TW200410963A - Heterocyclic derivatives - Google Patents

Heterocyclic derivatives Download PDF

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TW200410963A
TW200410963A TW092124801A TW92124801A TW200410963A TW 200410963 A TW200410963 A TW 200410963A TW 092124801 A TW092124801 A TW 092124801A TW 92124801 A TW92124801 A TW 92124801A TW 200410963 A TW200410963 A TW 200410963A
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alkyl
mono
crc6
crc4
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TW092124801A
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TWI314555B (en
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Heiki Gielen
Volkhart Li
Ulrich Rosentreter
Karl-Heinz Schlemmer
Swen Allerheiligen
Telan Leila
Barfacker Lars
Keldenich Jorg
F Fitzgerald Mary
Nash Kevin
Albrecht Barbara
Meurer Dirk
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Bayer Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

This invention relates to novel heterocyclic derivatives, processes for their preparation, and their use in medicaments, especially for the treatment of chronic obstructive pulmonary diseases, acute coronary syndrome, acute myocardial infarction and heart failure development.

Description

200410963 A7200410963 A7

[發明所屬之技術領域] 本發明乃有關新穎之雜環衍生物，其製法及其於藥劑 上，特別是用於治療慢性阻塞性肺病、急性冠狀動脈症候 群、急性心肌梗塞及心臟衰竭形成之用途。 、 5 [先前技術] 纖維狀彈性蛋白-其構成-些組_丨如_…㈣ 10 15 經濟部智慧財產局員工消費合作社印製 帶、肺與心臟)所有蛋白質含量相當顯著之比例—可被歸類 於彈性蛋白酶的選定組群之酵素所水解或者破壞。人類白 血球彈性蛋白酶(HLE，EC 3.4.21.37)，亦即所謂人類嘻中 性白錢彈性蛋白酶(HNE)，係被糖基化之強驗性絲ς酸 蛋白酶，見於人類多形核白血球細胞(ρΜΝ)之嗜笨胺鹽顆 粒。ΗΝΕ自活化ΡΜΝ釋出，被認為與急性及慢性炎:疾 病之發病原因有所牽連。ΗΝΕ能降解寬廣範圍之基質蛋 白包括彈性蛋白及膠原蛋白，除了對結締組織之彼等作用 外，ΗΝΕ具有寬廣範圍之炎性作用，包括向上調節正_8 基因表現、水腫形成、黏液腺增生及黏液分泌過多；同時 亦經由水解膠原蛋白結構而扮演傷害組織之介質角色，例 如，於心臟中，在急性心肌梗塞之後或於形成心臟衰弱期 間，因而傷害内皮細胞、促進黏附於内皮的嗜中性白血球 20 之外滲及影響本身之黏著程序。 被認為HNE負有重責之肺部疾病包括肺部纖維化、 肺炎、急性呼吸窘迫症候群(ARDS)、肺氣腫（包括抽煙誘 發之氣腫）、慢性阻塞性肺病（COPD)及囊胞性纖維症。於 心血管疾病中，HNE涉及提高缺血組織傷害產生，隨後 本紙張尺度適用中國國家標準(CNS)A4規格（210 X297公釐） 200410963 A7 B7 五、發明說明（2 ) 於急性心肌梗塞後心肌功能異常，及涉及形成心臟衰竭期 間發生改組病變(remodeling processes)。HNE亦有原因地 牽連風濕性關節炎、動脈硬化、腦創傷、癌症及涉及嗜中 性白血球參與之相關症狀。 5 因此，HLE活性抑制劑潛在地可用於治療許多炎性 疾病，尤其是慢性阻塞性肺病[R.A. Stockley， and protease/antiprotease imbalance，Am. J. Respir. Crit. Care 1605 S49-S52 (1999)]。HLE活性抑制劑亦潛在地可 用於治療急性心肌症候群、不穩定之心絞痛、急性心肌梗 10 塞及冠狀動脈間道移植(CABG) [CJP· Tiefenbacher et al.， 經濟部智慧財產局員工消費合作社印製 inhibition of elastase improves myocardial function after repetitive ischaemia and myocardial infarction in the rat heart, Eur. J. Physiol. 433, S563-S570 (1997) ； Dinerman et al., Increased neutrophil elastase release in unstable angina 15 pectoris and acute myocardial infarction, J. Am. Coll. Cardiol· 11，1559-1563 (1990)]，及治療心臟衰竭之形成 [S.J. Gilbert et al·， Increased expression of promatrix metalloproteinase-9 and neutrophil elastase in canine dilated cardiomyopathy, Cardiov. Res. 34, S377-S383 20 (1997)]與動脈硬化[Dollery et al.5 m human atherosclerotic plaque, Circulation 107. 2829-2836 (2003)] 〇 5-乙氧羰基-1-苯基-6-甲基-4-(3_硝苯基)-3,4-二氫嘧 唆-2(1Η)-_之合成見述於 J. Heterocyclic Chem, 38^ 1051 -4- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公嫠） 200410963 A7 B7 五、發明說明（3) (2001)。此化合物之藥理活性未見述及 [發明内容] 本發明乃有關具下式（I)之化合物[Technical field to which the invention belongs] The present invention relates to a novel heterocyclic derivative, a method for preparing the same and its use in medicaments, especially for the treatment of chronic obstructive pulmonary disease, acute coronary syndromes, acute myocardial infarction and heart failure . , 5 [Prior art] Fibrous elastin-its composition-some groups _ 丨 such as _... ㈣ 10 15 All the protein content of the Intellectual Property Bureau of the Ministry of Economic Affairs's Consumer Cooperative Printed Band, Lungs and Hearts is quite significant-can be Enzymes hydrolyzed or destroyed by selected groups of elastase. Human leukocyte elastase (HLE, EC 3.4.21.37), also known as human neutrophil leukocyte elastase (HNE), is a glycosylated strong serine protease, found in human polymorphonuclear leukocytes ( ρMN) particles. ΗΝΕ is released from activated PMN and is thought to be implicated in the causes of acute and chronic inflammation: disease. ΗΝΕ can degrade a wide range of matrix proteins including elastin and collagen. In addition to their effects on connective tissue, ΗΝΕ has a wide range of inflammatory effects, including up-regulation of positive 8 gene expression, edema formation, mucinous gland hyperplasia and Excessive secretion of mucus; it also acts as a mediator of tissue damage by hydrolyzing collagen structure, for example, in the heart, after acute myocardial infarction or during the formation of heart failure, thereby harming endothelial cells and promoting neutrophil adhesion to the endothelium Leukocytes 20 extravasate and affect the adhesion process itself. Pulmonary diseases considered to be responsible for HNE include pulmonary fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), emphysema (including smoking-induced emphysema), chronic obstructive pulmonary disease (COPD), and cystic fibrosis . In cardiovascular diseases, HNE is involved in increasing the production of ischemic tissue injury. Subsequently, this paper size applies the Chinese National Standard (CNS) A4 specification (210 X297 mm) 200410963 A7 B7 V. Description of the invention (2) Myocardium after acute myocardial infarction Dysfunction, and remodeling processes involved in the development of heart failure. HNE is also implicated in rheumatoid arthritis, arteriosclerosis, brain trauma, cancer, and related symptoms involving neutrophil involvement. 5 Therefore, HLE activity inhibitors are potentially useful in the treatment of many inflammatory diseases, especially chronic obstructive pulmonary disease [RA Stockley, and protease / antiprotease imbalance, Am. J. Respir. Crit. Care 1605 S49-S52 (1999)] . HLE activity inhibitors are also potentially useful in the treatment of acute myocardial syndrome, unstable angina pectoris, acute myocardial infarction of 10 plugs, and coronary artery transplantation (CABG) [CJP · Tiefenbacher et al., Printed by Consumers ’Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs Suppression of elastase improves myocardial function after repetitive ischaemia and myocardial infarction in the rat heart, Eur. J. Physiol. 433, S563-S570 (1997); Dinerman et al., Increased neutrophil elastase release in unstable angina 15 pectoris and acute myocardial infarction, J. Am. Coll. Cardiol · 11, 1559-1563 (1990)], and the treatment of the formation of heart failure [SJ Gilbert et al ·, Increased expression of promatrix metalloproteinase-9 and neutrophil elastase in canine dilated cardiomyopathy, Cardiov. Res. 34, S377-S383 20 (1997)] and arteriosclerosis [Dollery et al. 5 m human atherosclerotic plaque, Circulation 107. 2829-2836 (2003)] 〇5-ethoxycarbonyl-1-phenyl-6- The synthesis of methyl-4- (3-nitrophenyl) -3,4-dihydropyrimidine-2 (1Η) -_ is described in J. Heterocyclic Chem, 38 ^ 1051- 4- This paper size applies to China National Standard (CNS) A4 (210 X 297 cm) 200410963 A7 B7 V. Description of Invention (3) (2001). The pharmacological activity of this compound has not been described. [Summary of the Invention] The present invention relates to a compound having the following formula (I)

R6 R7 R3 (I)， 5 式中 A 代表芳基或雜芳環； R1、R2與R3各自獨立地代表氫、鹵素、硝基、氰基、 C6-烷基、羥基或CkC6-烷氧基，其中Q-CV烷基與R6 R7 R3 (I), 5 where A represents an aryl or heteroaryl ring; R1, R2 and R3 each independently represent hydrogen, halogen, nitro, cyano, C6-alkyl, hydroxyl or CkC6-alkoxy Where Q-CV alkyl and

CrC6-烷氧基可進一步被一至三個相同或不同之選自 10 包括鹵素、羥基及CrC4-烷氧基之基團取代； 經濟部智慧財產局員工消費合作社印製 R4 代表三氟甲基羰基、CrC6-烷基羰基、CVC6-烷氧基 羰基、Ci-Cp烯氧基羰基、羥羰基、胺羰基、單-或 二-C1-C4-烧基胺幾基、Cs-CiQ-芳基胺幾基、芳基幾 基、雜芳基羰基、雜環基羰基、雜芳基、雜環基或氰 15 基，其中CrC6-烷基羰基、CrC6-烷氧基羰基、單-及 二-crc4-烷基胺羰基可進一步被一至三個相同或不 同之選自包括c3-c8-環烷基、羥基、crc4-烷氧基、 -5- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（4 ) C1-C4-烧氧幾基、羥幾基、胺幾基、單-及二 烷基胺羰基、CrCV烷基羰胺基、（crc4-烷基戴基)-CrCU-烧胺基、氰基、胺基、單·及二-crc4-烧胺 基、雜芳基、雜環基及三-(CrC6_院基)-碎燒基之基 5 團取代，及其中雜芳基羰基、雜環基羰基、雜芳基及 雜環基可進一步被Ci-Cr烷基取代； R 代表C1-C4-烧基’其可被一至三個相同或不同之選 自包括鹵素、羥基、CrCV烷氧基、C]rC6-烯氧基、 Ci-CV烧硫基、胺基、單-及二_crC6-烧胺基、芳胺 10 基、羥羰基、CnO烷氧羰基及-〇-CrC4-烷基-〇-Cr C4-烷基之基團取代； 或 R5代表胺基； R6代表氫、CrQ-烧基、甲醯基、胺羰基、單_或二-Cr 15 C4_烷基胺羰基、CrCV環烷基羰基、烷基羰 經濟部智慧財產局員工消費合作社印製 基、Ci-CV烧氧羰基、N-(CrC4-烧基確醯基）_胺羰 基、N-(CrC4·烧基續醢基)_N_(Ci-C4-烧基)_胺幾基、 雜芳基、雜環基、雜芳基羰基或雜環基羰基，其中 Ci-C6_烧基、單-及二·CrQ-烧基胺幾基、q-Q-烧基 20 羰基、CrCV烷氧羰基、雜芳基及雜環基可被一至三 個相同或不同之選自包括芳基、雜芳基、羥基、Cr 烷氧基、羥羰基、CrC6-烷氧羰基、胺羰基、單_ 及二-Ci-CV烧基胺幾基、胺基、單-及二_(^-€4-烧胺 基、CrCV烧基羰胺基、三_(crc6燒基)-矽烷基、氰 -6- 本紙張尺度適用中國國家標準(CNS)A4規格（2]〇χ297公釐） 200410963 A7 B7 五、發明說明（5 ) 基、N_(單_及二-C1-C4-烧胺基_CrC4-烧基)-胺羰基、 N_(ci<V烷氧基-CrCV烧基l·胺羰基及鹵素之基團取 代； 或 5 R6代表具下式之基團CrC6-alkoxy can be further substituted by one to three groups which are the same or different and are selected from 10 including halogen, hydroxyl and CrC4-alkoxy; printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, R4 represents trifluoromethylcarbonyl , CrC6-alkylcarbonyl, CVC6-alkoxycarbonyl, Ci-Cp alkenyloxycarbonyl, hydroxycarbonyl, aminecarbonyl, mono- or di-C1-C4-alkylaminoamine, Cs-CiQ-arylamine Hexyl, aryl, aryl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl, or cyano-15, of which CrC6-alkylcarbonyl, CrC6-alkoxycarbonyl, mono- and di-crc4 -The alkylamine carbonyl group may be further selected from the group consisting of c3-c8-cycloalkyl, hydroxy, crc4-alkoxy, and -5- which are the same or different. This paper size applies to China National Standard (CNS) A4 specifications ( (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (4) C1-C4-oxoyl, hydroxy, yl, amine, mono- and dialkylamine carbonyl, CrCV alkylcarbonylamino, ( crc4-alkyldailyl) -CrCU-alkylamino, cyano, amine, mono- and di-crc4-alkylamino, heteroaryl, heterocyclic and tri- (CrC6_yuan) Motoki 5 Group Generation, and the heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, and heterocyclyl groups thereof may be further substituted with Ci-Cr alkyl groups; R represents C1-C4-alkyl, which may be one to three identical or different Selected from the group consisting of halogen, hydroxyl, CrCV alkoxy, C] rC6-alkenyloxy, Ci-CV thiothio, amine, mono- and di-crC6-thioamino, arylamine 10, hydroxycarbonyl, CnO Alkoxycarbonyl and -0-CrC4-alkyl-0-Cr C4-alkyl group substitution; or R5 represents an amine group; R6 represents hydrogen, CrQ-alkyl, formamyl, aminecarbonyl, mono- or di- -Cr 15 C4_Alkylamine carbonyl, CrCV cycloalkylcarbonyl, Alkali carbonyl, Intellectual Property Bureau, Ministry of Economic Affairs, Employees' Cooperative Printing Base, Ci-CV Oxyoxycarbonyl, N- (CrC4-Carbonyl Confirmation) _ Amine carbonyl, N- (CrC4 · alkynyl) -N_ (Ci-C4-alkyl) _amidoyl, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl, of which Ci-C6 _Alkyl, mono- and di · CrQ-alkylamino, alkynyl, qQ-alkyl 20 carbonyl, CrCV alkoxycarbonyl, heteroaryl and heterocyclic groups can be one to three same or different and selected from the group including aryl , Heteroaryl, hydroxyl, Cr alkoxy, hydroxycarbonyl, CrC6-alkane Oxycarbonyl, aminecarbonyl, mono- and di-Ci-CV alkylamino, amine, mono- and di-(^-€ 4-alkylamino, CrCV alkylcarbonyl, tri- (crc6) Base) -silyl, cyano-6- This paper size applies to Chinese National Standard (CNS) A4 specifications (2) 0 × 297 mm 200410963 A7 B7 V. Description of the invention (5) Base, N_ (single_ and di-C1 -C4-alkylamino-CrC4-alkyl) -aminocarbonyl, N_ (ci < V alkoxy-CrCV alkyl-aminocarbonyl and halogen group substitution; or 5 R6 represents a group of the formula

經濟部智慧財產眉員工消費合作社印製 式中 R A 係選自氫與C1-CV烧基，及 n 代表整數1或2; 10 R7代表鹵素、硝基、氰基、Crc6-烧基、羥基或CVC6-烷氧基，其中Crc6-烷基及CrCV烷氧基可進一步被 一至三個相同或不同之選自包括鹵素、羥基及Ci_C4_ 燒氧基之基團取代； 及 15 γ1、γ2、γ3、γ4與Y5各自獨立地代表CH或N，其中該 環含有〇、1或2個氮原子。 根據本發明之化合物亦可呈其鹽、水合物及/或溶劑 合物形式存在。 本發明中，以生理上可接受之鹽較佳。 20 根據本發明之生里上可接^皇為不具毒性之鹽，其 通常可由化合物（I)與習用於此目的之無機或有機鹼或酸 反應而製得。化合物⑴之醫藥上可接受鹽之非限制性實 }纸張尺度適用中國國家標準(CNS)A4規格（21C)x297 &f------- 200410963 A7 B7 10 15 經濟部智慧財產局員工消費合作社印製 20 五、發明說明（6 例包含驗金屬鹽例如鐘、鉀及納鹽、驗土金屬鹽例如鎮及 鈣鹽、四級銨鹽例如三乙銨鹽、乙酸鹽 '苯磺酸遵、苯γ 酸鹽、二碳酸鹽、二硫酸鹽、二酒石酸鹽、硼酸鹽、：臭化 物、碳酸鹽、氣化物、檸檬酸鹽、二鹽酸鹽、富馬酸睡 葡萄糖酸鹽、麵胺酸鹽、己基收斂酸鹽、氳漠化物、=氣 化物、羥基萘甲酸鹽、碘化物、羥乙磺酸鹽、乳酸雖月 桂酸、蘋果酸鹽、馬來酸鹽、杏仁酸鹽、甲續酸鹽、甲某 溴化物、甲基硝酸鹽、甲基硫酸鹽、硝酸鹽、油酸輯、草 酸鹽、棕櫚酸鹽、泛酸鹽、攝酸鹽、二磷酸鹽、聚半、飞糖 醛酸鹽、柳酸鹽、硬脂酸鹽' 硫酸鹽、琥珀酸鹽、酒石酸 鹽、對甲苯磺酸鹽、戊酸鹽、及用於醫藥目的之龙 類。 、他鹽 本發明化合物或其鹽之主全|為化合物與水之化風叶 量組成物，例如半·、單_、或二水合物。 子In the printed version of the Intellectual Property Employee Cooperative Cooperative of the Ministry of Economic Affairs, RA is selected from hydrogen and C1-CV alkyl groups, and n represents an integer of 1 or 2; 10 R7 represents halogen, nitro, cyano, Crc6-alkyl, hydroxyl or CVC6-alkoxy, wherein Crc6-alkyl and CrCV alkoxy may be further substituted by one to three groups which are the same or different and are selected from the group consisting of halogen, hydroxyl and Ci_C4_oxy; and 15 γ1, γ2, γ3, γ4 and Y5 each independently represent CH or N, wherein the ring contains 0, 1 or 2 nitrogen atoms. The compounds according to the invention may also exist in the form of their salts, hydrates and / or solvates. In the present invention, a physiologically acceptable salt is preferred. 20 In accordance with the present invention, the non-toxic salt is generally prepared by reacting the compound (I) with an inorganic or organic base or acid customarily used for this purpose. Non-restrictive substance of pharmaceutically acceptable salt of compound}} Paper size applies Chinese National Standard (CNS) A4 (21C) x297 & f ------- 200410963 A7 B7 10 15 Intellectual Property Bureau, Ministry of Economic Affairs Printed by employee consumer cooperatives 20 V. Description of the invention (6 cases include metal test salts such as bell, potassium and sodium salts, soil test metal salts such as town and calcium salts, quaternary ammonium salts such as triethylammonium salt, acetate 'benzenesulfonate Acid compliance, benzene gamma salt, dicarbonate, disulfate, ditartrate, borate, odorant, carbonate, gaseous, citrate, dihydrochloride, fumarate gluconate, flour Amine salt, hexyl astringent salt, desertate, = gaseous, hydroxynaphthoate, iodide, isethionate, lactic acid, lauric acid, malate, maleate, mandelate, Formic acid salt, methyl bromide, methyl nitrate, methyl sulfate, nitrate, oleic acid, oxalate, palmitate, pantothenate, photoate, diphosphate, polyhemi, Flyuronic acid salt, salicylate, stearate 'sulfate, succinate, tartrate, p-formate Sulfonates, valerates, and dragons used for medical purposes. Other salts of the compounds of the present invention or their salts | is a compound of compound and water, such as semi-, mono-, or Dihydrate

本發明化合物或其鹽之翻^為化合物與 學計量組成物。 J 本發明包含根據本發明化合物之個別鏡像異構物或非 鏡像異構物及對朗旋物或麵㈣構_合物 ，類。此外，上述化合物所有可能互變異構形式均涵蓋於 ^^額之内。非鏡像異構魏合物可彻層析法分離 ^為個別異構物。消旋物可於對料目上彻層析法或利用 解析法析離成為各個鏡像異構物。 ^本發明朗書中，除非另外陳述，否麟取代基通 果具有下述意義： 200410963 A7 B7 五、發明說明（7 ) 痪盖通常代表具有1至6個、較佳為1至4個碳原子 之直鏈或分支鏈烴基團。其非限制性實例包含甲基、乙 基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三 丁基、戊基、異戊基、己基、異己基。相同之界定亦應用 5 於例如烧氧基、烷胺基、烷氧羰基及烷氧羰胺基等基團。 褒氧·基之較佳代表性實例為甲氧基、乙氧基、正丙氧 基、異丙氧基、第三丁氧基、正戊氧基及正己氧基。 .迄基基.通常代表具有1至6個、較佳為1至4個碳 原子，於連接位置具羰基官能度之直鏈或分支鏈烴基團。 10其非限制性實例包含甲醯基、乙醯基、正丙醯基、正丁醯 基、異丁醯基、三甲基乙醯基、正己醯基。 迄氧羰基之較佳代表性實例為甲氧羰基、乙氧羰基、 正丙氧羰基、異丙氧羰基、第三丁氧羰基、正戊氧羰基及 正己氧羰基。 15 迄篮羞·代表具有一或二個（獨立地選定之)烷基取代基 經濟部智慧財產局員工消費合作社印製 之烷胺基，其較佳代表性實例為甲胺基、乙胺基、正丙胺 基、異丙胺基、第二丁胺基、正戊胺基、正己胺基、％, 二甲胺基、iV，#-二乙胺基、JV-乙基^^甲胺基、#_甲基· 正丙胺基、tV-異丙基亦正丙胺基、^^第三丁基善甲胺 20基、’乙基善正戊胺基及#·正己基_^甲胺基。 迄碁胺羰基代表具有一或二個（獨立地選定之)烷基取 代基之縣胺幾基，其較佳代表性實例為甲基胺絲、乙 基胺Μ基、正丙基胺幾基、異丙基胺幾基、第三丁基胺幾 基、正戊基胺幾基、正己基胺縣、移二甲基胺㈣、The compounds of the present invention or salts thereof are compound and stoichiometric compositions. J The present invention encompasses individual enantiomeric or non-enantiomeric isomers and para-orthomorphs of the compounds according to the present invention. In addition, all possible tautomeric forms of the above compounds are included in the amount. Non-mirromeric isomers can be separated by chromatography to separate isomers. Racemates can be chromatographed on the opposite material or separated by analytical methods to form the respective mirror isomers. ^ In the book of the present invention, unless otherwise stated, the non-substituent group has the following meanings: 200410963 A7 B7 V. Description of the invention (7) Paralyzed cap usually represents having 1 to 6, preferably 1 to 4 carbons. Atomic straight or branched hydrocarbon groups. Non-limiting examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, third butyl, pentyl, isopentyl, hexyl, isohexyl. The same definition applies to groups such as alkoxy, alkylamino, alkoxycarbonyl and alkoxycarbonylamino. Preferred representative examples of fluorenyl are methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy, and n-hexyloxy. So faryl. Usually represents a straight or branched chain hydrocarbon group having from 1 to 6, preferably 1 to 4 carbon atoms, having carbonyl functionality at the attachment position. 10 Non-limiting examples thereof include methylamyl, ethylamyl, n-propylamyl, n-butylamyl, isobutylamyl, trimethylethylamyl, n-hexylamyl. Preferred representative examples of oxocarbonyl are methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tertiary butoxycarbonyl, n-pentoxycarbonyl and n-hexyloxycarbonyl. 15 To date, it represents alkylamine groups printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs with one or two (independently selected) alkyl substituents. The preferred representative examples are methylamine and ethylamino groups. , N-propylamino, isopropylamino, second butylamino, n-pentylamino, n-hexylamino,%, dimethylamino, iV, # -diethylamino, JV-ethyl ^^ methylamine, # _Methyl-n-propylamino, tV-isopropyl-n-propylamino, ^^-tert-butylsynamine 20, 'ethyls-n-pentylamino, and # -n-hexyl_ ^ methylamine. So far, the amine carbonyl group represents an amine group having one or two (independently selected) alkyl substituents, and its preferred representative examples are methylamine silk, ethylamine M group, n-propylamine group , Isopropylamine, tributylamine, n-pentylamine, n-hexylamine, dimethylamine,

200410963 A7 B7 五、發明說明（8) 5 10 15 經濟部智慧財產局員工消費合作社印製 20 二乙基胺Μ基、#"乙基曱基胺幾基、I甲基正 丙基胺•基、#*異丙基正丙基胺幾基、’第三丁基"Ί* 甲基胺羰基、沁乙基-沁正戊基胺羰基及沁正己基甲基 胺羰基。 烷基磺醯基通常代表具有1至6個、較佳為1至4個 碳原子’於連接位置具續酿基s能度之直鍵或分支鍵煙基 團。其非限制性實例包含甲基磺醯基、乙基磺醯基、正丙 基績酿基、異丙基績酿基、正丁基確醢基、第三丁基績醢 基。 環炼羞通常代表具有3至8個、較佳為3至6個碳原 子之環狀飽和烴基團。其非限制性實例包含環丙基、環丁 基、環戊基、環己基及環庚基。 蓋羞..IL.甚本盖及於芳羰基中代表具有ό至η個碳原 子之單-至三環芳族碳環基團，其較佳代表性實例為苯 基、萘基及啡基(phenanthrenyl)。 羞ΑΜΑ之較佳代表性實例為苯甲醯基及萘甲醯美 隻芳基就其本身及於雜芳基羰基中存喪通^具土 10個，較佳為5或6個環原子及多達5個及較佳至 個選自包括S、0及Ν的雜原子之芳族單_或雙产I運‘ 其較佳代表性實例為噻吩基、呋喃基、吡咯基、衣土團， σ号峻基、咪峻基、咩二唾基、嗟二唾基、 4 噻唑基、 基、塔σ井基、㈣基"弓卜坐基、苯并w夫喃 喊咬 基、苯并嘆嗤基、啥琳基、異啥琳基。、苯并疏苯 蔓蓋之較佳代表性實例為噻吩λ土每基、呋喃基 本紙張尺度適財S國家鮮(CNS)A4規格（21Q χ 29；7公麓） 200410963 A7 B7200410963 A7 B7 V. Description of the invention (8) 5 10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Diethylamine M-based, # " Ethylamidoamine, I-methyl-n-propylamine • Group, # * isopropyl-n-propylamine group, 'third butyl " Ί * methylamine carbonyl group, qinethyl-p-n-pentylamine carbonyl group and qin-n-hexylmethylamine carbonyl group. The alkylsulfonyl group generally represents a straight or branched tobacco group having 1 to 6, preferably 1 to 4 carbon atoms' having a continuous group s energy at the attachment position. Non-limiting examples thereof include methylsulfonyl, ethylsulfonyl, n-propylpyrrolyl, isopropylpyrrolyl, n-butylpyrrolyl, and tert-butylpyrrolyl. Cyclones generally represent cyclic saturated hydrocarbon groups having 3 to 8, preferably 3 to 6 carbon atoms. Non-limiting examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Gai..IL. Even Bengai represents a mono- to tricyclic aromatic carbocyclic group having 6 to η carbon atoms in the arylcarbonyl group. The preferred representative examples are phenyl, naphthyl, and phenyl (phenanthrenyl). The preferred representative examples of AMMA are benzamyl and naphthylmethyl aryl groups, which are themselves and in the heteroaryl carbonyl group, have 10, preferably 5 or 6 ring atoms, and Up to 5 and preferably to aromatic mono- or di-generation of heteroatoms selected from heteroatoms including S, 0, and N. The preferred representative examples are thienyl, furyl, pyrrolyl, and clay. , Sigma, stilbyl, stilbyl, bisdisyl, bisdisyl, 4thiazolyl, stilbene, stilbyl, stilbyl, " bendyl, benzow sulfonyl, benzene And sighed Ji Yan, Han Linki, Yi Han Link. The best representative examples of benzoxene manganese are thiophene λ soil per base, furanyl. Paper size suitable for the country S (CNS) A4 specifications (21Q χ 29; 7 male feet) 200410963 A7 B7

五、發明說明（9) 5 10 15 經濟部智慧財產局員工消費合作社印製 20 幾基、料基縣、輪基絲、W料基、料基幾 基、吡啶基羰基、嘧啶基羰基、嗒啩基羰基、吲哚基羰 基、啊絲基n㈣基減、料絲基幾基、啥 琳基羰基、異啥琳基羰基。 龜垄基就其毛農屋玄雜環基轶基 1代表通常具有4至 10個，較佳5至8個環原子，及多達3個，較佳多達2 個選自包括N、〇、S、SO及S〇2之雜原子及/或雜基團 之單-或多環’較佳為單或雙環之⑽麵環基團。該雜 環基團可為飽和或部分我和，佳者為具有多達2個選 自包括Ο、N及S的雜原子之5至M單環飽和雜環基 團，其較佳代表性實例為四氫呋喃_2_基、吡咯啶_丨_基、 吡咯啶-2-基、吡咯啶·3_基、吡咯啉基、哌啶基、； 基、全氫吖庚因基。 祖缝Α之較佳代表性㈣為四|^喃_2_幾基、 料咬幾基、°比略咬_2_幾基”比略咬-3-減、 羰基、哌啶羰基、嗎啉羰基、全氫吖庚因羰基。 ϋ代表氟、氣、溴及碘。 於與Y5代產^4 I之敘迷中 亦代表被取代基R3或R7取代之環碳原子。 緊鄰鍵結之符號*代表在分子中之連接點。 於另一具體實例中，本發明係有關具式（I)之作人 物，其中 匕合 代表芳基或雜芳環；V. Description of the invention (9) 5 10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20, Jiji County, Luji County, Wujiji, Jijiji, Pyridylcarbonyl, Pyrimidylcarbonyl, Da Fluorenylcarbonyl, indolylcarbonyl, ahselyl n-fluorenyl, sulfalyl, halinylcarbonyl, isohalinylcarbonyl. The turtle ridge group is represented by its hairy farmhouse heterocyclyl 1, which usually has 4 to 10, preferably 5 to 8 ring atoms, and up to 3, preferably up to 2 selected from N, 〇 A mono- or polycyclic ring of a heteroatom and / or a hetero group of S, SO, and S02 is preferably a mono- or bicyclic fluorene ring group. The heterocyclic group may be saturated or partially heterocyclic, preferably a 5 to M monocyclic saturated heterocyclic group having up to 2 heteroatoms selected from the group consisting of 0, N, and S. Preferred representative examples thereof It is a tetrahydrofuran-2-yl group, a pyrrolidinyl group, a pyrrolidin-2-yl group, a pyrrolidin-3-yl group, a pyrrolidinyl group, a piperidinyl group, and a perhydroazepine group. The best representative of ancestral joint A is four | ^ _2_ jiji, jiji jiji, ° ratio slightly _2_ jiji "ratio slightly -3-min, carbonyl, piperidine carbonyl,? Phenyl carbonyl, perhydroazepine carbonyl. Ϋ represents fluorine, gas, bromine and iodine. In the narration with Y5 generation ^ 4 I also represents a ring carbon atom substituted by a substituent R3 or R7. Close to the bond The symbol * represents the point of attachment in the molecule. In another specific example, the present invention relates to a character with formula (I), wherein the dagger represents an aryl or heteroaryl ring;

A R】 R2與R3各自獨立地代表氫、南素、碼基、氛基、 11- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）A R] R2 and R3 each independently represent hydrogen, southern element, code base, atmosphere base, 11- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

200410963 A7 B7 五、發明說明（10) 烷基、羥基或CrCV烷氧基，其中CrCp烷基與 CrCr烧氧基可進一步被一至三個相同或不同之選自 包括鹵素、羥基及CrCr烷氧基之基團取代； R 代表Ci-CV烧基幾基、Ci-Cs·院氧基幾基、••烯 5 氧基羰基 '羥羰基、胺羰基、單-或二-CrC4_烷基胺 幾基、C6-C1G_芳基胺幾基、雜芳基幾基、雜環基幾 基、雜芳基、雜環基或氰基，其中crc6_烷基羰基、 Ci-C6_烧氧基幾基、单-及二-C1-C4-烧基胺幾基可進 一步被一至三個相同或不同之選自包括C3<v環烷 10 基、羥基、CrC4-烷氧基、CrCV烷氧羰基、羥羧 基、胺羰基、單-及二-CrC4-烷基胺羰基、CrC4-烷 基幾胺基、胺基、單-及二-C1-C4-烧胺基、雜芳基、 雜環基及三-(crc6-烷基)-矽烷基之基團取代； R5 代表CrCV烷基，其可被一至三個相同或不同之選 15 自包括鹵素、羥基、CrC6-烷氧基、〔!-(：6_烯氧基、200410963 A7 B7 V. Description of the invention (10) Alkyl, hydroxy or CrCV alkoxy, in which CrCp alkyl and CrCr alkoxy may be further one to three same or different and selected from halogen, hydroxy and CrCr alkoxy Group substitution; R represents Ci-CV alkyl group, Ci-Cs · oxy group, alkene 5 oxycarbonyl'hydroxycarbonyl group, amine carbonyl group, mono- or di-CrC4-alkylamine group , C6-C1G_arylamine, aryl, heteroaryl, heterocyclyl, heteroaryl, heterocyclyl, or cyano, among which crc6-alkylcarbonyl, Ci-C6_alkyloxy May be further selected from the group consisting of C3 < v cycloalkanoyl, hydroxyl, CrC4-alkoxy, CrCV alkoxycarbonyl, Hydroxy carboxyl, amine carbonyl, mono- and di-CrC4-alkylamine carbonyl, CrC4-alkylpolyamino, amine, mono- and di-C1-C4-alkylamino, heteroaryl, heterocyclic and Tri- (crc6-alkyl) -silyl group substitution; R5 represents CrCV alkyl, which can be selected from one to three same or different. 15 Including halogen, hydroxyl, CrC6-alkoxy, [!-( : 6_enoxy,

CrC6-烷硫基、胺基、單-及二-CrC6-烷胺基、芳胺 基、羥羰基、CrC6-烷氧羰基及-Ο-CrCV烷基-0-Q· C4-烷基之基團取代； 經濟部智慧財產局員工消費合作社印製 或 20 R5 代表胺基； R6代表氫、CrC6-烧基、甲醯基、胺羰基、單或二-Ci-C4-烧基胺幾基、C3-C8-環烧基叛基、CrCV烧基羰 基、CrC6-烷氧羰基、N-(CrC4_烷基磺醯基）-胺羰 基、N-(CrC4-烷基磺醯基)-N-(CrCr烷基)-胺羰基、 -12- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 經濟部智慧財產局員工消費合作社印製 200410963 A7 B7 五、發明說明（11) 雜芳基、雜環基、雜芳基羰基或雜環基羰基，其中 CrC6-烧基、單及二_CrC4-垸基胺幾基、C!_c6-炫基 羰基、CrCr烷氧羰基、雜芳基及雜環基可被一至三 個相同或不同之選自包括芳基、雜芳基、羥基、Cr 5 C4-烷氧基、羥羰基、CrC6-烷氧羰基、胺羰基、單- 及二-C!-C4-烷基胺羰基、胺基、單_及二_crC4-烷胺 基、Ci-CV烧基羰胺基、三-(Q-Q-烧基)-碎烧基、氰 基、N·(單-及二_CrC4_燒胺基_CVC4-烧基)-胺羰基、 N-(CrC4-烷氧基_CrC4-烷基)_胺羰基及鹵素之基團取 10 代； 或 R6 代表具下式之基團CrC6-alkylthio, amine, mono- and di-CrC6-alkylamino, arylamino, hydroxycarbonyl, CrC6-alkoxycarbonyl and -0-CrCV alkyl-0-Q · C4-alkyl groups Group replacement; printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy or 20 R5 represents amine; R6 represents hydrogen, CrC6-alkyl, methylamino, aminecarbonyl, mono- or di-Ci-C4-alkylamino, C3-C8-cycloalkyl, CrCV alkyl, CrC6-alkoxycarbonyl, N- (CrC4-alkylsulfonyl) -aminocarbonyl, N- (CrC4-alkylsulfonyl) -N- (CrCr alkyl) -amine carbonyl, -12- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 200410963 A7 B7 V. Description of the invention (11 ) Heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl, in which CrC6-alkyl, mono- and di-CrC4-fluorenylamine, C! _C6-hexylcarbonyl, CrCralkoxycarbonyl, Heteroaryl and heterocyclyl may be one to three which are the same or different and are selected from the group consisting of aryl, heteroaryl, hydroxyl, Cr5C4-alkoxy, hydroxycarbonyl, CrC6-alkoxycarbonyl, aminecarbonyl, mono- And di-C! -C4-alkylamine carbonyl, amine , Mono- and di-crC4-alkylamino groups, Ci-CV alkyl carbonylamino groups, tri- (QQ-alkyl) -crucyl groups, cyano, N · (mono- and di-CrC4_alkylamino groups _CVC4-alkenyl) -aminocarbonyl, N- (CrC4-alkoxy_CrC4-alkyl) -aminocarbonyl and halogen groups take 10 generations; or R6 represents a group having the formula

式中 15 R6A 係選自氫與CVCV烷基，及 η 代表整數1或2 ; R7代表鹵素、硝基、氰基、烷基、羥基或CrCV* 烷氧基，其中CrC^烷基及Cl_C6-烷氧基可進一步被 一至二個相同或不同之選自包括鹵素、羥基及 20 烷氧基之基團取代； 及 Y、Y、Y3、Y4與Υ5各自獨立地代表cH*N，其中該 -13- 本紙張尺度適財@ 0家標準(CNS)A4規格（210 X 297公£5In the formula, 15 R6A is selected from hydrogen and CVCV alkyl, and η represents an integer of 1 or 2; R7 represents halogen, nitro, cyano, alkyl, hydroxyl, or CrCV * alkoxy, in which CrC ^ alkyl and Cl_C6- The alkoxy group may be further substituted with one or two groups which are the same or different and are selected from the group consisting of halogen, hydroxyl and 20 alkoxy groups; and Y, Y, Y3, Y4 and c5 each independently represent cH * N, wherein- 13- The paper size is suitable for financial @ 0 house standard (CNS) A4 specifications (210 X 297 Kg £ 5

200410963 A7 B7 五、發明說明（12) 環含有0、1或2個氮原子。 於另一具體實例中，本發明係有關具式（I)之化合 物，其中 A 代表苯基、萘基或啦啶基環； 5 R1、R2與R3各自獨立地代表氫、氟、氣、溴、硝基、氰 基、甲基、乙基、二氟甲基或三氟甲氧基； R4 代表CrC6-烷基羰基、CrC6-烷氧基羰基、羥羰基、 胺羰基、單-crc4-烷基胺羰基或氰基，其中 基羰基、crc6-烷氧基羰基及單-crc4-烷基胺羰基可 10 被一至三個相同或不同之選自包括c3-c8-環烷基、經 基、CrCr烷氧基、CrCr烷氧羰基、胺基、單-及 二-C1-C4"·烧胺基、雜芳基及雜環基之基團取代， R3 代表甲基或乙基； R6 代表氫、CrC6-烷基、單-或二-CrCr烷基胺羰基、 15 cvcv烷基羰基、cvc6-烷氧羰基或雜環基羰基，其 經濟部智慧財產局員工消費合作社印製 中CrC6-烷基及CrC6-烷氧羰基可被一至三個相同或 不同之選自包括雜芳基、羥基、CrC4-烷氧基、羥羰 基、Ci-C6-烧氧幾基、胺魏基、早-及二_Ci_C4_烧基 胺羰基、氰基、胺基、單-及二-CVCr烷胺基之基團 20 取代； 或 R6 代表具下式之基團 -14- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（13) ·αο〆 α0〆 式中 R6A 係選自氫與CVCr烷基，及 π 代表整數1或2; 5 R7 代表鹵素、硝基、氰基、三氟甲基、三氟甲氧基、 曱基或乙基； 及 γ1、γ2、γ3、Y4 與 γ5 各自代表 CH。 於另一具體實例中，本發明係有關具式（I)之化合 10 物，其中 A 代表苯基或ϋ比唆基環； R1與R3各自代表氫； R2 代表氟、氣、溴、硝基或氰基； R4 代表氰基、CrC4-烷基羰基或CrC4-烷氧基羰基，其 15 中CKC4-烷氧基羰基可被選自包括羥基、CrC4-烷氧 經濟部智慧財產局員工消費合作社印製 基、C1-C4-烧氧獄基、早·及二-C1-C4-烧胺基、雜芳 基及雜環基之基團取代； R5 代表甲基； R6 代表氫、CrC4-烷基、單-或二-Ci-Cr烷基胺羰基、 20 CrC4-烷基羰基或CrC4-烷氧羰基，其中CrCr烷基 及CrC4-烷氧羰基可被選自包括雜芳基、羥基、Cr C4-烷氧基、羥羰基、胺羰基、單-及二-CrC4-烷基胺 -15- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（14) 羰基、胺基、單-及二-CrCr烷胺基之基團取代； 或 R6 代表具下式之基團200410963 A7 B7 V. Description of the invention (12) The ring contains 0, 1 or 2 nitrogen atoms. In another specific example, the present invention relates to compounds of formula (I), wherein A represents a phenyl, naphthyl or pyridyl ring; 5 R1, R2 and R3 each independently represent hydrogen, fluorine, gas, bromine , Nitro, cyano, methyl, ethyl, difluoromethyl or trifluoromethoxy; R4 represents CrC6-alkylcarbonyl, CrC6-alkoxycarbonyl, hydroxycarbonyl, aminecarbonyl, mono-crc4-alkane Aminoamine carbonyl or cyano, wherein the carbonyl, crc6-alkoxycarbonyl and mono-crc4-alkylamine carbonyl groups may be one to three identical or different and selected from the group consisting of c3-c8-cycloalkyl, meridian, CrCr alkoxy, CrCr alkoxycarbonyl, amine, mono- and di-C1-C4 ". Substituted by amine, heteroaryl and heterocyclic groups, R3 represents methyl or ethyl; R6 represents hydrogen , CrC6-alkyl, mono- or di-CrCr alkylamine carbonyl, 15 cvcv alkylcarbonyl, cvc6-alkoxycarbonyl or heterocyclic carbonyl, printed by CrC6-alkyl in the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs And CrC6-alkoxycarbonyl may be one to three same or different and selected from the group consisting of heteroaryl, hydroxyl, CrC4-alkoxy, hydroxycarbonyl, Ci-C6-alkoxycarbonyl, amine , Early- and di_Ci_C4_alkylaminocarbonyl, cyano, amine, mono- and di-CVCr alkylamino groups of 20; or R6 represents a group of the formula -14- Applicable to this paper standard Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (13) · αο〆α0〆 where R6A is selected from hydrogen and CVCr alkyl, and π represents an integer 1 or 2; 5 R7 represents halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, fluorenyl, or ethyl; and γ1, γ2, γ3, Y4, and γ5 each represent CH. In another specific example, the present invention relates to a compound of formula (I), wherein A represents a phenyl or fluorenyl ring; R1 and R3 each represent hydrogen; R2 represents fluorine, gas, bromine, and nitro Or cyano; R4 represents cyano, CrC4-alkylcarbonyl or CrC4-alkoxycarbonyl, among which 15 CKC4-alkoxycarbonyl can be selected from the group consisting of hydroxy, CrC4-alkoxy, the Intellectual Property Bureau, the Consumer Consumption Cooperative of the Ministry of Economic Affairs Substituents for printed groups, C1-C4-oxybenzyl, early and di-C1-C4-alkylamino, heteroaryl and heterocyclic groups; R5 represents methyl; R6 represents hydrogen, CrC4-alkane Group, mono- or di-Ci-Cr alkylamine carbonyl, 20 CrC4-alkylcarbonyl or CrC4-alkoxycarbonyl, wherein CrCralkyl and CrC4-alkoxycarbonyl can be selected from the group consisting of heteroaryl, hydroxyl, Cr C4-alkoxy, hydroxycarbonyl, aminecarbonyl, mono- and di-CrC4-alkylamine-15- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 200410963 A7 B7 V. Invention Explanation (14) carbonyl, amine, mono- and di-CrCr alkylamino groups are substituted; or R6 represents a group of the formula

*乂0< 或 5 式中 R6A 係選自氫及甲基， R7 代表三氟曱基或硝基； 及 γ1、γ2、γ3、γ4 與 γ5 各自代表 CH。 10 於另一具體實例中，本發明係有關根據式(I)之化合 物，其中A為苯基或11比咬基者。 於另一具體實例中，本發明係有關根據式（I)之化合 物，其中R1為氫者。 經濟部智慧財產局員工消費合作社印製 於另一具體實例中，本發明係有關根據式(I)之化合 15 物，其中R2為氰基，尤其是其中A為苯基或吼啶基者， 及相對於中心二氫嘧啶酮環，R2為對位氰基者。 於另一具體實例中，本發明係有關根據式⑴之化合 物，其中R3為氫者。 於另一具體實例中，本發明係有關根據式⑴之化合 20 物，其中R4為視需要被羥基取代之CrC4-烷氧羰基，尤 其是2-羥基乙氧羰基者；或其中R4為CrC4-烷基羰基， 尤其是甲基羰基者。 -16- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐) 200410963 A7 B7 五、發明說明（15) 於另一具體實例中，本發明係有關根據式⑴之化合 物，其中R5為甲基者。 於另一具體實例中，本發明係有關根據式⑴之化合 物，其中R6為氫者。 5 於另一具體實例中，本發明係有關根據式⑴之化合 物，其中R7為三氟甲基或硝基者，尤其是相對於中心二 氫嘴唆酮環，R7為間位三氟曱基者。 於另一具體實例中，本發明係有關具下式(IA)之化合 物 10* 乂 0 < or 5 where R6A is selected from hydrogen and methyl, R7 represents trifluorofluorenyl or nitro; and γ1, γ2, γ3, γ4, and γ5 each represent CH. 10 In another embodiment, the present invention relates to compounds according to formula (I), wherein A is phenyl or 11-bityl. In another embodiment, the present invention relates to compounds according to formula (I), wherein R1 is hydrogen. Printed in another specific example by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics, the present invention relates to compounds according to formula (I), wherein R2 is cyano, especially those in which A is phenyl or amidino And relative to the central dihydropyrimidinone ring, R2 is the para-cyano group. In another embodiment, the present invention relates to a compound according to formula (I), wherein R3 is hydrogen. In another specific example, the present invention relates to the compound 20 according to formula (I), wherein R4 is a CrC4-alkoxycarbonyl group, especially 2-hydroxyethoxycarbonyl group, if necessary, substituted by a hydroxyl group; or wherein R4 is CrC4- Alkylcarbonyl, especially methylcarbonyl. -16- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (15) In another specific example, the present invention relates to a compound according to formula (1), where R5 is a methyl group. In another embodiment, the present invention relates to a compound according to formula (I), wherein R6 is hydrogen. 5 In another embodiment, the present invention relates to compounds according to formula (I), wherein R7 is trifluoromethyl or nitro, especially relative to the central dihydrofluorenone ring, R7 is meta-trifluorofluorenyl By. In another embodiment, the present invention relates to a compound having the formula (IA) 10

(IA), 式中 經濟部智慧財產局員工消費合作社印製 Z 代表CH或N;及(IA), printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy, Z represents CH or N; and

Rl、R3、R4與R6具有上文指示之意義。 R6為氫之本發明化合物可烯醇化成為對應之羥基脒 15 類： -17- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（16)R1, R3, R4 and R6 have the meanings indicated above. The compound of the present invention where R6 is hydrogen can be enolized into the corresponding hydroxyl group 脒 15: -17- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (16)

RR

Η R3Η R3

RR

CHO 經濟部智慧財產局員工消費合作社印製Printed by CHO Consumer Cooperative, Intellectual Property Bureau, Ministry of Economic Affairs

Rs^〇 (ΙΠ) 式（I)化合物之合成可利用使具下式（II)之化合物 (H) 式中 5 A'R1與R2具有上文指示之意義； 與具下式（III)之化合物Rs ^ 〇 (ΙΠ) The compound of formula (I) can be synthesized by using compound (H) of formula (II) where 5 A'R1 and R2 have the meanings indicated above; and of formula (III) Compound

式t R4與R5具有上文指示之意義； 1〇 及具下式（IV)之化合物 -18- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（17 ) NH, ΗΝ、ΌFormula t R4 and R5 have the meanings indicated above; 10 and compounds with the following formula (IV) -18- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200410963 A7 B7 V. Invention description (17) NH, ΗΝ, Ό

Yj^Y5 R3 •R7 0V) 式中 R3、R7、及Y1至Y5具有上文指示之意義； 於酸存在下，以三成分/一個步驟反應，或者連續反應 得到具下式（IB)之化合物Yj ^ Y5 R3 • R7 0V) where R3, R7, and Y1 to Y5 have the meanings indicated above; in the presence of an acid, react in three components / one step, or continuously react to obtain a compound of the following formula (IB)

OB), 經濟部智慧財產局員工消費合作社印製 10 式中 A、R1至R5、R7、及Y1至Y5具有上文指示之意義 隨後視需要使式(IB)化合物與具下式(V)之化合物OB), printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs10 where A, R1 to R5, R7, and Y1 to Y5 have the meanings indicated above, and then if necessary, the compound of formula (IB) and Compound

R6*-X (V) 式中 R6+具有如上文R6指示之意義，惟不代表氫；及 X 代表釋離基，例如_素、對甲苯磺醯基、曱磺醯基或硫酸 根； -19- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（IS) 於鹼存在下進行反應。 式⑴化合物中’ R代表氰基、R5代表胺基及R6代表 氫者，可替代地利用使式(π)化合物與式(IV)化合物及具 下式（VI)之化合物 5 NC—CH2—CN (VI) 於酸存在下，以三成分/一個步驟反應，或者連續反應予 以製備。 適用於（II) + (ΠΙ)/(νΐ) + (IV) _ (IB)程序之溶劑 為於反應條件下不發生變化之習知有機溶劑，包括醚類例 10如乙醚、異丙醚、i，2-二甲氧乙烷、二咩烷或四氫呋喃、 乙酸乙酯、丙酮、乙腈、二甲亞碾、二甲基甲醯胺、或醇 類例如甲醇'乙醇、正丙醇、異丙醇、正丁醇或第三丁 醇、或烴例如戊烷、己烷、環己烷、苯、甲苯或二甲苯、 或i基烴例如二氯甲烷、二氣乙烷、三氯甲烷或氣苯。亦 15可使用前述溶劑之混合物。此程序之較佳溶劑為四氡呋 喃。 經濟部智慧財產局員工消費合作社印製 適用於（II) + (III)/(VI) + (IV) — (IB)程序之酸為 一般無機或有機酸，較好包含羧酸例如乙酸或三氟乙酸、 磺酸例如曱磺酸或對曱苯磺酸、鹽酸或磷酸類例如多磷酸 20類，較佳者為多填酸乙醋。所用酸之量相對於1莫耳气 (III)化合物為0.25莫耳至100莫耳。 此程序通常於+20t至+ 150。(：，較佳為十⑹它至^㈨ V之溫度範圍内進行。 -20- 200410963 五、發明說明（19) 此程序通常於常摩下進行。然而 下（例如，在0 5 s j於加壓或減壓 •主5巴範圍内）進行。 適用於（ΙΒ) + ίν、 ， 下不發生變化之以 1：>斜之#料於反應條件 鰱、u-二甲氧=有機溶劑’包括醚類例如乙鍵、異丙 網、乙猜、二甲亞t二极或四氮乙酸乙醋、丙 烧、環己烧、苯、甲笨:甲基甲酿胺、或烴例如戊烧、己 p 一翁，p _ 或一甲苯、或鹵基烴例如二氣甲 ==7燒或氣苯。亦可使用前述溶劑之混 口物此程序之較佳_為四氫 10 15 經濟部智慧財產局員工消費合作社印製 20 適用於（IB) + (v)—⑴程序之驗為一般無機或有 機驗較好包含環狀胺例如嗓淀或 4-ν|ν-2^胺基口比 咬、或(CrC4)_:垸胺例如三乙胺或二異丙基乙胺、或氣 化物例如氮彳’較佳者為氮化納。所帛驗之量相對於$ 莫耳式(IV)化合物為（U莫耳至1〇莫耳，較佳為1莫耳 至3莫耳。 此程序通常於（TC至+15(rc，較佳為十加艺至+⑽它之 溫度範圍内進行。 此程序通常於常壓下進行。然而，亦可於加壓或減壓 下（例如，在0.5至5巴範圍内）進行。 式（II)、（III) ' (IV)、（V)與(VI)化合物為本質上已知 者，或者可利用習知方法製備。 上述方法可利用下述反應圖式予以說明： 21- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（2〇R6 * -X (V) where R6 + has the meaning as indicated by R6 above, but does not represent hydrogen; and X represents a releasing group, such as _ prime, p-toluenesulfonyl, sulfonylsulfonyl or sulfate; -19 -This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200410963 A7 B7 5. Description of Invention (IS) The reaction is performed in the presence of alkali. In the compound of formula ⑴, R represents a cyano group, R5 represents an amine group, and R6 represents hydrogen. Alternatively, a compound of the formula (π) and a compound of the formula (IV) and a compound of the following formula (VI) 5 NC—CH2— CN (VI) is prepared in the presence of an acid in a three-component / one-step reaction, or in a continuous reaction. Solvents suitable for (II) + (ΠΙ) / (νΐ) + (IV) _ (IB) procedures are conventional organic solvents that do not change under the reaction conditions, including ethers such as ether 10, isopropyl ether, i 2,2-dimethoxyethane, dioxane or tetrahydrofuran, ethyl acetate, acetone, acetonitrile, dimethyl arylene, dimethylformamide, or alcohols such as methanol 'ethanol, n-propanol, isopropanol , N-butanol or tertiary butanol, or a hydrocarbon such as pentane, hexane, cyclohexane, benzene, toluene or xylene, or an i-based hydrocarbon such as dichloromethane, digas ethane, chloroform, or gas benzene . It is also possible to use a mixture of the aforementioned solvents. The preferred solvent for this procedure is tetramethylfuran. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, suitable for (II) + (III) / (VI) + (IV) — (IB) procedures. The acids are generally inorganic or organic acids, preferably containing carboxylic acids such as acetic acid or tricarboxylic acid. Fluoroacetic acid, sulfonic acid such as sulfonic acid or p-toluenesulfonic acid, hydrochloric acid, or phosphoric acid such as polyphosphoric acid 20, and more preferably ethyl polyacetate. The amount of acid used is 0.25 to 100 moles relative to 1 mole of the gas (III) compound. This procedure is usually from + 20t to +150. (:, Preferably in the temperature range of ⑹⑹ to ㈨㈨ V. -20- 200410963 V. Description of the invention (19) This procedure is usually performed under constant friction. However, (for example, at 0 5 sj in Canada Pressure or reduced pressure (within the main 5 bar range). Applicable to (ΙΒ) + ίν,, which will not change if the following: 1: > oblique # expected in the reaction conditions, u-dimethoxy = organic solvent ' Includes ethers such as ethyl bonds, isopropyl network, ethidium, dimethylacetate, diethyl or tetrazine, ethyl acetate, propylene, cyclohexane, benzene, methylbenzyl: methyl methylamine, or hydrocarbons such as pentyl , A p-one, p_ or a toluene, or a halogenated hydrocarbon such as dichloromethane == 7 or gas benzene. Mixtures of the aforementioned solvents can also be used. This procedure is better _ tetrahydro 10 15 Ministry of Economic Affairs Printed by the Intellectual Property Bureau's Consumer Cooperatives. 20 Applicable to (IB) + (v) —The tests for procedures are generally inorganic or organic. It is better to include cyclic amines such as Sodium or 4-ν | ν-2 ^ amino Specific bite, or (CrC4) _: amines such as triethylamine or diisopropylethylamine, or gaseous products such as nitrogen, 'preferable is sodium nitride. The amount tested relative to $ Morse ( IV) Chemical The substance is (U Moore to 10 Moore, preferably 1 Moore to 3 Moore. This procedure is usually performed at a temperature range of (TC to +15 (rc, preferably ten Jiayi to + ⑽). This procedure is usually carried out under normal pressure. However, it can also be carried out under elevated or reduced pressure (for example, in the range of 0.5 to 5 bar). Formulas (II), (III) '(IV), (V) Compounds with (VI) are known in nature, or can be prepared by conventional methods. The above methods can be illustrated using the following reaction schemes: 21- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297) Mm) 200410963 A7 B7 V. Description of the invention (2〇

CHO +CHO +

NH 2NH 2

板據本發明之化合物具有不可預知、有用之藥理及藥 物動力學活性譜，因此適用於作為藥劑以治療及/或預防 人類與動物之疾病。 5 10 經濟部智慧財產局員工消費合作社印製 15 令人驚奇地’本發明化合物顯示人類嗜中性白血球彈 性蛋白酶(HNE)抑制活性，因此適用於製備供治療 活性相關疾病之藥劑，而提供下述疾病之有效治療：急性 與慢性炎症，例如風濕性關節炎、動脈硬化、尤其是急性 與慢性肺部疾病例如肺部纖維化、囊胞性纖維症、肺炎、 急性呼吸窘迫症候群(ARDS)、特別是肺氣腫（包括抽煙誘 發之氣腫）、及慢性阻塞性肺病（C0PD)、慢性支氣管炎與 支氣管擴張。本發明化合物可進一步提供心血管缺血性疾 病例如急性冠狀動脈症候群、急性心肌梗塞、不穩定及穩 定性心絞痛、冠狀動脈間道移植（CABG)及心臟衰蝎形 成、動脈硬化、二尖瓣疾病、心房中隔缺損、心臟冠狀動 脈氣球擴張術(PTCA)、開心臟手術後之炎症及肺動脈高 -22-本紙張尺度適用中國國家標準(CNS)A4規格(210x297公爱丁 200410963 A7 B7 五、發明說明（21) 壓之有效治療；並證明可用於風濕性關節炎、急性炎性關 節炎、癌症、急性胰臟炎、潰瘍性結腸炎、牙周病、邱 利·史挫氏症候群（Chury-Strauss syndrome)、急性與慢性 異位性皮膚炎、牛皮癣、全身性紅斑狼瘡、大皰性類天皰 5 瘡、敗血症、酒精性肝炎、肝纖維化、貝賽特氏症 (Behcet’s disease)、過敏性黴菌型鼻竇炎、過敏性鼻竇 炎、克隆氏症（Crohn’s disease)、川崎症（Kawasaki disease)、腎血管球性腎炎、急性腎盂腎炎、大腸直腸疾 病、慢性化膿性中耳炎、慢性靜脈性腿部潰爛、炎性腸 10疾、細菌及病毒性感染、腦創傷、中風及涉及嗜中性白血 球參與之相關症狀之有效治療。 本發明進一步提供含有至少一種根據本發明的化合 物，較好連同一或多種藥理上安全之賦形劑或載劑物質之 醫藥劑，及其作為上述目的之用途。 15 活性成分具有全身性及/或局部作用。欲達此目的， 可以適當方式予以施用，例如經口、非經腸、經肺、經 經濟部智慧財產局員工消費合作社印製 鼻、舌下、經舌、經頰、經直腸、經皮、經結膜、經耳或 呈楂入物投與。 供彼等施用途徑時，可使活性成分呈適當施用形式投 20 與。 有用的經口施用形式包含迅速釋放活性成分及/或呈 改良开》式之施用形式，例如旋劑（未被覆之錠劑及被覆例 如腸衣之包衣錠劑）、膠囊、糖衣錠劑、粒劑、丸劑、粉 劑、乳液、懸浮液、溶液及氣溶膠。 -23- i紙張尺度適^中國國家標準(CNS)A4規格（210x297公釐） '""""" ----- 、發明說明（22) 非經腸投與可以避開吸收步驟(經靜脈内、動脈内、 ^内 '椎管内或腰_)或包含吸收步驟（經肌内 ^内、經皮或經腹膜内）而進行。有用的非經腸 开)包含呈溶液'懸浮液、乳液、冷滚乾燥物及無菌粉劑 化式之注射及注入製劑。 適於其他施用途徑之形式包含例如吸入性醫 (咖概入劑、喷霧劑)、鼻滴劑/溶液、喷霧液;供： 、舌下或經紐與之_鱗囊、㈣、耳及 ==性，用藥水、振祕物)、親腸性 ;;軟膏、霜劑、乳汁、糊劑、細粉劑或植入物。 雜成分可以本質上已知之方法轉化成前述施 ί等=使用惰性無毒、醫藥上適當之賦形劑予以進行Γ =賦_包括載劑（例如微晶纖維素）、溶劑（例 :乙二醇類)、乳化劑(例如十二基 :、 :)乙稀)、合成及天然生物性聚合物(例如C 白）、安定劑（例如抗氧化劑如抗壞 ^ 白蛋 機色素如氧化鐵類）或味道及/或氣味續正齊^色劑(例如無 供人類用途時，於經口投與棒 ：；001"50 5 么斤。於非經腸投與（例如靜脈 毫克/ 經由黏膜投與)情形下，適當之投頰或吸入等 .斤至0.5毫克/公斤。 與劑里為請1亳克/公 儘管如此，於特定情形下，可 亦即取決於體重、施用途徑:對‘成反 200410963 A7The compounds according to the present invention have an unpredictable and useful spectrum of pharmacological and pharmacokinetic activity and are therefore suitable for use as a medicament for the treatment and / or prevention of diseases in humans and animals. 5 10 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 15 Surprisingly, the compound of the present invention exhibits human neutrophil elastase (HNE) inhibitory activity and is therefore suitable for the preparation of a medicament for treating an activity-related disease, and provides the following Effective treatment of these diseases: acute and chronic inflammation, such as rheumatoid arthritis, arteriosclerosis, especially acute and chronic lung diseases such as pulmonary fibrosis, cystic fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), special Emphysema (including smoking-induced emphysema), chronic obstructive pulmonary disease (COPD), chronic bronchitis, and bronchiectasis. The compounds of the present invention can further provide cardiovascular ischemic diseases such as acute coronary syndromes, acute myocardial infarction, unstable and stable angina pectoris, coronary artery graft (CABG) and heart failure, arteriosclerosis, mitral valve disease Atrial septal defect, cardiac coronary balloon dilatation (PTCA), inflammation after open heart surgery, and high pulmonary arteries-22-This paper size applies Chinese National Standard (CNS) A4 specifications (210x297 male Eding 200410963 A7 B7 V. Description of the invention (21) effective treatment of pressure; and proved to be useful for rheumatoid arthritis, acute inflammatory arthritis, cancer, acute pancreatitis, ulcerative colitis, periodontal disease, and Chulley's syndrome -Strauss syndrome), acute and chronic atopic dermatitis, psoriasis, systemic lupus erythematosus, bullous pemphigoid 5 sores, sepsis, alcoholic hepatitis, liver fibrosis, Behcet's disease, Allergic fungal sinusitis, allergic sinusitis, Crohn's disease, Kawasaki disease, renal glomerulonephritis, acute Effective treatment for pyelonephritis, colorectal and rectal diseases, chronic suppurative otitis media, chronic venous leg ulcers, inflammatory bowel disease, bacterial and viral infections, brain trauma, stroke and related symptoms involving neutrophil involvement. The invention further provides a pharmaceutical agent containing at least one compound according to the invention, preferably with the same or more pharmacologically safe excipients or carrier substances, and its use for the above purpose. 15 The active ingredient has a systemic and / or Local effect. To achieve this purpose, it can be administered in an appropriate manner, such as oral, parenteral, pulmonary, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed by the nose, sublingual, translingual, cheek, transrectal, Transdermal, transconjunctival, transauricular or hawthorn administration. For their route of administration, the active ingredient can be administered in a suitable application form. 20. Useful oral administration forms include rapid release of the active ingredient and / or Modified application forms such as spines (uncoated tablets and coated tablets such as casings), capsules, dragees, granules, Pills, powders, emulsions, suspensions, solutions and aerosols. -23- i Paper size is suitable ^ Chinese National Standard (CNS) A4 specification (210x297 mm) '" " " " " ---- -, Description of the invention (22) Parenteral administration can avoid the absorption step (intravenous, intraarterial, intravertebral or intraspinal) or include the absorption step (intramuscular, transdermal or transcutaneous) Intraperitoneal). Useful parenteral preparations) include injections and injectable preparations in the form of solutions, suspensions, emulsions, cold-rolled dry matter, and sterile powder formulations. Forms suitable for other routes of administration include, for example, inhaled medicine (caffeine, sprays), nasal drops / solutions, sprays; for: sublingual or transdermal_squamous, sacral, ear And == sex, use of potions, vibration secretions), enteric; ointment, cream, milk, paste, fine powder or implant. Miscellaneous ingredients can be converted into the aforementioned methods in a manner known per se = using inert, non-toxic, medically appropriate excipients to carry out Γ = including carrier (such as microcrystalline cellulose), solvents (eg, ethylene glycol Type), emulsifiers (such as twelve-based :, :) ethylene), synthetic and natural biopolymers (such as C white), stabilizers (such as antioxidants such as anti-bad ^ white egg machine pigments such as iron oxides) Or the flavor and / or odor are renewed. (For example, when not for human use, the oral administration stick: 001 " 50 5 kg. For parenteral administration (for example, intravenous mg / via mucosal administration) ) In the case, appropriate chewing or inhalation, etc. from 0.5 kg / kg to 1 mg / g in the preparation. However, under certain circumstances, it may depend on body weight, and the route of administration: to '成Anti 200410963 A7

應、製備方法及施用發生的時間或間隔。於一些情形下， 可能使用較上述最小劑量少之量即夠，而於其他情形下， Y能必須超過上述劑量之上限。施用較大量時，可將彼等 劑量分成一日數次投與較為適當。 除非另行陳述，下文試驗及實例甲之百分比為重量 二、’份數亦為重量比；溶劑比例、稀釋比例及液體/液體 夜所記述之濃度各為以容積計。 [實施方式] 活性評估 本發明化合物抑制嗜中性白血球彈性蛋白酶活性之潛 力’舉例而言，可使用下述試驗予以證明·· L么寒A中性白血球彈性蛋白璩(HNE)之活艚外辞土， m 、Application, method of preparation, and time or interval of application. In some cases, it may be sufficient to use a smaller amount than the above minimum dose, while in other cases, Y energy must exceed the upper limit of the above dose. When a larger amount is applied, it may be appropriate to divide their doses into several times a day. Unless otherwise stated, the percentages of the following tests and examples A are weight. The parts are also weight ratios; the solvent ratio, dilution ratio, and concentration described in liquid / liquid night are each based on volume. [Embodiment] Activity Evaluation Potential of Compounds of the Invention for Inhibiting Neutrophil Elastase Activity 'For example, the following test can be used to demonstrate ... Ci soil, m,

試驗緩衝液：0·1 M HEPES-NaOH緩衝液pH 7.4、 M NaCl、0· 1% (w/v)牛血·清白蛋白； 經濟部智慧財產局員工消費合作社印製 適當濃度（見下文）之HNE (18 U/毫克冷凍乾燥物， #2〇927·〇ΐ，SERVA Electrophoresis GmbH，Heidelberg， Germany)，於試驗缓衝液中； 適當濃度（見下文）之基質，於試驗緩衝液中； 適當濃度之測試化合物，以試驗緩衝液稀釋其於 DMS〇中之mM貯存液。 使用鸯光性胜肽基質（連續讀出訊號，384 MTP試驗版本) -25- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200410963 A7 B7 五、發明說明（24 ) 之活體外抑制HNE : 此實驗流程47，係使用彈性蛋白酶MeOSuc_Ala-Ala_ Pro-Val-AMC (#324740， Calbiochem-Novabiochem Corporation, Merck KGaA，Darmstadt，Germany)。測試溶 5 液之製備係分別混合10微升測試化合物稀釋液、20微升 HNE酵素稀釋液(最終濃度8 - 〇·4//U/毫升，常規濃度 2.1#U/毫升)與2〇微升基質緩釋液(最終濃度i mM - μ Μ，常規濃度20/ζΜ)。於37°C，保溫此溶液〇 - 2小時 (常規1小時）。於37°C，測量由於酵素反應釋放的AMC 10之螢光(TECANSpectΓaFluor加培養盤讀取計）。螢光(eχ 395奈米，em· 460奈米）的增加速率與彈性蛋白酶活性成 正比。利用RFU對[I]作圖決定諸IC5〇值。1^與Km(app) 值則以Lineweaver-Burk作圖決定，並利用Dixon作圖轉 換成IQ值。 15 諸製備例在此試驗中具有範圍在5 nM - 5/zM之IC50 值。其代表性數據如表1所示： 經濟部智慧財產局員工消費合作社印製 本纸張尺度適用中國國家標準(CNS)A4規格（21〇 χ 297公釐） 200410963 A7 B7 五、發明說明（25 ) 表1 實例編號 IC5〇 [nM] 1 8 9 40 14 5 15 8 16 10 20 700 24 13 26 10 28 50 58 1100 60 5 72 6 73 60 74 20 103 60 109 15 110 50Test buffer: 0.1 M HEPES-NaOH buffer pH 7.4, M NaCl, 0.1% (w / v) bovine blood · albumin; appropriate concentration printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (see below) HNE (18 U / mg lyophilizate, # 2〇927 · 〇ΐ, SERVA Electrophoresis GmbH, Heidelberg, Germany), in test buffer; matrix of appropriate concentration (see below) in test buffer; appropriate Concentration of test compound, dilute its mM stock solution in DMS0 with test buffer. Use of photopeptide matrix (continuous readout signal, 384 MTP test version) -25- This paper size is applicable to China National Standard (CNS) A4 (210x297 mm) 200410963 A7 B7 V. Living Instructions (24) Exogenous inhibition of HNE: This experimental procedure 47 uses the elastase MeOSuc_Ala-Ala_ Pro-Val-AMC (# 324740, Calbiochem-Novabiochem Corporation, Merck KGaA, Darmstadt, Germany). The test solution 5 was prepared by mixing 10 microliters of test compound dilution, 20 microliters of HNE enzyme dilution (final concentration 8-0.4 // U / ml, conventional concentration 2.1 # U / ml) and 20 microliters. 1 liter of matrix slow-release solution (final concentration i mM-μM, conventional concentration 20 / ζM). Incubate the solution at 37 ° C for 0-2 hours (normally 1 hour). At 37 ° C, the fluorescence of AMC 10 released by the enzyme reaction was measured (TECANSpectΓaFluor plus plate reader). The rate of increase in fluorescence (eχ 395 nm, em 460 nm) is directly proportional to elastase activity. ICU values were determined using RFU vs. [I] mapping. The values of 1 ^ and Km (app) are determined by Lineweaver-Burk mapping, and the Dixon mapping is used to convert them to IQ values. 15 Preparations in this test have IC50 values ranging from 5 nM to 5 / zM. The representative data is shown in Table 1: The paper size printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs is compliant with the Chinese National Standard (CNS) A4 (21〇χ 297 mm) 200410963 A7 B7 V. Description of the invention (25 ) Table 1 Example number IC5〇 [nM] 1 8 9 40 14 5 15 8 16 10 20 700 24 13 26 10 28 50 58 1100 60 5 72 6 73 60 74 20 103 60 109 15 110 50

實例B 經濟部智慧財產局員工消費合作社印製 使用螢光性、不溶性彈性蛋白基質（不連續讀出訊號，96 5 MTP試驗版本）之活體外抑制ηνε : 此實驗流程中，係使用彈性蛋白酶基質彈性蛋白-螢 光黃（#100620，ICN Biomedicals GmbH, Eschwege， Germany)。測試溶液之製備係將3微升測試化合物稀釋 液、77微升HNE酵素稀釋液(最終濃度0.22 U/毫升-2·2 10 mU/毫升，常規濃度21.7//U/毫升)與80微升基質缓釋液 -27- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200410963 A7 B7 五、發明說明（ (最終濃度2毫克/毫升）混合。於37°c ’些微振盪條件 下，保溫此懸浮液〇 - 16小時（常規4小時）。添加160微 升0.1 Μ乙酸至測試溶液(最終濃度50 mM)中，以終止酵 素反應。離心(EPPend〇rf 5804離心機，3·000 rpm，10分 5 鐘）使聚合之彈性蛋白-螢光黃沉澱下來。將上澄液移至新 的MTP中，測量由於酵素反應釋放的胜肽螢光黃(BMG Fluostar培養盤讀取計）。螢光(ex· 490奈米，em. 520奈 米）速率與彈性蛋白酶活g生成正比。利用RFU對[I]作圖決 定諸IC5G值。Example B: In vitro inhibition of fluorescent and insoluble elastin matrix (discontinuous readout signal, 96 5 MTP test version) printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs: In this experimental procedure, an elastase matrix was used Elastin-Fluorescent Yellow (# 100620, ICN Biomedicals GmbH, Eschwege, Germany). The test solution was prepared by mixing 3 microliters of test compound dilution, 77 microliters of HNE enzyme dilution (final concentration 0.22 U / ml-2 · 2 10 mU / ml, conventional concentration 21.7 // U / ml) and 80 µl Matrix slow-release solution-27- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200410963 A7 B7 V. Description of the invention ((final concentration 2 mg / ml) mixed. At 37 ° C, some shaking conditions Incubate this suspension for 0-16 hours (conventional 4 hours). Add 160 μl of 0.1 M acetic acid to the test solution (final concentration 50 mM) to stop the enzyme reaction. Centrifuge (EPPendorf 5804 centrifuge, 3. · (000 rpm, 10 minutes and 5 minutes) to precipitate the polymerized elastin-fluorescent yellow. Transfer the supernatant to a new MTP and measure the peptide fluorescent yellow (BMG Fluostar dish reader) released by the enzyme reaction. ). The rate of fluorescence (ex. 490 nm, em. 520 nm) is proportional to elastase activity g. Use the RFU to plot [I] to determine the IC5G values.

10 II·活體外人類嗜中性白血玻試鹼 實例A 活體外PMN彈性質溶解試驗： 此試驗係用於測定人類多形核細胞(P_s)之彈性質 溶解潛力及評估由於嗜中性白血球彈性蛋白酶引致之降解 15 比例[參考 Z.W· She et al·，Am· J· Respir. Cell· Mol· Biol. £， 386-392 (1993)] 〇 經濟部智慧財產局員工消費合作社印製 將含氚標記的彈性蛋白之懸浮液被覆於96槽培養 盤，每槽10微克。添加適當濃度之測試化合物與參考化 合物[ZD-0892 (J· Med. Chem.組 1876-1885，3173-3181 20 (1997)，WO 95/21855)及 α 1 蛋白酶抑制劑（α ιρι)]至諸 槽。自健康捐血者末梢靜脈血液分離人類p_s，使其再 懸浮於培養基中。添加嗜中性白血球至經被覆之諸槽，濃 度為每槽1 X 106至1 X 1〇5個細胞不等。以豬胰臟彈性蛋 白酶（1.3//M)作為此試驗之正對照組，並使用α lp][ 〇 2 -2 8_ 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公楚）— ---- 200410963 A7 B7 五、發明說明（27 //Μ)作為嗜中性白血球彈性蛋白酶之正抑制劑。細胞性 對照組為於各適當細胞密度下，不含化合物之pMNs。於 37 C ’在潮濕的保溫箱中，將加入化合物之細胞保溫4小 時。離心培養盤，僅收集細胞上澄液。以75微升之量， 將上澄液移至96槽LumaplateTM (含固體閃爍劑之諸盤）之 諸對應槽中。乾燥培養盤至未於諸槽中看到液體為止，於 泠計數器中讀取，每槽3分鐘。 10 Η -彈性蛋白之彈性質溶解造成上澄液中計數之增 加:相對於細胞對照組，此彈性質溶解之抑制顯示上澄液 中瓜之下降。α 1ΡΙ於12//Μ下，獲得幻私± 3 97% (平均值f s.e.m·)之抑制作用（η = 3個不同捐血者，每槽 15 經濟部智慧財產局員工消費合作社印製 20 200410963 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（28) 性白血球35分鐘，然後於1600 rpm離心。接著，於4 °C，以3%多聚甲醛及0.25%戊二醛處理3分鐘，使該膜 結合彈性蛋白酶固定於嗜中性白血球。然後將該等嗜中性 白血球離心，添加載體及擬評估之化合物，隨後添加濃度 5 200 # Μ 之基質 MeOSuc-Ala_Ala_Pro_Val-AMC (#324740,10 II · In vitro human neutrophilic lecithin casein A In vitro PMN elastolysis test: This test is used to determine the elastic lysis potential of human polymorphonuclear cells (P_s) and to evaluate the elasticity due to neutrophil leukocytes. Protease-induced degradation of 15% [Reference ZW · She et al ·, Am · J · Respir. Cell · Mol · Biol. £, 386-392 (1993)] 〇 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs will contain 氚A suspension of labeled elastin was plated in a 96-well culture plate at 10 micrograms per well. Add appropriate concentrations of test compound and reference compound [ZD-0892 (J. Med. Chem. Group 1876-1885, 3173-3181 20 (1997), WO 95/21855) and α 1 protease inhibitor (α ιρι)] to Various slots. Human p_s was isolated from peripheral venous blood from healthy blood donors and resuspended in culture. Add neutrophils to the covered troughs at concentrations ranging from 1 x 106 to 1 x 105 cells per well. Porcine pancreatic elastase (1.3 // M) was used as the positive control group of this test, and α lp] [〇 2 -2 8_ This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210x297).-- --- 200410963 A7 B7 V. Description of the invention (27 // M) as a positive inhibitor of neutrophil elastase. The cellular control group was pMNs without compounds at appropriate cell densities. The cells containing the compound were incubated at 37 C 'for 4 hours in a humidified incubator. Centrifuge the culture plate and collect only the supernatant on the cells. In 75 microliters, transfer the supernatant to the corresponding wells of the 96-well LumaplateTM (plates containing solid scintillator). The culture plate was dried until no liquid was seen in the tanks, and read in a pit counter for 3 minutes per tank. 10 Η-The elastolytic dissolution of elastin causes an increase in the count in the upper solution: Compared to the cell control group, the inhibition of this elastolytic dissolution shows a decrease in the melon in the upper solution. α 1ΡΙ obtained the inhibition effect of magic private ± 3 97% (average f sem ·) at 12 // Μ (η = 3 different blood donors, 15 per slot printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 20 200410963 A7 B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the Invention (28) Sexual white blood cells were centrifuged at 1600 rpm for 35 minutes. Then, treated at 4 ° C with 3% paraformaldehyde and 0.25% glutaraldehyde. The membrane-bound elastase was immobilized on neutrophils for 3 minutes. The neutrophils were then centrifuged, the carrier and the compound to be evaluated were added, and then the matrix MeOSuc-Ala_Ala_Pro_Val-AMC (# 324740,

Calbiochem-Novabiochem Corporation, Merck KGaA， Darmstadt, Germany)。於 37°C 保溫 25 分鐘後，以 PMSF (苯基甲績醢氟)終止反應，讀取ex : 400奈米及em ·· 505 奈米處之螢光。利用插入法，自相對螢光對抑制劑濃度之 10 作圖決定諸IC5〇值。Calbiochem-Novabiochem Corporation, Merck KGaA, Darmstadt, Germany). After incubating at 37 ° C for 25 minutes, the reaction was stopped with PMSF (phenyl methyl fluorocarbon), and the fluorescence at ex: 400 nm and em · · 505 nm was read. The IC50 values were determined by plotting the relative fluorescence versus inhibitor concentration using the interpolation method.

III.活體内模式 實例A 大鼠急性肺傷害之活體内模式： 將人類嗜中性白血球彈性蛋白酶(HNE)緩缓滴注入大 15 鼠肺中’以引發急性肺傷害。其傷害程度可利用測量肺出 血予以評估。 以Hypnorm/Hypnovel/水麻醉大鼠，並以微量噴霧器 遞送方式，將HNE或食鹽水緩緩滴注入肺中。測試化合 物係在投與HNE之前，於設定的時間點，利用靜脈内注 20射、經口強飼或吸入法投與。在投與彈性蛋白酶60分鐘 後，以過量麻醉劑（戊巴比妥鈉）殺死動物，以2毫升肝素 化之磷酸鹽緩衝食鹽水(PBS)灌洗肺臟。記錄支氣管肺泡 灌洗液(BAL)量，於冰上保存試樣。於4_1〇c>c，9〇〇 r p m. 下，離心各BAL試樣1〇分鐘。丟棄上澄液，將細胞沉殿III. In vivo model Example A In vivo model of acute lung injury in rats: Human neutrophil elastase (HNE) was slowly dripped into the lungs of rats to induce acute lung injury. The extent of the damage can be assessed by measuring lung bleeding. Rats were anesthetized with Hypnorm / Hypnovel / water, and HNE or saline was slowly dripped into the lungs using a micro-spray delivery method. The test compound was administered by intravenous injection, oral gavage or inhalation at a set time point before administration of HNE. 60 minutes after elastase administration, the animals were killed with an anesthetic (sodium pentobarbital), and the lungs were lavaged with 2 ml of heparinized phosphate buffered saline (PBS). The amount of bronchoalveolar lavage fluid (BAL) was recorded and the samples were stored on ice. Each BAL sample was centrifuged for 10 minutes at 4-10c > c, 900 r p m. Discard the supernatant and sink the cells

-30--30-

200410963 A7 五、發明說明（29) 物再懸浮於PBS中，再離心此試樣。再次丟棄上澄液， 將細胞沉澱物再懸浮於1毫升〇1%溴化鯨蠟基三甲銨 (CTAB)/PBS中，使細胞溶解。冷凍保存試樣至進行血液 内容分析為止。於出血試驗之前，將試樣解凍，予以混 5合。取1⑻微升各試樣置於96槽平底盤之分隔槽中。所 有試樣均進行二重複試驗，並包括1〇〇微升〇 ι% CTAB/PBS之空白對照組。使用分光光度計測定槽中内容 物於415奈米之吸光度。測定於〇 1% CTAB/pBs中不同 濃度血液於415奈米之吸光度，作出標準曲線。針對該標 10準曲線(涵蓋於各培養盤中）進行比較，計算血液内容值， 並將所得BAL流體量常態化。200410963 A7 V. Description of the invention (29) The substance was resuspended in PBS, and the sample was centrifuged. The supernatant was discarded again, and the cell pellet was resuspended in 1 ml of 0% cetyltrimethylammonium bromide (CTAB) / PBS to lyse the cells. Samples were stored frozen until analysis of blood contents. Before the bleeding test, the samples were thawed and mixed. Take 1⑻ microliter of each sample and place it in a separate slot of a 96-slot flat bottom plate. All samples were tested in duplicate and included a 100 μL CTAB / PBS blank control group. A spectrophotometer was used to measure the absorbance of the contents of the tank at 415 nm. The absorbance of blood at 415 nm at different concentrations in 0.01% CTAB / pBs was measured and a standard curve was made. Compare this standard curve (covered in each culture plate), calculate the blood content value, and normalize the amount of BAL fluid obtained.

於大鼠由HNE誘發出血之此模式中，評估本發明化 合物經靜脈内、經口或利用吸入法投與之抑制活性。 實例B 15 大鼠急性心肌梗塞之活體内模式·· 經濟部智慧財產局員工消費合作社印製 以大鼠線梗塞模式測試諸彈性蛋白酶抑制劑。進行手 術前30分鐘，使威星(Wistar)公大鼠（重量>300克）接受 10毫克/公斤阿斯匹靈。整個手術期間，以異氟蘭 (isofluran)進行麻醉並使用氧氣罩（120-130壓縮次數/分 20 鐘 ’ 200-250 微升壓縮輸出量；MiniVent Type 845，HugoIn this mode of HNE-induced bleeding in rats, the inhibitory activity of the compounds of the present invention administered intravenously, orally or by inhalation is evaluated. Example B 15 In vivo model of acute myocardial infarction in rats · Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. The elastase inhibitors were tested in rat infarct mode. Thirty minutes before surgery, Wistar male rats (weight> 300 g) received 10 mg / kg aspirin. During the entire operation, anesthesia was performed with isofluran and an oxygen mask was used (120-130 compression times / minute 20 minutes ’200-250 microliters of compression output; MiniVent Type 845, Hugo

Sachs Elektronik，Germany)。於第四肋間進行左胸廓切開 術後，打開心包膜腔，使心臟暫時外露(exteriorized)。以 線纏繞左冠狀動脈(LAD)而不使其堵塞。該線通過皮膚下 面至動物頸部。緩緩滴注入大鼠肺中，以引發急性肺傷 -31- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 五、發明說明（30) 10 害。其傷轉射缝肺ώ血予崎估 令動物康復4天。*5天，使用⑻分鐘麻醉=靡’ 線繫緊，使lad堵塞(ECG控制τ)。於LAD墙塞 =經口：膜内或靜脈内(推注或固定輸注)投與:試 ^ ^小時後，打開線，令其再灌流 。割丄二 贓，以伊凡氏藍（Evans blue胸再堵塞之心臟染色，隨 後以TTC(氣化三苯基时鑌）進行2毫米心臟切片之染 色’48小時後’測定梗塞大小。正常(未堵塞組織)區域染 成藍色’缺血(堵塞惟线之組織）區域染成紅色，壞死 (堵塞社組織）區域則仍保持白色。掃描各組織切片，利 用電腦測圖器測定梗塞大小。 B.實例 縮窝： 經濟部智慧財產局員工消費合作社印製 15 甲基甲酿胺 二曱亞楓 電子撞擊電離法 電灑電離法 高壓液相層析法 液相層析法組合質譜分析 質譜分析法 核磁共振光譜術 滯留時間（用於HPLC0 四氩呋喃 -32- 200410963 A7 _____ B7 五、發明說明（31) 二粒 除非另行說明，否則所有反應均於氬氣氛圍下進行。 所用溶劑係購自Aldrich，不需進一步純化。「矽膠」或 「石夕石」係指得自Merck KGaA公司之矽膠60 (0.040毫 5 米-〇·〇63毫米）。熔點係使用Btichi 512或類似之熔點裝置 獲得，未經校正。 以製備性HPLC純化之化合物係於RP18-管柱上，以 乙腈及水為溶洗液，使用1:9至9:1之梯度進行純化。 L^iMSOmLC 方法: 10 LC_MS 法 1 儀器：Micromass Quattro LCZ，HP 1100 ;管柱： Uptisphere HDO，50毫米χ 2·0毫米，3微米；溶洗液 A :水+ 〇,〇5%甲酸，溶洗液Β :乙腈+ 〇·〇5%甲酸；梯 度·· 0·0 分鐘 1〇〇〇/。A — 0.2 分鐘 100% A — 2.9 分鐘 15 30% A 4 3·1 分鐘 10% A 4.5 分鐘 10% A ;烘箱： 55 C ’速· 〇·8毫升/分鐘，UV-檢測：208-400奈米。 經濟部智慧財產局員工消費合作社印製 LC-MS方法2 儀器：Waters Alliance 2790 LC ;管柱：Symmetry C18，50毫米χ 2·1毫米，3.5微米；溶洗液A :水+ 20 〇·1°/〇曱酸，溶洗液B :乙腈+ 0.1%曱酸；梯度：〇.〇分鐘 5% Β — 5.0 分鐘 10% Β — 6.0 分鐘 10% Β ;溫度： 50°C ;流速：1.0毫升/分鐘；UV-檢測：210奈米。 -33- 本紙張尺度適用中國國家標準(CNS)A4規格（210 χ 297公釐） 200410963 A7 B7 五、發明說明（3〇 LC-MS—方法 3 儀器：Micromass Platform LCZ，HP 1100 ;管柱： Aquasil C-18 ’ 50毫米χ 2.0毫米，3微米；溶洗液A : 水+ 0·05%曱酸，溶洗液B :乙腈+ 0.05%甲酸；梯度： 5 0.0 分鐘 1〇〇% A — 0.2 分鐘 100% A — 2.9 分鐘 30% A — 3.1 分鐘 10% A — 4.5 分鐘 10% A ;烤箱：55 °C ;流速：〇·8毫升/分鐘；UV-檢測：208-400奈米。 LC_MS方法4 儀器：具有DAD-檢測之HP 1100 ;管柱：Kromasil 10 RP-18，60毫米x2毫米，3.5微米；溶洗液：A = 5毫升 HCKV升H20，B =乙腈；梯度：0分鐘2% B — 0.5分 鐘 2% B 4.5 分鐘 90% B 6.5 分鐘 90% B ;流 速：0.75毫升/分鐘；溫度：30°C ; UV-檢測：210奈米。 LC-MS方法5 15 儀器：Micromass TOF-MUX_Interface 4 倍平行射 經濟部智慧財產局員工消費合作社印製 入，具有 HPLC Waters 600 ;管柱：Uptisphere HDO，50 毫米X 2·0毫米，3微米；溶洗液A : 1升水+ 1毫升 50%甲酸，溶洗液B : 1升乙腈+ 1毫升50%甲酸；梯 度：〇·〇 分鐘 100% A — 0.2 分鐘 100% A 2.9 分鐘 20 30% A — 3.1 分鐘 10% A 4.5 分鐘 10% A — 4.6 分鐘100% A 6·5分鐘100% A ;烘箱：室溫；流 速：0.8毫升/分鐘；UV-檢測：210奈米。 -34- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200410963 A7 B7 五、發明說明（33 ) LC-MS方法6 儀器：Micromass Platform LCZ，具有 HPLC Agilent Serie 1100 ;管柱：Grom_SIL 120 ODS_4 HE，50 毫米 x 2.0毫米，3微米；溶洗液A : 1升水+ 1毫升50%甲 5 酸，溶洗液B ·· 1升乙腈+ 1毫升50%甲酸；梯度：0·0 分鐘 100% A — 0.2 分鐘 100% A — 2,9 分鐘 30% A —3.1 分鐘 10% A — 4.5 分鐘 10% A ;烘箱：55°C ; 流速：0.8毫升/分鐘；UV_檢測：208-400奈米。 LC-MS方法7 10 儀器：Micromass Quattro LCZ，具有 HPLC AgilentSachs Elektronik, Germany). After a left thoracotomy in the fourth intercostal space, the pericardial cavity was opened to temporarily expose the heart. Wound the left coronary artery (LAD) in a wire without occluding it. The line passes under the skin to the animal's neck. Slowly instilled into the lungs of rats to cause acute lung injury -31- This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) 200410963 V. Description of invention (30) 10 Harm. His injury turned to squirt the lungs and sold blood to Yu Saki, and the animals recovered for 4 days. * For 5 days, use ⑻ minutes of anesthesia = Mi ’thread to fasten and block lad (ECG control τ). At LAD Wall Plug = Oral: Intra-membrane or intravenous (bolus or fixed infusion) Administration: Trial ^ ^ hours, open the line and let it perfuse again. The second incision was cut, and the heart was stained with Evans blue (thorax-reoccluded chest), and then the infarct size was measured 'after 48 hours' by staining a 2 mm heart section with TTC. Areas that are not blocked) are stained blue. Areas that are ischemic (blocked tissue) are stained red, while areas that are necrotic (blocked social tissue) remain white. Scan each tissue section and use a computer to measure the infarct size. B. Examples of shrinkage: printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, 15 methylmethanamine, diazepam, electron impact ionization, ionization, high pressure liquid chromatography, liquid chromatography, combined mass spectrometry, and mass spectrometry NMR spectroscopy retention time (for HPLC0 tetrahydrofuran-32- 200410963 A7 _____ B7 V. Description of the invention (31) Unless otherwise stated, all reactions were performed under an argon atmosphere. The solvents used were purchased from Aldrich, no further purification required. "Silicon" or "Shi Xi Shi" refers to Silicone 60 (0.040 mm-0.063 mm) from Merck KGaA. Melting point is Btichi 512 or A similar melting point device was obtained without correction. The compound purified by preparative HPLC was purified on a RP18-column, using acetonitrile and water as the eluent, and purified using a gradient of 1: 9 to 9: 1. L ^ iMSOmLC Method: 10 LC_MS method 1 Apparatus: Micromass Quattro LCZ, HP 1100; Column: Uptisphere HDO, 50 mm x 2.0 mm, 3 μm; Eluent A: water + 0, 05% formic acid, eluent B : Acetonitrile + 0.005% formic acid; gradient · 0 · 0 minutes 100% A.-0.2 minutes 100% A-2.9 minutes 15 30% A 4 3.1 minutes 10% A 4.5 minutes 10% A Oven: 55 C 'speed · 0.8 ml / min, UV-detection: 208-400 nanometers. LC-MS method 2 printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 2 Instrument: Waters Alliance 2790 LC; Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; Eluent A: water + 20 ° 1 ° / 〇 acetic acid, Eluent B: acetonitrile + 0.1% acetic acid; gradient: 0.0 minutes 5 % Β — 5.0 minutes 10% Β — 6.0 minutes 10% Β; temperature: 50 ° C; flow rate: 1.0 ml / min; UV-detection: 210 nm. -33- This paper scale applies to China Standard (CNS) A4 specification (210 x 297 mm) 200410963 A7 B7 V. Description of the invention (30 LC-MS-Method 3 Instrument: Micromass Platform LCZ, HP 1100; column: Aquasil C-18 '50 mm x 2.0 Mm, 3 microns; Eluent A: Water + 0.05% acetic acid, Eluent B: Acetonitrile + 0.05% Formic acid; Gradient: 5 0.0 minutes 100% A — 0.2 minutes 100% A — 2.9 minutes 30 % A — 3.1 minutes 10% A — 4.5 minutes 10% A; oven: 55 ° C; flow rate: 0.8 ml / min; UV-detection: 208-400 nm. LC_MS Method 4 Apparatus: HP 1100 with DAD-detection; Column: Kromasil 10 RP-18, 60 mm x 2 mm, 3.5 μm; Eluent: A = 5 ml HCKV to H20, B = acetonitrile; Gradient: 0 minutes 2% B — 0.5 minutes 2% B 4.5 minutes 90% B 6.5 minutes 90% B; flow rate: 0.75 ml / min; temperature: 30 ° C; UV-detection: 210 nm. LC-MS method 5 15 Apparatus: Micromass TOF-MUX_Interface 4x parallel shot Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, with HPLC Waters 600; Column: Uptisphere HDO, 50 mm X 2.0 mm, 3 microns; Eluent A: 1 liter of water + 1 ml of 50% formic acid, Eluent B: 1 liter of acetonitrile + 1 ml of 50% formic acid; Gradient: 0.00 minutes 100% A — 0.2 minutes 100% A 2.9 minutes 20 30% A — 3.1 minutes 10% A 4.5 minutes 10% A — 4.6 minutes 100% A 6. 5 minutes 100% A; oven: room temperature; flow rate: 0.8 ml / min; UV-detection: 210 nm. -34- This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) 200410963 A7 B7 V. Description of Invention (33) LC-MS Method 6 Instrument: Micromass Platform LCZ with HPLC Agilent Serie 1100; column: Grom_SIL 120 ODS_4 HE, 50 mm x 2.0 mm, 3 microns; Eluent A: 1 liter of water + 1 ml of 50% formic acid, Eluent B ·· 1 liter of acetonitrile + 1 ml of 50% formic acid; Gradient: 0 · 0 minutes 100% A — 0.2 minutes 100% A — 2,9 minutes 30% A — 3.1 minutes 10% A — 4.5 minutes 10% A; oven: 55 ° C; flow rate: 0.8 ml / min; UV detection: 208 -400 nm. LC-MS Method 7 10 Instrument: Micromass Quattro LCZ with HPLC Agilent

Serie 1100 ;管柱：Uptisphere HDO，50 毫米 χ 2·0 毫 米，3微米；溶洗液A : 1升水+ 1毫升50%甲酸，溶洗 液B : 1升乙腈+ 1毫升50%甲酸；梯度：0.0分鐘100% A — 0·2 分鐘 100% A — 2.9 分鐘 30% A — 3.1 分鐘 15 10% A 4·5 分鐘 10% A ;烘箱：55°C ;流速：〇·8 毫 升/分鐘；UV-檢測：208-400奈米。 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（34 ) 起始物質··Serie 1100; column: Uptisphere HDO, 50 mm x 2.0 mm, 3 micron; Eluent A: 1 liter of water + 1 ml of 50% formic acid, Eluent B: 1 liter of acetonitrile + 1 ml of 50% formic acid; gradient : 0.0 minutes 100% A — 0.2 minutes 100% A — 2.9 minutes 30% A — 3.1 minutes 15 10% A 4.5 minutes 10% A; oven: 55 ° C; flow rate: 0.8 ml / minute; UV-detection: 208-400 nm. Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper is sized to the Chinese National Standard (CNS) A4 (210 X 297 mm) 200410963 A7 B7 V. Description of the Invention (34) Starting Substances ··

實例1A 2->臭-5-(1，3-二0亏壞戊烧-2-基）啦唆Example 1A 2- > Odor-5- (1,3-di-0 is degraded by pentan-2-yl)

經濟部智慧財產局員工消費合作社印製 5 於備有回流冷凝器及汀-史達克氏氣液分離器（Dean-Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5 Equipped with a reflux condenser and a Ting-Stark gas-liquid separator (Dean-

Stark trap)之圓底燒瓶中，使6-溴-3-0比唆甲藤(500毫克， 2.7莫耳）與1，2-乙二醇（200毫克，3·2毫莫耳）連同 Amberlyst 15 (100毫克)溶於曱苯(50毫升）中。回流加熱 此溶液隔夜，然後冷卻至室溫，過濾，真空濃縮。此粗產 10 物於矽膠上進行色層分析，以環己烷及乙酸乙酯為溶洗 液，得到呈無色油之標題化合物。 產率：0.489克（理論值之79%) HPLC (方法4) : 3.46分鐘 MS (ESIpos): m/z = 231 (M+H)+ lH-NMR (300 MHz, CDC13)： δ = 8.46 (d, 1H), 7.64 (m, 1H), 7.49 (m, 1H), 4.15^.00 (m, 4H) ppm· -36- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x 297公釐） 200410963 A7 _ B7 五、發明說明（35)Stark trap) in a round-bottomed flask, with 6-bromo-3-0 than Metrolatum (500 mg, 2.7 mol) and 1,2-ethylene glycol (200 mg, 3.2 mmol) together with Amberlyst 15 (100 mg) was dissolved in toluene (50 ml). The solution was heated at reflux overnight, then cooled to room temperature, filtered, and concentrated in vacuo. This crude product was analyzed by color chromatography on silica gel using cyclohexane and ethyl acetate as the eluent to obtain the title compound as a colorless oil. Yield: 0.489 g (79% of theory) HPLC (Method 4): 3.46 minutes MS (ESIpos): m / z = 231 (M + H) + lH-NMR (300 MHz, CDC13): δ = 8.46 ( d, 1H), 7.64 (m, 1H), 7.49 (m, 1H), 4.15 ^ .00 (m, 4H) ppm · -36- This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) %) 200410963 A7 _ B7 V. Description of Invention (35)

tMJA 5·(1，3-二吟環戊烧-2-基)-2_°比咬甲腈tMJA 5. · (1,3-Diindanecyclopentyl-2-yl) -2_ ° specific bitonitrile

5 經濟部智慧財產局員工消費合作社印製 使實例ΙΑ (2·8克，12,5毫莫耳）、氮化鋅（丨6克， 13.8毫莫耳)與肆_(三苯基膦)鈀(〇) (1 4克，〗3莫耳)溶於 二甲基甲醯胺(100毫升)中’於80t攪拌隔夜(18小時)。 追加肆(三絲膦)把⑼’克），於8〇。〇再授掉此反應隔 夜(18小時），然後於室溫靜置2天(48小時）。真空去除溶 劑，加水（100毫升）於殘留物，以乙酸乙酯（1升^萃取產 物。其有機相以食鹽水(200毫升）洗務’以硫酸鎮單水人 物脫水，過渡，真空濃縮。此粗產物於上進行色層: 析，以環己燒及乙酸乙酯為溶洗液，得到呈白色非日 之標題化合物。 產率：〇·94克（理論值之42%) 15 HPLC (方法 4) : 3.21 分鐘 MS (ESIpos): m/z = 177 (M+H)+ 4.13 ^-NMR (400 MHz, DMSO^): δ - 8.81 (s, 1H), 8.09 (s> 2h> 5 95 3.94 (m, 4 H) ppm. ( ’ 1^)， -37- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公爱） 200410963 A7 B7 五、發明說明（36)5 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, Example IA (2.8 g, 12,5 mmol), Zinc Nitride (丨 6 g, 13.8 mmol), and (-triphenylphosphine) Palladium (0) (14 g, 3 moles) was dissolved in dimethylformamide (100 ml) and stirred overnight (18 hours) at 80t. Add extra (trisiphosphine) (⑼'g) to 80. 〇 The reaction was taught overnight (18 hours), and then left at room temperature for 2 days (48 hours). The solvent was removed in vacuo, water (100 ml) was added to the residue, and the product was extracted with ethyl acetate (1 liter. The organic phase was washed with brine (200 ml). The solution was dehydrated with sulfuric acid, transitioned, and concentrated in vacuo. This crude product was subjected to color chromatography on the above, using cyclohexane and ethyl acetate as the eluent to give the title compound as a white non-Japanese. Yield: 0.94 g (42% of theory) 15 HPLC ( Method 4): 3.21 minutes MS (ESIpos): m / z = 177 (M + H) + 4.13 ^ -NMR (400 MHz, DMSO ^): δ-8.81 (s, 1H), 8.09 (s > 2h > 5 95 3.94 (m, 4 H) ppm. ('1 ^), -37- This paper size applies to China National Standard (CNS) A4 (210x297 public love) 200410963 A7 B7 V. Description of the invention (36)

實例3A 5-甲醮基-2-吡啶甲腈Example 3A 5-methylamido-2-pyridinecarbonitrile

〇户Η 經濟部智慧財產局員工消費合作社印製 方法a): 5 以類似 Dodd，D· W a/· [J·⑽· C/2⑽，7外2, 57, 7226_ 7234]之程序進行製備：於含5-(1，3-二咩環戊烷-2-基)-2_ 吡啶甲腈（實例2A ; 850毫克，4·8毫莫耳）之丙酮/水 85:15 (59.5毫升）攪拌溶液中，添加對甲苯磺酸（102毫 克，0.59毫莫耳）；回流攪拌此反應隔夜(18小時），然後 10 追加對甲苯磺酸(50毫克)及水(5毫升）；再回流攪拌反應 48小時；冷卻該溶液至室溫，以飽和碳酸氫鈉溶液終止 反應；其產物以乙酸乙酯（3 X 100毫升）萃取，並以硫酸錐 早水合物脫水’過遽’真空7辰縮，此粗產物利用製備卜生 HPLC進行純化，得到淡黃色固體。 15 產率：0.66克（理論值之93%)〇 Household printing method of employee cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs a): 5 Prepared by a procedure similar to Dodd, D · W a / · [J · ⑽ · C / 2⑽, 7 Wai 2, 57, 7226_ 7234] : In acetone / water 85:15 (59.5 ml) containing 5- (1,3-dioxocyclopentane-2-yl) -2-pyridinecarbonitrile (Example 2A; 850 mg, 4.8 mmol) To the stirred solution, p-toluenesulfonic acid (102 mg, 0.59 mmol) was added; the reaction was stirred at reflux overnight (18 hours), then 10 additional p-toluenesulfonic acid (50 mg) and water (5 ml) were added; and then stirred at reflux Reaction for 48 hours; cooling the solution to room temperature, stopping the reaction with saturated sodium bicarbonate solution; extracting the product with ethyl acetate (3 X 100 ml), and dehydrating with cone sulfate early hydrate, dehydrating and vacuuming for 7 days This crude product was purified by preparative PBS HPLC to give a pale yellow solid. 15 Yield: 0.66 g (93% of theory)

熔點：80-82°C HPLC (方法4) : 2.13分鐘 MS (ESIpos): m/z = 133 (M+H)+ 】H-NMR (400 MH2; DMSOO: δ = 10.18 (s，1H)，9·21 ㈣ 1H)，8·49 (功 (m, 1H) ppm. ，8·27 -38- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（37) 方法b): 使1.04克(8.2毫莫耳）草醯氣溶於8毫升二氯甲烧 中。於-78°C，逐滴添加1.28克（16.4毫莫耳)二曱亞颯。 於-78°C攪拌此溶液20分鐘，然後添加溶於7毫升二氯甲 5 烷中之1克(7.46毫升)實例5A化合物，持續於-78°C再授 拌2小時。接著逐滴添加3.4克(33.6毫莫耳）三乙胺，於 加溫至室溫後，利用管柱層析法（砍石，溶洗液為環己烧 至環己烷/乙酸乙酯2:1)純化該混合物。 產率：〇·76克（理論值之77%) 10 分析數據：見上。 實例4Α 5 -甲基·2-ϋ比咬甲猜Melting point: 80-82 ° C HPLC (Method 4): 2.13 minutes MS (ESIpos): m / z = 133 (M + H) +] H-NMR (400 MH2; DMSOO: δ = 10.18 (s, 1H), 9 · 21 ㈣ 1H), 8.49 (work (m, 1H) ppm., 8 · 27 -38- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (37) Method b): Dissolve 1.04 g (8.2 millimoles) of grass gas in 8 ml of dichloromethane. At -78 ° C, 1.28 grams (16.4 millimoles) of hydrazone is added dropwise. The solution was stirred at -78 ° C for 20 minutes, then 1 g (7.46 ml) of the compound of Example 5A dissolved in 7 ml of dichloromethane was added, and the mixture was further stirred at -78 ° C for 2 hours. Then, 3.4 g (33.6 mmol) of triethylamine was added dropwise, and after warming to room temperature, column chromatography (chopping stone, the washing solution was cyclohexane to cyclohexane / ethyl acetate 2) : 1) The mixture is purified. Yield: 0.76 g (77% of theory) 10 Analytical data: see above. Example 4Α 5 -methyl · 2-pyridine

ch3 經濟部智慧財產局員工消費合作社印製 於500毫升二甲基甲醯胺中，將36克(209毫莫耳) 15 2-溴-5-甲基吡啶與37.5克(418毫莫耳）氰化銅回流加熱2 小時。冷卻至50°C後，於攪拌下，添加10%氨水溶液 (500毫升）。以二氣甲烷萃取產物，其有機相以硫酸鎂脫 水，真空去除溶劑。利用管柱層析法(梦石，溶洗液環己 烷/乙酸乙酯9:1)純化產物。 20 產率：18克（理論值之73%) ^-NMR (300 MHz, CDC13)： δ = 2.4 (s, 3H), 7.6 (m, 2H), 8.6 (s, 1H) ppm. -39- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（38)ch3 Printed in 500 ml of dimethylformamide by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 36 g (209 mmol) of 15 2-bromo-5-methylpyridine and 37.5 g (418 mmol) Copper cyanide was heated under reflux for 2 hours. After cooling to 50 ° C, 10% ammonia solution (500 ml) was added with stirring. The product was extracted with methane, the organic phase was dehydrated with magnesium sulfate, and the solvent was removed in vacuo. The product was purified by column chromatography (Dreamstone, eluent cyclohexane / ethyl acetate 9: 1). 20 Yield: 18 g (73% of theory) ^ -NMR (300 MHz, CDC13): δ = 2.4 (s, 3H), 7.6 (m, 2H), 8.6 (s, 1H) ppm. -39- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (38)

實例5A 5-(羥甲基)-2-吨啶曱腈Example 5A 5- (hydroxymethyl) -2-tonilidine

CNCN

經濟部智慧財產局員工消費合作社印製 使化合物4A化合物（13克，110毫莫耳)溶於400毫 5 升四氣甲烷中，於其内添加29.4克（165毫莫耳）N-溴琥 珀醯亞胺及0.4克（1.6毫莫耳)二苯甲醯基過氧化物。回流 加熱此反應混合物3小時，冷卻至室溫後，予以過濾。此 溶液以硫代硫酸鈉水溶液洗滌，以硫酸鎂脫水，真空去除 溶劑。使殘留物溶於200毫升二崎烷及200毫升水中，添 10 加碳酸鈣(44克，440毫莫耳），回流下，攪拌此混合物2 小時。冷卻至室溫後，過濾混合物，添加二氯甲烷。進行 相分離後，其有機相以硫酸鎂脫水，真空去除溶劑。利用 層析法（石夕石，溶洗液環己烧/乙酸乙S旨2:1)純化產物。 產率：5.2克（理論值之35%) lH-NMR (300 MHz, DMSO-da)： δ = 4.7 (d, 2Η), 5.6 (t, 1H), 8.0 (m, 2H), 8 J (s, 1H) 15 ppm· -40- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x 297公釐） 200410963 A7 B7 五、發明說明（39 ) 製備實例： 實例1 4_(4_氰苯基)-6-甲基-2-酮基-1_[3-(三氟甲基）苯基]-1，2,3,4-四氫-5_嘧啶甲酸乙酯Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Compound 4A (13 g, 110 mmol) was dissolved in 400 mmol of 5 litres of tetragas methane, and 29.4 g (165 mmol) of N-bromoamber was added to it. Fluorenimine and 0.4 g (1.6 millimolar) of dibenzofluorenyl peroxide. The reaction mixture was heated at reflux for 3 hours, and after cooling to room temperature, it was filtered. This solution was washed with an aqueous sodium thiosulfate solution, dehydrated with magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in 200 ml of diazane and 200 ml of water, 10 calcium carbonate (44 g, 440 mmol) was added, and the mixture was stirred under reflux for 2 hours. After cooling to room temperature, the mixture was filtered and dichloromethane was added. After phase separation, the organic phase was dehydrated with magnesium sulfate, and the solvent was removed in vacuo. The product was purified by chromatography (Shi Xishi, eluent cyclohexane / ethyl acetate 2: 1). Yield: 5.2 g (35% of theory) lH-NMR (300 MHz, DMSO-da): δ = 4.7 (d, 2Η), 5.6 (t, 1H), 8.0 (m, 2H), 8 J ( s, 1H) 15 ppm · -40- This paper size is applicable to Chinese National Standard (CNS) A4 (210 x 297 mm) 200410963 A7 B7 V. Description of the invention (39) Preparation example: Example 1 4_ (4_cyanobenzene ) -6-methyl-2-keto-1_ [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester

CNCN

經濟部智慧財產局員工消費合作社印製 使7·0克(34.29毫莫耳）Ν·[3-(三氟甲基）苯基]脲、 8.99克(68.58毫莫耳）4-氰基苯曱醛、8.92克(68·58毫莫 耳）3-酮基丁酸乙酯與20克多磷酸乙酯懸浮於250毫升 THF中。回流加熱下，攪拌此混合物18小時。冷卻至室 10 溫後，真空去除溶劑，殘留物於秒石上利用管柱層析法進 行純化，以環己烷/乙酸乙酯為溶洗液。 產率：13.4 克(91%) lH-NMR (200 MHz, DMSO-^): δ = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (q, 2H); 5.4 (d, 1H); 7.6 (m, 3H); 7.7 (m, 3H); 7.9 (m, 2H); 8.4 (d, 1H) ppm. -41- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（4〇 ) 實例2 4_{5 -乙酿基-6-甲基-2 -嗣基-1-[3-(二乱甲基）苯基]-1，2,3,4-四氫-4-嘧啶基}苯甲腈The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed 7.0 grams (34.29 millimoles) of N · [3- (trifluoromethyl) phenyl] urea and 8.99 grams (68.58 millimoles) of 4-cyanobenzene Aldehyde, 8.92 g (68.58 mmol) of ethyl 3-ketobutyrate and 20 g of ethyl polyphosphate were suspended in 250 ml of THF. The mixture was stirred under reflux for 18 hours. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by column chromatography on spar, using cyclohexane / ethyl acetate as the eluent. Yield: 13.4 g (91%) lH-NMR (200 MHz, DMSO- ^): δ = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (q, 2H); 5.4 (d, 1H) ; 7.6 (m, 3H); 7.7 (m, 3H); 7.9 (m, 2H); 8.4 (d, 1H) ppm. -41- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (%) 200410963 A7 B7 V. Description of the invention (40) Example 2 4_ {5 -Ethyl-6-methyl-2 -fluorenyl-1- [3- (dioxanyl) phenyl] -1, 2,3,4-tetrahydro-4-pyrimidinyl} benzonitrile

經濟部智慧財產局員工消費合作社印製 5 使265毫克（1.3毫莫耳）N_[3-(三氟甲基）苯基]脲、 131毫克（1.0毫莫耳）4-氰基苯甲醛、與100毫克（1.0毫莫 耳）2,4-戊二酮懸浮於2毫升THF中，添加催化用量之濃 鹽酸。回流加熱下，攪拌此混合物18小時。冷卻至室溫 後，真空去除溶劑，殘留物於矽石上利用管柱層析法進行 10 純化，以環己烷/乙酸乙酯為溶洗液。 產率：29毫克(7%) ^-NMR (200 MHz, DMSO-d6): δ = 2.0 (s, 3H); 2.2 (s, 3H); 5.5 (d, 1H); 7.5 (m, 1H); 7.6 (m, 3H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 2H); 8.5 (4 1H) ppm. -42- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x 297公釐） 200410963 A7Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 265 mg (1.3 mmol) N_ [3- (trifluoromethyl) phenyl] urea, 131 mg (1.0 mmol) 4-cyanobenzaldehyde, Suspend it with 100 mg (1.0 mmol) of 2,4-pentanedione in 2 ml of THF, and add a catalytic amount of concentrated hydrochloric acid. The mixture was stirred under reflux for 18 hours. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by column chromatography on silica, using cyclohexane / ethyl acetate as the eluent. Yield: 29 mg (7%) ^ -NMR (200 MHz, DMSO-d6): δ = 2.0 (s, 3H); 2.2 (s, 3H); 5.5 (d, 1H); 7.5 (m, 1H) ; 7.6 (m, 3H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 2H); 8.5 (4 1H) ppm. -42- This paper size applies Chinese National Standard (CNS) A4 Specifications (210 x 297 mm) 200410963 A7

五、發明說明（41) 4 (4~臭本基)_6_甲基相基]_[3_(三&甲基)苯基]_ΐ 2,3,4· 四氫-5-嘧啶甲酸乙_ 〇-V. Description of the invention (41) 4 (4 ~ Oxyl) -6-methyl phase group] _ [3_ (tri & methyl) phenyl] _ΐ 2,3,4 · Tetrahydro-5-pyrimidinecarboxylic acid ethyl _ 〇-

5 10 經濟部智慧財產局員工消費合作社印製 使204毫克（1·0毫莫耳）邱-(三氟甲基)苯基]脲 142毫克(〇·77毫莫耳）4-漠笨曱齡、與100毫克(0.77毫 耳）％酮基丁酸乙_懸浮於2毫升THF中，添加催化用 之?農鹽酸。回流加熱下，授掉此混合物18小時。冷卻至 室溫後’真空去除溶劑，殘留物於石夕石上利用管枉層析法 進行純化，以環己烷/乙酸乙酯為溶洗液。 產率.：23毫克(6%) lH-NMR (200 MHz, DMSO^): δ = U (t, 3H); 2.0 (s, 3H); 4.〇 (q, 2H)； 5.3 (d, 1H)； 7.4 (m, 2H); 7.6 (m, 3H); 7.7 (m. 3H); 8.3 (d, 1H) ppm. ’ ’ 莫 量 -43- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200410963 A7 B7 五、發明說明（42 ) 實例4 4-(4-亂苯基）-6-甲基-2·嗣基_1-[4-乳苯基]-1，2,3,4-四鼠-5-* 嘧啶甲酸乙酯5 10 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 204 mg (1.0 mmol) Qiu- (trifluoromethyl) phenyl] urea 142 mg (0.777 mmol) 4- Moben Age, suspended with 100 mg (0.77 mil)% ethyl ketobutyrate in 2 ml of THF, and added agricultural hydrochloric acid for catalysis. This mixture was allowed to drain for 18 hours under reflux. After cooling to room temperature ', the solvent was removed in vacuo, and the residue was purified by tube chromatography on Shi Xiishi using cyclohexane / ethyl acetate as the eluent. Yield: 23 mg (6%) lH-NMR (200 MHz, DMSO ^): δ = U (t, 3H); 2.0 (s, 3H); 4.〇 (q, 2H); 5.3 (d, 1H); 7.4 (m, 2H); 7.6 (m, 3H); 7.7 (m. 3H); 8.3 (d, 1H) ppm. '' MoQ-43- This paper size applies Chinese National Standard (CNS) A4 Specifications (210x297 mm) 200410963 A7 B7 V. Description of the Invention (42) Example 4 4- (4-Ranylphenyl) -6-methyl-2 · fluorenyl_1- [4-lactylphenyl] -1, Ethyl 2,3,4-tetramidine-5- * pyrimidinate

CNCN

經濟部智慧財產局員工消費合作社印製 5 使154毫克（1.0毫莫耳）N-[4-氟苯基]脲、101毫克 (0.77毫莫耳）4_氰基苯甲链、與100毫克(0.77毫莫耳）3-酮基丁酸乙酯懸浮於2毫升THF中，添加催化用量之濃 鹽酸。回流加熱下，攪拌此混合物18小時。冷卻至室溫 後，真空去除溶劑，殘留物於矽石上利用管柱層析法進行 10 純化，以環己烷/乙酸乙酯為溶洗液。 產率：40毫克（14%) 'H-NMR (200 MHz, DMSO-d6): δ = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (q, 2H); 5.3 (d, 1H); 7,3 (m, 4H); 7.5 (m, 2H); 7.9 (m, 2H); 8.3 (d, 1H) ppm. -44- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200410963 A7 B7 五、發明說明（43 ) 實例5 4_(4_氰苯基)-6-甲基-2-酮基氣笨基^^‘四氫士 嘧啶曱酸乙酯Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 154 mg (1.0 mmol) of N- [4-fluorophenyl] urea, 101 mg (0.77 mmol) of 4-cyanobenzene chain, and 100 mg (0.77 mmol) ethyl 3-ketobutyrate was suspended in 2 ml of THF, and concentrated hydrochloric acid was added in a catalytic amount. The mixture was stirred under reflux for 18 hours. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by column chromatography on silica, using cyclohexane / ethyl acetate as the eluent. Yield: 40 mg (14%) 'H-NMR (200 MHz, DMSO-d6): δ = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (q, 2H); 5.3 (d, 1H ); 7,3 (m, 4H); 7.5 (m, 2H); 7.9 (m, 2H); 8.3 (d, 1H) ppm. -44- This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 (Mm) 200410963 A7 B7 V. Description of the invention (43) Example 5 4_ (4_cyanophenyl) -6-methyl-2-ketoaminobenzyl ^^ 'tetrahydropyrimidine ethyl acetate

10 經濟部智慧財產局員工消費合作社印製 使170毫克(1·0毫莫耳）n_[3-氣苯基]脲、1〇〇毫克 (0·77毫莫耳）4-氰基苯甲醛與1〇〇毫克(〇 77毫莫耳）弘酮 基丁酸乙㈣浮於2毫升THF t，添加催化用量之濃鹽 酸。回流加熱下，攪拌此混合物18小時。冷卻至室严 後，真空去除溶劑，殘留物於扣上利用管柱層析= 純化，以環己烷/乙酸乙酯為溶洗液。 行 產率：13毫克(4%) 乜腿(2〇〇碰，麵⑽):δ = U (t，邱;2 i (s，邱;* 〇⑷ 7.2 (m, 1H); 7.4 (m, 3H); 7.5 (m, 2H); 7.9 (xn, 2H); 83 (d, 1H) ppm. ^ ^ lH) -45- 200410963 A7 B7 五、發明說明（44) 實例6 4-(4-氛苯基)-6-甲基-2-酮基-1_[3_(三氣甲基）苯基]-1，2,3,4· 四風·5-哺唆甲酸（lS)-2 -甲氧基-1-甲基-2_晒基乙香旨 CN H3C〆10 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 170 mg (1.0 mmol) of n_ [3-Gaphenyl] urea, 100 mg (0.777 mmol) of 4-cyanobenzaldehyde Float with 100 mg (07 77 mmol) of acetone ketobutyrate in 2 ml of THF t, and add a catalytic amount of concentrated hydrochloric acid. The mixture was stirred under reflux for 18 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was snapped and purified by column chromatography = cyclohexane / ethyl acetate as the eluent. Yield: 13 mg (4%) 乜 leg (200 〇, noodle): δ = U (t, Qiu; 2 i (s, Qiu; * 〇 7.2 (m, 1H); 7.4 (m , 3H); 7.5 (m, 2H); 7.9 (xn, 2H); 83 (d, 1H) ppm. ^ ^ LH) -45- 200410963 A7 B7 V. Description of the invention (44) Example 6 4- (4- Alanyl phenyl) -6-methyl-2-keto-1_ [3_ (trifluoromethyl) phenyl] -1,2,3,4 · Four wind · 5-Frulic acid (lS) -2- Methoxy-1-methyl-2_sunylacetic acid purpose CN H3C〆

經濟部智慧財產局員工消費合作社印製 5 使200毫克(0·98毫莫耳）N-[3-(三氟甲基)苯基]脲、 129毫克(0·98毫莫耳）4-氰基苯甲醛、92毫克(0,49毫莫 耳）3-嗣基丁酸(lS)-2-甲乳基-1-甲基-2-嗣基乙醋、與295 毫克多磷酸乙酯懸浮於3毫升THF中。回流加熱下，攪 拌此混合物18小時。冷卻至室溫後，真空去除溶劑，殘 10 留物於矽石上利用管柱層析法進行純化，以環己烷/乙酸 乙酯為溶洗液。獲得非鏡像異構物之混合物。 產率：96毫克(40%) !H-NMR (200 MHz, DMSO-Φί): δ = L3 (d, 3H); 1.4 (d, 3H); 2.0 (s, 3H+3H); 3.6 (s， 3H); 3.6 (s, 3H); 5.0 (m, 1H+1H); 5.4 (m, 1H+1H); 7.6-7.9 (m, 8H+8H); 8.4 (m, 1H+1H) ppm. -46- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（45 ) 實例7 4-{6-甲基-5-(4-嗎啉基羰基基q-p-(三氟甲基)苯基卜 1，2,3,4-四氫-4_喷咬基}苯甲腈 J!Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives 5 Make 200 mg (0.998 mmol) of N- [3- (trifluoromethyl) phenyl] urea, 129 mg (0.998 mmol) 4- Cyanobenzaldehyde, 92 mg (0,49 mmol) 3-methylbutyric acid (lS) -2-methyllactyl-1-methyl-2-methylethylacetate, and 295 mg of ethyl polyphosphate Suspended in 3 ml of THF. The mixture was stirred under reflux for 18 hours. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by column chromatography on silica using cyclohexane / ethyl acetate as the eluent. A mixture of non-mirromeric isomers was obtained. Yield: 96 mg (40%)! H-NMR (200 MHz, DMSO-Φί): δ = L3 (d, 3H); 1.4 (d, 3H); 2.0 (s, 3H + 3H); 3.6 (s , 3H); 3.6 (s, 3H); 5.0 (m, 1H + 1H); 5.4 (m, 1H + 1H); 7.6-7.9 (m, 8H + 8H); 8.4 (m, 1H + 1H) ppm. -46- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (45) Example 7 4- {6-methyl-5- (4-morpholinyl) Carbonyl qp- (trifluoromethyl) phenylb, 1,2,3,4-tetrahydro-4_pentyl} benzonitrile J!

經濟部智慧財產局員工消費合作杜印製 5 使I50毫克(0·73毫莫耳）N-[3-(三氟甲基)苯基]脲、 96 $克(0.73毫莫耳）4-氰基苯甲駿、63毫克(〇 37毫莫耳） 4普嗎淋基)冰酮基-2-丁酮與220毫克多鱗酸乙酯懸浮於 3毫升THF中。回流加熱下，攪拌此混合物18小時。冷 卻至室溫後，真空去除溶劑，殘留物於矽石上利用管桎層 10析法進行純化，以二氣甲烷/甲醇為溶洗液。 產率：28毫克（16%) 'H^NMR (300 MHz, DMSO^): δ = L5 (s, 3H); 3.1 (m, 4H); 3.6 (m, 4H)； S3 ^ s 1H); 7.6 (m, 2H); 7 J (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H); 8,0 (br.s, 1H) ppm. ^^ -47- 200410963 A7 __________B7 _ 五、發明說明（4〇 實例8 4-(4_氰苯基)-N3N-二乙基-6-甲基-2-酮基三氟甲基) 笨基]-1，2,3,4_四氫-5-嘧咬甲醢胺Employees' Cooperation in Intellectual Property Bureau of the Ministry of Economic Affairs, Du printed 5 make I50 mg (0.73 mmol) N- [3- (trifluoromethyl) phenyl] urea, 96 $ g (0.73 mmol) 4- Cyanobenzyl, 63 mg (037 mmol) 4 propamoyl) cetonyl-2-butanone and 220 mg ethyl polyphosphonate were suspended in 3 ml THF. The mixture was stirred under reflux for 18 hours. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography on silica using digas methane / methanol as the eluent. Yield: 28 mg (16%) 'H ^ NMR (300 MHz, DMSO ^): δ = L5 (s, 3H); 3.1 (m, 4H); 3.6 (m, 4H); S3 ^ s 1H); 7.6 (m, 2H); 7 J (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H); 8,0 (br.s, 1H) ppm. ^^ -47- 200410963 A7 __________B7 _ V. Description of the invention (40 Example 8 4- (4-cyanophenyl) -N3N-diethyl-6-methyl-2-ketotrifluoromethyl) Benzoyl] 1,2,3,4 _Tetrahydro-5-pyrimidine

CNCN

5 使200毫克(0·98毫莫耳）N-[3-(三氟甲基)苯基]脲、 128毫克(0.98毫莫耳）仁氰基苯曱醛、77毫克(〇 49毫莫 耳）4-(4-二乙胺基‘酮基丁酮與295毫克多磷酸乙酯 懸浮於3毫升THF中。回流加熱下，攪拌此混合物18小 時。冷卻至室溫後，真空去除溶劑，殘留物於石夕石上利用 10管柱層析法進行純化，以二氯甲烷/甲醇為溶洗液。 產率·· 106毫克(47%) 經濟部智慧財產局員工消費合作社印製 ^-NMR (300 MHz, DMSO-d^): δ - 0.9 (m, 6H); 3.1 (m, 4H); 5.2 (br.s, 1H)； 7 6(^ 2H); 7.7 (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H); 8.0 (brs, 1H) ppm. -48- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐) "-------- 200410963 A7 B7 五、發明說明（47) 實例9 6_胺基_4-(4·氰苯基)-2-酮基_1_[3_(三氟甲基）苯基]-1，2,3,4· 四氫_5_嘧咬甲腈5 Make 200 mg (0.98 mmol) of N- [3- (trifluoromethyl) phenyl] urea, 128 mg (0.98 mmol) of cyanobenzophenone, 77 mg (〇49 mmol) (Ear) 4- (4-diethylamino 'ketobutyl ketone) and 295 mg of ethyl polyphosphate were suspended in 3 ml of THF. The mixture was stirred under reflux for 18 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was purified on Shi Xishi by 10-column chromatography using dichloromethane / methanol as the eluent. Yield ················································· Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs and printed on ^ -NMR (300 MHz, DMSO-d ^): δ-0.9 (m, 6H); 3.1 (m, 4H); 5.2 (br.s, 1H); 7 6 (^ 2H); 7.7 (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H); 8.0 (brs, 1H) ppm. -48- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) " ------- -200410963 A7 B7 V. Description of the invention (47) Example 9 6-Amino_4- (4 · cyanophenyl) -2-one-1-_1- [3_ (trifluoromethyl) phenyl] -1, 2, 3,4 · tetrahydro_5_pyridine

經濟部智慧財產局員工消費合作社印製 5 使400毫克（1.97毫莫耳）Ν-[3_(三氟甲基)苯基]脲、 199毫克（1.51毫莫耳）4-氰基苯曱醛、與100毫克（1.51毫 莫耳）丙二腈懸浮於2毫升THF中，添加催化用量之濃鹽 酸。回流加熱下，攪拌此混合物18小時。冷卻至室溫 後，真空去除溶劑，殘留物於矽石上利用管柱層析法進行 10 純化，以二氣甲烷/甲醇為溶洗液。 產率：4毫克（1%) ]H-NMR (400 MHz, DMSO^)： δ = 5.2 (d, 1H); 6.0 (s, 2H); 7.6 (m, 3H); 7.7 (m, 2H); 7.8 (m, 1H); 7.9 (m, 2H) 8.4 (d, 1H) ppm. -49- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公嫠） 200410963 A7 B7 五、發明說明（48 ) 實例10 4-(4-乳苯基)-3 -甲酿基-6-甲基_2_嗣基-1-[3-(二氣^甲基）苯 基]_1，2,3,4_四氮-5-喊唆甲酸乙S旨Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 Make 400 mg (1.97 mmol) N- [3_ (trifluoromethyl) phenyl] urea, 199 mg (1.51 mmol) 4-cyanobenzaldehyde And 100 mg (1.51 mmol) of malononitrile were suspended in 2 ml of THF, and a catalytic amount of concentrated hydrochloric acid was added. The mixture was stirred under reflux for 18 hours. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified on silica using column chromatography, using methane / methanol as the eluent. Yield: 4 mg (1%)] H-NMR (400 MHz, DMSO ^): δ = 5.2 (d, 1H); 6.0 (s, 2H); 7.6 (m, 3H); 7.7 (m, 2H) ; 7.8 (m, 1H); 7.9 (m, 2H) 8.4 (d, 1H) ppm. -49- This paper size applies to China National Standard (CNS) A4 (210 X 297 cm) 200410963 A7 B7 V. Invention Explanation (48) Example 10 4- (4-lactylphenyl) -3-methylmethyl-6-methyl_2-fluorenyl-1- [3- (difluoro ^ methyl) phenyl] 1,2 , 3,4_tetrazol-5-methylacetate

CNCN

經濟部智慧財產局員工消費合作社印製 5 使100毫克(0.23毫莫耳)實例1化合物溶於1毫升二 甲基甲醯胺中，添加35.7毫克(0.23毫莫耳)磷醯氣。於 70°C，攪拌此反應混合物2小時。冷卻至室溫後，利用 HPLC分離產物。 產率：43毫克(41%) ^-NMR (300 MHz, DMSO-d6)： δ = LI (t, 3H); 2.1 (s, 3H); 4Λ (q, 2H); 6.4 (s, 1H); ία 7.6 (m, 2H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 4H); 9.2 (s, 1H)ppm. 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（49 ) 實例11 4-(4-亂苯基)-6•甲基·2_鋼基_1-[3_(三氟甲基）苯基]-152,3,4_ 四氫-5-嘧啶甲酸Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 100 mg (0.23 mmol) of the compound of Example 1 was dissolved in 1 ml of dimethylformamide, and 35.7 mg (0.23 mmol) of phosphine gas was added. The reaction mixture was stirred at 70 ° C for 2 hours. After cooling to room temperature, the product was isolated by HPLC. Yield: 43 mg (41%) ^ -NMR (300 MHz, DMSO-d6): δ = LI (t, 3H); 2.1 (s, 3H); 4Λ (q, 2H); 6.4 (s, 1H) ; ία 7.6 (m, 2H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 4H); 9.2 (s, 1H) ppm. This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (49) Example 11 4- (4-Ranylphenyl) -6 • methyl · 2_steel-based_1- [3_ (trifluoromethyl) benzene Phenyl] -152,3,4_tetrahydro-5-pyrimidinate

CNCN

經濟部智慧財產局員工消費合作社印製 5 使3克(7毫莫耳)實例1化合物溶於50毫升水與100 毫升5% KOH之乙醇混合物中。此反應混合物於室溫攪 拌18小時。真空去除溶劑，殘留物於矽石上利用管柱層 析法進行純化，以二氣甲烷/甲醇為溶洗液。 產率：1.27 克(45%) lH-NMR (300 MHz, DMSO-^): δ = 2.0 (s, 3H); 5Λ (d, 1H); 7.6 (m, 1H); 7.6 (m, 1〇 2H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 3H); 8.3 (d, 1H); 12.5 (s, 1H) ppm. 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 3 g (7 mmol) of the compound of Example 1 was dissolved in a mixture of 50 ml of water and 100 ml of 5% KOH in ethanol. The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica using methane / methanol as the eluent. Yield: 1.27 g (45%) lH-NMR (300 MHz, DMSO- ^): δ = 2.0 (s, 3H); 5Λ (d, 1H); 7.6 (m, 1H); 7.6 (m, 1〇) 2H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 3H); 8.3 (d, 1H); 12.5 (s, 1H) ppm. This paper standard applies Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) 200410963

五、發明說明（50 ) 實例12 4-(4•氰苯甲基-2-_基養丙基心例王氟甲基)苯基]_ 1，2,3,4-四氫_5-嘧啶甲醯胺V. Description of the invention (50) Example 12 4- (4 • Cyanobenzyl-2-ylaminopropyl fluoromethyl) phenyl] _1,2,3,4-tetrahydro_5- Pyrimidine

5 使40毫克0·1毫莫耳)實例11化合物溶於2毫升二 甲基甲醯胺中，於其内添加7毫克(Q u毫升)正丙胺、15 毫克((m毫莫耳）1-經基_1H-苯并三唾水合物及12毫克 (〇·1毫莫耳）4-二甲胺基吡啶。於〇〇c攪拌此反應混合 物，然後添加21毫克(〇·11毫莫耳）1-(3_二甲胺基丙基)-10 3-乙基碳化二亞胺鹽酸鹽。此反應混合物於室溫攪拌18 經濟部智慧財產局員工消費合作社印製 小時，接著添加水與乙酸乙酯。其有機相以飽和KHS〇4 水溶液、水及食鹽水洗滌，以硫酸鈉脫水，真空蒸發至 乾。如果需要，則利用管柱層析法或製備性HPLC進一 步純化產物。 15 產率：29毫克(66%) h-NMR (300 DMS04): δ = 0.7 ^ 3H); 1.3 (六重峰，2H); 1.7 (s，3H); 3.0 (q, 2H); 5.4 (d, 1H); 7.6 (m, 3H); 7.7 (m, 2H); 7.8 (m, 2H); 7.9 (m, 1H); 8.1 (d, lH)ppm. -52- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200410963 A7 B7 五、發明說明（5!) 實例13 4-(4-氰苯基)-N-(2-甲氧乙基)_卜甲基-2_酮基三氟甲 基）苯基]-1，2,3,4-四氫-5-續咬甲醢胺5 Dissolve 40 mg (0.1 mmol) of the compound of Example 11 in 2 ml of dimethylformamide, and add 7 mg (Q u ml) of n-propylamine, 15 mg ((m mmol) of 1 -Chrysyl-1H-benzotrisialyl hydrate and 12 mg (0.1 mmol) 4-dimethylaminopyridine. The reaction mixture was stirred at 00c, and then 21 mg (0.11 mmol) was added Ear) 1- (3_dimethylaminopropyl) -10 3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred at room temperature for 18 hours, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, and then added Water and ethyl acetate. The organic phase was washed with saturated KHS04 aqueous solution, water and brine, dehydrated with sodium sulfate, and evaporated to dryness in vacuo. If necessary, the product was further purified by column chromatography or preparative HPLC. 15 Yield: 29 mg (66%) h-NMR (300 DMS04): δ = 0.7 ^ 3H); 1.3 (hexaplex, 2H); 1.7 (s, 3H); 3.0 (q, 2H); 5.4 ( d, 1H); 7.6 (m, 3H); 7.7 (m, 2H); 7.8 (m, 2H); 7.9 (m, 1H); 8.1 (d, lH) ppm. -52- This paper size applies to China Standard (CNS) A4 specification (210x297 mm) 200410963 A7 B7 V. Description of the invention (5!) Example 13 4- (4-cyanophenyl) -N- (2-methoxyethyl) -methyl-2-ketotrifluoromethyl) phenyl] -1,2,3,4- Tetrahydro-5-continuous methylamine

經濟部智慧財產局員工消費合作社印製 200410963 A7 B7 五、發明說明（52 ) 實例14 4-(4-氰苯基)-3>二甲基-2-酮基-1 -[3·(三氟甲基）苯基]-1，2,3,4-四氫-5-哺唆甲酸乙醋Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 200410963 A7 B7 V. Description of the Invention (52) Example 14 4- (4-cyanophenyl) -3 > dimethyl-2-keto-1-[3 · (Three Fluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-fumarate ethyl acetate

經濟部智慧財產局員工消費合作社印製 5 添加89毫克(0.21毫莫耳)實例1化合物至含12.4毫 克(0·31毫莫耳）60%氫化鈉(於礦物油中）之2毫升THF懸 浮液中。此混合物於室溫攪拌2小時。然後添加26毫克 (0.21毫莫耳）硫酸二甲酯，此混合物於室溫再擾拌2小 時。接著添加水與乙酸乙酯，其有機相以水及食鹽水洗 10 滌，以硫酸鈉脫水，真空蒸發至乾。如果需要，則利用管 柱層析法或製備性HPLC進一步純化產物。 產率：85毫克(93%) ^-NMR (200 MEiz, DMSO-c^): δ - U (t, 3H); 2.0 (s, 3H); 2.8 (s, 3H); 4.0 (q, 2H); 5,5 (s, 1H); 7.6 (m, 3H); 1Π (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H) ppm. -54- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x 297公釐） 五 、發明說明 53 A7 B7 酿基1(4-氰苯基基小[3_(三氟甲基）苯 土 L2,3,4·四氫-5_嘧啶甲酸乙酯Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 Add 89 mg (0.21 mmol) of Example 1 compound to 2 ml of THF containing 12.4 mg (0.31 mmol) of 60% sodium hydride (in mineral oil) In the liquid. This mixture was stirred at room temperature for 2 hours. Then 26 mg (0.21 mmol) of dimethyl sulfate was added and the mixture was stirred at room temperature for another 2 hours. Water and ethyl acetate were then added, and the organic phase was washed with water and brine, dried over sodium sulfate, and evaporated to dryness in vacuo. If necessary, the product is further purified using column chromatography or preparative HPLC. Yield: 85 mg (93%) ^ -NMR (200 MEiz, DMSO-c ^): δ-U (t, 3H); 2.0 (s, 3H); 2.8 (s, 3H); 4.0 (q, 2H ); 5,5 (s, 1H); 7.6 (m, 3H); 1Π (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H) ppm. -54- This paper scale applies Chinese national standards (CNS) A4 specification (210 x 297 mm) V. Description of the invention 53 A7 B7 Brewing group 1 (4-cyanophenyl small [3_ (trifluoromethyl) phenyl earth L2,3,4 · tetrahydro-5 _ Ethyl pyrimidinate

〇、CH. 5 10 經濟部智慧財產局員工消費合作社印製 添加100毫克(0·23毫莫耳)實例1化合物至含12毫 α(0·28毫莫耳）60%氫化鈉(於礦物油中）之2毫升THF懸 ^中。此混合物於室溫_ 2 _ n添加91毫克 .宅莫耳）㈣氣’此混合物於室温再騎2 者添加水與乙酸6醋，其有機相以水及食 、接 酸納脫水，真空蒸發至乾。如果需要，則利用管=層= 或製備性HPLC進一.步純化產物。 法 產率：93毫克(85%) lH-NMR (200 MHz, DMSO^)： δ ^ 1.2 (t, 3H); 2.1 (s, 3H); 2.5 (s, 3H). 4 2 r 6.7 (s, 1H); 7.4 (in, 1H); 7.5 (m, 2H); 7.6 (m, 1H)； 7.7 (m, 1H); 7 8 ^ 2H)ppm. vm， 55- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x 297公釐） 200410963 A7 B7 54 五、發明說明（ 免例」6 6-(心氣笨基)_‘甲基_2_酮基-3_[3_(三氟甲基）苯基]-3,6-二 氫-1，5(2H)-嘧啶二甲酸二乙酯〇, CH. 5 10 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, 100 mg (0.23 mmol) of Example 1 compound was added to contain 12 mmol α (0.28 mmol) of 60% sodium hydride (in mineral In oil) in 2 ml of THF. Add 91 mg of this mixture at room temperature _ 2 _ n. House mol) radon 'this mixture at room temperature and then add 2 water and acetic acid 6 vinegar, the organic phase is dehydrated with water and food, then with sodium acid, and evaporated in vacuo To dry. If necessary, the product is further purified using tube = layer = or preparative HPLC. Method yield: 93 mg (85%) lH-NMR (200 MHz, DMSO ^): δ ^ 1.2 (t, 3H); 2.1 (s, 3H); 2.5 (s, 3H). 4 2 r 6.7 (s , 1H); 7.4 (in, 1H); 7.5 (m, 2H); 7.6 (m, 1H); 7.7 (m, 1H); 7 8 ^ 2H) ppm. Vm, 55- This paper standard applies to Chinese national standards (CNS) A4 specification (210 x 297 mm) 200410963 A7 B7 54 V. Description of the invention (Exemption) 6 6- (Heart Qibenzyl) _ 'methyl_2_keto-3_ [3_ (trifluoromethyl ) Phenyl] -3,6-dihydro-1,5 (2H) -pyrimidinedicarboxylic acid diethyl ester

5 10 經濟部智慧財產局員工消費合作社印製 添加100毫克(0 23毫莫耳)實例1化合物至含12毫 克(〇·28毫莫耳）60%氫化鈉(於礦物油中）之2毫升THF懸 浮液中。此混合物於室溫攪拌2小時。然後添加126毫克 (1.16毫莫耳)氯化碳酸乙酯，此混合物於室溫再攪拌2小 時。接著添加水與乙酸乙酯，其有機相以水及食鹽水洗 務以硫酸納脫水，真空蒸發至乾。如果需要，則利用管 柱層析法或製備性HPLC進一步純化產物。 產率·· 92毫克(79%) lH-NMR (200 MHz, DMSO-^): δ = 1.2 (t, 3Η; t, 3H); 2.1 (s, 3H); 4.2 (m, 2H)； 4·3 (q, 2H); 6.4 (s, 1H); 7.4 (m, 1H); 7.5 (m, 3H); 7.7 (m, 1H)； 7.8 (m, 1H); 7.9 (m, 2H) ppm. -56- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（55) 實例17 4- (4-氰苯基)-6-甲基-1·(3-甲基苯基>2-酮基-1，2,3,4-四氫- 5- 嘧啶甲酸乙酯5 10 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, adding 100 mg (0 23 mmol) of Example 1 compound to 2 ml containing 12 mg (0.28 mmol) of 60% sodium hydride (in mineral oil) In THF suspension. This mixture was stirred at room temperature for 2 hours. Then, 126 mg (1.16 mmol) of ethyl chloride was added, and the mixture was stirred at room temperature for another 2 hours. Water and ethyl acetate were then added, and the organic phase was washed with water and brine, dried over sodium sulfate, and evaporated to dryness in vacuo. If necessary, the product is further purified using column chromatography or preparative HPLC. Yield: 92 mg (79%) lH-NMR (200 MHz, DMSO- ^): δ = 1.2 (t, 3Η; t, 3H); 2.1 (s, 3H); 4.2 (m, 2H); 4 3 (q, 2H); 6.4 (s, 1H); 7.4 (m, 1H); 7.5 (m, 3H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 2H) ppm -56- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (55) Example 17 4- (4-cyanophenyl) -6-methyl- 1 · (3-methylphenyl > 2-keto-1,2,3,4-tetrahydro- 5-pyrimidinecarboxylic acid ethyl ester

經濟部智慧財產局員工消費合作社印製 5 使15〇毫克(1.0毫莫耳）Ν_[3-甲基苯基]脲、1〇1毫克 (0.77毫莫耳）4-氰基苯甲醛與1〇〇毫克(〇 77毫莫耳）3-酮 基丁酸乙酯懸浮於2毫升THF中，添加催化用量之濃鹽 酸。回流加熱下，攪拌此混合物18小時。冷卻至室溫 後，真空去除溶劑，殘留物於石夕石上利用管柱層析法進行 10 純化，以環己烷/乙酸乙酯為溶洗液。 產率：8毫克(3%) !H-NMR (200 MHz, DMSO-d6>: δ - U (tf 3H)； 2.0 (s, 3H)； 2.3 (s, 3H); 4.0 (q, 2H); 53 (d, 1H); 7.0 (m, 2H); 7.2 (m, 1H); 7.3 (m> 1H); 7.6 (m, 2H); 7.9 (m, 2H); 8.2 (d, 1H) ppm. -57- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200410963 A7 B7 五、發明說明（56 ) 實例18 4_(4_氣苯基)-6_甲基-2-酮基_1-[3-(三氟甲基）苯基]-1，2,3,4· 四氫-5-嘧啶甲酸乙酯Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 Make 15 mg (1.0 mmol) of N_ [3-methylphenyl] urea, 101 mg (0.77 mmol) 4-cyanobenzaldehyde and 1 One hundred milligrams (0.777 millimoles) of ethyl 3-ketobutyrate was suspended in 2 ml of THF, and a catalytic amount of concentrated hydrochloric acid was added. The mixture was stirred under reflux for 18 hours. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by column chromatography on Shi Xishi, using cyclohexane / ethyl acetate as the eluent. Yield: 8 mg (3%)! H-NMR (200 MHz, DMSO-d6): δ-U (tf 3H); 2.0 (s, 3H); 2.3 (s, 3H); 4.0 (q, 2H) ; 53 (d, 1H); 7.0 (m, 2H); 7.2 (m, 1H); 7.3 (m >1H); 7.6 (m, 2H); 7.9 (m, 2H); 8.2 (d, 1H) ppm -57- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200410963 A7 B7 V. Description of the invention (56) Example 18 4_ (4_Gaphenyl) -6_methyl-2-one 1- [3- (trifluoromethyl) phenyl] -1,2,3,4 · ethyl tetrahydro-5-pyrimidinecarboxylic acid

CICI

經濟部智慧財產局員工消費合作社印製 5 使204毫克（L0毫莫耳）Ν_[3-(三氟甲基)苯基]脲、 108毫克(0·77毫莫耳）4-氯苯甲醛與100毫克(0.77毫莫耳） 3-酮基丁酸乙酯懸浮於2毫升THF中，添加催化用量之 濃鹽酸。回流加熱下，撲:拌此混合物18小時。冷卻至室 溫後，真空去除溶劑，殘留物於矽石上利用管柱層析法進 10 行純化，以環己烧/乙酸乙S旨為溶洗液。 產率：29毫克(9%) ]H-NMR (200 MHz, DMSO-da): δ = LI (t, 3H); 2.0 (s, 3H); 4.0 (q, 2H); 5.3 (d, 1H); 7.5 (m, 5H); 7.6 (m, 1H); 7.7 (m, 2H); 8.3 (d, 1H) ppm. -58- 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐） 200410963 A7 B7 五、發明說明（57 ) 實例19 6-(演甲基）·4_(4_乳苯基）-2-酮基_1-[3-(三氟甲基）苯基]_ 1，2,3,4-四氫_5_嘧咬曱酸乙酯Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 make 204 mg (L0 mmol) of N_ [3- (trifluoromethyl) phenyl] urea, 108 mg (0.777 mmol) 4-chlorobenzaldehyde Suspend it with 100 mg (0.77 mmol) of ethyl 3-ketobutyrate in 2 ml of THF, and add concentrated hydrochloric acid in a catalytic amount. With heating under reflux, puff: mix the mixture for 18 hours. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by column chromatography on silica using cyclohexane / ethyl acetate as the eluent. Yield: 29 mg (9%)] H-NMR (200 MHz, DMSO-da): δ = LI (t, 3H); 2.0 (s, 3H); 4.0 (q, 2H); 5.3 (d, 1H ); 7.5 (m, 5H); 7.6 (m, 1H); 7.7 (m, 2H); 8.3 (d, 1H) ppm. -58- This paper size applies to China National Standard (CNS) A4 (210 x 297) (Mm) 200410963 A7 B7 V. Description of the invention (57) Example 19 6- (methyl) · 4_ (4-lactyl) -2-one-1-_1- [3- (trifluoromethyl) phenyl ] _ 1,2,3,4-tetrahydro_5_pyrimidate

CNCN

經濟部智慧財產局員工消費合作社印製 5 使3克(7毫莫耳)實例1化合物溶於100毫升氯仿 中。於0°C，逐滴添加558毫克(3.48毫莫耳）溴。於室溫 攪拌此混合物2小時，然後真空去除溶劑。殘留物於矽石 上利用管柱層析法進行純化，以環己烷/乙酸乙酯為溶洗 液。 10 產率：3.2 克(90%) lH-NMR (200 MHz, DMSO-^): δ = 1.1 (t, 3H); 4.0 (q, 2¾ d, 1H); 4.6 (br d, 1H); 5,4 (d, 1H); 7.6 (m, 3H); 7.7 (m, 2H); 7.8 (m, 1H); 7.9 (m, 2H); 8.6 (d, 1H) ppm. -59- 本紙張尺度適用中國國家標準(CNS)A4規格（210X 297公釐） 200410963 A7 B7 五、發明說明（58 ) 實例20 4-(4-氰苯基）-6-[(二乙胺基）甲基]-2-酮基-1-[3-(三氟甲基） 苯基]"*1，2,3,4-四風_5-,唆甲酸乙酉旨Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 3 g (7 mmol) of the compound of Example 1 was dissolved in 100 ml of chloroform. At 0 ° C, 558 mg (3.48 mmol) of bromine was added dropwise. The mixture was stirred at room temperature for 2 hours, and then the solvent was removed in vacuo. The residue was purified by column chromatography on silica using cyclohexane / ethyl acetate as the eluent. 10 Yield: 3.2 g (90%) lH-NMR (200 MHz, DMSO- ^): δ = 1.1 (t, 3H); 4.0 (q, 2¾ d, 1H); 4.6 (br d, 1H); 5 , 4 (d, 1H); 7.6 (m, 3H); 7.7 (m, 2H); 7.8 (m, 1H); 7.9 (m, 2H); 8.6 (d, 1H) ppm. -59- Paper size Applicable to China National Standard (CNS) A4 specification (210X 297 mm) 200410963 A7 B7 V. Description of the invention (58) Example 20 4- (4-cyanophenyl) -6-[(diethylamino) methyl]- 2-keto-1- [3- (trifluoromethyl) phenyl] " * 1,2,3,4-tetrafeng_5-, acetic acid ethyl acetate

CNCN

經濟部智慧財產局員工消費合作社印製 10 使20毫克(0.04毫莫耳)實例19化合物溶於2毫升丙 酮中，於其内添加8毫克(0.10毫莫耳）二乙胺。於室溫攪 拌此混合物18小時，然後真空去除溶劑。殘留物以製備 性HPLC純化。 產率：15毫克(75%) JH-NMR (300 MHz, DMSO-d^): δ = 0.6 (t, 6H); U (t, 3H); 2.0 (m, 2H); 2.2 (m, 2H); 3.1 (br d, 1H); 3.9 (br d, 1H); 4.1 (q, 2H); 5.4 (d, 1H); 7.5 (m, 1H); 7.6 (m, 4H); 7.7 (m, 1H); 7.9 (m, 2H) ppm. -60- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（59) 實例21 6-(苯胺基甲基)-4-(4-氰苯基)-2-酮基-1 -[3-(三氟甲基）苯 基]-1，2,3,4-四氮-5-鳴唆甲酸乙醋 CN 0Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 10 20 mg (0.04 mmol) of Example 19 was dissolved in 2 ml of acetone, and 8 mg (0.10 mmol) of diethylamine was added thereto. The mixture was stirred at room temperature for 18 hours, and then the solvent was removed in vacuo. The residue was purified by preparative HPLC. Yield: 15 mg (75%) JH-NMR (300 MHz, DMSO-d ^): δ = 0.6 (t, 6H); U (t, 3H); 2.0 (m, 2H); 2.2 (m, 2H ); 3.1 (br d, 1H); 3.9 (br d, 1H); 4.1 (q, 2H); 5.4 (d, 1H); 7.5 (m, 1H); 7.6 (m, 4H); 7.7 (m, 1H); 7.9 (m, 2H) ppm. -60- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (59) Example 21 6- (aniline (Methyl) -4- (4-cyanophenyl) -2-keto-1-[3- (trifluoromethyl) phenyl] -1,2,3,4-tetraaza-5-anolinic acid Ethyl acetate CN 0

Ο CH, 經濟部智慧財產局員工消費合作社印製 5 使50毫克(0.10毫莫耳)實例19化合物溶於2毫升丙 酮中，於其内添加18毫克(0.20毫莫耳）苯胺。於室溫攪 拌此混合物18小時，然後真空去除溶劑。殘留物以製備 性HPLC純化。 產率：28毫克(55%) JH-NMR (300 MHz, DMSO-d6)： δ = 1.1 (t, 3H); 3.6 (d/d, 1H); 4.1 (q, 2H); 4.4 (d/d, 1H); 5.4 (m, 2H); 6.2 (m, 2H); 6.5 (m, 1H); 6.9 (in, 2H); 7.6 (m, 6H); 7.9 (m, 2H); l〇 8,4 (d, 1H) ppm. •61- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 ------ B7 五、發明說明（6〇) 實例22 (+)-4-(4_氰苯基）_6_甲基_2_酮基(三氟甲基）苯基]_ 1，2,3,4-四氫_5_嘧啶甲酸乙酯Ο CH, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 50 mg (0.10 mmol) of Example 19 was dissolved in 2 ml of acetone, and 18 mg (0.20 mmol) of aniline was added thereto. The mixture was stirred at room temperature for 18 hours, and then the solvent was removed in vacuo. The residue was purified by preparative HPLC. Yield: 28 mg (55%) JH-NMR (300 MHz, DMSO-d6): δ = 1.1 (t, 3H); 3.6 (d / d, 1H); 4.1 (q, 2H); 4.4 (d / d, 1H); 5.4 (m, 2H); 6.2 (m, 2H); 6.5 (m, 1H); 6.9 (in, 2H); 7.6 (m, 6H); 7.9 (m, 2H); l〇8 , 4 (d, 1H) ppm. • 61- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200410963 A7 ------ B7 V. Description of the invention (6〇) Example 22 (+)-4- (4_cyanophenyl) _6_methyl_2_keto (trifluoromethyl) phenyl] _1,2,3,4-tetrahydro_5_pyrimidinecarboxylic acid ethyl ester

CNCN

5 於對掌相上利用製備性HPLC分離實例1之鏡像異構 物：使100毫克化合物溶於15毫升乙酸乙酯，管柱 KBD 8361 (以單體曱基丙烯醯基白胺酸-1-甲基醯胺 為基底之對掌性矽膠選擇器，參考EP-A-379 917)，250 毫米X 20毫米，溶洗液乙酸乙酯，流速％毫升/分鐘， 10溫度23°C，注射量2500微升，檢測254奈米。 經濟部智慧財產局員工消費合作社印製 lH-NMR (300 MHz, DMSO-d<5): δ = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (q, 2H); 5.4 (d, 1H); 7,6 (m, 3H); 7.7 (m, 2H); 7.8 (m, 1H); 7.9 (m5 2H); 8.4 (4 1H) ppm.5 Preparative HPLC separation of the mirror image isomer of Example 1 on the opposite palm phase: 100 mg of the compound was dissolved in 15 ml of ethyl acetate, and column KBD 8361 (using the monomer fluorenyl propylene fluorenyl leucine -1- Methylamine-based dual palm silicone selector, refer to EP-A-379 917), 250 mm X 20 mm, ethyl acetate of the washing solution, flow rate% ml / min, 10 temperature 23 ° C, injection volume 2500 μl, detection 254 nm. Printed by lH-NMR (300 MHz, DMSO-d < 5): Employee Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs: δ = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (q, 2H); 5.4 (d , 1H); 7,6 (m, 3H); 7.7 (m, 2H); 7.8 (m, 1H); 7.9 (m5 2H); 8.4 (4 1H) ppm.

[α]2<) = +3·3° (λ = 589奈米，二氯甲烷，c = 535.0 毫克/100 毫升） -62- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200410963 A7 B7 五、發明説明（Μ ㈠-4-(4-乳苯基)·3,6-二甲基-2_酮基乳甲基）笨基j 1，2,3,4-四氫-5_嘴唆甲酸乙香旨[α] 2 <) = + 3 · 3 ° (λ = 589 nanometers, dichloromethane, c = 535.0 mg / 100 ml) -62- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200410963 A7 B7 V. Description of the invention (M Μ-4- (4-lactophenyl) · 3,6-dimethyl-2_ketomilk methyl) benzyl j 1,2,3,4-tetra Hydrogen-5_Ethyl Acetate

Ο CH 3 5 添加10〇毫克(〇·23毫莫耳)實例22化合物至含14毫 克(0·35毫莫耳）60%氫化鈉(於礦物油中）之2毫升了抑頻 浮液中。此混合物於室溫攪拌2小時。然後添加29毫克 (0·23毫莫耳）硫酸二甲酯，此混合物於室溫再攪拌2小 時。接著添加水與乙酸乙酯，其有機相以水及食鹽水洗 10 滌，以硫酸鈉脫水，真空蒸發至乾。於矽石上利用管柱層 析法純化產物，以環己烷/乙酸乙酯為溶洗液。 經濟部智慧財產扃員工消費合作社印製 產率：76毫克(74%) 'H-NMR (200 MHz, DMSO-^): δ = 1.1 (t, 3H); 2.0 (s, 3H); 2.8 (s, 3H)； 4.0 (q, 2H); 5.5 (s, 1H); 7.6 (m, 3H); 7.7 (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H) ppm.Ο CH 3 5 Add 100 mg (.23 mmol) of Example 22 compound to 2 ml of a frequency-suppressed suspension containing 14 mg (0.35 mmol) of 60% sodium hydride (in mineral oil). . This mixture was stirred at room temperature for 2 hours. Then, 29 mg (0.23 mmol) of dimethyl sulfate was added, and the mixture was stirred at room temperature for another 2 hours. Water and ethyl acetate were then added, and the organic phase was washed with water and brine, dried over sodium sulfate, and evaporated to dryness in vacuo. The product was purified by column chromatography on silica using cyclohexane / ethyl acetate as the eluent. Printed by Intellectual Property of the Ministry of Economic Affairs and Employee Cooperatives: 76 mg (74%) 'H-NMR (200 MHz, DMSO- ^): δ = 1.1 (t, 3H); 2.0 (s, 3H); 2.8 ( s, 3H); 4.0 (q, 2H); 5.5 (s, 1H); 7.6 (m, 3H); 7.7 (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H) ppm.

[oc]20 = -18· I。(λ = 589 奈米，二氣甲烷，c = 53〇·〇 毫克 / j 〇〇 毫升） -63- 本纸張尺度適用中國國家標準(CNS)A4規格（210 X 297公复） 200410963 A7 B7 五、發明說明（62 ) JLfeL24 4-(6_氰基-3·α比啶基)-6-甲基-2-酮基-1-[3-(三氟甲基）苯基]-1，2,3,4-四氫-5_嘴唆甲酸乙酯[oc] 20 = -18 · I. (λ = 589 nm, digas methane, c = 534.0 mg / j 〇mL) -63- This paper size applies to China National Standard (CNS) A4 (210 X 297 public) 200410963 A7 B7 V. Description of the invention (62) JLfeL24 4- (6-Cyano-3 · αpyridinyl) -6-methyl-2-keto-1--1- [3- (trifluoromethyl) phenyl] -1 , 2,3,4-tetrahydro-5_methylammonium ethyl formate

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經濟部智慧財產局員工消費合作社印製 ^ 於實例3A (76毫克，0.58毫莫耳)之四氫呋喃（5毫升） 攪拌溶液中，添加3-酮基丁酸乙酯（75毫克，0.58毫莫 耳）、N_〇(三氟甲基)苯基]脲（118毫克，0.58毫莫耳)與 多磷酸乙酯（200毫克；根據Cava w a/.，j. 〇rg. Chem. 1969, 3免2665之程序新鮮製備）。回流加熱此反應混合物 10 2天(48小時），隨後，以DMSO (2毫升)稀釋該溶液，利 用製備性HPLC予以純化。真空濃縮產物溶離份，於矽 石上再進行層析法，以環己烷與乙酸乙酯為溶洗液。 產率·· 92毫克(理論值之35%) MS (ESIpos) ： m/z = 431 (M+H)+ 15 HPLC (方法 4) = 4.63 分鐘 ^-NMR (300 MHz, DMS0^d6): δ « 8.76 (s, 1H), 8.36 (d, 1H), 8.16-8.00 (m> 2H), 7.83-7-74 (m，2H)，7.75·7·58 (m, 2H)，5.47 (d, 1H)，4·03 (四重峰,2H)，2·06 (s，3H)， 1.08 (t, 3H) ppm. -64- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x 297公釐） 200410963 A7 B7 五、發明說明（63 ) 實例25 4-{5-(1Η-咪唑-1-基羰基)-6-甲基-2_酮基·1-[3-(三氟甲基） 苯基]-1，2,3,4-四氫-4-嘧啶基}苯曱腈Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ^ To a stirred solution of Example 3A (76 mg, 0.58 mmol) in tetrahydrofuran (5 ml) was added ethyl 3-ketobutyrate (75 mg, 0.58 mmol) ), N_〇 (trifluoromethyl) phenyl] urea (118 mg, 0.58 mmol) and ethyl polyphosphate (200 mg; according to Cava wa /., J. 〇rg. Chem. 1969, 3 2665 procedure freshly prepared). The reaction mixture was heated at reflux for 102 days (48 hours), and then the solution was diluted with DMSO (2 ml) and purified by preparative HPLC. The product fractions were concentrated in vacuo and chromatographed on silica using cyclohexane and ethyl acetate as eluents. Yield · 92 mg (35% of theory) MS (ESIpos): m / z = 431 (M + H) + 15 HPLC (Method 4) = 4.63 minutes ^ -NMR (300 MHz, DMS0 ^ d6): δ «8.76 (s, 1H), 8.36 (d, 1H), 8.16-8.00 (m > 2H), 7.83-7-74 (m, 2H), 7.75 · 7 · 58 (m, 2H), 5.47 (d , 1H), 4 · 03 (quartet peak, 2H), 2 · 06 (s, 3H), 1.08 (t, 3H) ppm. -64- This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 200410963 A7 B7 V. Description of the invention (63) Example 25 4- {5- (1H-imidazol-1-ylcarbonyl) -6-methyl-2_keto · 1- [3- (trifluoro (Methyl) phenyl] -1,2,3,4-tetrahydro-4-pyrimidinyl} benzonitrile

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經濟部智慧財產局員工消費合作社印製 5 於含501毫克（1.25毫莫耳)實例11化合物之5毫升 無水二甲基甲醢胺溶液中，添加567毫克（3.5毫莫耳） Ν，Ν-羰基二咪唑。令反應混合物靜置隔夜後，真空蒸發 去除溶劑。使殘留物混於乙酸乙酯中，以水及食鹽水洗 滌。以硫酸鎂脫水後，真空蒸發去除溶劑。 10 產率：500毫克（理論值之88.6%) MS (El): m/z = 452 (M+H)^ 'H-NMR (200 MHz, DMSO^)： 6-1.40 (d, 3H), 5.5 (d, 1H), 7.0 (s, 1H), 7.55-8.0 (m, 9H), 8.4 (s, 1H), 8.45 (d, 1H) ppm. -65- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x 297公釐） 200410963 A7 B7 五、發明說明（64 ) f例26 4-(4-氰苯基)_6•甲基-2-酮基·1_[3-(三氟甲基）苯基]-1，2,3,4_ 四氫-5-嘧啶甲酸2-羥基乙酯Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 In a 5 ml anhydrous dimethylformamide solution containing 501 mg (1.25 mmol) of Example 11 compound, 567 mg (3.5 mmol) was added Ν, Ν- Carbonyldiimidazole. After allowing the reaction mixture to stand overnight, the solvent was removed by evaporation in vacuo. The residue was mixed with ethyl acetate and washed with water and brine. After dehydration with magnesium sulfate, the solvent was removed by evaporation in vacuo. 10 Yield: 500 mg (88.6% of theory) MS (El): m / z = 452 (M + H) ^ 'H-NMR (200 MHz, DMSO ^): 6-1.40 (d, 3H), 5.5 (d, 1H), 7.0 (s, 1H), 7.55-8.0 (m, 9H), 8.4 (s, 1H), 8.45 (d, 1H) ppm. -65- This paper standard applies to Chinese National Standard (CNS ) A4 size (210 x 297 mm) 200410963 A7 B7 V. Description of the invention (64) f Example 26 4- (4-cyanophenyl) _6 • methyl-2-keto · 1_ [3- (trifluoromethyl (Phenyl) phenyl] -1,2,3,4_tetrahydro-5-pyrimidinate 2-hydroxyethyl

CNCN

經濟部智慧財產局員工消費合作社印製 5 添加45·1毫克(0.1毫莫耳)實例25化合物至0·5毫升 乙二醇中，此反應混合物於大約100°C攪拌1小時。冷卻 後，以製備性 HPLC(管柱·· Agilent Zorbax Extend C18 20 毫米x 50毫米，5微米；溶劑A :乙腈，溶劑B :水+ 0.1%濃氨水；梯度：〇分鐘10% A，2分鐘10% A，6分 10 鐘 90% A，7 分鐘 90% A，7.1 分鐘 1〇% a，8 分鐘 10% A ;波長：220奈米；注射量：大約· 500微升；注射次 數：1)純化反應混合物。合併含溶離份之產物，並予以真 空濃縮。 產率：22毫克（理論值之49.4%) MS (El): m/z = 446 (M+H)+ ^H-NMR (300 MHz, DMSO-d,): δ = 2.05 (d, 3H), 3.5 2H), 3.95^.15 (m, 2H), 4,75 (tr, 1H), 5.45 (d, 1H), 7.55-7.75 (m, 5H), 7.75 (d, 1H), 7.85 (d, 2H), 8.35 15 (d, 1H) ppm. -66- ^紙張尺度適用中國國家標準(CNS)A4規格_(210 x 297公笼）-- 200410963 A7 B7 五、發明說明（65 ) 實例27 4-(4-氰苯基)-6-甲基-2-酮基小[3-(三氟甲基）苯基]-1，2,3,4_ 四氫-5-嘧啶曱酸2_(二甲胺基）乙酯 CN 〒h3Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 45.1 mg (0.1 mmol) of Example 25 compound was added to 0.5 ml of ethylene glycol, and the reaction mixture was stirred at about 100 ° C for 1 hour. After cooling down, use preparative HPLC (column Agilent Zorbax Extend C18 20 mm x 50 mm, 5 microns; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia water; gradient: 0 minutes 10% A, 2 minutes 10% A, 6 minutes, 10 minutes, 90% A, 7 minutes, 90% A, 7.1 minutes, 10% a, 8 minutes, 10% A; Wavelength: 220 nm; Injection volume: approx. 500 μl; Number of injections: 1 ) Purify the reaction mixture. The products containing the dissolved fractions were combined and concentrated in vacuo. Yield: 22 mg (49.4% of theory) MS (El): m / z = 446 (M + H) + ^ H-NMR (300 MHz, DMSO-d,): δ = 2.05 (d, 3H) , 3.5 2H), 3.95 ^ .15 (m, 2H), 4,75 (tr, 1H), 5.45 (d, 1H), 7.55-7.75 (m, 5H), 7.75 (d, 1H), 7.85 (d , 2H), 8.35 15 (d, 1H) ppm. -66- ^ The paper size applies the Chinese National Standard (CNS) A4 specification_ (210 x 297 male cage)-200410963 A7 B7 V. Description of the invention (65) Example 27 4- (4-cyanophenyl) -6-methyl-2-keto small [3- (trifluoromethyl) phenyl] -1,2,3,4_tetrahydro-5-pyrimidinidine acid 2_ ( Dimethylamino) ethyl ester CN 〒h3

經濟部智慧財產局員工消費合作社印製 5 添加45.1毫克(0.1毫莫耳)實例25化合物至0.5毫升 2-(二曱胺基）乙醇中，此反應混合物於大約100°C攪拌1 小時。冷卻後，以製備性HPLC(管柱·· Agilent ZorbaxPrinted by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5 Add 45.1 mg (0.1 mmol) of Example 25 compound to 0.5 ml of 2- (diamido) ethanol. Stir the reaction mixture at about 100 ° C for 1 hour. After cooling down, preparative HPLC (column · Agilent Zorbax

Extend C18 20毫米x 50毫米，5微米；溶劑A :乙腈， 溶劑B :水+ 0.1%濃氨水；梯度：0分鐘10% A，2分鐘 10 10% A，6 分鐘 90% A，7 分鐘 90% A，7.1 分鐘 10% A， 8分鐘10% A ;波長：220奈米；注射量：大約500微 升；注射次數：1)純化反應混合物。合併含溶離份之產 物，並予以真空濃縮。 產率：24毫克（理論值之50.8%) MS (El): m/z - 473 (M+H)+ 'H-NMR (300 MHz, DMSO-de): δ - 2.05 (d, 3H), 2.1 (s, 6H), 2.4 (m, 2H), 4.1 (m, 2H), 5.35 (d, 1H), 7.55 (d, 1H), 7.6 (d, 2H), 7.7 (m, 2H)S 7.8 (d, 1H), 7.85 (4 2H), 8.35 (d, 1H) ppm. -67- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200410963 A7 B7 五、發明說明（66) 實例28 4-(4-氰苯基)_6_甲基-2-酮基小[3-(三氟甲基)苯基]-1，2,3,4-四氫-5-嘧啶甲酸2-(4_吡啶基）乙酯Extend C18 20mm x 50mm, 5 microns; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia water; gradient: 0 minutes 10% A, 2 minutes 10 10% A, 6 minutes 90% A, 7 minutes 90 % A, 7.1 minutes 10% A, 8 minutes 10% A; wavelength: 220 nm; injection volume: about 500 microliters; number of injections: 1) purification reaction mixture. The products containing dissolved fractions were combined and concentrated in vacuo. Yield: 24 mg (50.8% of theory) MS (El): m / z-473 (M + H) + 'H-NMR (300 MHz, DMSO-de): δ-2.05 (d, 3H), 2.1 (s, 6H), 2.4 (m, 2H), 4.1 (m, 2H), 5.35 (d, 1H), 7.55 (d, 1H), 7.6 (d, 2H), 7.7 (m, 2H) S 7.8 (d, 1H), 7.85 (4 2H), 8.35 (d, 1H) ppm. -67- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200410963 A7 B7 V. Description of the invention (66) Example 28 4- (4-cyanophenyl) -6-methyl-2-keto small [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid 2 -(4-pyridyl) ethyl ester

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4 訂 5 添加45.1毫克(0.1毫莫耳)實例25化合物至0.5毫升4 Order 5 Add 45.1 mg (0.1 mmol) of Example 25 Compound to 0.5 ml

2-(4-吡啶基）乙醇中，此反應混合物於大約1(KTC攪拌1 小時。冷卻後，以製備性HPLC(管柱·· Agilent Zorbax Extend C18 20毫米x 50毫米，5微米；溶劑A:乙腈， 溶劑B :水+ 0.1%濃氨水；梯度：0分鐘10% A，2分鐘 10 10% A，6 分鐘 90% A，7 分鐘 90% A，7.1 分鐘 10% A， 經濟部智慧財產局員工消費合作社印製 8分鐘10% A ;波長：220奈米；注射量：大約.500微 升；注射次數：1)純化反應混合物。合併含溶離份之產 物，並予以真空濃縮。 產率：Π毫克（理論值之33.5%) MS (JET): m/z = 507 (Μ+Η)+ lH-NMR (300 MHz, DMSO-d^): δ = 2.0 (d, 3H), 2.9 (tr, 2H), 4.3 (tr, 2H), 5.25 (d, 1H), 7.15 (d, 2H), 7.45 (d, 2H), 7.5 (d, 1H), 7.65 (tr, 2H), 7.8 (m, 3H), 8.35 (d, 1H), 15 8.4 (d, 2H) ppm. -68- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（67 ) 實例29 4-(4_氰苯基)_6_甲基-2_酮基-1-[3-(三氟甲基）苯基]-1，2,3,4-四氫-5-嘧啶甲酸2-(2_吡啶基）乙酯In 2- (4-pyridyl) ethanol, the reaction mixture was stirred at approximately 1 (KTC for 1 hour. After cooling, preparative HPLC (column · Agilent Zorbax Extend C18 20 mm x 50 mm, 5 microns; solvent A : Acetonitrile, Solvent B: Water + 0.1% concentrated ammonia; Gradient: 10% A in 0 minutes, 10 10% A in 2 minutes, 90% A in 6 minutes, 90% A in 7 minutes, 10% A in 7.1 minutes, Intellectual Property of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperative for 10 minutes 10% A; Wavelength: 220 nm; Injection volume: approximately .500 μl; Number of injections: 1) Purification of the reaction mixture. The products containing dissolved fractions were combined and concentrated in vacuo. Yield : Π mg (33.5% of theory) MS (JET): m / z = 507 (Μ + Η) + lH-NMR (300 MHz, DMSO-d ^): δ = 2.0 (d, 3H), 2.9 ( tr, 2H), 4.3 (tr, 2H), 5.25 (d, 1H), 7.15 (d, 2H), 7.45 (d, 2H), 7.5 (d, 1H), 7.65 (tr, 2H), 7.8 (m , 3H), 8.35 (d, 1H), 15 8.4 (d, 2H) ppm. -68- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200410963 A7 B7 Intellectual Property Bureau, Ministry of Economic Affairs Printed by the Employee Consumption Cooperative V. Explanation of the Invention (67) Example 29 4- (4_cyanophenyl) _6_methyl -2_keto-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinate 2- (2-pyridyl) ethyl

CNCN

5 添加45.1毫克(0.1毫莫耳)實例25化合物至0.5毫升 2-(2_吡啶基）乙醇中，此反應混合物於大約100°C攪拌1 小時。冷卻後，以製備性HPLC(管柱·· Agilent Zorbax5 Add 45.1 mg (0.1 mmol) of the compound of Example 25 to 0.5 ml of 2- (2-pyridyl) ethanol, and stir the reaction mixture at about 100 ° C for 1 hour. After cooling down, preparative HPLC (column · Agilent Zorbax

Extend C18 20毫米x 50毫米，5微米；溶劑A :乙腈， 溶劑B :水+ 0.1%濃氨水；梯度：0分鐘10% A，2分鐘 10 10% A，6 分鐘 90% A，7 分鐘 90% A，7.1 分鐘 10% A， 8分鐘10% A ;波長：220奈米；注射量：大約500微 升；注射次數：1)純化反應混合物。合併含溶離份之產 物，並予以真空濃縮。 產率：22毫克（理論值之43.4%) MS (El): m/z - 507 (M+H)+ ^-NMR (300 MHz, DMSO-d^): δ = 2.0 (d, 3H), 3.0 (tr, 2H), 4.4 (tr, 2H)5 5.25 (d, 1H), 7.15-7.25 (m, 2H), 7.4 (d, 2H), 7.5 (d, 1H), 7.6-7.75 (m, 3H), 7.8 (m, 3H), 8.3 15 (d, 1H), 8.45 (d,lH) ppm. -69- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）Extend C18 20mm x 50mm, 5 microns; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia water; gradient: 0 minutes 10% A, 2 minutes 10 10% A, 6 minutes 90% A, 7 minutes 90 % A, 7.1 minutes 10% A, 8 minutes 10% A; wavelength: 220 nm; injection volume: about 500 microliters; number of injections: 1) purification reaction mixture. The products containing dissolved fractions were combined and concentrated in vacuo. Yield: 22 mg (43.4% of theory) MS (El): m / z-507 (M + H) + ^ -NMR (300 MHz, DMSO-d ^): δ = 2.0 (d, 3H), 3.0 (tr, 2H), 4.4 (tr, 2H) 5 5.25 (d, 1H), 7.15-7.25 (m, 2H), 7.4 (d, 2H), 7.5 (d, 1H), 7.6-7.75 (m, 3H), 7.8 (m, 3H), 8.3 15 (d, 1H), 8.45 (d, lH) ppm. -69- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

200410963 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（68) 實例30 4-(4-氰苯基)-6-甲基-2-酮基小[3_(三氟甲基）苯基]_1，2,3,4_ 四氫-5-嘧啶甲酸2-(2-酮基-1-吡咯啶基）乙酯200410963 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Description of the invention (68) Example 30 4- (4-cyanophenyl) -6-methyl-2-keto small [3_ (trifluoromethyl) Phenyl] 1,2,3,4_tetrahydro-5-pyrimidinate 2- (2-keto-1-pyrrolidinyl) ethyl ester

CNCN

5 添加45.1毫克(0.1毫莫耳)實例25化合物至0.5毫升 1-(2-羥乙基)-2-吡咯啶酮中，此反應混合物於大約100°C 攪拌1小時。冷卻後，以製備性HPLC(管柱：Agilent Zorbax Extend C18 20 毫米 X 50 毫米，5 微米；溶劑 A : 乙腈，溶劑B :水+ 0.1%濃氨水；梯度：0分鐘10% 10 A，2 分鐘 10% A，6 分鐘 90% A，7 分鐘 90% A，7.1 分 .鐘10% A，8分鐘10% A ;波長：220奈米；注射量：大 約500微升；注射次數：1)純化反應混合物。合併含溶離 份之產物，並予以真空濃縮。 產率：25毫克（理論值之48.8%) MS (El): m/z = 513 (M+H)+ 】H-NMR (300 MHz，DMSOO: δ = 1.8 (五重聲，2H)，2·0 (4 3H)，2·1 (tr，2H)，3·2 (tr，2Η)，3.4 (tr，2Η)，4·0-4·2 (m，2Η)，5·35 (d，1Η)，7·55 汍 1Η)，7·6 (4 2Η)，7.7 (tr, 15 2Η), 7.8 (d, 1Η), 7.9 (d, 2H), 8,4 (d, 1H) ppm. -70- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）5 Add 45.1 mg (0.1 mmol) of the compound of Example 25 to 0.5 ml of 1- (2-hydroxyethyl) -2-pyrrolidone, and stir the reaction mixture at about 100 ° C for 1 hour. After cooling down, preparative HPLC (column: Agilent Zorbax Extend C18 20 mm X 50 mm, 5 microns; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia water; gradient: 0 minutes 10% 10 A, 2 minutes 10% A, 90% A for 6 minutes, 90% A for 7 minutes, 7.1 minutes. 10% A for 10 minutes, 10% A for 8 minutes; wavelength: 220 nm; injection volume: about 500 microliters; number of injections: 1) purification Reaction mixture. The products containing the dissolved fractions were combined and concentrated in vacuo. Yield: 25 mg (48.8% of theory) MS (El): m / z = 513 (M + H) +] H-NMR (300 MHz, DMSOO: δ = 1.8 (pentagram, 2H), 2 0 (4 3H), 2.1 (tr, 2H), 3.2 (tr, 2Η), 3.4 (tr, 2Η), 4.0-4 · 2 (m, 2Η), 5.35 (d , 1Η), 7.55 汍 1Η), 7.6 (4 2Η), 7.7 (tr, 15 2Η), 7.8 (d, 1Η), 7.9 (d, 2H), 8,4 (d, 1H) ppm -70- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

200410963 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（69) 以類似實例14-16之程序，製備下述化合物： 實例 编號 結構 起始物質 產率 [%] 氏[分鐘] (方法） 質量 (M+HJ+ 31 〇6 h3c 八 h3c^^n人0 0 實例1 ; 溴乙酸乙酯 85 4.01 (1) 516 32 xa〇 H.C^N^O (X， 實例Π 環丙烷·羰基氯 79 4.09 (1) 498 33 h3c^o"^Y^n^ch3 H3C人N入。 (X, · 實例1 ; 溴乙烷 15 4.28 (2) 458 34 。乒 比。八。人]人N八^ ηΛ 人 〇〇 實例1; 4-嗎啉·羰基氯 97 3.97 (2) 543 -71- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（70 ) 經濟部智慧財產局員工消費合作社印製 實例 編號 結構 起始物質 產率 [%】 Rd分鐘] (方法） 質量 (Μ+ΗΓ 35 CN CH Η3(ΛΑ)叫 實例1; 二甲基-胺甲醢氣 98 4.00 (2) 523 [M+Na]+ 36 CN CH H3C 人 0，CH3 h3cT^n人0 實例1; 氣化碳酸甲酯 96 4.10 (2) 488 37 〇6 ^：AC〇 (X, 實例1; 苄基溴 58 4.59 (2) 520 38 CN h3c人N人。 實例1; 丙逋氩 43 4.42 (2) 486 -72-200410963 Printed by A7 B7, Consumer Cooperatives, Bureau of Intellectual Property, Ministry of Economic Affairs, V. Description of Invention (69) The following compounds were prepared using a procedure similar to that of Examples 14-16: Example Number Structure Starting Material Yield [%] Fahrenheit [Minutes] (Method) Mass (M + HJ + 31 〇6 h3c eight h3c ^^ n human 0 0 Example 1; ethyl bromoacetate 85 4.01 (1) 516 32 xa〇HC ^ N ^ O (X, example Π cyclopropane · carbonyl Chlorine 79 4.09 (1) 498 33 h3c ^ o " ^ Y ^ n ^ ch3 H3C human N. (X, · Example 1; Ethyl bromide 15 4.28 (2) 458 34. Ping-pong ratio. Eight. People] Human N Eight ^ ηΛ Human 〇 Example 1; 4-morpholine · carbonyl chloride 97 3.97 (2) 543 -71- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200410963 A7 B7 V. Invention Explanation (70) Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economics Example number structure Initial material yield [%] Rd minutes] (Method) Mass (M + ΗΓ 35 CN CH Η3 (ΛΑ) is called Example 1; Dimethyl -Amine formaldehyde 98 4.00 (2) 523 [M + Na] + 36 CN CH H3C human 0, CH3 h3cT ^ n human 0 Example 1; vaporized methyl carbonate 96 4.10 (2) 488 37 〇6 ^: AC 〇 (X, Example 1; Benzyl bromide 58 4.59 (2) 520 38 CN h3c human N human. Example 1; propidium argon 43 4.42 (2) 486 -72-

4 訂4 Order

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（71) -73- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (71) -73- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) )

實例 編號 結構 起始物質 產率 [%] Rt【分鐘】 (方法） 質量 [M+Hf 39 A h3c^n^o 實例1; 氯化碳酸 2-甲氧乙酯 95 4.12(2) 532 40 CN 實例1 ; 氣化峻酸 異丙酯 67 4.55(2) 500 41 H3C八0人|^NsN人^l八CH3 h3c、人ο、η3 實例1; 二乙基-胺甲醯氯 18 4.25 (2) 529 42 CN H3C、1^n\!c 吨。人料入〇 CH3 實例1; 甲基（甲基-磺斑基> 胺甲醢氦 40 4.10 (2) 565 經濟部智慧財產局員工消費合作社印製 200410963 五、發明說明（72 ) A7 B7 經濟部智慧財產局員工消費合作社印製Example number Structure starting material yield [%] Rt [minutes] (method) Mass [M + Hf 39 A h3c ^ n ^ o Example 1; 2-methoxyethyl chlorocarbonate 95 4.12 (2) 532 40 CN Example 1; Gasoline isopropyl ester 67 4.55 (2) 500 41 H3C eighty people | ^ NsN people ^ eight CH3 h3c, human ο, η3 Example 1; diethyl-amine methyl chloride 18 4.25 (2 ) 529 42 CN H3C, 1 ^ n \! C tons. ○ CH3 Example 1; Methyl (methyl-sulfonylpyl) > Carbamidine Helium 40 4.10 (2) 565 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 200410963 V. Description of Invention (72) A7 B7 Economy Printed by the Ministry of Intellectual Property Bureau's Consumer Cooperative

-74--74-

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（73 ) -75- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (73) -75- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) )

實例 編號 結構 起始物質 產率 [%】 Rt【分鐘I (方法） 質量 [Μ+ΗΓ 47 . CN rCHa η广。人^〜〜外 ηΛ^ο 實例1; >H2-溪-乙基)-Ν*Ν-二乙胺 氫溴酸鹽； 2.5當量NaH 82 2.98 (2) 529 48 。卜 h3c 八 〇"\^^"YN、ch3 H3c乂0 A, 實例1; 2-溴-N-甲基-乙醯胺； 2.5當量NaH 65 3.70 (2) 501 49 CN ά.. 賁例1 ; 3-(氣甲基)吡啶 鹽酸鹽； 2.5當量NaH 15 3.68 (2) 521 50 CN ，名?〇 ^CF3 實例1; 4«(氣甲基)吡啶 里酸鹽； 2.5當量NaH 21 3.47 (2) 521 經濟部智慧財產局員工消費合作社印製 200410963 A7 B7 五、發明說明（74 ) 經濟部智慧財產局員工消費合作社印製 6 7 實例 編號 結構 起始物質 產率 [%] JM分鐘】 (方法） 質量 [M+Hf 51 CN 實例1; W溴甲基)-1Η-咪唑鹽酸鹽； 2.5當量NaH 6 2.97 (2) 510 52 CN h3c 人 入。 實例1 ; 3<氣甲基> 1；2,4« 啐二唑 37 4.0(3) 469 53 HjC^N^O ° 實例1 ; 2-溴-N-(2-甲氧乙基)-乙醢胺 91 3.77 (2) 545 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（75 ) 以類似實例6-8之程序，製備下述化合物： 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 實例 編號 結構 起始物質 產率 [%] Rt丨分鐘1 (方法） 質量 [Μ+ΗΓ …A 9 J 讣[3-<三氟甲基)- 54 #、〇ΥΝΗ H3C人Ν人。 ffS 苯基]-脲； 4-氰基·苯甲醛； 3-蹰基丁酸甲酯 79 3.68 (2) 416 N-P«{三氟甲基)- 苯基;1-脲； 55 4·氟基-苯甲醛； 58 4.09 (2) 456 Η^° 3·網基丁酸- (S 環丙基甲酯 X ^,〇Y Ν·[3-(三氟甲基)- 56 H3C 入 Ο^γ^ΝΗ ¥人人〇 itS 笨基]-脲； ‘氰基-苯甲醛； 85 4.03 (2) 444 3-嗣基丁酸異丙酯 -77- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公嫠） 200410963Example No. Structure Starting material Yield [%] Rt [minute I (method) Mass [M + ΗΓ 47. CN rCHa η wide. Human ^ ~~ ex. ΗΛ ^ ο Example 1; > H2-brook-ethyl) -N * N-diethylamine hydrobromide; 2.5 equivalents of NaH 82 2.98 (2) 529 48. H3c 80 " \ ^^ " YN, ch3 H3c 乂 0 A, Example 1; 2-bromo-N-methyl-acetamidine; 2.5 equivalents of NaH 65 3.70 (2) 501 49 CN ά .. 贲Example 1; 3- (Gas methyl) pyridine hydrochloride; 2.5 equivalents of NaH 15 3.68 (2) 521 50 CN, name? ^ CF3 Example 1; 4 «(gas methyl) pyridinate; 2.5 equivalents of NaH 21 3.47 (2) 521 Printed by the Consumers 'Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 200410963 A7 B7 V. Description of the Invention (74) Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 6 7 Example Number Structure Initial Material Yield [%] JM Minutes] (Method) Mass [M + Hf 51 CN Example 1; W bromomethyl) -1H-imidazole hydrochloride; 2.5 equivalents of NaH 6 2.97 (2) 510 52 CN h3c entered. Example 1; 3 < Gas methyl >1; 2,4 «oxadiazole 37 4.0 (3) 469 53 HjC ^ N ^ O ° Example 1; 2-bromo-N- (2-methoxyethyl)- Ethylamine 91 3.77 (2) 545 The paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (75) Using a procedure similar to that of Example 6-8, prepare the following Compound: Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, Example Number Structure, Starting Material Yield [%] Rt 丨 Minute 1 (Method) Mass [M + ΗΓ… A 9 J 讣 [3- < trifluoromethyl) -54 # 、 〇ΥΝΗ H3C people Ν person. ffS phenyl] -urea; 4-cyano-benzaldehyde; methyl 3-fluorenylbutyrate 79 3.68 (2) 416 NP «{trifluoromethyl) -phenyl; 1-urea; 55 4 · fluoro -Benzaldehyde; 58 4.09 (2) 456 Η ^ ° 3 · Nettyl butyric acid-(S cyclopropyl methyl ester X ^, 〇Y Ν · [3- (trifluoromethyl)-56 H3C ΟΟ ^ γ ^ ΝΗ ¥ renren〇itS Benzyl] -urea; 'cyano-benzaldehyde; 85 4.03 (2) 444 3-Isobutyric acid isopropyl-77- This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 males) 200410963

A B 五、發明說明（76 實例 編號 結構 起始物質 產率 1%] Rt [分鐘] (方法） 質量 [Μ+ΗΓ 57 ί Ν·[3·{三氟甲基)-苯基脲； 4·氰基·苯f醛； 3-酮基丁酸 (1R>2-甲氧基-1-甲基·2·酮基•乙酯 73 3.S2 (2) 48S h3c、 (三氟甲基)· 苯基]-脲； 58 Η〆 N IT HaC 八 N^O ‘氟基-苯甲醛； Ν,Ν·二甲基各 酮基丁殖胺 9 3^2(2) 429 實例59 4-(4_氰苯基)-6-甲基-3·[2-(4-嗎啉基)-2-酮乙基]-2-酮基-1-[3_(三氣甲基）苯基]_1，2,3,4_四氮_5_♦唆甲酸乙醋AB V. Description of the invention (76 Example No. Structure, starting material yield 1%) Rt [minutes] (method) Mass [M + ΗΓ 57 ί Ν · [3 · {trifluoromethyl) -phenylurea; 4 · Cyanobenzene aldehyde; 3-ketobutanoic acid (1R> 2-methoxy-1-methyl-2 keto • ethyl ester 73 3.S2 (2) 48S h3c, (trifluoromethyl) · Phenyl] -urea; 58 Η〆N IT HaC octa N ^ O 'fluoro-benzaldehyde; Ν, Ν · dimethylketobutylamine 9 3 ^ 2 (2) 429 Example 59 4- ( 4-cyanophenyl) -6-methyl-3 · [2- (4-morpholinyl) -2-ketoethyl] -2-keto-1--1- [3_ (trifluoromethyl) phenyl] _1,2,3,4_tetrazole_5_ ♦ ethyl acetate

CNCN

Ο 、CH 經濟部智慧財產局員工消費合作社印製 〇 3 使80毫克(0.16毫莫耳)實例44化合物溶於2毫升二 -78- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 5 10 7.9 五、發明說明（77) 甲基甲醢胺中，於其内添加16毫克(〇 18毫升)嗎啉、24 毫克(〇·18毫莫耳）〗·羥基-1H-苯并三唑水合物及20毫克 (0.16毫莫耳）4-二甲胺基π比啶。於〇艺攪拌此反應混合 物，然後添加35毫克(0·18毫莫耳）二甲胺基丙基)_ 3乙基奴化一亞私鹽酸鹽。此反應混合物於室溫擾拌18 小時，接著添加水與乙紅自旨。其麵細姊硫酸 水，真空蒸發至乾。如果需要，關μ柱 性HPLC進一步純化產物。 咸I锴 產率：78毫克(85%) ^-NMR (300 MHz, DMSO-de)： δ = 1.1 (t, 3H); 2.0 (s 4H); 3.7 (d, 1H); 4.1 (m, 2H); 4.5 (d, 1H); 5.5 (s, 1H); 7 6 ^ ^ ^ ^ (m，2H) ppm. 叫 5取 7·8 (¾ ijj); 以類似實例59之程序，製備下述化合物 訂 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200410963 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（7〇 實例 編號 結構 起始物質 產率 [%] 氏[分鐘】 (方法） 質量 [M+H】+ 60 實例44; N-甲基哌_ 90 2.93 (2) 570 61 。6： 實例44; N<2·胺基-乙基)-KN-二甲胺 87 2.93 (2) 558 62 〇 0人 fjl人 ch3 ^cf3 實例44; 2M二甲胺 之THF溶液 83 3.84 (2) 515 以類似實例6-8之程序，製備下述化合物：〇, CH Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs. 03 Dissolve 80 mg (0.16 mmol) of Example 44 compound in 2 ml of 2-78.- This paper applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 200410963 A7 B7 5 10 7.9 V. Description of the invention (77) Methylformamide is added with 16 mg (〇18 ml) of morpholine and 24 mg (0.18 mmol). Hydroxy-1H-benzotriazole hydrate and 20 mg (0.16 mmol) 4-dimethylamino π-pyridine. The reaction mixture was stirred at 0 ° C, and then 35 mg (0.18 mmol) of dimethylaminopropyl) -3ethyl slave hydrochloride was added. The reaction mixture was stirred at room temperature for 18 hours, and then water and ethyl red were added for the purpose. The surface is finely sulphuric acid and evaporated to dryness in vacuo. If necessary, the product is further purified by off-column HPLC. Yield of salt: 78 mg (85%) ^ -NMR (300 MHz, DMSO-de): δ = 1.1 (t, 3H); 2.0 (s 4H); 3.7 (d, 1H); 4.1 (m, 2H); 4.5 (d, 1H); 5.5 (s, 1H); 7 6 ^ ^ ^ ^ (m, 2H) ppm. Call 5 and take 7 · 8 (¾ ijj); Using a procedure similar to Example 59, prepare the following The above-mentioned compounds are printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. This paper is printed in accordance with the Chinese National Standard (CNS) A4 specification (210x297 mm) 200410963 A7 B7. Example No. Structure Yield of starting material [%] Degrees [minutes] (Method) Mass [M + H] + 60 Example 44; N-methylpiperium_90 2.93 (2) 570 61. 6: Example 44; N < 2.Amine-ethyl) -KN-dimethylamine 87 2.93 (2) 558 62 00 human fjl human ch3 ^ cf3 Example 44; 2M dimethylamine in THF solution 83 3.84 (2) 515 Similar to Example 6- The procedure of 8 prepares the following compounds:

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（79 ) -81- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (79) -81- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) )

經濟部智慧財產局員工消費合作社印製Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

經濟部智慧財產局員工消費合作社印製 200410963 A7 B7 五、發明說明（80 ) -82- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）Printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 200410963 A7 B7 V. Description of Invention (80) -82- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

200410963 A7 B7 五、發明說明（81) 實例70 4-(4-氰苯基)-6-甲基-2-酮基_1-[3-(三氟甲基)苯基]-1，2,3,4-四氫-5-嘴唆曱酿胺200410963 A7 B7 V. Description of the invention (81) Example 70 4- (4-cyanophenyl) -6-methyl-2-keto_1- [3- (trifluoromethyl) phenyl] -1, 2 , 3,4-tetrahydro-5-mouth melamine

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4 訂 5 使200毫克(0.5毫莫耳)實例11化合物溶於5毫升四4 Order 5 Dissolve 200 mg (0.5 mmol) of the compound of Example 11 in 5 ml of four

氩呋喃及6毫克(0.05毫莫耳）4-N，N-二曱胺基吡啶中，於 其内添加77毫克(0.6毫莫耳）N，N-二異丙基乙胺及115 毫克(0.6毫莫耳）六氟磷酸苯并三唑-1·基氧基-參（吼咯啶 基)鱗。於室溫攪拌此反應混合物15分鐘，然後添加5毫 10 升(2.5毫莫耳）氨水(於二畤烷中之0.5 Μ溶液）。此反應混 經濟部智慧財產局員工消費合作社印製 合物於室溫攪拌1小時，接著添加水與乙酸乙酯。其有機 相以硫酸鈉脫水，真空蒸發至乾。利用製備性HPLC進 一步純化產物。 產率：55毫克（理論值之28%) JH-NMR (200 MHz, DMSO-d6)： δ = 1.8 (s, 3H); 5,4 (d, 1H); 12 (br. s, 1H); 7.4 (br. 15 s, 1H); 7.6 (m, 5H); 7.7 (m, 1H); 7.9 (m, 2H); 8.1 (d, 1H) ppm. -83- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（82 ) 實例71 (+)-4-(4_氰苯基）-6_甲基-2·酮基-1-[3-(三氟甲基）苯基]· 1，2,3,4-四氫_5_嘧啶甲酸Argon furan and 6 mg (0.05 mmol) of 4-N, N-diaminopyridine, 77 mg (0.6 mmol) of N, N-diisopropylethylamine and 115 mg ( 0.6 millimolar) benzotriazol-1 · yloxy-shen (salrolidinyl) hexafluorophosphate scale. The reaction mixture was stirred at room temperature for 15 minutes, and then 5 mmol 10 liters (2.5 mmol) of ammonia water (a 0.5 M solution in dioxane) was added. This reaction was mixed with the printed product of the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs at room temperature for 1 hour, and then water and ethyl acetate were added. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The product was further purified using preparative HPLC. Yield: 55 mg (28% of theory) JH-NMR (200 MHz, DMSO-d6): δ = 1.8 (s, 3H); 5,4 (d, 1H); 12 (br. S, 1H) ; 7.4 (br. 15 s, 1H); 7.6 (m, 5H); 7.7 (m, 1H); 7.9 (m, 2H); 8.1 (d, 1H) ppm. -83- This paper size applies to Chinese national standards (CNS) A4 specifications (210 X 297 mm) 200410963 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (82) Example 71 (+)-4- (4_cyanophenyl) -6_ Methyl-2 · keto-1- [3- (trifluoromethyl) phenyl] · 1,2,3,4-tetrahydro-5_pyrimidinecarboxylic acid

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5 於對掌相上利用製備性HPLC分離實例11之鏡像異 構物：[管柱KBD 8361 (以單體甲基丙烯醯基_L-白胺 酸-1-甲基醯胺為基底之對掌性矽膠選擇器，參考EP-A-379 917)，250毫米X 20毫米，溶洗液：乙酸乙酯甲醇 —乙酸乙酯，流速25毫升/分鐘，溫度23°C，檢測254 10 奈米]。 lH-NMR (300 MHz, DMSO-c^): δ = 2.0 (s, 3H); 5.4 (d, 1H); 7.6 (m, 1H); 7.6 (m, 2H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 3H); 8.3 (d, 1H); 12.5 (s, 1H) ppm.5 Preparative HPLC separation of the mirror image isomers of Example 11 on the opposite palm phase: [column KBD 8361 (pair based on monomer methacrylfluorenyl_L-leucine-1-methylfluorenamine) Palm Silicone Selector, refer to EP-A-379 917), 250 mm x 20 mm, Eluent: ethyl acetate methanol-ethyl acetate, flow rate 25 ml / min, temperature 23 ° C, detection 254 10 nm ]. lH-NMR (300 MHz, DMSO-c ^): δ = 2.0 (s, 3H); 5.4 (d, 1H); 7.6 (m, 1H); 7.6 (m, 2H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 3H); 8.3 (d, 1H); 12.5 (s, 1H) ppm.

[cc]2。= +2·5。(λ = 589奈米，曱醇，c = 505毫克/100 毫升） 實例72 (+)-4-(4_氰苯基）-6-甲基-2- _基-1-[3-(三氟甲基）苯基]_ 1，2,3,4_四氫-5_嘧啶曱酸2-羥基乙酯 -84- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）[cc] 2. = + 2 · 5. (λ = 589 nm, methanol, c = 505 mg / 100 ml) Example 72 (+)-4- (4-cyanophenyl) -6-methyl-2-_yl-1- [3- ( Trifluoromethyl) phenyl] _1,2,3,4_tetrahydro-5_pyrimidinate 2-hydroxyethyl ester-84- This paper is sized for China National Standard (CNS) A4 (210 X 297) %)

200410963 A7 --- B7 五、發明說明（83 )200410963 A7 --- B7 V. Description of the invention (83)

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H0 氩氣下，添加1560毫克(3·89毫莫耳)實例71化合物 至19.6毫升DMF中。於添加1·〇95毫升(7.86毫莫耳)三 乙胺與1.11毫升（15.7毫莫耳）2-溴乙醇後，此反應混合 5物於大約70°C攪拌8小時。冷卻後，真空濃縮反應混合 物’使殘留物混於乙酸乙酯中，以水洗滌。以硫酸鎂脫水 後’真空濃縮其有機相。使殘留物混於8毫升甲醇中，利 用製備性 HPLC(管柱：Nucleosil 100-5 C 18 Nautilus，20 x 5〇毫米，5微米；溶劑A :乙腈，溶劑B :水+ 〇 3〇/c 10甲酸；梯度：〇分鐘10% A，2分鐘10% A，6分鐘90% 經濟部智慧財產局員工消費合作社印製 A，7 分鐘 90% A，7.1 分鐘 10% A，8 分鐘 1〇% A ;波 長·· 220奈米；注射量：大約500微升；注射次數·· 18) 予以純化。合併含溶離份之產物，並予以冷凍乾燥。 產率：1290毫克（理論值之74.5%) MS (El): m/z = 446 (M+H)+ WNMR (300 MHz，DMS04): δ = 2·05 (4 3H); 3·5 (四重峰，2H); 3,954·15 机 2H); 4.75 (tr, 1H); 5.45 (d, 1H); 7.55-7.75 (m, 5H); 7.75 (d, 1H); 7.85 (d, 2H); 835 (d,lH)ppm. 15 [a]20 = +14·3° (λ = 589奈米，甲醇，c = 455 毫克 /100 毫升） -85- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（84) 實例73 5_{5_乙醯基-6-甲基_2_酮基小[3-(三氟甲基）苯基]-1又3,4- 四氫-4-,淀基}·2-吨咬甲腈Under H0 argon, 1560 mg (3.89 mmol) of the compound of Example 71 was added to 19.6 ml of DMF. After adding 1.095 ml (7.86 mmol) of triethylamine and 1.11 ml (15.7 mmol) of 2-bromoethanol, the reaction mixture was stirred at about 70 ° C for 8 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue was mixed in ethyl acetate and washed with water. After dehydration with magnesium sulfate, the organic phase was concentrated in vacuo. The residue was mixed in 8 ml of methanol and subjected to preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus, 20 x 50 mm, 5 µm; solvent A: acetonitrile, solvent B: water + 0.30 / c 10 formic acid; gradient: 10% A for 0 minutes, 10% A for 2 minutes, 90% for 6 minutes 90% printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 90% A for 7 minutes, 10% A for 7.1 minutes, 10% for 8 minutes A; Wavelength 220 nm; Injection volume: about 500 microliters; Number of injections 18) Purified. The products containing the dissolved fractions were combined and lyophilized. Yield: 1290 mg (74.5% of theory) MS (El): m / z = 446 (M + H) + WNMR (300 MHz, DMS04): δ = 2 · 05 (4 3H); 3 · 5 ( Quadruple peak, 2H); 3,954 · 15 machine 2H); 4.75 (tr, 1H); 5.45 (d, 1H); 7.55-7.75 (m, 5H); 7.75 (d, 1H); 7.85 (d, 2H) ; 835 (d, lH) ppm. 15 [a] 20 = + 14 · 3 ° (λ = 589 nm, methanol, c = 455 mg / 100 ml) -85- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (84) Example 73 5_ {5_ethylfluorenyl-6-methyl_2_keto small [3- (trifluoromethyl) phenyl ] -1,3,4-tetrahydro-4-, Yodo-based

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經濟部智慧財產局員工消費合作社印製 5 於實例3Α (75毫克，〇·57毫莫耳)之四氫呋喃（5毫升） 攪拌溶液中，添加2,4-戊二酮(57毫克，0.57毫莫耳）、Ν-[3-(三氟曱基)苯基]脲(Π6毫克，〇·57毫莫耳)與多磷酸乙 酯（200 毫克）[根據 Cava ei a/·，J. Org. Chem. 2665 (1969)之程序新鮮製備]。回流加熱此反應混合物24小 10 時，隨後，以DMS0 (2毫升）稀釋該溶液，利用製備性 HPLC予以純化。 產率：101毫克（理論值之44%) ^-NMR (200 MHz, DMSO-^): δ - 2.02 (¾ 3H); 2.24 (s, 3H); 5.54 (d, 1H); 7.52-7.90 (m, 4H); 8.08 (d, 2H); 8.50 (d, 1H); 8.81 (s, 1H) ppm. -86- $纸張尺度適用中國國家標準(CNS)A4規格（210 x297公釐） 200410963 A7 B7 經濟部智慧財產局員工消費合作社印製Printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 To a stirred solution of Example 3A (75 mg, 0.57 mmol) of tetrahydrofuran (5 ml), 2,4-pentanedione (57 mg, 0.57 mmol) was added. Ear), N- [3- (trifluorofluorenyl) phenyl] urea (Π6 mg, 0.57 mmol) and ethyl polyphosphate (200 mg) [according to Cava ei a / ·, J. Org. Chem. 2665 (1969) was prepared fresh]. The reaction mixture was heated at reflux for 24 hours and then the solution was diluted with DMS0 (2 mL) and purified by preparative HPLC. Yield: 101 mg (44% of theory) ^ -NMR (200 MHz, DMSO- ^): δ-2.02 (¾ 3H); 2.24 (s, 3H); 5.54 (d, 1H); 7.52-7.90 ( m, 4H); 8.08 (d, 2H); 8.50 (d, 1H); 8.81 (s, 1H) ppm. -86- $ The paper size applies the Chinese National Standard (CNS) A4 specification (210 x297 mm) 200410963 A7 B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

五、發明說明（85) 實例74 (+)-5-{5-乙酿基-6-甲基-2-酮基-1_[3-(三氟甲基）苯基]_ 1，2,3,4-四氮_4_哺唆基}_2_11比咬甲猜V. Description of the invention (85) Example 74 (+)-5- {5-Ethyl-6-methyl-2-keto-1_ [3- (trifluoromethyl) phenyl] _1,2, 3,4-tetrazole_4_feeding base} _2_11

CN 5 於對掌相上利用製備性HPLC分離實例73之鏡像異 構物：[管柱KBD 8361 (以單體iV·甲基丙烯醯基-L-白胺 酸-1-曱基醯胺為基底之對掌性矽膠選擇器，參考EP-A-379 917)，250毫米X 20毫米，溶洗液：乙酸乙酯—甲醇 —乙酸乙酯，流速25毫升/分鐘，溫度23°C，檢測254 10 奈米]。 !H-NMR (300 MHz, CDC13): δ = 2.06 (s, 3H); 2.35 (s, 3H); 5.69 (d, 1H); 6.02 (d, 1H); 7.29-7.50 (m, 2H); 7.57-7.75 (m, 3H); 7.83 (dd, 1H); 8.74 (d, 1H) ppm. MS (ESIpos): m/z = 401 (M+H)+ [α]20 = +25·1°(δ = 589奈米，甲醇，c = 505毫克/100 毫升） 實例75 4-(4-氰苯基)-6-甲基-2-酮基小[3-(三氟甲基）苯基]-1，2,3,4- 四氫-5-嘧啶甲酸2_(2_吡啶基）甲酯 -87- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）CN 5 Isolate the mirror image isomers of Example 73 on the palm phase using preparative HPLC: [column KBD 8361 (using the monomer iV · methacrylfluorenyl-L-leucine-1-fluorenylamine as Silicone selector for base palm, refer to EP-A-379 917), 250mm x 20mm, Eluent: ethyl acetate-methanol-ethyl acetate, flow rate 25ml / min, temperature 23 ° C, test 254 10 nm]. ! H-NMR (300 MHz, CDC13): δ = 2.06 (s, 3H); 2.35 (s, 3H); 5.69 (d, 1H); 6.02 (d, 1H); 7.29-7.50 (m, 2H); 7.57-7.75 (m, 3H); 7.83 (dd, 1H); 8.74 (d, 1H) ppm. MS (ESIpos): m / z = 401 (M + H) + (α) 20 = + 25 · 1 ° (δ = 589 nm, methanol, c = 505 mg / 100 ml) Example 75 4- (4-cyanophenyl) -6-methyl-2-keto small [3- (trifluoromethyl) phenyl ] -1,2,3,4-Tetrahydro-5-pyrimidinate 2_ (2_pyridyl) methyl ester-87- This paper size applies to China National Standard (CNS) A4 (210x297 mm)

200410963 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（86 )200410963 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description (86)

於含40.1毫克(0.1毫莫耳)實例11化合物之0.4毫升 無水二甲基甲醯胺溶液中，添加48.6毫克(0.3毫莫耳） N，N-羰基二咪唑。令反應混合物靜置1小時後，以水稀 5 釋，並以二氣甲烷予以萃取。以硫酸鎂脫水後，真空蒸發 去除溶劑。添加0.5毫升(2-吡啶基）甲醇於殘留物。此反 應混合物於大約100°C攪拌1小時。冷卻後，利用製備性 HPLC(管柱：Nudeosil 100-5 C 18 Nautilus，20 毫米 X 50 毫米，5微米；溶劑A :乙腈，溶劑B :水+ 0.1%甲 10 酸；梯度：0分鐘10% A，2分鐘10% A，6分鐘90% A，7分鐘90% A，7.1分鐘10% A，8分鐘10% A ;流速 25毫升/分鐘；波長：220奈米；注射量：大約550微 升；注射次數·· 1)予以純化。合併含溶離份之產物，並予 以真空濃縮。 15 產率：17毫克（理論值之34.5%) MS (EI):m/z = 493 (M+H)+ !H-NMR (300 MHz, DMSO-d6): δ - 2.1 (d, 3H); 5,15 (dd, 2H); 5.45 (d, 1H); 7.05 (d, 1H); 7.3 (dd, 1H); 7.5-7.85 (m, 9H); 8.35 (d, 1H); 8.5 (d, 2H) ppm- -88- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）To a solution of 40.1 mg (0.1 mmol) of the compound of Example 11 in 0.4 ml of anhydrous dimethylformamide, 48.6 mg (0.3 mmol) of N, N-carbonyldiimidazole was added. After the reaction mixture was allowed to stand for 1 hour, it was diluted with water and then extracted with methane gas. After dehydration with magnesium sulfate, the solvent was removed by evaporation in vacuo. Add 0.5 ml (2-pyridyl) methanol to the residue. The reaction mixture was stirred at about 100 ° C for 1 hour. After cooling, use preparative HPLC (column: Nudeosil 100-5 C 18 Nautilus, 20 mm X 50 mm, 5 microns; solvent A: acetonitrile, solvent B: water + 0.1% formic acid; gradient: 10% for 0 minutes A, 10% A for 2 minutes, 90% A for 6 minutes, 90% A for 7 minutes, 10% A for 7.1 minutes, 10% A for 8 minutes; flow rate 25 ml / min; wavelength: 220 nm; injection volume: about 550 micrometers L; number of injections ... 1) to be purified. The products containing the dissolved fractions were combined and concentrated in vacuo. 15 Yield: 17 mg (34.5% of theory) MS (EI): m / z = 493 (M + H) +! H-NMR (300 MHz, DMSO-d6): δ-2.1 (d, 3H) ; 5,15 (dd, 2H); 5.45 (d, 1H); 7.05 (d, 1H); 7.3 (dd, 1H); 7.5-7.85 (m, 9H); 8.35 (d, 1H); 8.5 (d , 2H) ppm- -88- This paper size applies to China National Standard (CNS) A4 (210x297 mm)

200410963 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（87 ) 實例76 4-(4-氰苯基)-6-甲基-2-酮基小[3-(三氟甲基)苯基]-1，2,3,4-四氫-5-嘴唆曱酸2-(3-°比咬基）乙醋200410963 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Description of the invention (87) Example 76 4- (4-cyanophenyl) -6-methyl-2-one small [3- (trifluoromethyl) ) Phenyl] -1,2,3,4-tetrahydro-5-methylacetic acid 2- (3- ° specificity) ethyl acetate

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5 於含60.2毫克(0·15毫莫耳)實例11化合物之0.57毫 升無水二甲基甲醢胺溶液中，添加72.9毫克(0.45毫莫耳) Ν，Ν-羰基二咪唑。令反應混合物靜置1小時後，以水稀 釋，並以乙酸乙酯予以萃取。以硫酸鎂脫水後，真空蒸發 去除溶劑。添加185毫克（1.5毫莫耳）2-(3-吡啶基）乙醇與 10 20微升(0.27毫莫耳）三乙胺於殘留物。此反應混合物於大 約lOOt攪拌1小時。然後以0.4毫升甲醇予以稀釋，過 濾，利用製備性HPLC(管柱：Nucleosil Ϊ00-5 C 18 Nautilus，20毫米X 50毫求，5微米；溶劑A :乙腈，溶 劑B :水+ 0.1%甲酸；梯度：0分鐘10% A，2分鐘10% 15 A，6 分鐘 90% A，7 分鐘 90% A，7.1 分鐘 10% A，8 分 鐘10% A ;流速25毫升/分鐘；波長：220奈米；注射 量：大約550微升；注射次數：1)予以純化。合併含溶離 份之產物，並予以真空濃縮。 產率：44毫克（理論值之57.9%) -89- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）5 To a solution of 60.2 mg (0. 15 mmol) of the compound of Example 11 in 0.57 ml of anhydrous dimethylformamide, 72.9 mg (0.45 mmol) of N, N-carbonyldiimidazole was added. After the reaction mixture was allowed to stand for 1 hour, it was diluted with water and extracted with ethyl acetate. After dehydration with magnesium sulfate, the solvent was removed by evaporation in vacuo. Add 185 mg (1.5 mmol) of 2- (3-pyridyl) ethanol and 10 20 µl (0.27 mmol) of triethylamine to the residue. The reaction mixture was stirred at about 100 t for 1 hour. It was then diluted with 0.4 ml of methanol, filtered, and subjected to preparative HPLC (column: Nucleosil Ϊ00-5 C 18 Nautilus, 20 mm X 50 mmol, 5 microns; solvent A: acetonitrile, solvent B: water + 0.1% formic acid; Gradient: 10% A at 0 minutes, 15% A at 2 minutes, 90% A at 6 minutes, 90% A at 7 minutes, 10% A at 7.1 minutes, 10% A at 8 minutes; flow rate 25 ml / min; wavelength: 220 nm ; Injection volume: about 550 microliters; number of injections: 1) to be purified. The products containing the dissolved fractions were combined and concentrated in vacuo. Yield: 44 mg (57.9% of theory) -89- This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm)

200410963 A7 B7 五、發明說明（Μ) LC-MS (ΕΙ，方法 5) : m/z = 507 (M+H)+，Rt = 3·19 分鐘 實例Τ7 4-(4-氰苯基）-3,6-二甲基-2-酮基-1_[3-(三氟甲基）苯基]-1，2,3,4-四氫-5-嘴咬甲酸200410963 A7 B7 V. Description of the Invention (M) LC-MS (E1, Method 5): m / z = 507 (M + H) +, Rt = 3.19 minutes Example T7 4- (4-cyanophenyl)- 3,6-dimethyl-2-keto-1_ [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-mouth bite formic acid

CNCN

經濟部智慧財產局員工消費合作社印製 使4·1克(9·25毫莫耳)實例14化合物溶於100毫升乙 醇中，於此溶液中添加6.2毫升(27·6毫莫耳）氫氧化卸水 溶液(25重量％)。令此反應混合物於室溫靜置18小時。 然後又添加12·4毫升(55.2毫莫耳）氫氧化鉀水溶液(25重 10 量％)，攪拌此反應混合物2小時。以水予以稀釋，並以 乙酸乙酯萃取三次。其水相以1Ν鹽酸酸化，並以乙酸乙 酯萃取。此最終萃取物以硫酸鎂脫水，真空蒸發至乾。其 殘留物於石夕石上利用管柱層析法予以純化，以環己燒^乙 酸乙酯為溶洗液。 15 產率：1.5克（理論值之39%) MS (El): m/2 - 416 (M+H)+ iH-NMR (300 MHz，DMSO-也):δ = 2.0 (s，3H); 2』（s，3H); 5·5 (<UH); 7·6-7 8 (m 6H); 7.9(d, 2H); 12.6 (s, 1H) ppm. -90- >紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） " ---—__ 200410963 A7 B7 五、發明說明（89) 以類似實例76之程序，製備下述化合物： 經濟部智慧財產局員工消費合作社印製 實例 編號 結構 起始物質 產率 [%] 氏丨分鐘] (方法） 晳署 [Μ+Η】+ 78 CN 實例11; 3-吡啶基-甲酵 56.9 3.45 (5) 493 79 CN 實例11; 2-羥基-乙醯胺υ 61.1 338 (5) 459 SO CN 0 h3c*^n 人。 實例11; 2·羥乙基· (甲基)？蘿胺 80.9 3.5(5) 487 81 Η ,ό Η3〇γΝ^〇ΛΑ 0 H3c人Ν人。 實例11; 2-羥乙基-乙醢胺 56.2 3.44 (5) 487 -91-Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, dissolving 4.1 g (9.25 mmol) of Example 14 in 100 ml of ethanol, and adding 6.2 ml (27.6 mmol) of hydroxide to this solution The aqueous solution was discharged (25% by weight). The reaction mixture was allowed to stand at room temperature for 18 hours. Then, 12.4 ml (55.2 mmol) of an aqueous potassium hydroxide solution (25% by weight, 10% by weight) was added, and the reaction mixture was stirred for 2 hours. It was diluted with water and extracted three times with ethyl acetate. The aqueous phase was acidified with 1N hydrochloric acid and extracted with ethyl acetate. This final extract was dehydrated with magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by column chromatography on Shi Xishi, using cyclohexane and ethyl acetate as the eluent. 15 Yield: 1.5 g (39% of theory) MS (El): m / 2-416 (M + H) + iH-NMR (300 MHz, DMSO-also): δ = 2.0 (s, 3H); 2 』(s, 3H); 5 · 5 (<UH); 7 · 6-7 8 (m 6H); 7.9 (d, 2H); 12.6 (s, 1H) ppm. -90- > Paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) " -----__ 200410963 A7 B7 V. Description of the invention (89) Using a procedure similar to Example 76, the following compounds were prepared: Intellectual Property Bureau, Ministry of Economic Affairs Employee Consumption Cooperative Printed Example Number Structure Initial Substance Yield [%] Min 丨 Minutes] (Method) Clear Department [Μ + Μ] + 78 CN Example 11; 3-pyridyl-formylase 56.9 3.45 (5) 493 79 CN Example 11; 2-hydroxy-acetamido υ 61.1 338 (5) 459 SO CN 0 h3c * ^ n people. Example 11; 2 · Hydroxyethyl (methyl)? Ionamine 80.9 3.5 (5) 487 81 Η, ό Η3〇γΝ ^ 〇ΛΑ 0 H3c person N person. Example 11; 2-hydroxyethyl-acetamidamine 56.2 3.44 (5) 487 -91-

訂Order

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（90 ) -92- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (90) -92- This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm)

實例 編號 結構 起始物質 產率 [%】 氏[分鐘I (方法） 質量 (M+Hf 82 &4。 實例11; (1-甲基·m· 咪唑-5-基> 甲酹υ 45.8 2.87 (5) 496 83 cu0ixH h3c 人 rji 人。 實例11; 2-(1Η·吡唑· 1-基)乙醇 60.6 3*7(5) 496 84 ν^ο1ϊΝΗ h3c^n^o 實例11; 2-(1Η-1，2,4· 三嗤-1-基)· 乙醇1) 67.1 3.48 (5) 497 85 °Υ^° 11 ΝΗ H3c〜人。 "ός, 實例11; 乙酸2-羥乙酯 56.1 3.98 (5) 488 經濟部智慧財產局員工消費合作社印製 200410963 Α7 Β7 五、發明說明（91) 實例 編號 86 87 88 89 結構 起始物質 產率 [%】 氏[分鐘I (方法） 質量 ΙΜ+ΗΓ CH,Example No. Structure starting material yield [%] [[minutes I (method) mass (M + Hf 82 & 4. Example 11; (1-methyl · m · imidazol-5-yl > methyl 酹 υ 45.8 2.87 (5) 496 83 cu0ixH h3c human rji human. Example 11; 2- (1Η · pyrazole · 1-yl) ethanol 60.6 3 * 7 (5) 496 84 ν ^ ο1ϊΝΗ h3c ^ n ^ o Example 11; 2- (1Η-1, 2, 4 · tris-1-yl) · ethanol1) 67.1 3.48 (5) 497 85 ° Υ ^ ° 11 ΝΗ H3c ~ human. &Quot; ός, Example 11; 2-hydroxyethyl acetate 56.1 3.98 (5) 488 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 200410963 Α7 Β7 V. Description of the Invention (91) Example No. 86 87 88 89 Yield of Structure Starting Substance [%] [[minutes I (method) mass ΙΜ + ΗΓ CH,

H3C X Ο …NH HaC CH3 3 Η3(Τ、N一。 h3c、H3C X Ο… NH HaC CH3 3 Η3 (T, N-1. H3c,

γ、nh CH3 1*γ, nh CH3 1 *

實例11; 2-(二甲胺基)· 2·甲基小丙醇 實例11; 3*{二甲胺基> 丙醇 實例11; 1 -啦洛咬基)》 乙酵 34.6 54.8 56.2 2.9(5) 2.86 (5) 2.86 (5) 487 500 經濟部智慧財產局員工消費合作社印製Example 11; 2- (Dimethylamino) 2.methylmethylpropanol Example 11; 3 * (Dimethylamino > Propanol Example 11; 1-Laloryl) acetonitrile 34.6 54.8 56.2 2.9 (5) 2.86 (5) 2.86 (5) 487 500 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

實例77; 2·{3·吡啶基 乙醇 58.9 3.36(5) 522 -93-Example 77; 2. (3.pyridyl) ethanol 58.9 3.36 (5) 522 -93-

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（92 ) 經濟部智慧財產局員工消費合作社印製 實例 編號 結構 起始物質 產率 [%】 RJ分鐘】 (方法） 質量 [M+H]+ 90 CN CT矣 實例77; (3-nfc啶基> 甲醇 61.9 3.64 (5) 507 91 χό H2NY"〇JT"^CH3 0 η3(ΛΛ0 ，^ 實例77 ; 2·經基· 乙蘊胺1) 53.6 3.54 (5) 473 92 Η 丫 ^。人^為 0 ηζοΧΛο 0lcFs 實例77; 2-羥乙基· (甲基)甲醢胺 54.6 3.68 (5) 501 93 Η χό h3c 丫 1^〇人/，3 0 HjC^N^O .實例77; 2-羥乙基-乙醯胺 66.6 3.59 (5) 501 -94-This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (92) Example number printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Number structure Initial substance yield [%] RJ minutes] (Method) Mass [M + H] + 90 CN CT 矣 Example 77; (3-nfc pyridyl > methanol 61.9 3.64 (5) 507 91 χ H2NY " 〇JT " ^ CH3 0 η3 (ΛΛ0, ^ Example 77; 2 · Chrysene · Ethylamine 1) 53.6 3.54 (5) 473 92 丫 ^. Human ^ is 0 ηζοχΛο 0lcFs Example 77; 2-Hydroxyethyl (meth) methanamine 54.6 3.68 (5 ) 501 93 Η χό h3c ah 1 ^ 〇 person /, 30 HjC ^ N ^ O. Example 77; 2-hydroxyethyl-acetamidamine 66.6 3.59 (5) 501 -94-

4 訂4 Order

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（93 ) 經濟部智慧財產局員工消費合作社印製 實例 編號 結構 起始物質 產率 [%] 氏{分鐘】 (方法） 質量 【Μ+ΗΙ+ 94 CN VYr 實例77; (u甲基-m-咪唑基> 甲醇υ 34.0 3.02 (5) 510 95 1^3。人?人。 實例Τ7; 2·〇Η·吡唑-1-基)乙酵 61.5 3.91 (5) 510 96 o^〇i5n.ch3 H^C人N入。 實例77; 三嗤·1·基)· 乙酵η 71.8 3.64(5) 511 97 crH0r°YrH3 3 HX N^O 實例77; 乙酸2·羥乙81 53.2 4.12(5) 502 -95- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 Α7 Β7 五、發明說明（94 ) 經濟部智慧財產局員工消費合作社印製 實例 編號 結構 起始物質 產率 [%] 民丨分鐘1 (方法） 質量 [M+Hf 98 CN π Ά人 實例77 ; 2·{二甲胺基)· 2-甲基-1-丙醇 25.9 3.02 (5) 516 99 CH3 η3ο^ν^ο 實例77 ; 3«(二甲胺基> 丙醇 54.6 2.98 (5) 502 100 〇屢 〜。人^人。 實例77; 2·{1·吡咯啶基 乙酵 $5.9 2^8(5) 514 101 or矣 實例77; (2-吹啶基)· 甲酵 67.1 3.91 (5) 507 υ此實例中所用醇為固體，反應係於0.4毫升DMF存在下進行 -96-This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (93) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Example number structure Initial material yield [%] (Minutes) (Method) Mass [M + ΗΙ + 94 CN VYr Example 77; (umethyl-m-imidazolyl) > Methanol 34.0 3.02 (5) 510 95 1 ^ 3. Human? Human. Example Τ7; 2 · 〇Η · pyrazol-1-yl) acetic acid 61.5 3.91 (5) 510 96 o5i5n.ch3 H ^ C human N. Example 77; Tris (1, 1-based), Acetase η 71.8 3.64 (5) 511 97 crH0r ° YrH3 3 HX N ^ O Example 77; Acetic acid 2.hydroxyethyl 81 53.2 4.12 (5) 502 -95- Paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 200410963 Α7 Β7 V. Description of invention (94) Printed case number printed by employee consumer cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Number structure starting material yield [%] Min. 1 (Method) Mass [M + Hf 98 CN π Ά Example 77; 2 · (dimethylamino) · 2-methyl-1-propanol 25.9 3.02 (5) 516 99 CH3 η3ο ^ ν ^ ο Example 77 3 «(Dimethylamino group) Propanol 54.6 2.98 (5) 502 100 〇 Repeat ~. Human ^ human. Example 77; 2 · {1 · pyrrolidinylacetone $ 5.9 2 ^ 8 (5) 514 101 or矣 Example 77; (2-piperidinyl) · formylase 67.1 3.91 (5) 507 υ The alcohol used in this example is a solid, and the reaction is performed in the presence of 0.4 ml of DMF -96-

4 訂4 Order

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（95 ) 實例102 4-(4-氰苯基）-1-(3,5-二氯苯基）-6-甲基-2-酮基-1，2,3,4-四 氫-5-嘴唆甲酸乙醋This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (95) Example 102 4- (4-cyanophenyl) -1- (3,5-dichloro Phenyl) -6-methyl-2-keto-1,2,3,4-tetrahydro-5-acetone ethyl acetate

CNCN

經濟部智慧財產局員工消費合作社印製 5 氬氣下，於80°C，在0.5毫升二哼烷中，將30.8毫 克(0.15毫莫耳）N-(3,5-二氯苯基)脲連同39.3毫克(0.3毫 莫耳）4-甲醯基苯甲腈、39毫克(0·3毫莫耳）3-酮基丁酸 乙酯與90毫克多磷酸三甲基矽烷酯一起攪拌4小時。添 加少量DMSO後，過濾反應混合物，利用製備性 10 HPLC(管柱：Agilent Zorbax Extend C18 20 毫米 X 50 毫 米，5微米；溶劑A :乙腈，溶劑B :水+ 0.1%濃氨 水；梯度：0分鐘10% A，2分鐘10% A，6分鐘90% A，7分鐘90% A，7.1分鐘10% A，8分鐘10% A ;流速 25毫升/分鐘；波長：220奈米；注射量：大約500微 15 升；注射次數：1)予以純化。合併含溶離份之產物，並予 以真空濃縮。 產率：38.1毫克（理論值之59%) LC-MS (EI，方法 7) : m/z = 431 (M+H)+，Rt = 4.14 分鐘 -97- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 Α7 Β7 五、發明說明（96 ) 實例103 6-甲基本(3-墙苯基)-2·酮基-叩仏氟甲基)苯基]」，2,3，心 四氫_5_嘧啶甲酸乙酯 t: 〇rN〇s ° ΛΧ H3C^N^〇 0^cp3 5 於8〇C，在〇·5毫升二啐烷與〇丨毫升DMF中，將 經濟部智慧財產扃員工消費合作社印製 3〇·6毫克((U5毫莫耳）N-[H三氟甲基)苯基]腺連同心 毫克(〇·3毫莫耳）34基苯甲搭、39毫克(()3毫莫耳）㈣ 基丁酸乙酯與90毫克多磷酸乙酯[根據Cavaj 〇哏 Chem·乳2665 (1969)之程序新鮮製備]一起振盪18小 10時。於添加200微升DMF後，過濾反應混合物，利用製 備性 HPLC(管柱：Nudeosil 100-5 c 18 Nautilus，20 毫米 X 50耄米’ 5微米；溶劑A :乙腈，溶劑b :水+ 0.1% 甲酸；梯度：0分鐘10% A，2分鐘1〇% a，ό分鐘90% A，7分鐘90% A，7.1分鐘10% A，8分鐘10% A ;流速 15 25毫升/分鐘；波長：220奈米；注射量：大約800微 升’庄射次數：1)予以純化。合併含溶離份之產物，並予 以真空濃縮。 產率：34毫克（理論值之50.4%) LC-MS (EI，方法 6) : m/z = 450 (M+H)+，Rt = 3·94 分鐘 -98- 本纸張尺度適用中國國家標準(CNS)M規格（210 X 297公釐） 200410963 Α7 Β7 五、發明說明（97 ) 以類似實例102之程序，製備下述化合物： 實例 編號 104 105 m 107 結構Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5 Under argon at 80 ° C, in 0.5 ml of dihumane, 30.8 mg (0.15 mmol) of N- (3,5-dichlorophenyl) urea. Stir with 39.3 mg (0.3 mmol) of 4-methylfluorenylbenzonitrile, 39 mg (0.3 mmol) of ethyl 3-ketobutyrate and 90 mg of trimethylsilyl polyphosphate . After adding a small amount of DMSO, the reaction mixture was filtered and preparative 10 HPLC (column: Agilent Zorbax Extend C18 20 mm X 50 mm, 5 microns; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia water; gradient: 0 minutes 10% A, 2 minutes 10% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; flow rate 25 ml / min; wavelength: 220 nm; injection volume: about 500 micro 15 liters; number of injections: 1) purified. The products containing the dissolved fractions were combined and concentrated in vacuo. Yield: 38.1 mg (59% of theory) LC-MS (EI, Method 7): m / z = 431 (M + H) +, Rt = 4.14 minutes -97- This paper size applies the Chinese National Standard (CNS ) A4 specification (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (96) Example 103 6-methylbenzyl (3-wallphenyl) -2 · keto-fluorenylmethyl) phenyl] ", 2,3,4-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester t: 〇rN〇s ° Λ × H3C ^ N ^ 〇0 ^ cp3 5 at 80 ° C in 0.5 ml of dioxane and 〇 ml of DMF 3,6 mg ((U5 mmol) N- [H trifluoromethyl) phenyl] gland printed by the Intellectual Property of the Ministry of Economic Affairs and Employee Cooperatives together with 34 mg of cardiac mg (0.3 mmol) Benzoate, 39 mg (() 3 mmol) ethyl ethyl butyrate and 90 mg ethyl polyphosphate [freshly prepared according to the procedure of Cavaj 〇 哏 Chem · Milk 2665 (1969)] shake for 18 hours and 10 hours . After the addition of 200 μl of DMF, the reaction mixture was filtered and subjected to preparative HPLC (column: Nudeosil 100-5 c 18 Nautilus, 20 mm X 50 mm 2 '5 μm; solvent A: acetonitrile, solvent b: water + 0.1% Formic acid; gradient: 10% A in 0 minutes, 10% a in 2 minutes, 90% A in 7 minutes, 90% A in 7 minutes, 10% A in 7.1 minutes, 10% A in 8 minutes; flow rate 15 25 ml / min; wavelength: 220 nanometers; injection volume: about 800 microliters; number of shots: 1) to be purified. The products containing the dissolved fractions were combined and concentrated in vacuo. Yield: 34 mg (50.4% of theory) LC-MS (EI, Method 6): m / z = 450 (M + H) +, Rt = 3.94 minutes -98- This paper size applies to China Standard (CNS) M specification (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (97) Following the procedure similar to Example 102, the following compound was prepared: Example No. 104 105 m 107 Structure

起始物質 Ν-(3·硝笨基)-脲； ‘氩苯甲醛； 3-明基丁酸-乙酯 Ν»(3·硝苯基)-脲； 3-硝基苯甲醛； 3·網基丁酸-乙酯 Ν-(3·硝苯基)· 脲； 4·氟苯甲醛； 3-嗣基丁酸· 乙酯 產率 [%] 70.5 813Starting material N- (3 · nitrobenzyl) -urea; 'argon benzaldehyde; 3-benzyl butyric acid-ethyl ester N »(3 · nitrophenyl) -urea; 3-nitrobenzaldehyde; 3.net Butyric acid-ethyl ester N- (3 · nitrophenyl) · Urea; 4 · Fluorobenzaldehyde; 3-Aminobutyric acid · Ethyl ester yield [%] 70.5 813

56.S56.S

Rc [分鐘】 (方法） 質量 [M+HJ* 3.65 (6) 3.61 (6) 3.63 (6) 417 427 400 經濟部智慧財產局員工消費合作社印製Rc [minutes] (method) Quality [M + HJ * 3.65 (6) 3.61 (6) 3.63 (6) 417 427 400 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

BrBr

N Ν-(3·硝苯基)· 脲； 4·溴苯甲醛； 3-蹰基丁酸-乙酯 69.5 4.02 (5) 461 -99-N Ν- (3 · nitrophenyl) · Urea; 4 · Bromobenzaldehyde; 3-Aminobutyric acid-ethyl ester 69.5 4.02 (5) 461 -99-

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 五、發明說明（9〇 實例108 4-(4-氰苯基)-6-甲基-2-酮基_1-[3-(三氟甲基）苯基]_1，2,3,4· 四氫嘧啶-5-甲酸2-氰基乙酯 NC、This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 200410963 A7 B7 V. Description of the invention (90 Example 108 4- (4-cyanophenyl) -6-methyl-2-one group _1- [3- (trifluoromethyl) phenyl] _1,2,3,4 · tetrahydropyrimidine-5-carboxylic acid 2-cyanoethyl NC,

CNCN

訂 5 使9.87克(48.3毫莫耳）Ν·[3_(三氟甲基）苯基]脲'Order 5 makes 9.87 g (48.3 mmol) N · [3- (trifluoromethyl) phenyl] urea '

12.68克(96·68毫莫耳）4-氰基苯甲搭、15克(96·68毫莫耳） 3-酮基丁酸2-氰基乙酯與37.5克多磷酸乙酯懸浮於250 毫升THF中。攪拌下，回流加熱此混合物18小時。於冷 卻至室溫後，真空去除溶劑，其殘留物於矽石上利用管柱 10 層析法予以純化，以環己烷/乙酸乙酯為溶洗液。 產率：25克（理論值之100%) 經濟部智慧財產局員工消費合作社印製 ^-NMR (200 MHz, DMSO-^): δ = 2.1 (s, 3H); 2.8 (m, 2H); 4.2 (m, 2H); 5.4 (d, 1H); 7.6 (m, 4H); 7.7 (m, 2H); 7,9 (m, 2H); 8.5 (d, 1H) ppm. -100- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（99) 實例109 4-(4-氰苯基)-6·曱基_2_酮基·1-[3-(三氟^甲基）苯基]-1，2,354-四氳嘧啶-5-甲腈12.68 g (96.68 mmol) of 4-cyanobenzoate, 15 g (96.68 mmol) of 2-cyanoethyl 3-ketobutyrate and 37.5 g of ethyl polyphosphate were suspended in 250 Ml of THF. The mixture was heated at reflux for 18 hours with stirring. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by column chromatography on silica using cyclohexane / ethyl acetate as the eluent. Yield: 25 g (100% of theory) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ^ -NMR (200 MHz, DMSO- ^): δ = 2.1 (s, 3H); 2.8 (m, 2H); 4.2 (m, 2H); 5.4 (d, 1H); 7.6 (m, 4H); 7.7 (m, 2H); 7,9 (m, 2H); 8.5 (d, 1H) ppm. -100- this paper Standards are applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) 200410963 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (99) Example 109 4- (4-cyanophenyl) -6 · Fluorenyl_2_keto · 1- [3- (trifluoro ^ methyl) phenyl] -1,2,354-tetrapyrimidine-5-carbonitrile

CNCN

5 使0.609克（1.52毫莫耳)實例70化合物溶於60毫升 THF中，添加1·24克（12.93毫莫耳）（甲氧羰基胺磺醯基)- 三乙銨-Ν-甜菜鹼。此反應混合物於室溫攪拌1小時，真 空去除溶劑，其殘留物於矽石上利用管柱層析法予以純 化，以二氯甲烷/曱醇混合物為溶洗液。 ' 10 產率·· 249毫克（理論值之43%) ^-NMR (300 MHz, DMSO-^): δ - L8 (s, 3H); 5.4 (d, 1H); 7.7 (m, 4H); 7.8 (m, 2H); 8.0 (m, 2H), 8.4 (d, 1H) ppm. -101- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）5. Dissolve 0.609 g (1.52 mmol) of the compound of Example 70 in 60 ml of THF, and add 1.24 g (12.93 mmol) of (methoxycarbonylaminosulfonyl) -triethylammonium-N-betaine. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed in vacuo. The residue was purified by column chromatography on silica using methylene chloride / methanol mixture as the eluent. '10 Yield · 249 mg (43% of theory) ^ -NMR (300 MHz, DMSO- ^): δ-L8 (s, 3H); 5.4 (d, 1H); 7.7 (m, 4H); 7.8 (m, 2H); 8.0 (m, 2H), 8.4 (d, 1H) ppm. -101- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

200410963 A7 B7 五、發明說明（100) 實例110 6-甲基-4-(4-确苯基)-2-銅基-1-[3-(二鼠甲基）苯基]-1，2,3,4-四氫喷唆-5_甲酸乙酉旨200410963 A7 B7 V. Description of the invention (100) Example 110 6-methyl-4- (4-chlorophenyl) -2-copperyl-1- [3- (dimuryl) phenyl] -1, 2 , 3,4-tetrahydropentamidine-5_ethyl formate

經濟部智慧財產局員工消費合作社印製 5 使7.84克(38.4毫莫耳）N_[3-(三氟甲基）苯基]脲、 5.81克(38.4毫莫耳）4-硝基苯曱醛、5.0克(38.4毫莫耳） 3-酮基丁酸乙酯與15克多磷酸乙酯懸浮於100毫升THF 中。攪拌下，回流加熱此混合物18小時。於冷卻至室溫 後，真空去除溶劑，其殘留物於矽石上利用管柱層析法予 10 以純化，以曱苯/乙酸乙酯為溶洗液。 產率·· 8.75克（理論值之51%) ^-NMR (200 MHz, DMSO-d^): δ = 1.1 (t, 3H); 2.1 (s, 3H); 4.0 (m, 2H); 5.4 (d, 1H); 7.5-7.8 (m, 6H); 8.3 (m, 2H); 8.5 (d, 1H) ppm. -102- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x 297公釐） 200410963 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（ιοί) 實例111 5-乙醯基-6-甲基-4-(4-硝苯基)-2-酮基-l-[3-(三氟甲基）苯 基]_1，2,3,4-四氮痛淀Printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Make 7.84 g (38.4 mmol) of N_ [3- (trifluoromethyl) phenyl] urea, 5.81 g (38.4 mmol) of 4-nitrobenzaldehyde 5.0 g (38.4 mmol) of ethyl 3-ketobutyrate and 15 g of ethyl polyphosphate were suspended in 100 ml of THF. The mixture was heated at reflux for 18 hours with stirring. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by column chromatography on silica, using toluene / ethyl acetate as the eluent. Yield: 8.75 g (51% of theory) ^ -NMR (200 MHz, DMSO-d ^): δ = 1.1 (t, 3H); 2.1 (s, 3H); 4.0 (m, 2H); 5.4 (d, 1H); 7.5-7.8 (m, 6H); 8.3 (m, 2H); 8.5 (d, 1H) ppm. -102- This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 200410963 A7 B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Description of Invention (ιοί) Example 111 5-Ethyl-6-methyl-4- (4-nitrophenyl) -2-one- l- [3- (trifluoromethyl) phenyl] _1,2,3,4-tetraazepine

5 使0.407克(2.0毫莫耳）N-[3-(三氟甲基）苯基]脲、 0.302克(2·0毫莫耳）4-硝基苯甲醛、0.2克(2.0毫莫耳） 2,4-戊二酮與0.4克多磷酸乙酯懸浮於20毫升THF中。 攪拌下，回流加熱此混合物18小時。於冷卻至室溫後， 真空去除溶劑，其殘留物於矽石上利用管柱層析法予以純 10 化，以環己烷/乙酸乙酯為溶洗液。 產率：0.302克（理論值之36%) 1Η·ΝΜΚ (200 MHz，DMSO-d^): δ = 2·0 (s，3H); 2·2 (s，3H); 5.5 (d，1H); 7·5·7·8 (m, 6H); 8.3 (m, 2H); 8.5 (d, 1Η) ppm. -103- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）5 Make 0.407 g (2.0 mmol) N- [3- (trifluoromethyl) phenyl] urea, 0.302 g (2.0 mmol) 4-nitrobenzaldehyde, 0.2 g (2.0 mmol) ) 2,4-pentanedione and 0.4 g of ethyl polyphosphate were suspended in 20 ml of THF. The mixture was heated at reflux for 18 hours with stirring. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by column chromatography on silica using cyclohexane / ethyl acetate as the eluent. Yield: 0.302 g (36% of theory) 1Η · NMK (200 MHz, DMSO-d ^): δ = 2.0 (s, 3H); 2.2 (s, 3H); 5.5 (d, 1H ); 7 · 5 · 7 · 8 (m, 6H); 8.3 (m, 2H); 8.5 (d, 1Η) ppm. -103- This paper size applies to China National Standard (CNS) A4 (210 X 297) %)

200410963 A7 B7 五、發明說明（1〇2) C·輿醫藥组成物相關^操作實例 根據本發明之化合物可如下文所述轉化成醫藥組成 物·· 旋劑 5 組成 100毫克實例1化合物、50毫克乳糖(單水合物）、50 毫克玉米澱粉(原態）、10毫克聚乙烯基吡咯啶酮(PVP 25) (得自 BASF，Ludwigshafen，Germany)及 2 毫克硬脂酸鎮。 錠劑重212毫克，直徑8毫米，曲率半徑12毫米。 10 製備 以5% PVP於水中（m/m)之溶液，將活性成分、乳糖 與澱粉粒化。乾燥後，使粒劑與硬脂酸鎂混合5分鐘。使 用習知錠劑模壓機模製此混合物(錠劑規格如上）。所用模 製力典型地為15kN。 15 口服懸浮劑 組成 1000毫克實例1化合物、1000毫克乙醇(96%)、400 毫克 Rhodlgel (黃原糖膠，得自 FMC, Pennsylvania，USA) 及99克水。 20 10毫升口服懸浮劑提供1〇〇毫克根據本發明之化合 物單一劑量。 製備 使Rhodigel懸浮於乙醇中，添加活性成分於該懸浮 液中。搅拌下，添加水。持續授拌、約6小時，至Rhodigd •104- 4. •訂· 經濟部智慧財產局員工消費合作社印製 * f t Sr I V *· ^ 經濟部智慧財產局員工消費合作社印製 200410963 A7 B7 五、發明說明（103) 完全膨脹為止。 [圖式簡單說明] 無 -105- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）200410963 A7 B7 V. Description of the invention (102) C. Relevant pharmaceutical composition ^ Operating examples The compound according to the present invention can be converted into a pharmaceutical composition as described below. Rotary 5 Composition 100 mg Example 1 Compound 50 Mg of lactose (monohydrate), 50 mg of corn starch (as is), 10 mg of polyvinylpyrrolidone (PVP 25) (available from BASF, Ludwigshafen, Germany) and 2 mg of stearic acid. The tablets weigh 212 mg, have a diameter of 8 mm, and have a radius of curvature of 12 mm. 10 Preparation A solution of 5% PVP in water (m / m) was used to granulate the active ingredients, lactose and starch. After drying, the granules were mixed with magnesium stearate for 5 minutes. This mixture was molded using a conventional tablet press (tablet specifications as above). The molding force used is typically 15 kN. 15 Oral suspension Composition 1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodlgel (xanthan gum, obtained from FMC, Pennsylvania, USA) and 99 g of water. 20 10 ml of oral suspension provides a single dose of 100 mg of a compound according to the invention. Preparation The Rhodigel is suspended in ethanol, and the active ingredient is added to the suspension. With stirring, water was added. Continue mixing for about 6 hours until Rhodid • 104- 4. • Order · Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs * ft Sr IV * · ^ Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 200410963 A7 B7 DESCRIPTION OF THE INVENTION (103) until it is fully expanded. [Brief description of the drawings] None -105- This paper size is applicable to China National Standard (CNS) A4 (210x297 mm)

Claims (1)

200410963 A8 B8 C8 D8 六、申請專利範圍 1. 一種具下式⑴之化合物200410963 A8 B8 C8 D8 6. Scope of patent application 1. A compound with the formula ⑴ (D， 5 10 經濟部智慧財產局員工消費合作社印製 15 式中 A 代表芳基或雜芳環； R1、R2與R3各自獨立地代表氫、鹵素、硝基、氰基、％ 烧基、經基或燒氧基，其中CrC成基與CrQ 烧氧基可進-步被-至三個相同或不同之選自包括_ 素、經基及Q-Cr燒氧基之基團取代； 代表三氟曱基羰基、CrC6-烷基羰基、Ci-CV烷章 基羰基、CrCV烯氧基幾基、羥獄基、胺羰基、 單-或二-CrCr烷基胺羰基、C6-Cl(r芳基胺羰基、 芳基羰基、雜芳基羰基、雜環基羰基、雜芳基、 雜環基或氰基，其中CrC6-烷基羰基、CrCV娱 氧基羰基、單-及二-CrC4_烷基胺羰基可進一步梯 一至三個相同或不同之選自包括c3-c8-環烷基、 經基、CrC4-烧氧基、CrC4_烷氧幾基、羥羰基、 胺緩基、早-及二-Ci_C4-烧基胺幾基、C1-C4-烧基 羰胺基、（CrC4-烷基羰基)-CrC4-烷胺基、氰基、 -106 R4 本紙張尺度適用中國國家標準(CNS)A4規格（21〇 X 297公釐） 200410963 8 8 8 8 A B c D 六、申請專利範圍 胺基、單-及二-CrC4-烷胺基、雜芳基、雜環基及 三-(CrC6-烷基)-矽烷基之基團取代，及其中雜芳 基羰基、雜環基羰基、雜芳基及雜環基可進一步 被CrC4-烷基取代； 5 R5 代表C1-C4-烧基，其可被一至三個相同或不同之 選自包括_素、羥基、CrC6-烷氧基、-烯氧 基、Ci_C6-烧硫基、胺基、单-及二-Ci-C6-烧胺 基、芳胺基、羥羰基、CrCr烷氧羰基及-O-Cr C4-烧基-〇-Ci-C4_烧》基之基團取代， 10 或 R5 代表胺基； R6 代表氫、CrC6-烷基、甲醯基、胺羰基、單-或二- CrC4-烷基胺羰基、C3-C8-環烷基羰基、CrC6-烷 基羰基、CrC6-烷氧羰基、N-(CrCr烷基磺醯基)- 15 胺羰基、N-(CrC4-烷基磺醢基VN-(CrC4-烷基）- 胺幾基、雜芳基、雜環基、雜芳基羰基或雜環基 羰基，其中Crc6-烷基、單-及二-C^Cr烷基胺羰 經濟部智慧財產局員工消費合作社印製 基、CrC6-烷基羰基、CrC6-烷氧羰基、雜芳基及 雜環基可被一至三個相同或不同之選自包括芳 20 基、雜芳基、羥基、CrC4-烷氧基、羥羰基、（V C6-烷氧羰基、胺羰基、單-及二-Q-C4-烷基胺羰 基、胺基、單-及二-CrCr烷胺基、CrCr烷基羰 胺基、三-(Ci_C6_烧基)_碎烧基、氰基、单-及二- C1-C4-烧胺基-Ci-C4-烧基胺幾基、C1-C4*"烧氧基_ -107 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 8 8 8 A B c D 經濟部智慧財產局員工消費合作社印製 200410963 六、申請專利範圍 烷基胺羰基及產素之基團取代； 或 R6 代表具下式之基團 U〇 4 *αο- 5 式中 R6A 係選自氫與q-CV烷基，及 η 代表整數1或2 ; R7 代表鹵素、硝基、氰基、CrC6-烷基、羥基或Cr CV烷氧基，其中CrC6-烷基及烷氧基可進 10 一步被一至三個相同或不同之選自包括鹵素、羥 基及Ci-Cr烷氧基之基團取代； 及 γΐ、γ2、γ3、Y4與γ5各自獨立地代表CH或N， 其中該環含有0、1或2個氮原子 15 及其鹽、水合物及/或溶劑合物與其互變異構形式。 2·根據申請專利範圍第1項之式⑴化合物，其中 A 代表芳基或雜芳環； R、R2與R3各自獨立地代表氫、鹵素、硝基、氰基、CrQ_ 烧基、羥基或CrC6-烷氧基，其中CrCV烷基與CrC6- 20 烧氧基可進一步被一至三個相同或不同之選自包括鹵 素、羥基及CrCV烷氧基之基團取代； R4代表CrCV烧基羰基、CrC6_烷氧基羰基、CrC6_烯氧基 -108 本紙張尺度適用中國國家標準(CNS)A4規格（210X 297公楚） "(D, 5 10 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 15 where A represents an aryl or heteroaryl ring; R1, R2, and R3 each independently represent hydrogen, halogen, nitro, cyano,% alkanyl, Via radical or alkoxy radical, in which CrC-forming radical and CrQ alkoxy radical may be further-substituted by-to three groups which are the same or different and are selected from the group consisting of element, via radical and Q-Cr radical; Trifluorofluorenylcarbonyl, CrC6-alkylcarbonyl, Ci-CV alkyl carbonyl, CrCV alkenyloxy, hydroxycarbyl, aminecarbonyl, mono- or di-CrCr alkylamine carbonyl, C6-Cl (r Arylamine carbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl or cyano, among which CrC6-alkylcarbonyl, CrCV alkoxycarbonyl, mono- and di-CrC4_ The alkylamine carbonyl group may further be one to three identical or different selected from the group consisting of c3-c8-cycloalkyl, mesityl, CrC4-carboxy, CrC4-alkoxyquinyl, hydroxycarbonyl, amine retarder, early- And di-Ci_C4-alkylaminoamine, C1-C4-alkylaminocarbonyl, (CrC4-alkylcarbonyl) -CrC4-alkylamino, cyano, -106 R4 This paper size applies to Chinese national standards (CNS A4 Regulation (21 × X 297 mm) 200410963 8 8 8 8 AB c D 6. Application scope of patents Amine, mono- and di-CrC4-alkylamino, heteroaryl, heterocyclic and tri- (CrC6-alkyl )-Silyl group substitution, and the heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, and heterocyclyl groups may be further substituted with CrC4-alkyl; 5 R5 represents C1-C4-alkyl, which may be substituted by One to three of the same or different are selected from the group consisting of hydrogen, hydroxy, CrC6-alkoxy, -enoxy, Ci_C6-sulfanyl, amine, mono- and di-Ci-C6-sulfanyl, aromatic amines Group, hydroxycarbonyl group, CrCr alkoxycarbonyl group and -O-Cr C4-alkyl-O-Ci-C4-alkyl group, 10 or R5 represents amine group; R6 represents hydrogen, CrC6-alkyl, methyl Fluorenyl, aminecarbonyl, mono- or di-CrC4-alkylaminecarbonyl, C3-C8-cycloalkylcarbonyl, CrC6-alkylcarbonyl, CrC6-alkoxycarbonyl, N- (CrCralkylsulfonyl)- 15 Amine carbonyl, N- (CrC4-alkylsulfonyl) VN- (CrC4-alkyl) -amido, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl, of which Crc6-alkyl , Mono- and Di-C ^ Cr alkylamines Cooperative printed group, CrC6-alkylcarbonyl, CrC6-alkoxycarbonyl, heteroaryl and heterocyclic group may be one to three same or different and selected from the group consisting of aryl20, heteroaryl, hydroxyl, CrC4-alkoxy Group, hydroxycarbonyl, (V C6-alkoxycarbonyl, amine carbonyl, mono- and di-Q-C4-alkylamine carbonyl, amine, mono- and di-CrCr alkylamino, CrCr alkylcarbonyl, Tri- (Ci_C6_alkyl) _crucyl, cyano, mono- and di-C1-C4-alkylamino-Ci-C4-alkylamino, C1-C4 * " alkyloxy_- 107 This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 8 8 8 AB c D Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 200410963 VI. Application for patents Group substitution; or R6 represents a group of the following formula U〇4 * αο- 5 where R6A is selected from hydrogen and q-CV alkyl, and η represents an integer 1 or 2; R7 represents halogen, nitro, cyanide CrC6-alkyl, hydroxy or Cr CV alkoxy, wherein CrC6-alkyl and alkoxy can be further selected from one to three identical or different from one selected from halogen, hydroxy and Ci-Cr alkoxy Group substitution; and γΐ, γ2, γ3, Y4, and γ5 each independently represent CH or N, wherein the ring contains 0, 1, or 2 nitrogen atoms 15 and salts, hydrates, and / or solvates thereof and intervariates therewith Otic form. 2. The compound of formula 根据 according to item 1 of the scope of the patent application, wherein A represents an aryl or heteroaryl ring; R, R2, and R3 each independently represent hydrogen, halogen, nitro, cyano, CrQ_alkyl, hydroxyl, or CrC6 -Alkoxy, wherein CrCV alkyl and CrC6- 20 alkoxy may be further substituted with one to three groups which are the same or different and selected from the group consisting of halogen, hydroxyl and CrCV alkoxy; R4 represents CrCV alkoxy, CrC6 _Alkoxycarbonyl, CrC6_alkenyl-108 This paper size is applicable to China National Standard (CNS) A4 (210X 297 cm) " 200410963 ος 〇〇 8 A B c D 六、申請專利範圍 羰基、羥羰基、胺羰基、單-或二-CrC4-烷基胺羰基、 C6-C1(r芳基胺羰基、雜芳基羰基、雜環基羰基、雜芳 基、雜環基或氰基，其中CrC6-烷基羰基、CrC6-烷氧基 羰基、單_及二-CrCr烷基胺羰基可進一步被一至三個相 5 同或不同之選自包括CrCr環烷基、羥基、CrCr烷氧 基、CrCr烷氧羰基、羥羰基、胺羰基、單-及二-crC4-烷基胺羰基、CrC4-烷基羰胺基、胺基、單-及二-CrC4-烷胺基、雜芳基、雜環基及三-(Q-Q·烷基>矽烷基之基 團取代； 10 R5代表CrCr烷基，其可被一至三個相同或不同之選自包 括鹵素、羥基、CrC6-烷氧基、CrC6-烯氧基、CrC6-烷 硫基、胺基 '單-及二-CrC6_烷胺基、芳胺基、羥羰基、 Ci-Cr烧氧基及-O-Ci-C4-烧基_〇-C]-C4_烧基之基團取 代； 15 或 R5代表胺基； R6代表氫、Q-CV烧基、甲醯基、胺羰基、單-或二_CrQ_ 經濟部智慧財產局員工消費合作社印製 烷基胺羰基、CrCr環烷基羰基、crCV烷基羰基、Cr C6-烧氧戴基、N-(CpC4-烧基績醯基)-胺幾基、 20 烧基績酿基烧基)-胺幾基、雜芳基、雜環基、 雜芳基羰基或雜環基羰基，其中Q-CV烷基、單_及二_ CrCr烷基胺羰基、CrCV烷基羰基、Cr(V烷氧幾基、 雜芳基及雜環基可被一至三個相同或不同之選自包括芳 基、雜芳基、羥基、CrCr烷氧基、羥羰基、CKV燒氧 -109 本紙張尺度適用中國國家標準(CNS)A4規格（210 x 297公釐） 200410963 六、申請專利範圍 幾基、胺獄基、單-及二-CpC4_烧基胺幾基、胺基、單-及二_Ci_C4_烧胺基、C1-C4-炫基戴胺基、三-(Ci_C6·烧基)· 矽烷基、氰基、單-及二-CrCr烷胺基-CrC4-烷基胺羰 基、CrCr烷氧基-CrCr烷基胺羰基及產素之基團取 5 代； 或 R6代表具下式之基團 .乂〇 ，，Λ> 式中 10 R6A 係選自氫與CrC6-烷基，及 η 代表整數1或2 ; R7代表鹵素、硝基、氰基、CrCV烧基、羥基或Q· C6-烷氧基，其中CrC6-烷基及Ci-C^燒氧基可進 一步被一至三個相同或不同之選自包括鹵素、經 15 基及CrC4-烷氧基之基團取代； 經濟部智慧財產局員工消費合作社印製 及 Y1、Y2、Y3、Y4與Y5各自獨立地代表或N， 其中該環含有0、1或2個氮原子。 3.根據申請專利範圍第1或2項之式(1)化合物，其中 20 A 代表苯基、萘基或吼啶基環； R1、R2與R3各自獨立地代表氫、氟、氯、漠、硝基、氰基、 甲基、乙基、三氟甲基或三氟甲氧基； -110 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200410963 Αδ Β8 C8 D8 10 15 六、申請專利範圍 R4代表CrC6-烷基羰基、CrC6-烷氧基羰基、羥羰基、胺羰 基、單-CrC4-烷基胺羰基或氰基，其中Q-CV烷基羰 基、烧氧基羰基及單-CpC/r烧基胺幾基可被一至 三個相同或不同之選自包括CrC8-環烷基、羥基、CrC4_ 烧氧基、CrCr燒氧幾基、胺基、單-及二_crC4_烧胺 基、雜芳基及雜環基之基團取代； R5代表甲基或乙基； R6代表氫、CrQ-烧基、單-或二烷基胺羰基、crcv 烧基羰基、CrQ-烷氧羰基或雜環基羰基，其中crC6-燒 基及Q-CV烷氧羰基可被一至三個相同或不同之選自包 括雜芳基、羥基、CrCr烷氧基、羥羰基、CrCV烷氧羰 基、胺羰基、單-及二-CrCV烷基胺羰基、氰基、胺基、 • 單-及二-CrCp烧胺基之基團取代； 或 R6代表具下式之基團 訂 經濟部智慧財產局員工消費合作社印製 20 · u〇 或 ΟΙ 式中 R6A係選自氫與CrCr烷基，及 n 代表整數1或2 ; R7 代表鹵素、硝基、氰基、三氟甲基 基、甲基或乙基； 氟甲氧 及 -111 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200410963 8 8 8 8 A B c D 六、申請專利範圍 γ1、γ2、γ3、γ4 與 Y5 各自代表 CH。 4.根據申請專利範圍第1、2或3項之式(I)化合物，其中 A 代表苯基或咐啶基環； R1與R3各自代表氫； 5 R2代表氟、氣、溴、硝基或氰基； R4代表氰基、CrCr烷基羰基或CrQ-烷氧基羰基，其中 CrC4-烷氧基羰基可被選自包括羥基、CrC4_烷氧基、 CrCp烧氧叛基、單_及二·CrCp烧胺基、雜芳基及雜環 基之基團取代； 10 R5代表甲基； R0代表氫、烷基、單-或二-CrC4-烷基胺羰基、ClC4_ 烷基羰基或CrCr烷氧羰基，其中CrC4-烷基及cVCr 烷氧羰基可被選自包括雜芳基、羥基、CrCr烷氧基、 羥羰基、胺羰基、單-及二-CVCr烷基胺羰基、胺基、 15 早-及二-C1-C4-烧胺基之基團取代； 或 R6代表具下式之基團200410963 ος 〇〇8 AB c D 6. Application scope Patent, carbonyl, hydroxycarbonyl, amine carbonyl, mono- or di-CrC4-alkylamine carbonyl, C6-C1 (rarylamine carbonyl, heteroarylcarbonyl, heterocyclic Carbonyl, heteroaryl, heterocyclyl or cyano, in which CrC6-alkylcarbonyl, CrC6-alkoxycarbonyl, mono- and di-CrCr alkylamine carbonyl groups can be further one to three phases 5 the same or different Selected from the group consisting of CrCr cycloalkyl, hydroxyl, CrCr alkoxy, CrCr alkoxycarbonyl, hydroxycarbonyl, amine carbonyl, mono- and di-crC4-alkylaminocarbonyl, CrC4-alkylcarbonylamino, amine, mono -And di-CrC4-alkylamino, heteroaryl, heterocyclyl and tri- (QQ · alkyl > silyl groups; 10 R5 represents CrCr alkyl, which may be the same or different from one to three Selected from the group consisting of halogen, hydroxy, CrC6-alkoxy, CrC6-alkenyloxy, CrC6-alkylthio, amine'mono- and di-CrC6-alkylamino, arylamino, hydroxycarbonyl, Ci-Cr Substituted by alkoxy and -O-Ci-C4-alkyl-O-C] -C4-alkyl groups; 15 or R5 represents an amine group; R6 represents hydrogen, Q-CV alkyl, formamyl, amine Carbonyl, mono- or di_CrQ_ Ministry of Economy Intellectual Property Bureau employee consumer cooperatives printed alkylamine carbonyl, CrCr cycloalkylcarbonyl, crCV alkylcarbonyl, Cr C6-oxoyl, N- (CpC4-kilnyl) -amine, 20 Alkyl group)-amine, aryl, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl, of which Q-CV alkyl, mono- and di-CrCr alkylamine carbonyl, CrCV alkyl The carbonyl group, Cr (Valkoxy group, heteroaryl group and heterocyclic group may be one to three which are the same or different and are selected from the group consisting of aryl, heteroaryl, hydroxyl, CrCralkoxy, hydroxycarbonyl, CKV -109 This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 200410963 6. Application scope of patents Jiji, Amine, Mono- and Di-CpC4_Alkylamine, Amine, Mono- and di_Ci_C4_alkylamino, C1-C4-xylamino, tri- (Ci_C6 · alkyl), silyl, cyano, mono- and di-CrCr alkylamino-CrC4-alkyl The amine carbonyl group, CrCr alkoxy-CrCr alkylamine carbonyl group and element group are taken 5 times; or R6 represents a group having the formula: 乂 〇 ,, Λ> where 10 R6A is selected from hydrogen and CrC6- Alkyl and η Generation Integer 1 or 2; R7 represents halogen, nitro, cyano, CrCV alkyl, hydroxy, or Q · C6-alkoxy, where CrC6-alkyl and Ci-C ^ alkyl may be further the same or The difference is selected from the group consisting of halogen, substituted by 15-based and CrC4-alkoxy groups; printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs and Y1, Y2, Y3, Y4, and Y5 each independently represent or N, where The ring contains 0, 1 or 2 nitrogen atoms. 3. The compound of formula (1) according to item 1 or 2 of the scope of the patent application, wherein 20 A represents a phenyl, naphthyl or cylindinyl ring; R1, R2 and R3 each independently represent hydrogen, fluorine, chlorine, molybdenum, Nitro, cyano, methyl, ethyl, trifluoromethyl or trifluoromethoxy; -110 This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200410963 Αδ Β8 C8 D8 10 15 6 The scope of the patent application for R4 represents CrC6-alkylcarbonyl, CrC6-alkoxycarbonyl, hydroxycarbonyl, aminecarbonyl, mono-CrC4-alkylaminocarbonyl or cyano, among which Q-CV alkylcarbonyl, alkyloxycarbonyl and The mono-CpC / r alkylamino group may be one to three identical or different and selected from the group consisting of CrC8-cycloalkyl, hydroxyl, CrC4-alkyloxy, CrCroxyalkyl, amine, mono- and di-crC4 _Substituted by amine, heteroaryl and heterocyclic groups; R5 represents methyl or ethyl; R6 represents hydrogen, CrQ-alkyl, mono- or dialkylamine carbonyl, crcv alkyl, CrQ- Alkoxycarbonyl or heterocyclylcarbonyl, wherein crC6-alkyl and Q-CV alkoxycarbonyl may be one to three same or different and selected from the group consisting of heteroaryl, hydroxyl, CrCr alkoxy, hydroxycarbonyl, CrCV alkoxycarbonyl, amine carbonyl, mono- and di-CrCV alkylaminocarbonyl, cyano, amine, • mono- and di-CrCp alkylamino groups; or R6 Printed on behalf of a group with the following formula: Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 · u〇 or 〇Ι where R6A is selected from hydrogen and CrCr alkyl, and n represents the integer 1 or 2; R7 represents halogen and nitro , Cyano, trifluoromethyl, methyl or ethyl; fluoromethoxy and -111 This paper size is applicable to China National Standard (CNS) A4 (210x297 mm) 200410963 8 8 8 8 AB c D 6. Application The patent scopes γ1, γ2, γ3, γ4 and Y5 each represent CH. 4. The compound of formula (I) according to item 1, 2, or 3 of the scope of the patent application, wherein A represents a phenyl or pyridyl ring; R1 and R3 each represent hydrogen; 5 R2 represents fluorine, gas, bromine, nitro or Cyano; R4 represents cyano, CrCr alkylcarbonyl, or CrQ-alkoxycarbonyl, wherein CrC4-alkoxycarbonyl can be selected from the group consisting of hydroxyl, CrC4-alkoxy, CrCp alkyloxy, mono and di · CrCp amine, heteroaryl and heterocyclic group substitution; 10 R5 represents methyl; R0 represents hydrogen, alkyl, mono- or di-CrC4-alkylaminocarbonyl, ClC4-alkylcarbonyl or CrCralkane Oxycarbonyl, where CrC4-alkyl and cVCr alkoxycarbonyl can be selected from the group consisting of heteroaryl, hydroxyl, CrCr alkoxy, hydroxycarbonyl, amine carbonyl, mono- and di-CVCr alkylamine carbonyl, amine, 15 Early- and di-C1-C4-alkylamino group substitution; or R6 represents a group of the formula 經濟部智慧財產局員工消費合作社印製 〇， 式中 20 R6A 係選自氫及甲基， R7 代表三氟甲基或硝基； 及 . -112 本紙張尺度適用ΐ國國家標準(CNS)A4規格（210 X 297公釐) ----- 200410963 A8 B8 C8 _D8_ 六、申請專利範圍 γ1、γ2、γ3、γ4 與 γ5 各自代表 CH。 5. 根據申請專利範圍第1至4項之任一項之式(I)化合 物，其中A為苯及或°比咬基。 6. 根據申請專利範圍第1至5項之任一項之式(I)化合 5 物，其中R1為氫。 7. 根據申請專利範圍第1至6項之任一項之式(I)化合 物，其中R2為氰基。 8·根據申請專利範圍第1至7項之任一項之式(I)化合 物，其中R3為氩。 10 9.根據申請專利範圍第1至8項之任一項之式(I)化合 物，其中R4為視需要被羥基取代之CrC4-烷氧羰基或 其中R4為CVC4-烷基羰基。 10·根據申請專利範圍第1至9項之任一項之式(I)化合 物，其中R5為曱基。 15 11.根據申請專利範圍第1至10項之任一項之式⑴化合 物，其中R6為氫。 經濟部智慧財產局員工消費合作社印製 12·根據申請專利範圍第1至11項之任一項之式(I)化合 物，其中R7為三氟曱基或硝基。 13. —種具下式（IA)之化合物 -113 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 A8 B8 C8 D8 六、申請專利範圍 5Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, where 20 R6A is selected from hydrogen and methyl, R7 represents trifluoromethyl or nitro; and -112 This paper applies the national standard (CNS) A4 Specifications (210 X 297 mm) ----- 200410963 A8 B8 C8 _D8_ VI. Patent application scopes γ1, γ2, γ3, γ4 and γ5 each represent CH. 5. The compound of formula (I) according to any one of claims 1 to 4 of the scope of the patent application, wherein A is benzene and or a specific group. 6. The compound of formula (I) according to any one of claims 1 to 5, wherein R1 is hydrogen. 7. The compound of formula (I) according to any one of the claims 1 to 6, wherein R2 is a cyano group. 8. The compound of formula (I) according to any one of claims 1 to 7 of the scope of the patent application, wherein R3 is argon. 10 9. The compound of formula (I) according to any one of claims 1 to 8 of the scope of the patent application, wherein R4 is a CrC4-alkoxycarbonyl group optionally substituted with a hydroxyl group or wherein R4 is a CVC4-alkylcarbonyl group. 10. The compound of formula (I) according to any one of claims 1 to 9 of the scope of the patent application, wherein R5 is a fluorenyl group. 15 11. The compound of formula (I) according to any one of claims 1 to 10 of the scope of the patent application, wherein R6 is hydrogen. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 12. The compound of formula (I) according to any one of the items 1 to 11 of the scope of patent application, wherein R7 is trifluorofluorenyl or nitro. 13. —A compound with the following formula (IA) -113 The paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 200410963 A8 B8 C8 D8 6. Scope of patent application 5 (ΙΑ), 式中 Ζ 代表CH或Ν;及 R^R^R4與R6具有申請專利範圍第1至12項指示之意 14. 一種合成分別如申請專利範圍第1至13項界定之式 (I)或式(IA)化合物之方法，該方法包括使具下式（II)之 化合物(ΙΑ), where Z represents CH or N; and R ^ R ^ R4 and R6 have the meaning of indications 1 to 12 of the scope of patent application 14. A synthesis is the formula defined by the scope of claims 1 to 13 of the patent application ( I) or a compound of formula (IA), which method comprises using a compound of formula (II) CHO (Π) 經濟部智慧財產局員工消費合作社印製 10 式中 A、R1與R2具有申請專利範圍第1至13項指示之意義； 與具下式（III)之化合物 -114 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 經濟部智慧財產局員工消費合作社印製CHO (Π) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, where A, R1 and R2 have the meanings of the indications in the scope of patent applications Nos. 1 to 13; and compounds with the following formula (III) -114 This paper size applies China National Standard (CNS) A4 Specification (210 X 297 mm) 200410963 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 至13頊游 具有申請專利範圍第 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200410963 A8 B8 _ C8 -----D8_ 六、申請專利範圍 - 至13項指示之意義； 隨後視需要使式(IB)化合物與具下式(V)之化合物 R6*-X (V) 式中 5 R0*具有如申請專利範圍第1至13項指示之Μ之意 義，惟不代表氫；及 代表釋離基，例如鹵素、對甲苯確醯基、甲確醢 基或硫酸根； 於鹼存在下進行反應。 1〇 15· #組成物’其含有如巾請專利翻第1至υ項界 定之至j/ 一種式①或（IA)化合物及藥理上可接受之稀 釋劑。 16·根據中請專利範圍第15項之組成物，係供治療急性 及漫〖生炎症、缺血性及/或改組病變（remodeling 15 processes) 〇 17· —種製備根據申請專利範圍第15及16項之組成物之 經濟部智慧財產局員工消費合作社印製 方法，其特徵為使如申請專利範圍第〗至13項界定之 式（I)或(IA)化合物連同習知佐劑一起成為適當施用形 式。 y 20 I8· 一種使用如申請專利範圍第}至13項界定之式⑴戋 (IA)化合物製備藥物之用途。 19·根據申請專利範圍第18項之用途，係用於製傷藥物 以治療急性及慢性炎症、缺血性及/或改組病 /、 -116 ° 本紙張尺度適用中國國家標準(CNS)A4規袼（21〇 x 297公爱） 200410963 A8 B8 C8 D8 5 經濟部智慧財產局員工消費合作社印製 六、申請專利範圍 20·根據申請專利範圍第19項之用途，其中該病變為慢 性阻塞性肺病、急性冠狀動脈症候群、急性心肌梗塞 或心臟哀竭形成。 21. —種方法，係藉由投與嗜中性白血球彈性蛋白酶抑制 活性量之至少一種根據申請專利範圍第丨至13項之住 一項之化合物調控人類及動物之慢性阻塞性肺病、 性冠狀動脈症候群、急性心肌梗塞或心臟衰竭开/ 、 -117 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200410963 (一) 、本案指定fft表圖處:〖第靈21圖tk'): ί - ; ν：;：ν：：：,：;：.：ν：;：·ν：ν：·：：ν：.：ν；χ：ν：：：νΧ;：ν：ν：;；;； 1·'：·：·；·：ν：·>χν%·：ν：·ν·νΧ··ν!：Χχί：!>>；ν>>：·>ί>：!>>>：·：'χ^!>>：·,:Χ〇ν;：·^·：·：·ν·Χ·：ν·：·Χ^ . .· (二） 、本代表圖之元件代表符號簡單說明I # ^ ^ ^ < , - μ、、 ί 、 、、、 ; 、 lllllllllllililllllllllllie 本案若有化·麵酵Migration to 13 has the significance of applying for the patent scope of the first paper size applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200410963 A8 B8 _ C8 ----- D8_ VI. The scope of patent application-to 13 instructions; Then, if necessary, the compound of the formula (IB) and the compound of the following formula (V) R6 * -X (V) where 5 R0 * has the meaning of M as indicated in items 1 to 13 of the patent application scope, but does not represent hydrogen ; And represents a releasing group, such as halogen, p-tolyl, methyl, or sulfate; the reaction is performed in the presence of a base. 1〇 15 · # COMPOSITION ’, which contains a compound of formula ① or (IA) and a pharmacologically acceptable diluent, as defined in item 1 to υ of the patent. 16. The composition according to item 15 of the patent scope is for the treatment of acute and diffuse inflammation, ischemic and / or remodeling 15 processes. 〇17 · —A kind of preparation according to the scope of patent application A method for printing a consumer cooperative of an employee of the Intellectual Property Bureau of the Ministry of Economic Affairs of the composition of 16 items, characterized in that the compound of formula (I) or (IA) as defined in the scope of application for patents Nos. 13 to 13 together with a conventional adjuvant becomes appropriate application form. y 20 I8 · A use for the preparation of a medicament using a compound of the formula (IA) as defined in the scope of application for patents} to 13. 19. The application according to item 18 of the scope of the patent application is for use in wound-prevention drugs for the treatment of acute and chronic inflammation, ischemic and / or reorganized diseases, -116 ° This paper standard applies Chinese National Standard (CNS) A4 regulations袼 (21〇x 297 public love) 200410963 A8 B8 C8 D8 5 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 6. Application for a patent scope 20 · According to the use of item 19 in the scope of patent application, where the lesion is chronic obstructive pulmonary disease , Acute coronary syndromes, acute myocardial infarction or heart failure. 21. A method for regulating chronic obstructive pulmonary disease and sexual coronation in humans and animals by administering at least one compound of the neutrophil elastase inhibitory activity amount according to claims 1 to 13 of the patent application scope Arterial Syndrome, Acute Myocardial Infarction or Heart Failure On /--117 This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200410963 (1) The designated fft table in this case is as follows: 〖Di Ling 21 tk '): ί-; ν:;: ν :::,:;:. ν:;: · ν: ν: · :: ν:.: ν; χ: ν ::: νχ;: ν: ν: ;;; 1 · ': ·: ·; ·: ν: · > χν% ·: ν: · ν · νχ ·· ν !: χχί:! > >; ν > >: · > ί >:! > > > ::: 'χ ^! > >: ·,: × 〇ν ;: ^ · ::: ν · χ ·: ν ·: χ ^ .. (II) Brief description of the component representative symbols of this representative diagram I # ^ ^ ^ <,-μ ,, ί,,,,;, lllllllllllililillllllllllll # (Ό, 第2-1頁# (Ό, page 2-1
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