TW552260B - Endothelin antagonists - Google Patents

Abstract

A compound of the formula (1) or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin. A substantially pure compound selected from group consisting of (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; [2S,3R,4S]-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; [2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; [2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; [2S,3R,4S]-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; or a salt or ester thereof.

Description

552260 A7 B7 V. Description of the Invention (This is a partial continuation of the U.S. Patent Application No. 0 8 / 905,9 No. 13 filed on August 4, 1997, which is 1 " February 4, 7 Partial continuation application of the filed US patent application serial number 08/79 heart No. 506, which is part of the continuation application of the filed US patent application serial number 0 8 / 600,625 on February 13, 1996 , Which is a partial continuation application of US Patent Application Serial No. 08 / 497,998 filed on August 2, 1995, and US Patent Application No. 0 8/442 filed on May 30, 1995 Partial continuation application No. 5, 75, which is a partial continuation application No. 08/3 3 4,7 1 7 of the US patent application filed on November 4, 1994, which is August 1994 Partially continued applications of U.S. Patent Application Serial No. 08/2 93; 3 49, filed on the 19th. Technical Field The present invention relates to compounds that are endothelin antagonists, and methods for making such compounds. Synthetic intermediates and methods and compounds for combating endothelin. BACKGROUND OF THE INVENTION j; j (Please read the back first Note: Please fill in this page again.) Endothelin (ET) is a peptide of 21 amino acids produced by endothelial cells. ET is a Trp- Val bonds are produced. The incision is flared by endothelin-converting enzyme (ECE). Endothelin has been shown to contract arteries and veins, increase average arterial blood pressure, reduce cardiac output, increase cardiac contractility in vitro, and in vivo Stimulate mitosis of vascular smooth muscle cells externally, contract non-vascular smooth muscle in vitro, including guinea pig trachea, strips of human bladder and rat uterus, increase airway resistance in vivo, and in vitro and in vivo Issue-4 This paper is a standard of SS in China (CNS) Λ4 specification (210 X 297 mm) 552260 A7 B7 V. Description of the invention (2) Gastric ulcer formation, stimulation of atrial natriuretic factor release, and increase of blood vessels in plasma The content of vasopressin, aldosterone and catecholamines inhibits the release of renin in vitro and stimulates the release of gonadotropins in vivo.

It has been shown that vasoconstriction is caused by the binding effect of endothelin and its receptor on vascular smooth muscle (Nature 332 41 1 (1998), FEBS

Letters 440 (1998) and Biochem. Biophys. Res. Commun. Lil 868 (198 8)). Preparations that inhibit endothelin production, or preparations that bind endothelin, or preparations that inhibit endothelin and endothelin receptor binding, will have a beneficial effect in various therapeutic areas. In fact, anti-endothelin antibodies have been shown to improve the adverse effects of renal ischemia on renal vascular resistance and silk ball filtration rate when infused in the kidney (Kon et al., J. Clin. Invest. 1 762 (1 989)). In addition, anti-endothelin antibodies reduce the nephrotoxic effects of intravenous administration of cyclosporine (Kon et al., Kidney Int. 12 14 8 7 (1 9 9 0)) 'and reduce coronary connection- The size of myocardial infarction (Watanabe et al., Nature 344 1 14 (1 990)) °

Clozel et al. (Nature 365: 759-76 1 (1993)) reported Ro46-2005, a non-peptide ET-A / B antagonist that prevents renal vasoconstriction after ischemia in rats Prevent the reduction of cerebral blood flow caused by the known subarachnoid hemorrhage (SAH) in rats, and reduce MAP in sodium-depleted squirrel monkeys when administered orally. Recently, a linear tripeptide-like ET-A antagonist, BQ-485, has also been reported to have similar effects on the diameter of dynamic brewing after SAH (S. Iton, T. Sasaki, K. Ide, K. Ishikawa, M. ι

Nishikibe and M. Yano, Biochein. Biophys. Res. Comm., 195 | ί: 969-75 (1993)). These results point to anti-ET-ET receptor binding |

I

I -5- ί The size of this paper is appropriate; 丨] Chinese national standard ((:) ^) / \ 4 specifications (210,297 male 1) (Please read the precautions on the back before filling this page)

552260 A7 B7 Medium

h-T f A Description of the Invention (The formulation will provide therapeutic benefit to a specified disease condition. Formulations capable of combating ET / ET binding by ft have been shown to be active in animal models of many human diseases For example, Hogaboam et al. (EUR. J. Pharmacol. 1996, 309_, 261-269) showed that endothelin was reduced by fa # 技 力 j 'in the rat model of colitis. Et al (Transplant Int 1996, B, 201-207) have proven similar formulations to prevent allergic-reperfusion injury during kidney transplantation. Similar studies have been proposed using endothelin antagonists to treat heart pain, pulmonary hypertension, Raynaud's ) And migraine. (Ferro and Webb, Drugs 1996 ,, 12-27). Abnormal endothelin or endothelin receptor levels are also associated with many disease states. Stables include prostate cancer (Nelson et al., Nature Medicine 1 995 '1' 944-94 9), suggesting the role of endothelin in the pathophysiology of these diseases 3

Wu-Wong et al. (Lfe Sciences 1996, 58, 1839-1847) showed that both the endothelial sequence and the endothelin antagonist are tightly bound to plasma proteins', such as A albumin. Binding of the plasma protein reduces the effectiveness of the antagonist in inhibiting the effect of endothelin. Therefore, endothelin antagonists with reduced plasma protein junctions may be more effective than their high-binding counterparts. Content The compound of formula (I) according to the present invention (please read the precautions on the back before filling this page) -6-552260 A7 B7 V. Description of the invention (4)

I (CH2) n (Please read the notes on the back before filling out this page) ⑴ where Z is -C (R1S) (R19)-or -C (0)-, where R18 and r19 are selected from hydrogen and low Number base; η is 0 or 1; R is-(CHOm-W, where m is an integer from 0 to 6, and W is (a) -C (0) 2-G, where G is hydrogen or carboxy protected (B) -P03H2, (c) -P (0) (〇H) E, where E is hydrogen, a lower alkyl or aralkyl group, (d) -CN, (e) -C (0 ) NHR17, where R17 is a lower carbon alkyl group, (f) an alkylaminocarbonyl group, (g) a dipitamino group, (h) a tetrakisyl group, (I) a hydroxyl group, (J) an alkoxy group, ( k) sulfaminyl, (l) -C (0) NHS (0) 2R16, where R16 is a carbon number alkyl, haloalkyl, aryl, or two: fet moonyl, (m) -S (〇) 2NHC (0) R16, where Ri6 is as defined above, ΛΜ -7- This paper size applies to the national valve standard (CNS) Λ4 specification (210X297 mm) 552260 A7 B7 V. Description of the invention (5

HO

〇

OH

〇 ⑺ 〇 (Please read the notes on the back before filling out this page} ⑻

s = o 〇 'CF3 ⑴ η, or (u) λ ^ / in nhso2cf3

A

R i and R 2 are selected from hydrogen, lower carbon alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, ialkyl, autoalkoxyalkyl, alkoxyalkane Oxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, -8- National Standard (CNS) Λ4 Specification (210X297 mm) 552260 A7 B7 V. Description of the Invention (6 Aminocarbonylalkyl, Alkylaminocarbonylalkyl, Dialkylaminocarbonylalkyl, Aminecarbonyl Alkenyl, Aminoalkyl, Dioxoamino Group, Mensyl, Aryl, aryl, aryloxymethyl, aryloxy, (N-chain fluorenyl_N-alkyl) amine alkyl, alkyl sulfonamido alkyl, heterocyclyl, (heterocyclyl ) Alkyl and (UCRbiON-Re.- 'where Raa is aryl or aralkyl, is hydrogen or alkanoic acid group, and R "is an alkylene group, and the restrictions are both Xinhe and Zhong ^ $ Is other than hydrogen; R3 is (a) R4-C (0) -R5-, R4-R5a-, r4-C (〇) u (R6) _, ^ S (〇) 2-R7-or R26 -S (0) -R 27 " where R5 is a ⑴ covalent bond, (π) fluorenyl, ㈤) 某, (ιν or RSa-N (R2 ())-R8-; where Rs and R8a Be selected from the group consisting of 1. alkylene and alkylene A r2q are hydrogen, low integer number base, homeotropic, ^ alkoxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, or cycloalkyl Alkyl, + public ~ or (v) -〇-R9_t 〇-R9-, where R9 and R9a are selected from alkylene respectively; 4 k9a- R5a is (1) alkylene or (11) alkylene; R7 Is a covalent bond, (ii) an alkylene group, (ill) an alkynyl group <) N < -R i 0a-N (R2 1) -Rl0- ', where RlO and Han 10%%' ^ , A i) fe group or elongation group, and R2 i is hydrogen, and the low-carbon number group 0a is selected from the group including elongation (please read the precautions on the back before suppressing this page, in which A is an oxygen radical, ii. Oxyalkyl, aryl, or aromatic radical: R4 and R6 are selected from (◦ (RnKRiJN-, where Rn and R12 are selected from hydrogen, respectively, and (2) a lower carbon number alkyl group, an alkyl group, and Alkane, alkane 9-scale 丨 〇] Zhongwei national standard grass (CNS) Λ4 specification ('210X297) while ^ --_ 552260 A7 B7 V. Description of the invention (7 (3) #alkyl (4) alkane Oxyalkyl, (5) alkoxyalkyl, (6) fluorenyl, (7) alkynyl, (8) cycloalkyl, (9) cycloalkylalkyl, (10) aryl, (11)Cyclic, (12) aralkyl, (13) (heterocyclyl) alkyl (14) hydroxyalkyl, (15) alkoxy, (16) amine alkyl, (17) trialkylamine alkyl (1 8) Amine group, (19) Dialkylamino alkyl group, (20) Carboxyl group, (π) Low carbon number alkyl group, (III) Alkenyl group, (IV) Alkinyl group, (V) Cycloalkyl, (vi) cycloalkylalkyl, (VII) aryl, and -10- (Please read the notes on the back before filling this page)

This paper is suitable for tH National Standard (CNS) A4 specification (210 X 297 mm) 552260 A7 B7 5. Description of the invention (8 (VU1) aralkyl, (ix) heterocyclyl, (X) (heterocyclic (Alkyl) alkyl (xi) alkyloxy, (xii) #alkyl, (X111) haloalkyl, (xiv) alkyl, (xv) from alkoxyalkyl, (xvi) from alkoxy , (Xvii) alkoxyhalo (xviii) alkylaminoalkyl, (xix) diamidoamino (XX) alkoxy, and (Please read the notes on the back before filling this page) ( CHt / N ^ Y (xxi) ο Η 'Rya- in Λ f A ii where Z is 0-5 and R7a is an extrinsic group; R26 is ⑴lower-carbon alkyl, (Π) haloalkyl, (m ) Alkenyl, (IV) alkynyl, (V) cyclohexyl, (vi) cycloalkynyl, (vii) aryl, (viii) aryl, j: fluorenyl, (IX) heterocyclyl, (X) (heterocyclyl) alkyl, (XI) alkoxyalkyl or (XII) alkoxy-substituted alkynyl: and R27 is alkyl or alkenyl; (b) R22-〇- C (〇) -R23-, in which R22 is a carboxy protecting group or heterocyclic group, and the paper size is / 丨] tSS standard (CNS) Λ4 specification (210 X 297 mm) 552260 A7 B7 V. The invention It is clear that (9) R23 is a fluorene covalent bond, (π) alkylene, (n〇 alkylene, or (ιν) -N (R24) -R25-, where R25 is alkylene and R24 is hydrogen or low Carbon number alkyl, (c) lower carbon number alkyl, (d) alkenyl, (e) bulk, (f) cycloalkyl, (g) cycloalkylalkyl, (h) aryl, (i ) Aralkyl, (J) aroxyalkyl, (k) heterocyclyl, (l) (heterocyclyl) alkyl, (m) alkoxyalkyl, (η) alkoxyalkoxyalkyl, Or (〇) R13-C (0) -CH (R14)-, where R! 3 is amine, alkylamino or dialkylamino, and R14 is aryl or R15-C (〇)-, where R15 Is an amino group, an alkylamino group, or a dialkylamino group: or a pharmaceutically acceptable salt thereof. A preferred embodiment of the present invention is a compound of the formula (Π) (please read the precautions on the back before filling this page) * ir; 中 A ii R2 ^ R ,,,

(CH2) r

Ri (II) -12- This paper is suitable in size / 丨] China National Standard (CNS) Λ4 Specification (2 丨 0X297 mm) (v 552260 A7 B7 Medium

>/; f A 5. Description of the invention (10 wherein the substituents -R2, -R and -Ri exist in a reverse and reverse relationship, and Z, η, R, Ri, R2 and R3 are as defined above. Other preferred embodiments of the present invention are compounds of formula (I) or (II) where η is 0 and Z is -CH2-. Other preferred embodiments of the present invention are where η is 1 and Z A compound of formula (I) or (II) which is -CH2-. Another preferred embodiment of the present invention is where η is 0, Z is -CH:-'and R3 is R4-C (〇) -R5_ , R6-S (0) 2-R7-or R26-S (〇) -R27- compounds of formula (I) or (π), wherein r4, r5, r6, r7, r26 and R27 are as defined above Other preferred embodiments of the present invention are compounds of formula (I) or (Π) wherein η is 0, Z is -CH2-, and R3 is an alkoxyalkyl or alkoxyalkoxyalkyl group. A more specific embodiment of the present invention is a compound of formula (I) or (II) wherein η is 0, Z is -CH2-, and R3 is R4-C (0) -R5-, wherein R4 is (Rm ) (Ri2) N-, as defined above, and R5 is alkylene or R3 is R6-S (〇) 2-R7- or R26-S (〇) -R27-, where R 7 is an alkylene group, R27 is an alkylene group, and R6 and R26 are as defined above. In another preferred embodiment of the present invention, η is 0, Z is -ch2-, and r3 is r4-c. (〇) -n (r20) -r8- or r6-s (〇) 2-n (r21) -r! 〇- compounds of formula (I) or (II), wherein Rs and R10 are alkylene groups, and R4, R20, and R21 are as defined above. A more preferred embodiment of the present invention is a compound of formula (I) or (II), wherein η is 0, R is tetrazolyl or -C (〇) 2 -G, where G is hydrogen or carboxyl. 13- The paper size is the national standard of China Valves (CNS) Λ4 specification (2 丨 0/297 mm) (Please read the precautions on the back before filling this page)

55226〇A7 V. Description of the invention (11) Residue, or R is tetrabenzyl, or R is -C (〇) -NHS (0) 2R16, which is a low carbon number alkyl, haloalkyl or aryl group, z is -ch2-,

Ri and R2 are respectively selected from (i) a low retarding alkyl group, (ii) a cycloalkyl group, and (iii) a substituted square group, wherein the aryl group is a basic group with one, one, or two substituents, and Substituents are selected from the group consisting of low-carbon alkyl, alkoxy, halogen, alkoxyalkoxy, and alkoxy groups, (iv) substituted or unsubstituted heterocyclic groups, (v) field groups , (Vi) heterocyclyl (alkyl), (νϋ) aralkyl, (viii) aryloxyalkyl, (ix) d-alkanoyl-N-alkyl) aminoalkyl, and (X) Alkylsulfonamidoalkyl, and r3 is R4-C (0) -R5-, where r4 is (RhXR ^ N- 'where R11 and r12 are each selected from low-carbon, alkynyl, Pit group, halogen version i-oxalanyl group, aryl group, aralkyl group, heterocyclic group, hydroxyalkyl group, alkoxy group, amine alkyl group and trialkylamine alkyl group, and R5 is an alkylene group: or 3 is Κ4-[(〇) -Ν (Κ2 ())-ίν, or R6-S (O) 2-N (R21) -R10-, where R4 is a lower carbon number alkyl, aryl, alkoxy , Alkylamino, aryloxy, or aralkoxy, and rule 6 is a low-carbon number alkynyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, or arylhexyl 'R8 and Rio for Alkylene, and R2q and R2i are low-carbon alkyl groups; or R3 is R6-S (0) 2-R7- or R26-S (0) -R27-, where R6 is a carbodonyl or a box Group, R7 is an alkylene group, R26 is a low carbon number alkyl group, and ursinyl group ° A more preferred embodiment of the present invention is a compound of formula VII or (π) where η is 0 and R is -C (〇) 2-G, where G is hydrogen or stilbene, tetrazolyl, or -C (〇) -NHS (0) 2r16, where Rk is a lower alkyl, haloalkyl, or aryl , Z is, & is a low-carbon alkane group; VH) alkenyl (i) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, and fluorenyl , (Viii) substituted or unsubstituted 4-methoxybenzyl, 4-qi exhaustion & '. -14- _ ^ _-Chuanzhongwei National Standards (<?] ^) / \ 4 specifications ('21 〇 \ 297 public trend) of this paper (Please read the notes on the back before filling in this page j

552260 A7 B7

: Price: Ministry of il I II

A. V. Description of the invention (12-pentyl, 4-ethoxybenzyl, 4-ethylphenyl, 4-methylbenzyl, 4-dioxenylphenyl, 4-pentylethylbenzyl, 3- Gas-4-methoxyphenyl, 3-gas-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxyoxymethoxyphenyl, 4-hydroxyphenyl, 4-tert-butyl Phenyl, 153-phenylhydrazone dioxolane, 1,4-benzodioxanyl, or dihydrobenzofluorenylfuranyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy And carboxyalkoxy, (IX) heterocyclyl (alkyl), (X) aralkyl, (XI) aryloxyalkyl, (χι) (N-alkanoyl-N-alkyl) Aminealkyl, or (X111) alkylsulfonamidoalkyl, R2 is substituted or unsubstituted 1,3-phenylhydrazone dioxolenyl, 7-fluorenyloxy-1,3 -Benzene-dioxolenyl, phenylarbioxanyl, 8-methoxy-1,4-phenylarbioxinyl, dihydrophenylarsinofuranyl, phenylarsinofuranyl, 4- Phenoxyphenyl, dimethoxyphenyl, fluorophenyl, or difluorophenyl, and & 3 is R4-C (〇) -N (R2〇) -Rs- or R6_S (0) 2-N (R21 ) -Ri〇 · 'where 1 ^ 8 and Rio are extrinsic radical' R21 is low carbon Pit roll, R4 is a low carbon number resist, aryl, pit oxygen, pit amine roll, aryloxy or aralkoxy, and R6 is a low carbon number alkyl, haloalkyl, alkoxyalkyl, aromatic Or aralkyl. Other preferred embodiments of the present invention are compounds of formula (I) or (Π), where η is 0, R is -C (0) 2-G, where G is hydrogen or carboxyl protected Group, tetrazolyl or -C (〇) -NHS (〇) 2Ri6, where Ri6 is a low-carbon alkyl, haloalkyl or aryl group, Z is -CH2-, and R! Is (1) a low-carbon alkane , (Η) alkenyl, (111) alkoxyalkyl, (IV) cycloalkyl, (V) phenyl, (VI) pyridyl, (VII) furanyl, (viii) substituted or unsubstituted 4-Methoxyphenyl, 4-Fluorophenyl, 3-Atomyl, 4-Ethyloxy, 4-Ethylphenyl, 4-Methyl, 4-Dimethynylphenyl , 4-pentaethylethylphenyl, 3-fluoro-4-methoxyxy, 3-fluoro--15- This paper is based on the National Standard (CNS) Λ4 specification (210 乂 297 mm) ( Please read the precautions on the back before filling out this page) 552260 A7 B7 V. Description of the invention (13

A 4-ethoxyphenyl, 2-fluorophenyl, 4-methoxyphenyloxyphenyl, 4-hydroxyphenyl, 4-third-butylphenyl, 1,3-phenylhydrazine dioxo Heteropentenyl, 1,4-phenylarylene, or dihydrobenzocranyl, wherein the substituents are selected from the group consisting of alkoxy, alkoxy, and alkynyl. (Ix) heterocyclyl (alkyl), (X) aralkyl, (XI) aryloxyalkyl, (xii) (N-alkanoyl_1 ^ _alkyl) aminoalkyl, or ( X111) alkylsulfonamidoalkyl, R2 is substituted or unsubstituted 1,3-phenylhydrazone dioxopentenyl, 7-methoxy-1,3-phenylhydrazone dioxy Heteropentylamyl, 1,4-Benzamidinedihenyl, 8-methoxy-1,4-Benzamidinedihenyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxy Phenyl, dioxophenyl, fluorophenyl, or difluorophenyl, and R3 is R4-C (0) -R5-, where R5 is an alkylene group, and R4 is (RnJCRJN ·, where Rh and R12 are respectively Is selected from the group consisting of low-carbon alkyl, i-alkyl, alkoxyalkyl, alkoxyalkyl, aryl, aralkyl, heterocyclic, hydroxyalkyl, alkoxy, aminealkyl, and trialkyl Amine alkyl. Other preferred compounds of the invention Examples are compounds of formula (I) or (Π), where η is 0 and R is -C (0) 2-G, where G is hydrogen or a carboxy protecting group, tetrazolyl or -C (〇) -NHS (〇) 2-R16, wherein Ri0 is a low-carbon alkyl group, haloalkyl group or aryl group, Z is -CH2-, heart is a low-carbon alkyl group, (η) alkenyl group, (m) heterocyclic group (Alkyl), (iv) aryloxyalkyl, (v) aralkyl, (v0 aryl, (νπ) (N-alkaminoalkyl) aminoalkyl, or (νιπ) alkyl Sulfonylaminoalkyl, R2 is substituted or unsubstituted benzo-dioxolenyl, 7-methoxy-1,3-phenylhydrazine-dioxolenyl, 1, 4-Benzamidinedialkyl, 8-methoxy-1,4-phenylamidinedialkyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dioxanyl , Fluorophenyl or Difluorophenyl-16- This paper is not on the scale; 丨] Chinese national standard ((: ^) six 4 specifications ('210/297 mm) (Please read the precautions on the back before filling in this Page li-:-1 --- --1 ίί 一 i 一 i 1— 墨 ml— I--—1 -1

A 5. Description of the invention (14, wherein the substituent is selected from the group consisting of a lower carbon number alkyl group, an alkoxy group and a dentin, and R3 is R4-C (〇) -R5-, wherein R5 is an alkylene group, and R4 is (RhKUN-, where Rn is a lower carbon number alkyl group, and R12 is an aryl group, an aralkyl group, a hydroxyalkyl group, a carboxy group, an amine group, a trialkyl group, or a heterocyclic group. A preferred embodiment is a compound of formula (I) or (Π), wherein η is 0, R is -C (0) 2-G, wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C (〇 ) -NHS (0) 2-Ri6, where Ri6 is a lower carbon number alkyl, haloalkyl or aryl group, Z is -CH2-, R! Is a fluorene lower carbon number alkyl group, (ii) an alkenyl group, (m ) Heterocyclyl (alkyl), (iv) aroxyalkyl, (v) aralkyl, (ν: ί) (N-alkanoyl-N-alkyl) aminoalkyl, or (vii ) Alkylsulfonamidoalkyl, (vu) phenyl or (ix) substituted or unsubstituted 4-fluorenylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-Fluoro-4-ethoxyphenyl, 2-Fluorophenyl, 4-Methoxyfluorenyl lactyl, 1,3-Phenylmetoxydioxoamylpentyl, 1,4 -Dongkaiji Alkanyl or dihydrobenzofuranyl, which The substituent is selected from the group consisting of a low-carbon alkyl group, a haloalkyl group, an alkoxy group, a alkoxyalkoxy group, or a alkoxy group, and R2 is a substituted or unsubstituted U3-phenylhydrazine dioxane Pentenyl, 7-fluorenyl-1,3-phenylfluorenyldioxane, 1,4-phenylfluorenyldialkyl, 8-fluorenylbenzodialkyl, dihydro Phenylfuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl, or difluorophenyl, wherein the substituent is selected from the group consisting of lower alkyl, alkoxy, and halogen, and R3 is R6 -S (〇) 2-N (R2i) -R10-, where R! 〇 is an alkylene group, and R6 is a low-end alkyl group, a haloalkyl group, an alkoxyalkyl group, a haloalkoxyalkyl group, and an aryl group Or aralkyl, and R21 is a lower carbon number alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, or aralkyl group. A more specific embodiment of the present invention is represented by the formula ( Compounds of I) or (Π), -17- This paper is the size of the National Standard of China (CNS) Λ4 specification (210X 297 mm) (Please read the notes on the back before filling this page) 552260 A7 B7 k: \-k Meaning:] 5. Description of the invention (15 where η is 0, R is -C (0) 2-G, where G is hydrogen or carboxyl Protecting group, tetrazolyl or -C (〇) -NHS (0) 2-R16, where R16 is a lower carbon number alkyl, haloalkyl or aryl group, Z is -CH2-, and Ri is substituted or unsubstituted Substituted 4-fluorenylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyfluorenyl, 4-methoxyfluorenyloxyphenyl, 1 1,3-Benzamidinedioxolenyl or 1,4-phenylarbioxinyl, wherein the substituent is selected from the group consisting of a lower carbon alkyl group, a haloalkyl group, an alkoxy group, and an alkoxyalkoxy group , (Π) lower carbon number alkyl, (in) alkenyl, (iv) heterocyclyl (alkyl), (v) aryloxyalkyl, (vi) aralkyl, (vii) (N- Slit test base-pit base) amine pit ^ (viii) fe-based transverse SS amino-fe 'or (ix) phenyl, R2 is substituted or unsubstituted 1,3-benzo-dioxane Cyclopentyl, 7-methoxy-1,3-phenylhydrazine, 1,4-benzopyridinyl, 8-methoxy-1,4-benzobis 4 Entertainment: base, dihydrophenylhydraxanyl, 4-methoxyphenyl, dioxophenyl, fluorophenyl, or difluorophenyl, wherein the substituent is selected from the group consisting of a low-carbon alkyl group and an alkoxy group And halogen, and R3 is R6-S (〇) 2-N (R2i) -R10-, where R1 0 is an alkylene group, R6 is a low-carbon number alkyl group, a haloalkyl group, a oxyalkyl group, or an oxyalkyl group, and R: n is a low-carbon number oxo group, a haloalkyl group, an alkoxyalkyl group, or _Alkoxyoxyalkyl. Other preferred embodiments of the present invention are compounds of formula (I) or (Π), wherein η is 0, R is -C (〇) 2-G, wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C (0) -NhTS (0) 2-RK), where Ri6 is a low-carbon alkyl or haloalkyl group, Z is -CH2-, and R! Is a low-carbon alkyl, alkenyl, and heterocyclic group ( Alkyl), aryloxy, aryl-fe, aryl, (N-bond-pyridyl-N-alkyl) amine, / filler, or SS amino amine fe group, and is R4-C ( 0) -R5- 'in which Rf is an alkylene group, and R4 is (Rn) (Ri2) N-, where R] 1 and Ru are each selected from alkane-18 This paper is described in Sichuan National Standard (CNS) A4 specification (210X297 males) (Please read the precautions on the back before filling out this page) 552260 A7 B7 V. Description of the invention (13) Base, aryl, pit base, pit oxygen, amine resistant group, difeamine fe-based and heterocyclyl. ; r and A 卬 (read the precautions on the back and then fill out this page) A more preferred embodiment of the present invention is a compound of formula (I) or (Π), where η is 0 and R is -C (〇 ) 2-G, where G is hydrogen or a carboxy protecting group, tetrazolyl or -C (〇) -NHS (〇) 2R16, where R16 is a low-carbon alkyl or haloalkyl group, and Z is -CH2- ,! ^ Is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethyl Phenyl, 4-methoxymethoxyoxyphenyl, 4-¾benzyl, 4-ethylphenyl, phenylhydrazone dioxopentenyl, 1,4-phenylhydrazinyl, or diphenyl Hydroxyphenylsulfanyl, wherein the substituent is selected from the group consisting of alkoxy, alkoxyalkoxy, and polyalkoxy, (ii) a lower alkyl group, (iii) an alkenyl group, (iv) a heterocyclic ring (Alkyl), (V) aroxyalkyl, (VI) aralkyl, (vn) (N-alkanoyl-N-alkyl) aminoalkyl, (VU1) alkylsulfonamine Alkyl, or (lx) phenyl, I is 1,3-phenylhydrazine, 1,4-phenylhydrazinyl, dihydrobenzofuranyl, benzofuranyl , 4-Methoxyphenyl, dimethoxyphenyl, fluorophenyl, or difluorophenyl, and R3 is R4-C (0) -R5-, where R5 is an alkylene group, and R4 is (Rh) ( R12) N-, wherein Rh and R12 are selected from the group consisting of a lower carbon number alkyl group, an aryl group, an aryl fe group, a cyano group, a fe milk group, an amine group, a secondary antibody amine group, or a heterocyclic group. Other preferred embodiments of the present invention are compounds of formula Π) or (π), wherein η is 0, R is -C (0) 2-G, wherein G is hydrogen or a carboxy protecting group, tetrazolyl or- C (0) -NHS (〇) 2-R16, where R16 is low-carbon alkyl or haloalkyl, Z is -CH2-, Ri is low-carbon alkyl, alkenyl, heterocyclic (alkyl) , Aryloxyalkyl, aralkyl, (N-alkanoyl-N-alkyl) amine alkyl, alkanes 19 This paper is suitable for the standard / 丨] National Standard (CNS) Λ4 Specification C 210 X 297 5. General description of the invention (17) (Read the precautions on the back before filling this page) Sulfonamidoalkyl, phenyl or alkoxyalkyl, R2 is 1,3-benzodioxy Heteropentenyl, 1,4-benzodiurinyl, dihydrobenzofuranyl, benzobiranyl, 4-oxophenyl, dioxanyl, murine, or difluorobenzene And R3 is R4-C (0) -R5-, where R5 is an alkylene group, and R4 is (RhXRJN-, where Ri i and R12 are each selected from a lower carbon alkyl group, an aryl group, an aralkyl group, Hydroxyfe group, oxo group, amine fe group, dialkylamino group or heterocarboxyl group. The most preferred embodiment of the present invention is formula (II) or (II) Compounds where η is 0, R is -C (0) 2-G, where G is hydrogen or a carboxy protecting group, and Z is -CH2-, which is a substituted or unsubstituted 4-methoxyphenyl, 4 -Fluorophenyl, 2-aminobenzyl, 4-fluorenylcurtain, 4-dimurylmethylxy, 4-pentamylethylepoxy, 4-fluorenyloxyphenyl, 4-¾ Phenyl, 4-ethylphenyl, 1,3-pyrido-dioxolanyl, 1,4-benzopyridinyl, or dihydrobenzofuranyl, wherein the substituent is selected from Alkoxy, alkoxyalkoxy, and double alkoxy,} 12 is 1,3-phenylhydrazone dioxopentenyl, 1,4-phenylhydrazone, dihydrophenylhydrazone Furyl, benzofuranyl, 4-methoxyphenyl, dioxophenyl, fluorophenyl, or difluorophenyl, and R3 is R4-C (0) -R5-, where R5 is an alkylene group, R4 is (RhKRJN-, where Rh and R12 are each selected from a low carbon number alkyl group. Other preferred embodiments of the present invention are compounds of formula (I) or (Π), where η is 0 and R is -C (0) 2-G, where G is hydrogen or a carboxy protecting group, Z is -CH2-, and heart is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl 4-tridunylmethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxylanyl, 4-ethylphenyl, 1,3-benzyldiphenyl Oxepinyl, 1,4-benzodihexyl or dihydrobenzyl-20-Paper scale suitable for China National Standard (CNS) Λ4 Specification C 210 乂 29 * 7 mm) 5. Invention Note (1S) (Please read the notes on the back before filling this page)) Furanyl, where the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is 1,3_ Benzo metadioxenyl, 1,4-phenylhydrazine, dihydrobenzouranyl, benzofluorenyl, 4-fluorenylphenyl, dimethoxyfluorenyl, gas Qinyl or dioxophenyl 'and trans 3 is R4_C (〇) -R5-' where R5 is an alkylene group and R4 is (Rh) (R12) N- where Rn is a lower carbon alkyl group and R12 Is aryl. Other preferred embodiments of the present invention are compounds of formula (I) or (Π), where η is 0, R is -C (0) 2-G, where G is hydrogen or a carboxy protecting group, and Z is -CH2 -, The heart is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-fluorenyloxy, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyfluorene Group, 4-fluorenylmethoxyphenyl, 1,3-phenylfluorenyldioxolenyl, 1,4-phenylphosphonidinylalkyl, or dihydrophenylfluorenylfuranyl, wherein the substituent It is selected from the group consisting of a low carbon number group, a thiol group, a ceryloxy group, an antioxyl group, and a thiol group. The ft2 is a substituted or unsubstituted 1,3-benzo metadioxy group. Heteropentyl, 7-methoxy-U3-benzo-dioxo # yl, 1,4-phenylhydrazone, 8-methoxy-1,4-benzodi-4 A substituent, a dihydrobenzobenzoyl group, a 4-fluorenyloxy group, a difluorenyloxy group, a fluorophenyl group, or a difluorophenyl group, wherein the substituent is selected from the group consisting of a low carbon number alkyl group, an alkyloxy group, and Halogen, and R3 is R6-S (〇) 2-N (R21) -R1〇-, wherein R10 is an alkylene group, and R6 is a low-carbon alkyl group, a haloalkyl group, an alkoxyalkyl group, or a pinaneoxy group Alkyl, and R2! Is low carbon Alkyl group, from alkyl or alkoxyalkyl. Other preferred embodiments of the present invention are compounds of formula (I) or (II), where η is 0, R is -C (〇) 2-G, where G is hydrogen or a carboxy protecting group, and Z is -C Η 2-, R! Horse substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4--21-This paper is described in Sichuan China National Standard (CNS) A4 specification (210 × 297 mm) 552260 A7 B7 Part V. Description of the invention (19 oxophenyl, 3-fluorophenyl, 2-fluorophenyl, 3-qi-4-ethoxylactyl, 4-methoxymethoxymethoxyphenyl, 1,3-benzisodioxolanyl, 1,4-benzoxanthene, or dihydrobenzofuranyl, wherein the substituent is selected from the group consisting of a lower alkyl group, a fluorenyl group, Carbooxy, carbooxy, and alkylalkoxy, R2 is substituted or unsubstituted 1,3-phenylhydrazone dioxopentyl, 7-fluorenyl-1,3 -Benzo-dioxelenyl, 1,4-benzodiazinoyl, 8-methoxy-1,4-benzodihumidyl, dihydrobenzofuranyl, 4-methyl Oxyphenyl, dioxophenyl, fluorophenyl or difluorophenyl, wherein the substituent is selected from the group consisting of lower alkyl, alkoxy and halogen, and R3 is R4-C (0) -R5- , Where R5 is an alkylene group, and R4 is (RhKUN-, where Rh is an alkyl group, and Ri2 is selected from the group consisting of an aryl group, an amine alkyl group, a trialkylamine alkyl group, and a heterocyclic group. Other preferred specifics of the present invention Examples are compounds of formula (I) or (II), where η is 0, R is -C (0) 2-G, where G is hydrogen or a carboxy protecting group, Z is -CH2-, and h is a low carbon number Alkyl, alkenyl, heterocyclyl (alkyl), aryloxyalkyl, aralkyl, aryl, (N-alkanoyl-N-alkyl) aminoalkyl or alkylsulfonamidoalkyl And R3 is R4-C (〇) -R5-, where R5 is an alkylene group, and R4 is (Rn) (R12) N-, where Rn and R12 are selected from alkyl, aryl, and ash ,, Alkoxy, amine alkoxy, diylamino, and heteroalkyl group, the limitation is that one of R 1 1 and R 1 2 is an anti-group. Another preferred embodiment of the present invention is the formula (I ) Or (II), where n is 0, Z is -CH2-, and R3 is R4-C (〇) _R5-, where R4 is (Rn) (R) 2) N-, as defined above And R5 is an alkylene group. Other preferred embodiments of the present invention are compounds of formula (I) or (Π), where η is 0, Z is -CH2-, and R! Is Carbon alkyl, and R3 is R4- -99. This paper suitable scale power] Chinese National Standard (CNS) A4 size (_210X297 public spittle) (Please read the notes on the back of this page and then fill Φ set R52260 A7 B7

部 屮 • 失 乂; J f 合 五, Description of the invention (20C (0) -R5-, where R4 is (ΪΙη) (Ι112) N-, as defined above, and r5 is an alkylene group. Other preferred embodiments of the invention are compounds of formula (I) or (II), where η is 0, Z is -CH2-, Ri is alkenyl, and R3 is R4-C (0) -R5-, where r4 is (rh) (r12) n-, as defined above, and r5 is an alkylene group. Other preferred embodiments of the present invention are compounds of formula VII or (Π), where η is 0 and Z is -CH2-, Ri is heterocyclyl (alkyl), and R3 is R4-C (0) -R5-, where R4 is (RhKUN-, as defined above, and r5 is an alkylene group. Others of the invention The most preferred embodiment is a compound of formula (I) or (II), where η is 0, Z is -CH]-, Ri is an aromatic milk fe group, and R3 is R4-C (0) -R5-, where R4 Is (Rm) (R 丨 2) N-, as defined above, and r5 is a p-based group. Other preferred embodiments of the present invention are compounds of formula (I) or (II), where η is 0. , Z is -CH2-, Ri is an aromatic group, and R3 is R4-C (0) _R5-, where R4 is (Rn) (Ri2) N-, as defined above, and R5 is a server Alkyl · 3 Other preferred embodiments of the present invention are compounds of formula (I) or (II), where η is 0, Z is -CH:-,! ^ 1 is ^, and R4-C (0 )-R 5-, wherein R 4 is (Ru) (R12) N-, as defined above, and R 5 is an alkylene group 3 The most preferred embodiment of the present invention is formula (I) or (Π) Compounds, where η is 0, Z is -CH2-, and R! Is (N-alkanoyl-N-alkyl) aminoalkane 23- Λ4 specification f 210X297 mm) (Please read the precautions on the back before filling in this page) Γ552260 Α7 Β7 V. Description of the invention (21) group and R3 is R4-C (〇) -R5-, where r4 is (ru ) (r12) n-, as defined above, and R5 is an alkylene group. Other preferred embodiments of the present invention are compounds of formula (I) or (H), where η is 0 and Z is -CHr , Ri is an alkylsulfonamidoalkyl group, and R3 is R4-C (〇) -R5_ 'where R4 is (Ru) (r12) n-, as defined above, and R5 is elongation group. The speed of the rebels, the second speed, and the main i are ~ intermediate gray, the intermediates used. The present invention also relates to the need as here A method of 'anti-endothelin' in a mammal, preferably a human, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or (II). The present invention is more about endothelin antagonism A composition comprising a pharmaceutical carrier and a compound of formula (I) or (II) in a therapeutically effective amount. The compounds of the present invention include two or more asymmetric substituted hinders. As a result, racemic mixtures of compounds of the invention, mixtures of diastereomers, and single diastereomers are included in the present invention. n S " and " R " configuration, as defined by IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30. When the term "carboxy-protecting group" is used in wood, it means an ester group that protects a carboxylic acid and is used to block or protect the functionality of the carboxylic acid when reactions involving other functional parts of the compound are performed. In Greene, " Protective Groups in Organic Synthesis, " i52-1 86 (1981), it is disclosed that Fu Ji Baoji's choice is here for reference. In addition, -24- Zhang Jiandu Shi National Standard Cui (CNS) Λ4 Specification C 210X 297 ^ 1 ~ 1 (Please read the precautions on the back before filling this page)

Γ552260 A7 B7] < _τ a 卬 V. Explanation of the invention (22 Carboxyl protecting group is used as a prodrug, so that the carboxy protecting group can be easily cleaved in vivo. Parent. T. Higuchi and V. Stella provided a thorough discussion of the concept of prodrugs in Pro-drugs as Novel Delivery Systems ", ACS Symposium Series, Volume 14, American Chemical Society (1975). This is for reference. Such protective groups are known to those skilled in the art, and have been widely used in the field of cyanogenin and cephalosporins to protect carnosyl groups, as in US Patent Nos. 3,840,556 and The description in No. 3,719,667, the disclosure of which is incorporated herein for reference. An example of the @Target class used as a prodrug containing several groups of compounds can be found in MBioreversible Carriers in Drug Design: Theory and Application ", EB Roche Editor, Pergamon Press, New York (1987), pp. 14-21, incorporated herein by reference. Representative carboxy protecting groups are Ci to C8 alkanes (Such as methyl, ethyl, or third butyl and the like); haloalkyl; alkenyl; cycloalkyl and its substituted derivatives, such as cyclohexyl, cyclopentyl, and the like: Cycloalkyl, and its substituted derivatives, such as cyclohexylmethyl, cyclopentylmethyl, and the like; arylfe groups, such as phenethyl or hexyl, and their substituted derivatives, Such as oxoyl or nitrate and their analogs: aryl allyls, such as styryl and its analogs; aryls and their substituted derivatives, such as 5-hydrogen and its analogs; dife Fe group (such as dimethylaminoethyl and its analogs): alkanoyloxyalkyl, such as ethoxymethyl, butylmethyloxy, pentyloxymethyl, isopropyl Butanyloxymethyl, isoamylSioxymethyl, 1- (propylmethyloxy) -1-ethyl, 1- (trimethylethylgtoxy) -1 -ethyl, b 25-benzyl Paper size is suitable for Sichuan National Standard (CNS) Λ4 Specification C 210X 297 mm) A (Please read the precautions on the back before filling this page)

552260 A7 B7 V. Description of the invention (23) 1-1- (propanyl though oxy) -1-ethyl, trimethylethyl SS oxyfluorenyl, propyl SS oxyfluorenyl, and the like; naphthenes Alkoxyalkyl, such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxyfluorenyl, cyclopentylcarbonyloxyfluorenyl, cyclohexylcarbonyloxymethyl, and the like; arylfluorenyloxyalkyl , Such as benzamyloxymethyl, benzamyloxyethyl, and the like; aralkylcarbonyloxyalkyl, such as ammonium carbonyloxymethyl, 2-benzylcarbonyloxyammonium ethyl, and the like Alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, bumethoxycarbonyl-1-ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxy Methyl, tertiary-butoxycarboxyoxyfluorenyl, 丨 -ethoxyhexyloxyl-ethyl, 1-hexylmonomethyl * 1 * ethyl and its head analogs; Amine resistance groups such as second-butanylaminomethyl and the like: alkylaminocarbonylaminoalkyl groups, such as methylaminocarbonylaminomethyl and the like; alkanylaminoalkyl groups, such as Acetylaminomethyl and its analogs; heterocyclylcarbonyloxyalkyl, such as 4-methylhexahydropyridyl Oxymethyl and its analogs; dialkylaminocarbonylalkyl groups, such as diamidocarbonylcarbonyl, diethylaminocarbonylcarbonyl and co-analogs; (5-(low carbon number pit group) -2 -Oxo-1,3 -dilactenyl-4 -yl) alkyl, such as (5-third-butyl-2-oxo-1,3-dioxopenten-4-yl) methyl And its analogs: and (5-phenyl-2-oxo-1,3-dioxolen-4-yl) alkyl, such as (5-phenyl-2-oxo-1,3-di Oxypenten-4-yl) fluorenyl and its analogs.中 i: 4 丨 meaning {] h JT > /: combined (please read the notes on the back before filling this page) When using 'f N -protecting group "or" N -protected "in this article Words mean groups intended to protect the N-terminus of an amino acid or peptide, or to protect an amine group against unwanted reactions during synthesis. Frequently used N-protecting groups are disclosed in Greene, MProtective Groups In Organic Synthesis " (John Wiley & Sons, New York (1981)) ^ It is incorporated here as a decathlon. N-protecting groups include SS groups, such as formazanyl, ethylethyl, propyl-26-benzyl Paper size 迖 / 丨] National Standard (“like”) / \ 4 size [210 乂 297mm] 552260 A7 B7 屮 f Combined 5. Description of the invention Ethylethenyl, 2-chloroethenyl, 2-bromoethenyl, tris-acetic acid, trichloroethenyl, acetyl, o-nitrophenoxyethyl, α-chlorobutyryl, Phenylfluorenyl, 4-chlorophenylfluorenyl, 4-bromophenylfluorenyl, 4-nitrobenzyl, and the like; SS groups such as benzoic acid, p-toluenesulfonyl and Analogs; carbamoyl groups, such as fluorenyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxy Carbonyl, 3,4-dimethoxyfluorenyloxycarbonyl, 3,5-dimethoxyfluorenyloxycarbonyl, 2,4-dimethoxyfluorenyloxycarbonyl, 4-fluoromethoxyfluorenyloxycarbonyl, 2-nitro -4,5-dimethoxyfluorenyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenyl: methylethoxycarbonyl, α, α-dimethyl- 3,5 -dimethoxy + oxo, diphenylfluorenyloxy, di-butoxyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, fluorenyloxycarbonyl , Allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, gold steel alkoxy Carbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; alkyl groups, such as fluorenyl, triphenylfluorenyl, fluorenylmethyl, and the like; silyl groups, such as trimethylsilyl and the like The preferred N-protecting groups are formamyl, acetate, phenylamidine, SS, triamidine, and di-butyl. SS, sulfonylsulfonyl, benzyl, tert-butoxycarbonyl (Boc) and fluorenyloxycarbonyl (Cbz). When the term "alkanoyl" is used herein, it means an alkane as previously defined Group, attached to the parent molecular moiety through a carbonyl (-c (o)-) group. Chains> End Si: Examples of radicals include ethyl alcohol, propyl SS, and the like. When used herein The term "alkanoamido" means that an alkyl group is appended to an amine group as previously defined. Examples of alkanylamines include ethylamines, -27- this paper size 迖 / 丨] China National Standard (CNS) Λ4 specification f 210X 297 mm) (Read the precautions on the back before filling in this (Page 5) Description of the invention (25) Propylamino and its analogs. (Read the precautions on the back before you fill in this page.) When the term "alkanoaminoalkyl" is used in this article, it means R43-NH-R44-'where R43 is a 1-base bond and R 4 4 is a stretch gauge. When the term `` alkalkoxyalkyl '' is used herein, it means r30-o-R31-, where R3G is an alkanoyl group and R31 is an alkylene group. Alkanyloxyalkyl Examples of radicals include ethenyloxyethyl, ethenyloxyethyl, and the like. When the term "fluorenyl" is used herein, it means a straight or branched chain hydrocarbon group containing from 2 to 15 Carbon atoms, and also contains at least one carbon-carbon double bond. Examples of alkenyl include ethylammonium (ethenyl), amidino (propylamyl), butyl phenyl, 1-methyl-2-butan-1- And its analogs. When the term "alkenyl" is used herein, it means a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least One carbon-carbon double bond. Examples of fluorenyl include -CH = CH-, -CH2CH = CH-, -C (CH3) di-CH-, -CH2CHdi-CHCH2-, and the like. When used herein " The term "alkenyloxy" means that the alkenyl group is attached to the parent molecular moiety via a fluorenyl (-0-) linkage as described above. Examples of alkenyloxy include propylpropoxy, butoxy, and the like When in this article When the term "alkoxy" is used, it means R41o-, where R4i is a lower carbon alkyl group as defined above. Examples of alkoxy include, but are not limited to, ethoxy, tertiary-butoxy, and When used in this text, the term "tigoxy" is used to mean Rsq0-foot 81o- ', where foot 80 is a low carbon number stilbene group as defined above and Rsi Is an alkyl group. Representative examples of alkoxyalkoxy groups include alkoxy alkoxy, ethoxy methoxy, tri-butoxy fluorenyl and its rhyme 2-28- Zhang Zhishu State China National Standard (CNS) Λ4 specification (210X 297 mm) 552260 A7 B7 V. Invention description (26) (Please read the notes on the back before filling this page) When using "alkoxy" in this article Alkoxyalkylπ, when used, means that an alkoxyalkoxy group is appended to an alkyl group as previously defined. Representative examples of alkoxyalkoxyalkyl include methoxyethoxyethyl, methoxymethoxymethyl and the like. When the term `` alkoxyalkyl '' is used herein, it means that an alkoxy group as previously defined is appended to an alkyl group as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl Group, methoxyethyl group, isopropyloxy group, and the like. When the term "alkoxycarbonyl group" is used herein, it means that the tiger group as previously defined is attached to the parent molecule via a Tibetan group. In part. Examples of alkoxy groups include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like. When the term "alkoxycarbonylalkenyl" is used herein, it means as previously defined An alkoxycarbonyl group is attached to a fluorenyl group. Examples of alkoxycarbonylalkenyl include methoxycarbonylvinyl, ethoxycarbonylvinyl, and the like. When the term "alkoxycarbonylalkyl〃" is used herein , Means r34-C (〇) -R35-, where R34 is an alkoxy group and is an alkylene group. Examples of the alkoxycarbonylalkyl group include fluorenyloxymethyl, methoxycarbonylethyl, ethoxycarbonylfluorenyl, and the like. When the term "alkoxycarbonylaminoalkylπ" is used herein, it means Rw-C (0) -NH-R39-, where R3S is an alkoxy group, and R39 is an alkylene group. When used herein "Alkoxycarbonyloxyalkyl" means R36-C (0) -0-R37-, where R36 is alkoxy and R37 is alkylene. When the term "(alkoxycarbonyl) thioalkoxy" is used herein, it means an alkoxycarbonyl group, as previously defined, appended to a thioalkoxy group. (-29- This paper Appropriate scale / 彳] Chinese National Standard (CNS) Λ4 specification f 21〇X 297 public trend) 552260 ΑΊ Β7

lk 乂: J A India V. Description of the Invention Examples of (27 alkoxycarbonyl) thioalkoxy groups include fluorenylcarbonylthiofluorenyloxy, ethoxylated thiofluorinyloxy, and the like. When the term "alkoxydentyl" is used herein, it is meant a haloyl group to which a phenoxy group is attached. When the term "alkyl" and "low-carbon alkyl" is used herein, it means a straight or branched alkyl group containing from 1 to 15 carbon atoms, including but not limited to fluorenyl, ethyl Methyl, n-propyl, iso-propyl, n-butyl, iso-butyl, second-butyl, third-butyl, n-pentyl, 1-methylbutyl, 2,2-di Methylbutyl, 2-methylpentyl, 2,2-difluorenyl, n-hexyl and the like. When the term "(N-alkanoyl-N-alkyl) aminoalkyl" is used herein, it means R85C (0) N (R86) RS7-, where R85 is a chain as previously defined: ¾ The test group, R 8 6 is a low-end number pit group, and R 8 7 is an alkene group. When the term "alkylamino" is used herein, it means r51nh-, where r51 is a low-end number group. , Such as ethylamine, butylamine and the like. When the term "alkylaminoalkyl" is used herein, it means a lower carbon number alkyl group to which an alkylamino group is added. When the term "alkylaminocarbonyl" is used herein, it means that the alkylamino group, as previously defined, is attached to the parent molecular moiety through a carbonyl (-c (o)-) linkage. Examples of the amine amino group include amidino group, ethylamino group, isopropylaminocarbonyl group and the like. When the term "alkylaminocarbonylalkenyl" is used herein, it means an alkenyl group to which an alkylaminocarbonyl group is attached. When the term ' alkylaminocarbonylalkyl ' is used herein, it is meant that the amine amino group I is a low number radical. -30- The size of this paper is suitable / 彳] Chinese National Standard (CNS) A4 size (210 X 297 mm) (Please read the precautions on the back before filling this page) 5. Description of the invention (23) (Please read first Note on the back, please fill out this page again) When the term "alkylaminocarbonylaminoalkyl" is used in this article, it means r40-C (〇) -NH-R41-, where R40 is an amine group, and R41 For Yan Maoji. The term "alkylene" refers to a divalent group derived by removing two hydrogen atoms from a straight or branched saturated hydrocarbon having 1 to 15 carbon atoms, such as -CH]-, -CH2CH2 -, -CH (CH3)-, -CH2CH2CH2-, -CH2C (CH3) 2CH2-, and the like. When the term "alkylsulfonamidoalkyl" is used herein, it means R88S (〇) 2NHR89-, where R88 is a lower carbon number alkyl group, and R89 is an alkylene group. When used herein The term "alkylsulfoamido" means an alkyl group, as previously defined, appended to the parent molecule via a diamino group (-S (〇) 2-N Η-). Examples of fluorenyl groups include sulfenylamino, ethylsulfonylamino, isopropylsulfonamido, and the like. When the term "decyl" is used herein, it is meant to mean that Straight or branched hydrocarbon groups of 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of decisyl groups include-CeC-H, HC tri-C-CH], HC = C-CH (CH3 )-And its analogs "" alkynyl π-the word means by removing two from a straight or branched non-cyclic hydrocarbon group containing 2 to 15 carbon atoms and also a carbon-carbon triple bond A divalent group derived from a hydrogen atom. Examples of the extension group include -C three C-, -C three C-C Η 2-, -oc-ch (ch3)-, and the like. When the term "aminoalkyl" is used herein, it means -nh2, an alkylamino group or a dialkylamino group, attached to the parent molecular moiety through an elongation group. When used herein Aminocarbonyl π — when used, it means H2N-C (0)-. When the term "aminocarbonylalkenyl" is used herein, it means -31 added to it-Dimensions of this paper / 丨] Chinese National Standard (CNS) Λ4 specification (210X297 male f) 552260 A7 B7 V. Description of the invention (29) Alkenyl group of amine carbonyl (NH2C (0)-) hydrazone. When the term "aminocarbonylalkane" is used herein The term "oxy" means that h2n-c (o)-is appended to an alkoxy group as previously defined. Examples of aminoamino groups include aminocarbonylmethoxy, aminocarbonylethoxy, and Analogs. When the term "aminocarbonylalkyl" is used herein, it means a lower carbon number alkyl group to which an aminecarbonyl (nh2c (0)-) group is added. When used herein "trioxane" The term "aminoaminoalkyl" means (R90) (R91) (R92) N (R93)-, wherein R90, R91, and R92 are each selected from a low-carbon alkyl group, and R93 is a pendant group. When in As used in this article The term "alkylalkyl" means R32-C (〇) -〇-R33-, where R32 is aryl and R33 is alkylene. Examples of arylfluorenyl radicals include phenylfluorenylfluorenyl Benzyloxyethyl and its analogues. Part 屮. Mismatch 卬 (Please read the notes on the back before filling out this page} When the word "aryl π" is used in this article, it means having a Or a single or bicyclic carbocyclic ring system of two or more aromatic rings, including but not limited to phenyl, fluorenyl, tetrahydronaphthyl, hydroindenyl, indenyl, and the like. Aryl groups may be unsubstituted, Or use one, two, or three selected from the group consisting of fluorene, carbon, halogen, halo, halo, alkoxy, alkoxy, alkenyl, carboxy, oxo, alkoxy, and alkoxy Carbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl) thioalkoxy, thioalkoxy, amine, alkylamino, dialkylamino, amine alkyl, trialkylamine alkyl, amine carbonyl , Aminocarbonylalkoxy, alkanoylamino, aralkoxy, aryloxy, mirror group, cyano, nitro, carboxaldehyde, carboxyl, carboxyalkenyl, carboxyalkoxy, alkylsulfonyl Cyanane Substituents for phenyl, (heterocyclyl) alkoxy, mesyl, phenyl, alkoxy, oxo, and tetrakisoxy groups are taken from the national standard (CNS) in -32- Λ4 specification (2 × 297 mm) 552260 A7 B7 Part V. Invention description (30 generations. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl. When used herein "arene" The term "alkyl" means an alkenyl group having an aryl group attached thereto, such as styryl and the like. When the term "aralkoxy" is used herein, it means R420-, where R42 is an aralkyl group such as fluorenyloxy and the like. When the term "aralkoxyalkyl" is used herein, it means a lower carbon number alkyl group to which an aralkoxy group is attached, such as methyloxymethyl and the like. When the term "aralkyl" is used herein, it means that, as previously defined, an aryl group is desired to be added to a lower carbon number alkyl group, such as benzyl and the like. When the term "aryloxy" is used herein, it means R45O-, where R45 is an aryl group, such as phenoxy and the like. When the term "aralkylcarbonyloxyalkyl" is used herein, it means a low-end number resist group (that is, R7 2 C (Ο) -0) to which an arylalkyloxy group is added. -, Wherein R62 is an aralkyl group). The term "f'aryloxyalkyl" means an aryloxy group, as previously defined, appended to an alkyl group. Examples of aryloxyalkyl include phenoxyfluorenyl, 2-phenoxyethyl, and the like. When the term "complex π" is used herein, it means the phosphonate group '-C (〇) Η. When the term "complex" is used herein, it means the complex acid group, -C (0) 0H. When the term "carboxyalkenyl" is used herein, it means that a carboxyl group as previously defined is appended to an alkenyl group as previously defined. Examples of carboxyalkenyl include 2-carboxyvinyl, 3-carboxy-1-vinyl and the like. When the term "carboxyalkoxy" is used herein, it means that a carboxy group is added to an alkoxy group as previously defined. -33 of a carboxyalkoxy group National Standard (CNS) Λ4 specification (210X 297 feet) (Please read the precautions on the back before filling out this page) 552260 A7 B7 V. Description of the invention (31) Examples include leptoxy, ethoxy and the like Thing. (Please read the notes on the back before filling this page.) When the term "cyanooxy" is used in this article, it means an alkoxy group with a cyano (-CN) group attached to it. Examples of cyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like. When the term "cycloalkanoyloxyalkyl" is used herein, it is meant to append a cycloalkanoyloxy group (R60-C (〇) -〇-, where R60 is cycloalkyl ) Low carbon number alkyl. When the term "cycloalkylπ" is used herein, it means an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl , N-fluorenyl, gold steel alkyl, and the like. Cycloalkyl can be substituted, or one, two, or two selected from the group consisting of low-carbon alkynyl, 12-alkyl, alkoxy, and Substituted by oxo, amine, oxamine, dioxoamine, warpyl, halide, weyl, nitro, succinyl, carboxyl, oxo and carbamide. When the term "cycloalkylalkyl" is used herein, it means that a cycloalkyl group is added to a low-end number, including, but not limited to, cyclohexylfluorenyl. When used in this document " The term "amino" means R56R57N-, wherein R 5 6 and R 5 7 are each selected from a low alkyl group such as diethylamino, methpropylamine, and the like. When used herein "di When the term "amine group: radical" is used, it means a low alkyl group to which a dialkylamino group is added. When the term "dialkylaminocarboxyl" is used herein, it means Like the dialkylamino hydrazone previously defined, it is attached to the parent molecular moiety via a carbonyl (-C (O)-) linkage. Examples of the dialkylamino carbonyl include diamido carbonyl, diethyl paper The scale is applicable to Gion National Standard ([> ^) 8 specifications (210 to 297 mm) 552260 A7 B7 V. Description of the invention (32) Amino group and its analogs. (Please read the precautions on the back first (Fill in this page) When the term "dialkylaminocarbonyl" is used herein, it means a fluorenyl group appended with a dialkylamino #carbon group. When the term "dialkylamino-based alkyl" is used herein, it means 50-C (0) -R5I-, where R50 is a dialkylamino group and R51 is an alkylene group. When the term π halogen "or π halogen f 'is used herein, it means I, Br, C1, or F. When the term" dentenyl "is used herein, it means that at least one is appended thereto A fluorenyl group from a prime substituent. When the term "dentinoalkoxy" is used herein, it means an alkoxy group, as defined above, bearing at least one halogen substituent, such as 2-fluoroethoxy, 2,2,2 -Trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3-pentafluoropropoxy and the like. When the term `` haloalkoxyalkyl '' is used herein, it means a lower carbon number alkyl group to which a haloalkoxy group is added. When `` halohalo '' is used herein When it is used, it means a low carbon number alkyl group as defined above, such as chloromethyl, fluoroethyl, trifluoromethyl, or pentafluoroethyl, and the like, with at least one #thio substituent attached thereto. When the term "heterocyclic ring" or "heterocyclyl" or "heterocyclic" is used herein, it means any 3-or 4-membered ring containing a heteroatom selected from oxygen, nitrogen, and sulfur. ; Or it contains one, two, or three nitrogen atoms: one oxygen atom; one sulfur atom, one nitrogen, and one sulfur atom: one nitrogen and one oxygen atom; two oxygen atoms in a misaligned position: one oxygen atom Non-adjacent positions with one sulfur atom: or 5-, 6-or 7--35- two sulfur atoms at non-adjacent positions This paper is applicable to the national standard apple (CNS) Λ4 specification (210 × 297 public trend) 552260 屮 ίί ?! 卬

A7 B7 5. Invention description (33) Member ring. 5-membered rings have 0-2 double bonds, and 6- and 7-membered rings have 0-3 double bonds. If necessary, the nitrogen heteroatoms can be quaternized. The term "heterocyclyl" also includes bicyclic rings in which any of the above heterocyclic rings are fused to a benzene ring or a cyclohexane ring or other heterocyclic rings (such as indyl, dihydroindyl, 1 " Quei 4 Base, iso-4 ρ-based group, tetrahydro ρ-β-thyl phenyl group, tetrahydro-isopropyl phenyl group, deca-hydro quinyl group, deca-hydroisopropyl group, benzofuranyl group, dihydrobenzofuranyl group Or benzofluorenyl and its analogs). Heterocyclic groups include: aziridinyl, azetidinyl, pyrrolyl, P, P, linyl, P, pyrrolidyl,? Than Jiji, Eye P Linji, p Bijundian, Mi Bieji, Mi. Zhelinki, Mi Junxyl, Gorbityl, Hexahydrogen p than Gynyl, higher (h 〇m 〇) Hexahydrogen P than Gynyl, said ρ well base, hexahydro said π well base, shouting base, tower. Iridyl, oxazolyl, oxazolyl, isoxazolyl, isoxazolyl, morphyl, thiomorpholinyl, oxolinyl, oxazolyl, isoxazolyl, isoxazole Pyridyl, carbamoyl, glutamyl, isoamyl, phenylimidyl, benzamyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuryl, mouth plug Phenyl, 4-oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, hydrazyl, p-diphenyl, p-pyridyl, hydrazyl, and benzo-p-phenyl Phenylheterocyclyl also includes compounds of the formula °, where X is -CH2- or -O- and is -C (O)-or [-C (R ") 2-] v, where Rn is hydrogen or Ci -O alkyl, and v is 1, 2 or 3, such as 1,3-phenylhydrazone dioxolyl, 1,4-phenylbioxalate, and the like. Heterocyclyl is also Including bicyclics, such as quinacridyl and its analogs. Heterocyclic groups can be unsubstituted or selected from hydroxyl, nansin, and -36- This paper is in accordance with China National Standard for China Net (CNS) A4 specifications (210 X 297) ((Please read the notes on the back before filling out this page) 552260 A7 B7 V. Invention Ming (34) oxo (= 0), alkylimine (R < N two, where R # is a lower carbon number alkyl), amine, alkylamino, dialkylamino, alkoxy, alkyl Oxyalkoxy, amine alkyl, trialkylamino, sulfanyl, cycloalkyl, aryl, aromatic, -COOH, -S03H, alkoxycarbonyl, nitro, cyano, and low carbon The alkyl group may be mono- or di-substituted. In addition, the nitrogen contained in the heterocyclic group may be N-protected. When the term "(heterocyclyl) alkoxy" is used herein, it means A heterocyclic group as defined above is appended to an alkoxy group as defined above. Examples of (heterocyclyl) alkoxy include 4-pyridylmethoxy, 2-pyridylfluorenyl and the like. When the term "(heterocyclyl) alkyl" is used herein, it means that a heterocyclyl group as defined above is appended to a lower carbon number alkyl group as defined above. When the term "heterocyclylcarbonyloxyalkyl" is used herein, it means R46-C (0) -0-R47-, where R46 is a heterocyclyl and R47 is an alkylene. When the term "hydroxy" is used herein, it means -OH. When the term "hydroxyalkenyl" is used herein, it means an alkenyl group to which a hydroxyl group is attached. When the term "hydroxyalkoxy" is used herein, it means an alkoxy group to which a hydroxy (-OH) group is added as previously defined. Examples of hydroxyalkoxy include 3-¾propoxy, 4-transbutoxy and the like. When the term "hydroxyalkyl" is used herein, it means a lower carbon number alkyl group to which a hydroxyl group is added. When the term "release group" is used herein, it means halogenation (Such as C1, Br, or I), or sulfonate (such as sulfonate, toluene sulfonate, Sanqi -37- This paper is suitable for 1¾ national standard vehicles (CNS) in the state of Λ4 size C 210X 297 mm) Please read the notes on the back before filling out this page 1 #

, 1T Φ—— 552260 Description of the invention (35 A7 B7 dibasic acid salts and their analogs). ^ In this article, when making Zhou "tieji"-the word, it means _sh. When the terms "fluorenylenedioxy" and "ethylenedioxy" are used, the sound refers to two sub-chains of the field f, attached by two oxygen atoms to the parent molecular moiety; In the example, a fused 5-membered ring is formed. In the case of ethylene dioxy, a fused 6-membered ring is formed. Substituting methylenedioxy on a stupid ring results in a benzene ring Formation of oxocyclopentyl group] Wp0 on the benzene ring. 0. LA0 replaces ethylene dioxy, resulting in the formation of phenylarbiinolyl alkyl group. When used herein "substantially" The term means 95% or more of the specified compound. Η. Λ a compound (please read the precautions on the back before filling this page)

As used herein, the term "quaternary" is a radical, or a tautomer thereof. When the term "tetrazolylalkoxy" is used herein, it means that a tetrazolyl group as defined above is appended to an alkoxy group as defined above. Examples of tetrazolylheptyloxy include tetrazolyloxy, tetrazolylethoxy, and the like. When the term "thioalkoxy" is used herein, it means R70s'_, Its _R70 is a low carbon number base. Examples of thioalkoxy include, but are not limited to, methylthioj, ethylthio, and the like. When the term "thioalkoxyalkoxy" is used in this article, the tone refers to the formula -38- National Standard for Valves (CNS) Λ4 Specification (210 X 297 cm) 552260 A7 B7 V. Description of the invention (36

Rsi0-, where Rs0 is a low-carbon radical as defined above, and is an alkylene group. Representative examples of thioalkoxyalkoxy include CH3SCH20-, EtSCH20-, t-BuSCH20- and the like. When the term "thioalkoxyalkoxyalkyl" is used herein, it is intended to mean that the alkoxy group is attached to an alkyl group. Representative examples of thioselectoxyalkoxyalkyl include (: Η35 (: Η2 (: Η2〇 (: Η, <: 1 · ί2_, CH3SCH2OCH2-, and the like. When used herein) The term "reverse, reverse" means the orientation of the substituents (I and R2) relative to the R of the central substituent as shown R2i R Λ〆

R1 Z \ / R3 NI (PH2) n When the term "trans, cis" is used herein, it means a substituent as indicated by the orientation of (Ri and R2) relative to the central substituent R (read first read Note on the back, please fill out this page) — 0 Order

R \ ^ * \ ^ ΡΗ2) π R1 R3I (? Η2) η or

Ri. This definition includes two cases where R and trans 2 are cis and R and R! Are anti, and R2 and R are anti, and R and Rl are ci. When the term "cis'cis" is used herein, it means the position of the currency + substituents d and R2) relative to the central substituent R -39- This paper is sized / 丨] China National Standard 隼(CNS) Λ4 specification "210X 297 male 牦" 552260 A7 B7 V. Description of the invention (37) R2 々YA Z \ n / R3 (Please read the precautions on the back before filling this page) ^. Preferred compounds of the present invention Is selected from the group consisting of: trans-trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- [3- (N- Propyl-N-n-pentylamino) propyl] -p-bilodine- ^ acid; trans, trans-2 · (4-methoxymethoxyphenyl) -4- (1,3- Benzo metadioxol-5-yl) -1- [2- (N-propyl-N-n-pentanesulfonamido) ethyl] -pyrrolidine-3-carboxylic acid; trans , Trans-2- (3,4-dimethoxyphenyl) -4- (1,3-benzo-dioxol-5-yl) -1- [2- (N-propyl- N-n-pentanesulfonamido) ethyl] -pyrrolidine-3-carboxylic acid: trans, trans-2- (3,4-dioxophenyl) -4- (1,3-benzene Bis-dioxol-5-yl) -1- [2- (N-propyl-N-n-hexanesulfonamido) ethyl] -pyrrolidine-3-benzyl, trans, trans -2- (4-propoxyphenyl) -4- (l 3-benzene # metadioxol-5-yl) -1- [2- (N-propyl-N-n-pentanesulfonamido) ethyl] -pyrrolidine-3-carboxylic acid : Trans, trans-2- (3,4-difluorophenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- [N, N-bis (n -Butyl) aminocarbonylmethyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (3,4-difluorophenyl) -4- (1,3-benzo-dioxane En-5-yl) -1- [2- (N-propyl-N-n-pentanesulfonamido) ethyl] -pyrrolidine-3-carboxy-40-Dimensions of this paper / 彳] China National Standards (CNS) A4 Specification "210X 297 Gm" 552260 A7 B7 V. Description of the Invention (38) Acid; trans, trans-2- (3-fluoro-4-oxophenyl) -4- (1 , 3-phenylhydrazone dioxol-5-yl) -1- [2-@-propyl-! ^-N-hexanesulfonamido) ethyl] -pyrrolidine-3-role § Father, trans, trans-2- (3-fluoro-4-methoxyphenyl) -4- (1,3-benzo-dioxol-5-yl) -1- [2- (N-propyl-N- (3-chloropropanesulfonyl) amino) ethyl] -pyrrole-3-caused by the parent; trans, trans-2- (3-fluoro-4-methoxyphenyl ) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- [2- (N-isobutyl-N- (3-chloropropanesulfonyl) amine ) Ethyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (3-fluoro-4-methoxyphenyl) -4- (1,3-phenylhydrazine-5 -Yl) -1- [2- (N-propyl-N- (4-methylbutanesulfonyl) amino) ethyl] -pyridine, each bite-^-several, trans, trans-2 -(4-methoxy-3-fluorophenyl) -4- (7-methoxy-1,3-phenylhydrazinedioxol-5-yl) -1- [2- (Ν -Propyl-N- (n-pentanesulfonyl) amino) ethyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (3-fluoro-4-methoxyphenyl) -4 -(1,3-benzo-dioxol-5-yl) -1- [2- (N-propyl-N- (252,3,3,3-pentafluoropropoxyethane Sulfonyl) amino) ethyl] -pyrrolidin-3-carboxylic acid; trans, trans-2- (1,4-phenylhydrazone-6-yl) -4- (7-fluorenyloxy -1,3-phenylhydrazone dioxol-5-yl) -1- [2- (N-propyl-N- (n-pentanesulfonyl) amino) ethyl]-? Than p each bite-^-ene fei; trans, trans-2- (3-fluoro-4-fluorenyloxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- [2- (N-isobutyl-N-pentanesulfonamido) ethyl] -pyrrolidine-3--41-This paper uses the Chinese National Standard (CNS) Λ4 specification (' 2IOX 297 mm) (Please read the back Please fill in this page on the matter of interest 11 ilgi r ——- · order it --- --- ij 552260 A7 B7 V. Description of the invention (39) Carboxylic acid; trans, trans-2- (3-fluoro-4- Phenoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- [2- (N- (2-methoxyethyl) -N- (3- Chloropropanesulfonyl) amino) ethyl]-? Billot bite-: > -Po § Ai; trans, trans-2- (3-fluoro-4-oxophenyl) -4- (1, 3-Benzamidine-dioxolane # -5-yl) -Bu [2- (N- (2-methoxyethyl) -N- (pentanesulfonyl) amino) ethyl] -pyrrole Pyridin-3-carboxylic acid; trans, trans-2- (3-fluoro-4-fluorenyloxyphenyl) -4- (1,3-phenylhydrazinedioxol-5-yl) -1- [2- (N-propyl-N-((2,2,2-trifluoroethoxyethane) sulfonamido) amino) ethyl l. Pyrrolidine-3-carboxylic acid; trans, trans- 2- (3-fluoro-4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- [2- (N- (2-methoxy Ethyl) -N- (butanesulfonamido) ethyl] -pyrrolidin-3-zanoic acid; trans, trans-2- (3-fluoro-4-oxophenyl) -4- (1 , 3-phenylhydrazone dioxol-5-yl) -1- [2- (N-propyl-N- (2-fluorenylpropanesulfonyl) amino) ethyl] -pyridine Each bite -3-get acid ; Trans, trans-2-(3 -fluoro-4 -fluorenyloxyphenyl) -4-(1,3 -phenylhydrazone dioxolyl every 7-5-yl)-; ί- [2- ( N-isobutyl-N- (butanesulfonamido)) ethyl] -pyrrolidin-3-carboxylic acid; trans, trans-2- (2-fluorenyl) -4- (1,3- Phenylhydrazone dioxane'-5 -ylbis (n-butyl) aminocarbonylmethyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2,2-dimethylpentyl ) -4- (1,3-Benzamidine dioxol-5-yl) -1- [N, N-di (n-butyl) aminocarbonylmethyl] -pyrrolidine-3-carboxyl Acid: trans, trans-2- (2- (1,3-dioxol-2-yl) ethyl) -4- (1,3-benzyl-42- ] Zhongyuan National Standard (CNS) Λ4 specification f 210 X 297 mm) (Please read the notes on the back before filling in this page__ 丁, y5 552260 A7 B7 V. Description of the invention (4〇) Dioxane Cyclopentyl-5-yl) -1- [N, N-di (n-butyl) aminocarbonylfluorenyl] -ρ ratio ρ each syndrome -3-lean theory; trans, trans-2_ (2- (2 -Tetrahydro-2'-piranyl) ethyl) -4- (1,3-benzo-dioxol-5-yl) -1- [N, N-bis (n-butyl) amine Carbonylmethyl] -pyrrolidin-3-carboxylic acid; trans, trans-2- (2 , 2,4-trimethyl-3-fluorenyl) -4- (1,3-benzobenzodioxol-5-yl) -1- [Ν, Ν-bis (n-butyl ) Aminocarbonylfluorenyl] -pyrrolidin-3-carboxylic acid; trans, trans-2- (2- (2,2-difluorenyl-2- (1,3-dioxolane-2-yl) Ethyl) _4- (i, 3-phenylhydrazine-5-oxen-5-yl) -1- [N, N-di (n-butyl) aminomethyl]-? Ratio p Each disease-3-acid acid; trans, trans-2- (2- (1,3-m-dioxol-2-yl) ethyl) -4- (1,3- -m-dioxo Heterocyclopenten-5-yl) -1-[[N-4-heptyl-N- (2-fluorenyl-3-fluorophenyl)] aminocarbonylfluorenyl] -pyrrolidine-3-carboxylic acid; Trans, trans-2- (2- (1,3-dioxo-2-enyl) ethyl) -4- (7-fluorenyloxy-1: 3-phenylhydrazine dioxane Pentamidine '-5 -yl) -1-[N, N -bis (n-butyl) aminocarbonylmethyl] -pyrrolidine-3-carboxylic acid: trans, trans-2-((2-methoxybenzene (Oxy) -methyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -i- [N, N-di (n-butyl) aminocarbonylmethyl]- Pyrrolidine-3-carboxylic acid; (28: 311,48) -2- (2,2-Difluorenyl) -4- (1,3-phenylhydrazone dioxol-5-yl ) -I- [N-4 -heptyl-N- (4-fluoro-3-tolyl) Hiddenylmethyl]-Qiao A A seal (please read the precautions on the back before filling in this page) u_ ^ * Not selfish, anti, anti-2- (2- (2- -oxobiha bite- i-based) ethyl) -4- (1,3-Minamiji-43) The paper size is Shizhou Standard (CNS) Λ4 Specification C210 乂 297 male Zhao): '屮 次 IV: ftx-XJvI : 552260 A7 B7 V. Description of the invention (41) Oxetene-5-yl) -1- [N, N-di (n-butyl) aminocarbonylmethyl] -pyrrole-a few; trans, trans -2- (2- (1,3-m-dioxol-2-yl) ethyl) -4- (7-fluorenyl-], 3-benzyl-dioxolane- 5-yl) -1- [N-4 -heptyl-N- (4-fluoro-3-tolyl) aminocarbonylmethyl] -pyrrolidin-3-carboxylic acid; trans, trans-2- (2, 2-Dimethylpentyl) -4- (7-methoxy-1,3-benzo-dioxol-5-yl) -1- [N, N-bis (n-butyl) Aminocarbonylfluorenyl] -pyrrolidin-3-carboxylic acid; trans, trans-2- (2,2-dimethylpentyl) -4- (2,3-dihydrophenylfluoren-5-yl)- 1- [N, N-bis (n-butyl) aminocarbonylfluorenyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2,2-dimethyl-2- 2- (1,3- Dioxolane-2 -yl) ethyl) -4- (7-fluorenyl-1,3-furan Cyclopenten-5-yl) -1- [N, N-bis (n-butyl) aminocarbonylfluorenyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (2-methyl Oxyphenyl) ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- [N, N-di (n-butyl) aminocarbonylmethyl]- Pyrrolidine_3-carboxylic acid; trans, trans-2- (2,2-difluorenyl-3- (E) -pentanylτyl) -4- (7-fluorenyloxy-1,3-benzenel Inter-dilactate heteropentaminyl-5-yl) -1- [N, N -— (n-butyl) amine non-volume nail volume] -said bite-3-acid: trans, trans-2- (2- (2-pyridyl) ethyl) -4- (1,3-benzo-dioxol-5-yl) -1- [N, N-bis (n-butyl) amine Carbonylmethyl] -pyrrolidin-3-carboxylic acid: (2S, 3R, 4S) -2- (2- (2-oxopyrrolidin-1-yl) ethyl) -4- (1,3-benzene Benzodioxane-5-yl) -1- [Bing 1 \ 1 bis (n-butyl) amine carbonyl fluorenyl group? Bi ρ each eat -3 -Cause: -44-Tai paper music Dimension description / 丨] China Garden Standard (CNS) Λ4 specification (210 X 297 cm) (Please read the precautions on the back before filling this page)

552260 Part A7 B7 and Part V. Description of the Invention (42 (2S, 3R, 4S) -2- (2- (2-oxopyrrolidine-phenyl) ethyl) -4- (1,3-phenylhydrazone M-dioxol-5-yl) -1- [N-4 -heptyl-N- (4-fluoro-3 · fluorenyl) amidomethyl] p-bilodine-3-induced Acid; trans, trans-2- (2- (1-pyrazolyl) ethyl) -4- (1,3-benzobenzodioxol-5-yl) -1- [Ν, Ν -Bis (n-butyl) aminocarbonylfluorenyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxane Cyclopenten-5-ylbutyl-N- (4-diamidinobutyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; (23,311,45) -2- (3-fluoro -4-fluorenoxyphenyl) -4- (153-phenylhydrazone dioxol-5-yl) -1- [2- (N-propyl-N-pentanesulfonamido) ethyl Yl] -pyrrolidin-3 -acid; trans, trans-2- (2,2-xylyl) -4- (1,3-benzo-dioxol-5-yl) -1 -[(N-butyl · N- (4-dimethylamino) butyl) aminocarbonylfluorenyl] -pyrrolidine-3-carboxylic acid: trans, trans-2- (2,2-difluorenylphenyl) ) -4- (7-fluorenyl-1,3-phenylhydrazone dioxol-5-yl) -1- [N-4-heptyl-N- (4-fluoro-3 -toluene ) Aminocarbonyl Methyl] -bit ratio 17 each bite-)-belief, trans, trans-2- (2,2-difluorenylphenyl) -4- (7-fluorenyl-1,3-phenylhydrazine Oxeten-5-yl) -1-[(N-butyl-N- (4-dimethylamino) butyl) aminocarbonylmethyl] -p than p each bit-)-ren ; Trans, trans-2- (2,2-dimethylpentan-3-enyl) -4- (1,3-diisolactam heteropentapentyl-5 -yl) -1- [Ν- 4 -heptyl-N- (4-fluoro-3-tolyl) amine hidden methyl] -Qiaodiaodong-3 -Acid: trans, trans-2- (2,2-dimethylpentyl-yl ) -4- (1 to make up one oxygen (although 戌 衣 戌 -45- this paper size Chuchuan Zhongwei National Standard (CNS) Λ4 specification C 210X 297 mm) (Please read the precautions on the back before filling in this Page) 552260 A7 B7 V. Description of the invention (43) En-5-yl) -1-[(N-butyl-N- (4-diamido) butyl) aminocarbonylfluorenyl] -pyrrolium · 3-Chinoic acid; trans, trans-2- (2,2-dimethylpent-3-yl) -4- (7-methoxy-1,3-benzobenzodioxolene- 5-yl) -1- [N, N-bis (n-butyl) aminocarbonylfluorenyl] •• pyrrolidine-3 -chinic acid; trans, trans-2- (2,2-difluorenyl-3 -Alkenyl) -4- (7-fluorenyl-1,3-phenylhydrazone dioxol-5-yl) -1-[(N-4-heptyl-N- (4-fluoro-3 -fluorenyl)) aminocarbonylmethyl] -p bilobita-3-several; trans, trans-2- (2 di Methylpent-3-enyl) -4- (7-methoxy-1,3-phenylhydrazone dioxol-5-yl) -1-[(N-butyl-N- (4 -Dimethylamino) butyl) aminocarbonylmethyl] -p-pyrrolidine-3 _-acid; trans, trans-2- (2,2,4-trifluoren-3-enyl) -4- (1,3 -Pri-m-dioxopentene-5-yl) -MN-4-heptyl-N- (4-fluoro-3 -fluorenyl) aminocarbonylmethyl] -erroline- 3-double acid; trans, trans-2- (2,2,4-triamyl-3-enyl) -4- (1,3-phenylhydrazine dioxol-5-yl)- 1-[(N-butyl-N- (4-diamido) butyl) aminocarbonylmethyl] -carbohydrate-3-polyacid; a and hf: AA 1 (please first Read the notes on the back and fill in this page again} trans, trans-2- (2,2,4-trimethylpent-3-enyl) -4- (7-fluorenyl-1,3-phenylhydrazine dioxo Heteropentene-5-yl) -1- [N, N-di (n-butyl) aminocarbonylfluorenyl]-呲 p each bite -j -rebel; trans, trans-2- (2, 2,4-trimethylpent-3-olyl) -4- (7-methoxy-1,3-benzene # m-dioxol-5-yl) -1- [N-4-heptyl -N- (4-fluoro-3 -tolyl) aminocarbonyl Vol] -p ratio ρ each bite -3-rebel | father; trans, trans-2- (2,2,4-triamyl-3-propenyl) -4- (7-methoxy-1,3 -豕 开 _ -46- The size of this paper is described in the Central Sichuan 1¾ National Standard (CNS) Λ4 Specification Γ210 × 297 mm) 552260 A7 B7 Jk f: A ii In the fifth, the description of the invention (44 Dioxolene-5 -Yl) -l-[(N-butyl-N- (4 · dimethylamino) butyl) aminocarbonylmethyl] -Pycnogenol-3 -chinic acid; trans, trans_2- (2- (1,3_m-dioxolen-2-yl) ethyl) -4- (1,3_phenylmethylene-dioxol-5-yl) -1-[(N-but -N- (4-dimethylaminobutyl) amino) carbonylfluorenyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (1,3-dioxolan Alkenyl-2-yl) ethyl) -4- (7-fluorenyloxy-U3-phenylhydrazone dioxol-5-yl)-: l-[(N-butyl-N- (4 -Diamidoaminobutyl) amino group) fluorenyl group] Kyodo-3-Gu § text; trans, trans-2- (2,2-difluorenyl-2- (1,3-dioxo Cyclopentenyl) ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1-[(N-4-heptyl-N- (4-fluoro-3 -Tolyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2,2-diamidino-2- (1,3-dioxo Cyclo-2-yl) ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1-[(N-butyl-N- (4-dimethylamino Butyl) amino) carbonylmethyl l-pyrrolidin-3-carboxylic acid, trans, trans-2- (2,2-dimethyl-2- (1,3-didioxolene- 2-yl) ethyl) -4- (7-methoxy-1,3-phenylhydrazone-dioxol-5-yl) -1- [N-4-heptyl-N- (4 -Fluoro-3-fluorenylphenyl) aminocarbonylfluorenyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2,2-dimethyl-2- (1,3-dioxolane- 2-yl) ethyl) -4- (7-methoxy-1,3-benzyldioxol-5-yl) -1-[(N-butyl-N- (4- Dimethylaminobutyl) amino) Talk volume]-? Than bite -3-polyacid; trans, trans-2- (2- (2-methoxy allyl) ethyl) -4- (1 , 3 -Hundred and one-oxygen radicals ('G-5-yl) -1-[N-4-heptyl-N- (4-murine-methanyl) version of the methyl group] * pyrrolidine -3-carboxylic acid; trans, trans-2- (2- (2-fluorenyloxyethyl) ethyl) -4- (1,3-phenylhydrazone dioxane 47 This paper is suitable for Sichuan 1¾¾ standard Ping (CNS) Λ4 specification (210 乂 297 mm) (Please read the notes on the back before filling out this page) 552260 A7 B7 V. Description of the invention (45 pentene-5-yl -1-[(N-butyl-N- (4-dimethylaminobutyl) amino) carbonylfluorenyl] -carbohydrate-3 -chinic acid; trans, trans-2- (2_ (2 -Methoxyphenyl) ethyl) -4- (7-fluorenyl-1,3-benzene # m-dioxol-5-yl) -1- [N, N-bis (n-butane ) Aminocarbonylmethyl] -pyridine, 3-methyl; trans, trans-2- (2- (2-methoxyphenyl) ethyl) -4- (7-fluorenyl-1,3 -Phenylhydrazine-5-yl) -1- [N-4-heptyl-N- (4-fluoro-3 -tolyl) aminocarbonylmethyl] -p Bija syndrome-3 -Beta: trans, trans-2- (2- (2-methoxyphenyl) ethyl) -4- (7-methoxy-1,3-phenylhydrazone dioxol-5-yl ) -1-[(N-butyl-N- (4-diamidinobutyl) amino) fluorenyl]-? Biharto * 3 -acid; trans, trans-2-((2 -Methoxyphenoxy) -methyl) -4- (1,3-phenylhydrazone dioxol-5-ylheptyl-N- (4-fluoro-3 -tolyl) amino) Carbonylfluorenyl] -pyrrolidine-3- double acid: trans, trans-2-((2-fluorenoxyphenoxy) -methyl) -4- (1,3-phenylhydrazine dioxolane Alken-5-yl) -1-[(N-butyl-N- (4-dimethylaminobutyl) amino) carbonylmethyl] -indigo 17 each bite-3-carboxylic acid: 〆: south . Medium-λ (Please read the back first Note that please fill in this page again) trans, trans-2-((2-methoxyphenoxy) -fluorenyl) -4- (7-fluorenoxy-1,3-phenylhydrazine dioxolene -5-yl) -1- [N5N-bis (n-butyl) aminocarbonylmethyl] -pyrrolidine-)-rejection; trans, trans-2-((2-fluorenoxyphenoxy)- Methyl) -4- (7-methoxy-1,3-phenylhydrazone dioxol-5-yl) -1-[(N-4-heptyl-N- (4-fluoro- 3-tolyl) amino) carbonylmethyl l-pyrrolidin-3-carboxylic acid; trans, trans-2- (2- (2-methoxyphenoxy) -methyl) -4- (7-methyl Oxy-U3-Benzene 48-This paper is based on the National Standard of the Central Park (CNS) 8-4 specification (2 丨 0 乂 297 mm) 552260 A7 B7 V. Description of the invention (46) (Please read the note on the back first Matters need to be refilled on this page) m-dioxol-5-yl) -1-[(N-butyl-N- (4-dimethylaminobutyl) amino) fluorenyl] ** p Bihadian-3-acidogenic; trans, trans-2- (2- (2-oxo-1,2-dihydro. Specific bite-1-yl) -ethyl) -4- (1,3-benzo-dioxol-5-yl) -1- [N, N-di (n-butyl) aminocarbonyl Fluorenyl] -pyrrolidin-3-chinic acid; trans, trans-2- (2- (2-oxopyridine-1-yl) -ethyl) · 4- (1,3-phenylhydrazine dioxo Heteropentyl-5-yl) -1-[(N-4 -heptyl-N- (4-fluoro-3-tolyl) amino) post-methyl] -Sortoline-3 -acidic acid; Trans, trans-2- (2- (2-oxopyridine-1-yl) -ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl)-: l- [(N-butyl-N- (4-dimethylaminobutyl) amino) carbonylfluorenyl] -tap. Each bite -3-thin; trans, trans-2- (2- (2- (oxo-ratio-1-yl) -ethyl) -4- (7-methoxy-1,3-phenylhydrazone M-dioxol-5-yl) -1-[(N, N-bis (N-butyl) aminocarbonylfluorenyl] • pyrrolidine-3-carboxylic acid; trans, trans-2- (2 -(2-oxo-p-ratio-1-yl) -ethyl) -4- (7-methoxy-1,3-benzo-dioxol-5-yl) -1- [ (N-4-heptyl-N- (4-fluoro-3 -tolyl) amino) Tibetan vol.]-P than each way -3 -reversion; trans, trans-2- (2- (2 -Oxo-p-ratio-1-yl) -ethyl) -4- (7-methoxy-1; 3-benzo-dioxol-5-yl) -1-[(N- Butyl-N- (4-diamidoaminobutyl) amino) carbonylamido l. Pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (2-oxohexahydro-pair 1: -1--1-yl) -ethyl) -4- (1,3-phenylhydrazine-5-oxo-5-yl) -1-[(N, N-di (n-butyl) aminecarbonyl Methyl] -pyridine-3-no; trans, trans-2- (2- (2-oxohexahydropyridine-butyl) -ethyl) -4- (1,3-phenylamidine- 49- The size of this paper conforms to the Chinese National Standard (CNS) Λ4 specification [210 X 297 gong] 5. Description of the invention (47) (Read the precautions on the back before reading the copy ) Dioxol-5-yl) -1-[(N-4-heptyl-N- (4-fluoro-3 -fluorenyl) amino) carbonylfluorenyl] -pyrrolidine-3 -Carboxylic acid; trans, trans-2- (2- (2-oxohexahydropyridin-1-yl) -ethyl) -4- (7-methoxy-1.3-phenylhydrazone dioxolane Alken-5-yl) -1-[(N, N · -bis (n-butyl) aminocarbonylfluorenyl] -r-pyrrolidine-3 -acid; trans, trans-2- (2- (2 -Oxohexahydroρ ratio lake-1-yl) -ethyl) -4- (7-methoxy-1,3-phenylhydrazone dioxolidine-5-yl) -1-[( N, N-di (n-butyl) aminocarbonylfluorenyl] -p-Bilolide-3 -drum acid; trans, trans-2- (2- (2-oxohexahydropyridin-1-yl)- Ethyl) -4- (7-methoxy-1.3-phenylhydrazone dioxol-5-yl) -1-[(N-4-heptyl-N- (4-fluoro-3- Fluorenyl) amino) carbonylfluorenyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (2-oxohexahydroρ than 1-1-yl) -ethyl) -4 -(7-fluorenyloxy-1.3-benzo-dioxol-5-yl) -1-[(N-butyl-N- (4-dimethylaminobutyl) amino) carbonyl Fluorenyl] -pyrrolidin-3-carboxylic acid; trans, trans-2- (2- (2-oxo-1-yl) -ethyl) -4- (1,3-epi-dioxane Heterocyclopenten-5-yl) -1-[(N-butyl-N- (3- Propyl) amino) carbonyl methyl] - opening ratio. Each bite-^-metanoic acid; trans, trans-2- (2- (2-oxopyrrolidin-1-yl) -ethyl) -4- (1,3-benzo-dioxane -5-ylbutyl-N- (propyl) amino) carbonylmethyl] -pyridine-3 -acid: trans, trans-2- (2- (2-oxopyrrolidin-1-yl) ) -Ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1-[(N-butyl-N- (4-dimethylaminobutyl) amine ) Carbonylcarbonyl] -pyrrolidin-3-carboxylic acid: trans · trans-2- (2- (2-oxopyrrolidin-1-yl) -ethyl) -4- (1,3-phenylbenzene Jianer-50-50- This paper uses the national standard (CNS) Λ4 specification C 210X 297 while taking advantage of 552260; f: again in the ministry;] ii 1 '卬 A7 B7 V. Description of the invention (48 oxygen Heterocyclopenten-5-yl) -1-[(N-butyl-N- (4 · trimethylammonylbutyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; trans, trans -2- (2- (2-oxopyrrolidin-1-yl) -ethyl) -4- (7-fluorenyloxy-1,3-phenylhydrazine dioxol-5-yl) -1- [N, N-bis (n-butyl) aminocarbonylfluorenyl] -ρbilodine-3-not § parent; trans, trans-2- (2- (2-oxopyrrolidine-1) -Yl) -ethyl) -4- (7-methoxy-1,3-phenylhydrazone-dioxol-5-yl) -bu [(N-butyl-N- (3-hydroxypropyl) amino) carbonylfluorenyl] -pyrrolidine-3-carboxylic acid; trans, trans 2- (2- (2-oxo-glyo-1 -Yl) -ethyl) -4- (7-methoxy-1,3-phenylhydrazone dioxol-5-yl) -1-[(N-4-heptyl-N- ( 4-fluoro-3 · tolyl) amino) carbonylmethyl] -pyrrolidin-3-carboxylic acid; trans, trans-2- (2- (2-oxopyrrolidin-1-yl) -ethyl) -4- (7-fluorenyloxy-I, 3-phenylhydrazone dioxopent-5-yl) -1-[(N-butyl-N- (propoxy) amino) carbonylfluorene ] -Pyrrolidin-3-carboxylic acid: trans, trans-2- (2- (2-oxopyrrolidin-1-yl) -ethyl) -4- (7-fluorenyl-1,3- Phenylhydrazine-5-yl)-[[N-butyl-N- (4-diamidoaminobutyl) amino) carbonylmethyl] -pyrrolidine-3-carboxy Acid: trans, trans-2- (2- (2-oxopyrrolidin-1-yl) -ethyl) -4- (7-methoxy-1,3-phenylhydrazine dioxolene -5-yl) -1-[(N-butyl-N- (4-trimethylammonylbutyl) amino) carbonylfluorenyl l · pyrrolidine-3-carboxylic acid; trans, trans-2- (2 -(2-oxopyrrolidin-1-yl) -ethyl) -4- (2,3-dihydrobenzofuran-5-yl) -1- [N, N-bis (n-butyl) Amine) carbonylsulfonyl] -pyrrolidin-3-carboxytrans, trans-2- (2 -(2-oxopyrrolidin-1-yl) -ethyl) -4- (2,3 · dihydrophenylhydrazone-51-Specification of this paper / 丨] ts National Standard (CNS) 8 4 Specification f 210 X 297 male f) (Read the precautions on the back before writing this page)

552260 A7 B7 V. Description of the invention (49) Bran-5 -yl) -1-[(N-4 -heptyl-N- (4-Ga-3-methylamidino) amino) peptone] _ Pyrrolidin-3-carboxylic acid; trans, trans-2- (2- (2-oxo-pyrrozoline-1-yl) -ethyl) -4- (2,3-dimur epifuran-5 -Yl) -1-[(N-butyl-N- (4-dimethylaminobutyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; han, han-2- (2- (3,3-Difluorenyl-2-oxoexo-1,1-yl) -ethyl) -4-(1,3-phenylhydrazine-dioxolyl-5-yl)- 1- [N, N-bis (n-butyl) aminocarbonylmethyl] -1: 7 each disease-3 -retemic acid; trans'trans-2- (2- (3,3-dimethyl-2 -Oxo ratio. Each symptom-1-yl) -ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- [N-4-heptyl- N- (4-fluoro-3-fluorenyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid: trans, trans-2- (2- (3,3-dimethyl-2-oxo Pyrrolidin-1-yl) -ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1-[(N-butyl-N- (4-di Amidobutyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid: trans, trans-2- (2- (4,4-diamidino-2-oxo ^ 7 1-yl) -ethyl) -4- (1,3-benzo metadioxolane -5-yl) -1- [N, N-bis (n-butyl) aminocarbonylfluorenyl] -pyrrolidine-3-carboxylic acid: trans, trans-2- (2- (4,4-dimethyl -2 -oxo p biharium-1-yl) -ethyl) -4-, (1,3-benzo-dioxol-5-ylheptyl-N- (4-fluoro -3- I tolyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid: medium-fire trans, trans-2- (2- (4,4-diamidino-2-oxopyrrolidine) -1-yl) -ethyl) -4-% (U3-phenylhydrazone-dioxol-5-ylbutyl-N- (4-dimethylamine) butyl) amino) carbonylfluorene -Yl] -pyrrolidin-3-carboxylic acid: trans, trans-2- (2- (1-propanesulfonylamino) -ethyl) -4- (1,3-benzyl 2-Paper Standard description Chuanwei National Standard (CNS) Λ4 specification [210 X 297 mm] (Please read the precautions on the back before filling out this page, 11 552260 A7 B7 V. Description of the invention (50 oxetene, 5. Acid; group) Ί [N, N-dibutylaminocarbonylmethyl] • pyrrolidine-3-trans, transoxetan-5 _ agricultural continuous amino amine group) ethyl) -4_ (1, 3 _Bentamyl dicarbonylfluorenyl] -pyrrole '' w (N-4_heptyl-N- (4_Ga_3_tolyl) amino) a few acid; trans, anti-blank Burning inside Amido) -ethyl) -4- (1,3-phenylhydrazone dioxolene-5, United States)] "^" · Κ [(Ν •• 丁 ρ 比 洛 症 -3 · bet Acid; group -N- (3-hydroxypropyl) amino) carbonylfluorenyl] dialkylsulfonylaminoamino) -ethyl) -4- (1,3-phenylhydrazine (please read the Note: Please fill in this page again.) A:% 'in the middle) <, τ f; fi 卬 oxeopene_5, radical) a. Butyl-N- (propoxy) amino) carbonyl Phenyl] -pylopodoline-3-valanic acid; trans- (~ (bupropanylsulfonylamino) -ethyl) -4- (1,3-benzo-dioxolene-5, Agricultural); '-Butyl-N- (propoxy) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; trans, trans-di (:-propanesulfonylamino) -ethyl)- 4- (7-methoxy_1,3-dioxomonooxy) ▲ 5-prenyl (n-butyl) aminocarbonylmethyl] -pyhalidine-3-guinic acid; trans, trans-2 -(2- (1-propanesulfonylaminopyridyl 4-ethyl (4-methoxy-7-, 3-phenylphenylm-dioxo, although cyclopentene-heptyl ('fluoromethylphenyl) amino) Carboxymethyl l. Pyrrolidine-3-carboxylic acid: trans, trans-2- (2- (1-propanesulfonylamino) _ethyl) _4- (7-methoxy-υ-benzene Oxetan-5-yl) -1-[(N-butyl-N- (4-dimethylaminobutyl) amino) carbonylmethyl] • pyrrolidine-3-carboxylic acid; trans, Trans- 2- (2- (1 -propanesulfonyl_amino) _ethyl) _4- (2,3-dihydrobenzo 53- This paper is in the standard state of China valve (CNS) Λ4 specification " 210 x 297 g) 552260 A7 B7 V. Description of the invention (51) Furan-5-yl) -1- [N, N-bis (n-butyl) aminocarbonylmethyl] -pyrrolidine-3-carboxylic acid ; Trans, trans-2- (2- (1-propanylaminoamino) -ethyl) -4- (2,3-difluorobenzofuran-5-yl) -1-[(Ν- 4-heptyl-N- (4-fluoro-3-fluorenylphenyl) amino) carbonylfluorenyl] -pyrrolidin-3-carboxylic acid; trans, trans-2- (2- (1-propanesulfone Fluorenylamino) -ethyl) -4- (2,3-dihydrobenzofuran-5-yl) -l-[(N-butyl-N- (4-dimethylaminobutyl) amino ) Carboxymethyl] -pyrrolidin-3-carboxylic acid: trans, trans-2- (2- (1-pyrazolyl) -ethyl) -4- (1,3-phenylhydrazone dioxane Pentene-5-yl) -1-[(N-4-heptyl-N- (4-neon-3-fluorenyl) amino) carbonylfluorenyl] -pyrozine-3-double acid; trans , Inverse -2-(2-(1-? Ratio. (Cyclo) -ethyl) -4-(15 3 -benzo-dioxol-5-yl) -1-[(N-butyl-N- (3-hydroxypropyl) amino) Carboxymethyl] -pyrrolidin-3-, ¾-acid: trans, trans-2- (2- (l-p-pyridyl) -ethyl) -4- (1,3-phenylhydrazine dioxane Pentene-5-yl) -1-[(N-butyl-N- (propoxy) amino) carbonylmethyl] -pyrrolidine-3-chinic acid; trans, trans-2- (2- ( 1-ρ bilyl) -ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl H (N-butyl-N- (4-diamidoaminobutyl) ) Amine) carbonylmethyl] -pyrrole (Please read the precautions on the back before filling this page) iV 部 中 消 fa ii Ο Bite-3 -Mao: Anti, trans-2- (2- (1- Oxazolyl) -oxopenten-5-yl) -l- (N, N- # succinic acid: trans, trans-2- (2- (1-pyrazolyl) -ethyl) -4- (7-Methoxylactyl-1,3 -m-di-diaminoamine supporting methyl) -p ratio ° Each syndrome-3-Phenyl-m-di-54-This paper uses 1¾ national standard (CNS) Λ4 specification [210 X 297 g t] 552260 A7 B7 V. Description of the invention (52) Oxetene-5-yl) -1-[(N-4-heptyl-N- (4- Fluoro-3-fluorenyl) amino) carbonylcarbonyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (1-? Beryl) -ethyl) -4- (7-methyllactyl-1,3-fluorenedioxol-5-yl) -1-[(Ν- Butyl-N- (4-dimethylaminobutyl) amino) carbonylfluorenyl] -P-biloxo-dioic acid; trans, trans-2- (2- (1-ρbicyclo) -ethyl ) -4- (2,3 -diargyrenyl-5-anyl) -1- (N, N-dibutylaminecarbonylmethyl) -pyrrolidine-3-carboxylic acid; trans, trans- 2- (2- (1-p than benzyl) -ethyl) -4- (2,3-dihydrophenylhydrazone-5-yl)-; l-[(N-4-heptyl-N -(4-fluoro-3-tolyl) amino) carbonylfluorenyl] -pyrrolidin-3-carboxylic acid; i trans, trans-2- (2- (1-pbiyl) -ethyl)- 4- (2: 3 -dihydrophenylsulfan-5-yl) -1-[(N-butyl-N- (4-dimethylaminobutyl) amino) carbonylmethyl] -pyrrolidine -3-carboxylic acid; trans, trans-2- (2- (2-pyrazolyl) -ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1 -[N, N-bis (n-butyl) aminocarbonylmethyl] -pyrrolidin-3-carboxylic acid; trans, trans-2- (2- (humazol-2-yl) ethyl) -4- (1; 3-phenylhydrazone dioxol-5-yl) -1-[(N-4-heptyl-N- (4-fluoro-3-tolyl) amino) carbonylfluorenyl] -Pi Hee bite -3-number acid; Γ 屮 fi 卬 (Please read the back Note for refill this page) trans, trans-2- (2- (humazol-2-yl) ethyl) -4- (1,3-benzo-dioxol-5-yl) -1-[(N-butyl-N- (3-hydroxypropyl) amino) carbonylmethyl] -pyrrolidin-3-carboxylic acid; trans, trans-2- (2- (humazole-2- ) Ethyl) -4- (1,3-benzo-dioxol-5-yl) -1-[(N-butyl (propoxy) amino) carbonylmethyl] -pyrrole Pyridin-3-carboxylic acid; -55- This paper is in accordance with the National Standards of China (CNS) Λ4 specification Γ 210X 297 public 茇 552260 A7 B7 V. Description of the invention (53 Trans, trans-2- (2- ( Hexazol-2-yl) ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl) · 1-[(N-butyl-N- (4-dimethylamine Butyl) amino) carbonylmethyl] -pyridine each bit -3 &; trans, trans-2- (2- (humazol-2-yl) ethyl) -4- (7_ 曱Oxy-1,3-phenylhydrazone dioxol-5-yl) -1- [N, N-bis (n-butyl) aminocarbonylfluorenyl] -pyrrole-3 -polyacid; Trans, trans-2- (2- (humazol-2-yl) ethyl_4_ (7-fluorenyloxy-I, 3-phenylhydrazone-dioxol-5-yl) -1- [ (N-4-heptyl-N- (4-fluoro-3 -fluorenyl) amino) gives methyl] -pyrrolidine-3-carboxylic acid; trans, -2- (2- (indazol-2-yl) ethyl) -4- (7-methoxy-1,3-phenylhydrazone-dioxol-5-yl) -1-[( N-butyl-N- (4-dimethylaminobutyl) amino) carbonylfluorenyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (5-methylhumazol- 2-yl) ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- [N, N-di (n-butyl) aminocarbonylmethyl]- Pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (5-methylindazolyl) ethyl) -4- (1,3-benzene # m-dioxol-5-yl ) -1-[(N-4-heptyl-N- (4-fluoro-3-fluorenylphenyl) amino) carbonylfluorenyl] -p than pyrrolidine-3 -carboxylic acid; trans, trans-2- (2- (5-Pyridinazol-2-yl) ethyl) -4- (1,3-benzo-dioxol-5-yl) -1-[(N-butyl- N- (4-dimethylaminobutyl) amino) carbonylmethyl] m ρ each disease · 0-bet § text: trans, trans-2- (2- (2,5-dioxopyrrolidine- 1-yl) ethyl) -4- (1,3-benzo-dioxol-5-yl) -1- [N, N-di (n-butyl) aminocarbonylfluorenyl]- Qiao Diao Luo Bite -3-Re-acid; -56- This paper measures the national standard (CNS) Λ4 size f 210X297 mm in the state of the paper (read the precautions on the back before filling in this )

552260 A7 B7 V. Description of the invention (54) trans, trans-2- (2- (2,5-dioxopyrrolidin-1-yl) ethyl) -4- (1,3-benzo-dioxo Heterocyclopenten-5-yl) -1-[(N-4-heptyl-N- (4-fluoro-3-tolyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; trans , Trans-2- (2- (2,5-dioxopyrrolidin-1-yl) ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1 -[(N-butyl-N- (3-hydroxypropyl) amino) carbonylfluorenyl] ·-said p each way of 3- carboxylic acid; trans, trans-2- (2- (2,5- Dioxopyrrolidin-1-yl) ethyl) -4- (1,3-benzo-dioxol-5-yl) -1-[(N-butyl (propoxy) amine Carbonyl) carbonylmethyl] -said p-Yodo-3 -chinoic acid; trans, trans-2- (2- (2,5-dioxopyrrolidin-1-yl) ethyl) -4- (1, 3-Benzamidinedioxol-5-yl) -1-[(N-butyl-N- (4-diamidoaminobutyl) amino) carbonylfluorenyl l · pyrrolidine-3 -Carboxylic acid; trans, trans-2- (2- (2,5-dioxopyrrolidin-1-yl) ethyl) -4- (7-methoxy-i, 3-phenylhydrazine dioxo Heteropentene-5-yl) -1- [N, N-bis (n-butyl) aminocarbonylfluorenyl] -pyrrolidine-3-carboxylic acid; trans'Han-2- (2- (2, 5 -dioxo. Than p each lake -1- (Yl) ethyl) -4- (7-fluorenyl-1,3-phenylhydrazine-5-yl) -1-[(N-4 -heptyl-N-(4- GA-3 -Tolyl) Amine) Carbonyl] -pyrrolidin-3-carboxylic acid; -C ^ rXJ, ': Λκ'7 ^-· " * (Read the precautions on the back before filling (This page) trans, trans-2- (2- (Morphyl-2-yl) ethyl) -4- (1,: > -Dongdongma—milk 'Isipene-5-yl)- 1-[(N-4-heptyl-N- (4-fluoro-3-tolyl) amino) carbonylmethyl] -pyrrolidine-3-double acid; trans, trans-2- (2- ( Pyridin-2-yl) ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl) butyl-N- (3-hydroxypropyl) amino) carbonylfluorenyl] -Pyrrolidin-3-chinoic acid: -57- This paper is in the same national standard (CNS) Λ4 specification "2 丨 0X 297" while 552260 A7 B7; r '• Lost r'j A Description (55) trans'trans-2- (2- (titanium-2-yl) ethyl) -4- (1,3-benzobenzodioxol-5-yl) -1- [ (N-butyl (propoxy) amino) carbonylmethyl] -pyrrolidine-3-chinic acid; trans'trans-2- (2- (pyridin-2-yl) ethyl) -4- (1 , 3-phenylhydrazone dioxol-5-yl) -1-[(1 butyl_N- (4-di Aminobutyl) amino) carbonylmethyl] -pyrrolidin-3-carboxylic acid; trans'trans-2- (2- (pyridin-2-yl) ethyl) -4- (7-methoxybenzene Dioxo-5-yl) -ην, N-di (n-butyl) aminocarbonylfluorenyl] -pyrrole-3 -chinic acid; trans'trans_2 gas 2- (pyridine- 2-yl) ethyl) -4- (7-fluorenyloxy-1,3-phenylhydrazone dioxandroylpentanyl) -1-[(N-4-heptyl-N- (4-fluoro -3 -Tolyl) amino) carbonylfluorenyl] -pyrrolidinecarboxylic acid; trans'trans-2_ (2 · (pyridin-2-yl) ethylfluorenyloxy-1,3-phenylhydrazone WWII Pentene_5-yl) -1-[(N-butyl · N- (4-diamidinobutyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; trans-7trans-2_ (2- (Pyrimidin-2-yl) ethyl) -4- (1,3-phenylhydrazine-dioxolyl (n-butyl) aminocarbonylfluorenylpyrrolidin-3-valerate : Trans, trans-2_ (2- (pyrimidin-2-yl) ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl M-[(N-4 · heptyl Small- (4-fluoro_3-tolyl) amino) carbonylsulfanylpyridine-3 -chinoic acid: trans'trans-2- (2- (pyrimidin-2-yl) ethyl) -4 -(1,3-Benzo-dioxolene 1-yl) 'M (N-butyl-N- (4-dimethylaminobutane ) Amine) Carboxymethyl] -Bihartidin-3 -Amino acid: trans'trans-2- (2- (1.3-benzyldioxol-4-yl) ethyl) _4- -58- Ben · Shaoxin 4/1] Towel 1 Lai Jiabiao ^ 7 ^ 7 ^ 77 ^ 297 male i (Please read the precautions on the back before filling in this page j 、 " 552260 A7 B7 V. Description of the invention (53) (1,3-phenylhydrazone dioxol-5-yl) -1- [N, N-bis (n-butyl) aminocarbonylmethyl] -pyrrolidine-3-carboxylic acid; trans, Trans-2- (2- (1,3-phenylphenoxadioxen-4-yl) ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl ) -1-[(N-4-heptyl-N- (4-fluoro-3-fluorenylphenyl) amino) carbonylfluorenyl] -pyrrolidine-3-carboxylic acid; and trans, trans-2- ( 2- (1,3-Benzo-dioxopentyl-4-yl) ethyl) -4- (1,3-benzopyrene-dioxol-5-yl) -1- [ (N-butyl-N- (4-diamidinobutyl) amino) carbonylmethyl] -pyrrolidin-3-carboxylic acid: (2S, 3R, 4S) -2- (2,2-di Fluorenylpentyl-4- (1,3-phenylhydrazone dioxol-5-yl) "-[N, N-bis (n-butyl) aminocarbonylfluorenyl] -pyrrolidine-3 -Carboxylic acid; (2S, 3R, 4S) -2- (2,2-dimethylpentyl- (E) -3-tallowyl) -4- (1,3-benzene Bis-dioxol-5-yl) -1- [N, N-di (n-butyl) aminocarbonylmethyl] -pyroline-3 -Mein; (2 8,311,45)- 2- (252-Difluorenylpenta- (£) -3-alkenyl) -4- (7-methoxy-1: 3-phenylhydrazone-dioxol-5-yl) -1- [Ν, Ν-bis (n-butyl) aminocarbonylfluorenyl]-? Ratio ρ each bit-3-prostitute;? I: middle part-fire 乂: j 卬 (please read the notes on the back before filling This page) (2S, 3R, 4S) -2-((2-fluorenoxyphenoxy) fluorenyl) -4- (1,3-benzo-dioxol-5-yl) -1 -[N, N-bis (n-butyl) aminocarbonylfluorenyl] -pyrrolidine-3 -Resveratrol; (2S, 3R, 4S) -2- (2- (2-oxophenyl) ethyl ) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- [N, N-bis (n-butyl) aminocarbonylfluorenyl] -pyrrolidine- Pharmacologically acceptable salt-59- This paper is suitable for tS National Standard (CNS) Λ4 specification (—210 x 297 male f) 552260 A7 B7

A 5. Description of the invention (57 The best compound of the present invention is selected from the group consisting of: trans, trans-2- (2- (l, 3-dioxolan-2-yl) ethyl) -4- ( 1,3_phenylhydrazone dioxol-5-yl) -1- [N, N-bis (n-butyl) aminocarbonylfluorenyl] -pyrrolidine-3-carboxylic acid; trans, trans -2- (2,2-Difluorenyl-2- (l, 3-dioxolane-2-yl) ethyl) -4- (i, 3-phenylhydrazone-dioxolene-5 -Yl) -1- [N, N-bis (n-butyl) aminocarbonylfluorenyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (l, 3-methylenedioxy Heteropentene-2-yl) ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1-[[N-4-heptyl-N- (2 -Methyl-3-fluorophenyl)] aminocarbonylfluorenyl] -pyrrolidin-3-carboxylic acid; trans, trans-2- (2- (l, 3-dioxopenten-2-yl ) Ethyl) -4- (7-fluorenoxy-1,3-phenylhydrazone dioxol-5-yl) -1- [N, N-di (n-butyl) aminocarbonylmethyl ] -Pyrrolidin-3-carboxylic acid; trans, trans-2-((2-methoxyphenoxy) -fluorenyl) -4- (1,3-phenylhydrazone dioxolene-5 _Yl-bis (n-butyl) aminocarbonylfluorenyl] -pyrrolidine-3-carboxylic acid: trans'trans-2- (2- (2-lacto ^ bibiter-] yl) ) -4- (1,3 -pyridine · monooxepin-5-yl) -1- [N; N-di (n-butyl) aminocarbonylfluorenyl] -pyrrole_ 3 -Lean acid: trans, trans-2- (2- (1,3-dioxol-2-yl) ethyl) -4- (7-fluorenyl-1,3-epoxy Dioxazepine: fefp -5 -yl) -1-[(N-4 -heptyl-N- (4-gas-3-tolyl) aminocarbonylfluorenyl] -pyrrolidine-3-carboxylic acid; Trans'trans-2- (2,2-dimethylfluorenyl) -4- (7-fluorenyl-1,3-benzo-m-oxo though -5-vol)-1-[N , N-bis (-j-amino) aminomethyl] -7 ratio slightly 疋--60 This paper size is in the middle of the state ® National Standard (CNS) Λ4 specifications [210X297 cm] (Please read the note on the back first Please fill in this page again for matters) 552260 A7 B7 V. Description of the invention (53 parts 屮 ii 卬 ί: 3-carboxylic acid; trans, trans-2- (2,2-dimethyl_2- (1,3_dioxo Pentyl-2 · yl) ethyl) -4- (7-methoxy-1,3-phenylhydrazone dioxolene-5-yl) -1- [Ν, Ν-bis (n- · Butyl) aminocarbonylfluorenyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (2-fluorenoxyphenyl) -ethyl) -4- (1,3-phenylhydrazine Oxopent-5-yl) -1- [N, N-di (n-butyl) Carbonylfluorenyl] -pyrrolidin-3-carboxylic acid; trans, trans-2- (2,2-dimethyl-3- (£) -pentenyl) -4- (7-methoxy-1, 3-Benzo-dioxol-5-yl) -l- [N, N-bis (n-butyl) aminocarbonylmethyl]-? Biloxan-3 -chinic acid; trans, trans -2- (2- (2-pyridyl) ethyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- [N, N-bis (n-butane ) Aminocarbonylmethyl] -pyrrolidin-3-carboxylic acid; (2S, 3R, 4S) -2- (2- (2-oxopyrrolidine-butyl) ethyl) -4- (1,3 -Phenylhydrazine-5-yl) -1- [N, N-bis (n-butyl) aminocarbonylfluorenyl] -pyrrolidine-3-carboxylic acid; (28,311,45)- 2- (2,2-Difluorenylpentyl) -4- (7-fluorenyloxy-173-phenylhydrazine dioxol-5-yl) -1- [Ν, Ν-bis (n -Butyl) aminocarbonylmethyl] -pyrhodidine-3 -i acid; (2S, 3R, 4S) -2- (2- (2-oxopyrrolidin-1-yl) ethyl) -4 -(1,3-phenylhydrazone dioxol-5-yl) -1-[(N-4-heptyl-N- (4-fluoro-3-fluorenylphenyl) aminocarbonylfluorenyl] -Pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (pyrazolyl) ethyl) -4- (1,3_phenylhydrazinedioxol-5-yl)- 1- [Ν, Ν-bis (n-butyl ) Aminocarbonylmethyl; h-pyrrolidin-3-carboxylic acid; (2S, 3R, 4S) -2- (3-fluoro-4-methoxyphenyl) -4- (1,3-phenylhydrazine dioxo Heterocyclic-61-Specification of this paper / 彳] Chinese National Standard (CNS) Λ4 Specification C 210 × 297 mm) (Please read the precautions on the back before filling in this page, --- Order --- .552260 Jk il meaning: j $ Heshi: 印 A7

V. Description of the invention (5S pentene-5-yl) · K [((N · propyl_N-pentanesulfonyl) amino) ethyl] _pyrrolidine ** 3 -Chinic acid; (2S ' 3 4 S) -2- (2,2-Difluorenylpentyl) ice 3 _phenylhydrazone dioxol-5-yl > K [(Ν, Ν _ :( n-butyl) amine Carbonylfluorenyl] • pyrrolidine ·% potential acid; & mono = 3'3 = '48) -2- (2,2-dimethylpentyl_ (£;)-3-alkenyl) -4_ (1 , 3-Phenyl-m-lactam / co-linked-5-yl (n-butyl) aminocarbonylfluorenyl] -pyrrolidine-3-carboxylic acid; methylpentyl-fluorene · 3 · alkenylbenzene 4〆 '曱 _ _ 幵 幵 dioxetenyl)-[[N, N-di (n-butyl) aminocarbonylmethyl] -pyrrolidine-3-carboxylic acid; one " (-SjR , 4S) -2-((2-methoxyphenoxy) _methylphenylhydrazone dioxo (n-butyl) aminocarbonylfluorenyl] -pyrrolidine-3 -carboxylic acid; (2S, 3R , 4S) -2- (2- (2-methoxyphenyl) _ethyl) -4- (1,3-benzo-m-di-f; indeed, isopenteno-yl) _1- [N, N- Di (n-butyl) aminocarbonylmethyl l · pyrrole: 3-carboxylic acid; 1, or its musically acceptable salt. The method for preparing the compound of the present invention is shown in Jizhao I to XV. ° Stroke 1 Domain release preparation of β-ketoesters in which η and m are 0, Z is -CH2 ·, and is a common method of the compounds of the present invention, where e is a low residue or a protective group of several groups. , In the presence of a base (for example, 1,8-diazo ~ pj ·-, shelf [3,4 · 〇] undec-7-ene (DBU) or sodium ethoxide or sodium gasification and the like, Specs such as toluene, benzene, tetrahydrofuran or ethanol and their exempt substances -62- Α4 (· 210X 297mm) (Please read the precautions on the back before filling this page), 11 552260 B7

JA A

'^ 4 A A7 V. Description of the invention (60 in an inert solvent, such as 60%, 1 ^ $ ethoxylated A A 2__ reaction. The condensation [reduction (for example, using Raney nickel or palladium catalyst for hydrogenation) The resulting amine is cyclized to obtain: hydrogen hydrazone H such as ethanol or methanol and 2 analogues of t type proton solvent reduction of L (for example, sodium cyanoborohydride = catalytic hydrogenation and the like) to obtain For the cis-cis, trans, anti- and master, the anti-product < the pyrrolidine compound 5 in the form of a mixture. = = Cis-cis isomers, leaving the trans, trans and cis, trans isomers of L, and then further processing Epi-isomerization of cis-cis isomers (eg, sodium ethoxide in ethanol) can be used to trans, isomers, and then proceed as follows. Jiang pyrrole nitrogen (1) using R3_X (R3 is RfC (〇)-or Ur, and X is a releasing group, such as a halide (C1 is preferred), or X and ^ (〇) _ or R6 · s (〇) 2_-did not form activated vinegar, including Derived from esters or anhydrides of acetic acid, acetic acid, and the like, dentified alkoxycarbonyl, N-hydroxysuccinimide, N-pyridylphthalimide, N-hydroxybenzotriazole, N _Hydroxy_5_n-sulene_253-monomethylamine, 2,4,5-trichlorophenol, and the like) or desulfonated or sulfonated 'or (2) in diisopropyl Ethylamine or triethylamine, and the like, by alkylating it with RrX, where χ is a releasing group (for example, X is a halide (such as Cl, Br, or I), or X is a releasing group, such as a sulfonate (such as mesylate, tosylate, trifluorosulfonate, and the like)), to give a derivative of pyrrolidine L, which is still trans, trans and cis , A mixture of anti-isomers. Hydrolysis of the fermentation (for example, using a base such as sodium hydroxide in E t 0 H / Η 2 0), selective hydrolysis of the trans, trans ester, to obtain easily separable A mixture of 1 and 1. Plan II explains the preparation where η is 1, ζ is -CH2-, and W is -63. This paper & scale extension] Zhongguanjiajia 210 χ 297 ^ C Please read North e : Please fill in this page before the above matters}

552260 A7 grams, description of the invention (61 B7 Λ

Common procedure for compounds of the invention. The substituted benzyl chloride is reacted with lithium dipyrimidine & in an inert solvent such as rp] LI P JU > n. An anion such as n-butyllithium is used to form the anion of compound 1, and then reacted with KY2-X, where X 'is a releasing group such as a halide or a sulfonate to obtain a compound ^. The dioxane protecting group is cut (for example, a mercury salt is made in water) to obtain a ketone compound k ° M13 and a reaction with benzylamine and formaldehyde to obtain a ketohexahydropyridine compound JJ-. Treatment of compound u with an activated nitrile such as trimethylsilyl cyanide, followed by treatment with a dehydrating agent such as phosphonium chloride affords the isomeric trinitrile hydrazone I. The reaction of the double bond (for example using sodium borohydride) gives hexapyridine nitrile 16. The nitrile is hydrolyzed with hydrochloric acid in the presence of a protecting group (such as hydroxy alcohol) to obtain an ester in which E is a carboxy protecting group). Debenzylation is performed by catalytic hydrogenation under acidic conditions to obtain free hexahydropyridine compounds. By further processing compound ϋ through the procedure described for compound ^ _ in Plan I, the final product compound u is obtained. Scheme III explains the common procedure for preparing compounds of the invention where m and n are 0, z is -C (O)-and W is a compound of the invention. Let β-ketoesters welcome (where E is a low-density amino group or a tertiary protecting group) 'in the presence of a base such as Na Η or di-difluorobutane or lithium diisopropylamide , In an inert solvent such as THF or dioxo 6 pits, react with α-haloester 2 ± (where J is a low-carbon alkyl or carboxy protecting group, and the halogen is bromine, iodine or chlorine) , To obtain the diester 11 5 so that the compound 2_1_ is reacted with R3-NH2 and heated in acetic acid to obtain a cyclic compound. Reduction of double bonds (for example, by catalytic hydrogenation using a carbon palladium catalyst or sodium cyanoborohydride reduction method) to obtain pyrrolidine 2A 64- (Please read the precautions on the back before filling this page)

I. National Standard for Chuanxiong Valve (CNS) Λ4 specification (210 乂 297 mm 552260-& > 1-4 f A Qiaoi A7 B7 V. Description of the invention (62. Use of B material for epimerization in ethanol To get the desired inverse: reverse configuration, '㈣ carry out the hydrolysis of the hydroxide of this § purpose to get the desired inverse, inverse leptin 25. Plan iV interpretation to prepare where ...,-is b Z is CH2- And 'V is C02H t The common program mrndt_Eistert of the compound of the present invention was synthesized in the pair borrowed in Plan I; ,, γI prepared ~ trans, the anti-compound B is homolytic. Activate the carboxyl terminal (for example, Gogo from, VIII * ” i3 耆 uses sulfenyl chloride to make fluorenyl chloride), and it is obtained that: Shiyi, /, and L are release groups (in the case of fluorenyl chloride, L is C1). A in A: compounds present at k Pan, to obtain the diazolone river. The rearrangement of the compound river (such as Chuan Zhou Jin, #: ^ 〖本本 or alcohol 'and silver oxide or silver benzoate, and triethyl ^ produced in the presence of ^ water or drunk Heating or photolysis) to obtain acetic acid compound t = one or decomposable ester. Among them, m is a compound from 2 to 6, which can be returned by the compound And obtained. The best specific examples are shown in V.V. and V. VI. The heavy bicyclo [5.4 · 〇] undec-7-ene (DBU) was used as a base in toluene to make benzophenone acetate Signed vinylbenzene hydrazone dioxeplenyl compound reaction to obtain 51] 4 ^ ^ 〇η⑺ 4. The catalytic hydrogenation of Raney nickel, resulting in the inversion of the nitro group into an amine group, and then Cyclization to obtain dihydropyrrole. Reduction with cyano collar sodium hydride and Chiang's double bond gives cis-cis, trans, trans and cis, trans isomers < mixture of pyrrolidine compounds I. Separation of cis Cis isomers, leaving the trans, trans and cis, trans isomer mixtures (1L). Plan VI explains the further processing of the trans, isomers, so that the trans, trans A mixture of cis and transpyrrolidine (11) in acetonitrile in the presence of ethyl diisopropylamine, reacted with N-propylacetamidinium bromide, -55- paper & appropriate size / 丨 10 X 297 mm (Please read the notes on the back before filling out this page)

552260 A7 B7

〆: Department Middle and: J

A. V. Description of the invention (63) The alkylated pyrrolidine compound & is still a mixture of trans, trans and cis, trans isomers. Sodium hydroxide in ethanol-water, hydrolysis reaction, reaction Ethyl esters, but leaving the ethyl esters of the cis and trans compounds intact, thus allowing the separation of trans, transcarboxylic acids from the cis and trans esters. Plan VII explains the preparation of specific hexahydropyridyl compounds. The benzo metadioxolyl methyl chloride ^ is reacted with lithium dioxane ^^ to obtain the alkyl compound μ_Z_. In the presence of an isopropylpropylated bell, 4_methoxy Treatment with larvae lice yields compound 1. In a solution containing mercury, a 1% w protective group is used to cut open to give § the same as 39. Treatment with amine and methylg to sign 3 9 gives ketohexahydropyridine 1. To trimethylsilane The compound 1 was treated with cyanocyanine and then treated with phosphonium chloride to obtain the acrylonitrile as a mixture of isomers. The double bond was reduced with sodium hydride to obtain hexahydropyridylnitrile 2_. In the presence of ethanol with hydrogen Hydrolysis of chloric acid gives ethyl esters. Through catalytic hydrogenation, 移 *, N-下 基Huji 'obtains free hexahydropyridine compound 44. By further processing compound 31 according to the procedure described for compound 31 in plan V, the compound is further processed, resulting in the formation of N-derived quinic acid 45 3 The plan is shown in plan VIII A preferred specific embodiment of the method shown in the presence of NaH, in the presence of NaH, 4-fluorenyloxybenzyl acetate 4i_ (where E is a low-carbon alkyl or carboxy protecting group) and α-bromoacetic acid Phenylhydrazone dioxolene ester (wherein E is a low-carbon alkyl group or a carboxy protecting group) is reacted to obtain a diester. Compound 1 is treated with ethoxypropylamine and heated in acetic acid to obtain a ring The compound is reduced by the hydrogenation of the catalyst using a palladium-carbon catalyst to reduce the double bond to give pyrrolidine 5_0_. Using sodium ethoxide in ethanol for epimerization to obtain the desired inverse, inverse configuration, then -66- The size of this paper is suitable; 彳] Garden Standard (CNS) Λ4 size f 2ι〇χ 297 mm) (Please read the precautions on the back before writing this page) ^^ 260 A7 V. Description of the invention (64, " Λ '· rm ^ Nr' ^ :: tr / i / T- ^ UT /.0- ^ ΛΜ. Sodium hydroxide hydrazone plan IX explained which μ 〇 widely used to reach the desired anti, anti-Laijiang. The preparation of compounds. Editors, 丄 ... m heart person outsiders% 55 test in the plan IV The procedures described below are used to prepare the amidine coupling conditions, such as N • methyl ?, Erdedi II in the presence of ammonia τ ′ or other amidine formation reactions) a ′ < Hydrogenation of carboxyamidoamine (for example, using chlorine in pyridine) to obtain nitrile. Stop at the bar formed by the standard four-peak group (sodium azide, diethylamine hydrogen hydride, or trimethylsilyl azide and tin oxide) so that the reaction can be obtained in the presence of money (4 m). (Such as fresh acid, sodium carbonate, sodium hydroxide, triethylamine, sodium methanol, or NaH) In: π DMF, DMSO, or trimethylacetamide, etc. The compound reacts to obtain Minjiang River. Allow this amine to be tested in traditional organic solvents (such as chloroform, dichloromethane, dioxane, or fluorene), such as triethylamine, fluorene, potassium carbonate, and k sodium), ethyl chlorochloroacetate or ethyl ester was reacted to obtain 0_dongyou 6. The 0-fluorenyl compound is heated in an inert solvent such as benzyl, toluene, xylene, dioxane, i HF, dioxane, or chloroform and the like, and the result of the% conversion is compound ^. In addition, the amidoxime can be reacted with thionyl chloride in an inert solvent (such as chloroform, dichloromethane, dioxane PU, and its analogs) to obtain oxepine ridge 61_. Ji Jian X explains the preparation of compounds in which the fluorenylmethylene group is. In a dichloromethane solution containing N, N-dimethylamidamine in a catalytic amount, the carboxylic acid 41 (where R4 is as previously defined herein) is treated with early-bond chlorine to give _yl chloride. The hydrazone gas is treated with an excess of hydrazone diazene to obtain

Read the first note on the back A $ Order 67-______-—— ^ ______-______ This paper describes the financial standards: material: (CNS) Λ4 specifications (, 21Gx " ^ 57 · 552260 A7 B7 V. Description of the invention (65) Diazones are then treated with anhydrous HC1 in dioxane to obtain α-chloro '1-. The pyrrolidine ester 1 prepared in Plan I is alkylated with α-chloroketone, where E is Low carbon number alkyl or carboxy protecting group to obtain alkylated pyrrolizide 1. Deprotect the carboxyl group (for example, in ethanol-water, using lithium hydroxide or steel hydrolysis) to obtain alkylated pyrrolidine Acid ^ _. Plan XI explains the preparation of "antamidin and sulfonamide". The carboxyl-protected pyrrolidine group prepared in Plan I is reacted with a dual-function compound x_R8-x, where is alkylene and X is Release groups (such as halides, of which Br is preferred) to obtain N-alkylated compounds. Treatment of I with an amine (R2GNH2) yields a secondary amine. This amine can be activated and activated. Fluorenyl compounds (eg 'R4-C (0) -C1) reaction' and then deprotection of the leptin group (such as hydrolysis of vinegar or hydrazone base Amines can be obtained. In addition, amines can also be reacted with activated sulfonyl compounds (such as R6-S (0) 2-C1), and the carboxyl groups can be deprotected (such as hydrolysis of esters). Action or hydrogenation of the fluorenyl moiety) to give sulfamethoxamine 69. Plan XII explains the synthesis of p-pyrrole by the azomethine internal phosphonium salt formula [3 + 2] -cycloaddition of acrylate How to bite. Add a known common structure such as compound ZiL to unsaturated esters such as: LJL to get mouth-to-mouth syndromes, such as compound 12 (0. Tsuge, S. Kanemasa, K. M. at sud a, Chem. Lett. 1 1 3 1 -4 (1 983) ^ O. Tsuge, S. ΐ ii 卬 (Please read the notes on the back before filling this page}

Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem 52 2523-30 (1 987), and S. Kanemasa, K. Skamoto, O. Tsuge, Bull. Chem Soc. Jpn. 62. 1960-68 ( 1989)). Specific examples are also shown in Plan XII. The hydrazine imino group and acrylate 2iL_, in the trifluoro-68- wood sizing scale / 丨] in the valve national standard (CNS) Λ4 size f210X297 mm) 552260 A7 B7 V. Description of the invention (66 · ,, r, 屮 Jk and ii reacted in the presence of trislyl acetic acid and tetrabutylammonium fluoride to obtain the desired ratio of isomers in the form of u-pyridine 7 5. May be modified, Xian Manxiong directly provides N-ethylamine derivatives, and by making Jianghe 1 and appropriate desertified ethyl turtles (such as dibutyl oxamine acetamide), in the filling of tetrabutyl chloride and gasification absolute reaction, get Compound 21. Plan XIII explains the pure flavor of heart 4 I produced in the enantiomorphic form, which can be further processed into heart money. The intermediate racemization (eg, prepared by the procedure described in Plan V) is performed (eg, prepared with BoC2〇), and then the target is aquatic. = Methanol and water using sodium hydroxide or bell), to obtain the tertiary-butagromine methyl succinyl C each acid 1. Convert this chitosan to its ⑴_Xin Kebao chain, for example, from ethyl acetate and hexane, or gas imitation and hexad "): Tsai steal the enantiomerically pure salt. This non :) ::: (Example: sodium carbonate or citric acid), obtained in the enantiomorphic form = two deprotection of the heart (for example, using trioxoacetic acid), the vinegar is reformed by hydrazine hydrogen acid, and salt toe is obtained. In the step of: = one, the protecting group is cut with ethanol to form the hydrazone; the emei nitrogen is processed (for example, by using acetonitrile at:: ί =; below, dibutyl bromide diamine Subsequent processing two: b, a compound with a progeny m nature, S. ^ / J anti-enantiomer. A ^ '(+ Xin Koning will get 3 to get 4 strokes XIV described other preparations of pyridine. Et al. 1 ~: Same]) As described in the description of acyl acetate derivatives ^ —---—-—__-00 Machine scale suitable for IΦ (Please read the precautions on the back before writing this page}

Is— j-I ----I- -I! · Ding ii 552260 A7 V. Description of the invention B7 67, ^ Mod addition effect to synthesize pyrrolidine. Therefore, under acidic conditions, the azomethine internal phosphonium salt precursor i2X (where r55 is hydrogen or fluorenyl) and the substituted valproate §J_ (R2 is as defined herein and Rw is low carbon A number of alkyl groups ", to obtain a substituted pyrrolidine M_. Removal of the N-protecting group (for example, the hydrogenolysis of hunting N-benzyl) to obtain ^, which can be obtained under the conditions described above The basic ester hydrolysis of N-substituted p-bilodine 86_. 86 provides the desired ton of Luodian acid. Ministry shows the better method in plan XV. Make nitro vinyl compounds (Ambiguity) 'In the presence of a test, such as sodium ethoxide and its analogs, or trialkylamine, such as diethylamine or diisopropylethylamine and its analogs, or glands, such as Dbu and its analogs , In an inert solvent such as THF, toluene, DMF, acetonitrile, ethyl acetate, isopropyl quatrate, or digas methane and the like, at a temperature from about 0 ° C to about 100 ° C During the reaction with the ketone ester from about 15 minutes to overnight, compounds are obtained. The nitro group is reduced, followed by cyclization, such as by catalysis. Chemical hydrogenation, using hydrogen pressure from about one atmosphere to 300 pounds per square inch, for about 1 hour to about 1 day, so that Compound 1 is in an inert solvent such as THF, ethyl acetate, ammonium, Ethyl, isopropanol, DMF or acetonitrile and the like, using hydrogenation catalysts, such as Raney nickel, palladium carbon, platinum catalysts, such as platinum oxide, platinum carbon or pin oxidation # and their analogues' or rhodium catalysts, Such as rhodium carbon or rhodium alumina and similar kisses, and the like, get the intermediate nitrone 91a, or nitrone 9〗 a ^, 卬 (please read the precautions on the back before filling this page

* 1T mixture. Treating a reaction mixture containing a nitrate or nitrate / imine mixture with an acid such as trifluoroacetic acid or acetic acid, or sulfuric acid or phosphoric acid, or pinanesulfonic acid and the like, and continuing the hydrogenation to obtain -70- This paper uses the Chinese National Standard (CNS) Λ4 specification ('210X 297 Gongchu) 552260 rl · 乂: j Y', a description of the invention, and a pyrrolidine compound in the form of cis · isomer. By using an inert solvent such as ethanol, ethyl acetate, isopropyl acetate, THF, toluene, or DMF, and the like, at a temperature ranging from about -20 t to about 120 C, a solution such as sodium ethoxide, Potassium tri-butoxide, lithium tert-butoxide or potassium tert-pentoxide, and the like, or trialkylamines, such as triethylamine or diisopropylethylamine, and the like, such as DBU And its analogs to treat compound 92 to complete epimerization at C, and to obtain anti- and anti-compounds. It can be seen that before the treatment with X_R3, the trans and trans compounds should be resolved into enantiomers. By using a solvent such as acetonitrile, ethyl acetate, isopropyl acetate, diethyl ether, or isopropyl alcohol, and the like, S-(+)-almond, D-tartaric acid, or D-benzoyl Treatment of fluorenyl tartaric acid and its analogs & Di ^ \ Kaidandanchuhe (mixture of 0-isomers, to obtain substantially pure (that is, '3 9 5 ^ desired isomers), Optically active compounds = structures. The (+) _ isomer of ^ is selectively crystallized into a salt, and the (, and isomer) is dissolved. In addition, by making 93 (ten)- The mixture of isostaridine di-ditch is reacted with L-tartaric acid, L-diphenylfluorenyl diglutamine, and the like to make the compound & substantially pure and at least 95% isomerized. The isomers selectively stand at π ,,,. Where the 生 生 is born ~ (Xi ^ into crystals, leaving the vivid Leopard 叱 Character 9 3 and (+) -isomers in the solution. Tian 心心 的'Dhop right words extravagant j mouth y yuezhu with M,' Ί THF, toluene, DMF or ethanol and the like in an inert solvent, such as Er Yu Bingzhang at 0 C to about 100 τ At temperature Analogs of amines, fethylamine, chlorocarbonate or bell carbonate, and their k-like compounds h_ (racemic or optically active) and ~ —— --- --- _____________ This paper scales inverse, in, J Λ 71 W specifications [210: < 297 gong (Please read the precautions on the back before reading and writing this page)

552260 A7 B7 V. Description of the invention (69) (where X is a releasing group (such as a halide or a sulfonate), and & has the same meaning as previously defined), and the intermediate ester 1 is obtained. Hydrolyzates can be used, such as alkalis such as sodium hydroxide or lithium hydroxide or potassium hydroxide and the like, in situ in solvents such as ethanol-water or THF-ethanol and the like The ester is isolated or converted to a meta-acid (U). A more detailed description of the preparation of specific analogs is provided in plan χποοα. An aliphatic β- can be prepared by Gcatan reagent (such as propylmagnesium bromide) for copper-catalyzed addition of unsaturated vinegar, ethyl 3,3-dimethacrylate. Ketoester (plan χνι). The resulting ester is hydrolyzed, for example using sodium hydroxide in a water-containing alcohol, and it is cracked into corresponding β-ketoesters in a stepwise manner, for example by using carbonyldiimidazole to activate, and magnesium-ethyl Oxymalonate is condensed. In addition, the ethylenic ketone ester can be prepared by the Clalsen rearrangement of the corresponding allyl alcohol; like the hydrolysis and homolytic action described above, the desired β-ketoester is produced. Middle A i: i: j (Please read the notes on the back before filling in this page. J Prepare N-alkyl, 0-alkyl bromide hydroxylamine 3 according to plan XVII. N-Boc-O-allyl using alkyl halide Alkylation of hydroxylamine, for example using sodium hydride; selective reduction of double bonds, for example using hydrogen and palladium catalysts. After removing the Boc group, for example, with FA, the resulting amine is acidified, for example using Ethyl bromide bromide.

The β-ketoesters described in Plan χνί can be converted to pyrrolidine derivatives as described in Plan XVIII. A base, such as DBU or potassium tert-butoxide, can be used to catalyze the Mitchell production of p-based styrene derivatives: the resulting addition compound is hydrogenated, for example using Raney town as a catalyst to obtain an imine 'boat Reduce it, for example, at a controlled pH -72- this paper size is suitable for the National Standard of Zhongzhou (CNS) Λ4 Specification ΰίΟχ] 97 mm) ii Part 乂; "^ 2260 'Invention description (70. I 下' Oxygen rotten gasification steel is used. Reed; ^ 1 / ^^ ^ A mixture of healthy and healthy products, of which 6 is the best anti-reverse. Plan XIX foretell several solutions. 折 1J _斫 The above mentioned strategy of racemic pyrrolidine. Treatment with a hand-on acid, such as (s) _ (+) _ Tarenic acid, P ,, U σ 彳 phthaloyl wood treatment, to provide a crystalline derivative: -Step through recrystallization to make it more abundant. The base can be used to rinse this :, the analytical reagent is taken, and the bite product with optical activity is brought. Second, the amino group ΝΝ- can be protected (for example, by Boc-liver), and then hydrolyzed (for example, with steel hydroxide) to obtain the relative 钤 J 'J, the corresponding N_ protected amino acid. Jiang this ^ β ^ cheng Defafenyl esters, followed by chiral non-racemic phosphonium hydrazone anion coupling 'provide the corresponding phosphonium phase diastereoisomeric isomorphism' which can be separated in a chromatographic manner. Species 醯 m㈣ 非Enantiomerization: Conjugation, followed by cleavage of the N-protecting group, to bring about optically active amine groups. Coupling of amino acids with chiral, diisopropyl, and triphenylenes and chiral non-racemic amino alcohols The effect completes a similar transformation. After the chromatographic separation of the obtained diastereomers, the amidine is cut and the protective group is removed to provide an optically rich house 3 3 using various electrophilic substances, such as Dibutylacetamide bromide, N • butyl, N-alkoxyacetamide bromide, N- (4-heptyl) _N · (3_fluorenylfluorophenyl) acetamide bromide, Or N- (Ω-hydroxyalkyl) -N-alkyl halogenated ethylammonium amine, alkylates the optically active amine ester prepared according to the above (plan χχ). Hydrolysis of the resulting diester (for example in water Sodium hydroxide) is used in alcohols to provide this product. There is a specific class of electrophilic substances, N- (m 蚬 yl) _ν-alkynyl_acetamide, which may be alkylated into The product was further transformed (73- scale of this paper states that ten S National Standards (CNS) Α4 specifications "qe 210 297 mm) (read first read the note and then fill in the back of this page)

552260 A7 B7 Fifth and fourth, talk clearly (71) Plan XXI). The activation of an alcohol (for example, using methanesulfonyl chloride), followed by replacement with a halogen (for example, lithium bromide per week) provides the corresponding halide. Substituting amines with amines, such as dimethylamine, provides corresponding amine esters, which can be hydrolyzed as described previously to obtain the product. (Please read the precautions on the back before filling out this page) Thousands 屮 而 λ and] &A; A 卬 -74- This paper is the size of Shizhou Zhongwei National Standard (CNS) Λ4 specification (210X 297 cm) 552260 A7 B7 V. Description of the Invention (Plan 72) ^ R2 c〇2e +

2 [H] Η N R2

Ri co2e N R2

Ri co2e Please read the notes on the back before filling in this page.

Ri φι. N R2

Ri C02E c〇2h anti-trans [H20] anti-trans, cis-trans mixture r2 ... * / R3 Guang N c〇2e cis-trans-75- paper & standard Shizhou Zhongyuanyuan Standard (CNS) Λ4 specification (HOX 297 mm) 552260 A7 B7 V. Description of the invention (73

Plan II

R2… CI

s, Li ^ S * 10 r2

s- 11 〇 R2 ^ J ^ Rl " " s r2., S- (Please read the notes on the back before filling out this page 13

Rt 12

OXC cr 14

Ri

CN r2 15

Ri isomers or

r2 co2e cr 17

r2 CN Ri Φ—,

JS, li;? · In i:

•, c〇2h 19

Rt -76- This paper is in accordance with National Standards (CNS) of 屮 4 size Γ210 × 297 mm 552260 A7 B7 V. Description of the invention (74

Plan III

R r2

C〇2E +

Halo (halogen) VJ

2Q

21 Halo = Cl, Br, or I

n

n

2i 〇 R2

Ri 25 R, C02H Anti-Anti Chinese ik Η Η Η X; il A 卬 -77- (Please read the notes on the back before filling this page)

This paper & standard tracking / 彳] China National Standard (CNS) Λ4 Specification C 210X297 mm) 552260 A7 B7 V. Description of Invention

Plan IV

52 7

o ^ chn2 (Please read the precautions on the back before filling out this page) 、-口

C02H Μ 53 yf \ Department t Lost $ 乂: j η t -73- The paper size is Shizhou Zhongwei National Standard (CNS) A4 specification (21 OX 297 mm) 552260 A7 B7 V. Description of the invention (76

Plan V ch3o

+ 〇 〇

, No.2 D8U

ZL 〇 CH3〇

COOEt cis-cis ’trans-trans, cis-trans mixture OCH3

OCH3 NaCNBH3 Chromatographic Separation (Read the precautions on the back before filling in this page — ^ ------ Order-cis + Trans-trans and cis-trans mixture 31 -79- China National Standard Apple (CNS) Λ4 Specification C 210X297 mm) 552260 A7 B7 V. Description of Invention (77

Plan VI

och3

BrCh ^ CONHC ^ j C

〇

(Please read the notes on the back before filling this page) 〇

+

Cis-trans 34 A 卬 -80- The standard of this paper is the National Standard of China Central Park (CNS) A4 size f 210X 297 mm 552260

A7 B7 V. Description of Invention (78)

Plan VII -81-Specification of this paper / 彳] China National Standard (CNS) Λ4 Specification C 2 丨 0X 297 mm) (Please read the precautions on the back before filling this page)

552260 A7 B7 V. Description of Invention (79) Plan VII continued

-82- (Please read the notes on the back before filling this page)

Dimensions of this paper / 丨] Chinese Standard (CNS) Λ4 Specification C2 丨 0X 297 mm) 552260 A7 B7 V. Description of the invention (Plan 80 νπι ch3o

co2e +

〇 CH3o

Chch3 〇ch3 (Read the precautions on the back before filling this page) ”ί; · τ; Ministry Jk > /] f · \\ λ \ 卬

Anti-anti-S3- This paper is suitable for national standards in Sichuan (0 milk) 8 4 specifications (: 210 乂 297 mm) 552260 A7 B7 V. Description of invention (81

Plan IX r3 R3 N R2

Ri N R2

R1

(CH2) mI c〇2h K (CH2) mI c〇nh2 N r2

(CH2) r R3

(Please read the notes on the back before filling in this page n ^ nh n = n

(CH2) mI CN5Z Order R2

N R3 / R3 / R3 NN NN -R1 r2— ^ R2— ^ \ > -Ri €; · Γ in $ $ y ^ · 卬 (CH2) m — Λ

HN 〇 N / 〇 h2n

(CH2) m Into NOH (CH2) m HN 丄 7 s-〇 〇 61 -84- This paper is suitable / i] National Standard for Prisoners (CNS) Λ4 Specification [210 X 297 mm] 552260 A7

B7 V. Description of Invention (82) Plan X

The paper size is in accordance with China State Standard (CNS) Λ4 specification (210X 297 public dredging) 552260 A7 B7 V. Description of the invention (83

Plan XI Η, r8 ~ x Ν

co2e 5

R2—X Ν R2

Ri C02E (Please read the notes on the back before filling this page

O

Rg — N r8 ~ nhr2〇 R;

N

Ri c〇2h N R2

co2e

Ri order g7 o. Re

/ f part 屮 A N R2

co2h

Rel 〇 © -86- The size of this paper is suitable for National Standards (CNS) A4 size f 210 X 297 mm 552260 A7 B7 V. Description of the invention (84

Plan XII

N ch2 * IQ .C02Et • r2 71

Ri

(Please read the notes on the back before filling this page

Me3Si ’N

73 + / 〇 II 〇CH3 〇

C02Et

, 1T

I 1 ($ 卬

〇 74

巳 u2N

OCH, O

s -37- The size of this paper is the National Standard of S in China (CNS) Λ4 Specification 010 × 297 mm 552260 A7 B7 V. Description of Invention (85

Plan XIII

1. Boc2〇 2. NaOH, ΕίΟΗ Η20 OCH η

[(+)-Sinconine 2. Recrystallized from EtOAc / hexanes 3. Na2C03 OCH η

HCI Et〇H och3

(+) IS

巳 u2NC (〇) CH2Br EtNiPr2, CH3CN t ik guide _τ elimination f · ii Ϋ Ϋ

-83- (Please read the notes on the back before filling this page)

Dimensions of this paper / 丨] Gion National Standard (CNS) Λ4 specification [210 X 297 mm] 552260 A7 B7 V. Description of the invention (86

Plan XIV

Me3Si ^ R2 \ ^ \ CO2R56, OMe TFA, CH2C12

CO2R56 (Please read the notes on the back before filling this page ΙΦ

h2Pd (OH) 2 / C

CO2R50 R2 R3BrB114NI or Nal ~~ CH3CN ~ * D R,

CO2R56

NaOH or LiOH Et〇H, H20 R,

, N

C〇2H r2 Although

Intermediate guidance f 'in SL Department: -89 Specifications of this paper; i] Medium® National Standard (CNS) Λ4 Specification c 210X297 mm) 552260 A7 B7 V. Description of the invention (87 Project 彳 XV' r2 + ect ν Ri m 〇

co2e

co2e o2n

aii R2 Ri co2e 90

• NH

co2e 92

Ri R2 / 3/3

co2h 2S co2e 94 -90- (Please read the precautions on the back before filling this page)

This paper is in Shizhou 1¾ national standard (CNS) Λ4 specification Γ210 × 297 public trend) 552260 A7 B7 V. Description of invention (88

Plan XVI

COOEt nPrMg day r Na〇H CD! 0% OEt catalyst CuCl

HOOC

〇: EtOOC

OEt OH J < OEl # 〇Et NaOH Λ CDI 〇 OEt H +, heating \ φ $ ηι

HOOC

〇 EtOOC

(Please read the notes on the back before filling this page

Plan XVII, -port

R-X Pd-C

BocN TFA has rCH2C〇8r

Plan XVIII —Middle Time · Γ

EtOOC +

Q 〇 or catalyst KOtBu Ra-Ni

DBU

R 〇 一 -91-The size of this paper is suitable / 丨] China National Standard (CNS) Λ4 Specification C 210X 297 mm) 552260 A7 B7 V. Description of Invention (89

Plan XIX R (s) -w · Mannamic acid recrystallization Neutralization

〇-

R

R (racemic)

V f J t

〇- (Single Enantiomer) (Read the notes on the back before filling in this page)

R

(Racemic >

ED AC

〇- 1. EDAC, H〇〇 巳 t 1. B〇c2 0 0 5L / 〇H 1.HCI. Heating

2 · NaOH 3. Separation of diastereomers 1 HCI, EtOH

cr isomers (racemic) (single enantiomer) -92- Paper size 迖 / Π 屮 S National Standard (CNS) Λ4 size Γ210 × 297 mm) 552260 A7 B7 V. Description of the invention (90)

Plan XX

R

〇 Βγ, Λ0 r2

NaOH nr! R2

(Please read the notes on the back before filling this page)

Plan XXI

, 〇H I. MsC!

R 2. LiBr

(CH3) 2NH NaOH

R

-93 This paper is the national standard (CNS) of Sichuan Chuanwang Net (A4 size C 210X 297 mm) 552260 A7 B7 5. Description of the invention (91 In order to prepare the compound of the present invention, the compound that can be used as an intermediate is: r2.

NH

I (CH2) m

Ri (Please read the notes on the back before filling this page) (ch2) 「

W (III) where n is 0 or 1;. M is 0 to 6; W is (a) -C (0) 2-G, where G is hydrogen or a complex group of 1 '(b) -P03H2, (c) -P (0) (〇H) E, where E is hydroxy, low-carbon alkyl or aralkyl, (d) -CN, (e) -C (0) NHR17, where R17 is low carbon Alkyl, (f) alkylaminocarbonyl, (g) dialkylamino '(h) tetrakisyl, (l) hydroxyl, (J) alkoxy, (k) continuous amino, 胺- c (〇) nhs (o) 2r16, where r16 is a lower carbon number alkyl, haloalkyl, phenyl or dialkylamino group, (m) -S (〇) 2NHC (〇) R16, -94- Zhang Zhishi / i] Chinese due to national standards (CNS) Λ4 specification C 210X 297 male 茇 552260 A7 B7 V. Description of invention (92

HO

(P) (q) (0 (S) OH 彳,

〇 〇

NH 〇 〇

〇 N〆0,

A s = o CF ^ ⑴ Π, or /) one NHS〇2CF3 ⑼ and (Please read the precautions on the back before filling this page) 消 $ 卬

Ri and R2 are selected from hydrogen, low-carbon alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, iS alkyl, from alkoxyalkyl, alkoxy-95 -The standard of this paper is Sichuan National Standard (CNS) Λ4 Specification (110/297 Gongchu) 552260 A7 B7 V. Description of the Invention (93) Oxycarbyl radical, Thioxalyl radical, Ring Alkyl, cyclofluorenyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylfluorenyl, hydroxy Fluorenyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, (N-alkanofluorenyl-N-alkyl) amine, alkynyl, SS, amine Ring group, (hetero 4 ring group) alkyl and (Raa) (Rbb) N-Rcc-, where Raa is aryl or aralkyl, Rbb is hydrogen or alkanyl, and is alkylene, which is restricted With the proviso that either or both of R1 and R2 are not hydrogen; or a salt thereof; or a compound of formula (I): (CH2):

Or r2 w

Ri

kNH I (V)

7 "-口-* ^ 、 " 々 ^^: 1 T- MJ, M— and * V where n is 0 or 1; m is 0 to 6 ·· W is (a) -C (0) 2_G, Where G is hydrogen or carboxy protecting group, (b) -P03H2, (c) -P (0) (0H) E, where E is hydroxyl, lower carbon or aralkyl, (d) -CN, ( e) -C (0) NHR17 'where R17 is a low carbon number alkyl group, (f) an alkylaminocarbonyl group, -96- this standard is suitable for the national standard (_CNsYA4 ^ Tf2) 297 ££ (please read first) Note on the back then fill out this page}

552260 A7 B7 V. Description of the invention (94) (g) dialkylaminocarbonyl, (h) tetradecyl, fluorenyl hydroxyl, (J) alkoxy, (k) continued gS amine, (l) -C ( 0) NHS (0) 2R16, where R16 is a lower carbon number alkyl, haloalkyl, phenyl or dialkylamine, (m) -S (0) 2NHC (0) R16,. (Please read the back (Please fill in this page again)

The standard of this paper is Chinese state standard ((: milk) / \ 4 size (: 210297297297 牦) 552260 Α7 Β7 V. Description of invention (95)

(Please read the notes on the back before filling this page)

Ri and R2 are selected from the group consisting of hydrogen, low-carbon alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkynyl, trialkyl, alkynyl, sulfanyl, and alkoxy Alkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, amine carboxyl, alkylamino carbonyl, dialkylamino carboxyl, amine carboxyl , Triamino, diamino, alkenyl, alkynyl, aryl, aryl, aryl, aryl, aryloxy, aryl, aryloxy, and (N-chain alkyl) (Amino), amino, alkyl, alkyl, heterocyclic, (heterocyclyl) amido, and (Raa) (Rbb) NR "-'where Raa is aryl or aryl, is hydrogen or The bond is a 4-membered acid group and Ree is an elongation group, with the limitation that one or both of I and R are not hydrogen; or a salt thereof. Preferred intermediates include formulae (III), (IV) and ( V) a compound in which m is zero or 1; W is -C〇2_G, where G is hydrogen or a carboxy protecting group, and R! And R2 are as defined above; or substantially pure (+) _ 4 ( -)-Isomers. Particularly preferred intermediates are compounds of formulae (III), (IV) and (V), which are -98- 55226 0 Α7 _Β7 ^ ____ V. Description of the invention (96) η and m are both 0; W is -C02-G, where G is hydrogen or carboxy protecting group; and Ri is fluorene low-carbon alkyl, (ii) alkenyl , (Hi) oxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl, or (viii) substituted or unsubstituted 4-fluorenyloxy 1 Epoxy, 4-pyrenyl, 3-pyroyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-fluorenylphenyl, 4-trifluorofluorenylphenyl, 4-pentafluoroethyl Phenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-fluorenyloxyphenyl, 4-hydroxyphenyl, 4- Tertiary-butylphenyl, 1,3-phenylfluorenyldioxolenyl, 1,4-benzodioxanyl, or dihydrophenylfluorenylfuranyl, wherein the substituent is selected from a low carbon number Alkyl, ii-alkyl, alkoxy, alkoxy, and alkynyl radicals ('ix) aryl xanthine, (X) aryloxy alkyl, (xi) heterocyclyl (alkyl) , (Xii) (N-alkanoylalkyl) aminoalkyl, and (xin) alkylsulfonamidoalkyl, and R2 is a substituted or unsubstituted 1,3-phenylhydrazone dioxo Heteropentenyl, 7-methoxy-L3-phenylhydrazone Dioxolyl, 1,4-phenylhydrazinyl, 8-methoxy-1,4-phenylarbioridinyl, dihydrophenylsulfanyl, phenylsulfanyl, 4-methoxyphenyl, dioxobenzyl, fluorophenyl or difluorophenyl, wherein the substituent is selected from the group consisting of low alkyl, alkoxy and halogen; or substantially pure (+)- Or (-)-isomers. (Please read the notes on the back before filling out this page. In order to prepare the compounds of the present invention, other compounds that can be used as intermediates are: fr

/.S ν: 552260 A7 B7 V. Description of the invention (97)

(Please read the notes on the back before filling out this page) where η is 0 or 1; m is 0 to 6;

Rsb is elongation group; Q is release group; W is (a) -C (0) 2-G, where G is hydrogen or carboxy protecting group, (b) -P03H2, (c) -P (0) (〇H) E, wherein E is a hydroxyl group, a lower carbon number alkyl group, or an aralkyl group, (d) -CN, '(e) -C (0) NHR17, wherein R17 is a lower carbon number alkyl group, (f) Alkylaminocarbonyl, (g) Dialkylamino, (h) tetralingyl, fluorenyl hydroxyl, (J) alkoxy, (k) sulfonylamino, (l) -C (〇) NHS ( 0) 2R16, where r16 is a lower carbon number alkyl, haloalkyl, phenyl, or dialkylamino group, (m) -S (0) 2NHC (〇) R16, -100- In accordance with domestic standards (CNS) Λ4 specifications Γ210 × 297 mm) 552260 A7 B7 V. Description of the invention (98

HO

〇

OH

N- (Read the notes on the back before filling in this page) (Γ) 〇 s = 〇 (S) N Η Ν ⑴

CF,, or nhso2cf3 and (U) R and R2 are respectively selected from hydrogen, low carbon number alkyl, alkenyl, alkynyl, and alkoxyalkyl group 101-National Paper Standard (CNS) ) Λ4 specification C 210X297 mm) 552260 A7 — ^ 一 __ — __________ 5. Description of the invention (99), alkoxycarbonylalkyl, hydroxyalkyl, southalkyl, self-alkoxyalkyl, alkoxy Oxygen-resistant group, thioalkoxy group, cycloalkyl group, cycloalkyl group, cycloalkyl group, amine carboxyl group, tiger amino carboxyalkyl group, dialkylamino group, amine carboxyl group, alkyl Aminocarbonyl, naphthyl, dialkylaminocarbonylalkenyl, hydroxyfluorenyl, aryl, aralkyl, aryloxyalkyl, aralkyloxyalkyl, (~ alkanoyl-N-alkyl ) Aminealkyl, alkylsulfonamidoalkyl, heterocyclyl, (heterocyclyl) alkyl and (Raa) (Rbb) N-Rcc- 'where Raa is a square or aryl group and Rbb is hydrogen Or an alkylalkynyl group, and it is an alkylene group, and the restriction is that one or both of R! And R2 are not hydrogen; or a salt thereof; or a compound of the formula: 阅读 Read the precautions on the back before filling in this page R2 'y ^ \ N / RSb-〇 | R2V / \ N ^ R5b-Q (C 心 | I (p H2) n (CH2) m W Ri I-or W (VII) (VIII), where η is 0 or 1; m is 0 to 6; R5b is an alkylene group; Q is a releasing group; W is (a ) -C (0) 2-G, where G is hydrogen or a protecting group, (b) -P03H2, (c) -P (〇) (〇H) E, where E is a hydroxyl group, a lower alkyl group Or sintered base, -102- State of the paper standard (CNS) grid [210X 297 public factory ^ ~-552260 A7 B7 V. Description of the invention (100) (d) -CN, (e) -C (0) NHR17, where R17 is a lower carbon number alkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetradecyl, (i) hydroxyl, (J) alkoxy Group, (k) continuing amine group, (l) -C (0) NHS (0) 2R16, where R16 is lower alkyl, haloalkyl, phenyl or dialkylamine, (m) -S (0) 2NHC (0) R16, (Please read the precautions on the back before filling this page)

-103- National Standard (CNS) for this paper standard Λ4 specification (—210X 297 mm) 552260 A7 B7 V. Description of the invention (101) (0

⑻ ⑴

• Park Ye and (please read the notes on the back before writing this page), 1T and R1 and R2 are selected from hydrogen, lower carbon alkyl, alkenyl, alkynyl, alkoxyalkyl, and alkoxy Carbonylalkyl, hydroxyalkyl, self-alkyl, self-alkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonyl Base, alkylaminocarbonylalkyl, dihexylaminoalkyl, aminoaminoalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxymethyl, aryl, aralkyl, aromatic Oxyalkyl, aralkoxyalkyl, (N-alkanoyl-N-alkyl) aminoalkyl, alkylsulfonamidoalkyl, heterocyclyl, (heterocyclyl) alkyl, and da) (Rbb) N-Rcc- 'where Raa is aryl or aryl, Rbb is hydrogen or alkanyl, and Ree is alkylene, and the restrictions are that one or both of Ri and R2 are not Hydrogen; or a salt thereof. Preferred intermediates include compounds of formula (VI), (VII), and (VIII), where is zero or 1;

Rsb is an elongation group; -104- 'eight-dimensional standard ^ ^ family standard ([NS) A4 specifications (' 210X 297 Gongzi ii 552260 A7 ____ B7 V. Description of the invention (102) Q is the release group; W is -C0_2, where G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or a substantially pure (+)-or (-)-isomer thereof. Particularly preferred intermediate Including compounds of formulae (VI), (VII), and (VIII), where η and m are both 0; R 5 b is elongation; Q is a releasing group; W is -C02_G, where G is hydrogen or A carboxy protecting group; and Ri is a fluorenyl group, (ii) an alkenyl group, (iii) an oxyalkyl group, (iv) a cycloalkyl group, 0) a phenyl group, (vi) a pyridyl group, and (vii) a Aryl, or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methyl Phenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-fluorenylphenyl, 3-fluoro-4-ethoxyphenyl, 2-benzylphenyl, 4-methoxymethoxyphenyl, 4-¾phenyl, 4-tert-butylbennon, 1,3-benzo-dioxolyl, 1,4-benzodiuridine Diaminobenzofuran Wherein the substituent is selected from the group consisting of a low-carbon alkyl group, an alkyl group, an alkyl group, a pitoxy group, and a double alkoxy group, (ix) an aryl group, (x) an aryl group, (Xi) heterocyclyl (alkyl), (xii) (N-alkanoyl-NN alkyl) amine, and (xiii) alkylsulfonamidoalkyl, and R2 is substituted or unsubstituted Substituted 1,3-phenylhydrazone dioxolenyl, 7-methoxy-1,3-phenylhydrazone dioxolyl, 1,4-phenylhydrazone di 17 alkyl , 8-methoxy-1,4 · phenylpyridine, p-diphenyl, dihydrobenzopyranyl, benzopyranyl, 4-methoxyphenyl, dimethoxybenzyl, fluorophenyl or Difluorophenyl, where the substituent is selected from a low-boiler-105-benzyl & 仄 standard extension ^ Bu national standard extract ("milk" 8 4 specifications (21 (^ 297 mm)) (Please read first (Notes on the back then fill out this page)

552260 A7 B7 5. Description of the invention (103), alkoxy and halogen; or its substantially pure (+)-or (-)-isomer. In order to prepare the compounds of the present invention, other compounds that can be used as intermediates are: R2 \ / \ N ^ R5b-NHR20a I (ch2) "(CH2) m

Ri

W (IX) where n is 0 or 1; m is 0 to 6; R5b is an alkylene group; R 2 0 a is nitrogen, a low-carbon pit group, an alkenyl group, a self-resistance group, an anti-lactation group, a letter group Oxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; W is (a) -C (〇) 2-G, where G is hydrogen or carboxy protecting group, (b) -P03H2 , Where E is mesityl, low-carbon alkynyl or arylfluorenyl, (Please read the notes on the back before filling out this page} 卬 (c) -P (0) (0H) E (d) -CN, (e) -C (〇) NHR17, pinaneaminocarbonyl, (g) dialkylaminocarbonyl (h) tetralingyl, (i) hydroxyl, where R17 is a low-carbon alkyl-106- main paper ft Standard iiW Standard (CNS) Λ4 Specification Γ210 × 297 male 牦 552260 A7 B7 V. Description of the invention (104) (J) Alkoxy, (k) Sulfonamido, ⑴-C (0) NHS (0) 2R16, where Ri6 is a lower carbon number alkyl, haloalkyl, phenyl or dialkylamino, (m) -S (0) 2NHC (0) R16,

(〇)

HO 〇 (P)

OH

〇 (Please read the notes on the back before filling this page) (q) 〇

In the NH 〇 part, the fire h _τ disappears (r) (s)

s = o 〇 〇 -107- The standard of this paper is Shuzhou National Valve Standard (CNS) Λ4 Specification Γ210 × 297 Gong) 55226〇 A7 B7 5 Description of the invention (〖〇5)

⑴, ... \ 〇 ~ and (U) ^: and R1 and R2 are respectively selected from hydrogen, lower carbon alkyl, fluorenyl, alkynyl, alkoxyalkyl 'alkoxycarbonylalkyl, hydroxyalkyl, and Alkyl, alkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkyl Alkylaminocarbonylalkyl, aminecarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl , (N-alkanoyl-N-, oxanyl) aminoalkyl, alkylsulfonamidoalkyl, heterocyclyl, (heterocyclyl) alkyl, and (Raa) (Rbb) N-Rcc- Where Raa is aryl or aralkyl, Rbb is hydrogen or alkynyl 'and Ree is elongation', with the limitation that R1 and one or both are not hydrogen; or a salt thereof: or Compound:

'4: 屮 centric 1 丨, 〆R5b-NHR20a y N j (ch2): I, k (CH2) n 1 * I w Rl. 1 i or w R1 (X) (XI) n is 0 or 1; m is 0 to 6: 108 «·

This paper is a scale of Shizhou Zhongyuan National Standard (CNS) Λ4 specification (210 X (Please read the precautions on the back before filling this page)

552260 Α7 Β7 V. Description of the invention () ^

Rsb is an elongation group; R: 20a is hydrogen, a low-end alkyl group, amidino group, a halogenated group, an oxygenated group, a fluorene, a halogenated oxyalkyl group, a cycloalkyl group, a cycloalkyl group An alkyl group, an aryl group, or an aryl group; w is fluorene-C (0) 2-G, where G is hydrogen or a carboxy protecting group, (b) -P03H2, (c) -P (0) (0H) E, Where E is hydroxy, low-carbon alkyl or aralkyl, (d) -CN, (e) -C (0) NHR17, where R17 is low-carbon alkyl, (f) alkylaminocarbonyl, (g ) Dialkylaminocarbonyl, (h) Tetracyl, (i) Hydroxyl, (J) Alkoxy, (k) Sulfonamido, (l) -C (0) NHS (0) 2R16, where Ri6 Is a low-carbon alkyl group, haloalkyl group, phenyl group or dialkylamino group, (m) -S (0) 2NHC (0) R16, (诮 Please read the notes on the back before filling in this page. -", φ—-^ 3, ^ ', · JUJ X 1- τ- vnj

_-109- Ben, Λ ^, Standards for Humanity (CNS) ~ M specifications (210 乂 297 GMT 552 260 A7 B7 V. Description of the invention (107)

OH

(「） 〇 • 〇 (Please read the notes on the back before filling in this page) Η ⑻ 屮

I ⑴ (U)

CF3 or NHS〇2〇F3 and

Ri and R2 are selected from hydrogen, lower carbon alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, self-alkyl, self-alkoxyalkyl, alkoxyalkane Oxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminecarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminecarbonylalkenyl, alkyl Aminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxyalkyl, (N-chain: fe SS-N-pit Group) amine alkyl, alkyl benzaminoalkyl, heterocyclyl, (heterocyclyl) alkyl and (Raa) (Rbb) N-Rcc-, where Raa is aryl or aralkyl and Rbb is Hydrogen or chain 110-, paper size national standard (CNS) Λ4 specification (210 乂 297 mm) 552260 A7 B7; f: 发明 Bureau invention description (108) 8 base, and Rec is the Grafting group 'has the limitation that one or both of Ri and R2 are not hydrogen; or a salt thereof; preferred intermediates include compounds of formula (IX), (X) and (XI), where m is zero or 1 ;

Rsb is elongation group; R20a is hydrogen, low carbon number alkyl, alkenyl, haloalkyl, alkoxyalkyl, halooxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, or Aralkyl; W is -C02_G, where G is hydrogen or a tether protecting group, and Ri and R2 are as defined above; or a substantially pure (+)-or (-)-isomer thereof. Particularly preferred intermediates include compounds of formula (IX), (X) and (XI), where both η and m are 0;

Rsb is an alkylene group; R20a is hydrogen, a low-carbon alkyl group, an alkenyl group, a haloalkyl group, a oxyalkyl group, a oxyalkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, or Aromatic groups; W is -C02-G, where G is hydrogen or carboxy protecting group; and Ri is fluorene lower carbon alkyl group, (ii) alkenyl group, (ill) alkoxyalkyl group, (1V) ring Zyl, (v) phenyl, (vi) pyridinyl, (vii) ranyl 'or (viii) substituted or substituted 4-fluorenylphenyl, 4-fluorophenyl, 3- Fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-fluorenylphenyl, 4-trifluoromethylphenyl, 4-pentaethylethylphenyl, 3-fluoro-4-methyl Oxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, tert-butylphenyl, 1,3- Benzene, dioxolenyl, 1,4-benzene # diamondyl group or diazine-111 paper size iiU] depressing prisoner-like apple (CNS) Λ · 4 size C 210X 297 male (%) (Please read the precautions on the back before filling out this page-5 Φ; 552260 A7 B7 屮 A iV again: j / ~, ί 5 'invention description (109)) Furan f: where the substituent is selected from Low carbon number alkyl, commercial alkane Group, pitoxy group, alkoxyalkoxy group and carboxyalkoxy group, (ix) aralkyl group, a) aryloxyalkyl group, (χ〇 heterocyclyl (alkyl), (magic 1) (1 chain Alkyl _N_alkyl) amine = ri, and (xm) alkylamino, and h is a substituted or dipolar dioxanyl 3-oxodifluorenyl, 7_methoxy_ 丨, 3_benzo metadioxolenyl, 1,4-benzodifluorenyl, 8_fluorenyloxy_ 丨, 4_benzofluorenyl diazinyl, di Hydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl, or difluorophenyl, wherein the substituent is selected from the group consisting of low-carbon alkyl, carboxy, and Or its substantially pure (+)-or (_) · isomer. The foregoing may be made more thorough by reference to the following examples, which provide explanations rather than attempt to limit the scope of the inventive concept. Use the following Abbreviations: Boc is tertiary-butoxycarbonyl, Cbz is fluorenyloxycarbonyl, DBU is 1,8-diazobicyclo [5.4.0] undec-7-fluorene, and EDCI is 1- (3-dimethyl Amine) propyl_3_ ethyl hydrazine diimide hydrochloride, EtOAc is ethyl acetate, EtOH is ethanol, and HBt is 1-hydroxyl Bing triazole, EHN is triethylamine, TFA is trifluoroacetic acid, and the bite is tetrahydropyran T H F Nom. Example 1

Transmethoxyphenyl) -4- (1.3-Mo # meta-dioxetane # -5-ylcan 1- (propylaminocarbonylmethyl pyrrolidine-3-carboxylic acid example 1A g- (4-fluorenoxy Benzoyl) -4-nitropyridyl-3- (1,3-benzene # m-dioxopent-5-yl) -ethyl butyrate will be 1,8-diazobicyclo [5.4.0 ] 11 completed-7- 晞 (DBU '0 65 grams) added to (ti read the precautions on the back before filling out this page) 112- This paper describes Chuanxi valve national standard (CNS) Λ4 size C 210x 297 male %)

N. 0Ρ °° 552260 A7 B7 V. Description of the invention (11〇)

A was dissolved in 180 ml of toluene, heated to 8th generation, and (4_methoxybenzyl) acetic acid ethyl acetate (23.0) prepared by Krapch0 et al. Syng Note 2_, 20 (1967). G, 0.14 mol) and 5- (2-acryl) M-phenylhydrazone dioxolane (i7, 00888 mol), and stirred. This mixture is heated 'until all of the nitro starting material is dissolved. The solution was stirred without heating for 30 minutes, and then an additional 065 g of qing was added. After an additional 45 minutes, thin-layer chromatography (ethyl acetate in dioxane) showed no nitro starting material. Toluene (200 ml) was added and the organic phase was washed with dilute hydrogen acid and NaCl solution. The organic phase was dehydrated with sodium sulfate and then concentrated under reduced pressure. The obtained residue was chromatographed on silica gel, eluting with 3: i hexane. Acetic acid, to obtain 21.22 g of the desired product in the form of a mixture of isomers, and recover 9 g of (4-fluorenoxybenzene) Formamyl) ethyl acetate. Example 1B Phenylfluorenyl) -4,5-diplex: 3H-pyrrole-3- # acid under 4 atmospheres of hydrogen pressure using Raney nickel 2800 catalyst (5 μg), in 500 ml of ethanol, The compound from Example 1At (21 g) was hydrogenated. (Raney nickel was rinsed three times with ethanol before use.) The catalyst was removed by filtration and the solution was concentrated under reduced pressure. The obtained residue was chromatographed on crushed gel to elute 85% ethyl acetate in dichloromethane to give 12.3 g of the desired product. Example 1 The existence of k in the form of a mixed t of structure C. Please read the notes on the back before filling out this page. 1 · Ordering 丨 -113- The standard of this paper is appropriate, around the national standard (CNS) Λ4 specifications (· 21 〇χ 297 公 楚 552260 'k 合 ίί A7 V. Description of the invention (111) oxapentene-5_ylpyrrolidine-3 diquinic acid) Acetyl ether The compound from Example 1B (1 89 grams) (0,324 moles) was dissolved in 27 ml of tetrahydrofuran and 54 ml of ethanol. Add sodium cyanoborohydride (2.3 $ g, 0.374 moles) and 5 mg of bromocresol green. Add 1-2 concentrated HC1 in ethanol at a rate that keeps the color at a light yellow_green color dropwise in ethanol. After the yellow color persisted without additional HC1, the solution was stirred for another 20 minutes. The solution was concentrated in the air, and then distributed between chloroform and an aqueous potassium hydrogen oxalate solution. The organic phase was separated, dehydrated with sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 85:15 ethyl acetate-hexane, to give 5.96 g of a mixture of 64% trans, trans-compound and 34% cis, trans-compound. Further elution was performed with pure ethyl acetate. After 3.044 g of pure cis, cis-compound, 0.505 g of an unknown solid was obtained.

Example 1D trans, trans ^ 111 ^ _1 ^ phenyl) -4- (1,3-phenylhydrazone dioxol-5-yl liliL noaminocarbonylmethyl pyrrolidine-3-chinic acid will be in A mixture of 64% trans, trans- and 34% cis-trans-pyrrolidine in 30 ml of acetonitrile (from the mixture from Example 1C) (5.72 g, 15 50 mmol), (Ethyl "is propylamine 20 G, 32.56 mmol) and N-propylacetamidinium bromide prepared by the method of Weaver, WE and Whaley, W · M ·, J. Amer. Chem. Soc., 69_: 5 15 (1947) (3.42 g, 19.0 mmol) was heated to 50 ° C for 1 hour. The solution was concentrated in the air. The residue was dissolved in formazan, shaken away with the carbon solution, and covered with sulfur. NA-114 This paper refers to the state of the China Open Prisoner Standard (CNS) Λ4 specification (210X297 public trend) (Please read the precautions on the back before filling this page)

552260 A7 B7 Medium

f: A 5. Description of the invention (112 dehydrated and concentrated in the air to obtain 7.16 g of the product in the form of a mixture of trans, trans_ and cis, trans_ethyl Q. This mixture was dissolved in 5.00 g of hydroxide Sodium in a mixture of 50 ml of ethanol and 15 ml of water and stirred at room temperature for 3 hours. The solution was concentrated in the air and 60 ml of water was added. The mixture was extracted with ethyl bonds to remove unreacted Cis, trans-ethyl vinegar. Treat the liquid phase with hydrochloric acid until slightly cloudy. Then neutralize further with acetic acid to obtain a crude acidic product. Consider the crude product and decompose it by It was dehydrated with sodium sulfate and dried in sodium sulfate, concentrated in the air, and crystals were formed from diethyl ether to purify it to obtain 3.230 grams of the title compound. Melting point 1 5 1 -1 5 3 ° C 1Η NMR (CD 3 0D, 300 MHz) 3 0 8 7 (15 J = 7 Hz, 3 Η), 1.49 (hexaplex, J = 7 Hz, 2 Η), 2.84 (d, j 2 16 Hz, iH), 2.95-3.20 (m, 4H), 3.20 (d, J 2 16 Hz, 1H), 3 34-3 42 (m, 1H), 3.58-3.66 (m, 1H ), 3.78 (s, 3H), 3.88 (d Hz, 1H), 5.92 (s, 2H), 6.75 (d, J 2 8 Hz, 1H), 6 86 (dd, J = 8 Hz, J 2 1 Hertz, 1H), 6.90 (d5 J 2 9 Hz, 2H), 7 〇2 (d, J = 1 Hertz, 1H) '7.40 (d, J 2 9 Hz, 2H). 〖Dagger ~ Convention 2 r Ά To the trans, transphenyl) -4- (1,3-phenoxyheterocycle) di 1- (amine chinomethyl)-< chinoic acid, the method described in Example 1D was used such that: > 0 0 A mixture of 64 mg of trans, trans- and 34% cis-trans-hazitis (obtained from Example 1C), 220 mg of diisopropylethylamine and 184 mg of acetamidinium iodide, in 45. (3 T was reacted in 1 ml of ethyl wax to obtain 291 mg of trans, trans, and cis-trans.--115- The paper size is described in the state valve national standard (CNS) A4 specification (-210 X 297 mm) ) It is said that you must first read the notes on the back before you fill in this one hundred; order ii 552260 A7 B7 V. Description of the invention (113 N-alkylated esters mixture. 200 mg NaOH in 1 ml of water and 3 ml of ethanol A portion (270 mg) was hydrolyzed; extraction was performed with chloroform to remove unreacted cis, trans-ethyl ester. Using the separation and purification procedure described in Example ID, 134 mg of the title compound was obtained. Melting point 246- 24 8 ° C. 4 NMR (DMSO-d6, 300 MHz) δ 2.61 (d, J 2 16 Hz, 1H), 2.71 (t, J = 9 Hz, 1H), 2.90 (t, J = 9 Hertz, 1H), 2.98 (d, J = 16 Hertz, 1H), 3.25-3.35 (m, 1H), 3.45-3.55 (m, 1H), 3.71 (s, 3H), 3.75 (d, J = 10 Hertz, 1H), 6.00 (s, 2H), 6.8 1 (s, 2H), 6.90 (d, BU 8 Hz, 2H), 7.10 (s, 1H), 7.17 (s, lH), 7.34 (s, lH ), 7.38 (d, J = 8 Hz, 2H). Example 3 Trans, trans_2_ (methyllactino) -4- (1,3- And m-amyl lactate race associated soil _ _ 5-yl) -1- (4-fluorobenzyl) - pyrrolidine-3-carboxylic acid portion (Read precautions and then fill the back side of this page)

Using the method described in Example 1D, 300 mg of a 64% trans, trans- and 34% cis, trans-p ratio mixture (obtained from the mixture of Example 1 C), 220 mg of diisopropylethylamine It was reacted with 185 mg of 4-fluorofluorenyl bromide in 1 ml of acetonitrile at room temperature for 3 hours to obtain 3,87 mg of a mixture of trans, trans- and cis, trans-N-alkylated esters. A portion (360 mg) was hydrolyzed with 250 mg of NaOH in 1 ml of water and 4 ml of ethanol to give 160 mg of the title compound as an amorphous powder. Melting point is 246-248 ° C. 4 NMR (CDC13, 3 00 MHz) δ 2.74 (t, J = 9 Hz, 1H), 2.95 (t, J 2 7 Hz, 1H), 2.98 (d, J 2 14 Hz, 1H), 3.07 (dd , J 2 9 Hz, 1 Hz, 1H), 3 42-3.53 (m, 1H), 3 70 (d, J = 9 Hz, 1H), 3 78 (d, J 2 14, 1H), 3 81 ( s, 3H), 5.92 (s, 2 H), 6 70 (d, -116) This paper uses the national standard (CNS) Λ4 specification Γ210 × 297 mm in the paper size specification 552260 A7 B7 V. Description of the invention (114) (Please read the notes on the back before filling this page} J = 8 Hz, 1H), 6.77 (dd3 J = 8 Hz, 1 Hz, 1H), 6.91 (d, J = 9 Hz, 2H), 6.94-7.00 (m, 3H), 7.20-7.25 (m, 1H), 7.44 (d, J = 9 Hz, 2H). Example 4 Trans, trans-2- (4-fluorenyloxy) -4- (1,3-benzo-dioxol-5-yl V 1- (2-ethoxyethyl) -pyrrole Pyridin-3-carboxylic acid used the method described in Example 1D to make 300 mg of a 64% trans, trans- and 34% cis-trans-r ratio bite mixture (derived from the mixture of Example 1 C), 22 0 Diisopropylethylamine and 152 mg of 2-bromoethylethyl ether were refluxed in 1.5 ml of acetonitrile for 3 hours (at a bath temperature of 95 ° C) to obtain 346 mg of trans, trans- and cis, trans- S mixture. Hydrolyzed with 250 mg of NaOH in 1 ml of water and 4 ml of ethanol to give 140 mg of the title compound. Melting point 88.90 ° C. NMR (CDC13, 300 MHz) δ 1.25 (ί , J = 7 Hz, 3Η), 2.21-2.32 (m, 1 Η), 2.70-2.80 (m, 1 Η), 2.85-2.94 (m, 2H), 3.3 8-3.55 (m, 6H), 3.67 ( d, J = 10 Hz, 1H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, J = 8 Hz, 1H), 6.84 (m, lH), 6.84 (d, J = 9 Hertz, 2H), 7.08 (d, J =: 1 Hertz, 1H), 7.33 (d, J = 9 Hertz, 2H). Example 5 Trans, trans-2- (4-methoxyphenyl) -4- ( 1,3-phenylhydrazone dioxane -5-yl) -1- (2-propoxyethyl) -pyrrolidine-3-carboxylic acid Using the method described in Example 1 D, 520 mg of the mixture obtained from Example i C, 3 64 mg of diiso Propylethylamine, 50 mg of potassium iodide and 350 mg of 2-chloroethylpropyl ether, trans-117 at 125 ° C in 0.5 ml of acetonitrile. Milk) / \ 4 specifications (210 乂 297 Gongchu) ~ 552260 A7 B7 Jk Yi; J]] ii ii. Description of the invention (115 should be 4 hours to get 5 1 7 Ike anti 'anti-heshun 'A mixture of anti-S moieties. A portion (500 mg) was hydrolyzed with 3 15 mg NaOH in 1 ml of water and 4 ml of ethanol to give 225 mg of the title compound as an amorphous powder. 4 NMR ( CDC13, 300 MHz) δ 0.87 (t, J 2 7 Hz, 3H), 1.53 (hexaplex, J = 7 Hz, 2H), 2.28-2.41 (m, 1H), 2.71-2.83 (m, 1 Η) ), 2.92-3.08 (m, 2H), 3.30 (t, J 2 7 Hz, 2H), 3.40-3.60 (m, 4H), 3.72-3.83 〇, 1H), 3.76 (s, 3H), 5.92 (s , 2H), 6.71 (d, J = 8 Hz, 2H), 6.74 (dd, J = 8 Hz, 1 Hz), 6.71 (d, J 9 Hz, 2H), 7.07 (d, J two 9 Hz, 2H), 7.73 (d, J = 9 Hz, 2H). Example 6 trans, trans_2_ (4-methyl milk epitope) -4- (1,3 -winter bound --- milk soil pentapentyl_5-yl) 1_ [2_ (2_methoxyethoxy) Ethyl] -p than each bite

Example 6A trans, trans-2_ (4 · methyllactyl) _4_ (1,3_epi-meta-dioxopentyl-5 · yl) ethylpyrrolidine-3-carboxylic acid ethyl ester 20 drops in ethanol 21% of the sodium ethoxide solution was added to the pure cis-cis-compound (3.02 g) obtained in Example 1 C in 10 ml of ethanol. The reaction mixture was refluxed overnight and thin layer chromatography in ethyl acetate showed no starting material. The solution was concentrated in HCI and NaoEt in ethanol and in the air. The residue was dissolved in toluene and extracted with potassium bicarbonate in water. Toluene was dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain 2.775 g of the title compound, which was found to be pure by TLC (ethyl acetate). 3 -118- This paper applies the Chinese National Standard ( CNS) Λ4 specification (210X 297 mm) (Please read the notes on the back before filling this page) 552260 A7 B7 i. Description of the invention (11S) Example 6B Trans, trans-2- (4-methoxyphenyl)- 4- (1,3 -Epi-meta-dioxo-isopentyl-yl _)-1- "2- (2-methoxyethoxy) ethyl 1-pyrrolidinedi 3-Fengfa-B Ester Using the method described in Example 1D, 250 mg of the compound from Example 6A, 150 mg of 2- (2-methoxyethoxy) ethyl bromide, and 1 75 mg of diisopropyl in 1 ml of acetonitrile -Ethylamine was heated to 100 ° C for 3 hours to obtain 229 mg of trans, trans-ester. A portion (200 mg) was neutralized with 125 mg of NaOH in 1 ml of water and 2 ml of ethanol to obtain 151 mg of the title compound as an amorphous powder. iHNMRCCDsOD, 300 MHz) δ 2.9-3.9 (π, 13Η), 3.81 (s, 3H), 4.49 (d, J = 10 Hz, 1Η) '5.94 (s, 2Η), 6.79 (d, JNS Hz , 1Η), 6.89 (dd, J = 8 Hz, 1 Hz, 1H), 7.00 (d, J = 9 Hz, 2H), 7.05 (d, J = 1 Hz, 1H), 7.49 (d5 J = 9 Hz, 2H). Example 7 屮 if / :; ji; /; f. 卬 (Please read the precautions on the back before filling out the oxybenzyl group on this page) -4- (1,3-Benzo-dioxetane-5- Pyridyl) ethylpyrrolidine-3-carboxylic acid The compound from Example 6A (250 mg), 2-vinylpyridine (355 mg) and 1 drop of acetic acid were dissolved in methoxyethanol and 〇〇 下 stirred at 2. $ hours. Toluene was added and the solution was rinsed with a potassium bicarbonate solution. Known; Each solution was dehydrated with potassium bicarbonate and concentrated in the air. Toluene was added. This step is carried out until the 2-ethylenyl P ratio of 17 is gone. The residue was dissolved in hot heptane, filtered to remove a small amount of non-dropping impurities, and concentrated in the air to obtain 225 mg of the intermediate ester. The ester was hydrolyzed by the method described in Step 1D, Obtained 202 mg of anti-reflection 4 Vi'_ house mark 芊 (CNS) M specification -119- Γ210 × 297 mm 552260 A7 B7 V. Description of the invention (117 (Please read the precautions on the back before filling this page) is dihydrate The title compound in the form of a substance. Melting point 77-80 ° C. IH NMR (CDC13, 300 MHz) δ 2.8-3.3 (m, 6H), 3.55-3.70 (m, 2H), 3.76 (s, 3H), 3.99 ( d, J = 10 Hz, 1H), 5.92 (d, J = 1 Hz, 2H), 6.72 (d5 J = 8 Hz, 1H), 6.80 (dd, J = 8 Hz, 1 Hz), 6.85 (d, J = 9 Hz, 2H), 6.92 (d, J = 1 Hz, 1H), 7.20 (d, J = 9 Hz, 2H), 7.20-7.32 (m, 2H), 7.70-7.80 (m, 2H), 8.40 (d, J = 4 Hz, 1H). Example 8 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) _ 1 _ (qiaomakoulin_ 4 -1 ^ |-口 比 口 ji Add 146 mg of 1-morpholine carbonyl chloride to 2 ml In chloromethane, and cooled in an ice bath, the compound from Example 6 A (300 mg) and 164 mg of triethylamine. The mixture was stirred at room temperature for 3 hours. Toluene was added and hydrogen carbonate was added. The solution was washed with potassium solution, dehydrated with sodium sulfate and concentrated in the air to give the intermediate ester. This ester was hydrolyzed by the method described in Example 1 D to give 288 mg of the title compound. Melting point 244-246. 4 NMR (DMS 0-d6, 3 00 MHz) δ 2.96 (dd, J = i2 Hz, 13 Hz, 1H), 3.03-3. 13 (m, 2Η), 3.20-3.30 (m, 2H), 3.40-3.60 (m, 5H), 3.74 (s, 3H), 3.70-3.85 (m, 3H), 5.10 (d, J = 10 Hz, 1H), 5 99 (d, J = 1 Hz, 2H), 6.80-6.90 (m, 2H), 6.87 (d, J 2 9 Hz, 2H), 7.07 (s, 1H), 7.25 (d, J = 9 Hz, 2H). Example 9 Inverse, trans-2- (4 -Methoxyphenyl) -4- (1,3benzo-dioxol-5-yl)--120- Dimensions of this paper / 丨] China National Standard (CNS) Λ4 Specification "210X 297 public) 552260 A7 B7 V. Description of the invention (118) Φ Λ leads to 卬

LiiJUJ ^ yl cleavage group) -Gugui-3-篆 jii · 88 mg of butyl isocyanate was added to 2 ml of tetrahydrofuran and cooled in an ice bath to obtain the compound obtained from Example 6 A ( 300 mg). After 40 minutes at room temperature, toluene was added and concentrated in the air to obtain the intermediate ester. This ester was hydrolyzed by the method described in Example ID to give 232 mg of the title compound. Melting point 220_221 t. iH NMR (DMSO-d6, 300 MHz) 50.78 (t, J = 7 Hz, 3H), 1.10 (hexaplex,] 2 7 Hz, 2H), 1.22 (quinta peak J = 7 Hz, 2H) , 2 78_3 05 (m3H), 3.40-3.56 (m, 2H), 3.74 (s, 3H), 3.95-4.05 (m5 1H), 4.93 (d, J-2 9 Hz, ih), 5.80 (t, broad spectrum Band, j = 7 Hz, 1H), 5.99 (s, 2H), 6.78-6.86 (m, 2H), 6.88 (d, J = 9 Hz, 2H), 70 (d, J = 1 Hz, iH ), 7.12 (d, J 2 9 Hz, 2H). Example 1 0 trans_2- (4-methoxy ^ · 41γ4- (1,3-benzyl # dioxol-5-yl-1 — (4 -methylamine sidyl) -3-ρ Bihar Bite-3-Acidification Using the procedure described in Example 9, the compound obtained from Example 6A (300 mg) was treated with 3 mg of isocyanate 4-oxoepoxyacetate. Use the Method 'The obtained ester was hydrolyzed with NaOH to obtain 279 mg of the chemotactic compound. Melting point 185-187 T. 1H NMR (CDC13, 3 ⑽ MHz) 5 3.23 (0 1012 Hz, 13 Hz, 1] 9) , 3 55_3 68 (111, 2H) 'j.72 (s,] H)' 3.83 (S, 3H), 4.50 · 4 · 65 (η, 1Η), 5.06 (d, J = 10 Hz, 1Η) , 5 9〇 (S, 1Η), 5.95 (s, 1H), 6.72 (d, J 2 9 Hz, 2H), 6 7-6.8 (m, 3H), 6 92 (d, BU 9 Hz 2H) , 6.97 (d, J 2 9 Hz l2H), 7 37 (d, J = 9 Hz, 2H). (诮 Please read the notes on the back before filling this page)

, 1T, φι. -121-552260 A7 B7 V. Description of the invention (119 Please read the following 5 notes before filling out this page ^ Heteropentene-5-ylpyridin-3-carboxylic acid treated with 200 mg of acetic anhydride The compound from Example 6A (250 gram) in 0.05 ml of toluene. After stirring at room temperature for 2 hours, water was added and the acetic acid was neutralized with potassium bicarbonate. The mixture was extracted with toluene to obtain 273 mg The intermediate vinegar. This part of the ester (200 gram) was hydrolyzed by the method of Example 1D to give 211 mg of the title compound. Melting point 248-250 aC. The meso isomer was seen in NMR. ± NMR (DMSO-d6, 300 MHz) δ 1.55 and 2.00 (s, 3H), 2 94 and 3 03 (dd, Bu 12 Hz, 13 Hz, 1 R, 3.3-3.6 (1! 1, 2 seals, 3.72 and 3.76 (5,311), 4.12 and 4.28 (dd, 12 Hz, 7 Hz, 1H), 4 95 and 5 04 (Hz, one. (S, 2H), 6.75_6 • a ^ (d , J 2 9 Hz, 2H), 7.18, and 7 32 (d, Br 9 Hz, 2H). Example 12 Loss of sulfanyl group V 巧 哈 淀 淀 -3 -3 ^^^ 138 mg of 2-furan sulfonium chloride Add to dissolve in? 4 Yield ~ Mao Sheng ~ Chlorophyll -才-部 中 灰 rXJm τ- A ：: Compound τ. ^ 印 f ′ and cooled in an ice bath. The compound obtained from Example 6 A (? ⑽ ☆ 上, „, ，% brother) and 164 Mg of triethylamine. The mixture was stirred at room temperature for 3 knives !, and then processed by the procedure described in Example 8 to obtain the hydrolyzate of the ester in the procedure described in Example 1 D to obtain 269 裒. ^ ~ The title compound was found to be amorphous and powdery. 1HNMR (DMS〇-d6, " Dead Hertz) § 3.06 (dd, J = 12 Hz, 13 Hz, 1Η), 3.3-3 6 k 〇τΤχ Where 2H), 4.25 -122- Specifications of this paper / 丨] Lao National Standard Pool- (CNS) Λ4 Specification (—210X297 mm) 552260 A7 B7 V. Description of the Invention (120 (m, 1H), 5.19 (d , J = 10 Hz, 1 India, 6.6-7.4 (111,811), 7.8-7 · 9 (m, 1H). Example 13 Trans, trans-2- (4-fluorenoxyphenyl) -4- (l , 3-Benzo-dioxol-5-yl) -1- (phenylaminecarbonyl) -pyrrolidine-3-carboxylic acid from the compound obtained in Example 6A, phenyl isocyanate and the examples The procedure described in 9 begins to prepare the title compound. Melting point 209-2 1 1 ° C. iHNMR (DMS 0-d6, 3 00 MHz) δ 3.03 (dd, 1H), 3.55 (m, 1H), 3.70 (m, 1H), 3.72 (s, 3H), 4.15 (m, 1H), 5.13 ( d, 1H), 6.00 (s5 2H), 6.88 (m, 5H), 7.07-7.20 (m, 3H), 7.30 (d, 2H), 7.38 (d, 2H), 8.20 (bs, 1H) Example 14 σ Trans, trans- 2- (4-methoxyphenidyl) _4 (1,3-benzo-oxetan-5 ') -1- (allylaminocarbonylmethyl) -pyrrolidine-3 -The carboxylic acid uses the procedure described in Example 1 to prepare the title compound. Melting point 13 8- 140 ° C. 4 NMR (CDC13, 300 MHz) δ 2.84 (d, 1H), 2.90-3 · 10 (dt, 2H), 3.28 (d, 1H), 3.35 (dd, 1H), 3.62 (m, 1H), 3.72-3.97 (m, 3H), 3.80 (s, 3H), 5.13 (bd, 2H), 5.80 (m, 1H), 5.97 (s, 2H), 6.74-6.97 (m, 5H), 7.38 (d, 2H): Example 1 5 \\ (Please read the precautions on the back before filling out this page) trans, trans-2- (4-fluorenylphenyl) -4- (1,3-phenylhydrazine Oxetene-5-yl) -1- (n-butylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. Melting point -123- The dimensions of this paper are described in Central Sichuan due to National Standards (CNS) 8-4 specifications (210X 297 male f) 552260 A7 B7 Part lk η, f A ii 卬 5, 4 Be sure to explain (121 105-107 ° C. 4 NMR (CDC13, 300 MHz) δ 0.90 (t, 3H), 1.30 (m, 2H), 1.45 (m, 2H), 2.80 (d, 1H), 2.87-3.35 (m, 6H), 3,62 (m, lH), 3.80 (s, 3H), 5.97 (s, 2H), 6.75-6.92 (m, 5H), 7.28 (d, 2H). Example 1 6 Trans, trans-2- (4-methoxy Fluorenyl) -4- (1,)-winter benzo-oxazepinepentyl-5-yl) -l- (N- (n-propyl) -N-fluorenylaminocarbonylmethyl) -pyrrolidine The 3-carboxylic acid was used in the procedure described in Example 1 to prepare the title compound as an amorphous solid. Meso isomers were seen in NMR. h NMR (CDC13, 3 00 MHz) δ 0.73, 0.84 (2t, 3Η), 1.49 (m, 2H), 2.80 (dd, 1H), 2.85 (2s, 3H), 2.95-3.20 (m, 3H ), 3.20-3.40 (m? 1H), 3.40 (d, 1H), 3.60 (m, 1H), 3.79 (s, 3H), 5.93 (s, 2H), 6.73 (d, 1H), 6.86 (m, 2H), 7.03 (m,) H), 7.32 (d, 2H). Example 17 trans, trans-2- (4-fluorenoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- (pyrrolidin-1-ylcarbonylmethyl) ) -Pyrrolidine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound as an amorphous solid. 1HNMR (CDC13, 300 MHz) δ 1.40-1.70 (m, 6H), 2.80 (d, 1H), 3.00 (m, 2H), 3.24-3.43 (m, 5H), 3.60 (m5 2H), 3.73 (d, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.74 (d, 1H), 6.80-6.90 (m, 3H), 7 04 (d, 1H), 7.30 (d, 2H) . Example 18 Inverse, inverse _2-(4-曱 milk epidermal) _4_ (1,3_ Table and inter-dioxane; pentium:%-5_ basic paper & standard description; 彳] 屮 1¾ national standard ( CNS) Λ4 Specification C 210X297 mm) (Read the precautions on the back before filling out this page) -124- 552260 A7 _ B7 V. Description of the invention (122) (Read the precautions on the back before filling out this page)) -1- (Isobutylaminomethyl) _ _ _ _ _ _ _ _ _ 3 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ ~ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ HER using the procedure described in Example 1 to prepare the title compound. Melting point 1 75 -177 ° C. 4 NMR (CD3OD, 3 00 MHz) δ 0.87 (dd, 6H), 1.75 (seventh peak, 1H), 2.85 (d, 1H), 2.90-3.10 (m, 4H), 3.23 (d, 1H) , 3.40 (m, 1H), 3.58-3.67 (m, 1H), 3.78 (s, 3H), 3.89 (d, 1H), 5.92 (s, 2H), 6.76 (d, 1H), 6.86 (dd, 1H) ), 6.91 (d, 2H), 7.02 (d, 1H), 7.40 (d, 2H). Example 1 9 trans, trans-2- (4-methoxyphenyl) -4- (l, 3-phenylhydrazone dioxol-5-yl) -1- (isopentylaminocarbonylmethyl) ) -Pyrrolidine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. Melting point 13 7 -139 ° C. 4 NMR (CDC13, 3 00 MHz) δ 1.34 (m, 2H), 1.62 (m, 4H), 1.90 (m, 2H), 2.76 (d, 1 Η), 2.90 (t, 1 Η), 3.04 (dd, 1H), 3.22 (d, 1H), 3.28 (dd, 1H), 3.40 (m, 1H), 3.80 (s, 3H), 4.15 (m, 1H), 5.97 (d, 2H), 6.75 -6.95 (m, 5H), 7.27 (m, 2H). Example 2 0 trans, trans_2_ (4_methoxyphenidyl) -4_ (l, 3 -benzoma --- oxaza-peroxolamine _ 5 -volume)-: [_ (morpholine_4_yl Aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound as an amorphous solid. 1H NMR (CDC13, 300 MHz) δ 2.82 (d, 1H), 3.00 (m, 2H), 3.24 (m, 1H), 3.30-3.52 (m, 4H), 3.52-3.75 (m, 8H), 3 80 (s, 3H), 5.95 (s, 2H), 6.75 (d, 1H), 6.84 (d, 3H), 7.00 (s, 1H), 7.28 (d, 2H). -125- This paper describes China National Solid Standard (CNS) Λ4 specification Γ210 乂 297mm) 552260 A7 B7 ^ / Ministry of China ^ :: ^-^; π I ΛΜ 5. Description of the invention (123 Example 2 1 Trans, trans-2- (4-fluorenoxyphenyl) -4- (1,3 -epi-dioxo-3apenten-5-yl) -1- (2-fluorenethyl) Bite each bite_3 Sun acid uses the procedure described in Example 4 to prepare the title compound as an amorphous solid. 1H NMR (CD3OD, 300 MHz) δ 2.82 (m, 1H), 2.96 (dd, 1H), 3.13 (m, 1H), 3.32 (m, 1H), 3.51-3.70 (m, 2H), 3.77 (s, 3H), 4.00 (d, 1H), 4.07 (m, 2H), 5.91 (s , 2H), 6.72 (d, 1H), 6.80-6.95 (m, 6H), 7.03 (d, 1H), 7.22 (dd, 2H), 7.39 (d, 2H). Example 22 Anti, trans-2- ( 4-Methoxyphenyl) -4- (1,3-Dibenzo-pentaoxol-5-yl) -1- (2-oxoethylaminocarbonylmethyl) _pyrrolidine-3 -The carboxylic acid was prepared using the procedure described in Example 1. Melting point 1 07-109 ° C. 4 NMR (CD3OD, 3 00 MHz) δ 2.82 (d, 1H), 2.97 (q, 2H), 3.21 (d, 1H), 3.38 (m, 1H), 3.32 (s, 3H), 3.44 (m, 4H), 3.62 (m, lH), 3.79 (s, 3H), 3.86 (d, lH), 5.93 (s, 2H), 6.76 (d, 1H), 6.85 (dd, 1H), 6.91 (d, 2H), 7.01 (d, 1H), 7.38 (d, 2H). Example 23 Trans, trans-2- (4-fluorenylphenyl) -4- (1,3-benzo-dioxol-5-yl ) -1- (2-butoxyethyl) -pyrrolidine-3-carboxylic acid was prepared using the procedure described in Example 4. Melting point 53 0 ° C. 4 NMR (CDC13, 3 00 MHz) δ 0.88 (t, J = 7 Hz, 3H), 1 32 (hexaplex, J = 7 Hz, 2H), 1.50 (quintet, J = 7 Hz-126- This paper describes the state ’s national standards (CNS) A4 specification [210 X 297 mm] " (Read the precautions on the back before filling in this page) 552260 A7 B7, j • / r- Ministry 屮-AA 卬 5. Description of the invention (124, 2H), 2.27 (tt, J 2 6 Hz, 6 Hz, 1H), 2.92 (q, J = 10 Hz, 2H), 3.35 (t, J 2 7 Hz, 2H), 3.42-3.56 (τη, 4H) , 3.68 (d, J 2 10 Hz, 1H), 3.78 (s, 3H), 5.94 (s, 2H), 6.73 (d, J 2 8 Hz, 1H), 6.83 (d, J = 9 Hz, 2H) , 6.82-6.87 (m, 1H), 7.06 (d, J = 2 Hz , 1H), 7 · 32 (d, J two 9 Hz, 2H). MS m / e 442 (M + H) —. Example 24 Trans, trans-2- (1,3_Benzo-dilactite heteroallylpenta-5-yl) -4- (4-methylepithio) -1- (propylaminocarbonylmethyl) -pyrrole Pyridin-3-carboxylic acid uses the procedure described in Example 1 and replaces (4-methoxybenzyl) with (1,3-phenylhydrazine 5-oxocarbonyl) ethyl acetate ) Ethyl acetate and 5- (2-nitrovinyl) -1,3-benzo-dioxol-5-yl substituted with 4- (2-nitrovinyl) anisole, The title compound was obtained. Melting point 97 -99 ° C. 4 NMR (CDC13, 300 MHz) δ 0.78 (t, J = 7 Hz, 3H), 1.39 (hexaplex, J = 7 Hz, 2H), 2.72 (d, J = 16 Hz, 1H), 2.74 ( t, 10 Hz, 1H), 2.80-3. 10 (m, 4H), 3.26-3.38 (m, 1H), 3.53 (m, 1H), 3.73 (s, 3H), 3.80 (d, J = 10 Hz, 2H), 7.80 (t, J = 6 Hz, 1H). MS (DCI / NH3) m / e 441 (M + H), Example 25 trans, trans-2- (1,3-phenylhydrazine dioxane; pentamidine 5-yl)-4-(4 -Methoxyphenyl) _ 1 brain (propoxyethyl) _ Mouth-to-Mouth _ 3-Complex § Yttrium using the procedure described in Example 5 and starting with (1,3-Benzo-dioxane Cyclopenten-5-ylcarbonyl) ethyl acetate to replace (4-methoxymethylformyl) acetic acid ethyl-127- wood paper it scales this;]] Prisoner National Finger Extraction (CNS) Λ4 specification (210X297) Li) (Please read the notes on the back before filling out this page) 552260 A7 B7 a (. And

A V. Description of the invention (125 ester, and 4- (2-nitrovinyl) anisole is used to replace 5- (2-nitrovinyl) -1,3-phenylhydrazone dioxolene- 5-yl to give the title compound. Melting point 6 7-69 ° C. 4 NMR (CDC13, 300 MHz) δ 0.89 (t, J = 7 Hz, 3H), 1.56 (hexaplex, J = 7 Hz, 2H ), 2.33 (m, 1H), 2.7 8-3.0 0 (m, 3Η), 3.3 2 (t, J = 7 Hz, 2H), 3.45-3.57 (m, 4H), 3.7 3 (m, 1H), 3.79 (s, 3H), 5.93 (s5 2H), 6.22 (d, J 2 8 Hz 51H), 6.85 (d, J = 8 Hz 53H), 6.98 (s, iH), 7.37 (d, J = 8 Hz, 2H). MS (DCI / NH3) m / e 428 (M + H) +. Example 26 Trans, trans-2- (l, 3-phenylhydrazone dioxol-5-yl) -4- (4-methoxyphenyl) -1- [2_ (2-methylethoxy) ethyl] _ p is lower than each mouth and mouth -3-The father uses the procedure described in Example 4, And replace the starting material described in Example 25. Alkylation of pyrrolidine nitrogen with 2- (2-fluoroxyethoxy) ethyl bromide to give the title compound. Melting point 85-86 ° C. HNiMRCCDsOD, 3 00 MHz) δ 3. 18-3.90 (m, 15Η), 3.79 (s, 3Η), 4.57 (d , J = 10 Hz, 1Η), 6.02 (s, 2y), 6.91 (d, J = 8 Hz, 1Η), 6.95 (d, J = 9 Hz, 2H), 7.06 (dd, J = 8 Hz, 1H), 7.12 (dd, J = 1 Hz, 1H), 7.37 (d, J = 9 Hz, 2H). MS (DCI / NH3) m / e444 (M ~ TH) ° Example 27 Trans, trans-2- (1,3-phenylhydrazinedioxol-5-yl) -4- (4-methoxy Phenyl) _1_ (butoxyethyl) _ each bite bite_]-§ The parent used the procedure described in Example 4 and replaced the starting material described in Example 25 with 2-ethoxyethyl Bromine alkylates pyrrolidine nitrogen to obtain the standard -128 This paper is in the state of China (CNS) Λ4 size Γ210 × 297 mm (please read the precautions on the back before filling this page) 552260 A7 B7 Zhong A 卬 5. Description of the invention (126 compounds). Melting point 54-56 ° C. 4 NMR (CDC13, 300 MHz) δ 0.89 (t, J = 7 Hz, 3H), 1.44 (Sixfold peak, J = 7 Hz, 2H), 1.52 (quintet, J = 7 Hz, 2H), 2.40 (in, 1H), 2.74-2.9 8 (m, 3H), 3.46 (i, J-2 7 Hz, 2H), 3.42-3.56 (m, 4H), 3.68 (d, J-10 Hz, 1H), 3.80 (s, 3H), 5.93 (dd, J-2 6 Hz, 1 Hz, 2H), 6.72 (d, J 8 Hz, 1H), 6.74 (dd, J = 9 Hz, 3H), 6.96 (s, 1H), 7.36 (d, J = 9 Hz, 2H). Example 2 8 Anti, anti_2_ (4_ 甲Oxyphenyl) -4- ( 1,4-Epipyridine-6-yl) -1-(propylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid

Using the procedure described in Example 1 and replacing 5- (2-nitrovinyl) -1,3-phenylhydrazone with 6- (2-nitrovinyl) -1, isophenylhydrazone No. 17 M-dioxolane to give the title compound. Melting point 80-8 1 ° C. 4 NMR (CDC13, 300 MHz) δ 0.89 (t, J = 7 Hz, 3H), 1.49 (hexaplex, J = 7 Hz, 2H), 2.78 (d, J = 16 Hz, 1H), 2.92 ( t, J = 10 Hz, 1H), 3 05-3 43 (m, 5H), 3.24 (d, J = 16 Hz, 1 Η), 3.52-3.62 (m, 1Η), 3.80 (s, 3H) , 3.80 (t5 J = 10 Hz, 1H), 4.27 (s, 4H), 6.74-6 93 (m5 5H), 7.29 (d, J 2 9 Hz, 2H). MS (DCI / NH3) m / e 455 (M + H), Example 29 Inverse, inverse _2_ (4_methylamino) -4- (1,4 -Complete --- α 可 fe-ό_ 基) -1_ (N_fluorenyl-N-propylaminocarbonylfluorenyl) -pyrrolidine-3-carboxylic acid using the procedure described in Example 1, and starting with 6- (2-nitrovinyl) -1.4-benzyl Dioxane to replace 5- (2-nitrovinylbenzene) Dioxane-129- This paper uses the National Standard for Valves (CNS) A4 specification (2; 0 × 297 mm) (Please refer to Read the precautions on the back before filling in this page} 552260 A7 B7 V. Description of the invention (127 Η 'Λ: Chinese and pentene, and burn the pyrrolidine nitrogen with N-methyl-N-propyl acetamide bromide Alkylation to give the title compound. Melting point 74-76 ° C. Meso isomers are seen in NMR. IHNMR fCDCls, 300 MHz) δ 0.73, 〇83 (? T J = 7 Hz, 3H), 1.48 ( m, 2H), 2.78 (dd, 1H), 2.85 (2S, 3H), 2.96-3.15 (m, 3H), 3.27-3.42 (m, 3H), 3.52-3.60 (m, 1H), 3.75 ( d, lH), 3.78 (s, 3H), 4.22 (s, 4H), 6.80-6.98 (m, 5H), 7.32 (d, 2H), MS (DCI / NH3) m / e 469 (M + H) '. Example 30 ~' trans- 2- (4-methylphenidyl) -4- (1,3-table M-dioxolyl) -1- (N-methyl-N-butylaminocarbonylfluorenyl) -pyrrolidine-3-volume ^ The title compound was prepared using the procedure described in Example 1. Meso isomers are seen in ΝίΜΙι. I NMR (CD3OD, 300 MHz) δ 0.86 (2t, 3H), 1.04-1.50 (m, 4H), 2.85 (2s, 3H), 2.93-3.20 (m , 4H), 3 40 (m, 2H) '3.52 (dd, lH), 3.60 (m, 1H), 3.80 (s, jH), 3.85 (m, lH), 5.91 (s, 2H), 6.74 (d , LH), 6.83-6.95 (m, 3H), 7.03 (dd, 1H), 7.35 (dd, 2H). Example 3 丄 4-Ψ_κ & i2j ... oxymethoxy ~ _ ^ yl) -4- ( 1,3-Benzamidine-m-dihydrofluorenyl) -pyrrolidinium-acid-decoryl-1,2-benzyl-methanedihydropyridinium-dioxine-diisopyridinediacetate "was used in Examples 1 A and 1 The procedure described in B, and replace the methoxybenzyl) acetic acid with (4-methoxy-2-methylmethoxybenzylmethyl) acetate (Please read the precautions on the back before filling out this Page), 11, violently-130- 552260 A7 ___________ B7 V. Description of the invention (128) Ethyl vinegar 'gives 2- (4-methoxy-2-methoxyfluorenoxyphenyl) -4- (1,3- Benzo metaoxetan-5 -yl) -4,5- Hydrogen - 3H-P Bulow several -3- carboxylate. The above dihydrop-pyrrolidine acid (3.0 g, 7.0 mmol) was dissolved in 20 ml of methanol, treated with 500 mg of 10% Pd / C, and placed under hydrogen I 3 2 hour. The catalyst was removed by filtration and concentrated under reduced pressure. Chromatography on silica gel was performed with ethyl acetate to give the title compound (1.9 g, 63%) as a cis-cis isomer.

Example 3 1 B 'trans-2- (4-Methoxy-2-methyloxybenzyloxybenzyl) 3_Macro # 1 $ piece-^ yl) -1- (N-methyl-N-butylpropylcarbonylamidine )-Ton polypic acid isomerized the compound from Example 3a by the procedure described in Example 6A. The resulting anti-, anti-compound (100 g, 0.23 mmol) was then processed by the procedure described in Example ID to replace N-propyl bromide with; Acetylamine, to obtain the title compound < sentence (75 brother, 62%). $ 谷 点 65-67 C. In the NMR, the isomer isomer ° HNMR (CDCl3,] 00 MHz) §〇64, 0.68 (9t 1 == 7 Hz, 3H), [14, 1.12 (hexaplex, J 2 7 Hz, 2H), 1.40-1.48 (m, 2H), 2.86, 2.89 (2s, 3H), 2.95-3.42 (m, 6H), 3.50 (s, 3H), 3.43-3.65 (m, 2H), 3.78 ( s, 3H), 4.30 (t, J = 7 Hz, 1H), 5.09 (q, J = 7 Hz, 2H), 5.92 (s, 2H), 6.55 (dd, J = 3 Hz, 1H), 6,68 (s, 1H), 6.72 (s, 1H), 6.85 PI Hz, 1H), 7.04 (t, J-2 1Hz, 1H), 7.42 (dd, J-2 3Hz, ih). Example 3 2 Dioxo [Oxybenzene_Cap 丄 iM 丨, 3-Benzo-Hydrocyclopentane ^ 5- complex (Please read the precautions on the back before filling this page)

Order -131-552260 ^ • # 部 中 夹 ^. ^-/. Jm τ_ 消 # 合 M. ^ 卬;, >: A7 B7 " " " — One — — ------ -----V. Description of the invention (129)) _Iri ·? -Ethyloxypropyl ketone Η Α 32Α -5 -Propionate Na 480 g of NaH was added in batches; each solution was dissolved in 20 ml of thf Medium gadolinium (4-ammoniumoxybenzyl) acetate (4.44 g, 0.02 mmol). The mixture was deaerated at ambient temperature for 30 minutes. (1,3-Benzo-dioxolene-5-yl) phosphonium acetate bromide (5.46 g, 0.02 mmol) was added in $ ml of THF. The mixture was stirred at ambient temperature overnight, diluted with 200 strokes of EtOA-c, and rinsed with water and brine. The organic phase was dehydrated with sodium sulfate 'and concentrated in the air to give the title compound (767 g, 92%), which was used directly without further purification.

t PI 32B j mono (J -ethoxyneqin)-2- (4-fluorenyloxy) -4-(1,3 -Cizman-man heterocyclic ring-5 -yl) · 4,5 -Dihydro-5 -oxo_ 1 H_? Pyrrole 3 -Ethyl chicanoate. The compound obtained from Example 3 2 A (70 mg, 1.69 mmol) in a sealed test tube, 3 -A mixture of ethoxypropylamine (348 g, 3.38 mmol) and 1 liter of acetic acid is heated to 1 2 5 ° C for 18 hours. Allow the contents of the tube to cool at ambient temperature, add 5 ml of water, and extract the mixture with ethyl acetate (2 x 100 ml). The mixed organic extract was washed with saturated sodium bicarbonate solution, water and water, dried over sodium sulfate, and concentrated under reduced pressure of 7 ^ .7. The resulting residue was chromatographed on silica gel, eluting with hexane-ethyl acetate ^ 3 ^ to obtain 330 mg (42%) of the title compound ^ -132- National Standard (CNS) Λ4 Specification Γ210X 297 mm) (Please read the precautions on the back before filling this page)

Φ 552260 A7 B7 V. Description of the invention (13)

Example 32C Ethyloxybenzyl V4-H.3- 苽 # Interdioxane (please read the precautions on the back before filling in this page)-Elo-5-§ Same as -3-Volume Acetic acid was used to reduce the compound obtained from Example 32B (300 mg, 0.64 mmol) in 15 ml of methanol at 100 mg 10% Pd / C under ambient temperature for 3 hours under hydrogen. The catalyst was removed by filtration, and the filtrate and liquid were concentrated under reduced pressure to obtain the title compound.

Example 32D

, 1T oxyphenyl) -4- (1,3-benzene # m-diazacyclopentene-5-some lllld: ethoxypropyl) -pyrrolidin-5-one-3-leptic acid 2% of sodium ethoxide in ethanol was added to the compound of Example 3 2C (100 g, 0.21 mmol) dissolved in 1 ml of ethanol. The mixture was heated to 70-80. (: 3 hours, then add a solution of sodium oxide (100 mg) in 1 ml of water and continue heating for another 1 hour. The reaction mixture is cooled to ambient temperature, the ethanol is removed under reduced pressure, and Water was added to the residue, and it was washed with ether. The political layer was neutralized with 3 toe HC1, and Yagu Xu was left standing overnight. The white crystalline solid was collected by filtration to obtain the title compound (60 mg, 64%). Melting point 134-140 ° C. 4 NMR (DMS 0-d6, 300 MHz) δ 1.04 (t, J = 7 Hz, 3H), L55 (hexaplex, j 2 7 Hz, 2H), 2 48_2 56 ( m 1H), 2 93 (paper J 2 9 Hz, 1H), 3.25 (t, J 2 7 Hz, 2H), 3.28-3.40 (m, 2H), 3.48-3.57 (m, 1H), 3.78 (s, 3H), 3.88 (d, J = 10 Hz, 1H), 4.72 (d, J = 10 Hz, 1H), 6.02 (S, 2H), 6 74 (dd, J: = s_ z, i Hz, 1H) , 6.87 (d, J = 8 Hz, 2H), 6.98 (d, J = 8 Hz -133- > • Paper scale 中 Longzhou Zhongwei National Ticket iTTcNS) 210 X 297g t) ----- 55226〇A7 B7 V. Description of the invention (131 company, 2H), 7.38 (d, J 2 8 Hz, 2H). MS (DCI / NH3) m / e 442 (M + H) +. Example 3 3 radicals. "Transphenylene dioxo" -5--5-yl) -1- (3--methoxyfluorenyl) bilodine _5-g 同 -3- # The basis is given in the examples: > The procedure described privately in 2 and replacing 3-ethoxypropylamine with 3-methoxy; amine to give the title compound (123 mg, 65%). Melting point: 15 °-152 ° C. 1h NMR (CD3OD, 3 00 MHz) δ 2.90 (dd, J 2 8 Hz, 10 Hz, 1H), 3.72 (s, 3H), 3.80 (s, 3H), 4 〇6 (d, J = 10 Hz, 1H), 4.58 (d, J 2 8 Hz, 1H), 4.92 (q, J = 16 Hz, 2H), 5.92 (s, 2H), 6.55-6.63 (m, 2H), 6.82 (d J = 8 Hz, 4H), 6.94 (d, J = 8 Hz, 2H), 7.15-7.22 (m, 3H). MS (DCI / NH3) m / e 475 (M + H), Example 34 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylbenzene dioxane) 5- (i))-1-((N, N-diisoamylaminocarbonyl))-Hydroxyl-Chloric Acid Using the procedure described in Example 1, the title compound was prepared as an amorphous solid. 4 NMR (CDC13, 300 MHz) δ 0.70-0.90 (m, 12H),] 10-1.60 (m, 10H), 2.75 (d, J = 13 Hz, 1H), 2 90-3.1〇 (m, 4H), 3.15-3.30 (m, 2H), 3.40 (d, J 2 10 Hz, 1H) '3.40-3.52 (m, 2H), 3.55-3.62 (m, 1H), 3.75 (d J 2 12 Hz, ih), 3.79 (s, 3H), 5.9 3 (dd, J = i Hz, 3 Hz, 2H), 6.72 (d, J = 8 Hz, 1H), 6.82-6.90 (m, 3 Η), 7.03 ( d5 J = 2 Hz, ih), 7.30 (d, J = 9 Hz, 2H). -134- The size of this paper is 1 ^^ quasi (CNS) in Shizhou, ^ 4 size, Π10 × 297mm) ~~ '~ (Read the notes on the back of the book first, fill in this book 1J;) Order Φ ·. 552260 A7 B7 5 、 Explanation of the invention (132 Example 35 oxetan-5 _ group (please read the precautions on the back before filling out the ItT page) trans, trans-2- (4-methoxyethenyl) -4- (1, 3-Epi)-dipentylaminocarbonylsulfonyl)-pyrrolidine-3 -carboxylic acid The procedure described in Example 1 was used to prepare the title compound as an amorphous solid. 1HNMR (CDC13, 300 MHz) 50.82 (t, J = 7 Hz, 6H), 0.95- 1.03 (m, 2H), 1.10-1.30 (m, 8H), i.40-1.51 (m, 2H), 2.72 (d5 J = 13 Hz, 1H), 2.90-3.08 (m, 4H), 3.25-3.50 (m, 3H), 3 · 3 7 (d, J 2 1 3 Hz, 1H), 3.52-3.60 (m, 1H), 3.70 (J = 10 Hz, 1H), 3.75 (s, 3H), 5.92 (dd, J = 2 Hz, 5 Hz, 2H), 6.72 (d5 J = 8 Hz, 1H), 6.80-6.88 ( m, 3H), 7.03 (d, J = 2 Hz, 1H), 7.30 (d, J = 9 Hz, 2H). Example 3 6 trans, trans- 2- (4-oxooxyyl) -4- (1,3-benzo-dilactide heteropentan · 5-yl) -1- (Ν, Ν-bis (2 -Phenoxyethyl) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. Melting point 120-122 Torr. iHNMR (CDCl3, 300 MHz) 32.82 (d, J-2 13, 1H), 2.94-3.08 (m, 2H), 3.12 (s, 3H), 3.23 (s, 3H), 3.20-3.70 (m, 11H) , 3.73 (d, J = 10 Hz, 1Η), 3.79 (s, 3H), 5.92 (dd, J = 2 Hz, 2 Hz, 2H), 6.72 (d, J = 8 Hz, 1H), 6.80-6.90 (m, 3H), 7.04 (d, J = 2 Hz, 1 H), 7.30 (d, J = 9 Hz, 2H). Example 37 f ·. A ii Anti-trans, trans-2-(4- -oxoepoxy)-4- (1,3 -epi-dioxane; Mu Wu Zhi _ 5 -yl) _ 1-(2 -Ji, Jieji)-mouth to mouth bite -j-to § text paper size in the state @ 国 标准 (CNS) Λ4 specifications (· 210 < 297 mm) -135- δ226〇A7 B7 Description of the invention ( 133 Using the procedure described in Example 4, 200 mg of the compound obtained from Example 6A, pure trans, trans isomers and 109 mg, by Perkm I., 2004 (1987) The bromo-2-hexyne prepared by the method described in the above, was reacted at 55 ° C to obtain 226 mg of the intermediate. When using Na / O in ethanol-water, The g is hydrolyzed for 3 hours' to 1 7 grams of the title compound. INMRCCDCh, 300 MHz = 7 Schitz, 3H), 1.54 (m, 2Η), 2.14–2.22 (m, 2Η), 2.96 (dd, J = 7 Hz, 13 Hz, 1H), 3.07 (dd, Jr = 18 Hz, 2 Hz, 1H) 5 3. 15 (dd, J = 9 Hz, 2 Hz, ih), 3.26 ( t, J 2 9 Hz, 1H) '3. (dd, J = i8 Hz, 2 Hz, ih), 3.47-3.55 (m, 1H), 3 79 (S, 3H), 3.88 (d, J = 9 Hz, ih), 5.95 (s, 2H), 6.72 (d, J 2 8 Hz, 1H), 6.80-6.88 (m, 3H), 7.03 (d, J 2 2 Hz, 1H) '7 · 22 (d, J = 9 Hz, 2H). Example 3 8 Benzo metadioxol-5-yl l-iM-propylaminocarbonylsulfonyl) _p-pyrrolidine-3_carboxylic acid The procedure described in Example 1 was used to prepare the title compound . Melting point 167-169 C. Meso isomers were seen in NMR. iH NMR (CD (: i3 part and j1 Λ elimination) (Xu first read the precautions on the back and fill in this page to order-'J〇〇 兆 * I) mOO, 0.05 (m), 〇 12-0.25 (m ), 0.32 -0.) 1 (m) '0.67 and 0.74 (2 triplet, π), 〇9㈡⑼㈤, 1 20-i.)) (M), 2.72 (d, J = 13 Hz, 1Η) , 2 85_3 29 (m, 4Η) '3 3〇_3.) 0 3H), 3.52-3 62 (m, 1H), 3.65-3.73 (2 doublet, J = 10 Hz, 2 Hz, 1H), 3 78 (s3H), 5 95 (2 singlet, 2H) '6.72 (2 doublet, 2H), 6 8-0-6 90 (m, 3H), 700 and 7 05 (2-136 paper) Zhang Shuangsi Financial Standard (CNS) 552260 A7 B7 V. Description of the Invention (134) Doublet, J 2 9 Hz, 2H). (Read the precautions on the back before you fill in this page) Example 3 9 Trans, trans-2- (4-fluorenylphenyl) -4- (1,3-benzo-dioxolene-5- Amidino-N-pentylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid was used to prepare the title compound as an amorphous solid using the procedure described in Example 1. Meso isomers were seen in NMR. 4 NMR (CDC13, 300 MHz) δ 0.85 (t, J = 7 Hz, 3H), 1.00- 1.08 (m), i. 13-i.3 2 (m), 1.3 5- 1.5 0 (m ), 2.72-2.8 2 (2 doublet, J = 13 Hz, 1H), 2.83 and 2.86 (2 singlet, 3H), 2.92-3.20 (m, 3H), 3.22-3.45 (m, 3H ), 3.52-3.62 (m, 1H), 3.72 (2 doublet, 1H), 3.75 and 3.76 (2 singlet, 311), 5.92 (2 singlet, 211), 6.72 (1 J = 8 Hz, 1H), 6.80-6.87 (m, 3H), 7.03 (2 doublet, > 2 2 Hz, 1H), 7 30 (d, J = 9 Hz, 2H). Example 40 trans, trans-2- (4-methoxyphenyl) -4- (l, 3-phenylhydrazone dioxol-5-yl) -1- (N, N-diisobutylamine Carbonylmethyl) -pyrrolidine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. Melting point 14 1-143 ° C. 4 NMR (CDC13, 300 MHz) δ 0 54 (d, J = 7 Hz, 3H), 0.70-0.90 (3 doublet, J = 7 Hz, 9H), 1.60-1.75 (m, 1H), i 90 -2 02 (m, iH), 2.67 (d, J = 13 Hz, 1H), 2 70 (d: J two Hz, 1H), 2.84 (dd, J = 6 Hz, 15 Hz, 1H), 2.96 -3.06 (m, 2H), 3.20 (dd, J = 9 Hz, 15 Hz, 1 H), 3 35 (dd, J = 2 Hz, 10 Hz, 1H), 3.44-3.60 (m, 4H), 3.70 (d, J = 9 Hertz, 1H), 3.79 (s, 3H), 5.94 (dd, J = 2 Hertz, 2 Hertz, -137- Therefore, the scale is suitable for the Chuanxi National Standard (CNS) / \ 4 Specifications (210 X 297) 552260 A7 B7 5. Invention Description (135) (Please read the notes on the back before filling this page) 2H), 6.72 (d, J 2 9 Hz, iH), 6.82-6.90 (m, 3H), 7.03 (d, Hertz, 1H) '7.3 1 (d, J = 9 Hertz, 2H). Example 4 1 Congdi-2-(_ 4-mono-methoxybenzodioxofluorene bis (N_m- (kpropynyl) aminocarbonylmethyl) -pyrrolidine-3-carbohydrate_ Use in Example 1 To describe the title compound as an amorphous solid. The meso isomer was seen in NMR. 1H NMR (CDC13, 300 MHz) δ 2.09 and 2.32 (2 triplet, J = 2 Hz, 1H) , 2.80-3.10 (m, 3H), 2.90 and 2.99 (2 single school, 3H), 3.35-3.50 (m, 2H), 3.52-3.62 (m, 1H), 3.78 (s, 3H), 4.03 (d, J: 13 Hz, 1H), 4.00-4.3 0 (m, 3Η), 5.93 (s, 2Η), 6.72 (2 bimodal, J = 8 Hz, 1H), 6.80-6.90 (m, 3H), 7.02 and 7.11 (2 bimodal, J 2 2 Hz, 1H), 7.30 (2 bimodal, J 2 9 Hz 5 2H). Example 42 Inverse, a cluster of di 2- (4-_yoxyphenyl) -_ 4-π, 3-Benzyl dioxopent-5-yl) -1- (N-fluorenyl-N- (n-hexyl) amine 1-yl) · pilolide-3- double acid The procedure described in Example 1 was used to prepare the title compound as an amorphous solid. 1 Η NMR (CD C13, 300 MHz) g 0 8 5 (2 triplet, J = 7 Hz, 3H), 1.00-1 50 (m, 8H), 2.72-2.82 (2 doublet, J 2 1X 3 Hz, 1] H), 2.81 and 2.86 (2 unimodal 5 3H), 2.92-3.20 (m, 3H), 3.22-3.45 (m, 3H), 3.52-3.62 (m, lH), 3.72 (2 Doublet, 1H), 3.75 and 3.76 (2 doublet, 3 ^ 1), 5.94 (2 single +, 211), 6.72 (^, j = 8 Hz, 1H), 6.80-6.87 (m, 3H), 7 03 (2 doublet, J = 2 Hz, 1H), 7 30 (d, J = 9 Hz, 1H). -138- Standard (CNS) A4 specification Γ210χ 297 male 漦) ~~~ ^ 552260 A7 B7 V. Description of the invention (136 Example 43 Anti, trans-2- (4-Oxo-epoxy) -4- (1,3 -Metadioxa-3-pentyl-5-yl) -1- (N, N-bis (n-butyl) aminocarbonylfluorenyl) -pyrrolidine-3-carboxylic acid utilization is described in Example 1 Procedure to prepare the title compound. Melting point 123-125 ° C. 4 NMR (CDC13, 3 00 MHz) δ 0.79 (t, J = 7 Hz, 3H), 0.85 (t, J = 7 Hz, 3H), 1.00 -1 · 50 (m, 8H), 2.74 (d, J = 13 Hz, 1H), 2.90-3.09 (m, 4H), 3.23-3.50 (m, 3H), 3.38 (d, J 2 13 Hz, 1H ), 3.52-3 · 62 (m, 1 H), 3.75 (d, J = 10 Hz, 1H), 3.78 (s, 3H), 5.93 (dd, J = 2 Hz, 4 Hz), 6.7 (d, J = 8 Hz, 1H), 6.81-6.89 (m, 3H), 7.03 (d, J = 2 Hz, 1H), 7.30 (d, J = 9 Hz, 2H). MS (DCI / NH3) m / e511 (M + H) —. Analytical calculations for C29H38N206: ，: C, 68.2 1; H, 7.50; N, 5.49. Experiment 値: C, 68.07; H, 7.47; N, 5.40. Example 44 Inverse, Trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxy Cyclopentene-5-base hydrazone (read the precautions on the reverse side and then fill out this page) Diethylaminocarbonylfluorenyl) -pyrrolidine-3-carboxylic acid Use the procedure described in Example 1 to prepare the title compound Melting point 13 2-1 34 ° C. 4 NMR (CDC13, 300 MHz) δ 0.98 (t, J = 7 Hz, 3H), 1.06 (t, J = 7 Hz, 3H), 2.78 (d, J = 13 Hz, 1H), 2.95-3.20 (m, 4H), 3.30-3.50 (m, 4H), 3.55-3.65 (m, 1H), 3.76 (d, J = 12 Hz 71H), 3 79 (s, 3H), 5.93 (s, 2H), 6.72 (d, J = 8 Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (d, J = 2 Hz, 1H), 7.32 (d, J = 9 Hertz, 2H). 139- This paper is of suitable size / 丨] Chinese National Standard (CNS) Λ4 specification (210X 297 cm) 552260 A7 B7 V. Description of the invention (137 Example 45 Please read the notes on the back page A On this page, trans-2- (4-methylaminofluorenyl) -4- (1,3-benzo-di-dicyclocyclopenten-5-yl-methyl-aniline -Acid acid_ The procedure described in Example 1 was used to prepare the title compound as an amorphous solid. 1H NMR (CD3OD, 300 MHz) δ 2.75-2.85 (m, 2H), 3.05-3.13 (m, 1H), 3.18 (s5 3H), 3.40-3.58 (m, 2H), 3.78 (s, 3H), 3.88 (d, J = 12 Hz, 1H), 5.92 (s, 2H), 6.72 (d, J = 8 Hz, 1H), 6.75-6 · 85 (m, 3H), 7.00-7.12 (m? 5H), 7.82-7.92 (m, 3H). Example 46 Methoxyphenylphenylhydrazone dioxolylmethyl-N-cyclohexylaminocarbonylmethyl) -pyrrolidin-3-carboxyl §1 The procedure described in Example 1 was used to prepare an amorphous The title compound as a solid. Meso isomers were seen in NMR. NMR (CD3OD, 3 00 MHz) δ 1.00-1.85 (m, 1 OH), 2.72 and 2.78 (2 singlet 3H)) 40-3.65 (m, 3Η), 3.68 and 3.82 (2 Doublet, J = 10 Hz, 1H), 3.77 and 3.78 (2 singlet, 3H), 5 92 (s, 2H), 6 72 (2 doublet, μHz, 1H), 6.82-6.88 (m, 3H ), 7.02 (2 doublet 5b 2 Hz, Chuan) '7.30-7.40 (2 doublet, j = 9 Hz, 2H). Phenylhydrazone-dioxo-yl-methyl) -pyrrolidine diacid The procedure described in Example 1 was used to prepare the title compound. Melting point The degree of paper shape i㈣Zhongguanliang (CNS) -140-552260 A7 B7 V. Description of the invention (138) (Please read the precautions on the back before filling this page) 170-172 ° C. NMR (CDC 13, 3 00 MHz) δ 0.69 (t, J = 7 Hz, 3H), 0.85 (t, J = 7 Hz, 3H), 1.20- 1.5 5 (m, 4H), 2.72 (d, J = 13 Hz, iH), 2.90-3.10 (m, 4H), 3.25-3.47 (m, 4H), 3.35-3.62 (m, iH), 3.72 (d, J = 9 Hz, 1H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, d, J = 8 Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (d, J = 2 Hz, 1H), 7.30 (d , J 2: 9 Hz, 2H). Example 4 8 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-ylmethyl-N-isobutylaminocarbonylmethyl ) -Pyrrolidine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound as an amorphous solid. Meso isomers were seen in NMR. NMR (CD3OD, 3 00 MHz) δ 0.65-0.85 (4 doublet, J = 7 Hz, 6H), 1.75-1.95 (m, m), 2.80 and 2 90 (2 箪 peak, 3H), 2.90 -3. 10 (m, 4H), 3.10-3.65 (m, 4H), 3.74 (9S, 3H), 3.81 and 3.88 (2 doublet, J = 10 Hz, 1H), 5.93 (s, 2H), 6 72 (d, J = 8 Hz, 1H), 6.8 0-6.90 (m, 3H), 7.02 (2 doublet, J = 2 Hz, 1 H), 7.80-7.90 (2 doublet, J = 9 Hz, 2H). Example 49 Another Preparation of 2- (4-methoxybenzylidene) -4-nitropyridyl-3- (1benzylidene

Dioxo I cyclopentazone-5-yl) -butyric acid ethyl ester 49A E-2- (3,4-methylenedioxyphenyl) -i-nitroethylene nitronitromethane ( 27.1 ml, 500 millimolars, 1 equivalent) was added to piperonal (75 g, 500 -141-75 g, 500 -141) in methanol (120 ml) at i0 ° C. 1] tra national standard (CNS) Λ4 specification (210X2W mm) loose 26〇

(139) A7 B7 pen mole), followed by dropwise addition of a sodium hydroxide solution (21 g, 525 mol, 105 angstroms) in a volume of 50 ml < The temperature is maintained between 10_15 ° C. The reaction mixture became cloudy and turned into a thick paste. When the addition was complete, the mixture was stirred for 30 minutes, then the mixture was diluted with ice-water (about 350 ml), and the temperature was maintained below 5 ° C until the solution was completed. The solution obtained by Jiang was poured into a thin stream (so that it could not be separated into water droplets) in a 36% solution of hydrochloric acid (100 ml) in water (150 ml). A yellow solid (nitrophenylacetamidine) precipitated, which was collected by filtration and rinsed with water (1.5 liters) until the filtrate was neutral. The filter cake was air-dried and then recrystallized from hot ethanol (3 liters) to obtain yellow needle-like E-2- (3,4-methylenedioxy) -nitrostyrene (53 g, 55% ). NMR (300 MHz, CDC13) δ 7.94 (Za 1'b 135 Hz), 7.47 (111) 2 13.5 Hz), 7.09 (11 ^ dd, BU 5 & 2 Hz), 7.01 (1Η, d5 J 2 2 Hz), 6.87 (1Η, d J 2 7 5 Hz), 6.06 (2H, s) ° MS (DCI / NH3) m / e 194 (M + H) D, 2 11 (Μ Ten H + NH3),

Example 49B K4-methoxy! Nitro-3- (3,4-methylenedioxybenzyl) butyric acid Z1 — — — — ^ Ethyl acetate will be ethyl (4-methoxyphenylfluorenyl) acetate in THF (50 ml) Ester (11.5 g, 51.7 mmol), followed by 1,8-diazabicyclo [5.4.0] undec-7-fluorene (DBU) (0.45 ml, 3.0 mmol, 0.05 equivalent) ) Was continuously added to a mixture of inner-2-fresh (75 ml) and tetrazine (1.75 liters) i at room temperature to obtain the nitrostyrene (14 17 g, 73 34 mmole -142- in the state _ family sample (⑽) M specifications (-210X 297 male f) I In In m! I--HI ^ T—is-HI— 1--j-· -1 · (Please read the precautions on the back before filling in this page) There are medium times i- iV- and 552260 A7 B7 V. Description of the invention (14〇S ----, 1.2 equivalents) in the stirred solution. At room temperature The resulting mixture was stirred for 1 hour, and then additional DBU (0.45 ml, 3.0 millimoles, 0.05 equivalent) was added. The mixture was then sacrificed for another hour and then the volatiles were removed in the air The residue was purified on 500 g of crushed gel by flash chromatography and washed with 20% ethyl acetate-hexane The product elutes when it becomes 25% ethyl acetate-hexane. The solvent is removed in the air to obtain a nitroketo ester (19.36 g, 76%) with viscous dripping. It is seen in NMR that the Enantiomers: HNMR (30 MHz, CDCI3) δ 8.06 (2H, d, J = 9 Hz), 7.89 (2H, d, J = 9 Hz), 6.96 (2H, d, J = 9) Hz), 6.91 (2H, d, J = 9 Hz), 6.77 (1H, dd, J = 9 Hz, 3 Hz), 6.73 (1H, d, J = 9 Hz), 6,65 (1H, d, J = 3 Hz), 5.95 (2H, s), 5.89 (1H, d, J 4 Hz), 5.S8 (1H, d, J = 4 Hz), 4.9CU4.60 (3H, m), 4.39 (1H, m), 4.18 (2H, q, J = 7 Hz), 3.94 (2H, m), 3.80 (3H, s), 3.78 (3H, s), 1.19 (3H, i, J = 7 Hz) ), 0.99 (3H, t, J 2 7 Hz), MS (DCI / NH3) m / e 416 (m + H) ', 433 (M + H + NH3) +. Example 50

A (谙 Please read the precautions on the back before filling in this page j, Yi Dingfan, trans-2-(4 -methoxyphenyl) -4-(1,3 -benzene-dioxolane- 5 -yl tertiary-butoxycarbonylfluorenyl) -pyridine? 3-carboxylic acid Diisopropylethylamine (70 μl, 0.40 mmol, 15 equivalents) and tert-butyl bromoacetate (48 microliters, 0.29 millimoles, 11 equivalents) was continuously added to the effluent of the compound obtained from Example 1C (100 mg, 0.27 house mol) in acetonitrile (2 ml). Grab The mixture was dropped for 2 hours', and then the solvent was removed in the air to obtain the crude diester. At room temperature, the paper size in water will be suitable / 丨] Chinese National Standard (CNS) Λ4 specification (_210 乂 29 * 7mm Ii) 552260 A7 B7 Part ik _τ > /] ii ii 卬 5 'invention description (141 50% weight / weight of hydroxide steel (300 mg, 3 75 square A "woolen bucket) added to ethanol ( 1 ml) of the diester in the stirred-off solution. Remove the stranger for 2 hours, then remove the volatiles in the air. Dissolve the residue in water (5 ml) and rinse the solution with ether. To The liquid phase was acidified with acetic acid (300 μl) and then extracted with ethyl acetate (2x). The combined organic extracts were dehydrated (NadCU), filtered, and concentrated to give the title compound (74 mg) as a white solid , 60%). NMR (300 MHz, CDCh) § 7.36 (2 Gen1> 8 Hz), 7.13 (1 to 1: 1,] 2 3 Hz), 69 (111 cores) = 3 Hz, 8 Hz ), 6.88 (211, (1, 8 Hz), 6 76 (111 (1 J 2 8 Hz), 5.96 (2H, s), 3.96 (lH, d, J 2 9 Hz), 3810h '' 5) '〇.58 (11'1, (1 (1 (1, 41 = 12, 10 Hz, 3 Hz), 3.52 (111, (1 < 1 < 1 = 9 Hz, 3 Hz), 3.32 (1 (1 拎 17 Hz), 3.08 (] ^ 乂 ^ 10), 2.9 2 (1Η, dd, J = 9 Hz, 7 Hz), 2.8 3 (1H, d, J = 1 7 Hz). MS (DCI / NH3) m / e 456 (M + H) 2. Analysis and calculation of C29H29N〇7 · 0.3 H2Q 値 · c, 65.07; Η, 6 48; Ν, 3.04. Experimental 値 · c , 65.02; Pyrene, 6.42; N, 2.93. Example 5 1 1-Phenyldioxyphenyl on the soil 1 (1-fluorenylmethyl-N-propyl,) aminofluorenyl)-? Billot bite- 3-Chinic acid By following the procedure described in Examples 1 and 49, the sulfanyl group in Example 49 was replaced with fluorene-1-carboxaldehyde to prepare the title compound. The meso isomer was seen in nmR. 1HNMR (300 MHz, CDCl3) 58.29 (lH, bd, J = 8 Hz) '7 86 (2H, d, J = 8 Hz), 7.75 (1H, d, J = 8 Hz), 7.49 (3H, m), 7.34 (2H, dd, J 2 3 Hz, 9 Hz), 6. 8 3 (2H, -144- (please read the precautions on the back before filling this page), ν5 Qin 丨 Paper size Inverse / IphUg standard (CNS) Λ4 specification [2Ϊ ^ X 297 mm] 552260 A7 B7

A a ri 卬 5. Description of the invention (142 dd, J = 9 Hz, 2 Hz), 4.50 (1H, m), 3.94 (1H, dd5 J = 9 Hz, 2 Hz), 3.78 (3H, s), 3.65 (lH, m), 3.49 (lH, d, J = 14 Hz), 3.40-2.93 (5H, m), 2.91, 2.83 (3H, s), 1.48 (2H, seven-peak, j = 7 Hz), 0.83 , 0.77 (3H, t, J = 7 Hz). MS (DCI / NH3) m / e 461 (M + ΗΓ. Analysis and calculation of C29H29N07 · 0.5 HOAc 値: X, 71.00; H, 6.99; N5 5.71. Experiment71: C, 70.95; H, 7.00; N, 5.46 〇 Example 52 trans, trans-2- (4- -oxoepoxy) -4- (2,3_ two winds and fufang_ 5 _yl) -1-((N_ fluorenyl-N-propyl) Aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid

Example 52A 2,3-Dihydrobenzylfuran-5-carboxaldehyde Add tin tetrachloride (1.65 g, 17 mmol, 1.2 eq.) To methylene chloride (30 ml) at -40 ° F. α, -Dichloromethyl methyl acid (2.15 g, 19 mmol, 1.35 eq.) was added to the stirred solution, and after 15 minutes, it was added to (: 112 (: 12 (5 ml)) 2, 3 -Dihydrobenzofuran (168 g, 14 mmol), maintaining the temperature below -3 5 ° C. The mixture was warmed to 0 ° C, stirred for 1 hour, then poured into ice-water, and then Stir for another 30 minutes. Dilute the mixture with ether and separate the phases. The organic phase is concentrated in the air and the residue is purified by air distillation to give the title compound as a colorless liquid (1.25 g, 60%). The lower point of the 0.3 mm Hg is 119-12 1 ° C.

Example 52B trans, trans-2- (4-fluorenylphenyl) -4- (2,3-dihydrophenylphosphoniumfuran-5-yl) -1-((N-145- National Standards (CNS) Λ4 Specification C 210 X 297 male f) (Read the precautions on the back before filling in this page) 552260 A7 B7 V. ^ Service instructions (143 曱 棊 di-N-di- ^ yl) aminocarbonyl Pyrrolidine_3_carboxylic acid ^ The title compound was prepared by following the procedure described in Examples 1 and 49, using Example 5A as a substitute for piperazine in Example 49A. See in NMr To meso isomers. WNMR (300 MHz, CDC13) δ 7 ^ (1 & (1,] = 8 Hz), 7 28 (11 ^ 111), 7.19 (111, 111), 6.8 7 (1 { ^ d, J 2 8 Hz), 6.73 (1Η, d5 J = 8 Hz), 4.56 (1Η, t, Hertz), 3.83 (11 (1, 1 2 10 Hertz), 3.80 (31 " 1, 5), 3.63 (call from 111, 3.4-3.0 (9H, m), 2.87, 2.84 (3H, s), 1.5] ί (2 七, Seven Tongue Peak, Bu 7 Hz), 0.88, 0.78 (3H, t, J = 7 Hz). (DCI / NH3) m / e 453 (M + ΗΓ. ^ Calculated by analysis at C26H32N205 · 0.95 u ^ ^ 20: ，: c, 68.33; H, 7 · 17; N, 6 · 13 Experimental letter. C, 68.60; hydrazone, 6.88; N, 5.80. Example 53 group, bis (phenyloxyphenyl) -bu ((N-methylpropyl) amine) -inch bite -3- The reacid was prepared by the procedure described in Examples 1 and 49, replacing the pepper blanket in Example 4 9 A with 4-oxobenzophenamine. The meso isomer was seen in n MR. 4 NMR (300 MHz, CDC13) δ 7 · 3 7 (2H, 4 J = 7.5 Hz), 7.32 (2H, d, J = 7.5 Hz), 6'86 (4H, m), 3.83 (1H, m), 3 81 (3H, s), 3.79 (3H, s), 3.64 (1H, m), 3.48-2.97 (6H, m), 2.87, 2.83 (3H, s), 2.85 (1H, m), 1.45 (2H, m), 0.84, 〇74 (3H t, J = 75 Hz). MS (DCI / NH3) m / e 44 1 (Μ + ΗΓ. Analysis and calculation of c25h32N2 05 · 0.5 H20 値: C, 66 80; H, 7.40; N, 6.23. Experimental values: C, 67.15: 146- National Standard for Valves (CNS) specifications of this paper Γ2ι〇χ 297 & ^ f Please read the note on the back Js, and then fill out this page j Order 552260 A7 B7 V. Invention Explanation (144 H, 7.31; N, 6.00. Example 54

Trans, trans-2- (4 • fluorenoxyphenyl) -4- (3,4-dioxophenylfluorenyl-N-propyl) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid The procedure described in Examples 1 and 49 replaced the piperonaldehyde of Example 49A with 3,4-dimethoxyphenylaldehyde to prepare the title compound. Meso isomers were seen in NMR. 1H NMR (300 MHz, CDC13) δ 7.33 (2H7 d, 7.5 Hz), 7.07 (11 ^ (1,! = 2.0 Hz), 6.98 (1gen111), 6.85 (1 仏 (1, 7.5 Hz) , 6.82 (21 (1, 7.5 Hz), 3.91 (3) 1, 5), 3.86 (3H, s), 3.83 (1H, m), 3.79 (3H, s), 3.64 (1H, m ), 3.50-2.95 (6H, m), 2.87 (1H, m), 2.85, 2.83 (3H, s), 1.45 (2H, m), 0.84, 0.74 (3 H, t, J 2 7.5 Hz) MS (DCI / NH3) m / e 471 (M + H) +. Analytical calculations for C26H34N2 06 · 0.5H2 0: C5 65.12; H, 7.36; N, 5.84. Experiment: C, 65.22; 7 · 27; N, 5.59. Example 55 • 4 'part 屮 i Again:] (Please read the precautions on the back before filling out this page) Trans' trans-2- (4-fluorenyloxy) -4- (3 -Methyllactinoyl) -1-((N-fluorenyl-Nn)) aminocarbonylfluorenylpyrrolidin-3-carboxylic acid with the procedure described in Examples 1 and 49, Instead of the pepper blanket in Example 49A, the title compound was prepared. The meso isomer was seen in NMR. 4 NMR (300 MHz, CDC13) δ 7.33 (2H, d, J 2 7.5 Hz), 7.24 (1H, t, J = 7.5 Hz), 7.05 ( 2H, m), 6.85 (2H, dd, J = 7 5 & 2 Hz), 6 76 (1H, m), 3.83 (1H, m), 3.81 (3H, s), 3 79 (3H, s) , 3.64 (1H, m), 3.48-2.97 (6H. -147- The paper scale is applicable to the Chinese valve national standard (CNS) Λ4 specification f 210X 297 mm) 552260 A7 B7 V. Description of the invention (145 (please read first Note on the back page, please fill in this page again) m) '2.87, 2.83 (3H, s), 2.85 (1H, m), 1.45 (2H, m), 0.84, 0.74 (3H, t, J = 7.5 Hz) MS (DCI / NH3) m / e 441 (M + ΗΓ. Analytical calculation for c25H32N205 · 0.5 h2〇: C, 66.80; H, 7.40; N, 6.23. Experiment 値: C, 66.76; H, 7.36; N, 6.05. Example 56 Pyridoxine dioxophenylfluorenylmethyl-N-propyl) aminocarbonylmethyl) -pyrrolidine-3- # acid by the procedure described in Examples 1 and 49, The aldehyde was substituted for the piperic acid in Example 49A to prepare the title compound. The mesostructure is seen in nmr. 1H NMR (300 MHz, CDC10δ 7 82 (4H, m), 7 69 7 47 (2H, m), 68) (2H, dd, J 2 7.5 & 2 Hz), 3.90 (1H, d, J = 8 Hz), 3.78 (jH, s), 3.57 (1H, m), 3.52-2.97 (6H, m), 2.93, 2.85 (jH, s) '2.90 (lH, m), 1.52 (2H, m), 0.86, 0.76 (3H, t, J 7.5 * this) α MS (DCI / NH3) m / e 461 (M + H) t. Analytical calculations for C28H32N204. 05h20: ，: c, 7162; H, 7.08; N, 5.97. Experiment 値: c, 71.58; Η, 7.11; N, 6.01. Example 57 Methoxyphenyl) -4- (l, 3-phenylhydrazone dioxane 1ΐ! Ζ (2- (ethylsulfinyl) ethyl) -pyrrolidine-3-carboxyl 10 liters of κ I and 0.5 ml of diisopropylethylamine were added to 6 liters of acetonitrile, and the compound obtained from Example 1C (100 mg, 0.27 mmol) and chloroethylethylsulfide Ether (67.5 mg, 0.5 millimolar, 2 eq.) Medium ° Back -148- This paper is the standard of the state of Zhongzhou Garden Store (CNS) 8 4 specifications C210X 297 mm) 552260 A7 B7 V. Description of the invention (146

, J 7r 屮 iK

The mixture was flowed for 4 hours and then concentrated in the air. The resulting residue was purified on a chewing gum by scintillation chromatography and washed with 4: 1 hexane-ethyl acetate to obtain 93 mg (75%) of ethylthioethyl compound. 68 mg of 3-chloroperoxybenzoic acid was added to sulfide (90 mg, 0.2 mmol) dissolved in 5 ml of CH2C12 in an ice bath. The mixture was dropped in an ice bath for 40 minutes, and stirred at room temperature for 3 hours. 10% of an oxide steel falling liquid (2 ml) was added, and the mixture was extracted with Et OC (2 X 50 ml). The combined organic extracts were washed with water and brine, dried over sodium sulphate and concentrated in the air. The resulting residue was chromatographed on silica gel, eluting with EtOAC and 10% MeOH in CH2C12 to give thallium (62 mg, 65%). This ethyl ester was hydrolyzed using the procedure described in Example ID to give the title compound as a mixture of diastereomers. Melting point 61 -63. (: MS (DCI / NH3) m / e 446 (M + H plant. 1H NMR (CDC13, 300 MHz) δ 1 25, ί .32 (t, J = 9 Hz, 3Η), 2.45-2 · 75 (m, 4Η), 2.84-2.96 (m, 3H), 3.02-3.08 (m, 1H), 3.32, 3.36 (d, J-2 3 traces, 1H), 3 47-3.58 (m, 2H), 3.65, 3.68 (d, J = 7.5 Hz, 3.76, 3.80 (s, 3H), 5.94 (s, 2H), 6.72 (d, J = 7.5 Hz, i H) '3 8 4-3.8 9 (m, 3 H), 7.0 2 (d, J 2 6 Hz, ih), 7.30, 7.34 (d, J = 7.5 Hz, 2H). Example 5 8 — ~ (4 -Homooxyl) -4- (1,3-Phenylhydrazine-5-yl-2- (isopropylsilyl) ethyl)-? Bihadien-Release 1 equivalent of Et. N is added to 2- suspended in anhydrous ch3CN Bromoethylamine-149- This paper is the size of the national standard (CNS) of the state of Zhongzhou (CNS) Λ4 specification (210x 297 cm) (Please read the precautions on the back before filling this page)

1T 552260 Α7 Β7 V. Description of the invention (147; r in part 消: Hydrobromide (1 mmol). Stir the mixture for 30 minutes, then add equivalents of isopropylsulfonyl chloride and i EtsN equivalent. The resulting mixture was stirred at room temperature for 2 hours' and then a solution of the compound from Example 1 (185 g, 0.05 mmol) in 3 ml of CH2CN was added. The mixture was warmed 2 hours to 5 0-60 ° C, cooled to room temperature, treated with water and extracted with EtoAc. The mixed organic extracts were washed with water and brine, dehydrated and concentrated in the air. The obtained The residue was chromatographed and eluted with 3: 2 hexane-EtoAe to give 195 mg (75%) of the ethyl ester. The ethyl ester was hydrolyzed by the procedure described in Example iD (160) (160 Mg, 0.3 1 millimolar), to give the title compound (133 g, 88%). Melting point 94-96 ° C. NMR (CD30D, 3 00 MHz) δ 126 (d, J = 6 Hz , 6H), 1.97 1H), 2.38 (m, 1H), 2.77 (m7 1H), 2.88 (t, J = 9 Hz, 1H ^, 3.04 (m, 1H), 3.14 (t5 J = 7.5 Hz, 2H) , 3.35 (m) 3.46 (m, lH), 3.58 (m, lH), 3,78 (S, 3H), 5 92 (s, work, 6.74 (d, J = 9 Hz, 1H), 6.86 (dd, Hz, 3 Hz, 6.92 (d, J = 9 Hz, 2H), 7.00 (d, J = 3 Hz, 1H) ') J 2 9 Hz, 2H). MS (DCI / NH3) m / e (M + H Example 5 9m (4-Hydroxyphenyl "heterocyclic isoisobutoxy) ethyl) -pyridine; -Chinic acid (Please read the precautions on the back before filling this page, a ^ τ.36 ( d The procedure described in Example iD was used to prepare the title compound from the chemical compound 2- (isobutoxy) acetate obtained from Example 1C. Point 68_70 ′ ^ and NMR (CDC13, 300 MHz) δ 0.88 (dj 20 earth bucket, 〇 v. East 幺 幺, ό tl), jg ^ (Wu Zhongfeng, J = 6 Hz, 1H), 2.22 (ηι, 2H),? / '~ -./2 -2.79 (m, -150-) The paper ft scale is applicable to the National Standard for Valves (CNS) Λ4 specification (· 210 × 297 mm) 552260 A7 B7 杳 'Medium A and: jf A ίί 5. Description of the invention (148)' H95 (m, 2H), 3.13 (d, ~ z, 2H), 3 45_3 56 (m, 4H) '3.68 (d, J = 9 Hz, 1H)' 3 79 (s 3h), 5 94 (s 2H) , 6.72 (d 'J = 7.5 Hertz, 1H), 6.85 ⑽, ㈣Hertz, 7 5 Hertz, 3H), 7.08 (s, 1H), 7.34 (d, J = 9 Hertz 0γτλ / v, trace money, 2H) 〇MS (DCI / NH3) m / e 442 (M + H), examples of trans'trans-2- (4-oxophenyl) -4- (1,3-xiaoyi called — ---- oxetan-5-

IzU: Butylsulfonyl. I-Butylsulfonyl chloride (46.7 mg, u equivalent) and diisopropylethylamine (53 mg, 1.5 equivalent) were added to 10 mL of τΗρ Nothing was obtained from the stomach of Example 1C (0.271 mmol). The resulting mixture was stirred at room temperature for 2.5 hours, and then the solvent was evaporated. The crude product was purified on a silica gel by a scintillation layer and eluted with 3: 2 hexane_EtOAc to give 120 mg (90%) of ethyl ester. This ester (20 mg, 0.244 mmol) was dissolved in χ ml of EtOH 'and a solution of 100 mg of NaOH in 1 ml of water was added. The mixture was stirred at room temperature for 3 hours, and then concentrated under reduced pressure. Water (3 liters) was added and the solution was rinsed with ether to remove unhydrolyzed trans-cis isomers. The aqueous solution was acidified to approximately pH 6 with acetic acid and then extracted with EtoAc (2 X 50 mL). The combined organic extracts were washed with brine, dehydrated with thiosulfur and concentrated under reduced pressure to give the pure title compound (60 mg, 53%) as a white solid. Melting point 67-69 ° c. NMR (CD C13 'j 00 MHz) s 082 (t, J = 7.5 Hz ?, 3 Η), 1.20-1.33 (m, 2H), 158-168 (m, 2Η), 2.48-2.69 (m, 2H), 3.28 (dd,-151-

Four standards for wood paper (^ TX ^ T ^ .x 297 ^ iT (please read the precautions on the back before filling out this page). Order the milliliter of EtOH from the compound obtained in Example 61A (450 mg). The mixture was heated to 80 ° C for 1 hour, and then the solvent was removed in the air. Jue residue 552260 A7 B7 V. Description of the invention (149 called Chez, 1H), 3.49 (t, J = 12 Hz, m) 3 65 (dd j = i2 Hz, m) '3.82 (s, 3H)' 4.32 (ddj = i2 Hz, ih), $ 叩, J = 9 Hz, 2H), 5.95 (s 2H), 6 7Π 6 7 », V 5} 6.70_6.78 3H), 6.92 (d, J — 9 Hz! Mody, 211) '7.3.5 (d J = 9 Prostitute A / fc. W, J v. &Quot; Yi Xuan, 2H ). MS (DCI / NH3) m / e 462 (M + H), 5 base) soil (2-

Example 6 1A-trans ^ transethyl) ^ bispyridine-3-miao color 0.7 ml of diisopropylethylamine and 30 mg of sodium iodide were added to dissolve in 9 liters of 1,2-dixiethyl Fe in fe was obtained from a mixture of cis, trans and trans, trans p-biharidine (400 mg) of conventional example. The resulting mixture was heated to 100 tF hours, and then the solvent was removed in the air. The residue was dissolved in EtoAc, and continuously washed with water and brine, dehydrated and contracted under reduced pressure, and the crude product was purified by flash chromatography on Shixi gum, with 4 ·· 1 hexane Wash in an oven and pt o'e to obtain 470 mg of the title compound.

Example 6 1B

Trans, trans-2-Sycyl) -4- (1,3-phenylhydrazone & dioxane ρ 1-(2_ · (methylamino) ethyl) -p ratio bite di 3-carboxylic acid Add 0.5 milliliter of 40% aqueous ammonium amine and 50 mg of sodium iodide to dissolve in IQ-152- This paper is in the standard state of China (CNS) Λ4 size Γ210 × 297 mm) (Please read the note on the back first) (Fill in this page again)

552260 A7 ----------- V. Description of the invention (150) ~ ^ The residue is dissolved in EtOAc, and continuously washed with water and brine, dehydrated and concentrated in the air. The resulting product was carried on to the next step without further purification. Example base_'trans-2_ (present-fluorenylphenyl) -4-Π · 3 di-methane: pentamidine-5-some lllr.m1! -Methyl-N-isobutyl_kyl) ethyl _) —_- Also-Acid acid 0.3 ml of diisopropylethylamine was added to the compound obtained in Example 61B (approximately 15 mg) dissolved in 5 ml of dichlorodichloroethane. The solution was cooled to -40 ° C, isobutyridine chloride (0.7 ml) was added, the ice bath was removed, and the solution was allowed to warm to room temperature and stirred] for 5 hours. The solvent was removed in the air; the residue was dissolved in EtOAc and washed successively with a 1: 1 sodium bicarbonate solution / water and saline, dehydrated and concentrated in the air. The product was purified by flash chromatography on silica gel, eluting with a gradient of 1 · 1 EtOAc-hexane to EtOAc, and finally eluted with 10% MeOH-EtOAc.

The ester was decomposed in 1.5 ml of EtOH; 0.75 ml of a 17% aqueous NaOH solution was added, and the resulting mixture was stirred at ambient temperature for 3 hours. The solvent was removed in the air; the residue was dissolved in water , And rinse with B. The liquid phase was acidified to pH 3 with liHsPO4 and extracted twice with ether. The combined organic extracts were washed with brine and dried over Na 2 SO 4. The solvent was removed in the air to give 82 mg of the title compound as a white foam. Helix isomers were seen in NMR. 1H NMR (CDC13 '300 MHz) of major helix isomers δ 1 06 (d, 3Η, J 2 10 Hz), 1.12 (d, 3H, J 2 10 Hz), 2 15 (m, 1H) , 2 μ 〇 (m, 3H), 2 91 (s, Ά), "2 (m, 2H), 3.) 0 (m, 2H), 3 65 (m, 2H), 3.77 (s, -153 -This paper is suitable for countries in the garden ^^ TcNsTmS C 210X 297 ^ JT -—- (Please read the precautions on the back before filling in this page j

552260 〆 · 部 屮 A7 B7 V. Description of the invention (151) 3Η), 5.92 (s, 2Η), 6.73 (d, 1Η, J 2 8 Hz), 6 75-6 9 (m, 4H), 6.96 (d , 1H, J 2 2 Hz), 7.29 (m, lH). MS (DCI / NH3) m / z 469 (M + ΗΓ. Analysis and calculation of C26H32N206 · 0.3 but FA: 丁: C, 63.55; H, 6, 48; N, 5.57. Experiment 値: c, 63 44; H, 6.71; N, 5 · 24. 例 6 2 trans-di-^^ (· 4-fluorene-cyclopentene 12: 1. (2- (N-fluorenyl) ethyl: l. The procedure described in Example 61 was used to replace isobutyridine chloride in Example 6c with propidium chloride to prepare the title compound. LH NMR (CDCl3, 300 MHz) of the main spiral isomers si 13 (t, 3H, BU 8 Hz), 2 (m, 1H), 2.30 (m, 2H), 2.65-3.0 (m, 3H), 2.85 (s, 3H), 3.25-3.4 (m, 2H), 3.5-3.7 ( m, 3H), 3.79 (S, 3H), 5.92 (s '2H)' 6.74 (d, 1H, J-2 8 Hz), 6,75-6.9 (m, 4H), 700 (bd s, 1H), 7.29 (bd s, 1H). MS (DCI / NH :,) m / z 455 (Μ + ΗΓ. Analysis and calculation of C25H30N2 06 · 1.0 H20 値: c, 63.55; H, 6.83: N, 5.93. Experiment 値: C, 63.55; H, 6 52; N, 5.73. Example 63-(4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxolene Nong Ijll-(N-methyl-N-Ethylaminomethyl)-? Than p bite -3-I The acid uses the procedure described in Example 1 to prepare the title compound. 1H NMR (CDC13, 300 MHz) δ 2 · 79 (s, 3H)-2 · 8-3 2 (m, 2H) for the main helical isomer. , 3.48 (m, 2Η), 3.61 (m, 2H), 3.77 (s, 3H), 3 78 (m JH), 4.3-4.5 (m, 2H), 5.95 (d, 2H, J = 2 Hz -154- National Standards (CNS) Λ4 Specification C210X 297 mm in Paper Size Use (Please read the precautions on the back before filling this page)

552260 A7 B7 V. Description of the invention (152) (Please read the notes on the back before filling this page), 6.7-6.9 (m, 4H), 7.00 (m, 1H), 7.15-7.35 (m, 7H) . MS (FAB / NBA) m / z 503 (M + H) +. Analysis and calculation of C29H30N2O6 · 0.5 H20 値: C, 68.36; H, 5.74; N, 5.50. Experiment 値: C5 6 8 · 41; H, 5.74; N? 5.36. Example 64 trans, trans- 2- (4-methoxyphenyl) _4-(1,3 -epi-dioxopentaza-5-yl) -1- (N-ethyl-N-butylamine Carbonylcarbonyl) -pyrrolidine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. 1H NMR of major helix isomers (CDC13, 300 MHz) δ 0.88 (t, 3H, J-2 7 Hz), 1.06 (t5 3H, J-2 7 Hz), 1.27 (m, 2H), 1.45 (m, 2H), 2.83-3.60 ”11H), 3.79 (s, 3H), 3.80 (m, 1H), 5.92 (bd s, 2H), 6.75 (d, 1H, J 2 8 Hz), 6.85 (d, 1H, J = 8 Hz), 6.92 (d, 2H, J = 8 Hz), 7.03 (s, 1H), 7.3 3 (d, 1H, J = 8 Hz). MS (DCI / NH3) m / z 483 (M + H)-. Analysis and calculation of C27H34N20. 0.5 HO Ac 0.5: C, 65.6 i; H, 7.08; N, 5.46. Experiment 。: C, 65.5i; H, 6.70; N, 5.66. Example 65 Trans, trans-2- (4-methoxyphenyl) -4- (13-benzo-dioxol-5-yl) -1- (N-methyl-N- ( 2,2-Dimethylpropyl) aminocarbonylfluorenyl) -pyrrolidine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. 1H NMR of the major helical isomer (CDC13, 300 MHz) δ 0.90 (s, 9H), 2.8-3.1 (m, 4Η), 2.94 (s, 3Η), 3.3-3.5 (m, 3Η), 3.61 (m, 1H), 3.80 (s, 3H), 3 82 ( m, 1H), 5.94 (bd s, 2H), 6.74 (cL 1H, J = 8 Hz), 6.86 (d, 2H, J = 8 Hz), 6 87 (m, -155- the paper size is appropriate / 丨] Chinese National Standard (CNS) A4 specification C210X 297 mm) 552260 A7 B7 V. Description of the invention (153 ( Read the notes on the back before filling in this page) 1H), 7.03 (d, 1H, J = 2 Hz), 7.33 (d, 2H, J = 8 Hz). MS (DCI / NH3) m / z 483 ( Μ + ΗΓ. Example 66 Trans, trans- 2- (4-fluorenoxyepidyl) -4- (1,3-benzobenzodioxolylpentyl · 5 _yl) _ 1- (2- (Ν _Methyl_N_ butyl continuous amino amine) ethyl)-mouth to mouth bite acid 0.2 ml Et3N and 22 mg (0.143 mmol, 1.1 equivalent) bubutane sulfonium chloride to dissolve The compound from Example 6 1B (60 mg, 0.13 mmol) in 5 ml of CH3CN. The mixture was stirred at room temperature for 1 hour and then concentrated in the air. The crude product was purified by column chromatography on silica gel, eluting with 1: 1 EtOAc-hexane to give 64 mg (90%) of the ester. This ester was hydrolyzed by the procedure described in Example ID to give the title compound. Melting point 64-66 ° (: 1: 9 仏 \ 111 (€ 0 € 13,300 MHz) 50.92 (t, J = 7.5 Hz, 3H), 1.39 (six peaks, J = 7.5 Hz, 2H), 1.68- 1.76 (m5 2H), 2.16-2.25 (m, 1 Η), 2.72 (s, 3Η), 2.75-2.92 (m, 5H), 3.12-3.20 (m5 1H), 3.25-3.34 (m, 1H) , 3.46-3.55 (m, 2H), 3.65 (d, J = 9 Hz, 1 H), 3.78 (s, 3H), 5.53 (s, 2H), 6.72 (d, J = 7.5 Hz, 1H) , 6.82 (dd, J = 7.5 Hz, 3 Hz, m), 6.86 (d, J-2 9 Hz, 2H), 7.02 (d, J-3 Hz, 1H), 7.34 (d, J = 9 Hz, 2H ). MS (DCI / NH3) m / e519 (M + ΗΓ. Example 6 7 Trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazine dioxolene) -5-yl) -Bu (2- (N-methyl-N-propylsulfonamido) ethyl) -pyrrolidine-3-carboxylic acid Sulfur gas to replace 1-156- This paper size states the National Park National Standard (CNS) A4 specification ('210 X 297 mm) 552260 A7 B7 5' Description of the invention (154) Butanesulfonyl chloride, preparation Title compound. Melting point 69-70 ° C. 4 NMR (CDci3, 300 MHz) 3 1.02 (t, J-7.5 Hertz, 3H), 1.78 (κ peaks, J = 7.5 Hertz, 2H) '2.18-2.26 (m, 1H)' 2.72 (s, 3H), 2.75-2.95 (m, 6H), 313.3.22 (m, 1H), 3.25-3.35 (m, 1H), 3.47-3.58 (m, 2H), 3.66 (d, J = 9 Hz, ih), 3.80 (s, 3H), 5.96 (s, 2H), 6.74 (d5 J = 7.5 Hz, 1H), 6.84 (d, d, JU Hz, 3 Hz, 1H), 6.87 (d, J = 9 Hz, 2H), 7.04 (d, J == 3 Hz, 1H ), 7.43 (d, J = 9 Hz, 2H). MS (DCI / NH3) m / e 50 (M + H). Example 6 8 Tail one, trans-2-14-methoxyphenyl) Di ^-(1,3-benzenexanylenedioxalpinenyl) -1-(2- (propyl-continyl) ethyl) -koubihide-3-# Under nitrogen pressure, 632 mg (26.32 mmol) of NaH was added portionwise to 1-propanethiol (3.5 g, 46.05 mmol) dissolved in 10 ml of anhydrous THF. The mixture was heated to 60-70. (: 1 hour. To this mixture was added the compound from Example 61A (180 mg, 0.38 mmol) in 2 liters of THF. Heating was continued to 60-70. For another 2 hours, then reduced The volatiles were removed under reduced pressure. The crude propylthioethyl addition compound was purified on silica gel by flash chromatography ...: 2 Hexane_EtoAc to elute to 170 mg (95%). In 0.3¾ liters of: Butanol ^ Ya'y Ding & a solution of Tetrapyridine (10 mg) plus ff 20 ml of Propionate and 5 ml of Tetramethylol (0.36 mg of pyridine) And 93 μg (0.8 mol)? ^ Methyl? 咩 than oxide (!. 〇) in I't. Stir the resulting mixture overnight at I, then ~ 157- (Please read first (Notes on the back then fill out this page)

552260 A7 B7 ----- Medium-Illegal; j

A Description of the invention (155 Concentrated under reduced pressure. The residue is distributed between EtoAc and H2O. The organic phase is washed with brine, covered with NkSCU, water, and concentrated in the air. Scintillation chromatography gives 177 mg (98%) ethyl ester, which was hydrolyzed by the procedure described in Example 1D to give the title compound. Melting point 73-75. IHNMRfDCh, 300 MHz) 3 1.04 (1,) = 7.5 Hz , 3; «) '178 (six peaks, J 2 7.5 Hz, 2H), 2.59-2.66 (m, 1Η), 2.84-3.08 (m, 7Η), 3.43 (dd, J 2 9 Hz, 3 Hertz, 1Η), 3.5 3-3.60 (m, 1H), 3.68 (d, J 2 9 Hz, 1H), 3.82 (s, 3H) '5.96 (s, 2H), 6.75 (d, J = 7.5 Hz, 1H), 6.82 (dd, J = 7.5 Hz, 3 Hz, 1H), 6.88 (d, J = 9 Hz, 2H), 6.99 (d, J. 3 Hz, 1H), 7.32 (d, J = 9 Hz, 2H). MS (DCI / NH3) m / e 476 (M + H). Example 69 Phenoxyphenyl) di 4- (1,3-phenylhydrazone dioxol-5-yl ^ i-1-N- (trans-5-methylhex-2-enyl) Example 69A of pyridinecarboxylic acid: 々trans-5-fluorenylhex-2-enoic acid was washed with hexane to disperse the oil-dispersible sodium hydride (0.85 g), suspended in thF (20 ml), and placed on an ice bath The mixture was cooled to 0.0%. Diisopropyl (ethoxycarbonylmethyl) phosphonate (5.0 ml) was slowly added, and the mixture was stirred for 4 minutes at 0.0 ° C for 20 minutes. Within five minutes Isoprene (2.0 mL) was added dropwise in THF (5 mL). The ice bath was removed and the mixture was allowed to stir at ambient temperature for 18 hours. Saturated chlorinated solution (50 mL) was added, and Extract the mixture with diethyl ether (3 X 50 亳 liters). Mix the ethyl acetate extract with Na2s〇4-158-size 4 and use the national standard specification of "2l0x 297". C Please read the notes on the back first Fill in this matter

55226〇 A7 B7 Ⅴ Description of the invention (156) --- Tax Yong, and evaporated to give a colorless oil, purified on silica gel by flash chromatography, and eluted with hexane. The title compound was isolated as a colorless drip.

Example 69B trans-5-methylhexano-2-ol-I-ol The compound (2.0 g) obtained from Example 69A was dissolved in toluene and cooled to 0 ° C on an ice bath. Diisobutylaluminum hydride (1.51 in toluene, 20 ml) was added dropwise, and the solution was stirred at 0 ° C for 2 hours. To the cooled solution, add the citric acid solution (25 ml) very slowly. The resulting mixture was stirred at ambient temperature for 18 hours. Diethylpyrene (50 ml) was added, solids were removed by filtration and washed with additional ethyl bonds (2 X 2 5 ml). The mash was extracted with acetic acid (2 X 2 5 liters). The ether extract and the washing solution were mixed, and the water was evaporated and evaporated to give a colorless oil. The product was purified by flash chromatography on silica gel and washed with 25% EiOAc-hexane. The title compound was isolated as a colorless oil (1.25 g).

Example 69C Bean-i-bromo-5-methyl-en-ene '1 * yr part (Please read the precautions on the back before filling this page

1T The compound (1 g) from Example 69B was dissolved in diacetic acid and cooled to 0 C in an ice bath. Phosphoric acid (2.5 g, 0.87 ml) was added dropwise, and the solution was stirred at 0 ° C for two hours. The solution was poured into ice, the layers were separated, and the layers were extracted with additional ether (3 x 2 5 ml). The mixed layer 'was water-free and a colorless method was obtained after consultation, which can be used without further purification (0.95 g). t Μ 69D_ Anti-dioxane-159 This paper is the national standard (CNS) of 屮 4 specification (· 21〇χ 297 mm) 552260 A7 B7 V. Description of the invention (157) ~~~ --- --- '/ · 部 屮 人') > /] 合) -1- ~ (-^ 二 ^-^-^-^-^ 2-alkenyl)-生 只 忧 -3- # multiplex acid use The title compound was synthesized in the manner detailed in Example ID, but with N-propylacetamidinium bromide substituted with the compound obtained from Example 69C. 1ρί NM] p (CDC13, 300 MHz) δ 0.84 (d, 6H, Hertz), i 57 (Six peaks 51 and 8 Hz), 1.8 7〇, 211, > 6 Hz), 26〇 (( ^, 1; 9 [J = 8 Hz, 14 Hz), 2.86 (t, 1H, j = 10 Hz), 2 96 (dd, m > 8 Hz, 10 Hz), 3.20 (dd, Hz 14 Hertz), 3 2S (dd, 1H, J 2 3 Hertz, i0 Hertz), 3.50 (m, 1H), 3 700 (J = 10 Hertz), 3.78 (s, 3H), 5.47 (m, 2h ), 5% (s, 2H),, 7.32 (d, 2H, J 2 9 Hz). MS (DCI / NHOM / e 438 (M + H)-. Analytical calculations for C26H31N05: C, 71.37; H 714; N 3.20. Experiments: C, 71.16; H, 7.24; N 3 17 Dioxol-5-yl-pyrrolidine-3-carboxylic acid was prepared by the procedure described in Example 69, but replaced with 4-methyl-2-pentanone in Example 69. Isovaleraldehyde in the solution to give a trans / cis-olefin mixture of about 7: 1. Purification of the crude product by preparative HPLC (Vydac uCi8) 'CH, m in 0 1% TFA with a gradient of 0-70% The resulting fraction was cold-dried and dried to obtain a white solid product (and-', Yi Yi Ying Xing handle). Second, (trans) isomer 1h nmr (CDc ^ (Please read the back Matters needing attention

, 1T -160 g five 2 ί ......... 2,, don't " ^-^^, · Xu Erding, rA f combined: ςΓ? Ί- 印 " &'; 5 A7 ～ _________B7__ Description of the invention (158) (m, 4H), 3.78 (s, 3H), 3.9-4.0 (m, 1H), 5.22 (m, 1H), 5.9 ((1,211, 1 = 12 Hertz), 6.63 (111, 1, 6.78 (111, 311), 6.95 (s, 1H) '7.45 (d, 3H, J = 8 Hz). MS (DCI / NH3) m / e 438 (M + H ) +. Analytical calculated values for C27H33N0 · 1.0 TFA: c, 61.59; H, 6.06; N, 2.48. Experiment 値: C, 61.36; H, 6.10; N, 2.34. Example 7 1

Diphenyl) -4- (1,3-benzoxantri-A # cyclopenten-5-yl) -1- (4-heptylcarbonylmethylpyrrolidine-3 Example 7 1A 1-chloro-3-propane 2-hexanone DMF (3 µl, 4 mole%) was added to 2-propylvaleric acid (156.6 µl, 1.00 mole) dissolved in anhydrous dichloromethane (2 ml). , F The solution was cooled to 0 ° C under nitrogen pressure. Within a few minutes, the test chlorine (94.3 μl '1.08 mmol) was added dropwise to the solution. The reaction was a small ^' at the same time Warm to ambient temperature. Cool the mixture to Q. Add an excess of about 0.3M_ of diazopine solution in ether. Stir the reaction mixture for 18 hours while warming to ambient temperature. Take 1M-sodium hexahydrate solution (30 ml) The reaction mixture was rinsed, dehydrated with anhydrous sodium sulfate, worked up, and concentrated under reduced pressure. The residue was dissolved in ether (2 ml) and cooled to 0 3c under nitrogen pressure. Hydrogen chloride solution (275 microliters, 1.10 millimoles) made into a solution of 41 in dioxane was added dropwise within a few minutes. The reaction was stirred for 18 hours while warming to ambient temperature The reaction mixture was concentrated under reduced pressure, and the resulting oil was used in the next step. In the report, _ -161- the paper size is appropriate / 丨] Chinese valve national standard (CNS) A4 specification (210X297) ) (Please read the notes on the back before filling in this page to order%, 552260 A7 B7 V. Description of the invention P59 No further purification required.

^^ 1 71B trans-2- (4-fluorenoxybenzene.yl) _lld_L1: L ^^ AjLcyclopentene_5_yl) -1- (4-affected "minyl ^) _ pyrrolidine · 3_ 袅Acetate was obtained from the reverse of Example ic, a solution of ethyl transcarboxylate (295 mg, 080 mmoles as a 50% solution in toluene), diisopropylethylamine (700 ' Zheng Sheng, 4.00 pen moles) and acetonitrile (4 ml) were added to the compound obtained from Example 7a (1.00 millimoles, maximum theoretical yield). To the resulting solution was added sodium iodide (12 mg, 10 mol%), and the reaction mixture was stirred under a nitrogen atmosphere at a temperature of 18 ° C for 18 hours. Additional sodium iodide (24 mg, 20 mole%) and acetonitrile (4 ml) were added, and the reaction mixture was heated to 50 ° C while stirring for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was chromatographed on silica gel, eluting with ethyl acetate: hexane of 9: 237 mg (46%) of the title compound as a yellow oil. %?

Example 7iC II (4- 3 -Cyclopentamidine_5 · ^ h :. '4: (Please read the precautions on the back before filling in this page)) -m: first cover the base) -p ratio p each ridge -3 Lithium hydroxide (38 mg, 0.909 mmol) in water (2.5 ml) was added to a solution dissolved in ethanol (10 ml) to obtain (˜〇1ι) G, 0.4: > 32 mmol). Stir the solution under nitrogen pressure; 18 峙, add additional lithium hydroxide (19 mmol) in water (0.5 mL). 4) 32 millimoles), and continue stirring for 24 hours. Under reduced pressure-ά 4 Saki reaction mixture in order to remove ethanol and dilute it with water (45 ml) ^ -162 degrees This state siege national standard (eNS) eight 4 specifications 〇χ 297 公 漦 ii 552260 A7 B7 Five 'invention description (160 2 = 1 rinse with ether (50 ml). The liquid is said to be rich with a professional acid, and then add water citric acid (please read the precautions on the back before filling this page) ) About the heart. Then 10% ethanol (4X25 milligrams = bath organic compound in aerosol) was covered with anhydrous sulphuric acid, filtered and concentrated under reduced pressure. The gel was purified by preparing residues. The product was eluted with 1: 1 ethyl acetate-hexane to give 86 mg (39%) of the title compound as an off-white powder. 1H NMR (CDCl3, 300 MHz) s 0.73-0.97 (m, 6H), 1.06 -1.33 (m? 6H) ^ 1.36-1.58 (m, 2H), 2.46 (m, 1H), 2.80-2.98 (m, 3H), 3.38-3.64 (m, 3H), 3.75-3.90 ( m, 1H), 3 79 (s, 3H), 5 94 (s, 2H), 6 75 ⑷ 1H), 6.86 (d, 2H), 6.92 (d, 1H), 7.12 (s, 1H), 7 · 32 (d, 2H). MS (FAB) m / e 482 (M + ΗΓ. Analysis and calculation of C28H35N06 値: C, 69.83; H, 7.32; N, 2.91. Experiment 値: C, 69.57; H, 7.41; N, 2.73. Example 72 Trans', radical, _2_ (4-methoxyphenyl) -4_ (l , 3-Benzo-dioxane) 1- (pentylmethyl V pyrrolidine-3-carboxylic acid Example 72A 1 -Chloro-2- -Hexyl function; Γ Department 屮 $ Utilization is described in Example 7 1A Procedure and replacing 2-propylvaleric acid with valeric acid to give the title compound as an oil, which can be used directly in the next step without further purification.

Example 72B trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzo-dioxolyl-163- This paper is suitable for the standard / 丨] China National Standard 隼 ( CNS) Λ4 specification f 210 乂 297 mm) 552260 A7 B7 V. > r Ministry of Central / V] A 卬 Description of invention (161)) -1- (pentylmethyl) -leaf | ^ each bite-3- Ethyl chitoate replaced the 1-air-3-propyl · 2 · hexane with the compound obtained from Example 72A. The procedure described in Example 71B was used, except that the addition effect of the first squatting steel was deleted. In addition, it was stirred at ambient temperature for 8 hours, and purified by stone gel chromatography, eluting with 3: 17 ethyl acetate-hexane, to obtain 305 mg (65%) of the title compound as a white bitter oil. . Example 72C ^ Di__trans- 2- (4-methoxyphenyl) -4- (1,3-phenylhydrazine dioxane; Therapy-$ _ yl) -1- (pentylmethyl each bite- 3-Flavoric acid by replacing trans, trans-2- (4-methoxyphenyl) -4- (1,3benzo-dioxol-5-yl) with a compound obtained from Example 72B -1- (4-heptylcarbonylmethyl) _t-pyrrolidine-3-carboxylic acid ethyl ester, and using the procedure described in Example 71C, except that only one lithium hydroxide (81.5) in water (3.5 ml) was added Gram, 1.942 millimolar) solution, followed by stirring for 18 hours to obtain 130 mg (46%) of the title compound as an off-white powder. IHNMR iCDCh, 300 MHz, δ 0.87 (t, 3H), 1.26 (m , 2H), 1.49 (m, 2H), 2.37 (m, 2H), 2.79-2.98 (m, 3H), 3.31-3.49 (m, 2H), 3.56 (m, 1H), 3.77, 3.79 (d, s , 4H), 5.94 (s, 2H), 6.75 (d, 1H), 6.81-6.93 (m, 3H), 7.09 (d, 1H), 7.33 (d, 2H). MS (FAB) m / e 440 (M + Η), C25H29N06: C, 68.32; H, 6.65, · N, 3.19. Experiment 値: C, 67.95; H, 6.64; N, 3.05. Example 73 branch, trans-2- (4-fluorenylphenyl) -4- (1,3-phenylhydrazine di-iLlUt carbamidine di 1 ^ ~ difluorenyloxy) fluorenylaminocarbonylammonium each. .3.Α ^ · -164 Knowledge, Zhang scale appropriate / 丨] Chinese National Standard ((^ 5) / \ 4 specifications (_210 乂 297)) (Please read the precautions on the back before filling this page), 1: mouth 552260 5.

/: Ministry of Education ί · ί, J A7 B7 Invention Description (162)

f. Example 73A. Slit-5- 臬 V 1-((3,4-dihydrofluorenyl) aminothiomethyl) -pyrrolidine- 3-. Junic acid uses the procedure of Example 1D, paragraph 1, with 3 Instead of dipropyl bromide, 4,4-dioxoammonium bromide is obtained to obtain the desired poplar-producing mixture in the form of a white foam with a yield of 8 10/0. Example 73B, trans, trans- and cis, trans-2- (4-methylphenyl) -4- (1,3-benzene # m-dioxafluoren-5-yl) _ 1- (N- ( 3,4-Dimethylaminofluorenyl) -N-methylamine, carbonylmethyl, and pyrrolidine-3-carboxylic acid ethyl ester. The product from Example 73A (220 mg, 0.44 mmol) was dissolved. In 2 ml of anhydrous HF and under argon pressure, add dropwise in 0.2 ml of THF, after stirring, cooled (0) sodium hydride (23 mg of 60% by weight mineral oil suspension, 16 5 mg, 0 69 mmol) in suspension. The resulting mixture was stirred at 0 ° C for 1 hour, then methyl iodide (28 liters, 64 mg, 0.45 mmol) was added. The reaction was stirred at (TC The mixture is in minutes. TLC (Et2O) indicates that the reaction is incomplete. An additional portion of methyl was added (28 μl, 64 μg, 0.45 mmol) and anhydrous i, dimethyl dimethyl group: 3 , 4,5,6-tetrahydro-2 (1H) pyrimidone (50 microliters, 0.41 mmol). The reaction mixture was stirred at ambient temperature for 2 days. The reaction was poured into 25 liters 0.5M Aqueous citric acid and extracted with 2 X 25 ml of EtoAc. In% ^ water and 30 The mixed organic extracts were continuously rinsed with liters of brine, and then dehydrated: (NaaSOd, filtered and concentrated under reduced pressure to produce more than 2700 g of crude material. Flash chromatography on silica gel, eluting with EGO, gave To -165 /, paper music again this Chuanxiong ® standard (CNS) eight 4 specifications [2l0X297 mm (please read the precautions on the back before filling in 3 pages)}

ii 552260 A7 __________ V. Description of the Invention (163) The title compound was obtained in the form of a 43% inseparable mixture. lH NMR (CDC13, 300 MHz) δ 2.79 (s) and 2.81 ⑴ for Μ% signals. MS m / z 591 (M + H) '.

Example 73C I, pentene-5_yl mN- (3,4_dimethoxyacetoxycarbonylmethylchinoic acid) in 0.5 ml of H2O lithium hydroxide monohydroxide (17 mg, 0.41 MM) was added to the compound from Example 73B (98 mg, 0.17 mmol) dissolved in 1 ml of EtOH and cooled to 0 ° C. The resulting solution was stirred under nitrogen for 16 hours The solution was concentrated in the air, and the residue was distributed between 15 ml of H20 and 15 ml of Et20. The solution was taken with 5 liters of EtaO; The liquid phase was acidified. The acidic liquid phase was saturated with NaCl and extracted with 3 X 15 ml of EtOAc. The EtOAc extracts were mixed, dehydrated (Na2S04), then filtered and concentrated in the air to give 40 mg ( 42%) of the title compound as a white foam.! H NMR (CD30D, 300 MHz, two mediate isomeric forms) δ 2.85 (s, 3H), 2.94-3.25 (br m, 3H), 3 · 3 5 -3.7〇 (br m) and 3.64 (s, sum of 4H), 3.70-3.97 (brIIl), 3.74 (s), 3.7 (s), 3.78 (s), 3 79 (s), 3.81 ( s) and 4.03 (br d, money, sum), 4 43 (AB, 1H), 5.91 (s) and 5.93 (s, 2H total), 6.50 · 6.60 6.67-7.02 (brm, 6H), 7.29 (brd) and 7 35 (brd, 2H total) HRMS for C3iH35N20s (M + Hr Calculated 値: 563.2393. Experimental 値: 563.23 85. -16S-This paper is suitable for National Standards (CNS) Α4 size (210x 297 mm) (please read the precautions on the back before filling this page), order 552260 A7 B7. Description of the invention (164, multiple example 7 4) WN- (i, tertomethyl) -pyridine yn. Using the procedure of Example 73C I, the compound obtained from Example 73a was substituted for the compound obtained from Example 73B to obtain Title compound. Lfj nmr (CD3Od'3 00 MHz) δ 2.85 (d, J = i6 Hz, 1H), 2 92 (br t, J = 9 Hz, Moda, 1 field, 2.98 (brt, J = 10 Hz), 332-3.39 (brm, 2H), 54-). 65 (br m, 1H), 3.67 (s, 3H), 3.78 (s, 3H), 3.80 (s, 3H), 3.85 ( d, J = 10 Hz, iH), 421 (d J = 15 Hz, 1H) '4.41 (d, J = 15 Hz, iH), 5 91 (s, 2H), 6 67 (d, j = 8 Hz (IH), 6.75-6.95 (m, 7H), 7 33_7 40 (m, 2H). About the calculated HRMS of C30H32N2O8 (m + h) +: 549.2237. Experiment 54: 549.2224. Example 75 11 ^, 311,411) Di 2- (4-^^ phenyl,) _ 4_ (1,3_pyridine dioxane (Please read the precautions on the back before filling out this page, 11

Part t λ I

Aii India; ^ > 1-((1den) _: 1- (1 ^ dipropylaminocarbonylbutyrate vpyrrole acid Example 75A Liangyi'trans-2_ (4-fluorenoxyH:) -4- (1,3-Bin # metadioxo iron) butyl) -pyrrolidine-3-boronic acid ethyl I Adapted from the procedure of Fung et al., J Med. Chem., 35 (10): 1722_34 (1992) The compound from Example 6A (103 mg, 0.279 mmol) was dissolved in 0.7 ml of nitromethane and 07 mmol and H20, and ammonium carbonate (34 mg, 0.35 mmol) was added. ) And 2 · Bromovaleric acid (2S) -fluorenyl ester (78 -167- wood paper, suitable for Chinese Standards " National Standard (CNS) Α4ϋ ^ ι〇χ 297 mm each; ^. 部 屮 央 ^: ^ -x; ui 7 ^ 必 合 ^: ^ 卬 ^ :. 552260 A7 B7 ------- ----------- One ~ ----------- --- one-five, description of the invention (165) grams, 0.30 millimoles). The reaction was refluxed for 24 hours. The reaction was distributed between 15 ml of 1M aqueous Na2CO3 and 25 ml of CH2CI2. 2 x Extract the liquid phase with 10 ml of CH2C12 and rinse the combined organic extracts with 15 ml of brine, dehydrate (Na2S04), then filter and concentrate under reduced pressure to a brown oil (169 mg). By silicone The crude product was purified analytically and eluted with 3: 2 CH2Cl2-hexane to give 106 mg (68%) of the title compound as a waxy solid. PG NMR showed the presence of two diastereomeric houses. Example 75B Phenyl) -4- (1,3-benzisodioxolene- · ίΊ (dipropylamine storage group) -1-butyl)-? Bilodine-3-ethyl The reaction from Example 75 < Compound (101 mg, 0.180 mmol) and 30 mg of 10% palladium carbon was stirred under 1 atmosphere of H2 in 2 ml of EtOAc for 4 hours. The reaction was filtered through a plug of diatomaceous earth. The mixture was subjected to ice-washing of the catalyst using 15 ml of < e0Η. The mixed mash and rinsing solution was concentrated in the air, to 81.4 g (96%) of crude acid as a white solid. In 2 ml of anhydrous DMF, combine the above crude acid with HOBt hydrate (41 grams, 0.27 mmol), dipropylamine (26 mg, 0.26 mmol), and methyl (37 mg, 0.3 7 millimoles). The solution was cooled to 15 C 'and then ethyl ethyl 3- (3-dimethylaminopropyl) amine diimide (44 Don's 0.23 mmol) was added. At -15. (: The mixture is stirred and allowed to slowly return to room temperature overnight. By distillation under reduced pressure, the solvent is removed so that the residual poplar is distributed in 20 ml of EtOAc and 10 ml of 11- — -163-'(0 ^ 77 ^ 7 ^ 210x 297mm ^ ^-(Please read the notes on the back before filling in this page, = 口% ». 552260' 4 '··

A A7 s________B7____ 5. Description of the Invention (166)

Na2CO; between 3. The organic phase was washed with 10 ml of brine, dehydrated (Na2S04), then filtered and concentrated in the air. The crude product was purified by flash chromatography on silica gel, eluting with Et20-hexane of 1 ·· 2. The overlapping fractions were further purified by preparative HPLC and eluted with 1: 2 Et20-hexanes to yield 32 mg (34%) of a non-polar product and 44 mg (46%) of a more polar product.

Example 75C (2-foot, 3,1,41〇-2- (4-methoxyphenyl) -4- (1,3-benzene # [^ dioxolane-5-yl) -1-(( 1 RVWN, N-dipropylaminecarbonyl) -1-butyrrolidine acid According to the procedure of Example 73 C, the product obtained from Example 73B was replaced with the non-polar isomer from Example 75 B. The yield was 94%. [Cc] D-: -52 ° C (c = 0.235, CH3OH). IHNMRCCD.sOD, 300 Hz, δ 0.55 (t, J = 7 Hz, 3H), 0.87 (t, J 2 7 Hz) and 0 8 7-0.94 (m, 6H total), 1.03-1.25 (br m, 2H), 1.251 · 68 (br m, 4H), 1.90-2.07 (br m, iH), 2.75-2.94 (br m, 2H), 2.94-3.02 (brm, 2H), 3.20-3.40 (m, with signal repetition of CD2HOD®) '' 6040-3.60 (br m, 2H), 3.79 (s, 3H), 4.04 (br d, J = 9 Hz, 1H), 5.92 (dd, J = 3.5 Hz, 2H), 6.72 (d, J = 8 Hz, 1H), 6.79 (dd, J = 1.5, 8 Hz, 1H), 6.92 6.98 (br m, 3H), 7.29-7.39 (m, 2H). MS m / z 525 (M + H) ~. (Read the precautions on the back before filling in the vdc binding stamp f -159- this paper Dimensional description / 丨] China National Standard (CNS) Λ4 Specification (2 丨OXW) 552260} r Department ί / ν • ji 卬 f A7 B7 V. Description of the invention. (167 Example 76

Ig.S, —3-S _, _ 4S methoxyphenyl) -4_Π, 3_benzo-dioxolene_5_ •): —Li ((LR) -i- (N, N- Dipropylamine carbonyl) -1-butyl) -pyrrolidine-3-rollic acid. The product obtained from Example 73B was replaced with the more polar isomer from Example 75B according to the procedure of Example 73C. Yield was obtained. 88% of the title compound. [a] D = +58. (C = 0.37, CH3OH). 4 NMR (CD3OD, 3 00 MHz) δ 0.57 (br t, J = 7 Hz, 3H), 0.88-0.98 (m, 6H), 1.08-1.35 (br m, 2H), 1.35- 1.68 (br m, 4H), 1: 75-1.90 (br m, 1H), 2.75-2.86 (br m, 2H), 3.10-3.30 (br m5 2H), 3.51-3.65 (brm, 2H), 3.69 (s, 3H ), 4.03-4.16 (brm, 2H) '5.91 (s, 2H), 6.71-6.83 (m, 2H), 6.86-6.97 (m, 3H), 7.32 (br d5 J = 9 Hz, 2H). MS m / z 525 (M + H) ten. Example 77 (2S, _3—§ · 2Λ§ϋ: (4-methoxyphenyl) -4- (l, 3 · benzene # m-dioxolene-5-yldipropylaminecarbonyl) -1- Butyl) _Pyrrolidine-3 · carboxylic acid_

Example 77A Trans'bis (4-methoxyphenyl) -4- (1,3-phenylhydrazine-dioxol-5-yldipropylaminecarbonyl) -1-butyl) -pyrrolidine -3-Carboxylic acid ethyl_ Dissolve (2R) -N, N-dipropyl 2-hydroxypentanamide (106 mg '0.528 mmol, manufactured by standard procedures) in 2 ml thf under argon pressure Add diisopropylethylamine (75 mg, 0.58 mmol), and then cool the solution to -20 ° C. Mix trigas methanesulfonic anhydride (95 micron, within 1 minute, (诮 Read the precautions on the back before writing this page})

-170- 552260 A7 _______B7_ V. Description of the invention (168) 159 mg, 0.565 millimoles) is added to the cooled solution, and you — ^ stir the reaction mixture at 20 ° C for 1 hour, and then in the room Stir for another 3 hours at warm temperatures. The resulting slurry was re-cooled to 0 ° C and the compound from Example 6A (195 mg, 0.528 mol) was added to 3 ml of cH and 2 isopropylethylamine (101 µl, 75 mg, 0.58 mmol), the reaction was stirred at ~ 4 ° for 3 hours at 0 ° C, and stirred at room temperature for another 20 TLC (Et20-hexane 1: 2) showed that the starting material remained, So the eight readings were heated to reflux for 4 hours. The reaction was chilled and then distributed between 3 > EtOAc and 15 ml of 1 M Na2CO3 in water. 15 times

The liquid phase was extracted with EtOAc, then the combined organic phases were rinsed with 20 mL of brine, dried (Na2SO4), filtered and concentrated in vacuo to a yellow oil. Purified by scintillation chromatography on this knee, eluted with 1: 2 Et20-hexane to obtain 19.9 mg (7%) of a non-polar product and 20.1 mg (7%) of more polar Thing. The 1H NMR mass spectrum and MS were the same as those of Example 76B.

Example 77B (2S, 3S, 4S) -2- (4-methoxyepiyl) -4- (1,3-phenylbenzene dioxetane-5_〆: ·-'^ * iN τ- / U ^ M · * / Μ φ— (please read the precautions on the back before suppressing this page) group) -l-((lS) -l- (N, N-dipropylamine) Ding) Biloxidine-3-chinoic acid according to Example 7 j C & the order is replaced by the non-polar isomer from Example 7 7 A, the product obtained from Example 73B, yield loo% Title compound. 4 NMR (CD3OD, 300 MHz) and MS are the same as those of Example 75 (:. -171-This paper size ii;}] Zhongyuan National Standard (CNS) Λ4 specification [2 丨 0 丨 297 mm] 552260 A7 V. Description of the invention (Lake Example 78 (that is, read the precautions on the back and then fill out this page) l AizirCiim-c ^ N-dipropylaminecarbonyl) -ιbutyl cloth Follow the procedure of Example 73C to obtain from Examples? 7a compared with the polar structure of the product to replace the product obtained from Example 73B to obtain the title compound of 8 *. 1-Λ 8 / 〇. H NMR (CD3OD, 300 MHz) and MS blood per The same as those of Ling example 76. Example 79 was, trans-2- (4-fluorenylphenyl) -4- (1,3-benz # 间 二 5) -1- (Ν, Ν 二 ^ 1 ^ _-1_yl) Aminocarbonylmethyl soil Add carbonyldiimidazole (5 10 mg, 3.148 mmol) to too? —One —./liter-% ». 1.020 g (2.00 mmol) in THF ) The compound from Example 43, the mixture was heated to 50 ° C for 40 minutes. The reaction mixture was cooled in an ice bath and a 25% solution of ammonia in methanol was added. Within 30 minutes, the reaction mixture was filtered. The formed solid was rinsed with ethanol and finally with Ethane to give 850 mg (83%) of 3-famidine. Melting point: i94-196 ° C. Add hydrazine chloride (1.0 6 g) to In 7 ml of the amidine in p-pyridine, and the mixture was stirred at room temperature for 1 hour. Dioxane was added, and the solution was washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated .Into the residue on Shi Xijiao Chromatography was performed, eluting with 2: 1 hexane-ethyl acetate, to obtain 790 mg (96%) of a 3-nitrile compound. Add 3 85 trimethyltin chloride and 126 mg of sodium azide to 5 In the milliliter of toluene, the essence is heated. The mixture is heated to 125 ° C (bath temperature) for 20 hours -172- the paper 烺 scale inverse / 彳] China National Standards (CNS) A4 size "210X 297 public (Centi) 552260 A7 B7 Part-ik Λ 卬 5. Description of the invention (17). After cooling, 'methanol (5 ml) was added, and the solution was concentrated in the air. 6 ml of methanol was added to the resulting residue. And 6 ml of water containing 0.2 g of phosphoric acid. After stirring for 1 hour at 1: temperature, water was added and the mixture was extracted with dichloromethane. The mixed organic extracts were dehydrated and concentrated, and the resulting residue was Crystals were formed from acetamidine to obtain a solid. This solid was dissolved in a steel oxynitride solution, the insoluble material was filtered off, and acidified with acetic acid to give 532 mg (62%) of the title compound. Melting point i65_167 ° c. IHNMR ( CDC13 '300 MHz) δ〇85 ^,] = 7 Hz, 3H), 087 (t J 2 7 Hz,) H), Ll -1.50 (m, 8H), 3.0-3.6 (m, 8H), 3.70 (S, 3H) '3.7-38 (work, 1H), 3.90 (t, J 2 9 Hz, 1H), 4.37 (d , J == 9 Hz, '5.86 (s, 2H), 6.62 (d, J 2 8 Hz, 1H), 6.6) -6 7, (m, 3H), 6.95 (d, j 2 2 Hz, m), 7.11 (d, J-2 9 Hz, 2H). Example 80 Phenylhydrazone dioxol-5-yl is fluorenated! Aminocarbonylfluorenyl) -pyrrolidine-3-carboxylic acid The procedure described in Examples 1 and 43 is described from (4-fluoro Phenylhydrazine) Ethylpyridine Chiwa)-(2-nitrovinylbenzo metadioxolene, to the title compound of "amorphous solid in a 4-crystalline form. NMR (CDC13, 300 trillion,%) δ 0.8 1 (t, j = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H), 1.0-l.:> (m, 8H), 2.81 (d, J = 13 Hz , 1H), 2.90-3J〇 (m, 4H) ^ 3.15-3.30 (mi 1H), 3 32-3.45 (m, 3H) ^ 3.55-3.65 (m, i H) 3.8 6 (d, J — iq Hz , Ih), 5 9 4 (dd, J 2 2 Hz, 4 Luran, 2h) '6.72 (d, J 2 8 Hz, 1H), 6 86 (d, J 2 8 Hz, 1H), -173- (Please read the precautions on the back before filling this page) 552260 A7 B7 V. Description of the invention (171 medium fire * 6.95,7 · 07 (m, 3H), 7.32-7.45 (m, 2H). TJlj 81 Phenyl) -Earthine], 3-phenylarseno-dioxo) -1- (N, N-di (n-butyl) amine carboxymethyl) -pyrroline, at 138 g (0.852¾ Mo Ear) of carbonyl diimide buried too a THF in the middle, borrow Bowman, RE, J. Chem. Soc. 1346 (1950), N, N-dibutyl glycine (150 mg, 0.813 mmol) prepared by Wanfa, and heated to 50 ° C for 30 minutes. After cooling to room temperature, 25 gram (0.678 mmol) trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazine dioxin-3) Ene-5 · yl) -pyrrolidine-3-carboxylic acid ethyl ester, obtained from the compound of Example 6A 'and the mixture was heated to 45 ° C for 30 minutes. The product was subjected to chromatographic chromatography on silica gel at 1: 1 The hexane-ethyl acetate was eluted to give 306 mg of the intermediate ethyl ester. The ester was hydrolyzed with sodium hydroxide in water and ethanol to give 265 mg of the title compound as a white powder. IHNMRCCDCh, 300 trillion Hertz) δ-rotomers -0.75 and 085 (2t · 7 Hertz, 3H), ▲ M ″ 5 (m, 8H), 2 65-3.20 (m, 6H), 3.43-3.70 (m, 3H ), 3.72 (s, 3H) '3.8 7 (d, J 2 15 Hz, 1H), 4.49 (dd, J 2 12 Hz, 6 Hz) m.2 3 (dd, J = 12 Hz, 8 Hz, 2H ), 5.90 (dd, J 2 2 Hz, 4 Hz, 2H), 6.63-6.78 (m, 3H), 6.86 and 7 04 (d, J 2 9 Hz , 2H), 7.22 (d, J 2 9 Hz, 2H). Example 82 Group) -4- (1,3-phenylhydrazone dioxol-5-yl (n-propyl) aminocarbonylfluorenyl) -pyrrolidine-3-carboxylic acid («Read the first Please fill in this page again for attention) ♦ Order I— ml fiaii-— …… I g Medical II | two 1 mm— 174 552260 A7 B7 Λ i: 乂: j Hop five, description of the invention (172 used in The procedure described in Example 1 was used to prepare the title compound. Melting point 160-162 ° C. 4 NMR (CDC13, 300 MHz) Helix structure δ 0.69, 0.80, 0.84, 0.87 (four triplets, J = 7 Hz 6H), 1.00-1.52 (m, 6H), 2.63 and 2.66 (two bimodal, J = 13 Hz 1H), 2.90-3.10 (111,411), 3.23-3.61 (111,511), 3.71 and 3.75 (two doublets, J = 10 Hz, 1H), 3.78 (S, 3H), 5.92-5.96 (ιη, 2Η :), 6.72 (d, J-8 Hz, IH), 6.83-6.89 (m, 3H), 7.03 (d J =? Hertz, 1H), 7.81 (d, J = 9 Hertz, 2H). Example 83 Trans, trans-2.- 丄 Ml withered) -4- (1,3 -Benzene-dioxo-1pentene_5 · yl) -1-[2-(jj, _N-((n-propyl) aminopeptyl) ethyl) _ ρbibiter —3 _ borrow acid In 0.75 liters of methoxyethanol, will be obtained from The compound of Example 6A (250 mg ' 0.677 mmol), 205 mg (1.36 mmol) diallyl amidamine Polysciences, Inc.) and 10 mg acetic acid were heated to 85 ° C for 1 hour. Toluene was added, and the solution was washed with sodium bicarbonate solution, dehydrated and concentrated. Chromatography on stone gum was carried out, eluting with 3: 1 hexane-ethyl acetate, to obtain 283 mg (80%) of diallyl compound. The di-dipropyl compound was hydrogenated in ethyl acetate (25 ml) under hydrogen pressure using 10% Pd / C catalyst (27 mg). The catalyst was removed by filtration 'and the filtrate was concentrated to obtain dipropylamidinoethyl ethyl g with a yield of 100%. This ester was hydrolyzed to the title compound by the method of Example 1D with a yield of 83%. NMR (CDC13, 300 MHz) δ 0.82 and 0.83 (two triplets, J = 7 Hz, 6H), 1.39-1.54 (m, 4H), 2.35-2.60 (m, 3H), 2 80-3.07 (m , 5H), 3.14-3.21 (m, 2H), 3.31-3.38 (m, 175- this paper & scale towels (CNS) Fill out this page again) Order 552260 Five 'Invention Note (173 A7 B7: H)' 3.5l-3.61 (m, 1H), 3 73 (d J = 12 Hz, m), 3 75 (s,: H) ' ) .94 (s, 2H), 6.71 (d, J = 9 Hz, m), 6 79 · 6.85 (π,) 7.04 (d, J-2 Hz, ih), 7.32 (d, J = 9 Hertz, 2H). Example 84 Base) 4- (1,3-Benzophenoxadioxo-n-butyl) amido) -p-bilolide-3-complex acid The procedure described in, using dibutylamine methyl chloride prepared by the method of Hoshino et al., Syn. Comm., 17: 1887-1892 (1987) as the starting material to prepare the title compound. lHNMR (CDCl3 '300 MHz) δ 0.86 (t, J-2 7 Hz, 6H), 1.14-1.28 (m, 4H)' L35-1. "(m, 4H), 2.81-2.94 (m, 2H), 3. 1 1 (t5 J-2 12 Hz, 1H) '3.30-3.41 (m, 2H), 3.59-3.68 (m, 2hT), 3.76 (s, 3H)' 3.78-3.85 (m, 1H), 581 (d, j 2 9 Hz, m), 5.94 (s5 2H) '6.73-6.86 (m, 5H), 7 24 (d, J 2 9 Hz, 2H). Example 85 Phenylbenzobenzodioxo Heteropentene-5-yl (read the notes on the back and fill in this note)

-^ C ^ -x ;, '^ J 7 > nf in the 1T part, and ^ (1) (1 ^ (N ^^^ butyl) aminocarbonylmethyl) _pyrrolidine-3_carboxyl Sodium salt of sodium hydroxide in 2 ml of MeOH (48.2 mg, 98.3% purity, 1.184 mmol) was added to the compound from Example 43 (6 1 0 mg, i. 丨 96 millimoles). The solution was concentrated to dryness, and the resulting powder was stirred with heptane. The heptane was removed in the air to obtain a powder 'which was dehydrated in an air oven at 60 ° C for 2 hours to obtain 627 "mg of the title compound. -176- Wood Paper Standard Shizhou t® National Standard (CNS) Λ4 specification f 210X 297 male f) A7 B7 reverse 552260 I. Description of the invention (174

Xji column 8 6 dioxobenzene-pendene dii | Cyclopentene j "iK ^ (y" _N_bis (J ^ IAIamino) ethyl 1-pyrha ~ bit-3-carboxyl 1 will be at 0.75 A solution of the ethyl ethyl compound (150 mg), monobutylamine (1) (0.08 g), and sodium iodide (18 mg) in ethanol from Example 61A was heated to 80 C for 1 hour in ethanol. After the cold section <, toluene was added, and the solution was washed with a potassium bicarbonate solution, dried over NhSO and concentrated. More toluene was added and the solution was concentrated again to remove excess dibutylamine. The residue was dropped into hot heptane, and a small amount of insoluble matter was filtered off. The heptane was removed in the tritium to give 143 mg (87%) of the intermediate ethyl ester. This solution was hydrolyzed by the method of Example 1D to obtain the title as a white powder. 刀口 刀 H NMR (CD300D, 300 MHz) § 089 (t ,; 2 7 Hz, 6H), i Hugh i 56 (m 4H), 2 48 ^ Ο ″ 1H) '2 80-J.08 (m, 8H), 3 14_3 25 (m, 1H), 3 3 bu 3 38 Ο ”1H),)) 9- 3.60 (m, 1H), 3 74 (s, 3H), 3 75 ⑷ J = i〇). 89 (s, 2H) '6.7i (dJ 2 9 Hz, 1H), 681 (dd, W Hz, 2 Hertz, 1H), 69 ° (d, ρ10Hz, 2H), 6 96 (top) 2 Hz, 1H), 7 37 (d, ρ10Hz, 2H). Phenylhydrazone dioxane 0-yl (massyl) -N-fluorenylamino 1ethylpyrrole p-butylamine methyl chloride (135 mg) was added to 1 ml of dichloromethane It was obtained from the compound of Example 61B (250 mg) and 150 mg of triethylamine. This paper is of the right size (refer to the precautions on the back before filling out this page)

、 1T 乂 j -177 i) 552260 A7 V. Description of the invention (175 B7 After stirring 1 small dark at stem temperature, add formazan, 、,,, and ^ add Y 苳, and rinse with potassium bicarbonate solution. Cover with Na2S04 and dehydrate it. Concentrate the residue on a light basis and elute with a mixture of 38% EtoAe and 62% hexane to give 194 g of ethyl ester intermediate. The ester was hydrolyzed in 3 cases by the method of D.D. to give} 4 丨 mg of the titled ”lH NMR (CD3OD, 300 MHz) s 099 (t J = 7 Hz, 6H) \ 12H. 32 (m, 4H ), L42] .53 (m, 4H), 2.62 (s, 3H), 2.6) -2.76 (m, 1H), 3.00-3.32 (m; 8H), 3 4 heart 3 55 (m, 1H) '3.62 -3.78 (m, 2H), 3.80 (S, 3H), 4.07 (d J =: 12 Hz'1H), 5.9j (s, 2H), 6.75 (d, J = 9 Hz, 1H), 687 (dd, J 2 9 Hz, 2 Hz, 1H), 6.94 (d, J = 10 Hz, 2H), 7.04 J 2 2 Hz, 1 H), 7.04 (d5 J = 10 Hz, 2H) Example 8 8 Liangzhu ^ -2- (4-fluoranoxyphenyl) -4- (l, 3-dioxolane dilli_lXg __ [KN, N-di (n-butyl) amine , Two] ^ _ methylamine some 1 ethyl on the bite -3-Jun acid acid carbonyl Diimidazole (75 mg, 0.463 mmol) was added to 150 mg (0.294 mmol) of tetrahydrofuran in 0.4 mL of tetrahydrofuran.

(Read the notes on the back first and fill in the IJ'C order ^ :; r 部 屮, owe c ^ -x ;, ht,!. 山 f and c? Ί- 卬 ^, and stir at 60 ° C 2 hours. After cooling, add 50 mg (0.526 mmol) of pinanesulfonamide and 6S (0.447 mmol) DBU in 0.3 THF. Stir the mixture at 45 ° C for 2 hours. : The solvent was removed in and the residue was dissolved in water. Add several and freeze-dry the solution to give 121 mg (70%) of the title melting point 170-173 ° C. 4 NMR (CDC13, 3 00 trillion Hertz) -178- This paper size applies to the national standard (cns) Λ4 specification (210 to 297 mm) mg. The compound 82 552260

Medium A again; JA fc A fi India A7 B7 V. Description of the invention (176) (t, J = 7 Hz, 3H), 0.88 (t, J 2 7 Hz, 3H), 1.05-1.51 (m, 8H), 2.75-2.86 (m, 2H), 2.83-3.25 (m, 4H), 3.17 (s, 3H), 3.32-3.50 (m, 3H), 3.70-3.78 (m, 1H), 3.80 (s, 3H), 3.87 (d, J = 10 Hz, 1H), 5.96 (dd, J = 2 Hz, 4 Hz, 2H), 6.74 (d, J = 9 Hz, 1H), 6.84 (dd, J 2: 9 Hertz, 2 Hertz, 1H), 6,90 (d, J = 10 Hertz, 2H), 7.01 (d, J = 2 Hertz, 1H), 7.34 (d, J =] 0 Hertz, 2H). Example 89 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzo-dioxol-5-yl) -1- (N, N-bis (n- Butyl) aminocarbonylmethyl) -pyrrolidin-3- (N-benzenesulfonyl) f complex S Lanyueto By the method of Example 88, the compound obtained from Example 43 was converted to the title compound using benzenesulfonate Sulfonamide to replace methanesulfonamide. The melting point of the sample recrystallized from acetonitrile was 169-171 ° C. 4 NMR (CDC13, 300 MHz) δ 0.81 (t, J = 7 Hz, 3H), 0.89 (t, J = 7 Hz, 3H), 1.02-1 50 (m, 8H) ^ 2.65-2.80 (m, 2Η) ^ 2.90-3.25 (m, 4H), 3 80-3 95 (m, 3H), 3.50-3.60 (m, 1 Η), 3 · 65 (d, J = 1 0 Hz, 1H), 3 81 (s, 3H), 5.94 (s, 2H), 6.70 (s, 2H), 6.81-6.90 (m, 3H), 7.17 (d, J 2 10 Hz, 2H), 7.55 (t, J 2 7 Hz, 2H), 7.66 (t, J 2 7 Hz, 1H), 8.95 (d, J 2 7 Hz, 2H). Example 90 trans, trans- 2- (4-methoxyphenyl) _4_ (1,3_phenylhydrazine-dioxocyclopentyl-5 -yl) -1- 〖N, N-di (n-butyl ) Aminosulfonylfluorenyl 1-pyrrolidin-3-carboxylic acid by E Vilsmaier in Liebigs Ann. Chem. 1055-1063 (1980) -179- The paper size is in accordance with the National Standard (CNS) Λ4 specification of Shizhou C 210X 297 mm) (Please read the notes on the back before filling out this page) 552260 A7 Β7 V. Description of the invention (177 Zhongyi: j > /] The method described in the combination makes use of Brintzinger et al., Chem Ber. §J_: 45 5-4 :) 7 (1952) method of chloromethyl sulfenyl chloride reacted with dibutylamine 'kd N, N-monobutyl gas methylsulfonyl chloride. In addition, it is also possible to react the difluorenyl (fluorenylthio) fluorene tetrafluoroborate with dibutylamine to obtain N, N-dibutylmethylsulfinylsilyl chloride 'via the E. Vilsmaier Method: Chlorinated with N-chlorosuccinimide to obtain chloromethylsulfenyl chloride. The N, N-dibutylchloromethylsulfenyl chloride was reacted with the compound obtained from Example 6A to give trans, trans. 2- (4-fluorenoxyphenyl) -4- (1,3-phenylhydrazone M-Dioxol-5-ylbis (n-butyl) aminosulfinylfluorenyl] •• pyrrolidine-3-acid ethyl § Purpose. By S. Kaldor and M. Hammond , Tet. Lett .: Method of 5 0 4 3-5 0 4 5 (1 9 9 1), using tetroxide and N-fluorenyl group to form N-oxide, its oxidation, hydrolysis of ethyl ester After that, the title compound 0 was obtained. Example 9 JL trans, trans-2- (4-fluorenylbenzyl) -4- (1,3-ylpyridine dioxopentyl, VKN, N-di (positive -Butyl) amine carboxyl-ethyl acetic acid Example 9 1Λ (±) -Dibutyl-2-ethyl 2-bromopropionic acid (510 mg, 3.33 mmol) and cardiac methyl (0.74 Ml, 6.73 mmoles) were dissolved in 10 ml of CH'h, and the solution was cooled to ΰ ° C under M: pressure, and then dropwise with isobutyl chloroformate (0.45 mmoles 35 mmoles) Treat it. After 10 minutes at 0 ° C, add liters of butylamine (57 ml, 3.4 mmol). The reaction is performed at 0 ° C. Chuanyuwei National Standard (CNS) Λ4 specification (210X 297 gong) (Please read the precautions on the back before filling out this page, 11 552260 A7 B7 V. When explaining the invention (178), please stir at room temperature; drop For an additional 16 hours, separate the mixture with 25 ml of 1.01 aqueous Na2C03 solution, then rinse the organics, phases continuously with 25 ml of aqueous NaHS04 and 25 ml of S water, dehydrate (Na2s〇4), and mix Concentration under reduced pressure gave 698 g (2.64 mmol, 79%) of crude ammonium bromide in colorless form. IHNMRCCDCh, 300 MHz) δ 0.93 (t, J = 7 Hz ) And 0.97 (t, J = 7.5 Hz, 6H total), 1.26-1.60 (m, 7H), 1 60-1.78 (m, 1H), 1.82 (d, J = 6 Hz, 3H), 3.04-3.27 ( m, 2H), 3.42-3.64 (m, 2H), 4.54 (q, J = 7 Hz, 1H). MS (DCI / NH3) m / e 264 and 266 (M + H) +.

Example 9 1 B trans, trans- and cis, trans-2-(4-fluorenyloxyphenyl) -4-(1,3-phenylhydrazinedioxy ^ i · cyclopentyl_5_yl) _1, N-bis (n-butyl) amino) alkyl-1- (RS) _ethyl] _oripyridine-3-carboxylic acid ethyl ester 屮-! K with diisopropylethylamine (0 · 22 ml '1.3 millimoles) treated in 2 ml of CH3CN the inverse, trans and cis, anti-compounds from Example 1C (232 mg, 0.628 mmol) and the compounds from Example 91A (183 mg, 0.693 Millimolar) solution ° Under N2 pressure, the solution was stirred at 60-80 ° C for 16 hours. The reaction was concentrated under reduced pressure and the residue was distributed between 30 ml of Et20 and 10 ml of an aqueous Na2CO3 solution. The organic phase was washed with 20 milliliters of water and 20 ml of brine, dehydrated with NajSC »4, filtered, and concentrated under reduced pressure to give crude amineamine (3 39 mg, 98% crude) as a brown oil. The product was obtained by flash chromatography on silica gel. Four non-comparisons (Please read the precautions on the back before filling this page. Order—

, Eluting with 20% EtoAc-hexane, to give 224 mg (70%) of the title compound as a mixture of isomers. I Η NMR -181-the paper is thicker than the standard; CNS) Λ4 specification (210X 297mm 552260 A7 B7 V. Description of the invention (179 (CDC13, 300 MHz) δ 0.66- 1.55 (several m, 19H), 2.63-3.00 〇 ”3H), 3.05-3.39 (m , 2H), 3.40-3 76 (m, 4H), 3.78 -3 · 80 (4s, 3Η), 3.84-4.2 5 (m, 2 · 6Η), 4.38 (d, 10.5 Hz, 0.2H), and 4.5 8 (d, 10.5 Hz, 0.2Η), 5.90-5.97 (m, 2H), 6.68-6.96 (m, 5Η), 7.38-7.43 (m5 2Η). MS (DCI / NH3) m / e 553 (M + H) —.

Example 9 1 C trans, trans-2- (4-fluorenoxyphenyl) -4- (l, 3-benzo-dioxol-5-yl) -1-((N, N-di Butylamino) carbonyl-l- (RS) -ethyl) -pyrrolidine-3-carboxylic acid The procedure from Example 73 C was used to replace the compound from Example 73B with the compound from Example 9 1 B to obtain Yield 61% of the title compound. 1Η NMR (CD3OD, 300 MHz) δ 0 · 70-1 · 05 (several m, 8H), 1.14 (d, J = 6 Hz, 2Η), 1 17-1 55 (m5 6Η), 2.79-3.03 (m, 3.5H), 3 20-3.65 (br m, 4.6H plus CD2H0D), 3.70-3 78 (m: 0 · 4Η), 3.79 (5,311), 3.98 ((1,) = 8 Hz 50.611), 4.06 (^ 5: [two 7.5 Hz, 0.4H), 4.25 (d, J = 8 Hz, 0.4Η), 5.92 (s) and 5.94 (s, 2H combined 6H), 6.73 (d , Bu 2.5 Hz) and 6.75 (d, J = 3 Hz, sum of iH), 6.78-6.85 (m, 1Η), 6.91-7.00 (m, 3H), 7.30-7.38 MS (DCI / NH3) m / e 525 (M + H) —. Analysis and calculation of C3〇H4〇N206 • 0.5 H2〇 値: C, 67.52: H, 7 74; N, 5.25-fire (Please read the precautions on the back before filling this page

, 1T. Experiment 値: C, 67 63: Η, 7 65; N, 5.21. Example 92 Trans, trans-2-(pentyl) -4-(ί, 3 -benzyldioxol-5-yl) -1-((N, N-di (n-butyl) Aminocarbonylfluorenyl) -pyrrolidin-3-carboxylic acid-182 This paper is the size of this paper / 丨] 屮 1¾National Standard 挲 (CNS) Λ4 specification ('210 X 297) ii 552260 A7 B7 V. Description of the invention (180 ~ Sj ^ j 92A) -4-Nitro ^^ Benzoxopene · The first 0 A. Indica § will be in 10 ml of isopropanol Φ ;, mono-oxo-6-octanoate A (502 亳 g, -.95¾mol), add ^ — 5- (2-nitroethylbenzene) -dicyclopentadiene (712mg, 3.69 *) in 10 liters of THF Add DBU (22 μl, 0.15 mmol) at room temperature. At room temperature: the red solution obtained in Ding 2 for 20 minutes. TLC (ethyl tallowate-hexane 1: 3) Head: It was completely consumed. The solution was concentrated in the air, and subjected to U-chromatography on hard gels, eluting with 1 80 / 〇 ethyl acetate in hexane, yielding +79 g (2.24 mmol) (82%), diastereomers: 1: 1 in the ratio of 1 to 1 of the title compound. 1H NMR (CDCl3,): MHz) δ L)) · 1,66 (m, 3H ), 2.02 -2.17 (bi * m, 1H), ~ .H37 (m, L5H) '2.49-2.76 (m, 1.5H), 3.57 (s, 1.5H) "Two 74 (S, 1) H)' 3 · 97 (d, J = 7.5 Hz, 0.5H) and 4.05 (d, J 2 8 0 ... H) ^ 4.10-4.20 (m? 1H)? 4.68-4.82 (m, 2H) ^ ϋ '52 ( m, 2H), 5.9) (2S, 2H), 6.65 (m, 1H), 6.68 (bi * '1H)' 6 7) (d, 7 ·) Hz, 1H). Ms (dci / NHq oil 38i ( H). Analytical calculations for ClsHnNO7: c, 59 50: H, 5 82 'N, 3 85. Experiment: C, 59 32; & 5 71; N, 3 72. Example 92B Watt-I Diylcyclopentene 0-yl) pyrrolidine ij -Heptanoic acid I Example 1B and Example 1C to obtain the compound -183- ("> ^) 8 4 specifications from Example 92a [21〇乂 297 Gongchu) (please read the notes on the back before filling out this page), 11 552260 Μ B7 V. Description of the invention (181); r 屮 k $ Mj

A

"Substitution was obtained from the compound of Example_, and the compound obtained from Appreciation Example 1B was replaced with the obtained compound to obtain the crude compound in the crude form as a yellow oil. The crude compound was isomerized under the following conditions: A solution of sodium alkoxide (manufactured by adding sodium metal (14 mg, 0 61 mol) to 丄 ml of methanol) treated the crude compound (66 mol mol) in 3 ml of mel The solution was heated to reflux for 18 hours. The reaction was concentrated under reduced pressure and the residue was distributed between 25 ml of saturated NaHC03 diluted with 10 liters of water and 30 liters. (2 X 30 liters cj ^ d2) extract the liquid phase, then rinse the mixed organic phase with 20 ml of brine, dehydrate with NajCU, filter, and concentrate the mash with reduced pressure to obtain the crude product. Borrow on silicone Purification by scintillation chromatography 'eluting with methanol in CH2C12, yielding 336 mg (57%) of the title compound as a yellow oil. 1H NMR (CDC13, 300 MHz) δ 0 90 (br t, 3Η), 1.25-1.70 (br m, 8Η), 1.83-2.02 (br s, 2Η) '' 2.3 8 (dd, J = 8, 9 Hz, ih), 2.99 (dd, J = 8, 14 Hz, 1H) '3.34-3.45 (m, 2H), 3.53 (q, J = 9 Hz, 1H), 3 66 (s, 3H],). 94 (s, 2H), 6.65-6.75 (m, 3H). MS (DCI / NH3) m / e 32C (M 丄 H), analysis and calculation of Ci8h25N04 : C, 67 69 :: N, 4.39. Experimental 値 ·· C, 67 · 39; H, 7.84; N, 4.37 c Example 92C H, 7 benzene # m-dioxane Ding) amine carbonyl fluorenyl) -pyrimidine-3-generation acid-using the procedure of Example 1 3-1 D, the compound obtained from the compound name Example 1 B of Example 92A, to obtain a white foam coating Title Combined Miscellaneous -184 Paper Ruler / ^ Caiguanjia Standard Soldier (CNS) Λ4 Specification (H297 Public Trends (诮 Please read the precautions on the back before filling this page) 552260 A7 B7 V. Invention Description (182) 4 NMR (CDC13, 3 00 MHz) δ 0.87 (br t) and 0.89 (br t, 6H total), 0.97 (t, J = 7.5 Hz, 3H), 1.21-1.42 (brm, 10), 1.43-1.78 (br m, 6H ), 2.76 (t, J = 7 Hz, 1H), 3.02-3.30 (br m, 6H), 3.40-3.60 (m, 3H), 3.73 (d, J = 14 Hz, 1H), 5.98 (AB, 2H ), 6 · 7 0 (d, J = 7 Hz, 1H), 6.77 (dd, J = 1.5, 7 Hz, 1H), 6.89 (d, J = 1.5 Hz, 1H). MS (DCI / NH3) m / e 475 (M + ΗΓ. Analysis and calculation of C27H42N205 · 0.5 H20 0.5: C, 67.05; H, 8.96; N, 5.79. Experiment9: C, 6 7.30; H, 8.77; N, 5.68. Example 9 3 Trans, trans-2- (pentyl) -4- (l, 3-phenylhydrazone dioxane (N-propyl-N-propyl continued 8 amino)) ]]-咐; 3-A few examples of 93A trans'trans-2- (pentyl) -4- (1,3-benzo-dioxo > ^ "陆-; 5 __ ^ 上 上 ^ · ^ · Bromoethyl) -pyrrolidin-3-carboxylic acid ethyl ester using the procedure of Example 61A, replacing the compound from Example 1C with the compound from Example 92B to give the title compound as a yellow oil ° Η Η) (Please First read the note on the back of this page for the town's writing page. \ 呑 中 NMR (CDC13, 300 MHz) δ 0.89 (br t, J = 7 Hz, 1 24-1.40 (br m, 6H), 1.60-1.80 (br m, 2H), 2.6 ^ 2.75 (m, 2H), 2.76-2 91 (m, 2H), 3 "0-3.22 (m.2H), 3 36-3.4 7 (m, 2H), 3.68 (s, 3H), 5.92 (s, 2H), 6.69-6.77 (nh 2H) '6 90-6.94 (m, 1H). MS (DCI / NH3) m / e 426,428 (M + H) 〇 Example 93B reverse Trans-2- (pentyl) -4- (1,3-phenylhydrazone dioxolane- 5-Shame ^ -185- This standard is suitable for Sichuan M71¾¾ Icon Standard (CMS) Λ4 specification (21 Οχ 297 mm ^ i; 552260 A7 Β7

部 屮 Jk Zaoyi; J ί 5. Description of the invention (183 Propyl-N-propyl Continued Test_yl) Ethyl Pyrididin_3 Phosphonic acid methyl ester treated with propylamine (60 μl, 0.73 mmol) A solution of the compound from Example 93A (102 mg, 0.24 mmol) and iodinated: butylammonium (6 mg, 16 μmol) in 1 ml of EtOH. The solution of Jiang Yao was warmed to 80cjc for 4 hours. The reaction was concentrated under reduced pressure, and the residue was dissolved in liter of ethyl acetate and extracted with 2 X 15¾ liters of aqueous Na2co. The organic phase was washed with 15 ml of brine, then dehydrated with Na 2 SO 4, filtered, and concentrated under reduced pressure to give a crude yellow oily monoamine (94.2¾ g). This crude amine was decomposed into 1 ml of ch, c12 'and isopropylethylamine (65 μl, 0.373 mole) was added followed by propylsulfonyl chloride (29 μl, 0.26 mmol ear). The solution was stirred at room temperature for 4 hours. The reaction was stopped with 10% aqueous citric acid (to pH 4), and the mixture was extracted with 2 X 3 liters of CΗ2 C12. The combined organic extracts were washed with 2 ml of brine, dried over NkSO4, filtered and concentrated in the air. Purification by flash chromatography, eluting with 20% ethyl acetate in hexane, gave 65.0 mg (53%) of the title compound as a waxy solid. Rf 207 (20% EtOAc-hexane). MS (DCI / NH3) m / e 511 (M out of ten.

Example 93C (pentyl) -4- (1,3-phenylhydrazine dioxane propyl-N-propylmethylamino) ethyl] -pyridine.

According to the procedure of Example 7 1 C, the compound obtained from Example 9 3 B was used to replace the compound obtained from Example 7 1 B to obtain a white vesicular target cancer compound (47 mg, 80%), Rf 20 14 (5% Me〇H-CH2Cl2) ° I] fi NMR (CDC'i3, 300 MHz) δ 0.88 (br t) and 0.92 (t, hertz, 6H -186- this silk scale is suitable for Π phase countries fe ^ CNS) A ^ TITOX 297: ^ t (Please read the notes on the back before filling this page)

、 1T 552260 A7 B7 V. Description of the invention (184) (Please read the notes on the back before filling this page) (Sum), 1.22-1.52 (brm, 6H), 1.63 (six peaks, J 2 8 Hz, 2H) , 1.75-2.10 (br m, 4H), 2.8 9-2.9 8 (m, 2H), 3.05 (brt, J-2 9 Hz, 1H), 3.10-3.30 (m53H), 3.30-3.80 (brm, 7H), 5.94 (s, 2H), 6.71 (t, J = 8 Hz, 1H), 6.77 (dd, J = 1.5, 8 Hz, 1H), 6.89 (d, J = 1.5 Hz, 1H). MS (DCI / NH3) m / e 497 (M + ΗΓ. Example 94 trans, trans_2_ (propyl) -4- (l, 3_phenylhydrazine-5-yl) _1_ ( Example of Ν, Ν · bis (n-butyl) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid 94A 2- (4-butylfluorenyl) -4-nitro-3- (1,3-phenylhydrazine Oxepenten-5-yl) butyric acid B. In accordance with the procedure of Example 92 A, the ethyl 3-butyl-6-octanoate was replaced with ethyl butylacetate to obtain the trans and cis isomers. The title compound as a mixture (47 mg, 80%), Rf 0.28 (25% EtOAc-hexanes). NMR (CDC13, 3 00 MHz) δ 0.74 (t, J = 7.5 Hz) and 0.91 (t, J = 7.5 Hz, 3H total), 1.08 (t, J = 7 Hz) and 1 28 (t, J = 7 Hz, 3H total), 1.45 (hexaplex, J = 7 Hz, 1.51), 1 · 63 (hexaplex, J = 7 Hz, approximately 1.5H), 2.i7 (t, J = 7 Hz) and 2.24 (t, J = 7 Hz, 0.5H total), 2.40-2.54 (m, 1H) , 2.60 (t, J = 7.5 Hz) and 2.67 (t, J = 7.5 Hz, 0.5H total), 3 93-4.09 (m, 2H), 4.10-4.20 (br 1H), 4.23 (q, J = 7 Hertz, 1H), 4 67-4.85 (m , 2H), 5.94 (s, 2H), 6.62-6.75 (m, 3H). MS (DCI / NH3) m / e 369 (M + NH4) —. Analysis and calculation of C17H21N07: c, c, 58.11: H, -187- This paper conforms to the standard / ΐ] China National Standards (CNS) Λ4 specification f 210X297 mm) 552260 A7 B7 V. Description of the invention (185) 6.02; N, 3.99. Experiment 値: C, 58.21; 5.98; N, 3.81.

Example 94B trans, trans_ 2 _ (propyl) _ 4 _ (1,3 _ benzo-dioxo I cyclopentyl-5 -yl) _ p-pyridine-3-carboxylic acid ethyl ester according to the example Procedure for 92B, replacing the compound from Example 92 A with the compound from Example 94 A to give the title compound. MS (DCI / NH3) m / e 306 (M + H) one.

Example 94C Trans, trans-2- (propyl) -4- (1,3-phenylhydrazine-5-yl) -1- (N, N-di (n-butyl) amine Carboxymethyl) -pyrrolidine-3-carboxylic acid According to the procedure of Example 92C, the compound obtained from Example 94B was used in place of the compound obtained from Example 92B to give the title compound. NMR (CDC13, 300 MHz) δ 0.89 (t, J = 7.5 Hz), 0.92 (t, J = 7.5 Hz) and 0.9 7 (t, J = 7.5 Hz, 9H total), 1.22- 1.80 (br m, 12H), 2.83 (t, J = 7.5 Hz, 1H), 3.40-3.5 5 (br m, 2H), 3.5 5-3.68 (m, 1H), 3.78 (d, J = 15 Hz, 1H), 5.92 (q, Hz, 2H), 6.70 (d, J = 8 Hz, 1H), 6.79 (dd, J = 1 Hz, 8 Hz, 1H), 6.90 (d, J = 1 Hz, H). MS (DCI / NH3) m / e 447 (M + ΗΓ. 分析 Analysis and calculation on C25H3SN205 · 0.5 H20 値: C, 65.91: Η, 8.63; N, 6 15 .. Experiment 値: C, 65.91; H, 8.68: N, 5.94. Example 95 (2R, 3R, 4S)-(+)-2- (4-methoxyphenyl) -4- (1,3-benzo-dioxolane- 5-yl) -1- (Third-butoxycarbonyl-aminocarbonylmethylpyrrolidine-3-carboxylic acid-188- The power of this paper] Chinese Standard (CNS) Λ4 Specification (: 210 X 297 public trend) (Please read the notes on the back before filling out this page

1T 552260 A7 B7 V. Description of the invention (186

Example 95A trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzo-dioxol-5-yl VM third-butoxycarbonylaminocarbonylmethyl 1- Pyrrolidine-3-carboxylic acid A mixture of 64% trans, trans- and cis, trans-pyrrolidine (3.0 1 g, 8.15 mmol) from Example 1 C was dissolved in 50 ml of dichloromethane. Under nitrogen pressure, di-third-butyl dicarbonate (1.96 g, 8.97 mmol) in 20 ml of dichloromethane was added dropwise thereto, and the resulting solution was stirred for 30 minutes, at which time TLC ( Ethyl acetate: hexane 1: 1) indicates that all starting materials have been consumed. The reaction mixture is concentrated and dehydrated under high vacuum to give 3.94 g of ethyl ester as a yellow-brown oil. 4 NMR (CDC13, 300 MHz) δ 0.99, 1.07 (br t, br t, J = 7 Hz, 3Η), 1.11-1.62 (several brm, 9H), 3.05 (brm, 1H), 3.44-3.95 (m, 3H), 3.81 (s, 3H), 4.04 (q, J = 7 Hz, 1H), 4.14-4.28 (br m, 1H), 4.89-5.24 (br 1H), 5.94 (d, J = 3 Hz, 2H), 6 69-6.90 (ιη, 5Η), 7.06-7.20 (m, 2H). MS (DCI / NH3) m / e 470 (M + H) _. ≫ /] f 丨 A 卬 (please first Read the notes on the reverse side and rewrite this page) Dissolve the ethyl ester in 170 ml of ethanol, and add a solution of lithium hydroxide (1.06 g, 25.17 mmol) in 60 ml of water. Under nitrogen pressure The reaction mixture was shaken vigorously for 18 hours. The reaction mixture was concentrated to remove ethanol, diluted with 250 ml of water, and extracted three times with 250 ml of ethyl chain. The organic phase was acidified with hydrochloric acid to a slightly Cloud-like (pH 値 about 7), then acidified to pH 4 with 10% citric acid, and extracted with 5% ethanol in methane (3 X 100 ml). The mixed organic layer was water ( Na2S04), filtered, concentrated, and dehydrated at high altitude to obtain white -189- This paper is suitable for Sichuan 1¾ National Standard (CNS) Λ4 Specification Γ2Ι0 × 297 mm) 552260 ΑΊ Γ -------------- --------- B7 V. Description of the invention (187) ^ The title compound as a foam (2.19 g, 60%). 4 NMR (CDC13, 300 MHz) 3l.i6 (vbrs, 9H), 3.11 (brm, 1H), 3.50-3.64 (m, 2H), 3.81 (s, 3h), 4.24 (br m, 1H), 4.96 (br m, 1H), 5.94 (s, 2H), 6.71-6.79 (m, 3H), 6.84-6.91 (m, 2H), 7 19 (d, J-2 9 Hz, 2H). MS (DCI / NH3) m / e 442 (M + H) +.

Example 95B (2R, 3H ^ Hll) 2- (4-Azophenylphenylbenzyldioxane ^ en-5-yl iLl tri-butoxycarbonyl-aminocarbonylmethyl) -pyrrolidine-3 -Carboxyl The compound obtained from Example 95A (2.15 g, 4.86 mmol) and (+) Sinconine (1.43 g, 4.86 mmol) were added to 100 ml of dichloromethane; The suspension was agitated and warmed to dissolve all the solids. Then the 'cereal' was concentrated green and taxed to a white foam at the end of Nandu. The substance was refluxed from chloroform (64 ml) and hexane. The crystals were recrystallized from a mixture of alkane (360 ml). The resulting crystals were separated by filtration and recrystallized several times under the same conditions. The resulting crystals and filtrate were monitored by 1H NMR and chiral HPLC each time. First Reduce the content of (2S, 3S, 4R)-(-) _ enantiomers in the crystal, and then reduce the amount in the filtrate by reaching a predetermined end point, at which time (2S, 3S can no longer be detected in the filtrate , 4R)-(_)-enantiomer. So obtained: Pure (2R: 3R, 4S)-(+)-parasite is distributed between 100 ml of citric acid I and 100 ml of ether. again The 100 ml ether extract layer was washed twice. The mixed organic ether layer was washed with brine, dehydrated (Na ^ SCU), filtered, concentrated, and dehydrated to a white powder (550 mg '55% theory ^値, 50% maximum 値, > 99.5 ee). 4 NMR (CDC13, 300-Hertz) δ! 05- 1 50 (br m, 9H), 3. 12 (br m ″ H), 3 50- 3.65 (m, (that is, read the precautions on the back before filling in this page j

1 -190- (CNS) A4 ^ C 210X 297 ^ #) 552260 A7 B7 V. Description of the invention (188 2H), 3.81 (s, 3H), 4.24 (m, 1H), 4.96 (br m, 1H), 5.95 (s, 2H), 6.70-6.79 (m, 3H), 6.86 (d, J = 9 Hz, 2H), 7.19 (d, J = 9 Hz, 2H). MS (DCI / NH3) m / e 442 (M + H) +.

Example 95C (1 ^, 311,48)-(+) -2- (4-methoxyphenyl) -4- (1,3-phenylhydrazine-dioxolane-5-yl) -1 -P-acetic acid was dissolved in a compound of Example 95B (251 mg, 0.568 mmol) in 20 ml of a saturated solution of anhydrous HC1 (g) in absolute ethanol. The resulting solution was heated to 50 ° C and stirred for 18 hours, at which point all precipitated solids had dissolved. The reaction mixture was concentrated to a solid and distributed between 0.8 ton of aqueous sodium carbonate (50 mL) and diclofenac (50 mL). The liquid layer was further extracted with dichloromethane (2 X 50 ml). The mixed organic layer was dehydrated (NaJCU), filtered, concentrated, and dehydrated under a high degree of air to give the title compound (158 mg, 69%) almost in the form of a babble. iRNMl ^ CDCl:} 'J00 MHz) δ 1. 11 (t, J = 7 Hz, 3Η)' 2 · 1 8 (v br s, 1 Η) '2.9 j (t, J = 9 Hz, 1 Η ), 3. 19, 3.22 (dd, J = 7 Hz, i η), J.50-3.69 (m, 2H), 3.80 (s, 3H), 4.07 (q, j = 7_g |, 2H) k '-y; · Central • 1 丨, (Please read the notes on the back before filling out this page, 11 ^ w!

’4.49 (d, J = 9 Hz, 1H), 5.94 (s, 2H), 6 73 (^) = 2 Hz, 2H), 6.81-6.92 (m, 3H), 7.34-7.41 (m, 2H). MS (DCI / CH3) m / e 370 (m + H; T.

Example 95D + Methoxyphenylcyclopentadiene vol. IIi-(Third-butoxyzanyl-aminezanyl biloline-3'4h Compound 9 in Example 5 (1 3) mg '0.3 5 5 ears, China and Canada -191' Human warfare 1 county (CNS) Λ4 size H1QX297 male thin) 552260 A7 Guang ________ ^ __ 5. Description of the invention (189) Diisopropylethylamine (137 mg, 185 μl '106 μmol), acetonitrile (2 μl), N, N-di- (n-butyl) bromoacetamide (133 μg, 0.531 mmol), and The mixture was heated to 50 ° C for 1 · 5 hours. The reaction mixture was concentrated to a solid and dehydrated under a high degree of emptiness. The purpose-elution of ellipse has been detected as a colorless oily pure ester. 4 NMR (CDC13, 300 MHz) δ 0.81 (t, J 2 7 Hz, 3H), 0.88 (t, J = 7 Hz, 3H), 1.1〇 (t, J = 7 Hz, 3H) '1.00-1.52 (m, 8H), 2.78 (d, J = 14 Hz, 1H), 2.89-3.10 (m, 4H), 3.23-3.61 (m, 5H ), 3.71 (d, J = 9 # ^, lH), 3.80 (s5 3H), 4.04 (9, Bu 7 Hz, 2H), 5.94 (dd, J = 1.5 Hz, 2 H) '6.74 (d, j = 9 Hz, 1H), 6.83-6.90 (m, 3H), 7.03 (d, J = 2 Hz, 1H), 7 30 (d, J = 9 Hz , 2H). MS (DCI / NH3) m / e 539 (M + HV.) Add a solution of lithium hydroxide (45 mg, 1.06 mmol) in water (2.5 ml) to 7 ml ethanol The ethyl vinegar was stirred at ambient temperature for 1 hour, and then slowly warmed to 40 ° C in 2.5 hours, at which time all starting materials were consumed. The reaction mixture was concentrated In order to remove the ethanol 'diluted with 60 ml of water' and extracted with acetic acid (3 x 40 ml). The aqueous falling liquid was treated with 1 aqueous hydrochloric acid 'until a cloud shape' and then 10% Aqueous citric acid adjusted pH to approximately 40. The bound compound was extracted with 1 to 19 ethanol-dichloromethane (3 X 50 ml). The combined extracts were dehydrated (Na; 2S04) and filtered. ,, and concentrated and dehydrated under a high degree of air to obtain the title compound (150 mmol, 83%) as a white foam. WNMRCCDCl ;, 300 MHz) 5 0.80 (t, J = 7 -192- house standard 297 Public address) * (please first Notes ^ then read back the written page)

1T 552260 A7 B7 V. Description of the invention (190

Hz, 3H), 0.88 (t, J = 7 Hz, 3H), 1.08 (m, 2H), 1.28 (m, 3H), 1.44 (m, 3H), 2.70-3.77 (svr br m, 12H), 3.79 (s, 3H), 5.95 (m, 2H), 6.75 (d, J 2 8 Hz, 1H), 6.87 (brd, J = 8 Hz, 3H), 7.05 (brs, 1H), 7.33 (v br s, 2H). MS (DCI / NH3) m / e 511 (M + H) [a] 22 74.42 ° About

And $]] _τ elimination j1-. A C29H38N20. 0.5 H20 analysis and calculation 値: C, 67.03; H, 7.56; N, 5.39. Experiment 値: C, 67.03; H, 7.59; N, 5.33. Example 95E Another preparation of (211,311,48)-(+)-2- (4-methoxyphenyl) -4- (1,3-benzo-dioxolanpenta-5-yl)- 1- (Di-butoxyt-amino-aminomethyl) -pyridine-3-carboxylic acid method The product of Example 95A (2.858 g) was suspended in 10 ml of EtOAc. 0.7833 g of R (+) afluorenamide in 3 ml of ethyl acetate was added. All solids were dissolved while stirring. Remove ethyl acetate in the air. To the residue was added diethyl ether (13 ml). When all the residue has been dissolved, add 5 mg of seeds and crush them with a metal spatula while cooling in ice. The product formed crystals very slowly. After 1 hour, the solid was filtered and rinsed with acetic acid to give] 4213 g, melting point 163-167 ° C. The filtrate was concentrated, cooled, and gently scratched with a spatula to obtain a second yield of 0.13 g, melting point 1 64-1 68 ° C. The filtrate was concentrated again and left in the refrigerator overnight to obtain 1.6906 g, melting point 102-1 10 ° C. (Its HPLC showed 20% desired and 80% unwanted enantiomers). Mix the first two batches of crystalline material ′ and Zhao) in 20 liters of gas. (Note: unwanted isomers are easier to dissolve in dichloromethane) and stir for 2 minutes. Concentrated 193- This paper is based on the standard of the Central China Garden (CNS) Λ4 specification (· 210 × 297 mm) (Please read the precautions on the back before writing this page) 552260 Α7 Β7 Five 'invention description (191 shortened) Mix, but do not dehydrate, and add ether (1 οml). After filtering for several minutes, crystallize. Yield: 1.401 g, melting point 164-172. (Please read the precautions on the back before filling in this page. The crystalline product was treated with 10% citric acid and diethyl ether according to the method described in Example 95B to give the title compound. Example 96 Group, trans-2- (4-methoxybenzyl) -4- (1,3- Benzo-dioxolene-5--1) -1- [2- (N-propyl-N-butyl-Spanamine) ethyl 1-orbital bite-3 The title compound was prepared by the method described in Example 61, but propylamine was used to replace the methylamine in Example 6 1B and butylammonium chloride was used to replace the isobutylammonium chloride in Example 61C. By preparative HPLC (Vydac pC18 ) To purify the product, eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were freeze-dried to give the product as a white solid. 1H NMH (CDC13, 3 00 MHz) δ 0.80 (m, 3H), 0.90 (t, 3H, J = 8 Hz), 1.42 (m, 2H), 1.58 (seventh peak, 2H, J = 8 Hz), 2.20 ( t, 3H, J = 8 Hz), 2.94 (brm, 2H), 3.10 (brm, 2H), 3.48 (br m, 4H), 3.76 (br 2H), 3.78 (s, 3H), 4.30 (br s, 1H), 5.95 (s, 2H), 6.75 (d, 1H, J = 8 Hz), 6.84 (m, 1H), 6.85 (1211 to 8 Hz), 7.04 ((1,111, 1 Hz), 7.40 ((1, 21 ^, > 8 Hz). MS (DCI / NH3) m / e 497 (M + ΗΓ. Analysis and calculation of C28H36N2 06 • 1.0 TFA 値: C5 58.82: H, 6.42; N; 4.57 Experimental 値: C, 58.77; H, 6.30; N, 4.42. Example 97 Oxyphenyl) -4- (1,3-phenylhydrazine dioxolene): ϋ (N-propyl-N -(Ethylaminocarbonyl) amino) ethyl 1-pyrrolidine-3- # Cool " a '~' " ^, -194- The paper size is suitable for the medium store standard (CNS) Λ4 specification ( '210X 297 mm) 552260 A7 B7 V. Description of the invention (192 The title compound was prepared by the method described in Example 61 1 except that the methylamine in Example 6 1B was replaced by a Cube text, and Cyanide B g Cheng Li aims to replace the chlorine. 61C Yoshioki butoxy test. The crude product was purified by trituration with 1: 1 bisacetic acid-hexane. The obtained solid was dissolved in CH3CN and water, and freeze-dried to obtain the product as a white solid. iH NMR (CDC1: '300 MHz): a mixture of rotational isomers δ 080 (t, J = 8 Hz) and 1.0 5 (t, J 2 8 Hz) and 1.20 (m) and i.42 ( m), the sum of the four peaks is 8H, 2.35 (br s5 1H), 2.70 (m, 1H), 3.0 (m, 3H), 3.2 (m5 3H: '3.2 5 (dq, 1H, J = 1.8 Hz) , 3 42 (m, iH), 3.6 (m, 1H: '3.75 (m, lH), 3.78 (s, 3H), 4.8 (brS, lH), 5.95 (s, 2H;' 6.74 (d, 1H, J 2 8 Hz), 6.85 (m, 3H), 7.00 (s, 1H), 7.30 (d, 2H, J 2 8 Hz), MS (DCI / NH3) m / e 498 (M + Hf. Analytical calculations for C27H35N30.6.75.200. 値: c, 63.45; H: 7.20; N, 8.22. Experiment 値: C, 63 38: H, 7.29: N, 8.44. In Example 98, again; J.1 Heart: 卬 (read the precautions on the back and then fill out this page) Shame—phenyl V4- (1.3-benzo-dioxol-5-yl 1ΐΐ! [2- (Ν- 丁-N-butylamido) ethyl μpyrrolidin-3-carboxyl §1 The title compound was prepared by the method described in Example 61, but the butanidine in Example 6 1B was replaced with butyl butoxide. And replaced with isobutyl chloride in Example 6lC with dichloromethane Chlorine. The crude product was purified by trituration with 1: 1 bisacetic acid-hexane. The resulting solid was dissolved in CH3CN and water and cold-dried to give the product as a white solid. 1H NMR (CDC13, 30C trillion Hertz) δ 0.80 (m, 3H), 〇 90 (t, 3Η · J = 8 Hertz), 1.45 (m: 4H) '16 (m, 2H), 2.20 (t, 3H, J = U ^^), 2.94 (brm, 2H), general standard return -195-(CNS) Λ4 specification (210 乂 297 public) 552260 A7 B7 V. Description of the invention (193, 3.10 (brm, 2H), 3.5 (brm54H), 3.80 ( brm, 2H), 3.82 (s, 3H), 4.30 (br s, 1H), 5.95 (s, 2H), 6.75 (d, 1H, J 2 8 Hz), 6.84 (111, 111), 6.85 ((1,211, 8 Hz), 7.04 ((1,1 ^ 1, J-2 1 Hz), 7.40 (d, 2H, J = 8 Hz). MS (DCI / NH3) m / e 511 (M + HF. About the HRMS calculation of C29H38N2 06: 511.2808. Experiment: 5 1 1.2809. Example 99 trans, trans-2- (4-fluorenoxyphenyl Sergeant (1,3-benzyl-diazacyclopenten-5-yl) -1- 〖2- (N-propyl-N- Ethylcarbonylamino) Ethyl 1-pyrrolidine-3-carboxylic acid was prepared by the method described in Example 61, but propylamine was used in place of the amidine in Example 61 1B, and chlorine was used. Ethyl formate was used to replace the isobutylphosphonium chloride in Example 6 1 C. The crude product was purified by trituration with 1: 1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water, and freeze-dried. The product was obtained as a white solid. 4 NMR (CDCh, 3 00 MHz) δ 0.80 (t, 3H, J = 8 Hz), 1.05 (m, 2H), 1.22 Λ (read the precautions on the back before filling This page) (m, 3H), 1.45 (m, 3H), 2.08 (br s, 1H), 2.75 (m, 1H), 2.88 (br q, 2H, J 2 8 Hz), 3.08 (br m, 2H ), 3.27 (br m3 2H), 3.44 (m, 1H), 3.54 (dt, 1H, J = 1, 8 Hz), 3.63 (d, iH, J = 8 Hz), 3.78 (s, 3H), 4.02 (br d, 2H), 5.93 (s, 2H), 6.72 (d, lH, J = 8 Hz), 6.81 (dd, lH, J = U8 Hz), 6.85 (d, 2H, J = 8 Hz) ), 7.00 (s, 1H), 7.30 (d, 2H, J = 8 Hz). MS (DCI / NH3) m / e 499 (M + HF. Analysis and calculation for C27H34N2 07 · 0.5 H] 値: C, 68.39: H, 6.95: N, 5.52. Experiment 値: C, 64.03; H, 6 71; N, 5.30. -196- Description of this paper / 丨] China National Standard (CNS) Λ4 Specification (210X297 Mm) 4 552260 A7 B7 Ά ,: in the middle and f: 卬 卬, the description of the invention (194 Example 100 series ^ Α_ ^ · ΐίυ ^^ ΑΐΐΜΐ, _3-phenylhydrazine dioxol-5-yl Glucobutanyl) amino) ethyl [pyrrolidin_3_carboxylic acid Will HOBt (60 mg), EDCI (85 mg), N-methyl. Lin (50 μl) and DMF (2 mL) be added to dissolve The compound from Example 61B (190¾ g) was added in thF (2 mL). 2-ethylbutyric acid was added and the solution was stirred at ambient temperature. Water (10 mL) was added and EtOAc ( 2 x 25 ml). The mixture was extracted. The combined organic extracts were rinsed with a saturated sodium bicarbonate solution, ικηΡ04 and brine. It was dehydrated with Na2S04, evaporated and passed to an oil ', which was purified by flash chromatography on Shixi as above, eluting with 1: 3 EtOAc-hexane. The ethyl ester obtained by the procedure described in Example 61C was saponified. The crude product was dissolved in CHbCN and water, and cooled; dried to obtain the product as a white solid. 4 NiMR (CDC13, 300 MHz) (mixture of mediating isomers) δ 0.66, 0.74, 0.80, 0.88 (all fluorene heavy peaks, the sum is 6H5J = 8 Hz), i.〇5 (m , 2H), 1.25-1.75 (buckle, 5H), 2.16 (m, 1H), 2.32 (m, 1H), 2,45 (m, iH), 2.70 (m, 1H), 2.86, 2.94 (s, Sum 3H), 2 95 (m, 1Η), 3 35 (speak, 1H), 3.52 (m, 2H), 3.65 (m, 1H), 3.80 (s, 3H), 5.94, 5.96 (s, sum 2H), 6.73 (m, 1H), 6.84 (m, 3H), 6.97 (m, 1H), 7.30 (m, 2H). MS (DCI / NH3) m / e 497 (M + Hr. Analytical calculation for C28H36N20..25H2O: C, 67.11; H, 7.34: N, 5.59. Experiment: C, 67.13: H, 7.24: N 5.56. (Please read the notes on the back before filling out this page) -5 197 552260 A7 ________ B7 ------ —________ ___ V. Description of the invention (195)

Xjh 101 (Please read the precautions on the back before writing this page)! _, Trans-2- (4-fluorenylphenyl) dioxo 13-benzyldioxol-5-yl Ill .- [2- (N-fluorenyl-N- (2-propyl ^^ amino) amino) ethylpyrrolidine_3_ridge

The title compound was prepared by the method described in Example 100, but replacing 2-ethylbutanoic acid with 2-propylvaleric acid. The crude product was purified by preparative HPLC (Vydac pC18), eluting with a gradient of 1CU700 / g CH :, CN in 010 / 〇 TFA. The desired fractions were freeze-dried to give the product as a white solid. 1HNMR (CDC13, 300 MHz) 30.79 (t, 3H, J = 8 Hz), 0.8 2 (t, 3H, J = 8 Hz), 1 10 (m, 4H), L2-1.5 〇, 4H), 2.55 (m, 1H), 2.96 (s, 3H), 3.15 (br m, 1H), 3.32 (br m, 1H), 3.56 (m, 2H), 3.68 (m, 1H), 3.68 (s , 3H), 3.70 (m, 1H), 3.80 (m, 2H), 4.65 (brd, 1H), 5.92 (s, 2H), 6.75 (〇1, 111,] = 8 Hz), 6.84 (111, 1 India, 6.85 ((1, 2 to 1 2 8 Hz), 7.05 (s, 1H), 7.42 (d, 2H, J 2 8 Hz). MS (DCI / NH3) m / e 525 (M + H). About the analysis and calculation of C30H40N2O6 · 1.25 TFA t 値: C, 58.51; Η, 6.23; N: 4.20. Experimental values: C, 58.52; Η, 6.28; Ν, 4.33 Phenyl) -4- (1,3-phenylhydrazone diazapinepine-5-yl-N- (third-butoxycarbonylfluorenyl) amino) ethylpyrrolidine The title compound was prepared following the method described in Example 61, but the methylamine in Example 6 1 B was replaced with propylamine and the third-butyl bromoacetate was used to obtain the paper & CNS (-2 ! 〇x 297 ^ t) --- 552260 A7 B7 V. Description of the invention (196) (Read the precautions on the back before you fill in this page and substitute isobutyridine chloride in Example 6 1C. The crude product was purified by trituration with i: i diethyl ether-hexane. The obtained solid was dissolved in CH3CN And water and freeze-dried to give the product as a white solid. NMR (CDC13, 300 MHz) δ 0.82 (t, 3Η, J = 8 Hz), 1.18 (m, 2H), 1.19 (s, 9H), 2.12 (m, lH), 2.46 (π, 2Η), 2.70 (ι, 3Η), 2,85 (m, 2H), 3.20 (s, 2H), 3.40 (dd, 1H, J 2: 2, 8 Hz), 3.50 (dt5, J 2: 2,8 Hz), 3.62 (d, 1H, J 2: 8 Hz), 3.78 (s, 3H), 5.95 (s, 2H), 6.72 ( d, lH, J 2 8 Hz), 6.84 (m, 1H), 6.85 (d, 2H, J = 8 Hz), 7.05 (s, iH), 7.16 (d, 2H, J 2 8 Hz) MS (DCI / NH3) m / e 541 (M + H plant. Analytical calculations for C3OH4ON207 · l.0H20 値 · C, 64.50; Η, 7.58; N, 5.01. Test 値: C5 64 75; Η, 7.35; N, 4.86. Example 103 trans, trans-2- (4--oxophenyl) -4- (1,3-benzyl-dioxanthine-5-yl) -1- "2- (N-propyl-N -(N-propylaminocarbonyl) amino) ethyl_41 ^ pyrrolidine-3-carboxylic acid The title compound was prepared by the method described in Example 61, but with propylamine in place of the compound in Example 6 1B The amine was replaced by N-propylacetamide bromide to replace the isobutylphosphonium chloride in Example 61C. The crude product was purified by the preparation of HpLC (Vydac 1! ≪: 18) and eluted with a 10-70% gradient of CH3CN in 0.1% 71%. The desired dissolution fraction is cold) and dried to obtain the product as a white solid. 1H NMR (CDC13, 300 MHz) δ 0 78 3H, J = 8 Hz), 0.88 (1311,] 2 8 Hz), 1.45 (111, 2 ^ ,: 1, 48〇, 311, j 2 S Hz) , 2 55-2.7 (m, 2H), 2.90 (m, 1H), 3.04 (m,} H) -199- _ This paper size is suitable for National Standards (CNS) Λ4 specification (210 ^ 297) ^ " 552260 A7 B7 V. Description of the invention (197, 3.15 (m, 3Η), 3.28 (t, 1Η, P8 Hz), 3 45 (t, 1Η, J = 8 Hz), 3.60 (m, 2H) , 3.70 (d, 2H, J = 8 Hz), 3.75 (m, 1H), 3.80 (s, 3H), 4.25 (d, 1H, J 2 8 Hz), 5.95 (s, 2H), 6.75 (d, 1H, J 2 8 Hz), 6.86 (dt, 1H, J = 1, 8 Hz), 6.88 (d, 2H, J = 8 Hz), 7.04 (d5 1H, J 2 1 Hz), 7.40 (d, 2H , J 2 8 Hz). MS (DCI / NH3) m / e 526 (M + ΗΓ. Analysis and calculation of C29H39N3 06 · 1.85 TFA 値: C, 53.32 ·, H, 5.59; N, 5.70. Experimental 値: C, 53.45; Hf, 5.62; N, 5.63. Example 104 trans, trans-2- (4-methoxyphenyl V4- (l, 3-phenylhydrazine dioxol-5-yl) -1 -〖2- (~ propyl-? ^ (4-methoxyphenoxy (Amino) amino) ethylpyrrolidine-3 -carboxylic acid. The title compound was prepared by the method described in Example 61, but with propylamine in place of the amidine in Example 6 1 B and chloroformic acid 4 -Methoxyphenyl ester to replace the isobutylphosphonium chloride in Example 61C. The crude product was purified by trituration with 1: 1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and frozen Dry to give the product as a white solid. 1 H NMR (CD3OD, 3 00 MHz) a mixture of rotational isomers δ 0.88 (m, 3Η) missing in the part ίΐ'ί Λ ίί (Please read the precautions on the back before (Fill in this page), 1.57 (m, 2H), 2.45 (br s) and 2.60 (br s, the total is 1H), 2.90-3 15 (m, 4H), 3.42 -3 7 (m, 5H), 3.78 ( s, 3H), 3.80 (s, 3H), 3 85 (m) and 4.0 (m, the total is ih), 5.95 (s) and 5.98 (s, the total is 2H), 6.63 (m, 1H), 6.72 ( d, 1H, J 2 8 Hz), 6.81 (m7 2H), 6 93 (m, 5H), 7.40 (m, 2H). MS (DCI / NH3) m / e 5 77 (M + H)-. About the analysis and calculation of C32H36N2Os · i.〇h20 値: 200- this paper size 迖; 彳] Zhongwei National Standard (CNS) Λ4 specification (210X 297 Gongchu) 552260 Α7 Β7 V. Description of the invention (198) C, 64.63; H, 6.44; N, 4 71. Experiment 値: c, 64 7〇; H, 6 38; N, 4.63. (Please read the precautions on the back before filling in this page. Example 105 ^! ._ ^ 二 2- (4 二 ^^ > 4- (1,3-benzene roll ^ dioxolylpropoxybenzyl Fluorenyl) amino) ethyl 1-pyrrolidin-3-carboxylic acid The title compound was prepared by the method described in Example 61, but the propylamine was used in place of the methylamine in Example 61 1B, and the anise was Rhenium chloride was used to replace the isobutylene chloride at the center of Example 6. The crude product was purified by trituration with diethyl ether-hexane of i: j. The solid obtained was dissolved in ch3cn and water, and freeze-dried. The product was obtained as a white solid. IH NMR < CDCh, 3 00 MHz) A mixture of rotational isomers δ 〇78 (m) and 〇% (t Hertzer's sum is 3H) 'I.47 (m) and 1.52 (q, J = 8 Hz, total 2H), 2.25 (br s, 1H), 2.78 (br s, 1H), 290 plus t, ~ 2H), 3.12-3.6S (m, 7H) , 3.S0 (s, 3H), 3.82 (s, 3H), 5 94 (s, 7.22 (m, 4H). MS (FAB) m / e 561 (M + H) +. About C "H Analytical calculation of N2 07. 075 H20: c, 66.94; H, 6 58; N 4.8 8. Experiment 値 · C, 6 7. 〇; h, 6.38: N , 4.5 9. Example 1 06 to Dibenzylcyclopropyl, propyl,.: Wei-yl1amino) Acetic acid The title compound was prepared by the method described in Example 61, but substituted with propylamine In the example 61B, the amidine was replaced by benzamidine chloride in Fen __ -201-This paper is selected from the Chinese country of Sichuan; (CNS) Λ4 size (2ΐ ϋ) 97 public dreams) ~ One — 552260 A7 B7 V. Description of the invention (199 (please read the precautions on the back before filling out this page) The isobutyric acid gas in Example 61C. The crude product was purified by diethyl ether-hexane-burning with distillate. The solid obtained Dissolved in ch3CN and water and freeze-dried π to give the product as a white solid. 1h NMR (CDC13 300 MHz) a mixture of rotomers 506 and 009 (111, the total is 3H), 1.4 and 1.55 (m, the physical knowledge of ΤΤ, 、, Xin and Ma 2Η), 2.05 and 2.15 (m, the total is 1H), 2.6. · 6㈣, 8H), 5 92 (s, 2H) , 6.70 (d, 1H, J 2 8 Hz / ')' 6.82 (m '4H)' 7.2-7.4 (m, 6H). MS (DCI / NH〇m / e 531 (M + H) _ . Analytical calculations for 0 to be · 0.3 H2O: C'69.46'H, 6.) l'N, 5.23. Experiment 値: C 69 48; H, 6.i9; N, 4.84. i07 '4- JK]: -T W1: f. A ii di-2-^ (4-methoxy ^ humiliated ^ metadioxolene-yl propyl hydrazone U to amine) ethyl group The pyrrolidine_3_carboxylic acid was prepared following the procedure described in Example 61, but the methylamine in Example 61 1B was replaced with propylamine, and the benzyl chloroacetate was used in Example 61C. Isobutyryl chloride. The crude product was purified by preparative HPLC (Vydac.uClS) and washed with CH3CN in 10/70 tfa at a 10-70% gradient. The desired fractions were cold-bundled and dried to give the product as a white solid. 1Η NMR (CDC13, 3 00 MHz) δ 0.8 (m, 3Η), 1.45 (m, 2H), 2.20 (brm, 1H), 2.75 (m, 1Η), 2.93 (m, 1H), 3.15 (m, 2H), 3.32 (m, 3H), 3.52 (m, 2H), 3.66 (m, 1H), 3.78 (s, 3H), 5 00 (m, 2H), 5 94 (s, 2H), 6.72 (d , 1H, J = 8 Hz), 6.82 (m, 3H), 7.0 (brd, 1H, J = 15 Hz), 7.2 (s, 4H), 7.30 (m, 3H). MS (FAB) m / e 561 (M + H) —. About C32H36N2〇7 · -202-This paper is in accordance with the standard / 丨] 1¾ national standard (CNS) Λ4 specification (210X29 * 7 male) 552260 V. Description of the invention (200 1.0TFA analysis and calculation): Inspection: C , 60.66; η 5, 2; H, 5.53; N, 4.15. Real η,) ·] 4; N, 4.28. Example 108 (Amino) Ethyl 3-Chloric Acid ~ The method described in Example 6 1 was used to prepare the translated subject matter, μ was replaced with propylamine in the example of the "" ... Propylene, methylidene chloride is substituted with 4-methoxybenzyl chloroarsinate to replace isobutylarsine chloride in Example 61C. Example 109 ~~ Benzylidene-dioxolane-5-ylcarbonylamino) ethyl Pyrrolidine-3 diacid was prepared in the same manner as described in Example 61, except that the amidin in Example 61B was replaced with a butyl plate and the ethyl chloride was used in Example 61C Isobutane gas. The crude product was purified by preparative HPLC (VydaC.uCl8), eluting with a 10-70% gradient of CH3CN in 0% TFA. The desired fractions were freeze-dried to give a white solid NMR (CDC13, 3 00 MHz) δ 0.82 (t, 3Η, J = 8 Hz),! 20 (m, 5Η), 1.3 4 (m, 2Η), 3.08 (m, 2Η), 3. 17 (m, 2Η), 3.5 2 (m, 2H), 3.75 (m, 2H), 3.78 bar), 4.35 (br s, 1H), 5.94 (s, 2H),), 6.92 ( d, 2H, J 2 8 Hz), 7.03 (brs, lH), 7.17 (bi * s, lH), 7.7 (br s, 2H). MS (FAB) m / e 513 (Μ + ΗΓ. Analysis and calculation of C2SH 0.5 TFA 値: C, 61.15 ”— (s, 3H), 4.06 (q, 2H, J 2 8 Hz 6 · 7 6 (d, 1 Η, J = 8 Hz 3 6 (Please read the notes on the back before filling out this page) N2〇7 H, 6.46 N. 203- This paper is the standard of China National Standard (CNS) Λ4 for this paper (-210X297 mm) 552260 A7 _ B7 V. Description of the invention (2101) • 4.92. Experiment 値: C, 60.99; H, 6.80; Ν, 4.93. (Read the precautions on the back before filling in this Page) Example 110 Trans, trans-2- (4-fluorenoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-ylbutyl-N-propoxycarbonylamino) Ethyl 1-pyrrolidin-3-carboxylic acid was prepared by the method described in Example 61, but butylamine was used to replace the amidine in Example 6 1B, and propyl chloroformate was used to replace the Isobutylammonium chloride in Example 61C. The crude product was purified by trituration with 1: 1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and freeze-dried to give the product as a white solid .IHNMRCCDCh, 300 MHz) δ 0.80 (br s , 1H), 0.85 (t, 3H, J 2 8 Hz), 0.92 (br s, 1H), 1.22 (m, 3H), 1.40 (m, 3H), 1.62 (br m, lH), 2.15 ( brs, lH), 2.72 (m, lH), 2.87 (m, lH), 3.1-3.45 (m, 5H), 3.55 (m, lH), 3.64 (d, lH, 1 = 8 Hz), 3.79 (s , 3H), 3.88 (br s, 1H), 3.97 (br s, 1H), 5.95 (s, 2H), 6.73 (d, iH, J = 8 * ^), 6.85 (m, 3H), 7.0 (s , LH), 7.30 (d, 214, J = 8 Hz). MS (FAB) m / e 527 (M + H) +. Off; ^ C29H38N207 • Analysis and calculation of 0.15 H20 値: C, 65.80; H, 7.29; N, 5.29. Experiment 値: C: 65.79; H, 7.30: N, 5.21 ^ Example 1 11 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazine dioxolene- 5-ylpropyl-N-propoxycarbonylamino) ethyl 1-pyrrolidin-3-carboxylic acid was prepared by the method described in Example 61, with propylamine substituted in Example 6 1 B The methylamine was replaced by propyl formate in Λίί Example 6 1 C. By cooperating with Si-Si-204-204, the paper ft scale is suitable for Chuan T ® Standard (CNS) A4 (210X 297 mm) 552260 A7 —___________ B7 V. Description of Invention (20.2) Development To purify the crude product. The obtained solid was dissolved in ch3cn and water and freeze-dried to obtain the product as a white solid. NMR (CDC13, 300 MHz) 50.80 (1 :, 3 ^ 1, = 8 Hz), 0.93 (111, 3 buckle, 1.43 (m, 3H), 1.62 (m, 1H), 2.15 (brs, lH), 2.68-3.45 (m, 8H), 3.54 (m, 1H), 3.66 (m, 1H), 3.78 (s, 3H), 3.94 (m, 2H), 5.94 (s, 2H), 6.72 (d , 1H, J 2 8 Hz), 6 82 (m, 1H), 6.84 (d, 2H, J = 8 Hz), 7.00 (br s, 1H), 7.33 (m, 2H). MS (DCI / NH3 ) m / e 513 (M + H), analysis and calculation of C28H36N207 · 0.15 HUO 値: C5 65.26; H, 7.10; N, 5.44. Experiment 値: C, 65.22; H, 6.74; N, 5.06. Example 1 12 Ranthodi (n-butyl) aminocarbonyl a m-M 3_FU # between (¾read the precautions on the back before writing this page)

^ Missing ^ r: rx; .h (f conjugated M-oxopentyl-5 -yl) -π-bipyrene-3 -glycolic acid initially with 3,4-methylenedioxyacetamidine Methylphenone instead of 4-methoxyethenylbenzyl § Same as' by the method of Krapcho et al., Org. Syn 47-, 20 (1967) to prepare (3,4-methylenedioxybenzidine Ethyl) ethyl acetate, which was treated by the procedure described in Example 1 to give the title compound as a white solid. Melt S 58-60 ° C. 4 NMR (CDC13, 3 00 MHz) δ 〇87 (five-fold peak, J 2 6 Hz, 6 ，), 1. 12 (six-fold peak, J = 6 Hz,) ^, ^ '1-51 (m, 6H), 2.80 (d, J-2 13 Hz, 1H), 2.94-3.12 (m · 4H), 3.28-3.50 (m, 4H), 3.58-3.62 (m, 1H), 3 78 (d, j = 9 Hz, 1H), 5 95 (s, 4H), 6.73 (dd, J = 8 Hz, 3 Hz, 2H), 6 84-6.89 (m, 2H), 6.92 (d, J = 1 Hz, 1H ), 7 (d, Η == 1 Hz, 1H). MS (DCI / ΝΗ;) m / e 525 (M + H), -205- This paper is applicable to the national standard (CNS) Λ4 specification ⑺ 〇χ 297 mm) 玎

I 55226〇A7 B7 U-monthly description (203 Example 11 3 (Please read the precautions on the back before filling out this page) (n-butyl) -N-propylsulfonamido) ethyl) -2- (4 -MA MA4> 4- (1,3-phenylhydrazone dioxol-5-yl V pyrrolidine-3-carboxylic acid Using the procedure described in Example 66, the title compound was prepared as a white solid. Melting point 64-65. (: .H NMR (CDC13, 300 MHz) δ 0.83 (LJ = 7 Hz, 3Η), 0.98 (t, J = 7 Hz, 3M), 1.12-1.25 (m, 2H), 1.32- 1.41 (m, 2H), 1.75 (hexaplex,> 7 Hz, 2H), 2.23-2.31 (m, 2H), 2.72-3.32 (m, 8H), 3.43 (dd, J 2 9 Hz, 3 Hz , 1H), 3.53-3.59 (m, 1H), 3.65 (d, J 2 9 Hz, 1H) '3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J = 8 Hz, 1H) , 6.83 (dd, J = 8 Hz, 1 Hz, 1H), 6.88 (d, J = 9 Hz, 2H), 7.02 (d, J = 1 Hz, 1H), 7.33 (d, J = 9 Hz, 2H ). MS (DCI / NH3) m / e 547 (M + H), Example 1 14 1, trans-1- (Team ~ bis (n-butyl) aminocarbonylfluorenyl) -2- (4-methyl gas Benzyl) -4-(1,3 -phenylhydrazone dioxol-5-yl -p ratio p each lake-3 -chinoic acid The title compound was prepared as a white solid using the procedures described in Examples 28 and 43. Melting point 74-76 C. 4 NMR (CDCI 3, 300 MHz) δ 0.8 0 (t, J = 6 Hz, 3H), 0.88 (i, J 2 8 Hz, 3H), ϊ .08 (hexaplex, J 2 8 Hz, 2Η), 1.21-1.48 (m, 6Η) , 2.75 (d, J 2 12 Hz, 1H), 2.95-3.09 (m, 4H), 3.26-3.59 (m, 5Η), 3.75 (d, J 2 9 Hz, 1Η), 3.79 (s, 3Η ), 4.28 (s, 4Η), 6.78 (d, J = 9 Hz, iH), 6.85 (d, J = 9 Hz, 2H), 6.91 from 0, 1, 2 3 Hz, 9 Hz, 1H), 6.98 (d, J 2 3 Hz, 1H), 7.32 (d, J 2 9 Hz, 2H) -203- & Zhang scale timely / close family standard (CNS) A4 specifications Π10χ 297) 552260 A7 B7 ; Fifth, the description of the invention (204. MS (DCI / NH3) m / e (M + ΗΓ. Example 1 1 5 trans, trans-1- (2- (N-propyl-N-propylsulfonamido) ethyl) -2- (4 -Methoxyphenyl) -4- (1,3-benzo-dioxol-5-yl) -pyrrolidine-3-carboxylic acid Using the procedure described in Example 66, a white solid was prepared The title compound. Melting point 72-73 ° C. 4 NMR (CDC13, 300 MHz) δ 0.79 (t, J 2 8 Hz, 3Η), 0.98 (t, J = 8 Hz, 3Η), 1.43 (sixfold peak , J = 8 Hz, 2H), 1.75 (hexaplex, J 2 8 Hz, 2H), 2.22-2.32 (m, 1H), 2.69-3.32 (m, 9H), 3.42 (dd, J 2 3 Hz, 12 Hz, 1H), 3.5 2 -3.5 8 (m, 1H), 3.64 (d, J 2 12 Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J 2 1 1 Hz, 1H), 6.83 (dd, J 2 1 Hz, 1 1 Hz, 1H), 6.87 (d, J 2 1 1 Hz, 2H), 7.0 (d, 1 = 2 Hz, 1H), 7.32 (d , J 2 11 Hz, 2H). MS (DCI / NH3) m / e533 (M + H) —. Example 1 1 6 Trans, trans-1- (2- (N-butyl-N-butylsulfonium) Amino) ethyl) -2- (4-fluorenoxyphenyl) -4- (1,3-benzo-dioxol-5-yl) -pyrrolidine-3-carboxylic acid Using the procedure described in Example 66, the title compound was prepared as a white solid. Melting point 62-63 ° C. 4 NMR (CDC13, 300 MHz) δ 0.82 (t, J = 6 Hz, 3Η), 0.91 (t, J = 6 Hz, 3Η), 1.20 (hexaplex, J 2 6 Hz, 2H), 1.33- 1.42 (m, 4H), 1.68 (quintet, J = 6 Hz, 3H), 2.23-2.32 (m, 1H) ^ 2 70-3.2 8 (m, 9H), 3 41 (d, J = 8 Hz, 1H), 3.52-3.58 (m, 1 Η), 3 65 (d, J = 8 Hz, 1H), 3 79 (s, 3H), 5.95 (s, 2H), 6 72 (d, J = 8 Hz, 1H), 6 82 207- and standard Su Zhou National Standard (CNS) Λ4 specifications ( : 210 X 297 Gongchu) (Please read the notes on the back before filling this page) 552260 A7 ___ B7 V. Invention Description (205) (Please read the notes on the back before filling this page} (d, J = 8 Hz, 1H), 6.87 (d, J = 8 Hz, 2H), 7.01 (s, 1H), 7.32 (d, J = 8 Hz, 2H). MS (DCI / NH3) m / e 561 (M + H) ’. Example 11 7 trans, trans-1- (2 · (N, N-bis (n-butyl) aminocarbonylfluorenyl) -2- (4-methoxymethoxyphenyl) -4- (1,3 -Phenylhydrazine-5-yl) -pyrrolidine-3-carboxylic acid treated with chloromethyl methyl ether and triethylamine in THF at room temperature Benzophenone to give ethyl 4-methoxymethoxybenzylidene ethyl acetate, which was processed by the procedure described in Example 1 to give the title compound as a white solid. Melting point 48-49 X: .4 NMR ( CDC13, 3 00 MHz) δ 0.8 1 (t, J 2 7 Hz, 3H), 0.88 (t, J = 7 Hz, 3H), 1.06 (hexaplex, J = 7 Hz, 2H), 1.20-1.35 (m, 4H), 1.44 (quintet, J 2 7 Hz, 2H), 2.75 (d, J = 12 Hz, 1H), 2.94 -3.10 (m, 4 prints, 3.25-3.35 (111, 111), 3.40 ((1, 12 Hz, 111), 3.43-3.52 (m, 2H), 3.47 (s, 3H), 3.55-3.62, 3.77 (d, J = 9 Hz, 1H), 5 15 (s, 2H), 5.94 (m, 2H), 6.73 (d, J = 8 Hz, 1H), 6.86 (dd, J = 1 Hz, 8 Hz, 1H), 7.0 (d, J-8 Hz , 2H), 7.04 (d, J = 1 Hz, 1H), 7.32 (d, J = 8 Hz 2H). MS (DCI / NH3) m / e 541 (M + H) r. Example 1 1 8 'trans, trans-1- (2- (N, N-di (n-butyl) aminocarbonylfluorenyl ) -2- (4-hydroxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -pyrrolidine-3-carboxylic acid hydrochloride The compound obtained from Example 1 16 was treated with concentrated HC1 in THF-isopropanol to give the title compound as a white solid. Melting point 21 2 2 ° C. 4 NMR (CD3OD, 3 00 MHz) δ 0.90 (t ,] 2 8 Hz-203-This paper size is in accordance with the National Standard of China (CNS) Λ4 specification (210X 297 cm) 552260 Α7 Β7 V. Description of the invention (2ce), 6H), 1.12-1.27 (m, 6H) ), 1.36- 1.45 (m, 2H), 3.04 (bs5 111), 3.14-3.35 (^ 2 9 Hz, 1 India, 3.90 05, 3 Tian, 4.17 ((1, > 15 Hz, 1H), 5.96 (s, 2H), 6.82-6.93 (m, 4H), 7.03 (d, J = 1 Hz, 1H), 7.42 (bs, 2H). MS (DCI / NH3) m / e 497 (M + H) —. Example 11 9 trans, trans-1- (2- (N-isobutyl-N-propylsulfonamido) ethyl) -2- (4-fluorenoxyphenyl) -4- (i, 3- Phenylhydrazone dioxopent-5-yl) -pyrrolidine-3-carboxylic acid The procedure described in Example 66 was used to prepare the title compound as a white solid. Melting point 73-74 ° 0. 4 ~ ^ 111 (00 (: 13,300 MHz) 5 0.80 (d, J 2 6 Hz, 6H), 0.98 (t5 J = 8 Hz, 3H), i.62 (6 Heavy peak, J 2 6 Hz, 1H), 1.74 (Sixfold peak, J = 8 Hz, 2H), 2.23 -2.34 (m, 1H), 2.68-2.98 (m, 7H), 3.08-3.18 (m, lH ), 3.26-3.42 (m, 2Η), 3.5 2-3.58 (m, 1H), 3.6 5 (d, J = 9 Hz, 1H), 3.80 (s, 3H), 5.90 (s, 2H), 6.74 (d, J = 8 Hz, 1H), 6.82 (d, J = 8 Hz, 1H), 6.86 (d, J = 8 Hz, 2H), 6.98 (d, J = 1 Hz, lhT), 7.33 (d , J 2 8 Hz, 2H). MS (DCI / NH3) m / e 547 (M + H) '. Example 120 r trans, trans-1- (2- (~ benzenesulfonyl-isopropylamino) ethyl Phenyl) -2- (4-fluorenyloxyphenyl / 中 中 Aί;: ^-χ; πΐ; 4 i compound (please read the notes on the back before filling in this page)) -4-(1,3- Phenylhydrazone dioxo I like cyclopentazone-5 -yl) bilopridine-3 -i acid. Using the procedure described in Example 66, the title compound was prepared as a white solid. Melting point 89-91 ° C. 4 NMR (CDC13, 3 00 MHz) & 0.74 (t, J = 6 Hz 7 3H), 1 33 (hexaplex, J = 6 Here, 2H), 2.20-2 30 (m,] H), 2 62-2.72 (m, 1H), 2 85-3.05 (m, 4H), 3.12-3.22 -209-This paper describes the country of the country Standard (CNS) Λ4 specification (210 X 297 mm) 552260 A7 B7 V. Description of the invention (207); A-T ii printed in the r section (m, 1H), 3.38 (dd, J = 3 Hz, 9 Hertz, m), 3 49_3 57 (m, 1H), 3.62 (d, J = 9 hertz, 1H), 3 82 (s, 3H), 5.96 (s, 2H), 6.73 (d, J = 8 hertz, 1H), 6.84 (dd, J = 1 Hertz, 8 Hertz, 1H), 6.85 (d, J = 9 Hertz, 2H), 7.02 ((^ Hertz, IH), 7.28 (d, ㈣Hertz, 2H), 7.39 -7.54 (m, 3H), 7.70 (d, J 2 7 Hz, 2H). MS (DCI / NH3) m / e 567 (M + H) ". Group, tail oxyamphetamine) ethyl) -2- (4-methylfluorenyl-fluorene,)-4 · ^ 1,3-! Bis-dienen-5-yl) -pyrrolidine-3-carboxylic acid Using the procedure described in Example 66, the title compound was prepared as a white solid. Melting point 96-97 ° C. iHNMR (CDCl3, 300 MHz) δ 0.73 (t, J 2 7 Hz, 3 Η) '1.34 (hexaplex, j 2 7 Hz, 2 Η), 2. 2 0. 2 3 0 (m, iH), 2.62-2.71 (m, lH), 2.82_3.03 (m, 4H), 3.08-3 · 18 (m, 2H), 3.38 (dd, J 2 3 Hz, 9 Hz, 1H), 3 48_3 56 (m, 1H), 3.62 (d, J 2 9 Hz, 1H), 3.81 (s, 3H), 3.86 (s, 3H) ') 95 (s, 2H), 6.73 (d, J 2 8 Hz, m ), 6.81-6.89 (m, 5H), 7.01 (d, J = 2 Hz, 1H), 7.28 (d, J = 8 Hz, 2H), 7.62 (d, J = 8 Hz, 2H). MS (DCI / NH3) m / e 597 (M + H wide. Example 122 Tail 1_ ^ 1- (N, N-bis (n-butyl) aminocarbonyl fluorene) -2- (2-methoxyethyl Oxy-il ^ Si-wildyl) -4.Γίll.3 di-wild-oxo-dioxolenyl-5-yl) -pyrrolidine-3-chitoic acid at 70 X: in THF Sodium hydride and bromoethyl methyl acid were used to treat 2-benzyl-5-methoxyethoxybenzylbenzene snapper to obtain 2-methoxyethoxyethoxybenzidine. (Please read the notes on the back before writing On this page, 11% ». -210- ft standard 逑 standard (CNS 210 ^ 1 ^ centimeter) 552260 A7 B7 V. Description of the invention (2?) Ethyl ethyl acetate, as described in Example 1 This was worked up to give the title compound as a white solid. Melting point 63-65 ° C. iHNMRCCDCU, 300 MHz) δ 0.84 (t, J 2 7 Hz, 3H), 0.89 (t, J 2 7 Hz, 3H), 1.16 (hexaplex, J = 7 Hz, 2H), 1.28 (hexaplex , J 2 7 Hz, 2H), 1.45-1.52 (m, 4H), 2.8 7-2.94 (m, 2H), 3.00-3.16 (m, 3H), 3.26-3.36 (m, 2H), 3.43 (s, 3H), 3.47-3.54 (m, 3H), 3.66-3.72 (m, 2H), 3.78 (s, 3H), 3.76-3.84 (m, iH), 4.02-4.10 (m, 2H), 4.25 (d, J 2 9 Hz, 1H), 5.92 (s, 2H), 6.40 (d, J = 2 Hz, 1H), 6.52 (dd, J 2 2 Hz, 9 Hz, 1H), 6.70 (d, J = 8 Hz, 1H), 6.83 (dd, J 2 1 Hz, 8 Hz, 1H), 5.98 (d, J = 2 Hz, 1H), 7.53 (d, J 2 9 Hz, 1H). MS (DCI / NH3) m / e 585 (M + H), Example 123 trans, trans-l- (2- (N-propyl-N- (2,4-dimethylbenzenesulfonyl) amino) ) Ethyl) -2- (4 -fluorenyloxyphenyl) -4- (1,3-phenylhydrazinedioxol-5-yl) -Salopenia-3-carboxylic acid Procedure described in 66 to prepare the title compound as a white solid. Melting point 88-90 ° C. iHNMRCCDCh, 300 MHz) δ 0.69 (t, J = 7 Hz, 3Η), 1.32 (hexaplex, J = 7 Hz, 2Η), 2.12-2.20 (m, 1H), 2.32 (s, 3H), 2.47 (s, 3H), 2.62-2.69 (m, 1H), 2.78 (t, J = 9 Hz, 1H), 2.89 (dd, J = 8 Hz, 1H), 3.02 (hexaplex, J = 9 Hz , 2H), 3.15-3.32 (m, 3H), 3.46-3.55 (m, 1H), 3.60 (d, J = 9 Hz, 1H), 3.82 (s, 3H), 5.96 (s, 2H), 6.72 ( d, J = 7 Hz, 1H), 6.80 (dd, J 2 1 Hz, 9 Hz, ΓΗ) -211-This paper is suitable for the national standard (CNS) A4 specification f 210 × 297 mm) (Please read the notes on the back before filling in this page 1-1: 1 * _ I ..... —- · 552260 A7 B7 V. Description of the invention (209), 6.86 (d, J = 9 Hz) , 2H), 6.97 (d, J = 1 Hz, 1H), 7.03 (bs, 2H), 7.29 (d, J = 9 Hz, 1H). MS (DCI / NH3) m / e 595 (M + H) Example 124 trans, trans-l- (2- (N-propyl-N- (3-chloropropylsulfonyl) amino) ethyl) -2- (4-methoxyphenyl) -4- Jk λ in (1,3-phenylhydrazone dioxol-5-yl) -pyrrolidin-3-carboxyl; $ ok! The title compound was prepared as a white solid by the procedure described in Example 66. Melting point 75-76 ° C. IHNMRCCDCh, 300 MHz) δ 0.80 (t, J 27 Hz, 3 Η), 1.45 (hexaplex, J 2 7 Hz, 2Η), 2.15-2.31 (m, 3H), 2.70-2.80 (m, 1H), 2.8 5-3. 1 0 (m, 6H), 3.23-3.3 1 (m, 2H), 3.43 ( bd, J = 9 Hz, 1H), 3.5 5-3.66 (m5 4H), 3 · 8 i (s, 3H), 5.94 (s, 2H), 6.73 (d, J 2 8 Hz, 1H), 6.82 ( d, J = 8 Hz, 1H), 6.86 (d, J = 8 Hz, 2H), 7.00 (s, 1H), 7.33 (d, J = 8 Hz, 2H). MS (DCI / NH3) m / e 567 (M + H) 卞. Example 125 trans, trans-1_ (2_ (N_propyl-N_ (2-fluorenylethylhexyl) amino) ethyl) -2-(4-methoxyphenyl) -4- (1,3 -Phenylhydrazine-5-yl) -pyrrolidine-'3-carboxylic acid Using the procedure described in Example 66, trans, trans-1- (2- (N-propyl-N -(Vinylsulfonyl) amino) ethyl-2- (4-fluorenoxyphenyl) -4- (1,3-phenylhydrazinedioxol-5-yl) -pyrrolidine -3-carboxylic acid. This ester was hydrolyzed with aqueous sodium hydroxide in methanol to obtain the title compound as a white solid. Melt 黠 62-64Ό. 4 NMR (CDC13, 3 00 dead Hz) δ 0 7S ( ί. -212 The paper size is applicable to the China National Standard (CNS) Α4 size C 210 × 297 g t) (Please read the precautions on the back before filling in this page, 1Τ '' #. 552260 A7 B7 V. Description of the invention ( 21〇) J = 7 Hz, 3H), 1.42 (hexaplex, Bu 7 Hz, 2H), 2.23-2.32 (m, 1H), 2.72-2.79 (in, 1H), 2.86-3.05 (m, 4H) , 3.10 · 3.27 (m, 4H), 3.32 (s, 3H), 3.4 3 (dd, J = 3 Hz, 9 Hz, 1H), 3.53-3.58 (m, 1H), 3.65 (d, J 2 9 Hz, 1H), 3.69 (t, J 2 6 Hz, 2H), 3.80 (s, 3H), 5.94 (s, 2H), 6.73 (d, J 2 8 Hz, 1H), 6.82 (dd5 J 2 1 Hz, 8 Hz, 1H), 6.87 (d, J = 8 Hz, 2H), 7.02 (d, J = 1 Hz, 1H), 7.33 (d, J = 8 Hz, 2H). MS (DCI / NH3) m / e 549 (M + H), Example 126 trans, trans_ 1_ (2- (N -fluorenyl_N_ (2_ethoxyethyl stone more acidic) amino) ethyl) _ 2- (4_methoxyphenyl)-4_ (1 , 3 p-phenylene hydrazone dioxo I-cyclopentaschyl _5 _yl) _? Pyrrolidine-3-carboxylic acid

部 屮 A, τ >/; f A (Please read the notes on the back before filling this page} Using the procedure described in Example 66, prepare the title compound as a white solid. Melting point 58-60 ° C. IRNMRCCDCh, 300 MHz) δ 0.78 (t, J = 7 Hz, 3Η), 1.18 (t, J = 7 Hz, 3Η), 1.43 (hexaplex, J = 7 Hz, 2H), 2.24-2.33 (m, 1H), 2.70-2.80 (m5 1 Η), 2.87-3.05 (m, 4Η), 3.13-3.20 (m, 2Η), 3.22-3.32 (m, 2Η), 3.42 (dd, J = 2 Hz, 9 Hz, 1H), 3.40 (q, J = 7 Hz, 2H), 3.52-3.58 (m, 1H), 3.65 (dJ = 9 Hz, 1H), 3.72 (t, J 2 6 Hz, 2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J = 7 Hz, 1H), 6.83 (dd, J = 1 Hz, 7 Hz, 1H), 6.87 (d, J = 8 Hz , 2H), 7.00 (d, J = 1 Hz, 1H), 7.32 (d, J = 8 Hz, 2H). MS (DCI / NH3) m / e 563 (Μ + ΗΓ. -213- Specifications of this paper / 1] Chinese National Standard (CNS) Λ4 Specification ('210 × 297 mm) 552260 A7 B7 Jk I- Τ f: A, V. Explanation of the invention (211 f Example 127 trans, trans-1: (2 丄 N-propyldiyl-l-^^^ yl) amine) ethyl) -2- (4- 曱Oxyphenyl) _4- (1, _3 ^: ^^^ oxy 'pyrrolidin-3-guinic acid The title compound was prepared as a yellow solid using the procedure described in Example 66. Melting point 102-104 ° C. LTri NMR (CDC13, 300 MHz) s 0.62 (t, J = 7 Hz, 3H), 1.28 (ττ weight ^ φ ·, J = 7 Hz, 2H), 2.12-2.20 (m, 1 Η), 2.78 (t , J = 9 Hz, 1H), 2.88 (s, 6H), 2.72-2.89 (m, 1H), 3.05_3.12 (m, 2H), 3.26-3.45 (m, 3H), 3.45-3.52 (m, 1H), 3.58 (d, J = 9 Hz, 1H), 6.97 (d, J = 1 Hz, 1H), 7.13 (d, J = 7 Hz, 1H), 7.26 (d, J = 8 Hz, 1H) , 7.42-7.50 (m, 2H), 8.08 (dd, J 2 1 Hz, 7 Hz, 1H), 8.20 (d, J 2 8 Hz, 1H), 8.48 (d, J 2 8 Hz, 1H). MS (DCI / NH3) ra / e 660 (M + H) '. Example i28 A, trans_W2- (N-propyl-N- (Ethylsulfonyl) amino) ethyl) -2- (4-fluorenyloxy) -4- (1,3-benzyl-dioxol-5-ylpyrrolidine-3- The carboxylic acid was prepared using the procedure described in Example 66 to prepare the title compound as a white solid. Melting point 70-72 Ό. IHNMRCCDCh, 300 MHz) δ 0.79 (LJ = 8 Hz, 3 Η), 1.28 (t, J = 7 Hz, 3Η), 1.43 (q, J 2 8 Hz, 2H), 2.22-2.30 (m, lH), 2.71-2.80 (m, lhT), 2.82-3.10 (m, 6H), 3. 18-3.32 (m, 2H), 3.43 (dd, J 2 3 Hz, 9 Hz, iH), 3 53-3.60 (m, 1H), 3.65 (d, J 2 9 Hz, 1H), 3.80 (s, ° H) , 5 96 (s, 2H), 6,73 (d, J 2 7 Hz, 1H), 6.82 (dd, J = 1 _____ _- 214-° " Xinzhou Zhongyuan National Standard (CNS) M Specification ( 2l0x 297 mm (please read the notes on the back before filling in this page j- 丁 -5 552260 A7 Β7 V. Description of the invention (212) Hertz, 7 Hertz, 1H), 6.88 (d, J = 8 Hertz, 2H) , 7.00 (d, J = 1 Hz, 1H), 7.32 (d, J = 8 Hz, 2H). MS (DCI / NH3) m / e 519 (M + ΗΓ. Real trans-l- (2- (N-propyl-N- (4-methylbenzenesulfonyl) amino) ethyl)! Oxybenzene ) -4- (1,3-benzo-meta-bicyclopentene-5-yl) -pyrrole The title compound was prepared as a white solid using the procedure described in Example 66. Melting point 78-79 ° C. hNMRCCDCh, 3 00 MHz) δ 0.73 (t, J 2 7 Hz, 3Η), 1.33 (hexaplex, j 2 7 Hz, 2Η), 2.20-2.30 (m, 1Η), 2.40 (s , 3Η), 2.61-2.72 (m, 1Η), 2.83-3.05 〇, 4H), 3 08 · 3. 19 (m, 2H), 3.4S (dd, J 2 3 Hz, 9 Hz, 1H), 3.4 9-3.57 (m, 1H), 3.62 (d5 J = 9 Hz, 1H), 3.8 1 (s, 3H) '5.95 (s, 2H)' 6.73 ((1, Bu 8 Hz, 1H), 6.82 ((1, 1, 2, 8, 2, 1H) '6.87 (d, J = 8 Hz, 2H), 7.00 (s5 1H), 7.21 (d, J = b Hz, 2H), 7.29 (d, J 2 8 Hz, 2H), 7.57 (d5 J 2 8 Hz, 2H). MS (DCI / NH3) m / e 581 (M + H),

Example 1 M;; r Bean mono, trans-1- (N, N-di (n-butyl) aminocarbonylmethyl) -2- (3-pyridine on il (1,3 -phenylene metadi Oxygenate--5 -yl)-ρbilodine-3 leptate _ f λ, 卬 (Please read the notes on the back before filling this page) Use the procedure described in Example 1 to process borrowing The method described by Wenkert et al., J. Org. Chem. 48: 5006 (1983) yielded the title compound as a white solid. Melting point i 67-1 68 ° C. 1 Η NMR (CDC1 ;, 300 MHz) § 0 82 (t, J 2 7 Hz, 3Η), 89 89-215 Ό Ό, / 乂 乂 乃] 乃 National Standard Car (CNS) Λ4 specification (210x 297 cm) 552260 lk A Hz, 1H), 5.93 (s5 2H) J = 2 Hz, 8 Hz, 1H) J = 4 Hz, 8 Hz, 1H) J = 2 Hz, 4 Hz, 2H) A7 B7 V. Description of the invention (213) (t, J 2 7 Hz, 3H), 1.14 (hexaplex, J = 7 Hz, 2H), 1.23-1.48 (m, 6H), 2.68-3.20 (m, 6H), 3.3 4-3.43 (m, 2H), 3.57 (dd? J 2 3 Hz 5 9 Hz, 1H), 3.75-3.83 (m, 1H), 4.08 (d, J 2 9 Hz 6.73 (d, J = 8 Hz) , 1H) 6.90 (dd, 7.03 (d, J 2 2 Hz, 1H), 7.38 (dd, 8.04 (d, J 2 8 Hz, 1H), 8.48 (dd? MS (DCI / NH3) m / e 482 (M + H ), Example 1 3 1 trans, trans-l- (2- (N-propyl-N- (n-butylsulfonyl) amino) ethyl) -2- (4-methoxyphenyl) _4 · (1,3_Benzo-dioxopentyl-5-yl) _ Orbitalol-3-folic acid Using the procedure described in Example 66, the title compound was prepared as a white solid. Melting point 65 -66 ° C. 4 NMR (CDC13, 300 MHz) δ 0.78 (t, J = 7 Hz, 3Η), 0.92 (t, J 2 7 Hz, 3Η), 1.31-1.46 (m, 4H), 1.68 ( Fivefold peak, J = 7 Hz, 2H), 2.21-2.32 (m, i Η), 2 70-3.0 8 (m, 7 Η), 3. 1 2-3.23 (m, 2H), 3.42 (dd, J 2 2 Hz, 9 Hz, 1H), 3.52-3.58 (m, 1 Η), 3 64 (d, J = 9 Hz, 1H), 3.80 (s, 3H), 5.96 (s, 2H), 6.72 (d , Bu 7 Hz, 1H), 6.83 ((1 ^) = 1 Hz, 7 Hz, 11 ~ 1), 6.86 ((1, 2 8 Hz, 211), 7.00 (〇1: J = 1 Hz, 1H ), 7.32 (d, J 2 8 Hz, 2H), 7.00 (d, J 2 1 Hz, 1H), 7.32 (d, J = 8 Hz, 2H). MS (DCI / NH3) m / e 547 (M + H), Example 1 3 2 trans, trans-l- (2- (N-propyl-N- (4-chlorobenzenesulfonyl) amino) ethyl Base) -2- (4-A216 This paper size is described in the National Park Standard (CNS) A4 specification (210X 297 cm)) (Please read the precautions on the back before filling this page} 552260 A7 B7 屮 Jk and 5, jl 合 ίί 5. Description of the invention (214 oxyphenyl) -4- (1,3-phenylhydrazine dioxol-5-yl) -pyrrolidine-3-carboxylic acid utilization is described in Example 66 Procedure to prepare the title compound as a white solid. Melting point 105-106 ° C. 4 NMR (CDC13, 300 MHz) δ 0.72 (t, J 27 Hz, 3Η), 1.34 (hexaplex, J 2 7 Hz, 2Η), 2.56-2.62 (m, 1Η), 2.78-2.86 (m, 1Η), 2.96-3.03 (m, 3Η), 3. 13-3.26 (m, 3H), 3.5 · 1 (dd, J = 5 Hz, 9 Hz, 1H), 3.62-3.68 (m, lH), 3.80 (s, 3H), 3.94 (d, J = 9 Hz, 1H), 5.92 (s, 2H), 6.75 (d, J = 8 Hz, 1H), 6.84 (dd, J = 2 Hz, 8 Hz, 1H), 6.94 (d, J = 8 Hz, 2H), 6.98 (d5 1 2 2 Hz, 1H), 7.36 (d, J 2 8 Hz, 1H), 7.49 (d, J = 8 Hz, 1H), 7.6 8 (d, J 2 8 Hz, 1H). MS (DCI / NH3) m / e 601 (M + H), Example 1 3 3

Trans, trans-1- (2- (N-propyl-N- (benzenesulfonyl) amino) ethyl) -2- (4-fluorenyloxy) -4- (1,3-phenylhydrazone M-dioxol-5-yl) -pyrrolidin-3-carboxylic acid The procedure described in Example 66 was used to prepare the title compound as a white solid. Melting point 88-89 ° 〇. 1: 9 1 \ 411 (匸 0 (: 13,300 dead Hz) 3 0.72 (t, J = 7 Hz, 3H), 1.32 (hexaplex, J = 7 Hz, 2H), 2.06-2.16 (m, 1H), 2.56-2.67 (m, 1H), 2.75-3.10 (m, 6H), 3.30 (dd, J 2 2 Hz, 9 Hz, 1H), 5.95 (s, 2H), 6.73 (d, J = 7 Hertz, 1H), 6.80 (dd, J 2 1 Hz, 7 Hz 7 1H), 6.86 (d, J = 8 Hz, 2H), 6.79 (d, J = 1 Hz, 1H), 7.27-7.35 (m, 7H). MS (DCI / NH3) m / e 581 (M + H), -217- This paper size is applicable 屮 1¾ National Standard (CNS) Λ4 size (210 乂 297 mm) (Please read the note on the back first Please fill in this page again for details) 552260 A7 V. Description of the invention (215) i Example 134 (Please read the precautions on the back before filling in this page amine) Ethyl ygjUiX · cock-5-ylpyrrolidine-3-Ajl Use In the procedure described in Example 66, the title compound was prepared as a white solid. Melting point 9HC. IHNMR (CDci3, 300 MHz) s 0.73 (t, J-7 Dunz, 3H), 1.44 (sixfold Peak, J =: 7 Hz, 2H), 218-227 (m, 1H), 2.) 6-2.67 (m, 1H), 2.7 8-2.87 (m, 2H), 2.97 (, heavy peak, J 2 8 Hz , 2H), 3.11-3 16 (m, 2H), 3 33 (machine 2 Hexuan, 9 Hz money, 1H), 3.43-3.50 (m5 1H), 3.57 (d, J = 9 Hz, ^ H) '). 78 (s, 3H), 7.08 (t, J = 8 Hz, 2H), 7.24 (d5 J = 8 Hz, 2H)' 7.69 (dd, J = 5 Hz, 8 Hz, 2H) . MS (DCI / NH3) m / e 585 (M + H) +. Order example 135 Aminocarbonylfluorene ν2 · (4 · methoxyphenyl) _4_ (4-Signature squeak a certain Bihadian-3- 衮 Weng Example 135 A Benzene sulphan-4-¾ will be in DMF (5 ml) of 3-bromophenol (13.8 g, 80 mmol) was added to 0 ° (: 60% sodium hydride in 0 "? (60 ml) in sulfonate oil (4.00 g, 10%). 0 mmol, 1.25 equivalents). After 10 minutes, bromoacetaldehyde diethyl acetal (14.9 ml, 96.6 mmol, 1.24 equivalents) was added and the resulting mixture was heated to 120 ° C for 2.5 hours. The mixture was cooled to room temperature, poured into water, and extracted once with ether. The organic solution of Jiang was covered with MgS04, water was filtered, evaporated, and distilled in vacuo to produce a colorless liquid -218-, paper Appropriate size / 丨] Chinese National Standard (CNS) A4 specification (210X 297 mm) 552260 samples 1V combined 5. Description of invention (A7 B7 216 body (household 17 "grams, 74%). At G'4 mm The lower point of the mercury column is 163r. In warm, acid (15-3g), add benzene (5. mM. A solution of the compound (173 g, 59.3 mM <the above-mentioned adduct, and stir vigorously ... I washed the lower layer with sautéed pork; carefully pour out the benzene layer afterwards, and / person. After concentrating in the orchid, distill it in the air and distill, 徂 $ 丨 〃 4 k,, 'job / combined, and then two, A typical colored liquid (8.13 g, 70%). The boiling point is 62-67 ° C under a column of 0.6 gm. Moore, add to the above solution of the above compound in ether (80 ml) (0. 5 g, 毛. 5 mol), and keep the temperature not higher than -70 X:. Then, add a solution of DMF (6.5 ml, 83 亳, 222 gas) in diethyl ether (20 ml), and allow the mixture to pour in 2 hours. The phases were separated. The organic solution was dehydrated with MgS04 and concentrated in the air. The residue was purified by flash chromatography on hair gel, and α 10% was eluted with ether in hexane. Benzofuran-6-carboxaldehyde (122 g) and benzofurancarboxaldehyde (186 g) were obtained, both of which were colorless oils. Example 1 3 5 β-N-propylaminocarbonylmethyl) -2- (4-methoxybenzyl) benzene # 咗A certain V p bilobita-3-borrowed the acid to prepare the title compound using the procedure described in Examples 1 and 49, replacing the piperonal in Example 49 A with the compound from Example 1 3 5 A. 1 H NMR (300 MHz, CDCh) (less rotational isomers) δ 7,59 (1 Η 3 Hz), 7.4, 7.2 (611! 1), 6.8 (21 (1,) 2 8 Hz), 4 〇3 (Please read the notes on the back before filling in this page j 1-I as

--- I---I-II f, order &lt; wooden paper 仏 scale 埒 埒 gawa prisoner's house mark $ -219-(, NS) Λ4 size (210X29 / male) 552260

乂 中 乂; J 卬 A7 B7 V. Description of the invention (217) (111, 111), 3.94 (111, 4 (1,) ^ 8 Hz, 3 Hz), 3.77 (311, 5), 3.61 (1H, dd , J 2 8 Hz, 73 Hz), 3.42 (1H, dd, J = 11 Hz, 5 Hz), 3.40-2.90 (5H, m), 2.82 (2.81) (3H, s), 1.50 ( 2Η, 7-peak, J 2 7 Hz), 0.82 (0.75) (3H, t, J = 7 Hz). MS (DCI / NH3) m / e 451 (M + H) +. Analysis of C26H30N2O5 · AcOH Calculated 値: C, 65.87; H, 6.71; N, 5.49. Experimental 値: C, 66.04; H, 6.42; N, 5.60. Example 13 6 Trans, trans-1- (N-methyl-N-propylaminocarbonyl) Methyl) -2- (4-methoxyphenyl) -4- (6-oxapyranyl) -supplied Luodian-J-Xan using the procedures described in Examples 1 and 49 to prepare the title compound, Piperonaldehyde in Example 49 A was replaced with a compound prepared as described in Example 1 3 5 A. 4 NMR (300 MHz, CDC13) (less rotational isomers) 57.65 (lH, bd), 7.60 ( lH, d, J = 2 Hz), 7.55 (lH, d, J = 8 Hz), 7.35 (3H, m), 6.85 (2H, dd, J = 8 Hz, 3 Hz), 6.75 (1 ratio (1 (1,1 = 3 Hertz, 2 Hertz), 3.83 (21 {, 111), 3.79 (3 Gens), 3.60-3.0 (7H, m), 2.91 (2.83) (s, 3H), 1.51 (2H, Seven Heavy Peaks,) 2 7 Hertz), 0.83 (0.78) (3 ^ 1, 1, 12 and 7 Hertz). 1 ^ 8 (〇 €: 1 / &gt; ^ 3) m / e 45 1 (Μ + ΗΓ. About C26H30N205. 0.5 Analytical calculations for H20: ，: C, 67.96; Η, 6.80; N, 6.10. Experimental 値: C, 67.90; Η, 6.71; Ν, 6 07 〇 Example 1 3 7 trans, transmethyl-N-propylamino Carboxymethyl) -2- (4-fluorenyloxyphenyl) -4- (6-phenylhydrazine_2,3_diazepinolanyl) Paper size this / 丨] China National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling out this page) 552260 A7 B7 Description of the invention (218) Catalytic hydrogenation of the compound (4 atm of tritium in AcOH, followed by preparative HPLC) to prepare the title compound. 1H NMR (300 MHz, CDC13) (less rotational isomers) δ (lH, m), 7.82 (3H, m), 5.40 (1 (1 (1,)-11 Hz 57 Hz), 4.58 (2H, t, J = 8 Hz), 4.18 (1H, m), 4.10 (1H, m), 3.88 (1H, m), 3.79 (3H, s), 3.60 (1H, m) , 3 35 (m, m), 3.19 (2H, t, J 2 8 Hz), 3.00 (4H5m), 2.9i (2 78) (s3H), 1.53 (1.40) (2H, sevenfold peak, J = 7 Hz ), 0.88 (〇.78) (3H, t, J == 7 Hz). MS (DCI / NH3) m / e 453 (iM + H) +. Analysis and calculation of C26H ”N20.5 · 1.25 TFA 値: C, 57.53; H 5 63; N 4.7]. Experiment 値 · C, 57.68; H, 5.68; N, 4.70. Example i 3 8 Group 2 trans-di (n-butyl) aminocarbonylmethyl 4- (4 -Benzosulfanyl) _ρ 比 口 基 各 _3 By the procedure described in Examples 1 and 49, the title compound was prepared, substituting benzalfuran-4-carboxaldehyde for piperonal of Example 49A, and NN / Butylamidine substituted N-fluorenyl-N-endo &lt; acetamidine. 1 η n μ &amp; p⑻ # Hz, CDC13) δ 7.62 (1H, d, j = 3 Hz), 7 39 (1H dt J = 8 green, 2 Hz), 7.34 (3H, m ), 7.26 (lH, d, h2 Hertz), '723 UH, d, J = 8 Hertz), 6.84 (2H, d, J = 8 Hertz), 4.09 (J ~ 8, Six, Uz, 4 (Hertz) '3.8 9 (1 H, d, J 2 9 Hz), 3 7 9 (3 H $) 3.67 (1 [{. &Lt; 1 (1, 1 2 1 10 What is it, 3 Hz), 344 () ,,, 3 b (3H, m), 3.00 (2H, m), 2.84 (1H, d, hl4 hertz), i 43 -221 --- --- Unclassified scale ❿ 冈 National Standard- (CNS) Λ4 specification (210X 297 public holidays) (Please read the precautions on the back before filling this page}

1T 552260 A7 B7 V. Description of the invention (219) (3H, m), 1.23 (3H, m), i.〇8 (2H, m), 087 (3H, t, j 2 7 Hz), 0 · 82 (3H, t, J = 7 Hz). MS (DCI / NH3) m / e 507 (M + H) +. Calculation of the fraction of C3〇H38N205: c, 71 12; H, 7 56; N, 5.53. Experiment 値 · C5 70.86; H, 7.45; N, 5.24. Example 13 9 is di-trans-1- (N, N-di1-yl) aminocarbonylfluorenyl) -2- (4-methoxyphenyl) -4_ (5-.furanopyrimidine-3- The carboxylic acid was prepared by the procedure described in Examples 1 and 49 to the title compound to the benzofuran-5- prepared by the procedure described in Example 1 3 5 A, but replacing 3-bromophenol with cardiobromophenol. Chinoic acid was used to replace the pepper of Example 49A, and N-methylpropylbromoacetamide was replaced with N, N-dibutylbromoacetamide. ΙΗ NMR (3 00 MHz, CDC13) δ 7.64 ( 1H, bd), 7.59 (1H, d, J = 2 Hz), 7,43 (2H, m), 7.3 3 (2H, d, J = 8 Hz), 6.85 (2H, d, J = 8 Hertz), 6.73 (1H, dd, J = 3 Hertz, 51 Hertz), 3.82 (1 Gen (1, Bu 11 Hertz), 3.89 (111, (15;) ^ 9 Hertz), 3 79 (3 to 0 ^ # 部 中 λ1Γ ^ · ^ ηΐ &gt; / ί # 合 0 杉 卬 1: (Please read the precautions on the back before filling this page), 3.53 (1H, dd, J = 10 Hz, 3 Hz), 3 44 (2H, m), 3.30 (lH, m), 3.20-2.95 (5H, m), 2.82 (lH, d, J = 14 Hz), 1.43 (3H, m), 1.23 (3H, m) 1.08 (2H, m), 0.87 (3H: t, J 2 7 Hz) , 0.82 (3H, t, J = 7 Hz) MS (DCI / NH3) m / e 507 (M + ΗΓ). Analytical calculated value for C30H38N205: c, 71.12; H, 7 56; N, 5.53 .Experiment 値: c, 70.73; H5 7.45; N, 5.29. Example 140 Di-d-butyl) aminocarbonylfluorenyl) -2- (4-methoxybenzyl) -4di-1anyl) -pyrrolidine -3-Carboxylic acid paper size (CNS)-552260; Jk engine A 卬 A7 B7 in the r part 5. Description of the invention (22) Using the procedures described in Examples 1 and 49 to prepare the title compound, Benzalfuran-6-carboxaldehyde was used to replace the piperonal of Example 49A, and N-methylpropylbromoacetamide was replaced with N, N-dibutylbromoacetamide. 1H NiMR (300 MHz, CDC13 ) δ 7.63 (1H, bd), 7.59 (1H, d, J = 2 Hz), 7.53 (1H, d, J = 8 Hz), 7.36 (3H, m), 6.85 (2H, d, J = 8 Hz) ), 6.73 (111, (1 (1,) 2 3 Hz 51 Hz), 3.82 (111, (1, 1 2 11 Hz), 3.89 (lH, d, J 2 9 Hz), 3.79 (3H, s) , 3.53 (] H, dd, J = 10 Hz, 3 Hz), 3.44 (2H, m), 3.30 (lH, m), 3.20-2.95 (5H, m), 2.80 (lH, d, J 2: 14 Hertz), 1 .43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, i, J = 7 Hz), 0.82 (3H, t, J = 7 Hz). MS (DCI / NH3) m / e 507 (M + H) +. Analytical calculations for C30H38 N205 • 0.75 H20: C, 69.28; H, 7.65; N, 5.39. Experiment 値: C, 69.] 1; H, 7.33; N, 5.32. Example 141 trans, trans-1- (N, N-di (n-butyl) aminocarbonylfluorenyl) -2- (4-fluorenylphenyl) -4- (6-phenylhydrazone-2,3-di Hydrofuryl) -pyrrolidine-3-carboxylic acid was prepared by catalytic hydrogenation of the compound obtained from Example 140 (4 Ac atmosphere, H2 in AcOH, followed by preparative HPLC). 1H NMR (300 MHz, CDC13) δ 7 · 40 (2H, d, J = 8 Hz), 7.16 (1H, d, J = 8 Hz), 6.97 (iH, dd, J = 8 Hz, 2 Hz) , 6.89 (3H, m), 5.90 (1H, bs), 4.57 (2H, t, J = 9 Hz), 4.93 (2H, m), 3.80 (3H, s), 3.70-3.58 (2H, m), 3.40 (1H, m), 3.30-2.90 (8H, m), 1 40 (2H, m), 1 29 (3H, m), i .08 (2H, m), 0 92 (3H: t, J 7 Hz), 0 · 82 (3 J = 7 Hz). -223- The size of this paper is the National Standard for Prisoners in Prison (CNS) Λ4 Specification (210X 297 Gong) (Please read the notes on the back before filling this page) 552260 A7 B7 V. Description of the invention (221 MS (DCI / NH3) m / e 509 (M + HriWc3 () H4 () N20.5.085 TFA analysis calculation: 値: C, 62.88; H, 6.8G; N, 4 63. Experiment 63: C, 63.04; H, 6.66 N, 4.60.t 142 trans' 4 — .. 1 0-methylfluorenyl) _2- (4_oxobenzylpyrrolidine-3- # age f Example 142A Windmark-5-renegade acid Under conditions described in 32A for 2,3-dihydrophenylhydrazine furan, hydroindenoic acid was prepared by the methylation of 々Λ 4. The resulting 4- and aldehyde mixture was purified as follows: aniline (22 g , 23 millimoles, \ equivalent) in a 6: 1 mixture of the main hydrogen-imprinted 4-carboxaldehyde and indenecarboxaldehyde (PM g, M millimoles). The resulting solution slowly solidifies into an imine mixture, It was recrystallized from hot ethyl wax to give 5-aldimine as a white solid. While imine (2,65 g) was suspended in water (6 ml), 41 chlorodilactate was used. Ring 00 liters). The mixture was boiled for 1 hour, and the mixture was cooled and poured into ether. The organic solution was dehydrated with MgS04, filtered and concentrated in the air. Distillation of the residue into a colorless liquid

Treason (1.:> 4 g, 88%). The boiling point at 0,9 mmHg is Example 142B Aminocarbonylmethyl) _2_ (4,2) iAJO-pyrrolidine-3-carboxylic acid-The title can be prepared by the procedure described in Examples 1 and 49. Indane carboxaldehyde replaces piperonal of Example 49A. IHNMR (

88-谇 * ° C

物, νλ; 〇〇 一 (Please read the precautions on the back before filling in this page to order-. Preparation ---- H--1 I j I —II II! --- -224-) 552260 A7 B7屮 f 々ίί 5. Description of the invention (222 Hz, CDC13) (less rotational isomers) δ 7 25H (5H, m), 6 78 (211, (), 1 = 8 Hz) '3.89 (11 (1,] = 8 Hz), 3.75 (311,5), 3.50 (2,90) (6Η, ιη), 2.88 (6H, t, J = 6 Hz), 2.82 (2.80) (3H, s ), 2.04 (2H, t, J = 8 Hz), 1 48 (2H, seven-peak, J = 7 Hz), 0.83 (0.73) (3H, t, J = 7 Hz). MS (DCI / NH3 ) m / e 45 j (M + H wide, 473 (M + Na) +. Analysis and calculation of c27H34N204 · 2.5H2 0 値: C, 65.44; H; 7.93; N, 5.65. Experiment 値: C, 65.36; H, 7.45; N, 5.53. Example 143: "Transmethyl-N-propylaminocarbonylmethyl) -2- (4-methoxybenzyl)-? Bikouge syndrome-3-Acid by The procedure described in Examples 1 and 49 was used to prepare the title compound to replace the pepper of Example 49A with indole-6-carboxaldehyde prepared by the method of Rapoport, J. Org. Chem. 5 1: 5 106 (1986) Aldehyde. 1H NMR (300 dead Hertz, CDC13) (less rotational isomers) δ 8.43 (1Η, br s), 7 57 (111) 2 8 Hz), 7.43 (1gen5), 7.31 (2; 9 ,, (1 (1, BU 6 Hertz, 73 Hertz), 7.22 (1H, d, J = 8 Hertz), 7. 1 (1H, t, J = 3 Hertz), 6 78 (21 ~ 1, (^ 1 2 6 Hertz, 3 Hz), 6.45 (1111), 3.93 (11 (1 (1, &gt; 6

Hertz, 3 Hertz), 3.80 (lH, m), 3.73 (3H, s), 3.60-2.90 (6H, 2.86 (2.82) (3H, s), 1.47 (2H, Seven Heavy Peak, Bu 7 Hz), 0.83 ( 0.73) (3H, t, J = 7 Hz). MS (DCI / NH3) m / e 45〇 (M + ΗΓ. Analysis and calculation of c26h31N304. 0.75 H2O: ，, c, 67.44: H, 7 07 N, 9.07. Experiment 値: C, 67.42; H: 7.09; N, 8.91 ^ 225- (Please read the precautions on the back before filling out this page) 4. Mysterious ruler A 戍) A4 ^ m (210 X 297 ^ ¾ 7 552260 A7 B7 V. Description of the invention (223 Example 144 trans, trans-1- (N-methyl-N-propylaminocarbonylmethyl) -2- (4-fluorenoxyphenyl) -4- (3, 4-Difluorophenyl) -pyrrolidin-3-carboxylic acid was prepared by the procedure described in Examples 1 and 49, and 3,4-difluorobenzaldehyde was used to replace the piperonal of Example 49A. 1HNMR ( 300 MHz, CDC13) (less rotational isomers) δ 7.60-7.3 (4Η, m), 7.13 (1) ^ 9, 1 to 9 Hz), 6.90 (211, (1,) ^ 8 Hz) , 3.90 (11 &quot;: 5 m), 3.79 (3H, s), 3.60-2.95 (6H, m), 2.92 (2.78) (3H, s), 1.5 5 (2H, sevenfold peak, J = 7 Hz), 0.8 8 (0.73) (3H t, J = 7 Hz). MS (DCI / NH3) m / e 447 (Μ + ΗΓ. Analysis and calculation of C24H2SF2N204 • 1.80 H20: ，: C, 60.19; H, 6.65; N, 5.85. Experiment 値: C, 60.13; H, 6.34; N, 5.84. Example 145 trans, trans-1- (N-methyl-N-propylaminocarbonylmethyl) -2- (4-fluorenylphenyl) -4- (benzene Base) _ mouth to mouth bite -3 _ | § Parent &gt;/; ii 卬 (Please read the notes on the back before filling out this page) Prepare the title compound by the procedure described in Examples 1 and 49 to Benzaldehyde was used to replace the piperonal of Example 49A. 1H NMR (300 MHz, CDC13) (less rotational isomers) δ 7.53 (4Η, d, J = 6 Hz), 7.40-7.20 (3H, m ), 6.88 (2H, d, J 2 8 Hz), 3.90 (lH, m), 3.79 (3H, s), 3.70_2.95 (8H, m), 2.90 (2.79) (3H, s), 1.50 ( 2H, 7-peak, J = 7 Hz), 0.87 (0.72) (3H, t, J = 7 Hz). MS (DCI / NH3) m / e 41 1 (M + H)-. About the analysis and calculation of C24H30N2 04 · 2.00 K20 値 · C, 64.55: H, 7.67: N, 6 27. Experiment 値: C, 64.37: H, 7 43; N, 6 29. 226- Size of this paper 迖 / i] Chinese National Standard (CNS) Λ4 size f 210X 297 mm) 552260 A7 B7 Central A 卬 -227- V. Description of the invention (224) Example 146 Methyl-N-propyl 1-based Talking about methyl) -2- (4-methoxybenzophenone) -bilobilodine · 3_ # _ The title compound was prepared by the procedure described in Examples 1 and 49, with 4-Epiphenylhydrazone A blanket was used to replace the pepper butter of Example 49A. 1H NMR (300 MHz, CDC13-CD30D) (less rotational isomers) 7.35 (2H, d, J = 8 Hz), 7.28 (2H, dd, J 2 7 Hz, 3 Hz), 6.90 ( 2H, dd J = 7 Hz, 3 Hz), 6.89 (2H, d, J = 8 Hz), 3.81 (3H, s), 3 65 UH, d, J 2 8 Hz), 3.70-3.00 (8H M), 2.92 (2.83) (3H, S), 1.50 (2H, 7-peak 5 J = 7 Hz), 0.87 (0.77) (3Η5 t, J = 7 Hz). MS (DCI / NH3) m / e 427 (M + H) +. Analytical calculations for C24H30N205 · loo H20: ，: C, 64.85; Η, 7.26; N, 6.30. Experiment 値: C, 64.82; H, 7.39; N, 6.46. Example 147: trans-WN-fluorenyl-N-propylaminocarbonylmethyl) -2- (4-fluorenazyl-monooxy)-? Ratio. Each Yodo-3-chinic acid was prepared by the procedure described in Examples 1 and 49 to replace the piperonal of Example 49A with 2,4-dimethoxybenzaldehyde. 1HNMRC300 MHz, CDC13-CD30D) (less rotational isomers) 57.61 (lH; d, &gt; 8 Hz), 7.30 (2H, d, J = 8 Hz), 6.82 (2H, d, J 2: 8 Hz), 6.55 (1H, d, J = 8 Hz), 6.45 (lH, d: J = 3 Hz), 3.90 (1Η, m), 3.81 (3Η, s), 3.79 (3Η , S), 3.77 (3Η, s), 3.70-2.90 (8H, m), 2 85 (3H, s), 1.50 (2H, seven-peak, J 2 7 Hz) '0.87 (0 77) (3H , T, J = 7 Hz). MS (DCi / NH3) m / e 471 Paper &amp; Standard Applicable to Chinese National Standard (CNS) A4g (21〇x 297 mm (Please read the notes on the back before filling this page) 552260 ^-^ h J 合 w. ^ 印 5 · ', A7 B7 V. Description of the invention (225) (M + ΗΓ. Analysis and calculation of C26H34N20.6 · 75 · 20 H20: C, 64.51; H, 7.39; N, 5.79. Experiment 値: C, 64.65; 7.07; N, 5.75. Example 14 8 Trans, trans-1- (N, N-di (n-butyl) aminocarbonylfluorenyl) -2- (4 -Phenoxyphenyl) -4- (5-benzo-2,3-dihydrofuryl) -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedure described in Examples 1 and 49, starting with 2 , 3-dihydrobenzofuran-5-carboxaldehyde to replace piperonal of Example 49A. 1Η NMR (3 00 MHz, CDC13) δ 7 · 3 1 (2Η, d, J = 8 Hz), 7.27 (1 ! 1, (1, &gt; 2 Hz), 7.18 (113 ^ 1 = 7 Hz, 3 Hz), 6.86 (211, (1, 1 = 8 Hz), 6.72 (111, (1, 1 2 8 Hz)) , 4.56 (2 ^ 1, 11 to 7 Hz), 3.78 (3H, s), 3.62 (lH, m), 3.50-3.25 (4H, m), 3.17 (2H, t, J = 7 Hz), 3. 15-2.90 (5H, m), 2.79 (1H, d, J = 14 Hz), 1.4 3 (3H, m), 1.26 (3H, m), L08 (2H, m), 0.87 (3H, t, J = 7 Hz), 0.81 (3H, t, J 2 7 Hz). MS (DCI / NH3) m / e 509 (M + ΗΓ. Calculation of the fraction of C30H40N205. 0.25 H20: ，: C, 70.22; H, 7.95; N, 5.46. Experiment 値: C, 70.21; Η, 7.92; N, 5.36. Example 149 trans, trans-1- (N, N-di (n-butyl) aminocarbonylfluorenyl) -2- (4-fluorenyloxy Phenyl) -4- (4-fluorenoxyphenyloctapyrrolidin-3-carboxylic acid was prepared by the procedure described in Examples 1 and 49, and 4-phosphonobenzoaldehyde was substituted for Piperonal. 1H NMR (300 MHz, CDC13) δ 7.38 (2Η, d, J = 8 Hz), 7.30 (2H, d, J = 8 -223- This paper is suitable for the standard] Zhongyuan National Standard (( : Milk) / \ 4 size (210 乂 297mm) (Please read the precautions on the back before filling in this page)

552260 and A 卬 A7 B7 V. Description of the invention (226 Hz), 6.87 (4H, dd, J 2 7 Hz, 3 Hz), 3.78 (3H, s), 3.76 (3H, s), 3.63 (lH, m), 3.50-3.20 (4H, m), 3.15-2.90 (5H, m), 2.78 (1H, d, J-2 14 Hz), 1.43 (3H, m), 1.27 (3H, m), 1.09 (2H, m), 0.87 (3H, t, J = 7 Hz), 0.81 (3H, t, J = 7 Hz). MS (DCI / NH3) m / e 497 (M + H) +. Analysis and calculation of C29H40N2O5 値: C, 70.13; H, 8.12; N, 5.64. Experiment 値: C, 69.78; H, 8.iO; N, 5.54. Example 150 trans, trans-1- (N, N-di (n-butyl) aminocarbonylmethyl) -2- (4-fluorenylphenyl) -4- (3,4-dimuryl) Orthopyrene-3-acid The title compound was prepared by the procedure described in Examples 1 and 49, replacing 3,4-difluorobenzaldehyde with piperonal of Example 49A. 1HNMR (300 MHz, CDC13) δ 7.35 (1H, m), 7.30 (2H, d, J 2 8 Hz), 7.20-7.00 (2H, m), 6.87 (2H, d, J = 8 Hz), 3.78 (3H, s), 3.79 (1H: m), 3.62 (1H, m), 3.50-3 30 (3H, m), 3.23 (lH, m), 3.15-2.90 (4H, m), 2.78 (lH, d, J = 14 Hz), 1.43 (2H, m), 1.27 (4H, m), 1.08 (2H, m), 0.85 (3 H, t, J-2 7 Hz), 0 · 80 (3H, t, J = 7 Hz). MS (DCI / NH3) m / e 503 (M + H) one. Analytical calculations for C28H36F2N204 · i H2 0: C, 64.60; H, 7.36: N, 5.38. Experiment 値: C, 64.59; H, 7.20; N, 5.35 〇 Example 1 5 1 trans, trans-1- (N, N-di (n-butyl) aminocarbonylmethyl) -2- (4-fluorene oxygen Phenyl) -4-(2,4-dioxophenyl) -p-biloxo-3 -polyacid-229 This paper is sized to fit the China National Standard (CNS) Λ4 Specification C 210X 297 mm) ( Please read the notes on the back before filling this page) 552260 A7 B7 V. Description of the invention (227) (Please read the notes on the back before filling this page) Prepare the title compound by the procedure described in Examples 1 and 49 In place of piperonal of Example 49A, 2,4-dimethoxybenzaldehyde was used. 1H NMR (300 MHz, 〇 &lt; 313) 5 7.37 (2gen 1> 8 Hz), 7.20 (111, (1, 2 8Hz), 6.92 (2Η, d, J = 8 Hz) , 6.60 (1Η, d, J = 3 Hz), 6.49 (1H, dd5 J = 6 Hz, 2 Hz), 5.35 (1H, d, J = 8 Hz), 4.20 (3H, m), 4.10 ( 3H, s), 3.83 (3H, s), 3.81 (3H, s), 3.75 (3H, m), 3.17 (2Η, 7-peak, J-27 Hz), 3.05 (2H, t, J-2 7 Hertz), 1.30 (4H, m), 1.07 (4H, m), 0.87 (3H? T, 1 = 7 Hertz), 0.80 (3H, t, J = 7 Hertz). MS (DCI / NH3) m / e 527 (M + H) +. Analysis and calculation of C30H42N206 · 1.30 TFAFA: C, 58.02; H, 6.47; N, 4.15. Experiment 値: C, 57.92; H, 6.43; N, 4.07. Examples 152 trans, trans-1- (N, N-di (n-butyl) aminocarbonylfluorenyl) -2-phenyl-4- (l, 3-benzo-dioxolidine-5-yl ) -Pyrrolidine-3-carboxylic acid by the procedure described in Examples 1 and 49 to prepare the title compound 'Substituted with ethyl phenylfluorenylacetate in Example 49B. 1H NMR (300 MHz, CDC13) δ 7.50 -7.25 (5Η, m), 7.04 (1Η d, J 2 3 Hz), 6.87 (111, (1 (15 &gt; 7 Hz, 3 Hz)), 6.74 (111, 1 &gt; 8 Hz), 5.94 (1H, d, J = 4 Hz), 5.92 (1H, d, J = 4 Hz), 3.85 (lH, d, J = 8 Hz), 3.64 (lH, m), 3.42 (3H, m), 3.27 (2Η, m), 3.20-2.90 (5H, m ), 2.81 (lH, d, J = 14 Hz), 1.43 (2Η, m), 1.27 (4H, m), 1.05 (2H, m), 0.85 (3 H, t, J = 7 Hz), 0 80 (3H, J 2 7 Hz), MS (DCI / NH3) m / e 48 1 (M + H) — -230- This paper describes Chuanzhong National Standard (CNS) Λ4 specification C 21 OX 297 male (Centi) 552260 A7 B7 V. Description of the invention (228

部 t-失 4J 4 fc Aίί. Analysis and calculation of C2sH36N205: c, 69.98; H, 7.55; N, 5.83. Experiment 値: C, 69.69; Η, 7.63; N, 5.71. Example 1 g trans 1-A ^ 1- (N, N-bis (n-butyl) aminocarbonylfluorenyl) -2-phenyl-4- (5-phenylhydrazone-2,3-dihydrohananyl)- p-to-p each bite 3-3-chinic acid The title compound was prepared by the procedure described in Examples 1 and 49, substituted with ethyl phenylfluorenylacetate in Example 49B, and 2,3 in Example 49A. -Dihydrophenylhydrazone-5-acid to replace piperonic acid. 4 NMR (300 MHz, CDCl3) 57.53 (2H, m), 7.40 (4H, m), 7.13 (1Η, dd, J = 7 Hz, 3 Hz), 6.72 (1Η, d, J = 8 Hz ), 5.40 (1Η, d, J = 10 Hz), 4.5 6 (2H, t, J = 8 Hz), 4.18 (1H, d, J = 14 Hz), 4.07 (2H, m), 3.79 (2H , M), 3.48 (1H, d, J = 14 Hz), 3.35 (1H, m), 3.28 (3H, m), 2.95 (2H, m), 1.47 (2H, tn), i.2 8 (4H, m), 1 · 10 (2H, m), 0.93 (3H, t, J = 7 Hz), 0 78 (3H, t, J = 7 Hz). MS (DCI / NH3) m / e 479 (M + ΗΓ. Analytical calculation of C: 29H3sN2O4 · 1.10 TFA: C, 62.04; H, 6.52; N, 4.64. Experiment: C, 61.89: H, 6.44; N, 4.57. Example 154, trans-1- (N, N-di (n-butyl) aminocarbonylfluorenyl) -2- (4-tert-butylbenzyl) -4- (5- Phenylhydrazone-2,3-dihydrocranyl) -pyrrolidine- 3-¾ acid was prepared by the procedure described in Examples 1 and 49, and in Example 49B by Krapcho et al., Syn. 47: 20 (1967). Substituted tert-butyl acetomethylacetate prepared from 4-tert-butylacetophenone and replaced with 2, in Example 49A. 3-Dihydrophenylbenzofuran- -231-This paper is a standard of Shizhou Zhongwei National Standard (CNS) Λ4 specification (2ι〇χ 297 mm (please read the precautions on the back before filling this page)

* 1T Μ ··. 552260 A7 B7) (Middle-k X;

A 5. Description of the invention (229 5-carboxaldehyde to replace piperonal. NMR (300 MHz, CDC13) δ 7.60-7.30 (6Η, m), 6.90 (1H, m), 4.50 (2H, m) , 3.95 (1H, 111), 3.85-2.95 (1 111, 111), 2.90 (111, (1,) = 14 Hz), 1.58 (2H, m), 1.50 (7H, m), 1.41 (6H, s), 1.10 (2H, m), 1.00 (3H, t, J = 7 Hz), 0.90 (3H, t, J = 7 Hz). MS (DCI / NH3) m / e 535 (M + H) +. Analytical calculations for C33H46N2 04 · 0 · 25Η20, 値 · C, 73.50; Η, 8.69: N, 5. · 19. Experimental 値 ·· C5 73.57; Η, 8.58; N, 5.14. Example 1 5 5 Trans, trans-2- (N, N-di (n-butyl) aminocarbonylmethyl) -2- (4-methoxyphenyl) -4- (4-fluorophenyl) -pyrrolidine-3- The carboxylic acid was prepared by the procedure described in Examples 1 and 49 to prepare the title compound, replacing piperonal in Example 49A with 4-fluorobenzaldehyde. 4 NMR (300 MHz, CDC13) δ 7.50 (1H3 m), 7.42 (1H, dd, J = 7 Hz, 3 Hz), 7.36 (2H, d, J = 8 Hz), 7.00 (3H, t, J = 8 Hz), 6.87 (lH, d, J = 8 Hz), 3.83 (lH, m), 3.8 (3H, s), 3.67 ( 1Η, η), 3.47 (3H, m), 3.3 0-2.9 0 (5 H, m), 2.8 2 (1 H, d, 14 Hz), 1.43 (2H, m), 1.28 (4H, m), 1 · 08 (2H, m), 0.90 (3H, i, J = 7 Hz), 0.82 (3H, t, J = 7 Hz). MS (DCI / NH3) m / e 485 (M + H) one. About C28H37FN204: C, 69.40: H, 7.70; N, 5.78. Experiment 値: C, 69.03; H, 8.00; N, 5.74. Example 1 5 6 Trans, trans-di (n-butyl) aminocarbonylmethyl ) -2- (3-furanyl) -4-U, 3-m-dioxol-5-yl) -pyrrolidine-3-carboxylic acid-232- (CNS) Λ4 specification Γ210χ297 mm) (Please read the precautions on the back before filling this page) 552260 A7 B7 V. Description of the invention (23〇) (Please read the precautions on the back before filling this page) By the example The procedure described in 1 and 49 was used to prepare the title compound, which was replaced with β-oxo-furanpropionate in Example 49B. h NMR (300 MHz, CDC13) δ 7.41 (2H, m), 6.97 (1H, d, J = 3 Hz), 6.85 (1H, dd, J = 7 Hz, 3 Hz), 6.72 ( 1H, d5 J 2 8 Hz), 6.42 (111, 5), 5.94 (111, (1, &gt; 4 Hz), 5.92 (111, (1, &gt; 4 Hz)), 3.90 (1H, m), 3.70 -3.25 (5H, m), 3.20-2.90 (4H, m), 2.85 (1H, d, J = 14 Hz), 1.43 (2H, m), 1.40-1.05 (6H, m), 0.90 (6H , M). MS (DCI / NH3) m / e 471 (M + H) +. Analytical calculations for C26H34N20 ，: C, 66.36; 7.28; N, 5.95. Experiment: C, 66.09; H, 7.24 N, 5.87. Example 157 trans, trans-1- (N, N-di (n-butyl) amine succinylmethyl) -2- (isopropyl) -4- (1,3-methylenedioxy Hepta-5pyridin-5-yl) -p-bilodine--Guino prepared the title compound by the procedure described in Examples 1 and 49, replacing it with ethyl isobutylfluorenylacetate in Example 49B. 1H NMR (300 MHz, CDC13) δ 6.85 (1Η, d, 2 Hz), 6.76 (1Η, dd7 J = 6 Hz, 2 Hz), 6.71 (1 to 0, 8 Hz), 5,92 (211, 5), 3.75 (1H, d, J = 14 Hz) 3.66 (1H, q, 1 2 7 Hz), 3.42 (3H, m), 3 25 (3H, m), 3. 1 1 (2H, m), 2.83 (1H, t, J = 7 Hz), 1.88 (] H, m), 1.55 (4H, m), 1 3 2 (4H, m), 0.92 (1 2H, m). MS (DCI / NH3) m / e 447 (M + H: T. About C25H38N205 · Analysis and calculation of 0.50 H20: 〇: C, 65.91; H, 8.63; N, 0.15. Experiment 値: C, 66.07; Η, 8.10; N, 6.03., J! A 卬 -233 Standard (CNS) A4 size C 210X 297 mm) 552260 A7 B7 V. Description of the invention (231 Example 158 trans, trans-1- (N, N-di (n-butyl) aminocarbonylmethyl) -2- ( 4-Third-butylphenyl) _4 ~ (1,3 · m-dioxolane / ¾Shaox-5_yl) -Kupirodian 0-By father described in Examples 1 and 49 To prepare the title compound, in Example 49B 4-prepared starting from 4-tert-butylacetophenone by Krapcho et al., Org. Syn. 47:20 (1 967) Tert-butylbenzyl ethyl acetate. WNMRpOO MHz, CDC13) δ 7.32 (4H, d, J = 3 Hz), 7.04 (1H, d, J = 2 Hz), 6.87 (1H, (1 (1,) = 8 Hz, 3 Hz) , 6.74 (1 ^ {, ^ 2 9 Hz), 5.94 (1 ratio (1, J = 4 Hz), 5.92 (lH, d, J = 4 Hz), 3.77 (lH, d, J = 14 Hz), 3.65-3.25 (5H, m), 3.15-2.85 (4H, m), 2.73 (1H, d, J-2 14 Hz), 1.45 (2H, m), 1.29 (13H, s), 1.0 0 (2H , M), 0.86 (3H, t, J = 7 Hz), 0.76 (3H, t, J = 7 Hz). MS (DCI / NH3) m / e 53 7 (M + HF. Analysis and calculation of C32H44N205 値: C, 71.61; H, 8.26; N, 5.22. Experiment 値: C, 71.43; Η, 8.09; N, 5.11. Example 1 5 9 • Jk in Part A (Please read the notes on the back before filling in this Page) trans, trans-1- (N, N-di (n-butyl) aminocarbonylfluorenyl) -2- (4-third-butylphenyl) -4- (5-phenylhydrazone-2, 3-Dihydrofuryl) -pyrrolidin-3-carboxylic acid was prepared by the procedure described in Examples 1 and 49, substituting ethyl isobutylammonium acetate in Example 49B, and in Example 49A 2,3 -dihydrophenylhydrazone -5-Chisui to replace pepper. 1 Η NMR (3 0 0 尨 Hz, CDC13) δ 7.3 0 (1Η, s), 7.13 (1Η, dd, J = 7 Hz, 2 Hz), 6 82 ( 1 H, d, J = 8 Hertz), 4.68 (2H, t, J = 8 Hertz), 234 This paper size is the national standard of S in China (CNS) Λ4 specification (210X 297 mm) 552260 A7 B7 Η ψ Λ Yin V. Description of the invention (232) ~ 4.48 (1Η, s), 3.19 (3Η, m), 3.80 (3Η, m), 3 48 (2H m), 3.3 (5H, m), 2.41 (1H, m ), 1.65 (4H? M), 1 44 (4H? M), 1.21 (3H, d, J = 5 Hz), 1.17 (3H, d, j = 5 Hz), j05 (6H, m). MS (DCI / NH3) m / e 445 (M + H) +. Analysis and calculation of c26H4ON20.4 • 1.2 TFA 値: C, 58.67; H, 7.14; N, 4 8 2. Experiment 値: C, 58.54; H, 7.25; N, 4.74. Example 160 trans, trans-l ^ N, N ^ (n-butyl) aminocarbonylfluorenyl pendylmethylhexyl) -4- (1,3-M-dioxolene_5_yl_ Example 160A Co-inverted and contralateral 4-methoxycyclohexyl hydrazone is designed to stir off the ipsilateral, contra--4-oxocyclohexanecarboxylic acid (5.00 in anhydrous tetrahydrofuran (50 ml) below the chamber). G, 31.6 millimoles) and carbonyl diorum ^ (6.15 grams, 37.9 millimoles, 1.2 equivalents) for 6 hours. At the same time, magnesium chloride (301 grams) was stirred in anhydrous tetrahydrofuran (75 mL) at 50 ° C. , 3 16 millimoles) and ethyl malonate potassium salt (7.52 g, 44.2 moles, 4 lux) for 6 hours. The mixture was cooled to room temperature, and the imidazole-acid mixture was pushed into it. The reaction was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was dissolved in chloroform / water. The organic phase was washed with 5% hydrogen sulfate and brine, dried over magnesium sulfate, and filtered. And concentrated under reduced pressure. The residue was purified by flash chromatography on 175 g of silica gel, eluting with 20% ethyl acetate in hexane. I-cyclohexyl on the ipsilateral and contralateral sides were obtained β- Pure soluble fraction of vinegar. Remove the solvent under reduced pressure, ρ to trans-4-methoxycyclohexyl β-ketoester (9 14 g) as a colorless oil, and a 1 already 235- paper Standards for Sichuan Chuanyuan National Standard (CNS) A4 (2ΐ〇χ 297mm (Please read the precautions on the back before filling in this page Φ! 552260

1, a part of the k iV- meaning; J 卬 A7 B7 V. Description of the invention (233 cis 4_methoxycyclohexyl β phosphonium ester (1.07 g).

Example 160B trans, trans-1- (N, N-di (n-butyl) aminocarbonylmethyl) -2- (p-4--4-oxocyclohexyl) -4- (1,3-benzo Dioxol-5-yl) -pyrrolidine-3-carboxylic acid was prepared by the procedure described in Examples 1 and 49, and in Example 49B as the contra-compound obtained from Example 160A. To replace. NMR (3 00 MHz, CDC13) δ 6.84 (1Η, d, J = 2 Hz), 6.76 (1H, dd, J = 7 Hz, 2 Hz), 6.61 (1H, d, J = 8 Hertz), 5.92 (2H, s), 3.69 (2H, m), 3.50-3.27 (5H, m), 3.26 (3H, s), 3.25-3.00 (3H, m), 2.88 (1H, m), 1.95 (2H, m), 1.62 (7H, m), 1.33 (9H, m), 0.97 (3H, t, J 2 7 Hz), 0.92 (3H, t, J = 7 Hz). MS (DCI / NH3) m / e 5 17 (M + H) —. Analytical calculations for C29H44 N2 06 · 0.5 0 H2 0: C, 66.26; H, 8.63: N, 5.33. Experiment 値: C, 66.27; H, 8.50; N, 5.13. Example 161 trans, trans-1- (N, N-di (n-butyl) aminocarbonylfluorenyl) -2- (isoside-4-methoxycyclohexyl) -4- (1,3-benzo Dioxol-5-yl) -pyrrolidin-3-carboxylic acid was prepared by the procedure described in Examples 1 and 49, and in Example 49B as the ipsilateral-compound obtained from Example 160A. To replace. NMR (3 00 MHz, CDC13) δ 6.84 (1H, d, J = 2 Hz), 6.77 (1H, dd, J = 6 Hz, 2 Hz), 6.6 1 (1H, d, J = 8 Hz), 5.92 (2H, s), 3 65 (2H, m), 3.42 (2H, m), 3.32 (3H, s), 3.30-3.00 (6H, m), 2.82 (1H, m), 2.10 (2H, m ), 1 83 (2H · m), i 52 (6H, m), 1 33 (4H, m), 1.20-1 00 (4H, m), 0 96-236-This paper is suitable for the standard / 丨] Zhongyuan National Standard (CNS) A4 size f 210X 297 mm) (Please read the precautions on the back before filling this page)

552260 A7 B7 V. Description of the invention (234) (3H, i, J 2 7 Hz), 0.91 (3Η, t5 J = 7 Hz). MS (DCI / NH3) m / e517 (M + H) +. Analysis and calculation of C29H44N2 06 · 0.3 · 20 20 Silly: C, 66.72; H, 8.61; N, 5.37. Experiment 値 · C, 66.76; Η, 8.65; Ν, 5.28. Example 162 Pentamidine di (n-butyl) aminocarbonyl (a certain fluorenyl group) -2,4_bis (5_benzy-2,3-dihydrofuryl Vpyrridine-3- # 醢 _

Example 162 A 5-Ethyl-2,3-difluorene # 咗 i To tin chloride (2.49 ml, 21.3 mmol, h2 eq) was added to the ethyl in dimuridine (30 ml).醯 Chlorine (i 64 ml, 23 mM, 1.3 equivalents) in solution and maintain the temperature at 5X: below. The solution was stirred for 15 minutes at τ, and then a solution of &lt; 2, &gt; dihydrofuran (2.00 ml, 17.7 mmol) in methylene chloride (5 ml) was added dropwise. 8 τ or less. ▲ Stir the dark red solution at 1 ° C at 2 ° C, pour 5G ml of ice water. The solution is then stirred for an additional 30 knives: &apos; and the layer &amp; is separated. The organic layer was washed with water and water-containing bicarbonate, and the magnesium silicate was dehydrated, dried, and concentrated under reduced pressure. The residue was purified by scintillation chromatography at 150% and 18% was eluted in hexane. The solvent was removed under reduced pressure to obtain a yellow solidified compound (2 68 g, 93%). Example 162 ^ '-transphenylhydrazone-Jangsan 1 yuryl) -pyridine (Please read the precautions on the back before filling this page ▼

、 1T • 丨 The paper scale side-237- A4 specification [21 〇χ 297mm] 552260 A7 B7 V. Description of the invention (235 Prepared by the procedure described in Examples 1 and 4 9 Replace with the compound obtained from Example 162A and replace it with 2, fluorene. "H Nm transdihydrobenzoxan-5 -reconstitution to replace Example 4 A Hubanfa (300 MHz, CDC13) δ 7.43 (iH , S), 7.38 (1H (2H, m), 6.75 (1H, d, J = 6 Hz), 6.70 / ^ '7 * ° 6 \ d, j, 5.40 (1H, d, J = 9 Hz), 4.58 (4H, q,: 6

Hertz), (111, (1, 14 Hz), 4.09 (211, 111), 3.82 (21111), `` 4 ,; 16 d, J 2 14 Hz), 3.38 (1H, m), 3.30-3.05 (6H m, (l ^ ~ * 9: &gt; (2H part times ;; q, J = 6 Hz)), 1.50 (2H, m), 1.30 (4H, m), 0.94 (3H, t, J = 7 Hz), 0.83 (3H, t, (DCI / NH3) m / e 521 (M + H) f. Analysis and calculation of C31H40N2c ^): C, 60.67; H, 6,27; N, 4.22 C , 60.49: H, 6.18; N, 4.13. Example 163 trans, trans-i- (N, N_di (n-butyl) aminocarbonylmethyl) -2- (3diophonic p,: ~ · , Benzo-2,3-dihydroxanyl)-? Biluodian-3-using the procedures described in Examples 1 and 49 to prepare standard life, redundant compounds, in Example 49B with β- Replace with ethyl oxo-3-furanpropionate, and dihydrobenzofuran-5-carboxaldehyde to replace piperonate of Example 49A. (300 MHz, CDCl3) 5 7.42 (lH, m), 7.38 (lti ( 1 ^ 1, 3), 7.16 (11 (1 (1 ,: ^ 7 Hz, 3 Hz), 6.70 (11 ^ Hz), 6.4 1 (1H, m), 4.57 (2H, t, J 2 7 Hz) 3% J 2 8 Hz), 3.63 (1H, m), 3.55 (1H, d, J = 14), (4H: m), 3 18 (2H: t, J = 6 Hz), 3.15-2 · 95 (3h 15 m) Ms ^ 25 tfa only test 値 · Hertz). (5. In 2, 3, and 1 H Nmr, enter 13 d, ! H, d 35〇-.25 Hi) ,, m) 2.87 -238- This paper size is suitable for National Standard Xin (CNS) Λ4 size Γ 21〇χ 297 mm

(It is said that you must read the precautions on the back before filling in this page J

552260 A7 B7 ^ ·· νΓ &quot; Ministry of Intermediate KA and MV 卬 5. Description of the invention (236 (lH, d, J 2 14 Hz), 145 (41 ^ 111), 1.35-1.10 (4H, m), 0.85 (6H, m). MS (DCI / NH3) m / e 469 (M + H) +. Analysis and calculation of C27H36N205 • 0.25 H200.25: c, 68.55; H, 7.78; N, 5.92. Experiment Hydrazone: C5 68.62; H, 7.68; N, 5.82. Example 164 is di. Transbis (n-butyl) aminocarbonylmethyl) -2- (4-methoxyphenyl) -4- (3-fluorobenzene ) -Pyrrolidin-3-carboxylic acid The title compound was prepared by the procedure described in Examples 1 and 49, replacing the piperonal in Example 49A with a 3-fluorobenzenecarboxyl blanket. NMR (300 MHz, CDC13) δ 7 · 30 (2H, d, J = 8 Hz), 7.22 (2H, m), 6.91 (lH, m), 6.86 (2H, d, J = 8 Hz), 3.79 (lH, m), 3.78 (3H, s), 3.68 (1H, m), 3.55-3.37 (3H, m), 3.29 (1H, m) '3. 1) -2.9 0 (5H, m) , 2.78 (1H, d, J = i4 Hz), L43 (2H, m), 1.25 (4H: m), 1.07 (2H, m), 0.87 (3H, t, J: 7 Hz), 0.80 (3H, t, hertz). MS (DCI / NH3) m / e 485 (A / HH) +. Analytical calculations for c2Sh37fn2o4 ··· 25Η2〇 値, c, 68 76: H, 7 73; N, 5.73. Experiment 値: c, 6S 87; 7 69; N, 5 67. Example 165 (n-butyl) aminocarbonylmethyla certain oxophenyl) _j ~ (3-pyridyl) -pyrrolidine-3- # The title compound was prepared using the procedure described in Examples 1 and 49, to = Pyridinecarboxaldehyde to replace piperonal in Example 49A. Preparing Nimev by the method of Bouguignon Temple, can j.Chem 63: 2354 (1985). 1hNMR (3 (). Megahertz, CDCl3) S8.82 (iH ,, 8.73 939- This paper is from ㈣1 〇χ— 了 -------- • 衣 ------ 1T ------ Φ— (Please read the precautions on the back before filling in this page) 552260 A7 B7 Description of the invention (237) '(111 ^ 4 拎 9 Hz), 8.62 (11 ^ (1, Bu 7 Hz), 7.78 (111, 5 (1 (1, J 2 9 Hz, 3 Hertz), 7.38 (2H, d, J = 10 Hz), 6.90 (2H, d, J = 10 Hz), 4.39 (lH, d, J = 12 Hz), 3.95 (1H, m), 3.80 (3H, s) , 3.79 (lH, m), 3.68 (lH, d, J 2 18 Hz), 3.50-3.30 (3H, m), 3.25-2.90 (6H, m), 1.47 (2H, m), 1.3 1 (4H, m), 1.20 (2H, m), 0.92 (3H, i, J = 7 Hz), 0.83 (3H, t, J = 7 Hz). MS (DCI / NH3) m / e 468 (M + H) + About the analysis and calculation of C27H37N204 • 1.65 TFA 値: C, 55.50; H, 5.94; N, 6.41. Experiment 値: C5 55.53; H, 5.90; N, 6, 27. Example 166 Anti, trans-1- (N, N-bis (n-butyl) aminocarbonylmethyl) -2- (2-fluorophenyl) -4- (Please Read the notes on the back and fill in this page again.) Borrowing an example (300 7.25 (i, 3 _ benzo-dioxo-pentanyl 5-pentyl) -port ratio p each lake _ 3 _ a few § parent by example The procedure described in 1 and 49 was used to prepare the title compound, substituting 2-fluorobenzylidene ethyl acetate in 49B

H NMR

; r part 屮 Jh); .1 f, A (1Η, m), m),, 0. About 7.11 MHz, CDC13) δ 7.52 (1H, dt, J = 7 Hz, 3 Hz), (1 仏111), 7.13 (111, (^, L = 7 Hz, 3 Hz), 7.02 (2) 1, 111) 88 (1H, dd, J = 7 Hz, 3 Hz), 6.73 (1H, d, J = 8 Hz) 93 (1H, d, J = 4 Hz), 5.92 (1H, d, J = 4 Hz), 4.25 d, J = 9 — ^), 3.68 (lH, m), 3.42 (3H, m), 3.39 (lH, 3.20-2.95 (4H, m), 2.9 1 (1 H, d, J-2 14 Hz), 1.4 5 (3 H, 1.26 (3H, m), 1.08 (2H, m), 0.87 (3 H, t, J = 7 Hz) 81 (3H, t, J = 7 Hz). MS (DCI / NH3) m / e 499 (M + H) —. Analysis and calculation of C2SH35FN205 / 0.25 H20値: C, 66.85: H, ： N, 5 57. Experiment 値: C, 66.51; H, 6.67: N, 5.18. -240- This paper is a standard SS family standard (CNS) / \ 4 in Shizhou. (210 乂 297 mm) 552260 A il- Λ i &lt; j / '/ i ji Λ fi A7 B7 V. Description of the invention (238) Example 1 6 7 Tail ~ ^ -1 (N, N-II ( N-butyl) aminocarbonyl, a methyl) _2 · (3difluorophenyl) -4- (1, j -each M-oxapentamyl-5-yl) -T? Bilodine-Efficacy The title compound was prepared by the procedure described in Examples 1 and 49, in Example 49B with 3-fluorobenzylacetic acid Ethyl ester to replace. NMR (3 00 MHz, CDC13) δ 7.38 (1H, m), 7.18 (1H, d, J 2 7 Hz), 7.15 (111, 111), 7.00 (1 ^ 1, 1 2 Hertz), 6.95 (1 Gen 111), 6.86 (1H, dd, J = 7 Hertz, 2 Hertz), 6.75 (1H, d, J = 8 Hertz), 5.93 (1H, d5 J = 4 Hertz), 5.92 (1H, d, J 2 4 Hz), 3.94 (111, (1, 12 14 Hz), 3.63 (11111), 3.42 (31 * 1, 111), 3.35-2.95 (5H, m), 2.87 (1H, d5 J = 14 Hz), 1.44 (3H, m), 1.27 (3H, m), 1.10 (2H, m), 0.88 (3H, t, J-2 7 Hz), 0.81 (3Η , T, J = 7 Hz). MS (DCI / NH3) m / e 499 (M + ΗΓ. Analysis and calculation of C2SH35 FN205 値: C5 67.45; Η, 7.08; N, 5.62. Real ... Shiyi '7.32; H, 7.05; N, 5.40. Examples 168 trans, trans-l- (4-N, N-bis (n-butyl) aminophenyl) -2- (4-methoxyphenyl) -4- (1,3-benzyldioxa Cyclopentamidine-5 -yl)-? Than each peptidyl-3 -acid acid heated in 7?% Dioxo 4-nitro-1-fluorobenzene, trans, trans-2- (4-methoxyphenyl ) -4-(1,3-benzyl-dioxol-5-yl) -p-bisanthine-ethyl 3-glycine (derived from the compound of Example 6A) and diisopropylethyl Amine to give trans, trans-methoxyphenyl) -4- (1,3-benzo-dioxolene-5-ylshoben |) -pyrrolidine-3-carboxylic acid ethyl ester. This nitro compound is hydrogenated to obtain a corresponding aminephenyl compound. According to Borch, J. Am Chem. Soc. 93: ~ b 9 7 -241-This paper is based on the National Standard of China (CNS) Λ4 Specification Γ210 乂 297 mm) (Read the precautions on the back before filling (This page)

A7 B7 552260 Description of the invention (239) (1971) The method of reacting the amine phenyl compound with butyraldehyde and cyanoborohydride to the corresponding N, N-dibutylamine phenyl compound. Using the method of Example 1D, this was hydrolyzed with sodium hydroxide to obtain the title compound. Example 169 dibis-dibutylaminopyrimidine-4-a methoxybenzyl) -4-m-dioxo-dicyclopyridine-5-yl) -p-bilodine-3 Gershon, J. Heterocyclic Chem. 24: 205 (1987) formula '2- (dibutylamino) -4-chloropyrimidine was prepared from 2,4-dichloropyrimidine and allowed to react with dioxane in dioxane. Trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazine, although cyclopenten-5-yl) · pyrrolidine-3-carboxylic acid ethyl ester (from an example The compound of 6A) is reacted with diisopropylethylamine and heated to obtain the intermediate ethyl ester.] It was hydrolyzed to the title compound with sodium hydroxide by the method of Example 1D. Examples 170-266 The following compounds were prepared using the procedures described in Examples 1, 4, 5, 7, 8, and 9, and Plan X. Case number name 170 trans, trans_2_ (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- (isopropylamine cleavage group Methyl) -pyridine pyridine-3-carboxylic acid; 17 1 trans, trans-2- (4-fluorenoxyphenyl) -4- (1,3-phenylhydrazine dioxolane-5 -Yl) -1- (Ethylaminocarbonylamidobihalate): 172 (Please read the notes on the back before filling out this page) trans, trans-2- (4-methoxyphenyl) -4- (i, 3-Benzamidinedioxol-5-yl) -1-(1-methylpropylaminocarbonylmethyl) _7 than p each bit _ 3 -1 acid: Ben__242_ ~! ^ Chinese storehouse standard (〇 阳) 8 4 specifications (210 乂 297 mm) 552260 A7 B7 5. Invention description (240) (Please read the precautions on the back before writing this page) 173 Anti-Anti-2 -(4-methoxy ^ amidino-winter mesomonolactam% 1 penten-5-yl) -1- (anilinocarbonylmethyl) -pyrrolidine-3-carboxylic acid; 174 trans, trans-2 -(4-methoxyphenyl) -4- (1,3-benzo-dioxol-5-yl) -1- (hexahydro group is methyl group)-? Billow disease- 3-carboxylic acid; 175 trans'trans-2- (4-fluorenyllactenyl) -4- (1,3-benzo-dioxopenten-5-yl) _ 1- (1- (propylamine base ) Ethyl) -pyrrolidine-3-carboxylic acid; 176 trans'trans-2- (4-methoxyphenyl) -4- (1,3-benz-dioxa perpenten-5-yl (Propylamino sulphonyl) -p-p-pyridine-3-carboxylic acid; 177 trans, trans-2- (4-fluorenylphenyl) -4- (1,3-phenylhydrazine dioxane Cyclopentene_5 _yl) _ 丨 _ (bis_ (propylaminocarbonyl) methyl) -pyrrolidine-3-carboxylic acid; 178 trans, trans-2- (4-fluorenylphenyl) -4- ( I, 3-phenylhydrazone-dioxol-5-yl) -1- (2- (propylaminocarbonyl) ethyl) -pyrrolidine-3-carboxylic acid: 179 trans, trans-2- (4 -Fluorenylphenyl) -4- (1,3-phenylhydrazone dioxolidine-5-yl) -1-(propylaminocontinylmethyl) -bibiter-3 -acid; 180 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- (2-phenethyl) -pyrrolidine -3-carboxylic acid; 18! Trans, trans-2- (4-fluorenoxyphenyl) -4- (1,3-phenylhydrazine dioxol-5-yl) -bu (pentamidine -)-Pyrrolidin-3-carboxylic acid; -243- The paper size is in the state of China (CNS) A4 specification (210X 297 mm) 552260 A7 B7 5. Description of the invention (241 (read the first Precautions (Fill in this page) 182 trans, trans-2- (4-fluorenoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- (phenylhydrazine methyl ) -Pyrrolidin-3-carboxylic acid; 183 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- (Hexyl) -pyrrolidin-3-carboxylic acid; 184 trans, trans-2- (4-fluorenyloxy) -4- (1,3-benzo-dioxol-5-yl)- 1- (2-hexynyl) -pyrrolidin-3-carboxylic acid; 185 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazine dioxolene -5-yl) -1- (propoxymethylcarbonyl) -pyrrolidine-3-carboxylic acid; 186 trans, trans-2- (4-fluorenylphenyl) -4- (1,3-phenylamidine Dioxol-5-yl) -1-(phenylethylfluorenyl) -p ratio bite-3 -renyl acid; 187 trans, trans-2- (4-fluorenoxyphenyl) -4- (1,3-Benzamidinedioxol-5-yl) -1- (anilinecarbonyl) -pyrrolidine-3-carboxylic acid; 188 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxolane: ^ · -5-yl) -1- (2-ethylaminoaminoethyl)-? Bipyridosis; complex acid; 189 trans, Trans-2- (4_methoxyphenyl) -4- (丨, 3-phenylhydrazone-dioxol-5-yl) -1- (2-phenoxyethyl ) -Pyrrolidine-3-carboxylic acid: 190 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxane *-5-yl) -1 -(2-Exhaust Dioxo / ¾Cyridinyl)-? Billokorol-3-carboxylic acid; 191 trans, trans-2- (4-methoxyphenyl) -4- (1,3- Phenylhydrazine-5-yl) -1- (2-tetrahydrofuranmethyl) -pyrrolidine-3-carboxylic acid: 192 trans, trans-2- (4-fluorenoxyphenyl) -4_ (1,3-Benzene-dioxane-244- The paper size is suitable / i] Chinese National Standard (CNS) A4 size (210X 297 mm) 552260 A7 B7 V. Description of the invention (242) Pentene- 5-yl) -1- (2- (propylaminocarbonylmethyl) vinyl) -pyrrole-3 -acidogenic; 193 trans, trans-2- (4-fluorenoxyphenyl) -4- (1 , 3-Benzamidinedioxol-5-yl) -1- (2- (propylaminocarbonylfluorenyl) ethyl) -pyrrolidin-3_S parent; 194 trans, trans-2- ( 4-methoxyphenyl) -4- (1,3-benzene # m-dioxol-5-yl) -1- (3-oxohex-1-enyl) -p ratio 17 each 〇-arsenic acid; 19 5 trans, trans-2- (2,4-dimethoxyphenyl) -4- (1,3-benzobenzodioxy &gt; heterocyclopenten-5-yl)- 1- (propylaminocarbonylsulfanyl) -pyrrolidine-3-chinic acid; 196 , Trans-2- (2-carboxy-4-fluorenyloxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- (propylaminocarbonylfluorenyl)- Pyrrolidine-3-carboxylic acid; 197 trans, trans-2- (2-aminecarboxy-4-oxophenyl) -4- (1,3-benzo-dioxol-5-yl) -1- (propylaminocarbonylmethyl) -pyrrolidine-3-acid; and C ^ -XJ in the sacrum, mixed with M · ^ 印 ^ · (Please read the precautions on the back before filling (This page) 19 8 trans, trans-2- (2-Methanoylamino-4 -fluorenylphenyl) -4- (1,3-benzo-dioxol-5-yl)- 1- (propylaminocarbonylmethyl)-. Pyrrozia-3 -Ichiic acid: 199 trans, trans-2- (2-aminocarbonylmethoxy-4-methoxyphenyl) -4- (l53-phenylhydrazone dioxolene-5- ) -L- (propylaminocarbonylfluorenyl) -coupling each -3-¾ acid: 200 trans, trans-2- (2-methoxyethoxy-4-methoxyphenyl) -4- (1,3_ -245-This paper is suitable for the National Standard of Sichuan Valve (〇 奶) 4 Specification (210 公 297 公 楚) 552260 A7 B7;, r and V. Description of the invention (243: Benzo-dioxane Cyclopenten-5-yl) -1- (propylaminocarbonylfluorenyl) -p-pyrrolidone-3 -acrylic acid; 201 trans, trans-2- (2-carboxymethoxy-4-fluorenyloxyphenyl) ) -4- (1,3-benzisodioxol-5-yl) -1- (propylaminocarbonylfluorenyl) -pyrrole-3-rumor; 202 trans, trans-2- ( 4-Methoxy-2-tetrazolylmethoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- (propylaminocarbonylfluorenyl) Dagger bite-3 -carboxylic acid: 203 trans, trans-2- (2-allyloxy-4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxolene-5 -Yl) -1- (propylaminocarbonylfluorenyl) -pyrrolidine-3-carboxylic acid; 204 trans, trans-2,4-bis (4-methoxyphenyl) -1- (propylaminocarbonylmethyl) -Pyrrolidine-3-carboxylic acid: 205 Trans, trans-2,4-bis (1,3-benzidinedioxol-5-yl) -1- (propylaminocarbonylmethyl) -pyrrolidin-3-carboxylic acid; 206 trans, Trans-2- (4-methoxyphenyl) -4- (1,3-benzo-dioxol-5-ylfluorenyl-N-propylaminocarbonylmethyl) -blocline-3 -¾ acid; 207 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-ylmethyl-N-butylaminocarbonyl) -Pyrrolidine-3-carboxylic acid: 208 trans, trans-2- (4-fluorenoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- ( Ν-methyl-N- (4-methoxyphenyl) aminocarbonyl)-? Pyrrolidine-j-residue, -246- This paper is of suitable size; 彳] Gion National Standard ([阳) 8 4 specifications (: 210 乂 297mm) (Please read the notes on the back before filling this page) 552260 A7 B7 V. Description of the invention (244)

屮 部 屮 义; J 4 a $ 卬 209 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzo-dioxol-5-yl) -1- (N-fluorenyl-N-anilinecarbonyl) -pyrrolidine-3-carboxylic acid; 210 trans, trans-2- (4-fluorenylphenyl) -4- (1,3-phenylhydrazine dioxane Cyclopenten-5-yl) -1- (N-methyl-N-allylaminocarbonylmethyl) -pyrrole-3 -acid generator; 211 trans, trans-2- (4 · oxophenyl) -4- (1,3-Benzamidine-dioxolene-5-yl) -l_ (N-methyl (n-butyl) aminocarbonylmethyl) -ρ Billotian-3-§ Parent; 212 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- (N-fluorenyl-N- Isobutylaminocarbonylmethyl) -pyridine-3-thin; 213 trans, trans-2- (4-methoxyphenyl) -4- (13-phenylhydrazone dioxolene-5 -Yl) -1- (N-methyl-N-cyclopentylaminocarbonylfluorenyl) -pyrrolidine-3-carboxylic acid; 214 trans, trans-2- (4-methoxyphenyl) -4- ( 1,3-phenylhydrazone-dioxolenyl-5-yl) -bu (N-fluorenyl-N- (2-fluorenylethyl) aminecarbonyl) -p Biha-3-carboxylic acid; 2 15 trans, trans-2- (4-fluorenoxyphenyl) -4- (1,3-benzo-dioxol-5-yl) -1- (N-methyl-N-but oxygen Amine carbonyl) pyrrolidine-3-carboxylic acid; 216 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-ylmethyl -N-propylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid; -247- Standard description of this paper / 彳] China National Standards (CNS) Λ4 specification f 210 乂 297 male f) (Please read the back first Please fill in this page for the precautions I ..... --- In · --- -1 ----nn I ml i. Hu I--、 一--1 = 1 I--i-n Is 11 I! -I ---- 1-552260 A7 B7 V. Description of the invention (245) (Please read the notes on the back before filling out this page) 217 trans, trans-2- (4-methoxyphenyl)- 4- (1,4-phenylhydrazone dioxolane-6-ylmethyl-N- (2-fluorenylethyl) aminecarbonyl) -pyrrole-3 -polyacid; 2 18 trans, trans-2- (4-Methoxyphenyl) -4- (1,3-m-m-dioxocyclopenten-5-yl) -1- (N-methyl-N-isopropylaminocarbonylmethyl) -pyrrole Pyridin-3-carboxylic acid; 2 19 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) · 1- (Ν -Methyl-N-ethylaminocarbonylmethyl) -pyrrolidone-3 -October; 220 trans, trans-2- (4-fluorenylphenyl) -4- (1,3-benzo-dioxo Heteropenten-5-yl) -1- (N- Methyl-N- (l-methylpropyl) aminocarbonylmethyl) -p-bilodine-3 -No: 221 trans, trans-2- (4-amidooxyphenyl) -4- (1,3 -Phenylhydrazone dioxol-5-yl) -1- (N · fluorenyl-N-benzene, aminocarbonylmethyl) -pyrrole-3-double acid; 222 trans, trans-2 -(4-fluorenylphenyl) -4- (1,3-benzo-dioxol-5-yl) -1- (1- (N-fluorenyl-N-propylaminocarbonyl) ethyl ) -Pyrrolidin-3-carboxylic acid; 223 trans, trans-2- (4-fluorenoxyphenyl) -4- (1,3-phenylhydrazinedioxol-5-yl)-: 1- (α- (N-methyl-N-propylaminocarbonyl) fluorenyl) -π Bihadian-3 -metanoic acid; 224 trans, trans-2- (4-fluorenoxyphenyl) -4- ( 1,3-Benzamidinedioxol-5-ylethyl-N-propylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid: -248- This paper is in accordance with Zhongzhou National Standard ((: Yang) / \ 4 specifications (210 乂 297) 牦 552260 A7 B7 V. Description of the invention (246) (Please read the precautions on the back before filling this page) 22 5 Anti'Anti-2- (4- Methoxyphenyl) -4- (1, j &gt; -Winter bis-dioxopentene-5 · ylethyl-N-butylaminocarbonyl) -pyrrolidine-3-carboxylic acid; 226 trans, trans -2- (4-methoxyphenyl) -4- (1, 3-Benzamidine-dioxol-5-yl) -1- (N-ethyl-N- (4-methoxyphenyl) aminecarbonyl) -Rhobia-3 -acid; 22 7 trans, Trans-2- (4 -pyridinyl) -4- (1,3 -pentamethylene-5-pentyl-5-phenyl) -1- (N -ethyl-N-private Radical) -port ratio ρ_3-carboxylic acid; 2 2 8 trans'trans-2- (4-methoxyphenyl) -4- (1,3 -epi-di-diaminomethylpentane-5 -Yl) -1- (N-ethyl-N-propylamine aminomethyl) -p each bite -3-caused; 22 9 trans'trans-2- (4-methoxyphenyl) -4 -(1,3-Phenylhydrazinepenten-5-yl) -1- (N-ethyl-isobutylaminocarbonylmethyl) -pyrrole-3 -read ^; 2 3 0 Trans'trans-2- (4-methyllactamyl) -4-(1,: &gt; -total and pentyl-5-yloxypentyl-5-yl) -1- (N-ethyl-N- Cyclopentylaminocarbonylammonium) -Hydroxypyridine-3 -Re-acid; 2 3 1 trans, trans-2- (4-methoxyepiyl) -4- (1,]-Winter and &gt; Mono-androstapenten-5-yl) -1- (N-ethyl · N-methoxyethylaminecarbonyl) -pyridoline-3-chinic acid; 232 trans, trans-2- (4-methyl Oxyphenyl) -4-(], 3-phenylhydrazone dioxol-5-ylethyl-N-butoxyethylamine carbonyl Wc each bite -3-acid;- 249-L scale conforms to national standard (CNS) A4 specification (210X297 mm) 552260 A7 B7 V. Description of the invention (247) 233 Trans, trans-2- (1,3-benzodioxolene-5) -Yl) -4- (4-fluorenoxyphenyl) -1- (N-ethyl-N-propylaminocarbonylfluorenyl) -pyrrolidin-3-carboxylic acid; 2 3 4 trans'trans-2- (4-Pyridoxyphenyl) -4- (1,4-benzodioxoline-6-yl) -1- (N-ethyl-N-propylaminocarbonylfluorenyl) -pyrrolidine-3_carboxy Acid; 2 3 5 trans, trans-2- (4--oxophenyl) -4- (i, 3-phenylhydrazine dioxandoxen-5-ylethyl-N-isopropylaminocarbonyl ) -Pyridine p-bite-3 -acid generator; 236 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzo-dioxol-5-yl) -i- (N, N-diethylaminocarbonylfluorenyl) -pyrrolidine-)-treason; 237 trans, trans-2- (4-methoxyphenyl) -4- (i, 3-benzo M-dioxol-5-yl) -1- (N-ethylmethylpropyl) aminocarbonylfluorenyl) -huan bite-3 -carboxylic acid; 238 trans, trans-2- (4- Methoxyphenyl) -4- (1,3-phenylhydrazone dioxane-5-yl) -1- (N-ethyl-N-anilinocarbonylfluorenyl) -pyrrole-3 -Read_; 部 屮 AI 』(Please read the notes on the back first Fill out this page again) 239 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzo-dioxol-5-yl) -1- (1- (N -Ethyl-N-propylaminocarbonyl) ethyl) -orbital bite-3 -rebel: 240 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone M-dioxetylcyclopenten-5-yl) -1- (α- (N-ethyl-N-propylaminocarbonyl) fluorenyl) -orbitalol-3 -acidic acid; -250- paper Standard Shizhou t-net national standard apple (CNS) Λ4 specifications [210 × 297 mm] 552260 A7 B7 V. Description of invention (248) JA i in the ministry; j

A 241 trans, trans-2- (4-fluorenoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-ylfluorenyl-N-isobutylaminocarbonylfluorenyl) -Pyrrole-3-acid; 242 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzo-dioxol-5-ylmethyl-N- Cyclohexylaminocarbonylmethyl) -pyrrolidine-3 -acid generator; 243 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxolene -5-yl) -1- (N, N-dipropylaminocarbonylmethyl) -pyrrolidine-3 -chinic acid; trans, trans-2- (4-methoxyphenyl) -4- (1,3 -Phenylhydrazine-5-yl) -1- (isobutoxyethyl) -pyrrolidine-3-carboxylic acid; trans, trans-2- (4-methoxyphenyl)- 4- (1,3-Benzamidinedioxol-5-yl) -1- (butylsulfonyl) -pyrrolidine-3-carboxylic acid: trans, trans-2- (4-form Oxyphenyl) -4- (1,3-benzo-dioxol-5-yl) -1- (isopropylsulfonamidoethyl) -pyrrolidine-3-carboxylic acid; 247 Trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazine dioxocycline-5 -yl) -1- (ethoxyfluorenylsulfenyl)-? Biloxi-3-¾ §Yttrium; 248 trans, trans-2- (4-fluorenoxyphenyl) -4- (1,3-phenylhydrazone dioxolene -5-yl) -1- (2-ethylbutyl_fluorenyl) -pyrrolidine-3-carboxylic acid; 249 trans, trans-2- (4-methoxyphenyl) -4- (1,3- Phenylhydrazine-5 -yl) -1-(N -fluorenyl-N-(3,4-dimethoxymethyl) amine 244 245 246 -251-suitable for this paper II] Chinese National Standard (CNS) Λ4 specification (210 X 297 mm) (Please read the precautions on the back before filling out this page) 552260 A7 B7 V. Description of the invention (249)

A-carbonylcarbonyl) -pyrrolidine-3-carboxylic acid; 250 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzo-dioxolane-5- Group) -1-[(111) -1-(&gt; 1-methyl- &gt; ^ propylaminocarbonyl) butyl] -p birlobito-short, 2 5 1 trans, trans-2- ( 4- (methoxyphenyl) -4- (1,3-benzo-monooxy) pentene-5-yl) -l-[(lS) -l- (N-fluorenyl-N-propylaminocarbonyl) Butyl] -p-pyrrole-3 -acrylic acid; 252 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzisodioxol-5-yl ) -1- (3-isopropoxypropyl) -ρΛρ each bite-3-Junic acid; trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzo metadi Oxopent-5-yl) -1- (5-methylhexyl) -pyrrolidine-3-carboxylic acid; trans, trans-2- (4-methoxyphenyl) -4- (1,3- Benzo metadioxolene-5-yl) -1- (5-methyl-2-hexenyl) -pyrrolidine-3-carboxylic acid; 255 trans, trans-2- (4-methoxy Phenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- (5-methyl_4-hexenyl) -pyrrolidin-3-carboxylic acid; 256 Trans, trans-2- (4-fluorenoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- (3,5-dimethyl-2- Hexyl) -pyrrolidin-3-carboxyl : 257 trans, trans-2_ (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) methyl-N-isobutylamidinoamino) ethyl) -peach disease- ^ -Read _ S Yi, 25 3 254 -252- This paper applies the national standard (CNS) Λ4 specification (210X 297 mm) according to the standard (Please read the precautions on the back before filling in the transcript Page) 552260 A7 B7 Part K $ 5. Description of the invention (25〇258 trans, trans-2- (4-fluorenylphenyl) -4- (I, 3-phenylhydrazone dioxolene-5 -Yl) -1- (N-fluorenyl-N- (2,2-dioxopropyl) aminocarbonylmethyl) -p-pyrrole-3 -unsaturated acid; 259 trans, trans-2- (4- Phenoxyphenyl) -4- (1,3-benzo-dioxol-5-yl) -1- (N-ethyl-N-butylaminocarbonylmethyl) -pyrrolidine-3 -Carboxylic acid; 260 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazinedioxopenten-5-yl) -1- (N-fluorenyl- N-fluorenylaminocarbonylfluorenyl) -pyrrolidine-3-carboxylic acid; 261 trans, trans-2- (4-fluorenoxyphenyl) -4- (5-hydroindenylmethyl-N-propylaminocarbonyl Fluorenyl) -pyrrolidin-3-carboxylic acid; 262 trans, trans-2- (4-fluorenyloxyphenyl) -4- (2,3-dihydrophenylfluoren-5-yl) -l- (N -Fluorenyl-N-propylaminocarbonylmethyl) -pyridine Pyridin-3-carboxylic acid; 263 trans, trans-2- (4-fluorenoxyphenyl) -4- (1-fluorenylsulfan-5-yl) -1- (N-fluorenyl-N-propylamino Carboxyfluorenyl) -pyrrolidine · 3-carboxylic acid; 264 trans, trans-2- (4-fluorenyloxy) -4- (2-fluorenyl) -1- (N-fluorenyl-N-propylamino Carbonylmethyl) -pyrrolidine-3-carboxylic acid; 265 trans, trans-2- (4-methoxyphenyl) -4- (1,2-dimethoxy-4-phenylmethyl-N- Propylaminocarbonylfluorenyl) -pyrrolidine · 3-carboxylic acid; 266 trans, trans-2- (4-fluorenyloxyphenyl) -4- (1-fluorenyloxy-3-phenyl) -1- (N -Fluorenyl-N-propylaminocarboxyfluorenyl) -pyrrolidine-3-carboxylic acid; Examples 267-288 According to the procedures described in Example 1 and Plan II, the following chemical compounds can be synthesized -253- W Chinese National Standard (CNS) Λ4 specification (210X297 mm) (Please read the precautions on the back before filling out this page) 552260 A7 B7 V. Description of the invention (251 compounds: 267 268 269 270 270 271 272 27:

4 :; part λ meaning: J 274 275 trans, trans-3- (4-methoxyphenyl) -5- (I, 3-phenylhydrazone dioxol-5-yl) -1- ( Propylamino fluorenyl) -hexahydro p-pyridine-4 -chinoic acid; trans, trans-3- (4-fluorenoxyphenyl) -5- (1,3-phenylhydrazone dioxolene- 5-yl) -1- (aminocarbonylmethyl) -hexahydropyridine-4-carboxylic acid; trans, trans-3- (4-methoxyphenyl) -5- (1,3-phenylhydrazine Oxepin-5-yl) -1- (4-pyridinylpyridine π Biyodo-4-rebellion '; trans, trans-3- (4-oxophenyl) -5- (1 , 3-Benzamidine-dioxol-5-yl) -1- (2-ethoxyethyl) -hexahydropyridine-4-carboxylic acid; trans, trans-3- (4-methoxybenzene ) -5- (1,3-phenylhydrazone dioxolidine-5-yl) -1- (2-propoxyethyl) -hexahydropyridine-4-carboxylic acid, trans, trans- 3- (4-methoxyphenyl) -5- (1,3-phenylhydrazone-dioxol-5-yl) -1- [2- (2--oxoethoxy) ethyl] -Hexahydropyridine-4 -n; trans, trans-3- (4-methoxyphenyl) -5- (1,3-phenylhydrazone dioxol-5-yl) -1- [ 2- (2_pyridyl) ethyl] • hexahydropyridine-cardiocarboxylic acid; trans, trans-3- (4-fluorenylphenyl) -5- (13-phenylhydrazine-dioxolane- 5-base ) -1-(? 4-4 -ylcarboxyl) -hexahydro p ratio bite-4 -polyacid; trans, trans-3- (4-fluorenylphenyl) -5- (1,3-benzo Dioxane 戍 -5 -yl) -1-(butylamino)-rat p than bite -4-complex, -254- paper size Xiao / 彳] Chinese National Standard (CNS) Λ4 specifications (210X 297 public dredging) (Please read the precautions on the back before filling out this page) 552260 A7 B7 V. Description of the invention (252; r Part 乂; j JT f- A 卬 276 Anti, anti-3- (4- Methoxyphenyl) -5- (1,3-benzisodioxol-5-yl) -1- (4-methoxyphenylaminecarbonyl) -3-hexahydropyridine-4-lean Acid; trans, trans- (4-methoxyphenyl) -5- (1,3-phenylhydrazone dioxol-5-yl) -1-ethenylhexahydropyridine-3-carboxylic acid ; Trans, trans-3- (4-fluorenoxyphenyl) -5- (1,3-benzo-dioxol-5-yl-kivranylsulfonyl) -TT-nitropyridine-3- Reacid; trans, trans-3- (4-methoxyphenyl) -5- (1,3-benzo-dioxol-5-yl) -1- (anilinyl) -ττ Nitrogen is better than bite-4-, trans, trans-3- (4-fluorenylphenyl) -5- (1,3-phenylhydrazone dioxol-5-yl) -1- ( Allylaminocarbonylmethyl)- Hydropyridine-4-carboxylic acid; 281 trans, trans-3- (4-methoxyphenyl) -5- (1,3-phenylhydrazone dioxol-5-yl)-〗-(n -Butylaminocarbonylfluorenyl) -hexahydropyridine-4-carboxylic acid; 282 trans, trans-3- (4-fluorenoxyphenyl) -5- (1,3-benzo-dioxolene -5-yl n-butyl-N-methylaminocarbonylfluorenyl) -hexaaza p-ratio-4-, 283 trans, trans-3- (4-methoxyphenyl) -5- (M-benzene Hydrazone dioxol-5-yl) -1- (pyrrolidin-1-ylcarbonylmethyl) -hexahydropyridine-4-carboxylic acid: 284 trans, trans-3- (4-fluorenoxybenzene ) -5- (1,3-Benzo-dioxol-5-yl) -1- (isobutylaminocarbonylfluorenyl) -hexahydropyridine-4- 277 278 279 280-255- The size of this paper is suitable / 丨] 屮 National Standard (CNS) Λ4 Specification C 210X 297 mm) (Please read the precautions on the back before filling this page) 552260 A7 B7 V. Description of the invention (253) Carboxylic acid; (Please Read the notes on the back before filling this page) 285 trans, trans-3- (4-methoxyphenyl) -5- (1,3-phenylhydrazone dioxol-5-yl) -1 -(Cyclopentylaminomethylhexahydropyridine-4-renyl acid; 286 trans, trans-3- (4-methoxyphenyl) -5- (1,3-benzo-dioxo Cyclopenten-5-yl) -1- (morpholin-4-ylaminocarbonylmethyl) -hexahydropyridine-4-carboxylic acid; 287 trans, trans-3- (4-methoxyphenyl)- 5- (1,3-Benzo-dioxolane-5-yl) -1- (2-phenoxyethyl) 7T p-oropod-4-polyacid; 288 trans, trans- 3- (4 • methoxyphenyl) -5- (1,3-phenylhydrazone dioxol-5-yl) -1- (methoxyethylaminocarbonyl) -hexahydropyridine-4 -Carboxylic acid; Example 289 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- (4-dibutyl Aminopyrene)-? Pyrrolium-j-multipyrene heating 4-nitro-fluorobenzene, trans, trans-2- (4-oxophenyl-4- (1, 3-Benzamidine-dioxol-5-yl) -pyrrolidine-3_carboxylic acid ethyl ester (Example 6A) and diisopropylethylamine to give trans, trans-2- (4- Phenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- (4-nitrophenyl) -pyrrolidine-3-carboxylic acid ethyl ester. This nitro compound is hydrogenated to the corresponding amine-phenyl compound. According to the method of Borch (J. Am Chem. Soc., 93, 2897, 1971), it is reacted with butyraldehyde and sodium cyanoborohydride to obtain a phase. The corresponding N, N-dibutylamine phenyl compound was hydrolyzed with sodium hydroxide using the method of Example 1 D-256- This paper is suitable for the National Standard of Sichuan S (CNS) Λ4 specification f 210 乂 297 ^) 552260 # 部 中 λ ^ Γ ^ -i ·; · ^ A 合 wy 卬; ^ A7 B7 V. Description of the Invention (254) The title compound was obtained. Example 290: 4- (1,3-benzyl #digas heterocycle) on trans A: AiLi methyl phenyl; -1- (2-amino 7 Each bite-3-metanoic acid ^ According to the method of Gershon (J. Heterocyclic Chem. 24, 205, 1987), 2- (dibutylamino) -4-chloropyrimidine was prepared from 2,4-chloropyrimidine. Heating the compound in dioxane, trans, trans_2_ (4_methoxyphenyl) benzyldioxo, although cyclopenten-5-yl) ** pyrrolidine-3-carboxylic acid ethyl ester (example 6A) and diisopropylethylamine to give the intermediate ethyl ester, which was hydrolyzed with sodium hydroxide by the method of Example jD to give the title compound. Example 29i Phenyl) -4- (1,3-phenylhydrazine-dioxolene-N-anilinofluorenyl) -17 Bihadien-3-guinic acid The title was prepared according to the common procedure of Example 1 Compound. NMR (CD3OD): δ 0.87 (t, 3H, J-8); 1.2-1.35 (m, 2H); 1.35-1.5 (m, 2H); 2.78 (m, 2H); 3.10 (t? 1H, J = 9); 3.26 (d, 1H? J = 15); 3.44 (dd, 1H, J 2: 5, 10); 3.5-3.7 (m, 3H); 3.77 (m, 1H); 3.78 (s, 3H); 5.93 (s, 2H); 6.7-6.9 (m, 4H); 7.0- 7.2 (m, 3H); 7.4 (m, 3H). MS (DCI / NH3) m / e 531 (M + H plant. Analytical calculations for C3iH34N2 06: 値: C, 7〇. 17; H, 6.46: N, 5.28. Experiment 値: C, 70.36 ·: H, 6.52; N, 4.99. Example 292 Oxyphenyl) -4- (1,3-benzo-dioxol-5-yl-p-butyl) aminopyridyl) -7Bilodo- 3-Sodium acid f Please read the notes on the back first

552260 A7 B7 Shao Zhongk f. A ί E. Description of the invention (255 't case 2 9 plex h_ (4-methoxy_vegetyl) _3_ ethylpropionate in a 65-liter reactor and 35-liter The reaction was carried out simultaneously in the reactor, which had the same reflux system. The nitrogen gas pressure was maintained in both. Filled with 4 · 00 kg (100 旲) of 60% sodium hydride in accumulation oil and 32 liters of toluene. Into the reactor at ambient temperature. Stir the mixture for 5 minutes and allow it to stand. Aspirate 20 liters of toluene solution. Add 28 liters of toluene, stir and stir) for a few minutes and allow to stand, then aspirate. 28 liters of toluene solution. Add 68 liters of formazan and 84 liters (69.7 mol) of diethyl carbonate. Start agitation and start the Syhherm flow on the reactor sleeve (Note 4). At 20 minutes R, 50 kg (33 3 mols) of [Tick Acetylphenylbenzene] in 12 liters of toluene was added, the sleeve temperature was lowered to 10 t, and stirring was continued for 16 hours to compare with the first A B The same rate was used for fluorenone, which was fed with 6.7 liters (U 7 moles) of glacial acetic acid in 23 liters of water. When the additive effect is 7G, the ITO stops / sees the 4 sub-sub-separation levels. The layer was rinsed with 13 liters of toluene. The mixed organic layer was washed twice with 67 liter portions of 7% (weight: weight) aqueous sodium bicarbonate. Rinse the ammonium solution once with 6 7 liters of 23% (by weight) water sodium chloride. The organic solution was dehydrated with 10 kg of sodium iodide, filtered, and the solvent was removed on a rotary evaporator to obtain the desired product. Example _j92B_ —-4 &quot; ^ Nitrovinyl) -Benzene • One hundred volt anchor stirrer 45_ liter low temperature reactor at 1: &gt; -〇C r kg (36 9 mol) Piperonal dissolved in 9 liters of wood paper ruler (please read the precautions on the back before reading and writing this page) -258- 552260 A7 B7 V. Description of the invention (256

Department T .T &gt; / ί 合 卬 V (Please read the notes on the back before filling out this page) Methanol and 2.252 kg (3 6.9 moles) of nitropane. Set the sleeve temperature to -5 Ό and cool the reaction solution to +3.5 X :. Pump a solution of 3.10 kg (38.8 mol) of 50% (weight: weight) aqueous sodium hydroxide diluted in 3.7 liters of water at 21 ° C. The reaction temperature was maintained between 10 and 15 ° C. When the addition is complete, set the casing temperature to 1 I again, and continue to teach for 30 minutes. Add 7 kg of ice mixture in 19 liters of water to dissolve most of the solids. The reaction mixture was filtered through canvas and then through a 27R10SV droop filter. The filtered solution was calculated as a 21 ° C mixture of 7.4 liters of concentrated IL chloric acid in Π · 1 liters of deionized water. The final reaction temperature was 2 6 C. The resulting product was centrifuged and rinsed until the pH of the rinse solution was raised to at least 6 (by means of pH 値 indicator paper). The crude product was dissolved in 92 liters of digas and the layers were separated. Rinse the solution once with 8 liters of chloroform. The mixed organics were dehydrated with 1 3 2 kg of broken acid 锾 and passed through Whatman # 1 遽 paper. Reduce the volume to 20% and cool the solution to 4 ° C. It was filtered through Whatman # 1 filter paper, and then dehydrated at ambient temperature in the airspace with leaky seams to obtain the first harvest of 1.584 kg (22%). Concentrated with MLS to 25%, followed by the same cooling, filtration and dehydration, to obtain 0.262 kg (4%) of the second harvest 3, which is left under light and air, and the yellow product will become dark °

Example 292C Ethyl 2- (4-methylphenylbenzyl) -3- (1,3-phenylhydrazone dioxol-5-yl) -4-nitrobutanoate at ambient temperature, Charge 5.619 kg (30.1 mol) of 3,4-methylenedioxy-1-(2-nitrovinylbenzene and 24 liters of ethyl acetate into 45-liters through -259. Weiwei National Standard (CNS) M specification (2H) x 297 mm) 552260 A7 B7, &gt; '4 \

S f: /-, 5. Description of the invention (257 stirred reactor. 5.3 5 5 kg (24.1 mole) 3- (4-fluorenylphenyl) -3- in 16 liters of ethyl acetate) A solution of ethyl oxopropionate. Over a period of 2.5 hours, 280 g (275 ml, 2.84 moles) of 1,8-diazobicyclo [5.4.0] undec-7- The ene was passed through dicalite; considering the reaction mixture, the resulting filtered solution was used directly in the next step without further purification.

Example 292D 2_ (4_ 甲 乳 表 基) _4_ (1,3_Pyramid dioxane daughter-in-law-5 -based) -4,5 -_——-3ΙΊ · mouth to mouth _ 3-定 定§ Father Ethyl is intended to produce the product of Example 292C (13 16 ml solution, including 300 g of 2- (4-methoxymethylfluorenyl) -3- (3,4-fluorenyldioxyphenyl) -4-nitrate Ethyl butyrate) was charged to a glass reactor containing RaNi # 28 (300 g). The reaction mixture was shaken at room temperature under a hydrogen atmosphere of 4 atmospheres for 18 hours and filtered through a 0.20 micron 47 mm micropore of nylon. The mash was concentrated to a dark solution of 1.4 kg and purified by normal phase gel chromatography and eluted with 85:15 hexane: ethyl acetate. The pure fractions were mixed and concentrated (as above) until crystals formed. The solution was cooled to 0 ° C and filtered. Rinse the solid with 2 liters of 85: 1 5 hexane: ethyl acetate (0 ° C). The solid was dehydrated in a radon atmosphere at 50 ° C to a constant weight of 193.4 g (21% yield, melting point 80-8 1 ° C) of the title compound. An additional 200 grams (23% yield) of product was obtained from the mother liquor.

Example 292E 2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -pyrrolidine-3-carboxylic acid ethyl ester-260 Use national valve national standard (0 $) / \ 4 specifications (210 乂 297 mm) (Please read the precautions on the back before filling this page) ii 552260 A7 B7 Part λ and

A 5. Description of the invention (258) In a 12-liter flask equipped with a magnetic stirrer, an addition funnel, a temperature probe and a nitrogen inlet, 0.460 kg of 2- (4-methoxyphenyl) -4- ( 3,4-Fluorenyldioxyphenyl) -4,5-dihydro-3H-pyrrole-3-carboxylic acid ethyl ester (1.25 moles). The reaction vessel was degassed with nitrogen. Add anhydrous 3.7 liters of ethanol and 1.12 liters of THF. 31 mg of bromocresol green and 94.26 g of sodium cyanohydrochloride (1.5 mol) were added. Then a solution containing 400 ml of absolute ethanol and 200 ml of 12M HC1 was added. After the addition was completed, the reaction mixture was stirred for 30 minutes. After the starting material was consumed, 0.5 liters of 7% aqueous NaHC03 was added. The reaction mixture was concentrated and diluted with 5 liters of ethyl acetate. Rinse the organic layer twice with 2 liters of 7% aqueous NaHC03, and once with 2.5 liters of 23% aqueous 1%, cover with 190 g &gt; &gt; ^ 80, dehydrate, filter and concentrate 447 g of the title compound were obtained as a viscous yellow oil.

Example 292F 2- (4-Phenoxyphenyl) -4- (1,3-benzo-dioxol-5-yl) -1- (N, N-bis (n-butyl) amine Carbonylmethyl) -pyrrolidine-3-carboxylic acid ethyl ester In a 22-male flask equipped with a top stirrer, a radon inlet and a condenser, 2- (4-methoxyphenyl) -4 -(3,4-Methylenedioxyphenyl) -pyrrolidine-3-carboxylic acid ethyl ester (2.223 kg, 6.02 moles). The reaction vessel was degassed with nitrogen. Add 13.2 liters of acetonitrile, 3 66 liters of diisopropylethylamine (2.71 kg, 20.9 mol), and 1.567 kg of dibutylphosphonium methyl bromide (6.26 mol). The mixture was refluxed at 78 ° C for 17 hours. After the starting material disappeared, the mixture was concentrated until crystals formed. The solid was filtered and rinsed with 4 liters of ethyl acetate (0 ° C). Continue to concentrate the filtrate as above until all volatiles are removed. Dilute the residue with 40 liters of ethyl acetate -261-this paper &amp; appropriate size / 彳] Chinese National Standard (CNS) Λ4 size (210X 297 mm) (Please read the precautions on the back before writing this page) 552260 A7 B7 V. Description of the invention (Λ * Μ 中 in 259, and rinse with 20 liters of deionization. Rinse the organic layer with 8 liters of 23% water-containing NaCi, cover with 0.399 kg of MgSCU, and dehydrate and filter. Concentrate as above to obtain 3.112 kg (96% yield) of the title compound as a dark oil. Example 292G Trans, trans-2- (4-methoxyphenyl 3-benzodilactin per · penten-5-yl) _ Bamboo syndromes-3- # double acid salt, trans-2- (4- hydrazone phenyl) -heart (3,4-dioxophenylpyrrolidine-3 · # acid ethyl ester Junjun · In a 35-liter reactor equipped with a top stirrer, a nitrogen inlet and a condenser, 3.112 kg of 2- (4-methoxyphenyl) -4- (3,4-fluorene dioxane Phenyl) -pyrrolidine-3-carboxylic acid ethyl ester (5.78 moles), 16.4 liters of absolute ethanol was added, and the reaction vessel was degassed with nitrogen. 0.115 kg of sodium ethoxide (1.69 moles) was added. ) And reflux at 79 ° C The mixture was allowed to cool for 1 hour. The mixture was cooled to 15 ° C. and 5 liters of 7. 6 M N a Η liquid (3 8.1 mol) was added. The mixture was stirred off at 15 ° C for 18 hours. The residue was dissolved in 15.8 liters of deionized water and extracted with 28 liters of ether. The ether solution was rinsed with 9.5 liters of deionized water. The aqueous rinse was extracted with 3 liters of ether. 0.340 liters of 12M HC1 was added to The liquid layer was extracted with 24 liters of ethyl acetate. The organic layer was rinsed with 9 liters of 23% water-containing MaCl, dehydrated with 0.298 kg of MgS04, filtered, and concentrated to a 2 2 kg dark oil. The oil was mixed with 18 liters of diethyl ether were developed together. Unwanted solids were filtered and saved for later use. The mother liquor was concentrated to obtain 1.102 kg of light-colored foam. The foam was dissolved in 5.5 liters of ethyl acetate and heated to 65 ° C. Add 14 liters of hexane slowly enough to keep the solution refluxing. Cool the reaction mixture to 10 ° C and filter it. (Please read the precautions on the back before filling this page) Order f -262- Pizhou Zhongyuan National Standard (CNS) A4 Specification f 210 X 297 mm) 552260 A7 B7 V. Description of the invention (26〇) —---- Ether (0 C) Rinse and crystallize, and dehydrate to constant weight in the air at 50 ° C to obtain 0.846 kg (43 % Yield, melting point 119-120. The crude product can be further purified by normal phase gel chromatography. Example 292H Benzene D ^-(l, 3-benzene # m-dioxane ^ 111 :. (Team, --Shifang n-butyl) aminocarbonylmethyl) -pyrrolidine-31: ^^ A 2 0-liter flask was charged with trans, trans 2- (4-fluorenoxyphenyl)> 4- (3,4-methyldioxybenzyl) -1- (N, N-dibutylamino-carboxymethyl) Gibpyrrolidine-3 edge acid (0 927 kg, 1.819 mol). A solution of 0.070 kg NaOH (1.80 mol) dissolved in 4.65 liters of methanol was added. The reaction mixture was concentrated to form Add pentamidine (4) and concentrate the solution again. Add glutamate (4 liters) and then> Chen Huayuan> Valley, to light yellow brown bubbles. In the air, at 50 ° C The foam was dehydrated to a counter-example of a selective compound having a weight of 903 kg (97% yield). 293_ j-2- (4 -Phenoxyphenyl) -4- (1,3- 笨 # 间 二Gas Miscellaneous)-&gt; [Decahydroisoquinolinyl-2-carboxymethylpyrrolidine- ^: acid • group (Please read the precautions on the back before filling this page)

In Part 1T Aii, the procedure described in Example 1 was used to prepare the title compound. NMR (CD30D, 300 MHz) showed a mixture of isomers. (Dci / nh3) m / z; 521. Analysis and calculation of c3GH36N206 · 1 · 3 TFA 値: 58, 58 54; H, 6 62; N, 4.19. Experiment 値: C, 58, 34; H, 5.58; 400. Example 294_yl-2- (4 -fluorenyloxyphenyl) _4_ (l3 · benzene ^^. 5- ^ 1- 丄:. [3 Hexapine, less radicals? Better than rabbits ^ 3-reading acid-263- Dimensions of this paper /!] China National Standards (CNS) Λ4 specification f 210X 297 public 筵 Τ 552260 A7 B7 V. Description of the invention (261

I

f A The procedure described in Example 1 was used to prepare the title compound. NMR (CDsOD, 300 MHz) showed the presence of rotamers. s 0.84 (S, 3H), 0.86 (s5 3H), 1.35- 1 · 6 (m, 4H), 3.83 (s, 3H), 5.96 (s, 2H), 6.81 (d, 1H, J = 8), 6.90 (dd, 1H, J = 1, 8), 7.01 (d, 2H, J = 9), 7.03 (s, 1H), 7.47 (d, 2H, J: 9). MS (DCI / NH3) m / z 495 (M + H) +. Analysis and calculation of c28H34N206 · 1.4 TFA: C, 56.55; H, 5.45; N, 4.28. Experiment 値: C, 56.52; H, 5.83; N, 4.26. Example 295 trans, trans-2- (jdimethoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -W2- (N-propyl-N-iso -Butoxyamido) ethyl 1-pyrrolidine-3-carboxylic acid The title compound was prepared by the method described in Example 61, but in Example 6 i B, propylamine was substituted for amidine and Example 6 Isobutyl chloroformate was replaced with isobutyl chloroformate in 1 C. The crude product was purified by trituration with 1: 1 diethyl ether / hexane. The obtained solid was dissolved in CH3CN and water, and freeze-dried to obtain the product as a white solid. 4 NMR (CDCl3, 300 MHz) δ 0.80 (t, 3H, J = 7), 0.92 (m, 3H), 1.43 (h, 2H, J-2 7 Hz), 1.7-1.9 (m, 1 Η ), 2.72 (m, 1 Η), 2.90 (m, 2H), 3.10 (m, 2H), 3.25 (m, 2H), 3.40 (m, 1H), 3.55 (m, 1H), 3.62 (m , 1H), 3.7-3.9 (m, 2H), 3.78 (s5 3H), 5.95 (s, 2H), 6.72 (d, 1H, J = 8 Hz), 6.82 (m, 3H), 7.00 (s, iH ), 7.30 (d, 2H, J = 8 Hz). MS (DCI / NH3) m / e 527 (M + ΗΓ. Analytical calculations for C29H3SN2 06 · 0.5 H2 0: C5 65.03; H, 7.34: N, 5 23. Experimental: C, 65.13: H, 6 96: N, 4.95. -264- This paper size is applicable to the National Standard of China (CNS) Λ4 specification (21 × 297 mm) (Please read the precautions on the back before filling this page

, 1T

• I 552260 A7 B7 V. Description of the invention (ik Λ 〇 in Part 262 Example 296 group 'trans_2_ (4-oxothioyl) -heart (1,3-benzo-Mepta-Heptadecyl ^ heteropentene-5 The procedure described in Example 1 was used to prepare the title compound. NMR (CD3OD, 300 MHz) showed the presence of rotational isomers. Δ29? (M, 2Η), 4.68 (s, 3Η), 5.97 (s5 2Η), 6.83 (d, 1Η, J 8), 6.9-7.0 (m, 3H), 7.03 (d5 1H, J 2 2), 7,1-7.3 (m5 4H), 7.4 -7.5 (m, 2H). MS (DCI / NH3) m / e 515. Example 297 QMi. Recognition d ~ Office: "trans_2 · (4 · methoxyphenyl) -4- (1,3-phenylhydrazine 4-pentene-5-yl) -1 · [2- (N-propyl-N-dimethylaminosaminyl) ethylpyrrole-3-guinic acid was prepared by the method described in Example 61, but in Example 6 1B was replaced with propylamine and dimethylamine formamidine chloride was used in place of isobutylammonium chloride in Example 61C. The crude product was purified by preparation of hTPLC (Vydac pC18) in a 10-70% gradient. CH3CN elution in 0.1% TFA 3 will dissociate Freeze-dried to give the product as a white solid. NMR (CDCi3, 3 00 MHz) δ 0.70 (t, 3H, J 27), 1.28 (m, 2H), 2.75 (s, 3H), 2.82 (m52H), 3.1-3.45 (m, 4H), 3.70 (m, 1H), 3.80 (s, 3H), 3.90 (m, 3H), 4.72 (m, 1H), 5.95 (s, 2H), 6.75 (d, 1H, J = 8 Hz), 6.87 (m, 3H), 7.05 (s, 1H), 7.40 (d, 2H, J = 8 Hz). MS (DCI / NH3) m / e 498 (M + ΗΓ. About C27H35N3. 6 · Analysis and calculation of 1.25TFA 値: C, 55.35: H, 5.71: N, 6.56. Experiment 値: C, 55 4 1; H, 5.71; N, 6.41. -265- This paper is suitable for the national standard of Sichuan valve ( CNS) A4 specification (21 OX 297 race (please read the precautions on the back before filling this page)

, 1T 552260 A7 B7 V. Description of the invention (2S3,

I / x Printed example 29 8 Methoxy_stem „. 碁)-” bis (1,3-benzyl dioxane) -1- (2- (N-propyl-NM Second volume Vol. J: Sulfur Fluorenyl) amino) ethylcarboxylic acid Using the procedure described in Example 66, a rod solid was prepared as a yellow solid. 4 NMR (CDC13, 300 MHz) δ 0.77 (t, j .3 Hz, 3H ), 1.38 (hexaplex, J = 7.5 Hz, 2H), 2.20-2.90 (mm), 2.57-2.66 (m, 1H), 2.82-3.15 (m, 4H), 3.22 (t, j " 5 Hz, 2H), 3.38 (dd, J = 3 Hz, j = 9 Hz, ih), 3 49 · 3 57 (m, 1H), 3.59 (d, J = 9 Hz, 1H), 3 83 (s, 3H), 5 96 (s buckle), 6.73 (d, J = 8 Hz, 1H), 6.82 (pulling j =) Hertz, 8 Hz '6.87 (d, J = 9 Hz, 2H), 6 98 (d, J = 1 Hz, 1H), my J 2 9 Hz, 2H), 7.82 (d, J = 9 Hz, 2H), 8.23 (d, J = = 9 Hz 2H). MS (DCI / NH3) m / e 612 (M + ΗΓ. Take 5 complexes_Example 299 笨 # metadioxolane; ^^ sulfonamido) ethyl) -pyrrolidine-3 ^^ week The procedure described in Example 66 was used to prepare the title compound as a white solid. Melting point 59-61 ° C. NMR (CDC13, 300 MHz) § 0.79 (U 2 7.5 Hz, 3Η), 0.90 (t, j = 6 Hz, 3H), 1.26-1.32 (m, 4Η) 'heavy peak, j = 7 5 Hertz, 2Η), 167] 76 (m, 2H), 2.23-2.32 (m, m), 2.70-3.08 (m, 7Η), 3.15-3.32 (m, 2Η) '3.42 (dd, J 2 3 Hertz.j 2 9 Hz, m), 3.52-3.57 (m, 1H), J 63 (d, J = 9 Hz, 1H), 3 80 (s, 3H), 5.95 (s, 2H), 6.73 (Please read the notes on the back JI before writing this page. J. I. -263-Ben Tenderly 21 〇x 2-9 π 552260 A7 B7 V. Description of the invention (234 (d, J = 7.5 Hz , 1H), 6.83 (dd5 J = 1 Hz, J = 7.5 Hz, 1H), 6.87 (d, J = 8 Hz, 2H), 7.00 (d J = i Hz, 1H), 7.32 (d, Hz, 2H ). MS (DCI / NH3) m / e 561 (M + H) +. Example 3 00 I, trans-2- (A-methoxyphenyl) di 1 di (1,3-phenylhydrazine dioxo Heteropentyltrimethoxymethoxysulfonyl) amino) ethane ^ carboxylic acid The title compound was prepared as a white solid using the procedure described in Example 66. Melting point 122-124 ° C. IHNMR ^ CDsOD, 300 MHz) δ 0.75 (t, Bu 7.5 Hz, 3Η), 1.25-1.45 (m, 2Η), 2.96-3.08 (m, 2H), 3.23 (bs, 2H), 3.35-3.45 (m, 2H), 3.52 (t, J 2 10 Hz, 1H), 3 81 (d, J 2 9 Hz, 2H), 3,86 (s, 3H), 3.92 (t, J 2 9 Hz, 1H), 4.63 (d, J 2 10 Hz, 1H), 5 97 (S, 2H), 6.82 (d, J = 9 Hz, 1H), 6.93 (dd, J = 3 Hz, J = 9 Hz, 1 «〇, 7.06-7.08 (m, 3H), 7.46 (d, J = 9 Hz) , 2H), 7.56 (d, J 2 9 Hz, 2H), 7.89 (d, J 2 9 Hz, 2H). MS (DCI / NH3) m / e 651 (M + H), Example 3 0 1 _ 矣·-2 monooxanyl) -4-(1,3-phenylbenzene dioxane j: rabbit ^ 5 _ 某 央 ii _τ A ii Print (please read the precautions on the back before filling this page) ) Θ-N- (2v_fluorenyl-2-propenylsulfonyl) amino) ethylpyrrolidine-3-carboxylic acid Using the procedure described in Example 66, the title compound was prepared as a white solid. Melting point 69-71 ° C. 4 NMR (CDC13, 300 MHz) δ 〇7 ((ί, J = 7.5 Hz, 3 Η), 1.93 (hexaplex, J = 7 · 5 Hz, 2Η), | -267 National Standards (CNS) 210X 297 male f 552260 A7 B7

Medium A

A V. Description of the invention (265 (s, 3H), 2.25-2.35 (m, 1H), 2.68-2.77 (m, lH), 2.85-3.28 (m, 7H), 3.40 (d, J = 9 Hz, 1H ), 3.52-3.68 (m, 2H), 3.66 ((1,) = 9 Hz, 111), 3.80 (5, 3 ^ 1), 4.92 (5, 1 ^ 1), 5.07 (5, 1 «〇, 5.97 (s, 2H), 6.74 (d, J 2 7 Hz, 1H), 6.82-6.89 (m, 3H), 7.01 (s, 1H), 7.33 (d, J = 9 Hz, 2H). MS (DCI / NH3) m / e 545 (M + H) —. Example 302 Trans, trans 2- (4-methoxyepoxy) female 4- (1,3 -benzyl dioxane Pentamyl-5-yl) -1- "2-ethylhexahydropyridyl-carbonylmethyl1-pyrrolidine-3-carboxylic acid was prepared using the procedure described in Example 1. NMR (CD3. D, 300 MHz) shows a mixture of isomers. Δ 0 · 75 (t, 3H, J = 7), 1.4-1.7 (m5 8H), 3.84 (s, 3H), 5.96 (s, 2H), 6.83 (d, lH, J = 8), 6.91 (d, lH, J = 8), 7.0-7.1 (m, 3H), 7.52 (d, 2H, J = 9). MS (DCI / NH3) ra / z 495. Analysis and calculation of C28H34N20.6 · 1.6 TFA 値: C, 55.35: H, 5.30; N, 4.14. Experiment 値: C \ 55.26; Η, 5.3 7; N, 4.01. Example 303 , Trans- 2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxo | cyclocyclopentyl-5-yl) _l- 『2- (N-propyl-N- ( 2-methylpropanesulfonyl) amino) ethyl) -pyrrolidine-3-carboxylic acid The title compound was prepared as a white solid using the procedure described in Example 66. Melting point 72-73 ° C. WNMI ^ CDCh , 300 MHz) δ 0.82 (t, J = 7.5 Hz, 3Η), 1 04 (d, J = 6 Hz, 6Η), 1.44 (q, J-7.5 Hz, 2H), 2.15-2.33 ( m, 2H), 2.57-2.75 (m, 2H), 2 84- -268- The size of this paper is suitable / 丨] China National Standard (CNS) Λ4 specification (210X297 male f) (Please read the notes on the back first Fill out this page again) 552260 A7 B7 V. Description of the invention (266) 3.〇8 (m, 3H), 3.12 · 3.21 (τη, 1Η), 3.23-3.45 (m, lH), 3.43 Hz, 1H), 3.55-3.62 (m, 1H), 3.66 (d, J = 9 Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, J = 9 Hz, 1H ), 6.83 (dd, J = 1 Hz, J = 9 Hz, 1H), 6.87 (d, J = 9 Hz, 2H), 7.02 (d, J = 1 Hz, 1H), 7.33 (d, J = 9 Hertz, 2H). MS (DCI / NH3) m / e 547 (M + H), Example 304-based 'trans-2- (4-fluorenylbenzyl) -4- (1,3 -phenylbenzidine dilactate heteropentyl- 5 -yl) -1- (2- (N-propyl-N-heptanylamino) ethyl) bilobitate-3-conic acid Using the procedure described in Example 66, a white solid was prepared Title compound. Melting point 58-59 ° C. iHNMRCCDCh, 300 MHz) δ0 · 80 (t, J = 7.5 Hz, 3Η), 0.88 (t, J 2 7 Hz, 3Η), 1.23-1.36 (m, 8H) '1.94 (q, J = 7.5 Hz, 2H), 1.7 1 (quintet, J 2 7 Hz, 2H), 2.23-2.32 (m, 1H), 2.70-3.09 (m, 7H), 3.13-3.32 (m, 2H), 3.43 (dd, J 2 3 Hz, j = 9 Hz, 1H), 3 52 · 3 58 (ηι1Η), 3.65 (d, J 2 9 Hz, 1H), 3.80 (s, 3H), 5.96 (S, 2H), 6.73 (d, J = 9 Hz, 2H), 7.01 (d, J: 1 Hz, iH), 7.32 (d, j: 9 Hz

β-,; ί · 部 屮 失 ^: ^-χ; ’,; &lt; _τί / ί # 合 w. ^ 卬 V (Please read the notes on the back before filling this page

, 1T

• I Hyun, 2H). MS (DCI / NH3) m / e 589 (M + H) +. Example 305 Trans-di 4- (l, 3-benzene ^^ = Ξ: ^ | ^ cyclopentene · 5_ylsulfanyl.yl ^ yl) _PlL pluralimidine_3_guinealyl ^ By the method described in Example 61 It was prepared by the method, but in the example 6ιβ, ethylamine was used to replace amidine, and in example 61C, ethyl chloroformate was used to replace iso______ &gt; 269- this standard Shizhou China (cns) I ^ 77I. χ297 mm)-__ 552260 A7 B7 V. Description of the invention (267 Butan chloride. Purify the crude product by preparative HPLC (Vydac μ (: 18), wash with 10-70% gradient of CH3CN in 0.1% TFA The desired fractions were freeze-dried to give the product as a white solid. NMR (CDC13, 300 MHz) δ 0.90 (t, 3H, J 27), 1.22 (m, 3Η), 3.0-3.2 (m, 4H), 3.42 (m, 2H), 3.78 (s, 3H), 3.82 (m, 4H), 4.10 (q, 2H, J-2 7 Hz), 3.5 (br s, 1H), 5.97 (dd , 2H, J = 1, 7 Hz), 6.72 (d, 1H, J = 8 Hz), 6.84 (m, 3H), 7.00 (s, 1H), 7.42 (d, 2H, J = 8 Hz) MS (DCI / NH3) m / e 485 (M + H) +. About C26H32N207. 1.2 Analysis of TFA 値: C, 54.90; H, 5.39: N, 4.51. Experiment 値C, 55.01; H, 5.36: N, 4.56. Example 306 λ &gt;/; $ il 卬 (Please read the notes on the back before filling this page) Anti-trans 2- (4 · • methoxyphenyl) -4- (1,3-phenylhydrazone dioxolidine-5-yl) -i- (2- (N-propylhexanesulfonamido) ethyl) -pyrrolidine-3-carboxyl The acid was prepared using the procedure described in Example 66 to prepare the title compound as a white solid. Melting point 59-60 ° C. WNMRCCDCh, 300 MHz) δ 0 · 80 (1, J 2 7.5 Hz, 3Η), 0.89 (t, J 2 7 Hz, 3Η), 1.25- 1.36 (m, 6H), 1.53 (hexaplex, J 7.5 Hz, 2H), 1.72 (quintet 5 J = 7 Hz, 2H), 2.23-2.32 (m , lH), 2.72-3.08 (m, 7H), 3.15-3.32 (m, 2H), 3.43 (d, J 2 9 Hz, 1H), 3.55-3 62 (m, 1H), 3.65 (d, J 2 10 Hz, 1H), 3.80 (s, 3H), 5.96 (s, 2H), 6.74 ((1, 75 75 Hz, 111), 6.82 ((1, 1 2 7.5 Hz, 1 seal, 6.87 (1 J = 9 Hz, 2H), 7.01 (s, 1H), 7.32 (d, J 2 9 Hz, 2H), MS (DCI / NH3) m / e 575 (M + H), -270- Applicable to this paper standard Middle valve due to home standard (factory milk) / \ 4 specifications (: 210 乂 297 mm 552260 A7 —— _ B7 one one--.. _ one _-_____ | V. Description of the invention (268) Example 3 0 7 (Please read the precautions on the back before filling this page) '' _ 反 -2_ ( 4-Ethylphenylhydrazone) -4- (1,3 · phenylhydrazone dioxolene-5-ylbis (n-butyl) aminocarbonylmethyl μpyrrolidine-3-carboxylic acid is used in examples The procedure described in 1 and 49 was used to prepare the title compound, which was prepared in the procedure 49B using 1 ethyl benzamidine ethyl acetate (by the method of Krapch 0 et al., Org. Syn., 20 (1967), Beginning at 4, _ethylethoxybenzophenone) seeking substitution. NMR (CDC13, 300 MHz) δ 7 3} (2H, (1,1 = 8 Hz), 7.16 (2 (1, &gt; 1 2 8 Hz), 7.03 (111, (1, 1 = 3 Hz), 6.86 (1H, dd, J = 8 &amp; 3 Hz), 6.73 (1H, d, J = 9 Hz) '5.94 (1H, d, J = 4 Hz), 5.92 (1H, d, J = 4 Hz), 3.77 (out, 4 Lu 9 Hz), 3.60 (Sichuan, 111), 3.53-3.23 (511, 111), 3.13 -2.90 (4H, m), 2.73 (1H, dT J = 14 Hz) , 2.62 (2H, q, J = 9 Hz), 1.45 (2H5m), 1.40-1.10 (6H, m), 1.02 (2H, m), 0.87 (3H, t, J-2 7 Hz), 0.78 ( 3H 乂 J 27 Hz). M / e (DCI, NH3) 509 (ΜΗ '). Analysis and calculation of C30H4C) N205205: C, 70.84; Η, 7.93; N, 5 51. Experiment 値: C , 70.80; Hf, 7.85; N, 5.25. Example 308, trans-phenyl V 4-(1,3-phenylhydrazine-dioxolane-5 -ylchloroethan) carbonylamino) ethyl 1-pyrrolidin-3- was prepared by the method described in Example 61, but in Example 6 1 B was replaced by propylamine and obviously in Example 6 1 C was 2-chloroethyl chloroformate To replace isobutyl chloride. Develop with 1: 1 diethyl ether / hexane to purify the granules. Dissolve the obtained solid in CH3CN and water, and freeze-dry 271-This paper is suitable for Chuanzhong Valve Standard (CNS) Λ4 specification (210 X 297) 552260 A7 B7 in Section A 卬 f V. Description of the invention (269:, product obtained as white solid. IlNMRCCDCh, 300 MHz) δ 0.80 (t, 3H, J 2 7), 1.22 (m, 3H), 2.15 (m, 1H), 2.75 (m, 1H), 2.85 (m, 1H), 3.1 (m, 2H), 3.25 (m, 2H), 3.5 (m, 3H), 3.65 (m, 2H ), 3.80 (s, 3H), 4.18 (m, 1H), 4.30 (m, 1H), 5.98 (s, 2H), 6.72 (m, 1H), 6.82 (m, 3H), 7.00 (m, 1H) , 7.30 (m, 2H). MS (DCI / NH3) m / e 533 (M + H) +. Analysis and calculation of C27H33N207C1 7 · C, 60.84; H, 6.24; N, 5.26. Experiment 値: C, 60.48; H, 6.04; N, 5.10. Example 309 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-ylbis (n-butyl) aminocarbonylfluorenyl 1- Pyrrolidine-3-carboxylic acid was prepared using the procedure described in Example 1 to replace the 4-methoxyphenylfluorenyl group with ethyl 5-methoxy-3-oxopentanoate in real fluorene 1A. Ethyl acetate g. The title compound is a yellow bubble bed. 1 Η NMR (CD C13, 3 00 MHz) δ 0.91 (t, J = 7 Hz) and 0.95 (t, J 2 7 Hz, 6Η total), 1.28 -1.41 (brm, 4H), 1.45- 1.63 (brm, 4H), 2.00-2.20 (br m, 2H), 3.06 (br t, J = 9 Hz, 1H), 3.30 (s), and 3.20- 3 68 (br m, 1 1H total), 3.72-4. 1 0 (br m, 4H), 5.92 (s, 2H), 6.72 (d, J = 8.5 Hz, 1H), 6.82 (dd, 8.5 Hz, 1H), 6 91 (d, J = 1.5 Hz, 1H). MS (FAB) m / e 463 (M + H) '. Analysis and calculation of C25H3SN205. H20: ，: C, 62.48; 8.39: N, 5.83 . Shi Weng 値: C, 62.13: H, 8.15: N, 5.69. Example 3 1 0 Inverse, Han-2- (4-methoxyfluorenyl) -4 _ (1,3 -Mujianma two gas while meal Pentyl _ 5-base-272-this paper is of appropriate size / ] China National Standard (CNS) Λ4 specification f 210X 297 male t) -------- • Cloth ------ 1T ------ (Please read the precautions on the back before filling in this Page) 552260; ί ik meaning: j f. A 卬 A7 B7 V. Description of the invention (27〇)) _1- (2- (N-ethyl-N-n-pentanylamino) ethyl) -Orbirollia-3-lean§ The parent used the procedure described in Example 66 to prepare the title compound as a white solid. Melting point 57-58 ° C. ^ HNMRCCDCh, 300 MHz) δ 0.89 (t, J = 7 Hz, 3Η), 1.06 (t, J = 7.5 Hz, 3Η), i.26-1.37 (m, 4H), 1.72 (Fivefold, J 2 7.5 Hz, 2H), 2.22-2.3 2 (m, 1 Η), 2.71-2.96 (m, 5 Η), 3.08-3.30 (m, 4 Η), 3.95 (d, J 2 9 Hz, 1H), 3.53 -3.60 (m, lH), 3.67 (d, J 2 9 Hz, 1H), 3.80 (s, 1H), 5.97 (s, 2H), 6.73 (d, J 2 9 Hz, 1H), 6.82 (d , J 2 9 Hz, 1H), 6.88 (d, J 2 9 Hz, 2H), 7.02 (s,] H), 7.33 (d, J = 9 Hz, 2H). MS (CDI / NH3) m / e 547 (M + H) +. Example 3 1 1 trans, trans-2- (4-methyllactinoyl) -4- (1,3 · bendemadic dilactone is difficult to hurt penta_5_yl) -l-fN, N-dicyclohexyl Aminocarbonylmethyl 1-pyrrolidin-3-carboxylic acid was prepared using the procedure described in Example 1 to the title compound. NMR (CD3OD, 300 MHz) δ 1.0-2.0 (m, 20H), 3.0-3. 1 (m, 2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, 1H, J 2: 8), 6.86 (dd, 1H, J = 2,8), 6.95 (d, 2H, J = 9), 7.04 (d, 1H, J = 2), 7.38 (d J 2: 9). MS (DCI / NH3) m / z 563. Analytical calculations for C33H42N20. 0.5 H2O: C, 69.33: H, 7.58; N, 4.90. Experiment 値: C, 69.42; H, 7.29: N, 4.78. Example 3 1 2 trans, trans_2_ (4_methoxy table roll) _4_ (1,3_ table and to dioxo, butyl-5 -yl) -1- [2- (N-propyl third -Butoxycarbonylamino) ethyl 1-pyrrolidin-3-carboxylic acid- 273-The size of this paper; 丨] Chinese National Standard (CNS) Λ4 specification [210X 297 mm] (Please read the note on the back first Please fill in this page again) 552260 A7 ------------- -__ V. Description of the invention (271) The procedure described in Example 61 1 was used to prepare the title compound. In Example 6 1B, propylamine was used. The water-containing methylamine was replaced, and in Example 6 1C, isobutylphosphonium chloride was replaced with di-tertiary-butyl dicarbonate. NMR (CD3OD, 300 MHz) suggests the presence of rotamers. δ 0.S1 (t, 3H, J = 7), 1.2-1.5 (m, 11H), 3 78 (s, 3H), 5.92 (dd, 2H, Bu 1, 2), 6.74 (d , 1H, J 2 8), 6.84 (dd, 1H, J = 2, 8), 6.92 (d, 2H, J = 9), 6.99 (bd s, 1H), 7 35 (d, 2H, J = 9). MS (DCI / NH3) m / z 527. Analysis and calculation of C29H38N207: 2 C5 66 · 14; H, 7.27; N, 5.32. Experiment 値: c, 66.05; H, 7.36; N, 5.15. Example 3 13 Pyridyl_di 1-.. (4-fluorenyloxyphenyl) -4- (1,3-phenylhydrazine dioxolene ^) _ 1- [1 ^, 1 ^ 1 ^! ^ -Butyl) aminocarbonylfluorenyl 1-pyrrolidin-3-# __ The title compound was prepared by the method described in Examples 1 and 43, using 4-fluorenoxy-3-fluoroethylfluorenyl phenone instead of acetamidine Methylphenone. Melting point 42_143 C ° NMR (CDCl3, 3 00 MHz) § 0.82 (t, J 2 7 Hz, 3H), 0.8 8 (i, J = 7 Hz, 3H), 1.03-1.50 (m, 8H), 2.82 ( d, J = π 4 obtained, 1H), 2 90-3 · 13 (m, 4H), 3.2 0-3.50 (m, 3H), 3 39 (a, J = 13H, 1H), 3.55-3.65 (m , LH), 3.82 (d, J = 10 Hz, 1H) '3J7 (S, 3H)' 5.9l (dd, J = 2 Hz, 4 Hz, 2H), 6.72 (d J -8 Hz, 1H), 6.83-6.91 (m, 2H), 6.99 (d, J = 2 Hz 5 1H) '7.06 (m, 2H). Analytical calculations for C29H37N206F: c, 6) .89; H, 7.06; N, 5 30. Experiment 値: c, 65 82; H, 7 u; N, 5.29. (Please read the notes on the back before filling this page

^ T? 552260 A7 __________J1______ V. Description of the invention (272) f Example 3 14 trans, trans-2- (propyl) -4- (1,3diphenylhydrazinedioxol-5-yl) l-r2- (N-propyl-pentanesulfonamido) ethyl) -pyrrolidine-3-carboxylic acid Example 3 14 A Propylpentanesulfonamide pentanesulfonyl chloride (687 mg, 4.03 MM) was dissolved in 5 ml of CH2C12, and n-propylamine (0.40 ml, 4.82 mmol) and ethyl diisopropylamine (0.85 ml, 4.88 mmol) were added in 5 ml of CH2C12 under nitrogen pressure. ) Ice cold solution. The reaction was stirred at 0 ° C for 30 minutes and then at 25 ° C for 4 hours. The solution was distributed between 20 ml of 1.0 M aqueous NaHS04 and 25 ml of CH2C12. The organic phase was washed successively with 25 ml of H20 and 25 ml of brine, then water (Na2s04), filtered, and concentrated in the air to give 739 mg (3.83 mmol, 95%) of the title compound as a white solid. TLC ( 25% EtOAc-hexane) Rf 0.23; 1Η NMR (CDC13, 300 MHz) δ 0.92 (t, J 2 7 Hz, 3Η), 0.97 (t, J 2 7 Hz, 3H), 1.28-1.50 (brm, 4H), 1.52-1.68 (m, 2H), 1.75-1.90 (br m, 2H), 2.98-3.06 (m, 2H), 3 08 (q, Bu 6 Hz, 2H), 4.10-4.23 (br m, 1H); MS (DCI / NH3) m / e 211 (M + H),., Part Λ (Please read the precautions on the back before filling this page)

Example 3 14B Benzene # m-dioxolenyl-5-yl) -1- (2-bromoethyl) -2-propylfluorene 7 Biloxidine-3 -acrylic acid g According to Example 6 1 A The procedure was used to prepare the title compound. The compound of Example 94B was used in place of the p-to-p mixed structure. -275 This paper is suitable for / 1] China National Standard (CNS) Λ4 specification (21〇χ 297 public trend) 552260 A7 B7 V. Description of the invention (273 Example 3 14C suffering from L amine group with sodium hydride (2 mg, 60% method dispersant, 19 a + \ T _,… Mao Xiong NaH, 50 μ 旲) Example 314a, M, <100 million compounds (6.6 μg, 34 μM) treated in 0.1 ml DMF Ear) solution. The resulting mixture was stirred at room temperature for eight minutes, and then an example in 0.1 ml of DMF was added! A solution of the compound 89B (9 kDa, 22 micromolar) was added, followed by 0. 5 mg of tetra-n-butyl iodide. Sealed under argon pressure and stirred at 60 T: overnight. The reaction was concentrated under high vacuum and the residue was distributed over 2 ml of saturated aqueous NaHC03, Between 1 ml of water and 5 ml of EtOAc. Rinse the organic phase with 1 ml of brine, dehydrate by passing through a stopper of NaaSO4, and paint the filtrate into oil in the air. By preparing TLC (Shi Xijiao, 8 X 9 〇cm 0.2 mm 5 mm thick, and the crude product was purified at 20 ° /. Ac_hexane to give 8.4 mg (73%) of the title compound as a wax. Example 3 14D '' ------ Benzene Dioxane House ---- ^^ 衣-(诮 Please read the notes on the back before filling this page) Order t 'r) in the section and ) i -T f Aii 卬 (fluorenyl-pentanesulfonamido) The title compound was prepared according to the procedure of Example 71C. "(CDCI3'j0 MHz)? δ0 88-1.00 (^ 91 ^), 1 20-1.55 (br 6H), 1 55- 1.68 (m, 3H), 1.70-1.85 (brm 2H), 1.90-2.1 (br m, 2H), 2.84-3.26 (br m, 6H), 3.26-3.90 (br m, 6H, 5 95 (s, 2H), 6.76 (d, J = 8 Hz, iH), 6 79 (m, 1H), 6.9) (bi s, 1H); HRMS (FAB) on c25h41N2. Calculation of () S

H NM] -276- This paper is in ft size, the National Standard for Valves in China (CNS) A4 specification c 210 乂 297 Gongchu 552260 A7 B7 V. Description of the invention (274) (Μ + Η) &quot; 497.2685, Experiment 値 497.2679. Example 3 1 5 trans, trans-2- (4-fluorenylbenzyl) -4- (1,3-benzene # meta) -1- (2- (N-propyl-N-diamidosulfenyl) Aminoamino) ethyl The procedure described in Example 66 was used to prepare the title compound as a white solid. Melting point 59-61 Ό. 4 NMR (CDC13, 300 MHz) δ 〇79 (t, J = 7.5 Hz, 3Η) , 1.45 (hexaplex, J = 7.5 Hz, 2H), 2.22-2.31 (m, lH), 2.65 (s, 6H), 2.7 0-2.79 (m, lH), 2 85 -3.04 (m, 4H) , 3.09-3.3 2 (m, 2H), 3.40 (d, J = 9 Hz, ι H), 3.5 5 (t, J = 9 Hz, 1H), 3.65 (d, J = 9 Hz, 1H), 3 si (s, 3H), 5.96 (s, 2H), 6.7 5 (d, J = 9 Hz, 1H), 6.83 (d5 J = 9 Hz, 1H), 6.88 (d, J = 9 Hz, 2H ), 7.02 (s, 1H), 7 34 (d, J 2 9 Hz, 2H). MS (DCI / NH3) m / e 534 (M + H) +. Example 3 16 Inverse, trans-2- (4 -Methybenzyl V4- (l, 3-phenylhydrazone dioxetanyl-5_ylpropanone) -N- [4-methoxyphenyl 1sulfonamido) propyl bihadine_3_ carboxylic acid

Example 3 16 A ', J yr Λ j ^ ί Please read the precautions on the back, and then write this page j trans-trans and cis-trans 2- (4-methoxyphenyl) -4- (1 , 3_Benzamidine dioxo-heterocyclic pentamidine · -5 v a certain V M3-bromopropyl) -pyrrolidine-3-carboxylic acid ethyl ^ will be trans · trans and cis-trans 2- (4-fluorene oxygen Phenyl) -4- (1,3-phenylhydrazone-dioxolane-5-ylpyrrole-3-chitoic acid ethyl g 2: 1 mixture (4 g: according to Example 1 C Preparation), 32 ml of dibromopropane and 200 mg of sodium iodide are heated to 100 ° C for 1.2 5 hours. Remove excess dibromopropane in the air, -277- (CNS) Λ4 specifications (210X 297 mm) 552260 A7 ---------- ~ --- ^ 67 V. Description of the invention (275) (Please read the precautions on the back before filling this page} and The residue / grain was dissolved in methylbenzyl. After shaking with potassium bicarbonate, the solution was dehydrated (Na2SO4), and the solution was concentrated. The residue was chromatographed on silica gel with a size of 5.1 Burned with Et0Ac. Washed. 5.22 (98%) of the title compound was obtained.

Example 3 16B Red 丞 and "-trans-2- (4 ^^ yl) _heart (心 3_benzo-dioxolene-5- 蓦 on 1: _. (3 -_ ^^ propyl The compound described in Example 316A (5.22 g) was heated with 35 ml of ethanol, 2.5 g of propylamine and 35 mg of sodium iodide to 80.0 hours. The solvent was removed in the air. The residue The material was dissolved in toluene, shaken with potassium bicarbonate, and Naecu was removed. The solution was concentrated in the air to obtain 4 96 g of the title compound as an orange oil. It was used directly in the next step. No further purification is required. Example 3 1 is bis (2- (4-methyloxyphenyl ^ heteropenten-5-yl) -M_2- (N-propyl-N- 丨 4-methoxyphenyl μ) Pyrrolidine_3_carboxylic acid

Using the method described in Example 66, the compound prepared in Examples 3 to 16B was reacted with dimethoxybenzenesulfonyl chloride in acetonitrile containing diisopropylethylamine. The resulting product was chromatographed on silica gel (30% EtOAc in hexanes) 'and the title compound was hydrolyzed following the method described in Example ID. lH 1.52 (m, 2H), 1.56- 1.70 (m, 2H), 2.00-2.11 (m, 1H), 2.40-2 51 (m, 1H), 2.69-2.78 (m, 1H), 2.S4-3.03 (m, 4H) -278- This paper is compliant with the national standard (CNS) α ^ Γ (210 X 297 / ^ 7 ^ ----- 552260 A7 B7 V. Description of the invention (276) (Please read first Note on the back, fill in this page again), 3.19-3.34 (m, 2H), 3.48-3.59 (m, 2H), 3.80 (s5 3H), 3.8 6 (s, 3H), 5.95 (s, 2H), 6.74 (d, J = 8 Hz, 1H), 6.85 (d, J = 8 Hz, 3H), 6.93 (d; J 2 8 Hz, 2H), 7.02 (d, J = 2 Hz, 1H), 7.29 ( d, J = 8 Hz, 2H), 7.69 (d, J = 8 Hz, 2H). Analysis and calculation of C32H3SN208S 値: C, 62.93; Η, 6.27; N, 4.59. Experiment 値: C, 62.97; Η, 6.39; Ν, 4.45. Example 3 1 7 Reverse-reverse drawing 2_ (4_fluorenyloxyphenyl) _4- (1,3-benzo-dioxopentanyl_5_ 呑) _ C -N-propylsulfonamido) propyl1-pyrrolidine-3-carboxylic acid Using the method described in Example 66, the propylamine compound prepared in Example 3 16B was Acetonitrile is reacted with propanesulfonyl chloride. The resulting product was chromatographed on silica gel (30% EtOAc in hexanes) and the title compound was hydrolyzed by the method of Example ID. NMR (CDC13, 3 00 MHz) δ 0.85 (t, J = 7 Hz, 3Η), 1.02 (t, J = 7 Hz, 3H), 1.47-1.60 (m5 2H), 1.65- 1.85 (m, 4H) , 2.04-2.16 (m, 1H) ^ 2.42-2.57 (m7 1H) ^ 2.72-3.11 (m, 5H), 3.25-3.41 (m, 2H), 3.5 0-3.62 (m, 2H), 3.80 (s, 3H), 5.85 (s, 2H), 6.72 (d, J = 8 Hz, 1H), 6.80-6.90 (m5 3H), 7.02 (d, J = 2 Hz, 1H), 7.30 (d, J = 9 Hz , 2H). . Analysis and calculation of C28H38N207S 値: C, 61.52; H, 7.01; N, 5.12. Experimental values: C, 61.32: H, 7.01; N, 5.01. Example 3 1 8 trans, trans-2- (3-fluoro-4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- (2- (N-propyl-N-pentanesulfonamido) ethyl) -pyrrolidine-3-carboxylic acid-279- This paper is suitable for Sichuan National Standard (CNS) A4 size (210X 297 mm) ~ 552260 ί: &gt; r Part-loss A7 —_____________ B7 ___ V. Description of the Invention (277) Using the procedures described in Examples 3 1 3 and 66, the title compound was prepared as a white solid. Melting point: 66-68 ° C. NMR (CDCI3, 300 MHz) δ 0 · 81 (t, J = 7.5 Hz, 3H), 0.89 (t, J = 7 Hz, 3H) '1.26-1.35 (m, 4H), 1,45 (six Ridge, J = 7.5 Hz, 2H), 1.68-1.76 (m, 2H), 2.25-2.33 (m, 1H), 2.72-2.92 (m, 5H), 2.97-3.12 (m, 2H), 3.16-3.33 ( m, 2H), 3.43 (dd,> 3 Hz, J = 9 Hz, 1H), 3.53-3.60 (m, 1H), 3.66 (d, J = 10 Hz, 1H), 3.88 (s, 3H), 5.95 (s, 2H), 6.74 (d, J = 8 Hz, 1H), 6.82 (dd, J = 1 Hz, j = 8 Hz, 6.92 (t, J = 8 Hz, 1H), 6.97 ( Shanbu 1 Hz, 1 Hz, 7.12 ((1, 1 2 8 Hz, 1 ^ 1), 7.18 ((14> 1 Hz, J 2 12 Hz, 1H). MS (DCI / NH3) m / e 579 ( Μ + ΗΓ. Example 3 1 9 Phenylhydrazine-5-di (_i £ dioxo) aminocarbonylfluorenylpyrrolidine-3_carboxylic acid The method described in Examples 1 and 43 was used To prepare the title compound, methyl 3-oxo-3- (4-P than pyridyl) propanoate (j Am. Chem. Soc. 1993 '1' 1 1705) was used instead of (4-fluorenyloxyphenylhydrazone) Ethyl). Ethyl acetate. Melting point 13 1.132 ×:. NMR (CDCl3, 300 MHz) δ 82 (t, j = 7 Hz, 3H) '0.88 (t, J = 7 Hz, 3H), 1.05-1.50 (m, 8H), 2.90 (dd, J = 7 Hz, J = 9 Hz, 1H), 2.97 (d, J 2 13 Hz, 1H), 00-3.25 (m, 4H), 3.32 (m lH), 3 39 (d J = 13 Hz, iH) '3.4) -3.52 (m, 1H) , 3.67 · 3.78 (m, 1H), 4 1〇 (d ,; two 9 Hz, 1H), y92 (dd, J: = 2 Hz, 4 Hz, 2H), 6.75 (d, J 2 9 Hz , 1H), 6.90 (dd, J = 9 Hz, 2 Hz, 1H), 7 〇2 (d, J = 2 Hz. · Two — ______-280-"Zhang Jiu Shi Shi (called ^ (please read first (Notes on the back then fill out this page)

_____1 552260 Α7 Β7 V. Description of the invention (278 Hz, 1 Hz), 7.4) (d, J == 8 Hz, 2H), 85 ° (d J = 8 Hz, 2%). About the analysis of C27H35N3O): c, 67.34; Η, 7.33; Ν, 8.73 Λ, ·. Experiment 値: C, 67 · 39 ′ · Η, 7.45; N, 8.61. 〇Μ &gt; (Please read the notes on the back before filling out this page) AJ ^ L320_ Digas jM pentene-5-yl) -1ι ethyl L pyrrolidin-3-carboxylic acid Utilization described in Example 61 Procedure to prepare the title compound, replacing propylamine 'with propylamine in Example 61B and isobutyridine chloride with diethylamine formamidine chloride in Example 61C. NMR (CD300D, 300 MHz) δ 0.74 ( ί, 3Η, J 2 7), 1.09 (t, 6Η, J = 7), ^ 33 (m, 2Η), 3 17 (q, 4Η, J = 7), 3.78 (s, 3H) '4.04 (m , LH), 5.93 (s, 2H), 6.86 (d, 1H, J: 8), 7.06 (dd, 1H, J = 2, 8), 6.94 (d, 2H, J2 9), 7.04 (d5 1H, J 2: 2), 7.40 (d, 2H, J = 9). MS (DCI / NH3) m / z 526. Analysis and calculation of C29H39N30.6 · 0.1 TFA 値: c, 65 3 1; H, 7.34; N, 7.82. B. Test: c, 65.33; H, 7.43 ^ 'N, 8.14 0 iH 3 21, ^ VCU \ The middle radical of trans-2-2 (4 ^ sheng! Benzene and oxopenta 1 [_3, landifluorenyl-ylpyrrolidine_ 3 _carboxylic acid_ The title compound was prepared using the procedure inserted in Example 1. NMR (CD30D, 300 MHz) showed a mixture of isomers σδ 〇88 ((ΐ, 3Η, J = 7), 0.93 (d, 3Η, J = 7), 3.82 (s, 3Η), 5.95 (s, 2Η), 6.82 (d, 1H, J2 8), 6.89 (dd, 1H5 8), 7 00 (d, 2H7 P9), 7.03 (m, 1H), 7.47 (d, 2H, J: 9). MS (DCI / NH3) m / z 495 3 卬 -281 This paper is a national standard (CNS) 屮 4 specification (210X 297 male f) 552260 A7 Β7 ο 'Λ: Ministry of V. Description of the invention (279) Example 322 County Second Anti-2 -(4 ^ 比 呢 碁,)-4- (1,3dibenzene # meta S oxetanyl, _5_ group "N, N-((first-butyl) amine sulphonylmethyl" -ΐ Biloxacin uses the procedure described in Example 1 to prepare the title compound. NMR (CD30D, 300 MHz) shows a mixture of isomers. G 083 (t, 6 °, J = 8) , 1.27 (d, 6Η, J = 7), 1.6 (m, 2Η) 3.79 (s, 3Η), 5.93 (s, 2H), 6.75 (d, 1H, J: 8), 6.86 (d, 1H, J 2: 8), 6.94 (d, 2H, J = 9), 7.03 (d , LH, J = 2), 7.35 (d, 2H, J = 9). MS (DCI / NH3) m / z 5 1 1. Example 323 Presentation-trans-2- (4-Edianyl) -4- (1,3-benzyl-dioxo-5-yl) -1-fN- (2-tolyl) -N-butylamine, a carbonylmethyl] -pyrrolidine, was prepared using the procedure described in Example 1. The title compound. IMS (DCI / NH3) m / z 545. Analytical calculations for c32H36N206 · 0.9H2 0 C · C, 68.53; Η, 6.79; N, 4.99. Experiment 値: C, 68.56; Η , 6.62; N, 4.71. Example 324 trans-trans- 2- (4- ^ pyridyl) -4- (1,3-benzene # methylenedioxane ^ Jnetyl) _ [N- (3-toluene Butylamidocarbonylpyridine 1-pyridine was used to prepare the title compound using the procedure described in Example 1. NMR (CD3OD, 300 MHz) d 0.88 (t, 3H, J = 7), 1.2-1.5 (m 4H), 2.31 (s, 3H), 2.8 (m, 2H), 3.14 (t, 1H, J 2 10), 3.3 (m, 1H) '3.44 (dd, 1H, J = 5, 10 ), 3.53 (m, 1H), 3.60 (t, 2H, J 2 7), 3 79 (s, 3H), 3.82 〇, 1H), 5.93 (s, 2H), 6 74 (d, -282- Paper &amp; scale appropriate states around 1¾ table Standard (CNS) Λ4 Specification (2 Shu 〇x 297 public Xu (Please read the notes and then write the town on the back of this page)

1T 552260 A7 B7 V. Description of the invention (28〇) 1H, J: 8), 6.8-6.9 (m, 5H) '7.0 · 6 (d, m,]: 2), 7 〇9 (d, 2H , J = 9), 7.18 (d, 1H, J = 7) ^ 7 * 27 (t, ih, j-7) ^ MS (DCI / NH3) ni / z 545. Analytical calculations for C32H36N2 0 6 · 8 H 2 0: c, 68.75; H, 6.78; N, 5. (H. Experiment 値: c, 68 7〇; H, "7; N, 4.85.

Aj ^ L325_ group "trans-4- (1,3-phenylhydrazone_ metadioxo-5-yl) _2_ (benzyloxyfluorenyl) -1-((N, NS.-butylamino group) ^^ Pyrrolidine_3_carboxylic acid is di_trans-4- (1,3-benzene-1 metadioxo ^^-5-yl) -2_ (benzyloxymethyl) _j: X_ (N, N- Di (n-J: j) amine carboxy-pyrrolidine-3_carboxylic acid ethyl ester According to the procedure of Examples 1A-1D, 4-methoxybenzene was replaced with ethyl benzyloxyoxobutanoate in Example 1A. Methyl ethyl acetate to give the title compound as a colorless hydrazone. TLC (30% EtOAc-hexane) Rf 0.18; 4 NMR (CDC13, 3 00 MHz) δ 0.88 (t, J = 7 Hz, 6H), 1.17 (t, J = 7 Hz; 3H), 1.20-1.3 4 (br m5 4H), 1.40-1.56 (br m5 3H), 2.85 (t, J 2 8 Hz, 1H), 2.98-3.30 (m, 5H ), 3.39-3.60 (m, 3H), 3.64-3.75 (m, 2H), 3.92 (d, J = 14 Hz, 1H), Ministry (read the precautions on the back before filling this page) 4. 10 (Two overlapping q, J 2 6.5 Hz, 2H), 4.53 (s, 2H),). 91 (m, 2H), 6.69 (d, J 2 9 Hz, ih), 6.7 7 (dd, J = 1.5 '9 Hz, 1H), 6.91 (d, J 1.5 Hz, 1H); MS (DCI / NH3) m / e 553 (M + H ) +.

Example 325B Tail bis 4- (1,3-phenylhydrazone dioxolenyl) -2- (fluorenylmethyl)--283- This paper is suitable for the national standard (CNS) Λ4 specification (21〇χ297297, 552260 hi t head> /) f, λ, A7 B7 Description of the invention (281 1-((N, N-di-C-n-butyl) aminocarbonyl a methyl) _pyrrolidine_ 3-carboxylic acid The title compound was prepared as a colorless glass according to the procedure of Example 71c. Butyl LC (5% MeOH-CH2Cl2) Rf 0.13; lti NMR (CDC13 ^ 300 MHz) δ 0 · 86 (t, J = 7 Hz) and 0.90 (t, j = 7 Hz, 6H total), 1.15-1.52 (br m, 8H), 2.96-3.35 (br m5 5H), 3.50-3.75 (br m, 2H), 3.80 (dd , J-3, 13 Hz, 1H), 3.88-4.40 (br m, 6H), 4.45 (AB, 2H), 5.90 (s, 2H), 6.70 (d, J 2 8 Hz, 1H), 6.84 (dd, J = 1, 8 Hz, 1H), 6.93 (d, J = 1 Hz, ih), 7.28-7.39 (m, 5H); MS (DCI / NH3) m / e 524 (M + H) + Example 326 County bis'trans-4- (1,3-phenylhydrazine-5-oxo (epiamido) _ ^ _ ((N, N-di (n-butyl) amine A few methyl groups) -p bilobit

Example 326A Di-trans- (4- (1,3-wilt dioxol-5-yl) -2- (¾methyl) -L (N, N-mono (n-butyl) Amine # and methylmethyl)-p Billolite -3-Ethyl Acetate was stirred in 7 ml of EtOH under 1 atm of hydrogen to give the product from Example 325a (128 mg, 0.232 mmol) and 25 mg 20. /. Pd (OH) 2 was sufficient on activated carbon for 48 hours. The mixture was filtered through a plug of diatomaceous earth, and the catalyst was washed with 2 × 10 ml of EtOH, and then the mixed filtrate and the washing solution were concentrated under reduced pressure to obtain a crude product. Purification by flash chromatography (40% EtOAc-hexane) gave the title compound.

Example 326B Group I! _ ^ _ Bis 4- (1,3-Benzo-dioxol-5-yl sulfonium) -B (Xjt N-bis (n-butyl) amine Base)-? Ling-284 Paper &amp; Standard Returns 1¾ National Standard Rate (CNS) Λ4 Specification (21〇χ 297 Gongchu (Read the precautions on the back before filling this page)

ii 552260 A7 B7 V. Description of the invention (282 The title compound was prepared according to the procedure of Example 71C. Example 3 22 Example 327A Spermidine Example j26A &lt; Selective Oxidation of Compound (e.g., using Sw oxidation, DMS, § Chlorine, ethyldiisopropylamine, or Dess-Martin periodlnane to make the title compound. Example 327 Denier Dioxolyl) _2_ (〇_ Third -Butyl A ^ ill 棊 W_ (dN_bis (n-butylcarbonylmethyl) _pyrrolidine_3_ ethyl acetic acid) The compound of Example 327A and triphenyl orthophosphine were prepared by CH / h solution (Phosphoranylidine) acetic acid tertiary-butyl ester is condensed to produce the title compound. ^ Example 327g _ ^ _ 1 ^: ^: :( 1,3-phenylhydrazine dioxol ^: ^ yl) _2_ (acrylic-3 _Hydroxy-bis (n-butyl) amine carboxymethyl methacrylate) -Hydroxybenzyl-3-quinic acid ethyl ester was prepared in CH / h. The compound of Example 327B and trifluoroacetic acid (i: 1 ) Reaction to produce the title compound. -285- This paper is suitable for the size of the paper. 十] National Garden Standard (CNS) Λ4 Specification (210X 297 mm) (Please read the Precautions to fill out this 1TC)

55226〇 Five central X; f A 卬 A7 B7, invention description (283

Example 327D trans-4- (l, g-wilt-one; oxepin-5_yl) -2_ (N- 曱 a certain feminine) -bu ((N, N-di (n-d Methyl) pyrrolidin-3-ethyl amine carbonyl via carbodiimide (eg N-ethyl-N- (3 · • dimethylamino) propyl carbide-imine, DCC) The title compound was prepared by condensing the compound of Example 327C with ammonium hydrochloride in the presence.

Example 327E Phenylhydrazine-5-yl) -2- (N-methylpropionyl || ^ 3-yl) -1-((Team 1 ^ bis (n-butyl) aminecarbonyl Fluorenyl) -pyrrolidine-3_carboxyl The title compound was prepared by reacting the compound of Example 3 27D with lithium hydroxide according to the procedure of Example 7 1 C. t M 328 Congyi, trans-4- (1 , 3-phenylhydrazine dioxetanyl-5 -yl) _2_ (fluorene-hydroxy_2-propionedi-3-yl) -1-((N, N-di (n-butyl) amine (Rikimidinyl) · Pyrrolidine_3_carboxylic acid

Example 328J — ~ -_Base- 4- (1 + Meta-oxa-soiled soil "Gui-5-yl) -2- (1-¾yl-2-propanyl 2-3-yl) -l- ( (N, N_di (n-butyl) amine star fluorenyl) _pyrrolidine_3_carboxylic acid ethyl ester was produced by reacting the compound of Example 327C with a borane difluorenylsulfide complex. The title compound. Example 328 bis-trans-Earth- (1,3-phenylhydrazine dioxane) "Tr-5-yl" -2- (1-¾yl-2-propane-286-Paper Zhang scale Shizhou National Valve National Standard (CNS) Λ4 specification (210X 297 mm (please read the precautions on the back before filling this page)

552260 A7 B7 V. Description of the invention (284) Alken-3-yl) -1-((N, N-di (n-butyl) aminocarbonylmethylpyrrolidine_3_carboxylic acid According to the procedure of Example 7 1C, The title compound was prepared by condensing the compound of Example 328A with lithium hydroxide. Example 329 Trans, trans-di-4 _- (1 ″ 3-wild-di-dioxol-5-yl) _2_ (ν- Benzylaminomethyl ^^^^^^^^^^^^ Butylaminocarbonylmethylpyrrolidine ^ -carboxylic acid example 329A trans, transdi 4- (M-stem dioxolene -5-yl) _2- (N-fluorenylaminofluorenyl group · 1.1: .N, N: · tris. (Main-indigo) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid ethyl acetate The title compound was prepared by condensing the compound of Example 327A with amidine in ethanol in the presence of sodium cyanoborohydride.

Example 329B trans- '.. trans 4- (1-1-pendioxol-5-yl) -2- (1-hydroxy-2-propanedi-1-yl) -l-((N , N _-_ dioxanyldibutyl) aminocarbonyl, amidino) _pyrrolidine-3_carboxylic acid The title was prepared according to the procedure of Example 7 1 C, by reacting the compound of Example 329A with hydroxide. Compound. Example 3 3 0 part missing 3; J f (Please read the notes on the back before filling this page) Anti .._ 二., Trans-4- (1,3 -Sign_jf 乳 三 ^ cyclopentene -5-yl) -2- (N-ethylfluorenyl-N-zhimethyl n-butyl) aminocarbonylmethyl) _pyrrolidine_3_

Example 330A 翌-£ ^ _cyclopentene-5-yl) -2- (N-ethylfluorenyl-N-methylfluorenylmethyl) -pyrrolidine-3-ethyl carboxylate 287-paper size The Chinese National Standard (CNS) Λ4 specification (210x29? Gongqing 552260 A7 B7 Reverse A 〇 Ze X; f ii 5. Description of the invention (285 By example in the presence of symptoms or diethylamine, make Example 3 2 9 A compound is reacted with acetic anhydride to produce the title compound.

Example 330B branch ... 'trans-4- (1,3 dibifluorenyl dioxol-5-yl) _2_ to -ethyl ethyl -N-i amino fluorenyl):-1 di (jN , N · bis (n-butyl) aminofluorenylpyrrolidine_3-chitoic acid According to the procedure of Example 7 1 C, the title compound was prepared by reacting the compound of Example 3 3 〇a with lithium hydroxide. Compounds Example 3 3 1

1_, trans-4- (l, 3-phenylhydrazone dioxolene-5_some) -2- (ethynyl) _ρ di (n-butyl) aminocarbonylmethyl pyrrolidine-3-z Examples of acids 3 3 1A. Transphenylene dioxol-5-yl) -2- (ethynyl) -butriol to-butyl) aminofluorenyl V pyrrolidine-3- Ethyl Acetate produced the title compound using the procedure of Corey and Fuchs (Tetrahedron Lett. 1972, 3769-72) using the compound of Example 327A.

Example 3 3 1B to, trans.-4 ·: .. , 3-Benzamidine-dioxol-5-ylΛynyl) -Bu ((N, N-bis (n-butyl) aminocarbonylfluorenyl) -pyrrolidine_3_carboxyl according to Example 7 In the procedure of 1 C, the title compound was prepared by reacting the compound of Example 3 3 1A with lithium hydroxide. Example 3 3 2 '' H1,3-benzene # m-dioxol-5-yl ) -2- (formed as j-losing group) -1 di ((N "j: bis (macro-butyl) aminocarbonylfluorenyl) -pyrrolidine-3-carboximide-288 (Read the precautions on the back before reading) (Fill in this page) The paper music scale uses the Chinese National Standard (CNS) Λ4 specification (21〇 乂 297 Gongmeng 552260 A7 B7 V. Description of the invention (286

f Example 332A Watt'-heterocyclopentenylpentyl) small ((NJi ·· ^ ((furanyl) _pyrrole) _pyrrole 2 g_carboxyl bombardment using Taylor et al. (J. Org. Chem. 1989, 54 ( 15), 3618-24) procedures to produce the title compound by palladium-catalyzed coupling of the compound of Example 206A with propyl iodide.

Example 332B group, m1,3 · benzyl pentamynyl) _b, 'N-(n- ~ methylmethyl) -ρ ratio is only taken into account-a few acids according to the procedure of Example 71C, by making Example 332 eight The compound is reacted with the bell hydroxide to produce the title compound. Example 3 3 3 Trans-di-^-(4-methoxybenzene covered with pentamyl-5-one I: 1 diLK2,6-dioxy acid The compound of Example 6 1A was added to the dimethylformamidine Amylamine in amine—in the sodium salt solution of imine. After stirring for 24 hours, add Av &quot; _ octahydrate, and extract the mixture with acetic acid. By the method of Example 1D, dip everything ^ 1 ~ The hydrazone diimide is hydrolyzed to the title compound. Example 334 • y-'rt -lk (ti read the precautions on the back before filling in this page, -mouth presentation "^ 二 2- (4-methoxyphenylhydrazone! _4 -(1,3-Benzyl_5_some) -1 · [N, N -diphenylamine carbonylfluorenyl ip ratio? Each ^. The title compound was prepared according to the procedure described in Example 1. 1H] ^] \ 411 (3〇〇 MHz '00:; 〇0)? 52.83 ((1 (1, 1, a = 8197) 99-289- this paper Cao Chuan Chuang scale applicable national standards (CNS) A4 size (210 X 297 mm) 552260 A7 B7 · $ 〆 in the crotch:

&quot;, f A V. Description of the invention (287) (dd, 1, J 2 4.6, 9 · 5), 3.57 (xn, l), 3.79 (s, 3Η), 3.85 (d J = 9.5 ), 5.90 (s, 2), 6.71 (d5l, Bu 80), 6 84 (Melon, Nai, 7, 1, (d, 1, J 2: 1.6), 7.14-7 · 16 (m, 6 ), 7 19-7 '°' 7 04

, M, 6); MS (DCI / NH3) m / z 551. Regarding C33H3〇N2〇6. 〇 65 〇 〇 is C2H5OCOCH3 &lt; Analytical calculation 値: c 69 77; Η 5 π, rt,) · 77; N, 4 76. Experiment 値: C, 69.75; H, 5.55; N, 4.64. Example base, trans_2bis (4.-m-based phenylbenzene dioxin ^) bis [N, diisopropylamine, succinylmethyl] _ p-bilolite di + ^ root as described in Example 1 Procedure to prepare the title compound. ^ NMR (300 MHz, CD3OD) S 095 (d, 3, J = 65),} 24 (3, J = 6.4), 1.30 (d, 6, 6.8), 2.85 (d, 1, Bu; 12.5), 3 4.0 (dd, 1, J = 8.1, 9.8), 3.14 (t, 1, J = 9.7), 3.32-3.55 (m, 3), 3.63 (m, 1), 5.92 (s, 2), 6.75 (d, 1, J = 8.1), 6.85 (dd, 1 J, 1.7, 8.1), 6.93 (m, 2), 7.02 (d, 1, J = 1.7), 7.35 (m, 2). MS (DCI / NH3) m / z 483. Regarding the c27H34N206 · 〇.65Et〇Ac points Γ different values · C, 6 5.8 6; H, 7.3 2; N, 5 · 19. Experiment 値: C, 5.74; H: 7.26; N, 5.52. Example 3 Congji · A · ^ 13: · Fluoro-4-methoxyphenyl) -4- (1,3-benzo metadioxol-5-yl: 1-di-I1-N-propyl -N-butane sulfonamide Some) ethyl) -pyrrolidine-3-guinic acid The title compound was prepared as a white solid using the procedure described in Example 3 13 and Example 66. 65-66 ° C. 4 NMR (CDC13, 300 MHz) δ 0 82 (t, J 2 7.5 Hz, 3H), 0.92 (t, J 2 7.5 Hz, 3H) -290- This paper is suitable for this standard (CNS) Λ4 specification (210X 297 mm 41 ^ clothing 1T ------ AW. (Please read the notes on the back before filling in this page j 552260 A7 B7 V. Description of the invention (288), 1.34-1.52 (m, 4H), 1.72 (quintet, J = 7.5 Hz, 2H), 2.25-2,35 (m, 1H), 2.72-2.94 (ni, 5H), 2.97-3.12 (m, 2H) , 3.19-3.46 (m, 2H), 3.44 (d, J 2 9 Hz, 1H), 3.53-3.60 (m, 1H), 3.67 (d, J, 9 Hz, 1H), 3.89 (s, 3H ), 5.95 (s, 2H), 6.74 (d, J = 8 Hz, 1H), 6.82 (d, J = 8 Hz, 1H), 6.92 (t, J = 9 Hz, 1H), 6.97 (s, lH ), 7.12 (d, J = 9 Hz, 1H), 7.18 (d, J = 12 Hz, 1H). MS (DCI / NH3) m / e 565 (M + H) +. Example 337 is used in the example above The method described in the above can be used to prepare the compounds disclosed in Table 1. (Please read the precautions on the back before filling this page)

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364.

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245. V 〇 248.

250.

252. 387 This paper size is applicable to China National Standard (CNS) Λ4 specification (210X 297)

249. Girl

552260 Λ V. Description of the invention (385 Table 2B continued

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265.

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264.

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The Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

N 280.

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552260 Λ Β V. Description of the invention (387) Table 2B continued

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This paper size applies to China National Standard (CNS) A4 specifications (210X 297 while 552260 Λ &quot; Β 'V. Description of the invention (388) Table 2B continued

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331. 332.

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A V. Description of the invention (392) Table 2B continued

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A V. Description of the invention (393 Table 2B continued

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This paper size is applicable to China National Standard (CNS) Α4 size (2l〇 × 297 cm 552 260

A V. Description of the invention (398) Table 2B continued

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552260 Λ V. Description of Invention (399 Table 2B continued

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520. 521. 522. I # -404- This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X 297)

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534.

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A &quot; FT V. Invention Description (408 Table 2B continued

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Table 2B continued R

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AT B1 V. Description of Invention (412)

Table 3B -415- This paper size is in accordance with Chinese national standard (〇 ~ 5) and 8 size (210 乂 297mm)

552260

A

IT V. Invention Description (413) Table 3B continued

R R Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

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R R R

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126.

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130.

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A V. Description of the invention (419 Table 3B continued

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154. 155.

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161.

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172.167, 〇 170.

173. 168.

171.

174. Printed by Cooperatives, Staff, Central Bureau of Standards, Ministry of Economic Affairs

175.

176.

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190.

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207. 426- This paper size is applicable to China National Standard (CNS) A4 (210X 297 cm) 552260

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250.

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267. 552260 A. B- V. Description of the invention (428 Table 3B continued

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Λ7 IT V. Description of Invention (429) Table 3B continued

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296.

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This paper size applies Chinese National Standard (CNS) A4 specification (210X29 * 7mm) 552260 Λ. Β * 5. Description of the invention (43〇) Table 3B continued

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325.323.

326.

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339. 340. * no2 341.

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356. 354.

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R

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This paper size applies to China National Standard (CNS) Α4 specification (210 × 297 males) 552260 Α · Β * 5. Description of the invention (438) Table 3B continued

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451. 452. 453.

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This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297). 552260 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (442) Table 3B continued

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518. 519.

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543.

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A V. Description of the invention (446) Table 3B continued

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A. FT V. Description of Invention (447 Table 3B continued

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Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

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A V. Description of the invention (448) Table 3B continued

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612. 452 This paper size applies Chinese National Standard (CNS) Λ4 specification (210X 297) while 552260 Λ * Β &quot; V. Description of invention (45〇) R Table 3B continued RR 613. 614. 615. Μοα ^ Ογν ^ / 〇〇616. 617. 618. ν ^ 〇ο 619. XX: 620. ο ν1 ^

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632. &gt; r: A Umbrella 0 U _τ elimination in the middle part 340 Example of dioxolene 5-yl) -2- (4-methoxyphenyl 1 ^ Ιΐ (ΐ_ (3- Methyl butane jjA> N-phenyl) aminocarbonylmethyl) -pyrrolidin-3-carboxylic acid The title compound was prepared using the procedure described in Example 1. NMR (300 MHz, CD3OD) δ 〇85 (d, J = 6 Hz, 6H), 1 25 (q, J-7 Hz, 2H), 1.42-1.56 (m, 1H), 3.43-3.85 (m, 9H) '). 88 s (3)' 5.95 (s, 2H), 6.80 (d, J = 7 Hz, 1H), 6.86 (dd, J = 9 Hz, ih), 6.89-7.00 (m, 2H), 6.97 (d, J = 1 Hz, 1H ) '7.04 (d, J = 9 Hz, 2H), 7.37 (d, J = 9 Hz, 2H), 7.40-7.47 (m 53H). MS (C.I.) m / e C (53.12, 53.11), -454-National Standard for Valves (CNS) A4 Specification (210X 297 mm) (Please read the precautions on the back before filling this page)

552260 A7 ____________ B7 V. Description of the invention (452) H (4.63, 4.80), n (3 33, 3 28). Example 341 trans'trans 4-dioxolene-5_yl) · 2_ (4_methylhydroone) 1 (N _ isoamyl-tolylaminecarbonylmethyl)-? Bilodine-3- Read acid uses the procedure described in Example 1 to prepare the title compound. 1Η NMR (300 MHz, Cd3Od) δ 〇87 (t, J = 7 Hz, 3 seals, 1.20-1.47 (m, 4Η), 2.37 (s, 3Η), 2.83 (q, J = 7 Hz , 2Η) '3 〇6 · °. 2) (m, 2H), 3, 40-3.50 (m, 1H), 3.5 1-3.63 (m, dH)' 80 (s, 3H), 3.87 (d, J = 9 Hz, 1H), 5.92 (s, 2H) '6 74 (d, J = 8 Hz, 1H), 6.80-6 · 86 (τη, 3H), 6.89 (d, J = 8 Hz, 2H) '7.04 (d, J = 2 Hz, 1H), 7.12 (d, J = 8 Hz, 2H)' 7.19 (d, J = 8 Hz, 2H). MS (DCI) m / e 545 (M + H) +. About C32H36N206 &lt; Analysis and calculation 値: C, 70.57; Η, 6.66; N, 5.14. Experiment 値: C5 70.20; Η, 6.81; Ν, 5.03. Example 342 Tail interoxoylenyl) -2- (4-propanyl U ·-(N, -N dibutyl) aminocarbonylmethyl W Bihabbit-3- The procedure described in the above was used to prepare the title compound. Η NMR (300 MHz, cDCl3) 37.30 (2H5d, J = 9), 7.03 (1H, d, J 22), 6.83 (3H5 m), 6.72 (1H, d, J = 9), 5.95 (1H, d, Bu 2), 5.93 (lH, d, J = 2), 3.88 (2H: t, J = 7), 3.73 (lH, d, j = 12), 3.58 (1H, m) '3.53-3.20 (4H, m), 3.10-2.90 (4H, m), 2.72 (1H, d, J = 15) ^ 1.79 (2H, q, J -8) ^ 1.50- 1.05 (8H, m), 1.02 (3H, t, &gt; 7), 0.87 (3H, t, Bu 7), 0.80 (3H, t, j 2 7) -455- Paper size Shizhou Zhongwei National Standard) Λ4ϋ &quot; (210 X 297 Gong) --- (Please read the precautions on the back before filling this page)

552260 A7

广 # 先 叫 读 ft ^ M 法 意 #Continued to fill in the book,

V. Description of the invention (454: Jk 4 A 卬 f = (S, 3H), 5.95 (S, 2H), 6 73 (〇8 Hz, m), 6.8-6.97 (: 1Η) in A7 B7, 6-85 (d ^ -9 ^^^), 7.02 (d, J = 2 #, 3lH), 7.80 (d, J = 9 Hz, 2Η). Real tL345 basis) -WN, N- di (-then -Butyl) aminopyridine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. NMR (300 MHz, CDCl3) s 7 4〇 (3H, 妁, 7 22 (2H, d, J = 8), 7.13 (1H, dd, 1 = 8, 3), 6 72 (1H, d, Bu 9), 5 28 (ih, d, J = 12) '4.55 (2H, U = 9), 4.15 (lH, d, J = 18), 4.03 (2H, m), 3.75 (2H, no, 3.40 (2H, m), 3 2 0 (2H t, Bu 9), 3 i5 (1H, m), 3.1Q-2.90 (2H, m), 2.63 (2H, q, H), L47 (2H, m), 1.31 (4H, m), 1.12 (3H, t, J = 8), l.io (2H, m), 0.92 (3H, t, J = 9) '0.80 (3H, t, J = 9 ). MS (DCI / NH3) m / e 507 (M + H). Analysis and calculation of C31H42N204.io TFA 値: c, 63.86; H, 6.98; N, 4.51. Experiment 値: C, 63 95; H, 7 12; N, 4.43. Example 3 4 6 trans-, trans-phenyl fluorene J dioxol-5-yl) -2- (4-fluorenoxyphenyl). = Ll ( (N- (3-Pentyl) -N-aniline) carbonyl) methylpyrrolidine-3-carboxylic acid was prepared using the procedure described in Example 1. 1 n NMR (300 MHz, CD3OD) δ0 .93 (t, J = 7.3 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3Η), 1.33 (m, 4H), 2.72 (d, J = 15.2 Hz, 1H), 2.81 ( m, lH), 3.11-3.23 (m, 2H), 3.45-3.5 7 (m, 2H) -457- The size of this paper is suitable for China S country ¾ ^ standard (CNS) A4 size (210 乂 297 male axe) (Please read the precautions on the back before filling this page) 55226〇

Description of the invention (455, A7 B7 -----. · 79 (s, 3H) '3.83 (d, Bu 9.8 Hz, 1H), 4.54 (m5 1H) j 5.92 (s, 2H), 6 · 73 (d, J = 7 8 Hz, ih), 6 83 — 3 圯 6.98 (bs, 2H) '7.04 (d, J = 1.7 Hz, m), 7 〇7 (2), 7 37 (m '3H). MS (DCI) m / e 545 (M + H +). Analytical calculations for C32H33N2 06 ~ 35 H2 0: c, 69? 6; h, 6 7i; N, $ ⑽. Test results: C5 69.72; H, 6.66; N, 4 94. ~ ^ Di ^ di (.1,% Benzene dioxo, although cyclopenta-5-yl) -2- (4-methoxybenzyl) ) -N_ (3-trifluoromethyl Iphenyl) amino) carbonyl) methylpyridine · 3-rollic acid

The procedure described in Example 1 was used to prepare the title compound. !! H NMR (300 MHz, cD3OD) δ 0.87 (t, J = 6.6 Hz, 3H), 117]. 45 (m, 4H), 2.65 (d, J = 16.5 Hz, 1H), 2.72 (m, lH) 'l0 (t5 J = 9.5 Hz, 1H), 3.21-3.27 (m, 1H), 3.40 (dd, J — 4.1, 9.9 Hz, 1H), 3.54 (m, 1H), 3.61-3.74 (m , 3H), J · 77 (s, 3H), 5.93 (s, 2H), 6.73-6.85 (m, 4H), 7.02 (m,) H) '7.33 (d, J = 7 ^ Wg, 1H), 7.40 (s, lH), 7.58 (i, J = 7.8 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H). MS (DCI) m / e 599 (M + H +). Analysis and calculation of c32H33F3N206 値: c, 64.21; H, 5.56 'N, 4.68. Experiment 値: c, 64.09; H, 5.63: N, 4.57. Example 348 Phenylhydrazine-5-yl) -2- (4-methylphenyl-N- (4-morpholinecarbonyl) aminocarbonylmethyl) _pyrrolidine-3-carboxylic acid _ The procedure described in Example 1 was used to prepare the title compound. 1Η -458- f Please read the notes on the back 'before filling in this page j • li red: only' the center of the part ^ -XJm 丁-'七 于 合 M, 7 ::-卬 i-, the paper size is appropriate / ¾¾National 彳 ϋ &quot; (CNS) A4 specification (210X 297 mm) 552260 A7 B7 V. Description of the invention (456) (Please read the notes on the back before filling in this page) nmr (3〇o megahertz, CD3OD) S0.78 (1, J = 7 Hz, 3H), 143 (q, J = 7 Hz prostitute, 2H), 2.07-3.01 (m 1H), 2 76 (dd, J 2 7, 9 Hz ?, 2H ) '2.77-3.00 (m, 5Η)' 3.05 (3.70, J = m Hz, 11H) '3.76 (s, 3H)' 5.88 (s, 2H), 6.67 (d, J = 8 Hz, 1H), 6.80 (dd5, 7 Hz, 1H), 6.83-6.90 (m, 2H), 6 98 (d, J = 2 Hz, 1H) '7.32-7.39 (m, 2H). MSm / e Analysis and calculation of (m + H) C29H39N307 307 · (M + H) 540.2710. Experiment 値 (M + Hi54〇2713., Trans-ilGL · 3 ·· -phenylene metadioxapenten-5-yl) -2-¾-methoxyphenyl lll- (cis--H ·: ; -Methylhexahydropyridine 21: yl) carbonylpyridine-3-pyridine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. 1Η NMR (300 MHz, CD3OD) δ 0 · 94 (d, J = 7 Hz, 3Η), 1.15 d (7, 3H), 1.10-1.70 (m, 6H), 1.70-1.90 (m, 1H), 2 · 9 (d5 J = 13 Hz, 1H), 3.00-3.20 (m, 2H), 3.50 (3.70, J = m Hz, 2H), 3.79 (s, 3H), 3.80-4.00 (m, 1H), 4.10-4.65 (m, 2H), 5.95 (s, 2H), 6.70 (7.10, J = m Hz, 5H), 7.35 (m, 2H). MS m / e Calculation of (M + ΗΓ C28H35N206): (M + H) 495.2495. Experiment (M + H) 495.2493. Example 3 50 Oxygen, trans-2- (4-methoxymethoxybenzyl) ) -4- (1, m-dioxo JjAiL group) -1- (2- (N-propyl-n-pentaneamido) ethyl) carboxylic acid using the procedure described in Example 1 to prepare the title Compounds, and isolated a white solid. H NMR (CDC13, 300 MHz) δ 〇.78 (t, 459 paper size / 丨] China National Standard (CNS) A4 size (210x 297 mm 552260 A7 B7 V. Description of the invention (457) (Please read the notes on the back before filling this page) Hertz, 3H) '0 · 90 (t, J = 7 Hertz, 3H), 1.28-1.36 (m, 4H), 1 · 93 (six peaks, J = 7 Hz, 2H), i.72 (t5 is 7 Hz, 2H), 2.20-2.32 (m, 1H) '2.72-3.10 (m, 7H), 3.18-3.41 (m, 2H), 3.43 (dd, J = 3 Hz, J = 9_gJ, iH), 3.48 (s, 3H), 3.52-3.59 (m, 1H), 3.68 (d, J = 9 Hz, 1H), 5.15 ( s, 2H), 5.94 (s, 2H) '6.73 (d, J = 8 Hz, ih), 6.82 (dd, Hz, J = 8 Hz, 1H), 6.98-7.02 (m, 3H), 7.32 (d , J 9 Hz, 2H). MS (DCI / NH3) m / e 591 (M + H) + 〇, φ Example 35 1 〇 ^ / 一, (4 scoops of a 'tail two 4- (1,3 -benzene) M-Dioxane 晞 -5 _some) -2 ^ 4-methylbenzylbutyl) -N-anilino) kisyl) methylpyridine-3 complex acid using the procedure described in Example 1 To prepare the title compound. 1 n NMR (300 MHz, CD3OD) S0 7, 089 (m 6H), i μ] 21 (m, 1Η), 1.25-1.40 (m, 1Η), 2.64 ( dd, j 4.6, 15.4 Hz, 1H), 2.76 (t, J 9.0 #g, 1H), 305_3l3 (m, 2H), 3 37-3.49 (m, 2H), 3.70 (S, 3H) , 3.80 (dJ = 98 Hz, 1H), 453 (m, 1H) '5.83 (m, 2H), 6.65 (d, Ps "Hz, 1H), 6 72 (-6.76, ^ Hz, 311), 6.87 (111, 2, 6 95 °, 17 Hz, 1H) '7.0] (m, 2H), 7 29 (m, 3H). Ms (dc) extinguishes 53i (M + "). Analysis and calculation of C31H34N20.6 · 0.4H2〇 値: c, 69., H, 6.52, N, 5.21. Check 値: c, 69 l9; H, 6 52; N, 5.03. Example 352_ Oxychavaloxyphenyl 460- 552260 A7 _________B7 V. Description of the invention (458) (Read the precautions on the back before filling this page)) -1-((Ν- (2 -Propyl-1) .N-anilino "| yl) methyl) -pyrrolidine-3-^^ The procedure described in Example 1 was used to prepare the title compound. 1Η NMR (3 00 MHz, CD3OD) δ 0.99 (d, J = 6.8 Hz, 6Η), 2.7l (d, J = 15.6 Hz, 1H), 2.84 (m, lH), 3.13-3.18 (m, 2H ), 3.45-3.58 (m, 2H), 3.79 (s, 3H), 3.88 (d5 J = 9.8 Hz, 1H), 4.80 (m, lH), 5.92 (s, 2H), 6.74 (d, J = 8.1 Hertz 1H), 6.83 (m, 3H), 6.96 (br s, 2H), 7.04 (d, J = 1.7 Hertz, ih), 7.13 (m, 2H), 7.38 (m, 3H), MS (DCI) m / e517 (M + H) ten. Analysis of C3〇H32N206 · 0.4 H2〇 · 〇, 〇8 CH3C〇2C2H5 Calculate 値 · C, 68.65; H, 6.28; N, 5.28. Experiment 値: C, 68.64; H, 6.35; N, 5.14 〇 Example. 3 5g_ group, trans-4- (4-propoxyphenyl) -2- (4-methylphenyl) -1-(&gt; ^-(^: ^-Butyl) aminecarboxymethyl) -pyrrolidine-3-propanoic acid The procedure described in Example 1 was used to prepare the title compound. 1 η NMR (30 (UU ^^, CDCl3) 5 7.42 (2H, d5J = 1 (^ ii ^), 738 (2H, d, J = 10 Hz)), 6.92 (2H, d, J = 10 Hz), 6.88 (2H, d, &gt; 10 Hz), 5.13 (115 (1,212 Hz), 4.02 (211,111), 39 °

(2H, t, J 2 8 Hz), 3.80 (3H, s), 3.71 (3H, m), 3.40 (2H m), 3.19 (lH, m), 3.10-2.90 (2H, m), 1.80 (2H , M), 148 (2H, m), 1.29 (4H, m), 1.13 (2H, m), 1.03 (3H, t, J = 8 Hz), 0.92 (3H, t, J = 9 Hz), 0.82 (3H, t, J = 9 Hz MS (DCI / NH3) m / e 525 (M + H0. Analysis of C31H44N205. L tFa): C, 62.06; H, 7.10; N, 4.39. Experiment 値 · -461-This paper is sent to Sichuan China National Standard ((^ 5) / \ 4 size (210/297 mm) 552260 A7 B7 -----—. V. Description of the invention (459) C, 62.43 H, 7.28; N, 4.39. Example 354 trans-4- (J_Lg-wilt-and-dioxolene-5-volume} 9

—X 1-1-((1,2,1? __ 4: 1 ^ quin 4-4-1-yl) carboxyl) fluorenyl) di ^^^ · ^^, using the procedure described in Example 1 to prepare the title compound 7 NMR (300 MHz, CD3OD) si.88 (quintet, ^ 65 Hz 2H), 2.67 (t, J = 6.4 Hz, 2H), 2.87 (t, J = 8.6 Hz, 1H) ^ '^ i4 (m, 2H), 3.42 (dd, J = 4.6, 9 ^^, lH), 3.53-3.70 (m, 3H), 3.72-378 (m, 1H), 3.77 (S, 3H), 3.86 (d, ㈣ 6 Hz 'lH), 5.91 (s, 2H), 6.73 (d, J = 8.1 Hz, ih), 6.83 (m, 3H), 6.98 (d, J = 1.1 Hz, ih), 7.02-7.23 (m, 6H). MS (DCI) m / e 515 (M + H,). Analytical calculations for C3OH3ON2O6 · 03 h2 0 · 0.15 CH3C0 2C2H5 値: C, 68 93; H, 6 0; N, 5 25. Experiment 値: C, 68.91; H, 5.86; N, 5.19. t 3 ^ 5 'trans_2bis (3 ·' · 4-diphenyl. 4- 丄 1,3-benzyl-co-dihydrofluorene cyclopentene-5_ D: 1- (N, N-Shifang Raw-Butyl J. Bisylmethylpyrrolidine-3-folic acid The procedure described in Example 1 was used to prepare the title compound, and a white solid ft ° melting point 64-65 C was isolated. NMR (CDC13, 300 Megahertz) δ 0.79 (t, J = 7 Hz, 3H), 0.88 (t5 J = 7 Hz, 3H), 1.07 (hexaplex, J-2 7 Hz, 2H), 1.2 (M.35 (m, 4H ), M3 (hexaplex, J-7 Hz *, 2H), 2.83 (d, J = 13.5 Hz, iH), 2.94-3.17 (m, 4H), 3.22-3.42 (m, lH), 3.40, 3.48 (m, 3H), 3.58-3.65 (ιη, 1H), 3.82 (s, 3H), 3.85 (s, 4H), 5.92 (s, 2H), 6.73 (d, -462) Laos National Standard (CNS) Λ4 specification (210X297 male) (Please read the precautions on the back before filling this page)

、 1T good jealous ministry c ^ -XJn <_T &gt;/]; ^ Μ 初初 5: &gt; 552260 ^ •, ^ ministry times ^-^-nai ,, only 5 7 川 # 合 ^ ^^ 卬 4: · ^ A7 ____________B7 V. Description of the invention (46〇) ό · 73 (d, J = 8 Hz, 1H), 6.81 (d5 J = 8 Hz, 111), 6.86-6.96 (m, 3H) , 7.07 (d, J = 3 Hz, 1H). MS (DCI / NH3) m / e 541 (M + H) +. Example 356-_'trans-methoxyphenyl) · 4 · (1,3-phenylhydrazone-dioxolane-5_ 碁 &gt; Bu [2- (~ propyl-N-n-pentanesulfonate Amidino) ethyl μpyrrolidin-3-carboxylate was prepared using the procedure described in Example 1 and the white solid was isolated. Melting point 75-86 ° C. 4 NMR (CD3OD, 300 MHz) δ 0 75 (t, J = 7 Hz, 3H), 0.82 (t, J = 7 Hz, 3H), 1.32-1.43 (m, 6H), 1.65-1.77 (m, 2H), 3.0-3.09 (m, 4H ), 3.23-3.27 (m, 2H), 3.44 (t, J = 6 Hz, 1 H), 3.47-3.56 (m? 2H), 3.78 (d, J = 9 Hz, 1H), 3.83-3.93 (m , 2H), 3.87 (s, 3H), 3.92 (s, 3H), 4.63 (d, J 2 13 Hz, 1H), 5.97 (s, 2H), 6.82 (d, J = 7 Hz, 1H), 6.93 (d, J = 7 Hz, 1H), 7.06 (d, J = 7 Hz, 1H), 7.08 (d, J = 3 Hz, 1H), 7.16 (dd, J = 3 Hz, BU 7 Hz, 1H) , 7.27 ('d, J 2 3 Hz, 1H). MS (DCI / NH3) m / e 591 (M + H), Example 357 trans, trans-2- (3,4-dimethoxymethane V4- (l, 3-Benzo-dioxolyl) -l-f2- (N-propyl-N-n-hexanesulfonamido) ethyl 1- Pyridine-3-zoic acid uses the procedure described in Example 1 to prepare the title compound and isolates a white solid. Melting point 65-66. (: 4 NMR (CDC13, 300 MHz ___ -463-) State Central Park National Standard (CNS) A4 specification (210x297 mm) (Please read the notes on the back before filling this page) Order # 1 552260 A7 B7 0 V. Description of the invention (I) δ 0.80 (t5 J = 7 Hz , 3H), 0.89 (t, J = 7 Hz, 3H), 1.23-1.48 (m, 6H), 1.43 (hexaplex, J = 7 Hz, 2H), 1.72 (hexaplex, J = 7 Hz, 2H), 2.25-2.3 5 (m, 1 Η), 2.73-3,10 (m, 7 Η), 3.19-3.32 (m, 2 Η), 3.45 (dd, J = 3 Hz, J = 9 Hz, 1Η) , 3.53-3.59 (m, lH), 3.68 (d, J = 9 Hz, 1H), 3.87 (s, 6H), 5.95 (s, 2H), 6.74 (d, J 2 8 Hz, 1H), 6.79- 6.86 (m, 2H), 6.92-6.97 (m, 2H), 7.02 (s, 1H), MS (DCI / NH3) m / e 605 (M + H) +. Example 3 5 8 ^ trans, trans-2- (4-methoxybenzyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- [2 Amino) ethyl 1-pyrrolidin-3-carboxylic acid The compound of Example 1C (250 mg), N-bromoethylphthalimidine (206 mg) and diisopropylethylamine (175 mg) 1 ml of acetonitrile and heat to 95 ° C for 2.5 hours. Toluene was added and the mixture was rinsed with KHC03 solution. The solution was dehydrated (Na2.S04) and concentrated. The crude product was purified by chromatography on silica gel, eluting with 3: 1 EtOAc-hexane, to give 2 16 mg of the intermediate ethyl ester, which was hydrolyzed by the method of Example 1D to obtain 13.0 g. The title compound is a white powder. 1H NMR (300 MHz, CDCl3) 33.12-3.26 (m, 2H), 3.60-3.7 5 (m, 2H), 3.70 (s, 3H), 3.98-4.12 (m, 2H), 4.45-4.5 5 (m , 1 Η), 4.69 (d, J = 9 Hz, 1H), 4.76-4.88 (m, 1H), 5.96 (s, 2H), 6.55 (d, J = 8 Hz, 1H), 6.60-6.70 (m , 3H), 6.79 (d, J 2 8 Hz, 1H), 7.05-7.45 (m, 5H), 7.75 (d, J = 7 Hz, 1H). -464- The scale of this paper is inverse / 丨] China National Standards (CNS) Λ4 specification (210X29 * 7 male f) (Please read the precautions on the back before filling this page) ί _τ &gt; /] ί- A ii 卬 552260 A7 B7 V. Description of the invention (462) Example 359 (Please read the notes on the back before filling out this page) trans, trans-4- (l, 3-phenylhydrazine dioxolene-5- ) -2- (4-fluorenoxyphenyl) -1-(((N- (2-pentyl) -N-aniline) carbonyl) methyl) -pyrrolidine-3-carboxylic acid was used in Example 1 The procedure described in to prepare the title compound. iH NMR (300 MHz, CD3OD) 3 0.86-0.98 (m, 6H), 1.17-1.22 (m, 1H), 1.23-1.41 (m, 3Η), 2.70 (dd, J 2 1 1.2, 15.3 Hz , 1H), 2.83 (m, 1H), 3. 1 0-3.2 1 (m, 2H), 3.45 · 3.60 (m, 2H), 3.79 (s, 3H), 3.86 (m, 1H), 4.74 (m, 1H), 5.91 (m, 2H), 6.73 (dd, J = 1.1, 7.7 Hz, 3H), 6.82 (m, 2H), 7.04-7.14 (m, 3H), 7.36 (m, 3H) ) MS (DCI) m / e 545 (M + H) —. About the analysis of C32H36N20. 0. 25 CH3C02C2H5, 値 · C, 69.95; Η, 6.76; Ν, 4.94. Experiment 値: C, 70.03; H, 6.54; N, 4.78. Example 360 trans, trans-4- (1,3-Benzo-dioxopine-coordination-5 -yl) -2- (4-oxoepitoylbutyl-N_ (2_alanyl) amine (Methyl) -p ratios are:->-The title compound was prepared using the procedure described in Example 1. 1Η NMR (300 MHz, CD3OD) δ 0.83 (t, J 2 7 Hz, 3Η), 1.23- 1.39 (m, 4H), 1.40-1.55 (m, 3Η), 2.60-2.72 (m, 2Η), 3.00 -3.80 (m, 5H), 3.66 (s, 3H), 5.87 (s, 2H), 6.39 (d, J = 9 Hz, 2H), 6.74-6.85 (m, 3H), 7.17 (d, J = 2 Hz, 1H), 7.40 (dd, J 2 8 Hz, 1H), 7.52-7.62 (m, 3H), 7.80-7.90 (m, 1H), 7.90-8.00 (m5 2H). MS (DCI) m / e 581 (M + H). About the analysis and calculation of C35H36N2 06 · 0.3 H2 0: C, 71 73; H, -465-This paper size is suitable for the National Standard of Chuanwei (CNS) Λ4 specification (210X 297 mm) 552260 A7 ----. _________________B 7 V. Description of the Invention (463) 6.29; N, 4.78. Experiment 値: c, 7174; H, 6 26; N, 4 72. Example 3 Utilization of 6 1 I 'trans-dioxobenzo-dioxolene-5-yl group 2- (N_ · Dioxane difluorenylamino) ethyl 1-pyrrolidin-3-dicarboxylic acid The procedure described in Example 66 was used to prepare the title compound and a white solid was isolated. Melting point is 53-54 ° C. 1h NMR (CDC13, 300 MHz) δ 0.79 (t, J = 7 Hz, 3H), 〇89 (t, J = 7 Hz, 3H), 〇3 (t 'J — 7 Hz, jH), 1.24-1.34 (m, 4H), 143 (hexaplex, j = 7 Hz, 2H), 1.67_1.75 (m, 2H), 1.80 (hexaplex, 2H), 2.23-2.33 (m, 1H ), 2.72-2.93 (m, 5H), 3.05 (seventh peak, J = 7 Hz, 2H), 3.15-3.3 5 (m, 2H), 3.42 (d, J = 9 Hz, 1H), j.54- 3.62 (m, 1H) '3.67 (d5 J = 9 Hz, 1H), 4.90 (t, J 2 7 Hz, 2H), 5.95 (s, 2H), 6.73 (d, J 2 8 Hz, 1H), 6.85 (d, J = 8 Hz, 2H), 7.02 (S, 1H), 7.32 (d, J = 8 Hz, 2H), MS (DCI / NH3) m / e 589 (M + H) +. Example 362 Tail 'trans-4- (l, 3_phenylhydrazine-5-oxomethoxyphenyl ll.l-((2 -fluorenyl) 丨 laryn-1 -yl) (Methyl) methyl) -p-to-p-dose-3_ carpetic acid The procedure described in Example 1 was used to prepare the title compound. NMR (300 MHz, CD3D) A mixture of 3 indole C2 diastereomers. 0.95 (m, 1.5 (CH3)), 1.05 (d, 6, 3H, 1.5 (CH3)), 2.62 (m, lH), 3.01 (m, 2H), 3.14-3.25 (m, lH), 3.37 -3.52 (m, 1.5 H), 3 56-3.80 (m, 2H), 3.65 (s, 1.5 (CH30)), 3.76 (s, 1.5 (CH30)), 3.93 (m, 0.5H) , 4.05-4.13 (m, 0.5H), 4.42-466- Degrees of China National Standard (CNS) Λ4 specification (210X 297 mm) '~~~-(Please read the precautions on the back before filling in this page to order Φ, 552260 A7 _ _________B7 V. Description of the invention (464) (m, 〇5Η), 4.65_4.74 (m, 1H), 5 91 (m, 2H), 6 72 (d, J = 8.1 Hz, 0.5H), 6.75 (m, 0.5H), 6.85 (m, 2H), 6.92 (d, J = 8.5 Hz, 1H) '7.00-7.06 (m, 2H), 7 14 (t, J = 7 7 Hz, 1H), 7.21 (t, J 2 6.6 Hz, 1H), 7 38 (m 2H), 7 99 (m lH). MS (DCI) m / e 515 (M + H). About C3〇H3 〇N2〇6 · 〇35 H2〇 • 0.3 CH3C02C2H5 Analytical calculation 値: c, 68 47; H, 6 10; N, 5.12. Experiment 値: C, 68.46; H, 597; N, 5.07. Example 363

Cong di_trans-4- (1,3-pyrido-dioxen_5-yl) _2_ (4_methoxybenzyl kl- (2-hydroxy-3-propylhexyl pyrrolidine_3_carboxy The acid uses the procedure described in Example 1 to prepare the title compound. 1H NMR (300 MHz, CD3OD) δ 1.06 (m, 6H), 1.26-1.60 (m, ^ 浐 ^ | 中 火 c ^ rx; ,, il .-T-; /] f combined 0, ^ print 1: (Please read the notes on the back before filling this page) Φ— ， 1H), 3.44 (d, J = 2.0 Hz, ih), 3 61 ( t, j =; n Hz, 1H) '). 73 (t, J = 11.0 Hz, m), 3 85 (m lH), 3 96-417 (m, -H) 4.02 (s, 1.5 (CH30 non Enantiomers)), 4.03 (s, 1.5 (CH30 diastereomers)), 6 15 (s, 2h), 70i (d, j = 8i Hz '0.) H), 7.00 (d, J = 8.1 Hz, 05H), 7 10 (m, 1H), 7 23 (m,] H) '7.77 (m, 2H). MS (DCI) m / e 484 (M + IT). Analytical calculations for C28H37N0 ··· 33 h3P04: c, 65 34; h, 7.44; N, 2.72. Experiment 値: C, 65 3 0; H, 7 4 0; N, 2 60. t penten-5-yl) -2- (4-methoxyphenylfluorenyl) amino) carbonyl) methylpyridine __________-467-this paper from 552260 A7 B7 V. Description of the invention (465) Pyridine_ The 3-carboxylic acid was prepared using the procedure described in Example 1 to prepare the title compound. iH NMR (300 MHz, CD3OD) 1: 1 mixture of delta isomers. 0.6i (t, J = 7.1 Hz, 1.5Η), 0.72 (7.3, 1.5 °), 0.76 (t, J = 7.1, 1.5, 0.83, t, 7.3 Hz, 1.5Η), 1.505-1 60 (m, 8H), 2.84-3.10 (m, J = 2.5, 3.18, t, 9.7 Hz, 0.50), 3.41-3.52 (m5 2H), 3.47-3.69 (m, 2H), 3.66 (s , 1.5H), 3.73 (s, 1.5Η), 3.77 (s, 1.5H), 3.78 (s, 1.5H), 3.79 (s, 1.5H), 3.86 (d, J = 9.8 Hz, 0.5H) , 4.19 (d, J = 17.7 Hz, 0.5Η), 4.29 (d5 J = 15.2 Hz, 0.5H), 4.40-4.49 (m, 0.5H), 4.47 (d, J = 15.3 Hz, 0.5H ), 4.60 (d, J = 17.6 Hz, 0.5H), 5.93 (m, 2H), 6.46 (dd, J = 1.7, 8.2 Hz, 0.5H), 6.52 (d, J 2.0 Hz, 0.5H), 6.74 (m, 2.5H), 6.80 (s, 1H), 6.83-6.88 (m, 1H), 6.92 (111, 1.51 ^), 7.03 ((1 (1,) two 1.7, 6.8 Hz, 1 India, 7.19 (111, 1H), 7.36 (m, 1H). MS (DCI) m / e 647 (M + H —). Analysis and calculation of C37H46N208: C: C, 68.71; Η, 7.17: N, 4.33. Experiment値: C, 68.41; H, 7.26; N, 4 · 11. Example 365 yr. Part A] (j compound $ 印 (Please read the notes on the back first Please fill in this page again.) Trans, trans-4- (1,3 -Benzene-dioxopentyl-5_yl) -2- (4--oxofluorenyl) -1-((pyridoline 1-yl) carbonyl) methyl) -pyrrolidine-3-carboxylic acid was prepared using the procedure described in Example 1. NMR (300 MHz, [0300] 52.97 ((^ &gt; 1 = 8.1, 9.5 Hz, 1] ^), 3.10 (t, J = 8.1 Hz, 2H), 3.16-3.22 (m, 2H), 3.51-3.68 (m, 3H), 3.73 (m, 3H), 3.83-4.05 (m , 3H), 5.90 (m, 2H) -468- This paper is suitable for size / 丨] 屮 S National Standard (CNS) Λ4 specification (210X 297 mm) 552260 A7 _________ ^ ____ 5. Description of the invention (466) '6.73 (d, J 2 8.1 Hz, 1H), 6.86 (m, 3H), 6.99 (dt, J = 1.1, 7.4 Hz, 1H), 7.0 8 (d, J = 0.7 Hz, ih) , 7.11 (m, 1H), 7.18 (d, J = 7.1 Hz, 1H), 7.38 (d5 J = 8.5 Hz, 2H), 8.02 (8.1, 1H). MS (C.I.) m / e 501 (M + H +). Analysis and calculation of C29H28N2〇6 · 0.5 H20 · 0.15 CH3C02C2H5 c · c, 68 〇i; H, 5.82; N, 5.36. Tests: C, 68.03; H, 5.65; N, 5.25.例 3 6 6 Tail di_trans-4_ (1,3-benzo-dioxopentene_5_yl) -2_ (4_methylphenylphenylchlorophenyl) aminomethyl Pyrrolidine-3 acid was prepared using the procedure described in Example 1 to prepare the title compound. 1 η NMR (300 MHz, CD3OD) δ 0.89 (dt, J = 7 Hz, 3H), 1.23-1.51 (m, 4H), 2.52-4,00 (m, 8H), 3.78 (d, J 2 6 Hertz, 3H), 5.92 (d, J = 6 Hertz, 2 buckles, 6.70-6.8 7 (111,411), 7.02-7.21 (m, 4H), 7.27-7.52 (m, 3H). MS ( DCI) m / e 565 (M + H). Analytical calculations for C31H32N206C1.0.6H2O: c, 64.66; H, 5.99; N, 4.86. Experiment: c, 64.59; H, 6.00; N , 4.64 〇 Example 3 ^^^ 1 ^ .. (4-. 曱 _oxyphenyl 茇 斿 dioxol-5-yl kim5-trimethylpyridine 芊 -pyrrolidine -3-carboxylic acid At room temperature, the compound from Example 1C (0.25 g) was mixed with 0.169 g of 0,4,5-dioxofluorenyl chloride and 0.175 g of diisopropylethylamine in 1 ml of acetonitrile. The reaction was carried out for 2 hours. The obtained ester was separated and then hydrolyzed by the method of Example 1D to obtain 0193 g of the title compound. Melting point 108_n〇 _____ -469- This paper standard description (CNS) Λϋ ^ Γ72Η) χ2—97 公 6 ------ (Please read the precautions on the back before filling this page), 1T f 552260 A7 B7 V. Description of the invention (467) ° C. Ifi NMR ( 300 MHz, CDC13) δ 2.75 (t, J 2 9 Hz, 1H), 2.95-3.05 (m, 2H), 3.20 (d, 11 Hz, 1 Η), 3.45-3.55 (m, 1 Η), 3.7 · 3 · 8 (m, 2Η), 3.84 (s5 3Η), 5.95 (dd, 2 Hz, 6 Hz, 2H), 6.55 (s5 2H), 6.70 (d, J = 8 Hz, 1H), 6.30-6.35 (m, 1H), 6.90 (d, J = 9 Hz, 2H), 7.13 (d, J = 2 Hz, 1H), 7.43 (d, J = 9 Hz, 2H). Example 368

Trans, trans_4- (1,3-benz-'dioxopenten-5-yl) -2- (4-methyllactoyl) -1_ (N-butyl-N- (3- Carbobenzyl) azurezylmethyl) -pyrenepyrene-reuse the procedure described in Example 1 to prepare the title compound. iH NMR (300 MHz, CD3OD) δ 0.89 (t, J = Hertz, 3H), 1.20 -1.42 (m, 4H), 3.42-3.87 (m, 9H), 3.9 (s, 3H), 5.96 (s, 2H), 6.75 (7.10, J = m Hz, 7H), 7.33-7.50 (m, 4H). MS (C.I.) m / e 565 (M + H). Analysis and calculation of C31H33N2O6Cl. 1.0 CF3COOH: C, 58.37; H, 5.05; N, 4.13. Experiment 値: C, 58.41; H, 4.99; N, 4.08. Example 369 ^ 浐 部 中 ^^-^-而 ： ^ 工 消 仏 合 ^ :: 杉 印 '^: (Please read the precautions on the back before filling out this page) Anti-trans-2- (4-methoxy Phenyl) -4- (1,3-phenylhydrazone-dioxolane-5-yl) -1_ [2_ (di-n-butylamino) oral bite 3-Cause §1 The compound from Example 1C (0.25 g) and 0.1 1 g of 2,4-dichloropyrimidine and 0.175 g of diisopropylethylamine in 1 ml of acetonitrile at room temperature The reaction was performed for 2 hours to obtain 0.218 g of 2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- (2-chloro-4- Pyrimidinyl) -pyrrolidine-3-carboxylic acid ethyl ester. Make the compound at 125 ° C in 2 ml of toluene with 1 ml of di-470- This paper is the standard of the state of China (CNS) Λ4 specification (210 乂 297 mm) 552260 k B7 _______ __________________ — ______ 5. Description of the invention (468) Butylamine reacts for 17 hours. The obtained ethyl ester was hydrolyzed by the method of Example 1D to obtain 0.12 g of the title compound as a white powder. 1H NMR (300 MHz, CDCh) δ 0.75-0.90 (wide band, 6Η) ,! n.3 (br, 4H), 1.35-1.55 (br, 4H), 3.05 (m, 1H), 3,3-3.5 (br, 2H), 3.55-3.67 (m, 2H) '3.75 (s, 3H ), 4.6 (br, ih), 5.2 (br, 1H), 5.45 (br, lH), 5.87 (s, 2H), 6.3 (br, lH), 6.67 (d, J = 8 Hz, 1H), 6.7 -6.85 (m, 4H), 7.10 (d, J = 9 Hz, 2H). Example 370 Anti, anti-wild-per-dioxol-5-yl) -2- (4-fluorenylbenzyl) -1-(((N- (2-methylbutane-bromo J-N _ Anilino) kisyl) methyl) -p-bilolite-3-polyacid The title compound was prepared using the procedure described in Example 1. 1Η NMR (300 MHz, CD3OD) δ 0.90 (t, J = 7.5 Hertz, 3Η), 1.12 (s, 3H), 1.14 (s, 3H), 2.06 (q, J = 7.5 Hz, 2H), 2.73 (d, J = 15.3 Hz, 1H), 2.91 (t, J = 9.5 Hertz, 1H), 3. 1 1 (d, J 2: 15 · 6 Hertz, 1H), 3.21 (t, J 2: 8.8 Hertz, 1H), 3.50-3.61 (m, 2H), 3.80 (s, 3H), 4.00 (d, J = 10.2 Hz, 1H), 5.91 (s, 2H), 6.74 (d, J = 7.8 Hz, 1H), 6.85 (m, 3H), 6.93 (m, 1H) Central Standards of the Ministry of Economic Affairs Printed by the Bureau ’s Consumer Cooperative (please read the notes on the back before filling this page), 6.98 (m, 1H), 7.03 (d, J = 1.7 Hz, 1H), 7.17 (m, 2H), 7.36 (m, 3H). MS (DCI) m / e 545 (M + H-1). Analysis and calculation of C32H36N206 値: C, 70.57; Η, 6.66: N, 5.14. Experiment 値: C5 70.17; Η, 6.53; Ν, 4.97. Example 3 7 1 Reverse : · (4-B-epiyl) -4- (5-Hydroxyphenyl) -1- (N, N-di (n-butyl) amine Tan-471-This paper size applies to Chinese National Standards (CNS ) A * 4 specification (210X 297 revolutions) &quot; 552260 A7 B7 V. Description of the invention (shed) methylmethyl) _g specific bite _ 3-lean acid The procedure described in Example 1 was used to prepare the title compound. 1ah NMR (3 00 MHz, CDC13) δ 7.25 (3H, m), 7.21 (1H, d, 3 Hz), 7.17 (3H, m), 3.80 (1H, d, 10 Hz), 3.65 (1H , Ddd5 6, 5, 3 Hz), 3.4 (4H, m), 3.10 (2H, m), 2.98 (2H, m), 2.88 (5H, m), 2.79 (1H, d, 16 Hz), 2.62 (2H, q, 7 Hz), 2.05 (2H, m), 1.42 (2H, m), 1.32 (1H, m), 1.21 (3H, t, 7 Hz), 1.05 (2H, hexaplex, 7 Hz) ), 0.87 (3H, t, 7 Hz), 0.79 (3H, t, 7 Hz). MS (DCI, NH3) m / e 505 (M + H ,. Analysis and calculation of C32H44N203: C, 76.15; H, 8.79; N, 5.55. Experiment: C, 75.96; H, 8.75; N, 5.36 Example 372 ^ ?; ί · 部 次 次 irr leads to T _) / i 公 合 ^ 印 Jr, (Please read the precautions on the back before filling this page) Anti, anti-2- (3,4-difluoro Phenyl) -4- (1,3-phenylhydrazone dioxolene-5 · • yl) -1- (N, N-di (n-butyl) aminocarbonylmethyl) -pyrrolidine- 3-carboxylic acid was prepared using the procedure described in Example 1 and the white solid was isolated. Melting point 62-63 ° C. h NMR (CDC13, 300 MHz) δ 0.8 3 (t, J 2 7 Hz, 3H), 0.88 (t, J 2 7 Hz 5 3H), 1.13 (hexaplex, J 2 7 Hz, 2H), 1.20 -1.32 (m, 3H), 1.36-1.49 (m, 3H), 2.85-2.93 (m, 2H), 2.98-3.23 (m, 4H), 3.36-3.45 (m, 3H), 3.58-3.66 (m, lH), 3.94 (d, J = 8 Hz, 1H), 5.93 (s, 2H), 6.72 (d, J = 7.5 Hz, 1H), 6.84 (dd, J = 1 Hz, J = 7.5 Hz, 1H) , 6.98 (d, J = 7.5 Hz, 1H), 7.08-7.15 (m, 2H), 7 22-7.28 (m, 1H). MS (CDI / NH3) m / e 517 (M + H) one. -472- Specification of this paper / 丨] Chinese Valve National Standard (CNS) A4 specification (210X 297g t) 552260 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (47〇) ^^ 1J73 [1 Γ9, \ τ $ 苴 \ τ 弁 Dioxane ^ 5 &lt;! ~-~~ · propyl-N-n- 戍 -detected, ~ amino group) Emu μ pyrrolidine A jealousy used in examples The # 7Γ ~~~, ,,,% sequence described in 1 was used to prepare the title compound, and a white solid was fractionated. Melting point 71-7? R i ♦ L. 4 NMR (CDC13, 300 MHz, δ δ 0.82 (t, j = 7 Hz North Hz, σ 1 1 Η), 0.90 (t ,: [2 7 Hz, 3 Η), Ul. 38 (m , 4Η), 1 46 r Erdo (,, heavy peak, J = 7 Hz, 2H), 1.74 (Five-strike front, J = 7 Hz, 2H), 2 9a.) 2.26 &quot; ··· 36 ( m, 1H), 2.72-2.95 5H), 2.98-3.12 (m 2H), κ 5} 0.15-3.34 (m, 2H), 3.45 (dd, J = 3 Hz, ㈣Hz, 1H), 3.53_3 6 〇 (m, ih), 3 7i (d,; = 9 Hz, 1H), 5.96 (S, 2H), 6 75 (d, ㈣Hz, m), 3 82 (H Hz, J = 9 Hz, 1H), 5% ⑷ j = 2 Hz, ih), 7 〇9_7 i8 〇, 2H) '7.2) -7.34 (m, 1H). MS (CDI / NH3) m / e 567 (m + h). t ± i22 ± cyclopentene-5_yl) _2 ^^ _ ethoxyfluorenylcarbonylmethyl) -pyrrolidine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. TLC (10% MeOH-CH2Cl2) Rf 2053. 1H NMR (CDC13, 3 00 MHz, rotatory isomer form) δ 0.70 (t, J = 7 Hz), 0.80 (t, J = 7 Hz) and 0.96-1.04 (m, 6H total), 1.04-1.75 (m, 1 1 Η), 1.34- 1.5 3 (br m, 4Η), 2.65 (ΑΒ) and 2.8-3.08 (m, 2Η total), 3.10-3.82 (br m, 12H), 4.03 (m) and 4.22-4.45 (br m5 2H total), 5.90 (s) and 5.91 (s, 2H total), 6.65-6 · 84 (m) and two gas茇 葚 (Please read the notes on the back before filling this page)

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、 1T -473 This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 Gongchu 552260 ___ Β7) V. Description of the invention (471) 6.93 (πι) * 6 · 99 (ιη53ΕΚ · *) αΜ8 (ΡΑΒ ) η &amp; 463 (M + Η) +. Analytical calculations for C25H38N2O6 · 1.5 H2O: C, 61.33; H, 8.44; Ν, 5.72. Experiment 値: C, 61.28; Η, 7.78; Ν , 5.62. Example 375 trans, trans-4_ (1,3-benzyl-dioxane; penta-5-yl) _2_ (n-butyl) _1_ (N, N-di (n-butyl) Amino) amine-chiralmethyl) -P-bilodine-3-chinic acid The title compound was prepared using the procedure described in Example 1 and the colorless wax was isolated. TLC (10% MeOH-CH2Cl2) Rf = 0.37. 4 NMR (CDC13, 3 00 MHz, rotatory isomer form) δ 0 · 71 (t, J = 7 Hz) and 0.77-1 · 05 (m, 9H total), 1.05--1.20 (ιη52Η ), 1.20-1.72 (br m, i3H), 2.48-2.52 (m, 1Η), 2.87-3.00 (m, iH), 3.05-3.60 (m, 5H), 3 · 60-3 · 80 (br m, 2H), 3.88-4.05 (br m, 1H), 4.28 (brd, J = 15 Hz, 1H total), 5.90 (s) and 5.92 (s, 2H total), 6.67-6.82 (m, 3 H total). MS (FAB) m / e 461 (M 十 H) —. Analysis and calculation of C26H40N2O5 · 1.75H20 値: C, 63.45; H, 8.90; N, 5.69. Experiment 値: C, 63.18: H, 8.22; N, 5.60. Example 376 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Anti-trans-4_ (1,3-Benzamidine diazacyclopentene -5-yl) -2- (2-fluorenylbutyl) -i_ (N, N-di (n-butyl) aminocarbonylfluorenyl V pyrrolidine-3 · • carboxylic acid using the procedure described in Example 1 To prepare the title compound and separate colorless glass. TLC (10% MeOH-CH2Cl2) Rf 0.49. 4 NMR (CDC13, 300 MHz, mixture of rotamer forms and diastereomers) δ 0.69 ( br t, J = 7 Hz) and 0.75-2.15 (several br m, -474-) This paper size applies to Chinese national standards (0 ~ $) / \ 4 specifications (21〇 乂 297 cm) 552260 A7 B7 5 Description of the invention (472 is about 26H total), 2.48-2.65 (brm, 1H), 2.87-3.01 (brm, 1H), 3.06-3.82 (br m, 7H), 3.90-4.40 (br m, 2H) , 5.90 (s) and 5.92 (s, 2H total) '6.67-6.90 (m Total 3H). MS (FAB) m / e 475 (M + H) + 0 Declaration Example 377 trans, trans-4- (l, 3-penyi ^ oxetan-5-yl) -2- (3-methylbutane ) -1- (N, N-bis (n-LAljlcarbonylmethyl) -pyrrolidine-3-boronic acid using the procedure described in Example 1 to prepare the title compound. TLC (10% MeOH-CH2Cl2) Rf = 0.41 ° 1HNMR (CDCl3, 30 (M! L Hz, rotatory isomer form) δ 0.73 (t, J = 7 Hz) and 0.77-1.05 (m, 12H total), 1.07-1.75 (m, approximately 14H plus H20), 2.48-2.63 (m, 1H) '2.87-3.05 (m, 1H), 3.05-3.60 (several br m, 5H), 3.62-4.02 (br m, 2H), 4.29 (brd, J = 15 Hertz, 1H), 5.89 (s) and 5.93 (s, 2H total), 6.65-6.90 (m, 3H total). MS (FAB) m / e 475 (M + H) +. 〆X1L378 ^ Οχ-ΛΙ propyl Propylpropylamino) sulfofluorenyl) amino) ethyl μ β ^ in the 呔 ^: ^ · ^ ρ]] _ τ &gt; /] # 合 Μ. ^ 卬 1 :: (Please read the notes on the back before filling On this page), the carboxylic acid was prepared using the procedure described in Example 66 and the white solid was isolated. Melting point 58-59. iH NMR (CDC13, 300 MHz) δ 0.78 (t less 7 Hz, 3H), 〇〇〇 (t, Bu 7 Hz, 3h), i 27 (π 圼 peak, J-7 Hermes, 2H) ' 1.48 (m, 4H), 2.22-2.30 〇, 1H), 2.62 (s, 3H), 2.68-2.78 (m, 1H), 2.84-3.03 (m, 5H), -475 552260 A7 B7 V. Description of the invention ( 473) 3.0 8-3.31 (m, 3H), j.39 (dd, J = 3 Hz, j = 9 Hz, 1H), 3.50-3.58 (m, 1H), 3.63 (d5 J = 9 Hz, 1H) , 3 79 (s, 3H), 5.95 (s, 2H), (d, J = 8 Hz, 1H), 6 83 (dd, J = 2 Hz, J 2 8 Hz, 1H), J · 87 (d , J = 9 Hz, 2H), 701 (d, J = 2 Hz, 1H), 7.33 (d, J = 9 Hz, 2H). MS (DCI / NH3) m / e 576 (Μ + ΗΓ. Example 379 trans, trans-2,4-bis (3,4:; fluorophenyl) dibis (n-butyl) amine drug methyl) -The ratio was used to prepare the title compound using the procedure described in Example 1. 1 pj NMR (3 00 MHz, CDC13) δ 7.35 (2H, m), 7.18 (4H, m) '4.87 (1H, d, J = 12), 4.00-3.60 (5h ,, 3.60-3.10 (3H, m), 3.10-2.90 (2H, m), 1.45 (2H, m), 129 (4H, m), 1.15

(2H, m), 0.91 (3H, t5 J = 9), 83 (3H, J = 9). MS (DCI / NH3) m / e 509 (M + H). Analysis and calculation of c27H32f74N203 / 0.75 TFA l: C, 57.62; H, 5.56; n, 4.72. Experiment 値: C, 57.72; H, 5.67; N, 4.66 〇 Example 380 anti- ,. a 4_-4- (3,4-dimethylmethyl ashes) -2- (4-hydrazino ^ 1 ^ 1 "team Di (n-butylmethyl) -pyridine The title compound was prepared using the procedure described in Example 1. i H NMR (300 MHz, CDCl3) S 7.43 (2H but7 2 η ⑻, 7.18 (1H, dm3) , 7.11 (1Hd, ㈣), 69Q (2Hd, 'J 2:10), 5.48 (1H, d, J 爿 2), 4.26 (1H d, j: 18), 4 16 (2H, -476- Dimension II Sichuan China National Standard (CNS) Λ4 specification (210 乂 297 g t) '----- --------- 01 — (Please read the precautions on the back before filling this page)

, 1T 552260 A7 B7 V. Description of the invention (474) m), 3.83 (2Η, m), 3.81 (3Η, s), 3,56 (1Η, bd, J = 18), 3.37 ( 1Η, m), 3.20 (1Η, m), 2.96 (2Η, m), 2.24 (3Η, s), 2.22 (3H, s), 1.47 (2H, m), 1.27 (4H, m), 1.10 (2H, m), 0.93 (3H, t, J = 9), 0.81 (3H, t, J = 9). , MS (DCI / NH3) m / e 495 (M + H +). Analysis and calculation of C30H42N204 / 1.25 TFA 値: C, 61.26; H, 6.84; N, 4.40. Experiment 値: C, 61 · 16; H, 7.05; N, 4.38. Example 3 8 1 trans, trans-2,4-bis (3-fluoro-4_methoxyphenyl) -l-(((N- (n-butyl) aminocarbonyl) methyl) -pyrrolidine-3 -Carboxylic acid using the procedure described in Example 1 to prepare the title compound. H NMR (3 00 MHz, CDC13) δ 7.20 (2H, m), 7.17 (2H, m), 6.93 (2H, m), 5.48 (lH, m), 4.26 (lH, m), 4.16 (2H, m), 3.83 (2H, m), 3.87 (6H, s), 3.56 (lH, m), 3.37 (lH, m), 3.20 (lH, m), 2.96 (2H, m), 1.47 (2H, m), 1.27 (4H, m), 1.10 (2H, m), 0.93 (3H, t, J 2 9), 0.81 (3H, t , J 2: 9). MS (DCI / NH3) m / e 533 (M + IT). Off: Analysis and calculation of C29H38F2N205 · 0.75 H20 値: C, 63.78; H, 7.29; N, 5.13. Experiment 値: C , 63.77; H, 7.08; N, 4.99. In the middle of ίΚ it and] (_t A f: \\ (Please read the precautions on the back before filling this page) Example 382 Anti, anti-4- (1,3- Benzo metadioxol-5-yl) -2- (4-methoxyphenyl) -1-(((N- (2-pentyl) -N- (3-tolyl) amino ) Carbonyl) methyl) -pyrrolidine-3-carboxylic acid The title compound was prepared using the procedure described in Example 1. 1Η-477- paper Degree of China National Standard (CNS) Λ4 specification (210X 297 mm) 552260 A7 B7 V. Description of the invention (475) NMR (300 J — ', CD3OD) 3 0.90 (m, 3H), 0.95 (t, J = 7.3 Hz, 3H), 1.13-1.37 (m, 4H), 2.30 (s, 3H), 2.34 (s, (CH3 rotamer)), 2.73-2.91 (m5 2H), 3.17-3.26 (m, 2H ), 3.32-3.62 (m; 2H), 3.77_4 · 08 (m, 1H), 3.80 (s, 3H), 4.7 1 (m, lH), 5.92 (m, 2H), 6.61-6.84 (m, 6H), 7.04-7.16 (m, 3H), 7.23-7.29 (m, 2H). MS (DCI) m / e 559 (M + H +). Analysis and calculation of C33H38N2〇6 · 0.35 H20 · 0.05 CH3C02C2H5 値: C, 70.03; H, 6.92; N, 4.92. Experiment 値: C, 70.08; H, 6.82: N, 4.95. Example 383 1 ′ Li 14- (121 ^^ — yintrioxolane. Di 51 ^ 1; ^: 11 ^^ phenyl)-(N-butyl)-^ 1- (1-nayl) Amine-Tanyl) 2 tons-—— is prepared using the procedure described in Example 1 檩 is ρ ~ compound Hertz, 3H), office * 2.80 (m 2Η), 2.85-4.00 (m, 6Η) , 3.77 (d, J = 1.5 Hz ,, (m, lH), 5.94 (d, J = 2 Hz, 2H), 6.6 ((1 (15κ9, 6.70-6.85 (m, 4H), 6.95-7.02 (m5 2H), 7 * 17 (dd, 8H? 1/2), 7.25 (dd, 8H, 1/2), 7.38-7.60 (m, 4H), .87-8. 〇〇 (m, 2H) MS (ESI) m / e (M + H) 581. About c, u H20: c, 69.38; H, 6.45; N, 4.62. Experiment; H, 6.07 NMR (300 MHz, CD3OD) δ 0.87 (t5 j: * 1.20-1.40 (m, 2Η), 1.40-1.60 (m, 2Η), 2 4) 7 4.05-4.20 10 Hz, 1H) 20.6 · 1.4 N, 4.41 (Please read the back first Please note this page and fill in this page) 値: C, 69.36 Example 384 hoof _ 5 -Base-478 &gt; Paper Standards State Standards (CNS) A4 Specification (210X 297 mm) 552260 A7 B7-— _____________ —- V. Description of the Invention (47δ) Methylpyrrolidine-3-carboxyl The title compound was prepared using the procedure described in Example 66. 1H NMR (CD3OD, 300 MHz) δ 0.88 (t, BU 7 Hz, 3H), 1.25-1.40 (m, 6H) '1.73 (quintet) , J = 7 Hz, 2), 2.13_ 2.23 (m, 1H) '2.64-2.8 8 (m, 3H), 3 · 02 (hexaplex, J = 8 Hz, 2H)' 3.44-3.53 (m, 2H) '3.58 (d, J = 9 Hz, 1 is 3.56-3'75 (m, 1H), 3.78 (s, 3H), 3.88-3.98 (m, ih), 5.93 (s , 2H), 6.72 (d; J = 9 Hz, 1H), 5.78-5.84 (m, 3H), 6.96 (d5 J = 2 Hz, 1H) '7.20 (d5 J = 9 Hz, 2H), 7.27 -7.36 (m, 5H). MS (DCI / NH3) m / e 609 (M + H) +. Example 385 trans, trans-4- (l, 3-phenylhydrazone dioxolene-5-ylmethoxyphenyl) -1 · (2-methyl-1,2,: &gt;, 4- Four mice Junlinji) Aid methyl) _p was better than p various diseases _3_ days acid ## 中 中 次 ^ •• ^-/. JhJTi / i 于 合 w. ^^ pi: * (Please read the back page first Note Refill this page) The procedure described in Example 1 was used to prepare the title compound. i η NMR (3 00 MHz, CD3OD) δ 1.03 (m, 3Η), 1.10-1.45 (m, 1H), 2.10-2.85 (m, 4H), 2.90_4.00 (m, 7H), 3.76 (s, 1.5H), 3.77 (s, 1.5H, isomers), 5.90 (m, 2H), 6.70-7.40 (m, 11H). MS (DCI) m / e 5 29 (M + H) ten. Analysis and calculation of C3iH32N206 · 0.3H2O 値: C, 69.73; H, 6.15; N, 5.25. Experiments: C, 69.74; H, 6.10; N, 51. Example 386 trans, trans-4- (1,3-phenylhydrazine dioxol-5-yl) _2_ (4_methoxyphenyl-479- This paper describes the national standard, (CNS ) Λ4 ^ cell (2 丨 〇 乂 297mm) — 55226〇

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, and a description of the invention (477))-1 · (3-butyl-hept-2-en-1-yl) -pyrrolidine-3-carboxylic acid Described procedure to prepare the title compound. ιΗ

NiV [R (3 00 MHz, CD3OD) δ 0 · 86 (t, J = 7.0 Hz, 3Η), 0.90 (t, J = 7.0 Hz, 3H), 1.20-1.41 (m, 8H), 1.95 -2.06 (m5 4H), 3.24 (d, J = 110.0 Hz, 1H), 3.51-3.59 (m, 3H), 3.60, 3.7l (m5lH), 3.77-3.84 (m, lH), 3.81 (s , 3H), 4.45 ((1, ^ 11.0 Hz, 111), 5.52 (^ = 7.4 Hz, 111), 5.93〇, 211) '6.77 (d, J = 8.1 Hz, 1H), 6.87 (dd, J2 1.8, 8.1 Hz, '6.99 (m, 3H), 7.46 (m, 2H). MS (DCI) m / e 494 (M + H +). Analysis and calculation of C3〇H39N05 値: C , 72.99; H, 7.96; N, 2.84. Experiment 値: C, 72.73; H, 7.89; N, 2.64. Examples :) 11 oW〆, ~ 2-(3-Ga-4-methoxybenzyl) -4- (1,3-Phenylhydrazinocyclopentene) 丨 2 · (N-propyl-N-n-hexanesulfonamido) ethyl 1-pyridine-3-carboxylic acid The title compound was prepared using the procedure described in Example 66, and a white solid was isolated. Melting point 63-65 ° C. 4 NMR (CDC13, 300 MHz?) Δ 0.82 (t, J-27 Hz, 3H), · 88 (t, J = 6 Hz, 3H), 1.23-1.47 (m, 6H), 1.44 (hexaplex J 2 7 Hz, 2H), 1.71 (quintet, j = 6 Hz, 2H), 2.24-2.34 (m, 1H), 2.70-2.93 (m, 5H), 2.96-3.12 (m, 2H), 3.15 -3.35 (m, 2H), 3.43 (dd, J = 3 Hz, J 2 9 Hz, 1H), 3.52-3.59 (m, 1H), 3.66 (d, J = 9 Hz, 1H), 3.87 (S, 3H), 5.95 (s, 2H), 6.74 (d, J = 8 Hz, 1H), 6.82 (d, J = 8 Hz, 1H), 6.42 (t, J = 8 Hz, 1H), 6.96 (s, -480- This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X 297 cm)-0 ------ 1T ------ (Please read the precautions on the back before filling this page ) 552260 A 'B- V. Description of the invention (478) 1H), 7.12 (d, J 2 9 Hz, 1H), 7.17 (d, J = 12 Hz, 1H). MS (DCI / NH3) m / e 593 (M + H) +. Example 388 trans, trans-4- (1,3-benzisodioxol-5-yl) -2- (4-methoxyphenyl) -1-((3-ρbiphenyl) Pyridoxolol-3- complex fel prepared the title compound using the procedure described in Example 1. iH NMR (300 MHz, CD3OD) δ 2.87 (m, 2H), 3.04 (dd, 3.2, 9.7 Hz, 111), 3.21 ((1,) 2 13.7 Hz, 111), 3.51 (111, 1H), 3.76-3.85 (m, 2H), 3.79 (s, 3H), 5.90 (m, 2H), 6.71 (m, 1H), 6.79 (dd, J = 1.7 Hz, 7.8H), 6.94 (m, 3H), 7.36-7.45 (m, 3H), 7.81 (m, lH), 8.39 (m, lH), 8.46 (dd, J = 1.4 Hz, 1H). Analysis and calculation of C25H24N205 · 0 · 70 H20 · 0.05 CH3C02C2H5 値: C, 67.34; H, 5.79; N, 6.23. Experiment 値: C5 67.31; H, 5.63; N, 5.90. Examples 389 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) trans'trans-2- (n-hexyl) -4- (1,3-benzo-dioxane Pentyl-5-yl) -1- (N, N-bis (n-butyl) aminothiomethyl) -P-Biloxidine · 3-polyacid The title compound was prepared using the procedure described in Example 1. 1Η NMR (CDC13, 300 MHz) δ 0.82-1.00 (m, 9H), 1.20-1.40 (m, 12H), 1.45-1.60 (m, 4H), 1.70-1.90 (brm, 2H), 3.10-3.4 6 (m, 6H), 3.65 (t, 10.8 Hz, 1H), 3.76 (t, J = 1 1.0 Hz, 1H), 3.92-4.06 (m, 2H), 4.14-3.65 (t5 J = 10.8 Hz, 1H), 3.76 (t, J 2 11.0 Hz, 1H), 3 92-4.06 (m, 2H), 4.14-4.34 (m, 2H), 5.94 (s, 2H), 6.73 (d , J 2 8.1 Hz, 1H) -481-This paper & size applies to Chinese National Standard (CNS) A4 specification (210X 297 cm) 552260 A 'B * 7 5. Description of the invention (479, 6.79 (dd, J = 8 ″, 1.8 Hz, 1H), 6.87 (〇1, 1 = 1.8 Hz, 1 bid. MS (DCI / NH3) m / e 489 (M + H) +. Analysis and calculation of C28H44N205 · 0.9 · TFA T: c, 60 · 53; Η, 7.65; Ν, 4.74. Experiment 値: C, 60.62; Η, 7.69; Ν, 4.61. Example 390 was di .. exhausted. Τ4-(. Υ ^ 幷 dioxopent-5-yl) -2- (4-methylamino 芨 il-(((N- (2-pent Octa N- (4-fluoro-3-fluorenyl) amino) carbonyl) fluorenyl) -Tan Luodian-3 -Rescisic acid ~ &quot; system compound. 1H was prepared using the procedure described in Example 1. Title: τ = 7 1 〇 (L, J / · 1 NMR (300 MHz, CD3OD) δ 0.92 (m, 3Η), 9 58_) 74 Hz, 3H), 1.13-1.40 (m, 4H), 2.22 (m5 3) (m, lH), 2.78-2.87 (ιη, 1Η), 3.09-3.25 (m, # 'μ ^ 1XJ, 4 7U <in, h) (m, 2H), 3.70 -3.90 (m, 1H), 3.80 (s, 3H), .0 t 1 j, 6.1, 5.93 (m, 2H), 6.70-6.76 (m, 1H), 6.75 ('4H). Ms Hz, 1H) , 6.80-6.94 (m5 4H), 6.96-7.13 (Let's 0.25 n20 (DCI ·) m / e 577 (M + H +). About C33H37FN2 06 · ··, 。. Experiment 値: C, analysis and calculation 値: C5 68.20; H, 6.50; N, 4.82 &quot; ... (Please read the notes on the back before filling out this page) i0. 、 = Α Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 6 8.21; Η, 6.46 ; Ν, 4.74 〇 Example 3 91

4-Methoxyl-4_, trans-4- (1,3-phenylhydrazone dioxane-5-yl) i-1-((2-pyridyl) methyl) _pyrrolidin ~ γ i compound. H. The procedure described in Example 1 was used to prepare the title ^ 9 7 Chunyong Mo, 1Η) NMR (300 MHz, CD3OD) δ 2.97 (dd J 27,9,. V 'j Hz, 9.9 Η)' 3.04 (t, J = 9.6 Hz, 1Η), 3.18 (dd, * 1 2 4 ·· -482- This paper size applies to the Chinese National Standard (CNS) Λ4 specification (210X 297)) 552260 A 7 B7 V. Invention Explanation (48〇), 3.47 (d, J = 14.0 Hz, 1H), 3.59 (m, 1H), 3.78 (s, 3H), 3.96 (d, J 2 9.9 Hz, 1H), 3.97 (d, J 2 13.6 Hz, 1H), 5.90 (m, 2H), 6.73 (d, J 2 8 · 1 Hz, 1H), 6.8 3 (dd, Bu 1 · 7, 7.9 Hz, 1H), 6.92 (m, 2H), 6.96 (d, J = 1.8 Hz, 1H), 7.28 (m, 1H), 7.44 (m, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.80 (dt, J = 1.8, 7.7 Hz, 1H), 8.42 (m, 1H). MS (DCI) m / e 433 (M + iT). Analytical calculation for C25H24N205 · 0.35 H22: C, 68.43; H, 5.67; N, 6.38. Experiment 値: C, 68.44; H, 5.61; N, 6.24. Example 392 trans, trans-2- (3-phenylpropyl) -4- (1,3-phenylhydrazone dioxolene-5- Radical) -i- (Ν, Ν- 二 (正- Group) aminecarbonylfluorenyl) -pyrrolidine-3-carboxylic acid The title compound was prepared using the procedure described in Example 1. NMR (CDC13, 300 MHz) δ 0.89-0.97 (m, 6H), 1.22-1.36 ( m, 4H), 1.41-1.55 (m, 4H), 1.63- 1.95 (m, 4H), 2.62 (dt, J = 7.2, 2.1 Hz, 2H), 3.05-3.44 (m, 7H), 3.53-3.60 ( m, 2H), 3.65 · 3.7 6 (m, 1H), 3.82-3.90 (m, 1H), 3.96-4. 10 〇, 1H), 5.92 (s, 2H), 6.71 (d, J 2 8.1 Hertz, 1H), 6.77 (dd, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling out this page) J II 8.1, 1.5 Hz, 1H), 6.86 (d, J II 1.2 Hz , 1H), 7.10-7.28 (m, 5H). MS (DCI / NH3) m / e 523 (M + H; T. Analysis and calculation of C31H42N205 • 0.6 TFA 値: C, 65.41; H, 7.26: N, 4.74. Experiment: C, 65.28; H, 7.29; N, 4.50. Example 393 trans, trans-4- (4-methoxy-3-fluorophenyl) -4- (7-methoxy-1,3-phenylhydrazine-483-paper size Applicable to China National Standard (CNS) A4 specification (210X 297 males) 552260 A · R 'V. Description of invention (481

(Please read the notes on the back before filling out this page.) Account: Use the procedure described in Example 1 to prepare the title compound and isolate the solid. Melting point 115_117. . . 4 NMR (300 MHz, C fl3) 5 0.82 (t, 1 = 7 Hz, 3H), 0.88 (t, J = 7 Hz, 3H), 15 (m, 8H) '2.85 (d, J = i3 Hz, 1H), 290_3 17 (m,), 20m (m, 1H), 3.35-3.50 (m, 3H), 3.55-3 · 65 (χη, I ° 84 (d, 1 = 10 Hz, iH), 3.87 (s, 3H), 3.92 (s, 3H) f · 9 · ⑽, J = 4 Hz, 2 Hz, 2H), 6.62 (s, 1H), 6.70 ( s, lHj 6.90 (t, J = 8 Hz, called, 7.05-7.20 (m, 2H). Example 3 9 4 Fluorenyl-1,3-phenylhydrazine bis (n-butyl) amine carbonyl amidine ) -Pyrrolidine-3 -chinoic acid ^ The title compound was prepared using the procedure described in Example 1 and the white solid was isolated. Melting point 107-11 ° C. 4 NMR (300 MHz, CDC10S 0.82, B 7 Hz, 3H), 0.88 (t, J 2 7 Hz, 3H), 1.05-1.) 0 (m, 8H), 2 75 (d, B 13 Hz, ih), 2 9〇-3 (㈤, printed by the cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, 4H) '3.32-3.60 (m, 5H), 3 69 (d, J = 8 Hz, 1H), 3 9〇 (s, jH) '4.2j (s, 4H), 5.95 (dd, J = 4 Hz, 2 Hz, 2H), 6.62 (S, 1H), 6.70 (s, 1 H), 6.78-6.93 (m, 3H). Example 395 bis-dioxol-5-yl) -2- (4-fluorenylphenyl- ~~~ yl J-2-fluoro-hept-2-fluoren-1-yl)-? Bihe Yodo-3-chinic acid

_C Yi Erbu C, CrCrG -484- 1 Applicable to Chinese national standard specifications (210x 297 public 1: 552260 Λ Βη V. Description of the invention (482) The procedure described in Example 1 was used to prepare the title compound. NMR (300 trillion Hertz 'CD3OD) δ 0.84 (t, J = 7.0 Hz, 3H), 0.88, 1 = 7.0 Hz, 311), 1.16-1.37 (111, 811), 1.8 3 08.5 Hz, 2H), 2.03-2.08 (m, 2H), 2.76-2.92 (m, 2H), 3.02 (t, 9.3 Hz, 1H), 3.32-3.42 (m, 2H), 3.50 (m, 1H), 3.71 (d, J 2 9.2 Hz, 1H), 3.78 (s, 3H), 5.91 (m, 2H), 6.72 (d, 7.8 Hz, 111), 6.83 (4 (15 1.7, 8.1 Hz, 111), 6.90 (111, 2H), 7.02 (d, J 2 1.7 Hz, 1H), 7 34 (m, 2H). MS (DCI) m / e 5 12 (M + H +). Analysis and calculation of c30H3SFNO5 値: c, 70 · 43; Η, 7.49; N, 2.74. Experiment 値: C, 70.58; H, 7.54; N, 2.66 〇 Example 396 ^ 1__trans-2- (3-fluoro-4-ethyl main benzene Interstitial diaza 1A] _- ι · [2- (ν-propyl-n-pentanesulfonamide, Ethyl ^ py ^^ di-carboxylic acid The procedure described in Example 66 was used to prepare the title compound ,even Off-white solid. Melting point 65-66 ° C. 4 NMR (CDC13, 300 MHz Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling out this page}) δ 0.82 (t, J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H), 1.26-1.36 (m, 4H), 1.41-1.52 (m, 5H), 1.73 (quintet peak Hertz, 2H ), 2.23-2.33 (m, 1H), 2.69-2.96 (m, 5H), 2 97 3.12 (m, 2H), 3.16-3.37 (m, 2H), 3.43 (d, J-2 9 Hz, 1H), 3 · 52-3.59 〇 ”1Η), 3.66 (d, J 2 9 Hz, 1H), 4.08 (q J =; 7 Hz, 2H), 5.95 (s, 2H), 6.74 (d, J = 8 Hz, 1H), 6.82 (d J = 8 Hz, 1H), 6.92 (t, J = 8 Hz, 1H), 6.97 (s, 1H), 707 485- This paper standard applies Chinese National Standard (CNS) A4 Specifications (210X 297 public office 552260 A R_ V. Description of the invention (483 (d, J-8 Hz, 1H), 7 15 (d, J =; 12 Hz, 1H). Ms (DCi / N) H [3) m / e 593 (M + H) t 〇 Tail dimethoxymethoxy-13-phenylhydrazine-diyl-propylamino) Hydroxymethyl) _ pyrrolidine The procedure described in Example 1 was used to prepare the title compound, and a white solid was isolated. Melting point i 18-12 ot. iH NMR (300 MHz, CDC13) δ 0.70-0.90 (4 triple +, J = 7 Hz), i 05] 55 (m, 8H), 2.80-3.50 (m, 9H), 3.55-3.65 (m, 1H), 3.82 (d, J = 10 Hz, 1H) '3.85 (s, 3H), 3.92 (S, 3H), 5.96 (s, 2H), 6.62 (s, IH)' 6.70 (s, ih) , 6.90 (t, J 2 8 Hz, 1H), 7.08-7.22 (m, 2H). t iH 3 98 metadioxol-5-yl) _2_ (4-methoxyphenyl-(Please read the precautions on the back before filling this page)

、 1T Printed by the Central Bureau of Standards of the Ministry of Economy

___ FT V. Description of the invention (484) ^ An example 399 ---------- radical _ 'trans- 4- (1,3-benzo-dioxopentyl-5-yl-formyl Oxyphenyl) -1- (4-methyl-1,2,3,4-tetrahydrolin-yl) carboxymethylfluorene · ρ-pyrrolidine-3-chinic acid — using the one described in Example 1 Procedure to prepare the title compound. 4 NMR (3 00 MHz, CD3OD) δ 1.27 (d, J = 7 Hz, 1.5 Η), 1.28 (d, 7H, 1.5-diastereomer), 139-155 (m, iH) , 2.02-2.15 (m, 1H), 2.60-3.25 (m, 5H), 3.33-4.00 (m, 5H), 3.78 (s, 3H), 5.92 (d, J = 3 Hz, 2H), 6.73 (dd , J = 8 Hz, 1H), 6.75-6.90 (m, 3H), 6.91-7.35 (m, 7H). MS (DCI) m / e 529 (M + H) +. Analysis and calculation of C31H32N206 値: C, 70.44; H, 6.10; N7 5.30. Experiment 値: C5 70.16; H, 6.04; N, 5.04. Example 400 trans, trans-2- (3-fluoro-4-methoxybenzyl) -4- (1,3-benzo-dioxo-7cyclopenten-5-yl) -1- 丨 2- (N-propyl-N- (2-ρ Bi Lake-1-yl) Ethyl Burning Continyl Amino) Ethyl 1-pyrrolidin-3-carboxylic acid Printed and used by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The procedure described in Example 1 was used to prepare the title compound and a white solid was isolated. 95-96 ° C. 4 NMR (CDC13, 300 MHz) δ 0.8 2 (t, J 2 7 Hz, 3H), 1.43- 1.55 (m, 4H), 1.63-1.72 (m, 4H), 2.29-2.38 (m, 1H), 2.64-2.78 〇, 5H), 2.87 (t, J 2 8 Hz, 1H), 2.95-3.04 (m, 5H), 3.20-3.30 (m, 1H) ^ 3.32-3.43 (m, 4H), 3.54-3.63 (m, lH), 3.78 (d, J = 8 Hz, 1H), 3 87 (s, 3H), 5.92 (s, 2H), 6.72 (d, J — 8 Hz, 1H), 6.78 (dd, J = 2 Hertz, J = 8 Hertz, 1H), 6.88 (t, J = 8 Hertz, ih) -487-This paper size applies the Chinese National Standard (CNS) A4 specification (21 OX 297 feet) 552260 Β * 7 V. Description of the invention (485), 6.94 (d, Bu 2 Hz, 1H), 7 0-8_20 (m, 2h). MS (DCI / NH3) m / e 620 (M + H) + 〇 Example 401 —'anti-heptazone] _Heart (U-phenylhydrazone dioxol-5-yl) -1 · (n- Butyl) amine carboxymethyl) · Bichyl_3 bislambitate uses the procedure described in Example 1 to prepare the title compound. lH NMR (CDC13, 3 00 MHz) δ 〇83-〇98 (s, 9H), i 4〇 (m, 14H), 1.44-1.60 (m, 4H), 1.72-1.96 (brm, 2H), 3.12 -3.45 (m, 6H), 3.65 (t, J = 10.5 Hz, 1H), 3 76 (t, J = u 2 1H), &gt; · 90-4 · 60 (m, 2H), 4.13-4.33 (m, 2H), 5.93 (s 2H), 6.73 ((1, << 12 7.8 Hz, 1 ^ 1), 6.79_, Bu 7.8, 1.7 Hz, 111), 6.87 (d, J = 1.7 Hertz, 1H). MS (DCI / NH3) m / e 503 (M + H) +. Analysis and calculation of C29H46N205. 0.75 TFA 値: c, 62.28; 8.01: N, 4.76. Experiment 値: c5 62.20: H, 7.99; N, 4.50. Example 402 • 4-one ", trans-4- (13-benzom-dioxalpinenyl) _2_ (4 • methylhydrofluorenyl): 1- (3-fluorenyl_1,2,3, ^ g_J ^ quinoline-buyl ^ fa [基] _Pyrrolidine is printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) using the procedure described in Example 1 to The title compound was prepared. !! η NMR (300 MHz, CD3od) δ 〇99 (d, i 5H), i 〇3 (d, J = 6 Green Hyun, 1.5H, the first diastereomer), 2.60-4.00 m (12), 3.78 (s, 1.5Η), 3.79 (s, 1.5H, second diastereomer), 5.92 (s, 1Η) '). 9 3 (s, 1H, diastereomer), 6 65-7 7 (m, UH). MS (DCI) m / e 529 (M + H) —. About c3lH32N2〇6. 〇 8 -488- Caiguan Xuzhun (7ns) grid (210X297) while taking ~~-552260

AT B1 V. Analysis and calculation of invention description (486) H20 値: C, 68.57; H, 6.24; N, 5.16. Experiment 値: C5 70.44; H, 6.10; N, 5.30. Example 403 trans, trans- 4- (1,3 -epi-meta-dioxopentyl-5-yl) -2- (4-methyllactyl) -1- (N-butyl-N- ( 4. · Phenyl) aminylmethyl) -methylpyridin-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. NMR (300 MHz, CD3OD) δ 0.87 (t, J = 7 Hz, 3H), 1.2-1.47 (m5 4H), 2.7 (d, J = 12 Hz, 1H), 2.80 (t, J = 9 Hz, 1H), 3.09 (t, J = 9 Hz, 1H), 3.25 (d, J = 15 Hz, 1H), 3.40-3.47 (m, 1H), 3.49-3.65 (m, 3H), 3.75 (d, J 2 12 Hz, 1H), 3.80 (s, 3H), 5.94 (s, 2H), 6.72-6.86 (m, 4H), 7.00-7.15 (m, 7H). MS (DCI) m / e 549 (M + H) +. Analysis and calculation of C31H33N206F. 0.4H2O 値: C, 66.99; Η, 6.13; N, 5.04. Experiment 値: C, 66.99; H, 5, 94: N, 4.99. Example 404 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) trans'trans-butyl-N- (3-methylbenzyl) amine (Cyclomethyl) -2- (4-Methoxybenzyl) -4- (5-benzobenzyl) -ρ-bipyridyl-3-metanoic acid The procedure described in Example 1 was used to prepare the title compound. NMR (3 00 MHz, CDC13) δ 7.66 (1H, bs), 7.60 (1H, d, J 2 3 Hz), 7.4 5 (2H, s), 7.15 (4H, m), 6.7 5 (5H, m ), 3.96 (111, (1, &lt; 1 = 10 Hz), 3.78 (31 * 1, 5), 3.74 (11 ^, 111), 3.59 (3H, m), 3.2 1 (lH, t, J = 9 Hz), 3. 19 (1H, d, J = 16 Hz), 2 92 (1H, t, J = 9 Hz), 2.70 (1H, d, J = 16 Hz), 2. 9 (3H, s) , 1.41 (2H, m), 1.24 (2H, m), 0 85 (3H, t, J = 7 Hz-489- This paper size applies to the Chinese National Standard (CNS) Λ4 specification (210X 297 cm) 552260

Printed by the Ministry of Economic Affairs t Central Standard Consumer Cooperatives. 5. Description of Invention (Ming 7). MS (DCI, NH3) m / e541 (M + H +). Analysis and calculation of c33H34N20 · 1 H20 値: C, 71.21; H, 6.52; N, 5.03. Experiment 値: C, 71.31; H, 6.30; N, 4.98. Example 405 [_, trans-1- (N-butyl-N- (3 · fluorenyl) amine produced methyl group) · 2_ (4-fluorophenylh4- (5-phenylarsine) -E π each bite roll age was prepared using the procedure described in Example 1. ι 实例 NMR (300 MHz, CDC13) δ 7.67 (1H, bs), 7.60 (1H, d, J = 3 Hz), 7.45 (2H M), 7.18 (3H, m), 7.12 (1H, d, J = 7 Hz) '6.93 (2H, m), 6.76 (1H, d, J = 3 Hz), 6.70 (2H, bd), 4.02 (lH, m), 3.77 (lH, m), 3.59 (3H, m), 3.29 (1Η, m), 3.19 (lH, m), 2.94 (lH, m), 2.71 (lH , M), 2.30 (3H, s) '1.45 (2H, m), 1.26 (2Η, hexaplex,] 2 7 Hz), 0 84 (3H, t, J = 7 Hz). MS (DCI , NH3) m / e 529 (M + H +). Analytical calculations for C33H34N205 · 0.2 HOAc 値: C, 71.98; H, 6.30; N, 5.18. Experiment 値: c5 71 · 68; H, 5.89; N , 5.25Θ ^ 406-%-"read

Twenty-one volumes of diphenylhydrazone dioxol-5-yloxyphenyl) di 1-((ΝΑ ·· (mono- (3-tolyl) amino) carbonyl) methyl) -Bilo Benzene-3-junic acid was prepared using the procedure described in Example 1 to prepare the title compound. 1H NMR (300 MHz, cd30D) S2.27 (s, 6H), 2.81 (dd, J 2 8.1, 9.5 Hz, 1 out, 2.98 (1) 2 15.3 Hz, 1 field, 3.20 (1,) = 16-6 Hz, 1H), 3.47-3.60 (m, 3H), 3.80 (s, 3H), 3.85 (d, &gt; 9. 'Hz, 1H), 5 2H), 6.73 (d, J = 7.8 Hertz, 1H) -490- (Please read the notes on the back before filling out this page) This paper size applies Chinese National Standard (Cns) A4 specification (2 丨 OX 297 mm) 552260 A * quot &quot; 488), 6.85 (m, 3H), 6.95 (m, 4H), 7.05 (d, J = 1.7 Hz, 1), 7.06-7.24 (m, 6H). MS (DCI) m / e 579 ( M + H +). Analytical calculated values for C35H34N206 · ○ · 15 H2 · 0 · 20 CH3C02C2H5: C, 71.79; H, 6.04; N, 4.68. Experiment 値: C, 71.81; η 5.79; N, 4.51. Example 407 Ex. Trans-4- (1,2-dihydrophenylsulfan-5-yl) -2- (4-methoxyphenylyl-N- (3-tolyl) amine Yl) several kisyl) methyl) ergoline-3_ dibasic acid The procedure described in Example 1 was used to prepare the title compound. 1h NMR (300 MHz, CDC13) δ 7.73 (2H, m), 7.40-7.10 (4¾ m), 6.92 (2H, m), 6.72 (2H, d, J-2 9), 6.63 (1H, m), 5.40 (lH, m), 4.55 (2H, t, J = 9), 4.30-4.10 (3H, m), 3.84 (3H s), 3.82 (lH, m), 3.65 (lH, m), 3.39 ( lH, m), 3.21 (2H t, J = 9), 3.10-2.90 (2H, m), 2.26 (3H, s), 1.55 (2H, m), 1.45 (2H, m), 0.92 (3H, t, J = 9). MS (DCI / NH3) m / e543 (M + H ~). Analytical calculations for C33H38N205.0.565h20: [71.50: H, 7.15; N, 5.05. Experiment 値: c5 7 1.47; 6j6; N, 4.83. ^ S〇yCM \ Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, i 丄 trans-2- (3-fluoro + dioxo diamido)] ethane bis ^ amino) pyridin-3-carboxylic acid The procedure described in Example 66 was used to prepare the title compound and the colored solid was isolated. Melting point 8112. (: IH NMR (CDCl3, 300 MHz) This paper is applicable to the Chinese National Standard (CNS) 491 552260 B7 V. Description of the invention (489) (Please read the notes on the back before filling this page) δ 0.8 0 (t, J = 7 Hz, 3H), 1.43 (hexaplex, J-2 7 Hz, 2H), 2.15-1.24 (m, 1H), 2.36 (s, 6H), 2.66, 2.76 (m, 1H), 2.83-3.04 (m, 6H), 3.18-3.41 (m, 5H), 3.55-3.63 (m, lH), 3.72 (d, J 2 8 Hz, tH), 3.85 (s, 3H), 5.90 (d, J = 6 Hz, 2H), 6.67 (d, J = 8 Hz, 1H), 6.78 (dd, J = 2 Hz, J = 8 Hz, 1H), 6.84 (t, J = 8 Hz, 1H), 7.94 (d, J = 2 Hz, 1H), 7.09 (d, J = 8 Hz, 1H), 7.20 (dd, J = 2 Hz, J = 12 Hz, 1H). MS (DCI / NH3) m / e 580 (M + H) +. Example 409 trans, trans-1- (N, N-dibutylaminomasthenyl) -2- (4 -Gabenzyl) -4- (5 -benzofuran)- Kobikou-koyodo-3 The acid was prepared using the procedure described in Example 1. NMR (300 MHz, CDC13) δ 7.88 (1H, bs), 7.80 (2H, m), 7.61 (1H , D, J = 3 Hz), 7 .55 (1H, bd, J = 8 Hz), 7.46 (1H, d, J = 8 Hz), 7.07 (2H, t, J = 8 Hz), 6.76 (m, d, J = 3 Hz) , 5.53 (lH, bd, J = 11 Hz), 4.18 (2H7m), 3.91 (3H, m), 3.55 (lH, d, J = 16 Hz), 3.30 (3H, m), 3.12 (m, dd, J = 10 & 9 Hz), 2.95 (1H, m), 1.51 (2H, m), 1.3 1 (4H, m) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1.12 (2H, m), 0.92 (3H, m), 0.83 (3H, t, J = 7 Hz). MS m / e (DCI, NH3) 595 (M + H +). Example 4 1 0 Inverse, inverse-4- (1,2 -Diazobenzofuran-5-yl) -2- (4-ethylethoxy) -l-(((N -butyl_ &gt; 1- (3-fluorenyl) amino) carbonyl) methyl ) -Pyrrolidine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. 1Η -492- This paper size applies Chinese National Standard (CNS) Λ4 specification (210X 297g t) 552260 A7 V. Description of the invention (49〇) (Please read the precautions on the back before filling this page) NMR (300 trillion Hertz, CDCl3) 37.35 (2H, m), 7.20-7.00 (7Η, m), 6.70 (2H, d, J = 9), 5.38 (1H, m), 4.55 (2H, t, J = 9) , 4.05 (lH, m), 3.64 (2H, m), 3.45 (lH, m), 3.21 (2H, t, Bu 9), 2.95 (1H, m), 2.75 (1H, m), 2.63 ( 2H, q, J = 8), 2.38 (2H, m), 3.37 (3H, s), 1.43 (2H, m), 1.30 (2H? M), 1.22 (3H, t, J = 9), 0.89 (3H, t, J = 9). MS (DCI / NH3) m / e 541 (M + ΗΓ). Analysis and calculation of C34H4〇N204 · 1.6 AcOH Ac: C, 70.17; H, 7.34; N, 4.40. Experiment 値: C, 70.11; H, 7.06; N, 4.80. Example 4 1 1 Inverse,-4- (1,2--^ ^ ^ l) -1- (N? N-

Printed by Staff of the Central Bureau of Standards, Ministry of Economic Affairs, Cooperative Co., Ltd. Bis (n-butyl) aminocarbonylfluorenyl) -pyrrolidine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. 1Η NMR (3 00 MHz, CDC13) δ 7.40 (2Η, m), 7.28 (1Η, bs), 7.18 (1H, dd, Bu 8, 3), 7.00 (2H, t, J 2 9), 6.72 ( 1H, d, J = 9), 4.53 (2H, t, J = 9), 3.92 (1H, m), 3.65 (1 H, m), 3.42 (3H, m), 3.19 (2H, t, J = 9), 3.15-2.90 (6H, m), 1.43 (3H, m), 1.25 (3H, m), 1. 10 (2H, m), 0.90 (3H, t, J 2: 8), 0.83 (3H, t, J = 8). MS (DCI / NH3) m / e 497 (M + FT). Analytical calculations for C29H37 FN204..25H2O: C, 69.51; H, 7.54; N, 5.59. Experiment 値: C, 69.45; H, 7.60; N, 5.44. Example 4 1 2 trans, trans_4_ (1,2_dihydrobenzene, huffan · 5_yl) -2- (4-airanyl) -l _ (((N -butyl_N- (3 -Tolyl) amino) carbonyl) methyl) -pyrrolidine-3-carboxylic acid-493- This paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (210 X 297 cm) 552260 Λ / 1Γ 5. Description of the invention (491) The procedure described in Example 1 was used to prepare the title compound. NMR (300 MHz, CDCl3) 57.28 (lH, bs), 7.25-7.00 (5Η, m), 6.91 (2H, m), 6.72 (3H, d, J = 9), 4.54 (2H, t, J = 9), 4.00 (lH, m), 3.60 (3H, m), 3.45 (lH, m), 3.19 (2H, t, J = 9), 3.11 (2H, m), 2.84 (1H, m), 2 67 (1H, bd, J-18), 2.26 (3H, s), 1.42 (2H, m), 1.25 (2H, m), 0.88 (3H, t, J = 8). MS (DCI / NH3) m / e 53 1 (M + H +). Analysis and calculation of C32H35FN204 • 0.25 H20 値: C, 71.82; H, 6.69; N, 5.23. Experiment 値: C, 71.66; H, 6.55; N, 5.03. Example 4 1 3 trans, trans-4- (chloroin-5-yl) -2- (4-fluorenyllactenyl) -l- (N, N-di (n-butyl) aminomethyl)- Mouth-by-mouth_3-Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economics (Please read the precautions on the back before filling this page) The procedure described in Example 1 was used to prepare the title compound. 1Η NMR (3 00 MHz, CDC13) δ 7.32 (3Η, m), 7. 18 (2Η, m), 6.85 (2H, d, Bu 9), 3.83 (1H, m), 3.79 (3H, s) , 3.67 (lH, m), 3.50-3.20 (4H, m), 3.20-2.92 (4H, m), 2.87 (5Η, m), 2.79 (1H, bd5 J 2:15), 2.06 (2H, m ), 1.43 (2H, m), i.27 (4H, m), 1.08 (2H, m), 0.8 8 (3 H, t, J = 8), 0.82 (3H, t, J 2: 8). MS (DCI / NH3) m / e 507 (M + FT). Analytical calculations for C31H42N204... C, 73.49; H, 8.36; N, 5.53. Experiment 値: C, 73.18; Η, 8.29; N, 5.17 〇 Example 414 trans, ^^)-4- (3,4- — phenylphenyl) amino) carbonylfluorenyl l · pyrrolidine-3-carboxylic acid -494- This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 total) 552260 A * B '5. Description of the invention (492) The procedure described in Example 1 was used to prepare the title compound. iH NMR (3 00 MHz, CDC13) δ 0.86 (t, J = 7 Hz, 3H), 1.10 -1.35 (m, 2H), 1.35-1.52 (m, 2Η), 2.29 (s, 3Η), 2. · 63 (d5 J = 13 Hz, 1H), 2.76 (t, J = 7 Hz, 1H), 3.06-3.20 (m, 2H), 3.42-3.53 (m, 1H), 3.50-3.64 (m, 3H), 3.80 (s, 3H), 3.86 (d, J = 9 Hz, 1H), 6.66-6.82 (m, 4H), 7.02-7.22 (m, 6H), 7.30-7.40 (m, 1H). Example 4 1 5 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) trans'trans-butyl-N- (3-chlorobenzyl) amine-aid methyl)- 2- (4-Morphyl) -4- (5-benzylhexofranyl) -orbilopyridine-3-valeric acid The procedure described in Example 1 was used to prepare the title compound. NMR (300 MHz, CDC13) δ 7.64 (1H, d, J = 2 Hz), 7.61 (lH, d, J = 3 Hz), 7.47 (lH, d, J = 8 Hz), 7.41 (lH, dd, 1 = 8 &amp; 3 Hz), 7.30 (111, heart, * 1 = 8 &amp; 2 Hz), 7.21 (111, (1, J 2 8 Hz), 7.19 (2H, m), 7.00 ( 1H, bs), 6.94 (2H, t, J = 8 Hz), 6.83 (1H, bd, J = 8 Hz), 6.74 (1H, dd, J = 2 &amp; 1 Hz), 3.96 (111, 4 1 = 10 Hz), 3.75 (111, (1 (1 (1,655 &amp; 3 Hz), 3.59 (3H, m), 3.23 (lH, t, J = 10 Hz), 3.18 (lH, d, J 16 Hz), 2.92 (1H, dd, J = 10 &amp; 9 Hz), 2.69 (1H, d, J = 16 Hz), 1.41 (2H, m), 1.23 (2H, m), 0.8 7 (3 H , T, J 2 7 Hz). MS (DCI, NH3) 549, 55 1 (M + H +). Analysis and calculation of C31H30C1FN20: C: C, 67.82; H, 5.51: N, 5.10. Experiment 値: C , 67.43: H; 5.33: N, 4.78. -495- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 cm) 552260 A7 R7 V. Description of the invention (493) f iH £ 16_ Anti, anti -4- (1 , 3-phenylhydrazone-dipenten-5-yl) -2- (4-methanone)-propyl-N- (4-epioxoyl) amino group) methyl)- ? Bijat-3 _ Guinea acid uses the procedure described in Example 1 to prepare the title compound. IH NMR (300 MHz, CDC13) δ 7.40-7.20 (5H, m), 7.13 (2Η, m), 6.98 (2H, m), 6.93-6 · 60 (7H, m), 5.93 (1H, d, J = 2), 5.88 (5 · 85) (1Η, d5 J = 2), 4.90 ( 4.50) (1H, d, J = 15), 4.10 (4.25) (1H, d, J = 15), 3.77 (3 · 73) (3Η, s), 3.72 (1H, m), 3.60 (lH, m ), 3.53-3.20 (3H, m), 3.15-2.75 (4H, m), 1.60-1.20 (2H, m), 0.83 (0.64) (3H, t, J = 8). MS (DCI / NH3) m / e 623 (M + tT). About the analysis and calculation of C37H3SN207. 0.25 to 20: ，: C, 70.8 5; H, 6.19; N, 4.47. Experiment 値: C5 70.68; H, 6.10; N, 4.42. Example 4 1 7 Inverse,-SL ^-5- ^)-2- (4-^) -i-(((N- (2- Printing of amyl by the Consumer Cooperatives of the Central Standard Bureau of the Ministry of Economic Affairs) -N- ( 4-fluoro-3-fluorenyl) amino) carbonyl) methyl) -pyrrolidinecarboxylic acid The procedure described in Example 1 was used to prepare the title compound. NMR (300 MHz, CDCl3) 37.30 (lH, bs), 7.20-7.00 (5H, m), 6.87 (1H, m), 6.73 (2H, d, J = 9), 6.57 (1H, m) , 4.81 (lH, m), 4.55 (2H, t, J 2 9), 3.92 (lH, bd, J = 11), 3.60 (1H, m), 3.43 (1H, m), 3.18 (2H, t, J 2: 9), 3.17 (1H, m), 3.06 (lH, dd, J = 15, 6), 2.88 (lH, dd, J = ll, 9), 2.61 (2H, q, J 2: 8) , 2.59 (1H, m), 2.18 (3H, m), 1.40-1 10 (4H, m), 1.22 -496- This standard is applicable to the Chinese National Standard (CNS) Λ4 &amp; grid (210X 297) ) — ~ '552260 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A: B * 7 V. Description of Invention (494) (3H, t, J = 9), 1.00-0.80 (6H, m). MS (DCI / NH3) m / e 573 (M + H +). Analytical calculations for C35H41FN204..75H2O: C, 71.71; H, 7.31; N, 4.78. Experiment 値: C, 71.56; H, 7.33; N, 4.56 〇f Example 4 1 8 trans, trans-2- (4-methoxyphenyl) -4- (1.3-benzyldioxolidine- 5-yl) -1- [2- (N -propyl-N- "2-pyrimidine 1 amino) ethyl μpyrrolidine-metanoic acid in 2 ml of acetonitrile will be prepared by the procedure of Example 61B 2- (4-fluorenoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -1- [2- (cardipropylamino) propyl] pyrrolidine- Ethyl 3-carboxylate (300 mg), 138 mg of 2-bromopyrimidine and 150 mg of diisopropylethylamine were heated to 95 μh. The resulting intermediate, trans-transethyl ester, was separated by chromatography on silica gel to 5-10. / O was eluted with EtoAc in CH2C12 and hydrolyzed with NaOH in ethanol / water to give 95 mg of the title compound. NMR (30Q megahertz, CDC13) δ 0.82 (t, J = 7 Hz, 3H), 1.50 (hexaplex, J = 7 Hz, 2H), 2.15-2.30 (m, lH), 2.75-2.97 (m, 3H), 3.40-3.55 (m, 4H), 3.60-3.70 (m, 3H), 3.75 (s, 3H), 5.95 (S, 2H), 6.34 (t, J = 4 Hz, ih), 6.65 (d , J 2 8 Hz, m), 6.75-6.82 (m, 1H), 6.78 (d, J 2 9 Hz, 2H), 6.96 (d, j 2 2 Hz, 1H), 7.27 (d, J — 9 Hz, 2H), 8.20 (d, J = 4 Hz 2H). Example 4 1 9 Inverse, —pyrene-benzo-dioxo; radical) • Methoxybenzoyl-2-chloro-hept-2-ene-1 diximirole The procedure described in 1 was used to prepare the title compound. 1Η _ _ 497-This paper size applies to China (CNS) eight 4 ^ grid (2iOX2m &gt; fp ^ ---

Aw1T ------ IP— (Please read the notes on the back before filling out this page) 552260 A * B- V. Description of the invention (495 1 and (° 〇〇 匕 Hz Hertz 'CD3OD) δ 0.84 (t, J = Hertz 5 3H) '〇.88 (t, J = 6.7 Hertz, 3H), 1.19-1.39 (m, 8H), 2.05-2.09 (m, 2H), 2.17-2, 23 (m, 2H), 2.78 (dd, J = 6.6, 9.2 Hz, 111), 2.9) (t, J = 9.2 Hz, 1H), 3.32-3.37 (m, 2H), 3.49 (m, 1H) '3'7〇 (d, J = 9.2 Hz (1H), 3 77 (s, 3H), 5.91 (m, 2H) '6.72 (4,] = 8.1 Hz, 111), 6.85 ((1 (1, 1.9, 8.1 Hz, 111) '6.89 (m, 2H), 7.08 (d, J = 1.5 Hz, 1H), 7.36 (m, 2H). 乂 5 (〇 (: 1) 111 528 (% + 11 +). About (: 30 ^ 138〇1 &gt; ^ 〇5.0.25 112〇 Analytical calculation: C, 67.66; H, 7.29; N, 2.63. Experiment: C, 67 · 62; H, 7.18; N, 2.40 Example 420 ^^ 11 ^ 1,2-Dihydrobenzofuran-5-yl) -2- (4-foxyphenyl) -Bu 1ίΙΝ_ (2.pentafluoro-3-methylbenzyl) amine)蕤 D methyl) -pyrrolidine- 0_ (Please read the precautions on the back before filling this page

'1T M Ministry of Economic Affairs, Central Bureau of Standards, Consumer Consumption Co., Ltd. 11 3-¾ Acid The procedure described in Example 1 was used to prepare the title compound. NMR (3 00 MHz, CDC13) δ 7.28 (1H, bs), 7.15 (3H, m), 6.90 (1H, m), 6. 7 (2H, dd, J = 9, 3), 6.71 (2H, d J, 9), 6.56 (1H, m), 4.80 (1H, m), 4.53 (2H, t, J = 9), 3.92 (lH, m), 3.79 (3H, s), 3.60 (lH, m ), 3.45 (1H, m), 3.19 (2H, t, J 2 9), 3.18 (1H, m), 3.03 (1H, dd, J = 15, 6), 2.85 (1H, m), 2.55 (1H , M), 2.18 (3H, m), 1.40-1.05 (4H? M) '1.00-0.80 (6H, m). MS (DCI / NH3) m / e 575 (M + H +). Analytical calculations for C34H39FN205.0.35h2O: C, 70 29; H, 6.89; N, 4.82. Experiment 値: c, 70.37; H, 6.92; N, 4.30. -498 The scale of this paper is applicable to China National Standard (CNS) A4 (210 X 297 cm) I f 552260 A7 B &quot; 7 V. Description of the invention (496) Example 421 Anti, anti-4_ (1,2,2) Chlorobenzoxan-5-yl) -2- (4 -fluorenyloxyphenyl) -1-(((N-butyl-N- (3-chlorophenyl) amino) carbonyl) fluorenyl)- Pyrrolidine-3-carboxylic acid uses the procedure described in Example 1 to prepare the title compound. iH NMR (300 MHz, CDC13) δ 7.29 (lH, d, J = 3), 7.25-7.05 (5H, m), 6.98 (1H, bs), 6.80 (2H, m), 6.72 (2H, d, J = 9), 4.53 (2H, t, J 2 9), 3.85 (1H, d, J = 10), 3.79 (3H, s), 3.58 (3H, m), 3.42 (1H, dd, J = 1 0, 6), 3.18 (4H, m), 2.87 (lH, m), 2.66 (lH, m), 1.40 (2H, m), 1.25 (2H, m), 0.86 (3H, t, J 2: 9) . MS (DCI / NH3) m / e 563 (M + H +). Analysis and calculation of C32H35 CINSOs · 0.25 H20 値: C; 67.72; H, 6.30; N, 4.94. Experiment 値: C5 67.72; H, 6.21; N, 4,55. Example 422 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Anti-anti- (1,3 -Benzo-dioxopentan-5 -yl) 2- (5-Ethylhuffan-2-yl) -1- (N, N-bis (n-butyl) aminocarbonylfluorenyl) -pyrrolidine-3-carboxylic acid utilization is described in Example 1 Procedure to prepare the title compound. iH NMR (3 00 MHz, CDC13) δ 7.77 (1H, bs), 7.11 (1H, d, J = 3), 7 02 (1H, dd, J = 9, 3), 6.82 (1 H, d , J 2 9), 6.52 (1H, d, J = 4), 6.08 (1H, d, J = 4), 5.98 (2H, s), 5.80 (1H, d, J = 6), 4.70 (1H, bd, J = 15), 4.37 (2H, m), 3.70 (2H, m), 3.39 (2H, m), 3.20 (1H, m), 3.10-2.82 (2H, m), 2.76 (2H, q, J 2: 8), 1.45 (2H, m), 1.32 (3H, t, J = 9), 1.30-1.10 (6H? m), 0.87 (3H, t, J 2: 9), 0.85 (3H , T, J = 9). MS (DCI / NH3) m / e 499 (M + HT). About the analysis and calculation of C28H3SN2〇6 · 1.75HC1 値: -499- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X29? G t) 552260 Λ 'B- V. Description of the invention (497) C, 5 9.80; H, 7.12; N, 4.98. Experiment 値: C, 59.51; H, 6.96; N, 4.88. (Please read the notes on the back before filling this page) Example 423 Pentyl) -N- (4-fluoro-3-tolyl) amino) carbonyl) methyl) -pyrrolidine-3-carboxylic acid The procedure described in 1 was used to prepare the title compound. iH NMR (300 MHz, CDCl3) 37.30-7.10 (4H5m), 6.92 (3Η, m), 6.73 (2H, d, J 2 9), 6.59 (lH, m), 4.80 (lH, m), 4.53 (2H, t, J = 9), 4.00 (1H, bd5 J = 10), 3.62 (lH, m), 3.45 (1H, m), 3.22 (1H, m), 3 · 2 1 (2H, t , J = 9), 3.02 (1 H, dd, J = 1 5, 6), 3.85 (1H, t5 J-20), 2.58 (1H, bd, J = 18), 2.20 (3H, bs), 1.40 -1.30 (3H, m), 1.15 (1H, m), 1.00-0 · 80 (6H, m). MS (DCI / NH3) m / e 5 63 (M + H +). Analysis of C33H36F2N2O4 Calculation: C, 70.44; H, 6.45; N, 4.98. Experiment 値: C, 70.06: H, 6.47; N, 4.71. Example 424 An employee of the Central Standards Bureau of the Ministry of Economic Affairs printed the anti-cooperative, anti-4- (1,2-dihydrobenzofuran-5-yl) -2- (4-fluorophenyl) -l-((( N-Butyl-N- (3-chlorophenyl) amino) carbonyl) methyl) -pyrrolidine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. NMR (300 MHz, CDCl3) 57.30 (2H, m), 7.25-7 · 10 (4Η, m), 6.95 (3H, m), 6.82 (1 H, bd, J = 9), 6 73 (1 H, d, J 2 9), 4.55 (2H, t, J = 9), 3.92 (1H, bd, J = 1), 3.60 (3H, m), 3.43 (1H, dd, J = 9, 6), 3 · 2 1 (2H, t, J 2 9), 3.16 (2H, m), 2.87 (1H, m), 2.69 (1H, m), 1.42 (2H, m), 1.26 (2H, m)-500- This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297). 552260 A 7 _________ B * 7 5. Description of the invention (498), 0.87 (3H, t, J = 9). MS (DCI / NH3) m / e 551 (M + H ten). Analysis and calculation of C31H32C1FN204 · 0.25H2O 値: C, 67.02; H, 5.90; N; 5.04. Experiment 値: C, 66.98; H, 5.71; N, 4.76. t P] 425 fluorene, trans-4- (1,2- 二 氪 茉 # 畦 -5--5ethylethylphenyl m ((N-butyl-N- (3-aminophenyl) amino) carbonyl) Methylpyrrolidine-3-carboxylic acid was prepared using the procedure described in Example 1. NMR (300 MHz, CDC13) δ 7.30 (1H, m), 7.21 (1H, d5 J = 9), 7.15 ( 2H, m), 7.09 (4H, bs), 6.96 (1H, bs), 6.80 (1H, bd, J = 9), 6.73 (1H, d, J = 9), 4.54 (2H, t, J = 9), 3.89 (lH, bd, J = ll), 3.60 (3H, m), 3.43 (lH, m), 3.22 (2H, i, J = 9), 3.18 (2H, m), 2.92 (1H, m), 2.72 (1H, m), 2.62 (2H, q, Bu 8), 1.41 (2H, m), 1.26 (2H, m), 1.23 (3H, t, J = 9 ), 0.87 (3H, t5 J = 9). MS (DCI / NH3) m / e 561 (M + H +) Analysis and calculation on C33H37C1N204 · 25 · 2Η20: C, 70.08; H, 6.68; N, 4.95. Experiment 値: C 7013; H, 6.59 〇N, 4.65. Example 426 _C ^^ Mx Star fluorenyl dibutyl hydrophenyl) Carboxamide methylmethoxybenzene Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please first Read the notes on the reverse side and fill out this page) Base) -4- (5-Benzamidine ", furanyl) · ^ ρ Each Yodo-3-Rebrewing%) One: ". 丨. / 一 ^ The title was prepared using the procedure described in Example 1; (Diamond compound. ΙΗ NMR (3 00 MHz, CDC13) δ 7.67 (1H, bs), 7.60 (1H, d, J = 3 Hz), 7.48 (1H, d, J = g Hz), 7.42 (1H, dd, J = 8 &amp; 3 Hz) '7.29 (1! 1, 7-5 ] ^ 8 &amp; 3 Hz), 7.21 (111, (1, 8 Hz), 7.14 (2H, m), 6.99 (lH, bs), 6.76 (4H, m), 3.88 (1H, -501- This paper size is subject to China's National Standards (CNS) regulations ^^ 乂 297 public momentum) 552260

AT H * 7 V. Description of the invention (499) d, J = 10 Hz) '3 75 (1H, ddd, J = 6, 5 &amp; 3 Hz), 3.59 (2H, m), 3.53 (1H , Dd, J = 10 & 3 Hz), 3 22 (1H, t, J = 9 Hz), 3.19 (lH, m), 2.96 (lH, m), 2.70 (1H d J = 16 Hz), 1.42 (2H, m) '1.26 (2H, m)' 0.87 (3H, t, J = 7 Hz). MS (DCI, NH3) m / e 563, 561 (M + H). Analysis and calculation of c32h33C1N205 · 0.5 H20 値: C, 67.42; H, 6.01; N, 4.91. Experiment 値: C, 67.45; Η, 5.82; N, 4.68. Example 427 trans, trans-4- (1,3_: Mao_bayordioxane-5_yl) _2_ (4_fluorenylphenyl) -1-(((N-cyclo $ 棊 _- (N-butylamino) carbonyl 1-methylpyrrolidine-3-carboxylic acid was prepared using the procedure described in Example 1. NMR (300 MHz 'CDC13) (rotatory isomer) 3078 ( 86) (t, 3H, J = 7 Hz), 0.90-1.90 (Bracket, 14H), 2.69 (2.80) (d5 1H, J = 12 Hz) '2.9-3.8 (Bracket, 10H), 3.78 (3.8 0) (s, 3H), 5.92 (s, 2H) '6.72 (d, 1H, J = 9 Hz), 6.86 (m, 3H), 7.03 (d, 1H, J = 6 Hz), 7.34 ( m, 2H). MS (DCI / NH3) m / e 537 (M + H) +. Analytical calculations for C31H4ON2 06 · 1 h20 値: c, 67.13; Η, 7.63; N, 5.05. Experiment 値: C, 67 〇9; H, 7 34; N, 4%. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Example 428 Dioxane Alken-5-yl) -2- (4-ethylphenyl) -1-butylamino) carbonyl a) fluorenyl) -pyrrolidine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. 1Η NMR (j00 MHz, CDCh) δ 0.86 (t, 3Η, J: 7 Hz), 1.22 (t, = 7 Hz), 1.25 (m, 2H), 1.43 (m, 2H), 2.26 (s, this The recording scale is applicable-552260 V. Description of the invention (500) 3H), 2.6 (q, 2H, J = 7 Hz), 2.68 (d, 1H, J = 12 Hz), 2.86 (1, 111,) = 8 Hz), 3.19 (9,211, 127 Hz), 3.44 ((1 (1, 111,) = 3 Hz, 10 Hz), 3.59 (m, 3H), 3.94 (d, lH, 9 Hz), 5.92 (s, 2H), 6.75 (m, 3H), 6.86 (dd, 1H, J = 2 Hz, 8 Hz), 7.08 (m, 6H), 7.17 (t, 1H, J = 8 Hz). MS (DCI / NH3) m / e 543 (M + H) +. Analysis and calculation of C33H38N205 · 0.60H20 値: C, 71.61; H, 7.14; N, 5.06. Experimental6 ·· C , 71.57; H, 6.80; N, 4.87. Example 429 trans, trans-4- (thiafuran-5-yl) -2- (4-ethylphenyltolyl) -N · butylamino) carbonyl) fluorene ) -Pyrrolidinecarboxylic acid The procedure described in Example 1 was used to prepare the title compound. NMR (300 MHz, CDC13) δ 0.90 (t, 3H, J = 7 Hz), 1.30 (t, 3H, J = 7 Hz), 1.31 (m, 2H), 1.43 (m, 2H), 2.2 7 (s, 311), 2.73 (9, 211,] [= 7 Hz), 3.15 ((1, 211, 拎 17 Hz), 3.61 (t, 2H, J = 8 Hz), 3.82 (m, 2H ), 4.00 (t, 1H, 12 Hz), 4.26 (m, 2H), 5.53 (brd, 1H), 6.54 (brs, 2H), 6.76 (d, 1H, J = 2 Hz), 7.14 (m, 3H ), 7.28 (s, lH), 7.40 (m, 3H) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page), 7.48 (d, lH, J = 8 Hz) , 7.63 (d, lH, J = 2 Hz), 7.73 (s, 1H). Calculation of HRMS.C34H39N204 (M + H) + 値: 539.29 10. Experiment 値: 539.2891. Example 43 0 荩, trans-4- (l, 4-phenylarbidinyl-5-yl) -2- (4-ethylphenylarsinoyl) -N-butylamino) anyl) fluorenyl) -p-bihadine-3-complex Acid-503- This paper size applies to Chinese National Standards (CNS) A «4 specifications (210X 297 cm) &quot; &quot; -552260 A / B7 V. Description of the invention (5〇1) k π Title compounds. Utilizing the private sequence wooden clothes described in Example 1 \ ^ 〇87ft 3 二 (He Er)) '1.22 NMR (300 MHz, CDCh) S ϋ δ 1 ,, ... ▲ (t, 3Η, J = 7 Hertz), 1.24 (^ 4, 2.67 (d5 1H, 3H), 2.61 (q, 2H, J = 7 green?) ', 3 l8 (q, 2H, J = 7 Hz), 3.41 (dd5 3H) , 3.93 (d, 1H, J = 10 Hz) 2H), 6.80 (d, 1H, J = 8 Hz) 2H), 1.42 (m, 2H), 2.30 (s, 14 Hz), 2.86 ( t, 1H, J = 8 Hz) 1H, J = 4, 10 Hz), 3.59 (m 4.25 (m, 4H), 6.74 (bi * s, hertz), 6.99 (d, 1H, J = 2 hertz, 6.93 (dd, 1H, J = 2 Hz j = 8 Hz). MS (DCI / NH3) m / e, 7_07 (m, 5H), 7.17 (t, 1H, J 557 (M + H) +. About C34H4. ^ 05 C, 72.42; H, 7.29; N ,; N, 4.62 analytical calculation of H20 4 4 97. Experiment 値: C, 72.49; H, 7.16 anti, anti-2_ (3-fluoro_4_ Methoroxa-di- 5-yl) -M2- (N-propyl-N-2 diyl dioxalamino) ethyl (Please read the notes on the back before filling this page) Central Bureau of Standards, Ministry of Economic Affairs Printed by the Industrial and Consumer Cooperatives 丄 丄 U The title compound was prepared and split and transferred using the shift described in Example 66. ^, 〇〇〇〇〇HH NMR (CDCI3 ^ 30 ft white solid. Melting point 80-82 U nine hertz) δ 0.69 ( t, J 2 7 Hz, 3H), L37 (hexaplex, J = 7 Hz, 2H), 2.09-2.17 (m, 1H), 2.24 (s, jH) '2.5j (s, 6H), 2.54- 2.64 (m, lH), 2.73-2.86 (π, 2Η) '3.02 (hexaplex 5b 7Hz, 2Η), 3. 13-3.2 8 (m, 3Η), 3.44-3.53 (m, 1 Η), 3.5 7 (d, j = 9 Hz, 1H), 3.89 (s, 3H), 5.94 (s, 2H), 6.74 (d, J = 8 Hz, 1H), 6.78 (dd, J = 2 Hz , J 2 8 Hexuan, 1H), 6.85 (s, 2H) 幺 幺 -504- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (2i0x 297 kilometers) 552260 Λ7 ______R7 V. Description of the invention ( 502) — '6.92 (d, J = 8 Hz, 1H), 9.94 (d, J = 2 Hz, 1H), 7.06 (d, j = 8 Hz, 1H), 7.13 (dd, J = 2 Hertz, J = 12 Hertz, 1H). Ms (DCI / NH3) m / e 627 (M + H) + 〇 Example 432 trans, trans-2- (4-methylbenzyl) -4- (3,4-difluorophenyl peptidyl) amine Base) Tibetan mastyl lp Bilodoline-3-propane_ The title compound was prepared using the procedure described in Example 1. 1h NMR (300 MHz, CDC13) δ 0.86 (t, J = 7 Hz, 3H), 1.18-1.32 (m, 2H), 1.35-1.48 (m, 2H), 2.64 (d, ! 3 Hz children, 1H), 2.71 (t5 J = 7 Hz, 1H), 3.08-3.18 (m, 2H), 3.42 _ 3.48 (m, 1H), 3.53-3.64 (m, 3H), 3.77 (s, 3H), 3.S0 (d J 2 9 Hz, 1H), 6.73-6.85 (m, 3H), 6.94 (s, 1H), 7.04-7.40 (m, 7H). Example 433 group ... 'trans-2_ (3.fluorofluorooxyphenylpyrene # m-dioxetane-! Di-yl)-propyl-N- (3-chloropropanyl) Based) Ethyl propyridine-3 · carboxylic acid printed by the staff of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling out this page} The title compound was prepared using the procedure described in Example 1. η NiMR (CD3OD, 300 MHz) δ 0 · 80 (t, 3Η, J = 7), 1.47 (bd hex, 2H, J = 8), 2.15 (pen, 2H, J = 7), 2.32 ( τη, 1Η), 2.7-3.2 (m, 9H), 3.46 (dd, 1H, J2 4, 10), 3.57 (m, 1H), 3.64 (t, 2H ,: [2 6), 3.67 (d, 1H, J 2 9), 3.86 (s, 3H), 5.92 (s, 2H), 6.74 (d5! H, J = 8), 6.84 (dd, 1H, J = 2, 8), 6.96 (d5 1H, J = 2), 7.06 (t, lH, J = 9), 7.18 (m, 2H). MS (DCI / NH3) m / e-505- This paper size applies to China National Standard (CNS) Λ4 specifications ( 21 〇x 297 public dream) 552260 A 7 B7 V. Description of the invention (503) 585 (M + H; 35Cir 〇587 (M + H; 37C1 wide. Analysis and calculation of C27H34N207 C1FS 値: C, 55.43; Η, 5 · 86; N, 4.79. Experiment : C5 55 · 65; Hf, 5.81; N, 4.70. Example 434 trans, trans-2- (3-fluoro-4-fluorenoxyphenyl) -4- (1,3-phenylhydrazone dioxolane Alken-5-yl) -1- (2- (N-isobutyl-N- (3-chloropropanesulfonyl) amino) ethyl 1-pyrrolidine-3-guinic acid was used in Example 6 6 To prepare the title compound. 1 程序 NMR (CD3OD, 3 00 MHz) δ 0.79 (d, 3Η, J 2 7), 0.84 (d, 3H, J = 7), 1.68 (hept, 1H, J 2 7), 2.18 (pen, 2H, J = 7), 2.8-3.4 (m, 10H), 3.5-3.8 (m, 3H), 3.65 (t, 2H, J = 6), 3.90 (s, 3H) , 5.94 (s, 2H), 6.77 (d, 1H, J = 8), 6.87 (dd, 1H? J-2? 8), 6.99 (d, 1H, J 2: 2), 7.13 (t, 1H, Bu 9), 7.27 (m, 2H). MS (DCI / NH3) m / e 599 (M + H) +. Analysis and calculation of C28H36N207C1FS · 0.3TFA 値: C, 54.24; H, 5.78; N, 4.42. Experiments: C, 54.19; H, 5.71; N, 4.01. Example 435 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Hi (Please read the precautions on the back before filling this page) Anti-trans-2_Propylmethyl-4- (1,3-Benzodioxane Dipentyl-5-yl) -1-(N, N-di (n-butyl) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid was prepared using the procedure described in Example 1 to prepare the title compound. 1Η NMR (300 MHz, CDCl3) 3 0.87-0.98 (m, 9H), 1.21-1.39 (m, 4H), 1.43-1.57 (m, 4H), 1.58- 1.70 (m, 2H), 3.13-3.29 ( m, 4H), 3.34-3.43 (m, 3H), 3.45-3.5 5 (m, 3 H), 3.69 (dd, 10.2, 4.5 Hz, 1H), 3.80-4.20 (m, 4H), 5.93 (s, 2H), -506-This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X 297)

AT B7 V. Description of the invention (504) 6.7] (d, J-7.8 Hz, 1H), 6 84 (8, 7 Hz, ih), (Please read the precautions on the back before filling this page) 6.93 (d, J 1 · 7 Hexuan, 1H). Ms (DCI / NH〇m / e 477 (M + H) +. Analytical calculation of ~ Η40N2〇6 · 0.5〇TFa 値: c, 6〇77 'Η, / · 6 :)' N,) · 2 ) ° Experiment 値: C, 60.73; Η, 7.74; Ν, 5.22-ίΐ436 di 4- (1,3-phenylhydrazine-dioxolene-butanesulfonyl) amino) ethyl group Pyrocarboxylic acid was prepared using the procedure described in Example 66 to prepare the title compound, and a solid tank for the separation of white bars. Melting point 65_67. (: IH NMR (CDCl3, 300 MHz)? Δ 0.82 (t, J-7 Hz, 3H), 088 (d, BU 5 Hz, 6 seals, 46 (hexaplex, J 2 7 Hz) , 2Η), 1.56 · 164 (ιη, 3Η), 2 24 _2 33 (m, 1H), 2 68-2.93 (m, 5H), 2.98-3.12 (m, 2H), 3.15-3.35 (m, 2H) '3.43 (dd, J = 3 Hz, ㈣Hz, iH), 3 52-3 58 (, ih)). 6) (d, J 12 Hz, iH), 3 87 (s, 3H), 5% ( s, 2H), 6.7j (d,) 8 Hz, 1H), 6.82 (dd, J = 2 Hz, J = 8 Hz, 1H), 6.92 (t, J — 8_ ^, iH), 6.97 (d5J = 2 * g5lH), 7.10 (d, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs J = 9 Hz 4, 1 Hz), 7 16 (dd, J =; 2 Hz, J = i2 Hz, ih). MS (DCI / NH3) m / e 579 (M + H) +. Example 43 7 trans-dimethoxy-3-fluorobenzene, methoxy-u-phenylhydrazine dioxymj ^ 5-yl) -1- "2- (Ν_propyl-N- (n-pentane Sulfonyl) amino) Ethyl 1-pyrrolidin-3-miao acid 507 The standard of this paper is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 cm) 552260 A7 ------ ΒΊ V. Invention Explanation (505)-The procedure described in Example 66 was used to prepare the title compound. iH NMR (3 00 MHz, CDC13) δ 〇8i (t, J = 7 Hz, 3H), 0.90 (t, J = 9 Hz, 3Η), 1.25-1.35 (m, 4H), 1.44 (six Heavy peak, J = 7 Hz, 2H), 1.67-1.7 8 (m, 2H), 2.22-2.34 (m, 1H), 2.30 -2.95 (m, 5H), 2.95-3.10 (m, 2H), 3.15- 3.33 (m, 2H), 3.45 ((14) = 3 Hz, 9 Hz, 111), 3.47-3.56 (111, 111), 3.65 ((1,) = 9 Hz, 111), 3.88, 3 buckles, 3.94 Bu, 311), 5.95 (5, 2 India, 6.55 (s, 1H), 6.65 (s, 1H), 6.92 (t, J = 7H, 1H), 7.U (d, J = 9 Hz, 1H ), 7.17 (d, J = 12 Hz, 1H). TjH 43 8 trans, trans-2- (3-fluoro-4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxane Pentene-5-yl) -1- [2-(! ^-Propyl-^!-(2,2,3,3,3-pentafluoropropoxyethenyl) amino) ethyl 1-Pulloline-3-polyacid uses the procedure described in Example 66 to prepare the title compound and isolates a white solid. Melting point 63-64 ° C. 4 NMR (CDC13, 300 MHz) δ 0.82 (t, J 2 7 Hz, 3H), 1.45 (hexaplex, J = 7 Hz, 2H), 2.24-2.33 (m, 1H), 2.70-2.82 (m, 1H), 2.85-3.09 (m, 5H), 3.14 -3.2 8 (m, 4H), 3.43 (dd, J = 3 Hz, J = 9 Hz, 1H) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page), 3.52-3.58 (m, lH), 3.65 (d, J = 9 Hz, 1H), 3.87 (s, 3H), 3.92-3.98 (m, 3H), 5.94 (s, 2H), 6.74 (d, J = 8 Hz, 1H) '6.82 (dd, J = 2 Hz, J = 8 Hz, 1H), 6.92 (1 :, 1 = 8 Hz ih), 6.97 (d, J = 2 Hz, 1H), 7.10 (d, J = 9 Hz, 1H), 7.17 (dd, J 2 2 Hz, J = 12 Hz, 1H). MS (DCI / NH3) m / e 685 (Μ + ΗΓ. -508- The guilty scale of this paper applies Chinese national standards ( CNS) Λ4 specification (210X 297 males) 552260 PC '

_______JT V. Description of the invention (506) t Μ 43_9 plexes, trans · 2_ (1,4 · benzene to di ^ ane: 6 · rolloxyl_1,3_phenylhydrazine dicyclopentazone-5- "L-1-d-propyl ^ g-pentanesulfonyl) amino) ethyl1-pyrrolidine The title compound was prepared using the procedure described in Example 66. 1H NMR (CDC13) δ 0.81 (t, J = 7 Hz, 3H), 0.9 (t, J = 7 Hz, 3H), 1.23-1.3 6 (m, 4H) '1.45 (hexaplex, Jr = 7 Hz, 2H), 1.65-1.78 (m, 2H), 2.20-2.30 (m, 1H), 2.30-2.95 (m, 5H), 2.95-3.10 (m, 2H), 3.15-3.35 (m, 2H) , 3.42 (dd, J 2 3 Hz, 9 Hz, 1H), 3.46-3.56 (m, 1H), 3 59 (d, J = 9 Hz, 1H), 3.91 (s, 3H), 4.24 (s , 4H), 5.95 (s5 2H), 6.57 (s, 1H), 6.68 (s, 1H), 6.82 (d, J 2 8 Hz, 1H), 6 88 (dd, J = 2 Hz, 8 Hz , 1H), 6.95 (d, J = 2 Hz, 1H). Example 44: trans, trans-4- (1,3-benzyldioxol-5-even) -2- (4-methoxyphenyl) -1-(((N · butyl- N- (4-Methoxybenzyl) amino) miao) methyl) -pyrrolidine-3-carboxylic acid Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page) The procedure described in Example 1 was used to prepare the title compound. 1Η NMR (300 MHz, CDC13) δ (rotatory isomer) 7.32 (1H, d, BU 10), 7.22 (lH, m), 7.10 (lH, d, J = 9), 7.03 (6.98) ( lH, d, J = 3), 6.90-6.80 (4H, m), 6.79 (2H, d, J = 9), 6.77 (1H, t, J = 8), 5.85 (2H, s), 4.92 (4.10) (lH, d, J 2: 15), 4.42 (4.22) (lH, d5J = 15), 3.81 (lH, m), 3.79 (3 78) (3H, s), 3.76 (3H, s), 3.62 (1H, m), 3.43 (2H, m), 3.30-2.70 (5H, m), 1.42 -509- This paper size applies to the Chinese National Standard (CNS) Λ4 specification (210X 297 cm) 60 2 2 5 5 Printed A7 by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Inventory Note (507) (1H, Π1), 1.23 (2H, m), 1.01 (1H, m), 0.83 (0.75) (3Η , T, J ~ 8) Q MS (DCI / NH3) m / e 575 (M + H +). Analysis and calculation of C33H38N207 • 0 · 5 H20 値: C, 67.91; H, 6.73; N, 4.80. Experiment 値: C, 67.78; H, 6.44; N, 4.55. Example 441 2- (3 • Fluoro-4-methoxyphenyl) -4-Π, 3-benzene # m-dioxolane-fluorene-1- (2- (N-isobutyl jN- (pentyl Alkylsulfonylamino) ethyl) -pyrrolidine-3-metanoic acid was prepared using the procedure described in Example 66. 1。 NMR (CD3OD, 3 00 MHz) δ 0 · 76 (d, 3Η, j 2: 7), 0.84 (d, 3H, J = 7), 0.92 (t, 3H, J = 7), 1.36 (m, 4H), 1.70 (m, 3H), 2.90 (m, 2H ), 3.02 (m, 2H), 3.1-3.8 (m, 7H), 3.84 (d, 2H, J = 8), 3.91 (s, 3H), 5.96 (s, 2H), 6.80 (d, 1H, J 2: 8), 6.88 (dd, 1H, J = 2, 8), 7.00 (d, 1H, J = 2), 719 (t, 1H, Bu 9), 7.35 (m, 2H). MS (DCI / NH3) m / e 593 (M + Hr. Analysis and calculation of C30H41N2O7F · 0.5TFA 値: C, 5 7 · 31; H, 6.44; N5 4.31. Experiment 値: C, 57.08; H, 6.15; N, 3 95 Example 442 trans, trans-4- (1,3-phenylhydrazone dioxol-5-yl) -1- (N-butyl-N- (3-fluorophenylamino) carbonylfluorene The compound was prepared using the procedure described in Example 1. 1H NMR (300 dead Hz, CD3OD) δ 0.87 (t, J &lt; 7 Hz, 3H), 1 10-1.30 (m, 4H), 2.70-2.9 0 (m, 2H), 3. I3 〇, Bu 8 Hz, iH), 3.40-3.90 (m, 6H), 3.79 (s, 3H), 5.0 (S, 2H) '6.75 This paper size is applicable to China Standard (CNS) A4 size (210X 297mm t) (Please read the precautions on the back before filling this page)

552260 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

A V. Description of the invention (508)

(d, J 2 8 Hz, 1H), 6.80-7.20 (in, 9H), 7 40 (m, 1H). MS (DCI) m / e 549 (M + H) +. For the analysis of C3iH33N206F. 0.8 H2O, 値: C, 66.13; Η, 6.19; N, 4.98. Experiment 値: C, 66.21; Η, 5.83; Ν, 4.84. Example 441 1, _, trans-4- (1? _3-Benzo-dioxocyclic meso_5_ylν2_ (cardiofluorophenyl · E-(3-fluorophenylaminopyrrolidine- 3-carboxylic acid using the procedure described in Example 1 to prepare the title compound. 1H NMR 00 MHz, CD3OD) δ 0.87 (t, J = 7 Hz, 3H), 1.20-1.50 (m, 4H), 2.65-2.85 (m, 2H), 3 〇5_3 85 (m, 7H), &gt; .93 (s, 2H), 6.75 (d, J = 8 Hz, 1H), 6 85 (dd, J = 8 Hertz, 111) '6.90-7.10 (111541 ^), 7.10-7.25 (111,311), 7.33-7.45 (m, 2H). MS (DCI) m / e 553 (M + H) +. About C30H30N2O5 FC1; C, 65 · 16; H, 5.47; N, 5.07. Experiment 値: C5 65.3 7; H, 5.41; N, 4.98. Example j: 44 trans, trans-4- (l, 3-phenylhydrazone dioxane Cyclopenten-5-ylmethoxyphenyl) -1-(((N-butyl-N- (3,4-dioxobenzyl) amino) carbonyl) fluorenyl) -pyrrolidine-3- The osmic acid used the procedure described in Example 1 to prepare the title compound. 1 η NMR (300 MHz, CDC13) δ (rotomer) 7.33 (1 (, d, J = 10), 7.23 (1H, m ), 7.03 (6.97) (1H, d, J = 3), 6.90-6.60 (6H, m), 6.47 (1H, m), 5.93 (2H, m), 4.83 (4.09) (1Η, d, J 2: 15), 4.45 (4.22) (lH, d, J =) 5), 3.83 (3.86) (3H, s), 3.79- 511-This paper size applies Chinese National Standard (CNS) Λ4 specification (1ΐΟΧ 297ϋΠ '~ .--- 0 ------ IT ------ (Please read the precautions on the back before filling this page) 552260 A7 _________B7 _ V. Description of the invention (509) (lH, m), 3.77 (3.76) (3H, s), 3.75 (3.65) (3H, s), 3.60 (1Η, ra), 3.43 ( 2H, m), 3.28 (lH, m), 3.20-2.70 (4Η, ιη), 1.43 (1H, m), 1.23 (2H, m), 1.02 (1H, m), 0 · 84 (0 · 77) (3Η, t, J = 8). MS (DCI / NH3) m / e 605 (M + H +). Analytical calculated values for C34H40N2O8: C, 67.53; H, 6.67; N, 4.63. Experiment 値: C, 67.28; H, 6.63; N, 4.38. Example 445 Di 4- (1,3-phenylhydrazone diacyclopenten-5-yl) -2- (4-methoxyphenyl IllkilK-butyl-N- (2-methoxyfluorenyl) amine (Carbonyl) carbonyl) methyl)-pyrrolidine-3-carboxylic acid Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling this page) Li Zhou's procedure described in Example 1 to prepare the title Compound. 1H NMR (300 MHz, CDC13) δ (rotatory isomer) 7.33 (lH, d,, 7.11 (2H, m), 7.03 (1H, dd, J = 8, 3), 6.90-6.60 (7H M), 5.93 (2H, m), 4.83 (4 · 15) (1Η, d, J 2:15), 4.47 (4.30) (ih, d, Bu 15), 3.81 (1H, m), 3.78 (3.73) (3H, s), 3.72 (3H, s), 3.59 (1H, m), 3.43 (2H, m), 3.30 (1H, m) '3.20-2.70 (4H, m), 1.42 (1H, m), 1.23 (2H, m), 1.01 (1H, m), 0.83 (0.77) (3H, t, J = 8). MS (DCI / NH3) m / e 575 (M + H). Analytical calculations for c33H38N207: c, 68.97; H, 6.66 ·, N, 4.87. Experiment 値: c, 68.70; H, 6.56; N, 4.61. Example 44 6 3-Benzene is ^ dioxy Heterocyclyl-5-yl) -2- (4-methoxyphenylfluorenyl) amine 4) carbonyl) fluorenyl) _pyrrolidine-3-leptic acid —__ -512- National Standard (CNS) Λ4 Specification (210X 297) 552260 A · B- 5. Description of the invention (51) The procedure described in Example 1 was used to prepare the title compound. iH NMR (300 MHz, CDC13) δ (rotatory isomer) 7.31 (1H, d, J = 10), 7.13 (lH, d, J = 9), 7.16 (lH, dt, J = 8, 3) , 7.03 (1H, dd, J = 10, 2), 6.90-6.60 (6H, m), 6.50 (lH, m), 5.94 (2H, m), 4.82 (4.19) (1H, d, J = 15) , 4.50 (4.23) (1H, d, J = 15), 3.78 (3.76) (3H, s), 3.77 (lH, m), 3.75 (3.67) (3H, s), 3.59 (lH, m), 3.57 -3.35 (2H, m), 3.25 (lH, m), 3.20-2.70 (4H, m), 1.43 (1H, m), 1.23 (2H, m), 1.02 (1H, m), 0.84 (0.77) ( 3H, t, J 2: 8). MS (DCI / NH3) m / e 575 (M + lT). Analysis and calculation of C33H3SN207 値: C, 68.97; H, 6.66; N, 4.87. Experiment 値: C, 68.72; H, 6.55; N, 4.60 〇 Example 447 tail, trans-2- (3-fluoro-4-methoxyphenyl) -4- (1,3-benzene! M-dioxane Phenyl-5-yl) -1_ (2- (N- (2_methoxyethyl) -N_ (3_chloropropane and succinyl) amino) ethyl)-each bite -3 -Acidification The procedure described in Example 66 was used to prepare the title compound. 1 η NMR (CD3OD, 3 00 MHz) δ 2.15 (pen, 2Η, J 2 7), 2.33 (m, 1H), 2.81 (m, 2H), 2.93 (t, 1H, Bu 9), 3.1 -3 6 (m, 10H) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling out this page, 11, 3.24 (s, 3H); 3.65 (t, 2H, J = 6), 3.70 (d, ih, J = 9), 3.78 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1H,, 6.84 (dd, 1H, J = 2,8), 6.97 (d, lH, J = 2), 7.07 (t, lH, J = 9), 717 (m, 2H). MS (DCI / NH3) m / e 601 (M + ΗΓ. Analysis on C27h34N208CIFS Calculated 値: C, 53.95; H, 5.70; N, 4.66. Experimental 値: C, 53.65; Η, 5.49; N, 4.26. -513- This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X 297 Gong) ~ ~-552260 A "--------- V. Description of the invention (511) Real {£ ^ 44 8 was _. ·· 'trans-2- (3-fluorobenzene 弁M-dioxolyl) i- (2- (K2-methylsulfanylsulfonyl) amino) ethanoic octapicanoic acid The procedure described in Example 66 was used to prepare the title compound.! H NMR (CD3OD, 300 MHz) δ 〇 93 (m, 3H), i 34 ㈤, 4h), 1.69 (m, 2H), 2.33 (m, 1H), 2.75-3.l (m, 7H), 3.23 (s, 3H), 3.3-3.6 ( m, 6H), 3.70 (d, 1H, ㈣), 3% &amp; 3H), 5.92 (s, 2H), 6.74 (d, 1H, J = 8), 6 84 (dd, m, J = 2, 8), 6.97 (d, 1H, J = 2), 7.07 (t, 1H? J = 9), 7.18 (m, 2H) 〇MS (DCI / NH3) m / e 595 (M + H) +. About Analytical instruments for C29H39N208Fs: C, 38.57; H, 6.61; N, 4.71. Experiment: C, 58 · 21; H, 6.29; N, 4.29. Example 449-This table contains a ring of oxygen. Pentene-5-yl) -2- (4-methoxyphenyl) -n- (4-fluoro-3carbonyl) methyl) -pyrrole-3-borrowed from acid using the procedure described in Example 1 Title compound. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) NMR (300 MHz, CD3〇D) s 089 (m, 6H), i 181 36 (m, 8H) '2. 15 (bs, 1.5 (CH3 rotomer)), 2 28 (bs,} 5 (CH3 rotomer)), 2.64 (t, J = 14.9 Hz, ih), 2.82 (m, 1H ), 3.07-3.29 (m, 2H) ^ 3.32-3.41 (m, iH), 3.53-3.60 (m, 1H), 3.70-3.79 (m, 1H), 3.79 (s, 3H), 4.68 (m, 1H) ), 5.92 (m, 2H), 6.69-6.90 (m, 6H), 6 93-7007 (m 4H). Hall -514, This paper size applies to China's CNs) A4 size (210 X 297 Gongchu)-552260 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

A V. Description of the invention (512) ^ (DCI) m / e 605 (M + H +). About r, x L M ^) J々C35H41FN, 06 Analytical calculation 値: C, 69.52; H, 6.83; N 4 O N ′ 4.63. Experiment 値: C, 69.31; H, 6.78; N, 4.35. -Benzene-meta-oxenyl-methoxyphenyl succinyl) (4-fluorobenzytyl) fluorenyl) ′ anion The procedure described in Example 1 was used to prepare the title compound. lH NMR (30 (^ WM, CD3OD) 50.8] U () 9 () (m, 6H), 13 () (m, 12H) '2.14 (s, l.) (CH3 rotamer)) , 2 3〇 (s, i 5 (Ch3 rotates on the structure)), 2.60 (t, J 2 14.8 Hz, 1H), 2 80 (m, 1H), 3.09-3.24 (m, 2H), 3.33-3.42 (m, 1Η), 3 50-3 55 (m lH), 3.65-3.77 (m, 1H), 3.79 (s, 3H), 4.64 (m5lH), 5.93 (m, 2H), 6.70- 6.84 (m, 5H), 6.91-7.13 (m5 5H). MS (DCI) m / e 63 3 (M + H '). Analysis and calculation of C37H45FN206 値: C, 70.23; Η, 7.17; N, 4.43. Experiment 値: c, 70.14; H, 7.13; N, 4.19. Example 45 1 plex_1_ to -4- (1,3-benzo-dioxol-5-yl) -2- (4-fluorenylbenzyl) -1-((N- (5 -Nonylamino) carbonyl) fluorenyl) -pyrrolidin-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. 1 η NMR (300 MHz, CD30D) δ 0.80 (t, J = 7.0 Hz, 3Η), 0.84 (t, J = 7.1 Hz, 3Η), 1.15 plane 1.55 (m, 12H), 2.88 (d , 515- This paper size applies to Chinese National Standard (CNS) A4 specifications (210X 297 total 1T ------ IP_ (please read the precautions on the back before filling this page) 552260 Central Standards Bureau of the Ministry of Economic Affairs Printed by the Industrial and Consumer Cooperatives 5. Invention Description (513), 3.36 (dd, J = 4.4, 9.8 Hz, 1H), 3.64 (m, lH), 3.76 (m, 1H) '3.79 (s, 3H)' 3.9 8 (d, J = 9.5 Hz, iH), 5.93 (m, 2H), 6.77 (d, J = 7.8 Hz, 1H), 6.85 (dd, Bu 1.7, 8.1 Hz, 1H), 6. 93 (m, 2H), 6.99 (d, J = 1.7 Hz, 1H), 7.39 (m, 2H). MS (DCI) m / e 525 (M + IT). About C30H46N2〇6 · 0 · 35Η20 Analytical calculation C: C, 67.86; H, 7.73; n, 5.28. Experimental 値 ·· C, 67.87: H, 7.63; N, 5.11. Example 452 plex_'trans-4- (1,3 Erquan Fi-Dioxane into ene-5-some) -2- (4-methylhydrofluorenyl) diVr ((N-butylphenyl) amino) carboxyfluorenyl) _pyrrolidine-3-carboxylic acid Utilization in Example 1 Describe the procedure to prepare the title compound. 1 'NMR (j00 MHz' CD3OD) δ 0. 87 (dt, J = 7 Hz, 3H), 1. 15-1.32 (m, 4H), 3. 7 (d, J = 2 Hz, 3H), 2.65-5.92 (m, 9H), 5,93 (d, J = 4-L2H), 6.70-6.90 (m, 4H), 7.00-7.45 (m, 7H). MS ( DCI) m / e 549 (M + H: T. Analysis and calculation of C31H33N206 • 0.4 H20: C5 66.99; H, 6.13; N, 5.04. Experiment: C, 67.01; H, 6.23; N, 4 68. Example trans-2- (4- 曱 _oxy „benzene 碁) -4- (1, dibenzyl diazacyclopentene-5_a certain propyl-N- (2-benzopyrimidine) Ethyl] _pyrrolidin_3_carboxylic acid was prepared by the method of Example 4 1 8 to replace the 2-bromopyrimidine with 2-chlorobenzidine-4azole. 1H NMR (300 MHz, CDC13) δ 0.88 (t, J 2 7 Hz, 3H), 1.59 (sixfold peak, Jy Hz 2H), 2.25-2.37 (m, -516- This paper is applicable to China Standard (CNS) Λ4 specification (210X 297 public (please read the precautions on the back before filling this page)

Order 552260 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (514 1H), 2.85-2.97 (m, 3H), 3.28-3.36 (m, 2H), 3.50-3.58 (m, 3H), 3.60-3.65 (m, 1H), 3.67 (d, J = 9 Hz, 1H), 3 71 (s, 3H), 5.87 (d, J = 2 Hz, 1H), 5 91 (d, J = 2 Hz , 1H), 6.57 (d, J = 8 Hz, 1H), 6.73 (dd5 J = 2 Hz, 9 Hz, π), 6.76 (d, J = 8 traces | Mod, 2H) '6.91 (d, J = 2 Hz, 1H), 7.01 (t, j = 8 Hz, 1H), 7.22 (t, J = 8 Hz, 1H), 7.29 (d, J = 8 Hz, 2H), 7.40 (d, J = 7 Hz, 1H), 7.55 (d, J = 7 Hz, ih). f Example 454 Good_, trans-K, 2-ethoxyethyl) Kl, 3-phenylhydrazone dioxolene_5_some Ili- (N, N-bis (n-butyl &amp; aminocarbonyl) Methyl) -pyrrolecarboxylic acid was prepared using the procedure described in Example 1 to prepare the title compound. Η NMR (CDC13, 3 00 MHz) δ 0.91 (t5 J = 7.4 Hz, 3Η), 〇94 (ί, J 2 7 4 Hz, 3Η), 1.19 (t, J = 7.0 Hz, 3Η), 1.24-1.38 (m, 5H), 1.46-1.60 (m, 4H), 2.03-2.i2 (m, 2H) , 3.07 (t, J 2 8.0 Hz, 1H), 3.07-3.34 (m, 6H), 3.43-3, 52 (m, 3H), 3.59-3.74 (m, 3H), 3.80_4.01 (m, 2H ), 5.93 (S, 2H), 6.72 (d, J = 8.i Hz, 1H), 6.79 (dd, J = 8.2 Hz, i 7 Hz, iH), 6.87 (d, J: 1. 7 Hz, 1H). MS (DCi / NH3) m / e477 (M + ΗΓ. About c26h40N20. 0.4TFA analysis meter i · c ⑽ 一 .... 36. Experiment 値: C, 6 ::; different two; Ν ， 5 · 29 〇 Example 45 5 Dioxolamine ethyl) ethyl bu -517 The paper scale is applicable to the Chinese National Standard (CNS) Λ4 specification (2l0x 297 public 牦 -------- -· 1, (Please read the notes on the back before filling this page) Order f 552260

A _ one-five, description of the invention (515) p-pyridine 3 acid at room temperature using the methoxyfluorophenyl prepared by the procedure of Example 125) -4- (1,3-phenylamidine Dioxol-5-yl) -Bu [2- (propyl-N- [2-vinylsulfonyl] amino) ethyl] pyrrolidine-3-etanoate ethyl acetate, with excess The morpholine was reacted for 4 hours. Chromatography on silica gel, eluting with Et0Ac, yielded a 65% yield of the intermediate ethyl ester, which was hydrolyzed to the title compound with NaOH in ethanol / water. 1H NMR (300 MHz 'CDCl3) δ 0.81 (t, J = 7 Hz, 3Η), 1.46 (hexaplex,] 2 7 Hz, 2H)' 2.43-2.52 (m, 4H), 2.70-2.92 (m, 5H), 2.97-3.33 (m, 6H), 3.60 (dd, J = 3 Hz, 9 Hz, 1H), 3.51-3.59 (m, 1H), 3.62-3.70 (m, 5H), 3.88 ( s, 3H), 5.95 (s, 2H), 6.72 (d, J = 8 Hz, 1H), 6.70 (dd, J = 2 Hz, 8 Hz, 1H), 6.90 (t, J = 9 Hz, 1H) , 6.96 (d, J = 2 Hz, 1H), 7.10 (d, J = 8 Hz, ih) '7.18 (dd, J = 2 Hz, 12 Hz, 1H). Example 456 (Please read the notes on the back before filling this page

, 1T 1 _: — trans-2- (upper 1 | 1-4: methoxy_ ^ yl) -4- (1,3-phenylhydrazine

Ethyl) ethyl 1-p to p-coefficient yttrium-3-carboxylic acid Printed by the Central Consumers Bureau of the Ministry of Economic Affairs and Consumer Cooperatives The procedure described in Example 66 was used to prepare the title compound and separate a white solid. 95-96 ° C. 4 NMR (CD3OD, 300 MHz) δ 0.80 (t, J = 7 Hz, 3H), 1.35- 1.48 (m, 2H), 3.07 (doublet, J-2 7 Hz, 2H), 3.23 · 3.55 (ιη, 8Η), 3.80-3.87 (m 2H), 3.93 (S, 3H), 3.94_4.02 (m4H), 4 66 (dj = i2Hert, 5.96 (S, 2H), 6.83 (d, J == 8 Hz, 1H), 6 94 (dj = 8 Hz-518- this paper size is suitable for household standard pCNS) 552260 Λ. R- 5. Description of the invention (516), put), 7.06 (d, J = 2 Hz, 1H), 7.23 (t, J = 9 Hz, 1H), 7.43 (d, J = 9 Hz, 1H), 7.49 (dd, J = 2 Hz, J = 12 Hz, 1H). MS (DCI / NH3) m / e 635 (M + H) +. Example 457-4- (1,3-Benzo-dioxol-5-yl) -2- (4-fluorophenyl) -1- (N-butyl-N- (3-tolyl ) Aminocarbonylfluorenyl) -pyrrolidine-3-carboxylic acid hydrazone I (Please read the notes on the back before filling out this page. Use the procedure described in Example 1 to prepare the title compound NMR (300 MHz, CD3〇D) δ 0.87 (t, J = 7 Hz, 3H), 1.20-1.50 (m; 4H), 2.31 (s, 3H), 2.65-2.80 (m, 2H), 3.19 (t, J-7 Hz, 1H ), 3.25 (d, J = 10 Hz, 3 35-3 65 (m, 4H), 3.79 (d, J = 10 Hz, 1H), 5 93 (s, 2H), 6 74 (d, j = 7 Hz 5 1H), 6.80-6.90 (m, 3H), 6.91-7.09 (m 3H), 7 10-135 (m, 4H). MS (DCI) m / e 533 (M + H), about Analytical calculation of C3iH ”N205F: C, 69.91; H, 6.25; N, 5%. Experiment 値: c, 69.56; H: 6.26; N, 5.23. Example 45 8, trans-2- (3-fluoro -4_Methoxyphenyldioxolene ^ l: W2- (N- (2-methoxyethyl onyl) ethyl) _Pyrrole Printed by Piker Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs_ 3 _ a few acids

The procedure described in Example 66 was used to prepare the title compound. lH NMR (CD3OD, 3 00 MHz) δ 0.94 (m, 3H), i 23 (hex? HJ = 8), UMmJH), 3.08 (m, 2H), 3.20 (s3H), 33_35 3.77 (m, 2H), 3.92 (S, 3H), 4 6 (m iH), 5% (s, 2H), 6.81 (d, 1H, J = 8), 6.88 (dd, 1H, J = 2, 8), 6 99 (d, 519) This paper size applies to China National Standard Car (CNS) A4 specifications (21 Ox 297 male pair 552260 Λ7 V. Description of the invention (517) 1H, J = 2), 7.22 (t, 1H T = cn, ~ 9), 7.38 (m, 2H) ° MS (APCI) m / e 581 (M + H) '. About c2sh \ τ γλ r (Please read the notes on the back before filling in this page 8H37N2〇 8FS. L. Analysis and calculation of iTFA: C, 51.37; H, 5 44 · \ T 〇, N, '97. Experiment: C, 51.27; H, 5.35; N, 4.11. Cyclopentene-Sm) -1-[2: Dipropanesulfonium sulfonium) Amine) Ethyl 1-pyridine The title compound was prepared using the t sequence enumerated in Example 66 and isolated White solid. Melting point τ ΐττ 6 L ° H NMR (CDC13, 300 MHz) δ 0.83 (t, J = 7 Hz Λ Ban Xuan Mo, 0H), 1.0ό (d, J = 6 Hz, 6H), 1.45 (9, = 7 Hz, 211), 2 2 0 (Shiyu owes /, 11 U (seventh peak, J = 6 Hz, 1H), 2.26-2 · 36 (m, 1Η) ^ 2.62-2.70 ( m? 3H), 2.85-2.95 (m, 2H) ^ 2.97-3.10 (ιη'2Η) 'xl: &gt; m (m, 2H), 3 43 (dd j = 3 Hz,) 2 9 Hz, 1H) 'DM.62 (m, lH), 3.66 (d, J = 9 Hz, 1H), 3.88 (s,] H)'). 95 (s, 2H) '6.74 (d, J = 8 Hz, ih) , 6.82 (dd, J 2 2 Hz, 8 Hz, 1H), 6.92 (U = 8 Hz, 1H), 6.97 (d, J 2 2 Hz, 1H), 7.12 (d, 2 Hz, 1H), 7 18 (dd, 2 Hertz, printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, J: 12 Hertz, 1H). MS (DCI / NH3) m / e 565 (M + H) +. iH 46j0 radical-'trans-4- (1,3-benzenesulfonyltripenten-5-yl V2-M-methoxyphenylcarbonyl), a certain pyrrolidine-3-carboxylic acid — use in examples The procedure described in 1 was used to prepare the title compound. 1Η -520 This paper size applies to China National Standard (CNS) A4 specification (210 × 297 public momentum 552260 Λ: B1 V. Description of the invention (518) NMR (300 MHz, CDC13) δ (Rotating isomer) 8.11 ( 2H, m), 7.32 (3H, dd, J = 2), 7.16 (7 · 07) (1 H, bd, J = 10), 6.98 (6.94) (1H, d, J = 2), 6 · 85 (2H, d, J = 9), 6.83-6.70 (2H, m) '5.9 9 (5.9 7) (2 H, d, J = 2)' 5.0 2 (4.1 8) (1H, d, J 2 1 5), 4.6 3 (4.38) (lH, d, J = 15), 3.79 (3.77) (3H, s), 3, 72 (lH, d, J = 10), 3.61 (1H, m), 3.48 (1H, bd, J 2: 15), 3.43-3.20 (2H, m), 3.06 (2H, m), 2.90 (1H, m), 3.79 (1H, bd, J 2: 14), 1.43 ( 1H, m), 1.23 (2H, m), 1.02 (1H, m), 0.84 (0.7 8) (3H, t, J = 8). MS (DCI / NH3) m / e 590 (M + H. Analysis and calculation of C32H35N3Os 値: C, 65.18; H5 5.98; N, 7.13. Experiment 値: C, 65.89; Η, 5.85; N, 6.85. Example 461 anti-, anti-2- (4-Ethylphenyl) -4- (3,4-difluorophenylbis (n-butyl) aminocarbonylmethyl) -bit ratio p_3 Employees of Central Standards Bureau, Ministry of Economic Affairs f Printed by a cooperative (please read the notes on the back before filling out this page) The title compound was prepared using the procedure described in Example 1. 1Η NMR (CD3OD, 3 00 MHz) δ 0 · 78 (t, 3Η, J 2: 7), 0.87 (t, 3H, J-2 7), 1.02 (hex, 2H, J = 7), 1.22 (t, 3H, J-7) ^ 1.27 (m, 2H), 1.45 (m, 2H, J = 7), 2.63 (q, 2H, J = 7), 2.77 (d, 1H, J = 14), 2.94 (dd, 1H, J = 7, 9), 3.05 (m, 3H), 3.3-3.5 (m5 3H), 3.44 (d, lH, J = 14), 3.66 (m, lH), 3.75 (d, lH, J = 10), 7.20 (td, 2H, J = 1, 8), 7.22 (m , 2H), 7.32 (td, 2H, J = 1, 8), 7.43 (ddd, 1H, J = 2, 8, 12). MS (DCI / NH3) m / e 501 (M + H). Analysis and calculation of C29H38N203F2 · 0.6H2O 値: C, 68.11: H, 7.73; N, 5.48. Experiment 値: C, 68.03: H, 7.53 -521-This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210X 297 cm) 552260 A: R ~ V. Description of the invention (519; N, 5.37. Example 462 (Please read the precautions on the back before filling this page) L trans-4- (1,3-Benzylbenzene ... Butyl (4 lanes using the procedure described in Example i to prepare the title compound. ^ NMR ( 300 MHz, CD3OD) δ〇87 (t, j = 7 Hz, called, 1.20-1.50 (m, 4H), 2.21 (d, J = 2 Hz, 3H), 2 64 ((1,14 Hz , 1H), 2_75 (dd, J = 10 Hz, 1H), 3 05 (t, J = 7 Hz, 3.2) (d, J = 1) Hz, iH), 3.35-3.70 (m, 5H ), 3. 7 (s, 3HH, 5.92 (s, 2H), 6.70-6.92 (m, 6H), 6.96-7, 10 (m, 4H). MS (DCI) m / e 563 (M + ΗΓ. About C32h35N206F · Analysis and calculation of 0.5 h2 h: C, 6 7 · 2 4; H, 6.35; N, 4 · 9 0. Experiment 値: C, 67.16; H, 6.06; N, 4.81 〇 Example 463 -4- (l, 3-phenylhydrazine-5-yl) -2- (4-methoxybenzyl) -1- (M-butyl-N-((3-isobutyl I) benzene _3_ Printed by the Central Standards Bureau of the Ministry of Economics, Peigong Xiao Fang Cooperative, using the procedure described in Example 1 to prepare the title compound. Ipl NMR (3 00 MHz, CD3OD) δ 0.87 (t, 3H), 1.17 (d, J 2 7 Hz, 6H), 1.20-1.50 (m, 4H), 2.63 (d, J 2 15 Hz, 1H), 2.75 (t, J = 7 Hz, 1H), 2.85 (m, 1H), 3.00 ( t, J = 7 Hz, 1H), 3.25 (d, J = 15 Hz, 1H), 3.40-3.70 (m, 5H), 3.75 (S, 3H), 5 90 (s, 2H), 6.65-6.80 ( m, 3H), 6.71 (dt, J 2 7 Hz, 3H)-522- This paper size applies to China National Standard (CNS) A4 specification (210X 297 cm) 552260 A7 ---- ----- R * 7 V. Description of the invention (520) — '7.07 (m, 3H)' 7.20-7.35 (m, 2H). MS (DCI) m / e 573 (M + H), Analytical calculation for C34H40N2O6 · 0 · 15η3ρ〇4 値: c, 69.52; Η, 6.94; N, 4.77. Experiment 値 ·· c, 63 3 1; H, 6 72; N, 4.43. 464 heart. Trans + (M: · hydrazene-5-yl) 2-(4-methoxyphenylbutyl: and methyl)-pyrrolidine-3-boronic acid using the procedure described in Example 66 To prepare the title compound.咜 NMR (300 MHz, CD3OD) S0.87 (m, J = 7 Hz, 3Η), 1.16 (t, J = 7 Hz, 3Η) '1.20-1.47 (m, 4Η), 2.50 ( q, J 2 7 Hz, 2Η) '2.70-2.8 5 (m, 2Η)' 3.13 (t, J = 7 Hz, 1H), 3.20-4.5 (m, 6H), 3.78 (s, 3H), 3.83 (d, J = 8 Hz, 1H), 5.92 (s, 2H) '6.72 (d, J — 8 Hz, ih), 6.80-6.90 (m, 5H), 7.02-7.13 (m, jH)' 7.15 -7.25 (m, 2H). MS (DCI) m / e 5 5 9 (M + H) '. Analytical calculations for C33H3SN206 · 0.3 · 2 h2〇: C, 70.27; H, 6.90; N, 4.97. Experiment 値: C 70; n; Η, 6.63; N, 4.60. Example 4 6 5 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling in this page. Ethyl phenyl) _Bu 01 (3-1 benzene 1): ν- xj anthyl) carbonyl lake trilateral acid

The procedure described in Example 1 was used to prepare the title compound. 1] H NMR (300 MHz, CD3OD) δ 0.87 (t, 3H, J 2 7 Hz), ^ 3 (t, 3H, J 2 7 Hz), 1.28 (m, 2H), 1.41 (m, 2H )? 2.63 (q? 2 and 7 Hz) '2.67 (111, 1 out, 2.92 0, 1, 3, 20 (111, 2 India-523- ik Zhang scales apply Chinese National Standard (CNS) Λ4 specifications (21 OX 297 male-552260 Λ 7 B7 V. Description of the invention (521), 3.42 (m, 1Η), 3.60 (q, 2Η, J = 7 Hz), 3.93 (m, 1Η), 5.92 ($, 211) , 6.75 ((1,111 ,: ^ 8 Hz), 6.84 (111,311), 6.95 (br s, 1H), 7.02 (s, 1H), 7.10 (br s, 3H), 7.25 (m, 2H) MS (APCI) m / e 563 (M + H). Analysis and calculation of C32H35N205C1. 0.80 H3P04: C, 59.92; H, 5.88; N, 4.37. Experiment: C, 59.90 H, 5.83; N, 4.07. Example 466 trans, trans_4- (1,3-benzyl) -6 ()-2- (4-ethylepiyl) -1-(((N- (: &Gt; -chlorophenyl) -N-butylamino) carbonyl) fluorenyl) -pyrrolidin-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. NMR (300 MHz, CDC13) δ 0 · 86 (t, 3H, J 2 7 Hz), 1.23 (ί, 3H, J 2 7 Hz), 1.25 (m, 2H), 1.40 (m, 2H), 2.64 (q, 2H, J = 7 Hz), 2.70 (m, 1H), 2.95 (m, lH), 3.20 (m, 2H), 3.40 (m, lH), 3.57 (m, 3H), 3.90 (m, iH), 4.25 (s, 4H), 6.80 ((1, 111,) two 8 Hz) , 6.95 ((1,1) 1, &gt; 2 Hz), 6.95 (111, 2H), 7.07 (brs, 3H), 7.22 (m, 3H). MS (APCI) m / e 577 (M + H) '. Analysis and calculation of C33H37N2055C1. 0.85 H2〇 値: C, 6 6.90; H, 6.58; N, 4.73 〇 Experiment 値 · C, 66.92; H, 6.25: N, 4.36. Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by Consumer Cooperative (please read the precautions on the back before filling out this page) Example 467 Anti, anti_4_ (benzohuffan-5_yl) -2- (4 -ethylbenzyl) -l-(( (N- (3-Atomyl) -N-butylamino) carbonyl) methyl) -pyrrolidine-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. 1Η NMR (300 MHz, CDC13) δ 0.85 (t, 3Η, J 2 7 Hz), 1.26 -524- This paper size applies to China National Standard (CNS) Λ4 specification (210 乂 297 male bag) 552260 A? ___ B7 V. Description of the invention (522) (t, 3H, J = 7 Hz) '1.30 (m, 2H)' 1.40 (m, 2H), 2.60 (q, 2 z) 2 7 Hz), 2.72 (1 ! 1, 111), 2.93 (111, 1 buckle, 3.22 (1115211), 3.50 (m, 1H), 3.55 (m, 2H), 3.75 (m, ih), 3.90 (br d, 1H), 6.75 (d , 1H, J 2 1 Hz), 6.80 (br d, 1H), 6.95 (brs, 1H), 7.08 (m, 4H), 7.20 (t, 1H, J = 8 Hz), 7.28 (t, 1H, J = 8 Hz), 7.42 (m, 2H), 7.58 (d, lH, J = i Hz), 7.63 (s, IH). MS (APCI) m / e 559 (M + H) +. About c33H35N204C1 · Analytical calculation of 0.45 H20: C, 69.88; H, 6.38; N, 4.94. Experimental values: C, 69.83; H, 6.04; N, 4.87. Example 468 Dimethoxy-3-fluorophenyl)- 4- (7-Rhenium-L3-phenylhydrazone-dioxo-pentan-5-5-yl-butyl-N-anilinoethylpyrrole) Fan (please read the back first Please fill in this page again.) Make 2- (4-methoxy-3-fluorophenyl) -4- (7-fluorenyloxy-i, 3-phenylhydrazine dioxane) prepared by the procedure of Example 61A. Cyclopentenyl) bromoethyl)] Bilodine-3-carboxylic acid ethyl ester (300 mg) was reacted with N-τ group in 1 ml dioxane containing 130 mg diisopropylethylamine Aniline (190 mg) reacted '4 inches to B volume g. This g was hydrolyzed with sodium hydroxide to obtain 14 mg of the title compound in the form of white A at the end. NMR (300 MHz, CDC13) 50.90 (t, J = 9 Hz, 3H), 1.28 (hexaplex, J = 7 Hz, 2H), 1.46 (Lirie +, J = 7 Hz 2H), 2.20 -2.32 (m, 1 Η), 2.68-2.77 (m, 1Η) '2.82-2.95 (m, 2H), 3.12-3.22 (m, 2H), 3.30-3.44 (m, 3H)' 3.45-3.55 (m , IH), 3.62 (d, J = 9 Hz, 1H), 3.83 (s, 3H), 3.90 (s, 3H), 5% (s, 2H), 6 51 (d, BU 7 Hz, 2H) ___ -525-Applicable to the Chinese National Government) ~-552260 V. Description of the invention (523) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs' 6.55-6.62 (m, 2H), 6.69 (d J = 2 Du Cong 0 ./, τ_〇 ', J 2 Hz, m), 6 84 (t, J-8 Hz, 1H), 7.02-7.15 (m5 3H), 7 1Q / With &gt; 砘 V' Λ19 (dd, J = 2 Hz, I2 Hz, 1H). Example Dioxane-6 ^^ ethylphenyl ^ XA.). Carbonyl) _3-carboxylic acid The procedure described in Example 1 was used to prepare a camphor compound. H Hz), 1.28 (m, 2H), 1.45 (m, 2H), 2 64 (q, 2H, J = 7 Hz), 2.78 (m, 1H), 2.9-3.2 (surrounding, 4H), 3 3 〇 (m, 1H), J.40 (m, 3H), 3.60 (m, 1H), 3.80 (m, [Η), 4.25 (s, 4H) '6.8 0 (d, 1H, J = 8 Hz) , 6.90 (m, 1H), 6.9 8 (d, 1H, J = 2 Hz), 7.17 ((1, 2gen> 1 = 8 Hz), 7.30 (111, 211). 1 ^ (eight? &Lt; : 1) m / e 523 (M + H) T. Analysis and calculation of C31H42N205 · i.ihOAc Ik: C, 67.73; H, 7.94; N, 4.76. Experiment 値: C, 67.81; H, 7.55; N, 4.48. Example 470 1, trans-4- (1,4-benzyl-dinane-6-yl) -2- (4-methanone) -1-((\ ^ butyl-N- (3 -Fluorenylphenylamino) carbonyl) fluorenyl) -p ratio p each of Yodo-3-acid acid The procedure described in Example 1 was used to prepare the title compound. 1 'NMR (3 00 MHz, CD3OD) δ 0.87 (t , J = 7.1 Hz, 3Η), 1.30 (m, 2H), 1.44 (m, 2H), 2.30 (s, 3H), 2.80 (d, J = 15.2 Hz, 1H), 2.85 (t, J = 9.3 Hz, 1H), 3. 19 (t, J = 9.3 Hz, 526) This paper size applies to China National Standard (CNS) A4 (210X) 297 公 楚) --------- # 1 (Please read the notes on the back before filling this page

, 1T f 552260 AB 'V. Description of the invention (524) 111), 3.33 ((1, &lt; 10.2 Hz, 1 ^ 1), 3.42-3.6 1 (1115311), 379 (s, 3H), 3.91 ( d, J = 9.8 Hz, 1H), 4.22 (m, 4H), 6 75-6 86 (m, 6H), 6.95 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 8.8 Hz 2H) , 7.22 (d, J = 10.2 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H). MS (DCI) m / e 559 (M + H +). Analysis of C33H38 N2 06 · 0.4 CH3C02C2H5 Calculate 値: C, 69.97; H, 6.99; N, 4.72. Experimental 値: C, 0.06; H, 6.66; N, 4.48. Example 471 Anti, trans-4- (1,4 -benzene hydrazone two deficit pits- 6-Base) -2- (4-methoxybenzyl-D printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs --------- ·! (Please read the precautions on the back before filling out this page )

IT fluorenyl-N- (3-aminophenylamino) poly) methyl) -ρ ratio p each symptom 3-volume administration The procedure described in Example 1 was used to prepare the title compound. 1 η NMR (300 MHz, CD3OD) δ 0.87 (t, J = 7.0 Hz, 3Η), 1.25 (m, 2H), 1.40 (m, 2H), 2.78 (d, J = 14.6 Hz, ih), 2.86 (t, J = 9.0 Hz, 1H), 3.16 (t, J = 9.5 Hz, 111), 3.34-3.43 (m5 2H), 3.48-3.62 (m, 3H), 3.79 (s, 3H) , 3.85 (d, 9.5 Hz, iH), 4.22 (m, 4H), 6.78 (d, J = 8.5 Hz, 1H), 6.81-6.86 (m, 3H), 6.93-7.09 (m, 5H) , 7.33-7.38 (m, 2H). MS (DCI) m / e 579 (M + H +). Analytical calculations for C32H35ClN2O6 · 1.1 CH3C02C2H5 · 0.15 H3P04: C, 63.30; H, 6.46: N, 4.06. Experiment 値: C5 63.54; H, 6.09; N, 3.98. Example 472 trans, trans-4- (l, 3-phenylhydrazone dioxol-5-yl) -2- (4-methoxyphenyl) -1- (4-pyridylmethyl)- Pyrrolidine-3-carboxylic acid uses the procedure described in Example 1 to prepare the title compound. 1Η -527 This paper size applies Chinese National Standard (CNS) Λ4 specification (210X 297) while 552260 Λ * 7 _______________ B7 V. Description of invention (525) — NMR (300 MHz, CD3OD) s 2 84 ( t ，; 2 9 6 Hz, ιη), (Please read the notes on the back before filling this page)-· 88 (dd, J = 9.6, 7.3 Hertz, 1Η), 3.09 (dd, J = 3.3, 9.6 Hz, _, 3.21 ((!, Bu 14.3 Hz, 111), 3.53 (111, 1 India, 3.78 (5, jH) '3.8l (m, 2H), 5.92 (m, 2H), 6.73 (d, J = 8.1 Hertz, m), 6.82 (dd, J leaves 8, 8.1 Hertz, 1H), 6.93 (m, 2H), 6 95 (d, J == 1.5 Hertz, 1H), 7.43 (m , 4H), 8.44 (d, J = 5 2 Hz, 2H). MS (DCI) m / e 433 (M + H +). Analysis and calculation of C25h24 n2〇5 · 〇3 CH3C02C2H5 値: c, 68 · 57; H, 5.80; N, 6.10. Experiment Jun: C, 68.68; H, 5.60; N, 5.81. Example 473 Phenylhydrazine 1- (5-methoxy) -2- (4-methoxybenzene) Tertiary bis jf aniline) lysine, methyl) -pyrrolidine-3-carboxylic acid

The procedure described in Example 1 was used to prepare the title compound. i H Printed by NMR (3 00 MHz, CD3OD) δ 0.88 (t, J = 7.2 Hz, 3H), 1.23 (s, 9H), 1.23 (s, 9H), 1.26-1.45 (m, 4H), 2.74 (dd5 J 2 15.1 Hz, 1H) '2 84 (m, 1H), 3.13 (t, J = 9.0 Hz, 1H), 3.29 (d, J 2 15.1 Hz, ih), 3.50-3.66 (m, 4H), 3.77 (s, 3H), 3.84 (d, J = 9.0 Hz, ih), 5.92 (s, 2H), 6.74 (d, J = 7.7 Hz, 1H) '6.79-6.85 (m, 4H), 6.86-6.90 (m, 1H), 6.99 (t, J = 1.8 Hz, 1H), 7.06 (d, J = 1.8 Hz, 1H), 7.13 (m, 2H), 7.33 (t, J = 7.7 Hertz, ih), 7.42 (m, 1H). MS (DCI) m / e 587 (M + H). Analysis and calculation of c35H42N206 値: C, 71.65: H, 7.22: N, 4 77. Experiment 値: c, 71%; h, 7.33: N, 4.69. -528-This paper ruler applies to China) Λ4 size (2 丨 0 / 297mm ^ 1 ~

IV IV Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Consumer Cooperatives 552260 V. Description of the Invention (526) Tail two &quot; transpenten-5-yl) -2- (4-pentoxyphenyl LL ((N butyl ) Carboxyl) methyl) _pbilodine_3- The title compound was prepared using the procedure described in Example 1. iH NMR 〇〇〇terahertz 'CD3〇D) δ 〇88 b 7 3 Hz, 3 ⑴, 0.92 (t, J: 7.3 Hz, 3H), 123-159 (m, 8H), 2 58 (t, J = 7 6 # ^, 2H) '2.75 (d, J = 15 ^^ 5lH), 28〇 (dd, j = 85,9.5 Hz, 1H), 3.l2 (t, J = 9.3 Hz, 1H), 3 29 (d, j = 15.6 Hz, 1H) '乂 46 (dd, J = 4.9, 97 Hz, 1H), 3 52_3 64 (m, 3H)' x78 (s, jH) '3.83 (d, J = 9.8 Hz, ih), 5.92 (s, 2H), 6.74 ((1,) 28.1 Hz, 111), 6 79-6, 8H, 41 ^, 70.05 (4 = 17 Hz, 1H), 7.1〇 ( d, J = 8.8 Hz, 2H), 72 (d78H), 729 (t, J = 7.6 Hz, 1H). MS (DCI) m / e 587 (M + tT). About C3: &gt; H42N2〇6 Analytical calculation 値 ·· c, 71.65; H, 7.22; N, 4.77. Experimental silly: C, 71.33; H, 7.28; N, 4.74. Example 475 -4- (3-Gaphenyl) -2- ( 4-Ethyl-n-butyl) -N-aminocarbonylmethyl The title compound was prepared using the procedure described in Example 1. 1 n NMR (CD3OD, 3 00 MHz) δ 0 · 87 (t, 3H, J = 7), 1.19 (t, 3H, J = 7), 1.28 (m, 2H), 1.43 (m, 2H), 2.28 (s, 3H), 2.60 (q, 2H, J = 7), 2.66 (m, 2H), 3.06 (m, 1H), 3.21 (d, 1H, J = 15), 3.42 (dd, 1H, J = 4, 9) , 3.58 (m, 3H), 3.71 (d, 1H, this paper size applies Chinese National Standard (CNS) Λ4 specification (2l0x 297)) --------- Aw— (Please read first Note on the back page, please fill in this page again), 11 552260 Λ, B7 V. Description of the invention (527) J = 9), 6.80 (s, 2H), 7.06 (s, 4H), 7.18 (m, 4H), 7.45 ( m5 1H). MS (APCI) m / e 535 (M + H) +. Analysis and calculation of C32H36N203F2 · 1.3 HOAc 値: C, 67.83; H, 6.78; N, 4.57. Experiment 値: C, 67.83; H, 6.46; N, 4.70. Example 476 trans, trans-2- (4-ethylphenyl) -4- (3,4-difluorophenyl (n-butyl) -N- (3-chlorophenyl) aminocarbonylfluorenyl) -pyrrole Pyridin-3-carboxylic acid was prepared using the procedure described in Example 1 to prepare the title compound. NMR (CD3OD, 3 00 MHz) δ 0.82 (t, 3H, J = 7), 1.16 (t? 3H, Bu 7), 1.23 (m, 2H), 1.35 (m, 2H), 2.55 (q, 2H , J 2 7), 2.66 (m, 2H), 3.01 (t, 1H, J = 9), 3.16 (d, 1H, J = 15), 3.32 (dd, 1H5 J = 4, 9), 3 56 (m, 3H), 3.67 (d, 1H, J = 9), 6.94 (d, 1H, J-2 7), 7.02 (m, 5H), 7.14 (m, 2H), 7.32 (m, 3H) . MS (APCI) m / e 555 (M + H) +. Analysis and calculation of C31H33N203C1F2 .0.6 TFA C · C, 61.88: H, 5.42; N, 4.48. Experiment 値: C, 61.90; H5 5.62; N, 3.98. Example 477 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Anti, Anti-4- (1,4 -Benzobenzene Loss of Burning _6_Base)-2- (4-Phenyl) -1- (1 ^ -butan-N- (3-chlorophenyl) aminocarbonylfluorenyl) -pyrrolidine-3-carboxylic acid The title was prepared using the procedure described in Example 1 Compound. 1Η NMR (300 MHz, CD3OD) δ 0.87 (t, J = 7 Hz, 3Η), 1.10-1.30 (m, 4H), 2.60-2.75 (m, 2H), 3.03 (t, J = 7 Hz, 1H ), 3. 15-3.75 (m, 6H), 4.02 (m, 4H), 6.75 (d, J = 6 Hz, 1H), 6.85 (dd, J = 7 Hz, 1H), 6.90 (7.19, two 111 Hz, 6; ») -530- This paper size is in accordance with Chinese National Standard (CNS) Λ4 specification (210X29? Male) 552260 A · B 'i, invention description (528)' 7.32-7.43 (m, 3H) . MS (DCI) m / e 567 (M + H) +. Analysis and calculation of C3lH32N205FCl · 1.6 H20 1.6: C, 62.49; H, 5.95; N, 4.70. Experiment 値: C, 62 · 20; Η, 5.54; Ν, 4.42. Example 478 1- (N, N- (JE-T ^) aminocarbonylmethyl V pyrrolidine-3-carboxylic acid The title compound was prepared using the procedure described in Example 1. 1Η NMR (300 MHz, CDC13) δ 0.78 (t, 3Η, J = 7 Hz), 0.84 (1,311 ,: ^ 7 Hertz), 1.05 ^, 211, 拎 7 Hertz), 1.21〇, 3 ^ 1, Bu 7 Hertz), 1.25 (m, 2H), 1.45 (m, 2H), 2.62 (q, 2H, J = 7 Hz), 2.80 (4 111,] = 13 Hz), 3.0 (111, 21 &quot; 1), 3.15 (111 , 211), 3.35 (m, 1H), 3.43 (m, 2H), 3.52 (m, 1H), 4.40 (m, 2H), 6.73 (d, 1H, J 2 1 Hz), 7.14 (d, 2H, J 2 8 Hz), 7.26 (s, 1H), 7.3 1 (d, 2H, J = 8 Hz), 7.44 (s, 2H), 7.60 (d, 1H, J = 1 Hz), 7.65 (s, 1H ). MS (APCI) m / e 505 (M + H) +. Analytical calculations for C31H4ON204: C, 73.78; H, 7.99; N, 5.55. Experiment 値: C, 73.69; H, 7.97; N, 5.21. Example 47 9 trans, trans-2- (4-methoxy-3-fluorophenyl) -4- (7-methyllactyl-1,3-phenylhydrazinedioxol-5-yl) -1- 丨 2- (N-propyl-N- (pyrrolidine-1-carbonylmethyl) amino) ethmidine-pyridine-3-carboxylic acid in 1 ml of acetonitrile will be prepared according to the procedure of Example 61B 2- (4-Methoxy-3-fluorophenyl) -4- (7-methoxy-1,3-benzobenzodioxol-5-yl) -1- [2- ( N-propyl-aminoethyl] -pyrrolidine-3-carboxylic acid ethyl ester (300 mg), -531-This paper size applies to China National Standard (CNS) A4 (210X297 cm) (Please read the back first For the matters needing attention, please fill out this page and order it from the Central Consumers Bureau of the Ministry of Economic Affairs.

、 Explanation of the invention (5 diethyl donkey pyrrolidine (132 Kuroda fever 'to 50). (^ 1 gross weight) 丨 Ethyl propyl ethylamine (154 mg) plus (Please read the precautions on the back before filling in this Page) method, age +,], the intermediate ethyl ester is known. By the example ID method CDC1 ': § daily hydrolysis to the title compound. 1H NMR (300 MHz, • W3 S〇.88 (t, ^ Hertz, Qiu, ⑺ 2 70 'Γ 4Η), 2 30-2 4 () (% 1Η), 2.47-2.58 (m, 2Η),;; 8 ^ 3, 4.3, 5 (m? 6H), 3,0., 0 (m, 2H) ('〇H)' 3 86 (d, J == 9 Hz, 1H), 3.88 (s, 3H), 5.93 'H)' 6.58 (dj = 9 then 4 1LJ, ./ 1, "Hertz, 1H), 6.70 (d5 J = 2 Hz, 1H), T__〇-, Η) 7. · 10 (d, J = 9 Hz, 1H), 7.21 (dd, —-Hertz, 12 Hertz, 1H). Example 48 Wedebenzo-dioxolene 0-ylleucine fluorenyl) amino) ethyl>

Example of pyrrolidine-3-volume 480A D-Leucine O-Methyl Ester, Jasmonate, D-Leucine (5.0 g) and p-Benzene Sulfonic acid monohydrate (80 g) was added to benzyl alcohol (8.2 g) dissolved in benzene (30 ml). The reaction was warmed to reflux overnight to remove water. Once TLC showed that the starting material was consumed, the reaction was cooled and the resulting solid was filtered and rinsed with EtOAc to give the title compound as a white powder (14.26 g, 99%).

Example 480B N-perhydroazephenylcarbonyl-D-leucine O-fluorenyl ester. Triethylamine (0.4 ml) was added to aerosol (20 ml) and obtained from real-532-paper The 掁 scale is applicable to the Chinese National Standard 隼 (CNS) Λ4 specification (210X 297 g of carboxylic acid) 552260 V. Description of the invention (53 ° Example 4 8 A compound (1.0 gram). The solution is cooled to 〇t) And add carbonyldiimidazole. After 1.5 hours, TLC showed complete depletion of the starting material, at which time hexamethyleneimine (0.327 ml) was added. After i hours, an additional amount of hexamethyleneimine (0.330 liters) was added and the reaction was stirred overnight at ambient temperature. Dehydrate with sodium bicarbonate solution (2 X 20 mL), H3PO4 (2 X 20 mL) and brine (20 mL), cover with Na2SO4, slowly decant and evaporate the supernatant. The residue was purified by flash chromatography on silica gel, eluting with 25-50 / 100% EtoAc in hexane to give the title compound (0.835 g, 89%) as a crystalline solid.

Example 480C Indylcarbonyl-D-homamine hydrazone 10% palladium on carbon (10 mg) was added to the compound (200 mg) from Example 480B dissolved in absolute ethanol (10 ml). After the flask was flushed with nitrogen, the reaction was stirred vigorously under hydrogen pressure for one hour. The reaction was filtered through celite and evaporated to give the title compound (40 mg).

t ίΗ 480D --- (1 ^ oxophenyl) di-tertene1,3-benzidine-dioxolane-5_very) -Ep-pyridine-3-acetic acid ethyl ester Central Standard Printed by the Bureau's Consumer Cooperative (please read the notes on the back before filling this page) The compound from Example 1C (510 mg of 50% by weight solution in methylbenzyl) dissolved in acetonitrile (2.0 ml) To this was added diisopropylethylamine (0.24 liters), followed by bromoacetonitrile (0.072 ml). After 2 hours' TLC showed depletion of starting material. The solvent was evaporated, and the residue was purified by flash chromatography on silica gel, eluting with 20-40% EtoAc in hexane 'to the title compound as a colorless oil (0,28 g, 99%). -533- 552260

Example of printing cracks at the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 48 ^ A_ ^ 1 ^^ 1-4-(_ 1, .3-A di ^ oxodiyl) -pyrrolate is dissolved in triethyl Raney nickel catalyst (02 g) from the compound of Example 48D (275 mg) in 10 liters of amine and ethanol each, and the reaction was exposed to hydrogen pressure (4 atmospheres) for 3 days. The reaction was filtered and evaporated. The residual $ was dissolved in dichloromethane (10 ml) and extracted with 1M HC1 (5 X 1 milligram) to determine the mixed aqueous extract. take. The mixed organic extracts were dehydrated using MgSCU, and the title compound (0 14 g) was obtained as an unstable oil after filtration of the trip bath. Example 4 8 0f ^ ~ ^ 1111- oxo. ^)-4- (1, 3-Buty ^^ Dioxolene-5_1 Hydrocarbyl acryl .. fluorenylcarbonyl) methylenefluorenyl) amine) Ethyl octapyridine 3-pyridine-3-valerate ethyl ester will be obtained from Example 480E The compound (0.10 g) was dissolved in dichloromethane (30 liters) and the compound from Example 480C (0.07 g) was added. The solution was cooled to (TC) and EDCI (0.052 g) was added. After 4 hours, the hair strands reacted and were distributed between water (1 ml) and EtoAc (10 liters). The organic solution was washed with water (1 mL) and brine (1 mL), covered with MgSCh and filtered and evaporated. The residue was purified by flash chromatography on silica gel with 50-60% EtOAc in hexanes Elution gave the title compound as a colorless oil (0.075 g, 48%).

Example 480G _anti 4 -2, .- (4 2nd D diphenyl n -534- The standard of this paper is applicable to China National Standard (CNS) A4 specification (210X29? Public t) -------- #! Please read the insincere matters first and complete this one.

IT 552260

A. V. Description of the invention (532 printed by the Ministry of Standards, Central Bureau of Work and Consumer Cooperatives) argon azepine carbonyl) leucine fluorenyl) amine a) ethyl) -pyridine-3-carboxylic acid will be obtained from examples 480F compound (0.75 g) was dissolved in ethanol (1.0 liter), and 5M NaOH (0.050 ml) was added. After 2 hours, an additional 5M_NaOH (0,090 ml) was added. After another 35 hours, the reaction was evaporated. The residue was dissolved in water (5 ml) and washed with diethyl ether x 2 ml). The aqueous solution was acidified to a pH of about 3 with 1N λλPO4. When the mixture was extracted with chloroform (3 × 3 ml), the precipitated solid dissolved. The chloroform extract was washed with brine (2 ml), dehydrated with MgS04, filtered and evaporated to give the title compound (0.053 g) as a tan solid. Purified by HPLC (VydacmCl8) and eluted with CHsCN in 01% TFA with a gradient of lc ^ 70%. After freeze-drying the desired fractions, the appropriate material (0.049 g) was obtained. iHNMRCCDCh, 300 MHz) δ 0.8 2 (dd, 6.4, 4.4 Hz, 6Η), 0.87 (dd, J = 5.7, 5.7 Hz, 6Η) '1.04-1.28 (m, 3H), 1.34-1.65 (m, 19H ), 2.95 (brm, 2H) '3.15-3.40 (m, 14H), 3.40-3.55 (m, 4H), 3.58-3.68 (m, 2H), 3.70-3.76 (br m? 2H) ^ 3.80 (s5 3H ), 3.81 (s? 3H) ^ 41) (br m, 2H), 5.10 (br m, 2H), 5.93 (s5 3H), 5.95 (s5 3H), 6.70-6.97 (m, 13H), 7.43-7.56 (brm, 3H), 8.2 (brs, 1H), 8.5 (br s, 1H). MS (DCI / NH3) m / e 623 (M + H), analysis of A C34H46N40.7 · 2.00 TFA 値: c, 53.65; H,) · 69; N, 6.58. Experiment 値: c, 53 66; H, 5 66; NT, 6 54. Example 48 1 Phenyldioxolyl) -2- (4-fluorenylphenyl 535

f Please read the notes on the back before filling in this page) .1 #

'1T Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 552260 A' B7 ------------------____ V. Description of Invention (533)) -MN, N-II ( N-hexyl) aminocarbonylmethyl) -pyridin-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. 1Η NMR (3 00 MHz, CD3OD) δ 0.80-0.95 (m, 6Η), 1.0 (m, 2H), 1.07 (1.55, J 2 m Hz, 14H), 2.70 (d, J = i3 Hz, 1H) , 2.85-3.15 (m, 4H), 3.20-3.60 (m, 9H), 3.64 (d, J-2 10 Hz, 1H), 3.79 (s, 3H), 5.90 (m, 2H), 6.70 (d, 8H ), 6.80-6.93 (m, 3H), 7.05 (2, 1H), 7.35 (d, J = 10 Hz, 2H). Analysis and calculation of C33H46N206 · 1.7 H20 値: C, 66.35; H, 8.34; N, 4.69. Experiment 値: C, 66 · 32; H, 8.04; N, 4.52. Example 482 trans, trans-4- (1,4-phenylbioridin-6-yl) -2- (4-fluorophenyl) -1- (1 ^ -butyl-N- (3-fluorene Amino) Methylmethylbilodol-3-metanoic acid was used to prepare the title compound using the procedure described in Example 1. NMR (300 MHz, CD3OD) δ 0.87 (t, J = 7 Hz, 3Η), 1.20 -1.35 (m, 2H), 1.35-1.40 (m5 2H), 2.32 (s, 3H), 2.55 -2.70 (m, 2H), 2.97 (t, J = 7 Hz, ih), 3.22 (d, J-2 14 Hz, 1H), 3.25-3.7 0 (m, 5H), 4.20 (m, 4H), 6.97 (d, J = 2 Hz, iH), 7.09 (m, 2H), 7.15-7.35 (m, 2H). MS (DCI) m / e 547 (M + ΗΓ. Analysis and calculation of C32H35N205F · 1.2H20 値: C, 67.64; H, 6.63; N, 4.93. Experiment93: C, 67.73; H, 6.37: N5 4.70 〇-536- This paper is suitable for financial purposes --------- f (Please read the precautions on the back before filling this page

、 1T 552260 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, A? ________R, V. Description of the invention (534) ~~ Example 483 trans-4- (1,3 dioxolene_5_, 2 "4-Methoxyphenyl ((&amp; butyl) carbonyl) methyl V 咄 呔 Ha-3 -miao acid Use the procedure described in Example 1 to prepare the title compound. IH NMR (300 mega Hertz, CDCl3) δ (rotatory isomer) 8 14 (2Η, ⑷, 8.05 (7,83) (1H, m), 7.60-7.30 (3H, m), 7.13 (1H, m), 7.10- 6.70 (5H, m) '5.94 (2H, m), 5.43 (5.33) (1H, d, J 2 12), 4.75 (1H, bd5 J = 15), 4.60-4.20 (2H, m) , 4.10 (2H, m) '3.80 (3.76) (3H, s), 3.75-3.40 (3H, m), 3.20-2.80 (2H, m), 1.50 (lH, m), 1.30 (lH, m), 1.20-1.0. (2H, m), 0.91 (0.78) (jH, t, J = 8). MS (DCI / NH3) m / e 590 (M + ΗΓ). Analysis and calculation of C32H35N308 · 2.1 TFA値: C, 52.44; H, 4.51; N, 5.07. Experimental 値 ·· c, 52.25; H, 4.83; N, 5.71. Example 484 trans_ ^ trans-4- (1 ^ 2-dihydrophenylsulfonium -5-A certain V2- (4-ethylbenzyl) -bu (((N-butyl jN- (3,4 Oxymethyl) amine) carbonyl) methylpyrrolidine-3-carboxylic acid The title compound was prepared using the procedure described in Example 1. 11 1 ^ yiyi (300 MHz, 00 (: 13) 3 (rotation Isomers) 7.40 (211,111), 7.30-7.10 (4Η, πm), 6.90-6.70 (3H, m), 6.48 (lH, m), 5.45 (1H, m), 4.65 (1H, d, J -15), 4.57 (2H, dt, J2 9, 3), 4.40-4.00 (5H, m), 3.87 (3.85) (3H, s), 3.84 (lH, m), 3.83 (3.79) (3H, s), 3.56 (2H, m), 3.20 (2H, t, J = 10), 2.90 (1Η, m), 2.64 (2H, q, J = 8), 1.52 (1H, m), 1.31 ( 2H, m), 1.22 -537- This paper size applies Chinese National Standard (CNS) Α4 size (21〇χ 297 cm) (Please read the precautions on the back before filling in this page I #

、 1T 552260 B1 V. Description of the invention (535) (Please read the notes on the back before filling this page) (3H, dt, J = 9, 2), 〇92 (〇78) (3H t, j = 8) . MS (DCI / Nh3) m / e 601 (M + H &gt; Analysis and calculation of c36H44N2 06 6 35 tfa 値: C, 6i.59; H, 6.06; N, 3 71. Experiment 値: C, 61.69; H , 6.04; N, 3.63. Example 485

Tail difluorene-. Benzoxan .. Hydrazine tritium. LHlOil. Butyl 3- (4-heptazone) amino) carbonyl) ". Pyrrolidine-3_carboxylic acid is used as described in Example 1. Procedure to prepare the title compound. 1H NMR (300 MHz, [0300) 3 0.71-1104 (111, 1111), 1.07-L35 (m, 6H), 1.73-1.53 (m, 4H), 2.79-3.25 ( m, 5H), 3.35 -3.44 (m, 1H), 3.5 1-3.68 (m, 3 Η), 3.78-3 · 89 (m, 1 Η), 3.79 (s, 3H), 5.92 (m, 2H) , 6.74 (dd, J = 1.7, 8.1 Hz, 1H), 6.85〇 (1, [[1.7, 8.1 Hz, 111), 6.93〇, 2 India, 7.02 ((11 J = 1.7, 9.5 Hz) , 1H), 7.36 (m, 2H). MS (CI) m / e 553 (M + H '). Analysis and calculation of C32H44N206 値: C, 69.54; Η, 8.02; N, 5.07. Experimental 値: C, 69.31; Η, 7.89; N, 5.06. Example 486 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, trans-2- (4-methylcyclohexyl) -4- (1,3-phenylhydrazone di Acyclopentene 0-yl) -1- (N, N-bis (n-butyl) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid using the procedure described in Example 1 to prepare the title compound, And separated amorphous solid. 1HNMR (CDC13, 300 MHz) δ 0 88 (3Η, d, J = 7 Hz), 0.92 (3Η, t, J 2 7 Hz), 0.96 (3Η, t, J 2 7 Hz), 1.05 (1H, m ), 1.22- 1.40 (7H, m), 1.45-1.65 (6H, m), 1.67-1.84 (4H, m), 3. 17-3.45 (6H, m), 3.70 (1H, br m) -538 copies Paper wave scale is applicable to China National Standard (CNS) specifications (210X 297 mm) 552260 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Ⅴ. Description of the invention (536) ---- 3.82 (lH, dd, J = 9 Herby] ^ ^ \. No, Hexuan), 3.86 (1H, d, J = 15 Hz), 5.93 (2H, s), 6 73 Π w ′ τ) (1H, d, Hertz), 6.78 (1H, dd, J = 2 Hz, 8 Hz), 6 88 (1Η, d, J = 2 Hz). MS (DCI / NH3) m / e 501 (M + H) +. About c, nR χΤ ^, ~ 9H44N205 · 0.25 CF3C02H analysis and calculation 値: C5 66.96; H 8 43 · m, ^, N,). 29. Experiment 値: C, 66 79; H, 8.60; N, 4.87 〇. Leg two (positive-using the amorphous solid described in Example 1. 1HNMR (CDC13, 300 MHz) and separation m ), 0.92 (3H, t, J = 7 Hz), 〇97 (3H t, Bu 7 Bu, 85 (Ming, -1.40 (13H, m), 1.42-1.68 (6H; m), 2.90 (1 &quot; 3.30 (2H, m), 3.33 (4H, m), 3.72 (lH, brm), 39.0 °. 14 'm)' 5.9) (2H, dd, J = 2 Hz, 4 Hz), 6 73 (iH d, 5 br)), 6.78 (1H, dd, J = 2 Hz, 8 Hz), 6 88 (1H, / y traces). MS (DCI / NH3) m / e 517 (M + H)-. With regard to the mouth 'J = 2 Hz', ^ 〇 ^ 4δN〇〇. 0.35 CF3C02: H Analytical calculation 値: c, 66.24; Η, 8.76. '. Experiment 値: C, 66.26; Η, 8.82; Ν, 4.98. '5 · 0] Example 488 Tail. Trans-4- (1,4--Amerized slogan fe-6-yl) -2- (4-fluorophenyl on k-n-butyl) amine -P Billow's disease-3-¾ |, (Procedure described in Example 1 to prepare the title compound.}

NMR (300 MHz, CD3〇D) δ 0.83 (t, J 2 7 Hz H, 〇89-539 This paper music scale is applicable to the Chinese National Standard (CNS) Λ4 specification (210X 297 KRW) (please read ^ first Notes on φ? Matter iirc {cfM4 pages) I #,-口 552260 Λ &quot; Β &quot; V. Description of the invention (537) (t, J = 7 Hz, 3H), 0.9 (M · 17 (m, 4H) ), 1.20-1.65 (m, 5H), 2.77 &lt; 1 (13,11 * 1), 2.87 ((1 (1, Lu 8, 2 Hz, 1 India, 2.95-3.60 (m5 7H), 3.71 (d , J = 9 Hz, 1H), 4.21 (s, 4H), 6.72 (d, 1H), 6.91 (dd, J = 8 Hz, 1H), 6.97 (d, J = 2 Hz, 1H), 7.05 (t , J = 7 Hz, 2H), 7.40-7.50 (m, 2H). MS (DCI) m / e 513 (Μ + ΗΓ. Analysis and calculation of C29H37N205F · 1.2 CH3COOH OH: C, 58.07; H, 5.93; N , 4.31. Experiment 値: C, 57.94; H, 5.81; N, 4.56. Example 489 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 3-Ripyl) -4- (1,3-benzyl-dioxol-5-yl) -1- (1 ^,-di- (n-butyl) aminonorylfluorenyl) -Pyrrolidine-3- The acid was prepared using the procedure described in Example 1 and the amorphous solid was isolated. 1H NMR (CDC13, 300 MHz) δ 0 · 83 (3H, t, J = 7 Hz), 0.85 (35, d5 Bu 7 Hz), 0.91 (3 °, t, J = 7 Hz), 0.97 (3H, t, J = 7 Hz), 1.05-1.22 (2H, m), 1.22-1.41 (7Η, m), 1.43- 1.68 (5Η, m), 1.89 (1Η, m), 2.94 (1Η, t, J 26 Hz), 3.15-3.27 (3H, m), 3.29-3.60 (5H , M), 3.72 (lH, brd, J = 6 Hz), 3.92 (lH, brd, J = 13.5 Hz), 5.93 (2h, dd, J = 2 Hz, 4 Hz), 6.73 (lH, d, J 2: 8 Hz), 6.78 (lH5dd, J = 2 Hz, 8 Hz), 6.88 (1H, d, J = 2 Hz). MS (DCI / NHs) m / e 489 (M + H) +. Analysis of C28H44N205 · 0.30CF3C02H Calculation 値: C, 65.70; H, 8.54; N, 5.36. Experiment 値: C, 65.93; H, 8.81; N, 4.84 〇 -540- This paper size is applicable to China National Standard (CNS) Α4 ^ Μ (210 × 297λ &gt; ^.) 55226.

V. Description of the invention (538) ^ Example 490 Tail ^ 12- (2-ethylbutyl) -4- (1,3-benzyldicyclopentene_5_yl) -1-LN, N-di (N-Butyl) aminocarbonylamidino-3: carboxylic acid The procedure described in Example 1 was used to prepare the title compound, and an amorphous solid was isolated. 1H NMR (CDC13, 300 MHz) δ 0.85 (6H, m), 0.92 (3Η, t, J = 7 Hz), 0.97 (3Η, t, J = 7 Hz), 1.13 ^ • 41 ( 13H, m) ^ 1.43-1.72 (6H5 m)? 2.96 (1H, brm) ^ 3.12 _3.52 (6H, m), 3.55-3.70 (1H, m), 3.70-3.86 (2H, m), 3.99 ( 1 heart 1) 1 * 111), 5.93 (2 ^ 1, 〇11: ^ 2 Hz, 4 Hz), 6.73 (111, ^ = 8 Hz), 6.78 (111, 4 (151 = 2 Hz, 8 Hz) , 6.88 (111, (15 J = 2 Hz). MS (DCI / NH3) m / e 489 (M + H), analysis and calculation of C2sH44N205 • 0.45 CF3C02H 値: C, 64.28; H, 8.30; N , 5.19. Experiment 値: C5 64.16; H, 8.38; N, 5.08. Example 491 trans, trans-2- (3-fluoro-4 -fluorenylphenyl) -4- (1,3-benzo-dioxo Heteropentyl-5-yl) -1- (2- (N-isobutyl-N- (butanesulfonamido) ethyl) -pyrrolidine-3-carboxylic acid Printed by a consumer cooperative (please read the notes on the back before filling this page) The title compound was prepared using the procedure described in Example 66. lTri NMR (CD3OD, 3 00 MHz) δ 0 · 74 (d, 3H, J = 7), 0.83 (d, 3H, 7) '0.94 (t, 3H, J = 7), 1.44 (hex, 2H), 1.67 (m, 4H), 2.91 (d, 2H, J = 8), 3.04 (dd, 2H, J-8, 10), 3.1-3.6 (m, 5H), 3.78 (m, 2H), 3.92 (s, 3H), 4.60 (m, 1H), 5 97 (s, 2H), 6.82 (d, 1H, J = 8 ), 6.89 (dd, 1H, J = 2,8), 7.01 (d, 1H, j 22), 7.22 (t, 1H, Bu 9), 7.39 (m, 2H), MS (ESI) m / e 579 -541-Size of this paper ^ Chinese National Standard (CNS) Λ4 specification (210X 297) while 552260 Λ, β · Five (Μ + η) + 〇 Example 491 trans-2- (4-fluorenoxy- 3-Fluorophenyl) -4-Ι1, · 1, wilting, and description of the invention (539) Oxycyclic ring | L: yl) -l42- (N-propyl · N- "4-ethyl group ^ 2 2-yl] amino) ethyl) pyridine &amp; pyridin-3-carboxyl

By the method of Cllem. Ber. 97, 33 97 (1964), 1-dimethylamino-1- using guanidine to be prepared by the method described in Syn. Comm. 12 (1), 35 (1982) Pentene-3-fluorene is converted to 2-amino-4-ethylpyrimidine. This material was converted to 2-bromo-4-ethyl-pyrimidine by using the method of Helv. 〇 "111.VIII (^ &amp; 75, 162 9 (1992) using \ 4 ^^ 02 and 1131 *. Use Example 418 The procedure was performed by using the bromopyrimidine and 2- (4-fluorenylphenyl) -4- (1,3-phenylhydrazinedioxol-5-ylb [2- (N-propylaminopropyl) -pyrrole-3-carboxylic acid ethyl ester to give the title compound as a white powder. 1H NMR (300 MHz, cdC13) δ 0.8 3 (i5 J = 7 Hz, 3H), 1 · 1 1 (t, J 2 7 Hz, 3H), ι · 45 (hexaplex, J = 7 Hz, 2H), 2.18-2.27 (ΙΏ, 1H), 2.45 U, J = 7 Hz, 2H), 2.80-2.97 (m5 3H), 3.40-3.75 (m, 7H), 3.83 (s, 3H), 5 95 (s, 2H), 6 25 (d, J-4 Hz, ih) '6.68 (d5 J 2 8 Hz, 1H), 6.79 (dd5 J = 2 Hz, 8 Hz, 1H), 6.82 (t, J 2 9 Hz, 1H), 6.92 (d, J = 2 Hz, 1H ) 7 〇) (d, J = 9 Hz, 1H), i · 5 (dd, J = 2 Hz, 12 Hz 1H) '8 · 10 (d, J =: 4 Hz, 1H). IT ^ ( (Please read the notes on the back before filling out this page) Central Bureau of Standards, Ministry of Economic Affairs Workers Co-op print

552260 Α · Β · V. Description of the invention (540) Ministry of Economic Affairs t Central Standards Bureau X Xf Cooperative Printing Example "^ I trans-4- (1 ·, 3: benzene ^ [pentene-5_yl) _2 -(4 • oxophenyl IlhGN-butylcarbonyl) methyl) · pyrrolidine-3-carboxyl The procedure described in Example 1 was used to prepare the title compound. 1; H NMR (3 00 MHz, CD3OD) δ 〇87 (t, J = 7.3 Hz, 3H), 1.23-1.36 (m3 2H), 1.3 8-1.43 (m? 2H) ^ 2.22 (s? 3H )? 2.29 (s,] H), 2.79 (d, J = i4 9 Hz, 1H), 2 84 (dd, J = 8 6, 9 7 Hz, 1H), 3.16 (t, j =: 9.5 Hz, 1H), 3 32 (d J = 15 3 Hz, m), 3.43-3 · 61 (m, 4H), 3 79 (s, 3H), 3 88 (d, ㈣ 8 Hz, m), ) · 93 (s, 2H), 6.74 (m, 3H), 6 83 (m, 3H), 70 (4, J 17 Hero, 1H) '7. Π (m, 3H). MS (C.I.) m / e 559 (MH +). Analytical calculations for C33H38N206 · 0.3 H2O: c, 7027; H, 690; N, 4.97. Experiment 値 · C, 70.24; H, 6.62; N, 4.58. Example 494 was di- ^: (% mevaleryl-dioxolene-diaminecarbonylmethylpyrrolidinic acid) The title compound was prepared using the procedure described in Example 1, and amorphous solids were isolated. ^ hnmrkdc ^, 300 MHz) S 0 92 (3H and 7 Hz), 0.97 (3H, t, J = 7 Hz), i 22-1 4〇 (5H m), ^ 4'1 * 61 (8H ^ m), 182 (1H, brm), 2.02 (2H? m), 3.05-D0 (4H, m), u.8 (lH, m), 3 55 (1H brm), 3 85 (2H, m) : t.12 (1H, brd, J = 15 Hz), 5.11 (1H, dd, J = 6 Hz, 12 Hz), 5.93 (2H, s), 6.73 (1HdJ = 8 Hz), 6 78 (iHdd, -543-

(21 Ox 297 mm (please read the precautions on the back before filling out this page L0 Φ— 552260 Α7 Β7 V. Description of the invention (541) &gt; 2 Hz, 8 Hz), 6.88 (1H, d, J = 2 Hz ). MS (DCI / NH3) m / e 487 (M + H) +. Analysis and calculation of C28H42N205 · 0 · 7 CF3C02H 値: C, 62.34; Η, 7.60; Ν, 4.95. Experiment 値: C5 62.49; H, 7.43; N, 4.73 〇f Example 495 1 ^ (N-phenylaminecarbonylfluorenyl) -2- (4-fluorenyloxy) -4- (l, 3-phenylhydrazine dioxane · Sorry -5-base)-? J-roll acid Example 495A N-Benzene bromacetamide Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economy ¾ (Please read the precautions on the back before filling in this page to order Continuously add N at a temperature of -50 ° C in a stirred solution of aniline (7.40 mmol) in dichloromethane (2.5 ml) so that the temperature does not exceed -4.00. N-diisopropylethylamine (1.58 ml, 8.14 mmol, 1.1 equivalents) and acetamidine bromide (0.72 ml, 7.40 mmol, 1 equivalent). When the addition is complete, remove the ice bath And allowed the reaction mixture to warm to room temperature. After further stirring for 30 minutes, the mixture was diluted with ether (70 ml) and poured into a 1 i hydrogen sulfate steel solution. The phases were separated and the upper layer was continuously washed with water and brine. The organic phase was dehydrated (Na2s. 4), and the solvent was evaporated in half of the product 2, at which time the product formed crystals. The crystals were removed by vacuum filtration to obtain the title compound.

Example 495B based on fluorenyl) -2- (4-methoxyphenyl) -4- (1,3-benzopenten-5-yl) -pyrrolidine-3-carboxylic acid. J was used in Comparative Example 1 The described procedure and the compound from Example 495a were used to prepare the title compound. iHNMR (300 MHz, CDC13) 58.8 — _______-544-552260 Λ * 7, ,, ___ ^ V. Description of the invention (542) (bs, lH), 7.49 (2H, d, J = 8 Hz), 7.38 ( 4H, m), 7.11 (1Η, U 'J 2 δ &amp; 2 Hz), 6 99 (1H, d, J = 2 Hz), 6 91 (2H, d, J = 8 Hz), 6.86 (1H , D, J = 2 Hz), 6.8 1 (1H, d5 J = 8 Hz), ^ 99 (111, (1, 1 = 2 Hz), 5.98 (19 :, (15) = 2 Hz), 3.94 ( 111, (1 ,: ^ 10 Hz), 3.78 (3) 1, 5), 3.70 (111, (1 (1 弋) = 6,5 &amp; 3 Hz) '3.42 (1H, dd, J = i 〇 &amp; 3 Hz), 3.41 (1H, d, J = 16 Hz from) '3.18 (111, (1 (1, &gt; ^ 11 &amp; 9 Hz), 3.01 (111, 1: [two 10 Hz)' 2.93 (1H, d, J = 16 Hz). MS (DCI, NH3) m / e 475 (M + H +). Analysis and calculation of C27H26N206 · 1H20: 〇: C, 65.85; H, 5.73 'N, 5.69. Experiment 値: C, 65.95; H, 5.52; N, 5.38. Example 496 ^^^ 1-(^ bis (2,3-di-1phenyl) aminocarbonylmethyl) -2- (4-fluorenyloxyphenyl) ) -Metadipenten-5-yl) -pyrrolidine-3-carboxylic acid utilization described in Example 1 Procedures to prepare the title compound. 1H R (300 MHz, CDC13) δ 8.68 (1H, bs), 7.64 (d, J = 8 Hz), 7.38 (2H, d, J = 8 Hz) ), 7.09 (1H, t, j = 8 Hz), 6.97 (1H, d, J = 8 Hz), 6.90 (1H, d, J = 2 Hz), 6.88 (2H, (1, &lt; 1 = 8 Hz), 6.82 (111, (} (1 ,: [= 8 &amp; 3 Hz), 6.76 (11'1, (1, 1 2 8) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ----- ---- #! (Please read the notes on the back before filling this page) Hertz), 5.97 (1H, d, J = 2 Hertz), 5.96 (1H, d5 J = 2 Hertz), 3.95 (lH, d , Bu 10 Hz), 3,80 (3H, s), 3.70 (lH, ddd, J = 6, 5 &amp; 3 Hz), 3.48 (1H, dd, J 2 10 &amp; 3 Hz), 3.44 (1H , D, J = i6 Hz), 3.18 (lH: dd, J II ii &amp; 9 Hz), 3.06 (lH, t, J = 10 Hz), 2.96 (1H, d, J II 16 Hz), 2.3 1 (3H, s), 2.16 (3H, s). MS (DCI: NH3) m / e 503 (M + H —). About C29H3〇N2〇6 ·-545- This paper size is applicable to China National Standard (CNS) A4 specification (21〇Τϋpublished) ... 552260 A · B · 5. Description of the invention (543) (Please read the first Note: Please fill in this page again) Analysis and calculation of 0.5H2〇: C, 68.09, H, 6.11, N, 5.48. Experiments: C, 68.13, H, 5.91, N, 5.29. Example 497 trans, trans-1- (N- (2,4-difluorenylphenyl) aminocarbonylmethyl) -2- (4-fluorenylphenyl) -4- (1,3-benzomethylenedioxy Cyclopenten-5-yl) -pyrrolidin-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. iH NMR (3 00 MHz, CDC13) δ 8.60 (1H, bs), 7.78 (d, J = 8 Hz), 7.38 (2H, d, J = 8 Hz), 6.99 (1H, m), 6.95 (1H, d, J = 8 Hz), 6.94 (1H, d5 J = 2 Hz), 6.88 (2H, d5 J = 8 Hz), 6.82 (1 ^ 1, 0 (1, 1 = 8 & amp 3 Hz), 6.77 (111, (^ 1 to 8 Hz), 5.97 (111, (1,) = 2 Hz), 5.96 (111, (1,) = 2 Hz), 3.92 (111, 〇1, &gt; 10 Hz), 3.79 (311, 5), 3.68 (1115〇1 (1 £ 1,] ^ 6, 5 &amp; 3 Hz), 3.43 (1H, dd, J = 10 &amp; 3 Hz), 3.42 (1H, d, J = 16 Hz), 3.18 (1 ^ 1, (11: ^ 11 &amp; 9 Hz), 3.04 (111,1> 10 Hz), 2.95 (lH, d, J = 16 Hz), 2.29 (3H, s), 2.24 (3H, s). MS (DCI, NH3) m / e 503 (M + H +). Analytical calculations for C29H30N2 06 · 0.75 H2 0: C, 67.50; H, 6.15; N, 5.43. Experiment 値 ·· C, 67.42; H, 5.95; N, 5.13. Employees of the Central Standards Bureau of the Ministry of Economic Affairs, Cooperative Cooperative Printed Example 498 Anti-Anti-l- (N- (2,5 -Xylyl) aminocarbonylmethyl) -2- (4-fluorenyloxy) -4- (1,3-phenylhydrazone M-dioxol-5-yl) -pyrrolidin-3-carboxylic acid, the procedure described in Example 1 was used to prepare the title compound. 1Η NMR (3 00 MHz, CDCi3) δ 8.62 (1Η, bs ), 7.79 (1Η, bs), 7.38 (2H, d, J = 8 Hz), 7.03 (1H, d, J = 8 Hz), 6.95 -546- This paper standard applies to the Chinese National Standard (CNS) Λ4 specifications (210X 297 Gong) 552260 A 'V. Description of the invention (544) A ^ _ (Please read the notes on the back before filling in this page (1 &amp; 1 8 Hz)' 6.94 (11 ^, 1 = 2 Hz) , 6.88 (211, (1,) = 8 Hz), 6.82 (1H, dd, J = 8 &amp; 3 Hz), 6 77 (m, d, J = 8 Hz)?). 97 (2H, s) '3.92 (iH, d, J = 10 Hz), 3.78 (3H, s), 3.70 (111, (1 (1 (1,) = 6,5 &amp; 3 Hz), 3 48 (111 〇1 (1, Bu 10 &amp; 3 Hz), 3.42 (1H, d, J = 16 Hz), 3 18 ㈤, rod J = 11 &amp; 9 Hz), 3.04 (lH, t, J = 10 Hertz), 2 95 (ih, d J = 16 Hertz) '2.29 (3H, s)' 2.24 (3H, s). MS (DCI, NH3) m / e 503 (M + H). Analytical calculations for C29H30N2 0 6 · H 2 0: c, 68.09; H, 6.11; N, 5.48. Experiment 値: c, 67 72; H, 5.89; N, 5.25. 499 l bis-l- (N- (3,4 bis-diamine aminocarbonylmethylmethoxyphenyl) __ 4- (l, 3-phenylhydrazenyl) _pyrrolidine_3_carboxylic acid is used in The title compound was prepared using the procedure described in Example 1. NMR (3 00 MHz 'CDC13) δ 8.73 (1H, bs), 7.38 (2H, bd, (1H, d, J 2 8 Hz)), 7.01 (1H, bs ), 690 (2H, d, 8 Hz), 6.85 (lH, bS), 6, 8O (iH5d5J: W ^), 5.09 (lH, d, J = 3 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Hertz), 5.98 (lH, d, J = 3 Hertz), 3 92 (1H, d, J = 10 Hertz), 3.78 (311, 5), 3.70 (114 (1 (1, Bu 6, 5 &amp; 3 Hz), 3.48 (11 (1 (1, J II 10 &amp; 3 Hz)), 3_42 (lH, d, J = i6 Hz), 3.18 (1H, dd, J II 11 &amp; 9 Hz), 3.04 ( lH, t, Bu 10 Hz), 2 95 (1Hd, J = 16 Hz), 2.25 (3H, s) '2.21 (3H, s). MS (DCI, NH3) m / e503 (M + H _) About the analysis and calculation of C29H30N2〇6 · 0 · 75 H2〇 値: C, -547- &amp; Wave scale is applicable to Chinese National Standard (CNS) Λ4 specification (210 X 297 male; ^ 552260 Λ7 ----- B7 5 Description of the invention (545) 67.50; H, 6.15 n, 5.43. Experiment 値: C, 67.24; H, 5.94; N, 5.20. Example 500

) Aminocarbonylmethyl) -2- (4-fluorenylphenyl) -oxocyclopenten-5-yl) -pyrrolidin-3-carboxylic acid The procedure described in Example 1 was used to prepare the title compound. iH NMR (300 MHz, CDC13) δ 8.75 (1H, bs), 7.35 (2H, d, J = 8 Hz), 7.10 (2H, s), 7.02 (lH, d, J = 3 Hz) , 6.90 (2Η, d, J = 8 Hz), 6.84 (1H, d, J = 2 Hz), 6.80 (1H, d, J = 8 Hz) '6.76 (lH, bs), 5.99 (lH, d, J = 3 Hz), 5.98 (lH, d, J = 3 Hz), 3.92 (lH, d, J = 10 Hz), 3.79 (3H, s), 3.68 (1H, ddd 'J = 6, 5 & 3 Hz), 3 40 (2H, m), 3 18 (1H, dd, J = U &amp; 9 Hz), 2.98 (lH, t, J = 10 Hz), 2.88 (lH, d , J 2: 16 Hz) '2.3 (6H, s). MS (DCI, NH3) m / e 503 (M + H +). Analytical calculations for C29H3QN2 06 · 0 "」: c, 68 009; H, 6, 11; N '5.48. Experiment 値: c, 67 93: H, 601; N, 519. Example 501 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Example of oxepent-5-yl) _pyrrole-3-valrate hydrochloride 501A N, N-dibutyl &gt; ethyl benzene, which will be added to toluene (220 ml) via an addition funnel Dibutylamine (280.0 ml, 1.66 mol) solution was added to cool to 0, in toluene (5 ⑻ml) -548- This paper size applies to China's CNS) A4 size (2K) χ 29 * 7 male )-~-Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 55226〇A7 '^ ---- --- B7 V. Description of the Invention (546) Medium ^ Bromoacetamidine (72.3 liters, 83 mol) ) Solution, the reaction temperature of Yijiang is maintained below UTC. When the addition is complete ... c is stirred

The reaction mixture was dropped for 15 minutes. A 2.5% aqueous solution of HJCU (100 mL) was slowly introduced, and the reaction mixture was allowed to warm to room temperature and stirred vigorously with inflammation. This solution was 2.5% by weight phosphoric acid. The layers were separated, and the organic phase was washed with water (500 ml), and then concentrated to give bromoacetamide in the form of a solution in benzene.

Example 5 0 1B Benzamidine dioxolene was mechanically stirred and ammonium acetate (13.4 kg, 173.8 mol), acetic acid (45.2 kg) and nitromethane (184 kg, (0014 moles) was continuously added to piperonal (15.55 kg, 103.5 moles). The mixture was warmed to 70 ° C. After about 30 minutes, the yellow product started to crystallize. The reaction temperature was raised to 80 X: and stirred for about 10 hours until the minimum piperaldehyde remained. The slightly viscous reaction mixture was cooled to 10 ° C and filtered. Rinse the precipitate with acetic acid (2 X 8 kg) and then with water (2 X 90 kg). Under nitrogen purge and then at 50 ° C. The product was dehydrated in an empty oven for 2 days to obtain 15.94 kg (80%) of the title compound as a pale yellow solid.

Example 501C 4-methoxyphenylhydrazone an acetate in 3 hours (within 'will be mechanically expanded; dropped, under air gas' cooled to 5 ° C in toluene (15.2 kg) Potassium acid (25 wt./0, 50,8 kg, 99.26 moles), 4-methoxyethyl SS benzophenone-549-toluene added in toluene- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 public hair ^ ~ ---------— (Please read the notes on the back before filling out this page, 11 552260 ---------- B, __________ V. Description of the invention (547 ) (6.7 55 kg, 44 98 mol) and diethyl carbonate (6.40 kg, 54.18 mol), and the temperature was maintained below 10. The reaction mixture was heated to 60 eC for 8 hours until detected by HPLC Until 4-methoxyethyl benzophenone is not available, the mixture is cooled to 20 ° C and stopped by adding a mixture of acetic acid (8 kg) and water (90 kg) over 30 minutes while maintaining the temperature &lt; 20 ° C. Separate the layers, rinse the organic layer with 5% sodium bicarbonate solution (41 kg), and concentrate to 14.65 kg. During evaporation Was maintained at 50 degrees or less. By HPLC, analyzed for yellow product concentrate external standard and found to yield 9.40 kg (94%).

Example 501D Phenyl) -4-nitromethyl 1-3- (1,3-phenylhydrazine diazine_5 · yl) -acetic acid butyrate (Please read the precautions on the back before filling in this page} In a 50% suspension of THF (56 kg) under nitrogen with mechanical stirring, add the compound from Example 50 1B (7.5 kg, 37.9 moles), add The compound obtained from Example C (8.4 kg, 37.9 moles). The mixture was cooled at 17 ° C. Sodium ethoxide (64 g, 0095 moles) was added and the reaction was stirred for 30 minutes. At about 15 After minutes, the nitrostyrene had completely dissolved. Sodium ethoxide (6.4 g, 0.095 mol) was added and the mixture was stirred at 25 ° C for 15 minutes until HPLC showed that less than 1 area% of the keto ester remained. The reaction was concentrated to 32.2 kg, which was determined by HPLC analysis to be approximately 14.9 kg (95%).

Example 5 0 i E methoxymonophenyl1-4- (1,3-phenylhydrazone dioxolene-5_some) _ pyrrolidine-3- leptate ethyl-550- This paper is for China National Standard (CNS) Λ4 specification (210X 297 hours) '-Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 552260 A7 _____R7 V. Description of the invention (548) Raney nickel (20.0 g) from which water has been poured Put into a stirred hydrogenator equipped with a thermocouple. THF (20 ml), the crude compound from Example 501D (40.82 g, 0.0482 mole) and acetic acid (2.75 ml, 0.0482 mole) were added continuously. The mixture was placed under a lice pressure of 60 pounds per square inch 'until the intake of hydrogen was dramatically slowed. TFA was added and the mixture was hydrogenated at 200 psi until HPLC showed no residual imine and &lt; 2 area% nitrone. The catalyst was filtered off and rinsed with 100 ml of methanol. The filtrate was analyzed by HPLC and found to contain 13.3 g (75% yield f) of cis, cis-p ratio p each compound. The mash was concentrated and additional THF (200 ml) was added to give a final volume of 100 ml. The mixture was neutralized with a 2K NaOH solution (50 ml), diluted with water (200 ml), and extracted with ethyl acetate (2 x 100 ml). Analysis of the external standard by HPLC The mixed almost colorless ethyl acetate layer was 13.0 g (73%) of the title compound.

Example 5 0 1F Fluorenyl) -4- (1,3-phenylhydrazone dioxolene-5-some pyrrolidine-3-carboxylic acid ethyl ester in the compound obtained from Example 5 0 1E (3 8.1 g, 0.1 03 mol) solution was added ethanol (200 ml) to a final volume of 100 ml, and ethanol was added

(3.40 g, 0.05 mol). The mixture was heated to 75. (: When HPLC showed no &lt; 3% cis, cis isomers left, the mixture was cooled to room temperature. The product was analyzed by HPLC external standards and found to contain 34.4 g (90% yield) The title compound. Concentrate the crude compound solution and dissolve the residue in isopropyl acetate (400 ml). Rinse with water (2 X 150 ml) -551-this paper is suitable for 210X 297 public funds)-1 — _________0_ 丨 (Please read the notes on the back before filling this page) Order 552260 Α: Β1 V. Description of the invention (549) '' Wash the organic layer, and then use 0.25M &gt; phosphoric acid solution (2 X 400 XL) Extract it. The mixed phosphoric acid layer was stirred with ethyl acetate (200 ml) and neutralized to pH 7 with sodium bisulfate (21 g). The organic layer was separated and found to contain 32.9 g (87%) of the title compound.

Example 501 G (1R, 3R, 4S)-(+)-2- (4-fluorenylphenyl) -4- (1,3-phenylhydrazine dioxolane) -pyridine- 3- # j # a ester was added with acetonitrile (00 ml) to the solution of Example 5 1 OF to obtain a final volume of 50 ml. Add (S)-(+)-mandelic acid (2.06 g, 0.0136 mol) and allow it to dissolve. The mixture was seeded with the product and allowed to stir for 16 hours at room temperature. The reaction mixture was cooled to 0 and stirred for 5 hours. The product was filtered and flushed with nitrogen and dehydrated in an air oven at 50 ° C for 1 day to give 5.65 g (40%) of the title compound. Chiralpak AS can be used to determine the purity of the product by chiral HPLC, eluting with hexane-ethanol-diethylamine with a solvent of 95: 5: 0.05; flow rate-i ml / min; UV at 227 nm Detection. Holding time: (+)-enantiomer: 15.5 minutes; (-)-enantiomer: 2 1.0 minutes. Example 501Η. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs --------- #! (Please read the precautions on the back before filling in this page) 〔2R, 3R, 4S)-(+)-2 -(4-Methoxyphenyl) -4- (1,3-benzylidene) || Like cyclopentanyl V WN, N-di (n-butyl) aminocarbonylmethyl and its Vbiha _ ^-夂 #Acid The compound obtained from Example 510G (20.0 g, 0.03 83 moles) was suspended in ethyl acetate (150 ml) and a 5% hydrogen acid steel solution (150 ml). Remove it in the room hni; Mixture 'until the salt is dissolved and the soil / oxidation is released. Separate the organic layer and concentrate it. Add acetonitrile (200 -552-this paper size applies the national standard (CNS) Λ4 specification (210X297)漦) ^ 'one 552260 Λ five, description of the invention (550) (please read the notes on the back before filling this page) ml), to a final volume of 100 ml, and cool to M. Add diisopropylethylamine (1 1.8 gross liters, 0 0) 74 moles) and the compound obtained from Example A (10.5 g, 0.0421 moles), and the mixture was stirred off at room temperature for 12 hours. The reaction mixture was concentrated and ethanol (200 ml) was added to a final volume of 100 ml. Sodium hydroxide solution (40%, 20 ml, 0.02 mol) was added, and the mixture was heated to 4 hours until HPLC showed no starting material 夤. The reaction mixture was poured into water (400 mL) and rinsed with hexane (2 X 50 mL). The layer was washed with hexane (2 x 20 ml). The mixture of the stirred liquid layer and ethyl acetate (400 liters) was neutralized to pH 5 with concentrated HC1 (12 liters). The organic layer was separated and found to contain 18.3 g (94% yield) of the title compound. Example 5011 Methoxyphenylisoamidinedioxolyltrij-n-butyl) aminocarbonylmethyl) -pyrrole ^ Block ^ a few blankets_ Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Hydrochloride To a solution of Example 50 1H compound in ethyl acetate was added 39.4 liters of HC1 in ethanol (0.0394 mol) in a mechanically stirred container equipped with a thermocouple at room temperature. . The resulting solution was filtered to remove foreign matter, concentrated in the air, and ethyl acetate (400 ml) was added. The solution was seeded repeatedly and the solvent was removed until crystals started to form. The condensate was concentrated to a volume of 100 liters, and the product was filtered 'and rinsed with ethyl acetate Ss (25 ml). The resulting white solid was dehydrated in a 50X: emptying oven under a nitrogen purge to obtain 17.6 g (90%) of the title compound. -553 This paper size applies to China National Standard (CNS) A4 specifications (210X 297 Gongchu 552260 A7 —------- B ^ V. Description of the invention (551) &quot; ~ Example 502 (Please read the Note: Please fill in this page again), hydrazone: (2-formamidine i) -4_ (l, 3-benzene # meta-di-air turtle cyclopentene-5_yl inverse "_chemical bis (n-butyl) amine Carbonylmethyl V pyrrolidine-3_Miaoling Example 502A 3-methylhexanoyl ester Add phosphonium triethyl acetate (10.3 ml, 52 mmol) to 60% in 10 ml hexane % Sodium hydride (2.26 g, 57 mmol). Once the gas evolution ceases, 2-pentamidine (6.0 ml, 64 mmol) is added. After 3 hours at 1: temperature, use water to make The reaction was stopped and distributed in ether. The organic layer was washed with water and brine, filtered over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was dissolved in 50 ml of ethanol And 10% palladium on carbon (6.0 g) was added. The vessel was pressurized to 4 atmospheres &lt; hydrogen and shaken at room temperature for 3 hours. The reaction was filtered and the solvent was removed under reduced pressure to give 3.0 Gram of the title compound.

Example 502B 5 -methyl-3-oxooctanoic acid (Shi)-B g Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, sodium hydroxide (2.3 g, 57.6 mmol) was added to In solution of ethyl 3-fluorenylhexanoate. After 48 hours at room temperature, the solvent was removed under reduced pressure and the residue was dissolved in 150 ml of water. The solution was washed with ether, then acidified with concentrated hydrogen, and washed with dichloromethane. The organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 2_7 grams of the corresponding acid. Via Vi 1 kas, B u 1. 0 ^ 111.3〇 (:.? ]:., Method of 945 (1964), from which 3.9 g of the title compound was prepared. -554- The scale of the wave is applicable to China (CNsT ^ specifications (210X 297))

552260 V. Description of the invention (552)

f Example 502C Transbenzo-dioxo ^^ 5-yl) hepta (N, N-di (bioxofluorenyl) -p-biloxal acid Use the procedure described in Example 1 and use 5- Methyl_3 • oxooctanoic acid ethyl ester was used to replace (4-methoxybenzyl) ethyl acetate to obtain the title compound, which was separated from the diluted aqueous TFA / CH3CN by freeze-drying. Note that Multiple signals in the aryl region reflect a 1: i mixture of diastereomers on the alkyl chain. IH NMR (CDC13, 300 MHz) δ 0 · 8-1 · 〇 (χη , 12H), 12-14 (m7H), 145_16 (melon, 6H), 1.6-1.74 (m, 1H), mo (m, 1H), 31_3 4 (m, 5H), 3.67-3.78 (m, 1H) , 3.8-3.91 (m, 1H), 4.0 · 4 · 2 (m, 2H) '4.3-4.5 (m, 2H), 5.93 (d, J = 1.5 Hz, 2H), 6.73 (dd, Bu 8.1, 1.2 Hz, 111), 6.79 ((1 (1 (1, 拎 7.8, 1.8, 1.8 Hz, 1 field '6.80 (dd, J = 3.9, 1.5_g, iH)) MS (DCI / NH3) m / e489 (M + H) _. Analysis of C28H44N205 · 1.0 TFA · 0.5 H2O: C, 58.91; H, 7.58; N, 4.58. Experiment: c, 58.91; H, 5.78; N , 4.45. Example 50 3 Good., Trans-2- (2,2-Dimethylpentyl) -4- (1,3-benzo-dioxol-5-yl) -l- (N, N-bis ( N-butyl) aminocarbonylmethylpyrrolidine-3-carboxylic acid was prepared using a common procedure of Cahiez et al., Tetrahedron Lett., Ϋ_, 7425 (1990) to prepare ethyl 3,3-dimethylhexanoate. The procedure described in Example 502 and substituting ethyl 3,3 · difluorenylhexanoate for ethyl 3-fluorenylhexanoate gave the title compound, which was lyophilized from the diluted water by freeze-drying-555- The scale applies to the Chinese national standard PcNS) Α4 specification (210 × 29? Gongchu) &quot; First (Please read the precautions on the back before filling in this page.

1T printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 552260 A7 R7 printed by the Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and printed by the cooperatives V. Invention Description (553 TFA / CH3CN Separation Officer. I. τ Knife Feeder. H NMR ( CDC13, 300 MHz) δ 0.80-0.99 (m, 15Η), l.10_137 (m 8H), l 43_l 58 (m 4H) 1.77-1.97 (m5 2H), 3.48-3.12 (m, 5H), 3.60- 3.69 (m5 1H), 3.75-3.86 (m? 1H), 3.95-4.1 6 (m? 2H), 4.28-4.4 (m5 2H) '5.94 (s, 2H)' 6.74 (d, J = 7.8 Hz, ih ), 6.8 (dd5 ㈣ 丄 L5 Hz, 1H), 6.87 (d, J = 18 Hz, 1H). Ms (dci / NH3) m / e 503 (M + H) +. About C29H46N205 · i 〇5TFA Analytical calculation: ，: C, 60.01; H, 7.62; N, 4.50. Experimental 値: C, 60.21; Η, 7.37; N, 4.33 (Recommendation 5 0 4 1, pentene · 2 · yl) Ethyl, 3 苽 舁 1 monooxodi (n-butyl) aminocarbonylmethyl

唉 -3- # Acid Example 504A klkli methylenedioxy only) _ 3-oxopentanoic acid ethyl ester According to the procedure of Huckin and Weiler, Tetrahedron Lett. 3927 (1971), ethyl acetate and 2-bromo Fluorenyl-,,, dihenane to synthesize the title compound. In a 250 ml flask, 4.97 g (0.124 mole) of 60% mineral oil dispersant sodium hydride was weighed, and 80 ml of tetrahydrofuran was directly added thereto. The flask was capped with a septum cap, flushed with nitrogen, and cooled in an ice bath. To the above stirred slurry, 15.0 ml (0.118 mol) of ethyl acetoacetate was added dropwise. After the addition was complete, the resulting mixture was stirred at 0 ° C for an additional 10 minutes. Then in the above mixture, -556 This paper size applies the Chinese National Standard (CNS) A4 specification (h0x297 g), order (please read the precautions on the back before filling this page) 552260 A7 ---- --- «2 V. Description of the invention (554) Add 48.4 ml (0.121 mole) of a 2.50M solution of n-butyllithium in hexane in a dropwise manner. The resulting orange-red solution was stirred for 10 minutes before adding 13.5 ml (0.130 mol) of bromofluorenyl-1,3-dioxazane in one batch. The reaction mixture was then allowed to warm to room temperature and was stirred for an additional 120 minutes before the reaction was stopped by slowly adding 9.8 ml (about 0.12 mol) of concentrated hydrochloric acid. The two-phase mixture was poured into 50 ml of water and extracted with 150 ml of ether. The liquid phase was extracted thoroughly with additional ether. The ether extract was mixed, rinsed with 2 X 50 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a brown oily residue. The crude product was purified by silica gel flash chromatography to 20. Ethyl ether / hexane was eluted to obtain 5.40 g (20%) of the b-ketoester as a pale yellow oil.

Example 504C trans, -trans-2- (Ki, 3-m-dioxolen-2-yl) ethyl V4-n.3-benzyl #

M. Trioxol-5-yl VI-ΓΝ · Ν-bis (n-butyl) aminocarbonyl methyl V ρ bilo bite &gt; 3_ Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Please read the notes on the back before filling this page.) Use the procedure described in Example 502 and replace it with 5- (1,3-m-dioxolyl) -2-oxopentanoate Ethyl 3-methylhexanoate gave the title compound. 1HNMR (CDCl3, 300 MHz) δ 0.93 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7 2 Hz, 3H), i 23-1 38 (m, 4H), 1.52 ( ,, heavy peak, j = 7.9 Hz, 4H), 1.85- 1.95 (m, 2H) ^ 2.02-2 · 1 / 2H), 3.18 (dd, J = 6.0 Hz, 9.0 Hz, 2H), 3.30 (dd, BU 9.0 Hz, 180 Hz, 2H), 3 35 (m, 1H), 3 79 (machine frequency of 3.6 Hz, 6.9 Hz, 1H), 3.83-3.88, 3 H), 3.97 (dd, J 2 4.8 Hz, 60 Hz, 4 〇5 (q, J = 9 6 Hz, 2H), -557 This paper is suitable for financial use _ home turn (CNS) Λ specifications (21Qx2m &gt; Chu) 552260 A7 --- ^ _ !: __ — V. Description of the invention (555) ~ 4 3〇-4.40 (m, 1H), 4.37 (s, 2H), 4.87 (t, Bu 3.6 Hz, out) '5.94 (s, 2H), 6.73 (d, J = 8.1 Hz, 1H), 6.79 (dd, J = i.8 Hz, 8.1 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H). Ms (APCI) (m + h) + at m / e 505. Analysis and calculation of C27H40 N20. 1.2TFA 値 · C, 55.05; H, 6.47; N, 4.37. Experimental 値 · c, 55 · 12; H, 6.44; N, 4.27. Example 505 Phenyltetrahydro-2H-piperan) Ethyl V 4- (l, 3-phenylhydrazine heterocarbyl) -1- (N, N-bis (n-butyl) aminocarbonylmethylpyrrolidine_3 dimetanoic acid

Example 505A Ethyl 5- (2-tetrazol-2H-oxanthran) -3-oxovalerate Using the procedure of Huckin and Weiler5 Tetrahedron Lett. 3927 (1971), ethyl acetate and 2- ( Bromomethyl) tetrahydro-2H-piran to prepare the title compound as a pale yellow saccharine.

Example 505B Plexahydro-2H-piranyl) ethyl) -4- (1,3-benzo-dioxane Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs-(Please read the precautions on the back before Fill out this page} Di (n-butyl) aminocarbonylfluorenyl V pyrrolidine-3-carboxylic acid using the procedure described in Example 5 02 and starting with 5-(2 -tetrahydro-2 fluorene-yell) Substituting ethyl-2-oxopentanoate for ethyl 3-methylhexanoate to give the title compound as an amorphous solid. HNMRCCDCh, 300 MHz) A mixture of two diastereomers: δ 0.89 (t , J = 8.1 Hertz, 3H), 0.89 (t, J = 8.1 Hertz, 3H), 0.91 (t, J = 8.1 Hertz, 3H), 0.91 (t, J = 8.1 558 This paper is applicable to China National Standard (CNS) A4 specification (210X297) while 552260 A '_ B7 V. Description of the invention (556) Hertz, 3H), 1.20-1.40 (m, 10H), 1.42-1.66 (m, 1 8H), 1.71 (brm, 2H), 1.85 (brm, 2H), 1.96-2.23 (brm, 4H), 3.10-3.29 (m, 8H), 3.29-3 · 52 (m, 6H), 3. 54-3.8 1 (m, 6H), 4.01 (q, J = 9 Hz, 2H), 4.12-4.25 (m, 4H), 4.43 (d, J = 9 Hz, 2H), 4.50 (d, J = 2.7 Hz, 2H), 5.94 (s, 2H), 5.95 (s, 2H), 6.76 (s, 2H), 6.76 (s, 2H), 6.81 (s5 1H), 6.81 (s, 1H) ). MS (APCI) (M + H) + atm / e 517. Analysis and calculation of C29H44N20.6 · 1.4TFA 値: C, 56.48; H, 6.77; N, 4.14. Experiment 値: C, 56.46; H, 6.99; N, 3.83. Example 506 trans, trans-2- (2,2,4 · trimethyl-3-pentamyl) -4- (1,3-phenylhydrazine dihydrogen M pentamidine-5 -Yl) -1- (N, N-bis (n-butyl) aminocarbonylfluorenyl) -pyrrolidine-3- # acid

Example 506A 3,3,5-trisino-4-hexenoic acid ethyl ester produced by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 27 ml of a 1.6 M solution in hexane, 43 mmol) was added to the silt of isopropyltripentyl basic scales (205 g, 47 mmol) in 200 ml of tetrahydrofuran. And the solution was briefly warmed to 0 ° C. After re-cooling, 3,3-difluorenyl-4-oxobutyrate was prepared in 10 ml of tetrahydrocran according to the procedure of Hudlicky et al., Synth. Commun., I 6 169 (1986). (5.7 g, 40 mmol) and the reaction was warmed to 0 C for 30 minutes. The reaction was stopped with dilute hydrochloric acid and partitioned with ethyl acetate. The organic layer was rinsed with water and brine, dehydrated with anhydrous sulphuric acid, decanted and removed under reduced pressure. -559- This paper &amp; standard applies Chinese National Standard (CNS) A4 specification (210X297) 552260 A: Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (557) Scintillation chromatography on silicone The residue was purified and eluted with 10% ethyl acetate in hexane to give 2.1 g (30%) of the title compound. Example 506 Danliang'trans_2- (2,2,4-trimethylpentene) U_n3-dioxo-dioxan-5-yl-N-di (n: butyl) amine Pyrrolidine · 3_ # acid Using the procedure described in Example 502 and substituting 3,3,5-trimethyldimethylacetate for ethyl 3-methylhexanoate, the title compound was obtained by freezing Drying method separates it from diluted aqueous TFA / ch3CN. 4 NMR (CDCl3, 300 MHz) δ 0.92 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.2 Hz, 3H) , 1.1 · 1 1 (s, 3H), 1. 13 (s, 3H), 1.24-1.37 (m, 4H), 1.46-1.59 (m, 4H), 1.61 (d, J = 1.2 Hz, 3H), 1.69 (d, J = 1.2 Hz, 3H), 2.04-2.ll (m, 2H), 3.10-3.20 (m, 2H), 3.30-3.39 (m, 3H), 3.67-3.82 (m, 2H), 3.95-4.08 (m, 1H), 4.32 (m, 2H), 4.37-4.47 (m, 1H), 4.99 (s51H), 5.95 (s, 2H), 6.73 (d, J = 7.8 Hz, 1H), 6.78 (dd, J = 8.4, 1.2 Hz, 1H), 6.84 (d, J = 1.2 Hz, 1H). MS (DCI / NH3) m / e515 (M + H plant. About C3〇H46N205 · 1.05 TFA Analytical calculation 値: C, 60.77; H, 7.48; N, 4.42. Experiment 値: C, 60.83; H, 7.20; N, 4.43. Example 507 trans, trans-2-(2,2-dimethyl-yl-2di i 13-dioxolane_2-yl) ethyl) -4- (1,3 -Benzylhydrazine-dioxane _ ^ _ 1 ^ !! ^)-1- (N, N-bis (n-butyl) aminopyridylpyrrolidin-3-carboxylic acid-560- In use Guan Jiabiao Rate (CN ^ S &quot;(21GX; Public Burn) &quot; &quot; '(Please read the precautions on the back before filling out this page) L # 、 \ 5 5 Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Consumer Cooperatives 552260 A ? s ______ ll ^ V. Description of the invention (558) s ~ ———— fm 507 ^ 3_ and: _ dihydrazyl-1:. (. 1 _ ，. 1_ 二 直 ”^ 1 ^ ： 1 ^^^ 1 ^ 3,3-Difluorenyl-4-oxobutanoic acid methyl ester (10 g, 70 mg) was prepared according to the procedure of HudHcky et al., Synth.commmun. To 40 ml of benzene was added ethylene glycol (20 ml) of cis-toluene acid monohydrate (1.3 g). The reaction was refluxed for a total of 1 hour of water stagnation. The reaction was poured into 200 ml of diethyl ether, washed with saturated sodium bicarbonate, water and brine, dehydrated with anhydrous magnesium sulfate, and filtered. ^ The solvent was removed under reduced pressure to obtain 12 4 g (94%) of Title compound.

Example 507B group, trans-? _ '(2,2-trimethyl-2. (1,3-dioxolane_2_yl) ethyl) -center. "Di-Epi-Dioxolene-5-yl) -1- (N, N-bis (n-butyl) amine jimomethyl) -pyrrolidin-3-methyl was used in Example 502 Described in the procedure and replacing methyl 3-methylhexanoate with methyl 3,3-difluorenyl-dioxolane-2-yl) propanoate to give the title compound, which was diluted by freeze-drying from dilution It was separated in aqueous TFA / CH3CN. 1H NMR (CDC13, 300 MHz) δ 0.82-1.00 (m, 12H), 1.24-1.40 (m, 4H), 1.43-1.64 (m, 5H), 1.76-1.84 (m, 1H), 2.93-3.00 ( m, lH), 3.15-3.47 (m, 6H), 3.60-3.70 (m, 3H), 3.74-3.95 (m, 5H), 4.48 (s, 1H), 5.94 (m5 2H), 6.72 (d , J 2 8 Hz, iH), 6.83 (dd, J = 8.0, 1.2 Hz, 1H), 6.94 (d, J 2 i. 2 Hz, 1H). MS (DCI / NH3) m / e 533 (M + H) +. About C29H44N2〇7 · 1. 1 TFA · 0.2 H2〇 Analytical calculation-: -561-This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 public carboxylic acid) (Please read the precautions on the back before Fill out this page}

552260 Printed by the Consumer Cooperatives of the Central Bureau of the Ministry of Economic Affairs Λ * '^ --- ~~------ £ 1 _____- ---- V. Description of the invention (559) ~ C, 5 6.63; Η, 6.93 ; Ν, 4.23. Experiment 値 ·· C, 56.60; Η, 6.96; N, 4.25 0 A ^ L5 0 8-yl-m-dioxolen-2-yl) ethyl) -4- (1,3-benzyloxazine? Di5-yl) heptyl_N_ (2_fluorenyl_3-fluorobenzene)] Avoiding group 曱 ^^^^ Each bit _3- double acid A_ ^ L &gt; 08A ^ i ^ S | _ Add 370 mg (10.0¾ mole) of Li A1H4 in portions to an ice-cold solution of 1.14 g (10.0 mmol) of 4-heptanone in 20 ml of diethyl ether in order to maintain the reflux of the ether to a minimum . After 45 minutes, the reaction was stopped by successively adding 0.4 ml of Η20, 0.4 ml of 15% (w / v) NaOH (aq), and 1.2 ml of H2O. After stirring for an additional 45 minutes, MgSO was added until the salts flowed positively, and then the reaction was filtered. The salts were washed with diethyl ether (3 x 5 ml), and the filtrate and washings were concentrated to a colorless, yield 1.16 g (100%). t 5 08Β_Homo-methanesulfonium% ^ heptane 1.5 ml of triethylamine was added to an ice-cold solution of 834 mg (7.19 mmol) of 4-heptanol in 35 ml of CH2C12. Then, 1 · 7 liters (9 耄 moles) of methyl chloride continued to be added dropwise over 1 minute. The mixture was stirred at 0 ° C for 30 minutes' and then extracted with H20 (1 X 15 ml), 5% NH4OH (2 X 15 ml), 1MHC1 (2 x 15 ml) and brine (mL x ml) and covered with MgS04 was dehydrated, filtered and concentrated to an oil. Yield i.3 1g (94%) -562-Use Chinese national standard iTcNS) Λ4 specification (210X 297 male ^ ~ --- -------- clothing __ (Please read the precautions on the back before (Fill in this page)

, 1T ♦ 552260 ___ Βη — -— ~ 1 V. Description of the invention (560) 1. 4 NMR (3 00 MHz, CDC13) d 0 · 96 (t, 6, J = 9), 1.43 (m, 4), 1.64 (m, 4), 3.00 (s, 3), 4.73 ( Fivefold peak, 1 J = 5).

Example 508C 1 -Fluoro-3 -fluorenylaniline-a solution of 2 g of 10% Pd-C in 400 g of ethanol (29 mmol) of 2-fluoro-5-nitrotoluene in. The mixture was shaken at 45 psi H2 until the uptake of hydrogen ceased. The catalyst was filtered off and rinsed with ethanol. The combined filtrate and rinse were then concentrated to 152 g (94%) of a colorless oil.

Example 508D N-heptyl · 4-fluoro-3-fluorenylbenzylamine 7.64 g (3.93 Emole) of 4-pyrene-continuous oxyheptan and 3.4 g (4.1 mmol) of NaHC0⑴ And added to a solution of 4.10 g (3.28 mmol) of 4-fluoro-3-fluorenylaniline in 30 l of acetonitrile. The mixture was stirred under reflux for 24 hours 'and then poured into 150 liters of h2O' and obtained with diacetic acid (2 X jO liters). The mixed bond layer was counter-stripped with saline (1 × 30 mL), dehydrated with MgSCU, filtered and concentrated to form a solution. It was purified by silica gel chromatography, eluting with 9 7.5: 2 · 5 of ethyl acetate: ethyl acetate, to obtain 2.5 6 grams (35%) of light yellow oil printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. .

Example 508E N, N- (4-heptyl V 丄 4-fluoro-3-methyl) phenanthrene: Benzene-acetamide will be 49.0 ml (56 2 mmol) bromoethyl in 7 ml toluene A solution of fluorene bromide was added to 4 88 g (21.9 mol) of N- (4-heptyl) -4-fluoro-3-methylaniline and 4 9 ml (61 1 mol) in 100 ml of toluene. ) Pyridine's ice-cold-563- (210X297 total) • Approval-(Please read the precautions on the back before filling out this page) J · This paper size applies to China National Standard (CNS) A4 specification 552260 A * B &quot; 5. Description of the invention (531) in solution. Stir the solution for 24 hours, gradually return to 25 ° C, and extract it with 1M HC1 (1 X 100 ml). Back extract the layers with diacetic acid (1 X 50 mL), then rinse the mixed organic layers with Η20 (2 X 50 mL), saturated NaHC03 (aq) (2 X 50 mL), and brine (1 X 50 mL). Covered with MgS04 strands: water, filtered and concentrated in air. It was purified by silica gel chromatography, eluting with 90:10 hexane: ethyl acetate, to give 7.48 g (99%) of a pale yellow oil. iHNMR (300 MHz, CDCl3) d0.94 (t, 6, J = 5), 1.33 (m, 4), 1.43 (m, 4), 2.30 (s, 1.5), 2.3 1 (s , 1.5), 3.54 (s, 2), 4.72 (quintese peak, 1, J = 5), 6.96-7.04 (m, 2), 7.07 (d, 1, J-2 7).

Example 508F Trans-Han-2- (2- (1,2,3-di-dilactate heteropyridine_2-yl) ethyl) -4- (1,: &gt; -pyrene-dioxolene 5--5-Heptyl-N- (2-fluorenyl-3-fluorophenyl) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 1 Aminocarbonylmethyl 1 -Pyrrolidine-3-carboxylic acid using the procedure described in Example 502, replacing 3-methylhexyl with ethyl 5- (1,3-m-dioxolenyl) -2-oxopentanoate Acid ethyl ester, and replacing N, N-dibutylbromoacetamide with N, N- (4-heptylfluorene 4.fluoro-3-methyl) phenyl-bromoacetamide to obtain an amorphous solid The title compound. NMR (CDC13, 3 00 MHz) δ 0.93 (brt, 6H), i. 23- 1.47 (m, 8H), 1.67.2.10 (m, 4H), 2.32 (s, 3H), 3.16 ( t, J = 9.0 Hz, 1H), 3.5 2-3.67 (brm, 2H), 3.73 (t, J = 9.0 Hz, 1 ^ 1), 3.8 1-4 · 02 (m, 6H), 4.13 (brm , 1H), 4.72 (Five-fold peak, J 2 6.9 Hz, 1H), 4 86 (t, J 2 4.0 Hz, 1H), 5 93 (s, 2H), 6.72 (d, J 2 8 1 Hz. 1H), 6.7 8 (dd, 8 Hz, 8. 1 Hz, 1H), 6.85 (d, -564- paper Zhang scale is applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) 552260 A7 Ri 5. Description of the invention (562) 1.8 Hz, 1H), 6.96 (m, 2H), 7.08 (t, J = 9.0 Hz , 1H). MS (DCI / NH3) (M + H) + atm / e 599. Analysis and calculation of C33H43N207F · 0.8TFA 値: C, 60.24; Η, 6.40; N, 4.06. Experiment 値: C, 60.21; Hf, 6.14; N, 3.86. Example 509 trans'trans-2- (2- (1,3-didioxane% penten-2-yl) ethyl) -4- (1 , 3 • Benzene-dioxol-5-yl) -1- (N, N-bis (n-butyl) amine The procedure described in Example 502 'replaces ethyl 3-methylhexanoate with ethyl 5- (1,3-dioxoyl) -2-ethyloxopentanoate $ Methoxypiperonal was used instead of piperonal to obtain a labeled character in the form of an amorphous solid. 1H NMR (CDC13, 300 MHz) δ 0.93 (t b ,. &gt; 3H), 0.95 (t, J = 7.8 Hz, 3H), 1 · 3 1 (m, 4H), i 5 3 (m cents), I · 90 (m, 2H), 2.09 (m, 2H) , 3.19 (dd, 48.4 Hz, 8 4 Hz, 2H), 3.30 (q, J 29.6 Hz, 2H), 3.25-3.4? 1H), 3.73 (q5 J 2 10.5 Hz, 1H) , 3.78-3.94 (m, 4H), 3 88 (s 3H), 3.96 (dd, J = 5.1 Hz, 6.0 Hz, 1H), 4 〇3 V cl d? J — j. 0 Hz, 6.3 Hz , 2H), 4.33 (m, 3H), 4 87 (t, j 2 3 a * u _ 幺 幺, 1 H) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -------- «^- -(Please read the notes on the back before filling this page) '5.94 (s, 2H)' 6.5 :) (d, J—1.8 Hz, ih), 663 (d j_ jg Hz, 1H). MS (DCI / NH3) (M + H) + at m / e 535. Analysis and calculation of C28H42N208 · 1.05 TFA 値: c, 55.25. U, ′ ′ H, 6.63; N, 4.28. Experiment 値: c, 55.39; H, 6.66; N, 4.26. Example 510 Anti- "trans-2- (U di ^ methyl) -methyl" -t (1,3_benzoheteropentyl __ _ 565-^ paper size applies Chinese national standard UcNS) A4 specification (210X 297) ---_ 552260

A B7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the Invention (563) 晞 -5-yl) -1- (N, N-di (n-butyl) aminocarbonylmethyl) pyridine-3_ The reacid was prepared using the procedure described in Example 502 to replace 3-fluorenylhexanoic acid with o-methoxyphenoxyacetic acid to prepare the above compound as an amorphous solid. ifj NMR (CDCI3 '3 00 MHz) δ 0 · 85 (t5 J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H), 1.15-1.35 (m, 4H), 1.40-1.55 (m5 4H), 3.05-3.25 (m, 4H), 3.28-3.55 (m, 4H), 3.58-3.68 (m, 1H), 3.75-3.80 (m, 1H), 3.82 (s, 3H), 3.91 (d, J = 14 Hz, 1H), 4.05-4.15 (m, 1H), 4.23-4.33 (m, 1H), 5.91 (s, 2H), 6.70 (d, J = 8 Hz, ih), 6.82-6.95 (m, 5H), 7.03 (s, 1H). MS (DCI / NH3) (M + H) + atm / e541. Analysis and calculation of C3〇H40N207N: C, 66.65; Η, 7.46; N, 5.18. Experiment 値: C, 66 37; H, 7.61; N, 5.09 〇 Example 5 1 1 (lR, 3R, 4S) -2- (2,2 di ^ pentyl) -4- (13-phenylamidine Dioxane &gt; 1- (N · 4-heptyl ^^ 4_fluoro_3 · 曱 benzyl) aminocarbonylmethyl) _ ton 丨 -carboxylic acid

Example 5 The 11A-based 2- (2,2-dimethylpentyl) -4- (1,3-ceryl and dien-5-yl v pyrrolidine-3-acid will be prepared according to the reverse of Example 503, Trans-2- (2,2-di-amylpentyl) -4, (1 3-dioxo-mono-oxo 3-isopentenyl) _pyrrolidine_3_carboxylic acid ethyl ester (2.5 g, 6 = fluorene (Ear) was dissolved in 50 liters of dichloromethane, and di-arsinobutyl diacetate (^ · 5 g) was added. After stirring overnight at room temperature, it was moved down with a reduced trowel Remove the solvent, and purify the residue by flash chromatography on silica gel: This paper size applies the Chinese national standard (-566- (Please read the precautions on the back before filling this page) Order 55226〇A7 ΕΓ Five Invention Instructions ( 564) -------- • Batch— 丨 (Please read the precautions on the back before filling this page) 'Elute with 10 ° /. Ethyl acetate / hexane to get the title as a colorless oil Compounded ethyl ester (2.8 g). This ester was dissolved in ethanol (50 liters), followed by the addition of sodium hydroxide (10 ml of a 5 M aqueous solution). After stirring at room temperature for 20 hours, The solvent was removed under the pressure of 5% and the residue was dissolved in 150 Liter of water and acidified with concentrated phosphoric acid. The mixture was extracted with chloroform (3 X 50 ml), and the organic layer was washed with brine, covered with anhydrous magnesium sulfate tax, filtered and the solvent was removed under reduced pressure, The title compound was obtained as a white foam (2.4 g).

Example 5 11B ^! ^ 2- (2,2-Dimethylpentyl) -4- (1,3-phenylhydrazone-dihydropentapentene-5-some 4-heptyl-N · (4-fluoro -3 -Phenyl) amine, a certain methyl) ·? Bilodine_3-Carboxylic acid: printed for a single enantiomer, the Ministry of Economic Affairs, Central Standards Bureau, Consumer Cooperative, and the product obtained from Example 510A (1.97 g, 4.5 mmol) was dissolved in 20 μL of #THF and cooled to 0 ° C., followed by the addition of DMF (0.017 mL, |)%) and chloramphenyl chloride (0437 mL, 5.00 mmol) ). After 1 hour, remove Qi Qi at 0 ° C. The residue was dissolved in $ ml of benzene and evaporated. In a different flask, (S) -4-benzyl-2-indazolidine (1.2 g '6.8¾ mole) was dissolved in 30 ml of THF, followed by the addition of n-butyl chloride at 0 ° C. (4.0 ml of a 1.6 M solution in hexane), and the slurry was stirred off for 15 minutes. The fluorenyl chloride was dissolved in 20 ml of thf, the stem was cooled to 0 c ', and then an oxazoHde suspension was added dropwise via a cannula. After 30 minutes, the reaction was distributed between ether and saturated bicarbonate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. On silica gel, by flash chromatography, the pure -567- scale is applicable to the Chinese National Standard (CNS) Α4ϋΓ7Τ ^^ 97 public potential _____ 552260 V. Description of the invention (fine) 1 ~-Residue to 15 % Ethyl acetate / hexane elutes to give the undesired diastereomers (1.17 g '43%). When eluting with 20% ethyl acetate / hexane, the desired Diastereomers (104 g, 38%). π The desired diastereomer of N-oxooxazolidone (0.84 g, ^ • 42 mol) was dissolved in 2.5 liters of dichloromethane, and 2.5 was added Clarify monofluoroacetic acid. After 30 minutes, the volatiles were removed under nitrogen vapor, and the residue / combination was performed twice in 5 liters of toluene, and then reduced under reduced pressure. A pair of TF A salts was mixed with 4¾ liters of acetonitrile, followed by addition of diisopropylethylamine (1.0 ml, 5.7 mol) and N_4-heptyl-N- (4 in the form of a solution in 2 ml of acetonitrile. -Fluoro-3-tolyl) bromoacetamide (589 mg, 17 mmol). After 21 hours, the reaction was warmed to 5 (rc 3 · 5 hours. The reaction was cooled, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel at 20-30% Ethyl acetate / hexane elution yielded 0.939 g of ammonium as a colorless oil. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) , 0.26 mmoles) was dissolved in 20 ml of THF and 0.7 * liters of water. At 0 °, solid lithium hydroxide monohydrate (22¾ g '0.53 mmoles) was added, followed by 30% hydrogen peroxide ( (0050 ml, 0.55 mol). After 1 hour, the reaction was warmed to room temperature 3 1 hour out of the face of the battle to make the reaction distributed in 1: 1 ethyl acetate g: hexane Between water and water, 0.1 5 g of sodium thiosulfate was added and the mixture was thoroughly mixed. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The crude The residue was dissolved in 2 ml of ether and 1 ml of methanol. Added dropwise in hexane Zhongzhi (Thirty-Three Crushed Burnt-568-: This paper size applies to the Chinese national standard Λ4 specification (210X 297 Gongchu) '552260 Λ, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of invention (566) ) Diazomethane solution until yellow remains. The reaction was stopped by adding 2 drops of glacial acetic acid and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on 10 g of silica gel. The title compound was eluted with 15-20% ethyl acetate / hexane to give 70 mg of the title compound as a crystalline solid (melting point 137.5. (:). Example 5110_ (gR, _3R, 4S) -trans,- Trans-2- (2,2-dioxopentyl 13 · phenylpyrene-di-mandiamine_Afluorenyl) -1- (N_4-heptyl-N- (4-4 ^ _3_tolyl) amine # 某(A))-mouth ratio p each bite -3-endanoic acid The product from Example 5 10B (65 mg, 010 mmol) was dissolved in 1.0 ml of methanol, and sodium hydroxide (01 ml of 5M aqueous solution). After 2 hours, the reaction was warmed to reflux. After 6 hours, the reaction was cooled and the solvent was removed under reduced pressure. The residue was dissolved in water ^ Acid to acidify it. Rinse the aqueous solution with chloroform (3 x 5 ml), then rinse with brine, cover with anhydrous magnesium sulfate to dehydrate, filter and evaporate under reduced pressure. By diluting from The title compound was isolated by freeze-drying in aqueous DFA / ch3cn. IH NMR (CDCl3, 300 MHz) d 0.78_95 (m, 15H), i 〇 heart} 仏 (claw, i2H)

'1.76-2.95 (m, 2H), 2.31 (s, 3H), 3.23-3.33 (m, Gang, 47 · 0.58 (m, ih), 3.6-3 · 75 (m5 2H), 3.80-3.95 ( m, 2H) '4.0:>-4.1 :) (m, iH), 4.7 3 (m, 1H), 5.94 (s, 2H), 6.70-6.80 (m, 2H), 6.82-6.93 (m, 2H) ), 6.96-7.14 (m, 2H). MS (DCI / NH3) m / e 597 (M + H) ten. About c35H49N2F〇5 · 〇〇5 仏 〇.〇 · 8 analysis of TFA 値: c, 63.81: H, 7.30; N, 4.07 Lu Yiyi-(Please read the precautions on the back before filling this page), ^ 1 1.569-552260

AT 5 Meming Instructions (567 R7 46 ° (c 2.7

Example 512A-_ oxygen> Substituted p-bilolone-1 -yl propionate for .1 ¾ liters of hydrochloride, 6.0 M aqueous solution was added to 5.0 ml (40.5 mmol) in η ml of dioxane ) 2-Oxypyrrolidinylpropionitrile in a stirred solution. Then at 110. (: The resulting mixture was refluxed overnight. Then Fe Guxu cooled the reaction mixture to room temperature, and extracted one / in with dichloromethane. The extracts were mixed and washed once with a saturated saline solution and covered with typical water. Sodium sulfate was dehydrated, filtered and evaporated under reduced pressure to give 1.60% (25%) ochre oily acid.

Example 512B 5_ (ϋ .. 代 淀-丨-基) -3-oxo 戍 辕 λ ester by adapting Bram and Vllkas, Bui. Chem soc Fi :, 945 employees of the Central Bureau of Standards of the Ministry of Economic Affairs, $: Co-operative printing -------- clothing — (Please read the instructions on the back of the page; and then fill out this page (1964) to prepare the title compound from the above acid.

Example _5 12C 晞 -5 3 -Acid acquisition Using the procedure described in Example 502, 5_ (2_oxopyrrolidine-570-) This paper applies Chinese National Standard (CNS) A4 specifications (21〇x29 * 7 gong 552 260 A 'Γ 5. Description of the invention (563)' ~ 'ethyl-yl gallate substituted ethyl 3-methylhexanoate to obtain the title compound as an amorphous solid. 1HNMR (CDC13, 300 trillion) Hertz) δ 0.99ΐ (t, J = 7.) Hertz, 3Η) '0.94 (t, J = 7.5 Hertz, 3Η), i.23-1.38 (m, 4H), 1.44-1.60 (111, 41 ^ 2 · 05 (Ή · 9 Hz 2} 1), 212-2.2) (m, 1Η) '2.3 8 (td, J = 4.2 Hz, 8.4 Hz, 211), 2.47- 2-61 (m , LH) '3.17 (dd, J = 6.0 Hz, 8.7 Hz, 2Η), 3 24 (ί, J 2 9 Hz,! Η), 3.32 (t, J = 7.8 Hz, 2Η), 3 38 -34S (m3H) '3.52 (t, J = 9 Hz, 1Η), 3.66 (t, BU 6 9 Hz 1Η), 3 96 (m, 2Η), 4.14 (m, 1Η), 4.38 (brs, 2Η), 5.93 (s, 2Η) '6.74 (d, J = 8.1 Hz, 1H), 6 89 (dd, J = i 8 Hz, 8 l Hz, 1H), 6.87 (d, J = 3 8 Hz, 1H). MS (DCI / NH3) (Μ + Η) τ at m / e 5 16. Analysis and calculation of c2Sh41N3 06 · 1.4 TFA 値: C, 54.78; h, 6.33; N, 6.22. Experiment 値: C, 54.69; Η, 6.33; N, 6.14. Example 5 1 3 A, metacyclopenten-2-yl) ethyl) -4- (7-toluenyltriene-5-some) -1- (N-4-heptyl-N- (4-ylfluorenyl) -Pyrrolidine-3-carboxylic acid printed by the Central Standards Bureau of the Ministry of Economic Affairs, China Industrial Cooperative Co., Ltd .---- Lu Piyi— 丨 (Please read the precautions on the back before filling this page) The procedure described in Example 502, replacing ethyl 3-methylhexanoate with ethyl 5- (1,3-dioxolenyl) -2-oxopentanoate and N-4-heptyl -N · (4-fluoro-3-tolyl) bromoethyl g-amine is used to replace n, n-dibutyl bromoacetamide, and 6-methoxyoxypiperazine is used to replace piperonal to obtain amorphous solid Title compound. 1H NMR (CDC13, 300 MHz) δ 0 93 (br t7 6H), 1.23- 1.47 (m, 8H)? 1.67-2.10 (m, 4H) ^ 2.32 (s, 3H) 7 -571-this Paper size applies Chinese National Standard (CNS) Λ4 specification (210X 297 Gongchu) 552260 A '1 —---——' ~ ^ _______ V. Description of invention (569) 3.16 (t, J = 9 Hz , 1H), 3.60-4.03 (m, 8H), 3.88 (s, 3Η), 4.21 (1 ^, 111), 4.72 (five-fold peak, ^ 6.6 Hz 5111), 4.86 (^, J == 3.6 Hz , IH), 5.93 (s, 2H), 6.49 (s, 1H), 6.61 (s, 1H), 6.96 (m, 2H), 7,08 (t, J = 9 Hz, 1H). MS (DCI / NH3) (M + H wide at m / e 629. Analysis and calculation of C34H45N208f. 1.0 TFA 値: C, 58, 21; H, 6.24; N, 3.77. Experiment 値: C, 58.11; H, 6.11; N, 3.58. 1, trans-2- (2,2-Dimethylpentyl) ^ 1112 ^^-1,3-benzene # m-dioxane-5-yl) · 1- (Ν, Ν- 二 二 XAUlJ Sciakylenyl V pyrrolidine-3-carboxylic acid Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page) Use in Example 502 The procedure described in substituting ethyl 3-methylhexanoate with ethyl 5-methyl-3-oxooctanoate and substituting piperonal with 6.methoxypiperonaldehyde gave the title compound as an amorphous solid. 1H NMR (CDCh, 300 MHz) 30.81 (5, 3 fields, 0.884, 311), 0.86 (11 to 6.9 Hz, 3H), 0.93 (t, J = 6.9 Hz, 3H), 0.96 ( t, J = 6.9 Hz, 3H), 1.09-1.38 (m, 8H), 1.45-1.59 (π54Η), 1.84-2.00 (m, 2Η), 3.15 (dd5 J = 6.9 Hz, 10 · 〇Hz 5 2Η), 3.30-3.42 (m, 3H), 3.72 (t, J 2 10.5 Hz, 1H) '3.86 (t, J = 10.5 Hz, 1H), 3.88 (5, 3 fields, 4.02 ( 4 , Bu 10.0.0 Hz, 1 India, 4.12 ((1,) 2 16.8 Hz, 1H), 4.29 (d, J 2 16.8 Hz, 1H), 4.41 (brm, 1H), 5.94 (s, 1H), 6.52 (d, J = 1, 8 Hz, 1H), 6.67 (d, J = 1.8 Hz, 1H). MS (DCI / NH3) (M + H) 'at m / e 533. About C30H48N2O6 • 0.9 TFA Analysis and calculation 値: c, 60 12: H, 7.76: N, 4.41 -572- The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 public) 552260 Β '5. Description of the invention (570. Experiment値: C, 60.18; H, 7.62; N, 4.33. Example 5 1 5 Good, trans-2- (2,2-dimethylpentyl) ethyl) -4- (2,3-dihydrobenzifurone ^) Di 1- (N, N-di (n-butyl) aminocarbonylmethylpyrrolidin-3-carboxylate to ethyl 3,3-dimethylhexanoate using the procedure described in Example 502 Substituting ethyl 3-methylhexanoate, and replacing pepper with 2,3-dihydrobenzocran-5 -sucrose, by freeze-drying method using CH3CN / TFA / H20 to obtain #crystalline solid Title compound. 1H NMR (300 MHz, CDCh) δ 0.83 (s, 3Η), 0.85 (s, 3H), 0.86 (t, J = 7.2 Hz, 3Η), 0.92 (t, J = 7.2 Hz, 3Η) ), 0.95 (t, J = 7.2 Hz, 3Η), 1.09-1.39 (m, 8Η) '1.44-1.59 (m, 4Η), 1.88 (dd, 15.0, 7.2 Hz, 1H), 2.00 (d , J = 15.0 Hz, 1H), 3.09 (m, 2H), 3.18 (t, J 2 9.0 Hz, 2H), 3.27-3.38 (m, 3H), 3.65-3.95 (m, 2H), 4.05 ( q, J = 10 Hz, 1H), 4 18 (d ,; 16 8 Hz, m), d4.45 (m, 2H), 4.55 (t, J = 9.0 Hz, 2H), 6.70 ( d, J = 8.4 _ ^, lH), 7.04 (dd, J = 8.4, 2.1_g, 1H), 7 23 (brs lH). MS (DCI / NH3) at m / e 501 (M + H: T. About c30H48N2O4 · Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economy -------- · € —— (Please read the note on the back first Please fill in this page) 丨 · 1.05 TFAi analysis and calculation 値: c, 62.14; h, 797; n, 4.51. Experiment 値: C, 62.19; H, 8.00; N, 4.43. Example 5 1 6 4- Di ^ 棊 di 2- (1,3-dioxy "i ring_2_yl) ethyl) -4_ (1_ 曱 [碁 -1,3_1 幷 dioxetene ^ (Team ... Two (N-Butyl) aminocarbonylfluorenyl) -p-biloxo ^ 3- # polyacid uses the procedure described in Example 5 02 to 3,3-dimethyl-3-(1,3- II-573 552260 A? ----------—__ Η 7 V. Description of the Invention (571) — ^ ί Please read the notes on the back before filling in this page) Lactamyl) The ester was substituted with ethyl 3-methylhexanoate, and 6-methoxypiperazine was used to replace piperonal. The title compound was obtained as an amorphous solid by cold drying using CH3CN / TFA / H20. 1H NMR (300 Hz, CDC13) δ 0.93 (t, J 2 7.2 Hz, 3H), 0.94 (t, J 2 7.2 Hz depleted, 0H) '0.95 (s, 3H), 0.96 (s, 3H), 1.31 (six peaks, BU 7 9 Hz, 4H) '1.45 (m, 4H), 1.93 (dd5 15.9, 6.0 Hz, 1H), 2.13 (d, J = 15.9 Hz, 1H), 3.20 (dd, J = 7.7,7.7 Hz, 1H) '26-3.40 (m, 3H), 3.60 (m5 1H), 3.75 -3.86 (m5 3H)' 3.88 (s, 3H), 3.93 4.01 (m, 3H), 4.00-4.11 (m, ih), 4.20 (d, J = 15.WHLlH), 4.37-4.48 (m, 2H), 4.49 (s, 1H) '&gt; .94 (s , 2H), 6.51 (d5 J = 2.i Hz, 1H), 6.64 (d, Bu 2.1 Hz 4, 1H). MS (DCI / NH3) at m / e 563 (M + H) +. About the analysis and calculation of C30H46N2 0 8 · 9 · 9 TFA c: c, 57.41; Η, 7. i i; N, 4.21. Experiment 値: C, 57 35; H, 6 S6; N, 4.05. Example 5 1 7 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Tail diphenyl) ethyl) -4- (1,3-phenylhydrazine-dioxa— ~ Σ ·… yl)-^ ι (N, N-mono (n-butyl) aminomethyl) -pbipyrrosis-3- ¾ acid Using the procedure described in Example 502, 3-methylhexanoic acid was replaced with o-pyroxyphenylpropanoic acid to prepare the above compound as an amorphous solid. iH NiMR (CDCl3,30 (Uii ^ 1) 5 0.85 (t, J = 7; ^^, 3H), 0.91 (t, J = 7 ^, 3H), 110-1.27 (m, 4H), 1.42- 1.60 (m, 4H), 1.72-1.89 (m, il · :), 1.91-2.02 (m, lH), 2.55-2.77 (m, 2H), 2.94 (t, J = 6 Hz, ih), 3.05- 3.30 (m, 6H), 3.59-3.82 (m, 3H), 3.73 (d, J 2 14 Hz, 1H), 3.77 (s, 3H), 5.91 (s, 2hT), ___ -574- Paper The k-scale is applicable to the China National Standard (CNS) Α · 4 specification (21 ×? 97 public power) 552260 Α7 Β * 7 V. Description of the invention (572) 6 · 70 (d5 J = 8 Hz, 1H), 6.78- 6.88 (m, 3H), 6.92 (d, J = 2 Hz, 1H), 7.08-7.19 (m, 2H). MS (DCI / NH3) (M + H) t at m / e 539. Analysis on C31H42N206 Calculate 値: c, 69.12; H, 7.86; N, 5.20. Experimental 値: C5 68 · 89; H, 7.70; N, 4.99. Example 5 1 8 Di-2- (2,2-dimethyl-3- ( E) -Pentenyl) -4- (1-fluorenyl-1,3-phenylfluorenyl-5-pentyl-5 · ylbis (n-butyl) aminocarbonylmethyl v pyrrolidine-3-yl _ Example 518A 4-methyl-3-penten-2-ol under N2 at 0X: a 3.0 M solution of methyl magnesium bromide in diethyl ether, 114 mmol ) Was added dropwise to a stirred solution of 3-fluorenyl-2-butenal (8.7 g, 103 mmol) in 10 ml of tetrahydrofuran. The resulting mixture was allowed to slowly warm to At room temperature, and before stopping with 25 ml of saturated NlCl, stir at room temperature for 1 hour. Distribute the resulting two-phase mixture between ether and water. Rinse the organic layer with brine, dehydrate with anhydrous sulfate, and filter The solvent was removed under reduced pressure to obtain 8.4 g (81%) of a colorless oily alcohol. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) U-2 Fluorenyl di 1: trans-ethyl acetate, 4-methyl-3-penten-2-ol (7.4 g, 74 mmol), triethyl orthoacetate (13.6 mL, 74 mmol) ) And propionic acid (0 28 ml, 37 mmol) and heated DO C for 7 hours. The product was then distilled under normal pressure (200-22.00) to give 5.0 g of crude ester as a colorless mash. .量 适 财 财 关 家 # --- Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 552260 A! __________ V. Description of Invention (573)

Example 518C watt__, trans-2- (2,2 · dimethyl-3- (E) -pentenylmethanyl-1,3-benzophenone__dioxolene_5 _Yl) -1- (N, N-di (n-butyl) aminocarbonylfluorenyl) -coupling ratio p each -3-sharp acid using the procedure described in Example 502 to 3,3-difluorene The title of #crystalline form solid was obtained from TFA / CH3CN by freeze-drying method by trans-ethyl ester of 4-pentenoic acid substituted with 3-fluorenylhexanoic acid and substituted with 6-methoxyoxypiperaldehyde. Compound. 4 NMR (CDC13, 300 MHz) δ 0.92 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H), 0.97 (s, 3H), 0.99 (s, 3H), i. 31 (hexaplex, j = 7.2 Hz, 4H), 1.52 (quintet, J = 7.2 Hz, 4H), 1.58 (d, J = 5.4 Hz, 3H), 1.92 (dd, J = 15.0, 6.6 Hz , M), 2.04 (d, J = 15.0 Hz, 1H), 3.15 (dd, J = 7.8, 7.8 Hz, 1H), 3.30-3.40 (m, 3H), 3.75 (m, 2H), 3.87 ( s, 3H), 3.99 (q, J = 9 Hz, 2H), 4.11-4.30 (m, 3hT), 5.29 (d, J = 15.6 Hz, 1H), 5.38 (dd, J = 15.6, 6 Hz) , IH) '5.94 (s, 2H)' 6.50 (d, J = 1.8 Hz, 1H) '6.63 (d, J = i 8 Hz, 1H). MS (DCI / NH3) at m / e 531 (M ten H) '. Analysis and calculation of 0.95TFA: C, 59.95: H, 7.41; N, 4.38. Experiment 値: C5 60.00; H, 7.33; N, 4.35 〇 Example 5 19 Swallow ...:. Trans_2_ (3pyridyl) ethyl) -4- (1,3-phenylhydrazine-5 _)-: 1- (N ″ N-bis (n-butyl) aminocarbonylfluorenyl) -pyrrolidine Example 519A 3- (2-pyridyl) -propionic acid ____ _576-Applicable to Chinese National Standards &quot; TcNS) Λ4 specification (210 乂 297 hours) &quot; ^-«batch of clothes-(Please read the notes on the back before filling in this page) Order I # 552260 Printed by the staff of the Central Standards Bureau of the Ministry of Economic Affairs

A B7 I _ ________ ____________- — V. Description of the Invention (574) In a 50 ml round bottom flask equipped with a stir bar, place 3- (2-pyridyl) -propanol (1 g, 7.6 mmol) , Water (13 ml) and concentrated sulfuric acid (0.5 g, 5.1 mmol). Within 30 minutes, potassium permanganate (1.8 g, 11.3 μmol) was added to the stirred solution while maintaining the reaction temperature at 50 ° C. After the addition was complete, the mixture was kept at 50 ° C until the color of the reaction mixture turned brown, then heated to 80 ° C for 1 hour and filtered. The filtrate was evaporated to dryness and the desired acid (1.14 g) was quantitatively produced and suitable for the next step without further purification. To prepare a pure acid, in the presence of activated carbon (0.1 g), the residue thus obtained was boiled in ethanol (10 ml) for 5 minutes, filtered and cooled to obtain 3- (2- Pyridyl) -propionic acid (0.88 g, 78%).

Example 519B trans, trans-2- (3- (2-? Pyridyl) ethyl) -4- (1,3-pyrido-dioxo-5-yl) -1- (N, N-bis (n-butyl) aminocarbonylmethyl) -pyrrolidine-3-miao acid Using the procedure described in Example 502, an amorphous solid was isolated by freeze drying from diluted aqueous TFA / CH3CN. The title compound. 1H NMR (CDC13, 300 MHz) δ 8.65 (d, J = 6.0 Hz, iH), 8.06 (t, J = 6.91 Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.5 1 (i, J = 6.91 Hz, 1H), 6.82-6.66 (m, 3H), 5.91 (s, 2H), 4.45 (s, 2H), 4.29-4.18 (m, 1H), 4.04 (dd, J2 20.1 Hertz, 10.5 Hz, 1H), 3.84 (t, J 2 12.6 Hz, 1H), 3.62 (dd, &gt; 13.8, 9.6 Hz, 11 ^), 3.46-3.13 (111, 711), 2.51 (wide band 5 , 2H), 1 60-1.43 (m, 4H), 1.37-1.22 (m, 4H), 0 91 (t, J = 8.4 Hz, 6H). MS (DCI / NH3) m / e 510 (M + H) +. About-577- This paper applies the Chinese National Standard (CNS) A4 specification (210 X 297) for &quot; (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 552260 A &quot; 7 ________ ηη _________________ V. Analysis and Calculation of the Invention Description (S75) C29H39N305 · 1.75TFA 値: C, 55.04; Η, 5.79; N, 5.92. Experiment 値: c, 55.08; Η, 5.64; N, 5.81. Example 520 ij_.S,) R, 4S) -2- (2- (2- (2-oxobilopido-1-yl) ethyl) -4- (1,3-phenylbenzenedioxolan Ene_5-Vj_ (N, N-bis (n-butyl) aminocarbonylmethyl) -pyridine

^-3-fei Example 520A (g_S, 3R, 4S) -2- (2- (2-oxopyrrolidin-1-yl) ethyl) -4- (l, 3-phenylhydrazine heterocyclic ring Pentamidine-5 -yl) -ρ ratio bite-3 -acid acid treatment with (S)-(+)-mandelic acid (0.75 g, 4.93 mmol) in 10 ml ethyl acetate is sufficient from Example 5 12 racemic amine g (3.4 5 g, 8.98 mmol). When a clear solution was formed, hexane was slowly added dropwise and stirred while the solution became a light cloud. Leave the solution: Stir overnight at temperature. The crystals were then collected by filtration and recrystallized twice from ethyl acetate / hexane, yielding 8000 mg (1.70 / 0) of pure salt.

Example 520B C2S ·., 3 oxopyrrolidin-1-yl) ethyltriyl) -MN, N-di (n-butyl) amine 2 ^ Glydine-3-ethyl benzyl acid, N, N-dibutyl bromoacetamide (84 mg, 0.34 mmol) and dipropylpropylamine (98 μl, 0.56 mmol) were added to the pure alginate in CHsCN ( 150 mg, 0.28 mmol) in a stirred solution. Stir at room temperature: stir in the mixture overnight. Then move the risk under reduced pressure 丨 Electricity 丨, ____ _ 578-This paper size is applicable) Specifications (2 丨 〇 乂 297 公 楚)----_____ (Please read the precautions on the back before filling in this Page), 552260 A * 7 ----__ V. Description of the invention (576) ~ ^-^ The crude product was purified by silica gel flash chromatography to obtain the title "0 mg (90% yield)" Compound (Please read the notes on the back before filling this page)

Example 520C Pyrrolidine-1-some) ethyl) -4-Π, 3-benzyl m-bis (n-butyl) aminocarbonylfluorenyl) -pyrrolidine 3- # _ · Utilized in Example 502 The procedure was described to prepare the title compound as an amorphous solid by using the ch3CN / TFA / amplifier's cold drying method. 1h Bandit R (CDCl3, 300 MHz) S0.91 (t, J: 7.5 Hz, 3H), 0.94 (t, J-2.) Hertz, 3H), 1.23-1.38 (m, 4H), 1.44-1.60 (m, 4H), 2.0) (t, J = 6.9 Hz, 2H), 2.12-2.25 (m, 1H), 2.38 (td, J = 4.2 Hz, 8.4 Hz, 2H), 2.47-2.61 (m, 1H ), 3.17 (dd, J = 6.0 Hz, 8.7 Hz, 2H), 3.24 (t, J = 9 Hz, 1H), 3.32 (t, J = 7.8 Hz, 2H), 3.38-3.48 (m, 3H), 3.52 (t, J = 9 Hz, 1H) '乂 66 (1:,! — 6.9 Hz, 1; ^), 3.96 (111, 211), 4.14 (111, 11'1), 4.38 (brs, 2H) , 5.93 (s, 2H), 6.74 (d, J = 8.1 Hz, 1H) Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 6.89 (dd, J = 1.8 Hz, 8.1 Hz, 1H), 6.87 (( 1. Bu 1.8 Hz, 1H). MS (DCI / NH3) (M + H), atm / e516. Analysis and calculation of C28H41N3〇6 • 0.85 TFAFA: c, 58.23; H, 6.89; N, 6.86. Experiment値: C, 58.37; H, 6.90; N, 6.84. Example 52 1 (2S, 3R, 4S) -2- (2- (2-oxopyrrolidin-1-yl) ethyl) -4- (1 , 3-benzene # metadioxol-5-yl) -1- (N-4-heptyl-N- (4-fluoro-3-methyl Phenyl) aminocarbonylfluorenyl) -Bilobbit-3 -Lean acid-579- The size of this paper applies to the Chinese National Standard (CNS) Λ4 specification (210X297g 漦) 552260 Λ7 ----- B * 7 — ~ ------— V. Description of the invention (577) Using the procedure described in Example 502, substituting n, N-4-heptyl_N_ (4_ι ^ _methyl) phenyl-bromoethenylamine N, N-Dibutyl bromoacetamide was obtained by the CH3CN / TFA / H2 0 core cooling / East drying method to obtain the title compound as an amorphous solid. 1HNMR (CDC13, 300 MHz) s0.85_0 98 (m, 6H), 1.22-1.55 (m, 8H), 2.04 (quintet, j = 7.9 Hz, 4H), 2.32 (s, 3H), 2.36 (t, J = 7.9 Hz, 2H), 2.61 ( m, lH), 3.14 (m, lH), 3.25-3.61 (m, 5H), 3.66-3.77 (m, 1Η), 3.79-3.90 (m, 2H), 3.94-2.03 (m, 1H), 4.69 ( Fivefold peak, ρ6.8 Hz, m), 5.95 (s, 2H), 6,71 (s, 2H), 6.78 (s, lH), 6.93-7.13 (m, 3H); MS (DCI / NH3) atm / e610 (M + Hr. Analysis and calculation of CwHqNsOA.1.45 TFA 値: C, 57.18; H, 5.91; N, 5.42. Experiment 値: C5 57.20; H, 5.62; N, 5.52. Example 522 trans, transpyridyl_yl) ethyl) · 4- (1,3-phenylhydrazine, methanedi-5-enyl) UN, N (n-butyl) amine, chiralmethyl) _? Than! 7 each shout q

Example 522A 3-(1 口 口 口 口 基) _ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Propionic Acid --------— (Please read the precautions on the back before filling in this page to install In a 10 ml round-bottomed flask with a condenser and a stir bar, Ejun (0.50 g '7.3¾ mol), propionic acid (0.50 ml, 7.3 mmol), and triethylamine (3 ml) were placed. The reaction mixture was refluxed for 6 hours. After removing diethylamine, the viscous oil was dehydrated for 12 hours in a high level of air to quantitatively produce the desired acid (1.0 g), suitable for the next step, without Need further purification.-580- This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210X 297 KRW) 552260 A. V. Description of the invention (578)

Example 522B (Please read the precautions on the back before filling in this page. Inverse, trans_2- (2- (1-pyrazolyl) ethyl) -4- (1,3 · phenylhydrazone dioxolane Alken-5-yl) -MN, N-di (n-butyl) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid. Using the procedure described in Example 502, lyophilization was performed from the diluted water The title compound was isolated as an amorphous solid in TFA / CH3CN. iHNMR (CDCl3, 300 MHz) 57.56 (d, J = 3.0 Hz, 1H), 7.50 (d, J = 3 Hz, 1H), 6.83-6.66 (m, 3H), 6.28 (t, J = 3 Hz, 1H), 591 (s, 2H), 4.55-3.98 (m, 6H), 3.83-3.72 (t, J-2 10.5 Hz, 1H), 3.61-3.40 (t, J-2 10.5 Hz, 1H),

3.36-3.12 (m, 5H), 2.69-2 · 43 (m, 2H), 1.59-1.42 (m, 4H), 1.38-1.21 (m, 4H), 0.91 (t, J = 7.5 Hz, 6H ). MS (DCI / NH3) at m / e 499 (M + H) +. Analysis and calculation of C27H38N40.5 · 0.75 TFAFA: C, 58.60; H, 6.69; N, 9.59. Experiment 値: C, 58.53; H, 6.45; N, 9.67. Example 523 Trans, trans-2- (4-fluorenylphenyl) -4- (i, 3-benzo-dioxol-5-ylbutyl-N- (3-hydroxypropyl) amine Example) Carboxymethyl 1-pyrrolidin-3-carboxylic acid Example 523 Α Ν · Butyl-N (3-trispropyl) -amine Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy 50 ml (0.35 mmol) 1.0 M LiA1H4 in diethylpyrene was added to a solution of 15.9 g (100 mmol) of 3-N- (n-butyl) aminopropionate in 150 ml of diethyl ether at 0 ° C. In the minimum reflow. The mixture was stirred at 0 ° C for 2.25 hours, and 1.9 ml of H2O, 1.9 ml of 15% weight / volume NaOH (acn and 5.7 ml of H2O-531) were added dropwise by continuous dropwise addition-this paper size applies Chinese national standards ( CNS) Λ4 specification (210X 297 public power) 552260

A B7 Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of Invention (579) Stop it. After stirring for 30 minutes, the salts were filtered and washed with diethyl ether, and then the filtrate was concentrated to 1.3 g (86%) of pale yellow.

Example 523B Acetyl) -chloroacetamide, a solution of 171 g (10.0 mmol) of chloroacetic anhydride in 10 ml of ethyl acetate was added to 1 · 3 1 of 20 ml of ethyl acetate. G (1 .0 mmol) of N-butyl, N- (3-hydroxypropyl) amine in an ice-cold solution. The mixture was stirred and gradually warmed to room temperature over 18 hours. The reaction was extracted with η20 (1 X 50 mL), saturated NaHC03 (aq) (2 x 50 mL), and brine (1 X 50 mL), dried over MgSCU, filtered, and concentrated to an oil. The product was purified by silica gel chromatography and washed with 80 · 20 hexane: ethyl acetate to give 723 mg (35%) of a pale yellow oil.

Example 523C Branch ——: Transpyrene) -4- (1,3-Benzo-dioxin VI · 丨 (N-butyl-N- (3-hydroxypropyl) amino) carbonylpyrrolidine Use the procedure described in Example 1D to replace N-propylbromoacetamide with N-butyl-NV3, Zhigongv Zhaopropyl) -chloroacetamide, and add DMSO as the The title compound was obtained from the dilute amidine by lyophilization. It was isolated from Tf / CHUCN of rhenium. 1H NMR (CD3OD, 300 MHz, p ^ 〇0.78 -0.95 (m, 3H) '1 · 00-1.80 (m, 4H), 2.8-3.65 ^-, i 5 Η), 3.80 (d, J = 1.5 Hz, 2 兹), 5.93 (s, 2H), 6.72-7 〇w vm? 5H), 7.33-7.40 (m, 2H). MS (DCI / NH3) at m / e 513 (m + h), Analysis and calculation of C2SH36N207 · 1.6 H2〇 H: C, 62

• ~ 'H 7.30; N, 5.17. Experiment 値: C, 62.04; H, 7.21; n J '' ^ * 〇8 〇- 582- This paper size applies to China National Standard (CNS) A4 specification (210X 297 cm) (Please read the notes on the back first Refill Ist page) ►Binding 552260 A * hi Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the Invention (580) t 524 dimethyldimethoxyphenyl) -4- (1,3-Mo # Inter-dioxane ζ} ζ1 [[(N-propyl-N-propoxyamine) number of methyl 1-pyrrolidin-3- # age example 524Α N-Boc-O-bromine · propyl O-allyl hydroxylamine hydrochloride hydrate (5.0 g) was dissolved in Thf (15 liters). The solution was cooled to 0 ° C in an ice bath. Diisopropylethylamine (8¾ liters) was added Di-tertiary acid di-tertiary-butanone (100 g). The mixture was stirred for 1 hour at 0.0, the ice bath was removed at this time, and the reaction was allowed to warm to room temperature 'and Stir overnight. Remove THF in the air, and dissolve the residue in EtOAc (25 ^: liter) with water (1 X 50 mL), saturated sodium bicarbonate solution (3 X 50 mL), 1N phosphoric acid ( 3 X 50 ml) and saline (1 X 50 ml) The organic layer was dehydrated with sodium sulfate, and evaporated to give a pale yellow oil (6.5), which was used directly without any further purification. Example 524B N-Boc-N-propyl-〇-propylpropyl light Amine The N-Boc-O-fluorenylpropyl obtained from the above procedure was dissolved in anhydrous THF (25 ml) via amine (6.5 g), and the solution was cooled to 0. 0 in an ice bath. Within 5 minutes Sodium hydride (1.5 g, 60% dispersant in oil) was added in portions. The resulting mixture was stirred at 0 C for 30 minutes. Buprene (3.8 ml) was added dropwise to the mixture. The reaction was stirred at 0 ° C for 1 hour, and then stirred overnight at room temperature. The THF was removed in the air, and the residue was dissolved in EtoAc (50 mL) and saturated with water (1 X 50 mL). Sodium bicarbonate falling liquid (3 X 50 ml), 1N phosphoric acid (3 X 50 ml), and brine (1 -583- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297); (Α ) (Please read the precautions on the back before filling in this page.—ΐφ 装 、 11 .I-I- 8 I I ------ I ------- 552260 Λ --______ __________________ _________ 5. Description of the invention (581) x 50 ml) Rinse, dehydrate the organic layer with sodium sulfate, evaporate to obtain a pale yellow oil, purify on silica gel by flash chromatography, and wash with 5% EtOAc / hexane. It was stripped to give the title compound (6.0 g) as a colorless oil. Example 524 N-Boc-N-propyl-N-propoxyamine N-Boc-N-propyl-0-propylpropylchiamine (60 g) was dissolved in EtoAc (100 ml) )in. Palladium on carbon (0.5 g) was added and the mixture was washed with nitrogen. The nitrogen line was replaced with a hydrogen balloon, and the mixture was stirred at room temperature for 6 hours. The catalyst was removed by filtration through diatomaceous earth, and the solvent was removed in the air to obtain a yellow oil, which was purified by flash chromatography on silica gel, eluting with 5% EtOAc / hexane to give a colorless oil. The title compound (58 g).

Example 524D N-propyl-N-propoxyamine hydrogen hydride &gt; ^ 〇 (^ ~ propyl- &gt; 1-propoxyamine (5.8 g) was dissolved in 41 ^ 11 (: 1/2 Oxygen ring (10 ml) and stirred at room temperature for 7 hours. Remove the eluent in the air, and triturate the residue with diethylamidine. Collect the resulting yellow solid (2.1 g by filtration ), And rinse it with diethyl ether.

Example 524E Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (Please read the precautions on the back before filling out this page. Order N-propyl-N-propoxy-bromoacetamide The amine (0.30 g) was dissolved in acetonitrile and cooled to -20 ° C. Pyridine (02 ml) was added. Ethyl bromide bromide (0 15 g) was added dropwise over 5 minutes. -2 (KC the solution was stirred for 30 minutes. The ice bath was removed and the solution was stirred at main / η for 6 hours. The solvent was removed in the air and the residue was dissolved in EtOAc (50 mL) with water (1 X 25 ml), -584- Printed by the Central Bureau of Standards of the Ministry of Economic Affairs, Co-operative Society, printed 552260 _________ B7 V. Description of the invention (582) ~ ^ 1N phosphoric acid (3 X 25 ml) and saline 0 25 ml) The organic layer was dehydrated with sodium sulfate and evaporated to give a dark orange-red oil (0.35 g). The product was a mixture of chloro- and bromoacetamide in a ratio of about 3: 1.

Example 524F t-2-2 (4-. Fluorene-oxophenyl, 3-phenylfluorene-dichlorocyclopentan-5-yl Iil = [(N-propyl 4. ·· -.Ν- (3- Hydroxypropyl) amino) carbonylmethylpyrrolidine ^ dipic acid was prepared according to the procedure of Example 523C, using N-propylpropoxy_ / ethylethylamine and 2- (4-methoxyphenyl) -4- (1,3-Benzo-dioxol-5-yl) -pyrrolidine-3-carboxylic acid ethyl ester. The crude product was purified by preparing HpLC (Vydac m (: 18)) to 10 -70% gradient gradient of CHgCN in 0 %% TFA

. The rich fraction was freeze-dried to obtain the product as a white solid. !! H NMR (CDC13, 3 00 MHz) δ 0.87 (m, 6H, J = 8 Hz), 1.49 (m, 2H, J = 8 Hz), 1.61 (m, 2H, J = 8 Hz), 3 55 (m, 6H), 3.80 (m, 2H), 3.81 (s, 3H), 4.00 (m, 2H), 413 (d, 2H, ㈣ 7 Hz), 5.96 (s, 2H), 6.77 (d, 1H) , ㈣Hertz), 6.90 (m, 7.05 (d, 1H, Hertz), 7.44 (d, 2H, J = 9 Hertz). (DCI / NH3) m / e 499 (M + H) +. About C27h34N2. 7 · Working time: C, 55.57; H, 5.58; N, 4.41. Experiment 値: c, 55 59; H 5.58: n, 4.55. (Please read the precautions on the back before filling in this Page)-Binding example 525

Example 525A N-butyl-N- (2-hydroxyethyl) -amine -585- Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 552260

A _ B 'V. Description of the invention (583)' In a thick-walled glass tube, condense 5 ml (100 millimolar) of ethylene oxide to -78 C ° Add 12.5 ml (120¾ Moore) to it ) Butylamine and seal the test tube. The resulting solution was allowed to heat to 50 ° C for 18 hours in an oil bath. The unreacted reagent was removed by evaporation to obtain the title compound. tiH 525B ^ __ ^ ^ ^ acetamide In 500 mg of N-butyl, N-2-hydroxyethylamine, 2 ml of thionyl chloride was added dropwise. After the initial reaction had stopped, the reaction was stirred for minutes and then concentrated to an oil. Adding diethyl ether and evaporating it will help to remove sulfite g and produce chlorine. The residue was dissolved in 10 ml of DMF and 1.0 g (16 mmol) of sodium azide was added. The reaction was stirred at 75 ° C for 2 hours, then poured into 50 ml of 0.6 M NaHC03 (aq) and extracted with diethyl ether (3 x 15 ml). The mixed ether layer was back-extracted with brine (1 X 15 ml), dried over MgS04 and filtered. To this ether solution was added 850 mg (4.97 mmol) of acetic anhydride. The reaction was stirred for 10 minutes and then concentrated to an oil. It was dissolved in 0 ml of saturated NaHC03 (aq) and extracted with diacetic acid (3 X 5 ml). The mixed ether layer was back-extracted with brine (1 X 5 mL), dried over MgS04, filtered and concentrated to an oil. Purified by silica gel chromatography, eluting with 30% ethyl acetate: hexane to give 161 mg (17%) of an oil.

Example 525C Phenyldimethoxyphenyl) -4-Π, 3-benzyldioxol-5-yl lliJly-butyl-N- (2-aminoethyl) amino) carbonylmethyl μ Pyrrolidine-3-carboxylic acid According to the procedure of Example 523C, N-butyl-N- (2-azidoethyl) -chloroethanamine and 2- (4-methoxyphenyl) -4- (1 , 3-benzyldioxane-5-yl)-_____-583 _ i Applicable paper size? (CNS) public ^-(Please read the precautions on the back before filling out this page} 1 Packing,-&quot; 552260 Printed by Shelley Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs: B / V. Description of the Invention (584) Pyrrolidine-3-carboxylic acid ethyl ester coupling. Chromatography of the crude product on silica gel, using 4 0% eluted with EtOAc in hexane. The product was dissolved in ethanol and an aqueous solution of sodium hydroxide 2 and stirred at room temperature for 3 hours. The solution was concentrated in the air and water was added. Extraction with ether The mixture was acidified to pH 4 with H 3 PO 4 and extracted with Et0Ac. The later organic extract was washed with brine and dried over NajO 4. Stacked at 100 mg (0 mmol) To the nitride was added 1 ml of HCl (aq &gt;, 0.5 ml Oxygen ring and 50% 10% Pd-C. The refractory liquid was stirred at 1 atmosphere of h2 for 5 hours, then filtered and concentrated to a white solid. The product was purified via hPLC to 0 to 70% at 0.1 Ch3CN gradient elution in% aqueous TFA gave the title compound as its TFA salt. 1; H nmr, CD30D, 300 MHz) δ 0.92 (t, J = 7.0 Hz, 3H), 0.96 (t , Rotamer), 1.23 (m, 2H), 1.41 (m, 2H), 3.06 (m, 4H), 3.39 (m, 2H), 3.69 (m, 2H), 3.84 (s, 3H), 3.94 (m, 3H) '4.18 (m, 2 H), 5.05 (bd, J = 10.7 Hz, 1H), 5.98 (s, 2H)' 6.84 (d, J = 7.7 Hz, 1H), 6.93 (dd , J = 1.8, 8.1 Hz, 1H), 7.05 (m, 3H), 7.56 (m, 2H). MS (DCI / NH3) at m / e 498 (Μ + ΗΓ. Analysis on c27H35N306 · 3.15 TFA Calculate 値: c, 46.68; H, 4.49; N, 4.90. Experimental 値: C, 46.61; H, 4.73; N, 4.79. Example 526 Radonyl phenyl) -4- (1,3-benzene hydrazone) Dioxopentene-5-some &quot;-~ '---'-) ~ LzlXN -Butyl-N- (3-Aminoamido) waist group) Tibetan methyl Ⅰ-p ratio p each disease -3-chinic acid will be 17 ml Sulfasulfonium chloride and 39 ml of triethylamine, added to 1 ml of -587- for China) Specifications (Xinxin 7 Gong) — '— --------—— (Please read the back (Please fill in this page again)

1T i · 552260 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the Invention (585) Example 523C compound (100 g, 019 Shinichi, I 'Mao Wu) in dichloromethane in ice-cold -In solution. The mixture was stirred for 20 minutes, then diluted with 5 a liter of chloromethane, extracted once with 5 ml of water, and then added: "% H3P04, and then 5% ammonium hydroxide (1 x 2 5 ml 2 : 2 x ml), rinsed with MgS04, filtered and concentrated to oil. 65 mg (10 mmol) of sodium azide was added to μ 亳 g (0.13 耄) in dmlf Mol) in a solution of formic acid salt. The mixture was mixed at 500% for 1 hour, then poured into 10 ml of water, and extracted with ^ ml). Back-extracted with brine (... ml) and mixed with MgS 〇4 dehydrated, filtered and concentrated to an oil. Purified by silica gel chromatography, eluting with 60:40 hexane: ethyl acetate to give 57 mg of colorless oil. The product was dissolved in ethanol and 2.5N hydrogen in water. In a solution of sodium oxide, and stirred at 1: 3 for 3 hours. The solution was concentrated in the air and water was added. The mixture was extracted with ethyl acetate; the liquid layer was acidified to pH 4 with IN HsPO4, and extracted with EtOAc. The subsequent organic extracts were washed with brine and dried over NadO4. To this azide was added 1 ml of H Cl (aq), 0.5 ml of dioxane, and 5 mg of 10% pd_c. The suspension was stirred for 5 hours under 1 atmosphere of H2, then filtered and concentrated to a white solid. The product was purified via HPLC from 0 to A gradient elution of 70/100 in aqueous 100% TFA gave the title compound as its TFA salt. H (D6-DMS0, 3 00 MHz) 3 0.85 (obvious q, 6.8 Hz, 3H), 1.17 (m, 2H), 1.30 (m, 2H), 1.67 (m, 2H), 2.71 (m, 2H), 3.04 (m, 1H), 3.21 (m, 3H) ), 3.45 (m, 1Η), 3.75 (m, 3H), 3.97 (s, 3H), 3.85-4.80 (broadband m, 3H) -588- This paper size applies to the Chinese National Standard (CNS) Λ4 specifications (Please read the precautions on the back before filling out this page) I Pack—— 1 · Printed by the Consumers and Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 552260 5. Description of the invention (586), 6.03 (m, 2H), 6.87 (dd, Bu 1.4, 8.1 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 7.16 (m, 1H), 7.55 (m, 2H), 7.72 (m5 2H), 7.85 (m, 1H) ; MS (DCI / NH3) (M + H) + at m / e 512. About C28H37N306. 3.0 TFA Zhi: C5 47.84; H, 4.72; N, 4.92. Experiment 値: C5 47.86; Η, 4.75; N, 4.97 〇 Example 527 trans, trans-2- (4-methoxypen cover with 'd, 3 · phenylhydrazone dioxol-5-yl ) -W (N-butylaminopropyl) amino) carbonylmethylpyrrolidine-3-carboxylic acid

Example 527A: Bromopropyl) bromoacetamide. 3 ml of 48% HBr (aq) and 1.5 ml of concentrated H2S04 were added to 1.50 g (11.4 mmol) of N-butyl) propylamine. The reaction was stirred at reflux for 3 hours, then cooled to room temperature and stirred for 22 hours. The mixture was poured onto 50 ml of ice, and the solution was treated with 50 ml of 2M NaOH (aq). The basic solution was extracted with ethyl acetate (3 X 25 ml), and the mixed ethyl acetate layer was back-extracted with brine (1 X 2 5 ml), dehydrated and filtered. 3 ml of triethylamine was added to the ice-cold ethyl acetate solution, and then 1.5 ml of acetamidine bromide in 3.5 ml of ethyl acetate was added. The reaction was stirred at 0 ° C for 30 minutes, and then extracted with iM HCl (aq) (2 X 25 mL), saturated NaHC03 (aq) (1 X 25 mL), and brine (1 X 25 mL). The organic layer was dried over MgS04, filtered and concentrated to an oil. Purified by 甴 silica gel chromatography, washed with 30% ethyl acetate in hexane, and obtained -589- ^ Zhang scale applicable to China's national standard (CNS) λ &quot; ^ Γ (210X 297) while --- -(Please read the precautions on the back before filling out this page-Binding · Ordering 552260 Λ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (587) 1.47 g of colorless oil. Example 527B Anti-^^ (4-Methoxyphenyl) -4- (1,3-phenylhydrazinedioxo) -1-l-N-butyl-N- (3-bromopropyl) amino) carbonylmethyl according to Example 5 2 ： &Gt; The private order of C 'will be N-butyl-N-(3-Mo Liangyi), stinky amine and 2_ (4- -oxophenyl) -4- (1,3-phenylhydrazine dioxo Cyclopentamidine · 5) Coupling ethyl pyrrolidine-3-carboxylate. The crude product was chromatographed on silica gel, eluting with 40% EtOAc in tritium. Example 527C group ..., trans-2_11 dimethoxybenzene D_4- (l, 3 · phenylhydrazone dioxane-butyl roll-N- (3_monomethylaminopropyl) amine roll) cleavage group ι_ρ Hiramaki 勹 ~~-Carboxylic acid 1.2 ml of 2.0 M Me2NH in THF was added to 400 ml (0.6663 mmol) of the compound of Example 527B in 4 ml of non-EtOH. The reaction was heated to 50 ° C for 3 hours, and then stirred at room temperature for 18 hours. The mixture was concentrated and then re-concentrated from CHsCN to remove most of the triamine. The product was purified by silica gel chromatography and washed with about 2 (1) liters of crushed gel with 9: 1 Ch2ci2: MeOH to give the ethyl ester. The conversion product was decomposed in ethanol and an aqueous 2.5N sodium hydroxide solution, and stirred at room temperature for 3 hours. The solution was concentrated in the air and water was added. The mixture was extracted with Yijun; the liquid layer was acidified to pH 4 with IN HsPCU, and the product was purified by preparative HPLC 3 4 NMR (CD30D, 300 MHz) δ 0.92 (t, J = 7.0 Hz 3H) , 122 (m, 2H), 139 (m, 2H), l9〇§1. Please read the notes on the back before filling in this page. J -pack-, order- 590- Scale ((\) 552260 Λ 7 --B7 V. Description of the invention (S88) (m, 2Η), 2.87 (s, 6Η), 3.07 (m, 4Η), 3.24 (m5 1Η), 3.43 (m, 1H ), 3.62 (m, 1H), 3.84 (s, 3H), 3.88 (m, 3H), 4.07 (m, lH), 4.17 (m, lH), 4.97 (m, lH), 5.97 ( s, 2H), 6.83 (d, Jr = 8.1 Hz, ih), 6.93 (dd, J = 1.7, 8.1 Hz, 1H), 7.05 (m, 3H), 7.53 (m, 2H). MS (DCI / NH3 ) at m / e 540 (M + H) —. Calculate the points of C3〇H41N3〇6 2.95TFA 値 · c, 49.22; Η, 5.06; N, 4.80. Experiment 値: C, 49 i6; H , 5 · 11; N, 4.62. 528 l ~ LA-2- (4-fluorene), Π, 3 · benzo-dioxolane-5-butyl-N- ( 3-trimethylammonylpropyl) amino) carbonylfluorene 1-groan m acid was prepared according to the procedure of Example 527C Substituted in aqueous MesN

Me2NH. 4 NMR (CD30D, 300 MHz) δ 0.91 (Hi, 3H), 1.24 (m, 2H), 1.40 (m, 2H), 1.99 (m, 2H), 3.13 (s, 9H), 3.18 (s , Rotational isomers), 3 20 (m, 3H), 3 39 (m, 4H), 3.72 (m, iH), 3.84 (s, 3H), 4.03 (m, 3H), 4.35 (m, 1H) , 5.19 (m, 1H), 5,9 7 (s, 2H), 6.84 (d, J = Hertz, 1H), 6.96 ((14 &gt; 1.7, 7.9 Hertz, 111), 7.10 (111, 311), 7.62 (111, 2H). MS (DCI / NH3) at m / e 554 (M + H) ~. Analysis and calculation of C31H44N3〇6. 〇H20 · 1.6 5 TFA 値: C5 47.25: H, 4.96; N , 4.32. Experiment 値: c, 47.25; H, 4.74: N, 4.75. Example 529 Phenyldioxobenzyl) -4- (1,3-phenylhydrazone diazacyclopentene-5- 碁_ hllKNiTj. -N- (4-Aminobutyl) amino) carbonylmethyl 1-pyrrolidin-3-carboxylic acid-591-This paper size applies to Chinese National Standard (CNS) Λ4 specification (21〇21297) (Interesting) -------- · $ —, (Please read the notes on the back before filling out this page) Ordered by the Central Bureau of Standards of the Ministry of Economic Affairs-Industrial and Consumer Cooperatives Printed 552260 Printing

A V. Description of the invention (589) Example 5jjA ----------- nj Allow 81 g (110 mmol) of n-butylamine and 50 g of methylbenzene to be refluxed in 50 ml of methylbenzene under nitrogen pressure and A solution of 8.6 grams of diacetic acid for 50 hours. Moving in the air = volatile solvents. 120 mg (120 mmol) of dibal (25% by weight) was added to a solution of 3.18 g (20 mmol) of 50 mg of toluene in 50 ml of toluene. The solution was heated to 70 r and stirred for 8 hours. After cooling to 0 ° C, the reaction was stopped with methanol (using a solution containing DI / 3 of DI / 3 content), and then a saturated solution of Rochelle's salt was added. The mixture was extracted twice with EtOAc; the organic extracts were washed with brine and covered with Na 2 SO 4 tax. t 529 ^ N-Butyl phase I re-chloracetamide added ice-cold bite (2 ml) to 0.58 g (4 mmol) of N-butylbutyl) -amine in 10 liters of EtOAc in ice-cold In solution. In this solution, 0.769 g (4.5 mmol) of chloroacetic anhydride was added in small portions. The reaction mixture was allowed to stir at 0 ° C for 5 hours and then allowed to warm to room temperature. Bicarbonate was added and the resulting mixture was extracted with EtO Ac. Rinse the organic layer with water and brine. The crude material was purified by column chromatography.

t M 529CI and trans-2- (4 :: U ^ phenyl) -4- (1 ^ -phenylhydrazone dicyclopenten-5-yl 1-[[N-butyl-Nλ (4- Butyl) Pyridyl) 蕤 methyl bilobita-3 -chitoic acid § | _ According to the procedure of Example 52SC, Jiang N _ butyl hydroxybutyl) _ chloroethyl 醯 human paper music scale applicable Chinese national standard () specifications ( 210 × 297 public money ------ IT ------ (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 552260 A7 ______ B7 V. Description of Invention (590 ) Amine is coupled with 2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxolidine) _pyramine-3. It is coupled to acetol Analyze the crude product.

Example 529D trans, trans-2- (4-fluorenoxyphenyl) -4- (1,3-phenylhydrazone dioxolene-5-ylbutyl-N- (4-bromobutyl) amine Carboxymethylcarbonylpyrrolidine-3-carboxylic acid ethyl. 0.086 (1 mmol) bell bromide and 0 120 ml (0.66 mmol) of PBr3 were added to 0.180 g (0.33) in 2 ml of DMF. Millimoles) in solution of the compound of Example 529C. The reaction mixture was allowed to stir for 2 hours at 0x: and allowed to warm to room temperature. Bicarbonate was added, and the resulting mixture was extracted with e t o a c. The organic layer was rinsed with water and brine. The crude material was purified by column chromatography.

Example 529E See, Trans-Methoxyphenyl) -4- (1,3-Benzamidine-1,1-heterocyclopentene · 5-yl LJ-[(N-Di-yl-N-bis (cardioaminobutyl) amino) ) A carbonyl pyrrolidine carboxylic acid 0.1 g of sodium azide was added to a solution of 0.135 g (0.21 mmol) of the compound of Example 529D in 2 ml of DMF. Allow to stand under nitrogen pressure The mixture was stirred for 12 hours and reacted for 18 hours. After adding water, the product was extracted into EtOAc. The crude product (117 mg) was dissolved in 10 liters of ethanol under nitrogen pressure. 45 mg of a 10% catalyst was added thereto. The reaction flask was purged with nitrogen and flushed with hydrogen by placing a balloon filled with hydrogen. The reaction was allowed to stir under hydrogen pressure for 4 hours, and the product was dissolved in ethanol and treated with crushed permafrost. Aqueous 2. $ n sodium oxide solution and stirred at room temperature for 8 hours. Concentrated in the air-593- This paper size is applicable to China National Standard (CNS) A4 specification (210χ) 97 male you) ~ &quot; ~~ '------------ (Please read the precautions on the back before filling out this page) ▼ Stapling and Cooperating with Staff of Central Standards Bureau, Ministry of Economic Affairs Print 552260 A7 ______B7____ V. Description of the invention (591) The solution is added with water. The mixture is extracted with ether, the liquid layer is acidified to pH 4 with IN H3P04, and the product is purified by preparative HPLC. If! NMR (CD30D , 300 MHz) δ 0.90 (t, J = 7 Hz, 3H), 1.10-1.65 (ιη, 6Η), 2.85-2.95 (m, 2H), 3.00-4.10 (m, 14H), 5.50 (d, J = 3 Hz, 2H), 5.97 (s, 2H), 6.82 (d, J = 8 Hz, 1H), 6.91 (dd, J = 7 Hz, 1H), 7.00-7.06 ( m, 3H), 7.45-7.55 (m, 2H). MS (DCI / NH3) at m / e 526 (M + H) +. Analysis and calculation of € 29! 139! ^ 3〇6 · 2.2TFA 値: C, 51.75; H, 5.35; N, 5.41. Experiment 値: C, 51.75; Η, 5.31; N, 5.30. Example 530 trans, trans-2- (4-methoxyphenyl) -4- (1 , 3-Benzamidine-dioxaporyl-fluoren-5-ylbutyl-N- (4-dimethylaminobutyl) amino) carbonylmethyl] -pyrrolidine-3-acid use example 527C Procedure, the title compound was prepared from the compound of Example 529D. 1HNMR (CD3OD, 300 MHz) 50.90 (dt, J = 7 Hz, 3H), 1.1-1.75 (m, 8H), 2.75 (d, J = 7 Hz (6H), 3.0-4.25 (m, 16H), 5.97 (s, 2H), 6.8 3 (d, J = 8 Hz, 1H) '6.93 (dd, J = 8 Hz, 1H), 7.02-7.08 ( m, 3H), 7.49-7,56 (m, 2H). MS (DCI / NH3) at m / e 554 (M + H)-. Analysis and calculation of c31H43 N3 06 · 2 · 1 TFA 値: C, 53.31: H, 5.73; N, 5.30. Experiment 値: c, 53.50: H, 5.38: N, 5.34 〇 Example 53 1 allyloxyphenyl) -4 · Π, 3-phenylhydrazine dioxane ^ _5_ylpyridyl) amino group ） Carbonyl 1-pyrrolecarboxylic acid-594- This paper size is applicable to Chinese national standard) A4 size (210X 297 cm) (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 552260 A '__ _— __ίΓ V. Description of the Invention (592) ~ *

Example 53 1A tert-butyl-N · (3-pyridine Vamine Jiang 10 ml glacial acetic acid was added to 941 mg (10 mol) of 3-aminopyridine and 0.9 ml in 30 ml of CH3OH. In a solution of butyraldehyde. Stir the mixture at room temperature for 1 hour 'and then cool the reaction in an ice bath. Add 6 50 0 gram (10. 3 mol) sodium cyanoborohydride. Remove the ice bath The reaction was stirred at room temperature for 4.5 hours. The mixture was poured into 300 mL of OH67m NaOH (aq) and extracted with ethyl acetate (3 X 50 mL). Brine (1 X 50耄) Back extraction of the mixed organic layer, covered with MgSO4 tax, filtered and concentrated to an oil. The product was separated by silica gel chromatography, eluting with 3: 1 ethyl acetate: hexane to obtain 1.18 g (79%) of a colorless solid. Example 53 1B trans'trans-2 '(raw-methoxy ^ yl) -4_ (1,3_phenylhydrazinedioxa-5-pentamin-5-yl) -l- [(NT? Pyridinyl) amino) carbonylmethyl 唉 3_ Junic acid 裉 The compound of Example 5 3 1A was reacted according to the procedure of Example 5 2 3 to give the title compound. 1H NMR (D6-DMSO, 300 MHz) s 0s (t, J = 6.4 Hz, 3H), 1. 15-1.99 (m, 4H), 2.59 (m, 1 Η), 3.05 (m, 2H ), 3.26 (m, 2H), 3.49 (m, 2H), 3.56 (^ = 7 "hertz, 2H), 3.73 (s, 3H), 6.0 (s5 2H), 6.80 (m, 3H), 6.85 (d J 2 8.1 Hz, 1H), 6.98 (m, 2H), 7.04 (m, 1H), 7 41 (dd, J 2 1.4.7 Hz, 8. 1H), 7.58 (m, 1H), 8.36 (bs, 1H), 8.54 (bs5 1H), 12.24 (bs, 1H). MS (DCI / NH3) at m / e 532 (M + H)-. Analytical calculations for C30H33N3〇6 · 0.1 H3P04: C, 66 55; H, 6 20; N, 7.76. Experimental value: C, 66.59; Η, -595- degrees are applicable to China National Standards (CNS) (210; &lt; 297 public ^ ~ &quot;-· $ IT ------ ^ (Please read the note on the back first Please fill in this page again for matters) 552260 Λ * B- V. Description of the invention (593) 6.06; N, 7.60. Example 532 trans, trans-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone) M-dioxol-5-ylbutyl-N- (3-aminofluorenylphenyl) amino) carbonylmethyl 1-pyrrolidin-3-carboxylic acid

Example 532A N-butyl-N- (3-hydroxyamidophenyl) · amine A 3.78 g (45 ml) solid NaHC03 and 2.91 ml (27 mmol) 1-bromobutane were added to 20 ml DMSO 3.69 g (30 mmol) of 3-aminofluorenol in a solution. Allow the reaction to stir at 50 ° C for 18 hours (overnight). The reaction was treated by adding 250 ml of water, and the product was extracted in ethyl acetate. Water was added, and the resulting mixture was extracted with EtoAc. Rinse the organic layer with water and brine.

Example 532B Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) N-butyl-N- (3-hydroxytolyl) -bromoacetamide- 30 millimoles) of pyridine was added to a solution of 3.42 g (I 9.2 millimoles) of the compound of Example 5 3 A in 20 milliliters of toluene. The mixture was cooled to 0 ° C; 4.025 g (20.0 mmol) of bromoethyl bromide (diluted in 5 ml of toluene) was added dropwise. Allow to stir at 0 C: drop the anti / S mixture for 5 hours, then allow to warm to room temperature. A saturated potassium carbonate solution was added, and the mixture was stirred vigorously for 2 hours. The mixture was extracted with EtOAc: and the organic layer was washed with IN H3PO4, water and brine.

Example 5 3 2 C trans, trans-2 _ (4 -methyl milk phenyl) _ 4 _ (1,3 _ each inter-dioxophosphate soil pentafluoride-5 _ base -596-This paper size applies to Chinese national standards (CNS) Λ4 specification (210X 297 mm) 552260 A 'R' V. Description of the invention (594))-1-KN-butyl-N- (3-chloromethylphenyl) amino) carbonylmethyl 1 -Pyrrolidine-3 · ethyl carboxylate According to the procedure of Example 523C, N-butyl-N- (3-hydroxymethylphenyl) -bromoacetamide and 2- (4-methoxyphenyl)- 4- (1,3-Benzamidine-dioxol-5-yl) · pyrrolidine-3-carboxylic acid ethyl ester coupling. The crude product (129 mg) was dissolved in 0.5 ml of DMF and cooled to 0 ° C; 19 mg of LiCi was added, followed by 85 microliters of thionyl chloride. The mixture was allowed to stir for 30 minutes; water was added and the mixture 3 was extracted with EtOAc to rinse the organic extract with brine and dried over Na2S04.

Example 532D Trans, trans-2- (4-fluorenoxyphenyl) -4- (1,3-phenylhydrazone dioxol-5-ylbutyl-N- (3-aminemethylphenyl ) Amino) carbonylcarbonyl1-pyrrolidin-3-carboxylic acid | 1 The compound of Example 532C (182 mg) was dissolved in 1 ml of DMF |. Add two drops of water, followed by 126 mg (2.0 millimoles, 6.5 equivalents) of sodium azide. The resulting solution was heated to 115 ° C for 3 hours. Water I was added and the mixture was extracted with EtOAc. The organic extract was washed with water and brine and dried over Na2S04. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page)

Example 532E trans, trans_2 ~ (4_methoxyepiyl) -4_ (1,3_benzo-meta --- rastandrolol-5 -ylbutyl-N- (3-aminofluorenylphenyl) ) Amine) carbonylpyrrolidine-3-carboxyl. A 50 ml round bottom flask was charged with 0.090 g of tin (II) chloride suspended in 1 ml of acetonitrile. Add triethylamine (0.2 ml), and then add 0.19 milligrams j | j-597- j _ i This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 cm) 552260 μ Β * 7 V. DESCRIPTION OF THE INVENTION (595) liters of sulfur; the reaction mixture turned yellow. The reaction flask was cooled to 0 ° C in an ice bath; 0.185 g of the compound of Example 532D was added in 2 ml of acetonitrile. The mixture was allowed to stir off for 30 minutes. Add acetamidine (10 mL), followed by 10 mL of 2N HC1. The aqueous extract was painted with 4N NaOH and extracted with dichloromethane. The organic layer was rinsed with water and brine. The crude product was dissolved in a solution of ethanol and 2.5N sodium hydroxide in water, and stirred at room temperature for 8 hours. The solution was concentrated in the air and water was added. The mixture was extracted with diethyl ether; the liquid layer was acidified to pH 4 with IN H3P04, and the product was purified by preparative HPLC. 4 NMR (CD3OD, 300 MHz) δ 0.88 (t, J = 7 Hz, 3H), 1.15-1.45 (m, 4H), 3.40 -4.20 (m, 14H), 5.97 (s, 2H), 6.82 (d, J = 8 Hz, 1H), 6.88 (dd, J = 8 Hz, 1H), 6.97-7.20 (m, 5H), 7.40 (d, J = 9 Hz, 2H), 7.56 (d, J = 5 Hz, 2H). MS (DCI / NH3) at m / e 560 (M + ΗΓ. Analysis and calculation of C32H37N30.6. 4.2 TFA 値: C, 46.72; H, 4.00; N, 4.05. Experiment 値: C, 46.66; H, 4.06 : N, 4.00. Example 533 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Anti-trans-2- (4 · methoxyphenyl) -4- (1, 3-Benzamidinedioxol-5-ylbutyl-N- (3-trimethylammoniumfluorenyl) amino) carbonylmethyl 1-pyrrolidin-3-carboxylic acid Trimethylamine solution was added to a stirred solution of 0.128 g of the compound of Example 532C in 0.5 ml of methanol. The mixture was allowed to stir at room temperature for 4 hours under nitrogen pressure. 1N HC1 was added: The liquid layer was washed with ether to cover organic impurities. To azeotrope with toluene-598- This paper size applies Chinese National Standard (CNS) Λ4 specification (210X 297) while 552260 Α · Η · Central Bureau of Standards, Ministry of Economic Affairs Printed by the Consumer Consumption Cooperative. 5. The invention layer (5%) is used to dehydrate the liquid layer, and the residue is dehydrated under high altitude. Produces 0.115 g. IHNMR (300 MHz D6_D MS〇) S〇83 2 7 Hz, 3H), 1.15] .40 (m54H), 2.62 (s, 2H), 3.35 (s 9H), 3.40-3.80 (m, 10H), 4.47 (S, 2H), 6.00 (s, J = 3 Hz, 2H), 6.75-6.90 (m, 3H), 7.25-7.3 7 (m, 2H), 7.45-7.60 (m 3H). MS (DCI / NH3) at m / e 602 (M + H) +. Example 534 Phenyl) -4- (1,3-benzene # methanediazapyridine) Every 2 ^ yl) _ 1 pentanesulfonamido) ethylpyrrole

Example 534A ΐA · 1 ± :, methyl%) phenylfluorenyl ethyl acetate Rinse sodium hydride (17 g of a 60% dispersion in mineral oil) three times with toluene. The powder was suspended in 38 ml of toluene, and 35 ml of diethyl carbonate was added. The mixture was heated to 90 ° and added in 50 ml portions of a solution of 25 g of 3-gas-4-methoxyacetamidone and 50 ml of diacetic acid. Heating was continued for 30 minutes, and then the reaction was cooled to room temperature. Slowly add 50 ml of concentrated HC1 solution in 75 ml of ice water and allow the mixture to settle. The mixture was extracted with toluene; the combined organic extracts were rinsed with brine and bicarbonate solution. The product was dried over Na2s04 and decolorized with activated carbon to give 34.5 g (97%) of the title compound.

Example 534B, 3-Benzo-dioxolene-5-yl) -to-ratio -3-carboxylic acid ethyl ester (Please read the precautions on the back before filling this page)

_-599-552260 A ”B7 V. Description of the invention (597) The compound of Example 534A (12.5 g) and 5- (nitrovinyl) -1,3-phenylhydrazone dioxolene (13.1 g (20% excess) was suspended in a mixture of 75 ml of THF and 13 ml of iPrOH. DBU (0.25 g) was added and the mixture was stirred at room temperature for 30 minutes. An additional 0.1 g of DBU was added and the solution was stirred for 1 hour. Remove the solvent in the air; add xylene with brine containing 3 ml of concentrated HC1. Extract the mixture twice with toluene, remove the organics with MgSOa and dehydrate. Chromatograph the residue on silica gel, elute with CH2C12 75% yield. In 250 ml of EtOAc, the substance (17.4 g) was mixed with 35 g of Raney nickel (rinsed). The mixture was shaken under 4 atmospheres of hydrogen for 18 hours. The mixture was concentrated in the air Solution; the residue was chromatographed on crushed gel, eluting with 4% EtOAc in CH2C12. Yield 10.13 g = 66%. The product was mixed with 26 ml of THF and 50 ml of EtOH; 2.18 g of NaBH3CN, Together with a small amount of bromophenol green as an indicator, add a 1: 2 solution of concentrated HCl / EtOH, In order to maintain the pH at green-yellow; after the color has continued, stir the mixture for an additional 20 minutes. Remove the solvent in the air; stir the residue with the mixture of toluene and KHC03 solution. Mix with water and The organic phase was washed with brine and dehydrated with MgS04. The product was purified by flash chromatography on silica gel and printed with 2: 1 by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling in This page) was eluted with EtOAc / hexanes. This gave 5.92 g (58%) of a 2. · 1 mixture of trans-trans and cis-trans isomers.

Example 534C (211,311,4 5) -2- (3-Fluoro-4-fluorenoxyphenyl) -4- (1,3-phenylhydrazine dioxolane> -b_3-yl)- Mouth-to-mouth bite-match · In the above-dissolved -600 dissolved in 75 ml of dichloromethane and cooled in an ice bath-This paper size applies Chinese National Standard (CNS) Λ · 4 size C 210X 297 male Trend) 552260 B * 7 V. Description of the invention (593) To the amino ester (15.0 g, 38.8 mmol), Boc anhydride (9.30 g, 42.7 mmol) was added. After stirring at room temperature for 2 hours, the solution was concentrated in the air; the residue was dissolved in 50 ml of ethanol and treated with a 3.75 g sodium hydroxide solution in 19 ml of water. The solution was warmed until it completely dissolved. After stirring at room temperature for 2 hours, the solution was concentrated and redissolved in 200 ml of water. It was extracted with 75 ml of diethyl ether. The tritium layer was extracted with 40 ml of water. The mixed liquid phases were acidified with 7.5 g of acetic acid; the mixture was stirred until a solid was formed. The solid was filtered, washed with water, and dissolved in dichloromethane. After dehydration with sodium sulfate, the solution was concentrated, and the residue was recrystallized from 1: 1 ether: hexane, which was printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling in this Page) 15.99 g of product, melting point 200-203 (90% yield). The crude acid was suspended in 80 ml of ethyl acetate and treated with 4.00 g (33.1 mmol) of (S)-(-)-a-fluorenylamine. After heating to dissolve the acid, 80 ml of diethyl ether was added. Scraping with a glass rod caused the product to crystallize. The solid was filtered and rinsed with acetamidine-ethyl acetate solution to obtain 8.22 g (81% yield based on 50% of maximum recovery), melting point 165-168 ° C. After one recrystallization, chiral HPLC analysis using a Regis Whelk-O column showed &gt; 99.5% ee. This salt was dissolved in 500 ml of 36% HC1 in ethanol; a white solid was formed. The suspension obtained by Jiang was heated to 52 Ό 16 hours. After concentrating in the air, the residue was mixed with toluene and stirred with potassium bicarbonate in water for 30 minutes. Toluene was isolated, dried (Na2S04) and concentrated. The residue was chromatographed on silica gel, eluting with 33% hexane-67% ethyl acetate, to give 6.9 g (99%) of the dissociated amino ester. -601-This paper &amp; size applies the Chinese National Standard (CNS) A4 specification (210X 297 cm) 552260 A, B &quot; V. Description of the invention (599)

Example 534D oxetan (2R, 3R, 4S) -2- (3-fluoro-4-fluorenyloxyphenyl) -4- (1,3-phenylamidine Please read the 5 notes on the back before filling in this page -5_yl) _propanyl) ethyl) Ikkiki &lt; -3-: ¾ Ai Ya dissolved the compound of Example 534C in 1,2-dibromoethane (10 ml per 1 g of starting material ); Diisopropylethylamine (1 ml per 1 g of starting material) and Nal (100 mg per 1 g of starting material) were added, and the mixture was stirred at 100 ° C for 1 hour. Toluene was added, and the mixture was rinsed with bicarbonate. The solvent was concentrated and the resulting black residue was chromatographed on silica gel, eluting with 4: 1 hexane-EtOAc to give N- (2-bromoethylpyrrolidine (85-92%). In ethanol (each 1 g of bromine (5 ml), the compound was mixed with n-propylamine (3.5 equivalents) and Nal (10% by weight of bromine) and heated to 80 ° C for 2 hours. Toluene was added and the mixture was washed with bicarbonate , Dehydrate (Na2S04) and concentrate it. Add more toluene and remove it in the air to remove the first cavity 1. Dissolve the residue in heptane and filter to remove a small amount of insoluble matter. Evaporate the solvent, The desired product is obtained (yield 86-93%), which can be used for the next step without further purification. Example 534E 1 _ Wu Shao Wan Shi Yellow Chlorine Ministry of Economic Affairs Central Standards Bureau Staff Consumer Cooperative Co Alkane sulfonic acid, sodium salt (10 g, 57.5 mmol) were placed in a 250 ml round-bottomed flask (allowing space at the top). Add thionyl chloride (20 mmol); give off gas and solids form The mixture was heated to 60 ° C for 3 hours. The solvent was removed in the air; toluene was added, and 2 in order to remove the residue of S0C12. The residue was also between CH2C12 and ice water; the organic layer of Chiang was dehydrated with Na2S0 ^ 1. The crude product was purified by distillation (-602- this paper size Applicable to China National Standard (CNS) A4 specification (210X 297 enthalpy) 552260 A. V. Description of the invention (60Q) Boiling point 54-5 6 3C @ 0.5mmHg), clarified thorium, 61% yield.

Example 534F (211,311,45) -2- (3-Fluoro-4-methoxyphenyl) -4- (1,3-phenylhydrazone-dioxolyl_5_yl) _propyl_ N-Pentyl Burning Continuum) Ethyl) _Kipbilodian-〇- Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economics of the Carboxylic Acid (Please read the precautions on the back before filling this page) The compound (200 mg, 0.43 mmol) was dissolved in 5 ml of CH3CN; 1 10 mg (2 equivalents) of N, N-diisopropylethylamine and 72.8 mg (1.2 equivalents) of 1-pentanesulfonyl chloride were added continuously. , Allow the resulting solution to stir at room temperature for 30 minutes. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc. Rinse the solution with saturated NaHC03 solution, IN H3P04 and brine, dehydrate with Na2S04 and evaporate to obtain yellow, 甴, purify by flash chromatography on silica gel with 40% EtOAc / hexane. The alkane eluted to give 220 mg of product (85%). This ester was dissolved in 5 ml of EtOH, and a solution of NaOH (46 mg, 3 equivalents) in 2 ml of H20 was added thereto. The mixture was stirred at room temperature for 3 hours. The solution was concentrated in low air with low heat (&lt; 40 ° C). Water (10 ml) and acetic acid (50 ml) were added; the ether layer was extracted with 5 ml of water. The mixed aqueous mixture was back-extracted with acetamidine, and then neutralized with cool acid. The solution was extracted twice with ether. The acid was dehydrated (Na2SO4) and concentrated in the air. EtOAc (1 mL) and acetic acid (1 mL) were added to dissolve the product, and hexane was added dropwise to give a white solid. The solid was collected and dehydrated in the air to give 125 mg of the title compound.

Example 534H (2R, 3R, 4S) -2- (3-Fluoro-4-fluorenylphenyl) -4- (i, 3-benzo-dioxolane-603-This paper is applicable to China Standard (CNS) Λ4 specification (210X 297 g t) Description (601-5-ylpropylpentaneamido) ethyl) dipyrrolid-3-carboxylic acid, hydrochloride chloramine is dissolved in iPrOH Medium; a slight excess of HC1 in iPrOH was added and the solution was concentrated in the air. More IPA was added and the solution was concentrated again. The resulting viscous material was stirred with ether overnight to give a white powder, which was collected by filtration and dehydrated in an air oven at 60 ° C overnight. Yield 95%. Example 535 Using the method described in the above example, compound 0 in Table 3C can be prepared.

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189

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(Please read the precautions on the back before writing this page.) -629-Specifications of this paper / 丨] Chinese Garden Standard (CNS) Λ4 specification (210X 297 mm) 552260 A7 B7 V. Description of the invention (627 ) 202 203

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236 237

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(Please read the notes on the back before filling in this page C ·, 11 -635-This paper size is described in the National Garden of China Jujube (CNS) Λ4 specification (210X 297 mm) 552260 A7 B7 V. Description of the invention (633 ) 250 251

(Please read the precautions on the back before filling in this page J,-口 -636- This paper is suitable for size / 丨] China National Standard Apple (CNS) Λ4 specification (210X 297 mm) 552260 A7 B7 V. Description of the invention (634) 258 259

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660- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X 297 Gongchu) 552260 A. R7 V. Description of the invention (658), printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 450 451

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700 701

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762 763

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A * FT V. Description of the invention (825) Example 536 "2S, 3R, 4S] -2-_i2,2-Diamylpentyl) -4- (7-methylazine, bis-dicyclopentane-5 -Yl- (n-butyl) amine with several methyl groups than p

3-carboxylic acid example 5 3 6 A 5,5-dimethyl-3-oxooctanoic acid ethyl ester 3,3-difluorene was prepared using a common procedure by Cahiez et al., Tetrahedron Lett., 3_1 7425 (1990) Ethylhexanoate. A solution of 63.8 g (3 70 mmol) of the compound in 400 ml of ethanol was cooled to 0 ° C, and a solution of 30 g of NaOH in 150 ml of water was added thereto. The resulting solution was warmed to ambient temperature and stirred: stir overnight. Remove the solvent in the air; dissolve the residue in 700 ml of water and extract it with 1: 1 ether / hexane. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out) This page) times. The liquid layer was acidified to p Η 3 with 1N H C1 and extracted twice with hexane. The mixed hexane extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. A sample of 20.2 g (150 mmol) of the crude product was dissolved in 150 ml of medium THF; 27.3 g of 1, Γ-pyrimidine was added in portions to control the evolution of gas. At the same time, 33.4 g of potassium ethylmalonate and 13.4 g of magnesium chloride (a mechanical stirrer on top) were mixed in 350 ml of THF and heated to 50 ° C for 3 hours. The mixture was cooled to ambient temperature and the acidic micosis solution described above was added. The resulting slurry was stirred overnight. Diethyl ether (600 ml), hexane (600 ml) and aqueous 1N phosphoric acid (500 ml) were added, and the mixture was stirred for 30 minutes. Separate the liquid layers; rinse the organics in succession with bicarbonate (2X), water, and brine. The organics were dehydrated with sodium sulfate, filtered and concentrated to obtain 30.2 g (95% yield) of a colorless liquid. -828- This paper scale applies Chinese National Standards (CNS) / \ 4 specifications (210X 297 public trend) ----- The double-printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. This technical standard is applicable to Chinese national standard 552260 5. Invention Instructions (826)

Example 536B: "Methoxybenzodioxolane f 'was mixed with 3-methoxyoxypiperonal (50 g) in 250 liters of acetic acid and 719 units: succinic methane; added 36 Grams of ammonium acetate and the mixture was heated to 50 ° C. for 1 h. Remove the solvent in the air; dissolve the residue in water and stir for 20 minutes. The solution was filtered; the filtrate was washed with water and then with ether to give 51.8 g of a yellow solid.

Example 53 The compound of Example 536A (6.42 g, 30 mol) was 5.79 g of 6C (phenylbenzene, meta-dioxoyl) -pyrrolidine-3- leptate, ethyl f: 0, and THF. The compound of Example 536B was mixed. Add 〇Βυ (〇 5 ^) :, W stir the mixture at ambient temperature for 6 hours, during this period = a ′ w is again, brown, and become homogeneous. The solvent was removed in the air; &lt; L &lt; &quot; &gt; is present in Eto-Ac, and the organic phase was successively dehydrated with sodium sulfate over water with 1N phosphoric acid and salts, filtered, and concentrated. The remaining work was mixed in 50 liters of THF; 2 g of Raney nickel catalyst (continuous ethanol washing) was added, followed by 10 ml of acetic acid. The resulting mixture was hydrogenated at 4 atmospheres of nitrogen until the uptake of hydrogen was stopped (eight'j J hours). The catalyst was removed by wrong filtration; the solvent was bursting out in the air. ^ The residue is dissolved in 90 ml of 2: 1 ethanol / THF: add, add 30 milligrams of green indicator, and then add 30 ml of 1N cyano group in THF = 7 nanometers of wind within 1 hour Concentrated HC1 was added dropwise to maintain PH 値 at π π .¾. The resulting solution was stirred at ambient temperature overnight. Add Carbonic Acid -829- (CNS) A4 Specification (210X 297 Gongchu (Please read the precautions on the back before filling this page)

552260 5 Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

A 发明 ·, description of the invention (827 hydrogen dihydrogen, and remove the eluent in 呉 殳; keep the residue / knife out of water and EtOAc. Rinse the organics with water (2X) and brine. ^ ^ To Baiji phase Covered with sodium sulfate ", filtered and condensed. The crude product was dissolved in 100 ml of ethyl acetate: 10 ml of Hannig ⑽ nig, s) base 'and the solution was warmed to two times. In the air Removal of the solvent gave 5.0 g of a yellow oil.

Example 53 6D Dimethylpentane is covered with terphenyldiphenylpentadiazene-5-pyridyl-5-pyrrolidine-3-carboxamidine. The crude compound of Example 536C (23 g) is mixed with 40 mL of THF. 4 ml of triethylamine were mixed; di-tert-butyl carbonate 2.0 was added, and the mixture was stirred at ambient temperature for 5 hours. The solvent was removed in the air, and the residue was ‘dissolved in 60 milligrams of ethanol. Aqueous sodium hydroxide (10 ml of a 2.5 N solution) was added and the resulting solution was stirred overnight. The solvent was removed in the air; the residue was dissolved in water and extracted with ether. The liquid phase was acidified with aqueous 1N acetic acid and extracted with EtOAc. The organic extract was washed with brine, dried over sodium thiosulfate, filtered and concentrated to give 1.0 g of a colorless oil. In 5 liters of DMF, a sample of this material (0.734 g, 1.58 mmol) was mixed with 0.35 g of pentafluorophenol and 0.364 g of EDAC. The resulting solution was stirred at ambient temperature for 1 hour, then poured into 50 ml of a 0.6 M sodium linate solution and extracted with ether (3 x 15 ml). The mixed ether extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in the air to give a foam, which was dissolved in 5 ml of THF and cooled to 0 ° C. At the same time, 0.418 g (2.37 mmol) of 11-4-benzyl-2-pyrimidinone was mixed with approximately 0.1 mg of acetic acid in 5 ml of butane and cooled to 0 °. C. Joined 830- This paper size applies to Chinese National Standard (CNS) Λ4 specification (210 X 297 cm) (Please read the precautions on the back before filling this page)

552260 A7 V. Description of the invention (828) 3 = (1 collapsed in hexane), to the red end point 乂 Search and turn; 10 minutes at night. The hydrazone solution was transferred to a solution of pentafluorophenyl vinegar, = the solution obtained at 0 ° C was cut for 4 G minutes. The solvent was removed in the air, and the residue was dissolved in bicarbonate and extracted with diethyl ether (3 x 10 liters). The mixed extract was washed with brine, covered with magnesium sulfate, water, filtered, and concentrated and concentrated in the air. On Shi Xijiao, a crude mixture of non-iso-isoisocyanate products was separated by a glittering layer to separate from 4: ^ &gt; 3: κ? Gradient elution with hexane / EtOAc gave 423 mg of the diastereomer moving faster and 389 mg of the diastereomer moving slowly. The faster moving diastereomers were dissolved in 2 ml of a 2.0 M sodium methoxide solution (freshly prepared containing 5% by weight of ethyl acetate) and stirred at ambient temperature for 16 hour. The solvent was removed in the air and the residue was distributed between ether and aqueous 1N sodium hydroxide. The ether layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in the air. The residue was purified by flash chromatography on silica gel, eluting with 4: 1 hexane / EtoAc. The obtained material was dissolved in 5 ml of TFA and stirred at the ambient temperature for 1 hour. The solvent was removed in the air; the residue was suspended in bicarbonate and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in the air to give 98 mg of product.

Example 53 6E

[2S, 3R, 4S1 曱 pentyl) -4- (7-A-Chloro-1,3-jasmine-metacyclopenten-5-yl) -1 di (n-butylacylcarbonylfluorenyl) ) -Ethyl pyrrolidine carboxylate in 3 milligrams of acetic acid, the compound of Example 536D (48 mg) and 35 cypress paper ruler bite. This is used in China National Standards (CNS) Λ4 specification (210X 297 mm) (诮 Please read the precautions on the back, then fill in the clothing page, -mouth 552260 A7 V. Description of the invention (829) grams of the compound of Example 501A; add 0.5 ml to allow the solution to mix overnight at ambient temperature.眞 air ;: check, suitable (please read the precautions on the back before filling this page) so that the residue is distributed in Et0Ac and water-containing m phosphorus 222 :; salt and brine after washing the organic layer 1 and covered with ㈣. The residue was purified by scintillation chromatography and eluted with alkane. The product was dissolved in 4 ml of ethanol; 2. water-containing sodium hydroxide was added to the mixture, and the mixture was stirred at a temperature of W. The solvent was removed from the whole solution; the residue was dissolved in water and extracted with acetic acid. The liquid phase was acidified to pH 3 with aqueous 1N phosphoric acid, and The organic extract was washed with brine, dehydrated with sodium sulfate, filtered and filtered to give a colorless oil. Freeze-dried from acetonitrile / 0.01% water-containing tfa to give a bright white solid in% H NMR (CDCh, 300 MHz) d0.81 (s, 3H), 0.84 (s, 3H), 0.86 (t, j = 6.9 Hz 3H:, 0.93 (t, P6.9 Hz, 3H) 〇96 (t, j 2 6 9 Hz, 3H), I. 09- 1.38 (m, 8H), 1.45-1.59 (m, 4H), 1.84-2.00 (m, 2H: '3.1) (dd, J 2 6.9 Hz, 20.0 Hz 2H), 3 30-3 42 (m 3H: '). 72 (t, J 2 10.5 Hz, 1H), 3.86 (t, J = 10.5 Hz, 1H), J 8 8 (s, 3H), 4.02 (q, J = i〇〇〇Hz, 1H), 4 12 (d, J = 16 s &gt;, »Hao Zhongik .τ f: A ii 卬 ί: Hertz , 1H), 4.29 (d, J = 16.8 Hz, 1H), 4.41 (brm, 1H), 5.94 (s, 1H), 6.52 (d, J = 1.8 Hz, 1H), 6.67 (d, J = 1.8 Hz IS, 1H). MS (ESI) (M + HT at m / e 533. Analysis and calculation of C30H48N20.6.OJ TFA 値: c, 61.57; H, 8.01; N, 4.5 7. Experiment 値: C , 61.59; H, 8.20; N, 4.63. -832- Wood paper dimensions are described in the Chuanxi State National Standards (CNS) Λ4 specification (210X 297 mm) Ministry of. Fire_τ ft and M 552260 A7-^ -_ _ B7 ~ ------- ---- __ __—— ---- V. Description of the invention (83〇) 537

IjS, 3R, 4S1-2- (2,2-dimethyl-pentyl) -4- (i, 3-phenylbenzenedioxo-5-yl) -l- (N, N-di (n: Ding J Aminomethyl) -p Billow

The 537A group 'trans-2- (2,2-di-amylpentyl) -4- (1,3-phenylhydrazine-dichlorohydrazine ")-3-carboxylic acid ethyl ester was prepared according to the procedure of Example 536C above, Substitute the compound 5-(2-nitroethylfluorenyl) -1,3 phenylhydrazine for Example 50 1B to replace 4-methoxy-6- (2-nitrovinyl) -1 , 3-phenylhydrazone dioxolene.

Example 53 7B [2 8,311,451-2- (2,2-Difluorenyl) -4- (1.3-fluorene interoxopentyl 5-yl) -dipyridine-3-carboxyl Ethyl Acetate The compound of Example 53 7A (6.8 g) was dissolved in 100 ml of diethyl ether; a solution of 1.6 g (SH +) -mandelic acid in 60 ml of diethyl ether was added to bring the total volume to about 200 ml, And the solution was seeded. The mixture was stirred slowly overnight. The resulting crystals were collected by filtration and recrystallized from EtOAc / EtoAc to obtain 1.8 g of a white solid. This material was distributed between bicarbonate and diethyl ether; the ether layer was washed with brine, dehydrated with sodium sulfate, filtered, and concentrated in the air to give the enantiomerically pure product (&gt; 98% ee).

Example 53 7C Dimethylpentyl) -4- (7-methylamino-i, 3phenylhydrazine dioxo (n-butyl) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid according to Example 53 6E The procedure was prepared from the compound of Example 53 7B. ιΗ -833 --------- m! (Please read the notes on the back before filling in this page) Order 552260 A7 B7 V. Description of the Invention (831) The person :) &lt; *, printed NMR (CDC13 '300 MHz) {10.80-〇99 (111, 1511), 1.10-1.37 (m, 8H)' 1.43-1.58 (m, 4H), 1.77-1.97 (m, 2H), 3.48-3.12 ( m, 5H), 3.60-3.69 (m? 1H) ^ 3.75-3.86 (m, 1H) '3.95-4.16 (m, 2H), 4.28-4.4 (m, 2H), 5.94 (s5 2H), 6.74 (d , J 2 7.8 Hz, 6 8 (dd, J = 8 丄 i 5 Hz, m), 6.87 (d5 J = 1.8 Hz, 1H). Ms (Apci +) m / e 5〇3 (M + H ) +. Example 53 8J; 2S 'methylpentyl [(ο,% Benzene metadioxolene-yl n-butyl) aminocarbonylmethylpyrrolidine Example 53 8A Butyl-0-allyl Hydroxylamine dissolves 0-endonyl via amine hydrochloride hydrate (5.0 g) in THF (15 liters). The solution is cooled to 0. 0 in an ice bath. Diisopropylethylamine (1 liters) is added) And di-tertiary-butyl dicarbonate (10.0 g). The mixture was stirred at 0 ° C for one hour 'at which time the ice bath was removed and the reaction was allowed to warm to room temperature and stirred overnight. The THF was removed in the air, and the residue was dissolved in EtoAc (2) liters) with water (i x 50 ml), saturated sodium bicarbonate solution (3 x 50 ml), 1N phosphoric acid ( 3 x 50 ml) and saline (i x 50 ml). The organic layer was dehydrated with sodium sulfate and evaporated to give a pale yellow solution (6.5 g). The crude product was dissolved in anhydrous thf (25 ml), and the solution was cooled to 0 in an ice bath. 〇. Sodium hydride (5 5, 60/0 in oil &lt; sub-carrier) was added in portions over five minutes. The resulting Kunsson conformation was dropped for 30 minutes.丨 _Iodobutane (4. 丨 ml) was added dropwise to the mixture 834 L-scale withdrawal 丨 丨] SS home standard (CNS) M specifications (2 丨 0χ 297 mm) (Please read the precautions on the back first Fill in this page again! Order 552260 A7 B7 5. In the description of the invention (832). Stir the reaction at 0 C for 1 hour, then stir at room temperature overnight. Remove TFA in the air and dissolve the residue in Et0AC (50 ml) with water (1 X:> 0 liters), saturated sodium bicarbonate solution (3 x 50 ml), 1N phosphoric acid (3 x 50 ml), and saline (5 x 50 ml) ) Rinse. The organic layer was dehydrated with sodium sulfate and evaporated to give a pale yellow oil, which was purified by flash chromatography on silica gel, eluting with 5% EtoAc / &amp; alkane to give the title as a colorless oil Compound (6.0 g). Example 538B ^ g_oc-N-butyl-〇-propylpropylhydroxylamine The compound of Example 538A (6.0 g) was dissolved in EtOAc (100 ml). 10% carbon-free ( 0.5 g), and the mixture was flushed with nitrogen. The nitrogen line was replaced with hydrogen &amp; parent, and the mixture was stirred at room temperature for 6 hours. By &amp; The catalyst was removed by filtration through a pulverized catalyst, and the solvent was removed in the air. The color method was purified on a silica gel by flash chromatography, and washed with 5% Et〇Ac / caustic to obtain Colorless oil (58 g). A sample (115 g) of the resulting material was dissolved in CHAh (5 ml) and cooled in an ice bath. Trifluoroacetic acid (0 liters) was added and the sandalwood was ice-cold. Stir the solution for two hours. Remove the intact 'caution' in the air. Be careful not to allow the solution to warm to room temperature. The residue contains TFA, which can be used directly without further purification.

Middle-T A (Please read the notes on the back before filling out this page)

f Example 53 8C N-Butyl-N-propoxy-oxethalamide Dissolve the salt of Example 53 8B (0.60 g) in acetonitrile (5 ml), and cool to -20 ° C. Slowly add Hannigan base (55 ml). Add desertified acetamidine (0.5 ml) dropwise over five minutes. Stir the solution at _2〇 3 ()

Paper heart 1 / lU -835 A4 size (210x 297 cm) 552260 A7 B7: r- part Φ j ^ Μ 5. Description of the invention (833) minutes. The ice bath was removed and stirred at room temperature for 6 hours. The solvent was removed in the air, and the residue was dissolved in Et0Ac (50 mL) and rinsed with water (1 X 25 mL), 1N phosphoric acid (3 X 25 mL), and brine (1 X 25 mL). After dehydrating and evaporating the organic layer with sodium sulfate, a dark orange-red color (0.65 g) was obtained, which was used directly without further purification.

Example 53 8D

[j_g, 3R, 4S] -2- (2,2-Dimethylpentanyl phenylhydrazone dioxopropoxy-N-ί n-butyl) amine sulfonium pyrrolidin according to Example 5 3 The procedure of OE reacts the compound of Example 5 37B with the compound of Example 538C. Example 539 H_§ ^ j_g ^, 4S] -2- (2,2-Difluorenyl) -4- (1,3-phenylhydrazone dioxane to propoxy-N_fluorene n-propyl ) Aminocarbonylmethylpyrrolidine-3 "|

Example 539A N Dipropylpropoxybromoacetamide was prepared according to the procedure of Examples 538 A-C, replacing the base butane in Example 538 A with iodopropane.

Example 539B

Iim, 4S] -2- (2,2-Dimethylpentyl V4- (l, 3-benzyl # -dioxolane 1- (N-propoxy-N- "n-butyl) aminecarbonyl曱 Base) -P Billodian-3 2 ^ § | _ According to the procedure of Example 536E, the compound of Example 53 7B and the example ____ -836- &gt; National Standard for Paper Music (CNS) Λ4 Regulation; ΓΓΤ 〇 &lt; 297 Gong Chu Γ

552260 A7 B7 V. Description of the invention (834) 539A Compound reaction. Example 540 f2S, 3R, 4S 2- (2,2-Dimethylpentyl) -4- (7-methoxy-1,3-phenylhydrazinedioxol-5-yl) -1 -(N-propoxy-N- (n-butyl) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid The compound of Example 536D was reacted with the compound of Example 538C according to the procedure of Example 536E. Example 541 f2S, 3R, 4S 2- (2,2 · Dimethylpentyl) -4- (7-methoxy-1,3-benzene # m-dioxol-5-ylpropoxy -N- (n-propyl) aminocarbonylfluorenyl) -pyrrolidine-3-carboxylic acid The compound of Example 536D was reacted with the compound of Example 539A according to the procedure of Example 536E. Example 542 [2S, 3R, 4S] -2_ (2,2-Dimethylpentan-3-yl) -4- (1,3 -epitamidate diamidopentyl-5-yl) -1- (N-propoxy-N- (n-butyl) aminocarbonylfluorenyl) -pyrrolidine-

Examples of 3-carboxylic acids 542A yr 屮 A $ _τ annihilation A · ^ 卬 (please read the precautions on the back before filling this page) trans-3,3 -difluorenyl-4-hexanyl feL ethane Ba 4- Fluorenyl-3-penten-2-ol (7.4 g, 74 mmol), triethyl orthoacetate (3.6 ml, 74 mmol) and propionic acid (0.28 mmol, 3.7 mmol) The mixture was heated to 150 ° C for 7 hours, and then the product was distilled under normal pressure (200-220 ° C) to obtain 5.0 g of a crude ester as a colorless oil. 837- This paper is written in the state of China_National Standards Complete (CNS) A4 specification (210X297 mm) 552260 A7 542B Anti, trans_2_ (2,2-dimethyl; benzene 幷 inter-heterocyclic ring ~ 乂 乂 乂 \ carboxylic acid ethyl Ester 5. Description of the invention (835 The title compound was prepared according to the procedure of substituting the compound of Example 536A and Example 542A for ^. T ° ^ 1 2 3 4- (2-nitroethylfluorenyl) -1,3-phenylhydrazone meta-oxopene substitution example 53 ^ ~ ,, 6C 4-methoxy-6- ( 2-nitroethyl 1,3-benzodilactone.

^^ 1 5 42C

[jj, 3R, 4S dimethyl tablets, w-based) -4- (1,3-phenylhydrazine digas ^-each pyridin-3-carboxylic acid ethyl ester is well known in Example 5 3 7 B, +, , Ma Jian's procedure to dissociate the compound of Example 542B. 0

XjH 542D) -4- (1,3-benzyl and dioxin j | ^ g (Please read the precautions on the back before filling in this page "DING 、-口 5 ^-·

At pentyl bis (n-propyl)) amine

夂 文 € This scale; 丨] The standard of prisoners in prison ([1 ^) / \ 4 specifications (2 丨 0 乂 297mm) 0 1 [Di (n-butyl) aminocarbonyl fluorenyl) -_ 2 Rabbit Γ-3 -carboxyt 3 According to the procedure of Example 536E, the compound of Example 542C was reacted with the compound of Example 4 3 8 C. Example 541 Interstitial Oxygen 552260 A7 _B7 V. Description of the Invention The reaction of the compound of (836) 539A. Example 544 [2S, 3R, 4S, 2- (2,2-tridimethoxy-1,3-benzo-dioxane to ene-5-volume butyl) aminocarbonylfluorenyl V-port ratio Luo bite

Example 544A trans, trans-2-Γ2.2-dimethylformamidine) -4- (7-. Formazanyl diazacyclopentadiazine_3_ complex ethyl ester according to Examples 536A and The procedure of 536C was used to prepare the title compound. The compound of Example 542A was used in place of the ethyl 3,3-diamidinohexanoate in Example 536A.

Example 544B L2S, 3R ^ 4Sl-9-r9 2-Dimethyldi I-fluorenyl group) -1 ΐ2 ^ oxy-1,3-benzyl-dioxo group) -pyrrolochadi ^ sensitive acid ethyl ester The compound of Example 544A was dissociated according to the procedure described in Example 536D.

Example 544C Pent-3-enyl) · Earthyl 2 ^ oxybenzene Ajf pentene-5-yl on bis ((N-propoxydibutylammonium) -aminosulfanyl i-pyrrolidine- 3- ^ R · According to the procedure of Example 536 £, the compound of Example 544B was reacted with the compound of Example 53 8C. Example 545 £ 2S, 3-, and) 2 ^^ ~ $ oxy-.. I, JZL Thai幷 三 三 pentamyl-5-on the base li (N-propoxypropyl 1) -based 曱--839- (Please read the precautions on the back before filling in this page)

%, \ 4 Chuanzhong Family Store Standard (CNS) A4 specification (21〇 &lt; 297 gong) 55226〇A7 B7 Part i especially) A, ii 5. Description of the invention (837) base)-pyrrolidine-3- The carboxylic acid was reacted with the compound of Example 544B and the compound of Example 539A according to the procedure of Example 536E. Example 546 £ 8,311,45] -2- (2- (2-!? Yodoyl) ethyl) -4- (1,3-Each bis ^^ cyclocycloene_5_yl)- Bu I7N-4 · heptylfluorophenyl)

Example of a l-pyrrolidin-3-carboxylic acid: 546A group of mono-trans- (2- (2- (2-p than phenyl) ethyl) -4- (1,3-benzobenzodioxane ~ pentyl) Glu-5 -yl) -P-bilodine-3-acetic acid acetic acid. The title compound was prepared according to the procedures of Examples 5 3 6 A and 5 3 6 C. The compound of Example 5 1 9 A was used in place of Example 5 3 6 A. 3,3 dimethylhexanoic acid.

Example 546B 1 ^ H, 3R, 4S1-2- (2- (2-p specific octyl) ethyl) -4- (1,3-phenylhydrazone dioxolidine-5-ylpyrrolidine- The compound of 3-carboxylic acid ethyl ester 546A (1.5 g) was dissolved in CH2C12 (25 ml), and di-third-butyl dicarbonate (0.9 g) was added. The solution was stirred at room temperature overnight.溶剂 The solvent was evaporated in air and the residue was dissolved in EtOAc (50 pens) and rinsed with water (1 X 50 mL), saturated sodium bicarbonate solution (3 X 50 mL), and brine (1 X 50 mL). The organic layer was dehydrated with sodium sulfate, and evaporated in 眞 2 to obtain an oil, which was purified by flash chromatography on stone gum, eluting with 1/10/10 of EtO Η / EtO Ac / hexane to obtain Colorless oil (1.5 g). This oil is dissolved in EtOH (10 ml) and 50% NaOH 'solution (0.5 ml) and water (5 ml) are added. Stir at room temperature; stir the mixture overnight- 840- $ Zhongyuan National Standard Rate (CNS) Λ4 specification (210X 297 mm) (Please read the notes on the back first and then fill out this page to order 552260 A7 B7 V. Description of the invention (838) (Please read the notes on the back first Matter filling (Write this page). The solvent was evaporated in 眞 2 and the residue was dissolved in EtoAc (25 mL) and acidified with 1N hPO4 (10 mL). The layers were separated and the organic layer was dehydrated with sodium sulfate and It was evaporated to give a white semi-solid (3 g). A previously obtained sample of Boc-protected amino acid (0.9 g) was dissolved in dMF (5 1 liter). (S) -Phenylalaninol ( phenylalaninOl (0.32 g), HOOBt (0.3 3 g) and EDCI (0.40 g), and the solution was stirred overnight at room temperature. Water (50 mL) was added and EtoAc (3 X 25 mL) was added. ) Extract the mixture. Mix the organic layers, rinse with water (2 X 50 mL), saturated sodium bicarbonate solution (3 X 50 mL) and brine (1 X 50 mL), and evaporate until a more oily TL · C shows the existence of two diastereoisomeric products. Separation of diastereoisomeric amidamine by flash chromatography on Shi Xijiao, with E10 H / E10 A of "12/12" c / Non-existing 'faster-moving isomers (450 mg) and slower-moving isomers (400 mg). Faster-moving non-isolated (400 mg) was dissolved in 6N HC1 and heated to reflux overnight. The solvent was evaporated and the residue was dissolved in toluene (75 ml) and evaporated. Repeated two more times to give a brown solid, which was Dissolved in EtOH (50 ml). 4NHC1 / dioxane (10 ml) was added and the solution was heated to reflux overnight. EtOH was evaporated and the residue was dissolved in EtoAc, treated with a post-sodium hydrogen acid solution (3 x 50 bright ml) and brine (1 x 50 ml), and a brown solid was obtained after evaporation. Scintillation chromatography on silica, eluting with 30% EtOH / EtOAc, gave a mixture of products (130 mg) with approximately 70Q / ❶ of the desired substance. The product can be carried on without additional purification ° -841-Original ruler ZiiiK China National Standard (CNS) A4 specification (210x 297 mm) ii 552260 A7 B7 ------ V. Description of the invention (839 )

Example 546C | ~ 2 5,311, ^ 1§1-2- (2- (2-Methyl))-4- (1,3-benzo-di-diman ^^ Vl-["N-4 -Heptyl.N- (2-methyl-3-fluorophenyl) 1 amine ^ 1-pyrrolidine-3-carboxylic acid The compound of Example 546B was reacted with the compound of Example 508E according to the procedure of Example 536E. Example 547 丨 2S, 3R.4Sl-2- (4-methoxyphenyl) -4- (1,3-phenylhydrazone dioxolane: UlldOj-butyl_N- (4_dimethylamino Butyl) amino) fluorenylmethylpyrrole

3-carboxylic acid Example 547A N-butyl-4-hydroxybutyramine To 30 ml (390 mmol) of g-butyrolactone was added 45 ml (455 mmol) of n-butylamine. The solution was heated to 85 ° C for 1.5 hours, and then excess n-butylamine was removed in the air. The product began to crystallize, yielding approximately 62 g of a colorless, low melting solid.

Example 547B N-butyl-4- # butylammonium acetamide. 2.4 ml of 98% H2S04 was added dropwise to 90 liters of butane HF ~ c 3.40 g (91.9 mmol) of an ice-cold solution of LiAiH4. After the bubbling ceased, 4.7 g of the compound of Example 547A in 10 ml of THF was added. The mixture was stirred under reflux for 24 hours, and then cooled in an ice bath, and stopped by successively adding 1.7 ml of H20 and 17 ml of 23% w / v of aqueous HaOH. Filter white Shen Dianwu, and -842- __— State in the same national standard (CNS) M specifications (210x 297 mm) ---------- m! A Please read the precautions on the back before filling (Clothing page)-Order 552260 in the A7 part of the combined B7 ___ ________________--------------- &quot; V. Description of the invention (_) Rinse with about 50 ml of THF. The combined filtrate and washings were concentrated to 3.85 g of oil. To an ice-cold solution of this material in 35 ml of ethyl acetate was added 5.0 g (29.2 mol) of acetic anhydride in 10 ml of ethyl acetate. The solution was stirred at 0 ° C for 30 minutes, and then a saturated aqueous NaHC03 solution (1 X 25 mL), 2M NaOH (1 x 25 mL), 5% NH4OH (1 X 25 mL), 1M HC1 (1 X 25 milliwells) and brine (1 x 25 mL), dehydrated with MgS04, filtered and concentrated in the air to an oil. The product was purified by silica gel chromatography, eluting with 98: 2 diethyl ether: methanol, to give 1.52 g (31%) of a colorless oil. Example 547C [2 5,311,45 2- (4-Fluorophenyl) -4- (1,3-benzo-dioxol-5-yl) -W (N-butyl-N- (4-Hydroxybutyl) amino) carbonylmethyl) -pyrrolidine-3-carboxylic acid ethyl § aims to 2.75 g (7.44 mmol) of [25,311,45] -2- (4-methoxyphenyl ) -4- (1,3-Benzo-dioxol-5-yl) -pyrrolidine-3-carboxylic acid ethyl ester (prepared by neutralizing the compound of Example 50 1G), 10 ml of DMSO And 2 ml of N, N-diisopropylethylamine were added to 1.52 g (6.85 mmol) of the compound of Example 547B. The solution was stirred at ambient temperature for 22 hours, then poured into 100 ml of water and extracted with diethyl ether (3 x 25 ml). Rinse the mixed puzzle with water (1 X 25 ml), 4% (vol / vol) H3P04 (1 X 25 ml), saturated aqueous NaHC03 solution (1 X 25 ml), and saline (1 X 25 ml) The layer was covered with MgS04, filtered, and concentrated to form a solution. Purified by silica gel chromatography, eluting with 98 ·· 2 bis acetamidine: methanol, to give 3.0 g (79%) of a colorless cure. 843 This demon Zhang scale uses the Chinese standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page f 552260 A7 B7 f 5. Description of the invention (841

Example 547D

Lj _ .., 3R, 4S, 2: H-methyl ^^)-4- (1,3_phenylhydrazine, dioxane, triyl) amino) carbonyl)) · pyrrole acid &quot; — -'—-— &gt; Ethyl acetate Add 1.4 ml (10 mmol) of triethylamine to 2.80 g (5.05 mmol) of the compound of Example 547C in 27 ml of diethyl ether, then add 58. Ml of methanesulfonyl chloride. A white precipitate formed and the suspension was stirred at 0 ° C for 20 minutes. The reaction was diluted with 75 liters of diethyl ether, and then extracted with saturated aqueous NaHC03 solution (2 X 25 mL), 5% NH4OH (2 X 25 mL), and brine (1 X 25 mL), and dried over MgS04. , Filtered and concentrated to .3.0 g of colorless oil. To a solution of this material in 45 ml of DMF was added 60 g (69 mol) of LiBr. The reaction was warmed to approximately 50 and then gradually cooled. The solution was stirred at ambient temperature for 4 hours, then poured into 450 ¾ liters of water and extracted with diethyl ether (3 x 100 ml). The combined acid layers were back-extracted with water (1 × 100 liters) and brine (1 × 100 ml), dried over MgS04, filtered, and concentrated in vacuo to an oil. The product was purified by silica gel chromatography and washed with 3: 1 diethyl ether: petroleum oil to give 2 65 g (90%) of a colorless oil.

Example 547E Oxyphenyl) -4- (1,3-phenylhydrazine dioxane j 晞 -5- 碁 工-基-^ 11: diamidobutyl) amino) carbonyl)) -_ Also pyridin-3 androsylic acid 5 ml of 407 iM dimethylamine in ethanol was added to a solution of the compound of Example 547D (0825 g, 134 mmol) in 3 ml of ethanol ---- -----? (Please read the notes on the back before filling this page}

1T Ρ-844- 552260 ^; # 部 中心?:. · ^ ΆΠ νΆ ， 合 竹. ^ Ri 卬; ^ A7 V. Description of the invention (842) '~, heat all the solutions to reflux for 75 minutes. The dissolved gas was removed in the air, and the residue was purified by flash chromatography on stone gelatin, eluting with 9: 1 chloroform / methanol. The obtained material was dissolved in 5 ml of 1.4 N NaOH in 5: 」，, and stirred at ambient temperature for 14 hours. Move the precipitant in 眞 2; dissolve the residue in water and adjust to pH 6-7 with 1M HC1 (approx. 7 liters). The mixture was extracted with EtOAc (3X); the layers were concentrated in Celite 2. The residue was washed 3X with acetonitrile; the washing solution was passed through diatomaceous solution Ma and concentrated to give 596 mg of a white foam. &quot; Example 548 Benzene, dioxane, ^ dimethylaminobutyl) amino) carbonylmethyl μ 1-pyridine-3-carboxylic acid was prepared according to the procedure of Example 547, in Example 547c using Example 537B Cardiac compound ([2S, 3R, 4S] -2- (2,2-Dimethylpentyl) -4- (1,3-phenylhydrazine dioxin %% _ 5_yl) _pyrrolidinate Ester). Example 549 Dimethylpentyl) -4- (7-fluorenyloxy-1,3-phenylsulfonyl-m-oxobutyl-NM-difluorenylaminobutyl) amino) carbonylfluorenyl 1-pyrrolidin-3- It was prepared according to the procedure of Example 547. In Example 547 (:, the compound 5S6D ([2S, 3R, 4S] -2- (2,2-Dimethylpentyl) -4- (7- 曱Oxy-1,3_benzo-dioxopentyl-5-yl than pyridin-3-carboxylic acid ethyl ester) to replace it. Example 5 5 0 Methen-3-enyl —---- ----S45-

f Please read the note on the back first? Then suppress this page J-In, may. 552260 A7 B7 V. Description of the invention (843) A (Dimethylmethylaminobutyl) amino) medicinal acid

Prepared according to the procedure of Example 47, in Example 547C, the compound of Example 542C ([2S, 3R, 4S] -2- (2,2-Dimethylpent-3-enyl) -4- (l, 3 -Benzo-dioxolene-yl) -pyrrolidine · 3-carboxylic acid ethyl ester). jjH_55l 1 ^ 3 ^ 5 2 2 &lt; 2'2 dienyl V4- (7-methoxy-1,3-benzyl # m-tricycloheteropentylbutyl-N- (4-dimethylaminobutyl) Group) amino group) pyrrolidine-3-carboxylic acid was prepared according to the procedure of Example 547, and the compound of Example 544A ([23,311,48] _2- (252-dimethylpenta-3-enyl)- 4- (7-methoxy-1,3-benzo-dioxol-5-yl) -pyrrolidinecarboxylic acid ethyl ester). f iH 552 .. U2,2 · di 1 pent-3-enyl) -4- (1,3-phenylhydrazone dioxane All · yl)-. LlL (N-butylmethylaminobutyl ) Amino group) Carboxymethyl 1-coordin-3-carboxylic acid, 17 r in the center and j · _T f ·. A ii 制备 was prepared according to the procedure of Example 1, and the compound of Example 541C ([2S, 3 R, 4S] -2- (2,2-Dimethylpent-3-enyl) -4- (1,3-phenylhydrazone dioxol-5-yl) -pyrrolidine-3-carboxyl Acid ethyl ester).

Drawing example 5 H 1 ^ 1 this, 48 Bu 2- (2,2-dimethyl "^ ι ^)-4- (7-methoxy-1,3-phenylhydrazone-cyclopentyl-5-yl-seven J-Butyl) amino) Tibetanyl]-? Pyrrolidine-3- -846- (Please read the precautions on the back before filling out this page} This paper is extended to standard- (CNS) 552260 Α7 Β7 Explanation of the five inventions (844) ^ • ν '&quot; Ά In the under owing- ^ 7 ^' h (.T: &r; r, f combined: ίτ ^-印 was prepared according to the procedure of Example 1, Example 544B The servant enters a dagger ([28,311,45] -2- (2,2-Dioxol-3-enyl &gt; 4- (7-fluorenyl_13ben) dioxolane Alkenyl-5-yl) -pyrrolidine-3-carboxylic acid ethyl ester) instead. 'X Because the compounds described herein have been shown to work by interacting with endothelin a, and sister, these compounds have been evaluated Capability of receiving endothelin from di-endothelin. ^ Binding test "Testing SIa receptors to prepare membranes from MMQ cells: Collect MMQ cells from 150 ml culture flasks by centrifugation (1000xg, 10 minutes) [MacLeod / MacQueen / Login cell line (rat pituitary cells that secrete qi: hormone)], and then use a microsonic apparatus (Kontes) It was homogenized in 25 ml of 1011 ^ to 1 ^ (1 ^ 7.4) in 25 ml of sucrose and a protease inhibitor [3 ^^ EDTA, 0.1 mM PMSF and 5 µg / ml pepsin]. The mixture was centrifuged at 1000% for 10 minutes. The supernatant was collected and separated at 60,000 × §. The pellet was resuspended in mM ins containing the above-mentioned protease inhibitor). , PH 7.4, and centrifugation again. The pellet finally obtained by Jiang was resuspended in 20 mM Tris, pH 7.4 containing protease inhibitor, and stored at -80 Cr until use. By Bi0-Rad The protein content determined by the dye-bound protein test. Binding effect: The binding test was performed in a 96-well microtiter plate treated with 0.1% BSA in advance. In the buffer solution BpOmMTns, iOOmMNaCl, 10mM_ _ -347- this new ruler μ -------- (Please read the precautions on the back before writing this page f D 552260 A7 -------------- B7 V. Description of the invention (845)

MgCl2 'pH 7.04 with 0.02% BSA, 0.1 PMSF, 5 μg / ¾ liter of pepsin A, 0025% bacitracin, and 3mMEDTA)' was diluted from the cell-prepared membrane approximately 100-fold, To 0.2 mg / ml &lt; final protein concentration. In a competition study, the membrane was cultured at 25 mg in the presence of increasing concentrations of unlabeled ET-1 or test compound at 25 nM_ in buffer solution B (final volume) : 0.2 liters) for 4 hours. After incubation, unbound ligands were separated from the bound ligands using glass fiber filter strips in a ρΗβ fine 'bubble harvester (Cambridge Technology, Inc, MA) by air filtration, followed by physiological saline. (1 ml) Rinse the filter strip three times. In the presence of μΜΕΤ]

Kben specific binding. The data are shown in Table 4. Shows the percentage of spoon at the concentration i mM. The data show that the chemical compound of the present invention binds to an endothelin receptor. _ -848- Non-paper crying standard (CNS) Λ4 specification (210 乂 297 Gong Chu_)

(Please read the notes on the back before filling in this one hundred C

552260 A7 B7 V. Description of the invention (846 Table 4 Combined data

Middle A 卬 Example% Inhibition of ETA at 1 μM Example% Inhibition of ETA at 1 μM 1D 96.4 34 95.5 2 58.4 35 91.8 J 42.2 36 94.5 4 78.2 37 47.9 5 95.1 38 100.0 6B 34.9 39 83.6 7 63.4 40 94.8 S 53.7 41 89.9 9 69.2 42 95.2 10 66.1 43 99.2 14 86.6 44 91.3 15 84.8 45 85.4 16 96.0 46 90.4 17 73.9 47 95.1 18 97.3 48 96.3 19 90.3 52 84.0 20 80.9 54 64.6 21 56.3 55 50.5 22 86.3 56 34.3 849 -The standard of this paper; 丨] National Standard for Prisoners (CNS) Α4 specification (210X 297mm) (Please read the precautions on the back before filling in this page # 1

552260 A7 B7 V. Description of the invention (847) Example% inhibition of ETA at 1 μM Example% inhibition of ETA at 1 μM 23 85.9 57 93.2 26 83.0 58 81.9 27 61.2 59 70.8 28 63.8 60 42.8 29 85.3 61C 90.6 30 80.0 62 94.1 31B 93.6 63 92.0 64 95.0 | 1 98 86.8 65 82.8 99 92.1 66 87.7 100 76.8 67 96.3 101 89.2 68 84.6 102 75.2 69D 37.4 103 69.0 70 62.7 104 98.0 71 81.4 105 98.6 72C 80.7 106 90.0 73C 96.3 107 97.2 74 95.6 109 96.8 75C 95.3 110 94.4 76 93.1 111 101.8 79 100.4 112 94.9 -850- (Please read the notes on the back before filling in {.: Γ 大二 贝

、 1T '%! The size of this paper / 丨] National Standard for Valves (CNS) 8 4 specifications (210X 297 mm) 552260 A7 B7 5. Description of the invention (848) ^;:-ϋ dl; 々r * ^ ii \ -T: &quot; W * f% inhibition of example ETA at 1 μM% inhibition of example ETA at 1 μM 80 89.4 113 94.3 82 90.3 114 86.2 83 85.0 115 88.4 84 65.3 116 79.3 86 52.6 117 95.2 87 62.4 118 93.2 88 84.3 119 86.6 89 84.6 120 99.5 91C 91.6 121 98.6 92C 107.4 122 95.3 93C 59.2 125 97.2 95D 82.1 126 91.7 96 86.1 127 91.4 97 89.0 128 95.4 123 89.7 156 92.6 124 91.0 157 83.8 129 100.1 158 91.8 130 91.0 159 36.2 131 89.5 160B 80.3 132 90.0 161 93.6 I jj 88.6 j 162B i 91.5 (Please read the precautions on the back before filling out this page to order -851-this ruler 1 is used in the national S standard 4M CNS) Λ4 specifications (210X297 mm) 552260 A7 B7 V. Description of the invention (8 milk 屮 η and A 卬 Example% inhibition of ETA at 1 μM Example of inhibition of ETa at 1 μM J 134 92.2 163 90.6 135B 77.7 164 98.6 136 79.4 165 54.1 138 83.0 166 91.6 139 98.6 167 94. 4 140 106.3 291 100.0 141 92.8 293 89.8 142B 78.7 294 77.7 143 20.6 295 93.0 144 78.2 296 87.1 145 32.4 297 84.4 146 25.0 298 93.3 147 73.0 299 90.4 148 94.7 300 96.1 149 84.6 301 96.7 150 93.6 302 86.6 151 80.5 303 87.2 152 86.9 304 89.7 153 97.1 305 87.4 154 80.2 306 93.3 155 92.7 307 92.2 (Read the precautions on the back first and then fill in the second shell) -852-This twisting scale is achieved by the prisoner's standard in Zhongwei (〇 &gt; ^) / \ 4 Specification (210 乂 297) 漦 552260 A7 B7 V. Description of the invention (85〇) Example% inhibition of ETA at 1 μM Example% inhibition of ETA at 1 μM 308 93.0 351 99.0 309 80.7 352 96.2 310 87.1 353 73.7 311 92.3 354 79.3 312 88.2 355 100 313 96.3 356 93.5 314 86.0 357 96.3 315 82.7 358 62.7 316 74.0 359 94.7 317 68.5 360 93.7 318 79.0 361 92.8 319 79.0 362 94.1 320 82.2 363 82.3 322 95.6 365 59.2 jZd 91.3 366 91.5 324 95.0 367 71.0 334 88.0 368 94.6 335 84.1 370 84.3 340 94.0 371 97.2 341 87.4 372 91.6 342 89.9 J / J 92.9 (Please read the notes on the back first Fill out this page _______ ^^ __ I-5 -853- This paper size is the national standard for t tS (CNS) Λ4 specification (210; &lt; 297 gong) 552260 A7 B7 V. Description of the invention (851) n-- J &quot; &quot; 丨 ^ &quot;: Ten, 0 ^^ ('' '乂' 1 ^ T *-^ ^ J Ar Λ * ηΛν,% Inhibition of ΕΤΑ at 1 μM Example ΕΤΑ at 1 μM % Of inhibition 343 98.7 374 91.4 344 95.6 375 97.8 345 86.6 370 90.2 346 88.9 377 85.6 348 91.3 378 91.1 349 73.0 379 90.7 350 92.1 380 99.0 381 95.7 408 100 382 96.8 409 89.4 383 91.4 410 91.4 384 79.4 411 93.5 385 86.2 412 86.4 386 47.8 413 99.5 387 98.7 414 91.4 388 69.2 415 87.3 389 100 416 86.4 390 98.2 417 98.7 391 45.6 418 100 392 93.7 420 100 393 100 421 100 394 1 97.8 422 96.6 (Please read the notes on the back before filling this page )-854- The scale of this grave is based on the national sample ([\ $) / \ 4 specifications (210/297 mm) 552260 A7 B7 V. Description of the invention (852 A 卬 ETA at 1 μM ETA % Inhibition Example% Inhibition of ETA at 1 μM 395 79.8 423 89.1 396 98.7 424 85. 8 397 100 425 90.8 398 90.0 426 97.2 399 59.9 427 100 400 93.0 428 100 401 96.5 429 100 402 80.5 430 94.1 403 96.1 431 99.1 404 95.4 432 95.5 405 86.4 433 99.6 406 94.5 434 100 407 100 435 97.8 436 100 459 97.4 437 100 460 91.6 438 94.3 461 99.6 439 94.3 462 98.3 440 100 463 96.1 441 98.3 464 97.1 442 100 465 95.1 443 100 466 94.2 (Please read the precautions on the back before filling this page) -855- This paper is in the standard S National Standard Feng (CNS) Λ4 specification (il0X 297 mm) 552260 A7 B7 Wu Wuming instructions (853 Example inhibition of ETA at 1 μM% 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 100 98.1 97.8 96.9 97.4 100.0 99.7 100 100 94.4 96.8 99.1 95.3 88.9 93.4 Example% inhibition of ETA at 1 μM 467 468 469 470 470 471 475 476 477 479 495 496 497 498 499 500 93.6 88.7 98.7 100 100 91.6 82.3 80.1 96.5 95.9 92.7 83.7 81.6 68.5 55.7 (Please read the notes on the back before filling in this page) 856- Follow this paper size 丨 丨] Chinese National Standard ((: &gt; ^) / \ 4 specifications (210 乂 297 %) 552260 A7 B7 V. Description of the invention (854)% inhibition of ETA at 1 μM of the examples 502 95.7 503 97.0 504 97.1 505 95.8 506 99.7 507 99.3 508 97.6 509 100 510 100 511 99.2 512 98.9 513 98.0 514 100 515 99.1 516 99.7 517 94.1 518 96.3 519 99.1 520 97.4 521 100 523 99.0 (Please read the notes on the back before filling in this page 0 ^ * 1Τ -857- This paper ruler 1 is used in the Zhongmaoin House Standard ([\ $) / \ 4 specifications (210; &lt; 297 gong) 552260 A7 B7, invention description (855 examples of Ί at 1 μM; 524 99.2 525 100 526 100 527 96.6 528 98.3 529 98.1 531 99.8 532 100 533 97.9 536 100 537 Inhibition of 97.2% Jk i: f, A In order to further confirm: the compound described as a functional endothelin antagonist? The effectiveness of H &lt; 1 was measured for the ability of the compounds described to inhibit the hydrolysis of phospholipids and inositol by Eτ_. q Measurement of the effects of jg 醯 inositol (PI) hydrazone in RPMI is marked by 10 microvariations / liters of "Η [inositol] to mark mmq thin monthly packs (0.4 X 106 cells / ml) 16 hours. Rinse the cells with pBS, and then choose to grow with buffer solution A containing protease inhibitor and mM mM LiCl for 60 minutes. Then incubate the cells with the test compound for $ minutes, and then 1 nM ET-1 Challenge. Stop the challenge of ET-1 by adding 15 ml i: 2 (v / v) chloroform-methanol. Add chloroform and water in order to make it 'like Berridge (Biochem J. 206 ,: 587-595 (1982 )) ^-^ ^ Clothing IT— (Please read the precautions on the back before filling out the dome page) -858 This paper size uses the standard of Maomao Prisoner (CNS) Λ4 (210X297 mm) 552260 A7 B7 V. Description of the invention (856: chloroform-methanol-water 1: 1 final ratio of 1: 1: 0.9 (volume / volume / volume), the entire inositol phosphate vinegar is extracted. Keep the upper liquid phase 0 ml), and a small amount of Partial U00 microliters) were counted. The remaining aqueous samples were analyzed by batch chromatography using anion-exchange resin AG1_X8 (BlG-Rad).%. The ET-induced increase in PI is required to reverse the concentration of the test compound at 50%. The results of the above studies clearly show that these compounds can be used as functional ET antagonists. Table 5 Hydrolysis of phospholipids inositol ( Please read the notes on the back before filling in the section on this page. \\ Guide Μ i Example IC50 μΜ 1D 0.025 14 0.017 15 0.010 16 0.009 18 0.009 19 0.024 30 0.001 31B 0.002 43 0.0001 46 0.002 47 0.0005 48 0.0004 291 0.0098 300 0.0012 534 0.05 553 0.0004, \ 5 -859 552260 Α7 Β7 V. Description of the invention (857) Table 6 The sense of I of ETa / ETb (please read the precautions on the back before filling this page) Use micro-ultrasonic cell division Device in 25 ml of 10 mM Hepes (pH 7.4) containing 0.25 M glucose and a protease inhibitor [50 mM EDTA, 0.1 mM PMSF, 5 μg / ml pepsin and 0.025% bacitracin], MMQ cells, porcine brain tissue (known to contain ETB receptors), and human ET a or ET b receptors were homogenized to permanently infect infected Chinese hamster ovary cells (CHO). The mixture was centrifuged at 1000xg for 10 minutes. The supernatant was collected and centrifuged at 60,000 xg for 60 minutes. The pellet was resuspended in 20 mM Tris, pΗ 7.4 containing a protease inhibitor, and centrifuged again. The final membrane pellet was resuspended in 20 mM Tris, pH 7.4 containing the protease inhibitor, and stored at -80 C until use. The protein content was determined by the Bio-Rad and dye-bound protein test.

The binding test was performed in a 96-well microtiter plate previously treated with 0.1% B SA. In buffer solution B (20 mM Ti * is, 100 mM NaCl, 10 mM MgCl2, pH 7, 4 with 0.2% BSA, 0.1 mM PMSF, 5 μg / ml pepsin A, 0.025% bacitracin and 50 mM EDTA), the membranes prepared from the cells were diluted approximately 100-fold to a final protein concentration of 0.2 mg / ml. In a competition study, in the presence of increasing concentrations of the test compound, the membrane (0.02 mg) was compared with [1251 ^ 丁 -1 ( For ETA test in MMQ or CHO cells infected with human £ 1 \ receptor transfer), or [125I] ET-3 (for j brain or CCo cells infected with human ETB receptor transfer) ETB test) (final volume: 0.2 ml) for 3 hours. After cultivation, _ -860- this paper size (CNS) 8 4 specifications (210 乂 297 public 韪) ~ &quot; one-one-552260 A7 _____________ B7 V. invention description (858) (may read the precautions on the back before (Fill in this page) By using the "2 pass method" in a PHD cell harvester (Cambridge Technology, Inc. 'ΜΑ), a glass fiber filter is used to separate unbound ligands from the bound ligands. The filter strip was rinsed three times with saline (丨 ml). Non-specific binding was determined in the presence of 1 μM ET-1. The IC50 was calculated using the average of at least two different assays. The data show that the compounds of the invention and endothelin Binding selectivity. Table 6 Example number γΕΤ-Α (% 1 @ 1 μΜ) rET-A IC50 (nM) ρΕΤ-Β IC50 (nM) Selectivity (rA / pB ratio) hET-A ic50 (nM ) hET-B ic50 (nM) Selectivity (hA / hB ratio) 502 95.7 3.0 71,000 23,000 503 97.0 1.4 50,000 35,000 0.92 52,000 56,000 504 97.1 3.1 &gt; 100,000 &gt; 32,000 4.6 &gt; 100,000 &gt; 21,000 505 95.8 2.0 60,000 30,000 5.7 68,000 12,000 506 99.7 3.2 &gt; 100,0 00 &gt; 31,000 3.0 61,000 20.000 507 99.3 3.0 &gt; 100,000 &gt; 33,000 1.63 &gt; 100,000 &gt; 60,000 508 97.6 1.9 45,000 23,000 2.1 51,000 24,000, ϊ yr · part 509 100 0.56 30,000 53,000 0.51 23,000 45,000 510 100 0.50 35,000 68,000 1.0 11,000 11,000 k 511 99.2 0.81 ND — 0.60 15,000 25,000 .T 512 98.9 0.42 &gt; 80,000 &gt; 190,000 0.58 60,000 &gt; 102,000 P in 513 98.0 0.30 8,800 29,000 0 36 14,000 37,000 514 100 1.0 26,000 26,000 0.36 9,800 29,000 ____- 861-The standard of this paper / 丨] National Standard for Prisoners (CNS) Λ4 Specification (210X 297 mm) 552260 A7 B7 V. Description of Invention (859) 515 99.1 1.6 &gt; 62,000 &gt; 37,000 6.7 &gt; 100,00 &gt; 15,000 516 99.7 0.71 29,000 40,000 1.8 37,000 21,000 517 94.1 1.0 30,000 30,000 0.43 12,000 29,000 518 96.3 1.3 85,000 63,000 0.31 38,000 124,000 519 99.1 0.38 14,000 36,000 0.23 19,000 83,000 520 97.4 0.20 28,000 130,000 521 100 0.67 37,000 54,000 523 99.0 0.42 360 880 0.33 290 880 524 99.2 0.79 l? 7.00,10 0 0.82 890 1,100 525 100 8.2 560 70 526 100 42 —… 17 7,400 440 527 96.6 7.9 10,000 1,300 528 98.3 11 43,000 3,800 529 98.1 3.6 6,300 1,700 531 99.8 1.2…… 0.71 870 1,200 532 100 5.1 3,200 630 33 J 97.9 76 7,900 100 40 22,000 560 534 0.12 0.36 3.0 0.08 0.28 3.5, middle part 536 100 0.52 17,000 33,000 0.92 52,000 56,000 JP h 537 97.2 0.96 5,900 6,200 0.23 1,900 8,200 η _τ 552 97.3 0.78 7100,000 7125,000 1.0 &gt; 96,000 &gt; 96,000: /, f. 553 100 0.26 42,400 160,000 0.29 39,500 136,000 厶 (Please read the notes on the back before filling out this page) -862- Wood paper scales are described in the state S National Standard (CNS) 8 specifications (210X 297) (Ii) ii 552260 A7 B7 V. Description of the invention (86) Determination of plasma protein knots The mother compound (2 mg / ml) of the test compound in 50% ethanol was diluted 10-fold in PBS. A 0.4 ml sample of the second mother liquor was taken, added to 3.6 ml of fresh plasma, and incubated at room temperature for 1 hour. A 1 ml sample of the culture mixture was transferred to a Centrifree ultrafiltration, tube. The sample was centrifuged in a fixed-bucket rotor 'for about 2 minutes, and the mash was discarded. Centrifuge the sample for another 15-30 minutes. Transfer more than 100 microliters of 遽 sample to a micro Η P L C sample vial containing 150 liters of Η P L C mobile phase and mix thoroughly. A 50 microliter sample was injected, and the HPLC analysis was performed to compare the standard sample prepared in the absence of plasma in the same manner to determine the drug concentration in the ultrafiltration solution. Formula:. Measure the concentration of nasal super saliva from the calibration curve meter. Calculate protein binding based on% PB = [l- (Cu / Ci)] * 100%. Where Cu is the concentration of ultrafiltrate and Ci is the initial plasma concentration. The percentages of the bound compounds are listed in Table 7. Example # 43 &gt; 99.5% binding Example # 530 78% binding Example # 531 92% binding Example # 532 96.8% binding Example # 533 82.6% binding -863-

丨〗) A4 specifications (210X 297 ^ tT (Please read the precautions on the back before filling in this ιίο

552260 A7 ____ B7 V. Description of the invention (861) ~ ^ 'In the literature (Wu-Wong et al., Life Sci. 1996, 58, 1839-1847, which is incorporated herein by reference), it has been confirmed that it is closely related to protein The combined compounds show reduced potency in vitro in the presence of plasma proteins. A reduction in efficacy in vitro is likely to result in a reduction in efficacy in live squats. It may be expected that endothelin antagonists, which have a protein binding-reducing effect, are less susceptible to this effect and are therefore useful as more potent in vivo preparations. The following experiments have confirmed that the "reducing protein binding" endothelin antagonist "shows the ability to enhance activity in the presence of serum albumin: each experiment was performed at increasing serum albumin concentrations, and A specific antagonist records a series of binding curves. Draft of albumin-binding binding mobile studies: Unless otherwise specified, binding tests were performed in 96-well microtiter plates previously coated with 0.1% BSA. In buffer solution B (20 mM Tris, 100 mM NaCl, 10 ηM MgCl2, ρΗ7.4, 0.1 lmMPMSF, 5 μg / ml pepsin inhibitor 8, 0.02 5% bacitracin, and 3 11 ^ £ 〇 丁 人) The membrane was diluted to a final concentration of 0.05 mg / ml of protein. Add human serum albumin (HSA) at various concentrations as directed. In a competition study, the membrane was combined with 0.1 nM [I] ET (final volume: 0.2 ml) in the presence of increasing concentrations of unlabeled test ligand at 25 ° C. ) Cultivate together for 4 hours. After incubation, the PHD cell harvester (Cambridge

Technology, lnc., Watertowm, MA) using glass fiber filter strips to separate unbound ligands from the bound ligands, followed by washing the filter strips three times with physiological saline (iΐ: liters). Buckwheat specificity determined in the presence of 1 μM ET-1 ____-864-National Standard (CNS) ^ 4 Regulations ^ 77 ^ 7297 Gong in this paper &amp; f | Think about the matter again {: · Γ ·· .τνΙΓ 'Order 552260 A7 B7 V. The combination of the invention description (862). Figure 1A 120____, J-I · I r-Λ-.-100806040200-20 ONos ^; s

1 (&gt; (Please read the notes on the back before filling in the page) 10,4 10 ,: 10 ': 10 · [Example 43], M &gt; 98% protein binding 1C,

Figure IB

Figure 1C

120 100-:

-20- 10- 10 ^ 800 0 0

1C50 -0% HSA 5 5 nW -C 23/2 6 5 nM -1% 5 0 nW -5〇 / o 5 0 nM

-20; Loss of 10: 10 in the r portion [Example 531], M &gt; 92% of the protein binds to 10 'Figure 10, 10: 10' 10 ^ 1 (T 1C &quot; [Example 530], M &gt; 78% of protein binding [125Ι] ET-1 binds to the human ETA receptor by inhibition of ETA antagonists. Each curve was determined in the presence of 0%, 0.2%, 1%, or 5% HSA, and -865- Dimensions of this paper / 丨] 屮 阄 National Standards (CNS) Λ4 specifications (210 乂 297 mm) 552260 A7 B7 V. Description of the invention (863) Talent ^, upper test for testing. The percentage of the combined effect of the control group To express the results, the binding effect on [125I] ET-1 in the absence of antagonists was set to 100%. Each point represents the average tritium (soil standard deviation) of three determinations. As observed in Table 1A, it has a high The combination of protein binding 4 (Bayer 4 &gt; 98% binding), in the presence of increasing albumin content, shows that the binding west line moves to the right (towards decreasing effectiveness). The protein binding is reduced to The compound of Example 53 丨 (Figure iB), which shows a practical decrease, moves to the right; after protein binding decreases to 78% The opening of Example 53 was (Fig. 1C), and movement was completely excluded. This experiment confirms the decrease in protein binding and use; instead, it increases the potency in the presence of plasma proteins, suggesting that such compounds may have enhanced activity in vivo. ★ The reduction observed in the protein-binding effect of the compound, which retains a high affinity for endothelin, is obviously related to the configuration of the "basic" functionality (positively charged groups at physiological pH 値) . 1 σ is also exhibited by the improved solubility in aqueous effluents, below = medium = solid (Table υ, in the experiment, at about 25.0 ° C, at various shocks. The largest dissolution is measured in this medium m ^ h ^, Ⅱ, 、. are not detected in acetaminophen; in the middle of the ministry again :) (Please read the precautions on the back before filling out this page to order compounds containing telomeres, in a wide range of 値， Increased solubility of 2: 2. Such increasing water solubility, combined with the enhanced potency caused by the reduced person = cooperation, can make these compounds more suitable for the preparation of the second intestine ... The side view of the compound _ Straight- / Solution Degree. 印 印 -866-

552260 A7 B7 V. Description of the invention (834) Table 8 pH 値 [Example 4 3] (mg / ml) [Example 531] (mg / ml) 5.1 0.08 &gt; J. J 6.5 0.51 &gt; 3.4 7.1 0.99 3.54 7.6 1.14 3.55 The present invention provides compounds that are less likely to bind to proteins, which have improved activity in vitro and in vivo in pharmaceutical preparations. The present invention also provides compounds capable of reducing the affinity of a water-repellent acid to plasma proteins by attaching an equilibrium charge to a biologically acceptable position. For example, by adding "basic" functionality (positively charged groups at physiological pH) to the amidine side chain (see formula, where R3 has a cool amine side chain) to reduce the protein's Combined effect. The present invention includes compounds having formula XII: (Please read the precautions on the back before filling in the too 'page) r2 ZO

3 R

: 1Η C η

&gt; 1 I

$ X in R section; -T 卬

XII where z is -C (R18) (R19)-or -C (O)-, where Rlg and R19 are selected from hydrogen and low-end alkyl, respectively; η is 0 or 1; 867- China National Standard (CNS) A4 specification (210X 297 mm) 552260 A7 V. Description of the invention (865) R is-(CH2) mW, where m is an integer from 6 to 6, and W is (a) -C ( 〇) 2-G, wherein G is hydrogen or a carboxy protecting group, (b) -P03H2, (c) -P (0) (〇H) E, wherein E is hydrogen, a low-carbon alkyl group or an aralkyl group, (d) -CN, (e) -C (0) NHR17, where R17 is a low-carbon alkyl group, (f) an alkylaminocarbonyl group, (g) a dialkylaminocarbonyl group, (h) a tetradecyl group, ( i) meridian, (J) alkoxy, (k) retested amine, (l) -C (〇) NHS (0) 2R16, where R16 is a lower carbon number alkyl, haloalkyl, aryl or Diamine group (m) -S (〇) 2NHC (0) R16, where R16 is as defined above, (Please read the precautions on the back before filling this page)

-868- This paper size is applicable to 1¾ national standard (CNS) Λ4 specification (210 X 297 mm) 552260 A7 B7 V. Description of the invention (866 Λ 〇

(q) / νη, 〇〇 〇

〇 〇 (r) (s)

(t)

Or nhso2cf3 (u) h and R2 are selected from hydrogen, lower carbon alkyl, alkenyl, alkynyl, alkoxyalkyl, oxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, Alkoxy, fluorenyl, thiol, oxalyl, sulfonyl, cycloalkyl, alkynyl: amine Chinese alkyl &amp; amine carbonyl alkyl, dialkylamino carbonyl alkyl, amine carbonyl alkenyl ^ alkyl Aminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, aryl aryl * s aryloxy phenyl, aryloxy phenyl, (N-chain alkyl phenyl-N-alkyl) ) Alkyl, aryl, alkyl, heterocyclyl, (heterocyclyl) alkyl, and (U (Rbb) N-Rcc- 'wherein' is aryl or aralkyl, and Rbb is hydrogen Or chain test group 'and Ree is an alkylene group, and the restriction is that one or both of R2 and R2 are other than hydrogen; R3 is ⑷r4-c (0) -r ”R4-c (o) -r5- n (r6)-、 Find a ruler 1 with a towel $ 彳 869- (Please read the precautions on the back before filling this page)

(210X 297) 552260 A7 B7 V. Description of the invention (867) where R5 is a fluorene covalent bond, (ii) alkylene, (iii) alkenyl, (iv) -N (R20) -R8- or R8a-N (R2〇) -R8- 'wherein Rs and RSa are respectively selected from the group consisting of alkylene and alkylene, and R20 is hydrogen, low-carbon alkyl, alkenyl, haloalkyl, alkyloxy, Fluorenyl radical, or (V)-Ο-R9-or -R9 a-〇- R9-'where R9 ,, 、 • / r part 屮 ih fr Λ ii cyclic cyclohexyl or cycloalkyl radical: And R9a are respectively selected from the alkylene groups R4 and R6 as (Rll) (Rl2) N- (1) hydrogen, (2) a lower carbon number alkyl group, (3) a halogenated group, (4) an alkoxyalkyl group, ( 5) from alkoxyalkyl, (6) alkenyl, (7) alkynyl, (8) cycloalkyl, (9) cycloalkylalkyl, (10) aryl, (11) heterocyclyl, ( 12) aralkyl, (13) (heterocyclyl) alkyl, (14) hydroxyalkyl, (15) alkoxy, (16) aminealkyl, (17) trialkylaminealkyl where Rn and R12 is selected from 870- this paper size is suitable for China National Standard (CNS) A4 specification (2IOX 297). (Please read the notes on the back before filling in the page) 552260 A7 __ B7 V. Invention (868) (18) alkylaminoalkyl, (19) dialkylaminoalkyl (20) carboxyalkyl, (21) (cycloalkyl) aminoalkyl, (22) (cycloalkyl) alkylamine Alkyl, (23) (heterocyclyl) amine alkyl, and (24) (heterocyclyl) amine alkyl, with the limitation that at least one of R11 and r12 is selected from heterocyclyl, amine alkyl, Alkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, (cycloalkyl) aminoalkyl, (cycloalkyl ) Alkylaminoalkyl, (heterocyclyl) aminoalkyl and (heterocyclyl) aminoalkyl; or a pharmaceutically acceptable salt thereof. Table 9A shows that it preferably has a protein binding reducing effect. Compounds in which R may be selected from the substituents shown in Table 9B. Table 9A (Please read the notes on the back before filling out this page)

_; _____ -871-Wood Paper State 7 Buwei National Standard 0 乂 297 Gong) 552260 A7 B7 V. Description of Invention (869) OCH,

R A.

... C〇〇H M〆 ,,

(Please read the notes on the back before filling this page

10 CH3〇 o 11

Aip in the booking department,

&gt;/; f: A

14

15

872- This paper is far / small] Chinese Gardener Standard (CNS) Λ4 specification (210X 297 mm) ii 552260 A7 B7 V. Description of invention (870) 16 19 22

20 〇

Cr

18

〇 21

twenty three

twenty four

(Please read the notes on the back first and then fill in the sophomore --- ^-

* 1T

26

27

R

〇 〇 、

COOH f \ Γ '/ jz ^

o 3

nnh -873- This paper size is based on the national standard of the park (€ ^ 5) / \ 4 specifications (210 漦 297 public 漦) 552260 A7 B7 V. Description of the invention (371)

Table 9B

H-xCNH! I, 〇

H.CNH --------- 丨 Please read the precautions on the back before filling in the second year, 11

HXNH -N ^ H A, νΛ

W H, N, 10 11

N H ^ ΝγΟ ^ 12 13

N H 〇 14 II 〇 15 H, N, 16 〇 17

NH νΛ 18 〇874- Square and A-size scales 丨 丨] Chinese National Standard (CNS) A4 specification (210 × 297) You 552260 A7 B7 V. Description of the invention (872 19 20 ο 21 'Nτ ^, 22 23 24 〇 25 h2n

(H3C) 2N / X ^ Ny 29 〇27 η2ν 28 〇 (H3C) 2N ^^ N ^ / 30 〇 (Please read the notes on the back before filling in this page (H3C) 2N ^^ 丨 1 〇 (H3C &gt; 2N Ν 丫-/, (ch3) 2n, ^ 32

(ch3) 3sT 34 37 40 43

C (CH3) 3N '(CH3) 3N &quot; 36

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L 、: (Please read the notes on the back before filling out this page. For the purpose of this disclosure, when using "(cycloalkyl) aminoalkyl,":

, 1T-@ 时 'means attaching a cycloalkyl moiety to a parent compound via an amine alkyl group. Examples of the (cyclopityl) amino group include (cyclohexane) aminopropyl, (cyclohexane) aminoethyl and the like. When the term "(heterocyclyl) aminoalkyl" is used in this context, it means that it is attached to the parent compound via an amine group. (Heterocyclyl) aminoalkyl Examples include (piperidine) aminopropyl, (phenylamidinefuran) aminopropyl, (tetrahydrofuran) aminoethyl and the like. &Quot; (Amidino) alkylaminoalkyl &quot; means via alkylaminoalkyl This group attaches the cycloalkyl moiety to the parent compound. Examples of the (cycloalkyl) alkylaminoalkyl group include (cyclohexane) ethylaminemethyl, (cyclohexane) methylaminoisopropyl, and the like. When the term "(heterocyclyl) alkylaminoalkyl" is used herein, it means that the heterocyclyl moiety is attached to the parent compound via the alkylaminoalkyl group. Examples of (heterocyclyl) alkylaminoalkyl include (pyridine) ethylaminopropyl, (benzofuran) methyl 876 552260 A ^ -XJn; &gt; A7 B7 5. Description of the invention (874) Aminoiso Butyl, (tetrahydrofuran) methylaminoethyl and the like. The method described in MatSUmura et al., Eur j pharmac〇1 1103 (1990) and Takata et al., Clin. Exp · Pharmacol. Physiol.! 0-13 1 (1983) can be used to confirm that the compounds of the present invention lower blood pressure Ability. The ability of the compounds of the invention to treat congestive heart failure can be demonstrated according to the method described in Margulies et al., Circulation S2 2226 (1990). The ability of the compounds of the present invention to treat myocardial infarction can be demonstrated according to the method described in Wat an abe et al.] Mature 344 114 (1990). The ability of the compounds of the present invention to treat coronary arterial colic can be according to the method described in Heistad et al., Circ. Res. Ϋ 71 1 (1984). The ability of the compounds of the invention to treat cerebral vasospasm can be demonstrated by methods described in Nakagomi et al., J Neurosurg. 66_915 (1987) or Matsumura et al., Life Sci. 49 841-848 (1991). The ability of the compounds of the present invention to treat cerebral infarction can be demonstrated according to the method described in Hara et al., European J. Pharmacol. 197: 75-82 (1 99 1). The ability of the compounds of the present invention to treat acute renal failure can be demonstrated according to the method described in Kon et al. 'J. Clin. Invest. 81. 1 762 (1 989). The ability of the compounds of the present invention to treat chronic renal failure can be demonstrated according to the method described in Benigni Temple, Kidney Int. 44_440-444 (1 993). The ability of the compounds of the invention to treat gastric ulcer can be demonstrated according to the method described in Wallace et al., Am. J. Physiol. 256 G661 (1989). According to -877- as described in Kon et al., Kidney Int. 12 1487 (1990), the paper size specification / 丨] S National Standard (CNS) Λ4 Specification (210X 297 mm)-(Please read first Note on the back page, please fill in this page, 1T 552260 A7 B7 V. Description of the invention (875) (Please read the notes on the back page before filling out this page) Method to confirm the ability of the compound of the present invention to treat cyclosporine-induced renal toxicity The ability of the compounds of the invention to treat endotoxin-induced toxicity (shock) can be demonstrated according to the method described in Takahashi et al. 'Clinical Sci. 2_9 619 (1990). According to Potvin and Varma, Can. J. Physiol. And The method described in Pharmacol. ^ 2 12 13 (1989) confirms the ability of the compound of the present invention to treat asthma. The compound of the present invention can be confirmed to treat transplant-induced asthma according to the method described in Foegh et al., Atherosclerosis 78_229-236 (1989). The ability of the compounds of the present invention to treat arteriosclerosis can be confirmed according to the methods described in Bobik et al., Am. J. Physiol. 258 C408 (1990) and Chobanian et al., Hypertension JL 327 (1990). The ability of pulse sclerosis. The ability of the compounds of the invention to treat LPL-associated lipoprotein disorders can be demonstrated according to the method described in Ishida et al., Biochem. Pharmacol. 44 143 1 -1436 (1992). According to Bunchman ET and CA Brookshire, Transplantation Proceed. 23.967-968 (1991); Yamagishi et al., Biochem. Biophys. Res. Comm. 191 840-846 (1993); and Shichm et al., J. Ciin. Invest. 82 1867-1871 (1991 ) To demonstrate the ability of the compounds of the present invention to treat proliferative diseases. Proliferative diseases include smooth muscle proliferation, systemic sclerosis, liver cirrhosis, dyspnea in adults, spontaneous cardiomyopathy, lupus erythematosus, Diabetic retinopathy or other retinopathy, psoriasis, scleroderma, ___- 878-wood paper ft scale tracking / 丨] Zhongguan Jiabiao Mou (CNS) 552260 A7 B7 5. Description of the invention (876) Prostatic hypertrophy, cardiac hypertrophy, Restenosis after arterial injury or other vascular pathological stenosis. The ability of the compounds of the present invention to treat acute or chronic pulmonary hypertension can be demonstrated according to the method described in Bonvallet et al., Am. J. Physiol. 2_Hl327 (1994). Pulmonary hypertension is associated with congestive heart failure, mitral stenosis, emphysema, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute dyspnea syndrome (ARDS), southern air disease, and chemical exposure. Or it may be spontaneous. The ability of the compounds of the invention to treat platelet aggregation or thrombosis can be demonstrated according to the method described in McMurdo et al., Eu. J. Pharmacol. 259 51 (1994). The ability of the compounds of the present invention to treat cancer can be demonstrated according to the method described in Shichiri et al., J. Clin. Invest. 87. 1867 (1991). The ability of the compounds of the present invention to treat IL-2 (and other cytokinin-regulated) cardiotoxic and vascular penetrating diseases can be demonstrated by the methods described in Klemm et al., Proc. Nat. Acad. Sci. 922691 (IQQg) . The ability of the compounds of the present invention to treat nociception can be demonstrated according to the method described in Yamamoto et al., Pharmacol. Exp. Therap. 2. ± 156 (1994). The ability of the compounds of the present invention to treat colitis can be demonstrated according to the method described in Hogaboam et al. (EUR. J. Pharmacol. 1996, 309, 26 269). According to the method described in Aktan et al. (Transplant Int 1996, 201-207), it is confirmed that the compounds of the present invention treat ischemia-reperfusion during kidney transplantation. Milk) 8 specifications (210; &lt; 297 mm) -----— (Please read the precautions on the back before writing this page). Packing-Order 552260 A7 B7 --One One One «-One — ___— _ 5. The ability of the invention to explain (877) ^ ~ a note of damage. The compound of the present invention can be used to treat colic, pulmonary hypertension, and the method described in Ferro and Webb (Drugs 1996, 12-27). Raynaud's disease and ability to migraine. The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include, but are not limited to, the following: acetate, adipic acid, alginate, lemon Acid salt, aspartate salt, benzoate salt, benzenesulfonate salt, hydrogen sulfate salt, butyrate salt, camphor salt, camphor sulfonate salt, digluconate, cyclopentane propionate salt Alkyl sulfate, ethane sulfonate, glucoheptanoate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, Butanedioic acid, hydrochloride, hydrobromide, hydroiodate, 2-hydroxy-ethanesulfate, lactate, maleate, methanesulfonate, nicotinate , 2-sulfonate, oxalate, parmamate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate Salts, tartrates, thiocyanates, p-toluenesulfonates and undecanoates. Also available are low-carbon alkyl fluorenes such as fluorenyl, ethyl, propyl and butyl chloride, Bromine and iodine; dialkyl sulfates, such as: dimethyl sulfate, diethylamidine, dibutyl g, and dipentyl g, long-chain compounds, such as decyl, lauryl meat diacid, and Stearic acid gas, &gt; Stinky and broken 'aryl pit group_' Preparations such as henyl and phenethyl bromide and others will quaternize nitrogen-containing basic groups. This produces water or oil- Soluble or dispersible products. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as lice acid, sulfuric acid, and phosphoric acid, and oxalic acid, maleic acid, Purine And organic acids such as citric acid. -880- This paper has passed the state standard (cNs) Λ4 specification (210 &gt; &lt; 297mm) (Please read the precautions on the back before filling this page) ▼ 装. 、 -0 552260 A7 B7 V. Description of the invention (878) (Please read the notes on the back before filling out this page) The final isolation and purification of the compound of formula (I), or by separately making the carboxylic acid The functionality is prepared in situ by reaction with a suitable base, such as a nitrogen emulsion of a pharmaceutically acceptable metal cation, a sodium salt or a carbon salt, or a primary, secondary, or tertiary amine, or organic Alkali addition salt. Such pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals and alkaline earth metals, such as sodium, lithium, potassium, calcium, aluminum salts and the like, as well as ammonium, quaternary ammonium And amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. Other representative organic amines that can be used to form base addition salts include diethylamine, ethylenediamine, ethanolamine, hexahydropyrine, and the like. The compounds of the present invention can also be used against human endothelin in humans or other mammals. In addition, the compounds of the invention can be used (in humans or other mammals) to treat hypertension, acute or chronic pulmonary hypertension, Raynaud's disease, congestive heart failure, myocardial infarction, reperfusion injury, coronary arterial colic , Cerebral infarction, cerebral vasospasm, chronic or acute renal failure, gastric ulcer caused by non-steroidal anti-inflammatory drugs, nephrotoxicity caused by cyclosporine, endotoxin-induced toxicity, asthma, fibrosis and proliferative diseases, including smooth muscle proliferation, Systemic sclerosis, liver cirrhosis, respiratory distress syndrome in adults, spontaneous cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathy, psoriasis, scleroderma, prostatic hypertrophy, cardiac hypertrophy, arteries Restenosis after injury or other vascular pathological stenosis, LPL-associated lipoprotein disorders, transplant-induced arteriosclerosis or general arteriosclerosis, platelet coagulation, thrombosis, cancer, prostate cancer, IL-2 or other Cytokinin. Zhou Jie's cardiotoxicity and penetrative disorders, as well as nociceptive, especially -881-this paper size Tongchuanzhong _ quasi (―CNS χ π⑽ 552260 A7 B7 V. Description of the invention (879 is to treat bone pain associated with bone cancer. The total daily dose of the host is administered in single or divided doses, such as from ^ Π to milligrams per kilogram of body weight per day, and for death, Tole's more common is from. The intestine for kilogram administration ranges from G to 1G mg / kg. The dosage unit composition can be a fraction of the content of this type to constitute a daily dose.: Mix the content of sexual ingredients with the carrier substance to produce a basis to be treated &lt; Single dosage form to be changed according to the administration form of King Stem .: 2: The specific agent for any particular patient will be known; the content will be based on various factors, including the activity of the specific compound used, and the weight of the year. General health status, gender, diet, time of administration 'administration' :: degree of excretion ', your rate, composition of the drug and the severity of the particular disease being treated. The compounds of the present invention may contain traditional non-toxic, pharmaceutical Acceptable dosage unit formulations for carriers, adjuvants, and vehicles include the following: administration of the second intestine 'sublingual, inhalation spray, rectal or local administration can also involve the use of transdermal administration For example, via 2 tablets or an iontophoresis device. Parenteral-words, packages are used in this article. Intravenous, intravenous, intramuscular, intrasternal injection, and infusion techniques are available. According to known techniques, use appropriate Dispersant or wetting agent and prefecture: ,, :: for injection products, such as sterile water for injection or: oil :, π. 4 囷 injection products can also be non-toxic non: Party's diluent or solvent for sterile injectable solutions or suspensions in propylene glycol. In acceptable vehicles and lysates U -----882-Clothing-(Please read the back first Please note ^ write this page) Order A7 Β7 552260 V. Description of the invention (88〇) Use water, Ringer's solution, and bodhi ^ &gt; ir-r ^ m ^ ^ &gt; 々 emulsified sodium solution. In addition, In the traditional way, you can also use the fixed oil as the horse / cereal or suspension medium. For this purpose, you can The use of mild glutamate ^ ψ, κ 'Father's mouth oil includes synthetic mono- or diglycerides 酉. In addition, π found that oils such as oil, α, and 11 types of fatty acids can also be used to inject straight monthly fat The medicated formulation can be prepared by mixing Zhikun Zhizhi with appropriate non-irritating excipients, such as 可可> 田 和 PEG, which is solid in normal conditions, but At the temperature of the rectum and the temperature of the intestine, the body will also melt, and the drug will be released from the intestine. The solid dosage form for oral administration can include capsules, lozenges, pills, tinctures And granules. In such solid dosage forms, the active compound can be mixed with an inert diluent such as sugar, lactose or starch. It is also customary for such dosage forms to include other inert diluents, such as wetting agents such as magnesium stearate. In capsules, lozenges and medicinal ::: II: Form 5F may include buffering agents. Lozenges and pills can also be prepared using known coatings. ':: For administration, liquid dosage forms may include pharmaceutically acceptable emulsions / mixtures / preservatives, syrups, and elixirs, and contain h-type diluents such as water in the art. Such compositions may also include adjuvants such as wetting agents, emulsifying agents and suspending agents, as well as sweeteners, flavoring agents and flavors. The compound of the invention of (2) can also be administered in the form of liposomes. As with this technique Θ-112 ', microgranules are usually derived from squamous lipids or other lipid substances. Microlipids are formed by 2 mono- or multi-layered hydrated liquid crystals, which are dispersed in an aqueous medium. Any non-toxic, capable of forming microfat particles can be used: ___- 883-This paper is suitable for A4 size (---- 111---I 11 ϋϋ---士 1— _ 2 (Please read the back first Please fill in this page for the matters needing attention} _ 丁 ____ 1 I --------------- 552260 A7 ___________________ B7 V. Description of the invention (881) v Physiologically acceptable and metabolizable Lipids. The composition of the present invention in the form of microfat granules may contain stabilizers, preservatives, excipients and the like in addition to the compounds of the present invention. Preferred microfat granules are natural or synthetic phospholipids And phospholipid donkey bile test (egg squat fat). The method of forming microlipids is well known in the art. See side edits by Prescott, Methods in Cell Riologv, Book XIV,

Academic Press, New York, ND (1976), p. 33 and below. Representative solid dosage forms, such as lozenges or capsules, include: Compounds of the invention: 35% weight / weight starch, pre-gelatinized, NF 50% weight / weight microcrystalline cellulose, NF 10% weight / weight talc, Powder, USP 5% w / w The compound of the present invention can be administered in the form of a single active pharmaceutical preparation, and it can also be administered together with one or more selected from diuretics, adrenergic blockers, vasodilators, and calcium channels. Blockers, renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin π antagonists, potassium channel activators, and other cardiovascular preparations are used in combination. Representative diuretics include hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, and benzthiazide , Ethacrynic acid, furosemide, indacrinone, metolazone, spiralonlactone, triamterene, chlorine Chlorthalidone and its analogs, or pharmaceutically acceptable salts thereof. -884- The size of this paper is suitable for the national standard (CNS) Λ4 specification of the valve (210X297 mm) ~-(Read the precautions on the back before filling this page -pack_

1T 552260 A7 B7 V. Description of the invention (882) (Please read the precautions on the back before filling out this page) Representative blocking agents with adrenaline function include phenytoline, phenoxy + amine, prazosin ), Terazosin, tolazine, atenolol, metopr〇i〇i, nadolol, propranol〇1 , Tamoxifen (tim001), carteolol and its analogs, or pharmaceutically acceptable salts thereof. Representative vasodilators include hydralaZine, minoxidil, diazoxide, nitroprusside and their analogs, or pharmaceutically acceptable salts thereof class. Representative calcium channel blockers include amrinone, bencyclane, diltiazem, fendiline, flunarizine, nica Nicardipine, nimododipine, perhexiiene, verapamil, gallopamil, nifedipine and their analogs, or their pharmacy Acceptable salt. Representative renin inhibitors include enalkiren, zankiren, RO 42-5892, PD-134672, and the like, or pharmaceutically acceptable salts thereof. Representative angiotensin II antagonists include DUP 753, A-8 1988, and their analogs. Representative ACE inhibitors include captoprn, enalapril, lisinopril, and the like, or pharmaceutically acceptable salts thereof. Representative 4A channel activators include pinacidil and its classes -885- OM 552260 A7 ________ B7 V. Description of the invention (883) analogs, or pharmaceutically acceptable salts thereof. (Please read the notes on the back before filling this page) Other representative cardiovascular preparations include anti-sympathetic agents such as methyldopa, clonidine, and guanabenz , Reserpine and its analogs, or pharmaceutically acceptable salts thereof. The maximum clinical doses may be recommended, or the compounds and cardiovascular formulations of the invention may be administered at lower doses. The dose content of the active compound in the composition of the present invention can be changed depending on the route of administration, the severity of the disease, and the patient's response in order to obtain the desired therapeutic response. The combination can be administered as separate compositions in a single dosage form containing two formulations. When administered as a combination, the therapeutic agent formulation &apos; composition &apos; may be administered at the same or different times, or the therapeutic agent may be administered as a single composition. This article is mainly to explain the present invention, and is not intended to limit the present invention to what has been disclosed. , Compounds, procedures, compositions, and methods. Changes and alterations will be apparent to those skilled in the art, and they are intended to be included within the scope and nature of the invention as defined in the appended patent application scope. _____— ___ —_____-886-This is the standard ㈣

Claims (1)

A8 B8 C8 D8 92. 552260 f 08 Gong 112783 patent application and applied for replacement of the patent scope (June 1992) 6. Application scope of patent 1. Kinetically pure compounds, which are selected from the following composition Group · [2 8,3 feet, 4 8] _2- (2,2-Dimethylpentyl) -4_ (7-methoxy-1,3-benzo-dioxolane-5- ) -1- (N, N-bis (n-butyl) aminocarbonylmethyl) -pyrrole_3-carboxylic acid and [2S, 3R, 4S] -2- (4-methoxyphenyl)- 4- (1,3-Benzo-dioxol-5-yl) -1-[(N-butyl-N- (4-dimethylaminobutyl) amino) lysyl] _ p ratio p each precipitate _ 3-double acid. 2. A substantially pure compound according to item 1 of the scope of patent application, which is [2S, 3R, 4S] -2- (252-dimethylmethyl) -4- (7-methoxy-1,3- Benzo metadioxol-5-yl) -1- (N, N-bis (n-butyl) aminocarbonylmethyl) -pyrrole-3-guinic acid. 3. A substantially pure compound according to item 1 of the scope of patent application, which is [2S, 3R, 4S] -2- (4-methoxyphenyl) -4- (1,3-benzo-dioxane Cyclopenten-5-yl) -ΐ · [(N-butyldimethylaminobutyl) amino) carbonylmethyl] pyrrolidine-3-carboxylic acid. Author 4. A treatment for hypertension, congestive heart failure, restenosis after arterial injury, renal failure, cancer, colitis, reperfusion injury, angina pectoris, lungs, blood pressure, migraine, brain or myocardial infarction ▲ or A pharmaceutical composition for arteriosclerosis, which comprises a therapeutically effective amount of a compound according to any one of claims 1 to ^ in the scope of the patent application. 5. · A kind of treatment for coronary artery colic, cerebral vasospasm, acute and chronic renal failure, gastric ulcer, nephrotoxicity caused by cyclosporine, maternal endotoxin, asthma, LPL-related lipoprotein disorders, Proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, regulated cardiotoxicity, nociceptive, colitis, dysregulation of vascular permeability 'O: \ 54 \ 54022-4-920627 DOO 1 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Medical re: injection injury, Raynaud's disease, prostatic hypertrophy, and migraine, two, and s, which contain a therapeutically effective amount of a compound according to any one of the three items of the scope of the patent application. 6. A pharmaceutical composition for treating cancer ', which comprises a compound having a therapeutically effective last name (according to any one of items i to 3 of the scope of patent application). 7 .: The pharmaceutical composition according to item 6 of the patent application scope, wherein the cancer is an adenocarcinoma. 8. A pharmaceutical composition for treating nociception, which comprises a therapeutically effective compound according to any one of claims 1 to $ of the patent application scope. 〃 -2 O: \ 54 \ 54022-4-920627 DOC \ This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) 552260 92 · 6 · Qiao No. 087112783 Chinese Supplementary Specification (92 June 2006) Compound bonding (in vitro) hum ETa (IC50) hum ETb (IC50) Selective examples 536 0.49 15,400 28,300 Examples 547 1.6 10,000 6,000 P: \ MLS \ 2003C \ Answer \ 54022RO2 Supplemental amendment DOC 2