥學上可接受的鹽類。 如在R6之定義中所引述的：芳基、雜芳基、芳氧基、雜芳 20 氧基、芳烷氧基以及雜芳烷氧基基團可被選擇性取代以一或更 多選自於由下列所構成之群組的取代基：（Ci_C6)_烧基、（C!-C6)-烷氧基、（crc6)-烷硫基、羥基、鹵素、（c2-c6)·烯基、（c2-c6)-炔基、（crc6)-鹵烷基、（crc6)-鹵烷氧基、（crc6)-羥烷基、烷 氧烧基、梢基、胺基、（Ci_C6)_胺烧基、（Ci_C6)-烧基胺-(Ci_C6)- 200406394 烷基、（crc6)-烷胺基、二(crc6)-烷胺基、醯胺基、（crc6)-烷 石黃酿基胺基、胺續驢基、（Ci_C6) -烧胺橫酿基、鼠基、胺被基、 N^CrQ)-烷胺羰基、N，N-二-(CrC6)-烷胺羰基，（CrC6)-烷氧羰 基、（CrC6)-烷羰基、甲醯基、烷羰烷基、烷醯基氧基烷基、 5 (CrC6)-烷胺羰基胺基、（CrC6)-烷亞磺醯基、（CrC6)-烷磺醯 基’以及Ν，Ν-二-(Ci-C6)-烧胺石黃酿基基團。 在較佳具體例中，Q代表-CH(OR2)-，其中R2係為如上面 所定義者。 在一較佳具體例中，本發明提供如上所定義之具有化學式 10 I之化合物，但有條件是：化學式I之該等取代基不會是會使得 同時有 氫或（Crc6)-烷基、素、Q=-C(0)-或-CH(OR2)-， 其中氫、R3=環烷基或烷基以及R4二一被取代以一選自於由 下列所構成群組中的成員的苯基：（CrC6)-烷基、（CrC6)-烷氧 基以及（Ci-Cs)-鹵烧氧基基團，A係為·鍵結’且n= 1。 15 在另一較佳具體例中，本發明提供如上面所定義之具有化 學式I之化合物，但有條件是：化學式I之該等取代基不會使 得同時有Q=-CH(OR2)，其中R2=H ; R3二環烷基；R=2-氟基、 Rf Η、R4二2-甲氧基苯基或2-(2,2,2-三氟乙氧基)-苯基，A= — 鍵結，且n=l。 20 此外較佳的係為一具體例，其中本發明提供如上面所定義 之具有化學式I之化合物，但有條件是：化學式I之取代基不 會使得同時有Q二-c(0)-或-CH(OR2)-，其中R2=氫；R严Η、苯 基或經鹵素取代之苯基、（CrC6)-烷基或(CrC6)-烷氧基；R=H、 (CrC6)-烷基、（CrC6)-烷氧基、鹵素、鹵烷基、硝基、胺基、 200406394Where: R represents hydrogen or one or more substituents selected from the group consisting of: (CrQ) -alkyl, (CrC6) -alkoxy, (CrC6) -alkylthio, hydroxyl, ^ 5 elements, (c2_c6l · alkenyl, (c2-c6) -alkynyl, (crc6) -ii alkyl, (crc6 > ^ alkenyloxy, (CrC6) -hydroxyalkyl, alkoxyalkyl, nitro, Amine group, (CrC stilbene group, (CrC6) -alkylamino group- (Crc6) -alkyl group, (Crc6) -alkylamino group, two-gas amine group, amine group, (Crc6) -alkanesulfonyl group Aminoamino, sulfamoyl, (CrC-sulfonylaminosulfonyl, cyano, aminecarbonyl, alkylaminocarbonyl, N, acetyl 2-10-(C "C6) -alkylaminocarbonyl, (Crc0) -alkyl Oxycarbonyl, (Crc6) -alkoxycarbonyl, alkoxyalkyl, fluorenyl, alkanoyloxyalkyl, (CrC6) -alkylaminocarbonylamino, (Crc6) -pyridine'6 & group, ( CrC6) -burntite stilbene, and N-di- (C ^ -Cg) -burntite sulfuryl group; R! Represents a member selected from the group consisting of: hydrogen, naphthene 15 Aryl, aryl, aryloxy, aralkyl, aralkyl, heterocyclic, heterocyclooxy, heterocycloalkyl, and heterocycloalkoxy groups Each group is optionally substituted with one or more substituents R as defined above; Q represents -c (〇)-or -CH (0R2) _, where R2 represents a member selected from the group consisting of : Hydrogen, (crC6) -alkyl, (cvc ^ alkenyl, (C2_C6) _alkynyl 20, and cycloalkyl groups, where each group is selectively substituted with one or more selected from 200406394 in R5 and R6 R5 is selected from the group consisting of: halogen, (CrC6) -alkoxy, (CrC6: 1 · haloalkoxy, cyano, (CrC6) -alkoxycarbonyl, CrC6) -alkylcarbonyl, alkoxyalkyl, aminecarbonyl, N- (CrC6) -alkylaminecarbonyl, N, N-di- (CrC6) -alkylaminecarbonyl group, and R6 is selected from the group consisting of 5 groups: aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, and heteroarylalkoxy groups (each group is optionally substituted with R), or R2 represents -C (0)-(Ci_C6) -alkyl, -C (0) 0_ (Ci-C6) -alkyl, -C (〇) NR7R8 or -C (S) NR7R8, where 仏 and ruler 8 are respectively Hydrogen or (CKC6) -alkyl; R3 represents nitrogen or mono (Ci-C6) -alkyl, (C2-C6) -fine, (C2-C6) -quick, 10 ring Alkyl, aryl or heterocyclyl groups, each group is optionally substituted with one or more substituents R or Ri as defined above; R4 represents an aryl or heterocyclic group, each of which is selectively substituted With one or more substituents R as defined above; A represents a bond or (CH2) n; and 15 η = 1 or 2, or one of the compounds isomers, optical isomers, non-mirror isomers Compounds, N-oxides (e.g., N-pentoxide), crystalline forms, hydrates, solvates, or pharmaceutically acceptable salts. As quoted in the definition of R6: aryl, heteroaryl, aryloxy, heteroaryl20oxy, aralkoxy and heteroaralkoxy groups may be optionally substituted with one or more options Substituents from the group consisting of: (Ci_C6) _alkyl, (C! -C6) -alkoxy, (crc6) -alkylthio, hydroxyl, halogen, (c2-c6) · ene (C2-c6) -alkynyl, (crc6) -haloalkyl, (crc6) -haloalkoxy, (crc6) -hydroxyalkyl, alkoxyalkyl, pinyl, amine, (Ci_C6) _Amine group, (Ci_C6) -Amentylamine- (Ci_C6)-200406394 alkyl group, (crc6) -Alkylamino group, bis (crc6) -Alkylamino group, amidoamine group, (crc6) -Alkyl yellow group Amine group, amine group, (Ci_C6) amine group, murine group, amine group, N ^ CrQ) -alkylamine carbonyl group, N, N-di- (CrC6) -alkylamine carbonyl group, ( CrC6) -alkoxycarbonyl, (CrC6) -alkoxycarbonyl, methylamino, alkylcarbonylalkyl, alkylfluorenyloxyalkyl, 5 (CrC6) -alkylaminocarbonylamino, (CrC6) -alkylsulfinyl Group, (CrC6) -alkanesulfonyl group ', and N, N-di- (Ci-C6) -carbamine pyrazinyl group. In a preferred embodiment, Q represents -CH (OR2)-, where R2 is as defined above. In a preferred embodiment, the present invention provides a compound having the chemical formula 10 I as defined above, provided that the substituents of the chemical formula I will not cause hydrogen or (Crc6) -alkyl, Element, Q = -C (0)-or -CH (OR2)-, in which hydrogen, R3 = cycloalkyl or alkyl and R4 are substituted with one selected from members of the group consisting of Phenyl: (CrC6) -alkyl, (CrC6) -alkoxy and (Ci-Cs) -halohaloxy group, A is 'bonded' and n = 1. 15 In another preferred embodiment, the present invention provides a compound of formula I as defined above, provided that the substituents of formula I do not cause Q = -CH (OR2) simultaneously, where R2 = H; R3 dicycloalkyl; R = 2-fluoro, Rf Η, R4 di2-methoxyphenyl or 2- (2,2,2-trifluoroethoxy) -phenyl, A = — Bonded, and n = l. 20 A further preferred system is a specific example, in which the present invention provides a compound having the formula I as defined above, provided that the substituent of the formula I does not cause the simultaneous presence of di-c (0)-or -CH (OR2)-, where R2 = hydrogen; R strictly, phenyl or halogen-substituted phenyl, (CrC6) -alkyl or (CrC6) -alkoxy; R = H, (CrC6) -alkane (CrC6) -alkoxy, halogen, haloalkyl, nitro, amine, 200406394

(Ci-C6)-烷胺基或二-(CrC6：l·烷胺基；R4係為一未經取代之芳 基、未經取代之雜芳基或一芳基或雜芳基基團經取代以一或更 多選自於由下列所構成之群組之取代基：（crc6)·烷基、（crc6)-烷氧基、鹵素、（crc6)-鹵烷基、硝基、胺基、（crc6)-烷胺基、 5 二-(CrC6)-烷胺基、羥基、（CrC6)-羥烷基、-CONR7R8，其中 R7與R8係分別為氫或（CVC6)-烷基，以及-NHS02-(CrC6)-烷基 基團；A係為一鍵結；而R3代表未經取代之芳基、未經取代之 雜芳基、或芳基或雜芳基經取代以一或更多選自於由下列所構 成之群組之取代基：（crc6)-烷基、（crc6)-烷氧基、鹵素、 10 (Ci_C6)-鹵烧基、石肖基、胺基、（Ci_C6)-烧胺基、二-(C]-C6)-烧 胺基、苯基、鹵苯基、（cKc6)-烷苯基以及(crc6)-烷氧苯基基 團。(Ci-C6) -alkylamino or di- (CrC6: l · alkylamino; R4 is an unsubstituted aryl, unsubstituted heteroaryl, or an aryl or heteroaryl group. Substitution with one or more substituents selected from the group consisting of (crc6) alkyl, (crc6) -alkoxy, halogen, (crc6) -haloalkyl, nitro, amine (Crc6) -alkylamino, 5 di- (CrC6) -alkylamino, hydroxyl, (CrC6) -hydroxyalkyl, -CONR7R8, where R7 and R8 are hydrogen or (CVC6) -alkyl, respectively, and -NHS02- (CrC6) -alkyl group; A is a single bond; and R3 represents unsubstituted aryl, unsubstituted heteroaryl, or aryl or heteroaryl substituted with one or more Substituents mostly selected from the group consisting of: (crc6) -alkyl, (crc6) -alkoxy, halogen, 10 (Ci_C6) -halohalo, stone oxo, amine, (Ci_C6)- Carboamino, di- (C) -C6) -carboamino, phenyl, halophenyl, (cKc6) -alkphenyl, and (crc6) -alkoxyphenyl groups.

此外較佳的係為一具體例，其中本發明提供如上面所定義 之具有化學式I之化合物，但有條件是：化學式I之取代基不 15 會使得同時有Q=-C(0)-或-CH(OR2)-，其中R2=氫；R严Η或未 經取代之環烷基或經(CVC6)-烷基取代之環烷基；R=H、（CrC6)-烷基、（CrC6)-烷氧基、鹵素、（CrC6)-鹵烷基、（CrC6)-烷硫基、 (C2-C6)-烯基或(C2-C6)-炔基；R4係為一未經取代之芳基、未經 取代之雜芳基、或一芳基或雜芳基經取代以一至三個選自於由 20 下列所構成之群組之取代基：（CrC6)-烷基、（CrC6)-烷氧基、 鹵素、（crc6)-鹵烷基、（CrC6)-烷硫基、（c2-c6)-烯基以及 (C2-C6)_炔基基團；A係為一鍵；而R3代表未經取代之苯基、 未經取代之萘基或未經取代之環烷基，或苯基、萘基或環烷基 經取代以一至三個選自於由下列所構成之群組之取代基： 10 200406394 (crc6)-烷基、（crc6)-烷氧基、鹵素、（crc6)-鹵烷基、（crc6)-烷硫基、（c2-c6)-烯基以及（c2-c6)-炔基基團。 在各個較佳具體例中，進一步較佳的，Q係為-CH(OR2)-。 化學式I化合物可以四種立體異構物的形式存在，其可以 5 外消旋混合物或以任何其他組合出現。外消旋混合物可被解 析，亦即被鏡像濃化以生成一特定的鏡像異構物被濃化的組成 物。鏡像異構的濃化可以如下所定義的ee (鏡像異構的過量）來 表示。 一些根據本發明之較佳的化合物係說明於實施例中。 10 本發明亦包括前述之具相同類型活性的化合物之代謝 物，在下文中被指為活性代謝物。 本發明亦意欲包含那些在體内會被代謝以生成任一前述 化合物之前驅藥物。 於另一實施例中，本發明提供藥學組成物，其包含有：化 15 學式I化合物或該化學式I化合物之鏡像異構物、光學異構物、 非鏡像異構物、N-氧化物、結晶形式、水合物、溶劑化物或藥 學上可接受的鹽類，並混合以一藥學上可接受的稀釋劑或載劑 (諸如那些已被揭示的）。 在另一具體例中，本發明提供有利於合成化學式I之化合 20 物的中間產物。這些當中的一些被包括在申請專利範圍中。 又另一實施例係為一種於一有需要降低因膀胱膨脹所致 的膀胱收縮之頻率的哺乳動物（諸如人類）體内降低膀胱收縮頻 率的方法，其係藉由投藥一有效量之至少一種本發明化合物給 該哺乳動物，俾以降低因膀胱膨脹所致之膀胱收縮的頻率。 200406394 又另一實施例係為一種於一有需要增加尿液膀胱容量的 哺乳動物（諸如人類）體内增加尿液膀胱容量的方法，此係藉由 投藥一有效量之至少一種本發明化合物給該哺乳動物，俾以增 加尿液膀胱容量。 5 又另一實施例係為一種於一有需要治療尿路失調的哺乳 動物（諸如人類）體内治療尿路失調的方法，此係藉由投藥一有 效量之至少一種本發明化合物，俾以改善至少一種以下狀況： 尿急迫、膀胱活動過度、尿頻率增加、尿依從減少（膀耽儲存容 量減少）、膀胱炎（包括間質性膀胱炎）、失禁、漏尿、遺尿、排 10 尿困難、排尿的遲疑及排空膀胱的困難。 於又另外的實施例中，本發明提供治療以上失調的方法， 其係藉由投藥一具有化學式I的化合物並結合其他試劑，諸 如，例如：一或多種額外的5HTM拮抗劑、抗葦毒作用 (antimuscarinic)藥物、od-腎上腺素拮抗劑、環加氧崎抑制,， 15該酶可抑制COX1與COX2同功酶二者，或任擇地可對 同功酶及NO供予體其衍生物具選擇性。 在又另一具體例中’本發明提供一種用以治療由於血清素 激導性官能障礙(serotoninergic dysfunction)而罹患中抱神柄系 統(CNS)病症之哺乳動物的方法，其係藉由投予一有效劑量之 20至少一本發明之化合物以治療該CNS病症。此等官能障礙包 括，但非被限制於，焦慮、抑鬱、壓力過高、睡醒週期病症 (sleep/wake cycle disorder)、進食、行為、性的官能障礙以及在 哺乳類動物中（特別地在人類）與撞擊、損傷、癡呆有關之認識 力病症，以及源自於神經學上的發展、注意力不足活動性過度 12 200406394 病症（attention-deficit hyperactivity，ADHD)、藥瘺、藥物脫痛 (drug withdrawal)、刺激性-腸徵候簇（irritable-bowel Syndrome) 以及自使用尼古丁或菸草中脫癮或部分脫癮所造成之徵狀。 在又另一具體例中，本發明提供一種藉由投予一本發明之 5化合物至一 5-HTia血清素激導性受體的環境中，例如至細胞 外培養基（或經由全身性地或局部性地投藥至一擁有此一 5-HT1A受體之哺乳動物），作為治療由於血清素激導性官能障礙 所造成之病症的方法，呈一數量之有效於治療由於血清素激導 性官能障礙所造成該病症的一本發明之化合物。 10 在一較佳具體例中，本發明提供藉由投予以一有效的去增 加膀胱靜止期間之劑量的至少一本發明之化合物至一 受體的環境中作為治療一罹患一尿道録之哺乳類動物（包括 人類）的方法。更大較佳地係其中增加膀胱靜止期間達到了在排 尿壓力上些微的或無影響（例如，減少或增加）。 15 【實方包方式】 較佳實施例之詳細說明 化合__ 本發明係關於如上所揭露之化學式之化合物。本發明包 括鏡像異構物、非對映異構物、.辰啡氧化物、結晶形式、水 20合物、溶劑化物或這些化合物在藥學上可接受的鹽類，還有 具有相同活性型態之這些化合物的活性新陳代謝物。 ”鹵烷基”該用詞包括經一個單一 _素原子（單•基)取代 之烷基以及那些經超過一個_素原子（聚齒烷基）所取代者。後 者之實例係為三-氟基甲基與2以三氟基乙基基團。“齒烧氧 13 200406394 基”該用詞應予以被對應地解釋。較佳的鹵烷氧基包括三氟曱氧 基與2,2,2-二氟乙氧基基團。 ’’芳基’’該用詞，單獨地或組合地，意指一包含1、2或3個 環之碳環芳族系統，其中此等環可以一串聯方式被繫附在一起 5 或可被併合。’’芳基π該用詞包括芳族自由基諸如苯基、萘基、 四氫萘基、氫茚以及聯苯。In addition, a preferred example is a specific example, in which the present invention provides a compound having the chemical formula I as defined above, provided that the substituent of the chemical formula I is not 15 will cause Q = -C (0)-or -CH (OR2)-, where R2 = hydrogen; R strictly or unsubstituted cycloalkyl or cycloalkyl substituted with (CVC6) -alkyl; R = H, (CrC6) -alkyl, (CrC6 ) -Alkoxy, halogen, (CrC6) -haloalkyl, (CrC6) -alkylthio, (C2-C6) -alkenyl or (C2-C6) -alkynyl; R4 is an unsubstituted Aryl, unsubstituted heteroaryl, or monoaryl or heteroaryl substituted with one to three substituents selected from the group consisting of (CrC6) -alkyl, (CrC6) -Alkoxy, halogen, (crc6) -haloalkyl, (CrC6) -alkylthio, (c2-c6) -alkenyl, and (C2-C6) -alkynyl groups; A is a single bond; and R3 represents unsubstituted phenyl, unsubstituted naphthyl or unsubstituted cycloalkyl, or phenyl, naphthyl or cycloalkyl is substituted with one to three selected from the group consisting of Substituents: 10 200406394 (crc6) -alkyl, (crc6) -alkoxy, halogen, (crc6)- Alkyl, (crc6) - alkylthio, (c2-c6) - alkenyl and (c2-c6) - alkynyl groups. In each preferred embodiment, it is further preferred that Q is -CH (OR2)-. Compounds of formula I may exist in the form of four stereoisomers, which may occur as racemic mixtures or in any other combination. The racemic mixture can be resolved, i.e., image-concentrated to produce a specific image-isomer-concentrated composition. Concentration of mirror image isomers can be expressed as ee (mirro image excess) as defined below. Some preferred compounds according to the invention are illustrated in the examples. 10 The present invention also includes the aforementioned metabolites of compounds of the same type of activity, which are hereinafter referred to as active metabolites. The invention is also intended to include prodrugs that are metabolized in the body to produce any of the foregoing compounds. In another embodiment, the present invention provides a pharmaceutical composition comprising: a compound of formula I or a mirror image isomer, an optical isomer, a non-image isomer, and an N-oxide of the compound of formula I , Crystalline form, hydrate, solvate or pharmaceutically acceptable salt, and mixed with a pharmaceutically acceptable diluent or carrier (such as those already disclosed). In another embodiment, the present invention provides an intermediate product which is advantageous for synthesizing the compound of Formula I. Some of these are included in the scope of patent applications. Yet another embodiment is a method for reducing the frequency of bladder contraction in a mammal (such as a human) in need of reducing the frequency of bladder contraction due to bladder inflation, by administering at least one effective amount of The compound of the present invention is administered to the mammal to reduce the frequency of bladder contraction due to bladder swelling. 200406394 Yet another embodiment is a method for increasing urine bladder capacity in a mammal (such as a human) in need of increasing urine bladder capacity by administering an effective amount of at least one compound of the present invention to The mammal gnawed to increase urine bladder capacity. 5 Yet another embodiment is a method for treating a urinary tract disorder in a mammal (such as a human) in need of treatment of a urinary tract disorder by administering an effective amount of at least one compound of the present invention to Improve at least one of the following conditions: urgency, overactive bladder, increased urinary frequency, decreased urinary compliance (decreased bladder storage capacity), cystitis (including interstitial cystitis), incontinence, leaking urine, enuresis, dysuria Hesitation to urinate and difficulty in emptying the bladder. In yet another embodiment, the present invention provides a method for treating the above disorders by administering a compound of formula I in combination with other agents, such as, for example, one or more additional 5HTM antagonists, anti-reed effects (antimuscarinic) drugs, od-adrenergic antagonists, cyclooxygenase inhibitors, 15 This enzyme can inhibit both COX1 and COX2 isoenzymes, or optionally derivatives of isoenzymes and NO donors Be selective. In yet another embodiment, the present invention provides a method for treating a mammal suffering from a CNS disorder due to serotoninergic dysfunction, which is administered by administering An effective dose of at least one compound of the invention is 20 to treat the CNS disorder. These dysfunctions include, but are not limited to, anxiety, depression, high stress, sleep / wake cycle disorder, eating, behavior, sexual dysfunction, and in mammals (especially in humans) ) Cognitive disorders related to impacts, injuries, and dementia, and derived from neurological development, attention deficit hyperactivity 12 200406394 Attention-deficit hyperactivity (ADHD), drug fistula, drug withdrawal ), Irritable-bowel syndrome, and symptoms caused by withdrawal or partial withdrawal from nicotine or tobacco use. In yet another specific example, the present invention provides an environment by administering a 5 compound of the present invention to a 5-HTia serotonin-stimulating receptor, for example, to an extracellular medium (or via a systemic or Topical administration to a mammal with this 5-HT1A receptor) as a method of treating conditions caused by serotonin-induced dysfunction, in a quantity effective for the treatment of serotonin-induced dysfunction A compound of the present invention that causes the disorder. 10 In a preferred embodiment, the present invention provides for the treatment of a mammal suffering from a urinary tract by administering an effective amount of at least one compound of the present invention to a recipient's environment during quiescence of the bladder. (Including humans). Larger and better are those in which a slight or no effect on urinary pressure (e.g., decrease or increase) is achieved during increased bladder quiescence. 15 [Solid package method] Detailed description of the preferred embodiment Chemical combination __ The present invention relates to a compound of the chemical formula disclosed above. The present invention includes mirror image isomers, diastereomers, cinnaphine oxides, crystalline forms, hydrates 20, solvates or pharmaceutically acceptable salts of these compounds, as well as having the same active form The active metabolites of these compounds. The term "haloalkyl" includes alkyl groups substituted with a single prime atom (mono) and those substituted with more than one prime atom (polydentyl). Examples of the latter are tri-fluoromethyl and 2-trifluoroethyl groups. The term "tooth burns oxygen 13 200406394 basis" should be interpreted accordingly. Preferred haloalkoxy groups include trifluorofluorenyl and 2,2,2-difluoroethoxy groups. The term `` aryl '', alone or in combination, means a carbocyclic aromatic system containing 1, 2, or 3 rings, where these rings can be tied together in a cascade 5 or may Be merged. The term ' aryl? Includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, hydrogenindene, and biphenyl.

”雜環狀(heterocyclic)’’與’’雜環(heterocyclo)’’該等用詞意指 飽和、部分飽和以及不飽和之含有雜原子的環形自由基，其中 該等雜原子係可選自於氮、硫以及氧。飽和雜環狀自由基之實 10 例包括：包含有1至4個氮原子之飽和雜單環基團（例如，^比 略σ定基、味°坐σ定基、N-六氫咕σ定基、六氫吼讲基）；包含有1 至2個氧原子以及1至3個氮原子之飽和雜單環基團（例如， 嗎福啉基）；包含有1至2個硫原子以及1至3個氮原子之飽和 雜單環基團（例如，四氫噻唑基）。部分飽和雜環狀自由基之實 15 例包括：二羥噻吩、二羥哌喃、二羥呋喃以及二羥噻唑。The terms "heterocyclic" and "heterocyclo" mean saturated, partially saturated, and unsaturated heteroatom-containing cyclic radicals, wherein the heteroatoms are selected from For nitrogen, sulfur, and oxygen. Examples of saturated heterocyclic free radicals include: saturated heteromonocyclic groups containing 1 to 4 nitrogen atoms (for example, ^ slightly sigma, sigma sigma, N -Hexahydrostilbyl, hexahydrocarbyl); saturated heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (eg, morpholinyl); containing 1 to 2 Saturated heteromonocyclic groups with 1 sulfur atom and 1 to 3 nitrogen atoms (for example, tetrahydrothiazolyl). Examples of partially saturated heterocyclic free radicals include: dihydroxythiophene, dihydroxypiperan, dihydroxy Furan and dihydroxythiazole.

“雜環”與”雜環狀”該等用詞包含該用詞”雜芳基”，其係意 指不飽和雜環狀自由基。’’雜芳基"自由基之實例包括：包含有 1至個4氮原子之不飽和的5至6員雜單環基團，例如，吡咯 基、π比洛。林基、π米哇基、ϋ比ϋ坐基、定基、3-。比咬基、4-。比 20 σ定基、。密°定基、井基、塔°井基、三哇基（例如，411-1，2,4-三嗤 基、1Η-1，2,3-三唑基、2Η-1，2,3-三唑基）、四唑基（例如，1Η-四 σ坐基、2Η-四σ坐基）；包含1至5個氮原子之不飽和經縮合的雜 環狀基，例如，，嗓基、異叫丨嗓基、卜井基、苯并味σ坐基、4 琳基、異11奎琳基、吲σ坐基、苯三σ坐基、四氮呃并塔讲基(例如， 14 200406394 四氮呃并[U-b]嗒啩基）；包含一個氧原子之不飽和3至6員雜 單環基團，例如，°底喃基、2-咬喃基、3-咬喃基；包含一個硫 原子之不飽和5至6員雜單環基團，例如，2-噻吩基、3-噻吩 基；包含1至2個氧原子以及1至3個氮原子之不飽和5至6 5 員雜單環基團，例如，4 σ坐基、異4 σ坐基、二嗤基(oxadiazolyl) (例如，1，2,4-噚二唑基、1，3,4-噚二唑基、1，2,5-哼二唑基）；包 含1至2個氧原子以及1至3個氮原子之不飽和經縮合的雜環 狀基團（例如，苯并坐基、苯并二哇基benzoxadiazolyl); 包含1至2個硫原子以及1至3個氮原子之不飽和5至6-員 10 雜單環基團，例如，嗔°坐基、嘆二吐基(thiadiazolyl)(例如，1，2,4-噻二唑基、1，3,4-噻二唑基、1,2,5-噻二唑基）；包含1至2個硫 原子以及1至3個氮原子之不飽和經縮合的雜環狀基團（例如， 苯并噻唑基、苯并噻二唑基）以及類似之物。該用詞’’雜芳基’’ 亦意指自由基，其中雜環狀自由基被併合以芳基自由基。此等 15 併合的雙環自由基之實例包括苯并呋喃、笨并噻吩，以及類似 之物。該”雜環狀基’’可具有諸如1至3個取代基，例如且不需 限定於，低級烷基、羥基、侧氧、胺基以及低級烷胺基。較佳 的雜環狀自由基包括五至十員之併合或非併合自由基。雜芳基 自由基之實例包括苯并呋喃基、2,3-二氫苯并呋喃基、苯并噻 20 吩基、吲嗓基、二羥吲嗓基、吱基、苯并°底喃、硫吱基、 苯并硫代°底喃、苯并二噚唑基(benzodioxolyl)、苯并二哼烧基 (benzodioxanyl)、吼。定基、嚷吩基、嚷。坐基、4σ坐基、吱σ南基， 以及0比σ井基。 ”環烷基”該用詞意指具有3至10個碳原子之飽和碳環自由 15 200406394 基。較佳環烷基自由基係為具有三至七個碳原子之，，紅2 m 低級環烷基 自由基。包括自由基之實例諸如環丙基、環丁基、 後戊基、環 己基以及環庚基。一最佳的環烷基係為環己基。 ’’醯基"該用詞，不論單獨使用，或在一諸如卜好 ^胺基”的用 5 詞中，代表一自一羧酸移除羥基後之殘餘基團所提供的自由 基。較佳的醯基係為烷醯基，諸如乙醯基。The terms "heterocyclic" and "heterocyclic" include the term "heteroaryl", which means an unsaturated heterocyclic radical. Examples of the '' heteroaryl 'include: an unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, π billow. Lin Ji, π Miwaji, ϋ Biϋ sitting base, fixed base, 3-. Than bite base, 4-. More than 20 σ fixed base. Dense °, well foundation, tower ° well foundation, triwaxy (for example, 411-1,2,4-trisyl, 1Η-1,2,3-triazolyl, 2Η-1,2,3- Triazolyl), tetrazolyl (e.g., 1Η-tetrasigma, 2Η-tetrasigma); unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as, Synonyms 丨 Horyl, Bujingi, Benzo sigma group, 4 linyl group, iso 11 quelinyl group, ind σ group, benzotris sigma group, tetrazine benzoyl group (for example, 14 200406394 Tetrazine [Ub] pyridyl); unsaturated 3- to 6-membered heteromonocyclic groups containing one oxygen atom, for example, ° -base, 2-branyl, 3-branyl; containing one Unsaturated 5- to 6-membered heteromonocyclic group of sulfur atom, for example, 2-thienyl, 3-thienyl; Unsaturated 5 to 6 5-membered heterocycle containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms Monocyclic groups such as, for example, 4 sigma, iso4 sigma, oxadiazolyl (for example, 1,2,4-fluoradiazolyl, 1,3,4-fluoradiazolyl, 1 , 2,5-humidazolyl); unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. Benzoxadiazolyl); unsaturated 5 to 6-membered 10 heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, Thiadiazolyl (eg, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl); contains 1 to 2 sulfur Atoms and unsaturated condensed heterocyclic groups of 1 to 3 nitrogen atoms (for example, benzothiazolyl, benzothiadiazolyl) and the like. The term '' heteroaryl '' also means a free radical in which a heterocyclic radical is combined with an aryl radical. Examples of these 15-combined bicyclic radicals include benzofuran, benzothiophene, and the like. The "heterocyclic group" may have, for example, 1 to 3 substituents, and is not limited to, lower alkyl, hydroxyl, pendant oxygen, amine, and lower alkylamino. Preferred heterocyclic radicals Includes five to ten members of fused or non-fused radicals. Examples of heteroaryl radicals include benzofuranyl, 2,3-dihydrobenzofuranyl, benzothio 20 phenyl, indyl, dihydroxy Indyl, acetyl, benzo ° anan, sulfanyl, benzothio ° anan, benzodioxolyl, benzodioxanyl, hydrazone Phenyl, fluorene. Sorry, 4sigma, sigma, and 0 to sigma. "Cycloalkyl" This term means a saturated carbocyclic free 15 200406394 group having 3 to 10 carbon atoms. A preferred cycloalkyl radical is a lower 2 m red cycloalkyl radical having three to seven carbon atoms. Examples of radicals include cyclopropyl, cyclobutyl, post-pentyl, cyclohexyl, and Cycloheptyl. A preferred cycloalkyl system is cyclohexyl. The term "fluorenyl", whether used alone or in an amino group such as 5 with the word, represents a radical from a carboxylic acid residue after the removal of hydroxyl groups provided. A preferred fluorenyl group is an alkylfluorenyl group, such as ethenyl.

此處所揭露之一化合物之，，新陳代謝物'’係為—化人物之 衍生物，其係當該化合物被新陳代謝時所形成的。該用1 “、舌 性新陳代謝物，，意指一化合物之生物學上的活性衍生物，其係者 10 該化合物被新陳代謝時所形成的。該用詞“新陳代謝，，音^ 一特 殊的物質在活體中被改變時過程之總合。所有出現在身體内之 化合物係經由酵素在身體中之處理為了衍生出能量與/或從身 體移除它們。特殊的酵素對該化合物產生特殊的構造上的改 變。例如細胞色素P450催化多樣的氧化與還原反應。尿核苔 15 二磷酸尿甘酸轉移酶（Uridine diphosphate glucuronyltransferases)，例如，催化一活化的尿甘酸分子轉移 至芳族醇、脂族醇、羧酸、胺以及自由氫硫基基團。更進一步 在新陳代謝上的資訊可自The Pharmacological Basis of ΤΤζπ叩9th Edition, McGraw-Hill (1996)，pages 11-17 中獲 20 得。 於此處所揭露之該等化合物之該等新陳代謝物可藉由將 化合物投藥至一宿主並分析由該宿主而來之組織檢體，亦或藉 由將化合物與肝臟細胞或其他活體外系統諸如細胞色素或原 16 200406394 漿微粒作培養，並且分析所產生的化合物而被鑑定。這兩種方 法已被本技藝所熟知。 如此處所用的，’’立體異構物’’此詞意指一由相同的原子經 由相同键的鍵結所構成但具有不同的三次元結構的化合物，其 5 係為不可互換的。該等三次元結構被稱為組態。如此處所用 的，’’鏡像異構物’’此詞意指二個立體異構物它們的分子係非超 級不可能互為鏡像。如此處所用的，’’光學異構物π此詞係為等 效於’’鏡像異構物’’此詞。相互為立體異構物，但相互不為鏡像 異構物之化合物被稱為非對映異構物。’’消旋物’’或’’消旋混合物 10 ’’此詞意指一鏡像異構物之相等部分的混合物。’’對掌中心’’此詞 意指一繫附有四個不同基團之碳原子。如此處所用的”鏡像異構 性強化"此詞係意指一鏡像異構物相較於另一者在數量上的增 加。一簡便的達到表示該鏡像異構性強化之方法係為鏡像超越 值的概念，或’’ee”，其係使用下列的方程式而被算出：Among the compounds disclosed herein, the metabolite '' is a derivative of a human figure, which is formed when the compound is metabolized. The use of "1", linguistic metabolites, means a biologically active derivative of a compound, which is 10 when the compound is metabolized. The term "metabolism, a special substance The sum of processes when changed in a living body. All compounds present in the body are processed in the body by enzymes in order to generate energy and / or remove them from the body. Special enzymes cause special structural changes to the compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions. Uridine diphosphate 15 Uridine diphosphate glucuronyl transferases, for example, catalyze the transfer of an activated uric acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free hydrogen sulfide groups. Further information on metabolism can be obtained from The Pharmacological Basis of ΤΤζπ 叩 9th Edition, McGraw-Hill (1996), pages 11-17. The metabolites of the compounds disclosed herein can be by administering the compound to a host and analyzing tissue specimens from the host, or by administering the compound to liver cells or other in vitro systems such as cells Pigment or original 16 200406394 Plasma particles were cultured and the compounds produced were analyzed and identified. These two methods are well known in the art. As used herein, the term '' stereoisomer '' means a compound composed of the same atom via a bond of the same bond but having a different three-dimensional structure, the 5 series of which are not interchangeable. These three-dimensional structures are called configurations. As used herein, the term '' mirror isomers '' means that the two stereoisomers cannot be mirror images of each other in a non-superior molecular system. As used herein, the term '' optical isomer π 'is equivalent to the term' 'mirror isomer'. Compounds that are stereoisomers to each other but are not mirror images of each other are called diastereomers. The term '' racemate '' or '' racemic mixture 10 '' means a mixture of equal parts of a mirror image isomer. The term "center of the palm" means a carbon atom with four different groups attached. "Mirror image isomerization enhancement" as used herein means an increase in the number of mirror image isomers compared to another. A simple way to achieve that isomerization enhancement is mirror image The concept of transcendental value, or "ee", is calculated using the following equation:

Eh~E2 其中El係為第一鏡像異構物的數量而E2係為第二鏡像異構物 的數量。因此，若該二鏡像異構物最初的比例係為50:50，諸 如係存在於一消旋混合物中，且一足以去產生一 50:30之最終 比例的鏡像異構性強化被達成，有關第一鏡像異構物的ee係為 20 25%。然而，若最後比例係為90:10，有關第一鏡像異構物的 ee係為80%。依據一本發明之具體例，一大於90%的ee係為 較佳的，一大於95%的ee係為最佳的而一大於99%的ee係為 最特別較佳的。鏡像異構性強化藉由具此領域中一般知識者使 17 200406394 用標準的技術與操作程序（諸如以一光學管柱之高效能液相層 析儀）而被容易地測定。選擇適當的在影響鏡像異構物對的分離 上所必要的光學管柱、洗提劑以及條件係在具此領域中一般知 識者的知識範圍内。另外，化學式〗化合物的鏡像異構物可為 5 一此蟄中具有通常技術者使用此技藝所熟知的標準技術所解 析’諸如那些由J· Jacques等人所敘述的，” Enami〇mers，Eh ~ E2 where El is the number of first mirror isomers and E2 is the number of second mirror isomers. Therefore, if the initial ratio of the two mirror image isomers is 50:50, such as in a racemic mixture, and a mirror image isomerization enhancement sufficient to produce a final ratio of 50:30 is achieved, the relevant The ee series of the first mirror isomer is 20 to 25%. However, if the final ratio is 90:10, the ee series for the first mirror isomer is 80%. According to a specific example of the present invention, an ee system of more than 90% is preferable, an ee system of more than 95% is optimal, and an ee system of more than 99% is most particularly preferable. Image isomerism enhancement is easily determined by those skilled in the art using standard techniques and operating procedures such as a high performance liquid phase analyzer with an optical column. The selection of appropriate optical columns, eluents, and conditions necessary to influence the separation of mirror image isomers is within the knowledge of those skilled in the art. In addition, the enantiomeric isomers of the compounds of the formula ?? can be analyzed by those skilled in the art using standard techniques well known to those skilled in the art '

Racemates，and Resolutions ”，John Wiley and Sons，Inc·，1981。 解析的實例包括再結晶技術或手性層析法。 非鏡像異構物不同於物理性質與化學反應性二者。一非鏡 1〇像異構物的混合物可以基於溶解度、分結晶作用或層析性質， 士 4層層析法、管柱層析法或HPLC，而被分離成鏡像對。 非鏡像異構物錯合物混合物純化成鏡像異構物典型地需 要〜個步驟。於第一個步驟中，非鏡像異構物的混合物如 、十、 丄/·7γ 15心的被解析成鏡像對。於第二個步驟中，鏡像對被進一步純化 成種或另一種鏡像異構物之濃化的組成物；或更佳地被解析 成包含有純鏡像異構物之組成物。鏡像異構物的解析典型地需 要與—手性劑，如一溶劑或管柱基質，進行反應或分子交互作 用鏡像異構物的解析，例如藉由透過與一第二種試劑（亦即一 2〇解析劑）之純鏡像異構物進行反應，將鏡像異構物的混合物（如 卜’肖旋混合物）轉化成一非鏡像異構物混合物而可被達成。所 化成的二種非鏡像的產物可隨後被分離。該被分離的非鏡像異 構物隨即藉由反向該初化學轉變而被再轉化成純鏡像異構物。 鏡像異構物的解析亦可藉由它們的非共價鍵結至—手性 貝之差異而達成’如藉由對同手性(homochiral)吸收劑層析 18 200406394 法。在鏡像異構物與層析吸收劑間的非共價鍵結建立了非鏡像 錯合物，導至於層析系統中流動狀態與結合狀態之差式分配 (differential partitioning)。因而此二種鏡像異構物係以不同的速 率移動通過此層析系統，如管柱，以使其得以分離。 5 手性解析管柱係為此技藝所熟知，且為商業上可得到的 (如得自 MetaChem Technologies Inc·，其為 ANSYS Technologies，Racemates, and Resolutions ", John Wiley and Sons, Inc., 1981. Examples of analysis include recrystallization techniques or chiral chromatography. Non-mirromeric isomers are different from both physical properties and chemical reactivity. -Non-mirror 1 〇Isomer mixtures can be separated into mirror-image pairs based on solubility, crystallization, or chromatographic properties, such as 4-layer chromatography, column chromatography, or HPLC. Non-mirromeric isomer mixtures Purification into mirror image isomers typically requires ~ steps. In the first step, a mixture of non-mirro isomers such as, ten, 丄 / · 7γ 15 is resolved into mirror pairs. In the second step The mirror-image pair is a concentrated composition that is further purified into one or another mirror-image isomer; or better, it is resolved into a composition containing pure mirror-image isomers. The resolution of mirror-image isomers typically requires -Chiral agents, such as a solvent or column matrix, for reaction or molecular interaction resolution of mirror isomers, for example by passing through pure mirror isomers with a second reagent (ie, a 20 resolving agent) React A mixture of isomers (such as a 'Xiao Xuan mixture) can be achieved by converting a mixture of non-mirror isomers. The two non-mirror products formed can then be separated. The separated non-mirror isomers It is then reconverted into pure mirror image isomers by reversing the initial chemical transformation. The resolution of mirror image isomers can also be achieved by their non-covalent bonding to-chiral shell differences, such as by Method for homochiral (homochiral) absorbent chromatography 18 200406394. The non-covalent bond is established between the non-covalent bond between the mirror isomer and the chromatographic absorbent, leading to the flow state and binding in the chromatography system. Differential partitioning of states. Therefore, the two mirror image isomers move through the chromatography system, such as a column, at different rates to separate them. 5 Chiral analytical column system is this skill Well known and commercially available (e.g. from MetaChem Technologies Inc., ANSYS Technologies,

Inc.，Lake Forest，CA之一分公司）。鏡像異構物可以，例如於 HPLC使用手性靜止相（CSPs)，以被分析與純化。手性hpLC管 柱典型地含有一型被固定在一矽石填充的物質上的鏡像化合 10物。為使手性解析發生，在CSP與一被分析物鏡像異構物間必 須有至少三個同時發生交互作用的點，且此等交互作用之—或 更多為立體化學上依賴的。 D-笨甘胺酸與L-白胺酸為第一型CSps ，且使用極性-極 性交互作用（p-p interaction)、氫鍵、偶極_偶極交互作用與立體 15父互作用之組合俾以達成手性識別。為了要於第一型管柱被解 析，被分析物鏡像異構物必須包含與csp互補的官能度 (functionality)，以使該被分析物與csp進行必需的交互作用。 樣品較佳地應含-種以下的官能基基團：㈣或一、氫鍵供 予體及/或受體或一醯胺偶極。衍生作用有時候被用來增加相互 20作用部位到那些缺少相互作用部位的化合物上。最普通的衍生 物涉及從胺與羧酸形成醯胺。Inc., a branch of Lake Forest, CA). Mirror isomers can be analyzed and purified, for example, using chiral stationary phases (CSPs) in HPLC. Chiral hpLC columns typically contain a type of mirror compound 10 that is fixed on a silica-filled material. For chiral resolution to occur, there must be at least three simultaneous interaction points between the CSP and an analyte mirror image isomer, and these interactions—or more of them—are stereochemically dependent. D-glycine and L-leucine are the first type of CSps, and use a combination of polar-polar interaction (pp interaction), hydrogen bonding, dipole-dipole interaction and stereo 15 parent interaction Achieve chiral recognition. In order for the first type column to be resolved, the analyte mirror image isomer must contain a functionality that is complementary to the csp in order for the analyte to interact with the csp as necessary. The sample should preferably contain one or more of the following functional groups: hydrazone or a hydrogen bond donor and / or acceptor or a amine dipole. Derivatives are sometimes used to add interaction sites to compounds that lack interaction sites. The most common derivatives involve the formation of amidines from amines and carboxylic acids.

MetaChiral 0DM™ 係為一第二型 csp n csp)。作 為形成溶質-CSP複合物之初始的反應機構係經由相吸相互作 用，但包含複合物亦扮演-重要的角色。氫鍵結、π4，以及 19 200406394 偶極堆疊對在該MetaChiral™ ODM上的光學解析而言係為重 要的。當該溶質分子不含有作為溶質-管柱相互作用所需要的基 團時’衍生化通常係為必須要的。衍生化，通常對於苯甲基畴 胺而言’亦被一些強極性分子如胺與羧酸所需要的，否則其將 5 經由非立體特異性相互作用（non-stereo-interactions)與該靜相 太強烈地反應。 在某些具體例中，上面所述之化學式I可包括一個但書條MetaChiral 0DM ™ is a type II csp n csp). As the initial reaction mechanism for forming the solute-CSP complex, they interact with each other via phase attraction, but the inclusion complex also plays an important role. Hydrogen bonding, π4, and 19 200406394 dipole stacking are important for optical resolution on this MetaChiral ™ ODM. When the solute molecule does not contain the groups required for solute-column interaction, the derivatization is usually necessary. Derivatization, usually for benzyl domain amines, is also required by some highly polar molecules such as amines and carboxylic acids, otherwise it will pass 5 to the static phase via non-stereo-interactions Too strong to react. In some specific examples, the formula I described above may include a proviso

件：排除藉由在美國專利第5,346,896號中所揭示的通式來表 不的化合物。 10 在某些具體例中，上面所述之化學式I可包括一個但書條 件：排除藉由在美國專利第6,358,958號中所揭示的通式來表 示的化合物。 在某些具體例中，上面所述之化學式I可包括一或更多個 但書條件：排除藉由在美國專利第5,346,896號與美國專利第 15 6,358,958號這兩者中所揭示的通式來表示的化合物。File: Excludes compounds represented by the general formula disclosed in U.S. Patent No. 5,346,896. 10 In some specific examples, the chemical formula I described above may include a proviso: Excluding compounds represented by the general formula disclosed in U.S. Patent No. 6,358,958. In some specific examples, the chemical formula I described above may include one or more proviso conditions: Excluding by the general formulas disclosed in both US Patent No. 5,346,896 and US Patent No. 15,6,358,958 Represented compound.

在某些具體例中，藉由化學式I來表示的化合物排除具有 在美國專利第5,346,896號中所揭示的通式之在化學式I内的 化合物。 R所代表之較佳的基團係為一氫或鹵素原子或(CrC6)-烷 2〇氧基、（CrC6)__烷氧基、N，N-二-(CrC6)-胺幾基或氰基基團。 一 R所代表之較佳的_烷氧基係為一聚鹵烷氧基，更佳地三氟 氧土 汉所代表之較佳的鹵素原子係為一氣原子。作為上 达原子與基團之較佳的位置係為在被它們所繫附之苯基的2號 位置上。 20 200406394 一 ^所代表之較佳的基團係為一氫原子。 此外較佳的係為當同時地，R代表一或更多選自於由下列 所構成之群組之成員：羥基、（CrC6)-鹵烷氧基、（CrC6)-羥烷 基、烷氧烷基、（CrQ)-胺烷基、（CKC6)-烷基胺-(CrC6)-烷基、 5 酿胺基、（Ci_C6)-烧續酿基胺基、胺基績驢基、（Ci_C6)-烧胺石黃 醯基、氰基、胺羰基、N-(CrC6)-烷胺羰基、N，N-二-(CrC6)-烷胺羰基、（CrC6)-烷氧羰基、（CrC6)-烷羰基、烷羰烷基、甲 醯基、烷醯基氧基烷基、（CrC6)-烷胺羰基胺基、（CrC6)-烷亞 磺醯基、（CrC6)-烷磺醯基，以及N，N-二-(CrC6)-烷胺磺醯基 10 基團；而R!代表一選自於由下列所構成之群組之成員：未經 取代之芳氧基、芳烷基、芳烷氧基、雜環氧基、雜環烷基以及 雜環烷氧基，或一選自於由下列所構成之群組之成員：芳氧 基、芳烷基、芳烷氧基、雜環氧基、雜環烷基、雜環烷氧基、 芳基、雜環狀基與環烷基被取代以一或更多選自於由R代表氫 15 所構成之群組之取代基，或一或更多選自於由下列所構成之群 組之取代基：（CrC6)-烷硫基、羥基、（C2-C6)-烯基、（C2-C6)-炔 基、（crc6)-鹵烷氧基、（crc6)-羥烷基、烷氧烷基、（crc6)-胺 烷基、（crc6)-烷基胺基-(crc6)-烷基、醯胺基、（crc6)-烷磺 酸基胺基、胺續酿基、（Cl-C6)-烧胺續酿基、氛基、胺魏基、 20 Ν-((νε6)-烷胺羰基、N，N-二-(CKC6)-烷胺羰基、（CrC6)-烷氧 羰基、（crc6)-烷羰基、烷羰烷基、甲醯基、烷醯基氧基烷基、 (Ci-C6)-烧胺獄基胺基、（Ci_C6)-烧亞石黃酿基、（C!-C6)_烧橫酿 基’以及N，N-二-(Ci-Ce)"·烧胺石黃酿基基團。 Q所代表之較佳的基團係為-C(O)-與-CH(OR2)-，其中 21 200406394 R2代表一氫原子或(Crc6)-烷基、（c2-c6)-烯基、（cvc6)-炔基、 -c(o)- (crc6)-烷基、-c(o)o-(crc6)-烷基、-C(0)NR7R8 或 -C(S)NR7R8，其中R7與R8係分別為氫或(CKC6)-烷基； R3所代表之較佳的基團係為一氫原子或一（crc6)-烷基、 5 (C2-C6)-烯基、（C2-C6)-炔基、環烷基、芳基或雜環基基團。此 外較佳的係為當R3代表氫或一（crc6)-烷基、（c2-c6)-烯基、 (c2-c6)-炔基時，各個基團被選擇性取代以一或更多如上所定義 之取代基R或Ri。更佳地，R3代表一環己基。 R4所代表之較佳的基團係為一芳基或雜環狀基，每一者被 10 選擇性取代以一或更多選自於由下列所構成之群組之取代 基：鹵素原子或(crc6)-烷氧基或(crc6)-鹵烷氧基。一作為一 個在R4上的取代基之較佳的鹵素原子係為氟。一作為一個在 R4上的取代基之較佳的烷氧基基團係為一甲氧基基團。一作為 一個在R4上的取代基之較佳的鹵烷氧基基團係為一聚鹵烷氧 15 基基團，最佳地為一個三氟乙氧基基團。一 R4所代表之較佳的 芳基基團係為一苯基基團。一 r4所代表之較佳的雜環狀基團係 為一雙環雜環狀基團。更佳地R4代表一雙環雜芳基基團，最佳 地為一 2,3-二羥-1，4-苯并戴奥辛基基團。 此外較佳的係為當R4代表一芳基或雜環狀基團時，被取 20 代以一或更多選自於由下列所構成之群組之取代基：（CrC6)-鹵烷氧基、烷氧烷基、（crc6)-胺烷基、（crc6)-烷基胺基 -(Ci_C6)-烧基、酿胺基、胺續S&基、（Ci-C6)-烧胺橫酿基、氛基、 (C]-C6)-烧氧獄基、（C!-C6)-烧戴基、烧魏烧基、曱酿基、烧酿 基乳基烧基、（Ci_C6)-烧胺幾基胺基、（Ci_C6)-烧亞續酿基、 22 200406394 ((^-(:士烷磺醯基，以及N，N-二-(c^C6)-烷胺磺醯基基團。 A較佳地代表一鍵。 η較佳地係為1。 此外較佳的係為其中化學式丨之化合物，同時地，R代表 5 一氫或_素原子或烷氧基、（crC6)-鹵烷氧基、n，N-二 _(CrC6)_胺羰基或氰基基團；Ri代表為_氫原子，Q代表 或-CH(OR2)-，其中r2代表_氯原子或（c「c士燒基、 (c2-c6)-烯基、（c2_c6)…炔基、-c(〇HCi-C6)_ 烷基、 -C(0)0-(CrC6)-垸基、-C(0)NR7R8 或 _C(S)NR7R8，其中 1〇與R8係分別為氫或仏从燒基基團；R3代表一氮原子或一 (Q C6)絲、（CVC士婦基、（CrC6)·炔基、環烧基芳基或雜 環基團；r4代表-芳基或雜環狀基團，每一者被選擇性取代以 或更夕k自於由下列所構成之群組之取代基：齒素原子或 (CVC㈣氧絲（CrC6)_岐氧基基團；A代表—鍵；且「2。 15 &外較佳的係為由該化學式所代表的化學式 I之化合物。 化子式I之化合物可被分離成為非對映異構物性對，例 如藉由TLC來分離。這些非對映異構物性對於此係指如具有 上方的TLC Rf之非對映異構物與具有下方的TLC Rf之非對 映異構物。料非對映異構物使用在本技射已熟知之方法(諸 此处所^述的那些）’可進_步地被富含作為—特殊的鏡像異 冓物或被解析成為_單_的鏡像異構物。 本發明之化合物的合成 本發明之化合物一般依據下面途徑被製備： 23 200406394In some specific examples, the compound represented by Chemical Formula I excludes compounds having Chemical Formula I having the general formula disclosed in U.S. Patent No. 5,346,896. The preferred group represented by R is a hydrogen or halogen atom or (CrC6) -alkoxy group, (CrC6) -alkoxy group, N, N-di- (CrC6) -amine group or Cyano group. A preferred alkoxy group represented by one R is a polyhaloalkoxy group, and a more preferred halogen atom represented by trifluorooxethan is a gas atom. The preferred positions for the atoms and groups are at position 2 of the phenyl group to which they are attached. 20 200406394 A preferred group represented by ^ is a hydrogen atom. In addition, it is preferred that when simultaneously, R represents one or more members selected from the group consisting of: hydroxyl, (CrC6) -haloalkoxy, (CrC6) -hydroxyalkyl, alkoxy Alkyl group, (CrQ) -amine alkyl group, (CKC6) -alkylamine- (CrC6) -alkyl group, 5-amino group, (Ci_C6) -continuous amino group, amine group, (Ci_C6 ) -Broadamine sulphamate, cyano, amine carbonyl, N- (CrC6) -alkylamine carbonyl, N, N-di- (CrC6) -alkylamine carbonyl, (CrC6) -alkoxycarbonyl, (CrC6) -alkyl Carbonyl, alkylcarbonylalkyl, methylamidino, alkylamidooxyalkyl, (CrC6) -alkylaminocarbonylamino, (CrC6) -alkylsulfinamidinyl, (CrC6) -alkylsulfinyl, and N , N-di- (CrC6) -alkylaminosulfonyl 10 group; and R! Represents a member selected from the group consisting of: unsubstituted aryloxy, aralkyl, arane Oxy, heterocyclooxy, heterocycloalkyl, and heterocycloalkoxy, or a member selected from the group consisting of: aryloxy, aralkyl, aralkoxy, heteroepoxy Group, heterocycloalkyl, heterocycloalkoxy, aryl, heterocyclyl and cycloalkyl are substituted with one or more A substituent selected from the group consisting of R representing hydrogen 15 or one or more substituents selected from the group consisting of: (CrC6) -alkylthio, hydroxyl, (C2-C6 ) -Alkenyl, (C2-C6) -alkynyl, (crc6) -haloalkoxy, (crc6) -hydroxyalkyl, alkoxyalkyl, (crc6) -aminoalkyl, (crc6) -alkyl Amine- (crc6) -alkyl, amidoamine, (crc6) -alkanesulfonylamino, amine continuous base, (Cl-C6) -amine continuous base, ammonium group, amine group, 20 Ν-((νε6) -alkylaminecarbonyl, N, N-di- (CKC6) -alkylaminecarbonyl, (CrC6) -alkoxycarbonyl, (crc6) -alkylcarbonyl, alkylcarbonylalkyl, formamidine, alkyl Fluorenyloxyalkyl, (Ci-C6) -carbamoylamine, (Ci_C6) -coalthionite, (C! -C6) _coalline, and N, N-di- (Ci-Ce) " · Salamine group. The preferred groups represented by Q are -C (O)-and -CH (OR2)-, of which 21 200406394 R2 represents a hydrogen atom. Or (Crc6) -alkyl, (c2-c6) -alkenyl, (cvc6) -alkynyl, -c (o)-(crc6) -alkyl, -c (o) o- (crc6) -alkyl , -C (0) NR7R8 or -C (S) NR7R8, where R7 and R8 are hydrogen or (CKC6) -alkyl, respectively The preferred group represented by R3 is a hydrogen atom or a (crc6) -alkyl, 5 (C2-C6) -alkenyl, (C2-C6) -alkynyl, cycloalkyl, aryl or hetero Cyclic group. In addition, when R3 represents hydrogen or mono (crc6) -alkyl, (c2-c6) -alkenyl, (c2-c6) -alkynyl, each group is selectively substituted. With one or more substituents R or Ri as defined above. More preferably, R3 represents a cyclohexyl group. The preferred group represented by R4 is an aryl or heterocyclic group, each of which is selectively substituted by 10 with one or more substituents selected from the group consisting of a halogen atom or (crc6) -alkoxy or (crc6) -haloalkoxy. A preferred halogen atom as a substituent on R4 is fluorine. A preferred alkoxy group as a substituent on R4 is a methoxy group. A preferred haloalkoxy group as a substituent on R4 is a polyhaloalkoxy group, most preferably a trifluoroethoxy group. A preferred aryl group represented by R4 is a phenyl group. A preferred heterocyclic group represented by r4 is a bicyclic heterocyclic group. More preferably R4 represents a bicyclic heteroaryl group, most preferably a 2,3-dihydroxy-1,4-benzodiocinyl group. In addition, when R4 represents an aryl or heterocyclic group, it is preferably substituted with one or more substituents selected from the group consisting of: (CrC6) -haloalkoxy Group, alkoxyalkyl group, (crc6) -aminoalkyl group, (crc6) -alkylamino group- (Ci_C6) -alkyl group, amino group, amine group S & group, (Ci-C6) -alkylamine group Brewing base, atmosphere base, (C) -C6) -oxygen base, (C! -C6) -fired base, roasted Wei base, steamed base, roasted milk base, (Ci_C6)- Benzylamine, phenylamino, (Ci_C6) -alkylene, 22 200406394 ((^-(: Shilfanesulfonyl, and N, N-di- (c ^ C6) -alkylaminesulfonyl) A. Preferably, A represents a bond. Η is preferably 1. In addition, a compound of the formula 丨 is preferred. Meanwhile, R represents 5 a hydrogen or a hydrogen atom or an alkoxy group. (CrC6) -Haloalkoxy, n, N-di_ (CrC6) _aminocarbonyl or cyano group; Ri represents _ hydrogen atom, Q represents or -CH (OR2)-, where r2 represents _ chlorine atom or (c "C-Salkenyl, (c2-c6) -alkenyl, (c2-c6) ... alkynyl, -c (〇HCi-C6) -alkyl, -C (0) 0- (CrC6) -fluorenyl, -C (0) NR7R8 or _C (S) NR7R8, where 1 And R8 are hydrogen or fluorenyl radicals; R3 represents a nitrogen atom or a (Q C6) silk, (CVC), (CrC6) · alkynyl, cycloalkenyl aryl or heterocyclic group ; R4 represents -aryl or heterocyclic group, each of which is selectively substituted or replaced by a substituent from the group consisting of: a halogen atom or (CVC㈣oxyfilament (CrC6) _ A oxy group; A represents a bond; and "2. 15 & Outer is preferably a compound of formula I represented by this formula. Compounds of formula I can be separated into diastereomers Physical property pairs, for example, separated by TLC. These diastereomeric properties refer to, for example, diastereomers with TLC Rf above and diastereomers with TLC Rf below. Enantiomers can be further enriched as—special mirror isomorphs or resolved to monomorphic mirror isomorphs—by methods known in the art (those described here). Synthesis of compounds of the invention The compounds of the invention are generally prepared according to the following route: 23 200406394

基團B、R係與基園A-R4相同’且(R+ Ri )分別地’如在 通式I中所示。R2與R3係為與如該通式中所示相同且Ra係 為一低級烧基基團。 5 起始物（1)以一鹼予以處理，較佳地係為叔丁醇鉀，繼而 以2-溴乙醛二烷基縮醛或其他羰基被保護的2-i乙醛(例如， 該Ra烷基基團亦可被加入至一循環中，俾以得到二氧戊烷或 二哼烷環）來烷基化。其他用來實行縮合反應之另擇方式與適當 的驗包括：醯胺鋰(lithium amides)、氫化鈉、氫氧化納、氫氧 10 化鉀、碳酸鉀、碳酸铯以及具有或無相轉移催化劑之幫助的類 似之物。 該反應較佳地係在一 〇°C至迴流的溫度下於一溶劑（諸如二 甲亞颯或甲苯）中進行。 藉由採用描述於上面途徑1中之相同反應條件，使用3-15 溴丙醛二烷基縮醛或其他羰基被保護的3-鹵丙醛，容許去獲得 如在該通式中所預知的具有n = 2之化合物I。 以一酸處理(2)，諸如配於一適合的有機溶劑之氫氯酸或對 甲苯石黃酸或三氟乙酸，來達到酸(3)。一般而言，該反應在自約 24 法^丙喃之混合物）中被引導…較佳的與相似的方 糸由在％境溫度下在—配於—氯化溶劑之三II乙酸水溶液 之混合物巾崎該反應所構成。 5 15The groups B and R are the same as those of the bases A-R4 'and (R + Ri) are respectively' as shown in the general formula I. R2 and R3 are the same as those shown in the general formula and Ra is a lower alkyl group. 5 The starting material (1) is treated with a base, preferably potassium tert-butoxide, followed by 2-bromoacetaldehyde dialkyl acetal or other carbonyl-protected 2-i acetaldehyde (for example, the Ra alkyl groups can also be added to a cycle to obtain alkylene oxide (dioxolane or dihumane ring). Other alternative methods and appropriate tests for performing condensation reactions include: lithium amides, sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, and with or without the aid of a phase transfer catalyst Something like that. The reaction is preferably carried out in a solvent such as dimethylsulfene or toluene at a temperature of from 0 ° C to reflux. By using the same reaction conditions described in Route 1 above, using 3-15 bromopropionaldehyde dialkyl acetals or other carbonyl-protected 3-halopropanals allows to obtain as predicted in the general formula Compound I with n = 2. Treating (2) with an acid, such as hydrochloric acid or p-toluene luteinic acid or trifluoroacetic acid, in a suitable organic solvent to achieve acid (3). Generally speaking, the reaction is conducted in a mixture of about 24% of lanthane). A better and similar formula consists of a mixture of tri-II-acetic acid aqueous solution at-%-chlorinated solvent at% ambient temperature. Kinasaki is composed of this reaction. 5 15

。酸(3)藉由還原性胺化反應操作程序被偶合以所欲的芳基 ㈣俾以製備(5)。該反應較佳地在環境溫度下於-非-反應 (諸如一氯乙院或二氯甲烧）中或氯仿在三醋酸基氯娜化 納的存在下被引導，且大體上在1至24小時被完成(參見例如 bdel Magid, et al·, J. 〇rg· Chem，61，3849 (1996))或其 σ 地在分子相存在下，在—有氰基氫爛化鈉的輔助之 貝子溶劑（例如，甲醇）中被引導。 (5)至醇⑴的還原反應容易地被完成，其係使用一還原劑諸 士硼氫化鈉或一異丁氫化鋁或其他氫化鋁或硼，或其他被那些 熟習此項技術者所熟知之用以進行轉化酮至醇之還原法，俾以 ‘備出$工基化合物（I)。該反應較佳地在自約_2〇。c至環境溫. The acid (3) is coupled with a desired aryl group by a reductive amination reaction procedure to prepare (5). The reaction is preferably conducted in a non-reaction (such as monochloroethane or dichloromethane) at ambient temperature or chloroform in the presence of clonazine triacetate, and is generally between 1 and 24 Hours are completed (see, for example, bdel Magid, et al., J. Org. Chem, 61, 3849 (1996)) or its σ field in the presence of the molecular phase, with the aid of shellfish with sodium cyanohydrogen decay. Solvent (for example, methanol) is directed. (5) The reduction reaction to alcohols can be easily accomplished by using a reducing agent such as sodium borohydride or aluminum isobutyl hydride or other aluminum hydride or boron, or others known to those skilled in the art It is used to carry out the reduction method for converting ketones to alcohols, so as to prepare the $ -based compound (I). The reaction is preferably at about -20. c to ambient temperature

度的溫度下在一有機溶劑（諸如曱醇或氯化亞甲基或四氫呋喃） 中被進行。It is carried out in an organic solvent such as methanol or methylene chloride or tetrahydrofuran.

途徑2 RRoute 2 R

(?) (1) 起始物（1)既係為商業上可得的亦或可藉由偶合適當的 20 Weinreb 醯胺⑹[參見 Nahm and Weinreb，Tetrahedron Lett.，22, 3815，（1981)]與(7)而被製備，如上面途徑2中所描述，其中 Μ係為一金屬鹽類，諸如鋰或鎮鹵化物。 25 200406394 該反應較佳地係在環境或降至-78°C之較低的溫度之氮 氣圍下，在一非質子溶劑（諸如四氫呋喃）中被進行。 另擇地，一具有R3COO烷基結構之酯在本技術中已熟知 的標準條件下，可以一經取代之苯曱基氯化鎂或苯甲基溴化鎂 5 或鋰衍生物予以處理俾以提供具有結構（1)之酮。 一用來獲得化合物（1)之另擇的途徑主要在於以一硝基醇 醛形式來反應適當的芳基醛與一烷基硝基衍生物，所形成的硝 基醇之脫水作用繼而雙鍵還原反應提供一 2-硝基(2-Ak)-苯乙 基衍生物，其可經歷Nef反應俾以生成所欲的酮衍生物1。此 10 類路徑在實驗的部份中與在文獻中已被充分的證實。 較佳的與相似的合成（1)之方法係為鈀所催化的一醯鹵化 物與一化合物(7)之偶合，其中Μ係為鋅_化物。 更特別地，該化學式（5)之化合物可採用描述於途徑3中之 操作程序而被製備。所有取代基，除非以別的方式指出，係如 15 前面所定義者。該等試劑與起始物對具此領域中一般知識者 而言係易於獲得的。(?) (1) The starting material (1) is either commercially available or can be obtained by using the appropriate 20 Weinreb amine [see Nahm and Weinreb, Tetrahedron Lett., 22, 3815, (1981) ] And (7), as described in Route 2 above, where M is a metal salt such as lithium or a halide. 25 200406394 The reaction is preferably carried out in an aprotic solvent (such as tetrahydrofuran) under ambient or nitrogen gas temperature lowered to -78 ° C. Alternatively, an ester having an R3COO alkyl structure may be treated with a substituted phenylphosphonium magnesium chloride or benzyl magnesium bromide 5 or a lithium derivative under standard conditions well known in the art, to provide a structure having (1) The ketone. An alternative way to obtain compound (1) is mainly to react the appropriate aryl aldehyde with an alkyl nitro derivative in the form of a mononitroaldol, and the dehydration of the formed nitroalcohol then double bonds The reduction reaction provides a 2-nitro (2-Ak) -phenethyl derivative, which can undergo a Nef reaction to form the desired ketone derivative 1. These 10 types of paths have been fully confirmed in the experimental part and in the literature. A preferred and similar method for the synthesis (1) is the coupling of a hafnium halide and a compound (7) catalyzed by palladium, where M is a zinc compound. More specifically, the compound of formula (5) can be prepared using the procedure described in Route 3. All substituents, unless otherwise indicated, are as defined above. These reagents and starting materials are readily available to those of ordinary skill in the art.

例如，在途徑3，步驟Α中，環己烷羰醯氯被加入至一適 26 200406394 合的苯甲基氯化或溴化鋅與一適當的鈀催化劑之混合物中，例 如，在〇 c下擾拌之配於一溶劑（諸如四氫吱喃）中之二氯（二笨 基膦)_鈀(11)。而後，在環境溫度下持續攪拌歷時4-24小時。接 而該反應以一例如氯化銨飽和水溶液予以終止。藉由萃取之一 5般的完成程序提供酮（8)。酮（8)可藉由在本技藝中已熟知之技術 被純化，諸如以一適合之洗提劑（諸如乙酸乙酯/己烷）在矽膠上 的閃蒸層析法，俾以提供純化的物質。另擇地，該粗製的鋼⑻ 可被繼續至步驟B中。 在途徑3,步驟B中，酮（8)在本技術中已熟知之條件下以 1〇 >臭乙二乙基縮料以烧化，俾以提供結構⑼之化合物。例 如，酮（8)被溶解在一適合之有機溶劑中（諸如二甲亞颯或曱苯) 並且以一輕微過量的一適合之鹼（諸如叔丁醇鉀）予以處理。在 -介於（TC與該溶劑的迴流溫度之間的溫度下，該反應被_ 歷時約15至3〇分鐘域、乙酸二乙基祕被逐滴添加至該反應 15中。具此領域巾—般知識者將容易地領會㈣乙酸二甲基縮 醛、溴伸乙基縮酸以及類似之物可被用來代替相對應的二乙基 縮酸。 在迷從3，步驟C中，化合物（9)以一相似於被描述在途 徑1中之操作程序的方法在酸性條件下被水解，俾以提供駿 20⑽。更特別地，例如，使化合物(9)溶於一適合之有機溶劑（諸 如二氯甲垸）中，並且以一適合之酸(諸如三氣乙酸水溶液)作處 理。於室溫下授拌該反應混合物歷時約i至6小時。接而將 該反應混合物以相同的溶劑稀釋，以鹽水予以洗務，有機層被 分開，經由無水硫酸鈉予以乾燥，在真空下過濾與濃縮俾以提 27 200406394 供酸（10)。酸（10)可藉由在本技術中已熟知之技術，諸如以一適 合之洗提劑（諸如乙酸乙酯/己烷）在矽膠上閃蒸層析，而被純 化。另擇地，粗製的醛（10)可被直接地使用在步驟D中。For example, in route 3, step A, cyclohexanecarbonylphosphonium chloride is added to a mixture of benzyl chloride or zinc bromide and a suitable palladium catalyst, such as at 0 ° C. Stir in dichloro (dibenzylphosphine) -palladium (11) in a solvent such as tetrahydrofuran. Thereafter, the stirring was continued at ambient temperature for 4-24 hours. The reaction is then terminated with a saturated aqueous solution of ammonium chloride, for example. The ketone (8) is provided by a one-step completion procedure such as extraction. Ketones (8) can be purified by techniques well known in the art, such as flash chromatography on silica gel with a suitable eluent (such as ethyl acetate / hexane) to provide purified substance. Alternatively, the crude steel reed may be continued to step B. In route 3, step B, the ketone (8) is calcined under conditions known in the art with 10 > ethylenediethyl condensate to provide a compound of structure VII. For example, ketone (8) is dissolved in a suitable organic solvent (such as dimethyl sulfene or toluene) and treated with a slight excess of a suitable base (such as potassium tert-butoxide). At a temperature between -TC and the reflux temperature of the solvent, the reaction is _ lasted for about 15 to 30 minutes, and diethyl acetate is added dropwise to the reaction 15. With this field towel -A general knowledgeable person will readily appreciate that acetic acid dimethylacetal, bromoethylacetic acid, and the like can be used in place of the corresponding diethylacetic acid. In 3, Step C, the compound (9) is hydrolyzed under acidic conditions in a manner similar to the procedure described in Route 1 to provide Jun 20 ⑽. More specifically, for example, compound (9) is dissolved in a suitable organic solvent ( Such as dichloromethane, and treated with a suitable acid (such as aqueous triacetic acid). The reaction mixture is stirred at room temperature for about i to 6 hours. The reaction mixture is then treated with the same solvent Diluted, washed with brine, organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide 27 200406394 acid (10). Acid (10) can be well known in the art Technology, such as using a suitable eluent (various Ethyl acetate / hexanes) flash chromatography on silica gel, and was purified. Choose another, the aldehyde (10) may be crude used directly in Step D.

在途徑3，步驟D中，酸（10)在本技術中已熟知之條件下， 5 以一相似於被描述在途徑1中之操作程序的方法藉由°瓜°井(4) 被還原性胺化，俾以提供該酮（5)。更特別地，例如，將醛（10) 溶於一適合之有機溶劑（諸如二氯甲烷）中。添加約1.05或更多 當量的哌畊(4)至此溶液中。乙酸可選擇性地加入以幫助該哌。井 (4)的溶解。而後加入約1.4至1.5當量的三醋酸基氫硼化鈉並 10 且於室溫下攪拌該反應歷時約3至5小時。該反應接而藉由添 加一適合之驗（諸如唆酸鈉水溶液或氫氧化物俾以提供一約8 至約12之Ph值）予以終止。該終止反應接而以一適合之有機溶 劑（諸如二氯甲烷）作萃取。有機萃取物被混合，以鹽水予以洗 滌，予以乾燥、過濾並在真空下予以濃縮俾以提供化學式（5) 15 之化合物。而後此物質可藉由在本技術中已熟知之技術予以純 化，諸如以一適合之洗提劑（諸如乙酸乙酯/石油醚或己烷）在矽 膠上閃蒸層析。In route 3, step D, the acid (10) is reduced under conditions well known in the art by a method similar to that described in route 1 by means of a well (4). Amination, hydrazone to provide the ketone (5). More specifically, for example, the aldehyde (10) is dissolved in a suitable organic solvent such as dichloromethane. Add about 1.05 or more equivalent of pipen (4) to this solution. Acetic acid can be optionally added to help the piper. Dissolution of the well (4). Then add about 1.4 to 1.5 equivalents of sodium triacetoxyborohydride and stir the reaction at room temperature for about 3 to 5 hours. The reaction is then stopped by adding a suitable test such as an aqueous sodium rhenium solution or hydroxide to provide a Ph value of about 8 to about 12. The termination reaction is then extracted with a suitable organic solvent such as dichloromethane. The organic extracts are mixed, washed with brine, dried, filtered, and concentrated under vacuum to provide the compound of formula (5) 15. This material can then be purified by techniques well known in the art, such as flash chromatography on silica gel with a suitable eluent such as ethyl acetate / petroleum ether or hexane.

28 200406394 另擇地’結構(5)之化合物可採用描述於途徑4中之操作程 序來被製備。所有取代基，除非以別的方式指出，係先前所定 義者。對具此領域中一般知識者而言，試劑與起始物是易於獲 得的。 5 在途徑4,步驟A中，醛（n)在本技術中已熟知之條件下28 200406394 Alternatively, compounds of the structure (5) can be prepared using the procedures described in Route 4. All substituents, unless otherwise indicated, are those previously defined. For those of ordinary skill in the art, reagents and starting materials are readily available. 5 In route 4, step A, the aldehyde (n) is under conditions well known in the art

被結合以一適合之有機金屬試劑（12)，俾以提供醇（13)。適合之 有機金屬試劑的貫例包括格任亞試劑、燒基鐘試劑、烧基鋅試 劑，以及類似之物。格任亞試劑係為較佳的。典型的格任亞試 劑與反應條件之只例’參見J· March, "Advanced Organic 10 Chemistry:Reactions? Mechanisms, and Structure'1, 2nd Edition, McGraw-Hill，pages 836-841 (1977)。更特別地，醛（11)被溶於 一適合之有機溶劑（諸如玛氫呋喃或甲苯）中，冷卻至約一 5°c並 以約1.1至1.2當量的一化學式（12)之格任亞試劑作處理，其 中Μ係為MgCl或MgBr。該反應被攪拌歷時約〇·5至6小時， 15接而予以終止，而醇（13)藉由已熟知的完成程序被分離出來。It is combined with a suitable organometallic reagent (12) to provide alcohol (13). Examples of suitable organometallic reagents include Grignard reagents, alkylated reagents, zincated reagents, and the like. Grenia reagents are preferred. For an example of typical Grignard reagents and reaction conditions ', see J. March, " Advanced Organic 10 Chemistry: Reactions? Mechanisms, and Structure' 1, 2nd Edition, McGraw-Hill, pages 836-841 (1977). More specifically, the aldehyde (11) is dissolved in a suitable organic solvent (such as methanefuran or toluene), cooled to about -5 ° C, and with a chemical formula (12) of Grenia about 1.1 to 1.2 equivalent The reagent is treated, where M is MgCl or MgBr. The reaction was stirred for about 0.5 to 6 hours, and was subsequently terminated by 15 while the alcohol (13) was separated by well-known completion procedures.

在途徑4，步驟Β中，醇（13)在本技術中已熟知的標準條 件下’遺如那些被描述於j March,，，Advanced Organic Chemistry: Reactions, Mechanisms, and Structure*', 2nd Edition, McGraw-Hill，pages l082_1084 (1977)，被氧化俾以提供酮⑴。 20 (酮（1)係為被使用在上述途徑1中之起始物。） 氧化作用亦可使用已被具此領域中一般知識者所熟知之 標準的Swern氧化條件來被進行(Marx，Tidwell - J. 〇rg. Chem 登，788 (1984)’或將該醇（13)溶於一適合之有機溶劑（諸如二氯 曱烧）中’孩/谷液以一濕性冰丙g同（wet ice acetone)浴予以冷卻， 29 200406394 並且以2·5至3.0當量之二甲亞礙予以處理。在攪拌歷時約3〇 分鐘後，該反應接而以約i·8當量之P2〇5予以處理。該反庶被 攪拌歷時約3小時，而後’較佳地，以約3.5當量之一適合之 胺（諸如三乙胺）予以處理超過約30分鐘。該冰浴接而被移除且 5 該反應被攪拌歷時約8至16小時。該酮（1)接而藉由在本技術 中已熟知之標準萃取技術被分離出來。In Route 4, Step B, the alcohol (13) is' under those standard conditions well known in the art 'as described in j March ,, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure *', 2nd Edition, McGraw-Hill, pages l082_1084 (1977), is oxidized to provide ketones. 20 (Ketone (1) is the starting material used in Route 1 above.) Oxidation can also be performed using standard Swern oxidation conditions that are well known to those having ordinary knowledge in the art (Marx, Tidwell -J. Org. Chem Deng, 788 (1984) 'or dissolving the alcohol (13) in a suitable organic solvent (such as dichloromethane) with a wet ice-column solution ( wet ice acetone) bath, cooled on 29 200406394 and treated with 2.5 to 3.0 equivalents of dimethyl ether. After stirring for about 30 minutes, the reaction was then applied with about i · 8 equivalents of P205. Treatment. The reaction is stirred for about 3 hours, and then 'preferably, treated with about 3.5 equivalents of a suitable amine such as triethylamine for more than about 30 minutes. The ice bath is then removed and 5 The reaction is stirred for about 8 to 16 hours. The ketone (1) is then isolated by standard extraction techniques well known in the art.

在途徑4，步驟C中，_(1)以一適合之驗予以處理繼而 添加烯（15)，其中X係為一適合的離去基團，俾以提供化合物 (14)。例如，酮（1)被混合以一過量之配於一適合之有機溶劑（諸 10 如四氫呋喃）中的烯（15)，並且以一濕性冰丙酮浴予以冷卻。適In route 4, step C, _ (1) is treated with a suitable test followed by addition of ene (15), where X is a suitable leaving group, and 俾 is provided to provide compound (14). For example, ketone (1) is mixed with an excess of ene (15) in a suitable organic solvent (such as tetrahydrofuran) and cooled in a wet ice-acetone bath. suitable

合之離去基的實例係為C1、ΒΓ、甲苯石黃酸(t〇Sylate)、曱石黃酸 (mesylate)，以及類似之物。較佳的離去基係為C1與Br。添加 約1.1當量之一適合之鹼並且容許該反應在室溫下攪拌歷時約 2小時。適合的鹼之實例係為叔丁醇鉀、氫化鈉、 15 NaN(Si(CH3)3)2、LDA、KN(Si(CH3)3)2、NaNH2、乙氧鈉、曱氧 鈉以及類似之物。叔丁醇鉀係為較佳的適合之鹼。該反應接而 以酸液予以終止且化合物（14)藉由一般的完成程序被分離出 來。 在途徑4，步驟D令，化合物（14)以一適合之氧化劑作處 20 理俾以提供醛(3)。（在途徑1中亦製備出醛(3))。適合的氧化劑 之實例係為臭氧、NaI04 /锇催化劑，以及類似之物。臭氧係為 較佳的氧化劑。適合的氧化試劑與條件之實例被描述於J. March, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure"，2nd Edition，McGraw-Hill，pages 1090-1096 (1977) o 30 200406394 例如，將化合物（Μ)溶於一適合的有機溶劑（諸如甲醇）中， 添加—小量的Sudanm ’並且使該溶液冷卻至約_2代。臭氧 被打泡至該溶液中歷時、約4小時直到粉紅色轉變成一淡普 色。而後加人-還原劑(諸如Me2 s或三丁膦）。濃縮提供即) 之中間產物二甲基祕。在標準酸性條件下立即水解此類二甲 基縮趁俾讀傾(3)。騎地，直接的酸性完絲製的反應混 口物提供了酸(3)。另擇地’藉由〇4)在—非韻形成溶飘諸 如二氯甲燒）中的臭氧化作用（〇z嶋㈣可直接獲得酸⑺。 ίο 广在途徑4 ’步驟E中’酸(3)在相似於那些被描述於上述 途化3，步驟D巾的條件下被還原性胺化，俾讀供化合物 (5)。（化合物5亦可在途徑j中被製備出）。Examples of combined leaving groups are C1, Γ, tosylate, mesylate, and the like. The preferred leaving groups are C1 and Br. Add about 1.1 equivalents of a suitable base and allow the reaction to stir at room temperature for about 2 hours. Examples of suitable bases are potassium tert-butoxide, sodium hydride, 15 NaN (Si (CH3) 3) 2, LDA, KN (Si (CH3) 3) 2, NaNH2, sodium ethoxylate, sodium oxate, and the like Thing. Potassium tert-butoxide is a suitable base. The reaction was then terminated with an acid solution and compound (14) was isolated by a general completion procedure. In route 4, step D, compound (14) is treated with a suitable oxidant to provide aldehyde (3). (Aldehyde (3) is also prepared in route 1). Examples of suitable oxidants are ozone, Na04 / rhenium catalysts, and the like. Ozone is the preferred oxidant. Examples of suitable oxidizing reagents and conditions are described in J. March, " Advanced Organic Chemistry: Reactions, Mechanisms, and Structure ", 2nd Edition, McGraw-Hill, pages 1090-1096 (1977) o 30 200406394 For example, a compound (M) Dissolve in a suitable organic solvent, such as methanol, add—a small amount of Sudanm 'and allow the solution to cool to about -2 generations. Ozone was bubbled into the solution for about 4 hours until the pink color changed to a light color. Then add a human-reducing agent (such as Me2s or tributylphosphine). Concentration provided i.e. the intermediate dimethyl ester. This type of dimethyl condensation is hydrolyzed immediately under standard acidic conditions (3). On the ground, the acidic (3) is provided by the reaction mixture made from the direct acid finish. Alternatively, the acid can be directly obtained by ozonation (such as dichloromethane) in a non-yin-forming solution (such as dichloromethane). Ίο Wide in route 4 'Step E' acid ( 3) Reductively aminated under conditions similar to those described in Scheme 3, Step D, and read for compound (5). (Compound 5 can also be prepared in route j).

CHO (3)CHO (3)

步驟A 途徑5Step A Path 5

N N-BN N-B

步驟BStep B

15 逆径5提供-種另擇的合成方式作為嗣⑺的製備。所有取 代基，除非以別的方式指出，係為如前所定義者。對具此領域 中-般知識者而言，試劑與起始物是易於獲得的。 在途徑5，步驟a φ，故:m 中酪(3)在本技術中已熟知之條件下被 縮合以哌讲(4)，俾以提供烯 t、钸胺（15)。例如，約1〇5當量之被溶 於一適合的有機溶劑（諸士分 名士乙I異丙酯或異丙醇）中的醛(3)被加 至純質的0底°丼(4)(自由心、由, 双）中。加入額外的有機溶劑俾以產生一 泥漿（slurry)並且攪拌該及雍 反應K犄約1至2小時。接而藉由標準 技術(諸如藉由過濾而收集）分離出該軸（15)。 20 200406394 在途徑5，步驟B中，該烯胺（15)在具此領域一般知識者 已熟知之條件下被氫化俾以提供化合物（5)。例如，在一 Parr bottle中，烯胺（15)被混合以一適合之有機溶劑（諸如異丙醇）與 一催化的量之5%壤上纪。該混合物被置於50 psi的氫下並且 5 在室溫下被震盪歷時約2天。接而該泥漿被過濾俾以移除催化 劑，且過濾物被濃縮俾以提供化合物（5)。15 Reverse diameter 5 provides an alternative synthetic method for the preparation of osmium. All substitutions, unless otherwise indicated, are as defined above. For those of ordinary skill in the art, reagents and starting materials are readily available. In route 5, step a φ, therefore: m (3) in m is condensed with piperidine (4) under conditions well known in the art to provide ene t, amidine (15). For example, about 105 equivalents of the aldehyde (3) dissolved in a suitable organic solvent (Ethyl Isopropyl Ester or Isopropyl Alcohol) is added to a pure 0 ° C (4) ( Free heart, freedom, double). Add additional organic solvent 俾 to produce a slurry and stir the König reaction K 犄 for about 1 to 2 hours. The shaft is then separated (15) by standard techniques, such as collection by filtration. 20 200406394 In Route 5, Step B, the enamine (15) is hydrogenated to give compound (5) under conditions well known to those skilled in the art. For example, in a Parr bottle, the enamine (15) is mixed with a suitable organic solvent (such as isopropanol) and a catalyzed amount of 5% Epizoic. The mixture was placed under 50 psi of hydrogen and 5 was shaken at room temperature for approximately 2 days. The slurry was then filtered to remove the catalyst, and the filtrate was concentrated to provide compound (5).

為了合成化合物I (其中R2係與Η不同），使用在途徑6 中所提供的方法。中間產物酮（2)以被使用在上述途徑1中針對 10 化合物（5)之相同的還原法來被還原，而提供中間產物（16)，其 係藉由與一驗（例如配於一適合的溶劑（例如四氫吱喃）之NaH 或叔丁醇鉀或NaNH2或LiNH2或其他者）反應來被it化，而提 供烷氧化物，其接而在自0°C至迴流溫度之溫度下，在原位 被反應以具有X離去基（鹵素或甲磺酸或甲苯磺酸)與R2=低級 15 烷基之適當的R2-X。所獲得之化合物（17)可經歷被描述在途徑 1中相同的反應而提供具有R2非為Η的產物I。 另擇地，化學式I之化合物（其中R2係非為一氫原子）可 藉由以被描述在上方作為化合物16烷基化之相同的方法，將 化學式I之化合物（其中R2=H)烷基化而被獲得，以非常反應 ^uu4〇6394 f生的鹵化物或甲磺酸/曱苯磺酸（例如苯曱溴）限制此操作程序 來達到烷基化作用，其可在時間/溫度控制反應條件下（較佳地 在至溫下）反應。 途徑7描述一種合成化合物（I)之雙重功能化方法。此種 5 方法可有助於化合物（I)之文庫的合成，而同時介紹不同的。底讲 部分與不同的R3基團。 藉由起始自化學式（I)之化合物（其中R2 = H)的烷基化或加 成反應可獲得化學式（I)之化合物（其中R2代表-C(0)Alk、 -C(0)0Alk、-C(0)NR7R8 或-C(S)NR7R8)。這類的反應可在一 10 室溫至80°c的溫度範圍下，選擇性地在一鹼（諸如TEA或NaH) 或另擇地（例如，針對異硫氰酸_) 一酸（諸如三氟乙酸）的存在 下，使用配於二氯曱烷、吡啶或DMF之適當的醯基鹵化物、 氯曱酸烧S旨（alkyl chloroformates)、異氰酸ϊ旨或異硫氰酸醋來被 進行。 200406394 途徑？To synthesize Compound I (where R2 is different from hydrazone), the method provided in Route 6 was used. The intermediate ketone (2) is reduced by the same reduction method used for the 10 compound (5) in the above route 1, and the intermediate product (16) is provided by combining with a test (such as Solvent (such as tetrahydrofuran) in NaH or potassium tert-butoxide or NaNH2 or LiNH2 or others) to be catalyzed to provide an alkoxide, which in turn is at a temperature from 0 ° C to reflux temperature Is reacted in situ to have an appropriate R2-X with an X leaving group (halogen or methanesulfonic acid or toluenesulfonic acid) and R2 = lower 15 alkyl. The obtained compound (17) can undergo the same reaction described in route 1 to provide a product I having R2 other than fluorene. Alternatively, a compound of formula I (where R2 is a non-hydrogen atom) can be alkylated by the same method described above as the alkylation of compound 16 as R16 = H It is obtained in a highly reactive manner, such as a halide or methanesulfonic acid / toluenesulfonic acid (such as phenylammonium bromide). This procedure is limited to achieve alkylation, which can be controlled in time / temperature. The reaction is carried out under reaction conditions, preferably at room temperature. Route 7 describes a dual functionalization method for the synthesis of compound (I). This 5 method can facilitate the synthesis of a library of compounds (I) while introducing different ones. The bottom part is different with different R3 groups. Compounds of formula (I) can be obtained by alkylation or addition reactions starting from compounds of formula (I) (where R2 = H) (where R2 represents -C (0) Alk, -C (0) 0Alk , -C (0) NR7R8 or -C (S) NR7R8). This type of reaction can be performed at a temperature ranging from room temperature to 80 ° C, optionally in a base (such as TEA or NaH) or alternatively (for example, for isothiocyanate) monoacid (such as three In the presence of fluoroacetic acid, use appropriate fluorenyl halides, dichloromethane, pyridine, or DMF, alkyl chloroformates, isocyanate, or isothiocyanate. get on. 200406394 Way?

在途徑7中，基團B與R係相同於基團A-R4,而（R+ RD 分別地如在該通式I中所示；R2與R3係相同於在該通式中所 示，而Ra係為一低級烷基基團或該二個基團被連接而形 5 成一 1，3-二氧戊烷基或1，3·-等烷基（i，3-dioxanyl)基團。 如那些熟習此項技術者所熟知的，一適當的商業上之苯甲 基衍生物（具有X =鹵素或甲磺醯基氧基或對甲苯磺醯基氧基 基團）可被反應俾以提供苯乙腈（19)。這些反應物可採用已知的 烷基化方法分別地以烯丙基i化物（或烯丙基甲磺酸或甲苯磺 10 酸）或鹵烷基醛以它們的羰基被保護之形式（縮醛或二氧戊烷基 衍生物或其他者）與它們反應，而被轉換成為化合物(20)或（28)。 200406394 這些烧基化反應可藉由驗的使用而被進行，俾以產生反應 性苯甲基碳陰離子。所使用的驗之實例係為在一自_78〇c至迴 流溫度的溫度範圍下，配於一適當的溶劑（諸如THF或Et20或 DMF或其他者）之一異丙基酿胺链[lithium 5 diisopropylamide(LDA)]或第三丁基鋰或NaH或叔丁醇鉀或鈉 胺或鉀胺或其他者。一較佳的烧基化方法包括在_78。匚至室溫 下’在六曱基偶磷三醯胺或DMPU的存在下，使用受阻的驗 (hindered bases)(諸如 LDA) 〇 化合物（20)可依次藉由在一自-78〇c至溶劑迴流的溫度 10範圍下，使用配於一適當的溶劑（甲苯、DMF、CH2C12或其他 者）之二異丁氫化鋁（DIBAL-H)而被還原。從而所獲得的醛（21) 接而採用被那些熟習此項技術者所熟知的方法而被羰基保 護，俾以產生化合物（22)，其可被催化地鑕化(〇smilated) (c. p.In route 7, groups B and R are the same as groups A-R4, and (R + RD are respectively as shown in the general formula I; R2 and R3 are the same as shown in the general formula, and Ra is a lower alkyl group or these two groups are connected to form a 1,3-dioxolyl or 1,3 ·-and other alkyl (i, 3-dioxanyl) group. As is well known to those skilled in the art, a suitable commercially available benzyl derivative (having X = halogen or methylsulfonyloxy or p-toluenesulfonyloxy group) can be reacted to provide Phenylacetonitrile (19). These reactants can be separately known as allyl iides (or allyl methanesulfonic acid or tosyl 10 acid) or haloalkyl aldehydes by their carbonyl groups using known alkylation methods. Protected forms (acetals or dioxolyl derivatives or others) react with them and are converted into compounds (20) or (28). 200406394 These calcination reactions can be carried out by inspection. In order to produce a reactive benzyl carboanion, an example of the test used is a temperature range from -78 ° C to the reflux temperature, formulated in a suitable solvent (Such as THF or Et20 or DMF or others) one of the lithium 5 diisopropylamide (LDA) chains or tertiary butyl lithium or NaH or potassium tert-butoxide or sodium amine or potassium amine or others. A preferred method of calcination includes the use of hindered bases (such as LDA) in the presence of hexafluorenylphosphinotriamide or DMPU at -78 ° C to room temperature. Compound (20 ) Can be used in order by using a diisobutylaluminum hydride (DIBAL-H) formulated in an appropriate solvent (toluene, DMF, CH2C12 or other) at a temperature ranging from -78 ° C to the reflux temperature of the solvent. Is reduced. The aldehyde (21) thus obtained is then protected by a carbonyl group using methods well known to those skilled in the art, to produce a compound (22), which can be catalytically oxidized (〇smilated) ( cp

Forbes J.C.S· Perkin Trans I，1979, 906-910)或經歷臭氧化作用 15俾以提供化合物（23)。化合物（23)可如上面所描述的被還原性 胺化俾以提供化合物（24)。藉由-般的方法之去保護基反應 (Deprotection)引導至醛(25)。 化合物（25)另擇地可由在化合物（2〇)上實施鑽化 (〇—η)或臭氧化作用操作程序而被獲得。從而所獲得的氰 20基丙搭(26)接而被還原性胺化成化合物(27)。在這些化合物上重 複上方所描述的該DIB AL_H還原反應來提供該等酸(Μ)。 藉由簡單的官能性叛基之去保護基作用，化合物(Μ)可容 易地自化合物(28)中被獲得。 L (其中Μ係為一金屬鹽類’諸如鋰或鎂南化物)與化 35 200406394 合物（25)之反應提供化合物（I)。一大數量之有機金屬性(諸如鋰 或鎂）衍生物係為商業上可得的或容易被製備的，且可在_78。0 迴流下，在一適當的溶劑（諸如THF或Et20或其他者）中被反 應0 5 立體化學 在途徑1、6以及7中，化合物I在帶有依所使用的該反 應條件之比例的非對映異構物之順向/反向混合物中被獲得。該 等非對映異構物可藉由對那些熟習此項技術者而言已知之通 常技術包括鹼或它們的鹽類之分段結晶或色層技術(諸如LC或 10閃蒸層析法）而被分離出來。就該等非對映異構物這兩者而言， 化學式la之(+)鏡像異構物可使用在本技術中已熟知之技術與 操作程序自㈠鏡像異構物中被分離出來，諸如被描述於j.Forbes J.C.S. Perkin Trans I, 1979, 906-910) or undergo ozonation for 15% to provide compound (23). Compound (23) can be reductively aminated with amidine as described above to provide compound (24). Deprotection is led to the aldehyde (25) by a general method. The compound (25) can alternatively be obtained by performing a drilling (0-η) or ozonation operation procedure on the compound (20). The obtained cyano 20-propyl group (26) was then reductively aminated into the compound (27). The DIB AL_H reduction reaction described above was repeated on these compounds to provide the acids (M). The compound (M) can be easily obtained from the compound (28) by a simple functional deprotection group. The reaction of L (wherein M is a metal salt such as lithium or a magnesium sulphide) with the compound (25) provides compound (I). A large number of organometallic (such as lithium or magnesium) derivatives are commercially available or easily prepared, and can be used under reflux at a suitable solvent such as THF or Et20 or other (0) Stereochemistry In Routes 1, 6, and 7, Compound I is obtained in a forward / reverse mixture with diastereomers in proportion to the reaction conditions used. These diastereomers can be obtained by conventional techniques known to those skilled in the art, including stepwise crystallization or chromatography of bases or their salts (such as LC or 10 flash chromatography). And separated. For both of these diastereomers, the (+) mirror isomers of chemical formula la can be separated from the mirror isomers using techniques and procedures well known in the art, such as Described in j.

Jacques，et al·，’’Enantiomers，Racemates、and Resolutions，，，JohnJacques, et al ·, ’’ Enantiomers, Racemates, and Resolutions ,, John

Wiley and Sons，Inc.，1981中者。例如，以一適合之有機溶劑（諸 15如乙醇/乙腈）之光學層析，而Chiralpak AD填充(2〇 micron)亦 可被利用來達成該等鏡像異構物的分離。 化學式I之自由驗，它們的非對映異構物或鏡像異構物 在本技術中已熟知之標準條件下可被轉換成為相對應之藥學 上可接受的鹽類。例如，化學式I之自由驗被溶於-適合之 20Wiley and Sons, Inc., 1981. For example, optical chromatography with a suitable organic solvent (such as ethanol / acetonitrile), and Chiralpak AD packing (20 micron) can also be used to achieve separation of these mirror isomers. In the free test of formula I, their diastereomers or mirror isomers can be converted into corresponding pharmaceutically acceptable salts under standard conditions well known in the art. For example, the free test of formula I is dissolved in

有機溶劑（㈣甲醇）中，以例如—t量的順τ稀二酸或乙二 酸，例如-或二當量的氫氯酸或甲磺酸予以處理，接而在“ 下予以濃縮俾以提供該相對應之藥學上可接受㈣類。殘_ 接而可措由再結晶’從—適合之有機溶劑或有機溶劑混合物（諸 如曱醇/二乙醚）中被純化出來。 36 4呢94 藉由那些熟習此項技術者已孰▲ ^ πα '、之簡單的氧化作用操作 鞋序可合成化學式I之化合物的 ^ 队氧化物。被描述於Ρ. Brougham et al. (Synthesis, 1015^1 m 7, 1987)中之氧化作用操 作程序，容許哌畊環的兩個氮被分为丨 J出來，而能夠獲得N-氧化 物與N，N’-二氧化物這兩者。 10 15 20 在某些具體例中，尿道病症藉由 積由一化學式I之化合物結 合以一額外的^ΗΊ^α拮抗劑或一個 ★壬a —或更多額外種類的受體 之枯抗劑來投樂而被治療。在較佳夏綱 具體例中，一化學式I之化 合物結合以一 αΐ-腎上腺素激導性的Γ n〇ci-adrenergic)、或簟毒驗 性的受體(muscarinic receptors)之拮抗劑而被投藥。 在又一具體例中’ 了泌尿道疾簡由-化學式〗之化合 物結合以-或更多環氧化酶酵素之抑制劑（其可抑制⑶幻與 C0X2異酶這兩者或其可，另擇地，被選擇針對⑺χ2異酶， 以及其NO給予體衍生物）之投藥而被治療。 作為與一化學式I之化合物結合投藥之抗簟毒作用性藥 物之實例係為奥斯必得寧（oxybutynin)、托特羅定(t〇lter〇dine)、 達非那新(darifenacin)，以及替米維林(temiverine)。 一化學式I之化合物可與αΐ-腎上腺素激導性的拮抗劑結 合來被投藥，作為下泌尿道徵狀之治療，無論這些是否與ΒΡΗ 相關。適合作為與一化學式I之化合物結合投藥之較佳的…— 腎上腺素激導性的拮抗劑係為，例如，普拉辛(prazosin)、多薩 坐辛（doxazosin)、特若辛（terazosin)、阿夫唑嗪（alfuzosin)，以 及他蘇洛辛(tamsulosin)。額外的適合作為與一化學式I之化合The organic solvent (methanol) is treated with, for example, t-cis dilute diacid or oxalic acid, such as-or two equivalents of hydrochloric acid or methanesulfonic acid, and then concentrated under "to provide The corresponding pharmaceutically acceptable amidines. Residues can then be purified by recrystallization from a suitable organic solvent or organic solvent mixture (such as methanol / diethyl ether). 36 4? 94 By Those skilled in the art have already used ▲ ^ πα ', a simple oxidation operation to synthesize ^ team oxides of compounds of formula I. They are described in P. Brougham et al. (Synthesis, 1015 ^ 1 m 7 , 1987) allows the two nitrogens of the pipering ring to be divided into J, and both N-oxides and N, N'-dioxides can be obtained. 10 15 20 In some specific examples, urethral disorders are caused by the combination of a compound of formula I with an additional ^ ΗΊ ^ α antagonist or a nona- or more additional type of receptor antagonist. Treatment. In a specific example of Xia Gang, a compound of formula I is combined with an α -adrenergic Γ n〇ci-adrenergic), or 簟 antagonists of muscarinic receptors, were administered. In yet another specific example, the urinary tract disease is simply-chemical formula The compound is combined with-or more inhibitors of cyclooxygenase enzymes (which can inhibit both CD3 and COX2 isomerase or alternatively, alternatively, it is selected to target ⑺χ2 isomerase, and its NO donor derivative The drug is treated with a drug. Examples of anti-toxic drugs that are administered in combination with a compound of formula I are oxybutynin, tolterodine, and dafil Darifenacin, and temiverine. A compound of formula I can be administered in combination with αΐ-adrenergic antagonists to treat lower urinary tract symptoms, whether or not they are associated with ΒΡΗ related. It is better to be administered in combination with a compound of the formula I. — The adrenergic antagonist is, for example, prazosin, doxazosin, teroxin (Terazosin), alfuzosin (alfu zosin), and tamsulosin. Additional suitable as a combination with a chemical formula I

37 200406394 物結合投樂之αΐ-腎上腺素激導性的拮抗劑係被描述於美國專 利第 5,9905114、6,306,861、6,365,59卜65387,909 以及 6,403,594 號中。 可與一化學式I之化合物結合而來被投藥之5_ΗΤια拮 5 抗劑的貝例係被發現於 Leonardi et al.，J.尸jExp. 77^r.37 200406394 Alpha-adrenergic antagonists that bind to Tola are described in U.S. Patent Nos. 5,9905114, 6,306,861, 6,365,59, 65387,909, and 6,403,594. Examples of 5_ΗΤια antagonists that can be combined with a compound of formula I to be administered as 5_ΗΤια antagonists have been found in Leonardi et al., J. Shi JExp. 77 ^ r.

1027-1037，2001 (例如，Rec 15/3079)，美國專利第 6,071，920號，其他苯基哌畊衍生物被描述於WO 99/06383以 及在審查中的美國專利申請案序號10/266,088與 10/266，1〇4(在2〇〇2年1〇月7曰提出申請）中。額外的孓HTia 10 拮抗劑包括DU-125530與被描述於美國專利第5,462,942號中 之相關的化合物以及robalzotan與被描述於WO 95/11891中之 相關的化合物。1027-1037, 2001 (e.g., Rec 15/3079), U.S. Patent No. 6,071,920, other phenylpiperin derivatives are described in WO 99/06383 and the pending U.S. patent application serial number 10 / 266,088 and 10 / 266,104 (application was made on October 7, 2002). Additional 孓 HTia 10 antagonists include DU-125530 and related compounds described in U.S. Patent No. 5,462,942 and robalzotan and related compounds described in WO 95/11891.

可與一化學式I之化合物結合而來被投藥之選擇性的 COX2抑制劑之實例係為，非限定，尼美舒利（nimesuiide)、美 15 洛西卡（meloxicam)、羅菲可西保（rofecoxib)、希樂操 (celecoxib)、帕瑞考昔(parecoxib)以及伐地考昔(valdecoxib)。 額外的選擇性的COX2抑制劑之實例係被描述於，非限定，US 6,440,963中。非選擇性的COX1-COX2抑制劑之實例係為，非 限定，乙酿水楊酸、尼福密酸（niflumic acid)、福納密酸 20 (flufenamic acid)、enfenamic acid、曱氯芬那酸(meclofenamic acid)、托芬那酸(tolfenamic acid)、thiaprophenic acid、α -甲基 -4·•異丁基-苯乙酸、（+)-6-曱氧基-α -曱基-2-萘乙酸、2-(3-苯基 酿苯基）丙酸、夫比普洛芬（flurbiprofen)、furprofen、叫卜朵甲阿 辛、acemethacin、proglumethacin、克多羅多克(ketorolac)、待 38 200406394 克菲那（diclofenac)、艾特多雷克（etodolac)、蘇林達克 (sulindac)、fentiazac、特若西卡（tenoxicam)、氯諾西康 (lornoxicam)、cynnoxicam、ibuproxam、男p 另,J 敏痛（nabumetone)、 甲‘苯美定、氨托美丁（amtolmetin)。因此，前述中的每一者係為 5 可與一化學式I之化合物結合而被投藥之COX抑制劑之非限 定實例。Examples of selective COX2 inhibitors that can be administered in combination with a compound of formula I are, without limitation, nimesuiide, meloxicam, roficoxib ( rofecoxib), celecoxib, parecoxib, and valdecoxib. Examples of additional selective COX2 inhibitors are described in, without limitation, US 6,440,963. Examples of non-selective COX1-COX2 inhibitors are, without limitation, ethyl alcohol salicylic acid, niflumic acid, flufenamic acid 20, enfenamic acid, clofenamic acid (meclofenamic acid), tolfenamic acid, thiaprophenic acid, α-methyl-4 · isobutyl-phenylacetic acid, (+)-6-fluorenyloxy-α-fluorenyl-2-naphthalene Acetic acid, 2- (3-Phenylphenyl) propanoic acid, flurbiprofen, furprofen, called badolacine, acemethacin, proglumethacin, ketorolac, wait 38 200406394 Diclofenac, etodolac, sulindac, fentiazac, tenoxicam, lonnoxicam, cynnoxicam, ibuproxam, male p. Nabumetone, mebendine, amtolmetin. Therefore, each of the foregoing is a non-limiting example of a COX inhibitor that can be administered in combination with a compound of formula I.

可與一化學式I之化合物結合而被投藥之cox抑制劑之 衍生物的實例係為帶有硝酸鹽（硝基氧基）或亞硝酸鹽基團之 COX抑制劑之衍生物，諸如那些提供在，例如，WO 98/09948 10 中，能在活體内釋放NO者。 藥學組成物Examples of derivatives of a cox inhibitor that can be administered in combination with a compound of formula I are derivatives of a COX inhibitor with a nitrate (nitrooxy) or nitrite group, such as those provided in For example, WO 98/09948 10 can release NO in vivo. Pharmaceutical composition

本發明進一步提供包含一化學式I之化合物或一鏡像異 構物、非對映異構物、Ν-σ瓜畊氧化物、、结晶形式、水合物、 溶劑化物、活性新陳代謝物或該化合物之藥學上可接受的鹽類 15 之藥學組成物。該藥學組成物亦可包括選擇性的添加劑，諸如 一藥學上可接受的載劑或稀釋劑、一芳香劑、一甜料、一防腐 劑、一染料、一黏合劑、一懸浮劑、一分散劑、一著色劑、一 崩解劑、一賦形劑、一稀釋劑、一潤滑劑、一吸收促進劑、一 殺菌劑以及類似之物、一安定劑、一可塑劑、一食用油、或二 2〇 或更多該等添加劑之任何組合。 適合之藥學上可接受的載劑或稀釋劑包括，但非被限制 於，乙醇、水、甘油（glycerol)、蘆薈膠(al〇e vera gel)、脲嚢素、 甘油（glycerine)、維他命-A與E油、礦物油、磷酸缓衝液（或生 理食鹽水？？）、 PPG2肉莖惹丙酸酷（ppG2 myristyl 39 200406394 propionate)、碳酸鎮、碟酸钟、植物油、動物油以及solketal。 適合之黏合劑包括，但非被限制於，澱粉、明膠、天然的 糖類諸如葡萄糖、蔗糖以及乳糖、玉米甜料、天然的與合成的 樹膠諸如阿拉伯膠、黃蓍膠、植物膠、海藻酸鈉、羧甲纖維素、 5 聚乙二醇、蠟以及類似之物。 適合之崩解劑包括，但非被限制於，澱粉（諸如玉米澱 粉）、曱基纖維素、洋菜、皂土、黃原膠以及類似之物。The present invention further provides a compound of Formula I or a mirror image isomer, diastereomer, N-sigma quaternary oxide, crystalline form, hydrate, solvate, active metabolite, or pharmacy of the compound. Pharmaceutically acceptable composition of salt 15. The pharmaceutical composition may also include optional additives such as a pharmaceutically acceptable carrier or diluent, a fragrance, a sweetener, a preservative, a dye, a binder, a suspending agent, a dispersion Agent, a colorant, a disintegrant, an excipient, a diluent, a lubricant, an absorption enhancer, a fungicide and the like, a stabilizer, a plasticizer, an edible oil, or Any combination of two or more of these additives. Suitable pharmaceutically acceptable carriers or diluents include, but are not limited to, ethanol, water, glycerol, aloe vera gel, urea, glycerine, vitamin- A and E oils, mineral oils, phosphate buffered saline (or physiological saline solution), PPG2 myristyl 39 200406394 propionate, carbonated water, dish acid bell, vegetable oil, animal oil, and soketal. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose, sucrose and lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth, vegetable gum, sodium alginate , Carmellose, 5 polyethylene glycols, waxes and the like. Suitable disintegrants include, but are not limited to, starch (such as corn starch), amyl cellulose, agar, bentonite, xanthan gum, and the like.

適合之潤滑劑包括，但非被限制於，油酸鈉、硬脂酸鈉、 硬脂酸鎂、苯甲酸鈉、乙酸鈉、氯化鈉以及類似之物。 10 適合之懸浮劑包括，但非被限制於，皂土。 適合之分散與懸浮劑包括，但非被限制於，合成的與天然 的樹膠諸如植物膠、黃箸膠、阿拉伯膠、海藻酸、聚葡萄糖、 羧甲纖維素鈉、甲基纖維素、聚乙烯吡咯酮以及明膠。 適合之食用油包括，但非被限制於，棉子油、芝麻油、椰 15 子油以及花生油。Suitable lubricants include, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. 10 Suitable suspending agents include, but are not limited to, bentonite. Suitable dispersing and suspending agents include, but are not limited to, synthetic and natural gums such as vegetable gum, tragacanth gum, acacia gum, alginic acid, polydextrose, sodium carmellose, methyl cellulose, polyethylene Pyrrolidone and gelatin. Suitable edible oils include, but are not limited to, cottonseed oil, sesame oil, coconut oil, and peanut oil.

額外的添加劑之實例包括，但非被限制於，山梨糖醇、滑 石、硬脂酸以及磷酸二鈣。 單位劑量形式 該藥學組成物可被配製為單位劑量形式，諸如藥錠、丸 20 劑、膠囊、大丸劑、粉末、顆粒、無菌非經腸的溶液、無菌 非經腸的懸浮液、無菌非經腸的乳劑、醜劑（elixirs)、g丁劑、定 量噴霧劑（metered aerosol)、液態喷霧劑（liquid sprays)、滴劑、 安瓶（ampoules)、自體注射器裝置（autoinjector devices)或栓 劑。該單位劑量形式可被使用作為口服、非經腸的、鼻内的、 40 200406394 舌下的或直腸的投藥，或藉由吸入或吹入、穿透皮膚的貼片， 以及一冷凍乾燥組成物來作為投藥。一般而言，任何致使全身 利用此等成份之活性成份的傳送可以被使用。較佳地，該單位 劑罝形式係為一口服劑量形式，最較佳地一固體狀口服劑量； 因此較佳的劑量形式係為藥錠、丸劑以及膠囊。然而、非經腸 的製品亦係為較佳的。 10 固體狀單位劑量形式可藉由將本發明之活性劑混合以一 藥學上可接受的載劑與任何其他如上面所描述之所欲的添加 d而被製備。該混合物典型地被混合直到—本發明之該等活性 劑的同質混合物被獲得且該_與任何其它所欲的添加劑被 开7成φ皮平均地分散遍及該組成物。在此例 中，該組成物可被形成有如乾的或濕的顆粒。 ^里形式可被配製為，例如，"直接釋出，，劑量形式。” 15 直接釋出”劑量形式典型地被配製為當被測試於—藥物溶解試 驗時，例如美國藥典標準<711>，在侧分鐘内釋出至少 6〇%撕°之活性成份的藥錠。在-較佳具體财，直接劑量形 式在約45分鐘内釋出75%的活性成份。 形式亦可被配製為，例如，”控制釋出，，劑量形式。” "，J轉、衫’’或"時間釋出，，劑量形式係為等效用詞， :描述當該活性料可經過—段時間，-般而言其係在分鐘、 天的等級上，典型地自約六十分鐘至約3天的範圍，以 可板知的與爾蝴自—彳㈣嶋物，而非當 ^至μ道或當接觸到胃㈣立即地被散料，所發生之活 麟运的形式。—控制釋出速率可變化作為—因子多樣性功 20 200406394 能。在控制釋出中影響傳送速率的因子包括粒子尺寸、組成 物、多孔性、電荷結構、及傳送載劑與活性成份之水合程度、 環境（傳送載劑内在的與外在的兩者之一）的酸度，以及活性劑 在生理學環境中（亦即，沿著消化道特別的位置）的溶解度。作 5 為控制釋出形式之溶解試驗之典型的參數被發現於美國藥典 標準<724>中。Examples of additional additives include, but are not limited to, sorbitol, talc, stearic acid, and dicalcium phosphate. Unit-dose form The pharmaceutical composition can be formulated in unit-dose forms such as tablets, pills, 20 capsules, boluses, powders, granules, sterile parenteral solutions, sterile parenteral suspensions, sterile parenteral Intestinal emulsions, elixirs, g-butans, metered aerosols, liquid sprays, drops, ampoules, autoinjector devices or suppositories . This unit dosage form can be used as an oral, parenteral, intranasal, 40 200406394 sublingual or rectal administration, or a patch that penetrates the skin by inhalation or insufflation, and a freeze-dried composition Come as medicine. In general, any active ingredient that causes the systemic use of these ingredients can be used. Preferably, the unit dosage form is an oral dosage form, most preferably a solid oral dosage form; therefore, the preferred dosage forms are tablets, pills, and capsules. However, parenteral products are also preferred. 10 Solid unit dosage forms can be prepared by mixing the active agent of the present invention with a pharmaceutically acceptable carrier and any other desired additions d as described above. The mixture is typically mixed until a homogeneous mixture of the active agents of the present invention is obtained and the other ingredients are dispersed uniformly throughout the composition. In this example, the composition can be formed as dry or wet particles. The form may be formulated as, for example, " direct release, " a dosage form. The "15 Direct Release" dosage form is typically formulated as a tablet that releases at least 60% of the active ingredient in a side minute when tested in a drug dissolution test, such as the US Pharmacopoeia Standard < 711 > . In the preferred embodiment, the direct dosage form releases 75% of the active ingredient in about 45 minutes. The form can also be formulated as, for example, "controlled release, a dosage form." &Quot;, J turn, shirt '' or " time release, and the dosage form is an equivalent term, which describes when the active ingredient is It can pass over a period of time, in general it is on the level of minutes and days, typically in the range of about sixty minutes to about three days. It is not a form of vitality that occurs when it is not in the μ channel or when it comes into contact with the gastric cavity immediately. -Controlled release rate can be varied as a factor diversity function. The factors that affect the delivery rate in controlling the release include particle size, composition, porosity, charge structure, and the degree of hydration of the delivery vehicle and the active ingredient, the environment (either the internal or external delivery vehicle) Acidity, and the solubility of the active agent in the physiological environment (ie, a particular location along the digestive tract). Typical parameters for a dissolution test to control the release form are found in the United States Pharmacopoeia Standard < 724 >.

劑量形式亦可被配製成以多相的階段來傳送活性劑，藉此 一活性成份之一第一部份在一第一速率下被釋出，且至少一活 性成份之第二部分在一第二速率下被釋出。在一較佳具體例 10 中，一劑量形式可被配製成以一雙相的方式來傳送活性劑，其 係包含一第一 ’’直接釋出相"，其中活性成份的一部份以一上面 所述之用以立即釋出劑量形式的速率被傳送，以及一第二"控制 釋出相π，其中該活性成份之殘餘部分以一如上面所述之用以控 制釋出劑量形式之控制釋出方式被釋出。 15 藥錠或丸劑可被塗覆或用別的方法被製備，俾以形成一具Dosage forms can also be formulated to deliver the active agent in a heterogeneous phase whereby a first part of an active ingredient is released at a first rate and at least a second part of an active ingredient is in a Released at the second rate. In a preferred embodiment 10, a dosage form can be formulated to deliver the active agent in a biphasic manner, which comprises a first `` direct release phase '', in which a portion of the active ingredient It is delivered at a rate as described above for immediate release dosage form, and a second " controlled release phase, where the remainder of the active ingredient is used as described above for controlled release dosage. The form of controlled release is released. 15 Tablets or pills can be coated or prepared by other methods to form a

有延遲與/或維持作用之單位劑量形式，諸如控制釋出與延遲釋 出之單位劑量形式。例如，該藥錠或丸劑可包含一内部的劑量 與一外在的劑量組成，後者係以一層或包膜的形式覆於前者。 該二組成可藉由一在胃中作為抵抗分解的腸層而被分離，且允 20 許該内部的組成完整的通過進入十二指腸或被延遲釋出。 用以控制該等活性劑釋出之可生物分解的聚合物包括，但 非被限制於，聚乳酸、Ipolyepsilon caprolactonel、聚經基丁酸、 聚正酯(Ipolyorthoesters)!、聚縮酸、聚二氫旅喃、聚氰基丙烯酸 _以及經交聯或兩性阻斷（amphipathic block)之水凝膠 42 200406394 (hydrogels)共聚物。 就液體狀劑量形式而言，活性物質或它們在生理學上可接 受的鹽類選擇性地以經常使用的物質諸如安定劑、乳化劑或其 他的助劑予以溶解、懸浮或乳化。作為活性結合與該等相對應 5 之生理學上可接受的鹽類之溶劑可包括水、生理的鹽類溶液或 醇，例如乙醇、丙二醇或甘油。此外，糖類溶液(諸如葡萄糖或 甘露醇溶液）可被使用。一種所提及之各種不同溶劑的混合物亦 可被使用於本發明中。 一穿透皮膚的劑量形式亦被本發明所預期。穿透皮膚的形 10 式可係為一利用一液態貯器（fluid reservoir)或一黏著劑包藥 (drug-in-adhesive)基質系統兩者之一的擴散穿透皮膚系統（穿透 皮膚的貼片）。其他穿透皮膚的劑量形式包括，但非被限制於， 局部藥膠、乳液、軟膏、穿過黏膜的系統與裝置，以及離子電 滲性（電性擴散)傳送系統。穿透皮膚的劑量形式可被用來作為 15 本發明之該等活性劑之延遲釋出與維持釋出。 作為非經腸的投藥（且特別地經由注射）之本發明的藥學 組成物與單位劑量形式典型地包括一如上面所描述之藥學上 可接受的載劑。一較佳的液體狀載劑係為植物油。注射可係 為，例如，靜脈内、硬膜外的、椎管内的、肌肉内、管腔内的、 20 氣管内的或皮下。 該等活性劑亦可以微脂粒傳送系統之形式（諸如小的單層 囊、大的單層囊以及多層囊）來被投藥。微脂粒可被形成自各種 不同的碟脂，諸如膽固醇、硬脂醯胺(stearylamine)或破酯醯膽。 本發明之該等活性劑亦可被結合以可溶解的聚合物（諸如 43 200406394 標的藥物載劑）。此等聚合物包括，但非被限制於、聚乙稀。比。各 酮、哌喃共聚物、聚羥丙基甲基丙烯醯胺基酚 (polyhydroxypropylmethacrylamidophenol)、聚羥乙基天冬酸醯 胺基酚（polyhydroxyethylaspartamidophenol)以及以棕櫚醯殘基 5 取代的聚乙嫦氧聚離胺酸(polyethylenoxyp〇lylySine)。 授藥 本發明之藥學組成物或單位劑量形式可藉由各種不同的 途徑被投藥，諸如口服與腸内的、靜脈内、肌肉内皮下、穿透 皮膚的、穿過黏膜的（包括直腸的與口的）以及經由吸入途徑。 10 口服或牙透皮膚的途控係為較佳的（例如，分別地，固體狀或液 體狀配方或皮膚貼片）。 包含一本發明之有效量的藥學組成物或單位劑量形式可 被投藥至一被 E· J.McGuire 描述於 “Campbeirs UROLOGY，5, 5 Ed·’ 616-638, 1986’ W.B· Saunders Company 中需要治療下泌 15尿道之神經與肌的官能障礙的動物（較佳地一人類），以及罹患 任何有關5-HT1A受體功能損傷之生理上官能障礙的病人。此 等吕月b障礙包括’非限定，中樞神經系統病症諸如抑鬱、焦慮、 飲食性病症、性官能障礙、成癌與相關問題。 如此處所用的，“有效量，，該用詞意指一致使一特殊病症 20之至少-個症狀或特徵有可預見的改善之數量。在一較佳具體 例中4化&物/α療尿道的病症，諸如尿急、膀胱過動症、尿 頻率增加、膀胱貯藏容量減少、膀胱炎（包括間質性膀胱炎）、 失禁、漏尿、遺尿、排尿困難、排尿遲緩與在排空膀胱上的困 難或由方、血，月促進素激導的官能障礙所致之中槐神經系統病 44 200406394 症（諸如焦慮、抑鬱、壓力過高、睡醒週期病症、進食行為、性 功能），與在哺乳類動物（特別地一人類）中有關於撞擊、損傷、 癡呆與由於神經學上的發展所造成之認識力病症，自有關於一 注意力不足(ADHD)之活動性過度而來之病症、藥癮、藥脫瘾、 5 大腸急躁症候群。 本發明之藥學組成物或單位劑量形式可依據一藉由依照 上述所提供的指導方針之常規的試驗所定義之劑量與投藥治 療而被給予，為了要獲得最理想的活性同時將對一特殊病人的 毒性或副作用減到最低。然而，此美好的調整之治療的療法係 10 依照此處所示之指導方針之例行程序。 本發明之該等活性劑的劑量可依據各種不同的因素諸如 潛在的疾病條件、個體的條件、體重、性別與年齡，以及投藥 的方式而有不同的變化。一用以治療一病症之有效量可藉由具 有此領域通常技術者已知之經驗上的方法而輕易地被決定出 15 來，例如藉由建立一劑量基礎與投藥頻率並且在該基礎中的各 個點去對照一實驗性的組或對象之群組。被投藥至一病人之確 切的數量將端視該病症之狀態與嚴重性以及該病人之身體條 件而有不同的變化。一任何症狀或特徵之可預見的改善可藉由 一熟習此項技術者來被判定或藉由病人對醫師而被報告出 20 來。將被了解的是任何尿道病症的症狀或特徵之任何臨床上或 統計上顯著的減少或改善係在本發明之領域範圍内。臨床上顯 著的減少或改善意指對病人與/或對醫師而言是可察覺的。 例如，一單一的病人可能同時地患有數個排尿困難的徵 狀，諸如，例如，急尿與排尿過度頻繁或這兩者，而這些可使 45 200406394 用本發明之方法予以降低。在失禁的案例中，任何在頻率上或 不需要通過之尿量上的減少係被視為一本治療方法之有益的 效果。Unit dose forms with delayed and / or sustained effects, such as controlled release and delayed release unit dose forms. For example, the tablet or pill may consist of an internal dose and an external dose, the latter being a layer or an envelope over the former. The two components can be separated by an intestinal layer that resists decomposition in the stomach, and allows the internal components to pass through the duodenum intact or be delayed. Biodegradable polymers used to control the release of these active agents include, but are not limited to, polylactic acid, Ipolyepsilon caprolactonel, polybutyric acid, poly (n-polyesters) !, polyacetic acid, polydiacetate Hydrogen travel, polycyanoacrylic acid, and hydrogels 42 200406394 (hydrogels) copolymers that are crosslinked or amphipathic block. In the case of liquid dosage forms, the active substances or their physiologically acceptable salts are optionally dissolved, suspended or emulsified with frequently used substances such as stabilizers, emulsifiers or other adjuvants. Solvents which actively bind physiologically acceptable salts corresponding to these may include water, physiological salt solutions or alcohols, such as ethanol, propylene glycol or glycerol. In addition, sugar solutions (such as glucose or mannitol solutions) can be used. A mixture of the various solvents mentioned can also be used in the present invention. A skin-penetrating dosage form is also contemplated by the present invention. The skin-penetrating form 10 can be a diffusion penetrating skin system (a skin-penetrating system) that utilizes either a liquid reservoir or a drug-in-adhesive matrix system Patch). Other skin-penetrating dosage forms include, but are not limited to, topical gels, lotions, ointments, systems and devices that pass through the mucosa, and iontophoretic (electrical diffusion) delivery systems. Skin-penetrating dosage forms can be used as delayed and sustained release of the active agents of the present invention. The pharmaceutical compositions and unit dosage forms of the present invention for parenteral administration (and particularly via injection) typically include a pharmaceutically acceptable carrier as described above. A preferred liquid carrier is a vegetable oil. Injections can be, for example, intravenous, epidural, intraspinal, intramuscular, intraluminal, 20 tracheal, or subcutaneous. These active agents can also be administered in the form of microlipid delivery systems such as small monolayer capsules, large monolayer capsules, and multilayer capsules. Microlipids can be formed from a variety of different lipids, such as cholesterol, stearylamine, or cholesterol. The active agents of the present invention can also be combined with a soluble polymer (such as 43 200406394 drug carrier). Such polymers include, but are not limited to, polyethylene. ratio. Ketones, piperan copolymers, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenol, and polyacetoxyl substituted with palmitoyl residue 5 PolyethylenoxypolylySine. Administration The pharmaceutical composition or unit dosage form of the present invention can be administered by a variety of routes, such as oral and enteral, intravenous, submuscular endothelium, transdermal, transmucosal (including rectal and Oral) and via the inhalation route. 10 Oral or transdermal route control is preferred (for example, solid or liquid formulations or skin patches, respectively). Containing an effective amount of a pharmaceutical composition or unit dosage form of the present invention can be administered to a drug described by E.J. McGuire in "Campbeirs UROLOGY, 5, 5 Ed. '616-638, 1986' WB · Saunders Company Animals (preferably humans) for the treatment of neurological and muscular dysfunction of the lower urinary tract 15, as well as patients suffering from any physiological dysfunction associated with 5-HT1A receptor dysfunction. These disorders include 'non- By definition, central nervous system disorders such as depression, anxiety, dietary disorders, sexual dysfunction, carcinogenesis and related problems. As used herein, "effective amount," the word means to consistently make at least one of a particular disorder 20 The number of predictable improvements in symptoms or characteristics. In a preferred embodiment, urinary tract disorders such as urgency, overactive bladder, increased urinary frequency, decreased bladder storage capacity, cystitis (including interstitial cystitis), incontinence, Leaky urine, enuresis, dysuria, dysuria, and difficulty in emptying the bladder, or dysfunction induced by prescription, blood, and stimulant-induced dysfunction, such as anxiety, depression, stress, etc. 44 200406394 Excessive, waking cycle disorders, eating behaviors, sexual function), and impacts, injuries, dementia, and cognitive disorders due to neurological development in mammals (especially a human) -Hyperactivity from ADHD, drug addiction, drug withdrawal, 5 large bowel irritability syndrome. The pharmaceutical composition or unit dosage form of the present invention can be administered in accordance with a dose and administration defined by routine trials in accordance with the guidelines provided above, in order to obtain the optimal activity and will be administered to a particular patient The toxicity or side effects are minimized. However, this wonderfully adjusted treatment regimen 10 follows the routines of the guidelines shown here. The dosage of the active agents of the present invention may vary depending on various factors such as underlying disease conditions, individual conditions, weight, sex and age, and the manner in which they are administered. An effective amount for the treatment of a condition can be easily determined by empirical methods known to those of ordinary skill in the art15, such as by establishing a dose basis and frequency of administration and each of the basis in the basis Click to compare an experimental group or group of subjects. The exact amount administered to a patient will vary depending on the condition and severity of the condition and the patient's physical conditions. A foreseeable improvement in any symptom or characteristic can be judged by a person skilled in the art or reported by a patient to a physician20. It will be appreciated that any clinically or statistically significant reduction or improvement in the symptoms or characteristics of any urethral disorder is within the scope of the present invention. A clinically significant reduction or improvement means perceptible to the patient and / or to the physician. For example, a single patient may have several symptoms of dysuria simultaneously, such as, for example, rapid and excessive urination or both, and these can be reduced by the method of the present invention. In the case of incontinence, any reduction in frequency or volume of urine that does not need to pass is considered a beneficial effect of this treatment.

被投藥之該劑的數量可在介於約0.01與約25 mg/kg/day 5 的範圍之間，較佳地介於約0.1與約10 mg/kg/day之間，而最 佳地介於0.2與約5 mg/kg/day之間。將被了解的是本發明之 藥學配方非必定需要含有在治療該病症上係為有效之該劑的 全部數量，因為此等有效量可藉由一複數劑量之此等藥學配方 的投藥而被達到。 10 在一本發明之較佳具體例中，該等化合物被配製於膠囊 或藥錠中（較佳地包含50至200 mg之本發明的化合物），且較 佳地以一 50至400 mg之總計每曰劑量來被投藥至一病人， 較佳地150至250 mg且最佳地約200 mg，在以5-HT1A受體 配位子的治療下用以減輕小便失禁與官能障礙。 15 一作為非經腸的投藥之藥學組成物包含就重量上自約The amount of the agent to be administered may be in a range between about 0.01 and about 25 mg / kg / day 5, preferably between about 0.1 and about 10 mg / kg / day, and most preferably Between 0.2 and about 5 mg / kg / day. It will be understood that the pharmaceutical formulations of the present invention need not necessarily contain the entire amount of the agent that is effective in treating the condition, because such effective amounts can be achieved by administration of multiple doses of these pharmaceutical formulations . 10 In a preferred embodiment of the present invention, the compounds are formulated in capsules or tablets (preferably containing 50 to 200 mg of the compound of the present invention), and preferably in the range of 50 to 400 mg. A total of one dose is administered to a patient, preferably 150 to 250 mg and most preferably about 200 mg, to relieve urinary incontinence and dysfunction under treatment with a 5-HT1A receptor ligand. 15 A pharmaceutical composition for parenteral administration

0.01%至約100%的本發明之該等活性劑，基於全部的藥學組成 物之100%重量之上。 一般而言，穿透皮膚的劑量形式含有就重量上相對於該劑 量形式之100%總重量之自約0.01%至約100%的該等活性劑。 20 該藥學組成物或單位劑量形式可以一單一每曰劑量來予 以投藥，或總計每日劑量可以經分配的劑量來予以投藥。此 外，作為此病症之治療的另一化合物的共同投藥或連續投藥可 令人所欲的。例如，本發明之該等化合物可結合以更多抗簟毒 作用性、ar腎上腺素激導性的拮抗劑、5-HT1A受體拮抗劑、或 46 200406394 cox抑制劑或其NO釋出衍生物來予以投藥，作為下泌尿道徵 λ療抗早毋作用性、α r腎上腺素激導性的拮抗劑、5 - Η Τ】Α 受體括抗劑、COX抑制劑以及其Ν〇釋出衍生物之實例係為上 面所述，非限定。 ίο0.01% to about 100% of the active agents of the present invention are based on 100% by weight of the entire pharmaceutical composition. Generally, skin-dosing dosage forms contain from about 0.01% to about 100% of these active agents by weight relative to 100% of the total weight of the dosage form. 20 The pharmaceutical composition or unit dosage form may be administered in a single daily dose, or the total daily dosage may be administered in divided doses. In addition, co-administration or continuous administration of another compound as a treatment for this condition may be desirable. For example, the compounds of the present invention may be combined with more antitoxic effects, ar adrenergic antagonists, 5-HT1A receptor antagonists, or 46 200406394 cox inhibitors or their NO-releasing derivatives To be administered as an anti-premature, anti-α-adrenergic antagonist of the lower urinary tract sign, α-adrenergic antagonists, 5-】] Α receptor antagonists, COX inhibitors, and its NO release Examples of the objects are as described above, without limitation. ίο

▲對於結合治療”’其中鱗化合物係在_的劑量配方 ^等化口物可同日可的被投藥，或各個可在個別錯開的時間 被投藥。例如，本發明之化合物可在早晨來予以投藥而該抗葦 毒作用性化合物可在傍晚來予以投藥，或反之亦然。額外的化 合物亦可在特定的_來被投藥。投_次序將端視各種不同 勺口素而疋包括病人的年齡、體重、性別與醫療狀態；被治 療之病症的嚴紐與_學、賴的賴、該病人之腎臟與肝 臟功能’賴人的治療史，以及病人的賴H欠序的決定 可被美好的調整且此美好的調整係依照於此處所提出的該等 指導方針之例行程序。 H治療之使用▲ For combined treatment "'wherein the squamous compound is in a dosage formula of ^ and other oral products can be administered on the same day, or each can be administered at individual staggered times. For example, the compound of the present invention can be administered in the morning The anti-reed toxic compound can be administered in the evening, or vice versa. Additional compounds can also be administered at specific times. The order of administration will depend on the different spoons, including the age of the patient. , Weight, gender, and medical status; the severity of the disease being treated, the science, the Lai's, the patient's kidney and liver function, the patient's history of treatment, and the patient's unordered decision can be beautifully made. Adjustments and this wonderful adjustment is a routine procedure in accordance with these guidelines presented here.

在不希望被理論所束缚下，據信5W1A受體拮抗劑之投 藥防止薦骨反射與/或控制排尿的皮質機制之不需要的活性。因 此，被預期的是一廣闊範圍之下泌尿道的神經與肌的官能障礙 可使用本發明之該等化合物予以治療，包括，非限定，排尿困 20難、失禁以及遺尿（膀胱過動症）。排尿困難包括頻尿、夜尿症 (nocturia)、急尿、尿適應性減低(膀胱貯存容量減低卜在排空 膀胱上的困難，亦即在排尿時一次理想的尿量被排出。失禁徵 候滅包括應力性失禁（stress incontinence)、急迫性失禁（urgency incontinence)與遣尿失禁（enuresis inc〇ntinence)，以及混合型失 47 200406394 禁。遺尿係有關在夜間或在睡眠時，尿液不受意志控制的通過。 本發明之該等化合物亦可用來作為由於血清促進素激導 的官能障礙所致之中樞神經系統病症之治療。 下面實施例代表如被廣泛地描述於上方之化學式I之該 5 等化合物的典型合成。這些實施利係僅做說明且非被意欲以任 何方法去限制本發明。試劑與起始物對具此領域中一般知識者 而言是易於獲得的。 實施例1 1-[4-環己基-3-(2-氟苯基)-4-甲氧丁基】-4-[2-(2,2,2- 三氟乙氧基)-苯基】-哌畊 10 1-玉哀己基-2-(2-氣苯基）乙酉同（4匕合物 la) 將2.14 ml的環己烷羰醯氯經由一注射器逐滴添加至一在 〇°C下攪拌的36 ml之2-氟苯甲基氯化鋅(0.5 Μ溶液，配於 THF中）與0.008 g之二氯（三苯基膦）-鈀(II)的混合物中。而 後，在室溫下攪拌該反應混合物歷時4小時，以一飽和的氯 15 化銨水溶液（25 ml)予以終止，以20 ml的EtOAc作萃取，使 其乾燥(Na2S04)並於真空下予以蒸發至乾燥，俾以提供3.52 g 有如一粗產物之標題化合物，在無進一步的純化下可將其使用 於下方的步驟。 ^-NMR {CDCl3, δ): 1.10-2.05 (m? 10H)? 2.47 (tt?lH)? 3.77 (s? 20 2H)，6.97-7.32 (m，4H) 4-環己基-4·氧-3-(2-氟笨基)-丁醛二乙基縮醛（化合物lb) 回流加熱一配於136 ml的曱苯之5.02 g的該化合物la之 溶液，藉由蒸德移除水分而回收3 5 ml的曱苯。而後，添加3.18 g的叔丁醇鉀且在回流時攪拌被持續歷時30分鐘；使該反應 48 200406394 混合物冷卻至80°C並添加4.27 ml的2-溴乙醛二乙基縮醛。回 流18小時之後，使該反應混合物冷卻至室溫’以一飽和的氣 化銨水溶液(3〇 ml)予以終止，以3〇 ml的EtOAc作萃取，使其 乾燥(NajO4)並於真空下予以蒸發至乾燥以生成一粗產物，其 係藉由閃蒸層析法（石油醚-EtOAc 92.5:7.5)予以純化，而提供 2.97 g之純的標題產物。 ^-NMR {CDCls, δ): 1.00-2.10 (m? 17H)5 2.20-2.52 (m? 2H) 3.30-3.72 (m? 4H)? 4.25-4.45 (m? 2H)? 6.90.7.35 (m5 4H) 4-環己基-3-(2-氟笨基)-4-經基丁酸二乙 ίοWithout wishing to be bound by theory, it is believed that the administration of 5W1A receptor antagonists prevents sacral reflexes and / or the unwanted activity of the cortical mechanisms controlling urination. Therefore, it is expected that a wide range of neurological and muscular dysfunction of the urinary tract can be treated with the compounds of the present invention, including, without limitation, difficulty in urination, incontinence, and enuresis (overactive bladder) . Difficulty urinating includes frequent urination, nocturia, urgency, and decreased urine adaptability (decreased bladder storage capacity and difficulty in emptying the bladder, that is, an ideal amount of urine is discharged during urination. Incontinence signs include stress Sexual incontinence, emergency incontinence and enuresis incontinence, and mixed incontinence 47 200406394. Enuresis is related to the uncontrolled will of urine at night or during sleep. The compounds of the present invention can also be used as a treatment for central nervous system disorders due to serotonin-induced dysfunction. The following examples represent the 5th class compounds of formula I as widely described above Typical synthesis of these. The implementation is for illustration only and is not intended to limit the invention in any way. Reagents and starting materials are readily available to those having ordinary knowledge in this field. Example 1 1- [4 -Cyclohexyl-3- (2-fluorophenyl) -4-methoxybutyl] -4- [2- (2,2,2-trifluoroethoxy) -phenyl] -pigen 10 1- Hexyl-2- (2-Gaphenyl) acetamidine (4d) La was added dropwise 2.14 ml of cyclohexane carbonyl chloride to a 36 ml of 2-fluorobenzyl zinc chloride (0.5 M solution, prepared at In THF) and 0.008 g of dichloro (triphenylphosphine) -palladium (II). Then, the reaction mixture was stirred at room temperature for 4 hours with a saturated aqueous solution of ammonium chloride 15 (25 ml) was terminated, extracted with 20 ml of EtOAc, dried (Na2S04) and evaporated to dryness under vacuum, to provide 3.52 g of the title compound as a crude product, which could be purified without further purification. Used in the following steps. ^ -NMR {CDCl3, δ): 1.10-2.05 (m? 10H)? 2.47 (tt? LH)? 3.77 (s? 20 2H), 6.97-7.32 (m, 4H) 4-ring Hexyl-4 · oxy-3- (2-fluorobenzyl) -butyraldehyde diethyl acetal (compound lb) was heated at reflux to a solution of 5.02 g of this compound la in 136 ml of toluene, and evaporated by evaporation. De remove the water and recover 3 5 ml of toluene. Then, 3.18 g of potassium tert-butoxide was added and stirring was continued at reflux for 30 minutes; the reaction was cooled to 80 ° C and 4.27 ml of 2-bromoacetaldehyde diethyl acetal was added. After 18 hours of refluxing, the reaction mixture was allowed to cool to room temperature. It was quenched with a saturated aqueous solution of ammonium vaporized (30 ml), extracted with 30 ml of EtOAc, dried (NajO4) and applied under vacuum. Evaporated to dryness to give a crude product, which was purified by flash chromatography (petroleum ether-EtOAc 92.5: 7.5) to provide 2.97 g of the pure title product. ^ -NMR (CDCls, δ): 1.00-2.10 (m? 17H) 5 2.20-2.52 (m? 2H) 3.30-3.72 (m? 4H)? 4.25-4.45 (m? 2H)? 6.90.7.35 (m5 4H ) 4-Cyclohexyl-3- (2-fluorobenzyl) -4-ethyl diethyl butyrate

Rf非對映異構物（化合物lc) 4-環己基-3-(2-氟苯基)-4-羥基丁醛二乙基縮醛，下方的tlc Rf非對映異構物 15 添加0.095 g的NaBH4至一在〇。(：下攪拌之配於乃加 的MeOH之0·84 g的該化合物lb的溶液中並於室溫下攪拌 該混合物歷時5小時。使溶劑蒸發且以Η" (15 ml)收取該反應 粗產物並以EtOAc (2 X ：l 5ml)作萃取。將有機層分開，以鹽水(2 X 洗⑤，予以乾燥㈣犯4)並於真空下予以蒸發至乾燥俾 以生成一粗產物，其係藉由閃蒸層析法早 啊/ίΓ予以純化(石油醚-EtOAc 梯度自92:8至85:15)，而提供化八 20 。物lc(上方的R以〇 56 g，63 醚-EtOAc 9:1 %)與具有下方的Rf (4.8%)之對應 ^ n 1 …〇化合物。TLC洗提劑石油 lc: ]H-NMR {CDCl^, S)\ 0.90-1 3^ and OH)? 2.00-2.10 (m5 2H)? 3.25^3 扣，h5(M·95 (m，5H 6.95-7.30 (m5 3H)，7.40-7.55 (m5 1H) (m，6H)，4.25 (t，1H)， 49 200406394Rf diastereomer (compound lc) 4-cyclohexyl-3- (2-fluorophenyl) -4-hydroxybutanal diethyl acetal, the lower tlc Rf diastereomer 15 added 0.095 g of NaBH4 to one in zero. (: Stirred in a solution of 0.84 g of the compound Ib added to Nougat's MeOH and stir the mixture at room temperature for 5 hours. The solvent was evaporated and the reaction crude was collected as Η " (15 ml) The product was extracted with EtOAc (2 X: 15 ml). The organic layer was separated, washed with brine (2 X washed ⑤, dried 4) and evaporated to dryness under vacuum to produce a crude product, which was Purified by flash chromatography Zao / Li (Petroleum ether-EtOAc gradient from 92: 8 to 85:15) to provide hydrazine 20 (1) R (the upper R is 0.56 g, 63 ether-EtOAc 9: 1%) corresponds to the compound with the following Rf (4.8%) ^ n 1… 〇. TLC eluent petroleum lc:] H-NMR {CDCl ^, S) \ 0.90-1 3 ^ and OH)? 2.00-2.10 (m5 2H)? 3.25 ^ 3 buckle, h5 (M · 95 (m, 5H 6.95-7.30 (m5 3H), 7.40-7.55 (m5 1H) (m, 6H), 4.25 (t, 1H), 49 200406394

4-環己基-3-(2-氟笨基)-4-曱氧基丁醛二乙基縮醛（化合物Id) 添加0.091 g的60% NaH至一在室溫下攪拌之配於2 ml 的無水DMF之0.514 g的化合物lc的溶液中。於室溫下攪:拌 該反應混合物歷時1小時，接而添加0.142 ml的碘甲烷並於 5 室溫下攪拌該所形成的混合物歷時2小時。而後，將該反應混 合物倒入水(30 ml)中，以2 X 20 ml的EtOAc作萃取，予以洗 滌，予以乾燥（Na2S04)並於真空下予以蒸發至乾燥，而提供有 如一粗產物之0.50 g的標題化合物，在無進一步的純化下可將 其使用於下方的步驟。 10 ^-NMR {CDCj3} δ): 0.90-1.40 (m? 12H)5 1.50-1.90 (m? 5H)5 1.92-2.20 (m5 2H)? 3.05 (t5 1H)5 3.20 (s? 3H)5 3.20-3.70 (m5 5H)? 4.05-4.18 (m，1H)，6.90-7.20 (m，3H)，7.40-7.55 (m，1H) 4-環己基_3-(2-氟笨基)-4-曱氧基丁醛（化合物le)4-Cyclohexyl-3- (2-fluorobenzyl) -4-methoxybutyraldehyde diethyl acetal (compound Id) Add 0.091 g of 60% NaH to 1 ml at room temperature and mix with 2 ml A solution of 0.514 g of compound lc in anhydrous DMF. Stir at room temperature: Stir the reaction mixture for 1 hour, then add 0.142 ml of methyl iodide and stir the resulting mixture at room temperature for 2 hours. Then, the reaction mixture was poured into water (30 ml), extracted with 2 X 20 ml of EtOAc, washed, dried (Na2S04) and evaporated to dryness under vacuum to provide 0.50 as a crude product. g of the title compound can be used in the next step without further purification. 10 ^ -NMR {CDCj3} δ): 0.90-1.40 (m? 12H) 5 1.50-1.90 (m? 5H) 5 1.92-2.20 (m5 2H)? 3.05 (t5 1H) 5 3.20 (s? 3H) 5 3.20 -3.70 (m5 5H)? 4.05-4.18 (m, 1H), 6.90-7.20 (m, 3H), 7.40-7.55 (m, 1H) 4-cyclohexyl_3- (2-fluorobenzyl) -4- Methoxybutyraldehyde (compound le)

於室溫下攪拌一 0.502 g的該化合物Id、3.5 ml的50%三 15 氟乙酸水溶液以及7 ml的CH2C12之混合物歷時2小時，且接 而以8 ml的CH2C12稀釋。使有機層分開，以鹽水（2 X 15ml) 洗滌，予以乾燥（Na2S04)並於真空下予以蒸發至乾燥俾以提供 一粗產物(0.365 g)，在無進一步純化下使用在下一步驟中。 ^-NMR {CDCl3y δ): 0.95-1.40 (m5 6H)? 1.41-2.00 (m5 5H)5 20 2.65-2.95 (m? 2H)? 3.05-3.15 (m? 1H)? 3.35? 3.37(2s? 3H)? 3.70-3.90 (m5 1H)? 6·90·7·25 (m，3H)，7.40-7.55 (m，1H)，9.65 (s，1H) 1-『4-玉哀己基-3-(2 -乱基-笨基)-4-曱氧丁基1-4-2,2-三氣乙氧 基V苯基V口底口丼 50 200406394 在至溫下攪拌一 0·212 g的該化合物le、〇 237 g的 l-[2-(2,2,2-三氟乙氧基卜笨基卜底讲HC1、〇·24 g的三醋酸基氫 棚化納、0.111111的入(：〇11以及61111的（：112(：12之混合物歷時1 小時，保持靜置過夜，以20% NaAO3水溶液予以鹼化。使有 機層分開，卩鹽水(2x3〇ml)予以洗務，予以乾燥⑽2S〇4)並真 空下予以蒸發至乾燥俾以生成—粗產離46g)，藉由閃蒸層析 法(石油醚—Et〇Ae7:3)予以—提供«題化合物（0.25 g ； 62%) 〇 ^-NMR {CDC13, δ): 0.95-1 3η ( ίο 15 20 i·30 (m5 6Η)，1.55-2.50 (m，9Η)， 2.45-270 (m? 4H)5 3.00-3.20 (m . v，5H)，3.20-3.38 (m5 4H)，435 (q5 2H)，6.85-7.20 (m，7H)5 7.抓7.55 (m，m) 實施例2 l-(4_氟基甲氡其梦甘λ 氧基本基)-4-[4-氧-3-(2-三氟甲氧基 苯基)-戊基】辰哨1 .三氟甲氧缝赴㈢2a) 在回流時攪拌一 1.9 g的wo 一产 3 二氟甲氧基)-苯甲醛、4 ml 的 EtOH、1.3 ml 的 96% 2-硝乙俨"n 沉以及0.10 ml的正丁胺之溶液 歷時18小時。而後，以h2〇蘇經 2 稀擇，以 EtOAc (2x30 ml)萃取， 以H20 (2x30 ml)、鹽水予以法 先I，予以乾燥（Na2S04)並在真 空下予以蒸發俾以提供一 2 47 σ + h • g之撥色的油，其係藉由閃墓層 析法(PE- Et〇Ae ·5)予以純化。所收集的部分之蒸發生成 ㈣§之有如—淡黃色的油之W基·3·(2·三H甲氧基笨基)· 丙-2-稀。 H-NMR {CDCl3, δ): 2.35 (s 314^ ι 0，州)，7·3(Κ7·55 (m, 4H)，8.10 (s，iH) 回流加熱並攪拌一 1 6 α # ·ϋ g的該上述化合物、0.〇24g的 51 200406394A mixture of 0.502 g of the compound Id, 3.5 ml of a 50% tri 15 fluoroacetic acid aqueous solution, and 7 ml of CH2C12 was stirred at room temperature for 2 hours, and then diluted with 8 ml of CH2C12. The organic layer was separated, washed with brine (2 X 15 ml), dried (Na2S04) and evaporated to dryness under vacuum to provide a crude product (0.365 g), which was used in the next step without further purification. ^ -NMR (CDCl3y δ): 0.95-1.40 (m5 6H)? 1.41-2.00 (m5 5H) 5 20 2.65-2.95 (m? 2H)? 3.05-3.15 (m? 1H)? 3.35? 3.37 (2s? 3H )? 3.70-3.90 (m5 1H)? 6.90 · 7 · 25 (m, 3H), 7.40-7.55 (m, 1H), 9.65 (s, 1H) 1- 『4- 玉 哀 hexadecyl-3- ( 2 -ranyl-benzyl) -4-fluorenylbutyl 1-4-2,2-trifluoroethoxy Vphenyl V bottom bottom port 50 200406394 Stir at 0.212 g of this at Compound le, 0237 g of l- [2- (2,2,2-trifluoroethoxybendyl), HC1, 0.24 g of sodium triacetate, 0.111111 ( The mixture of 〇11 and 61111 (: 112 (: 12) lasted for 1 hour, kept standing overnight, and alkalized with 20% NaAO3 aqueous solution. The organic layer was separated, washed with brine (2x30ml), and dried 2S 〇4) and evaporated to dryness under vacuum to produce-crude yield 46g), by flash chromatography (petroleum ether-Et〇Ae7: 3)-to provide «title compound (0.25 g; 62%) 〇 ^ -NMR {CDC13, δ): 0.95-1 3η (ίο 15 20 i · 30 (m5 6Η), 1.55-2.50 (m, 9Η), 2.45-270 (m? 4H) 5 3.00-3.20 (m. v, 5H), 3.20-3.38 (m5 4H), 435 (q5 2H) 6.85-7.20 (m, 7H) 5 7. Grab 7.55 (m, m) Example 2 l- (4-fluoromethylformamidine its lambda oxybenzyl) -4- [4-oxo-3- (2 -Trifluoromethoxyphenyl) -pentyl] Chenshao 1. Trifluoromethoxy sewn to ㈢2a) Stir a 1.9 g of wo under reflux to produce 3 difluoromethoxy) -benzaldehyde, 4 ml of The solution of EtOH, 1.3 ml of 96% 2-nitroacetamidine, and 0.10 ml of n-butylamine lasted 18 hours. Then, dilute it with H2〇 Su Jing 2 and extract with EtOAc (2x30 ml), give H20 (2x30 ml), brine, give it first, dry (Na2S04) and evaporate under vacuum to provide a 2 47 σ + h • g oil was purified by flash grave chromatography (PE-EToAe · 5). The evaporation of the collected part is like ㈣§—W-based · 3 · (2 · triHmethoxybenzyl) · propan-2-diluted oil. H-NMR {CDCl3, δ): 2.35 (s 314 ^ 0, state), 7 · 3 (Κ7 · 55 (m, 4H), 8.10 (s, iH), heat under reflux and stir for 1 6 α # · ϋ g of this compound, 0.024 g of 51 200406394

Fe(C104)3、3.0 g的Fe、6 ml的H20之混合物歷時7.5小時。 在室溫下靜置過夜之後，添加2.80 ml的37% HC1，加熱歷時 1小時。在冷卻之後，以EtOAc (3x40 ml)萃取該混合物，予以 乾燥（Na2S04)在真空下予以蒸發俾以生成有如一橙色的油之 5 該標題化合物（g 1.28)。 'H-NMR (CDCh, □)： 2.22 (s? 3H)? 3.77 (s? 2H), 7.15-7.40 (m? 4H) 生-氧K2-三氟甲—氧基笨某V成酸二乙基縮駿（化备物％、 10 15 20 在一氮氣流之下’逐滴添加一配於15 ml的DMF的化合 物2a之溶液至一配於1〇 mi的無水DMF的1·87 g之60% NaH 油懸浮液之懸浮液中經歷6分鐘，並在室溫下攪拌該反應混合 物歷時3小時。在靜置過夜之後，添加配於5mU^DMFi〇.447 g的2-溴乙酸二乙基祕（97%);在室溫下雜該混合物歷時 3〇秒，接而在,C下歷時3小時。而後，以H2〇 (25〇响稀 釋該混合物’以2NHC1予以酸化，以Et2〇(3x5〇mi)萃取以 H2〇(4〇ml)絲’予以乾燥⑽观）並於真空下予以蒸發，以 提供-粗產物（呈褐色的油），其係藉由閃蒸層析法（pE_Et〇Ac 幻予以純化俾以生成有如一略呈黃色的油之化合 物2b 〇 ]h卿（⑶aw): 32 (m, 6H)，丨 7m % ㈣ ih)， 2 08 (S，3H)，2·35'2·60 (m^ 1H^ 3·2〇-3·8〇 (m, 4H), 4.20-4.40 (2H)? 7.15-7.35 (4H)A mixture of Fe (C104) 3, 3.0 g of Fe, and 6 ml of H20 took 7.5 hours. After standing at room temperature overnight, 2.80 ml of 37% HC1 was added and heated for 1 hour. After cooling, the mixture was extracted with EtOAc (3x40 ml), dried (Na2S04) and evaporated under vacuum to give the title compound (g 1.28) as an orange oil. 'H-NMR (CDCh, □): 2.22 (s? 3H)? 3.77 (s? 2H), 7.15-7.40 (m? 4H) Raw-oxygen K2-trifluoromethyl-oxybenzyl V to diethyl acid Base shrinkage (preparation%, 10 15 20 under a nitrogen stream 'dropwise add a solution of compound 2a in 15 ml of DMF to 1.87 g of 10 ml in anhydrous DMF The suspension of 60% NaH oil suspension was allowed to stand for 6 minutes, and the reaction mixture was stirred at room temperature for 3 hours. After standing overnight, 5 g of 2-bromoacetic acid diethyl bromide was added. Baseline (97%); the mixture was mixed at room temperature for 30 seconds, and then at 3 C for 3 hours. Then, the mixture was diluted with H20 (25 °), acidified with 2NHC1, and Et20. (3x50mi) extraction with H2O (40ml) silk 'dried) and evaporated under vacuum to provide-crude product (brown oil) by flash chromatography pE_Et〇Ac was purified to generate a compound 2b as a slightly yellow oil (baw): 32 (m, 6H), 7m% (ih), 2 08 (S, 3H), 2 35'2.60 (m ^ 1H ^ 3.2〇-3.80 (m, 4H), 4.20-4.40 (2H)? 7.15-7.35 (4H)

戊醛（化合物W 如用被描述作為化合物ie之該操作程序獲得標題化合 52 200406394 物，但使用化合物2b代替化合物Id作為一起始物。在一般 的完成程序(work_up procedure)後，獲得該標題化合物（99%)並 且在無進一步純化下使用在下一步驟中。 ]H-NMR {CDCl3, δ): 2.12 (s5 3H)? 2.58 (dd5 1H), 3.40 (dd? 1H), 5 4.61 (dd，1H)，7.11-7.40 (m，4H)5 9.75 (s，1H) 1-(4-氟基-2-曱氣基苯基)-444-氣-3-(2-三氟曱氣基笨基)-戊基1- 口瓜畊 採用被描述作為實施例1之化合物之該操作程序獲得標 題化合物，但使用化合物2c代替化合物1 e作為一起始物，且 10 以1-(4-氟基-2-甲氧基苯基)-哌讲代替1-(2,2,2-三氟乙氧基苯 基)-哌讲。藉由閃蒸層析法（PE - EtOAc 7:3)純化俾以生成該標 題化合物（60%)。油。 ^-NMR (CDCl3) δ): 1.65-1.85 (m? 1H)5 2.10 (s? 3H)? 2.25-2.45 (m? 3H)9 2.50-2.70 (m? 4H)5 2.85-3.10 (m? 4H)? 3.82 (s? 3H)? 15 4.15-4.31 (m? 1H)? 6.50-6.68 (m? 2H)? 6.78-6.90 (m? 1H)? 7.20-7.35 (m5 4H) 實施例3 1-(4-氟基-2-甲氧基苯基)-4- [4-羥基-3-(2-三氟甲氧 基苯基)-戊基】-哌畊 使用被描述作為化合物lc的方法來合成標題化合物，但 20 起始自該實施例2之化合物代替化合物lb。在一般的完成程 序（work-up procedure)後，分離出該標題化合物（93.1%)且藉由 LC予以特徵分析如一非對映異構物之混合物(RS;SR- RS，RS 78.8 :20.5)。LC 純度·· 98.6% ]H-NMR {CDCls, δ): 0.95; 1.07 (2d? 3H), 1.80-2.10 (m? 2H)5 53 200406394 2.35-2.50 (m， 2H)， 2.60-2.85 (m， 4H)， 2.92-3.18 (m， 4H)， 3.18-3.35 (m，1H)，3.80 (s，3H)，4.00-4.20 (m，1H)，4.60-6.10 (b5 1H)，6.50-6.70 (m，2H)，6.78-6.95 (m，1H), 7.15-7.35 (m，3H)， 7.60-7.75 (m，1H) 5 實施例4 l-[5-(2,3-二羥-1，4-苯並戴奥辛基)】-4-[4-氧-3-(2-三 氟甲氧基苯基)-戊基]-哌畊Valeraldehyde (Compound W The title compound 52 200406394 was obtained using the procedure described as compound ie, but compound 2b was used instead of compound Id as a starting material. After a general work_up procedure, the title compound was obtained (99%) and used in the next step without further purification.] H-NMR {CDCl3, δ): 2.12 (s5 3H)? 2.58 (dd5 1H), 3.40 (dd? 1H), 5 4.61 (dd, 1H), 7.11-7.40 (m, 4H) 5 9.75 (s, 1H) 1- (4-fluoro-2-fluorenylphenyl) -444-gas-3- (2-trifluorofluorenyl) Base) -pentyl 1-mouth melon The title compound was obtained using this procedure described as the compound of Example 1, but using compound 2c instead of compound 1 e as a starting material, and 10 starting with 1- (4-fluoro group Instead of 1- (2,2,2-trifluoroethoxyphenyl) -piperyl, 2-methoxyphenyl) -piperyl. The amidine was purified by flash chromatography (PE-EtOAc 7: 3) to give the title compound (60%). oil. ^ -NMR (CDCl3) δ): 1.65-1.85 (m? 1H) 5 2.10 (s? 3H)? 2.25-2.45 (m? 3H) 9 2.50-2.70 (m? 4H) 5 2.85-3.10 (m? 4H )? 3.82 (s? 3H)? 15 4.15-4.31 (m? 1H)? 6.50-6.68 (m? 2H)? 6.78-6.90 (m? 1H)? 7.20-7.35 (m5 4H) Example 3 1- ( 4-Fluoro-2-methoxyphenyl) -4- [4-hydroxy-3- (2-trifluoromethoxyphenyl) -pentyl] -pigenin is described using the method described as compound lc The title compound was synthesized, but instead of compound lb, the compound starting from Example 2 was used. After a general work-up procedure, the title compound (93.1%) was isolated and characterized by LC as a mixture of diastereomers (RS; SR-RS, RS 78.8: 20.5) . LC purity · 98.6%] H-NMR {CDCls, δ): 0.95; 1.07 (2d? 3H), 1.80-2.10 (m? 2H) 5 53 200406394 2.35-2.50 (m, 2H), 2.60-2.85 (m , 4H), 2.92-3.18 (m, 4H), 3.18-3.35 (m, 1H), 3.80 (s, 3H), 4.00-4.20 (m, 1H), 4.60-6.10 (b5 1H), 6.50-6.70 ( m, 2H), 6.78-6.95 (m, 1H), 7.15-7.35 (m, 3H), 7.60-7.75 (m, 1H) 5 Example 4 l- [5- (2,3-dihydroxy-1, 4-Benzodioxin)]-4- [4-oxo-3- (2-trifluoromethoxyphenyl) -pentyl] -pigen

採用被描述作為實施例1之化合物之該操作程序獲得標 題化合物，但使用化合物2c代替化合物le作為一起始物且 1-(2,3-二氫苯並戴奥辛-5-基）哌畊代替1-(2,2,2·三氟乙氧 10 基苯基)-哌畊。藉由閃蒸層析法(？£$1〇八〇7:3)純化俾以生成該 標題化合物（33%)。油。 ^-NMR {CDCls, δ): 1.65-1.85 (m9 1H)? 2.10 (s? 3H)? 2.25-2.40 (m, 3H)? 2.50-2.70 (m? 4H)? 2.90-3.15 (m9 4H)? 4.18-4.40 (m? 4H)? 6.48-6.65 (m5 2H)? 6.70-6.82 (m? 1H)? 7.20-7.35 (m? 4H) 15 實施例5 l-[5-(2,3-二羥-1，4-苯並戴奥辛基)】-4- [4-羥基-3-(2-The procedure described as the compound of Example 1 was used to obtain the title compound, but using compound 2c instead of compound le as a starting material and 1- (2,3-dihydrobenzodioxin-5-yl) piperin instead of 1 -(2,2,2 · trifluoroethoxy 10 phenyl) -piperon. The amidine was purified by flash chromatography (£ 1080: 3) to give the title compound (33%). oil. ^ -NMR (CDCls, δ): 1.65-1.85 (m9 1H)? 2.10 (s? 3H)? 2.25-2.40 (m, 3H)? 2.50-2.70 (m? 4H)? 2.90-3.15 (m9 4H)? 4.18-4.40 (m? 4H)? 6.48-6.65 (m5 2H)? 6.70-6.82 (m? 1H)? 7.20-7.35 (m? 4H) 15 Example 5 l- [5- (2,3-dihydroxy) -1,4-Benzodioxinyl)]-4- [4-hydroxy-3- (2-

三氟甲氧基苯基)-戊基卜哌畊 使用被描述作為化合物lc的方法來合成標題化合物，但 起始自實施例4之化合物代替化合物lb。在一般的完成程序 (work-up procedure)後，分離出該標題化合物（92.7%)且藉由LC 20 予以特徵分析有如一非對映異構物之混合物（RS，SR- RS$S 72.9 :19.4)。LC 純度：92.3 %。 ^-NMR (CDCl3) δ): 0.95; 1.07 (2d5 3H)? 1.80 2.15 (m? 2H)? 2.30-2.50 (m? 2H)? 2.60-2.85 (m? 4H)? 3.00-3.20 (m? 4H)? 3.20-3.40 (m5 1H); 4.00-4.15 (m5 1H)? 4.15-4.40 (m? 4H), 54 200406394 6·20 (b，1H), 6·45-6·65 (m，2H)，6.65-6.85 (m5 1H)， 7.15-7.30 (m? 3H)? 7.60^7.75 (m5 1H) 實施例6 二經q，4苯並戴奥辛基)】_4_ [4羥基 三氟甲氧基苯基)-己基卜哌啡 ίο 15Trifluoromethoxyphenyl) -pentylbupigon The title compound was synthesized using the method described as compound lc, but starting with the compound of Example 4 instead of compound lb. After a general work-up procedure, the title compound (92.7%) was isolated and characterized by LC 20 as a mixture of diastereomers (RS, SR-RS $ S 72.9: 19.4). LC purity: 92.3%. ^ -NMR (CDCl3) δ): 0.95; 1.07 (2d5 3H)? 1.80 2.15 (m? 2H)? 2.30-2.50 (m? 2H)? 2.60-2.85 (m? 4H)? 3.00-3.20 (m? 4H )? 3.20-3.40 (m5 1H); 4.00-4.15 (m5 1H)? 4.15-4.40 (m? 4H), 54 200406394 6 · 20 (b, 1H), 6.45-6 · 65 (m, 2H) , 6.65-6.85 (m5 1H), 7.15-7.30 (m? 3H)? 7.60 ^ 7.75 (m5 1H) Example 6 Second warp q, 4 benzodioctyl)] _ 4_ [4-hydroxytrifluoromethoxyphenyl ) -Hexylbuperphine 15

三氟.里氡基基基）乙腈（化合物 逐滴添加配於20 ml的THF之2-(2-三氟甲氧基苯基）乙腈 至2·74 mi之一在—78〇c下冷卻之配於THF的2m LDA溶液 中，在相同的溫度下攪拌該混合物歷時10分鐘。而後，添加 mi的3-溴丙烯與〇 446 g的ΗΜρτΑ之混合物並且 C下视掉δ亥反應歷時2小時，接而藉由自發性的加熱使 其處於室溫狀態。在靜置過夜之後，以一飽和的NH4C1水溶液 予以終止並且以EtOAc予以萃取。將混合的萃取物乾燥（Na2 s〇4: 並予以蒸發至乾燥。該粗產物藉由閃蒸層析法（PE - m〇Ac 5 ·5)予以純化’而提供有如一淡黃色的油之標題產物（ίο Μ呂）。Trifluoro.trisyl) acetonitrile (compound was added dropwise to 2- (2-trifluoromethoxyphenyl) acetonitrile in 20 ml of THF to one of 2.74 mi and cooled at -78 ° C In a 2m LDA solution prepared in THF, the mixture was stirred at the same temperature for 10 minutes. Then, a mixture of 3-bromopropene and 0446 g of ΗΜρτΑ was added and the δH reaction was observed under C for 2 hours. Then, it was brought to room temperature by spontaneous heating. After standing overnight, it was terminated with a saturated aqueous NH4C1 solution and extracted with EtOAc. The mixed extracts were dried (Na2 s〇4: and was Evaporate to dryness. The crude product was purified by flash chromatography (PE-mAcAc · 5) to provide the title product (L0M) as a pale yellow oil.

H-NMR (CDCh 而：2.60 (t5 2H)，4.15-4.26 (m5 1H)，5.16-5.29 (m5 2H)? 5.79-5.91 (m? 1H)? 7.28-7.41 (m? 3H)5 7.51-7.67 (m5 1H).H-NMR (CDCh and: 2.60 (t5 2H), 4.15-4.26 (m5 1H), 5.16-5.29 (m5 2H)? 5.79-5.91 (m? 1H)? 7.28-7.41 (m? 3H) 5 7.51-7.67 (m5 1H).

Hgr三氟甲氧基苯基)-成烯-4_醛(化合物6b) 在室溫下逐滴添加4.01 ml的DIBAL-H(2M溶液，配於曱 20 苯中）至一配於無水甲苯（50 ml)之0.88 g的化合物6a溶液中 超過10分鐘。在室溫下攪拌該反應混合物歷時2小時，以〇.(u N HC1稀釋，以EtOAc (2 X 50 ml)萃取；以H20洗滌該混合的 萃取物，予以乾燥(Na2S04)並於真空下予以蒸發至乾燥。獲得 有如一淡黃色的油之化合物6b且在無進一步純化下使用於下 55 200406394 一步驟中。 ^-NMR (CDCl3} δ): 2.49-2.68 (m? 1Η)? 2.80-2.95 (m5 1Η)? 4.02-4.15 (m? 1Η)5 5.12-5.26 (m5 2Η)? 5.75-5.85 (m? 1Η)5 7.28-7.37 (m5 4Η)5 9.75 (bs ?1Η) 5 2-Π43-丁烯基-M2-三氟甲氡基笨基）11-1,3-二氣戍烷（化合物 6c)Hgr trifluoromethoxyphenyl) -ene-4-aldehyde (compound 6b) 4.01 ml of DIBAL-H (2M solution in benzene 20) was added dropwise at room temperature to one in anhydrous toluene (50 ml) of a solution of 0.88 g of compound 6a for more than 10 minutes. The reaction mixture was stirred at room temperature for 2 hours, diluted with 0.1 (u N HC1, and extracted with EtOAc (2 X 50 ml); the combined extracts were washed with H20, dried (Na2S04) and applied under vacuum. Evaporate to dryness. Compound 6b is obtained as a pale yellow oil and used in the next step 55 200406394 without further purification. ^ -NMR (CDCl3} δ): 2.49-2.68 (m? 1Η)? 2.80-2.95 (m5 1Η)? 4.02-4.15 (m? 1Η) 5 5.12-5.26 (m5 2Η)? 5.75-5.85 (m? 1Η) 5 7.28-7.37 (m5 4Η) 5 9.75 (bs? 1Η) 5 2-Π43- Butenyl-M2-trifluoromethylfluorenylbenzyl) 11-1,3-digaspinane (compound 6c)

回流加熱一 0.72 g的化合物6b、0.052 g的對甲苯續酸 單水合物、配於30 ml的甲苯之0.328 ml的乙二醇之溶液歷時 8小時。而後，藉由真空下之蒸發移除該溶劑，以EtOAc與 10 NaHC03水溶液予以稀釋；使該有機層分開，在Na2S04上予 以乾燥並於真空下予以蒸發至乾燥。該粗產物藉由閃蒸層析法 (PE - EtOAc 95:5)予以純化，而提供有如一淡黃色的油之該標 題產物（0.85 g)。 ^-NMR (CDCl3} δ): 2.39-2.51 (m5 1H)5 2.52-2.79 (m? 1H)5 15 3.46-3.57 (m? 1H) ,3.80-3.92 (m，4H)，4.88-4.95 (m，2H)，A solution of 0.72 g of compound 6b, 0.052 g of p-toluene acid monohydrate, and 0.328 ml of ethylene glycol in 30 ml of toluene were heated under reflux for 8 hours. The solvent was then removed by evaporation under vacuum, diluted with EtOAc and 10 NaHC03 aqueous solution; the organic layer was separated, dried over Na2S04 and evaporated to dryness under vacuum. The crude product was purified by flash chromatography (PE-EtOAc 95: 5) to provide the title product (0.85 g) as a pale yellow oil. ^ -NMR (CDCl3) δ: 2.39-2.51 (m5 1H) 5 2.52-2.79 (m? 1H) 5 15 3.46-3.57 (m? 1H), 3.80-3.92 (m, 4H), 4.88-4.95 (m , 2H),

4.96-5.12 (m，1H)，5.72-5.81 (m, 1H)，7.21-7.33 (m，3H)， 7.33-7-45 (m? 1H). 3-「l，3-二氧戊烷-2-基1-3-(2-三氟曱氧基笨基）1丙醛（化合物 6d) 20 添加0.196 ml的0s04至一強力攪拌之0.31 g的化合物 6c、10 ml的Et20以及10 ml的H20之雙相的混合物中，繼而 以一能整除的數量添加3.6 g的NaI04經過一 20分鐘的間期。 在6小時之後，該有機層被分開，以Et20萃取該水性層。將該 混合的有機層予以乾燥(Na2S04)並於真空下予以蒸發至乾燥。 56 200406394 該粗產物藉由閃蒸層析法（PE _ Et0Ac 8)予以純化俾以提供 0.311 g的該標題產物。 ]H-NMR (CDCI3, S): 2.52-2.69 (m5 1H)? 2.88-3.03 (m5 1H)? 3.81-3.93 (m，4H)，3.94-4.15 (m，1H)，5.03-5.08 (m5 1H)， 5 7*22-7.38 (m? 3H)9 7.39-7-55 (m? 1H)? 9.76 (bs? 1H). h(_2?3_ = ^ 辛 _5_ 基）冰r3_(L3·二氯 ah 基>3_(2-三丙基V喩哄（化合物6e) 採用被描述作為實施例丨之化合物之該操作程序以獲得 该標題化合物，但使用化合物6d代替化合物le作為一起始物 10且1_(2,3-二羥-1，4-苯並戴奥辛基卜哌畊代替1-(2,2,2_三氟乙 氧基苯基)-哌畊。藉由閃蒸層析法(PE - EtOAc 1:1)之純化生成 該標題化合物（61 %)。油。 'H-NMR (CDCl3f S): 1.80-2.01 (m5 1H)? 2.02-2.44 (m? 3H)? 2.45-2.71 (m，4H)，2.92-3.07 (m 4H)，3.41-3.61 (m，1H)， 15 3.81-3.93 (m? 4H)5 4.21-4.39 (m? 4H)? 5.01-5.05 (m5 1H)5 6.49·6·57 (m，2H)，6.71-6.82 (m5 1H)，7.21-7.39 (m5 3H)5 7.41-7-58 (m，1H)· 曱醯基-3-(2-三氟曱氣 20 在回流時授拌一 〇.12g的化合物66、〇〇〇5§的4.甲苯橫 酉文單水。物、1 mi的出〇以及7的二嘮烷之混合物歷時％ J日寸而後’藉由真空下之蒸發移除該溶劑，以Et〇Ac與Na〇H 水令液稀釋違殘餘物；該有機層被分開，在Ν^〇4上予以乾 秌並方、真工下予以瘵發至乾燥。在無進一步的純化之下將該粗 57 200406394 產物（獲得有如一淡黃色的油）使用於下一步驟中 ^-NMR {CDCl3, δ): 1.79-1.99 (m, 1H)? 2.25-2.49 (m5 3H)? 2.50-2.71 (m? 4H)? 2.91-3.12 (m 4H)? 4.07-4.15 (m? 1H)? 4.16-4.39 (m，4H)5 6.48-6.61 (m? 2H)5 6.73-6.86 (m? 1H)9 5 7.20-7.38 (m，3H), 9.81 (bs，1H). 4,4-二乙氣基-2-(2-三氟曱氣基笨基V氰丙烷（化合物6g)4.96-5.12 (m, 1H), 5.72-5.81 (m, 1H), 7.21-7.33 (m, 3H), 7.33-7-45 (m? 1H). 3- "l, 3-dioxolane- 2-yl1-3- (2-trifluoroalkoxybenzyl) 1 propionaldehyde (compound 6d) 20 Add 0.196 ml of 0s04 to a strong agitation of 0.31 g of compound 6c, 10 ml of Et20 and 10 ml of In a biphasic mixture of H20, 3.6 g of NaI04 was then added in a divisible amount for a period of 20 minutes. After 6 hours, the organic layer was separated and the aqueous layer was extracted with Et20. The mixed The organic layer was dried (Na2S04) and evaporated to dryness under vacuum. 56 200406394 The crude product was purified by flash chromatography (PE_Et0Ac 8) to provide 0.311 g of the title product.] H-NMR (CDCI3, S): 2.52-2.69 (m5 1H)? 2.88-3.03 (m5 1H)? 3.81-3.93 (m, 4H), 3.94-4.15 (m, 1H), 5.03-5.08 (m5 1H), 5 7 * 22-7.38 (m? 3H) 9 7.39-7-55 (m? 1H)? 9.76 (bs? 1H). H (_2? 3_ = ^ oct_5_ group) ice r3_ (L3 · dichloroah group) ; 3_ (2-tripropyl V hydrazone (compound 6e) The procedure described as the compound of Example 丨 was used to obtain the title compound , But use compound 6d instead of compound le as a starting material 10 and 1_ (2,3-dihydroxy-1,4-benzodiocinylbutyricin instead of 1- (2,2,2_trifluoroethoxybenzene Base) -piperin. The title compound (61%) was obtained by purification by flash chromatography (PE-EtOAc 1: 1). Oil. 'H-NMR (CDCl3f S): 1.80-2.01 (m5 1H) ? 2.02-2.44 (m? 3H)? 2.45-2.71 (m, 4H), 2.92-3.07 (m 4H), 3.41-3.61 (m, 1H), 15 3.81-3.93 (m? 4H) 5 4.21-4.39 ( m? 4H)? 5.01-5.05 (m5 1H) 5 6.49 · 6 · 57 (m, 2H), 6.71-6.82 (m5 1H), 7.21-7.39 (m5 3H) 5 7.41-7-58 (m, 1H) Fluorenyl-3- (2-trifluorofluorene 20) was refluxed with 0.12 g of compound 66 and 4. toluene horizontal monograph monohydrate in 2005. The mixture of the product, 1 mi of 0 and 7 dioxane lasted for% J days, and then 'removed the solvent by evaporation under vacuum, and diluted the residue with EtOAc and NaOH water; The organic layer was separated, dried on N ^ 04, and dried to dryness. The crude 57 200406394 product (obtained as a pale yellow oil) was used in the next step without further purification ^ -NMR {CDCl3, δ): 1.79-1.99 (m, 1H)? 2.25-2.49 ( m5 3H)? 2.50-2.71 (m? 4H)? 2.91-3.12 (m 4H)? 4.07-4.15 (m? 1H)? 4.16-4.39 (m, 4H) 5 6.48-6.61 (m? 2H) 5 6.73- 6.86 (m? 1H) 9 5 7.20-7.38 (m, 3H), 9.81 (bs, 1H). 4,4-diethylamino-2- (2-trifluorofluorenylbenzyl V cyanopropane (compound 6g)

採用被描述作為化合物6a之該操作程序以合成該標題化 合物，但使用2-溴乙醛二乙基縮醛代替3-溴丙烯。在自發性加 熱至室溫經歷2小時之後，回流該反應混合物歷時額外的2小 10 時。在一般的完成程序（work-up procedure)後，該粗產物藉由閃 蒸層析法(PE - EtOAc 95:5)予以純化，而提供有如一淡黃色的 油之該標題產物（47.7%)。 ^-NMR {CDC13j δ): 1.12-1.35 (m5 6H)? 2.07-2.27 (m? 2H)5 3·50_3·71 (m，4H)，4.22-4.38 (m 1H)，4.65-4.71 (m，1H)5 15 7.19-7.48 (m? 3H)? 7.49-7.63 (m5 1H). 4-氧-2-(2-三氟曱氣基笨基V氰丙烷（化合物6h)This procedure was described as compound 6a to synthesize the title compound, but using 2-bromoacetaldehyde diethylacetal instead of 3-bromopropene. After spontaneous heating to room temperature for 2 hours, the reaction mixture was refluxed for an additional 2 hours. After a general work-up procedure, the crude product was purified by flash chromatography (PE-EtOAc 95: 5) to provide the title product as a pale yellow oil (47.7%) . ^ -NMR {CDC13j δ): 1.12-1.35 (m5 6H)? 2.07-2.27 (m? 2H) 5 3.50_3 · 71 (m, 4H), 4.22-4.38 (m 1H), 4.65-4.71 (m, 1H) 5 15 7.19-7.48 (m? 3H)? 7.49-7.63 (m5 1H). 4-oxo-2- (2-trifluorofluorenylbenzyl V cyanopropane (compound 6h)

採用被描述作為化合物le之該操作程序以獲得該標題化 合物，但使用化合物6g代替化合物Id作為一起始物。在一 般的完成程序（work-up procedure)後，從而所獲得的標題化合物 20 在無進一步純化下被使用於下一步驟中。 !H-NMR (CDCh, δ): 2.98-3.31 (m? 2H)? 4.65-4.78 (m 1H)? 4.65-4.71 (m5 1H)，7.22-7.49 (m，3H)，7.51-7.66 (m，1H)，9.81 (bs? 1H). 1_「3_氣基_3麵(2_二氟甲氧基苯基）_丙基1-4-(2,3-二氮笨开_1，4_戴 58 採用被描述作為每 標題化合物，但使用：：例1之化合物之該操作程序以獲得該 响-二經·㈣並戴化合物16作為—起始物且 基苯基)制。藉由閃5^) H Μ2,2,2·三氟乙氧 標題化合物(93%)。^層析筆.職cl:1)之純化生成該 'H-NMR (CDCl3) δ)： -2.14 (m，1H)，2.49-2.71 (m 3H) 3.01-3.19 (m，4H) 4 ^ ? ’ ·2Μ.38 (m 4H)5 4.40^4.55 (m 6.49-6.65 (m5 3H) 〖，）， 10 im ·72'6·88 (m，1H), 7.24-W (m，3H), 7.52-7.68 (m，1H). 甲酿某^三氣甲氣 基苯基):内基 在-78°C下，逐滴夭 4力口 1.2 ml之配於甲苯的1 μ DIBAL-H 至一配於無水CH2CU An 15 ml)之〇 414 g的化合物&溶液。容 許該反應回溫並授拌過在· 促，而後，以水予以稀釋，以CHfh (2 X 50 ml)萃取，以 H9〇、、土、外 死4該混合的萃取物，予以乾燥（Na2S〇4)The procedure described as compound le was used to obtain the title compound, but compound 6g was used instead of compound Id as a starting material. After a general work-up procedure, the title compound 20 thus obtained was used in the next step without further purification. ! H-NMR (CDCh, δ): 2.98-3.31 (m? 2H)? 4.65-4.78 (m 1H)? 4.65-4.71 (m5 1H), 7.22-7.49 (m, 3H), 7.51-7.66 (m, 1H), 9.81 (bs? 1H). 1_ "3_Gas_3 face (2_difluoromethoxyphenyl) _propyl1-4- (2,3-diazabenzyl_1,4 _Dai 58 was described as each title compound, but using :: The procedure of the compound of Example 1 to obtain the ring-two classics, and the compound 16 as a-starter and phenyl). 55 ^) H Μ2,2,2 · trifluoroethoxy title compound (93%). ^ Chromatography. Purification of Cl: 1) yielded the 'H-NMR (CDCl3) δ): -2.14 (m , 1H), 2.49-2.71 (m 3H) 3.01-3.19 (m, 4H) 4 ^? '2M.38 (m 4H) 5 4.40 ^ 4.55 (m 6.49-6.65 (m5 3H) (),) 10 im · 72'6 · 88 (m, 1H), 7.24-W (m, 3H), 7.52-7.68 (m, 1H). Carbofuran (three gas methylphenyl): internal group at -78 ° C Then, dropwise 1.2 ml of 1 μ DIBAL-H in toluene to a solution of 414 g of compound & solution in anhydrous CH 2CU An (15 ml) dropwise. Allow the reaction to warm up and mix in water. · Promote, then dilute with water, extract with CHfh (2 X 50 ml), and extract with H9. Soil, the outer die 4 extracts were combined, to be dried (Na2S〇4)

並於真空下予以蒸發至乾燥。藉由閃蒸層析法（CH2Cl2-MeOH 95:5)之純化生成該標題化合物（〇 23 g; 55 3%)。油。 H5_(L4二苯並戴奧.查^]^ μ-羥基_3_(2_三氟甲氣某苯甚 20 基1-哌畊 將一配於THF (0.888 ml)之1M溴化（乙基)鎂溶液滴入至 一在0-5°C下冷卻之配於10 ml的THF之0.1 g的化合物6f溶 液中。容許該反應混合物回溫至室溫並在相同的溫度下攪拌歷 時3小時。而後，以一飽和的NH4C1水溶液予以終止，予以驗 59 200406394 化且以EtOAc萃取。將該混合的萃取物予以乾燥（Na2S04)並予 以蒸發至乾燥。該粗產物藉由閃蒸層析法(CH2C12-MeOH/NH3 97:3)予以純化，而提供有如一黃色透明的油之該標題產物（84.4 %)。 5 ^-NMR (CDCh, δ): 0.86-0.99 (m? 3H)? 1.21-1.35 (m9 2H)5 1.36-1.65 (m，1H)? 1.66-1.89 (m, 1H) 1.90-2.21 (m5 2H)? 2.25-2.95 (m? 6H)? 2.96-3.27 (m 4H)5 3.61-3.80 (m? 1H)? 4.21-4.41 (m? 4H)? 6.49-6.61 (m? 2H), 6.65-6.86 (m? 1H)?It was evaporated to dryness under vacuum. Purification by flash chromatography (CH2Cl2-MeOH 95: 5) gave the title compound (0 23 g; 55 3%). oil. H5_ (L4 Dibenzodio. Cha ^) ^ μ-Hydroxy_3_ (2_trifluoromethane, a benzoyl 20 group, 1-pipeline, 1M bromide (ethyl group in THF (0.888 ml)) ) The magnesium solution was dropped into a solution of 0.1 g of compound 6f in 10 ml of THF, cooled at 0-5 ° C. The reaction mixture was allowed to warm to room temperature and stirred at the same temperature for 3 hours. Then, it was terminated with a saturated aqueous solution of NH4C1, tested 59 200406394 and extracted with EtOAc. The mixed extract was dried (Na2S04) and evaporated to dryness. The crude product was subjected to flash chromatography ( CH2C12-MeOH / NH3 97: 3) was purified to provide the title product (84.4%) as a yellow transparent oil. 5 ^ -NMR (CDCh, δ): 0.86-0.99 (m? 3H)? 1.21- 1.35 (m9 2H) 5 1.36-1.65 (m, 1H)? 1.66-1.89 (m, 1H)? 1.90-2.21 (m5 2H)? 2.25-2.95 (m? 6H)? 2.96-3.27 (m 4H) 5 3.61- 3.80 (m? 1H)? 4.21-4.41 (m? 4H)? 6.49-6.61 (m? 2H), 6.65-6.86 (m? 1H)?

7.15-7.39 (m? 4H). 10 [M+H]+=481.6 實施例7 l-[5-(2,3-二羥-1，4-苯並戴奥辛基)卜4-[4-羥基-3-(2- 三氟甲氧基苯基)-己-5-烯基卜哌啡7.15-7.39 (m? 4H). 10 [M + H] + = 481.6 Example 7 l- [5- (2,3-dihydroxy-1,4-benzodioxinyl) 4- [4-hydroxyl -3- (2-trifluoromethoxyphenyl) -hex-5-enylbuperphine

藉由被描述作為實施例6之化合物之該相同操作程序以獲 得該標題化合物，但使用化合物6f與溴化（乙烯基)鎂（1M，配 15 於THF)代替配於THF之溴化（乙基)鎂。該粗產物藉由閃蒸層析 法（CH2Cl2-MeOH/NH3 95:5)予以純化，而提供有如一黃色透明 的油之該標題產物（42.6 %)。 ^-NMR {CDCls, δ): 1.76-1.98 (m5 1H) 1.99-2.28 (m? 1H), 2.29-2.51 (m，2H)5 2.52-2.89 (m 4H)? 2.89-3.25 (m5 6H), 20 4.20-4.43 (m，4H)，4.65-5.31 (m，3H)，5.61-5.70 (m，1H)， 6.49-6.62 (m5 2H)5 6.70-6.89 (m9 1H)? 7.15-7.42 (m? 4H). [M+H]+=479.5 實施例8 l-[5-(2,3-二羥-1，4-苯並戴奥辛基)】-4-[4-羥基-5-甲 基-3-(2-三氟甲氧基苯基)-己基]-哌畊 60 200406394 藉由被描述作為實施例6之化合物之該相同操作程序以 獲得該標題化合物’但使用化合物6f與氯化(異丙基)鎮㈣， 配於THF)代替配於THF之溴化其、沒#丄士， 兴化（乙基)鎂。該粗產物藉由閃蒗層 析法(CH2Cl2-Me〇H/NH3 97:3)予以純化，而提供有如_黃⑽ 明的油之該標題產物（30.9 %)。 Ή-NMR {CDCh, S): 0.78-0.98 (m, 6H) U5.M5 (m? 1.71-1.91 (m, 2H), 1.92-2.19 (m, 1H)? 2 25.2 ^ ^ ^ 2.52-2.95 (m, 4H), 3.01-3.29 (m, 5H), 3.51-3.72 (m, 1Η)? 4.19-4.40 (m, 4H)，6·47_6.63 (m，2H)，6 67 6 87 ⑽， ίο 7·15_7·41 (m，4H)· ’ ’ [Μ+Η]+=495·6 實施例9 1私(2,3_二經从苯並戴奥辛基)】邻甲氧基 -3-(2-二乱甲氧基苯基卜5-己稀基卜n辰畊 么4-乙氧基氟[氧基苯卷^ 15 採用被描述作為化合物6f(另擇方法)之該操作程序以製備 該標題化合物，但起始自化合物6g代替化合物6丨。該粗製的 藉由閃蒸層析法(CHfl2 -MeOH 99:1)予以純化，而提供有如一 黃色透明的油之該標題產物(41.9 °/〇)。 20 H-NMR {CDCl3, S)·. 1.11-1.34 (m, 6H); 1.85-2.04 (m, 1H) 2.41-2.62 (m, 1H)； 3.34-3.77 (m, 4H); 4.08-4.19 (m, 1H) 4.39-4.51 (m, 1H)； 7.19-7.42 (m, 4H); 9.66 (s, 1H). 6,6-二乙氧基^三氟甲氧基苯基 藉由被描述作為實施例6之化合物之該相同操作程序以 獲得該標題化合物，但使用溴化（6;^基)即M，配於伽)代 61 200406394 替配於THF之溴化（乙基)鎂並且起始自化合物9a。該粗產物藉 由閃蒸層析法（PE - EtOAc 4:6)予以純化。產率·· 63.1 %。 ^-NMR {CDCl3) δ): 1.04-1.32 (m? 6H); 1.93-2.09 (m? 1H); 2.01-2.39 (m9 1H); 2.51 (bs? 1H); 3.28-3.75 (m; 5H); 4.18-4.36 5 (m5 2H); 5.01-5.22 (m? 2H); 5.67-5.87 (m? 1H); 7.14-7.43 (m? 4H). 4-曱氧基-3-(2-三氟曱氧基笨基）-丁烯-3-醛二乙基縮醛（化合 物 9c)The title compound was obtained by the same procedure described as the compound of Example 6, but using compound 6f and (vinyl) magnesium bromide (1M, 15 in THF) instead of bromide (ethyl in THF) Base) magnesium. The crude product was purified by flash chromatography (CH2Cl2-MeOH / NH3 95: 5) to provide the title product (42.6%) as a yellow transparent oil. ^ -NMR (CDCls, δ): 1.76-1.98 (m5 1H) 1.99-2.28 (m? 1H), 2.29-2.51 (m, 2H) 5 2.52-2.89 (m 4H)? 2.89-3.25 (m5 6H), 20 4.20-4.43 (m, 4H), 4.65-5.31 (m, 3H), 5.61-5.70 (m, 1H), 6.49-6.62 (m5 2H) 5 6.70-6.89 (m9 1H)? 7.15-7.42 (m? 4H). [M + H] + = 479.5 Example 8 l- [5- (2,3-dihydroxy-1,4-benzodioxinyl)]-4- [4-hydroxy-5-methyl- 3- (2-trifluoromethoxyphenyl) -hexyl] -pigen 60 200406394 By the same procedure described as the compound of Example 6 to obtain the title compound 'but using compound 6f with chlorinated ( Isopropyl) sulfonium, mixed with THF), instead of brominated with THF, hydrazine, (ethyl) magnesium. The crude product was purified by flash chromatography (CH2Cl2-MeOH / NH3 97: 3) to provide the title product (30.9%) as an oil such as Huang Huangming. Ή-NMR (CDCh, S): 0.78-0.98 (m, 6H) U5.M5 (m? 1.71-1.91 (m, 2H), 1.92-2.19 (m, 1H)? 2 25.2 ^ ^ ^ 2.52-2.95 ( m, 4H), 3.01-3.29 (m, 5H), 3.51-3.72 (m, 1Η)? 4.19-4.40 (m, 4H), 6.47_6.63 (m, 2H), 6 67 6 87 ⑽, ίο 7 · 15_7 · 41 (m, 4H) · '' [Μ + Η] + = 495 · 6 Example 9 1private (2,3_two meridian from benzodiocinyl)] o-methoxy-3- ( 2-Dioxanyl methoxyphenyl, 5-hexyl, n-phenyl, 4-ethoxyfluoro [oxybenzene, vol. 15] The procedure described as compound 6f (alternative method) was used to prepare The title compound, but starting from compound 6g instead of compound 6. The crude was purified by flash chromatography (CHfl2-MeOH 99: 1) to provide the title product (41.9 as a yellow transparent oil). ° / 〇). 20 H-NMR {CDCl3, S) · 1.11-1.34 (m, 6H); 1.85-2.04 (m, 1H) 2.41-2.62 (m, 1H); 3.34-3.77 (m, 4H) 4.08-4.19 (m, 1H) 4.39-4.51 (m, 1H); 7.19-7.42 (m, 4H); 9.66 (s, 1H). 6,6-diethoxy ^ trifluoromethoxyphenyl The title compound was obtained by the same procedure described as the compound of Example 6 , But using bromide (6; ^ yl) i.e. M, in the gamma ligand) is substituted for 61200406394 with the bromide in THF (ethyl) magnesium and starting from compound 9a. The crude product was purified by flash chromatography (PE-EtOAc 4: 6). Yield ·· 63.1%. ^ -NMR (CDCl3) δ): 1.04-1.32 (m? 6H); 1.93-2.09 (m? 1H); 2.01-2.39 (m9 1H); 2.51 (bs? 1H); 3.28-3.75 (m; 5H) ; 4.18-4.36 5 (m5 2H); 5.01-5.22 (m? 2H); 5.67-5.87 (m? 1H); 7.14-7.43 (m? 4H). 4-Methoxy-3- (2-trifluoro (Methoxybenzyl) -butene-3-aldehyde diethyl acetal (compound 9c)

如針對化合物Id所描述並使用化合物9b代替化合物lc 10 作為一起始物來合成該標題化合物。在無進一步純化下將該粗 製的使用於下一步驟中。 ^-NMR (CDCl3} δ): 1.01-1.42 (m? 6H); 1.86-2.04 (m? 1H); 2.24-2.43 (m，1H); 3.24 (s，3H); 3.30-3.79 (m，6H); 4.13-4.28 (m， 1H); 4.98-5.17 (m? 2H); 5.50-5.71 (m9 1H); 7.13-7.29 (m5 3H); 15 7.31-7.48 (m，1H). 4-曱氣基-3-(2_三氟曱氣基笨基)-丁烯-3-醛（化合物9d)The title compound was synthesized as described for compound Id and using compound 9b instead of compound lc 10 as a starting material. This crude was used in the next step without further purification. ^ -NMR (CDCl3) δ): 1.01-1.42 (m? 6H); 1.86-2.04 (m? 1H); 2.24-2.43 (m, 1H); 3.24 (s, 3H); 3.30-3.79 (m, 6H ); 4.13-4.28 (m, 1H); 4.98-5.17 (m? 2H); 5.50-5.71 (m9 1H); 7.13-7.29 (m5 3H); 15 7.31-7.48 (m, 1H). 3- (2-trifluorofluorenylbenzyl) -butene-3-aldehyde (compound 9d)

採用被描述作為化合物le之該操作程序以獲得該標題化 合物，但使用化合物9c代替化合物1 d作為一起始物。在一般 的完成程序(work-up procedure)後，從而所獲得的標題化合物在 20 無進一步純化下被使用於下一步驟中。 ]H-NMR {CDCls, δ): 2.58-2.76 (m5 1H); 2.81-3.06 (m? 1H); 3.24 (s? 3H); 3.59-3.72 (m5 1H); 3.73-3.91 (m5 1H); 4.99>5.17 (m? 2H); 5.43-5.67 (m5 1H); 7.13-7.41 (m? 4H); 9.61-9.69 (m5 1H). 1-『5-(2,3-二羥-M-笨並戴奥辛基）1-444-甲氣基-3-(2-三氟曱氧 62 200406394 基苯基)·5 -己細基1-。瓜口井 使用被描述作為實施例1之化合物之該方法以製備該標 題化合物，但使用化合物9d代替化合物le且1-(2,3-二羥-1，4-苯並戴奥辛-5-基)-哌畊代替1-(2,2,2-三氟乙氧基苯基)-哌讲。在 5 閃蒸層析法後(ΡΕ -丙酮6:4)之產率係為34.5%。 ^-NMR (CDCl3} δ): 1.74-1.93 (m? 1H); 2.09-2.42 (m? 3H); 2.48-2.71 (m? 4H); 2.89-3.28 (m5 4H); 3.18-3.31 (m9 4H); 3.54-3.68 (m，1H); 4.17-4.38 (m9 4H); 4.96-5.30 (m? 2H);The procedure described as compound le was used to obtain the title compound, but using compound 9c instead of compound 1 d as a starting material. After a general work-up procedure, the title compound thus obtained was used in the next step without further purification. ] H-NMR (CDCls, δ): 2.58-2.76 (m5 1H); 2.81-3.06 (m? 1H); 3.24 (s? 3H); 3.59-3.72 (m5 1H); 3.73-3.91 (m5 1H); 4.99 > 5.17 (m? 2H); 5.43-5.67 (m5 1H); 7.13-7.41 (m? 4H); 9.61-9.69 (m5 1H). 1- 『5- (2,3-Dihydroxy-M- Benzodioxinyl) 1-444-methylamino-3- (2-trifluorofluorenyl 62 200406394 phenyl) · 5-hexyl 1-. Guakoujing used the method described as the compound of Example 1 to prepare the title compound, but used compound 9d instead of compound le and 1- (2,3-dihydroxy-1,4-benzodioxin-5-yl ) -Pigen instead of 1- (2,2,2-trifluoroethoxyphenyl) -piper. The yield after 5 flash chromatography (PE-acetone 6: 4) was 34.5%. ^ -NMR (CDCl3) δ): 1.74-1.93 (m? 1H); 2.09-2.42 (m? 3H); 2.48-2.71 (m? 4H); 2.89-3.28 (m5 4H); 3.18-3.31 (m9 4H) ); 3.54-3.68 (m, 1H); 4.17-4.38 (m9 4H); 4.96-5.30 (m? 2H);

5.47-5.68 (m，1H); 6.47-6.63 (m? 2H); 6.71-6.85 (m? 1H); 10 7.12-7.31 (m5 3H); 7.32-7.48 (m? 1H). 實施例10 l-[5-(2,3-二羥-1，4-苯並戴奥辛基)】-4-[(4-甲氧基 -3-苯基)-庚基】-11 辰讲 4-氧-3-笨基庚醛二乙基縮醛（化合物10a) 採用被描述作為化合物2b之該方法以製備該標題化合 15 物，但使用1-苯基-2-戊酮代替化合物2a。該粗產物藉由閃蒸 層析法（EtOAc-PE 95:5)予以純化。產率：59.2%。5.47-5.68 (m, 1H); 6.47-6.63 (m? 2H); 6.71-6.85 (m? 1H); 10 7.12-7.31 (m5 3H); 7.32-7.48 (m? 1H). Example 10 l- [5- (2,3-Dihydroxy-1,4-benzodiocinyl)]-4-[(4-methoxy-3-phenyl) -heptyl] -11 Chen 4-Oxy-3 -Bentylheptanal diethyl acetal (compound 10a) The method described as compound 2b was used to prepare the title compound 15, but 1-phenyl-2-pentanone was used instead of compound 2a. The crude product was purified by flash chromatography (EtOAc-PE 95: 5). Yield: 59.2%.

^-NMR {CDCls, δ): 0.78-0.88 (m? 3H)? 1.10-1.31 (m9 8H)9 1.42-1.72 (m，2H)? 2.38-2.50 (m, 3H)，3.31-3.90 (m，4H)， 4.18-4.35 (m, 1H)? 7.05-7.42 (m5 5H). 20 4-羥基-3-笨基庚醛二乙基縮醛（化合物10b) 採用被描述作為化合物lc之該操作程序以獲得該標題化 合物，但使用化合物10a代替化合物1 b作為一起始物。在一 般的完成程序(work-up procedure)後，該粗產物藉由閃蒸層析法 (EtOAc-PE 2:8)予以純化。產率：73.3 %。 63 200406394 ^-NMR {CDCl3, □): 0.70-0.82 (m? 3H)5 0.90-1.48 (m? 12H)? 2.10-2.57 (m，2H)，3.32-3.94 (m? 4H)5 4.08-4.30 (m? 1H)? 5.18-5.35 (m，1H)，7.05-7.42 (m，5H). 4-曱氣基-3-笨基庚醛二乙基縮醛（化合物10c) 5 採用被描述作為化合物Id之該操作程序以獲得該標題化 合物，但使用化合物1 〇b代替化合物1 c作為一起始物。該標 題產物在無進一步純化下使用於下一步驟中。^ -NMR {CDCls, δ): 0.78-0.88 (m? 3H)? 1.10-1.31 (m9 8H) 9 1.42-1.72 (m, 2H)? 2.38-2.50 (m, 3H), 3.31-3.90 (m, 4H), 4.18-4.35 (m, 1H)? 7.05-7.42 (m5 5H). 20 4-Hydroxy-3-benzylheptanedial diethyl acetal (compound 10b) The procedure described as compound lc was used. To obtain the title compound, but using compound 10a instead of compound 1b as a starting material. After a normal work-up procedure, the crude product was purified by flash chromatography (EtOAc-PE 2: 8). Yield: 73.3%. 63 200406394 ^ -NMR {CDCl3, □): 0.70-0.82 (m? 3H) 5 0.90-1.48 (m? 12H)? 2.10-2.57 (m, 2H), 3.32-3.94 (m? 4H) 5 4.08-4.30 (m? 1H)? 5.18-5.35 (m, 1H), 7.05-7.42 (m, 5H). 4-fluorenyl-3-benzylheptanedial diethyl acetal (compound 10c) 5 Adopted as described This procedure for compound Id was used to obtain the title compound, but compound 10b was used instead of compound 1c as a starting material. The title product was used in the next step without further purification.

^-NMR (CDCl3) δ): 0.70-0.82 (m? 3H)5 1.02-1.48 (m? 12H)5 2.02-2.15 (m5 1H)5 2.95-3.01 (m? 1H)5 3.20-3.80 (m? 7H)? 10 4.15-4.35 (m5 1H)，7.05-7.42 (m，5H). 4-甲氧基-3-笨基庚醛（化合物lOd) 採用被描述作為化合物le之該操作程序以獲得該標題化 合物，但使用化合物l〇c代替化合物lc作為一起始物。該標 題產物在無進一步純化下使用於下一步驟中。^ -NMR (CDCl3) δ): 0.70-0.82 (m? 3H) 5 1.02-1.48 (m? 12H) 5 2.02-2.15 (m5 1H) 5 2.95-3.01 (m? 1H) 5 3.20-3.80 (m? 7H)? 10 4.15-4.35 (m5 1H), 7.05-7.42 (m, 5H). 4-methoxy-3-benzylheptanal (compound 10d) The procedure described as compound le was used to obtain the The title compound but uses compound 10c instead of compound lc as a starting material. The title product was used in the next step without further purification.

15 ^-NMR {CDCls, δ): 0.70-1.59 (m? 7H)? 2.81-2.95 (m? 2H)5 3.22-3.61 (m? 5H)? 7.05-7.42 (m? 5H). 9.75 (s9 1H) l-「5-(2,3-二羥-M-苯並戴奧辛基曱氣基-3-茉基V庚 基~1-°底畊 使用被描述作為實施例1之化合物之該方法以製備該標 20 題化合物，但使用化合物10d代替化合物le且1-(2,3-二羥-1，4-苯並戴奥辛·5-基)-哌畊代替1-(2,2,2-三氟乙氧基苯基)-哌畊。在 閃蒸層析法後（EtOAc-PE-MeOH/NH3 1丄0.2至8:2:0.2)產率 係為39.5 %。 ^-NMR (CDCl3) δ): 0.78-0.91 (m? 3H)? 1.20-1.48 (m9 64 200406394 4H)?1.90-2.07 (m5 2H)5 2.19-2.33 (m5 2H)? 2.50-2.68 (m? 4H)? 2.80-2.91 (m5 1H)，2.99-3.12 (m，4H)，3.18-3.30 (m，1H)，3.35 (s， 3H)? 4.20-4.38 (m，4H)，6.48-6.62 (m，2H), 6.78 (s5 1H)5 7.25-7.33 (m? 5H). 5 實施例11 l-[5-(2,3-二羥-1，4-苯並戴奥辛基)]-4-[(4-甲氧基 -3-苯基)-戊基】-哌讲 4-氧-3-笨基戊醛二乙基縮醛（化合物11a)15 ^ -NMR (CDCls, δ): 0.70-1.59 (m? 7H)? 2.81-2.95 (m? 2H) 5 3.22-3.61 (m? 5H)? 7.05-7.42 (m? 5H). 9.75 (s9 1H ) l- "5- (2,3-Dihydroxy-M-benzodioxinylpyridinyl-3-mosylV-heptyl ~ 1- ° subtilization. The method described as the compound of Example 1 was used to The title 20 compound was prepared, but using compound 10d instead of compound le and 1- (2,3-dihydroxy-1,4-benzodioxin 5-yl) -pigenin instead of 1- (2,2,2- Trifluoroethoxyphenyl) -pigen. After flash chromatography (EtOAc-PE-MeOH / NH3 1 丄 0.2 to 8: 2: 0.2) the yield was 39.5%. ^ -NMR (CDCl3) δ): 0.78-0.91 (m? 3H)? 1.20-1.48 (m9 64 200406394 4H)? 1.90-2.07 (m5 2H) 5 2.19-2.33 (m5 2H)? 2.50-2.68 (m? 4H)? 2.80-2.91 (m5 1H), 2.99-3.12 (m, 4H), 3.18-3.30 (m, 1H), 3.35 (s, 3H)? 4.20-4.38 (m, 4H), 6.48-6.62 (m, 2H), 6.78 ( s5 1H) 5 7.25-7.33 (m? 5H). 5 Example 11 l- [5- (2,3-dihydroxy-1,4-benzodioxinyl)]-4-[(4-methoxy -3-phenyl) -pentyl] -piperidin 4-oxo-3-benzylvaleraldehyde diethyl acetal (compound 11a)

使用被描述作為化合物2b之該方法以製備該標題化合 物，但使用1-苯基丙酮（商業上可得的）代替化合物2a。該粗產 10 物在無進一步純化下被使用於下一步驟中。產率：93 %。 ^-NMR (CDC13, δ): 1.10-1.25 (m5 6H)5 1.82-2.17 (m? 4H)5 2.32-2.50 (m5 1H)9 3.30-3.70 (m5 4H)? 3.82 (t? 1H)5 4.23-4.33 (m? 1H)? 7.15-7.39 (m5 5H). 4-羥基-3-笨基戊醛二乙基縮醛（化合物lib) 15 採用被描述作為化合物lc之該操作程序以獲得該標題化The method described as compound 2b was used to prepare the title compound, but 1-phenylacetone (commercially available) was used instead of compound 2a. This crude product was used in the next step without further purification. Yield: 93%. ^ -NMR (CDC13, δ): 1.10-1.25 (m5 6H) 5 1.82-2.17 (m? 4H) 5 2.32-2.50 (m5 1H) 9 3.30-3.70 (m5 4H)? 3.82 (t? 1H) 5 4.23 -4.33 (m? 1H)? 7.15-7.39 (m5 5H). 4-hydroxy-3-benzylvaleraldehyde diethyl acetal (compound lib) 15 The procedure described as compound lc is used to obtain the title Turn into

合物，但使用化合物11 a代替化合物lb作為一起始物。在一 般的完成程序（work-up procedure)後，該粗產物在無進一步純化 下被使用於下一步驟中。產率：60 %。 ]H-NMR {CDCl3, δ): 1.00-1.32 (m5 9H)? 2.05-2.15 (m? 20 1H)?1.89-2.17 (m? 2H)5 2.68-2.81 (m5 1H)? 3.28-3.71 (m? 4H), 3.82-4.02 (m9 1H); 4.15-4.26 (m; 1H)? 7.12-7.41 (m? 5H). 4-曱氧基-3-笨基戊醛二乙基縮醛（化合物11c) 採用被描述作為化合物Id之該操作程序以獲得該標題化 合物，但使用化合物11 b代替化合物1 c作為一起始物。該粗產 65 200406394 物藉由閃蒸層析法（EtOAc5-PE95)予以純化。 4-甲氧基-3-笨基戊醛（化合物lid) 採用被描述作為化合物le之該操作程序以獲得該標題化 合物，但使用化合物11c代替化合物Id作為一起始物。該標題 5 產物在無進一步純化下使用於下一步驟中。 1-『5-(2,3-二羥笨並戴奧辛基甲氧基·3-笨基V戊 基 Vi1# 使用被描述作為實施例1之化合物之該方法以製備該標題 化合物，但使用化合物9d代替化合物le且1-(2,3-二羥-1，4-10 苯並戴奥辛-5-基)-哌啡代替l-(2,2,2-三氟乙氧基苯基)-哌讲。在 閃蒸層析法後作1〇八〇-?£_“6〇11以1138:2:0.1至8:2:0.3)該 產率係為15.5%。 JH-NMR {CDCl3) δ): 1.04 (d5 3H)5 1.88-2.05 (m5 2H),2.18-2.31 (m5 2H)? 2.50-2.68 (m? 4H)? 2.73-2.85 (m? 1H)? 2.97-3.12 (m? 4H)5 15 3.30 (s5 3H)? 3.42-3.50 (m5 1H); 4.18-4.38 (m5 4H)5 6.48-6.62 (m5 2H)，6.71-6.82 (t，1H)，7.15-7.33 (m，5H). 實施例12 l-[5-(2,3-二羥-1，4-苯並戴奥辛基)】-4-[(4-丙氧基 -3-苯基)-庚基】-旅13井 4_丙氧基_3晒苯基庚酸 (4匕合物 12a) 20 採用被描述作為化合物Id之該操作程序以獲得該標題化 合物，但使用化合物10b代替化合物lc作為一起始物。該粗 產物藉由閃蒸層析法(EtOAc 5-PE 95)予以純化。 4-丙氧基-3-笨基庚醛（化合物12b) 採用被描述作為化合物Id之該操作程序以獲得該標題化 66 200406394 合物，但使用化合物12a代替化合物1 c作為一起始物。該粗產 物在無進一步純化下使用於下一步驟中。 1- 「5-(2,3-二羥-笨並戴奧辛基）1-44(4-甲氣基-3-苯基庚 基"!-17底讲 5 使用被描述作為實施例1之化合物之該方法以製備該標題 化合物，但使用化合物12b代替化合物le且1-(2,3-二經-1,4-苯並戴奥辛-5-基)-哌讲代替1-(2,2,2-三氟乙氧基苯基)-哌畊。在 閃蒸層析法後（EtOAc-PE-MeOH/NH3 4:6:0.1 至 EtOAc-MeOH/NH3 97:3)該產率係為 9.5%。 10 ^-NMR {CDCls, δ): 0.72-0.92 (m5 6H)? 1.15-1.61 (m? 6H), 1.89-2.08 (m5 2H)5 2.18-2.31 (m? 2H)5 2.50-2.68 (m5 4H)5 2.78-2.92 (m5 1H)? 2.97-3.12 (m? 4H)5 3.28-3.43 (m? 3H)5 4.18-4.38 (m; 4H)? 6.48-6.62 (m9 2H)5 6.71-6.82 (t? 1H)? 7.15-7.33 (m? 5H). 15 實施例13 l-[3-(2-氰苯基)-4-環己基-4-側氧丁基】-4-[5-(2,3- 二羥-1，4-苯並戴奥辛基)]-哌畊 2- (2-環己基-2-側氣乙基笨曱腈（化合物13幻 添加 0.535 ml 的 1，3-二甲基-3,4,5,6-四氫 -2(lH)-pyrimidinone(DMPU)至一配於 4 ml 的 THF 之 0.47 g 的 20 2-苯乙腈溶液中且在-78°C下冷卻該混合物；滴入2.22 ml之一 配於THF之2M的LDA溶液經歷5分鐘，接而在相同溫度下 攪拌該反應混合物歷時15分鐘。繼而逐滴增加配於4 ml的THF 之0.757 g的N-甲基-N-甲氧基環己烷羧醯胺（carboxamide)。 在-78°C下攪拌1小時後，以一 10%的NH4C1水溶液終止該 67 200406394 反應混合物。容許該溫度提高至室溫且以EtOAc (2x20ml)萃取 該混合物，以30 ml的鹽水予以洗務，在Na2S04上予以乾燥 且於真空下予以蒸發至乾燥。該粗產物藉由閃蒸層析法（PE -EtOAc 85··15至1:1)予以純化俾以提供0.34 g的該標題化合 5 物。 ]H-NMR {CDClS) δ): 1.10-2.05 (m?10H); 2.45-2.602 (m?lH); 4?00 (m?2H); 7.20-7.43 (m?2H); 7.48-7.70 (m92H); 3-(2-氰笨基)-4-環己基-4-側氧丁醛二乙基縮醛（化合物13b)Compound, but using compound 11a instead of compound lb as a starting material. After a normal work-up procedure, the crude product was used in the next step without further purification. Yield: 60%. ] H-NMR (CDCl3, δ): 1.00-1.32 (m5 9H)? 2.05-2.15 (m? 20 1H)? 1.89-2.17 (m? 2H) 5 2.68-2.81 (m5 1H)? 3.28-3.71 (m 4H), 3.82-4.02 (m9 1H); 4.15-4.26 (m; 1H)? 7.12-7.41 (m? 5H). 4-Methoxy-3-benzylvaleraldehyde diethyl acetal (compound 11c ) The procedure described as Compound Id was used to obtain the title compound, but Compound 11b was used instead of Compound 1c as a starting material. The crude product 65 200406394 was purified by flash chromatography (EtOAc5-PE95). 4-methoxy-3-benzylvaleraldehyde (compound lid) was followed by the procedure described as compound le to obtain the title compound, but using compound 11c instead of compound Id as a starting material. The title 5 product was used in the next step without further purification. 1- "5- (2,3-Dihydroxybenzyl and dioxinylmethoxy 3-benzyl Vpentyl Vi1 # This method was used to prepare the title compound using the compound described in Example 1 but using the compound 9d replaces compound le and 1- (2,3-dihydroxy-1,4-10 benzodioxin-5-yl) -piperine replaces l- (2,2,2-trifluoroethoxyphenyl)- Pipen. After the flash chromatography was made 108-? £ _ "6010 at 1138: 2: 0.1 to 8: 2: 0.3) The yield was 15.5%. JH-NMR {CDCl3) δ): 1.04 (d5 3H) 5 1.88-2.05 (m5 2H), 2.18-2.31 (m5 2H)? 2.50-2.68 (m? 4H)? 2.73-2.85 (m? 1H)? 2.97-3.12 (m? 4H ) 5 15 3.30 (s5 3H)? 3.42-3.50 (m5 1H); 4.18-4.38 (m5 4H) 5 6.48-6.62 (m5 2H), 6.71-6.82 (t, 1H), 7.15-7.33 (m, 5H) Example 12 l- [5- (2,3-Dihydroxy-1,4-benzodiocinyl)]-4-[(4-propoxy-3-phenyl) -heptyl] -Bri 13 Well 4_propoxy_3 phenylphenylheptanoic acid (4D compound 12a) 20 The procedure described as compound Id was used to obtain the title compound, but compound 10b was used instead of compound lc as a starting material. The crude product was purified by flash chromatography (EtOAc 5-PE 95). This compound was used as the compound Id to obtain the title compound 66 200406394, but compound 12a was used instead of compound 1 c as a starting material. Further purification was used in the next step. 1- "5- (2,3-dihydroxy-benzodioxinyl) 1-44 (4-methylamino-3-phenylheptyl "!-17 Lecture 5 The method described as the compound of Example 1 was used to prepare the title compound, but compound 12b was used in place of compound le and 1- (2,3-Dijing-1,4-benzodioxin-5-yl) -Piperidine instead of 1- (2,2,2-trifluoroethoxyphenyl) -piperin. After flash chromatography (EtOAc-PE-MeOH / NH3 4: 6: 0.1 to EtOAc-MeOH / NH3 97: 3) The yield is 9.5%. 10 ^ -NMR {CDCls, δ): 0.72-0.92 (m5 6H)? 1.15-1.61 (m? 6H), 1.89-2.08 (m5 2H) 5 2.18- 2.31 (m? 2H) 5 2.50-2.68 (m5 4H) 5 2.78-2.92 (m5 1H)? 2.97-3.12 (m? 4H) 5 3.28-3.43 (m? 3H) 5 4.18-4.38 (m; 4H)? 6.48-6.62 (m9 2H) 5 6.71-6.82 (t? 1H)? 7.15-7.33 (m? 5H). 15 Example 13 l- [3- (2-cyanophenyl) -4-cyclohexyl-4- Oxobutyl] -4- [5- (2,3-dihydroxy- 1,4-Benzodioxin)]-pigen 2- (2-cyclohexyl-2-lanthylethylbenzonitrile (compound 13 and 0.535 ml of 1,3-dimethyl-3,4, 5,6-tetrahydro-2 (lH) -pyrimidinone (DMPU) into a 0.47 g solution of 20 2-phenylacetonitrile in 4 ml of THF and the mixture was cooled at -78 ° C; 2.22 ml was added dropwise One solution of 2M LDA in THF took 5 minutes, and then the reaction mixture was stirred at the same temperature for 15 minutes. Then, 0.757 g of N-methyl-N-methoxycyclohexanecarboxamide in 4 ml of THF was added dropwise. After stirring at -78 ° C for 1 hour, the 67 200406394 reaction mixture was quenched with a 10% aqueous NH4C1 solution. The temperature was allowed to rise to room temperature and the mixture was extracted with EtOAc (2x20 ml), washed with 30 ml of brine, dried over Na2S04 and evaporated to dryness under vacuum. The crude product was purified by flash chromatography (PE-EtOAc 85 ·· 15 to 1: 1) to provide 0.34 g of the title compound. ] H-NMR (CDClS) δ): 1.10-2.05 (m? 10H); 2.45-2.602 (m? LH); 4? 00 (m? 2H); 7.20-7.43 (m? 2H); 7.48-7.70 ( m92H); 3- (2-cyanobenzyl) -4-cyclohexyl-4-oxobutyraldehyde diethyl acetal (compound 13b)

使用被描述作為化合物2b之該方法以製備該標題化合 10 物，但使用化合物13a代替化合物2a。該粗產物藉由閃蒸層 析法（甲苯-EtOAc 97:3)予以純化。產率：39.1%。 ]H-NMR (CDC13, δ): 1.05-1.90 (m515H); 1.90-2.05 (m52H); 2.32-2.60 (m，2H); 3.20-3.70 (m，4H); 4.30 (t，lH); 4.55 (UH); 7.30-7.45 (m52H); 7.55 (dd5lH); 7.68 (dd5lH) 15 3-(2-氰笨基)-4-環己基-4-侧氣丁醛（化合物13c)The method described as compound 2b was used to prepare the title compound, but compound 13a was used instead of compound 2a. The crude product was purified by flash chromatography (toluene-EtOAc 97: 3). Yield: 39.1%. ] H-NMR (CDC13, δ): 1.05-1.90 (m515H); 1.90-2.05 (m52H); 2.32-2.60 (m, 2H); 3.20-3.70 (m, 4H); 4.30 (t, lH); 4.55 (UH); 7.30-7.45 (m52H); 7.55 (dd5lH); 7.68 (dd5lH) 15 3- (2-cyanobenzyl) -4-cyclohexyl-4-side gas butyraldehyde (compound 13c)

採用被描述作為化合物Id之該操作程序以獲得該標題化 合物，但使用化合物13b代替化合物1 c作為一起始物。該粗產 物在無進一步純化下被使用於下一步驟中。 ]H-NMR (CDCl3> δ): 1.00-1.90 (m，10H); 2.05-2.15 20 (m，lH);2.35-2.50 (m，lH); 2.70 (dd，lH); 3.45 (dd，lH); 4.85 (dd5lH); 7.25 (dd5lH); 7.30-7.40 (m?lH); 7.50-7.60 (m?lH); 7.75 (dd?lH) l-『3-(2-氰笨基)-4-環己基-4-側氧丁基1-445-(2,3-二羥-M-笨並 戴奧辛基)1-哌讲 68 200406394 使用被描述作為實施例1之化合物之該方法以製備該標題 化合物，但使用化合物13c代替化合物le且1-(2,3-二羥-1，4-苯並戴奥辛-5-基)-哌讲代替1-(2,2,2-三氟乙氧基苯基)-哌讲。該 粗產物藉由閃蒸層析法(PE :EtOAc 6:4)予以純化俾以提供該標 5 題化合物（79.5%)。 TH-NMR {CDCl3, δ): 1.10-2.10 (m5llH); 2.20-2.50 (m5 4H); 2.50-2.75 (m?4H); 2.92-3.20 (m?4H); 4.20-4.38 (m54H); 4.55 (t9lH); 6.48-6.65 (m?2H); 6.70-6.85 (m?lH); 7.30-7.45 (m?2H); 7.45-7.60 (m?lH); 7.65-7.75 (m?lH) 10 實施例 14 (RS，SR)-l-[3-(2-氰苯基）-4-環己基-4-羥丁 基]-4-[5-(2,3-二羥-1,4-苯並戴奥辛基)]-哌畊 使用被描述作為化合物lc之該方法以合成該標題化合 物，但起始自該實施例14之化合物代替化合物lb。在一般的 完成程序（work-up procedure)後，該粗產物藉由閃蒸層析法予以 15 純化(PE - EtOAc - NH3/MeOH 65:35:3)，而提供該標題化合物 (70.5%)。 ]H-NMR (CDClS) δ): 0.80-1.40 (m?7H); 1.45-1.80 (m?5H);1.85-2.05 (m?lH); 2.20-2.50 (m?2H); 2.50-2.80 (m94H); 2.95-3.20 (m?4H); 3.30-3.50 3.50-3.65 (m?lH); 4.20-4.40 20 (m，4H); 4.40-5.90 (bs，lH); 6.50-6.67 (m，2H);6.70-6.85 (m，lH); 7.20-7.40 (m，lH); 7.50-7.68 (m，2H); 7.93-8.08 (m，lH) 貫施例 14a_(RS)-1 -[3-(2-氣笨基）-4-玉哀己基-4-美里丁 基[445-(2,3-二羥-Μ-笨並戴奧辛基）1-哌咁（在Rt二30.298 分鐘之鏡像異構物） 69 200406394 自實施例14之該化合物所獲得的此類化合物藉由使用 Chiralpak AD (0.46x25 cm)之光學管柱層析來分析，以正己烷 -EtOH 95:5 (流速=1 ml/min ;偵檢器 uv 254 nm)洗提。 實UI (SRVl-r3_(2-氰|基V4-環己基-4-羥工· 5 基Μ·:·Ι1:·(Β-^里苯並戴奧辛基)ι_喻^井= H834分鐘 之鏡像異構物） 自實施例14之該化合物所獲得的此類化合物藉由使用 Chiralpak AD (0.46x25 cm)之光學管柱層析來分析，以正己烷The procedure described as Compound Id was used to obtain the title compound, but Compound 13b was used instead of Compound 1c as a starting material. This crude product was used in the next step without further purification. ] H-NMR (CDCl3 > δ): 1.00-1.90 (m, 10H); 2.05-2.15 20 (m, lH); 2.35-2.50 (m, lH); 2.70 (dd, lH); 3.45 (dd, lH) ); 4.85 (dd5lH); 7.25 (dd5lH); 7.30-7.40 (m? LH); 7.50-7.60 (m? LH); 7.75 (dd? LH) l- 『3- (2-cyanobenzyl) -4 -Cyclohexyl-4-oxobutyl 1-445- (2,3-dihydroxy-M-benzodioxinyl) 1-pipeline 68 200406394 using the method described as the compound of Example 1 to prepare the The title compound, but uses compound 13c in place of compound le and 1- (2,3-dihydroxy-1,4-benzodioxin-5-yl) -pipedine in place of 1- (2,2,2-trifluoroethoxylate Phenyl) -piperidine. The crude product was purified by flash chromatography (PE: EtOAc 6: 4) to provide the title compound (79.5%). TH-NMR (CDCl3, δ): 1.10-2.10 (m5llH); 2.20-2.50 (m5 4H); 2.50-2.75 (m? 4H); 2.92-3.20 (m? 4H); 4.20-4.38 (m54H); 4.55 (t9lH); 6.48-6.65 (m? 2H); 6.70-6.85 (m? lH); 7.30-7.45 (m? 2H); 7.45-7.60 (m? lH); 7.65-7.75 (m? lH) 10 Implementation Example 14 (RS, SR) -l- [3- (2-cyanophenyl) -4-cyclohexyl-4-hydroxybutyl] -4- [5- (2,3-dihydroxy-1,4- Benzodioxin)]-pigen uses the method described as compound lc to synthesize the title compound, but the compound starting from this Example 14 replaces compound lb. After a general work-up procedure, the crude product was purified by flash chromatography (PE-EtOAc-NH3 / MeOH 65: 35: 3) to provide the title compound (70.5%) . ] H-NMR (CDClS) δ): 0.80-1.40 (m? 7H); 1.45-1.80 (m? 5H); 1.85-2.05 (m? LH); 2.20-2.50 (m? 2H); 2.50-2.80 ( m94H); 2.95-3.20 (m? 4H); 3.30-3.50 3.50-3.65 (m? lH); 4.20-4.40 20 (m, 4H); 4.40-5.90 (bs, lH); 6.50-6.67 (m, 2H ); 6.70-6.85 (m, lH); 7.20-7.40 (m, lH); 7.50-7.68 (m, 2H); 7.93-8.08 (m, lH) Example 14a_ (RS) -1-[3- (2-Acetobenzyl) -4-Arysohexyl-4-Miributyl [445- (2,3-Dihydroxy-M-benzyl and Dioxinyl) 1-piperidine (mirror image difference at 30.298 minutes on Rt 2 Structure) 69 200406394 This compound obtained from the compound of Example 14 was analyzed by optical column chromatography using Chiralpak AD (0.46x25 cm) with n-hexane-EtOH 95: 5 (flow rate = 1 ml) / min; Detector UV 254 nm). Real UI (SRVl-r3_ (2-Cyano | V4-cyclohexyl-4-hydroxy) 5 group M :: Ι1: ((B- ^ lipobenzodioxinyl)) ^ ^ Well = H834 minutes Spectral isomers) Such compounds obtained from the compound of Example 14 were analyzed by optical column chromatography using Chiralpak AD (0.46x25 cm), and n-hexane

EtOH 95:5 (流速=! ml/min ;偵檢器 uV 254 nm)洗提。 10實施例15 Κ[3-(2-氰苯基)-4-環己基-4-侧氧丁基】-4-(4-氟基 -2-甲氧基苯基)底„井 使用被描述作為實施例1之該化合物之該方法以製備該標 題化合物’但使用化合物13c代替化合物le且1-(4-氟基-2-甲 氧基苯基>哌畊代替1-(2,2,2-三氟乙氧基苯基)-哌畊。該粗產物 15藉由閃瘵層析法予以純化（PE :EtOAc 6:4)俾以提供該標題化合 物（82 %)·EtOH 95: 5 (flow rate =! Ml / min; detector uV 254 nm) elution. 10 Example 15 K [3- (2-cyanophenyl) -4-cyclohexyl-4-oxobutyl] -4- (4-fluoro-2-methoxyphenyl) bottom The method as the compound of Example 1 is described to prepare the title compound 'but using compound 13c in place of compound le and 1- (4-fluoro-2-methoxyphenyl) > piperin instead of 1- (2, 2,2-trifluoroethoxyphenyl) -pigen. The crude product 15 was purified by flash chromatography (PE: EtOAc 6: 4) 俾 to provide the title compound (82%) ·

'H-NMR (CDC13)^ : 1.00-2.10 (m9llH); 2.15^2.75 (m?8H); 2.75-3.15 (m，4H); 3.90 (s，3H); 4.55 (t，lH); 6.50-6.70 (m，2H); 6.80-6.95 (m5lH)； 7.30-7.42 (m52H); 7.45-7.60 (m5lH);7.60-7.72 20 (m，lH) 實施例16 氰苯基M-環己基-4-經丁基]_4普氟基-2- 甲氧基苯基)-°底n井 使用被述作為化合物lc之該方法以合成該標題化合 物，但起始自實施例14之該化合物代替化合物lb。在一般的 70 200406394 完成程序(work-up procedure)後，該粗產物藉由閃蒸層析法予以 純化(PE - EtOAc - NH3/MeOH 65:35:3)，而提供該標題化合物 (51.3 %) 〇 ]H-NMR (CDCl3) δ): 0.90-1.20 (m，6H); 1.40-1.85 5 (m?5H);1.90-2.10 (m52H); 2.20-2.45 (m?2H); 2.50-2.85 (m54H); 2.90-3.15 (m54H); 3.32-3.50 (m?lH) 3.50-3.65 (m?lH); 3.95 (s?3H); 4.60-5.20 (bs9lH); 6.55-6.68 (m?2H); 6.80-6.92 (m?lH); 7.28-7.36 (m，lH); 7.45-7.68 (m，2H);7.95-8.05 (m，lH) 實施例17 1-(4-環己基-4-甲氧基-3-苯丁基）-4-[5-(2,3-二羥 10 -1，4-苯並戴奥辛基)】-哌畊 4.4- 二曱氣基-2-笨基丁腈（化合物17 a) 採用被描述作為化合物6b之該操作程序以合成該標題化 合物，但使用2-溴乙醛二曱基縮醛代替3-溴丙烯且苯乙腈代替 2-三氟曱氧苯乙腈。在自發性加熱至室溫經歷2小時後，使該 15 反應混合物回流歷時額外的2小時。在一般的完成程序 (work-up procedure)後，該粗產物藉由閃蒸層析法予以純化 (PE-EtOAc 9:1)，而提供有如一淡黃色的油之該標題產物 (72.1%)。 ]H-NMR (CDClS} δ): 2.02-2.36 (m? 2H); 3.39 (d5 6H); 3.76-4.01 20 (m? 1H); 4.41-4.54 (m, 1H); 7.30-7.48 (m, 5H). 4.4- 二甲氧基-2-笨基丁醛(化合物17b) 採用被描述作為化合物6f(另擇的方法）之該操作程序以獲 得該標題化合物，但使用化合物17a代替化合物6i作為一起 始物。在一般的完成程序(work-up procedure)後，該粗產物藉 71 200406394 由閃蒸層析法予以純化（CH2C12 - EtOAc 95:5 )俾以提供該標題 化合物（73.2 %)。 ]H-NMR {CDCls, δ): 1.83-2.02 (m? 1H); 2.39-2.58 (m? 1H); 3.32 (d，6H); 3.66-3.81 (m，1H); 4.23-4.38 (m, 1H); 7.07-7.48 (m5 5H); 5 9.61-9.70 (m，1H)· 4-環己基-4-羥基-3-笨基丁醛二曱基縮醛（化合物17c) 採用被描述作為實施例6之該化合物之該操作程序以獲得 該標題化合物，但使用化合物17b代替化合物6f作為一起始 物且氯化（環己基）鎂（2M溶液，配於THF中）代替氯化（乙基） 10 鎂。該粗產物藉由閃蒸層析法予以純化（CH2C12 -丙酮9:1)， 而提供該標題產物（55 %)。 ^-NMR {CDCls, δ): 0.97-2.09 (m5 12H); 2.27-2.45 (m? 1H); 2.88-3.03 (m5 1H); 3.31 (d5 6H); 3.41-3.53 (m? 1H); 4.11-4.22 (m? 1H); 7.21-7.43 (m? 5H). 15 單一的OH係無法偵測的。 4-環己基-4-曱氧基-3-笨基丁醛二曱基縮醛（化合物17d) 如針對化合物Id所描述的來合成該標題化合物，使用化 合物17c代替化合物lc作為一起始物。在E20萃取之後，該 粗產物藉由閃蒸層析法予以純化(PE - EtOAc 8」2)，而提供該標 20 題產物（71.4 %)。 !H-NMR (CDCIs, δ): 0.98-1.37 (m5 6H); 1.49-1.98 8m? 6H); 2.17-2.33 (m? 1H); 2.82-3.02 (m9 2H); 3.21 (dd? 6H); 3.37 (s5 3H); 3.94-4.08 (m? 1H); 7.17-7.39 (m? 5H). 4-環己基-4-曱氧基-3-笨基丁醛（化合物17e) 72 200406394 採用被描述作為化合物le之該操作程序以獲得該標題化 合物，但使用化合物17d代替化合物id作為一起始物。該標 題產物在無進一步純化下使用於下一步驟中。 'H-NMR (CDClS) δ)： 0.93-1.86 (m5 12H); 2.61-2.79 (m? 2H); 5 3.01-3.16 (m5 1H); 3·31 (s，3H); 3.41-3.59 (m5 1H); 7.15-7.39 (m5 5H); 9.53-9.61 (m5 1H) 環己基·4 ·3-笨丁基）_4_「5_(2·3_ 二羥 _ K4_ 笨 # 截色 辛基)1-哌啡'H-NMR (CDC13) ^: 1.00-2.10 (m9llH); 2.15 ^ 2.75 (m? 8H); 2.75-3.15 (m, 4H); 3.90 (s, 3H); 4.55 (t, lH); 6.50- 6.70 (m, 2H); 6.80-6.95 (m5lH); 7.30-7.42 (m52H); 7.45-7.60 (m5lH); 7.60-7.72 20 (m, lH) Example 16 Cyanophenyl M-cyclohexyl-4- Via butyl] _4 fluoro-2-methoxyphenyl)-° bottom n wells using the method described as compound lc to synthesize the title compound, but starting from Example 14 this compound replaces compound lb . After a general work-up procedure of 70 200406394, the crude product was purified by flash chromatography (PE-EtOAc-NH3 / MeOH 65: 35: 3) to provide the title compound (51.3% ) 〇] H-NMR (CDCl3) δ): 0.90-1.20 (m, 6H); 1.40-1.85 5 (m? 5H); 1.90-2.10 (m52H); 2.20-2.45 (m? 2H); 2.50-2.85 (m54H); 2.90-3.15 (m54H); 3.32-3.50 (m? lH) 3.50-3.65 (m? lH); 3.95 (s? 3H); 4.60-5.20 (bs9lH); 6.55-6.68 (m? 2H) ; 6.80-6.92 (m? LH); 7.28-7.36 (m, lH); 7.45-7.68 (m, 2H); 7.95-8.05 (m, lH) Example 17 1- (4-cyclohexyl-4-methyl) Oxy-3-phenylbutyl) -4- [5- (2,3-dihydroxy10 -1,4-benzodiocinyl)]-piperin 4.4-difluorenyl-2-benzylbutyronitrile (Compound 17a) The procedure described as compound 6b was used to synthesize the title compound, but 2-bromoacetaldehyde difluorenyl acetal was used instead of 3-bromopropene and phenylacetonitrile was used instead of 2-trifluoroacetoxybenzoacetonitrile . After spontaneously heating to room temperature for 2 hours, the 15 reaction mixture was refluxed for an additional 2 hours. After a general work-up procedure, the crude product was purified by flash chromatography (PE-EtOAc 9: 1) to provide the title product as a pale yellow oil (72.1%) . ] H-NMR (CDClS) δ): 2.02-2.36 (m? 2H); 3.39 (d5 6H); 3.76-4.01 20 (m? 1H); 4.41-4.54 (m, 1H); 7.30-7.48 (m, 5H). 4.4- Dimethoxy-2-benzyl butyraldehyde (compound 17b) This procedure was described as compound 6f (alternative method) to obtain the title compound, but compound 17a was used instead of compound 6i as A starter. After a general work-up procedure, the crude product was purified by flash chromatography (CH2C12-EtOAc 95: 5) using 71 200406394 to provide the title compound (73.2%). ] H-NMR {CDCls, δ): 1.83-2.02 (m? 1H); 2.39-2.58 (m? 1H); 3.32 (d, 6H); 3.66-3.81 (m, 1H); 4.23-4.38 (m, 1H); 7.07-7.48 (m5 5H); 5 9.61-9.70 (m, 1H) · 4-cyclohexyl-4-hydroxy-3-benzylbutyraldehyde diamidoacetal (compound 17c) Adopted as described as implementation The procedure of the compound of Example 6 was used to obtain the title compound, but using compound 17b instead of compound 6f as a starting material and (cyclohexyl) magnesium chloride (2M solution in THF) instead of (ethyl) chloride 10 mg. The crude product was purified by flash chromatography (CH2C12-acetone 9: 1) to provide the title product (55%). ^ -NMR (CDCls, δ): 0.97-2.09 (m5 12H); 2.27-2.45 (m? 1H); 2.88-3.03 (m5 1H); 3.31 (d5 6H); 3.41-3.53 (m? 1H); 4.11 -4.22 (m? 1H); 7.21-7.43 (m? 5H). 15 A single OH system cannot be detected. 4-Cyclohexyl-4-methoxy-3-benzylbutyraldehyde difluorenyl acetal (compound 17d) The title compound was synthesized as described for compound Id, using compound 17c instead of compound lc as a starting material. After E20 extraction, the crude product was purified by flash chromatography (PE-EtOAc 8 "2) to provide the title product (71.4%). ! H-NMR (CDCIs, δ): 0.98-1.37 (m5 6H); 1.49-1.98 8m? 6H); 2.17-2.33 (m? 1H); 2.82-3.02 (m9 2H); 3.21 (dd? 6H); 3.37 (s5 3H); 3.94-4.08 (m? 1H); 7.17-7.39 (m? 5H). 4-cyclohexyl-4-fluorenyl-3-benzyl butyraldehyde (compound 17e) 72 200406394 Adopted to be described This procedure was performed as compound le to obtain the title compound, but compound 17d was used instead of compound id as a starting material. The title product was used in the next step without further purification. 'H-NMR (CDClS) δ): 0.93-1.86 (m5 12H); 2.61-2.79 (m? 2H); 5 3.01-3.16 (m5 1H); 3.31 (s, 3H); 3.41-3.59 (m5 1H); 7.15-7.39 (m5 5H); 9.53-9.61 (m5 1H) cyclohexyl · 4 · 3-benzylbutyl) _4_ 「5_ (2 · 3_ dihydroxy_K4_benzyl # truncated octyl) 1-pipe coffee

使用被描述作為實施例1之該化合物之該方法以製備該 1〇標題化合物，但使用化合物I7e代替化合物le且1-(2,3-二經 -1，4-苯並戴奥辛基哌畊代替卜(2,2,2-三氟乙氧基苯基)_哌 _ °該粗產物藉由閃蒸層析法予以純化(PE :Me2C〇 75:25)俾以 提供該標題化合物（77.4 %)。 ^-NMR (CDClS} s): 0.97-1.31 (m? 6H); 1.48-1.99 (m5 6H)； 15 2.07-2.28 (m? 3H); 2.42-2.67 (m? 4H); 2.71-2.90 (m5 1H);The method described as the compound of Example 1 was used to prepare the 10 title compound, but compound I7e was used in place of compound le and 1- (2,3-diocycline-1,4-benzodiocinyl piperine was used instead (2,2,2-trifluoroethoxyphenyl) -piperone ° The crude product was purified by flash chromatography (PE: Me2CO75: 25) to provide the title compound (77.4% ^ -NMR (CDClS) s): 0.97-1.31 (m? 6H); 1.48-1.99 (m5 6H); 15 2.07-2.28 (m? 3H); 2.42-2.67 (m? 4H); 2.71-2.90 (m5 1H);

2.92-3.26 (m? 5H); 3.3 (s? 3H); 4.17-4.38 (m? 4H); 6.45-6.64 (m? 2H); 6.66-6.84 (m，1H); 7.12-7.34 (m，5H). 實施例18 1-(4-環己基-4-甲氧基-3-苯丁基)-4-(4-氟基-2-曱氧 基苯基)-11 辰11井 20 使用被描述作為實施例1之該化合物之該方法以製備該 標題化合物，但使用化合物l7e代替化合物le且1_(扣氟基_2_ 曱氧基苯基畊代替1-(2,2,2-三氟乙氧基苯基)-°底_。該粗產 物藉由閃蒸層析法予以純化(PE :Me2CO 75:25)俾以提供該標題 化合物（79.8 %)。 73 200406394 ^-NMR (CDCls, δ): 0.97-1.37 (m5 6H); 1.46-1.98 (m? 6H); 2.07-2.31 (m5 3H); 2.42-2.71 (m, 4H); 2.74-2.80 (m? 1H); 2.81-3.18 (m? 5H); 3.39 (s5 3H); 3.81 (s? 3H); 6.49-6.68 (m? 2H); 6.77-6.92 (m5 1H); 7.13-7.38 (m5 5H). 5 實施例19 1-(4-環己基-4-乙氧基-3-苯丁基）-4-[5-(2,3-二羥 -1，4-苯並戴奥辛基)]-哌畊 4-環己基-4-乙氧基-3-笨基丁醛二曱基縮醛（化合物19a)2.92-3.26 (m? 5H); 3.3 (s? 3H); 4.17-4.38 (m? 4H); 6.45-6.64 (m? 2H); 6.66-6.84 (m, 1H); 7.12-7.34 (m, 5H) ). Example 18 1- (4-Cyclohexyl-4-methoxy-3-phenylbutyl) -4- (4-fluoro-2-methoxyphenyl) -11 Chen 11 Well 20 used The method as the compound of Example 1 is described to prepare the title compound, but uses compound 17e in place of compound le and 1_ (oxofluoro_2_methoxyphenylphenyl) instead of 1- (2,2,2-trifluoro Ethoxyphenyl)-° C. The crude product was purified by flash chromatography (PE: Me2CO 75:25) to provide the title compound (79.8%). 73 200406394 ^ -NMR (CDCls, δ): 0.97-1.37 (m5 6H); 1.46-1.98 (m? 6H); 2.07-2.31 (m5 3H); 2.42-2.71 (m, 4H); 2.74-2.80 (m? 1H); 2.81-3.18 ( m? 5H); 3.39 (s5 3H); 3.81 (s? 3H); 6.49-6.68 (m? 2H); 6.77-6.92 (m5 1H); 7.13-7.38 (m5 5H). 5 Example 19 1- ( 4-cyclohexyl-4-ethoxy-3-phenylbutyl) -4- [5- (2,3-dihydroxy-1,4-benzodioxinyl)]-piperin 4-cyclohexyl-4 -Ethoxy-3-benzyl butyraldehyde difluorenyl acetal (compound 19a)

如針對化合物Id所描述的來合成該標題化合物，使用化 合物17c代替化合物lc作為一起始物且碘乙烷代替碘甲烷。 10 在E20萃取後，該粗產物藉由閃蒸層析法予以純化（PE -EtOAc 8:2)，而提供該標題產物(50.7 %)。 ^-NMR {CDClS) δ): 0.91-1.34 (m? 9H); 1.42-1.99 (m5 6H); 2.14-2.34 (m? 1H); 2.80-2.94 (m? 1H); 3.00-3.11 (m5 1H); 3.22 (d5 6H); 3.41-3.57 (m5 2H); 3.92-4.08 (m; 1H); 7.14-7.35 (m5 5H). 15 4-環己基-4-乙氧基-3-笨基丁醛（化合物19b)The title compound was synthesized as described for compound Id, using compound 17c instead of compound lc as a starting material and iodoethane instead of methyl iodide. 10 After E20 extraction, the crude product was purified by flash chromatography (PE-EtOAc 8: 2) to provide the title product (50.7%). ^ -NMR (CDClS) δ): 0.91-1.34 (m? 9H); 1.42-1.99 (m5 6H); 2.14-2.34 (m? 1H); 2.80-2.94 (m? 1H); 3.00-3.11 (m5 1H ); 3.22 (d5 6H); 3.41-3.57 (m5 2H); 3.92-4.08 (m; 1H); 7.14-7.35 (m5 5H). 15 4-cyclohexyl-4-ethoxy-3-benzidine Aldehyde (Compound 19b)

採用被描述作為化合物le之該操作程序以獲得該標題化 合物，但使用化合物19a代替化合物Id作為一起始物。該標 題產物在無進一步純化下使用於下一步驟中。 ^-NMR {CDCls, δ): 0.91-1.39 (m? 8H); 1.48-1.88 (m? 6H); 20 2.57-2.89 (m? 2H); 3.08-3-20 (m? 1H); 3.23-3.40 (m? 1H); 3.41-3.61 (m? 2H); 7.13-7.38 (m? 5H); 9.57-9.66 (m? 1H). 1-(4 -玉哀己基-4-乙氧基-3-笨丁基)-4-f5-(2,3 -二經-1，4 -笨並戴奥 辛基Vl·哌讲 使用被描述作為實施例1之該化合物之該方法以製備該 74 200406394 標題化合物，但使用化合物19b代替化合物le且l-(2,3-二羥 -1,4-苯並戴奥辛-5-基)-哌讲代替1-(2,2,2-三氟乙氧基苯基)-哌 畊。該粗產物藉由閃蒸層析法予以純化(PE :Me2CO 8:2)俾以提 供該標題化合物（60.6 %)。 5 ]H-NMR {CDCl3} δ): 0.97-1.32 (m9 9H); 1.42-1.99 (m? 6H); 2.04- 2.36 (m5 3H); 2.46-2.69 (m5 4H); 2.71-2.90 (m? 1H); 2.94-3.21 (m? 5H); 3.26-3.61 (m5 2H); 4.17-4.39 (m? 4H); 6.48-6.74 (m，2H); 6.68-6.83 (m，1H); 7.14-7.37 (m，5H)·The procedure described as compound le was used to obtain the title compound, but using compound 19a instead of compound Id as a starting material. The title product was used in the next step without further purification. ^ -NMR (CDCls, δ): 0.91-1.39 (m? 8H); 1.48-1.88 (m? 6H); 20 2.57-2.89 (m? 2H); 3.08-3-20 (m? 1H); 3.23- 3.40 (m? 1H); 3.41-3.61 (m? 2H); 7.13-7.38 (m? 5H); 9.57-9.66 (m? 1H). 1- (4 -Jadecyl-4-ethoxy-3 -Bentyl) -4-f5- (2,3 -Dijing-1,4 -Bentyldioxinyl Vl.Pidone This method of using the compound described as Example 1 to prepare the 74 200406394 title compound , But use compound 19b instead of compound le and l- (2,3-dihydroxy-1,4-benzodioxin-5-yl) -piperidine instead of 1- (2,2,2-trifluoroethoxybenzene ) -Pigen. The crude product was purified by flash chromatography (PE: Me2CO 8: 2) 俾 to provide the title compound (60.6%). 5] H-NMR {CDCl3} δ): 0.97- 1.32 (m9 9H); 1.42-1.99 (m? 6H); 2.04- 2.36 (m5 3H); 2.46-2.69 (m5 4H); 2.71-2.90 (m? 1H); 2.94-3.21 (m? 5H); 3.26 -3.61 (m5 2H); 4.17-4.39 (m? 4H); 6.48-6.74 (m, 2H); 6.68-6.83 (m, 1H); 7.14-7.37 (m, 5H) ·

實施例20 1-(4-環己基-4-乙氧基-3-苯丁基)-4-(4-氟基-2-甲氧 10 基苯基)-哌〃井 使用被描述作為實施例1之該化合物之該方法以製備該 標題化合物，但使用化合物19b代替化合物le且1_(4_氟基-2-甲氧基苯基)-哌畊代替1-(2,2,2-三氟乙氧基苯基)-哌啡。該粗 產物藉由閃蒸層析法予以純化(PE :Me2CO 75:25)俾以提供該標 15 題化合物（73 %)。Example 20 1- (4-Cyclohexyl-4-ethoxy-3-phenylbutyl) -4- (4-fluoro-2-methoxy10ylphenyl) -piperazine use is described as an implementation This method of the compound of Example 1 was used to prepare the title compound, but using compound 19b in place of compound le and 1- (4-fluoro-2-methoxyphenyl) -pigenin instead of 1- (2,2,2- Trifluoroethoxyphenyl) -piperidine. The crude product was purified by flash chromatography (PE: Me2CO 75:25) to provide the title compound (73%).

]H-NMR (CDCl3, δ): 0.96-1.40 (m? 9H); 1.44-1.99 (m? 6H); 2.05- 2.34 (m, 3H); 2.42-2.69 (m5 4H); 2.74-2.90 (m5 1H); 2.92-3.16 (m? 5H); 3.21-3.60 (m5 2H); 4.83 (s? 3H); 6.52-6.68 (m?2H); 6.78-6.93 (m? 1H); 7.12-7.36 (m? 5H). 20 實施例21 1-(4-烯丙氧基-4-環己基-3-苯丁基)-4- [5-(2,3-二羥 -1，4·苯並戴奥辛基)]-哌畊 4-烯丙氧基-4-環己基-3-笨基丁醛二甲基縮醛（化合物21a) 如針對化合物Id所描述的來合成該標題化合物，使用化 合物17c代替化合物lc作為一起始物且3-溴丙烯代替碘曱 75 200406394 烷。在室溫下攪拌該反應混合物歷時8小時且在45°C下歷時 5小時。以Et20萃取並藉由管柱層析(PE - EtOAc 85:15)之純 化生成該標題化合物（48.5%)。 ^-NMR (CDCl3f δ): 0.94-1.38 (m5 6H); 1.51-2.01 (m? 6H); 5 2·16-2.34 (m, 1H); 2.82-3.01 (m，1Η;) 3.07-3.19 (m，1H); 3.21 (d， 6H); 3.72-3.88 (m? 1H); 3.90-4.07 (m5 2H); 5.04-5.32 (m? 2H); 5.77-6.00 (m? 1H); 7.16-7.37 (m? 5H). 4-烯丙氧基-4-環己基-3-笨基丁醛（化合物21b) 採用被描述作為化合物le之該操作程序以獲得該標題化 10 合物，但使用化合物21a代替化合物Id作為一起始物。該標 題產物在無進一步純化下使用於下一步驟中（99.3%)。 ]H-NMR (CDCh, δ): 0.93-1.41 (m5 6H); 1.47-2.01 (m? 6H); 2.62-2.91 (m，1H); 3.14-3.29 (m，1H); 3.41-3.60 (m，1H); 3.71-4.03 (m9 2H); 5.01-5.32 (m? 2H); 5.73-5.98 (m ?1H); 15 7.08-7.41 (m; 5H); 9.56-9.69 (m5lH). 1-(4-細丙氧基-4_壞己基_3-苯丁基)-4-「5-(2,3_二經_1，4_笨並戴 奧辛基)1-哌畊 使用被描述作為實施例1之該化合物之該方法以製備該標 題化合物，但使用化合物21b代替化合物le且1-(2,3-二羥-1,4-20 苯並戴奥辛-5-基)-哌畊代替1-(2,2,2-三氟乙氧基苯基)-哌畊。該 粗產物藉由閃蒸層析法(PE :Me2C0 7:3)予以純化俾以提供該標 題化合物（64.1 %)。 ^-NMR (CDCh, δ): 0.98-1.40 (m? 6H); 1.48-1.98 (m5 6H); 1.88-2.00 (m? 2H); 2.08-2.31 (m，3H); 2.39-2.71 (m5 4H); 76 200406394 2.2.78-2.94 (m? 1H); 2.96-3.21 (m? 5H); 3.72-4.06 (m5 2H); 4.68-4.87 (m，4H); 5.05-5.34 (m，2H); 5.81-6.02 (m， 1H); 6.47-6.63 (m9 2H); 6.80-6.88 (m? 1H); 7.11-7.37 (m5 5H). [M+H]+= 491 5 實施例22 1-(4-烯丙氧基-4-環己基-3-苯丁基)-4-(4-氟基-2-甲 氧基苯基)-哌畊] H-NMR (CDCl3, δ): 0.96-1.40 (m? 9H); 1.44-1.99 (m? 6H); 2.05- 2.34 (m, 3H); 2.42-2.69 (m5 4H); 2.74-2.90 (m5 1H); 2.92-3.16 (m? 5H); 3.21-3.60 (m5 2H); 4.83 (s? 3H); 6.52-6.68 (m? 2H); 6.78-6.93 (m? 1H); 7.12-7.36 (m 5H). 20 Example 21 1- (4-allyloxy-4-cyclohexyl-3-phenylbutyl) -4- [5- (2,3-dihydroxy-1,4 · benzodioxine )]-Piperazine 4-allyloxy-4-cyclohexyl-3-benzylbutyraldehyde dimethyl acetal (compound 21a) The title compound was synthesized as described for compound Id, using compound 17c instead Compound lc was used as a starting material and 3-bromopropene replaced iodonium 75 200406394 alkane. The reaction mixture was stirred at room temperature for 8 hours and at 45 ° C for 5 hours. Extraction with Et20 and purification by column chromatography (PE-EtOAc 85:15) gave the title compound (48.5%). ^ -NMR (CDCl3f δ): 0.94-1.38 (m5 6H); 1.51-2.01 (m? 6H); 5 2 · 16-2.34 (m, 1H); 2.82-3.01 (m, 1Η;) 3.07-3.19 ( m, 1H); 3.21 (d, 6H); 3.72-3.88 (m? 1H); 3.90-4.07 (m5 2H); 5.04-5.32 (m? 2H); 5.77-6.00 (m? 1H); 7.16-7.37 (m? 5H). 4-allyloxy-4-cyclohexyl-3-benzyl butyraldehyde (compound 21b) The procedure described as compound le was used to obtain the title compound, but using the compound 21a replaces compound Id as a starting material. The title product was used in the next step without further purification (99.3%). ] H-NMR (CDCh, δ): 0.93-1.41 (m5 6H); 1.47-2.01 (m? 6H); 2.62-2.91 (m, 1H); 3.14-3.29 (m, 1H); 3.41-3.60 (m , 1H); 3.71-4.03 (m9 2H); 5.01-5.32 (m? 2H); 5.73-5.98 (m? 1H); 15 7.08-7.41 (m; 5H); 9.56-9.69 (m5lH). 1- ( 4-Finyloxy-4_badhexyl_3-phenylbutyl) -4- "5- (2,3_Dijing_1,4_benzyldioxinyl) 1-pigon use is described as implementation This method of the compound of Example 1 was used to prepare the title compound, but compound 21b was used in place of compound le and 1- (2,3-dihydroxy-1,4-20 benzodioxin-5-yl) -pigenin was used instead of 1 -(2,2,2-trifluoroethoxyphenyl) -pigen. The crude product was purified by flash chromatography (PE: Me2C0 7: 3) to provide the title compound (64.1%) ^ -NMR (CDCh, δ): 0.98-1.40 (m? 6H); 1.48-1.98 (m5 6H); 1.88-2.00 (m? 2H); 2.08-2.31 (m, 3H); 2.39-2.71 (m5 4H); 76 200406394 2.2.78-2.94 (m? 1H); 2.96-3.21 (m? 5H); 3.72-4.06 (m5 2H); 4.68-4.87 (m, 4H); 5.05-5.34 (m, 2H) ; 5.81-6.02 (m, 1H); 6.47-6.63 (m9 2H); 6.80-6.88 (m? 1H); 7.11-7.37 (m5 5H). [M + H] + = 491 5 Example 22 1- ( 4-allyloxy-4-cyclohexyl Phenyl-3-phenylbutyl) -4- (4-fluoro-2-methoxyphenyl) -piperon

使用被描述作為實施例1之該化合物之該方法以製備該 標題化合物，但使用化合物21b代替化合物le且1-(4-氟基-2-曱氧基苯基)-哌畊代替1-(2,2,2-三氟乙氧基苯基)-哌哜。該粗產 10 物藉由閃蒸層析法(PE :Me2CO 7:3)予以純化俾以提供該標題化 合物（77.1 %)。 ^-NMR {CDClS) δ): 0.98-1.41 (m? 6H); 1.47-2.01 (m? 6H); 2.09-2.28 (m5 3H); 2.41-2.70 (m? 4H); 2.79-2.92 (m? 1H); 2.93-3.09 (m5 4H); 3.11-3.22 (m? 1H); 3.77-3.89 (m? 4H); 15 3.39-4.08 (m9 1H); 5.07-5.34 (m， 2H); 5.79-6.01(m? 1H);The method described as the compound of Example 1 was used to prepare the title compound, but using compound 21b in place of compound le and 1- (4-fluoro-2-methoxyoxyphenyl) -pigenin instead of 1- ( 2,2,2-trifluoroethoxyphenyl) -piperidine. The crude product was purified by flash chromatography (PE: Me2CO 7: 3) to provide the title compound (77.1%). ^ -NMR (CDClS) δ): 0.98-1.41 (m? 6H); 1.47-2.01 (m? 6H); 2.09-2.28 (m5 3H); 2.41-2.70 (m? 4H); 2.79-2.92 (m? 1H); 2.93-3.09 (m5 4H); 3.11-3.22 (m? 1H); 3.77-3.89 (m? 4H); 15 3.39-4.08 (m9 1H); 5.07-5.34 (m, 2H); 5.79-6.01 (m? 1H);

6.51-6.68 (m5 2H); 6.69-6.92 (m5 1H); 7.13-7.37 (m? 5H). [M+H].= 481 實施例23 1-(4-環己基-3-苯基-4-炔丙基氧丁基)-4-[5-(2,3-二 羥-1，4-苯並戴奥辛基)]-哌畊 20 4-環己基-3-笨基-4-炔丙基氧丁醛二曱基縮醛（化合物23a) 如針對化合物Id所描述的來合成該標題化合物，使用化 合物17c代替化合物lc作為一起始物且溴化炔丙基代替填曱 烷。在室溫下攪拌該反應混合物歷時8小時並在45°C之下歷 時5小時。以Et2〇萃取並藉由管柱層析（PE - EtOAc 85:15) 77 200406394 之純化生成該標題化合物（50%)。 ^-NMR {CDCls, δ)： 0.90-1.41 (m? 6H)； 1.48-1.74 (m, 5H); 1.75-1.89 (m? 1H); 1.90-2.04 (m5 1H)； 2.18-2.37 (m9 1H); 2.38- 2.44 (m5 1H); 2.88-3.04 (m9 1H); 3.21 (d5 6H); 3.90-4.17 (m5 5 3H); 7.12-7.37 (m? 5H). 4二氣5基-3-苯基-4-炔丙某氧-3-笨基工屋（化合物23b)6.51-6.68 (m5 2H); 6.69-6.92 (m5 1H); 7.13-7.37 (m? 5H). [M + H]. = 481 Example 23 1- (4-cyclohexyl-3-phenyl-4 -Propargyloxybutyl) -4- [5- (2,3-dihydroxy-1,4-benzodioctyl)]-piperin 20 4-cyclohexyl-3-benzyl-4-propargyl Oxybutyraldehyde difluorenyl acetal (compound 23a) The title compound was synthesized as described for compound Id, using compound 17c in place of compound lc as a starting material and bromopropargyl in place of fluorene. The reaction mixture was stirred at room temperature for 8 hours and at 45 ° C for 5 hours. Extraction with Et20 and purification by column chromatography (PE-EtOAc 85:15) 77 200406394 gave the title compound (50%). ^ -NMR {CDCls, δ): 0.90-1.41 (m? 6H); 1.48-1.74 (m, 5H); 1.75-1.89 (m? 1H); 1.90-2.04 (m5 1H); 2.18-2.37 (m9 1H) ); 2.38- 2.44 (m5 1H); 2.88-3.04 (m9 1H); 3.21 (d5 6H); 3.90-4.17 (m5 5 3H); 7.12-7.37 (m? 5H). Phenyl-4-propargyloxy-3-benzyl Kobo (Compound 23b)

採用被描述作為化合物le之該操作程序以獲得該標題化 合物，但使用化合物23a代替化合物id作為一起始物。該標題 產物在無進一步純化下使用於下一步驟中（99 %)。 10 H-NMR {CDCl3y δ): 0.81-1.41 (m5 6H); 1.49-1.90 (m5 5H); 2.39- 2.51 (m， 1H); 2.66-2.88 (m， 1H); 2.89-3.08 (m， 1H); 3.31-3.42 (m5 1H); 3.43-6.59 (m? 1H); 3.97-4.19 (m? 2H); 7.12-7.39 (m5 5H); 9.57-9.69 (m9 1H). M4二I衰己基-3二基-4_炔丙基氣丁基菜祐 15 戴奥辛基哌The procedure described as compound le was used to obtain the title compound, but using compound 23a instead of compound id as a starting material. The title product was used in the next step without further purification (99%). 10 H-NMR {CDCl3y δ): 0.81-1.41 (m5 6H); 1.49-1.90 (m5 5H); 2.39- 2.51 (m, 1H); 2.66-2.88 (m, 1H); 2.89-3.08 (m, 1H ); 3.31-3.42 (m5 1H); 3.43-6.59 (m? 1H); 3.97-4.19 (m? 2H); 7.12-7.39 (m5 5H); 9.57-9.69 (m9 1H). 3 Diyl-4_propargyl butyl butanol 15 Dioxin

使用被描述作為實施例1之該化合物之該方法以製備該標 題化合物，但使用化合物23b代替化合物le且1(2,3 —二羥」，4_ 苯並戴奥辛-5·基)-哌畊代替三氟乙氧基苯基>哌畊。該 粗產物藉由閃蒸層析法(PE :Me2CO 7:3)予以純化俾以提供該標 20 題化合物（67.1 %)。 JH-NMR (CDCl3} δ): 0.98-1.39 (m9 6H); 1.48-1.99 (m? 6H); 2.11-2.29 (m5 3H); 2.39-2.46 (m, 1H); 2.47-2.71 (m? 4H); 2.82-3.96 (m，1H); 2.97-3.12 (m 4H); 3.17-3.29 (m5 ih); 3.95-4.16 (m? 2H); 4.17-4.38 (m? 4H); 6.48-6.72 (m? 2H)； 78 200406394 6.69-6.83 (m5 1H); 7.12-7.35 (m; 5H) [M+H]+二 489 實施例24 1-(4-環己基_3_苯基_4_炔丙基氧丁基)_4-(4_氟基_2_ 甲氧基苯基)-哌啡 5 使用被描述作為實施例1之該化合物之該方法以製備該 標題化合物，但使用化合物23b代替化合物le且1-(4_氟基-2_ 曱氧基苯基)-哌畊代替^(2,2,2-三氟乙氧基苯基)_哌呌。該粗產 物藉由閃蒸層析法(PE :Me2CO 8:2)予以純化俾以提供該標題化 合物(66.2 %)。 10 H-NMR {CDCl3) δ): 0.99-1.41 (m? 6H); 1.51-2.00 (m5 6H); 2.11-2.29 (m，3H); 2.39-2.46 (m，1H); 2.47-2.70 (m，4H); 2.78-3.12 (m? 5H)； 3.13-3.29 (m? 1H); 3.81 (s? 3H); 3.96-4.17 (m? 2H); 6.51-6.67 (m? 2H); 6.79-7.94 (m? 1H); 7.11-7.34 (m? 5H). [M+H]+=479 15實施例25 1-(4-環己基-3-苯基-4-丙氧丁基）-4-[5-(2,3-二羥 -1，4·苯並戴奥辛基)]-哌啡 丙氧基丁黾二甲基縮醛（化合物25a) 如針對化合物Id所描述的來合成該標題化合物，使用化 合物17c代替化合物lc作為一起始物且溴化丙基代替碘甲 20烧。在至溫下攪拌該反應混合物歷時8小時並在45°C之下歷 日才5小時。以EtaO萃取並藉由管柱層析(pE _ Et〇Ac 85:15)之 純化生成該標題化合物（32.7%)。 ^-NMR (CZ)C/, ^): 0.91 (t5 3H)； 0.99-1.32 (m5 6H); 1.45-1.98 (m? 10H); 2.19-2.38 (m? 1H); 2.83-2.99 (m5 iH); 3.01-3.10 (m? 79 200406394 1H)，3.16-3.29 (m，5H); 3.31-3.5 (m，1H); 3.91-4.08 (m, 1H); 7.13-7.34 (m9 5H). 4·二環己基_3-苯基基丁醛（化合物2逆 採用被彳田述作為化合物le之該操作程序以獲得該標題化 5合物，但使用化合物25a代替化合物Id作為一起始物。該標 題產物在無進一步純化下使用於下一步驟中（99 3%)。 H-NMR {CDCls, δ)： 0.80-0.95 (m9 3H); 0.96-1.37 (m5 6H); 1.41-1.88 (m，7H); 2.57-3.09 (m，3H); 3.11-3.59 (m，3H); 7.11-7.39 (m5 5H); 9.1〇.9.15 (m? 1H). 10 基ν4-「5·(2,3_二羥_14_苯並戴奧 辛基)l-plp井 使用被彳田述作為實施例1之該化合物之該方法以製備該 標題化合物，但使用化合物25b代替化合物le且^(2,3-二羥 _1，4-苯並戴奥辛基)-哌畊代替1-(2,2,2-三氟乙氧基苯基)_哌 15讲。該粗產物藉由閃蒸層析法(prmqCo 8:2)予以純化俾以提 供該標題化合物（5〇·7 %)。 ]H-NMR (CDCls, δ): 0.93 (t? 3H); 0.99-1.37 (m5 6H); 1.44-1.98 (m5 8H); 2.10-2.31 (m? 3H); 2.41-2.69 (m? 4H); 2.72-2.90 (m5 1H); 2.95-3.18 (m? 5H); 3.20-3.98 (m? 2H); 4.19-4.37 (m? 4H); 20 6.48-6.67 (m，2H); 6.69-6.83 (m，1H); 7.11-7.36 (m，5H)· [M+H]+=493 實施例26 l-[5-(2,3-二羥-1，4-苯並戴奥辛基)卜4-(4-羥基-3-苯 基)-己基°辰啡 4-^1/2-毛基氣丙烧（化合物26a) 80 200406394 採用被描述作為化合物le之該操作程序以獲得該標題化 合物，但使用化合物17a代替化合物Id作為一起始物。在一 般的完成程序（work-up procedure)後，該從而所獲得的標題化合 物在無進一步純化下使用於下一步驟中。 5 ^-NMR {CDClS) δ)： 2.94-3.29 (m? 2H)5 4.31-4.45 (m; 1H)? 7.30-7:48 (m，5H)，9.78 (bs，1H). H3-氰基基丙基)-4- (2,3-二氫苯 (化合物26b) 採用被描述作為實施例1之該化合物之該操作程序以獲 10得該標題化合物，但使用化合物26a代替化合物le作為一起 始物且1 -(2,3- 一备-154 -苯並戴奥辛-5-基辰啡代替卜(2,2,2-三 氟乙氧基苯基底啡。藉由閃蒸層析法(PE - EtOAc 4:6)之純化 生成該標題化合物（85 %)。油。 'H-NMR (CDCl3) δ)： 2.01-2.29 (m? 2H); 2.31-2.72 (m5 6H)5 15 3.02-3.22 (m，4H)，4.03-4.18 (m5 1H)，4.19-4.38 (m，4H)， 6.50-6.62 (m，2H)，6.73-6.85 (m，1H)，7.31-7.42 (m，5H). ]二(2，.3-二氫苯11，4-戴奥辛-5-基)-4-(3_甲醯基-3_1^^^^^ (化合物26c) 採用被描述作為化合物6 f (另擇的方法）之該操作程序以與 20得該標題化合物，但使用化合物26b代替化合物6h作為_起 始物。藉由閃蒸層析法(CH^kMeOH 95:5)之純化生成該標題 化合物（60 %)。油。 ^-NMR (CDCl3, s): 1.88-2.02 (m? 1H)? 2.30-2.51 (m? 3H) 2.52-2.98 (m5 4H)? 2.99-3.31 (m? 4H)? 3.63-3.77 (m? 1H) 81 200406394 4·20-4.41 (m，4H)，6.48-6.67 (m, 2H)，6.68-6.85 (m，1H)， 7.21-7.43 (m，5H)，9.79 (bs，1H)· l-「5-(2,3-二羥笨並戴奥辛基)1-4-(4-羥基-3-笨己基)_哌啫 採用被描述作為實施例6之該化合物之該操作程序以獲 5 得該標題化合物，但使用化合物26c代替化合物6f作為一起 始物。該粗產物藉由閃蒸層析法(CH2C12 - MeOH/NH3 97:3)予以 純化，而提供有如一黃色透明的油之該標題產物（22.6 %)。 ^-NMR (CDCl3} δ): 0.79-1.01 (m? 3H) 1.02-1.79 (m? 4H),The method described as the compound of Example 1 was used to prepare the title compound, but compound 23b was used in place of compound le and 1 (2,3-dihydroxy ", 4_benzodioxin-5.yl) -piperin Trifluoroethoxyphenyl > Pigen. The crude product was purified by flash chromatography (PE: Me2CO 7: 3) to provide the title compound (67.1%). JH-NMR (CDCl3) δ: 0.98-1.39 (m9 6H); 1.48-1.99 (m? 6H); 2.11-2.29 (m5 3H); 2.39-2.46 (m, 1H); 2.47-2.71 (m? 4H ); 2.82-3.96 (m, 1H); 2.97-3.12 (m 4H); 3.17-3.29 (m5 ih); 3.95-4.16 (m? 2H); 4.17-4.38 (m? 4H); 6.48-6.72 (m 2H); 78 200406394 6.69-6.83 (m5 1H); 7.12-7.35 (m; 5H) [M + H] + di489 Example 24 1- (4-cyclohexyl_3_phenyl_4_propargyl Oxybutyl) _4- (4-fluoro_2_methoxyphenyl) -piperine 5 This method was used to prepare the title compound described as the compound of Example 1 but using compound 23b instead of compound le In addition, 1- (4-fluoro-2-2-methoxyphenyl) -piperon replaces ^ (2,2,2-trifluoroethoxyphenyl) -piperidine. The crude product was purified by flash chromatography (PE: Me2CO 8: 2) to provide the title compound (66.2%). 10 H-NMR (CDCl3) δ): 0.99-1.41 (m? 6H); 1.51-2.00 (m5 6H); 2.11-2.29 (m, 3H); 2.39-2.46 (m, 1H); 2.47-2.70 (m , 4H); 2.78-3.12 (m? 5H); 3.13-3.29 (m? 1H); 3.81 (s? 3H); 3.96-4.17 (m? 2H); 6.51-6.67 (m? 2H); 6.79-7.94 (m? 1H); 7.11-7.34 (m? 5H). [M + H] + = 479 15 Example 25 1- (4-cyclohexyl-3-phenyl-4-propoxybutyl) -4- [5- (2,3-Dihydroxy-1,4 · benzodioctyl)]-piperidine propoxybutyrium dimethyl acetal (compound 25a) The title compound was synthesized as described for compound Id Using compound 17c instead of compound lc as a starting material and bromopropyl instead of iodomethyl 20. The reaction mixture was stirred at room temperature for 8 hours and at 45 ° C for 5 hours. Extraction with EtaO and purification by column chromatography (pE_EtoAc 85:15) gave the title compound (32.7%). ^ -NMR (CZ) C /, ^): 0.91 (t5 3H); 0.99-1.32 (m5 6H); 1.45-1.98 (m? 10H); 2.19-2.38 (m? 1H); 2.83-2.99 (m5 iH ); 3.01-3.10 (m? 79 200406394 1H), 3.16-3.29 (m, 5H); 3.31-3.5 (m, 1H); 3.91-4.08 (m, 1H); 7.13-7.34 (m9 5H). 4 · Dicyclohexyl_3-phenylbutyraldehyde (Compound 2 uses the procedure described by Putian as compound le to obtain the title compound, but uses compound 25a instead of compound Id as a starting material. This title The product was used in the next step without further purification (99 3%). H-NMR {CDCls, δ): 0.80-0.95 (m9 3H); 0.96-1.37 (m5 6H); 1.41-1.88 (m, 7H) ); 2.57-3.09 (m, 3H); 3.11-3.59 (m, 3H); 7.11-7.39 (m5 5H); 9.1〇.9.15 (m? 1H). 10 groups ν4- "5 · (2,3_ Dihydroxy_14_benzodiocinyl) l-plp This method was used by Putian as the compound of Example 1 to prepare the title compound, but using compound 25b instead of compound le and ^ (2,3-di Hydroxy-1,4-benzodioctyl) -pigen instead of 1- (2,2,2-trifluoroethoxyphenyl) -piper 15. The crude product was purified by flash chromatography (prmqCo 8 : 2) to be purified 俾To provide the title compound (50.7%).] H-NMR (CDCls, δ): 0.93 (t? 3H); 0.99-1.37 (m5 6H); 1.44-1.98 (m5 8H); 2.10-2.31 ( m? 3H); 2.41-2.69 (m? 4H); 2.72-2.90 (m5 1H); 2.95-3.18 (m? 5H); 3.20-3.98 (m? 2H); 4.19-4.37 (m? 4H); 20 6.48-6.67 (m, 2H); 6.69-6.83 (m, 1H); 7.11-7.36 (m, 5H) · [M + H] + = 493 Example 26 l- [5- (2,3-dihydroxy) -1,4-Benzodioxinyl) 4- (4-hydroxy-3-phenyl) -hexyl ° Cinnaphine 4- ^ 1 / 2-pilosyl (Compound 26a) 80 200406394 Adopted as described This procedure for compound le was used to obtain the title compound, but compound 17a was used instead of compound Id as a starting material. After a general work-up procedure, the title compound thus obtained was used in the next step without further purification. 5 ^ -NMR {CDClS) δ): 2.94-3.29 (m? 2H) 5 4.31-4.45 (m; 1H)? 7.30-7: 48 (m, 5H), 9.78 (bs, 1H). H3-cyano Propyl) -4- (2,3-dihydrobenzene (compound 26b) The procedure described as the compound of Example 1 was used to obtain 10 to obtain the title compound, but compound 26a was used instead of compound le as a group. The starting material and 1-(2,3-a preparation-154-benzodioxin-5-ylchenphine instead of (2,2,2-trifluoroethoxyphenyl endorphine. By flash chromatography ( Purification of PE-EtOAc 4: 6) gave the title compound (85%). Oil. 'H-NMR (CDCl3) δ): 2.01-2.29 (m? 2H); 2.31-2.72 (m5 6H) 5 15 3.02- 3.22 (m, 4H), 4.03-4.18 (m5 1H), 4.19-4.38 (m, 4H), 6.50-6.62 (m, 2H), 6.73-6.85 (m, 1H), 7.31-7.42 (m, 5H) .] Bis (2, .3-dihydrobenzene11,4-Dioxin-5-yl) -4- (3-methylamino-3_1 ^^^^^ (Compound 26c) Adopted as described for Compound 6 f ( (Alternative method) The procedure uses 20 to obtain the title compound, but uses compound 26b instead of compound 6h as the _ starter. The title is generated by purification by flash chromatography (CH ^ kMeOH 95: 5). Compound (6 0%). Oil. ^ -NMR (CDCl3, s): 1.88-2.02 (m? 1H)? 2.30-2.51 (m? 3H) 2.52-2.98 (m5 4H)? 2.99-3.31 (m? 4H)? 3.63 -3.77 (m? 1H) 81 200406394 4.20-4.41 (m, 4H), 6.48-6.67 (m, 2H), 6.68-6.85 (m, 1H), 7.21-7.43 (m, 5H), 9.79 (bs , 1H) l- "5- (2,3-dihydroxybenzidine and dioxinyl) 1-4- (4-hydroxy-3-benzylhexyl) -piperidine uses the compound described as Example 6 The procedure was used to obtain 5 to obtain the title compound, but compound 26c was used instead of compound 6f as a starting material. The crude product was purified by flash chromatography (CH2C12-MeOH / NH3 97: 3) and provided as yellow The title product (22.6%) of a clear oil. ^ -NMR (CDCl3} δ): 0.79-1.01 (m? 3H) 1.02-1.79 (m? 4H),

1.80- 1.98 (m，1H)? 1.99-2.24 (m? 1H)? 2.26-2.96 (m 6H)? 10 2.98-3.33 (m? 4H)? 3.41-3.79 (m? 1H)? 4.18-4.38 (m? 4H)? 6.45-6.68 (m，2H)5 6.69-6.87 (m，1H)，7.19-7.38 (m，5H)· [M+H]+二 397.4 實施例27 l-[5-(2,3-二羥-1,4-苯並戴奥辛基)】-4- (4-羥基-3- 苯基)-庚基]-哌讲 15 被一起獲得如主要的不純物之該標題化合物以及實施例1.80- 1.98 (m, 1H)? 1.99-2.24 (m? 1H)? 2.26-2.96 (m 6H)? 10 2.98-3.33 (m? 4H)? 3.41-3.79 (m? 1H)? 4.18-4.38 (m 4H) 6.45-6.68 (m, 2H) 5 6.69-6.87 (m, 1H), 7.19-7.38 (m, 5H) · [M + H] + 2 397.4 Example 27 l- [5- (2, 3-Dihydroxy-1,4-benzodiocinyl)]-4- (4-hydroxy-3-phenyl) -heptyl] -piperin 15 The title compound as well as the main impurities were obtained together with the examples

12之化合物。藉由閃蒸層析法(EtOAc- MeOH/NH3 95:5)予以 純化。 ^-NMR {CDCls, δ): 0.78-0.92 (m? 3H)? 1.15-1.3 (m5 5H), 1.80- 2.08 (m? 2H)? 2.28-2.40 (m? 2H)? 2.52-2.83 (m5 5H)5 20 3.02-3.18 (m，4H)，3.65-3.79 (m，1H)，4.16-4.32 (m，4H)， 6.48-6.62 (m? 2H)? 6.71-6.82 (t? 1H)? 7.15-7.33 (m5 5H). 實施例28 l-[5-(2,3-二羥-1，4-苯並戴奥辛基)】-4- (4-羥基-3- 苯基己-5-烯基)-哌畊 採用被描述作為實施例6之該化合物之該操作程序以獲 82 200406394 得該標題化合物，但使用化合物26c代替化合物6f作為一起 始物且氯化（乙烯基）鎂（1M，THF溶液）代替氯化（乙基)鎂。該 粗產物藉由閃蒸層析法(CH^Ch-MeOH/NH3 97:3)予以純化，而 提供有如一黃色透明的油之該標題產物（66 %)。 5 ]H-NMR (CDClS) s): 1.35-1.85 (br? 1H)? 1.86-2.28 (m? 2H)5 2.30-2.91 (m，7H)，2.98-3.25 (m，4H)，3·43·3·81 (m，1H)， 4.19-4.40 (m，4H)，4.90-5.35 (m5 2H)5 5.66-5.89 (m，1H)， 6.47-6.69 (m5 2H)? 6.71-6.85 (m? 1H)5 7.14-7.42 (m? 5H). [Μ+Η]+=395·3 10實施例29 l-[5-(2,3-二羥-1，4-苯並戴奥辛基)]-4-(4-羥基-5-甲 基-3-苯基)-己基卜井 採用被描述作為實施例6之該化合物之該操作程序以獲 得該標題化合物，但使用化合物26c代替化合物6f作為一起 始物且氯化（異丙基）鎂（2M，THF溶液）代替氯化（乙基）鎂。該 15 粗產物藉由閃蒸層析法(CH2C12-MeOH/NH3 98:2)予以純化，而 提供有如一白色固體之該標題產物（35 〇/0)。 ^-NMR (CDC13, δ): 0.73-0.95 (m? 6H)? 1.30-1.48 (m5 1H)? 1.76-1.95 (m5 1H)5 1.96-2.21 (m5 1H)? 2.22-2.48 (m9 2H)? 2.49-2.95 (m，5H)，2.96-3.28 (m，4H)，3.52-3.73 (m，1H)5 20 4.19-4.41 (m? 4H)? 5.02-5.68 (bs? 1H)? 6.49-6.63 (m9 2H)? 6.75-6.87 (m9 1H)? 7.15-7.39 (m9 5H).Compound of 12. Purified by flash chromatography (EtOAc-MeOH / NH3 95: 5). ^ -NMR (CDCls, δ): 0.78-0.92 (m? 3H)? 1.15-1.3 (m5 5H), 1.80- 2.08 (m? 2H)? 2.28-2.40 (m? 2H)? 2.52-2.83 (m5 5H ) 5 20 3.02-3.18 (m, 4H), 3.65-3.79 (m, 1H), 4.16-4.32 (m, 4H), 6.48-6.62 (m? 2H)? 6.71-6.82 (t? 1H)? 7.15- 7.33 (m5 5H). Example 28 l- [5- (2,3-Dihydroxy-1,4-benzodioxinyl)]-4- (4-hydroxy-3-phenylhex-5-enyl )-Pipen uses the procedure described as the compound of Example 6 to obtain 82 200406394 to obtain the title compound, but uses compound 26c instead of compound 6f as a starting material and (vinyl) magnesium chloride (1M, THF Solution) instead of (ethyl) magnesium chloride. The crude product was purified by flash chromatography (CH ^ Ch-MeOH / NH3 97: 3) to provide the title product (66%) as a yellow transparent oil. 5] H-NMR (CDClS) s): 1.35-1.85 (br? 1H)? 1.86-2.28 (m? 2H) 5 2.30-2.91 (m, 7H), 2.98-3.25 (m, 4H), 3.43 · 3 · 81 (m, 1H), 4.19-4.40 (m, 4H), 4.90-5.35 (m5 2H) 5 5.66-5.89 (m, 1H), 6.47-6.69 (m5 2H)? 6.71-6.85 (m? 1H) 5 7.14-7.42 (m? 5H). [Μ + Η] + = 395 · 3 10 Example 29 l- [5- (2,3-dihydroxy-1,4-benzodiocinyl)]- 4- (4-Hydroxy-5-methyl-3-phenyl) -hexylbuthine used the procedure described as the compound of Example 6 to obtain the title compound, but used compound 26c instead of compound 6f The starting material was magnesium (isopropyl) chloride (2M, THF solution) instead of magnesium (ethyl) chloride. The 15 crude product was purified by flash chromatography (CH2C12-MeOH / NH3 98: 2) to provide the title product (35 0/0) as a white solid. ^ -NMR (CDC13, δ): 0.73-0.95 (m? 6H)? 1.30-1.48 (m5 1H)? 1.76-1.95 (m5 1H) 5 1.96-2.21 (m5 1H)? 2.22-2.48 (m9 2H)? 2.49-2.95 (m, 5H), 2.96-3.28 (m, 4H), 3.52-3.73 (m, 1H) 5 20 4.19-4.41 (m? 4H)? 5.02-5.68 (bs? 1H)? 6.49-6.63 ( m9 2H)? 6.75-6.87 (m9 1H)? 7.15-7.39 (m9 5H).

[Μ+Η]+:411·7 實施例30 l-[5-(2,3-二羥-1，4-苯並戴奥辛基)】_4-(4-羥基-3-苯 基)-戊基l·哌哄 83 200406394 採用被描述作為實施例6之該化合 θ 物之该知作程序以獲 得該標題化合物，但使用化合物26c代 又 代曰化合物6f作為一起 始物且漠化（甲基)鎂(3M，THF溶液)代替氯化（乙細。兮粗 產物藉由閃蒸層析法(CH2Cl2 —他⑽贿⑽）予以純化，而提 供經特徵分析有如_ B (RS，RSMRS，SR)混合物之有如一白色 固體(42 %)之該標題產物。 H-NMR (CZ^,而：(m，3H)，i 4ΐ ι 67 加，邱， 1-74-1.95 (m, 1H), 1.96-2.24 (m, 1H), 2.25-3.29 (m, 10H), 3.81-3.99 (m, 1H), 4.19-4.39 (m, 4H), 6.50-6.65 (m, 2H), 10 6.72-6.87 (m，1H)，7.14-7.41 (m，5H).[Μ + Η] +: 411 · 7 Example 30 l- [5- (2,3-Dihydroxy-1,4-benzodioxinyl)] _ 4- (4-hydroxy-3-phenyl) -pentyl The base compound was used as the compound θ described in Example 6 to obtain the title compound, but the compound 26c was used instead of compound 6f as a starter and a desertified (methyl ) Magnesium (3M, THF solution) instead of chlorinated (Ethyl chloride. The crude product was purified by flash chromatography (CH2Cl2-tartar), and the analysis provided by the characteristics is as _ B (RS, RSMRS, SR ) The mixture is like the title product as a white solid (42%). H-NMR (CZ ^, and: (m, 3H), i 4 67 67 plus, Qiu, 1-74-1.95 (m, 1H), 1.96-2.24 (m, 1H), 2.25-3.29 (m, 10H), 3.81-3.99 (m, 1H), 4.19-4.39 (m, 4H), 6.50-6.65 (m, 2H), 10 6.72-6.87 ( m, 1H), 7.14-7.41 (m, 5H).

[M+H]+=383.6 實施例 m H5_(2，nm_M)ML_3_ 苯基庚-5-快基)-^底w井 採用被描述作為實施例6之該化合物之該操作程序以獲 15得該標題化合物，但使用化合物26c代替化合物訂作為一起 始物且溴化（1-丙炔基）鎂（0.5 M，THF溶液）代替氯化（乙基） 鎂。该粗產物藉由閃蒸層析法(CH2C12 - MeOH/NH3 99:1)予以純 化，而提供有如一淡黃色固體之該標題產物（35 %)。 H-NMR (CDC13j s): 1.72-1.89 (m5 3H)? 1.91-2.21 (m5 2H)9 20 2.30-2.50 (m5 2H)5 2.51-2.82 (m? 4H)9 2.83-3.24 (m? 5H)? 3.51-3.73 (m? 1H)? 4.20-4.41 (m5 4H)? 4.42-4.61 (m5 1H), 6·48-6·63 (m，2H)，6.73-6.82 (m，1H)，7.20-7.39 (m，5H).[M + H] + = 383.6 Example m H5_ (2, nm_M) ML_3_phenylhepta-5-quickyl)-^ bottom Well using this procedure described as the compound of Example 6 to obtain 15 The title compound, but using compound 26c instead of compound as a starting material and (1-propynyl) magnesium bromide (0.5 M in THF) instead of (ethyl) magnesium chloride. The crude product was purified by flash chromatography (CH2C12-MeOH / NH3 99: 1) to provide the title product (35%) as a pale yellow solid. H-NMR (CDC13j s): 1.72-1.89 (m5 3H)? 1.91-2.21 (m5 2H) 9 20 2.30-2.50 (m5 2H) 5 2.51-2.82 (m? 4H) 9 2.83-3.24 (m? 5H) ? 3.51-3.73 (m? 1H)? 4.20-4.41 (m5 4H)? 4.42-4.61 (m5 1H), 6.48-6 · 63 (m, 2H), 6.73-6.82 (m, 1H), 7.20- 7.39 (m, 5H).

[M+H]+=407.4 實施例32 l-[5-(2,3-二羥-1，4-苯並戴奥辛基)]-4_ (4-羥基-3- 84 200406394 苯基庚-5-烯基)-哌讲 採用被描述作為實施例6之該化合物之該操作程序以獲 得該標題化合物，但使用化合物26c代替化合物6f作為一起 始物且溴化（1-丙烯基）鎂（0.5 Μ，THF溶液）代替氯化（乙基） 5 鎂。該粗產物藉由閃蒸層析法(CH2Cl2-MeOH/NH3 99:1)予以純 化，而提供有如一淡黃色固體之該標題產物（83 %)。[M + H] + = 407.4 Example 32 l- [5- (2,3-dihydroxy-1,4-benzodiocinyl)]-4_ (4-hydroxy-3- 84 200406394 phenylheptan-5 -Alkenyl)-Piperin uses the procedure described as the compound of Example 6 to obtain the title compound, but uses compound 26c instead of compound 6f as a starting material and (1-propenyl) magnesium (0.5 M, THF solution) instead of (ethyl) 5 magnesium chloride. The crude product was purified by flash chromatography (CH2Cl2-MeOH / NH3 99: 1) to provide the title product (83%) as a pale yellow solid.

^-NMR (CDC13, δ): 1.31-2.31 (m? 8H)? 2.32-2.91 (m? 6H)? 2.92-3.28 (m9 4H); 4.17-4.33 (m? 4H)? 5.23-5.75 (m? 2H)? 6.48-6.63 (m, 2H)，6.71-6.84 (m5 1H)，7.12-7.39 (m，5H). 10 [M+H]+=409.6 實施例33 l-[5-(2,3-二羥-1，4-苯並戴奥辛基)】-4- (4-羥基-3- 苯基己-5-炔基)-哌畊^ -NMR (CDC13, δ): 1.31-2.31 (m? 8H)? 2.32-2.91 (m? 6H)? 2.92-3.28 (m9 4H); 4.17-4.33 (m? 4H)? 5.23-5.75 (m? 2H)? 6.48-6.63 (m, 2H), 6.71-6.84 (m5 1H), 7.12-7.39 (m, 5H). 10 [M + H] + = 409.6 Example 33 l- [5- (2,3 -Dihydroxy-1,4-benzodiocinyl)]-4- (4-hydroxy-3-phenylhex-5-ynyl) -piperon

採用被描述作為實施例6之該化合物之該操作程序以獲 得該標題化合物，但使用化合物26c代替化合物6f作為一起 15 始物且溴化（1-乙炔基）（0.5 Μ，THF溶液）代替氯化（乙基）鎂。 將該粗產物純化兩次，第一次藉由閃蒸層析法（CH2C12 -MeOH/NH3 99:1)接著以預備的LC以提供有如一白色固體之該 標題產物（8 %)。 ^-NMR (CDClS) δ): 1.11-1.99 (br? 1H)? 2.01-2.25 (m? 2H)? 20 2.27-2.31 (m， 1H)， 2.34-2.37 (m5 2H)， 2.61 -2.82 (m， 4H)， 2.85-3.22 (m? 5H)? 4.18-4.32 (m? 4H)? 6.47-6.62 (m9 2H)? 6.74-6.86 (m? 1H)? 7.19-7.41 (m? 5H).The procedure described as the compound of Example 6 was followed to obtain the title compound, but using compound 26c instead of compound 6f as the 15 starting compound and brominating (1-ethynyl) (0.5 M, THF solution) instead of chlorine (Ethyl) magnesium. The crude product was purified twice, the first time by flash chromatography (CH2C12-MeOH / NH3 99: 1) followed by a preparative LC to provide the title product (8%) as a white solid. ^ -NMR (CDClS) δ): 1.11-1.99 (br? 1H)? 2.01-2.25 (m? 2H)? 20 2.27-2.31 (m, 1H), 2.34-2.37 (m5 2H), 2.61 -2.82 (m , 4H), 2.85-3.22 (m? 5H)? 4.18-4.32 (m? 4H)? 6.47-6.62 (m9 2H)? 6.74-6.86 (m? 1H)? 7.19-7.41 (m? 5H).

[M+H]+二 393.7 實施例34 l-[5-(2,3-二羥-1，4-苯並戴奥辛基)]-4- (4-羥基-3- 85 200406394 苯基庚-6-婦基)-η辰哨： β採用被描述作為實施例6之該化合物之該操作程序以獲 得該標題化合物，但使用化合物26c代替化合物奸作為一起 始物且溴化（烯丙基)鎂〇 M，THF溶液）代替氣化（乙基)鎂。該 5粗產物藉由閃蒸層析法(Ct^Ch-MeOH/NH3 99:1)予以純化而 提供有如一呈褐色的油之該標題產物（27 %)。 ^-NMR (CDC1S) s): 1.41-1.72 (br5 1H)? 1.73^2.25 (m? 4H) 2·26·2·50 (m，2H)，2.51-2.91 (m，5H)，3·03·3·24 (m，4H)，[M + H] + di 393.7 Example 34 l- [5- (2,3-dihydroxy-1,4-benzodiocinyl)]-4- (4-hydroxy-3- 85 200406394 phenylheptan- 6-Women) -η Chen Shou: β used the procedure described as the compound of Example 6 to obtain the title compound, but used compound 26c instead of compound R as a starting material and brominated (allyl) Magnesium (M, THF solution) instead of gasified (ethyl) magnesium. The 5 crude product was purified by flash chromatography (Ct ^ Ch-MeOH / NH3 99: 1) to provide the title product (27%) as a brown oil. ^ -NMR (CDC1S) s): 1.41-1.72 (br5 1H)? 1.73 ^ 2.25 (m? 4H) 2.26 · 2 · 50 (m, 2H), 2.51-2.91 (m, 5H), 3.03 · 3 · 24 (m, 4H),

3.78-3.92 (m，1H)，4.20-4.39 (m5 4H)，4.92-5.17 (m，2H)， 10 5.73-5.95 (m? 1H)? 6.51-6.64 (m? 2H)? 6.67-6.84 (m? 1H)? 7.11-7.40 (m，5H).3.78-3.92 (m, 1H), 4.20-4.39 (m5 4H), 4.92-5.17 (m, 2H), 10 5.73-5.95 (m? 1H)? 6.51-6.64 (m? 2H)? 6.67-6.84 (m 1H)? 7.11-7.40 (m, 5H).

[M+H]+=409.7 實施例35 M5-(2,3-二羥-1，4_苯並戴奥辛基)卜4- (4-羥基-6- 甲基-3-苯基庚-5-烯基哌畊 15 採用被描述作為實施例6之該化合物之該操作程序以獲[M + H] + = 409.7 Example 35 M5- (2,3-dihydroxy-1,4-benzodioxinyl) 4- (4-hydroxy-6-methyl-3-phenylheptan-5 -Alkenyl pipecene 15 The procedure described for the compound described in Example 6 was used to obtain

得該標題化合物’但使用化合物26c代替化合物以作為一起 始物且溴化（2-甲基丙烯基）鎂（〇 5 μ，THF溶液）代替氣化 (乙基)鎭。藉由閃蒸層析法(CH2Cl2 一 Me〇H/NH3 99:1)雙重的純 化該粗產物，接著以預備的LC以提供有如一白色固體之該標 20 題產物（10 %)。 ^-NMR (CDCl3} δγ 1.12-1.85 (m? 8H)5 1.87-2.02 (m? 1H)5 2.03-2.29 (m? 1H)? 2.30-2.91 (m? 6H); 2.93-3.21 (m? 4H)9 4.17-4.35 (m? 4H)? 4.36-4.48 (m? 1H)? 4.96-5.22 (m? 1H)， 6.48-6.62 (m5 2H)5 6.75-6.85 (m? 1H)? 7.12-7.38 (m5 5H). 86 200406394 [Μ+Η]+=423·8 實施例36 1-[5-(2,3-二羥-1，4-苯並戴奥辛基)卜舡（4-經基·6_ 甲基-3-苯基)-庚基】-哌讲 添加0.226 g的LiC104至一配於3 ml的THF之〇·7〇8 ml的 5 2 Μ氯化（異丁基)鎮（配於THF)溶液中。在室溫下攪拌該混人 物歷時1小時；而後，逐滴添加配於3 ml的THF之〇·13 g的 化合物26c。容許在室溫下攪拌該反應混合物歷時3小時接而 以一飽和的NHjCl水溶液予以終止，鹼化並以m〇Ac萃取。乾 燥該混合的萃取物(NajO4)並予以蒸發至乾燥。該粗產物藉由 10閃蒸層析法（CH^Cl2 - MeOH 99·· 1)予以純化，而提供有如_乳白 色的固體之該標題產物（54.6 %)。 !H-NMR (CDC13j δ): 0.68-1.01 (m5 1.12-1.38 (m? 2H) 1.65-1.85 (m? 1H)? 2.03-2.29 (m? iH)5 2.30-2.52 (m? 1H) 2.53-2.83 (m9 2H)5 2.84-3.47 (m5 9H)5 3.73-3.92 (m? iH) 15 4·18-4·39 (m5 4H)，6·49-6·65 (m，2H)，6 67_6 87 (m，吼 7.10-7.40 (m, 5H).This title compound was obtained but using compound 26c instead of the compound as a starting material and (2-methylpropenyl) magnesium bromide (0.5 µ, THF solution) instead of gasified (ethyl) fluorene. The crude product was double purified by flash chromatography (CH2Cl2-MeOH / NH3 99: 1), followed by preparative LC to provide the title product (10%) as a white solid. ^ -NMR (CDCl3) δγ 1.12-1.85 (m? 8H) 5 1.87-2.02 (m? 1H) 5 2.03-2.29 (m? 1H)? 2.30-2.91 (m? 6H); 2.93-3.21 (m? 4H ) 9 4.17-4.35 (m? 4H)? 4.36-4.48 (m? 1H)? 4.96-5.22 (m? 1H), 6.48-6.62 (m5 2H) 5 6.75-6.85 (m? 1H)? 7.12-7.38 ( m5 5H). 86 200406394 [Μ + Η] + = 423 · 8 Example 36 1- [5- (2,3-Dihydroxy-1,4-benzodioxinyl) bu (4-meryl · 6_ Methyl-3-phenyl) -heptyl] -pidol was added with 0.226 g of LiC104 to 0.78 ml of 5 2 M (isobutyl) chloride (formulated in 3 ml of THF) THF) solution. The mixture was stirred at room temperature for 1 hour; then, 0.13 g of compound 26c in 3 ml of THF was added dropwise. The reaction mixture was allowed to stir at room temperature for 3 hours. It was quenched with a saturated aqueous NHjCl solution, basified and extracted with 〇Ac. The mixed extract (NajO4) was dried and evaporated to dryness. The crude product was subjected to 10 flash chromatography (CH ^ Cl2- MeOH 99 ·· 1) was purified to provide the title product (54.6%) as a milky solid.! H-NMR (CDC13j δ): 0.68-1.01 (m5 1.12-1.38 (m? 2H) 1.65-1.8 5 (m? 1H)? 2.03-2.29 (m? IH) 5 2.30-2.52 (m? 1H) 2.53-2.83 (m9 2H) 5 2.84-3.47 (m5 9H) 5 3.73-3.92 (m? IH) 15 4 · 18-4 · 39 (m5 4H), 6.49-6 · 65 (m, 2H), 6 67_6 87 (m, roar 7.10-7.40 (m, 5H).

[M+H]+=425.2 實施例37 l-[5-(2,3-二經-1，4-苯並戴奥辛基料⑷經基各 苯丁基)-°底讲 20 題化合物與實施例36之該化合物一起被獲得。藉由 閃蒸層析法之純化，而提供有如一油之該標題產物。 (m5 2H)? (m? 4H)5 (br，1H)5 ^-NMR (CDC6，外 1.36-1.64 (m，ιΗ), 181-2 〇5 2.50-2.73 (m5 4Η)，2·75-2·93 (m，2Η)，2 队3 27 3.62-3.72 (m? 2H)5 4.20-4.39 (m? 4H)5 6.10-6.45[M + H] + = 425.2 Example 37 l- [5- (2,3-Dijing-1,4-Benzodioxinylpyridine, each phenylbutyl group)-° Lecture 20 Compounds and Implementation The compound of Example 36 was obtained together. Purification by flash chromatography provided the title product as an oil. (m5 2H)? (m? 4H) 5 (br, 1H) 5 ^ -NMR (CDC6, outer 1.36-1.64 (m, ιΗ), 181-2 〇5 2.50-2.73 (m5 4Η), 2.75- 2.93 (m, 2Η), 2 teams 3 27 3.62-3.72 (m? 2H) 5 4.20-4.39 (m? 4H) 5 6.10-6.45

87 200406394 6.46-6.62 (m，2H)，6.70-6.83 (m，1H)，7 13-7 37 加，5H) [M+H]+=369.7 冰（4- 實施例38 (RS，叫wwm4-苯並戴奥辛基)】 羥基-3-苯戊基)-哌畊 5 該標題化合物與實施例11之該化合物-起被獲得。藉由 閃蒸層析法之純化以提供經特徵分析如純淨的⑽，SR)非對映 異構物之有如一油之該標題產物。 1087 200406394 6.46-6.62 (m, 2H), 6.70-6.83 (m, 1H), 7 13-7 37 plus, 5H) [M + H] + = 369.7 ice (4- Example 38 (RS, called wwm4- Benzodioxin)] hydroxy-3-phenylpentyl) -piperin 5 The title compound was obtained in combination with the compound of Example 11. Purification by flash chromatography provided the title product as an oil that was characteristically analyzed such as pure hydrazone (SR) diastereomers. 10

'H-NMR {CDClSi δ): 0.85-U2 2.32-2.45 (m? 2H)5 2.46-2.83 3.92-4.01 (m，1H)，4.18-4.37 (m, 3H), 1.80-2.21 (m? 3H) (m5 5H)，2.95-3.17 (m5 4H)， (m5 4H), 6.45-6.61 (m5 2H), 6.72-6.85 (m5 1H)5 7.11-7.38 (m? 5H) [M+H]+-383.6 實施例39 環己基-3-(2-二甲胺羰基苯基）_‘側氧丁 基卜4-[5-(2,3-二羥4 +苯並戴奥辛基)]哌畊 15 KgJ己基二甲I甲醯胺（化合物39a)'H-NMR {CDClSi δ): 0.85-U2 2.32-2.45 (m? 2H) 5 2.46-2.83 3.92-4.01 (m, 1H), 4.18-4.37 (m, 3H), 1.80-2.21 (m? 3H) (m5 5H), 2.95-3.17 (m5 4H), (m5 4H), 6.45-6.61 (m5 2H), 6.72-6.85 (m5 1H) 5 7.11-7.38 (m? 5H) [M + H] +-383.6 Example 39 Cyclohexyl-3- (2-dimethylaminecarbonylphenyl) -'- oxobutyl 4- [5- (2,3-dihydroxy4 + benzodioxinyl)] piperin 15 KgJ hexyl Dimethyl I formamidine (Compound 39a)

如針對化合物13a所描述的來獲得該標題化合物。在一般 的元成程序（work-up procedure)後，該粗產物藉由閃蒸層析法 (PE EtOAc 1.1)予以純化俾以提供該標題化合物。 H-NMR (CDClS) δ)： 1.1Μ.50 (m? 5H); 1.61-1.98 (m? 6H); 2.84 20 (d?3H); 3.04 (d? 3H)； 3.81-4.02 (m9 2H); 7.11-7.42 (m5 5H).The title compound was obtained as described for compound 13a. After a general work-up procedure, the crude product was purified by flash chromatography (PE EtOAc 1.1) to provide the title compound. H-NMR (CDClS) δ): 1.1M.50 (m? 5H); 1.61-1.98 (m? 6H); 2.84 20 (d? 3H); 3.04 (d? 3H); 3.81-4.02 (m9 2H) ; 7.11-7.42 (m5 5H).

[M+H]+= 274 基歲基）-4-測氧j醛二甲臬縮醛（化合物 39b) 使用被4¾述作為化合物2b之該方法以製備該標題化合 88 物，但使用化合物39a代替化合物2a。藉由閃蒸層析法(pE _[M + H] + = 274 bases) -4-oxo aldehyde dimethyl acetal (Compound 39b) This method described as Compound 2b was used to prepare the title compound 88, but using compound 39a Replaces compound 2a. By flash chromatography (pE_

Me2C0 75:25)純化該粗產物。產率：21.3 〇/〇。 H-NMR {CDClS) δ): 0.94-1.49 (m? 5H); 1.5M.83 (m9 5H); 1.84-2.01 (m5 1H); 1.36-1.69 (m, 2H); 2.88 (s5 3H); 3.18 (s, 3H); 5 3*31 (d5 6H); 4.12-4.34 (m? 2H); 7.12-7.39 (m5 4H). 二甲胺羰基）-4-側氣丁醪（化合物刊 採用被描述作為化合物ld之該操作程序以獲得該標題化 a物，但使用化合物39b代替化合物ic作為一起始物。該粗 產物在無進一步純化下被使用於下一步驟中。 10 H-NMR (CDClS) δ): 0.90-2.12 (m5 12 H); 2.60-3.32 (m5 8H); 4.39-4.58 (m5 1H)； 7.04-7.51 (m5 4H); 9.63-9.72 (m5 1H) 1^衰己基基笨基）_4_制i 丁其〗冰「5_〇二轉 ^1，4_苯並戴奧辛基喩— 使用被描述作為實施例1之該化合物2b之該方法以製備 15該標題化合物，但使用化合物39c代替化合物le且l-(2,3-二 經-1，4-苯並戴奥辛_5_基)^底畊代替1-(2,2,2_三氟乙氧基苯基)_ 嗓命。該粗產物藉由閃蒸層析法(PE :Me2C〇6:4)予以純化俾以 提供該標題化合物（65 %)。 ^-NMR (CDCl3} δ): 1.03-2.01 (m5 11H); 2.23-2.42 (m5 3H); 2〇 2.44-2.72 (m5 5H); 2.91 (s? 3H); 3.97-3.13 (m9 4H); 3.19 (s5 3H); 4.13- 4.38 (m? 5H); 6.48-6.63 (m? 2H); 6.70-6.84 (m, 1H); 7.13- 7.39 (m5 4H).Me2C0 75:25) purified the crude product. Yield: 21.3 0 / 〇. H-NMR (CDClS) δ): 0.94-1.49 (m? 5H); 1.5M.83 (m9 5H); 1.84-2.01 (m5 1H); 1.36-1.69 (m, 2H); 2.88 (s5 3H); 3.18 (s, 3H); 5 3 * 31 (d5 6H); 4.12-4.34 (m? 2H); 7.12-7.39 (m5 4H). The procedure described as compound Id was used to obtain the title compound, but compound 39b was used instead of compound ic as a starting material. The crude product was used in the next step without further purification. 10 H-NMR (CDClS ) δ): 0.90-2.12 (m5 12 H); 2.60-3.32 (m5 8H); 4.39-4.58 (m5 1H); 7.04-7.51 (m5 4H); 9.63-9.72 (m5 1H) 1 ^ Based) _4_ produced by Ding Qi〗 〖5_〇 二 转 ^ 1,4_benzodiocinyl hydrazone — using the method described as the compound 2b of Example 1 to prepare 15 of the title compound, but using Compound 39c replaces compound le and l- (2,3-Dijing-1,4-benzodioxin_5_yl) ^ subsoil replaces 1- (2,2,2_trifluoroethoxyphenyl) _ Throat. The crude product was purified by flash chromatography (PE: Me2C0: 6) to provide the title compound (65%). ^ -NMR (CDCl3} δ): 1.03- 2.01 (m5 11H); 2.23-2.42 (m5 3H); 2〇2.44-2.72 (m5 5H); 2.91 (s? 3H); 3.97-3.13 (m9 4H); 3.19 (s5 3H); 4.13- 4.38 (m 5H); 6.48-6.63 (m? 2H); 6.70-6.84 (m, 1H); 7.13- 7.39 (m5 4H).

[M+H]+:520 實施例40 l-[4-環己基-3-(2-二甲胺羰基苯基）-4-羥丁 89 200406394 基]-4-[5-(2,3-二羥-1，4-苯並戴奥辛基)】-哌畊 使用被描述作為化合物lc之該方法以合成該標題化合 物，但起始自實施例39之該化合物代替化合物lb。在一般的 完成程序（work-up procedure)後，該粗產物藉由閃蒸層析法 5 (PE - Me2CO- NH3/MeOH 7:3:0.2)予以純化，而提供該標題化合 物（65.2 %)。 [Μ+Η]+=522·45 實施例41 1-[4-環己基-3-(2-二甲胺羰基苯基）-4-側氧丁[M + H] +: 520 Example 40 1- [4-Cyclohexyl-3- (2-dimethylaminecarbonylphenyl) -4-hydroxybutyl 89 200406394 group] -4- [5- (2,3 -Dihydroxy-1,4-benzodiocinyl)]-Pigen uses the method described as compound lc to synthesize the title compound, but starting from Example 39, this compound replaces compound lb. After a general work-up procedure, the crude product was purified by flash chromatography 5 (PE-Me2CO- NH3 / MeOH 7: 3: 0.2) to provide the title compound (65.2%) . [Μ + Η] + = 522 · 45 Example 41 1- [4-Cyclohexyl-3- (2-dimethylaminecarbonylphenyl) -4-oxobutane

基】-4-(4-氟基-2-甲氧基苯基)哌讲 10 使用被描述作為實施例1之該化合物之該方法以製備該 標題化合物，但使用化合物39c代替化合物le且1-(4-氟基-2-甲氧基苯基)-哌畊代替1-(2,2,2-三氟乙氧基苯基)-哌畊。該粗產 物藉由閃蒸層析法(PE :Me2CO 6:4)予以純化俾以提供該標題化 合物（64.5 %)。Group] -4- (4-fluoro-2-methoxyphenyl) piperazine 10 This method was described using the compound described as Example 1 to prepare the title compound, but using compound 39c instead of compound le and 1 -(4-Fluoro-2-methoxyphenyl) -pigon instead of 1- (2,2,2-trifluoroethoxyphenyl) -pigon. The crude product was purified by flash chromatography (PE: Me2CO 6: 4) to provide the title compound (64.5%).

15 ^-NMR (CDCl3} δ): 1.03-2.02 (m? 11H); 2.17-2.37 (m5 3H); 2.41-2.73 (m? 5H); 2.94 (s? 3H); 2.95-3.12 (m9 4H); 3.17 (s? 3H); 3.85 (s5 3H); 4.11-4.27 (m9 1H); 6.51-6.69 (m? 2H); 6.78-6.92 (m9 1H); 7.12-7.41 (m? 4H).15 ^ -NMR (CDCl3) δ): 1.03-2.02 (m? 11H); 2.17-2.37 (m5 3H); 2.41-2.73 (m? 5H); 2.94 (s? 3H); 2.95-3.12 (m9 4H) ; 3.17 (s? 3H); 3.85 (s5 3H); 4.11-4.27 (m9 1H); 6.51-6.69 (m? 2H); 6.78-6.92 (m9 1H); 7.12-7.41 (m? 4H).

[M+H]+=510 20 實施例 42 l-[4-環己基-3-(2-二甲胺羰基苯基）-4-羥丁 基】-4-(4-氟基-2-甲氧基苯基） 使用被描述作為化合物lc之該方法以合成該標題化合 物，但起始自實施例41之該化合物代替化合物lb。在一般的 完成程序（work-up procedure)後，該粗產物藉由閃蒸層析法 90 200406394 (PE - Me2CO- NH3/Me〇H 75:25:0.2)予以純化，而提供該標題化 合物（64.2%)。 [M+H]+=512.6 實施例43 氰苯基)-4-側氧戊基卜M5_(2,3-二羥+4_ 5 苯並戴奥辛基)> η辰讲 聚本基(oxopentanaldehvde)二乙基縮醛（化合物 43 a) 使用被描述作為化合物2b之該方法J以製備該標題化合 物仁使用 1-(2-氧苯基)-丙烧-2·酮（R.A. Bruce, 〇rg. Prep. Proc. 1〇 Im· 4〇7_412，1999)代替化合物2a。該粗產物藉由閃蒸層析法 (PE-EtOAc 8:2)予以純化。產率：13〇/〇。 'H-NMR (CDCl3} D): 1.10.1.29 (m? 6H)5 1.87-2.04 (m? 1H)? 2.14 (s? 3H)? 2.42-2.59 (m? iH)? 3.31-3.71 (m9 4H)5 4.28-4.43 (m? 2H)? 7.30-7.41 2H)5 7.51-7.72 (m? 2H). 15 K2-氰本基)二戍酸(〇x〇pentanaldehyde)(也金物 43b) 採用被描述作為化合物Id之該操作程序以獲得該標題化 合物，但使用化合物43b代替化合物lc作為一起始物。該粗產 物在無進一步純化下被使用於下一步驟中。 側氧戊基1-4-「5-(2,3-二氣^-笨並戴奧辛 20 基Π-哌啡 使用被私述作為實施例1之該化合物之該方法以製備該 標題化合物’但使用化合物43b代替化合物^且1-(2,弘二經 -Μ·苯並戴奥辛基)♦井代替H2,2,2-三氟乙氧基苯基) 畊。該粗產物藉由閃蒸層析法(PE :EtOAc 6:4)予以純化俾以提 91 200406394 供該標題化合物（43·8 %)。 ]H-NMR (CDCl3) δ): 1.75-1.92 (m? 1H)5 2.21 (s5 3H)? 2.30-2.41 (m5 3H)5 2.41-2.69 (m? 4H)? 2.92-3.12 (m5 4H)9 4.19-4.40 (m? 5H)? 6.48-6.62 (m? 2H)? 6.71-6.82 (t9 1H)? 7.30-7.43 (m? 2H)5 5 7.51-7.72 (m? 2H). 實施例44 l-[4-環己基-3-(2-三氟甲氧基苯基）-4-側氧丁 基】_4-(4-吲哚基)-哌讲 1-環己基-2-(2-三氟曱氧基笨基）乙酮（化合物44a)[M + H] + = 510 20 Example 42 l- [4-cyclohexyl-3- (2-dimethylaminecarbonylphenyl) -4-hydroxybutyl] -4- (4-fluoro-2- (Methoxyphenyl) The method described as compound lc was used to synthesize the title compound, but the compound starting from Example 41 was used in place of compound lb. After a general work-up procedure, the crude product was purified by flash chromatography 90 200406394 (PE-Me2CO- NH3 / MeOH 75: 25: 0.2) to provide the title compound ( 64.2%). [M + H] + = 512.6 Example 43 Cyanophenyl) -4-oxopentanyl M5_ (2,3-dihydroxy + 4_ 5 benzodioxinyl) > ηopen oxopentanaldehvde Diethyl acetal (compound 43a) was prepared using the method J described as compound 2b to prepare the title compound using 1- (2-oxophenyl) -propan-2-one (RA Bruce, Org. (Prep. Proc. 10Im · 407_412, 1999) instead of compound 2a. The crude product was purified by flash chromatography (PE-EtOAc 8: 2). Yield: 13/0. 'H-NMR (CDCl3) D): 1.10.1.29 (m? 6H) 5 1.87-2.04 (m? 1H)? 2.14 (s? 3H)? 2.42-2.59 (m? IH)? 3.31-3.71 (m9 4H ) 5 4.28-4.43 (m? 2H)? 7.30-7.41 2H) 5 7.51-7.72 (m? 2H). 15 K2-cyano) dioxanoic acid (〇x〇pentanaldehyde) (also gold 43b) Adoption is described This procedure was performed as Compound Id to obtain the title compound, but Compound 43b was used instead of Compound lc as a starting material. This crude product was used in the next step without further purification. The pendant oxypentyl 1-4- "5- (2,3-digas ^ -benzyl-dioxine 20-yl-piperphine uses the method described privately as the compound of Example 1 to prepare the title compound ' Compound 43b was used instead of compound ^ and 1- (2, Hongjijing-M · benzodioctyl) was replaced by H2,2,2-trifluoroethoxyphenyl). The crude product was subjected to flash chromatography (PE: EtOAc 6: 4) was purified to provide 91 200406394 to provide the title compound (43.8%).] H-NMR (CDCl3) δ): 1.75-1.92 (m? 1H) 5 2.21 (s5 3H )? 2.30-2.41 (m5 3H) 5 2.41-2.69 (m? 4H)? 2.92-3.12 (m5 4H) 9 4.19-4.40 (m? 5H)? 6.48-6.62 (m? 2H)? 6.71-6.82 (t9 1H)? 7.30-7.43 (m? 2H) 5 5 7.51-7.72 (m? 2H). Example 44 l- [4-cyclohexyl-3- (2-trifluoromethoxyphenyl) -4-side Oxybutyl] _4- (4-indolyl) -piperidine 1-cyclohexyl-2- (2-trifluoroalkoxybenzyl) ethanone (Compound 44a)

將一 1.26 g的2-三氟甲氧基氯甲苯、鋅粉末(0.59 g)以及 10 1,2-DME之混合物予以迴流歷時3小時，在室溫下冷卻；而A mixture of 1.26 g of 2-trifluoromethoxychlorotoluene, zinc powder (0.59 g) and 10 1,2-DME was refluxed for 3 hours and cooled at room temperature; and

後，予以過濾並且在室溫下攪拌添加0.002 g的二氯雙（三苯基 膦）-鈀(II)接著以0.72 ml的環己烷羰醯氯至該過濾物中。而後， 回流攪拌該反應混合物歷時4小時，在室溫下冷卻。在一般的 完成程序（work-up procedure)後（參見化合物la)，該粗產物藉由 15 閃蒸層析法予以純化（甲基第三丁基醚-ΡΕ 96··4)俾以提供0·22 g之該標題化合物。 ]H-NMR {CDCl3, δ): 1.10-2.00 (m5 10H); 3.80 (s5 3H); 7.18-7.40 (m9 4H); 4 _玉哀己基-4_氧- 3- (2-二氣曱氣基苯基)-丁备二乙基縮酸（化合 20 物 44b) 在室溫下，添加叔丁醇鉀（0.091 g)至一配於 1 ml的 DMSO之0.22 g的化合物44a溶液中。15分鐘之後，添力口 0.12 ml的2-溴乙醛二乙基縮醛且在50°C之下加熱該反應混合物歷 時5小時。而後，予以冷卻至室溫，以水稀釋並以甲基第三丁 92 200406394 基醚予以萃取，予以乾燥（Na2S04)並於真空下予以蒸發至乾燥 以生成一粗產物，藉由閃蒸層析法（曱基第三丁基醚-PE 93:7) 予以純化，而提供0.092 g之該純的該標題產物。 ^-NMR {CDCl3) δ): 1.00-2.10 (m?17H); 2.10-2.45 (m? 2H); 3.75 5 (q，4H); 4.32 (t，lH); 4,50 (UH); 7.10-7.40 (m，4H) 4-環己基-4-氣-3-(2-三氟甲氣基笨基V丁醛（化合物44c)After that, it was filtered and 0.002 g of dichlorobis (triphenylphosphine) -palladium (II) was added to the filtrate with stirring at room temperature, followed by 0.72 ml of cyclohexanecarbonylphosphonium chloride. Then, the reaction mixture was stirred at reflux for 4 hours and cooled at room temperature. After a general work-up procedure (see compound la), the crude product was purified by 15 flash chromatography (methyl tert-butyl ether-PE 96 ·· 4) to provide 0 -22 g of the title compound. ] H-NMR (CDCl3, δ): 1.10-2.00 (m5 10H); 3.80 (s5 3H); 7.18-7.40 (m9 4H); 4 _Jadecahexyl-4_oxy- 3- (2-dioxan Gasophenyl) -butylated diethylacetic acid (Compound 20b 44b) At room temperature, potassium tert-butoxide (0.091 g) was added to a 0.22 g solution of compound 44a in 1 ml of DMSO. After 15 minutes, add 0.12 ml of 2-bromoacetaldehyde diethyl acetal and heat the reaction mixture at 50 ° C for 5 hours. Then, it was cooled to room temperature, diluted with water and extracted with methyl tert-butyl 92 200406394 based ether, dried (Na2S04) and evaporated to dryness under vacuum to produce a crude product by flash chromatography. Was purified by the method (fluorenyl tertiary butyl ether-PE 93: 7) to provide 0.092 g of the pure title product. ^ -NMR (CDCl3) δ): 1.00-2.10 (m? 17H); 2.10-2.45 (m? 2H); 3.75 5 (q, 4H); 4.32 (t, lH); 4,50 (UH); 7.10 -7.40 (m, 4H) 4-cyclohexyl-4-gas-3- (2-trifluoromethylaminobenzyl V-butyraldehyde (Compound 44c)

在室溫下攪拌〇.〇9g的化合物44b、1.1 ml的IN HC1以 及5 ml的丙酮歷時4小時。蒸發並以CH2C12萃取以提供該標 題化合物，其在無進一步純化下使用於下一步驟中。 10 ^-NMR {CDCls, δ): 0.80-1.95 (m?9H); 1.95-2.15 2.25-2.45 (m，lH); 2.52 (dd，lH); 3.40 (dd，lH); 4.80 (dd，lH); 7.10-7.40 (m，4H); 9.75 (s，lH) M4-環己基-3-(2-三氟曱氧基笨基M-側氧丁基吲哚基）- 口底口丼 15 使用被描述作為實施例1之該化合物之該方法以製備該0.99 g of compound 44b, 1.1 ml of IN HC1, and 5 ml of acetone were stirred at room temperature for 4 hours. Evaporate and extract with CH2C12 to provide the title compound, which is used in the next step without further purification. 10 ^ -NMR {CDCls, δ): 0.80-1.95 (m? 9H); 1.95-2.15 2.25-2.45 (m, lH); 2.52 (dd, lH); 3.40 (dd, lH); 4.80 (dd, lH) ); 7.10-7.40 (m, 4H); 9.75 (s, 1H) M4-cyclohexyl-3- (2-trifluoromethyloxybenzyl M-oxobutylindolyl)-bottom of mouth 15 The method using the compound described as Example 1 to prepare the

標題化合物，但使用化合物44c代替化合物le且1-(4-吲哚 基)-哌讲代替1-(2,2,2-三氟乙氧基苯基)-哌讲。該粗產物藉由閃 蒸層析法(PE :EtOAc 6:4)予以純化俾以提供該標題化合物（53 %)。 20 ^-NMR (CDCl3f δ): 1.00-2.10 (m?llH); 2.20-2.50 (m?4H); 2.50-2.80 (m，4H); 3.15-3.40 (m，4H); 4.50 (t，lH); 6.50 (d，lH); 7.60 (dd，lH); 7.007.20 (m，3H); 7.20-7.35 (m，4H); 8.15 (s，lH) 實施例45 (RS，SR) l-[4-乙醯氧基-4-環己基-3-(2-氟苯基)-丁 基卜4-(2-曱氧基苯基)-哌畊 93 200406394 45a) 在o°c下攪拌，經由_注射器 、，山妒友石 ·14 ml的環己烷 =乳至—36ml^_氟笨甲絲化_謂—，配於THF 中二及。侧g的二氯(三笨基鱗)娜)〜 在至，皿下攪拌該反應混合物歷時4 一 m ， 兔和的氯化銨 (25ml)水溶液終止，以⑼如的ΕωΑς 、，认古+ 了 W 乾燥（Na2S04) 亚於—下予以蒸發至乾燥’而提供有如一粗產物之3…的 該標題化合物，其在無進—步純化下可被使用心面步驟中。 礼騰⑽％ 外1·1〇_2·05 加，_，2.47 (tUH)，3 77 (s， ίο 2H)，6.97-7.32 (m，4H) 氟苯基)二乙基縮醛物45b) 加熱回流一配於136 ml的曱苯之5 〇2g的化合物45a溶 液，藉由蒸餾來移除水分而回收35 ml的曱苯。而後，添加3.18 g的叔丁醇鉀並持續回流攪拌歷時3〇分鐘；將該反應混合物冷 15卻至80〇C並加入4·27 ml的2_溴乙醛二乙基縮醛。在回流18 小時之後’將該反應混合物冷卻至室溫，以一飽和的氯化銨(3〇 ml)水溶液予以終止，以30 ml的Et〇Ac作萃取，予以乾燥 (NajO4)並於真空下予以蒸發至乾燥以生成一粗產物，藉由閃 蒸層析法（石油SI-EtOAc 92·5:7·5)予以純化，而提供2·97 g之 20 该純的標題產物。 ^-NMR {CDCls, δ): 1.00-2.10 (m? 17H^ 2.20-2.52 (m5 2H)? 3.30-3.72 (m? 4H)? 4.25-4.45 (m? 2H)? 6.90-7.35 (m? 4H) 苎環己基-4-氧-3-(2-氟苯羞)·丁^^匕合物45c) 在室溫下攪拌一 1.12g的該化合物45b、91111的50%三 94 200406394 氟乙酸水溶液以及18 ml的CH2C12之混合物歷時2小時，且 接而以10 ml的CH2C12予以稀釋。將該有機層分開，以鹽水 (2x15ml)洗滌，予以乾燥（Na2S04)並於真空下予以蒸發至乾燥 俾以提供一粗產物（0.88 g)，在無進一步純化下可被使用於下 5 一步驟中。 ^-NMR (CDC13, δ): 0.90-2.10 (m? 10H)? 2.25-2.70 (m5 2H)? 3.12-3.52 (m5 1H)，4.60-4.80 (m，1H)，6.95-7.40 (m，4H)，9.75 (s， 1H) 1-Γ4-壞己基-3-(2-氣苯基)-4-側氧丁基1-4-(2-曱氧基笨基丼 10 (化合物45d) 在室溫下攪拌一 0.88 g的該化合物45c、0.84 g的1-(2-曱 氧基苯基)-哌讲HC1、1.06 g的三醋酸基氫硼化鈉以及33 ml 的CH2C12之混合物歷時1小時，維持靜置過夜，以20% Na2C03.水溶液予以鹼化。將該有機層分開，以鹽水(2 X 30ml) 15 洗滌，予以乾燥（Na2S04)並於真空下予以蒸發至乾燥以生成一 粗產物（1.46 g)，其在無進一步純化下被使用於下一步驟中。一 樣品藉由閃蒸層析法（石油醚-EtOAc 6:4)予以純化，而提供一純 淨的樣品。 ^-NMR (CDCls, δ): 1.05-2.00 (m9 11H)5 2.20-2.44 (m? 4H)? 20 2.45-2.72 (m5 4H)5 2.90-3.20 (m, 4H)? 3.85 (s? 3H) (RS, SR) -1-『4-壞己基-3-(2-乱笨基)-4-經丁基甲氧基苯 基哌讲（化合物45e) 添加0.19 g的NaBH4至一在0°C下攪拌之配於33 ml的 MeOH之1.46 g的化合物45d溶液中且在室溫下攪拌該混合 95 200406394 物歷時4小時。將該溶劑蒸發且以h2o收取該反應粗產物並以 EtOAc作卒取。將該有機層分開，以鹽水（2 X i5mi)洗務，予 以乾燥（NhS〇4)並於真空下予以蒸發至乾燥俾以生成一粗產 物，藉由連續的閃蒸層析法（石油醚-EtOAc-2 N氨配於甲醇 75:25:2;石油醚_Et〇A〇2N氨配於甲醇80:20:2)予以純化，而 提供0.82g的化合物45e(上方的TLCRf;洗提劑：石油峻 -EtOAc-2N 氨配於甲醇 70:30:2)。 10 'H-NMR (CDCl3, S): 0.80-1.40 (m? 6Η)? 1.5〇.ι δ2 4H)，1.85-2.1〇(m，3 Η)，2.21-2.45 (m，2Η)，2.52Q.85 (m 4Η) 2.98-3.26 (m，4H)，3.28-3.42 (m，1H)，3.50-3.60 (m，m、 ’3 ·85 (s 3H)，6.80-7.30 (m，7H)，7.62-7.80 (m，1H); OH 波峰無法偵則’The title compound, but uses compound 44c instead of compound le and 1- (4-indolyl) -pipedine instead of 1- (2,2,2-trifluoroethoxyphenyl) -pipedine. The crude product was purified by flash chromatography (PE: EtOAc 6: 4) to provide the title compound (53%). 20 ^ -NMR (CDCl3f δ): 1.00-2.10 (m? LlH); 2.20-2.50 (m? 4H); 2.50-2.80 (m, 4H); 3.15-3.40 (m, 4H); 4.50 (t, lH ); 6.50 (d, lH); 7.60 (dd, lH); 7.007.20 (m, 3H); 7.20-7.35 (m, 4H); 8.15 (s, lH) Example 45 (RS, SR) l- [4-Ethyloxy-4-cyclohexyl-3- (2-fluorophenyl) -butylbenzene 4- (2-methoxyoxyphenyl) -pigon 93 200406394 45a) Stir at o ° c , Via a syringe, 14 ml of cyclohexane = milk to -36 ml ^ _fluorobenzyl methylsilicated _ said-, mixed with THF in two and. G of dichloro (tribenzyl scale) Na) ~ The reaction mixture was stirred under a dish for 4 m, the rabbit and ammonium chloride (25ml) aqueous solution was terminated, and the like was treated as ΕωΑς. In order to dry (Na2S04), the title compound is provided as a crude product of 3 ..., which can be used in the heart face step without further purification. Li Teng⑽% outside 1.1 · 2_2 · 05 plus, _, 2.47 (tUH), 3 77 (s, ίο 2H), 6.97-7.32 (m, 4H) fluorophenyl) diethyl acetal 45b ) Heat and reflux a solution of 502 g of compound 45a in 136 ml of toluene, and remove water by distillation to recover 35 ml of toluene. Then, 3.18 g of potassium tert-butoxide was added and stirring was continued under reflux for 30 minutes; the reaction mixture was cooled to 80 ° C. and 4.27 ml of 2-bromoacetaldehyde diethyl acetal was added. After 18 hours at reflux, the reaction mixture was cooled to room temperature, quenched with a saturated aqueous solution of ammonium chloride (30 ml), extracted with 30 ml of EtoAc, dried (NajO4) and under vacuum It was evaporated to dryness to give a crude product, which was purified by flash chromatography (Petroleum SI-EtOAc 92 · 5: 7 · 5) to provide 2.97 g of 20 the pure title product. ^ -NMR (CDCls, δ): 1.00-2.10 (m? 17H ^ 2.20-2.52 (m5 2H)? 3.30-3.72 (m? 4H)? 4.25-4.45 (m? 2H)? 6.90-7.35 (m? 4H ) Cyclohexyl-4-oxo-3- (2-fluorophenylsulfanyl) -butyrate 45c) Stir 1.12g of the compound 45b, 50% of 91111 at room temperature 94 200406394 fluoroacetic acid aqueous solution And a mixture of 18 ml of CH2C12 lasted 2 hours, and then diluted with 10 ml of CH2C12. The organic layer was separated, washed with brine (2x15ml), dried (Na2S04) and evaporated to dryness under vacuum to provide a crude product (0.88 g), which was used in the next 5 steps without further purification. in. ^ -NMR (CDC13, δ): 0.90-2.10 (m? 10H)? 2.25-2.70 (m5 2H)? 3.12-3.52 (m5 1H), 4.60-4.80 (m, 1H), 6.95-7.40 (m, 4H) ), 9.75 (s, 1H) 1-Γ4-badhexyl-3- (2-phenyl) -4-oxobutyl1-4- (2-fluorenylbenzylfluorene 10 (compound 45d) at At room temperature, a mixture of 0.88 g of the compound 45c, 0.84 g of 1- (2-methoxyoxyphenyl) -piperin HC1, 1.06 g of sodium triacetoxyborohydride, and 33 ml of CH2C12 was stirred for 1 Hours, left standing overnight, alkalized with 20% Na2C03. Aqueous solution. The organic layer was separated, washed with brine (2 X 30ml) 15 and dried (Na2S04) and evaporated to dryness under vacuum to produce a crude The product (1.46 g) was used in the next step without further purification. A sample was purified by flash chromatography (petroleum ether-EtOAc 6: 4) to provide a pure sample. ^- NMR (CDCls, δ): 1.05-2.00 (m9 11H) 5 2.20-2.44 (m? 4H)? 20 2.45-2.72 (m5 4H) 5 2.90-3.20 (m, 4H)? 3.85 (s? 3H) (RS , SR) -1- [4-Badhexyl-3- (2-randomyl) -4-butylbutylphenylphenyl (Compound 45e) was added with 0.19 g of NaBH4 to The mixture was stirred at 0 ° C in a solution of 1.46 g of compound 45d in 33 ml of MeOH and the mixture was stirred at room temperature 95 200406394 for 4 hours. The solvent was evaporated and the crude reaction product was collected at h 2 o and EtOAc The organic layer was separated, washed with brine (2 X i5mi), dried (NhS04) and evaporated to dryness under vacuum to produce a crude product by continuous flash chromatography. Method (petroleum ether-EtOAc-2 N ammonia in methanol 75: 25: 2; petroleum ether_Et〇A〇2N ammonia in methanol 80: 20: 2) was purified to provide 0.82 g of compound 45e (above TLCRf; eluent: petroleum alumina-EtOAc-2N ammonia with methanol 70: 30: 2). 10 'H-NMR (CDCl3, S): 0.80-1.40 (m? 6Η)? 1.5〇.ι δ2 4H) , 1.85-2.10 (m, 3Η), 2.21-2.45 (m, 2Η), 2.52Q.85 (m 4Η), 2.98-3.26 (m, 4H), 3.28-3.42 (m, 1H), 3.50-3.60 (m, m, '3.85 (s 3H), 6.80-7.30 (m, 7H), 7.62-7.80 (m, 1H); OH peak cannot be detected'

環己基曱氣基茉基）-哌哄 基)-丁-1-醇（化合物45eA) 15 藉由使用ChiralpakAD(0.46x25 cm)對化合物 管柱層析來獲得此類化合物，以正己烷-EtOH 95:5 ml/min ;偵檢器 UV 247 nm)洗提。 45e作光學 “丨〔速=q 5 ljg，2R) 1-環己基-444-(2-曱氣基笨基底畊-1^ D-丁-1-醇（化合物45eB)Cyclohexylfluorenyl molyl) -piperazinyl) -but-1-ol (compound 45eA) 15 Such compounds were obtained by column chromatography of compounds using ChiralpakAD (0.46x25 cm), and n-hexane-EtOH 95: 5 ml / min; detector UV 247 nm). 45e as optics "丨 [speed = q 5 ljg, 2R) 1-cyclohexyl-444- (2-fluorene-based benzene substrate Teng-1 ^ D-but-1-ol (compound 45eB)

20 藉由使用Chiralpak AD (0.46x25 cm)對化合物 管柱層析來獲得此類化合物，以正己烷-EtOH 95:5 ml/min ;偵檢器 UV 247 nm)洗提。 45e作光學 (流速> 〇 5 化合物45eB之絕對的立體化學，以它的鹽類與填化怎 、 氣的形 式，藉由如下之單晶體X-射線繞射（single cryst diffraction)被偵測出來。 96 200406394 單晶體X-射線繞射實驗： 一針狀的單晶體被挑選出來作為射線繞射分析且被安 置於一玻璃纖維上。數據在具有偵檢器口經=45 0 χ 25 6 Cm 之Rigaku Rapid圓筒顯像板X-射線面探測器被收集。該探測 5為係藉由一具有RaPld Aut0版本1〇6軟體(Rigaku, 2000)之 Windows 2000為基礎的PC電腦而被控制，在低的溫度㈠2〇〇κ) 下’以 Micromax-002 //-Confocal mirr〇rs CuK[]D[]radiati〇n [□(CuK：]D) =1·54〇5Α]。分度(Indexing)由三次被感光歷時 36〇 秒之3〇振盪架（oscillation frames)來被進行。所有的折射在五 10個景>像群組中被測量，各個群組具有六個架；曝光時間係為每 度160秒。在它們之中，五個影像群組係在角度$ = 〇。，9〇。，1〇, 270。與义=50。以及與χ=〇。，所有的架係為占Ω=3〇〇， 且其造成歷136.3。。樣品/探測器距離係為12 74 cm。該 數據還原程式，Rapid Auto版本1.06 (Rigaku，2000)，偵測出勞 15厄群(Laue group)係為-1，且總計7,986個折射被積合作為結 構解析與精算。 單晶體結果： 该結構係藉由利用SIR92 (Altomare et al. 1994)之直接方法 被解析出來。所有的計算利用CrystalStructure3.0(MSC/Rigaku， 20 2002; Watkin et al·，1996, Carruthers and Watkin，1979)結晶學軟 體套件被進行。試算結果獲得38個在非對稱性的晶格單元中 之非氫原子。最小平方精算包括所有非氫原子的座標與非等向 性熱苓數（anisotropic thermal parameters)。在F上之全矩陣最 小平方精算的最後循環係被基於具有I > 3σ(Ι)之6,297個折 97 200406394 射，被收斂以符合因子：R=〇.〇71、S=2.224、Rw=0.073。絕對 組態係藉由使用計算出的Flackx參數（其係為0·00,具有esd = 0.04)來被決定。期望值係為用來作為校正之0.0(在3 esd的範 圍内）與用來作為倒置絕對結構之+1·〇。 5 參考文獻：20 Such compounds were obtained by column chromatography of the compounds using Chiralpak AD (0.46x25 cm) and eluted with n-hexane-EtOH 95: 5 ml / min; detector UV 247 nm). 45e as optics (flow rate> 〇5 the absolute stereochemistry of compound 45eB, in the form of its salts and fillings, is detected by single crystal X-ray diffraction (single cryst diffraction) as follows 96 200406394 Single crystal X-ray diffraction experiment: A needle-shaped single crystal was selected for ray diffraction analysis and placed on a glass fiber. The data is in Rigaku with a detector mouth diameter = 45 0 χ 25 6 Cm The X-ray surface detector of the Rapid Cylinder Imaging Panel was collected. The detection 5 was controlled by a Windows 2000-based PC with RaPld Aut0 version 106 software (Rigaku, 2000). At a temperature of ㈠2〇κ) under Micromax-002 //-Confocal mirrors CuK [] D [] radiation [□ (CuK:] D) = 1.54〇5A]. Indexing is performed by three 30-oscillation frames that are exposed to light for 36 seconds. All refraction was measured in five groups of 10 scenes, each group having six frames; the exposure time was 160 seconds per degree. Among them, five image groups are at an angle of $ = 〇. , 90. , 10, 270. And righteousness = 50. And with χ = 〇. , All the frames are accounted for Ω = 300, and it caused 136.3. . The sample / detector distance is 12 74 cm. This data reduction program, Rapid Auto version 1.06 (Rigaku, 2000), detects that the Laue group is -1, and a total of 7,986 refractions are integrated for structural analysis and actuarial calculation. Single crystal results: The structure was resolved by a direct method using SIR92 (Altomare et al. 1994). All calculations were performed using the CrystalStructure 3.0 (MSC / Rigaku, 20 2002; Watkin et al., 1996, Carruthers and Watkin, 1979) crystallographic software suite. The trial results obtained 38 non-hydrogen atoms in the asymmetric lattice unit. Least-squares actuarial calculations include the coordinates of all non-hydrogen atoms and anisotropic thermal parameters. The final cycle of the least-squares actuarial calculation of the full matrix on F is based on 6,297 folds 97 200406394 with I > 3σ (Ι) and is converged to fit the factors: R = 0.071, S = 2.224, Rw = 0.073. The absolute configuration is determined by using the calculated Flackx parameters (which are 0 · 00 with esd = 0.04). The expected value is 0.0 (in the range of 3 esd) used as a correction and + 1 · 0 used as an inverted absolute structure. 5 References:

Altomare，A·，Cascarano，G·，Giacovazzo，C· Gualgliardi，Α·5 Burla，M·，Polidori，G.，and Camalli，M·，（1994) SIR92，J. Appl· Cryst.，27, 435.Altomare, A., Cascarano, G., Giacovazzo, C. Gualgliardi, A. 5 Burla, M., Polidori, G., and Camalli, M., (1994) SIR92, J. Appl. Cryst., 27, 435 .

Carruthers，J.R. and Watkin，D.J. (1979), Acta Cryst，A35, 10 698-699.Carruthers, J.R. and Watkin, D.J. (1979), Acta Cryst, A35, 10 698-699.

Rigaku (2000)，Rapid Auto, Rigaku Corporation，Tokyo, Japan· Rigaku and Rigaku/MSC? (2000-2002)? Crystal Structure Analysis Software, Crystal Structure Version 3.00, Rigaku/MSC， 9009 New Trails Drive, The Woodlands, TX5 USA 77381-5209. 15 Rigaku, 3-9-12 Akishima, Tokyo 196-8666, Japan.Rigaku (2000), Rapid Auto, Rigaku Corporation, Tokyo, JapanRigaku and Rigaku / MSC? (2000-2002)? Crystal Structure Analysis Software, Crystal Structure Version 3.00, Rigaku / MSC, 9009 New Trails Drive, The Woodlands, TX5 USA 77381-5209. 15 Rigaku, 3-9-12 Akishima, Tokyo 196-8666, Japan.

Watkin，D.J·，Prout，C.K. Carruthers，J.R. & Betteridge，P.W·， CRYSTALS Issue 10? Chemical Crystallography Laboratory, Oxford, UK. (RS，SRJ 乙醯氧基-4-環己某-3彳2-氤芏基丁基曱氧 20 基笨基)-哌讲 添加0.021 ml的乙醯氣至一在〇_5〇c下攪拌之0.135 g的 化合物45e以及配於5 ml的CH2C12之0.043 ml的TEA之 溶液。而後，在室溫下攪拌該反應混合物歷時4小時，以5%Watkin, DJ ·, Prout, CK Carruthers, JR & Betteridge, PW ·, CRYSTALS Issue 10? Chemical Crystallography Laboratory, Oxford, UK. (RS, SRJ ethoxyl-4-cyclohexyl-3 彳 2- 氤Fluorenylbutylfluorenyl 20-benzyl)-Piperon added 0.021 ml of acetonitrile to 0.135 g of compound 45e and 0.043 ml of TEA in 5 ml of CH2C12. Solution. Then, the reaction mixture was stirred at room temperature for 4 hours at 5%

NaHC03 水溶液（lxl〇mi)、H2〇(2xl5ml)予以洗滌，在 Na2S〇4 98 200406394 上予以乾燥並於真空下予以蒸發俾以提供該標題產物（〇，143 g) 0 ^-NMR (CDCls, δ): ^^0.80-1.25 (m?5H); 1.25-1.50 (m?lH); 1.50-1.90 (m9 7H); 1.95 (s53H); 2.10-2.40 (m?2H); 2.40-2.65 (m? 5 4H); 2.90-3.15 (m? 4H); 3.38-3.55 (m?lH); 3.85 (m5 3H); 5.05 (t?lH); 6.80-7.25 (m?7H); 7.30-7.45 (m?lH) 實施例46 (RS，SR) l-[4-環己基-3-(2-氟苯基)-4-甲氧基羰基 氧基丁基】-4-(2-甲氧基苯基)-哌畊 添加0.022ml的氯甲酸曱酯至一在0°C下攪拌之配於0.8 10 ml的ϋ比咬之0.112 g的化合物45e之溶液中。在室溫下擾拌 該反應混合物歷時4天並在40°C下歷時5小時。添加額外的 0.045 ml的氯曱酸甲醋，在40°C下加熱歷時4小時。在室溫 下3天之後，添加氯曱酸甲酯（0.045 ml)且在室溫下攪拌該混 合物歷時6小時。冷卻之後，將其倒入至水中並以 15 EtOAc(2xl5ml)萃取，以 2x15ml 的 H20 洗滌，予以乾燥（Na2S04) 並於真空下予以蒸發至乾燥。該粗產物藉由閃蒸層析法（PE -EtOAc-NH3/MeOH 75:25:2.5)予以純化俾以生成0.022g的該標 題產物。 ^-NMR (CDCh, δ): 0.80-2.05 (m?13H); 2.10-2.40 (m?2H); 20 2.40-2.75 (m54H); 2.90-3.20 (m?4H); 3.38-3.60 (m?lH); 3.70 (m53H); 3.85 (m,3H); 4.88 (t?lH); 6.80-7.25 (m57H); 7.38-7.50 (m?lH) 實施例47 (RS，SR) l-[4-環己基-4-乙基胺羰基氧基-3-(2-氟苯 基)-丁基】-4-(2-甲氧基苯基)-哌啼 99 200406394 添加0.113的異氰酸乙酯至一在0°C下攪拌之配於0.5 ml 的定之0.126 g的化合物45e之溶液中。在室溫下攪拌該反 應混合物歷時24小時並在50°C下歷時3小時。在冷卻之 後，將其倒入至水中並以Et20萃取，以H20洗滌，予以乾燥 5 (Na2S04)並於真空下予以蒸發至乾燥俾以提供0.108g的該標 題產物。 ^-NMR (CDC13, δ): 0.90-1.40(m? 9H); 1.60-2.10 (m57H);NaHC03 aqueous solution (lx10mi), H20 (2xl5ml) were washed, dried over Na2SO4 98 200406394 and evaporated under vacuum to provide the title product (0,143 g). 0-NMR (CDCls, δ): ^^ 0.80-1.25 (m? 5H); 1.25-1.50 (m? lH); 1.50-1.90 (m9 7H); 1.95 (s53H); 2.10-2.40 (m? 2H); 2.40-2.65 (m 5 4H); 2.90-3.15 (m? 4H); 3.38-3.55 (m? LH); 3.85 (m5 3H); 5.05 (t? LH); 6.80-7.25 (m? 7H); 7.30-7.45 (m lH) Example 46 (RS, SR) l- [4-Cyclohexyl-3- (2-fluorophenyl) -4-methoxycarbonyloxybutyl] -4- (2-methoxybenzene Base)-Pipen added 0.022 ml of ethyl chloroformate to a solution of compound 45e in 0.812 ml of 0.112 g of bitumen ratio stirred at 0 ° C. The reaction mixture was stirred at room temperature for 4 days and at 40 ° C for 5 hours. Add an additional 0.045 ml of methyl chloroacetate and heat at 40 ° C for 4 hours. After 3 days at room temperature, methyl chloroarsinate (0.045 ml) was added and the mixture was stirred at room temperature for 6 hours. After cooling, it was poured into water and extracted with 15 EtOAc (2 x 15 ml), washed with 2 x 15 ml of H20, dried (Na2S04) and evaporated to dryness under vacuum. The crude product was purified by flash chromatography (PE-EtOAc-NH3 / MeOH 75: 25: 2.5) to yield 0.022 g of the title product. ^ -NMR (CDCh, δ): 0.80-2.05 (m? 13H); 2.10-2.40 (m? 2H); 20 2.40-2.75 (m54H); 2.90-3.20 (m? 4H); 3.38-3.60 (m? lH); 3.70 (m53H); 3.85 (m, 3H); 4.88 (t? lH); 6.80-7.25 (m57H); 7.38-7.50 (m? lH) Example 47 (RS, SR) l- [4- Cyclohexyl-4-ethylaminecarbonyloxy-3- (2-fluorophenyl) -butyl] -4- (2-methoxyphenyl) -piperazine 99 200406394 Add 0.113 isocyanate To a solution of compound 45e in 0.5 ml of 0.126 g of compound, stirred at 0 ° C. The reaction mixture was stirred at room temperature for 24 hours and at 50 ° C for 3 hours. After cooling, it was poured into water and extracted with Et20, washed with H20, dried 5 (Na2S04) and evaporated to dryness under vacuum to provide 0.108 g of the title product. ^ -NMR (CDC13, δ): 0.90-1.40 (m? 9H); 1.60-2.10 (m57H);

2.10- 2.40 (m5 2H); 2.50-2.65 (m? 4H); 2.95-3.30 (m5 6H); 3.40-3.55 (m，lH); 3.85 (s，3H); 4.50 (t，lH); 4.90 (t，lH); 10 6.80-7.22 (m?7H); 7.32-7.45 (m?lH) 實施例48 (RS，SR) l-[4-胺羰基氧基-4-環己基-3-(2-氟苯基)-丁基】-4-(2-甲氧基苯基)-旅井2.10- 2.40 (m5 2H); 2.50-2.65 (m? 4H); 2.95-3.30 (m5 6H); 3.40-3.55 (m, lH); 3.85 (s, 3H); 4.50 (t, lH); 4.90 ( t, lH); 10 6.80-7.22 (m? 7H); 7.32-7.45 (m? lH) Example 48 (RS, SR) l- [4-aminocarbonyloxy-4-cyclohexyl-3- (2 -Fluorophenyl) -butyl] -4- (2-methoxyphenyl) -Lujing

添加氰酸鉀至一配於5 ml的CH2C12之0.124 g的化合物 45e之溶液中。在室溫下攪拌，添加0.087 ml的三氟乙酸至該 15 懸浮液中。在室溫下24小時且在40°C下5小時之後，添加額 外的三氟乙酸（0，17 ml)。在40°C下6小時之後，冷卻該反應 混合物，予以蒸發至乾燥，以水與2N NaOH予以稀釋，以 EtOAC作萃取；該萃取物以H20洗滌，予以乾燥（Na2S04)並 於真空下予以蒸發至乾燥。該粗產物藉由閃蒸層析法（PE -20 EtOAc-NH3/MeOH 75:25:2.5)予以純化俾以生成 0.064 g 的該 標題產物。 ^-NMR (CDCls, δ): 0.90-1.50 (m96H); 1.50-2.05 (m97H); 2.10- 2.40 (m?2H); 2.50-2.70 (m54H); 2.95-3.15 (m?4H); 3.40-3.55 (m?lH); 3.85 (s53H); 4.45 (s?2H); 4.85-4.95 (m?lH); 6.80-7.26 100 200406394 (m，7H);7.32-7.45 (m lH) 實施例 49 U[S^(2 ^ - vr t . 一勉-1，4_苯並戴奥辛基)卜4_ (扣羥基_5,5_ 二甲基-3-苯基)_己基卜哌哜 、抓用被4田速作為實施例％之該化合物之該操作程序以合 成爲題化口物，但使用氣化（第三丁基)鎂（IN，g己於THF中） 代替乳化(異丁基)鎂。在室溫下攪拌該混合物歷時3小時。該 粗產物:由閃②層析法(CH2Cl2 — Me〇H 99:听以純化，而提供 有如一呈褐色的固體之該標題產物（15%)。 ίο 15 ·· G.88 (m，9H)，丨 311，_肩，咖 97 (m5 1H)5 1.96-2.21 (m? m)? 2 22-2 4g 2 ^^ ^ ^ 2.99-3.28 (m，4H)，361〇73 扣，ih)，（am 扣伯）’ 6.49-6.63 (m，2H)，6J6W(m，1H)57.15-7.44 (m，5H)， [M+H]+=425.7 實施例5〇 1(4_氟基甲氧基苯基)·Η(4-經基-3-苯基)-庚_5. 炔基】-哌畊 (十氟基-2-甲羞羞辰讲（化立 物 50a) 採用被描述作為實施例1之該化合物之該操作程序以獲 得該標題化合物，但使用化合物26a代替化合物&作為一起始 20物且Η4ϋ2-甲氧基苯基井鋪H2,2,2_三氣乙氧基苯 基)_。辰畊。藉由閃蒸層析法(pE _ Et〇Ac 4:6)之純化生成該標題 化合物（90 %)。油。 'H-NMR (CDCl3) δ) L94-2.29 (m? 2H); 2.36-2.79 (m5 6H); 2.97-3.14 (m? 4H)； 3.85 (s? 3H)； 4.01-4.12 (m5 1H); 6.54-6.71 (m5 101 200406394 2H); 6.82-7.97 (m5 1H); 7.28-7.47 (m? 5H) M4-氟基-2-曱氧基笨基)-4-(3-曱醯基-3-笨基丙基)-哌讲（化合 物 50b) 採用被描述作為化合物6f (另擇的方法）之該操作程序以獲 5 得該標題化合物，但使用化合物50a代替化合物6h作為一起 始物。藉由閃蒸層析法(CH2Cl2-MeOH 95:5)之純化生成該標題 化合物（55 %)。油。Add potassium cyanate to a solution of 0.124 g of compound 45e in 5 ml of CH2C12. Stir at room temperature and add 0.087 ml of trifluoroacetic acid to the 15 suspension. After 24 hours at room temperature and 5 hours at 40 ° C, additional trifluoroacetic acid (0, 17 ml) was added. After 6 hours at 40 ° C, the reaction mixture was cooled, evaporated to dryness, diluted with water and 2N NaOH, and extracted with EtOAC; the extract was washed with H20, dried (Na2S04) and evaporated under vacuum. To dry. The crude product was purified by flash chromatography (PE-20 EtOAc-NH3 / MeOH 75: 25: 2.5) to give 0.064 g of the title product. ^ -NMR (CDCls, δ): 0.90-1.50 (m96H); 1.50-2.05 (m97H); 2.10- 2.40 (m? 2H); 2.50-2.70 (m54H); 2.95-3.15 (m? 4H); 3.40- 3.55 (m? LH); 3.85 (s53H); 4.45 (s? 2H); 4.85-4.95 (m? LH); 6.80-7.26 100 200406394 (m, 7H); 7.32-7.45 (m lH) Example 49 U [S ^ (2 ^-vr t. Yimian-1,4-benzodioxinyl) Bu 4_ (Hydroxyl_5,5_dimethyl-3-phenyl) _hexylbuperidine, 4 Tian Su as an example% of this compound. The procedure was based on synthesis, but gasified (third butyl) magnesium (IN, g in THF) was used instead of emulsified (isobutyl) magnesium. The mixture was stirred at room temperature for 3 hours. The crude product: purified by flash chromatography (CH2Cl2-MeOH 99: audible) to provide the title product (15%) as a brown solid. Ί 15 ·· G.88 (m, 9H ), 311, _ shoulder, coffee 97 (m5 1H) 5 1.96-2.21 (m? M)? 2 22-2 4g 2 ^^ ^ ^ 2.99-3.28 (m, 4H), 361〇73 buckle, ih) , (Am subbo) '6.49-6.63 (m, 2H), 6J6W (m, 1H) 57.15-7.44 (m, 5H), [M + H] + = 425.7 Example 5〇1 (4-Fluoromethyl Oxyphenyl) · fluorene (4-meryl-3-phenyl) -hepta-5. Alkynyl] -piperin (decafluoro-2-methylstilbene) (Chemical 50a) Adopted to be described The operation procedure of the compound as in Example 1 was used to obtain the title compound, but compound 26a was used instead of compound & as a starting 20 compound and Η4ϋ2-methoxyphenyl wells H2,2,2_trigas ethoxylate Phenyl)-. Chen Geng. Purification by flash chromatography (pE_EtoAc 4: 6) gave the title compound (90%). oil. 'H-NMR (CDCl3) δ) L94-2.29 (m? 2H); 2.36-2.79 (m5 6H); 2.97-3.14 (m? 4H); 3.85 (s? 3H); 4.01-4.12 (m5 1H); 6.54-6.71 (m5 101 200406394 2H); 6.82-7.97 (m5 1H); 7.28-7.47 (m? 5H) M4-fluoro-2-methoxyoxybenzyl) -4- (3-fluorenyl-3 -Benzylpropyl) -pipeline (compound 50b) The procedure described as compound 6f (alternative method) was used to obtain 5 to obtain the title compound, but compound 50a was used instead of compound 6h as a starting material. Purification by flash chromatography (CH2Cl2-MeOH 95: 5) gave the title compound (55%). oil.

^-NMR (CDClS} δ): 1.81-2.00 (m5 1H); 2.24-2.48 (m5 3H); 2.49-3.82 (m，4H); 3.87-3.19 (m，4H); 3.61-3.73 (m，1H); 3.84 (s; 10 3H); 6.53-6.71 (m? 2H); 6.80-6.94 (m5 1H); 7.12-7.45 (m? 5H); 9.68-9.79 (m5 1H).^ -NMR (CDClS) δ): 1.81-2.00 (m5 1H); 2.24-2.48 (m5 3H); 2.49-3.82 (m, 4H); 3.87-3.19 (m, 4H); 3.61-3.73 (m, 1H) ); 3.84 (s; 10 3H); 6.53-6.71 (m? 2H); 6.80-6.94 (m5 1H); 7.12-7.45 (m? 5H); 9.68-9.79 (m5 1H).

1_(4_氟基-2-曱氧基笨基羥基-3-笨基)·庚-5-炔基1-哌哄 採用被描述作為實施例36之該化合物之該操作程序以獲 得該標題化合物，但使用化合物50b代替化合物26c作為一起 15 始物且使用溴化（1-丙炔基)鎂（0.5 N，配於THF中）代替一氯化 (異丁基）鎂溶液。該粗產物藉由閃蒸層析法（CH2C12- MeOH 99:1)予以純化，而提供有如一黃色透明的油之該標題產物（22.6 %) 〇 ^-NMR {CDCl3y δ): 0.84-1.17 (m5 3H)? 1.40-1.70 (m5 2H)5 20 1.74-1.90 (m? 1H), 1.93-2.22 (m? 1H)? 2.25-3.29 (m? 10H)? 3.80 (s5 3H); 3.84-3.99 (m? 1H)? 6.50-6.65 (m? 2H)5 6.70-6.90 (m5 1H)? 7.14-7.38 (m? 5H).1- (4-fluoro-2-methoxyoxybenzylhydroxy-3-benzyl) · hept-5-ynyl1-piperazine adopts the procedure described for the compound of Example 36 to obtain the title Compound, but compound 50b was used instead of compound 26c as the starting material and (1-propynyl) magnesium bromide (0.5 N in THF) was used instead of (isobutyl) magnesium monochloride solution. The crude product was purified by flash chromatography (CH2C12-MeOH 99: 1) to provide the title product (22.6%) as a yellow transparent oil. ^ -NMR {CDCl3y δ): 0.84-1.17 ( m5 3H)? 1.40-1.70 (m5 2H) 5 20 1.74-1.90 (m? 1H), 1.93-2.22 (m? 1H)? 2.25-3.29 (m? 10H)? 3.80 (s5 3H); 3.84-3.99 ( m? 1H)? 6.50-6.65 (m? 2H) 5 6.70-6.90 (m5 1H)? 7.14-7.38 (m? 5H).

[M+H]+二 397.2 實施例51 (E,Z)-l-(4-氟基-2-甲氧基苯基)-4-[(4-羥基-3-苯 102 200406394 基)-庚-5-烯基]-哌讲（1:1混合物） 採用被描述作為實施例36之該化合物之該操作程序以獲 得該標題化合物，但使用化合物50b代替化合物26c作為一起 始物且使用溴化（1-丙烯基)鎂（0.5 N，配於THF中）代替一氯化 5 (異丁基）鎂溶液。該粗產物藉由閃蒸層析法（CH2C12 - MeOH 99:1)予以純化，而提供有如一黃色透明的油之該標題化合物 (30 %)。[M + H] + Di 397.2 Example 51 (E, Z) -1- (4-fluoro-2-methoxyphenyl) -4-[(4-hydroxy-3-benzene 102 200406394 group)- Hept-5-enyl] -piperidine (1: 1 mixture) The procedure described as the compound of Example 36 was used to obtain the title compound, but using compound 50b instead of compound 26c as a starting material and using bromine (1-propenyl) magnesium (0.5 N in THF) instead of 5 (isobutyl) magnesium monochloride solution. The crude product was purified by flash chromatography (CH2C12-MeOH 99: 1) to provide the title compound (30%) as a yellow transparent oil.

]H-NMR {CDCls, δ): 1.17-1.73 (m? 4H)5 1.92-2.51 (m5 2H)? 2.52-3.42 (m? 11H)5 3.83 (s5 3H)5 4.22-4.65 (m5 1H)5 5.28-5.75 10 (m? 2H)5 6.50-6.64 (m5 2H)5 6.72-6.91 (m? 1H)5 7.13-7.41 (m5 5H).] H-NMR (CDCls, δ): 1.17-1.73 (m? 4H) 5 1.92-2.51 (m5 2H)? 2.52-3.42 (m? 11H) 5 3.83 (s5 3H) 5 4.22-4.65 (m5 1H) 5 5.28-5.75 10 (m? 2H) 5 6.50-6.64 (m5 2H) 5 6.72-6.91 (m? 1H) 5 7.13-7.41 (m5 5H).

[M+H]+=399.2 藉由預備的LC-MS層析作進一步的純化以提供下列化合物之 分離： 15 實施例52 (Ε，Ζ)-1-(4-氟基-2-甲氧基苯基)-4-[(4-羥基-3-苯[M + H] + = 399.2 Further purification by preparative LC-MS chromatography provided the isolation of the following compounds: 15 Example 52 (E, Z) -1- (4-fluoro-2-methoxy Phenyl) -4-[(4-hydroxy-3-benzene

基)-庚-5-烯基]-哌畊（5:95混合物） ^-NMR (CDCls, δ): 1.24-1.43 (m? 3H)? 1.74-1.91 (m? 2H)? 1.92-3.12 (m，12H)，3.82 (s5 3H)，4.41-4.55 (m，1H)，5.18-5.65 (m9 2H)? 6.48-6.59 (m9 2H)5 6.71-6.91 (m? 1H)5 7.13-7.43 (m? 20 5H).) -Hept-5-enyl] -piperin (5:95 mixture) ^ -NMR (CDCls, δ): 1.24-1.43 (m? 3H)? 1.74-1.91 (m? 2H)? 1.92-3.12 ( m, 12H), 3.82 (s5 3H), 4.41-4.55 (m, 1H), 5.18-5.65 (m9 2H)? 6.48-6.59 (m9 2H) 5 6.71-6.91 (m? 1H) 5 7.13-7.43 (m 20 5H).

[M+H]+二 399.2 實施例53 (E)-l-(4-氟基-2-甲氧基苯基)-4-[(4-羥基-3-苯基)- 庚-5-烯基]-哌讲（RS，RS:RS，SR 9:1混合物） ]H-NMR (CDClS} δ): 1.44-1.59 (m? 4H)? 1.71-2.03 (m5 2H)? 103 200406394 2.32-3.15 (m? 11H) ^ qa r 3.84 (s5 3HX 4.09-4.12 (m5 1H)? 5.15^23 (m? 1H)5 5.34-5.49 (m ιττλ ^ , ，1H)，6.48-6.60 (m，2H)，6.70-6.92 (m，1 出 7.13-7.43 (m? 5H). ’ [Μ+Η]+=399·2 5 10 15 20 實施例54 二羥，扣苯並戴奥辛基)ΗΚ(4羥基 甲基3苯基)_己·5_埽基】♦井⑽邮職沾心句 知用被“述作為實施例36之該化合物之該操作程序以合[M + H] + di 399.2 Example 53 (E) -1- (4-Fluoro-2-methoxyphenyl) -4-[(4-hydroxy-3-phenyl) -hept-5- Alkenyl] -piperidine (RS, RS: RS, SR 9: 1 mixture)] H-NMR (CDClS} δ): 1.44-1.59 (m? 4H)? 1.71-2.03 (m5 2H)? 103 200406394 2.32- 3.15 (m? 11H) ^ qa r 3.84 (s5 3HX 4.09-4.12 (m5 1H)? 5.15 ^ 23 (m? 1H) 5 5.34-5.49 (m ιττλ ^,, 1H), 6.48-6.60 (m, 2H) , 6.70-6.92 (m, 1 out of 7.13-7.43 (m? 5H). '[Μ + Η] + = 399 · 2 5 10 15 20 Example 54 Dihydroxy, benzobenzodioctyl) ΗK (4hydroxymethyl 3phenyl) _Hex · 5_fluorenyl] ♦ The well-known sentence is used to describe the operation procedure of the compound described in Example 36 as follows

成該標題化合物使㈣化（異丙烯基)卿·5 N，配於挪 中）代替一氯化（里丁 I 、^1暴)鎂>谷液。在室溫下攪拌該混合物歷時3 小時。該粗產物藉A^ 4洛層析法（CH2CI2- MeOH 99:1)予以純 化’而提供有如一 g组么 王褐色的固體之該標題產物（38 %)。 b-NMR (CDC/? a、.，， ’ ^ ^65-1.79 (m? 3H)? 2.03-2.12 (m? 1H)? 2.32-2.48 (m，1H、 〇 ^ )，2.57-2.78 (m，1H)，2.79-3.42 (m5 12H), 4.21-4.45 (m 4H、 λ 5 ^ 4.65-4.95 (m9 2H)5 6.49-6.58 (m? 1H), 6.60-6.65 (m5 1H) fi 70 z： ^ U6.79 (m，1H)，7.19-7.41 (m5 5H).To this title compound, tritiated (isopropenyl) 5N, formulated in Norway, was used in place of monochloride (Riding I, ^ 1) magnesium > grain solution. The mixture was stirred at room temperature for 3 hours. This crude product was purified by A ^ 4L chromatography (CH2CI2-MeOH 99: 1) 'to provide the title product (38%) as a group g of a brown solid. b-NMR (CDC /? a,. ,,, ^ ^ 65-1.79 (m? 3H)? 2.03-2.12 (m? 1H)? 2.32-2.48 (m, 1H, 〇 ^), 2.57-2.78 (m , 1H), 2.79-3.42 (m5 12H), 4.21-4.45 (m 4H, λ 5 ^ 4.65-4.95 (m9 2H) 5 6.49-6.58 (m? 1H), 6.60-6.65 (m5 1H) fi 70 z: ^ U6.79 (m, 1H), 7.19-7.41 (m5 5H).

[M+H] =409.6 實施例55 1-丨5-0 i 一 u (，1_二羥_1，4-苯並戴奥辛基)卜4](4一羥基-6_ 甲基-3-苯基)ϋ歸基卜辰畊 ^ 、彳田込作為貫施例36之該化合物之該操作程序以合 成該標題化合物使用氯化（2_甲基烯丙基卿$ Ν，配於 THF中）代替一氯化（里 I、鎮〉谷液。在室溫下攪拌混合物歷時 104 1 小時。該粗產物藉由閃蒸層析法(CH2C12 一 Me0H 99:1)予以純 化而提ί、有如-呈褐色的固體之該標題產物(佩）。 200406394 5 !H-NMR (αΧ73,介 i 68_丨 73 (m，3H) 2.06-2.18 (m? 1H)5 2.19-2.31 (m9 1H)? 2.52-3.42 (m? 12H)? 4.23-4.44 (m5 4H)? 6.49-6.53 (m, 1H)5 6.62_6 65 (m，1H)， 7.21-7.48 (m5 5H). [M+H]+-423.6 1.94-2.05 (m? 2H)? 2.47-2.51 4.62-4.93 (m，2H)， 6.77-6.84 (m，ih)5 10 15 實施例 56 _(Wd1，4·本並戴奥辛基屮4和羥基 -4 - (2-嘴吩基)-3-笨丁基卜底畊私用被&述作為實施例36之該化合物之該操作程序以合 成該標題化合物’但使㈣化㈣吩細（1 Μ，配於THF中°)代替一氯化（異L錄。在室訂㈣該混合物料3小 時。雜產物藉由閃蒸層析法(CH2Cl2-MeOH99:1)予以純化， 而提供有如—呈褐色的固體之該標題產物(33 %)。 ]H-NMR (CDCL ^ ι -1-75-2.23 (m, 3H), 2.48-2.53 (m, 2H), 2.54-2.94 (m -> ，），3·05-3.32 (m，5Η), 4.23-4.41 (m, 4Η)， 5.12-5.21 (m? ifj\ ^ ς ’ )’ .50-6.93 (m5 5H)，7.11-7.48 (m5 6H) [Μ+Η]+=451·7 * 20 實施例57 1丨5々1(’ _二羥-1，4_苯並戴奥辛基)卜心[…羥基_3·苯基)辛基】·"呢畊 _ 4田處作為貫施例36之該化合物之該操作程序以合 成該標題化合物，彳 、 使用氯化（正丁基）鎂（2 Μ，配於THF中） 代替一氯化（異丁其、 二 ^ 土）鎂溶液。在室溫下攪拌混合物歷時3小時。 Α；藉由閃务層析法(CH2C12 - MeOH 99··1)予以純化，而提 么、有女_色的固體之該標題產物(48 %)。 105 200406394 5 ^-NMR (CDCh, δ): 0.61-0.78 (m? 3H)? 1.02-1.31 1.94-2.06 (m? 1H)，2.26-2.48 (m? 1H)? 2.51-2.61 2.62-3.32 (m5 10H)? 3.62-3.74 (m? 1H), 4.23-4.44 6.47-6.50 (m, 1H)，6.61-6.65 (m，1H)，6.79-6.84 7.21-7.51 (m? 5H). (m，(m? (m， (m， 6H)， 2H)5 4H)5 1H)， [M+H]+=425.4 實施例58 1-(4-氣基-2-甲氧基苯基)-4-[(4-甲氧基-3-苯基)-庚 -5-炔基】-哌讲[M + H] = 409.6 Example 55 1- 丨 5-0 i-u (, 1_dihydroxy_1,4-benzodioxinyl) b 4] (4-hydroxy-6-methyl-3-benzene Based on the procedure of ϋgui Jibu Chen Geng ^ and Putian 込 as the compound of Example 36 to synthesize the title compound using chlorination (2-methylallyl hydrazine $ Ν, formulated in THF) Instead of monochloride (Li I, Zhen> Valley). The mixture was stirred at room temperature for 104 1 hours. The crude product was purified by flash chromatography (CH2C12-Me0H 99: 1) and was as follows- The title product (pe) was a brown solid. 200406394 5! H-NMR (αχ73, 介 i 68_ 丨 73 (m, 3H) 2.06-2.18 (m? 1H) 5 2.19-2.31 (m9 1H)? 2.52 -3.42 (m? 12H)? 4.23-4.44 (m5 4H)? 6.49-6.53 (m, 1H) 5 6.62_6 65 (m, 1H), 7.21-7.48 (m5 5H). [M + H] +-423.6 1.94-2.05 (m? 2H)? 2.47-2.51 4.62-4.93 (m, 2H), 6.77-6.84 (m, ih) 5 10 15 Example 56 _ (Wd1,4. Benzodioxinium 4 and hydroxy- 4- (2-Methenyl) -3-benzylbutyrate was used as the compound of Example 36 in this procedure to synthesize the title compound, (1 M, formulated in THF) instead of monochloride (iso-L). The mixture was fixed in the chamber for 3 hours. The hybrid product was purified by flash chromatography (CH2Cl2-MeOH99: 1) and provided As—the title product (33%) as a brown solid.] H-NMR (CDCL ^ -1-75-2.23 (m, 3H), 2.48-2.53 (m, 2H), 2.54-2.94 (m- >), 3.05-3.32 (m, 5Η), 4.23-4.41 (m, 4Η), 5.12-5.21 (m? ifj \ ^ ς ')' .50-6.93 (m5 5H), 7.11-7.48 (m5 6H) [Μ + Η] + = 451 · 7 * 20 Example 57 1 丨 5々1 ('_ dihydroxy-1,4_benzodioxinyl) [Octyl] · " Nei Geng_ 4 Tian Chu as the compound of Example 36 to operate the procedure to synthesize the title compound, 彳, using (n-butyl) magnesium chloride (2 M, formulated in THF) It replaces the monochloride (isobutyl, di ^ earth) magnesium solution. The mixture was stirred at room temperature for 3 hours. A; Purified by flash chromatography (CH2C12-MeOH 99 ·· 1) to provide the title product (48%) as a female-colored solid. 105 200406394 5 ^ -NMR (CDCh, δ): 0.61-0.78 (m? 3H)? 1.02-1.31 1.94-2.06 (m? 1H), 2.26-2.48 (m? 1H)? 2.51-2.61 2.62-3.32 (m5 10H)? 3.62-3.74 (m? 1H), 4.23-4.44 6.47-6.50 (m, 1H), 6.61-6.65 (m, 1H), 6.79-6.84 7.21-7.51 (m? 5H). (M, (m (m, (m, 6H), 2H) 5 4H) 5 1H), [M + H] + = 425.4 Example 58 1- (4-amino-2-methoxyphenyl) -4- [ (4-methoxy-3-phenyl) -hept-5-ynyl] -Phenyl

4-羥基-3-笨基庚-5-醛二曱基縮醛（化合物58a) 10 採用被描述作為實施例6之該化合物之該操作程序以獲 得該標題化合物，但使用化合物17b代替化合物6f作為一起 始物且氯化（1-丙炔基）鎂（2M溶液，配於THF中）代替氯化（乙 基)鎂。該粗產物藉由閃蒸層析法(EtOAc - PE 3:7)予以純化，而 提供該標題產物（81 %)。4-Hydroxy-3-benzylhept-5-aldehyde difluorenyl acetal (compound 58a) 10 The procedure described for the compound described in Example 6 was used to obtain the title compound, but compound 17b was used instead of compound 6f As a starting material, (1-propynyl) magnesium chloride (2M solution in THF) was used instead of (ethyl) magnesium chloride. The crude product was purified by flash chromatography (EtOAc-PE 3: 7) to provide the title product (81%).

15 ^-NMR (CDCh, δ): 1.78-1.88 (m? 3H)5 1.91-2.21 (m; 3H); 2.92-3.08 (m5 1H)? 3.20-3.35 (m? 7H)? 4.18-4.24 (m? 1H)， 7.20-7.39 (m? 5H). 4-曱氣基-3-笨基庚-5-醛二曱基縮醛（化合物58b) 如針對化合物Id所描述的來合成該標題化合物，使用化 20 合物5 8a代替化合物1 c作為一起始物。在EtOAc萃取之後， 該粗產物在無進一步純化下被使用於下一步驟中步驟。 4-甲氣基-3-笨基庚-5-醛（化合物58c) 採用被描述作為化合物le之該操作程序以獲得該標題化 合物，但使化合物5 8b代替化合物1 d用作為一起始物。該標 106 200406394 題產物在無進一步純化下被使用於下一步驟中。 募基氧基-3二炔基l-f 使用被描述作為實施例1之該化合物之該方法以製備該 5標題化合物，但使用化合物58c代替化合物^且1-(‘氟基-2_ 曱氧基苯基)』底畊代替丨_(2二2_三氟乙氧基苯基)』底畊。該粗產 物藉由閃蒸層析法(PE_Et0Ac 3:7)予以純化俾以提供該標題化 合物（17.5 %)。 ]H-NMR (CDC!3j ^):.1.68 andl.83 (2 s5 3H); 1.88-2.05 (m5 2H)5 10 2.15-2.48 (m? 4H)? 2.48-2.78 (m5 4H)? 2.81-2.90 (m? 1H); 2.90-3.15 (m5 2H)； 3.25 and 3.40 (2 x s5 3H); 3.76 (m5 3H); 3.93-3.98 (m，1H)，6.48-6.57 (m，2H)，6·76 (dd5 1H) 7.22-7.48 (m 5H).15 ^ -NMR (CDCh, δ): 1.78-1.88 (m? 3H) 5 1.91-2.21 (m; 3H); 2.92-3.08 (m5 1H)? 3.20-3.35 (m? 7H)? 4.18-4.24 (m ? 1H), 7.20-7.39 (m? 5H). 4-Hydroxy-3-benzylhept-5-aldehyde difluorenyl acetal (compound 58b) The title compound was synthesized as described for compound Id, Instead of compound 1 c, compound 20 8a was used as a starting material. After EtOAc extraction, the crude product was used in the next step without further purification. 4-methylamino-3-benzylhept-5-aldehyde (compound 58c) The procedure described as compound le was used to obtain the title compound, but compound 5 8b was used instead of compound 1 d as a starting material. The target product of 2004 200406394 was used in the next step without further purification. This method is described as the compound of Example 1 to prepare the 5 title compound, but using compound 58c instead of compound ^ and 1-('fluoroyl-2_methoxyoxybenzene Base) "bottoming instead of 丨 _ (2-di-2-trifluoroethoxyphenyl)" bottoming. The crude product was purified by flash chromatography (PE_Et0Ac 3: 7) to provide the title compound (17.5%). ] H-NMR (CDC! 3j ^): 1.68 and 1.83 (2 s5 3H); 1.88-2.05 (m5 2H) 5 10 2.15-2.48 (m? 4H)? 2.48-2.78 (m5 4H)? 2.81- 2.90 (m? 1H); 2.90-3.15 (m5 2H); 3.25 and 3.40 (2 x s5 3H); 3.76 (m5 3H); 3.93-3.98 (m, 1H), 6.48-6.57 (m, 2H), 6 76 (dd5 1H) 7.22-7.48 (m 5H).

[M+H]+=411.13 15實施例59 (E，Z)-l-(4-氟基-2-曱氧基苯基)-4-[(4-甲氧基_3_苯 基)-庚-5-烯基卜旅畊（具有上方的TLC以之非對映異構物） 4二羥基-3-苯羞蓋烯-5-醛二曱基縮醛（化合物 採用被描述作為實施例6之該化合物之該操作程序以獲 得標題化合物，但使用化合物17b代替化合物6f作為一起始 20物且氯化（1-丙烯基)鎂（2M溶液，配於THF中）代替氯化（乙美） 镁。該粗產物藉由閃蒸層析法(PE _ EtOAc 7:3)予以純化，而提 供該標題產物(42 %)。 'H-NMR {CDCl3) δ): 1.50 and 1.60 (2 d5 3H)? 1.85-2.04 (m? 2H) 2.15-2.38 (m9 1H)? 2.78-2.92 (m? 1H); 3.22 and 3.38 (4 χ s? 6H) 107 200406394 4.10-4.24 (m? 1H)? 4.58 (dd? 1H)? 5.22-5.59 (m? 2H)? 7.20-7.39 (m，5H). 4-甲氧基-3-笨基庚烯-5-醛二曱基縮醛（化合物59b) 如針對化合物Id所描述的來合成標題化合物，使用化合 5 物59a代替化合物1 c作為一起始物。在EtOAc純化之後，該 粗產物在無進一步純化下被使用於下一步驟中。 ]H-NMR (CDCls, δ): 1.10 and 1.75 (m? 3H)? 1.85-2.35 (m5 2H)?[M + H] + = 411.13 15 Example 59 (E, Z) -1- (4-Fluoro-2-methoxyphenyl) -4-[(4-methoxy-3-phenyl) -Hept-5-alkenyl tripeptide (with diastereomers above TLC) 4 dihydroxy-3-benzymene-5-aldehyde difluorenyl acetal (compound adoption is described as implemented The procedure of the compound of Example 6 was used to obtain the title compound, but using compound 17b instead of compound 6f as a starting 20 and (1-propenyl) magnesium chloride (2M solution in THF) instead of chlorinated (ethyl US) magnesium. The crude product was purified by flash chromatography (PE_EtOAc 7: 3) to provide the title product (42%). 'H-NMR {CDCl3) δ): 1.50 and 1.60 (2 d5 3H)? 1.85-2.04 (m? 2H) 2.15-2.38 (m9 1H)? 2.78-2.92 (m? 1H); 3.22 and 3.38 (4 χ s? 6H) 107 200406394 4.10-4.24 (m? 1H)? 4.58 (dd? 1H)? 5.22-5.59 (m? 2H)? 7.20-7.39 (m, 5H). 4-methoxy-3-benzylhepten-5-aldehyde difluorenyl acetal (compound 59b) The title compound was synthesized as described for compound Id, using compound 5a instead of compound 1c as a starting material. After purification with EtOAc, the crude product was used in the next step without further purification. ] H-NMR (CDCls, δ): 1.10 and 1.75 (m? 3H)? 1.85-2.35 (m5 2H)?

2.63- 3.05 (m? 1H)? 3.12-3.52 (m? 9H)5 4.10-4.24 (m? 1H)? 4.58 (dd? 1H)? 5.22-5.59 (m9 2H)? 7.12-7.39 (m; 5H). 10 4-曱氣基-3-笨基庚烯-5-醛(化合物59c) 採用被描述作為化合物le之該操作程序以獲得標題化合 物，但使用化合物59b代替化合物Id作為一起始物。該標題 產物在無進一步純化下被使用於下一步驟中。 1-(4-乱基-2-曱氧基笨基)-4-「(4-曱氧基-3-笨基)-庚-5-炼基1-口瓜 152.63- 3.05 (m? 1H)? 3.12-3.52 (m? 9H) 5 4.10-4.24 (m? 1H)? 4.58 (dd? 1H)? 5.22-5.59 (m9 2H)? 7.12-7.39 (m; 5H) 10 4-fluorenyl-3-benzylhepten-5-aldehyde (compound 59c) The procedure described as compound le was used to obtain the title compound, but compound 59b was used instead of compound Id as a starting material. The title product was used in the next step without further purification. 1- (4-Methoxy-2-benzyloxybenzyl) -4-"(4-Methoxy-3-benzyl) -heptyl-5-alkenyl 1-mouth melon 15

使用被描述作為實施例1之該化合物之該方法以製備標 題化合物，但使用化合物59c代替化合物le且1-(4-氟基-2-甲 氧基苯基)-哌啩代替1-(2,2,2-三氟乙氧基苯基)-哌畊。該粗產物 藉由閃蒸層析法(PE :EtOAc 4:6)予以純化俾以提供該標題化合 20 物（13.2 %)。 ^-NMR (CDCls, δ): 1.45 andl.63 (2 d? 3H); 1.68-1.81 (m? 1H)5 1.88-2.05 (m? 1H)? 2.08-2.27 (m5 2H)? 2.42-2.58 (m? 4H); 2.63- 2.75 (m? 1H); 2.88-3.00 (m? 4H)? 3.08 and 3.13 (2 x s? 3H); 3.52 and 4.05 (2 d5 1H); 3.75 (s5 3H)? 5.05-5.23 (m? 1H)5 108 200406394 5.47-5.71 (m5 1H)，6.48-6.57 (m，2H)，6·76 (m，1H)，7.05-7.32 (m， 5H).The method described as the compound of Example 1 was used to prepare the title compound, but using compound 59c instead of compound le and 1- (4-fluoro-2-methoxyphenyl) -piperidine instead of 1- (2 , 2,2-trifluoroethoxyphenyl) -pigon. The crude product was purified by flash chromatography (PE: EtOAc 4: 6) to provide the title compound (13.2%). ^ -NMR (CDCls, δ): 1.45 andl.63 (2 d? 3H); 1.68-1.81 (m? 1H) 5 1.88-2.05 (m? 1H)? 2.08-2.27 (m5 2H)? 2.42-2.58 ( m? 4H); 2.63- 2.75 (m? 1H); 2.88-3.00 (m? 4H)? 3.08 and 3.13 (2 xs? 3H); 3.52 and 4.05 (2 d5 1H); 3.75 (s5 3H)? 5.05- 5.23 (m? 1H) 5 108 200406394 5.47-5.71 (m5 1H), 6.48-6.57 (m, 2H), 6.76 (m, 1H), 7.05-7.32 (m, 5H).

[Μ+Η]+=413·34 實施例60 (E，Z)-l-(4-氟基-2-甲氧基苯基)-4-[(4-甲氧基-3-苯 5 基)-庚-5-烯基】-哌讲（具有下方的TLC rf之非對映異構物） 經由實施例59之純化步驟分離出標題化合物。[Μ + Η] + = 413 · 34 Example 60 (E, Z) -1- (4-fluoro-2-methoxyphenyl) -4-[(4-methoxy-3-benzene5 ) -Hept-5-enyl] -piperidine (diastereomer with TLC rf below) The title compound was isolated via the purification procedure of Example 59.

^-NMR (CDCl3, δ): 1.48 andl.60 (2d? 3H); 1.79-2.12 (m5 2H)5 2.18-2.40 (m5 2H)5 2.22-2.78 (m? 5H); 2.92-3.13 (m? 4H); 3.25 and 3.30 (2s? 3H); 3.57 and 4.08 (2t? 1H); 3.85 (s? 3H)? 5.11-5.23 10 (m，1H)，5.39-5.65 (m，1H)，6.58-6.69 (m5 2H)，6.82-6.91 (m，1H)， 7.15- 7.35 (m? 5H).^ -NMR (CDCl3, δ): 1.48 and 1.60 (2d? 3H); 1.79-2.12 (m5 2H) 5 2.18-2.40 (m5 2H) 5 2.22-2.78 (m? 5H); 2.92-3.13 (m? 4H); 3.25 and 3.30 (2s? 3H); 3.57 and 4.08 (2t? 1H); 3.85 (s? 3H)? 5.11-5.23 10 (m, 1H), 5.39-5.65 (m, 1H), 6.58-6.69 (m5 2H), 6.82-6.91 (m, 1H), 7.15- 7.35 (m? 5H).

[M+H]+=413.34 實施例61 l-[4-環己基-3-(2-甲氧甲苄基)-4-侧氧丁基】-4-(4- 氟基-2-甲氧基苯基)-哌畊 15 2-曱氧曱基溴甲笨（化合物61a)[M + H] + = 413.34 Example 61 l- [4-cyclohexyl-3- (2-methoxymethylbenzyl) -4-oxobutyl] -4- (4-fluoro-2-methyl Oxyphenyl) -piperin 15 2-methyloxopentyl bromide (compound 61a)

在室溫下攪拌一 1.2g的2-曱氧甲基苯甲醇（J.Chem. Soc.， 1954, 2819-2826 )、2·5 g的三苯基膦、3· 14 g的四溴甲烷以及 50 ml的CH2C12之混合物歷時2小時。而後，在真空下將該反 應混合物蒸發至乾燥且藉由閃蒸層析法（CH2C12)予以純化俾 20 以提供1.62 g的該標題化合物。 ^-NMR (CDC13, δ): 3.42 (d5 3H)? 4.60 (s5 2H)? 4.65 (s? 2H)9 7.15- 7.30 (m，3H)5 7.22-7.45 (m，4H) 1-環己基-2-(2-甲氧曱苄基）乙酮（化合物61 b) 逐滴添加一 1 · 6 g的化合物61 a與配於10 ml的苯之1 · 17 109 200406394Stir at room temperature-1.2 g of 2-fluorenylmethyl benzyl alcohol (J. Chem. Soc., 1954, 2819-2826), 2.5 g of triphenylphosphine, 3.14 g of tetrabromomethane, and 50 ml of a mixture of CH2C12 took 2 hours. The reaction mixture was then evaporated to dryness under vacuum and purified by flash chromatography (CH2C12) 俾 20 to provide 1.62 g of the title compound. ^ -NMR (CDC13, δ): 3.42 (d5 3H)? 4.60 (s5 2H)? 4.65 (s? 2H) 9 7.15- 7.30 (m, 3H) 5 7.22-7.45 (m, 4H) 1-cyclohexyl- 2- (2-Methoxybenzyl) ethanone (Compound 61 b) Dropwise add 1.6 g of compound 61 a and 1 · 17 109 200406394 in 10 ml of benzene

ml的N，N-二曱基乙醯胺之溶液至一在氮氣之下，於室溫下攪 拌之配於5 ml的無水苯之1.44 g的Zn(Cu)(如於Org· Syn. 5, 855中所描述的來製備）之懸浮液中。在室溫下攪拌該混合物歷 時1小時，接而回流歷時4小時。在60°C下冷卻之後，添加 5 一配於3 ml的苯之0.073 g的肆（三苯基膦）鈀溶液繼而一配於 3 ml的苯之0.55 ml的環己烷羰醯氯溶液。在室溫下攪拌該反 應混合物2.5小時。在靜置過夜之後，以EtOAc稀釋該混合物 並在一 celite panel上予以過濾、；以一飽和的氯化銨水溶液、 NaHC03水溶液以及鹽水洗滌該過濾物，予以乾燥並予以蒸發 10 至乾燥。該粗產物藉由閃蒸層析法(PE-EtOAc 100 :4)予以純化 俾以提供lg的該標題化合物。 ^-NMR {CDCl3, δ): 1.10- 2.05 (m5 10H)5 2.25-2.48 (m5 1H)5 3.40 (s5 3H)，4.50 (s5 2H)，5.18 (s5 2H)5，7.25-7.50 (m，4H) 4-環己基-4-氧-3-(2-曱氧曱苄基V丁醛二乙基縮醛（化合物 15 61c)ml of a solution of N, N-dimethylacetamide to one under nitrogen, stirred at room temperature, 1.44 g of Zn (Cu) in 5 ml of anhydrous benzene (as in Org · Syn. 5 , As described in 855). The mixture was stirred at room temperature for 1 hour and then refluxed for 4 hours. After cooling at 60 ° C, a solution of 0.073 g of tris (triphenylphosphine) palladium in 3 ml of benzene was added followed by a solution of 0.55 ml of cyclohexanecarbonylphosphonium chloride in 3 ml of benzene. The reaction mixture was stirred at room temperature for 2.5 hours. After standing overnight, the mixture was diluted with EtOAc and filtered on a celite panel; the filtrate was washed with a saturated aqueous ammonium chloride solution, NaHC03 aqueous solution and brine, dried and evaporated for 10 to dryness. The crude product was purified by flash chromatography (PE-EtOAc 100: 4) 俾 to provide 1 g of the title compound. ^ -NMR {CDCl3, δ): 1.10- 2.05 (m5 10H) 5 2.25-2.48 (m5 1H) 5 3.40 (s5 3H), 4.50 (s5 2H), 5.18 (s5 2H) 5, 7.25-7.50 (m, 4H) 4-cyclohexyl-4-oxo-3- (2-fluorenyloxybenzyl V-butyraldehyde diethyl acetal (Compound 15 61c)

使用被描述作為化合物2b之該方法以製備該標題化合 物，但使用化合物61b代替1-(2-三氟甲氧基苯基)-丙烷-2-酮。 一般的完成程序並純化，而提供該標題化合物。 4-環己基-4-氣-3-(2-曱氧曱苄基V 丁醛（化合物61d) 20 採用被描述作為化合物le之該操作程序以獲得該標題化 合物，但使用化合物61c代替化合物Id作為一起始物。該標題 產物在無進一步純化下使用於下一步驟中。 1-「4-環己基-3-(2-曱氣曱¥基)-4-側氣丁基1-4-(4-氟基-2-曱氣基 笨基哌畊 110 200406394 使用被描述作為實施例1之該化合物之該方法以製備該 標題化合物，但使用化合物61d代替化合物le且1-(4-氟基》2-曱氧基苯基底畊代替卜(2,2,2-三氟乙氧基苯基)-兔啩。該粗產 物藉由閃蒸層析法(PE :EtOAc 6:4)予以純化俾以提供該標題化 5 合物。 [Μ+Η]+=483·6 實施例62 1-[4-環己基-4-羥基-3-(2-甲氧甲苄基丁 基】-4-(4-氟基-2-甲氧基苯基)_哌畊The method described as compound 2b was used to prepare the title compound, but compound 61b was used instead of 1- (2-trifluoromethoxyphenyl) -propane-2-one. The procedure was generally completed and purified to provide the title compound. 4-cyclohexyl-4-gas-3- (2-fluorenylbenzyl V butyraldehyde (compound 61d) 20 This procedure was described as compound le to obtain the title compound, but compound 61c was used instead of compound Id As a starting material. The title product was used in the next step without further purification. 1- "4-Cyclohexyl-3- (2-fluorenylsulfonyl) -4-oxobutyl 1-4- (4-Fluoro-2-fluorenylbenzylpiperon 110 200406394 This method was used to prepare the title compound described as the compound of Example 1 but using compound 61d instead of compound le and 1- (4-fluoro Substituted for 2- (2-methoxyoxyphenyl) substrate instead of (2,2,2-trifluoroethoxyphenyl) -rabbit. The crude product was obtained by flash chromatography (PE: EtOAc 6: 4). The amidine was purified to provide the title compound. [M + Η] + = 4833.6 Example 62 1- [4-Cyclohexyl-4-hydroxy-3- (2-methoxymethylbenzylbutyl)]- 4- (4-fluoro-2-methoxyphenyl) _pigen

使用被描述作為化合物1c之該方法以合成該標題化合 10物’但起始自實施例61之該化合物代替化合物lb。在一般的 完成程序（work-up procedure)後分離出該標題化合物。 [Μ+Η]+=485·5 實施例63 1[5-(2,3-二羥-1，4-苯並戴奥辛基）】-4_[4-環己基 -3-(2-甲氧甲苄基)_4_侧氧丁基卜哌畊 15 使用被描述作為實施例1之該化合物之該方法以製備該The method described as compound 1c was used to synthesize the title compound 10 but the compound starting from Example 61 was used instead of compound lb. The title compound was isolated after a general work-up procedure. [Μ + Η] + = 485 · 5 Example 63 1 [5- (2,3-Dihydroxy-1,4-benzodioxinyl)]-4_ [4-cyclohexyl-3- (2-methoxy (Methylbenzyl) -4-oxobutybupropion 15 This method using the compound described as Example 1 to prepare the

標題化合物，但使用化合物61d代替化合物le且二 羥-1，4-苯並戴奥辛基)]_哌畊代替卜(2,2,2_三氟乙氧基苯基)_哌 丼°玄粗產物藉由閃蒸層析法予以純化俾以提供該標題化合 物。 20 [Μ+Η]+=493·7 實施例64 Η4-環己基_4_羥基_3_(2_甲氧甲苄基卜丁 基]-4-(2,3-二羥苯並戴奥辛基)哌讲 使用被描述作為化合物lc之該方法以合成該標題化合 物，但起始自實施例63之該化合物代替化合物lb。在一般的 111 200406394 完成程序（work-up procedure)後分離出該標題化合物。 [Μ+Η]+=495·5 實施例65 (RS，SR) 1-[4-環己基_心甲基胺硫基羰基氧基-3_(2-氟苯基)-丁基]-4-(2-甲氧基苯基)_哌畊 5 添加0.073 g的異硫氰酸甲酯至一在0°C下攪拌之配於〇,6The title compound, but using compound 61d instead of compound le and dihydroxy-1,4-benzodiocinyl)] _ pigen instead of (2,2,2_trifluoroethoxyphenyl) _piperidine The product was purified by flash chromatography to provide the title compound. 20 [Μ + Η] + = 493 · 7 Example 64 环 4-Cyclohexyl_4-hydroxy_3_ (2-methoxymethylbenzylbutyl butyl) -4- (2,3-dihydroxybenzodioxinyl) piper The method described as compound lc was used to synthesize the title compound, but the compound starting from Example 63 was used instead of compound lb. The title compound was isolated after a general 111-200406394 work-up procedure. [Μ + Η] + = 495 · 5 Example 65 (RS, SR) 1- [4-Cyclohexyl-cardiomethylaminothiocarbonyloxy-3- (2-fluorophenyl) -butyl] -4 -(2-methoxyphenyl) _piperin 5 Add 0.073 g of methyl isothiocyanate to a mixture stirred at 0 ° C.

ml的吡啶之0.088 g的化合物45e之溶液中。在室溫下攪掉令亥 反應混合物歷時24 h並在l〇〇°C下歷時10小時。在冷卻之後。 將其倒入水中並以EkO予以萃取，以洗條，予以乾燥 (NazSCU)並於真空下予以蒸發至乾燥。藉由閃蒸層析法之純化 10 提供〇.〇4g的該標題產物。 [Μ+Η]+=514·4 實施例66··結合至重組型5-ΗΤ1α受體之放射性配位子 乂·才法：ml of a solution of 0.088 g of compound 45e in pyridine. The reaction mixture was stirred off at room temperature for 24 h and at 100 ° C for 10 hours. After cooling. It was poured into water and extracted with EkO to wash the bars, dried (NazSCU) and evaporated to dryness under vacuum. Purification by flash chromatography 10 provided 0.04 g of the title product. [Μ + Η] + = 514 · 4 Example 66 ·· Radioactive ligand bound to recombinant 5-ΗΤ1α receptor

編碼出針對人類5ΗΤια-血清促進素激導的受體之基因組選 15殖株被安定地轉染至一人類細胞株（HeLa)中。在37°C下，HeLa 細胞在含有10%胎牛血清、見大黴素(01 mg/ml)以及5%二氧 化碳的杜貝可氏改良的依格氏培養基(DMEM)中生長有如單一 層。藉由一細胞刮除器將該等細胞自有95%群集的生長瓶中分 離且予以溶解於冰的5 mM Tris與5 mM EDTA緩衝液中（pH 20 7.4)。均質物在4〇〇⑻ xg，20分鐘下予以離心且將該沉澱丸Genomic selections encoding human 5'Tαα-serotonin-induced receptors were stably transfected into a human cell line (HeLa). At 37 ° C, HeLa cells grew as a single layer in Dubco's Modified Eiger's Medium (DMEM) containing 10% fetal bovine serum, methamycin (01 mg / ml), and 5% carbon dioxide. The cells were separated from a 95% clustered growth bottle by a cell scraper and dissolved in 5 mM Tris and 5 mM EDTA buffer (pH 20 7.4) on ice. The homogenate was centrifuged at 400 × g for 20 minutes and the pellet was pelleted

再散浮於一小體積之冰的5 mM Tris與5 mM EDTA之緩衝液 (pH 7.4)中，並且立即地予以冷凍並貯存在一 7〇。〇下直到使用 之日守。在貫驗那天，將細胞膜再散浮於培育緩衝液中：50 niMResuspend in a small volume of ice in 5 mM Tris and 5 mM EDTA buffer (pH 7.4) and immediately freeze and store at 70. 〇 down until the day of use. On the day of the test, resuspend the cell membrane in incubation buffer: 50 niM

Tns HC1 (ΡΗ 7·4)、2.5 mM MgCl2、10 mM 優降寧（Fargin et al. 112 200406394Tns HC1 (PH 7 · 4), 2.5 mM MgCl2, 10 mM Euganin (Fargin et al. 112 200406394

Nature 3359 358-360, 1988)。在試驗化合物不存在或存在下，該 等細胞膜在30°C下以1 nM [3H]8-OH-DPAT予以培育在一 1 ml 之最終容積中歷時30分鐘。在10 μΜ 5-HT的存在下測定非專 一性的結合。藉由冰的Tris-HC 1緩衝液之添加停止培育並且 5 經由一被0.2%-聚乙稀亞胺（polyethyleneimine)預先處理的 Whatman-GF/B 或 Schleicher_&-Schuell-GF52 過濾器快速過 濾。 B.結果 藉由使用非線性曲線配製程式Allfit (De Lean et al.5 dm，乂 10尸/^/〇/· m E97-E102 (1978)評估該等試驗化合物的親和性 作為該放射性配位子對5-HT1A受體(ICm)專一性結合的抑制作 用。藉由 Cheng 與 Prusoff 的方程式（Cheng γ· c·，Prusoff w. Η 及-ocr/zem·尸/zwm此〇/· 3099-3108 (1973))將該 IC50 值轉換成 一親和性常數(Ki)。 15 紀錄於表1中的結果顯示出被測試的本發明之該等化合物 具有一針對該5-ΗΤ1Α受體之高親和性。 表1 針對5ΗΤ1Α受體之結合親和性 實施例 Ki (nM) 1 1.45 5 8.31 6 3.66 7 7.27 9 1.90 10 1.68 11 3.65 12 3.01 113 200406394 13 0.53 14 0.401 14a 0.878 14b 0.965 15 1.69 16 0.90 17 0.64 18 0.81 19 0.69 20 3.19 21 0.77 22 2.03 23 0.63 24 0.64 25 1.18 26 2.62 27 1.09 28 2.92 29 1.08 30 5.43 31 2.71 32 3.57 33 5.03 34 1.67 35 1.47 36 0,56 37 5.03 39 2.92 40 1.84 42 4.87 44 1.14 45 0.54 46 0.72 47 0.85 48 0.36 114 200406394 實_ 藉由在麻醉的大鼠之膀胱充填所誘發之對於節律性的 膀胱-排尿收縮的效用 A.方法： 使用體重 225-275 g (Crl: CD® (SD) IGS BR，Charles River 5 ItaHa)之雌的Sprague-Dawley大鼠。該等動物以自由取用食物 與水來被飼養並且在22-24QC下被維持在一強制的12-小時交 替的明亮-黑暗週期歷時至少一週，除了實驗期間之外。依據 Dray 的方法（Dray J” Ρ/ζα/"而13； 157, 1985)，與一 些如在 Guarneri (Guarneri，P/mrmwo/. ^2:173, 1993)中的 10 修飾來評估對於在節律性的膀胱排尿收縮上的活性。簡言之， 大鼠經由皮下注射1.25 g/kg (5 ml/kg)胺甲酸乙脂被麻醉，之 後使用經裝滿生理食鹽水之PE 50聚乙烯管經由尿道對膀胱 作插管。將該導管以一結紮線連繫於外尿道口周圍之處並予以 連接至傳統壓力轉換器（StathamP23 ID/P23 XL)。膀胱内的壓 15力被連績地顯示在一圖紀錄器上(Battaglia Rangoni KV 135與 DCI/TI放大裔）。接而該膀胱經由紀錄導管以增加量的溫鹽水 (37°C)予以裝滿直至膀胱-排尿收縮反射產生（通常0.8^5 ml)。為了作生物活性化合物之靜脈内注射，裝滿生理食鹽水之 PE 50聚乙烯管被插入至頸靜脈内。 2〇 自膀胱壓力描記圖中，紀錄在治療之前（基礎值）與之後15 分鐘的收縮次數，以及這些收縮的平均振幅（波峰的平均高度 以mmHg表示）被評估出來。 因為大多數的化合物產生一在開始時相對快速的效用並且 導致一完全的膀胱收縮停止，生物活性藉由測量膀胱靜止的期 115 200406394 間（亦即，當無收縮發生時，時間的長度）被方便地估計出來。 在收縮次數上顯示出較在基礎期間所觀察到的有高過30%的一 個降低之被測試的動物之數目亦被紀錄下來。Nature 3359 358-360, 1988). In the absence or presence of test compounds, these cell membranes were incubated at 30 ° C with 1 nM [3H] 8-OH-DPAT in a final volume of 1 ml for 30 minutes. Non-specific binding was determined in the presence of 10 μM 5-HT. Incubation was stopped by the addition of iced Tris-HC 1 buffer and 5 quickly filtered through a Whatman-GF / B or Schleicher_ & -Schuell-GF52 filter pretreated with 0.2% -polyethyleneimine. B. Results By using the non-linear curve formulation program Allfit (De Lean et al. 5 dm, 乂 10 dead / ^ / 〇 / · m E97-E102 (1978) to evaluate the affinity of the test compounds as the radiological coordination Inhibitor of 5-HT1A receptor (ICm) specific binding. By Cheng and Prusoff's equation (Cheng γ · c ·, Prusoff w. Η and -ocr / zem · cad / zwm this 〇 / · 3099- 3108 (1973)) converts this IC50 value to an affinity constant (Ki). 15 The results recorded in Table 1 show that the compounds of the invention tested have a high affinity for the 5-ΗΤ1Α receptor Table 1 Binding Affinity to 5T1A Receptor Example Ki (nM) 1 1.45 5 8.31 6 3.66 7 7.27 9 1.90 10 1.68 11 3.65 12 3.01 113 200406394 13 0.53 14 0.401 14a 0.878 14b 0.965 15 1.69 16 0.90 17 0.64 18 0.81 19 0.69 20 3.19 21 0.77 22 2.03 23 0.63 24 0.64 25 1.18 26 2.62 27 1.09 28 2.92 29 1.08 30 5.43 31 2.71 32 3.57 33 5.03 34 1.67 35 1.47 36 0,56 37 5.03 39 2.92 40 1.84 42 4.87 44 1.14 45 0.54 46 0.72 47 0.85 48 0.36 114 20 0406394 Actual_ Effect on rhythmic bladder-micturition contraction induced by bladder filling in anesthetized rats A. Method: Use weight 225-275 g (Crl: CD® (SD) IGS BR, Charles River 5 ItaHa) female Sprague-Dawley rats. These animals were reared with free access to food and water and maintained at 22-24 QC for a mandatory 12-hour alternating bright-dark cycle that lasted at least one week, except Outside the experimental period. According to Dray's method (Dray J "P / ζα / " and 13; 157, 1985), and some as in Guarneri (Guarneri, P / mrmwo /. ^ 2: 173, 1993) 10 Modified to evaluate activity on rhythmic bladder contractions. Briefly, rats were anesthetized by subcutaneous injection of 1.25 g / kg (5 ml / kg) ethyl carbamate, and then the bladder was intubated through the urethra using a PE 50 polyethylene tube filled with physiological saline. Connect the catheter with a ligature around the external urethral orifice and connect it to a conventional pressure transducer (Statham P23 ID / P23 XL). The pressure in the bladder is continuously displayed on a chart recorder (Battaglia Rangoni KV 135 and DCI / TI magnifier). The bladder was then filled with a warm saline (37 ° C) via a recording catheter until the bladder-urination contraction reflex (usually 0.8 ^ 5 ml) was generated. For intravenous injection of biologically active compounds, a PE 50 polyethylene tube filled with physiological saline was inserted into the jugular vein. 20 From the bladder plethysmogram, the number of contractions recorded before treatment (basic value) and 15 minutes after treatment, and the average amplitude of these contractions (average height of the peaks expressed in mmHg) were evaluated. Because most compounds produce a relatively rapid utility at the beginning and cause a complete cessation of bladder contraction, the biological activity is measured by measuring the period of bladder rest 115 200406394 (ie, the length of time when no contraction occurs). Easily estimate. The number of animals tested showing a reduction of more than 30% over the number of contractions observed during the basal period was also recorded.

為了比較該試驗化合物在抑制膀胱排尿收縮上的效力，致 5 使收縮消失達一 1〇分鐘的時間（ED1()min)之均等有效劑量 (equieffective doses)藉由使用最小平方方法之線性回歸的方 式被計算出來。在50%之經處理大鼠(ED50)中引起收縮次數減 少大於30%的外插劑量（extrapolated doses)藉由Bliss的方法 (Bliss C. 1.9 Quart J. Pharm. Pharmacol 旦，192-216，1938)被估 l〇 算出來。 經胺曱酸乙脂麻醉的大鼠之膀胱快速膨脹引起一連串的有 節律性的膀胱排尿收縮，它的特徵已經被描述出來（Maggi et al.? Brain Res. 380:83, 1986; Maggi et al.? J. Pharmacol Exp. 15 500, 1984)。這些收縮的頻率系有關於排尿反射之感In order to compare the efficacy of the test compound in inhibiting urinary contraction in the bladder, the equivalent effective doses of 5 times (ED1 () min) that caused the contraction to disappear for a period of 10 minutes were determined by linear regression using the least square method. The way is calculated. Extrapolated doses causing greater than 30% reduction in contractions in 50% of treated rats (ED50) by Bliss (Bliss C. 1.9 Quart J. Pharm. Pharmacol Dan, 192-216, 1938 ) Estimated 10 calculated. Rapid swelling of the bladder in rats anesthetized with ethidate causes a series of rhythmic bladder contractions, and its characteristics have been described (Maggi et al.? Brain Res. 380: 83, 1986; Maggi et al J. Pharmacol Exp. 15 500, 1984). The frequency of these contractions is related to the feeling of urination reflex

覺傳入肢與排尿中樞的健全，然而它們的振幅端視反射傳出肢 的功能而定。在此模式系統中，主要地作用在中樞神經系統上 的化合物（諸如嗎啡驗）造成在排尿收縮上的阻斷，而作用在逼 尿肌階段的藥物，諸如奥斯必得寧，降低了膀胱收縮的振幅。 20 所獲得的結果被顯示於表2中。 116 200406394 在靜脈内投藥後對於有節律性的膀胱_排尿收縮之效用 實施例 EDiOmin ^g/kg ed5〇 (頻率） ED50 (振幅） π g/ks 實施例45 584 127 n.a. 嗎啡驗 50 30 n.a. 奥斯必得寧 7770 >10000 240 5 n.a·=無活性；波峰之高度無顯著的降低 數據代表ED1Gmin數值（引起收縮消失1〇分鐘的外插劑 量）、EDm)(頻率）數值(在50%之經處理的大鼠中引起收縮次數 減少>30%的外插劑量），以及EDso (振幅）數值(在5〇%之經處理 的大鼠中引起收縮振幅減少30%的外插劑量）。 10 本發明之化合物抑制排尿的頻率，在它們的振幅上不具效用。 實確在口服投藥後之有意識的大鼠中，對於膀胱功能 測量參數之效用 Λ.^τ^ : 使用由Charles River Italia提供的300-400 g之雄性 15 Sprague-Dawley 大鼠[Cd: CD⑧（SD) IGS BR]。該等動物以自 由取用食物與水來予以飼養並且在22-24°C的溫度下維持在一 強制的12-小時-明亮/12-小時-黑暗週期，除了實驗期間之外。 為了定量在意識的大鼠中之泌尿動力參數，依據先前描述的該 操作程序（Guarneri et al.，Pharmacol· Res. 11: 175, 1991)來進行 117 200406394 膀胱壓力描記圖的研究。 簡言之，經由3 ml/kg的Equithenshi溶液（戍巴比特魯 (pentobarbital)30 mg/kg 與水合三氯乙醛（chloral hydrate) 125The sensory afferent limbs and the micturition center are sound, but their amplitude ends depend on the function of the reflex outgoing limbs. In this model system, compounds that act primarily on the central nervous system (such as the morphine test) cause blockages in urination contraction, while drugs that act on the detrusor phase, such as Osbitene, reduce bladder contractions The amplitude. 20 The results obtained are shown in Table 2. 116 200406394 For the rhythmic bladder after intravenous administration _ The effect of micturition contraction Example EDiOmin ^ g / kg ed50 (frequency) ED50 (amplitude) π g / ks Example 45 584 127 na Morphine test 50 30 na Austria Spinetnin 7770 > 10000 240 5 na · = inactive; no significant decrease in the height of the peaks. The data represents the ED1Gmin value (extrapolated dose that causes the contraction to disappear for 10 minutes), EDm) (frequency) value (within 50% Induced contraction frequency reduction > 30% extrapolated dose in treated rats) and EDso (amplitude) value (extrapolated dose caused 30% reduction in contractile amplitude in 50% of treated rats). 10 The compounds of the present invention inhibit the frequency of urination and are not effective in their amplitude. Indeed, in conscious rats after oral administration, the effect on measurement parameters of bladder function Λ. ^ Τ ^: 300-400 g male 15 Sprague-Dawley rats provided by Charles River Italia [Cd: CD⑧ (SD) IGS BR]. The animals were reared with free access to food and water and maintained at a temperature of 22-24 ° C for a mandatory 12-hour-bright / 12-hour-dark cycle, except during the experimental period. In order to quantify the urodynamic parameters in conscious rats, a study of 117 200406394 bladder plethysmography was performed according to the previously described procedure (Guarneri et al., Pharmacol. Res. 11: 175, 1991). Briefly, via 3 ml / kg of Equitenshi solution (pentobarbital 30 mg / kg and chloral hydrate 125

mg/kg)之腹膜内的投藥將大鼠麻醉並安置於一仰臥的姿勢。在 5 弟彳毛的過程中產生一大約1 Ο-mm長的中線切開線並清理腹 壁。將膀胱(urinary bladder)小心的自黏附的組織中脫開，排空 並接而使用一已經被絲線永久地缝合之聚乙烯套管 (cannula)(0.58-mm内部直徑，〇.96-mm外部直徑）經由一在膀胱 主體的切開線予以套管穿刺。經由一在後肩肝區域的皮下通道 10 使該套管趨於向外，而其被連接至一塑膠製的轉接器為了避免 被該動物移動的危險。為了藥物試驗，該大鼠在移植後被使用mg / kg). The rats were anesthetized and placed in a supine position. A midline incision of approximately 10-mm length was produced during the process of 5 younger hairs and the abdominal wall was cleared. The bladder (urinary bladder) was carefully disengaged from the adherent tissue, drained and connected using a polyethylene cannula (0.58-mm internal diameter, 0.96-mm external) that had been permanently sutured with silk thread. Diameter) The cannula is punctured through an incision in the body of the bladder. The cannula is directed outward through a subcutaneous channel 10 in the region of the rear shoulder liver, and it is connected to a plastic adapter to avoid the danger of being moved by the animal. For drug testing, the rat is used after transplantation

在實驗的那一天，該大鼠被安置於一經修改的Bollman蘢 子中，亦即，大到足以允許該大鼠採取一正常的蹲伏姿勢，但 15 狹窄到足以防止四處翻轉的限定籠子（restraining cages)中。在 一約20分鐘的安定期間之後，該膀胱套管的閒置尖端經由— T-型管被連接至一壓力轉換器（statham P23XL)與一用來以— 0.1 ml/minute的固定速率連續注入一溫的（37CC)鹽水溶液至該 膀胱中的螺動幫浦（Gilson minipuls 2)。在注入鹽水至該膀胱的 2〇 期間，管腔内的壓力訊號被連續地紀錄在一多項紀錄器 (^ctigrapli^gK San-ei with BM614/2 amplifier from'^omedixa] Mangoni)|上。該腠麻懕力描記圖被用來評估膀胱容積容量（BVC> 與排尿壓力（MP)的泌尿動力參數。BVC (ml)被定義為誘導逼尿 肌收縮繼而排尿所必需的被注入至該膀胱中的鹽水容積。 118 200406394 MP(mmHg)被定義為經由在排尿時收縮所造成的最大膀胱内的 壓力。基礎的BVC與MP數值被評估為在該膀胱壓力描記圖中 所觀察到的在一開始的30-60分鐘期間所紀錄的數值之平均 值。在測定基礎的BVC與MP之後，注入被中斷而該試驗化 5 合物藉由一胃管被口服地投藥。膀胱注入被繼續且在BVC與 MP上的變化自在治療之後，經過1、2、3、4以及$小時期 間所觀察到的在該膀胱壓力描記圖上所獲得的平均數值而被 評估出來。化合物以一 2 ml/kg的量被投藥且對照動物組口服 地接受相同數量的載劑（0.5%甲基纖維素，配於水中）。 10 統計學上的分析 數據被表示為平均值±表準誤差。BVC與MP相對於基礎 值之百分比變化，以及BVC與MP(在時間”χ”之BVC或MP 減去基礎值）之△數值（差別在ml或mmHg)，亦針對各個 rat/time而被估算出來。數據被紀錄為相對於基礎值之％變化。 15 在BVC與MP數值，以及在△數值上之統計學上的分析 藉由S.A.S./STAT軟體，6.12版本來被進行。在載劑（對照組） 與試驗治療之間所觀察到的差異在BVC與MP之△數值上被估 算出來’而在不同的時間下相對於基礎值之該等數值之間的差 異在原始的BVC與MP數據上被分析出來。 20寬—难例逆經由8-OH-DPAT在大鼠中所誘發之 的抑制作用（突觸後的拮抗作用） 5_HTw受體拮抗劑在經由於大鼠中8-OH-DPAT之皮下注 射所誘^之刻板的即板舉動上之抑制效用藉由具有如在下面 119 200406394 所描述之微小修飾的Tricklebank之方法（Tricklebank et al.5 J. Pharmacol., 117； 15, 1985)而被評估出來。On the day of the experiment, the rat was housed in a modified Bollman mule, that is, large enough to allow the rat to assume a normal crouching position, but 15 a confined cage narrow enough to prevent turning around ( restraining cages). After a stabilization period of about 20 minutes, the idle tip of the bladder cannula was connected via a T-shaped tube to a pressure transducer (statham P23XL) and a continuous injection at a fixed rate of -0.1 ml / minute- Warm (37CC) saline solution to the Gilson minipuls 2 in the bladder. During the 20th period of saline injection into the bladder, the pressure signal in the lumen was continuously recorded on a number of recorders (^ ctigrapli ^ gK San-ei with BM614 / 2 amplifier from '^ omedixa] Mangoni) |. The ramie force plethysmogram is used to evaluate the urodynamic parameters of bladder volume capacity (BVC) and micturition pressure (MP). BVC (ml) is defined as being necessary to induce detrusor contraction and then urinate into the bladder The volume of saline in the medium. 118 200406394 MP (mmHg) is defined as the maximum bladder pressure caused by contraction during urination. The basic BVC and MP values were evaluated as observed in this bladder plethysmogram. The average of the values recorded during the first 30-60 minutes. After the determination of basic BVC and MP, the injection was interrupted and the test compound was administered orally through a gastric tube. Bladder injection was continued and Changes in BVC and MP have been evaluated after treatment, with the mean values obtained on the bladder plethysmogram observed during 1, 2, 3, 4 and $ hours. The compound was measured at -2 ml / kg. The amount was administered and the control animal group received the same amount of vehicle (0.5% methylcellulose in water) orally. 10 Statistical analysis data were expressed as mean ± standard error. BVC vs MP to The percentage change of the base value and the delta value of BVC and MP (BVC or MP minus the base value at time "χ" minus the difference in ml or mmHg) are also estimated for each rat / time. Data are recorded Is a% change from the base value. 15 Statistical analysis of BVC and MP values and △ values was performed by SAS / STAT software, version 6.12. In vehicle (control group) and trial treatment The observed differences between the BVC and MP values are estimated 'and the differences between these values relative to the base value at different times are analyzed on the original BVC and MP data. 20 Kuan-Difficult to reverse the inhibitory effect induced by 8-OH-DPAT in rats (postsynaptic antagonism) 5_HTw receptor antagonists are induced by subcutaneous injection of 8-OH-DPAT in rats The inhibitory effect of the stereotyped slab behavior was evaluated by the method of Tricklebank with a slight modification as described in 119 200406394 below (Tricklebank et al. 5 J. Pharmacol., 117; 15, 1985).

使用來自Charles River Italia之體重150-175 g的雄性 Sprague-Dawley 大鼠[Crl: CD⑧（SD) IGS BR]。該等動物以自 5 由取用食物與水來予以飼養並且在22-24°C的溫度下維持在一 強制的12-小時-明亮/12_小時-黑暗週期。在實驗的那一天，在 載劑或被試驗的化合物之投藥的前10-15分鐘，該等大鼠被個 別地安置在透明的塑膠容器中。為了評估在口服投藥之後拮抗 劑的活性，該等化合物在藉由8-〇H-DPAT(l mg/kg，皮下地） 10之刻板症的誘導前1與4小時被投藥。觀察期持續3〇秒並在 8-OH-DPAT治療後3分鐘被開始且超過一 15分鐘的期間每3 分鐘被重複。150-175 g male Sprague-Dawley rats [Crl: CD [(SD) IGS BR] from Charles River Italia were used. The animals were reared with free food and water and maintained at a temperature of 22-24 ° C for a mandatory 12-hour-bright / 12_hour-dark cycle. On the day of the experiment, the rats were individually placed in transparent plastic containers 10-15 minutes before the administration of the vehicle or the tested compound. To evaluate the activity of the antagonists after oral administration, the compounds were administered 1 and 4 hours before the induction of stereotypes by 8-OH-DPAT (1 mg / kg, subcutaneously) 10. The observation period lasted 30 seconds and was started 3 minutes after 8-OH-DPAT treatment and repeated every 3 minutes over a period of 15 minutes.

經由5-HT1A受體之突觸後的刺激所誘發之症狀的出現被 註明出來，且強度利用一強度等級來被評分，其中：〇 =缺少 15的、1 =不明確的、2 =有的，而3 =強烈的。針對經處理的 大鼠之行為的分數被累積遍及整個觀察時間（5個觀察期）並且 被表示為4 rats/d〇se之平均值。與對照組（載劑）相較之下，在 經處理的動物之平均值上的改變，被表示如百分比抑制作用， 被用來定量拮抗劑活性。 20 B.結果 所獲传的結果被顯示於表3中。 本發明之化合物’特別地實施例45，顯示出由l〇h_DPAT 所誘發的刻板症之有效的且長久持續的抑制效用。 120 200406394 表 3 藉由8-OH-DPAT在大鼠中所誘發之即板舉動的抑制 作用（突觸後的拮抗作用） 實施例 劑量 即板舉動之抑制作用百分 比 (mg/kg ρ·ο·) 1 h 4 h 實施例16 10 40 17 實施例31 10 60 18 實施例45 10 100 81 實施例47 10 56 58 實施例48 10 90 74The occurrence of symptoms induced by post-synaptic stimulation through the 5-HT1A receptor is noted, and the intensity is scored using an intensity scale, where: 0 = missing 15, 1 = ambiguous, 2 = yes , And 3 = strong. The scores for the behavior of the treated rats were accumulated over the entire observation time (5 observation periods) and expressed as an average of 4 rats / dose. Changes in the mean value of treated animals compared to the control group (vehicle), expressed as percentage inhibition, are used to quantify antagonist activity. 20 B. Results The results obtained are shown in Table 3. The compound of the present invention, particularly Example 45, showed an effective and long-lasting inhibitory effect of stereotypes induced by 10h_DPAT. 120 200406394 Table 3 Inhibition of plate behavior (post-synaptic antagonism) induced by 8-OH-DPAT in rats Example dose is the percentage of plate behavior inhibition (mg / kg ρ · ο · ) 1 h 4 h Example 16 10 40 17 Example 31 10 60 18 Example 45 10 100 81 Example 47 10 56 58 Example 48 10 90 74

I：圖式簡單說明】 5 無 【圖式之主要元件代表符號表】 無I: Schematic description] 5 None [The main components of the diagram represent the symbol table] None

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Claims (1)

200406394 拾、申請專利範圍： 1. 一種具有通式I之化合物：200406394 Scope of patent application: 1. A compound with general formula I: 其中： 5 R係代表一氫原子或一或更多選自於下列之取代基：鹵素 原子與(c「c6)-烷基、（crc6)·烷氧基、（crc6)-烷硫基、羥 基、（c2-c6)-稀基、（c2-c6)-炔基、（crc6)-i烷基、（crc6)-鹵烷氧基、（crc6)-羥烷基、烷氧烷基、硝基、胺基、（crc6)-胺烧基、（C1-C6)-烧胺基-(C!-C6)-烧基、（C1-C6)-烧胺基、二 10 -(Ci-C^)-烧胺基、酿胺基、（Ci_C6)-烧續基胺基、胺續酿 基、（CrC6)-烷胺磺醯基、氰基、胺羰基、N-(CrC6)-烷胺羰 基、N，N-二-(CrC6)-烷胺羰基、（CrC6)-烷氧羰基、（CrC6)· 烷羰基、烷羰烷基、甲醯基、烷醯基氧基烷基、（crc6)-烷 胺羰基胺基、（CkQ)-烷亞磺醯基、（crc6)-烷磺醯基以及 15 N，N-二- (Ci-C^) -烧胺石黃酿基基團， Ri係代表一氫原子或一或更多選自於下列之取代基：環烧 基、芳基、芳氧基、芳烷基、芳烷氧基、雜環狀基、雜環 氧基、雜環烷基以及雜環烷氧基基團，各個基團被選擇性 的取代以一或更多如上面所界定之取代基R; 20 Q 代表一化學式-C(O)-、-CH(OH)-或-CH(OR2)-之基團， 122 200406394 ίο 15 20 其中R2代表一（CrC6)-烷基、（C2-C6)-烯基、（C2-C6)-炔基或 環烷基基團，其各個係被選擇性取代以一或更多被擇自於 R5與R6之基團，其中R5代表一鹵素原子或一（crc6)-烷氧 基、（CrC6)-鹵烷氧基、氰基、（CrC6)-烷氧羰基、（CkQ)-烷羰基、烷氧烷基、胺羰基、N-(CrC6)-烷胺羰基或N，N-二-(CrC6)-烷胺羰基基團，而R6代表一芳基、雜芳基、芳 氧基、雜芳氧基、芳烷氧基或雜芳烷氧基基團，其各個係 被選擇性取代以一個如上面所界定之基團R，或R2代表一 化學式·(：(0)- (CrC6)-烷基、-C(0)0-(CrC6)-烷基、 -C(0)NR7R8或-C(S)NR7R8之基圑，其中117與&8每一者分 別地代表一氫原子或一（CrCJ-烷基基團； R3代表一氫原子或一（crc6)-烷基、（c2-c6)-烯基、（c2-c6)-炔基、環烷基、芳基或雜環狀基團，各個基團係被選擇性 取代以一或更多如上面所界定之取代基R或R!; R4代表一芳基或雜環狀基團，各個係被選擇性取代以一或 更多如上面所界定之取代基R; A代表一鍵或一亞甲基或伸乙基基團；以及 η 二 1 或 2， 但有條件是排除化合物，其中同時地Q代表-C(O)-或 -CH(OH)- ; R代表一氫原子或一或更多鹵素原子或烷基、 烷氧基、鹵烷基、硝基、胺基、烷胺基或二-烷胺基團；Rj 代表一氫原子、一未經取代之苯基基團或一經取代以一或 更多鹵素原子或烷基或烷氧基基團之苯基基團；R4代表一 未經取代之芳基或雜芳基基團或一芳基或雜芳基基團經取5 R represents a hydrogen atom or one or more substituents selected from the group consisting of a halogen atom and (c "c6) -alkyl, (crc6) · alkoxy, (crc6) -alkylthio, Hydroxyl, (c2-c6) -diluted, (c2-c6) -alkynyl, (crc6) -i alkyl, (crc6) -haloalkoxy, (crc6) -hydroxyalkyl, alkoxyalkyl, Nitro, amine, (crc6) -aminoalkyl, (C1-C6) -alkylamino- (C! -C6) -alkyl, (C1-C6) -aminoamine, di 10-(Ci- C ^)-Amino-amino, Amino-amine, (Ci_C6) -A-amino-amine, Amine-amine, (CrC6) -Alkylaminesulfonyl, cyano, aminecarbonyl, N- (CrC6) -alkane Aminocarbonyl, N, N-di- (CrC6) -alkylaminecarbonyl, (CrC6) -alkoxycarbonyl, (CrC6) · alkylcarbonyl, alkylcarbonylalkyl, formamyl, alkylamidooxyalkyl, ( crc6) -Alkylaminocarbonylamino, (CkQ) -Alkylsulfinyl, and (crc6) -Alkylsulfonyl, and 15 N, N-di- (Ci-C ^)-carbamine Ri represents a hydrogen atom or one or more substituents selected from the group consisting of cycloalkyl, aryl, aryloxy, aralkyl, aralkoxy, heterocyclic, heterocyclic, Heterocycloalkyl and heterocycloalkoxy Groups, each group is optionally substituted with one or more substituents R as defined above; 20 Q represents a chemical formula -C (O)-, -CH (OH)-or -CH (OR2)- Group, 122 200406394 ίο 15 20 where R2 represents a (CrC6) -alkyl, (C2-C6) -alkenyl, (C2-C6) -alkynyl or cycloalkyl group, each of which is selective Substitution with one or more groups selected from R5 and R6, where R5 represents a halogen atom or a (crc6) -alkoxy, (CrC6) -haloalkoxy, cyano, (CrC6) -alkane Oxycarbonyl, (CkQ) -alkylcarbonyl, alkoxyalkyl, aminecarbonyl, N- (CrC6) -alkylaminecarbonyl or N, N-di- (CrC6) -alkylaminecarbonyl groups, and R6 represents an aryl group , Heteroaryl, aryloxy, heteroaryloxy, aralkoxy or heteroaralkoxy groups, each of which is selectively substituted with a group R as defined above, or R2 represents a chemical formula (: (0)-(CrC6) -alkyl, -C (0) 0- (CrC6) -alkyl, -C (0) NR7R8 or -C (S) NR7R8 based hydrazone, of which 117 and & 8 each represents a hydrogen atom or a (CrCJ-alkyl group; R3 represents a hydrogen atom or a (crc6) -alkyl, (c2-c 6) -alkenyl, (c2-c6) -alkynyl, cycloalkyl, aryl or heterocyclic groups, each group is selectively substituted with one or more substituents R as defined above or R !; R4 represents an aryl or heterocyclic group, each of which is selectively substituted with one or more substituents R as defined above; A represents a bond or a methylene or ethylene group ; And η di 1 or 2, but with the proviso that compounds are excluded, in which Q represents -C (O)-or -CH (OH)-; R represents a hydrogen atom or one or more halogen atoms or alkyl groups, Alkoxy, haloalkyl, nitro, amine, alkylamino, or di-alkylamine groups; Rj represents a hydrogen atom, an unsubstituted phenyl group, or one substituted with one or more halogen atoms Or an phenyl group of an alkyl or alkoxy group; R4 represents an unsubstituted aryl or heteroaryl group or an aryl or heteroaryl group. 123 200406394 代以一或更多i素原子或烷基、烷氧基、ii素、ii烷基、 硝基、胺基、烧胺基、一烧胺基、經基、雖炫基、 或-NHSCV烷基基團；而R3代表一未經取代之芳基或雜芳 基基團或一芳基或雜芳基基團經取代以一或更多鹵素原子 或烷基、烷氧基、ii素、_烷基、硝基、胺基、烷胺基、 二烷胺基、苯基、ii苯基、烷苯基或烷氧苯基基團； ίο 但有進一步的條件是排除化合物，其中同時地Q代表_C(〇y 或-CH(OH)- ; R代表一氫或鹵素原子或一烷基、烷氧基、 鹵烷基、烷硫基、烯基或炔基基團；&代表一氫原子或_ %烧基或烧基％烧基基團，R4代表一未經取代之芳基或雜 芳基基團或一芳基或雜芳基基團經取代以自一至三個齒素 原子或烧基、烧氧基、ή烧基、烧硫基、婦基或炔基基團； 而R3代表一未經取代之苯基、萘基或環烷基基團，或一笨 基、萘基或環烷基基團經取代以一或二個鹵素原子或烷 基、烧氧基、i素基、巍基、㈣基、縣錢基基團； 或该化合物之一鏡像異構物、光學異構物、非鏡像異構物、 N-氧化物（例如，N-嘴。井氧化物）、結晶形式、水合物、溶劑 化物或藥學上可接受的鹽類。123 200406394 Substitute one or more i atom or alkyl group, alkoxy group, ii element, ii alkyl group, nitro group, amine group, amine group, amine group, meridian group, alkenyl group, or- NHSCV alkyl group; and R3 represents an unsubstituted aryl or heteroaryl group or an aryl or heteroaryl group substituted with one or more halogen atoms or alkyl, alkoxy, ii Element, alkyl, nitro, amino, alkylamino, dialkylamino, phenyl, iiphenyl, alkylphenyl, or alkoxyphenyl groups; but there is a further condition that compounds are excluded, where Simultaneously Q represents _C (〇y or -CH (OH)-; R represents a hydrogen or halogen atom or an alkyl, alkoxy, haloalkyl, alkylthio, alkenyl or alkynyl group; & Represents a hydrogen atom or _% alkyl or% alkyl group, R4 represents an unsubstituted aryl or heteroaryl group or an aryl or heteroaryl group substituted from one to three A halogen atom, or an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, or an alkynyl group; and R3 represents an unsubstituted phenyl, naphthyl, or cycloalkyl group, or Benzyl, naphthyl or cycloalkyl The group is substituted with one or two halogen atoms or an alkyl group, a carboxy group, an i-synyl group, a stilbyl group, a fluorenyl group, or a oxanyl group; or a mirror image isomer, optical isomer, or Mirror isomers, N-oxides (eg, N-mouth. Well oxides), crystalline forms, hydrates, solvates, or pharmaceutically acceptable salts. 表一環烷基、芳基或雜芳基基團，貝:Table 1 Cycloalkyl, aryl or heteroaryl groups, shell: 胺烧基、酿胺基、 l土、i烷氧基、羥烷基、烷氧烷基、烷 烷％醯基胺基、胺磺醯基、烷胺磺醯基、 124 200406394 氰基、胺羰基、N-烷胺羰基、N，N-二烷胺羰基、烷氧羰基、 烷羰基、烷羰烷基、曱醯基、烷醯基氧基烷基、烷胺羰基 胺基、烧亞確隨基、烧橫驢基或Ν,Ν-二烧胺續醯基基團。 3.如申請專利範圍第1項之化合物，其中： 5 R代表一或更多羥基、（CrC6)-鹵烷氧基、（CrC6)-羥烷基、Amine, amino, alkoxy, i-alkoxy, hydroxyalkyl, alkoxyalkyl, alkane% fluorenylamino, sulfanilino, alkaminosulfanyl, 124 200406394 cyano, amine Carbonyl, N-alkylaminocarbonyl, N, N-dialkylaminecarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylalkyl, fluorenyl, alkylfluorenyloxyalkyl, alkylaminocarbonylamino, alkyl A radical, a sulfonyl group, or a N, N-dialkylamine group. 3. The compound according to item 1 of the scope of patent application, wherein: 5 R represents one or more hydroxyl groups, (CrC6) -haloalkoxy, (CrC6) -hydroxyalkyl, 烧氧烧基、（Ci_C6)-胺烧基、（Ci_C6)_烧胺基-(Ci_C6)_烧基、 酿胺基、（Ci_C6)-烧續酿基胺基、胺績酿基、（Ci_C6)-烧胺石黃 醯基、氰基、胺羰基、N-(CrC6)-烷胺羰基、N，N·二-(CrC6)-烷胺羰基、（CrC6)-烷氧羰基、（CrC6)-烷羰基、烷羰烷基、 10 甲醯基、烷醯基氧基烷基、（crc6)-烷胺羰基胺基、（crc6)- 烷亞磺醯基、（CrC6)-烷磺醯基以及N, N-二-(CrC6)-烷胺磺 醯基基團；或 I代表一未經取代之芳氧基、芳烷基、芳烷氧基、雜環氧 基、雜環烷基或雜環烷氧基基團，或一芳氧基、芳烷基、 15 芳烷氧基、雜環氧基、雜環烷基、雜環烷氧基、芳基、雜Oxygen radical, (Ci_C6) -Amine radical, (Ci_C6) _Amine radical- (Ci_C6) _Atomium radical, (Ci_C6) -Atomium radical, Amine radical, (Ci_C6) ) -Bakelite sulphamate, cyano, amine carbonyl, N- (CrC6) -alkylamine carbonyl, N, N · di- (CrC6) -alkylamine carbonyl, (CrC6) -alkoxycarbonyl, (CrC6) -alkane Carbonyl, alkylcarbonylalkyl, 10methylamido, alkylamidooxyalkyl, (crc6) -alkylaminocarbonylamino, (crc6) -alkylsulfinamidinyl, (CrC6) -alkylsulfinyl, and N , N-di- (CrC6) -alkylaminosulfonyl group; or I represents an unsubstituted aryloxy, aralkyl, aralkoxy, heterocyclooxy, heterocycloalkyl or heterocyclic ring Alkoxy group, or monoaryloxy, aralkyl, 15 aralkoxy, heterocyclooxy, heterocycloalkyl, heterocycloalkoxy, aryl, hetero 環狀基或環烷基基團經取代以一或更多（CrQ)-烷硫基、羥 基、（C2-C6)-烯基、（(：2<6)4夬基、（CKC6)-鹵烷氧基、（CrC6)-羥烷基、烷氧烷基、（CkQ)-胺烷基、（CrC6)-烷胺基-(CrC6)_ 烧基、酿胺基、（Cj-C^)-烧續S&基胺基、胺橫S蠢基、（Ci-Ce)-20 烷胺磺醯基丨氰基、胺羰基、N-(CVC6)-烷胺羰基、N，N- 二烷胺羰基、（crc6)-烷氧羰基、（crc6)-烷羰基、 烷羰烷基、曱醯基、烷醯基氧基烷基、（crc6)-烷胺羰基胺 基、（CrC6)-烷亞磺醯基、（CrC6)-烷磺醯基或N, N-二 -(Ci_C6)-烧胺石黃酿基基團。 125 200406394 4.如申請專利範圍第！或2項之化合物，其中R代表一氯或 南素原子或一（C]-C6)- —氧基、氰基、n,n_:_(Ci_C6)-胺 羰基或（CVQ)-烷氧基烷基基團。 5·如申請專利範圍第4項之化合物，其中尺代表一氯或氣原 子或-個三氟甲氧基、氛基、Ν，Ν_:甲胺幾基或甲氧甲基 基團。 6·如申請專利範圍第4或5項之化合物，其中該取代基义附 聯在該苯基基團的2號位置。 7.如申請專鄕圍第卜2或4至6項中任何—項之化合物， 其中R3代表-氫原子或一（CrC6)_院基、（C2_c6)·稀基、 (q-c：6)-炔基基團，各個基團係被選擇性取代以一或更多如 在申請專利範圍第1項中所界定之取代基。 8·如申請專利範㈣7項之化合物，其t &代表一氫原子或 甲基、乙基、丙基、異丙基、丁基、異丁基、三級丁基、 乙烯基、稀丙基、丙-1-稀基、1-甲基乙稀基、2-甲基稀丙 基、乙炔基或丙-1-炔基基團。 9.如中請專利範圍第1、2或4至6項中任何—項之化合物， 其中R3代表一環己基或2-噻吩基基團。 10·如申請專利範圍第卜2或4至9項中任何一項之化合物， 其中I代表一未經取代之雜環狀基團或一苯基基團經取代 乂或更多鹵素原子或（Cl-C士烧基、士烧氧基或 (Ci-Q)-鹵烷氧基基團。 η·如申請專利範圍帛10項之化合物，其巾&代表— 二羥-1，4-苯並戴奥辛基）、4_吲哚基、8_喳啉基、孓甲氧基 126 200406394 苯基、2,6-二曱基苯基、4-氟基-2-曱氧基苯基或2-(2,2,2_ 二氟乙氧基)-苯基基團。 12 ·如申晴專利範圍第1、2或4至11項中任何一項之化合物， 其中 Q 代表一化學式-C(O)-、-CH(OH)-、-CH(OR2)、 5 烷基）、-CH(0-C(0)0-(CrC6)-烷基）、 -CH(0-C(0)NR7R8)或-ch(o-c(s)nr7r8 之基團，其中 R2 代表一（CrC6)-烷基、（c2-c6)-烯基或(CrC6)-炔基基團，且Cyclic or cycloalkyl groups are substituted with one or more (CrQ) -alkylthio, hydroxyl, (C2-C6) -alkenyl, ((: 2 < 6) 4fluorenyl, (CKC6)- Haloalkoxy, (CrC6) -hydroxyalkyl, alkoxyalkyl, (CkQ) -aminoalkyl, (CrC6) -alkylamino- (CrC6) _alkyl, amine, (Cj-C ^ ) -Continuous S & amino, amine sulfonyl, (Ci-Ce) -20 alkylaminosulfonyl, cyano, amine carbonyl, N- (CVC6) -alkylamine carbonyl, N, N-di Alkylaminocarbonyl, (crc6) -alkoxycarbonyl, (crc6) -alkoxycarbonyl, alkoxyalkyl, fluorenyl, alkanoyloxyalkyl, (crc6) -alkylaminecarbonylamino, (CrC6)- Alkylenesulfinyl, (CrC6) -alkanesulfanyl, or N, N-di- (Ci_C6) -carbosulfanite group. 125 200406394 4. If the compound of the scope of patent application! Or 2 items, Wherein R represents a chlorine or a southern atom or a (C] -C6) -oxy, cyano, n, n _: _ (Ci_C6) -aminocarbonyl or (CVQ) -alkoxyalkyl group. 5 The compound according to item 4 of the scope of patent application, wherein the ruler represents a chlorine or gas atom or a trifluoromethoxy group, an aryl group, N, N_: a methylamine group or a methoxymethyl group. For the compound in the scope of patent application No. 4 or 5, the substituent is attached at the position 2 of the phenyl group. 7. If you apply for a compound in any one of No. 2 or 4 to 6 Where R3 represents a -hydrogen atom or a (CrC6) _yuan group, (C2_c6) · diluted group, (qc: 6) -alkynyl group, each group is selectively substituted with one or more as in the application Substituents defined in item 1 of the patent scope. 8. As for the compound in item 7 of the patent application, t & represents a hydrogen atom or methyl, ethyl, propyl, isopropyl, butyl, isobutyl Group, tertiary butyl, vinyl, dipropyl, prop-1-yl, 1-methylethlyl, 2-methyl dipropyl, ethynyl or prop-1-ynyl group. 9 The compound of any one of the items in the patent scope 1, 2, or 4 to 6, wherein R3 represents a cyclohexyl or 2-thienyl group. 10. In the scope of patent application scope 2 or 4 to 9 A compound according to any one of which, I represents an unsubstituted heterocyclic group or a phenyl group substituted with fluorene or more halogen atoms or (Cl-C sulfonyl, sulfonyl, or (Ci- Q) -halane Η. For example, for compounds with a scope of 10 patent applications, the & representative-dihydroxy-1,4-benzodioxinyl), 4-indolyl, 8-fluorinyl, fluorenylmethoxy Group 126 200406394 phenyl, 2,6-difluorenylphenyl, 4-fluoro-2-methoxyoxyphenyl or 2- (2,2,2-difluoroethoxy) -phenyl group. 12 · A compound as claimed in any of items 1, 2, or 4 to 11 in the scope of Shen Qing's patent, where Q represents a chemical formula -C (O)-, -CH (OH)-, -CH (OR2), 5 alkane Group), -CH (0-C (0) 0- (CrC6) -alkyl), -CH (0-C (0) NR7R8), or -ch (oc (s) nr7r8, where R2 represents a (CrC6) -alkyl, (c2-c6) -alkenyl or (CrC6) -alkynyl groups, and R7與Rs中每一者分別地係代表一氫原子或—（CrC6)_烧基 基團。 10 13·如申請專利範圍第12項之化合物，其中Q代表一幾基、經 亞基甲基、甲氧基亞甲基、乙氧基亞甲基、丙氧基亞曱基、 婦丙氧基亞甲基、丙-2-炔基氧亞甲基、乙酿氧基亞曱基、 甲氧基羰氧基亞曱基、胺羰基氧基亞曱基、N_乙胺羰基氧 亞甲基或N-甲胺硫羰基氧基亞甲基基團。 15 I4·如申請專利範圍第1項之化合物，該化合物係為下列中之 一者： • 1-[4_環己基-3-(2-氟苯基)-4-甲氧丁基；μ4-[2-(2,2,2_三氟 乙氧基)-苯基]-哌畊； • ^(心氟基甲氧基苯基)-4-[4-氧-3-(2-三氟甲氧基苯 20 基)-戊基]-哌啫； • 1-(4_氟基甲氧基苯基)-4-[‘羥基-3-(2-三氟甲氧基苯 基)-戊基]-σ底畊； • 1-[5仏3-二經-154-苯並戴奥辛基)]|[4秦3必三氣甲 氧基苯基)-戊基]-哌畊； 127 200406394 • 1-[5-(2,3-二羥-l，4-苯並戴奥辛基）]-4_屮羥基_3_(2_三 氟甲氧基苯基)-戊基]-哌畊； • 二羥-I，4-苯並戴奥辛基）>4_ [‘經基1(2_三 氟甲氧基苯基)-己基]-哌畊； • ^[5-(2,3-二羥-1，4-苯並戴奥辛基心[4·羥基_3_(2_三氟 曱氧基苯基)-己-5-烯基]-哌畊； • HM2,3-二經-I，4-苯並戴奥辛基）]-4-[4_羥基j曱基 -3-(2-三氣曱氧基苯基)-己基]-η底啡； ίο • 1-[5-(2,3-二經-1，4-苯並戴奥辛基)]冰[4-甲氧基_3_(2二 氟甲氧基苯基)-5-己烯基]·哌畊； • 1-[5-(2,3-二經-1，4-苯並戴奥辛基）]冬[(‘曱氧基_3_苯 基)-庚基]-哌讲； • 1-[5-(2,3-二經-1，4-苯並戴奥辛基）]|[(4-曱氧基_3_苯 基)-戊基]-哌畊； 15 • 1-[5-(2,3-二經-1，4-苯並戴奥辛基)]-4-[(4-丙氧基_3-苯 基)-庚基]-哌畊； • 1-[3-(2-氰苯基）-4-環己基-4-氧-丁基]_4-[5-(2,3-二經 -1，4-苯並戴奥辛基)]·哌。井； • (RS，SR)-l-[3-(2-氰苯基)-4-環己基-4-羥 丁基]_4-[5-(253- 20Each of R7 and Rs represents a hydrogen atom or a-(CrC6) -alkyl group, respectively. 10 13. The compound according to item 12 in the scope of patent application, in which Q represents a dimethyl group, a methylene group, a methoxymethylene group, an ethoxymethylene group, a propoxyfluorenylene group, and a propionyloxy group Methylene, prop-2-ynyloxymethylene, ethynyloxymethylene, methoxycarbonyloxymethylene, aminocarbonyloxymethylene, N-ethylaminocarbonyloxymethylene Or N-methylaminethiocarbonyloxymethylene group. 15 I4. If the compound in the scope of patent application is the first one, the compound is one of the following: • 1- [4-cyclohexyl-3- (2-fluorophenyl) -4-methoxybutyl; μ4 -[2- (2,2,2-trifluoroethoxy) -phenyl] -piperon; • ^ (cardiofluoromethoxymethoxyphenyl) -4- [4-oxo-3- (2- Trifluoromethoxybenzene 20-yl) -pentyl] -piperidine; • 1- (4-fluoromethoxymethoxyphenyl) -4-['hydroxy-3- (2-trifluoromethoxyphenyl ) -Pentyl] -σ subsoil; • 1- [5 仏 3-Dijing-154-Benzodioxinyl)]] | [4Qin 3 Bistrisylmethoxyphenyl) -pentyl] -pipeline ; 127 200406394 • 1- [5- (2,3-Dihydroxy-l, 4-benzodioxinyl)]-4_ 屮 hydroxy_3_ (2_trifluoromethoxyphenyl) -pentyl]- Pipen; • Dihydroxy-I, 4-benzodiocinyl) > 4_ ['Cyclo 1 (2-trifluoromethoxyphenyl) -hexyl] -pipen; • ^ [5- (2, 3-Dihydroxy-1,4-benzodioxinyl [4 · hydroxy_3_ (2_trifluoroamidooxyphenyl) -hex-5-enyl] -pigenin; HM2,3-Dijing -I, 4-Benzodioxinyl]]-4- [4-hydroxyj-fluorenyl-3- (2-trifluorocarbyloxyphenyl) -hexyl] -η-dimorphine; 1- [5- (2,3-Dijing-1,4-Benzodioxinyl)] ice [4-form _3_ (2difluoromethoxyphenyl) -5-hexenyl] · pigeng; • 1- [5- (2,3-Dijing-1,4-benzodioxinyl)] winter [ ('Methoxy_3_phenyl) -heptyl] -piperidine; • 1- [5- (2,3-Dijing-1,4-Benzodioxinyl)] | [(4-fluorenyloxy -3_phenyl) -pentyl] -piperin; 15 • 1- [5- (2,3-Dijing-1,4-benzodioxinyl)]-4-[(4-propoxy _3-phenyl) -heptyl] -piperin; • 1- [3- (2-cyanophenyl) -4-cyclohexyl-4-oxo-butyl] _4- [5- (2,3- Dijing-1,4-benzodiocinyl)] piper. Well; • (RS, SR) -l- [3- (2-cyanophenyl) -4-cyclohexyl-4-hydroxybutyl] _4- [5- (253-20 二經-1，4-苯並戴奥辛基)]-f σ井； • (RS)-l-[3-(2-氰苯基)-4-環己基-4-羥丁基]_4_[5-(2,3-二 羥-M-苯並戴奥辛基)]_哌讲； • (SR)-l-[3-(2-氰苯基）-4-環己基-4-羥丁基]_4_[5-(2,3-二 經-1，4-苯並戴奥辛基)]_σ底讲；Dijing-1,4-Benzodioxin)]-f σ well; (RS) -1- [3- (2-cyanophenyl) -4-cyclohexyl-4-hydroxybutyl] _4_ [5 -(2,3-Dihydroxy-M-benzodiocinyl)]-Pidenone; • (SR) -l- [3- (2-cyanophenyl) -4-cyclohexyl-4-hydroxybutyl] _4_ [5- (2,3-Dijing-1,4-Benzodioxinyl)] _ σ bottom lecture; 128 200406394 • l-[3-(2-氰苯基)-4-環己基-4-側氧丁基]-4-(4-氟基-2-甲 氧基苯基)-哌畊； • 1-[3-(2-氰苯基）-4-環己基-4-羥丁基]冬(4-氟基-2-甲氧 基苯基)-σ辰啡； 1-(4·環己基-4-甲氧基-3-苯丁基)-4-[5-(2,3·二羥-1，4-苯 並戴奥辛基)]-哌。丼； 1-(4-環己基-4-甲氧基-3-苯丁基)-4-(4-氟基-2-甲氧基苯 基)-。辰°井； 1 (4-環己基-4-乙氧基-3-苯丁基）-4-[5-(2,3-二經-1,4-苯 並戴奥辛基)]-哌啡； 1-(‘環己基-4-乙氧基-3-苯丁基)-4-(4-氟基-2-甲氧基苯 基)-。辰啡； 129 200406394 • l-[5-(2,3-二羥-1，4-苯並戴奥辛基)]-4- (4-羥基-3-苯庚 基井； • 1-[5-(2,3-二羥-M-苯並戴奥辛基)]-4- (4·羥基-3-苯基己 -5 -細基)-嗓ϋ井， 5 · 1-[5-(2,3 -二經-1，4 -本並戴奥辛基)]- 4-(4 -輕基-5-曱基-3_ 苯己基)-°瓜σ井， • 1-[5-(2,3-二說-1，4-本並戴奥辛基）]-4-(4-控基_3-苯戍 基)-哌讲； • 1-[5-(2,3-二沒-1，4·苯並戴奥辛基)]-4· (4-經基-3-苯基庚 10 -5-炔基）-哌啡； • 1-[5-(2,3-二羥-1，4-苯並戴奥辛基)]-4- (4_羥基-3-苯基庚 -5 -卸基)-°底σ井， • (Ε，Ζ)-1-(4-氟基-2-曱氧基苯基)-4-[(‘曱氧基-3-苯基)-庚-5-烯基]-哌讲(上方的TLC rf非對映異構物）， 15 · (Ε，Ζ)-1-(4-氟基-2-甲氧基苯基)-4-[(4-甲氧基-3-苯基)- 庚-5-烯基]-哌讲(上方的TLCrf非對映異構物）， • 1-[5-(2,3-二羥-1,4-苯並戴奥辛基)]-4- (4-羥基-3-苯基己 -5-炔基)-哌讲； • 1-[5-(2,3-二控-1，4-苯並戴奥辛基)]-4- (4_經基-3-苯基庚 20 -6-烯基)-哌π井； • 1-[5-(2,3 -二經-1，4·苯並戴奥辛基）]-4- (4_控基-6-甲基 -3 -苯基庚-5-細基)-ϋ瓜σ井， • Μ5-(2,3·二羥-1，4-苯並戴奥辛基)]-4- (4-羥基-6-曱基 苯庚基)-旅^井， 130 200406394 • 1-[5-(2,3-二沒-1，4-苯並戴奥辛基）]-4-(4-說基-3-苯丁 基井； • (RS，SR)小[5-(2,3-二羥-1，4·苯並戴奥辛基)]-4- (4-羥基 -3-苯戍基)-^u井， • 1-[4-壞己基-3-(2-二甲胺魏基苯基）-4-側氧丁 基]-4-[5-(2,3-二經-1，4·苯並戴奥辛基)]-°底0井， • 1-[4-壞己基-3-(2-二曱胺_炭基苯基）-4-經丁 基]-4-[5-(2,3-二羥-1,4-苯並戴奥辛基)]-哌讲； ίο • 1 -[4-壞己基-3-(2-二甲胺被基苯基）-4-側氧丁基]-4-(4· 氟基-2-曱氧基苯基)-^σ井； • 1-[4-環己基-3-(2-二甲胺羰基苯基）-4-羥丁基]-4-(4-氟 基-2-甲氧基苯基井， • 1-[3-(2-氣苯基)-4-側氧戍基]-4-[5-(2,3-二經-1，4-苯並戴 奥辛基)1-111井； 15 • 1-[4-壞己基-3-(2-二氣甲氧基苯基）-4-側氧丁基]-4-(4_ 吲嗓基)-ϋ^σ井； • (RS，SR) 1-[4-乙醯氧基-4-環己基-3-(2-氟苯基）-丁 基]-4-(2-甲氧基苯基)-°底。丼， 20128 200406394 • l- [3- (2-cyanophenyl) -4-cyclohexyl-4-oxobutyl] -4- (4-fluoro-2-methoxyphenyl) -piperon; • 1- [3- (2-cyanophenyl) -4-cyclohexyl-4-hydroxybutyl] dong (4-fluoro-2-methoxyphenyl) -sigmaphine; 1- (4 · cyclo Hexyl-4-methoxy-3-phenylbutyl) -4- [5- (2,3.dihydroxy-1,4-benzodiocinyl)]-piper.丼; 1- (4-cyclohexyl-4-methoxy-3-phenylbutyl) -4- (4-fluoro-2-methoxyphenyl)-. Chen ° well; 1 (4-cyclohexyl-4-ethoxy-3-phenylbutyl) -4- [5- (2,3-Dijing-1,4-benzodiocinyl)]-piperidine ; 1-('cyclohexyl-4-ethoxy-3-phenylbutyl) -4- (4-fluoroyl-2-methoxyphenyl)-. Cinnaphine; 129 200406394 • l- [5- (2,3-dihydroxy-1,4-benzodiocinyl)]-4- (4-hydroxy-3-phenylheptyl well; • 1- [5- (2,3-Dihydroxy-M-benzodiocinyl)]-4- (4-Hydroxy-3-phenylhex-5 -fine group) -Herowell, 5 · 1- [5- (2, 3-Dijing-1,4 -Bendioxinyl)]-4- (4-Lightyl-5-fluorenyl-3_phenylhexyl)-° gua σ well, • 1- [5- (2,3- Two say -1,4-benzo-dioxinyl]]-4- (4-controller_3-phenylfluorenyl) -piperidine; • 1- [5- (2,3-dibenzyl-1,4 · Benzodioxin)]-4 · (4-Cycyl-3-phenylheptyl 10-5-alkynyl) -piperine; • 1- [5- (2,3-dihydroxy-1,4-benzene And dioxinyl]]-4- (4-hydroxy-3-phenylheptan-5 -unyl)-° bottom σ well, • (Ε, Z) -1- (4-fluoroyl-2-fluorenyloxy) Phenyl) -4-[('fluorenoxy-3-phenyl) -hept-5-enyl] -piperidine (above TLC rf diastereomer), 15 · (E, Z)- 1- (4-Fluoro-2-methoxyphenyl) -4-[(4-methoxy-3-phenyl) -hept-5-enyl] -piperidine (TLCrf diastereomer above Isomers), • 1- [5- (2,3-dihydroxy-1,4-benzodioctyl)]-4- (4-hydroxy-3-phenylhex-5-ynyl) -piper Speaking; • 1- [5- (2,3-di-controll-1,4-benzodio )]-4- (4-Cycloyl-3-phenylheptyl 20-6-alkenyl) -piperidine; • 1- [5- (2,3 -Diocene-1,4 · benzodioxine )]-4- (4-Cyclo-6-methyl-3 -phenylhept-5-fine) -Square σ well, • M5- (2,3 · Dihydroxy-1,4-benzene Benzodioctyl)]-4- (4-hydroxy-6-fluorenylphenylheptyl) -Brigade, 130 200406394 • 1- [5- (2,3-Dimethyl-1,4-benzodioxinyl )]-4- (4-Selecyl-3-phenylbutyl wells; • (RS, SR) small [5- (2,3-dihydroxy-1,4 · benzodioxinyl)]-4- ( 4-hydroxy-3-phenylfluorenyl)-^ u well, • 1- [4-badhexyl-3- (2-dimethylamineweilylphenyl) -4-oxobutyl] -4- [5 -(2,3-Dijing-1,4 · Benzodioxinyl)]-° Bottom 0, • 1- [4-Badhexyl-3- (2-diamidoamine_carbonylphenyl) -4 -Bytyl] -4- [5- (2,3-dihydroxy-1,4-benzodiocinyl)]-piperidine; 1- [4-badhexyl-3- (2-dimethyl Amine is phenyl) -4-oxobutyl] -4- (4 · fluoro-2--2-oxyphenyl)-^ σ well; • 1- [4-cyclohexyl-3- (2- Dimethylaminocarbonylphenyl) -4-hydroxybutyl] -4- (4-fluoro-2-methoxyphenyl wells, • 1- [3- (2-Gaphenyl) -4-side oxygen Fluorenyl] -4- [5- (2,3-Dijing-1,4-Benzodioxine ) 1-111; 15 • 1- [4-Badhexyl-3- (2-digasmethoxymethoxyphenyl) -4-oxobutyl] -4- (4-indolinyl) -ϋ ^ σ Well; • (RS, SR) 1- [4-Ethyloxy-4-cyclohexyl-3- (2-fluorophenyl) -butyl] -4- (2-methoxyphenyl)-° bottom. Oh, 20 • (RS，SR) 1-[4-環己基-3-(2-氟苯基)-4-曱氧基羰基氧丁 基]-4-(2-甲氧基苯基)-σ瓜p井， • (RS，SR) 1-[4-環己基-4-乙基胺羰基氧基-3-(2-氟苯基)-丁基]-4·(2-曱氧基苯基)-°瓜〇井； • (RS，SR) 1-[4-胺羰基氧基-4-環己基-3-(2-氟苯基）-丁 基]-4-(2-甲氧基苯基)-哌畊； 131 200406394 ίο 15 20 l-[5-(2,3-二羥-1，4-苯並戴奥辛基)]-4- (4-羥基-5,5-二曱 基-3-苯己基)-°底。井， 1-(4-氟基-2-甲氧基苯基)-4-(4-羥基-3-苯基庚-5-炔基)- 口底口丼； (Ε，Ζ)-1-(4-氟基-2-甲氧基苯基）-4-(4-羥基-3-苯基庚-5-稀基)-σ瓜啡； (E)-1-(4-就基-2-甲氧基苯基)-4-(4- ^基-3 -苯基庚-5-稀 基)-哌畊； 1-[5-(2,3-二羥-1，4-苯並戴奥辛基)]-4-(4-羥基-5-甲基-3-苯基己-5-細基)-°底ϋ井， 1-[5-(2,3-二羥-1，4-苯並戴奥辛基)]-4-(4-羥基-6-曱基_3_ 苯基庚-6-細基)-σ^σ丼， 1-[5-(2,3-二羥-1，4-苯並戴奥辛基)]-4-[4-羥基-4-(2-噻吩 基)-3 -苯丁基]-°瓜π井， 1-[5-(2,3-二羥-1,4-苯並戴奥辛基）]-4-(4-羥基-3-笨辛 基)-哌畊； 1-(4-氟基-2-曱氧基苯基）-4-(4-甲氧基-3-苯基庚-5-快 基)-σ辰讲； 1-[4-環己基-3-(2-曱氧甲苯基）-4-侧氧丁基]-4-(4-氟基 -2-曱氧基苯基)-哌。井； 1-[4-環己基-4-羥基-3-(2-甲氧曱苯基)-丁基]-4-(4-氟基 -2-甲氧基苯基)-哌畊； 1-[5-(2,3-二羥-1，4-苯並戴奥辛基)]-4-[4-環己基-3-(2-甲 氧曱苯基)-4-側氧丁基]-哌讲；• (RS, SR) 1- [4-Cyclohexyl-3- (2-fluorophenyl) -4-methoxycarbonyloxybutyl] -4- (2-methoxyphenyl) -σ guap Well, • (RS, SR) 1- [4-cyclohexyl-4-ethylaminecarbonyloxy-3- (2-fluorophenyl) -butyl] -4 · (2-methoxyphenyl) -° Well Guara; • (RS, SR) 1- [4-Aminocarbonyloxy-4-cyclohexyl-3- (2-fluorophenyl) -butyl] -4- (2-methoxybenzene ) -Piperon; 131 200406394 ίο 15 20 l- [5- (2,3-dihydroxy-1,4-benzodioxinyl)]-4- (4-hydroxy-5,5-difluorenyl- 3-phenylhexyl)-° bottom. Well, 1- (4-Fluoro-2-methoxyphenyl) -4- (4-hydroxy-3-phenylhept-5-alkynyl)-mouth bottom mouth Ε; (E, Z) -1 -(4-fluoro-2-methoxyphenyl) -4- (4-hydroxy-3-phenylhept-5-diyl) -σ citrulline; (E) -1- (4-yl 2-methoxyphenyl) -4- (4- ^ yl-3 -phenylhept-5-diyl) -piperon; 1- [5- (2,3-dihydroxy-1,4- Benzodioxin)]-4- (4-hydroxy-5-methyl-3-phenylhex-5-fine)-° Bottomwell, 1- [5- (2,3-dihydroxy-1 , 4-Benzodioxinyl]]-4- (4-hydroxy-6-fluorenyl-3_phenylheptan-6-fine) -σ ^ σ 丼, 1- [5- (2,3-dihydroxy -1,4-Benzodioxinyl)]-4- [4-hydroxy-4- (2-thienyl) -3 -phenylbutyl]-° guai, 1- [5- (2,3- Dihydroxy-1,4-benzodioctyl)]-4- (4-hydroxy-3-benzyloctyl) -piperon; 1- (4-fluoroyl-2-methoxyphenyl) -4- (4-Methoxy-3-phenylhept-5-yl) -σ-Chen; 1- [4-Cyclohexyl-3- (2-fluorenyltolyl) -4-oxobutyl]- 4- (4-Fluoro-2-methoxyphenyl) -piper. Well; 1- [4-cyclohexyl-4-hydroxy-3- (2-methoxyfluorenylphenyl) -butyl] -4- (4-fluoroyl-2-methoxyphenyl) -piperon; 1- [5- (2,3-Dihydroxy-1,4-benzodiocinyl)]-4- [4-cyclohexyl-3- (2-methoxyfluorenyl) -4-oxobutyl ]-Pipeline; 132 • Η4-環己基-4-羥基-3-(2-甲氧甲苯基）_丁基]= 經-1，4-苯並戴奥辛基)_哌讲；以及 • (RS，SR) 1-[‘環己基-4-甲基胺硫羰基氧_3_(2_氟苯基 丁基]-4-(2-甲氧基苯基)_。辰吨。 種藥學組成物，其包含有一如申請專利範圍第丨至Μ項 中任一項之化合物，並混合以一藥學上可接受的稀釋劑、 賦形劑或載劑。 一種以下列化學式來表示之化合物：132 • Η4-cyclohexyl-4-hydroxy-3- (2-methoxytolyl) _butyl] = via -1,4-benzodioctyl) _pipeline; and • (RS, SR) 1- ['Cyclohexyl-4-methylaminethiocarbonyloxy_3_ (2-fluorophenylbutyl] -4- (2-methoxyphenyl)]. Ton. A pharmaceutical composition comprising a Apply for a compound in any one of the scope of the patent, and mix with a pharmaceutically acceptable diluent, excipient or carrier. A compound represented by the following chemical formula: 其中： Μ代表基團Where: Μ stands for group R代表氫或一或更多被選自於由下列所構成之群組的取代 基：（CrC6)-烷基、（CrC6)-烷氧基、（crc6)-烷硫基、羥基、 鹵素基、（CVC6)-烯基、（CVC6)-炔基、（crc6)-鹵烧基、 (CrC0)-鹵烧氧基、（CKC6)-經烧基、烧氧烧基、硝基、胺基、 (CrC6)-胺烷基、（crc6)-烷胺基-(CrC6)-烷基、（cKc6)-烷 胺基、二-(CrC6)-烷胺基、醯胺基、（crc6)-烷磺醯基胺基、 胺石黃醯基、（CrC6)-烷胺讀醯基、氰基、胺羰基、N-(CrC6)-烧胺魏基、N，N-二-(C]-C6)-烧胺幾基、（crC6)·烧氧幾基、 200406394 (crc6)-烷羰基、烷羰烷基、甲醯基、烷醯基氧烷基、（crc6)-烷胺羰基胺基、（CrC6)-烷亞磺醯基、（CrC6)-烷磺醯基，以 及N，N-二-(CrC6)-烷胺磺醯基基團； R!代表一被選自於由下列所構成之群組的成員：氫、環烷 5 基、芳基、芳氧基、芳烷基、芳烷氧基、雜環狀基、雜環 氧基、雜環烷基以及雜環烷氧基基團，各個基團係被選擇 性取代以一或更多如上面所界定之取代基R; Q代表-C(O)-或-CH(OR2)-，其中R2代表一被選自於由下列 所構成之群組的成貝·氫、（C】-C6)-烧基、（C2-C6)-稀基、 10 (c2-c6)-炔基以及環烷基基團，其中各個基團係被選擇性取 代以一或更多被選自於r5與r6之基團，其中r5係被選自 於由下列所構成之群組·鹵素基、（Ci-C6)·烧氧基、（Ci-C6)-鹵烷氧基、氰基、（crc6)-烷氧羰基、（crc6)-烷羰基、烷氧 烷基、胺羰基、N-(CrC6)-烷胺羰基、N，N-二-(CVC6)-烷胺 15 羰基基團，而R6係被選自於由下列所構成之群組：芳基、 雜芳基、芳氧基、雜芳氧基、芳烷氧基，以及雜芳烷氧基 基團，各個係被選擇性取代以R，或R2代表-C(〇)- (CrC6)-烷基、-c(o)o-(crc6)-烷基、-C(0)NR7R8 或-C(S)NR7R8， 其中仏與R8係分別為氫或（crc6)-烷基； 20 r3 代表氫或一（CVC6)-烷基、（c2-c6)-烯基、（c2-c6)-炔基、 環烷基、芳基或雜環基基團，各個基團係被選擇性取代以 一或更多如上面所界定之取代基R或R!; Ra代表互為相同或不相同之(CrC6)-烷基基團，或為一起形 成一個3至5碳之伸烷基鏈；以及 134 200406394 但有條件是排除化合物，其中同時地Q代表-C(〇)-;Μ代 表-CHO ; R代表氫、烷基、烷氧基、鹵素、鹵烷基、烷硫 基、烯基或炔基；心代表氫或未經取代之環烷基或經取代 以烷基之環烷基；而R3代表一未經取代之苯基、未經取代 之萘基或未經取代之環烷基基團，或苯基、萘基或環烷基 經取代以一或二個被選自於由下列所構成之群組的取代 基：烧基、烧氧基、鹵素、鹵烧基、烧硫基、稀基以及炔 基基團。 ίο 17. —種以下列化學式來表示之化合物： RR represents hydrogen or one or more substituents selected from the group consisting of (CrC6) -alkyl, (CrC6) -alkoxy, (crc6) -alkylthio, hydroxy, halo (CVC6) -alkenyl, (CVC6) -alkynyl, (crc6) -haloalkyl, (CrC0) -haloalkyl, (CKC6) -alkyl, oxyalkyl, nitro, amine (CrC6) -aminoalkyl, (crc6) -alkylamino- (CrC6) -alkyl, (cKc6) -alkylamino, bis- (CrC6) -alkylamino, amidoamine, (crc6)- Alkylsulfonylamino, ammonium luteanyl, (CrC6) -alkylamine sulfonyl, cyano, amine carbonyl, N- (CrC6) -carbamino, N, N-di- (C) -C6) -Carbamoyl, (crC6) · oxalyl, 200406394 (crc6) -alkylcarbonyl, alkylcarbonylalkyl, formamyl, alkylamidooxyalkyl, (crc6) -alkylaminocarbonylamino, ( CrC6) -alkanesulfenyl, (CrC6) -alkanesulfonyl, and N, N-di- (CrC6) -alkylaminesulfonyl groups; R! Represents a group selected from the group consisting of Members of the group: hydrogen, naphthyl, aryl, aryloxy, aralkyl, aralkoxy, heterocyclic, heterocyclooxy, heterocycloalkyl, and heterocycloalkoxy groups Each group is optionally substituted with one or more substituents R as defined above; Q represents -C (O)-or -CH (OR2)-, where R2 represents a group selected from the group consisting of The group consisting of hydrogen, (C) -C6) -alkynyl, (C2-C6) -diluted group, 10 (c2-c6) -alkynyl and cycloalkyl groups, each of which is a group Is optionally substituted with one or more groups selected from r5 and r6, wherein r5 is selected from the group consisting of halo, (Ci-C6), alkoxy, and (Ci -C6) -haloalkoxy, cyano, (crc6) -alkoxycarbonyl, (crc6) -alkoxycarbonyl, alkoxyalkyl, aminecarbonyl, N- (CrC6) -alkylaminecarbonyl, N, N-di -(CVC6) -alkylamine 15 carbonyl group, and R6 is selected from the group consisting of aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, and hetero Aralkyloxy groups, each of which is optionally substituted with R, or R2 represents -C (〇)-(CrC6) -alkyl, -c (o) o- (crc6) -alkyl, -C (0 ) NR7R8 or -C (S) NR7R8, where 仏 and R8 are hydrogen or (crc6) -alkyl, respectively; 20 r3 represents hydrogen or mono (CVC6) -alkyl, (c2-c6) -alkenyl, (c2 -c6)-alkynyl, cycloalkyl, aryl or heterocyclyl groups, each group is selectively substituted with one or more substituents R or R as defined above; Ra represents the same as each other Or different (CrC6) -alkyl groups, or together to form an alkylene chain of 3 to 5 carbons; and 134 200406394 but with the proviso that compounds are excluded, in which simultaneously Q represents -C (〇)-; M represents -CHO; R represents hydrogen, alkyl, alkoxy, halogen, haloalkyl, alkylthio, alkenyl or alkynyl; heart represents hydrogen or unsubstituted cycloalkyl or substituted with alkyl Cycloalkyl; and R3 represents an unsubstituted phenyl, unsubstituted naphthyl, or unsubstituted cycloalkyl group, or phenyl, naphthyl, or cycloalkyl is substituted with one or two Substituents selected from the group consisting of alkyl, alkoxy, halogen, halo, thio, dilute and alkynyl groups. ίο 17. —A compound represented by the following chemical formula: R 其中： W 代表基團 I /0—Ra 1 \〇一RaWhere: W represents the group I / 0—Ra 1 \ 〇Ra >~CHO 或> ~ CHO or 15 20 R代表氫或一或更多被選自於由下列所構成之群組的取代 基：（CVC6)-烷基、（CrC6)-烷氧基、（CVC6)-烷硫基、羥基、 鹵素基、（c2-c6)-烯基、（c2-c6)-炔基、（crc6)-ii 烷基、 (Ci-C6)-鹵烧氧基、（Ci_C6)-經烧基、烧氧烧基、确基、胺基、 (crc6)-胺烷基、（crc6)-烷胺基-(crc6)-烷基、（crc6)-烷 胺基、二-(crc6)-烷胺基、醯胺基、（crc6)-烷磺醯基胺基、 Γ ο 135 200406394 胺石黃酿基、（Ci-C6)-烧胺續酿基、氮基、胺魏基、N-(Ci_C6)-烷胺羰基、N，N-二-(CrC6)-烷胺羰基、（CrC6)-烷氧羰基、 (CrC6)-烷羰基、烷羰烷基、甲醯基、烷醯基氧烷基、（CrC6)-烷胺羰基胺基、（crc6)-烷亞磺醯基、（crc6)-烷磺醯基，以 5 及N，N-二烧胺石黃酿基基團， Ri代表一被選自於由下列所構成之群組的成員：氫、環烷 基、芳基、芳氧基、芳烷基、芳烷氧基、雜環狀基、雜環 氧基、雜環烷基以及雜環烷氧基基團，各個基團係被選擇 性取代以一或更多如上面所界定之取代基R; 10 Z代表一個-CHO、氰基或-CH(ORa)2基團， -.....代表一單或雙鍵， Ra代表互為相同或不相同之(CrC6)-烷基基團，或為一起形 成一個3至5碳之伸烷基鏈；而 L代表一個芳基或雜環狀基團，各個係被選擇性取代以一或 15 更多如上面所界定之取代基R ; A代表一個鍵或（CH2)n;以及 η = 0 或 1 〇 136 200406394 柒、指定代表圖： (一) 本案指定代表圖為：第（ ）獨。（無圖) (二) 本代表圖之元件代表符號簡單說明： 捌、本案若有化學式時，請揭示最能顯示發明特徵的化學式： R15 20 R represents hydrogen or one or more substituents selected from the group consisting of (CVC6) -alkyl, (CrC6) -alkoxy, (CVC6) -alkylthio, hydroxyl, Halo, (c2-c6) -alkenyl, (c2-c6) -alkynyl, (crc6) -ii alkyl, (Ci-C6) -haloalkyl, (Ci_C6) -alkyl Alkyl, acyl, amine, (crc6) -aminoalkyl, (crc6) -alkylamino- (crc6) -alkyl, (crc6) -alkylamino, di- (crc6) -alkylamino, Fluorenylamino group, (crc6) -alkanesulfonylamino group, Γ ο 135 200406394 amine yellow yellow group, (Ci-C6) -burning amine continuation group, nitrogen group, amine group, N- (Ci_C6)- Alkylaminocarbonyl, N, N-di- (CrC6) -Alkylaminocarbonyl, (CrC6) -Alkoxycarbonyl, (CrC6) -Alkylcarbonyl, Alkylcarbonyl, Formamyl, Alkyloxyalkyl, ( CrC6) -alkylaminocarbonylamino, (crc6) -alkylsulfinamidinyl, (crc6) -alkylsulfinamidinyl, with 5 and N, N-dialkylamine pyrite groups, Ri represents one selected From a member of the group consisting of: hydrogen, cycloalkyl, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heterocyclooxy, heterocycloalkyl, and hetero Alkoxy groups, each group is optionally substituted with one or more substituents R as defined above; 10 Z represents a -CHO, cyano or -CH (ORa) 2 group,-.. ... represents a single or double bond, Ra represents (CrC6) -alkyl groups which are the same or different from each other, or to form an alkylene chain of 3 to 5 carbons together; and L represents an aryl or Heterocyclic groups, each of which is optionally substituted with one or 15 more substituents R as defined above; A represents a bond or (CH2) n; and η = 0 or 1 〇136 200406394 柒, designated representative Picture: (1) The designated representative picture in this case is: () independence. (No picture) (II) Brief description of the representative symbols of the components in this representative diagram: 捌 If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: R RsRs
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