TWI314555B - Heterocyclic derivatives - Google Patents

Heterocyclic derivatives Download PDF

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TWI314555B
TWI314555B TW092124801A TW92124801A TWI314555B TW I314555 B TWI314555 B TW I314555B TW 092124801 A TW092124801 A TW 092124801A TW 92124801 A TW92124801 A TW 92124801A TW I314555 B TWI314555 B TW I314555B
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group
compound
crc4
substituted
formula
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TW200410963A (en
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Gielen Heiki
Li Volkhart
Rosentreter Ulrich
Schlemmer Karl-Heinz
Allerheiligen Swen
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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  • Organic Chemistry (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Medicinal Chemistry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

13145551314555

五、發明說明（1 ) [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] 經濟部智慧財產局員工消費合作社印製 纖維狀彈性蛋白-其構成一些組織(例如動脈、一些韌 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)，亦即所謂人類唁中 10性白血球彈性蛋白酶(HNE)，係被糖基化之強鹼性絲胺酸 蛋白酶，見於人類多形核白血球細胞(PMN)之嗜苯胺鹽顆 粒。HNE自活化PMN釋出，被認為與急性及慢性炎性疾 病之發病原因有所牽連。HNE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 15外’ HNE具有寬廣範圍之炎性作用，包括向上調節乩_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组織之介質角色，例 如，於心贜中，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、促進黏附於内皮的考中性白血球 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)、肺氣踵（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 X 297公釐） 1314555 A7 B7 五、發明說明（2) 於急性心肌梗塞後心肌功能異常，及涉及形成心職衰竭期 間發生改組病變(remodeling processes)。HNE亦有原因地 牵連風濕性關節炎、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，尤其疋慢性阻塞性肺病[R.A. Stockley, and protease/antiprotease imbalance, Am. J. Respir. Crit. Care 160, 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 經濟部智慧財產局員工消费合作社印製 10 塞及冠狀動脈間道移植(CABG) [C.P. Tiefenbacher et al., 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. U，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.，e/aWaie />i human atherosclerotic plaque, Circulation 107. 2829-2836 (2003)]。 5-乙氧羰基-1-苯基-6-甲基-4-(3-硝苯基)-3,4-二氫嘧 咬-2(1Η)-_之合成見述於 J. Heterocyclic Chem. 38, 1051 -4- 本纸張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 1314555 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V. INSTRUCTION DESCRIPTION OF THE INVENTION (1) [Technical Field to Which the Invention Is Alonged] The present invention relates to a novel heterocyclic derivative, a process for the preparation thereof, and a medicament thereof, particularly for the treatment of chronic obstructive pulmonary disease, acute coronary syndrome, acute myocardium Infarction and the use of heart failure. 5 [Prior Art] Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed fibrillar elastin - which constitutes a fairly significant proportion of all proteins (eg arteries, some ligaments, lungs and heart) - can be classified as elastase The selected group of enzymes are hydrolyzed or destroyed. Human leukocyte elastase (HLE, EC 3.4.21.37), also known as human leukocyte elastase (HNE), is a glycosylated strong alkaline serine protease found in human polymorphonuclear leukocytes ( PMN) aniline salt particles. The release of HNE from activated PMN is thought to be implicated in the pathogenesis of acute and chronic inflammatory diseases. HNE can degrade a wide range of matrix proteins including elastin and collagen, in addition to their role in connective tissue 15 'HNE has a wide range of inflammatory effects, including up-regulation of 乩8 gene expression, edema formation, mucinous gland hyperplasia And mucus secretion too much; also plays a mediator role in the damage tissue by hydrolyzing the collagen structure, for example, in the heart palpitations, after acute myocardial infarction or during the formation of heart failure, thereby damaging endothelial cells and promoting adhesion to the endothelium. Test the leucorrhea 20 extravasation and affect the adhesion process itself. Pulmonary diseases that are considered to be responsible for HNE include pulmonary fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), pulmonary gas sputum (including smoking-induced emphysema), chronic obstructive pulmonary disease (COPD), and cystic fibrosis . In cardiovascular disease, HNE is involved in the development of ischemic tissue damage. The paper size is then applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1314555 A7 B7 V. Description of the invention (2) After acute myocardial infarction Abnormal myocardial function and remodeling processes that occur during the formation of heart failure. HNE is also implicated in rheumatoid arthritis, arteriosclerosis, brain trauma, cancer, and related symptoms involving neutrophil involvement. 5 Thus '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 160, S49-S52 (1999) ]. HLE inhibitors are also potentially useful in the treatment of acute myocardial syndrome, unstable angina, acute myocardial infarction, Ministry of Economic Affairs, Intellectual Property Office, Staff Cooperatives, 10 Saddle and Intercoronary Artery Transplantation (CABG) [CP Tiefenbacher et al., 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. U, 1559-1563 (1990)], and the treatment 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., e/aWaie /> i human atherosclerotic plaque, Circulation 107. 2829-2836 (2003)]. Synthesis of 5-ethoxycarbonyl-1-phenyl-6-methyl-4-(3-nitrophenyl)-3,4-dihydropyrimidine-2 (1Η)-_ is described in J. Heterocyclic Chem 38, 1051 -4- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1314555 A7 B7 V. Invention description (3) (2001). The pharmacological activity of the compound is not described [invention] The present invention relates to a compound of the following formula (I)

R6 Ο R7 R3 C0, 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、Cr C6-烷基、羥基或Q-Cp烷氧基，其_ 烷基與R6 Ο R7 R3 C0, 5 wherein A represents an aryl or heteroaryl ring; R1, R2 and R3 each independently represent hydrogen 'halogen, nitro, cyano, Cr C6-alkyl, hydroxy or Q-Cp alkoxy Base, its _ 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Ci-Cr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、CrCs-烷氧基 幾基、Ci-C6_稀氧基幾基、經幾基、胺幾基、單-或 二-crc4-烷基胺羰基、C6-C1G-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 15 基，其中Q-CV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、CVC4-烷氧基、 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 1314555 A7 B7 五、發明說明（4) C1-C4-烧氧幾基、經幾基、胺幾基、單-及二-CI-C4-烷基胺羰基、Q-Cr烷基羰胺基、（Q-C4-烷基羰基）-C1-C4-烧胺基、氮基、胺基、单-及二-C1-C4-烧胺 基、雜芳基、雜環基及三-(Q-C6-烷基）-矽烷基之基 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Q-C4-烷基取代； 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、CVC6-烷氧基、Ci-CV烯氧基、 Ci_C6-烧硫基、胺基、单-及二-Ci-C6-烧•胺基、芳胺 10 基、羥羰基、crc6-烷氧羰基及-o-crc4-烷基-o-cr c4-烷基之基團取代； 或 R5 代表胺基； R6 代表氫、Q-CV烷基、甲醯基、胺羰基、單-或二-Cr 15 C4-烧基胺幾基、C3-C8-環烧基幾基、Ci-C6-烧基幾 基、CrCV烷氧羰基、N-(CrC4-烷基磺醯基）-胺羰 基、N-(Ci_C4-烧基續酿基）-N-(Ci_C4-烧基)-胺叛基、 經濟部智慧財產局員工消費合作社印製 雜芳基、雜環基、雜芳基幾基或雜環基叛基，其中The CrC6-alkoxy group may be further substituted by one to three identical or different groups selected from the group consisting of halogen, hydroxyl and Ci-Cr alkoxy; Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative printed R4 represents trifluoromethyl Carbonyl, CrC6-alkylcarbonyl, CrCs-alkoxy, Ci-C6-dioxyoxy, benzyl, amine, mono- or di-crc4-alkylaminecarbonyl, C6-C1G- An arylamine carbonyl, an arylcarbonyl, a heteroarylcarbonyl, a heterocyclic carbonyl, a heteroaryl, a heterocyclic or a cyanyl group, wherein Q-CV alkylcarbonyl, CrC6-alkoxycarbonyl, mono- and di -crc4-alkylamine carbonyl may further be one to three of the same or different selected from the group consisting of c3-c8-cycloalkyl, hydroxy, CVC4-alkoxy, this paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1314555 A7 B7 V. INSTRUCTIONS (4) C1-C4-Alkoxy group, a few groups, an amine group, a mono- and a di-CI-C4-alkylamine carbonyl, Q-Crane Alkylamino group, (Q-C4-alkylcarbonyl)-C1-C4-alkylamine group, nitrogen group, amine group, mono- and di-C1-C4-alkylamine group, heteroaryl group, heterocyclic group and Tri-(Q-C6-alkyl)-decyl group 5 Substituted, and the heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl and heterocyclic groups thereof may be further substituted by Q-C4-alkyl; R5 represents a CrCr alkyl group which may be selected from one to three identical or different Including halogen, hydroxyl, CVC6-alkoxy, Ci-CV alkenyloxy, Ci_C6-sulfanyl, amine, mono- and di-Ci-C6-burning amine, arylamine 10, hydroxycarbonyl, crc6 - alkoxycarbonyl and -o-crc4-alkyl-o-cr c4-alkyl group substituted; or R5 represents an amine group; R6 represents hydrogen, Q-CV alkyl, methionyl, amine carbonyl, mono- Or a di-Cr 15 C4-alkylamine group, a C3-C8-cycloalkyl group, a Ci-C6-alkyl group, a CrCV alkoxycarbonyl group, an N-(CrC4-alkylsulfonyl)-amine Carbonyl, N-(Ci_C4-alkyl-based)-N-(Ci_C4-alkyl)-amine tare, Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperative, printing heteroaryl, heterocyclic, heteroaryl Or a heterocyclic group, where

CrC^-烷基、單-及二-CrCr烷基胺羰基、Cj-Cs-烷基 20 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基、雜芳基、羥基、C!- C4-烷氧基、羥羰基、CrC6-烷氧羰基、胺羰基、單- 及二-Ci-C4-烧基胺幾基、胺基、单-及二-C1-C4-烧胺 基、C1-C4-炫基幾胺基、三-(Ci_C6-烧基)-碎烧基、氰 -6- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X297公釐） 1314555CrC^-alkyl, mono- and di-CrCr alkylamine carbonyl, Cj-Cs-alkyl 20 carbonyl, CrC6-alkoxycarbonyl, heteroaryl and heterocyclic group may be selected from one to three identical or different Including aryl, heteroaryl, hydroxy, C!-C4-alkoxy, hydroxycarbonyl, CrC6-alkoxycarbonyl, amine carbonyl, mono- and di-Ci-C4-alkylamine groups, amine groups, single -and di-C1-C4-Acetylamine, C1-C4-Hexylamino, Tri-(Ci_C6-alkyl)-calcinyl, cyan-6- This paper scale applies to China National Standard (CNS) A4 Specifications (210 X297 mm) 1314555

經濟部智慧財產局員工消費合作社印製 式中 R6A 係選自氩與CrC6-烷基，及 1〇 n 代表整數1或2; 代表鹵素、硝基、氰基、CVC6-烷基、羥基或cvc6- 燒氧基，其中Cl_C6_烷基及CVC6-烷氧基可進一步被 ~至三個相同或不同之選自包括鹵素、羥基及C^-Cr 燒氧基之基團取代； 及 15 γι 2 、Υ、Υ3、Υ4與Υ5各自獨立地代表CH或Ν，其中該 環含有0、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。 2〇 根據本發明之生理上可接受之轉急；κ且森柹夕睡，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R6A is selected from the group consisting of argon and CrC6-alkyl, and 1〇n represents the integer 1 or 2; representing halogen, nitro, cyano, CVC6-alkyl, hydroxy or cvc6. - an alkoxy group, wherein the Cl_C6_alkyl group and the CVC6-alkoxy group may be further substituted with up to three identical or different groups selected from the group consisting of halogen, hydroxy and C^-Cr alkoxy; and 15 γι 2 , Υ, Υ3, Υ4 and Υ5 each independently represent CH or oxime, wherein the ring contains 0, 1 or 2 nitrogen atoms. The compounds according to the invention may also be present in the form of their salts, hydrates and/or solvates. In the present invention, a physiologically acceptable salt is preferred. 2. Physiologically acceptable excursions according to the present invention; κ and 睡, which are usually prepared by reacting compound (I) with an inorganic or organic base or acid conventionally used for this purpose. Non-limiting form of pharmaceutically acceptable salt of compound (1)

本紙張尺度適用中國國家標準(CNS)A4規格（210 X297公嫠） 1314555 A7 B7 五、發明說明（6) 10 經濟部智慧財產局員工消費合作社印製 例包含鹼金屬鹽例如鋰、鉀及鈉鹽、鹼土金屬鹽例如鎂及 鈣鹽、®級銨鹽例如三乙銨鹽、乙酸鹽、苯磺酸鹽、苯甲 酸鹽、二碳酸鹽、二硫酸鹽、二酒石酸鹽、硼酸鹽、溴化 物、破酸鹽、氣化物、棒檬酸鹽、二鹽酸鹽、富馬酸鹽、 葡萄糖酸鹽、麩胺酸鹽、己基收斂酸鹽、氫溴化物、氫氣 化物、羥基萘甲酸鹽、碘化物、羥乙磺酸鹽、乳酸鹽、月 桂酸、蘋果酸鹽、馬來酸鹽、杏仁酸鹽、甲磺酸鹽、曱基 溴化物、曱基硝酸鹽、甲基硫酸鹽、硝酸鹽、油酸鹽、草 酸鹽、稼禍酸鹽、泛酸鹽、鱗酸鹽、二碟酸鹽、聚半乳糖 链酸鹽、柳酸鹽、硬脂酸鹽、硫酸鹽、璩域酸鹽、酒石酸 鹽、對甲苯姐鹽、戊酸鹽、及用於醫藥目的之其他鹽 類。 本發㈣合物或其鹽之錢|為化合物財之化學計 量組成物，例如半-、單_、或二水合物。 15 本發明化合物或其鹽之錢立鱼為化合物與溶劑之化 學計量組成物。 20 本發明包含根據本發明化合物之個別鏡像異構物或非 鏡像異構物及對應消旋物或非鏡像異構型混合物與其各個 鹽類。此外’上述化合物所有可能互變異構形式均涵蓋於 本發明範圍之内。.非鏡像異構型混合物可利用 離 成為個別異構物。消旋物可於對掌相上利用層析法或利^ 解析法析離成為各個鏡像異構物。 於本發明說明書中，降非£ k泰 常具有下繼：’爾取代基通 本紙張尺度適用中國國家標準(CNS)A4 ^(^7297-^¾) A7 B7 經濟部智慧財產局員工消費合作社印數 1314555 i、發明說明（7 ) 通常代表具有1至6個、較佳為！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於例如烷氧基、烷胺基、烷氧羰基及烷氡羰胺基等基團。 迄重A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。 疼基叛基..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 遂座羞代表具有一或二個（獨立地選定之)烷基取代基 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、第三丁胺基、正戊胺基、正己胺基、况沁 二甲胺基、二乙胺基、乙基甲胺基、尽甲基_#· 正丙胺基、異丙基正丙胺基、#_第三丁基_ΛΤ_甲胺 20基、乙基正戊胺基及7V·正己基甲胺基。 _烧基胺羰基代表具有一或二個（獨立地選定之)烷基取 代基之烷基胺羰基，其較佳代表性實例為甲基胺羰基、乙 基胺羰基、正丙基胺羰基、異丙基胺羰基、第三丁基胺羰 基、正戊基胺羰基、正己基胺羰基、况#_二甲基胺羰基、 -9- 本紙張尺度^用中國國家標準(CNS)A4規格（"210 X 297公爱)--------This paper scale applies to China National Standard (CNS) A4 specification (210 X297 public) 1314555 A7 B7 V. Invention description (6) 10 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative prints containing alkali metal salts such as lithium, potassium and sodium Salts, alkaline earth metal salts such as magnesium and calcium salts, ® grade ammonium salts such as triethylammonium salts, acetates, besylate, benzoates, dicarbonates, disulfates, ditartrates, borates, bromine Compound, acid salt, gasification, citrate, dihydrochloride, fumarate, gluconate, glutamate, hexyl astringent, hydrobromide, hydrogen, hydroxynaphthoate , iodide, isethionate, lactate, lauric acid, malate, maleate, mandelate, methanesulfonate, decyl bromide, sulfhydryl nitrate, methyl sulfate, nitric acid Salt, oleate, oxalate, sulphate, pantothenate, sulphate, dimonate, polygalactose, salicylate, stearate, sulphate, sulphate Salt, tartrate, p-toluene salt, valerate, and other salts for medical purposesThe money of the present invention (tetra) or its salt is a chemically compositing composition of the compound, such as a hemi-, mono-, or dihydrate. 15 The compound of the present invention or a salt thereof is a stoichiometric composition of a compound and a solvent. 20 The invention comprises individual mirror image or non-image isomers of the compounds according to the invention and corresponding racemates or non-image areomer mixtures and their respective salts. Furthermore, all possible tautomeric forms of the above compounds are encompassed within the scope of the invention. Non-image-isomeric mixtures can be used as individual isomers. The racemate can be separated into the individual image isomers by chromatography or by analytical methods on the palm phase. In the specification of the present invention, the reduction is not the following: the replacement of the paper is based on the Chinese National Standard (CNS) A4 ^(^7297-^3⁄4) A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative Printing number 1314555 i, invention description (7) usually represents 1 to 6, preferably! A linear or branched hydrocarbon group of up to 4 carbon atoms. Non-limiting examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl 't-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl. The same definition also applies to groups such as alkoxy groups, alkylamino groups, alkoxycarbonyl groups and alkanocarbonylamino groups. Preferred representative examples of the weight A are methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentyloxy and n-hexyloxy. It is generally a linear or branched hydrocarbon group having from 1 to 6, preferably from 1 to 4 carbon atoms, having a carbonyl functionality at the point of attachment. 10 Non-limiting examples thereof include a decyl group, an ethyl fluorenyl group, a n-propyl fluorenyl group, a n-butyl fluorenyl group, an isobutyl fluorenyl group, a trimethyl acetyl group, a n-hexyl group. Preferred representative examples up to this are methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl and n-hexyloxycarbonyl. 15 羞 羞 represents an alkylamine group having one or two (independently selected) alkyl substituents, preferably a representative example of which is methylamino, ethylamino, n-propylamino, isopropylamino, third Amino, n-pentylamino, n-hexylamino, dimethylamino, diethylamino, ethylmethylamino, methyl _#· n-propylamino, isopropyl n-propylamine, #_第Tributyl-hydrazine-methylamine 20-base, ethyl-n-pentylamino group and 7V·n-hexylmethylamino group. The alkylaminocarbonyl group represents an alkylamine carbonyl group having one or two (independently selected) alkyl substituents, and preferred representative examples thereof are methylaminecarbonyl, ethylaminecarbonyl, n-propylaminecarbonyl, Isopropylaminecarbonyl, tert-butylaminecarbonyl, n-pentylaminecarbonyl, n-hexylaminecarbonyl, ## dimethylaminecarbonyl, -9- This paper scale ^ uses Chinese National Standard (CNS) A4 specification ( "210 X 297 public love) --------

1314555 B7 五·、發明說明（Ο 况二乙基胺羰基、JV-乙基-iV-曱基胺羰基、曱基^正 丙基胺羰基、W異丙基-AL正丙基胺羰基、#_第三丁基 甲基胺羰基、，乙基-vV-正戊基胺羰基及正己基•甲基 胺羰基。 土 5 _燒基項..鱗基通常代表具有1至6個、較佳為1至4個 碳原子，於連接位置具磺醯基官能度之直鏈或分支鏈烴基 團。其非限制性實例包含曱基磺醯基、乙基磺醯基、正丙 基磺醯基、異丙基磺醯基、正丁基磺醯基、第三丁基磺醯 基。 1〇 星座羞通常代表具有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^ 基、環戊基、環己基及環庚基。 芳基就，其本身-及於芳羰基乞代表具有6至u個碳 子之單-至二環芳族碳環基團，其較佳代表性實例二 15 基、萘基及啡基(phenanthrenyl) 本 經濟部智慧財產局員工消費合作社印數 趣_芳棊就其本身及於雜关其雜早中产^通:丨从 ° 10個’較佳為5或6個環原子及多達5個及較鮮5至 個選自包括S、0及N的雜原子之芳族單_或 2〇其較佳代表性實例為嗟吩基、料基、鱗基、嗟ς ’ ^基、咪唾基、吟二絲、紅絲、_基、=1314555 B7 V. INSTRUCTION DESCRIPTION (DETERMINATION OF ETHYLENE ETHYLENE carbonyl, JV-Ethyl-iV-decylaminecarbonyl, decyl-n-propylaminecarbonyl, W-isopropyl-AL-propylaminecarbonyl, # _ tert-butylmethylamine carbonyl, ethyl-vV-n-pentylamine carbonyl and n-hexyl-methylamine carbonyl. Soil 5 _ burning base term: squaring usually represents 1 to 6, preferably 1 a linear or branched hydrocarbon group having a sulfonyl functionality at a linking position to 4 carbon atoms. Non-limiting examples of which include a mercaptosulfonyl group, an ethylsulfonyl group, a n-propylsulfonyl group, and a different Propylsulfonyl, n-butylsulfonyl, tert-butylsulfonyl. 1〇 Constellation usually represents a cyclic saturated hydrocarbon group having 3 to 8, preferably 3 to 6 carbon atoms. Non-limiting examples include cyclopropyl, cycloalkyl, cyclopentyl, cyclohexyl and cycloheptyl. Aryl, by itself - and arylcarbonyl represents uni to bicyclic having 6 to u carbons. Aromatic carbocyclic group, preferably a representative example of a hexyl group, a naphthyl group, and a phenanthrenyl. The Intellectual Property Office of the Ministry of Economic Affairs, the employee consumption cooperative, prints the number of interesting _ 棊 棊Miscellaneous miscellaneous and intermediate production ^ Tong: 丨 from ° 10 'preferably 5 or 6 ring atoms and up to 5 and fresher 5 to an aromatic single selected from hetero atoms including S, 0 and N Preferred examples of _ or 2 嗟 are porphinyl, sulfenyl, fluorenyl, 嗟ς '^, propyl, stilbene, red silk, _ base, =

基、塔m絲“引嗤基、笨并対基、苯并硫苯 基、苯并噻唑基、喹啉基、異喹啉基。 L 輕讀似祕㈣料吩_基、 -10- 經濟部智慧財產局員工消費合作社印製 1314555 A7 __ B7 五、發明說明（9) 羰基、咕咯基羰基、噻唑基羰基、畤唑基羰基、咪唑基羰 基、扯啶基羰基、嘧啶基羰基、嗒畊基羰基、吲哚基羰 基、吲唑基羰基、苯并呋喃基羰基、苯并硫苯基羰基、喳 琳基羰基、異喹琳基羰基。 5 雜環基.毯其本身^^環基羰某中代表通常具右4 g 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-或雙環之非芳族雜環基團。該雜 環基團可為飽和或部分不飽和。較佳者為具有多達2個選 10自包括〇、N及S的雜原子之5至8員單環飽和雜環基 團，其較佳代表性實例為四氫呋喃_2_基、β比咯咬•基、 吡咯啶-2-基、吡咯啶基、吡咯啉基、裱啶基、嗎啉 基、全氫吖庚因基。 麵顧A之較佳代表性實例為四纽喃_2_叛基、 15比洛疋_1_幾基、°比嘻°^-2-幾基、吡咯咬_3_幾基、吡咯啉 幾基、娘錢基、嗎賴基、全氣α丫庚因叛基。 直复代表氟、氣、溴及碘。 於 Y4 ^ £L之敘述中， 區亦代表被取代基R3或R7取代之環碳原子。 20 $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)之化合 物，其中 A 代表芳基或雜芳環； R R與R各自獨立地代表氫、由素、頌基、氛基、 -11-Base, tower m wire "inducing sulfhydryl, stupid and fluorenyl, benzothiophenyl, benzothiazolyl, quinolyl, isoquinolinyl. L light reading like secret (four) material pheno-based, -10- economy Ministry of Intellectual Property, Staff Consumer Cooperatives, Printing 1314555 A7 __ B7 V. INSTRUCTIONS (9) Carbonyl, fluorenylcarbonyl, thiazolylcarbonyl, oxazolylcarbonyl, imidazolylcarbonyl, pyridinecarbonyl, pyrimidinylcarbonyl, hydrazine Plowing carbonyl, mercaptocarbonyl, carbazolylcarbonyl, benzofuranylcarbonyl, benzothiophenylcarbonyl, fluorenylcarbonyl, isoquinolinylcarbonyl. 5 heterocyclyl. blanket itself ^^ ring group The representative of carbonyl usually has 4 g 10, preferably 5 to 8 ring atoms, and up to 3, preferably up to 2 hetero atoms selected from N, 〇, S, SO and S〇2. And/or a mono- or polycyclic ring of a hetero group, preferably a mono- or bicyclic non-aromatic heterocyclic group. The heterocyclic group may be saturated or partially unsaturated. Preferably, it has up to 2 5 to 8 membered monocyclic saturated heterocyclic groups including hetero atoms of hydrazine, N and S, and preferred representative examples thereof are tetrahydrofuran-2-yl, β specific octyl group, pyrrolidine-2 -base , pyrrolidinyl, pyrrolinyl, acridinyl, morpholinyl, perhydroazepine. A preferred representative example of A is tetraam-2-repo, 15 piroxime_1_ a few bases, ° than 嘻 ° ^ -2- groups, pyrrole bites _3_ several groups, pyrroline groups, Niang Qianji, yahyl, all gas α 丫 因 叛 。 。 。 。 。 。 。 。 。 , bromine and iodine. In the description of Y4 ^ £L, the region also represents a ring carbon atom substituted by a substituent R3 or R7. The symbol of the 20 $ort bond represents a point of attachment in the molecule. In the present invention, the invention relates to a compound of the formula (I), wherein A represents an aryl or heteroaryl ring; and RR and R each independently represent hydrogen, a fluorenyl group, a fluorenyl group, an aryl group, -11-

經濟部智慧財產局員工消費合作社印製 1314555 五、發明說明（10 ) c：6·烷基、羥基或CrC6·烷氧基，其中Ci_c^烷基與 Q-C6-烷氧基可進一步被一至三個相同或不同之選自 包括齒素、羥基及Ci-Cr烷氧基之基團取代； R4代表CrG-烷基羰基、CVC6·烷氧基羰基、Ci_C6_烯 5 氧基羰基、羥羰基、胺羰基、單-或二-CVC4-燒基胺 羰基、C6-C1Q-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Cl_C6_烷基羰基、 CrCV烷氧基羰基、單-及二·<：1_(：4_烷基胺羰基可進 一步被一至二個相同或不同之選自包括C3-C8-環烧 10 基、羥基、C1-C4·烷氧基、CrCV烷氧羰基、羥羰 基、胺幾基、單-及二-Ci-C4-烧基胺幾基、q-Cr烧 基羰胺基、胺基、單-及二-C^C：4-烧胺基、雜芳基、 雜環基及三-(Ci-C6·烧基)-矽烷基之基團取代； R5代表CrCr烷基，其可被一至三個相同或不同之選 15 自包括_素、羥基、Q-CV烷氧基、Ci-C6-烯氧基、Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 1314555 V. Description of Invention (10) c: 6 · Alkyl, hydroxy or CrC6·alkoxy, wherein Ci_c^alkyl and Q-C6-alkoxy can be further Three identical or different substituents selected from the group consisting of dentate, hydroxyl and Ci-Cr alkoxy; R4 represents CrG-alkylcarbonyl, CVC6. alkoxycarbonyl, Ci_C6-ene 5-oxycarbonyl, hydroxycarbonyl , amine carbonyl, mono- or di-CVC 4-alkylamine carbonyl, C6-C1Q-arylamine carbonyl, heteroarylcarbonyl, heterocyclylcarbonyl 'heteroaryl, heterocyclyl or cyano, wherein Cl_C6-alkane a carbonyl group, a CrCV alkoxycarbonyl group, a mono- and a bis-<:1_(:4-alkylamine carbonyl group may further be one or two identical or different selected from the group consisting of a C3-C8-cyclic alkyl group, a hydroxyl group, C1-C4·alkoxy, CrCV alkoxycarbonyl, hydroxycarbonyl, amine, mono- and di-Ci-C4-alkylamine, q-Cr alkylcarbonyl, amine, mono- and Substituted with a group of 2-C^C: 4-alkali, heteroaryl, heterocyclic and tris-(Ci-C6.alkyl)-decyl; R5 represents a CrCr alkyl group which may be one to three Same or different choices 15 from _ Hydroxy, Q-CV-alkoxy, Ci-C6- alkenyloxy,

Ci-C：6·院硫基、胺基、單-及二-CVC6-烧胺基、芳胺 基、羥羰基、CVC6-烷氧羰基及-0-CrC4-烷基-0-CV C4-烧基之基團取代； 或 20 R5 代表胺基； R6 代表氫、CrC6-烷基、甲醯基、胺羰基、單-或二-Cr C4-烷基胺羰基、C3-C8-環烷基羰基、CrC6-烷基羰 基、Ci_C6-统氧幾基、N-(Ci-C4·烧基績酿基）-胺幾 基、NKCrCV烷基磺醯基)-N-(CrC4-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）Ci-C: 6·院thio, amine, mono- and di-CVC6-alcoholyl, arylamino, hydroxycarbonyl, CVC6-alkoxycarbonyl and -0-CrC4-alkyl-0-CV C4- Substituted by a group of a burnt group; or 20 R5 represents an amine group; R6 represents hydrogen, CrC6-alkyl, formamyl, aminecarbonyl, mono- or di-Cr C4-alkylaminecarbonyl, C3-C8-cycloalkyl Carbonyl group, CrC6-alkylcarbonyl group, Ci_C6-oxyl group, N-(Ci-C4·alkyl base)-amine group, NKCrCV alkylsulfonyl)-N-(CrC4-alkyl)- Amine carbonyl, • 12- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)

1314555 A7 B7 五、發明說明（11) 雜芳基、雜環基、雜芳基幾基或雜環基幾基，其中 CrC6-烷基、單-及二-Q-Q-烷基胺羰基、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基、雜芳基、羥基、Q-5 C4-烷氧基、羥羰基、CrC6-烷氧羰基、胺羰基、單- 及二-C1-C4-烧基胺幾基、胺基、早-及二-C1-C4-烧胺 基、C1-C4-娱1基幾胺基、三-(Ci_C6-烧基)-碎烧基、氰 基、N-(早-及二-C1-C4-烧胺基-C1-C4-烧基)-胺幾基' N-(Ci-C4-烧氧基-C1-C4-烧基)-胺幾基及鹵素之基團取 10 代； 或 R6 代表具下式之基團 經濟部智慧財產局員工消費合作社印製 1 式中 15 R6A 係選自氫與CVC6-烷基，及 η 代表整數1或2 ; R7 代表鹵素、硝基、氰基、CVCV烷基、羥基或CkQ-烷氧基，其中CrC6-烷基及Ci-CV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CrCr 20 烷氧基之基團取代； 及 Υ1、Y2、Y3、Υ4與Υ5各自獨立地代表CH或N，其中該 -13- 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 1314555 Α7 Β7 五、發明說明（12) 環含有〇、1或2個氣原子。 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、萘基或吼啶基環； 5 R1、R2與R3各自獨立地代表氫、氟、氣、溴、硝基、氰 基、甲基、乙基、三氟甲基或三氟甲氧基； R4 代表Q-CV烷基羰基、Q-C6-烷氧基羰基、羥羰基、 胺羰基、單-Q-Cr烷基胺羰基或氰基，其中CrC6-烷 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、羥 基、CrC4-烷氧基、CrC4-烷氧羰基、胺基、單-及 二-CrCV烷胺基、雜芳基及雜環基之基團取代； R5 代表甲基或乙基； R6 代表氫、CrC6-烷基、單-或二-Ci-Cr烷基胺羰基、 15 Q-C6-烷基羰基、Q-C6-烷氧羰基或雜環基羰基，其 中CrC6-烷基及CVC6-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、Ci-Cr烷氧基、羥羰 基、Ci_C6-烧氧Μ基、胺叛基、单-及二-C1-C4-院基 胺幾基、氰基、胺基、單-及二-C1-C4-烧胺基之基團 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）1314555 A7 B7 V. INSTRUCTIONS (11) Heteroaryl, heterocyclic, heteroaryl or heterocyclic, wherein CrC6-alkyl, mono- and di-QQ-alkylamine carbonyl, CrC6- The alkylcarbonyl group, the CrC6-alkoxycarbonyl group, the heteroaryl group and the heterocyclic group may be the same or different one to three selected from the group consisting of an aryl group, a heteroaryl group, a hydroxyl group, a Q-5 C4-alkoxy group, a hydroxycarbonyl group, CrC6-alkoxycarbonyl, amine carbonyl, mono- and di-C1-C4-alkylamine groups, amine groups, early- and di-C1-C4-aramidyl groups, C1-C4-iso 1 ylamino groups , tri-(Ci_C6-alkyl)-calcinyl, cyano, N-(early- and di-C1-C4-Acryl-C1-C4-alkyl)-amine-based N-(Ci- C4-alkoxy-C1-C4-alkyl)-amine group and halogen group take 10 generations; or R6 represents a group with the following formula: Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed in the formula 15 R6A Is selected from hydrogen and CVC6-alkyl, and η represents an integer of 1 or 2; R7 represents halogen, nitro, cyano, CVCV alkyl, hydroxy or CkQ-alkoxy, wherein CrC6-alkyl and Ci-Cv alkane The oxy group may be further substituted by one to three identical or different groups selected from the group consisting of halogen, hydroxy and CrCr 20 alkoxy groups. And Υ1, Y2, Y3, Υ4 and Υ5 each independently represent CH or N, where the -13- paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative Printed 1314555 Α7 Β7 V. Description of the invention (12) The ring contains 〇, 1 or 2 gas atoms. In another embodiment, the invention relates to compounds of formula (I), wherein A represents phenyl, naphthyl or acridinyl ring; 5 R1, R2 and R3 each independently represent hydrogen, fluorine, gas, bromine , nitro, cyano, methyl, ethyl, trifluoromethyl or trifluoromethoxy; R4 represents Q-CV alkylcarbonyl, Q-C6-alkoxycarbonyl, hydroxycarbonyl, amine carbonyl, mono- Q-Cr alkylamine carbonyl or cyano group, wherein CrC6-alkylcarbonyl, CrC6-alkoxycarbonyl and mono-CrC4-alkylaminecarbonyl can be one to three identical or different selected from the group consisting of c3-c8- a group substituted with a cycloalkyl group, a hydroxyl group, a CrC4-alkoxy group, a CrC4-alkoxycarbonyl group, an amine group, a mono- and di-CrCV alkylamino group, a heteroaryl group and a heterocyclic group; R5 represents a methyl group or an ethyl group R6 represents hydrogen, CrC6-alkyl, mono- or di-Ci-Cr alkylamine carbonyl, 15 Q-C6-alkylcarbonyl, Q-C6-alkoxycarbonyl or heterocyclylcarbonyl, wherein CrC6-alkyl And CVC6-alkoxycarbonyl may be one to three the same or different selected from the group consisting of heteroaryl, hydroxy, Ci-Cr alkoxy, hydroxycarbonyl, Ci_C6-pyroxyl, amine tracing, mono- and di- C1-C4-homoamine group, cyano group, a group of mono-, mono-, and di-C1-C4-alkylamine groups; or R6 represents a group of the formula:-14- This paper scale applies to 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 1314555 A7 B7 五、發明說明（13) 、认〇> * 式中 R6A 係選自氫與CVC4-烷基，及 η 代表整數1或2 ; 5 R7 代表鹵素、硝基、氰基、三氟曱基、三氟甲氧基、 甲基或乙基； 及 Υ1、Υ2、Υ3、Υ4 與 Υ5 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 Α 代表苯基或°比啶基環； R1與R3各自代表氫； R2 代表氟、氯、溴、硝基或氰基； R4 代表氰基、CrC4-烷基羰基或Q-CV烷氧基羰基，其 15 中CrC4-烷氧基羰基可被選自包括羥基、CkCV烷氧 基、CrCr烷氧羰基、單-及二-CrCr烷胺基、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-CrCr烷基胺羰基、 20 CrCV烷基羰基或CVC4-烷氧羰基，其中CrC4-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）Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Cooperatives, Printing 1314555 A7 B7 V. INSTRUCTIONS (13), 〇 〇 * * where R6A is selected from hydrogen and CVC4-alkyl, and η represents an integer of 1 or 2; 5 R7 represents Halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, methyl or ethyl; and Υ1, Υ2, Υ3, Υ4 and Υ5 each represent CH. In another embodiment, the invention relates to a compound of formula (I) wherein Α represents phenyl or pyridine ring; R1 and R3 each represent hydrogen; R2 represents fluoro, chloro, bromo, nitro Or cyano; R4 represents cyano, CrC4-alkylcarbonyl or Q-CV alkoxycarbonyl, wherein 15 CrC4-alkoxycarbonyl can be selected from the group consisting of hydroxyl, CkCV alkoxy, CrCr alkoxycarbonyl, single And a group of a di-CrCr alkylamino group, a heteroaryl group and a heterocyclic group; R5 represents a methyl group; R6 represents hydrogen, CrC4-alkyl, mono- or di-CrCr alkylamine carbonyl, 20 CrCV alkyl A carbonyl group or a CVC4-alkoxycarbonyl group, wherein the CrC4-alkyl group and the CrC4-alkoxycarbonyl group are selected from the group consisting of heteroaryl groups, hydroxyl groups, Cr C4-alkoxy groups, hydroxycarbonyl groups, amine carbonyl groups, mono- and di-CrC4- Alkylamine-15- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm)

1314555 A7 B7 五、發明說明（14 ) 壤基、胺基、早-及二-C1-C4-烧胺基之基團取代， 或 R6 代表具下式之基團1314555 A7 B7 V. INSTRUCTIONS (14) Substituents of soil, amine, early- and di-C1-C4-alkaline groups, 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 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⑴之化合 物，其中A為苯基或π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。 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Α為苯基或。比啶基者， •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（I)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CrCV烷氧羰基，尤 其是2-羥基乙氧羰基者；或其中R4為q-CV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現格（210 X 297公釐） 1314555 A7 B7 五、發明說明（15) 於另一具體實例中 物，其中R5為甲基者。 於另一具體實例中 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（I)之化合 本發明係有關根據式（I)之化合 物 本發明係有關根據式（I)之化合 其中R7為三氟甲基或硝基者，尤其是相對於中心二 氫嘧啶酮環，R7為間位三氟甲基者。 於另一具體實例中，本發明係有關具下式(IA)之化合 物 10Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, where R6A is selected from hydrogen and methyl, R7 represents trifluoromethyl or nitro; and γ1, γ2, γ3, γ4 and γ5 each represent CH. In another embodiment, the invention relates to a compound according to formula (1) wherein A is phenyl or π is a bite base. In another embodiment, the invention relates to a compound according to formula (I) wherein R1 is hydrogen. In another embodiment, the invention relates to a compound according to formula (I), wherein R2 is cyano, especially wherein hydrazine is phenyl or. For the cyano group, and for the central dihydropyrimidinone ring, R2 is the para-cyano group. In another embodiment, the invention relates to a compound according to formula (I) wherein R3 is hydrogen. In another embodiment, the invention relates to a compound according to formula (1), wherein R4 is a CrCV alkoxycarbonyl group optionally substituted by a hydroxy group, especially a 2-hydroxyethoxycarbonyl group; or wherein R4 is q-CV Alkylcarbonyl, especially methylcarbonyl. -16- This paper scale applies to China National Standard (CNS) A4 (210 X 297 mm) 1314555 A7 B7 V. Inventive Note (15) In another specific example, where R5 is methyl. In another embodiment, wherein R6 is hydrogen. 5 In another embodiment, the invention relates to a compound according to formula (I). The invention relates to a compound according to formula (I). The invention relates to a compound according to formula (I) wherein R7 is trifluoromethyl or nitro In particular, relative to the central dihydropyrimidinone ring, R7 is a meta-trifluoromethyl group. In another embodiment, the invention relates to a compound having the following formula (IA) 10

(IA), 經濟部智慧財產局員工消費合作社印製 式中 Z 代表CH或N ;及 R1、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） 1314555 A7 B7 五、發明說明（16 )(IA), Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative printing system where Z stands for CH or N; and R1, R3, R4 and R6 have the meaning indicated above. The compound of the present invention wherein R6 is hydrogen can be enolized to the corresponding hydroxy hydrazine 15 class: -17· The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1314555 A7 B7 V. Invention Description (16)

CHO 經濟部智慧財產局員工消費合作社印製 m 式（I)化合物之合成可利用使具下式（II)之化合物 (Π) 式中 A'R1與R2具有上文指示之意義； 與具下式（III)之化合物The synthesis of the compound of formula (I) can be obtained by the CHO Ministry of Commerce, Intellectual Property Office, and the Consumer Cooperative. The compound of formula (II) can be used to have the meaning of A'R1 and R2 in the above formula; Compound of formula (III)

'0 式中 R4與R5具有上文指示之意義； 10 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） 1314555 經濟部智慧財產局員工消費合作杜印製 五、發明說明（I7 nh2 HN人。R0 and R5 have the meanings indicated above; 10 and compound -18 with the following formula (IV) - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1314555 Ministry of Economics Property Bureau staff consumption cooperation Du printing system five, invention description (I7 nh2 HN people.

Yj^Y5 -R7 (IV) 10 R3" 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 -R7 (IV) 10 R3" wherein R3, R7, and Y1 to Y5 have the meanings indicated above; in the presence of an acid, in a three component/one step reaction, or a continuous reaction to give the following formula (IB) Compound

FF

R7 R3 OB)， 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R7 R3 OB), wherein A, R1 to R5, R7, and Y1 to Y5 have the meanings indicated above. Subsequent to the compound of formula (IB) and a compound of the following formula (V)

R6*-X (V) 式中 R6t具有如上文R6指示之意義，惟不代表氫.；及 X 代表釋離基，例如鹵素、對甲苯磺醯基、甲磺醯基或硫酸 根； -19-R6*-X (V) wherein R6t has the meaning indicated by R6 above, but does not represent hydrogen; and X represents a cleavage group such as halogen, p-toluenesulfonyl, methanesulfonyl or sulfate; -

本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 1314555 五、發明說明（IS) 於鹼存在下進行反應。 式⑴化合物中’ r4代表氰基、r5代表胺基及r6代表 氫者，可替代地利用使式(II)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) + (niV(VI) + (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、異丙酿、1，2-二甲氧乙烧、二嘮貌或四氫咬哮、 乙酸乙酯、丙嗣、乙腈、二甲亞颯、二曱基甲醯胺、或醇 類例如甲醇、乙醇、正丙醇、異丙醇、正丁醇或第三丁 醇、或烴例如戊院、己院、環己院、苯、甲苯或二甲苯、 或鹵基烴例如二氯甲烷、二氣乙烷、三氣甲烷或氣苯β亦 15可使用前述溶劑之混合物。此程序之較佳溶劑為四氫呋 喃0 經濟部智慧財產局員工消費合作社印製 適用於（II) + (IIIWVI) + (IV) _ (ΙΒ)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、 續酸例如甲橫酸或對甲苯績酸、鹽酸或魏類例如多鱗酸 20類，較佳者為多磷酸乙酯。所用酸之量相對於丨莫耳式 (III)化合物為0·25莫耳至1〇〇莫耳。 此程序通常於+2(rCM15(rc，較佳為十紙至侧 °c之溫度範圍内進行。 -20- 1314555 五、發明說明（19 Α7 Β7 經濟部智慧財產局員工消費合作社印製 此程序通冑於讀下 下（例如，在0.5至s P # 然而，亦可於加壓或減壓 5巴範圍内）谁仁 適用於（IB) + (v )進仃。 下不發生變彳b之習知右 程序之溶㈣於反應條件 醚、u-二甲氧乙户—溶劑’包括醚類例如乙醚、異丙 酮 '乙腈、二甲亞二：;:或四氣咬喃、乙酸乙醋、丙 烷、環己烧、笨、甲笼:基甲酿胺、或烴例如戊烧、己 ^ λ - %7 ^ _ 或一甲笨、或鹵基烴例如二氣甲 広一氣甲烷或氣苯。亦可使用前述溶劑之混 合物。此程序之較佳溶 適用於（IB) + ; _ z, 5 (1)程序之驗為一般無機或有 機鹼，較好包切_或倾，Ν·4胺基”比 咬或(C^C4)—燒胺例如三乙胺或二異丙基乙胺、或氮 化物例如氫化納’較佳者為氣化納。所用驗之量相對於^ 莫耳式_匕合物為〇」莫耳至1〇莫耳，較佳為i莫耳 15至3莫耳。 此程序通常於〇t>C至+ 150X：，較佳為+2(TC至+8(TC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(νϊ)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： 10 20 -21- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm). 1314555 V. Inventive Note (IS) The reaction is carried out in the presence of a base. In the compound of the formula (1), 'r4 represents a cyano group, r5 represents an amine group, and r6 represents hydrogen. Alternatively, a compound of the formula (II) and a compound of the formula (IV) and a compound of the following formula (VI) 5 nc-ch2- may be used. Cn (VI) is prepared in the presence of an acid in a three-component/one-step reaction' or a continuous reaction. The solvent suitable for the (II) + (niV(VI) + (IV) - (IB) procedure is a conventional organic solvent which does not change under the reaction conditions, including ethers such as diethyl ether, isopropyl alcohol, 1, 2 -Dimethoxyethane, diterpene or tetrahydroteranol, ethyl acetate, propanil, acetonitrile, dimethyl hydrazine, dimercaptocaramine, or alcohols such as methanol, ethanol, n-propanol, iso Propyl alcohol, n-butanol or tert-butanol, or hydrocarbons such as pentylene, hexa, cyclohexyl, benzene, toluene or xylene, or halogenated hydrocarbons such as dichloromethane, di-ethane, tri-methane or A mixture of the above solvents may be used for the gas benzene β. The preferred solvent for this procedure is tetrahydrofuran. 0 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed for (II) + (IIIWVI) + (IV) _ (ΙΒ) Procedure The acid is a general inorganic or organic acid, preferably comprising a carboxylic acid such as acetic acid or trifluoroacetic acid, a continuous acid such as metoponic acid or p-toluic acid, hydrochloric acid or a class of Wei such as polyphosphate, preferably B. The amount of acid used is from 0. 25 moles to 1 mole per mole of the compound of the formula (III). This procedure is usually at +2 (rCM1). 5 (rc, preferably in the temperature range of ten paper to side °c. -20- 1314555 V. Invention description (19 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed this procedure wanted to read the next ( For example, in the range of 0.5 to s P # However, it can also be applied to (IB) + (v) in the range of 5 bar under pressure or decompression. The dissolution of the conventional right program does not occur. (d) in the reaction conditions ether, u-dimethoxy-household - solvent 'including ethers such as diethyl ether, iso-acetone' acetonitrile, dimethyl bis:: or four gas urethane, ethyl acetate, propane, cyclohexane, Stupid, cage: base amine, or hydrocarbons such as pentane, λ - %7 ^ _ or a phenyl group, or a halogenated hydrocarbon such as dimethyl hydrazine monomethane or gas benzene. The above solvents can also be used. Mixture. The best solubility of this procedure applies to (IB) + ; _ z, 5 (1) The procedure is generally inorganic or organic, preferably _ or pour, Ν · 4 amine" than bite or ( C^C4) - a burnt amine such as triethylamine or diisopropylethylamine, or a nitride such as sodium hydride, preferably a gasified sodium. The amount used is relative to the mole-type chelating compound. " Mohr to 1 〇 mole, preferably i mole 15 to 3 moles. This procedure is usually carried out in the temperature range of 〇t > C to + 150X:, preferably +2 (TC to +8 (TC) This procedure is usually carried out under normal pressure, however, it can also be carried out under pressure or reduced pressure (for example, in the range of 0-5 to 5 bar). (II), (III), (IV), (v) The (νϊ) compound is known per se or can be prepared by a conventional method. The above method can be illustrated by the following reaction scheme: 10 20 -21- This paper scale is applicable to the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm)

4 訂4 order

1314555 at I ------ B7 五、發明說明（20) R21314555 at I ------ B7 V. Description of invention (20) R2

根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 令人驚奇地，本發明化合物顯示人類嗜中性白血球彈 經濟部智慧財產局員工消費合作社印製 性蛋白酶(HNE)抑制活性，因此適用於製備供治療與厕£ 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、 10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)及心職衰蝎形 15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)、開心贜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公釐） A7 B7 1314555 五、發明說明（2i) 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、牛皮癬、全身性紅斑狼瘡、大皰性類天跑 5 瘡、敗血症、酒精性肝炎、肝纖維化、貝赛特氏症 (Behcet’s disease) '過敏性黴菌型鼻竇炎、過敏性鼻寶 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， 經濟部智慧財產局員工消費合作社印製 可以適當方式予以施用，例如經口、非經腸、經肺、經 鼻、舌下、經舌、經頰、經直腸、經皮、經結膜、經耳或 呈植入物投與。 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 改良形式之施用形式，例如錠劑（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- 本紙張尺度適用宁國國家標準(CNS)A4規格（210x297公釐) ~ A7 B7 1314555 五、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、 心臟内、椎管内或腰髓内）或包含吸收步驟（經肌内、皮 下、皮内、經皮或經腹膜内）而進行。有用的非經腸施用 形式包含呈溶液、懸浮液、乳液、冷凍乾燥物及無菌粉劑 5 形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藥形式 (包括粉劑吸入劑、喷霧劑）、鼻滴劑/溶液、喷霧液；供經 舌、舌下或經頰投與之錠劑或膠囊、栓劑、耳及眼製劑、 陰道膠囊、水性懸浮液(外㈣水、振盡混合物）、親脂性 10懸浮液、軟膏、霜齊！、乳汁、糊劑、細粉劑或植入物。 活性成分可以本質上已知之方法轉化成前述施用形 式，此係使用惰性無毒、醫藥上適當之賦形劑予以進行。 彼等賦形劑包括載劑（例如微晶纖維素）、溶劑（例如液態 聚乙二醇類）、乳化劑（例如十二基硫酸鈉）、分散劑（例如 15聚乙烯吡咯啶酮）、合成及天然生物性聚合物（例如白蛋 白）、安U(例如抗氧化劑如抗壞血酸）、著色劑（例如無 機色素如氧化鐵類）或味道及/或氣味矯正劑。 經濟部智慧財產局員工消費合作社印製 供人類用途時’於經口投與情形下，適當之投與劑量 約㈣01至50毫克/公斤，較佳0.01毫克/公斤至2〇毫克/ 20公斤。於非經腸投與（例如靜脈内或經鼻、經頰或吸入等 經由黏膜投與)情形下，適當之投_量為Q顧毫克/公 .斤至〇,5毫克/公斤。 儘管如此，於特定情形下，可能需要偏離上述劑量， 亦即取決於體重、施職徑、對活性成分之個別行為反 -24- 314555The compounds according to the present invention have unpredictable, useful pharmacological and pharmacokinetic activity profiles and are therefore useful as pharmaceutical agents for the treatment and/or prevention of diseases in humans and animals. 5 Surprisingly, the compounds of the present invention show that the Human Neutrophil White Blood Bomb Economics Intellectual Property Office employee consumption cooperative printed protease (HNE) inhibitory activity is therefore suitable for the preparation of a medicament for the treatment of diseases related to the activity of the toilet, and Provides effective treatment for the following diseases: acute and chronic inflammation, such as rheumatoid arthritis, arteriosclerosis, especially acute, and chronic lung diseases such as pulmonary fibrosis, cystic fibrosis, pneumonia, 10 acute respiratory distress syndrome ( ARDS), especially emphysema (including smoking-induced emphysema), and chronic obstructive pulmonary disease (C0PD), chronic bronchitis and bronchiectasis. The compound of the present invention can further provide cardiovascular ischemic diseases such as acute coronary syndrome, acute myocardial infarction, unstable and stable angina pectoral coronary artery bypass graft (CABG), and 15% of heart failure, arteriosclerosis, and second Valvular disease, atrial septal defect, coronary artery balloon dilatation (PTCA), inflammation after sputum surgery and pulmonary artery -22- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) A7 B7 1314555 V. INSTRUCTIONS (2i) Effective treatment of pressure; and proved to be useful in rheumatoid arthritis, acute inflammatory arthritis, cancer, acute pancreatitis, ulcerative colitis, periodontal disease, Qiuli-Shi Shou Chry-Strauss syndrome, acute and chronic atopic dermatitis, psoriasis, systemic lupus erythematosus, bullous genital 5 sores, sepsis, alcoholic hepatitis, liver fibrosis, Behcet's Disease) 'Allergic fungal sinusitis, allergic rhinitis, Crohn's disease, Kawasaki disease, renal glomerulonephritis, acute Pyelonephritis, colorectal diseases, chronic suppurative otitis media, chronic venous leg ulcers, inflammatory bowel disease 10, bacterial and viral infections, brain trauma, stroke and effective treatment involving white blood neutrophil participation of the associated symptoms. The invention further provides a pharmaceutical agent comprising at least one compound according to the invention, preferably one or more pharmaceutically safe excipients or carrier materials, and the use thereof as the above object. 15 The active ingredient has a systemic and/or local effect. To achieve this goal, the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing can be applied in an appropriate manner, such as oral, parenteral, transpulmonary, nasal, sublingual, translingual, buccal, rectal, transdermal, Conjunctiva, ear or implant. For their route of administration, the active ingredient may be administered in a suitable form. Useful oral administration forms include rapid release of the active ingredient and/or application forms in modified form, such as lozenges (uncoated lozenges and coated lozenges such as enteric coatings), capsules, dragees, granules, pills , powders, emulsions, suspensions, solutions and aerosols. -23- This paper scale applies to National Standard (CNS) A4 (210x297 mm) ~ A7 B7 1314555. V. Description of invention (22) Parenteral administration can avoid the absorption step (intravenous, intra-arterial, Intracardiac, intraspinal or intrathoracic) or including an absorption step (either intramuscularly, subcutaneously, intradermally, transdermally or intraperitoneally). Useful parenteral administration forms include injection and injectable preparations in the form of solutions, suspensions, emulsions, lyophilizates, and sterile powders. Forms suitable for other routes of administration include, for example, inhaled pharmaceutical forms (including powder inhalers, sprays), nasal drops/solutions, sprays; tablets or capsules for translingual, sublingual or buccal administration. , suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (external (four) water, vibrating mixture), lipophilic 10 suspensions, ointments, creams! , milk, paste, fine powder or implants. The active ingredient can be converted into the aforementioned forms of administration by methods known per se, using inert, non-toxic, pharmaceutically suitable excipients. These excipients include carriers (eg microcrystalline cellulose), solvents (eg liquid polyethylene glycols), emulsifiers (eg sodium dodecyl sulfate), dispersants (eg 15 polyvinylpyrrolidone), Synthetic and natural biopolymers (such as albumin), An U (such as antioxidants such as ascorbic acid), colorants (such as inorganic pigments such as iron oxides) or taste and / or odor correcting agents. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives for human use. In the case of oral administration, the appropriate dosage is about (4) 01 to 50 mg/kg, preferably 0.01 mg/kg to 2 mg/20 kg. In the case of parenteral administration (for example, intravenous or nasal, buccal or inhalation via mucosal administration), the appropriate dose is Q mg/kg to 5 mg/kg. However, in certain circumstances, it may be necessary to deviate from the above doses, that is, depending on the body weight, the employment path, and the individual behavior of the active ingredients -24-314555

五、發明說明（23 經濟部智慧財產局員工消費合作社印製 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， 可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。 t除非另行陳述，下文試驗及實例中之百分比為重量 〜伤數亦為重量比；溶劑比例、稀釋比例及液體/液體 4液所記述之濃度各為以容積計。 [實施方式]活性評估 本發明化合物抑制唁中性白血球彈性蛋白酶活性之潛 ’舉例而言，可使用下述試驗予以證明： 性白血玻彈牦蛋白酶(HNE)之活艚外酵素試 m - 執驗緩衝液：（U M HEPES-NaOH緩衝液pH 7.4、 5 M KaCl、〇· 1% (w/v)牛血清白蛋白； 適當濃度（見下文）之HNE (18 U/毫克冷凍乾燥物， ^7.01，SERVA Electrophoresis GmbH，Heidelberg， Germany) ’於試驗緩衝液中； 適當濃度（見下文)之基質 適當濃度之測試化合物 DMS〇中之10mM貯存液。使用骛光性胜肽基質(連續讀出訊號，384 ΜΤΡ試驗版本） -25- 本纸張尺度適用^標準(CNS)A4規格（210x297公釐) 一 5 10 15 20 於試驗緩衝液中； 以試驗緩衝液稀釋其於 A7 B7 1314555 五、發明說明（24) 之活體外抑制HNE : 此實驗流程中，係使用彈性蛋白酶MeOSuc-Ala-Ala-Pro-Val-AMC (#324740， Calbiochem-NovabiochemV. Description of invention (23 Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative printing, preparation method and time or interval of application. In some cases, it may be sufficient to use less than the above minimum dose, and in other cases It may be necessary to exceed the upper limit of the above dosage. When a larger amount is administered, it may be appropriate to divide the dose into several times a day. t Unless otherwise stated, the percentages in the following tests and examples are weights ~ the number of injuries is also the weight ratio. The solvent ratio, the dilution ratio, and the concentration of the liquid/liquid 4 liquid are each in terms of volume. [Embodiment] Activity Evaluation The compound of the present invention inhibits the sputum neutrophil elastase activity. For example, the following can be used. Test to prove: Live white blood cell chymotrypsin (HNE) live enzyme test m - test buffer: (UM HEPES-NaOH buffer pH 7.4, 5 M KaCl, 〇 · 1% (w / v) cattle Serum albumin; appropriate concentration (see below) of HNE (18 U/mg lyophilizate, ^7.01, SERVA Electrophoresis GmbH, Heidelberg, Germany) 'in assay buffer; suitable When the concentration (see below) is the appropriate concentration of the substrate in the test compound DMS 之 10 mM stock solution. Use the tanning peptide matrix (continuous read signal, 384 ΜΤΡ test version) -25- This paper scale applies ^ standard ( CNS) A4 size (210x297 mm) a 5 10 15 20 in assay buffer; diluted in assay buffer at A7 B7 1314555 5. Inventive Inhibition of HNE in Inventive Note (24): In this experimental procedure, use Elastase MeOSuc-Ala-Ala-Pro-Val-AMC (#324740, Calbiochem-Novabiochem

Corporation, Merck KGaA，Darmstadt, Germany)。刻試溶 5 液之製備係分別混合l〇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以1；/毫升，常規濃度 2.1#U/毫升)與20微升基質緩釋液(最終濃度1 - 1， Μ ’常規濃度20/zM)。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）β螢光(ex 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。Km與Km(app) 值則以Lineweaver-Burk作圖決定，並利用Dix〇n作圖轉 換成IQ值。 15 諸製備例在此試驗中具有範圍在5 ηΜ _ 5# Μ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Corporation, Merck KGaA, Darmstadt, Germany). The preparation of the test solution 5 was mixed with 10 μl of test compound dilution, 20 μl of HNE enzyme dilution (final concentration 8 - 〇.4 to 1; / ml, conventional concentration 2.1 #U / ml) and 20 Microliter matrix sustained release solution (final concentration 1 - 1, Μ 'conventional concentration 20/zM). The solution was incubated at 37 ° C for _ 2 hours (conventional 1 hour). At 37 ° C, the rate of increase of beta fluorescence (ex 395 nm, em. 460 nm) of AMC 10 released by the enzyme reaction (TECAN SpectΓaFluor plus plate reader) was measured in proportion to elastase activity. Mapping the [I] using the RFU determines the IC5 threshold. The Km and Km(app) values are determined by the Lineweaver-Burk plot and converted to IQ values using Dix〇n. 15 The preparation examples have IC50 values in the range of 5 η Μ _ 5 # Μ in this test. The representative data is shown in Table 1: Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative

1314555 A7 B7 五 發明說明（25) 表1 實例編號 IC5〇 [nM] 1 δ 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 經濟部智慧財產局員工消費合作社印製 5 ο 11 實例B 使用螢光性、不溶性彈性蛋白基質（不連續讀出訊號，96 MTP試驗版本）之活體外抑制HNE : 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 mU/毫升，常規濃度21.7"U/毫升)與80微升基質緩释液 -27- 尺 張 紙 本 .適用中國國家標準(CNS)A4規格（210X 297公釐） A7 B7 1314555 五、發明說明（26) ，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(最终濃度50 mM)中，以終止酵 素反應。離心(Eppendorf 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）。勞光(ex. 490奈米，em. 520奈 米）速率與彈性蛋白酶活性成正比。利用RFU對[I]作圖決 定諸IC5G值。1314555 A7 B7 Five invention descriptions (25) Table 1 Example number IC5〇[nM] 1 δ 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 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 5 ο 11 Example B In vitro inhibition of HNE using a fluorescent, insoluble elastin matrix (discontinuous read signal, 96 MTP test version): In this experimental procedure, Elastase matrix elastin-fluorescent yellow (#100620, ICN Biomedicals GmbH, Eschwege, Germany) was used. The test solution was prepared by dissolving 3 μl of test compound dilution, 77 μl of HNE enzyme dilution (final concentration 0.22 U/ml _ 2 2 mU/ml, conventional concentration 21.7 " U/ml) and 80 μl of substrate buffer. Release liquid -27- ruler paper. Applicable to China National Standard (CNS) A4 specification (210X 297 mm) A7 B7 1314555 V. Invention description (26), keep the suspension at 37 ° C under slight vibration conditions 〇 - 16 hours (conventional 4 hours). Add 160 μl of 0.1 hydrazine acetic acid to the test solution (final concentration 50 mM) to stop the enzyme reaction. The polymerized elastin-fluorescent yellow was precipitated by centrifugation (Eppendorf 5804 centrifuge ' 3.000 rpm, 10 minutes 5 minutes). The supernatant was transferred to a new MTP and the peptide yellow fluorescent (BMG Fluostar plate reader) released due to the enzyme reaction was measured. The rate of Luguang (ex. 490 nm, em. 520 nm) is directly proportional to elastase activity. The ICU is used to determine the IC5G values for [I] mapping.

10 II.活艚外人類嗜中性白血珐諕腌 實例A 訂 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(PMNs)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.么 386-392 (1993)] » 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.幽 1876-1885, 3173-3181 20 (1997)，WO 95/21855)及αΐ蛋白酶抑制劑1PI)]至諸 槽。自健康捐血者末梢靜脈血液分離人類PMNs，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 105個細胞不等。以豬胰臟彈性蛋 白酶（1.3/zM)作為此試驗之正對照組，並使用α 1PI (1.2 -28- 本紙張尺度適用中國國家棵準(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 1314555 Α7 Β7 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， 5將上澄液移至96槽LumaplateTM (含囡體間爍劑之諸盤）之 諸對應槽中。乾燥培養盤至未於諸槽中看到液體為止’於 冷計數器中讀取，每槽3分鐘。 3H-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 10 中氤之下降。α 1PI於1.2//M下，獲得83.46 ± 3.97% (平均值± s.e.m·)之抑制作用（η = 3個不同捐血者，每槽 3.6 X 105個細胞）。參考化合物ZD-0892獲得45.50 ± 7.75 ηΜ (平均值土 s.e_m_)之IC50 (η = 2個不同捐血者， 每槽3.6 X 1〇5個細胞）。 15 已知ZD-0892為ΡΜΝ彈性蛋白酶之選擇性抑制劑， 加上flilPI抑制作用之數據，彼等結果表示大部分彈性蛋 白之被PMNs降解係由於嗜中性白血球彈性蛋白酶之释 放，而非由於其他彈性質溶解酵素例如基質金屬蛋白酶 (MMPs)之故。於此嗜中性白血球彈性質溶解之hne依存 20 模式中，評估本發明化合物之抑制活性。10 II. Extracorporeal human neutrophil white blood pickling Example A In vitro PMN elastic dissolution test: This test is used to determine the elastic solubility potential of human polymorphonuclear cells (PMNs) and to assess due to neutrophil Degradation of 15 by leukocyte elastase [Refer to ZW She et al., Am. J. Respir. Cell. Mol. Biol. 386-392 (1993)] » Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives will contain The suspension of labeled elastin was coated on a 96-well culture dish at 10 micrograms per well. A test compound of the appropriate concentration is added to the reference compound [ZD-0892 (J. Med. Chem. 1876-1885, 3173-3181 20 (1997), WO 95/21855) and α-chymotrypsin inhibitor 1PI)] to the tanks. Human PMNs were isolated from peripheral blood of healthy donors and resuspended in culture medium. Neutrophils are added to the coated troughs at concentrations ranging from 1 x 106 to 1 X 105 cells per well. Porcine pancreatic elastase (1.3/zM) was used as a positive control for this test, and α 1PI was used (1.2 -28- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1314555 Α7 Β7 5, invention description (27) #Μ) as a positive inhibitor of neutrophil elastase ° cell control group at each appropriate cell density, PMNS without compounds . The cells to which the compound was added were incubated for 4 hours at 37 ° C in a humid incubator. Centrifuge the plate and collect only the cells. In an amount of 75 microliters, 5, the supernatant was transferred to the corresponding tanks of the 96-well LumaplateTM (the tray containing the steroidal agent). The plates were dried until they were not seen in the tanks and were read in a cold counter for 3 minutes per tank. The dissolution of the elastic substance of 3H-elastin causes an increase in the count in the supernatant. This inhibition of the dissolution of the elastomer showed a decrease in sputum in the supernatant 10 relative to the cell control group. α 1PI at 83//M achieved an inhibitory effect of 83.46 ± 3.97% (mean ± s.e.m·) (η = 3 different donors, 3.6 X 105 cells per well). The reference compound ZD-0892 obtained an IC50 of 45.50 ± 7.75 η Μ (average soil s.e_m_) (η = 2 different donors, 3.6 X 1 〇 5 cells per well). 15 It is known that ZD-0892 is a selective inhibitor of ΡΜΝ elastase, plus data on the inhibition of flilPI. These results indicate that most of the elastin is degraded by PMNs due to the release of neutrophil elastase, not due to Other elastic lysozymes such as matrix metalloproteinases (MMPs). The inhibitory activity of the compound of the present invention was evaluated in the hne dependent 20 mode in which the neutrophil elastin was dissolved.

實例B 膜結合彈性蛋白峰之活禮外抑制： 使用人類嗜令性白血球試驗測定結合於嗜中性白血球 膜的彈性蛋白酶之抑制作用。於37〇c，以Lps刺激嗜中 -29- 本紙張尺度適用中國國家棵準(CNS)A4規格⑽χ 297公爱)--—----Example B Out-of-the-box inhibition of membrane-bound elastin peaks: The inhibition of elastase binding to neutrophils was determined using a human eutrophic leukocyte assay. At 37〇c, stimulate the episode with Lps -29- This paper scale applies to China National Green (CNS) A4 specifications (10) 297 297 public)------

A7 B7 1314555 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,A7 B7 1314555 V. INSTRUCTIONS (28) White blood cells for 35 minutes, then centrifuged at 1600 rpm. Subsequently, the membrane was treated with 3% paraformaldehyde and 0.25% glutaraldehyde for 3 minutes at 4 ° C to immobilize the membrane with elastase in neutrophils. The neutrophils are then centrifuged, the carrier and the compound to be evaluated are added, followed by the addition of a substrate of concentration 5 200 # Me 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 (苯基甲續酿氟)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 incubation at 37 ° C for 25 minutes, the reaction was terminated with PMSF (Phenylmethyl fluorinated) and the fluorescence of ex : 400 nm and em : 505 nm was read. Using the insertion method, the IC5 〇 value was determined from the relative fluorescence versus the inhibitor concentration of 10 .

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。 經濟部智慧財產局員工消費合作社印製 以Hypnorm/Hypnovel/水麻醉大鼠，並以微量喷霧器 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 化之磷酸鹽缓衝食鹽水(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，9〇〇 r.p.m. 下，離心各BAL試樣1〇分鐘。丟棄上澄液，將細胞沉澱 -30- _本紙張尺度適用中國國家標準(CNS)A4規格（210x297公爱）" —------- Μ Β7 經濟部智慧財產局員工消費合作社印製 1314555 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0.1%溴化鯨蠟基三甲錢 (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1〇〇微升各試樣置於96槽平底盤之分隔槽令。所 有試樣均進行二重複試驗，並包括100微升〇1〇/。 CT AB/PB S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0.1% 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。 於大鼠由ΗΝΕ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Β 15 大鼠急性心肌梗塞之活禮内模式： 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，HugoIII. In vivo mode Example A In vivo mode of acute lung injury in rats: Human neutrophil elastase (HNE) was slowly instilled into the lungs of large rats to induce acute lung injury. The degree of injury can be assessed by measuring lung output. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, rats were anesthetized with Hypnorm/Hypnovel/water, and HNE or saline was slowly instilled into the lungs by micro-spray delivery. The test compound is administered by intravenous injection, oral gavage or inhalation at a set time point prior to administration to HNE. After 60 minutes of elastase administration, the animals were sacrificed with an excess of 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. At 9 〇〇 r.p.m., each BAL sample was centrifuged for 1 minute. Discard the supernatant and precipitate the cells -30- _ This paper scale applies to China National Standard (CNS) A4 specification (210x297 public)" —------- Β Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative System 1314555 V. Description of the invention (29) The object was resuspended in PBS' and the sample was centrifuged again. The supernatant was again discarded, and the cell pellet was resuspended in 1 ml of 0.1% clofibrate triacetin (CTAB)/PBS to dissolve the cells. The sample is stored frozen until the blood content is analyzed. The samples were thawed before the bleeding test and mixed. Take 1 〇〇 microliter of each sample placed in a 96-slot flat bottom plate. All samples were tested in duplicate and included 100 microliters of 〇1〇/. CT AB/PB S empty. White control group. The absorbance of the contents of the tank at 415 nm was measured using a spectrophotometer. A standard curve was determined by measuring the absorbance at 415 nm for different concentrations of blood in 0.1% CTAB/PBS. The comparison was performed for the standard curve (covered in each plate) to calculate the blood content value and normalize the amount of BAL fluid obtained. In this mode in which the rat is induced by sputum, the inhibitory activity of the compound of the present invention administered intravenously, orally or by inhalation is evaluated. Example Β 15 Intrauterine mode of acute myocardial infarction in rats: Tests for elastase inhibitors in a rat line infarction mode. 30 minutes before surgery, Wistar rats (weight > 300 g) were accepted. 10 mg/kg aspirin. During the entire procedure, anesthesia with isofluran and an oxygen mask (120-130 compressions per minute, 200-250 microliters of compressed output; MiniVent Type 845, Hugo)

Sachs Elektronik，Germany)。於第四肋間進行左胸麼切開 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) "Sachs Elektronik, Germany). After the left thoracic incision in the fourth intercostal space, the pericardial cavity is opened, and the heart is temporarily exposed. Wrap the left coronary artery (LAD) in a line without clogging it. This line passes under the skin to the neck of the animal. Slowly drip into the lungs of rats to induce acute lung injury -31- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) "

1314555 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（3。） 害。其傷害程度可利用測量肺出血予以評估。閉合胸廓， 令動物康復4天。第5天，使用乙醚3分鐘麻醉大鼠，將 線繫緊，使LAD堵塞(ECG控制下）。於LAD堵塞之前與 之後，經口、腹膜内或靜脈内（推注或固定輸注)投與測試 5 化合物。堵塞1小時後，打開線，令其再灌流。割除心 臟，以伊凡氏藍(Evans blue)將該再堵塞之心臟染色，隨 後以TTC(氯化三苯基四唑鑌）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.(堵塞惟生還之組織）區域染成紅色，壞死 10 (堵塞死亡組織）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 縮寓： DMF 况，二甲基甲醯胺 DMSO 二甲亞楓 EI 電子撞擊電離法 ESI 電灑電離法 HPLC 高壓液相層析法 LC-MS 液相層析法組合質譜分析法 MS 質譜分析法 NMR 核磁共振光譜術 Rt 滯留時間（用於HPLC) THF 四氫呋喃1314555 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (3.) harm. The degree of injury can be assessed by measuring pulmonary hemorrhage. The thorax was closed and the animals were allowed to recover for 4 days. On the fifth day, the rats were anesthetized with ether for 3 minutes, and the line was tightened to block the LAD (under ECG control). Test compound 5 was administered orally, intraperitoneally or intravenously (bolus or fixed infusion) before and after LAD occlusion. After blocking for 1 hour, open the line and allow it to reperfuse. The heart was excised, and the reoccluded heart was stained with Evans blue, followed by staining with 2 mm heart sections with TTC (triphenyltetrazolium chloride), and after 48 hours, the infarct size was measured. Normal (unblocked tissue) areas are stained blue, ischemia (blocking of the tissue) is stained red, and necrosis 10 (blocking dead tissue) remains white. Each tissue section was scanned and the size of the infarct was measured using a computer mapper. B. Example reduction: DMF condition, dimethylformamide DMSO dimethyl sulfoxide EI electron impact ionization ESI electrospray ionization HPLC high pressure liquid chromatography LC-MS liquid chromatography combined mass spectrometry MS Mass spectrometry NMR nuclear magnetic resonance spectroscopy Rt residence time (for HPLC) THF tetrahydrofuran

4 訂4 order

本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 1314555 Λ7 _ B7 五、發明說明（3!) 一般方％ 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Rpi8_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。 LC-MS / HPLC 方法： 10 LC-MS 方 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+ 0.05%甲酸，溶洗液b :乙腈+ 〇 〇5〇/〇曱酸；梯 度：〇.〇 分鐘 100% A — 0.2 分鐘 1〇〇〇/0 a — 2.9 分鐘 15 30〇/〇 A 3.1 分鐘 10% A — 4.5 分鐘 1〇% A ;烘箱： 55°C ;流速：0.8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%甲酸，溶洗液B :乙腈+0.1%曱酸；梯度：〇·〇分鐘 5% B -> 5.0 分鐘 10% B — 6.0 分鐘 i〇〇/0 b ;溫度： 50°C ;流速：1.0毫升/分鐘；UV_檢測：210奈米。 -33- 表纸張尺度適用中國國家標準(CNS)A4規格（210 χ 297公S ) ' -- A7 B7 1314555 五、發明說明（32 ) LC-MS方法3 儀器：Micromass Platform LCZ，HP 1100 ;管柱： Aquasil C-18，50毫米x 2.0毫米，3微米；溶洗液A : 水+ 0.05%甲酸，溶洗液B :乙腈+ 0.05%甲酸；梯度： 5 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 ;烤箱：55 °C ;流速：0.8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X 2毫米，3.5微米；溶洗液：A = 5毫升 HC104/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，M!S 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棵準(CNS)A4規格（210 X 297公釐） ~ " A7 B7 1314555 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：〇.〇 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 AgilentThis paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 1314555 Λ7 _ B7 V. Invention description (3!) Normal% Unless otherwise stated, otherwise all reactions are carried out under argon atmosphere. The solvent used was purchased from Aldrich and no further purification was required. "Coffee" or "Shi Xi Shi" means silicone 60 (0.040 mM - 5 〇 毫米 63 mm) from Merck KGaA. The melting point was obtained using Btichi 512 or a similar melting point device. The compound purified by preparative HPLC was applied to a Rpi8_ column and purified using a gradient of 1:9 to 9:1 using acetonitrile and water as a solvent. LC-MS / HPLC Method: 10 LC-MS Instrument: Micromass Quattro LCZ, HP 1100; Column: Uptisphere HDO, 50 mm χ 2.0 mm, 3 μm; Eluent A: Water + 0.05% formic acid, solvent b: acetonitrile + 〇〇5〇/capric acid; gradient: 〇.〇 min 100% A — 0.2 min 1〇〇〇/0 a — 2.9 minutes 15 30〇/〇A 3.1 minutes 10% A — 4.5 minutes 1 〇% A; oven: 55 ° C; flow rate: 0.8 ml / min; UV-detection: 208-400 nm. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed LC-MS Method 2 Instrument: Waters Alliance 2790 LC; Column: Symmetry C18 '50 mm χ 2·1 mm, 3.5 μm; Solution A: Water + 20 〇·1 % formic acid, solvent B: acetonitrile + 0.1% citric acid; gradient: 〇 · 〇 minutes 5% B -> 5.0 minutes 10% B - 6.0 minutes i 〇〇 / 0 b ; temperature: 50 ° C; 1.0 ml/min; UV_detection: 210 nm. -33- Table paper scale is applicable to China National Standard (CNS) A4 specification (210 297 297 s S ) ' -- A7 B7 1314555 V. Description of invention (32 ) LC-MS method 3 Instrument: Micromass Platform LCZ, HP 1100 ; Column: Aquasil C-18, 50 mm x 2.0 mm, 3 μm; Eluent A: Water + 0.05% formic acid, Eluent B: Acetonitrile + 0.05% formic acid; Gradient: 5 0.0 min 100% A — 0.2 min 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-test; column: Kromasil 10 RP-18, 60 mm X 2 mm, 3.5 μm; solvent: A = 5 ml HC104/liter H20, B = acetonitrile; Gradient: 0 min 2% B - 0.5 min 2% B 4.5 min 90% B - 6.5 min 90% B; flow rate: 0.75 ml/min; temperature: 30 ° C; UV-detection: 210 nm. LC,M!S Method 5 15 Instrument: Micromass TOF-MUX-Interface 4x Parallel Injection Ministry of Economics Intellectual Property Office Staff Cooperatives printed with HPLC Waters 600; Column: Uptisphere HDO, 50 mm X 2.0 mm, 3 Micron; Solution A: 1 liter of water + 1 ml of 50% formic acid, solution B: 1 liter of acetonitrile + 1 ml of 50% formic acid; Gradient: 〇.〇 min 100% A — 0.2 min 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 is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ~ " A7 B7 1314555 V. Inventive Note (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 μm; Eluent A: 1 liter of water + 1 ml of 50% methyl 5-acid, solution B: 1 liter of acetonitrile + 1 Milliliter 50% formic acid; Gradient: 〇.〇 min 100% A 0.2 min 100% A — 2.9 min 30% A — 3.1 min 10% A 4.5 min 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 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1〇〇% A — 0.2 分鐘 1〇〇% 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 本紙張尺度適用卞國國家標準(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 1314555 A7 B7 五、發明說明（34 ) 起始物質:Serie 1100; Column: Uptisphere HDO, 50 mm x 2.0 mm, 3 μm; Eluent A: 1 liter of water + 1 ml of 50% formic acid, solution B: 1 liter of acetonitrile + 1 ml of 50% formic acid; Gradient: 〇 〇min 1〇〇% A — 0.2 minutes 1〇〇% A — 2.9 minutes 30% A — 3_1 minutes 15 10% A — 4.5 minutes 10% A ; oven: 55°C; flow rate: 〇·8 ml/min; UV-detection: 208-400 nm. Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed Paper Scale Applicable to National Standard (CNS) A4 Specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1314555 A7 B7 V. Invention Description (34) Starting material:

實例1A 2->臭-5-(1，3-二11亏環戊烧-2-基）11比唆Example 1A 2->Smelly-5-(1,3-Di 11 Cyclopentan-2-yl) 11 唆

5 於備有回流冷凝器及汀-史達克氏氣液分離器（Dean-5 with reflux condenser and Ting-Stark gas-liquid separator (Dean-

Stark trap)之圓底 燒瓶中 ，使 6-溴-3-吡啶曱醛 (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)+ ^-NMR (300 MHz, CDC13)： δ = 8.46 (d, 1H), 7.64 (m, 1H), 7.49 (m, 1H), 4.15-4.00 (m, 4H) ppm. 15 -36- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）Stark trap) in a round bottom flask with 6-bromo-3-pyridylfurfural (500 mg, 2.7 mol) and 1,2-ethanediol (200 mg, 3.2 mmol) along with Amberlyst 15 (100 mg) ) dissolved in toluene (50 ml). This solution was heated at reflux overnight then cooled to rt. filtered and concentrated in vacuo. The crude product was chromatographed on silica gel eluting with hexanes and ethyl acetate. Yield: 0.489 g (79% of theory) HPLC (Method 4): 3.46 min MS (ESIs): m/z = 231 (M+H) + NMR (300 MHz, CDC13): δ = 8.46 ( d, 1H), 7.64 (m, 1H), 7.49 (m, 1H), 4.15-4.00 (m, 4H) ppm. 15 -36- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 PCT)

!314555!314555

五、發明說明（35)V. Description of the invention (35)

tMjA 5-(l，3-二畤環戊烷-2-基)-2-吡啶曱腈tMjA 5-(l,3-dioxacyclopentan-2-yl)-2-pyridinonitrile

經濟部智慧財產局員工消費合作社印製 使實例1A (2.8克’ 12,5毫莫耳）、氰化鋅（1 6克， 5 13.8毫莫耳)與肆-(三苯基膦)把(〇) (1_4克，h3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-(三苯基膦)鈀(0) (0.1克）’於80°c再攪拌此反應隔 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 10 物。其有機相以食鹽水(200毫升）洗蘇，以硫酸鎮單水合 物脫水，過濾，真空濃縮。此粗產物於矽膠上進行色層分 析’以環己烷及乙酸乙酯為溶洗液，得到呈白色非晶固體 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)+ •H-NMR (400 MHz, DMSO-di): δ = 8.81 (s, 1H), 8.09 (s, 2H), 5.95 (s, 1H), 4 13. 3.94 (m, 4 H) ppm. -37- 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 1314555 A7 B7 五、發明說明（36)The Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed the example 1A (2.8 g '12,5 mmol), zinc cyanide (1 6 g, 5 13.8 mmol) and 肆-(triphenylphosphine) (1 _ 4 g, h3 mol) was dissolved in dimethylformamide (100 mL) and stirred overnight (18 hr) at 80 s. Further, hydrazine-(triphenylphosphine)palladium(0) (0.1 g) was stirred at 80 ° C for further overnight (18 hours), and then allowed to stand at room temperature for 2 days (48 hours). The solvent was removed in vacuo, and water (100 mL) was evaporated. The organic phase was washed with brine (200 ml), dehydrated with sulphuric acid monohydrate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel eluting with hexanes and ethyl acetate. Yield: 〇_94 g (42% of theory) 15 HPLC (Method 4): 3.21 min MS (ESIs): m/z = 177 (M+H) + H-NMR (400 MHz, DMSO-di ): δ = 8.81 (s, 1H), 8.09 (s, 2H), 5.95 (s, 1H), 4 13. 3.94 (m, 4 H) ppm. -37- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1314555 A7 B7 V. Invention description (36)

實例3A 5-甲醯基-2-吡啶甲腈Example 3A 5-Mercapto-2-pyridinecarbonitrile

方法a): 5 以類似 Dodd, D· ei a/. [J. Org. C&w. 7992, 57, 7226- 7234]之程序進行製備：於含5-(1,3-二啐環戊烷-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，並以硫酸鎂 單水合物脫水，過濾，真空濃縮；此粗產物利用製備性 HPLC進行純化，得到淡黃色固體。 15 產率：0.66克（理論值之93%)Method a): 5 Prepared in a procedure similar to Dodd, D. ei a/. [J. Org. C&w. 7992, 57, 7226-7234]: in the presence of 5-(1,3-dioxencyclopentane) Alkyl-2-yl)-2-pyridinecarbonitrile (Example 2A; 850 mg, 4.8 mmol) in acetone/water 85:15 (59.5 mL) stirred solution with p-toluenesulfonic acid (102 mg, 0.59 m) Mol); the reaction was stirred under reflux overnight (18 hours), then 10 additional p-toluenesulfonic acid (50 mg) and water (5 ml); and the reaction was stirred under reflux for 48 hours; the solution was cooled to room temperature to sat. The sodium solution was quenched with EtOAc (EtOAc)EtOAc. 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)+ ^-NMR (400 MHz, DMSO-di): δ = 10.18 (s, 1H), 9.21 (in, 1H), 8.49 (m, 1H), 8.27 (m, 1H) ppm. -38- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）Melting point: 80-82 ° C HPLC (method 4): 2.13 min MS (ESI pos): m/z = 133 (M+H) + NMR (400 MHz, DMSO-di): δ = 10.18 (s, 1H ), 9.21 (in, 1H), 8.49 (m, 1H), 8.27 (m, 1H) ppm. -38- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm)

1314555 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毫升二氣甲烷 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毫升二氣曱 5 烷中之1克(7.46毫升)實例5A化合物，持續於-78°C再攪 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（矽石，溶洗液為環己烷 至環己烷/乙酸乙酯2:1)純化該混合物。 產率：0.76克（理論值之77%) 10 分析數據：見上。1314555 A7 B7 V. INSTRUCTIONS (37) Method b): 1.04 g (8.2 mmol) of grass cockroach gas is dissolved in 8 ml of di-methane. 1.28 g (16.4 mmol) of diterpenoid was added dropwise at -78 °C. This 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 dioxane was added and the mixture was stirred at -78 °C for an additional 2 hours. Then, 3.4 g (33.6 mmol) of triethylamine was added dropwise, and after heating to room temperature, column chromatography was used (the vermiculite, the solvent was cyclohexane to cyclohexane / ethyl acetate 2 : 1) Purify the mixture. Yield: 0.76 g (77% of theory) 10 Analytical data: see above.

實例4A 5-甲基-2-°比啶曱腈Example 4A 5-Methyl-2-°pyridinonitrile

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）。以二氣曱烷萃取產物，其有機相以硫酸鎂脫 水，真空去除溶劑。利用管柱層析法(碎石，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%) h-NMR (300 MHz, CDC13): δ = 2.4 (s，3H)，7.6 (叫 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） 1314555 A7 B7 五、發明說明（38)CH3 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed in 500 ml of dimethylformamide, 36 g (209 mmol) of 15 2-bromo-5-methylpyridine with 37.5 g (418 mmol) The copper cyanide was heated under reflux for 2 hours. After cooling to 50 ° C, a 10% aqueous ammonia solution (500 ml) was added with stirring. The product was extracted with dioxane, the organic phase was taken from magnesium sulfate and solvent was evaporated in vacuo. The product was purified by column chromatography (crude, solvent eluting hexane/ethyl acetate 9:1). 20 Yield: 18 g (73% of theory) h-NMR (300 MHz, CDC13): δ = 2.4 (s, 3H), 7.6 (called 2H), 8.6 (s, 1H) ppm. -39- The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1314555 A7 B7 V. Description of invention (38)

實例5A 5-(羥甲基）-2-啦啶甲腈Example 5A 5-(Hydroxymethyl)-2-eridine carbonitrile

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毫升二畤烷及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（矽石，溶洗液環己烷/乙酸乙酯2:1)純化產物。 產率：5.2克（理論值之35%) *H-NMR (300 MHz, DMSO-d^): δ = 4.7 (d, 2Η), 5.6 (t, 1H), 8.0 (m, 2H), 8.7 (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） 1314555 μ B7 五、發明說明（39) Μ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The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed compound 4A compound (13 g, 110 mmol) dissolved in 400 ml of 5 liters of four-gas methane, and added 29.4 g (165 mmol) of N-brominated amber. Indole and 0.4 g (1.6 mmol) of benzhydryl peroxide. The reaction mixture was heated under reflux for 3 hours, cooled to room temperature and then filtered. This solution was washed with an aqueous sodium thiosulfate solution, dried over magnesium sulfate, and evaporated in vacuo. The residue was dissolved in 200 ml of dioxane and 200 ml of water, and then 10 portions of 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 dried over magnesium sulfate and the solvent was removed in vacuo. The product was purified by chromatography (mite, solvent eluting hexane/ethyl acetate 2:1). Yield: 5.2 g (35% of theory) *H-NMR (300 MHz, DMSO-d^): δ = 4.7 (d, 2 Η), 5.6 (t, 1H), 8.0 (m, 2H), 8.7 (s, 1H) 15 ppm. -40- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1314555 μ B7 V. Description of invention (39) Preparation example: Example 1 4-(4 -Cyanophenyl)-6-methyl-2-keto-1-(3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

CNCN

4 訂 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）N-[3-(三氟甲基）苯基]脲、 8.99克(68.58毫莫耳）4-氰基苯甲醛、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，殘留物於矽石上利用管柱層析法進 行純化，以環己烧/乙酸乙醋為溶洗液。 產率：13.4 克(91%) !H-NMR (200 MHz, DMS0-4): 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)M規格(210x297公釐）4 Ordered by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed 7.0 g (34.29 mmol) of N-[3-(trifluoromethyl)phenyl]urea, 8.99 g (68.58 mmol) of 4-cyanobenzene Formaldehyde, 8.92 g (68.58 mmol) of ethyl 3-ketobutanoate 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 celite, using cyclohexane/ethyl acetate as solvent. Yield: 13.4 g (91%) !H-NMR (200 MHz, DMS0-4): 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 scale applies to the Chinese National Standard (CNS) M specification (210x297 mm) )

經濟部智慧財產局員工消費合作社印製 1314555 A7 B7 五、發明說明（40 ) 實例2 4-{5-乙醯基-6-甲基-2-酮基-1-[3-(三氟甲基）苯基]-l,2,3,4-四氫-4-嘧啶基}苯曱腈Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, Printing 1314555 A7 B7 V. Description of Invention (40) Example 2 4-{5-Ethyl-6-methyl-2-keto-1-[3-(trifluoromethyl) Phenyl]-l,2,3,4-tetrahydro-4-pyrimidinyl}benzonitrile

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%) ]H-NMR (200 MHz, DMSO-de): δ = 2.0 (s, 3H); 2.2 (s, 3H); 5.5 (d, 1H); 7.5 (m, 1H); 7.6 (m, 3H); 7.7 (in, 1H); 7.8 (m, 1H); 7.9 (m, 2H); 8.5 (d, 1H) ppm. -42- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）5 265 mg (1.3 mmol) of N-[3-(trifluoromethyl)phenyl]urea, 131 mg (1.0 mmol) of 4-cyanobenzaldehyde, with 100 mg (1.0 mmol) The 2,4-pentanedione 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. Yield: 29 mg (7%)]H-NMR (200 MHz, DMSO-de): δ = 2.0 (s, 3H); 2.2 (s, 3H); 5.5 (d, 1H); 7.5 (m, 1H) ); 7.6 (m, 3H); 7.7 (in, 1H); 7.8 (m, 1H); 7.9 (m, 2H); 8.5 (d, 1H) ppm. -42- This paper scale applies to Chinese national standards (CNS) )A4 size (210x297 mm)

經濟部智慧財產局員工消費合作社印製 1314555 B7 五、發明說明（4!) 實例3 4-(4->臭苯基)-6-曱基-2-嗣基-1-[3-(三乱甲基）苯基]-1,2,3,4. 四氳-5-嘧啶甲酸乙酯Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1314555 B7 V. Invention description (4!) Example 3 4-(4-> stinyl phenyl)-6-mercapto-2-mercapto-1-[3-( Tris-methyl)phenyl]-1,2,3,4. tetradec-5-pyrimidinecarboxylic acid ethyl ester

Br 0Br 0

5 使204毫克（1.0毫莫耳）N-[3-(三氟甲基）苯基]脲、 142毫克(0.77毫莫耳）4-溴苯曱醛、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，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 10 進行純化，以環己烷/乙酸乙酯為溶洗液。 產率：23毫克(6%) ^-NMR (200 MHz, DMSO-d«): δ = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (q, 2H); 5.3 (d, 1H); 7.4 (m, 2H); 7.6 (m, 3H); 7.7 (m. 3H); 8.3 (d, 1H) ppm. -43- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）5 204 mg (1.0 mmol) of N-[3-(trifluoromethyl)phenyl]urea, 142 mg (0.77 mmol) of 4-bromobenzaldehyde, with 100 mg (0.77 mmol) Ethyl 3-ketobutanoate 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. Yield: 23 mg (6%) ^-NMR (200 MHz, DMSO-d«): δ = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (q, 2H); 5.3 (d, 1H) ); 7.4 (m, 2H); 7.6 (m, 3H); 7.7 (m. 3H); 8.3 (d, 1H) ppm. -43- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) )

經濟部智慧財產局員工消費合作社印製 1314555 A7 B7 五、發明說明（42 ) 實例4 4-(4-乳苯基）-6·甲基-2-嗣基-l-[4-氣苯基]-l,2,3,4-四氣-5 嘧啶甲酸乙酯Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed 1314555 A7 B7 V. Description of Invention (42) Example 4 4-(4-Lactylphenyl)-6-methyl-2-indenyl-l-[4-phenylphenyl ]-l,2,3,4-tetraqi-5 pyrimidinecarboxylic acid ethyl ester

CNCN

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，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-de): 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（210 X 297公釐）5 154 mg (1.0 mmol) of N-[4-fluorophenyl]urea, 101 mg (0.77 mmol) of 4-cyanobenzaldehyde, and 100 mg (0.77 mmol) of 3-ketobutyl The acid ethyl ester 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. Yield: 40 mg (14%) 'H-NMR (200 MHz, DMSO-de): 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 scale applies to 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 1314555 A7 B7 五、發明說明（43 實例5 4-(4-乳苯基）-6-甲基-2-嗣基-l-[3-乳苯基]-1，2,3,4-四鼠-5· 嘴咬曱酸乙醋Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1314555 A7 B7 V. Description of Invention (43 Example 5 4-(4-Lactylphenyl)-6-methyl-2-indolyl-l-[3-lactylphenyl] -1,2,3,4-four mice-5· mouth bite vinegar

CNCN

0 CH, 5 使170毫克（1.0毫莫耳）N-[3-氣苯基]脲、100毫克 (0.77毫莫耳）4-氰基苯曱醛與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，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：13毫克(4%) 'H-NMR (200 MHz, DMSO-d6): δ = 1.1 (t, 3H); 2.1 (s, 3H); 4.0 (q, 2H); 5.3 (d, 1H); 7.2 (m, 1H); 7.4 (m, 3H); 7.5 (m, 2H); 7.9 (m, 2H); 8.3 (d, 1H) ppm. -45- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）0 CH, 5 170 mg (1.0 mmol) of N-[3-phenylphenyl]urea, 100 mg (0.77 mmol) of 4-cyanobenzaldehyde with 100 mg (0.77 mmol) 3- Ethyl 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. Yield: 13 mg (4%) 'H-NMR (200 MHz, DMSO-d6): δ = 1.1 (t, 3H); 2.1 (s, 3H); 4.0 (q, 2H); 5.3 (d, 1H) ); 7.2 (m, 1H); 7.4 (m, 3H); 7.5 (m, 2H); 7.9 (m, 2H); 8.3 (d, 1H) ppm. -45- This paper scale applies to Chinese national standards (CNS) )A4 size (210 X 297 mm)

1314555 A7 B7 五、發明說明（44 ) 實例6 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（lS)-2-曱氧基-1-甲基-2-酮基乙酯1314555 A7 B7 V. INSTRUCTIONS (44) Example 6 4-(4-cyanophenyl)-6-methyl-2-keto-1-(3-(trifluoromethyl)phenyl]_1,2, 3,4_ Tetrahydro-5-pyrimidinecarboxylic acid (lS)-2-decyloxy-1-methyl-2-ketoethyl ester

CNCN

4 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-氰基苯曱醛、92毫克(0.49毫莫 耳）3-酮基丁酸（lS)-2-甲氧基-1-甲基-2-酮基乙酯、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-^): δ = 1.3 (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） 訂 經濟部智慧財產局員工消費合作社印製4 5 200 mg (0.98 mmol) of N-[3-(trifluoromethyl)phenyl]urea, 129 mg (0.98 mmol) of 4-cyanobenzofural, 92 mg (0.49 mmol) 3-ketobutyric acid (lS)-2-methoxy-1-methyl-2-ketoethyl ester, 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, and residue residue was purified by column chromatography on silica eluting with cyclohexane/ethyl acetate as solvent. A mixture of non-image isomers is obtained. Yield: 96 mg (40%) 'H-NMR (200 MHz, DMSO-^): δ = 1.3 (d, 3H); 1.4 (d, 3H); 2.0 (s, 3H+3H); , 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 applies to China National Standard (CNS) A4 specification (210 X 297 mm). Printed by the Intellectual Property Office of the Ministry of Economic Affairs.

經濟部智慧財產局員工消費合作社印製 1314555 A7 B7 五、發明說明（45 ) 實例7 4-{6-甲基-5-(4-嗎啉基羰基)-2-酮基-1-[3-(三氟甲基）苯基]-1，2,3,4-四氮-4-°¾咬基}苯甲猜Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1314555 A7 B7 V. Description of Invention (45) Example 7 4-{6-Methyl-5-(4-morpholinylcarbonyl)-2-one-1-[3 -(Trifluoromethyl)phenyl]-1,2,3,4-tetrazole-4-°3⁄4 bite}benzole

CNCN

5 使150毫克(0.73毫莫耳）N-[3-(三氟甲基)苯基]脲、 96毫克(0.73毫莫耳）4-氰基苯曱醛、63毫克(0.37毫莫耳） 4-(4-嗎啉基)-4-酮基-2-丁酮與220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，殘留物於矽石上利用管柱層 10 析法進行純化，以二氯曱烷/曱醇為溶洗液。 產率：28毫克（16%) 'H-NMR (300 MHz, DMSO-dfi): δ = 1.5 (s, 3H); 3.1 (m, 4H); 3.6 (m, 4H); 5.3 (br.s, 1H); 7.6 (m, 2H); 7.7 (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H); 8.0 (br.s, 1H) ppm. -47- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）5 150 mg (0.73 mmol) of N-[3-(trifluoromethyl)phenyl]urea, 96 mg (0.73 mmol) of 4-cyanobenzofural, 63 mg (0.37 mmol) 4-(4-Morolinyl)-4-keto-2-butanone was suspended in 3 ml of THF with 220 mg of ethyl polyphosphate. 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 a vermiculite by column chromatography, using dichloromethane / methanol as solvent. Yield: 28 mg (16%) 'H-NMR (300 MHz, DMSO-dfi): δ = 1.5 (s, 3H); 3.1 (m, 4H); 3.6 (m, 4H); 5.3 (br.s , 1H); 7.6 (m, 2H); 7.7 (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H); 8.0 (br.s, 1H) ppm. -47- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)

經濟部智慧財產局員工消費合作社印製 1314555 μ B7 五、發明說明（46) 實例8 4-(4-氰苯基）-N,N-二乙基-6-甲基-2-酮基-1-[3-(三氟甲基) 苯基]-1，2,3,4 -四風- 5-°¾唆甲醒胺Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1314555 μ B7 V. Description of invention (46) Example 8 4-(4-cyanophenyl)-N,N-diethyl-6-methyl-2-keto- 1-[3-(Trifluoromethyl)phenyl]-1,2,3,4 - four winds - 5-°3⁄4唆甲醒amine

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）4-氰基苯甲醛、77毫克(0.49毫莫 耳）4-(4-二乙胺基)-4-酮基-2-丁酮與295毫克多磷酸乙酯 懸浮於3毫升THF中。回流加熱下，擾拌此混合物18小 時。冷卻至室溫後，真空去除溶劑，殘留物於矽石上利用 10 管柱層析法進行純化，以二氯甲烷/甲醇為溶洗液。 產率：1.06毫克(47%) ^-NMR (300 MHz, DMSO-d<i): δ = 0.9 (m, 6H); 3.1 (m, 4H); 5.2 (br.s, 1H); 7.6 (m, 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）5 200 mg (0.98 mmol) of N-[3-(trifluoromethyl)phenyl]urea, 128 mg (0-98 mmol) of 4-cyanobenzaldehyde, 77 mg (0.49 mmol) 4 -(4-Diethylamino)-4-keto-2-butanone was suspended in 3 ml of THF with 295 mg of ethyl polyphosphate. The mixture was disturbed for 18 hours under reflux heating. After cooling to room temperature, the solvent was removed in vacuo. Yield: 1.06 mg (47%) ^-NMR (300 MHz, DMSO-d <i): δ = 0.9 (m, 6H); 3.1 (m, 4H); 5.2 (br.s, 1H); m, 2H); 7.7 (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H); 8.0 (brs, 1H) ppm. -48- This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210x297 mm)

經濟部智慧財產局員工消費合作社印製 1314555 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-嘧啶曱腈 ΪΝMinistry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1314555 A7 B7 V. Description of Invention (47) Example 9 6-Amino-4-(4-cyanophenyl)-2-keto-1-[3-(trifluoro Methyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidine

5 使400毫克（1.97毫莫耳）N-[3-(三氟甲基)苯基]脲、 199毫克（1.51毫莫耳）4-氰基苯甲醛、與100毫克（1.51毫 莫耳）丙二腈懸浮於2毫升丁HF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%) ^-NMR (400 MHz, DMSO-de): 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公釐）5 make 400 mg (1.97 mmol) of N-[3-(trifluoromethyl)phenyl]urea, 199 mg (1.51 mmol) of 4-cyanobenzaldehyde, and 100 mg (1.51 mmol) The malononitrile was suspended in 2 ml of butyl HF, 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 celite, using di-methane/methanol as solvent. Yield: 4 mg (1%) ^-NMR (400 MHz, DMSO-de): 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 the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

A7 1314555 B7 五、發明說明（48 ) 實例10 4-(4-氰苯基）-3-曱醯基-6-甲基-2-酮基-1-[3-(三氟曱基）苯 基]-1,2,3,4-四氫-5-嘧啶甲酸乙酯A7 1314555 B7 V. INSTRUCTIONS (48) Example 10 4-(4-Cyanophenyl)-3-indolyl-6-methyl-2-keto-1-yl-1-[3-(trifluoromethyl)benzene Ethyl]-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 5 使100毫克(0.23毫莫耳)實例1化合物溶於1毫升二 曱基曱醯胺中，添加35.7毫克(0.23毫莫耳)磷醯氣。於 7〇°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%) lH-NMR (300 MHz, DMSade): δ = 1.1 (t, 3H); 2.1 (s, 3H); 4.1 (q, 2H); 6.4 (s, 1H); ia 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） A7 B7 1314555 五、發明說明（49 ) 實例11 4-(4-氰苯基)-6-曱基-2-酮基-1-[3-(三氟甲基）苯基]-1,2,3,4-四氫-5-痛咬甲酸Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Staff Consumer Cooperative 5 5 Dissolve 100 mg (0.23 mmol) of the compound of Example 1 in 1 ml of decylguanamine and add 35.7 mg (0.23 mmol) of phosphonium. The reaction mixture was stirred at 7 ° C for 2 hours. After cooling to room temperature, the product was isolated by HPLC. Yield: 43 mg (41%) lH-NMR (300 MHz, DMSade): δ = 1.1 (t, 3H); 2.1 (s, 3H); 4.1 (q, 2H); 6.4 (s, 1H); 7.6 (m, 2H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 4H); 9.2 (s, 1H) ppm. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1314555 V. INSTRUCTION DESCRIPTION (49) Example 11 4-(4-Cyanophenyl)-6-mercapto-2-one-1-[3-(trifluoromethyl)phenyl ]-1,2,3,4-tetrahydro-5-bite formic acid

CNCN

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%) 'H-NMR (300 MHz, DMSO-d^): δ = 2.0 (s, 3H); 5.4 (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. 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） 經濟部智慧財產局員工消費合作社印製 1314555 A7 B7 五、發明說明（50 ) 實例12 4-(4-氣苯基)-6-甲基-2-嗣基-N-丙基-1 - [3-(二氣甲基)苯基]-1,2,3,4-四氫-5-嘧咬甲醯胺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 on a vermiculite by column chromatography using di-methane/methanol as solvent. Yield: 1.27 g (45%) 'H-NMR (300 MHz, DMSO-d^): δ = 2.0 (s, 3H); 5.4 (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. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative The paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1314555 A7 B7 V. Invention Description (50) Example 12 4-(4-Phenylphenyl)- 6-methyl-2-indolyl-N-propyl-1 -[3-(dimethylmethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidine

CNCN

j it Η O^N^CH, 5 使40毫克(0.1毫莫耳)實例11化合物溶於2毫升二 曱基甲醯胺中，於其内添加7毫克(0.11毫升)正丙胺、15 毫克(0.11毫莫耳）1-羥基-1H-苯并三唑水合物及12毫克 (0.1毫莫耳）4-二曱胺基吡啶。於0°C攪拌此反應混合 物，然後添加21毫克(0.11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 小時，接著添加水與乙酸乙酯。其有機相以飽和KHS04 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%) W-NMR (300 DMS04): δ = 0.7 ⑺ 3H); 1.3 (六重兔 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（210 X 297公釐）j it Η O^N^CH, 5 40 mg (0.1 mmol) of the compound of Example 11 was dissolved in 2 ml of dimethylformamide, and 7 mg (0.11 ml) of n-propylamine, 15 mg ( 0.11 mmol of 1-hydroxy-1H-benzotriazole hydrate and 12 mg (0.1 mmol) of 4-diguanidinopyridine. The reaction mixture was stirred at 0 ° C, then 21 mg (0.11 mmol) of 1-(3-dimethylaminopropyl)-10 3-ethylcarbodiimide hydrochloride was added. The reaction mixture was stirred at room temperature for 18 hours then water and ethyl acetate were added. The organic phase was washed with aq. EtOAc EtOAc (EtOAc)EtOAc. If desired, the product is further purified by column chromatography or preparative HPLC. 15 Yield: 29 mg (66%) W-NMR (300 DMS04): δ = 0.7 (7) 3H); 1.3 (six rabbits 2H); 1.7 (s, 3H); 3.0 (q, 2H); 7.6 (m, 2H); 7.8 (m, 2H); 7.9 (m, 1H); 8.1 (d, lH)ppm. -52- This paper scale applies to Chinese national standards (CNS) A4 size (210 X 297 mm)

00

經濟部智慧財產局員工消費合作社印製 1314555 A7 B7 五、發明說明（51) 實例13 4-(4-乳苯基)-N-(2-甲氧乙基）-6-甲基-2-嗣基-1-[3-(三氟甲 基）苯基]-1,2,3,4-四氫-5-嘧啶甲醯胺Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1314555 A7 B7 V. Description of Invention (51) Example 13 4-(4-Lactylphenyl)-N-(2-methoxyethyl)-6-methyl-2- Mercapto-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinamide

CN 5 使48毫克(0.12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10毫克(0.13毫莫耳）2-甲氧 乙胺、18毫克(0.13毫莫耳）1-羥基-1H-苯并三唑水合物及 15毫克（0.12毫莫耳）4-二甲胺基吡啶。於0°C攪拌此反應 混合物，然後添加25毫克(0.13毫莫耳）1-(3-二甲胺基丙 10 基)-3-乙基碳化二亞胺鹽酸鹽。此反應混合物於室溫攪拌 18小時，接著添加水與乙酸乙酯。其有機相.以飽和 KHS04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：22毫克(40%) 'H-NMR (300 MHz, DMSO-d^): δ = 1.7 (s, 3H); 3.2 (s, 3H); 3.3 (m, 4H)； 5.4 (d, 1H); 7.6 (m, 3H); 7.7 (m, 3H); 7.9 (m, 2H); 8.1 (m, 1H) ppm. -53- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）CN 5 48 mg (0.12 mmol) of the compound of Example 11 was dissolved in 2 ml of dimethylformamide, and 10 mg (0.13 mmol) of 2-methoxyethylamine and 18 mg (0.13 m) were added thereto. Molar) 1-hydroxy-1H-benzotriazole hydrate and 15 mg (0.12 mmol) of 4-dimethylaminopyridine. The reaction mixture was stirred at 0 ° C, then 25 mg (0.13 mmol) of 1-(3-dimethylaminopropenyl)-3-ethylcarbodiimide hydrochloride was added. The reaction mixture was stirred at room temperature for 18 hours, then water and ethyl acetate were added. The organic phase was washed with saturated aqueous KHS04, water and brine, dried over sodium sulfate and evaporated If desired, the product is further purified by column chromatography or preparative HPLC. 15 Yield: 22 mg (40%) 'H-NMR (300 MHz, DMSO-d^): δ = 1.7 (s, 3H); 3.2 (s, 3H); 3.3 (m, 4H); , 1H); 7.6 (m, 3H); 7.7 (m, 3H); 7.9 (m, 2H); 8.1 (m, 1H) ppm. -53- This paper scale applies to China 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 1314555 A7 B7 五、發明說明（52 ) 實例14 4-(4-孔苯基）-3,6-二甲基-2-嗣基-1-[3-(三氣甲基）苯基]-1，2,3,4-四氫-5-嘧咬曱酸乙酯Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1314555 A7 B7 V. Description of Invention (52) Example 14 4-(4-Phenylphenyl)-3,6-dimethyl-2-indenyl-1-[3- (trismethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidine ethyl ester

CNCN

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）硫酸二曱酯，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。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%) 'H-NMR (200 MHz, DMSO-d<；): 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. -54- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）5 89 mg (0.21 mmol) of the compound of Example 1 was added to a suspension of 12.4 mg (0.31 mmol) of 60% sodium hydride (in mineral oil) in 2 ml of THF. This mixture was stirred at room temperature for 2 hours. Then, 26 mg (0.21 mmol) of dinonyl sulfate was added, and the mixture was further stirred at room temperature for 2 hours. Next, water and ethyl acetate were added, and the organic phase was washed with water and brine, dried over sodium sulfate and evaporated. If desired, the product is further purified by column chromatography or preparative HPLC. Yield: 85 mg (93%) 'H-NMR (200 MHz, DMSO-d <;): 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. -54- This paper scale applies to Chinese national standards (CNS) A4 size (210x297 mm)

1314555 A7 B7 五、發明說明（53 ) 實例15 3-乙醢基-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-嘧咬甲酸乙酯1314555 A7 B7 V. INSTRUCTIONS (53) Example 15 3-Ethyl-4-(4-cyanophenyl)-6-methyl-2-keto-1-[3-(trifluoromethyl)phenyl -1,2,3,4-tetrahydro-5-pyrimidine ethyl ester

CNCN

經濟部智慧財產局員工消費合作社印製 5 添加100毫克(0.23毫莫耳)實例1化合物至含12毫 克(0.28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91毫克 (1.16毫莫耳）乙醯氣，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滌，以硫 10 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：93毫克（85%) ^H-NMR (200 MHz, DMSO-di): δ = 1.2 (t, 3H); 2.1 (s, 3H); 2.5 (s, 3H); 4.2 (m, 2H); 6.7 (s, 1H); 7.4 (in, 1H); 7.5 (m, 2H); 7.6 (m, 1H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 2H) ppm. -55- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 1314555 A7 B7 五、發明說明（54 ) 實例16 6-(4-乳苯基）-4-曱基-2-嗣基-3-[3-(三氟曱基）苯基]-3,6-二 氫-1，5(2H)-嘧啶二甲酸二乙酯Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Print 5 Add 100 mg (0.23 mmol) of the compound of Example 1 to a 2 ml THF suspension containing 12 mg (0.28 mmol) of 60% sodium hydride (in mineral oil) . This mixture was stirred at room temperature for 2 hours. Then 91 mg (1.16 mmol) of acetonitrile was added and the mixture was stirred at room temperature for a further 2 hours. Water and ethyl acetate were added, the organic phase was washed with water and brine, dried over sodium sulfate, and evaporated to dryness. If desired, the product is further purified by column chromatography or preparative HPLC. Yield: 93 mg (85%) ^H-NMR (200 MHz, DMSO-di): δ = 1.2 (t, 3H); 2.1 (s, 3H); 2.5 (s, 3H); 4.2 (m, 2H) 6.7 (s, 1H); 7.4 (in, 1H); 7.5 (m, 2H); 7.6 (m, 1H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 2H) Ppm. -55- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1314555 A7 B7 V. Description of invention (54) Example 16 6-(4-lacylphenyl)-4-fluorenyl 2-mercapto-3-[3-(trifluoromethyl)phenyl]-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylic acid diethyl ester

0 、CH,0, CH,

4 5 添加100毫克(0.23毫莫耳)實例1化合物至含12毫 克(0.28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）氣化碳酸乙酯，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 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：92毫克(79%) 'H-NMR (200 MHz, DMSO-de): 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_國國家標準(CNS)A4規格（210 X 297公釐） 訂 經濟部智慧財產局員工消費合作社印製4 5 Add 100 mg (0.23 mmol) of the compound of Example 1 to a suspension of 12 mL (0.28 mmol) of 60% sodium hydride (in mineral oil) in 2 mL THF. This mixture was stirred at room temperature for 2 hours. Then, 126 mg (1.16 mmol) of vaporized ethyl carbonate was added, and the mixture was further stirred at room temperature for 2 hours. Next, water and ethyl acetate were added, and the organic phase was washed with water and brine, dried over sodium sulfate and evaporated. If desired, the product is further purified by column chromatography or preparative HPLC. Yield: 92 mg (79%) 'H-NMR (200 MHz, DMSO-de): δ = 1.2 (t, 3 Η; t, 3H); 2.1 (s, 3H); 4.2 (m, 2H); (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 applies _ National Standard (CNS) A4 specification (210 X 297 mm) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

經濟部智慧財產局員工消費合作社印製 1314555 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Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1314555 A7 B7 V. Description of Invention (55) Example 17 4- (4-Cyanophenyl)-6-methyl-1-(3-methylphenyl)-2- Ketopropyl-1,2,3,4-tetrahydro. 5-pyrimidinecarboxylic acid ethyl ester

CNCN

5 使150毫克(1.0毫莫耳）N-[3-甲基苯基]脲、101毫克 (0.77毫莫耳）4-氰基苯甲醛與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，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：8毫克(3%) !H-NMR (200 MHz, DMSO-de): δ = 1.1 (t, 3H); 2.0 (s, 3H); 2.3 (s, 3H); 4.0 (q, 2H); 5.3 (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, lH)ppm. -57- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）5 150 mg (1.0 mmol) of N-[3-methylphenyl]urea, 101 mg (0.77 mmol) of 4-cyanobenzaldehyde and 100 mg (0.77 mmol) of 3-ketobutyl The acid ethyl ester 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. Yield: 8 mg (3%) !H-NMR (200 MHz, DMSO-de): δ = 1.1 (t, 3H); 2.0 (s, 3H); 2.3 (s, 3H); 4.0 (q, 2H) 5.3 (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, lH) Ppm. -57- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm)

1314555 ； 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]-1,2,3,4-四氩-5-嘧啶甲酸乙酯1314555; V. INSTRUCTIONS (56 Example 18 4-(4-Phenylphenyl)-6-methyl-2-keto-1-(3-(trifluoromethyl)phenyl]-1,2,3 , 4-tetraar-5-pyrimidinecarboxylic acid ethyl ester

0 CH, 5 使204毫克（1.0毫莫耳）N-[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，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 10 行純化，以環己烷/乙酸乙酯為溶洗液》 產率：29毫克(9%) 經濟部智慧財產局員工消費合作社印製 'H-NMR (200 MHz, DMSO-de): δ = 1.1 (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） 1314555 A7 B7 五、發明說明（57 ) 實例19 6-(溴曱基）-4-(4-氰苯基）-2-酮基-1-[3-(三氟甲基）苯基]-1,2,3,4-四氫-5-哺咬曱酸乙醋0 CH, 5 makes 204 mg (1.0 mmol) of N-[3-(trifluoromethyl)phenyl]urea, 108 mg (0.77 mmol) of 4-chlorobenzaldehyde with 100 mg (0.77 mmol) Ethyl 3-ketobutanoate 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 EtOAc EtOAc EtOAc EtOAc. Intellectual Property Bureau employee consumption cooperative printed 'H-NMR (200 MHz, DMSO-de): δ = 1.1 (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 scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 PCT) 1314555 A7 B7 V. INSTRUCTIONS (57) EXAMPLE 19 6-(Bromoindolyl)-4-(4-cyanophenyl)-2-keto-1-[3-(trifluoromethyl)phenyl ]-1,2,3,4-tetrahydro-5-sucking vinegar

CNCN

5 使3克(7毫莫耳）實例1化合物溶於100毫升氣仿 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%) 經濟部智慧財產局員工消費合作社印製 •H-NMR (200 MHz, DMSO-4): δ = 1.1 (t, 3H); 4.0 (q, 2H, 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（210x297公釐） A7 1314555 B7 五、發明說明（58 ) 實例20 4-(4-氰苯基)-6-[(二乙胺基）曱基]-2-酮基-1-[3-(三氟甲基） 苯基]-1，2,3,4-四氫-5-嘧咬甲酸乙酯5 3 g (7 mmol) of the compound of Example 1 was dissolved in 100 ml of gas. 558 mg (3.48 mmol) of bromine was added dropwise at 0 °C. 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 vermiculite using cyclohexane / ethyl acetate as solvent. 10 Yield: 3_2 g (90%) Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative • H-NMR (200 MHz, DMSO-4): δ = 1.1 (t, 3H); 4.0 (q, 2H, d, 4.6 (m, 3H); 7.7 (m, 2H); 7.8 (m, 1H); 7.9 (m, 2H); 8.6 (d, 1H) ppm. -59- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) A7 1314555 B7 V. Description of invention (58) Example 20 4-(4-cyanophenyl)-6-[( Ethyldiethyl)mercapto]-2-keto-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

CNCN

'0 八 CH3 ,/-ch3 ^-ch3 ：3 5 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%) 經濟部智慧財產局員工消費合作社印製 W-NMR (300 MHz> DMSOO δ = 0.6 ^ 6H); 1.1 (t，3H); 2.0 (取 2H); 22 (取 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); jq 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 x297公釐） 1314555 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（59 ) 5 10 實例21 6-(苯胺基甲基）-4-(4-乳苯基）-2-嗣基-1-[3-(二乳甲基）苯 基]·1,2,3,4-四氫-5-嘧淀甲酸乙酯'0 八 CH3 , /-ch3 ^-ch3 : 3 5 20 mg (0.04 mmol) of the compound 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%) W-NMR (300 MHz > DMSOO δ = 0.6 ^ 6H); 1.1 (t, 3H); 2.0 (take 2H); 22 (taken) 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); jq 7.7 ( m, 1H); 7.9 (m, 2H) ppm. -60- This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1314555 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention Description (59) 5 10 Example 21 6-(anilinomethyl)-4-(4-lactophenyl)-2-mercapto-1-[3-(dilacmethyl)phenyl]·1,2 , 3,4-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester

CNCN

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%) 'H-NMR (300 MHz, DMSO-di): 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 (m, 2H); 7.6 (m, 6H); 7.9 (m, 2H); 8.4 (d, 1H) ppm. -61- 本紙張尺度適用令國國家標準(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 1314555 A7 B7 五、發明說明（6〇 實例22 (+)-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-嘧咬甲酸乙酯50 mg (0.10 mmol) of the compound of Example 19 was dissolved in 2 ml of acetone and 18 mg (0.20 mmol) of aniline was added. 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%) 'H-NMR (300 MHz, DMSO-di): δ = 1.1 (t, 3H); 3.6 (d/d, 1H); 4.1 (q, 2H); /d, 1H); 5.4 (m, 2H); 6.2 (m, 2H); 6.5 (m, 1H); 6.9 (m, 2H); 7.6 (m, 6H); 7.9 (m, 2H); d, 1H) ppm. -61- This paper scale applies to the national standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1314555 A7 B7 V. Invention description (6〇 example 22 (+)-4-(4-cyanophenyl)-6-methyl-2-keto-1 -[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro -5-pyrimidine ethyl ester

CN 0CN 0

0 CH, 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1.5毫升乙酸乙酯，管柱 KBD 8361 (以單體iV-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，溶洗液乙酸乙醋，流速25毫升/分鐘， 10 溫度23°C，注射量2500微升，檢測254奈米。 !H-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 (m, 2H); 8.4 (d, 1H) ppm.0 CH, 5 Separation of the mirror image isomer of Example 1 by preparative HPLC on the palm phase: 100 mg of the compound was dissolved in 1.5 ml of ethyl acetate, column KBD 8361 (monomer iV-methacryl fluorenyl- L-leucine-1-methyl decylamine is a substrate-based palmitic gel selector, refer to EP-A-379 917), 250 mm X 20 mm, solvent wash ethyl acetate, flow rate 25 ml/min, 10 Temperature 23 ° C, injection volume 2500 μl, detection of 254 nm. !H-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 (m, 2H); 8.4 (d, 1H) ppm.

[a]20 = +3.3° (λ = 589奈米，二氣甲烷，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）[a]20 = +3.3° (λ = 589 nm, di-methane, c = 535.0 mg / 100 ml) -62- This paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm)

1314555 B7 五、發明說明（61) 實例23 ㈠邻-氰苯基)_3,6-二甲基-2,基.丨识王氣甲基)苯基]· 1，2,3,4-四氫_5_嘧唆甲酸乙酯1314555 B7 V. INSTRUCTIONS (61) EXAMPLE 23 (a) o-Cyanophenyl)_3,6-dimethyl-2,yl.丨王王 methyl)Phenyl]· 1,2,3,4-tetrahydro _ 5_pyrimidinecarboxylic acid ethyl ester

〇 、CH, 經濟部智慧財產局員工消费合作社印製 5 添加100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毫升懸 浮液中。此混合物於室溫攪拌2小時。然後添加Μ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i先 10滌，以硫酸鈉脫水，真空蒸發至乾。於矽石上利用管杈層 析法純化產物，以環己烷/乙酸乙酯為溶洗液。 產率：76毫克(74%) *H-NMR (200 MHz, DMSO-d^): δ = 1.1 (t, 3H); 2.0 (s, 3H); 2.8 (s, 3H)； 4>〇 (q 2 5.5 (s, 1H); 7.6 (m, 3H); 7.7 (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H) ppm. ’2H); [a]2() = -18.1° (λ = 589奈米，二氣甲烷，c = 530.0 $克/ loo 毫升） -63- 本紙張尺度適用t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 1314555 m B7 五、發明說明（62) 實例24 4-(6-氰基-3-°比啶基)-6-甲基-2-酮基-1-[3-(三氟甲基）苯基]-1，2,3,4·四氫-5-嘧咬甲酸乙酯〇, CH, Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative Print 5 Add 100 mg (〇.23 mmol) of Example 22 compound to 14 mg (0.35 mmol) of 60% sodium hydride (in mineral oil) 2 ml suspension. This mixture was stirred at room temperature for 2 hours. Then, Μ mg (0.23 mmol) of dimethyl sulfate was added, and the mixture was further stirred at room temperature for 2 hours. Water and ethyl acetate were added, and the organic phase was washed with water and brine, dried over sodium sulfate and evaporated to dryness. The product was purified by column chromatography on a vermiculite using cyclohexane/ethyl acetate as a solvent. Yield: 76 mg (74%) *H-NMR (200 MHz, DMSO-d^): δ = 1.1 (t, 3H); 2.0 (s, 3H); 2.8 (s, 3H); 4> q 2 5.5 (s, 1H); 7.6 (m, 3H); 7.7 (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H) ppm. '2H); [a]2() = - 18.1° (λ = 589 nm, digas methane, c = 530.0 $ g / loo ml) -63- This paper scale applies to national standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Office Employee Consumption Cooperative Printed 1314555 m B7 V. Description of Invention (62) Example 24 4-(6-Cyano-3-pyridinyl)-6-methyl-2-keto-1-[3-(III Fluoromethyl)phenyl]-1,2,3,4·tetrahydro-5-pyrimidine ethyl ester

CNCN

5 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-[3-(三氟甲基）苯基]脲（118毫克，0.58毫莫耳)與 多磷酸乙醋（200毫克；根據Cava ei a/·，J. Org. 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, DMSO-^): 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 (四重年，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（210x297公釐）5 In a stirred solution of Example 3A (76 mg, 0.58 mmol) in THF (5 mL), ethyl 3-ketobutyrate (75 mg, 0.58 mmol), N-[3-(trifluoro) Methyl)phenyl]urea (118 mg, 0.58 mmol) and ethyl polyphosphate (200 mg; freshly prepared according to the procedure of Cava ei a/., J. Org. Chem. 1969, 3, 2665). The reaction mixture was heated under reflux for 10 2 (48 hr) then diluted with EtOAc (2 mL) and purified by preparative HPLC. The product was dissolved in vacuo and the residue was chromatographed on silica eluting with cyclohexane and ethyl acetate. Yield: 92 mg (35% of theory) MS (ESIs): m/z = 431 (M+H) + 15 HPLC (method 4) = 4.63 mins ^-NMR (300 MHz, DMSO-^): 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 (quadruple year, 2H), 2.06 (s, 3H), 1.08 (t, 3H) ppm. -64- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm)

經濟部智慧財產眉員工消費合作社印製 1314555 at 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Ministry of Economic Affairs, Intellectual Property, Eyebrow Workers, Consumer Cooperatives, Printing 1314555 at B7 V. Inventive Note (63) Example 25 4-{5-(1Η-Imidazol-1-ylcarbonyl)-6-methyl-2-keto-1- [3-(Trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-4-pyrimidinyl}benzonitrile

CNCN

5 於含501毫克（1.25毫莫耳)實例11化合物之5毫升 無水二甲基甲醯胺溶液中，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)+ ^-NMR (200 MHz, DMSO-d^}: δ = 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（210x297公釐）5 567 mg (3.5 mmol) of hydrazine, hydrazine-carbonyldiimidazole was added to a solution of 501 mg (1.25 mmol) of the compound of Example 11 in 5 ml of anhydrous dimethylformamide. After allowing the reaction mixture to stand overnight, the solvent was evaporated 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) + NMR (200 MHz, DMSO-d^}: δ = 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 scale applies to Chinese national standards ( CNS) A4 size (210x297 mm)

1314555 at B7 五、發明說明（64 ) 實例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1314555 at B7 V. INSTRUCTIONS (64) Example 26 4-(4-Cyanophenyl)-6-methyl-2-keto-1-(3-(trifluoromethyl)phenyl]-1,2 , 3,4-tetrahydro-5-pyrimidinecarboxylic acid 2-hydroxyethyl ester

CNCN

4 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：0分鐘10% A，2分鐘10% A，6分 10 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49.4%) MS (El): m/z = 446 (M+H)+ iH-NMR (300 MHz，DMSO-d^): δ = 2.05 (d，3H)，3.5 (四重峰，2H)，3·95·4·15 (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- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 訂 經濟部智慧財產局員工消費合作社印製4 5 mg (0.1 mmol) of the compound of Example 25 was added to 0-5 ml of ethylene glycol, and the reaction mixture was stirred at about 100 ° C for 1 hour. After cooling, preparative HPLC (column: Agilent Zorbax Extend C18 20 mm x 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% concentrated aqueous ammonia; gradient: 0 min 10% A, 2 min 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: approximately 500 μl; Injection times: 1) Purification reaction mixture. The product containing the dissolved fractions was combined and concentrated in vacuo. Yield: 22 mg (49.4% of theory) MS (El): m/z = 446 (M+H) + iH-NMR (300 MHz, DMSO-d^): δ = 2.05 (d, 3H), 3.5 (quadruple, 2H), 3·95·4·15 (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- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). system

1314555 a7 B7 五、發明說明（65) 實例27 4-(4-氰苯基)-6-曱基-2-酮基-l-[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 C 3 Η CH-/1314555 a7 B7 V. INSTRUCTIONS (65) Example 27 4-(4-Cyanophenyl)-6-mercapto-2-one-l-[3-(trifluoromethyl)phenyl]-1,2 , 3,4-tetrahydro-5-pyrimidine decanoic acid 2-(dimethylamino)ethyl ester C 3 Η CH-/

v、cf3 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-(二甲胺基）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 Zorbaxv, cf3 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Print 5 Add 45.1 mg (0.1 mmol) of Example 25 compound to 0.5 ml of 2-(dimethylamino)ethanol, and stir the reaction mixture at approximately 100 ° C. hour. After cooling, 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 (ά, 3H), 2.1 (s, 6H), 2.4 (τη, 2H), 4.1 (m, 2H), 5.35 (d, 1H), 7.55 (d, 1H), 7.6 (d, 2H), 7.7 (m, 2H), 7.8 (d, 1H), 7.85 (d, 2H), 15 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） 經濟部智慧財產局員工消費合作社印製 1314555 at B7 五、發明說明（66 ) 實例28 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-嘧啶曱酸2-(4-吡啶基）乙酯Extend C18 20 mm x 50 mm, 5 μm; Solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia; 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: approximately 500 μL; number of injections: 1) Purification of the reaction mixture. The product containing the dissolved fractions was combined and concentrated in vacuo. Yield: 24 mg (50.8% of theory) MS (El): m/z = 473 (M+H) + NMR (300 MHz, DMSO-de): δ = 2.05 (ά, 3H), 2.1 (s, 6H), 2.4 (τη, 2H), 4.1 (m, 2H), 5.35 (d, 1H), 7.55 (d, 1H), 7.6 (d, 2H), 7.7 (m, 2H), 7.8 (d, 1H), 7.85 (d, 2H), 15 8.35 (d, 1H) ppm. -67- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative Printed 1314555 at B7 V. Inventive Note (66) Example 28 4-(4-Cyanophenyl)-6-methyl-2-keto-1-yl-1-[3-(trifluoromethyl)phenyl]-1 , 2,3,4-tetrahydro-5-pyrimidine phthalate 2-(4-pyridyl)ethyl ester

5 添加45.1毫克(0.1毫莫耳)實例25化合物至0.5毫升 2-(4-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 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：17毫克（理論值之33.5%) MS (El): m/z = 507 (M+H)+ !H-NMR (300 MHz, DMSO-di): δ = 2.0 (d, 3H), 2.9 (tr, 2H), 4.3 (ΐτ, 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- 本纸張尺度適用中國國家標準(CNS)A4規格（210 x 297公釐)5 45.1 mg (0.1 mmol) of the compound of Example 25 was added to 0.5 ml of 2-(4-pyridyl)ethanol, and the reaction mixture was stirred at about 100 ° C for 1 hour. After cooling, preparative HPLC (column: Agilent Zorbax Extend C18 20 mm x 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% concentrated aqueous ammonia; gradient: 0 min 10% A, 2 min 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: approximately 500 μl; Injection times: 1) Purification reaction mixture . The product containing the dissolved fractions was combined and concentrated in vacuo. Yield: 17 mg (33.5% of theory) MS (El): m/z = 507 (M+H) + !H-NMR (300 MHz, DMSO-di): δ = 2.0 (d, 3H), 2.9 (tr, 2H), 4.3 (ΐτ, 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- The paper size applies to 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 1314555 A7 B7 五、發明說明（67) 實例29 4-(4-亂苯基)-6-甲基-2-嗣基-1-[3-(三氟甲基）苯基]-1,2,3,4-四氩-5-嘧啶甲酸2-(2-吡啶基）乙酯Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed 1314555 A7 B7 V. Description of Invention (67) Example 29 4-(4-Treatylphenyl)-6-methyl-2-indolyl-1-[3-(trifluoro 2-(2-pyridyl)ethyl ester of methyl)phenyl]-1,2,3,4-tetraar-5-pyrimidinecarboxylate

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 45.1 mg (0.1 mmol) of the compound of Example 25 was added to 0.5 ml of 2-(2-pyridyl)ethanol, and the reaction mixture was stirred at about 100 ° C for 1 hour. After cooling, 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)+ 'H-NMR (300 MHz, DMSO-cU): δ = 2.0 (d, 3H), 3.0 (tr, 2H), 4.4 (tr, 2H), 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, 1H) 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 20 mm x 50 mm, 5 μm; Solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia; 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: approximately 500 μL; number of injections: 1) Purification of the reaction mixture. The product containing the dissolved fractions was combined and concentrated in vacuo. Yield: 22 mg (43.4% of theory) MS (El): m/z = 507 (M+H) + "H-NMR (300 MHz, DMSO-cU): δ = 2.0 (d, 3H), 3.0 (tr, 2H), 4.4 (tr, 2H), 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, 1H) ppm. -69- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

1314555 A7 B7 五、發明說明（68 )1314555 A7 B7 V. Description of invention (68)

實例30 4-(4-氰苯基)-6-甲基-2-酮基-1-[3-(三氟甲基）苯基]-1,2,3,4-四風-5- ♦咬甲酸2-(2 -嗣基-1 - 0比嘻交基）乙S旨 CNExample 30 4-(4-Cyanophenyl)-6-methyl-2-keto-1-(3-(trifluoromethyl)phenyl]-1,2,3,4-tetrapent-5- ♦ biting formic acid 2-(2-indolyl-1 - 0 is more than hydrazine)

5 添加45.1毫克(0.1毫莫耳)實例25化合物至0.5毫升5 Add 45.1 mg (0.1 mmol) of Example 25 compound to 0.5 mL

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：AgilentIn 1-(2-hydroxyethyl)-2-pyrrolidone, the reaction mixture was stirred at about 100 ° C for 1 hour. After cooling, 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% 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 經濟部智慧財產局員工消費合作社印製 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): myz = 513 (M+H)+ (300 MHz，DMSO-de): δ = 1.8 (五重♦，2H)，2.0 (4 3H)，2.1 (tr，2H)，3.2 (tr, 2H), 3.4 (ίτ, 2H), 4.0-4.2 (m5 2H), 5.35 (d, 1H), 7.55 (d, 1H), 7.6 (d, 2H), 7.7 (tr, 15 2H), 7.8 (d, 1H), 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 X297公釐） 1314555 at B7 五、發明說明（69 ) 以類似實例14-16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 结構 起始物質 產率 [%] RJ分鐘I (方法） 質量 [Μ+Η]+ 31 。§ H,c 八。 H3c人Ν人0 〇 I, 實例1 ; 溴乙酸乙酯 85 4.01 (1) 516 32 xa〇 實例1; 環丙烷-羰基氯 79 4.09(1) 498 33 HSC 八 八 CH3 H3C人N入。 實例1 ; 溴乙烷 15 4.2S (2) 458 34 。么 H3d 人义 H3C 人 N 入。、 ίΧ, 實例1 ; 4-嗎啉-羰基氣 97 3.97 (2) 543 -71-Zorbax Extend C18 20 mm X 50 mm, 5 μm; Solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia; gradient: 0 minutes 10% 10 A, 2 minutes 10% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; Wavelength: 220 nm; Injection volume: Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives limit 500 microliters; number of injections: 1) purification reaction mixture. The product containing the dissolved fractions was combined and concentrated in vacuo. Yield: 25 mg (48.8% of theory) MS (El): myz = 513 (M+H) + (300 MHz, DMSO-de): δ = 1.8 (five ♦, 2H), 2.0 (4 3H ), 2.1 (tr, 2H), 3.2 (tr, 2H), 3.4 (ίτ, 2H), 4.0-4.2 (m5 2H), 5.35 (d, 1H), 7.55 (d, 1H), 7.6 (d, 2H) ), 7.7 (tr, 15 2H), 7.8 (d, 1H), 7.9 (d, 2H), 8.4 (d, 1H) ppm. -70- This paper scale applies to China National Standard (CNS) A4 specification (210 X297) PCT) 1314555 at B7 V. INSTRUCTIONS (69) The following compounds were prepared in a similar manner to the procedures of Examples 14-16: Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed Example Number Structure Starting Material Yield [%] RJ minutes I (method) quality [Μ+Η]+ 31 . § H, c VIII. H3c human 0 0 〇 I, Example 1; ethyl bromoacetate 85 4.01 (1) 516 32 xa 实例 Example 1; cyclopropane-carbonyl chloride 79 4.09 (1) 498 33 HSC VIII CH3 H3C human N. Example 1; ethyl bromide 15 4.2S (2) 458 34 . H3d Humanity H3C People N In. , ίΧ, Example 1; 4-morpholine-carbonyl gas 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） A7 1314555 B7 五、發明說明（7〇) 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 [%] IM分鐘] (方法） 質量 ίΜ+ΗΓ 35 CN CH HSC人入叫 ^cf3 實例I; 二甲基-胺甲醯氣 98 4.00 (2) 523 [M+Na]+ 36 CN CH h3c o 入rj* 人〇〆 CH3 H3c人N人。 實例1; 氣化碳酸甲酯 96 4,10 (2) 488 37 ^:Xco 乂. 實例1; 苄基溴 58 4.59 (2) 520 38 CN h3c"^n 人。 實例1 ; 丙醯氯 43 4.42 (2) 486 -72- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 1314555 A7 B7 五、發明說明（71) 經濟部智慧財產局員工消費合作社印製 實例 編號 结構 起始物質 產率 [%】 R«[分鐘1 (方法） 質量 IM+H]+ 39 A H3C 八。人|j^N 人0^*^。、。' H3C人N入0 實例1 ; 氯化破豉 2-甲氡乙瘅 95 4.12(2) 532 40 CN hsc^o^^0C-^YCH3 h3c人入％ 實例1; 氣化碳酸 異丙酯 67 4.55 (2) 500 41 HsC：A。人人 N|ACHj H3C^tji入0、h3 實例1 ; 二乙基-胺甲醯氯 18 4.25 (2) 529 42 CN H3c-〇^VC h3c"^n人0 CH3 實例1 ; 甲基(甲基-磺殖基)* 胺甲醯氯 40 4.10(2) 565 -73- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 1314555 … B7 五、發明說明（72 ) 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 IM+H]* 43 CN HjC 八。人^-γΝΗ: H3C乂'Ν入0 〇 實例1; 2-溴-乙醯胺； 2.5當量NaH 54 3.7 (3) 487 44 CN 實例1 ; 2-溴-乙酸； 2.5當董NaH 67 3.8(3) 488 45 CN %。八。人八^州2 H3C人Ν人。 實例1 ; 2-溴-乙胺 氫溴酸璺； 2.5當量NaH 28 2.9(2) 473 46 CN ，这:〇 實例1 ; 2-(氩甲基)吡啶 鹽酸麋； 2.5當量NaH 37 4.0(3) 521 -74-This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) A7 1314555 B7 V. Invention description (7〇) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing example number structure starting material yield [% IM minutes] (method) quality Μ+ΗΓ 35 CN CH HSC entry is ^cf3 example I; dimethyl-amine methotrexate 98 4.00 (2) 523 [M+Na]+ 36 CN CH h3c o into rj * People 〇〆 CH3 H3c people N people. Example 1; gasified methyl carbonate 96 4,10 (2) 488 37 ^:Xco 乂. Example 1; benzyl bromide 58 4.59 (2) 520 38 CN h3c"^n person. Example 1; Propylene Chloride 43 4.42 (2) 486 -72- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1314555 A7 B7 V. Invention Description (71) Ministry of Economic Affairs Intellectual Property Bureau employees Consumer Cooperatives Printed Example Number Structure Starting Material Yield [%] R«[minute 1 (method) quality IM+H]+ 39 A H3C VIII. People|j^N people 0^*^. ,. 'H3C human N into 0 example 1; chlorinated ruthenium 2-methyl acetamidine 95 4.12(2) 532 40 CN hsc^o^^0C-^YCH3 h3c human into % Example 1; gasified isopropyl carbonate 67 4.55 (2) 500 41 HsC: A. Everyone N|ACHj H3C^tji into 0, h3 Example 1; diethyl-amine formazan chloride 18 4.25 (2) 529 42 CN H3c-〇^VC h3c"^n人0 CH3 Example 1; Methyl (A) Base-sulfonycyl)* Aminoguanidine chloride 40 4.10(2) 565 -73- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1314555 ... B7 V. Invention Description (72) Ministry of Economic Affairs Property Bureau Staff Consumer Cooperative Printed Example Number Structure Starting Material Yield [%] RJ min] (Method) Quality IM+H]* 43 CN HjC VIII. Human ^-γΝΗ: H3C乂'Ν0Ν Example 1; 2-bromo-acetamide; 2.5 equivalents of NaH 54 3.7 (3) 487 44 CN Example 1; 2-bromo-acetic acid; 2.5 when Dong NaH 67 3.8 ( 3) 488 45 CN %. Eight. People eight ^ 2 2 H3C people swearing. Example 1; 2-bromo-ethylamine hydrazide hydrobromide; 2.5 equivalents of NaH 28 2.9 (2) 473 46 CN , this: hydrazine example 1; 2-(argonmethyl)pyridine guanidine hydrochloride; 2.5 equivalents of NaH 37 4.0 (3 ) 521 -74-

本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 1314555 μ B7 五、發明說明（73 ) 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 [%] IM分鐘】 (方法） 質量 (M+H]+ 47 CN χΦ rCHs ηΛΛο 實例1 ; N-<2-溴-乙基) NJN-二乙胺 氩溴酸S ; 2.5當量NaH 82 2.98 (2) 529 48 CN H3C 八 h3c^n^o 0 灰 實例1; 2-溴-N_甲基-乙醯胺； 2J當量NaH 65 3.70 (2) 501 49 CN ，症:〇 實例1 ; 3·(氩甲基)咄啶 鹽酸里； 2.5當量NaH 15 3.68 (2) 521 50 CN ，这：〇 實例1; 4*(氣甲基)吡啶 鹽酸鹽； 2.5當量NaH 21 3.47 (2) 521 -75-This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1314555 μ B7 V. Description of invention (73) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing example number structure starting material yield [%] IM minutes 】 (Method) Mass (M+H)+ 47 CN χΦ rCHs ηΛΛο Example 1; N-<2-bromo-ethyl) NJN-diethylamine argon bromate S; 2.5 equivalents NaH 82 2.98 (2) 529 48 CN H3C 八h3c^n^o 0 ash example 1; 2-bromo-N-methyl-acetamide; 2J equivalent NaH 65 3.70 (2) 501 49 CN , disease: 〇 example 1 ; 3 · (argon methyl Acridine hydrochloride; 2.5 equivalents of NaH 15 3.68 (2) 521 50 CN , this: 〇 Example 1; 4 * (gas methyl) pyridine hydrochloride; 2.5 equivalents of NaH 21 3.47 (2) 521 -75-

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） A7 1314555 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 [%] RJ分鐘] (方法） 質量 (M+H]* 51 CN 實例1; 2-(溴甲基)-1Η-咪唑鹽酸鹽； 2.5當量NaH 6 2.97 (2) 510 52 CN H3c 八 八 CN HSC 人 ϊ|ί 入。 實例1 ; 3·(氯甲基)· U2,4>«f 二唑 37 4.0(3) 469 S3 〇ό Η h3c^〇-^Y^n^YNv^〇^ch, η,〇ΑΛ> 〇 實例1 ; 2-溴->H2-甲氧乙基)-乙趄肢 91 1 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） 1314555 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： 實例 編號 結構 起始物質 產率[%} 良[分鐘] (方法） 質量 [M+Hf 54This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) A7 1314555 B7 V. Invention description (74) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 6 7 Example number structure starting material yield [ %] RJ min] (method) mass (M+H)* 51 CN Example 1; 2-(bromomethyl)-1Η-imidazole hydrochloride; 2.5 equivalents of NaH 6 2.97 (2) 510 52 CN H3c 八八CN HSC 人ϊ|ί 入. Example 1; 3·(Chloromethyl)· U2,4>«f Diazole 37 4.0(3) 469 S3 〇ό Η h3c^〇-^Y^n^YNv^〇^ch , η, 〇ΑΛ > 〇 Example 1; 2-Bromo->H2-methoxyethyl)-B-limb limb 91 1 3,77 (2) 545 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1314555 A7 B7 V. INSTRUCTIONS (75) The following compounds were prepared in a similar manner to the procedures of Examples 6-8: Example number structure starting material yield [%} good [min] (method) mass [M +Hf 54

{三氟甲基)-苯基]-脲； 4-氱基-笨f醛； 3-SH基丁酸甲酯 79 3.68 (2) 416 55{trifluoromethyl)-phenyl]-urea; 4-mercapto-stupylaldehyde; methyl 3-SH-butyrate 79 3.68 (2) 416 55

Ν·[3*(三氣甲基)-苯基]-脲； 4·氱基-笨甲醛； 3-網基丁酸-環丙基甲酯 S8 4.09 (2) 456 4 訂Ν·[3*(trimethylmethyl)-phenyl]-urea; 4·decyl-benzaldehyde; 3-methylbutyric acid-cyclopropylmethyl ester S8 4.09 (2) 456 4

56 H3c 0〆 γ 'NH人。56 H3c 0〆 γ 'NH people.

CF, Ν-[3·(三氟甲基)-笨基]•脲； 4*氰基·笨甲醛； 3-酮基丁酸異丙酯 85 4.03 (2) 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） A7 B7 1314555 五、發明說明（76 )CF, Ν-[3·(trifluoromethyl)-phenyl] urea; 4* cyano-benzaldehyde; isopropyl 3-ketobutanoate 85 4.03 (2) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative The printed paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1314555 V. Description of invention (76)

實例59 4-(4-氰苯基)-6-曱基-3-[2-(4-嗎啉基）-2-酮乙基]-2-酮基-1-[3-(三氟甲基）苯基]-1,2,3,4-四氫-5-嘧啶甲酸乙酯Example 59 4-(4-Cyanophenyl)-6-mercapto-3-[2-(4-morpholinyl)-2-oneethyl]-2-keto-1-[3-(trifluoro) Methyl)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 ^O^CH3 ch3 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） A7 1314555 B7 五、發明說明（77) 甲基甲醯胺中，於其内添加16毫克(0.18毫升）嗎啉、24 毫克(0.18毫莫耳）1-羥基-1H-苯并三唑水合物及20毫克 (0.16毫莫耳）4-二甲胺基吡啶。於0°C攪拌此反應混合 物，然後添加35毫克(0.18毫莫耳）1-(3-二甲胺基丙基)-5 3-乙基碳化二亞胺鹽酸鹽。此反應混合物於室溫攪拌18 小時，接著添加水與乙酸乙酯。其有機相以飽和硫酸鈉脫 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：78毫克(85%) ^-NMR (300 MHz, DMSO-dfi): δ = 1.1 (t, 3H); 2.0 (s, 3H); 3.4 (m, 4H); 3.6 (m, 4H); 3.7 (d, 1H); 4.1 (m, 2H); 4.5 (d, 1H); 5.5 (s, 1H); 7.6 (m, 5H); 7.8 (m, 1H); 7.9 l〇 (m, 2H) ppm. 以類似實例59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 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） A7 1314555 B7 五、發明說明（78 ) 實例 編號 结構 起始物質 產率 [%] 民[分鏤1 (方法） 質量 [M+H]+ 60 队。〇, ° o^nAch3 實例44; N-甲基哌畤 90 2.93 (2) 570 61 H,i ηντ^ιλ °^CHa 實例44; Ν·(2·胺基· 乙基)-Ν>Ν-二甲胺 87 2.93 (2) 558 62 CN 〇 0人!人 CH3 實例44; 2Μ二甲胺 之THF溶液 83 3.S4 (2) 515 經濟部智慧財產局員工消費合作社印製 以類似實例6-8之程序，製備下述化合物： 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 1314555 at B7 五、發明說明（79 ) 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） 質量 [Μ+Η]+ 63 6 η〜ν X Wo N-[3-(三氟-甲基)苯基]脲； 4- 氣基· 苯甲醛； K3·甲基-1,2,4·哼二唑- 5- 基)丙酮 23 3.80 (3) 440 64 CM N-[3-(三氟-甲基)苯基】脲； 4·氰基-苯甲醛； 噻唑-2-基> 丙明 23 4.42 (2) 491 65 CN Ά Ά人 Ν·[3·(三氟· 甲基)笨基]脲； 4·氣基-苯甲醛； 5·甲基·2,4-己二阐 33 4-3(1) 428 66 H3C"〇Vv^TiVNH hA人。 Ν-Ρ-(三氟· 甲基)苯基]脲； 4·氱基- 笨甲醛； 1-甲氧基-2,4· 戊二酮 3 3.47 (2) 430 -81-Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed ^O^CH3 ch3 80 mg (0.16 mmol) of Example 44 compound dissolved in 2 ml 2-78- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) A7 1314555 B7 V. INSTRUCTIONS (77) In methylformamide, 16 mg (0.18 ml) of morpholine, 24 mg (0.18 mmol) of 1-hydroxy-1H-benzophenone were added thereto. Triazole hydrate and 20 mg (0.16 mmol) of 4-dimethylaminopyridine. The reaction mixture was stirred at 0 ° C, then 35 mg (0.18 mmol) of 1-(3-dimethylaminopropyl)-5 3-ethylcarbodiimide hydrochloride was added. The reaction mixture was stirred at room temperature for 18 hours then water and ethyl acetate were added. The organic phase was dehydrated with saturated sodium sulfate and evaporated to dryness in vacuo. If desired, the product is further purified by column chromatography or preparative HPLC. Yield: 78 mg (85%) ^-NMR (300 MHz, DMSO-dfi): δ = 1.1 (t, 3H); 2.0 (s, 3H); 3.4 (m, 4H); 3.6 (m, 4H) ; 3.7 (d, 1H); 4.1 (m, 2H); 4.5 (d, 1H); 5.5 (s, 1H); 7.6 (m, 5H); 7.8 (m, 1H); 7.9 l〇(m, 2H) Ppm. In the same manner as in Example 59, the following compounds were prepared: Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed on this paper scale, applicable to China National Standard (CNS) A4 specification (210 X 297 mm) A7 1314555 B7 V. Invention Description (78) Example number structure Starting material yield [%] Min [Bifurcation 1 (method) quality [M+H] + 60 teams. 〇, ° o^nAch3 Example 44; N-methylpiperidin 90 2.93 (2) 570 61 H,i ηντ^ιλ °^CHa Example 44; Ν·(2·amino·ethyl)-Ν>Ν- Dimethylamine 87 2.93 (2) 558 62 CN 〇0 people! Human CH3 Example 44; 2 dimethylamine THF solution 83 3.S4 (2) 515 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed similar example 6- Procedure for preparation of the following compounds: The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1314555 at B7 V. Description of invention (79) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing example number Structure starting material yield [%] 丨 min] (method) mass [Μ+Η]+ 63 6 η~ν X Wo N-[3-(trifluoro-methyl)phenyl]urea; 4-gas Benzoaldehyde; K3·methyl-1,2,4·oxadiazole- 5-yl)acetone 23 3.80 (3) 440 64 CM N-[3-(trifluoro-methyl)phenyl]urea; 4·cyano-benzaldehyde; thiazol-2-yl> propylamine 23. 4.42 (2) 491 65 CN Ά Ά人Ν·[3·(trifluoromethyl)phenyl]urea; 4·gas-based Benzaldehyde; 5·methyl·2,4-hexane II 33 4-3(1) 428 66 H3C"〇Vv^TiVNH hA person. Ν-Ρ-(trifluoromethyl)phenyl]urea; 4·fluorenyl-benzaldehyde; 1-methoxy-2,4·pentanedione 3 3.47 (2) 430 -81-

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 1314555 五、發明說明（80 ) A7 B7 經濟部智慧財產局員工消費合作社印製This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1314555 V. Invention description (80) A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-82- 4. •訂· 本紙張尺度適用中國國家標準(CNS)A4現格（210 X297公釐） A7 1314555 B7 五、發明說明（^) 實例70 4-(4-氛苯基)-6-甲基-2-嗣基-1-[3-(二氣甲基）苯基]-1,2,3,4_ 四氫-5-嘴咬甲醯胺-82- 4. • Set · This paper scale applies to China National Standard (CNS) A4 (210 X297 mm) A7 1314555 B7 V. Description of Invention (^) Example 70 4-(4-Aromatic Phenyl)-6 -Methyl-2-mercapto-1-[3-(dimethylmethyl)phenyl]-1,2,3,4_tetrahydro-5-mouth acetaminophen

CNCN

經濟部智慧財產局員工消費合作社印製 5 使200毫克(0.5毫莫耳)實例11化合物溶於5毫升四 氫呋喃及6毫克(0.05毫莫耳）4-N，N-二甲胺基吡啶中，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（吹咯啶 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(於二啐烷中之0.5 Μ溶液）。此反應混 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%) 'H-NMR (200 MHz, DMSO-d6): δ = 1.8 (s, 3H); 5.4 (d, 1H); 7.2 (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) 1314555 a7 B7 五、發明說明（82 ) 實例71 (+)-4-(4-孔苯基）-6-甲基-2-_基-1-[3-(三氟甲基）苯基] 1,2,3,4-四氫-5-嘧咬曱酸Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative 5, 200 mg (0.5 mmol) of the compound of Example 11 was dissolved in 5 ml of tetrahydrofuran and 6 mg (0.05 mmol) of 4-N,N-dimethylaminopyridine. Add 77 mg (0.6 mmol) of N,N-diisopropylethylamine and 115 mg (0.6 mmol) of benzotriazol-1-yloxy-hexafluorophosphate Base) scales. The reaction mixture was stirred at room temperature for 15 minutes, then 5 10 liters (2.5 mmol) of aqueous ammonia (0.5 Μ solution in dioxane) was added. The reaction mixture was stirred at room temperature for 1 hour, 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 by preparative HPLC. Yield: 55 mg (28% of theory) 'H-NMR (200 MHz, DMSO-d6): δ = 1.8 (s, 3H); 5.4 (d, 1H); 7.2 (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 scale applies to Chinese national standards ( CNS) A4 size (210 x 297 mm) 1314555 a7 B7 V. Description of invention (82) Example 71 (+)-4-(4-Phenylphenyl)-6-methyl-2-yl-1-[ 3-(trifluoromethyl)phenyl] 1,2,3,4-tetrahydro-5-pyrimidine

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經濟部智慧財產局員工消費合作社印製 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]。 !H-NMR (300 MHz, DMSO-dfi): 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, lH)ppm.Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives 5 Separation of the image isomers of Example 11 by preparative HPLC on the palm of the hand: [column KBD 8361 (with monomer, methacryloyl-L-leucine) -1-Methylguanamine is a base-based silicone resin selector, refer to EP-A-379 917), 250 mm X 20 mm, solvent solution: ethyl acetate-methanol-ethyl acetate, flow rate 25 ml/ Minutes, temperature 23 ° C, detection 254 10 nm]. !H-NMR (300 MHz, DMSO-dfi): 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, lH) ppm.

[a]20 =+2.5。（λ = 589奈米，甲醇，c = 505 毫克 / 100 毫升） 實例72 (+)-4-(4-氰苯基）-6-甲基-2-酮基-l-[3-(三氟甲基）苯基]-1,2,3,4-四氫-5-嘧啶甲酸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） 1314555 A7 B7 五、發明說明（83)[a]20 =+2.5. (λ = 589 nm, methanol, c = 505 mg / 100 ml) Example 72 (+)-4-(4-cyanophenyl)-6-methyl-2-keto-l-[3-(three Fluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid 2-hydroxyethyl ester-84- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1314555 A7 B7 V. Description of invention (83)

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經濟部智慧財產局員工消費合作社印製 氬氣下，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1.095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毫升甲醇申，利 用製備性 HPLC(管柱：Nucleosil 100-5 C 18 Nautilus，20 x 50毫米，5微米；溶劑A :乙腈，溶劑B :水+ 0.3% 10 甲酸；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 ;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，並予以冷凉乾燥。 產率：1290毫克（理論值之74.5%) MS (El): m/z = 446 (M+H)+ W-NMR (300 MHz，DMSOO: δ = 2.05 (4 3H); 3.5 (四重峰，2H); 3,95-4.15 机 2H); 4.75 (tr, 1H); 5.45 (d, 1H); 7.55-7.75 (m, 5H); 7.75 (d, 1H); 7.85 (d, 2H); 8.35 (d, 1H) ppm. 15 [α]20 = +14·3〇(λ = 589奈米，甲酵，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） A7 1314555 B7 五、發明說明（84 ) 實例73 5-{5-乙醯基-6-甲基-2-酮基-1-[3-(三氟甲基）苯基]-1,2,3,4-四風-4-喷咬基} -2-0比咬甲赌Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, under argon, 1560 mg (3.89 mmol) of Example 71 compound 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. After dehydration with magnesium sulfate, the organic phase was concentrated in vacuo. The residue was mixed with 8 mL of methanol by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus, 20 x 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.3% 10 formic acid; 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; Wavelength: 220 nm; Injection volume: approximately 500 μl ; number of injections: 18) to be purified. The product containing the dissolved fractions was combined and cooled and dried. Yield: 1290 mg (74.5% of theory) MS (El): m/z = 446 (M+H) + W-NMR (300 MHz, DMSOO: δ = 2.05 (4 3H); 3.5 (quadruple , 2H); 3, 95-4.15 machine 2H); 4.75 (tr, 1H); 5.45 (d, 1H); 7.55-7.75 (m, 5H); 7.75 (d, 1H); 7.85 (d, 2H); 8.35 (d, 1H) ppm. 15 [α]20 = +14·3〇(λ = 589 nm, methyl leaven, c = 455 mg/100 ml) -85- This paper size applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) A7 1314555 B7 V. Description of the invention (84) Example 73 5-{5-Ethyl-6-methyl-2-keto-1-[3-(trifluoromethyl) )phenyl]-1,2,3,4-four wind-4-spray base} -2-0 than bite

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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3A (75毫克，0.57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）、N-[3-(三氟甲基)苯基]脲(116毫克，0.57毫莫耳)與多磷酸乙 S旨（200 毫克）[根據 Cava ei a/·, J. Org. Chem. 34, 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, DMS0-d«): δ = 2.02 (s, 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- 本纸張尺度適用中國國家標準(CNS)A4規格（210 x 297公釐） 1314555 A7 B7 五、發明說明（85 ) 實例74 (+)-5-{5-乙酿基-6-甲基-2-嗣基-1 - [3-(三氣甲基）苯基]· 1,2,3,4-四乳-4-°^咬基}-2-0比咬甲猜Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumers Co., Ltd. 5 In a stirred solution of Example 3A (75 mg, 0.57 mmol) in tetrahydrofuran (5 mL), add 2,4-pentanedione (57 mg, 0.57 mmol) , N-[3-(Trifluoromethyl)phenyl]urea (116 mg, 0.57 mmol) and polyphosphoric acid B (200 mg) [according to Cava ei a/·, J. Org. Chem. 34 , 2665 (1969) procedures for fresh preparation]. The reaction mixture was heated to reflux for 24 hours, then was diluted with EtOAc (2 mL) and purified using preparative HPLC. Yield: 101 mg (44% of theory) ^-NMR (200 MHz, DMS0-d«): δ = 2.02 (s, 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- This paper scale applies to China National Standard (CNS) A4 specification (210 x 297) PCT) 1314555 A7 B7 V. INSTRUCTIONS (85) EXAMPLE 74 (+)-5-{5-Ethyl-6-methyl-2-indolyl-1 - [3-(trimethylmethyl)phenyl ]· 1,2,3,4-four milk-4-°^bite base}-2-0 than bite

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經濟部智慧財產局員工消費合作社印製 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-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]。 !H-NMR (300 MHz, CDCls)： 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)+ [a]2() =+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-l-[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（210 X 297公釐） 1314555 A7 B7 五、發明說明（86 )Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives 5 Separation of the image isomers of Example 73 by preparative HPLC on the palm of the hand: [column KBD 8361 (with monomeric iV-methacryloyl-L-amine) Acid-1-methyl decylamine is a substrate-based palmitic gel selector, refer to EP-A-379 917), 250 mm X 20 mm, solvent solution: ethyl acetate-methanol-ethyl acetate, flow rate 25 ml /min, temperature 23 ° C, detection 254 10 nm]. !H-NMR (300 MHz, CDCls): 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) + [a]2() = +25.1. (δ = 589 nm, methanol, c = 505 mg / 100 ml) Example 75 4-(4-cyanophenyl)-6-methyl-2-keto-l-[3-(trifluoromethyl) Phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid 2-(2-pyridyl)methyl ester-87- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1314555 A7 B7 V. Description of invention (86)

NN

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經濟部智慧財產局員工消費合作社印製 於含40.1毫克(0.1毫莫耳)實例Π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） Ν,Ν-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：Nucleosil 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 (El): m/z = 493 (M+H)+ ^-NMR (300 MHz, DMS0-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（210 X 297公釐） 1314555 A7 B7 五、發明說明（87 ) 實例76 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-嘲咬甲酸2-(3-0比唆基）乙S旨The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed in a solution containing 40.1 mg (0.1 mmol) of hydrazine compound in 0.4 ml of anhydrous dimethylformamide, adding 48.6 mg (0.3 mmol) of hydrazine, hydrazine-carbonyl Diimidazole. After allowing the reaction mixture to stand for 1 hour, it was diluted with water and extracted with dioxane. After dehydration with magnesium sulfate, the solvent was removed by evaporation in vacuo. 0.5 ml of (2-pyridyl)methanol was added to the residue. This reaction mixture was stirred at about 100 ° C for 1 hour. After cooling, use preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus, 20 mm X 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% methyl 10 acid; 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 550 micro l; number of injections: 1) to be purified. The product containing the dissolved fractions was combined and concentrated in vacuo. 15 Yield: 17 mg (34.5% of theory) MS (El): m/z = 493 (M+H) + NMR (300 MHz, DMS0-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- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1314555 A7 B7 V. Inventive Note (87) Example 76 4-(4-Cyanophenyl)-6-methyl 2-keto-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-bracket acid 2-(3-0-indenyl)B

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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 升無水二甲基甲醯胺溶液中，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 經濟部智慧財產局員工消費合作社印製 約l〇〇°C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 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%曱酸；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） A7 B7 1314555 五、發明說明（μ ) LC-MS (EI ’ 方法 5) : m/z = 507 (M+H)+，Rt = 3.19 分鐘 實例77 4-(4-氰苯基）-3,6-二甲基-2-酮基-1-[3-(三氟曱基）苯基]-1,2,3,4-四氫-5-嘧啶甲酸5 To a solution of 60.2 mg (0.15 mmol) of the compound of Example 11 in 0.57 ml of dry dimethylformamide, 72.9 mg (0.45 mmol) of hydrazine, hydrazine-carbonyldiimidazole was added. After allowing the reaction mixture 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 to 10 20 μl (0.27 mmol) of triethylamine in the residue. The reaction mixture was mixed for about 1 hour at about 10 °C in the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs. Then diluted with 0.4 ml of methanol, filtered, using preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus, 20 mm X 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% citric acid; Gradient: 0 minutes 10% A, 2 minutes 10% 15 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: approximately 550 μl; number of injections: 1) Purification. The product containing the dissolved fractions was combined and concentrated in vacuo. Yield: 44 mg (57.9% of theory) -89- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1314555 V. Description of invention (μ) LC-MS (EI ' Method 5): m/z = 507 (M+H)+, Rt = 3.19 min Example 77 4-(4-Cyanophenyl)-3,6-dimethyl-2-keto-1-- (trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid

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經濟部智慧財產局員工消費合作社印數 使4.1克(9.25毫莫耳)實例14化合物溶於1〇〇毫升乙 醇中’於此溶液中添加6.2毫升(27.6毫莫耳）氫氧化鉀水 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 殘留物於矽石上利用管柱層析法予以純化，以環己燒/乙 酸乙醋為溶洗液。 15 產率：1·5克（理論值之39%) MS (ΕΙ): ταίζ « 416 (M+H)+ lH-NMR (300 MHz, DMSO-di): 5 = 2.0 (s, 3H); 2.8 (s, 3H); 5.5 (d, 1H)； 7.6-7 8 (m 6H); 7.9(d, 2H); 12.6 (s, 1H) ppm. ' -90· 本紙張尺度適用中國國家標準(CNS)A4現格（210 x 297公釐) . ' --— 1314555 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[分鐘] (方法） 質量 [M+H]+ 78 CN 〇0 0^：χχ〇 實例11; 3-°tt咬基-甲酵 56.9 3.45 (5) 493 79 CN ^V;Yxo 實例11; 2·羥基-乙通胺U 61.1 3.38 (5) 459 80 0 h3c"^n 入。 實例11; 2-羥乙基· (甲基)甲醯胺 80.9 3-5 (5) 487 81 Η3〇^Ν^〇1λ 0 η3οΛΛο 實例11; 2-羥乙基-乙醯胺 56.2 3.44 (5) 487 -91-The Ministry of Economic Affairs Intellectual Property Bureau staff consumption cooperative printed a number of 4.1 grams (9.25 millimoles) of the compound of Example 14 dissolved in 1 ml of ethanol 'Add 6.2 ml (27.6 mmol) of potassium hydroxide solution to this solution (25 weight%). The reaction mixture was allowed to stand at room temperature for 18 hours. Then, 12.4 ml (55.2 mmol) of aqueous potassium hydroxide solution (25 wt%) 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 1 mL of 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 vermiculite using cyclohexane/ethyl acetate as a solvent. 15 Yield: 1-5 g (39% of theory) MS (ΕΙ): ταίζ « 416 (M+H) + lH-NMR (300 MHz, DMSO-di): 5 = 2.0 (s, 3H); 2.8 (s, 3H); 5.5 (d, 1H); 7.6-7 8 (m 6H); 7.9(d, 2H); 12.6 (s, 1H) ppm. ' -90· This paper scale applies to Chinese national standards ( CNS) A4 grid (210 x 297 mm) . ' --- 1314555 A7 B7 V. INSTRUCTIONS (89 ) In the same manner as in Example 76, the following compounds were prepared: Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing example No. Structure Starting material yield [%] [min] [Method] Mass [M+H]+ 78 CN 〇0 0^: χχ〇 Example 11; 3-°tt 咬-甲酵56.9 3.45 (5) 493 79 CN ^V; Yxo Example 11; 2·Hydroxy-ethylamine U 61.1 3.38 (5) 459 80 0 h3c"^n In. Example 11; 2-Hydroxyethyl·(methyl)formamide 80.9 3-5 (5) 487 81 Η3〇^Ν^〇1λ 0 η3οΛΛο Example 11; 2-Hydroxyethyl-acetamide 56.2 3.44 (5 ) 487 -91-

本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 1314555 a7 B7 五、發明說明（90 ) 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[分錢】 (方法） 質量 (Μ+Η]+ 82 CN 4。 實例11; (1-甲基-1Η· 味嗅-5-基)* 甲酵υ 45.8 2.87 (5) 496 83 HjC^N^O I 實例11; 2·(1Η-吡唑· 1-基)乙酵 60.6 3.7 (5) 496 84 〇0 u^0IX H.C^N^O 實例11; 2-(1Η-132,4-三嗓-1-基)· 乙醇1) 67.1 3.48 (5) 497 85 〇0 CH3 t 實例11; 乙酸2-羥乙酯 56.1 3.98 (5) 488 -92-This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1314555 a7 B7 V. Invention description (90) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing example number structure starting material yield [%] Dividends] (Method) Mass (Μ+Η)+ 82 CN 4. Example 11; (1-Methyl-1Η·味嗅-5-yl)* 甲υυ 45.8 2.87 (5) 496 83 HjC^N^ OI Example 11; 2·(1Η-pyrazole·1-yl) Ethanol 60.6 3.7 (5) 496 84 〇0 u^0IX HC^N^O Example 11; 2-(1Η-132,4-三嗓- 1-Base)·Ethanol 1) 67.1 3.48 (5) 497 85 〇0 CH3 t Example 11; 2-hydroxyethyl acetate 56.1 3.98 (5) 488 -92-

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 1314555 A7 B7 五、發明說明（9i) 經濟部智慧財產局員工消費合作社印製 實例 编號 結構 起始物質 產率 ί%1 氏[分鐘1 (方法） 晳吾 {Μ+Η]+ 86 CN HsC；X° IX 3 3 h3c^n^o ‘ t 實例11; 2·(二甲胺基)· 2-甲基-1-丙酵 34.6 2.9(5) 502 87 CHs Η,Ο-^Ν^Ο 實例11; 3·(二甲胺基)· 丙醇 54.8 2.86(5) 487 88 o 〜。 h3c 人 i|J 入。 ‘ 實例11; 2*(1-*1^略咬基)-乙酵 56.2 2.86(5) 500 89 HgC^N^O 實例77; 2气3-吡啶基)-乙醇 58.9 3.36 (5) 522 -93-This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1314555 A7 B7 V. Invention description (9i) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed example number structure Starting material yield ί% 1 氏 [minute 1 (method) 吾吾{Μ+Η]+ 86 CN HsC; X° IX 3 3 h3c^n^o ' t Example 11; 2·(dimethylamino)· 2-methyl-1 -Protease 34.6 2.9(5) 502 87 CHs Η,Ο-^Ν^Ο Example 11; 3·(dimethylamino)·propanol 54.8 2.86(5) 487 88 o ~. H3c person i|J entry. 'Example 11; 2*(1-*1^ slightly bite base)-Bylace 56.2 2.86(5) 500 89 HgC^N^O Example 77; 2 gas 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） A7 1314555 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 [%] R«【分鐘】 (方法） 質量 [M+H]+ 90 CN ζτ矣， 實例77 ; (3-吡啶基) 甲醇 61.9 3.64 (5) 507 91 CN Η*ΝΎ^0 II n"CHs 0 hscAn^o ，l 實例77; 2·羥基-乙臻胺w 53.6 3.54 (5) 473 92 ΗγΝ^〇Χ$Ν^Η3 H-C^N^O I 實例T7; 2-羥乙基-(甲基)甲》胺 54.6 3.6S (5) 501 93 Η Αό Η3〇γΝ>^^〇ΛνΑ.Ν^〇Η3 0 η3Α^ο 實例77; 2-羥乙基· 乙通胺 66.6 3.59 (5) 501. -94- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） A7 1314555 B7 五、發明說明（93) 經濟部智慧財產局員工消費合作社印製 實例 編號 結構 起始物質 產率 [%】 氏[分鐘】 (方法> 質量 [Μ+Η]+ 94 CN V卷 H3C入 N 人。 實例77; (1-f 基-1H-节味-5·基) 甲醇Η 34.0 3.02 (5) 510 95 實例77; 2·(1Η·吡唑-1-基)乙酵 61.5 3.91 (5) 510 96 0ν^〇Χαν^η3 HjC人Μ人。 實例77; 2-(lH-lt2,4-三唉-1-基)· 乙醇υ 71.8 3.64 (5) 511 97 χ6 ίΎ〇ΛγνΗ3 CHa ° HjC^N^O s 6., 實例77; _ 乙酸2-羥乙瘅 53.2 4.12(5) 502 -95- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 1314555B7 五、發明說明（94 ) 經濟部智慧財產局員工消費合作社印製 實例 編號 結構 起始物質 產率 [%] 馬丨分鐘] (方法） 質量 [Μ+Η]+ 98 CN c οφ Η<^：Χχ： 實例77 ; 2·{二曱胺基> 2-甲基-1-丙酵 25.9 3.02 (5) 516 99 CHj Η,σ^Ν^Ο ός, 實例77 ; 3·(二甲胺基> 丙醇 54.6 2.98 (5) 502 100 Ο ^ H3C人Ν入ο 實例77; 2·{1-吡咯啶基> 乙酵 55.9 2^8 (5) 514 101 cr^Xx： 實例77; (2-吼啶基)-甲酵 67.1 3,91 (5) 507 1此實例中所用醇為固體，反應係於0.4毫升DMF存在下進行 -96-This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) A7 1314555 B7 V. Description of invention (92) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing example number structure starting material yield [%] R«[minutes] (method) mass [M+H]+ 90 CN ζτ矣, example 77; (3-pyridyl) methanol 61.9 3.64 (5) 507 91 CN Η*ΝΎ^0 II n"CHs 0 hscAn^ o ,l Example 77; 2·hydroxy-acetamide w 53.6 3.54 (5) 473 92 ΗγΝ^〇Χ$Ν^Η3 HC^N^OI Example T7; 2-Hydroxyethyl-(methyl)methylamine 54.6 3.6S (5) 501 93 Η Αό Η3〇γΝ>^^〇ΛνΑ.Ν^〇Η3 0 η3Α^ο Example 77; 2-Hydroxyethyl·Ethylamine 66.6 3.59 (5) 501. -94- Ben Paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) A7 1314555 B7 V. Invention description (93) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing example number structure starting material yield [%] [Minute] (Methods > Mass [Μ+Η]+ 94 CN V-volume H3C into N. Example 77; (1-f-based-1H-nodular-5·yl) Methanol Η 34.0 3.02 (5) 510 95 Example 77; 2·(1Η·pyrazole -1-yl) Ethanol 61.5 3.91 (5) 510 96 0ν^〇Χαν^η3 HjC Μ人. Example 77; 2-(lH-lt2,4-tridec-1-yl)·ethanol υ 71.8 3.64 ( 5) 511 97 χ6 ίΎ〇ΛγνΗ3 CHa ° HjC^N^O s 6., Example 77; _ 2-hydroxyacetamidine acetate 53.2 4.12(5) 502 -95- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1314555B7 V. Description of invention (94) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing example number structure starting material yield [%] Ma Wei Min] (method) quality [Μ+Η]+ 98 CN c οφ Η<^:Χχ: Example 77; 2·{didecylamine> 2-methyl-1-propanyl 25.9 3.02 (5) 516 99 CHj Η, σ^Ν^Ο ός, Example 77 ; ·(dimethylamino)> propanol 54.6 2.98 (5) 502 100 Ο ^ H3C intrusion ο Example 77; 2·{1-pyrrolidinyl> Ethanol 55.9 2^8 (5) 514 101 cr^ Xx: Example 77; (2-Acridine)-methylase 67.1 3,91 (5) 507 1 The alcohol used in this example is a solid, and the reaction is carried out in the presence of 0.4 ml of DMF-96-

本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） A7 B7 1314555 五、發明說明（95 ) 實例102 4-(4-乳苯基）-1-(3,5 -二氣苯基）-6-甲基-2-嗣基-1,2,3,4-四 氫-5-嘧啶曱酸乙酯This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) A7 B7 1314555 V. Inventive Note (95) Example 102 4-(4-lactylphenyl)-1-(3,5-di-phenylene) Ethyl-6-methyl-2-mercapto-1,2,3,4-tetrahydro-5-pyrimidine decanoate

CNCN

5 氬氣下，於80°C，在0.5毫升二畤烷中，將30.8毫 經濟部智慧財產局員工消費合作社印製 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（210x297公釐） 1314555 五、發明說明（96 ) 實例103 6-甲基-4-(3-石肖苯基)-2-嗣基-1-[3-(三氣甲基）苯基]-1,2,3,4-四氫-5-嘧啶甲酸乙酯5 Under argon, at 80 ° C, in 0.5 ml of dioxane, 30.8 mAh Ministry of Intellectual Property's employee consumption cooperative printed gram (0.15 mmol) N-(3,5-dichlorophenyl) The urea was stirred with 39.3 mg (0.3 mmol) of 4-methylmercaptobenzonitrile, 39 mg (0.3 mmol) of 3-ketobutyrate and 90 mg of trimethyldecyl polyphosphate. hour. After adding a small amount of DMSO, the reaction mixture was filtered using a preparative 10 HPLC (column: Agilent Zorbax Extend C18 20 mm X 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% concentrated aqueous ammonia; gradient: 0 min 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 : approximately 500 μl 15 liters; number of injections: 1) to be purified. The product containing the dissolved fractions was 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 min -97- The paper size applies to the Chinese National Standard (CNS) A4 size (210x297 mm) 1314555 V. Description of the invention (96) Example 103 6-Methyl-4-(3-stone phenyl)-2-mercapto-1-[3-(trimethyl) Ethyl phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

5 於80°C，在0.5毫升二畤烷與0.1毫升DMF中，將 經濟部智慧財產局員工消費合作社印製 30.6毫克(0.15毫莫耳）N-[3-(三氟甲基)苯基]脲連同45.3 毫克(0.3毫莫耳）3-硝基苯曱醛、39毫克(0.3毫莫耳）3-酮 基丁酸乙酯與90毫克多磷酸乙酯[根據Cava以a/., J. Org. Chem. 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：Nucleosil 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 15 25毫升/分鐘；波長：220奈米；注射量：大約800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：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- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 1314555 A7 B7 五、發明說明（97 ) 以類似實例102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 [%】 IU分錢] (方法） 質量 ΓΜ+ΗΓ 104 t；0 Ν-(3-硝笨基)-脲； 4·氩苯甲醛； 3-明基丁酸-乙酯 70.5 3.65 (6) 417 105 cc σΝϋ2 ηΛΛο Ν<3-硝笨基)-脲； 3-硝基笨甲醛； 3-萌基丁後-乙酯 S1J 3.61 (6) 427 106 c^6 ηΛΧ Ν-(3·硝苯基)-脲； 4·氟苯甲醛； 3-明基丁酸-乙酯 56.S 3.63 (6) 400 107 t；6 H3C人Ν入。 I, Ν-(3-硝苯基)· 脲； 4·溴苯甲醛； 3-酮基丁酸-乙酯 69.5 4.02 (5) 461 -99-5 Print 30.6 mg (0.15 mmol) of N-[3-(trifluoromethyl)phenyl at 80 ° C in 0.5 ml of dioxane and 0.1 ml of DMF. Urea with 45.3 mg (0.3 mmol) of 3-nitrobenzaldehyde, 39 mg (0.3 mmol) of ethyl 3-ketobutanoate and 90 mg of ethyl polyphosphate [according to Cava as a/., The procedure of J. Org. Chem. 2665 (1969) was freshly prepared] shaking 18 hours and 10 hours together. After addition of 200 μl of DMF, the reaction mixture was filtered using preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus, 20 mm X 50 mm, 5 μm; Solvent A: Acetonitrile, Solvent B: Water + 0.1% formic acid) 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 15 25 ml / min; Wavelength: 220 Nai Rice; injection volume: about 800 μl; number of injections: 1) to be purified. The product containing the dissolved fractions was 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 min -98- The paper size applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) 1314555 A7 B7 V. Description of invention (97) The following compounds were prepared in a similar manner to Example 102: Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Example Number Structure Starting Material Yield [%] IU cents] (method) mass ΓΜ + ΗΓ 104 t; 0 Ν-(3-nitrophenyl)-urea; 4 argon benzaldehyde; 3-benyl butyrate-ethyl ester 70.5 3.65 (6) 417 105 cc σΝϋ2 ηΛΛο Ν<3-nitrophenyl)-urea;3-nitrobenzaldehyde; 3-mercaptobutyl-ethyl ester S1J 3.61 (6) 427 106 c^6 ηΛΧ Ν-(3·nitrophenyl - urea; 4 · fluorobenzaldehyde; 3-benyl butyrate-ethyl ester 56.S 3.63 (6) 400 107 t; 6 H3C intrusion. I, Ν-(3-nitrophenyl)·urea; 4·bromobenzaldehyde; 3-ketobutyric 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） A7 B7 1314555 五、發明說明〇 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-曱酸2-氰基乙酯This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1314555 V. INSTRUCTION DESCRIPTION 〇 Example 108 4-(4-Cyanophenyl)-6-methyl-2-keto-1 -[3-(Trifluoromethyl)phenyl]-1,2,3,4·tetrahydropyrimidine-5-decanoic acid 2-cyanoethyl ester

CNCN

NC- 5 使9.87克(48.3毫莫耳）Ν_[3-(三氟甲基）苯基]脲、 12.68克(96.68毫莫耳）4-氰基苯甲醛、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。擾拌下，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-de): 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- 本紙張尺度適用申國國家標準(CNS)A4規格（210 X 297公釐） A7 B7 1314555 五、發明說明（99 ) 實例109 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-甲腈NC-5 gave 9.87 g (48.3 mmol) of Ν[3-(trifluoromethyl)phenyl]urea, 12.68 g (96.68 mmol) of 4-cyanobenzaldehyde, 15 g (96.68 mmol) 2-cyanoethyl 3-ketobutanoate and 37.5 g of ethyl polyphosphate were suspended in 250 ml of THF. The mixture was heated under reflux for 18 hours with stirring. After cooling to room temperature, the solvent was removed in vacuo. Yield: 25 g (100% of theory) Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Cooperatives, ^-NMR (200 MHz, DMSO-de): 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 size applies Shen Guo National Standard (CNS) A4 Specification (210 X 297 mm) A7 B7 1314555 V. Inventive Note (99) Example 109 4-(4-Cyanophenyl)-6-methyl-2-keto-1- [3-(Trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

CNCN

4 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-N-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，以二氣甲烷/曱醇混合物為溶洗液。 ^ 10 產率：249毫克（理論值之43%) 'H-NMR (300 MHz, DMSO-di): δ = 1.8 (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（210x297公釐） 訂 經濟部智慧財產局員工消費合作社印製 經濟部智慧財產局員工消費合作社印製 1314555 A7 B7 五、發明說明（100) 實例110 6-曱基-4-(4-硝苯基)-2-酮基-1-[3-(三氟曱基）苯基]-1,2,3,4-四氫嘧啶-5-曱酸乙酯40.9 A solution of 0.609 g (1.52 mmol) of Example 70 was dissolved in 60 mL of THF, and 1.24 g (12.93 mmol) of (methoxycarbonylaminesulfonyl)-triethylammonium-N-betaine was added. The reaction mixture was stirred at room temperature for 1 hour, the solvent was removed in vacuo, and the residue was purified by column chromatography on the vermiculite, using a mixture of di-methane/decanol as solvent. ^ 10 Yield: 249 mg (43% of theory) 'H-NMR (300 MHz, DMSO-di): δ = 1.8 (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 scale applies to China National Standard (CNS) A4 specification (210x297 mm). Cooperatives Ministry of Printing and Economy Ministry Intellectual Property Bureau Staff Consumer Cooperatives Printed 1314555 A7 B7 V. Description of Invention (100) Example 110 6-Mercapto-4-(4-nitrophenyl)-2-keto-1-(3- (trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-decanoic acid ethyl ester

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-dfi): 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（210x297公釐）5 7.84 g (38.4 mmol) of N-[3-(trifluoromethyl)phenyl]urea, 5.81 g (38.4 mmol) of 4-nitrophenylfurfural, 5.0 g (38.4 mmol) Ethyl 3-ketobutanoate and 15 g of ethyl polyphosphate were suspended in 100 ml of THF. The mixture was heated under 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 eluting with benzene/ethyl acetate. Yield: 8.75 g (51% of theory) ^-NMR (200 MHz, DMSO-dfi): δ = 1.1 (t, 3H); 2.1 (s, 3H); 4.0 (m, 2H); , 1H); 7.5-7.8 (m, 6H); 8.3 (m, 2H); 8.5 (d, 1H) ppm. -102- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)

A7 1314555 B7 五、發明說明（ιοί) 實例111 5-乙醢基-6-曱基-4-(4-硝苯基）-2-酮基-l-[3-(三氟甲基）苯 基]-1，2,3,4-四氫嘧啶A7 1314555 B7 V. INSTRUCTIONS (ιοί) Example 111 5-Ethyl-6-mercapto-4-(4-nitrophenyl)-2-keto-l-[3-(trifluoromethyl)benzene 1,1,2,3,4-tetrahydropyrimidine

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%) 經濟部智慧財產局員工消費合作社印製 'H-NMR (200 MHz, DMSO-de): 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, 1H) ppm. -103- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 1314555 五、發明說明（102) C.輿醫藥组成物相關之操作實例 根據本發明之化合物可如下文所述轉化成醫藥組成 物： 錠劑 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、乳楗 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 經濟部智慧財產局員工消費合作社印製 1000毫克實例1化合物、1000毫克乙醇(96%)、4〇〇 毫克 Rhodigel (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。撥拌下，添加水。持續搜拌約6小時’至Rhodigel -104- 本紙張尺度適用令國國家標準(CNS)A4規格（210x297公爱） 1314555 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（103)完全膨脹為止。 [圖式簡單說明] 無 -105-5 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 under 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 celite, using cyclohexane/ethyl acetate as solvent. Yield: 0.302 g (36% of theory) Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, 'H-NMR (200 MHz, DMSO-de): 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, 1H) ppm. -103- This paper scale applies to China National Standard (CNS) A4 specification (210x297 PCT) 1314555 V. INSTRUCTION DESCRIPTION (102) C. Operational Examples Related to Pharmaceutical Compositions The compounds according to the present invention can be converted into pharmaceutical compositions as described below: Tablets 5 Composition 100 mg of Example 1 compound, 50 mg of lactose ( Monohydrate), 50 mg corn starch (as-is), 10 mg polyvinylpyrrolidone (PVP 25) (available from BASF, Ludwigshafen, Germany) and 2 mg of stearic acid. The lozenge weighs 212 mg, has a diameter of 8 mm and a radius of curvature of 12 mm. 10 Preparation The active ingredient, chyle and starch were granulated with a solution of 5% PVP in water (m/m). After drying, the granules were mixed with magnesium stearate for 5 minutes. This mixture was molded using a conventional tablet molding machine (the tablet size is as above). The molding force used is typically 15 kN. 15 Oral Suspension Composition Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1000 mg of Example 1 compound, 1000 mg of ethanol (96%), 4 mg of Rhodigel (xanthose gum, available from FMC, Pennsylvania, USA) and 99 Gram water. 20 10 ml of oral suspension provides 1 mg of a single dose of the compound according to the invention. Preparation Rhodigel is suspended in ethanol and the active ingredient is added to the suspension. Mix and add water. Continue to search for about 6 hours' to Rhodigel -104- This paper scale applies to the national standard (CNS) A4 specification (210x297 public) 1314555 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (103) Completely expanded. [Simple diagram] No -105-

本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

13 Β8 C8 D8 專利申請案第92124801號 ROC Patent Appln. No.92124801 修正後無劃滅之ΐ請4利範圍中文本-附件(二） Amended Claims in Chinese - Encl/ID 六、申請專利範圍 (民國98年6月25曰送呈） (Submitted on June 25,2009) 1. 一種具下式（i)之化合物 F13 Β8 C8 D8 Patent Application No. 92124801 ROC Patent Appln. No.92124801 After the amendment, there is no slashing. Please use the text in the range of 4 - Annex (II) Amended Claims in Chinese - Encl/ID VI. Patent Application Scope (Republic of China) Submitted on June 25, 1998) (Submitted on June 25, 2009) 1. A compound of formula (i) F R6 R7 R3 (I), <曰修（更)正本 5 10 經濟部智慧財產局員工消費合作社印製 15 式中 A代表苯基或吼啶基； R1、R2與R3各自獨立地代表氫、鹵素、硝基或氰基； R4代表三氟曱基羰基、CVCV烷基羰基、羥羰基、 胺幾基、氰基、苯基幾基、嗎α林基幾基、σ米11坐基 羰基、呋喃基羰基、苯并噻唑基、經Q-C4-烷基 取代之二唑基、視情況經CrCr烷氧基取代之 早·•或二-C1-C4-烧基胺幾基、或視情況經經基、鼠 基、二-C1-C4-烧胺基、C1-C4-烧氧徵基、胺数 基、Q-C4-烷基胺羰基、CrC4-烷基羰基-CrCr烷 胺基、C1-C4-烧基幾胺基、C3-C8-環炫基、11比σ定 基、吡唑基、三唑基、視情況經酮基取代之吡咯 啶基、或經Q-Cr烷基取代之咪唑基所取代之 C!-C6-烧氧基数基； R5代表胺基或視情況經鹵素、二烷胺基或苯 基胺基取代之CrC4-烷基； -106 - 訂 線 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 92434claim_ 接 3 • 1314555 os -____D8 六、申請專利範圍 R6代表氫、曱醯基、二-CrC4-烷基胺羰基、CrC6-烷氧羰基、N_(CrC4_烷基磺醯基）-N-(CrC4-烷 基)-胺羰基、嗎啩基羰基、單-或二-CrC4-烷基胺 羰基、視情況經CrC4-烷氧基取代之CrC6-烷基 5 羰基、或視情況經胺基、氰基、羥羰基、胺羰 基、CrC6-烷氧羰基、二_crC4-烷胺基、CrC4-烷 胺基氣基、一_Ci_C4-烧胺基-Ci-C4-烧胺基幾基、 CrCr烷氧基crC4-烷胺基羰基、苯基、吡啶基 或咪唑基取代之（^-(：6-烷基； 10 或 R6代表具下式之基團 15 式中 經濟部智慧財產局員工消費合作社印製 r6A係選自crc6-烷基，及 R7代表鹵素、硕基、或視情形經鹵素取代之C^-C6-烧基； 及 20 γ1、Y2、Y3、Y4 與 Y5 代表 CH， 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i項之式(I)化合物，其中 -107 - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 1314555 ^ ------- D8 六、申請專利範圍 A 代表苯基或吼啶基； R1、R2與R3各自獨立地代表氫、鹵素、硝基、或氰基； R4代表crc6-烷基羰基、羥羰基、胺羰基、氰基、苯基幾 基、嗎咁基羰基、咪唑基羰基、呋喃基羰基、苯并噻嗤 5 基、經Crc4-烷基取代之嘮二唑基、視情況經CrC4-燒 氧基取代之單-或二-CKV烷基胺羰基、或視情況經經 基、亂基、二-CrQ-院胺基、Q-C4-烧氧幾基、胺幾 基、CrC4-烷基胺羰基、CrC4-烷基羰基-CrC4-烷胺基、 Ci-Gr烧基幾胺基、C3-C8-環烧基、吼。定基、°比°坐基、三 10 唑基、視情況經酮基取代之吡咯啶基、或經CrC4-烷基 取代之咪唑基所取代之crc6-烷氧基羰基； 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、二-Ci-C6_烧胺基或苯基胺基之基團取代； 或 15 R5代表胺基； 經濟部智慧財產局員工消費合作社印製 R6代表氫、曱醯基、二-CrQ-烷基胺羰基、Q-Q-烷氧羰 基、N-(C丨-Q-烧基石黃醯基)-N-(C]-C4-院基)-胺羰基、嗎咁 基羰基、單-或二-CrQ-烷基胺羰基、視情況經 氧基取代之Q-Q-烷基羰基、或視情況經胺基、氰基、 20 羥羰基、胺羰基' CrQ-烷氧羰基、二_Ci_C4_^胺基、 Q-Cr烧胺基羰基、二-Q-Cr烷胺基_crc4-烷胺基羰基、 C1-C4-烧氧基C1-C4-烧胺基幾基、笨基、π比咬基或Π米β坐基 取代之Ci-CV烧基； 或 -108 - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 1314555 cs D8 六、申請專利範圍 R6代表具下式之基團R6 R7 R3 (I), <曰修(more)本本本 5 10 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 15 where A represents phenyl or acridinyl; R1, R2 and R3 each independently represent hydrogen, Halogen, nitro or cyano; R4 represents trifluorodecylcarbonyl, CVCV alkylcarbonyl, hydroxycarbonyl, amine, cyano, phenyl, αα linyl, σm 11 carbonyl, a furylcarbonyl group, a benzothiazolyl group, a Q-C4-alkyl substituted diazolyl group, optionally substituted by a CrCr alkoxy group, or a di-C1-C4-alkylamine group, or optionally By base group, murine group, di-C1-C4-alkylamine group, C1-C4-burning oxygen group, amine number group, Q-C4-alkylamine carbonyl group, CrC4-alkylcarbonyl-CrCr alkylamine group, C1-C4-alkylamino, C3-C8-cyclohexyl, 11-pyridyl, pyrazolyl, triazolyl, optionally keto-substituted pyrrolidinyl, or substituted by Q-Cr alkyl a C!-C6-alkoxy group substituted by an imidazolyl group; R5 represents an amine group or a CrC4-alkyl group optionally substituted by a halogen, a dialkylamino group or a phenylamino group; -106 - a paper size Applicable to China National Standard (CNS) A4 Specifications (210 X 297 mm) 92434claim_ Connect 3 • 1314555 os -____D8 VI. Patent Application R6 stands for hydrogen, mercapto, di-CrC4-alkylamine carbonyl, CrC6-alkoxycarbonyl, N_(CrC4_alkyl sulfonate Indenyl)-N-(CrC4-alkyl)-aminecarbonyl, decylcarbonyl, mono- or di-CrC4-alkylaminecarbonyl, optionally CrC4-alkyl-5carbonyl substituted by CrC4-alkoxy, Or optionally, via an amine group, a cyano group, a hydroxycarbonyl group, an amine carbonyl group, a CrC6-alkoxycarbonyl group, a bis-crC4-alkylamino group, a CrC4-alkylamino group, a _Ci_C4-anisole-Ci-C4- Substituted with an amine group, a CrCr alkoxy crC4-alkylaminocarbonyl group, a phenyl group, a pyridyl group or an imidazolyl group (^-(:6-alkyl; 10 or R6 represents a group of the formula 15) The Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative printed r6A series selected from crc6-alkyl, and R7 represents halogen, base, or halogen-substituted C^-C6-alkyl; and 20 γ1, Y2, Y3, Y4 and Y5 represent CH, and its salts, hydrates and/or solvates and tautomeric forms thereof. 2. According to the compound of formula (I) of claim i, wherein -107 - the paper The scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1314555 ^ ------- D8 VI. Patent application scope A stands for phenyl or acridinyl; R1, R2 and R3 each independently represent hydrogen, Halogen, nitro, or cyano; R4 represents crc6-alkylcarbonyl, hydroxycarbonyl, aminecarbonyl, cyano, phenyl, fluorenylcarbonyl, imidazolylcarbonyl, furylcarbonyl, benzothiazepine-5 An oxadiazolyl substituted with a Crc4-alkyl group, optionally a mono- or di-CKV alkylamine carbonyl substituted by a CrC4-alkoxy group, or optionally a trans-group, a chaotic group, a di-CrQ-amine amine Base, Q-C4-alkoxy group, amine group, CrC4-alkylamine carbonyl, CrC4-alkylcarbonyl-CrC4-alkylamine, Ci-Gr alkylamino, C3-C8-cycloalkyl ,Roar. a Crc6-alkoxycarbonyl group substituted by a ketone group, a trisazozolyl group, a keto group-substituted pyrrolidinyl group, or a CrC4-alkyl substituted imidazolyl group; R represents C1-C4- An alkyl group which may be substituted by one to three identical or different groups selected from the group consisting of halogen, di-Ci-C6-anisole or phenylamine; or 15 R5 represents an amine group; Consumer cooperatives printed R6 for hydrogen, mercapto, di-CrQ-alkylamine carbonyl, QQ-alkoxycarbonyl, N-(C丨-Q-alkyl sulphate)-N-(C]-C4-household -Aminocarbonyl, decylcarbonyl, mono- or di-CrQ-alkylaminecarbonyl, optionally substituted by oxy-substituted QQ-alkylcarbonyl, or optionally amino, cyano, 20 hydroxycarbonyl, amine Carbonyl 'CrQ-alkoxycarbonyl, di-Ci_C4_^ amine, Q-Cr acrylcarbonyl, bis-Q-Cralkylamino _crc4-alkylaminocarbonyl, C1-C4-alkoxy C1-C4- a Ci-CV alkyl group substituted with an amine group, a stupid base, a π ratio biting group or a gluten β group; or -108 - the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm) 1314555 cs D8 VI. Application for patent scope R 6 represents a group having the following formula 八^或 式中 5 R6A 係選自CrC6-烷基，及 R7 代表鹵素、硝基、或CrC6-烷基，其中CrC6-烧 基可進一步被一至三個相同或不同之選自函素之 基團取代； 及 10 Y1、Y2、Y3、Y4與Y5各自獨立地代表CH。 3.根據申請專利範圍第1或2項之式(I)化合物，其中 A 代表苯基或。比啶基； R1、R2與R3各自獨立地代表氫、氟、氯、溴、硝基或氰基； R4代表Q-C6-烷基羰基、羥羰基、胺羰基、視情況經Cr 15 C4-烷氧基取代之單-CrC4-烷基胺羰基、氰基、或可被一 經濟部智慧財產局員工消費合作社印製 至三個相同或不同之選自包括C3-C8-環烷基、羥基、Cr C4-烷氧基、CrC4-烷氧羰基、二-Q-C4-烷胺基、吡咬 基、吡唑基、三唑基、視情況經酮基取代的吡咯啶基、 及經CrC4-烷基取代的咪唑基之基團取代之Q-C6-烷氧 20 基羰基； R5代表曱基或乙基； R6代表氮、二-C!-C4-烧基胺裁基、視情況經C1-C4-烧氧基 -109 - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） * DO 1314555 cs D8 六、申請專利範圍 取代的CrC6-烷基羰基、嗎啉基羰基、CrC6-烷氧羰基、 或可被一至三個相同或不同之選自包括雜芳基、羥基、 羥羰基、CrC6-烷氧羰基、胺羰基、單-及二-CrC4-烷基 胺羰基、氰基、胺基、及二-Q-Cr烷胺基之基團取代之 5 CrC6-烷基； 或 R6代表具下式之基團In the formula, R 6A is selected from the group consisting of CrC6-alkyl, and R 7 represents a halogen, a nitro group, or a CrC 6-alkyl group, wherein the CrC 6 -alkyl group may be further one to three of the same or different selected from the group of the element Group substitution; and 10 Y1, Y2, Y3, Y4 and Y5 each independently represent CH. 3. A compound of formula (I) according to claim 1 or 2, wherein A represents phenyl or. R1, R2 and R3 each independently represent hydrogen, fluorine, chlorine, bromine, nitro or cyano; R4 represents Q-C6-alkylcarbonyl, hydroxycarbonyl, aminecarbonyl, optionally Cr 15 C4- Alkoxy-substituted mono-CrC4-alkylamine carbonyl, cyano, or may be printed by an Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative to three identical or different selected from the group consisting of C3-C8-cycloalkyl, hydroxy , Cr C4-alkoxy, CrC4-alkoxycarbonyl, bis-Q-C4-alkylamino, pyridyl, pyrazolyl, triazolyl, optionally keto-substituted pyrrolidinyl, and CrC4 -Alkyl-substituted imidazolyl-substituted Q-C6-alkoxycarbonylcarbonyl; R5 represents fluorenyl or ethyl; R6 represents nitrogen, di-C!-C4-alkylamine base, optionally C1-C4-alkoxy-109 - This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) * DO 1314555 cs D8 VI. CrC6-alkylcarbonyl, morpholinylcarbonyl substituted by patent application scope CrC6-alkoxycarbonyl, or may be one to three the same or different selected from the group consisting of heteroaryl, hydroxy, hydroxycarbonyl, CrC6-alkoxycarbonyl, amine carbonyl, mono- and di-CrC4 a group substituted with a group of an alkylamine carbonyl, a cyano group, an amine group, and a bis-Q-Cr alkylamino group; or R6 represents a group having the formula: 式中 10 r6A 係選自crc4-烷基， R7 代表鹵素、硝基、三氟甲基、曱基或乙基； 及 γ1、γ2、γ3、γ4 與 γ5 各自代表 CH。 4.根據申請專利範圍第1或2項之式（I)化合物，其中 15 A 代表苯基或。比啶基環； 經濟部智慧財產局員工消費合作社印製 R1與R3各自代表氫； R2代表氟、氯、漠、确基或氰基； R4代表氰基、CrC4-烷基羰基或CrC4-烷氧基羰基，其中 CVCV烷氧基羰基可被選自包括羥基、CrC4-烷氧基、 20 CrC4-烷氧羰基、二-CrC4-烷胺基、吡啶基、吡唑基、 三唑基、視情況經酮基取代之吡咯啶基、及經-crc4-烷 基取代之咪唑基之基團取代； -no - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） DO 1314555 cs D8 六、申請專利範圍 R5代表曱基； R6代表鼠、二-C1-C4-烧基胺幾基、C1-C4-炫基裁基、C1-C4-烷氧羰基，或可被選自包括吡啶基、咪唑基、羥羰基、 胺羰基、單-及二-q-c4-烷基胺羰基、胺基、及二-crc4-5 烧胺基之基團取代之-C1-C4-烧基； 或 R6代表具下式之基團Wherein 10 r6A is selected from the group consisting of crc4-alkyl, R7 represents halogen, nitro, trifluoromethyl, decyl or ethyl; and γ1, γ2, γ3, γ4 and γ5 each represent CH. 4. A compound of formula (I) according to claim 1 or 2 wherein 15 A represents phenyl or. Bixidinyl ring; Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed R1 and R3 each representing hydrogen; R2 represents fluorine, chlorine, desert, exact or cyano; R4 represents cyano, CrC4-alkylcarbonyl or CrC4-alkane An oxycarbonyl group, wherein the CVCV alkoxycarbonyl group is selected from the group consisting of a hydroxyl group, a CrC4-alkoxy group, a 20 CrC4-alkoxycarbonyl group, a di-CrC4-alkylamino group, a pyridyl group, a pyrazolyl group, a triazolyl group, The situation is replaced by a keto-substituted pyrrolidinyl group and a group substituted with a -crc4-alkyl substituted imidazolyl group; -no - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) DO 1314555 cs D8 6. Patent application scope R5 represents a sulfhydryl group; R6 represents a mouse, a di-C1-C4-alkylamine group, a C1-C4-hydryl base, a C1-C4-alkoxycarbonyl group, or may be selected from the group consisting of pyridine a -C1-C4-alkyl group substituted with a group of a group, an imidazolyl group, a hydroxycarbonyl group, an amine carbonyl group, a mono- and di-q-c4-alkylaminecarbonyl group, an amine group, and a di-crc4-5 aromatide group; Or R6 represents a group having the formula 式中 10 R6A 係選自曱基， R7 代表三氟曱基或硝基； 及 γ1、γ2、γ3、γ4 與 γ5 各自代表 CH。 5. 根據申請專利範圍第1或2項之式（I)化合物，其中A 15 為苯及或°比啶基。 經濟部智慧財產局員工消費合作社印製 6. 根據申請專利範圍第1或2項之式(I)化合物，其中R1 為氫。 7. 根據申請專利範圍第1或2項之式(I)化合物，其中R2 為氰基。 20 8.根據申請專利範圍第1或2項之式(I)化合物，其中R3 為氮。 9.根據申請專利範圍第1或2項之式(I)化合物，其中R4 -111 - 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 1314555Wherein R 6A is selected from the group consisting of fluorenyl groups, R 7 represents a trifluoromethyl group or a nitro group; and γ1, γ2, γ3, γ4 and γ5 each represent CH. 5. A compound of formula (I) according to claim 1 or 2 wherein A 15 is benzene and or pyridyl. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives 6. According to the compound of formula (I) of claim 1 or 2, wherein R1 is hydrogen. 7. A compound of formula (I) according to claim 1 or 2 wherein R2 is cyano. 20. A compound of formula (I) according to claim 1 or 2 wherein R3 is nitrogen. 9. According to the compound of formula (I) of claim 1 or 2, where R4 -111 - this paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1314555 經濟部智慧財產局員工消費合作杜印製 為視需要被經基取代之CKV燒氧羰基或其中r C1-C4-烧基幾基。 … 10.根據中請專利範圍第！或2項之式⑴化合物， 為甲基。 ' 5 11.根據申請專利範圍第！或2項之式⑴化合物其 為氫。 12. 根據申請專利範圍第J或2項之式⑴化合物，其中y 為三氟甲基或硝基。 〃 13. 根據中請專利範圍第丨項之化合物，其中該化合物為 10 5-{5_乙醯基_6_甲基-2-氧基三氟甲基）苯基 1，2,3,4-四氫_4_嘧啶基卜2_吡啶甲腈及其鹽類、水合物 及/或溶劑合物及互變異構形式。 14. 根據申請專利範圍帛i項之化合物，其中該化合物為 (+)-5-{5-乙醯基_6_甲基_2_氧基(三氟甲基）苯基卜 15 I，2,3,4·四氫嘧啶基}-2·吡啶甲腈及其鹽類、水合物 及/或溶劑合物及互變異構形式。 15. —種具下式(ία)之化合物Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperation, du-printing, CKV-burning oxycarbonyl group or r C1-C4-alkyl group in which it is replaced by a thiol group. ... 10. According to the scope of the patent application! Or a compound of the formula (1), which is a methyl group. ' 5 11. According to the scope of the patent application! Or a compound of the formula (1) which is hydrogen. 12. A compound of formula (1) according to claim J or 2, wherein y is trifluoromethyl or nitro. 〃 13. The compound according to the scope of the patent application, wherein the compound is 10 5-{5-ethenyl-6-methyl-2-oxytrifluoromethyl)phenyl 1,2,3, 4-Tetrahydro-4-pyrimidinyl-2-pyridinecarbonitrile and its salts, hydrates and/or solvates and tautomeric forms. 14. A compound according to the scope of the patent application, wherein the compound is (+)-5-{5-ethinyl-6-methyl-2-oxo(trifluoromethyl)phenyl b 15 I, 2,3,4·tetrahydropyrimidinyl}-2·pyridinecarbonitrile and its salts, hydrates and/or solvates and tautomeric forms. 15. A compound of the formula (ία) i 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） B8 C8 D8 1314555 六、申請專利範圍 式中 Z 代表CH或N ;及 R1、；^3、！^與R6具有申請專利範圍第1至12項指示之意 義。 16. —種合成分別如申請專利範圍第1至15項界定之式⑴ 或式(IA)化合物之方法’該方法包括使具下式（11)之化 合物 10 式中i This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 mm) B8 C8 D8 1314555 VI. Patent application range Where Z stands for CH or N; and R1, ;^3,! ^ and R6 have the meaning of the requirements of items 1 to 12 of the patent application scope. 16. A method of synthesizing a compound of formula (1) or formula (IA) as defined in claims 1 to 15 respectively, the method comprising: formulating a compound of formula (11) CHO (Π) A、R1與R2具有申請專利範圍第1至15項指示之意 義； 與具下式（III)之化合物CHO (Π) A, R1 and R2 have the meaning of the scope of the patent application range 1 to 15; and the compound of the following formula (III) 經濟部智慧財產局員工消費合作杜印製 5 11 R5"^〇 瞬 式中 R4與R5具有申請專利範圍第i至15項指系之意義 及具下式（IV)之化合物 -113 - 本紙張尺度適用中國國家標準(CNS)A4規格（21〇χ297公釐） 1314555 六、申請專利範圍 BS C8 D8 NH, HN 、〇 〆 R7 (IV) 式中 R、R、及Y1至Y5具有申請專利範圍第i至15項指 示之意義； 於存在下，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 R1Ministry of Economic Affairs, Intellectual Property Office, Employees' Consumption Cooperation Du Printing 5 11 R5"^〇In the instant, R4 and R5 have the meaning of the patent application range i to 15 and the compound of the following formula (IV)-113 - the paper The scale applies to China National Standard (CNS) A4 specification (21〇χ297 mm) 1314555 6. Patent application scope BS C8 D8 NH, HN, 〇〆R7 (IV) where R, R, and Y1 to Y5 have patent application scope The meaning of the indications in items i to 15; in the presence of three components/one step reaction, or a continuous reaction to obtain a compound R1 having the following formula (IB) r5/^n^〇 R3 γΐ^γδR5/^n^〇 R3 γΐ^γδ R7 (IB), 經濟部智慧財產局員工消費合作社印製 ο 1A 式中 △、:^至尺^厌^及/至/具有申請專利範圍第i 至15項指示之意義； 隨後視需要使式(IB)化合物與具下式之化合物 R6*-X (V) 式中 6 * R 具有如申請專利範圍第1至15項指示之R6之 意 -114 - 本紙張尺度 t _家標準(CNS)A4規格（2K) x 297公幻 1314555R7 (IB), Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Cooperative, Printed ο 1A where △, :^ to 尺^ ^^ and / to / have the meaning of the indications in the scope of application for patents i to 15; (IB) a compound and a compound of the formula R6*-X (V) wherein 6 * R has the meaning of R6 as indicated in the scope of claims 1 to 15 - 114 - the paper size t _ home standard (CNS) A4 specification (2K) x 297 public fantasy 1314555 六、申請專利範圍 義’惟不代表氫；及 X 代表釋離基，例如齒素、對甲苯項醯基、曱磺醯 基或硫酸根； 於鹼存在下進行反應。 5 17‘種用於治療與人類嗜中性白企球彈性蛋白酶(HNE) 活性相關的疾病之組成物，其含有如申請專利範圍第 1至15項界定之至少一種式⑴或(IA)化合物及藥理上 可接受之稀釋劑。 18. 根據申請專利範圍第17項之組成物，係供治療急性及 10 慢性炎症、缺血性及/或改組病變（remodeling processes)。 19. 一種製備根據申請專利範圍第17及18項之組成物之 方法，其特徵為使如申請專利範圍第〗至丨5項界定之 式⑴或（IA)化合物連同習知佐劑一起成為適當施用形 15 式。6. The scope of application for patents means 'only does not represent hydrogen; and X stands for excipients, such as dentate, p-toluene, sulfonyl or sulphate; the reaction is carried out in the presence of a base. 5 17 'A composition for treating a disease associated with human neutrophil elastase (HNE) activity, comprising at least one compound (1) or (IA) as defined in claims 1 to 15 and a pharmacological agent Acceptable diluent. 18. A composition according to item 17 of the scope of the patent application for the treatment of acute and 10 chronic inflammation, ischemic and/or remodeling processes. 19. A method of preparing a composition according to clauses 17 and 18 of the patent application, characterized in that a compound of the formula (1) or (IA) as defined in the scope of claims of the patents, together with a conventional adjuvant, is suitably administered. Shape 15 style. 20. —種使用如申請專利範圍第！至15項界定之式⑴或 (IA)化合物製備藥物之用途，該藥物係用於治療與人 類嗜中性白血球彈性蛋白酶(HNE)活性相關的疾病。 21. 根據申請專利範圍第20項之用途，係用於製備藥物以 治療急性及慢性炎症、缺血性及/或改組病變。 22. 根據申請專利範圍第21項之用途，其巾該病變為慢性 阻塞性肺病、急性冠狀動脈症候群、急性心肌梗塞或 心臟衰竭形成。 23. 根據申料觀圍第18項之組成物，其雜調控人類 -115 - ' 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 1314555 ?8 _D8_ 六、申請專利範圍 及動物之慢性阻塞性肺病、急性冠狀動脈症候群、急 性心肌梗塞或心臟衰竭形成。 經濟部智慧財產局員工消費合作社印製 6 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）20. One type of use as claimed in the patent scope! The use of a compound of formula (1) or (IA) defined in 15 for the preparation of a medicament for the treatment of a disease associated with human neutrophil elastase (HNE) activity. 21. For use in the preparation of a medicament for the treatment of acute and chronic inflammatory, ischemic and/or shuffling lesions, according to the scope of application No. 20. 22. According to the use of claim 21, the lesion is chronic obstructive pulmonary disease, acute coronary syndrome, acute myocardial infarction or heart failure. 23. According to the composition of the 18th item of the application, the heterogeneous regulation of human-115 - 'this paper scale applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 1314555 ?8 _D8_ VI. Patent application scope and animal Chronic obstructive pulmonary disease, acute coronary syndrome, acute myocardial infarction, or heart failure. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives. 6 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm).
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TW200808763A (en) 2006-05-08 2008-02-16 Astrazeneca Ab Novel compounds I
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US9290457B2 (en) * 2014-07-31 2016-03-22 Boehringer Ingelheim International Gmbh Substituted dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
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US9657015B2 (en) 2014-07-31 2017-05-23 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity

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