TW200536844A

TW200536844A - Piperidinoyl integrin antagonists

Info

Publication number: TW200536844A
Application number: TW93113028A
Authority: TW
Inventors: Bart De Corte; William A Kinney; Bruce E Maryanoff; Shyamali Ghosh; Li Liu
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2004-05-10
Filing date: 2004-05-10
Publication date: 2005-11-16

Abstract

This invention is directed to piperidinoyl compounds useful as integrin receptor antagonists and methods for treating an integrin mediated disorder.

Description

200536844 A7 B7 五、發明說明（i) 發明領域本申請案主張2003年8月16曰申請的美國臨專利申請案序號60/404,239之優先權，該案内容併入本文以資參考。 5 本發明乃有關一種新穎化合物及其用於治療整合素傳介的疾病之方法。詳言之，本發明係有關作為選擇性整合素受體拮抗劑用之哌啶醯基羧酸化合物及其治療整合素傳介的疾病之方法。發明背景 10 整合素屬跨膜受體族，各者係由一對異源二聚體、單經濟部智慧財產局員工消費合作社印製價結合的醣蛋白（稱為α及冷鏈)所構成。α次單元含有重鏈及輕鏈為其細胞外功能部位之一部分，具有3至4個二價陽離子結合位點；其輕鏈亦含有跨膜及細胞内功能部位。/3次單元含有極大之細胞外功能部位，以及跨膜及細 15 胞内功能部位。整合素為細胞表面受體，其與細胞外基質黏合蛋白例如血纖維蛋白原、纖維網蛋白、透明質蛋白與造骨蛋白結合。彼等跨膜醣蛋係根據/5次單元分類。於新近之藥物發現成杲中，整合素族之yS3類受到最大的矚目 (W.J. Hoekstra, Current Medicinal Chemistry, 1998, 5, 20 195)，然而，冷5類亦成為矚目焦點。於其病原學上與強 /53及/55整合素成分有關連的一些疾病狀態為血拴形成 (a 2b召3，亦稱為 GPIIb/IIIa);不穩定型心絞痛 (GPIIb/IIIa);動脈再狹窄（GPIIb/IIIa 及整合素 av/3 3); 關節炎、血管性疾病或骨質疏鬆症（a v/5 3);腫瘤血管新本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 五、發明說明（2 10 15 生、多發性硬化症、神經疾病、氣喘、血管傷害或糖尿病視網膜病變（a v/3 3或α v冷5)及腫瘤轉移（a v泠3)。參見 S.A, Mousa? et al.5 Emerging Therapeutic Targets, 2000, 4(2)148-149，及 W.H. Miller, et al.，Discovery Tbtiay， 2000, 5(9)，397-40。於動物模式中，抗體及/或低分子量化合物拮抗劑αν/33已顯示對抗彼等各個疾病狀態之效力（J. Samanen, Current Pharmaceutical Design, 1997, 3 545-584) ’因而可提供作為治療劑之用途。有幾個專利已述及能與彼等整合素相互作用的化合物。例如，美國專利案5,919,792 Bl、6,211，191 B1、及 WO 01/96334，WO 01/23376則敘述αν/53與αν冷5整合素受體拮抗劑。本發明提供新類別之哌啶醯基化合物，其為供治療寬廣種類的整合素傳介疾病狀態有用之石3、沒5或雙重整合素(例如，αν泠3與αν召5)受體拮抗劑。發明概述本發明乃有關下式（I)之哌啶醯基化合物：經濟部智慧財產局員工消費合作社印製 20 丫200536844 A7 B7 V. Description of the Invention (i) Field of Invention This application claims the priority of US Provisional Patent Application No. 60 / 404,239, filed on August 16, 2003, the contents of which are incorporated herein by reference. 5 The present invention relates to a novel compound and a method for treating integrin-mediated diseases. Specifically, the present invention relates to a piperidinylcarboxylic acid compound used as a selective integrin receptor antagonist and a method for treating integrin-mediated diseases. BACKGROUND OF THE INVENTION 10 Integrins belong to the family of transmembrane receptors, each of which is composed of a pair of heterodimers, a glycoprotein (called alpha and cold chain) printed by a consumer cooperative of the Intellectual Property Bureau of the Ministry of Economy . The α-subunit contains a heavy chain and a light chain as part of its extracellular functional site, and has 3 to 4 divalent cation binding sites; its light chain also contains transmembrane and intracellular functional sites. The / 3 unit contains extremely large extracellular functional sites, as well as transmembrane and fine intracellular sites. Integrins are cell surface receptors that bind to extracellular matrix adhesion proteins such as fibrinogen, fibrin, hyalin, and osteoblasts. Their transmembrane sugar eggs are classified according to / 5 units. Among the recent discoveries of drugs, the yS3 class of integrin family has received the most attention (W.J. Hoekstra, Current Medicinal Chemistry, 1998, 5, 20 195), however, the cold class 5 has also become the focus of attention. Some disease states associated with strong / 53 and / 55 integrin components in its etiology are thrombosis (a 2b call 3, also known as GPIIb / IIIa); unstable angina pectoris (GPIIb / IIIa); arteries Restenosis (GPIIb / IIIa and integrin av / 3 3); arthritis, vascular disease or osteoporosis (av / 5 3); new tumor paper size applies Chinese National Standard (CNS) A4 (210x297) (Centre) 200536844 A7 B7 V. Description of the invention (2 10 15 students, multiple sclerosis, neurological disease, asthma, vascular injury or diabetic retinopathy (av / 3 3 or α v cold 5) and tumor metastasis (av 3) See SA, Mousa? Et al. 5 Emerging Therapeutic Targets, 2000, 4 (2) 148-149, and WH Miller, et al., Discovery Tbtiay, 2000, 5 (9), 397-40. In animal mode Antibodies and / or low molecular weight compound antagonists αν / 33 have been shown to be effective against their various disease states (J. Samanen, Current Pharmaceutical Design, 1997, 3 545-584) 'so they can be used as therapeutic agents. There are Several patents have described compounds capable of interacting with their integrins. U.S. Patent Nos. 5,919,792 Bl, 6,211,191 B1, and WO 01/96334, and WO 01/23376 describe αν / 53 and ανcol-5 integrin receptor antagonists. The present invention provides a new class of piperidinyl compounds, which Stone 3, 5 or dual integrin (e.g., ανι3 and ανCall 5) receptor antagonists useful for treating a wide variety of integrin-mediated disease states. SUMMARY OF THE INVENTION The present invention relates to the following formula (I) Piperidinyl Compound: Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

{O^zh 式⑴{O ^ zh style ⑴

式中 W係選自下述組群：_cG3烷基(Ri)、_Ci_3烷基(Ru)、-C〇3 -4- 本紙張尺度刺巾 0 S^^(CNS)A4 ^ (210x297 ) 200536844 A7 B7 五、發明說明（3) 烷基-芳基(Ri，RS)、-C(M烷基-雜環基(RhR8)、-C(M烷氧墓(D、-Cq·3烧氧基-芳基(Rl5R8)、及_c〇_3烧氧基-雜環基(R^Rs);In the formula, W is selected from the following groups: _cG3 alkyl (Ri), _Ci_3 alkyl (Ru), -C〇3 -4- stab towel of paper size 0 S ^^ (CNS) A4 ^ (210x297) 200536844 A7 B7 V. Description of the invention (3) Alkyl-aryl (Ri, RS), -C (M alkyl-heterocyclic (RhR8), -C (M alkoxy tomb (D, -Cq · 3) Aryl- (Rl5R8), and _c0_3 alkoxy-heterocyclyl (R ^ Rs);

Ri係選自下述組群：氫、_N(R4)2…n(r4)(R5)、-5 N(R4)(R6)、-雜環基(R8)及-雜芳基(R8);Ri is selected from the group consisting of: hydrogen, _N (R4) 2 ... n (r4) (R5), -5 N (R4) (R6), -heterocyclic group (R8) and -heteroaryl (R8) ;

Ru 係選自下述組群：_(：(1^4)(,-114)、_(：(,_114)- N(R4)2、-C(=N-R4)_N(R4)(R6)、-C(=N_R4)-N(R4)-C(=0)-R4、_c(=N-R4)-N(R4)-C(=〇)-N(R4)2、-C(=N_ R4)-N(R4)-C02.R4 > -C(=N-R4)-N(R4)-S02-C1.g ^^(R7) 10 及-C(=N-R4)-N(R4)-S〇2-N(R4)2 ; R4係選自下述組群：氫及-Ci.8烷基(R7); R5 係選自下述組群：-C(=〇)-R4、-(：(=〇)-Ν(Ι14)2、-c(=o)-環烷基（R8)、-c(=〇)-雜環基（R8)、-c(=〇)-芳基 (R8)、-C(=〇)-雜芳基（r8)、-C(=〇)-N(R4)-環烷基 15 (Rs)、-c(=〇)-n(r4)-芳基(R8)、-C〇2-R4、_co2-環烷經濟部智慧財產局員工消費合作社印製基(R8)、-C〇2-*S(R8)、-C(R4)(=N-R4)、-C(=N-R4)-N(R4)2、-C(=N-R4)-N(R4)(R6)、-C(=N-R4)-N(R4)-c(=〇)-r4、-c(=n-r4)-n(r4)-c(=〇)-n(r4)2、-c(=n-R4)-N(R4)-C02-R4 > -C(=N-R4)-N(R4)-S02-C1.8 ^ ^ 20 (R7) 、 -C(=N-R4)-N(R4)_S02-N(R4)2 、 -N(R4)- c(r4)(=n-r4)、-n(r4)-c(=n-r4)-n(r4)2、-n(r4)-C(=N-R4)-N(R4)(R6) ^ -N(R4)-C(=N-R4)-N(R4)-C(=0)-r4、-n(r4)-c(=n-r4)-n(r4)-c(=〇)-n(r4)2、-n(r4)-c(=n-r4)-n(r4)-c〇2-r4 、-n(r4)-c(=n-r4)-n(r4)- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 五、發明說明（4) 5 10 15 經濟部智慧財產局員工消費合作社印製 20 SOyCw 烷基（r7)、-N(R4)-C(=n_R4)-N(R4)-S〇2-N(A)2、-SCVCw 烷基(r7)、-S〇2-N(R4)2、-SCV環烷基(R〇及-s〇2-芳基(R8); R6係選自下述組群：-環烷基(R8)、-雜環基(R8)、·芳基(¾) 及-雜芳基(R8); R7係獨立地選自下述組群之一至二個取代基：氫、_Ci_8 烷氧基(R9)、-NH2_、-NH_Ci_8 烷基(R9)、-l^Cw 烷基 (R9))2、-C(==〇)H、_c(=〇)_Ci8 烷基（R9) ' _c(=〇)-NH2、_c(=〇)-NH_Cl 8 烷基(r9)、_c(=〇)_N(Ci 8 烷基 (r9))2、<(=〇)_丽-芳基（Rig)、·ε(=〇)_ 環烷基 (R10)、_C(=0)_ 雜環基（Ri〇)、_c(=0)_ 芳基（U、-CH3)_雜芳基(R10)、-C〇2h、_c〇2_Ci 8 烷基(R9)、-C02-芳基（r1(3)、-C(=NH)_NH2、_SH、各Ci 8 烷基 (R9)、-S-Cw 烷基-S-Cw 烷基(R9)、-S-Cw 烷基-Cm 烷氧基(R9)、-S-Cw 烷基-NH-Cw 烷基(r9)、-S〇2_Cl· 8 烷基(R9)、-S02-NH2、-SCh-NH-Cw 烷基(R9)、_s〇2_ N(Ci_8 烷基(r9))2、_s〇2-芳基(R10)、氰基、（鹵基） 3、羥基、硝基、酮基、·環烷基（Riq)、_雜環基 (Rio)、-芳基(R10)及-雜芳基(R10); Rs於連接於氮原子時，係獨立地選自下述組群之一至四個取代基·氫、-Cu烧基(r9)、_c(=〇)h、_c(=〇)-Ci 8 烷基（r9)、-c(=〇)-nh2、_c(=〇)-NH_c“8 烧基 (R9)、-CpCO-Nds 烷基（r9))2、{卜外丽·芳基 (Rio)、-C(—〇)·環烧基(R1G)、-C(=〇)-雜環基(r )、Ru is selected from the group: _ (:( 1 ^ 4) (,-114), _ (: (, _ 114)-N (R4) 2, -C (= N-R4) _N (R4) ( R6), -C (= N_R4) -N (R4) -C (= 0) -R4, _c (= N-R4) -N (R4) -C (= 〇) -N (R4) 2, -C (= N_ R4) -N (R4) -C02.R4 > -C (= N-R4) -N (R4) -S02-C1.g ^^ (R7) 10 and -C (= N-R4) -N (R4) -S〇2-N (R4) 2; R4 is selected from the following group: hydrogen and -Ci.8 alkyl (R7); R5 is selected from the following group: -C (= 〇) -R4,-(: (= 〇) -N (Ι14) 2, -c (= o) -cycloalkyl (R8), -c (= 〇) -heterocyclyl (R8), -c ( = 〇) -aryl (R8), -C (= 〇) -heteroaryl (r8), -C (= 〇) -N (R4) -cycloalkyl 15 (Rs), -c (= 〇) -n (r4) -aryl (R8), -C〇2-R4, _co2-Nanthane Intellectual Property Bureau, Ministry of Economic Affairs, Employee Consumer Cooperative Printed Base (R8), -C〇2- * S (R8),- C (R4) (= N-R4), -C (= N-R4) -N (R4) 2, -C (= N-R4) -N (R4) (R6), -C (= N-R4 ) -N (R4) -c (= 〇) -r4, -c (= n-r4) -n (r4) -c (= 〇) -n (r4) 2, -c (= n-R4)- N (R4) -C02-R4 > -C (= N-R4) -N (R4) -S02-C1.8 ^ ^ 20 (R7), -C (= N-R4) -N (R4) _S02 -N (R4) 2, -N (R4) -c (r4) (= n-r4), -n (r4) -c (= n-r4) -n (r4) 2, -n (r4)- C (= N-R4) -N (R4) (R6) ^ -N (R4) -C (= N-R4) -N (R4) -C (= 0) -r4, -n (r4) -c (= n-r4) -n (r4) -c (= 〇) -n (r4) 2, -n (r4) -c (= n-r4) -n (r4) -c〇2-r4, -n (r4) -c (= n-r4) -n (r4)-This paper standard applies Chinese national standard ( CNS) A4 specification (210x297 mm) 200536844 A7 B7 V. Description of invention (4) 5 10 15 Printed by SOE Cw Alkyl (r7), -N (R4) -C (= n_R4) ) -N (R4) -S〇2-N (A) 2, -SCVCw alkyl (r7), -S〇2-N (R4) 2, -SCV cycloalkyl (R0 and -s〇2- Aryl (R8); R6 is selected from the group: -cycloalkyl (R8), -heterocyclyl (R8), · aryl (¾) and -heteroaryl (R8); R7 is independently Selected from one to two substituents of the group: hydrogen, _Ci_8 alkoxy (R9), -NH2_, -NH_Ci_8 alkyl (R9), -l ^ Cw alkyl (R9)) 2, -C (= = 〇) H, _c (= 〇) _Ci8 alkyl (R9) '_c (= 〇) -NH2, _c (= 〇) -NH_Cl 8 alkyl (r9), _c (= 〇) _N (Ci 8 alkyl (r9)) 2, < (= 〇) _Li-aryl (Rig), · ε (= 〇) _cycloalkyl (R10), _C (= 0) _heterocyclyl (Ri〇), _c (= 0) _aryl (U, -CH3) _heteroaryl (R10), -C02h, -c02_Ci 8 alkyl (R9), -C02-aryl (r1 (3), -C ( = NH) _NH2, _SH, Ci 8 alkyl (R9), -S-Cw alkyl-S-Cw alkyl (R9), -S-Cw alkyl-Cm alkoxy (R9), -S-Cw alkyl-NH-Cw alkyl (r9), -S〇2-Cl8 alkyl (R9), -S02-NH2, -SCh-NH-Cw alkyl (R9), _s 〇2_ N (Ci_8 alkyl (r9)) 2, _s〇2-aryl (R10), cyano, (halo) 3, hydroxyl, nitro, keto, cycloalkyl (Riq), _hetero Cyclic group (Rio), -aryl group (R10) and -heteroaryl group (R10); When Rs is attached to a nitrogen atom, it is independently selected from one to four substituents of the following groups: hydrogen, -Cu (R9), _c (= 〇) h, _c (= 〇) -Ci 8 alkyl (r9), -c (= 〇) -nh2, _c (= 〇) -NH_c "8 alkyl (R9), -CpCO-Nds alkyl (r9)) 2, {Brexylaryl (Rio), -C (-〇), cycloalkyl (R1G), -C (= 〇) -heterocyclyl (r) ,

200536844 A7 B7 五、發明說明 (—0)-芳基（R1())、-c(=〇)-雜芳基（RiG)、-C〇2H、· C02-CW 烷基(R9)、_C〇2_ 芳基(R】〇)、_C(=NH)_NH2、-Sh-Cw 烷基（R9)、-S〇2_NHr、烷基 (¾)、烷基(r9))2、-S〇2_芳基(Ri〇)、_環烷基(Rio)、與-芳基(R1G);又，於連接於碳原子時，係獨立地選自下述組群之一至四個取代基··氫、_C18 烷基(¾)、-Ci_8烷氧基氓9)、_〇_環烷基(Ri〇)、_〇_芳基(Rig)、-C(=0)H、/(=0)-(^.8 烷基（r9)、-C(=〇y NH2、-CCOhNH-Cu 烷基(R9)、-C(K))_N(Ci_8 烷基 10 (r9))2、-c(=〇)-nh-芳基（R1G)、_C(==〇)_ 環烷基 (Rh>)、_C(=〇)-雜環基（R10)、-C(=〇)_ 芳基（Ri。）、-C(K)>雜芳基(r1〇)、_C〇2h、_c〇2-Ci-8 烷基识9)、-C〇2_芳基(R1())、-C(=NH)-NH2、-SOrCw 烷基(R9)、-S〇2-NH2、-SOfNH-Cw 烷基(R9)、-SCVNCCw 烷基 15 (R9))2、-S〇2-芳基(R10)、-SH-、-S-Cw 烷基(R9)、-S-200536844 A7 B7 V. Description of the invention (-0) -aryl (R1 ()), -c (= 〇) -heteroaryl (RiG), -C〇2H, · C02-CW alkyl (R9), _C 〇2_aryl (R) 〇), _C (= NH) _NH2, -Sh-Cw alkyl (R9), -S〇2_NHr, alkyl (¾), alkyl (r9)) 2, -S〇2 Aryl (Ri0), cycloalkyl (Rio), and -aryl (R1G); and when attached to a carbon atom, it is independently selected from one to four substituents of the following group ... Hydrogen, _C18 alkyl (¾), -Ci_8 alkoxy group 9), _〇_cycloalkyl (Ri〇), _〇_aryl (Rig), -C (= 0) H, / (= 0 )-(^. 8 alkyl (r9), -C (= 〇y NH2, -CCOhNH-Cu alkyl (R9), -C (K)) _ N (Ci_8 alkyl10 (r9)) 2, -c (= 〇) -nh-aryl (R1G), _C (== 〇) _cycloalkyl (Rh >), _C (= 〇) -heterocyclyl (R10), -C (= 〇) _aryl (Ri.), -C (K) > heteroaryl (r1〇), -C02h, -c02-Ci-8 alkyl group 9), -C02-aryl group (R1 ()), -C (= NH) -NH2, -SOrCw alkyl (R9), -S〇2-NH2, -SOfNH-Cw alkyl (R9), -SCVNCCw alkyl 15 (R9)) 2, -S〇2- Aryl (R10), -SH-, -S-Cw alkyl (R9), -S-

Cw烷基-S-Ci_8烷基(R9)、-S-Cw烷基-Cw烷氧基 (R9)、烧基-NH-Ci.g 烧基(R9)、_NH2、-NH-Ci-8 烧基(R9)、-N(Ci_8烧基(Rs〇)2、氰基、鹵基、經基、硝基、酮基、-環烷基(Rio)、-雜環基(R1G)、-芳基(R10) 20 與-雜芳基(R10); R9係選自下述組群：氫、-Cw烷氧基、_NH2、-NH-Cw 烷基、烷基）2、-C(=〇)H、-C(=0)-NH2、-烷基、名(=〇)小(〇^8 烷基）2、-C〇2H、_C〇2-Ci.8 烧基…S〇2_Ci.8 院基、-S〇2-NH2 ' - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 4 訂經濟部智慧財產局員工消費合作社印製 200536844 A7 B7 五、發明說明 scvnh-c"烧基、S(VN(Ci8 縣）2、氛基、（齒基）1·3、羥基、硝基及酮基；Cw alkyl-S-Ci_8 alkyl (R9), -S-Cw alkyl-Cw alkoxy (R9), alkyl-NH-Ci.g alkyl (R9), _NH2, -NH-Ci-8 Carbo (R9), -N (Ci_8 Carbo (Rs〇) 2, cyano, halo, meridian, nitro, keto, -cycloalkyl (Rio), -heterocyclic (R1G),- Aryl (R10) 20 and -heteroaryl (R10); R9 is selected from the group consisting of: hydrogen, -Cw alkoxy, _NH2, -NH-Cw alkyl, alkyl) 2, -C (= 〇) H, -C (= 0) -NH2, -alkyl, name (= 〇) small (〇 ^ 8 alkyl) 2, -C〇2H, _C〇2-Ci. 8 alkyl ... S〇2_Ci .8 Yuanji, -S〇2-NH2 '-This paper size applies to China National Standard (CNS) A4 (210x297 mm) 4 Order printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives 200536844 A7 B7 V. Description of invention -c " Bake group, S (VN (Ci8 county) 2, atmosphere group, (dentate group) 1.3, hydroxyl, nitro and ketone group;

Rio於連接於氮原子時，係獨立地選自下述組群之一至四個取代基·氫、-Cw烷基、-C(=〇)H、烷基、-(：(=〇)-νη2、-C(=0)-NH_Cl s 烷基、<(=〇)_ Nds 烧基(R9))2、-c〇2h、-CCVCm 烷基、-SOi-Cw 烧基、-s〇2-nh2-、-S〇2-NH_CK8 烧基與-s〇2-n(c“8 10 15 經濟部智慧財產局員工消費合作社印製 20 烧基)2 ;又，於連接於碳原子時，係獨立地選自下述組群之一至四個取代基：氫、-C1_8烷基、-C1_8烷氧基、-C(=〇)H、烷基、-C(=〇)-NH2、_ CpCO-NH-Cu 烧基、-0(=0)^((^.8 烧基）2、-C〇2H 、 -CCVCw 烷基、 -SCVCw 烷基、 -S02-NH2 、 -S〇2-NH-Cw 烷基、-SOyNCCw 烷基)2、-NH2 …NH-Ci_8烧基、-Ν((：ν8院基)2、氰基、鹵基、經基、确基與酮基；心係選自下述組群：氫、-Cm烷基（R7)、-C2-8烯基 (R7)、-C2_8 炔基(R7)、-環烷基(R8)、-雜環基(R8)、-芳基(R8)與-雜芳基(R8);及 q為 0、1、2 或 3; Z係選自下述組群：羥基、-NH2、-NH-Cm烷基、-Ν((^8 烷基)2、O-Cw烷基-〇Η、-O-Cw烷基Cw烷氧基、-OCU8烷基羰基Cw烷基、-O-Cw烷基-C02H、-〇-Cw烷基-C(〇)〇-C!_8烷基、-O-Cw烷基-〇-(：(〇)(^8 烷基、-〇-Cw烷基-NH2、_〇-Ci_8烷基-NH-Cu烧本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 五、發明說明（7 ) 基、-O-Cw烷基-Ν((^8烷基)2、-OCw烷基醯胺… O-Cw 烷基-CCO^NH-Cu 烷基、-OCw 烷基-C(〇)- Ν((^_8烷基)2及-NHC(〇)Cn8烷基、-O-Cw烷基；及其醫藥上可接受之鹽、消旋混合物與鏡像異構物。 5 本發明亦有關該等哌啶醯化合物及其醫藥組成物與藥劑之製法。本發明進一步有關治療或改善由整合素受體傳介的疾病之方法。發明之詳細說明 10 本發明之態樣包含式⑴中W為-C〇_3烷基(R!)或-C〇_3_ 烧基-芳基(Ri，R8)之化合物。本發明之另一態樣包含式(I)中W為-C〇.3烷基(R〇或-C〇·3烧基-苯基(Rl5R8)之化合物。本發明之態樣包含式⑴中Rla_N(R4)(R6)、·雜環基 15 (R〇或-雜芳基(R8)之化合物。經濟部智慧財產局員工消費合作社印製本發明之另一態樣包含式⑴中R1為小(114)(116;)、-二氫-1/7-。比咯并[2,3-小比啶基（R8)、-四氫嘧啶基（r8)…四氫-1，8-萘啶基(rs)、_四氫吖庚因并^刃^比啶基(R8) 或-啦咬基(r8)之化合物。 20 本發明之另一態樣包含式（I)中Ri為-N(R4)(R6)、-四氫嘧啶基或-四氫-1，8·萘啶基(R8)之化合物。本發明之態樣包含式⑴*Riag-C(R4)(=N-R4)、_ C(=N-R4)-N(R4)2 . -C(=N-R4).N(R4)(R6) . -C(=N-R4)- N(R4)-C(-0).r4 , -C(=N-R4)-N(R4).C(=〇).N(R4)2 ^ -C(=N- -9-When Rio is attached to a nitrogen atom, it is independently selected from one to four of the following groups: hydrogen, -Cw alkyl, -C (= 〇) H, alkyl,-(: (= 〇)- νη2, -C (= 0) -NH_Cl s alkyl, < (= 〇) _ Nds alkyl (R9)) 2, -c02h, -CCVCm alkyl, -SOi-Cw alkyl, -s〇 2-nh2-, -S〇2-NH_CK8 base and -s〇2-n (c "8 10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 20 bases) 2; Also, when connected to a carbon atom Is independently selected from one to four substituents of the following group: hydrogen, -C1_8alkyl, -C1_8alkoxy, -C (= 〇) H, alkyl, -C (= 〇) -NH2, _ CpCO-NH-Cu alkyl, -0 (= 0) ^ ((^. 8 alkyl), -C〇2H, -CCVCw alkyl, -SCVCw alkyl, -S02-NH2, -S〇2 -NH-Cw alkyl, -SOyNCCw alkyl) 2, -NH2 ... NH-Ci_8 alkyl group, -N ((: ν8 alkyl group) 2, cyano, halo, meridian, alkoxy, and ketone; Is selected from the group consisting of: hydrogen, -Cm alkyl (R7), -C2-8 alkenyl (R7), -C2_8 alkynyl (R7), -cycloalkyl (R8),-heterocyclyl (R8 ), -Aryl (R8) and -heteroaryl (R8); and q is 0, 1, 2 or 3; Z is selected from the group consisting of: hydroxyl, -NH2, -NH-C m alkyl, -N ((^ 8 alkyl) 2, O-Cw alkyl-〇Η, -O-Cw alkyl Cw alkoxy, -OCU8 alkylcarbonyl Cw alkyl, -O-Cw alkyl -C02H, -0-Cw alkyl-C (〇) 〇-C! _8 alkyl, -O-Cw alkyl-〇- (: (〇) (^ 8 alkyl, -〇-Cwalkyl-NH2 _〇-Ci_8 alkyl-NH-Cu sintered paper size applicable to Chinese National Standard (CNS) A4 specification (210x297 mm) 200536844 A7 B7 V. Description of the invention (7) group, -O-Cw alkyl-N ( (^ 8alkyl) 2, -OCw alkylamine ... O-Cw alkyl-CCO ^ NH-Cu alkyl, -OCw alkyl-C (〇)-Ν ((^ _ 8alkyl) 2 and- NHC (〇) Cn8 alkyl, -O-Cw alkyl; and pharmaceutically acceptable salts, racemic mixtures and mirror isomers thereof. 5 The present invention also relates to the piperidine hydrazone compounds and their pharmaceutical compositions and Preparation method of medicament. The present invention further relates to a method for treating or ameliorating a disease mediated by an integrin receptor. DETAILED DESCRIPTION OF THE INVENTION 10 An aspect of the present invention includes W-C0_3 alkyl (R!) In formula (I) Or a -C0_3_alkenyl-aryl (Ri, R8) compound. Another aspect of the present invention comprises W in the formula (I) is -C0.3 alkyl (R0 or -C0.3 Alkyl-phenyl (Rl5R8) compounds. Aspects of the invention include compounds of Rla_N (R4) (R6), · heterocyclyl 15 (R0 or -heteroaryl (R8)) in formula (I). The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed another copy of the invention One aspect includes formula (1) where R1 is small (114) (116;), -dihydro-1 / 7-. Than pyrrole [2,3-smaller than pyridyl (R8), -tetrahydropyrimidyl (r8 ) ... A compound of tetrahydro-1,8-naphthyridinyl (rs), _tetrahydroazepine and pyridinyl (R8) or -laquinyl (r8). 20 Another aspect of the present invention Examples include compounds of formula (I) wherein Ri is -N (R4) (R6), -tetrahydropyrimidinyl, or -tetrahydro-1,8 · naphthyridinyl (R8). Aspects of the invention include formula ⑴ * Riag-C (R4) (= N-R4), _ C (= N-R4) -N (R4) 2 .-C (= N-R4) .N (R4) (R6) .-C (= N -R4)-N (R4) -C (-0) .r4, -C (= N-R4) -N (R4) .C (= 〇) .N (R4) 2 ^ -C (= N-- 9-

200536844200536844

五、發明說明（8) R4)-N(R4)-C02-R4 ' _C(’叫N(R4)-S〇2_c“8 烧基㈣或-c(=n_r4)_n(R4)_scvn(R4)2 之化合物。本發明之態樣包含式⑴中r4為氫或_c^烷基(R7)之化合物。 5 本發明之另一態樣包含式（I)中R4為氫之化合物。本發明之態樣包含式①中R5為_C(=〇>R4、<(=〇)_ N(R4)2、-c(=0)-環烧基（r8)…雜環基（Rs)、_ c(哪芳基(R8)、-c(=〇)-雜芳基(r8)、_c(哪N(R4)_環烷基(R8)、-C(=〇)-N(R4)-芳基(r8)、-C〇2-R4、-c〇2-環烷基 10 (¾)、-C〇2_ 芳基（私）、_(：(114)(=队114)、-(：(=^-114)- N(R4)2、-C〇=N-R4)-N(R4)(R6)、-C(=N-R4)-N(R4)-C(=〇)-R4、-C(=N-R4)-N(R4)-C(=〇)-N(R4)2、-C(=N-R4)-N(R4> C〇2-R4、-CeND-NCRJ-SOrCM ：^*(R7)、-C(=N-R4)-n(r4)-s〇2-n(r4)2、-n(r4)-c(r4)(=n-r4)、-n(r4)-c(=n- 15 R4)-N(R4)2、-N(R4)-C(=N-R4)-N(R4)(R6)、-N(R4)-C(=N- R4)-N(R4)-C(=0)-R4 、 -n(r4)-c(=n-r4)-n(r4)-c(=〇)_ n(r4)2、-n(r4)-c(=n-r4)-n(r4)-c〇2-r4、-n(r4)-c(=n- 經濟部智慧財產局員Η消費合作社印製 R4)-N(R4)-S〇2*"Ci-4 烧基(R7)、-N(R4)-C(=N-R4)-N(R4)-S〇2- n(r4)2、-so2-cN4 烷基（r7)、-s〇2-n(r4)2、-so2-環烷基 20 (R8)或-S〇2-芳基(R8)之化合物。本發明之另一態樣包含式（I)中R5為<(=〇)_114、- C(=〇)-N(R4)2、-C〇2-R4、-C(R4)(=N-R4)、-C(=N-R4)- N(R4)2、_C(=N-R4)，N(R4)(R6)、-N(R4)-C(R4)(=N-R4)、_ N(R4)-C(=N-R4)-N(R4)2、-N(R4)-C(=N-R4)-N(R4)(R6)、· -10- i紙張尺度適用中國國家標準(CNS)A4規格（210x297公爱） 200536844V. Description of the invention (8) R4) -N (R4) -C02-R4 '_C (' Called N (R4) -S〇2_c "8 alkyl group or -c (= n_r4) _n (R4) _scvn (R4 ) 2. Compounds of the present invention include compounds wherein formula R4 is hydrogen or _c ^ alkyl (R7). 5 Another aspect of the invention include compounds of formula (I) where R4 is hydrogen. Aspects of the invention include the formula ① in which R5 is _C (= 〇 > R4, < (= 〇) _N (R4) 2, -c (= 0) -cycloalkyl (r8) ... heterocyclyl ( Rs), _c (which aryl (R8), -c (= 〇) -heteroaryl (r8), _c (which N (R4) _cycloalkyl (R8), -C (= 〇) -N (R4) -aryl (r8), -C〇2-R4, -c〇2-cycloalkyl 10 (¾), -C〇2-aryl (private), _ (:( 114) (= team 114 ),-(: (= ^-114)-N (R4) 2, -C〇 = N-R4) -N (R4) (R6), -C (= N-R4) -N (R4) -C (= 〇) -R4, -C (= N-R4) -N (R4) -C (= 〇) -N (R4) 2, -C (= N-R4) -N (R4 > C〇2- R4, -CeND-NCRJ-SOrCM: ^ * (R7), -C (= N-R4) -n (r4) -s〇2-n (r4) 2, -n (r4) -c (r4) ( = n-r4), -n (r4) -c (= n- 15 R4) -N (R4) 2, -N (R4) -C (= N-R4) -N (R4) (R6),- N (R4) -C (= N- R4) -N (R4) -C (= 0) -R4, -n (r4) -c (= n-r4) -n (r4) -c (= 〇) _ n (r4) 2, -n (r4) -c (= n-r4) -n (r4) -c〇2-r4, -n (r4) -c (= n- Member of Intellectual Property Bureau, Ministry of Economic Affairs ΗPrinted by consumer cooperatives R4) -N (R4) -S〇2 * " Ci-4 alkyl (R7), -N (R4) -C (= N-R4) -N (R4) -S〇2 -n (r4) 2, -so2-cN4 alkyl (r7), -s〇2-n (r4) 2, -so2-cycloalkyl 20 (R8) or -S02-aryl (R8) Compound. Another aspect of the present invention comprises R5 in formula (I): <(= 〇) _114, -C (= 〇) -N (R4) 2, -C〇2-R4, -C (R4) (= N-R4), -C (= N-R4)-N (R4) 2, _C (= N-R4), N (R4) (R6), -N (R4) -C (R4) (= N-R4), _ N (R4) -C (= N-R4) -N (R4) 2, -N (R4) -C (= N-R4) -N (R4) (R6), -10 -i paper size applies to China National Standard (CNS) A4 (210x297 public love) 200536844

、，"〜儿公初Ο 本發明之態樣包含式⑴中1為_雜 (R8)之化合物。、W X雜方基本發明之另一態樣包含式⑴ ▲ /n、 ^ ^ w τ尺6為-二虱口米。坐某 (Rs)、-四風^比咬基(r8)、_四氮喊化合物。風街疋基队）或-吨咬基恥)之本發明之態樣包含式⑴十R7係獨立地選自下述之一至二個取代基之化合物：氫u氧基㈣、· 10 nh2_、_nh_Ci_4 烷基（R9)、-N(Ci 4 烷基叫、_ C(=0)H、-C(=0)-Cl.4 院基(R9)、·ε(=〇)_丽2、_c(=〇)_ 15 NH-Cl.4 縣(r9)、c(哪n(Cm 烧基(R9))2、_c(=〇)_丽· 芳基(R10)、-(：(=0)、環烷基(Ri〇)、<(=〇)_雜環基(Ri。）、_ C(=〇)-芳基(R10)、-C(=0)_雜芳基(Ri〇)、_c〇2H、_c〇2_c“ 4 烷基(R9)、-C〇2•芳基(Rl〇)、C卜NH)_NH2、_SH、各烷基(R9)、_S-C“4 烷基_s_Cl 4 烷基(r9)、-S_Ci 4 烷基4 烧氧基(R9)、-S-Cw 烷基-NH-Cw 烷基(R9)、-SOrCM 烷基(R9)、-S〇2_NH2、-SC^-NH-Cm 烷基（R9)、-SCVNCCm 經濟部智慧財產局員工消費合作社印製烧基(R9))2、-S〇2·芳基(r10)、氰基、（虐基）13、經基、石肖基、酮基、-環烷基(R1G)、-雜環基(R1G)、-芳基(R1Q)或-雜 20 芳基(R10)。本發明之另一態樣包含式（I)中R7係獨立地選自下述組群之一至二個取代基之化合物··氫、-Cl-4烧乳基 (R9)、-NH2-、-NH-Q-4 烷基(R9)、烷基(R9))2、（鹵基）1-3、羥基或酮基。 -11- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 ΒΊ 五、發明說明（10 ) 本發明之進-步態樣包含式(㈣為氫之化合物。本發明之態樣包含式⑴中R8於連接於氣原子時，係獨立地選自下述組群之一至四個取代基：氫、_c“烷基 (R9)、-C(K))H、-C(，-Cl.4 燒基（R9)、_c(哪丽2、 5 Cd-NH-CM 烧基（R9)、-C(=0)_N(Ci 4 烷基⑽2、_ c(=〇>nh·芳基(RlG)、_c(哪我基(R】。）、_c(=〇)_雜環基（心〇)、-C(=0)-芳基（R10)、_C(=〇)_ 雜芳基（Ri〇)、· co2h、-ccvcu 烷基(r9)、·〇：〇2_ 芳基(Ri。）、_c(=nh)_ nh2、-scvCm 烧基(r9)、-S〇2_NH2·、_s〇2_NH_Ci 4 烧基 10 (R9)、-SCVNCCm 烷基(R9))2、·3〇2_ 芳基(Ri〇)、_環烷基 (Rio)、或-芳基(R1G);又，於連接於碳原子時，係獨立地選自下述組群之一至四個取代基：氫、_Ci4烷基(R9)、_ Ci-4烷氧基（R9)、-〇-環烷基（RlG)、七-芳基⑻❹）、-C(=〇)H、<(=0)4.4 烷基（R9)、_c(=〇)-Nh2、（(=〇)_ 15 NH-Cw 烷基(R9)、-(:(=0^((^.4 垸基-Ru)2、芳基(R10)、-C(=〇)-環烷基(R10)、-c(=〇)-雜環基(Ri〇)、_ C(=〇)-芳基(R1())、-C(=0)-雜芳基(R1〇)、_c〇2h、<02^ 經濟部智慧財產局員工消費合作社印製 4 烧基(R9)、-C〇2-芳基(R10)、_C(=NH)-NH2、-SCVCi 4 烧基(R9)、_S〇2_NH2、-SOrNH-Cw 烷基(R9)、_s〇2-N(C14 20 烧基(R9))2、_S〇2_芳基(R1())、_SH-、-S-Cw 烷基(r9)、各 Ci-4 烧基-S-Cm 烧基(R9)、-S-Cm 烧基-Cm 统氧基(r9)、· S-Cm 烷基-NH-Cm 烷基（r9)、-NH2、-NH-CM 烧基 (R9)、-N(Cl-4烷基(R9))2、氰基、鹵基、羥基、硝基、嗣基、-環烷基(R1G)、_雜環基(r1g)、_芳基(111())或_雜芳基 -12- 本紙張尺度適用f國國家標準(CNS)A4規格（210 X 297公爱） '~ --— - 200536844 A7 B7 五、發明說明（11) (Rio)之化合物。本發明之另一態樣包含式（I)中Rs於連接於氮原子時，係獨立地選自下述组群之一至四個取代基··氫、-Cl·4 烷基(R9)、-C(=0)H、乂 C(=〇)-NH2烷基 5 (¾)、-CPCO-NCCh 烷基(R9))2 …C〇2H …CA-Cm 烷基 (R9)或-s〇2-nh2-;又，於連接於破原子時’係獨立地選自下述組群之一至四個取代基：氫、，Cm烷基(R9)、-Cl-4 烷氧基（r9)、芳基（r1g)、_c(=〇)h、-c(=〇)-nh2、-COOhNH-CM 烷基（R9)、-(：(=0)-Ν(<^4 炼基（R9))2、-10 C〇2H、-c〇2-cu4 烷基(R9)、-s〇2-NH2 …即2、-NH_Cl·4 烷基(¾)、-ΝβΜ烷基(R9))2、氰基、鹵基、經基、硝基或酮基之化合物。本發明之另一態樣包含式⑴中以8於連接於氮原子時，係獨立地選自氫或-Cm烷基(r9)之一至四個取代基； 15 又於連接於碳原子時，係獨立地選自氫、-Ci-4烧基 (R9)、-Cm 烷氧基(R9)、_〇_芳基(Rig)、_NH2、_NH_Ci 4 烷經濟部智慧財產局員工消費合作社印製基(¾)、-Ν((^4燒基（r9))2、鹵基、經基或酮基之一至四個取代基之化合物。本發明之進一步態樣包含式(I)中Rs於連接於氮原子、係獨立地選自氫或-Ci·4烷基(R9)之一至四個取代基；又，於連接於碳原子時，係獨立地選自氩、七Μ烷基、）C“4烷氧基(R9)、_〇·芳基(Riq)或羥基之一至四個取代基之化合物。樣包含式⑴中R9為氫、_Cm烧氧基、_ ___ -13- 200536844 A7 B7 五、發明說明（12) NH2、-NH-Cm 烷基、-Nfw 烷基)2、-C(=〇)H、-C(=〇)-NH2、七 «^nh-Cm 烷基…烷基）2、-C〇2H、-COrCM 烷基、-SOrCM 烷基、-SCVNH2、-S02-NH-Cw烧基、-SC^-NCCm烧基)2、氰基、（鹵基）13、經 5 基、硝基或闕基之化合物。本發明之另一態樣包含式⑴中r9為氫、_Cl_4烷氧基、-NH2、-NH-Cm 烷基、-NCw 烷基)2、毛(=0)11、- C〇2H、-0(=0)-(^4烷氧基、（鹵基）1-3、羥基或酮基之化合物。 1〇本發明之進一步態樣包含式(I)中R9為氫、-Cm烷氧基、-丽2、-NH-Cm烷基、_N(C“4烷基)2、（齒基)1-3或羥基之化合物。本發明之態樣包含式(I)中R10於連接於氮原子時，係獨立地選自下述組群之一至四個取代基：氫、_Ci_4烷 15 基、-C(=〇)H、-(3(=0)-0^.4 烧基、-C(=〇)-NH2、-C(=0)- NH-Cm 烷基、-CpCO-Nfw 烷基)2、-C〇2h、_c〇2-Ci_4 烧基、-SCVCm 烷基、-S〇2-NH2-、-SCVNH-Cm 烷基或- 經濟部智慧財產局員工消費合作社印製 SO^Nfi·4烷基)2 ;又，於連接於碳原子時，係獨立地選自下述組群之一至四個取代基：氫、_Ci_4烷基、-c】_4烷 20 氧基、-C(=〇)H、-(3(=0)-(^4 燒基…c(=〇)-NH2、-&Quot; ~ 〜公初〇 An aspect of the present invention includes a compound in which Formula 1 is _hetero (R8). , W X heterosexual group Another aspect of the present invention includes the formula ⑴ ▲ / n, ^ ^ w τ rule 6 is-two lice mouth rice. A certain (Rs), -four wind ^ than bite (r8), _ tetrazine compounds. The style of the present invention of the wind street group) or -t-biting group) includes the compound of formula ⑴ R7 which is independently selected from one to two substituents: hydrogen uoxy㈣, · 10 nh2_, _nh_Ci_4 alkyl (R9), -N (Ci 4 alkyl is called, _ C (= 0) H, -C (= 0) -Cl. 4 Yuan (R9), · ε (= 〇) _ 丽 2, _c (= 〇) _ 15 NH-Cl. 4 counties (r9), c (which n (Cm alkyl) (R9)) 2, _c (= 〇) _ li aryl (R10),-(: (= 0), cycloalkyl (Ri0), < (= 〇) _heterocyclyl (Ri.), _C (= 〇) -aryl (R10), -C (= 0) _heteroaryl ( Ri〇), _c〇2H, _c〇2_c "4 alkyl (R9), -C02 aryl (RlO), CNH) NH2, _SH, each alkyl (R9), _S-C" 4 alkyl_s_Cl 4 alkyl (r9), -S_Ci 4 alkyl 4 alkyloxy (R9), -S-Cw alkyl-NH-Cw alkyl (R9), -SOrCM alkyl (R9),- S〇2_NH2, -SC ^ -NH-Cm alkyl (R9), -SCVNCCm, printed by the consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (R9)) 2, -S〇2 · aryl (r10), cyano , (Bradyl) 13, mesityl, schottyl, keto, -cycloalkyl (R1G), -heterocyclyl (R1G), -aryl (R1Q) or -hetero20 aryl (R10). Another aspect includes R7 in formula (I). A compound selected from the group consisting of one to two substituents of hydrogen, hydrogen, -Cl-4 alkyl, (R9), -NH2-, -NH-Q-4 alkyl (R9), alkyl (R9 )) 2, (halo) 1-3, hydroxyl or keto. -11- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200536844 ΒΊ 5. Description of the invention (10) The advanced-step aspect of the present invention includes a compound of the formula (㈣ is a hydrogen compound. State of the present invention In the formula, when R8 is attached to a gas atom, it is independently selected from one to four substituents of the following group: hydrogen, —c ”alkyl (R9), -C (K)) H, -C ( , -Cl.4 alkyl (R9), _c (Neri2, 5 Cd-NH-CM alkyl (R9), -C (= 0) _N (Ci 4 alkylfluorene 2, _c (= 〇 > nh · aryl (RlG), _c (None (R).), _c (= 〇) _heterocyclyl (Heart 〇), -C (= 0) -aryl (R10), _C (= 〇 ) _Heteroaryl (Ri〇), co2h, -ccvcu alkyl (r9), 〇: 〇2_aryl (Ri.), _C (= nh) _nh2, -scvCm alkyl (r9),- S〇2_NH2 ·, _s〇2_NH_Ci 4 alkyl 10 (R9), -SCVNCCm alkyl (R9)) 2, 30-2 aryl (Rio), cycloalkyl (Rio), or -aryl ( R1G); when attached to a carbon atom, it is independently selected from one to four substituents of the group: hydrogen, -Ci4 alkyl (R9), -Ci-4 alkoxy (R9),-. -Cycloalkyl (RlG), hepta-arylfluorene), -C (= 〇) H, < (= 0 ) 4.4 alkyl (R9), _c (= 〇) -Nh2, ((= 〇) _ 15 NH-Cw alkyl (R9),-(: (= 0 ^ ((^. 4 fluorenyl-Ru) 2 , Aryl (R10), -C (= 〇) -cycloalkyl (R10), -c (= 〇) -heterocyclyl (Ri〇), -C (= 〇) -aryl (R1 ()) , -C (= 0) -heteroaryl (R1〇), _c〇2h, < 02 ^ Printed by the Consumers' Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 4 Ranyl (R9), -C〇2-aryl (R10 ), _C (= NH) -NH2, -SCVCi 4 alkyl (R9), _S〇2_NH2, -SOrNH-Cw alkyl (R9), _s〇2-N (C14 20 alkyl (R9)), _S 〇2_aryl (R1 ()), _ SH-, -S-Cw alkyl (r9), each Ci-4 alkyl group-S-Cm alkyl group (R9), -S-Cm alkyl group-Cm system oxygen (R9), S-Cm alkyl-NH-Cm alkyl (r9), -NH2, -NH-CM alkyl (R9), -N (Cl-4 alkyl (R9)) 2, cyano , Halo, hydroxy, nitro, fluorenyl, -cycloalkyl (R1G), -heterocyclyl (r1g), -aryl (111 ()), or -heteroaryl-12-This paper is applicable to country f National Standard (CNS) A4 Specification (210 X 297 Public Love) '~ ----200536844 A7 B7 V. Compound of Invention Description (11) (Rio). Another aspect of the present invention includes that when Rs in the formula (I) is attached to a nitrogen atom, it is independently selected from one to four substituents of the following groups: · hydrogen, -Cl · 4 alkyl (R9), -C (= 0) H, 乂 C (= 〇) -NH2 alkyl 5 (¾), -CPCO-NCCh alkyl (R9)) 2 ... C〇2H ... CA-Cm alkyl (R9) or -s 〇2-nh2-; and, when attached to a broken atom, is independently selected from one to four substituents of the following group: hydrogen, Cm alkyl (R9), -Cl-4 alkoxy (r9 ), Aryl (r1g), _c (= 〇) h, -c (= 〇) -nh2, -COOhNH-CM alkyl (R9),-(: (= 0) -N (< ^ 4 (R9)) 2, -10 C02H, -c〇2-cu4 alkyl (R9), -s〇2-NH2 ... that is, -NH_Cl · 4 alkyl (¾), -NβM alkyl (R9 )) 2, cyano, halo, meso, nitro or keto compounds. Another aspect of the present invention includes that in formula (8), when attached to a nitrogen atom, it is independently selected from one to four substituents of hydrogen or -Cm alkyl (r9); 15 when attached to a carbon atom, It is independently selected from hydrogen, -Ci-4 alkyl (R9), -Cm alkoxy (R9), _〇_aryl (Rig), _NH2, _NH_Ci 4 A compound of one to four substituents (¾), -N ((^ 4alkyl (r9)) 2, halo, meridian, or keto. Further aspects of the present invention include Rs in formula (I) in Attached to a nitrogen atom, independently selected from one to four substituents of hydrogen or -Ci · 4 alkyl (R9); and attached to a carbon atom, independently selected from argon, heptamyl, C "4 alkoxy (R9), -0 · aryl (Riq) or a compound of one to four substituents of hydroxyl group. Includes in formula R R9 is hydrogen, _Cm alkoxy, _ _ 13- 200536844 A7 B7 V. Description of the invention (12) NH2, -NH-Cm alkyl, -Nfw alkyl) 2, -C (= 〇) H, -C (= 〇) -NH2, hepta ^ nh-Cm alkyl ... Alkyl) 2, -C02H, -COrCM alkyl, -SOrCM alkyl, -SCVNH2, -S02-NH-Cw alkyl, -SC ^ -NCCm Compounds), cyano, (halo) 13, 5-alkyl, nitro or fluorenyl groups. Another aspect of the present invention includes in formula r r9 is hydrogen, _Cl_4 alkoxy, -NH2, -NH -Cm alkyl, -NCw alkyl) 2, gross (= 0) 11, -C〇2H, -0 (= 0)-(^ 4alkoxy, (halo) 1-3, hydroxyl or keto 10. A further aspect of the present invention comprises the formula (I) in which R9 is hydrogen, -Cm alkoxy, -Li 2, -NH-Cm alkyl, -N (C "4 alkyl) 2, (dent A compound of 1-3 or hydroxy. Aspects of the present invention include that when R10 in formula (I) is attached to a nitrogen atom, it is independently selected from one to four substituents of the group: hydrogen, _Ci_4 alkane 15 Group, -C (= 〇) H,-(3 (= 0) -0 ^ .4 alkyl group, -C (= 〇) -NH2, -C (= 0) -NH-Cm alkyl group, -CpCO- Nfw alkyl) 2, -C〇2h, _c〇2-Ci_4 alkyl, -SCVCm alkyl, -S〇2-NH2-, -SCVNH-Cm alkyl SO ^ Nfi · 4alkyl) 2; and when attached to a carbon atom, it is independently selected from one to four substituents of the following group: hydrogen, _Ci_4alkyl, -c] _4alk20oxy, -C (= 〇) H,-(3 (= 0)-(^ 4 alkyl group ... c (= 〇) -NH2,-

CtOhNH-CM 烷基、烷基)2、_c〇2H、- C02-CM 烷基、-SOrCM 烧基、-s〇2-NH2、-S〇2-NH-Ci-4 烷基、-S〇2-N(Ci-4 烧基)2、-NH2、-NH-Cw 烧基、-N(Ci-4 烷基)2、氰基、函基、羥基、硝基或嗣基之化合物。 -14- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 五、發明說明（13) 本發明之另一態樣包含式（I)中（Rl0)14於連接於碳原子時，為氫、-Ci-4烷基、烷氧基、-C(=〇)H、. COOXm 烷基、-C02H、-C02-CU4 烷基、_NH2、-丽-Ci· 4烷基、-Nfi·4烷基)2、氰基 '羥基、硝基或酮基之化合 5 物。本發明之進一步態樣包含式（1)中Rl〇為氫之化合物。本發明之態樣包含式(I)中R2為氫、_Cl 4烷基(r7)、· Cm烯基(I)、-Cm炔基（R7)、·環烷基识8)、_雜環基 (R8)、-芳基(R8)或-雜芳基(Rs)之化合物。 10 本發明之另一態樣包含式（I)中R2為氫、-環烷基 (¾)、-雜環基(¾)、-芳基(R〇或-雜芳基识8)之化合物。本發明之另一態樣包含式（I)中r2為氫、-環烷基 (Rs)、-雜環基(¾)、-苯基(¾)、-萘基(R8)或-雜芳基(R8)之化合物。 15 本發明之另一態樣包含式(I)中R2為氫、-四氫嘧啶基經濟部智慧財產局員工消費合作社印製 (R8)、^3-苯并二啐環戊烯基(R8)、-二氫苯并呋喃基 (R8)、-四氫喹啉基(R8)、-苯基(r8)、·萘基(Rs)、-σ比啶基 (Rs)、-嘧啶基(r8)或-喹啉基(r8)之化合物。本發明之態樣包含式(I)t q為0、1、2或3之化合 20 物。本發明之態樣包含式（I)中Z為選自下述組群：羥基、-NH2、-NH-Cu 烷基、-N(Ci-8 烷基)2、O-Cw 烷基-〇H、-O-Cw烷基C!-4烷氧基、-O-Cw烷基羰基Cm烷基、-O-Cw 烷基_C〇2H、-O-Cw 烷基-CCCOOCw 烷基、- -15- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公复） 200536844 A7 B7 五、發明說明（Μ) 〇-Ci_8 烧基-〇-C(〇)Ci_8 烧基、-〇-Ci-8 烧基-ΝΗ2、-O-Cu 烧基-NH-Cu烧基、-〇-Ci.8烧基-N(Ci_8烧基)2、-O-Ci.8烧基醯胺、-O-Cw烷基-CCOVNH-Cw烷基、-O-Cw烷基-CCCO-NCw烷基)2及-NHCf^Cw烷基、-O-Cw烷基之化 5 合物。本發明之態樣包含含有下式（I)化合物之組成物 0CtOhNH-CM alkyl, alkyl) 2, -co2H, -C02-CM alkyl, -SOrCM alkyl, -s〇2-NH2, -S〇2-NH-Ci-4 alkyl, -S. Compounds of 2-N (Ci-4 alkyl) 2, -NH2, -NH-Cw alkyl, -N (Ci-4 alkyl) 2, cyano, halide, hydroxyl, nitro or fluorenyl. -14- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200536844 A7 B7 V. Description of the invention (13) Another aspect of the present invention includes formula (I) (Rl0) 14 connected to At the carbon atom, it is hydrogen, -Ci-4 alkyl, alkoxy, -C (= 〇) H, .COOXm alkyl, -C02H, -C02-CU4 alkyl, _NH2, -Li-Ci · 4 alkane Compound, -Nfi · 4 alkyl), cyano'hydroxy, nitro or keto group. A further aspect of the present invention includes a compound in which R10 is hydrogen in formula (1). Aspects of the present invention include R2 in formula (I) is hydrogen, —Cl 4 alkyl (r7), —Cm alkenyl (I), —Cm alkynyl (R7), —cycloalkyl group 8), — (R8), -aryl (R8) or -heteroaryl (Rs) compounds. 10 Another aspect of the present invention comprises a compound of formula (I) wherein R2 is hydrogen, -cycloalkyl (¾), -heterocyclyl (¾), -aryl (R0 or -heteroaryl group 8) . Another aspect of the present invention includes that in formula (I), r2 is hydrogen, -cycloalkyl (Rs), -heterocyclyl (¾), -phenyl (¾), -naphthyl (R8), or -heteroaryl (R8) compounds. 15 Another aspect of the present invention includes (2) in formula (I) where R2 is hydrogen, -tetrahydropyrimidinyl printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs (R8), ), -Dihydrobenzofuranyl (R8), -tetrahydroquinolinyl (R8), -phenyl (r8), naphthyl (Rs), -σ than pyridyl (Rs), -pyrimidinyl ( r8) or -quinolinyl (r8) compounds. Aspects of the invention include compounds of formula (I) where t q is 0, 1, 2 or 3. Aspects of the present invention include that in formula (I), Z is selected from the group consisting of: hydroxyl, -NH2, -NH-Cu alkyl, -N (Ci-8 alkyl) 2, and O-Cw alkyl-. H, -O-Cw alkyl C! -4 alkoxy, -O-Cw alkylcarbonyl Cm alkyl, -O-Cw alkyl_C02H, -O-Cw alkyl-CCCOOCw alkyl,- -15- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210x297 public copy) 200536844 A7 B7 V. Description of invention (M) -8-carbyl-NΗ2, -O-Cu-carbyl-NH-Cu-carbyl, -0-Ci.8-carbyl-N (Ci_8-carbyl) 2, -O-Ci.8-carbylamine, -O -Cw alkyl-CCOVNH-Cw alkyl, -O-Cw alkyl-CCCO-NCw alkyl) 2, and -NHCf ^ Cw alkyl, -O-Cw alkyl compound. Aspects of the invention include a composition containing a compound of formula (I)

式(I) 其中該化合物係選自下述組群： JNJ CpdFormula (I) wherein the compound is selected from the group consisting of: JNJ Cpd

WW

Ri R2 q 立禮化學 -NH-1,4,5,6- 經濟部智慧財產局員工消費合作社印製 1 . -CH2-Ph(3-R1) 四氫·嘧啶·2·基 Η 0 ΟΗ -ΝΗ-1,4,5,6. 2 -CH2-Ph(3-R1) 四氫·嘧啶-2-基 Η 0 ΟΗ -ΝΗ-1,4,5,6- 四氫-5-ΟΗ- ΟΗ 3 -CHyPhO-Ri) 嘧啶-2-基喹啉-3-基 0 -5,6,7,8-四氩· 4 -(CH2)3-Ri [1，8]萘啶-2-基喹啉-3-基 0 ΟΗ -5,6,7,8-四氫- 1，2,3,4-四氫- 5 -(CH2)3-Ri [1，8]萘啶·2·基喧啤-3-基 0 ΟΗ •5,6,7,8-四氩_ 1，2,3,4-四氫- -1 -(CH2)3-Ri [1，8]萘啶-2-基喹啉-3-基 0異構物1 ΟΗ -16- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公麓） 200536844 A7 B7 五、發明說明（I5 經濟部智慧財產局員工消費合作社印製Ri R2 q Lili Chemical-NH-1,4,5,6-Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1. -CH2-Ph (3-R1) Tetrahydro · Pyrimidine · 2 · Base Η 0 ΟΗ- ΝΗ-1,4,5,6. 2 -CH2-Ph (3-R1) tetrahydro · pyrimidin-2-ylΗ 0 ΟΗ -ΝΗ-1,4,5,6-tetrahydro-5-ΟΗ- ΟΗ 3 -CHyPhO-Ri) Pyrimidin-2-ylquinolin-3-yl 0 -5,6,7,8-tetraargon 4-(CH2) 3-Ri [1,8] naphthyridin-2-ylquinyl Porphyrin-3-yl 0 0Η-5,6,7,8-tetrahydro-1,2,3,4-tetrahydro-5-(CH2) 3-Ri [1,8] naphthyridine · 2 · Beer-3-yl 0 ΟΗ • 5,6,7,8-tetraargon_1,2,3,4-tetrahydro- -1-(CH2) 3-Ri [1,8] naphthyridin-2-yl Quinoline-3-yl 0 isomer 1 〇Η -16- This paper size applies Chinese National Standard (CNS) A4 specification (210x297 feet) 200536844 A7 B7 V. Description of invention (I5 Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives) system

5-2. •(CH2)3-Ri [1，8]萘啶-2-基喹啉-3-基 0 異構物2 OH 5-3 -(CH2)3-Ri -5,6,7,8-四氫-[1，8]秦咬-2-基 1，2,3,4-四氫-喧淋-3 -基 0 異構物3 OH 5-4 -(CH2)3-Ri -5,6,7,8-四氫· [1，8]萘啶-2-基 1，2,3,4-四氫-喹啉-3-基 0 異構物4 OH 6 Ph(3-R!) -NH-1，4,5,6-四氩-嘧啶-2-基 °比咬-3 -基 2 OH 7 PhQ-Ri) -NH-1，4,5,6-四氫-5-OH-嘧啶-2-基吡啶-3-基 2 OH 8 -(CH2)2-Ri -5,6,7,8-.四览-[1，8]备咬-2-基 °比咬-3 -基 2 OH 9 -(CH2)3-Ri -NH-«比啶-2-基 °比咬-3 -基 2 OH 10 Ph(3-R〇 -NH-1，4,5,6-四氣-5-OH-嘧啶-2-基 (6-OCH3)-B比淀-3-基 2 OH 11 -(CH2)2-Ri 5,6,7,8-四氮· [1，8]萘啶-2-基 1，3-苯并二呤環戊烯-5-基 1 OH 12 Ph(3-R〇 -NH-1，4,536-四氫-嘧啶-2-基喹啉-3-基 2 OH 13 -(CH2)2 - Ri 5,6,7,8-四氫-[1，8]萘啶-2-基苯基 1 OH 14 -(CH2)2-Ri 5,6,7,8-四氫-[1,8]萘啶-2-基 1，3-苯并二哼環戊烯-5-基 0 OH 15 -(CH2)3-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基 1，3-笨并二4環戊烯-5-基 0 OH 16 -CH2-R! 5,6,7,8-四氫-[1，8]萘啶-2-基 1，3_笨并二哼環戊烯-5-基 0 OH 17 -(CH2)3-Ri 5,6,7,8-四氩-[1，8]萘啶-2-基 (6-OCH3)-吼啶-3-基 0 OH 18 5,6,7,8-四氫-[1，8]萘啶-2-基 1，4,5,6-四氫-2-Me-喊咬-5-基 1 0H 19 -(CH2)2-R1 5,6,7,8-四氫-[1，8]萘啶-2-基 1,2,3,4-四氫-喹啉-3-基 1 OH -17- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 五、發明說明（16) 經濟部智慧財產局員工消費合作社印製5-2. • (CH2) 3-Ri [1,8] naphthyridin-2-ylquinolin-3-yl0 isomer 2 OH 5-3-(CH2) 3-Ri -5,6,7 , 8-tetrahydro- [1,8] tetrahydro-2-yl1,2,3,4-tetrahydro-noisin-3 -yl 0 isomer 3 OH 5-4-(CH2) 3-Ri -5,6,7,8-tetrahydro · [1,8] naphthyridin-2-yl1,2,3,4-tetrahydro-quinolin-3-yl 0 isomer 4 OH 6 Ph (3 -R!) -NH-1,4,5,6-tetraargon-pyrimidin-2-yl ° specific bit-3 -yl 2 OH 7 PhQ-Ri) -NH-1,4,5,6-tetrahydro -5-OH-pyrimidin-2-ylpyridin-3-yl 2 OH 8-(CH2) 2-Ri -5,6,7,8-. Specific bite -3 -yl 2 OH 9-(CH2) 3-Ri -NH- «Pididin-2-yl ° Specific bite -3 -yl 2 OH 10 Ph (3-R〇-NH-1,4,5 , 6-Tetraki-5-OH-pyrimidin-2-yl (6-OCH3) -B than Lake-3-yl 2 OH 11-(CH2) 2-Ri 5,6,7,8-tetrazine [ 1,8] naphthyridin-2-yl1,3-benzodipyrylcyclopenten-5-yl 1 OH 12 Ph (3-R0-NH-1,4,536-tetrahydro-pyrimidin-2-ylquine Porphyrin-3-yl 2 OH 13-(CH2) 2-Ri 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylphenyl 1 OH 14-(CH2) 2-Ri 5 , 6,7,8-tetrahydro- [1,8] naphthyridin-2-yl 1,3-benzodihumcyclopenten-5-yl 0 OH 15-(CH2) 3-Ri 5,6, 7,8-tetrahydro- [1,8] naphthyridin-2-yl 1,3-benzidobicyclo Alken-5-yl 0 OH 16 -CH2-R! 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl 1,3-benzodicyclopentene-5-yl 0 OH 17-(CH2) 3-Ri 5,6,7,8-Tetra argon- [1,8] naphthyridin-2-yl (6-OCH3) -armidin-3-yl 0 OH 18 5,6 , 7,8-tetrahydro- [1,8] naphthyridin-2-yl1,4,5,6-tetrahydro-2-Me-snid-5-yl1 0H 19-(CH2) 2-R1 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl1,2,3,4-tetrahydro-quinolin-3-yl 1 OH -17- This paper is applicable to China Standard (CNS) A4 specification (210x297 mm) 200536844 A7 B7 V. Description of the invention (16) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

19-1 -(CH2)2-Ri 5，6，7，8 -四氣-[1，8]萘啶-2-基 1，2,3,4-四氫-喹啉-3-基 1 異構物1 OH 19-2 -(CH2)2-Rl 5,6,7,8-四氩-[1，8]萘啶-2·基 1，2,3,4-四氫-喹啉-3-基 1 異構物2 OH 19-3 -(CH2)2-Ri 5,6,7,8-四氩-[1，8]萘啶-2-基 1，2,3,4-四氫-喹啉-3-基 1 異構物3 OH 19-4 -(CH2)2-Ri 5,6,7,8·四氫-[1，8]萘啶-2-基 1，2,3,4-四氫-喹啉-3-基 1 異構物4 OH 20 -(CH2)2-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基 1，3-苯并二呤環戊烯-5-基 2 OH 21 -(CH2)2-R1 5,6,7,8-四氫-[1，8]萘啶-2-基 (6 -0 CH3)- -3·基 2 OH 21-a -(CH2)2-Ri -ΝΗ-1,4,5,6-四氫-5-ΟΗ-嘧啶-2-基 (6-OCH3)-吡啶-3-基 2 異構物a OH 21-b -(CH2)2_Ri -ΝΗ-1，4,5,6-四氫-5-ΟΗ-咬-2-基 (6-OCH3)*·~ 3·基 2 異構物b OH 22 -(CH2)3-Ri -NH-吡啶-2-基喹啉-3-基 2 OH 23 -(CH2)3-Ri -NH-吡啶-2-基 1，3-笨并二嘮環戍稀-5 -基 2 OH 24 -(CH2)3_Ri -NH-吡啶-2·基 1，3-苯并二呤環戊烯-5-基 0 OH 25 -(CH2)3-Ri -NH-吡啶-2-基 (6-OCH3)-吡啶-3-基 2 OH 26 -(CH2)3，Ri 5,6,7,8-四氫-[1，8]萘啶-2-基 1，3-笨并二吟環戊烯-5-基 1 OH 27 Ph(3-R〇 -NH-1,4,5,6-四氫-5-OH-啦咬-2·基 1，3-笨并二呤環戊烯_5-基 1 OH 28 -(CH2)2-Rl 5,6,7,8-四氫-[1，8]萘啶-2-基 (6-OCH；3) -w比 _ 3-基 1 OH 28a -(CH2)2-Ri 5,6,7,8-四氩-[1，8]萘啶-2-基 (6-OCH3)-吡啶-3-基 1 異構物a OH -18- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200536844 A7 B7 五、發明說明（17) 經濟部智慧財產局員工消費合作社印製19-1-(CH2) 2-Ri 5,6,7,8-tetrakis- [1,8] naphthyridin-2-yl1,2,3,4-tetrahydro-quinolin-3-yl 1 Isomer 1 OH 19-2-(CH2) 2-Rl 5,6,7,8-tetraargon- [1,8] naphthyridin-2 · yl1,2,3,4-tetrahydro-quinoline -3-yl 1 isomer 2 OH 19-3-(CH2) 2-Ri 5,6,7,8-tetraargon- [1,8] naphthyridin-2-yl1,2,3,4- Tetrahydro-quinolin-3-yl 1 isomer 3 OH 19-4-(CH2) 2-Ri 5,6,7,8 · Tetrahydro- [1,8] naphthyridin-2-yl1,2 , 3,4-tetrahydro-quinolin-3-yl 1 isomer 4 OH 20-(CH2) 2-Ri 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl 1,3-Benzodibenzocyclopenten-5-yl 2 OH 21-(CH2) 2-R1 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl (6- 0 CH3)--3.yl 2 OH 21-a-(CH2) 2-Ri -ΝΗ-1,4,5,6-tetrahydro-5-ΟΗ-pyrimidin-2-yl (6-OCH3) -pyridine -3-yl 2 isomers a OH 21-b-(CH2) 2_Ri -NΗ-1,4,5,6-tetrahydro-5-ΟΗ-bite-2-yl (6-OCH3) * · ~ 3 · Group 2 isomer b OH 22-(CH2) 3-Ri -NH-pyridin-2-ylquinolin-3-yl 2 OH 23-(CH2) 3-Ri -NH-pyridin-2-yl 1, 3-Benzobifluorenylcyclohexyl-5 -yl 2 OH 24-(CH2) 3_Ri -NH-pyridin-2 · yl 1,3-benzodioxin cyclopenten-5-yl 0 OH 25-(CH2 ) 3-Ri -NH-pyridin-2-yl (6-OCH3) -pyridine -3-yl 2 OH 26-(CH2) 3, Ri 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl 1,3-benzodicyclopentene-5- Group 1 OH 27 Ph (3-R0-NH-1,4,5,6-tetrahydro-5-OH-la-bite-2 · yl 1,3-benzodibicyclocyclopentene_5-yl 1 OH 28-(CH2) 2-Rl 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl (6-OCH; 3) -w ratio_ 3-yl 1 OH 28a-( CH2) 2-Ri 5,6,7,8-tetraargon- [1,8] naphthyridin-2-yl (6-OCH3) -pyridin-3-yl 1 isomer a OH -18- paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 200536844 A7 B7 V. Description of invention (17) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

28b· -(CH2)2-Ri 5，6，7，8 -四氣-Π，8] 咬-2-基 (6-OCH3)-吡啶-3·基 1 異構物b OH 29 .(CH2)3-R! 5,6,7,8-四氫-[1，8]萘啶·2-基喹啉-3-基 1 OH 30 5,6,7,8-四氩-[1，8]萘啶-2-基 (3-F)苯基 1 OH 30a -(CH2)2-Ri 5,6,7,8-四氩-[1，8]萘啶-2-基 (3-F)苯基 1 異構物a OH 30b •(CH2)2-Ri 5,6,7,8-四氫-[1，8]萘交-2·基 (3-F)苯基 1 異構物b OH 31 -(CH2)3-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基 (3-F)苯基 1 OH 32 -(CH2)2-Ri 5,6,7,8-四氩· [M]萘咬-2-基啥琳-3 -基 1 OH 33 -(CH2)2-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基 (4-F)苯基 1 OH 34 -(CH2)3-Ri 5,6,7,8-四氩-[1，8]萘啶-2-基 (4-F)笨基 1 OH 35 -(CH2)2-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基 (2-CH3)嘧啶-5-基 1 OH 36 -(CH2)2-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基 2,3-二氫-苯并呋喃-6-基 1 OH 36a -(CH2)2-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基 2,3-二氫-苯并咬味-6-基 1 異構物a OH 36b :(CH2)2-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基 2,3-二氫-苯并。夫0^ -6 -基 1 異構物b OH 37 -(CH2)2-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基 (3,5-二氟）-苯基 1 OH 38 -(CH2)3-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基 (3,5-二氟）-笨基 1 OH 39 -(CH2)2-Ri 5,6,7,8-四氣-[1，8]萘咬-2-基 (3-CF3)-笨基 1 OH 40 -(CH2)2-Ri 5,6,7,8-四氩-[1,8]萘啶-2-基 (4-OCF3)-苯基 1 OH -19- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 經濟部智慧財產局員工消費合作社印製五、發明說明（18) 5，6，7，8 -四氣·28b ·-(CH2) 2-Ri 5,6,7,8-tetrakis-Π, 8] bite-2-yl (6-OCH3) -pyridine-3 · yl 1 isomer b OH 29. (CH2 ) 3-R! 5,6,7,8-tetrahydro- [1,8] naphthyridine 2-ylquinolin-3-yl 1 OH 30 5,6,7,8-tetraargon- [1, 8] naphthyridin-2-yl (3-F) phenyl 1 OH 30a-(CH2) 2-Ri 5,6,7,8-tetraargon- [1,8] naphthyridin-2-yl (3- F) Phenyl 1 isomer a OH 30b • (CH2) 2-Ri 5,6,7,8-tetrahydro- [1,8] naphthyl-2 · yl (3-F) phenyl 1 isomer Compound b OH 31-(CH2) 3-Ri 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl (3-F) phenyl 1 OH 32-(CH2) 2-Ri 5,6,7,8-Tetra argon · [M] naphthalene-2-ylsalin-3 -yl 1 OH 33-(CH2) 2-Ri 5,6,7,8-tetrahydro- [1, 8] naphthyridin-2-yl (4-F) phenyl 1 OH 34-(CH2) 3-Ri 5,6,7,8-tetraargon- [1,8] naphthyridin-2-yl (4- F) Benzyl 1 OH 35-(CH2) 2-Ri 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl (2-CH3) pyrimidin-5-yl 1 OH 36- (CH2) 2-Ri 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl 2,3-dihydro-benzofuran-6-yl 1 OH 36a-(CH2) 2 -Ri 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl 2,3-dihydro-benzobite-6-yl 1 isomer a OH 36b: (CH2) 2-Ri 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl 2,3-dihydro-benzo. 0 ^ -6 -yl 1 isomer b OH 37-(CH2) 2-Ri 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl (3,5-difluoro ) -Phenyl 1 OH 38-(CH2) 3-Ri 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl (3,5-difluoro) -benzyl 1 OH 39 -(CH2) 2-Ri 5,6,7,8-Tetragas- [1,8] naphthalene-2-yl (3-CF3) -benzyl 1 OH 40-(CH2) 2-Ri 5,6 , 7,8-Tetra argon- [1,8] naphthyridin-2-yl (4-OCF3) -phenyl 1 OH -19- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200536844 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description (18) 5, 6, 7, 8-Siqi ·

41 -(CH2)2.R1 [1，8]萘啶-2-基 (3-F-4-Ph)-笨基 1 OH 42 -(CH2)2-Ri 5,6,7,8-四氫· [1，8]萘啶-2-基 (3-F-4-OCH3)- 苯基 1 OH 43 -(CH2)2-Ri 5,6,7,8-四氩· [1，8]萘啶-2·基 (4-〇ph)-笨基 1 OH 44 -(CH2)2-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基異喹淋-4-基 1 OH 45 -(CH2)2-R1 5,6,7,8·四氫-[1，8]秦咬-2-基吡啶-3-基 1 OH 46 -(CH2)2-Ri .5,6,7,8-四氫-[1，8]萘啶-2-基二氫笨并呋喃-5-基 1 OH 47 -(CH2)2-R1 5,6,7,8-四氩-[1，8]萘啶-2-基 (2,4-OCH3)-喊咬-5-基 1 OH 48 •(CH2)2-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基 (2-OCH3)-嘧啶-5-基 1 OH 49 Ph(3-R〇 -ΝΗ-1,4,5,6-四氫-5-ΟΗ-嘧啶-2-基喹琳-3-基 2 OH 50 Ph(3-R〇 -ΝΗ-1，4,5,6-四氫-υ比咬-2-基喹啉-3-基 2 OH 51 -(CH2)2-R1 5,6,7,8-四氫-[1，8]萘啶-2-基喹淋-3-基 2 OH 52 Ph(3-R〇 -ΝΗ-3,4,5,6-四氫-嘧啶-2-基 1，3-苯并二呤環戍稀-5·基 2 OH 53 Ph(3-R〇 -ΝΗ-3,4,5,6-四氫-nt咬-2-基 1，3-笨并二哼環戊烯-5-基 2 OH 54 Ph(3-R〇 -NH-1,4,5,6-四氫-5-OH-嘧啶-2-基 1，3-苯并二十環戊烯-5-基 2 OH 55 -CH2-Ri 5,6,7,8-四氫· [1，8]萘啶-2-基 1，3-苯并二啐環戍烯-5·基 2 OH 56 -(CH2)2_Rl 5,6,7,8 -四氮-[1,8]茶咬-2·基茶-2-基 1 OH -20- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 經濟部智慧財產局員工消費合作社印製五、發明說明（w) 5,6,7,8_四氩_ 56a. [1，8]萘啶-2-基蔡-2-基 1 異構物a OH 56b -(CH2)2-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基备-2-基 1 異構物b OH 57 -(CH2)2-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基 5,6,7,8-四氫-喹啉-3-基 1 消旋性 OH 58a -(CH2)3-Ri 5,6,7,8·四氫-[1，8]萘啶-2-基 5,6,7,8-四氫-啥琳-3-基 0 異構物a OH 58b -(CH2)3-Ri 5,6,7,8-四氫-[1，8]蔡咬-2-基 5,6,7,8·四氫-喹琳-3-基 0 異構物b OH 59 •(CH2)2-Ri 5，6，7，8 -四氣-[1，8]萘啶-2-基 (3-OCH3)苯基 1 消旋性 OH 60 •(CH2)2-Ri 5,6,7,8-四氫· [1，8]萘啶-2-基 (4-OCH3)笨基 1 消旋性 OH 61 -(CH2)2-Ri 5,6,7,8-四氮* [1，8]萘啶-2-基不存在 1 OH 62 -(CH2)2-Ri 5,6,7,8-四氩-[1，8]萘啶-2-基四氫呋喃-3-基 1 消旋性 OH 63 -(CH2)2·!^ 5,6,7,8-四氫-[1，8]萘啶-2-基售吩-2-基 1 消旋性 OH 64 -(CH2)2-Ri 5,6,7,8-四氫-[1，8]茶咬-2-基 (3-F)苯基 1 消旋性 nh2 65 -(CHU 5,6,7,8 -四氮-[1，8]萘啶-2-基 2,3-二氩-苯并[1，4]_ 二呤英-6-基 1 消旋性 OH 66 -(CH2)2-Ri 5,6,7,8-四氫-[M]萘啶-2-基 (3-SCH3)笨基 1 消旋性 OH 67 -(CH2)2-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基甲基-1，2,3,4-四氣-啥淋-3·基 1 消旋性 OH 68 -(CH2)2-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基不存在 1 -0-乙基 69 -(CH2)2-Ri 5,6,7,8-四氫-[1，8]萘啶-2-基不存在 1 -0-2- 丙基 70 -(CH2)2.Rl 5,6,7,8-四氫· [1，8]萘啶_2-基不存在 1 -0-第三丁基 -21- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） .200536844 A7 B7 五、發明說明（2〇 71· -(CH2)2-R】 72 -(CH2)2-R! 73 -(CH2)2-R! 74 -(CH2)2-Ri 75 -(CYL2)2-Ri 76 -(CH2)2-Ri 76a •(CHOj-Ri 77 Ph(3-R〇 78 -(CH2)2-Ri 79 -(CH2)2_Ri 80 -(CH2)2-Ri 不存在 (3-(Nme2)笨基 (3-OMe-4-OH)苯基 (3-OMe-4-OH)笨基 (3-F)笨基 (4-(2-OH-乙氧基）-3-OMe)-苯基 (3-NHEt)苯基 (3-NHMe)笨基 1 5.6.7.8- 四氮- [1，8]萘啶-2-基不存在 5.6.7.8- 四氫- [1，8]萘啶-2-基不存在 5.6.7.8- 四氮- [1，8]茶咬·2-基不存在 5.6.7.8- 四氫-[1，8]萘啶-2-基 5,6,7,8_ 四氣-[1，8]萘啶-2-基 5.6.7.8- 四氫-[1，8]萘啶-2-基 5.6.7.8- 四氫-[1，8]萘啶-2-基 -ΝΗ-4,5-二氫-1/f-咪唑-2-基 5.6.7.8- 四氫· [1,8]萘啶-2-基 5.6.7.8- 四氩-[1，8]萘啶-2-基 5.6.7.8- 四氩-[1，8]萘啶-2-基 -0- 正辛基 -0-第二丁基 1 ·〇-曱基 OC(O)-第三丁 1 消旋性基41-(CH2) 2.R1 [1,8] naphthyridin-2-yl (3-F-4-Ph) -benzyl 1 OH 42-(CH2) 2-Ri 5,6,7,8-tetra Hydrogen [1,8] naphthyridin-2-yl (3-F-4-OCH3) -phenyl 1 OH 43-(CH2) 2-Ri 5,6,7,8-tetraargon [1,8 ] Naphthyridin-2 · yl (4-〇ph) -benzyl 1 OH 44-(CH2) 2-Ri 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylisoquine Phenyl-4-yl 1 OH 45-(CH2) 2-R1 5,6,7,8 · tetrahydro- [1,8] pyridin-2-ylpyridin-3-yl 1 OH 46-(CH2) 2 -Ri .5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yldihydrobenzfuran-5-yl 1 OH 47-(CH2) 2-R1 5,6,7, 8-tetra argon- [1,8] naphthyridin-2-yl (2,4-OCH3) -snack-5-yl 1 OH 48 • (CH2) 2-Ri 5,6,7,8-tetrahydro -[1,8] naphthyridin-2-yl (2-OCH3) -pyrimidin-5-yl 1 OH 49 Ph (3-R0-ΝΗ-1,4,5,6-tetrahydro-5-ΟΗ- Pyrimidin-2-ylquinolin-3-yl 2 OH 50 Ph (3-R0-ΝΗ-1,4,5,6-tetrahydro-υ ratio bite-2-ylquinolin-3-yl 2 OH 51 -(CH2) 2-R1 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylquinin-3-yl 2 OH 52 Ph (3-R〇-ΝΗ-3,4 , 5,6-tetrahydro-pyrimidin-2-yl1,3-benzodioxinylcyclopentane-5 · yl 2 OH 53 Ph (3-R0-ΝΗ-3,4,5,6-tetrahydro -nt bit-2-yl 1,3-benzodicyclopenten-5-yl 2 OH 54 Ph (3-R0-NH-1,4,5, 6-tetrahydro-5-OH-pyrimidin-2-yl 1,3-benzo eicospenten-5-yl 2 OH 55 -CH2-Ri 5,6,7,8-tetrahydro · [1, 8] naphthyridin-2-yl1,3-benzodifluorenecyclopenten-5-yl 2 OH 56-(CH2) 2_Rl 5,6,7,8 -tetraaza- [1,8] Tea bite- 2 · Base Tea-2-Base 1 OH -20- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200536844 A7 B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5,6,7,8_tetraargon_56a. [1,8] naphthyridin-2-ylcae-2-yl 1 isomers a OH 56b-(CH2) 2-Ri 5,6,7,8 -Tetrahydro- [1,8] naphthyridin-2-yl preparation-2-yl 1 isomer b OH 57-(CH2) 2-Ri 5,6,7,8-tetrahydro- [1,8] Naphthyridin-2-yl 5,6,7,8-tetrahydro-quinolin-3-yl 1 racemic OH 58a-(CH2) 3-Ri 5,6,7,8 · tetrahydro- [1, 8] naphthyridin-2-yl 5,6,7,8-tetrahydro-harin-3-yl 0 isomer a OH 58b-(CH2) 3-Ri 5,6,7,8-tetrahydro- [1,8] Tsai-2-yl 5,6,7,8 · tetrahydro-quinolin-3-yl 0 isomer b OH 59 • (CH2) 2-Ri 5,6,7,8- Tetrakis- [1,8] naphthyridin-2-yl (3-OCH3) phenyl 1 racemic OH 60 • (CH2) 2-Ri 5,6,7,8-tetrahydro · [1,8] Naphthyridin-2-yl (4-OCH3) benzyl 1 racemic OH 61-( CH2) 2-Ri 5,6,7,8-tetrazine * [1,8] naphthyridin-2-yl is absent 1 OH 62-(CH2) 2-Ri 5,6,7,8-tetraargon- [1,8] Naphthyridin-2-yltetrahydrofuran-3-yl 1 racemic OH 63-(CH2) 2 ·! ^ 5,6,7,8-tetrahydro- [1,8] naphthyridine-2 -Methylphenphen-2-yl 1 racemic OH 64-(CH2) 2-Ri 5,6,7,8-tetrahydro- [1,8] Tetra-2-yl (3-F) phenyl 1 racemic nh2 65-(CHU 5,6,7,8 -tetraaza- [1,8] naphthyridin-2-yl 2,3-diargon-benzo [1,4] _ dirinin- 6-yl 1 racemic OH 66-(CH2) 2-Ri 5,6,7,8-tetrahydro- [M] naphthyridin-2-yl (3-SCH3) benzyl 1 racemic OH 67- (CH2) 2-Ri 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-ylmethyl-1,2,3,4-tetrakis-Halene-3 · yl-1 OH 68-(CH2) 2-Ri 5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl does not exist 1 -0-ethyl69-(CH2) 2-Ri 5 , 6,7,8-Tetrahydro- [1,8] naphthyridin-2-yl does not exist 1 -0-2-propyl70-(CH2) 2.Rl 5,6,7,8-tetrahydro · [1,8] Naphthyridin-2-yl does not exist 1 -0-Third-butyl-21- This paper size applies to China National Standard (CNS) A4 (210x297 mm). 200536844 A7 B7 V. Description of the invention ( 2〇71 ·-(CH2) 2-R] 72-(CH2) 2-R! 73-(CH2) 2-R! 74-(CH2) 2-Ri 75- (CYL2) 2-Ri 76-(CH2) 2-Ri 76a • (CHOj-Ri 77 Ph (3-R〇78-(CH2) 2-Ri 79-(CH2) 2_Ri 80-(CH2) 2-Ri No Presence of (3- (Nme2) benzyl (3-OMe-4-OH) phenyl (3-OMe-4-OH) benzyl (3-F) benzyl (4- (2-OH-ethoxy) -3-OMe) -phenyl (3-NHEt) phenyl (3-NHMe) benzyl 1 5.6.7.8- tetrazine- [1,8] naphthyridin-2-yl is absent 5.6.7.8- tetrahydro- [1,8] Naphthyridin-2-yl is absent 5.6.7.8-tetrazine- [1,8] Tea bite · 2-yl is absent 5.6.7.8- Tetrahydro- [1,8] naphthyridin-2- Radical 5,6,7,8_ tetrakis- [1,8] naphthyridin-2-yl5.6.7.8- tetrahydro- [1,8] naphthyridin-2-yl5.6.7.8- tetrahydro- [1, 8] naphthyridin-2-yl-NΗ-4,5-dihydro-1 / f-imidazol-2-yl5.6.7.8-tetrahydro · [1,8] naphthyridin-2-yl5.6.7.8-tetra Argon- [1,8] naphthyridin-2-yl5.6.7.8- Tetraargon- [1,8] naphthyridin-2-yl-0-n-octyl-0-second butyl1.〇-fluorenyl OC (O) -tertiary butyl 1 racemic group

1 消旋性〇H1 racemic 〇H

1 消旋性〇H 1異構物a oh 1 消旋性 oh 1 消旋性 oh 1 消旋性 oh 1 消旋性 oh 經濟部智慧財產局員工消費合作社印製本發明之態樣包含含有下式（la)化合物之組成物1 racemic 0H 1 isomers a oh 1 racemic oh 1 racemic oh 1 racemic oh 1 racemic Composition of compound of formula (la)

WW

NN

la) 式本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 五、發明說明（21 式中 JNJ Cpdla) Type This paper size is in accordance with China National Standard (CNS) A4 (210x297 mm) 200536844 A7 B7 V. Description of the invention (21 type JNJ Cpd

Ri R2 q 立艘化學 z 5,6,7,8-四氩_ 2589939 81 -(CH2)3_Ri n，_^2•基（3·ρ)苯基 0 消旋性 Οίί 之組成物，其中本發明之態樣包含含有式（I)化合物該化合物係選自下述組群：式(I)中w為-CHrPhp%) ; Ri為-顺汰^芥四氫％ 5 淀I基，R2為H;q為〇及z為OH之化合物；式(I)中 w 為_(CH2)2.Ph(3_Ri); Ri ιΝΗ_Μ，5,6,ι 嘧啶-2-基；R2為Η ; q為〇及Z為〇H之化合物；式(I)中W為^呵从）；Ri為视^上卜四氫士 OH-喊咬i基；R2為3-喹啉基；q為〇及z為〇h之 10 化合物；式⑴中 W A_(CH2)3-Rl; Ri 基；R2為3-喹啉基；q為0及z為OH之化合物；式⑴中W為-(0¾% ;心為5,6,7,8_四氮-认蔡啶_2_ 經濟部智慧財產局員工消費合作社印製Ri R2 q zhanghuo chemical z 5,6,7,8-tetra argon_ 2589939 81-(CH2) 3_Ri n, _ ^ 2 • yl (3 · ρ) phenyl 0 racemic composition of which Aspects of the invention include a compound containing formula (I). The compound is selected from the group consisting of: in formula (I), w is -CHrPhp%); Ri is -Shuyi ^ stetrahydrogen%. H; q is 0 and z is an OH compound; in formula (I), w is _ (CH2) 2.Ph (3_Ri); 〇 and Z are OH compounds; W in the formula (I) is ^ Hangong); Ri is the above-mentioned tetrahydros-OH-group i; R2 is 3-quinolinyl; q is 0 and z 10 compound of 0h; W A_ (CH2) 3-Rl; Ri group in formula (I); R2 is 3-quinolinyl; compounds in which q is 0 and z is OH; Heart is 5,6,7,8_Tetrazine-Recognition Cai_2_2 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

基’ R2為1，2,3,4-四氩-3-喹啉基；q為〇及z為〇H 15 之化合物；式(I)中 W 為-PhO-Ri);心 A-NH-1，4,5,6-四氫-嘧啶-2-基；R2為3-吡啶基；q為2及Z為〇H之化合物；式（I)中 W 為·Php-RD ; R4-NH-154,5,6-四氫-5-OH-嘧咬-2-基；&為3-吼啶基；q為2及z為〇H之化合 20 物； •23- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200536844 A7 B7 五、發明說明 22 5 ο 11R 'is 1,2,3,4-tetraargin-3-quinolinyl; compounds in which q is 0 and z is 0H 15; W in formula (I) is -PhO-Ri); A-NH -1,4,5,6-tetrahydro-pyrimidin-2-yl; R2 is 3-pyridyl; compound with q being 2 and Z being 0H; W in the formula (I) is Php-RD; R4- NH-154,5,6-tetrahydro-5-OH-pyrimidin-2-yl; & is 3-carbamyl; compound 20 with q being 2 and z being 0H; • 23- paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 200536844 A7 B7 V. Description of invention 22 5 ο 11

5 IX 經濟部智慧財產局員工消費合作社印製 20 式⑴中W為兴^2)2·!^ ; ^為-以乂^四氫义^萘啶：基〔R2為3-咄啶基；q為2及Z為OH之化合物；式（I)中 W 為-(CH2)3-Rl ; Rl 為 NH-吡啶 1基；R2 為 3- 。比咬基；q為2及Z為〇H之化合物；式（I)中 W 為-Ph(3-Ri) ; 1^為-]^11-1，45556-四氫-5-〇m 咬-2-基；&為_(6_Me〇)咣啶-3_基；q為2及z為〇H 之化合物；式⑴中 W 為-(CH2)2-Ri，Ri 為·5,6,7,8-四氫-1，8-萘咬-2- 基’ R2為1，3-苯并二咩環戊稀_5-基；q為1及Z為〇H之化合物；式(I)中 W 為.-P]1(3-R1);R1為-NH-l，455,6-四氫，啶-2-基；R2為3-喹啉基；q為2及Z為OH之化合物；式(I)中 W 為-(CH2)2-Ri ; 1^為_5,6,758-四氫-1,8-萘啶| 基；R2為-Ph ; q為1及Z為〇H之化合物；式(I)中 W 為-(CH2)2·!^ ; R1為_5,6,7,8-四氫-l58-萘啶-2-基；R2為l，3-苯并二呤環戊烯-5-基；q為0及Z為〇H之化合物；式(I)中 W 為-(CHA-Ri ; R1為-5,6,7,8-四氫_l，8-萘啶-2-基；R2為l，3-苯并二啐環戊烯-5_基；q為o及z為〇H之化合物；式（I)中 W 為-CHpR! ; Ri 為-5,6,7,8-四氫-1，8-萘啶-2-基；R2為1，3-苯并二呤環戊烯_5-基；q為〇及z為〇H之化合物；式(I)中 W 為-((¾)3% ; R1為_5,657,8-四氫-l，8-萘啶-2- -24- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） .200536844 A7 B7 五、發明說明（23 ) 基；R2為-(6-MeO)11比沒-3-基；q為0及Z為〇H之化合物；式(I)中 W 為-(CH2)2-Ri ; Ri 為-5,6,7,8-四氮-138-蔡咬_2-基；R2為·1，4,5,6_四氫-2-Me-哺咬-5-基；q為1及z 為OH之化合物；式(I)中 W 為-(CHA-R! ; Ri 為-5,6,7,8_四氫-1，8_萘啶-2-基；R2為1，2,3,4-四氫-3-喹啉基；q為1及Z為〇h 之化合物；式(I)中 W 為-(CHA-Ri ; R1為-5,6,7,8-四氫-l，8-萘啶-2-基；R2為l53-苯并二噚環戊烯-5-基；q為2及z為〇H之化合物；式(I)中 W 為-(CH2)2-Ri，Ri 為-5,6,758-四氮-1,8-蔡咬-2-基；R2 &_(6-Me〇)吡啶-3-基；q為2及Z為OH之化合物；式(I)中W為-(CHA-Ri ; R〗為-NH』比啶_2-基；R2為3-喹啉基；q為2及Z為OH之化合物；經濟部智慧財產局員工消費合作社印製式⑴1f W為-(CHJrRi ; Ri為-NH^比淀-2-基；R2為 1，3-苯并二啐瓖戊烯_5_基；q為2及z為〇H之化合物；式（I)中 W 為-(CHA-Ri ; Ri 為-NH-吡啶-2-基；R2 為 1，3-苯并二u号環戊烯-5·基；q為〇及z為〇H之化合物；式(I)中 W 為-(CH2)3~Ri ; Ri 為基，R2 為-(6-MeO)吼啶-3-基；q為2及ζ為ΟΗ之化合物； -25- 本紙張尺度適ft國國家標準((^幻八4規格^_21(^297公釐)------ i2005368445 IX Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 In the formula, W is Xing ^ 2) 2 !! ^; A compound in which q is 2 and Z is OH; in the formula (I), W is-(CH2) 3-Rl; Rl is NH-pyridinyl; R2 is 3-. Specific octyl groups; compounds where q is 2 and Z is 0H; W in formula (I) is -Ph (3-Ri); 1 ^ is-] ^ 11-1,45556-tetrahydro-5-〇m -2-yl; & is _ (6_Me〇) pyridin-3_yl; compounds where q is 2 and z is 0H; in formula ⑴ W is-(CH2) 2-Ri, Ri is · 5,6 , 7,8-tetrahydro-1,8-naphthalenyl-2-yl 'R2 is 1,3-benzodifluorenecyclopenta 5-yl; q is 1 and Z is 0H; I) where W is .-P] 1 (3-R1); R1 is -NH-1,455,6-tetrahydro, pyridin-2-yl; R2 is 3-quinolinyl; q is 2 and Z is OH compounds; W in the formula (I) is-(CH2) 2-Ri; 1 ^ is _5,6,758-tetrahydro-1,8-naphthyridine; R2 is -Ph; q is 1 and Z is OH compound; in the formula (I), W is-(CH2) 2 !! ^; R1 is -5,6,7,8-tetrahydro-l58-naphthyridin-2-yl; R2 is 1,3- Benzobiline cyclopenten-5-yl; compounds where q is 0 and Z is 0H; in formula (I) W is-(CHA-Ri; R1 is -5,6,7,8-tetrahydro_ l, 8-naphthyridin-2-yl; R2 is 1,3-benzodifluorenylcyclopenten-5-yl; compounds in which q is o and z is 0H; W in formula (I) is -CHpR! ; Ri is -5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R2 is 1,3-benzodilinocyclopentene-5-yl; q is 0 and z is 〇H compounds; W in formula (I) It is-((¾) 3%; R1 is _5,657,8-tetrahydro-l, 8-naphthyridin-2- -24-. This paper size applies to China National Standard (CNS) A4 specification (210x297 mm). 200536844 A7 B7 V. Explanation of the invention (23) group; R2 is-(6-MeO) 11 than methan-3-yl; compounds with q being 0 and Z being 0H; in formula (I) W is-(CH2) 2 -Ri; Ri is -5,6,7,8-tetraaza-138-Caiwei_2-yl; R2 is · 1,4,5,6_tetrahydro-2-Me-pyridyl-5-yl ; Q is 1 and z is OH; W in the formula (I) is-(CHA-R !; Ri is -5,6,7,8_tetrahydro-1,8_naphthyridin-2-yl; R2 is 1,2,3,4-tetrahydro-3-quinolinyl; compounds in which q is 1 and Z is 0h; in formula (I) W is-(CHA-Ri; R1 is -5,6, 7,8-tetrahydro-l, 8-naphthyridin-2-yl; R2 is l53-benzodifluorenylcyclopenten-5-yl; compound with q being 2 and z being 0H; in formula (I) W is-(CH2) 2-Ri, Ri is -5,6,758-tetrazine-1,8-Caiyi-2-yl; R2 & _ (6-Me〇) pyridin-3-yl; q is 2 And Z is an OH compound; in formula (I), W is-(CHA-Ri; R is -NH "than pyridin-2-yl; R2 is 3-quinolinyl; q is 2 and Z is OH Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, 1f W is-(CHJrRi; Ri is -NH ^ Biyodo-2-yl; R2 1,3-Benzodibenzopenten-5-yl; compounds with q being 2 and z being 0H; in formula (I) W is-(CHA-Ri; Ri is -NH-pyridin-2-yl R2 is a 1,3-benzodiu cyclopentene-5 · group; a compound in which q is 0 and z is 0H; in formula (I), W is-(CH2) 3 ~ Ri; Ri is a group, R2 is-(6-MeO) amidine-3-yl; q is 2 and ζ is 0% of the compound; -25- the paper size is suitable for the national standard of ft ((^ 幻八 4 ^^^ 21 (^ 297mm) ) ------ i200536844

式(I)中 W 為-(CH2)3-Ri ; R^-5,6,7,8-四氫-1，8-萘咬-2-基’尺2為1，3-苯并二啐環戊烯-5-基；q為1及z為〇H之化合物；式⑴中W為氺⑽也）；&為以仏1，455,6,氫-5-OH-2-哺咬基；&為1，3-苯并二啐環戊烯-5-基；q為1及z 為〇H之化合物；式⑴中 W 為-(CH^-Ri ; R1為-5,6,758-四氫-l，8-萘啶-2-基；R2為_(6-MeO)n比啶-3-基；q為l及z為OH之化合物； 1〇式(I)中 W 為-(CH2)3-Ri ; Ri 為-5,6,7,8-四氫-1，8-萘咬-2- 基；R2為3-喹啉基；q為1及z為OH之化合物；式(I)中 W 為 _(Ch2)2-Ri ;心為_5,6,7,8_四氫-1，萘啶| 基；R2為-(3-F)Ph ; q為1及z為OH之化合物；式(I)中 W 為-(CHA-Ri ; R1為-5,6,7,8-四氫_l58_萘咬-2-l5 基；R2為-(3-F)Pli ; q為1及z為〇H之化合物；式⑴中W為-(CHA-Ri ; R1為-5,6,758-四氫-1，8_萘啶！基；R2為-3喹啉基；q為l及z為OH之化合物；經濟部智慧財產局員工消費合作社印製式(I)中 W 為-(CHA-Ri ; m6,7,8jn84<_2_ 基，R2為_(44)?11 ; q為1及z為〇H之化合物； 2〇式(1)中^/為-(^2)3-111;111為-556,7,8_四氫_1，8-萘啶-2- 基；R2 g-(4-F)Ph ; q為1及z為〇h之化合物；式(I)中 W 為-(ch^K ;心為_5,6,7,8_四氫_1，8-萘啶_2_ 基；R2為-(2-Me)嘧啶·5-基；q為！及z為OH之化合物； -26- ^紙張尺度適用家標準(ci)A4規格(2i〇x^7^y—- .200536844 A7 B7 五、發明說明（25) 式(I)中 W 為-(〇12)2-心；&為_5,6,7,8_四氫_1，8-萘啶-2_ 基〔I為-2,3-二氫-苯并呋喃-6-基；q為1及Z為〇H之化合物；式⑴中W為-(ch.K ;心為_5,6,7>四氫义8_萘啶1 5 基；R2為-(3>F2)Ph ; q為1及z為0H之化合物；式⑴中 W 為-(CHA-Ri ; 1^為-556,7,8_四氫·1，8-萘啶-2-基；R2為-(3,5-F2)Ph ; q為1及ζ為0Η之化合物；式(I)中 W 為-(CH^Ri ; &為_5,6,7,8_四氫_1，8-萘啶_2_ 基；R2為-(3-CF3)P1i ; q為1及z為0H之化合物； 10 式(1)中 W 為-(CHA-Ri ;心為-556,7,8_四氫_；t，8_萘啶 1 基；R2為-(4-〇CF3)Ph ; q為1及z為0H之化合物；式(I)中 W 為-(CHA-R! ; 1^為-556,7,8-四氫-1，8-萘啶-2- 基；R2為-(3-F-4-Ph)Ph ; q為1及z為0H之化合 15 物；式(I)中 W 為-((¾)2% ; 1^為-556,7,8-四氫-1,8-萘咬-2-基；為-(3_F_4-〇Me)Ph ; q為1及z為〇H之化合經濟部智慧財產局員工消費合作社印製物；式(I)中 W 為-(CHJrRi ; 1^為-5,65758-四氫-1，8_萘啶-2-20 基；R2 &-(4-〇Ph)ph ; q為1及Z為〇H之化合物；式(I)中 W 為-(CHA-Ri ; Ri 為·5,6,7,8-四氫-1,8-萘啶-2- 基，R2為-4-異喹啉基；q為}及ζ為〇Η之化合物；式(I)中 W 為-(CHA-Ri ; 1^為-5,6,7,8-四氫-1，8-萘啶-2· -27- 本紙張尺度適用中國國家標準(CN^)A4規格（210 X 297公f 200536844 A7 B7 五、發明說明（26 ) 基，R2為吡啶基；q為1及z為〇η之化合物；式(I)中w為_(CH2)2_Ri ;心為^上入^四氮^^蔡淀^ 基，R2為-5-二氫苯并呋喃基；q為i及z為〇H之化合物； 5 式⑴中W為-仰丄也；Ri為-5,6,7,8-四氫-1，8K2_ 基’ &為-2,4-(OMe)2_嘧啶I基；q為1及ζ為OH 之化合物；式(I)中 W 為-(CH2H ; Κ^_5,6,7,8_四氫β1，8_萘啶-2- 基，R2為-(2-〇Me)嘴啶-5-基；q為1及ζ為0Η之 10 化合物；式(I)中 W 為-Ph(3-Ri);尺1為^^1，4,5,6-四氫-5_〇1^嘧啶-2-基；&為·3-喹啉基；q為2及z為〇H之化合物；式（I)中 W 為-Php-Ri) ; Ri 為_腿-3,4,5,6-四氫-口比咬-2-15 基；R2為喹啉基；q為2及Z為OH之化合物；式(I)中W為-(CH^-Ri ; ，四氩心，^萘啶基·，R2為-3-喹啉基；q為2及z為OH之化合物；經濟部智慧財產局員工消費合作社印製式（I)中W為-Php-Ri) ; R〗為以11-3,4,5,6_四氫-嘧啶_2- 基；R2為-1，3-苯并二啐環戊烯-5-基；q為2及z為 20 OH之化合物；式（I)中W為-PhQ-RD ; &為_NH_3,4,5义四氩比啶基；R2為·1，3-苯并二嘮環戊烯基；q為2及ζ為〇Η之化合物；式(I)中W為-Php-RD ; -28- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公$ ) 200536844 A7 B7 五、發明說明（27 ) 啶-2-基；R2為-1，3-苯并二啐環戊烯-5-基；q為2及 Z為0H之化合物；式⑴中W為-CH^Ri ; &為-5,6,7,8-四氫-1，8-萘啶-2-基；R2為1，3-苯并二啐環戊烯-5-基；q為2及Z為 5 〇H之化合物；及，式(I)中 W 為-(CHA-R!;心為-5,6,7,8-四氫_1，8_萘啶-2-基；R2為2-萘基；q為1及Z為0H之化合物。本發明之另一態樣包含含有式（I)化合物之組成物，其中該化合物係選自下述組群： 10 式⑴中 W 為-(CH2)3·!^ ; R!為-5,6,7,8_四氫-1，8-萘啶-2-基；R2為-1，2,3,4-四氫-3-喹啉基；9為〇及2為〇11 之化合物；式(I)中 W 為-((：Η2)3-Κ4 ; R1為-5,6,7,8-四氫-l，8-萘啶-2-基；R2為·l，3-苯并二哼環戊烯-5-基；q為0及Z為 15 〇Η之化合物；經濟部智慧財產局員工消費合作社印製式(I)中 W 為 _(CH2)2-Ri ; Rl為_5,657,8四氫l58-萘咬-2-基；R2為-l，2,3,4-四氫冬啥啉基；q為l及Z為OH 之化合物；式(I)中 W 為-(CH2)2·!^ ; 1^為-5,65758-四氫_1，8_萘啶-2-20 基；R2為-(6-Me〇)吡啶-3·基；q為1及Z為OH之化合物；式(I)中 W 為-(CHA-Ri ; 1^為-5,65758-四氫-1，8-萘啶-2- 基；R2為-(3-F)Ph ; q為1及Z為OH之化合物；式(I)中 W 為 _(CH2)2·!^ ; R1為-5,6,7,8-四氫-l，8-萘啶-2- -29- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 28 五、發明說明（土 ’ R2為-3-喧琳基；q為1及z為〇H之化合物；式⑴中 w 為_(CH2)2_Rl; R]為·5,6,7,8_四氮基；心為-(2她)鳴咬-5-基；q為1及z為0H之化合物； 5式⑴中〜為-仰丄也义為从入心四氫妙萘咬士基’ ^為-2’3-二氫-苯并咳兔_6_基；q為1及z為〇H之化合物；式⑴中 W 為_(CH2)2_Rl; n5,6,7,8_四氮·u-蔡咬_2_ 基’ R2為-4-異啥琳基；q為1及z為0H之化合 10 物；式(1)中 W 為 _(CH2)2_Rl ;尺1為_5,6,7,8_四氮_1，8_蔡啶1 基，反2為-3-咣啶基；q為][及z為〇H之化合物；In the formula (I), W is-(CH2) 3-Ri; R ^ -5,6,7,8-tetrahydro-1,8-naphthalene-2-yl 'rule 2 is 1,3-benzodi啐 cyclopenten-5-yl; q is 1 and z is 0H; in the formula W W is 氺 ⑽ also); & is 仏 1,455,6, hydrogen-5-OH-2- Benzyl; & is 1,3-benzodifluorenylcyclopenten-5-yl; compound where q is 1 and z is 0H; W in the formula is-(CH ^ -Ri; R1 is -5, 6,758-tetrahydro-l, 8-naphthyridin-2-yl; R2 is _ (6-MeO) n than pyridin-3-yl; q is l and z is OH; 10 W in formula (I) Is-(CH2) 3-Ri; Ri is -5,6,7,8-tetrahydro-1,8-naphthalene-2-yl; R2 is 3-quinolinyl; q is 1 and z is OH Compound; in formula (I), W is _ (Ch2) 2-Ri; heart is _5,6,7,8_tetrahydro-1, naphthyridinyl; R2 is-(3-F) Ph; q is 1 and z are OH compounds; W in the formula (I) is-(CHA-Ri; R1 is -5,6,7,8-tetrahydrol58-naphthalene-2-l5 group; R2 is-(3 -F) Pli; q is 1 and z is 0H; W in the formula is-(CHA-Ri; R1 is -5,6,758-tetrahydro-1,8-naphthyridine! Group; R2 is -3 Quinolinyl; compounds in which q is l and z is OH; printed in formula (I) by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, W is-(CHA-Ri; m6,7,8jn8 4 < _2_ group, R2 is _ (44)? 11; compound where q is 1 and z is 0H; 20 in formula (1) ^ / is-(^ 2) 3-111; 111 is -556,7 , 8-tetrahydro_1,8-naphthyridin-2-yl; R2 g- (4-F) Ph; compounds with q of 1 and z of 0h; W in formula (I) is-(ch ^ K ; The heart is _5,6,7,8_tetrahydro_1,8-naphthyridin_2_ group; R2 is-(2-Me) pyrimidin · 5-yl; q is! And z is OH compound;- 26- ^ Paper size applies home standard (ci) A4 specification (2i0x ^ 7 ^ y--.200536844 A7 B7 V. Description of the invention (25) W in formula (I) is-(〇12) 2- heart; & is _5,6,7,8_tetrahydro_1,8-naphthyridin-2-yl [I is -2,3-dihydro-benzofuran-6-yl; q is 1 and Z is. Compound of H; in the formula, W is-(ch.K; heart is _5,6,7 > tetrahydrosense 8-naphthyridine 1 5 group; R2 is-(3 > F2) Ph; q is 1 and z A compound of 0H; in the formula, W is-(CHA-Ri; 1 ^ is -556,7,8-tetrahydro · 1,8-naphthyridin-2-yl; R2 is-(3,5-F2) Ph; a compound in which q is 1 and ζ is 0Η; W in formula (I) is-(CH ^ Ri; & is a _5,6,7,8_tetrahydro_1,8-naphthyridin_2_yl group; R2 is-(3-CF3) P1i; q is 1 and z is 0H; 10 in formula (1) W is-(CHA-Ri; heart is -556,7,8_tetrahydro_; t, 8 _Naphthyridine 1 group; R2 is-(4- CF3) Ph; a compound with q being 1 and z being 0H; in formula (I) W is-(CHA-R !; 1 ^ is -556,7,8-tetrahydro-1,8-naphthyridine-2- R2 is-(3-F-4-Ph) Ph; Compound 15 where q is 1 and z is 0H; W in formula (I) is-((¾) 2%; 1 ^ is -556,7 , 8-tetrahydro-1,8-naphthalene-2-yl; is-(3_F_4-〇Me) Ph; q is 1 and z is 0H printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics and Chemical Industry; (I) W is-(CHJrRi; 1 ^ is -5,65758-tetrahydro-1,8-naphthyridin-2-20; R2 &-(4-〇Ph)ph; q is 1 and Z A compound of 0H; in the formula (I), W is-(CHA-Ri; Ri is · 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl, and R2 is 4-iso Quinolinyl; compounds in which q is} and ζ is 0 ；; in formula (I) W is-(CHA-Ri; 1 ^ is -5,6,7,8-tetrahydro-1,8-naphthyridine- 2 · -27- This paper size is in accordance with Chinese National Standard (CN ^) A4 (210 X 297 g f 200536844 A7 B7) 5. Description of the invention (26), R2 is pyridyl; q is 1 and z is 0 Compound; in formula (I), w is _ (CH2) 2_Ri; heart is ^ tetrazine ^^ Caidian ^ group, R2 is -5-dihydrobenzofuranyl group; q is i and z is 0H Compound; 5 in formula ⑴W is-丄 also; Ri is -5,6,7,8- tetra -1,8K2_ group 'is -2,4- (OMe) 2_pyrimidine I group; a compound in which q is 1 and ζ is OH; W in formula (I) is-(CH2H; κ ^ _5,6, 7,8_tetrahydroβ1,8_naphthyridin-2-yl, R2 is-(2-〇Me) apridin-5-yl; 10 compounds with q being 1 and ζ being 0Η; W in formula (I) Is -Ph (3-Ri); 1 is ^^ 1,4,5,6-tetrahydro-5_〇1 ^ pyrimidin-2-yl; & is 3-quinolinyl; q is 2 and z is a compound of 0H; W in the formula (I) is -Php-Ri); Ri is -3,4,5,6-tetrahydro-orbital-2-15; R2 is quinolinyl ; Q is 2 and Z is OH; in formula (I), W is-(CH ^ -Ri ;, tetragonal, ^ naphthyridinyl, R2 is 3-quinolinyl; q is 2 and z OH compound; W is -Php-Ri in the formula (I) printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs; R is a 11-3,4,5,6_tetrahydro-pyrimidine_2- group ; R2 is -1,3-benzodifluorenylcyclopenten-5-yl; compounds in which q is 2 and z is 20 OH; W in formula (I) is -PhQ-RD; & is _NH_3,4 , 5 means tetrapyridyl; R2 is · 1,3-benzodifluorenylcyclopentenyl; compound with q being 2 and ζ being 0Η; W in formula (I) is -Php-RD; -28 -This paper size applies to China National Standard (CNS) A4 (210 X 297 dollars) 200536844 A7 B7 V. Description of the invention (27) Pyridin-2-yl; R2 is -1,3-benzodifluorene cyclopenten-5-yl; compound with q being 2 and Z being 0H; W in the amidine is -CH ^ Ri; & is -5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R2 is 1,3-benzodifluorene cyclopentene-5 -Group; a compound in which q is 2 and Z is 5 0H; and, in formula (I), W is-(CHA-R !; the heart is -5,6,7,8-tetrahydro_1,8_naphthalene Pyridin-2-yl; compounds in which R2 is 2-naphthyl; q is 1 and Z is 0H. Another aspect of the present invention includes a composition containing a compound of formula (I), wherein the compound is selected from the following group: 10 wherein W is-(CH2) 3 ·! ^; R! Is -5, 6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R2 is -1,2,3,4-tetrahydro-3-quinolinyl; 9 is 0 and 2 is 011 ; In formula (I), W is-((: Η2) 3-K4; R1 is -5,6,7,8-tetrahydro-l, 8-naphthyridin-2-yl; R2 is · l, 3- Benzodicyclocyclopenten-5-yl; compounds in which q is 0 and Z is 15 〇；; W in the formula (I) printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs is _ (CH2) 2-Ri; Rl Is -5,657,8 tetrahydrol58-naphthyl-2-yl; R2 is -1,2,3,4-tetrahydrodongasolinyl; q is l and Z is OH; W in formula (I) Is-(CH2) 2 ·! ^; 1 ^ is -5,65758-tetrahydro_1,8-naphthyridin-2-20 group; R2 is-(6-Me〇) pyridine-3 · yl; q is 1 and Z are OH compounds; W in formula (I) is-(CHA-Ri; 1 ^ is -5,65758-tetrahydro-1,8-naphthyridin-2-yl; R2 is-(3-F ) Ph; compounds where q is 1 and Z is OH; W in the formula (I) is _ (CH2) 2 !! ^; R1 is -5,6,7,8-tetrahydro-l, 8-naphthyridine- 2- -29- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 2005 36844 A7 B7 28 V. Description of the invention (Earth 'R2 is -3- oxalinyl; compound where q is 1 and z is 0H; in formula w w is _ (CH2) 2_Rl; R] is · 5,6, 7,8_ tetrazyl group; the heart is-(2 she) ringing -5- group; the compound of q is 1 and z is 0H; in formula 5 ~~ is -yang 丄 also means from the heart into the tetrahydrogen Naphthyl stilbene is -2'3-dihydro-benzocetyl-6-yl; compounds with q being 1 and z being 0H; in formula WW is _ (CH2) 2_Rl; n5,6, 7,8_tetrazine · u-Cai bit_2_ group 'R2 is 4-isokhalinyl; compound 10 with q being 1 and z being 0H; W in formula (1) is _ (CH2) 2_Rl; Chi1 is _5,6,7,8_tetraaza_1,8_Ceadidine 1 group, trans 2 is -3-pyridinyl group; q is] [and z is 0H compound;

式(1)中W為-(CHA-Ri ; &為-5,6,7,8-四氫-萘啶冬基’反2為-2,4-(〇Me)2-♦咬-5-基；q為1及Z為OH 15 之化合物；及，式(1)中W為_(CH2)2·!^ ; &為·5,6,7,8_四氫」，8-萘啶冬基，R2為-(2-〇Me)嘧啶-5-基；q為1及ζ為〇H之經濟部智慧財產局員工消費合作社印製化合物。本發明之另一態樣包含式⑴中W為-(CHy^R〗；！^ 2〇為-5,6,7,8-四氫_1，8_萘啶-2-基；；^為_152,3 +四氫_3_喹啉基；q為〇及z為oh之化合物。本發明之另一態樣包含式⑴中W為-(CHA-R^Ri 為-5,6,7,8-四氩-1，8-萘啶-2-基；112為-1，3-苯并二啐環戊烯-5-基；q為〇及z為〇h之化合物。 -30- 本紙張尺度·中國國家標?規格（210 X 297公幻 200536844In the formula (1), W is-(CHA-Ri; & is -5,6,7,8-tetrahydro-naphthyridinyl), trans-2 is -2,4- (〇Me) 2- 5-group; a compound in which q is 1 and Z is OH 15; and, in formula (1), W is _ (CH2) 2 ·! ^; &Amp; is · 5,6,7,8_tetrahydro ", 8 -Naphthyridinyl, R2 is-(2-OMe) pyrimidin-5-yl; compounds printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs, q is 1 and ζ is 0H. Another aspect of the present invention includes In the formula, W is-(CHy ^ R〗; ^ 2〇 is -5,6,7,8-tetrahydro_1,8-naphthyridin-2-yl; ^ is _152,3 + tetrahydro _3_quinolinyl; compounds in which q is 0 and z is oh. Another aspect of the present invention comprises W in the formula 为-(CHA-R ^ Ri is -5,6,7,8-tetraargon- 1,8-naphthyridin-2-yl; 112 is -1,3-benzodifluorenylcyclopenten-5-yl; compounds where q is 0 and z is 0h. -30- This paper scale · China Standard specifications (210 X 297 public magic 200536844

五、發明說明（29 ) 本發明之另一態樣包含式⑴中w &_(CH2)2_Ri;Ri 為-5,6,7,8’氫-；ι，8-萘咬-2_基；&為义^-四氫冬喹啉基；q為1及Ζ為0Η之化合物。本發明之另一態樣包含式(I)中w g_(CH2)2_Ri;Ri 5為·5,6,7,8-四氩-i，8_萘啶_2-基；r2為咖Me〇)吼啶冬基； q為1及Z為〇H之化合物。本發明之另一態樣包含式(1)中w為_(〇112)2士1;111 為-5,6,7,8-四氫-1，8-萘咬-2-基；R4mph ; q 為 1 及 ζ 為Ο Η之化合物。 10 本發明之另一態樣包含式(I)中w為-(CHA-Ri ; Κ 為_5,6,7,8_四氫_1，8_萘咬-2-基；尺2為_3_喧啉基；q為i及 Z為OH之化合物。本發明之另一態樣包含式(1)中w 為-5,6,7,8-四氫-1，8-萘咬-2-基；！12為_(2抵)嘴啶_5_基4 15 為1及Z為OH之化合物。經濟部智慧財產局員工消費合作社印製本發明之另一態樣包含式(1)中w為_((^2)2_^;111 為-5,6,7,8-四氫-1，8-蔡咬-2-基；112為_2,3_二氫_苯并11夫。^ 6-基；q為1及Z為OH之化合物。本發明之另一態樣包含式（I)中 20為-5,6,7,8_四氫-1，8-萘淀-2-基；&為|異喹啉基；q為玉及Z為OH之化合物。本發明之另一態樣包含式(I)中w 為-5,6,7,8-四氫-1，8-萘咬-2-基；汉2為冬处啶基；q為ι及 Z為OH之化合物。 •31- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） A7 200536844 五、發明說明（30) 本發明之另-態樣包含式(1)中w ^(CH2)2_Ri;Ri 為-5,6,7;8·四氫·1，8-萘紅基；& 為_2,4_(·^务5_ 基；q為1及Z為OH之化合物。 5 本發明之另-態樣包含式(1)中w t(CH2)2_Ri;Ri 為_5,6,7,8·四氫-1，8·萘咬-2·基；R2 為_(2-0Me)射-5-基； q為1及Z為OH之化合物。本發明之態樣包含具下式（I)之化合物： ΟV. Explanation of the invention (29) Another aspect of the present invention includes the formula w & _ (CH2) 2_Ri; Ri is -5,6,7,8 'hydrogen-; ι, 8-naphthalene bit-2_ &Amp; is a compound of the meaning ^ -tetrahydroquinolinyl; q is 1 and Z is 0Η. Another aspect of the present invention includes w g_ (CH2) 2_Ri in formula (I); Ri 5 is · 5,6,7,8-tetraargon-i, 8_naphthyridin_2-yl; r2 is Me 〇) pyrimidyl; compounds in which q is 1 and Z is 0H. Another aspect of the present invention includes: in formula (1), w is _ (〇112) 2 ± 1; 111 is -5,6,7,8-tetrahydro-1,8-naphthalene-2-yl; R4mph ; q is 1 and ζ is 0 Η. 10 Another aspect of the present invention includes that in formula (I), w is-(CHA-Ri; K is _5,6,7,8_tetrahydro_1,8_naphthalene-2-yl; ruler 2 is _3_ group; compounds in which q is i and Z is OH. Another aspect of the present invention includes formula (1) where w is -5,6,7,8-tetrahydro-1,8-naphthalene -2-base;! 12 is a compound of _ (2 arrivals) aziridin_5_base 4 15 is 1 and Z is OH. Another aspect of the present invention printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs includes the formula ( 1) w is _ ((^ 2) 2_ ^; 111 is -5,6,7,8-tetrahydro-1,8-Caiwei-2-yl; 112 is _2,3_dihydro_benzene 11-membered ^ 6- group; a compound in which q is 1 and Z is OH. Another aspect of the present invention comprises 20 in formula (I) as -5,6,7,8_tetrahydro-1,8- Naphthyl-2-yl; & is | isoquinolinyl; q is jade and Z is OH. Another aspect of the invention comprises formula (I) where w is -5,6,7,8- Tetrahydro-1,8-naphthalene-2-yl; Han 2 is pyridyl in winter; q is ι and Z is OH. • 31- This paper size applies to China National Standard (CNS) A4 (210x297) A7 200536844 V. Description of the invention (30) Another aspect of the present invention includes w ^ (CH2) 2_Ri in formula (1); Ri is -5,6,7; 8 · tetrahydro · 1,8-naphthalene Red base & is a _2,4_ (· ^ 5 group); a compound in which q is 1 and Z is OH. 5 Another aspect of the present invention includes wt (CH2) 2_Ri in formula (1); Ri is _5,6 , 7,8 · tetrahydro-1,8 · naphthalene-2 · yl; R2 is _ (2-0Me) e-5-yl; q is 1 and Z is OH. Aspects of the present invention include Compound of formula (I): 〇

Z 式（I) U)式中^^、，、…如先前界定：及，較佳為，其中 w 為-C0:3 烷基(Ri)4-Cq_3 烷基·笨基(Ri，R8);Z Formula (I) U) where ^^ ,,, ... are as previously defined: and, preferably, wherein w is -C0: 3 alkyl (Ri) 4-Cq_3 alkyl · benzyl (Ri, R8) ;

Ri 為-NH(R6); 經濟部智慧財產局員工消費合作社印製 R2為氫、-四氫嘧啶基（¾)、-U-苯并二呤環戊烯基 15 (Rs)、·二氫苯并呋喃基(¾)、-四氫喹啉基(R8)、-苯基(Rs)、-萘基(Rs)、-吡啶基、_嘧啶基_或_喹琳基(Rs);Ri is -NH (R6); Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, R2 is hydrogen, -tetrahydropyrimidinyl (¾), -U-benzodioxinylcyclopentenyl 15 (Rs), · dihydro Benzofuranyl (¾), -tetrahydroquinolinyl (R8), -phenyl (Rs), -naphthyl (Rs), -pyridyl, _pyrimidinyl_ or _quinolinyl (Rs);

Re為-二氫咪唑基(rs)、_四氫,比啶基(Rs)、·四氫嘧啶基(A) 或-°比啶基(R8); 20 Rs於連接於氮原子時，係獨立地選自氫或-Cm烷基(R9)之 -32- K張尺度適用中國"ϋ標準(CNS)A4規格（21〇 x 297公楚） 200536844 A7 B7 五、發明說明（31) 一至四個取代基；又，於連接於破原子時’係獨立地選自氫、-Ci.4烷基(R9)、-Cw烷氧基(R9)、-〇-芳基 (Rio)或羥基之一至四個取代基； R9為氫、-Cw烷氧基、-NH2、-NH-Cw烷基、-ΝΘμ烷 5 基)2、（鹵基h-3或羥基；及， q 為 0、1、2 或 3 ; Z係選自下述組群：經基、-NH2、-ΝΗ-Cu烧基、-N(Ci_8 烷基)2、O-Ci.8烷基-OH、-O-Cw烷基Cm烷氧基、· 〇-Ci.8烧基幾基Ci.8烧基、-〇-Ci.8烧基-CO2H、-〇 10 Ci_8 烧基-C(〇)0-Ci.8 烧基、-〇"*Ci.8 烧基-0_C(0)Ci_8 烧基、-0-Ci_8 烧基-NH2、-〇""Ci-8 烧基-NH-C1-8 烧基、-O-Cm烷基-Ν((^.8烷基)2、-O-Cw烷基醯胺、-O-Cm 烷基-CCOhNH-Cw 烷基、-O-Cw 烷基-C(〇)-Ν((^_8 烷基)2 及-NHC^C^Cu 烷基、-O-Cw 烷基； 15 及其醫藥上可接受之鹽、消旋混合物與鏡像異構物。本發明之態樣包含式（I)化合物中，該化合物為具下式（1.2)之化合物： ΟRe is -dihydroimidazolyl (rs), _tetrahydro, pyridyl (Rs), tetrahydropyrimidyl (A) or-° pyridyl (R8); 20 Rs when attached to a nitrogen atom, Independently selected from hydrogen or -Cm alkyl (R9), the -32-K Zhang scale is applicable to China " ϋS (CNS) A4 specification (21 × 297 Gongchu) 200536844 A7 B7 V. Description of the invention (31) Four substituents; and, when attached to a broken atom, are independently selected from hydrogen, -Ci.4 alkyl (R9), -Cw alkoxy (R9), -0-aryl (Rio), or hydroxyl One to four substituents; R9 is hydrogen, -Cw alkoxy, -NH2, -NH-Cw alkyl, -NΘμalk5yl) 2, (halo h-3 or hydroxyl; and q is 0, 1, 2 or 3; Z is selected from the group consisting of: via group, -NH2, -NH-Cu alkyl, -N (Ci_8 alkyl) 2, O-Ci.8 alkyl-OH, -O- Cw alkyl Cm alkoxy, o-Ci.8 alkyl group Ci.8 alkyl group, -0-Ci.8 alkyl group -CO2H, -0 10 Ci-8 alkyl group -C (〇) 0-Ci. 8-carbyl, -〇 " * Ci.8-carbyl-0_C (0) Ci_8-carbyl, -0-Ci_8-carbyl-NH2, -〇 " Ci-8-carbyl-NH-C1-8 Group, -O-Cm alkyl-N ((^. 8 alkyl) 2, -O-Cw alkylamidoamine, -O-Cm alkyl-CCOhNH-Cw alkyl, -OC w alkyl-C (〇) -Ν ((^ _ 8alkyl) 2 and -NHC ^ C ^ Cu alkyl, -O-Cw alkyl; 15 and its pharmaceutically acceptable salts, racemic mixtures and mirror images Isomers. Aspects of the invention include compounds of formula (I), which are compounds of formula (1.2): 〇

0 式(1.2) 20 式中W_、&、r6、R8、R9、q與Z如先前界定；及，較佳 -33- 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） 200536844 A7 A7 B7 五、發明說明（32) 為，其中 W為-C〇:3烷基(RD或-C〇.3烷基-苯基(U8);0 Formula (1.2) 20 In the formula, W_, &, r6, R8, R9, q, and Z are as previously defined; and, preferably -33- Printed by the Intellectual Property Bureau Staff Consumer Cooperatives of the Ministry of Economic Affairs This paper applies Chinese national standards (CNS) A4 specification (210x297 mm) 200536844 A7 A7 B7 5. Description of the invention (32) is, wherein W is -C〇: 3 alkyl (RD or -C 0.3 alkyl-phenyl (U8);

Ri為_NH(R6)、-二氫-l/ί』比咯并[2,3-刃。比啶基(¾)、-四氫嘧啶基(R8)、-四氫-1，8-萘啶基(R8)、-四氫-1好-吖庚因 5 并[2,34]。比啶基(R8)或-η比啶基(R8); R6為-二氫咪唑基(r8)、_四氫啦啶基(r8)、-四氫嘧啶基(¾) 或比咬基(R8); R8於連接於氮原子時，係獨立地選自氫或-Cm烷基(R0之一至四個取代基；又，於連接於碳原子時，係獨立地 1〇選自氫、-Cm烷基(R9)、-Cm烷氧基(R9)、芳基 (Rio)或羥基之一至四個取代基； R9為氫、-Cm烷氧基、-NH2、-NH-Cm烷基、烷基)2、（鹵基）1-3或經基；及， q為 0、1、2或 3; 15 Z係選自下述組群：羥基、-Nh2、-NH-Cw烷基、_N(Cm 烷基)2、O-Cw烷基-OH、-O-Cw烷基Cm烷氧基、- O-Cw烷基羰基Cw烷基、-O-Cw烷基-C02H、-0- 經濟部智慧財產局員工消費合作社印製Ri is _NH (R6), -dihydro-l / ί "than slightly [2,3-edge. Better than pyridyl (¾), -tetrahydropyrimidinyl (R8), -tetrahydro-1,8-naphthyridinyl (R8), -tetrahydro-1 -azepine 5 and [2,34]. Than pyridyl (R8) or -n than pyridyl (R8); R6 is -dihydroimidazolyl (r8), -tetrahydropyridinyl (r8), -tetrahydropyrimidinyl (¾) or R8); when connected to a nitrogen atom, R8 is independently selected from hydrogen or -Cm alkyl (one to four substituents of R0; and when connected to a carbon atom, is independently 10 selected from hydrogen,- Cm alkyl (R9), -Cm alkoxy (R9), aryl (Rio) or one to four substituents of hydroxyl group; R9 is hydrogen, -Cm alkoxy, -NH2, -NH-Cm alkyl, Alkyl) 2, (halo) 1-3 or meridian; and q is 0, 1, 2 or 3; 15 Z is selected from the group consisting of: hydroxyl, -Nh2, -NH-Cw alkyl, _N (Cm alkyl) 2, O-Cw alkyl-OH, -O-Cw alkyl Cm alkoxy, -O-Cw alkylcarbonyl Cw alkyl, -O-Cw alkyl-C02H, -0- Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

Cw 烷基-CCCOO-Cw 烷基、-O-Cw 烷基-O-CCCOCm 烧基、烧基-NH〗、烧基-NH-Ci_8烧 20 基、七-Cm烷基-Ν(<^8烷基)2、-O-Cw烷基醯胺、一 O-Cw 烷基-CCCO-NH-Cw 烷基、-O-Cm 烷基·(；：(〇)- 烷基)2 及-NHCCOfu 烷基、-0-CK8 垸基；及其醫藥上可接受之鹽、消旋混合物與鏡像異構物。本發明之態樣包含式（I)化合物中，該化合物為具下 -34- 本紙張尺度適用中國國家標準(CNS)A4規格（21〇x297公釐） 200536844 Α7 Β7 五、發明說明（33) 式（1.3)之化合物： 0Cw alkyl-CCCOO-Cw alkyl, -O-Cw alkyl-O-CCCOCm alkyl, alkyl-NH], alkyl-NH-Ci_8 alkyl, hep-Cm alkyl-N (< ^ 8 alkyl) 2, -O-Cw alkylamidoamine, mono-O-Cw alkyl-CCCO-NH-Cw alkyl, -O-Cm alkyl · (; :( 〇) -alkyl) 2 and- NHCCOfu alkyl, -0-CK8 fluorenyl; and its pharmaceutically acceptable salts, racemic mixtures and mirror isomers. Aspects of the present invention include the compound of formula (I), the compound has the following -34- This paper size applies the Chinese National Standard (CNS) A4 specification (21 × 297 mm) 200536844 A7 B7 V. Description of the invention (33) Compound of formula (1.3): 0

0 式(1.3) 式中W、Ri、R2、R6、Rs、R9與Z如先前界定；及，較 5 佳為，其中 W為-C〇-3烷基(R〇或_C〇-3烷基-苯基(R^Rs);0 Formula (1.3) where W, Ri, R2, R6, Rs, R9, and Z are as previously defined; and, preferably, more than 5, wherein W is -C0-3 alkyl (R0 or _C〇-3 Alkyl-phenyl (R ^ Rs);

Ri 為-NH(R6)、二氣比洛弁[2,3-6]。比咬基(Rg)、-四風，咬基(Rs)、-四風·1，8-蔡咬基(Rg)、-四風_ϋ·σ丫庚因并[2,3-ZTh比啶基(R8)或-处啶基(R8); 10 R2為氫、-四氫嘧啶基（R8)、-1，3-苯并二啐環戊烯基 (R8)、-二氫苯并呋喃基(R8)、-四氫喹啉基(R8)、-苯基(R8)、-萘基(R8)、-啦啶基(R8)、-嘧啶基(R8)或-喹味基(Rg); 經濟部智慧財產局員工消費合作社印製 R6為-二氫咪唑基(R8)、-四氫°比啶基(¾)、-四氫嘧啶基(¾) 15 或^比啶基(R8); R8於連接於氮原子時，係獨立地選自氫或-Cm烷基(R9)之一至四個取代基；又，於連接於碳原子時，係獨立地選自氫、-Cm烷基(R9)、-Cm烷氧基(R9)、-〇-芳基 (Rio)或羥基之一至四個取代基；及， 20 R9 為氫、-Cw 烷氧基、-NH2、-NH-Cm 烷基、-Ν(<^_4 烷 -35- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200536844 A7 B7 五、發明說明（34) 基)2、（鹵基）1·3或經基； Ζ係選自下述組群：羥基、-NH2、-NH-Cw烷基、烷基)2、O-Ci-8烷基-OH、-O-Cw烷基CK8烷氧基、-〇-Ci-8烧基^基Ci_8烧基、-〇-Cu烧基-C〇2H、-〇_ 5 Cu 炫基-CXC^O-Cu 烧基、-O-Cu 烧基-0-(1:(0)(^.8 烷基、-O-Cw 烷基-NH2、-O-Ci.8 烷基-NH-Cw 烷基、-〇-Ci_8烧基-N(Ci_8烧基)2、-O-Cu烧基酿胺、-O-Cw 烷基-CXCO-NH-Cw 烷基、-O-Cw 烷基-C(O)-NCCu烧基)2及-NHC^Cu烧基、-O-Cu烧基； 10及其醫藥上可接受之鹽、消旋混合物與鏡像異構物。本發明之另一態樣包含式（Ι·3)化合物中，Rl為一 ΝΙί(Ι16)、_四氫嘴咬基(r8)或-四氫-萘咬基(Rg);及，所有其他變數如先前界定者。本發明之態樣包含式（I)化合物中，該化合物為具下 15 式（1.4)之化合物：Ri is -NH (R6) and digas biloxan [2,3-6]. Specific bite base (Rg), -Four wind, bite base (Rs), -Four wind · 1,8-Cai bite base (Rg), -Four wind_ϋ · σ 丫庚因并 [2,3-ZTh 比Pyridyl (R8) or -pyridyl (R8); 10 R2 is hydrogen, -tetrahydropyrimidinyl (R8), -1,3-benzodifluorenylcyclopentenyl (R8), -dihydrobenzo Furyl (R8), -tetrahydroquinolinyl (R8), -phenyl (R8), -naphthyl (R8), -radylyl (R8), -pyrimidyl (R8), or -quinolyl ( Rg); Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, R6 is -dihydroimidazolyl (R8), -tetrahydro ° pyridyl (¾), -tetrahydropyrimidyl (¾) 15 or ^ pyridyl ( R8); when connected to a nitrogen atom, R8 is independently selected from hydrogen or -Cm alkyl (R9) to one to four substituents; and when connected to a carbon atom, is independently selected from hydrogen, -Cm One to four substituents of alkyl (R9), -Cm alkoxy (R9), -0-aryl (Rio), or hydroxyl; and 20 R9 is hydrogen, -Cw alkoxy, -NH2, -NH -Cm alkyl, -N (< ^ _ 4 alk-35-) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200536844 A7 B7 V. Description of the invention (34) base) 2, ( Halo) 1 · 3 or meridian; Z is selected from the following group: hydroxyl , -NH2, -NH-Cw alkyl, alkyl) 2, O-Ci-8 alkyl-OH, -O-Cw alkyl CK8 alkoxy, -0-Ci-8 alkyl, Ci_8 alkyl , -〇-Cualkyl-C〇2H, -〇_ 5 Cu alkyl, -CXC ^ O-Cualkyl, -O-Cualkyl-0- (1: (0) (^. 8 alkyl, -O-Cw alkyl-NH2, -O-Ci.8 alkyl-NH-Cw alkyl, -0-Ci_8alkyl-N (Ci_8alkyl), -O-Cualkylamine, -O -Cw alkyl-CXCO-NH-Cw alkyl, -O-Cw alkyl-C (O) -NCCu alkyl) 2 and -NHC ^ Cu alkyl, -O-Cu alkyl; 10 and its medical use Acceptable salts, racemic mixtures and mirror isomers. Another aspect of the present invention comprises a compound of formula (1.3), wherein R1 is a ΝΙί (Ι16), _tetrahydrocarbyl (r8) or- Tetrahydro-naphthalene (Rg); and, all other variables are as previously defined. Aspects of the present invention include a compound of formula (I), which is a compound of formula (1.4) below:

式(1.4) 式中&與Z如先前界定；及，進一步地，R2係選自下述組群.-2-笨并呋喃基、_3_苯并呋喃基、_4_笨并呋喃 2〇基、I苯并呋喃基、_6-苯并呋喃基、_7_笨并呋嘀基笨并间噻吩-2-基、-苯并㈨噻吩_3•基、笨并經濟部智慧財產局員工消費合作社印製噻吩_4_基、-苯并[ό]噻吩·5·基、-苯并[6]噻吩_6一 -36- I紙張尺度適用中國國___ 200536844 A7 發明說明（35 10 15 經濟部智慧財產局員工消費合作社印製 20 基、-笨并⑻嘍吩_7•基、你吲哚一 …一。 :1丹引ή-基、巧凡叫卜朵·5_基、丑弓|木-7-基、笨并啐唑基、_4_苯并咩唑 5苯并、唑基、·6_笨并喝唑基、苯并卩号唑 2苯并噻唑基、_3_苯并噻唑基、苯并噻唑 5苯并噻唑基、_6_笨并噻唑基、苯并噻唑 1凡苯并咪唑-2·基、_丨札苯并咪唑_心基、苯并^坐一基、收笨并味唾冬基、擺苯并咪唾_ 7基-2-啥啉基、_3-嘻啉基、_4_喧啉基、_5_哇啉基6喹啉基、_7_啥琳基、_8·啥琳基、·+笨并比南2-基、-2凡1-苯并11比喘i基、韻]_笨并吨。南_ 4-基U1-笨并吨喃·5_基、.l苯并㈣冰基、II-苯并σ比喃_7•基、-2/Μ_苯并^南冬基、 4^小苯并咄喃_2•基、_4糾_苯并吡喃_3_基、_极小笨并比南-4-基、-4/M-苯并口比口南_5_基、_4况苯并。比喃各基、-4/M-笨并咣喃_7_基、-4札[苯并π比喃_8· 基、-1射-笨’并吡喃_丨_基、他士笨并吡喃冬基、· 1仏2·苯并吡喃_4•基、苯并吡喃丨·基、苯并吡喃-6-基、4/7-2-苯并吡喃-7_基、_1/7_2_苯并吡鳴冬基、-1，2,354-四氫小萘基、-1，253,4_四氫-2_萘基、-1，2,3,4-四氫-5-萘基、-1，2,354-四氫_6_萘基、 -2,3-二氩·2·笨并呋喃基、_2,3_二氫-3-笨并呋喃基、 -2,3-二氫-4-笨并呋喃基、_2,3-二氫-5-笨并呋喃基、 -2,3-二氫-6-苯并呋喃基、_2,3·二氫-7-笨并呋喃基、基基基基基 •37· 200536844In formula (1.4), & and Z are as previously defined; and further, R2 is selected from the group consisting of: 2-benzfuranyl, _3_benzofuranyl, _4_benzfuran2. Group, I-benzofuranyl group, _6-benzofuranyl group, _7_benzylfurfuryl group, benzo-m-thiophene-2-yl group, -benzobenzothiophene_3-yl group, employees of Intellectual Property Bureau, Ministry of Economic Affairs Cooperative printed thiophene_4_ group, -benzo [ό] thiophene-5 group, -benzo [6] thiophene_6-a-36- I paper size applicable to China ___ 200536844 A7 Description of invention (35 10 15 Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs's Consumer Cooperatives 20-based, -Ben and 7-based, you indole one ... one.: 1 Dan Yin-ji, Qiao Fan called Budu · 5_ji, ugly Bow | wood-7-yl, benzoxazolyl, _4_benzoxazol 5 benzo, oxazolyl, 6_benzyl oxazolyl, benzopyrazole 2 benzothiazolyl, _3_benzene Benzothiazolyl, benzothiazolyl 5 benzothiazolyl, _6_benzothiazolyl, benzothiazole 1 vanbenzimidazole-2 · yl, _azabenzimidazole_cardiyl, benzobenzoyl, Stupid and sialyl, pennylbenzyl-7-yl-2-hydroxyline, _3-hexolinyl, _4_noline, _5_Walolinyl 6quinolinyl, _7_Halinyl, _8 · Hallinyl, · + Benzobinan 2-yl, -2Van 1-benzo11biphenyl i, rhyme] _Bendi Ton. South_4-yl U1-benzylpyridine · 5-yl, .l benzopyrene ice-based, II-benzoσpyran-7-yl, -2 / M_benzopyrene, 4 ^ small benzopyran-2-yl group, _4pyridine_benzopyran_3_yl group, _very small benzopyran-4-yl group, -4 / M-benzopyranyl group _5_yl group , _4 state benzo. Pyranyl, -4 / M-benzylpyran_7_yl, -4z [benzoπpyran_8 · yl, -1 shot-benzyl'pyran _Yl, tarbenpyranyl, 1 笨 2, benzopyran_4, benzopyranyl, benzopyran-6-yl, 4 / 7-2-benzene Benzopyran-7-yl, 1 / 7_2_benzopyrimidinyl, -1,2,354-tetrahydrosmallnaphthyl, -1,253,4_tetrahydro-2naphthyl, 1,2, 3,4-tetrahydro-5-naphthyl, 1,2,354-tetrahydro-6-naphthyl, -2,3-diargon · 2 · benzyfuranyl, _2,3_dihydro-3-benzyl Benzofuranyl, -2,3-dihydro-4-benzfuranyl, _2,3-dihydro-5-benzfuranyl, -2,3-dihydro-6-benzofuranyl, _2, 3 · Dihydro-7-benzylfuranyl, phenylyl group · 37 · 200536844

-y' 5 ο 1—·-y '5 ο 1— ·

5 IX 經濟部智慧財產局員工消費合作社印製 20 ;虱本开㈨噻吩-2-基、-2,3·二氫苯并⑷噻吩_3 基、2,3-二氫笨并[_吩_心基、_2,3_二氮苯并[咐吩i基、二氫苯并㈨噻吩+基、_2,3_二 ⑼噻吩-7-基、-μ -气Ί/7 a凡井丞 2,3-—虱吲哚-2-基、_2,3-二氫· -2,3-二氫-1/f-吲哚基 -2,3-二氫-lif-。引哚 _6·•基 2,3-一"風-2 -本并今基 -2’3-一氮-5 -苯并σ寻η坐基 _2,3-二氫-7-苯并咩唑基 —___ 1扒苯并咪唑_2-基、_2,3·二氫凡苯并咪唑_心基、 -2,3·二氫-1凡苯并味嗅-5-基、2,3-二氫孤苯并，唑-6-基、_2,3-二氫·ι斤-苯并咪唑_7_基、 -3,4-二氫-1(2//)_啥琳基、义2,3,4_四氮_2_啥啉基、 1二3,4-四氫-3-喧琳基、-ι，2,3,4-四氫-4-喹琳基、 -1，2,3,4，氫-5-喹啉基、]32,3,4:四氫_6_喹啉基、 -1，2,3,4-四氫_7_喹啉基、义2,3,4_四氫_8_喹啉基、 -3,4-二氫笨并。比_|基、3，心二氫μ小苯々比喃3-基、_3,4_ 一氫-2i7-l_笨并π比味冰基、_3,4_二氫-2/M·苯并吡喃_5_基、-3,4_二氫·2/7_i_苯并吡喃基、-3,4-二氫-2/^1-苯并吡喃_7_基、_3,4_二氫苯并咣喃_8_基、-3,4-二氫·4凡1_苯并吡喃基、 3,4-二氫-4//-1-苯并咄喃-3-基、_3,4_二氫-4//-1-苯爿啦喃-4_基、-3,4-二氫-4/Μ·笨并吡喃_5_基、'4-二氫-GM-苯并吡喃-6-基、-3,4-二氫-4/Μ-苯并吡喃_7 -38- 1仏吲哚：基 177·吲哚_5_基 1凡吲哚-7_基 4-笨并吟唑基 6-苯并啐唑基 -2,3-二氫 -2,3-二氫 -2,3_ 二氫 _253-二氫 •2,3-二氫 200536844 A7 B7 五、發明說明（37) 基、_3,4_二氮-4//-1 -苯并σ比喃-8-基、-3,4-« —-SLΊΗ-1 -苯并吡喃-2-基、·3,4_二氫-1/M-苯并吡喃-3-基、_ 3,4-二氫-I//小苯并吡喃-4-基、-3,4-二氫-1丹_1-苯并吡喃-5-基' -3,4-二氫苯并吡喃-6-基、-3,‘二 5 氮-1沒-1-笨并°比啥-7-基及-3,4-二氮-1//-1-本并^比11南- 8- 基’該等基團於連接於氮原子時，得以利用有效價數視需要被獨立地選自曱基之至多達7個取代基取代；又，於連接於碳原子時，得以利用有效價數視需要被獨立地選自甲基、曱氧基或氟之至多達7個取代基取 10 代； Z係選自下述組群：羥基、-NH2、-NH-Cw炫基、-Νπυ 烷基)2、O-Cw烷基-OH、-O-Cw烷基Cw烷氧基、-〇-Ci-8烧基幾基Ci-8烧基、-〇-Ci.8烧基-C〇2H、-〇_ Cw 烷基-cccoo-Cw 烷基、-o-Cw 烷基-o-qcocw 15 烷基、·〇<“烷基-NH2、-O-Cw烷基-NH-Cw燒經濟部智慧財產局員工消費合作社印製基、-O-Cu烧基-N(Cu烧基)2、-〇-Ci.8烧基酿胺、· Q-Ci.8 烧基-C(0)-NH-Ci_8 烧基、-0-Ci_s 烧基-C(〇)-N(Ci_8 烧基)2 及-NHC(0)Ci.8 烧基、-O-Ci.8 烧基；及其醫藥上可接受之鹽、消旋混合物與鏡像異構物。 20 本發明化合物亦可呈醫藥上可接受之鹽型存在。供醫藥用途時，本發明化合物之鹽係指無毒性之「醫藥上可接受之氬」（參照 Internationa! Pharm·，1986，33，2QU 217 ; J· P/^服如··，1977 (Jan)3 ⑽ 7, 1)。然而，其他鹽類可用於製備根據本發明之化合物或其醫藥上可接受之 -39-5 IX Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs; 20; Thiophan-2-yl, -2,3 · dihydrobenzothiophene_3, 2,3-dihydrobenzo [_phen] _Cardinyl, _2,3_diazino [Command phenyl group i, dihydrobenzofluorenylthiophene + group, _2,3_difluorenylthiophene-7-yl group, -μ -air tritium / 7 afanjing 2 , 3--Lindol-2-yl, _2,3-dihydro-2,3-dihydro-1 / f-indolyl-2,3-dihydro-lif-. Indole_6 · yl-2,3-a " Wind-2 -benzylidene-2'3-azo-5 -benzosigma η sitting group_2,3-dihydro-7-benzene Benzozolyl — ___ 1 benzimidazole_2-yl, _2,3 · dihydrovan benzimidazole_cardiyl, -2,3 · dihydro-1 benzobenzyl-5-yl, 2 , 3-dihydroisobenzo, oxazole-6-yl, _2,3-dihydro · ι-kg-benzimidazole_7_yl, -3,4-dihydro-1 (2 //) _ Ha Lin Radical, 2,3,4_tetraaza_2_shaolinyl, 1,2,3,4-tetrahydro-3-quinolinyl, -2,2,3,4-tetrahydro-4-quinolinyl , -1,2,3,4, hydro-5-quinolinyl,] 32,3,4: tetrahydro-6-quinolinyl, -1,2,3,4-tetrahydro-7-quinolinyl Radical, 2,3,4-tetrahydro-8-quinolinyl, -3,4-dihydrobenzo. Than _ | group, 3, cardio dihydroμ small benzopyrene 3-yl, _3,4_ monohydro-2i7-1_benzyl π specific ice base, _3,4_dihydro-2 / M · benzene Benzopyran_5_yl, -3,4_dihydro 2 / 7_i_benzopyranyl, -3,4-dihydro-2 / ^ 1-benzopyran_7_yl, _3, 4_dihydrobenzopyran_8_yl, -3,4-dihydro4fan 1_benzopyranyl, 3,4-dihydro-4 //-1-benzopyran-3 -Yl, _3,4_dihydro-4 //-1-phenylgalan-4_yl, -3,4-dihydro-4 / M · benzopyran_5_yl, '4-di Hydrogen-GM-benzopyran-6-yl, -3,4-dihydro-4 / M-benzopyran_7 -38-1 1 indole: group 177 · indol_5_yl 1 where Indole-7_yl 4-benzinazolyl 6-benzoxazolyl-2,3-dihydro-2,3-dihydro-2,3_ dihydro_253-dihydro • 2,3- Dihydro 200536844 A7 B7 V. Description of the invention (37) group, _3,4_diazine-4 //-1 -benzo-σ-pyran-8-yl, -3,4- «—-SLΊΗ-1 -benzene Benzopyran-2-yl, · 3,4-dihydro-1 / M-benzopyran-3-yl, _3,4-dihydro-I // small benzopyran-4-yl, -3,4-dihydro-1dan_1-benzopyran-5-yl '-3,4-dihydrobenzopyran-6-yl, -3,' di-5 nitrogen-1an-1 -Ben and ° Bihan-7-base and -3,4-diazine-1 //-1-benzyl ratio 11 South-8-base When connected to a nitrogen atom, the available valence number can be independently substituted with up to 7 substituents independently selected from a fluorenyl group, and when connected to a carbon atom, the available valence number can be independently selected as needed. 10 generations from up to 7 substituents of methyl, fluorenyloxy or fluorine; Z is selected from the group consisting of: hydroxyl, -NH2, -NH-Cw, alkyl, -Nπυ alkyl) 2, O- Cw alkyl-OH, -O-Cw alkylCw alkoxy, -0-Ci-8 alkyl, Ci-8 alkyl, -0-Ci.8 alkyl-C02H, -〇_ Cw Alkyl-cccoo-Cw Alkyl, -o-Cw Alkyl-o-qcocw 15 Alkyl, · 0 < "Alkyl-NH2, -O-Cw Alkyl-NH-Cw Burned employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Consumer Cooperative Printing Base, -O-Cu Alkenyl-N (Cu Alkenyl) 2, -0-Ci.8 Alkenyl Fermented Amine, Q-Ci.8 Alkenyl-C (0) -NH-Ci_8 -0-Ci_salkyl-C (〇) -N (Ci_8alkyl) 2 and -NHC (0) Ci.8alkyl, -O-Ci.8alkyl; and pharmaceutically acceptable salts thereof , Racemic mixtures and mirror isomers. 20 The compounds of the present invention may also exist in the form of pharmaceutically acceptable salts. When used for medical purposes, the salt of the compound of the present invention refers to a non-toxic "pharmaceutically acceptable argon" (see Internationa! Pharm., 1986, 33, 2QU 217; J. P / ^ Servo ..., 1977 (Jan ) 3 ⑽ 7, 1). However, other salts can be used to prepare the compounds according to the invention or their pharmaceutically acceptable -39-

200536844 A7 B7 五、發明說明（38 鹽。代表性有機或無機酸包含，惟不限於，鹽酸、氮漠酸、氫碘酸、過氣酸、硫酸、硝酸、磷酸、乙酸、丙酸、乙醇酸、乳酸、琥珀酸、馬來酸、富馬酸、蘋果酸、酒石酸、檸檬酸、笨甲酸、杏仁酸、甲磺酸、羥乙磺酸、苯項 5酸、草酸、雙經萘酸、2-萘項酸、對甲苯績酸、環己基胺磺酸、柳酸、糖精酸或三氟乙酸。代表性有機或無機鹼包含，惟不限於，鹼性鹽或陽離子性鹽例如苄星 (benzathine)、氣普魯卡因（chi〇r〇procaine)、膽驗、二乙醇胺、伸乙二胺、曱基葡胺、普魯卡因、鋁、舞、兹、鎂、 10 鉀、納及鋅。經濟部智慧財產局員工消費合作社印製本發明化合物之前驅藥物亦包含於本發明範圍之内。一般而言’此等前驅藥物為化合物之官能性衍生物，其易於活體内轉化成所需化合物。因此，於本發明之治療方法中，「投與」一詞係涵蓋以具體揭示之化合物或以可能未 15具體揭示，惟於投與病患後，在活體内轉化成具體指定的化合物之化合物治療各種所述疾病。挑選及製備適當前驅藥物诉生物之習知程序見述於，例如，’’Design of Prodrugs.，ed. Η· Bundgaard，Elsevier，1985。當根據本發明之化合物具有至少一個對掌中心時，則 20彼等可能因而呈鏡像異構體存在。當該化合物具有兩個或兩個以上對掌中心時，則彼等可能又以非鏡像異構體存在。於根據本發明之化合物製備方法中，若得到立體異構物之混合物，則該等異構物可利用習知技術（例如製備性層析法)予以分離。製備化合物時可呈消旋體形式，或可 -40· 本紙張尺度適用中^國家標準(CNS)A4規格（210x297公麓） 200536844200536844 A7 B7 V. Description of the invention (38 salts. Representative organic or inorganic acids include, but are not limited to, hydrochloric acid, nitric acid, hydroiodic acid, peroxy acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid , Lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, stearic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzene termin 5 acid, oxalic acid, amphoteric naphthalene acid, 2 -Naphthalene acid, p-toluene acid, cyclohexyl sulfamic acid, salicylic acid, saccharinic acid, or trifluoroacetic acid. Representative organic or inorganic bases include, but are not limited to, basic salts or cationic salts such as benzathine ), Gas procaine (chioroprocaine), bile test, diethanolamine, ethylenediamine, fluorenylglucamine, procaine, aluminum, dance, germanium, magnesium, 10 potassium, sodium and zinc The prodrugs printed by the employees' cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs are also included in the scope of the present invention. Generally speaking, these prodrugs are functional derivatives of the compounds, which are easily converted into the required in vivo. Compounds. Therefore, in the method of treatment of the present invention The term "administration" encompasses compounds that are specifically disclosed, or compounds that may not be specifically disclosed, but which, after being administered to a patient, are converted into specifically designated compounds in vivo to treat a variety of these diseases. The conventional procedure for the preparation of appropriate prodrugs and organisms is described in, for example, "Design of Prodrugs., Ed. Η · Bundgaard, Elsevier, 1985. When the compound according to the present invention has at least one palm center, then 20 And so on may exist as mirror isomers. When the compound has two or more palm centers, they may exist as non-image isomers. In the method for preparing a compound according to the present invention, if Mixtures of stereoisomers, these isomers can be separated using conventional techniques (such as preparative chromatography). Compounds can be prepared in the form of racemates, or -40 · This paper is applicable to the standard ^ National Standard (CNS) A4 specification (210x297 male foot) 200536844

五、發明說明 5 内生合成法或析離法製備各個鏡像異構物。例非#傻μ '準技挪化合物析離為其組成異構物或鏡=構物。需瞭解的是，所有立體異構物、消旋混合物、非鏡像㈣物錢像㈣物邮纽本發明範圍之 10 15 經濟部智慧財產局員工消費合作社印製 20 於製備本發明化合物之任何程序期間，可能需要及/ ’望保w蔓任何相關分子上之敏感性或反應性基團，此可利用習知料基達成，其實例如Protectlve G_s m地 J.F.W· Mc〇mie，pl_m press，及丁.W. Greene & p g.M. Wuts，Protective Groups 迦幽£-Sinthesis，John Wiley & Sons, 1991 中所述。該等保護基可於方便之接續階段，使用技藝中已知之方法予以移除。再者’該等化合物的一些結晶型可能存在多晶型物，其亦擬包含於本發明。此外，有些化合物可能與水（亦即’水合物）或一般有機溶劑形成溶劑合物，該等溶劑合物亦擬涵蓋於本發明範圍之内。本文所用之如下文劃底線之名詞乃意指下述意義：「Cu」（其中a與b為與指定碳原子個數相關之整數) 一詞係指含有α至△個碳原子之烷基、烯基、炔基、烷氧基或環烷基或基團中烷基呈字首根出現之烷基部分，例如’ CK3代表含1、2或3個碳原子之基團。「烷基」一詞係指從鏈烷分子之單一碳原子移除一個氫原子，從而形成連接點所衍生之視需要經取代之飽和或 -41- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 Α7 ____ B7 五、發明說明Go) 部分飽和、八士去 — 刀支鏈、直鏈或環狀單價烴基團。「烯基」一 W司係私從鏈烯分子之單一碳原子移除一個氫原子，從而形成連接點所衍生之視需要經取代之部分不飽和之分支鏈或直鍵單價煙基團。該基團於雙鍵處可能以順式或反式組態 5 存在。「炔基」一詞係指從鏈炔分子之單一碳原子移除一個氫原子’從而形成連接點所衍生之視需要經取代之部分不飽和之分支鏈或直鏈單價烴基團。「烷氧基」一詞係指從鏈烷、烯或炔分子之單一氧原子移除一個氩原子，從而形成連接點所衍生之視需要經取代之飽和或部分飽和、分 10支鏈或直鏈單價烴基團。該等烷基、烯基、炔基或烷氧基視需要於其基團内或於終端碳原子(為鏈時)上，以有效飽和價數容許之取代基數量被取代。烷基(Rx)」（其中x為與指定取代基相關之整數）一詞係指可於烷基鏈内或於終端碳原子上被取代及可 15同樣地於烯基、炔基或烷氧基上以有效化學鍵價數容許之取代基指定數量被取代之^取代基。「4院基(Rx)」一詞係指亦可於連接點直接被取代而無烷基連接基團（其經濟部智慧財產局員工消費合作社印製中CG為與連接點直接鍵結的&取代基之位置標蕺）之& 取代基。 20 「環烷基」一詞係指與烷基、烯基及炔基之界定一致之飽和或部分不飽和環狀單價烴基團。詳言之，涵蓋於環烷基界定範圍内者為其一或多個環為芳香族及一或多個環為餘和或部分不飽和之稠合多環系。例如，此等環烧基為具有3至8個碳原子(衍生自例如環丙烷、環丁烷、環戊 -42- ^紙張尺度適用中國國家標準(CNS)A4 &格（210 X 297 -------- 200536844 A7 B7 五、發明說明（4!) 烷、環己烷或環庚烷之分子）之飽和或部分不飽和或單環烷基基團；具有9至12個碳原子之飽和或部分不飽和稠合或笨并稠合環狀烧基基團；或，具有13至20個碳原子之飽和或部分不飽和稠合或苯并稠合三環或多環烷基基 5團。中之 10 雜環基」一詞係指飽和或部分不飽和環狀烷基基團或多個碳原子獨立地被相同或不同雜原子置換者。詳5之，涵蓋於雜環基界定範圍内者為其一或多個環為芳香族及一或多個環為飽和或部分不飽和之稠合多環系。置換碳原子之典型雜原子包含，惟不限於，N、〇、s等。例如，雜環基基團為飽和或部分不飽和五員單環烷基環， ”中至/環員被Ν、〇Μ原子置換，及視需要含有置換該絲環其他環員之一另外0原子或置換該烧基環環 f之-另外Ν原子；飽和或部分不飽和六員單環烧基 15 竦，其中該烷基環之一、-痞二個瑷g 、衣次一個環員被N原子置換，及視需要地，該烷基環之一環昌祐 L 0或S原子置換或該烷基環的兩個環員被〇或s原子置 · 原卞罝換，稠合於下文界定經濟部智慧財產局員工消費合作社印製先前界定之5至6員雜環;餘和、部分不餘 2〇或"^雙魏基，其㈣紅至少一環 -咬兩個1'或3原子置換’及視需要地，該雙環烧基之成兩個其他環員被Ν、〇或s原子 =和她合η至2。員多魏基員被ν、〇或s原子丹甲至^壤或：個該多環烷基之二 a—個其他環員被n原子置換。嗲 -43 - ^張尺度適用中、^荨餘和或部分不飽和 -43- 200536844 A7 B7 42 五、發明說明 2環基團之實例包含，惟不限於，2·料餘、3_料淋二”比_基、U·二料狀基、料基、味嗤咬二、-Μ唾基、2.対琳基、対絲、μ基、嗎琳 5 Ϊ、、四—氫㈣基、^井基、二氫_1Η嘱并[2,3仲比咬土四H，8·萘咬基、四氫·1Η_。丫庚因并[2,3仲&咬基、苯環勝5·基、U，3,4H料基或二氮二芳基」—詞係指從芳族環系之單—碳原子移除一個二：從=基I:連接點所街生之單價芳族烴基族單jt 含5至6個碳原子之不飽和芳不飽Γ 苯基，衍生自苯）；含9至1G個碳原子之 14^芳族雙環系（例如萘基，衍生自蔡）；或，含^至固^子之不飽和芳族三環_如蕙基，魅自葱）。 15 和環詞St有「芳族」共_子系之不餘次夕壤系。詳吾之’不包括於芳基之界定者為其一丄夕:環為飽和或部分不飽和之稍合環系。典型的芳基包惟不.限於’蒽基、萘基、奠基、苯基等。經濟部智慧財產局員工消費合作社印製 20 -個-雜芳基」—詞係指從雜芳族環系之單—碳原子移除氧原子，從而形成該基團之連接點所衍生之單價雜芳地二圏。「雜芳族環系」一詞係指其一或多個碳原子獨立八:雜原子置換之芳族環系。置換碳原子之典型雜原子包系之准Γ限於’N、〇、S等。詳言之，不包括於雜芳環系、。界々者為其-或多個縣姊或部分獨和之稠合環、例如，雜芳基係衍生自含有五個環員，其令至少一者 200536844 A7 五、發明說明（43 ) 原子且視需要含有一、二或三個細原 ^方矣單味系；具有六個環員，其中一、二或三個環員原子之雜芳族單環系；具有九個環員，1中至少V. Description of the invention 5 Endo-synthesis or dissociation method to prepare each mirror image isomer. For example, the non-quasi-technical compound is isolated as its constituent isomer or mirror structure. It should be understood that all stereoisomers, racemic mixtures, non-mirror materials, money, money, etc. are within the scope of the present invention. 15 15 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. During this period, it may be necessary to / / hope to protect sensitive or reactive groups on any relevant molecule, this can be achieved using conventional materials, in fact, for example, Protectlve G_sm JFW · Mc〇mie, pl_m press, and Ding .W. Greene & p GM Wuts, Protective Groups-Sinthesis, John Wiley & Sons, 1991. These protecting groups can be removed at a convenient continuation stage using methods known in the art. Furthermore, there may be polymorphs in some crystalline forms of these compounds, which are also intended to be included in the present invention. In addition, some compounds may form solvates with water (i.e., 'hydrates') or general organic solvents, and these solvates are intended to be included within the scope of the present invention. As used herein, the underlined term means the following meaning: "Cu" (where a and b are integers related to the number of specified carbon atoms) means an alkyl group containing α to △ carbon atoms, An alkenyl, alkynyl, alkoxy, or cycloalkyl group or an alkyl moiety in which an alkyl group appears as a radical, for example, 'CK3 represents a group containing 1, 2, or 3 carbon atoms. The term “alkyl” refers to the removal of a hydrogen atom from a single carbon atom of an alkane molecule, thereby forming a connection point, and optionally substituted saturation or -41- This paper applies Chinese National Standard (CNS) A4 Specifications (210x297 mm) 200536844 Α7 ____ B7 V. Description of the invention Go) Partially saturated, stubborn—knife branched, linear or cyclic monovalent hydrocarbon group. "Alkenyl"-W is a privately removed hydrogen atom from a single carbon atom of an alkenyl molecule, thereby forming a partially unsaturated branched chain or a straight-bonded monovalent tobacco group derived from the connection point, if necessary. This group may exist in cis or trans configuration at the double bond 5. The term "alkynyl" refers to the removal of a hydrogen atom 'from a single carbon atom of an alkyne molecule to form an optionally substituted partially unsaturated branched or straight chain monovalent hydrocarbon group derived from the point of attachment. The term `` alkoxy '' means the removal of an argon atom from a single oxygen atom of an alkane, alkene, or alkyne molecule to form a point of attachment, optionally substituted saturated or partially saturated, branched or straight Chain monovalent hydrocarbon group. These alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted in their group or on the terminal carbon atom (when in the chain) with the number of substituents allowed by the effective saturation valence. The term "alkyl (Rx)" (where x is an integer associated with the specified substituent) means that it may be substituted within the alkyl chain or at the terminal carbon atom and may be the same as alkenyl, alkynyl, or alkoxy ^ Substituents substituted on the base with a specified number of substituents allowed by the number of effective chemical bonds. The term "4yuan-based (Rx)" means that it can also be directly substituted at the connection point without an alkyl linking group. The position of the substituent is marked 蕺) of the & substituent. 20 The term "cycloalkyl" means a saturated or partially unsaturated cyclic monovalent hydrocarbon group consistent with the definition of alkyl, alkenyl and alkynyl. In particular, those encompassed within the definition of a cycloalkyl group are fused polycyclic ring systems in which one or more rings are aromatic and one or more rings are residual and partially unsaturated. For example, these cycloalkyl radicals have 3 to 8 carbon atoms (derived from, for example, cyclopropane, cyclobutane, cyclopentane-42- ^ paper size applicable Chinese National Standard (CNS) A4 & grid (210 X 297- ------- 200536844 A7 B7 V. Description of the invention (4!) Alkanes, cyclohexane or cycloheptane molecules) saturated or partially unsaturated or monocyclic alkyl groups; with 9 to 12 carbons Atomically saturated or partially unsaturated fused or fused and fused cyclic alkynyl groups; or, saturated or partially unsaturated fused or benzo-fused tricyclic or polycyclic alkyl groups having 13 to 20 carbon atoms The term “10 heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group or a group in which multiple carbon atoms are independently replaced by the same or different heteroatoms. Details 5 cover heterocycles Within the scope of the definition of a radical is a fused polycyclic ring system in which one or more rings are aromatic and one or more rings are saturated or partially unsaturated. Typical heteroatoms for replacing carbon atoms include, but are not limited to, N, 〇 , S, etc. For example, the heterocyclyl group is a saturated or partially unsaturated five-membered monocyclic alkyl ring, and the "to" / ring member is replaced by N, 0M atoms And optionally contains another 0 atom replacing one of the other ring members of the silk ring or the other N atom of the alkyl ring f; a saturated or partially unsaturated six-membered monocyclic alkyl group 15 15, wherein the alkyl ring One,-痞 two 瑷 g, one ring member is replaced by an N atom, and if necessary, one of the alkyl rings is replaced by L0 or S atom or two ring members of the alkyl ring are replaced by 〇 or s atomic replacement, condensed in the following definition of the Ministry of Economic Affairs Intellectual Property Bureau employee consumer cooperative printed a previously defined 5- to 6-membered heterocyclic ring; Yu He, part of the remaining 20 or " ^ Weiji, Its red ring is at least one ring-biting two 1 'or 3 atom substitutions' and if necessary, the two ring ring members are formed by two other ring members by N, 0, or s atoms = and she is η to 2. Yuan Duowei The base member is replaced by ν, 〇, or s atom Dan to the soil or: one of the polycycloalkyl group a and the other ring members are replaced by the n atom. 嗲 -43-^ scale applies to medium, ^ net residue and or Partial Unsaturation-43- 200536844 A7 B7 42 V. Description of the Invention Examples of 2-ring groups include, but are not limited to, 2 · material residue, 3_material leaching Ratio_base, U · base material base, base material, miso bite II, -M salyl group, 2. 対 linyl, 対 silk, μ 、, morphine 5 Ϊ, 、 -hydro hydrazone, ^ well Base, dihydro_1Η, and [2,3 Zhongbi bite soil tetraH, 8 · naphthyl, tetrahydro · 1Η_. Yagenin benzo [2,3 Zhong & bitenyl, phenylcyclohexyl 5. ", U, 3, 4H base or diazadiaryl"-the word refers to the removal of a two from a single-carbon atom of an aromatic ring system: a monovalent aromatic hydrocarbon group derived from the radical I: junction Single jt unsaturated aryl unsaturated phenyl group containing 5 to 6 carbon atoms, derived from benzene); 14 ^ aromatic bicyclic ring system containing 9 to 1G carbon atoms (such as naphthyl, derived from Cai); or, Unsaturated aromatic tricyclic ring containing ^ to solid ^ _ such as hydrazone, charm from green onions). 15 and the ring St has the remaining "fragrant" sub-line of the remaining Yuxi soil. The detailed definition of 'I' is not included in the definition of the aryl group. The ring is a slightly or partially unsaturated ring system. A typical aryl group is not limited to anthracene, naphthyl, phenyl, phenyl and the like. Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs' Consumer Cooperatives "20-piece-heteroaryl" —the word refers to the unit price derived from the removal of oxygen atoms from the mono-carbon atom of the heteroaromatic ring system, thereby forming the connection point of the group Heterogeneous eruption. The term "heteroaromatic ring system" refers to an aromatic ring system in which one or more carbon atoms are independent. The standard Γ of a typical heteroatom package for replacing carbon atoms is limited to 'N, 0, S, and the like. Specifically, it is not included in the heteroaromatic ring system. Boundaries are fused rings for one or more counties or partly exclusive, for example, the heteroaryl system is derived from containing five ring members, which makes at least one 200536844 A7 V. Description of the invention (43) Atoms and Contains one, two, or three succinctose monosaccharids as required; heteroaromatic monocyclic systems with six ring members, one, two, or three ring members of atoms; nine ring members, at least one of 1

5 =::〇或8原子且視需要含有-、二或三個另外N 原子之雜方族祠合雙環系；具有十個環員，兑中一【個為N原子之雜芳族雙環系；含有…：環吲異 15 、/、中至少—者為N、Q或s原子且視需要含有一、二或二個另外N原子之雜芳族稍合三環系；或，含 2〇個環員’其中至少-者為N、^s原子且視需要含 1〇有二一或三個另外N原子之雜芳族稠合多環系。典型之雜芳基包含，惟不限於，嗜淋基、吱嚷基、味嗤基嗤基、’杀基、.㈣琳基、井基、異苯并吱喝基a 喹啉基、異噻唑基、異啐唑基、萘啶基、喝唑基、啡啶基啡啉基、嘌呤基、σ比喃基、吡畊基、吼唑基、嗒畊基比啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹0寻淋土四°坐基、嗟二唾基、嗟唾、嗟吩、三口坐等。 20 、「獨立地」一詞意指當一個基團被一個以上取代基取代時，該等取代基可相同或不同。「從屬」意指該等取代基被具體指定諸結構變數之表明組合。於整個揭示内容所用之標準命名規則下，先敘述表明側鏈的終端部分，隨後敘述其連接點之相鄰官能性。因此，例如，「苯基Cl_6烷基醯胺基ci 6烷基」取代基係指下述基團： -45- 本紙張尺度適用+國票準(CNS)M規格（21〇 χ 297~^y A7 B7 200536844 五、發明說明（44 ) 如 c^ N〆 c一基一0^ Η ο 取代基之連接點亦可以破折號表示，示出諸連接點，隨後為相鄰官能性，最後為終端官能性，例如，_((31-6)烧基-獄基-NE^Ck)烷基·笨基。 5 於分子中特定部位的任何取代基或變數，其界定與其於該分手其他地方之界定互不相關，因此，可瞭解的是，熟習此項技藝人士可挑選本發明化合物中之取代基及取代樣式，以提供具化學穩定性且易於利用技藝中已知之技術以及本文敘述之方法合成之化合物。 10 整合素為含鈣或鎂依存性α或点異源二聚體性細胞表面受體之廣為表現之家族，其與細胞外基質黏合蛋白例如血纖維蛋白原、纖維網蛋白、透明質蛋白與造骨蛋白結合。該等整合素受體為跨膜醣蛋白（GP，s)，因其極大之細胞外功能部位而聞名，並根據至少8種已知之卢次單元及 15 14種α次單元分類（S.A. Mousa，et al·，五似咖叹經濟部智慧財產局員工消費合作社印製 TTzer叩⑼价 2000, < (2)，143-153)。例如，/3 1亞族具有各種α次單元與各種点次單元 (泠3、召5、冷6與冷8)結合之大量整合素(S.A· Mousa，et al·，Emerghg Targeh，2000，4，（2)，144-147) 〇 20 於其病原學上具有強α v/?3、a v/35及allb冷3(亦稱為 GPIIb/IIIa)整合素成分的一些疾病狀態為不穩定型心絞痛、栓塞性血栓疾病或動脈硬化（GPIIb/IIIa);血栓形成或 -46- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200536844 A7 B7 五、發明說明（45 ) 動脈再狭窄（GPIIb/IIIa或a vy53);動脈再狹窄（雙重a v yS3/GPIIb/IIIa);風濕性關節炎、血管性疾病或骨質疏鬆症（αν；5 3);腫瘤血管新生、腫瘤轉移、腫瘤生長、多發性硬化症、神經疾病、氣喘、血管傷害或糖尿病視網膜病 5 變（αν/53或av/5 5);及血管新生（雙重avyS3/av/5 5) (S. A. Mousa5 et al., Emerging Therapeutic Targets, 2000? 4, (2) 148-149 J W. H. Miller, et al.? Drug Discovery Today, 2000, 5 (9)，397-407 ;及 S· A· Mousa，et al·，五叩·办汍 Γ/zer· P咖1999, 9 (9)，1237-1248)。万 3 次單元已於新 10 近之藥物發現成果中受到明顯的矚目（W. J. Hoekstra， Current Medicinal Chemistry，1998，5，195)。坑體反/或低分子量化合物拮抗劑αν^53已於動物模式中顯示效力（j. Samanen5 Current Pharmaceutical Design, 199 75 3, 5 45) ^ 因此，可提供作為治療劑之用途。 15 整合素拮抗劑典型地係根據衍生自初級配位體透明質經濟部智慧財產局員工消費合作社印製蛋白的胜肽之生物活性精胺酸-甘胺酸-天冬胺酸(RGD)構形而設4。該RGD主結構於大約20個已知整合素之半數與含RGD之黏合配位體結合時，係許多細胞外基質、血液與細胞表面蛋白之普遍性細胞連接序列。為了發現具 20整合素選擇性之RGD胜肽，已針對具有限制構形及更改側接殘基二者之胜肽進行研究。詳言之，RGD序列與 GPIIb/IIIa相互作用的結構需求及一系列非胜肽模擬物對血小板凝集及與細胞外基質相互作用之抑制可能性均已被敘述(D· Varon，et al·，//aemoy如以，1993，70⑹， •47- 本紙張尺度適用中國國家標準(CNS)A4規格（21〇χ297公釐） A7 B7 200536844 五、發明說明（46) 1030-1036)。環狀與非環狀胜肽之反覆合成及電腦模擬設計已為非胜肽αν (如於中）整合素拮抗劑設計舞台提供強有力、選擇性製劑。 10 15 經濟部智慧財產局員工消費合作社印製整合素拮抗劑與用於抑制骨質耗損（bone resorption) 5 有所牽連（S.B. Rodan and G.A. Rodan，Integrin Function In Osteoclasts, Journal 〇f Endocrinology^ 1997? 154； S47-S56)。於脊椎動物中，骨質耗損係由所謂蝕骨細胞（直徑高達約400 mm之多核大細胞，其耗損礦質化組織，主要為碳酸鈣及磷酸鈣）的作用所傳介。蝕骨細胞為積極移動的細胞，其沿著骨骼表面遷移，可與骨骼結合，分泌必要的酸與蛋白酶，因而引致礦質化組織自骨骼之實際耗損。詳言之，一般相信蝕骨細胞以至少兩種生理狀態存在，亦即，分泌狀態及遷移或移動狀態。於分泌狀態中，蝕骨細胞是平的，經由緊密連接區（密封區）連接於骨骼基質，成為高度極化，形成皺起的邊緣並分泌溶酶體酵素與質子而耗損骨質。蝕骨細胞黏著於骨骼表面為骨質耗損中重要的起始步驟。於遷移或移動狀態中，姓骨細胞穿過骨絡基質遷移，直到再與骨骼連接之前並未參與耗損作用。整合素涉及料細胞連接、活化及遷移。料細胞 20 (例如大鼠、鷄、小鼠及人類姓骨細胞）上最大量的整受體為a”3整合素受體，其被認為在骨絡中與含\°gd 序列之基質蛋白質相互作用。_3之抗體遏阻活體外骨質㈣’表不此整合素在耗損過程中扮演關鍵角色來愈多證據暗示…3配:體可有效地用於抑制魏二 ^紙張尺度適用中國國家標準(CNS)A4規格 200536844 A7 B7 五、發明說明（47) 物中由蝕骨細胞傳介之活體内骨質耗損作用。目前大眾關注的主要骨骼疾病為骨質疏鬆症、惡性腫瘤之高鈣血症、由於骨轉移之骨質缺少症、牙肩病、副甲狀腺機能宄進、風濕性關節炎中之關節周圍骨質腐損、柏 5 哲德氏症(Paget’s disease)、固定誘發之骨質缺少症、糖皮質激素誘發之骨質疏鬆症。所有彼等疾病之特徵為由骨質耗損間之不平衡（亦即，分解及骨質形成）造成的骨質流失，其於整個生命週期中以平均每年約14%之速率持續進行。然而，各個部位之骨質轉換率不同；例如，於椎骨 10 之小樑骨及顎部齒槽骨，其骨質轉換率較長骨之皮質中者高。骨質流失的可能性與骨質轉換直接相關，於停經期後之椎骨’每年會超過5%，導致增加骨折風險。在美國，目前大約2千萬民眾由於骨質疏鬆而具有可看出之椎骨骨折。此外，每年有大約250,000件髖關節骨 15 折歸因於骨質疏鬆。此臨床狀況牽扯到頭兩年内12%之死亡率，同時有30%病患於發生骨折後需要居家護理照顧。罹患上列所有症狀的個體將因以骨質耗損抑制劑治療而獲利。經濟部智慧財產局員工消費合作社印製此外，αν召3配位體已被發現可用於治療及/或抑制 20動脈再狹窄（亦即於心瓣膜校正手術後再復發動脈狹窄）、動脈硬化症、糖尿病視網膜病變、黃斑病變及血管新生 (亦即形成新血管）及抑制病毒性疾病。再者，一般假設腫瘤生長取決於適當的血管供應，人取決於新血管之生長成為腫瘤；因而，抑制血管新生可於 -49- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200536844 A7 B7 五、發明說明（48) 動物模式中引致腫瘤退化(Harrison’s Principles of Interaal5 = :: 0 or 8 atoms and optionally containing-, two, or three other N atoms of the heterosexual family bicyclic system; with ten ring members, one of N [a heteroaromatic bicyclic system of N atoms ; Contains :: at least one of the cyclic indiso 15 and / or N, Q or s atoms and optionally one, two or two other N atoms of the heteroaromatic tricyclic ring system; or, containing 2 Each of the ring members is at least one of N, ^ s atoms, and optionally contains a heteroaromatic fused polycyclic ring system having two or three other N atoms. Typical heteroaryl groups include, but are not limited to, lyophilyl, stilbyl, misoyl, stilbyl, styrenyl, stilbyl, isobenzoyl, quinolinyl, isothiazole Base, isoxazolyl, naphthyridinyl, pyrazolyl, morpholinyl, morpholinyl, purinyl, σ-pyranyl, pyrimidinyl, oxazolyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrrolyl , Quinazolinyl, quinolinyl, quinoline, four-degree sitting group, bisdisalyl, sialyl, stilbene, three-mouth sitting and so on. 20. The term "independently" means that when a group is replaced by more than one substituent, the substituents may be the same or different. "Subordinate" means an indicated combination of structural substituents that are specifically designated by the substituents. Under the standard nomenclature used throughout the disclosure, the terminal portion of the side chain is described first, followed by the adjacent functionality of its attachment point. Therefore, for example, the "phenyl Cl_6 alkylamido ci 6 alkyl" substituent refers to the following groups: -45- Applicable to this paper standard + National Standard (CNS) M specification (21〇χ 297 ~ ^ y A7 B7 200536844 V. Description of the invention (44) For example, c ^ N〆c one base one 0 ^ Η ο The connection point of the substituent can also be indicated by a dash, showing the connection points, followed by adjacent functionalities, and finally the terminal Functionality, for example, _ ((31-6) alkenyl-hexanyl-NE ^ Ck) alkyl · benzyl. 5 Any substituent or variable at a specific part of the molecule, which is defined as it is elsewhere in the breakup The definitions are irrelevant. Therefore, it can be understood that those skilled in the art can choose the substituents and substitution patterns in the compounds of the present invention to provide chemical stability and easy to synthesize using techniques known in the art and the methods described herein. 10 Integrins are a well-represented family of calcium or magnesium-dependent alpha or point heterodimer cell surface receptors that bind to extracellular matrix adhesion proteins such as fibrinogen, fibrin, Hyalurin binds to osteoblasts. The integration Receptors are transmembrane glycoproteins (GP, s), known for their extremely large extracellular functional sites, and are classified according to at least 8 known subunits and 15 to 14 alpha subunits (SA Mousa, et al · , Wusi Katan printed the TTzer price of 2000, < (2), 143-153) by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. For example, the / 31 subgroup has various α subunits and various point subunits ( Ling 3, Zhao 5, Leng 6 and Leng 8) have a large number of integrins (SA · Mousa, et al ·, Emerggh Targeh, 2000, 4, (2), 144-147) 〇20 has a strong etiology α v /? 3, av / 35, and allb cold 3 (also known as GPIIb / IIIa) some of the integrin component disease states are unstable angina, embolic thrombosis or arteriosclerosis (GPIIb / IIIa); thrombosis or -46- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200536844 A7 B7 V. Description of the invention (45) Arterial restenosis (GPIIb / IIIa or a vy53); Arterial restenosis (double av yS3 / GPIIb / IIIa); rheumatoid arthritis, vascular disease or osteoporosis (αν; 5 3); tumor angiogenesis, tumor metastasis Tumor growth, multiple sclerosis, neurological disease, asthma, vascular injury, or diabetic retinopathy 5 changes (αν / 53 or av / 5 5); and angiogenesis (dual avyS3 / av / 5 5) (SA Mousa5 et al. , Emerging Therapeutic Targets, 2000? 4, (2) 148-149 J WH Miller, et al.? Drug Discovery Today, 2000, 5 (9), 397-407; and S.A. Mousa, et al., 5叩 · 汍汍 / zer · PCa 1999, 9 (9), 1237-1248). Unit 3 has been noticeably noticed in recent drug discovery efforts (W. J. Hoekstra, Current Medicinal Chemistry, 1998, 5, 195). Pit body anti / or low molecular weight compound antagonist αν ^ 53 has shown efficacy in animal mode (j. Samanen5 Current Pharmaceutical Design, 199 75 3, 5 45) ^ Therefore, it can be provided as a therapeutic agent. 15 Integrin antagonists are typically based on the biologically active arginine-glycine-aspartate (RGD) structure of peptides derived from the protein printed by the consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs of the primary ligand. Metaphysically set 4. The RGD main structure is a universal cell-linking sequence of many extracellular matrix, blood, and cell surface proteins when half of about 20 known integrins bind to RGD-containing adhesion ligands. In order to discover RGD peptides with 20 integrin selectivity, studies have been performed on peptides with both a restricted configuration and altered flanking residues. In detail, the structural requirements for the interaction of RGD sequences with GPIIb / IIIa and the possibility of a series of non-peptide mimetics to inhibit platelet aggregation and interaction with the extracellular matrix have been described (D. Varon, et al., // aemoy such as, 1993, 70⑹, • 47- This paper size applies to the Chinese National Standard (CNS) A4 specification (21 × 297 mm) A7 B7 200536844 V. Description of the invention (46) 1030-1036). The iterative synthesis and computer simulation of cyclic and non-cyclic peptides have provided powerful and selective formulations for the design of non-peptide αν (as in) integrin antagonists. 10 15 The integrin antagonists printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs have been implicated in inhibiting bone resorption 5 (SB Rodan and GA Rodan, Integrin Function In Osteoclasts, Journal 〇f Endocrinology ^ 1997? 154 ; S47-S56). In vertebrates, bone loss is mediated by the action of so-called osteoclasts (multinucleated large cells up to about 400 mm in diameter, which deplete mineralized tissues, mainly calcium carbonate and calcium phosphate). Bone etch cells are actively moving cells that migrate along the bone surface and can bind to the bone to secrete the necessary acids and proteases, thus causing the actual loss of mineralized tissue from the bone. In detail, it is generally believed that osteoclasts exist in at least two physiological states, that is, a state of secretion and a state of migration or migration. In the secretory state, osteoclasts are flat and connected to the skeletal matrix through tight junctions (sealed areas), becoming highly polarized, forming wrinkled edges and secreting lysosomal enzymes and protons to deplete bone. The adhesion of osteoclasts to the bone surface is an important initial step in bone loss. In the state of migration or movement, the bone cells of the surname migrate through the bone matrix and do not participate in depletion until they are connected to the bone again. Integrins are involved in cell attachment, activation, and migration. The largest intact receptor on feed cells 20 (such as rat, chicken, mouse, and human surname osteoblasts) is the a ”3 integrin receptor, which is thought to interact with matrix proteins containing \ ° gd sequences Interaction. The antibody of _3 inhibits in vitro osteoporosis 表 indicates that this integrin plays a key role in the process of depletion. More and more evidence suggests that ... 3 ligands can be effectively used to inhibit Wei Er ^ Paper size applies Chinese national standards (CNS) A4 specification 200536844 A7 B7 V. Description of invention (47) The bone loss in vivo is mediated by osteoclasts. The main bone diseases that the public is concerned about are osteoporosis, hypercalcemia of malignant tumors, Osteopenia due to bone metastases, dental shoulder disease, parathyroid function invasion, bone erosion around joints in rheumatoid arthritis, Page 5's disease, fixation-induced osteodystrophy, glucocortico Hormone-induced osteoporosis. All of these diseases are characterized by bone loss caused by an imbalance between bone loss (ie, breakdown and osteogenesis), which occurs at an average annual rate throughout the life cycle The rate of 14% is continuous. However, the bone conversion rate is different in each part; for example, in vertebra 10 trabecular bone and jaw alveolar bone, the bone conversion rate is longer in the cortex of the longer bone. The possibility of bone loss Sexuality is directly related to osteogenesis. The vertebrae after menopause can exceed 5% annually, leading to an increased risk of fractures. In the United States, approximately 20 million people currently have vertebral fractures visible due to osteoporosis. In addition, there are annual 15% of approximately 250,000 hip bones are attributed to osteoporosis. This clinical condition involves a 12% mortality rate in the first two years, while 30% of patients require home care after a fracture. Individuals with all of the symptoms listed above Will benefit from treatment with bone depletion inhibitors. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. In addition, the ανzol 3 ligand has been found to be useful for the treatment and / or suppression of 20 arterial restenosis (that is, in heart valves). Recurrence of arterial stenosis after correction surgery), arteriosclerosis, diabetic retinopathy, macular degeneration, and angiogenesis (ie, the formation of new blood vessels) and inhibition of virality In addition, it is generally assumed that tumor growth depends on the proper supply of blood vessels, and humans depend on the growth of new blood vessels to become tumors; therefore, the inhibition of angiogenesis can be -49- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200536844 A7 B7 V. Description of Invention (48) Harrison's Principles of Interaal

Medicii^，1991，12th ed·)。因此，抑制血管新生之 α 3 拮抗劑可利用抑制腫瘤生長而用於治療癌症(Bro〇ks et al.， CW/5 1994，7P，1157-1164)。已有暗示血管新生為開始與 5 持續關節炎疾病的中心因素，及血管整合素α Vyg 3可能為炎性關節炎的較佳標的之證據被提出。因此，可抑制血管新生的αν/93拮抗劑可能代表治療關節炎疾病（例如風濕性關節.炎）之新穎治療方式（C.M. Storgard, et al.5 Decreased Angiogenesis and Arthritic Disease in Rabbits 10 Treated with an ανβ3 Antagonist, J. Clin. Invest., 1999, 103, 47-54) 〇抑制av/95整合素受體亦可防止血管增生。之單株抗體已被證實於兔角膜及鷄絨毛尿囊模式中抑制由 VEGF 誘發之血管新生（M.C· Friedlander，et al·，Sc/wce， 15 1995，270，1500-1502)。因此，5拮抗劑可用於治療及預防黃斑病變、糖尿病視網膜病變、癌症及轉移性腫瘤生長。經濟部智慧財產局員工消費合作社印製抑制αν整合素受體亦可藉由具有其他沒次單元（例如avyS6與αν/3 8)拮抗劑之作用而防4血管新生及炎症 20 (Melpo Christofidou-Solomidou, et al.? Expression and Function of Endothelial Cell on Integrin Receptors in Wound-Induced Human Angiogenesis in Human Skin/SCID 25 Mice Chimeras, American Journal of Pathology, 1997, /5/，975-83 ;及，Xiao-Zhu Huang，et al.，Inactivation of -50- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 五、發明說明（49 ) the Integrin β 6 Subunit Gene Reveals a Role of Epithelial Integrins in Regulating Inflammation in the Lungs and Skin, Journal of Cell Biology, 1996, 133, 92\-2名、。本發明之一態樣為含有製藥上之適當載劑及本發明任 5何化合物之組成物或藥劑。本發明之一例證為由混合本發明化合物與製藥上之適當載劑製造之組成物或藥劑。本發明之另一例證為组成物或藥劑之製法，該製法包括使上述任何化合物與製藥上之適當載劑混合。本發明之進一步例證為由一或多種本發明化合物與製藥上之適當載劑結合所 10 構成之組成物或藥劑。本文所用之「組成物」一詞意欲涵蓋含有特定量的特疋成刀之產㉗以及直接或間接組合特定量的特定成分以 m療或改善由αν整合素傳介的疾病或作為義用途所產生之任何產物。 15 經濟部智慧財產局員工消費合作社印製 20 本發明化合物為用於治療或改善由Μ整合素傳介的疾病之αν整合素抑制劑。本發明之-態樣包含為Μ整合素受體或其亞型之選擇性抑制劑之化合物。於本發明另 1樣中，該抑制_立地對❹…整合素受體或㈣ 5入^合素受體具選擇性。本發明之-態樣亦包含細ν整合=或其亞型的組合之抑制劑之化合物。於本發明另 =:去該化合物抑制劑同時拮抗"…整合素及❹ /35整α素受體等亞型。 αν 二態樣包含對有其需要的病患治療或改善由Medicii ^, 1991, 12th ed.). Therefore, α 3 antagonists that inhibit angiogenesis can be used to treat cancer by suppressing tumor growth (Brooks et al., CW / 5 1994, 7P, 1157-1164). Evidence has been suggested suggesting that angiogenesis is a central factor in the onset of persistent arthritis, and that angiointegrin α Vyg 3 may be a better target for inflammatory arthritis. Therefore, αν / 93 antagonists that inhibit angiogenesis may represent a novel treatment for arthritic diseases such as rheumatoid arthritis (CM Storgard, et al. 5 Decreased Angiogenesis and Arthritic Disease in Rabbits 10 Treated with an ανβ3 Antagonist, J. Clin. Invest., 1999, 103, 47-54) 〇 Inhibition of av / 95 integrin receptor can also prevent angiogenesis. Monoclonal antibodies have been shown to inhibit angiogenesis induced by VEGF in rabbit corneal and chicken villous allantoic models (M.C. Friedlander, et al., Sc / wce, 15 1995, 270, 1500-1502). Therefore, 5 antagonists are useful for the treatment and prevention of macular degeneration, diabetic retinopathy, cancer and metastatic tumor growth. Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs to inhibit αν integrin receptors can also prevent 4 angiogenesis and inflammation by having antagonists of other subunits such as avyS6 and αν / 3 8 Solomidou, et al.? Expression and Function of Endothelial Cell on Integrin Receptors in Wound-Induced Human Angiogenesis in Human Skin / SCID 25 Mice Chimeras, American Journal of Pathology, 1997, / 5 /, 975-83; and Xiao-Zhu Huang, et al., Inactivation of -50- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200536844 A7 B7 V. Description of the invention (49) the Integrin β 6 Subunit Gene Reveals a Role of Epithelial Integrins in Regulating Inflammation in the Lungs and Skin, Journal of Cell Biology, 1996, 133, 92 \ -2. One aspect of the present invention is a composition containing a suitable pharmaceutical carrier and any of the compounds of the present invention or Medicinal agents. One example of the present invention is a composition or agent made by mixing the compound of the present invention with a suitable pharmaceutical carrier. Another example of the present invention A method of making a composition or medicament, which method comprises mixing any of the compounds described above with a suitable pharmaceutical carrier. A further illustration of the present invention is a composition consisting of one or more compounds of the present invention in combination with a suitable pharmaceutical carrier. The term "composition" as used herein is intended to cover a product containing a specific amount of special knives and a combination of specific amounts of specific ingredients, either directly or indirectly, to treat or ameliorate a disease or disease mediated by αν integrin. Any product produced for any purpose. 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 The compound of the present invention is an αν integrin inhibitor for the treatment or amelioration of diseases mediated by M integrin. A compound comprising a selective inhibitor of the M integrin receptor or a subtype thereof. In another aspect of the present invention, the inhibition is sterically selective for the integrin receptor or the integrin receptor. The aspect of the present invention also includes a compound that inhibits fine integration or a combination of its subtypes. In the present invention, another aspect of the present invention is to remove the compound inhibitor and simultaneously antagonize "... integrin and ❹ / 35 intact alpha subtype receptor. The αν dimorphism includes the treatment or improvement of a patient in need

整4傳介L之枝，財純括投與該病患治 __ -5U 張尺度適用中國國家標準(CNS)A4^^7?i^- 、210 X 297 公复） 200536844The 4 branches of L are introduced, and the pure money is included in the treatment of this patient. __ -5U Zhang scale is applicable to China National Standard (CNS) A4 ^^ 7? I ^-, 210 X 297 public reply) 200536844

五、發明說明（50) 療有效量之_化合物或其組成物。 =文所用轉有效量」或「有效量」等詞意指為研究人員、獸醫、西嫛 ^ m：3c具他臨床醫師所探索之於組織系㈣:或人體中誘出生物或醫藥反應之活性化合物或醫 =製狀量，該等反應包括減輕欲治療病症或疾病之症狀。 10 15 經濟部智慧財產局員工消費合作社印製 20 敫^月之態樣包含對有其需要的病患預防或防止由 αν二素傳介的疾病之方法，該方法包括投與該病患預防有效量之式⑴化合物或其組成物。本發明之另—態樣包含製備含有治療有效量之式(I) 化口物之藥劑，以對有其需要的病患預防、治療或改善由 αν整合素傳介的疾病。「投與」一詞擬被解釋為根據本發明方法從而使本發月之個別化合物或其組成物可分別於治療過程之不同時間或同犄呈分離或單一組合形式治療性地投與。預防性之投，、可發生於表現φαν整合素傳介的疾病之特徵症狀之月J俾使預防，或者，延緩該疾病或病症之進展。本發明因而擬破瞭解為涵蓋所有該等同時或交替治療或預防處理之療法。本文所用之「病患」係指動物，較佳為哺乳動物，最佳為人類，其為處理、觀察或實驗及具有（易於)逐漸形成疾病或病症或具有與表現αν整合素或其亞型相關的疾病或病症之風險之對象者。「由αν整合素傳介的疾病」一詞係指與表現αν整 -52- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 Α7 Β7 五、發明說明 10 15 經濟部智慧財產局員工消費合作社印製 20 癌癌變長指胞 -53- 51 合素或其亞型造成的病理性紊亂或未調控之細胞增生相關之疾病或病症。「紊亂」一詞係指調控細胞增生之程序故障，例如於腫瘤細胞中。「未調控」係指發病造成之不適當細胞生長。「亞型」一詞係指選自組成a v整合素類別的受體之特定αν整合素受體，例如整合素受體或整合素受體。「與紊亂或未調控之細胞增生相關之疾病或病症」係 4曰由一或多個細胞亞族於多細胞生物中之細胞增生對該生物造成傷害（例如不適或平均壽命降低)之疾病。該等疾病可發生於不同種類的動物與人類及包含，惟不限於，癌症、與癌症相關的病變、動脈硬化症、移植誘發之血管病變、血管壁膜再形成、乳頭狀瘤、肺纖維化、肺部纖維化、血管球性腎炎、腎血管球硬化症、先天多囊性腎發育不良、腎纖維化、糖尿病視網膜病變、黃斑病變、牛皮癬、骨質疏鬆症、骨質耗損、炎性關節炎、風濕性關節炎或動脈再狹窄。「癌症」一詞係指，惟不限於，神經膠質瘤癌、肺礼癌、大腸直腸癌、攝護腺癌、胃癌、食道癌、血黑色素瘤、基底細胞癌及淋巴瘤。「與癌症相關的病如私，惟不限於，紊亂或未調控之細胞增生、腫瘤生腫瘤脈管化、血管病變及血管新生。「血管新生」係惟不限於，新血管組織（包括，惟不限於，内皮細血管平滑肌細胞、周邊衛星細胞及纖維母細胞）紊亂 Κ張尺度格(210χ29_τ^V. Description of the invention (50) A therapeutically effective amount of the compound or its composition. The terms "effective amount" or "effective amount" as used in this article mean researcher, veterinarian, and serotonin ^ m: 3c, which is explored by other clinicians in the tissue system: or biological or medical response induced in the human body The amount of active compound or medicinal product is formulated, and such reactions include reducing the symptoms of the condition or disease to be treated. 10 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 The pattern of the month includes methods for preventing or preventing diseases that are mediated by αν di prime, which includes administering the patients for prevention. An effective amount of a compound of formula (I) or a composition thereof. Another aspect of the present invention includes the preparation of a medicament containing a therapeutically effective amount of a chelating substance of formula (I) to prevent, treat or ameliorate a disease mediated by αν integrin for a patient in need thereof. The term "administration" is intended to be interpreted to mean that the individual compounds or compositions thereof may be administered therapeutically at separate times or in the same group at different times during the course of treatment according to the method of the present invention. Prophylactic investment can occur during the month that manifests the characteristic symptoms of a φαν integrin-mediated disease, preventing prevention, or delaying the progress of the disease or condition. The invention is therefore intended to be understood to encompass all such simultaneous or alternating treatments or preventative treatments. "Patient" as used herein refers to an animal, preferably a mammal, and most preferably a human being, which is treated, observed, or experimental and has (prone to) gradually develop a disease or disorder or has and expresses αν integrin or its subtype Subjects at risk for related diseases or conditions. The term "disease mediated by αν integrin" refers to and expresses αν whole-52- This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200536844 Α7 Β7 V. Invention Description 10 15 Printed by the Consumer Affairs Cooperative of the Property Bureau. 20 Cancer Carcinogenesis refers to diseases or disorders related to pathological disturbances or unregulated cell proliferation caused by cytoplasm-53-51 or its subtype. The term "disorder" refers to a failure of a process that regulates cell proliferation, such as in tumor cells. "Unregulated" refers to inappropriate cell growth caused by disease. The term "subtype" refers to a specific αν integrin receptor selected from the receptors constituting the av integrin class, such as an integrin receptor or an integrin receptor. A "disease or disorder associated with a disordered or unregulated cell proliferation" is a disease in which a cell proliferation in one or more cell subgroups in a multicellular organism causes harm to the organism (such as discomfort or reduced average life span). These diseases can occur in different kinds of animals and humans and include, but are not limited to, cancer, cancer-related lesions, arteriosclerosis, transplant-induced vascular disease, vascular wall membrane reformation, papilloma, and pulmonary fibrosis , Pulmonary fibrosis, glomerulonephritis, glomerulosclerosis, congenital polycystic kidney dysplasia, renal fibrosis, diabetic retinopathy, macular degeneration, psoriasis, osteoporosis, bone loss, inflammatory arthritis, Rheumatoid arthritis or arterial restenosis. The term "cancer" means, but is not limited to, glioma cancer, lung cancer, colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, blood melanoma, basal cell carcinoma and lymphoma. "Cancer-related diseases are private, but are not limited to disordered or unregulated cell proliferation, tumor angiogenesis, vascularization, angiopathy and angiogenesis." Angiogenesis "is not limited to neovascular tissue (including, but Not limited to endothelial vascular smooth muscle cells, peripheral satellite cells, and fibroblasts) disordered K-scale scale (210χ29_τ ^

200536844 Α7 Β7 五、發明說明（52) 或未調控之增生。「骨質疏鬆症」一詞係指，惟不限於，姓骨細胞之形成或活性造成骨質耗損。「動脈再狹窄」一詞係指，惟不限於，血管支架狹窄及血管移植物動脈再狹窄。 5 「a v整合素表現」一詞係指： 1. 經由通常不表現αν整合素或其亞型之細胞； 2. 經由癌細胞； 3. 反應生長因子、組織缺氧、瘤形成或疾病過程； 4. 導使αν整合素或其亞型組成性表現的突變之結果； 10 導致紊亂或未調控的細胞增生之αν整合素或其亞型之表現。 αν整合素或其亞型之表現包含αν整合素或其亞型之選擇性表現、αν/33整合素或αν/35整合素等亞型之選擇性表現、多重αν整合素亞型之表現或3整合素 15 與αν/? 5整合素等亞型同時表現。檢測αν整合素或其亞型之表現量是否不適當或異常，可利用此項技藝中悉知之程序予以測定。經濟部智慧財產局員工消費合作社印製本發明之另一態樣包含對有其需要的病患治療或改善由選擇性αν/33整合素傳介的疾病之方法，該方法包括 20 投與該病患治療有效量之式（I)化合物或其組成物。本發明之另一態樣包含對有其需要的病患治療或改善由選擇性αν/35整合素傳介的疾病之方法，該方法包括投與該病患治療有效量之式（I)化合物或其組成物。本發明之另一態樣包含對有其需要的病患治療或改善 -54- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） A7 200536844 五、發明說明（53) 由整合素同時傳介的疾病之方法，該方法包括投與該病患治療有效量之式⑴化合物或其組成物。 / =明樣包含抑制由αν整合素傳介的贅瘤活二=與費瘤或該贅瘤周圍的小環境有效量之式（1)化合物或其組成物。「==」—詞係指紊亂或未調控之細胞增生及支樓該贅瘤肩圍内皮小環境中螫^ 管分怖形成。 d之“之血管新生程序或新血 θ係彳0腫瘤細胞’其為由於基目不穩定或突變具調控之增生之細胞，及其内皮細胞由於疾病狀亂或未調控之增生之内皮。於本發 ==需要表現”合素或其亞型，並未限定原發性腫2源，亦包含由原發性腫瘤轉移發生之續發 =至贅二=瘤」一詞係指投與本式(1)化合物或其 == 贅瘤細胞表面或至贅瘤周圍之内皮「抑制由αν整合素傳介的贅瘤活性」一詞包含利用限制腫瘤之血管供應減弱其生長及，進—步地 20血管新生程序預防新的支律血管分佈之形成。J用防止整態樣包含治療或改善由病理性地表現-整口素或/、亞型之細胞所傳介的疾病之方法。「由病理性地表現αν整合素之細胞所傳介係指’惟不限於，選自癌症、與癌症相關的病變、糖尿病 200536844 Α7 Β7 五、發明說明（54 獅膜病變、黃斑病變、„減症、骨質耗損、炎性關即炎、風濕性關節炎或動脈再狹窄之疾病。、本發明之-態樣包含於有其需要之病患中使贊瘤持續退化之方法’該方法包括投與該病患有致量之式⑴化合物或其組成物；其巾槪合物或其組成物係拼合及遞送治療劑至贅錢至贅瘤之小環境；及，其巾該治_誘發細胞凋亡或減弱紊亂或未調控的細胞增生。 10 15 經濟部智慧財產局員工消費合作社印製 20 「拼合」及「遞送治療劑」等詞係指以熟習此項技藝人士已知之拼合方式使式⑴化合物或其組成物與治療劑結合；其中該化合物或其組成物係作為拮抗贅瘤或其小環境之αν整合素觉體之標的導向劑；及，其中該拼合方式促進及選擇性地遞送該治療劑至該贅瘤或其小環境。「治療劑」一詞包含惟不限於Technethim99，係指熟習此項技藝人士已知之造影劑（imaging agents)。本發明之一態樣包含使用式⑴化合物或其組成物與或夕種抗腫瘤或細胞增生療法（包括化學療法、韓射療法、基因療法與免疫療法）有利地共同投與，以預防、治療或改善由αν整合素傳介的疾病之方法。該組合療法可包含： 1. 共同投與式⑴化合物或其組成物及化學治療劑，以預防、治療或改善α ν整合素傳介的疾病； 2. 連續投與式（I)化合物或其組成物及化學治療劑，以預防、治療或改善α ν整合素傳介的疾病； 3·投與含式（I)化合物之組成物及化學治療劑，以預防、 -56· 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公复） 200536844 A7 _________________ B7 五、發明說明（55) 冶療或改善Q；V整合素傳介的疾病；或， 4·同時投與一含式⑴化合物之分隔組成物及一含化學治療劑之分隔組成物，以預防、治療或改善a v整合素傳介的疾病； 5 例如，本發明化合物可與至少一種其他化療劑一起用於組合療法以治療許多不同的癌症，並有利地出現有助於使用較少之建議用於特定癌症或細胞增生疾病之化療劑劑量。因此，一般認為本發明化合物可於治療療程中，在投與建議用於治療特定癌症的特定化療劑之前、投與該化療 10劑期間、或以該特定化療劑處理之後使用。化學治療劑」一詞包含，惟不限於，抗血管新生劑、抗腫瘤劑、胞毒劑、細胞增生抑制劑等。「治療或改善」一詞包含，惟不限於，促進惡性腫瘤之根除、抑制其進展或促使其停止生長。例如，具有抗血管新生劑作用之 15 本發明抑制劑化合物可於給藥療法中，與至少一種其他胞毒性化合物，例如DNA烧化劑，一起投與。經濟部智慧財產局員工消費合作社印製較4之抗腫瘤劑係選自下述組群：克拉追平 (dadribine)(2-氯-2，_去氧-(召）-D_腺苷）、瘤可寧 (Chl〇rambucil)(4-(雙（2、氯乙基）胺基）苯丁酸）、DTIC七〇me 20 (5-(j>，3-一曱基-1-三II稀基)-口米。坐-4·甲醯胺）、链化療劑及非鉑化療劑。含鉑之抗腫瘤劑包含，惟不限於，順氣胺鉑 (CDDP)(順式-二氣二胺鉑）。不含鉑之抗腫瘤劑包含，惟不限於’亞德里亞徽素[小紅莓（doxorubicin)]、胺美嗓呤、博來黴素(bleomycin)、喜樹鹼、洋紅黴素、康布達矣 -57- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200536844 A7 B7 五、發明說明（56) (combretastatin)、環填醢胺、阿拉伯糖胞苷、更生黴素、道諾黴素（daunomycin)、表阿黴素（epirubicin)、依托泊苷 (etoposide)(VP-16)、5-氟尿嘧咬（5FU)、贺癌平 (herceptin)、放線菌素-D、胺曱喋呤、絲裂黴素c、塔莫 5 西芬（tamoxifen)、紫杉醇、效癌易（taxotere)、嗟替口辰 (thiotepa)、長春新驗、長春花驗、溫謹平（vinorelbine)及其衍生物與前驅藥物。各抗腫瘤劑以治療有效量投與，此劑量根據所用製劑、欲治療或改善之惡性腫瘤種類及其他狀況而異。 10 如熟習此項技藝人士所瞭解，化療劑之適當劑量通常經濟部智慧財產局員Η消費合作、社印製大約為單獨投與或與其他化療劑組合投與時已於臨床療法中使用之劑量。僅供例示，例如順氣胺鉑與其他DNA烧化劑等製劑，均廣泛地用於治療癌症。於臨床應用所用順氯胺鉑之有效劑量每隔三週5天為20毫克/平方米，共計 15 三個療程。順氯胺鉑不能經口吸收，必須經由靜脈内、皮下、腫瘤内或腹膜内注射遞送。進一步有用的製劑包含干擾DNA複製、細胞有絲分裂及染色體分離之化合物。此等化療劑包含亞德里亞黴素（亦為所謂小紅莓）、依托泊苷、異博停(verapamil)或鬼臼素等，於腫瘤治療臨床環境 20中廣泛使用。彼等化合物係經由快速靜脈注射投與，所用劑量範圍（亞德里亞黴素）為每隔21天約25至約75毫克/ 平方米，或靜脈内投與(依托泊苷）約35至約50毫克/平方米，或經口投與雙倍靜脈内劑量。瓦解多核苷酸前體合成及精確性(fidelity)之製劑例如5-氟尿嘧啶(5-Fu)被優先使 -58-200536844 Α7 Β7 5. Description of the invention (52) or unregulated hyperplasia. The term "osteoporosis" means, but is not limited to, bone loss due to the formation or activity of bone cells of the surname. The term "arterial restenosis" means, but is not limited to, stenosis of a vascular stent and restenosis of a vascular graft artery. 5 The term "av integrin expression" means: 1. Via cells that normally do not express αν integrin or its subtypes; 2. Via cancer cells; 3. Response to growth factors, tissue hypoxia, neoplasia, or disease processes; 4. The results of mutations that cause the constitutive expression of αν integrin or its isoforms; 10 The expression of αν integrin or its isoforms that cause disordered or unregulated cell proliferation. The expression of αν integrin or its subtype includes the selective expression of αν integrin or its subtype, the selective expression of αν / 33 integrin or αν / 35 integrin, the performance of multiple αν integrin subtypes, or 3 integrin 15 and αν /? 5 integrin and other isoforms. The detection of the expression of αν integrin or its isoforms is inappropriate or abnormal, and can be determined using procedures known in the art. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, another aspect of the present invention includes a method for treating or ameliorating a disease mediated by selective αν / 33 integrin for a patient in need thereof, the method comprising A therapeutically effective amount of a compound of formula (I) or a composition thereof in a patient. Another aspect of the invention comprises a method for treating or ameliorating a disease mediated by selective αν / 35 integrin in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) Or a composition thereof. Another aspect of the present invention includes the treatment or improvement of patients with their needs. -54- This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) A7 200536844 V. Description of the invention (53) by integrin A method for simultaneous transmission of a disease comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a composition thereof. / = Bright sample contains inhibitory activity of neoplasms mediated by αν integrin. Second = An effective amount of a compound of formula (1) or a composition thereof is associated with a tumor or a small environment surrounding the neoplasm. "==" — The word refers to the formation of disordered or unregulated cell proliferation and branching in the microenvironment of the shoulder endothelium. d "The angiogenesis procedure or new blood θ system 彳 0 tumor cells' are cells with regulated proliferation due to unstable or mutated bases, and endothelial cells with proliferated endothelial cells due to disorder or unregulated disease. The present == required to express "combinin or its subtype, does not limit the source of primary edema, but also includes the recurrence of primary tumor metastasis = to two = tumor" means the administration of this The compound of formula (1) or its == the surface of the neoplastic cells or the endothelium around the neoplasms. The term "inhibiting the neoplastic activity mediated by αν integrin" includes reducing the growth of tumors by limiting their vascular supply and, further— Di 20 angiogenesis procedures prevent the formation of new branching blood vessels. The method of preventing morphology involves treating or ameliorating a disease mediated by cells that pathologically express-osteoblasts or / and subtypes. "Mediated by cells that pathologically express αν integrin means' but not limited to, selected from cancer, cancer-related lesions, diabetes 200536844 Α7 Β7 5. Description of the invention (54 Lion's disease, macular disease, Disease, bone wasting, inflammatory disease, rheumatoid arthritis, or arterial restenosis.-The aspect of the present invention includes a method for continuously deteriorating the tumor in a patient in need thereof. The method includes investing The amount of the compound of formula (I) or a composition thereof is related to the patient; the compound or composition thereof is assembling and delivering a therapeutic agent to the small environment of the extraneous tumor; and Disturbance or reduction of disordered or unregulated cell proliferation. 10 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 The words "splicing" and "delivering therapeutic agents" refer to the use of splicing methods known to those skilled in the art. A compound or a composition thereof is combined with a therapeutic agent; wherein the compound or a composition thereof serves as a guide for antagonizing a neoplasm or a small environment of the αν integrin sensor; and, wherein the combination method promotes The therapeutic agent is selectively delivered to the neoplasm or its microenvironment. The term "therapeutic agent" includes, but is not limited to, Technethim99 and refers to imaging agents known to those skilled in the art. One aspect of the present invention Containing the beneficial use of a compound of formula (I) or a composition thereof together with an anti-tumor or cytoproliferative therapy (including chemotherapy, Korean radiotherapy, gene therapy, and immunotherapy) to prevent, treat, or improve αν integrin A method for transmitting disease. The combination therapy may include: 1. co-administration of a compound of formula (I) or a composition thereof and a chemotherapeutic agent to prevent, treat or ameliorate α ν integrin-mediated disease; 2. continuous administration Compound of formula (I) or its composition and chemotherapeutic agent to prevent, treat or ameliorate α ν integrin-mediated diseases; 3. administer composition and chemotherapeutic agent containing compound of formula (I) to prevent, -56 · This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public reply) 200536844 A7 _________________ B7 V. Description of the invention (55) Healing or improving Q; V integrin-mediated diseases Or, 4. A partition composition containing a compound of formula (I) and a partition composition containing a chemotherapeutic agent are simultaneously administered to prevent, treat, or ameliorate av integrin-mediated diseases; 5 For example, the compound of the present invention may be administered with At least one other chemotherapeutic agent is used together in combination therapy to treat many different cancers, and advantageously appears to facilitate the use of fewer chemotherapeutic agent doses recommended for specific cancers or cell proliferative diseases. Therefore, the compounds of the present invention are generally considered to be useful The term "chemotherapeutic agent" is used, but not limited to, during the course of treatment, before the administration of a specific chemotherapeutic agent recommended for the treatment of a specific cancer, during the administration of 10 doses of the chemotherapy, or after treatment with the specific chemotherapeutic agent. Anti-angiogenesis agents, anti-tumor agents, cytotoxic agents, inhibitors of cell proliferation, and the like. The term "treatment or improvement" includes, but is not limited to, promoting the eradication of malignant tumors, inhibiting their progress, or stopping them from growing. For example, an inhibitor compound of the present invention having an antiangiogenic effect can be administered in a drug therapy together with at least one other cytotoxic compound, such as a DNA burner. The antitumor agent printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs compared with 4 was selected from the following group: dadribine (2-chloro-2, _deoxy- (zhao) -D_adenosine) Chlorambucil (4- (bis (2, chloroethyl) amino) phenylbutyric acid), DTIC heme 20 (5- (j >, 3-monofluorenyl-1-tris II dilute base)-mouth rice. Sit-4 · methamidine), chain chemotherapy agents and non-platinum chemotherapy agents. Platinum-containing antineoplastic agents include, but are not limited to, cisplatin (CDDP) (cis-digas diamine platinum). Platinum-free antineoplastic agents include, but are not limited to, 'adriahuimin [doxorubicin], amine methoxine, bleomycin, camptothecin, erythromycin, and comb Tat-57- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200536844 A7 B7 V. Description of the invention (56) (combretastatin), cyclopentamine, arabinosyl cytidine, and mold Daunomycin, daunomycin, epirubicin, etoposide (VP-16), 5-fluorouracil bite (5FU), herceptin, actinomycin -D, Aminopterin, Mitomycin c, Tamoxifen, Paclitaxel, Taxotere, thiotepa, Changchun New Test, Changchun Flower Test, Wen Jinping ( vinorelbine) and its derivatives and prodrugs. Each antineoplastic agent is administered in a therapeutically effective amount, which amount varies depending on the preparation used, the type of malignant tumor to be treated or improved, and other conditions. 10 As the person skilled in the art understands, the appropriate dose of chemotherapeutic agent is usually a member of the Intellectual Property Bureau of the Ministry of Economic Affairs, consumer cooperation, and society. It is printed about the dose that has been used in clinical therapy when administered alone or in combination with other chemotherapeutic agents. . For illustration only, preparations such as cisplatin and other DNA burners are widely used in the treatment of cancer. The effective dose of cisplatin used in clinical applications is 20 mg / m 2 every three weeks and 5 days, for a total of 15 three courses. Cisplatin cannot be absorbed orally and must be delivered by intravenous, subcutaneous, intratumoral or intraperitoneal injection. Further useful formulations include compounds that interfere with DNA replication, cell mitosis, and chromosome segregation. These chemotherapeutics include adriamycin (also known as cranberry), etoposide, verapamil, or podophyllotoxin, etc., and are widely used in clinical settings for tumor treatment20. Their compounds are administered via rapid intravenous injection at a dose range (adriamycin) of about 25 to about 75 mg / m2 every 21 days, or intravenously (etoposide) of about 35 to about 50 mg / m², or double intravenous dose. Preparations that disintegrate polynucleotide precursor synthesis and fidelity such as 5-fluorouracil (5-Fu) are preferentially used -58-

200536844 A7 B7 五、發明說明（57) 用，以導向腫瘤細胞。5-FU雖然相當毒，惟常以約3至約丨5毫·克/公斤之日劑量經由靜脈内投與。本發明之另一態樣包含組合輻射療法投與本發明化合物之方法。本文所用之「輻射療法」係指將有其需要的病 5患曝路於輻射之療法。此等療法為熟習此項技藝人士所已 ^輻射/σ療之適▲療程與已於早獨使用轄射療法或與其他化療法併用之臨床療法中使用者類似。本發明之一態樣包含組合基因療法投與本發明化合物或使用本發明化合物作為基因治療工具之方法。「基因療 10法」一詞係指標的導向腫瘤形成期間之血管新生内皮細胞或腫瘤組織之療法。基因治療策略包含有缺陷的癌症抑制基因之重建、使用反義股DNA (對應於編碼生長因子及其受體的基因）之細胞轉導或轉染及使用r自殺基因」。「基因治療工具」一詞係指使用偶聯於αν導向配位體之 15 陽離子奈米顆粒組合構成之標的導向載體影響血管生物學；藉以將基因選擇性地遞送至新生之血管（如H〇〇d，J.D. et al.? Tumor Regression by Targeted Gene Delivery to the 經濟部智慧財產局員工消費合作社印製200536844 A7 B7 V. Description of the invention (57) It is used to target tumor cells. Although 5-FU is quite toxic, it is usually administered intravenously at a daily dose of about 3 to about 5 mg / kg. Another aspect of the invention includes a method of administering a combination of radiation therapy to a compound of the invention. As used herein, "radiation therapy" refers to the treatment of exposing patients with their needs to radiation. These therapies are suitable for those skilled in the art. The treatment course is similar to the users in clinical therapies who have used radiotherapy alone or in combination with other therapies. One aspect of the present invention includes methods of administering a compound of the present invention in combination gene therapy or using the compound of the present invention as a gene therapy tool. The term "gene therapy 10" refers to the therapy that targets angiogenic endothelial cells or tumor tissues during tumor formation. Gene therapy strategies include the reconstruction of defective cancer suppressor genes, cell transduction or transfection using antisense DNA (corresponding to genes encoding growth factors and their receptors), and the use of r suicide genes. " The term "gene therapy tool" refers to the use of a targeting vector consisting of a combination of 15 cationic nanoparticle coupled to αν targeting ligands to influence vascular biology; thereby selectively delivering genes to new blood vessels (such as H. 〇d, printed by JD et al.? Tumor Regression by Targeted Gene Delivery to the Intellectual Property Bureau, Ministry of Economic Affairs, Consumer Consumption Cooperative

Neovasculature，2002, 28 June，296, 2404-2407 所述）。 20 本發明之另一態樣包含對有其需要的病患治療或改善由αν整合素傳介的贅瘤之方法，該方法包括投與該病患有效量之含有式（I)化合物或其組成物及基因治療劑之基因治組合產物；其中該產物係藉拮抗該贅瘤或其小環境之 αν整合素受體被遞送或直接「接種」於贅瘤或其小環 -59- 本紙張尺度適用中國國家標準(CNS)A4規格（21〇 χ 297公复） 200536844 A7Neovasculature, described in 2002, 28 June, 296, 2404-2407). 20 Another aspect of the invention comprises a method for treating or ameliorating a neoplasm mediated by αν integrin in a patient in need thereof, which method comprises administering to the patient an effective amount of a compound containing formula (I) or a compound thereof Composition and gene therapy combination gene therapy product; wherein the product is delivered or "vaccinated" directly to the neoplasm or its small ring by an αν integrin receptor that antagonizes the neoplasm or its microenvironment -59- Standards are applicable to China National Standard (CNS) A4 (21〇χ 297 public reply) 200536844 A7

五、發明說明（5δ) 被遞送或直接接種”於贅瘤」一詞包含使用式⑴ 化合物或其組成物作為基因治療方式，其中該化合物或其組^物具有引導拼合體至其意指作用部位（亦即，至資瘤 5血管内皮細胞或至腫瘤細胞）之標的導向劑之功能。由於作為;^的導向劑的αν整合素抑制劑及其對應❹整合素又體ΙΜ立之專性相互作用，本發明化合物可於標的導向之αν整合素受體處或其附近以極高之局部濃度投與，因而更有效地治療由αν整合素傳介之疾病。 10 I發明之另一態樣包含組合免疫療法而投與本發明化合物之方法。本文所用之「免疫療法」係指經由對特定蛋白質具專一性之抗體，標的導向涉及腫瘤形成之該等蛋白質之療法。列如，於癌症治療中—直使用之對抗血管内皮生長因子之單株抗體。 15 本發明之一態樣包含對有其需要的病患進行腫瘤造影之方法、，該方法包括有利地共同投與該病患有效量之式(1) 化合物或其組成物；其中該化合物或其組成物係拼合或遞經濟部智慧財產局員工消費合作社印製送非侵入性之腫瘤造影劑至腫瘤或至腫瘤周圍之小環境。「拼合」及「遞送非侵入性之腫瘤造影劑」等詞係指 20利用熟習此項技藝人士已知之拼合方式結合於造影劑之式 (I)化合物或其组成物；其中該化合物或其組成物具有標的導向劑之作用，以拮抗贅瘤或其小環境之αν整合素受體；及，其中該拼合方式促進及選擇性地遞送該造影劑至該贅瘤或其小環境（見述於PCT Application -60- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200536844 A7 B7 五、發明說明（59) WOOO/35887 、 W〇〇〇/35492 、 WOOO/35488 或 W099/58162)。「造影劑」>—詞包含惟不限於丁echnetium99，係指熟習此項技藝人士已知之造影劑。「拼合方式」一詞包含惟不限於將化合物附加於連接基， 5隨後與造影劑螯合基拼合，係指熟習此項技藝人士已知之方式。冠狀動脈血管擴張術乃用於減少冠狀動脈阻塞嚴重性之高度有效程序；然而，其長期成功受限於高比率之動脈再狹窄。血管擴張術後動脈再狹窄的原因主要為血管平滑 10肌細胞活化、遷移與增生（R〇ss，R，Λ％ 1991, 3(52, 801-809)。本發明之一態樣為使用具式(I)之αν整合素抑制劑化合物或其組成物治療或改善動脈及靜脈再狹窄之方法；其中該化合物係充滿治療裝置表面。「治療裝置」一詞係 15指，惟不限於，血管擴張術氣球、動脈支架、靜脈支架、缝線、人工關節、楂入之義體或其他類似醫用裝置，因而引導樂物遞送至贊瘤。經濟部智慧財產局員工消費合作社印製本發明之一態樣包含一種組成物，其包括式（I)化合物、或其醫藥上可接受之鹽、以及醫藥上可接受之載劑。 20 隸屬本發明範圍内之組成物可根據習知製藥技術予以製備。醫藥上可接受之載劑亦可（惟不必然）於本發明組成物中使用。「醫藥上可接受」一詞係指適當地投與動物或人類時’不產生不利、過敏或其他不適反應之分子實體及組成 -61· —本紙張尺度適用中國國297公 --- 200536844 A7 B7 五、發明說明（6〇 5 10 15 經濟部智慧財產局員工消費合作社印製 20 物。獸醫用途同樣涵蓋於本發明範圍之内，晉藥上可接受」之調配物包含臨床及/或獸醫用途之調配物一者視投與[包含，惟不限於，靜脈内（推注及輪注二者）、經口、鼻、經皮、閉合或不閉合之局部投與1及= 膜内、皮下、肌内、腫瘤内或非經腸注射]所需製劑形式而定，組成物可採廣範圍之多種形式，所有使用形式均= 熟習醫藥技藝人士所悉知。組成物可包括例如錠劑、劑、膠囊、粉劑、顆粒、無菌非經腸溶液或懸浮液、叶量氣溶膠或液體噴霧劑、滴劑 '安瓿、自動注射裝置或栓劑等劑量單位；供經口、非經腸、經鼻内、舌下或直腸投與，或利用吸入或吹氣投與。適用於經口投與之組成物包含固體形式例如丸劑、錠劑、橢圓形、膠囊（各包括立即釋放、控制時間釋放及持續釋放型調配物）、粒劑與粉劑；及液體形式例如溶液、糖漿、酏劑、乳液及懸浮液。用於非經腸投與的形式包含無菌溶液、乳液及懸浮液。或者，組成物可呈適用於每週一次或每月一次投與之形式；例如，可使用活性化合物之不溶性鹽（例如癸酸鹽）來提供供肌内注射用之補給製劑。於製備經口劑量型時，可使用一或多種一般醫藥載劑，包括必需及惰性醫藥賦形劑，例如水、二醇類、油、醇、調味劑、防腐劑、著色劑、糖漿等；經口液體製劑情形下，可使用例如澱粉、糖類、稀釋劑、粒化劑、潤滑劑、黏合劑、崩解劑等載劑。含本文醫藥組成物之劑量單位（錠劑、膠囊、粉劑、注射劑、栓劑、量過之液體劑量）所含活性成分之量必須 -62- 本紙張尺度適用中國國家標準(CNS)A4規格（21〇χ297公釐） 200536844 Λ7 Β7 ——_________ 五、發明說明（6i) 足以遞送如上述之治療有效量。該组成物可含約〇〇〇1毫克至約·5000毫克活性化合物或其前驅藥物，及可構成適用於有需要的病患所選擇投與方式之任何形式。本發明之一態樣慮及使用每天約〇〇〇1毫克至1〇〇〇 5毫克/公斤體重範圍内之治療有致量；另—態樣包含每天約0.001至約500毫克/公斤體重之範圍；進一步態樣包含每天約0,，至約毫克/公斤體重之範圍。ς合物可根據每天約1至約5次，又更佳每天J、2或3次之劑量療法投與。 10 經口投與時，所提供之組成物較好呈含有0.01、〇·〇5 、 0·1 、 0.5 、 1.0 、 2.5 、 5.0 、 1〇.〇、 ΐ5·〇、 25.0 、 50.0、100、150、200、250及500毫克活性成分之錠劑形式，以對欲治療的病患進行劑量之症狀調整。所投與之最適劑罝易於由熟習此項技藝人士決定，且隨所治療特定 15病患相關的因素（年齡、重量、飲食及投與時間）、所治療狀況之嚴重性、所用化合物、投與模式及製劑強度而異。每天投表或定期後給藥（post-perioic dosing)均可。經濟部智慧財產局員工消費合作社印製於製備固體組成物例如錠劑時，使主要活性成分與醫藥載劑（例如習知製錠成分如玉米粉、乳糖、蔗糖、山 20 梨糖醇、滑石粉、硬脂酸、硬脂酸鎂、磷酸二鈣或樹膠）及其他醫藥稀釋劑（例如水）混合，形成含有本發明化合物或其醫藥上可接受之鹽的均質混合物之固體預配製組成物。此處指稱之呈均質狀之預配製組成物意指活性成分平均地分散於整個組成物，使該組成物易於細分為均等有效 -63- 本紙張尺度適用中國國家標準(CNS)A4規格（21〇 χ 297公釐） 200536844 B7 五 5 5 1Χ 經濟部智慧財產局員工消費合作社印製 20 發明說明（62) 之劑量形式，例如錠劑、丸劑及膠囊。再將此固體預配製組成物細分為含有0.001至約5000毫克本發明活性成分之上述種類單位劑量形式。含組成物之錠劑或丸劑可予以被覆或經摻和處理以提供具有長時作用優點之劑量形式。例如，錠劑或丸劑可由内劑及外劑成分組成，後者呈包覆於前者之形式。此二成分可利用腸衣層分隔開來，該腸衣層係用以於胃中抵抗崩解，容許内成分完整地通過十二指腸，或延缓釋放。多種材料可作為該等腸衣層或被覆層用，此等材料包括具有例如蟲膠、乙醯醇及纖維素乙酸酯等材質的許多聚合物酸。呈錠劑或膠囊形式供經口投與時，活性藥物成分可視需要組合經口、無毒之醫藥上可接受之惰性載劑例如乙醇、甘油、水等。此外，於希望或需要時，亦可於混合物中併入適當黏合劑、潤滑劑、崩解劑及著色劑。適當黏合劑包含，惟不限於，澱粉、明膠、天然糖類例如葡萄糖或 yS -乳糖、玉米增甜劑、天然及合成樹膠例如阿拉伯膠、黃耆膠或油酸鈉、硬脂酸鈉、硬脂酸鎂、苯甲酸鈉、乙酸鈉、氯化鈉等。崩解劑包含，惟不限於，澱粉、甲基纖維素、洋菜、膨潤土、黃原膠等。可併入式（I)化合物供經口或注射投與之液體形式包含水性溶液、適當調味的糖漿、水性或油性懸浮液、和以食用油例如棉軒油、芝麻油、椰子油或花生油調味的乳液，以及酏劑和類似之醫藥賦形劑。用於水性懸浮液之適當分散劑或懸浮劑包括合成及天然樹膠，例如黃耆膠、阿 -64- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） •200536844 A7 五、發明說明拉伯膠、治^ 素、聚乙、澡酸鹽、葡聚糖、緩甲基纖維素納、甲基纖維散劑基鱗相或明膠。呈適當調味的懸浮劑或分阿拉伯膠形式亦可包含合成及天然樹膠，例如黃耆膠、及溶液為二”維素等。供非經腸投與時，無菌懸浮液防腐劑之^^要靜脈内投與時，係使用通常含有適當活性成技藝中亦已知’化合物可替代地經由注射由與。、、主刀’各於惰性液體載劑中組成之調配物而非經腸投 10 15 經濟部智慧財產局員工消費合作社印製 20 成分庄射用調配物可包含與適當惰性液體載劑混合之活性、# Π接乂之液體載劑包含植物油例如花生油、棉籽 /由、之麻 ^ 寻’以及有機溶劑例如可溶縮酮、甘油等。亦 ^欠眭非經腸調配物作為替代品。例如，可接受之水性命剤=含水、林格氏溶液及等張水性食鹽溶液。進一步、通吊可使用無菌不揮發油，於水性調配物中作為溶劑或W浮刮之用。彼等調配物之製備可將活性成分溶解或懸浮於液體載劑中，俾使最終調配物含有〇⑻$至1〇重量 /〇之活性成分。其他添加劑包括防腐劑、等張劑、增溶劑、安定劑及鎮痛劑可適當使用。式（I)化合物可有利地呈單一曰劑量投與，或可將總曰劑量分為每天二、三或四次投與。進一步地，本發明化合物可呈經鼻内形式，經由局部使用適當鼻内賦形劑投與’或經由經皮途徑，使用熟習此項技藝人士悉知之皮膚貼片形式投與。欲呈經皮遞送系形式投與時，當然，整個療程中’所投與劑量為連續性而非間歇性。 -65- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） .200536844 Λ7 B7 五、發明說明（Μ 10 15 經濟部智慧財產局員工消費合作社印製 20 〜、π刃议興，因此代表敢有利之經·ί 里單触式’其中係使用固體醫藥載劑。如果需要，在 d可利用;^準技術被覆糖或腸衣。供非經腸投與時，載窄 =常由無菌水組成，惟亦可包含其他成分，以達例如增；i A解1±或防腐之目#。也可製備注射用懸浮液，此情子下’可使用適當液體載劑、懸浮劑等。本發明組成物亦包含供緩慢釋放本發明化合物之g 成物。此組成物包^ ^ ^釋载劑（典型地，聚合物載劑）及, 中。然彳4溶職分胁有機溶1 葡液。至水性毅巾，獲得水包油; ^，、該水性溶液中含有界面活性劑。接著，p ==，中之有機溶劑，獲得含有緩釋娜; 發明化合物的顆粒之膠態 < 怦則一此項技藝所悉知，1為；开:緩釋性生物降解載劑^ 如，水性、紐、驗性粒且於適當環境叩顆粒將活性化合物抓人1中=降解/溶解之材質’該3 釋出其中之活性化液中降解/溶解即，直徑在約1至_ I 較佳為奈米顆粒0 2。。奈米，最佳為直徑約以『内，較佳為約… 本發明亦提供本發明醫藥性成分之式⑴化合物根據習知醫藥摻=將作以密切摻和’該載劑視投與所與製樂栽I 之多種形式。於製備經1量形式^ =時可採廣編劑 -66· 200536844 A7 B7 五、發明說明（65 ) 何慣常製藥介質。用於固體經口劑量形式時，適當的載劑及添加劑包含澱粉、糖類、稀释劑、粒化劑、潤滑劑、黏合劑、崩解劑等。用於液體經口製劑時，適當的載劑及添加劑包含水、二醇類、油、醇、調味劑、防腐劑、著色劑 5等。此外’含活性藥物成分之液體形式可合併於經適當調味之懸洋劑或分散劑例如合成及天然樹膠，包括例如黃耆膠、阿拉伯膠、曱基纖維素等中。可使用之其他分散劑包括甘油等。經濟部智慧財產局員工消費合作社印製抗體標的導向劑包含與腫瘤細胞、腫瘤血管分佈或 10腫瘤基質之可標的導向成分或易接近成分結合之抗體或其抗原結合片段。腫瘤細胞、腫瘤血管分佈或腫瘤基質之「可標的導向成分或易接近成分」較好為表面_表現、表面-易接近或表面-局部化之成分。抗體標的導向劑亦包含與自壞死腫瘤細胞釋出之細胞内成分結合之抗體或其抗原 15結合片段。此等抗體較佳為與存在細胞中可被誘發成為具滲透性或存在含有實質上全部贅瘤及正常細胞之形骸細胞中，惟不存在或接近哺乳動物正常活細胞外部之不溶性細胞内抗原結合之單株抗體、或其抗原結合片段。本文所用之「抗體」一詞廣泛地意指任何免疫學結 20合劑例如IgG、IgM、IgA、IgE、F(ab，)2，單價片段例如 Fab、Fab、Dab，以及建造抗體例如重組抗體、人類化抗體、雙抗原特異性抗體等。抗體可為多株或單株抗體，惟以單株抗體較佳。有極寬廣陣列之抗體於此項技藝中已知對差不多任何實體腫瘤類型之細胞表面均具有免疫學特異 -67- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公复了 200536844 A7 _ B7 五、發明說明（66 10 性(參見T_e等之美國專利案5,855,866中，實體的單株抗紅概要表）。製造及單_抗腫瘤的標的劑抗體之方法為熟習此項技藝人士所已知（美國: 5,855,866 (Th〇rpe);及美國專利案 6 342 2i9(Th。了非抗體標的導向劑包含專—地與膣瘤血管分佈“ 之生長因子及其他標的導向成分例如附件素(咖exm)^ 關之配位體。此外，多種其他有機分子亦可作為腫瘤的導向劑用’其實例為專-地辨識結合玻尿糖的蛋白^ (-種於Μ細胞及内皮細胞遷移期間及似毛細管的小管形成期間表現之細胞表面蛋白質）之玻展糖寡聽（美國專二案5,902,795 (Toole等）），及聚陰離子性化合物，特別是聚硫酸化或聚磺酸化化合物例如N—及〇_硫酸化聚陰離= 性多醣、聚苯乙烯磺酸酯及其他聚陰離子性化合物（見述於美國專利案5,762,918 (Thorpe))，彼等選擇性地與血管 15 内皮細胞結合。經濟部智慧財產局員工消費合作社印製 20 使治療劑基團與抗體拼合的技術已悉知[Amon et al.， Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy, Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.)5 pp. 243-56 (Alan R. Liss, Inc. 1985) ； Hellstrom et al.? Antibodies For Drug Delivery, Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.)5 pp. 623-53 (Marcel Dekker, Inc. 1987) ； Thorpe, Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review,V. Description of the invention (5δ) The term "on neoplasm" is delivered or directly inoculated, which includes the use of a compound of formula 或其 or a composition thereof as a gene therapy method, wherein the compound or a combination thereof has the function of guiding the complex to its intended effect. The function of the target guide at the site (ie, to the tumor 5 vascular endothelial cells or to tumor cells). Due to the specific interaction of αν integrin inhibitor and its corresponding ❹ integrin as the directing agent of ^, the compounds of the present invention can be extremely high at or near the target-oriented αν integrin receptor. Local concentration administration makes it more effective to treat diseases mediated by αν integrin. Another aspect of the invention includes a method of administering a compound of the invention in combination with immunotherapy. As used herein, "immunotherapy" refers to therapies that target specific proteins by targeting antibodies that involve tumor formation. Listed in cancer treatment-monoclonal antibodies against vascular endothelial growth factor. 15 An aspect of the present invention includes a method of performing tumor angiography on a patient in need thereof, the method comprising advantageously co-administering an effective amount of a compound of the formula (1) or a composition thereof; wherein the compound or Its composition is assembled or delivered to the consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs to print and send non-invasive tumor contrast agents to the tumor or to the surrounding environment of the tumor. The terms "splicing" and "delivering a non-invasive tumor contrast agent" refer to a compound of formula (I) or a composition thereof combined with a contrast agent using a splicing method known to those skilled in the art; wherein the compound or its composition The target has the function of a target guide agent to antagonize the αν integrin receptor of the neoplasm or its microenvironment; and wherein the combination mode promotes and selectively delivers the contrast agent to the neoplasm or its microenvironment (see described in PCT Application -60- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 200536844 A7 B7 V. Description of the invention (59) WOOO / 35887, WOO〇 / 35492, WOOO / 35488 or W099 / 58162). "Contrast agent"-the term includes, but is not limited to, echnetium99, and means a contrast agent known to those skilled in the art. The term "splicing method" includes, but is not limited to, attaching a compound to a linker group, 5 and subsequent conjugation with a contrast agent chelating group, and means a method known to those skilled in the art. Coronary vasodilation is a highly effective procedure for reducing the severity of coronary occlusion; however, its long-term success is limited by a high rate of arterial restenosis. Arterial restenosis after vasodilation is mainly caused by the activation, migration, and proliferation of vascular smooth muscle cells (Ross, R, Λ% 1991, 3 (52, 801-809). One aspect of the present invention is the use of Method for treating or improving arterial and venous restenosis by an αν integrin inhibitor compound of formula (I) or a composition thereof; wherein the compound fills the surface of a therapeutic device. The term "therapeutic device" refers to 15 but is not limited to blood vessels Dilation balloons, arterial stents, venous stents, sutures, artificial joints, prostheses inserted into the hawk, or other similar medical devices, thus directing the delivery of the animals to Zanoma. The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed this One aspect comprises a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 20 Compositions falling within the scope of the present invention can be administered according to conventional pharmaceutical techniques. Preparation. A pharmaceutically acceptable carrier can also (but not necessarily) be used in the composition of the present invention. The term "pharmaceutically acceptable" means that it is 'not harmful' when properly administered to an animal or human 、 Allergic or other uncomfortable molecular entities and composition-61 · —This paper size applies to China 297 --- 200536844 A7 B7 V. Description of the invention (6055 10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Veterinary use is also encompassed within the scope of the present invention, and formulations that are "acceptable in Jin medicine" include formulations for clinical and / or veterinary use. One of these is administered visually [including, but not limited to, intravenous (bolus and Rotational injection of both), oral, nasal, transdermal, closed or non-closed local administration 1 and = intramembranous, subcutaneous, intramuscular, intratumoral or parenteral injection] depending on the form of preparation required, composition Can take a wide variety of forms, all forms of use are known to those skilled in medicine. Compositions can include, for example, lozenges, tablets, capsules, powders, granules, sterile parenteral solutions or suspensions, leaf aerosols Or liquid sprays, drops' ampoules, automatic injection devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or by inhalation or blowing. Applicable to Oral administration Contains solid forms such as pills, lozenges, ovals, capsules (each including immediate-release, time-release, and sustained-release formulations), granules, and powders; and liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions The forms for parenteral administration include sterile solutions, emulsions, and suspensions. Alternatively, the composition can be in a form suitable for administration once a week or once a month; for example, insoluble salts of the active compound ( (Such as decanoate) to provide supplements for intramuscular injection. In the preparation of oral dosage forms, one or more general pharmaceutical carriers, including essential and inert pharmaceutical excipients, such as water, glycols, Oils, alcohols, flavoring agents, preservatives, colorants, syrups, etc .; In the case of oral liquid preparations, carriers such as starch, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. can be used. The dosage unit containing the pharmaceutical composition of this article (tablets, capsules, powders, injections, suppositories, measured liquid doses) must contain the amount of active ingredients -62- This paper size applies to China National Standard (CNS) A4 specifications (21 〇χ297mm) 200536844 Λ7 B7 ——_________ 5. Description of the invention (6i) is sufficient to deliver a therapeutically effective amount as described above. The composition may contain from about 0.001 milligrams to about 5000 milligrams of the active compound or its prodrug, and may constitute any form suitable for the mode of administration selected for patients in need. One aspect of the present invention takes into account the use of a therapeutic amount in the range of about 0.001 mg to 1,000 mg / kg body weight per day; another aspect includes a range of about 0.001 to about 500 mg / kg body weight per day ; Further aspects include a range of about 0, to about mg / kg body weight per day. The compounds can be administered in doses of about 1 to about 5 times per day, and more preferably J, 2 or 3 times per day. 10 When administered orally, the composition provided preferably contains 0.01, 0.05, 0.5, 1.0, 2.5, 5.0, 10.0, ΐ5.0, 25.0, 50.0, 100, 150, 200, 250, and 500 mg of active ingredient in the form of lozenges to adjust the symptoms of the dose to the patient to be treated. The optimal dose to be administered is easily determined by those skilled in the art and depends on the factors (age, weight, diet, and time of administration) associated with the particular 15 patients being treated, the severity of the condition being treated, the compound used, Varies with model and formulation strength. Daily or post-perioic dosing is acceptable. The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs prints the main active ingredients and pharmaceutical carriers (such as corn flour, lactose, sucrose, sorbitol, talc, etc.) when preparing solid compositions such as lozenges. Powder, stearic acid, magnesium stearate, dicalcium phosphate or gum) and other pharmaceutical diluents (such as water) to form a solid pre-formulated composition containing a homogeneous mixture of a compound of the invention or a pharmaceutically acceptable salt thereof . The homogeneous pre-formulated composition referred to here means that the active ingredient is evenly dispersed throughout the composition, making the composition easy to subdivide into equal and effective -63- This paper size applies to China National Standard (CNS) A4 specifications (21 〇χ 297 mm) 200536844 B7 5 5 5 1 × Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Dosage forms of invention (62), such as tablets, pills and capsules. This solid pre-formulated composition is further subdivided into unit dosage forms of the above kind containing 0.001 to about 5000 mg of the active ingredient of the present invention. The composition-containing tablets or pills can be coated or blended to provide a dosage form having the advantage of prolonged action. For example, lozenges or pills may consist of internal and external ingredients, the latter in the form of coating the former. The two components can be separated by an enteric coating layer, which is used to resist disintegration in the stomach, allow the internal components to pass through the duodenum intact, or delay the release. A variety of materials can be used for such casings or coatings. These materials include many polymeric acids with materials such as shellac, acetol, and cellulose acetate. When it is administered orally in the form of a tablet or capsule, the active pharmaceutical ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc., as necessary. In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or yS-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth or sodium oleate, sodium stearate, stearin Magnesium acid, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Liquid forms which can incorporate compounds of formula (I) for oral or injection administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil. Emulsions, as well as elixirs and similar pharmaceutical excipients. Suitable dispersants or suspending agents for aqueous suspensions include synthetic and natural gums, such as tragacanth, A-64- This paper is sized to the Chinese National Standard (CNS) A4 (210x297 mm) • 200536844 A7 V. Invention Indicate labial, gelatin, polyethylene, bath salts, dextran, sodium methylcellulose, methylcellulose powder-based scale or gelatin. Suspensions or gum arabic in the form of appropriate flavors may also include synthetic and natural gums, such as tragacanth, and the solution is di "vitamin, etc. For parenteral administration, the requirements for sterile suspension preservatives ^^ For intravenous administration, formulations consisting of an inert liquid carrier instead of enteral administration, which are also known in the art as containing conventionally appropriate active compounds, can also be used instead of enteral administration. 10 15 Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Consumption Cooperatives. 20 Ingredients Formulations for shots may contain actives mixed with appropriate inert liquid carriers. # Π 乂乂 Liquid carriers include vegetable oils such as peanut oil, cottonseed / yue, hemp ^ Seek 'And organic solvents such as soluble ketals, glycerol, etc. Also ^ parenteral formulations as alternatives. For example, acceptable aqueous fate = aqueous, Ringer's solution and isotonic aqueous salt solution. Further, For suspension, sterile non-volatile oil can be used as a solvent in water-based formulations or as a floating scraper. The preparation of their formulations can dissolve or suspend the active ingredients in a liquid carrier to make the final The formulation contains the active ingredient in the range of 0 to 10 wt.%. Other additives include preservatives, isotonic agents, solubilizers, stabilizers, and analgesics. The compounds of formula (I) may be advantageously used in a single dosage. Administration, or the total daily dosage may be divided into two, three or four administrations per day. Further, the compounds of the present invention may be administered intranasally, via topical use of appropriate intranasal excipients, or via transdermal Route, using the skin patch form known to those skilled in the art. When it is administered in the form of a transdermal delivery system, of course, the dose administered throughout the course of treatment is continuous rather than intermittent. The paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm). 200536844 Λ7 B7 V. Description of the invention (M 10 15 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 ~, π is a blessing, so it stands to benefit The classic one-touch type which uses a solid pharmaceutical carrier. If necessary, it can be used at d; quasi-technical coating with sugar or casing. For parenteral administration, the narrow = often composed of sterile water, But can also include Other ingredients can be added, for example, i A solution 1 ± or antiseptic purpose #. Suspensions for injection can also be prepared, in which case appropriate liquid carriers, suspension agents, etc. can be used. The composition of the present invention also contains Slowly release the g of the compound of the present invention. This composition contains ^ ^ ^ release carrier (typically, polymer carrier) and, medium. Of course, 4 solvents and organic solvents 1 glucose solution. To water-based towel ^, The aqueous solution contains a surfactant. Then, p ==, the organic solvent in the, to obtain a sustained-release sodium; colloidal particles of the compound of the invention < It is known that 1 is; on: slow-release biodegradable carrier ^ such as water-soluble, biodegradable, test granules, and the active compound is captured by the granules in an appropriate environment 1 = degraded / dissolved material 'The 3 is released Among them, the degradation / dissolution in the activated solution, that is, the diameter is about 1 to -1, and the nano particles are preferably 02. . Nanometers, the best diameter is about "within, preferably about ... The present invention also provides the compound of formula (I) of the medicinal ingredient of the present invention. According to the conventional medicine, the compound is to be intimately mixed. And the various forms of music planting I. Can be used in the preparation of 1 quantity form ^ = -66 · 200536844 A7 B7 V. Description of the invention (65) What is the usual pharmaceutical medium. For use in solid oral dosage forms, suitable carriers and additives include starch, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. In the case of liquid oral preparations, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, colorants 5 and the like. In addition, the liquid form containing the active pharmaceutical ingredient may be incorporated in suitably flavored suspending or dispersing agents such as synthetic and natural gums, including, for example, tragacanth gum, acacia gum, amyl cellulose, and the like. Other dispersants that can be used include glycerin and the like. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. The antibody-targeted guides include antibodies or antigen-binding fragments thereof that bind to tumor cells, tumor blood vessels, or targetable or accessible components of the tumor matrix. The "targetable or accessible components" of tumor cells, tumor blood vessels, or tumor stroma are preferably surface-representative, surface-accessible or surface-localized components. The antibody-directed targeting agent also contains an antibody or antigen-binding fragment thereof that binds to an intracellular component released from a necrotic tumor cell. These antibodies are preferably bound to insoluble intracellular antigens present in cells that can be induced to be permeable or present in skeletal cells containing substantially all neoplasms and normal cells, but not in or near the outside of normal living cells in mammals Monoclonal antibodies, or antigen-binding fragments thereof. As used herein, the term "antibody" broadly means any immunological combination such as IgG, IgM, IgA, IgE, F (ab,) 2, monovalent fragments such as Fab, Fab, Dab, and constructing antibodies such as recombinant antibodies, Humanized antibodies, dual antigen-specific antibodies, etc. Antibodies can be multiple or single antibodies, but single antibodies are preferred. Antibodies with extremely wide arrays are known in the art to be immunologically specific to the cell surface of almost any solid tumor type -67- This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 published in 200536844 A7 _ B7 V. Description of the invention (66 10 (see the US Patent No. 5,855,866 by T_e et al., The entity's single anti-red summary table). The method of manufacturing and single-anti-tumor target agent antibody is already known to those skilled in the art (U.S .: 5,855,866 (Thorpe); and U.S. Patent No. 6 342 2i9 (Th. Non-antibody-targeted targeting agents include growth factors specific to terrestrial and tumor tumor distributions) and other target-oriented components such as accessory elements exm). Related ligands. In addition, a variety of other organic molecules can also be used as tumor guides. An example of this is to specifically identify proteins that bind to hyaluronic acid ^ (-during migration of M cells and endothelial cells and Glass-surface oligosaccharides (US patent 5,902,795 (Toole, etc.)), and polyanionic compounds, especially polysulfated or Acidified compounds such as N- and 0-sulfated polyanion = polysaccharides, polystyrene sulfonates, and other polyanionic compounds (see US Patent 5,762,918 (Thorpe)), which selectively interact with blood vessels 15 Endothelial cell binding. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics. 20 Technology for combining therapeutic groups with antibodies has been known [Amon et al., Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy, Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (Eds.) 5 pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al.? Antibodies For Drug Delivery, Controlled Drug Delivery (2nd Ed.), Robinson et al. (Eds .) 5 pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review,

Monoclonal Antibodies ’84: Biological And Clinical -68- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） A7 B7 200536844 五、發明說明（67 ) 却户/廳似，Pinchera et ai. (eds.)，ρρ· 475-506 (1985)]。同樣的技術亦可應用於使本發明化合物連接於非抗體標的導向劑。熟習此項技藝人士將知道，或能夠選擇，與非抗體標的導向劑（例如寡胜肽、多醣或其他聚陰離子性化合物） 5 形成拼合體之方法。雖然在血液中相當穩定的任何連接基團均可用於將本發明化合物連接於標標的導向劑，惟以可生物性地釋離之鍵結及/或可選擇性地裂解之隔距基或連接基較佳。「可生物性地釋離之鍵結」及「可選擇性地裂解之隔距基 10 或連接基」係指於循環中仍具合理之穩定性，惟僅或優先於特定條件（亦即，於特定環境中或與特定製劑接觸時）方可釋離、裂解或水解之連接基團。此等鍵結包含，例如，二硫鍵與三硫鍵及酸不穩定鍵（見述於美國專利案 5,474,765及5,762,918)，及酵素敏感性鍵結，包括胜肽鍵 15 結、S旨類、醯胺類、磷酸二酯類及糖苷類（見述於美國專利案5,4743765及5,762,918)。此等選擇性釋離設計之特徵為’也進化合物於意指標的導向位點自拼合體持續釋經濟部智慧財產局員工消費合作社印製離。與標的導向劑拼合的本發明化合物之治療有效劑量 20視個體、疾病種類、疾病狀態、投與方法及其他臨床變數而異。此等有效劑量易於使用得自動物模式之數據而決定。具有實體腫瘤之實驗動物常用來將適當治療劑量於轉化為臨床環境之前，予以最適化。此等模式於預測有效抗癌策略上已知非常可靠。例如，具有實體腫瘤的小鼠廣泛 -69-Monoclonal Antibodies '84: Biological And Clinical -68- The paper size applies to the Chinese National Standard (CNS) A4 (210x297 mm) A7 B7 200536844 V. Description of the invention (67) However, it is like a household / hall, Pinchera et ai. (Eds .), Ρρ · 475-506 (1985)]. The same technique can be applied to link the compounds of the present invention to non-antibody-targeted directors. Those skilled in the art will know, or be able to choose, a method of forming complexes with non-antibody-targeting agents (such as oligopeptides, polysaccharides, or other polyanionic compounds) 5. Although any linking group that is reasonably stable in blood can be used to link the compounds of the present invention to the target directing agent, it is bonded with a biologically dissociable bond and / or a selectively cleavable spacer or linker Basic is better. "Biologically dissociable bond" and "selectively cleavable spacer 10 or linker" means that they have reasonable stability in the cycle, but only or take precedence over specific conditions (ie, A linking group that can be released, cleaved, or hydrolyzed in a specific environment or when in contact with a specific formulation. These bonds include, for example, disulfide and trisulfide bonds and acid labile bonds (see U.S. Patent Nos. 5,474,765 and 5,762,918), and enzyme-sensitive bonds, including peptide bonds, 15 bonds, Amines, phosphodiesters, and glycosides (see US Patent Nos. 5,4743765 and 5,762,918). The characteristic of these selective release designs is the continuous release of the self-assembled body at the guiding site of the compound's target index. It is printed and released by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. The therapeutically effective dose of the compound of the invention in combination with the target guide agent 20 will vary depending on the individual, the type of disease, the state of the disease, the method of administration, and other clinical variables. These effective doses are easily determined using data from the animal model. Laboratory animals with solid tumors are often used to optimize the appropriate therapeutic dose before conversion to the clinical environment. These models are known to be very reliable in predicting effective anticancer strategies. For example, mice with solid tumors are widespread -69-

200536844 A7 B7 五、發明說明（68 ) 地用於臨床前試驗中，以決定以最小毒性得到有利抗腫瘤效果之治療劑操作範圍。本發明進一步提供含有與標的導向劑及醫藥上可接受之載劑拼合之有效量之本發明化合物的一種組成物。於 5 使用蛋白質例如抗體或生長因子、或多醣作為標的導向劑時，彼等較好呈可注射之組成物投與。該可注射抗體溶液將以約2分鐘至約45分鐘，較佳為約10至約20分鐘的時間，投藥至靜脈、動脈或脊髓液内。於特定情形下，對於受限於靠近皮膚特定部位及/或特定體腔等範圍之腫 10 瘤，以皮内及腔内投與為有利。此外，位於腦内之腫瘤，可使用腦脊髓膜内投與。經濟部智慧財產局員工消費合作社印製本發明之另一態樣包含對有其需要的病患治療與αν 整合素表現相關的疾病（特別是，動脈再狭窄、血管壁内皮增生或發炎）之方法，該方法包括利用控制釋放方式投 15 與該病患塗覆於腔内醫用裝置（特別是，氣球擴張導管或支架）之治療有效量之式（I)化合物或其組成物。該等裝置係藉由‘制ο; ν整合素活性而防止發生動脈再狭窄，因而預防内皮細胞過度增生。「腔内醫用裝置」一詞係指任何遞送裝置，例如血管 20 内藥物遞送導管、金屬絲、藥理支架與腔内鋪設。本發明範疇包含由具有溶洗或釋放治療有效量的本發明化合物的塗層或鞘之動脈或靜脈支架組成之遞送裝置。「控制遞送」一詞係指以部位指引及依存時間之方式釋放活性成分。或者，此等裝置之遞送系可含有以可變的控制速率遞 -70- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x297公釐） 200536844 A7 B7 五、發明說明（69 ) 送化合物之局部灌輸導管。「支架」_詞係指能藉由導管遞送之任何裝置。支架通常用以防止由於身體異常（例如由於手術外傷，血管組織不為所欲的向内生長）之血管閉合。它通常具有管狀、 5擴張的格子型結構，適於留置内腔或輸送管内側，以舒解阻塞。支架具有與内腔壁接觸的表面及曝露於内腔的表 /、内腔壁接觸的表面為管的外側表面，曝露於内腔的表面為管的内表面。支架材質可為聚合物、金屬或聚合物-金屬材質組合，及視需要可具生物降解性。 10 通兩，係將呈未擴張形式之支架插入内腔中，然後自仃擴張，或藉助於在原處之第二裝置擴張。典型的擴張方法係透過使用裴導管的血管擴張術氣球而發生，該氣球於狹窄的血管或身體通道内膨脹，以剪切或瓦解與血管壁成刀相關的阻塞而獲得擴大的内腔。亦可使用如審定中之美 15國專利申請案2002/0016625 A1 (Falotico等）敘述之自行擴張支架。支架與預防發炎及增生之藥物、製劑或化合物之組合可為血管擴張術後之動脈再狹窄提供最有效之治療。經濟部智慧財產局員工消費合作社印製本發明化合物可以多種方式併入或固定於支架中。含 20本發明化合物及生物相容性材料或聚合物之溶液可以多種 $式併人支架中歧架上。例如，可將含本發明化合物之溶液喷霧於支架上或可將支架浸入該溶液中，然後各令其乾燥。另一塗覆方法為將含本發明化合物之溶液充電至一極性，並將支架充電至相對極性。以此方式，溶液與支架 -71- 200536844 A7200536844 A7 B7 V. The description of the invention (68) is used in preclinical trials to determine the operating range of therapeutic agents that have a beneficial antitumor effect with minimal toxicity. The present invention further provides a composition containing an effective amount of a compound of the present invention in combination with a target directing agent and a pharmaceutically acceptable carrier. When proteins such as antibodies or growth factors, or polysaccharides are used as target guides, they are preferably administered as injectable compositions. The injectable antibody solution will be administered into a vein, artery or spinal fluid for a period of about 2 minutes to about 45 minutes, preferably about 10 to about 20 minutes. Under certain circumstances, intradermal and intracavitary administration is beneficial for tumors that are confined to a specific area of the skin and / or a specific body cavity. In addition, tumors located in the brain can be administered using the cerebrospinal membrane. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, another aspect of the present invention includes treating patients in need of diseases related to the expression of αν integrin (in particular, arterial restenosis, vascular endothelial hyperplasia or inflammation) A method comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a composition thereof coated with an intraluminal medical device (in particular, a balloon dilatation catheter or stent) using a controlled release method. These devices prevent the occurrence of arterial restenosis by inducing integrin activity, thereby preventing excessive proliferation of endothelial cells. The term "intraluminal medical device" refers to any delivery device, such as a drug delivery catheter, wire, pharmacological stent, and intraluminal placement within a blood vessel. The scope of the invention encompasses a delivery device consisting of an arterial or venous stent having a coating or sheath that dissolves or releases a therapeutically effective amount of a compound of the invention. The term "controlled delivery" refers to the release of active ingredients in a site-directed and time-dependent manner. Alternatively, the delivery of these devices may contain delivery at a variable control rate -70- This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 200536844 A7 B7 V. Description of the invention (69) Compound delivery The local infusion catheter. The term "stent" refers to any device capable of being delivered through a catheter. Stents are often used to prevent blood vessel closure due to abnormalities in the body (for example, due to surgical trauma, where the vascular tissue does not grow as desired). It usually has a tubular, 5-expanded lattice structure that is suitable for indwelling a lumen or inside a delivery tube to relieve obstruction. The stent has a surface in contact with the inner cavity wall and a surface exposed to the inner cavity. The surface in contact with the inner cavity wall is the outer surface of the tube, and the surface exposed to the inner cavity is the inner surface of the tube. The stent can be made of polymer, metal or polymer-metal material, and can be biodegradable if needed. The 10-way device is a stent in an unexpanded form inserted into the lumen and then self-expanding, or with the aid of a second device in place. A typical dilation method occurs through a vasodilation balloon using a Pei catheter, which expands within a narrow blood vessel or body passage to obtain an enlarged lumen by cutting or disintegrating a blockage associated with a vascular wall knife. A self-expanding stent as described in the pending US 15 patent application 2002/0016625 A1 (Falotico, etc.) can also be used. The combination of stents and drugs, preparations or compounds that prevent inflammation and proliferation can provide the most effective treatment for arterial restenosis after vasodilation. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs The compound of the present invention can be incorporated into or fixed in a stent in various ways. A solution containing 20 compounds of the present invention and a biocompatible material or polymer can be combined on a manifold in a stent. For example, a solution containing a compound of the present invention can be sprayed onto the stent or the stent can be immersed in the solution and then allowed to dry each. Another coating method is to charge the solution containing the compound of the present invention to a polarity and to charge the stent to a relative polarity. In this way, solution with stent -71- 200536844 A7

==引H法係使用超臨界溫度及壓力條件 ==物之溶液塗覆支架。使用。架:減少廢料，且可對塗層的厚度， =定於支架外側表面(與組織接觸之表面)，：:物某些化合物可塗覆整個支架。 …、而，當藥物的有效性受影響時，覆於支架上及一層或多層聚 ==塗 :物:成之組合產物，其中該聚合塗二:::: 10 物可《至少約6個月的時間自該支= 二：: 係以約3天至約6個月的時間;於另 …係以約7天至約3〇天的時間。任何生物相紐聚合物材料可結合本剌化合物: 用於（諸）聚合物塗層。 15 經濟部智慧財產局員消費合作社印製 20 於-具體實例中’係將化合物直接併入聚合物基質 (例如聚合物聚料）内，接著塗覆於支架外側表面。化合 1質上係通過聚合物分子概㈣基質雜。支架及於架^塗覆藥物之方法於PCT申請案w〇 96/329〇7中有 -丨之^ °於另-紐中’先於支架上塗覆由含化合物^乙稀乙酸乙稀自旨共聚物及聚丁基甲基丙稀酸醋組成的办液之基底層。然後，進―步於支架上塗覆含聚丁基甲基丙婦酸酯之外層。該外層具有擴散障壁之作用，防止化合物太快溶離進人·組織中。外層或頂層的厚度決定化合物自基質溶離的速率。支架及塗覆方法見述於審定中之美國專利申請案2002/0016625 A1。 -72- 200536844 A7 B7 五、發明說明（71) 重要的是，要注意不同支架可使用不同的聚合物。例如，上述乙烯-乙酸乙烯酯共聚物及聚丁基甲基丙稀酸酯基質與不銹鋼支架搭配得很好。以其他材料（包括展現超彈力性質之材料例如鎳與鈦的合金，或經體溫活化後「記 5得」及回復其原來形狀之保持形狀之聚合物材質）形成的支架可能使用其他聚合物更為有效。將支架引入身體内腔之方法為一般悉知。於本發明之態樣中，係使用導管引入塗覆化合物之支架。熟習此項技藝人士將察知，該等方法視楂入支架的部位而稍有差 10異。於植入冠狀動脈支架時，係將帶有支架的氣球導管嵌入冠狀動脈中，使支架位於需要的位置；使氣球膨脹，擴張支架。當支架擴張時，即與内腔壁接觸。一旦支架就位，即抽出氣球内的氣體，取出氣球。支架保持就位，其帶有化合物之與内腔接觸面直接接觸内腔壁面。如果需 15要，則支架之植入可伴隨抗凝血療法。經濟部智慧財產局員工消費合作社印製使用本發明支架遞送化合物之最適條件隨著所用不同局部表送系統，以及所用化合物之性質與濃度而異。可能之最適條件包含，例如，化合物濃度、遞送容積、遞送速率、谷器壁之滲透深度、近側之膨脹壓、孔量與大小及 2〇藥物遞送導管氣球之適合性。於受傷部位抑制平滑肌細胞 j生的條件可料最適化，使得由於動脈再狹窄產生的顯著動脈阻塞(例如，藉平滑肌細胞之增生能力，或藉血管阻力，内腔直徑的變化測得者）不再發生。最適條件可使用彳i行汁算方法，根據得自動物模式研究的數據予以決本纸張尺度適用中國 •73- 200536844 A7 B7 五、發明說明（72 ) 定。本發明化合物亦可呈微脂粒遞送系，例如單層小微脂粒、單層大微脂粒、及多層微脂粒等形式投與。此項技藝中悉知之含遞送系之微脂粒係由多種脂質（例如膽固 5 醇、硬脂醯胺或磷脂醯膽鹼）形成。本說明書中（特別是反應圖式及實例中）使用之縮寫如下：經濟部智慧財產局員工消費合作社印製== The H-induction method uses a solution of supercritical temperature and pressure conditions to coat the stent. Use. Shelf: reduce waste, and can be applied to the thickness of the coating, = determined on the outer surface of the stent (the surface in contact with the tissue), :: objects Certain compounds can coat the entire stent. …, And when the effectiveness of the drug is affected, it is covered with a stent and one or more layers of polymer == coating: substance: a combination product, wherein the polymer coating 2 :::: 10 substances can be at least about 6 The time of the month is from this branch = two: it is about 3 days to about 6 months; in another ... it is about 7 days to about 30 days. Any bio-phase polymer material can be combined with this compound: for polymer coating (s). 15 Printed by Consumer Affairs Agency, Intellectual Property Agency, Ministry of Economic Affairs 20 In the specific example, the compound is directly incorporated into a polymer matrix (such as a polymer polymer), and then coated on the outer surface of the stent. The compound 1 is essentially matrix-doped through polymer molecules. Stents and methods for coating drugs on PCs in PCT Application No. w96 / 329〇7--^^ in another-New Zealand 'before coating on the stent by the compound containing ^ ethyl acetate Copolymer and polybutyl methyl acrylic ester base solution. Then, the stent is further coated with a polybutylmethylpropionate-containing outer layer. This outer layer acts as a diffusion barrier, preventing the compound from dissolving into human tissues too quickly. The thickness of the outer or top layer determines the rate at which the compound dissolves from the matrix. The stent and coating method are described in pending US patent application 2002/0016625 A1. -72- 200536844 A7 B7 V. Description of the invention (71) It is important to note that different polymers can be used for different stents. For example, the above ethylene-vinyl acetate copolymer and polybutyl methyl methacrylate matrix work well with stainless steel stents. Stents formed from other materials (including materials exhibiting super-elastic properties such as nickel and titanium alloys, or polymer materials that retain the shape and retain their original shape after 5 minutes after activation by body temperature) may use other polymers. Is effective. Methods of introducing a stent into the body cavity are generally known. In one aspect of the invention, a catheter is used to introduce a compound-coated stent. Those skilled in the art will know that these methods differ slightly depending on where the hawk enters the stent. When a coronary stent is implanted, a balloon catheter with a stent is inserted into the coronary artery to place the stent in the desired position; the balloon is expanded to expand the stent. When the stent expands, it comes into contact with the lumen wall. Once the stent is in place, extract the gas from the balloon and remove the balloon. The stent is held in place with the compound's contact surface in direct contact with the lumen wall. If required, stent implantation can be accompanied by anticoagulation therapy. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs The optimal conditions for delivering compounds using the stent of the present invention will vary with the different local delivery systems used, and the nature and concentration of the compounds used. Possible optimal conditions include, for example, compound concentration, delivery volume, delivery rate, penetration depth of the trough wall, proximal inflation pressure, pore volume and size, and the suitability of a 20 drug delivery catheter balloon. Conditions that inhibit smooth muscle cell growth at the injured site can be optimally optimized so that significant arterial occlusion due to arterial restenosis (for example, measured by smooth muscle cell proliferation capacity or by vascular resistance, changes in lumen diameter) does not Happen again. The optimal conditions can be determined by using the calculation method based on the data obtained from animal model studies. The paper size is applicable to China • 73- 200536844 A7 B7 V. Description of the invention (72). The compounds of the present invention can also be administered in the form of microlipid delivery systems, such as single-layer small micro-lipids, single-layer large micro-lipids, and multi-layer micro-lipids. The liposomes with delivery systems known in the art are formed from a variety of lipids, such as cholesterol, stearylamine, or phosphatidylcholine. The abbreviations used in this manual (especially in the reaction diagrams and examples) are as follows: Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

Boc 第三丁氧羰基 BSA 牛血清白蛋白 Cod 環辛二烯 d/hr/min/rt 天/小時/分鐘/室溫 DBC 2,6-二氯苯曱醯氣 DCM 二氯甲烷 DIEA 二異丙基乙胺 DMA 二曱基乙醯胺 DMAP 二曱胺基吡啶 DMF 二曱基曱醯胺 DMSO 二曱亞颯 EDC 尽乙基I’-二曱胺基丙基碳化二亞胺鹽酸鹽 Et2〇乙醚 EtOAc 乙酸乙酯 EtOH 乙醇 HATU 0-(7-氮雜苯并三唑-1-基）-1丄3,3-四甲基蘇六氟雄酸鹽 HBTU 0-苯并三唑-1-基-iV,四曱基錁六氟磷酸鹽 HC1 鹽酸 HOBt 1-羥基苯并三唑 HPLC 高效能液相層析法 -74- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844Boc third butoxycarbonyl BSA bovine serum albumin Cod cyclooctadiene d / hr / min / rt day / hour / minute / room temperature DBC 2,6-dichlorobenzene tritium gas DCM dichloromethane DIEA diisopropyl Ethylethylamine DMA Diamidoacetamidamine DMAP Diamidopyridine DMF Diamidoamidine DMSO Diamidene sulfonium EDC Ethyl I'-diamidinopropylcarbodiimide hydrochloride Et2. Diethyl EtOAc ethyl acetate EtOH ethanol HATU 0- (7-azabenzotriazol-1-yl) -1 丄 3,3-tetramethylthreonate and HBTU 0-benzotriazole-1- -IV, tetramethylphosphonium hexafluorophosphate HC1 HOBt 1-hydroxybenzotriazole hydrochloride HPLC high-performance liquid chromatography-74- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200536844

二盤合成方法經濟部智慧財產局員工消費合作社印製 LDA 二異丙醢胺兹 LiHMDS /、曱基一石夕燒胺化裡 Me 曱基 MeOH 曱醇 MeCN 乙腈 NaHMDS 六甲基二矽烷胺化鈉 NaOH 氫氧化鈉 ND 未測定 NMM 曱基嗎琳 PBS 磷酸鹽緩衝液 Ph 笨基 RP-HPLC 逆相高效能液相層析法 SDS 十二基硫酸納 TEA 三乙胺 TFA 三氟乙酸 THF 四氩呋喃 Thi 噻吩基 TMS 四曱基矽烷 Tol 曱苯本發明之代表性化合物可根據下文敘述之一般合成方法予以今成，並以隨後反應圖式作更詳細之說明。由於該等反應圖式係藉以說明本發明中間體及標的化合物之製 5法，因此本發明不擬受限於所示反化學反應及條件。其他代表性化合物及其立體異構物、消旋混合物、非鏡像異構物及鏡像異構物可使用根據彼等反應圖式及熟習此項技藝人士已知之其他物質、化合物與試劑製備之中間體予以合成。所有該等化合物及其立體異構物、消旋混合物、非鏡 10像異構物及鏡像異構物均意欲涵蓋於本發明範圍内。諸反 -75- 本紙張尺度適财_ii^CNS)A4 i(_2iG χ 297公S- ,200536844 A7 ___B7 五、發明說明（74 ) 應圖式中使用的各種起始物質之製備係屬熟習此項技藝人士悉知之範圍内。Two-disc synthesis method Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, LDA Diisopropylamidazine LiHMDS /, Mesityl-Ishiyaki Amidation Me Methyl MeOH Methenol MeCN Acetonitrile NaHMDS Sodium Hexamethyldisilazide NaOH Sodium hydroxide ND Not determined NMM Methymorphine PBS Phosphate buffer Ph Phyl RP-HPLC Reverse phase high performance liquid chromatography SDS Sodium dodecyl sulfate TEA Triethylamine TFA Trifluoroacetic acid THF Tetraargfuran Thi Thienyl TMS Tetramethylsilyl Tol Benzene The representative compounds of the present invention can be prepared according to the general synthetic methods described below, and will be described in more detail with subsequent reaction schemes. Since these reaction schemes are used to illustrate the preparation of intermediates and target compounds of the present invention, the present invention is not intended to be limited to the anti-chemical reactions and conditions shown. Other representative compounds and their stereoisomers, racemic mixtures, non-image isomers and mirror isomers can be prepared according to their reaction schemes and other substances, compounds and reagents known to those skilled in the art. Body to be synthesized. All such compounds and their stereoisomers, racemic mixtures, non-mirror isomers and mirror isomers are intended to be encompassed within the scope of this invention. Zhu Fang-75- This paper is suitable for size_ii ^ CNS) A4 i (_2iG χ 297 S-, 200536844 A7 ___B7 V. Description of the invention (74) The preparation of various starting materials used in the drawings is familiar Those skilled in the art know.

反應圖式A 10 反應圖式A敘述式(I)標的化合物（式中R!如先前界定及W為-(CH2)〇-3烷基-)之製法。於酸性條件下（使用酸例如TFA與DCM之酸性混合物或於適當溶劑例如二哼烷中之無機酸）完成自Ra取代之（其中匕為CM烷基)化合物A1移除Boc-保護基之反應，形成旅咬化合物A2。使旅淀化合物A2與羧酸化合物A3於標準偶聯條件下(於適當驗例如NMM或DIEA存在下’❹偶聯航合物例如 H〇Bt/EDC、H〇贿BTU錢甲酸異丁酷）進行偶聯反應，得到i旨化合物A4。使S旨化合物A4於酸性或驗性條件下水解，獲得式（I)標的化合物。Reaction Scheme A 10 Reaction Scheme A describes the preparation of the compound of formula (I) (wherein R! Is as previously defined and W is-(CH2) 0-3 alkyl-). Removal of Boc-protecting group from Ra substituted (wherein C is alkyl) compound A1 under acidic conditions (using an acidic mixture of TFA and DCM or an inorganic acid in a suitable solvent such as dihumane) To form brigade compound A2. The Ludian compound A2 and the carboxylic acid compound A3 are subjected to standard coupling conditions (in the presence of a suitable test such as NMM or DIEA, '❹ coupling aviation compounds such as H0Bt / EDC, H0BTU isobutyrate) The coupling reaction was performed to obtain the compound A4. The S compound A4 is hydrolyzed under acidic or experimental conditions to obtain the compound of the formula (I).

反應圖式A A1 0Reaction Scheme A A1 0

R2 經濟部智慧財產眉員工消費合作社印製 TFA,R2 Printed by the Intellectual Property Employee Cooperative of the Ministry of Economic Affairs, TFA,

Λ4Λ4

Boc O OBoc O O

-76- .200536844 A7 B7 五、發明說明（75-76- .200536844 A7 B7 V. Description of the invention (75

反應圖式B 反應圖式B敘述式(I)標的化合物（式中心為， 10 及W為-(CHA·3烷基-)之替代製法。於標準偶聯條件^ (於適當鹼例如NMM或DIEA存在下，使用偶聯劑'、見人物例如H〇Bt/EDC、HOBt/HBTU或氯曱酸異丁略）使化二物A2與具有適當釋離基例如鹵基或甲磺酸根或對甲苯續酸根之化合物B1縮合，形成化合物B2。使化合物B2與經取代之胺化合物B3於適當鹼例如LiHMDS、NaHMDS 或LDA存在下反應，形成化合物B4。以鹽酸水溶液處理化合物B4造成該酯之水解，獲得式（I)標的化合物。Scheme B depicts a compound of the formula (I) (the center of the formula is 10 and W is-(CHA · 3 alkyl-)). Under standard coupling conditions ^ (in an appropriate base such as NMM or In the presence of DIEA, use a coupling agent ', see characters such as HOBt / EDC, HOBt / HBTU or isobutyl chloroacetate) to make the dimer A2 with a suitable release group such as halo or mesylate or Toluate compound B1 is condensed to form compound B2. Compound B2 is reacted with a substituted amine compound B3 in the presence of a suitable base such as LiHMDS, NaHMDS or LDA to form compound B4. Treatment of compound B4 with an aqueous solution of hydrochloric acid causes hydrolysis of the ester To obtain the compound of formula (I).

反應圖式B A2Reaction Scheme B A2

B4 經濟部智慧財產局員工消費合作社印製B4 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

HOBt EDC Br DEEAHOBt EDC Br DEEA

〇Ra R2 4MHC1 (aq.)〇Ra R2 4MHC1 (aq.)

反應圖式c 反應圖式C敘述製備化合物A1之替代方法。於適當 15活化劑例如H〇Bt、HBTU、HATU或氣甲酸異丁酷存在 -77- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公麓） 200536844 A7 B7 五、發明說明（76 5 10 下’以甲基甲基羥胺將羧酸化合物C1轉化成醯胺化合物_C2。使醯胺化合物C2與於原處製備之芳基經類、格林納試劑（Grignard reagent)等反應，形成酮化合物 C3。使酮化合物C3與適當經取代之磷烷或膦酸酯化合物 C4於鹼例如UHMDS、NaHMDS、LDA等存在下反應，轉化成不飽和酯化合物C5之順式與反式異構物之混合物。於適當觸媒例如5或10%坡鈀碳存在下及氫解作用條件下（其中使用約10至約50 psi之超壓氫氣），達成化合物C5成為化合物A1之轉化反應。Scheme C illustrates an alternative method for preparing compound A1. Appropriate 15 activators such as HOBt, HBTU, HATU or isobutyric acid -77- This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 foot) 200536844 A7 B7 V. Description of the invention (76 5 Under 10 ′, methyl carboxylamine is used to convert carboxylic acid compound C1 to ammonium amine compound_C2. The ammonium amine compound C2 is reacted with the aryl compounds, Grignard reagents, etc. prepared in situ to form a ketone compound. C3. The ketone compound C3 is reacted with a suitably substituted phosphane or phosphonate compound C4 in the presence of a base such as UHMDS, NaHMDS, LDA, etc., and converted into a mixture of cis and trans isomers of the unsaturated ester compound C5 In the presence of a suitable catalyst such as 5 or 10% palladium carbon and hydrogenolysis conditions (wherein about 10 to about 50 psi overpressure hydrogen is used), the conversion reaction of compound C5 to compound A1 is achieved.

反應圖式CReaction Scheme C

Boc〆Boc〆

(CHi)q Cl(CHi) q Cl

AhAh

NHMe(OMe).HCIfNMM HOBT, HBTU^ B〇c-z-BuOCOClNHMe (OMe) .HCIfNMM HOBT, HBTU ^ B〇c-z-BuOCOCl

(5¾ C2 Λ .OMc o(5¾ C2 Λ .OMc o

MeO, C2 R2Br n-BuLi 經濟部智慧財產局員工消費合作社印製MeO, C2 R2Br n-BuLi Printed by Employee Consumer Cooperatives, Bureau of Intellectual Property, Ministry of Economic Affairs

Bo〆 •78〇C BocBo〆 78〇C Boc

CO^ (CH2)c C3 ;P\/C02Ra R2 Me〇’ C4CO ^ (CH2) c C3; P \ / C02Ra R2 Me〇 ’C4

NaHMDS C5NaHMDS C5

(CH2)q C5(CH2) q C5

一 NOne N

Pd/C A1 H2 -78- • 200536844 at B7 五、發明說明（77 )Pd / C A1 H2 -78- • 200536844 at B7 V. Description of the invention (77)

反應圖式D 經濟部智慧財產局員工消費合作社印製反應圖式D敘述合成化合物A1(式中（CH2)q&(CH2)2. 3)之替代方法。使醯胺化合物C2與適當還原劑例如氫化链經等反應，形成搭化合物D1。使於原處產生之乙炔化 5 合物D2與酸化合物D1於低温進行縮合反應，形成快丙醇化合物D3。使用於咣啶中之林蠟氏觸媒（Lindlar’s catalyst)，於氫解作用條件下，使炔化合物D3選擇性還原成為順式烯烴化合物D4。使烯丙醇化合物D4於鹼例如TEA、DIEA等存在下與Ra取代之3-氣_3_酮基丙酸酯 10 化合物D5縮合，形成混合酯化合物D6。於適當驗例如氫化鈉、氫化鉀、LDA等存在下，以氣三曱基矽烷處理化合物D6，得到中間體石夕烧基乙稀酮縮駿，此中間體於適當溶劑例如THF或EbO中，經加熱進行重排反應，獲得混合酯化合物D7。真空下加熱化合物j)7後，達成酯 15 化合物D7之脫羧基反應，形成化合物D8。於標準氫化作用條件下，使用超壓氫氣（約10至約50 psi)，於適當觸媒例如'5或10%披鈀碳存在下，達成化合物〇8中雙鍵還原反應，形成標的化合物A1(其中（CH2)q為（CH2)2-3)。 -79- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） .200536844 A7 B7 五、發明說明（78Reaction Scheme D Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Reaction Scheme D describes an alternative method for synthesizing compound A1 (where (CH2) q & (CH2) 2.3). The amidine compound C2 is reacted with a suitable reducing agent such as a hydrogenated chain warp, etc., to form a compound D1. The acetylene pentoxide D2 generated in situ and the acid compound D1 are subjected to a condensation reaction at a low temperature to form a fast propanol compound D3. The Lindlar's catalyst used in pyridine is used to selectively reduce the alkyne compound D3 to the cis-olefin compound D4 under the condition of hydrogenolysis. The allyl alcohol compound D4 is condensed with Ra-substituted 3-gas-3 ketopropionate 10 compound D5 in the presence of a base such as TEA, DIEA, etc. to form a mixed ester compound D6. In the presence of a suitable test such as sodium hydride, potassium hydride, LDA, etc., the compound D6 is treated with tris (trimethylsilyl) silane to obtain the intermediate Shixyl ethyl ketal, which is in a suitable solvent such as THF or EbO A rearrangement reaction was performed by heating to obtain a mixed ester compound D7. After heating compound j) 7 under vacuum, decarboxylation reaction of ester 15 and compound D7 is achieved to form compound D8. Under standard hydrogenation conditions, using overpressure hydrogen (about 10 to about 50 psi) in the presence of a suitable catalyst such as' 5 or 10% palladium on carbon, a double bond reduction reaction in compound 08 is formed to form the target compound A1 (Where (CH2) q is (CH2) 2-3). -79- This paper size applies to China National Standard (CNS) A4 (210x297 mm). 200536844 A7 B7 V. Description of Invention (78

反應圖式D C2 设2〇 g〇c〆 L1AIH4Reaction scheme D C2 Let 20 g〇c〆 L1AIH4

0H (ζΗί)ο«】 D10H (ζΗί) ο «】 D1

SH D2 Λ-BuLi n /N •78 °C BocSH D2 Λ-BuLi n / N • 78 ° C Boc

0H0H

D3 林蠟氏觸媒D3 Lin wax catalyst

D4 OH 9 ci^^C〇2R% (CH^o-i D§ D6D4 OH 9 ci ^^ C〇2R% (CH ^ o-i D§ D6

NaH,THFNaH, THF

Et3N CH2C12 O O TMSC1Et3N CH2C12 O O TMSC1

Boc’ OBoc ’O

Al(q=2,3) 經濟部智慧財產局員工消費合作社印製反應圖式E敘述合成式(1.2)標的化合物（式(I)化合物 5 中之R2為氫，Ri如先前界定及w為-(CH2)〇_3烷基-)之替代方法。使用適當羰烷氧亞曱基三苯基磷烷(Wittig反應）或膦醯乙酸三烷酯（Horner_Emmons反應），使醛化合物 E1進行縮合反應，形成α 5 /3 -不飽和酯化合物E2。於酸性條件下（使用酸，例如TFA於DCM中之1:1混合物' 10 4Ν HC1之二呤烷溶液等）處理化合物Ε2，造成移除Boc- -80- 本紙張尺度適用中國國家標準(CNS)A4規格（2ι〇χ297公餐） .200536844 A7 _____ B7 五、發明說明（79 ) 保濩基，形成經取代之哌啶化合物E3。於標準偶聯條件下(於適·當鹼例如NMM或DIEA存在下，使用偶聯劑混合物例如HOBt/EDC、H〇Bt/HBTU或氯甲酸異丁酯），使該旅咬化合物E3與羧酸化合物A3偶聯，形成酯化合物 5 E4 °酸性或鹼性條件下，水解該酯化合物E4，獲得α，万-不飽和酸化合物Ε5。於標準氫化作用條件下，使用超壓氫氣（約10至約50 psi)，於適當觸媒例如5或10%披纪碳存在下，達成化合物E5中雙鍵還原反應，形成式 (1.2 )；f示的化合物。Al (q = 2,3) The reaction scheme E printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics describes the synthesis of the target compound of formula (1.2) (R2 in compound 5 of formula (I) is hydrogen, Ri is as previously defined and w is -(CH2) 0_3 alkyl-) alternative method. The aldehyde compound E1 is subjected to a condensation reaction using an appropriate carbonylalkoxymethylenetriphenylphosphorane (Wittig reaction) or a phosphinophosphonium trialkylacetate (Horner_Emmons reaction) to form α 5/3 -unsaturated ester compound E2. Treatment of compound E2 under acidic conditions (using acid, such as a 1: 1 mixture of TFA in DCM '10 4N HC1 diuridine solution, etc.), resulting in the removal of Boc- -80- This paper standard applies to Chinese national standards (CNS ) Specification of A4 (2 × 297 public meal). 200536844 A7 _____ B7 V. Description of the invention (79) The sulfonyl group forms a substituted piperidine compound E3. Under standard coupling conditions (in the presence of a suitable base such as NMM or DIEA, using a mixture of coupling agents such as HOBt / EDC, HOBt / HBTU or isobutyl chloroformate), the travel compound E3 and carboxylic acid The acid compound A3 is coupled to form the ester compound 5 E4. Under acidic or basic conditions, the ester compound E4 is hydrolyzed to obtain an α, 10,000-unsaturated acid compound E5. Under standard hydrogenation conditions, the use of overpressure hydrogen (about 10 to about 50 psi) in the presence of a suitable catalyst, such as 5 or 10% peridian carbon, to achieve a double bond reduction reaction in compound E5 to form formula (1.2); The compound shown by f.

10 反應圖式E10 Reaction Scheme E

Boc^Boc ^

4MHC1 E2 寻烷中^ (CH2)q El 人 C44MHC1 E2 alkanes ^ (CH2) q El human C4

NaHMDS Boc〆 (CH^ E2 or TFAA3CM(1:1)NaHMDS Boc〆 (CH ^ E2 or TFAA3CM (1: 1)

(CH2)q E3 A3 E4 經濟部智慧財產局員工消費合作社印製(CH2) q E3 A3 E4 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

HOBt EDO DffiAHOBt EDO DffiA

OO

(CH2>q E4 ΟΗΓ •ORa(CH2 > q E4 ΟΗΓ • ORa

R"IR " I

Ra (0¾Cf esRa (0¾Cf es

OO

OH -81- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公嫠） ,200536844 A7 _ B7 ---OH -81- This paper size applies to China National Standard (CNS) A4 (210x297 cm), 200536844 A7 _ B7 ---

五、發明說明（8〇 ) • /ohV. Description of the invention (80) • / oh

Pd/C ryiCH2)q E5 一 r^vN^J 式(L2) h2 R] 1 oPd / C ryiCH2) q E5-r ^ vN ^ J Formula (L2) h2 R] 1 o

反應圖式F 反應圖式F敘述製備化合物A1之替代製法泠-不飽和酯化合物E2消旋性E/Z-混合物與取使 5酸化合物Fl於適當過渡金屬觸媒例如铑或銦2代之醐應，獲得標的化合物A1。子在下反 E2Reaction Scheme F Reaction Scheme F describes an alternative method for preparing compound A1-unsaturated ester compound E2 racemic E / Z-mixture and substitution of 5 acid compound Fl with a suitable transition metal catalyst such as rhodium or indium 2 The target compound A1 was obtained. Child under counter E2

- b(oh>2 FI A1-b (oh > 2 FI A1

Rh(I)觸媒反應圖式Rh (I) catalyst reaction scheme

FF

' 反應圖式G 10 經濟部智慧財產局員工消費合作社印製 15 反應圖式G敘述合成式(U)標的化合物中之(CH2)q為、(CH2)23-，Ri如先前界定及^匕合物烧基-)之替代方法。於酸性條件下（使用酸，例如H2V3 DCM中之1_1思合物、4Ν Ηα之二姐溶液等）移除^ 物D BQe·倾基，獲得餘代之錢化合物G1 Γ 於k準偶聯條件下（於適當驗例如NMM或存在下’使用偶聯劑混合物例如HOBt/EDC、H〇Bt/HBTU或 -82- 本紙張尺度適用中國國豕標準(CNS)A4規格（210 X 297公爱） ,200536844 A7 B7 五、發明說明（81) 氯曱酸異丁酯），使該哌啶化合物G1與羧酸化合物A3偶聯，形成酯化合物G2。暴露於強酸或強鹼水性條件下（強酸或鹼例如濃HC1或NaOH存在下），使該酯化合物G2 轉化成化合物G3。於標準氫化作用條件下，使用超魔氯 5氣（約1〇至約50 Psi)，於適當觸媒例如5或10%披把碳存在下，使化合物G3中之雙鍵還原，形成式(1 3)標的化合物。'' Reaction Scheme G 10 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 15 Reaction Scheme G states that (CH2) q of the compound of the formula (U) is (CH2) 23-, Ri is as previously defined and Alkynyl-) alternative method. Under acidic conditions (using acid, such as 1_1 complex in H2V3 DCM, 4N Ηα 2nd solution, etc.) to remove ^ D BQe · tilt group to obtain the remaining compound G1 Γ under k quasi-coupling conditions (In appropriate tests such as NMM or in the presence of 'using coupling agent mixtures such as HOBt / EDC, HOBt / HBTU or -82- This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 public love) , 200536844 A7 B7 V. Description of the invention (81) Isobutyl chloroacetate) Coupling the piperidine compound G1 with a carboxylic acid compound A3 to form an ester compound G2. Exposure to strong acid or base aqueous conditions (in the presence of a strong acid or base such as concentrated HC1 or NaOH) converts the ester compound G2 to compound G3. Under standard hydrogenation conditions, using super magic chlorine 5 gas (about 10 to about 50 Psi), in the presence of a suitable catalyst such as 5 or 10% of carbon, the double bond in compound G3 is reduced to form the formula ( 1 3) The target compound.

反應圖式G D8 4MHC1 於二4烷中& i TFA/DCM(1:1)Reaction Scheme G D8 4MHC1 in dioxane & i TFA / DCM (1: 1)

、200536844 A7 B7 五、發明說明（Μ . 反應圖式Η 反應圖式Η敘述合成式(L3a)標的化合物（式(13)化合物中之Ri為-NH(R5)，W為_(CH2)〇_3烷基-及r5雜芳基取代基被還原為部分不餘和之雜環基取代基）之方法。於標準氫化作用條件下，使用超壓氫氣（約1〇至約5〇psi)，於適當觸媒例如5或10%披纪碳存在下，使化合物G3a (化合物G3中之心為-；^!!^5))之雙鍵還原，伴隨發生r5 之標準還原反應，獲得式(1.3)標的化合物。反應圖式Η 10 Η Ο5.200536844 A7 B7 V. Description of the invention (M. Reaction Scheme Η Reaction Scheme Η describes the synthesis of the compound of the formula (L3a) (Ri in the compound of formula (13) is -NH (R5) and W is-(CH2). _3 Alkyl- and r5 heteroaryl substituents are reduced to partially unsaturated heterocyclic substituents). Under standard hydrogenation conditions, overpressure hydrogen (about 10 to about 50 psi) is used. In the presence of a suitable catalyst such as 5 or 10% peridot carbon, the double bond of compound G3a (the heart of compound G3 is-; ^ !! ^ 5)) is reduced, and the standard reduction reaction of r5 occurs with the formula: (1.3) The subject compound. Reaction Scheme Η 10 Η Ο

G3a (R<5 =啦咬基，嘧啶基） ,co2hG3a (R < 5 = lathyl, pyrimidinyl), co2h

Pd/C H2 rY'Pd / C H2 rY '

(CH2ji^] 式(L3*) 四氫淀基，四氩嘴咬基〉(CH2ji ^) Formula (L3 *)

、反應圖式I 經濟部智慧財產局員工消費合作社印製 15 反應圖式I敘述合成標的化合物B4a (化合物Β4中之（CH2)q不限定為-(CH2)2·3·，R6如先前界定及w為-(CH2)Q_3烧基-)之替代方法。於標準偶聯條件下（於適當驗例如NMM或DIEA存在下，使用偶聯劑混合物例如 HOBt/EDC、HOBt/HBTU或氣甲酸異丁酯），使化合物A2 與經保護之胺基酸化合物進行縮合反應，形成標的化合物B4a。 -84· 本纸張尺度適用中國國家標準(CNS)A4規格（210 X 297公爱） 200536844 Λ7 B7 五、發明說明（83 A2, Reaction Scheme I Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 15 Reaction Scheme I describes the synthesis target compound B4a And w is an alternative method of-(CH2) Q_3alkyl-). Compound A2 is reacted with a protected amino acid compound under standard coupling conditions (in the presence of a suitable test such as NMM or DIEA using a coupling agent mixture such as HOBt / EDC, HOBt / HBTU or isobutyl formate) The condensation reaction forms the target compound B4a. -84 · This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 public love) 200536844 Λ7 B7 V. Description of the invention (83 A2

HOBt EDC DIEA 反應圖式I Ο r r Boc 〇 1HOBt EDC DIEA reaction scheme I 〇 r r Boc 〇 1

知為已被還原為部=:化合物 Ala (化合物Ai中代基)之方法。於標準氫彳=飽和雜環基取代基之雜芳基取 1〇至約50 psi)，於適作用條件下，使用超壓氫氣（約下，使化合物C5a (化:觸媒例如5或10%披鈀碳存在代基)之雙鍵還原，伴卜 C5中之&為不飽和雜芳基取 10的化合物Ala。疋發生R2之標準還原反應，獲得標It is known as a method which has been reduced to a moiety =: compound Ala (a substituent in compound Ai). Take 10 to about 50 psi for the standard heteroaryl group of saturated hydrogen alkoxide = saturated heterocyclyl substituent. Under appropriate conditions, use overpressure hydrogen (about, make compound C5a (chemical: catalyst such as 5 or 10) % Palladium on carbon has a double bond reduction, accompanied by & the compound Ala in C5 is an unsaturated heteroaryl group of 10. A standard reduction reaction of R2 occurs to obtain the standard

反應圖式JReaction Scheme J

反應圖式J 經濟部智慧財產局員工消費合作社印製Response Schematic J Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy

Boc，Boc,

CSa 885嘧啶基喹啉基），CSa 885 pyrimidinyl quinolinyl),

Pd/C Ala --- (r2 «四氫嘧啶基， H2 四氫喹啉基）成方法本發明之代表㈣定化合物可根據下述實例及反應序 -85- 200536844 a7 B7 五、發明說明（84) 列予以製備，所提供敘述反應序列之實例及反應圖式係供說明用途，以幫助瞭解本發明而決不擬對隨後之專利申請範圍構成侷限。本發明化合物亦可於接續實例中作為中間體用，以製造本發明之其他化合物。本發明中並未試圖將 5 任何反應所得收量最適化。熟習此項技藝人士即知道如何透過反應時間、溫度、溶劑及/或試劑之例行變化增加該等收量。經濟部智慧財產局員工消費合作社印製試劑係構自商業來源。微量分析在Robertson Microlit Laboratories，Inc.，Madison，New Jersey 進行，並 10 以每一總分子量各元素之重量百分比表示。諸氫原子之核磁共振(NMR)光譜係於所示溶劑中，以（TMS)為内標準，使用Bruker Avance (300 MHz)分光計予以測定，測定值以自TMS弱磁場方向位移之百萬分率表示。質譜儀(ms) 係使用電麗技術，於]VJicromass Platform LC分光計上呈 15 (ESI) m/z (M+H+)予以測定。立體異構型化合物可使用X 光結晶學及熟習此項技藝人士已知之其他方法，呈消旋混合物或呈分離之非鏡像異構物及鏡像異構物予以鑑定。除非另行備注，否則實例中使用的物質易於自工業供應商購得，或以熟習此項技藝人士已知之標準方法合成。除非另 20行備註，否則各實例間不同的取代基為氫。實例1 H[H(i，4,5,6,氫|喷啶基)胺基]笨基]乙醯基]·4_娘啶丙酸（化合物1) 添加甲基峨(3.21毫升，51·6毫莫耳)至含3,4,5,6-四 -86-Pd / C Ala --- (r2 «tetrahydropyrimidinyl, H2 tetrahydroquinolinyl) formation method The representative compounds of the present invention can be based on the following examples and reaction sequences -85- 200536844 a7 B7 V. Description of the invention ( 84) are prepared, and the examples and reaction schemes describing the reaction sequences are provided for illustrative purposes to help understand the present invention and are not intended to limit the scope of subsequent patent applications. The compounds of the present invention can also be used as intermediates in subsequent examples to make other compounds of the present invention. In the present invention, no attempt is made to optimize the yield of any reaction. Those skilled in the art know how to increase these yields through routine changes in reaction time, temperature, solvents and / or reagents. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, the reagent system is constructed from commercial sources. Microanalysis was performed at Robertson Microlit Laboratories, Inc., Madison, New Jersey, and is expressed as a weight percentage of each element of each total molecular weight. The nuclear magnetic resonance (NMR) spectrum of the hydrogen atoms is measured in the solvent shown, using (TMS) as the internal standard, and measured using a Bruker Avance (300 MHz) spectrometer. Rate indication. The mass spectrometer (ms) was measured using Electron technology at 15 (ESI) m / z (M + H +) on a] VJicromass Platform LC spectrometer. Stereoisomers can be identified using X-ray crystallography and other methods known to those skilled in the art, either as racemic mixtures or as isolated non-image isomers and mirror isomers. Unless otherwise noted, the materials used in the examples are readily available from industrial suppliers or synthesized by standard methods known to those skilled in the art. Unless otherwise noted on the other 20 lines, the different substituent between the examples is hydrogen. Example 1 H [H (i, 4,5,6, hydrogen | pyridinyl) amino] benzyl] ethenyl] · 4-anisine propionic acid (compound 1) methyl ethyl (3.21 ml, 51 (6 millimolar) to 3,4,5,6-tetra-86-

200536844 A7 B7 五、發明說明（85 ) 氩-2-嘧啶硫醇化合物U (6·00克，51·6毫莫耳）之無水酒精(45毫·升）溶液中。回流加熱此混合物3小時，濃縮，真空乾燥，獲得呈無色油之化合物lb。 MS (ES-f) mlz 172 (M-Kl) 〇 lE NMR (DMSO-^ 300 MHz) δ L89 (m，2H)，2·61 (s，3H)，3·61 (叫 4H)，9.56 (s，1H)。 5 於0°C，添加Boc2〇（11·33克，51.91毫莫耳）至含化合物lb (13.4克，51.9毫莫耳)與TEA (7.23毫升，51 9 宅莫耳)之DCM (70毫升）溶液中，此混合物於室溫攪拌2 天。其有機層以水(2 X 75毫升）洗滌，脫水(NaACU)，濃縮，得到化合物 lc。MS (ES+) m/z 231 (M+H+)。 10 加熱含化合物lc (0.91克，3.95毫莫耳)與3-胺笨基乙酸化合物Id (〇·59克，3.95毫莫耳）之DMA (5毫升）溶液至80-85°C4天。冷卻此混合物至室溫，以MeCN予以稀釋。過濾分離固體，以MeCN與EhO洗滌，然後真空乾燥。加水，逐滴添加濃HC1調整pH至1-2。將所得溶 15 液冷/東乾無’得到呈淡黃色固體之化合物k。ms m/z 234、(M+H+)。經濟部智慧財產局員工消費合作社印製於5°C，添加Boc2〇（19克，87毫莫耳）與TEA (13 毫升’ 96¾莫耳）至含4-派咬甲醇化合物u (1〇克，87毫莫耳）、DMAP (催化用量）、二啐燒(9〇毫升)與水⑷毫升) 20之溶液中。此反應混合物於室溫攪拌隔夜，以DCM (1〇〇毫升）稀釋。其有機層以飽和NH4C1洗滌，脫水 (Na2S〇4)，>農縮，得到化合物lg。MS (ES+)油216 (M+H+)。 -87- 本紙張尺度適用中國國家標準(CNS)A4規格（21〇 χ297公釐---- 200536844 A7 B7 五、發明說明（86 ) 於-78C ’ 以 15 分鐘，添 DMSO (4.28 毫升，60.38 毫莫耳）至草醯氣(2.63毫升，30.19毫莫耳)之DCM (11〇毫升)溶液中。於-78。(：攪拌30分鐘後，逐滴添加化合物 lg (5.0克，23.2毫莫耳）之DCM (1(3毫升）溶液。所得混 5合物於-78 C攪拌2小時。逐滴添加ΤΕΑ (19·42毫升， 139.3毫莫耳），使此混合物回升至室溫，以水終止反應。分離有機層，依序以飽和(75毫升）、水（75毫升）、飽和NaHC〇3 (75毫升）及飽和食鹽水（75毫升）洗滌，然後脫水(NaJCU)，濃縮，得到化合物ih。200536844 A7 B7 V. Description of the invention (85) A solution of argon-2-pyrimidinethiol compound U (6.0 g, 51.6 millimoles) in anhydrous alcohol (45 milliliters). This mixture was heated at reflux for 3 hours, concentrated, and dried in vacuo to obtain the compound lb as a colorless oil. MS (ES-f) mlz 172 (M-Kl) 〇lE NMR (DMSO- ^ 300 MHz) δ L89 (m, 2H), 2.61 (s, 3H), 3.61 (called 4H), 9.56 ( s, 1H). 5 At 0 ° C, add Boc20 (11.33 g, 51.91 mmol) to DCM (70 ml) containing the compound lb (13.4 g, 51.9 mmol) and TEA (7.23 ml, 51 9 mol). ) The solution was stirred at room temperature for 2 days. The organic layer was washed with water (2 X 75 mL), dehydrated (NaACU), and concentrated to give compound lc. MS (ES +) m / z 231 (M + H +). 10 Heat a DMA (5 ml) solution containing compound lc (0.91 g, 3.95 mmol) and 3-aminobenzyl acetate Id (0.59 g, 3.95 mmol) to 80-85 ° C for 4 days. The mixture was cooled to room temperature and diluted with MeCN. The solid was isolated by filtration, washed with MeCN and EhO, and dried under vacuum. Add water and add concentrated HC1 dropwise to adjust the pH to 1-2. The resulting solution was liquid-cooled / dry-dried 'to obtain compound k as a pale yellow solid. ms m / z 234, (M + H +). Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs at 5 ° C, adding Boc20 (19 g, 87 mmol) and TEA (13 ml '96 ¾ Mor) to a 4-pie bite methanol compound u (10 g , 87 mmol), DMAP (catalytic amount), dioxane (90 ml) and water (ml). The reaction mixture was stirred at room temperature overnight and diluted with DCM (100 mL). The organic layer was washed with saturated NH4C1, dehydrated (Na2SO4), and> agricultural shrinkage to obtain compound lg. MS (ES +) oil 216 (M + H +). -87- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (21 × 297 mm ---- 200536844 A7 B7 V. Description of the invention (86) at -78C '15 minutes, add DMSO (4.28 ml, 60.38 Mol) to a solution of grasshopper gas (2.63 ml, 30.19 mol) in DCM (110 ml). At -78. (: After stirring for 30 minutes, the compound lg (5.0 g, 23.2 mmol) was added dropwise. Ear) in DCM (1 (3 ml)). The resulting mixture was stirred at -78 C for 2 hours. TEA (19.42 ml, 139.3 mmol) was added dropwise, and the mixture was warmed to room temperature. The reaction was terminated with water. The organic layer was separated, washed sequentially with saturated (75 mL), water (75 mL), saturated NaHC03 (75 mL), and saturated brine (75 mL), then dehydrated (NaJCU), and concentrated to give Compound ih.

MS (ES+) m/z 214 (M+H4)。lH NMR (DMS〇.^, 300 MHz) δ 1.4 (s, 9H), L89 (m, 4H), 2.58 (m, 1H), 3.85 (m, 4H) l〇 9.65(s，lH)。 · 經濟部智慧財產局員工消費合作社印製於〇。(：，逐滴添加化合物lh (2·29克，10.7毫莫耳）之DCM (15毫升）溶液至羰乙氧亞曱基三苯基磷烷(411 克’ 10·7毫升）之DCM (20毫升)溶液中。使所得混合物回升至室溫，攪拌隔夜。濃縮此混合物，其殘留物利用急 15驟層析法（碎膠’ 15-30%乙酸乙S旨/己烧）進行純化，得到化合物 li。MS (ES+) m/z 284 (Μ+ΚΓν 4NMR (DMS04 300 MHz) δ 1.2 仏 > 7 Hz，3H)，1·39 (a> 9H), i,69 (m? 2H), 2.36 (m, 1H), 2.74 (m, 2H), 3,94 (m, 2H), 4.11 (q, 7 Hz, 2H), 5.86 (d, 15MS (ES +) m / z 214 (M + H4). 1H NMR (DMS 0.1, 300 MHz) δ 1.4 (s, 9H), L89 (m, 4H), 2.58 (m, 1H), 3.85 (m, 4H) l 9.65 (s, 1H). · Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. (:, A solution of compound lh (2.29 g, 10.7 mmol) in DCM (15 ml) was added dropwise to carbonylethoxymethylenetriphenylphosphine (411 g '10.7 ml) in DCM ( 20 ml) solution. The resulting mixture was warmed to room temperature and stirred overnight. The mixture was concentrated and the residue was purified by flash 15 chromatography (crushed gel '15-30% ethyl acetate / hexane) Compound li was obtained. MS (ES +) m / z 284 (M + KΓν 4NMR (DMS04 300 MHz) δ 1.2 仏 > 7 Hz, 3H), 1.39 (a > 9H), i, 69 (m? 2H) , 2.36 (m, 1H), 2.74 (m, 2H), 3,94 (m, 2H), 4.11 (q, 7 Hz, 2H), 5.86 (d, 15

Hz, 2H), 6.82 (dd, 15, 7 Hz, 2H) ^ 於室溫，攪拌含化合物li (1.6克，5.6毫莫耳）、TFA (10毫升）與曱苯醚（1滴）之DCM (10毫升）混合物1 5小Hz, 2H), 6.82 (dd, 15, 7 Hz, 2H) ^ At room temperature, stir DCM containing compound li (1.6 g, 5.6 mmol), TFA (10 ml), and anisole (1 drop) (10 ml) mixture 1 5 small

20 時。真空乾燥此混合物，得到呈TFA鹽之化合物η。MS -88- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公漦） 200536844 A7 A7 B7 五、發明說明（87 ) (ES+) m/z 184 (M+H+)。依序添加NMM (0.22毫升，2·07毫莫耳）、化合物le (0.29 克，1·〇4 毫莫耳）、NMM (0.114 毫升，1.04 毫莫耳）、Η〇ΒΤ (〇·〇7 克，0、51 毫莫耳)及 HBTU (0.46 克， 5 1.24毫莫耳）至化合物(0·308克，1〇4毫莫耳kMeCN (20毫升)與DMF (2.毫升)溶液中。於〇。(：攪拌此混合物i 小時，然後於室溫攪拌隔夜，以飽和NHUC1終止反應，濃縮，以EtOAc萃取。將有機層脫水(Na2S04)，過遽，真空、濃縮。粗產物利用急驟層析法（碎躁， 10 1 〇%EtOH/l .5%NH4OH/DCM 至 16%EtOH/1.5%NH4〇H/DCM)進行純化，得到呈無色固體之化合物 lk。MS (ES+) m/z 399 。經濟部智慧財產局員工消費合作社印製於〇°C，使化合物lk (0.27克）溶於冰冷的6Ν HC1 (20毫升）中，於室溫攪拌2天。濃縮此混合物，使用 15 MeCN (3 X 20毫升）作為恆沸物。所得固體以及2〇與 DCM 研製，並利用 RP-HPLC (10-90% MeCN/水，〇·1〇/0 TFA)進行純化，得到呈TFA鹽之化合物11。MS (ES+) m/z 371 (Μ+ΙΓ^ h NMR (DMSO-‘ 300 MHz) S 1·07 (m, 2H), 1.65 (m, 4H)， 1.7 (m, 2H), 2.41 (m, 1H), 3.05 (m, 2H), 3.72 (s, 2H), 3.91 (m, 2H), 4.37 (m, 2H), 5.74 (d, 16 Hz, 1H), 6.75 (m, 1H), 7.15 (m, 3H), 7.42 (τη, 1H), 8.15 (br sf 1H), 9.76 (s, 1H)。C2〇H26：N4CV1.57CF3COOH-0.38H20 之元素分析計算值：c, 49·96; Η, 5·14; N, 10,08; F, 16.09; H2O, 1.24。實測值：C, 49·δ2; H，5.00; Μ, 9.97; F, 15·98; H20,1.25。20 o'clock. This mixture was dried under vacuum to give compound η as a TFA salt. MS -88- This paper size applies to Chinese National Standard (CNS) A4 (210x297 cm) 200536844 A7 A7 B7 5. Description of the invention (87) (ES +) m / z 184 (M + H +). NMM (0.22 ml, 2.07 mmol) was added sequentially, compound le (0.29 g, 1.04 mmol), NMM (0.114 ml, 1.04 mmol), 〇〇ΒΤ (〇 · 〇7 G, 0, 51 mmoles) and HBTU (0.46 g, 5 1.24 mmoles) to a compound (0.308 g, 104 mmoles of kMeCN (20 ml) and DMF (2 ml)). Stir the mixture for 1 hour at 0 ° C, then stir overnight at room temperature, stop the reaction with saturated NHUC1, concentrate, and extract with EtOAc. Dehydrate the organic layer (Na2S04), pass through a vacuum, concentrate. The crude product uses the flash layer Analytical method (crushed, 10 10% EtOH / l.5% NH4OH / DCM to 16% EtOH / 1.5% NH4OH / DCM) was purified to obtain the compound lk as a colorless solid. MS (ES +) m / z 399. Printed at 0 ° C by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, the compound lk (0.27 g) was dissolved in ice-cold 6N HC1 (20 ml) and stirred at room temperature for 2 days. The mixture was concentrated and used 15 MeCN (3 X 20 ml) as azeotrope. The obtained solid was developed with 20 and DCM and purified by RP-HPLC (10-90% MeCN / water, 0.1 / 10/0 TFA) to obtain To compound 11 which is a TFA salt. MS (ES +) m / z 371 (M + ΙΓ ^ h NMR (DMSO- '300 MHz) S 1.07 (m, 2H), 1.65 (m, 4H), 1.7 (m , 2H), 2.41 (m, 1H), 3.05 (m, 2H), 3.72 (s, 2H), 3.91 (m, 2H), 4.37 (m, 2H), 5.74 (d, 16 Hz, 1H), 6.75 (m, 1H), 7.15 (m, 3H), 7.42 (τη, 1H), 8.15 (br sf 1H), 9.76 (s, 1H). C20H26: N4CV1.57CF3COOH-0.38H20 Elemental analysis calculation value: c, 49 · 96; Η, 5.14; N, 10,08; F, 16.09; H2O, 1.24. Found: C, 49 · δ2; H, 5.00; M, 9.97; F, 15 · 98; H20 , 1.25.

鼠氣下’添加10%披絶》碳（85毫克）至含化合物II 20 (〇·05克）之溫Et〇H (10毫升）溶液中，於帕爾（parr)裝置中進行氫化（40 psi)。通過矽藻土過濾此混合物，減壓濃 -89- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 五、發明說明（88 )Under mouse atmosphere, 10% perfluorocarbon (85 mg) was added to a warm EtOH (10 ml) solution containing Compound II 20 (0.05 g), and hydrogenated in a Parr apparatus (40 psi). Filter this mixture through diatomaceous earth and reduce the concentration under reduced pressure -89- This paper size is in accordance with China National Standard (CNS) A4 (210x297 mm) 200536844 A7 B7 V. Description of the invention (88)

縮，獲得呈黏稠固體之化合物1。MS (ES+) m/z 373 (M+H V laShrink to obtain Compound 1 as a viscous solid. MS (ES +) m / z 373 (M + H V la

SMe 丄NBSMe 丄 NB

ococ

H2NH2N

lbXXlbXX

COOHCOOH

Id H HJIC1 COOH leId H HJIC1 COOH le

lc DMAlc DMA

le， HOBTle, HOBT

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

-μ rNrNYV>N lj-μ rNrNYV > N lj

COOEt 6NHC1 k^NH 0 ik ^COOH N Pd/C (10% wt)COOEt 6NHC1 k ^ NH 0 ik ^ COOH N Pd / C (10% wt)

IIII

化合物JCompound J

COOH .90· 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 五、發明說明（89) 實例2 1-[L·酮基-3、[3-[(l54,5,6-四氫-2-嘧啶基）胺基]苯基]丙基]- 4_σ辰咬丙酸（化合物2) 添加化合物1c (0.84克，3.65毫莫耳）至含3-(3-胺苯 5基）丙酸化合物2a (0.60克，3.65毫莫耳)之DMA (5毫升) ’谷液中於⑽擾拌此反應混合物3天，冷卻至室溫，以MeCN (3〇毫升）稀釋，並予以過濾。加水至濾液中，逐滴添加濃HC1調整pH至丨_2。將所得溶液冷凍乾燥’得到化合物 2b。MS (ES+) m/z 248 (M+H+)。 10 於〇°C，逐滴添加4NHC1之二今烷(8毫升）溶液至化COOH .90 · This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200536844 A7 B7 V. Description of the invention (89) Example 2 1- [L · keto-3, [3-[(l54, 5,6-tetrahydro-2-pyrimidinyl) amino] phenyl] propyl]-4-sigmaquinone propionate (compound 2) Add compound 1c (0.84 g, 3.65 mmol) to 3- (3- Amine phenyl 5-yl) propionic acid compound 2a (0.60 g, 3.65 mmol) in DMA (5 ml). The reaction mixture was stirred in a valley solution for 3 days, cooled to room temperature, and MeCN (30 ml) Dilute and filter. Add water to the filtrate and add concentrated HC1 dropwise to adjust the pH to 丨 _2. The resulting solution was freeze-dried 'to obtain compound 2b. MS (ES +) m / z 248 (M + H +). 10 At 0 ° C, add a solution of 4NHC1 biskanane (8 ml) dropwise to

合物2c (1·〇克，3 9毫莫耳)之Me〇H (2()毫升)溶液中。於至/瓜授拌所得混合物隔夜，使用MeCN (3 X 2〇毫升)作為恆沸物予以濃縮。所得固體以Et：z〇與己烷研製，使其 /谷於水中冷/東乾燥，得到呈無色固體之化合物2d。MS 15 (ES+) m/z 172 (m+H+)〇經濟部智慧財產局員工消費合作社印製添加NMM (0.23毫升，2·η毫莫耳）至化合物2d (〇.2〇克，ο·7〇毫莫耳)之MeCN (Μ毫升)與DMF (2毫升) 溶液中。接著添加化合物2b (0·15克，0·70毫莫耳）、 ΝΜΜ (0·15毫升，L4〇毫莫耳）、Η〇ΒΤ (〇〇5克，〇 %毫 20莫耳)及HBTU (0.32克，〇·84毫莫耳），於攪拌此混合物1小時，隨後於室溫攪拌隔夜。添加飽和ΝΗΚΙ，濃縮此反應混合物，以EtOAc (25毫升）萃取。將有機層脫水（NajO4)，過濾，真空濃縮。粗產物利用Rp_HpLc (10-90% MeCN/水，0.1% tfa)進行純化，得到化合物 -91· 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公爱） 200536844 λ7 Β7 五、發明說明（90 ) 2e 〇 MS (ES+) m/z 401 (M+H十）。於(TC，使化合物2e (0·21克）溶於4N HC1 (20毫升) 中，於室溫攪拌此混合物隔夜。使用MeCN (3 X 25毫升) 作為恆沸物濃縮混合物，所得固體以EkO予以研製，得 5 到呈HC1鹽之化合物2。MS (ES+) m/z 387 (M+IT) ° lH NMR (DMSO-rftf, 300 MHz) S 0.93 (m, 4H), 1,46 (m, 4H), 1.67 (s, 1H), 1,88 (m, 2H), 2.25 (m, 2H)f 2.66 (m> 2H), 2.82 (m, 4H), 3.39 (m, 2H), 3.82 (d, y« 13 Hz, 1H), 4.39 (d, 7 =* 13 Hz, 1H), 7.15 (m, 3H)5 7.39 (m, 1H), 7.97 (br s, 1H), 9.45 (br s，1H> C2iH30N4Orl.S5 HCH.15 H20之元素分析計算值：C, 53.14; H，7 26;凡 11·81; H2〇, 4·37。實測值:C，53·19; H, 7,14; N, 11·91; H20· 4_62 ◊ 'Compound 2c (1.0 g, 39 mmol) in MeOH (2 (ml)). The resulting mixture was stirred overnight to melons and concentrated using MeCN (3 x 20 ml) as an azeotrope. The obtained solid was triturated with Et: z0 and hexane, and it was cooled / dried in water to obtain compound 2d as a colorless solid. MS 15 (ES +) m / z 172 (m + H +). Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs. Add NMM (0.23 ml, 2 · ηmmol) to compound 2d (0.20 g, ο · 70 mmol) in MeCN (M ml) and DMF (2 ml). Compound 2b (0. 15 g, 0. 70 mmol), NM (0. 15 ml, L40 mmol), ΗΒΤ (0.05 g, 0% mmol 20 mole) and HBTU were added next. (0.32 g, 0.84 mmol), the mixture was stirred for 1 hour, and then stirred at room temperature overnight. Saturated ΝΚΙΙ was added and the reaction mixture was concentrated and extracted with EtOAc (25 mL). The organic layer was dehydrated (NajO4), filtered, and concentrated in vacuo. The crude product was purified using Rp_HpLc (10-90% MeCN / water, 0.1% tfa) to obtain compound-91. The paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210x297 public love) 200536844 λ7 Β7 V. Description of the invention ( 90) 2e MS (ES +) m / z 401 (M + H). The compound 2e (0.21 g) was dissolved in 4N HC1 (20 ml) at (TC), and the mixture was stirred at room temperature overnight. The mixture was concentrated using MeCN (3 X 25 ml) as an azeotrope, and the resulting solid was EkO Developed to give compound 2 as HC1 salt. MS (ES +) m / z 387 (M + IT) ° lH NMR (DMSO-rftf, 300 MHz) S 0.93 (m, 4H), 1,46 (m , 4H), 1.67 (s, 1H), 1,88 (m, 2H), 2.25 (m, 2H) f 2.66 (m > 2H), 2.82 (m, 4H), 3.39 (m, 2H), 3.82 ( d, y «13 Hz, 1H), 4.39 (d, 7 = * 13 Hz, 1H), 7.15 (m, 3H) 5 7.39 (m, 1H), 7.97 (br s, 1H), 9.45 (br s, 1H > C2iH30N4Orl.S5 HCH.15 H20 Elemental analysis calculated value: C, 53.14; H, 7 26; Where 11.81; H2〇, 4.37. Found: C, 53 · 19; H, 7,14 ; N, 11 · 91; H20 · 4_62 ◊ ''

COOH 广N ^NH .HC1COOH Can N ^ NH .HC1

COOHCOOH

HC1 經濟部智慧財產局員工消費合作社印製 10HC1 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 10

Boc ' 2c 2d 4NHa(aq) 2bBoc '2c 2d 4NHa (aq) 2b

2e •HC1 化合物2 實例 /3-[1-[1>[(1，4,5,6-四氫-5羥基-2-嘧啶基）胺基]苯基]乙基]-4-旅咬基]-3-喹琳丙酸（化合物3) -92- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） A7 200536844 _____ _B7 五、發明說明（W) 添加祝〇-二甲基羥基胺鹽酸鹽（98%，2 55克，2617 毫莫耳）·、NMM (14.39毫升，13G 8毫莫耳）、臟τ (1 47 克’ 10.90毫莫耳)及HBTU (9 83克，％ 16毫莫耳）至化 σ物3a (5.00克’ 21.80毫莫耳)之MeCN (75毫升)溶液 5中。此混合物於（TC授拌！小時，於室溫麟隔夜，以飽和NH4C1終止反應，濃縮，以Et〇Ac (3 X %毫升）萃取。將有機層脫水(Na肌），真空濃縮。粗產物利用急驟管柱層析法(石夕谬，30-60%乙酸乙醋/己烧，添加數滴TEA)進仃純化，得到呈液體之化合物3][^ Ms (es 2乃 10 (Μ+Η+) ο 於-78C，以30分鐘，逐滴添加}BuU(25M己烷溶液7.34毫升，18.35毫莫耳）至含3-漠喹啉(3.81克， 18.35耄莫耳)之無水玢2〇（65毫升)攪拌溶液中。於攪拌此混合物30分鐘，以1〇分鐘逐滴添加含化合物外 15 (1·〇克，3.67毫莫耳)之Et2〇 (2〇毫升)溶液。所得混合物經濟部智慧財產局員工消費合作社印製於-78 C攪拌30分鐘，令其回升至室溫。於室溫攪拌2小時後，以飽和NHUCl終止反應，並以Et〇Ac予以稀釋。有機層以食鹽水洗滌，脫水(NaJO4)，真空濃縮。殘留物利用層析法（矽膠，15·25%乙酸乙酯/己烷）進行純化，得 2〇到呈液體之化合物3c。MS (ES+) m/z 341 (μ+η’。於〇C，氬氣下，以15分鐘添加含NaHMDS (1Μ， 3.17毫升，3·17毫莫耳）之Thf溶液至膦醯乙酸三甲酯 (0·5!毫升，3.17毫莫耳）之THF (15毫升)授拌溶液令。搜拌所得混合物20分鐘後，以15分鐘添加含化合物3c -93- 本紙張尺度適时_家標i^_s)A4規格⑽χ 297公爱） 200536844 A7 B7 五、發明說明（92 (0·27克，0.79毫莫耳）之丁HF (3毫升）溶液。此混合物於〇°C攪拌_30分鐘，回流加熱25小時，冷卻至室溫，以 EGO (30毫升)稀釋，並以飽和NaHC〇3溶液(2 χ 25毫升）與食鹽水(2 X 25毫升）洗滌。其水層以Et2〇萃取，將合併 5之有機層脫水(Na2S〇4)，真空濃縮。殘留物利用急驟管柱層析法（矽膠，10-30%乙酸乙酯/己烧）進行純化，得到呈五-與Z-異構物混合物之化合物3d。MS (ES+) m/z 397 (M+H+)。於氫氣壓（5 psi)下’在帕爾裝置中，振蘆化合物3d 10五-與厶異構物(0.25克，0.63毫莫耳)及1〇% Pd/C (0.12克) 之MeOH (15毫升）混合物隔夜。通過矽藻土過濾此混合物，並予以真空濃縮。粗產物利用急驟層析法（70%乙酸乙酉旨之己烧溶液）進行純化，得到呈油狀物之化合物3e。2e • HC1 Compound 2 Example / 3- [1- [1 > [(1,4,5,6-Tetrahydro-5hydroxy-2-pyrimidinyl) amino] phenyl] ethyl] -4-bite Base] -3-quinine propionic acid (Compound 3) -92- This paper size applies Chinese National Standard (CNS) A4 (210x297 mm) A7 200536844 _____ _B7 V. Description of the invention (W) Hydroxylamine hydrochloride (98%, 2 55 g, 2617 mmol), NMM (14.39 ml, 13G 8 mmol), dirty τ (1 47 g '10.90 mmol) and HBTU (9 83 G,% 16 mmol) to MeCN (75 ml) solution 5 of Sigma 3a (5.00 g '21 .80 mmol). This mixture was stirred at (TC! Hours, overnight at room temperature, quenched with saturated NH4C1, concentrated, and extracted with EtoAc (3 X% ml). The organic layer was dehydrated (Na muscle) and concentrated in vacuo. Crude product Purification using flash column chromatography (Shi Ximu, 30-60% ethyl acetate / hexane, adding a few drops of TEA) to obtain a liquid compound 3] [^ Ms (es 2 is 10 (M + Η +) ο At -78C, add} BuU (7.34 ml of 25M hexane solution, 18.35 mmol) to anhydrous 玢 2 containing 3-moquinoline (3.81 g, 18.35 mmol) at -78C over 30 minutes. (65 ml) was stirred. The solution was stirred for 30 minutes, and a solution of Compound 15 (1.0 g, 3.67 mmol) in Et20 (20 ml) was added dropwise over 10 minutes. The resulting mixture The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed it at -78 C and stirred it for 30 minutes to return it to room temperature. After stirring at room temperature for 2 hours, the reaction was terminated with saturated NHUCl and diluted with EtOAc. The organic layer was diluted with Washed with brine, dehydrated (NaJO4), and concentrated in vacuo. The residue was purified by chromatography (silica gel, 15.25% ethyl acetate / hexane). 20 to liquid compound 3c. MS (ES +) m / z 341 (μ + η ′. NaHMDS (1M, 3.17 ml, 3.17 mmol) was added at 0 ° C under argon for 15 minutes. Mol) of Thf solution to phosphonium phosphonium trimethyl acetate (0.5! Ml, 3.17 mmol) in THF (15 ml) as a stirring solution. After searching the resulting mixture for 20 minutes, add the compound containing 15 minutes. 3c -93- This paper is in a timely scale _ house standard i ^ _s) A4 size ⑽χ 297 public love) 200536844 A7 B7 V. Description of the invention (92 (0 · 27 g, 0.79 mmol) Ding HF (3 ml) This mixture was stirred at 0 ° C for 30 minutes, heated at reflux for 25 hours, cooled to room temperature, diluted with EGO (30 mL), and saturated with NaHC03 solution (2 x 25 mL) and brine (2 X 25 ml). The aqueous layer was extracted with Et20. The combined organic layers were dehydrated (Na2SO4) and concentrated in vacuo. The residue was subjected to flash column chromatography (silica gel, 10-30% ethyl acetate / hexane). Calcined) to obtain a compound 3d as a penta- and Z-isomer mixture. MS (ES +) m / z 397 (M + H +). Under hydrogen pressure (5 psi) in a Parr device, shake Luhuahe 3d 10 penta-mixture with osmium isomers (0.25 g, 0.63 mmol) and 10% Pd / C (0.12 g) in MeOH (15 ml) overnight. This mixture was filtered through celite and concentrated in vacuo . The crude product was purified by flash chromatography (70% acetic acid ethyl acetate solution) to obtain compound 3e as an oil.

MS (ES+) m/z 399 (M+H+)。4 NMR (DMSO^if 300 MHz) δ 1.38 (m, 4H), 1.41 (8> 9H), L80 (m, 1H), 2.53 (m, 2H)3 3.18 (m, 2H), 3.51 (s, 3H), 3.71 (m, 1H), 4.13 (m, 2H), 7.54 (t, 8 Hz, 1H), 7.69 (t,/* 8 15 Hz, 1H), 7.80 (d, 8 Hz, 1H), 7.89 (s, 1H), 8.09 (d, 8 ίίζ, 1H), 8.75 (s, 1H) 〇經濟部智慧財產局員工消費合作社印製使化合物3e (0.11克）溶於二呤烷(3毫升）中，添加1 滴甲苯醚及逐滴添加4N HC1之二呤烷(3毫升）溶液。於室溫攪拌此混合物2小時，使用MeCN作為恆沸物予以濃縮。所得固體以Et2〇及己烷研製，得到呈黏稠固體之 20 化合物 3f。MS (ES+) m/z -94- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 五、發明說明（93) 299 (M+H> NMR (DMS0-4 300 ΜΗζ) δ 1.34 (m，4H), ι·94 (m, 1H), 2 67 2H), 3.01 (m, 2H), 3.24 (m, 2H), 3.43 (s, 3H), 3.68 (m, 1H), 7.79 (t, 8 Hz itrN ^ * 丄灯)，7.94 (t,y= 8 Hz, 1H), 8.13 (d,y- 8 Hz, 1H), 8.23 (d,/-8 Hz, 1H), 8.48 (m, 1H), 8 7〇 1H)。CieH22>i202-2.2 TFA-0.4H2O之元素分析計算值：C，48·36; H, 4.53; \ 5 ⑽ m’ 22.54。實測值：C，4S.24; Η, 4·42; N, 4,99; F，22.56。 ' ’ F· 使1，3-二胺基-2-羥丙烷化合物3i (10·0克，1U毫莫耳）溶於乙醇（30毫升）及脫離子水(30毫升）中。維持溫声於25-33°C下，以35分鐘，經由添加漏斗逐滴添加二碎 5化碳(6.67毫升，110.95毫莫耳），得到乳白色混合物。將所得混合物回流加熱2小時，得到黃色溶液。於冰水中〆卻該混合物後，在維持混合物的溫度於25-26°C下，逐滴添加濃HC1 (7毫升）。接著提升此混合物之溫度至79t。授拌21小時後，冷卻混合物至2°C，以真空過濾法予以 10 過濾。收集白色固體，以冷乙醇與水之1:1混合物洗滌三次，於40°C真空乾燥，得到化合物3j。MS (ES+) m/zMS (ES +) m / z 399 (M + H +). 4 NMR (DMSO ^ if 300 MHz) δ 1.38 (m, 4H), 1.41 (8 > 9H), L80 (m, 1H), 2.53 (m, 2H) 3 3.18 (m, 2H), 3.51 (s, 3H ), 3.71 (m, 1H), 4.13 (m, 2H), 7.54 (t, 8 Hz, 1H), 7.69 (t, / * 8 15 Hz, 1H), 7.80 (d, 8 Hz, 1H), 7.89 (s, 1H), 8.09 (d, 8 ίζ, 1H), 8.75 (s, 1H) 〇 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs to dissolve compound 3e (0.11 g) in diuridine (3 ml) Add 1 drop of toluene ether and dropwise a solution of 4N HC1 bispyridine (3 ml). The mixture was stirred at room temperature for 2 hours, and concentrated using MeCN as an azeotrope. The resulting solid was triturated with Et20 and hexane to give compound 20f as a viscous solid. MS (ES +) m / z -94- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200536844 A7 B7 V. Description of the invention (93) 299 (M + H > NMR (DMS0-4 300 ΜΗζ ) δ 1.34 (m, 4H), ι · 94 (m, 1H), 2 67 2H), 3.01 (m, 2H), 3.24 (m, 2H), 3.43 (s, 3H), 3.68 (m, 1H) , 7.79 (t, 8 Hz itrN ^ * 丄 lamp), 7.94 (t, y = 8 Hz, 1H), 8.13 (d, y- 8 Hz, 1H), 8.23 (d, /-8 Hz, 1H), 8.48 (m, 1H), 8 7〇1H). CieH22 > i202-2.2 TFA-0.4H2O Elemental analysis calculated value: C, 48 · 36; H, 4.53; \ 5 ⑽ m ′ 22.54. Found: C, 4S.24; Η, 4.42; N, 4,99; F, 22.56. '' F · The 1,3-diamino-2-hydroxypropane compound 3i (10.0 g, 1 U mol) was dissolved in ethanol (30 ml) and deionized water (30 ml). Maintaining the temperature and sound At 25-33 ° C, 35 cm of carbon dioxide (6.67 ml, 110.95 mmol) was added dropwise through the addition funnel dropwise to obtain a milky white mixture. The resulting mixture was heated at reflux for 2 hours to obtain a yellow solution. After the mixture was decanted in ice water, concentrated HC1 (7 ml) was added dropwise while maintaining the temperature of the mixture at 25-26 ° C. The temperature of this mixture was then raised to 79t. After 21 hours of incubation, the mixture was cooled to 2 ° C and filtered by vacuum filtration. The white solid was collected, washed three times with a 1: 1 mixture of cold ethanol and water, and dried under vacuum at 40 ° C to obtain compound 3j. MS (ES +) m / z

174 (NTMeCN) ο ^ NMR (DMSO-cf^ 300 MHz) δ 2.96 (d, 15 Hz, 2H), 3.15 (d, J « 13 Hz，2H)，3.33 (吼 1H)，3.S9 扭 1H)。經濟部智慧財產局員工消費合作社印製添加曱基碘(2.9毫升，46毫莫耳）至含化合物3j (61 克，46毫莫耳)之無水乙醇(35毫升)攪拌溶液中，回流加 15熱此混合物1小時’冷卻至室溫。濃縮後，殘留物以 EGO研製，真空乾燥，得到呈白色固體之化合物3k。 MS (ES十）m/z 188 (M+MeCN)。咕 NMR (DMSO^, 300 MHz) δ 2.59 (s, 3H), 3,23 (d, J* 13 Hz, 2H), 3.43 (d, /-13 1H)。 ’ ’ 添加TEA (6.91毫升，49.61毫莫耳）至含化合物3k -95- 本紙張尺度適用中國g標準(CNS)A4規格（21〇χ297公嫠） --- 200536844 A7 B7 五、發明說明（94 ) (13.06克，49.61毫莫耳)之DCM (50毫升）與DMA (5毫升）溶液中。於冰浴中冷卻此混合物，於4°C，添加Boc2〇 (10.82克，49.61毫莫耳）。於41-43°C加熱此混合物丨8小時，得到淡黃色溶液。所得溶液以水(3 X 75毫升）洗滌， 5 脫水(NajCU)，真空濃縮，得到呈固體之化合物31。 MS (ES+) m/z 247(½^) 〇 4 NMR (DMSO·^，300 ΜΗζ) δ 1·46 0, 9田，1,95 (s， 3H)，2.14 (m，2H)，2.94 (m, 2H), 3·51 (m，1H)。添加3-胺苯基乙酸化合物id (2·60克，17.25毫莫耳）至化合物31 (5·1克，21毫莫耳）之DMA (5毫升）溶液中。此混合物於100 °C加熱2天，冷卻至室溫，以 10 MeCN(75毫升)稀釋。過濾所得沉澱，以MeCN與Et2〇洗滌，然後使其混於水中，並以濃HC1酸化。冷凍乾燥後，得到呈白色固體之化合物3m。MS (ES+) m/z 250 (M+H4)。hNMR(DMSO·办,300MHz)δ3,16 (d,13 Hz,23)，3,33 (4 J ** 13 Hz, 2H), 3.59 (s, 2H), 7.12 (m, 3H), 7.35 (m, 1H), 8.14 (s, lH}e174 (NTMeCN) ο ^ NMR (DMSO-cf ^ 300 MHz) δ 2.96 (d, 15 Hz, 2H), 3.15 (d, J «13 Hz, 2H), 3.33 (1H), 3.S9 1H) . Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Add thallium iodide (2.9 ml, 46 mmol) to a stirred solution of anhydrous ethanol (35 ml) containing compound 3j (61 g, 46 mmol). This mixture was warmed for 1 hour and cooled to room temperature. After concentration, the residue was triturated with EGO and dried under vacuum to give compound 3k as a white solid. MS (ES 10) m / z 188 (M + MeCN). NMR (DMSO ^, 300 MHz) δ 2.59 (s, 3H), 3,23 (d, J * 13 Hz, 2H), 3.43 (d, / -13 1H). '' Add TEA (6.91 ml, 49.61 mmol) to the compound containing 3k -95- This paper size is applicable to the Chinese g standard (CNS) A4 specification (21〇χ297 cm) --- 200536844 A7 B7 V. Description of the invention ( 94) (13.06 g, 49.61 mmol) in DCM (50 mL) and DMA (5 mL). The mixture was cooled in an ice bath, and Boc20 (10.82 g, 49.61 mmol) was added at 4 ° C. This mixture was heated at 41-43 ° C for 8 hours to obtain a pale yellow solution. The resulting solution was washed with water (3 X 75 ml), dried (NajCU), and concentrated in vacuo to give compound 31 as a solid. MS (ES +) m / z 247 (½ ^) 〇4 NMR (DMSO · ^, 300 ΜΗζ) δ 1.46 0, 9 fields, 1,95 (s, 3H), 2.14 (m, 2H), 2.94 ( m, 2H), 3.51 (m, 1H). 3-Aminophenylacetic acid compound id (2.60 g, 17.25 mmol) was added to a solution of compound 31 (5.1 g, 21 mmol) in DMA (5 ml). The mixture was heated at 100 ° C for 2 days, cooled to room temperature, and diluted with 10 MeCN (75 mL). The resulting precipitate was filtered, washed with MeCN and Et20, then mixed in water and acidified with concentrated HC1. After freeze-drying, 3 m of the compound was obtained as a white solid. MS (ES +) m / z 250 (M + H4). hNMR (DMSO · 300MHz) δ3,16 (d, 13 Hz, 23), 3,33 (4 J ** 13 Hz, 2H), 3.59 (s, 2H), 7.12 (m, 3H), 7.35 ( m, 1H), 8.14 (s, lH) e

使用實例2所述化合物2d轉化成化合物2e之程序轉 15 化化合物3m ’提供呈固體之化合物3n。MS 經濟部智慧財產局員工消費合作社印製 (ES+) m/z 530 (M+H4)。lHNMR (DMSO-办,300 MHz) δ 0.92 (m, 4H), I33 机 2H)， 1 ·90 (m，1H)，2.8S (m, 4H), 3·17 (m，3H)，333 (m，2H), 3.43 (s, 3H)· 4加㈣2Η)， 4.32 (m, 1H), 6.98 (m, 3H), 7.27 (m, 1H), 7.48 (m, 1H), 7.66 (m, 1H), 7.79 (m, 1H), 8.01 (m, 3H), S.25 (br s, 1H), 8.83 (br 8, lH)〇The procedure for converting compound 2d to compound 2e described in Example 2 into compound 3m 'was used to provide compound 3n as a solid. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (ES +) m / z 530 (M + H4). lHNMR (DMSO-office, 300 MHz) δ 0.92 (m, 4H), I33 machine 2H), 1.90 (m, 1H), 2.8S (m, 4H), 3.17 (m, 3H), 333 ( m, 2H), 3.43 (s, 3H) · 4 plus ㈣2Η), 4.32 (m, 1H), 6.98 (m, 3H), 7.27 (m, 1H), 7.48 (m, 1H), 7.66 (m, 1H ), 7.79 (m, 1H), 8.01 (m, 3H), S.25 (br s, 1H), 8.83 (br 8, lH).

使用實例2所述化合物2e轉化成化合物2之程序轉化化合物3n，提供呈固體之化合物3。MS -96· 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 經濟部智慧財產局員工消費合作社印製Compound 3n was converted using the procedure for converting compound 2e to compound 2 described in Example 2 to provide compound 3 as a solid. MS-96 · This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200536844 A7 B7 Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

200536844 A7 B7 五、發明說明（96 ) 使用實例3之程序，及熟習此項技藝人士已知之適當試劑與起始物質，可製備本發明其他化合物包含，惟不限於：化合物_名稱 _ MS (m/z) 14 /5-(1,3-苯弁二〇亏琢戍稀-5-基466 酮基-3-(5,6,7,8-四氫-1，8-萘咬_2_基）丙基]-4-旅咬丙酸 15 冷-(1，3-苯并二啐環戊烯-5-基480 酮基_4-(5,6,7,8-四氫-1，8-萘啶-2-基）丁基]-4-哌啶丙酸 16 召-(1，3-苯并二啐環戊烯-5-基）-1- 452 [(5,6,7,8-四氫-1,8-萘咬-2-基）乙醯基]-4-哌啶丙酸 17 6-曱氧基-yS -[1-[1-酮基-4-(5,6,7,8-四 467 氫-1，8-萘啶-2-基）丁基]-4-哌啶基]-3- 吡啶丙酸實例4 5 冷-酮基-4-(5,6,7,8-四氫-1,8-萘啶-2-基）丁基]-4-哌咬基]-3-喧琳丙酸(化合物4) 經濟部智慧財產局員工消費合作社印製如WO 99/31061所述製備化合物4a。使用實例2所述化合物2d轉化成化合物2e之程序轉化化合物4a，並利用RP-HPLC (10_70%乙腈/水，0.1% TFA)進行純化，得 10 到化合物4b。 MS (ES+) m/z 501 (Μ+ίΤ) 〇 JH NMR (DMS^, 300 MHz) δ L02 (m, 4H), L33 (m, 1H), 2.86 (m, 4H), 2.29 (m, 2H), 2.61 (m, 2H) 172 (m, 2H), 2.86 (m, 2H), 2.98 (m, 2H), 3.17 (m$ 1H), 3.44 (s, 3H), 3.78 (m, 2H), 4.35 (m, 2H), 6.52 (d, /- 7 Hz, 1H), 7 (d, /- 7 Hz, 1H), 7.78 (m, 2H), 7.99 (m, 2H), 8.41 (g, 1H), 8.91 (s, 1H)。 -98- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 五、發明說明（97 使用實例2所述化合物2e轉化成化人化化合物4b，提供呈黏稠固體之化合物j々2之程序轉 MS (ES+) m/z 487 (M+H4) ^ NMR (DMSO-d^, 3〇〇 t* 1H)，186 (m, 4H)，2,30 (m，2H), 2·69 (m，2H)，2.81 (洱 1H^ 2 9〇'" (¾ 4H), 1·49 (取 2H), 3·33 (叫 1H)，3.79 (m，2H)· 4·4】（m, 2H), 6·55 (d^· 7’也2 (m，2H), 3·13 机 Hz, 1H)，7·86 (m, 1H), 7.98 机 2H), 8.72 (取 2H), 8·83 (s· 1H)、7·56 (cU= 7 (：29擊403-3.5 HC1-H20之元素分析計算值:Q 55.09; H•心9，1S (4,1H> 實測值：C，54.S3; Η, 6·53; N, 9,08; H20, 3·24。 ’、8批;H20, 3·24» 3f,200536844 A7 B7 V. Description of the invention (96) Using the procedure of Example 3, and appropriate reagents and starting materials known to those skilled in the art, other compounds of the present invention can be prepared, but not limited to: Compound_Name_ MS (m / z) 14 / 5- (1,3-Benzenebioxo-2-oxo-5-yl466 keto-3- (5,6,7,8-tetrahydro-1,8-naphthalene bite_2 _) Propyl] -4-propanyl propionate 15 cold- (1,3-benzodifluorene cyclopenten-5-yl 480 keto_4- (5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl) butyl] -4-piperidinepropanoic acid 16- (1,3-benzodifluorenecyclopenten-5-yl) -1- 452 [(5,6 , 7,8-tetrahydro-1,8-naphthyl-2-yl) ethenyl] -4-piperidinepropionic acid 17 6-fluorenyloxy-yS-[1- [1-keto-4- (5,6,7,8-tetra467-Hydro-1,8-naphthyridin-2-yl) butyl] -4-piperidinyl] -3-pyridinepropanoic acid Example 4 5 Cold-keto-4- (5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl) butyl] -4-piperidinyl] -3-propanepropionic acid (Compound 4) Employee, Intellectual Property Bureau, Ministry of Economic Affairs Consumer Cooperative printed compound 4a as described in WO 99/31061. Compound 4a was converted using the procedure for converting compound 2d to compound 2e described in Example 2, and RP-HPLC (10_70% acetonitrile / water, 0.1 % TFA) to obtain 10 to compound 4b. MS (ES +) m / z 501 (Μ + ίΤ) 〇JH NMR (DMS ^, 300 MHz) δ L02 (m, 4H), L33 (m, 1H), 2.86 (m, 4H), 2.29 (m, 2H), 2.61 (m, 2H) 172 (m, 2H), 2.86 (m, 2H), 2.98 (m, 2H), 3.17 (m $ 1H), 3.44 ( s, 3H), 3.78 (m, 2H), 4.35 (m, 2H), 6.52 (d, /-7 Hz, 1H), 7 (d, /-7 Hz, 1H), 7.78 (m, 2H), 7.99 (m, 2H), 8.41 (g, 1H), 8.91 (s, 1H) -98- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200536844 A7 B7 V. Description of the invention (97 The compound 2e described in Example 2 was used to convert the humanized compound 4b to provide the compound j 程序 2 as a viscous solid. MS (ES +) m / z 487 (M + H4) ^ NMR (DMSO-d ^, 3) 〇t * 1H), 186 (m, 4H), 2,30 (m, 2H), 2.69 (m, 2H), 2.81 (洱 1H ^ 2 9〇 '" (¾ 4H), 1.49 (Take 2H), 3.33 (called 1H), 3.79 (m, 2H), 4 · 4] (m, 2H), 6.55 (d ^ · 7 'also 2 (m, 2H), 3 · 13 Machine Hz, 1H), 7.86 (m, 1H), 7.98 machine 2H), 8.72 (take 2H), 8.83 (s · 1H), 7.56 (cU = 7 (: 29 hits 403-3.5 HC1 -H20 elemental analysis calculation value: Q 55.09; H • Heart 9, 1S (4,1H > found: C, 54.S3; 3, 6.53; N, 9,08; H20, 3.24. ’, 8 batches; H20, 3.24» 3f,

經濟部知曰慧財產局員工消費合作社印製 5 實例5 1，2,3,4-四氫-泠_[1-[1-酮基-4-(5,65758-四氫、丁基]-4-哌啶基]-3-喹啉丙酸萘啶_2_基） ^ 4b 使用實例3所述化合物3d轉化成^匕人# ) 惟係於氬氣壓(30 psi H2)下，使化合物二^之程序’ Μ進行氫化反應 10 48小時，並予以純化，得到化合物5a。MS (ES+) m/zPrinted by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 Example 5 1,2,3,4-Tetrahydro-Ling_ [1- [1-keto-4- (5,65758-tetrahydro, butyl] 4-piperidinyl] -3-quinolinpropionate naphthyridin-2-yl) ^ 4b The compound described in Example 3 3d was converted to ^ 匕人 #) only under argon pressure (30 psi H2), so that The procedure of Compound 2 was hydrogenated for 10 48 hours and purified to obtain Compound 5a. MS (ES +) m / z

403 (M+HV *H NMR (DMSO^, 300 MHz) δ 0.94 (m, 4H), 1,35 (s, 9H), L69 (m, 1H), L79 (m, 3H), 2.71 (m, 2H), 2.81 (m, 2H), 2.83 (m. 2H)f 3.32 (s, 3H), 3.94 (m, 1H), 4.02 (m, 2H), 7.21 (m, 2H), 7·61 (m, 1H), 7.91 (m, 1H)。 -99- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） .200536844 A7 B7 五、發明說明（98403 (M + HV * H NMR (DMSO ^, 300 MHz) δ 0.94 (m, 4H), 1,35 (s, 9H), L69 (m, 1H), L79 (m, 3H), 2.71 (m, 2H), 2.81 (m, 2H), 2.83 (m. 2H) f 3.32 (s, 3H), 3.94 (m, 1H), 4.02 (m, 2H), 7.21 (m, 2H), 7.61 (m , 1H), 7.91 (m, 1H). -99- This paper size is applicable to China National Standard (CNS) A4 (210x297 mm). 200536844 A7 B7 V. Description of the invention (98

使用實例3所述化合物3e轉化成化合物3f之程序轉化化合物5a ’提供呈固體之化合物5b。MS (ES+)m/z 303 (M+H4)» 4NMR (DMS04 300 MHz) δ 1·61 (m，4H)，1·82 机 1H)， Ζ32 (m, 1H), 2.44 (m, 2H)f 2.78 (m, 2H), 3.25 (m, 2H), 3.35 (m, 2H), 3.62 (s, 3H), 3·78 (m，3H)，7·16 (m, 2H), 8.76 (m, 2H)。使用實例2所述化合物2d轉化成化合物2e之程序’ 使化合物4a與化合物5b反應，並利用RP-HPLC (10-70%乙腈/水，〇.l%TFA)純化，得到化合物5c。MS (ES+) m/z 505 NMR (DMSO·*，300 MHz) δ 1.11 (m, 4H)，1.S6 (m» 1H), 1.79 (m, 6H), 2.32 (m, 4H), 2.66 (m, 2H), 2.77 (mt 2H), 2.91 (m, 2H), 3.16 (m, 2H)# 3.5 (m, 2H), 3.62 (s, 3H), 3,82 (m, 2H), 4.43 {m, 2H), 6.58 (¾ 3H), 7.63 (d, 7 Hz, 1H), 7,93(ιη·2Η)β 使用實例2所述化合物2e轉化成化合物2之程序轉Conversion of compound 5a 'using the procedure for converting compound 3e to compound 3f described in Example 3 provides compound 5b as a solid. MS (ES +) m / z 303 (M + H4) »4NMR (DMS04 300 MHz) δ 1.61 (m, 4H), 1.82 machine 1H), ZE32 (m, 1H), 2.44 (m, 2H) f 2.78 (m, 2H), 3.25 (m, 2H), 3.35 (m, 2H), 3.62 (s, 3H), 3.78 (m, 3H), 7.16 (m, 2H), 8.76 (m , 2H). Using the procedure for converting compound 2d to compound 2e described in Example 2 ', compound 4a was reacted with compound 5b and purified by RP-HPLC (10-70% acetonitrile / water, 0.1% TFA) to obtain compound 5c. MS (ES +) m / z 505 NMR (DMSO · *, 300 MHz) δ 1.11 (m, 4H), 1.S6 (m »1H), 1.79 (m, 6H), 2.32 (m, 4H), 2.66 ( m, 2H), 2.77 (mt 2H), 2.91 (m, 2H), 3.16 (m, 2H) # 3.5 (m, 2H), 3.62 (s, 3H), 3,82 (m, 2H), 4.43 { m, 2H), 6.58 (¾ 3H), 7.63 (d, 7 Hz, 1H), 7,93 (ιη · 2Η) β The procedure for converting compound 2e to compound 2 described in Example 2 is used.

化化合物5c，提供呈HC1鹽之化合物5。MS (ES+) m/z 491 {M+HO »1HNMR (DMSO-iitf, 300 MHz) δ 1.13 (m, 4H), L54 (m, 2H), 1.77 (ms 4H), 2.21 (m, 4H), 2.37 (m, 1H), 2.64 (m, 2H), 2.71 (m, 2H), 2.96 (m, 2H), 3.23 (m, 2H)S 3.45 (β, 2H), 3.84 (m, 2H), 4.45 (m, 2H), 6.54 (m, 3H), 6.98 (m, 2H), 10 7*61 (d, & Hz, 1H)，8.01 (br s, 1H)。經濟部智慧財產局員工消費合作杜印製Compound 5c is provided to provide Compound 5 as a HC1 salt. MS (ES +) m / z 491 (M + HO »1HNMR (DMSO-iitf, 300 MHz) δ 1.13 (m, 4H), L54 (m, 2H), 1.77 (ms 4H), 2.21 (m, 4H), 2.37 (m, 1H), 2.64 (m, 2H), 2.71 (m, 2H), 2.96 (m, 2H), 3.23 (m, 2H) S 3.45 (β, 2H), 3.84 (m, 2H), 4.45 (m, 2H), 6.54 (m, 3H), 6.98 (m, 2H), 10 7 * 61 (d, & Hz, 1H), 8.01 (br s, 1H). Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs

5c 4NHC1 (aq) •HC1¢0^f 化合物55c 4NHC1 (aq) • HC1 ¢ 0 ^ f Compound 5

HH

-100- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） .200536844 A7 B7 99 五、發明說明（使用實例5之程序，及熟習此項技藝人士已知之適當試劑與起始物質，可製備本發明其他化合物包含，惟不限於：化合物名稱 MS (m/z) 18 19 1，4,5,6-四氫-2-甲基_/3-[[1-[1-酮基-3_(5,6,7,8_ 四氫-1ί8萘咬 _2-基）丙基]_ 4_派3淀基]曱基嘴咬丙酸 (/5 1^35>1，2,3,4-四氫_冷-[[1-[1-酮基_3-(5,6,7,8-四氫-1，8·萘啶_2_基）丙基]-4-哌啶基喹啉丙酸 456 491 10 經濟部智慧財產局員工消費合作社印製 f例6 冷-[2_0[3_[(M，5,6-四氫|嘧啶基）胺基]苯甲醯基]_4, 啶基]乙基]-3·%啶丙酸(化合物6) 使用實例3所述化合物3a轉化成化合物31)之卷序，將JV-Boc-哌啶-4-丙酸化合物2c轉化成化合物以[每色液體；利用急驟層析法(於碎膠上，以3〇·5〇%乙酸乙齡 /添加數滴TEA之己燒溶洗）純化]〇MS (ES+)m/z301 =㈣丨.45 講，1 购满 1,8 (m, 2H), 2.44 7.5 HZ, 2H), 2.63 (π, 2H)> 3.18 (s, 3H), 3.68 (S> 3H), 4.08 (. 使用實你]3所述化合物3b轉化成化合物&之程序，將化合物6a轉化成化合物6b (於於脚 (於石夕膠上利用急驟層析沒進行純化，以30-50%乙酸乙酷/夭^ 曰/添加數滴TEA之己烷淳 15 洗）。MS (ES+) m/z 319 (M+H+)。使用實例3所述化合物3c轉化成化合物3d之程序， -10U · 本紙張尺度適用中國國家標準(CNS)A4規格（210x297 200536844 a7 B7 五、發明說明（100) 將化合物6b轉化成化合物6C (於矽膠上利用急驟層析法進行純化，以30-50%乙酸乙酯/添加數滴丁EA之己烷溶洗）。MS (ES+) m/z 375 (M+H )。使用實例3所述化合物3d轉化成化合物3e之程序， 5 將化合物6c轉化成化合物6d (於矽膠上利用急驟層析法進行純化，以15-35%乙酸乙酯/添加數滴TEA之己烧溶洗）。 MS(ES-h)m/z377(M+ir)° 1HNMR(DMSO^,300MHz)60.91 (m, 4H), U2 (m, 2H), 1.29 (m, 1H), 1.41 (s, 9H)f 1.53 (m, 3H), 2.63 (m, 2H), 3.98 (m, 2H), 3.35 (s, 3H), 3.48 (m, 1H), 3.88 (m, 2H), 7.34 (m, IH), 7.68 (m, 1H), 8.43 (m, 2H)« 使用實例3所述化合物3e轉化成化合物3f之程序， 10 將化合物6d轉成化合物6e (白色固體）。MS (ES+) mJz 277 (M+H4)« lH NMR (DMSO^, 300 MHz) δ 0.91 (m, 2H), 1.19 (m, 4H), 1.44 (m, 1H), 1.71 (mt 2H)f 2.71 (m, 2H), 2.82 (m, 2H), 3.08 (mf 2H), 3,21 (m, lii), 3.49 (s, 3H), 7.51 (m，1H), 7·94 (nUH)· 8·53 (¾ 2H)。經濟部智慧財產局員工消費合作社印製使用實例1所述化合物lc轉化成化合物le之程序，使化合物lc與3-胺基苯甲酸化合物6f反應，得到呈白色非晶固體之化合物6g。 MS (ES+) m/z 220 (M+H")。冶 15 NMR (DMS04, 300 ΜΗζ) δ 4·13 (m, 2H), 5·42 仏 5 Hz，4H), 6·81 (m, 4H)。使用實例1所述化合物lj轉化成化合物lk之程序，使化合物6g與化合物6e反應，產生化合物6h (經由RP-HPLC 純化：5-50%乙腈/水，〇·1〇/0 TFA)。MS (ES+) m/z 478 (M+H+) 〇 -102- 厂紙張尺度適用中國國家標準(CNS)A4規袼（210x297公*) " 200536844 A7 B7 五、發明說明（H31) 使用實例2所述化合物2e轉化成化合物2之程序，轉化化合物6h成為化合物6 (經由RP-HPLC純化·· 5-50% 乙腈/水，0.1% TFA)。 MS(ES+)m/z464(M+tf> ^NMRpMSCX, 300 MHz) δ 1.11 (m, 2Η), L19 (m, 2H), 1.49 (m9 4H), 1.68 (m, 1H), 1.72 (m, 4H), 2.72 (m, 4H), 3.15 (m, 1H), 165 (m, 2H), 4.38 (m, 2H), 7.12-7.51 (m, 4H), 7.73 (m, 1H), 8.21 (m，IH)，8,65(1¾ 2H)。-100- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm). 200536844 A7 B7 99 V. Description of the invention (use the procedure of Example 5 and appropriate reagents and starting materials known to those skilled in the art Other compounds of the present invention can be prepared including, but not limited to: Compound name MS (m / z) 18 19 1,4,5,6-tetrahydro-2-methyl_ / 3-[[1- [1-one -3_ (5,6,7,8_ Tetrahydro-1ί8naphthalene-2-yl) propyl] _ 4_Py3Yridyl] fluorenyl mouth bite propionic acid (/ 5 1 ^ 35 > 1,2, 3,4-tetrahydro_cold-[[1- [1-keto_3- (5,6,7,8-tetrahydro-1,8 · naphthyridin_2_yl) propyl] -4- Piperidinylquinolinepropionic acid 456 491 10 Example f printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. Cold- [2_0 [3 _ [(M, 5,6-tetrahydro | pyrimidinyl) amino] benzylidene ] _4, pyridyl] ethyl] -3 ·% pyridylpropionic acid (compound 6) Using the sequence of converting compound 3a to compound 31) described in Example 3, JV-Boc-piperidine-4-propionic acid compound 2c The compounds were converted into compounds and purified by [per color liquid; purified by flash chromatography (on crushed gel with 30.50% acetic acid in ethyl acetate / fired with a few drops of TEA)] MS (ES +) m / z301 = ㈣丨 .45, 1 Purchase 1,8 (m, 2H), 2.44 7.5 HZ, 2H), 2.63 (π, 2H) > 3.18 (s, 3H), 3.68 (S > 3H), 4.08 (. Use real you) as described in 3 Procedure for converting compound 3b into compound & convert compound 6a to compound 6b (on Yujiao (on Shi Xijiao, using flash chromatography without purification, 30-50% ethyl acetate / 夭 ^ / added number) Drop of TEA's Hexane 15 wash). MS (ES +) m / z 319 (M + H +). Use the procedure of compound 3c described in Example 3 to convert compound 3d, -10U · This paper size applies Chinese National Standard (CNS ) A4 specification (210x297 200536844 a7 B7 V. Description of the invention (100) Conversion of compound 6b to compound 6C (purified by flash chromatography on silica gel with 30-50% ethyl acetate / a few drops of EA) Solvent wash). MS (ES +) m / z 375 (M + H). Using the procedure described in Example 3 to convert compound 3d to compound 3e, 5 convert compound 6c to compound 6d (using flash chromatography on silica gel). Purify and wash with 15-35% ethyl acetate / diluted TEA in hexane. MS (ES-h) m / z377 (M + ir) ° 1HNMR (DMSO ^, 300MHz) 60.91 (m, 4H ), U2 (m, 2H), 1.29 (m, 1H) , 1.41 (s, 9H) f 1.53 (m, 3H), 2.63 (m, 2H), 3.98 (m, 2H), 3.35 (s, 3H), 3.48 (m, 1H), 3.88 (m, 2H), 7.34 (m, IH), 7.68 (m, 1H), 8.43 (m, 2H) «Using the procedure described in Example 3 to convert compound 3e to compound 3f, 10 Convert compound 6d to compound 6e (white solid). MS (ES +) mJz 277 (M + H4) «lH NMR (DMSO ^, 300 MHz) δ 0.91 (m, 2H), 1.19 (m, 4H), 1.44 (m, 1H), 1.71 (mt 2H) f 2.71 (m, 2H), 2.82 (m, 2H), 3.08 (mf 2H), 3,21 (m, lii), 3.49 (s, 3H), 7.51 (m, 1H), 7.94 (nUH) · 8 53 (¾ 2H). Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Using the procedure for converting compound lc into compound le as described in Example 1, the compound lc is reacted with 3-aminobenzoic acid compound 6f to obtain 6g of compound as a white amorphous solid. MS (ES +) m / z 220 (M + H "). 15 NMR (DMS04, 300 ΜΗζ) δ 4.13 (m, 2H), 5.42 仏 5 Hz, 4H), 6.81 (m, 4H). Using the procedure for converting compound lj to compound lk described in Example 1, compound 6g was reacted with compound 6e to produce compound 6h (purified via RP-HPLC: 5-50% acetonitrile / water, 0.1 / 10/0 TFA). MS (ES +) m / z 478 (M + H +) 〇-102- The paper size of the factory applies the Chinese National Standard (CNS) A4 Regulation (210x297 male *) " 200536844 A7 B7 V. Description of the Invention (H31) Application Example 2 The procedure for converting compound 2e into compound 2 and converting compound 6h into compound 6 (purification via RP-HPLC · 5-50% acetonitrile / water, 0.1% TFA). MS (ES +) m / z464 (M + tf > ^ NMRpMSCX, 300 MHz) δ 1.11 (m, 2Η), L19 (m, 2H), 1.49 (m9 4H), 1.68 (m, 1H), 1.72 (m, 4H), 2.72 (m, 4H), 3.15 (m, 1H), 165 (m, 2H), 4.38 (m, 2H), 7.12-7.51 (m, 4H), 7.73 (m, 1H), 8.21 (m , IH), 8,65 (1¾ 2H).

經濟部智慧財產局員工消費合作社印製 -103- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 102 五、發明說明Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -103- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200536844 A7 B7 102 V. Description of the invention

lclc

召-[2-[1-[3-[(1，4,5,6-四氫-5-羥基-2-嘧啶基）胺基]苯曱醯基]-4-哌啶基]乙基>3-吡啶丙酸（化合物7) 5 使用實例3所述化合物31轉化成化合物3m之程序，使化合物31與3-胺基苯甲酸化合物6f反應，得到呈白色非晶固體之化合物7a。Call- [2- [1- [3-[(1,4,5,6-Tetrahydro-5-hydroxy-2-pyrimidinyl) amino] phenylfluorenyl] -4-piperidinyl] ethyl > 3-Pyridinepropionic acid (compound 7) 5 Using the procedure for converting compound 31 described in Example 3 to compound 3m, compound 31 was reacted with 3-aminobenzoic acid compound 6f to obtain compound 7a as a white amorphous solid.

MS (ES+) mJz 235 (Μ+ϊΤ) 〇 !H NMR 經濟部智慧財產局員工消費合作社印製 (DMSO^, 300 MHz) δ 3.18 12 Hz, 2H), 3.35 (d, 12 Hz, 2H), 4.09 (m, 1H), 7,55(m,2H)，7.84(m，2H)。使用實例3所述化合物3m轉化成化合物3ri之程 10 序，使化合物7a與化合物6e反應，產生化合物7b (白色固體；利用 RP-HPLC純化：2-30%乙腈/水，0.1%MS (ES +) mJz 235 (Μ + ϊΤ) 〇! H NMR Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs (DMSO ^, 300 MHz) δ 3.18 12 Hz, 2H), 3.35 (d, 12 Hz, 2H), 4.09 (m, 1H), 7,55 (m, 2H), 7.84 (m, 2H). The procedure for converting compound 3m to compound 3ri described in Example 3 was used to react compound 7a with compound 6e to produce compound 7b (white solid; purified by RP-HPLC: 2-30% acetonitrile / water, 0.1%

TFA)。MS (ES+) m/z 494 (M+HV 使用實例3所述化合物3n轉化成化合物3之程序轉 -104- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x297公釐） 200536844 A7 B7 五、發明說明（1〇3 化化合物7b，得到呈白色固體之化合物7。 MS (ES+) m/z 480 (M+H4) 〇 NMR (DMSO^ 300 MHz) δ 1.03 (m, 2H), 2.22 (xn, 4H), L49 (m, 1H), 1.66 (m, 2H), 2.65 (m, 2H), 2.76 (m, 2H), 3.06 (m, 2H), 3.18 (m, 4H), 3.34 (m, 1H), 4.13 (s, 1H), 7.12-SJ8 (m, 8H), 9.91 (s, 1H) 〇TFA). MS (ES +) m / z 494 (M + HV Procedure for conversion of compound 3n into compound 3 described in Example 3 -104- This paper size applies to Chinese National Standard (CNS) A4 (210 x297 mm) 200536844 A7 B7 V. Description of the invention (Compound 10b was compounded to obtain compound 7 as a white solid. MS (ES +) m / z 480 (M + H4) NMR (DMSO ^ 300 MHz) δ 1.03 (m, 2H), 2.22 (xn, 4H), L49 (m, 1H), 1.66 (m, 2H), 2.65 (m, 2H), 2.76 (m, 2H), 3.06 (m, 2H), 3.18 (m, 4H), 3.34 ( m, 1H), 4.13 (s, 1H), 7.12-SJ8 (m, 8H), 9.91 (s, 1H).

SMe H2N C〇OH HSMe H2N C〇OH H

4NHC14NHC1

經濟部智慧財產局員工消費合作社印製 7b 、實例8 5 /9 -[2-[ 1 -[ 1 -嗣基-3-(5,6,7,8-四氮 1，8-蔡咬-2-基）丙基]-4-口底啶基]乙基]-3-吡啶丙酸（化合物8) 酸化合物8a係如WO 99/31061所述，衍生自對應乙酯，其合成法見述於WO 00/72801。使用實例5所述化合物4a轉化成化合物5c之程序， 10 使化合物8a與化合物6e反應，得到化合物8b (利用RP-HPLC 進行純化：10-90%乙腈/水，0.1% TFA)。MS (ES+) -105- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公漦） 200536844 A7 B7 五、發明說明（1〇4)Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 7b, Example 8 5/9-[2- [1-[1 -fluorenyl-3- (5,6,7,8-tetrazole 1,8-Cai bite- 2-yl) propyl] -4-methylpyridinyl] ethyl] -3-pyridinepropionic acid (compound 8) The acid compound 8a is as described in WO 99/31061 and is derived from the corresponding ethyl ester. For the synthesis method, see It is described in WO 00/72801. Using the procedure for converting compound 4a to compound 5c described in Example 5, 10 reacting compound 8a with compound 6e to obtain compound 8b (purification by RP-HPLC: 10-90% acetonitrile / water, 0.1% TFA). MS (ES +) -105- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 cm) 200536844 A7 B7 V. Description of invention (104)

m/z 465 (M+HV 使角實例5所述化合物5c轉化成化合物5之程序轉化化合物8b，得到呈HC1鹽之化合物8。 MS (ES+) m/z 451 (M+H4) 〇 lK NMR pMSO^, 300 MHz) δ 1.03 (m, 2H), U9 (m, 2H), 1.49 (m, 4H), 1.68 (m, 1H), 1.72 (m, 4H), 2.72 (m, 2H), 2.98 (m,2H), 3,18 (m, 1H), 3.65 (m, 2H), 4.33 7.25 (m, 2H), 7.51 (m, 1H), 7.73 (m, 1H), 8.21 (m, 1H), 8.31 (s, 1H)，8.65 (m，2H)。m / z 465 (M + HV Procedure for converting compound 5c described in Example 5 into compound 5 to convert compound 8b to obtain compound 8 as HC1 salt. MS (ES +) m / z 451 (M + H4) 〇1K NMR pMSO ^, 300 MHz) δ 1.03 (m, 2H), U9 (m, 2H), 1.49 (m, 4H), 1.68 (m, 1H), 1.72 (m, 4H), 2.72 (m, 2H), 2.98 (m, 2H), 3,18 (m, 1H), 3.65 (m, 2H), 4.33 7.25 (m, 2H), 7.51 (m, 1H), 7.73 (m, 1H), 8.21 (m, 1H) , 8.31 (s, 1H), 8.65 (m, 2H).

COOHCOOH

4N HC1 (aq)4N HC1 (aq)

8b 使用實例8之程序，及熟習此項技藝人士已知之適當試劑與起始物質，可製備本發明其他化合物包含，惟不限於：、化合物名稱 MS (m/z) 經濟部智慧財產局員工消費合作社印製 ο 11 20 β-(1，3-笨弁二。亏壤戍稀-5-基）-1-[ 1 - 494 酮基-3·(5,6,7,8-四氫-1，8-萘咬-2-基）丙基]-4-哌啶戊酸 21 6-曱氧基-/5 -[2-[1-[1-酮基-3- 481 (5,6,7,8-四氣-1，8-秦咬-2-基）丙基]-4- 哌啶基]乙基]-3·吡啶丙酸本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） -106- 2005368448b The procedure of Example 8 and appropriate reagents and starting materials known to those skilled in the art can be used to prepare other compounds of the present invention, including, but not limited to:, Compound name MS (m / z) Consumption by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the cooperative ο 11 20 β- (1,3-benzidine II. Depleted soil dilute-5-yl) -1- [1-494 Keto-3 · (5,6,7,8-tetrahydro- 1,8-naphthalene-2-yl) propyl] -4-piperidinevaleric acid 21 6-fluorenyloxy-5-[2- [1- [1-keto-3- 481 (5,6 , 7,8-tetrakis-1,8-qinyi-2-yl) propyl] -4-piperidinyl] ethyl] -3 · pyridinepropionic acid This paper is sized for China National Standard (CNS) A4 (210 X 297 mm) -106- 200536844

五、發明說明（105) [[1酮基-4-(2-晚咬基胺基）丁基]_4_略咬基]乙奸 3-咄啶丙酸（化合物％於^溫，攪拌含化合物&(〇14克，〇44毫莫耳)之毫升)與NMM(0·”升，〇89毫莫耳)混合物時’然後於冰浴中冷卻。添加4-漠丁醢氣化合物9a •毫升，〇·5δ毫莫耳)與(0.09毫升，0.89毫莫 :)，此反應混合物於〇t攪拌6小時，於室溫擾拌隔 10 15 經濟部智慧財產局員工消費合作社印製 20 夜以，和ΝΗΚΙ >容液(5毫升）、水(5毫升)及1N腦ο X #毫升）洗滌該反應混合物。將有機層脫水(Na2S〇4)，真二/辰縮，得到呈黏稠油之化合物外。ms (es+) m/z 345 (M-Br) 〇添加DIEA (0·73毫升，4·23毫莫耳）至含化合物9bV. Description of the invention (105) [[1 Keto-4- (2-late bitylamino) butyl] _4_slightly bityl] acetic acid 3-pyridinepropionic acid (compound% at temp. Compound & (0,14 g, 0,44 millimoles) in ml) and NMM (0 · L, 0,89 millimoles) was then mixed 'and then cooled in an ice bath. 4-Mobutane gas compound 9a was added • ml, 0.5δ mmol) and (0.09 ml, 0.89 mmol :), the reaction mixture was stirred at 0 t for 6 hours, and stirred at room temperature for 10 15 printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 The reaction mixture was washed at night with ΝΗΚΙ > volume solution (5 ml), water (5 ml) and 1N brain × X ml. The organic layer was dehydrated (Na2S〇4), Shinji / Ten Shrink, to obtain Viscous oil outside the compound. Ms (es +) m / z 345 (M-Br) 〇 Add DIEA (0.73 ml, 4.23 mmol) to compound 9b

(〇·60克’ ι·4ΐ毫莫耳）與2-胺基吡啶化合物9c (〇 %克， 4.23毫莫耳)之曱苯(10毫升)攪拌溶液中。回流加熱此混合物隔夜，然後予以真空濃縮。其殘留物利用Rp_HpLC (2-30%乙腈/水，〇.1% TFA)進行純化，得到呈油狀物之化合物 9d。MS (ES+) m/z 439 (M+H+)。使用實例6所述化合物6h轉化成化合物$之程序轉化化合物9d成為化合物9 (利用RP-HPLC進行純化· 2 30% 乙腈/水，0.1% TFA)。(0. 60 g '4 m mmol) and 2-aminopyridine compound 9c (0% g, 4.23 mmol) in a stirred solution of toluene (10 ml). The mixture was heated at reflux overnight and then concentrated in vacuo. The residue was purified by Rp_HpLC (2-30% acetonitrile / water, 0.1% TFA) to obtain 9d as an oily compound. MS (ES +) m / z 439 (M + H +). Using the procedure for converting compound 6h to compound $ described in Example 6 to convert compound 9d to compound 9 (purification by RP-HPLC · 2 30% acetonitrile / water, 0.1% TFA).

MS (ES-f) m/z 425 (M+H〇« lH NMR (DMSO-4 300 MHz) δ 1·01 (m，2H)，U1 (m，4H), U6 (m，1H), 49 加 4印 2 (m, 2H), 2.39 (m, 2H), 3 21 (m, 2H), 3.76 (π, 2H), 4.26 (π, 2H), 4.6； 8.72(m，8H)。 -107- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200536844 A7 B7 五、發明說明（ 106MS (ES-f) m / z 425 (M + H〇 «1H NMR (DMSO-4 300 MHz) δ 1.01 (m, 2H), U1 (m, 4H), U6 (m, 1H), 49 4 (2, m, 2H), 2.39 (m, 2H), 3 21 (m, 2H), 3.76 (π, 2H), 4.26 (π, 2H), 4.6; 8.72 (m, 8H). -107 -This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200536844 A7 B7 V. Description of Invention (106

Br ΎϊBr Ύϊ

6e DMAP6e DMAP

使用實例9之程序，及熟習此項技藝人士已知之適當試劑與起始物質，可製備本發明其他化合物包含，惟不限於：化合物經濟部智慧財產局員工消費合作社印製 5 名稱 MS (m/z) 22 /3 -[2-[1-[1-嗣基-4-(2-°比咬基胺基）丁基]-4-旅唆基]乙基]-3-啥琳丙酸 475 23 ' /3-(l，3-苯并二。寻環戊烯-5-基）_l-[l-酮基-4-(2/比啶基胺基）丁基；H-哌啶基戊酸 468 24 /3 -(1，3-苯弁二0亏環戍稀-5-基)-1-[1-酮基-4-(2-吡啶基胺基）丁基]-4-哌啶基丙酸 440 25 6-甲氧基-/? 酮基-4-(2^比啶基胺基）丁基]-心旅咬基]乙基]-3-°比咬丙酸 455 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） -108- A7 B7 200536844 五、發明說明（W7) f例10 6_曱氧基-yg -[2-[Η3-[(1，4,5,6-四氫-5-羥基-2-嘧啶基)胺基] 苯曱醯基]-4-哌啶基]乙基]-3-吡啶丙酸（化合物1〇) 使用實例6所述化合物6c轉化成化合物6d之程序轉 5 化化合物10a成為化合物l〇b (無色液體；於;ς夕朦上利用急驟層析法進行純化，10-15%乙酸乙酯/添加數滴TEA之己烷）。MS (ES+) m/z 407 (M+IT)，為消旋性混合物，使用對掌性OJ管柱進行鏡像異構物性分離，以己烷/乙醇 (75:25)溶洗。 'H-NMR (DMSO^, 300 MHz) δ 1.04 (m, 4H), L19 (m, 2H), 1.47 (S> 9H), 1.61 (m, 1H), 1.73 (m, 2H), 2,66 (m, 4H), 3.02 (m, 2H)S 3.61 (s, 3H), 3.92 (s, 3H), 4.01 10 (nUH)，6.S1 (4 7 Hz, 1H)，7·38 (4> 7 Hz，1H), 8.05 (s, 1H)。使用實例6所述化合物6d轉化成化合物6e之程序轉化化合物10a，得到呈HC1鹽之化合物l〇c。 MS (ES+) 3»/2 307 (M4fT)。NMR (DMSO-办，300 MHz) S 0·98 (m, 2H)，U8 (m, 1H), 1.53 (m, 4H), 1.81 (m, 2H), 2.62 (m, 2H), 2.81 (m, 4H), 3.22 (m, 1H), 3.53 (s, 3H), 3.83 (s, 3H), 6.76 (d, /- 9 Hz, 1H), 7.63 (m, 1H), 8.04 (m, 1H) ^ 〇πΗ2$Ν2〇3·1·63 CI^COOH-iU H2O之元素分析計算值：C, 49,08; H，5.70; N，5.65; H20, 0.73。實測值：c，49,10; Η, 5·66; N，5·65; H20, 0·93» 經濟部智慧財產局員工消費合作社印製使用實例7所述化合物7a轉化成化合物7b之程序 15 使化合物7a與化合物l〇c反應，產生化合物l〇d。使用實例3所述化合物3n轉化成化合物3之程序轉化化合物 10d ’製得呈HC1鹽之化合物1〇 (以rp-HPLC純化：5- 50% 乙腈/水，〇·〇ΐ〇/。TFA)。MS (ES+) m/z 510 (M+H+)。 -109- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公麓） 200536844 A7 B7 五、發明說明（1〇8 'H NMR (DMSO-^, 300 MHz) δ 0.99 (m, 2H), L14 (m5 1H), L53 (m, 6H), 1.67 (m, 2K), 2.58 (m, 2H), 2.94 (m, 1H), 3.15 (d, J- 11 Hz, 2H), 3.33 (d, 12 Hz, 2H), 3.81 (s, 3H), 3.86 (m, 2H), 4.09 (m, 1H), 6.75 (d, J* 9 Hz, 1H), 7.12-7.29 (m, 4H), 7.63 (m, 1H), 8.03 (m, 1H)« OMe OMeUsing the procedures of Example 9 and appropriate reagents and starting materials known to those skilled in the art, other compounds of the present invention can be prepared including, but not limited to: Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Compound Economy 5 Name MS (m / z) 22/3-[2- [1- [1-fluorenyl-4- (2- ° specific sulfanylamino) butyl] -4-propanyl] ethyl] -3-halinpropanoic acid 475 23 '/3-(l,3-benzodi.cyclopentene-5-yl)-l-[l-keto-4-(2/pyridinylamino)butyl; H-piperidine Valeric acid 468 24/3-(1,3-phenylhydrazine dicyclohexyl-5-yl) -1- [1-keto-4- (2-pyridylamino) butyl] -4 -Piperidinylpropionic acid 440 25 6-methoxy- /? Keto-4- (2 ^ pyridinylamino) butyl] -cardiolyl] ethyl] -3- ° propionylpropionic acid 455 This paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210x297 mm) -108- A7 B7 200536844 V. Description of the invention (W7) f Example 10 6_methoxy-yg-[2- [Η3-[( 1,4,5,6-tetrahydro-5-hydroxy-2-pyrimidinyl) amino] phenylphenyl] -4-piperidinyl] ethyl] -3-pyridinepropionic acid (Compound 10) used Procedure for converting compound 6c to compound 6d described in Example 6 into compound 5 0a becomes compound 10b (colorless liquid; purified by flash chromatography on cyanide, 10-15% ethyl acetate / hexane with a few drops of TEA). MS (ES +) m / z 407 (M + IT), which is a racemic mixture, was separated on a palm OJ column using mirror-isomeric properties and washed with hexane / ethanol (75:25). 'H-NMR (DMSO ^, 300 MHz) δ 1.04 (m, 4H), L19 (m, 2H), 1.47 (S > 9H), 1.61 (m, 1H), 1.73 (m, 2H), 2,66 (m, 4H), 3.02 (m, 2H) S 3.61 (s, 3H), 3.92 (s, 3H), 4.01 10 (nUH), 6.S1 (4 7 Hz, 1H), 7.38 (4 > 7 Hz, 1H), 8.05 (s, 1H). Compound 10a was converted using the procedure for converting compound 6d to compound 6e described in Example 6 to give compound 10c as the HC1 salt. MS (ES +) 3 »/ 2 307 (M4fT). NMR (DMSO-office, 300 MHz) S 0 · 98 (m, 2H), U8 (m, 1H), 1.53 (m, 4H), 1.81 (m, 2H), 2.62 (m, 2H), 2.81 (m , 4H), 3.22 (m, 1H), 3.53 (s, 3H), 3.83 (s, 3H), 6.76 (d, /-9 Hz, 1H), 7.63 (m, 1H), 8.04 (m, 1H) ^ 〇πΗ2 $ N2〇3 · 1.63 CI ^ COOH-iU H2O elemental calculated value: C, 49,08; H, 5.70; N, 5.65; H20, 0.73. Measured values: c, 49, 10; Η, 5.66; N, 5.65; H20, 0 · 93 »Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, the procedure for converting compound 7a to compound 7b described in Example 7 15 Compound 7a is reacted with compound 10c to produce compound 10d. Using the procedure for converting compound 3n to compound 3 described in Example 3 to convert compound 10d 'to obtain compound 10 as the HC1 salt (purified by rp-HPLC: 5- 50% acetonitrile / water, 〇〇〇〇〇.TFA) . MS (ES +) m / z 510 (M + H +). -109- This paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210x297 feet) 200536844 A7 B7 V. Description of the invention (108'H NMR (DMSO- ^, 300 MHz) δ 0.99 (m, 2H), L14 (m5 1H), L53 (m, 6H), 1.67 (m, 2K), 2.58 (m, 2H), 2.94 (m, 1H), 3.15 (d, J-11 Hz, 2H), 3.33 (d, 12 Hz, 2H), 3.81 (s, 3H), 3.86 (m, 2H), 4.09 (m, 1H), 6.75 (d, J * 9 Hz, 1H), 7.12-7.29 (m, 4H), 7.63 ( m, 1H), 8.03 (m, 1H) «OMe OMe

COOCH, OMe 10c lOdCOOCH, OMe 10c lOd

經濟部智慧財產局員工消費合作社印製實例11 使用實例8所述製備化合物8之程序，製得化合物 21並利用RP-HPLC (5-50%乙腈/水，0.01% TFA)予以純化0 -no- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 五、發明說明（1〇9) 獲得化合物21兩種鏡像異構物：（/935>6-曱氧基-/5-[2-[ 1-[ 1 -嗣基-3-(5,65 7,8-四氣-1，8-蔡咬-2-基）丙基]-4-派咬基]乙基]-3-吡啶丙酸21a (使用對掌性分離法，自化合物 21中間產物之速移鏡像異構物製得）及（/54)-6-甲氧基-5 /3 -[2-[ 1-[ 1 -嗣基-3-(5,6,7,8,四鼠-1，8-秦咬-2-基）丙基]-4-口底啶基]乙基]-3-吡啶丙酸21b (使用對掌性分離法，自化合物21中間產物之另一鏡像異構物製得），各者具有與化合物21相同的MS。實例12 10 -(1，3-苯并二呤環戊烯-5-基酮基-3-(5,6,7,8-四氫- 1,8-萘啶-2-基）丙基]-4-哌啶丁酸（化合物11) 於-20°C，氮氣下，在含化合物12a (5克，20.55毫莫耳）與NMM (4.96毫升，45_11毫莫耳)之無水THF (50毫升）溶液中，經由注射器添加氣曱酸異丁酯（2.67毫升， 15 20.58毫莫耳）。攪拌此混合物30分鐘，接著一次加入經濟部智慧財產局員工消費合作社印製二曱基羥基胺（2克，20.5毫莫耳）。使混合物緩缓加溫至室溫，攪拌2天。真空濃縮後，使殘留物分配於 EtOAc與1 N HC1之間。分離有機相，以H2〇與飽和 NaHC〇3洗滌，脫水(Na2S〇4)，真空濃縮，得到呈油狀物 20 之化合物12b。化合物12b不需進一步純化，直接於下一反應使用。於-78°C，逐滴添加丁基鋰（2.5M己烷溶液， 4.19毫升，10.48毫莫耳）至4-溴-1,2-(亞曱二氧基）苯化合物12c (1.26毫升，10.48毫莫耳）之THF (40毫升）中。 -111- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x297公*) 200536844 A7 B7 五、發明說明（110) 於-78°C攪拌此混合物30分鐘，逐滴添加化合物12b (2 克，6.98毫莫耳）之THF (1〇毫升）溶液。此混合物於-78 C攪拌分鐘後，移除冷卻浴。於室溫再攪拌混合物2 小時，以飽和NHWl溶液終止反應。分離有機相，以食 5鹽水洗滌，脫水(Na2S〇4)，並予以濃縮。其殘留物以RP-HPLC純化，得到呈油狀物之化合物。於〇C，逐滴添加六曱基二矽烷胺化鈉（1〇 M THF溶液，2.07毫升，2.07毫莫耳）至膦醯乙酸三曱酯（〇.33毫升，2.07毫莫耳）之THF (1〇毫升）溶液中。所得混合物於 10 〇 C授摔30分鐘後，逐滴添加含化合物12d (〇 18克， 0·52毫莫耳)之THF (5毫升）溶液。回流加熱此混合物16 小時，接著於室溫再攪拌24小時，冷卻，以Et2〇（3Q毫升）稀釋，並以飽和NaHC〇3溶液與食鹽水洗滌。將有機層脫水（Na2S〇4)，並予以濃縮。殘留物以RP-HPLC純 15化，得到化合物。於4〇 psi氏，10%披把碳(〇 2克）存在下’使化合物l2e(0.5克，124毫莫耳)之Me〇H(2() 經濟部智慧財產局員工消費合作社印製毫升）溶液進行氫化反應16小時。通過矽藻土過濾去除觸媒，真空濃縮濾液，得到呈油狀物之化合物l2f。化合物 12f不需進一步純化，直接於下一反應使用。添加tfa卩 20毫升）至化合物12f (〇 37克，〇 %毫莫耳)之(⑽毫升）溶液中。此混合物於室溫攪拌3〇分鐘，真空濃縮，其殘留物以RP_HPLC純化，得到呈油狀物之化合物以。、於至/皿氬氣下，在化合物8a (0.28克，1 15毫莫耳）之DMF (4〇毫升）溶液中，添加卜H〇Bt (0.135克，1.0 •112- ^ 張尺^用中國國(2H) X 297 ~ - 200536844 B7Printed by Example 11 of the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives Using the procedure for preparing compound 8 described in Example 8, compound 21 was prepared and purified by RP-HPLC (5-50% acetonitrile / water, 0.01% TFA) 0 -no -This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210x297 mm) 200536844 A7 B7 V. Description of the invention (109) Two image isomers of compound 21 are obtained: (/ 935 > 6-fluorenoxy- / 5- [2- [1- [1-fluorenyl-3- (5,65 7,8-tetrakis-1,8-Caiyi-2-yl) propyl] -4-pyridyl] B [Methyl] -3-pyridinepropionic acid 21a (prepared from the fast-shifting mirror isomer of the intermediate product of compound 21 using the isotropic separation method) and (/ 54) -6-methoxy-5 / 3-[2 -[1- [1 -fluorenyl-3- (5,6,7,8, tetral-1,8-cinnazol-2-yl) propyl] -4-orididinyl] ethyl]- 3-pyridinepropionic acid 21b (prepared from the other mirror isomer of the intermediate product of compound 21 using a palladium separation method), each having the same MS as compound 21. Example 12 10-(1,3-benzene Cyclopenten-5-ylketo-3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -4-piperidinebutanoic acid (compound 11) at -20 ° C under nitrogen To a solution of Compound 12a (5 g, 20.55 mmol) and NMM (4.96 ml, 45_11 mmol) in anhydrous THF (50 ml), isobutyl pirate (2.67 ml, 15 20.58 mmol) was added via a syringe. Ear). Stir the mixture for 30 minutes, and then add the dihydrazyl hydroxylamine (2 g, 20.5 mmol) printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Allow the mixture to slowly warm to room temperature and stir for 2 days. After concentration in vacuo, the residue was partitioned between EtOAc and 1 N HC1. The organic phase was separated, washed with H2O and saturated NaHC03, dehydrated (Na2S04), and concentrated in vacuo to give the compound as an oil 20 12b. Compound 12b was used directly in the next reaction without further purification. At -78 ° C, butyllithium (2.5M hexane solution, 4.19 ml, 10.48 mmol) was added dropwise to 4-bromo-1, 2- (Acetylenedioxy) benzene compound 12c (1.26 ml, 10.48 mmol) in THF (40 ml). -111- This paper size applies to China National Standard (CNS) A4 (210 x 297 male *) 200536844 A7 B7 V. Description of the invention (110) Stir the mixture at -78 ° C for 30 minutes, drop by drop Was added compound 12b (2 g, 6.98 mmol) of THF (1〇 mL). After the mixture was stirred at -78 C for minutes, the cooling bath was removed. The mixture was stirred at room temperature for another 2 hours, and the reaction was stopped with a saturated NHW1 solution. The organic phase was separated, washed with brine, dried (Na2SO4), and concentrated. The residue was purified by RP-HPLC to give the compound as an oil. At 0 ° C, sodium hexafluorenyldisilazide (10M THF solution, 2.07 ml, 2.07 mmol) was added dropwise to the phosphonium trimethylacetate (0.33 ml, 2.07 mmol) in THF. (10 ml) solution. After the resulting mixture was shaken at 100 ° C for 30 minutes, a solution of compound 12d (0 18 g, 0.52 mmol) in THF (5 ml) was added dropwise. The mixture was heated at reflux for 16 hours, then stirred at room temperature for another 24 hours, cooled, diluted with Et20 (3Q ml), and washed with saturated NaHC0 solution and brine. The organic layer was dehydrated (Na2SO4) and concentrated. The residue was purified by RP-HPLC to give the compound. In the presence of 40 psi, 10% petrol carbon (0 g), MeOH (2 (2)) of the compound l2e (0.5 g, 124 mmol) was printed in ml by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ) The solution was subjected to a hydrogenation reaction for 16 hours. The catalyst was removed by filtration through diatomaceous earth, and the filtrate was concentrated in vacuo to obtain Compound 12f as an oil. Compound 12f was used without further purification in the next reaction. Tfa (20 ml) was added to a solution of compound 12f (37 g, 0% millimoles) (⑽mL). The mixture was stirred at room temperature for 30 minutes and concentrated in vacuo. The residue was purified by RP-HPLC to give the compound as an oil. 1. Under a argon atmosphere, in a solution of compound 8a (0.28 g, 115 mmol) in DMF (40 ml), add HOBt (0.135 g, 1.0 China (2H) X 297 ~-200536844 B7

毫莫耳）、EDC (0.192克，1.0毫莫耳)及DffiA (〇 35毫升，2毫莫耳）。此混合物於室溫攪拌45分鐘。添加含化合物12g (0.28克，0.067毫莫耳）與DIEA (0·35毫升^ 2 毫莫耳）之DMF (10毫升）溶液至該含化合物8a之混合物 5中。所得混合物於室溫攪拌隔夜。添加水(2毫升），隨後添加DCM (20毫升）。分離有機層，脫水(Na2S〇4)，並予以濃縮。所得粗產物化合物12h直接於下一反應使用。使粗化合物12h溶於MeOH (20毫升）中，於其内添加3N NaOH水溶液(6毫升）。此混合物於室溫授拌5小時，並 10以2N HC1中和。蒸發溶劑後，殘留物以rp-HPLC純化，得到化合物 11。MS (ES+) m/z 480 (M+H+)。 CH3 r^V^V0H MeONHMe,HCl 經濟部智慧財產局員H消費合作社印製 υ J n i-BuOCOCl Boc" ^ ^ 12a NMM,THF 12bMillimoles), EDC (0.192 g, 1.0 millimoles) and DffiA (0.35 milliliters, 2 millimoles). This mixture was stirred at room temperature for 45 minutes. A solution of 12 g (0.28 g, 0.067 mmol) of the compound and DIEA (0.35 ml ^ 2 mmol) in DMF (10 ml) was added to the mixture 5 containing compound 8a. The resulting mixture was stirred at room temperature overnight. Water (2 mL) was added, followed by DCM (20 mL). The organic layer was separated, dried (Na2SO4), and concentrated. The resulting crude compound was used directly in the next reaction for 12 h. The crude compound was dissolved in MeOH (20 mL) for 12 h, and a 3N aqueous NaOH solution (6 mL) was added thereto. The mixture was stirred at room temperature for 5 hours and neutralized with 2N HC1. After evaporation of the solvent, the residue was purified by rp-HPLC to obtain compound 11. MS (ES +) m / z 480 (M + H +). CH3 r ^ V ^ V0H MeONHMe, printed by H Consumer Cooperative, Intellectual Property Bureau, Ministry of Economic Affairs υ J n i-BuOCOCl Boc " ^ ^ 12a NMM, THF 12b

-113- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公爱） 200536844 Α7 Β7 五、發明說明 112-113- This paper size is in accordance with China National Standard (CNS) A4 (210x297 public love) 200536844 Α7 Β7 V. Description of the invention 112

DIEA, DMFDIEA, DMF

1. NaOH/McOH 2. RP-HPLC 純化1. NaOH / McOH 2. RP-HPLC purification

使用實例12之程序，及熟習此項技藝人士已知之適當試劑與起始物質，可製備本發明其他化合物包含，惟不限於：化合物名稱 MS (m/z) 經濟部智慧財產局員工消費合作社印製 26 、召-(1,3-苯并二呤環戊烯-5-基）-1-[1_ 494 .明基-4-(5,6,758·四風-1，8-蔡咬-2-基）丁基]-4-哌啶丁酸 27 /5 _(1，3-苯弁二環戍稀-5-基)-1-[3- 509 [(1，4,5,6-四氮-5-經基_2-嘴咬基）胺基]苯甲醯基]-4-哌啶丁酸 28 6-曱氧基-/9-[[1-[1-調基-3-(55657,8- 467 四氮-1，8-秦咬-2-基）丙基]-4-略咬基]· 曱基]-3-吡啶丙酸 29 /5 _[[1-[1-酮基-4-(5,6,7,8-四氫-1，8·萘 501 啶-2-基）丁基]-4-哌啶基]-甲基]-3-喹啉丙酸 -114- 本紙張尺度適用中國國家標準(CNS)A4規格（210 x297公釐） •200536844Using the procedure of Example 12 and appropriate reagents and starting materials known to those skilled in the art, other compounds of the present invention can be prepared including, but not limited to: Compound name MS (m / z) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Preparation 26, Zhao- (1,3-benzodolinylcyclopenten-5-yl) -1- [1_494. BenQ-4- (5,6,758 · Four Wind-1,8-Cai bite-2- ) Butyl] -4-piperidinebutanoic acid 27 / 5_ (1,3-phenylhydrazonebicyclofluorene-5-yl) -1- [3- 509 [(1,4,5,6-tetra Nitro-5-Cycloyl_2-methylamino) amino] benzylidene] -4-piperidinebutyric acid 28 6-fluorenyloxy // 9-[[1- [1- 调基 -3- (55657,8- 467 tetrazol-1,8-pyridine-2-yl) propyl] -4-succinyl] · fluorenyl] -3-pyridinepropionic acid 29/5 _ [[1- [1 -Keto-4- (5,6,7,8-tetrahydro-1,8 · naphthalene501 pyridin-2-yl) butyl] -4-piperidinyl] -methyl] -3-quinolinpropan Acid-114- This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) • 200536844

五、發明說明 113 化合物 ~30^ 名稱V. Description of the Invention 113 Compound ~ 30 ^ Name

MS 31 32 33 34 35 36 37 38 經濟部智慧財產局員工消費合作社印製 39 40 泠"(3-氣本基）-l-[l -酮基-3-(5，6,7,8-四風-1，8_蔡咬_2_基）丙基]-4-^咬丁酸冷二(3_ 氟苯基酮基-4-(5,6,7,8-四氩-1，8-萘啶_2_基）丁基]_4_哌啶丁酸召-[[1-[1-_基-3-(5,657,8-四氫-1，8-萘啶-2-基）丙基]-4-哌啶基]-曱基]-3-喹啉丙酸 β -(4-氣本基酌基 _3_(5,6,7,8-四氫-1，8-萘啶-2-基）丙基]-4-哌啶丁酸/9 -(4_ 氟苯基嗣基-4-(5,6,7,8-四氮-1，8-蔡咬_2_基）丁基]-4-旅咬丁酸 2-甲基 m[l-酮基-3-(5,6,7,8-四氫-1，8-萘啶-2-基）丙基]-4-哌啶基]-曱基]-5-嘧啶丙酸 /9 -(2,3_二氫-6-苯并咬味基基-3-(5,6,7,8-四氫-1,8-萘淀_2·基）丙基]-4-哌啶丁酸 /3 -(3,5-二氟苯基）-1-[1-酮基-3-(5,6,7,8-四氫-1，8-萘咬-2-基）丙基]-4-派唆丁酸 ’/? -(3,5-二氟苯基 H-[l-酮基-4-(5,657,8-四氫-1,8-萘咬-2-基）丁基]-4-哌啶丁酸1- [1-酮基-3-(5,6,7,8-四氫-1,8-萘啶- 2- 基）丙基-[3-(三氟曱基）苯基]-4-派咬丁酸1- [1_酮基-3-(5,6,7,8_ 四氫-l，8-萘啶-2- 基）丙基]_点_[4_(三氟曱氧基）苯基]-4-哌啶丁酸 454 468 487 454 468 452 478 472 486 504 -115- 本紙張尺度適用中國固家標準(CNS)A4規格（210 x 297公笼） 520 200536844 A7 B7 五、發明說明（1H) 化合物 _ _ MS (m/z) 41 /3 -(2-氟聯苯]-4-基)-1-[1-_基- 3- (5,6,7,8-四氩-1，8_ 秦交-2-基）丙基]_ 4- 派咬丁酸 530 42 /5 -(3-氟-4-曱氧苯基）-1-[1·酮基-3: (5,6,7,8-四氫 _1，8_ 萘咬-2-基）丙基]-4-哌啶丁酸 484 43 1- [1-酮基-3-(5,6,7,8-四氫-1,8-萘咬- 2- 基）丙基]-万-(4-苯氧苯基)-4-旅咬丁酸 528 44 -[[1-[1-酮基-3-(5,6,7,8-四氫-1，8-萘啶-2-基）丙基]_4_哌啶基]曱基]-4-異啥琳丙酸 487 45 /3，[[1-[1-酮基-3-(556,7,8_四氫-1,8-萘啶-2-基）丙基]-4-哌啶基]曱基]-3-。比啶丙酸 437 46 冷-(2,3-二氫-5-苯并咬啥基)-1-[1-洞基-3-(5,6,7,8-四氫-1，8-萘咬_2_基）丙基]-4-哌啶丁酸 478 47 2,4-二曱氧基-召-[[1-[1-酮基-3-(5,6,7,8-四氫-1，8-萘咬-2-基）丙基] 旅咬基]甲基]-5-喊唆丙酸 498 48 2-曱氧基-/5 -[[1-Π-酮基-3-(5,6,7,8-、四氫-1，8-萘淀-2-基）丙基]-4-派咬基] 曱基]-5-嘧啶丙酸 468 經濟部智慧財產局員工消費合社印製實例13 /S -[2-[1-[3-[(Μ，5,6_四氫-2-嘧啶基）胺基]苯曱醯基；μ4•哌变基]乙基]-3-噎琳丙酸（化合物12) 於-55°C，氬氣下，冷卻含氩化鋁鋰（3.11克，0.082 5 莫耳）之Et20 (250毫升）懸浮液。以15分鐘，使溫度不超過-50°C下，逐滴添加含化合物3b (18.5克，0.068莫耳) -116- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200536844 五、發明說明（U5 之Et2〇 (75毫升）溶液。移除冷卻浴，將混合物加溫至.5 。(：，再冷卻至-35°C，添加矽藻土（50克）。保持溫度於_3〇 C下’緩緩以硫酸氫鹽溶液（15.30克，於43毫升H2〇中）終止該混合物。使所得混合物加溫至，通過矽藻土予 5 以過濾，濾器上的殘留物以EtOAc (750毫升）及H20 (500 毫升）洗滌。分離有機層，以〇·5Ν HC1 (100毫升）、餘和 NaHC〇3 (100毫升）及食鹽水（1〇〇毫升）洗滌。其水層以 EtOAc (500毫升）萃取，將合併之有機層脫水，過濾及蒸發。所得殘留物利用Kugelrohr蒸餾法（120-140°C，1.5-2 10 毫米Hg)予以純化，得到呈無色油之化合物13a。於密封管中，加熱含3-溴喹啉（10.40克，0.05莫耳）、三甲基矽烷基乙炔（8.48毫升，0.06莫耳）、碘化亞銅(〇·5克)與反式-二氣雙(三苯基膦)鈀（1克)及TEA (15毫升）之混合物1小時。添加H2〇（150毫升），隨後添加 15 EkO (300毫升）。分離有機層，其水層以Et2〇（200毫升）經濟部智慧財 ή 局員工消費合作社印製萃取。將合併之有機層脫水(Na2s〇4)，並予以濃縮。其残留物利用急驟管柱層析法（溶洗液：100% DCM)進行純化，得到呈褐色油之3-(三曱基矽烷基乙炔基）喹啉。使3-(三甲基矽烷基乙炔基）喹啉溶於無水MeOH (100毫升） 20 中，添加K2C〇3 (0.69克，5毫莫耳）。於室溫攪拌此潙合物1小時，添加DCM (250毫升）。通過矽藻土過濾此浪合物’蒸發濾液，其殘留物利用急驟管柱層析法予以純化，得到呈米白色固體之化合物13b。氬氣下，逐滴添加丁基鋰（2.5M己烷溶液，9·44毫 -117-MS 31 32 33 34 35 36 37 38 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 39 40 LING " (3-Gabenzyl) -l- [l -keto-3- (5,6,7,8 -Four Wind-1,8_Caiwei_2_yl) propyl] -4- ^ butyric acid cold bis (3-fluorophenylketo-4- (5,6,7,8-tetraargon-1) , 8-naphthyridin-2-yl) butyl] -4_piperidinebutyric acid-[[1- [1-_yl-3- (5,657,8-tetrahydro-1,8-naphthyridin-2- )] Propyl] -4-piperidinyl] -fluorenyl] -3-quinolinepropanoic acid β-(4-aminobenzyl-3- (5,6,7,8-tetrahydro-1,8 -Naphthyridin-2-yl) propyl] -4-piperidinebutanoic acid / 9-(4-fluorophenylfluorenyl-4- (5,6,7,8-tetraaza-1,8-Cai bite_2 _Yl) butyl] -4-bromobutyric acid 2-methylm [l-keto-3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propane Yl] -4-piperidinyl] -fluorenyl] -5-pyrimidinpropanoic acid / 9-(2,3-dihydro-6-benzopyridinyl-3- (5,6,7,8- Tetrahydro-1,8-naphthalene-2-yl) propyl] -4-piperidinebutyric acid / 3-(3,5-difluorophenyl) -1- [1-keto-3- (5 , 6,7,8-tetrahydro-1,8-naphthyl-2-yl) propyl] -4-pyridinebutyric acid '/?-(3,5-difluorophenyl H- [l-one 4- (5,657,8-tetrahydro-1,8-naphthyl-2-yl) butyl] -4-piperidinebutanoic acid 1- [1-keto-3- (5,6,7, 8-tetrahydro-1,8-naphthyridin-2-yl Propyl- [3- (trifluorofluorenyl) phenyl] -4-pyridinebutanoic acid 1- [1-keto-3- (5,6,7,8_tetrahydro-1,8-naphthyridine- 2-yl) propyl] _dot_ [4_ (trifluorofluorenyloxy) phenyl] -4-piperidinebutyric acid 454 468 487 454 468 452 478 472 486 504 -115- This paper size applies to Chinese solid standard (CNS) A4 specification (210 x 297 male cage) 520 200536844 A7 B7 V. Description of the invention (1H) Compound _ _ MS (m / z) 41/3-(2-fluorobiphenyl) -4-yl) -1 -[1-_yl- 3- (5,6,7,8-tetraargon-1,8_qinjiao-2-yl) propyl] _ 4-pyroxybutyric acid 530 42/5-(3-fluoro -4-Methoxyphenyl) -1- [1 · keto-3: (5,6,7,8-tetrahydro_1,8_naphthyl-2-yl) propyl] -4-piperidine Acid 484 43 1- [1-keto-3- (5,6,7,8-tetrahydro-1,8-naphthalene-2-yl) propyl] -m- (4-phenoxyphenyl) -4-Bite butyric acid 528 44-[[1- [1-keto-3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] _4_ Piperidinyl] fluorenyl] -4-isoharsylpropionate 487 45/3, [[1- [1-keto-3- (556,7,8_tetrahydro-1,8-naphthyridin-2 -Yl) propyl] -4-piperidinyl] fluorenyl] -3-. Pyridine propionate 437 46 cold- (2,3-dihydro-5-benzobenzoyl) -1- [1-holeyl-3- (5,6,7,8-tetrahydro-1,8 -Naphthyl-2-yl) propyl] -4-piperidinebutanoic acid 478 47 2,4-dimethoxyoxy-zhao-[[1- [1-keto-3- (5,6,7, 8-tetrahydro-1,8-naphthyl-2-yl) propyl] methyl] methyl] -5-propanoic acid 498 48 2-methoxy- / 5-[[1-Π- Keto-3- (5,6,7,8-, tetrahydro-1,8-naphthyl-2-yl) propyl] -4-pyridyl] fluorenyl] -5-pyrimidinepropionic acid 468 economic Printed by the Intellectual Property Agency of the Ministry of Intellectual Property, 13 / S-[2- [1- [3-[(M, 5,6_tetrahydro-2-pyrimidinyl) amino] phenyl}; μ4 • Piperanyl] ethyl] -3-carbopropanoic acid (compound 12) was suspended at -55 ° C under argon, and Et20 (250 ml) containing lithium aluminum argon (3.11 g, 0.082 5 mol) was cooled. liquid. Add the compound 3b (18.5 g, 0.068 mol) dropwise at a temperature of not more than -50 ° C for 15 minutes. -116- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm). 200536844 V. Description of the invention (U5 in Et20 (75 ml) solution. Remove the cooling bath and warm the mixture to .5. (:, Then cool to -35 ° C, add diatomaceous earth (50 g). Keep The mixture was quenched with a bisulfate solution (15.30 g, in 43 ml H20) slowly at -30 ° C. The resulting mixture was warmed to, filtered through diatomaceous earth to 5 and the residue on the filter The material was washed with EtOAc (750 ml) and H20 (500 ml). The organic layer was separated and washed with 0.5N HC1 (100 ml), Yu and NaHC03 (100 ml) and brine (100 ml). The aqueous layer was extracted with EtOAc (500 ml), and the combined organic layers were dehydrated, filtered, and evaporated. The resulting residue was purified by Kugelrohr distillation (120-140 ° C, 1.5-2 10 mm Hg) to give a colorless oil. Compound 13a. Heat in a sealed tube containing 3-bromoquinoline (10.40 g, 0.05 mol), Of silyl acetylene (8.48 ml, 0.06 mole), cuprous iodide (0.5 g) and trans-digas bis (triphenylphosphine) palladium (1 g) and TEA (15 ml) 1 Hours. H20 (150 ml) was added, followed by 15 EkO (300 ml). The organic layer was separated and its aqueous layer was printed and extracted with Et20 (200 ml) by the Consumer Cooperative of the Bureau of Intellectual Property of the Ministry of Economic Affairs. The combined organics The layer was dehydrated (Na2s〇4) and concentrated. The residue was purified by flash column chromatography (eluent: 100% DCM) to give 3- (trimethylsilylethynyl) as a brown oil. Quinoline. 3- (Trimethylsilylethynyl) quinoline was dissolved in anhydrous MeOH (100 ml) 20, and K2CO3 (0.69 g, 5 mmol) was added. The mixture was stirred at room temperature. After 1 hour, DCM (250 ml) was added. The volatile compound was evaporated through celite, and the residue was purified by flash column chromatography to obtain compound 13b as an off-white solid. Dropwise under argon Add butyl lithium (2.5M hexane solution, 9.44 milli-117-

規格（210 x297公釐）本紙張尺度+ @ ®賴準(CNS)A4 A7 200536844 _ B7 五、發明說明（π6) 升，23·6毫莫耳)至化合物13b (3.62克，23.6毫莫耳)之丁 HF (15Ό毫升）中，使其溫度不超過-60°C，接著將混合物冷卻至-70°C。於-7〇°C攪拌混合物15分鐘，保持溫度於 -60與-70°C間下，逐滴添加化合物13a之THF (40毫升） 5 溶液。於-70°C攪拌30分鐘後，用20分鐘將混合物加溫至0°C，添加H2〇（1耄升）。所得混合物以K2C〇3脫水，過濾，並予以蒸發。其殘留物利用急驟管柱層析法（溶洗液梯度：DCM/MeOH : 100:0至95:5)進行純化，得到呈油狀物之化合物13c。於1 psi氫氣，林蠟氏觸媒（1克)存 10 在下，使含化合物13c (6.05克）之吡啶（100毫升）混合物進行氫化反應7小時。通過矽藻土過濾濾除觸媒，蒸發溶劑。其殘留物利用急驟管柱層析法（溶洗液梯度：己烷 /EtOAc : 9:1至1:1)進行純化，得到呈固體之化合物 13d ° 15 於〇 C ’鼠氣下’以30分鐘，逐滴添加3-氯·3-_基經濟部智慧財產局員工消費合作社印製丙酸曱酯（1.24毫升，11.53毫莫耳）之DCM (20毫升）溶液至含化合物13d (4.25克，ιι·53毫莫耳）與TEA (1.81毫升’ 13毫莫耳）之DCM (80毫升）溶液中。此混合物於室温攪拌隔夜。添加NH^Cl水溶液(5〇毫升）及DCM (150毫 20升）。分離有機層，以飽和NaHC〇3 (1〇〇毫升）及食鹽水 (1〇〇毫升）洗滌，脫水(Na2S〇4)，過濾及濃縮。其殘留物利用急驟管柱層析法（溶洗液梯度：己烷/Et〇Ac : 4··1至 1:1)進行純化，得到呈油狀物之化合物i3e。於60。(：，氬氣下，逐滴添加化合物13e (4.45克，9.5 -118- 本紙張尺度適用中國國家標準(⑶私^格（21Qx297公爱）---- — 200536844 A7 B7 五、發明說明（m) 毫莫耳）之THF (20毫升）溶液至含氫化鈉（6〇%，於礦物油中，0.57克，14.25毫莫耳，以己烷洗滌三次（3 χ 25毫升）)之燒瓶中。加熱此混合物至60°C 15分鐘。經由注射器添加氣三甲基矽烷(2.41克，19毫莫耳），此混合物於 5 60°C加熱4小時。添加水(0.5毫升），於室溫攪拌此混合物隔夜。蒸發該反應混合物，添加DCM (25〇毫升），將所得混合物脫水(NajO4)。過濾及蒸發後，真空下，於 130°C加熱殘留物2小時。利用急驟管柱層析法（溶洗液： 1% MeOH之DCM溶液）予以純化，得到呈黃色油之化合 10 物 13f。於1 psi氫氣，10%披鈀碳（1克)存在下，使含化合物13f (0.375克，0.88毫莫耳）之Me0H (50毫升）溶液進行氫化反應2小時。通過矽藻土過濾濾除觸媒，蒸發溶劑得到粗化合物13g，直接於下一反應使用。添加TFA (1〇 15毫升）至含化合物(〇·35克，〇·82毫莫耳)之DCM (10 毫升）溶液中。此混合物於室溫攪拌1小時，真空濃縮，得到粗化合物13h，直接於下一反應使用。經濟部智慧財產局員工消費合作社印製於〇°C，氬氣下，添加氣甲酸異丁酯（〇·ιΐ8毫升， 0.90毫莫耳）至含化合物6g (23〇毫克，〇9〇毫莫耳）與 20 NMM (0.385毫升，3.5毫莫耳）之DMF (8毫升）溶液中。於〇°C攪拌此混合物5分鐘，然後逐滴添加含化合物13h (0.455克，0.82毫莫耳）之DMF (7毫升）溶液。添加完Specifications (210 x 297 mm) Paper size + @ ® 赖准 (CNS) A4 A7 200536844 _ B7 V. Description of the invention (π6) liters, 23.6 millimoles) to compound 13b (3.62 grams, 23.6 millimoles ) HF (15Όml), keep the temperature not higher than -60 ° C, and then cool the mixture to -70 ° C. The mixture was stirred at -7O ° C for 15 minutes. While maintaining the temperature between -60 and -70 ° C, a solution of compound 13a in THF (40 ml) 5 was added dropwise. After stirring at -70 ° C for 30 minutes, the mixture was warmed to 0 ° C over 20 minutes, and H20 (1 liter) was added. The resulting mixture was dehydrated with K2CO3, filtered, and evaporated. The residue was purified by flash column chromatography (eluent gradient: DCM / MeOH: 100: 0 to 95: 5) to obtain compound 13c as an oil. A mixture of pyridine (100 ml) containing compound 13c (6.05 g) was subjected to a hydrogenation reaction at 1 psi of hydrogen with lin wax catalyst (1 g) for 7 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent was evaporated. The residue was purified by flash column chromatography (eluent gradient: hexane / EtOAc: 9: 1 to 1: 1) to obtain the compound as a solid 13d ° 15 at 30 ° C under 'rat gas' at 30 ° C. In minutes, a solution of 3-chloro · 3 -_- based Intellectual Property Bureau of the Intellectual Property Bureau of the Ministry of Economic Affairs, a consumer cooperative, printed propyl propionate (1.24 ml, 11.53 mmol) in DCM (20 ml) was added dropwise to the compound 13d (4.25 g , 53 mmol) and TEA (1.81 ml '13 mmol) in DCM (80 ml). The mixture was stirred at room temperature overnight. Aqueous NHCl solution (50 mL) and DCM (150 mmol and 20 liters) were added. The organic layer was separated, washed with saturated NaHC03 (100 mL) and brine (100 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient: hexane / EtoAc: 4 · 1 to 1: 1) to obtain compound i3e as an oil. At 60. (: Under argon, add compound 13e dropwise (4.45 g, 9.5 -118-) This paper size is applicable to Chinese national standard (3) (2005Q844), 200536844 A7 B7 5. Description of the invention ( m) THF (20 mL) solution into a flask containing sodium hydride (60% in mineral oil, 0.57 g, 14.25 mmol, washed three times with hexane (3 x 25 mL)) .Heat this mixture to 60 ° C for 15 minutes. Add gas trimethylsilane (2.41 g, 19 mmol) via syringe and heat this mixture at 5 60 ° C for 4 hours. Add water (0.5 ml) at room temperature The mixture was stirred overnight. The reaction mixture was evaporated, DCM (25.0 mL) was added, and the resulting mixture was dehydrated (NajO4). After filtration and evaporation, the residue was heated at 130 ° C for 2 hours under vacuum. Using flash column chromatography (Eluent: 1% MeOH in DCM) was purified to obtain compound 13f as a yellow oil. Compound 13f (0.375 g) was contained in the presence of 1 psi hydrogen and 10% palladium on carbon (1 g). , 0.88 mmol) of Me0H (50 ml) for 2 hours. Passing through diatoms The catalyst was removed by filtration through filtration, and the solvent was evaporated to obtain 13 g of the crude compound, which was directly used in the next reaction. TFA (1015 ml) was added to the compound (0.35 g, 0.82 mmol) in DCM (10 ml ) Solution. The mixture was stirred at room temperature for 1 hour, and concentrated in vacuo to obtain the crude compound for 13 hours, which was used directly in the next reaction. Printed by the consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs at 0 ° C under argon and adding formic acid Isobutyl ester (0.8 mL, 0.90 mmol) to a solution of 6 g (230 mg, 0.9 mmol) of the compound in DMF (8 mL) with 20 NMM (0.385 mL, 3.5 mmol) The mixture was stirred at 0 ° C for 5 minutes, and then a solution of the compound 13h (0.455 g, 0.82 mmol) in DMF (7 ml) was added dropwise. End of addition

後，移除冷卻浴。於室溫攪拌混合物隔夜。添加η2〇（α5 毫升），於80°C真空濃縮此混合物。殘留物以RP_HpLC -119- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公复） 200536844 A7 B7 五、發明說明（11 8 ) 純化，得到呈白色粉末之化合物13i。添力π IN Na〇H水溶液（10毫升）至含化合物13i (0.15 克，〇·2毫莫耳）之1,4-二哼烷（10毫升）溶液中。於室溫攪拌反應混合物20小時，以IN HC1 (10毫升）予以中和。 5 以RP-HPLC純化，冷凍乾燥後，得到呈白色粉末之化合物 12。MS (ES+) m/z 514 (Μ+Η+)。After that, the cooling bath was removed. The mixture was stirred at room temperature overnight. Η20 (α5 ml) was added and the mixture was concentrated in vacuo at 80 ° C. The residue is RP_HpLC -119- This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 public copy) 200536844 A7 B7 V. Description of the invention (11 8) The compound 13i is obtained as white powder. Add π IN NaOH solution (10 ml) to a solution of compound 4-i (0.15 g, 0.2 mmol) in 1,4-dihumane (10 ml). The reaction mixture was stirred at room temperature for 20 hours and neutralized with IN HC1 (10 ml). 5 Purified by RP-HPLC and freeze-dried to give Compound 12 as a white powder. MS (ES +) m / z 514 (M + H +).

3b Me3b Me

Boc-N L1AIH4 /\ P N-OMe -- Boc-N Et20 H 13aBoc-N L1AIH4 / \ P N-OMe-Boc-N Et20 H 13a

林蠟氏觸媒 BocLin wax catalyst Boc

0Me 13e 13d0Me 13e 13d

Et3NcH2a2 經濟部智慧財產局員工消費合作社印製 13cEt3NcH2a2 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 13c

-120- 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公簏） 200536844 Α7 Β7 五、發明說明 119 COjMe-120- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 X 297 male) 200536844 Α7 Β7 V. Description of the invention 119 COjMe

13g 13b 13f 10% Pd/C MeOH, H2 Boc TFA CH2C12 013g 13b 13f 10% Pd / C MeOH, H2 Boc TFA CH2C12 0

使用實例13之程序，及熟習此項技藝人士已知之適當試劑與起始物質，可製備本發明其他化合物包含，惟不限於：化合物名稱 MS (m/z) 經濟部智慧財產局員工消費合作社印製 49 /3 -[2-[l-[3-[(l，4,5,6-四氮-5-經基-2- 530 嘧啶基）胺基]苯曱醯基]-4-哌啶基]乙 '基]-3-喹啉丙酸 50 -[2-[1-[3·[(3,4,5,6-四氮-2-σΛ 咬基） 513 胺基]笨曱酿基]-4-旅咬基]乙基]-3-啥琳丙酸 51 /? -[2-[1-[1-嗣基-3-(556,7,8-四氮-1,8- 501 蔡咬-2-基）丙基]-4-派咬基]乙基]-3- 喹啉丙酸 52 /5 -[2-[ 1-[ 1 -嗣基〇-(5，6,7,8-四風-1，8- 507 秦咬-2 -基）丙基]-4-旅咬基]乙基]-3- 啥琳丙酸 -121- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公笈） A7 B7 200536844 五、發明說明（120 ) 化合物名稱_ MS (m/z) 53 54 55 冷-(1,3-苯并二σ夸環戊稀基)小[3-[(3,4，i，6-四氫-2-吡啶基）胺基]苯甲醯基]-4·哌啶戊酸 /3 -(1，3-苯并二17夸環戊烯基 [(1，4,5,6-四氫士羥基咬基）胺基]苯曱醯基l·4·承咬戊酸冷-(1,3 -苯并二ϋ寻環戊稀基）小 [(5,6,7,8-四氫-1，8-萘咬_2·基）乙酿基]-4-哌啶戊___ 506 523 480 f例14 1-[1·酮基-3-(5,6,7,8-四氫-1，8-萘啶基）丙基]-泠-苯基4- 哌啶丁酸（化合物13) 10 經濟部智慧財產局員工消費合作社印製 15 於〇。(：，一次添加二碳酸二第三丁酯（41.25克189毫莫耳）至含4-(2-羥乙基)派咬化合物14a (24·42克，189毫莫耳）之DMF (200毫升）溶液中。1小時後，移除冷卻浴，於室溫令反應混合物攪拌20小時。接著以Et2〇（200 毫升)及H2〇（500毫升）處理反應混合物。分離有機層，以NH4gi (200毫升）及食鹽水（200毫升）洗滌，脫水 (MgS〇4)。過濾及蒸發後，得到呈透明油狀物之化合物 14b，不需進一步純化，直接使用。於-78°C，使溫度不超過-60°C下，以1.5小時逐滴添加DMSO (14克，179毫莫耳）之DCM (80毫升）溶液至含草醯氯(62·8毫升，I25.6毫莫耳)之無水DCM (200毫升) 溶液中。於，以50分鐘於其内逐滴添加含化合物 14a之DCM (30毫升)溶液。於-78t攪拌3〇分鐘後，移 -122- 本纸張尺度適用中國國家標準(CNS)A4規袼（21〇 χ 297公釐' 200536844 A7 B7 五、發明說明（ 121 10 15 經濟部智慧財產局員工消費合作社印製 20 除冷卻浴，以30分鐘令反應混合物之溫度回升至jot。添加TEA (25.41克，251毫莫耳），於室溫令反應混合物攪拌1小時。過濾去除形成之固體沉澱，其濾液以〇3N HC1 (2 X 1〇〇毫升)及食鹽水(2〇〇毫升）洗滌。將有機相脫水(NajO4)，蒸發，其殘留物利用急驟管柱層析法（溶洗液梯度：己烷/EtOAc 100/0至70/30)純化，得到化合物 14c 〇於-78 C’氬氣下，經由注射器添加iM LiHMDS (73 宅升，73愛莫耳）溶液至含膦醢乙酸三曱g旨（nag克，73 毫莫耳)之THF (200毫升）溶液中。所得混合物於_78艽攪拌20分鐘後，以30分鐘添加含化合物14c (8 3克，36.5 毫莫耳)之THF (50毫升)溶液。於-78°C攪拌15分鐘後，移除冷卻浴，回流加熱反應混合物2天。令反應混合物冷卻至室溫，添加飽和ΝΗπΐ溶液（40毫升）。接著添加 EkO (2〇〇毫升），分離有機層，以食鹽水洗滌（14〇毫升）及脫水(NajCU)。過濾及蒸發後，殘留物利用急驟管柱層析法（溶洗液梯度：己烷/EtOAc 100/0至85/15)純化，得到化合物14df與Z-異構物之混合物。氮氣氣圍下’於H2〇（15毫升）中，結合化合物 ⑷、笨基 _酸（1.55 克，12.32 毫莫耳）、[RhC1(c〇d)]2 (0·1克，0.227毫莫耳)與Cod (0·557克，5.15毫莫耳），加熱至lOOt 3小時。再添加苯基_酸（1.〇克，8·2毫莫耳），將反應混合物再加熱至l〇〇t： 6小時。令反應混合物冷卻至室溫，添加EGO (1〇〇毫升），分離有機層。其水 -123- 本紙張尺度適用中國國家標準(CNS)A4規格（21〇χ297公釐）訂 200536844 A7 B7 五、發明説明（122 層以EtaO (2 x 100毫升）洗滌，將合併之有機層脫水 (NaJO4)，過濾及蒸發。殘留物利用急驟管柱層析法純化，得到化合物14e。添加TFA (6毫升）至含化合物14e (1.48克，4 〇9毫 5莫耳）之DCM (14毫升）溶液中。所得混合物於室溫攪拌 20分鐘，真空濃縮，以RP-HpLC純化，得到呈三氟乙酸鹽之化合物14f。氬氣下’在化合物8a (0.64克，2.64毫莫耳)之 (30毫升）’谷液中’添加HOBt (0·333克，2.46毫莫耳）、 10 EDC (0.47 克，2.46 毫莫耳)及 ΝΜΜ (0.68 克，5.28 毫莫耳）。此混合物於室溫攪拌i小時，然後於其内添加含化合物1^(0.66克，1.76毫莫耳)與NMM (0.68克，5.28毫經濟部智慧財產局員工消費合作社印製莫耳）之DMF (1〇毫升）溶液。所得混合物於室溫授拌隔夜。添加水(2毫升），隨後添加DCM (20毫升）。分離有 15 機層，脫水(NaJCU)，並予以濃縮。所得粗產物化合物 14g直接於下一反應使用。於含化合物14g之二嘮烷(2毫升）與H2〇（1毫升）溶液中，添加NaOH (0.78克，19·5毫莫耳）。此混合物於室溫攪拌5小時，並以2NHC1中和。蒸發溶劑後，殘留物以RP-HPLC純化，冷卻乾燥後，得 20 到化合物13。 -124-本紙張尺度適用中國國家標準(CNS)A4規格（21〇χ297公釐） 200536844 A7 B7 五、發明說明（l23Using the procedure of Example 13 and appropriate reagents and starting materials known to those skilled in the art, other compounds of the present invention can be prepared including, but not limited to: Compound name MS (m / z) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 49/3-[2- [l- [3-[(l, 4,5,6-tetrazol-5-yl-2-530pyrimidinyl) amino] phenylfluorenyl] -4-pipeline Pyridyl] ethyl'yl] -3-quinolinepropanoic acid 50-[2- [1- [3 · [(3,4,5,6-tetraaza-2-sigma) 513 amino] benzyl Alkyl] -4-branzyl] ethyl] -3-harinylpropionate 51 /?-[2- [1- [1-fluorenyl-3- (556,7,8-tetrazol-1, 8-501 zeol-2-yl) propyl] -4-pyridyl] ethyl] -3-quinolinpropionic acid 52/5-[2- [1- [1 -fluorenyl group 0- (5, 6,7,8-Four Wind-1,8- 507 Qin bite-2 -yl) propyl] -4-branthyl] ethyl] -3-harine propionic acid -121- This paper is applicable to China Standard (CNS) A4 specification (210x297 cm) A7 B7 200536844 V. Description of the invention (120) Compound name_ MS (m / z) 53 54 55 Cold- (1,3-benzodiσquacyclocyclopentyl) Small [3-[(3,4, i, 6-tetrahydro-2-pyridyl) amino] benzylidene] -4 · piperidinevaleric acid / 3-(1,3-benzodi 17 quart Cyclopentenyl [(1 , 4,5,6-Tetrahydros-hydroxyhydroxy) amino] phenylfluorenyl l · 4 · valeric acid cold- (1,3-benzobenzofluorenylcyclopentyl) small [(5 , 6,7,8-tetrahydro-1,8-naphthalene-2-yl) ethynyl] -4-piperidinepentyl ___ 506 523 480 f Example 14 1- [1 · keto-3- ( 5,6,7,8-tetrahydro-1,8-naphthyridinyl) propyl] -Ling-phenyl 4-piperidinebutyric acid (compound 13) 10 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 15 〇. (:, Add the third tert-butyl dicarbonate (41.25 g 189 mmol) to DMF containing 4- (2-hydroxyethyl) pie compound 14a (24.42 g, 189 mmol) in one portion. (200 mL) solution. After 1 hour, the cooling bath was removed and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was then treated with Et20 (200 mL) and H20 (500 mL). The organic layer was separated to NH4gi (200 ml) and brine (200 ml) were washed and dehydrated (MgS04). After filtration and evaporation, compound 14b was obtained as a transparent oil. It was used without further purification. At -78 ° C, At a temperature not exceeding -60 ° C, DMSO (14 g, 179 mmol) in DCM (80 ml) was added dropwise over 1.5 hours. ) Solution into a solution of chloral chloride (62 · 8 ml, I 25.6 mmol) in anhydrous DCM (200 ml). Then, a solution of Compound 14a in DCM (30 ml) was added dropwise thereto over 50 minutes. After stirring at -78t for 30 minutes, move -122- This paper size applies the Chinese National Standard (CNS) A4 Regulation (21〇χ 297 mm '200536844 A7 B7 V. Description of the invention (121 10 15 Ministry of Economic Affairs Intellectual Property Printed by the Consumer Cooperative of the Bureau. 20 Remove the cooling bath, raise the temperature of the reaction mixture to jot in 30 minutes. Add TEA (25.41 g, 251 mmol), and stir the reaction mixture at room temperature for 1 hour. Filter to remove the formed solids The precipitate was precipitated, and the filtrate was washed with 03N HC1 (2 X 100 ml) and brine (200 ml). The organic phase was dehydrated (NajO4) and evaporated, and the residue was subjected to flash column chromatography (washing Liquid gradient: Hexane / EtOAc 100/0 to 70/30) purification to obtain compound 14c. Under -78 C 'argon, iM LiHMDS (73 liters, 73 Emole) solution was added via syringe to phosphine Trimethyl acetate (nag, 73 mmol) in THF (200 ml). The resulting mixture was stirred at -78 ° F for 20 minutes, then compound 14c (83 g, 36.5 mmol) was added over 30 minutes. ) In THF (50 ml). After stirring at -78 ° C for 15 minutes, the cooling bath was removed and refluxed. The reaction mixture was warmed for 2 days. The reaction mixture was allowed to cool to room temperature, and a saturated NHΗπΐ solution (40 ml) was added. Then EkO (200 ml) was added, and the organic layer was separated, washed with brine (14 ml) and dehydrated (NajCU After filtration and evaporation, the residue was purified by flash column chromatography (eluent gradient: hexane / EtOAc 100/0 to 85/15) to obtain a mixture of compound 14df and the Z-isomer. Nitrogen Surrounded by H20 (15 ml), the compound hydrazone, benzyl acid (1.55 g, 12.32 mmol), [RhC1 (c〇d)] 2 (0.1 g, 0.227 mmol) With Cod (0.557 g, 5.15 mmol), heated to 100 t for 3 hours. Phenyl-acid (1.0 g, 8.2 mmol) was added and the reaction mixture was heated to 100 t : 6 hours. Allow the reaction mixture to cool to room temperature, add EGO (100 ml), and separate the organic layer. Its water -123- This paper size applies the Chinese National Standard (CNS) A4 specification (21 × 297 mm). 200536844 A7 B7 V. Description of the invention (122 layers were washed with EtaO (2 x 100 ml), and the combined organic layers were dehydrated (NaJO4), Filtered and evaporated. The residue was purified by using flash column chromatography purification, to give compound 14e. Was added TFA (6 mL) to a solution of compound 14e (1.48 g, 5 mmol 〇9 4 mole) of DCM (14 mL). The resulting mixture was stirred at room temperature for 20 minutes, concentrated in vacuo, and purified by RP-HpLC to give compound 14f as a trifluoroacetate salt. Under argon, HOBt (0.333 g, 2.46 mmol), 10 EDC (0.47 g, 2.46 mmol) were added to the 'Valley' of Compound 8a (0.64 g, 2.64 mmol) in 30 ml ) And NMM (0.68 g, 5.28 mmol). This mixture was stirred at room temperature for i hours, and then DMF containing compound 1 ^ (0.66 g, 1.76 mmol) and NMM (0.68 g, 5.28 mmol printed by the Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs, Moore) was added thereto (10 ml) solution. The resulting mixture was stirred at room temperature overnight. Water (2 mL) was added, followed by DCM (20 mL). 15 layers were separated, dehydrated (NaJCU), and concentrated. 14 g of the obtained crude compound was directly used in the next reaction. To a solution containing 14 g of the compound in dioxane (2 ml) and H20 (1 ml), NaOH (0.78 g, 19.5 mmol) was added. The mixture was stirred at room temperature for 5 hours and neutralized with 2NHC1. After evaporation of the solvent, the residue was purified by RP-HPLC. After cooling and drying, 20 to 13 were obtained. -124- This paper size applies Chinese National Standard (CNS) A4 specification (21 × 297 mm) 200536844 A7 B7 V. Description of the invention (l23

14&14 &

OH (Boc)20 DMF BocOH (Boc) 20 DMF Boc

.N.N

14b OH C114b OH C1

DMSO Et;N DCMDMSO Et; N DCM

Boc- •N.Boc- • N.

CHO a 14c B(〇H)2CHO a 14c B (〇H) 2

BocBoc

•N• N

C〇2Me 14d [RhCl(cod)]2 cod H2〇C〇2Me 14d [RhCl (cod)] 2 cod H2〇

Boc·Boc ·

C02Me tfA CH2C12C02Me tfA CH2C12

DIEA, DMFDIEA, DMF

C〇2MeC〇2Me

LSNNaOH 二啐烷LSNNaOH Dioxane

2. RP-HPLC 純化2. RP-HPLC purification

經濟部智慧財產局員工消費合作社印製使用實例13之程序，及熟習此項技藝人士已知之適當試劑與起始物質，可製備本發明其他化合物包含，惟不 -125-本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 200536844 A7 _ B7 五、發明說明（I24) 限於：化合物名稱 56 万-(2-萘基）-1-[1- _ 基-3-(5,6,7,8-四 486 __氣-1，8-萘唆-2-基）丙基]酸生物實驗實例如表1所示，由下文敘述之生物學研究證明，本發明 5化合物為可用於治療由整合素傳介的疾病之αν^3 & αν 召5整合素受體拮抗劑。實例1 試管内固相純化αν/53結合試驗The procedure of printing use case 13 by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs and the appropriate reagents and starting materials known to those skilled in the art can be used to prepare other compounds of the present invention. Standard (CNS) A4 specification (210 X 297 mm) 200536844 A7 _ B7 V. Description of the invention (I24) Limited to: Compound name 560,000- (2-naphthyl) -1- [1-_yl-3- (5 , 6,7,8-tetra486__gas-1,8-naphthyl-2-yl) propyl] acrylic acid Biological experimental examples are shown in Table 1, and it is proved by the biological research described below that the compound of the present invention 5 It is an αν ^ 3 & ανα5 integrin receptor antagonist that can be used to treat diseases mediated by integrin. Example 1 Solid phase purification αν / 53 binding test in a test tube

透明質蛋白/αν;53結合試驗方法係衍生自Mehta et 10 al·(价％如w·人 1998，33(9，861)。於 4°C，將溶解於 Tris 緩衝液(20 mM Tris、ImM CaCl2、1 MgCl2、10//M 經濟部智慧財產局員工消費合作社印製Hyalin / αν; 53 binding test method is derived from Mehta et 10 al. (Valence% such as w. Human 1998, 33 (9, 861). At 4 ° C, it will be dissolved in Tris buffer (20 mM Tris, ImM CaCl2, 1 MgCl2, 10 // M Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

MnCl2、150 mM NaCl)中，濃度為1微克/毫升之人類^ v 3 (Chemicon International Inc·，Temecula, CA)固定於 Immulon 96 槽培養盤(Dynex Technologies，Chantilly，VA) 15隔夜。於37 °C，洗滌培養盤，並以封阻緩衝液（3% BSA，於Tris缓衝液中）處理2小時。接著以由Tris缓衝液組成的試驗緩衝液清洗培養盤2次。以二重複添加合成化合物至諸槽後，隨即添加2 nM透明質蛋白（Sigma, St. Louis，M〇）。於37°C培養3小時後，以試驗緩衝液洗滌培 20 養盤5次。添加抗人類透明質蛋白jgG兔多株抗體 (Calbiochem，San Diego, CA) (1:2000)，於室溫培養培養盤 -126- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 五、發明說明（125) 1小時。使用利用生物素標記抗兔IgG之VectaStain ABC 過氧化醻套組試劑（Vector Laboratories, Burlingame，CA) 檢測結合抗體。於 Molecular Devices (Sunnyvale，CA)微培養盤讀取計上讀取490奈米處之培養盤數據。表1示出 5 本發明代表性化合物之試管内固相純化a v /5 3結合試驗結果° 實例2 試管内固相純化GP Ub/llla結合試驗以50微升/槽之量，於96槽Immulon-2微力價培養經濟部智慧財產局員工消費合作社印製 10 盤(Dynatech-Immulon)上塗覆於 10 mM HEPES、150 mM NaQ、1 mM MgCl2、pH 7.4 中之 RGD_親和性純化之 GP-Ilb/IIIa (有效範圍0.5-1.0微克/毫升）。將培養盤加蓋，於 4C培養隔夜。丟棄GP-IIb/IIIa溶液，添加150微升5% BSA ’於室溫培養1-3小時。以經改良之Tyrodes緩衝液 15 廣泛地洗滌培養盤。於含測試化合物（25微升/槽）之諸槽中，添加2 X最終濃度之生物素化之血纖維蛋白原（25微升/槽）。將培養盤加蓋，於室溫培養2-4小時。終止培養之20分鐘前，添加一滴試劑a (VectaStain ABC辣根過氧化酶套組，Vector Laboratories，Die.)及一滴試劑b，於 20 5毫升經改良之Tyrodes緩衝液中混合，靜置。丟棄配位體溶液，以經改良之Tyrodes緩衝液洗滌培養盤（5 χ 2〇〇微升/槽）。添加 Vectra Stain HRP_Biotin-Avidin 試劑（5〇微升/槽，如上述製備），於室溫培養15分鐘。丟棄該 Vectra Stain溶液，以經改良之Tyrodes緩衝液洗滌培養 -127- 本紙張尺度適用中國國家標準(CNS)A4規格（210 χ 297公麓） A7 200536844 B7 '~1 -------^ 五、發明說明（I26 ) 盤（5 X 200微升/槽）。添加展開溶液（1〇毫升5〇 mM檸檬酸鹽/麟酸鹽缓衝液@ pH 5.3、6毫克鄰伸苯基二胺、6微升30% H2〇2 ; 50微升/槽），於室溫培養3d分鐘，然後添加2 ϋ H2S〇4 (50微升/槽）。讀取49〇奈米處之吸光 5度。表1示出本發明代表性化合物之試管内固相純化Gp Ilb/IIIa結合試驗結果。實例3 試管内固相純化αν冷5結合試驗以如實例1之透明質蛋白/αν;3 3結合試驗之相同方 10法，進行透明質蛋白/αν泠5結合試驗，惟係將1微克/毫升人類純化 a v/3 5(Chemicon International Inc.)而非 α ν/5 3 固定於 Immulon 96 槽培養盤(Dynex Technologies)。試驗的所有其他方面包括緩衝液、試劑及培養時間均保持不變。 15 表1 化合物 OrMQoCttM) ανβ5 IC5« (uM) anbps IC50 (nM) 經濟部智慧財產局員工消費合作社印製 0.0560 ± 0.007 N-2 5.4000 土 N»1 >5 4.33 ±0.15 4,78 士 1.013 N=2 N=2 -128- 本纸張尺度適用中國國家標準(CNS)A4規格（21〇χ297公釐） 200536844 A7 B7 五、發明說明（m) 表1 化合物 OvPsICso (ηΜ) 〇νβδ ICs〇 (uM) αιη»β3 IC50 (uM) 經濟部智慧財產局員工消費合作社印製MnCl2, 150 mM NaCl), human ^ v 3 (Chemicon International Inc., Temecula, CA) at a concentration of 1 μg / ml was fixed to an Immulon 96-well culture plate (Dynex Technologies, Chantilly, VA) for 15 overnights. The plate was washed at 37 ° C and treated with blocking buffer (3% BSA in Tris buffer) for 2 hours. Then, the culture plate was washed twice with a test buffer consisting of Tris buffer. After the compound was added to the tanks in duplicate, 2 nM hyalin (Sigma, St. Louis, Mo) was added. After 3 hours of incubation at 37 ° C, the dishes were washed and cultured 5 times with test buffer. Anti-human hyalin protein jgG rabbit polyclonal antibody (Calbiochem, San Diego, CA) (1: 2000) was added, and the culture plate was cultured at room temperature -126- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200536844 A7 B7 V. Description of the invention (125) 1 hour. VectaStain ABC peroxidase kit (Vector Laboratories, Burlingame, CA) using biotin-labeled anti-rabbit IgG was used to detect bound antibodies. Read the plate data at 490 nm on a Molecular Devices (Sunnyvale, CA) microplate reader. Table 1 shows the results of 5 av / 5 3 solid-phase purification test results of representative compounds of the present invention in a tube. Example 2 GP Ub / llla binding test of solid phase purification in a test tube at 50 μl / tank in 96-channel Immulon -2 Printed 10 plates (Dynatech-Immulon) of the Intellectual Property Bureau of the Ministry of Economic Affairs, Ministry of Economic Affairs, printed on 10 plates (Dynatech-Immulon) coated with RGD in 10 mM HEPES, 150 mM NaQ, 1 mM MgCl2, pH 7.4_ affinity purified GP-Ilb / IIIa (effective range 0.5-1.0 μg / ml). Cover the plate and incubate overnight at 4C. Discard the GP-IIb / IIIa solution, add 150 µl of 5% BSA 'and incubate at room temperature for 1-3 hours. Wash the plates extensively with modified Tyrodes buffer 15. To the wells containing the test compound (25 µl / slot), biotinylated fibrinogen (25 µl / slot) was added at a final concentration of 2 X. The plate was capped and incubated at room temperature for 2-4 hours. Twenty minutes before the termination of culture, a drop of reagent a (VectaStain ABC horseradish peroxidase kit, Vector Laboratories, Die.) And a drop of reagent b were added, mixed in 20 5 ml of modified Tyrodes buffer, and left to stand. The ligand solution was discarded, and the plates were washed with modified Tyrodes buffer (5 x 200 μl / well). Add Vectra Stain HRP_Biotin-Avidin reagent (50 μl / well, prepared as above) and incubate at room temperature for 15 minutes. Discard the Vectra Stain solution, wash and culture with modified Tyrodes buffer -127- This paper size applies the Chinese National Standard (CNS) A4 specification (210 χ 297 foot) A7 200536844 B7 '~ 1 ------- ^ V. Description of the invention (I26) plate (5 X 200 microliters / slot). Add the developing solution (10 ml of 50 mM citrate / linate buffer @ pH 5.3, 6 mg of o-phenylenediamine, 6 μl of 30% H2O2; 50 μl / slot) in the chamber Incubate at room temperature for 3d minutes, and then add 2〇 H2SO4 (50 μl / slot). Read 5 degrees absorbance at 49nm. Table 1 shows the results of in-tube solid-phase purification of Gp Ilb / IIIa binding tests for representative compounds of the present invention. Example 3 Solid-phase purification of αν cold 5 binding test in a test tube Using the same method as in Example 1 for hyaluronan / αν; 3 3 binding test, a hyaluronan / ανLING5 binding test was performed, except that Ml human purified av / 3 5 (Chemicon International Inc.) instead of α ν / 5 3 was fixed to Immulon 96-well culture plate (Dynex Technologies). All other aspects of the test, including buffers, reagents, and incubation times remain unchanged. 15 Table 1 Compound OrMQoCttM) ανβ5 IC5 «(uM) anbps IC50 (nM) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 0.0560 ± 0.007 N-2 5.4000 Soil N» 1 > 5 4.33 ± 0.15 4,78 ± 1.013 N = 2 N = 2 -128- This paper size is in accordance with Chinese National Standard (CNS) A4 (21〇 × 297 mm) 200536844 A7 B7 V. Description of the invention (m) Table 1 Compound OvPsICso (ηΜ) 〇νβδ ICs〇 ( uM) αιη »β3 IC50 (uM) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

3 0.0036^0.0004 N=5 2.5 0,21 N=1 4 0.0005 士 0,0009 N=3 0.0355 i 0.0089 N-4 0.87 土 0,19 N-2 5 0.0037 ±0.0014 N=3 0.2607 ± 0,0569 N=3 14.84 ± 0.68 N=2 5-3 0.1613 N=1 >5 N»1 ND 5*4 0.0054 ±0.0002 0.1616 ±0.0627 N-3 9.82 N=1 6 0.0076 ± 0,0021 N-2 0.54 N-l 1·62 士 0.05 N«2 7 0.0082 i 0.0014 N=2 0.0395 ± 0.0085 N-2 1.67 i 0.74 N-2 8 0.0179 ±0.0034 N=4 0.253 N=1 1.36 士 0·43 N«2 9 >1 Nel ND S.51 土 2·36 N-2 10 0.0024 ±0.0013 N-2 0.0335 i 0.0075 N艦2 L67 N-l 11 0.0011 i 0.0002 N*3 0.0023 i 0.0009 N=3 2.52 土 0·30 N«2 12 0.0042 士 0.0014 N*3 0.078 士 0.07S N«2 0.14 N«2 13 0.0032 ± 0.0006 N«2 0,036 ± 0.0133 N=2 11.09 ±3.40 N=2 14 0.0361 土 0.0001 N=2 0.108 土 0.034 N=1 5.04 N«1 15 0,0008 ± 0.0023 N55^ 0.0334 土 0.0063 N=4 4.03 ± 0·43 N*2 16 .0.2810 N-l 0.775 N-l 253S N«1 17 0.0008 0.0001 Ν·=4 0.0313 i 0.0060 N«4 6.60ϋΛ2 N=2 18 >5 N-l >5 N-l >50 N*1 19 0.0025 ± 0.0004 N*3 0.0171 士 0.0025 N»3 13.77 ±9.69 N*2 19-1 0.0367 N«1 1,12 N=1 >50 N=1 19-2 0,0013 士 0.0023 N-=2 0.0092 ± 0.0004 N=2 12.9 N-l 19-3 0,0447 ± 0.0204 N=2 U7±0.02 N-2 ND -129- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 ___B7__ 五、發明說明（l28) 表1 化合物· 〇νΡ3ΙΟ^〇ΐΜ) 〇vPs ICsc (uM) _ρ3 IC5〇 (uM) 經濟部智慧財產局員工消費合作社印製 19-4 0.0013 ±0.0007 N=3 0.0075 ±0.0018 N-3 4,86 N*1 20 0.1417 士 0,027 N=3 0.995 N=1 1.80 N篇1 21 0.0280 士 0.0031 N:3 0.78 N-l 1.80 i 0,63 N-2 21a 0.405 N-l 0.28 N«1 1.97 N-l 21b 0,0213 士 0.0019 N*3 0.8413 ± 0.4054 N-3 5.31 N*1 22 0,0046 士 0·0008 N=3 0,195 N*1 0.43 ± 0.07 N*2 23 0_2980 土 0·1460 N*2 2.010 N*! 4.93 N-l 24 03070 N«1 0.387 N*1 19,30 N=1 25 0.0456^0.0066 N«2 0,773 土 0,118 N«2 S.67 士 1/72 N«2 26 0.0277 i 0.0053 N«2 0.5 N雇1 5.92 N_1 27 0.0480 N*1 0.81 Ν*=1 1.62 i 0.56 N*2 28 0·0007 士 0-0002 N«3 0,0027 ±0.0008 N=4 6.10 ± 2.44 N«2 28a 0.0003 土 0.0002 N=2 0.0042 ^0.0018 N*2 1.83 ± 0.57 N;2 28b 0.0208 i 0.0053 N-2 0,1262 士 0、0448 N«2 24.26 N-l 29 0.0022 i 0.0008 N*3 0·119±0·0150 >1=3 1.74 i 0.89 N«2 30 0.0010 ±0.0002 N*3 0.0028 土 0,0001 N*3 14.39^5,98 N*2 30» 0.0004 ± 0.0002 N»3 0.0019 ±0.0004 Na3 2.93 ± 1-S6 N=2 30b 0.0317 士 0.0147 N*2 0.0482 ± 0.0028 N*2 >50 N-l 31 0.0330 N隹1 0.3 N**l 21.57 士 4.S7 N*=2 32 0.0008 ± 0.0008 N-3 0.0022 士 0,0007 N=3 1.055 i 0.56 N*2 33 0.0013 土 0.0004 N-3 0.0226 ± 0.0052 N*3 >50 N=1 34 0.1476^0.1004 N=2 1.041 ±0.109 N*2 >50 N*1 -130- 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 200536844 A7 B7 五、發明說明（129) 表1 化合物 OypalQo (uM) 〇vPs IC$〇 (uM) α^β3 IC50 (uM) 經濟部智慧財產局員工消費合作社印製 35 0.0007 =b 0,0004 N=2 0,0007 i 0.0002 N=3 0.965 ± 0.07 N-2 36 0.0008 士 0,0001 N=4 0.0007 士 0,0002 N-3 3.11 ±0.04 N-2 36a 0.0004 N=3 0.0009 士 0,0006 N=2 0/79 士 0.05 Νε=3 36b 0.084 N«1 0.129 N=1 >50 N=1 37 0.0158 土 0.0043 N-2 0.0897 土 0.0116 N=3 >50 N*1 38 0.4840 N«1 2.11 N=1 >50 N*1 39 0,0066 土 0.0018 N-2 0.0287 ±0.0133 N«2 >50 N-l 40 0,0052 =b 0.0002 N=2 0J08 i 0.0630 N*2 23.95 i 9.89 N-2 41 0.0018 i 0.0010 N=2 0.8725 0,1575 N=2 19.3 土 2.60 N-2 42 0.0007 ± 0.0003 N=3 0.0189^0.0046 N=3 5 i 0.74 N*2 43 0.0079 ± 0.0007 N*2 0.2225 ± 0.0885 N=2 28.82 i 15.8 N-2 44 0,0022 ± 0Ό009 N=3 0.002 士 0.0006 N=3 5.44 dbl.l N-2 45 0.0008 ± 0.0001 N=3 0.0017 db 0,0003 N«3 6.61 i 2.85 N»2 46 0.0035 ± 0.0006 N=2 0.0659 =k 0.0171 N*2 13.64 ± 1.33 N*2 47 0.0014 士 0.0007 N*3 0.0046 i 0.0017 N=3 L47i0.37 N*2 48 0.00 U1 土 0.0005 N»3 0.0033 ± 0.0014 N-3 1·21 土 0·20 N=2 49 0,0008 ± 0.0002 N=3 0.0158 ±0.0009 N«2 0.27 ±0.13 N费3 SO 0.0156 士 0.0044 N«4 0.676 N=1 0.19 i 0,04 N«2 51 0,0030 ±0.0006 N*4 0.169 士 0.019 N«2 〇·48±0·01 N«2 52 0.0064 ±0.0014 N=4 >50 N-l 0·57±0·04 N*2 53 0.0298 ±0.0137 N=5 0.1375 ±0.0415 N«2 0.94 i 0.05 N-2 54 0.0017 ±0.0005 N=3 0.0347 ±0,0117 Ne3 0.24 K-l -131- 本紙張尺度適用中國國家標準(CNS)A4規格（210x 297公釐） 200536844 A7 B7 五、發明說明（13〇) 表1 化合物〇vMC50 (UM) 〇νβ5 IC5〇 (uM) anbp3 IC50 (uM) 經濟部智慧財產局員工消費合作社印製 55 0.0950 N=1 0.737 N^l 15.59 N=1 56 0.0014 i 0.0006 N*3 0.0245 ± 0,0065 N-2 39.12 土 0·785 N-2 56a 0.0005 士 0.0002 N-3 0.0265 ± 0·0034 N=3 14.66 Ν=1 56b 0.3263 ± 0.0894 N=3 0.8096 士 0,1045 N-3 ND 57 0·0016 士 0,0007 N=3 0.0109 ±0.0042 N;3 3.04 i 0.55 N=2 58a 0,0004士 0,0003 N=3 0.0323 ± 0.0082 N=3 1.44 i 0.39 N-2 S8b 0.083 ± 0.020 K=2 0.5760 士 0· 1490 N-2 35.5 N«1 59 0·0026 士 0,0014 N*2 0.0096 =b 0.0038 N=2 7.805 i 4.67 N«2 60 0,0010 士 0.0008 N*2 0.0309 ± 0.0006 N*2 4.53 ± 2.47 N*2 61 0.0045 土 0·000? N=3 0.0253 ± 0.0073 N=3 N=2 62 0.0900 ± 0.0020 N«2 0.1700 i 0.0810 N-2 >50 N-l 63 0.0018 i 0.0008 N-3 0.0070 i 0.0008 N，3 10.23 i 6.41 N-2 64 0.0615 ±0.0055 N-2 0.1473 i 0.0847 N*2 >50 K-l 65 0.0008 N=2 0.0346 ± 0.0002 N-2 3.84 N-l 66 0.0012 i 0.0001 N=3 0.0103^0.0014 N*3 28.27 N=1 67 0.048 土 0.0030 N=2 0.176 i 0.0350 N*2 7.82 N=1 68 0.413 N这1 >1 N-l 35.6 N*1 69 >0.5 N*1 >1 N=1 >50 N=1 70 >0.5 N达1 >1 N=1 >50 N®1 71 >0.5 N=1 >1 N道1 >50 N*1 72 >0.5 N-l >1 N*1 >50 N-l 73 >0.5 N-l >1 N*1 >50 N-l -132- 本紙張尺度適用中國國家標準(CNS)A4規格（210x 297公釐） 200536844 A7 B7 五、發明說明（m) 表1 化合物· 〇rp3IC5〇(uM) 〇νβδ IC5〇 (uM) anbPa IC50 (uM) 74 0.193 N=1 >1 N*1 >50 N-l 75 0.0053 i 0.0010 N=2 0.0419 i 0.0052 N=3 >50 N-l 76 0.0018 ±0.0003 N=2 0.0397 士 0.0121 N=2 5.38 N=1 76a 0.0011 0.0169 10.38 77 0.138 N=1 0.789^0.065 N=2 ND 78 0.0014 ±0.0002 N=3 0.0499 ± 0.0055 N=3 25.74 N-l 79 0.0057 ±0.0001 N«2 0.0260 i 0.0030 N-2 2472 N«1 80 0,0035 士 0.0015 N=3 0.025 ± 0,0060 N*2 40.23 N*1 81 0.0067 ± 0.0002 N=3 0.0101 i 0.0017 N-=3 22.73 N灌1 在前文說明書教示本發明原則，及提供實例以達說明之目的下，可以瞭解的是，本發明之實施涵蓋下文專利 5 申請範圍内及其對等物的所有一般變化、適應性變化及/ 或修飾。經濟部智慧財產局員工消費合作社印製 -133- I紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）3 0.0036 ^ 0.0004 N = 5 2.5 0,21 N = 1 4 0.0005 ± 0,0009 N = 3 0.0355 i 0.0089 N-4 0.87 soil 0,19 N-2 5 0.0037 ± 0.0014 N = 3 0.2607 ± 0,0569 N = 3 14.84 ± 0.68 N = 2 5-3 0.1613 N = 1 > 5 N »1 ND 5 * 4 0.0054 ± 0.0002 0.1616 ± 0.0627 N-3 9.82 N = 1 6 0.0076 ± 0,0021 N-2 0.54 Nl 1 62 ± 0.05 N «2 7 0.0082 i 0.0014 N = 2 0.0395 ± 0.0085 N-2 1.67 i 0.74 N-2 8 0.0179 ± 0.0034 N = 4 0.253 N = 1 1.36 ± 0 · 43 N« 2 9 > 1 Nel ND S.51 soil 2.36 N-2 10 0.0024 ± 0.0013 N-2 0.0335 i 0.0075 N ship 2 L67 Nl 11 0.0011 i 0.0002 N * 3 0.0023 i 0.0009 N = 3 2.52 soil 0 · 30 N «2 12 0.0042 0.0014 N * 3 0.078 ± 0.07SN «2 0.14 N« 2 13 0.0032 ± 0.0006 N «2 0,036 ± 0.0133 N = 2 11.09 ± 3.40 N = 2 14 0.0361 soil 0.0001 N = 2 0.108 soil 0.034 N = 1 5.04 N« 1 15 0,0008 ± 0.0023 N55 ^ 0.0334 soil 0.0063 N = 4 4.03 ± 0 · 43 N * 2 16 .0.2810 Nl 0.775 Nl 253S N «1 17 0.0008 0.0001 Ν · = 4 0.0313 i 0.0060 N« 4 6.60ϋΛ2 N = 2 18 > 5 Nl > 5 Nl > 50 N * 1 19 0.0025 ± 0.0004 N * 3 0.0171 ± 0.0025 N »3 13.77 ± 9.69 N * 2 19-1 0.0367 N «1 1,12 N = 1 > 50 N = 1 19-2 0,0013 ± 0.0023 N- = 2 0.0092 ± 0.0004 N = 2 12.9 Nl 19-3 0,0447 ± 0.0204 N = 2 U7 ± 0.02 N-2 ND -129- This paper size applies Chinese National Standard (CNS) A4 specification (210x297 mm) 200536844 A7 ___B7__ V. Description of the invention (l28) Table 1 Compounds 〇νΡ3ΙΟ ^ 〇ΐΜ) 〇vPs ICsc (uM) _ρ3 IC5〇 (uM) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 19-4 0.0013 ± 0.0007 N = 3 0.0075 ± 0.0018 N-3 4,86 N * 1 20 0.1417 ± 0,027 N = 3 0.995 N = 1 1.80 N Chapter 1 21 0.0280 ± 0.0031 N: 3 0.78 Nl 1.80 i 0,63 N-2 21a 0.405 Nl 0.28 N «1 1.97 Nl 21b 0,0213 ± 0.0019 N * 3 0.8413 ± 0.4054 N-3 5.31 N * 1 22 0,0046 taxi 0.0008 N = 3 0,195 N * 1 0.43 ± 0.07 N * 2 23 0_2980 soil 0 · 1460 N * 2 2.010 N *! 4.93 Nl 24 03070 N «1 0.387 N * 1 19,30 N = 1 25 0.0456 ^ 0.0066 N «2 0,773 dirt 0,118 N« 2 S.67 taxi 1/72 N «2 26 0.0277 i 0.0053 N« 2 0.5 N hire1 5.92 N_1 27 0.0480 N * 1 0.81 Ν * = 1 1.62 i 0.56 N * 2 28 0 · 0007 Taxi 0-0002 N «3 0,0027 ± 0.0008 N = 4 6.10 ± 2.44 N« 2 28a 0.0003 soil 0.0 002 N = 2 0.0042 ^ 0.0018 N * 2 1.83 ± 0.57 N; 2 28b 0.0208 i 0.0053 N-2 0,1262 ± 0, 0448 N «2 24.26 Nl 29 0.0022 i 0.0008 N * 3 0 · 119 ± 0 · 0150 > 1 = 3 1.74 i 0.89 N «2 30 0.0010 ± 0.0002 N * 3 0.0028 soil 0,0001 N * 3 14.39 ^ 5,98 N * 2 30» 0.0004 ± 0.0002 N »3 0.0019 ± 0.0004 Na3 2.93 ± 1-S6 N = 2 30b 0.0317 ± 0.0147 N * 2 0.0482 ± 0.0028 N * 2 > 50 Nl 31 0.0330 N 隹 1 0.3 N ** l 21.57 ± 4.S7 N * = 2 32 0.0008 ± 0.0008 N-3 0.0022 ± 0, 0007 N = 3 1.055 i 0.56 N * 2 33 0.0013 soil 0.0004 N-3 0.0226 ± 0.0052 N * 3 > 50 N = 1 34 0.1476 ^ 0.1004 N = 2 1.041 ± 0.109 N * 2 > 50 N * 1 -130 -This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200536844 A7 B7 V. Description of Invention (129) Table 1 Compound OypalQo (uM) 〇vPs IC $ 〇 (uM) α ^ β3 IC50 (uM) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 35 0.0007 = b 0,0004 N = 2 0,0007 i 0.0002 N = 3 0.965 ± 0.07 N-2 36 0.0008 ± 0,0001 N = 4 0.0007 ± 0,0002 N- 3 3.11 ± 0.04 N-2 36a 0.0004 N = 3 0.0009 ± 0,0006 N = 2 0/79 ± 0.05 Νε = 3 36b 0 .084 N «1 0.129 N = 1 > 50 N = 1 37 0.0158 soil 0.0043 N-2 0.0897 soil 0.0116 N = 3 > 50 N * 1 38 0.4840 N« 1 2.11 N = 1 > 50 N * 1 39 0,0066 soil 0.0018 N-2 0.0287 ± 0.0133 N «2 > 50 Nl 40 0,0052 = b 0.0002 N = 2 0J08 i 0.0630 N * 2 23.95 i 9.89 N-2 41 0.0018 i 0.0010 N = 2 0.8725 0, 1575 N = 2 19.3 soil 2.60 N-2 42 0.0007 ± 0.0003 N = 3 0.0189 ^ 0.0046 N = 3 5 i 0.74 N * 2 43 0.0079 ± 0.0007 N * 2 0.2225 ± 0.0885 N = 2 28.82 i 15.8 N-2 44 0 , 0022 ± 0Ό009 N = 3 0.002 ± 0.0006 N = 3 5.44 dbl.l N-2 45 0.0008 ± 0.0001 N = 3 0.0017 db 0,0003 N «3 6.61 i 2.85 N» 2 46 0.0035 ± 0.0006 N = 2 0.0659 = k 0.0171 N * 2 13.64 ± 1.33 N * 2 47 0.0014 ± 0.0007 N * 3 0.0046 i 0.0017 N = 3 L47i0.37 N * 2 48 0.00 U1 soil 0.0005 N »3 0.0033 ± 0.0014 N-3 1 · 21 soil 0 · 20 N = 2 49 0,0008 ± 0.0002 N = 3 0.0158 ± 0.0009 N «2 0.27 ± 0.13 N fee 3 SO 0.0156 ± 0.0044 N« 4 0.676 N = 1 0.19 i 0,04 N «2 51 0,0030 ± 0.0006 N * 4 0.169 ± 0.019 N «2 〇 · 48 ± 0 · 01 N« 2 52 0.0064 ± 0.0014 N = 4 > 50 Nl 0 · 57 ± 0 · 04 N * 2 53 0.0298 ± 0.0137 N = 5 0 .1375 ± 0.0415 N «2 0.94 i 0.05 N-2 54 0.0017 ± 0.0005 N = 3 0.0347 ± 0,0117 Ne3 0.24 Kl -131- This paper size applies to China National Standard (CNS) A4 (210x 297 mm) 200536844 A7 B7 V. Description of the invention (13〇) Table 1 Compounds OVMC50 (UM) 〇νβ5 IC5〇 (uM) anbp3 IC50 (uM) Printed by the Consumer Consumption Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 55 0.0950 N = 1 0.737 N ^ l 15.59 N = 1 56 0.0014 i 0.0006 N * 3 0.0245 ± 0,0065 N-2 39.12 Soil 0 · 785 N-2 56a 0.0005 ± 0.0002 N-3 0.0265 ± 0 · 0034 N = 3 14.66 Ν = 1 56b 0.3263 ± 0.0894 N = 3 0.8096 people 0,1045 N-3 ND 57 0 · 0016 people 0,0007 N = 3 0.0109 ± 0.0042 N; 3 3.04 i 0.55 N = 2 58a 0,0004 people 0,0003 N = 3 0.0323 ± 0.0082 N = 3 1.44 i 0.39 N-2 S8b 0.083 ± 0.020 K = 2 0.5760 people 0 · 1490 N-2 35.5 N «1 59 0 · 0026 people 0,0014 N * 2 0.0096 = b 0.0038 N = 2 7.805 i 4.67 N« 2 60 0,0010 ± 0.0008 N * 2 0.0309 ± 0.0006 N * 2 4.53 ± 2.47 N * 2 61 0.0045 ± 0? 000? N = 3 0.0253 ± 0.0073 N = 3 N = 2 62 0.0900 ± 0.0020 N «2 0.1700 i 0.0810 N-2 > 50 Nl 63 0.0018 i 0.0008 N-3 0.0070 i 0 .0008 N, 3 10.23 i 6.41 N-2 64 0.0615 ± 0.0055 N-2 0.1473 i 0.0847 N * 2 > 50 Kl 65 0.0008 N = 2 0.0346 ± 0.0002 N-2 3.84 Nl 66 0.0012 i 0.0001 N = 3 0.0103 ^ 0.0014 N * 3 28.27 N = 1 67 0.048 soil 0.0030 N = 2 0.176 i 0.0350 N * 2 7.82 N = 1 68 0.413 N this 1 > 1 Nl 35.6 N * 1 69 > 0.5 N * 1 > 1 N = 1 > 50 N = 1 70 > 0.5 N up to 1 > 1 N = 1 > 50 N®1 71 > 0.5 N = 1 > 1 N track 1 > 50 N * 1 72 > 0.5 Nl > 1 N * 1 > 50 Nl 73 > 0.5 Nl > 1 N * 1 > 50 Nl -132- This paper size applies to China National Standard (CNS) A4 (210x 297 mm) 200536844 A7 B7 5 Description of the invention (m) Table 1 Compounds · 〇rp3IC5〇 (uM) 〇νβδ IC5〇 (uM) anbPa IC50 (uM) 74 0.193 N = 1 > 1 N * 1 > 50 Nl 75 0.0053 i 0.0010 N = 2 0.0419 i 0.0052 N = 3 > 50 Nl 76 0.0018 ± 0.0003 N = 2 0.0397 ± 0.0121 N = 2 5.38 N = 1 76a 0.0011 0.0169 10.38 77 0.138 N = 1 0.789 ^ 0.065 N = 2 ND 78 0.0014 ± 0.0002 N = 3 0.0499 ± 0.0055 N = 3 25.74 Nl 79 0.0057 ± 0.0001 N «2 0.0260 i 0.0030 N-2 2472 N« 1 80 0,0035 ± 0.0015 N = 3 0.025 ± 0,0060 N * 2 40.23 N * 1 81 0.0067 ± 0.0002 N = 3 0.0101 i 0.0017 N- = 3 22.73 N irrigation 1 In the foregoing description, the principles of the present invention are taught, and examples are provided for the purpose of illustration. It can be understood that The implementation of the present invention covers all general changes, adaptive changes, and / or modifications within the scope of the following Patent 5 applications and their equivalents. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -133- I Paper size applies to China National Standard (CNS) A4 (210x297 mm)

Claims

0200536844 A8 B8 C8 D8 6. Scope of patent application 1. A compound with the following formula (I):

ζ Formula (I) In the formula 5 10 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 15 20 W is selected from the following groups: -cQ · 3alkyl (Rl), _Ci 3alkyl (R., -C 〇-3 alkyl-aryl (RUR8), -CG · 3 alkyl · heterocyclyl (Ri, R8), -C0_3 alkoxy (Ri), -C0-3 unoxy_aryl (Ri, R0, and -C (M alkoxy-heterocyclyl (Rl, Rs); Ri is selected from the group consisting of: hydrogen, -N (R4 > 2, -N (R4) (R5) , -N (R4) (R6), -heterocyclyl (R8) and -heteroaryl (R8); Ru is selected from the following N (R4) 2, -C (= N-R4) -N (R4) (R6), -C (= N-R4) -N (R4) -C (= 〇) -R4, -C (= N-R4) .N (R4) -C (= 〇) -N (R4) 2.-C (= N-R4) -N (R4) -C02.R4 > -C (= N-R4) -N (R4) -S02- Ci_8 Alkenyl (R7) and -C (= N- R4) -N (R4) _s〇2-N (R4) 2; R4 is selected from the group: hydrogen and -Cl-8 alkyl (R7); R5 is selected from the group: -C ( = 〇) -R4, _c (= 〇) -N (R4) 2, -c (= 〇) -cycloalkyl (r8), _c (= 〇) · heterocyclyl ... c (= 〇 > aryl (R8), _C (= 〇) -heteroaryl group 8), _c (= 〇) -N (R4y cycloalkyl (R8), -C (= 〇) -N (R aryl (R8), _c (vR4, -134

200536844 A8 B8 C8 D8 VI. Patent application scope -c02-cycloalkyl (r8), -c〇2-** (r8), -c (r4) (= n-R4), -C (= N -R4) -N (R4) 2, -C (= N-R4) -N (R4) (R6), -C (= N-R4) -N (R4) -C (= 0) -R4,- C (= N-R4) -N (R4)-c (= 〇) -n (r4) 2, -c (= n-r4) -n (r4) -c〇2-r4, -C (= N -5 R4) -N (R4) -S〇2-C1.8 ^ ^ (R7) > -C (= N-R4) -N (R4)-s〇2-n (r4) 2, -n (r4) -c (r4) (= n-r4), n (r4) -c (= n-r4) -n (r4) 2, -n (r4) -c (= n-r4) -n (r4) (r6), -n (r4)-C (= N-R4) -N (R4) -C (= 〇) -R4, -N (R4) _C (= N-R4)-N (R4 ) -C (= 0) -N (R4) 2, -n (r4) -c (= n-r4) -n (r4)-10 C〇2-R4, -N ^ d-CpN-RO-NdhSCVCM Alkyl (R7), -N (R4) -C (= N-R4) -N (R4) -S〇2-N (R4) 2, -so2-Ci_8 alkyl (R7), -S〇2- N (R4) 2, -S02-cycloalkyl (R8) and -S〇2-aryl (R8); R6 is selected from the following group: -cycloalkyl (R8), -heterocyclyl (R8 ), -Aryl15 (r8) and -heteroaryl (r8); R7 is independently selected from one to two substituents of the following group: hydrogen, -Cw alkoxy (R9), -NH2-, -NH-Cw Alkyl (R9), printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs -N ((Ι ^ · 8 alkyl (R9)) 2, -C (= 〇) H, -C (= 〇) -Ci_8 base (R9), -C (= 〇) -NH2, -CpOyNH-Cw alkyl (R9), 20 · (= 0) -N ((^ 8 alkyl (R9)) 2, -C (= 〇) _NH-aryl (RiG ), -C (= 〇) -cycloalkyl (R1G), -c (= 〇) -heterocyclyl (Rio), -C (= 〇) -aryl (Ri〇), -C (= 〇)- Heterosquare (R10), -C02H, alkyl (R9), -C02-aryl (R10), -C (= NH) -NH2, -SH, -S-Cm alkyl (R9),- S-Cm alkane-135 This paper is sized for China National Standard (CNS) A4 (210 X 297 mm) 200536844 as B8 C8

5 o IX 5 IX Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20. Soil-S-Cw alkyl (R9), -SC “8 alkyl-Cl 8 alkoxy (R9) alkyl_NH々8 alkane (R9), _s〇2_Ci diyl (R9), -S〇2-NH2, -SCVNH-Cu alkyl (r9), _s〇2 · N (c "8 alkyl (R9)), _s. 2-aryl (R) 〇), cyano, (southyl) 1.3, hydroxyl, nitro, keto, -cycloalkyl (Rig), -heterocyclyl (Rio), -aryl (R1Q ) And -heteroaryl (Ri0); when Rs is attached to a nitrogen atom, it is independently selected from one to four substituents of the following group: hydrogen, _Cb8 alkyl (r9), _C (= 〇) H, Alkyl (r9), -C (== 〇) _NH2, _c (= 〇) _Nl ^ Ci.8 alkyl (r9), _c (= 〇 > N (Ci 8 alkyl (R9)) 2, _c (== 〇) _NH_aryl (R1 ()), _ C (= 〇) _cycloalkyl (r) g), _ c (= 〇) _heterocyclyl (Rio), -C (= 〇) -Aryl (RlG), -c (= 〇) -heteroaryl (Rio), -C02H, -COrCy alkyl (r9), -c〇2-aryl (R1〇), -C (= NH)- NH2, -SCVCm alkyl (r9), -s〇2_ NH2_, -SOrNH-Cw alkyl (r9), _s〇2_N (Cl 8 alkyl is called)) 2, -scv aryl (RlQ), naphthene (Riq), and · aryl (Rio); Also, when attached to a carbon atom, Independently selected from one to four substituents of the group: hydrogen, -Cw alkyl (R9), -Cw alkoxy (R9), -cycloalkyl (Rig), -〇_aryl ( R1〇), -C (= 〇) H, < (= 〇χ8alkyl (R9), < (= 〇) -NH2, -CCK ^ NH-Cw alkyl (R9), _C (= 〇) _N (Ci 8 alkyl (R9)) 2, -C (= 〇) -NH-aryl (R1G), -c (= 〇) _cycloalkyl (RhO, -c (= 〇) _heterocyclyl (Ri〇), -cpo), aryl (Ri〇), -c (= 0) -heteroaryl (Rio), -C〇2H, -CCVCw alkyl-136 This paper is in accordance with China National Standard (CNS ) A4 specification (21〇X 297 public love) 200536844 A8 B8 C8 D8 VI. Patent application scope (R9), -C〇2-aryl (R10), -c (= NH) -NH2, -SCVCw k group ( R9), -S〇2-NH2, -SOrNH-Cu alkyl (R9), -S〇2-N (Ci_8 alkyl (R9)) 2, -S〇2 ~ aryl (Rio), -SH- -S-Cu alkyl (R9), -S ** Ci_8 alkyl-S-Cu alkyl (R9), 5-S-Cw alkyl-Cw alkoxy (R9), -S-Cw alkyl -NH-Cw alkyl (R9), -NH2, -NH-Cw alkyl (R9), alkyl (R9)) 2, cyano, halo, hydroxy, nitro, keto, -cycloalkyl ( Rh >), -heterocyclic (R1 ()), -aryl (R10) and -heteroaryl (Rio); · 10 R9 is selected from the following groups: hydrogen, -Cw alkoxy, -NH2, -NH-Cw alkyl, -NCCu alkyl) 2,-(: (= 0) 11,-(: (= 0)-NH2, -CO-O ^ NH-Cu alkyl, -CpCO-NCCw alkyl) 2, -CO2H, -COyCw alkyl, -SCVCw alkyl, -S〇2-NH2, -SOrNH- Cw alkyl, · sOfNCCw alkyl 15), cyano, (i), 3, hydroxyl, nitro, and keto; Rio, when attached to a nitrogen atom, is independently selected from one of the following groups to Four substituents: hydrogen, _〇b 8 alkyl, _C (= q) h, < (= 0)-Ci_8 alkyl printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, _C (= 0) -NH2, -CpOyNH-Cw alkyl,-(: (= 0 ^ ((^. 8 alkyl (R9)) 2, -C〇2h, -C〇2_Ci 4 垸 20 group, -S〇2_Cl · 8 alkyl group, _ S〇2-NH2-, .SCVNH-Cu alkyl and -SCVNfu alkyl) 2, and 'when attached to a carbon atom' are independently selected from one to four substituents of the following group: wind -Ci- 8 phenyl group, -Ci.8 alkoxy group, -C (= 〇) H, _C (= 0) -Cw fluorenyl group, -Cbu 0) _nh2, -C (= 0) _NH_Ci 8 alkyl group, -137 This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200536844 A8 B8 C8 D8 VI.Applicable patent scope -CpCO-l ^ Cw alkyl) 2, -C02H, -CCVCw alkyl, alkyl, -S〇2-NH2, -SCVNH-Cw alkyl, -SOpNXCw alkyl) 2, -NH2, -NH-Cu alkyl, -Nfu alkyl), cyano, halo, meridian, succinyl, and keto 5; R2 is selected from the following group: hydrogen, -Cw alkyl (R7 ), -C2_8 alkenyl (R7), -C2.8 alkynyl (R7) '-cycloalkyl (R8),-heterocyclyl (R8),-aryl (R8) and-heteroaryl (R8) And q is 0, 1, 2 or 3; 10 Z is selected from the group consisting of: hydroxy, _NH2, -NH-Cw alkyl, Ν ((^ · 8 alkyl) 2, O-Cw alkyl- 〇H, -O-Ci.8 alkyl Cw oxy, -0-Ci.8 alkynyl Ci.8 carbyl, -0-Ci_8 carbyl-C02H, -O-Cw alkyl-CCCOO- Cw alkyl, -OCw alkyl-0-C (〇) Ci-8 alkyl, -0-Ci.8 alkyl-NH2, 15 alkyl-NH-Ci_8 alkyl, -0-Ci.8 alkyl -N (Ci.8alkyl) 2, -O-Ci.8 alkylamidoamine, -O-Cw alkyl-CCOyNH-Cu alkyl, -OCw alkyl-C ^ CO-NKCw alkyl) 2 and Consumption cooperation between employees of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed -NHCCCOCw alkyl, -O-Cw alkyl; and their pharmaceutically acceptable salts, racemic mixtures Structuring 20 things. 2. The compound according to item 1 of the scope of patent application, wherein W is selected from the following group: -CG_3 alkyl (R0 and -C0-3 alkyl-aryl (R15R8). 3. If the scope of patent application The compound of item 1, wherein W is <: 0_3xyl (heart) or -CQ.3 alkyl-phenyl (Rl5R8). -138 This paper size applies the Chinese National Standard (CNS) A4 specification (21 〇χ 297 public love) 200536844

', Application% patent scope 4. The compound according to item 1 of the patent application scope, wherein Ri is selected from the group: -N (R4) (R6), -heterocyclyl (R8), and -heteroarylation 8). 5. The compound according to item 1 of the scope of patent application, wherein & is selected from the following group: -N (R4) (R6), -dihydro-pyrolo [2,3-Z?] 5 (Rs), _tetrahydropyrimidinyl (R8), -tetrahydro-1,8-naphthyridinyl (R8), -tetrahydro R8) and -rimidinyl (R8). 6. The compound according to item 1 of the scope of patent application, wherein R1 is selected from the following groups ... N (R4) (R6), -tetrahydronaphthyl (R8) and -tetrahydronaphthyl (R0) 10 7. The compound according to item 1 of the scope of patent application, wherein Rla is selected from the group: -C (R4) (= N-R4), -C (= N-R4) -N (R4) 2 , -C (= N-R4)-N (R4) (R6), -C (= N-R4) -N (R4) -C (= 0)-. R4 ^ -C (= N-R4 > N (R ± C (= 〇) -N (R4) 2, -C〇 = N-R4) -N (R4> C〇2-R4, -C (di-N-alkyl (r7) and _c (= n-r4) -n (r4) -s〇2- 15 N (R4) 2. 8. The compound according to item 1 of the scope of patent application, wherein R4 is selected from the group consisting of hydrogen and -Cw alkyl ( R7). Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 9. If the compound in the scope of patent application is item 1, where r4 is hydrogen. 10. As the compound in the scope of patent application item, where R5 is selected from the following 20 Group: -C (= 〇) -R4, -C (= 〇) -N (R4) 2, -C (= 〇) -cycloalkyl (¾), -C (= 〇) _heterocyclyl ( R8), < (= 〇) -aryl (R8), -c (= 0) -heteroaryl (r8), -C (= 〇) -N (R4) -cycloalkyl (r8),- C (= 〇) -N (R4) -aryl (r8), -C02-R4, -c02-cycloalkyl (r8), -C02-aryl (R8), -C (R4) ( = N-R4), -C (= N-R4) -N (R4) 2, -C (= N-R4)--139 This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) ) .200536844 A8 B8 C8 D8 Six, the scope of patent application N (R4) (R6), -C (= N-R4) -N (R4) -C (= 0) -R4, -C (= N-R4) ^ n (r4): c (= o) -n (r4) 2, -c (= n-r4) -n (r4) -co2-r4, -c〇 = n- R4) -N (R4)- S02-C1_4 ^ ^ (R7) ^ -C (-N-R4) -N (R4) -S〇2-N (R4) 2, -N (R4) -C (R4) (= N-R4), -N (R4) -C (= N-R4> 5 n (r4) 2, -N (R4) -C and n-r4) -n (r4) (r6), -n (r4) -c (= n-r4)-n (r4) -c (= 〇) -r4, -n (r4) -c (= n-r4) -n (r4) -c (二〇)-n (r4) 2, _n (r4) -c (= n-r4) -n (r4) -co2_r4, -n (r4) -c (= n-R4) -N (R4) -S02-C1.4 ^^ (Rt) ^- N (R4) -C (= N.R4) .N (R4) -S〇2-N (R4) 2, -SC ^ -Cm alkyl (r7), -s〇2-n (r4) 2, -scv ring 10 alkyl (Rs) and -S02-aryl (R8). 11. The compound according to item 1 in the scope of patent application, wherein R5 is selected from the group: -C (= 0) -R4, -C (= 〇) -N (R4) 2, -C〇2-R4 , -C (R4) (= N-R4), -C (= N-R4> N (R4) 2, -C (= N-R4)-N (R4) (R6), -N (R4)- C (R4) (= N-R4), -N (R4) -C (= N-R4) -15 N (R4) 2, -N (R4) -C (= N-R4) -N (R4) (R6), · SCVCw alkyl (R7) and -S02-N (R4) 2. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 12. If the compound in the first scope of the patent application, R6 is selected from the following Groups:-Heterocyclyl (R8) and-Heteroaryl (R8). 13. For the compound in the scope of patent application item 1, wherein R6 is selected from the following 20 groups:-Dihydroimidazolyl (R8) , -Tetrahydropyridyl (R8), -tetrahydropyrimidinyl (R8), and j-pyridinyl (R8). 14. The compound according to item 1 of the scope of patent application, wherein r7 is independently selected from the following group One to two substituents: hydrogen, -Cw alkoxy (R9), -NH2-, -NH-Cw alkyl (R9), -Nfw alkyl (R9)) 2, -140 This paper is applicable to China Standard (CNS) A4 specification (210 X 297 mm) 200536844 A8 B8 C8 D8 VI. Patent application scope -C〇〇H, -CpOyCw alkyl (R9 ), -C (= 〇) -NH2, alkyl (R9), 4 (= 0) ^ ((^ 4 alkyl (R9)) 2, _C (= 〇) -NH-aryl (R10),- C (K)) _ cycloalkyl (R10), -c (= 〇) -heterocyclyl (R10), -C (= 〇) -aryl (R1〇), -c (= 〇) -heteroaryl Group 5 (R10), -C02H, alkyl (R9), -C02-aryl (R10), -COH) -NH2, -SH, -S-Ci.4 alkyl (R9), -S-Cm alkyl-s-Cw alkyl (R9), -S-Cw alkyl-Cm alkoxy (R9), -S-Cm alkyl-NH-Cm alkyl (R9), -S. 2_Cl 4 alkyl (R9), _s〇2 · NH2, -SOrNH-CM alkyl (r9), -SCVNO ^ M alkyl10 (R9)) 2, -S〇2 · aryl (Rio), cyano, (Halo) 1-3, hydroxy, nitro, keto, -cycloalkyl (R1G), -heterocyclyl (Rig), -aryl (R- and -heteroside (R10). 15. For example, the compound in the scope of application for item i, wherein ^ is independently selected from one to two substituents of the following group: hydrogen 'alkoxy 15 (R9), _NH2-, -NH-Cm alkyl (R9) _N (Cl 4 alkyl (R9)) 2, (halo) 1-3, hydroxyl and keto. 16. The compound according to item 1 of the scope of application, wherein R7 is hydrogen. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 17. For example, the compound of scope 1 of the declared patent, in which Rs, when attached to a gas atom, is independently selected from one to four of the following groups ... 2 Hydrogen'_Cl · 4 alkyl (R9), _C (= 〇) H,-(: (= 0) / ^ alkyl (R9), -c (= 〇) -nh2, < (= 〇) _ΝΗ · ι4 alkyl (R9), < (= 〇νΝ (ί: ι · 4 alkyl (R9)) 2, -C (= 〇) -NH-aryl (RlG), -cpo) · cycloalkyl ( R1〇), -c (= 〇) -heterocyclyl (R10), -c (= 〇) -aryl (Ri0), -C (-〇) -heteroaryl (Ri〇), -C. 2H, Alkyl (R9), -141 This paper size is applicable _ Home Standard (CNS) X7 ^ (2lG x 297 Public Love ---- 200536844

、 Applicable patent scope-C02-aryl (Ri〇), _C (= NH > NH2, _s〇2_c ^ alkyl (R0, s〇2 NH2-, -SCVNH-Cw alkyl (D, -S. 2-N (Ci 4 alkyl (R9)) 2, -SCV aryl (R1 ❹), -cycloalkyl (Rio), and -aryl (R10); In addition, when connected to a carbon atom, it is independent Is selected from one of the following groups from 5 to four substituents: hydrogen, alkynyl (r9), -C " oxo (R9), o-cycloalkyl (Rio), -o-aryl (R1 〇), -C (= 〇) H, -C (= 0) _Cm alkyl (R9), -C (= 〇) -NH2, -C (= 〇) -NH-Ck4 alkyl (R9), alkane -Ru) 2, _C (= 〇) _NH_aryl (Rig), _C (= 〇 > cycloalkyl (RlQ), -c (== 〇) _heterocyclyl (Ri〇), 10- c (一〇) -aryl (Ri〇), -C (= 〇) -heteroaryl (Ri〇), -CO2H, COz-Ch alkyl (r9), -C〇2-aryl (R- _C (= NH) _NH2, alkyl (R0, _s〇2_NH2, alkyl (R9) -S〇2_N (Ci-4 alkyl (R9)) 2, -so2_aryl (R1〇), -SH- -S-CM alkyl (R0, _S-Ci 4 alkyl_S_CM alkyl 15 Ci-4 alkyl-Ch alkoxy group 9), 3- (: ι · 4 alkyl-NH-Cw Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Alkane Economy (R9) ', _NH2, _ΝΗ < 1 · 4 Basic Lecture 9), small ((: " alkyl (119)) 2, cyano, halo, hydroxy, nitro, gangyl, cycloalkyl (R1G), _heterosyl (Chi (1 () ), -Aryl (Rig), and -heteroaryl (R10). 18. The compound according to item 丨 of the patent application, wherein when R8 is connected to the nitrogen 20 atom, it is independently selected from one of the following groups to Four substituents: hydrogen, -CM, radical (r9) ... C (= 〇) H, _c (= 〇) -NH2, _c (= 〇) _NH-Cm alkyl (R9) '_ c (= 〇) _N (Cw alkyl (R9) h, _c〇2H, -ccvc] · 4 alkyl (M and _s〇2_NH2_); and when attached to a carbon atom, it is independently selected from one to four of the following groups Substituents · hydrogen, -142

.200536844 A8 B8 C8 D8 VI. Patent application scope -Cw alkyl (r9), -Cl_4 alkoxy (R9), -0-aryl (R1 ()), -CH ^ H, -C (= 〇) -NH2, -CpOyNH-CM alkyl (R9), -CpOyNCw alkyl (R9)) 2, -C〇2H, -CCVCm alkyl (R9), _S02-NH2, -NH2, -NH-Cm alkyl ( R9), fluorene ((^ -4 alkyl5 group d)) 2, cyano, halo, hydroxyl, nitro, and keto. 19. The compound according to item 1 of the scope of patent application, wherein when R8 is attached to a nitrogen atom, it is independently selected from one to four substituents of hydrogen or -Ch alkyl (R9); and when attached to a carbon atom Is independently selected from the group consisting of hydrogen, < 1.4 alkyl group (R9), -Ci_4 alkyloxy group (R9), _〇 * · aryl group (Rio), 10-nh2, -NH-Cm alkyl group (R9 ), -NΘμ alkyl (R9)) 2, halo, hydroxy and keto one to four substituents. 20. The compound according to item 1 of the scope of patent application, wherein when R8 is attached to a nitrogen atom, it is independently selected from one to four substituents of hydrogen or -Cw alkyl (R9), and when attached to a carbon atom Is independently selected from one to four substituents of hydrogen'15 alkyl (¾), -Cw alkoxy (R9), -0-aryl (RiQ), and hydroxyl. 21 · The compound in item 1 of Shen Qing's patent scope, which is selected from the group printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs: hydrogen, -Cw alkoxy, -NH2, -NH-Ch alkyl, • ^ (Cm alkyl) 2, _C (= 0) H, _C (= 〇) _NH2, heptamidine hydrazone 20 alkyl, alkyl) 2, -C〇2h, _C (VCi_4 alkyl, -SOrC & quot Yuan group, -S02-NH2, -SOrNH-CM system, -S02-N (Cl · 4 alkyl) 2, cyano, (halo) 1-3, hydroxyl, nitro and keto. 22 · If the compound in the scope of the application for the item}, where r9 is selected from the following -143 This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm), 200536844 A8 B8 C8 D8 Patent scope 5 10 15 Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs in 20 groups · Wind, -Ci · 4-Hydroxy, -NH2, -NH-Cl4, -N (Α_4 alkyl) 2, -C (= 〇) H , -C〇2H, C (= 〇) -CM alkoxy, (_yl) 1-3, mesityl and fluorenyl. 23. The compound according to item i in the scope of patent application, wherein r9 is selected from the following group : Hydrogen, -Cl_4 alkoxy, -NH2, -NH-Ch alkyl, alkyl), (halo) 1-3 and hydroxyl. 24. The compound according to item i in the scope of patent application, wherein when Ri () is attached to a nitrogen atom, it is independently selected from one to four substituents of the following group: wind, -Ci_4 alkyl, -C (= 0) H, -0 (= 0)-(^. 4), -C (= 〇) -NH2,-(: (= 0) -Ν-(^ 4 alkyl, -C (= 〇)- N (Ci_4 alkyl) 2, -C02H, -CC ^ -Cm alkyl, -SCVCw alkyl, -S02-NH2-, -SCVNH-Cm alkyl, and -SOrNCCM alkyl) 2; and, When attached to a broken atom, it is independently selected from one to four substituents of the group: hydrogen, -Cl-4 alkyl, -〇1-4alkoxy, -C (= 0) H,- CtCO-CM alkyl, -C (= 〇) -NH2, -C (= 〇) -NH-Cm alkyl, -alkyl) 2, -C〇2H, -C〇2_Cm alkyl, -SCVCw alkyl , -S〇2-NH2, -SOi-NH-Ch alkyl, -SCVl ^ Cw alkyl), -NH2, -NH-Cw alkyl, -NXC ^ 4 alkyl), cyano, halo , Jingji, Shishaoji and keto. 25. The compound according to item i in the scope of patent application, wherein (Ri〇) i 4 when attached to a carbon atom is selected from the group consisting of hydrogen, -Cw alkyl, -Cw alkoxy, -C ( = 〇) H, alkyl, -C02H, -C〇2-Cm alkyl, · NH2, -NH-Cm alkyl, -N (C! _4 alkyl), cyano, hydroxyl, nitro, and ketone base. 144 200536844 A8 B8 C8 D8, declared patent scope 26. For example, the compound in the scope of the patent application, which is hydrogen. 27. The compound according to item 1 of the scope of patent application, wherein R2 is selected from the group consisting of: hydrogen, -Ch alkyl (R7), -C2_4 alkenyl (R7), _c2 # 4 alkynyl (D, · ring Alkyl (R8), -heterocyclyl (R8), -aryl (R8), and -heteroaryl (anil 8) 〇28. The compound as claimed in item 1 of the patent application, wherein R2 is selected from the following group Group: hydrogen, -cycloalkyl (R8), -heterocyclic (R8), -aryl (r8), and -miscellaneous (trans 8). 10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 29 · The compound according to item 1 of the scope of patent application, wherein R2 is selected from the following groups: · hydrogen, -cycloalkyl (R8), -heterocyclyl (R8), · phenyl (R8), -fluorenyl (Footer 8) and -heteroaryl (r8) ... 30. The compound according to item 1 of the scope of patent application, wherein R2 is selected from the group consisting of: hydrogen, -tetrahydropyrimidinyl (r8), -U- Benzodifluorene cyclopentenyl (R8), -dihydrobenzofuranyl (r8), -tetrahydroquinolinyl (r8), -phenyl (¾), -naphthyl (R8), pyridyl (R8), -pyrimidinyl (R8), and -quinolinyl (D. 31. As the compound in the scope of patent application, item 1, wherein q is 0, 1, 2, or 3. 32. In the scope of patent application, item 1 Transform Compounds, wherein Z is selected from the group consisting of: hydroxyl, -NH2, -NH-Cw alkyl, -IsKCu alkyl) 2, -O-Cw alkyl Cw alkoxy, -O-Cw alkylcarbonyl Cw Alkyl, -O-Cw alkyl-C02H, -O-Cw alkyl-CODP-Cw alkyl, -O-Cw alkyl-NH2, -O-Cw alkyl-NH-Cw alkyl,- O-Cw alkyl-N (CK8 alkyl) 2, -O-Cw alkylamidoamine and -O-Cw -145 This paper size applies to China National Standard (CNS) A4 (210x297 public love) ^ 200536844 33. One; ir is a composition of a compound of formula (I) W y nJ 0 formula ⑴ wherein the compound is selected from the group

A8 B8 C8 D8_ 6. Scope of patent application Burning base. 0 5 JNJ W Ri R2_Q z -ΝΗ · 1,4,5,6- Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs-CH2-Ph (3-R1) Tetrahydro-pyrimidin-2-ylΗ 0 0Η -NH -1,4,5,6- -C ^ -PhCB-RO tetrahydro-pyrimidin-2-ylΗ 0 0Η -NH-1,4,5,6-tetrahydro-5-0H- 0Η -CHrPhG-Ri ) Pyrimidin-2-ylquinolin-3-yl 0 -5,6,7,8-tetrahydro--(CH2) 3-R! [1,8] naphthyridin-2-ylquinolin-3-yl 0 ΟΗ -5,6,7,8-tetrahydro-1,2,3,4-tetrahydro--(CH2) 3-Ri [1,8] naphthyridin-2-ylquinolin-3-yl 0 0Η -5,6,7,8 -tetrakis-1,2,3,4-tetrahydro--(CH2) 3-Ri [1,8] naphthyridin-2-ylsaucon-3-yl 0 0Η -5,6,7,8-tetraaza-1,2,3,4-tetrahydro ·-(CH2) 3-Ri [1,8] naphthyridin-2-ylquinolin-3-yl 0 0Η- 5,6,7,8-tetra argon-1,2,3,4-tetragas- (CH2) 3-Ri [1,8] naphthyridin-2-ylquinolin-3-yl 0 0Η -5 , 6,7,8-tetrahydro-1,2,3,4-tetrahydro- (CH2) 3-Ri [1,8] naphthyridin-2-ylkhalin-3 · group 0 0Η -146 Paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 200536844 A8 B8 C8 D8 6. Application scope of patents-NH-1,4,5,6-Rh (3-R!) Tetra-Arg-Pyrimidine-2 -Yl-NH-1,4,5,6-tetrahydro- 5-OH-pyrimidine-σ specific bit-3 -yl 2 OH Ph (3-R〇2-yl ° specific bit _-3 -yl 2 OH -5,6,7,8-tetrahydro ·-(CH2 ) 2-Ri [1,8] naphthyridin-2-yl ° ratio-based 2 OH-(CH2) 3-Ri -NH-pyridin-2-ylσ ratio-3 * based 2 OH -NH-1,4 , 5,6-tetrahydro-5-OH- (6-OCH3) -pyridine-3- Ph (3-R〇 pyrimidin-2-yl 2 OH 5,6,7,8-tetrahydro- [1, 8] 1,3-Benzodibicyclocyclopenta- (CH2) 2-Rl Benzene-2-ylen-5-yl 1 OH -NH-1,4,5,6- Php-RD Four Winds-Shout Bite-2 -yl 5,6,7,8-tetrahydro- [1,8] quinolin-3-yl 2 OH-(CH2) 2-Ri Naphthyridin-2-ylbenzyl 1 OH Ministry of Economic Affairs Intellectual Property Printed by the Consumer Cooperative of the Bureau of the People's Republic of China, 5,6,7, S-tetrahydro- [1,8] 1,3-benzodioxin-cyclopentane- (CH2) 2-Rl 5.6.7.8- tetrahydro- [1,8] 1,3-benzodicyclopenta- (CH2) 3-Ri naphthyridin-2-ylen-5-yl 5.6.7.8- tetrahydro- [1, 8] 1,3 · Benzodicyclopentyl-CH2-R! Naphthyridin-2-ylen-5-yl, 5,6,7,8-tetraargon- [1,8] (6-0 « 13) -pyridine-3--(CH2) 3-Ri naphthyridin-2-yl 5.6.7.8- tetrahydro- [1,8] 1,4,5,6-tetrahydro-2--(CH2) 2-Ri Naphthyridin-2-yl Me · pyrimidin-5-yl 5.6.7.8- tetrahydro- [1,8] l, 2,3,4-tetrahydro--(CH2 ) 2-R1 Naphthyridin-2-ylquinolin-3-yl 5.6.7.8- tetrahydro- [1,8] 1,2,3,4-tetrahydro--(CH2) 2-R1 naphthyridin-2 -Ylquinolin-3-yl 5.6.7.8- tetrahydro- [1,8] 1,2,3,4-tetrahydro--(CH2) 2-R! Naphthyridin-2-ylquinoline-3- 5.6.7.8- tetrahydro- [1,8] 1,2,3,4-tetrahydro--(CH2) 2-R naphthyridin-2-ylquinolin-3-yl 0H 0H 0H 0H 0H 0H 0H 0H 0H -147 This paper size is applicable to China National Standard (CNS) A4 (210x297 mm). 200536844 A8 B8 C8 D8 t. Patent application scope. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5,6,7,8- Tetra argon- [1,8] 1,2,3,4-tetrahydro-naphthyridin-2-ylquinolin-3-yl 1 OH 5,6,7,8-tetrahydro- [1,8] 1 , 3-Benzodibenzocyclopenta- (CH2) 2-Ri tea bite-2-ylen-5-yl 2 OH 5,6,7,8-tetraargon- [1,8] (6-0 ( : 113) -pyridine-3--(CH2) d octyl-2-yl 2 OH -NH-1,4,5,6-tetrahydro-5-OH- (6-OCH3) -pyridine-3- -(CH2) 2-Ri 啦 Bit-2 * • radical 2 OH -NH-1,4,5,6-tetrahydro-5-OH- (6-OCH3) -ringbite-3--(CH2) 2-Ri pyrimidine-2 · yl 2 OH-(CH2) 3-Ri -NH-pyridin-2-ylquinolin-3-yl 2 OH 1,3-benzodihumapto- (CH2) 3- Ri -NH-pyridine-2 -Yl di-5 -yl 2 OH 1,3-benzodihumcyclopentyl- (CH2) 3-R! Amidin-2-ylen-5-yl 0 OH (6-OCH3) -pyridine-3- -(CH2) 3-Ri-NH-pyridin-2-yl 2 OH-5,6,7,8-tetra-argon- [1,8] 1,3-benzodiincyclopentane- (CH2) 3_Ri tea bite 2-yl di-5-yl 1 OH -NH-1,4,5,6-tetrahydro-5-OH-1,3-benzodibicyclocyclopentaph (3-R〇 pyrimidine- 2-ylen-5-yl 1 OH 5,6,7,8-tetrahydro- [1,8] (6-0 (: 113) -pyridine-3--(CH2) 2-Ri% 'bit- 2-yl 1 OH 5,6,7,8-tetrahydro- [1,8] (6-OCH3) -pyridine-3--(CH2) 2-Rnaphthyridin-2-yl 1 OH 5, 6,7,8-tetrahydro- [1,8] (6-OCH3) -pyridine · 3--(CH2) 2-Rnaphthyridin-2 · yl 1 OH 5,6,7,8-tetrahydro -[1,8]-(CH2) 3-Ri Naphthyridin-2-ylquinolin-3-yl 1 OH 5,6,7,8-Tetraargon- [1,8]-(CH2) 2-R1 Qin bite-2-yl (3-F) phenyl 1 OH -148 This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) -200536844 A8 B8 C8 D8 Patent Application Range 5.6.7.8- 4 Hydrogen- [1,8] naphthyridin-2-yl (3-F) benzyl 丨〇H 5.6.7.8- tetrahydro- [1,8] naphthyridin-2-yl (3-F) phenyl] H 5.6.7.8- tetrahydro- [1,8] naphthalene 2-yl (3-F) phenyl 1 0H 5.6.7.8- tetrahydro- [1,8] naphthyridin-2-ylquinolin-3-yl 1 0H 5.6.7.8- tetrahydro- [1 , 8] Naphthyridin-2-yl (4-F) phenyl 1 0H 5.6.7.8- Tetrahydro- [1,8] Naphthyridin-2-yl (4-F) benzyl 1 0H 5.6.7.8 -Tetrahydro- [1,8] (2-(: 113) pyrimidin-5-ylpyridin-2-yl1 0H 5.6.7.8- Tetrahydro- [1,8] 2,3-dihydro-% Bite-2-Basic. Carrot beetle 6-yl-1 OH 5.6.7.8- tetrazol- [1,8] 2,3-diazine_ Bistetra-2-ylbenzopyridyl 1 OH 5,6,7,8 · Tetrahydro- [1,8] 2,3-dihydro-naphthyridin-2-ylbenzofuran-6 · yl 1 OH 5.6.7.8- tetrahydro- [1,8] naphthyridin-2-yl (3,5- Difluoro) -phenyl 1 〇H 5.6.7.8- tetrahydro- [1,8] cinnazyl-2-yl (3,5-difluoro) -phenyl 1 〇H 5.6.7.8- tetrahydro- [1 , 8] Naphthyridin-2-yl (3-CF3) -phenyl 1 OH Printed by Consumer Property Cooperative, Member of Intellectual Property Bureau, Ministry of Economic Affairs- (CH2) d-(C ¥ L2) 2-R {-(CH2) 3- R1-(CH2) 2-Ri-(CH2) 2-Ri-(CH2) 3, Ri-(CH2) 2-Ri-(CH2) 2-Ri-(CH2) 2-Ri-(CH2) 2-Ri -(CH2) 2, Ri-(CH2) 3-Ri-(CH2) 2-Ri-(CH2) 2-Ri-(CH2) 2-Ri-(CH2) 2-R1 5.6.7.8- tetrahydro- [ 1,8] Naphthyridin-2-yl (4-OCF3) -phenyl 1 OH 5.6.7.8- Tetrahydro- [1,8] Naphthyridin-2-yl (3-F-4-Ph) -benzyl 1 OH 5.6.7.8- tetrahydro- [1,8] (34-4-0 (: 113) -naphthyridin-2-ylbenzyl 1 OH 5.6.7.8- tetrahydro- [1,8] tea bite- 2-based (4-Oph) -phenyl 1 OH -149 This paper size applies to China National Standard (CNS) A4 (210x297 public love) 200536844 A8 B8 C8 D8 Patent application scope -CCHA-Ri-(CH2) 2_Ri- (CHdd Printed by the Consumers' Cooperative of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the People's Republic of China 5.6.7.8-tetrahydro- [1,8] Qin Biao-2-jiyisha ^ f-4-based1 〇H 5.6.7.8- tetrahydro- [1,8 ] Naphthyridin-2-ylpyridin-3-yl 1 0H 5.6.7.8- tetraargon- [1,8] diargonbenzofuran-5-naphthyridin-2-yl 1 〇H 5.6.7.8- tetra Hydrogen, [1,8] (2,4-〇0113) -naphthyl-2-ylpyridin-5-yl1 0H 5.6.7.8-tetrahydro- [1,8] (2-0 (: 113 ) -Naphthyridin-2-ylpyrimidin-5-yl 1 0H -NH-1,4,5,6-tetrahydro-5-0H- Ph (3-R〇0 1,4,5,6- Harlem-3-yl 2 OH Ph (3-R〇 quaternary- ° specific bite _-2 -yl 5,6,7,8-tetrahydro- [1,8] Lynn-3 -yl 2 OH-(CH2) 2-Ri Qinyi-2-yl-NH-3,4,5,6-quinolin-3-yl 1,3-benzodioxin cyclopentane 2 OH Ph (3-R〇 tetrakis-lazin-2-yl-NH-3,4,5,6-en-5-yl 1,3-benzodioxin cyclopentane 2 OH Ph (3-R〇 tetrahydro -° Specific bite-2-yl-NH-1,4,5,6-tetraargon-5-OH- dilute 5-yl 1,3benzobenzoate cyclopentyl 2 OH Ph (3-R〇 nozzle Tetra-2-yl 5,6,7,8-tetraargon- [1,8] en-5-yl 1,3-benzodihumapto 2 OH -CHs-Ri tetra-2-yl 5, 6,7,8-tetra argon- [1,8] dilute -5 -yl 2 OH-(CH2) 2 * -Rl sacral-2-yl 5,6,7,8-tetra -[1,8] naphthyl-2-yl1 OH-(CH2) 2-Ri naphthyridin-2-yl 5,6,7,8-tetrahydro- [1,8] naphthyl-2-yl1 OH- (CH2) 2-Ri stripe-2-yl preparation-2-yl 5,6,7,8-tetraargon- [1,8] 5,6,7,8-tetrahydro-1 OH-(CH2 ) 2-Ri Naphthyridin-2-ylquinolin-3-yl 1 OH 150 This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 200536844 Α8 Β8 C8 D8 Patent Application Scope Intellectual Property of the Ministry of Economic Affairs Bureau's Consumer Cooperatives printed 5.6.7.8- Tetrahydro- [1,8] 5,6,7,8-Tetrahydro--(CH2) 3-Ri Naphthalene-2-ylhaline-3-yl 5.6. 7.8- tetrahydro- [1,8] 5,6,7,8-tetrahydro--(CH2) 3-Ri naphthyridin-2-ylquinolin-3-yl 5.6.7.8- tetrahydro- [1, 8]-(CH2) 2-Ri Naphthyridin-2-yl (3-OCH3) phenyl 5.6.7.8- tetraargon- [1,8]-(CH2) 2.R1 Naphthyridin-2-yl (4- OCH3) Benzoyl 5.6.7.8- tetraargon- [1,8]-(CH2) 2-Ri Naphthyridin-2-yl is absent 5.6.7.8- tetrahydro- [1,8] tea bit-2-yltetrayl Hydrogen bite-3-yl5.6.7.8-tetrahydro- [1,8] naphthyridin-2-ylthiophen-2-yl5.6.7.8-tetrahydro- [1,8] naphthyridin-2-yl (3 -F) phenyl 2,3-dihydro- 5.6.7.8-tetrahydro- [1,8] benz [1,4]--(CH2) 2_Ri I stilbyl-2-yl diimine-6-yl 5.6.7.8- tetrahydro- [1,8]-(CH dyRi Naphthyridin-2-yl (3-SCH3) benzyl 5.6.7.8- tetrahydro- [1,8] #-methyl-1,2,3,4-tetra- (CH2) 2-Rl naphthalene bite- 2-Hydroxy-Lynyl-3-yl, 5,6,7,8-Tetrahydro- [1,8]-(CR2) 2- ^ i Naphthyridin-2-yl does not exist 5.6.7.8- Tetrahydro · Π, 8]-(CH2) 2-R1 Naphthyridin-2-yl does not exist 5.6.7.8- Tetrahydro- [1,8]-(CH2) 2-R! Naphthyridin-2-yl does not exist 5.6. 7.8- Tetra argon- [1,8]-(CU2) 2-Kl Naphthyridin-2-yl does not exist 5,6,7,8 · Tetra argon- [1,8]-(CH2) 2-R1 Naphthyridine -2-yl is absent 5.6.7.8- tetraargon- [1,8]-(CH2) 2-R1 naphthyridin-2-yl is absent 0 0H 0 0H 0H 0H 0H 0H 0H nh2 OH OH OH -0 -B -0-2-propyl-0-third butyl-0- n-octyl · 0-% dibutyl-0-methyl-151 This paper size applies to China National Standard (CNS) A4 (210x297) (Centi) 200536844 Α8 Β8 C8 D8 6. Scope of patent application-5,6,7,8-tetrahydro- [1,8] oc (o)-tert-butyl- (CH2) 2_R 1 naphthyridin-2-yl group Presence of 1- (CH; 2) 2-Rl 5,6,7,8-¾ naphthyridin-2-yl hydrogen- [1,8] (3- (Nme2) phenyl 1 OH-(CH2) 2- Ri 5,6,7,8-tetra-4-tetra-2-ylhydro-U, 8] (3-OMe-4-OH) phenyl 1 OH-(CH2) 2-Ri 5,6,7,8- ¾ Naphthyridin-2-yl hydrogen- , 8] (3-〇Me-4-OH) phenyl 1 OH Ph (3 ~ R1) -NH-4,5-dihydroimidazol-2-yl (3-F) phenyl 1 OH-(CH2) d 5,6,7,8-1¾ tea bit-2-yl (4- (2-OH-ethoxyhydro- [1,8] yl) -3-〇Me) -phenyl 1 OH-(CH2) 2-Rl 5,6,7,8-tetramethyl-2-yl hydrogen-Π, 8] (3-NHEt) benzyl 1 OH _ (CH2) 2-Ri 5,6,7,8-tetraqin Bite-2-ylhydrofluorene, S] (3-NHMe) phenyl 1 OH species composition, which includes the compound 5 as claimed in the scope of patent application 5 printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 10 of which The compound is selected from the group: w vcH2_Ph (3_Ri) in formula (I); Ri ^ NH_M, 5,6_tetrahydro · mouth bite-2-yl; R2 is Η; q is 0 and z is 0H Compounds; in formula (I), w is _ (CH2) 2_Ph (3_Ri); & is from tetrahydrogen. Mouthbital-2-yl, R2 is H; q is 0 and 2 is 011; In formula (I), w iCH2_Ph (3_Rl); Ri is a compound of 5,6 • tetraki_5_OH-bite-2-yl; R2 is 3-halyl; q is 0 and z is 0H ; In formula w, w is _ (CH2) 3_Rl; Rl is · 5,6,7,8_tetraki · ι; 8_Caiwei-2 · group; R2 is 3-pyridine group; q is 0 and ζ Compound of 〇化合物; -152 Applicable in paper size National Standard (CNS) A4 Specification (210 X 297) --- 200536844 A8 B8 C8 D8 々, in the scope of the patent application (W) in the formula (I) is Xing Ke Shi also; & is 5,6,7,8- Tetrahydro-1 >naphthyridin-2-yl; R2 is 1,253,4-tetrahydro-3-quinolinyl; compounds in which q is 0 and z is 0H; in formula (I), W is -Ph ( 3-Rl); R1 is -NH-l, 4,5,6-tetrahydro-pyrimidin-2-5; R2 is 3-amidino; q is 2 and Z is 0H; compound of formula (I ) In W is -Ph (3-Ri); Ri is -NH-1,4,5,6-tetrahydro-5-0H-pyrimidin-2-yl; R2 is 3-pyridyl; q is 2 and Z A compound of 0H; in the formula (I), W is-(CHA-Ri; 1 ^ is -556,7,8-tetraargon · 1,8-naphthyridin-2-10 group; I is 3-amidino group Q is a compound of 2 and Z is 0Η; W in the formula (I) is-(CHA-Ri; NH is a pyridin-2-yl group; R2 is a 3-pyridyl group; q is 2 and Z is OH Compounds of the formula (W) is -PhQ-Ri) in the formula (I); the heart is 11-1,455,6-tetrahydro-5-〇quinimidin-2-yl; R2 is-(6 »^ 0) pyridine Compounds; q is 2 and Z is OH 15; printed in formula (I) by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, W is-(CH2) 2 ·! ^; R1 is -5,657,8-tetrahydro-l , 8-naphthyridin-2-yl; R2 is 1,3 · benzodifluorene A pentene group; a compound in which q is l and z is 0H; in the formula (I), W is -PhQ-Ri); R] is -NH-l54,5,6-tetramethylpyridin-2-20 group R2 is 3-quinolinyl; q is 2 and Z is OH; W in formula (I) is-; 1 ^ is -5,65758 · tetrahydro-1,8-naphthyridin-2-yl, A compound in which R2 is * -Ph, q is 1 and Z is 0H; in formula (I) W is-(CH2) 2-Ri; R1 is _5,6,7,8-tetraH8-naphthalene bit-2 -Group; R2 is 1,3-benzodifluorenylcyclopentene-5_ group; q is o and z is -153 This paper size applies to China National Standard (CNS) A4 (210x297 public love) 200536844 A8 B8 C8 D8 VI. Compounds with a patent scope of 0H; Formula (1) + W is-(CHA-R !; Ri is -5,6,7,8-tetrahydronaphthyridin-2-yl; R2 is 1,3 -Benzodi4-cyclopentene "5-yl; compounds in which q is 0 and z is 0H; 5 in formula (I) W is -CHyRi; Ri is _5,6,758_tetrahydro-1,8_naphthalene Benzene-2-yl; R2 is 1,3-benzodihumcyclopenten-5-yl; compounds in which q is 0 and Z is 0H; W in the formula (I) is (CHA-Ri; Ri is- 5,6,7,8-tetrahydro-I, 8.naphthyl-2-yl; R2 is _ (6-MeO) pyridin-3-yl; 10 compounds with q being 0 and Z being 0H; formula (I ) In W is-(CHA-Ri; Ri is 5,6,7, 8-tetrahydro-l, 8-naphthyridin_2-yl; R2 is -l, 45556-tetrahydro-2-Me-bromo-5-yl, q is l and Z is 0H; I) W is-(CHA-Ri; Ri is -5,6,7,8-tetrahydro-1,8-naphthyridin-2-15; R2 is U, 3,4-tetrahydro-3- Quinolinyl; compounds with q being 1 and Z being 0H; W in the formula (I) printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy; Ri is -5A7,8-tetrahydronaphthyridine; R2 is 1 3, benzobenzoatecyclopenten-5-yl; compounds where q is 2 and Z is OH; 20 in formula (I) W is-(CH2) 2-Ri; Ri is -5,6,7, 8-tetrahydro-1,8-naphthyl-2-yl; R2 is-(6-Me〇) pyridin-3-yl; compound with q being 2 and Z being 0H; W in formula (I) is- (CH2) 3 ·! ^; R! Is -NH ·. Bipyridin-2-yl; R2 is 3-quinolinyl; q is 2 and Z is OH; -154 This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 public love). 200536844

Scope of patent application 5 ο 1X 5 ΊΧ Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 In formula (I), W is-(CH2) 3-Rl; Ri 4_nh_d ratio bit _2_ base; r2 is 1, 3: Benzodicyclocyclopentyl-5-yl group; compounds with q being 2 and z being 0H; W in formula (I) is-((¾) 3%; Ri is cis- "pyridinyl; is 1 , 3-benzobisπ cyclopentene-5-yl; compounds with q being 0 and z being 0h; W in formula (I) is-(0 ^) 3%; Ri is -NH ^ pyridine | R2 is a _ (6-Me0h than _3_ group; a compound of q is 2 and z is 0h; in formula (I) W is-(CHA-Ri; tetrahydro-w naphthyridine 1 group , R2 is a 1,3-benzodihumcyclopenten-5-yl group; a compound in which q is j and z is 0H; W in formula (I) is -PhORd; & , 6-tetrahydro-5-〇111 pyrimidinyl; R2 is 1,3-benzodihumcyclopenten-5-yl; compound in which q is fluorene and z is 0H; W in formula (I) is- (CH2) 2: ^; R1 is _5,6,7,8-tetrahydrol58 · naphthyridin_2-yl; R2 is-(6-Me〇 thiopyridin-3-yl; q is 1 And z is a compound of OH; in the formula (I), W is-(CH2) 3 !! ^; Ri is-^ tetrahydronaphthyridinyl; R2 is 3-quinolinyl; q is 1 and z is 〇H compounds; in the formula (I) W is-(CH2) 2 ·! ^ Ri is a compound of -5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl, R2 is-(jF) Ph, q is 1 and z is 0H; W in formula (I) Is-(CH2) 3-! ^; 1 ^ is -5,6,738-tetrahydro-1,8-naphthyridin-2-yl, R is · (3-F) Ph, q is 1 and Z is 0H Compounds in formula (I): W is-(CH2) 2-Ri; R is -5,6,7,8-tetra-argon-1,8-naphthyridine-2- -155 This paper is applicable to China Standard (CNS) A4 specification (210x297 mm) 200536844 Λδ Βδ C8 D8 VI. Patent application scope, group: R2 is _3 quinolinyl 1 is 1 and Z is 0H; Formula 00 Let W be-(CH ^ R !; R is 5,6,7,8-tetrahydro], naphthyl; H (4-F) Ph, compounds in which q is i and z is 0H; 5, radical; RK4-F) Ph; a compound in which q is 1 and Z is OH; in formula W, W is-(CHH; heart is _5,6,7,8-tetrazine--Cai bite 1 group; R2 is common steal) d group; A compound in which q is 1 and Z is 0H; in the formula (1), W is -caffeine% is -5,6,7,8-tetrahydro-W-naphthalene-2- 1oyl 'is known as · 2, 3_dihydrobenzyl and 11-fluoro-6-yl; compounds where q is 1 and Z is 0H; W t (CHH R is also 5,6,7,8-tetrahydronaphthalene-2-yl in formula ⑴ , R2 is-(3,5-F2) Ph; compound with q being 1 and z being 0H; W g in formula (I) jCHA-Ri; R1 is _5,6,7,8_tetrahydro-1,8-naphthyridine-2_l5, the group 'Rl is-(3,5-F2) Ph; q is 1 and Z is 0H Compounds; W in the formula (I) is-(CHA-Ri ;: ^ is ^ into ^ tetrahydrosense ^ naphthyridine! The compound 'R2 is-(3-CF3) Ph; a compound with q being 1 and z being 0H; W in the formula (1) printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs is-(0's); H5,6 , 7,8-tetrahydro-1,8-naphthyridin-2-yl, R2 is-(4-〇〇? 3)? 11; q is 1 and z is 0H of the compound 20; Formula (I ) In which W is-(CHH; ^ tetrahydro], 8naphthyridin-2-yl; R2 is · (3-F-4-Ph) Ph; q is a compound in which z is 0H; Formula (1) Medium \ ¥ is-(〇: 112) 2-111; 111 is _5,657,8-tetrahydro-1,8_naphthyridine-2- -156 This paper size applies to China National Standard (cns) A4 (210x297) f 200536844 A8 B8 C8 D8 applied for patent 5 ο 1X 5 1 20 bases printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, R 2 is a compound of (3H〇Me) Ph; q is i and z is 0h; W is _ (CH2) 2_Ri; heart is _5,6,7,8_tetrakis ^, ^ Caidian 1-based 'R also (4-〇Ph) Ph; q is i and z is 0H compounds; In the formula (1), ^ is-(〇12) 2; 111 is _5,6,758_tetrahydro_1,8-naphthyridin-2-yl; the heart is -4 · isoquinolinyl; q is 1 and z is a compound of 0h; w 4_ (CH2) 2_Ri in the formula (I); Ri is a · 5,6,7,8 tetrahydro-π-caebit-2-yl group, and R2 is a 3-pyridyl group; q is 1 and ζ are compounds of on; in formula (1), w is _ (CH2) 2_Ri; heart is _5,6 乂 8_tetrahydro · w • Caidin_2_ group, and R2 is -5-dihydrobenzo Furyl; compounds in which q is i and z is 0H; in formula ⑴ W is-(CH2) 2-R1; Ri is _5,6,7,8-tetraargon-1,8-naphthyridin-2- The group 'is -254- (〇Me) 2-, pyridyl- group; a compound in which q is 1 and z is 0H; in the formula ^ is ~ (CH2) 2-ri; Ri is -5,6,7 , 8-tetrahydro-1,8K2_ group 'R2 is-(2_〇Me) apridin_5 group; q is 1 and ζ is OH; W in formula (I) is _ph (3-Ri ); R4_nH-1,4,5,6-tetrahydro-5-0H · pyrimidin-2-yl; & is 3-quinolinyl; q is 2 and z is 0H compound; formula (I) In which W is -Ph (3-Ri); Ri is->^-354,5,6-tetrahydro-sound-2-yl; R2 is 3-quinolinyl; q is 2 and Z is 0H Compounds of formula; in formula (I) W is-(ch2) 2-Ri; Ri is -5,6,7,8-tetrahydro-1,8-naphthalene bite -2 -157

This paper size applies to China National Standard (CNS) A4 specification (210x297 public love) 200536844 Α8 Βδ C8 D8 Six, the scope of the patent application, R2 is -3-Hallenyl, q is 2 and z is 0H compounds; In (I), W is the place (3 also); the heart is regarded as _3,4,5,6_tetrazine_mouth biter base; R2 is -1,3 · benzodi ° cyclopentene_5_ A compound in which q is 2 and Z is 0H; in Formula 3, W is -which is long); Ri is -Li-3,4,5 > tetrahydro "bifuran 2-group, R2 is -1, 3-Benzodifluorenylcyclopenten-5-yl; compounds with q being 2 and z being 0H; W in formula (I) is -PhQ-RD; &Pyridin-2-yl; & is benzodihumcyclopentenyl; compounds where q is 2 and 10 Z is 0H; W in formula (I) is -CH2-R !; &Benzenepyridinyl; & is 1,3-benzodifluorenylcyclopenten-5-yl; q is 2 and z is 0H; and, in formula (I), W is-(0¾ ) 2%; R1 is _5,657,8-tetrahydro_1,8_naphthyridin-2_15 group; R2 is 2-naphthyl group; q is 1 and z is 0H. 35. The compound according to item 34 of the scope of patent application, wherein the compound is selected from the following groups: W in the formula (I) printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs is-(CH2) 3%; R1 is- 5,6,7,8-tetrahydro-l, 8-naphthyridin-2-yl; R2 is -1,2,354-tetrahydrodongolinolyl; compounds in which q is 0 and Z is 0H 20; formula ( I) in which W is-(CHA-Ri; R1 is -5,6,758-tetrahydro-l, 8-naphthyridin-2-yl; R2 is -U-benzodioxincyclopenten-5-yl; q Compounds where 0 and Z are 0H; W in formula (I) is _ (CH2) 2-Ri; 1 ^ is -56556575-tetrahydro-1,8-naphthyridine-2- -158 This paper is applicable to China National Standard (CNS) A4 specification (21 × 297 mm). 200536844 A8 B8 C8 D8 6. The scope of patent application, 2 is -U, 3,4-tetrahydro-3, quinolinyl; q is i and z It is a compound of 0H; 5 5 τ Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 2 W in the formula (I) is-(ch2) 2-Ri; Rl is -5,6,7,8_4 Nitrogen, 8_ 蔡咬 _2_ group '¾ is-(6_Me〇). Specific bite, 3, group; q is 1 and z is OH compound; in formula (I) w is _ (CH2) 2_Rl; 1 ^ Is -5,6,7,8_tetranitro], 8_Ceadidine_2_ group, and R2 is-(3-F) Ph; q Is a compound with 1 and z being 0H; in formula (I), w is < CH2) 2-Rl; the heart is-from tetrazine-to-zelidinyl, R2 is quinolinyl; q is i and z is. Compound of H; in formula (I), W is-(CHA-Ri; Ri is _5,6,7,8tetrahydro-1,8naphthyridin_2-yl, and R2 is-(2-Me) pyrimidine- 5-group; q is] [and z is an OH compound; in the formula, W is _ (CH2) 2-Ri '· R1 is -5,6,7,8_tetrahydro-l, 8-naphthyridine- 2-group; R2 is -253-dihydro-benzofuran-6-yl; compounds where q is 1 and z is 0H; in formula (I) W is-(CH ^ -Ri; R1 is -5, 6,758-tetrahydro-l, 8-naphthyl-2-yl; R2 is 4-isoquinolinyl; compounds in which q is 1 and z is 0H; W in formula (I) is-(CHJd; R1 is -556,7,8-tetrahydrol, 8-naphthyridin-2-yl; R2 is 3-pyridyl; q is 1 and z is 0H; in formula (I) W is-(CH2) 2-Ri; R! Is -5,6,7,8-tetrahydro-1,8-naphthalenyl-2-yl; R2 is -2,4- (〇Me) 2-pyrimidin-5-yl; q is A compound in which 1 and Z are 0H; and, in formula (I), W is-(CH2) 2-Ri; Ri is · 5,6,7,8-tetraargon-1,8-naphthalene-2--2- 159 This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public love) 200536844 A8 B8 C8 D8 Around 51 015 Intellectual Property Office employee Economic Co-op printing group 20, foot is - (2- 〇Me) pyrimidin-5-yl; Q 1 and 7 of the preparation thereof.夂 2 is 36 of OH. The compound according to item 1 of the scope of patent application, in which w trans Rl 'Ri is -5,6,7,8-tetrahydro-1,8. Naphthalene_2_yl; R2 is, (CH2) 3 hydrogen · 3 · quinolinyl; q is 0 and Z is oh. ., ’, 3, 4 4 37. Such as the scope of patent application! Compound of the above item, wherein% R 1 ·-(0112) 3- 'I is -5,6,2-8-tetrahydro-i, 8-naphthyridin-2-yl; R "two discs, LX X * present -1,3 -benzyl-5cyclopenten-5-yl; q is 0 and z is OH. The compound in the scope of application of the patent application, wherein% R, · ^ is also rr ^-(ChL2) 2- 'R1 is -5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; r A wind-3-khalinyl; q is 1 and ζ is η. 39. If applying for a patent Compounds in the range 丨, where * r > Trojan _ (CH2) 2_ 'ri is -5,6,7,8-tetrahydro-1,8-naphthyridine 1yl; R χ pyring, Zeng ~ is K6 -MeO) 疋 · >group; q is 1 and Z is 0H. 40. The compound of the scope of application for patent j, wherein 1 '1 is -5,6,7,8-tetrahydro-1, 8-naphthalene-2-yl; ruler 2 is divided into 17) 1 ^; q is 1 and Z is 0H. 41. The compound according to item 1 of the scope of patent application, wherein w 1 'Ri is -5,6, 7,8-tetrahydro-1,8-naphthalene-2-yl; is _3 · side lye; q is 1 and Z is 〇Η. 42. The compound according to item 1 of the patent application, wherein w is _ (〇112) 2- 2; I is -5,6,7,8, argon-U-naphthalenyl-2-yl; r2 is stealth) and bite -5-yl; q is 1 and ζ is. h. 3. If applied for patent The compound around item 1, which is-(CH2) 2_ .160 This paper size is applicable to Chinese specifications ⑵0x297 Public Love 2005 200536844 A8 B8 C8 D8 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 6. Application scope of patent Inverse 1 is -5,6,7,8-tetrahydro-1,8-naphthalenyl-2-yl; is 2 3-1 benzene succinyl; q is 1 and Z is 0H. 44. Such as The compound in the first scope of the patent application, wherein% · ^-(CH2) 2-1, R1 is -5,6,7,8-tetrahydro-1,8-naphthalene-2-yl; r2 is 4, _Isoamidine 5 groups; q is 1 and z is 0h. 45. For example, the compound of the scope of application for the first item, wherein% is _ (CD 仏 ^ 1 is -5,6,7,8-tetrahydro- 1,8-naphthalenyl-2-yl; Han 2 is _3_Hou 2 diyl; q is 1 and z is 0h. 46 'Compound as in item 1 of Shen Qing's patent scope, where w is _ (ch ) 10 Rl; Ri is -5,6,7,8-tetrahydro-1 > naphthyridine 2-yl; & is _2 ((Me) r pyrimidine 5-yl; q is 1 and Z is 47 'The compound as described in the first item of the patent scope of Shenyin, wherein W * _ (ch2) 2 R1; the center is -5,6,7,8-tetrahydro-1,8 · naphthyridin-2_yl; r2 is _ (2_〇 ·) Jing bit_5_ group; q is 1 and z is 0H. 15 48 · —A compound having the following formula (1):

In the formula, W is selected from the following groups: -Cq_3 alkyl (Rl) and _cG3 alkyl · phenyl (Ri >R8); -161 This paper is applicable to t® i ^^ (CNS) A4 ^ ( 210 X 297) ~~ 一 '— 200536844 A8 B8 C8 D8 々, patent application scope Ri g-NH (R6); R2 is selected from the following groups: wind, -four winds Difluorenylcyclopentenyl (R8), -dihydrobenzofuranyl (R8), -tetrahydroquinolinyl (R8), -phenyl (R8), -naphthyl (R8), -carbamyl (R8), -pyrimidinyl (R8), and -quinolinyl (R8); R6 is selected from the group consisting of: -diargylimazolyl (¾), -tetrahydropyridyl (R8), -four wind, Rg and Rs. When R8 is attached to a nitrogen atom, it is independently selected from one to four substituents of the following group: hydrogen and -C! -4 alkyl (R9) Also, when connecting 10 to a carbon atom, it is independently selected from one to four substituents of the group: hydrogen, -Ci.4 alkyl (R9), -Cm alkoxy (R9),- O-aryl (R10) and hydroxyl; R9 is selected from the group consisting of: hydrogen, -Cm alkoxy, -NH2, -NH-Ci_4 alkyl, alkyl) 2, (halo) 13 and hydroxyl; Employee Consumption of Intellectual Property Bureau, Ministry of Economic Affairs When printed to 15 carbon atoms, R1G is independently selected from the following groups: hydrogen, -Cw alkyl, -Cw alkoxy, -C (= 〇) H, _C (= 〇) -Cw Alkyl, -C〇2H, -CCVCm alkyl, -NH2, -NH-Ci_4 alkyl, -N (Ci_4 alkyl) 2, halo, meridian, schottyl, and keto; 20 q is 0, 1, 2 or 3; Z is selected from the group consisting of: hydroxyl, -NH2, -NH-Cu alkyl, -Nfw alkyl) 2, O-Cw alkyl-OH, -O-Cm alkyl Cw Base, alkynyl Ci_g alkynyl, -0-Ci_8 alkynyl-C〇2H, -O-Cw alkyl-CCOP-Cm alkyl, -O-Cw -162 This paper size applies to Chinese National Standards (CNS) A4 specification (210x297 mm) 200536844 A8 B8 C8 D8, patent application scope -0-C (〇) Cu alkyl, -0-Ci_8 alkyl-NH2, -0-Ci_8 • alkyl-NH-Cw alkane Group, -O-Cw alkyl-Nfw alkyl group), -O-Cu alkyl group, -OC alkyl group -C (〇) -NH-Cu alkyl group, -O-Cw alkyl group-ccoyi ^ Cu alkyl) 2 and -NHC ^ OWu alkyl, -0-Ci_8 alkyl; and pharmaceutically acceptable salts, racemic mixtures and mirror isomers thereof. 49 · A compound having the following formula (1.2):

W is selected from the following groups ... -CG_3 alkyl (Ri) and -Cq3 alkyl_phenyl (Ri, R8); Member of the Intellectual Property Bureau of the Ministry of Economic Affairs I Cooperatives 15 20 Ri is selected from the following groups -NHd), -dihydro- 丨 / ^ pyrrolo [2,3-έ] pyridyl (¾), -tetrahydropyrimidinyl (Rs), -tetrahydrosynthesis 8-naphthyridinyl (D, -tetrahydro -If azepine [2,3_pyridinyl (R8) and pyridinyl (R8); Han 6 is selected from the following group:-dihydroimidazolyl (R8),-tetrahydrolaridine (I), -tetrahydropyrimidinyl (RS), and pyridinyl (R8); 8 when attached to a nitrogen atom, is independently selected from one to four substituents of the following group: hydrogen and- CM alkyl (r9); Also, in connection with this application ^^^^ (210x297 public love) A8 B8 C8 D8 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 200536844 6. When applying for a patent covering carbon Independently from one to four substituents of the following groups: hydrogen, -Ci_4 alkyl (R9), -Cw alkoxy (R9), -0-aryl (Riq), and hydroxyl; R9 is selected From the following groups: hydrogen, -Cw alkoxy, -NH2, -NH-5 Cl_4 alkyl, ~ N (Cl-4 alkyl) 2, (halo) i-3, and hydroxyl; Rio When attached to a carbon atom, it is independently selected from one to four of the following groups: hydrogen, -Cw alkyl, -Ch alkoxy, -C (= 0) H, < (= 0 ) 4-4 alkyl group, -C02H, -CCVCm alkyl group, NH2, -NH-Cm alkyl group, alkyl group), halo 10 group, hydroxyl group, nitro group, and keto group; q is 0, 1, 2 or 3; Z is selected from the group consisting of: hydroxyl, _NH2, _NH_Ci s alkyl, -N ((^ · 8 fluorenyl) 2, O-Cu alkyl-OH, -O-Cw alkyl Cw Alkoxy, -O-Cualkyl, Cu-alkyl, -O-Cw 15-C02H, -O-Ci-g alkyl-Ccop-Cw alkyl, -O-Cw alkyl- 0-(:( 0) (^ 8 alkyl, -ΟΤμ alkyl-NH2, · -O-Cm alkyl, -NH-Cw alkyl, -O-Cw alkyl-Nfw alkyl) 2, -O-Cw Alkylamine, -O-Cualkylalkyl, -O-Cualkyl- < 2 (〇) -N ((^ · 8alkyl) 2 and

20-NHC ^ OKw alkyl, -0-Cl-8 alkyl; and pharmaceutically acceptable salts, racemic mixtures and mirror isomers thereof. 50. The compound according to item 47 of the scope of patent application, the center of which is selected from the group consisting of: -NH (R0), -tetrahydropyrimidinyl (rs), and hydrogen 〇 and all other variables are as previously defined. -164

A8 B8 C8 D8 .200536844 t 、 Scope of patent application

In the formula (I · 3), 5 W is selected from the following group: -C0_3 alkyl (RD and -C0_3 alkyl-phenyl (Ri? Rs) Γ Ri is selected from the following group Groups -NH (R6), -dihydro-1ug-pyrrolo [2,3_ Office] Methylpyridyl (Rg), -tetraazapyridine (R * 8), -tetraazepine (Rg), -tetrazol-I / f-yiaheptene [2,3-ban] σ-ratio (Rg) and -ratio 10 pyridyl (r8); R2 is selected from the following group : Hydrogen, -tetrahydropyrimidinyl (R8), -1,3-benzodihumcyclopentenyl (R8), -dihydrobenzofuranyl (R8), -tetrahydroquinolinyl (R8), -Phenyl (R8), -naphthyl (R8), -laridinyl (R8), -pyrimidinyl (R8), and -quinolinyl (R8); 15 R6 is -dihydroimidyl (¾), _Tetrahydro. Specific hydrogen (¾), tetrahydropyrimidyl (R8) or -rotidinyl (R8); r8 when attached to a nitrogen atom is independently selected from one to four of the following groups Substituents: hydrogen and -Ci_4 alkyl (R9); and when attached to a carbon atom, it is independently selected from one of the following groups to 4 to 20 substituents · hydrogen, -Ci_4 alkyl (R9 ), -Ci_4 oxy-165 This paper size applies to China National Standard (CNS) A4 (210x297 mm)

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 200536844 A8 B8 C8 D8 VI. Patent application scope (R9), -0-aryl (RlG) and hydroxyl group; R9 'is selected from the following groups: hydrogen, -CV4 alkane An oxygen group, -NH2, -NH-C1-4 alkyl group, -N (Ci_4 alkyl group) 2, (¾yl group) 1.3, and a vial group. When R10 is connected to a carbon atom, it is independently selected from the following Group 1 to 5 Four substituents: hydrogen, -Cw alkyl, -Cm alkoxy, -C (= 〇) H, alkyl, -C〇2H, -C02-Q.4 alkyl,- NH2, -NH-Cm alkyl, -NCCm alkyl) 2, halo, hydroxyl, nitro, and keto; q is 0, 1, 2, or 3; z is selected from the following group: hydroxyl,- Nh2, -NH_Cl 8 alkyl, -N (Ci_8 alkyl) 2, O-Cw alkyl-OH, -0-Ck8 alkyl Cw, lactyl, -O-Cu, alkyl, Ci.8 _〇-Ci.8 alkyl-C02H, O-Cm alkyl-CCCOO-Cw alkyl, -O-Cw alkyl-O-CCOKw alkyl, -O-Cw alkyl-NH2,- O-Cw 15 alkynyl-NH-Ci_8 alkynyl, -0-Ci.8 alkynyl-N (Ci_8 alkynyl) 2, printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs -O-Cu alkynylamine,- O-Cu alkyl-(^ (CO-NH-Cu alkyl, -O-Ci.8 alkyl-CC OVNCCw alkyl) 2 and -NHqcOCw alkyl, -O-Cw alkyl; and pharmaceutically acceptable salts, racemic mixtures, and mirror isomers thereof. 20 52. If the compound of the scope of patent application No. 51, The central system is selected from the group: -NH (R6), -tetrahydropyrimidinyl (Rs) and -tetrahydro-fluorene, 8.naphthyridinyl (Rs) and all other variables are as previously defined. 53 · — A compound with the following formula (1.4): -166 This paper size applies to Chinese National Standard (CNS) A4 (210x297 public love) 200536844 Α8 Β8 C8 D8

coz formula (1.4) The chemical system is selected from the group: _2_benzobenzoyl, _3 · benzoyl, * 4-benzofuranyl, _5-benzofuranyl, benzofuran Group, -7-benzylfuranyl group, benzobenzothienyl group, -benzylthiophene-3-yl group, benzofluorenylthiophene-4 group, benzofluorenylthiophene I group, -benzofluorenylthiophene I group, -benzopyrenethiophene_7_ group, -indoline-2_ group, -indoline_3_ group, _indoline_10 10 15 printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 20 groups, -Fluorindol-5-yl, -indololyl, t-indol-7-yl, 2-benzoxazolyl, _4-benzoxazolyl, _5-benzoxazolyl,- 6-benzozazolyl, _7-benzazolyl, benzofluorenyl, i-benzoxyl, i-benzofluorenyl, ^ benzothiazolyl, -6-benzothiazolyl, benzo Thiazolyl, benzophenazyl-2-yl, -1 benzobenzimidazol_4-yl,-丨 benzobenzimidazol-5_yl, -1 ^ benzimidazole_6_yl ... benzene Benzimidazol-7-yl, 2-quinolinyl, _3-quinolinyl, _quinolinyl, _5-quinolinyl, each oxolinyl, 1 helynyl, helynyl, rhyme ^ • Benzopyran-2- Phenyl group, -2 / M-benzopyranyl group, ???: Where Benzene benzo-4-nan, benzopyranyl group 5_yl, small benzo ton. South-6-yl, -2 //-1-benzopyran_7_yl ... so small benzo. Better than benzo_8-yl, -4 is smaller than benzo, than benzo_2 · yl, valence is less benzoσ than ranyl, -4 //-1-benzopyran_4_yl, _4 // Xiaoben and pyran j _ 167-This paper size applies to China National Standard (CNS) A4 (210x297) | 200536844

2 U20 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, Benben Pyramid, _4, Benben Pyramid_7_, _4 / ^ _ benzylpyran_8, and ι / 7 winter Benzopyranyl group--1 //-2-benzopyranyl,] pyrene-2-benzopyran_4_, _ 丨 benzopyranyl, benzpyran-6 · Base, -1 2-benzylpyran_7_yl, '' 2-benzopyranyl, '' pyridinetetrahydro + naphthyl ... ^ 'tetrahydronaphthyl, 1,2,3, 4, hydrogen · 5-naphthyl, 2-naphthyl-4-tetrahydronaphthyl, -2,3-dihydro-2-benzofuranyl, -2,3_dihydro-3-benzofuranyl, -2,3-dihydro-4-benzyfuranyl, -2,3_dihydro_5-benzyfuranyl, '3-dihydro_6_benzofuranyl, 3_dihydro_7 -Benzofuranyl, -2,3-dihydrobenzofluorenethiophene-2-yl, _2,3-dihydrobenzofluorenethiophene-3-yl, _2,3-dihydrobenzofluorenethiophene-4_ Radical, · 2.3-dihydrobenzo-m-thiophene I radical, Moho dihydrobenzo-fluorene-thiophene-6-yl, _2,3-dihydrobenzopyrene] thiophene 7-yl, _2,3_dihydro · 1 / 7-indole-2-yl, -2,3-dihydro-1 / 7-indole-3-yl, _2,3-difluoro-177-ϋ5 | σdor-4-yl, -2, 3-dihydro-177- ^ introduction of sigma-5-yl, _2 3 · «dihydro-1 //- Indole-6-yl, _2,3_dihydro-1, good-indol-7.yl, 2.3-dihydro-2-benzoxazolyl, -2,3-dihydro_cardiacene Oxazolyl, -2,3-dihydro-5-benzoxazolyl, -2,3-dihydro-6-benzo. Oxazolyl, -2,3-dihydro-7-benzoxazolyl, -2,3-dihydrofluorenebenzimidazol-2-yl, -2,3-dihydro-1 //-benzo Imidazol-4-yl, _2,3 _- * Hydroxy-1 from the original benzo °° -5-yl, -2,3-dihydro-1 / Λbenzyl. Meter. Perylene 6-yl, -2,3-dihydro_1 fluorenylbenzimidazole-7-yl, -3, 'digas · 1 (2 //)-nosyl, 1,2,3,4- Tetrahydro-2- 嗤 LinkiΊ 2,3 4 · »-168 '

200536844 A8 B8 C8 D8 6. Application scope 5 10 15 20 Tetra-3-quinolinyl, · u, 3,4_tetrahydroquinolinyl, _ 丨, 2,3, cardiac tetrahydro, 5-wh Linyl, -u, 3,4_tetrahydrohafnium, -m-tetrahydro-7-quinolinyl, tetraargon_8_quinolinyl, -3,4 • dihydro-2 //-1 -Ben and σ are more than flank_2-base, · 3,4 · diazol_2 Dan Xiaoben, Dongji, _3,4 · dihydro-2 仏 1_benzopyran_4_base, _3 , 4_dihydrobenzo.Bee_5 · yl, 3,4_diazepine than T-Dongyl, -3, dihydro_pyrene and benzopyridine_7_yl, _3,4 · di Hydrogen-2 ugly little benzo. Biran_8 • yl, _3,4_diazepine-your benzo-2-anyl group 〇, 4-dihydro_ extremely small and benzopyranyl group, _3,4 · mi-benzylpyran _4_, 3,4_dihydro_ 术 _benzo ~ ^ 5-based, -3,4-dihydro_4, good small and benzopyranyl, ^, heart two wind special 1-benzyl ㈣ ,, 3, the diazonium must be stupid, and -8-yl, _3,4-dihydro ϋ stupid. Than bee · 2_base, _3, Xinerfeng-1 can be stupid and tonyl: radical, 3, XinH small benzoxan-4_yl, _3,4-dihydropyrenebenzopyrazine_5_ Radicals, _3,4_dihydro-1 / M-benzoxanthene groups, radicals from diazepine-7-yl, and 354-fluorene; μbenzoxyl groups, such groups When attached to a nitrogen atom, the titer number can be optionally selected from up to 7 substituents of the methyl group, and when attached to the rhyme, the titer number can be independently selected from A Group, foxy, or fluorine to substituents; z is selected from the group consisting of: via group, hydration group 2, side <] ceryl group, • N (Cl · 8 alkyl) 2, 0-CM alkane Group _〇h, _〇_Ci 8 alkyl-169 · 8 疋 pyridine% t t Ci This paper size Guzhong @ 丝鲜 (CNS) a / · (210 200536844 Α8 Β8 C8 D8 六、 Scope of patent application ίο 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Oxyoxy, -O-Cw alkylcarbonyl Cw alkyl, -O-Cw alkyl-c〇2H, _〇 <: "alkyl-ccop-Cw Alkyl, -O-Cw alkyl, -O-CCOKw alkyl, -O-Cw alkyl-NH2, -0-CK8 fluorenyl-NH-Cw alkyl, -O-Cw alkyl-Nds alkyl) 2 , -O-Ci.8 alkyl Amine, -0-cI 8 alkyl-C (〇) _NH_Ci 8 alkyl, -o-Cw alkyl 8 alkyl) 2 and -NHCCCOCw alkyl, -O-Cw alkyl; and pharmaceutically acceptable Salts, racemic mixtures and mirror isomers. 54_ — A composition comprising a compound as claimed in the scope of the patent application and a pharmaceutically acceptable carrier. The treatment or improvement of a patient in need thereof is integrated by A method for treating a disease mediated by a disease, which method comprises administering to the patient a therapeutically effective amount of a compound such as in the scope of patent application. 56. The method in the scope of patent application, wherein the disease is selectively inhibited It is selected from ❹ integrin receptors that include and avy55 integrin receptors. A The method according to item 55 of the patent application, wherein the disease is mediated by at least two integrin receptors at the same time. See application The method of patent scope f 55, wherein the integrin receptors are αν / 33 and αν / 95 integrin receptors. The method as described in the scope of patent application No. 55, wherein the disease mediated by the receptor is Selected from the group: cancer, cancer-related lesions, arteriosclerosis, transplantation Vascular lesions, blood film reformation, papilloma, pulmonary fibrosis, pulmonary fibrosis, blood vessels-170 paper rulers-thin; (2ΐχ297297)-200536844 Α8 Β8 C8 D8 々, patent application scope ball Nephritis, glomerulosclerosis, congenital polycystic kidney dysplasia, renal fibrosis, diabetic retinopathy, macular degeneration, psoriasis, osteoporosis, bone loss, inflammatory arthritis, rheumatoid arthritis and arterial recanalization narrow. 5 60. The method of claim 55, wherein the therapeutically effective amount of the compound of claim 1 is about 0.001 mg / kg / day to about 1000 mg / kg / day. 61. The method of claim 55, wherein the method further comprises preventing a patient in need thereof a method for preventing a disease mediated by αν integrin, which method comprises administering to the patient an effective amount of prevention For example, the compound in the scope of patent application No. 1. 62. The method of claim 55_, wherein the method further comprises a method of inhibiting the activity of neoplasms mediated by αν integrin, the method comprising administering an effective amount of a neoplasm or a small environmental surrounding the neoplasm Such as the application of 15 patent scope of the first compound. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 63. If the method of the scope of application for patent No. 55, the method further includes the treatment or improvement of diseases mediated by cells that pathologically express αν integrin or its subtype method. 64. The method of claim 63, wherein the disease mediated by cells that pathologically express αα integrin is selected from the group consisting of cancer, cancer-related lesions, diabetic retinopathy, Macular disease, osteoporosis, bone loss, inflammatory arthritis, rheumatoid arthritis, and arterial restenosis. 65. If the method of applying for the scope of the patent No. 55, which is further -171 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210x297 male *) 200536844 Α8 Β8 C8 D8范围 The scope of patent application includes the beneficial use of compounds such as the one in the scope of patent application and one or more antitumor or cell proliferation therapies selected from the group consisting of chemical method, radiation therapy, gene therapy and immunotherapy to prevent A method for treating or ameliorating diseases mediated by αν integrin. 5 66. The method of claim 55, wherein the method further includes a method of performing tumor angiography on a patient in need thereof, the method comprising advantageously co-administering an effective amount of the patient as in the patent application range The compound of item 1; wherein the compound according to item 1 of the patent application is a non-invasive tumor contrast agent that is assembled or delivered to a tumor or to a small environment around the tumor. 67. A method as claimed in claim 55, wherein the method further comprises a method for treating or improving arterial and venous restenosis using a compound as claimed in claim 1; wherein the compound as described in claim 1 is Fill the treatment device surface. -172 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 200536844

(II) Brief description of the component representative symbols of this representative map: None

^ (CH2) ^ ^ 2

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