TW581760B - Pyprolidine carboxylic acid derivatives having endothelin antagonism - Google Patents

Abstract

A compound of formula (I), 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.

Description

581760 A7 ______B7 V. Description of the invention (1) This case is the sequel to the US patent case serial number 08 / 600,625 (published on February 13th, 1996), which is the US serial number NO.os / 497, " 8 (announced on August 2, 1995), which is part of the US serial number No. 08 / 442,575 (announced on i " May 30, 5), which is followed by Part of the sequel to US Patent Serial No. 08 / 334,717 (published on November 4, 1994), and then US Patent Serial No. 08 / 293,349 (published on I " August 19, 4) Partial sequel. TECHNICAL FIELD The present invention relates to an endothelin antagonist compound, a method for preparing the same, a synthetic intermediate used in these processes and methods, and a composition that antagonizes endothelin. BACKGROUND OF THE INVENTION Endothelin (ET) is a 21 amine Acid-based peptides are produced by endothelial cells. ET is produced by the enzyme dissociation of the precursor peptide large endothelin (Large ET) * Trp_Val bond. This dissociation is caused by endothelin converting enzyme (ECE). Endothelin no longer shrinks arteries and veins, increases average arterial blood pressure, reduces cardiac output, increases cardiac contractility in the test tube, stimulates vascular smooth muscle mitosis in the test tube, and contracts non-vascular smooth muscle in the test tube including guinea pig air 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) Tubes, human urine, cysts, and rat uterus, increase respiratory resistance in vivo, defame the formation of gastric ulcers, and stimulate Anterior chamber natriuretic factor (released in vitro and in vivo) increases plasma levels of vasopressin, aldosterone, and catecholamines, inhibits the release of renal hormones in the test tube, and stimulates the release of gonadotrophins in the test tube. Blood vessels have been shown Contraction is the binding of endothelin to its receptors on vascular smooth muscle. -4-This paper is suitable for financial standards (CNS) M specifications (B0χ; public director) ---- 581760 A7 B7 V. Description of the invention (2) (Nature 332 411 (1988), FEBS Letters 231 440 (1988) and Biochem. Biophys. Res. Commun. 154 868 (1988)). Can inhibit endothelin production or bind to endothelin Or it can inhibit the binding of endothelin and endothelin receptor, which can have beneficial effects in various therapeutic fields. In fact, it has been shown that anti-endothelin antibodies can relieve renal hemostasis in renal vascular resistance once intrarenal infusion. And the adverse effects on the filtration rate of vascular bulbs (Kon, et al., J. Clin. Invest. 83. 1762 (1989)). In addition, anti-endothelin antibodies can reduce the renal toxicity of intravenous administration of cyclosporine ( Kon, et al., Kidney Int. II 1487 (1990)), and the size of infarcts that can be reduced in coronary arterial myocardial infarction (Watanabe, et al., Nature 344 114 (1990)) 〇 Central Ministry of Economic Affairs Printed by the Bureau of Consumers of the Bureau of Consumption (Please read the precautions on the back before filling this page)

Clozel et al. (Nature 365: 759-761 (1993)) reported that Ro 46-2005, a nonapeptide ET-A / B antagonist, can prevent gluteal vasoconstriction in rats after hemorrhage when taken orally , To prevent the reduction of cerebral blood flow (SAH) caused by subarachnoid hemorrhage in rats, and to reduce MAP in sodium depleted squirrel monkeys. Recently, it has been reported that a linear tripeptide ET-A antagonist, BQ485, has a similar effect on the arterial canal after SAH (S. Itoh, T. Sasaki, K. Ide, K. Ishikawa, M. Nishikibe, and M. Yano, Biochem. Biophys. Res. Comm., 195: 969-75 (1993)). These results show that agents that antagonize ET / ET receptor binding can provide therapeutic benefits in the disease conditions shown. Agents with the ability to antagonize ET / ET receptor binding have been shown to be active in animal models of many human diseases. For example, Hogaboam et al (EUR. J. Phamacol. 1996, 309_, 261-269), has shown that endothelin is affected by -5- This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 581760 Β7 V. Description of the Invention (3) Antagonists can reduce the damage in rat models of colitis. Aktanet al (Transplant Int 1996, Mod. 201_207) has shown that similar agents can prevent hemorrhage-reperfusion injury in kidney transplantation. Similar studies have suggested the use of endothelin antagonists for angina pectoris, pulmonary hypertension, Raynaud's disease, and migraine (Ferro and Webb, Drugs 1996, 51, 12-27). Abnormal levels of endothelin or endothelin receptors are also associated with many disease conditions, including prostate cancer (Nelson et al, Nature Medicine 1995, 1, 944-949), suggesting the role of endothelin in the pathology of these diseases. Wu-Wong et al (Lfe Sciences 1996, 58, 1839-1847) have shown that both endothelin and endothelin antagonists can bind tightly to plasma proteins, such as serum albumin. This plasma protein binding reduces the effectiveness of the antagonist in inhibiting the effects of endothelin. Therefore, endothelin antagonists with reduced plasma protein binding will be more potent than their highly binding counterparts. DISCLOSURE OF THE INVENTION The compound of formula (I) is proposed according to the present invention: (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 where Z is -C (R18) (R19) _ or _c (〇) _, where Ri8 and r19 are independently selected from hydrogen and lower alkyl groups; η is 0 or 1; -6- This paper size applies to Chinese National Standards (CNS) μ specifications (2 × 〇297mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 ________B7___ 5. Description of the invention (4) R is-(CH2) mW Where m is an integer from 0 to 6, and W is (a) -C (0) 2_G, where G is hydrogen or a carboxy protecting group, (b) _po3h2, (c) · P (0) (〇Η) Ε Where E is hydrogen, lower alkyl or arylalkyl, (d) -CN, (e) -C (0) NHR17, where r17 is lower alkyl, (f) alkylamine carbonyl, (g) Dialkylamine carbonyl, (h) tetradecyl, (i) hydroxyl, fluorenyloxy, (k) sulfonamido, (l) —C (0) NHS (0) 2R16, where R16 is a low-carbon alkyl , _Fluorenyl, aryl or dialkylamino, (m) -S (0) 2NHC (0) R16, where R16 is as defined above, (Please read the precautions on the back before filling this page)

581760 A7 B7 V. Description of the invention (5

(Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 1 ^ and 112 are independently selected from hydrogen, lower alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy Carbonylalkyl, hydroxyalkyl, alkyl, alkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminecarbonylalkyl, Alkylaminocarbonylalkyl, dialkylaminecarbonylalkyl, aminecarbonylalkenyl, alkylaminocarbonylfluorenyl, dienylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkyl Oxygenated groups, (N-fluorenylalkyl) aminomethyl'alkyl, pyridinyl, aminomethyl, heterocyclyl, heterocyclyl, (heterocyclic) amino and (Raa) (Rbb) N-Rcc- ' Where Raa is aryl or arylalkyl, Rbb is fluorenyl or alkylfluorenyl and R. . Is an alkylene group, and the restriction bar is accompanied by one or both of the heart and trans-2; R3 is ⑷ R4-C (0) -R5-, R4-R5a ·, R6.s (〇) 2-R "or ⑼ · -8 This paper size applies Chinese National Standard (CNS) A4 specification (21〇 > < 297 public shame) ^ 1760 A7 _B7 1. Description of the invention (6) where R5 is a ⑴ covalent bond, (ii) extension Alkyl, (out) alkenyl, (iv) -N (R20) -R8_ or -R8a-N (R20) _R8_, where R8 & R8a is independently selected from the group consisting of alkenyl and alkenyl, and r2G is Hydrogen, lower alkyl, alkenyl, fluorenyl, alkoxyalkyl, from alkoxyalkyl, cycloalkyl or cycloalkylalkyl or (ν) -0-R9- or -R9a_〇 _R9_, wherein H9 and R9a are independently selected from the group consisting of arylene; R5a is aralkylene or (ii) alkenyl; R? Is (i) a covalent bond, (ii) alkylene, and (iii) alkene Alkenyl or (iv) -N (R21) -R10- or _R10a-N (R21) -R10 ·, wherein r1o and R10a are independently selected from the following including alkylene and alkenyl, and r21 is hydrogen , Lower alkyl, alkenyl, fluorenyl, alkoxyalkyl, alkoxyalkyl, aryl or arylalkyl; 114 and 6 are independently selected from the following: (i) (Rii) (Ri2 ) N ·, In and r12 are independently selected from (please read the note and then fill in the back of this page)

, 1T printed by the Consumer Cooperative of the Central Standard Bureau of the Ministry of Economic Affairs, ⑴ hydrogen, ⑺ low-carbon alkyl, (3) haloalkyl, (4) oxoalkyl, (5) haloalkoxyalkyl, (6) naphthene (7) Decyl, (8) Cycloalkyl, (9) Cycloalkyl, -9-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 581760 A7 B7 V. Description of the invention (7) (10) aryl, (11) heterocyclyl, (12) arylalkyl, (13) (heterocyclyl) alkyl, (14) hydroxyalkyl, (15) alkoxy , (16) amine alkyl, and (17) trialkylamine alkyl, (ii) lower alkyl, (iii) fluorenyl, (iv) bulk, (v) cycloalkyl, (vi) cycloalkane Alkyl, (νϋ) aryl, (viii) arylalkyl, (ix) heterocyclyl, (x) (heterocyclyl) alkyl, (xi) alkyloxy, (xii) alkyl, (xiii) haloalkyl, (xiv) haloalkyl, (xv) haloalkyl (xvi) halooxy, (xvii) alkoxy i alkyl, -10

Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China (Please read the precautions on the back before filling this page) This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of invention (8) (xviii) alkylamino, (xix) alkylamino, (XX) alkyloxy, and

(xxi) where Z is 0-5 and R7a is an alkylene group; printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, R26 is a fluorene lower alkyl group, (ii) a haloalkyl group, (ii) an alkenyl group, (iv) Block group, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclyl, (X) (heterocyclyl) alkyl (Xi) alkyloxy or (xii) alkyloxy-substituted haloyl; and R27 is dialkyl or diphenyl; (b) R22-〇-C (0) -R23- ' Where R22 is a tertiary protecting group or heterocyclic group and R23 is a fluorene covalent bond, (ii) an alkylene group, (iii) an alkenyl group, or (iv) -N (R24) -R25- 'wherein R25 is an Alkyl and Alkyl are hydrogen or low-carbon alkenyl, (C) low-carbon tiger, (d) fluorenyl, 0) bulk, (f) cycloalkyl, (g) cycloalkylalkyl, (h ) Aryl, (i) arylalkyl, -11-This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

T 581760 A7 B7 V. Description of the invention (9) (j) aryloxyalkyl, (k) heterocyclyl, (l) (heterocyclyl) alkyl, (m) alkoxyalkyl, (η) alkoxy Alkoxyalkyl, or (°) Ri3-C (0) -CH (Ri4)-where R13 is amine, alkylamino or dialkylamino, and Ri4 is aryl or Ri5-C (0)- Wherein R15 is an amine group, an alkylamino group or a dialkylamino group; or a pharmaceutically acceptable salt thereof. The preferred embodiment of the present invention is a compound of formula (II) below (please read the precautions on the back before filling this page)

Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, where the substituents _R2, -R and -Ri exist in a trans, trans relationship, and Z, η, R, Ri, 112 and 113 are as defined above. Another preferred embodiment of the present invention is a compound of formula (j) or (ii), wherein η is 0 and Z is · CH2-. Another preferred embodiment of the invention is a compound of formula G) or (ii), wherein η is 1 and Z is -CHr. Another preferred embodiment of the invention is a compound of formula (1) or (11), wherein η is 〇 'and ZS_CH2-, and R3SR4_C (0) _R5_, R6_S (0) 2_R7- or -12- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (1) ) R26-S (0) -R27-, where r4, R5, R6, R7, r26 and r27 are as defined above. Another preferred embodiment of the present invention is a compound of formula (I) or (Π), wherein n is 0, Z is -CH2-, and R3 is an alkoxyalkyl or alkoxyalkoxyalkyl group. Preferred specific examples of the present invention are compounds of formula (I) or (II), where η is 0, and Z is -ch2_, and R3 is R4_ (CO) -R5_, where R4 is (Rii) (R12) N_, as above As defined herein and R5 is an alkylene or r3 * R6_S (〇) 2_R7_ * R26_S (0) _R27-, where R7 is an alkylene, R27 is an alkylene and R6 and R26 are as defined above. Another preferred embodiment of the present invention is a compound of formula (I) or (II), wherein η is 0, and Z is -ch2_, and R3 is R4-C (0) -N (R2q) _R8-4R6-S ( 0) 2-N (R21) -R10_, where r8kr10 is an alkylene group and r4, R20 and R21 are as defined above. Printed by the Consumers' Cooperative of the Ministry of Economic Affairs of the Ministry of Economic Affairs (please read the notes on the back before filling out this page). The preferred embodiment of the present invention is a compound of formula (I) or (π), where n is 0 and R is Tetrazolyl or -C (0) 2_G, where G is hydrogen or a carboxy protecting group, or R is tetrazolyl or R is -C (0) -NHS (0) 2R16, where R16 is a lower alkyl group, halogen Alkyl or aryl, Z is · CH2-, I and I are independently selected from ⑴lower alkyl, (ii) cycloalkyl, (iii) substituted aryl, where aryl is phenyl is 1, 2 or 3 substituents, independently selected from lower alkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy, (iv) substituted or unsubstituted heterocyclic groups, (V) fluorenyl, (vi) heterocyclic (kylyl), (vii) aralkyl, (viii) aryloxyalkyl, (ix) (N-alkylfluorenyl-N-alkyl) aminoalkyl, and (X) Alkylsulfonylamidoamino alkyl, and R3 is r4-C (0) -R5- where R4 is -13- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (11) (RU) (R12) N-, where Rn and R12 are independently selected from low-carbon kneeling group and halogenated alkyl group , Alkoxyalkyl, alkoxyalkyl, aryl, aralkyl, heterocyclyl, hydroxyalkyl, alkoxy, aminealkyl, and trialkylamine alkylamine, and R5 is an alkylene group; or R3 Is 114-(:( 〇)-: ^ (1120) -118- or 116-8 (〇) 2-: ^ (1121) -1110-, where 114 is lower alkyl, aryl, alkoxy, Alkylamino, aryloxy or aralkoxy, and R6 is lower alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or aralkyl, 118 and 111 () are extensions Alkyl, and R2G and R21 are lower alkyl; or R3 疋 R (5-S (0) 2-R7 · 'or R26-S (0) _R27 ·' where R26 is a low-carbon alkyl or haloalkyl R7 is an alkylene group, R26 is a lower alkyl group and r27 is an alkylene group. Also, a preferred embodiment of the present invention is a compound of formula (I) or (II), wherein η 疋 0 'R is -C (0 ) 2_G 'Where G is hydrogen or a sulphonyl protecting group, Sijun group or _C (0) -NHS (0) 2R16, where R16 is a lower alkyl group, alkyl group or aryl group, employee of Central Standards Bureau Printed by the Consumer Cooperative (please read the notes on the back before filling out this page) Z is _CH2-, Ri is ⑴lower alkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) ring pit , (V) phenyl, (vi) p ratio, (vii) succinyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl , 4-Ethyllactyl '4-ethylphenyl' 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl , 3-fluoro-4_ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-tert-butylphenyl, 1,3-benzobis Fluorenyl, 1,4-benzodifluorenyl or dihydrobenzofuranyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocycle (alkyl ), (X) aralkyl, (xi) aroxyalkyl, (Xii) (N-alkylfluorenyl-N-alkyl) aminoalkyl, or (xiii) alkylsulfonamidinylaminoalkyl , R2 is substituted or unsubstituted 1,3-benzodifluorenyl, 7-methoxy-1,3-benzodifluorenyl, 1,4-benzodifluorenyl, 8-methyl Oxy-1,4-benzodioxane-14- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 581760 A7 B7 V. Description of the invention (12), dihydrobenzofuranyl , Benzofuranyl, 4-methoxyphenyl Dimethoxyphenyl, fluorophenyl, or difluorophenyl, and R3 * R4-C (0) -N (R2 ())-R8- or R6-S (0) 2_N (R21) -R10 · ' Among them, Rs and Rio are alkoxy groups, R20 and Chi 21 are lower alkyl groups, R4 is lower alkyl group, aryl group, alkoxy group, alkylamino group, aryloxy group or aralkyloxy group, and r6 is low Carboalkyl, haloalkyl, alkoxyalkyl, aryl or aralkyl. Yet another preferred embodiment is a compound of formula (I) or (II), wherein η is 0 and R is -C (0) 2-G, wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C ( 0) _NHS (0) 2R16, where R16 is a lower alkyl, _alkyl or aryl, 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) Z is -CH2 -,: ^ is a fluorene lower alkyl group, (ii) an alkenyl group, (iii) an alkoxyalkyl group, (iv) a cycloalkyl group, (v) a phenyl group, (vi) a p-based group, (vii) Ranyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methyl Phenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro · 4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-tert-butylphenyl, 1,3-benzodialyl, 1,4-benzodifluorinyl or dihydrobenzene Benzofuranyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (X) arylalkyl, (xi) aryloxyalkyl (Xii) (N-alkylfluorenyl-N_ Alkyl) aminoalkyl, or (xiii) alkylsulfonamidinylaminoalkyl, R2 is substituted or unsubstituted 1,3-benzodifluorenyl, 7-methoxy-1,3 -Pyridinyl '1,4-benzodiazinyl' 8-methoxy ^ -1,4-benzodifluorinyl, dihydrobenzofuranyl, benzofuranyl, 4 -Methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl, and R3 is R4-C (0) _R5-, where R5 is an alkylene group and R4 is (RU) (R12) N_ Among them, Rn and R12 are independently selected from low carbon -15- This paper size is applicable to China National Standard (CNS) A4 (210 X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Description of Invention (13) Alkyl, i-alkyl, alkoxyalkyl, from alkoxyalkyl, aryl, aralkyl, heterocyclyl, hydroxyalkyl, alkoxy, aminealkyl, and trialkaminealkyl. Yet another preferred embodiment of the present invention is a compound of formula (I) or (II), wherein η is 0, R is -C (0) 2-G, where G is NHS (0) 2R16, and R16 is low carbon. Alkyl, haloalkyl or aryl, Z is -CH2-, I is fluorene lower alkyl, (ii) alkenyl, (iii) heterocyclyl (alkyl), (iv) aryloxyalkyl, (v ) Aralkyl, (vi) aryl, (vii) (N-alkylfluorenyl-N · alkyl) amine, or (viii) alkylsulfonamidoalkyl, R2 is substituted or unsubstituted Substituted 1,3-benzodiazinyl, 7-methoxy-1,3-benzodiazinyl, 1,4-benzodiazinyl, 8-methoxy-1,4-benzene Benzodialkyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl, wherein the substituent is selected from lower alkyl, Alkoxy and halogen, and 113 is R4-C (0) -R5 ·, where R5 is an alkylene group and R4 is (RU) (R12) N_, wherein Ru is a lower alkyl group and R12 is an aryl group, Aryl, alkynyl, alkoxy, amine, trisamino, or heterocyclyl. Another preferred compound of the present invention is a compound of formula (I) or (II), wherein n is 0 and R is -C (0) 2-G, wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C ( 0) -NHS (0) 2R16, where R16 is lower alkyl, haloalkyl or aryl, Z is -CH2-, & is lower alkyl, (⑴) alkenyl, (⑴) heterocycle (Alkyl), (iv) aroxyalkyl, (v) aralkyl, (vi) (N-alkylfluorenyl-N-alkyl) amine alkyl, or (vii) alkylsulfonamidinium amine Alkyl, (viii) phenyl, or (ix) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4 -Ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 1,3-benzodifluorenyl, 14-benzodihumidyl or dihydrobenzofuran -16 -This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) Order 581760 A7 ____B7 __ V. Description of the invention (14) The alkano group, of which the substituent is selected From lower alkyl, from alkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodifluorenyl , 7-methoxy · 1,3-benzodifluorenyl, L4-benzodifluorenyl, 8-methoxy-1,4-benzodi-p-oxo, dihydrobenzo Group, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl, wherein the substituent is selected from lower alkyl, alkoxy and _, and R3 is R6_S (〇) 2_N (R2i ) -Rio_, where Rio is a dialkyl group, R6 is a low carbon alkyl group, a halogenated alkyl group, an oxygenated alkyl group, a halooxyalkyl group, an aryl group or an aralkyl group, and R21 is a lower alkyl group, Alkyl, alkoxyalkyl, alkoxyalkyl, aryl or arylalkyl. Another embodiment of the present invention is a compound of formula (I) or (II), wherein η is 0, R is -C (0) 2-G, wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C ( 0) -NHS (0) 2Ri6 'where Ri6 is a low-carbon burned base, self-made or aryl, 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) Z is- CH2-'^ is (i) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzodiazyl, or 1,4-benzodiazyl, wherein the substituent is selected from the group consisting of lower alkyl, alkyl, alkoxy and Alkoxyalkoxy, (ii) lower alkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), (v) aroxyalkyl, (Vi) aralkyl, (vii) ( N-alkylfluorenyl-N-alkyl) aminoalkyl, (viii) alkyl fluorenylfluorenaminoalkyl, or (ix) phenyl, R2 is substituted or unsubstituted 1,3-benzene Benzodifluorenyl, 7-methoxy-1,3 · benzodihumenyl, 1,4-benzodifluorenyl, 8-methoxy-1,4-benzodifluorenyl, di Hydrobenzofuranyl, 4-methoxy Group, dimethoxyphenyl, fluorophenyl or difluorophenyl, wherein the substituent is selected from lower alkyl, alkoxy and halogen, and R3 is alkoxycarbonyl or R6-S (0) 2-N ( R21) -R10-, where R10 is an alkylene group, R6 is a lower alkyl group, a haloalkyl group, -17- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm " Central Ministry of Economic Affairs Printed by the Consumer Cooperative of the Bureau of Standards Bureau 581760 A7 ______ B7___ 5. Description of the invention (15) Alkoxyalkyl or oxalkoxyalkyl, and R21 is a lower alkyl, _alkyl, alkoxyalkyl or oxalkoxyalkyl Yet another preferred embodiment of the present invention is a compound of formula (I) or (II), wherein η is 0, R is _C (0) 2-G, wherein G is hydrogen or a carboxy protecting group, and tetrazolyl. Or -C (0) -NHS (0) 2R16, where r16 is lower alkyl or haloalkyl, Z is -CHy, I is lower alkyl, alkenyl, heterocyclic (alkyl), aryloxyalkane Aryl, aralkyl, aryl, (N-alkylfluorenyl-N-alkyl) aminoalkyl, or alkylsulfonylphosphoniumaminoalkyl, and R3 is r4_C (0) -R5, where R5 is Alkylene and R4 is (RU) (R12) N_, where ru and r12 are independently selected from alkyl, aryl, hydroxyalkane Group, alkoxy group, amine alkyl group, trialkylamine alkyl group, and heterocyclic group. Also preferred embodiments of the present invention are compounds of formula (I) or (II), wherein n is 0 and R is -C (0 ) 2-G, where G is hydrogen or carboxy protecting group, tetrazolyl, or -C (0) -NHS (0) 2R16, where r16 is lower alkyl or fluorenyl, and z is _CH2-, 1 ^ Is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4.trifluoromethylphenyl, 4-pentafluoroethyl Phenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodifluorenyl, 1,4-benzodifluorenyl or dihydrobenzo Furyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ii) lower alkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), (v ) Aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkylfluorenyl-N-alkyl) aminoalkyl, (viii) alkylsulfonylfluorenylamino, or ( ix) Phenyl, 112 is 1,3-benzodiainyl, ι, 4-benzodifluorenyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxy Phenyl, fluorophenyl or difluorophenyl And meaning 3 is r4_C (〇) -R5 •, where R5 is an alkylene group and R4 (Rn) (R12) N_, where Ru and r12 are independently selected from low -18- This paper size applies Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) (Please read the notes on the back before filling this page)

、 1T 581760 A7 _____B7 ____ 5. Description of the invention (16) Carbocarbon, aryl, aryl, supercarbon, alkoxy, amine pit, trimethylamine or heterocyclic group. Yet another preferred embodiment of the present invention is a compound of formula 0) 4 (11), wherein η is 0, R is -C (0) 2-G, wherein G is hydrogen or a carboxy protecting group, tetrazolyl, or- C (0) -NHS (0) 2R16, where r16 is a low-carbon or halogenated group, and _ (: 112-, R! Is a lower-carbon alkyl, alkenyl, heterocyclic (alkyl), aromatic Oxyalkyl, aralkyl, (N-alkylfluorenyl-N-alkyl) amine alkyl, alkylsulfonylfluorenylamino alkyl, phenyl, or alkoxyalkyl, R2 is 1,3- Benzodifluorenyl, 1,4-benzodifluorenyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl And R3 is R4_C (0) -R5-, where R5 is an alkylene group and R4S (Ru) (R12) N ·, wherein Ru and R12 are independently selected from the group consisting of a low-carbon pit group, an aryl group, an aryl group, and Pit base, alkoxy group 'amine pit group', diamine amine group or heterocyclic group. 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) The best of the invention Specific examples are compounds of formula (I) or (II), where n is 0, R is -C (0) 2-G, where G is hydrogen or a carboxy protecting group, and Z is -CH2-, Heart is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethyl Phenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodifluorenyl, 1,4-benzodifluorenyl or dihydrobenzo Furyl, in which the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, is 1,3-benzodialinyl '1,4-benzo-p-sulphonyl *, -rat Benzo p-furanyl'benzo p-furanyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl, and R3 is R4-C (0) -R5 ·, where R5 is an alkylene group, and R4 is (RU) (R12) N_, where Ru and Rl2 are independently selected from lower alkyl groups. -19- ί The paper size applies the Chinese National Standard (CNS) A4 specification (21〇 > < 297 mm 1 ~ 581760 Printed by A7 _ B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (17) Another preferred embodiment of the present invention is a compound of formula (I) or (II), where η is. , R is -C (0) 2-G, where G is hydrogen or carboxy protecting group, Z is -CH2-, 1 ^ is, substituted or unsubstituted 4-methoxy Phenyl, 4-fluorophenyl, 2-fluorophenyl, 4-tolyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4- Hydroxyphenyl, 4-ethylphenyl, 1,3-benzodifluorenyl, 1,4-benzodifluorenyl or dihydrobenzofuranyl, wherein the substituents are selected from alkoxy, alkoxy Alkoxy and carboxyalkoxy, R2 is 1,3-benzodifluorenyl, 1,4-benzodifluorenyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl , Dimethoxyphenyl, fluorophenyl or difluorophenyl, and R3 is R4-C (0) -R5_, where R5 is an alkylene group, and R4 is (Ru) (R12) N ·, where Rn is Lower alkyl and R12 is aryl. The most preferred embodiment of the present invention is a compound of formula (I) or (II), wherein η is 0, R is _C (Q) 2-G, where G is hydrogen or a carboxy protecting group, and Z is -CH2-, Ri Is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4 -Methoxymethoxyphenyl, 1,3-benzodihumyl, 1,4-benzodifluorenyl, or difluorenylbenzofuranyl, wherein the substituent is selected from lower alkyl, , Alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodifluorenyl, 7-methoxy-1,3-benzodi Hexyl, 1,4-benzodifluorenyl, 8-methoxy-1,4-benzodifluorenyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxybenzene Group, fluorophenyl or difluorophenyl, wherein the substituent is selected from the group consisting of lower alkyl, alkoxy and fluorene, and the anion 3 is 116-8 (〇) 2-; ^ (1121) -1110-, where 10 is an alkylene group, and R6 is a lower alkyl group, a haloalkyl group, an alkoxyalkyl group, or a haloalkoxyalkyl group, and R21 is a lower alkyl group, a haloalkyl group, or an alkoxyalkyl group. -20- This paper size applies to China National Standard (CNS) A4 (210 X297 mm) ~ (Please read the precautions on the back before filling this page), 11 581760 A7 B7 V. Description of the invention (18) A preferred specific example is a compound 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 1 is Substituted or unsubstituted 4-methoxyphenyl, 3-fluoro · 4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methyl Oxymethoxyphenyl, 1,3-benzodiciyl, 1,4-benzodifluorenyl or dihydrobenzocranyl, wherein the substituents are selected from lower alkyl, fluorenyl, Alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodifluorenyl, 7-methoxy-1,3-benzodifluorenyl , 1,4-benzodifluorenyl, 8-methoxy-1,4-benzodihumidyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorine Phenyl, or difluorophenyl, wherein the substituent is selected from lower alkyl, alkoxy, and halogen, and R3 is R4-C (0) -R5-, where R5 is an alkylene group and R4 is (R n) (R12) N-, wherein Rn is an alkyl group and R12 is selected from the group consisting of an aryl group, an amine alkyl group, a trialkylamine alkyl group, and a heterocyclic group. 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) and the best specific examples of the present invention are compounds of formula (I) or (II), where η is 0 and R is -C (0) 2-G, where G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is a low-carbon alkyl group, an alkenyl group, a heterocyclic group (alkyl group), an aryloxy group, an aromatic group, a square group '(N-pyridyl-N-pityl) amine tiger group, or fluorenyl amine group, and R3 is R4-C (0) -R5_, where Rs is an alkylene group, and r4 is (RU) (R12) N-, wherein Ru and R12 are independently selected from the group consisting of alkyl, aryl, alkynyl, alkoxy, amine alkyl, trialkylamine alkyl, and heterocyclic group, and the restriction is Rii And one of R12 is an alkyl group. Another preferred specific example is a compound of formula (VII) or (II), where η is 0, z is -CH2-, and RjR4-C (0) _R5_, wherein RA (Rn) (Ri2) N_, as described above Is defined, and R5 is alkylene. _____- 21-This paper size applies to Chinese National Standard (CNS) M specifications (210'x 297 public directors 1-printed by the Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 ___B7_____ 5. Description of the invention (19) Another best Specific examples are compounds of formula (I) or (II), where n is 0, Z is -CH2-, I is a lower alkyl group, and R3 is R4-C (0) _R5-, where R4 is (Rn) ( Ri2) N-, as defined herein, and R5 is an alkylene group. Another preferred specific example is a compound of formula (I) or (II), where η is 0, Z is -CH2-, and I is an alkenyl group, And R3 is R4-C (0) -R5-, where R4 is (Rn) (Ri2) N-, as defined herein and R5 is an alkylene group. Another best specific example is formula (I) or (II) ) Compounds, where n is 0, Z is -CH2-, I is heterocyclic (alkyl), and R3 is R4-C (0) _R5-, where R4 is (Rn) (R12) N_ as defined herein And R5 is an alkylene group. Another preferred specific example is a compound of formula (I) or (II), where n is 0, Z is -CH2-, & is an aryloxyalkyl group, and R3 is R4-C ( 0) -R5_, wherein R4 is (Rii) (Ri2) N · as defined in the above, and R5 is an alkylene group. Another preferred specific example is formula (I) or ( II) Compounds in which η is 0, Z is -CH2-, 1 is aralkyl, and R3SR4_C (0) _R5_, wherein ruler 4 is (Rii) (Ri2) N- as defined above, and R5 is an alkylene A further preferred specific example is a compound of formula (I) or (II), where η is 0, Z is -CH2-, Ri is aryl, and R3 is R4-C (0) -R5-, where R4 Is (Ru) (Rl2) N-, as defined herein, and R5 is an alkylene group. Another preferred specific example is a compound of formula (I) or (II) where η is 0 and Z is -CH2 ·, 1 ^ is (1 ^ alkylfluorenyl_N-alkyl) aminoalkyl, and r3 is R4-C (0) _R5_, where R4 is (Ru) (R12) N-, as defined herein, and R5 is Another preferred embodiment is a compound of formula (I) or (II), in which η is 0, Z is -CH2 · 'I is a sulfanyl sulfanylaminoamino group, and R3 is R4- c (0)-(Please read the precautions on the back before filling this page) Article 22- Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 Α7 Β7 V. Description of the invention (2〇) R5, where R4 is (Rn ) (R12) N_, as defined herein and R5 is an elongation group. The present invention is also a method for preparing compounds of formulae (I) and (II), and should be Synthetic intermediates in these processes. The present invention also relates to a method for antagonizing endothelin in a mammal (preferably a human) in need thereof, which method comprises administering to the mammal a therapeutically effective dose of formula (I) or (Π) Compounds. The present invention further relates to an endothelin antagonist composition comprising a pharmaceutically acceptable carrier and a therapeutically effective dose of a compound of formula (I) or (Π). The compounds of the invention include more than two asymmetrically substituted carbon atoms. As a result, racemic mixtures, diastereoisomeric mixtures, and single diastereoisomers of the compounds of the present invention are included in the present invention. The so-called S " and "R" configurations are as defined by IUPAC 1974 Recommendations for Section, E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13_30. The so-called "carboxy-protecting group" as used herein refers to a carboxylic acid-protecting ester group for blocking or protecting a carboxylic acid functional group, while a reaction involving the functional group position of another compound is still proceeding. The carboxy-protecting group is disclosed in Greene, " Protective Groups in Organic Synthesis " ρρ · 152-186 (1981), which is incorporated herein by reference. In addition, the carboxy-protecting group can be used as a prodrug, since the carboxy-protecting group can be easily dissociated in vivo, for example, through enzyme hydrolysis to release a biologically active parent. Τ. Higuchi and V. Stella raised the concept of prodrugs in nPro-drugs as Novel Delivery Systems' Vol. 14 of the ACS · Symposium Series, American Chemical Society (1975)-This paper is based on Chinese national standards ( CNS) A4 specification (210 ×: 297 mm) (Please read the notes on the back before filling out this page) Order printed by the Central Consumers Bureau of the Ministry of Economy Staff Consumer Cooperative 581760 A7 B7 V. Description of the invention (21) For a complete discussion Therefore, it is also included in this case for reference. Such carboxy protecting groups are well known to those skilled in the art, and have been used to protect leptin in the fields of penicillin and cephalosporins, as described in US Patent Nos. 3,840,556 and 3,719,667. reference. Examples of vinegars that can be used as prodrugs containing carboxyl compounds can be found in Bioreversible Carriers in Drug Design: Theory and Application, edited by E.B. Roche, Pergamon Press, New York (1987), p. 14-21, which is incorporated herein by reference. Representative reading "The protecting group is C 1-C 8 pit group (such as methyl, ethyl or tertiary-butyl and others); self-alkyl group; alkenyl group; cycloalkyl group and its substituted derivatives' Such as cyclohexyl'cyclopentyl, etc .; cycloalkenyl and its substituted derivatives, such as cyclohexylmethyl, cyclopentylmethyl, etc .; arylalkyl, such as phenethyl or benzyl and its Substituted derivatives, such as alkoxybenzyl or nitrobenzyl, etc .; arylalkenyl, such as phenylvinyl; etc .; aryl and its substituted derivatives, such as 5-hydroindenyl, etc .; (Eg, dimethylaminoethyl, etc.); alkoxyalkyl groups such as ethoxymethyl, butyloxymethyl, pentyloxymethyl, isobutyloxymethyl, isopentyloxymethyl Group, 1- (propanyloxy) · 1 · ethyl, 1_ (trimethylethylfluorenyloxy) -1-ethyl, 1_methyl-1 · (propanyloxyethyl, trimethylethyl Ethoxymethyl, propionyloxymethyl, etc .; cycloalkanoyloxyalkyl; such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl Aryloxyalkyl, such as benzyloxymethyl, benzyloxyethyl, etc .; aralkylcarbonyloxane , Such as benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl, etc .; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-1-ethyl, etc. Burning oxycarbonyloxy groups, such as methoxycarbonyloxymethyl, third-butoxycarbonyloxymethyl, 1-ethoxycarbonyloxy · ethyl, ^ cyclohexyloxycarbonyl _____- 24- Applicable to this paper size China National Standard (CNS) A4 Specification (210X297 mm) (Please read the notes on the back before filling this page) Order 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7_ V. Description of Invention (22) Oxygen-1 -Ethyl, etc .; Alkoxycarbonylaminoalkyl, such as tertiary-butoxycarbonylaminomethyl; etc .; Tigeraminecarbonylamino, such as methylamine carboxyaminomethyl; etc .; Fermenting aminomethyl, etc .; Heterocyclic carboxyoxyalkyl groups, such as 4-methylhexamethyl, phenylcarbonyloxymethyl, etc .; Dialkylaminecarbonylalkyl groups, such as dimethylaminocarbonylmethyl, diethylaminecarbonylmethyl And other groups; (5- (lower alkyl) -2-keto-1,3-difluoren-4-yl) alkyl, such as (5-third · butyl · 2-keto-1, 3-dipinen-4-yl) methyl and the like; and 1,5-phenyl-2-keto-1,3 · di Limonen-4-yl) alkyl, such as (5-phenyl-2-keto-1,3-dipinen-4-yl) methyl and the like. The so-called π N-protecting group π or "N-protected" as used herein refers to protecting the N-terminus of an amino acid or peptide, or protecting a group that antagonizes a non-desired reaction in a synthetic step. Commonly used N-protecting groups are disclosed in Greene, " Protective

Groups In Organic Synthesis, " (John Wiley & Sons, New York (1981)), which has been included as a reference in this case. Alkyl groups include fluorenyl groups such as formate, ethenyl, propionyl, trimethylethylfluorenyl, tertiary-butylethylfluorenyl '2-aminoethylfluorenyl, 2-bromoethylfluorenyl, Fluorethenyl, trichloroethenyl, perylene, ortho-nitrophenoxyethenyl, chlorobutenyl, benzamidine, 4-chlorofluorenyl, 4-bromobenzyl, 4-nitro Sulfenyl groups, etc .; sulfonyl groups such as phenylsulfenyl groups, etc .; carbamate-forming groups, such as benzyloxycarbonyl, para-phenylphenoxycarboxyl, para-methoxyphenyloxycarbonyl, para-nitro Benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4_dimethoxy Benzyloxycarbonyl, anisylmethoxybenzyloxy, 2_nitro_4,5_dimethoxybenzyloxycarbonyl, 3,4,5_trimethoxybenzyloxycarbonyl 1 (para-bibenyl) -1 -Methylethoxycarbonyl, "From · Dimethyl-3,5_dimethoxybenzyloxycarbonyl, diphenylfluorenyloxycarbonyl, tertiary butoxycarbonyl, dione____ -25- National Standards (CNS) Μ specifications (2lG > < 297 mm) (Please read the precautions on the back before filling in this page)

1T f-581760 A7 B7 V. Description of the invention (23) Isopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, ammonium propoxycarbonyl, 2,2,2-trichloroethoxycarbonyl , Phenoxycarbonyl, 4 · nitrophenoxy, alkoxy-9-methoxypentyl, cyclopentyloxy, amantadine, oxygenated weyl, cyclohexyloxy, phenylthio, etc .; Groups such as benzyl, triphenylfluorenyl, ethoxymethyl and the like; and silane groups such as trimethylsilyl and the like. Preferred] SM protective groups are methyl ethyl, ethyl ethyl, ethyl ethyl, trimethyl ethyl ethyl, tert-butyl ethyl ethyl, phenyl ethyl ethyl, benzyl, tert-butyl Oxocarbonyl (Boc) and ethoxycarbonyl (Cbz). "Alkino" as used herein refers to an alkyl group, as previously defined, appended to the parent molecular moiety through a fluorenyl group (-C (O) ·). Examples of sulfenyl include ethynyl, propionyl and the like. The term "alkylamino" as used herein means that an alkylamino group is attached to an amine group as previously defined. Examples of tiger amines include ethylamino, propylamino, etc. The so-called "alkylamino" "Aminoaminoalkyl" as used herein refers to R43-NH-R44-, where R43 is alkyl and R44 is alkylene. 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 in this page) The so-called `` alkoxyalkyl '' refers to R30-0-R31-, where r30 is alkyl and RS1 is alkylene. An example of alkyloxyalkyl is ethoxymethyl Group, ethoxyethyl, etc. As used herein, "alkenyl" refers to a straight or branched hydrocarbon group containing 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. A fluorenyl group such as ethenyl , Allyl, butenyl, 1-methyl_2_but-1-enyl, etc. The so-called "alkenyl" means that it contains 2 to 15 carbon atoms and also contains at least one carbon · carbon double bond Divalent radical derived from a straight or branched hydrocarbon radical. Dendene-26- This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) '~~ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 Α7 Β7 V. Examples of Invention (24) include- CH = CH-,-(: Η2 (: Η = (: Η ·, -C (CH3) = CH-, -CH2CH = chch2_, etc.). The so-called "alkenyl group" refers to an alkenyl group, as previously As defined, it is connected to the parent molecular moiety through an oxygen (-〇-) link. Examples of alkenyloxy include allyloxy, butenyloxy, etc. • 'Branyloxy' as used herein refers to R41. -, Wherein r41 is a lower alkyl group, as defined herein. Examples of the alkoxy group include, but are not limited to, ethoxy group, tertiary-butoxy group, etc. πalkoxyalkoxy group, as used herein Refers to r80〇-r81〇-, where r80 is a lower alkyl group as defined above, and R81 is an alkylene group. Representative examples of alkoxyalkoxy include methoxymethoxy, ethoxymethyl Oxy, tertiary-butoxymethoxy, etc. "Alkoxyalkoxyalkyl" as used herein refers to alkoxyalkoxy, as previously defined, appended to alkoxy Representative examples include methoxyethoxyethyl, methoxymethoxymethyl, etc. The so-called "alkoxyalkyl" as used herein refers to an alkoxy group as previously defined, appended to it as previously defined Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl, and the like. As used herein, refers to an alkoxy group as previously defined. Group, attached to the parent molecular moiety through a carbonyl group. Examples of alkoxy groups include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, etc. '• alkoxycarbonylalkenyl' as used herein refers to an alkoxycarbonyl group, as previously The definition is attached to the alkenyl group. Examples of alkenyloxy alkenyl groups include methoxycarbonylvinyl, ethoxycarbonylvinyl, etc. -27- This paper size applies to China National Standard (CNS) A4 (210 × 297 mm) ( Please read the notes on the back before filling this page) Ding 581760 Μ B7 V. Description of the invention (25) '· alkoxycarbonylalkyl' as used herein refers to r34_c (〇) _R35_, where Rs4 is alkoxy and R35 is Alkyl. Examples include methoxycarbonylmethyl, methoxy Ethyl, ethoxycarbonylmethyl, etc. •• alkoxycarbonylaminoalkyl • 'as used herein refers to R38_c (〇) _NH-R39_, where R38 is an alkoxy group and R39 is an alkylene group. •• alkane Oxycarbonyloxyalkyl ', as used herein refers to r36_c (0) _0_R37_, where & is an alkoxy group and R37 is an alkylene group. N (feoxyalkyl) thioalkyloxy' ', as used herein An alkoxycarbonyl group, as previously defined, is attached to a thioalkoxy group. Examples include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy, etc. • 'alkoxy_alkyl' as used herein refers to Alkyl, which has a carboxy group attached. " Branyl · 'and π low-carbon alkyl, as used herein, refers to a straight or branched alkyl chain containing 1 to j 5 carbon atoms, but is not limited to the following examples: methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, second butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2 · dimethylpropyl, n-hexyl and the like. The Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs printed the so-called "(N-alkylfluorenyl-N-alkyl) aminoalkyl" as used herein refers to R85C (0) N (R86) R87_ 'where R85 is The radical is as defined previously, and is a lower alkyl group, and R87 is an alkylene group. The π alkylamino group "RMNH_" as used herein, where RM is a low carbon alkyl group, such as ethylamino, butylamino, etc. • "Alkylaminoalkyl" as used herein refers to a lower-carbon alkyl group, which has an additional amine group 0 -28- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 581760 A7 B7 5 2. Description of the invention (26) The so-called "alkylamine carbonyl group" as used herein refers to an alkylamine group, as previously defined, attached to the parent molecular moiety through a carbonyl (-c (o)-) link. Examples of alkylamine carbonyl groups include Methylamine carbonyl, ethylamine carbonyl, isopropylamine carbonyl, etc. "π alkylamine carbonyl alkenyl" as used herein refers to alkenyl groups which have an additional alkyl amine carbonyl group. "• Alkylaminocarbonylalkyl" as used herein refers to a lower alkyl group, with an additional alkylamine carbonyl group. "Alkylaminocarbonylaminoalkyl group, as used herein, refers to R4 (rc (0) -NH-R41-, where R40 is an alkylamino group and R41 is an alkylene group. 0 •• alkylene group means a divalent group derived by removing two hydrogen atoms from a straight or branched saturated hydrocarbon having 1 to 15 carbon atoms, such as _ c H2-, -CH2CH2- 9 -CH (CH3)-? -CH2CH2CH2- 9 -CH2C (CH3) 2CH2- and so on. "" Continuation of the alkyl amidino group "refers to R88s (〇 ) 2NH89-, where the ruler 88 is a low-carbon fe group and the ruler 89 is a nonyl group. The "M alkyl group" refers to an alkyl group as previously defined, via a continuation of the amino group (S (0 ) 2-NH-) is added to the parent molecular moiety. Examples of tiger sulfonylamino include methylsulfonamido, ethylsulfonamido, isopropylsulfonamido, etc. Central Bureau of Standards, Ministry of Economic Affairs Printed by an employee consumer cooperative (please read the notes on the back before filling out this page) π alkynyl " as used herein refers to a straight or branch containing 2 to 15 carbon atoms and also containing at least one carbon-carbon bond Hydrocarbyl Examples include CeC-H, H-CeC-CH2-, H-CeC-CH (CH3)-, etc. • "Alkynyl" refers to a group consisting of 2 to 15 carbon atoms and also containing a carbon-carbon hydrazone bond. Divalent derived from the removal of two hydrogen atoms by a straight or branched acyclic hydrocarbon group -29- This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm 1 581760 Printed by A7, Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs ____ B7 V. Description of invention (27) group. Examples of decyl group include -CeC-, _C ^ C_CH2_, _C ^ C-CH (CH3)-, etc. 3 The so-called πaminoalkylπ means _NH2, Alkylamino or dialkylamino groups are added to the parent molecular moiety through sulfo groups. The so-called " aminocarbonyl group " refers to h2n-c (o) _ as used herein. Πaminocarbonylalkenyl refers to as used herein Alkenyl, which has an amine carbonyl (NH2C (0)-) attached. Πaminocarbonyloxy "as used herein refers to H2N-C (0)-, appended to an alkoxy group as previously defined. Aminecarbonylalkoxy Examples of amine groups include aminecarbonylmethoxy, aminecarbonylethoxy. "Aminopyridyl" refers to a low-carbon pentyl group, with an additional amine group (NH2C (0) _). ', Trialkylamine Alkyl, as used herein refers to (R90) (R91) (R92) N (R93)-, where R90, R91 and R92 are independently selected from lower alkyl groups, and R93 is an alkylene group. Oxyalkyl n as used herein refers to R32-C (0) -0-R33 ·, where r32 is an aryl group and r33 is an alkylene group. Examples of arsenyloxyalkyl include benzyloxymethyl ' ethanoyloxyethyl and the like. The term "πaryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or more aromatic rings and includes phenyl, fluorenyl, tetrahydrofluorenyl, hydroindenyl, indenyl, and the like. Aryl May be 1, 2 or 3 substituted or unsubstituted with a substituent independently selected from the group consisting of lower alkyl, fluorene, alkyl, alkoxy, alkynyl'enoxy, carboxy, Oxyalkyl, carboxyl, oxyalkyl, alkenyl, (alkoxycarbonyl) thioalkoxy, thioalkoxy, amine, amine, dialkylamino, amine alkyl, trioxane Amine alkyl, amine carbonyl, and amine carboxyl oxygen -30- ^ _ This paper size applies to Chinese National Standard (CNS) A4 (210 × 297 mm) (Please read the precautions on the back before filling this page) Order 581760 A7 B7 V. Description of the invention (28) group, alkylamino, aralkyloxy, aryloxy, mercapto, cyano, nitro, leptaldehyde, leptyl, leptenyl, carboxyalkoxy, alkylsulfonyl Amine, cyanoalkoxy, (heterocyclic) alkoxy, #yl, #alkoxy, phenyl and tetrazolyloxy. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorobenzene. base The so-called "arylalkenyl" refers to an alkenyl group, which is added with an aryl group, such as styryl, etc. •• aralkoxy "refers to R420-, where R42 is an aralkyl group, as Oxygen, etc. •• Aralkoxyalkylπ refers to a lower alkyl group as used herein, with additional aralkyloxy groups such as benzyloxymethyl and the like. &Quot; Aryl radical " As used herein refers to an aryl group, as previously defined, appended to a lower alkyl group, such as amidino and the like. "Squareoxy" as used herein refers to R450- 'wherein R45 is an aryl group, such as phenoxy, etc. "" Aromatic carbonyloxyalkanoyl "as used herein refers to a lower-carbamoyl group, with an additional arylalkylcarbonyloxy group (Ie R62C (0) 0-, where R62 is arylalkyl). "πaryloxy: fe-based" refers to aryloxy, which is attached to tigeryl as previously defined. Examples of aryloxyalkyl include phenoxymethyl, 2-phenoxyethyl, etc. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling out this page) •• Carboxaldehyde ”as used herein means formaldehyde group, -C (0) H. &Quot; Carboxy •• As used herein means carboxylic acid group, -C ( 0) 0H. •• Carboxenyl " as used herein refers to a carboxyl group as previously defined, appended to an alkenyl group 'as previously defined. Examples of carboxyalkenyl include 2-vinyl, 3-carboxy-1-ethylene And so on. •• Sulfuryloxy M refers to a carboxyl group, as defined previously, with the addition of _ -31-This paper size is suitable for financial and family scale (CNS) A4 specifications (21 () \ 297 mm 1 & quot 581760 A7 ___________B7 ___ V. Description of the invention (29) to alkoxy, as previously defined. Examples of carboxyalkoxy include carboxymethoxy, ethoxylate, etc .; Used refers to an alkoxy group as previously defined, appended with a cyano group (-CN). Examples of cyanoalkoxy groups include 3-cyanopropoxy, 4-propanebutoxy And others. "F-Cycloalkyloxyalkyl" as defined herein refers to a lower alkyl group with an additional cycloalkoxy group (ie, R60-C (O) -〇-, where r60 is a cycloalkyl group) • 'Cycloalkyl' as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings, including cyclopropyl, cyclopentyl, cyclohexyl, n-singyl, adamantane But not limited thereto. Cycloalkyl may be unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of lower alkyl, haloalkyl, alkoxy, and thioalkoxy , Amino, alkylamino, dialkylamino, hydroxyl, halogen, mercapto, nitro, carboxaldehyde, carboxyl, alkoxycarbonyl and carboxamido. Cycloalkylalkyl " refers to cycloalkyl, as used herein, Appended to lower alkyl groups, including but not limited to cyclohexylmethyl. "Dialkylamino" as used herein refers to R56R57N-, where R56 and r57 are independently selected from lower alkyl groups, such as diethylamino, Methylpropylamino, etc. "Dialkylaminoalkyl" as used herein refers to a lower alkyl group, which is appended to the dialkylamino group. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please Read the notes on the reverse side and fill out this page) •• Dipitylamine carboxyl "as used herein refers to a diamine group, as previously defined, attached to the parent molecular moiety via a fluorenyl (-C (O)-) link Examples of dialkylaminofluorenyl groups include dimethylaminocarbonyl, diethylaminecarbonyl, etc. π dialkylaminecarbonylalkenyl refers to alkenyl as used herein, with additional dialkylaminecarbonyl groups 0 -32- This paper standard Applicable to China National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs i. Description of the invention (30) Means, wherein trans 50 is a dialkyl group and R51 is a dialkyl group. "Halogen" as used herein refers to I, Br, C1 or F. •• Haloalkenyl ”as used herein means an alkenyl group, which is appended with at least one radical. Πhaloalkoxy” as used herein refers to an alkoxy group as defined above, carrying at least one fluorene substituent, such as 2 -Fluoroethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2,2,3,3,3-pentafluoropropoxy and the like. The so-called "π-alkoxyalkyl" refers to a lower alkyl group, which is added with a halooxy group. "Haloalkyl" as used herein refers to a lower alkyl group, as defined above, which has at least one additional substituent such as chloromethyl, fluoroethyl, trifluoromethyl or pentafluoroethyl, and the like. "Heterocycle" as used herein refers to containing any 3- or 4-membered ring selected from the group consisting of oxygen, nitrogen and sulfur heteroatoms; or containing 1, 2 or 3 nitrogen atoms; 1 oxygen atom; i sulfur atoms 1 nitrogen and 1 sulfur atom; 1 nitrogen and 1 oxygen atom; 2 oxygen atoms at non-adjacent positions; 1 oxygen and 1 sulfur atom at non-adjacent positions; or 2 sulfur atoms at non-adjacent positions 5-, 6_ or 7-membered rings in adjacent positions. 5-membered rings have 0-2 double bonds and 6- and 7-membered rings have 0-3 double bonds. Nitrogen heteroatoms can be quaternized as required The so-called "heterocyclic ring" also includes bicyclic groups, in which any of the above heterocyclic rings may be fused with a benzene ring or a cyclohexane ring or another heterocyclic ring (such as: indolyl, indolinyl, junlin Base, istholinyl, tetrahydro 4: linyl, tetrahydroisolinyl, decahydro 4-lyl, decahydroisoquinyl, benzofuranyl, dihydrobenzofuranyl or benzopyrim (Phenyl, etc.). Heterocyclics include: aziridinyl, butane-33- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

581760

A7 B7 V. Explanation of the invention (31) Symptom group, say Loki, say Loki, p Bihadian, p Bijundi, π than Junlin, say Jundian, Mi Junji, Mi Junlin Base, Mijundo base, P than Yodo base, hexahydro says Yodo base, high hexahydrogen P ratio Yodo base, t p well base, hexahydro? Than Pingji, Shoutianji, Tower Pingji ·, Chejunji, Chejunji, Yiumjunji, Yiming 《Junedianji, Movilinji, Thiomorphinji, Hunjunji , P, succinyl, isoTI, stilbenyl, isoxazolyl, oxolyl, quinolyl, isoquinolyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, ethyl Oxyalkyl, furanyl, tetrahydrosuccinyl, p-secenyl, p-secretinyl, iso-synthetyl, trisynyl, tetrazyl, isostearyl, naruto, dijune, P Selenium, eryl, alkynyl and benzothienyl, and heterocycles also include compounds of formula 'where X * is -CH2 · or -0, and Y * is -C (O) · or [ -C (R ") 2_] V, where R " is hydrogen or C1-C4-alkyl, and v is 1, 2 or 3, such as 1,3-benzodiainyl, 1,4-benzodiphenyl Alkyl, etc. Heterocyclic rings also include bicyclic rings, such as tiquinidyl, etc. Heterocyclic rings may be unsubstituted or mono- or di-substituted by substituents independently selected from the group consisting of alkyl, halo, and keto ( = 0), alkylamino (R * N = where R * is a lower alkyl group), amine, alkylamino, dialkylamino, alkoxy, alkoxy Alkoxy, amine alkyl, trialkylamine alkyl, fluorenyl, aryl, aralkyl, -COOH, -S03H, alkoxycarbonyl, nitro, cyano and lower alkyl. In addition, nitrogen A heterocyclic ring may be protected by N-. So-called '(heterocyclic) alkoxyπ means a heterocyclic group, as defined above, appended to an alkoxy group, as defined above. (Heterocyclic) alkane Examples of oxy include 4-pyridylmethoxy, 4-pyridylmethoxy, etc. -34- This paper size applies to China National Standard (CNS) A4 specification (21 × 297 mm) (Please read the back Note: Please fill in this page again.) 1T printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Printed by the Central Consumers Bureau of the Ministry of Economic Affairs. The term "heterocyclic group" as used above is appended to the low-carbon alkyl group as defined above. The so-called "heterocyclic carbonyloxyalkyl group" refers to RwC ^ CO-O1147-where R46 is a heterocyclic group and R47 is an alkylene group. "π hydroxyl" as used herein refers to -OH. π # is an alkenyl group, as used herein refers to an alkenyl group, with a meridian group attached. I appended "hydroxyalkoxy" as used herein refers to an alkoxy group, as previously defined, 'r ^ A plus a hydroxyl group (-OH). Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4-oxy and the like. "Hydroxyalkyl" as used herein refers to a lower alkyl group with a hydroxyl group appended. " Leaving group " as used herein means a halide (such as Cl, Br or I) or hard (such as mesylate, tosylate, trifluoromethanesulfonate, etc.). • '馋 基' refers to -SH as used in this. 〆 " methylenedioxy " and "ethylenedioxy " means that one or two carbon chains pass through 〆„

Irin I son is attached to the parent molecule. In the methylenedioxy example, a 5-membered ring of and is formed. In the case of ethylenedioxy, the formation of a fused 6-member rod of methyldioxy on the benzene ring results in the formation of benzodifluorenyl. Ethylenedioxy substitution on the benzene ring results in the formation of a benzodifluorenyl group ’

The so-called "substantially pure", as shown in the above-indicated compound of 95 //-35- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) Matters need to be filled in this book) 1Τ 581760 A7 B7 V. Description of Invention (33)

A group of N or its mutual f-tetrazolyl " as used herein refers to a isomer. " Tetrabenzyloxy "as used herein refers to a tetrabenzyl radical, as defined above, and appended to the tetrabenzyloxy radical as defined above. Examples of tetrabenzyloxy radicals include tetramethylmethoxy, tetrabenzyl Oxygen, etc. "Thioalkoxy" as used herein refers to R70S-, where R70 is a lower alkyl group. Examples of thioalkoxy include methylthio, ethylthio, and the like. "πthioalkoxyalkoxy" as used herein refers to R80S_R81〇-, where R80 is a lower alkyl group as defined above, and RS1 * alkylene. Representative examples of alkoxy groups include CH3SCH20 -, EtSCH20-, t-BuSCH20-π-thio-pitoxy-feoxy-graft "as used herein refers to a thio-alkoxy group and a cyano group, which is added to the alkyl group. Representative examples of alkoxyalkoxyalkyl include CH3SCH2CH2OCH2CH2-, ch3sch2och2-, and the like. The so-called "trans, trans" refers to the direction of the substituent (R1 & R2) compared to the central substituent R, as shown: (Please read the precautions on the back before filling this page) Ministry of Economic Affairs Printed by the China Consumers' Cooperatives

The so-called " trans, cis " as used herein refers to the direction of the substituents (1 and 1) compared to the central substituent R, as shown: 36- 581 Gang A7 B7 V. Description of the invention (34)

R2々々YA, Z, R3 r2, s (CH2) a R

Or,. This synonym includes examples in which R and R2 are cis-forms, and ruler and heart are trans-forms, and ^^ and hate are trans-forms, and R and Ri are cis-forms. -•• cis, cis "means that the substituents (heart and trans 2) are opposite to the central substituent; the direction of R is as shown ...

The staff of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the Ministry of Economic Affairs and Cooperation of the preferred compounds of the present invention are selected from the following: trans-trans-2- (4-methoxyphenyl) -4- (1,3-benzodi唠 _5-yl) _1propyl-N-n-pentanesulfonamido) propyl] pyrrolidine-3-carboxylic acid; trans, trans-2- (4-methoxymethoxyphenyl) -4- (1,3-benzodiazyl) _ 1- [2- (N-propyl-N_n-pentamylamino) ethyl] pbiha—fluorene-3-carboxylic acid ; Trans, trans-2_ (3,4-dimethoxyphenyl) -4- (1,3-benzodifluorene-f,) _yl) hepta [2- (N-propyl-N · N-pentamyl aminoamino) ethyl] V Bihar bite, Λ I carboxylic acid; [3-〇su trans, trans-2- (3,4-dimethoxyphenyl) -4- (1,3-Benzodi-1 .- [2- (N-propyl-N-n-hexanesulfonylamino) ethyl] pyroxalic acid 37 This paper is sized to the Chinese National Standard (CNS) A4 Specifications (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7___ 5. Description of the invention (35) trans, trans-2-('propoxyphenyl) -4_ (13-benzodifluorene) 5-yl) _1- [2-(] ^-propyl-N · n-pentanesulfonylamino) ethyl] pyrrolidine-3-carboxylic acid; Formula, trans-2- (3,4-difluorophenyl) 4- (1,3-benzobenzozine_5_yl) _1_ (((N, N-dibutylamino) carbonyl) methyl ) _Pyrrolidine_3 · carboxylic acid; trans, trans_2- (3,4 · difluorophenyl) · 4- (1,3-benzobisfluoren-5 · yl) _1- [2- (N-propyl-n-pentanylfluorenylamino) ethyl] pyhalidine-3-retanoic acid; trans, trans-2- (3-fluoro-4-methoxyphenyl) -4- ( 1,3-Benzodiphen-5-yl) -1- [2- (N-propyl-N · n-hexanesulfonylamino) ethyl] pyrrolidine-3-carboxylic acid; trans, trans Formula-2- (3-fluoro-4 · methoxyphenyl) -4_ (1,3-benzobenzofluoren-5-yl) -1- (2- (N-propyl-N- (3-chloro Propanesulfonyl) amino) ethyl) pyrrolidine-3-carboxylic acid; trans'trans-2- (3-gas-4 · methoxyphenyl) -4_ (1,3 · fluorene and one loss -5 · yl) -1 _ (2- (N-isobutyl-N- (3-chloropropanylpyridinyl) amino) ethyl) p-pyrrolidine-3-carboxylic acid; trans, trans Formula · 2- (3-fluoro · 4-methoxyphenyl) _4- (1,3_benzodifluorene_5_yl) -1- [2- (N · propyl · N- (4-methyl Butanesulfonyl) amino) ethyl] pyrrolidine-3-carboxylic acid; trans, trans-2- (4-methoxy-3-fluorophenyl) -4- (7 · methoxy Yl-1,3-benzodihum-5 -Yl) -1- [2- (N-propyl-N- (n-pentanesulfonyl) amino) ethyl] pyrrolidine-3-chinic acid; trans, trans-2_ (3 · Fluoro-4_methoxyphenyl) -4- (1,3-benzodifluorene_5-yl) -1_ [2_ (N-propyl-N- (2,2,3,3,3 · 5 Fluoropropoxyethanesulfonyl) amino) ethyl] pyrrolidine-3-carboxylic acid; -38- _ This paper size applies to China National Standard (CNS) A4 (210 × 297 mm) (Please read the back Note: Please fill in this page again.) Order 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (36) Trans, trans-2- (l, 4-benzodioxane-6 · yl ) -4- (7-methoxy-1,3_benzodiam-5-yl) -1- [2- (N_propyl-N- (n-pentanesulfonyl) amino) ethyl Group] pyrrolidine-3-carboxylic acid; trans, trans-2- (3-fluoro-4-methoxyphenyl) -4- (1,3-benzobenzofluorenyl-5-yl) -bu ( 2- (N · isobutyl-N- (pentanesulfonamido) ethyl) pyrrolidine-3-carboxylic acid; trans, trans-2- (3 · fluoro-4_methoxyphenyl ) -4- (1,3-benzobisfluoren-5-yl) -1- (2- (N-methoxyethyl-N- (3-chloropropanesulfonyl) amino) ethyl) pyrrole Yodo · 3 · acid; trans, Formula _2- (3-fluoro-4-methoxyphenyl) -4- (1,3-benzodiν--5-yl) -1- (2- (N- (2-methoxyethyl ) _N_ (pentanesulfonyl) amino) ethyl) pyrrolidine • 3-carboxylic acid; trans, trans-2- (3-fluoro-4-methoxyphenyl) _4- (1,3_ Benzodi-17-l-5-yl) -1- [2- (N-propyl-N · ((2,2,2-trifluoroethoxyethane) sulfonyl) amino) ethyl] Pyrrolidine-3-carboxylic acid; trans, trans-2- (3-fluoro-4-methoxyphenyl) -4- (1,3_benzobisfluoren-5-yl) · 1_ (2_ ( Ν- (2-methoxyethyl) -N- (butanesulfonylamino) ethyl) pyrrolidine-3-carboxylic acid; trans, trans-2- (3-fluoro-4-methoxy Phenyl) -4 · (1,3-benzodifluoren-5-yl) -1 · [2- (N-propyl-N- (2-methylpropanesulfonyl) amino) ethyl] Pyrrolidine-3-carboxylic acid; trans, trans-2 · (3-fluoro-4-methoxyphenyl) -4- (1,3 · benzodiyl) _1 · (2- (N-iso Butyl (butyl succinylamino)) ethyl) ergoline _3. Ginic acid; -39- This paper size applies Chinese National Standard (CNS) A4 size (2⑴X297 male sauce) (Please read the back first (Notes on this page, please fill out this page), ιτ 581760 Α7 Β7 V. Description of the invention (37) trans Trans-2- (2-methylpentyl) _4_ (1,3-benzobenzofluorenyl-5 · yl) -1- (N, N-dibutylaminecarbonylmethyl) -pyrrolidine-3-carboxyl Acid; trans, trans-2 · (2,2-dimethylpentyl) -4- (1,3-benzodifluoren-5-yl) -1_ (N, N_dibutylaminecarbonylmethyl) ) Pyrrolidin-3-carboxylic acid; trans'trans-2_ (2- (l, 3-a alpha-2-yl) ethyl) _4- (1,3 -benzodi slogan-5- ) _1 · (N, N_: butylaminecarbonylmethyl) -pyrrolidine-3_carboxylic acid; trans, trans-2- (2- (2_tetrahydro-2Η · pyran) ethyl)- 4- (1,3-Benzodifluoren-5-yl) -l- (N, N-dibutylaminecarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, trans_2_ (2 , 2,4_trimethyl_3_pentenyl) _4_ (1,3 · benzobisfluoren-5-yl) -1- (N, N-dibutylaminocarbonylmethyl) -pyrrolidine- 3-carboxylic acid; trans, trans_2_ (2,2-dimethyl_2_ (1,3 · dioxane_2 · yl) ethyl (1,3 · benzodifluoren-5-yl ) -1_ (N, N_dibutylaminocarbonylmethyl) -pyrrole-3-unsuccinic acid; trans, trans-2- (2- (l, 3-difluoren-2-yl) ethyl ) _4 · (l, 3-Benzodifluoren-5-yl) -1 _ [[N-4-heptyl · N (2-methyl-3_fluorophenyl)] aminocarbonylmethyl; j pyrrole -3-carboxylic acid; trans, trans-2_ (2- (1,3_difluoren-2-yl) ethyl) -4_ (7-methoxy-1,3-benzodifluorene-5 -Base) -1- (N, N-dibutylaminecarbonylmethyl) -pyrrolidine-3_carboxyl 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) Acid; Trans'trans-2-((2-methoxyphenoxy) -methyl) -4- (1,3-benzodiain-5-yl) -1- (N, N-dibutyl Aminocarbonylmethyl) -pyrrolidine · 3 · carboxylic acid; (28,311,48) _2- (2,2_dimethylpentyl) _4_ (1,3-benzodifluorene_5-yl) -1 -(1 ^ · 4-heptyl-N- (4-fluoro-3-methylphenyl)) aminomethyl) P ratio ρ_3_ carboxylic acid; _-40 -__ Applicable to this paper size China National Standard (CNS) Α4 Specification (210 × 297 mm) 1 '~ Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7_____ V. Description of the Invention (38) Trans' Trans-2- (2- (2- (2- P-pyrrolidine-1 · yl) ethyl) -4_ (1,3-benzodiβ-deletive_5_yl) _1- (1 ^, 1 ^ -dibutylaminomethyl)- "E" 7 Gedian_3-acid acid; trans, trans-2- (2- (1,3_diamidino-2-yl) ethyl) -4- (7-methoxy-1 3-Benzodifluorenyl-5-yl) -1- (N-4_heptyl-N- (4-fluoro-3 -methylphenyl)) aminocarbonylmethyl) -pyrrolidine-3-carboxyl Acid; trans, trans-2- (2,2-dimethylpentyl) -4- (7-methoxy-1,3-benzodifluoren-5-yl) -1- (1 ^ , 1 > 1-dibutylaminomethyl) -1? Biloline-3-fascid; trans, trans-2- (2,2-dimethylpentyl) -4- (2, 3-dihydro-benzofuran-5-yl) -1- (N, N-dibutylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid; trans, trans-2- (2,2 _Dimethyl-2_ (1,3-dioxan-2-yl) ethyl) -4- (7-methoxy · 1,3-benzodifluoren-5-yl) -1- (Ν , N · dibutylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (2-methoxyphenyl) -ethyl) -4- (1,3 -Benzobisfluoren-5-yl) -1- (N, N · dibutylaminocarbonylmethyl) -pyrrolidin-3-carboxylic acid; trans, trans-2- (2,2-dimethylformate) -3- (E) -pentenyl) · 4 · (7-methoxy · 1,3-benzyl-1-benz-5-yl) -1- (N, N-dibutylamine Group) -ρ-bilodine-3-effect acid; trans, trans_2- (2- (2-pyridyl) ethyl) -4 · (1,3-benzobisfluoren_5_yl) 1- (N, N-dibutylaminocarbonyl (Methyl) · pyrrolidin-3-carboxylic acid; (2S, 3R, 4S) _2_ (2_ (2 · ketopyrrolidin-1-yl) ethyl) -4- (1,3_benzodifluorene- 5-yl) -1- (N, N-dibutylaminocarbonylmethyl) pyrrolidine-3-carboxylic acid; (2S, 3R, 4S) _2- (2- (2-ketopyrrolidine_1_ Group) ethyl) _4- (1,3-benzobisfluoren-5-yl) -1_ (N-4-heptyl-N- (4-fluoro-3-fluorenylphenyl)) aminocarbonylmethyl -)-Pyrrolidin-3-carboxylic acid; -41-_ This paper size applies to China National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page)

581760 Α7 Β7 V. Description of the invention (39) trans, trans-2- (2- (1-pyrazolyl) ethyl) -4 · (1,3-benzodifluorene_5_yl) -1_ (N, N-dibutylaminocarbonylmethylbiloline_3-acid acid; trans, trans-2- (4-methoxyphenyl) _4- (1,3 · benzodiazine · 5 · Yl) -1 _ [(N-butyl-N- (4-dimethylaminobutyl) amino) carbonylmethyl μpyrrolidine | carboxylic acid; (211,311,48) -2- (3- Fluoro-4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) -1- (2- (N-propyl · N-pentanesulfonamido) ethyl) P-pyrrolidin-3-carboxylic acid; trans, trans-2- (2,2-dimethylpentyl) -4_ (1,3-benzodifluoren-5-yl) -1- ( (N-butyl-N- (4-dimethylamino) butyl) aminocarbonylmethyl) · pyrrolidine-3-carboxylic acid; trans, trans · 2- (2,2-dimethylpentyl ) -4- (7-methoxy-1,3-benzodiazin-5-yl) -1- (N · 4-heptyl-N · (4 · fluoro-3-methylphenyl)) Aminocarbonylmethyl) -pyrrolidin-3-acid; trans, trans-2- (2,2-dimethylpentyl) -4- (7-methoxy-1,3-benzo Difluoren-5-yl) -1-((N-butyl-N- (4-dimethylamino) butyl) aminocarbonylmethyl) -p-bilodine-3 , Trans-2- (2,2_dimethylpent_3_alkenyl) _4- (1,3_benzodifluoren-5-yl) -1- (N-4_heptyl-N_ ( 4-Fluoro_3 · methylphenyl)) aminocarbonylmethyl) -pyrrolidin-3-carboxylic acid; printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Trans, trans-2- (2,2-dimethylpent-3-enyl) _4- (1,3-benzodifluoren-5-yl) -1-((N-butyl_N -(4-dimethylamino) butyl) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid; trans, trans-2- (2,2-dimethylpent-3-enyl) -4- (7-methoxy-1,3-benzodifluoren-5-yl) _1-((N, N · dibutyl) aminocarbonylmethyl) -pyrrolidine-3- • 42- This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 581760 Α7 Β7 V. Description of the invention (4〇) Metabolic acid; trans, trans-2- (2,2-dimethylpentan-3 -Alkenyl) -4_ (7-methoxy-1,3-benzodifluorenyl) _1- (N_4 · heptane-N- (4 · fluoro-3-methylphenyl)) aminocarbonylmethyl ) -Pyrrolidine-3-carboxylic acid; trans, trans-2- (2,2-dimethylpent-3 · enyl) -4- (7-methoxy-1,3-benzodi唠 -5-yl) -1-((Ν_ 丁· N · (4-dimethylamino) butyl) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid; trans'trans-2- (2,2,4-trimethylpenta- 3-fluorenyl) -4_ (1,3-benzobis 4-5_ylheptyl-N- (4-fluoro-3-methylphenyl)) aminocarbonylmethyl) -pyrrolidine-3-carboxyl Acid; trans, trans_2- (2,2,4-trimethylpent-3-enyl) -4- (1,3-benzodihum-5-yl) -1-((Ν · Butyl-N- (4 · dimethylamino) butyl) aminocarbonylmethyl) -p-bilodine-3_ leptin; trans, trans-2- (2,2,4-tri Methylpent-3-amidino) · 4- (7-methoxy-1,3-benzodifluoren-5-yl)-; l-((N, N-dibutyl) aminocarbonylmethyl ) · Pyrrolidine-3-carboxylic acid; trans'trans-2- (2,2,4 · trimethylpent-3-enyl) -4- (7-methoxy-1,3-benzene Benzene_5_yl) -1- (N-4-heptyl-N- (4-fluoro-3_methylphenyl)) aminomethyl) -p-bilodine-3 -read ^ Acid; 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) trans, trans-2- (2,2,4_trimethylpent-3-enyl ) -4- (7-methoxy-1,3-benzodifluoren-5-yl) -1-((N_butyl-N- (4-dimethylamino) ) Aminocarbonylmethyl) -pyrrolidine-3-chinic acid; trans, trans-2- (2- (1,3-di-2-enyl) ethyl) · 4- (1,3 -Benzodifluoren-5-yl) -1 · [(N · butyl-N- (4-dimethylaminobutyl) amino) carbonylmethyl) _ -43- This paper size applies to Chinese national standards (CNS) A4 specification (210X297 mm) 581760 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (41) Pyrrolidine_3_carboxylic acid; trans, trans_2_ (2- (1 , 3_difluoren-2-yl) ethyl) -4- (7_methoxy-1,3-benzodi-5-yl) · 1-[(N-butyl_N- (4 · Dimethylaminobutyl) amino) carbonylmethyl) -pyrrolidin-3-carboxylic acid; trans, trans_2- (2,2 · — methyl_2- (1,3 -digin -2 · yl) ethyl) -4 · (1,3-benzobenzoz-5-yl) -1- (N-4-heptyl-N- (4 · fluoro-3 -methylphenyl) amine Carbonylmethyl) -pyrrolidin-3-carboxylic acid; trans, trans-2- (2,2-monomethyl-2_ (1,3-benzobenzo-2-yl) ethyl)- 4- (I, 3-benzobisfluoren-5-yl) -1-[(N-butyl-N- (4-dimethylaminobutyl) amino) carbonylmethyl] -pyrrolidine-3- Carboxylic acid trans, trans-2_ (2 , 2 · dimethyl · 2_ (1,3 · diolin-2-yl) ethyl) · 4 · (7 · methoxy-1,3-benzodifluorene · 5-yl) -1_ (Ν · 4-heptyl-N- (4-fluoro-3 · methylphenyl)) aminothiomethyl) -ρ bilobitan-3-guinic acid; trans'trans · 2_ (2,2 -Dimethyl_2- (1,3_benzodiazinyl) ethyl) _4_ (7 · methoxy-I, 3 · benzobisfluorene · 5 · yl) -1-[(Ν- 丁-N- (4-dimethylaminobutyl) amino) carbonylmethyl] -pyrrolidine-3_carboxylic acid; trans, trans-2- (2- (2-methoxyphenyl)- Ethyl) -4- (1,3-benzobisfluoren-5-yl) -1- (N-4-heptyl-N- (4-fluoro-3-methylphenyl) amino) carbonylmethyl [] Yl] -exosulfoline-3-leptic acid; trans, trans_2- (2- (2-methoxyphenyl) · ethyl) _4_ (1,3_benzodihum_5_ group ) -1-[(N-butyl_N_ (4-dimethylaminobutyl) amino) carbonylmethyl] -p Bilolide-3-Jun; trans, trans-2_ (2- (2-methoxyphenyl) ethyl) -4- (7-methoxy-1,3-benzodifluoren-5-yl) -1 _ [((N, N-dibutyl) amino ） Carbonylmethyl] • pyrrolidine · -44-This paper size is applicable to China National Standard (CNS) A4 specification (2 丨 〇 > < 297 mm) (please first Read the notes on the back and fill in this page again.) Clothing. Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs and printed 581760 A7 ____B7___ V. Description of the invention (42) 3-carboxylic acid; trans, trans-2- (2- ( 2-methoxyphenyl) -ethyl) -4- (7-methoxy-1,3-benzodiam-5-yl) · 1 · (N_4-heptyl-N- (4-fluoro · 3-methylphenyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (2-methoxyphenyl) -ethyl) -4- ( 7-methoxy-1,3-benzodiam-5-yl) -1- (N-butyl-N- (4-dimethylaminobutyl) amino) carbonylmethyl] -pyrrolidine -3-carboxylic acid; trans, trans-2-((2-methoxyphenoxy) -methyl) -4- (1,3-benzobisfluoren-5-ylheptyl-N- ( 4-fluoro-3-methylphenyl) amino) carbonylmethyl] -exocarpy-3-carboxylic acid; trans, trans-2 · ((2 · methoxyphenoxy) · methyl ) -4_ (1,3-Benzodifluoren-5-yl) -Bu [(N-butyl_N- (4-dimethylaminobutyl) amino) carbonylmethyl] · p-pyridine -3-carboxylic acid; trans, trans-2-((2-methoxyphenoxy) -methyl) -4- (7-methoxy-1,3-benzodifluoren-5-yl ) _1 · [((N, N_dibutyl) amino) carbonylmethyl] Pyrrolidine 3-carboxylic acid; trans, trans-2-((2-methoxyphenoxy) _methyl) -4- (7 · methoxy-1,3-benzodifluorene-5 -Yl) -1_ (N-4-heptyl_N- (4-fluoro-3_methylphenyl)) amino) carbonylmethyl] -pyrrolidin-3-carboxylic acid; trans, trans- 2- (2- (2-methoxyphenoxy) -methyl) _4- (7-methoxy-1,3-benzodifluoren-5-yl) -1 · (N-butyl_ Ν- (4-dimethylaminobutyl) amino) carboxymethyl] -pyrrolidin-3-acid; trans, trans_2- (2- (2 · keto-1,2-di Hydropyridine_1-yl) _ethyl) · 4- (1,3-benzodifluoren-5-yl) -1-[(N, N-dibutyl) amino) carbonylmethyl] • pyrrole -45- This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) (please read the precautions on the back before filling out this page), 1T 581760 Printed by A7 B7, Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Description of the Invention (43) Yodo-3-Complete Edition, trans, trans-2- (2- (2- (2-amino-p-pyridine-1-yl) -ethyl) _4- (1,3_benzobis Methyl-5-yl)-[[N-4-heptyl-N- (4-fluoro-3 · methylphenyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; trans , Trans -2- (2- (2-fluorenyl p than yodo_1-yl) -ethyl) -4- (1,3-benzodiazepine-5-yl) -1 · [(N-butyl -N- (4-Dimethylaminobutyl) amino) carbonylmethyl] -p Bihadian-3-Jun; trans, trans_2- (2- (2-Hexyl 0 Biyodo- 1-yl) -ethyl) _4_ (7_methoxy-1,3-benzodifluoren-5-yl) -1-[(N, N-dibutyl) amino) carbonylmethyl]- Pyrrolido-3-complex acid; trans, trans-2- (2- (2-ketopyridin-1-yl) -ethyl) _4_ (7_methoxy · 1,3-benzodifluorene _5_yl) -1-[(N-4-heptyl-N- (4-fluoro-3-methylphenyl) amino) carbonylmethyl] · pyrrolidine-3-carboxylic acid; trans, Trans-2- (2- (2-fluorenylρ than dian-1-yl) -ethyl) · 4 · (7-methoxy_1,3_benzobisfluoren-5-yl) -1- [(N · butyl_N · (4-dimethylaminobutyl) amino) carbonylmethyl] _pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (2--嗣Hexaazine-1-Hydro-1-yl) -ethyl) _4- (1,3-Benzobenzoz-5-yl) -1-[(N, N-dibutyl) amino) []] Bihadian_3_ carboxylic acid; trans, trans-2- (2_ (2_fluorenylhexazine? Biyodo-1_yl) -ethyl) _4- (1,3-benzodiazin-5-yl) -1-[(N-4-heptyl-N- (4-Ga-3-methyl) Phenyl) amino) phenylmethyl] -pyrrolidin-3-carboxylic acid; trans, trans-2_ (2- (2-fluorenylpyridylazonitropyridine-1-yl) -ethyl)- 4- (7-methoxy-1,3-benzobisfluoren-5-yl) -1 _ [(N, N_dibutyl) amino) carbonylmethyl-46- This paper is in accordance with Chinese national standards ( CNS) A4 specification (2 丨 〇 > < 297 mm) (Please read the notes on the back before filling this page) Order--f 581760 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (44) yl] -pyrrolidin-3-carboxylic acid; trans, trans-2 · (2- (2-ketohexahydropyridine-yl) · ethyl) -4- (7 · methoxy -1,3-benzobisfluoren-5-yl) -1 · [(N, N_dibutyl) amino) carbonylmethyl] -ρ-bilodine-3 -unacid; trans, trans Formula 2- (2- (2-ketohexahydro υ bido-1-yl) _ethyl) _4- (7-methoxy_1,3 · benzodifluorene_5_yl) -1 -[(N-4-heptyl_N · (4 · fluoro_3_methylphenyl) amino) arylmethyl] -p-bilodine-3-metanoic acid; trans, trans-2 -(2- (2-ketohexahydropyridine_1 _Yl) _ethyl) _4- (7 · methoxy-1,3-benzodifluoren-5-yl) _1 · [(N · butyl-N- (4_dimethylaminobutyl) Amine group) -Tanylmethyl] -p-Bilodoline-3-polyacid; trans, trans-2- (2- (2-ketopyrrolidin-1-yl) -ethyl) -4- ( l, 3-benzobisfluoren-5-yl) -1-[(N-butyl_N_ (3-hydroxypropyl) amino) carbonylmethyl] pyrrolidine-3-carboxylic acid; trans, trans Formula 2- (2- (2-ketopyrrolidin-1-yl) -ethyl) -4- (1,3-benzodihum-5-yl) -1-[(N-butyl- N- (propoxy) amino) carbonylmethyl] -pyrrole • pyridine-3-carboxylic acid; trans'trans-2_ (2- (2-keto ρ than p each -1-yl)- Ethyl) -4- (1,3-benzodifluoren-5-yl) -1-[(N-butyl-N_ (4-dimethylaminobutyl) amino) carbonylmethyl] -pyrrolidine -3-carboxylic acid; trans, trans-2- (2- (2-ketopyrrolidin · 1-yl) -ethyl) _4 · (1,3-benzodifluorene-5 · yl)- 1 _ [(N-butyl-N · (4 · trimethylammonylbutyl) amino) carbonylmethyl] -ρ Bihadian-3-unsaturated acid; trans, trans-2- (2- (2 -Ketopyrrolidin-1-yl) · ethyl) -4- (7-methoxy-1,3-benzobisfluoren-5-yl) -1- (Tetramethyldibutylaminocarbonylmethyl ) -Pyrrolidine- -47- Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) Γ 581760 A7 B7 V. Description of the invention (45) 3-Reciprocal acid; trans' trans _2- (2- (2-keto p-pyridyl-1-yl) _ethyl) _4_ (7_methoxy_I, 3-benzodifluorene_5_yl) -1 _ [(Ν -Butyl_N- (3-hydroxypropyl) amino) carbonylmethyl] -pyrrolidin-3-carboxylic acid; trans'trans-2- (2- (2-_yl? Pyrrolidine-1-yl) _ethyl) _4_ (7 • methoxy · 1,3-benzodifluoren-5-yl) · 1 [(N_4-heptyl-sense (4_fluoro_3 _Methylphenyl) amine) fluorenylmethyl] -ρ than slightly lake-3-chinic acid; trans, trans-2 · (2 · (2-ketoerololine_1_yl) _ Ethyl) _4_ (7_methoxy · 1,3_benzobisfluoren-5-yl) -1 _ [(N · butyl-N- (propoxy) amino) carbonylmethyl] -pyrrolidine -3-carboxylic acid; trans'trans-2- (2_ (2-_ylρbipyridin-1-yl) _ethyl) -4- (7-methoxy-1,3-benzo Dizaki-5-yl) -1-[(N-butyl-N- (4-dimethylaminobutyl) amino) fluorenylmethyl] -pyloride-3-leptic acid; trans' Trans-2- (2_ (2_keto is p-1-yl) · ethyl) _4_ (7_methoxy1,3-benzodiazin-5-yl) -1-[( N-butyl-N- (4-trimethylammonylbutyl) amino group) -ylmethyl] _erodoline-3-polyacid; trans, trans-2- (2- (2- Keto p-bilopido · 1-yl) _ethyl) · 4_ (2,3-dihydrobenzofuran-5-yl) -1- (N, N-dibutylaminecarbonylmethyl) _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) trans, Formula 2- (2- (2-ketopyrrolidin-1-yl) _ethyl) 4- (2,3 · dihydrobenzofuran-5-yl) -1-[(N_4-heptyl- N_ (4-fluoro-3-methylphenyl) amino) Talking methyl] Bihadian-3-acid acid; trans, trans-2_ (2- (2-keto-r-pyrodoline-1) -Yl) -ethyl) _4_ (2,3_dihydro-benzofuran-5-yl) -1-[(N-butyl-N- (4-dimethylaminobutyl) amino)- 48- This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) 581760 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (46) Carbonylmethyl] -pyrrolidine-3- Carboxylic acid; trans'trans-2- (2- (3,3-dimethyl-2-_yl1? Bilodyn-1-yl) -ethyl) -4- (1,3-benzene Benzodifluorene · 5-yl) · 1 · (N, N-dibutylaminocarbonylmethyl) -pyrrolidin-3-carboxylic acid; trans, trans_2- (2- (3,3-di Methyl-2-ketopyrrolidin-1-yl) -ethyl) -4- (1,3-benzodiazine-5-yl) -1-[(N_4 · heptyl · 1 < [-( 4-fluoro-3 -methylphenyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; trans'trans-2- (2- (3,3-dimethyl-2-one Pirloline-1-yl) -ethyl) _4_ (1,3 · benzodifluorene -5-yl) -1 · [(N-butyl-N_ (4-dimethylaminobutyl) methyl] • pyrrolidine-3-carboxylic acid; trans'trans · 2- (2 · ( 4,4-dimethyl-2 · ketoρbiloden-1-yl) -ethyl) -4- (1,3-benzodihum-5-yl) -1- (Ν, Ν_ Dibutylaminocarbonylmethyl) -pyrrolidin-3-carboxylic acid; trans, trans-2_ (2 · (4,4-dimethyl-2-ketopyrrolidin-1-yl) -ethyl ) -4- (I, 3-benzodifluorene_5_yl) · 1 _ [(ν_4_heptyl · N_ (4-fluoro-3 · methylphenyl) amino) carbonylmethyl] -pyrrolidine -3-carboxylic acid; trans'trans-2- (2- (4,4--methyl-2. Self-isomeric p-bihadien-1-yl) -ethyl) -4_ (1,3 _Benzodifluoren-5-yl) -1 _ [(N_butyl-N_ (4-dimethylaminobutyl) amino) carboxymethyl] bilodine-3-carboxylic acid; trans'trans _2- (2- (1_Bingzhu Jiangmeng Amino) ethyl) _4- (1,3-benzobenzo-5-yl) -1- (N, N-dibutylamine carbonyl Methyl) -pyrrolidin-3-carboxylic acid; trans, trans-2- (2- (1-propane sulfonylamino) ethyl (1, ^ benzobenzoin)) _ 1- [ (N · 4-heptyl-N- (4-fluoro-3 -methylphenyl) amino) -49-This paper size applies to Chinese National Standards (CNS ) A4 specification (210X297 mm) " " (Please read the precautions on the back before filling in this page) ^ Order 581760 A 7 B7___ 5. Description of the invention (47) Carbonyl methyl pyrrolidin-3-carboxy Acid; trans, trans-2- (2- (1-propane sulfonylamino) ethylbenzodifluoren-5-yl) -1-[(N-butyl-N- (3 -Hydroxypropyl) amino) carbonylmethyl] -Epgodate-3 -Arylic acid; trans, trans-2- (2- (1-propanesulfonylamino) ethyl) -4 -(i, 3-benzodiazin-5-yl) -1-[(N-butyl-N- (propoxy) amino) fluorenylmethyl] -orbitalol-3-junic acid ; Trans, trans-2- (2- (1-propane sulfonylamino) ethyl) -4- (1,3 · benzodifluoren-5-yl) -1-[(Ν_ 丁-N- (4-dimethylaminobutyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (1-propanesulfonamide) ) Ethyl) -4- (7-methoxy-1,3-benzobisfluoren-5-yl) -1- (N, N · dibutylaminocarbonylmethyl) -pyrrole-3- Endonic acid; trans, trans-2- (2- (1-propanenaphthylsulfonamido) ethyl) -4- (7-methoxy-1,3-benzodiazine-5-yl ) -1-[(N-4-heptyl-N- (4-fluoro-3- Phenyl) 'amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (1-propane-sulfonamido) ethyl) -4- ( 7-methoxy-1,3-pyridobisaki-5-yl) -1 · [(N-butyl-N- (4-dimethylaminobutyl) amino) carbonylmethyl] -pyrrole Pyridine-3_carboxylic acid; 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) ) Ethyl) -4- (2,3 · dihydrobenzofuran-5-yl) -1- (N, N-dibutylaminocarbonylmethyl) -pyrrolidin-3-acid; trans , Trans-2- (2- (l-propane-sulfonamido) ethyl) _4- (2,3-dihydro-benzofuran_5-yl) _1-[(N-4-heptyl · N- (4-fluoro-3 · methylphenyl) amine-50- This paper size applies to Chinese National Standard (CNS) A4 specification (210x ^ 7 public shame) —— 581760 A7 B7 V. Description of the invention (48) ) Carbonylmethyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (1-propanenaphthylsulfonamido) ethyl) -4- (2,3 · dihydrazone Benzofuran-5-yl) -1-[(N-butyl-N- (4-dimethylaminobutyl) amino) carbonylmethyl] -pyrrolidine-3 -Carboxylic acid; trans, trans_2- (2_ (1_pyrazolyl) ethyl) -4- (1,3_benzobisfluorene_5_yl) -1-[(N-4- Heptyl-N- (4-fluoro-3-methylphenyl) amino) carbonylmethyl] pyrrolidine-3-carboxylic acid; (trans'trans-2- (2- (1-p ton (Yl) ethyl) _4- (1,3-epi-aminomethyl-5_yl) -1 _ [(N-butyl_N- (3-hydroxypropyl) amino) carbonylmethyl] -pyrrole Pyridin-3-carboxylic acid; trans'trans-2- (2- (1-p than benzyl) ethyl) -4- (1,3 -epidi-5-5 -yl) -1_ (N -Butyl-N- (propyl lactyl) amino) hexylmethyl] -p-bilodine-3-polyacid; trans'trans-2- (2- (1-exocarbyl) ethyl ) -4- (1,3 -benzodi-5-yl) -1 _ [(N-butyl-N_ (4-dimethylaminobutyl) amino) carbonylmethyl] • pyrrolidine- 3-carboxylic acid; trans'-trans-2- (2- (1-p than benzyl) ethyl) -4- (7-methyllactyl-1,3 · benzobis.fluoren-5-yl ) -1- (N, N-dibutylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid; trans'trans-2- (2_ (1-p than benzyl) ethyl) -4_ ( 7 · methyllactyl-1,3 · benzodifluoren-5-yl) -1-[(N-4-heptyl · N- (4-fluoro-3-methylphenyl) amino) carbonylmethyl ] -Pyrrolidine-3-carboxylic acid; in the Ministry of Economic Affairs Printed by the Central Bureau of Standards Consumer Cooperatives (please read the notes on the back before filling this page) trans, trans-2- (2_ (1 · pyrazolyl) ethyl) -4_ (7_methoxy- I, 3-benzobisfluoren-5-yl) _1-[(N-butyl-N- (4-dimethylaminobutyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; Trans'trans-2- (2- (1-ρbidenyl) ethyl) -4- (2,3- —murine-benzoxan-5 · yl) -1- (Ν, Ν- Dibutylaminocarbonylmethyl) -pyrrolidin-3-carboxylic acid; -51-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 __ _B7_ V. Explanation of the invention (49) trans'trans-2- (2 · (1 · ρbijunyl) ethyl) _4- (2,3- · —rat-benzopyran-5_yl )-; L-[(N-4-heptyl-N- (4 · fluoro-3 · methylphenyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; trans'trans_ 2- (2- (1 · Ejunyl) ethyl) -4_ (2,3 -—windo-benzoanan-5_yl) -1 · [(Ν-butyl_Ν_ (4_dimethylamine Butyl) amino) carbonylmethyl] · ρ-Bilodo-3-sharp acid; trans'trans-2- (2- (2-17 -4- (1,3-benzobenzo-5-yl) -1- (N, N-dibutylaminecarbonylmethyl) -pyrrolidine-3-carboxylic acid; trans, trans-2_ (2_ (Oxazol-2-yl) ethyl) 4- (1,3-benzobisfluorene-5 · yl) -1-[(N-4 · heptyl-N_ (4 · fluoro-3_methylbenzene ) Amino) carbonylmethyl] pyrrolidine-3-: ¾; trans, trans-2- (2- (oxazole-2 · yl) ethyl) _4 · (1,3-benzodifluorene -5-yl) -1-[(N-butyl-N- (3-hydroxypropyl) amino) carbonylmethyl] -pyrrolidin-3-carboxylic acid; trans, trans_2_ (2_ ( Oxazole_2 · yl) ethyl) -4- (1,3-benzodifluoren-5-yl) -1-[(N-butyl-N_ (propoxy) amino) carbonylmethyl] · Pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (oxazol · 2 · yl) ethyl) -4 · (1,3 · benzodifluorene · 5 · yl) -1 -[(N-butyl · N_ (4-dimethylaminobutyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (oxazole- 2-yl) ethyl) -4- (7-methoxy-1,3-benzobisfluorene · 5 · yl) · 1- (N, N-dibutylaminecarbonylmethyl) -pyrrolidine-3- Carboxylic acid; trans, trans-2- (2- (oxazol-2-yl) ethyl) _4_ (7_methoxy · 1,3_benzobisρ-5-yl) -1- [(N-4-heptyl- Ν- (4-Gas-3 -methylphenyl) amino group) -52- This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) (Please read the precautions on the back before filling in this Page) Order printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 581760 A7 _____B7 _ 5. Description of the invention (50) Methyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (唠Azole-2-yl) ethyl) -4- (7-methoxy_1,3-benzobenzofluoren-5-yl) -1 · [(N-butyl · N- (4-dimethylamine Butyl) amino) carbonylmethyl] _ Billow's disease -3-Junic acid; trans, trans-2- (2 · (5-methyloxazol-2-yl) ethyl) -4_ (1 , 3-Benzodifluorene · 5-yl) -1- (N, N-dibutylaminecarbonylmethyl) -pyrrolidine-3 · carboxylic acid; trans, trans · 2- (2_ (5-form Oxazolyl-2-yl) ethyl) -4_ (1,3-benzobenzofluoren-5-yl) -1-[(N-4 -heptyl-N_ (4_Ga-3_methylbenzene (Amino) amino) phenylmethyl] -pyrrolidin-3-carboxylic acid; trans, trans · 2- (2- (5 • methyloxazol-2-yl) ethyl) -4_ (1,3 · Benzodifluoren-5-yl) -1-[(N_butyl-N- (4-dimethylaminobutyl) amino) carbonylmethyl] • Pyrrolidine-3-carboxylic acid; trans, trans -2- (2- (2,5-difluorenylρ ratio ρ each yt-1-yl) ethyl) -4- (1,3-benzobenzofluoren-5-yl) _1_ (N, N- Dibutylaminecarbonylmethyl) -pyrrolidin-3-carboxylic acid; trans, trans-2- (2- (2,5-diketopyrrolidin-1-yl) ethyl) -4_ (1, 3-Benzodifluoren-5-yl) -1- (N-4-heptyl-4- (4-fluoro-3-methylphenyl) amino) carbonylmethyl] -pyrrolidine-3-carboxyl Acid; trans, trans-2- (2- (2,5-diketopyrrolidin-pyridyl) ethyl) -4- (1,3-benzodifluorene_5_yl)-; 1 -[(N · butyl-N- (3-hydroxypropyl) amino) carbonylmethyl] -p-Biloxidine-3 -read_, trans, trans-2- (2- (2,5 -Diketopyrrolidin-1-yl) ethyl) -4- (1,3-benzodifluoren-5-yl)-: 1 · [(N_butyl-N_ (propoxy) amino) Carbonylmethyl] -pyrrolidin-3-carboxylic acid; -53- This paper size applies to Chinese National Standard (CNS) M specification (210x297 mm) (Please read the precautions on the back before filling this page)

581760 Α7 Β7 V. Description of the invention (51) trans, trans-2- (2_ (2,5-diketonyl said Luodian-1-yl) ethyl) _4- (1,3-benzodifluorene -5-yl) -1-[(N_butyl · N- (4 · dimethylaminobutyl) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (2,5-diketopyrrolidin-1-yl) ethyl) -4- (7-methoxy-1,3-benzobisfluoren-5-yl) -1_ (Ν, Ν _Dibutylaminocarbonylmethyl) -pyrrolidin-3-carboxylic acid; trans, trans-2- (2- (2,5-diketopyrrolidin-1-yl) ethyl) -4- ( 7-methoxy_1,3 · benzodiazine_5 · yl) _1-[(N · 4-heptyl-N- (4-fluoro-3 -methylphenyl) amino) carbonylmethyl ] -Pyrrolidine-3-carboxylic acid; trans'trans-2- (2- (p than yodo-2-yl) ethyl) -4- (1,3-benzobenzoz-5-yl) _ 1-[(N-4 · heptyl_N- (4-fluoro-3_methylphenyl) amino) carbonylmethyl] _pyrrolidin_3_carboxylic acid; trans'trans_2- (2- (p ratio lake-2_yl) ethyl) -4_ (1,3_benzodi p-5-yl) -1-[(N-butyl-N- (3.hydroxypropyl ) Amino) carbonylmethyl] -pyrrolidin_3_carboxylic acid; trans'trans_2- (2- (andodian-2-yl) ethyl) -4 · (1,3-benzobis Yin-5_ base) _ 1_ [(N-butyl-N- (propoxy) amino) carbonylmethyl] -pyrrolidine-3-carboxylic acid; printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (This page) trans, trans_2 · (2_ (pyridine · 2-yl) ethyl) -4- (1,3-benzodioxin_5_yl) -1-[(N-butyl- N- (4-dimethylaminobutyl) amino) carbonylmethyl] -pyrrolidin-3-carboxylic acid; trans, trans-2- (2- (pyridin-2-yl) ethyl) -4 -(7-methoxy · 1,3 · benzodifluoren-5-yl) -1- (N, N-dibutylaminocarbonylmethyl) -pyrrolidin-3-carboxylic acid; trans, trans Formula-2- (2_ (pyridin-2-yl) ethyl) -4- (7-methoxy-1,3-benzodi-54- This paper size applies to China National Standard (CNS) A4 Specification (21 〇χ297mm) 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (52) 唠 -5-yl) -1-[(N-4-heptyl-N- (4-fluoro- 3-methylphenyl) amino) carbonylmethyl] -p-bilodine-3 -pyridine; trans, trans-2- (2- (pyridin-2-yl) ethyl) -4- (7-methoxy-1,3-benzodifluoren-5-yl) -1-[(N-butyl-N- (4-dimethylaminobutyl) amino) carbonylmethyl ] -Pyrrolidine-3-carboxylic acid; trans'trans-2- (2_ (★ _2_yl) ethyl) -4- (1,3_benzodi-17--5-yl) _ 1- (N, N-dibutylaminocarbonylmethyl) _pyrrolidine · 3-carboxylic acid; trans, trans-2- (2- (pyrimidin-2-yl) ethyl) -4- (1,3 -Benzodifluorenyl-5 · yl) -1-[(N-4-heptyl-N- (4-fluoro-3_methylphenyl) amino) carbonylmethyl] • pyrrolidine-3-carboxyl Acid; trans, trans-2- (2- (pyrimidin_2 · yl) ethyl) · 4_ (1,3_benzobisfluorene_5_yl) -1-[(N-butyl_1 ^-(4-Dimethylaminobutyl) amino) carbonylmethyl] -pyrrole-3-unsuccinic acid; trans'trans-2- (2- (1,3 -benzodiphenylbenzene) 4-yl) ethyl) -4- (1,3-benzodi-5-yl) · 1 · (N, N-dibutylaminocarbonylmethyl) _pyrrolidin-3-carboxylic acid; trans , Trans_2_ (2 · (1,3 · benzodifluorene_4 · yl) ethyl) _4- (1,3_benzodifluoren-5-yl) -1-[(Ν-4- Heptyl-N- (4-fluoro-3_methylphenyl) amino) carbonylmethyl] -r pilodol-3-carboxylic acid; trans, trans-2_ (2- (1,3_ Benzodifluoren-4-yl) ethyl) -4- (1,3-benzodiamid-5-yl) -1-[(N-butyl · N- (4-dimethylaminobutyl) Amino) carbonylmethylpyrrolidine- 3-carboxylic acid; or a pharmaceutically acceptable salt thereof. The preferred compounds of the present invention are selected from the following: trans, trans_2 · (2- (1,3-dibromo-2_yl) ethyl) -4- (1,3-benzodifluorene-5 -__ -55- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

1T 581760 A7 B7 V. Description of the invention (53) group) -l- (N, N-dibutylaminocarbonylmethyl) -pyrrolidine_3_carboxylic acid; trans, trans_2_ (2,2 -Dimethyl · 2 · (1,3_diamidinolane · 2-yl) ethyl) -4- (1,3-benzodifluoren-5-yl) _1 · (Ν, Ν-dibutyl Aminocarbonylmethyl) -pyrrole-3-carboxylic acid; trans, trans-2 · (2 · (1,3_diamidino-2 · yl) ethyl) -4- (1,3 · benzene Benzodiamidinyl_5-yl) _ [[N_4-heptyl-N- (2-methyl-3 · fluorophenyl)] aminocarbonylmethyl] -pyrrolidine-3-carboxylic acid; trans, Trans-2- (2 · (1,3_difluoren-2-yl) ethyl) -4- (7-methoxy-1,3-benzodiazine_5-yl) -1- ( 1 ^, > 1-dibutylaminomethyl)-? Bilodine-3-metanoic acid; trans, trans-2-((2-methoxyphenoxy) -methyl) -4- (1,3-benzobenzoz-5-yl) -1- (N, N_dibutylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid; trans, trans · 2 · (2 · (2 · Ketopyrrolidin-1-yl) ethyl) -4- (1,3 · Benzodifluoren-5-yl) -1- (N, N-dibutylaminocarbonylmethyl) -Pyrrolidine-3-carboxylic acid; trans'trans-2- (2- (1,3-: ρ _2_2yl) ethyl) -4- (7-methoxy-1,3- Benzo 1 ^ thio-5-yl) _1 · (N-4_heptyl-N_ (4 · fluoro-3 -methylphenyl) aminochiridylmethyl) -pyrrolidine-3-carboxylic acid; trans, Trans-2 · (2,2-dimethylpentyl) _4 · (7-methoxy-1,3-benzobisfluoren-5 · yl) _1- (N, N-dibutylaminocarbonyl Methyl) -pyrrolidine · 3_carboxylic acid; 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) trans, trans · 2 · (2,2_dimethyla Group_2- (1,3 · Difluorenyl-2-yl) ethyl)-'(7-methoxy · 1,3 · benzodifluoren-5-yl) -1- (Ν, Ν -Dibutylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (2-methoxyphenyl) -ethyl) -4- (1,3-benzene Benzodifluorene · 5_yl) -1- (N, N-dibutylaminecarbonylmethyl) pyrrolidine-3-carboxylic acid; -56- This paper size applies to China National Standard (CNS) A4 specification (21〇 × 297) ) 581760 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (54) trans, trans-2- (2,2_dimethyl · 3- (E) · pentenyl)- 4- (7-methoxy-1,3 · benzodi-5-5-yl) -1- (N, N-dibutylamino post-methyl) -i? Luodian-3-carboxylic acid; trans, trans-2- (2- (2-pyridyl) ethyl) _4_ (1,3_benzodifluorene_5 · yl) -1- (Ν, Ν -Dibutylaminecarbonylmethyl) _pyrrolidin-3-carboxylic acid; (2S, 3R, 4S) -2- (2- (2-ketopyrrolidin-1-yl) ethyl) -4- (1 , 3-Benzodifluoren-5-yl) _1_ (N, N_dibutylaminocarbonylmethyl) -pyrrolidine · 3-carboxylic acid; (2S, 3R, 4S) -2- (2- (2 -Ketopyrrolidin-1-yl) ethyl) · 4 · (1,3-benzodiamid-5-yl) -1- (N-4-heptyl-N- (4-fluoro-3- Methylphenyl)) aminocarbonylmethyl) -ρ Billodinium 3-; trans'trans-2- (2- (1-p than benzyl) ethyl) -4- (1,3 · Benzodiazine_5_yl) _ 1 ((N, N-dibutylaminecarbonylmethyl) -pyrrolidin-3-carboxylic acid; and (2S, 3R, 4S) -2_ (3_fluoro_4_methyl) Oxyphenyl) · 4- (1,3-Benzodifluoren-5-yl) -1-[(((N, N-propyl-N-pentanyl) amino) ethyl) -P Billow's disease-3-metanoic acid; or a pharmaceutically acceptable salt thereof. Methods for preparing compounds of the invention are shown in Schemes I-XV. Scheme 1 illustrates the general method for preparing compounds of the invention where η and m are 0, Z is -CH2-, and W is -C02H. /?-Ketoester, 1_, where E is a lower alkyl group or a carboxy protecting group, reacts with a nitrovinyl compound 2_ „in the presence of a base (such as 1,8_diazidine bicyclo [5.4.0] Undecyl-7-ene (〇311) or sodium ethoxide or sodium hydride, etc.) in an inert solvent such as toluene, benzene, tetrahydrofuran or ethanol, etc. Reduction of condensation products (such as hydrogenation using Raney nickel or platinum catalyst). Amine cyclization to generate dihydropyrrole. Reduction (such as cyanoborohydride __ -57- This paper size applies to China National Standard (CNS) M specifications (21〇 > &297; 297 mm) (Please read first (Notes on the back then fill out this page)

1.1T printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 Α7 B7 5. Description of the invention (55) Sodium or catalytic hydrogenation, etc.), in a protic solvent such as ethanol or methanol, to generate pyrrolidine compounds, showing cis Formula-a mixture of cis, trans, trans, and cis, trans products. Chromatographic separation removes the cis-cis isomer ' to leave the trans ' trans and cis, trans isomer mixtures, which are done as best as possible. The cis-cis isomers can be epimerized (e.g., using sodium ethoxide in ethanol) to form the trans, trans isomers, and then completed as follows. Erodonium nitrogen (1) tritiated or continued tritiated, using (R 3 is C (0)-or R6_s (0) 2_, and X is a leaving group such as a halide (Cl is preferred) or X plus κ (0)-or R6_S (0) 2 " Formation of activated esters, including esters or livers derived from formic acid, acetic acid, etc., alkoxy carboxylic halides, N- # stem-based succinimine, N. Fluorenimine, N. #! Benzobenzotriazole, N-hydroxy-5-n-sullofluorenyl-2,3-dicarboxamide, 2,4,5-trichlorophenol, etc.) or (2) to R3_X alkylation, where X is a leaving group (such as X is a dentate (such as Cl, Br or I) or X is a leaving group such as a sulfonate (such as mesylate, tosylate, trifluoromethane Sulfonate, etc.)) in the presence of a base such as diisopropylethylamine or triethylamine to form N-derivatized pyrrolidine, which is still trans, trans and cis, trans iso A mixture of structures. The ester I is hydrolyzed (e.g., by the use of sodium hydroxide in EtOH / HA) to selectively hydrolyze the trans, and the trans ester forms a mixture of ethyl and ethyl which can be easily separated. Scheme II illustrates the general procedure for the preparation of a compound of the invention, where n is 1, m is 0, Z is -CH2-, and W is < 302A. The substituted benzyl chloride is reacted with bell dipyridine UL, and it is burned in an inert solvent such as THF or dimethoxyethane to form an alkylated adduct.] The anion is formed using a base, such as n-butyl bell, and then Reacts with ΚΗ2-Χ, where X is a leaving group such as a halide ___ -58- This paper size is applicable to China National Standard (CNS) Α4 size (2KK) X297 mm) (Please read the precautions on the back before filling (This page)

581760 A7 ____ _B7 V. Description of the invention (56) or sulfonate to form compound &. The dioxane protecting group is dissociated (eg, using mercury salt in water) to form the ketone compound 丄 丄. Ketone 13 reacts with benzylamine and formaldehyde to form ketohexahydropyridine compound 1. Compound 14 is treated with an activated nitrile, such as trimethylstilbene cyanide, and then treated with a dehydrating agent, such as phosphorus sulfonium gas, to form isomeric nitrile 1 fluorene. Double bond reduction (such as with sodium borohydride) produces hexahydropyridylnitrile. Nitrile is hydrolyzed with hydrochloric acid, and in the presence of a carboxy protecting group (such as an alkyl alcohol), vinegar U (where E is a carboxy protecting group) can be formed. Catalytic hydrogenation will deactivate the benzylization of acid strips to form the free-state hexahydropyridine compound IX. The compound is further completed in the steps of Scheme 1 (for compound i) to produce the final product compound i 9. 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). K Chengin describes the preparation of the compounds of the present invention, where 0, z is _C (0) _ and w is -C02H. General steps. 0-Ketoester 2J_ (where E is a lower alkyl or carboxy protecting group) reacts with a heart halide (where J is a lower alkyl or carboxy protecting group and is self-bromo, iodine or chlorine) in the presence of a base For example, NOH or tertiary potassium butoxide or lithium diisopropylamidamine can be used to form diesters in an inert solvent such as THF or dimethoxyethane. The compound was treated with r3-NH2 and heated in acetic acid to form a cyclic compound 2 ^. Double bond reduction (such as catalytic hydrogenation, reduction using Pd / C catalyst or cyanoborohydride steel) to generate pyrrolidone. Derivative isomerization of sodium ethoxide in ethanol produces the desired trans, trans configuration, followed by hydrolysis of cool sodium nitrate to produce the desired trans, trans carboxylic acid11. Scheme IV illustrates the general procedure for the preparation of compounds of the invention where n is 0, m is 1, z is _CH2_, and W is _CO2H. The trans and trans compounds were prepared in Scheme I and homologized by Arndt_Eistert synthesis.基基 END_59_ This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 × 297 mm 1 ---- 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 __B7 V. Description of the invention (57) End activation (For example, using thionyl chloride or fluorenyl chloride) to generate compound ϋ, where L is a leaving group (in the case of fluorenyl chloride, L is C1). Compound ϋ is treated with azomethane to generate azo ketone. Rearrangement of compound 53 (such as the use of water or alcohol and silver oxide or silver benzoate and triethylamine, or heating or photolysis in the presence of water or alcohol) can generate acetate hydrazone, or ester, which can be hydrolyzed again Compounds, in which m is 2 to 6, can be obtained by repeating the above steps. Preferred specific examples are shown in Schemes V and VI. Benzyl acetoacetate 26 and nitrovinylbenzodifluorenyl compound 27 are reacted, Using 1,8-bilobate bicyclo [5 · 4 ·· 0] Η carbon-7-ene (DBU) as a base to generate compounds in toluene. Catalytic hydrogenation using Ruanlai nickel can cause reduction of nitro to amine, and then Cyclization can produce dihydropyrrole 2_2_. Reduction of double bonds with sodium cyanoborohydride can generate pyrrolidization Compound 2_〇_, which is a mixture of cis · cis, trans, trans and cis' trans isomers. Chromatography can separate cis, cis isomers, leaving the trans, A mixture of trans and cis, trans isomers (iL). Scheme VI illustrates the further completion of the trans' trans isomer. A mixture of trans, trans and cis, trans pyrrolidine (described in Scheme JV) Reaction with N-propyl bromoacetamidine to form alkylated pyrrolidine compounds in acetonitrile and ethyl diisopropylamine, still in trans, trans and cis, trans isomers Sodium hydroxide in ethanol_water can hydrolyze the ethyl esters of trans and trans compounds, but the ethyl esters of cis and trans compounds are not touched, so the trans can be separated from cis and trans ester 1. Formula, trans-rebel acid 3 3. Scheme VII illustrates the preparation of a specific hexahydro p-pyridyl compound. Benzo monomethyl chloride 2X reacts with lithium dipyrimidine to form an alkylated compound -60- Dimensions are applicable to China National Standard (CNS) A4 specifications (210X297 mm) '' --- (Please read the precautions on the back before filling this page)

Words 581760 A7 B7__ V. Description of the invention (58) U. Compound 2X is treated with 4-methoxyfluorenyl chloride to form compound VIII in the presence of lithium diisopropylfluorenamine. Dissociation of the dithiane protecting group with an mercury salt in an aqueous solution can generate the ketone u. Treatment with benzylamine and formaldehyde produces ketohexahydropyridine. The compound was treated with trimethylsilyl cyanide and then with phosphorochlorine to form a mixture of isenenitrile as isomer 41. Reduction of double bonds with sodium borohydride produces hexahydropyridylnitrile 2_. Hydrogenation in the presence of ethanol acid hydrolysis produces ethyl esters. The N-benzyl protecting group is removed by catalytic hydrogenation to generate a free-state hexahydrop-pyridine compound. Compound ^ _4_ is further processed in step V for compound 2_1_, which can result in the formation of N-derivatized carboxylic acid 45. A preferred specific example of the process shown in scheme in is shown in scheme VIII. 4-methoxybenzylacetate (where E is a lower alkyl or carboxy protecting group) reacts with benzoinyl bromoacetate ^ (where E is a lower alkyl or carboxy protecting Group), in the presence of NaH in THF can form diesters. Compound compounds i are treated with ethoxypropylamine and then heated in acetic acid to produce cyclic compound compounds! . The double bond can be reduced by Pd / C catalyst for catalytic hydrogenation to form pyrrolidone hydrazone. The epi-isomerization of sodium ethoxide in ethanol can generate the desired trans, trans configuration, followed by the hydrolysis of the sodium hydroxide of the ester can produce the desired trans, trans-carboxylic acid 51 〇 Central Ministry of Economic Affairs Printed by the Consumer Bureau of Standards Bureau (please read the precautions on the back before filling out this page) / JfL Process IX illustrates the compound 'where η is 0, Z is · 〇Η2_, and W is not a polyacid. Compound U, which can be prepared in the steps of Scheme Iv, and transformed (such as by using peptide coupling conditions such as N-methylmorpholine, EDCI and HOBt 'in the presence of ammonia or other amidine formation reactions) can generate carboxylic acid amines. Dehydration of carboxamide (such as the use of phosphonium chloride in pyridine) can generate nitriles. Nitrile-61-This paper size is applicable to Chinese National Standard (CNS) A4 specifications (---- 581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (59) Under the standard tetrazole formation conditions ( The reaction of sodium azide with triethylamine hydrochloric acid or trimethylsilyl azide and tin oxide) can generate tetrazole U. In addition, nitrile reacts with hydroxylamine hydrochloric acid in the presence of a base (such as carbonic acid, sodium carbonate, hydrogen Sodium oxide, triethylamine, sodium methoxide or NaH) in a solvent such as DMF 'DMSO or dimethyl ethyl donkey amine, can generate donkey amine groups and 5 ^ 9_. Amine group M and methyl or ethyl chloroformate Reaction in conventional organic solvents (such as gas imitation 'a gas methyl fe, diyin roast, THF, acetonitrile or ρ bidian), in the presence of the test (such as triethylamine, pyridine, potassium carbonate and sodium carbonate) can be generated 〇_fluorenyl compound. 0-fluoreniminoamino oxime is heated in an inert solvent (such as benzene, toluene, xylene, dioxane, THF, dichloroethane, or chloroform and others). In addition, amidoamine 5 9 reacts with thionyl chloride in an inert solvent (such as chlorine , Dichloromethane, Nisaki, and Thf, etc.) can generate pyrimidazole U. Scheme X illustrates that I is a method for the preparation of compounds of fluorenylmethylene. Carboxylic acid (where R4 is as previously defined) to Monochloro chloride treatment can generate hydrazine chloride in dichloromethane containing a catalyst amount of N, N-dimethylformamidine. Fluorenyl chloride can be treated with an excess of etheric diazomethane to generate diazones. Treatment with anhydrous HC1 in dioxane can generate f-chloroketones. The main pyrrolidine esters, where E is a lower alkyl group or a carboxy protecting group, are prepared in Scheme I, and the alkylation with "_chlorohydrazone" can produce alkylation. Deprotection of the pyrrolidine & carboxyl groups (such as hydrolysis with ethanol or sodium in ethanol-water) can generate alkylated pyrrolidin acids 6. 5. Process XI illustrates the preparation of "retroxamine and sulfonamide". Carboxyl Protected pyrrolidine is prepared in Scheme I and reacts with a bifunctional compound x_R8-x, where R8 is an alkylene group and X is a leaving group (such as a halide, where Br -62- This paper is for China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

11 581760 A7 B7 V. Description of the invention (60) is preferred) can generate N-alkylated compound ϋ. 66 treatment with amine (R2O_NH2) can form secondary amines. This amine can be reacted with an activated fluorenyl compound (e.g., R4_C (0) -C1) and deprotected by a carboxyl group (such as hydrolysis of an ester or hydrogenation of a benzyl moiety) to form amine 6 8. In addition, amine 67 can be reacted with an activated sulfonyl compound (eg, R6-S (0) 2-C1) and deprotected by a carboxyl group (such as hydrolysis of an ester or hydrogenation of a fluorenyl moiety) to form sulfonamide 69. Scheme XII illustrates a method for synthesizing pyrrolidine via methylimine alkynide type [3 + 2] • cycloaddition to acrylate. General structures such as compound 1 are known to be added to unsaturated esters, such as 2X, to form a compound; each compound is like a compound. (0. Tsuge, S. Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983), 0. Tsuge, S. Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem. 2523-30 ( 1987) and S. Kanemasa, K. Skamoto, 0. Tsuge, Bull. Chem. Soc. Jpn. 1960-68 (1989)). Special examples are also shown in Process XII. Silylimine reacts with acrylate Zi in the presence of trimethylsilyl trifluorosulfonate and tetrabutylammonium fluoride to form the desired pyrrolidine U as a mixture of isomers. This method can be modified to form N-acetamido derivatives, that is, hydrazone and 1 are directly reacted with a suitable bromoacetamide (such as: dibutyl bromoacetamide), tetrabutylammonium iodide and ammonium fluoride Compound 76 is formed in the presence. 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). Process XIII describes the method for producing pure ρ-bilobadian 80 on the enantiomer. Further completion. The middle racemic ρ Bihadide ester B (prepared by the method described in / pass V) is protected with Boc-nitrogen (such as treatment with bOC2O) and the ester is hydrolyzed (such as with sodium hydroxide and Lithium in ethanol and water) can generate tertiary butylaminomethylammonium n than p. Chitosan conversion or its (+) _ -63-This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) --- Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economy 581760 A7 B7 V. Description of the invention ( 61) Cinconine salt, which can be recrystallized (such as from ethyl acetate and hexane or chloroform and hexane) to form a diastereoisomerically pure salt. This diastereoisomerically pure salt can be neutralized (e.g. with sodium carbonate or citric acid) to form the enantiomerically pure carboxylic acid. Pyrrolidine nitrogen can be deprotected (for example, using trifluoroacetic acid) and ethanolic hydrochloric acid can be used to reform the ester to form a salt. In addition, ethanol HC1 can be used to dissociate the protecting group and form the ester in one step. Ϊ7 Pyrrolidine nitrogen can be further completed (such as dibutylphosphonium bromide in acetonitrile, and the presence of diisopropylethylamine) can produce optically active compounds. The use of (_) _ sinconium would rather generate the opposite enantiomer. Scheme XIV describes another step in the preparation of Luodian. Pirodine can be synthesized by cycloaddition of a methylene amine alkide to an acrylate derivative, such as Cottreii, F., et. al, m J. Chem. Soc., Perkin Trans, 1, 5: 1091-97 (1991). Therefore, the condensation of the methyleneamine precursor precursor ϋ (where R55 is hydrogen or methyl) with a substituted acrylate ϋ (where r5 is as described above, and R56 is a low-carbon alkynyl group) results in substitution under acidic conditions. P. Biluodian and Lord. ^ The protecting group can be removed (eg, via the hydrogenolysis of N-benzyl) to form u, which is alkylated under the conditions described above to form N-substituted pyrrolidine pyrene. The standard ester hydrolysis is performed to produce the desired P to P each carboxylic acid group. The preferred method is shown in process XV. A nitro vinyl compound reacts with a luoyl ester in the presence of a base, such as sodium ethoxide, or a trialkylamine, such as triethylamine or diisopropylethylamine, or hydrazone, such as DBU, and is inert In a solvent such as THF, toluene, DMF, acetonitrile, ethyl acetate, isopropyl acetate, or dichloromethane, etc., the temperature ranges from about 0 ° C to about 100 ° C for about 15 minutes to one night to form compound H . Nitroline reduction followed by cyclization can be performed in hydrogen ___ -64- ^ paper size suitable for financial standards (〇 called eight 4 specifications (21 (^ 297 mm)) (Please read the note on the back first (Fill in this page again)

1T 581760 A7 V. Description of the invention (62) The pressure is achieved by catalytic hydrogenation from about atmospheric pressure to 300 psi, which lasts about 1 hour to about 1 day, in an inert solvent such as THF, ethyl acetate, and the Ministry of Economic Affairs. Printed by the Consumer Standards Cooperative of the Central Bureau of Standards (please read the precautions on the back before filling this page) Benzene, ethanol, I-propanol, DMF < acetonitrile, etc., using chlorination catalysts such as Ruanlai nickel, Pd / C, saturated catalysts Oxidation pins, pt / c or equivalent, or germanium catalysts such as Rh / C or Rh / Al, etc., can form intermediates nitrone 91a, or a mixture of nitrone Mi and imine 21k. The reaction mixture containing nitrone or nitrone / imine mixture is treated with acid, such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methanesulfonic acid, etc., and the hydrogenation continues to form pyrrolidine compound 咯, which is cis · cis Isomers. The epimerization at C-3 can be achieved by treating compounds with alkalis, such as sodium ethoxide, third potassium butoxide, third lithium butoxide or third potassium pentoxide, etc., or trialkylamine Such as triethylamine or diisopropylethylamine, etc., and 脒 such as DBU, etc., in an inert solvent, such as ethanol, ethyl acetate, isopropyl acetate, THF, toluene or DMF, etc., the temperature from about -20 C to About 120 C can form trans, trans compounds. Compound 2X itself can be resolved into enantiomers as required, and then reacted with x_Rs. Substantially pure (ie at least 95% of the desired isomer) optically active compound @ (+)-isomer from a mixture of (+)-isomer and (-)-isomer, It is obtained by treating with S-(+)-mandelic acid, D-tartaric acid or D-ditartaric acid, etc., in a solvent such as acetonitrile, ethyl acetate, isopropyl acetate, ethanol or isopropanol. The (+)-isomer of 2X selectively crystallizes into a salt, leaving the (-)-isomer of 93 in solution. In addition, the compound is substantially pure (ie, the desired isomer is at least 95%) and the optically active (-)-isomer can be selectively crystallized, that is, the (+)-isomer and (-)-isomer of 93 The mixture reacts with L-tartaric acid, L-dimethyltartaric acid or L. pyromalic acid, etc., leaving the compound & desired isomerism--65. This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) 581760 A7 ____ B7-——------ _ V. Description of the invention (63) The substance is in solution. Compound ϋ (racemic or optically active) reacts with x_Rs (where X is a leaving group (such as a halide or phosphonate) and r3 is as previously defined using a test such as diisopropylethylamine, triethyl Amine, sodium bicarbonate or potassium carbonate, etc., in an inert solvent such as acetonitrile, THF, toluene, DMF or ethanol, etc., at a temperature from about 0 ° C to about 1000 ° C to form intermediate esters. The esters can be isolated or separated In situ conversion to carboxylic acid, using hydrolysis conditions such as alkali, such as sodium hydroxide or hydroxide surface or potassium hydroxide, etc., in solvents such as ethanol-water or THF-ethanol, etc. (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 -66-This paper size applies to the Chinese National Standard (CNS) A4 size (210X297 mm) 581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

Process I

Ri ~ ^ -co2e + 5

Ri co2e Η cis-cis trans-trans-cis_trans mixture X-R3

R2- ^ U 6 C02E R3 trans-trans cis-trans mixture R2

Ri 2

3 [H] co2e ά

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

Ri F »3 > -Rt 7 C02H trans-trans [H2〇l + r, < ^ L-Ri co2e δ cis-trans-67- This paper size applies Chinese National Standard (CNS) Α4 specifications (210X 297 mm) 581760 A7 B7

V. Description of Invention (65) Process II

This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of invention (66)

Process III

Halo Ri

3- V3-V-Ri co2h trans-trans (Please read the notes on the back before filling this page) Order -f- Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs __k 69- This paper size applies to Chinese national standards (CNS) A4 specifications (210X 297 mm) 581760 A7 B7 V. Description of the invention (67)

Process IV • 4: 1 ζ PR Office ·

(Please read the notes on the back before filling this page) V. Description of the invention (68

Process V ° η3〇-〇-λ + < ° Et〇2〇 °

No. 2 DBU

2S

ZL Ο ch3o

Ο

COOEt cis-cis 21 reverse chromatographic separation H2

OCHa (Please read the notes on the back before filling out this page) Clothing · a cis-cis + trans-trans and cis-trans mixture 21

、 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 71 This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of invention (69

Process VI och3

COOEt

BrCHgCONHCJHy

Trans-trans

Trans-trans and cis-trans (please read the precautions on the back before filling this page)

, 1T Ο

+ Trans-trans-Si COOEt_cis ~ -trans-trans Description of the invention (70)

Flow VII

This paper size applies to China National Standard (CNS) A4 (210X297 mm) 581760 A7 B7 V. Description of Invention (71) Process VII continued

(T

Ο

Q

(T

(Please: read the notes on the back and fill in this page)

〇r

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

0, 0〆 74- This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) 581760 A7 B7 V. Description of the invention (72)

Scheme VIII ch3〇 co2e ο +

Br Ο

OE Ο

(Please read the notes on the back before filling out this page) 47

Central Consumers Bureau of the Ministry of Economic Affairs, Consumer Cooperative Printing Factory CH3

Trans-trans -75 This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 581760A7B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy

Process IX r2

r3 Ri (CH2) mI co2h

Rs • Rl (CH2) mI conh2 55 R2

H R1 (CH2) m \ NH N-N m F 广 N〆 (CH2) m

(CH2) m I CN

Rs Rl

Rs Rl r2 57 < 1 R3 Rl r2

(CH2),

RaRl HNo Λν (CH2) m

H2N

-^ NOH

HN S-〇 5Θ

O

6L -76- (Please read the notes on the back before filling this page)

This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) 581760 A7 B7 V. Description of invention (74)

Process X

Cl R4, Ο

CI

co2e 5 (Please read the notes on the back before filling this page)

co2h

co2e order f Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -77 This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention ( 75)

Process XI

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

、 1T Lin -78- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 581760 A7 B7 V. Description of invention (76)

Process XII ~, J1 N + ch2- .C02Et + .¾

2D 21

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

Me3Si ^ N

OCHa + < 〇Xj ^ 73 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

O 24

-79 This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 581760 A7 B7 V. Description of the invention (77

Process XIII

Boc20

2. NaOH.EtOH H2O

1. (+)-Sinconine 2. Recrystallize from EtOAc / hexane 3. Na2C03 (Please read the precautions on the back before filling this page)

HCI EtOH

Bu2NC (0) CH2Br EtNiPr2, CH3CN Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs OCH3 O W Μ

co2h -80- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of invention (78)

Process XIV

CO2R56 TFA, CH2CI2

C〇2R $ 6 (Please read the notes on the back before filling this page)

Pd (o% 2 / c HN-CO2R56 R3B1 " Bu4NI or Nal CH3CN ~ R2 £ R3

CO2R56 r2 85

NaOH or UOH EtOH, H2〇 R3

• CO2H R2 SL · Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs This paper is printed to the Chinese National Standard (CNS) A4 (210X 297 mm) 581760 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (79

Process XV Μ

+ E〇W

Ri

Factory N Factory N Ri R2 ^ \ > -RiC02E + COgE

C02E 92

Ri Μ (Please read the notes on the back before filling this page) 91b co2e SSt Factory NHC02ES3 u ΓΝ / 3 R2 ^ \ ^ > ^ R1

COgE M -82- This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) 581760 A7 B7 V. Description of the invention (80) The compounds that can be used as intermediates in the preparation of the compounds of the present invention are:

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs where η is 0 or 1; m is 0 to 6; W is (a) -C (0) 2-G, where G is hydrogen or a carboxy protecting group, (b) · P03Η2, (c) P (0) (0Η) E, where E is hydrogen, lower alkyl or arylalkyl, (d) -CN, (e) _C (0) NHR17, where R17 is low carbon Alkyl, (f) alkylamine carbonyl, (g) dialkylamine carbonyl, (h) tetradecyl, (i) #yl, fluorenyloxy, (k) sulfonylamino, (l) _C (0 ) NHS (0) 2R16, where R; 6 is lower alkyl, alkane, phenyl or diamino, (m) -S (0) 2NHC (0) R16, -83- (Please read first Note on the back, please fill out this page again) f- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 Α7 Β7 V. Description of the invention (81)

(0) OH (P) ⑹ \-\ hrο κο rr ° x ⑻ H, 社 S 中央, or NHSP2CF3 ⑼ and 1 and 112 are independently selected from hydrogen, lower alkyl, and olefin. , Alkynyl, alkoxyalkyl, -84- (Please read the precautions on the back before filling this page)

This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 581760 A7 ___ B7 ____ V. Description of the invention (82) Alkoxycarbonylalkyl, hydroxyalkyl, alkyl, alkoxyalkyl, alkyl Oxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminecarbonylalkyl, alkylaminecarbonylalkyl, dialkylaminecarbonylalkyl, aminecarbonylalkenyl, Alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyfluorenyl, aryl, arylalkyl, aryloxyalkyl, aralkyloxyalkyl, (N-alkylfluorenylalkyl) amine alkyl, alkyl Sulfofluorenylamidoalkyl, heterocyclyl, (heterocyclyl) alkyl and (Raa) (Rbb) N-Rcc-, where Raa is aryl or arylalkyl, and Rbb is hydrogen or alkyl And R. . It is an alkylene group, and the restriction is that 1 or 112 or both are not hydrogen; or a salt thereof; or a compound of the following formula: (Please read the precautions on the back before filling this page)

(iv) (V) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs where η is 0 or 1; m is 0 to 6; W is (a) -C (0) 2-G, where G is hydrogen or carboxy protected Group, (b) -P03Η2, (c) -P (0) (OH) E, where E is hydrogen, lower alkyl or aryl group, (d) -CN, -85- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (83) (e) -C (0) NHR17, where R17 is a lower alkyl group, pinaneamine carbonyl group, (g) dioxane Aminocarbonyl, (h) tetradecyl, (i), alkanoyloxy, (k) sulfonamido, (l) -C (0) NHS (0) 2R16, where R16 is lower alkyl , Haloalkyl, phenyl or dialkylamino, (m) -S (0) 2NHC (0) R16, ⑹ ⑼

HOv γ ° Η / NH ο ϊΤ 1 OH (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

N ⑹ NHίΚ (r) -86- The size of this paper applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 581760 A7 B7 5. Description of the invention (84) ⑻ ⑴ 1ST. ,, Η 5 = 0

nhs〇2cf3 且 and printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 1 ^ and 112 are independently selected from hydrogen, lower alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, Alkyl, from alkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminecarbonylalkyl, alkylaminocarbonylalkyl , Dialkylaminocarbonylalkyl, aminecarbonylalkenyl, alkylaminecarbonylalkenyl, dialkylaminecarbonylfluorenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkylfluorenyl-N · alkyl) amine alkyl, alkyl sulfonylfluorenylamino alkyl, heterocyclyl, (heterocyclyl) alkyl and (Raa) (Rbb) N_Rcc_, where Raa is Aryl or arylalkyl, Rbb is hydrogen or alkyl, and R. . Is alkylene, the limiting condition is mindful! ^ One or both are not hydrogen; or their salts. Preferred intermediates include compounds of formulae (III), (IV) and (V), where m is 0 or 1; W is -C02-G, where G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above. Definition; or 'Its substantially pure (+)-or (_)-isomer. The best intermediates are formulas (III), (IV) and compounds, of which -87- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

1T 581760 A7 B7 V. Description of the invention (85) η and m are 0; w is -C02-G, where G is hydrogen or carboxy protecting group; (Please read the precautions on the back before filling out this page) ⑴lower alkyl, (ii) alkenyl, (iii) alkoxyl, (iv) cycloalkyl, (v) phenyl, (vi) blowing group, (vii) sulfanyl or (viii ) Substituted or unsubstituted 4-methoxyphenyl, 4-fluorobenzene, phenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4 · methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxy Methoxyphenyl, 4-hydroxyphenyl, 4-tert-butylphenyl, 1,3-benzodifluorenyl, 1,4-benzodifluorenyl or dihydrobenzofuranyl Where the substituent is selected from the group consisting of lower alkyl, alkoxy, alkoxy, alkoxyalkoxy, and carboxyalkoxy (ix) arylalkyl, (X) aryloxyalkyl, (xi) hetero Cyclic (alkyl), (xii) (N-alkylfluorenyl-N-alkyl) amine alkyl, and (xiii) alkylsulfonyl fluorenylamino alkyl, and R2 is substituted or unsubstituted 1,3-benzodifluorenyl, 7.methoxy-1,3-benzodifluorenyl, 1,4-benzodifluorenyl, 8.methoxy-1,4-benzodihumidyl, dihydrobenzofuranyl , Benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl, wherein the substituents are selected from the group consisting of low-carbon alkynyl, alkynyl or substantially pure (+ ) -Or (+ isomers. Other compounds printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs that can be used as intermediates in the preparation of the compounds of the present invention are:

-88-This paper size applies Chinese National Standard (CNS) A4 specification (210X 297mm) 581760 Α7 B7 V. Description of the invention (86) where η is 0 or 1; m is 0 to 6; R5b is alkylene; Q is a leaving group; W is (a) -C (0) 2-G, where G is hydrogen or a carboxy protecting group, (b) -P03Η2, (c) -P (0) (0Η) E, where E Is hydrogen, lower alkyl or arylalkyl '(d) -CN, (e) -C (0) NHR17, where R17 is lower alkyl, (f) alkylamine carbonyl, (g) dialkylamine Carbonyl, (h) tetrabenzyl, (i) hydroxyl, (j) alkoxy, (k) fluorenylamino, (l) —c (o) nhs (o) 2r16, where R16 is lower alkyl Fluorenyl, phenyl or dialkylamino, (m) -S (0) 2NHC (0) R16,

Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling in this page) ) 581760 A7 B7 -------____________ V. Description of Invention (87)

(Please read the precautions on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Ri and R2 are independently selected from hydrogen, lower alkyl, alkenyl, alkynyl'alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, self-alkyl, and self-alkoxyalkyl'alkoxyalkoxy Alkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminecarbonylalkyl, alkaminecarbonylalkyl, dialkylaminecarbonylalkyl, aminecarbonylalkenyl, alkylaminecarbonylene Alkyl, dialkylaminocarbonyl alkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkylfluorenyl-N-alkyl) amine alkyl, alkyl Sulfofluorenylamidoalkyl, heterocyclyl, (heterocyclyl) alkyl and (Raa) (Rbb) N_Rcc-, where Raa is aryl or arylalkyl, and Rbb is hydrogen -90-this paper The standard is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (88) or Alkyl and R. . Is an alkylene group, and the restriction is that one or both of the heart and the heart are non-hydrogen; or a salt thereof; or a compound of the formula: 广 广 -Q R2 / 々 丫 X \ N ^ R5b-Q (CHaJm (〇 »ώZ i 1 W Ri or w (VII) (VIII) where η is 0 or 1; m is 0 to 6; R5b is an elongation group; Q is a leaving group; W is (a) -C (0) 2_G, where G Is hydrogen or carboxy protecting group, (b) -P03Η2, (c) _P (0) (0Η) E, where e is hydrogen, lower alkyl or arylalkyl, (d) -CN, (e), Where r17 is a lower alkyl group, (f) an alkylamine carbonyl group, (g) a dialkylamine carbonyl group, '(h) tetradecyl group, (i) a benzyl group, -91-This paper standard applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

ο ο 581760 A7 B7 V. Description of the invention (89) (j) Alkoxy, (k) Amino, (l) _C (0) NHS (0) 2R16, where R16 is lower alkyl, haloalkane Group, phenyl or dialkylamino group, (m) -S (0) 2NHC (0) R16, ⑻ ο (Please read the precautions on the back before filling this page) ⑼ ⑼

HO, Λ) OH Λ, η (q)

\ Λ (sH Printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs ⑺ ⑻ ⑴

OR -92- This paper size applies Chinese National Standard (CNS) A4 (210X297mm) 581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (90) (U)

NHS〇2CF3 and R! And R2 are independently selected from hydrogen, lower alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkane Oxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminecarbonylalkyl, dialkylaminecarbonylalkyl, aminecarbonylalkenyl , Alkylaminocarbonyl alkenyl, dialkylamine carbonyl alkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, aralkoxyalkyl, (N-alkylfluorenyl-N-alkyl) Amine alkyl, alkynyl, amido, amino, heterocyclic, (heterocyclyl) alkyl and (Raa) (Rbb) N-Rcc_, where Raa is aryl or arylalkyl, and Rbb is Hydrogen or an alkyl group, and Ree is an alkylene group, with the limitation that one or both of Ri and 112 are not hydrogen; or a salt thereof. Preferred intermediates include compounds of formulae (VI), (VII) and (VIII), where m is 0 or 1; R5b is an alkylene group; Q is a leaving group; W is -C02-G, where G is hydrogen Or a carboxy protecting group, and 1 ^ and 112 are as defined above; or a substantially pure (+)-or (-) · isomer thereof. Particularly good intermediates are compounds of formula (VI), (VII) X (VIII), where η and m are both 0; R5b is an alkylene group; -93- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Invention Description (91) Q is the leaving base; W is -C02-G, Where G is a hydrogen or carboxy protecting group; and the heart is a fluorene low-carbon pit group, (ii) an alkenyl group, (iii) an alkoxyalkyl group, (iv) a cycloalkyl group, (v) a phenyl group, (vi) p Biyenyl, (vii) sulfanyl or (viii) substituted or unsubstituted 4-methoxyphenyl '4-aminobenzyl' 3-aminobenzyl '4-ethoxyphenyl' 4-ethyl Phenyl '4-methylphenyl' 4-difluoromethylphenyl '4. Pentafluoroethylphenyl, 3-fluoro-4 -methoxyphenyl, 3-fluoro-4-ethoxyphenyl , 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-tert-butylphenyl, 1,3-benzodifluorenyl, 1,4-benzo Dialkyl or dihydrobenzofuranyl, wherein the substituent is selected from lower alkyl, i-alkyl, alkoxy, alkoxyalkoxy And carboxyalkoxy, (ix) aralkyl, (X) aroxyalkyl, (Xi) heterocyclyl (alkyl), (xii) (N-alkylfluorenyl_N_alkyl) amine And (xiii) alkylsulfonamidinylaminoalkyl, and R2 is a substituted or unsubstituted 1,3-benzodifluorenyl, 7-methoxy_1,3_benzodi Fluorenyl, ι, 4-benzodifluorenyl, 8-methoxy-1,4-benzodifluorenyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, Dimethoxyphenyl, fluorophenyl or difluorophenyl, wherein the substituents are selected from lower alkyl, alkoxy and or, in fact, pure (+)-or (-)-isomers. Other compounds that can be used as intermediates in the preparation of the compounds of the present invention are:

-94- This paper size applies the Chinese National Standard (CNS) A4 Regulation iT! T297Xmm (Please read the precautions on the back before filling this page) Order 581760 A7 B7 Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the invention (92) wherein η is 0 or 1; m is 0 to 6; R5b is an alkylene group; R20a is a chlorine 'low-carbon pit group i-alkynyl group' Alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is (a) -C (0) 2-G, where G is hydrogen or a carboxy protecting group, (b) -P03Η2, (c) -P (0) (0Η) E, where E is hydrogen, lower alkyl or arylalkyl, (d) —CN, (e) —C (0) NHR17, where R17 is lower alkyl, (f) Alkylaminocarbonyl, (g) Diphosphinofluorenyl, (h) Tetrazolyl, (i) Hydroxyl, (j) Alkoxy, (k) Sulfonamido, (l) -C (0 ) NHS (0) 2R16 phenyl or dialkylamino group, (m) -S (0) 2NHC (0) R16 where R16 is a lower alkyl group, i alkyl group (please read the precautions on the back before filling this page) ) ⑻

-95- This paper size is in accordance with China National Standard (CNS) A4 (210 X297 mm) 581760 A7 B7 V. Description of the invention (93) ⑹ ΗΟ Ο (Ρ) ΟΗ

Ν Ο (q) ⑺ ⑻ 々. ‘ΊΚ 〇 A * 冬 ro (Please read the notes on the back before filling this page) (t) κι

CF3 Η • or ⑼

NHSO2CF3 and printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

Ri and R2 are independently selected from the group consisting of hydrogen, low-carbon alkyl, fluorenyl, bulk alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, self-alkyl, arylalkoxyalkyl, and oxyalkyloxy Alkyl, thioalkoxyalkoxyalkyl; cycloalkyl, cycloalkylalkyl 'aminecarbonylalkyl, alkylaminecarbonylalkyl, dialkylaminecarbonylalkyl, aminocarbonylalkenyl, alkylaminecarbonyl Alkenyl, Dialkylamine, Carbonyl Alkenyl, Hydroxyl, Aryl, 96 This paper size applies to China National Standard (CNS) A4 (210X297 mm)

(XI) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 __B7 V. Description of the invention (94) Arylalkyl, aryloxyfluorenyl 9aralkoxyalkyl, (N-alkylfluorenyl-N-alkyl Group) amine alkyl, alkyl sulfonyl amidino alkyl, heterocyclic, (heterocyclyl) alkyl and (Raa) (Rbb) N-Rcc_ 'where Raa is aryl or arylalkyl, Rbb is hydrogen or alkylfluorenyl, and R. . It is Shenyuanji, and the restriction is that one or both of 1 and 112 are non-hydrogen; or a salt thereof; or a compound of the formula: R2 ^ X \ NxR5b-NHR2〇a X (CH2) n

(CH2) m Y li (X) where n is 0 or 1; m is 0 to 6; R5b is dhenyl; R20a is hydrogen, low-carbon alkyl'alkenyl, haloalkyl, halooxy, halo Pitoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is (a) _C (0) 2-G, where G is hydrogen or a carboxy protecting group, (b) _P03Η2, (c) -P (0) (0H) E, where E is hydrogen, a lower alkyl or aralkyl group, (d) —CN, f (e) —C (0) NHR17, where R17 is a lower carbon group, (f) Alkylaminocarbonyl, -97 · This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

ο 581760 A7 B7 V. Description of the invention (95) (g) Dialkylaminocarbonyl, (h) Tetramethyl, fluorenyl hydroxyl, (j) alkoxy, (k) sulfonamido, (l) -C (0) NHS (0) 2R16, where R16 is lower alkyl, haloalkyl, phenyl or dialkylamino, (m) -S (0) 2NHC (0) R16, ο ⑹ (Please read the back first (Please note this page before filling in this page) ⑼ ο (Ρ) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ⑹ ⑻ ⑻

OH I Ο NH • A. . ’Z, * ^ H 98- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 58176〇 Α7 Β7 V. Description of the invention (96) ⑴

⑼

nhso2cf3 and the ruler 1 and R2 printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economics are independently selected from hydrogen, lower alkyl, alkenyl, alkynyl, oxoalkyl, oxoyl, and oxo Radicals 'sulky oxyalkyl', alkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dioxane Aminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, '( N-alkylfluorenyl-N-alkyl) aminoalkyl, alkylsulfonylfluorenaminoalkyl, heterocyclyl, (heterocyclyl) alkyl and (Raa) (Rbb) N-Rce-, where Raa is an aryl group or an arylalkyl group, Rbb is hydrogen or an alkyl group, and Rcc is an alkylene group, with 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 0 or 1; R5b is an alkylene group; R20a is hydrogen, a lower alkyl group, an alkenyl group, a haloalkyl group, an alkyl group Oxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; W is -C02-G, where G is hydrogen or carboxy protecting group; Group, (ii) alkenyl group, (iii) alkoxyalkyl group, (iv) cycloalkane-99-This paper size applies to China National Standard (CNS) A4 specification (210 × 297 mm) (Please read the precautions on the back before (Fill in this page) 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (97), (v) phenyl, (vi) Chengdian, (vii) sulfanyl or (viii) Substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoro Methylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxybenzene Methyl, 4-hydroxyphenyl, 4-tert-butylphenyl, 1,3-benzodiammenyl, 1,4-benzodiamidyl or Dihydrobenzofuranyl, wherein the substituent is selected from the group consisting of lower alkyl, ialkyl, alkoxy, alkoxyalkoxy, and carboxyalkoxy, (ix) aralkyl, (X) aroxyalkane , (Xi) heterocyclyl (alkyl), (xii) (N-alkylfluorenyl-N-alkyl) aminoalkyl, and (xiii) alkylsulfonylfluorenaminoalkyl, and R2 is Substituted or unsubstituted 1,3-benzodihumenyl, 7-methoxy-1,3-benzodifluorenyl, 1,4-benzodifluorenyl, 8-methoxy- 1,4-benzodifluorenyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl, wherein the substituent is selected from Lower alkyl, alkoxy, and self; or substantially pure (+)-or (-)-isomers thereof. Refer to the following examples to better understand the above, which is provided for illustration only and is not intended to limit the scope of the concept. The following abbreviations are used below: Boc is tertiary butoxycarbonyl, (^ 2 is benzyloxycarbonyl, 0611 and 1,8-diazinebicyclo [5.4.0] undec-7-ene, EDCI is 1 -(3-Dimethylaminopropyl-3 · ethylcarbodiimide hydrochloride, EtOAc is ethyl acetate, EtOH is ethanol, HOBt is 1-hydroxybenzotrimethylene, EhN is triethylamine, and TF A is Trifluoroacetic acid and THF are tetrahydrofuran. Example 1 Trans-trans-K4-methoxyphenyl) -4- (1,3 • benzodifluoren-5-yl) -1 propylamine-100- Applicable to this paper size China National Standard (CNS) A4 (2ΐ〇χ 297 mm) (Please read the notes on the back before filling this page)

581760 A7 B7 __ V. Description of the invention (98) Mono- (carbonylmethyl) -pyrrolidine-3-leptic acid_

Example 1 A fluorenyl) -4-nitromethyl 3-q.3-benzobisfluoren-5-yl) 1 ethyl acetate p- (4-methoxybenzyl) acetic acid ethyl acetate (23 Gram, 0.14 Moore), Yi

Prepared by Krapcho et al., Org. Syn. II, 20 (1967), and 5- (2-nitrovinyl) -1,3-benzobispyrene (170 g, 0088 mole) It was dissolved in 180 ml of formazan and heated to 80 ° C. To the stirrer was added 1,8 · di-p-bicyclo [5.4.0] undec-7-ene (DBU '0.65 g). The mixture was heated until all the nitro starting material was dissolved. The solution was stirred for 30 minutes without heating, and an additional 0.65 g of DBU was added. After stirring for an additional 45 minutes, thin layer analysis (5% ethyl acetate in dichloromethane) showed no nitro starting material. Toluene (200 ml) was added and the organic phase was diluted with dilute hydrochloric acid and NaCl solution. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel and dissolved in 3: 1 hexane-ethyl acetate to give 21.22 g of the desired product as an isomer and 9.98 g of ethyl (4-methoxybenzyl) acetate recovered. Purpose of the mixture.

Example 1 B 2- (4_methoxyphenyl) -4- (1,3-benzodi / number-5-yl) -4,5-di 1 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs-3 -The ethyl carboxylate was obtained from the compound of Example 1 A (21 g) in 500 ml of ethanol, and hydrogenated using Raney nickel 2800 catalyst (51 g) under 4 atmospheric hydrogen pressure. (Ruanlai Nickel was washed 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 silica gel with 8.5% Ethyl Acetate-101-this paper is suitable for Guancai County (CNS) A4 size (210X297 male sauce) 581760 A7 __B7 V. Description of the invention (99) in dichloride Methane dissolves to produce 12.34 grams of desired product.

Example 1 C U4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) -pyrrolidine ethyl g |, which is cis-cis; trans, trans; and cis The mixture of formula, trans-Arabic, and the compound from Example 1B (11.89 g, 0.324 mol) was dissolved in 27 liters of tetrahydrofuran and 54 ml of ethanol. Add sodium cyanoborohydride (2.35 g, 0.374 moles) and 5 mg of bromocresol green. To this blue solution, 1: 2 concentrated HC1 in ethanol solution was added dropwise, so that the color can be maintained in pale yellow-green. After no additional HC1 was added and the yellow color persisted, the solution was stirred for another 20 minutes. The solution was concentrated in vacuo and then partitioned between chloroform and an aqueous potassium hydrogen carbonate solution. The organic phase was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a colloidal gel and dissolved in 85:15 ethyl acetate-hexane to yield 5.96 g of a 64% trans, trans-compound and 34% cis, trans-compound mixture. Further dissociation with pure ethyl acetate yielded 0.505 g of an unknown solid, followed by 3.044 g of pure cis, cis-compound.

Example 1 D trans, trans-2- (4-methoxyphenyl) -4_ (1,3 · benzodifluorene-5_ 美 1 _ (propylaminocarbonylmethyl Vpyrrolidine-3-carboxylic acid economy Printed by the Consumer Standards Cooperative of the Ministry of Standards and Standards (please read the notes on the back before filling out this page) 64% trans, trans- and 34% cis, trans-biting (mixture obtained from Example 1C) (5.72 grams, 15.50 millimoles), ethyldiisopropylamine (4.20 grams, 32.56 millimoles), and N-propyl bromoacetamide (3.42 grams, 19.0 millimoles), with Wearer, WE and Whaley, WM ·, j Amer

Chem · Soc · Division: 515 (1947), prepared in 30 ml of ethoxylate-102- This paper size is applicable to China National Standard (CNS) A4 specifications (21〇x297) ^ 581760 A7 B7 V. Description of the invention (10 ()) compound, heated at 50 ° C for i hours. The solution was concentrated under air. The residue was dropped in toluene, shaken with potassium bicarbonate solution, dried on sodium sulfate and (please read the back (Notes on this page, please fill in this page again)) Concentrate immediately to produce 7.16 g of product, which is a mixture of trans, trans and cis, trans-ethyl ester. This mixture falls into 50 ml of ethanol and 15 ml In water containing 500 g of sodium hydroxide and stirred at room temperature for 3 hours. The mixture was extracted with ether to remove unreacted cis, trans-ethyl ester. The aqueous phase was treated with hydrochloric acid until slightly cloudy The crude product was then neutralized with acetic acid. The crude product was filtered and purified by dissolving in tetrahydrofuran, dried over sodium sulfate, concentrated under vacuum and crystallized from ether to give 3 230 grams of the title compound. mp 151-153 C 〇lR NMR (CD3OD, 300 MHz) δ 0.87 (t9 J =

7 Hz, 3H), 1.49 (six peaks, j = 7 Hz, 2H), 2.84 (d, J = 16 Hz, 1H), 2.95-3.20 (m, 4H), 3.20 (d, J = 16 Hz , 1H), 3.34-3.42 (m, 1H), 3.58-3.66 (m, 1H), 3.78 (s, 3H), 3.88 (d, J = 10 Hz, 1H), 5.92 (s, 2H), 6.75 ( d, J = 8 Hz, 1H), 6.86 (dd, J = 8 Hz, J = 1 Hz, 1H), 6.90 (d, J = 9 Hz, 2H), 7.02 (d, J = 1 Hz, 1H ), 7.40 (d, J = 9 Hz, 2H). Example 2 Printing of trans-, trans-2- (4-methoxyphenyl3-benzodifluoren-5-yl) -1- (aminothiomethylmethylpyrrole) Pyridin-3-carboxylic acid using the method described in Example 1 D, 300 mg 64% trans, trans- and 34% cis, trans-pyrrolidine mixture (from Example 1 C), 220 mg diisopropyl Ethylethylamine and 184 mg iodoacetamidamine were reacted in 1 ml of acetonitrile at 451 to produce 291 mg of trans, trans- and cis, trans-N-carbyl-103. This paper is applicable to China Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 ------------ 5. Description of the invention (101) A mixture of chemical esters. Take a portion (270 mg) to 200 mg NaOH was hydrolyzed in 1 ml of water and 3 ml of ethanol; extracted with chloroform to remove unreacted cis, trans-ethyl esters. The isolation and purification steps used as described in Example ID, yielding 134 mg of the title compound. mp 246-248 ° C. 4 NMR (DMSO-d6, 300 MHz) d 2.61 (d, J = 16 Hz, 1H), 2.71 (t, J = 9 Hz, 1H), 2.90 (t, J = 9 Hz, 1H), 2.98 (d, J = 16 Hz, 1H), 3.25-3.35 (m, 1H), 3.45-3.55 (m, 1H), 3.71 (s, 3H), 3.75 (d, J = 10 Hz, 1H), 6.00 (s, 2H), 6.81 (s, 2H) , 6.90 (d, J = 8 Hz, 2H), 7.10 (s, 1H), 7.17 (s, 1H), 7.34 (s, 1H), 7.38 (d, J = 8 Hz, 2H). Example 3 Trans, trans_2- (4-methoxybenzyl) -4- (1,3-benzodifluorenyl_5 · yl) -1- (4-aziridinyl) -1 • pyrrolidine_3 _ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economics of the Carboxylic Acid (please read the notes on the back before filling this page) Using the method described in Example 1D, 300 mg 64% trans, trans- and 34% cis, trans -A mixture of pyrrolidine (mixture of Example 1 C), 220 mg of diisopropylethylamine and 185 mg of 4-fluorobenzyl bromide, reacted in 1 liter of acetonitrile at room temperature for 3 hours to produce 387 mg of A mixture of trans, trans-, and cis, trans-alkylated esters. A portion (360 mg) was hydrolyzed with 250 g of NaOH in 1 ml of water and 4 ml of ethanol to yield 160 mg of the title compound. Crystal powder. 1H NMR (CDC13, 300 MHz) d 2.74 (t, J = 9 Hz, 1H), 2.95 (t, J = 7 Hz, 1H), 2.98 (d, J = 14, iH), 3 .07 (dd, J = 9 Hz, 1 Hz, 1H), 3.42-3.53 (m, 1H), 3.70 (d, j = 9 Hz, 1H), 3.78 (d, J = 14, 1H), 3.81 ( s, 3H), 5.92 (s, 2H), 6.70 (d, J = 8 Hz, 1H), 6.77 (dd, J = 8 Hz, 1 Hz, 1H), 6.91 (d, -104- This paper size applies China National Standard (CNS) A4 (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 _____ B7 V. Description of the invention (10.2) J = 9 Hz, 2H), 6.94-7.00 (m , 3H), 7.20-7.25 (M, 1H), 7.44 (d, J = 9 Hz, 2H) 0 Example 4 Formula oxyphenyl) _4 · Π, 3-mobi-IIzaki-5-yl) -1- (2-ethoxyethyl each 3-carboxylic acid using the method of Example 1 D, 300 mg of 64% trans, trans and 34% cis' trans-pyrrolidine (mixture obtained from Example i C) A mixture of 220 mg of diisopropylethylamine and 152 mg of 2-bromoethyl ether was refluxed in 1.5 ml of acetonitrile for 3 hours (at a bath temperature of 95 ° F) to yield 346 mg of trans, trans and cis, trans Formula-ester mixture. Hydrolysis with 250 mg of NaOH in 1 ml of water and 3 ml of ethanol yielded 14 mg of the title compound. mp 88-90〇C 〇lR NMR (CDC13? 300 MHz) d 1.25 (t? J = 7 Hz, 3H), 2.21-2.32 (m, 1H), 2.70-2.80 (m, 1H), 2.85-2.94 ( m, 2H), 3.38-3.55 (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, 1H), 6.84 (d, J = 9 Hz, 2H), 7.08 (d, J = 1 Hz, 1H), 7.33 (d, J = 9 Hz, 2H). Example 5 Formula I, trans-2- (4-methoxybenzyl) -4- (1,3_benzodifluorene_5-yl) -1- (2-propoxyethyl) -Ethan -3 -Acid using the method of Example 1 D, 52 mg of the mixture from Example 1 C, 364 mg of diisopropylethylamine, 50 mg of potassium iodide and 3 50 mg of 2-chloroethylpropyl ether, at 125 ° C was reacted in 0.5 ml of acetonitrile for 4 hours to produce 517 mg of trans, trans and cis, trans-cool mixture. Take a part (500 mg) of 315 mg of NaOH in 1 ml of water and 4 ml of ethanol to hydrolyze, raw -105- This paper size applies to China National Standard (CNS) A4 size (210X 297 mm) (Please fill in this page again)

581760 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 V. Description of the invention (103) 225 mg of standard pass compound, which is an amorphous powder. ijj NMR (CDCI3, 300 MHz) β 0.87 (t, J = 7 Hz, 3H), 1.53 (six peak, Bu 7 Hz, 2H), 2.28-2.41 (m, 1H), 2.71-2.83 (m, 1H), 2.92 · 3 · 08 (m, 2H), 3.30 (t, J = 7 Hz, 2H), 3.40-3.60 (m, 4H), 3.72-3.83 (m, 1H), 3.76 (s, 3H), 5.92 (s, 2H), 6.71 (d, J = 8 Hz, 2H), 6.74 (dd, J = 8 Hz, 1Hz), 6.71 (d, J = 9 Hz, 2H), 7 · 07 (d, J = 9 Hz, 2H), 7.73 (d, J = 9 Hz, 2H) 0 Example 6 Basic formula, transphenyl) _4_ (13_benzodifluorene_5_ group, Bu " 2 彳 2-yl) ethyl 1_ leaf I: rollidine-3- # _

Example 6 A plex, trans-benzene-yl-H-P, stilbenedifluorene, and its pyrrolidin-3-ethyl caprylate pair obtained from the pure cis, cis-compound of Example 1c G) Dissolved in 10 ml of ethanol, and added 20 drops of a solution of 21/0 sodium ethoxide in ethanol. The reaction mixture was refluxed overnight, at which time thin layer chromatography in ethyl acetate showed a lack of starting material. NaOEt was neutralized with HC1 / ethanol, and the solution was concentrated under vacuum. The residue was taken up in toluene and extracted with potassium bicarbonate in water. The toluene was dried over sodium sulfate and concentrated under reduced pressure to give 2.775 g of the title compound, which was further purified by TLC (ethyl acetate). Example 6 Β trans'trans-2- (4-methoxyethenyl) _4_ (1,3_benzo-p_5 · curtain) 1 [2 (2 methoxyethoxy) ethyl 1- Epipyridine-Using the method described in Example ID, 250 mg of the compound L · _ ^ ___- 106- ^ obtained from Example 6a is applicable to the Chinese National Standard (CNS) A4 specification (210'〆297 mm) --- (Please read the notes on the back before filling this page)

、 1T Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 ____B7 V. Description of Invention (104)

Substance, 150 grams of 2- (2-methoxyethoxy) ethyl bromide and 175 mg of diisopropylethylamine in 1¾ liters of acetonitrile, heated at 100X for 3 hours to produce 229 g of trans , Trans-ester. A portion (200 mg) was hydrolyzed with 125 mg of NaOH / ¾ liter of water and 2 ¾ liter of ethanol to produce 151 mg of the title compound as a typical crystalline powder. 1H NMR (CD3OD, 300 MHz) J 2.9-3.9 (m, 13H), 3.81 (s, 3H), 4.49 (d, J = 100 Hz, 1H), 5.94 (s, 2H), 6.79 (d, J = 8 Hz, 1H), 6.89 (dd, J = 8 Hz, 1 Hz, 1H), 7.00 (d, J = 9 Hz, 2H), 7.05 (d, J = i Hz, m), 7 49 (d , J = 9

Hz, 2H). Example 7 trans, lane-type-2 · (4 · methoxyphenyl) -4- (l, 3_disenodiazyl) _b 丨 2_ (2 · bendyl) ethyl 1-erlotidine _3_ Miao_ The compound from Example 6A (250 mg), 2-vinylpyridine (355 mg) and 1 drop of acetic acid were dissolved in 2-methoxyethanol at 100. . Blow down for 2 5 hours. Toluene was added and the solution was washed with a potassium bicarbonate solution. The solution was dried over potassium bicarbonate and concentrated with Ganoderma lucidum. Toluene was added and the solution was concentrated again. This was done until the odor of 2-vinyl Edo disappeared. The residue was taken up in hot heptane, filtered to remove a small amount of insoluble impurities, and concentrated in vacuo to produce 225 mg of intermediate vinegar. The vinegar was hydrolyzed in the same manner as in Example 1D to produce 202 mg of the title compound in the form of a monohydrate. m Ρ 77 · 8〇πιΗ NMR (cd3〇d, 300 MHz) d 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 (d, 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, -107-1) Paper standards are applicable to Chinese national standards ( CNS) A4 size (210X297mm) (Please read the precautions on the back before filling this page)

581760 A7 B7 V. Description of the invention (105) 2H), 7.70-7.80 (m, 2H), 8.40 (d, J = 4 Hz, 1H). Example 8 Trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodiazine-5-yl Vl-10 Manfrolin-4-ylfluorenyl) -pyrrolidine The compound (300 mg) produced by 3-Lean acid in Example 6 A and 164 mg of triethylamine were dissolved in 2 ml of dichloromethane and cooled in an ice bath. 146 mg / monomorpholine carbonyl chloride was added. The mixture was stirred at room temperature for 3 hours. Toluene was added, and the solution was washed with a potassium bicarbonate solution, dried over sodium sulfate, and air-concentrated to form an intermediate ester. The ester was hydrolyzed in the same manner as in Example 1D to give 288 mg of the title compound. m.p. 244-246 ° C. 4 NMR (DMS0-d6, 300 MHz) d 2.96 (dd, J = 12, Hz, 13 Hz, 1H), 3.03-3.13 (m, 2H), 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 = 9 Hz, 2H), 7.07 (s, 1H), 7.25 (d, J = 9 Hz, 2H). Example 9 trans'trans-2- (4-methoxyphenyl) -4- (1,3-benzodiazin-5-yl) -1- (butylaminecarbonyl) pyrrolidine-3-carboxyl Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Acid Economy (please read the precautions on the back before filling this page)

The compound produced in Example 6A (300 mg) was dissolved in 2 ml of tetrahydrofuran and cooled in an ice bath, and 88 mg of butyl isocyanate was added. After 40 minutes at room temperature, toluene was added and the solution was concentrated under vacuum to form an intermediate ester. The ester was hydrolyzed in the same manner as described in Example ID to give 232 mg of the title compound. m.p. 220-221 ° C. 4 NMR (DMS0-d6, 300 MHz) 6 0.78 (t, J = 7 Hz, 3H), 1.10 (six peaks, J = 7 Hz, 2H), 1.22 (five peaks, J -108- Applicable to this paper scale China National Standard (CNS) A4 specification (210X297 mm) 581760 A7 _ B7 ------------------- 5. Description of the invention (1 06) = 7 Hz, 2H), 2.78-3.05 (m , 3H), 3.40-3.56 (m, 2H), 3.74 (s, 3H), 3.95-4.05 (m, 1H), 4.93 (d, J = 9 Hz, 1H), 5.80 (t, width , J = 7 Hz, 1H), 5.99 (s, 2H), 6.78-6.86 (m, 2H), 6.88 (d, J = 9 Hz, 2H), 7.00 (d, J = 1 Hz, 1H), 7.12 (d, J = 9 Hz, 2H). Example 1 0 trans, trans-2- (4-methoxybenzyl V4- (l, 3-mosabifluoren-5-yl) -1 di {'I_oxyphenylaminocarbonyl) -3 -Pyrrolidin-3-miaopi The compound from Example 6 A (300 mg) was treated with 133 mg of 4-methoxyphenyl isocyanate using the procedure of Example 9. The resulting ester was hydrolyzed with NaOH using the method of Example ID to give 279 mg of the title compound. m.p. 185-187X :. 4 NMR (CDC13, 300 MHz) d 3.23 (dd, J = 12 Hz, 13 Hz, 1H), 3.55-3.68 (m, 2H), 3.72 (s, 3H), 3.83 (s 3H), 4.50- 4.65 (m, 1H), 5.06 (d, J = 10 Hz, 1H), 5.90 (s, 1H), 5.95 (s, lH), 6.72 (d, J = 9Hz, 2H), 6.7-6.8 (m, 3H), 6.92 (d, J = 9 Hz, 2H), 6.97 (d, J = 9 Hz, 2H), 7.37 (d, J = 9 2H) 〇 Example 1 1 trans, trans-2- (4 · Methoxyphenyl) -4 · Π, 3 · Benzodifluoren-5_yl) -1-Ethylpyrrolidin-3-miao acid Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Γ Please read the back Note: Please fill in this page again.) The compound (250 mg) from Example 6 A in 0.5 ml toluene was treated with 200 g of acetic anhydride. Stir at room temperature; after 2 hours, add water and neutralize acetic acid with potassium bicarbonate. Extraction of the mixture with toluene yielded 273 mg of intermediate ester. A part of the ester (200 mg) was hydrolyzed by the method of Example 1 D to give 21 j mg of the title compound. m.p. 248-250 ° C. b NMR (DMSO_d6 -109- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 581760 A7 __B7 V. Description of the invention (107) 300 MHz) θ 1 · 55 and 2.00 ( s, 3H), 2.94 and 3.03 (dd, J = 12 Hz, 13 Hz, 1H), 3.3-3.6 (m, 2H), 3.72 and 3.76 (s, 3H), 4.12 and 4.28 (dd, J = 12 Hz, 7 Hz, 1H), 4.95 and 5.04 (d, J = 10Hz, 1H), 6.00 (s, 2H), 6.75-6.87 (m, 3H), 6.95 and 7.04 (d, J = 9 Hz, 2H), 7.18 and 7.32 (d, J = 9 Hz, 2H). Example 1 2 Trans, trans_2_ (4_methoxybenzyl) -4- (1,3 · benzyldifluorene-5_some private W2-turanmethylpyrrolidine-3- # acid is obtained From the compound of Example 6 A (300 mg) and 164 mg of triethylamine were dissolved in 2 ml of monomethyl formamidine, and then cooled in ice cream and added with 13 8 Aike 2 _ sulfanylmethyl chloride. The mixture was stirred at room temperature. After 30 minutes, it was processed by the procedure of Example 8 to form an intermediate ester. The ester was hydrolyzed by the procedure of Example 1 D to give 269 g of the title compound as an amorphous powder. 1H NMR (DMSO-d6, 300 MHz) d 3.06 ( dd, J = 12 Hz, 13 Hz, 1H), 3.3-3.6 (m, 2H), 4.25 (m, lH), 5.19 (d, J = 10Hz, lH), 6.6-7.4 (m, 8H), 7.8 · 7.9 (m, 1H). Example 1 3 Trans, trans-2_ (4-methoxybenzyl) -4- (1,3-benzobisfluoren-5-yl) -1- (aniline carbonyl V Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of Pyrrolidine-3-carboxylic acid The title compound can be prepared. Mp209-2lΓC. 1HNMR (DMSO-d6, 300 MHz) ci 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 (s, 2H), 6.88 (m, 5H), 7.07 · 7 · 20 (m, 3H), 7.30 (d, 2H), 7.38 (d, 2H), 8.20 (bs, -110-) This paper size applies to China National Standard (CNS) A4 (210X297 mm) 581760

Example 1 4 Trans is' trans-methoxybenzyl) -4- (1,3-benzodiazin-5-yl) -1- (allyl carboxy-methylmethyl pyrrolidine-3-carboxylic acid The title compound was prepared by the method of Example 1. mp 138_140χ: 4 NMR (CDC13, 300 MHz) β 2.84 (d, 1Η), 2.90-3.10 (dt, 2Η), 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 trans, trans_2- (4-methoxyphenyl) -4- (1.3-macro # 二 崎 -5- Base > > -1- ^ Ding (Please read the precautions on the back before filling this page)

Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Aminocarbonylmethyl) -erodoline-3- # acid The title compound was prepared by the method of Example 1. m.p. 105_107. (: LR NMR (CDCls, 300 MHz) ά 0.90 (t9 3Η) 9 1.30 (m, 2Η), 1.45 (m, 2Η), 2.80 (d, 1Η), 2.87-3.35 (m, 6Η), 3.62 (m, 1Η), 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 • methoxybenzyl) _4_ (ι · 3_benzodiazine-5_yl (n-propylamidine): N_methylaminecarbonylmethylpyrrolidine_3-carboxylic acid can be prepared using the procedure described in Example 1 The title compound is an amorphous solid. Optical isomers can be seen in NMR. B NMR (; CDC13, 300 MHz) d 0.73, 0.84 (2t, 3H), 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), 111-This paper size applies the Chinese National Standard (CNS) A4 specification (21 × 297 mm) Order 581760 A7 B7 V. Description of the invention (1〇 9) 7.03 (m, 1H), 7.32 (d, 2H). Example 1 7 trans, trans-2_ (4-methoxyphenyl) -4- (1,3-benzodi $ -5- ) _1_Bibihalidine-1 diylcarbonylmethyl V pyrrolidine-3 · # 醢 Using the steps of Example 1 The title compound can be prepared as an amorphous solid in a single step. Χΐί NMR (CDCI3, 300 MHz) 1.40-1.70 (m? 6H)? 2.80 (d 1H) 3.00 (m, 2H), 3.24 · 3 · 43 (m , 5H), 3.60 (m, 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) 〇 Example 1 8 trans, trans-2- (4-methoxyphenylbenzodiazine-5-yl (isobutylaminecarbonylmethyl) -P Bihadian-3-guinic acid Using the procedure described in Example 1, the title compound was prepared. ^^^; ^% 177 ° C. 4 NMR (CD3OD, 300 MHz) d 0.87 (dd, 6H) , 1.75 (seven peaks, 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) 0 Example 1 9 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) trans, trans-2- (4-methoxybenzene ) -4- (1,3-benzobisfluoren-5-yl) -1- (cyclopentylaminocarbonylmethyl V pyrrolidine_3_ # Step 1 The title compound can be prepared. m.p. 137-139Ό. 4 NMR (CDC13, 300 ΜΗζ) β 1.34 (m, 2H), 1.62 (m, 4H), 1.90 (m, 2H), 2.76 (d, 1H), 2.90 (t, 1H), 3.04 ( dd, 1H), 3.22 -112- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 ______ B7 V. Description of the invention (11) (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 cluster Ai · trans H (4-methoxyphenyl) -4_: pyrene-1,3-benzobenzo-5-5-yl, pyrene-4-ylaminocarbonylcarbonyl vol.) · Pyrrolidine-3 -Sesame color Using the procedure of Example 1, the title compound was prepared as an amorphous solid. 1H NMR (CDC13, 300 MHz) d 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). '' Example 2 1 trans, transmethoxyphenyl y4_ (13_benzyldioxooxyethylethyl aziridine Miaoling Using the procedure of Example 4, the title compound having an amorphous solid can be prepared. IH NMR (CD3OD5 300 ΜΗζ) ί 2.82 (m, 1H), 2.96 (dd, 1H), 3.13 (m, 1H), 3.32 (m, 1H), 3.51 to 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 (d5 2H). 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 2 2 trans-anti-dimethicone ) -4- (1,3-benzyldi-g-5-yl) · ι · (2 · methylvalylethylaminecarbonylmethyl 1) _pyrrolidine_3_ 焱 _ The title can be prepared using the procedure in Example 1 Compounds. mp 107-109x :. lU NMR (CD3OD5 300 MHz) δ 2.82 (d, 1H), 2.97 (q? 2H), 3.21 (d9 1H)? 3.38 (m? 1H)? 3.32 (s? 3H)? 3.44 (m, 4H)? 3.62 -113- This paper is suitable for household food (CNS) A4 size (2i0x ^ 7mm) 581760 A7 B7 V. Description of the invention (111) (m, 1H), 3.79 (s, 3H), 3 · 86 (d5 1H), 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 2 3 Cluster of trans 2_ (4-methoxyphenyl) _4_Π · 3-mozo dihum-5-yl) -1- (2-butoxyethyl biweidian_3-teaching acid utilization example 4 of Procedure, the title compound can be prepared. M p. 53-55-. 4 NMR (CDC13, 300 MHz) d 0.88 (t, J = 7Hz, 3H), 1.32 (Liu Ling, J = 7Hz, 2H), 1 · 50 (five peaks, J = 7Hz, 2H), 2.27 (tt, J = 6Hz, 6Hz, 1H), 2.92 (q, J = 10Hz, 2H), 3.35 (t, J = 7Hz, 2H), 3.42-3.56 ( m, 4H), 3.68 (d, J = 10Hz, 1H), 3.78 (s, 3H), 5.94 (s, 2H), 6.73 (d, J = 8Hz, 1H), 6.83 (d, J = 9Hz, 2H), 6.82-6.87 (m5 1H), 7.06 (d, J = 2Hz, 1H), 7.32 (d, J = 9Hz, 2H). MS m / e 442 (M + H). Example 2 4 trans, trans-2- (1,3-benzodiam-5-yl) -4- (4-methoxyphenyl VI- (propylaminomethyl) -p-pyrrolidine-3- Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economics (Please read the precautions on the back before filling this page) Use the procedure of Example 1 and use (1,3-benzodifluoren-5-ylcarbonyl) ethyl acetate Replaces (4-methoxyfluorenyl) ethyl acetate and 4- (2-nitroethylfluorenyl) anisole in place of 5- (2-nitrovinyl) -1,3 -Benzodi-5-yl group to give the title compound. Mp 97-99 ° C. 4 NMR (CDC13, 300 MHz) d 0.78 (t, J = 7Hz, 3H), 1.39 (six peak, J = 7Hz , 2H), 2.72 (d, J = 16Hz, 1H), 2.74 (t, J = 10Hz, 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 = 10Hz, 2H), 7.80 (t, J = 6Hz, 1H). MS (DC1 / NH3) m / e 441 (M + H) + -114- This paper size applies Chinese National Standard (CNS) A4 (210X 297mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Description of the invention (112) An example 2 5, trans & quot ^ 彳 1,3 · Benzodifluoren-5-yl) -4- (4-methyl exhaustion · phenyl) _ι_ (2-propoxyethyl ehalide-3- # 醴 using the steps of Example 5, Replace (4-methoxybenzyl) acetate with (ι, 3-benzodifluorenyl-5-ylcarbonyl) acetic acid ethyl acetate and replace 5- (2-nitroethylfluorenyl) _ι 3 -benzo-2_5 · group, which can be formed

Title compound. m.p · 67_69 ° C. 4 NMR (CDC13, 300 ΜΗζ) β 0 · 89 (t, J = 7Hz, 3Η), 1.56 (six peak, j = 7Hz, 2Η), 2.33 (m, 1Η), 2.78-3.00 (m, 3H ), 3.32 (t, J = 7Hz, 2H), 3.45_3 · 57 (m, 4H), 3.73 (m, 1H), 3.79 (s, 3H), 5.93 (s, 2H), 6.22 (d , J = 8Hz, 1H), 6.85 (d, J = 8Hz, 3H), 6.98 (s, 1H), 7.37 (d, J = 8Hz, 2H). MS (DC1 / NH3) m / e 428 (M + H) + 〇 Example 2 6 Basic formula, trans benzodifluorene_5_yl) -4_ (4_methoxybenzene some νι_ 『2- (2 · foxyethoxy) ethyl) 1. Eloyl-3-glycolic acid was used in the procedure of Example 4 and replaced with the starting material described in Example 25, and 2- (2 · methoxyethyl Oxy) ethyl bromide to burn erlotine nitrogen to give the title compound. m.p. 85-86 ° C. h NMR (CD ^ OD, 300 MHz) β 3.18-3.90 (m, 15H), 3.79 (s, 3H), 4.57 (d, J = 10Hz, 1H), 6.02 (s, 2H), 6.91 (d , J = 8Hz, 1H), 6.95 (d, J = 9Hz, 2H), 7.06 (dd, J = 8Hz, 1H), 7 · 12 (dd, J = lHz, 1H), 7.37 (d , J = 9Hz, 2H). MS (DC1 / NH3) m / e 444 (M + H) + 〇 Example 2 7 Expanded, trans_2- (l, 3-benzobis4.5-yl) -4- (4-methoxy Phenyl) -1- (butoxy-115-) This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

, 1T • f · 581760 Α7 __-- _ Β7 V. Description of the invention (113) ^-)-pyrrolidine_3-polyacid (please read the precautions on the back before filling this page) Use the steps described in Example 4 Substituting the starting materials described in Example 25 and using 2-ethoxyethyl bromide to alkylate pyrrolidine nitrogen, the title compound can be formed. 111 | 54_56. 0 :. 111 > ^ 11 (.0 (: 13,30〇) ^ 1 ^) (^ 〇.89〇 ,: [• 7Hz, 3H), 1.44 (six lead, J = 7Hz 2H),! 52 (Five Peaks, J = 7Hz, 2H), 2.40 (m, 1H), 2.74-2.98 (m, 3H), 3.46 (t, J = 7Hz, 2H), 3.42-3.56 (m, 4H), 3.68 (d, j = i〇 Hz, 1H), 3.80 (s, 3H), 5.93 (dd, J = 6Hz, 1Hz, 2H), 6.72 (d, J = 8Hz, 1H), 6.74 (dd, J = 9Hz, 3H), 6.96 (s , 1H), 7.36 (d, J = 9Hz, 2H). Example 2 8 trans'trans-2- (4-methylphenyl) _4_ (i, 4 • benzodiinyl) -i_ (Propylamine blanket methyl pyrrolidine-3-carboxylic acid Printed using the procedure described in Example 1 by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, and using 6- (2-nitrovinyl) -1,4-benzodi Substituted 5- (2-nitrovinyl) -13-benzodihydrazene to generate the title compound. Mp · 80-81 ° C. B NMR (CDC13, 300 MHz) d 0.89 (t, J-plane 7Ήζ , 3H), 1.49 (six fronts, j = 7Hz, 2H), 2.78 (d, J = 16Hz, 1H), 2.92 (t, J = 10Hz, 1H), 3.05-3.43 (m, 5H) , 3.24 (d, J = 16Hz, 1H), 3.52-3.62 (m, 1H), 3.80 (s, 3H), 3.80 (t, J = 10Hz, 1H), 4.27 (s, 4H), 6.74-6.93 ( m, 5H), 7.29 (d J = 9Hz, 2H). MS (DCI / NH3) m / e 455 (M + H) + 〇 Example 2 9 trans, trans-2- (4-methoxyphenyl) -4- (1,4 -Benzodiazin-6-yl V1_ (N-methyl-N · propylamine benzoylmethyl) pyridine-3-carboxylic acid using the procedure of Example 1 to 6_ (2_nitrovinyl) _1 ， 4-Benzodioxane-116- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 _B7 V. Description of the invention (114) Replace 5- (2-nitrovinyl)- 1,3-Benzodiorophosphonium, and N-methyl-N-propyl thiamine ethylamine for entertainment? Bilodinium nitrogen can produce the title compound. mp 74 · 76 ° C. Optical isomers Visible in NMR. 4 NMR (CDCI3, 300 MHz) β 0.73, 0.83 (2t, J = 7Hz, 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, 1H), 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 3 0 trans, trans-2- (4-methoxyphenyl) _4 · (1,3_benzodifluorene_5_yl) _1-〇 ^ _methylbutaminecarbonylmethyl V pyrrolidine -3- # Acid Using the procedure described in Example 1, the title compound can be prepared. Optical isomers are visible in NMR. 4 NMR (CD3OD, 300 MHz) 0.86 (2t, 3Η), 1.04-1.50 (m, 4H), 2.85 (2s, 3H), 2.93-3.20 (m, 4H), 3.40 (m, 2H), 3.52 (dd, 1H), 3.60 (m, 1H), 3.80 (s, 3H), 3.85 (m, 1H), 5.91 (s, 2H), 6.74 (d5 1H), 6.83-6.95 (m, 3H), 7.03 (dd, 1H), 7.3 5 (dd, 2H). Example 3 1 trans, trans-2- (4-methoxy-2-methoxymethoxybenzyl) -4 · Π, 3-benzodiazin-5-ylmethyl-N-butylamine Chitomethyl) · ρbilodine _3_ Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of Guizhou (Please read the precautions on the back before filling this page) Example 31Α 2- (4-methoxy-2 -Methoxymethoxyphenyl-4- (1,3-benzodifluoren-5-yl V pyrrolidin-3-carboxylic acid ethyl ester. The method of Examples 1 A and 1 B was used, and 4-methoxy (2-methoxymethoxybenzyl) ethyl acetate instead of (4-methoxybenzyl) ethyl acetate, can be -117- This paper size applies to China National Standard (CNS) A4 specifications (21 〇'〆297 mm) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 581760 A7 B7 V. Description of the invention (115) Generate 2- (4-methoxy-2-methoxymethoxyphenyl) -4 -(1,3-Benzodibenz-5-yl) -4,5-dihydro-3H_pyrrole_3_metanoate. The aforementioned dihydropyrrole carboxylic acid ester (3.0 g, 7.0 mmol) ) Dissolved in 20 ml of methanol, and then treated with 500 mg 〇 / 0Pd / C and placed under hydrogen atmosphere for 32 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Analysis of the upper layer silica gel, eluting with ethyl acetate to generate the title compound (1.9 g, 63%) as a cis - cis isomer.

Example 31B trans, trans-2- (4-methoxy-2-methoxymethoxyphenyl) -4- (1,3-benzodolin-5-ylmethylbutylaminecarbonylmethyl Pyrrolidine-3_carboxylic acid Example 3 1 A Compound, epimerized in the same manner as in Example 6 A. The resulting trans, trans compound (100 mg, 0.23 mmol) was then treated with Example 1 D Method reaction, replacing N-propyl bromoacetamide with N-methyl-N-butyl bromoacetamide to give the title compound (75 mg, 62%). Mp 65-67 ° c. Optical isomers may See NMR. 4 NMR (CDC13, 300 MHz) β 0.64, 0 · 68 (2t, J = 7Hz, 3H), 1.14, 1.12 (2 six peaks, J = 7Hz, 2H), 1.40-1.48 (m , 2H), 2.86, 2.89 (2s, 3H), 2.95 · 3 · 42 (m, 6Η), 3.50 (s, 3Η), 3.43-3.65 (m, 2Η), 3.78 (s, 3Η), 4.30 (t, J = 7Hz, 1H), 5.09 (q, J = 7Hz, 2H), 5.92 (s, 2H), 6.55 (dd, J = 3Hz, 1H), 6.68 (s, 1H), 6.72 (s, 1H), 6.85 (2t, J = lHz, 1H), 7.04 (t, J = lHz, 1H), 7.42 (dd, J = 3Hz, 1H). Example 3 2 trans, trans-2 -(4-methoxymolybdenum V4_ (l, 3-benzobenzofluoren-5-yl) · M3-ethoxypropyl V pyrrolidin-5-one-3-carboxyl -118- This paper scales applicable Chinese National Standard (CNS) A4 size (210X297 mm) (Please read smell precautions to fill out the back of this page) clothes · Order 581760 A7 B7 V. Description (116) invention

Example 32A Ethyl 2- (4-methoxyfluorenyl V3-methoxycarbonyl-1,3-benzodifluorene-5-propionate) (4-methoxybenzyl) dissolved in 20 ml of anhydrous THF Fluorenyl) ethyl acetate 4.44 g, 0.02 mmol. NaH was added in portions. The mixture was stirred at ambient temperature for 30 minutes. Add 5 ml of THF methyl (1,3-benzodihum-5-yl) bromoacetate (5.46 g, 0.02 mole). The mixture was stirred at ambient temperature overnight, diluted with 200 mL of EtOAc, and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to give the title compound (7.67 g, 92%), which was used directly without further purification.

Example 32B 1_ (3_ethoxypropyl) -2- (4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) -4.5_ Employee Consumer Cooperative of Central Standards Bureau, Ministry of Economic Affairs Printed (please read the notes on the back before filling this page) Dihydro_5_keto 1H-pyrrole-3_carboxylic acid ethyl ester obtained from the compound of Example 32A (700 mg, 1.69 mmol), 3- A mixture of ethoxypropylamine (348 mg, 3.38 mmol) and 1 ml of acetic acid was heated in a sealed bottle at 125 ° C for 18 hours. After the contents of the bottle were cooled to ambient temperature, 5 ml of water was added, The mixture was then extracted with ethyl acetate (2x100 ml). The combined organic extracts were washed with a saturated sodium bicarbonate solution, then with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was on silica gel Chromatography and dissociation with 3: 2 hexane-ethyl acetate gave 330 μg (42%) of the title compound.

Example 32C 1- (3-ethoxypropyl) -2- (4-methoxyphenyl) -4- (1,3-benzobisfluoren_5-yl) _pyrrolidine_5 · one-3- Example of Ethyl Carboxylate Compound 32B (300 mg, 0.64 mmol) in 15 ml of methanol-119- This paper size applies Chinese National Standard (CNS) A4 (21 × 297 mm) 581760 A7 B7 Central Bureau of Standards, Ministry of Economic Affairs Printed by the Employee Consumption Cooperative 5. In the description of the invention (117), 100 mg of 10% Pd / c was used for reduction for 3 hours under hydrogen and ambient temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound.

Example 32D trans' 甲 式 甲 — 基 豕 基) · 4 · (1,3_Mo # 二 阴 _5 · 基 ethoxypropyl) · Command; ρ 各 淀 _5-_ -3 · # _ Examples Compound 32C (100 mg, 0.21 mmol) was dissolved in 1 ml of ethanol. 'Add 3 drops of a solution of 21% sodium ethoxide in ethanol. The mixture was heated to 70-80 ° C for 3 hours, then a solution of sodium hydroxide (100 g) in 1 ml of water was added, and heating was continued for another 1 hour. The reaction mixture was cooled to ambient temperature, the ethanol was removed under reduced pressure, water was added to the residue and the residue was washed with ether. The water layer was neutralized with 3M HC1 and allowed to stand overnight. The white crystalline solid was collected by filtration to obtain the title compound (60 mg, 64%), mp · 134_140 ° C 0 4 NMR (DMSO-d6, 300 MHz) A 1.04 (t, J = 7Hz, 3H), 1.55 (six Peak, J = 7Hz, 2H), 2.48 · 2 · 56 (m, 1H), 2.93 (dd, J = 9Hz, 1H), 3'25 (t, J = 7Hz, 2H), 3.28-3.40 ( m, 2H), 3.48-3.57 (m, 1H), 3.78 (s, 3H), 3.88 (d, J = 10Hz, 1H), 4.72 (d, J = 10Hz, 1H), 6.02 (s, 2H), 6.74 (dd, J = 8Hz, 1Hz, 1H), 6.87 (d, J = 8Hz, 2H), 6.98 (d, J = 8Hz, 2H), 7.38 (d, J = 8Hz, 2H). MS (DCI / NH3) m / e 442 (M + H) +. Example 3 3 trans, trans-2- (4-methoxyphenyl) -4 · (1,3-benzodihum-5-yl) -1- (3-methoxyfluorenyl V pyrrolidine- 5. · Keto-3-carboxylic acid Follow the method of Example 32 and replace it with 3-methoxybenzylamine (3-ethoxy-120- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) ---------------- IT ------ 0— (Please read the precautions on the back before filling this page) 581760 A7 __B7 _ __ V. Description of the invention (118) Propylamine to give the title compound (123 mg, 65%). Mp 150-152 ° C. 4 NMR (CD3OD, 300 MHz) d 2.96 (dd, J = 8Hz, 10Hz, 1H), 3.72 (s, 3H) , 3.80 (s, 3H), 4.06 (d, J = 10Hz, 1H), 4.58 (d, J = 8Hz, 1H), 4.92 (q, J = 16Hz, 2H), 5.92 (s, 2H), 6.55-6.63 (m, 2H), 6.82 (d, J = 8Hz, 4H), 6.94 (d, J = 8Hz, 2H), 7.15-7.22 (m, 3H). MS (DCI / NH3) m / e 475 (M + H) +. Example 3 4 Trans, trans-2- (4_methoxybenzylbenzodifluorenyl_5-yl) -i_ (N, N-diisopentylaminocarbonyl, some methyl, some V Pyrrolidine-3_ # acid Using the method of Example 1, the title compound was prepared as an amorphous solid.! H NMR (CDCls, 300 MHz) δ 0.70-0 .90 (m, 12Η)? 1.10-1.60 (m, 10Η), 2.75 (d, J = 13Hz, 1Η), 2.90_3.10 (m, 4Η), 3.15_3 · 30 (m, 2H), 3.40 (d, J = 10 Hz, 1H), 3.40-3.52 (m, 2H), 3.55-3.62 (m, 1H), 3.75 (d, J = 12 Hz, 1H), 3.79 (s, 3H), 5.93 (dd, J = 1 Hz, 3 Hz, 2H), 6.72 (d, J = 8Hz, 1H), 6.82-6.90 (m, 3H), 7.03 (d, J = 2Hz, 1H), 7.30 (d, J = 9Hz, 2H). Example 3 5 trans-'trans-2- (4 • methoxymolyl benzodifluorene_5_yl) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the first Note: Please fill in this page again.) Dipentylaminocarbonyl V pyrrolidine_3_ Borrow_ The title compound can be prepared as an amorphous solid according to the method of Example 1. ιΗ N1V1R (CDC13, 300 MHz) d 0 · 82 (t , J = 7 Hz, 6H), 0.95-1 · 03 (m, 2H), 1.10-1.30 (m, 8H), 1.40-1.51 (m, 2H), 2.72 (d, J = 13Hz, 1H) , 2.90-3.08 (m, 4H), 3.25-3.50 (m, 3H), 3.37 (d, J = 13Hz, 1H), 3.52-3.60 (m, 1H), 3.70 (J = 10Hz, 1H), 3.75 (s, -121-This paper size applies to China National Standard (CNS) A4 size (210X297 male thin) ~ 581760 Central Ministry of Economic Affairs Printed by the Consumer Bureau of the Associate Bureau A7 __ _B7 V. Description of the Invention (119) 3H), 5.92 (dd, J = 2HZ, 5Hz, 2H), 6.72 (d, J = 8Hz, lH), 6.80-6.88 (m, 3H), 7.03 (d, J = 2Hz, 1H), 7.30 (d, J = 9Hz, 2H). Example 3 6 trans, trans--2- (4-methoxybenzyl) -4- (1,3-benzodi-2--5-ylbis (2-methoxyethyl) aminocarbonylmethyl ν pyrrolidine_3_carboxylic acid The title compound can be prepared by the method in Example 1. mp 120-122 ×: 'H NMR (CDC13? 300 MHz) d 2.82 (d, J = 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 = 10Hz, 1H), 3.79 (s, 3H), 5.92 (dd , J = 2Hz, 2Hz, 2H), 6.72 (d, J = 8Hz, 1H), 6,80-6.90 (m, 3H), 7.04 (d, J = 2Hz, 1H), 7.30 (d, J = 9Hz, 2H) 〇 Example 3 7 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodi-2-hyl) -1- (2-hexyne ) -Pyrrolidin_3-guinic acid Using the method of Example 4, 200 mg of the pure trans, trans isomer from Example 6 A, and 109 mg of 1 · bromo-2-hexyl block (perkin 1) , (2004) (prepared by the method of 2004 (1987)) at 55 ° C for 1 hour to produce 226 mg of the intermediate ester. Vinegar was hydrolyzed with NaOH in ethanol · water, and 175 mg of the title compound was produced at room temperature for 3 hours. 4 NMR (CDCU, 300 ΜΗζ) β 1.00 (t, J = 7Hz, 3H), 1.54 (m, 2H), 2. 14-2.22 (m, 2H), 2.96 (dd, J = 7Hz, 13Hz, 1H), 3.07 (dd, J = 18Hz, 2Hz, 1H), 3.15 (dd, J = 9Hz, 2Hz, 1H), 3.26 ( t, J = 9Hz, 1H), 3.36 (dd, J = 18 Hz, 2Hz, 1H), 3.47-3.55 (m, 1H), 3.79 (s, 3H), 3.88 (d, J = 9Hz, 1H), 5.95 (s, 2H), 6.72 (d, J = 8Hz, 1H), 6.80-6.88 (m, 3H), -122-1 Paper size applies to China National Standard (CNS) A4 specification (210X297 mm) " ( Please read the precautions on the back and fill in this purchase first) tr 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 _______B7_ V. Description of the invention (12) 7.03 (d, J = 2Hz, 1H), 7.22 (d , J = 9Hz, 1H). Example 3 8 Formula 'trans-2- (4-methoxymolybdenum V4- (l, 3-benzodifluorene-5 · yl ring mutual production of propylaminocarbonylmethyl) -The pyrrolidine-3-carboxylic acid title compound was prepared by the method of Example 1. m p 167_169 ° C. Optical isomers are visible in NMR. 4 NMR (CDC13, 300 MHz) d -0.1 (m), 0.05 (m), 0.12-0.25 (m), 0.32-0.51 (m), 0.67 and 0.72 (2 Sanlings, 3H), 0.90- 1.00 (m) 9 1.20-1.55 (m)? 2.72 (d, J = 13Hz, 1H)? 2.85-3.29 (m, 4H), 3.30-3.50 (m, 3H), 3.52-3.62 (m, 1H), 3.65-3.73 (2 double peaks, j = 10Hz, 2Hz, 1H), 3 78 (s, 3H), 5 95 (2 single peaks, 2H), 6,72 (2 double peaks, 2H), 6.80 -6.90 (m, 3H), 7.00 and 7.05 (2 double peaks, j = 9Hz, 2H). Example 3 9 Well-formed 'trans_2- (4-methanazine) _4 · (1,3-benzidobifluorenyl_5_ylmethylpentylamine posterior methylpyrrosis_3_ complex acid The title compound can be prepared as an amorphous solid by the method of Example 1. Optical isomers can be seen in NMR. NMR (CDC1% 300 MHz) d 0.85 (t, J = 7Hz, 3H), 1.0--0.-. 8 (m), 1.13-1.32 (m), 1.35-1.50 (m), 2.72-2.82 (2 double peaks, j = 13Hz, 1H), 2.83 and 2.86 (2 single peaks, 3H), 2.92-3.20 (m, 3H), 3.22-3.45 (m, 3H), 3.52-3.62 (m, 1H), 3.72 (2 bimodal, ih), 3.75 and 3.76 (2 single nets, 3H), 5.92 (2 Singlet, 3H), 5.92 (2 singlet, 2H), 6.72 (d, J = 8Hz, 1H), 6.80-6.87 (m, 3H), 7.03 (2 doublet, j = 2Hz, 1H ), 7.30 (d, J = 9Hz, 2H). __ -123- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ---------------- Order ------ 0— (Please read the precautions on the back before filling this page) 581760 A7 B7 V. Description of the invention (121) Example 4 0 trans, trans-2- (4-methoxybenzyl) Yl) -4- (1,3-benzodihum-5-yl) -1- (N, N-diisobutylaminocarbonylmethyl -Pyrrolidine-3-carboxylic acid can be prepared according to the method of Example 1. mp 141-143 ° C. 4 NMR (CDC13? 300 MHz) d 0.54 (d9 J = 7Hz, 3H), 0.70-0.90 (3 Doublet, J = 7Hz, 9H), 1.60-1.75 (m, 1H), 1.90-2.02 (m, 1H), 2.67 (d, J = 13Hz, 1H), 2_70 (d, J = 13Hz, 1H), 2.84 (dd, J = 6Hz, 15Hz, 1H), 2.96-3.06 (m, 2H), 3.20 (dd, J = 9Hz, 15Hz, 1H), 3.35 (dd, J = 2Hz, 10Hz, 1H), 3.44- 3.60 (m, 4H), 3.70 (d, J = 9Hz, 1H), 3.79 (s, 3H), 5.94 (dd, J = 2Hz, 2Hz, 2H), 6.72 (d, J = 9Hz, 1H) , 6.82-6.90 (m, 3H), 7.03 (d, J = 2Hz, 1H), 7.31 (d, J = 9Hz, 2H). Example 4 1 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) trans, trans-2- (4-methoxybenzyl V4- (l, 3-benzo) Dimethyl-5-ylmethyl-N- (2-propanyl) aminocarbonylmethylpyrrolidine-3_carboxylic acid The title compound can be prepared as an amorphous solid according to the method of Example 1. The optical isomers can be See NMR. 4 NMR (CDC13, 300 ΜΗζ) Θ 2.09 and 2.32 (2 tri-peaks, J = 2 Hz, 1H), 2.80-3.10 (m, 3H), 2.90 and 2.99 (2 single-peak, 3Η), 3.35- 3.50 (m, 2Η), 3.52 · 3 · 62 (m, 1Η), 3.78 (s, 3H), 4.03 (d, J = 13Hz, 1H), 4.00-4.30 (m, 3H), 5 · 93 (s, 2H), 6.72 (2 double peaks, j = 8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 and 7.11 (2 double peaks, J = 2Hz, 1H), 7.30 (2 double peaks, J = 9Hz, 2H). Example 4 2 trans, trans_2 彳 4 · methoxybenzyl) · 4 · (1,3 · benzodifluoren-5-ylmethyl_- 124- The paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 581760 A7 B7 V. Description of the invention (122)

N-carbonylmethyl V pyrrolidine_3_miao acid According to the method of Example 1, the title compound was prepared as an amorphous solid. lH NMR (CDC13, 300 MHz) d 0.85 (2 trimodal, J = 7Hz, 3H), 1.00_ 1.50 (m, 8Η), 2.72-2.82 (2 bimodal, J = i3Hz, 1Η), 2.81 and 2.86 (2 single peaks, 311), 2.92-3.20 (〇, 311), 3.22-3.45 (111,311), 3.52 · 3.62 (m, 1Η), 3.72 (2 double peaks, iH), 3.75 and 3.76 (2 singlet, 3Η), 5.94 (2 singlet, 2H), 6.72 (d, J = 8Hz, 1H), 6.80-6.87 (m, 3H), 7.03 (2 doublet, J = 2Hz, 1H), 7.30 (d, J = 9Hz, 1H). Example 4 3 Beam-form 'trans-2- (4-methoxybennon) -4- (1,3-benzodifluorene-5 · A certain VI-ίΝ.Ν-dibutylaminocarboxymethyl)- Pbilodine-3- # acid The title compound can be prepared by the method described in Example 1. m p. 123-125 ° C. 4 NMR (CDC13, 300 MHz) 0 · 79 (t, J = 7Hz, 3H), 0.85 (t, J = 7HZ, 3H), 1.00-1.50 (m, 8H), 2.74 (d, J = 13Hz, lH ), 2.90-3.09 (m, 4H), 3.23-3.50 (m, 3H), 3.38 (d, J = 13Hz, lH), 3.52-3.62 (m, 1H), 3.75 (d, J = 10 Hz, 1H ), 3.78 (s, 3H), 5.93 (dd, J = 2Hz, 4Hz), 6.71 (d, J = 8Hz, 1H), 6.81-6.89 (m, 3H), 7.03 (d, J = 2Hz, 1H), 7.30 (d, J = 9 Hz, 2H). MS (DCl / NH3) m / e 511 (M + H) +. Analysis estimates C29H38N206: C, 68.21; H, 7.50; N, 5.49. Found 値: C, 68 · 07; H, 7.47; N, 5.40. Example 4 4 trans'trans-2- (4-methoxyphenyl) _4_ (1,3-benzodi-p--5-yl) -1- (N, N_diethylaminomethyl) ) -P-Biloxidine 3-acid acid The title compound was prepared by the method described in Example 1. mp. 132-134 ° C. -125 This paper size applies to China National Standard (CNS) A4 specification (2 丨 〇 < 297 mm) ---------- βΐΗ-- (Please read the precautions on the back before filling in this Page) Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 __; ______B7 V. Description of the Invention (123) lU NMR (CDC13, 300 MHz) ά 0.98 (t, J = 7Hz? 3H), 1 · 〇6 J = 7Hz, 3H), 2.78 (d, J = i3Hz, 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, 1H), 3.79 (s, 3H), 5.93 (s, 2H), 6.72 (d, J = 8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (d, J = 2Hz, 1H), 7.32 (d, J = 9Hz, 2H). Example 4 5 trans, trans-2_ (4 · ϋphenyl) _4 彳 13 · jamodi 噚 _5 · Carbonylmethyl Vpyrridine-3- # 醢 The title can be prepared by the method described in Example 1. Compound as an amorphous solid. 11 ^^ 01 (€ 03〇〇, 300) ^ 1 ^) 6 2.75-2.85 〇, 211), 3.0-5-3 · 13 (m, 1H), 3.18 (s, 3H), 3.40-3.58 ( m, 2H), 3.78 (s, 3H), 3.88 (d, J = 12Hz, 1H), 5.92 (s, 2H), 6.72 (d, J = 8Hz, 1H), 6.75-6.85 (m , 3Η), 7.00-7.12 (m, 5Η), 7.82 · 7 · 92 (m, 3Η). Example 4 6, transphenyl) -4 · η · 3 · 1 祓 Di 唠 -5- 篡 νΐ- (ϊϋ carbonylmethyl V pyrrolidine-3-carboxylic acid The method of Example 1 was used to prepare the title compound as No crystalline solid. Optical isomers can be found in NMR. 4 NMR (CD3OD, 300 MHz) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Read the notes on the back and fill in this page) 1.00-1.85 (m, 10H), 2.72 and 2.78 (2 single peaks, 3H), 2.75-2.82 (2 double peaks, J = 12Hz, 1Η) , 2.96-3.22 (m, 3Η), 3.40-3.65 (m, 3Η), 3.68 and 3.82 (2 double peaks, J = 10 Hz, 1H), 3 77 and 3 78 (2 single peaks, 3H), 5.92 (s, 2H), 6.72 (2 double peaks, J = 8Hz, 1H), 6.82-6.88 (m, 3H), 7.02 (2 double peaks, j = 2Hz, 1H0, 7 3〇 -7 4〇 (2 double peaks, J = 9Hz, 2H) 〇-126- This paper size applies to China Standard S (CNS) A4 specification (210X297 mm) 581760 Α7 Β7 V. Description of the invention (124) Example 4 7 trans, trans-2- (4-methoxyphenyl) _4_Π_3-benzodiain-5-yl) · 1 ((N, N · bis (n-propyl) amino) Wei methyl methyl ole Lake _3- Jun acid is shown in Example 1. The title compound was prepared as described above. Mp 170-172 ° C.! H NMR (CD3〇? 300 MHz) ά 0.69 (t? J = 7Hz, 3H)? 0.85 (t, J = 7Hz, 3H), 1.20- 1.55 (m, 4H), 2.72 (d? J = 13Hz, 1H), 2.90-3.10 (m, 4H), 3.25-3.47 (m, 4H), 3.35-3.62 (m, 1H), 3.72 (d, J = 9Hz, 1H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, d, J = 8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (d, J = 2Hz, 1H), 7.30 (d, J = 9Hz, 2H). Example 4 8 Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) trans, trans-2- ( 4 • methoxyphenyl V4_ (l, 3_benzodifluoren-5-ylmethyl-N-isobutylaminetylmethyl bihalide_3_polyacid The title compound was prepared by the method described in Example 1. Optical isomers can be found in NMR. 4 NMR (CD3OD, 300 MHz) d 0.65-0.85 (4 double peaks, J = 7Hz, 6H), 1.75-1.95 (m, 1H), 2.80 and 2.90 (2 Single peaks, 3H), 2.90-3.10 (m, 4H), 3.10-3.65 (m, 4H), 3.74 (s, 3H), 3.81 and 3.88 (2 double peaks, J = 10Hz, 1H), 5.93 (s, 2H), 6.72 (d, J = 8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (2 double peaks, J = 2Hz, 1H), 7.80-7.90 (2 double peaks, J = 9Hz, 2H). Example 4 9 2 · (4-methoxyfluorenyl) -4-nitromethyl-3-Π, 3-benzodifluoren-5-yl) butyrate Paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of invention (125)

Example 49A A stirred solution of methylenedioxyphenylnitroethylene p-piperaldehyde (75 g, 500 mmol) in methanol (120 ml), nitromethane (27 1 ml, 50 ml) was added at 10 ° C. 0 millimolar, 1 s) and then dropwise add sodium hydroxide (21 grams, 525 millimoles, 1.05 equivalents) in sufficient water to reach a total volume of 50 milliliters, while maintaining the temperature at 1 〇_ 15 C room. The reaction mixture became cloudy and thickened. The mixture was stirred for 30 minutes to complete the addition, and the mixture was diluted with ice water (~ 350 ml) to maintain the temperature below 5 ° C until a solution was reached. The resulting / valley solution was poured into a rapidly stirred solution of 36% hydrochloric acid (100 ml) in water (150 ml) in a narrow fluid manner (so that it did not split into drops). The colored solids will come out of Shen Dian (nitrostyrene), and then collected by filtration and washed with water (1.5 liters) until the filtrate is neutral. The filter block was air-dried and recrystallized from hot ethanol (3 liters) to form E_2 < 3,4_methylenedioxy) _nitrophenylethyl 晞 'as yellow needles (53 g, 55%). NMR (300MHz, CDC13) Ί94 (1H, d, J = 13.5Hz), 7.47 (1H, d, J = 13.5Hz), 7.09 (1H, dd, J = 7.5 & 2Hz), 7.01 (1H , D, J = 2Hz), 6.87 (1H, d, J = 7.5Hz), 6.06 (2H, s). MS (DCI / NH3) m / e 194 (M + H) +, 211 (M + H + NH3) +.

Example 49B Ethyl) keto-4-nitro-3 · (3,4-methylenedioxyphenyl) butyric acid ethyl ester Nitrostyrene (14.17 g, 73.34 mmol) from Example 49 A, 1.2 equivalents) in a sandalwood solution of a mixture of propan-2-ol (75 ml) and tetrahydrofuran (175 ml), ethyl acetate (4 · methoxybenzyl) (11.5 g, 51.7 mmol) was successively added at room temperature. Moore) Yu Ding 1 ^ (50 ml) solution and 1,8-diacridine-128- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) I --------- #II (Please read the notes on the back before filling this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T 581760 A7 B7 V. Description of the invention (126) Ring [5.4.0] Undecyl-7-ene (DBU) (0.45 liters, 30 mol, 〇〇 5 equivalents). The resulting mixture was stirred at room temperature for 1 hour, and additional DBU (0.45 ml, 3.0 mmol, 0.05 equivalent) was added. The mixture was stirred for an additional 1 hour, after which the volatile matter was removed under vacuum, and the residue was purified by flash chromatography with 500 g of crushed gum, and then changed to 20% ethyl acetate-hexane and then dissolved to 25% ethyl acetate-hexane. , Soluble products. The solvent was removed under vacuum to form a nitroketoester (19.36 g, 76%) as a thick oil. Diastereoisomers can be seen in NMR. " H NMR (300 MHZ, CDCIJ d 8 · 〇6 (2H, d, J = 9Hz), 7.89 (2H, d, J = 9Hz), 6.96 (2H, d, J = 9Hz), 6.91 (2H, d, J = 9Hz), 6.77 (1H, dd, J = 9Hz, 3Hz), 6.73 (1H, d, J = 9Hz), 6.65 (1H, d, J = 3Hz ), 5.95 (2H, s), 5.89 (1H, d, J = 4Hz), 5.88 (1H, d, J = 4Hz), 4.90-4.60 (3H, m), 4.39 (1H, m), 4.18 (2H, q, J = 7Hz), 3.94 (2H, m), 3.80 (3H, s), 3.78 (3H, S), 1.19 (3H, t, J = 7Hz), 0.99 (3H, t, J = 7HZ). MS (DCI / NH3) m / e 416 (M + H) +, 433 (M + H + NH3) +. Example 50 0 Employee Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs Printed (Please read the precautions on the back before filling this page) Formula-2_ (4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl second-butoxycarbonylmethyl ) -Pyrrolidine-3-carboxylic acid To a stirred solution of the compound of Example 1 C (100 mg, 0.27 mmol) in acetonitrile (2 ml), diisopropylethylamine (70 µl, 0.40) was added successively. Millimoles, 1.5 equivalents) and tertiary-butyl bromoacetate (48 microliters, 0. 29 μmol '1 · 1 equivalent). The mixture was allowed to stir for 2 hours, and the solvent was removed under empty space to remove A crude diester was formed. A 50% w / w sodium hydroxide (300 mg, 3.75 mmol) was added to the diester in ethanol (1 ml) at __ _-129- ___ This paper size applies to China National Standard (CNS) A4 (210X297 mm) 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ______B7 V. Description of the invention (127) Water. Stir the mixture; mix for 2 hours. Remove under reduced pressure. The residue is dissolved in water (5 ml) and the solution is washed with ether. The aqueous phase is acidified with acetic acid (300 μl) and extracted with ethyl acetate (2 ×). The combined organic extracts are dried ( NaaSO4), filtered, and concentrated to give the title compound (74 mg, 60%) as a white solid. 4 NMR (300 MHz, CDC13) d 7.36 (2H, d, J = 8Hz), 7.13 (1H, d , J = 3Hz), 6.90 (1H, dt, J = 3Hz, 8Hz), 6.88 (2H, d, J = 8Hz), 6.76 (1H, d, J = 8Hz), 5.96 (2H, s), 3.96 ( 1H, d, J = 9Hz), 3.81 (3H, s), 3.58 (1H, ddd, J = 12, 10Hz, 3Hz), 3.52 (1H, dd, J = 9Hz, 3Hz), 3.32 (1H, d, J = 17Hz), 3.08 (1H, t, J = 10Hz), 2.92 ( 1H, dd, J = 9Hz, 7Hz), 2.83 (1H, d, J = 17Hz). MS (DCi / NH3) m / e 456 (M + H) +. Analysis estimates C29H29N07 · 0.3 H20: C, 65.07; H, 6.48; N, 3.04. Measured 値 ·· C, 65 · 02; H, 6.42; N, 2.93. Example 5 1

Basic formula, trans-2- (4-methoxyphenyl V4_n, stubyl Vi-QSi, methyl-N-propyl, aminocarbonylmethyl V pyrrolidine-3- # acid. Examples 1 and 49 The title compound was prepared by substituting pyrene-; U-carboxaldehyde for the piperonyl group of Example 49A. Optical isomers were found in NMR. 4 NMR (300 MHz, CDC13) d 8.29 (1H, bd, J = 8Hz), 7.86 (2H , D, J = 8Hz), 7.75 (1H, d, J = 8Hz), 7.49 (3H, m), 7.34 (2H, dd, J = 3Hz, 9Hz), 6.83 (2H , Dd, J = 9Hz, 2Hz), 4.50 (1H, m), 3.94 (1H, dd, J = 9Hz, 2Hz), 3.78 (3H, s), 3.65 (1H, m), 3.49 ( 1H, d, J = 14Hz), 3.40-2.93 (5H, m), 2.91, 2.83 (3H, s), 1.48 (2H, seven peaks, J = 7Hz), 0.83, 0 · 77 (3H, t , J = 7Hz). MS (DCi / NH3) m / e -130- $ Paper size applies to China National Standard (CNS) A4 specification (210X297 mm) " 'IT ~ (Please read the precautions on the back before filling (This page) 581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (128) 461 (M + H) +. Analytical estimates C29h29N〇7 · 〇5 H0Ac: C, 71.00; H, 6.99; N , 5.71. Found 値: c, 7〇95; H, 7 N, 5 46. Example 5 2 "4-Formula, transoxyphenyl) _4_ (2 · 3_dihydrobenzfuran_5_yl) aminocarbonylmethyl) _pyrrole_3_ Example of a naphthenic acid 52A Dihydrobenzofuran-5-miao acid pong, dichloromethyl methyl ether (2.15 g, 19 mmol, J 35 equivalents) in dichloromethane (30 liters) To the stirred solution, tin chloride (1.65 g, 17¾ mol, 12 eq.) Was successively added at _40 t, and after 15 minutes, 2,3_dihydrobenzocran (1.68 g, 14 mmol) was added to A solution of ch2C12 (5 ml), the temperature was maintained below -35 ° C. The mixture was warmed to it, stirred for j hours, then poured into ice water, and stirred for another 30 minutes. The mixture was diluted with ether and was phased. The organic phase was concentrated under vacuum, and the residue was purified by a vacuum distillation method to give the title compound (25 g, 60%) as a colorless liquid. Bp 119-121 ° C under 0.3 mm Hg.

Example 52B K, Basic methoxyphenyl) -4 ^ 2,3-dipyranofuran-5-yl VI-propyl) aminocarbonylmethylpyrrolidine-3_carboxylic acid The title compound was prepared, but the compound obtained in Example 52A was used in place of the piperonal of Example 4 9 A. Optical isomers can be found in NMR. H NMR (300 MHz, CDC13) 7.33 (1H, d, J = 8Hz), 7.28 (1H, m), 7.19 (1H, m), 6.87 (1H, d, J = 8Hz), 6.73 (1H, d, J = 8Hz), 4.56 (1H, t, J = 8Hz), 3.83 (1H, d, J = 10Hz), 3.80 (3H, 131-This paper size applies to Chinese national standards ( CNS) A4 specification (2i〇X297 public director) --------- L --- (Please read the precautions on the back before filling this page)

I Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 ΒΊ V. Description of the Invention (129) s), 3.63 (1H, m), 3.4-3.0 (9H, m), 2.87, 2.84 (3H, s), 1.51 (2H, seven peaks, J = 7Hz), 0.88, 0.78 (3H, t, J = 7Hz). MS (DCi / NH3) m / e 453 (M + H) +. Analysis estimates C26H32N205 · 0.25 H20: C, 68.33; H, 7.17; N, 6.13. Found 値: C, 68.60; H, 6.88; N, 5.80. Meeting Example 5 3 trans, trans-2,4-bis (4-methoxyphenyl) 1-N-methyl-N-propyl) aminocarbonyl a methyl V pyrrolidine-3-carboxylic acid Prepared as described in Examples 1 and 49. 4-Tolylbenzaldehyde was used instead of piperonal of Example 49A. Optical isomers are found in NMR. iH NMR (300 MHz, CDC13) β 7.37 (2H, d, J = 7.5 Hz), 7.32 (2H, d, J = 7.5 Hz), 6.86 (4H, m), 3.83 (1H, m), 3.81 (3H, m), 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, 0.74 (3H, t, J = 7.5 Hz). MS (DC! / NH3) m / e 441 (M + H) + 0 Analytical estimation C25H32N205 · 0.5 H20: C, 66 · 80; H, 7.40; N, 6.23. Found 値: c, 67.15; H, 7.31; N, 6.00. Example 5 4 trans, trans-2- (4-methoxyphenyl) -4- (3,4-dimethylhydrophenylphenylmethyl-N-propyl) amine methyl)-^ Each of the titled 3-carboxylic acid title compounds was prepared by the methods of Examples 1 and 49, and 3,4.dimethoxybenzaldehyde was used in place of the piperonal in Example 49A. Optical isomers can be found in NMR 〇4 NMR (300 MHz, CDC13) d 7 · 33 (2H, d, J = 7.5 Hz), 7.07 (1H, d, J = 2.0 Hz), 6.98 (1H, m) , 6.85 (1H, d, 7.5 Hz), 82 (2H, d, 7.5 Hz), 3.91 (3H, s), 3.86 (3H, s), 3.83 (1H, m), -132- This paper The scale is applicable to the Chinese National Standard (CNS) A4 specification (21 × 297 mm). I -------------- Order ------ ίί— (Please read the note on the back first Please fill in this page for matters) 581760 A7 B7 .......---__________ 4 ----- --- V. Description of Invention (130) (Please read first Note on the back page, please fill in this page) 3.79 (3H, s), 3.64 (1H, m), 3.50-2.95 (6H, m), 2,87 (m, m), 2.85, 2 83 (3H, s), 1.45 (2H, m), 0.84, 0.74 (3H, t, J = 7.5 Hz). MS (DC " NH3) m / e 471 (M + H) +. Analysis and estimation (: 261134) ^ 206 · 0,5 H20: C, 65 · 12; H, 7.36; N, 5.84. Measured 値: C, 65.22; H, 7 · 27; N, 5 „59 Example 5 5

Expanded, trans_2_ (4-methoxyphenyl) -4_ (3-methoxyphenyl) · 1- (N-methyl-N · propyl) aminocarbonylmethylpyrridine-3-carboxyl The title compound was prepared using the method of Examples 1 and 49, and 3-piperoic acid was used in place of piperonal of Example 49A. Optical isomers are found in NMR. 4 NMR (300 MHz, CDC13) d 7.33 (2H, d, J = 7.5 Ηζ), 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, 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 (DC1 / NH3) m / e 441 (M + H) +. Analysis estimates C25H32N205 · 0.5 H2 0: C, 66.80; H, 7.40; N, 6.23. Found 値: C, 66.76; H, 7.36; N, 6.05. Example 5 6 Printed by the Consumer Cooperatives of the Standards Bureau of the Ministry of Economic Affairs, trans · 2_ (4_methoxyphenyl) -1- (meaning methyl · N_propyl) aminomethyl) The title compound picolinic acid was prepared according to the methods of Examples 1 and 49, and the carboxylic acid was substituted for the piperonic acid in Example 49A. Optical isomers can be found in nmr. 4 NMR (300 MHz, CDC13) d 7.82 (4H, m), 7.69 (1H, m), 7.47 (2H, m), 7.37 (2H, dd, J = 7.5 & 2 Hz), 6.85 (2H , Dd, J = 7.5 & 2 • 133- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 _______B7 _ V. Description of the invention (131)

Hz), 3.90 (lH, d, J = 8HZ), 3.78 (3H, S), 3-57 (m, m), 3.52-2.97 (6H, m), 2.93, 2.85 (3H, s), 2.90 (1H, m), 1.52 (2H, m), 0.86, 0,76 (3H, t, J = 7.5 Hz). MS (DCi / NH3) m / e 461 (M + H) +. Analysis estimates c28H32N204 · 0.5 H20: C, 71 · 62; H, 7.08; N, 5.97. Found 値 · c, 71 · 58; H, 7.11; N, 6.01. Example 5 7 Tail ... Formula 'trans-oxyphenyl) · 4 · Π · 3_jamobispyridin-5-yl Vl- (2-yl subenzyme group) E) -p-pyrrolidine_3 · Leptin is obtained from a compound of 1 c (100 mg, 0 27 mmol) and 2 • ethyl ethylsulfur (67.5 mg, 0.5 mmol, 2 equivalents) dissolved in 6 ml of acetonitrile, plus 10 G of KI and 0.5 l of diisopropylethylamine. The mixture was refluxed for 4 hours' and concentrated in the air. The obtained residue was purified by silica gel flash chromatography 'and dissociated with 4: 1 hexane-ethyl acetate to give 93 mg (750 / ❶) of ethylthioethyl compound. For sulfide (90 mg, 0.2 mmol) dissolved in 5 ml of CHWh, 68 mg of 3-chloroperoxybenzoic acid was added to the ice cream. The mixture was stirred in an ice bath for 40 minutes and then at room temperature for 3 hours. 10% sodium hydroxide solution (2 mL) was added and the mixture was extracted with EtOAc (2 X 50 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was chromatographed on silica gel and isolated with EtOAc and 10% MeOH / CH2ClJS to obtain arsenic (62 mg, 65%). The ethyl ester was hydrolyzed in the same manner as in Example 1D to give the title compound as a diastereoisomeric mixture. m.p. 61-63X :. MS (DC1 / NH3) m / e 446 (M + H) +. 4 NMR (CDC13, 300 MHz) d 1 · 25, 1.32 (t / -134- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) " ~---------- ------- 1T ------ Φ— (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 ___B7 V. Description of Invention (132) J = 9Hz, 3H), 2.45-2.75 (m, 4H), 2.84-2.96 (m, 3H), 3.02-3.08 (m, 1H), 3.32, 3.36 (d, J = 3Hz, 1H), 3.47-3.58 ( m, 2H), 3.65, 3.68 (d, J = 7.5Hz, 1H), 3 76, 3.80 (s, 3H), 5.94 (s, 2H), 6.72 (d, J = 7, 5Hz, 1H), 3.84-3.89 (m, 3H), 7.02 (d, J = 6Hz, 1H), 7.30, 7.34 (d, J = 7.5Hz, 2H). Example 5 8-Watt __, trans_2- (4-methoxyphenyl) -4 · Π, 3-benzodioxin_5_ylνι_Γ2 · isopropylpyridylamino) ethyl) Bilopidine-3-## 2-bromoethylamine hydrobromide (1 mmol) was suspended in anhydrous ch3CN, and 1 equivalent of EtsN was added thereto. The mixture was stirred for 30 minutes, and 1 equivalent of isopropylpyridine and 1 equivalent of Et3N were added. The resulting mixture was stirred at room temperature for 2 hours' and added to a solution of the compound of Example 1C (185 mg, 0.5 mmol) in 3 ml of CE ^ CN. The mixture was warmed at 50-60 ° C for 2 hours, cooled to room temperature, treated with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried and concentrated in vacuo. The residue was separated on silica gel and dissolved in 3: 2 hexane-EtOAc to give 195 mg (75%) of ethyl ester. Hydrolysis of acetamidine (160 mg, 0.31 mmol) in the procedure of Example 1D yielded the title compound (133 mg, 88%), m.p. 94-96 ° C. 4 NMR (CD3OD, 300 MHz) 1.26 (d, J = 6Hz, 6H), 1.97 (s, 1H), 2.38 (m, 1H), 2.77 (m, 1H), 2.88 (t, J = 9Hz, 1H) , 3.04 (m, 1H), 3.14 (t, J = 7.5Hz, 2H), 3.35 (m, 2H), 3.46 (m, 1H), 3.58 (m, 1H), 3.78 (s, 3H), 5.92 (s, 2Η), 6.74 (d, J = 9Hz, 1H), 6.86 (dd, J = 9Hz, 3Hz, 1H), 6.92 (d, J = 9Hz, 2H), 7.00 (d, J = 3Hz, 1H), 7.36 (d, J = 9Hz, 2H). MS (Da / NH3) m / e (M + H) +. _-135 -___ This paper size applies to China National Standard (CNS) A4 (210X 297 mm) " '---------- ^-(Please read the notes on the back before filling in this Page) Order printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 _B7 V. Description of Invention (133)

Example 5 L trans, trans_2_ (4-methoxyphenyl) -4- < X Benzene diaz-5-yl) -1- (2- (isobutoxyQ 棊 i ethyl Above: The title compound of each carboxylic acid is prepared by the method of Example 1 D, starting from the compound of Example ic and 2- (isobutoxy) ethyl bromide. Mp · 68-70 ° C. 4 NMR ( CDC13, 300 MHz) β 0 · 88 (d, J = 6Hz, 6H), ΐ · 82 (five peaks, J = 6Hz, 1Η), 2 · 22 (m, 2H), 2.72-2.79 (m, 1H), 2.86_2 · 95 (m, 2H), 3.13 (d, J = 6Hz, 2H), 3.45-3.56 (m, 4H), 3.68 (d, J = 9Hz, 1H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, J = 7.5Hz, 1H), 6.85 (dd, J = 7.5 Hz, 3H), 7.08 (s, 1H), 7.34 (s, J = 9Hz, 2H) DCI / NH3) m / e 442 (M + H), Example 6 0 trans'trans_2- (4 · methoxyphenyl) -4_ (l, 3-l and diin_5_yl) · ι_ (Butylsulfanyl) -pyrrolidine-3- # _ For 100 mg (0.271 mmol) of the compound of Example 1C was dissolved in 10 ml of THF, and 1-butanyl phosphine chloride (46 · 7 mg, 11 equivalents) was added ) And diisopropylethylamine (53 mg, 1.5 eq.). The resulting mixture was stirred at room temperature for 2.5 hours, and the solvent was evaporated. The crude The product was purified by flash chromatography on silica gel and dissolved in 3: 2 hexane-EtOAc to give 120 mg (90%) of ethyl ester. (120 mg, 0.244 mmol) was dissolved in 1 ml of EtOH, and then added to 100. A solution of mg of NaOH in 1 ml of water. The mixture was stirred at room temperature; dropped for 3 hours and concentrated under reduced pressure. Water (5 ml) was added and the solution was washed with ether to remove any unhydrolyzed trans-cis-iso The aqueous solution was acidified with acetic acid to pH ~ 6 and then extracted with EtOAc (2 X 50 ml). Mixed organic extracts ____- 136 -___ This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) ------------ (Please read the precautions on the back before filling this page) Order f Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy 581760 A7 __B7 _ V. Description of the invention (134) Salt water Washed, dried over sodium sulfate, and concentrated under reduced pressure to give the pure title compound (60 mg, 53%) as a white solid. Mp 67-69 ° C. 4 NMR (CDC13, 300 MHz) d 0.82 (t, J = 7.5 Hz, 3H), 1.20-1.33 (m, 2H), 1.58-1.68 (m, 2H), 2.48-2.69 (m, 2H), 3.28 (dd, J = 9Hz, 1H), 3.49 (t , J = 12Hz, 1H), 3.65 (dd, J = 12Hz, 1H), 3.82 (s, 3H), 4.32 (dd, J = 12Hz, 1H), 5.17 (d, J = 9Hz, 2H), 5.95 (s , 2H), 6.70 · 6 · 78 (m, 3H), 6.92 (d, J = 9Hz, 2H), 7.35 (d, J = 9Hz, 2H). MS (DCI / NH3) m / e 462 (M + H) +. Example 6 1 trans, trans-2- (4-methoxybenzene V4- (l, 3 · benzodifluoren-5-yl) -1- (2- (N-methyl-N-isopropyl Carbonylamino) ethylpyrrolidine-3-carboxylic acid

Example 61A trans, trans_2- (4_methoxybenzyl) _4_Π, 3-benzodifluoren-5-yl) _1 · Γ2 · fluorethyl ethyl pyrrolidine-3-carboxylic acid Example 1 C mixture of cis, trans and trans, and pyrrolidine (400 mg) was dissolved in 9 ml of 1,2-dibromoethane, and 0,7 ml of diisopropylethylamine and 30 were added. Mg of sodium iodide. The resulting mixture was at 100. (: Heating under i for 1 hour, then the solvent was removed under vacuum. The residue was taken up in EtOAc, washed with water and brine successively, dried and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel with 4: 1 hexane -EtOAc dissociation yielded 470 mg of the title compound.

Example 61B trans, trans-2- (4-methylphenyl) -4- (1,3-benzobisfluoren-5-yl) -1_ (2- (methyl_amino) ethyl Vpyrrole Pyridin-3-carboxylic acid ethyl ester 137- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) ^ a ^ Order ~ (Please read the precautions on the back before filling this page) Central Bureau of Standards, Ministry of Economic Affairs Printed by Employee Consumer Cooperative 581760, Description of the Invention (135) Compound 6A of Example 6 (450 mg) was dissolved in 〇 亳升 Et〇H, added. 0.5 入 liter 40% methylamine aqueous solution and 50 Milligrams of sodium iodide. The mixture was heated at 80 ° C for 1 hour, and the solvent was removed under emptiness. The residue was taken up with EtoAc and washed successively with water and brine. It was dried and concentrated in vacuo. The resulting product could continue The reaction did not require further purification.

Example 61C Group name ~ 1 trans-2_ (4_methoxyphenyl) -4- (1,3-benzenedi $ _5-yl) _1_ (2_ (N · methylisobutylamino) ethyl) _Pyrrolidine-3_miao 酩 To Example 6 1 B compound (~ 150 mg) was dissolved in 5 ml, 孓 digas ethane, and 0.3¾ liter of monoisopropylethylamine was added. The solution was cooled to, isobutyl hydrazone base gas (0.17 liters) was added, the cooling bath was removed, and the solution was allowed to warm to ambient temperature 'and stirred for an additional 15 hours. The solvent was removed under vacuum; the residue was taken up in EtOAc, and then washed sequentially with 1: 1 sodium bicarbonate solution / water and brine, dried and different; Chen shrink. The product was purified by flash chromatography on stone gum, burned with 1.1 EtoAc to EtOAc and finally 10% MeOH-EtOAc gradient. The ester was dissolved in 1.5 ml of EtOAc; 0.75 ml of a 17% NaOH aqueous solution was added, and the resulting solution was stirred at ambient temperature for 3 hours. The solvent was removed under vacuum and the residue was taken up with water and washed with ether. The aqueous layer was triturated at 1 to pH 3 and extracted with ether. The combined organic extracts were washed with brine and dried over NajO4. The solvent was removed under vacuum to yield 82 mg of the title compound as a white foam. Optical isomers can be seen in NMR. 4 NMR (CDC13, 300 MHz) main optical j 1 〇6 (d, 3H, J = 10Hz), 1.12 (d, 3H, J = 10Hz), 2.15 (m, 1H), 2.5-3.0 (m, 3H ), 2.91 (s, 3H), 3.32 (m, 2H), 3.50 (m, 2H), 3.65 (m, 2H), 3.77 -138 This paper size applies to China National Standard (CNS) Α4 specifications (210 X 297 male) Li) ---------- ^-(Please read the notes on the back before filling this page)

, 1T 581760 A7 B7 V. Description of the invention (136) (s, 3H), 5.92 (s, 2H), 6.73 (d, 1H, J = 8Hz), 6.75-6.9 (m, 4H), 6.96 (d, 1H , J = 2Hz), 7 · 29 (m, 1H). MS (DCI / NH3) m / z 469 (M + H) +. Analysis estimates C26H32N206 · 0.3 TFA: C, 63.55; H, 6.48; N, 5.57. Found 値: C, 63.44; H, 6.71; N, 5.24. Example 6 2 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) -1- (2- (N-methyl-N · Propidylamino) ethyl V pyrrolidine-3-carboxylic acid The title compound was prepared as described in Example 61, and propidyl chloride was used to replace the isobutyridine chloride in Example 61C. 1H NMR (CDC13, 300 MHz) Main optical rotation Object β 1.13 (t, 3H, J = 8Hz), 2.19 (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 = 8Hz), 6.75-6.9 (m, 4H), 7.00 (bd , S, 1H), 7.29 (bd s, 1H). MS (DC1 / NH3) m / z 455 (M + H) +. Analyzed and estimated C25H30N2 06 · 1.0 H20: C, 63 · 55; H, 6.83; N, 5.93. Measured ，: C, 63 · 55; H, 6.52; N, 5.73. Example 6 3 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-2- (4-methoxyphenyl) -4- (l, 3-benzobisfluoren-5-yl-N-fluorenylaminocarbonylmethylpyrridine-3-carboxylic acid The title compound was prepared by the method. IH NMR (CDC13, 300 MHz) The main optically active substance d 2.79 (s, 3H) 2.8-3.2 (m, 2H), 3.48 (m, 2H), 3.61 (m, 2H), 3.77 (s, 3H), 3.78 (m, 1H), 4,3-4.5 (m, 2H), 5.95 (d, 2H, J = 2Hz), 6.7-6.9 (m, 4H), 7.00 (m, 1H), 7.15-7.35 (m, 7H). MS (FAB / NBA) m / z 503 (M + H ) +. Analyze and estimate C29H30N2 06 · 0 · 5 H20: C, 68 · 36; H, 5.74; N, 5.50. Measured -139- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) ) 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ___ B7 V. Description of the invention (137) 値: C, 68, 41; Η, 5.74; N, 5.36. Example 6 4 trans form, trans form 2- ( 4-methoxyphenyl) -4- (1,3-benzobisfluoren-5-ylethyl-N-butylaminecarbonylmethyl) _pyrrolidine_3_carboxylic acid The title can be prepared using the method in Example 1 Compounds. NMR (CDC13, 300 MHz) Main optically active substances j 〇88 (t, 3H, j = 7Hz), i 〇6 (t, 3H, J = 7Hz), 1.27 (m, 2H), 1.45 (m, 2H), 2.8-3.6 (m, 11H), 3.79 (s, 3H), 3.80 (m, 1H), 5.92 (bd s, 2H), 6.75 (d, 1H, J = 8Hz), 6.85 (d, 1H, J = 8Hz), 6.92 (d, 2H, J = 8Hz), 7.03 (s, 1H), 7.33 (d, 1H, J = 8Hz). MS (DC1 / NH3) m / z 483 (M + H) +. Analytical estimation C27H34N206 · 0.5 HOAc: C, ό 5.61; H, 7.08; N, 5.46. Found 値: C, 65.51; H, 6.70; N, 5.66. Example 6 5 trans, trans-2- (4-methoxybenzyl) -4- (1,3-benzodihum-5-some-N- (2,2-dimethylpropyl) Amidomethyl) ratio ρ_3_ | acid Using the method of Example 1, the title compound can be prepared. 1H NMR (CDC: 13, 300 MHz) main optically active matter d 0 · 90 (s, 9H), 2.81-3.1 (m, 4H), 2.94 (s, 3H), 3.3-3.5 (m, 3H), 3.61 (m, 1H), 3.80 (s, 3H), 3 82 (m, 1H), 5.94 (bd s, 2H), 6.74 (d, 1H, J = 8Hz), 6.86 (d, 2H , J = 8Hz), 6.87 (m, 1H), 7.03 (d, 1H, J = 2Hz), 7.33 (d, 2H, J = 8Hz). MS (DC1 / NH3) m / z 483 (M + H) ten. Example 6 6 trans, trans-2- (4-methoxyphenyl) -4- (1,3_benzobisfluorene-5-^^ (2 (N-methyl_N_butylphenylamino)) (Ethyl)-? Bi-P-Ethyl-3-Generic ^ Acid-140- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm)-IT ~ (Please read the precautions on the back before filling this page ) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 ______ B7 V. Description of the Invention (138) Example 61B Compound (60 mg, 0.13 mmol) was dissolved in 5 ml of CH3CN, 0.2 ml of Et3N and 22 mg (0.143 millimoles, equivalent) 1-butanesulfonium chloride. The mixture was stirred at room temperature for 1 hour, and then under Xing i; Chen !. The crude product was purified by chromatography on crushed gel, with 1 : 1 Et〇A〇 dissociation can produce 64 mg (90%) of the ester. The ester was hydrolyzed in Example 1 d to generate the title compound. Mp 64-66 ° C. 4 NMR (CDC13 300 MHz) d 0.92 (t, J = 7.5Hz, 3H), 1.39 (six peaks, j = 7.5Hz, 2H), 1.68-1.76 (m, 2H), 2.16-2.25 (m, 1H), 2.72 (s, 3H), 2.75- 2.92 (m, 5H), 3.12 · 3 · 20 (m, 1H), 3.25-3.34 (m, 1H), 3.46-3.55 (m, 2H) 3.65 (d, J = 9Hz, 1H), 3.78 (s, 3H), 5.53 (s, 2H), 6.72 (d, J: 7.5Hz, 1H), 6.82 (dd, J = 7.5 Hz, 3Hz, 1H), 6.86 (d, J = 9Hz, 2H), 7.02 (d? J = 3Hz, 1H), 7.34 (d, J = 9Hz? 2H) 〇MS (DC1 / NH3) m / e 519 (M + H), Example 6 7 trans, trans-2 · (4-methoxyphenyl) _4- (l, 3_benzodiazine-5_yl) -l_ (2- (N-form -N_propylcontanoic acidamino) ethyl) -p ratio p each p. · 3-leptic acid The title compound was prepared in the same manner as in Example 66, except that 1-butanesulfonic acid was replaced with 1-propanesulfonic acid.醯 Chlorine. Mp 69-7 (TC. 4 NMR (CDC13, 300 MHz) d 1.02 (t, J = 7.5Hz, 3H), 1.78 (six peak, J = 7.5 Hz, 2H), 2.18 · 2 · 26 (m, 1H), 2.72 (s, 3H), 2.75-2.95 (m, 6H), 3.13-3.22 (m, 1H), 3.25-3.35 (m, 1H), 3.47_3 · 58 (m , 2H), 3.66 (d, J = 9Hz, 1H), 3.80 (s, 3H), 5.96 (s, 2H), 6.74 (d, J = 7.5Hz, 1H), 6.84 (dd, J = 7.5Hz, 3Hz, 1H), 6.87 (d, J = 9Hz, 2H), 7.04 (d, J = 3Hz, 1H), 7.43 (d, J = 9Hz, 2H). MS (DCl / NH3) m / e 505 (M + H) +. -141-This paper size applies to Chinese National Standard (CNS) A4 specification (210x297 mm) ------------ (Please read the precautions on the back before filling this page) Order f 581760 A7 ___ _B7 V. Explanation of the invention (139) Example 6 8 (Please read the notes on the back before filling this page) Basic formula ~~ -_trans-2- (4-methoxyphenyl) -4- (1,3 -Cebo Di tr_5_ group) _U2_ (propyl phenyl group) ethyl group)-command ^ each pyridine _3_ Lou 酴 pair 1-propan antithiol (3.5 g, 46.05 mmol) It was dissolved in 10 ml of anhydrous THF, and 632 mg (26.32 mol) of NaH was added in portions under a nitrogen atmosphere. The mixture was heated at 60-70 ° C for 1 hour. To this mixture was added the compound from Example 61A (180 mg, 0.38 mmol) in 2 ml of THF. Heating was continued at 60-70 C for 2 hours, and the volatiles were removed under reduced pressure. The crude propylthioethyl adduct was purified by flash chromatography on crushed gel and dissolved in 3.2 x hexane_EtOAc to give 170 mg (95%). Printed in 170¾ g (0.36 mmol) sulfide and 93 g (0.8 mmol) N-methylmorpholine N-oxide (NMO) in 20 ml To a solution of a mixture of acetone and 5 ml of H20, a solution of iron tetraoxide (10 mg) in 03 ml of tert-butanol was added. The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was partitioned between EtOAc and H20. The organic phase was washed with brine, dried over Na2S04 and concentrated under air. Flash chromatography yielded 177 mg (98%) of ethyl ester, which was hydrolyzed by the method of Example ID to yield the title compound. m.p. 73-75 ° C. 4 NMR (CDC13, 300 MHz) d 1.04 (t, J = 7.5Hz, 3H), 1.78 (six peak, J = 7.5Hz, 2H), 2.59-2.66 (m, 1H), 2.84-3.08 (m, 7H ), 3.43 (dd, J = 9Hz, 3Hz, 1H), 3.53-3.60 (m, 1H), 3.68 (d, J = 9Hz, 1H), 3.82 (s, 3H), 5.96 (s, 2H), 6.75 (d, J = 7.5Hz, 1H), 6.82 (dd, J = 7.5Hz, 3Hz, 1H), 6.88 (d, J = 9Hz, 2H), 6.99 (d, J = 3Hz, 1H), 7.32 (d , J = 9Hz, 2H). MS (DCI / NH3) m / e 476 (M + H) +. -142- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297mm) 581760 A7 B7 V. Description of Invention (140) Example 6 9

Trans, trans_2- (4-methoxyphenyl) _4-Π, 3-benzodiyl) _l-N- (trans-5 · methylhexan-2-branthyl) -ρ ratio Luodian-3_Gunic Acid Example 69A Trans-5-methylhexa-1-acetic acid acetic acid sodium hydride oil dispersed phase (0.85 g) was washed with hexane and resuspended in THF (20 ml). Cool to 0 ° C in an ice bath. Diisopropyl (ethoxycarbonylmethyl) phosphonate (5.0 ml) was added slowly, and the mixture was expanded at 0 ° C; 20 minutes. Isovaleraldehyde (2.0 mL) was added dropwise over 5 minutes in THF (5 mL). The ice bath was removed and the mixture was stirred at ambient temperature for 18 hours. A saturated ammonium chloride solution (50 ml) was added, and the mixture was extracted with diethyl ether (3 x 50 ml). The ether extracts were mixed, dried on NajCU and evaporated to give a colorless oil, which was purified by flash chromatography on Shixi gum and dissolved with hexane. The title compound was isolated as a colorless oil (2.1 g).

Example 69B Trans-5 · methylhexan-2-ol-1-ol Printed by the Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs Example 69A Compound (2.0 g) was dissolved in toluene and cooled to 0 ° C in an ice bath . Diisobutylaluminum hydride (5 to toluene, 20 ml) was added dropwise and the solution was stirred at 0 ° C for 2 hours. The citric acid solution (25 ml) was added very slowly to the cooling solution. The resulting mixture was stirred at ambient temperature for 8 hours. Diethyl ether (50 ml) was added, the solid particles were removed by filtration, and the strip was washed with additional ether (2 x 25 milliwells). The filtrate was extracted with ether (2 x 25 x liters). The ether extract and the washings were mixed, dried and evaporated to form a colorless oil, which was then purified by flash chromatography on the crushed gel and dissolved in 25% EtOAc-hexane. Title -143-

581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (141) The compound was isolated as a colorless oil (1.25 g).

f you j ^ 9C Well-formed 1-bromo-5J; 2-Hexyl-2. The compound of Example 69B (1.0 g) was dissolved in diethyl ether and cooled in an ice bath. Phosphorous tribromide (2.5 g, 087 ml) was added dropwise and the solution was stirred at 0 C for 2 hours. The solution was poured into ice, the layers were separated, and the aqueous layer was extracted with additional ethyl acetate (3x25 mL). The ether layers were mixed, dried and evaporated to give a colorless oil, which was used without further purification (0.95 g).

Example soil 9D

Plexiform 'trans -_-, M4-methoxyphenyl) -U1,3-benzodioxin_5_yl private methylhexyl-2_fluorenyl) _ 埃 P 各 淀 _3_ The title compound was prepared by the method of Example 1, but replacing the N'propylbromoacetamide with the ubiquitin of Example 69c. ifj NMR (CDC13, 300 MHz) J 0.84 (d, 6H, J = 8Hz), 1.57 (seven peaks, 1H, J = 8Hz), 1.87 (t, 2H, J = 6Hz), 2.60 (dd , 1H, J = 8Hz, 14Hz), 2.86 (t, 1H, J = 10Hz), 2.96 (dd, 1H, J = 8Hz, 10Hz), 3.20 (dd, 1H, J = 5Hz, 14Hz), 3.29 (dd , 1H, J = 3Hz, 10Hz), 3.50 (m, 1H), 3.70 (d, 1H, J = 10Hz), 3.78 (s, 3H), 5.47 (m, 2H), 5.93 (s, 2H), 6.71 (d, 1H, J = 8Hz), 6.83 (d, 3H, J = 9Hz), 7.05 (s, 1H), 7.32 (d, 2H, J = 9Hz). MS (DC1 / NH3) m / e 43 8 (M + H) +. Analysis estimates C26H31N05 ·· C, 71.37; H, 7.14; N, 3.20. Measured fluorene: C, 71.16; H, 7.24; N, 3.17 〇 Example 7 0 trans, trans-2- (4-methoxybenzyl) _4-Π, 3-benzodifluorene_5-yl VhN · (Anti-144 This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) -ϋ.---- I--I -II I-=! II (Please read the precautions on the back before filling This page)-Order 581760 A7 B7 V. Description of the invention (142) (Please read the precautions on the back before filling this page) Formula-3,5-dimethylhex-2-enyl V pyrrolidine-3 • carboxy The title compound was prepared using the method described in Example 6 9 but replacing 4-valerone with isovaleraldehyde of Example 69A to give a 7: 1 mixture of trans / cis chain alkane. Crude product Purification by preparative HPLC (Vydac " C18 > dissociates with a gradient of 10-70% CHsCN in 0.1% TFA. Freeze-drying of the desired fraction can produce the product (and its diastereoisomeric) as a white solid. 4 The main (trans) isomers of NMR: (CDCl3 300MHz) j 〇83 (d 6H, J = 8Hz), 1.56 (s, 3H), 1.74 (m, 1H), 1.92 (2H, J = 6Hz) 3.3-3.5 (m, 3H), 3.6-3.8 (m, 4H), 3.78 (s, 3H), 3.9-4.0 (m 1H), 5.22 (m, 1H), 5.90 (d, 2H, J = 12Hz)? 6.63 (m, 1H) 6 78 (m, 3H), 6.95 (s, 1H), 7.45 (d, 3H, J = 8Hz). MS (DCI / NH3) m / e 438 (M + H) +. Analyzed and estimated C27H33N05 · 1.0 TFA: C, 61.59. H, 6.06; N, 2.48. Found 値: C, 61.36; H, 6.10; N, 2.34. Example 7 1 trans, trans-2- (4-methoxyphenyl) -4- (i, 3-benzodi

Phenylmethyl) -ρ ratio p-Yodo-3- # acid Example 71A 1-Chloro-3-propyl-2-hexanone 2-propylvaleric acid (156.6 micro Liters, l.oo millimoles) were dissolved in anhydrous digas (2 ml), DMF (3 microliters, 4 mole%) was added, and the solution was cooled to 0 C under a nitrogen atmosphere. Chlorchlor (94 3 μl, 1.08 mmol) was added dropwise to this solution over several minutes. The reaction was stirred for 18 hours while warming to ambient temperature. The mixture was cooled to 0 ° C, and an additional amount of de-ethyl ether diazomethane solution was added. The reaction mixture was stirred for 18 hours and then allowed to warm to ambient temperature. -145- This paper size is applicable to Chinese National Standard (CNS) A4 (21 × 297 mm) 581760 A7 B7 V. Description of the invention (143) The reaction mixture was washed with 1 sodium carbonate aqueous solution (30 ml) in anhydrous sodium sulfate Dry over 'filter and concentrate under reduced pressure. The residue was dissolved in ether (2 liters) and cooled to 0 ° C under a nitrogen atmosphere. A solution of 4 g of hydrogenated gas in a second gas pit (275 µl, 1.10 mmol) was added over several minutes. The reaction was stirred for 18 hours and then warmed to ambient temperature. The reaction mixture was concentrated under reduced pressure and the remaining oil was used in the next step without further purification.

Example 71B 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.) Goodness "trans_2_ (4 · —methoxyphenyl) · 4-Π, 3-benzo Diamidine-5 · yl) -1_ (4-heptyl ^ ylmethyl) -pyridine_3_ # acid ethyl ester Example 7 1 Compound A (1.00 mmol, maximum theoretical yield) was added to Example 1C Trans'transethylchitoate (295 mg, 080 mmol, 50/0 in toluene solution), diisopropylethylamine (700 μl, 400 mmol ) And acetonitrile (4 ml). To the resulting solution was added sodium iodide (12 mg '10 mol%), and the reaction mixture was stirred at ambient temperature under nitrogen for 18 hours. Additional sodium pyrolysis (24 mg, 20 mole%) and acetonitrile (4 ml) were added, and the reaction mixture was heated with stirring at 45-5 ° C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was Chromatography on silica gel dissociated with 1: 9 ethyl acetate-hexane to give 237 mg (460 / 〇) of the title compound as a butter.

Example 71C Formula · 2- (4-methoxybenzylbenzodifluorene-5 · yl VI- (4-heptylcarbonylmethyl) -p-bilodine-3-leptic acid. Example 71B compound (23 1 mg , 0.4532 millimoles) dissolved in ethanol (10 liters), and a bell hydroxide (38 mg, 〇9065 millimoles) was added to water _-146- This paper standard is applicable to household standards (CNS) A4 Specification (21 () χ 297 public envy) 581760 A7 B7 grams, solution (2.5 halo) of invention description (H4). The solution was stirred under nitrogen atmosphere for 8 hours, and additional lithium hydroxide (19 mg, 〇 4532 millimoles) in water (05 ml), followed by stirring for 24 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol, and the aqueous residue was diluted with water (45 ml) and ether. (50 ml) was washed. The aqueous layer was neutralized with 1 anti-hydrochloric acid to turbidity, and then a 10% aqueous solution of citric acid was added to adjust the pH to ~ 5. The solution was extracted with 10% ethanol in chloroform (4 × 25 ml). Mix The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel, and dissolved in 1: 1 ethyl acetate-hexane. 86 mg (39/0) of the title compound was produced as a white powder 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 (d, 1H), 6.86 (d, 2H), 6.92 (d , 1H), 7.12 (s, 1H), 7.32 (d, 2H). MS (FAB) m / e 482 (M + H) +. Analyzed and estimated C28H35NO6 · C, 69 · 83; H, 7.32; N , 2.91. Measured fluorene: (^, 69.57 · H, 7.41; N, 2.73. Example 7 2 trans, trans Table II 2- (4-methyllactylphenyl) -4 · (1,3-benzodioxin -5-yl) -1- (pentylmethyl) · pyrrolidine-3-miao _ 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)

Example 72A 1-Rat-2-Hexane Using the procedure of Example 7 1 A and substituting valeric acid for 2-propylvaleric acid, the title compound, 'as an oil,' was used in the next step without further purification. -147- This paper size applies to Chinese National Standard (CNS) A4 (210X297mm) 581760 A7 B7 V. Description of the invention (145)

Example 72B trans'trans-2- (4-methoxyfluorenyl) -4- (1,3-benzobis-5-yl) · 1- (pentylmethyl) -pyrrolidine-3- The ethyl carboxylate was replaced with the compound of Example 7 2 A by 1-chloro · 3-propyl-2-hexanone, and the method of Example 7 1 B was used, except that the first addition of sodium iodide was omitted, and the ambient temperature Stir down: drop for 8 hours and purify by gel chromatography. Dissolve with 3:17 ethyl acetate · hexane to give the title compound as a butter, 305 mg (65%).

Example 72C trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodiazine · 5-yl) -1- (pentylmethyl) -pyrrolidine-3- Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Carboxylic Acid Economics, replacing the trans compound with the compound of Example 7 2 B, trans_2_ (4_methoxyphenyl) -4- (1,3-benzodiyin · 5- Group) -1- (4-heptylcarbonylmethyl) -pyrrolidine · 3-acrylic acid ethyl ester, and in the same manner as in Example 7 1 C, except that only lithium hydroxide (81.5 mg, 1.942 mmol) was added ) In water (3.5 ml) and stirred for another 18 hours. 130 mg (46%) of the title compound was obtained as a white powder. NMR (CDC13, 300 MHz) d 0.87 (t, 3Η), 1'26 (m, 2Η), 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 + H) +. Analysis estimates c25H29N06: C, 68.32; H, 6.65; N, 3.19. Found 値: C, 67 · 95; H, 6.64; N, 3.05. Example 7 3 trans, trans-2- (4-methylazine) · 4 · (1,3 · benzodifluoren-5-yl (3,4-dimethoxybenzyl)-: ^ -Methylaminocarbonylmethyl) -pyrrolidin-3-carboxylic acid_ -148- This paper size applies to China National Standard (CNS) A4 (210X297 mm) Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 _____B7 V. Description of the Invention (146)

Example 73A trans, trans and cis, trans-2- (4-methoxyphenyl) -4- (1,3-benzo ^ present-5-yl) -1-1 (3,4 -Dimethoxybenzyl) aminoamidomethyl) _erlotidine_3-glycolic acid ethyl ester Using the method of paragraph 1 D, 1 of the example, 3,4_dimethoxyamidobromoacetamidine Instead of dipropyl bromide, the desired product mixture was obtained in the form of a white foam with a yield of 81%.

Example 73B Formula, trans and cis, trans_2- (4-methoxyphenyl V4- (l, 3-benzodiazyl) -1- (N- (3,4-dimethoxy (Methenyl) -N-methylaminocarbonyl methyl V pyrrolidine_3_ carboxylic acid ethyl ester Example 73A The product (220 mg, 0.404 mmol) was dissolved in 2 ml of anhydrous THF and added dropwise to sodium hydride (23 mg of a 60% by weight inorganic oil suspension, 16.5 mg, 0.69 mmol) in a suspension of 0.2 ml of THF and cooled (0 ° C) in an argon atmosphere The resulting mixture was stirred for 1 hour, then methyl iodide (28 μl, 64 mg, 0.45 mmol) was added. The reaction mixture was stirred at 0 ° C for 4 5 minutes. TLC (Et20) showed incomplete reaction. Again Add additional methyl iodide (28 microliters, 64 mg, 0.45 mmol) and anhydrous 1,3-dimethyl-3,4,5,6-tetrahydro_2 (111) -pyrimidone ( 50 μl, 0.41 mmol). The reaction mixture was stirred at ambient temperature for 2 days. The reaction was poured into 2.5 ml of 0.5 M citric acid aqueous solution and extracted with 2 X 2 5 ml of EtOAc. The mixed organic extracts were The sequence was washed with 30 ml of water and 30 ml of brine, and then dried (NajO4). Filter and concentrate under reduced pressure to produce 270 mg of crude material. Flash chromatography on silica gel, dissolve with Et20-149- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 'I-- -------- (Please read the precautions on the back before filling this page) Order 581760 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (147) The title compound was' inseparable ' The mixture yielded 43% of the product. 4 NMR (CDCl3, 300 MHzW 2 79 ⑷ and 2 81 ⑷, which are signals of 仏 CD ^. MS m / z 591 (M + Η) +.

Example 73C Di_trans-2 · (4-methoxyphenyl) · 4- (1,3-benzyl dihum · 5_qi, _um · monomethoxymethyl) -N-methylaminocarbonylmethyl Base _3_ roll acid was dissolved in 1 ml of EtOH to the compound of Example 73B (98 mg, 0.17 mmol), cooled to 0 ° C and then added lithium hydroxide monohydroxide (7 mg, 0.41 pen). Mol) in 0.5 ml of HW. The resulting solution was disturbed under a nitrogen atmosphere for 16 hours. The solution was concentrated under vacuum, and the residue was partitioned between 5 mL of Ethanol and 15 mL of EkO. The aqueous phase was extracted with 5 ml of Et20, and the aqueous phase was acidified with a 10% aqueous citric acid solution. The acidic aqueous phase was saturated with NaCl and extracted with 3 x 15 mL of EtOAc. The EtOAc extracts were mixed, dried (Na2SO4), filtered and concentrated in vacuo to yield 40 mg (42%) of the title compound as a white foam. 4 NMR (CD30D, 300 MHz, two optically active forms) j 2.85 (s, 3Η), 2.94–3.25 (br m, 3Η), 3.35–3.70 (br m) and 3.64 (s, 4 H total), 3.70 -3.97 (br m), 3 „74 (s), 3.76 (s), 3.78 (s), 3.79 (s), 3.81 (s), and 4.03 (br d, J = 14 Hz, 8H total) , 4.43 (AB, 1H), 5.91 (s) and 5.93 (s, 2H total), 6.50-6.60 (m, 1H), 6.67-7.02 (br m, 6H), 7.29 (br d) and 7.35 (br d , 2H total). HRMS estimate C31H35N208 (M + H) +: 563.2393. Found 値: 563.2385. Example 7 4 Expansion, trans-2- (4-methoxyphenyl) -4- (1,3-benzene Benzodi-5-yl V1- (N- (3,4-dimethoxy) amine sulfomethyl bihadine-3-weiric acid-150- This paper is in accordance with Chinese National Standard (CNS) A4 Specifications (210X297 mm)-(Please read the notes on the back before filling this page) Order f 581760 A7 ____B7 V. Description of the invention (148) Use the method of Example 73C and replace the compound of Example 73A with the compound of Example 73A. The title compound was generated. 1 2H NMR (CD3〇D, 300 (Please read the notes on the back before filling this page) 2.85 (d, J = 16Hz, 1H), 2 · 9 2 (br t, J = 9Hz, 1H), 2.98 (br t, J-10Hz, 1H), 3.32-3.39 (br m, 2H)? 3,54-3.65 (br rn 1H) 3 67 (s , 3H), 3.78 (s, 3H), 3.80 (s, 3H), 3.85 (d, J = ioHz 1H), 4.21 (d, J = 15Hz, 1H), 4.41 (d, J = 15Hz, 1H ), 5.91 (s, 2H), 6.67 (d, J = 8Hz, 1H), 6.75-6.95 (m, 7H), 7.33-7.40 (m, 2H). HRMS estimate C30H32N208 (M + H) +: 549.2237. Measured plutonium: 549.2224 c Example 7 5 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 1 (2R, 3R, 4R) -2- (4-Artioxyphenyl) -4_ (1,3_benzodipyrene) 2-(N, N-diisopropylyl) _1 · butyl) p-bilodine_3_ Borrowing Age

Example 75A trans, trans-2- (4-methoxyphenyl, 3-benzodihydro-5-((oxocarbonyl) butyl) eryl) -3.carboxylic acid ethyl ester using Fung, et al., J. Med. Chem., 3 5 (10): 1722_34 (1992), Example 6 Compound A (103 mg, 0.279 mmol) was dissolved in 0.7 ml of nitromethane and 0.7 ml of Η20. Add ammonium carbonate (34 mg, 0.35 mmol) and (2-bromovalerate (2S) -fluorenyl ester (78 mg, 0 30 mmol). The reaction is refluxed for 2 to 4 hours. The reaction is partitioned into 15 ml 1 M Na2S03 was dissolved in water and 25 ml of CH2C12. The aqueous phase was extracted with 2x10 ml of CH2C12. The combined organic phases were washed with 15 ml of brine, dried (Na2S04), filtered, and concentrated under reduced pressure to a brown oil (169 mg). The crude product was purified by silica gel chromatography and dissolved in 3: 1 CH2C12-hexane to produce 106 mg (68%) of the title compound. -151-This paper is in accordance with China National Standard (CNS) A4 (210 > < 297 mm) — printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 581760 A7 B7 V. Description of the invention (149) Wax solid. NMR shows two diastereomeric The presence of isomeric products.

Example 75B trans, trans_-2- (4-methoxyphenyl) _4-Π, 3-benzodiazin-5-yl) -1 ((1R)-(N, N · dipropylaminofluorenyl) ) -1-Butyl) p-biletone 3-acetic acid ethyl acetate Example 75A compound (101 mg, 0.018 mol) and 30 mg 100 / 〇Pd / C in 2 ml EtOAc The mixture was stirred at 1 atmosphere h2 for 4 hours. The reaction mixture was filtered through a plug of Celite and the catalyst was washed with 5 ml of MeOH. The combined filtrate and washings were concentrated under vacuum to yield 81.4 mg (96%) of crude acid as a white solid. The above crude acid was mixed with HOBt hydrate (41 μg, 0.27 mmol), dipropylamine (26¾ g '0.26 mmol) and 4-methylmorpholine (37 μg, 0.37¾ Mol) in 2 ml of anhydrous DMF. The solution was cooled to -15 ° C, and 1-ethyl-3- (3-dimethylaminopropyl) carbonyldiimide hydrochloride (44 mg, 0.23 mmol) was added. The mixture was stirred at 5 ° C, and then allowed to slowly warm to room temperature overnight. The solvent was removed by distillation under reduced pressure, and the residue was partitioned between 20% #EtOAc and 10 ml of aq. NaM03. The organic phase was washed with 100 ml of brine, dried (NasSCU), filtered and concentrated under air. The crude product was purified by flash chromatography on silica gel and dissolved with 1: 2Et20-hexane. The overlapping fractions were further purified by preparative TLC. Dissociation with 1: 2 Et20-hexane yielded 3 2 g (34%) of a less polar product, and 44 mg (46%) of a more polar product. .

Example 75C (H3R, 4R on methoxyphenyl) _4- (1,3-benzodiazine_5_yl-152- This paper size is applicable to China ^ standard (CNS) M specifications (no'〆297 public director) --- ------------ (Please read the precautions on the back before filling out this page) Order # 581760 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (15〇 ) 1- (N, N-diisopropylaminecarbonyl VI-butyl) pyrrolidine-3-carboxylic acid follows the method of Example 73C and replaces the product of Example 73B with the less polar isomer of Example 75B to produce the title compound. 94% yield. [From] D = _52. (C = 0.235, CH3OH). 4 NMR (CD3OD, 300 MHz) β 0.55 (t, J = 7Hz, 3Η), 0.87 (t, J-7Hz), and 0.87 -0.94 (m, 6Η total), 1 03-1.25 (br m, 2H), 1.25-1.68 (br m, 4H), 1.90-2.07 (br m, 1H), 2.75-2.94 (br m, 2H), 2.94-3.02 (br m, 2H), 3.20-3.40 (m overlaps with CD2HOD signal), 3.40-3.60 (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, 2 H). MS m / z 525 (M + H) +. Example 7 6 (1 ^, 38,48) -2- (4-methoxyphenyl) _4_ (1,3-benzodizaki-5- Group) -1-((1! 〇-1bis (N, N-dipropylaminecarbonyl) _1-butyl) pyrrolidine · 3 · carboxylic acid Follow the method of Example 73C and use the more polar isomer of Example 75B Substituting the product of Example 73B, the title compound can be produced with a yield of 88%. [From] d = + 58. (c = 0.37, CH3OH). 4 NMR (CD3OD, 300 ΜΗζ) ά 0.57 (br t, J = 7Hz, 3Η ), 0.88-0.98 (m, 6Η), 1.08 · 1 · 35 (br m, 2Η), 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 m, 2H), 3.51-3.65 (br m, 2H), 3.69 (s, 3H), 4.03-4.16 (br m, 2H), 5.91 (s, 2H)? 6.71 -6.83 (m, 2H)? 6.86-6.97 (m, 3H), 7.32 (br d, J = 9Hz, 2H). MS m / z 525 (M + H) +. Example 7 7 (lg, 3S, 4SV2- (4-methylphenyl) -4- (1,3-benzodifluoren-5-yl-153-)-This paper size applies to China National Standard (CNS) A4 specifications ( 210X297 mm) — II—-I ϋ- HI 1 ^ 1 m -li_i I (Please read the precautions on the back before filling this page)

1T f 581760 A7 B7 V. Description of the invention (151)

Example of carbonyl VI-butyl) pyrrolidine_3_lepic acid Printed by the employee consumer cooperative I ----------- (Please read the precautions on the back before filling out this page) # · k (N, N-Diryan ^ yl VI-butyl) pyrrolidine- Ethyl 3-carboxylate (2R) -N, N-dipropyl 2-hydroxypentanehydrazone (106 mg, 0528 mmol) prepared in a standard method was dissolved in 2 ml of THF and argon. Diisopropylethylamine (75 mg, 0.58 mmol) was added to the atmosphere, and the solution was cooled to -2 (TC. Trifluoromethanesulfonic anhydride (95 μl, ι59 mg, 0.565 mmol) was added. Ear) to the cooling solution for 1 minute, and the reaction mixture was stirred at -20. (:: stirred for 1 hour, and at room temperature for another 1 hour. The resulting slurry was cooled down again, and the compound of Example 6A (195 mg, 0.528 mmol) was added. Mol) and diisopropylethylamine (101 μl, 75 mg, 0.58 mol) in 3 ml of CH2C12. The reaction was stirred at 0 ° C for 3 hours and at room temperature for another 2 days. TLC (Et20-hexane 1: 2) showed that the starting material remained, so the mixture was added It was refluxed for 4 hours. The reaction was cooled, and then partitioned into 30 ml of Et0Ac and 5 ml! Μ Na2C03 aqueous solution. The aqueous phase was extracted with 15 ml of EtOAc, and the organic phase was mixed and washed with 20 ml of brine, and dried (NajO4). , Filtered and concentrated (under empty space) to produce a yellowish oil. Purified by flash chromatography on silica gel, and dissolved with 1: 2 EhO-hexane to produce 19.9 mg (7%) of less polar products and 20 · 1 g of Polar product. 1H NMR spectrum and MS are the same as Example 76B. Example 77B (2S, 3S, 4SV2- (4-methoxybenzyl) -4- (1,3-benzobis ((1SV1- (N, N-dipropylamine carbonyl) -1_butyl) pyrrole rabbit di 3_carboxylic acid Follow the method of Example 73C, with the less polar isomers of Example 77A -154- ^ Paper size applies Chinese National Standard (CNS) A4 specifications (BOX 297 mm) '581760 A7 B7 V. Description of the invention (152) Substitute the compound of Example 73B to produce the title compound with a yield of 100%. IH NMR (CD3OD, 300 MHz) and MS are the same as Example 75C. Example 7 8 (1,311,41〇-2- (4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) -1-((18) -1- (N, N-dipropylamine carbonyl) _1_butyl ) Pyrrolidine-3-carboxylic acid to follow the procedure of Example 73C, but examples of the more polar isomer 77A may be substituted for the product of Example 73B, the title compound can be generated, 88% yield. NMR (CD3OD, 300 MHz) and MS are the same as in Example 76. Example 7 9 Basic formula 'trans-2- (4-methoxyphenyl) · 4- (1,3-benzodiazine-5-yl) dibutylaminocarbonylmethyl V3_ (5 · tetrazolyl) pyrrole Pyridylcarbonyldiimidazole (51 mg, 3.148 mmol) was added to 1.020 g (2.00 μmol) of the compound of Example 43 in 2.7 ml of THF, and the mixture was heated at 50 ° C. for 40 minutes. The reaction mixture was cooled to an ice bath, and a 25% ammonia in methanol solution was added. After 30 minutes, the formed solid was filtered and washed with ethanol and then with ether to produce 850 mg of 3-carboxamide compound. m.p. 194-196 ° C. 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). Add phosphorous tritium (1.06 g) to the amidine in 7 ml of pyridine, and mix the mixture at A hour. Dichloromethane was added, and the solution was washed with potassium bicarbonate falling solution, dried over sodium sulfate, and concentrated. The residue was separated on silica gel and dissolved in 2: 1 hexane-ethyl acetate to produce 7900 mg (96%) of the 3-glycemic compound. For nitrile in 5 ml of toluene, 385 mg of trimethyltin chloride and 126 mg of sodium azide were added. The mixture is heated in l25t (bath temperature) for 20 minutes. __— ___ -155- This paper size is applicable to China National Standard (CNS) 8 4 specifications (210X297 mm)-~ 581760 Α7 Β7 Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs At the time of printing 5. Description of Invention (153). After the cold part, methanol (5 ml) was added, and the solution was concentrated under vacuum. The resulting residue was added with 6 ml of methanol and 6 ml of water containing 0.2 g of phosphoric acid. After stirring at room temperature for 1 hour, water was added, and the mixture was extracted with dichloromethane. The combined organic extracts were dried and concentrated, and the resulting residue formed a solid when it was precipitated from ether. The solid was dissolved in sodium hydroxide solution, and the insoluble matter was filtered off and acidified with acetic acid to give 532 mg (62%) of the title compound. m.p. 165_167 C. H NMR (CDC13, 300 MHz) d 0.85 (t, J = 7Hz, 3H), 0.87 (t, J = 7Hz, 3H), 1.10-1.50 (m, 8H), 3.0-3.6 (m, 8H), 3.70 (s, 3H), 3.7-3.8 (m, 1H), 3.90 (t, J = 9Hz, 1H), 4.37 (d, J = 9Hz, 1H), 5.86 (s, 2H), 6.62 (d, J = 8Hz, 1H), 6.65-6.73 (m, 3H), 6.95 (d, J = 2Hz, 1H), 7.11 (d, J = 9Hz, 2H). Example 8 0 Phenylphenyl) -4- (1,3-benzobisfluoren-5-yl Vl-OsLN-dibutylaminecarbonylmethyl) pyrrolidine-3-carboxylic acid The title compound is from (4-fluorofluorene Methyl) acetate and 5- (2-nitrovinyl) -1,3-benzyl difluorene, using the methods of Examples i and 43, to prepare an amorphous solid. 4 NMR (CDC13, 300 ΜΗζ) β 0.81 (t, J = 7Hz, 3H), 0.90 (t, J = 7Hz, 3H), 1.0-1.55 (m, 8H), 2.81 (d, J = 13 Hz , 1H), 2.90_3.10 (m, 4H), 3.15-3.30 (m, 1H), 3.32-3.45 (m, 3H), 3.55-3.65 (m, 1H), 3.86 (d, J = l〇 Hz, 1H), 5.94 (dd, J = 2Hz, 4Hz, 2H), 6.72 (d, J = 8Hz, lH), 6,86 (d, J = 8Hz, lH), 6.95-7.07 (m, 3H) , 7.32-7.45 (m, 2H). Example 8 1 trans, trans-2- (4-methoxybenzyl) -4- (1,3-benzodifluorene_5_yl) -1_ (Ν · Ν- -156- Applicable to this paper standard China National Standard (CNS) Α4 Specification (210 > < 297 mm) ---------- ^ clothing-(Please read the precautions on the back before filling this page)

, 1T 581760 A7 B7 V. Description of the invention (154) Di (n-butyl) aminomethylcarbonyl) pyrrolidine-3- # acid N, N_dibutylglycine (150 mg, 0.813 Emole) , Prepared by the method of Bowman, RE, J. Chem. Soc. 1346 (1950), treated with 0.7 ml of THF, treated with 138 mg (0.852 mmol) of carbonyldiimidazole, and heated at 50 ° C for 30 minutes. minute. After cooling to room temperature, 250 mg (0.678 mmol) of trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) pyridine 17 was added. Each of the ethyl-3-valerate, the compound of Example 6 A, and the mixture was heated at 45 ° C for 30 minutes. The product was chromatographed on Shi Xijiao, and was dissolved in ethyl acetate: ethyl acetate to obtain 306 mg of intermediate ethyl ester. The vinegar was hydrolyzed with sodium hydroxide in water and ethanol to give 265 mg of the title compound as a white powder. 1H NMR (CDC13, 300 MHz) d optical isomers -0.75 and 0.85 (2 t5 J = 7Hz, 3H), 1.05-1.5 (m, 8H), 2.65-3 · 20 (m, 6Η), 3.43 -3.70 (m, 3Η), 3.72 (s, 3Η), 3.87 (d, J = 15Hz, 1H), 4.49 (dd, J = 12Hz, 6Hz) and 5.23 (dd, J = 12Hz, 8Hz) 2H , 5.90 (dd, J = 2Hz, 4Hz, 2H), 6.63-6.78 (m, 3H), 6.86 and 7.04 (d, J = 9Hz, 2H), 7.22 (d, J = 9Hz, 2H). Example 8 2 Trans-trans-trimethoxyphenyl V4_ (L3-1 and difluorene_5_yl) · 1- (N-Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back first) Fill out this page again) propyl) aminocarbonylmethyl) pyrrolidine-3-carboxylic acid The title compound was prepared using the procedure described in Example 1. mp. 16〇_162〇c1h NMR (CDC13, 300 MHz) optical isomers j 0.69, 0.80, 0.84, 0.0087 (four trimodal peaks, J = 7Hz, 6H), 1.00-1.52 (m, 6H) , 2.63 and 2.66 (two bimodal J = 13Hz, 1H) 2 903 10 plus, 4Η), 3 23 3 6m (m, 5Η), 3 71 and 3 75 (two bimodal, J = 10Hz, 1Η), 3.78 (s, 3Η), _- _-157 _) (2i0xl ^ F)-581760 Α7 Β7 V. Description of the invention (155) 5.92-5.96 (m, 2H), 6.72 ( d, J = 8Hz, 1H), 6.83-6.89 (m, 3H) 7.03 (d, J = 2Hz, 1H), 7.81 (d, J = 9Hz, 2H). Example 8 3 trans, trans-2- (4-methoxyphenyl V4- (l, 3-benzodihum (N, N-di (n-propyl) aminofluorenyl) ethyl Ip Billow Yodo · 3_ # 醢 Example 6A compound (250 mg, 0.677 mmol), 205 g (136 mmol) dipropylpropylpropylamine (Polysciences, Inc.) and 1.0 g of acetic acid at 85 ° It was heated at C under 0.75 ml of methoxyethanol for 1 hour. Toluene was added and the solution was washed with bicarbonate solution, dried, and concentrated. Chromatographed on crushed gel with 3. · 1 hexane-ethyl acetate Chromatography yielded 283 mg (80%) of bis-propyl propyl compounds. The diallyl compounds were hydrogenated with 100/0 Pd / c catalyst (27 mg) in ethyl acetate (25 ml) under a hydrogen atmosphere. The catalyst was removed by hydrazone method, and the mash was concentrated to produce dipropylamidoethylamine in a yield of 1000/0. The ester was hydrolyzed to the title compound by the method of Example 1 D, yield 83%. 4 NMR ( CDC13, 300 MHz) d 0.82 and 0.83 (two trimodal, J = 7Hz, 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, 1H), 3.51-3.61 (m, 1H) ), 3.73 (d, J = 12H, 1H), 3.75 (s, 3H), 5.94 (s, 2H), 6.71 (d, J = 9Hz, 1H), 6.79-6.85 (m, 3H) , 7.04 (d, J = 2Hz, 1H), 7.32 (d, J = 9Hz, 2H) 0 Example 8 4 trans, trans-2- (4-methoxybenzyl) -4- (1,3- Benzodifluorene_5-yl) -1- (Team: ^ ·; (n-propyl) aminocarbonyl) pyrrolidine-3 · carboxylic acid-158- This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 (Mm) (Please read the notes on the back before filling out this page) -5 'to Τ Printed by the Central Consumers Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 581760 A7 B7 V. Description of the Invention (156) The title compound was prepared by the method of Example 8, The starting material was dibutylaminoformamidine chloride prepared by Hoshino et al., Syn. Comm., 17: 1887-1892 (1987). 4 NMR (CDC13, 300 MHz) d 0.86 (t, J = 7Hz, 6H), 1.14-1.28 (m, 4H), 1.35-1.48 (m, 4H), 2.81-2.94 (m, 2H), 3.11 (t, J = 12Hz, 1H), 3.30-3.41 (m , 2H), 3,59.3.68 (m, 2H), 3.76 (s, 3H), 3.78-3.85 (m, 1H), 5.81 (d, J = 9Hz, 1H), 5.94 (s, 2H), 6.73 -6.86 (m, 5H), 7.24 (d, J = 9Hz, 2H). Example 8 5 Expanded, trans-2- (4-methoxybenzyl) _4- (l, 3-benzobisfluoren-5-yldibutylaminecarbonylmethyl) pyrrolidine-3-carboxylic acid sodium salt Sodium hydroxide (48.2 mg of 98.3% pure, 1.184 mmol) was added to 2 ml of MeOH to the compound of Example 43 (6 10 mg, 1.196 mmol) in 5 ml of MeOH. The solution was concentrated to dryness and the resulting powder was stirred with heptane. The heptane was removed under vacuum to form a powder, which was dried in a vacuum oven at 60 ° C for 2 hours to yield 627.5 mg of the title compound. Example 8 6-bundle 'trans-2- (4-fluorenoxyphenyl) -4- (1,3 · benzodi-5-yl) · 1 · [~ 2- Consumption by Employees of Central Bureau of Standards, Ministry of Economic Affairs Printed by the cooperative (please read the notes on the back before filling out this page) Di (n-butyl) amino) ethyl] pyrrolidine j · Youling from the bromoethyl compound of Example 61 (150 mg), two A solution of butylamine (15.0 g) and sodium iodide (18 mg) in 0.75 ml of ethanol was heated at 80 ° C for 1 hour. After cooling, toluene was added and the solution was washed with a potassium bicarbonate solution, dried over NadO4 and concentrated. More toluene was added and the solution was concentrated again to remove excess two amines. The residue was dissolved in warm heptane and filtered off). The heptane was removed under the sky to produce 143 mg (87%) ____ Two 159- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (21GX297 mm) '--- printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 __ ____B7 V. Intermediate ethyl ester of invention description (157). It was hydrolyzed by the method of Example 1 D to give the title compound as a white powder. NMR (CD3OD, 300 MHz) ά 0.89 (t? J = 7Hz, 6H), 1.16-1.30 (m, 4H), 1.44-1.56 (m, 4H), 2.48-2, 57 (m, 1H), 2.80-3.08 (m, 8H), 3.14-3.25 (m, 1H), 3.31-3.38 (m, 1H), 3.59-3.60 (m, 1H), 3.74 (s, 3H), 3.75 (d, J = 10Hz , 1H), 5.89 (s, 2H), 6.71 (d, J = 9Hz, 1H), 6.81 (dd, J = 9Hz, 2Hz, 1H), 6.90 (d, J = 10Hz, 2H), 6.96 (d, J = 2Hz, 1H), 7.37 (d, J = 10Hz, 2H). Example 8 7. Formula, trans-2 · (4-methoxybenzyl) _4_Π · 3-benzobisfluoren-5-ylbis (n-butyl) aminocarbonylmethylamine 1ethyl} pyrrolidine_ Dibutylaminocarboxylic acid 3-carboxylic acid dichloride (135 mg) was added to the compound of Example 61B (250 grams) and 150 ¾ grams of diethylamine in 1 ml of digas. After incubation at room temperature for 1 hour, toluene was added, and the solution was washed with a potassium bicarbonate solution, dried over Na 2 SO 4 and concentrated. The residue was chromatographed on silica gel and dissolved with a mixture of 38% EtOAc and 62% hexane to give 194 mg of ethyl intermediate. The vinegar was hydrolyzed in the same manner as in Example 1 D to give 14 µm of the title compound. 1η NMR (CD30D, 300 MHz) d 0.92 (t, J = 7Hz, 6Η), 1.21-1.32 (m, 4H), 1.42-1.53 (m, 4H), 2.62 (s, 3H), 2.65-2.76 (m , LH), 3.00-3.20 (m, 8H), 3.44-3.55 (m, 1H), 3.62-3.78 (m, 2H), 3.80 (s, 3H), 4.07 (d, J = 12 Hz, 1H), 5.93 (s, 2H), 6.75 (d, J = 9Hz, 1H), 6.87 (dd, J = 9Hz, 2Hz, 1H), 6.94 (d, J = 10 Hz, 2H), 7.04 (d,- 160- This paper size applies to Chinese National Standard (CNS) A4 (210X297mm) " " (Please read the precautions on the back before filling this page) Clothing · 581760 A7 ______B7 V. Description of the Invention (158) J = 2Hz, 1H), 7.40 (d, J = 10Hz, 2H). Example 8 8 (Please read the precautions on the back before filling this page) Well-formed 'trans · 2_ (4 · methoxyphenyl) · 4_ (1,3_benzo + triyl) amine carboxyl) methyl V Pyridine_3_ΓΝ_methyl, sulfamoyl) carboxylic acid carbonyldiimidazole (75¾: g, 0.463 mmol) was added to 150 mg (〇294 mmol) of Example 43 compound in 0.4 ml tetrahydrofuran The solution was at 60. 〇 Stir: Mix for 2 hours. After cooling, 50 mg (0.526 mmol) of methylamine and 68¾ g (0.447 ¾mol) of DBU in 0.3 ml of THF were added. The mixture was stirred at 45 ° C for 2 hours. The solvent was removed in vacuo and the residue was dissolved in water. A few drops of acetic acid were added and the solution was freeze-dried to produce 121 mg (70%) of the standard compound. π · ρ · 170-173C. NMR (CDCI3 300 MHz) d 0.82 (t, J = 7Hz, 3H), 0.88 (t, J = 7Hz, 3H), 1.05 surface 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 = 10Hz, 1H), 5.96 (dd , J = 2Hz, 4Hz, 2H), 6.74 (d, J = 9Hz, 1H), 6.84 (dd, J = 9Hz, 2Hz, 1H), 6.90 (d, J = 10 Hz, 2H), 7 〇1 ( d J = 2Hz, 1H), 7.34 (d, J = 10Hz, 2H). Example 8 9 The consumer cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed trans, trans-2- (4-methoxybenzyl) _4 · (1,3 -benzodi slogan-5 _even) · 1 _ (ν , v · bis (n-butyl) aminoalkyl) methyl) ρ Billodinium-3-(N-Benzene) ^ Example 4 Compound was converted to the title compound by the method of Example 8 8 However, benzsulfuron is used instead of methanesulfonamide. m.p. 169-171 ° C for samples recrystallized from azureol. 1H NMR (CDC13, 300 MHz) d 0.81 (t, J = 7

Hz, 3H), 0.89 (t, J = 7Hz, 3H), 1.02-1.50 (m, 8H), 2.65-2.80 (m, -161-This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm ) 581760 A7 B7 V. Description of the invention (159) 2H), 2.90-3.25 (m, 4H), 3.80-3.95 (m, 3H), 3.50-3.60 (m, 1H), 3.65 (d, J = 10Hz , 1Η), 3.81 (s, 3H), 5.94 (s, 2H), 6.70 (s, 2H), 6.81-6.90 (m, 3H), 7.17 (d, J = 10Hz, 2H), 7.55 (t, J = 7 Hz, 2H), 7.66 (t, J = 7Hz, 1H), 8.95 (d, J = 7Hz, 2H). Example 9 0 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodiaz-5-yl) -1- 丨 N, N-di (n-butyl) Aminosulfomethylmethylpyrrolidin-3-carboxylic acid A chloromethylsulfinamido chloride prepared by the method of Brintzinger et al, Chem Ber Ber: 455-457 (1952), and dibutyl The amine is reacted in the manner described by E. Vilsmaier in Liebigs Ann. Chem. 1055-1063 (1980) to form N, N.dibutylchloromethylsulfenyl chloride. In addition, dimethyl (methylthio) tetrafluoroborate base reacts with dibutylamine to form N, N-dibutylmethylidenefluorenyl chloride, which is chlorinated with N-chlorosuccinimide to form chloromethyl The sulfinyl sulfenyl chloride was carried out by the E. Vilsmaier method described above. N, N_dibutylchloromethylidenefluorenyl chloride reacts with the compound of Example 6 to form trans, trans-2_ (4-methoxyphenyl) -4- (1,3-benzodi Fluoren-5-yl)-[N, N-di (n-butyl) aminomethylenefluorinylmethyl] Ethyl 3-Ethyl Ester. This is printed with iron tetroxide and N-methylmorphine n_ oxide using 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)

Kaldor and M. Hammond, Tet. Lett. 3_2: 5043.5045 (1991). The title compound can be formed by hydrolysis of ethyl ester. Example 9 1 trans-, trans-2- (4-methoxyphenyl) -4- (1.3-benzodiazine-5-yl VI- | ~ (N, N-dibutylamino) yl- 1- (RS) _Ethylpyrrolidate_3_Lean acid-162- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 581760 Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs , Description of invention (160)

Example 91A (±) -Dibutyl-2-bromopropionamine 2-bromopropionic acid (510 mg, 3.33 mmol) and 4-methylmorpholine (0.74 ml, 6.73 mmol) In 10 ml of CH2C12, the solution was cooled to 0 ° C, and then treated with isobutyl chloroformate (0.45 ml, 3.5 mmol) dropwise under N2 atmosphere. After 10 minutes at TC, dibutylamine (0.57 ml, 3.4 mmol) was added. The reaction was stirred at 0 ° C for 1 hour and then at room temperature for 16 hours. The mixture was mixed with 25 ml of 1.0 M Na2C03 aqueous solution was partitioned, and the organic layer was washed successively with 25 ml of a 1 M NaHS04 aqueous solution and 25 ml of brine, dried (NajCU), filtered and concentrated under reduced pressure to yield 698 mg (2.64 mmol, 79%) of crude bromidine. Amine as a colorless oil. IH NMR (; CDC13, 300 MHz) d 0.93 (t, J = 7Hz) and 0.97 (t, J = 7.5Hz, 6H combined), 1.26-1.60 (m, 7H), 1.60-1.78 (m, 1H), 1.82 (d, J = 6Hz, 3H), 3.04-3.27 (m, 2H), 3.42-3.64 (m, 2H), 4.54 (q, J = 7H, 1H). MS (DCl / NH3) m / e 264 and 266 (M + H) +.

Example 91B trans, trans, and cis, trans-2- (4-methoxyphenyl) -4_Π, 3-benzodiamidino-5.yldibutylamino) carbonyl-1_ (RS) _ethyl Methyl) pyrrolidine_3_carboxylic acid ethyl ester Example 1C The trans, trans and cis, trans compounds (232 mg, 0.628 mmol) and the compound of Example 91 A (183 mg, 0.693 mmol) in 2 ml of a mixed solution of CH3CN was treated with diisopropylethylamine (0.22 ml, 1.3 mmol). The solution was stirred at 60-80 ° C (under N2 atmosphere) for 16 hours. The reaction was concentrated under reduced pressure, and the residue was partitioned into 30 ml of Et20 and 10-163- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) C Please read the notes on the back first to fill in this purchase )

1T. Spring-581760 A7 B7 V. Description of the invention (161) in 1 M NaWO3 aqueous solution. The organic phase was washed with 20 ml of water and 20 ml of brine, dried over NasSO4, filtered and concentrated under reduced pressure to give a crude amine group as a brown oil (339 mg, 98% crude). The product was flash chromatographed on silica gel and dissolved in 20% EtOAc-hexane to give 224 mg (70%) of the title compound as a mixture of 4 diastereoisomeric forms. 4 NMR (CDC13, 300 MHz) d 0.66-1.55 (several 111, 1911), 2.63-3.00 (m, 3H), 3.05-3.39 (m, 2H), 3.40-3.76 (m, 4H), 3.78-3.80 (4 s, 3H), 3.84-4.25 (m, 2.6H), 4.38 (d, J = 10.5Hz, 0.2H) and 4.58 (d, J = 10.5Hz, 0.2H), 5.90-5.97 (m , 2H), 6.68-6.96 (m, 5H), 7.38-7.43 (m, 2H). MS (DCI / NH3) m / e 553 (M + H) +.

Example 91C 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) trans, trans-2- (4-methoxymolyl) -4- (1,3-benzene Benzenedi-5-yl VI-((N, N-dibutylamino) fluorenyl_1- (RS) -ethyl) external I: Luodian-3- # acid The procedure of Example 73C is used as an example The 91B compound replaced the 73B compound, yielding the title compound in 61% yield. NMR (CD3OD, 300 MHz) d 0.70-1.05 (several m, 8H), 1.14 (d, J = 6Hz, 2H), 1.17 -1.55 (m, 6H), 2.79-3.03 (m, 3.5 ·), 3.20-3.65 (br m, 4 · 6Η plus CD2HOD), 3.70-3.78 (m, 0.4H), 3.79 (s, 3H), 3.98 (d, J = 8Hz, 0.60), 4.06 (t, J = 7.5Hz, 0.4H), 4.25 (d, J = 8Hz, 0.40), 5.92 (s), and 5. · 94 (s, 2H sum 6H), 6.73 (d, J = 2.5Hz) and 6.75 (d, J = 3Hz, 1H sum), 6.78-6.85 〇, 111), 6.91-7.00〇, 311), 7.30-7.38 (m, 2H). MS (DC1 / NH3) m / e 525 (M + H) +. Analytical estimates of C30H40N2O6 · 0 · 5Η20: C, 67 · 52; H, 7.74; N, 5.25. Measured 値: C, 67 · 63; H, 7.65; N, 5.21, -164- This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) 581760 A7 ____ B7 V. Description of the invention (162) Examples 9 2 trans'trans-2- (pentyl) _4 · (1,3-benzodiazine-5-yl) _i_ (n, N-dibutylamine

Talking about the methyl methyl ratio of 3-Chinoic acid Example 92A

2-(4 -Self-fermenting group) -4 · nitro-3-(1,3 -benzobisazine_5_yl) formyl methyl butyrate (502 mg; 2.95 mmol) in 10 ml of isopropanol solution was added to 5- (2-nitrovinyl) _1,3-benzodiyin (712 mg, 3.69 mmol) at 1 0 mL of ThF, plus DBU (22 μl '0.15 mmol). The resulting reddish solution was stirred at room temperature for 20 minutes. TLC (ethyl acetate-hexane, 1: 3) showed complete consumption of the ketoester. The solution was concentrated. Flash chromatography on Shixi gum, dissolving with 18% ethyl acetate / hexane, can produce 879 mg (2.42 mmol, 82%) of the title compound in a 1: 1 ratio of diastereomers mixture. iH NMR Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (please read the notes on the back before filling this page) (CDC13, 300 MHz) β 1.55-1.66 (m, 3H), 2.02-2.17 (br m, 1H) , 2 · 20 · 2 · 37 (m, 1.5Η), 2.49-2.76 (m, 1.5H), 3.57 (s, 1.5H), 3.74 (s, 1.5H), 3.97 (d, J = 7.5H , 0.5H) and 4.05 (d, J = 8Hz, 0.5Η) 4.10-4.20 (m, 1H), 4.68-4.82 (m, 2H), 5.06-5.52 (m, 2H), 5,95 (2s, 2H), 6.65 (m, 1H), 6.68 (br s, 1H), 6.75 (d, 7.5 Hz, 1H). MS (DC1 / NH3) m / e 381 (M + NH4). Analysis estimates C18H21N07: C 59.50; H, 5.82; N, 3.85. Found 値: c, 59 · 32; H, 5.71; N, 3.72.

Example 92B trans, trans-2- (pentyl) -4- (1,3-benzodiazine-5-yl) p-bilodonate formamidine The procedure of Examples 1 B and 1 C was followed to Example 92A Compound Substitute Real-165- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210x ^ 97 male " " '581760 A7 B7

—I ... I. I. 5. Description of the invention (163) The compound of Example 1 A, and the resulting compound replaced the compound of Example 1 B to produce the title compound in a buttery crude form. This crude compound was epimerized using the following conditions. A solution of the crude compound (660 mg, 2.07 mmol) in 3 ml of methanol was treated with sodium methoxide solution (made by adding sodium metal (14 mg, 0.61 mmol) to 1 ml of methanol). The resulting solution was heated at reflux for 18 hours. The reaction was concentrated under reduced pressure, and the residue was partitioned into 25 ml of saturated NaHC03 (diluted with 10 ml of water) and 30 ml of CH2C12>. The aqueous phase was extracted (2x30 ml, CH2C12), and the combined organic phases were washed with 20 ml of brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. Purification by flash chromatography on silica gel and dissociation with 3.5% methanol / CI ^ Cl2 yielded 336 mg (57%) of the title compound as a butter. 4 NMR (CDCI3, 300 MHz) d 0.90 (br t, 3H), 1.25-1.70 (br m, 8H), 1.83-2.02 (br s, 2H), 2.58 (dd, J = 8,9Hz , 1H), 2.99 (dd, J = 8, 14Hz, 1H), 3.34-3.45 (m, 2H), 3.53 (q, J = 9Hz, 1H), 3.66 (s, 3H), 5.94 (s, 2H) , 6.65-6.75 (m, 3H). MS (DC1 / NH3) m / e 320 (M + H) +. Analysis estimates C18H25N04: C, 67.69; H, 7.89; N, 4.39. Found 値: C, 67.39; H, 7.84; N, 4.37

Example 92C 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-2- (pentyl) -4- (1,3 benzodi "number base V1-Butylaminomethyl) pyrrolidine-3-carboxylic acid

Using the procedures of Examples 1B-1D and replacing the compound of Example 1B with the compound of Example 92A, the title compound was obtained as a white foam. !! η NMR (CDC13, 300 MHz) d 0 · 87 (br t) and 0.89 (br t, 6H total), 〇97 -166- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) '' '581760 A7 V. Description of the invention (164) (t, J = 7.5Hz, 3H), 1.21-1.42 (br m, 10), 1.43-1.78 (br m, 6H), 2.76 (t, J = 7Hz, 1H ), 3.02-3.30 (br m, 6H), 3.40-3.60 (m, 3H), 3.73 (d, J = 14Hz, 1H), 5.98 (AB, 2H), 6.70 (d, J = 7Hz , 1H),

6.77 (dd, J = 1.5, 7Hz, 1H), 6.89 (d, J = 1.5Hz, 1H). MS (DCI / NH3) m / e 475 (M + H) +. Analysis estimates C27H42N205 · 0.5 H20: C, 67.05; H, 8.96; N, 5.79. Measured 値: C, 67.30; H, 8.77; N, 5.68 0 Example 9 3

Trans, trans-2- (pentyl) _4_ (1,3-benzodiazine_5-yl) -1- 丨 2- (N-propyldi-N-propylcontinuous amino) ethyl 1 p Bihadian-3-complex fe Example 9 3 A trans'trans-2 · (pentyl) -4- (1,3_benzodi-5-yl) -1- (2- Australian Ethyl) Pyrrolidine-3-carboxylic acid methyl ester 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), 1T usage examples In the method of 61A, the compound of Example 1 was replaced by the compound of Example 93B to give the title compound as a butter. 1H NMR (CDC13, 300 MHz) d 0.89 (br t, J = 7Hz, 3H), 1.24-1.40 (br m, 6H), 1.60-1.80 (brm, 2H), 2.61-2.75 (m, 2H), 2.76 -2.91 (m, 2H), 3.10-3.22 (m, 2H), 3.36-3.47 (m, 2H), 3.68 (s, 3H), 5.92 (s, 2H), 6.69-6.77 (m, 2H), 6.90 -6.94 (m, 1H). MS (DC1 / NH3) m / e 426; 428 (M + H) + 0

Example 93B trans, trans-2- (pentyl V4V1.3-benzodifluorene_5-a certain propyl ^ 1 N-propylcontinylamino) ethyl 1 p bilodo_3 acid methyl vinegar example Compound 93A (102 mg, 0.24 mmol) and tetrabutylammonium base (6 -167 581760 A7 _ B7 ------------------____ V. Description of the invention (165) mg A solution of 16 micromoles of Et0H was treated with propylamine (60 microliters, 0.73 millimoles). The solution was warmed to 8 (rC over 4 hours. The reaction was concentrated under reduced pressure, and the residue was redissolved in 35 ml It was extracted with ethyl acetate and extracted with 2 X 5 ml of 1 M NazCO3 aqueous solution. The organic phase was washed with 15 ml of brine, dried on NkSCU, filtered and concentrated under reduced pressure to form a crude secondary amine, which was buttery. (94.2 mg). The crude amine was dissolved in 1 liter of CH2Ch. Diisopropylethylamine (65 μl, 0.373 moles) was added, followed by propylsulfonyl chloride (29 μl, 0.26 mmoles). The solution was stirred at room temperature for 4 hours. The reaction was quenched with a 10% aqueous solution of citric acid (pH 4), and the mixture was extracted with 2 x 3 ml of CHsCl2. The mixed organic extract was washed with 2 ml of brine and dried on NaJO4 'filter Concentrate in the air and purify by flash chromatography. Dissolve in 20% ethyl acetate / hexane to give 65.0 mg (53%) of the title compound as a gaseous solid. Rf = 0.17 (20% EtOAc-hexane). .MS (DC1 / NH3) m / e 511 (M + H) +.

Example 93C 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) trans-2- (pentyl) -4- (1,3-benzodifluorene-5-yl Propyl-N-propyl (continuous amine group) ethyl 1 ρ Biloxidine-3-leic acid Follow the method of Example 71C and replace the compound of Example 71B with the compound of Example 93B to form the title compound as a white foam (4 7 mg, 80%), Rf = 0.14 (5% MeOH-CH2Cl2) 0 4 NMR (CDC13, 300 MHz) d 0.88 (br t) and 0.92 (t, J = 7Hz, 6H total), 1.22-1.52 (br m, 6H), 1.63 (six peaks, j = 8Hz, 2H), 1.75-2.10 (br m, 4H), 2.89-2.98 (m, 2H), 3.05 (br t, J = 9Hz, 1H), 3.10- 3.30 (m, 3H), 3.30_3.80 (br m, 7H), 5.94 (s, 2H), 6.71 (t, J = 8Hz, 1H), 6.77 (dd, J = 1.5, -168- present) Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (彳 66) 8Hz, 1H), 6.89 (d, J = 1.5Hz, 1H). MS (DCi / NH3) m / e 497 (M + H) +. (Please read the precautions on the back before filling this page) Example 94 Cong Li-, trans · 1 · (propyl number_5_yl V1_ (N, N dibutylamine sulfonyl methyl) pyrimidine-3 -Jun acid

Example 94A g: Ethyl bis (4-butanoyl) _4-nitro-3- (1,3-benzodiazine_5_yl) butyrate Follow the method of Example 9 2 A to ethyl butylammonium acetate Replacement of 3-keto-6-octanoic acid methyl ester yielded the title compound as a mixture of trans and cis isomers (47 mg '80%) 'Rf = 〇.28 (25% EtOAc in hexanes). 4 NMR (CDC13, 300 MHz) d 0.74 (t, J = 7.5Hz) and 0.91 (t, J = 7.5Hz, 3H total), ΐ〇8 (t, J = 7Hz) and 1.28 (t, J = 7Hz, 3H total), 1.45 (six peaks, J = 7Hz, 1.5H), 1.63 (six peaks, j = 7Hz, approx. 5H), 2 17 (t, printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs, J = 7Hz) and 2.24 (t, J = 7Hz, 0.5Η total) 2.40-2.54 (m, 1H), 2.60 (t, J = 7.5Hz) and 2.67 (t, J = 7.5Hz, 0.5H total), 3.94 -4.09 (m, 2H), 4.10-4.20 (br m, 1H), 4.23 (q, j = 7Hz, 1H), 4.67-4.85 (m, 2H), 5.94 (s, 2H), 6.62-6.75 (m , 3H). MS (DCimH3) m / e 369 (M + NH4) +. Analysis estimates C17H21N07: c, 58.11; H, 6.02; N, 3.99. Found 値: c, 58.21; H, 5.98; N, 3.81.

Example 94B Cluster of trans-2_ (propyl) _4- (1,3 · benzylidene-5-yl) pyrrolidin-3-carboxylic acid ethyl ester Following the method of Example 92B, replace the Example 92A compound with the Example 94A To generate the title compound. MS (DCI / NH3) m / e 306 -169- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297), 581760 A7 B7 V. Description of the invention (167) (M + H),

Example 94C trans, trans-2- (propyl) -4Π, 3-benzobisfluoren-5-yl) -1 _ ((N, N · dibutylamino) carboxyl) methyl pilolide- 3-Lean acid followed the method of Example 92C and replaced the compound of Example 92B with the compound of Example 94B to generate the title compound. 1H NMR (CDC13, 300 MHz) d 0.89 (t, J = 7.5Hz), 0.92 (t, J-7.5Hz), and 0.97 (t, J = 7.5Hz, 9H total), 1.22-1.80 (1 ^ 111, 1211), 2.83 (1 :, > 7.51 ^, 111), 3.40-3.55 (br m, 2H), 3.55-3.68 (m, 1H), 3.78 (d, J = 15Hz, 1H), 5.92 (q, J = lHz, 2H), 6.70 (d, J = 8Hz, 1H), 6.79 (dd, J = 1Hz, 8Hz, 1H), 6.90 (d, J = 1Hz, H). MS (DC1 / NH3) m / e 447 (M + H) +. Analysis estimates C25H38N205 · 0.5 H20: C, 65.91; H, 8.63; N, 6.15. Found 値: C, 65.91; H, 8.68; N, 5.94. Example 9 5 (2R, 3R, 4SV (+) _ 2_ (4 · methoxyphenyl) -4- (1,3-benzodiazine-5-yl) -1- (third-butoxycarbonyl-amine Carbonylcarbonylpyrrolidine-3-carboxylic acid

Example 95A 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) trans, trans-2_ (4-methoxyphenyl) -4- (1,3-benzo Difluoren-5-yl third-butoxycarbonylaminocarbonylmethyl 1 pyrrolidine-3-carboxylic acid Example 14 64% of trans, trans and cis, trans pyrrolidine (3.01 g , 8 · 15 mmol) was dissolved in 50 ml of dichloromethane. To this was added dropwise di-tert-butyl dicarbonate (I. 96 g, 8.97 mmol) in 20 ml of dichloromethane. The solution of methane is stirred in a nitrogen atmosphere for 30 minutes. At this time, TLC (ethyl acetate: hexane, 1: 1) shows all the starting materials. -170- This paper is in accordance with Chinese National Standards (CNS) A4 specification (210 × 297 mm) 581760 A7 B7 V. The description of the invention (168) is consumed. The reaction mixture is concentrated and dried under high vacuum to produce 3 94 g of ethyl ester as a yellow-brown oil. IH NMR (CDCL3, 300 MHZ) J 0.99, 1.07 (br t, br t, J = 7 Hz, 3H), 1.11-1 · 62 (several br m, 9H), 3.05 (br m5 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 m, 1H), 5.94 (d, J = 3 Hz, 2H), 6.69-6.90 (m, 5H), 7.06-7.20 (m, 2H). MS (DC1 / NH3) m / e 470 (M + H) +. A solution of ethyl acetate in 170 liters of ethanol was added with a solution of lithium hydroxide (106 g, 25.17 mmol) in 60 ml of water. Reaction The mixture was vigorously stirred under nitrogen atmosphere 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 ether. The organic layer was acidified to a slightly turbid (pH ~ 7) with 1 anti-hydrochloric acid. Then, it was extracted with 10% citric acid to pH 4, and extracted with 5% ethanol / dichloromethane (3 x 100 ml). The mixed organic layer was dried (NajO4), filtered, concentrated and dried under high vacuum. Generates white foam

The standard compound (2.19 g, 60%). if! NMR (CDC13, 300 MHz) d 1.16 (v br s, 9H), 3.11 (br m, 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 = 9 Hz , 2H). MS printed by I --------- ^ clothing of the Central Consumers Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page) (DCl / NH3) m / e 442 (M + H),

Example 95B (2R, 3R, 4S) _ (+) _ 2- (4-methoxyphenyl) -4 · (1,3-benzodihum-5 · yl) -l_ (butoxyalkylamino Talking about methyl methyl V? Ratio p-Ethyl-3-Leptanoic acid Example 9 5 A compound (2.15 g, 4.86 mmol) and (+)-sinconyl (1.43 g '4.86 mol) added to 100 ml of dichloromethane; this suspension -171-this paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 581760 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention ( 169) If necessary, heat and vortex to dissolve all solid particles. The solution is concentrated and dried under high airspace to form a white foam. This material is from a mixture of refluxing chloroform (64 4 liters) and hexane (360 ml). Crystallization. The resulting crystals were separated by hydration and recrystallized several times under the same conditions. The crystals and filtrate of each time were tracked by iHNMR and p-HPLC. (2s, 3S, 4R)-(·) -enantiomer The amount is first reduced in the crystal and then in the filtrate, and the (2S, 3S, 4RH_) · enantiomer is no longer measured in the filtrate, and the predetermined end point can be reached in time. In this way, the pure 4S)-(+)-enantiomer, partitioned between 100 ml of 10% citric acid and 100 ml of ether. The aqueous layer was extracted twice with 100 ml of ether. The mixed ether layer was brine Washed, dried (NkSO4), filtered, concentrated and dried under high vacuum to form a white powder (550 mg, 55% of theoretical tritium 50% maximum tritium, > 99.5 ee). 4 NMR (CDC13, 300 MHz) J 1.05-1.50 (br m, 9H), 3.12 (br m, 1H), 3.50-3.65 (m, 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) + o

Example 95C (211,31 ^ 48)-(+)-2- (4-methoxyphenyl) -4- (1,3-benzodifluorenyl_5-yl) _pyridine-3 ethyl acetate The compound 95B (25 耄 g, 0.568 mmol) of xizhibei example was dissolved in 20 ml of anhydrous HC1 (gas) in a saturated solution of absolute ethanol. The resulting solution was heated with stirring at 50 ° C for 18 hours, at which point all precipitated solids had dissolved. The reaction mixture was concentrated to a solid, which was partitioned between 08 µa aqueous sodium carbonate (50 mg) and dichloromethane (50 ml). The water layer is dichloromethane (2 -172- this paper size applies to China National Standard (CNS) 8 4 specifications (210 × 297 mm) II (Please read the precautions on the back before filling this page)-1T Central Standard of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperatives 581760 A7 -----------___ B7_ V. Description of the invention (17〇) X 50 ml) for further extraction. The combined organic layer was dried (Na2SO4), filtered, 'concentrated and dried under Nanzhao space to give the title compound as a colorless oil (158 g) (69%). 1H NMR (CDC13, 300MHz) d 1 · 11 (t, J = 7 Hz, 3H), 2.18 (v br s, iH), 2.93 (t, J = 9 Hz, 1Η), 3.19, 3.22 (dd , J = 7 Hz, 1H), 3 · 50 · 3 · 69 (m, 2H), 3.80 (s, 3H), 4.07 (q, J = 7 Hz, 2H), 4.49 (d, J = 9 Hz, 1H), 5.94 (s, 2H), 6.73 (d, J = 2 Hz, 2H), 6.81-6.92 (m, 3H), 7.34-7.41 (m, 2H). MS (DC1 / NH3) m / e 3 70 (M + H) +.

Example 95D (l_R? 3R, 4S)-(+ V2_ (4 · methoxybenzyl, _4_ (i, 3_benzobis,: _ 5 • yl) small (Zhubutoxycarbonyl-aminocarbonyl methylpyrrole) Pyridin-3-carboxylic acid was added to the compound of Example 95C (131 mg, 0355 mmol), diisopropylethylamine (U7 mg, I85 μl, 106 μmol), acetonitrile (2 mL). N, N-Di- (n-butyl) bromoacetamide (us mg, 0531 mmol), and the mixture was heated at 50 ° C for 1.5 hours. The reaction mixture was concentrated to a solid 'dried at 鬲 眞 S and dried at Chromatographic purification on Shi Xijiao, using 1: 3 ethyl acetate-Hex $ 丨 Gu Li can produce pure colorless oily purpose. Ijj NMH (CDCI3 300MHz) β 〇81 (t, J = 7 Hz, 3H), 0.88 (t, J = 7 Hz, 3H), 1 · 10 (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 Hz, 1H), 3.80 (s, 3H), 4.04 (q, J = 7 Hz, 2H), 5.94 (dd, J = 1.5 Hz, 2H), 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) 〇MS (DCl / NH3) m / e 53 9 (M + H), Liters of ethanol, ethyl bell hydroxide (45 mg, -173- this paper scale applicable Chinese National Standard (CNS) Α4 Specification (210Χ297 mm) (Please read the back of the precautions to fill out this page) clothes ·

1T 581760 A7 B7 V. Description of the invention (171) 1.06 mmol) in water (2.5 ml). The mixture was produced at ambient temperature, stirred for 1 hour, and then slowly warmed to 40 ° C for 2.5 hours, at which time the starting material was consumed. The reaction mixture was concentrated to remove ethanol, diluted with 60% water and extracted with ether (3 × 40 ml). The aqueous solution was treated with an iN aqueous solution of hydrochloric acid until turbidity, and ρΗ 値 was adjusted to about 45 with 10% citric acid. This mixture was extracted with 1:19 ethanol-dichloromethane (3 X 50 ml). The combined extracts were dried (NajO4), filtered, concentrated and dried under high vacuum to give the title compound (150 mg, 83%) as a white foam. ιΗ NMR (CDC13, 300 MHz) NMR (CDC13, 300 MHz) d 0.8 · (t, J = 7 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 = 8 Hz, 1H) , 6.87 (br d, J = 8 Hz, 3H), 7.05 (br s, 1H), 7.33 (v br s, 2H). MS (DC1 / NH3) m / e 511 (M + H) +. [Π ] 22 = +74.42. Analyzed and estimated C29H38N206 · 0.5 H20: C, 67.03; H, 7.56; N, 5.39. Found: C, 67.03; H, 7.59; N, 5.33 〇 Example 95E (2R, 3R, 4S) -(+)-2- (4_T oxyphenyl) -4 · Π, 3-benzo-two-zaki-5-yl) -1- (No. (Please read the precautions on the back before filling in this page), τ -Γ Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs of the Consumers Cooperative Di-butoxyamino-L-methyl) p-pyridian-3-acid Example 95 eight products (2.858 g) suspended in 10 ml of acetone. Add 0.7333 g of R (+) a methylbenzylamine to 3 ml of ethyl acetate. Once shaken, all solid particles are dissolved. The ethyl acetate is removed under vacuum. Such as ether (13 ml) to the residue. When all Residue dissolves Add 5 mg of seed crystals. These crystals are ground with a metal spoon and cooled in ice. The product is very slowly -174- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 Central Bureau of Standards, Ministry of Economic Affairs Printed by employee consumer cooperative A7 _________ B7 V. Description of the invention (172) Crystallization. After 1 hour, the filtered solid was washed with ether to produce 14213 g, mP · 163-167. The filtrate was concentrated, cooled and scraped with a medicine spoon to produce the first Secondly obtained, 0.1313 g, mp 164-168 ° C. The filtrate was concentrated again and placed in the refrigerator to let it stand overnight to produce 1.6906 g, η · ρ · 102 · ιιο. (This jjPLC shows 20% of the desired antipodal And 80% of the unwanted enantiomers. The first two batches of crystalline material were mixed, suspended in 20 ml of dichloromethane (Note: unwanted isomers are more soluble in dichloromethane) and stirred for 2 minutes. Mixture Concentrate, place without drying, add diethyl ether (10 ml). After stirring for several minutes, filter the crystals. Yield: 1.401 g, mp 64_172. ^. The title compound was obtained by treating the crystalline product with 10% citric acid and diethyl ether according to the method of Example 95B. Example 9 6 ~ Formula ~~ Well-formed formula 2-di-1_4-methoxyfluorenyl) -4- (1,3-benzodiazin-5_yl) -1_ | ~ 2-() ^-propyl-N -Butylamido) ethyl p-pyrrolemic acid The title compound was prepared as described in Example 61, using propylamine instead of methylamine of Example 61B and butylammonium chloride replacing isobutylammonium chloride of Example 01c. The product was purified by preparative HPLC (Vydac # C18) and eluted with CH3CN in a 10-70% gradient of 0.01% TFA. For lyophilization of fractions to produce a white solid product, 4 NMR (CDC13, 300 MHz) d 0.80 (m, 3H) 0.90 (t, 3H, J = 8Hz), 1.42 (m, 2H), 1.58 (Seven Peaks , 2H, J = 8Hz) 2.20 (t, 3H, J = 8Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3 48 (br m, 4H), 3.76 (br m, 2H) , 3.78 (s, 3H), 4.30 (br s, 1H),

5.95 (s, 2H), 6.75 (d, 1H, J = 8Hz), 6.84 (m, 1H), 6.85 (d, 2H J = 8Hz), 7.04 (d, 1H, J = lHz), 7.40 ( d, 2H, J = 8Hz). Ms ___- 175-_ This paper size is applicable to China National Standard f (CNS) A4 specification (210X297mm) '' ~ —— (Please read the precautions on the back before filling this page)

1T p. 581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (173) (DCl / NH3) m / e 497 (M + H). Analysis estimates C28H36N206 · 1.0 TFA: C, 58.82; H, 6.42; N, 4.57. Measured fluorene: C, 58.77; H, 6.30; N, 4.42 〇 Example 9 7 trans' trans_2_ (4_methoxyphenyl) · 4- (1,3-benzobizaki-5-yl VI -丨 2-Qsl · Monyl-N- (ethylamino) amino) ethyl 1 ρ ratio ρ each dian_3-chinic acid The title compound was prepared according to the method in Example 61, but propylamine was used instead of the compound in Example 61B. Methylamine was replaced by ethyl isocyanate of isobutylfluorenyl chloride of Example 61C. The crude product was purified by trituration with 1: 1 diethyl ether-hexane. The resulting solid was dissolved in CHsCN and water, and then freeze-dried to produce the product as a white solid. ιΗ NMR (CDC13, 300 MHz) Mixture of geometric isomers d 0 80 (t, J = 8Hz) and 1.05 (t, J = 8Hz) and 1.20 (m) and 1.42 (m) 8H, 2.35 (bi * s, 1H), 2.70 (m, 1H), 3.0 (m, 3H), 3.2 (m, 3H), 3.25 (dq, 1H, J = 1, 8Hz), 3.42 (m, 1H ), 3.6 (m, 1H), 3.75 (m, 1H), 3.78 (s, 3H), 4.8 (br s, 1H), 5.95 (s, 2H), 6.74 (d, 1H, J = 8Hz) , 6.85 (m, 3H), 7.00 (s, 1H), 7.30 (d, 2H, J = 8Hz). MS (DC1 / NH3) m / e 498 (M + H). Analysis estimates C27H35N306.0.75 H20: C, 63.45; H, 7.20; N, 8.22. Found 値: C, 63 · 38; H, 7.29; N, 8.44. Example 9 8 trans, trans-2- (4-methoxyphenyl) -4- (l, 3-benzodiazin-5-yl (N-butyl-N-butyric acid amino) ethyl The title compound was prepared as described in Example 61 except that butylamine was used instead of methylamine of Example 61B, and butylammonium chloride was used instead of isobutylammonium chloride of Example 61C. The crude product was 1: 1 diethyl ether-hexane was purified by grinding. The resulting solid was dissolved in 176- (Please read the precautions on the back before filling this page)

， 1T • Γ. This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297mm) 581760 A7 ___B7_ V. Description of the invention (174) CH ^ CN and water are dried in cold water to produce a white solid product. 1η NMR (CDC13, 300 MHz) β 0.80 (m, 3Η), 0.90 (t, 3Η, J = 8Hz), 1.45 (m, 4H), 1.6 (m, 2H), 2.20 (t, 3H, J = 8Hz ), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.5 (br m, 4H), 3.80 (br m, 2H), 3.82 (s, 3H), 4.30 (br s, 1H), 5.95 (s, 2H), 6.75 (d, 1H, J = 8Hz), 6.84 (m, 1H), 6.85 (d, 2H, J = 8Hz), 7.04 (d, 1H, J = lHz), 7.40 (d, 2H, J = 8Hz). MS (DCI / NH3) m / e 511 (M + H) +. HRMS estimate C29H38N206: 511.2808. Found 値: 511.2809. Example 9 9 trans, trans-2_ (4 · methoxyphenyl) -4 (l, 3-benzodiain 5-yl) l- "2- (N-propyl_N-ethoxyfluorenyl Amino) ethyl lppyrrole-3. Leptin The title compound was prepared in the same manner as in Example 61, but with propylamine in place of methylamine in Example 61B, and ethyl chloroformate in place of isobutylphosphonium chloride in Example 61C. The crude product was purified by trituration with 1: 1 diethyl ether-hexane. The resulting solid was dissolved in CH ^ CN and water and dried in a cold beam to produce the product as a white solid. 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) NMR (CDC13, 300 MHz) β 0.80 (t, 3H, J = 8Hz), 1.05 (m, 2H), 1.22 (m, 3H), 1.45 (m, 3H), 2.08 (br s, 1H), 2.75 (m, 1H), 2.88 (br q, 2H, J = 8Hz), 3.08 (br m, 2H) , 3.27 (br m, 2H), 3.44 (m, 1H), 3.54 (dt, 1H, J = 1, 8Hz), 3.63 (d, 1H, J = 8Hz), 3.78 (s, 3H) , 4.02 (br d, 2H), 5.93 (s, 2H), 6.72 (d, 1H, J = 8Hz), 6.81 (dd, 1H, J = 1, 8Hz), 6.85 (d, 2H, J = 8Hz) , 7.00 (s, 1H), 7.30 (d, 2H, J = 8Hz). MS (DCl / NH3) m / e 499 (M + H) +. Analysis estimates C27H34N207 · 0.5 H20: C, 63.89; H, 6.95; N, 5.52. Found 値: C, 64.03; H, 6.71; N, 5.30. -177- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (175) Example 100 Anti-Begging, Trans- 2_ ( oxophenylbenzobisfluorene-5-f-yl-butyridinyl) amino) ethyl 1 pyrrolidine Example 61B Compound (丨 ⑽ mg) was dissolved in THF (2 ml), and HOBt (60 mg) was added , EDCI (85 mg), N-methylmorpholine (50 microliters) and DMF (2¾ liters). 2-ethylbutyric acid was added and the solution was stirred at ambient temperature overnight. Water (10 ml) was added and the mixture was extracted with Et0Ac (2 x 25 ml). The combined organic extracts were washed with saturated sodium bicarbonate solution, 1 HJO4 and brine, dried over sfa2S04, and evaporated to form an oil, which was purified by flash chromatography on silica gel with 1: 3 EtOAc • hexane to produce The ethyl ester was saponified using the procedure of Example 61C. The crude product was dissolved in CH3CN and water, and then freeze-dried to produce a white solid product. 1H NMR (CDC13, 300 MHz) (mixture of geometric isomers) j 0.66, 0.74, 0.80, 0.88 (all three peaks, total 6H, J = 8Hz), 1.05 (m, 2H), 1.25-1.75 (m, 5H), 2.16 (m, 1H), 2.32 (m, 1Η), 2.45 (m, 1Η), 2.70 (m, 1Η), 2.86, 2.94 (s, 3H total), 2.95 ( m, 1H), 3.35 (m, 1H), 3.52 (m, 2H), 3.65 (m, 1H), 3.80 (s, 3H), 5.94, 5.96 (s, total 2H), 6.73 (m, 1H) ), 6.84 (m, 3H), 6.97 (m, 1H), 7.30 (m, 2H). MS (DC1 / NH3) m / e 497 (M + H) +. Analytical estimates are C28H36N206. 0 · 25 H20 · C, 67.11; H, 7.34; N, 5.59. Found 値: C, 67.13; H, 7.24; N, 5.56. Example 101 trans, trans-2-M-methoxyphenyl) 4- (l, 3-benzodifluoren-5-yl) ^^ 2- (N-methyl-N 彳 2_ Propylpentyl) amino) ethyl l-pyrrolidin-3-carboxamidine_ The title compound was prepared in the same manner as in Example 100, but with 2-propylvaleric acid instead of -178- The Chinese paper standard (CNS) applies to this paper A4 specifications (210 X 297 mm) ^ clothing-(Please read the precautions on the back before filling out this page) Order 581760 A7 B7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (176) On behalf of 2_ Ethyl butyric acid. The crude product was purified by preparative Ηρΐχ (vydac " ci8) pure with a gradient of 10-70% CH3CN in 0.1% TFA. The desired trauma was lyophilized to produce the product as a white solid. 1H NMR (CDC13, 300 MHz) d 0 · 79 (t, 3H, J = 8Hz), 0.82 (t, 3H, J = 8Hz), 1 · 10 (m, 4H)? 1.2-1.5 (m? 4H) ? 2.55 (m? 1H)? 2.96 (s? 3H)? 3.15 (br m9 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 (br d, lh), 5.92 (s, 2H), 6.75 (d, 1H, J = 8Hz), 6.84 (m, 1H), 6.85 (d, 2H, J = 8Hz), 7.05 (s, 1H), 7.42 (d, 2H, J = 8Hz). MS (DC1 / NH3) m / e 525 (M + H) +. Analysis estimates C30H40N206. 1.25 TFA: c, 58.51; H, 6.23; N, 4.20. Found 値: c5 58.52; H, 6.28; N, 4.33. Example 102 Plexiform 'transoxyphenyl) -4- (1,3-benzodiazine--"9- ^ TsT- peroxy-N- (third butoxycarbonylmethyl) amino) ethyl 1 Pyrrolidine_3_ oleic acid was prepared according to the method of Example 61, and propylamine was also used to replace the methylamine of Example 61B, and third-butyl bromoacetate was used to replace the isobutylfluorenyl chloride of Example 61. The crude product was prepared as 1: 1 Diethyl ether-hexane was purified by trituration. The resulting solid was dissolved in CH / N and water, and then freeze-dried to produce the product as a white solid. LR NMR (CDC13? 300 MHz) ά 0.82 (t, 3Η? J = 8Hz)? 1.18 (m, 2H), 1.19 (s, 9H), 2.12 (m, 1Η), 2.46 (m, 2H), 2.70 (m, 3H), 2.85 (m, 2H), 3.20 ( s, 2H), 3.40 (dd, 1H, J = 2, 8Hz), 3.50 (dt, 1H, J = 2, 8Hz), 3.62 (d, 1H, J = 8Hz), 3.78 (s, 3H), 5 95 (s, 2H), 6.72 (d, 1H, J = 8Hz), 6.84 (m, 1H), 6.85 (d, 2H, J = 8Hz), 7.05 (s, 1H), 7.16 (d, 2H, J = 8Hz). MS (DC1 / NH3) m / e 541 (M + H) +. Min -179- This paper size applies Chinese National Standard (CNS) Α4 specification (210 > < 297mm) (please first (Read the notes on the back and fill out this page)

1T 581760 A7 B7 V. Description of the invention (177) Analytical estimates C3qH4ON207 · 1 · 〇 H20: C, 64.50; Η, 7.58; Ν, 5.01. Measured 値: C, 64.75; Η, 7.35; Ν, 4.86. Example 103 trans, trans-2- (4-methoxymolybdenum V4- (l, 3-benzobisfluoren-5-yl) -1- 丨 2_ΓΝ-propyl_N_ (n-propylaminocarbonylmethyl) Amino) ethyl 1 pyrrolidine-3-carboxylic acid The title compound was prepared by the method described in Example 61, except that propylamine was used in place of methylamine in Example 61B, and N-propyl bromoacetamide was used in place of isobutyl in Example 61C. Chlorine, the crude product was purified by preparative HPLC (Vydac // C18) with a gradient of 10-70% CH3CN in 0.1% TFA. The desired fraction was lyophilized to produce the product as a white solid. 1H NMR (CDC13, 300 MHz) d 0 · 78 (t, 3H, J = 8Hz), 0.88 (t, 3H, J = 8Hz), 1.45 (m, 2H), 1.48 (m, 3H, J = 8Hz), 2.55-2.7 (m, 2H), 2.90 (m, 1H), 3.04 (m, 1H), 3.15 (m, 3H), 3.28 (t, 1H, J = 8Hz), 3.45 (t, 1H, J = 8Hz), 3.60 (m, 2H), 3.70 (d, 2H, J = 8Hz), 3.75 (m, 1H), 3.80 (s, 3H), 4.25 (d, 1H, J = 8Hz), 5.95 (s, 2H), 6.75 (d, 1H, J = 8Hz), 6.86 (dt, 1H, J = 1, 8Hz), 6.88 (d, 2H, J = 8Hz), 7.04 (d, 1H, J = lHz), 7.40 (d, 2H, J = 8Hz). MS (DCl / NH3) m / e 526 (M + H) +. Analysis Estimates C29H39N306 · 1.85 TFA: C, 53.32; H, 5.59; N, 5.70. Measured radon: C, 53.45; H, 5.62; N, 5.63. 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) Example 104 trans, trans_2_ (4-methoxyphenyl) _4- (l, 3-benzodi 5_5_yl) —- propyl-N-M-methoxyphenylcarbonyl) amino) ethyl IP Bimedoline-3-leptic acid The title compound was prepared as described in Example 61, but with propylamine instead The methylamine of Example 61B was replaced by 4-methoxyphenylchloroformate. The difference of Example 61C-180- This paper size applies the Chinese National Standard (CNS) M specification (210x297 mm) " " 581760 A7 B7 5 Description of the invention (178) Chlorobutyrate. The crude product was purified by trituration with 1: 1 diethyl ether-hexane. The resulting solid is dissolved in CHWN and water, and can be produced as a white solid by cold image drying. A mixture of 1111 ^^ (^^ 13,300 dishes 1 ^) geometric isomers (^ 〇88 (m, 3H), i.57 (m, 2H), 2.45 (br s), and 26 60 s total, 29 〇 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, total 1H), 5.95 (s) and 5% (s, total 2h), 6w (m, 1H), 6.72 (d, 1H, J = 8Hz), 6 81 (m 2H), 6% ㈨ 5h) 7.40 (m, 2H). MS (DChemH3) m / e 577 (M + H) +. Analytical estimates 〇32113 Office 〇 · ι · ο 1 ^ 0: c, M · 63; H, 6 M; N 4? 1. Measured C: C, 64.70; Η, 6.38; N, 4.63. Examples Liangli, trans-2- (4-methoxyphenyl benzoin ^ -benzodihum_5 · some vi- 丨 2 彳 n_ M-N · (4 · methoxybenzylethyl 1 Pyrrolidine was prepared in the same manner as in Example 61 except that propylamine was used in place of methylamine in Example 61B, and anisyl chloride was used in place of isobutylphosphonium chloride (Example 61 (:). The crude product was 1: 1 diethyl ether- It was purified by grinding with hexane. The resulting solid was dissolved in CHgCN and water, and the product was produced as a white solid by freeze-drying. Lfj NMR (CDC13, 300 MHz) Mixture of geometric isomers J 078 (m) and central standard of the Ministry of Economic Affairs Printed by the Bureau ’s Consumer Cooperative (please read the notes on the back before filling this page) 0.98 (t, J = 8Hz), a total of 3H, 1.47 (m) and 1.52 (q, J = 8Hz), a total of 2H, 2.25 (br s, 1H), 2.78 (br * s, 1H), 2.90 (br t, 2H), 3.12-3.68 (m, 7H), 3.80 (s, 3H), 3.82 (s, 3H), 5.94 (s , 2H), 6.75 (d, 1H, J = 8Hz), 6.83 (m, 5H), 6.94 (m, in) 7 22 (m, 4H). MS (FAB) m / e 561 (M + H) + Analyzed and estimated C32H36N2 07 · 0 75 h2 0: c, 66 94; H, 6.58; N, 4.88. Measured 値 ·· c, 67 0; H, 6 38; N, 4 59.! I ........ 181-The paper size is applicable to the Chinese National Standard (CNS) A4 size * 771 ^ -297g ^ 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 _______B7 V. Description of the invention (179 ) Example 106, trans (1,4-phenyl) ice (1,3_benzodimethyl 5jVl_r2_m_amino) ethyl 1 pyrrolidine-3-miao

The title compound was prepared in the same manner as in Example 61 except that propylamine was used in place of the methylamine of Example 61B and benzylfluorenyl chloride was used in place of the isobutylfluorenyl chloride of Example 61C. The crude product was purified by trituration with 1: 1 diethyl ether-hexane. The resulting solid was dissolved in CHgCN and water 'and freeze-dried to produce the product as a white solid. 1H NMR (CDC13, 300 MHz) geometric isomer mixtures J 〇65 and 〇9 (m, total 3H), 1.4 and 1.55 (m, total 2H), 2.05 and 2.15 (m, total 111), 2.6- 3.6 (m, 8H), 5.92 (s, 2H), 6.70 (d, 1H, J = 8Hz), 6.82 (m, 4H), 7.2-7.4 (m, 6H). MS (DC1 / NH3) m / e 531 (M + H) +. Analytical estimates C31H34N206 · 0.3 H2 0: C, 69 · 46; H, 6.51; N, 5.23. Found 値: C, 69.48; H, 6.19; N, 4.84. Example 107: Trans'H, methylbenzyl, I, benzene, diyin-5-, octyl-N-benzyloxycarboxamido) ethyl, p-pyridine, 3-boric acid Prepared by the method, but using propylamine instead of methylamine of Example 61B and benzyl chloroformate instead of isobutylphosphonium chloride of Example 61C. The crude product was purified by preparative HPLC (Vydac e C18) using 10-70% CHgCN in a 0.1% TFA gradient. The desired fraction is freeze-dried to give the product as a white solid. 4 NMR (CDC13, 300 MHz) 0.8 0.8, 3H), 1.45 (m, 2H), 2.20 (br m, 1Η), 2.75 (m, 1H), 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 = 8Hz), 6.82 -182- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) ________ »(Please read the precautions on the back before filling this page) Order 581760 A7 B7 5 Description of the invention (18) (m, 3H), 7.0 (br d, 1H, J = 15Hz), 7.2 (s, 4H), 7.30 (m, 3H). MS (FAB) m / e 561 (M + H) +. Analysis estimates C32H36N207 · 1.0 TFA: C, 60.53; H, 5.53; N, 4.15. Found 値: C, 60 · 66; H, 5.34; N, 4.28 〇 Example 1 0 8 trans, trans-2- (4 • methoxyphenyl) -4- (1,3-benzyl Saki-5-yl) -1_ [2- (N-propyl-N- (4-methoxyfluorenyloxycarbonyl) amino) ethyl 1 pyrrolidine-3-carboxylic acid The title compound was prepared according to the method in Example 61 Replace the methylamine of Example 61B with propylamine, and replace the isobutylphosphonium chloride of Example 61c with 4-methoxybenzyl chloroformate. Example 109 trans, trans-2- (4-methoxyphenyl # difluoren-5-yl) -1 · 丨 2-fN-butyl-N-ethoxycarbonylamino) ethyl 1 pyrrolidine_ The 3-carboxylic acid title compound was prepared in the same manner as in Example 61 except that butylamine was used in place of methylamine in Example 61B and ethyl mutamate was used to replace the isobutyl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac " C18) and eluted with a gradient of 10-70% CHgCN in 0.1% TFA. The desired fraction is lyophilized to produce a white solid product. 1H NMR (CDC13, 300 MHz;) d 0.82 (t, 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) Order f 3H, J = 8Hz), 1.20 (m, 5H), 1.34 (m, 2H), 3.08 (m, 2H), 3.17 (m, 2H), 3.52 (m, 2H), 3.75 (m, 2H), 3.78 (s, 3H), 4.06 (q, 2H, J = 8Hz), 4.35 (br s, 1H), 5.94 (s, 2H), 6.76 (d, 1H, J = 8Hz), 6.92 (d, 2H, J = 8Hz), 7.03 (br s, 1H), 7.17 (br s, 1H), 7.7 (br s, 2H). 4MS (FAB) m / e 513 (M + H) +. Analytical estimates (: 281133207 · 0.5 TFA: C, 61.15; H, 6.46; N, 4.92. Measured 値: c, 60.99; H, 6.80; N, 4.93 ° -183- This paper standard applies to Chinese national standards (CNS) 8-4 specification (210X297 mm) 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ___ B7 V. Description of the invention (181) Example 110 Trans, trans-2- (4-methoxybenzyl) 4- (1,3-Benzodibenzo-5-yl VI- 丨 2-OSl · butyldi-N-propoxycarbonylamino) ethyl 1 pyrrolidine-3_carboxylic acid The title compound is shown in Example 6 It was prepared by the method of 1, but butylamine was used instead of methylamine of Example 61B, and propyl chloroformate was used instead of isobutylphosphonium chloride of Example 61C. The crude product was purified by trituration with 1: 1 diethyl ether-hexane. The resulting solid was dissolved in CHgCN And water, and freeze-dried to produce a white solid product. ΙΗ NMR (CDC13, 300 MHz) β 0.80 (br s, 1H), 0.85 (t, 3H, J = 8Hz), 0.92 9br s, 1H), 1.22 (m, 3H), 1.40 (m, 3H), 1.62 (br m, 1H), 2.15 (br s, 1H), 2.72 (m, 1H), 2.87 (m, 1H), 3.1-3.45 (m, 5H ), 3.55 (m, 1H), 3.64 (d, 1H, J = 8Hz), 3.79 (s, 3H), 3.88 (br s, 1H), 3.97 (br s, 1H), 5.95 (s, 2H), 6.73 (d, 1H, J = 8Hz), 6.85 (m, 3H, 7.0 (s, 1H), 7.30 (d, 2H, J = 8Hz). MS (FAB) m / e 527 (M + H). Analyzed and estimated c29H38N207 · 0.15 H20: C, 65.80; H, 7.29; N, 5.29. Measured 値 ·· C, 65 · 79 H, 7.30; N, 5.21. Example 111 trans, trans-2- (4-methoxyphenyl V4- (l, 3 · benzodifluorenyl-5-ylperoxy-s-propoxycarbonylamino) ) The title compound of ethyl 1-pyrrolidin-3-carboxylic acid was prepared according to the method of Example 6i, but propylamine was used instead of methylamine of Example 61B, and propyl chloroformate was used instead of isobutylphosphonium chloride of Example 61. The crude product was prepared as 1 · · 1 diethyl ether-hexane trituration and purification. The resulting solid was dissolved in CHgCN and water and freeze-dried to produce a white solid product. IH NMR (CDC13, 300 MHz) d 080 (t, 3H, J = 8Hz), 0.93 (m , 3H), 1.43 (m, 3H), 1.62 (m, 1H), 2.15 (br s, 1H), 2.68-3.45 (m, 8H), ___ -184- This paper size applies to the Chinese National Standard (CNS) A4 Specifications (210X297 mm) (Please read the precautions on the back before filling this page)

, 1T 581760 A7 B7 V. Description of the invention (182) 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 = 8Hz), 6.82 (m, 1H), 6.84 (d, 2H, J = 8Hz), 7.00 (br s, 1H), 7.33 (m, 2H). MS (DC1 / NH3) m / e 513 (M + H) +. Analytical estimates of C28H36N207 · 015 h20: c, 65.26; H, 7.10; N, 5.44. Found 値: c, 65.22; H, 6.74; N, 5.06. Example l α-bundle, trans-n-butylcarbonyl) methyl_24_bis (13-benzene-5_5-yl selenium _3_ retetraic acid (3,4-methylenedioxybenzidine Ethyl) ethyl acetate, prepared by the method of amidine (: 11 () with & 1 ·, Org · Syn. 42, 20 (I967), starting from 3, 'methylenedioxyacetophenone instead of 4 -Methoxyacetophenone, reacted according to the method of Example j to give the title compound 'as a white solid. Mp 58-60 ° C. 4 NMR (; CDC13, 300 MHz) d 0.87 (five peaks, j = 6Hz, 6H) , 1.12 (Liu Ling, J = 6Hz, 2H), 1.24-1.51 (m, 6H), 2.80 (d, J = 13Hz, 1Η), 2.94-3.12 (m, 4H), 3.28-3.50 (m, 4H) , 3.58-3.62 (m, 1H), 3.78 (d, J = 9Hz, 1H), 5.95 (s, 4H), 6.73 (dd, J = 8Hz, 3Hz, 2H), 6.84-6.89 (m, 2H), 6.92 (d, J = lHz, 1H), 7.01 (d, Η = 1Ηζ, 1H). MS (DC1 / NH3) m / e 525 (M + H) +. Example 113 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling this page) trans, trans-1-QSK n-butylpropylsulfonamido) ethyl_2 彳 4_methoxyphenyl) _4- (1, 3_ Benzobifluoren-5-yl) pyrrolidine-3-leptoic acid utilization The procedure of Example 66, the title compound was prepared as a white solid of the title compound m.p. 64-65 ° C. 4 NMR (CDC13, 300 MHz) d 0.83 (t, J = 7Hz, 3H), 0.98 (t, J = 7Hz, 3H), 1.12-1.25 (m, 2H), -185- This paper size applies to Chinese national standards (CNS) A4 specification (210 X 297 mm) 581760 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 __ B7 _ V. Description of the invention (183) l. 32-1.41 (m, 2H), 1.75 (six Peak, J = 7Hz, 2H), 2.23-2.31 (m, 2H), 2.72-3.32 (m, 8H), 3.43 (dd, J = 9Hz, 3Hz, 1H), 3.53-3.59 (m, 1H), 3.65 (d, J = 9Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J = 8Hz, 1H), 6.83 (dd, J = 8Hz, 1Hz, 1H ), 6.88 (d, J = 9Hz, 2H), 7.02 (d, J = 1Hz, 1H), 7.33 (d, J = 9Hz, 2H). MS (DC1 / NH3) m / e 547 (M + H) +. Example 114 trans, trans-1- (N, N-di (n-butyl) aminocarbonylmethyl) -2- (4-methoxyphenyl) -4- (1,3-benzodifluorene- 5-yl) pyrrolidine-3-carboxylic acid Following the procedure of Examples 28 and 43, the title compound was prepared as a white solid. m. p. 74-76Ό. 4 NMR (CDC13, 300 MHz) d 0.80 (t, J = 6Hz, 3H), 0.88 (t, J = 8Hz, 3H), 1.08 (six peak, J = 8Hz, 2H), 1.21-1.48 (m , 6H), 2.75 (d, J = 12Hz, 1H), 2.95-3.09 (m, 4H), 3.26-3.59 (m, 5H), 3.75 (d, J = 9Hz, 1H), 3.79 (s, 3H) , 4.28 (s, 4H), 6.78 (d, J = 9Hz, 1H), 6.85 (d, J = 9Hz, 2H), 6.91 (d, d, J = 3Hz, 9Hz, 1H), 6.98 (d, J = 3Hz, 1H), 7.32 (d, J = 9Hz, 2H). MS (DCi / NH3) m / e 525 (M + H) +. Example 115 trans'trans-1- (2- (N-propyl-N-propylcontinuous amino) ethyl) -2- (4-methoxyphenyl) -4 · (1,3- Benzobifluoren-5-yl) pyrrolidin-3-carboxylic acid The procedure of Example 66 was used to prepare the title compound as a white solid. mp 72-73〇C 〇XH NMR (CDC13? 300 MHz) ^ 0.79 (t? J = 8Hz? 3H), 0.98 (t, J = 8Hz, 3H), 1.43 (six peak, J = 8Hz, 2H), 1.75 (six peaks, J = 8Hz, 2H), 2.22-2.32 (m, 1H), 2.69-3.32 (m, 9H), 3.42 (dd, -186-) This paper size applies to China National Standard (CNS) A4 specifications ( 210X297 mm) (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 581760 A7 B7 _ _ V. Description of the invention (184) J = 3Hz, 12Hz, 1H), 3.52- 3.58 (m, 1H), 3.64 (d, J = 12Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J = llHz, 1H), 6.83 (dd, J = lHz , 11Hz, 1H), 6.87 (d, J = 11Hz, 2H), 7.0 (d, J = 2Hz, 1H), 7.32 (d, J = llHz, 2H). MS (DC1 / NH3) m / e 533 (M + H) + 0 Example 116 trans'trans-l- (2- (N-butyl-N-butylamino) ethyl) -2- ( 4-Methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) pyrrolidine-3-carboxylic acid The method of Example 66 was used to prepare the title compound as a white solid. mp 62-63 〇C 0 4 NMR (CDC13, 300 MHz) d 0.82 (t, J = 6Hz, 3H), 0.91 (t, J = 6Hz, 3H), 1.20 (six peak, J = 6Hz , 2H), 1.33-1.42 (m, 4H), 1.68 (five peaks, J = 6Hz, 3H), 2.23-2.32 (m, 1H), 2.70-3.28 (m, 9H), 3.41 (d, J = 8Hz, 1H), 3.52-3.58 (m, 1H), 3.65 (d, J = 8Hz, 1H), 3.79 (s, 3H), 5.95 (s, 2H), 6.72 (d, J = 8Hz, 1H), 6.82 ( d, J = 8Hz, 1H), 6.87 (d, J = 8Hz, 2H), 7.01 (s, 1H), 7.32 (d, J = 8Hz, 2H). MS (DCl / NH3) m / e 561 (M + H) +. Example 117 Well-formed, trans-: ί- (2_ (N, N-dibutylaminecarbonylmethyl) -2- (4 · methylhydrogen a certain phenyl group) _4_ (1,3 · benzodifluorene Group) pyrrolidine-3-carboxylic acid 4-treated with acetophenone with chloromethyl methyl ether and triethylamine at thf at room temperature to give 4-methoxymethoxybenzylacetate ethyl acetate, which The title compound was obtained as a white solid by the procedures of Example 1. mp 48-49 ° C. 4 NMR (CDC13? 300 MHz) d 0.81 (t? J = 7Hz? 3H)? 0.88 (t? J = 7Hz, 3H ), 1.06 (six peaks, J = 7Hz, 2H), 1.20-1.35 (m, 4H), 1.44 (five peaks, J = 7Hz, 2H), 2.75 (d, J: 12Hz, 1H), 2.94-3.10 (m, 4H), -187- The paper size is suitable for Noodles County (CNS) A4 size (210X297 mm) " '---------- ^ 衣-(Please read the (Please fill in this page again)

, 1T-Toad-Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Description of the invention (185) 3.25-3.35 (m, 1H), 3.40 (d, J = 12HZ, 1H), 3.43-3.52 (m , 2H), 3.47 (s, 3Η), 3.55 · 3 · 62 (m, 1Η), 3.77 (d, J = 9Hz, 1Η), 5.15 (s, 2H), 5.94 (m, 2H) , 6.73 (d, J = 8Hz, 1H), 6.86 (dd, J = lHz, 8Hz, 1H), 7.0 (d, J = 8Hz, 2H), 7.04 (d, J = lHz, 1H), 7.32 (d , J = 8Hz, 2H). MS (DCi / NH3) m / e 541 (M + H), Example 118 trans, trans-dibutylaminocarbonylmethyl) -2- (4-and phenyl) -4- (1,3-benzo Difluoren-5-yl) pyrrolidin-3-carboxylate stem 1 Example 116 The compound was treated with concentrated HC1 in 1: 1 THF-isopropanol to give the title compound as a white solid, mp 211-212 ° C. 4 NMR (CD3OD, 300 MHz) d0.90 (t, J = 8Hz, 6H), 1.12-1.27 (m, 6H), 1.36-1.45 (m, 2H), 3.04 (bs, 1Η), 3.14-3.35 ( t, J = 9Hz, 1H), 3.90 (bs, 3H), 4.17 (d, J = 15Hz, 1H), 5.96 (s, 2H), 6.82-6 · 93 (m, 4H) , 7.03 (d, J = 1 Hz, 1H), 7.42 (bs, 2H), MS (DC1 / NH3) m / e 497 (M + H) +. Example 119 trans, trans-iso-butyl-N-propylsulfonamido) ethylmethoxyphenyl) -4- (1,3-benzobisfluoren-5-yl) pyrrolidine-3-carboxyl Acid Using the procedure of Example 66, the title compound was prepared as a white solid. m.p. 73-74 ° C. 4 NMR (CDC13, 300 MHz) d 0.80 (d, J = 6Hz, 6H), 0.98 (t, J = 8Hz, 3H), 1.62 (six peak, J = 6Hz, 1H), 1.74 (six peak, J = 8Hz, 2H), 2.23-2.34 (m, 1H), 2.68-2.98 (m, 7U), 3.08-3.18 (m, 1H), 3.26-3.42 (m, 2H), 3.52-3.58 (m, 1H ), 3.65 (d, J = 9Hz, 1H), 3.80 (s, 3H), 5.90 (s, 2H), 6.74 (d, J = 8Hz, -188- This paper size applies to China National Standard (CNS) A4 specifications (210X297 Gongchu) (Please read the precautions on the back before filling this page) Clothing · Order 581760 A7 B7 V. Description of the invention (186) 1H), 6.82 (d, J = 8Hz, 1H), 6.86 (d, J = 8Hz, 2H), 6.98 (d, J = lHz, 1H), 7.33 (d, J = 8Hz, 2H). MS (DC1 / NH3) m / e 547 (M + H) +. Example 120 trans, trans benzenesulfonyl-N · propylamino) ethyl) -2- (4-methoxybenzyl) -4- (1,3-benzodi 4-5-yl) p ratio Hardian-3. Metabolic acid The procedure of Example 66 was used to prepare the title compound as a white solid. m.p. 89-91Ό. 4 NMR (CDC13, 300 MHz) d 0 · 74 (t, J = 6Hz, 3Η), 1.33 (six axe,] = 61 ^, 211), 2.20-2.30 〇, 111), 2.62-2.72 (m , 1H), 2.85-3.05 (m, 4H), 3.12_3.22 (m, 1H), 3.38 (dd, J = 3Hz, 9Hz, 1H), 3.49-3.57 (m, 1H), 3.62 ( d, J = 9Hz, 1H), 3.82 (s, 3H), 5.96 (s, 2H), 6.73 (d, J = 8Hz, 1H), 6.84 (dd, J = lHz, 8Hz, 1H), 6.85 (d , J = 9Hz, 2H), 7.02 (d, J = lHz, 1H), 7.28 (d, J = 9Hz, 2H), 7.39-7.54 (m, 3H), 7.70 (d, J = 7Hz, 2H). MS (DC1 / NH3) m / e 567 (M + H) +. Example 121 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) trans, trans-l- (2- (N- (4 -methoxybenzone continuous brewing base) — N-propylamino) ethyl) -2- (4-methoxyphenyl) -4- (1,3-benzodiazine-5-yl) bamboo 1: pyridin-3- # acid utilization example 6 6 In step, the title compound was prepared as a white solid. m.p. 96_97 ° C. 4 NMR (CDC13, 300 MHz) d 0_73 (t, J = 7Hz, 3H), 1.34 (six peak, J = 7Hz, 2H), 2.20-2.30 (m, 1H), 2.62-2.71 (m, 1H), 2.82-3.03 (m, 4H), 3.08-3.18 (m, 2H), 3.38 (dd, J = 3Hz, 9Hz, 1H), 3.48-3.56 (m, 1H), 3.62 (d, J = 9Hz, 1H), 3.81 (s, 3H), 3.86 (s, 3H), 5.95 (s, 2H), 6.73 (d, J = 8Hz, 1H), 6.81 · 6.89 (m, 5H), 7.01 (d, J = lHz, 1H), 7.28 (d, J = 8Hz, 2H), 7.62 -189- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (187) ( d, J = 8Hz, 2H). MS (DC1 / NH3) m / e 597 (M + H). Example 122 Condensate, trans-1-OSLN-bis (n-butyl) aminocarbonylmethyl) -2- (2-methoxy-2-methoxy-4-methoxyphenyl) -4- (1,3- Benzobifluoren-5-yl) pyrrolidine_ 2-hydroxy-5-methoxyacetophenone is treated with sodium hydride and bromoethyl methyl ether in THF at 70 ° C to produce 2-methyl Ethoxyethoxy-4-methoxyfluorenylacetate. m.p. 63_65 ° C. 4 NMR (CDC13, 300 MHz) d 0.84 (t, J = 7Hz, 3H), 0.89 (t, J = 7Hz, 3H), 1.16 (six peak, J = 7Hz, 2H), 1.28 (six peak, J = 7Hz, 2H), 1.45-1.52 (m, 4H), 2.87-2.94 (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, 1H), 4.02-4.10 (m, 2H), 4.25 (d, J = 9Hz , 1H), 5.92 (s, 2H), 6.40 (d, J = 2Hz, 1H), 6.52 (dd, J = 2Hz, 9Hz, 1H), 6.70 (d, J = 8Hz, 1H), 6.83 (dd, J = lHz, 8Hz, 1H), 5.98 (d, J = 2Hz, 1H), 7.53 (d, J = 9Hz, 1H) 〇MS (DC1 / NH3) m / e 585 (M + H) + 〇 Example 123 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-1_ (2- (N-propyl-N- (2,4-dimethylamine Phenylbenzenesulfonyl) amino) ethylmethoxybenzyl) _4- (1,3-benzodihum-5-yl) pyrrolidine-3-carboxylic acid can be prepared using the method of Example 66 The title compound as a white solid, mp 88-90 ° C. 4 NMR (CDC13, 300 MHz) d 0.69 (t, J = 7Hz, 3H), 1.32 (six peak, J = 7Hz, 2H), 2.12-2.20 (m, 1H), 2.32 (s, 3H), 2.47 ( s, 3H), 2.62-2.69 (m, 1H), 2.78 (t, J = 9Hz, 1H), 2.89 (dd, J = 8Hz, 1H), 3.02 (six peaks, J = 9Hz, 2H), 3.15- 3.32 (m, 3H), 3.46 · 3 · 55 (m, 1H), 3.60 (d, J = 9Hz, 1H), 3.82 (s, 3H), -190-This paper size applies to Chinese National Standards (CNS ) A4 specification (210X 297 mm) 581760 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (188) 5.96 (s, 2H), 6.72 (d, J = 7Hz, 1H), 6.80 (dd , J = lHz, 9Hz, 1H), 6.86 (d, J = 9Hz, 2H), 6.97 (d, J = lHz, 1H), 7.03 (bs, 2H), 7.29 (d, J = 9Hz, 1H ). MS (DCl / NH3) m / e 595 (M + H) +. Example 124 trans'trans-propyl-N- (3-chloropropylcontinuous) amino) ethyl 2- (4-methyllactyl) -4- (1,3-benzodizaki (-5-yl) p-biloline-3-facial acid Using the procedure in Example 66, the title compound was prepared as a white solid, mp 75-76 ° C. 4 NMR (CDC13, 300 MHz) d 0.80 (t, J = 7Hz, 3H), 1.45 (six peaks, > 7112,211), 2.15-2.31〇, 311), 2.70-2.80〇, 1H), 2.85- 3.10 (m, 6H), 3.23 · 3 · 31 (m, 2H), 3.43 (bd, J = 9Hz, 1H), 3.55-3.66 (m, 4H), 3.81 (s, 3H), 5.94 (s, 2H), 6.73 (d, J = 8Hz, 1H), 6.82 (d, J = 8Hz, 1H), 6.86 (d, J = 8Hz, 2H), 7.00 (s, 1H), 7.33 (d, J = 8Hz, 2H). MS (DCl / NH3) m / e 567 (M + H) + 〇 Example 125 trans, trans-propyl-N- (2-methoxyethylsulfonyl) amino) ethylmethylphenyl ) -4 · (1,3 · Benzodifluoren-5-yl) pyrrolidine-3-carboxylic acid Using the procedure of Example 66, trans, trans-1- (2- (N-propyl) -N- (vinylsulfonamido) amino) ethyl-2- (4-methoxyphenyl) · 4 · (1,3 · benzodiain_5-yl) ρ / pyridine-3- Re-acid. Ester hydrolysis of steel hydroxide in an aqueous methanol solution yields the title compound as a white solid. Mp 62-64 ° C. 4 NMR (CDC13, 300 MHz) (ί 0.78 (t, J = 7 Hz, 3H ), 1.42 (six peak, j = 7Hz, 2H), 2.23-2.32 (m, 1H), 2.72-2.79 (m, 1H), 2.86-3.05 (m, 4H), 3.10-3.27 (m, 4H), 3.32 (s, 3H), 3.43 (dd, -191-This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back before filling in this page))-581760 A7 B7 V. Description of the invention (189) J = 3Hz, 9Hz, 1H), 3.53-3.58 (m, 1H), 3.65 (d, J = 9Hz, 1H), 3.69 (t, J = 6Hz, 2H), 3.80 (s, 3H), 5.94 (s, 2H), 6.73 (d, J = 8Hz, 1H) 6.82 (dd, J = lHz, 8Hz, 1H), 6.87 (d, J = 8Hz, 2H), 7.02 (d, J = lHz, 1H), 7.33 (d, J = 8Hz, 2H). MS (DC1 / NH3) m / e 549 (M + H) +. Example 126 trans, trans-1- (2- (N · propyl-N- (2-ethoxyethylsulfonyl) amino) ethyl ) -2- (4-methoxyphenyl) -4- (1,3-benzodihum-5-yl) pyrrolidin-3-carboxylic acid According to the procedure of Example 66, the title can be prepared as a white solid Compound, mp 58-60 ° C 〇! H NMR (CDC13? 300 MHz) d 0.78 (t? J = 7Hz? 3H), 1.18 (t, J = 7Hz, 3H), 1.43 (six peak, J = 7Hz, 2H), 2.24-2.33 (m, 1H), 2.70-2.80 (m, 1H), 2.87-3.05 (m, 4H), 3.13-3.20 (m, 2H), 3.22-3.32 (m, 2H), 3.42 ( dd, J = 2Hz, 9Hz, 1H), 3.46 (q, J = 7Hz, 2H), 3.52-3.58 (m, 1H), 3.65 (d, J = 9Hz, 1H), 3.72 (t, J = 6Hz, 2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J = 7Hz, 1H), 6.83 (dd, J = lHz, 7Hz, 1H), 6.87 (d, J = 8Hz , 2H), 7.00 (d, J = lHz, 1H), 7.32 (d, J = 8Hz, 2H). MS (DC1 / NH3) m / e 563 (M + H) + 〇 Example 127 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) trans, trans -l- (2- (N-propyl-N · (5-dimethylamino-1-benzenesulfonyl) amino) ethyl) -2- (4-methoxybenzyl) -4- (1,3 -Benzodifluoren-5-yl) pyrrolidine-3-carboxylic acid The procedure of Example 66 was used to prepare the title compound as a yellow solid, mp 102-104 ° C. 4 NMR (CDC13, 300 ΜΗζ) Θ 0.62 (t, J = 7Hz, 3H), 1.28 (six peak, J = 7Hz, 2H), 2.12-2.20 (m, 1H), 2.78 -192- Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (19) (t, J = 9Hz, 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 = 9Hz, 1H), 6.97 (d, J = llHz, 1H ), 7.13 (d, J = 7Hz, 1H), 7.26 (d, J = 8Hz, 1H), 7.42-7.50 (m, 2H), 8.08 (dd, J = lHz, 7Hz, 1H), 8.20 (d, J = 8Hz, 1H), 8.48 (d, J = 8Hz, 1H). MS (DC1 / NH3) m / e 660 (M + H) +. Example 128 trans 9 trans-1 propyl-N- (ethylammonium) amino) ethyl) · 2- (4 · methoxyphenylbenzodiazin-5-yl) pyrrolidine-3 -Carboxylic acid Using the procedure of Example 66, the title compound was prepared as a white solid, mp 70-72 ° C. 4 NMR (CDC13, 300 MHz) d 0.79 (t, J = 8Hz, 3H), 1.28 (t, J = 7Hz, 3H), 1.43 (q, J = 8Hz, 2H), 2.22-2.30 (m, 1H) , 2.71-2.80 (m, 1H), 2.82-3.10 (m, 6H), 3.18_3 · 32 (m, 2H), 3.43 (dd, J = 3Hz, 9Hz, 1H), 3.53 · 3 · 60 ( m, 1H), 3.65 (d, J = 9Hz, 1H), 3.80 (s, 3H), 5.96 (s, 2H), 6.73 (d, J = 7Hz, 1H), 6.82 (dd, J = lHz, 7Hz , 1H), 6.88 (d, J = 8Hz, 2H), 7.00 (d, J = lHz, 1H), 7.32 (d, J = 8Hz, 2H). MS (DC1 / NH3) m / e 519 (M + H) +. Example 129 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-1-propyl_N_ (4-synyl methyl this continuation base) amino group) B 2- (4-methoxymolybdenum V4- (l, 3-benzodifluoren-5-yl) pyrrolidin-3-carboxylic acid Using the procedure of Example 66, the title compound can be prepared as a white solid, mp 78- 79〇C NMR (CDC13? 300 MHz) d 0.73 (t, J = 7Hz? 3H), 1.33 (six peak, j = 7Hz, 2H), 2.20-2.30 (m, 1H), 2.40 (s, 3H) ， -193- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 581760 A7 B7___ V. Description of the invention (191) 2.61-2.72 (m, 1H), 2.83-3.05 (m, 4H), 3.08-3.19 (m, 2H), 3.48 (dd, J = 3Hz, 9Hz, 1H), 3.49-3.57 (m, 1H), 3.62 (d, J = 9Hz, 1Η), 3.81 (s, 3H), 5.95 (s, 2H), 6.73 (d, J = 8Hz, 1H), 6.82 (d, J = 8Hz, 1H), 6.87 (d, J = 8Hz, 2H), 7.00 (s, 1H), 7.21 (d, J = 8Hz, 2H), 7.29 (d, J = 8Hz, 2H), 7.57 (d, J = 8Hz, 2H) o MS (DC1 / NH3) m / e 581 (M + H) + 0 Example 130 trans , Trans-1- (N, N-di (n-butyl) aminocarbonyl Pyridyl) -4- (1,3-benzobisfluoren-5-yl) pyrrolidin-3-carboxylic acid was prepared by the method of Wenkert, et al., J. Org. Chem. 48: 5006 (1983) Methylnicotinyl acetic acid acetate and treated as in Example 1 to give the title compound as a white solid. Mp 167-168 ° C. 4 NMR (CDC13, 300 MHz) d 0.82 (t, J-7Hz, 3H ), 0.89 (t, J = 7Hz, 3H), 114 (six peaks, up = 7112,211), 1.23-1.48 (111,611), 2.86-3.20 (111,611), 3.34 · 3.43 (m, 2H ), 3.57 (dd, J = 3Hz, 9Hz, 1H), 3.75-3.83 (m, 1Η), 4.08 (d, J = 9Hz, 1H), 5.93 (s, 2H), 6.73 (d, J = 8Hz, 1H), 6.90 (dd, J = 2Hz, 8Hz, 1H), 7.03 (d, J = 2Hz, 1H), 7_38 (dd, J = 4Hz, 8Hz, 1H), 8.04 (d, J = 8Hz, 1H), 8.48 (dd, J = 2Hz, 4Hz, 2H). MS (DC1 / NH3) m / e 482 (M + H) +. 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) Example 131 trans, trans-propyl_N- (n-butylsulfonyl) amino) ethyl)- 2- (4 -Methoxyphenyl) _4_ (1,3_benzodioxo-5_yl) p-bilodine_3 · • Acid acid Using the procedure of Example 66, the title compound was made into a white solid, mp 65-66 ° C. NMR (CDC13, 300 MHz) 0.78 (t, J = 7Hz, 3H), -194- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (192) 0.92 ( t, J = 7Hz, 3H), 1.31 · 1 · 46 (m, 4H), 1.68 (Five Peaks, J = 7Hz, 2H), 2.21-2.32 (m, 1H), 2.70-3.08 (m, 7H) , 3.12-3.23 (m, 2H), 3.42 (dd, J = 2Hz, 9Hz, 1H), 3.52-3.58 (m, 1H), 3.64 (d, J = 9Hz, 1H), 3.80 (s, 3H ), 5.96 (s, 2H), 6.72 (d, J = 7Hz, 1H), 6.83 (dd, J = lHz, 7Hz, 1H), 6.86 (d, J = 8Hz, 2H), 7.00 (d, J = lHz, 1H), 7.32 (d, J = 8Hz, 2H). MS (DC1 / NH3) m / e 547 (M + H) +. Example 132 trans, trans-l- (2- (N-propyl-N- (4-chlorobenzenesulfonyl) amino) ethyl) -2- (4-methoxyphenyl) -4- (1,3 • Benzodifluoren-5-yl) pyrrolidine-3-carboxylic acid. Using the procedure in Example 66, the title compound was prepared as a white solid, mp 105-106 ° C. 4 NMR (CDC13, 300 MHz) β 072 (t, J = 7Hz, 3H), 1.34 (six peak, J = 7Hzm 2H), 2.56-2.62 (m, 1H), 2.78-2.86 (m, 1H), 2.96 _3.03 (m, 3H), 3.13-3.26 (m, 3H), 3.51 (dd, J = 5Hz, 9Hz, 1H), 3.62_3 · 68 (m, 1H), 3.80 (s, 3H), 3.94 (d, J = 9Hz, 1H), 5.92 (s, 2H), 6.75 (d, J = 8Hz, 1H), 6.84 (d, J = 2Hz, 8Hz, 1H), 6.94 (d, J = 8Hz, 2H ), 6.98 (d, J = 2Hz, 1H), 7.36 (d, J = 8Hz, 1H), 7.49 (d, J = 8Hz, 1H), 7.68 (d, J = 8Hz, 1H). MS (DC1 / NH3) m / e 601 (M + H) +. Example 133 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) trans, trans-propyl_N_ (benzylsulfonyl) amino) ethylmethoxyphenyl V4- (l, 3-benzobisazin-5-yl) pyrrolidine_3_carboxylic acid The procedure of Example 66 was used to prepare the target compound as a white solid, mp 88-89 ° C. 4 NMR (CDC13, 300 MHz) d 0.72 (t, J = 7Hz, 3H), 1.32 (six peak, J = 7Hz, 2H), 2.06-2.16 (m, m), 2.56- -195- paper Standards are applicable to Chinese National Standards (CNS) A4 (210X 297 mm). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy. , 3.30 (dd, J = 2Hz, 9Hz, 1H), 5.95 (s, 2H), 6.73 (d, J = 7Hz, 1H), 6.80 (dd, J = lHz, 7Hz, 1H), 6.86 (d, J = 8Hz, 2H), 6.97 (d, J = lHz, 1H), 7.27-7.35 (m, 7H). MS (DCl / NH3) m / e 581 (M + H) +. —Example 134 trans, trans-propyl-N- (4-fluorobenzylsulfonyl) amino) ethyl V2- (4-methoxyphenylbenzodifluoren-5-yl) pyrrolidine-3- Carboxylic acid Using the procedure of Example 66, the title compound was prepared as a white solid, mp 91-93 ° C. 'Η NMR (CDC13, 300 ΜΗζ) β 0.73 (t, J = 7Hz, 3H), 1.44 (A ,, J = 7Hz, 2H), 2.18_2.27 (m, lH), 2.56- 2.67 (m, 1H ), 2.78-2.87 (m, 2H), 2.97 (six peaks, J = 8Hz, 2H),

3.11-3.16 (m, 2H), 3.33 (dd, J = 2Hz, 9Hz, 1H), 3.43-3.50 (m, 1H), 3.57 (d, J = 9Hz, 1H), 3.78 (s, 3H) , 7.08 (t, J = 8Hz, 2H), 7.24 (d, J = 8Hz, 2H), 7.69 (dd, J = 5Hz, 8Hz, 2H). MS (DCl / NH3) m / e 5 85 (M + H) + 0 Example 135 trans, trans methyl-N-propylaminocarbonylmethyl V2- (4-methoxyphenylbenzofuranyl V Bipyridine-3-carboxylic acid example 135A Mopanil-4 leptate versus 60% sodium hydride in mineral oil (4.00 g, 100 mmol, 1.25 equivalents) DMF (60 ml) at 0 ° C To the suspension was added a solution of 3-bromophenol (13.8 g, 80 mmol) in DMF (5 ml). After 10 minutes, diethanol bromoacetaldehyde (14.9 ml, 96.6 mmol) was added. , 1.24 equivalents), and -196- This paper size applies to Chinese National Standards (CNS) A4 specifications (210X297 mm) (Please read the precautions on the back before filling this page)-Order IP- · 581760 A7 B7 V. Invention Explanation (194) The resulting mixture was heated at 120 ° C for 2.5 hours. The mixture was cooled to room temperature and poured into water, and extracted once more with ether. The organic solution was dried over Mgs04, filtered, evaporated and distilled under air to produce Colorless liquid (彳! G, 74%), mp 160-163 ° C, under 0.4 mm Hg. To a solution of benzene (50 ml) was added the above compound (171 g, 59 3 mol) in warm polyphosphoric acid (15.3 g). The resulting mixture was heated 'under reflux and stirred vigorously for 4 hours, after which the benzene layer was carefully decanted and the lower layer was washed once with hexane. The mixed organic solution was concentrated under vacuum, and then vacuum-distilled to a color manipulation liquid (8.13 g, 70%). b.p. 62-72Ό under 0.6 mmHg. To the above compound (8.11 g, 4.15 mmol) in a solution of ether (80 ml) in 78 C, ι · 7 n-butyllithium (48 8 ml, 83 mmol, 2 equivalents) , So the temperature does not exceed-^^^. After stirring for 15 minutes, a solution of DMF (6.5 ml, 83 mmol, 2 eq) in ether (20 ml) was added, and the mixture was warmed to room temperature for 2 hours. The mixture was poured into water and the phases were separated. The organic solution was dried over MgS04 and concentrated under air. The residue was purified on silica gel by flash chromatography and dissolved in hexane at 10% ether to form benzofuran-6-carboxaldehyde (1.22 g) and benzofuran carboxaldehyde (1.86 g), both of which were Colorless oil.

Example 135B Good. Formula 'trans-1- (N-methyl-N · propylamine, a carbonyl methylmethoxyphenyl) -4- (4.benzobenzoyl) p-bilodium · 3_ ^ The title compound was prepared using the methods of Examples 1 and 49, and the compound of Example 135A was used in place of the piperonic acid of Example 49. ijj NMR (300-197- This paper size applies to Chinese National Standards (CNS) A4 specifications (2KK) x297 public envy) (Please read the precautions on the back before filling out this page}-Order the staff of the Central Bureau of Standards of the Ministry of Economic Affairs Printed by the cooperative 581760 A7 B7 V. Description of the invention (195) MHz, CDC13) (secondary geometric isomer) d 7.59 (1H, t, J = 3Hz), 7 · 4 · 7 · 2 (6H, m) , 6.8 (2H, d, J = 8Hz), 4.03 (1H, m), 3.94 (1H, dd, J = 8Hz, 3Hz), 3.77 (3H, s), 3.61 (1H, dd, J = 8Hz , 7 3Hz), 3.42 (1H, dd, J = llHz, 5Hz), 3.40-2.90 (5H, m), 2.82 (2.81) (3H, s), 1.50 (2H, six peaks, j = 7Hz), 0.82 (0 · 75) (3 °, t, J = 7 Hz). MS (DC1 / NH3) m / e 451 (M + H) +. Analysis estimates c26H30N2O5 · AcOH: C, 65.87; H, 6.71; N, 5.49. Measured 値: C, 66 04; H, 6.42; N? 5.60-Example 136 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) trans, trans -1- ( N-methyl-N-propylamine carbonylmethyl) · 2-Γ4-methylargon HV 4- (6-benzocreanyl) said Luodian-3-carboxylic acid The title compound was prepared by the methods of Examples 1 and 49. In Example 13 5 A, the benzoic acid-6 · metanoic acid was used in place of the pepper salt in Example 49A. 1H NMR (300 MHz, CDC13) (minor geometric isomer) β 7 · 65 (1Η, bd), 7.60 (1Η, d, J = 2Hz), 7.55 (1H, d, J = 8Hz) , 7.35 (3H, m), 6.85 (2H, dd, J = 8Hz, 3Hz), 6.75 (1H, dd, J = 3Hz, 2Hz), 3.83 (2H, m), 3.79 (3H , S), 3.60-3.0 (7H, m), 2.91 (2.83) (s, 3H), 1.51 (2H, six peaks, J = 7Hz), 0.83 (0.78) (3H, t, J = 7Hz). MS (DC1 / NH3) m / e 451 (M + H) +. Analysis estimates C26H30N2O5 · 0.5 H20: C, 67.96; H, 6.80; N, 6.10. Found 値: C, 67.90; H, 6.71; N, 6.07. Example 137 trans, trans-a-N-propylaminocarbonylmethylmethoxyphenyl) -4- (6-benzo_2.3_dihydrocylanyl) p-bilodine-3_lean acid The compound was prepared by catalytic hydrogenation of Example 136 compound (private -198-) This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) " 581760 A7 B7 V. Description of the invention (196) 4 atmospheres, In AcOH followed by preparative hplc). 4 NMR (300 MHz, CDC13) (minor geometric isomer) π 7 · 49 (7 · 47) (2H, d, J = 8Hz), 7.19 (1H, d, J = 8Hz), 7.00 (1H , M), 7.82 (3H, m), 5.40 (1H, dd, J = llHz, 7Hz), 4.58 (2H, t, J = 8Hz), 4.18 (1H, m), 4.10 ( 1H, m), 3.88 (1H, m), 3.79 (3H, s), 3.60 (1H, m), 3.35 (1H, m), 3.19 (2H, t, J = 8Hz), 3.00 (4H, m), 2.91 (2.78) (s, 3H), 1.53 (1.40) (2H, six peaks, J = 7Hz), 0.88 (0.78) (3H, t, J = 7Hz). MS (DC1 / NH3) m / e 453 (M + H) +. Analysis estimates C26H32N205.1.25 TFA: C, 57.53; H, 5.63; N, 4.71. Found 値: C, 57.68; H, 5.68; N, 4.70. Example 138 trans, trans · 1- (N, N-dibutylaminecarbonylmethyl V2-M-methoxyphenyl) -4- (4-benzocreanyl) pyrrolidine-3 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) The title compound was prepared by the methods of Examples 1 and 49, but using benzofuran-4-carboxyfluorene instead of piperonal, and N, N-dibutylbromoacetamide replaces N-methyl-N-propylbromoacetamide. 1H NMR (300 MHz, CDC13) d 7.62 (1H, d, J = 3Hz), 7.39 (1H, dt, J = 8Hz, 2Hz), 7.34 (3H, m), 7.26 (1H, d, J = 2Hz) , 7.23 (1H, d, J = 8Hz), 6.84 (2H, d, J = 8Hz), 4.02 (1H, ddd, J = 8, 6Hz, 4Hz), 3.89 (1H, d, J = 9Hz) , 3.79 (3H, s), 3.67 (1H, dd, J = 10Hz, 3Hz), 3.44 (2H, m), 3.35-3.15 (3H, m), 3.00 (2H, m), 2.84 ( 1H, d, J = 14Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J = 7Hz), 0.82 (3H, t, J = 7Hz ). MS (DCi / NH3) m / e 507 (M + H) +. Analysis estimates C30H38N2O5: C, 71.12; H, 7.56; N, 5.53. Found 値: C, 70.86; H, 7.45; N, 5.24. -199- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 581760 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 ____ B7 V. Description of the Invention (197) Example 139 I type, trans type-1 -(N, N-dibutylaminecarbonylmethyl) _2- (4 · methoxymonon V4-M-benzofuran) pyrrolidine-3-carboxylic acid The title compound was prepared according to the methods of Examples 1 and 49, but The benzocrean-5 · leic acid prepared by the method of Example 1 3 5 A was used to replace the piperonic acid of Example 4 9 A, the 3-bromo test was replaced by the 4-bromo test, and the N, N-dibutyl bromoacetamidine was replaced by the 4-bromo test. Amines replace N-methyl-N-propylbromoacetamide. 1H NMR (300 MHz, CDC13) d 7.64 (1H, bd), 7.59 (1H, d, J = 2Hz), 7.43 (2H, m), 7.33 (2H, d, J = 8Hz), 6.85 (2H, d, J = 8Hz), 6.73 (1H, d, J = 3Hz, 1Hz), 3.82 (1H, d, J = llHz), 3.89 (1H, d, J = 9Hz), 3.79 (3H, s), 3.53 (1H, dd, J = 10Hz, 3Hz), 3.44 (2H, m), 3.30 (1H, m), 3.20-2.95 (5H, m), 2.82 ( 1H, d J = 14Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J = 7Hz), 0.82 (3H, t, J = 7Hz). MS (DCl / NH3) m / e 507 (M + H) +. Analysis estimates C30H38N2O5: C, 71.12; H, 7.56; N, 5.53. Found 値: C, 70 · 73; H, 7.45; N, 5.29. Example 140 Basic formula, trans-butylamine carbonylmethyl) -2- (4-methoxybenzyl) -4- (6-benzofuran) Say Luodian-3-carboxylic acid as in Examples 1 and 4 9 The title compound was prepared by substituting the benzofuran-6-carboxaldehyde of piperonal with the benzofuran-6-carboxaldehyde of Example 49A and replacing the N-methyl-N-propylbromoacetamide with n, N-dibutylbromoacetamide. 4 NMR (300 MHz, CDC13) d 7.63 (1H, bd), 7.59 (1H, d, J = 2Hz), 7.53 (1H, d, J = 8Hz), 7.36 (3H, m), 6.85 (2H , D, J = 8Hz), 6.73 (1H, dd, J = 3Hz, 1Hz), 3.82 (1H, d, J = llHz), 3.89 (1H, d, J = 9Hz), 3.79 (3H, s ), 3.53 -200-This paper size applies to China National Standard (CNS) A4 specification (210X297mm) ~ " (Please read the precautions on the back before filling this page) Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 _B7 V. Description of the invention (198) (1H, dd, J = 10Hz, 3Hz), 3.44 (2H, m) 5 3.30 (1H, rn), 3.20-2.95 (5H, m), 2.80 (1H , D, J = 14Hz), 1.43 (3H, m), i 23 (3H, m), 1.08 (2H, η), 0.87 (3H, t, J = 7Hz), 0.82 (3H , T, J = 7Hz). MS (DC1 / NH3) m / e 507 (M + H) +. Analytical estimates c3Oj38N2055. 7575 H20: C, 69.28; H, 7.65; N, 5.39. Found 値: c, 69.11; H, 7.33; N, 5.32. Example 141 trans, trans-1- (N, N-dibutylamineweilylmethyl) -2 (4_ [oxybenzyl) _4_ (6 · benzo-2,3-dihydrolanyl) ρ ratio The title compound was prepared by the catalytic hydrogenation of the compound of Example 14 with Example 14 at a pressure of 24 atmospheres at AcOH, followed by the preparative formula hplc. 4 NMR (300 MHz, CDC13) Θ 7.40 (2H, d, J = 8Hz), 7.16 (1H, d, J = 8Hz), 6.97 (1H, dd, J = 8Hz, 2Hz), 6.89 ( 3H, m), 5.90 (1H, bs), 4.57 (2H, t, J = 9Hz), 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), 1.08 (2H, m), 0.92 (3H, t, J = 7Hz), 0.82 (3H, t, J = 7Hz). MS (DC1 / NH3) m / e 509 (M + H) +. Analytical estimates of C3OH4 () N20.5 · 0.85 TFA: C, 62 · 88; H, 6.80; N, 4.63. Found 値: C, 63.04; H, 6.66; N, 4.60 ο Example 142

Trans, trans-m-N-propylaminecarbonylmethyloxyphenyl) -4- (5-hydroindenyl) pyrrolidin-3-carboxy edge · f iH 142A Paper size applies Chinese National Standard (CNS) A4 specification (2⑴X297). (Please read the precautions on the back before filling this page). Order 581760 A7 B7 V. Description of the invention (199) In Example 52A, p-2,3-dihydrobenzocran was prepared from thallium-containing methylation. The resulting 4- and 5-benzyl-mixtures were purified as follows: aniline (2.20 g) was added to a 6: 1 mixture of manganese-4-metanoic acid and manganese_5_benzaldehyde (3.46 g '23 mmol). , 23 millimoles, 1 equivalent). The resulting solution was slowly solidified into an imine mixture and recrystallized from hot acetonitrile to form 5-acid imine as a white solid. The aldimine (2.65 g) was suspended in water (6 ml), and then treated with 4 K hydrochloric acid (10 ml). The mixture was boiled > for 1 hour 'cooled to room temperature' and poured into acetic acid. The organic solution was dried over MgS04, filtered and concentrated under vacuum. Vacuum distillation of the residue gave indane-5-carboxaldehyde (1.54 g, 88%) as a colorless liquid. b.p. 88-90 ° C, at 0.9 mm Hg.

Example 142B 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) trans, trans-1- (N-methyl-N-propylaminocarbonylmethyl V2- (4-Methoxyphenyl) -4- (5-hydroindenyl V-bilodine-3- # acid The title compound was prepared by the methods of Examples 1 and 49, but indane-5 carboxaldehyde was used instead of Example 49A Piperonic acid. 1H NMR (300 MHz, CDC13) (minor geometric isomer) β 7 · 25-7 · 1 (5H, m), 6.78 (2H, d, J = 8Hz), 3 · 89 (1H, d, J = 8Hz), 3.75 (3H, s), 32.50-2.90 (6H, m), 2.88 (6H, t, J = 6Hz), 2.82 (2.80) (3H, s), 2.04 (2H, t, J = 8Hz), 1.48 (2H, six peaks, J = 7Hz), 0.83 (0.73) (3H, t, J = 7Hz). MS (DC1 / NH3) m / e 451 ( M + H) +, 473 (M + Na) +. Analyzed and estimated C27H34N204 · 2 · 5 H20: C, 65 · 44; H, 7.93; N, 5.65. Measured 値: C, 65.36; H, 7.45; N, 5.53. -202- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 581760 A7 _B7 _ ^ __ 5. Description of the invention (200) Example 143 trans, trans A -N-propylaminecarbonylmethyl) -2- (4-methoxyphenyl) -4- (6- < indolyl) pyrrolidine-3-carboxylic acid. The title compound was prepared according to the procedures of Examples 1 and 49, and 51. 5106 (1986) was used in place of piperonal of Example 49A. 1H NMR (300 MHz, CDC13) (minor geometric isomerism) Material) d 8 · 43 (1H, brs), 7.57 (1H, d, J = 8Hz), 7.43 (1H, s), 7.31 (2H, dd, J = 6Hz, 3Hz), 7.22 (1H, d, J = 8Hz), 7.1 (1H, t, J = 3Hz), 6.78 (2H, dd, J = 6Hz, 3Hz), 6.45 (1H, m), 3.93 (1H, dd, J = 6Hz, 3Hz), 3.80 (1H, m), 3.73 (3H, s), 3.60-2.90 (6H, m), 2.86 (2.82) (3H, s), 1.47 (2H, seven peaks, J = 7Hz), 0.83 (0.73) ( 3H, t, J = 7Hz). MS (DC1 / NH3) m / e 450 (M + H) +. Analysis estimates C26H31N304 · 0.75 H20: C, 67 · 44; H, 7.07; N, 9.07. Measured radon: C, 67 · 42; H, 7.09; N, 8.91. Example 144 trans-trans-1-ΓΝ-methyl-N-propylaminocarbonylmethyl V2- (4-methoxyphenyl) · 4- (3,4-difluorophenyl) pyrrolidine-3-carboxyl The acid title compound was prepared as in Examples 1 and 49, but 3,4-difluorobenzoic acid was used in place of the piperonal of Example 49A. 8 NMR (300 MHz, CDC13) (minor geometric isomer) d 7 60 · 7.3 (4H, m), 7 · 13 (1H, q, J = 9Hz), 6.90 (2H, d, J = 8Hz ), 3.90 (1H, m), 3.79 (3H, s), 3.60-2.95 (6H, m) 5 2.92 (2.78) (3H, s), 1.55 (2H, seven peaks, J = 7Hz), 0.88 (0.73) (3H, t, J = 7Hz). MS (DC1 / NH3) m / e 447 (M + H) +. Analysis estimated C24H28N2O4 · 1.80 H20: C, 60.19; H, 6.65; N, 5.85. Real _ -203- This paper size is applicable to China National Standard (CNS) a4 size (210X297 mm) ------------ (Please read the precautions on the back before filling this page), * ιτ 581760 A7 Β7 ___ V. Description of the invention (2001) Test 値: C, 60.13; Η, 6.34; Ν, 5.84. Example 145 trans, trans-methyl-N-propylaminocarbonylmethyl V2- (4-methoxy & yl) -4- (benzyl) pyrrolidine-3-carboxylic acid The title compound was prepared by substituting acetaldehyde for piperonal of Example 49A. 1H NMR (300 MHz, CDC13) (minor geometric isomer) β 7.53 (4H, d, J = 6Hz), 7.40-7.20 (3H, m), 6.88 (2H, d, J = 8Hz) , 3.90 (1H, m), 3.79 (3H, s), 3.70-2.95 (8H, m), 2.90 (2.79) (3H, s), 1.50 (2H, seven peaks, J = 7Hz), 0.87 (0.72) (3H, t, J = 7Hz). MS (DC1 / NH3) m / e 411 (M + H) +. Analysis estimates C24H300N204.2.00 H20: C, 64.55; H, 7.67; N, 6.27. Found 値: C, 64.37; H, 7.43; N, 6.29 ° Example 146 trans, trans_1- (N_methyl-N · propylaminocarbonylmethyl) -2- (4-methyl4 -(4-Hydroxybenzyl) pyrrolidine-3- # acid The title compound was prepared by the methods of Examples 1 and 49, but printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of 4-hydroxybenzaldehyde (please read the back Note that this page is to be filled in again} Substitute piperonal for Example 49 A. 1H NMR (300 MHz, CDC13_CD30D) (minor geometric isomer) d 7 · 35 (2H, d, J = 8Hz), 7.28 (2H, dd, J = 7Hz, 3Hz), 6.90 (2H, dd, J = 7Hz, 3Hz), 6.89 (2H, d, J = 8Hz), 3.81 (3H, s), 3.65 (1H, d, J = 8Hz) , 3.70-3.00 (8H, m), 2.92 (2.83) (3H, s), 1.50 (2H, seven peaks, J = 7Hz), 0.87 (0.77) (3H, t, J = 7Hz). MS (Dpi / NH3) m / e 427 (M + H) +. Analyzed and estimated C24H30N2O5 · 1.00 H20 ·· C, 64.85; H, 7.26; N, ·· 30. Measured 値: C, 64 · 82; H, 7 · 39; N, 6.46. -204- This paper is again applicable to the Chinese Compensation Standard (CNS) A4 size (2 × Υ97 mm) 581760 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (2202) Example 147 Star _ ^, trans-1- (N-methylpropylaminecarbonylmethyl) -2- (4-methoxybenzyl V 4- (2,4-dimethoxymolybdenum) The pyrrolidine-3-carboxylic acid title compound was prepared by the methods of Examples 1 and 49, but 2,4-dimethoxybenzaldehyde was used instead of the piperonal of Example 49A. 1HNMR (300 MHz, CDCl3-CD3OD) ( Minor geometric isomers) β 7 · 61 (1H, d, J = 8Hz), 7.30 (2H, d, J = 8Hz), 6.82 (2H, d, J = 8Hz), 6_55 (1H, d, J = 8Hz), 6.45 (1H, d, J = 3Hz), 3.90 (1H, m), 3.81 (3H, s), 3.79 (3H, s), 3.77 (3H, s), 3.70- 2.90 (8H, m), 2.85 (3H, s), 1.50 (2H, seven peaks, J = 7Hz), 0.87 (0 · 77) (3H, t, J = 7Hz). MS (DC1 / NH3) m / e 471 (M + H) +. Analyzed and estimated C26h34n20.6 · 0.75 H20: C, 64.51; H, 7.39; N, 5.79. Found 値: c, 64.65; H, 7.07; N, 5.75. Example 148 Plexiform, trans-dibutylamine carbonylmethyl) -2- (4-methylarginobenzyl-2,3-dihydroanhydropyranyl) p-pyrrolidine-3-carboxylic acid. Examples 1 and 49 The title compound was prepared in the same manner, but 2,3-dihydrobenzonan-5-carboxylic acid was used in place of the piperonal of Example 49A. 1H NMR (300 MHz, CDC13) cy 7.31 (2H, d, J = 8Hz), 7.27 (1H, d, J = 2Hz), 7.18 (1H, dd, J = 7Hz, 3Hz), 6.86 (2H, d, J = 8Hz), 6.72 (1H, d, J = 8Hz), 4.56 (2H, t, J = 7Hz), 3.78 (3H, s), 3.62 (1H, m), 3.50-3.25 (4H , M), 3.17 (2H, t, J = 7Hz), 3.15-2.90 (5H, m), 2.79 (1H, d, J = 14Hz), 1.43 (3H, m), 1.26 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J = 7Hz), 0.81 (3H, t, J = 7Hz). MS (DCVNH3) m / e 509 (M + H) + ° Analyzed and estimated C30H40N2O5 · 0.25 H20: C, 70.22; H, 7.95;-205- This paper size applies to China National Standard (CNS) M specification (2 丨〇 < 297 public envy) (Please read the notes on the back before filling out this page) Order 581760 A7 B7 V. Description of the invention (203) N, 5.46. Found 値: c, 70.21; H, 7.92; N, 5.36. Example 149 trans, trans-1- (N, N-dibutylaminomethyl) -2- (4-methoxyphenyl) -4- (4-methoxyphenyl) pyrrolidine-3- The carboxylic acid title compound was prepared in the same manner as in Examples 1 and 49, except that piperonaldehyde of Example 49A was replaced with 4-methoxyacetaldehyde. 1H NMR (300 MHz, CDC13) d 7.38 (2H, d, J = 8Hz), 7.30 (2H, d, J = 8Hz), 6.87 (4H, dd, J = 7Hz, 3Hz), 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 = 14Hz), 1.43 (3H, m), 1.27 (3H, m), 1.09 (2H, m), 0.87 (3H, t, J = 7Hz), 0.81 (3H, t, J = 7Hz). MS (DC1 / NH3) m / e 497 (M + H) +. Analysis estimated C29H4ON205: C, 70.13; H, 8.12; N, 5.64. Found 値: C, 69.78; H, 8.10; N, 5.54. Example 150 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) trans, trans-MN · N-dibutylaminecarbonylmethyl) -2- (4-methyl gas Benzoyl) -4- (3,4-monoanhydride)? The title compound of Bihalidin-3-actic acid was prepared by the methods of Examples 1 and 49, but 3,4-difluorobenzaldehyde was used instead of the pepper of Example 49A. aldehyde. 1H NMR (300 MHz, CDC13) d 7.35 (1H, m), 7.30 (2H, d, J = 8Hz), 7.20-7.00 (2H, m), 6.87 (2H, d, J = 8Hz) , 3.78 (3H, s), 3.79 (1H, m), 3.62 (1H, m), 3.50-3.30 (3H, m), 3.23 (1H, m), 3.15-2.90 (4H, m) , 2.78 (lH, d, J = 14Hz), 1.43 C >> H, m), 1.27 (4H, m), 1.08 (2H, m), 0.85 (3H, t, J = 7Hz), 0.80 (3H , T, J = 7Hz). MS (DC1 / NH3) m / e 503 (M + H), analysis estimate c28H36F2N204 · 1 H20: C, 64.60; H, 7.36; ___ -206- This paper size applies to China National Standard (CNS) A4 (210X297) (Mm) 581760 A7 B7 V. Description of the invention (204) N, 5,38. Found 値: C, 64.59; Η, 7.20; N, 5.35. Example 151 trans, trans-1- (N, N-dibutylaminecarbonylmethyl) -2- (4-methoxyphenyl) -4- (2,4-dimethoxyphenyl) erogen The title compound of 3--3-acid acid was prepared in the same manner as in Examples 1 and 49, except that piperonal of Example 49A was replaced with 2,4-dimethoxyacetic acid. 1H NMR (300 MHz, CDCU) d 7.37 (2H, d, J = 8Hz), 7.20 (1H, d, J = 8Hz), 6.92 (2H, d, J = 8Hz), 6.60 (1H, d, J = 3Hz), 6.49 (1H ,, dd, J = 6Hz, 2Hz), 5.35 (1H, d, J = 8Hz), 4.20 (3H, m), 4.10 (3H, s), 3.83 ( 3H, s), 3.81 (3H, s), 3.75 (3H, m), 3.17 (2H, seven peaks, J = 7Hz), 3.05 (2H, t, J = 7Hz), 1.30 (4H, m), 1.07 (4H, m), 0.87 (3H, t, J = 7Hz), 0.80 (3H, t, J = 7Hz). MS (DCl / NH3) m / e 527 (M + H) +. Analysis estimates C30H42N2O6 · 1.30 TFA: C, 58.02; H, 6.47; N, 4.15. Found 値: C, 57.92; H, 6.43; N, 4.07. Example 152 trans, trans_1_ (Team ^ dibutylaminecarbonylmethyl) _2_mosyl-4- (1,3-benzodi-4-_5-yl) p Billodine-3- # Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards (please read the notes on the back before filling this page). The title compound was prepared by the methods of Examples 1 and 49, but ethyl benzaldehyde acetic acid was used instead of Example 49B. 1HNMR (300 MHz, CDCl3) β7 · 50 7.25 (5H, m), 7.04 (1H, d, J = 3Hz), 6.87 (1H, dd, J = 7Hz, 3Hz), 6.74 (1H, d , J = 8Hz), 5.94 (1H, d, J = 4Hz), 5.92 (1H, d, J = 4Hz), 3.85 (1H, d, J = 8HzJ, 3.64 (1H, m) , 3.42 (3H, m), 3.27 (2H, m), 3.20-2.90 (5H, m), 2.81 (1H, d, J = 14Hz), 1.43 (2H, m), 1.27 (4H, m), 1.05 (2H, m), 0.85 (3H, t, J = 7Hz), 0.80 (3H, t, -207-This paper size applies to China National Standard (CNS) A4 specifications (2i0x ^ 97mm) ) &Quot; Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 581760 Α7 Β7 V. Description of the invention (205) J = 7Hz). MS (DC1 / NH3) m / e 481 (M + H) +. Analysis estimate C28H36N205: C , 69 · 98; Η, 7.55; N, 5.83. Measured c: c, 69 · 69; Η, 7.63; Ν, 5.7 Example 153 trans, trans-1- (Ν, Ν- 二Butylaminocarbonylmethyl) -2_phenyl ^ 5_benzo_2,3-dihydrofuryl) pyrrolidine-3_carboxylic acid The title compound was prepared in the manner of Examples 1 and 49, but in Example 49B. Ethyl benzamidine ethyl acetate and 2,3-dihydrobenzofuran-5 · carboxaldehyde Alternative Example 49A Piperonal1H NMR (300 MHz, CDC13) β 7.53 (2Η, m), 7.40 (4Η, m), 7.13 (1Η, dd, J = 7Hz, 3Ηζ), 6.72 (1Η, d, J = 8Hz) , 5.40 (1H, d, J = 10Hz), 4.56 (2H, t, J = 8Hz), 4.18 (1H, d, J = 14Hz), 4.07 (2H, m), 3.79 (2H, m), 3.48 (1H, d, J = 14Hz), 3.35 (1H, m), 3.28 (3H, m), 2.95 (2H, m), 1.47 (2H, m), 1.28 (4H, m), 1.10 ( 2H, m), 0.93 (3H, t, J = 7Hz), 0.78 (3H, t, J = 7Hz). MS (DC1 / NH3) m / e 479 (M + H) +. Analysis estimates C29H38N204 · 1.10 TFA: C, 62.04; H, 6.52; N, 4.64. Found 値: C, 61.89; H, 6.44; 4.57 ° Example 154 trans, trans · 1 · (N, N-dibutylaminocarbonylmethyl tert-butylphenyl) -4- (5- Benzo-2,3-dihydrofuryl) pyrrolidine-3-carboxylic acid The title compound was prepared in the same manner as in Examples 1 and 49, but as the example 49B zirconylacetic acid tert-butyric acid (by Krapcho et al ., Prepared by Org · Syn · 47: 20 (1967), starting from 4-tert-butylacetophenone) and 2,3-dihydrobenzofuran-5 · carboxaldehyde in place of piperonal of Example 49A . 1H NMR (300 -208- This paper size applies to Chinese National Standard (CNS) Α4 size (210X 297mm) (Please read the precautions on the back before filling this page). Order printed by the Central Consumer Bureau of the Ministry of Economic Affairs, Consumer Cooperatives 581760) A7 B7 V. Description of the invention (206) MHz, CDC13) d 7.60-7.30 (6H, m), 6.90 (1H, m), 4.50 (2H, m), 3.95 (1H, m), 3.85-2.95 ( 11H, m), 2.90 (1H, d, J = 14Hz), 1.58 (2H, m), 1.50 (7H, m), 1.41 (6H, s), 1.10 (2H, m) , 1.00 (3H, t, J = 7Hz), 0.90 (3H, t, J = 7Hz). MS (DC1 / NH3) m / e 535 (M + H) +. Analysis estimates C33H46N204 · 0.25 H20: C, 73.50; H, 8.69; N, 5.19. Found 値: C, 73.57; H, 8.58; N, 5.14. Example 155 trans, trans_2- (N, N-dibutylaminecarbonylmethyl) -2- (4-methoxyphenyl) -4- (4-fluorophenyl) pyrrolidine-3-carboxylic acid The title compound was prepared in the same manner as in Examples 1 and 49, except that piperonal of Example 49A was replaced with 4-fluorocarbaldehyde. 1H NMR (300 MHz, CDC13) d 7.50 (1H, m), 7.42 (1H, dd, J = 7Hz, 3Hz), 7.36 (2H, d, J = 8Hz), 7.01 (3H, t, J = 8Hz) , 6.87 (1H, d, J = 8Hz), 3.83 (1H, m), 3.8 (3H, s), 3.67 (1H, m), 3.47 (3H, m), 3.30-2.90 (5H, m) , 2.82 (1H, d, J = 14Hz), 1.43 (2H, m), 1.28 (4H, m), 1.08 (2H, m), 0 · 90 (3H, t, J = 7Hz), 0.82 ( 3H, t, J = 7Hz). MS (DC1 / NH3) m / e 485 (M + H) +. Analysis estimates c28H37FN204: C, 69.40; H, 7.70; N, 5.78. Found 値: C, 69.03; H, 8.00; N, 5.74. Example 156 Trans fluorene trans-di-dibutylamine carbonylmethyl) -2- (3-furanyl V4_ (1.3 · benzodifluoren-5-yl) pyrrolidine-3-carboxylic acid The title compound is given in Examples 1 and 4 Prepared according to the procedure of 9 but replaced by lu-keto-3-furanpropionic acid in Example 49B. 1η NMR (300 MHz, CDC13) d 7.41 (2H, m), 6.97 (1H, d, J = 3Hz), 6.85 (1H, dd, J = 7Hz, 3Hz), -209- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) Order 581760 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of Invention (207) 6.72 (1H, d, J = 8Hz), 6.42 (1H, s), 5.94 (1H, d, J = 4Hz), 5.92 (1H, d5 J = 4Hz), 3.90 (1H, m), 3.70 · 3 · 25 (5H, m), 3.20-2.90 (4H, m), 2.85 (1H, d, J = 14Hz), 1.43 (2H, m), 1.40-1.05 (6H, m), 0.90 (6H, m). MS (DC1 / NH3) m / e 471 (M + H). Analyze and estimate C26H34N206: C 66, 66 · 36; Η, 7.28; N, 5.95. Found 値: C, 66.09; Η, 7.24; N, 5.87. Example 157 trans, trans-1- (N, N-dibutylamine Carbonylmethyl V2, isopropyl ) Pyrrolidine-3- # _ The title compound was prepared in the manner of Examples 1 and 49, but was replaced by ethyl isobutylfluorenylacetate in Example 49B. 4 NMR (300 MHz, CDC13) d 6 · 85 (1H, d , J = 2Hz), 6.76 (1H, dd, J = 6Hz, 2Hz), 6.71 (1H, d J = 8Hz), 5.92 (2H, s), 3.75 (1H, d, J = 14Hz) , 3.66 (1H, q, J = 7Hz), 3.42 (3H, m), 3.25 (3H, m), 3.11 (2H, m), 2.83 (m, t, J = 7Hz), 1.88 (1H, m), 1.55 (4H, m), 1.32 (4H, m), 0.092 (12H, m). MS (DC1 / NH3) m / e 447 (M + H) +. Analytical estimation c25H38N20.5 · 0.50 H20: C, 65 · 91; H, 8.63; N, 6.15. Found 値: c, 66 07; H, 8.10; N, 6.03. Example 158 trans, trans-1- (N, N-dibutylamine) The method of the title compound of the title compound of methyl oxanylmethyl tertiary-butylphenyl) -4- (1,3-benzo- # thio-yl) p slightly slightly -3-carboxylic acid according to the examples 1 and 4 9 Preparation, but in Example 49B was replaced by 4-tert-butylbenzyl nasal acetate ethyl acetate, which was prepared by the method of Krapcho et al., Org · Syn 47:20 (1967), starting from Radi Tributyl styrene-210- This paper size applies to Chinese National Standard (CNS) A4 (2 丨 〇 > < 297 public shame) (Please read the notes on the back before filling out this page)-Order printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Description of Invention ketone). 4 NMR (300 MHz, CDC13) d 7.32 (4H, d, J = 3Hz), 7.04 (1H, d, J = 2Hz), 6.87 (1H, dd, J = 8Hz, 3Hz), 6.74 (1H, d, J = 9Hz), 5.94 (1H, d, J = 4Hz), 5.92 (1H, d, J = 4Hz), 3.77 (1H, d, J = 14Hz), 3.65-3.25 ( 5H, m), 3.15-2.85 (4H, m), 2.73 (1H, d, J = 14Hz), 1.45 (2H, m), 1.29 (13H, s), 1.00 (2H, m), 0.86 (3H, t, J = 7Hz), 0.76 (3H, t, J = 7Hz). MS (DCl / NH3) m / e 537 (M + H) +. Analysis estimates C32H44N205: C, 71 · 61; H, 8.26; N, 5.22. Measured 値 ·· C, 71.43; H, 8.09; N, 5.11. Example 159 trans'-trans-1-Dibutylaminomethyl V2- (4-tert-butylphenyl) -4- (5-benzino-2,3-dihydrofuryl) pyrrolidine The title compound of 3-carboxylic acid was prepared by the methods of Examples 1 and 49, but the isopiperanyl acetate of Example 49B and 2,3 · dihydrobenzofuran-5 · carboxaldehyde were used instead of piperonal of Example 49A. 1H NMR (300 MHz, CDC13) d 7.30 (1H, s), 7.13 (1H, dd, J = 7Hz, 2Hz), 6.82 (1H, d, J = 8Hz), 4.86 (2H, t, J = 8Hz) , 4.48 (1H, s), 3.19 (3H, m), 3.80 (3H, m), 3.48 (2H m), 3.3 (5H, m), 2.41 (1H, m), 1.65 (4H, m), i 44 (4h, m), 1.21 (3H, d, J = 5Hz), 1.17 (3H, d, J = 5Hz), 1.05 (6H, m). MS (DCi / NH3) m / e 445 (M + H) +. Analysis estimates C26h4 () n2O4 · L2 TFA: C, 58 · 67; H, 7.14; N, 4.82. Found 値 · C, 58.54; H 7 25. N, 4.74. Example 160 trans, trans-dibutylamine carbonylmethyloxycyclohexyl) _4 · (1,3-benzodihex-5-yl) pyrrole-211-This paper applies Chinese National Standard (CNS) 8-4 Specifications (2l〇X297mmΊ " " ^ ---- (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T 581760 A7 B7 V. Description of the Invention (209)

Example 160 A Ipsilateral and contralateral 4-methoxycyclohexylacetic acid ethyl acetate Isolateral, contralateral 4-methoxycyclohexanecarboxylic acid (5.00 g, 31.6 mol) and carbonyldiimidazole ( 6.15 grams, 37.9 millimoles, 1.2 equivalents) were stirred in anhydrous tetrahydrosquench (50 ml); dropped at room temperature for 6 hours. At the same time, magnesium chloride (3.01 g, 31.6 mmol) and potassium potassium malonate (7.52 g, 44.2 mmol) were added in anhydrous tetrahydrofuran (75 ml) at 5 Stirred at 0 ° C for 6 hours. The mixture was cooled to room temperature, and the midazoic acid mixture was added. The reaction fell at the main temperature overnight. The agent was removed under reduced pressure and the residue was taken up in aerosol / water. The organic phase was washed with 5% potassium bicarbonate, water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on 175 g of silica gel and isolated with 20% ethyl acetate / hexane. Pure fractions of iso- and contra-methoxycyclohexyl f-ketoester are obtained. The solvent was removed under reduced pressure to give trans-4-methoxyphosphinohexylfluorenyl ester (914 mg) as a colorless oil and cis-4-methoxycyclohexyl vinegar (1.07 g ) Was colorless oil.

Example 160 B trans'trans-1 · (N, N · dibutylamine peptidylmethyl opposite 4-methoxycyclohexyl) · 4- (1,3-benzodi-$-5 · yl ) The title compound of π Biledian · 3 · Falcon was prepared by the methods of Examples 1 and 49, but in Example 49B, the opposite compound of Example 160A was used instead. NMR (300 MHz, d 6.84 (1H, d, J = 2Hz), 6.76 (1H, dd, J = 7Hz, 2Ηζ), 6.61 (1H, d, J = 8Hz), 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 _ -212- This paper size is applicable to China National Standard (CNS) A4 specification (2io ^ 97mm) ------ --I--n, order (please read the precautions on the back before reading) (Fill in this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Description of the invention (21〇) (7H, m), 1.33 (9H, m), 0.97 (3H, t, J = 7HZ), 0.92 (3H, t, J = 7Hz). MS (DC1 / NH3) m / e 517 (M + H) +. Analyzed and estimated C29H44N2O6 · 50 · H2O · C, 66.26; H, 8.63; N, 5 33. Measured値: C, 66 · 27; H, 8.50; N, 5.13. Example 161 trans'trans-1 · (N, N-dibutylaminomethyl) _2 · (same side_4_form The oxycyclohexyl) -4- (1,3-benzodi $ -5-yl) ρ bipyridine_3-boronic acid title compound was prepared by the methods of Examples 1 and 49, but in Example 49B Substituted from the same side compound of Example 160A. 1η NMR (300 MHz, CDC13) d 6.84 (1H, d, J = 2Hz), 6.77 (1H, dd, J = 6Hz, 2Hz), 6.61 (1H, d, J = 8Hz), 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), 1.52 (6H, m), 1.33 (4H, m), 1.20 · 1 · 00 (4H, m), 0.96 (3H, t, J = 7Hz), 0.91 (3H, t , J = 7Hz). MS (DC1 / NH3) m / e 517 (M + H) +. Analyzed and estimated C29H44N206 · 0.30 H20: C, 66 · 72; H, 8.61; N, 5.37. Found 値: C, 66.76 H, 8.65; N, 5.28. Example 162 trans, trans-WN, N-dibutylaminocarbonylmethyl V2.4-bis (5-benzyl-2.3-di

Hydrofuran) pyrrole-3-miao hydrazone Example 162 A 5 · Ethyl-2-, 3-dibenzobenzone in acetamyl chloride (1.64 liters, 23.0 mmol, L3 equivalent) in dichloromethane (30 ml) of 0 ° C solution, stannous chloride (2.49 ml, 21.3 mmol, 1.2 equivalents) was added, and the temperature was maintained below 5 ° C. The solution is stirred under (TC • 213- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) " " (Please read the precautions on the back before filling this page)

1T 581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs V. Invention Description (211) Drop 15 as a bell, and then 2,3-a hydrogen squeak (200 ml, 177 millimoles) in one A solution of methyl chloride (5 liters) was added dropwise, and the temperature was maintained at 8. 〇 下。 〇 down. The dark red falling liquid was stirred at 2 C for 1 hour, and then poured into 50 ml of ice water. The reaction was stirred for another 30 minutes and the layers were separated. The organic layer was washed with water and an aqueous solution of sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 150 g of silica gel. Ethyl acetate was dropped in the pit. The solvent was removed under reduced pressure to give the title compound (2.68 g, 93%) as a yellow solid.

Example 162 B Trans'trans-1- (N, N · dibutylaminecarbonylmethyl v2 4-bis (5-mono-2,3-dihydroconanyl) elenomycin-3 acid title compound Prepared according to the methods of Examples 1 and 49, but in Example 49B, the compound of Example 162A, and 2,3_dihydrobenzofuran_5_carboxylic acid were used to replace the piperonic acid of Example 49A. 1H NMR (300 MHz , CDCU) d 7.43 (1H, s), 7.38 (1H, s), 7.06 (2H, m), 6.75 (1H, d, J = 6Hz), 6.70 (1H, d, J = 6Hz), 5.40 (1H, d, J = 9Hz), 4.58 (4H, q, J = 7Hz), 4.16 (1H, d, J = 14Hz), 4.09 (2H, m), 3.82 (2H, m), 3.57 ( 1H, d, j = 14Hz), 3.38 (1H, m), 3.30-3.05 (6H, m), 2.95 (2H, q, J = 6Hz), 1.50 (2H, m), 1.30 (4H, m ), 1.15 (2H, m), 0.94 (3H, t, j = 7Hz), 0.83 (3H, t, J = 7Hz). MS (DC1 / NH3) m / e 521 (M + H) +. Analyze C31H40N2O5 · 1.25 TFA: C, 60.67; H, 6.27; N, 4.22. Measured C: C, 60.49; H, 6.18; N, 4.13. Example 163 trans_1- (N, N-dibutyl Aminocarbonylmethyl) -2- (3-furanyl) -4- (5 • Ben-214-Chinese National Standard (€ can) 8 4 specifications (210 '乂 297) ) (Please read the precautions on the back before filling this page) Order 581760 A7 ________ B7 _ ^ _ V. Description of the invention (212) and _.2,3 · di-hydrogenan) Pyrrolidine-3-digit acid Method 1 and 49 to prepare the title compound 'but replaced by /?-Keto-3-octanopropanoate in Example 49B and 2,3-dibenzobenzopyran-5-carboxaldehyde Piperonal of Example 49A. IH NMR (300 MHz, CDC13) d 7.42 (1H, m), 7.38 (1H, m), 7.13 (1H, s), 7.1ό (1H, dd, J = 7Hz, 3Hz), 6.70 (1H, d, J = 8Hz), 6.41 (1H, m), 4.57 (2H, t, J = 7Hz), 3.95 (1H, d, J = 8Hz), 3.63 (1H, m), 3.55 (1H, d, J = 14), 3.50-3.25 (4H, m), 3.18 (2H, t, J = 6Hz), 3.15-2.95 (3H, m), 2.87 (1H, d, J = 14Hz), 1.45 (4H, m), 1.35-1.10 (4H, m), 0'85 (6H, m). MS (DC1 / NH3) m / e 469 (M + H) +. Analysis estimates C27H36N205.25H20: C, 68.55; H, 7.78; N, 5.92. Found 値: C, 68.62; H, 7.68; N, 5.82. Example 164 trans, trans-1- (N, N-dibutylaminecarbonylmethyl) · 2- (4-methoxyphenyl)- 4- (3-Fluorophenyl) pyrrolidine_3- # Acid 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) The title compound was prepared by the methods of Examples 1 and 4 9 However, in Example 49A, 3-fluorobenzaldehyde was substituted for piperonaldehyde. 1H NMR (300 MHz, CDClj d 7.30 (2H, d, J = 8Hz), 7.22 (2H, m), 6.91 (1H, m), 6.86 (2H, d, J = 8Hz), 3.79 ( 1H, m), 3.78 (3H, s), 3.68 (1H, m), 3.55-3.37 (3H, m), 3.29 (1H, m), 3.15-2.90 (5H, m), 2.78 ( 1H, d, J = 14Hz), 1.43 (2H, m), 1.25 (4H, m), 1.07 (2H, m), 0.87 (3H, t, J = 7Hz), 0.80 (3Ή, t, J = 7Hz). MS (DC1 / NH3) m / e 485 (M + H) +. Analyzed and estimated C28H37FN204 · 0.25 H20: C, 68 · 76; H, 7.73; N, 5.73. Found 値: C, 68.87; H , 7.69; N, 5.67. -215- This paper size applies to China National Standard (CNS) A4 (21 × 297 mm). Printed on 581760 A7 B7 by the Consumers' Cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the invention (213 ) Example 165 trans, trans-1-0SLN-dibutylaminecarbonylmethyl) -2- (4-methoxyphenyl) -4- (3-p-biphenyl) p-bihalide-3 leptate The title compound was prepared in the same manner as in Examples 1 and 49, but in Example 49A, the piperonic acid was replaced with a 3 · ρ ratio carboxaldehyde. Nitrophenylacetamidine was prepared by the method of Bourguignon, et al., Can. J. Chem. 63: 2354 (1985). 4 NMR (300 MHz, CDC13) d 8.82 (1H, bs), 8.73 (1H, bd, J = 9Hz), 8.62 (1H, bd, J = 7Hz), 7.78 (1H, bdd, J = 9Hz, 3Hz) , 7.38 (2H, d, J = 10Hz), 6.90 (2H, d, J = 10Hz), 4.39 (1H, d, J = 12Hz), 3.95 (1H, m), 3.80 (3H, s), 3.79 (1H, m), 3.68 (1H, d, J = 18Hz), 3.50-3.30 (3H, m), 3.25-2.90 (6H, m), 1.47 (2H, m), 1.31 (4H, m), 1.20 (2H, m), 0.92 (3H, t, J = 7Hz), 0.83 (3H, t, J = 7Hz). MS (DC1 / NH3) m / e 468 (M + H) +. Analysis estimates C27H37N304 · 1.65 TFA: C, 55 · 50; H, 5.94; N, 6.41. Found 値: C, 55.53; H, 5.90; N, 6.27. Example 166 trans, trans_1, N, N-dibutylaminecarbonylmethyl) -2- (2-fluorophenyl) _4_ (1,3-benzodiazine-5-yl V-pyridine- 3-Leptanoic acid The title compound was prepared by the methods of Examples 1 and 49, but was replaced by 2-fluorobenzylacetate ethyl acetate in Example 49B. 1H NMR (300 MHz, CDC13) β 7.52 (1Η, dt, J = 7Hz , 3Hz), 7.25 (1Η, m), 7.13 (1Η, dt, J = 7Hz, 3Hz), 7.02 (2H, m >, 6.88 (1H, dd, J = 7Hz, 3Hz), 6.73 ( lH, d, J = 8Hz), 5.93 (1H, d, J = 4Hz), 5.92 (1H, d, J = 4Hz), 4.25 (1H, d, J = 9Hz), 3.68 ( 1H, m), 3.42 (3H, m), 3.39 (1H, m), 3.20-2.95 -216- This paper size is applicable to China National Standard (CNS) A4 specification (21 × 297 mm) (please read the back first) (Notes on this page, please fill in this page), 11 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 581760 A7 B7 V. Invention Description (214)

(4H, m), 2.91 (1H, d, J-14Ηζ), 1.45 (3H, m), 1.26 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J = 7Hz), 0.81 (3H, t, J = 7Hz). MS (DC1 / NH3) m / e 499 (M + H) +. Analyze and estimate c28H35FN205. 〇25 112〇. (^, 66.85, 11, 7.11, 1 ^, 5.57. Found 値: (^, 66 51.11 6 07 · N, 5.18. Example 167 trans, trans · 1- (N, N-tributylaminecarbonylmethyl) _2_ (3_argonbenzylbenzodiazine_5_yl) pyridine_3_miao 酩 The title compound was prepared in the manner of Examples 1 and 49, but In Example 49B, 3-fluorofluoracetic acid ethyl acetate was used instead. 1H NMR (300 MHz, CDC1J d 7.38 (1H, m), 7.18 (1H, d, J = 7Hz), 7.15 (1H, m), 7.00 (1H, d, J = 2Hz), 6.95 (1H, m), 6.86 (1H, dd, J = 7Hz, 2Hz), 6.75 (1H, d, J = 8Hz), 5.93 (1H, d , J = 4Hz), 5.92 (1H, d, J = 4Hz), 3.94 (1H, d, J = 14Hz), 3.63 (1H, m), 3.42 (3H, m), 3.35 · 2 · 95 (5H, m), 2.87 (1H, d, J = 14Hz), 1.44 (3H, m), 1.27 (3H, m), 1.10 (2H, m), 0.88 (3H, t , J = 7Hz), 0.81 (3H, t, J = 7Hz). MS (DC1 / NH3) m / e 499 (M + H) +. Analyzed and estimated C28H35FN205: C, 67 · 45; H, 7.08; N, 5.62. Found 値: C, 67.32; H, 7.05; N, 5.40. Example 168 trans, trans-1_ (4-N, N-dibutylaminephenyl) -2- (4-methoxybenzene Base) -4 _ (l, 3-Benzodi-4--5 · yl) p-bihalidine-3 · carboxylic acid 4-nitro-1-fluorobenzene, trans, trans-2_ (4-methoxyphenyl)- 4- (1,3-Benzodifluorene · 5-yl) · pyrrolidine-3_carboxylic acid ethyl ester (the compound of Example 6 A) and diisopropylethylamine were heated in a di "depletion reaction to generate trans , Trans-2- (4-methoxyphenyl)--217- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) " (Please read the precautions on the back before filling this page) Order 581760 A7 B7 V. Description of the invention (215) 4_ (1,3_benzodiyin_5 · yl) -1- (4 • nitrophenyl) _pyrrolidine_3_acetic acid ethyl acetate. Nitrate Amino compounds are hydrogenated to form equivalent aminophenyl compounds. Aminophenyl compounds are combined with butyraldehyde and sodium cyanoborohydride according to Borch, J. Am Chem.

Soc. 93: 2897 (1971) to produce equivalent n, N-dibutylamine phenyl compounds. Hydrolysis with sodium hydroxide using the method of Example 1D yielded the title compound. Example 168 Formula, trans_1- (2-N, N-dibutylaminopyrimidine-4_ylmethoxybenzyl 4- (1,3-benzodifluoren-5-yl) pyrrolidine-3 -Carboxylic acid 2_ (dibutylamino) · 4_ chloropyridine according to the method of Gershon, J. Heterocyclic Chem. 24: 205 (1987), prepared from 2,4_dichloropyrimidine, and trans, trans -2- (4-methyllactinoyl) -4- (1,3-benzobisp--5-yl) -p-bilodine-3- leptate ethyl ester (Example 6 A compound) and diiso The propylethylamine is heated in dioxane to generate ethanol as an intermediate, which is then hydrolyzed with sodium hydroxide using the method of Example 1 D to form the title compound. Examples 170-266 Using Examples 1, 4, 5, 7, 8, and 9 And the method of Scheme X, the following compounds can be prepared. Example No. Name 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) 170 trans, trans-2- (4-A Oxyphenyl) -4- (1,3-benzodifluoren-5-yl) -1- (isopropylaminomethylmethylhadine-3 -leptic acid; 171 trans, trans-2- (4 -Methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) -1- (ethylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid; 172 trans, trans- 2_ (4-methoxyphenyl) -4- (1,3-benzodolin-5-yl)--218- This paper size applies to China National Standard (CNS) A4 specification (21 × 297 mm) 581760 A7 B7 V. Description of the invention (216) 1- (1-methylpropylaminecarbonylmethyl) -pyrrolidine-3-carboxylic acid; 173 trans, trans-2_ (4-methoxyphenyl) -4_ (1 , 3-Benzodifluorenyl) _ 1-(benzylaminomethyl) -erodoline-3-endanoic acid; 174 trans, trans-2_ (4-methoxyphenyl)-'(1 , 3 · benzobispyrene, 1) (1- (hexahydropyridylcarbonylmethyl) -pyrrolidine-3-carboxylic acid; 175 trans'trans-2- (4 · methoxyphenyl) _4 · (1,3_benzodiyl) 1- (1 · (propylaminecarbonyl) ethyl) -pyrrolidine-3-carboxylic acid; 176 trans, trans_2- (4_methoxyphenyl) _4_ (1,3-benzodiyl 1- (α- (propylaminecarbonyl) benzyl) -pyrrolidinecarboxylic acid; 177 trans, trans-2_ (4-methoxyphenyl)-'(1,3_ Benzenedi-5-yl) 1- (bis (propylaminecarbonyl) methyl) -pyrrolidine · 3-carboxylic acid; 178 trans'trans · 2- (4 · methoxyphenyl) _4- (1 , 3 · benzodig_5yl) 1- (2- (propylaminecarbonyl) ethyl) -pyrrolidinecarboxylic acid; 179 trans'trans-2- ( 4-methoxyphenyl) -4- (1,3-benzobenzoinyl) 1-C-propylaminocarbonylmethyl) -pyrrole-3-carboxylic acid; 180 trans'trans-2- (4-methoxy Phenyl) -4- (1,3_benzodi $ _5 meaning) 1-(2_benzyl) -p Bihadian -3 -read ^; Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs ( Please read the precautions on the back before filling out this page} Ρ 181 trans'trans-2- (4-methoxyphenyl) · 4- (1,3-benzodi p · 5 meaning) 1- ( Pentamylmethyl) -pyrrolidine-3-carboxylic acid; 182 trans'trans-2_ (4 • methoxyphenyl) _4_ (1,3_benzodigjyl) 1- (benzylfluorenylmethyl) -Pyrrolidine_3_carboxylic acid; 183 trans'trans-2- (4-methoxyphenyl) -4- (1,3-benzodi-5-yl) 1- (hexyl)-? Bilodine -3-Junic acid; 184 trans'trans_2- (4_methoxyphenyl) -4- (1,3-benzodiazine 7 0_yl)-219- This paper size applies to China Standard (CNS) Α4 specification (210 × 297 public envy 1 --- ^ 581760 A7 B7 V. Description of the invention (217) 185 186 187 188 189 190 191 192 193 Warp

Printed by Central Standard Member X Cooperative 194 195 196 1- (2-Hexyl) -pyrrolidine-3-carboxylic acid; trans'trans-2- (4-methyllactimyl) -4- (1 , 3-benzodiyl) _ 1- (propoxymethyl carbonyl gadoto-3_acid acid; trans'trans-2_ (4-methoxyphenyl) -4- (1,3-benzo Difluorenyl_5-yl) _ 1- (phenylethylfluorenyl) -pyrrolidine-3. Leptate; trans'trans_2- (4-methoxyphenyl) _4_ (1,3_benzo Diyl) _ 1- (aniline carbonyl) -pyrrolidine-3-carboxylic acid; trans'trans-2- (4-methyllactino) -4- (1,3-benzodi-5 • yl) 1- (2-Ethylaminoethyl) -pyrrolidine-3-carboxylic acid ·, trans'trans-2- (4-methoxyphenyl) · 4- (1,3-benzodiin Its) 1- (2 • phenoxyethyl) -pyrrolidine-3-carboxylic acid; trans'trans-2- (4-methoxyphenyl) -4_ (1,3-benzodiinyl) 1- (2-Benzodifluorenylmethyl) -pyrrolidin-3-acid; trans'trans-2- (4-methoxyphenyl) -4- (1,3_benzobis π group) 1_ (2_tetrahydrofurylmethyl) _pyrrolidin-3-carboxylic acid; trans'trans-2- (4-methoxyphenyl) -4- (1,3_benzodiyin ^ _) 1- (2- (propylamino alkynylamino) acetamido-3 -carboxy Acid; trans, trans_2- (4_methoxyphenyl) -4_ (1,3-benzodifluorene_5_yl) _ 1- (2_ (propylaminocarbonylamino) ethyl) -pyrrole Pyridin-3_carboxylic acid; trans, trans_2- (4-methoxyphenyl) · 4_ (1,3_benzodifluorene_5_yl) _ 1_ (3 · ketohexan_1 · ene ) -Pyrrolidin-3-carboxylic acid; trans'trans-2- (2,4-dimethoxyphenyl) -4- (1,3-benzodiyl) -1- (propylaminecarbonyl Methyl) · Pyrrolidine-3-carboxylic acid; trans, trans · 2 · (2-carboxy-4 · methoxyphenyl)-'(1,3_benzodibenzine) 220 papers are suitable for China again National Standard (CNS) Α4 Specification (210 × 297 mm) (Please read the notes on the back before filling out this page}, 1T 581760 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Α7 Β7 V. Description of Invention (218) -5- ) -B (propylaminecarbonylmethyl l.12-pyrrolidin-3-carboxylic acid; 197 trans, trans-2- (2-amine post-4-methyllactyl) -4- (1, 3-Benzodizaz-5-yl) -B (propylaminecarboxymethyl) · Pyrrolidinecarboxylic acid; 198 trans, trans-2- (2-methanesulfonyl-4-methoxyphenyl) · 4- (1,3_Benzodifluoren-5-yl) -b (propylaminocarbonylmethyl) -pyrrolidine- 3-carboxylic acid; 199 trans, trans-2- (2-aminocarbonylmethoxy-4-methoxyphenyl) -4- (1,3-benzobenzoz-5-yl) -1 -(Propanylmethyl) -p-bilodine-3 -Lean acid; 200 trans, trans-2- (2-methoxyethoxy_4-methoxyphenyl) -4 · (1 , 3-Benzodi-p-5-yl) -1- (propylaminomethylmethylbiloline-3-metanoic acid; 201 trans, trans-2- (2-carboxymethoxy · 4 · Methoxyphenyl) -4- (1,3-benzodiamm-5-yl) -1- (propylaminecarbonylmethyl) -pyrrolidine-3-carboxylic acid; 202 trans, trans-2- ( 4-methoxy-2_tetrazolylmethoxyphenyl) _4- (1,3-benzodiazin-5-yl) -1- (propylaminomethylmethylpyrrolidine_3_ lean acid; 203 trans'trans-2- (2-propanyl-4-methoxyphenyl) -4- (1,3-benzodiazine-5-yl) -1- (propylaminomethyl) ) · Ρbilodine-3-leptic acid; 204 trans, trans-2,4-bis (4-methoxyphenyl) _1_ (propylaminocarbonylmethyl) _pyrrolidine-3_leptic acid; 205 trans Formula, trans-2,4-bis (1,3-benzobisfluoren-5-yl) -1- (propylaminecarbonylmethyl) _ Kubilodian-3-Jun; 206 trans'trans · 2_ (4-Methoxybenzyl) -4- (l, 3 · benzodiazine-5-yl) -l- (N-methyl-N- Propylaminomethyl) · pilolide · 3-leptic acid; 207 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzobenzoin-5-yl ) _ 1-(N_methyl_N · butylamine tizo) -p-bilodine · 3 _ acidification; -221-This paper size applies to China National Standard (CNS) Α4 (210 X 297 mm) (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 Α7 Β7 V. Description of the invention (219) 208 trans'trans-2- (4-methyllactyl) ) -4_ (1,3 -Benzodiin-5-yl) _ 1- (N-methyl-N- (4-methoxyphenyl) aminocarbonyl) -pyrrolidine-3-carboxylic acid; 209 trans Formula, trans-2- (4-methoxyphenyl) -4- (1,3-benzobisfluoren-5-yl) _ 1- (N-methyl-N-phenylaminocarbonyl)- Pyrrolidine-3-carboxylic acid; 210 trans, trans_2- (4 · methoxyphenyl) -4_ (1,3_benzobisfluoren-5-yl) -1- (N-methylene Propylaminocarbonylmethyl) -pyrrolidin-3-carboxylic acid; 211 trans, trans_2- (4 · methoxyphenyl) -4_ (1,3_benzobisfluorene-5 · yl) -1- (N-methyl (n-butyl) aminocarbonylmethyl) -pyrrolidine_3-carboxylic acid; 212 trans'trans-2- (4 · methyllactyl)- 4- (1,3-Benzodizaki-5_yl) _ 1- (N-methyl-N-isobutylaminecarbonylmethyl) -pyrrolidine-3-carboxylic acid; 213 trans'trans- 2- (4-methyllactyl) -4- (1,3-benzodiazin-5-yl) _ 1- (N-methyl-N-cyclopentylaminocarbonylmethyl) -pyrrolidine-3 -Carboxylic acid; 214 trans, trans-2- (4-methoxyphenyl) _4- (1,3-benzodifluorene · 5-yl) -1- (N-methyl-N- (2 -Methoxyethyl) aminocarbonyl) -pyrrolidine-3-carboxylic acid; 215 trans, trans-2 · (4 · methoxyphenyl) · 4 · (1,3-benzodifluorene_5 _Yl) _ 1- (N-methyl-N-butoxyethylaminocarbonyl) -pyrrolidine-3-carboxylic acid; 216 trans, trans_2- (1,3-benzodihum-5 _Yl) -4_ (4-methoxyphenyl) -1- (N-methyl · N-propylaminecarboxymethyl) -pyrrolidine-3-carboxylic acid; 217 trans, trans-2- (4methyl Oxyphenyl) ··· (1,4-benzodiamidino-6-yl) -1- (N-methyl-N-propylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid; 218 trans, Trans_2_ (4_methoxyphenyl) -4_ (1,3_benzobisfluoren-5-yl) -1- (N-methyl-N-isopropylaminocarbonylmethyl) · pyrrolidine-3 -Carboxylic acid; 222- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please Read the notes on the back and fill in this page.) Order 581760 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (220) 219 trans, trans-2- (4-methoxyphenyl) -4 -(1,3-Benzodifluorenyl-5 · yl) · 1- (N-methylethylaminomethyl) _pbilodine_3-jun, 220 trans, trans-2- (4 -Methoxyphenyl) -4- (1,3 · benzodifluoren-5-yl) -1- (N-methyl-N- (l-methylpropyl) aminocarbonylmethyl) -pyroxol Pyridin-3-acid; 221 trans'trans-2- (4-methoxyphenyl) -4- (1,3_benzyl-1π-5-yl) _ 1- (N-methyl -N-aniline carbonylmethyl) -pyrrolidine-3-carboxylic acid; 222 trans, trans-2 · (4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl ) -1- (1- (N-methyl-N-propylaminecarbonyl) ethyl) -pyrrolidine · 3-carboxylic acid; 223 trans, trans-2- (4-methoxyphenyl) _4- ( 1,3-Benzodifluoren-5-yl) -1-O- (N-methyl_N-propylaminecarbonyl) benzyl) -pyrrolidine-3-carboxylic acid; 224 trans, trans-2- (4-methoxyphenyl) · 4- (1,3-benzodifluoren-5-yl) -1_ (N-ethyl-N-propylaminecarbonylmethyl) -pyrrolidine-3-carboxylic acid; 225 Trans, trans_2_ (4-methoxyphenyl) _4_ (1,3-Benzodifluoren-5-yl) -1 · (N_ethyl_N-butylaminecarbonyl) -pyrrolidine-3-carboxylic acid; 226 trans, trans_2- (4 _Methoxyphenyl) · 4 · (1,3_benzodifluorene_5_yl) _ 1- (N-ethyl_N- (4_methoxyphenyl) aminocarbonyl) -pyrrolidine_3 _Carboxylic acid; 227 trans, trans-2_ (4-methoxyphenyl) -4- (1,3 · benzodiazine_5_yl) _ 1- (N-ethyl-N · aniline carbonyl ) · Pyrrolidine-3-carboxylic acid; 228 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzobisfluoren_5_yl) _ 1-(N- Ethyl-N-alaninylmethyl) -p-bilodine-3-metanoic acid; 229 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzo 2--5-yl) _ 1- (N · ethyl-N-isobutylaminecarbonylmethyl) -pyrrolidine_3_carboxylic acid; 230 trans'trans_2- (4-methoxyphenyl ) -4- (1,3_Benzodiπ No._5_based) _ -223- This paper size applies to China National Standard (CNS) A4 specification (210 × 297 mm) (Please read the precautions on the back before filling (This page)

581760 A7 B7 V. Description of the invention (221) 1- (N-ethyl-N · cyclopentylaminocarbonylmethyl) -pyrrolidin-3-carboxylic acid; 23 1 trans'trans-2- (4-form Lactyl) -4- (1,3-benzodiazin-5-yl) · 1- (N-ethyl-N_methoxyethylaminecarbonyl) -pyrrolidine-3-carboxylic acid; 232 trans , Trans-2- (4-methoxyphenyl) -4- (1,3-benzobisfluoren-5-yl) -1-(N-ethylbutoxyethylaminecarbonyl) -pyrrolidinecarboxyl Acid; 233 trans, trans-2- (1,3 · benzodifluorene · 5-yl) -4 ·) 4- (methoxyphenyl) _- 1- (N-ethyl_N_propylamine Carbonylmethyl) -pyrrolidin-3-carboxylic acid; 234 trans, trans_2 · (4-methoxyphenyl) -4_ (1,4 · benzodioxane-6_yl) -1- ( Ν-ethyl-Ν-propylaminocarbonylmethyl) _pyrrolidin-3-carboxylic acid; 235 trans, trans_2_ (4_methoxyphenyl) -4- (1,3 · benzodifluorene- 5_yl) -1_ (N_ethyl · N_isopropylaminecarboxymethyl) pyridine-3-carboxylic acid; 236 trans, trans_2 · (4_methoxyphenyl) -4- ( 1,3-benzobisfluorene_5-yl) _ ^ (N, N · diethylaminecarbonylmethyl) -pyrrolidine_3_carboxylic acid; 237 trans, trans · 2_ (4_methoxybenzene ) -4- (1,3-benzobisfluoren-5-yl) -1- (N-ethyl-N- (l-formyl) Propyl) amine carboxymethyl) slightly bite carboxylic acid; 238 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodifluorenyl_5_yl) _ 1 -(N-ethyl-N-anilinecarbonylmethyl) · 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) 239 trans, Trans_2_ (4 · methoxyphenyl) -4_ (1,3_benzodifluorene_5_yl) _ 1- (1- (N-ethyl-N-propylaminecarbonyl) ethyl) -pyrrole Pyridin-3-carboxylic acid; 240 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzobisfluorenyl-5-yl) _ 1 _ (α-(N- Ethyl_N-propylamine alkynyl) -Epiyl) -p-bilodine-3-metanoic acid; 241 trans, trans · 2 · (4 · methoxyphenyl) _4_ (1,3 · benzodifluorene -5-yl) _ 1- (N-methyl-N-isobutylaminecarbonylmethyl) · pyrrolidine-3-carboxylic acid; -224- This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297) (%) &Quot; '~~ Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 581760 Α7 Β7 V. Description of the invention (222) 242 trans, trans_2_ (4 · methoxyphenyl) _4_ (1,3 _Benzodifluorene_5_yl) _ 1- (N-methyl-N-cyclohexylamine Methyl) -pyrrolidin-3-carboxylic acid; 243 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzobisfluoren_5_yl) _ 1- (N, N-dipropylaminecarbonylmethyl) -pyrrolidine_3-carboxylic acid; 244 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodifluorene_ 5_yl > 1_ (isobutoxyethyl) -pyrrolidine-3-carboxylic acid; 245 trans, trans · 2- (4-methoxyphenyl) · 4 · (1,3 · benzodi啰 _5_yl) -1- (butylcontinyl) -pyrrolidin-3-carboxylic acid; 246 trans, trans-2- (4-methoxyphenyl) -4 · (1,3- Benzodifluoren-5-yl) -1- (isopropylpyridinylaminoethyl) -ratio 17 Gyodo-3; acid; 247 trans, trans-2- (4-methoxyphenyl) -4_ (1,3-benzodifluoren-5-yl) -1- (ethoxymethylcarbonylmethyl) -pyrrolidine-3-carboxylic acid; 248 trans, trans · 2 · (4- Methoxyphenyl) -4- (1,3-benzobisfluoren-5-yl) -1- (2-ethylbutyridinomethyl) _pyrrolidin-3-carboxylic acid; 249 trans, trans -2 · (4-methoxyphenyl) -4- (1,3-benzodiolin-5-yl) -1- (N-methyl-N- (3,4-dimethoxybenzyl) ) Aminocarbonylmethyl) ·, Bihadian_ 3-carboxylic acid; 250 trans, trans_2- (4_methoxyphenyl) -4_ (1,3_benzobis -5-yl) -1-[(1R) -1- (N-methyl-N-propylaminecarbonyl) butyl] -pyrrolidin-3-carboxylic acid; 251 trans, trans-2- (4- Methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) -1 _ [(1S) -1- (N-methyl-N-propylaminecarbonyl) butyl] _pyrrolidine-3 -Year-old acid; 252 trans, trans-2- (4 · methoxyphenyl) -4_ (1,3_benzodifluoren-5-yl)--225- This paper size applies to Chinese national standards (CNS ) Α4 specification (210X297 mm) (please read the precautions on the back before filling this page), 1T 581760 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Α7 Β7 V. Description of the invention (223) 1-(3-isopropyl Lactyl) -Obiloline-3 -read > 253 trans, trans-2- (4 · methoxyphenyl) -4_ (l, 3-benzodifluorene-5_yl) _ 1- (5-methylhexyl) -pyrrolidine_3-carboxylic acid; 254 trans, trans_2 · (4-methoxyphenyl) -xin (1,3-benzodifluorene_5_yl ) _ 1- (5 • methyl-2-hexenyl) -pyrrolidine-3-carboxylic acid; 255 trans'trans-2- (4-methoxyphenyl) -4- (1,3- Benzenedi-5-yl) · 1- (5-methyl-4-hexenyl) -pyrrolidin-3-carboxylic acid; 256 trans, trans-2- (4 · methoxyphenyl) -4- (1,3- Benzobisfluorene_5_yl) _ ^ (3,5-dimethyl-2-hexenyl) _pyrrolidin-3-carboxylic acid; 257 trans, trans-2- (4-methoxybenzene ) -4- (1,3-Benzodifluorenyl_5_yl) _ 1- (2- (N-methyl · N-isobutyric acid amino) ethyl) _Elobitum · 3_ Acid; 258 trans'trans-2- (4-methoxyphenyl) _4_ (1,3_benzodiρ_5_yl) _ 1- (N-methyl-N- (2,2 -Dimethylpropyl) aminocarbonylmethyl) _pyrrolidine_3-carboxylic acid; 259 trans, trans · 2- (4-methoxyphenyl) -4 · (1,3 · benzodihydrazine _5_yl) _ 1-(N-ethyl-N · butylaminomethyl) -ρ Bihadian-3-Junic acid; 260 trans, trans_2- (4-methoxyphenyl ) -4_ (1,3_Benzodifluorenyl) _ 1- (N-methyl-N-benzylaminecarbonylmethyl) -pyrrolidine-3-carboxylic acid; 261 trans, trans-2- ( 4-methoxyphenyl) -4- (5-hydroindenyl) -l- (N_methyl-N-propylaminecarbonylmethyl) -pyrrolidine-3-carboxylic acid; 262 trans, trans-2_ (4-methoxyphenyl) -4 · (2,3-dihydrobenzofuran-5-ylmethyl-N-propylaminocarbonylmethylpyrrolidine-3 · carboxylic acid; 263 trans, trans-2 -(4-methoxyphenyl) · 4- (1-methylindole_5_yl) _ (N-methyl_N_propylaminecarbonylmethyl)- Pyridine-3-carboxylic acid; -226- This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page) 1 «， 1Τ Central Bureau of Standards, Ministry of Economic Affairs Printed by the employee consumer cooperative 581760 A7 B7 V. Description of the invention (224) 264 trans, trans-2 · (4-methoxyphenyl) -4_ (2-naphthylH_ (N_methyl_N-propylaminecarbonyl) Methyl) -pyrrolidine-3-carboxylic acid; 265 trans, trans-2- (4-methoxyphenyl) _4_ (1,2_dimethoxy_4_phenyl) -1-(N -Methyl-N-propylamine, methyl), pilolide_3_metanoic acid; 266 trans, trans-2- (4-methoxyphenyl) -4- (1-methoxy_ 3-phenyl) _1β (N-methyl-N-propylaminecarbonylmethyl) -pyrrolidinecarboxylic acid; Examples 267-288 Following the procedures described in Example 1 and Scheme II, the following compounds were prepared. 267 trans, trans_3- (4_methoxyphenyl) -5- (1,3_benzodiazine_5_yl) _ 1-(propylaminomethyl) hamster p-bide- 4 _End acid; 268 trans'trans-3- (4-methoxyphenyl) _5_ (1,3-benzodiinyl) 1 (Amine-L-methyl) 4_ Junic acid; 269 trans'trans_3- (4 · methoxyphenyl) -5- (1,3_benzodiazine_5_yl) _ 1 (4 _airoyl) -TT Ππ 比 淀 4 read ^ fe; 270 trans'trans · 3 · (4_methyllactyl) -5- (1,3-benzobisπ_5_yl) _ 1- (2- Ethoxyethyl) -hexahydropyridine-4-carboxylic acid; 271 trans, trans-3- (4-methoxyphenyl) -5- (1,3_benzodifluorene_5_yl) A 1- (2-propanolactamyl) nitrogen p ratio is 4 to ^^; 272 trans'trans-3- (4-methoxyphenyl) -5- (1,3-benzodi it 5-yl) _ 1- [2- (2-methoxyethoxy) ethyl] -hexahydropyridine-4-carboxylic acid; 273 trans, trans-3- (4 · methoxyphenyl) _5_ (1,3_benzodioxin · 5_yl) _ 1- [2 · (2-ρBidianyl) ethyl] · ά0 0dian_4_ Jun acid; 274 trans, trans _3- (4-methoxyphenyl) -5- (1,3 · benzobisfluorene-5_yl) _ 1- (Morphine_4 · yl-Tanylazapyridine · 4_ Junic acid -227- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling out this page), 11 581760 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Description of the invention (22S) 275 trans, trans-3- (4-fluorenoxyphenyl) -5- (1,3-benzobis 1-(butylamine ^ -yl)-hamster 1 ^ lake- 4_read ^, 276 trans, trans-3- (4-methoxyphenyl) -5_ (1,3-benzobis 1- (4-methoxyphenylaminecarbonyl) -3 · hexahydropyridine -4-carboxylic acid; 277 trans, trans-3- (4-methoxyphenyl) -5_ (1,3-benzobis-1-acetamidinehexahydropyridine-3-carboxylic acid; 278 trans, Trans_3- (4_methoxyphenyl) -5 · (1,3_benzobis1- (2-furanfluorenyl) · hexahydropyridyl_3_carboxylic acid; 279 trans, trans -3- (4-methoxyphenyl) · 5- (1,3 · benzobis 1- (aniline carbonyl) _hexahydropyridine-4-carboxylic acid; 280 trans, trans-3 · (4_ Methoxyphenyl) -5 · (1,3_benzobis1- (allylaminecarbonylmethyl) -hexahydropyridine-4-carboxylic acid; 281 trans, trans-3_ (4-methoxyphenyl ) -5_ (1,3-benzobis 1- (n-butylaminecarbonylmethyl) _hexahydropyridine-4-carboxylic acid, · 2 82 trans, trans-3- (4-methoxyphenyl) -5- (1,3-benzobis 1- (N-n-butyl-N-methylaminocarbonylmethyl) -hexahydropyridine- 4. 283 trans, trans_3_ (4-methoxyphenyl) -5- (1,3-benzobis 1- (exo-blodo-1-ylcarbonylmethyl) -hexahydro p-bito -4-carboxylic acid 284 trans, trans_3_ (4 • methoxyphenyl) _5_ (1,3_benzobis 1- (isobutylaminecarbonylmethyl) -hexahydropyridine-4-carboxylic acid; 285 trans, trans-3- (4-methoxyphenyl) -5- (1,3-benzobis 1- (cyclopentylaminocarbonylmethyl) · hexahydropyridine-4-carboxylic acid; 286 Trans, trans_3_ (4-methoxyphenyl) -5- (1,3-benzobis 1- (morpholine-4-ylaminecarbonylmethyl) -hexahydropyridine-4-chi • 228 This paper size applies to China National Standard (CNS) A4 specification (210 × 297 mm) 啰 -5-based) _ 啰 · 5 · based 唠 _5-based; μ 啰 -5-based 啰 -5-based) _ 啰-5-yl) _ 唠 -5-yl) _ carboxylic acid; 啰 -5-yl; 9 9-5-yl) _ 唠 -5-yl) _ slogan-5 _yl) _ acid; (please first Read the notes on the back and fill out this page)-Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Invention Description (226) 287 Trans, Trans-3_ ( 4_methoxyphenyl) _5_ (1,3 · benzodifluorene_5_yl) _ 1- (2-phenoxyethyl) -hexahydropyridinecarboxylic acid; 288 trans, trans-3- ( 4-methoxyphenyl) -5- (1,3-benzodifluoren-5-yl) -1_ (methoxyethylaminocarbonyl) -hexahydropyridine_4-carboxylic acid; Example 289 trans, trans Formula 2- (4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) -1- (4-dibutylaminephenyl) -Ehalide · 3-Chinic acid 4-Nitro-fluorobenzene, trans, trans-2- (4-methoxybenzyl) -4- (1,3-benzodiazin-5-yl) bilodine-3 _carboxylic acid ethyl Vinegar (Example 6A) and diisopropylethylamine were heated in dioxane to form trans, trans-2- (4-methoxyphenyl) -4_ (1,3-benzo-π-deficiency-5 -Yl) -1- (4-nitrophenyl) -p-bilodine 3-ethyl acetate. Nitro compounds are converted into equivalent aminophenyl compounds. This reacts with Ding Chen and cyanoborohydride steel according to the method of Borch (J. Am. Chem. Soc. 93, 2897, 1971) to generate equivalent N, N-dibutylaminophenyl compounds. Examples of its use The i D method hydrolyzes with sodium hydroxide to produce the title compound. Example 290 trans, trans-2_ (4-methoxyphenyl V4_ (l, 3-benzobisfluoren-5-yl VW2-dibutylamino-pyrimidin-4-yl) · pyrrolidine_3_carboxy Acid 2 · (dibutylamino) · 4 · gas. Miyado was prepared from 2,4-dichloropyrimidine according to the method of Gershon (J. Heterocyclic Chem. 24, 205, 1987). This compound, trans, trans 2- (4-methoxyphenyl-4- (1,3_benzobisfluorene_5_yl) -pyrrolidine_3_ carboxylic acid ethyl ester (Example 6 A) and diisopropylethylamine in difluorene Heating in alkane to produce the intermediate ethyl ester, which was hydrolyzed with sodium hydroxide using the method of Example 1 D to produce the title compound. -229- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read first Note on the back, please fill out this page) Order 581760 A7 _ B7 V. Description of the invention (227) Example 291 Trans, trans-2- (4 • 甲 气 m_4- (l, 3- 笨 和 二 崎 _5 · Butyl-N-anilinecarbonylmethyl) -pyrrolidine_3_carboxylic acid The title compound was prepared according to the general procedure of Example 1. 1H NMR (CD3OD): ά 0.87 (t, 3H, J = 8); 1.2-1.35 (m? 2H); 1.35-1.5 (m? 2H); 2.78 (m9 2H); 3.10 (t, lH, J = 9); 3.26 (d, lH, J = 15); 3.44 (dd, lH, J = 5, 10); 3.5-3.7 (m, 3H); 3.77 (m, lH); 3.78 (s, 3H); 5.93 (s, 2H); 6.7-6.9 (m, 4H); 7.0-7.2 (m (5H); 7.4 (m, 3H). MS (DCl / NH3) m / e 531 (M + H) +. Analyzed and estimated C31H34N206: C, 70.17; H, 6.46; N, 5.28. Measured 値 ·· C, 70.36; H, 6.52; N, 4.99. Example 292 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzylidene-5_yl-butylamine Example of methyl-p-bilodine-3-lean acid steel salt 292Α 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)

^ T 3- (4-methoxybenzene, V3-ketopropionate ethyl ester was simultaneously reacted in a 65-liter reactor and a 35-liter reactor (the common bisection reflux system). At 4.0 kg (100 Mo Ear) 60% sodium hydride is maintained in the atmosphere and in the 32 liters of methyl chloroform and added to the reactor at ambient temperature. The mixture is allowed to settle for 5 minutes before it is allowed to settle. Aspirate 20 liters of the toluene solution. Add 28 Liter toluene, stir for 5 minutes, allow it to settle and draw another 28 liters of toluene solution. Add 68 liters of toluene and 8.4 liters (69.7 mol) of diethyl carbonate. Start stirring, and then start the flow of Syltherm in the reaction tube (Note 4 ). 5.0 kg (33.3 moles) of 4-methoxyacetophenone in 12 liters of toluene was added over 20 minutes. After the addition was completed, the sleeve temperature was reduced to 10 ° C, and continued at -230-

581760 A7 B7 V. Description of the invention (228) 撗: Mix for 16 hours. 6.7 liters (117 moles) of glacial acetic acid was added at the same rate in 23 liters of deionized water, which was also previously applied to the acetophenone solution. When the addition is complete, stop stirring and separate again. The aqueous layer was washed once with 13 liters of toluene. The mixed organic layer was washed twice with 6.7 liters / part of a 7% (w: w) sodium hydrogen carbonate aqueous solution. The toluene solution was washed once with 6.7 liters of a 23% (w: w) aqueous sodium vaporized solution. The organic solution was dried over 10 kg of sodium sulfate, filtered, and the solvent was removed on a rotary evaporator to produce the desired product.

Example 292B 3,4 · methylenedioxynitrovinyl) · 茇 In a 45-liter capacity low-temperature reactor with a pressure and anchor stirrer, 5.537 kg (36.9 mole) of hexahydropyridine was dissolved in Liters of methanol and 2.252 kg (36.9 moles) of nitromethane at 15 ° -20 ° C. The envelope temperature was set at _5 ° C, and the reaction solution was cooled to + 3.5 ° C. 3.10 kg (38.8 mol) of 50% (w: w) sodium hydroxide solution at 21 ° C diluted in 3.7 liters of water was pumped into it. The reaction temperature was maintained between 10 · 15C. After the addition is complete, the casing is reprinted. It is 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) at 1 ° C and continue to stir for 30 minutes. 7 kg of ice in 19 liters of water was added to dissolve most of the solids. The reaction mixture was filtered through canvas and passed through a 27R10SV Honeycomb membrane. The filtered solution was metered into a 21 ° C mixture of 7.4 liters of concentrated hydrochloric acid and 11.1 liters of deionized water. The final reaction temperature was 26 ° C. The resulting product was centrifuged and washed until the p Η of the washing solution was at least 6 (using ρ Η indicator paper). The crude product was dissolved in 92 liters of dichloromethane and the layers were separated. The aqueous layer was washed once with 2 liters of dichloromethane. The combined organic layers were dried over 1.2 kg of sulphuric acid, and filtered through Whatman # 1, paper, and filtered. Reduce the volume by 20% and cool the solution to 4 ° C. Via Whatman # 1 paper over -231-This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 581760 A7 _ B7 V. Description of Invention (229) It was dried in the air at ambient temperature and produced 1.584 kg (22%) of the first harvest in the presence of air leakage. MLS was concentrated to 25%, cooled similarly, filtered and dried to yield a second yield of 0.262 kg (4%). The yellow product is darkened in the light and air.

Example 292C llijj oxybenzyl))-3_Π, 3 · benzodifluorene-5_ylnitro-butyric acid ^ At ambient temperature, a 45 liter dressing reactor was charged with 5.619 kg (30.1 mole) 3,4 · methylenedioxy-1- (2-nitrovinyl) · benzene and 24 liters of ethyl acetate. A solution of 5.355 kg (24.1 mol) of 3_ (4-methoxyphenyl) _3_ketopropionate in 16 liters of ethyl acetate was added. 280 g (275 ml, 1.84 moles) of 1,8-diazinebicyclo [5.4.0] undec-7-ene was added in 4 equal portions over 2.5 hours. The reaction mixture was filtered through diatoms, and the resulting filtered solution was used in the next step without further purification.

Example 292D Oxyphenyl) · 4 · (1,3-benzodiazine · 5-yl) · 4,5-dihydro-3H_pyrrole-3: Ethyl carboxylate Product of Example 292C (1316 ml of solution including 300 G of 2- (4-methoxybenzyl) -3- (3,4-methylenedioxyphenyl) -4-nitrobutanoate in ethyl acetate) was added to a mixture containing RaNi # 28 (300 g) in a glass reactor. The reaction mixture was shaken at room temperature under a hydrogen atmosphere for 4 hours and filtered through 47 mm millipore at 0.20 microns. The filtrate was concentrated to 1.4 kg of a dark solution, and then purified by normal-phase silica gel chromatography, and dissolved in ethyl acetate: 85: 15. Pure fractions are mixed and concentrated (as above) until crystals are formed. The solution was cooled down and filtered. GU —- 232-This paper size is suitable for Guancai County (⑽) A4 size (210X297 mm) " " (Please read the precautions on the back before filling this page} Order by the Central Consumers Bureau of the Ministry of Economic Affairs Preparation 581760 Α7 ___ B7 V. Description of the invention (230) The body particles are washed with 2 liters of 85:15 hexane: ethyl acetate (0x :). The solid particles are dried to a constant weight of 193 4 g under a vacuum at 50 ° C The title compound (21% yield, melting point 80-81 C). An additional 200 g (23% yield) of the product was obtained from the mother liquor.

Example 292E Methoxyphenylbenzene # difluorene-5-, pyrrolidin_3_ ethyl acetate is magnetically stirred in the device, a liquid addition funnel, a temperature probe and a nitrogen inlet are filled into a 12-liter flask with 0.460 Kg of 2_ (4_methoxyphenyl) -4- (3,4-methylenedioxyphenyl) _4,5_dihydro-3H_pyrrole · 3-acrylic acid ethyl ester (125 mol). The reaction vessel was degassed with nitrogen. Add 3-7 liters of absolute ethanol and 1 12 liters of THF. 3 1 g of bromocresol green and 94.26 g of sodium cyanoborohydride (5 mol) are added. A solution containing 400 ml of absolute ethanol and 200 ml of 12 M HC1 was added. The reaction mixture was stirred for 30 minutes after the addition was complete. After the starting material was consumed, 0.5 liter of a 7% NaHC03 aqueous solution was added. The reaction mixture was concentrated and diluted with 5 liters of ethyl acetate. The organic layer was washed twice with 2 liters of a 7% NaHC03 aqueous solution, once with 2.5 liters of a 23% NaCl aqueous solution, and dried over 190 g of MgS04, filtered and concentrated to give 447 g of the title compound as a thick yellow oil.

Example 292F 2- (4-methoxyphenyl V4-H, 3-benzodifluorenyl-5-yl V1- (N, N-dibutylaminecarbonylmethyl) pyrimidine-3- # acid ethyl ester in The 22-liter device was overhead-stirred, and the flask with nitrogen inlet and condenser was filled with 2- (4-methoxyphenyl) -4 · (3,4-methylenedioxyphenyl) -pyrrolidine-3-carboxyl. Ethyl Acetate (2.223 kg '6.02 moles). The reaction vessel is degassed with nitrogen. Add 13.2 liters of acetonitrile, 3.66 liters of diisopropylethylamine (2.71 kg, 20.9 mols) and -233-. Standard (CNS) Α4 specification (2! 〇χ297 mm) (Please read the notes on the back before filling out this page), 1T-Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 ----- ~ ___ B7 5 , Description of the invention (231) —-, Hui Shi a catty monobutylaminomethyl bromide (6.26 mol). The mixture was at H 17 Xiaori Temple at 78 ° C. After the starting material disappeared, the mixture was concentrated until Crystals were formed. The solid was filtered and washed with 4 liters of ethyl acetate. Concentration was continued as above until all volatiles were removed. The residue was diluted with 40 liters of ethyl acetate and then with 2.0. Lift off Minnow water. The organic layer was washed in 8 liters 23% NaC1 $ solution, then to the square MgS〇4 399 kg · dried and filtered. K may be generated as 3.112 kg (96% yield) of the title compound as a dark oil.

Example 292G ^^-^ 111 {11 ^ 1 ^ phenyl) -4- (1,3-benzodifluorene_5_some hydrazine_pyrrolidine_ formula · 2- (4-methoxyphenyl V4_m- Preparation of dipyrrolidin-3-carboxylic acid ethyl ester In a 35 liter unit with overhead stirring, 3.112 kg of 2- (4-methoxyphenyl) -4_ (3,4- Methylenedioxyphenyl) -pyrrole_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 the mixture was refluxed at 79 ° C for 1 hour. The mixture was cooled to 15 ° C, and then 5 liters of a 7.6 M NaOH solution (38.1 mol) was added. The mixture was stirred at 15. (: 18 hours under stirring. The solvent evaporated The residue was dissolved in 158 liters of deionized water and extracted with 28 liters of ether. The ether solution was washed with 9.5 liters of deionized water. The aqueous washing solution was extracted with 3 liters of ether. 0.340 liters of 12 M HC1 were added to the aqueous layer. The aqueous layer Extracted with 24 liters of ethyl acetate. The organic layer was washed with 9 liters of a 23% aqueous NaCl solution, dried over 0.298 kg of MgS04, filtered, and concentrated to produce 2.132 kg of a dark oil. The oil was triturated with 18 liters of ether. Non-desired solid particles filter 、 _- 234- __ This paper size applies to China National Standard (CNS) 8-4 specification (2.0 × 297 mm) (Please read the precautions on the back before filling this page) 丨 «Order 581760 A7 B7 V. Description of the invention (232) Leave it for later use. The mother liquor is concentrated to give 1.102 kg of light foam. The foam is dissolved in 5.5 liters of ethyl acetate and heated to 65 ° C. 14 liters of hexane are added, the rate is slow enough to keep the solution refluxing The reaction mixture was cooled to 10 ° C and then filtered. The crystals were washed with 2 liters of ether (0 ° C), and then dried to constant weight at 50 ° C under air, yielding 0.846 kg (43% yield, melting point 119-1). 20 ° C) crude product, which can be further purified by normal phase silica gel chromatography.

Example 292H Formula, trans-2_ (4-methoxyphenyl) -4- (1,3-benzobisfluoren-5-yl) -1_〇 ^ .1 ^ -dibutylaminecarbonylmethylpyrrole In a 20-liter flask, add trans, trans-2- (4-methoxyphenyl) -4- (3,4-methylenedioxyphenyl) -1-N, N -Dibutylaminecarbonylmethyl) pyrrole 3-carboxylic acid (0.927 kg, 1.819 moles). Add 0.0720 kg of NaOH (1.80 moles) in 4.65 methanol. The reaction mixture was concentrated to an oil. Pentane (4 liters) was added and the solution was concentrated again. Pentane (4 liters) was added again and the solution was concentrated to give a light brown foam. The foam was dried at 50 ° C under air to a constant weight of 0.937 kg (97% yield) of the title compound. Example 293 trans'trans-U4-methoxyphenyl) -4- (1,3-benzodihen-5-a) -1- 丨 + 氤 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please (Please read the notes on the back before filling this page) Isopyrine-2- 蕤, a methyl l-ρbilodine-3- # acid title compound was prepared using the procedure of Example 1. NMR (CD3OD, 300 MHz) shows a mixture of isomers. MS (DC1 / Nh3) m / z 521. Analysis estimated C30H36N206. 1.3 TFA: C, 58.54; H, 6.62; N, 4.19. Measured 値: C, 58 · 34; Η, 5.58; N, 4.00. -235- This paper size applies Chinese National Standard (CMS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (233) Example 294 Anti-Position "trans ^ phenyl" _4_ (1? 3_pen ^ 二5_5_ Jibu 丨 3,3-Dimethyl ττ p-pyridylmethyl__Salodine_ The title compound was prepared using the procedure in Example i. Nmr (CD3〇d, 3⑻ MHz) showed geometric variation The presence of the structure. D 〇84 (s, 3H), 〇% (s, '3h), 1.35-1.6 (m, 4H), 3.83 (s, 3H), 5.96 (s, 2H), 6 81 (d , M J = 8), 6.90 (dd, 1H, J = 1, 8), 7.01 (d, 2H, J = 9), 7.03 (s, m), 7 47 (d, 2H, J = 9 ). MS (DC1 / NH3) m / z 495. Analytical estimates C28H'34N2 06 · '1.4 TFA: C, 56.55; H, 5.45; N, 4.28. Found 値: c 56 52; H, 5.83; N, 4.26 ° '' Example 295 trans' 4 ^ -2- (4-methoxyphenyl) · 4 · (1,3 · phenyl ^ yl Vl_i2_m_propyl_N_isobutoxycarbonylamino) Ethyl〗 _ ^^ _ 3_ # Acid title compound was prepared according to the method of Example 61, but in Example 6 iB was replaced by propylamine for methylamine 'and in Example 6 1 C was replaced by isobutyl chloroformate. Crude product Take 1: 1 diethyl ether / Grinded and purified with hexane. The resulting solid is dissolved in (CH / N and water, and freeze-dried to produce a white solid product. 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) iH NMR (CDC13, 300 MHz) d 0.80 (t, 3H, J = 7), 0.92 (m, 3H) 1.43 (h, 2H, J-7Hz), 1.7-1.9 (m, 1H), 2.72 ( m, 1H), 2 90 (m 2H), 3.10 (m, 2H), 3.25 (m, 2H), 3.40 (m, 1H), 3.55 (m, m)

3.62 (m, 1H), 3.7-3.9 (m, 2H), 3.78 (s, 3H), 5.95 (s, 2H), 6.72 (d, 1H, J = 8Hz), 6.82 (m, 3H), 7.00 (s, 1H), 7.30 (d, 2H J = 8 Hz). MS (DC1 / NH3) m / e 527 (M + H) +. Analytical estimates of C29H38N2O6 · 0.5 · H2〇: C, 65.03; H, 7.34; N, 5.23. Measured 値: -236- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (234) ~ C, 65.13; H, 6.96; N, 4.95. Example 296 trans, trans-2- (4'fluorenyl) _4_ (1,3_benzodizaki-a-""-[1,2,3,4_difluorene_Tomb Yijun ρ strain_ 2-Pyrylomethylmethyl · pbilodine_3_ complex acid The title compound was prepared using the procedure described in Example 1. ijj NMR (CD3OD, 300 MHz) showed the presence of geometric isomers. &Amp; 2 a (m , 2Η), (μ (s, 3H), 5.97 (s, 2H), 6.83 (d, 1H, J = 8), 6.9-7.0 (m, 3H), 7.03 (d, 1H, J = 2 ), 7.1-7.3 (m, 4H), 7.4-7.5 (m, 2H). MS (DC1 / NH3) m / z 515 0 Example 297 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the note on the back first) Please fill in this page again) trans'trans-2- (4-methoxyphenylbenzodiazine_5_yl) _u2_ (Ng-N-dimethylaminocarbonylamino) ethyl ιρρ Bihadian _3_ The title compound of ammonium acid was prepared in the same manner as in Example 61 except that propylamine was used in place of methylamine in Example 61B and dimethylaminoformamidine was used in place of Isobutanol in Example 61C. The crude product was prepared to prepare Purified by HPLC (Vydac " C18), and dissociated with a gradient of 10-70% CH3CN in 0.1% TFA. The fraction was freeze-dried to produce the product as a white solid. 1H NMR (C DC13, 300 MHz) d 0.70 (t, 3H, J = 7), 1.28 (m, 2H), 2.75 (s, 3H), 2.82 (m, 2H), 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 = 8Hz), 6.87 (m, 3H ), 7.05 (s, 1H), 7.40 (d, 2H, J = 8Hz). MS (DC1 / NH3) m / e 498 (M + H) +. Analysis estimates C27H35N30.6 · 1.25 TFA: C, 55.35; H, 5.71; N, 6.56. Measured 値: C, 55.41; H, 5.71; N, 6.41. -237-This paper size applies to China National Standard (CNS) A4 (21 × 297 mm) 581760 Central Standard of the Ministry of Economic Affairs Printed by the Consumer Cooperative of the Bureau A7 B7 V. Description of the Invention (235) Example 298 1 ^^^ Formula-2- (4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) _1- (2-〇 ^ -Nitrobenzenesulfonyl) amino) ethyl V pyrrolidine-3-carboxylic acid The procedure of Example 6 6 was used to prepare the title compound as a yellow solid 'Wp 85-87 ° C . 4 NMR (CDC13, 300 ΜΗζ) β 0.77 (t, J = 7.5Hz, 3H), 1.38 (six peak, J = 7.5Hz, 2H), 2.20-2.29 (m, 1H), 2-57-2.66 (m? 1H)? 2.82-3.15 (m, 4H)? 3.22 (t? J = 7.5Hz? 2H)? 3.38 (dd, J = 3Hz, J = 9Hz, 1H), 3.49-3.57 (m, 1H) , 3.59 (d, J = 9Hz, 1H), 3.83 (s, 3H), 5.96 (s, 2H), 6.73 (d, J = 8Hz, 1H), 6 82 (dd, J = iHz, J = 8Hz, 1H), 6.87 (d, J = 9Hz, 2H), 6.98 (d, J = lHz, 1H), 7.27 (d, J = 9Hz, 2H), 7.82 (d, J = 9Hz, 2H), 8.23 (d , J = 9Hz, 2H). MS (DC1 / NH3) m / e 612 (M + H) +. Example 299 Formula · 2_ (4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) -1- (2 · (N · Nyl · N-n-pentanesulfonamide) Methyl) ethyl pyrrolidine-3-carboxylic acid The procedure of Example 66 was used to prepare the title compound as a white solid. Mp 59-61 ° C NMR (CDC13, 300 MHz) d 0.79 (t, J = 7.5Hz, 3H), 0'90 (t, J = 6Hz, 3H), 1.26-1.32 (m, 4H), 1.43 (six peak, J = 7.5Hz, 2H), 1.67-1.76 (m, 2H), 2.23-2.32 (m, 1H), 2.70-3.08 (m, 7H), 3.15 · 3 · 32 (m, 2H), 3.42 (dd, J = 3Hz, J = 9Hz, 1H), 3.52-3.57 (m, 1H ), 3.63 (d, J = 9Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J = 7.5Hz, 1H), 6.83 (dd, J = lHz, J = 7.5 Hz, 1H), 6.87 (d, J = 8Hz, 2H), 7.00 (d, J = lHz, 1H), 7.32 (d, J = 8Hz, 2H) 0 MS (DC1 / NH3) m / e 561 (M + H) +. -238- This paper size applies Chinese National Standard (CNS) A4 specification (21〇 > < 297mm) (Please read the notes on the back before filling this page) Order 581760 A7 B7 V. Description of the Invention (236) Example 300 trans-, trans-2- (4-methoxyphenyl) -4-Π · 3_pyridobifluoren-5-yl) -1- (2_ (Ν · Propyl-N- (4-trifluoromethoxybenzenesulfonyl) amine) Ethyl pyrrolidine_3_carboxylic acid The procedure of Example 66 was used to prepare the title compound as a white solid. Mp 122-124 ° C. 4 NMR (CD30D, 300 MHz) d 0.75 (t, J = 7.5Hz, 3H), 1.26-1.45 (m5 2H), 2.96-3.08 (m, 2H), 3.23 (bs, 2H), 3.35 -3.45 (m, 2H), 3.52 (t, J = 10Hz, 1H), 3.81 (d, J = 9Hz, 2H), 3.86 (s, 3H), 3.92 (t, J = 9Hz, 1H), 4.63 (d, J = 10Hz, 1H), 5.97 (s, 2H), 6.82 (d, J = 9Hz, 1H), 6.93 (dd, J = 3Hz, J = 9Hz, 1H), 7.06-7.08 (m, 3H), 7.46 (d, J = 9Hz, 2H), 7.56 (d, J = 9Hz, 2H), 7.89 (d, J = 9Hz, 2H). MS (DC1 / NH3) m / e 651 (M + H) +. Example 301 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 · (4-methoxyphenyl) -4- (l, 3_benzene Pyridin-5-yl) -1- (2-N-propyl-N- (2-methyl-2-propenesulfonyl) amino) ethylpyrrolidine-3-carboxylic acid use example 6 6 In this step, the title compound was prepared as a white solid. m.p. 69-71 ° C. 4 NMR (CDC13, 300 MHz) d 0.79 (t, J = 7.5Hz, 3H), 1.93 (six bees, = 7.5112,211), 1.92 (8,311), 2.25-2.35 (m, 1H), 2.68_2 77 (m, 1H), 2.85-3.28 (m, 7H), 3.40 (d, J = 9Hz, 1H), 3.52-3.68 (m, 2H), 3.66 (d, J = 9Hz, 1H), 3.80 ( s, 3H), 4.92 (s, 1H), 5.07 (s, 1H), 5.97 (s, 2H), 6.74 (d, J = 7Hz, 1H), 6.82-6.89 (m, 3H), 7.01 (s, lH), 7.33 (d, J = 9Hz, 2H). MS (DC1 / NH3) m / e 545 (M + H) +. Example 302 trans, trans-2- (4 · methoxyphenyl V4- (l, 3_benzodifluoren-5-yl) -1- 丨 2-ethyl-239-This paper is applicable to China Standard (CNS) A4 specifications (210X297 mm 1 581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (237) The carboxylic acid title compound was prepared using the procedures described in the example. NMR (cD3OD, 300 MHz) shows a mixture of isomers. D Q 75 (t, 3H, j = 7), i 4 i 7 (m, 8H), 3.84 (s, 3H), 5.96 (s, 2H), 6 83 ( dmj = 8) 69i (d, 1H? J 8)? 7.0-7.1 (m? 3H)? 7.52 (d? 2H? J = 9) 〇MS (DC1 / NH3) m / z 495 Knife analysis estimate c28H34N206 · 1.6 TFA: C, 55.35; H, 5.30; N, 4.14. Found 値: C, 55 · 26; H, 5.37; N, 4 〇i. Example 303 trans, trans phenyl) _4_ (13_ 笨Benzamidine_5p_W2_m_i-I-N- (2-methylsulfonyl) amino, ethyl 4) _pyrrolidine_3 • acetic acid Using the procedure in Example 66, the title compound can be prepared as a white solid. mp72-73 1, NMR (CDC13, 300 MHz) J 0.82 (t, J = 7.5Hz, 3H), 1.04 (d, J = 6Hz, 6H), 1.44 (q, J = 7.5Hz , 2H), 2.15-2.33 (m, 2H), 2.5 -2.75 (m, 2H), 2.84-3.08 (m, 3H), 3.12-3.21 (m, lH), 3.23_3.45 (m, lH), 3.43 (d, J = llHz, lH), 3.55-3.62 (m, 1H), 3.66 (d, J = 9Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, J = 9Hz, 1H), 6.83 (dd, J = lHz, J = 9Hz, 1H), 6.87 (d, J = 9Hz, 2H), 7.02 (d, J = lHz, 1H), 7.33 (d, J = 9Hz, 2H). MS (DC1 / NH3) m / e 547 (M + H) +. Example 304 trans, trans-2_ (4-methoxyphenyl V4- (l, 3-benzodifluoren-5-yl) -l- (2- (N- Propyl-N-heptanesulfonamido) ethyl V pyrrolidine-3_carboxylic acid The procedure of Example 66 was used to prepare the title compound as a white solid. Mp 58-59 ° C, iH NMR (CDC13, 300 MHz) d 0.80 (t, 240- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling out this page) Order 581760 A7 B7 V. Description of the invention (238 ) J = 7.5Hz, 3H), 0.88 (t, J = 7Hz, 3H), 1.23-1.36 (m, 8H), 1.94 (q, J = 7.5Hz, 2H), 1.71 (Five Peaks, J = 7Hz, 2H ), 2.23-2.32 (m, 1H), 2.70-3.09 (m, 7H), 3.13-3.32 (m, 2H), 3.43 (dd, J = 3Hz, J = 9Hz, 1H), 3.52-3 .58 (m, 1H), 3.65 (d, J = 9Hz, 1H), 3.80 (s, 3H), 5.96 (s, 2H), 6.73 (d, J = 7Hz, 1H), 6.83 (dd, J = lHz, J = 7Hz, 1H), 6.87 (d, J = 9Hz, 2H), 7.01 (d, J = lHz, 1H), 7.32 (d, J = 9Hz, 2H). MS (DC1 / NH3) m / e 589 (M + H) +. Example 305 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- (4-methoxyphenyl) -4- (1,3-benzene Benzodifluorene · 5-yl VI- 丨 2-ΓΝ-ethylethenylamino) ethyl 1 ρ Bilodoline-3 _Lean acid was prepared according to the method of Example 61, but in Example 6 1 B Methylamine was replaced by ethylamine, and isobutylfluorenyl chloride was replaced by ethyl chloroformate in Example 61C. The crude product was purified by preparative HPLC (Vydac " C18), and was eluted with 10-70% CH3CN in a gradient of 0.1% TFA. The desired fraction was freeze-dried to produce the product as a white solid, 4 NMR (CDC13, 300 MHz) d 0.90 (t, 3H, J = 7), 1.22 (m, 3H), 3.0-3.2 (m, 4H), 3.42 ( m, 2H), 3.78 (s, 3H), 3.82 (m, 4H), 4.10 (q, 2H, J = 7Hz), 3.5 (br s, 1H), 5.97 (dd, 2H, J = 1, 7Hz) , 6.72 (d, 1H, J = 8Hz), 6.84 (m, 3H), 7.00 (s, 1H), 7.42 (d, 2H, J = 8Hz). MS (DC1 / NH3) m / e 485 (M + H) +. Analyze and estimate (: 261132142〇7 * 1.2D? 8: (:, 54.90; 11, 5.39; 1 ^, 4.5 measured): C, 55.01; H, 5.36; N, 4.56. Example 306 trans, trans Formula 2- (4-methoxybenzyl) -4- (1,3-benzobisfluoren-5-yl) -W2 彳 N-propyl-N-hexanesulfonamido) ethyl)- Pyrrolidine-3-carboxylic acid-241-This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Standards Department of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Description of Invention (239) Use The method of Example 6 6 can be used to prepare the title compound as a white solid, η · ρ · 59-6OX: 1U NMR (CDC13, 300 MHz) δ 0.80 (t, J = 7.5Hz, 3H), 0.89 (t , J = 7Hz, 3H), 1.25-1.46 (m, 6H), 1.53 (Six bees, J = 7.5Hz, 2H), 1.72 (Five peaks, J = 7Hz, 2H), 2.23-2 · 32〇, 1H), 2.72-3.08 (m, 7H), 3.15-3.32 (m, 2H), 3.43 (d, J = 9Hz, 1H), 3.55-3-62 (m, 1H), 3.65 (d, J = 10Hz , 1H), 3.80 (s, 3H), 5.96 (s, 2H), 6.74 (d, J = 7.5Hz, lH), 6.82 (d, J = 7.5Hz, lH), 6.87 (d, J = 9Hz, 2H), 7.01 (S, 1H), 7.32 (d, J = 9Hz, 2H). MS (DC1 / NH3) m / e 575 (M + H) +. Example 307 trans, trans-2- (4-ethoxyphenyl) -4_ (l, 3-benzodifluoren-5-yl) -1- 丨 N, N-di (n-butyl) amino The carbonylmethyl V pyrrolidine-3-carboxylic acid title compound was prepared in the same manner as in Examples 1 and 49, but in 49B, it was replaced by ethyl 4-ethylamidoethyl acetate (Krapcho et al., Org. Syn. The method of 47? 20 (1967) started from 4'-ethylacetophenone). NMR (CDC13, 300 MHz) d 7 · 31 (2H, d, J = 8Hz), 7.16 (2H, d, J = 8Hz), 7.03 (1H, d, J = 3Hz), 6.86 (1H, dd , J = 8 & 3Hz), 6.73 (1H, d, J = 9Hz), 5.94 (1H, d, J = 4Hz), 5.92 (1H, d, J = 4Hz), 3.77 (1H, d , J = 9Hz), 3.60 (1H, m), 3.53 · 3.23 (5H, m), 3.13-2.90 (4H, m), 2.73 (1H, d, J = 14Hz), 2.62 (2H, q, J = 9Hz), 1.45 (2H, m), 1.40-1.10 (6H, m), 1.02 (2H, m), 0.87 (3H, t, J = 7Hz), 0.78 (3H, t, J = 7Hz ) 0 m / e (DCI, NH3) 509 (MH +) Anal. C3OH4ON205 C 70.84; H 7.93; N 5.51. Measured 値 C, 70.80, H, 7.85, N 5.25. -242- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 public directors) (Please read the precautions on the back before filling this page)

581760 Α7 Β7 V. Description of the invention (240) Example 308 trans, trans-2 · (4-methoxyphenyl V4_g, 3_benzodifluorene_5_ylpropyl-N- (2_chloroethoxy Group) carbonylamino) ethyl 1 · pyrrolidine-3-carboxylic acid_ Prepared in the same manner as in Example 61, but in Example 6 1 B, propylamine was used instead of methylamine, and in Example 6 1 C, chloroformic acid 2 was used. -Chloroethyl replaces isobutyrine chloride. 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. ιΗ NMR (CDC13, 300 MHz) d 0 · 80 (t, 3H, J = 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), 7.0 (m, 1H), 7.30 (m, 2H). MS (DC1 / NH3) m / e 533 (M + H) +. Analysis estimates C27H33N207C1: C, 60.84; H, 6.24; N, 5.26. Found 値: C, 60 · 48; H, 6.04; N, 5.10. Example 309 trans, trans-2- (2-methoxyethyl V4- (l, 3-benzodifluoren-5-yl) _14Ν, Ν- C Please read the precautions on the back before filling in this page} -^ 1 Bis (n-butyl) aminocarbonylmethyl 1-pyrrolidin-3-carboxylic acid title compound printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy was prepared using the procedure described in Example 1, but in Example 1 A In this example, ethyl 5-methoxy-3-ketovalerate was used instead of ethyl 4-methoxybenzylacetate. The title compound was a yellow foam. 4 NMR (CDC13, 300 MHz) 6 0.91 (t, J = 7Hz) and 0.95 (t, J = 7Hz, 6H total), 1.28-1.41 (br m, 4H), 1.45-1.63 (br m, 4H), 2.00_2 · 20 (br m, 2H), 3.06 ( br t, J = 9Hz, 1H), 3.30 (s) and 3.20-3.68 (br m, 11H total), 3.72 · 4.10 (br m, 4H), 5.92 (s, 2H), 6.72 (d, J = 8.5 Hz, 1H), 6.82 (dd, -243-) This paper size applies to the Chinese National Standard (CNS) A4 specification (2 丨 〇 > < 297 mm) 581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Explanation of the invention (241) J = 1.5, 8 · 5Ηζ, 1H), 6.91 (d, J = 1.5Hz, 1H); MS (FAB) m / e 463 (M + H) +. Analyze C25H38N205 · H20: C, 62.48; H, 8.39; N, 5.83. Found 値: C, 62 · 13; H, 8.15; N, 5.69. Example 310 trans, trans-2- (4- Methylphenyl) -4- (1,3-benzodihum-5-yl) -1- (2 · (N-ethyl-n-pentanesulfonylamino) ethyl) · pyrrolidine-3- The title compound was prepared as a white solid using the procedure described in Example 66. mp 57-58 ° C, 4 NMR (CDC13, 300 MHz) d 0.89 (t, J = 7Hz, 3H), 1.0. 6 (t, J = 7.5Hz, 3H), 1.26-1.37 (m, 4H), 1.72 (Five ,, J = 7.5Hz, 2H), 2.22-2.32 (m, 1H), 2.71-2.96 (m, 5H ), 3.08 · 3.30 (m, 4H), 3.95 (d, J = 9Hz, 1H), 3.53-3.60 (m, lH), 3.67 (d, J = 9Hz, 1H), 3.80 (s, 1H), 5.97 (s, 2H), 6.73 (d, J = 9Hz, 1H), 6.82 (d, J = 9Hz, 1H), 6.88 (d, J = 9Hz, 2H), 7.02 (s, 1H), 7.33 (d, J = 9Hz, 2H). MS (DC1 / NH3) m / e 547 (M + H) +. Example 311 trans-, trans-2_ (4-methoxyphenyl) -4- (1,3 · benzobisfluoren-5-yl) -14N, N-one-% ^ hexylaminomethyl The 1-p-pyrrolidine-3 -lepic acid title compound was prepared using the procedure of Example 1. NMR (CD3OD, 300 MHz) d 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 = 8) , 6.86 (dd, 1H, J = 2, 8), 6.95 (d, 2H, J = 9), 7.04 (d, 1H, J = 2), 7.38 (d, 2H, J = 9). MS (DC1 / NH3) m / z 563. Analysis estimates C33H42N206 · 0.5 H20: C, 69.33; H, 7.58; N, 4.90. Found 値: C, 69.42; H, 7.29; N, 4.78. (Please read the precautions on the back before filling this page) -244- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 _B7_______ 5. Description of the invention (242) Example 312 trans, trans_2- (4-methoxyphenyl) -4_α, 3-benzobisfluoren-5-ylpropyl-N-tert-butoxycarbonylamino) ethyl Propylidroline-3_H The title compound was prepared using the procedure of Example 61, but in Example 6 jb the aqueous solution of methylamine was replaced with propylamine, and in the case of Example 61C was replaced by di-tert-butyl dicarbonate. NMR (CDsOD, 300MHz) suggests the presence of geometric isomers β 0.81 (t, 3H, J = 7), 1.2-1.5 (m, 11H), 3.78 〇, 3H), 5.92 (dd, 2H, J = l, 2), 6.74 (d, 1H, J = 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 (DCl / NH3) m / z 527. Analysis estimates C29H38N207: C, 66.14; H, 7.27; N, 5.32. Found 値: C, 66.05; H, 7.36; N, 5.15. Example 313 trans, trans-2- (4-methoxy-3-fluorophenyl) -4- (1,3-benzodifluorene-5-some, -_1- "N, N-bis ( The title compound of n-butyl) aminocarbonylmethylpyrrolidine-3-carboxylic acid was prepared by the methods of Examples 1 and 43, but 4-methoxy-3fluoroacetophenone was used instead of 4-methoxyacetophenone. Ketone. Mp 142-143 ° C. NMR (CDC13, 300 MHz) d 0.82 (t, J = 7Hz, 3H), 0.88 (t, J = 7Hz, 3H), 1.03-1.50 (m, 8H), 2.82 (d, J = 13Hz, 1H), 2.90-3.13 (m, 4H), 3.20-3.50 (m, 3H), 3.39 (d, J = 13H, 1H), 3.55-3.65 (m, 1H), 3.82 (d, J = 10Hz, 1H), 3.87 (s, 3H), 5.91 (dd, J = 2Hz, 4Hz, 2H), 6.72 (d, J = 8Hz, 1H), 6.83-6.91 (m, 2H), 6.99 (d, J = 2Hz, 1H), 7.06 (m, 2H). Analyzed and estimated c29H37N206F: C, 65.89; H, 7.06; N, 5.30. Measured radon: C, 65 · 82; H, 7.13; N , 5.29. _____- 245- This paper size is applicable to Chinese National Standard (CNS) A4 (2i〇χ297 mm) (Please read the precautions on the back before filling this page)

581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (243) Example 314 trans'trans · 2- (propyl) _4- (1,3 · benzodiyin-5-some） _1_ (2 · (N-propylpentanesulfonamido) ethyl) pyrrolidine-3-carboxylic acid Example 314A Propylpentanol continued to make aminepentanesulfonyl chloride (687 mg, 4.03 mmol) In 5 ml of CH2C12, add n-propylamine (0.40 ml, 4.82 mmol) and ethyl diisopropylamine (0.85 ml, 4.88 mmol) of ice-cooled solution in 5 ml of CH2C12 under nitrogen atmosphere. The reaction was stirred at 0 ° C for 30 minutes and then at 25 ° C for 4 hours. The solution was partitioned into 20 ml of a 1.0 M NaHS04 aqueous solution and 25 ml of CHWl2. The organic phase was washed successively with 25 ml of H20 and 25 ml of brine, then dried (Na2S04), filtered and concentrated under vacuum to yield 739 mg (3.83 mole) of the title compound as a white solid. TLC (25% EtOAc_hexane) Rf 0.23; iHNMRCCDCUjOOMHz) d0.92 (t, J = 7HZ, 3H), 0.97 (t, J = 7Hz, 3H), 1.28-1.50 (brm, 4H), 1.52- 1.68 (m, 2H), 1.75-1.90 (br m, 2H), 2.98-3.06 〇, 2H), 3.08 (q, J = 6Hz, 2H), 4.10-4.23 (br m, 1H); MS (DC1 / NH3) m / e 211 (M + NH4) + 〇 Example 314B trans, trans-4-Π, 3_benzodihum-5-yl) -1- (2-bromoethyl V2-propylpyrrole The title compound of ethyl pyridine-3-carboxylic acid was prepared according to the method of Example 61A, but the compound to be precipitated was replaced by the compound of Example 94B. -246- (Please read the precautions on the back before filling this page)

This paper size applies to China National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Description of Invention (244)

Example 314C Expanded 'trans-2- (propyl) -4- (1,3_benzodiazine-5_yl) -1- (2_ (N-propylpentanesulfonamido) ethyl Solution) Compound 314A (6.6 mg, 34 μmol) in ml of DMF 'treated with sodium hydride (2 mg, 60% oil dispersed phase, 12 mg NaH, 50 Micro moles). The resulting mixture was stirred at room temperature for 15 minutes. The compound of Example 189B (9.0 mg, 22 micromoles) was added to 0.1 ml of DMF, and 0.5 mg of tetra-n-butylammonium was added to break it. The reaction was sealed under argon and stirred at 60 ° C; stirred overnight. The reaction was concentrated under high vacuum and the residue was partitioned between 2 ml of saturated aqueous NaHC03 solution, 1 ml of water and 5 ml of EtOAc. The organic phase was washed with 1 ml of brine, dried over a pad of Na 2 SO 4, and the filtrate was concentrated to an oil under vacuum. The crude product was purified by preparative TLC (silica gel, 8 X 20 cm, 0.25 mm thick, and dissolved in 20% EtOAc_hexane, yielding 8.4 mg (73%) of the title compound as a wax.

Example 314D trans, trans-4- (1,3-benzobisfluoren-5-yl) -2- (propyl) -1- (2-0 ^ -propylpentafluorenylamino) ethyl The title compound p-pyridian-3 -carboxylic acid was prepared by the method of Example 71C. 4 NMR (CDC13, 300 MHz) d 0 · 88 · 1 · 00 (m, 9H), 1.20-1.55 (br m, 6H), 1.55-1.68 (m, 3H), 1.70-1.85 (brm, 2H), 1.90-2.16 (brm, 2H), 2.84-3.26 (br m, 6H), 3.26-3.90 (br m, 6H), 5.95 (s, 2H), 6.76 (d, J = 8Hz, 1H), 6.79 (m , 1H), 6.93 (br s, 1H); HRMS (FAB) estimates C25H41N206S (M + H) + 497.2685, measured 値 497.2679. 247- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (21 × 297 mm) (Please read the precautions on the back before filling out this page) · — 1T Printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperatives 581760 A7 __B7 V. Description of the invention (245) Example 3 15 trans, trans · 2 · (4-methoxyphenyl_4-Cl, 3_benzodifluoren-5-yl) -1 "2-0 ^ -Propyl-N-dimethyl-sulfamoylamino) ethylpyrrolidine-3-carboxylic acid The procedure of Example 66 was used to prepare the title compound as a white solid, mp 59-61Ό. 4 NMR (CDC13 , 300 MHz) d 0.79 (t, J = 7.5Hz, 3H), 1.45 (six peak, J = 7.5Hz, 2H), 2.22-2.31 (m, 1Η), 2.65 (s, 6H), 2.70-2.79 ( m, 1H), 2.85-3.04, 4H), 3.09-3.32 (m, 2H), 3.40 (d, J = 9Hz, 1H), 3.55 (t, J = 9Hz, 1H), 3.65 ( d, J = 9Hz, 1H), 3.81 (s, 3H), 5.96 (s, 2H), 6.75 (d, J = 9Hz, 1H), 6.83 (d, J = 9Hz, 1H), 6.88 (d , J = 9Hz, 2H), 7.02 (s, 1H), 7.34 (d, J = 9Hz, 2H). MS (DC1 / NH3) m / e 534 (M + H) +. Example 316 trans' trans -2- (4-methoxyphenyl) -4- (1,3_benzodi-2--5-yl) -1- 丨 2- (Ν_propyl -N- "4-methoxyphenyl 1 stilbene amine) propyl lp bilide _ 3_ leptin Example 316A trans, trans and cis-trans 2- (4-methazine ) · 4 · (1,3-Benzodizaki-5-yl) -1 · (3-bromopropyl) p-bilodine_3_Leptonic acid ethyl ester 2: 1 trans, trans and cis Formula, trans 2- (4-methoxyphenyl) -4- (1,3-benzodiazin-5-yl) -yrolidine-3-carboxylic acid ethyl acetate mixture (4.0 g, Prepared according to Example 1C), 32 ml of dibromopropane, and 200 mg of sodium bromide, and heat at i0 (rc for 1.25 hours. The excess of dibromopropane was removed under vacant space, and the residue was dissolved in formazan. After the carbon version was shaken, the solution was dried (Na2S04) and the solution was concentrated. The residue was chromatographed on Shi Xijiao and dissolved with 5: 1 hexane: EtOAc to give 5.22 (98%) of the title compound. -248- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) — * — '(Please read the precautions on the back before filling this page)

581760 A7 B7 V. Description of the invention (246)

Example 316B trans, trans and cis-trans 2- (4-methoxyphenyl) -4- (1,3-benzyl-5-yl) -1- (3-propylaminopropyl) pyrrolidine_ Ethyl 3-carboxylate Example 316A compound (5.22 g) was heated at 80 ° C with 35 ml of ethanol, 25 g of propylamine and 35 mg of cracked steel for 2 hours. The solvent was removed under emptiness. The residue was dissolved in toluene, shaken with potassium bicarbonate and dried (Na2S04). Concentration of the solution under airspace gave 4.96 g of the title compound as an orange oil. This was used in the next step without further purification.

Example 316C Expanded 'trans_2_ (4_methoxyphenyl) -4_ (1,3-benzodi p_5_yl) · 1_ 『2_ (N · propyl-N- [4-methyl Oxyphenyl 1 amine amino) propyl 1-ergoline_3 · carboxylic acid The method prepared in Example 6 6 and the compound prepared in Example 3 1 6 B and 4-methoxybenzenesulfonyl chloride contained Diisopropylethylamine in acetonitrile. The resulting product was chromatographed on silica gel (30% EtOAc / hexane) and hydrolyzed to the title compound in the same manner as in Example 1D. NMR (CDC13, 300 ΜΗζ) θ 0.83 (t, J = 7Hz, 3H), 1.40-1.52 (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), 2.84-3.03 (m, 4H), 3.19, 3.34 (m, 2H), 3.48-3.59 (m, 2H), 3.80 (s , 3H), 3.86 (s, 3H), 5.95 (s, 2H), 6.74 (d, J = 8Hz, 1H), 6.85 (d, J = 8Hz, 3H), 6.93 (d, J = 8HZ, 2H) , 7 02 (d, J = 2Hz, 1H), 7.29 (d, J = 8Hz, 2H), 7.69 (d, J = 8Hz, 2H). Analysis estimates C32H38N208S: C, 62.93; H, 6.27; N, 4.59. Found 値: C, 62.97; H, 6.39; N, 4.45. Example 317 trans, trans_2- (4-methoxyphenyl) -4_ (1.3- 茇 # 二 唠 5_ 基) -142-〇 ^--249_ This paper size applies Chinese National Standard (CNS) A4 Specifications (210x797 mm)-_ (Please read the notes on the back before filling this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (247) Propyl-N-propylsulfonylamino) propylpyrrolidine-3 -Carboxylic acid Using the method of Example 66, the propylamine compound prepared in Example 3 16B was reacted with propanesulfonyl chloride in acetonitrile containing diisopropylethylamine. The resulting product was chromatographed on silica gel (30% EtOAc / hexane) and hydrolyzed to the title compound by the method of Example ID. NMR (CDC13, 300 ΜΗζ) β 0.85 (t, J = 7Hz, 3H), 1.02 (t, J = 7Hz, 3H), 1.47-1.60 (m, 2H), 1.65_1.85 (m, 4H ), 2.04-2.16 (m, 1H), 2.42-2.57 (m, 1H), 2.72-3.11 (m, 5H), 3.25-3.41 (m, 2H), 3.50-3.62 (m, 2H), 3.80 (s , 3H), 5.85 (s, 2H), 6.72 (d, J = 8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (d, J = 2Hz, 1H), 7.30 (d, J = 9Hz, 2H). Analysis estimates C28H38N207S: C, 61.52; H, 7.01; N, 5.12. Found 値: C, 61.32; H, 7.01; N, 5.01. Example 318 trans, trans-2- (3-fluoro-4-methoxyphenyl) -4- (1.3 • mobibis-5-yl VI- (2_ (N-propyl-N-pentane Sulfonylamino) ethylpyrrolidine-3_ # acid Using the procedures of Example 313 and Example 66, the title compound was prepared as a white solid, mp 66-68 ° C. 4 NMR (CDC13, 300 MHz) d 0.81 ( t, J = 7.5Hz, 3H), 0.89 (t, J = 7Hz, 3H), 1.26-1.35 (m, 4H), 1.45 (six peak,] = 7.5 £ ^, 211), 1.68 off 1.76〇, 211 ), 2.25-2.33〇, 111), 2.72-2.92 (m, 5H), 2.97-3.12 (m, 2H), 3.16-3.33 (m, 2H), 3.43 (dd, J = 3Hz, J = 9Hz, 1H ), 3.53 · 3.660, 1H), 3.66 (d, J = 10Hz, 1H), 3.88 (s, 3H), 5.95 (s, 2H), 6.74 (d, J = 8Hz, 1H), 6.82 ( dd, J = lHz, J = 8Hz, 1H), 6.92 (t, J = 8Hz, 1H), 6.97 (d, J = lHz, 1H), 7.12 (d, J = 8Hz, 1H), 7.18 (dd, J = lHz, J = 12Hz, 1H). MS (DC1 / NH3) m / e 579 (M + H) +. -250-(Please read the notes on the back before filling out this page) 1 ^. -Order_ This paper size applies to China National Standard (CNS) A4 (210X297 mm) 581760 A7 B7 Employees' Cooperatives of Central Standards Bureau, Ministry of Economic Affairs Printed 5. Description of the Invention (248) Example 319 trans, trans-2- (4-pyridyl) _4-Π, 3-benzodifluoren-5-yl) -l_nST Ν. (N-butyl) amine The title compound of the carboxymethylmethyl l-ρ ratio p_3-multiacid was prepared by the methods of Examples 1 and 43 using 3-keto-3_ (4-pyridyl) propionic acid (J · Am · Chem · Soc ·, 1993, 115, 11705) instead of (4-methoxyfluorenyl) ethyl acetate, mp 131-132 ° C. NMR (CDC13 300 MHz) d0.82 (t, J = 7Hz, 3H), 0.88 (t, J = 7Hz, 3H), 1.05_ 1.50 (m, 8H), 2.90 (dd, J = 7Hz, 9Hz , 1Η), 2.97 (d, J = 13HZ, 1H), 3.00-3.25 (m, 4H), 3.32 (m, 1H), 3.39 (d, J = 13Hz, 1H), 3.45-3.52 (m, 1H) , 3.67-3.78 (m, 1H), 4.10 (d, J = 9Hz, 1H), 5.92 (dd, J = 2Hz, 4Hz, 2H), 6.75 (d, J = 9Hz, 1H), 6.90 (dd, J = 9Hz, 2Hz, 1H), 7.02 (d, J = 2Hz, 1H), 7.45 (d, J = 8Hz, 2H), 8.50 (d, J = 8Hz, 2H). Analysis estimates C27H35N305: C, 67.34; H, 7.33; N, 8.73. Found 値: C, 67.39; H, 7.45; N, 8.61. Example 320 trans'trans-2_ (4-methoxyphenyl) -4- (1,3-benzodiaz-5-yl) -1- "2- (N-propyl-N-diethyl Amine alkanoyl) ethyl lp ratio p each _3_ leptin The title compound was prepared using the procedure in Example 61, with propylamine in place of the methylamine aqueous solution in Example 6 1 B, and diethyl ester in Example 61C. Aminomethyl chloride replaces isobutylphosphonium chloride. NMR (CD30D, 300 ΜΗζ) β 0.74 (t, 3H, J = 7), 1.09 (t, 6H, J = 7), 1.33 (m, 2H), 3.17 (q, 4H, J = 7), 3.78 (s, 3H), 4.04 (m, 1H), 5.93 (s, 2H), 6.86 (d, 1H, J = 8), 7.06 (dd, 1H, J = 2, 8), 6.94 (d, 2H , J = 9), 7.04 (d, 1H, J = 2), 7.40 (d, 2H, J = 9). MS (DC1 / NH3) m / z 526. Analyze and estimate C29H39N3〇6 · -251-This paper is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm)-'' '2f Please read the precautions on the back before filling in this page} «-Order 581760 A7 _____B7_ _ 5. Description of the invention (2-phase) 0.1 TFA · C, 65 · 31; H, 7.34; N, 7.82. Measured c: c, 65 33; Η 7.43; Ν, 8.14 〇 Example 321_ trans name, trans Ή 4-methoxyphenyl benzodiamid-5-yl) -143,5-hydropyridine-carbonylmethyl ratio The pyridin-3-carboxylic acid title compound was prepared by the method of Example i. NMR (CD300D, 300 MHz) shows a mixture of isomers. j 〇μ (d, 3H, J = 7), 0.93 (d, 3H, J = 7), 3.82 (s, 3H), 5.95 (s, 2H), 6.82 (d, 1H, J = 8) , 6.89 (dd, 1H, J = 1, 8), 7.00 (d, 2H, J = 9), 7.03 (m, 1H), 7.47 (d, 2H, J = 9). MS (DC1 / NH3) m / z 495 〇 Example 322 trans'trans_2_ (4 · methoxyphenyl) _4 · (1,3_mobierazaki · 5_yl) · 1 · 丨 N, The title compound of N.bis (di-butyl) amino-l-methyl-l-p-bilodine-3-polyacid was prepared according to Example 1. NMR (CD3OD, 300 MHz) d 0.83 (t, 6H, J = 8), 1.27 (d, 6H, J = 7), 1.6 (m, 2H), 3.79 (s, 3H), 5.93 (s, 2H) , 6.75 (d, 1H, J = 8), 6.86 (d, 1H, J = 8), 6.94 (d, 2H, J = 9), 7.03 (d, 1H, J = 2), 7.35 (d , 2H, J = 9). MS (DC1 / NH3) m / z 511 0 Example 323 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 · (4_methoxy Benzoyl) -4_ (l, 3-benzodifluoren-5-yl) -14N- (2-methylphenyl VN-butylaminecarbonylmethyl 1-pyrrolidin-3-carboxylic acid The title compound is according to Example 1 Prepared by the method. MS (DC1 / NH3) m / z 545. Analyzed and estimated C32H36N206 · 0.9 H20: C, 68 · 53; Η, 6.79; N, 4.99. Measured 値: C, 68.56; H, 6.62 N, 4.71. ___ -252-_ This paper size applies to the Chinese National Standard (CNS) A4 (210 X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 _ _ B7 V. Description of the invention ( 25〇) Example 3 Trans, trans_2 彳 4-methoxybenzoyl ^ (1,3-benzodifluoren-5-yl) _1- | ^ _ (3 · methylphenyl VN-butyl The amine methylpyrrolidine-3-carboxylic acid title compound was prepared as 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 = 10), 3.3 (m, 1H), 3.44 (dd, 1H, J = 5, 10), 3.53 (m, 1H ), 3.60 (t, 2H , J = 7), 3.79 (s, 3H), 3.82 (m, 1H), 5.93 (s, 2H), 6.74 (d, 1H, J = 8), 6.8-6.9 (m, 5H), 7.06 (d, 1H, J = 2), 7.09 (d, 2H, J = 9), 7.18 (d, 1H, J = 7), 7.27 (t, 1H, J = 7). MS (DC1 / NH3 ) m / z 545. Analyzed C32H36N206 · 0.8 H20: C, 68.75; H, 6.78; N, 5.01. Measured 値 ·· C, 68.70; H, 6.67; N, 4.85 o Example 325

Trans, trans-4- (1,3-benzodifluorene_5_some) -2 oxomethyl) _1-((team: ^-dibutylaminecarbonylmethyl) pyrrolidine-3- Example of carboxylic acid 325A trans, trans · 4- (1,3-benzodifluoren-5-yl) -2_ (fluorenylmethyl) -1-((N, N-dibutylaminecarbonylmethyl) Pyrrolidine-3-carboxyl di_.! The procedure follows the procedures of Examples 1A-1D, but in Example 1 A, 4-benzyloxy-3-ketobutyric acid ethyl ester is used instead of 4-methoxybenzylethyl Acid ester to give the title compound as a colorless oil. TLC (30% EtOAc-hexane) 0.18; 4 NMR (CDC13, 300 MHz) d 0.88 (t, J = 7Hz, 6H), 1.17 (t, J = 7Hz, 3H), 1.20-1.34 (br m, 4H), 1.40-1.56 (br m, 3H), 2.85 (t, J = 8Hz, 1H), 2.98-3.30 (m, 5H), 3.39-3.60 ( m, 3H), 3.64-3.75 (m, 2H), -253- This paper size applies to China National Standard (CNS) A4 specification (210X29? mm) (Please read the precautions on the back before filling this page) Order 581760 A7 B7 V. Description of the invention (251) 3.92 (d, J_14Hz, 1H), 4.10 (two overlapping q, J = 6.5Hz, 2H), 4.53 (s, 2H), 5.91 (m, 2H), 6.69 ( d, J = 9Hz, 1H), 6.77 (dd, J = 1.5, 9Hz, 1H), 6.91 (d, J = 1.5Hz, 1H); MS (DC1 / NH3) m / e 553 (M + H) + 〇

Example 325B trans, trans · 4- (1,3_benzobisfluoren-5-yl) -2 • (benzyloxymethyl V1- (YN, N-dibutylaminecarbonylmethyl) pyrrolidine-3 · The title compound of carboxylic acid was prepared according to the procedure of Example 71C and showed a colorless glass. TLC (5% MeOH-CH2Cl2) Rf = 0.13; lH NMR (CDC13? 300 MHz) ά 0.86 (t, J = 7Hz), and 0.90 (t, J = 7Hz, 6H total), 1.15-1.52 (br m, 8H), 2.96-3.35 (br m, 5H), 3.50-3.75 (br m, 2H), 3.80 (dd, J = 3 , 13Hz, 1H), 3.88-4.40 (br m, 6H), 4.45 (AB, 2H), 5.90 (s, 2H), 6.70 (d, J = 8Hz, 1H), 6.84 (dd, J = l, 8Hz, 1H), 6.93 (d, J = lHz, 1H), 7.28-7.39 (m, 5H); MS (DC1 / NH3) m / e 524 (M + H) + 〇 Example 326 trans, Trans_4_ (1,3-benzobione-5-yl) -2- (1 per methyl

Example of butylaminocarbonylmethyl) pyrrolidine-3-carboxylic acid 326A 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-4- (1,3 -Epi-dioxo-5 -yl) _2 · (no methyl) -ΐ · ((N, N-dibutylaminecarbonylmethyl) pyrrolidine-3 · carboxylic acid ethyl ester Example 325 A product ( I28 mg, 0 mmol) and 25 mg of 20% Pd (OH) 2 / carbon in 7 ml of EtOH and stirred under 1 atmosphere of hydrogen for 4 8 hours. The mixture was filtered through a plug of filler and the catalyst was filtered at 2 X 10 mmol -254- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297mm) ~ 581760 Α7 Β7 V. Description of the invention (252) liters of EtOH for washing. A crude product was produced. Purification by flash chromatography (40% EtOAc · hexane) gave the title compound (please read the precautions on the back before filling this page).

Example 326B trans'trans-4- (1,3-benzodiain-5_yl) -2- (chimethyl) _1 _ (() ^,; ^ _ dibutylamino) yl Ex-base 1: The title compound of Luodian-3-folic acid was prepared according to the method of Example 71C. Example 327 trans'trans-4_ (1,3-benzodiazine-5-yl) -2- (N-methylpropylamino-3-yl) · 1-((Ν, Ν- 二Butylaminomethyl) pyrrolidine-3- # acid

Example 327A trans, trans-4- (1,3-benzobisfluoren-5-yl) -2- (methylfluorenyl) -l- (〇SLN-dibutylaminocarbonylmethyl) pyrrolidine-3 -The title compound of ethyl carboxylate was prepared from the selective oxidation of the compound of Example 326A (such as by Swern oxidation of DMSO, chlorchloramine, ethyldiisopropylamine, or by Dess-Martin periodinane)

Example 327B The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed trans'trans-4- (1,3 · benzodi 17-5-yl) -2- (0-Second-Butylpentamyl Edition- 3-yldibutylaminecarbonylmethyl) pyrrolidine-3-carboxylic acid ethyl ester The title compound was prepared by condensing the compound of Example 327A with triphenylphosphineacetic acid third-butyl ester in CH2C12.

Example 327C trans, trans-4-II · 3-benzodiazin-5-yl) -2- (acrylic-3-yl) -1-((N, N-dibutylaminomethyl) Pyrrolidine_3_Ethyl Acetate-255-This paper size applies to Chinese National Standards (CNS) Α4 specifications (2 丨 〇 > < 297 public directors) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 Α7 ___ Β7 V. Description of the Invention (253) The title compound was produced from the reaction of Example 327B with trifluoroacetic acid in ch2C12 (1: 1).

Example 327D Expansive 'trans-4- (1,3-benzodiazine-5-yl) -2- (N-methapropionate ~ fermentamine_3-yl) -1-((Ν, Ν · Dibutylamine methyl group) ρ ratio p each -3- # acid ethyl acetate The title compound was produced from the condensation of the compound 327C in methylamine hydrochloride, and was carried out in the presence of carbodiimide (such as N-ethyl Propyl-s (3-dimethylamino) propylcarbodiimide, DCC). Example 327E trans'trans-4- (1,3-benzobis ^ 7thio-5-yl) -2- () ^-Methylpropanamine_3-yl) -1 _ ((N, N · dibutylaminomethyl) pilolide-3-weiric acid The title compound is shown in Example 327D Compound with lithium hydroxide It is generated according to the reaction of the step 71C. Example 328

Trans'trans-4- (1,3-benzobenzo-5-5-yl) -2- (1-meryl-2-propene-3-a certain V 1-((N, N-dibutylamine Example of carbonylmethyl) pyrrolidine-3 · carboxylic acid 328A trans'trans-4- (1,3-benzobenzo-5-yl) -2. (1-meryl-2 3_ Some) 1-((N, N-dibutylamine post-methyl) p Bihadien-3. Acetyl diisocyanate The title compound was prepared by reacting the compound of Example 327C with a borane methylsulfide complex. produce.

Example 328B trans, trans_4_ (1,3-benzodifluoren-5-yl V2- (l-hydroxy-2-propanyldi-3-yl) _; [_ ((Ν, Ν · 二 丁Aminocarbonylmethyl) pyrrolidine-3-carboxylic acid-256- This paper size applies to the Chinese National Standard (CNS) A4 size (210X297 mm) (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs, 1T 581760 Α7 B7 V. Description of the Invention (254) The title compound was produced by condensing the compound of Example 3 2 8 A with lithium hydroxide according to the method of Example 71C. Example 329

Trans, trans-4- (1,3-benzobis.thio-5-yl) -2- (N-methylaminemethyl) -1_ ((N, N-dibutylaminecarbonylmethyl) pyrrole Examples of pyridin-3-carboxylic acids 329A trans'trans-4_ (1,3 -benzodi-p--5-yl) -2- (N-neaminemethyl) -1_ ((N, N_di The butylamine carbonylmethyl) pyrrolidine-3.carboxylate ethyl title compound was produced from the condensation of the compound of Example 327A with benzylamine in the presence of sodium cyanoborohydride in the presence of ethanol.

Example 329B trans'trans-4- (1,3-benzodioxo-5-yl) -2 _ (! ^-Epiaminomethyl) -1 · ((N, N-dibutylaminecarbonylmethyl) Yl) pyrrolidine_3-miao 醢 The title compound was produced from the reaction of the compound of Example 329A with lithium hydroxide according to the procedure of Example 71C. Example 330 trans, trans_4_ (1,3-benzyl-Nisaki-5- ) · 2- (N · Acetyl-N · Aminomethyldibutylaminecarbonylmethyl) pyrrolidine-3- Example 330A trans'trans-4_ (1,3 _Yl) -2_ (N-ethynylmethylamine) -1-((N, N-dibutylaminomethyl) pilolide_3_acetic acid ethyl acetate title compound from Example 329A compound It is produced by reaction with vinegar and in the presence of pyridine or triethylamine. -257- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back before filling in this Page), 1T 581760 A7 B7 V. Description of the invention (255)

Example 330B trans, trans-4_ (1,3-benzodihum-5-yl) _2- (N-ethylfluorenyl-N_fluorenylmethyl) -1 · ((N, N_dibutyl Aminocarbonylmethyl) pyrrolidine-3 · # acid The title compound was produced from the reaction of the compound of Example 330A with lithium hydroxide according to the method of Example 71C. Example 331 5-yl) -2- (ethynyl) · 1-((Ν, Ν- 二

Example of butylaminocarbonylmethyl) pyrrolidine-3-carboxylic acid 331A trans, trans_4-α, 3-benzodiammine-5 · yl) _2- (ethynyl) -1 · ((Ν, Ν Dibutylaminecarbonylmethyl) pyrrolidine-3-carboxylic acid ethyl ester The title compound was prepared using the method of Corey and Fuchs (in Tetrahedron Lett. 1972, 3769-72) using the compound of Example 32: 7A.

Example 331B trans, trans-4- (1,3-benzobisfluorene_5-yl) _2- (ethynyl) -1-((Team: ^-bis-butylaminecarbonylmethyl) pyrrolidine- The 3-carboxylic acid title compound was produced from the reaction of Example 33 1A compound with lithium hydroxide according to the method of Example 71C. Example 332 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, trans-trans-4- (1,3 benzo Example: 332A trans, trans-4_ (1,3) 2- (1 pentyl 1-((N, N dibutylaminocarbonylmethyl) pyrrolidine-3-carboxylic acid example) _Benzodifluorene · 5 · yl) _2- (pentynyl V: L _ ((N, N-Dibutylaminecarbonylmethyl) pyrrolidine-3-carboxylic acid ethyl ester-258-) This paper is applicable to China Standard (CNS) A4 size (210x297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 _ B7 V. Description of the invention (256) The title compound was catalyzed by the coupling of Example 206A with palladium propyliodide Cheng's method using Taylor (J. Org. Chem. 1989, 54 (15) 3618-24) 0

Example 332B trans, trans_4_ (1,3-benzodihex-5_yl) _2-Π · Α: alkynyl-butanyl: ^^ methyl) p-ratio The compound was produced from the reaction of the compound of Example 3 3 2 A with the bell hydroxide according to the method of Example 71C. Example 333 trans'trans-2- (4 · methoxyphenyl) -4- (1,3-benzodiazin-5-yl) (2,6-dione hexahydrop-pyridyl) ethyl The compound 61A of Example 1-Elodoline-3-Folic Acid was added to a solution of glutaridine imine sodium salt in dimethylformamide. After stirring for 24 hours, water was added and the mixture was extracted with ether. The resulting glutariminium was hydrolyzed to the title compound by the method of Example ID. Example 334 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodi-17-5-yl) 1-diphenylaminecarbonylmethyl 1-pyrrolidin-3- The carboxylic acid title compound was prepared in the same manner as in Example 1. 4 NMR (300 MHz CD3OD) d 2.83 (dd, 1, J = 8.1, 9.7), 2.99 (d, 1, J = 15.4), 3.19 (t, 1, J = 9.5), 3.49 (d, 1 , J = 15.3), 3.51 (dd, 1, J = 4.6, 9.5), 3.57 (m, 1), 3.79 (s, 3), 3.85 (d, 1, J = 9.5), 5.90 (s, 2) , 6.71 (d, l, J = 8.0), 6.84 (m, 3), 7.04 (d, l, J = 1.6), 7.14-7.16 (m, 6), 7.19-7.34 (m, 6); MS ( DC1 / NH3) m / z 551 '· Analysis-259- _ This paper size applies to China National Standard (CNS) A4 (210x297 mm) (Please read the precautions on the back before filling this page)

581760 A7 B7 V. Description of the invention (257) Estimate C33H3〇N2〇6 ··· 65Η20 · 0.35C2H5OCOCH3: C, 69.77; H, 5.77; N, 4.76. Found 値: C, 69 · 75; Η, 5.55; N, 4.64. Example 335 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodihex-5-some-monoisopropylamidomethyl 1-? Bilodine-3 -The title compound of the acid acid was prepared according to the method of Example 1. 1H NMR (300 MHz CD3OD) β 0.95 (d, 3, J = 6.5), 1.24 (d, 3, J = 6.4), 1.30 (d, 6, J = 6.8 ), 2.85 (d, 1, J = 12.5), 3.04 (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 (DC1 / NH3) m / z 483. Analyzed and estimated C27H34N206 · 65.86 EtOAc: C, 65.86; H, 7.32; N, 5.19. Measured 値: C, 5.74; H, 7.26; N, 5.52. Example 336 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-trans-2- (3 -Ga-4-methoxyphenyl) -4- (1,3-benzyl di-5-yl (2-N-propyl-N-butanesulfonamido) ethylpyrrolidine- 3- # Acid Using the methods of Examples 3 13 and 6 6 to prepare the title compound as a white solid, mp · 65-66 ° C .4 NMR (CDC13, 300MHz) J 0.82 (t, J = 7.5Hz, 3H), 0.92 (t, J = 7.5Hz, 3H), 1.34-1.52 (m, 4H), 1.72 (Five peaks, J = 7.5Hz , 2H), 2.25-2.35〇, 1H), 2.72 · 2.29494, 5Η), 2.97-3.12 (m, 2H), 3.19-3.46 (m, 2H), 3.44 (d, J = 9Hz, 1H), 3.53-3.60 (m, 1H), 3.67 (d, J = 9Hz, 1H), 3.89 (s, 3H), 5.95 (s, 2H), 6.74 (d, J = 8Hz, 1H ), 6.82 (d, J = 8Hz, 1H), 6.92 (t, J = 9Hz, 1H), .6.97 (s, 1H), 7.12 (d, J = 9Hz, 1H), 7.18 (d, J = 12Hz , 1H). -260- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 581760 A7 B7 V. Description of the invention (258) MS (DC1 / NH3) m / e 565 (M + H) +. Example 337 Using the methods of the above examples, the compounds disclosed in Table 1 were prepared.

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557.

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

560 ·

561.

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567. 581760 A7 B7 V. Description of Invention (294) Table 1 continued

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682. 671.

674.

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675 ·

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681 ·

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Table 2A

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(Please read the precautions on the back before filling this page) 311-This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (3009) Table 2A continued

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88.

Table 2A continued

(Please read the precautions on the back before filling this page) -313- This paper size is applicable to the Chinese National Standard (CNS) A4 size (210X297 mm) 581760 A7 B7 V. Description of the invention (311) Printed by the Bureau's Consumer Cooperative

(Please read the precautions on the back before filling this page) -314- This paper size is applicable to the Chinese National Standard (CNS) A4 size (210X297 mm) 581760 A7 B7 V. Description of the invention (312) Table 2A continued

(Please read the precautions on the back before filling out this page) Clothing · Order Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

-315- This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 581760 A7 B7 V. Description of invention (313) Table 2A continued

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130.

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-322- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 581760 A7 B7

Table 2A continued

-323- (Please read the precautions on the back before filling this page) This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) 581760 A7 B7 V. Description of Invention (321) Table 2A continued

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-325- This paper size applies to Chinese National Standard (CNS) A4 (210X297mm) 581760 A7 B7 V. Description of Invention (323) Table 2A continued

241 · 242. 243. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

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253. 254. 255.

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272.

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275. 276 · Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

277.

-328 This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 581760 A7 B7 V. Description of invention (326) Table 2A continued

(Please read the notes on the back before filling out this page) 284. 285 ·

Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

292.

-329- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 581760 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Table 2A continued

299 ·

〇

-330-

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310. 311.

313.

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(Please read the notes on the back before filling out this page) 325. 326. 327 ·

328.

331. 332.

Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

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

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374 ·

-335- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of invention (333) Table 2A continued

376.

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385.

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Table 2A continued

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

423 ·

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432 ·

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137. (Please read the notes on the back before filling out this page) 138.

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581760 A7 B7 V. Description of the invention (349) Table 2B continued

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169.

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175. 173 ·

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184. 185. 186.

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220. 218.

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430.

MVv ΟΜβ Ο ΟΜβ O 431. 432.

Mect ^ OMe 〇〇Μθ O 433. 434.

OMo O 438.

440. OMe

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

This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 581760 A7 B7 V. Description of invention (367) Table 2B continued

R

R

R Β ^ 〇ίγΑ yyr4 446. 447. 445.

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

451 449.

452. 450

453.

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 454.

457. 455.

458. 456.

459. -370 This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 581760 A7 B7 V. Description of invention (368) Table 2B continued

R

R

R

462. 460.

464. (Please read the notes on the back before filling this page) 463 ·

467. 465.

468 ·

469. 470. Consumer Cooperatives of Central Standards Bureau of Ministry of Economic Affairs

472.

paV 471 ·

473. f ^^ ci 474. -371-This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 581760 A7 B7 V. Description of Invention (369) Table 2B continued

R

R

R

Bx ^ BXrV 478 · 477 ·

(Please read the notes on the back before filling this page) 479.

480.

, 1T 481.

482.

486. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487.

488. ^ v 489. -372- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (37〇) system

R 490 RO 491. R 492. * TWV / · Ο 494. 495. 493. ο 496. o 497. 498. ° 〇 AQQ o 500 · cX o 501. H \ 7C7. O 502. 〇vIx ^ o 503. o 504. 505. 506. 507. -373- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) (Please read the notes on the back before filling this page) 581760 A7 B7 V. Invention Explanation (371) Employees' Cooperatives, Central Standards Bureau, Ministry of Economic Affairs, India

Table 2B continued R Ψ 508. R 509 · R ν ^ γν; ςΐΠ 511 · 512. Ο IU. Σΐ × XxV1 515, w 1 〇 · 516. 〇 I 517. 518 519. W 1 w · x ^ V '520 . 521. 522. -374- (Please read the notes on the back before filling this page)

This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of invention (372) Table 2B continued

R

R

R

523. 〇 524. 525. 527. 528. (Please read the notes on the back before filling this page) 526.

529 Private 1 530. 531.

532. 533. 534. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

535. 536 · 537. -375- This paper size is applicable to China National Standard (CNS) A4 (210X297mm) 581760 A7 B7 V. Description of Invention (373) Table 2B continued

V 9 3 5

V---V

V V

(Please read the notes on the back before filling out this page) Order Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

ο 5 5 55 This paper size applies to Chinese national standards ((581760 Α7 Β7 V. Description of invention (374) Table 2B continued

R

R

R X7V xrr 553. XX V1 554.

557. 555.

558. (Please read the notes on the back before filling this page) 556.

559.

560.

563. 561.

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

566. 564.

567. 565. -377- This paper size applies to China National Standard (CNS) Α4 size (210X 297 mm) 581760 A7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

This paper size applies to China National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page)

581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

581760 Printed by the Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs

(Please read the precautions on the back before filling in this page) This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) '· Clothes · Order _ «581760 A7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

(Please read the precautions on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm)

1T 581760 A7 B7 V. Description of the invention (379) Table 2B continued

R

R

R

〇 629.

(Please read the notes on the back before filling this page) 631. 632. Example 339 Using the method of the above examples, compounds containing the parent structure disclosed in Table 3 A and the R substituent in Table 3B can be prepared. Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs -382- This paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) 581760 A7 B7 V. Description of the invention (38)

Table 3A

MOMO

(Please read the precautions on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

8·

10.

-383- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of invention (381) Table 3A continued

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

Printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs -384- This paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) 581760 Α7 Β7 V. Description of the invention (382) Table 3B

R

R

R 2 · 4 · 5. ° 3.

(Please read the notes on the back before filling out this page) V " 9 · 8 · 10 · 11. 12. ο Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 13.

ο

v ^ OyiL 15. 16. 19. 14.

ο 17. 20. H3〇CS ^ i 18. " 5 ^ 21. -385- This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 581760 A7 B7 V. Description of the invention (383) Table 3B Continued

R

R

R

3αΥΊι 22. 24.

25. 23.

27. f3〇 ^

26. FH2 (

29. fh2c < ^ v (Please read the notes on the back before filling out this page) 28. 30.

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 31. 32. 33. f = 2〇, 35. F3a ^ 2, 36. 34.

37.

38. 40. 39 ·

42. 41. 386- This paper size applies to Chinese National Standard (CNS) A4 (210X 297mm) 581760 A7 B7 V. Description of Invention (384)

(Please read the notes on the back before filling in this book) -387- 81760 A7 B7 V. Description of the invention (385) Table 3B continued

R

R or 61. 〇CHa

R

63.

cSV 62. (Please read the notes on the back before filling out this page) 64. 65. 66. 67. 68. 5v 69.

? h3 Guang 70. 71. 72. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 73. 76. 74. 75. 77. 78. _388- This paper size applies to China National Standard (CNS) A4 (210X 297 mm) ) 581760 A7 B7 V. Description of the invention (386) Table 3B continued

R

R

R

81 80. 79.

82.

85. 83 ·

86 ·

CK

87.

89.

cTo 90. f3c ^ 5 ^ Fa > 〇? ^ 91. 92. 93. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 94. 97. 98. 95. 96.

99. 389 The paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 581760 A7 B7 V. Description of the invention (387)

R

Table 3B continued R

R

100.

101. 102.

Hgcor ^ j 103 ·

h3co ^ S 105. (Read the precautions on the back before filling in this page)

106 ·

Fnf h3c〇T ^ 108.

Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

116. 117. -390- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 60 1 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 8 5 A7 B7 V. Description of Invention (388) Table 3B continued

R

R

R 119 · 120 · (Please read the notes on the back before filling out this page) 121 · 122. 123.

Qxa 124. 126.

S〇rV 125 ·

128. 127. 129.

132. 130 · 131. 391-This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 60 8 5 7 A7 B7 V. Description of invention (389)

R Table 3B continued

R

R 134. 133.

136.

? ρ3 Τ " ° X > V 135.

138. (Please read the notes on the back before filling this page) 137.

139.

141. Order 140. 143. 144. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 142.

145. 146. 147. -392- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (39〇) I i I R Table 3B continued RR 1 1 N 1 Please first 1 V 148. α ^ ΥΑ 149. α ^ (ΧΤΑ Read 1 Read back 1 | 1 thing 1 XrV. 151 · h trr% 150. cXrV < co item I refill 4 1 W Page 1 '^^ 1 1 154. 10 ^ 1 «ρ ^ γνί ιςς% r Η ΙΓβ 1 1 1 Order 1 1 Ψ 157. α ^ 〇ΎΑ IOO · yyrA -ICQ 1 1 1 1 m 158. {^ ΎΑ 10% / »1 1 1 1 1 160. 161. 162. 1 1 1 1 1 -393- 1 1 1 1 1 This paper size applies Chinese National Standard (CNS) A4 (210 X 297) 60) 60 1 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 8 5 A7 B7 V. Description of Invention (391)

R

163.

169. Table 3B continued

R

R

Ixrr " 164.

167. 165 ·

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

1T 170. 171 ·

Nax ^ r ^ 172. 173. 0 174. _ Lin | 175. 176. 177. -394- This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 581760 A7 B7 V. Description of the invention ( 392) Table 3B continued

R

R

R

180.

Ν Ο

A 182. 183 ·

186.

Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

190. 191. 192. -395- (Please read the notes on the back before filling this page)

This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 0 8 5 7i A7 B7 V. Description of invention (393) Table 3B continued

R

193. 196. R 194. \ yr 197.

R 195. (Please read the notes on the back before filling this page) 198.

201 ·, ... !! 199. 200.

\ yrA \ yxA 2202.203.

204. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

205.

206. 207. -396- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 30 8 5 yc A7 B7 V. Description of invention (394) Table 3B continued

R

R

R

\ yrA 208.

210. 211.

215. 216 ·

uCrV

uyrA 217. 218. 219. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

220. 221.

-397 (Please read the notes on the back before filling this page)

This paper size applies to the Chinese National Standard (CNS) A4 (210X 297 mm) 1 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs fs so A7 B7 V. Description of the invention (395)

R

223.

226. Table 3B continued

R

R xiyr 224. 225. 227.

228.

231 ·

Device A 232.

235. 233.

236. -398- This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297mm) 234 · 237. (Please read the precautions on the back before filling this page)

50 Jr% 11 8 5 A7 B7 V. Description of the invention (396) Table 3B continued

R

R

R

239. 240.

241. 243.

242.

245. 246 ·

247 ·

Printed by CcV Consumer Standards Cooperative of Central Bureau of Standards, Ministry of Economic Affairs

250. 248 ·

252. 249.

252 · -399- (Please read the notes on the back before filling this page)

This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 581760 A7 B7 V. Description of invention (397) Table 3B continued

R

R

R

253 ·

255. 254.

256. 257. 258. Each # must be 259. 260. 261.

264. (Please read the precautions on the back before filling this page)

, 1T The Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs rupture 262.

265. 263.

266.

267.-400-This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 0 8 5 A7 B7 V. Description of invention (398) Table 3B continued

R

R

R 268.

270. 269. \ y ^ \ γ ^ 271. 272. 273. 274. ^ 275 · 276 · \ y ^

^ y £ 278. \ γ ^ (Please read the notes on the back before filling this page)

, 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 279. 277 ·

281. 282. -401-This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 581760 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (399) Table 3B continued R 〇R QQA R 283. V, 286. o〇7 285. ooo 289. 290 288. 292 w · 293 · 291. 294. Cm ^ CL · 295. 296. 〇y ^ A 297. (Please read the back page first Note: Please fill in this page again.) Clothes--402- This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 581760 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 〇〇)

R

298. 301.

304 · 307. 310. Table 3B continued

R

R

299. 300αϊ 302.

308. 303 · 306. 309. 311 · 312. (Please read the precautions on the back before filling in this page) Clothing · Order i -403- This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 581760 A7 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) This paper size applies to Chinese National Standard (CNS) A4 specification (21 OX297 mm) 581760 A7 B7 V. Description of invention (402) Table 3B continued

R

R

R

329.

332 ·

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

335.

Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

339.ar 340.

341. 342 · 405- This paper size applies to Chinese National Standard (CNS) A4 (210X297mm) 581760 Α7 Β7 V. Description of the invention (4〇3) Table 3B continued

R

R

CcV

R

345. 343.

ο2ι 344.

347. 02 (Please read the precautions on the back before filling out this page) Clothing 346.

ο2ι

350 · 348 ·

Order

ο ο 353 · Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

355. 356. 354.

357. -406- This paper size applies to China National Standard (CNS) Α4 size (210X 297 mm) 581760 A7 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 out this page) This paper size is applicable to the Chinese National Standard (CNS) A4 size (210X297 mm) Clothing · 581760 Α7 Β7 V. Description of the invention (4〇5)

R

〇 373 ·

ο 379. ο 382.

Table 3B continued R

ο

R

375.ο 374.

Μβσ ο 378. (Please read the precautions on the back before filling out this page) Clothing ΜβΟ.

Ο 380.

381. Ο

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 385 ·

ο 388.

387. ο

389. ο yShC ^ 390. -408- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) 581760 Α7 Β7 V. Description of the invention (4〇6) Table 3B continued

R

R

R

ο 391.) 〇ύς ^ ο 393. 392.

(Please read the notes on the back before filling out this page) •-^ 衣 · 394.

ο ο 399. Order

398.

ο 402. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

ο 408. -409- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 581760 A7 B7 V. Description of invention (4〇7) Table 3B continued

R

R 409. 410. °

R

ο 413. ο 414. 415 · ° 416. 417. ο ο

419.

422. ο 420. ΜθΟ *

ΟΜθ Ο 423. (Please read the precautions on the back before filling out this page) Order Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 421.

ΜθΟ4

ΟΜθ Ο 425. ΜθΟ *

ΟΜθ Ο 426. 410- The paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (right) Table 3B continued

R

R

R OMe Ο 427.

ΟΜθ Ο 429. ΟΜθ Ο ΟΜθ Ο 430. 431 ·

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

1T

ΟΜθ Ο ΟΜθ Ο 437. 438. .—Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

ΟΜθ 441.

444. -411 This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 581760 A7 Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

(Please read the precautions on the back before filling out this page) This paper size is applicable to China National Standard (CNS) A4 (210X297 mm)-

1T t 581760 A7 B7 V. Description of the invention (41〇) Table 3B continued

R

R

R

466. 461.

3PDV 465.

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

1T 469. 470. 471

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

CcV 473. -413 · This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 581760 A7 B7 V. Description of invention (411) Table 3B continued

R

R

476 ·

R

478 477.

(Please read the notes on the back before filling this page) 479.

483. 481.

484 ‘482.

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

488. 487.

489 · -414- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 × 297 mm) 581760 A7 B7 V. Description of invention (412) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 3B Continued R 490 R 〇491 R 492. ~ WW · ΛΤ ο 494 · 495. 493. 496. o 497. o 498. o 499 500. c2C O 501. ~ ww · C ^ by * y £ 0 502. 503. ° o 504. 505 506. 507.-415- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling out this page) Clothes · Order 581760 A7 B7 Central Bureau of Standards, Ministry of Economic Affairs Printed by Employee Consumer Cooperatives V. Description of Invention (413) Table 3B continued R 508 · R 509. R ιο '^ yY'A 511. 512.1 1 W · 513 515, w 1 KJ · 516 · 014. 517. 518 519. 520. W 9 W · 521. 522. (Please read the precautions on the back before filling in this page) Clothing · Order -416- This paper size applies to China National Standard (CNS) Α4 size (210 X 297 mm) ) 581760 Α7 Β7 V. Description of the invention (414) Table 3B continued

R

R

R 523. 525. 524.

527. (Please read the notes on the back before filling this page) 526. 528. 529.

v 532 · 530 ·

531. 534. Fv ^ άν, 535 · 536 · 53 ^ 7. 〇-417- This paper size is applicable to Chinese National Standard (CNS) Α · 4 specifications (210 × 297 mm) 581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

R

538. Table 3B continued

R

R sir 539. 540. (Please read the precautions on the back before filling this page) Clothing · 541 · 542. 543 · Αν 544.

547. Order 545. 546. (： ύΎ ^ 548. 549 · 550. 551. 552. -418- This paper size applies to China National Standard (CNS) Α4 specification (210 × 297 mm) 581760 A7 B7 Employees of Central Bureau of Standards, Ministry of Economic Affairs Printed by Consumer Cooperatives V. Description of Invention (416) Table 3B continued

R

R

R xyYA χχυα Jb ^ 553. 554. ° 555. ο

558. (Please read the notes on the back before filling this page) 556.

559. 557.

560. 562 · 563. 1 561.

564.

565. 566. -419- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) c ^ CrV ^ 567 · 8 so A7 B7 V. Description of the invention (417) Table 3B continued

R

R

R (Please read the notes on the back before filling this page) 571. 572. 573. \ ^ ϋα 574 · 575. 576.

577. Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy

580 · 578 ·

581. 579.

582. -420- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 581760 A7 B7 V. Description of the invention (418 Table 3B continued

R

R

R 583.

585.

586.

(Please read the precautions on the back before filling out this page)-^ 衣 · 588. 589 ·

591. Order

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

-421-This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 581760 A7 B7 V. Description of invention (419) Table 3B continued

R

R

R

598.

601. 599.

600.

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

605. 603 ·

Order

607.

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

611 · 609.

-422- This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 581760 Α7 Β7 V. Description of the invention (42〇) Table 3B continued

R

R

614.

R

ο 619.

MeoXXV ^ Ο 618. 621. (Please read the notes on the back before filling this page)

ο 622 ·

624. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 625. 626. οο 627. -423 This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (421) Table 3B continued

R

R

R

V 628. 629.

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

631 · 632. Example 340 Printing of trans, trans-4- (1,3-benzodifluorene-5_yl) -2- (4_methoxyphenyl)- 1-〇4- (3.methylbutane.lyl VN-phenyl) aminocarbonylmethyl V pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. 1H NMR (300 MHz, CD3OD) d 0.85 (d, J = 6 Ηζ, 6Η), 1.25 (q, J = 7 Ηζ, 2Η), 1.42-1.56 (m, 1H), 3.43-3.85 (m, 9H) , 3.88s (3), 5.95 (s, 2H), 6.80 (d, J = 7 Hz, 1H), 6.86 (dd, J = 9 Hz, 1H), 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, 3H). MS (C.I.) m / e C (53.12, 53.11), H (4.63, 4.80), N (3.33, 3.28). -424- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (422) Example 341 Trans, trans-4_ (1,3 · benzodi-p-deficiency- 5-yl) _2- (4-methoxybenzene-butyl-N- (4-tolyl) aminocarbonylmethylpyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. 1H NMR ( 300 MHz, CD3OD) θ 0 · 87 (t, J = 7Hz, 3Η), 1.20-1.47 (m, 4Η), 2.37 (s, 3H), 2.83 (q, J = 7 Hz, 2H), 3.06-3.25 (m, 2H), 3.40-3.50 (m, 1H), 3.51-3.63 (m, 3H), 3.80 (s, 3H), 3.87 (d, J = 9 Hz, 1H), 5.92 (s, 2H), 6.74 (d, J = 8 Hz, 1H), 6.80_6 · 86 (m, 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) +. Analysis estimates C32H36N205: C, 70.57; H, 6.66; N, 5.14. Measured tritium: C, 70.2〇; H, 6.81; N, 5.03. Example 342 trans'trans-4- (1,3-benzodi-yl) -2- (4-propane (((N, N-dibutylamino) carbonyl) methyl) pyrrolidine-3-f ^ Using the procedure of Example 1, the title compound 1H NMR (300 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 out this page) MHz, CDC13) d 7 · 30 (2Η, d, J = 9), 7 · 03 (1Η, d, J = 2), 6.83 (3Η, m), 6.72 (1H, d, J = 9), 5.95 (1H, d, J = 2), 5.93 (1H, d, J = 2), 3.88 (2H, t, J = 7), 3.73 (1H, d, J = 12), 3.58 (1H, m), 3.53-.320 (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, J = 7), 0.87 (3H , T, J = 7), 0 · 80 (3H, t, J = 7). MS (DC1 / NH3) m / e 539 (M + H) +. Analysis estimates C31H42N206 · 0 · 5 H20: C, 67.98 H, 7.91; N, 5.11. Found 値: C, 68 · 24; H, 7.70; N, 5.03. -425- This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297mm) 581760 A7 V. Description of the invention (423) Example 343 Trans form, trans form 2 · 5_base) _2_ (4_propyl quan Gibb ... Bentin dibutylamino) fluorenyl) methyl) erlotin_3_ onion acid Using the steps in Example 1, the title compound can be prepared. lH NMR (300 MHz, CDC13) β 7.31 (2H, d, J = 9), 7.13 (2H, d, J = 9), 7.03 (1H, d, J = 2), 6.84 (1H, dd, J = 6, 2), 6.73 (1H, d, 5 95 (m, d, J = 2), 5.93 (1H, d, J = 2), 3.76 (1H, d, J = 10), 3.60 (1H, m), 3.55-3.20 (4H, m), 3.13_2 · 88 (4H, m), 2.75 (1H, d, J = 15), 2.55 (2H, t, J = 8), 1.62 (2H, q, J = 8), 1.50-1.00 (8H, m), 0.92 (3H, t, J = 7), 0.85 (3H, t, J = 7), 0.78 (3H, t, J = 7). MS (DC1 / NH3) m / e 523 (MH) +. Analyzed and estimated C3iH42N205 · 〇25 h2〇: c, 70.63, H, 8.13; N, 5.31. Measured 値: C, 70.55; H, 8.08; N, 5.18. Example 344 Formula, trans-2- (4 · methyllphenyl) _4- (1,3 · benzodifluorene_5 · group νι_ 『3_ (N_ to an amine of pentanesulfonium) propyl 1 pyrrolidine_3_ Reading acid Using the procedure of Example 316, the title compound can be prepared. IH nmr (300 Printed by the Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs (Please read first Note on the back, please fill in this page again) MHz, CDCl3) d0.85 (t, J = 7Hz, 3H), 0.90 (t, J = 7Hz, 3H), 1.3-1 · 4 (m, 4H), 1.5- 1.6 (six peaks, > 7,211), 1.65- 1.8〇, 411), 2.05-215 (m, 1Η), 2.43-2.56 (m, 1H), 2.72-3.1 (m, 7H), 3.27-3.4 (m, 2H), 3.5-3.6 (m, 2H) , 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J = 8Hz, 1H), 6.8-6.9 (m, ih), 6.85 (d, J = 9Hz, 2H), 7.02 ( d, J = 2Hz, 1H), 7.80 (d, J = 9Hz, 2H). -426-This paper is a standard for financial rewards (CNS) A4 specification (210 × 97mm) 581760 A7 B7 V. Description of the invention (424 ) Example 345 trans, trans_4- (1,2-dihydrobenzofuran-5-yl) -2 · (4-ethoxyphenyl VI-(((N, N-dibutylamino) (Carbonyl) methyl) pyrrolidine-3-endoic acid The procedure of Example 1 was used to prepare the title compound. 1H NMR (300 MHz, CDC13) d 7.40 (3Η, m), 7.22 (2Η, d, J = 8), 7.13 (1Η, dd, J = 8, 3), 6.72 (1H, d, J = 9), 5.28 (1H, d, J = 12), 4.55 (2H, t, J = 9), 4.15 (1H, d, J = 18), 4.03 (2H, m), 3.75 (2H , M), 3.40 (2H, m), 3.20 (2H, t, J = 9), 3.15 (1H, m), 3.10-2.90 (2H, m), 2.63 (2H, q, J = 9), 1.47 (2H, m), 1.31 (4H, m), 1.12 (3H, t, J = 8), 1.10 (2H, m), 0.92 (3H, t, J = 9), 0.80 (3H, t, J = 9). MS (DCl / NH3) m / e 507 (M + H +) 〇 Analytical estimation C31H42N204 · 1.0 TFA: C, 63.86; H, 6.98; N, 4.51. Found 値: C, 63.95; H, 7.12; N, 4.43. Example 346 trans, trans-4- (1,3-benzobisfluoren-5-yl) -2- (4-methoxyphenyl Vl-fmsr- (3-pentyl) -N-aniline) Carbonyl) methyl) pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. 1H NMR (printed by 300 Consumers' Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (please read the precautions on the back before filling this page) MHz, CD3OD) d 0.93 (t, J = 7.3 Ηζ, 3Η), 0.94 (t, J = 7.3 Ηζ, 3H), 1.33 (m, 4H), 2.72 (d, J = 15.2 Hz, 1H), 2.81 (m, 1H), 311-3.23 (m, 2H), 3.45 · 3 · 57 (m , 2H), 3.79 (s, 3H), 3.83 (d, J = 9.8 Hz, 1H), 4.54 (m, 1H), 5.92 (s, 2H), 6.73 (d, J = 7.8 Hz, 1H) , 6.83 (m, 3H), 6.98 (bs, 2H), 7.04 (d, J = 1.7 Hz, 1H), 7.07 (2), 7.37 (m, 3H). MS (DC1) m / e 545 (M + H.). Analysis estimates C32H33N206 · 0.35H2O: C, 69 · 76; H, 6.71; N, 5.08. Measured 値: -427- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 581760 A7 B7 V. Description of the invention (425) C, 69 · 72; Η, 6.66; N, 4.94 ° Example 347 Tail form, trans_4- (1,3-benzodiin-5-yl) _2 · (4-methylphenyl) -N- (3-difluoromethylphenyl) amino ) Carboxy) methyl) pr-bichon-3-leic acid Using the procedure of Example 1, the title compound can be prepared. 1H NMR (300 MHz, CD3OD) d 0.87 (t, J = 6.6 Ηζ, 3Η), 1.17_1 · 45 (m, 4Η), 2.65 (d, J = 16.5 Hz, 1H), 2.72 (m, 1H), 3.10 (t, J = 9.5 Hz, 1H), 3.21-3.27 (m, 1H), 3.40 (dd, J = 4.1, 9.9 Hz), 3.54 (m, 1H), 3.61-3.74 (m, 3H ), 3.77 (s, 3H), 5.93 (s, 2H), 6.73-6.85 (m, 4H), 7.02 (m, 3H), 7.33 (d, J = 7.5 Hz, 1H), 7.40 (s, 1H) , 7.58 (t, J = 7.8 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H). MS (DCl) m / e 599 (M + H +). Analysis estimates C32H33F3N206: C, 64.21; H, 5.56; N, 4.68. Measured 値 · C, 64.09; H, 5.63; N, 4.57. Example 348 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-4- (1,3-benzodifluoren-5-yl) -2- (4-methoxyphenylpropyl VN-I4-morpholin carbonyl) aminocarboxymethylerodoline-3-carboxylic acid was prepared by the procedure of Example 1 to obtain the title compound. 1H NMR (300 MHz, CD3OD) 0.78 (t, J = 7 Ηζ, 3Η), 1.43 (q, J = 7 Ηζ, 2H), 2.07-3.01 (m, 1H), 2.76 (dd, J = 7, 9 Hz, 2H), 2.77-3.00 (m, 5H), 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 (dd, J = 7Hz, 1H), 6.83-6.90 (m, 2H), 6.98 (d, J = 2 Hz, 1H), 7.32-7.39 (m, 2H). MS m / e estimate (M + H) C29H39N307: (M + H) 540.2710, measured radon (M + H) 540.2713. -428- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297 mm) 581760 A7 B7 V. Description of the invention (426) Example 349 trans, trans-4 · (1,3-benzodihum) -5_yl V2- (4-methoxyphenylcis-2.6-dimethylhexahydropyridin-1-yl) carbonylmethyl V pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound 1H NMR (300 MHz, CD3OD) d0.94 (d, J = 7Hz, 3H), 1.15d (7, 3H), 110.70 (m, 6H), 1.70-1.90 (m, 1H), 2.9 (d, J = 13Hz, 1H), 3.00-3.20 (m, 2H), 3.50 (3.70, J = mHz, 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 estimate (M + H) + C28H35N206: (M + H) 495.2495 Measured fluorene (M + H) 495.2493. Example 350 trans'trans-2- (4-methoxymethoxyphenyl) -4- (1,3-benzodiazin-5-yl V1- (2_ (N-propyl-N-n-pentafecontinylamino) ethyl ratio p each lake-3-guinic acid Using the procedure of Example 1, the title compound can be prepared and separated into the white standard of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperative (please read the note on the back first) (Please fill in this page if you have any questions)

solid. m.p. 57-59 ° C. 4 NMR (CDC13, 300 ΜΗζ) Θ 0.78 (t, J = 7Hz, 3H), 0.90 (t, J = 7Hz, 3H), 1.28-1.36 (m, 4H), 1.93 (six peaks, > 71 ^, 211), 1.72, [= 71 ^, 211), 2.20-2.32 (111, 111), 2.72-3 · 10 (m, 7H), 3.18-3.41 (m, 2H), 3.43 (dd, J = 3Hz, J = 9Hz, 1H), 3.48 (s, 3H), 3.52 · 3 · 59 (m, 1H), 3.68 (d, J = 9Hz, 1H), 5.15 (s, 2H), 5.94 (s, 2H), 6_73 (d, J = 8Hz, 1H), 6.82 (dd, J = 1lHz, J = 8Hz, 1H), 6.98-7.02 (m, 3H), 7.32 (d, J = 9Hz, 2H ) MS (DC1 / NH3) m / e 591 (M + H) +. Example 351 trans'trans-4- (l, 3-benzodipanthal-5-yl) _2- (4 · methoxyphenyl-429 · This paper size applies to China National Standard (CNS) A4 specifications ( 210X297 mm) '581760 A7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ________B7 ______ V. Description of the invention (427) (2_Butyl _)-Analyl) carbonyl) methyl) pyrrolidine-3_carboxy Acid Using the procedure of Example 1, the title compound was prepared. ijj NMR (300 MHz, CD3OD) (y0.79_0.89 (m, 6H), 1.14-1.21 (m, lH), 1.25-1.40 (m, lH), 2.64 (dd, J = 4.6, 15.4 Hz, 1H), 2.76 (t, J = 9.0 Hz, 1H), 3.05-3.13 (m, 2H), 3.37-3.49 (m, 2H), 3.70 (s, 3H), 3.80 (d, J = 9.8 Hz, 1H ), 4.53 (m, 1H), 5.83 (m, 2H), 6.65 (d, J = 8.1 Hz, 1H), 6.72 (-6.76, J = m Hz, 3H), 6.87 (m, 2H), 6.95 (d, J = 1.7 Hz, 1H), 7.03 (m, 2H), 7.29 (m, 3H). MS (DCi) m / e 531 (M + H +). Analytical estimation c31H34N206 · 0 · 4Η2Ο ·· C , 69 · 23; H, 6.52; N, 5.21. Measured fluorene: C, still H, 6 a; N, 5 0. Example 352 trans, trans or -4_IL3_benzobisfluoren-5-yl ). 2- (4-methoxyphenyl (2-prop-yl) bis-aniline, carbonyl) methyl) pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. NMR (300 MHz, CD3OD) d 0.99 (d, J = 6.8 Hz, 6H), 2.71 (d, J = 15.6 Hz, 1H), 2.84 (m, 1H), 3.13-3.18 (m, 2H), 3.45- 3.58 (m, 2H), 3.79 (s, 3H), 3.88 (d, J = 9.8 Hz, 1H), 4.80 (m, 1H), 5.92 (s, 2H), 6.74 (d, J = 8 Hz 1H), 6.83 (m, 3H), 6.96 (br s, 2H), 7.04 (d, J = 1.7 Hz, 1H), 7.13 (m, 2H), 7.38 (m, 3H). MS (DCt) m / e 517 (M + H +). Analysis estimates C30H32N2O6 · 0.4 H20 · 0.08 CH3C02C2H5: C, 68.65; H, 6.28; N, 5.28. Found 値: C, 68.64; H, 6.35; N, 5.14. Example 353 The trans form is: 4 · (4-propanylbenzene V2_ (4_methoxyphenyl) dibutyl-430- This paper size is applicable to China National Standard (CNS) A4 size (210 X 297 mm) ) (Please read the notes on the back before filling out this page) Order 581760 A7 B7 V. Description of the invention (428) Amino) Carboxyl) Methyl) Pyrrolidine-3- # Acid Using the steps in Example 1, the title compound can be prepared . 1H NMR (300 MHz, CDC13) d 7.42 (2Η, d, J = 10Hz), 7.38 (2Η, d, J = 10Hz), 6.92 (2H, d, J = 10Hz), 6.88 (2H, d, J = 10Hz), 5.13 (1H, bd, J = 12Hz), 4.02 (2H, m), 3.90 (2H, t, J = 8Hz), 3.80 (3H, s), 3.71 (3H, m), 3.40 (2H, m), 3.19 (1H, m), 3.10-2.90 (2H, m), 1.80 (2H, m), 1.48 (2H, m), 1.29 (4H, m), 1 · 13 (2H, m), 1.03 (3H, t, J = 8Hz), 0.92 (3H, t, J = 9Hz), 0.82 (3H, t, J = 9Hz). MS (DC1 / NH3) m / e 525 (MH) + 0 Analytical estimation C31H44N205 · 1 TFA: C, 62.06; H, 7.10; N, 4.39. Found 値: C, 62.43; H, 7.28; N, 4.39. Example 354 trans, trans-4- (1,3-benzodifluoren-5-yl V2- (4-methylpyridine) _1-((1,2,3,4tetrahydro-4 leaching · 1 _ Group) carboxyl) methyl ratio slightly bite _3_ The title compound can be prepared by using the procedure of Example 1. 1H NMR (300 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) MHz, CD3OD) d 1.88 (five peaks, J = 6.5 Ηζ, 2Η), 2.67 (t, J = 6.4 Ηζ, 2H), 2.87 (t, J = 8.6 Hz, 1H), 3.14 (m, 2H) , 3.42 (dd, J = 4.6, 9.7 Hz, 1H), 3.53-3.70 (m, 3H), 3.72-3.78 (m, 1H), 3.77 (s, 3H), 3.86 (d, J = 9.6 Hz , 1H), 5.91 (s, 2H), 6.73 (d, J = 8.1 Hz, 1H), 6.83 (m, 3H), 6.98 (d, J = 11 Hz, 1H), 7.02-7.23 (m, 6H) o MS (DC1) m / e 515 (M + H +). Analyzed and estimated C3OH3ONN206 · 0.3 H20 · 0.15 CH3C〇2C2H5: C, 68.93; H, 6.01; N, 5.25. Measured 値: C, 68 · 91; H, 5.86; N, 5.19 〇-431-This paper size applies to China National Standard (CNS) A4 (210X297 mm) 581760 A7 _B7 V. Description of the invention (429) Example 355 Formula _2- (3,4-Dimethoxybenzyl ) -4- (1,3-Benzodienediyl VI- ΓΝΓ · Ν-bis (n-butyl) amino) yl) methyl) p-biloxalic acid Using the procedure of Example 1, the title compound can be isolated As a white solid. m.p 64-65Ό. 4 NMR (CDC13, 300 MHz) d 0 · 79 (t, J = 7Hz, 3H), 0.8 (t, J = 7Hz, 3H), 1.07 (six peak, J = 7Hz, 2H), 1.20-1.35 (m , 4H), 1.43 (six peaks, J = 7Hz, 2H), 2.83 (d, J = 13.5Hz, 1H), 2.94-3.17 (m, 4H), 3.22-3.42 (m, 1H), 3.40-3.48 ( m, 3H), 3.58-3.65 (m, 1H), 3.82 (s, 3H), 3.85 (s, 4H), 5.92 (s, 2H), 6.73 (d, J = 8Hz, 1H), 6.81 (d, J = 8Hz, 1H), 6.86-6.96 (m, 3H), 7.07 (d, J = 3Hz, 1H). MS (DC1 / NH3) m / e 541 (M + H) +. Example 356 trans, trans-2- (3,4-dimethoxybenzyl) -4- (1,3-benzodifluorene-5 · a certain VU Γ2- (N-propyl-N_n-pentyl Fechi amine group) Ethylpyridine · 3_Lean acid Using the procedure of Example 1, the title compound can be prepared and printed as a white solid printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back first) Fill in this page) is separated. Mp 75-86 ° C. 4 NMR (CD3OD, 300 MHz) d 0.75 (t, J = 7Hz, 3H), 0.82 (t, J = 7Hz, 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 = 6Hz, 1H), 3.47-3.56 (m, 2H), 3.78 (d, J = 9Hz, 1H), 3.83-3.93 (m, 2H), 3.87 (s, 3H), 3.92 (s, 3H), 4.63 (d, J = 13Hz, 1H), 5.97 ( s, 2H), 6.82 (d, J = 7Hz, 1H), 6.93 (d, J = 7Hz, 1H), 7.06 (d, J = 7Hz, 1H), 7.08 (d, J = 3Hz, 1H), 7.16 (dd, J = 3Hz, J = 7Hz, 1H), 7.27 (d, J = 3Hz, 1H). MS (DC1 / NH3) m / e 591 (M + H) + 〇432- This paper size applies to China Standard (CNS) A4 specification (210 X 297 mm) 581760 A7 __B7 _ ^ _ V. Description of the invention (43〇) Example 357 Formula, trans-2- (3,4-dimethoxybenzyl) _4- (l, 3-benzobisfluoren-5-yl VI- "2- (N-propyl-N-n-hexanesulfonyl) Aminoamino) ethyl 1 pyrrolidine-3- # 醴 Using the procedure of Example 1, the title compound was prepared and isolated as a white solid. Mp 65-66 ° C. B NMR (CDC13, 300 MHz) d 0.80 (t , J = 7Hz, 3H), 0.89 (t, J = 7Hz, 3H), 1.23-1.48 (m, 6H), 1.43 (six peak, J = 7Hz, 2H), 1.72 (six peak, J = 7Hz, 2H ), 2.25 · 2 · 35 (m, 1H), 2.73-3.10 (m, 7H), 3.19-3.32 (m, 2H), 3.45 (dd, J = 3Hz, J = 9Hz, 1H), 3.53-3.59 ( m, 1H), 3.68 (d, J = 9Hz, 1H), 3.87 (s, 6H), 5.95 (s, 2H), 6.74 (d, J = 8Hz, 1H), 6.79-6.86 (m, 2H), 6.92-6.97 (m, 2H), 7.02 (s, 1H). MS (DCl / NH3) m / e 605 (M + H) +. Example 358 trans'trans_2- (4_methoxyphenyl) -4_ (1,3 · benzobis $ -5 • yl) 2_ (g tamidino) ethyl 1-pyrrolidine -3- # _ 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) Example 1C Compound (250 mg), N-Bromoethylphthalimide (206 mg ) And diisopropylethylamine (175 mg) were dissolved in 1 ml of acetonitrile and heated at 95 ° C for 2.5 hours. Toluene was added and the mixture was washed with KHC03 solution. The solution was dried (NasSCU) and concentrated. The crude product was purified by silica gel chromatography, and then dissolved in 3: J EyOAc-hexane to produce 216 mg of the intermediate ethyl ester, which was hydrolyzed in the same manner as in Example 1 D to produce 130 mg of the title compound as a white powder. ιΗ NMR (300 MHz, CDC13) d 3.12-3.26 (m, 2H), 3.60-3.75 (m, 2H), 3.70 (s, 3H), 3.98-4.12 (m, 2H), 4.45-4.55 (m, 1H) ), 4.69 (d, J = 9Hz, 1H), 4.76-4.88 (m, 1H), 5.96 (s, 2H), 6 55 (d, J = 8Hz, 1H), 6.60-6.70 (m, 3H), 6.79 (d, J = 8Hz, 1H), 7.05- 433-This paper size is applicable ^ National Standard (CNS) A4 Specification (210 X 297 mm) '' 581760 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 _____ _B7 V. Description of the invention (431) 7.45 (m, 5H), 7.75 (d, J = 7Hz, 1H). Example 359 trans form, trans form 4- (1 ^^ benzodifluoro_5_yl) _2_ (4_methoxybenzyl) _; [_ (() ^-(2_; l ^ J. ·: ^ i: ^ Amine) carbonyl) methyl) pyrrolidine The title compound was prepared using the procedure of Example 1. ljj NMR (300 MHz, CD3〇D) ά 0.86-0.98 (m? 6H)? 1.17-1.22 (m? 1H)? 1.23- 1.41 (m, 3H), 2.70 (dd, J = 11 2, 15 3 HZ , 1H), 2.83 (m, 1H), 3.10-3.21 (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 = 11, 7.7 Hz, 3H), 6.82 (m, 2H), 7.04-7.14 (m, 3H), 7.36 (m, 3H). MS (DC1) m / e 545 (M + H +). Analytical estimates of C32H36N2 0 6 · 0 25 ch3c0 2 C2H5: C, 69.95; H, 6.76; N, 4.94. Found 値: c, 70 · 03; H, 6.54; N, 4.78. Example 360 trans .. Formula, trans_4_ (1 ^ benzobisfluoren-5-yl) -2_ (4-methoxyphenyl) -l-〇Sl-butylaminocarbonylmethylpyrrolidine-3- Carboxylic acid The procedure of Example 1 was used to prepare the title compound. in NMR (300 MHz? CD3OD) ά 0.83 (t? J = 7 Hz? 3H)? 1.23-1.39 (m? 4H)? 1.40-1.55 (m, 3H), 2.60 face 2.72 (m, 2H), 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 = 8 Hz, 1H), 7.52-7.62 (m, 3H), 7.80-7.90 (m, 1H), 7.90-8.00 (m, 2H). MS (DC1) m / e 581 (M + H) +. Analysis estimates c35H36N206 · 0.3 H20: C, 71.73; H, 6.29; N, 4.78. Found 値: c, 71 74; H, 6 26; N, 4.72. -434- This paper size is applicable to Chinese National Standard (CNS) M specification (21 × 297 mm) (Please read the precautions on the back before filling out this page) Clothes · Order 581760 A7 B7 V. Description of Invention (432) Example 361 Trans, trans-2- (4-propanone) -4- (1,3_benzodiam-5-ylpropyl · N-n-pentanesulfonamido) ethyl 1 pyrrolidine -3-carboxylic acid Using the procedure of Example 66, the title compound was prepared and isolated as a white solid. m.p. 53_54 ° C. 4 NMR (CDC13, 300MHz) d 0.79 (t, J = 7Hz, 3H), 0.89 (t, J = 7Hz, 3H), 1.03 (t, J = 7Hz, 3H), 1.24_ 1.34 (m, 4H), 1.43 (six peaks, J = 7Hz, 2H), 1.67-1.75 (m, 2H), 1.80 (six octane, 2H), 2.23-2.33 (m, 1H), 2.72-2.93 (m, 5H), 3.05 (seven peaks, J = 7Hz, 2H), 3.15_3.35 (m, 2H), 3.42 (d, J = 9Hz, lH), 3.54-3.62 (m, 1H), 3.67 (d, J = 9Hz, 1H), 4.90 (t, J = 7Hz, 2H), 5.95 (s, 2H), 6.73 (d, J = 8Hz, 1H), 6.85 (d, J = 8Hz, 2H), 7.02 (s , 1H), 7.32 (d, J = 8Hz, 2H). MS (DC1 / NH3) m / e 589 (M + H) +. Example 362 Basic formula, trans-4_ (1,3-benzobis $ -5_yl) _2 · (4-methoxybenzylmethyl Θbdor-1-yl) fluorenyl) methyl, p ratio Luodian_3_Le__ The method of Example 1 was used to prepare the title compound. ijj NMR (300 MHz, CDsOD) d Indole C2 diastereoisomeric mixture, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. C Please read the notes on the back and fill in this page. (m, 1.5 (CH3)), 1.05 (d, 6.3H, 1.5 (CH3)), 2.62 (m, 1H), 3.01 (m, 2H), 3.14 · 3 · 25 (m, 1H), 3.37-3.52 ( m, 1.5H), 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, 0.5 H), 4.42 (m, 0.5H), 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 〇, 2H), 7.14 (t, J = 7.7 Hz, 1H), 7.21 (t, J = 6.6 Hz, 1H), 7.38 (m, 2H), 7.99 (m, -435-This paper size applies to the Chinese National Standard (CNS) A4 specification (2i0x) 97 public holiday) " ~ 一 ^ 81760 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (433) 1H). MS (DC1) m / e 515 (M + H +). Analytical evaluation # C3〇H3〇N2〇6 · 〇 35 Η 20 · 0.3 CH3C02C2H5: C, 68.47; H, 6.10; N, 5.12. Found 値: C, 68.46; H, 5.97; N, 5.07. Example 3 Including phenyl-form, trans-benzodiyl) _2- (4 · methylhydrophenylhydroxy · 3-¾ylhex-1-yl)? Biweiyuan_3_number acid The title compound can be prepared by using the procedure of Example 1 '. ijj NMR (300 MHz, CD3OD) d 1.06 (m, 6H), 1.26-1.60 (m, 9H), 3.16 (dd, J = 10.9, 12.6 Hz, 1H), 3.18 (d, J = ll Hz, 1H), 3.44 (d, J = 2.0 Hz, 1H), 3_61 (t, J = ll Hz, 1H), 3.73 (t, J = 11.0 Hz, 1H), 3.85 (m, 1Η) 3 · 96 · 4.17 (m, 2H), 4.02 (s, 1.5 (CH30 diastereoisomers)), 4.03 (s, 1.5 (CHsO diastereomers)), dagger !! 5 (s, 2H), 7.01 (d, J = 8.1 Hz, 0.5H), 7.00 (d, J = 8.1 Hz, 0.5H), 7.10 (m, 1H), 7.23 (m, 3H), 7.77 (m, 2H). MS (DCl ·) m / e 484 (M + H +). Analysis estimates C28H37N06 · 0.33 H3P04: C, 65.34; H, 7.44; N, 2.72. Found 値: C, 65.30; H, 7.40; N, 2.60. Example 364 trans, trans-4- (1,3 · benzenejidifluorene-5-a certain V2- (4-methoxyphenyl) -1_α (N- (4-heptyl) · N- (3, 4-Dimethoxyfluorenyl) amino) carbonyl) methyl) pyrrolidine-3.carboxylic acid The procedure of Example 1 was used to prepare the title compound. 4 NMR (300 MΗζ, CD3OD) d mixture of 1: 1 geometric isomers, 0.61 (t, J = 7.1 Ηζ, 1.5 ·). 0.72 (7.3, 1.5Η), 0.76 (t, J = 7.1, 1.5, 0.83, t, 7 · 3 Ηζ, 1.5 ·), 1.005 · 1 · 60 (m, 8Η), 2.84-3.10 (m, J = 2.5, 3_18, t, 9 · 7 Ηζ, 0.5Η ), 3.41_3 · 52 (m, 2Η), 3.47-3.69 (m, 2Η), 3.66 (s, 1.5Η), -436- This paper size applies to China National Standard (CNS) Α4 specification (210X297 Mm) (Please read the notes on the back before filling in this page)

581760 Α7 Β7 V. Description of the invention (434) 3.73 (s? 1.5H)? 3.77 (s? Ι.5Η)? 3.78 (s? 1.5H)? 3.79 (s9 1.5H)? 3.86 (d? J = 9.8 Hz 0.5H)? 4.19 (d? J = 17.7 Hz, 0.5H)? 4.29 (d? J = 15.2 Hz, 0.50), 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 0Hz, 0H), 6 74 (m, 2 5H), 6.80 (s? 1H)? 6.83-6.88 (m? 1H) 9 6.92 (m? 1.5H)? 7.03 (dd? J = 1.7? 6.8 Hz, 1H)? 7.19 (m? 1H)? 7.36 (m? 1H) oMS (Dd) m / e 647 (M + H +). Analysis estimates C37H46N208: c, 68 71; H, 7 17; N, 4.33. Measured 値 ·· C, 68.41; H, 7.26; N, 4.11. Example 365

Trans-rabbit, trans-bis-fluorenyl-: 5-ylphenyl); [_ (({I-l-l-yl-carbonyl) methyl) pyrrolidine-3) Using the procedure of Example 1, the title compound was prepared. 1; H NMR (300 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) MHz, CD3OD) 6 2.97 (dd, J = 8.1, 9.5 Hz, 1H), 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), 6.73 (d, J = 8.1 Hz, 1H), 6.86 (m, 3H), 6.99 (dt, J = ll, 7.4 Hz, 1H), 7.08 (d, J = 0.7 Hz, 1H), 7.11 (m, 1H), 7.18 (d, J = 7.1 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 8.02 (8.1, 1H). MS (C.l.) m / e 501 (M + H +). Analysis estimates C29H28N206 · 0.5 H20 · 0.15 CH3C02C2H5: C, 68.01; H, 5.82; N, 5.36. Measured fluorene: C, 68.03; H, 5.65; N, 5.25. Example 366 trans, trans-4- (1,3-benzodifluoren-5-yl) -2- (4-methylbenzidine Chlorophenyl) aminocarbonylmethyl) pyrrolidine-3-carboxylic acid-437- This paper size applies to Chinese National Standard (CNS) A4 (210 × 297 mm) 581760 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (435) Using the procedure of Example 1, the title compound can be prepared. lH nmr (300MHz? CD3OD). 0.89 (dt? J, 7 Hz? 3H)? 1.23-1.51 (m? 4H)? 2.52-4.00 (m, 8H), 3.78 (d, J = 6 Hz, 3H), 5.92 (d, J = 6 Hz, 2H), 6.70-6.87 (m, 4H), 7.02-7.21 (m, 4H), 7 27 · 7 52 (m, 3H). Genus (DCi) m / e 565 (M + H) +. Analytical estimation c3iH32N206C1. 〇6H2O: c 64.66; H, I " N, 4.86. Measured fluorene: c, μ π; H, 600; N, basic formula, trans-2- (4-methoxyiyl) _4_ (13_benzo ^ two_5_yltrimethoxybenzyl 1 Pyrrolidine was obtained from the compound of Example 1C (0.25 g) and 0.169 g of 3,4,5-trimethoxybenzyl chloride and 0.175 g of diisopropylethylamine in 1 ml of acetonitrile and reacted at room temperature 2 Hours. The resulting ester was separated and hydrolyzed in the same manner as in Example i D to give 0.193 g of the title compound. Mpi〇8_110 ° c. Ijj NMR 00 MHz, CDC13) d 2.75 (t, J = 9Hz, 1H), 2.95 3.05 (m, 2H), 3.20 (d, J = 11 Hz, 1H), 3.45 · 3.55 (m, 1H), 3.3.7 · 8 (m, 2H), 3.84 (s, 3H ), 5.95 (dd, J = 2Hz, 6Hz, 2H), 6.55 (s, 2H), 6.70 (d, J = 8Hz, 1H), 6.30-6.35 (m, 1H), 6.90 (d, J = 9Hz, 2H), 7.13 (d, J = 2Hz, 1H), 7.43 (d, J = 9Hz, 2H). Example 368 Basic formula, trans_4_ (1,3 · benzyl-2-yin-5-yl) -2- (4-methoxyphenylbutyl-N- (3-aminophenyl) aminocarbonylmethyl V Pyrrolidine_3-carboxylic acid The title compound was prepared using the procedure of Example 1. iH NMR (300 M ζ, CD3OD) β0 · 89 (t, J = 7 Ηζ, 3Η), 1.20-1.42 (m, 4Η), 3.42- 3.87 -438- This paper size applies to Chinese National Standard (CNS) A4 (210X297mm) (Please read the precautions on the back before filling this page), \

T 581760 A7 B7 V. Description of the invention (436) (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.l.) m / e 565 (M + H). Analysis estimates C31H33N206C1 · 1.0CF3COOH: C, 58.37; H, 5.05; N, 4.13. Measured radon: C, 58.41; H, 4.99; N, 4.08. Example 369 trans'trans-2- (4-methylbenzyl) -4- (1,3-benzodiazine_5-yl) _ 丨 2 _ (-n-butylamine) 1_bilodine_3_ # _ Use the compound of Example 1C (0.25 g) with 0.11 g of 2,4-dichloropyrimidine and 0.175 g of diisopropylethylamine in 1 ml of acetonitrile at room temperature After 2 hours of reaction, 0.218 g of 2- (4-methoxyphenyl) -4 · (1,3 · benzobisfluoren-5-yl) small (2 · chloro-4-pyrimidinyl) -pyrrolidine-3 -Ethyl carboxylate. This compound was reacted with 1 ml of dibutylamine in 2 ml of toluene at 125 ° C for 17 hours. The resulting ethyl ester was hydrolyzed by the method of Example 1D to give 142 g of the title compound as a white powder. 4 NMR (300 MHz, CDC13) Θ0.75-0.90 (width, 611), 1.1-1.3 (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 (bi *, 1H), 5.2 (br, 1H), 5.45 (br, 1H), 5.87 (S, 2H), 6.3 (br , 1H), 6.67 (d, J = 8HZ, 1H), 6.7-6.85 (m, 4H), 7.10 (d, J = 9Hz, 2H). Example 370 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) Trans, trans-4_ (1,3 · Benzodifluoren-5-ylmethyl molybdenyl) Bis (2-methylbut-2-yl) _N-anilino) yl) methyl) ρ ratioρ each lake_3-weilconic acid The procedure of Example 1 was used to prepare the title compound iHNMR (300 MHZ, CD3OD) J0.90 (t, J = 7.5 Hz, 3H), 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, -439- This paper size applies to the Chinese National Standard (CNS) A4 specification (2i0x97mm) '--- 581760 A7 B7 V. Description of the invention (437) J = 9.5 Hz, 1H ), 3.11 (d, J = 15.6 Hz, 1H), 3.21 (t, J = 8 8 hz, 1H), 3.50-3.61 (m, 2H), 3.80 (s, 3H), 4.00 (d, J = 10.2 Hz, m), 5.91 (s, 2H), 6.74 (d, J = 7.8 Hz, 1H), 6.85 (m, 3H), 6.93 (m, 1H), 6.98 (m, 1H), 7.03 (d, J = 1.7 Hz, 1H), 7 17 (m, 2H), 7 36 (m, 3H). MS (DC1) m / e 545 (M + H +). Analysis estimates C32H36N206: C, 70.57; H, 6.66; N, 5.14. Found 値: C, 7017; H, 6 53; N, 4.97. Example 371 trans, trans-2- (4-ethylphenyl) -4- (5-hydrothynyl, N-dibutylamino) carbonylmethyl) pyrrolidine-3- # ^ Use Example 1 This procedure prepares the title compound. NMR (300MHz, CDC13) Θ7 · 25 (3H, m), 7.21 (1H, d, 3Hz), 7.17 (3H, m), 3.80 (1H, d, 10Hz), 3.65 (1H, ddd, 6, 5, 3Hz), 3.4 (4H, m), 3.10 (2H, m), 2.98 (2H, m), 2.88 (5H, m), 2.79 (1H, d, 16Hz), 2.62 (2H, q, 7Hz), 2.05 (2H, m), 1.42 (2H, m), 1.32 (m, m), 1.21 (3H, t, 7Hz), 1.05 (2H, six peaks, 7Hz), 0.87 (3H , T, 7Hz), 0.79 (3H, t, 7Hz). MS (DC1, NH3) m / e 505 (M + H +). Analysis estimates C32H44N203: C, 76.15; H, 8.79; N, 5.55. Found 値: c, 75.96; H, 8.75; N, 5.36. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ---------- ^ 衣-(Please read the notes on the back before filling this page) Order example 372 trans, trans-2_ (3, 4-Difluorophenylbenzobis $ _5_some) _1 (((N, N-dibutylamino) carbonyl) methylpyrrolidine_3_green ^ Using the procedure in Example 1, the title compound can be prepared and White solid was isolated. m.p. 62-63 ° C. 4 NMR (CDC13, 300 MHz) d 0.83 (t, -440- This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Description of the invention (438) J = 7Hz, 3H), 0.88 (t, J = 7Hz, 3H), 1.13 (six peak, J = 7Hz, 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, 1H), 3.94 (d, J = 8Hz, 1H), 5.93 ( s, 2H), 6.72 (d, J = 7.5Hz, 1H), 6.84 (dd, J = lHz, J = 7.5Hz, 1H), 6.98 (d, J = 7.5Hz, 1H), 7.08-7.15 (m , 2H), 7.22-7.28 (m, 1H). MS (DC1 / NH3) m / e 517 (M + H) +. Example 373 trans, trans-2- (3,4-difluorobenzyl) · 4 · (1,3 · benzodiethyl-5-yl) _ 1 『2 (N · propyl · N_ N-pentanesulfonylamino) ethyl 1 pyrrolidine-3.carboxylic acid The title compound was prepared using the procedure of Example 1 and isolated as a white solid. m.p. 71-72 ° C. NMR (CDC13, 300 MHz) d 0.82 (t, J = 7Hz, 3H), 0.90 (t, J = 7Hz, 3H), 1.25-1.38 (m, 4H), 1.46 (six peak, J = 7Hz, 2H) , 1.74 (five peaks, J = 7Hz, 2H), 2.26_2.36 (m, 1H), 2.72-2.95 (m, 5H), 2.98-3.12 (m, 2H), 3.15_3 · 34 (m, 2H) , 3.45 (dd, J = 3Hz, J = 9Hz, 1H), 3.53_3 · 60 (m, 1H), 3.71 (d, J = 9Hz, 1H), 5.96 (s, 2H), 6.75 (d, J = 9Hz, 1H), 3.82 (dd, J = 2Hz, J = 9Hz, lH), 5.96 (d, J = 2Hz, lH), 7.09-7.18 (m, 2H), 7.23-7.34 (m, 1H) 0 MS (CD1 / NH3) m / e 567 (M + H) + 〇 Example 374 trans, trans-4- (1,3-benzodifluoren-5-yl) -2_ (ethane gas a methyl ( (N, N-dibutylamino) carbonyl) methyl) pyrrolidine-3-myoline Using the procedure in Example 1, the title compound can be prepared. TLC (10% MeOH-CH2Cl2) Rf = 0.53. 4 NMR (CDC13, 300 ΜΗζ, geometrically isomeric form) β 0 · 70 (t, J = 7Hz), 0 · 80 (t, J = 7Hz) and 0.96- 1.04 (m, -441-This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297mm) ------------ (Please read the precautions on the back before filling out this page)) Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 | _______B7 _ V. Invention Description (439) 6H Sum), 1.04-1.75 (m, UH), 134_153 (br m, 4H), 2 65 (AB) and 2.80-3.08 (m, 2H total), 3 1〇_3 82 (br m, 12H), 4 03 (m) and 4.22 · 4 · 45 (br m, New Zealand total), 5 9〇 and 5% (s, 2H total), 6.65-6.84 (m) and 6.93 (m) and 6.99 (m, 3H total). MS (FAB) m / e 463 (M + H). Analytical c25H38N2O6.i5H2O: c, 61 33; H, 8_44; N, 5.71. Found 値: c, 61 · 28; h, 7.78; N, 5.62. t ±] 375 trans, trans) -2_r-n-butanediamino) multiply) methyl) p-Biandian · 3- # 醢 Using the procedure in Example 1, the title compound can be prepared and isolated as a colorless wax . TLC (10 // MeOH-CH2Cl2) Rf = 0.37. NMR (CDC13, 300 MHz, geometric isomer) j 〇, 71 (t, J = 7Hz) and 〇 77] 〇5 (m,

9H total), 1.05_1 · 20 (m, 2H), 1.20-1.72 (br m, 13H), 2.48-2.52 (m, 1H), 2.87-3.00 (m, 1H), 3.05 · 3 · 60 (m, 5H), 3.60-3.80 (br m, 2H), 3.88-4.05 (br m, 1H), 4.28 (br d, J = 15Hz, 1H total), 5.90 (s), and 5.92 (s, 2H total), 6.67-6.82 (m, 3H total). MS (FAB) m / e 461 (M + H). Analytical estimation: C26h4 () N205 · i 75 H20: c, 63 · 45; H, 8.90; N, 5.69. Measured fluorene: c, 63 18; H, 8 22; N, 5.60 ο Example 3 76 trans .., trans ——4〆1,3 · benzodifluorene-5_some methylbutyl) _ (((N, N --- Butylamino) weiyl) methyl) t) each acetic acid. Using the procedure of Example 1, the title compound was prepared and presented as a colorless glass.

Be separated. TLC (10% MeOH-CH2Cl2) Rf = 0.49. Ugu NMR -442- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling out this page) Order printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperatives 581760 A7 B7 5 Description of the invention (440) (CDC13, 300 MHz, geometric isomers and diastereoisomeric mixtures) β 0.69 (br t, J = 7Hz) and 0.75-2.15 (several br m, about 26H total), 2.48-2.65 (br m, 1H), 2.87 · 3 · 01 (br m, 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, 3H total). MS (FAB) m / e 475 (M + H) +. Example 377 trans, trans-4_ (1,3_benzobisfluorene · 5-yl) -2- (3-methylbutyl) dibutylamino) carbonyl) methyl) pyrrolidine-3 · Carboxylic acid The procedure of Example 1 was used to prepare the title compound. TLC (10% MeOH-CH2Cl2) Rf = 0.41. 1H NMR (CDC13, 300 MHz, geometric isoform) d 0.73 (t, J = 7Hz) and 0.77-1.05 (m, 1205 total), 1.07 -1.75 (m, about 14H plus H20), 2.48-2.63 (m, 1Η), 2.87-3.05 (m, 1H), 3.05-3.60 (several br m, 5H), 3.62-4.02 (br m, 2H ), 4.29 (br d, J = 15Hz, 1H), 5.89 (s) and 5.93 (s, 2H total), 6.65-6.90 (3H total). MS (FAB) m / e 475 (M + H) +. Example 378 trans, trans-2- (4 • methoxyphenyl) 4- (l, 3-benzodifluoren-5-yl) -l-Γ2- (N-propyl_N- (N- Methyl-N.propylamino) sulfofluorenyl) amino) ethyl l pyrrolidine-3-carboxylic acid Using the procedure of Example 66, the title compound was prepared and isolated as a white solid. m.p. 58 · 59Ό. 4 NMR (CDC13, 300MHz) β 0.78 (t, J = 7Hz, 3Η), 0.90 (t, J = 7Hz, 3Η), 1.27 (six peaks, J = 7Hz, 2Η), 1.48 (m, 4H), 2.22-2.30 (m, 1H), 2.62 (s, 3H), 2.68-2.78 (m, 1H), 2.84-3.03 (m, 5H), 3.08-3.31 (m, 3H), 3.39 (dd, J = 3Hz, J = 9Hz, 1H), 3.50-3.58 (m, 1H), 3.63 (d, J = 9Hz, 1H), 3.79 (s, 3H), -443- This paper standard applies to the Chinese National Standard (CNS ) A4 specification (2 丨 〇 < 297 mm) (Please read the precautions on the back before filling this page) Order -t 581760 A7 B7 V. Description of the invention (441) 5.95 (s, 2H), 3 · 73 (d, J = 8Hz, 1H), 6.83 (dd, J = 2Hz, J = 8Hz, 1H), 3.87 (d, J = 9Hz, 2H), 7.01 (d, J = 2Hz, 1H), 7.33 ( d, J = 9Hz, 2H). MS (DC1 / NH3) m / e 576 (M + H) + 〇 Example 379 Another formula, trans-2,4-bis (3,4-difluorophenyl) -1- (7〇 ^,: ^ -Dibutylamino) carbonyl) methyl) p-bihadine-3-number acid The procedure of Example 1 was used to prepare the title compound. 1H NMR (300 MHz, CDC13) d 7.35 (2H, m), 7.18 (4H, m), 4.87 (1H, d, J = 12), 4.00-3.60 (5H, m), 3.60-3.10 (3H, m), 3.10-2.90 (2H, m), 1.45 (2H, m), 1.29 (4H, m), 1.15 (2H, m), 0.91 (3H, t, J = 9) .83 (3H, t, J = 9). MS (DC1 / NH3) m / e 509 (M + H +). Analysis estimates C27H32F4N203 · 0.75 TFA: C, 57.62; H, 5.56; N, 4.72. Found 値: C, 57.72; H, 5.67; N, 4.66. Example 380 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) trans, trans-4- (3,4-xylyl) -2- (4-methoxy Phenyl) -lq (N, N-dibutylamino) carbonyl) methyl) pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. 4 NMR (300 μΗ, CDC13) d 7.43 (2Η, d, J = 9), 7.25 (m, bs), 7.18 (1Η, dd, J = 8, 3), 7.11 (1H, d, J = 9), 6.90 (2H, d, J = 10), 5.48 (1H, d, J = 12), 4.26 (1H, d, J = 18), 4.16 (2H, m), 3.83 (2H, m), 3.81 (3H, s), 3.56 (1H, bd, J = 18), 3.37 (1H, m), 3.20 (1H, m), 2.96 (2H, m), 2.24 (3H , 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 (DC1 / NH3) m / e 495 (M + H +). Analyze and estimate C3〇H42N204 · 1.25 TFA: C, 61.26; 444-This paper is again applicable to China National Standard (CNS) A4 specifications (210, 乂 297 mm) 581760 A7 B7 V. Description of the invention (442) Η, 6 · 84; N, 4.40. Found 値: C, 61.16; Η, 7.05; N, 4.38. Example 381 trans, trans · 2,4-bis (3-fluoro-4-methoxyphenyl Vl_agsLN_dibutylamino) carbonyl) methyl) pyrrolidine-3-carboxylic acid The title compound was prepared. NMR (300MHz, CDC13) A 7.20 (2H, m), 7.17 (2H, m), 6.93 (2H, m), 5.48 (1H, m), 4.26 (1H, m), 4.16 ( 2H, m), 3.83 (2H, m), 3.87 (6H, s), 3.56 (1H, m), 3.37 (1H, m), 3.20 (1H, m), 2.96 (2H, m), 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 (DCl / NH3) m / e 533 (M + H +). Analysis estimates C29H38F2N205 · 0 · 75 H20: C, 63_78; H, 7.29; N, 5.13. Found 値: C, 63 · 77; H, 7.08; N, 4_99. Example 382 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-4- (1,3-benzodifluorene-5_yl) -2- (4-methoxyphenyl (2-pentyl), N_ (3-methylphenyl) amino) carbonyl) methyl) pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. NMR (300 MHz, CD3OD) d 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 geometric variation Structure)), 2.73-2.91 (m, 2H), 3.17-3.26 (m, 2H), 3.32 · 3.62 (m, 2H), 3.77-4.08 (m, 1H), 3.80 (s, 3H ), 4.71 (m, 1H), 5.92 (m, 2H), 6.61-6.84 (m, 6H), 7.04-7.16 (m, 3H), 7.23_7 · 29 (m, 2H). MS (DCl) m / e 559 (M + H +). Analysis estimates C33H38N2 0 6 · 0.35 H20 · 0.05 CH3C02C2H5: C, 70.03; H, 6.92; N, 4.92. Found 値: C, 70.08; H, 6.82; N, 4.95. -445- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 581760 A7 ________B7 V. Description of the invention (# 3) Example 383 trans, trans-4- (1,3-benzobis Yin 5-yl) -2- (4-methylphenylphenyl · N- (1-^: yl) amine carboxymethyl) p ratio p each p_3-carboxylic acid can be prepared using the procedure of Example 1 Title compound. iHNMR (300 MHz, CD3OD) d 0.87 (t, J = 7 Hz, 3H), 1.20-1.40 (m, 2H), 1.40-1.60 (m, 2H), 2.42-2.80 (m, 2H), 2.85 -4.00 (m, 6H), 3.77 (d, J = 1.5 Hz, 3H), 4.05-4.20 (m, 1H), 5.94 (d, J = 2 Hz, 2H), 6.6 (dd, J = 9, 10 Hz, 1H), 6.70-6.85 (m, 4H), 6.95-7.02 (m, 2H), 7.17 (dd, 8H, 1/2), 7.25 (dd, 8H, 1/2), 7.38-7.60 (m , 4H), 7.87-8.00 (m, 2H). MS (E.S.I.) m / e (M + H) 581. Analysis estimates C35H36N206 · 1.4 H20 · C, 69.38; H, 6.45; N, 4.62. Measured 値 · C, 69.36; H, 6.07; N, 4.41. Example 384 trans, trans-2_ (4-methoxyphenyl) 4_d, 3_benzobisfluoren-5-ylphenyl-N-n-hexanesulfonamido) ethyl 1pyrrolidine_3_carboxy Acid use, Example 6 In 6 steps, the title compound can be prepared and separated into the brown 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). m.p. 67-68 ° C. 4 NMR (CD3OD, 300 MHz) d 0.88 (t, J = 7Hz, 3H), 1.25-1.40 (m, 6H), 1.73 (iAJ = 7Hz, 2H), 2.13 · 2.23 (m, 1H), 2.64 -2.88 (m, 3H), 3.02 (six peaks, J = 8Hz, 2H), 3.44-3.53 (m, 2H), 3.58 (d, J = 9Hz, 1H), 3.56-3.75 (m, 1H), 3.78 (s, 3H), 3.88-3.98 (m, 1H), 5.93 (s, 2H), 6.72 (d, J = 9Hz, 1H), 5.78-5.83 (m, 3H), 6.96 (d, J = 2Hz, 1H), 7.20 (d, J = 9Hz, 2H), 7.27-7.36 (m, 5H). MS (DC1 / NH3) m / e 609 (M + H) +. -446- This paper standard IT account standard (CNS) A4 specification (21GX-297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 Α7 Β7 V. Description of the invention (444) Example 385 Formula_4_ (1,3 · benzodiazine-5 · yl) _2- (4-methoxyphenyl) -1- (2-methyl-1,2,3,4_tetrahydro p-quelin- 1-yl) fluorenylmethyl) p-bilodine-3.metanoic acid Using the procedure of Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) d 1.03 (m, 3Η), 1.10-1.45 (m, 1Η), 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 (DC1) m / e 529 (M + H) +. Analysis estimates C31H32N206 · 0.3 H20: C, 69.73; H, 6.15; N, 5.25. Found 値: C, 69.74; H, 6.10; N, 5.01. Example 386 trans, trans-4- (1,3-benzodifluoren-5-ylmethoxyphenyl) -1- (3butylheptan-2-en-1-yl) The title compound was prepared using the procedure of Example 1 using an acid. NMR (300 MHz, CD3OD) β 0 · 86 (t, J = 70 Hz, 3H), 0.90 (t, J = 7_0 Hz, 3H), 1.20-1.41 (m, 8H), 1.95 · 2.06 (m, 4H), 3.24 (d, J = 11.0 Hz, 1H), 3.51-3.59 (m, 3H), 3.60-3.71 (m, 1H), 3.77-3.84 (m, 1H), 3.81 (s, 3H ), 4.45 (d, J = 11.0 Hz, 1H), 5.52 (t, J = 7.4 Hz, 1H), 5.93 (s, 2H), 6.77 (d, J = 8.1 Hz, 1H), 6.87 (dd, J = 1.8, 8.1 Hz, 1H), 6.99 (m, 3H), 7.46 (m, 2H). MS (DCl) m / e 494 (M + H +). Analysis estimates C3OH39N05: C, 72.99; H, 7.96; N, 2.84. Measured pyrene: c, 72.73; H, 7.89; N, 2.64 ° Example 387 trans, trans-2_ (3-fluoro-4-methoxybenzyl) -4- (1,3-benzodifluorene_5 -A private 1_ "2_ (N_propyl_N · n-Hexitone continuous amine amino) ethyl IP Biluodian · 3_Jinic acid-447- This paper size applies Chinese National Standard (CNS) Α4 specification (210 X 297 mm) (Please read the precautions on the back before filling this page)

1T 581760 A7 B7 V. Description of the Invention (44S) Using the procedure of Example 66, the title compound can be prepared and isolated as a white solid. m.p. 63,65 ° C. 4 NMR (CDC13, 300MHz) d 0.82 (t, J = 7Hz, 3H), 0.88 (t, J = 6Hz, 3H), 1.23-1.47 (m, 6H), 1.44 (six peak, J = 7Hz, 2H) , 1.71 (five peaks, J = 6Hz, 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 = 3Hz, J = 9Hz, 1H), 3.52-3.59 (m, 1H), 3.66 (d, J = 9Hz, 1H), 3.87 (s, 3H), 5.95 (s, 2H), 6.74 (d , J = 8Hz, 1H), 6.82 (d, J = 8Hz, 1H), 6.42 (t, J = 8Hz, 1H), 6.96 (s, 1H), 7.12 (d, J = 9Hz, 1H), 7.17 ( d, J = 12Hz, 1H). MS (DCl / NH3) m / e 593 (M + H). Example 388 trans, trans-4,1,3-benzobis $ -5-yl) _2_ (4-methoxyphenyl) _1- (3-erimidinyl) methyl) pyrrolidine-3-carboxyl标题 The procedure of Example 1 was used to prepare the title compound. iH NMR (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 this page) CD3OD) β 2.87 (m, 2H), 3.04 (dd, J = 3.2, 9.7 Hz, 1H), 3.21 (d, J = 13.7 Hz, 1H), 3.51 (m, 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, 7.8 H), 6.94 (m, 3H), 7.36-7.45 (m, 3H), 7.81 (m, 1H), 8.39 (m, 1H), 8.46 (dd, J = 1.4 Hz, 1H). Analysis estimates C25H24N205 · 0.70 H20 · 0 · 05 CH3C02C2H5: C, 67.34; H, 5.79; N, 6.23. Measured fluorene: C, 67.31; H, 5.63; N, 5.90 ° Example 389 trans'trans-2- (n-hexyl) -4- (1,3-benzobisπ_5_yldibutyl Amine carboxymethyl) p-bitoline_3_ building_ The title compound was prepared using the procedure of Example 1 '. ijj NMR (CDC13, -448- This paper size applies to the Chinese National Standard (CNS) A4 specification (2i0χ 297 mm) 581760 A7 ___B7___ V. Description of the invention (secret) 300 MHz) d 0.82 · 1 · 00 (m, 9H), 1.20-1.40 (m, 12H), 1.45-1.60 (m, 4H), 1.70-1.90 (br m, 2H), 3.10 · 3 · 46 (m, 6H), 3.65 (t, J = 10.8 Hz, 1H), 3.76 (t, J = 110.0 Hz, 1H), 3.94.4.0.06 (m, 2H), 4.14-4.34 (m, 2H), 5.94 (s, 2H), 6.73 (d, J = 8.1 Hz, 1H), 6.79 (dd, J = 8.1, 1.8 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H). MS (DC1 / NH3) m / e 489 (M + H) +. Analytical estimates c28H44N205 · 0.9 TFA: C, 60.53; H, 7.65; N, 4.74. Measured fluorene: c, 60 · 62; H, 7.69; N, 4.6 Bu—Example 390 trans'trans-4- (l, 3_benzodiyin-5_yl) -2- (4 • A Oxyphenyl) _1-(((N- (2-pentyl) -N- (4-fluoro-3-tolyl) amino) carbonyl) methyl) pyrrolidine_3_carboxylic acid Procedure of Example 1 The title compound can be prepared. NMR (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 this page) CD3OD) d0.92 (m, 3H), 0.97 (t, J = 7.1 Hz, 3H), 1.13-1.40 (m, 4H), 2.22 (m, 3H), 2.58-2.74 (m, 1H), 2.78-2.87 (m, 1H), 3.09 · 3 · 25 (m, 2H), 3.39-3.60 (m, 2H), 3.70-3.90 (m, 1H), 3.80 (s, 3H), 4.70 (m, 1H), 5.93 (m, 2H), 6.70-6.76 (m, 1H), 6.75 ( dd, J = 1.4, 8.1 Hz, 1H), 6.80_6.94 (m 4H), 6.96-7.13 (m, 4H). MS (DCl ·) m / e 577 (M + H.). Analytical estimates (^ 331137 ?: ^ 206 · Ο.25 H2O: C, 68 · 20; H, 6.50; N, m. Found 値: c, 68.21; H, 6.46; N, 4.74 〇Example 391 trans, trans-4- (1,3-benzene_diafluoren-5-yl) _21 £ 4-methylphenyl) -1-((2-pyridyljmethyl) pyrrolidine The title compound can be prepared using the procedure of Example 1. NMR (300 MHz, -449- This paper size is in accordance with the Chinese National Standard (CNS) A4 specification (2i0χ 297 mm) 581760 A7 ----- —__— _B7 __ _______ 5. Description of the Invention (Private 8) Carboxylic Acid Using the procedure in Example 1, the title compound can be prepared and separated into a white solid. Mp · 115-117 ... 4 NMR (300 MHz, CDC13) d 0.82 (t, J = 7Hz , 3H), 0.88 (t5 J = 7Hz, 3H), 1.05_1 · 5 (m, 8H), 2.85 (d, J = 13Hz, 1H), 2.90-3.17 (m, 5H), 3.20-3.35 (m , 1H), 3.35-3.50 (m, 3H), 3.55-3.65 (m, 1H), 3 84 (d, J = 10Hz, 1H), 3.87 (s, 3H), 3.92 (s, 3H), 5.94 (dd, J = 4Hz, 2Hz, 2H), 6.62 (s, 1H), 6.70 (s, m), 6.90 (t, J = 8Hz, 1H), 7 05-7 20 (m, 2H). Examples 394 formula 'transform_2- (l, 4 ^ and two 唠 6_base) _4_ (7 · Oxy_13_benzodibutyl) amino) carbonylmethyl1pyrrolidine-3.carboxylic acid The title compound was prepared by the method of Example 1 and isolated as a white solid. Mp 107-110 ×:. NMR ( 300 MHz, CDC13) β 0.82 (t, J = 7Hz? 3H)? 0.88 (t? J = 7Hz? 3H), 1.05-1.50 (m? 8H), 2.75 (d9 J = 13Hz, 1H), 2.90-3.12 (m, 4H), 3.32-3.60 (m, 5H), 3.69 (d, J = 8Hz, 1H), 3.90 (s, 3H), 4.23 (s, 4H), 5.95 (dd, J 4Hz, 2Hz, 2H), 6.62 (s, 1H), 6.70 (s, m), 6.78 · 6 · 93 (m, 3H). Example 395 Printing of trans , Trans bis 4- (l? 3 di ^ bis difluoren-5-5-yl) _2 彳 4_methazine) buten-1-yl) pyrrolidine-3-carboxylic acid can be prepared by the method of Example 1 Title compound. iH NMR (300 MHz, CD3OD) Θ 0_84 (t, J = 7.0 Hz, 3H), 0.88 (t, J = 7.0 Hz, 3H), 1.16-1.37 (m, 8H), 1.83 (t, J = 8.5 Hz , 2H), 2.03-2.08 (m, 2H), 2.76-2.92 (m, 2H), 3.02 (t, J = 9.3Hz, 1H), 3.32-3.42 (m, 2H), _ _____- 451-this paper Standards are applicable to Chinese National Standard (CNS) A4 (210X 297 mm). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 581760 A7 B7. 5. Description of the invention (449) 3.50 (m, 1H), 3.71 (d, j = 9.2 Hz, 1H), 3.78 (s, 3H), 5.91 〇, 2H), 6.72 (d, J = 7.8 Hz, m), 6.83 (dd, J = 1.7, 8.1 Hz, 1H), 6.90 (m, 2H) , 7.02 (d, 7 Hz, 1H), 7.34 (m, 2H). MS (DCl) m / e 512 (M + H +). Analysis estimates c3 () h38FN05: C, 70.43; H, 7.49; N, 2.74. Found 値: C, 70.58; H, 7.54; N, 2.66. Example 396

Trans ........ 4-formula-2_ (3difluorodikethoxyphenyl) _4_ (1,3 · benzodifluorene · 5_yl H P- (N · propylcontinylamine) ) Ethyl 1 pyrrolidine_3 • carboxy | The title compound was prepared by the method in Example 6 and isolated as a white solid, mp 65-66 ° C. 4 NMR (CDC13, 300 MHz) β 0.82 (t, J = 7Hz, 3Η), 0.90 (t, J = 7Hz, 3Η), 1.26_1 · 36 (m, 4Η), 1.41-1 52 (m, 5H), 1.73 (Five Peaks, J = 7Hz, 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 = 9Hz, 1H) , 3.52-3.59 (m, 1H), 3.66 (d, J = 9Hz, 1H), 4.08 (q J = 7Hz, 2H), 5.95 (s, 2H), 6.74 (d, J = 8Hz , 1H), 6.82 (d, J, 8Hz 1H), 6.92 (t, J = 8Hz, 1H), 6.97 (s, 1H), 7.07 (d, J = 8Hz, 1H) 7.15 (d, J = 12Hz, 1H). MS (DC1 / NH3) m / e 593 (M + H) +. 'Example 397 trans' trans-2- (4-methoxy-3-fluorophenyl) -4- (7- Methoxy-1 dihumidyl-5-yl M4 (N · butyl-N · propylamino) carbonylmethyl 1 pyrrolidine-3 ^^ The title compound was prepared as a white solid by the method of Example 1. Hungry · ρ 118-120 ° C. / H NMR (300 MHz, CDC 13) d 0.70-0.90 (4'peaks J = 7Hz), 1.05-1.55 (m, 8H), 2.80-3.50 (m, 9H), 3.55-3.6S / (m, 1H), 3.82 (d, J = 10Hz, 1H), 3.85 (s, 3H), 3.92 (s, 3H), 5.96 -452-This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the back first Please pay attention to this page and fill in this page again)-Yikou I 丨 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ____—__ B7____ V. Description of Invention (450) 2H), 6.62 (s, 1H), 6.70 (s) , 1Η), 6.90 (t, j = 8Hz, 1H), 7.08-7.22 (m, 2H). Example 398 trans, trans-4- (l, 3i and di 噚 · 5_base) · 2_ (4-methoxyphenylbutyl-> L -_ (. 4__chloropen |) aminocarbonylmethyl) pyrrolidine-3-carboxylic acid The title compound was prepared by the method of Example 1. NMR (300 MHz, CD3OD) d 0 · 87 (t, J = 7 Hz, 3H), 1.20-1.50 (m, 4H), 2.66-4.00 (m, 9H), 3.81 (s, 3H), 5.95 (s, 2H), 6.77 (d, J = 7 Hz, 1H), 6.85 (d, J = 8 Hz, 3H), 7.05 (m, 5H), 7.33-7.42 (m, 2H). MS (C.I.) m / e 565 (M + H). Analytical estimates c3lH33N2O6C1. 〇25 jj3po4: c, 63.16; H, 5.77; N, 4.75. Measured fluorene: C, 63.14; H, 5.59; N, 4.53 ° Example 399 trans, trans- .. 4- (1,3 di! And dihydrazone-5-yl) _2 彳 4_methylargon i) 444-Methyl · 1? 2? 3? · 4-tetrahydrochrysyl) carbonylmethylsulfonium sulfonate compound The title compound was prepared by the method of Example 1. iH NMR (300MΗζ, CD3OD) d 1.27 (d, J = 7 Hz, L5H), 128 (d, 7Η, 15-diastereomer), 1.39-1.55 (m, 1Η) , 2.02 · 2 · 15 (m, 1Η), 2.60-3.25 (m, 5H), 3.33 · 4 · 00 (m, 5Η), 3.78 (s, 3H), 5% (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 (DC1) m / e 529 (M + H), analytical estimate C3iH32N2O6: c, 70.44; H, 6.10; N, HO. Found 値: c, 70%; H, 60%; where 5.04. -453_ ^ Paper size applies Chinese National Standard (CNS) A4 specification (210X297mm)-(Please read the precautions on the back before filling out this page) Clothes · Order 581760 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 4. Description of the invention (451) Example 400 Very di-form, trans-2- (3--fluoroifoxyphenyl-bis-diphenyl group), propyl-N- (2- {j £ hydro ^ pyridyl group ) Ethanesulfonylamino) ethyl 1 pyrrolidine-3-carboxylic acid The title compound was prepared by the method of Example 66 and isolated as a white solid. m.p. 95-96 C. 4 NMR (CDC13, 300 MHz) d 0.82 (t, J = 7Hz? 3H)? 1.43-1.55 (m? 4H)? 1.63-1.72 (m? 4H)? 2.29-2.38 (m, 1H), 2.64-2.78 (m, 5H), 2.87 (t, J = 8Hz, 1H), 2.95-3.04 (m, 5H), 3.20-3.30 (m, 1H), 3.32-3.43 (m, 4H), 3.54-3.63 (m, 1H), 3.78 (d, J = 8Hz, 1H), 3.87 (s, 3H), 5 92 (s 2H), 6 72 (d J = 8Hz, 1H), 6.78 (dd, J = 2Hz, J = 8z, 1H), 6.88 (t, J = 8Hz, 1H), 6.94 (d, J = 2Hz, 1H), 7.08-7.20 (m, 2H). MS (DC1 / NH3) m / e 620 (M + H) + 0 Example 401 trans-4, trans (Homoepoxy 1,2,3-benzodiyin · 5_yl V1_ (N Ν · Dibutylenol) Methyl) pyrrolidine_3_ # 醢 The title compound was prepared according to the method in Example 1. ifj NMR (CDC13, 300 MHz) β 0.83-0.98 (s, 9H), 1.18-1.40 (m, 14H), 1.44 -1 · 60 (m, 4H), 1.72-1.96 (br m, 2H), 3.12 · 3 · 45 (m, 6H), 3.65 (t, J = 10.5Hz, 1H), 3.76 (t, J = ii.2 1H), 3.90-4.06 (m, 2H), 4.13 · 4.33 (m, 2H), 5.93 (s, 2H), 6.73 (d, J = 7.8 Hz, 1H), 6.79 (dd, J = 7 · 8, 1 · 7 Hz, 1H), 6.87 (d, J = 1.7 Hz, 1H). MS (Dd / NH3) m / e 503 (M + H) +. Analyzed and estimated c29H46N205 · 0.75 TFA: C, 62.28; H, 8.01; N, 4.76. Measured 値: c, 62.2〇; H, 7.99; N, 4.50. -454- This paper size applies to China National Standard (CNS) A4 specification (210X297) Li) (Please read the notes on the back before filling this page)

581760 A7 _________B7_ V. Description of the invention (452) Example 402 Expansion, trans-4- (1,3_benzodiazine-5-yl) -2- (4_methylphenylphenyl-1,2 , 3,4_tetraargonium 4-yl-1 -yl) carbonylmethyl) p-bilodine-3 acid The title compound was prepared by the method of Example 1. 4 NMR (300 MHz, CD3OD) β 0.99 (d, 1.5H), 1.03 (d, J = 6 Hz, 1.5H, second diastereomer), 2.60-4.00m (12), 3.78 ( s, 1.5Η), 3.79 (s, 1.5Η, second diastereoisomeric), 5.92 (s, 1Η), 5.93 (s, 1Η, diastereoisomeric ), 6.65 · 7 · 40 (m, 1Η). MS (DCl) m / e 529 (M + H) +. Analysis estimates C31H32N206 · 0.8 H20: C, 68 · 57; H, 6.24; N, 5.16. Found 値: C, 70.44; H, 6.10; N, 5.30. Example 403 trans, trans · 4 · α, 3-benzodifluoren-5-ylmethoxyphenylbutyl-N- (4-fluorophenyl) aminocarbonylmethyl) pyrrolidine-3-carboxylic acid The title compound was prepared using the procedure of Example 1. NMR (300 MHz, printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (please read the notes on the back before filling this page) CD3OD) d 0 · 87 (t, J = 7 Hz, 3H), 1.2-1.47 (m , 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 = 12 Hz, 1H), 3.80 (s, 3H), 5.94 (s, 2H), 6.72 · 6.86, 4H), 7.00-7.15 (m, 7H). MS (DCl) m / e 549 (M + H) +. Analysis estimates C31H33N206F · 0.4 H20: C, 66 · 99; H, 6.13; N, 5.04. Found 値: C, 66 · 99; 5.94; Ν, 4.99. Example 404 trans, trans-butyl-N- (3-methylphenyl) aminocarbonylmethyl) -2- (4 = methoxybenzyl) _4 · (5-Qinylpyranyl) -3- Junic acid 455 · This paper is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) ~ 581760 A7 B7 V. Description of the invention (453) The title compound can be prepared by the method of Example 1. b NMR (300 MHz, CDC13) β 7.66 (1H, bs), 7.60 (1H, d, J = 3Hz), 7.45 (2H, s), 7.15 (4H, m), 6.75 (5H, m ), 3.96 (1H, d, J = 10Hz), 3.78 (3H, s), 3.74 (1H, m), 3.59 (3H, m), 3.21 (1H, t, J = 9Hz), 3.19 (1H, d, J = 16Hz), 2.92 (1H, t, J = 9Hz), 2.70 (1H, d, J = 16Hz), 2.29 (3H, s), 1.41 (2H, m), 1.24 ( 2H, m), 0.85 (3H, t, J = 7 Hz). MS (DC1, NH3) m / e 541 (M + H +). Analysis estimates C33H34N20 · 0.1 H20: C, 71.21; H, 6.52; N, 5.03. Found 値: C, 71.31; H, 6.30; N, 4.98. Example 405 trans, trans-1- (N-butyl-N- (3-tolyl) aminocarbonylmethyl) -2- (4-fluorophenyl) -4- (5-benzopyranyl ) P-to-p-Each-3-Leptanoic Acid Using the method of Example 1, the title compound can be prepared. 1H NMR (300 MHz, CDC13) xi 7.67 (1Η, bs), 7.60 (1Η, d, J = 3Hz), 7.45 (2Η, m), 7.18 (3H, m), 7.12 (1H, d, J = 7Hz), 6.93 (2H, m), 6.76 (1H, J = 3Hz), 6.70 (2H, bd), 4.02 (1H, m), 3.77 (1H, m), 3.59 (3H, m), 3.29 (1H, m), 3.19 (1H, m), 2.94 (1H, m), 2.71 (1H, m), 2.30 (3H, s), 1.45 (2H, m), 1.26 (2H, six peaks, J = 7Hz), 0.84 (3H, t, J = 7Hz). MS (DC1, NH3) m / e 529 (M + H +). Analysis and Estimates 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 this page) C33H34N205 · 0.2 HOAc: C, 71.98; H, 6.30; N, 5.18. Found 値: C, 71.68; H, 5.89; N, 5.25. Example 406 trans, trans-4- (l, 3-benzodifluorene · 5-yl V2- (4-methyliphenyl l · 1 · (di- (3-methylphenyl) amino) Carbonyl) methyl) Taste Check 456- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 581760 A7 B7 V. Description of the invention (454) The procedure of Example 1 can be used to prepare the title compound. iH NMR (300 MHZ, CD3OD) d 2.27 (s, 6H), 2.81 (dd, J = 8.1, 9.5 Hz, m), 2.98 (d, J = 15.3 Hz, 1H), 3.20 (t, J = 16.6 Hz , 1H), 3.47-3.60 (m, 3H), 3.80 (s, 3H), 3.85 (d, J = 9.5 Hz, 1H), 5.91 (s, 2H), 6.73 (d, J = 7.8 Hz, 1H) , 6.85 (m, 3H), 6.95 (m, 4H), 7_05 (d, J = 1.7 Hz, 1H), 7.06-7.24 (m, 6H). MS (DC1) m / e 579 (M + H +). Analysis estimates C35H34N206 · 0.15 H20 · 0 · 20 CH3C02C2H5: C, 71.79; H, 6.04; N, 4.68. Found 値: C, 71.81, H, 5.79, N, 4.51. Example 407 trans, trans-4- (1,2-dihydrobenzopyran-5-yl) -2- (4-methoxybenzyl VU (((N_butyl_N_ (3-toluene Base) amine a) carbonyl) methyl) pyrrolidine _3-borrow_ 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) The title compound can be prepared using the procedure in Example 1. iH NMR (300MHz, CDC13) β 7.73 (2H, m), 7.40-7.10 (4H, m), 6.92 (2H, m), 6.72 (2H, d, J = 9), 6.63 (1H, m), 5.40 (1H, m), 4.55 (2H, t, J = 9), 4.30-4.10 (3H, m), 3.84 (3H, s), 3.82 (1H, m), 3.65 (1H, m), 3.39 (1H, 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 (DC1 / NH3) m / e 543 (M + H +). Analytical estimation c33H38N205 · 0.65 H20: C, 71 · 50; H, 7.15; N , 5.05. Measured fluorene: c, 71.47; H, 6_96; N, 4.83 〇 Example 408 trans, trans-2 · (3-fluoro-4-methoxymozine benzodifluorene_5_yl μ] · {2- (Ν-propyl_Ν_ 丨 2_ (Ν, Ν_dimethylamino) ethane ethyl ether) ethyl} foliolidine-3- # acid ___- 457__ This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210x ^ 97 mm) 581760 A7 B7 V. Description of the invention (455) The title compound can be prepared by the method of Example 6 6 t and separated as a white solid. Mp · 81 -82X: .ijj NMR (CDC13, 300 ΜΗζ) β 0.80 (t, J = 7Hz, 3Η), 1.43 (six peak, J = 7Hz, 2Η), 2 15 2 24 (m, m), 2 36 (s , 6Η), 2.66-2.76 (m, in), 2.83-3.04 (m, 6Η), 3.18-3.41 (m, 5Η), 3.55-3.63 (m, 1Η), 3.72 (d, J = 8Hz, 1Η) , 3.85 (s, 3Η), 5.90 (d, J = 6Hz, 2H), 6.67 (d, J = 8Hz, 1H), 6.78 (dd, J = 2Hz, J = 8Hz, 1H), 6.84 (t, J = 8Hz, 1H), 7.94 (d, J = 2Hz, 1H), 7.09 (d, J = 8Hz, 1H), 7_20 (dd, J = 2Hz, J = 12Hz, IH). MS (DC1 / NH3) m / e 580 (M + H) + 〇 Example 409 trans-.,. Trans-diaminecarbonylmethylfluorobenzyl V4- (5-benzyl ^^) pyrrolidine- 3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. iH NMR (300 MHz, printed by the Consumer Cooperatives of the China National Standards Administration, Ministry of Economic Affairs (please read the precautions on the back before filling out this page) CDC13) (ί 7.88 (1H, bs), 7.80 (2H, m) , 7.61 (1H, d, J = 3Hz), 7.55 (1H, bd, J = 8Hz), 7.46 (1H, d, J = 8Hz), 7.07 (2H, t, J = 8Hz) , 6.76 (1H, d, J = 3Hz), 5.53 (1H, bd, J = llHz), 4.18 (2H, m), 3.91 (3H, m), 3.55 (1H, d, J = 16Hz), 3.30 (3H, m), 3.12 (1H, dd, J = 10 & 9Hz), 2.95 (1H, m), 1.51 (2H, m), 1.31 (4H, m), 1.12 (2H, m ), 0.92 (3H, m), 0.83 (3H, t, J = 7Hz). MS (DCl, NH3) m / e 595 (M + H +) ° Example 410 trans'trans 4- (1,2- Dihydrobenzowan-5_yl) _2_ (4-ethylphenyl) -1 · (((N-butyl-N —- (g-methylphenyl) amino, carboxyl) methyl) p Pyrrolidine · 3_Gunic acid The title compound can be prepared by the method of Example 1. NMR (300 ΜΗζ, -458- This paper is in accordance with the Chinese National Standard (CNS) A4 specification (210X297 mm): 581760 A7 B7 5 Description of the invention (456) CDC13) β 7 · 35 (2H, m), 7.20-7 · 00 (7H, m), 6.70 (2H, d, J = 9), 5.38 (1H, m), 4.55 (2H, t, J = 9), 4.05 (1H, m), 3.64 (2H, m), 3.45 (1H, m), 3.21 ( 2H, t, J = 9), 2.95 (1H, m), 2.75 (1H, m), 2.63 (2H, q, J = 8), 2.38 (2H, m), 2.27 (3H , S), 1.43 (2H, m), 1.30 (2H, m), 1.22 (3H, d, J = 9), 0.89 (3H, t, J = 9). MS (DC1 / NH3) m / e 541 (M + H +). Analyzed and estimated C34h4 () N2 04 ·! 6 AcOH: c 7〇 · 17; H, 7.34; N, 4.4. Found 値: c, 7〇11; H , 7 〇6; N, 4.80. Column 411 trans' trans-4_ (U-dihydro% ronfuran_5_yl) -2_ (4_fluorophenylfluorene-Gong-(((N, Ij_— Butylamino) fluorenyl) methyl) p-bilobaline-3 leptin The title compound was prepared using the procedure of Example 1. iH NMR (300 MHz, CDC13) β 7 · 40 (2H, m), 7.28 (1H, bs), 7.18 (1H, dd, J = 8, 3), 7.00 (2H, t, J = 9) , 6.72 (1H, d, J = 9), 4.53 (2H, t, J = 9), 3.92 (lH, m), 3.65 (lH, 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 = 8 ), 0.83 (3H, t, J = 8). MS (DC1 / NH3) m / e 497 (M + H +). Analysis estimates C29H37FN204 · 0.25 H20: C, 69.51; H, 7.54; N, 5.59. Found 値: C, 69.45; H, 7.60; N, 5.44. 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) Example 412 trans, trans_4_ (1,2-dihydrobenzofuran-5_ylfluorophenyl) -1-(((N-butyl-N · (3-methylbenzyl) amino) carbonyl) methyl) pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. 1H NMR (300 MHz, CDC13) d 7 · 28 (1Η, bs), 7.25-7.00 (5Η, m), 6.91 (2Η, -459-) This paper size is applicable to China National Standard (CNS) A4 specifications (210X 297mm) (Centi) 581760 A7 B7 V. Description of the invention (457) m), 6.72 (3H, d, J = 9), 4.54 (2H, t, J = 9), 4.00 (1H, m), 3.60 ( 3H, m), 3.45 (1H, 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 (DCl / NH3) m / e 531 (M + H +). Analytical estimates for C32H35FN204..25jj20: C, 71.82; H, 6.69; N, 5.23. Found 値: C, 71.66; H, 6.55; N, 5.03. Example 413 trans'trans_4bis (hydrogen ^: ^^) _ 2_ (4-methylbenzyldibutylamine methyl) pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. ijj NMR (300 MHz, CDC13) θ 7.32 (3H, m), 7.18 (2H, m), 6.85 (2H, d, J = 9), 3.83 (lH, m), 3.79 (3H, s), 3.67 (lH, m), 3.50-3.20 (4H, m), 3.20-2 · 92 (4H, m), 2.87 (5H, m), 2.79 (1H, bd, J = 15), 2.06 (2H , M), 1.43 (2H, m), 1.27 (4H, m), 1.08 (2H, m), 0.88 (3H, t, J = 8), 0.82 (3H, t, J = 8). MS (DCl / NH3) m / e 507 (M + H +). Anal. C31H42N204: c, 73.49; H, 8.36; N, 5.53. Found 値: c, 73.18; H, 8.29; N, 5.17. Example 414 trans, trans-diyl) · 4_ (3,4-difluorophenyl)-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-Tolyl) amino V carbonylmethyl 1 pyrrolidine-3-carboxylic acid The method of Example 1 was used to prepare the title compound. NMR (300 MHz, CDC13) d 0 · 86 (t, J = 7Hz, 3H), 1.10 · 1 · 35 (m, 2H), 1.35_1 · 52 (m, 2H), 2.29 (s, 3H ), 2.63 (d, J = 13Hz, 1H), 2.76 (t, J = 7Hz, 1H), 3.06-3.20 (m, 2H), 3.42-3.53 (m, 1H), 3.50-3.64 (m, 3H) 460- This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 581760 Printed by A7 B7, Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (458) 3.80 (s, 3H), 3.86 (d , J = 9 Hz, m), 6 66-6 82 (m 4H), 70 2 · 7.22 (m, 6H), 7.30-7 4 0 (m, 1H). Example 415 'Trans-chlorobenzyl) aminocarbonylmethyl benzofuranyl) pyrrolidin-3-carboxylic acid The title compound was prepared using the disc of Example 1. 1H NMR (300 MHz, CDC13) d 7.64 (1H, d, J = 2Hz), 7.61 (1H, d, J = 3Hz), 7.47 (m, d, J = 8Hz), 7.41 ( 1H, dd, J = 8 & 3Hz), 7.30 (1H, dt, J = 8 & 2Hz), 7.21 (1H, d, J = 8Hz), 7.19 (2H, m), 7.00 (1H, bs), 6 · 94 (2H, t, J = 8Hz), 6.83 (1H, bd, J = 8Hz), 6.74 (1H, dd, J = 2 & lHz), 3.96 (1H, d, J = 10Hz), 3 75 (1H, ddd, 6, 5 & 3Hz), 3.59 (3H, m), 3.23 (1H? T? J = 10Hz)? 3.18 (1H? D? J = 16Hz)? 2.92 (1H? Dd9 J = 10 & 9Hz), 2.69 (1H, d, J = 16Hz), 1.41 (2H, m), 1.23 (2H, m), 0.87 (3H, t, J = 7Hz). MS (DC1, NH3) m / e 549, 551 (M + H +). Analysis estimates C31H30C1FN20: c, 67.82; H, 5.51; N, 5.10. Found 値: C, 67.43; H, 5.33; N, 4.78. Example 416 trans, trans · 4- (1,3_benzobisfluoren-5-yloxyphenyl) propyl-N- (4-phenoxyfluorenyl) amino, carbonyl) methyl) pyrrolidine _3_ Carboxylic acid The procedure of Example 1 was used to prepare the title compound. ijl NMR (300 MHz, CDC13) d (geometric isomer) 7.40-7.20 (5H, m), 7.13 (2H, m), 6.98 (2Η, m), 6.93-6.60 (7Η, m), 5.93 (1Η, d, J = 2), 5.88 (5.85) (1H, d, J = 2), 4.90 (4.50) (1H, d, J = 15), 4.10 (4.25) (1H, d, J = 15 ), 3.77 (3 · 73) (3H, s), 3.72 (1H, m), 3.60 (1H, m), 3.53- -461-This paper size applies to China National Standard (CNS) A4 (210X297) (Please read the notes on the back before filling out this page) Clothing and Orders Printed by the Central Consumers Bureau of the Ministry of Economic Affairs and printed by the Consumer Cooperative 581760 A7 B7 V. Description of Invention (459) 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 (DC1 / NH3) m / e 623 (M + H +). Analysis estimated C37H38N207.25H20: C, 70.85; H, 6.19; N, 4.47. Measured fluorene: C, 70.68; H, 6.10; N, 4.42 〇 Example 417 trans, trans-4- (1,2-dihydrobenzoan-5_yl) -2- (4-ethylbenzene Group) -1-(((N- (2-pentyl) -N- (4-fluoro-3-methylphenyl) amine, fluorenylmethyl) pyrrolidine-3-carboxylic acid The title compound can be prepared. 1H NMR (300 MHz, CDC13) β 7.30 (1Η, bs), 7.20-7.00 (5Η, m), 6.87 (1Η, m), 6.73 (2H, d, J = 9), 6.57 (1H, m), 4.81 (1H, m), 4.55 (2H, t, J = 9), 3.92 (1H, bd, J = ll), 3.60 (1H, m), 3.43 (1H, m), 3.18 (2H, t, J = 9), 3.17 (1H, m), 3.06 (1H, dd, J = 15, 6), 2.88 (1H, dd, J = ll. 9), 2.61 (2H, q, J = 8), 2.59 (1H, m), 2.18 (3H, m), 1.40 · 1.10 (4H, m), 1.22 (3H, t, J = 9), 1 · 00 · 0 · 80 (6H, m). MS (DC1 / NH3) m / e 573 (M + H +). Analyzed and estimated C35H41FN2 04 · 0.75 H20: c, 71.71; H, 7.31; N, 4.78. Found 値: c, 71.56; H, 7.33; N, 4.56. Example 418 trans, trans-2-M-methoxyphenylbenzodifluoren-5-yl) · 1_Γ2_ (N -Propyl-N-Γ2 · pyrimidinyl 1amino) ethyl 1 pyrrolidine · 3-carboxylic acid 2- (4_ Methoxyphenyl) -4_ (1,3-benzodifluoren-5-yl) _1 · [2- (N-propylamino) propyl] pyrrolidin-3-carboxylic acid ethyl ester, following the procedure of Example 61B Preparation, 138 mg of 2-bromopyrimidine, and 150 mg of diisopropylethylamine in 2 ml of ethyl-462 at 95 ° C-this paper is again applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ( Please read the precautions on the back before filling in this page) Order 581760 A7 B7 V. Description of the invention (460) Heating in nitrile for 15 hours. The resulting intermediates, trans and ethyl esters, are separated by silica gel chromatography, and 10% EtOAc / CH2Cl2 was dissolved and then hydrolyzed with NaOH in ethanol / water to give 95 mg of the title compound. IH NMR (300 MHz, CDC13) β 0.82 (t, J = 7Hz, 3H), 1.50 (six peaks, J = 7Hz, 2H), 2.15-2.30 (m, 1H), 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 = 4Hz, 1H), 6.65 (d, J = 8Hz, 1H), 6.75 · 6 · 82 (m, 1H), 6.78 (d, J = 9Hz , 2H), 6.96 (d, J = 2Hz, 1H), 7.27 (d, J = 9Hz, 2H), 8.20 (d, J = 4Hz, 2H). Example 419 Employee of the Central Standards Bureau of the Ministry of Economic Affairs Printed by Fei Cooperative (please read the notes on the back before filling out this page) trans, trans-4- (1,3-benzodifluorene-5_yl) -2- (4-methoxyphenyl) 1- (3-Butyl-2-chloro-hept-2-en-1-yl) p-bihalide-3-metanoic acid The procedure of Example 1 was used to prepare the title compound. iH NMR (300 MHz, CD3OD) β 0.84 (t, J = 6.8 Hz, 3H), 0.88 (t, J = 6.7 Hz, 3H), 1.19-L39 (m, 8H), 2.05 · 2.09 (m, 2H), 2.17-2.23 (m, 2H), 2.78 (dd, J = 6.6, 9.2 Hz, 1H), 2.95 (t, J = 9.2 Hz, 1H), 3.32-3.37 (m, 2H), 3.49 (m , 1H), 3.70 (d, J = 9.2 Hz, 1H), 3.77 (s, 3H), 5.91 (m, 2H), 6.72 (d, J = 8.1 Hz, 1H), 6.85 (dd, J = 1.9, 8.1 Hz, 1H), 6.89 (m, 2H), 7.08 (d, J = 1.5 Hz, 1H), 7.36 (m, 2H). MS (DC1) m / e 528 (M + H +). Analysis estimates C3OH38C1N05 · 0.25 H20: C, 67.66; H, 7.29; N, 2.63. Found 値: C, 67 · 62; H, 7.18; N, 2.40 0 Example 420 trans, trans-4- (1,2-dihydrobenzofuran-5-yl) _2_ (4-methyl-oxybenzene Base) -1_ -463- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) '' Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Description of the invention (461) Amyl fluoride -3-methylphenyl) amino) carbonyl) methyl) pyrrole · 3 · carboxylic acid The procedure of Example 1 was used to prepare the title compound. ιΗ NMR (300 μΗζ, CDC13) d7.28 (1Η, bs), 7.15 (3Η, m), 6.90 (1Η, m), 6.77 (2Η, dd, J = 9, 3H), 6 · 71 (2H, d J = 9), 6.56 (1H, m), 4.80 (1H, m), 4.53 (2H, t, J = 9), 3.92 (1H, m), 3 · 79 (3H, s), 3.60 (1H, m), 3.45 (1H, m), 3.19 (2H, t, J = 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 (DC1 / NH3) m / e 575 (M + H +). Analysis estimates C34H39FN205 · 0.35 H20: C, 70.29; H, 6.89; N, 4.82. Found 値: C, 70.37; H, 6.92; N, 4.30. Example 421 Formula, trans-4 · (1,2-dihydrobenzofuran-5-ylmethoxyphenyl VI- (K_N · butyl_N- (3-chlorophenyl) amino) carbonyl) Methyl) pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. iH NMR (300 MHz, CDC13) d7.29 (1H, 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 = 9), 3.85 (1H, d, J = 10), 3.79 (3H, s), 3.58 (3H, m), 3 · 42 (1H, dd, J = 10, 6), 3.18 (4H, m), 2.87 (1H, m), 2.66 (1H, m), 1.40 (2H, m), 1.25 (2H, m), 0.86 ( 3H, t, J = 9). MS (DCl / NH3) m / e 563 (M + H +). Analysis estimates C32H35C1N205 · 0 · 25 H20: C, 67 · 72; H, 6.30; N, 4.94. Found 値: C, 67 · 72; H, 6.21; N, 4.55. Example 422 trans, trans 3-benzodihum-5-yl) -2- (5-ethylfuran-2-yl) -1- -464-This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the notes on the back before filling this page)

1T Lin 581760 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (462) ((((N? N-dibutylamino) chamoline-based) pyrrolidine_3_carboxylic acid utilization The title compound was prepared by the procedure of Example 1. 1H NMR (300 MHz, CDC13) 6 7.77 (1H, bs), 7.11 (iH, d, J = 3), 7.02 (1H, dd, J = 9, 3), 6.82 (1H, d, J = 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 (lH, m), 3.10-2.82 (2H, m) , 2.76 (2H, q, J = 8), 1.45 (2H, m), 1.32 (3H, t, J = 9), 1.30-1.10 (6H, m), 0.87 (3H, t, J = 9 ), 0.85 (3H, t, J = 9). MS (DC1 / NH3) m / e 499 (M + H +). Analyzed and estimated c28h38N2 06 · 75 HC1: C, 59 · 8〇; H, 7 · 12; N, 4.98. Measured fluorene: c, 59 S1; H, 6 96; N, 4.88. Example 423 trans, trans-4 · (1,2_dibenzobenzofuran_5_some) · 2 · (4-fluorophenyl (_ (. (Ν_ (2-4yl) -N · (4-fluoro-3_methylphenyl) amino) carbonyl) methyl) pyridine-3- The steps of carboxylic acid utilization example 1 can be The title compound was prepared. Ij! NMR (300 MHz, CDC13) d 7.30-7.10 (4H, m), 6.92 (3H, m), 6.73 (2H, d, J = 9), 6.59 (1H, m ), 4.80 (1H, m), 4.53 (2H, t, J = 9), 4.00 (1H, bd, J = 10), 3.62 (1H, m), 3.45 (1H, m), 3.22 (1H, m), 3.21 (2H, t, J = 9), 3.02 (1H, dd, J = 15, 6), 3.85 (1H, t, J = 10), 2.58 (1H, bd J = 18) , 2.20 (3H, bs), 1.40-1.30 (3H, m), 1.15 (1H, m), [· 〇〇_ 0.80 (6H, m). MS (DCl / NH3) m / e 563 (M + H +). The analysis estimates C33H36F2N204: C, 70.44; H, 6.45; N, 4.98. Found 値: 70.06; H, 6.47; N, 4.71. -465- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (You 3) Preferential Example 424 g Furan-5-yl) -2- (4-fluorophenyl VI · (1 (N · butyl · N_ (3-diyl) carbonyl, methyl, pyrrolidine_3 carboxylic acid The title compound was prepared using the procedure of Example 1. 1H NMR (300 MHz, CDC13) d 7.30 (2H, m), 7.25-7.10 (4H , M), 6.95 (3H, m), 6.82 (1H, bd, J = 9), 6.73 (1H, d5 J = 9), 4.55 (2H, t, J = 9), 3.92 (1H, bd , J = ll), 3.60 (3H, m), 3.43 (1H, dd, J = 9, 6), 3.21 (2H, t, J = 9), 3.16 (2H, m), 2. · 87 (1H, m), 2.69 (1H, m), 1.42 (2H, m), 1.26 (2H, m), 0.87 (3H, t, J = 9). MS (DCl / NH3) m / e 551 (M + H). Analyzed and estimated c31H32C1FN204 · 0.25 H20: C, 67.02; H, 5.90; N, 5.04. Found 値: c, 66.98; H, 5.71; N, 4.76. ―Example 425 Basic formula 'Trans_4- (l, 2-Difluorenylbenzoxan_5_some ethyl 1 (((N-butyl-N_ (3-chlorophenylkamino) carbonyl) methyl) pyrrolidine _3_carboxylic acid The title compound was prepared by the method of Example 1. iH NMR (300 MHz, CDC13) d 7.30 (1H, m), 7.21 (1H, d, 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 (1H, bd, J = ll), 3.60 (3H, m), 3.43 (1H, m >, 3_22 (2H, t, J = 9), 3.18 (2H, m), 2.92 (1H, m), 2.72 (1H, m), 2.62 (2H, q, J = 8), 1.41 (2H, m), 1.26 (2H, m), 1.23 (3H, t, J = 9), 0.87 (3H, t, J = 9). MS (DC1 / NH3) m / e 561 (M + H +). Analysis estimates C33H37Cm204 · 0.25 H20: C, 70.08; H, 6.68; N, 4.95. Found 値: C, 70.13; H, 6.59; N, 4.65. Example 426 -466- This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

581760 A7 B7 V. Description of the invention (464) trans, trans-1- (N · butyl-N_ (3-chlorophenyl) septamidinylmethyl) -2- (4-methoxyphenyl) 4- (5-benzopyranyl) pyrrolidin-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. iH NMR (300 MHz, CDC13) β 7.67 (1H, bs), 7.60 (1H, d, J = 3Hz), 7.48 (1H, d, J = 8Hz), 7.42 (1H, dd, J = 8 & 3Hz), 7.29 (1H, dt, J = 8 & 3Hz), 7.21 (1H, d, J = 8Hz), 7.14 (2H, m), 6.99 (1H, bs), 6.76 (4H, m), 3.88 ( 1H, d, J = 10 Hz), 3.75 (1H, ddd, J = 6, 5 & 3Hz), 3.59 (2H, m), 3.53 (1H, dd, J = 1 & 3Hz), 3 · 22 (1H, t, J = 9Hz), 3.19 (1H, m), 2.96 (1H, m), 2.70 (1H, d, J = 16Hz), 1.42 (2H, m) , 1.26 (2H, m), 0.87 (3H, t, J = 7Hz). MS (DC1, NH3) m / e 563, 561 (M + H +). Analysis estimates C32H33C1N205 · 0.5 H20: C, 67 · 42; H, 6.01; N, 4.91. Found 値: C, 67.45; H, 5.82; N, 4.68. Example 427 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-4- (l, 3-bun and eruzaki-5_base) -2- (4-methoxyphenylcyclohexyl-N-butylamino) carbonyl) methyl) pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. iH NMR (300 MHz, CDC13) (geometric isomer) 0.88 (0.86) (t, 3H, J = 7Hz), 0.90-1.90 (film, 14H), 2.69 (2 · 80) (d, 1H, J = 12Hz), 2.9-3.8 (film, 10H), 3.78 (3.80) (s, 3H), 5.92 (s, 2H), 6.72 (d, 1H, J = 9Hz), 6.86 (m, 3H), 7.03 (d, 1H, J = 6Hz), 7.34 (m, 2 H). MS (DC1 / NH3) m / e 537 (M + H) +. Analysis estimates C31H40N2O6 · 1 H2O: C, 67 · 13; H, 7.63; N, 5.05. Found 値: C, 67.09; H, 7.34; N, 4.92. Duplicate example 428 trans'trans-4- (1,3-benzodiz-5-yl) -2- (4-ethylphenyl) · 1 (((N- (3- -467- 本Paper size applies to China National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 Α7 Β7 V. Description of the invention (46S) methylphenyl) -N-butylamine) Wei (A) Methyl) p-pyrrolidine-3-folic acid The procedure of Example 1 was used to prepare the title compound. iH NMR (300 MHz, CDC13) d 0 · 86 (t, 3H, J = 7Hz), 1.22 (t, 3H, J = 7Hz), 1.25 (m, 2H), 1.43 (m, 2H), 2.26 (s, 3H), 2.6 (q, 2H, J = 7Hz), 2.68 (d, 1H, J = 12H), 2.86 (t, 1H, J = 8Hz), 3.19 (q, 2H, J = 7Hz), 3.44 (dd, 1H, J = 3Hz, 10Hz), 3.59 (m, 3H), 3.94 (d, 1H, 9Hz), 5.92 (s, 2H), 6.75 (m, 3H), 6.86 (dd, 1H, J = 2Hz, 8Hz), 7.08 (m, 6H), 7.17 (t, 1H, J = 8Hz). MS (DC1 / NH3) m / e 543 (M + H) +. Analysis estimates C33H38N2O5 · 0.60 H20: C, 71.61; H, 7.14; N, 5.06. Found 値: C, 71.57; H, 6.80; N, 4.87. Example 429 trans, trans-4- (benzofuran-5-yl) · 2-Γ4-ethylphenyltolylbutylamino) carbonyl) methyl) pyrrolidine-3_carboxylic acid The title compound can be prepared. iH NMR (300 MHz, CDC13) d 0.90 (t, 3 °, J = 7Hz), 1.30 (t, 3 °, J = 7Hz), 1.31 (m, 2H), 1.43 (m, 2H), 2.27 (s , 3H), 2.73 (q, 2H, J = 7Hz), 3.15 (d, 2H, J = 17Hz), 3.61 (t, 2H, J = 8Hz), 3.82 (m, 2H), 4.00 (t, 1 H , 12Hz), 4.26 (m, 2H), 5.53 (br d, 1H), 6.54 (br s, 2H), 6.76 (d, 1H, J = 2Hz), 7.14 (m, 3H), 7.28 (s 1H), 7.40 (m, 3H), 7.48 (d, 1H, J = 8Hz), 7.63 (d, 1H, J = 2Hz), 7.73 (s, 1H). HRMS estimate C34H39N204 (M + H) +: 539.2910. Found 値: 539.2891. Example 430 trans, trans-benzodioxane-6-yl) -2- (4-ethylphenyl) _1_ (((N · (3 · methylphenylVN-butylamino) carbonyl) methyl Base) pyrrolidine-3-carboxylic acid-468 · This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) Order 581760 A7 B7 V. Description of the invention (466) The title compound was prepared using the procedure of Example 1. iH NMR (300 MHz, CDC13) d 0.87 (t, 3H, J = 7Hz), 1.22 (t, 3H, J = 7Hz), 1.24 (m, 2H) , 1.42 (m, 2H), 2.30 (s, 3H), 2.61 (q, 2H, J = 7Hz), 2.67 (d, 1H, J = 14Hz), 2.86 (t, 1H, J = 8Hz), 3.18 ( q, 2H, J = 7Hz), 3.41 (dd, 1H, J = 4, 10Hz), 3.59 (m, 3H), 3.93 (d, 1H, J = 10Hz), 4.25 (m, 4H), 6.74 (br s, 2H), 6.80 (d, 1H, J = 8Hz), 6.93 (dd, 1H, J = 2Hz, 8Hz), 6.99 (d, 1H, J = 2Hz), 7.07 (m, 5H), 7.17 (t , 1H, J = 8Hz). MS (DC1 / NH3) m / e 557 (M + H) +. Analyzed and estimated C34H4〇N205 · 0.40 H20: C, 72.42; H, 7.29; N, 4.97. Measured 値: C , 72.49; H, 7 ″ 6; N, 4.62. Example 43 1 Central Ministry of Economic Affairs Printed by the Consumer Cooperatives of the Bureau of Standards (please read the precautions on the back before filling out this page) trans, trans-2- (3-fluoro-4-methoxyphenyl) -4- (1,3-benzo Difluoren-5-yl) -1- [2- (N · propyl-N-2-catosulfonamido) ethyl 1 pyrrolidine-3-carboxylic acid. Using the procedure in Example 6, 6, the title compound may be Prepared and separated into a white solid. Mp 80-82 ° C. 4 NMR (CDC13, 300 MHz) d 0.69 (t, J = 7Hz, 3H), 1.37 (six peak, J = 7Hz, 2H), 2.09-2.17 (m, 1H), 2.24 (s, 3H), 2.53 (s, 6H), 2.54-2.64 (m, 1H), 2.73-2.86 (m, 2H), 3.02 (six peaks, J = 7Hz, 2H), 3.13 · 3 · 28 (m, 3H), 3.44-3.53 (m, 1H), 3.57 (d, J = 9Hz, 1H), 3.89 (s, 3H), 5.94 (s, 2H), 6.74 (d, J = 8Hz, 1H), 6.78 (dd, J = 2Hz, J = 8Hz, 1H), 6.85 (s, 2H), 6.92 (d, J = 8Hz, 1H), 9.94 (d, J = 2Hz, 1H), 7.06 (d, J = 8Hz, 1H), 7.13 (dd, J = 2Hz, J = 12Hz, 1H). MS (DCl / NH3) m / e 627 (M + H), -469-This paper size applies to China National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 5 2. Description of the invention (# 7) Example 432 trans, trans 2 · (4 · methoxybenzyl) -4_ (3,4_difluorophenyl) -1- 丨 (N-butyl-chlorophenyl) Amino) carbonylmethyl 1 pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. 4 NMR (300 MHz, CDC13) " · 86 (t, J = 7Hz, 3Η), 1.18-1.32 (m, 2Η), 1.35-1.48 (m, 2H), 2.64 (d, J = 13Hz, 1H) , 2.71 (t, J = 7Hz, 1H), 3.08-318 (m, 2H), 3.42-3.48 (m, 1H), 3.53-3.64 (m, 3H), 3.77 (s, 3H), 3.80 (d, J = 9Hz, 1H), 6.73-6.85 (m, 3H), 6.94 (s, 1H), 7.04 surface 7.40 (m, 7H). Example 433 Transpyrene, trans-2- (3-fluoro · 4-methoxyphenyl) -4- (1,3-benzobenzofluoren-5-yl ^ 1 f2-rN-propyl-N · ( 3-chloropropanesulfonyl) amino) ethyl) pyrrolidine-3-chinic acid The title compound was prepared using the procedure of Example 1. NMR (CD3OD, 300 MHz) β 0.80 (t, 3H, J = 7), 1.47 (bd, six peaks, 2H, J = 8), 2.15 (five peaks, 2H, J = 7), 2.32 (m, 1H), 2.7-3.2 (m, 9H), 3.46 (dd5 1H, J = 4, 10), 3.57 (m, 1H), 3.64 (t, 2H, J = 6), 3.67 ( d, 1H, J = 9), 3.86 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1H, J = 8), 6.84 (dd, ih, J = 2, 8), 6.96 (d , LH, J = 2), 7.06 (t, 1H, J = 9), 7.18 (m, 2H). MS (DCl / NH3) m / e 585 (M + H; 35C1) +; 587 (M + H; 37C1) +. Analysis estimates C27H34N207C1FS: C, 55 · 43; H, 5.86; N, 4.79. Found 値: C, 55 · 65; 65, 5.81; Ν, 4.70 0 Example 434 trans, trans-2- (3-fluoro-4-methoxyphenyl) -4 · (1,3-benzobis Isobutyl-N- (3-chloropropanesulfonyl) amino) ethyl) pyrrolidine-3 ^ acid-470- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm 1 ~ (Please read the notes on the back before filling this page) ^ 1 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 _________B7 V. Description of the invention (468) The title compound can be prepared by using the procedures of Example 6 6. ijj NMR ( CD3〇d 300 MHz) d 0.79 (d, 3H, J = 7), 0.84 (d, 3H, J = 7), 1.68 (Seven Fronts, 1H, J = 7), 2.18 (Five Peaks, 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), 7.13 (t, 1H, J = 9), 7.27 (m, 2H). MS (DCl / NH3) m / e 599 (M + H) +. Analyzed and estimated C28H36N2 07ClFS · 0.3 TFA: C, 54 · 24; H, 5.78; N, 4.42. Found 値: C, 54 · 19; H , 5.71; N, 4.01. Example 435 trans'trans-2 -Propoxymethyl-4- (i, 3-benzodi $ -5_yldibutylaminecarbonylmethyl) ρ-bilodine-3.acid The title compound was prepared using the procedure of Example 1. ijj NMR ( CDC1% 300 MHz) d 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), 3.45-3.55 (m, 3H), 3.69 (dd, J = 10.2, 4.5Hz, 1H), 3.80-4.20 (m, 4H), 5.93 (s, 2H) , 6.73 (d, J = 7.8 Hz, 1H), 6.84 (dd, J = 8 · 2 Hz, 1.7 Hz, 1H), 6.93 (d, J = 1.7 Hz, 1H). MS (DCl / NH3) m / e 477 (M + H) +. Analysis estimates c26H40N2O6 · 0.5 TFA: C, 60 · 77; H, 7.65; N, 5.25. Found 値: c, 60.73; H, 7.74; N, 5.22. Example 436 trans'trans-2 · (3-fluoro-4 · formamidinephenyl) _4_ (1,3-benzodi-5-yl) -1-yl-N- (4 · methylbutane Alkylsulfonyl) amino) ethyl] pyrrolidine_3_carboxylic acid Using the procedures in Example 6 6 to prepare the title compound and isolate it into white ___________- 471 ~ _ This paper applies Chinese National Standard (CNS) Α4 Specifications (210 X297 male thin) " (Please read the precautions on the back before filling this page) Order 581760 A7 B7 V. Description of the invention (you 9) Solid. m.p. 65_67 ° C. 4 NMR (CDC13, 300MHz) d 0.82 (t, J = 7Hz, 3H), 0.88 (d, J = 5Hz, 6H), 1.46 (six peak, J = 7Hz, 2H), 1.56_1_64 (m, 3H) , 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 = 3Hz, J = 9Hz, 1H), 3.52_3.58 (, 1H), 3.65 (d, J = 12Hz, 1H), 3.87 (s, 3H), 5.95 (s, 2H), 6.73 (d, J = 8Hz, 1H ), 6.82 (dd, J = 2Hz, J = 8Hz, 1H), 6.92 (t, J = 8Hz, 1H), 6.97 (d, J = 2Hz, 1H), 7.10 (d, J = 9Hz, 1Hz), 7.16 (dd, J = 2Hz, J = 12Hz, 1H). MS (DC1 / NH3) m / e 579 (M + H) +. Example 437 trans, trans-2- (4-methoxy · 3-fluorobenzylmethoxy-1,3-benzodi-4--5-yl) · 1 · 丨 2- (N_propyl · Ν- (n-pentanylpyridinyl) amino) ethylpyrrolidine-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) Example 6 6 This procedure produces the title compound. in NMR (300 MHz, CDC13) d 0.81 (t, J = 7Hz, 3H), 0.90 (t, J = 9Hz, 3H), 1.25-1.35 (m, 4H), 1.44 (six peak, J = 7Hz, 2H ), 1.67-1.78 (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 (dd , J = 3Hz, 9Hz, 1H), 3.47-3.56 (m, 1H), 3.65 (d, J = 9Hz, 1H), 3.88 (s, 3H), 3.94 (s, 3H), 5.95 (s, 2H) , 6.55 (s, 1H), 6.65 (s, 1H), 6.92 (t, J = 7H, 1H), 7.11 (d, J = 9Hz, 1H), 7.17 (d, J = 12Hz, 1H) 0 Example 438 Trans, trans_2- (3-fluoro_4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) -1- "2_ (N-propyl_N_ ( 2,2,3,3,3-Pentafluoropropoxy ethyl sulfonyl) amine group) B-472- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 581760 A7 B7 —One 111. Description of the invention (470) yl] pyrrolidine-3-miaoyu Using the procedures in Example 66, the title compound can be prepared and isolated as a white solid. m.p. 63-64. 4 NMR (CDC13, 300MHz) Θ 0.82 G, J = 7Hz, 3H), 1.45 (A ^, J = 7Hz, 2H), 2.24-2.33 (m, 1H), 2.70 · 2.82 (m, 1H), 2.85-3.09 (m, 5H), 3.14-3.28 (m, 4H), 3.43 (dd, J = 3Hz, J = 9Hz, 1H), 3.52-3.58 (m, 1H), 3.65 (d, J = 9Hz, 1H), 3.87 (s, 3H), 3.92-3.98 (m, 3H), 5.94 (s, 2H), 6.74 (d, J = 8Hz, 1H), 6.82 (dd, J = 2Hz, J = 8Hz, 1H ), 6.92 (t, J = 8Hz, 1H), 6.97 (d, J = 2Hz, 1H), 7.10 (d, J = 9Hz, 1H), 7.17 (dd, J = 2Hz, J = 12Hz, 1H). MS (DC1 / NH3) m / e 685 (M + H) + 〇 Example 439 trans, trans_2 · (1,4 yin and yin-6-based) surface 4_ (7_methoxy- 1,3 -benzyl-1-yl-5-yl VI- 丨 2_ (N · propyl-N- (n-pentanesulfonyl) amino) ethyl 1pyrrole-3Jun acid employee of Central Standards Bureau of Ministry of Economic Affairs Printed by a consumer cooperative (please read the notes on the back before filling this page) The title compound can be prepared using the procedures of Example 6 6. iH NMR (CDC13) d 0.81 (t, J = 7Hz, 3H), 0.90 (t, J = 7Hz, 3H), 1.23-1.36 (m, 4H), 1.45 (six peaks, J = 7Hz, 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 = 3Hz, 9Hz, 1H), 3.46-3.56 (m, 1H), 3.59 (d, J = 9Hz, 1H), 3.91 (s, 3H), 4.24 (s, 4H), 5.95 (s, 2H), 6.57 (s, 1H), 6.68 (s, 1H), 6.82 (d, J = 8Hz, 1H), 6.88 (dd, J = 2Hz, 8Hz, 1H), 6.95 (d, J = 2Hz, 1H). Example 440 trans, trans-4- (1,3-benzodiazine-5-yl ) -2- (4-methoxyphenyl) -1 · (((N- -473- This paper size applies Chinese National Standard (CNS) A4 specification (2 丨 〇 > < 297) (%) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 ________ B7 V. Description of the invention (471) T-N- (4-Jamino) carbonyl) methyl) pyrrolidine_3_carboxylic acid use example 1 The title compound can be prepared by the following steps: iH nmr (300 mHz, CDC13) d (geometric isomer) 7 32 (m, d, J = 10), 7.22 (1H, m), 7.10 (1H, d, J = 9), 7.03 (6%) (m, d, J = 3), 690 (6.8) (4H, m), 6.79 (2H, d, J = 9), 6 77 (m, t, J = 8), 5 85 (2H, s), 4 92 (4 1〇) (1H, d, J = 15), 4.42 (4.22) (1H, d, J = 15), 3_81 (1H, m), 3.79 (3.78) (3H, s), 3.76 (3H, s), 3.62 (lH, m), 3.43 (2H, m), 3.30-2.70 (5H, m), 1.42 (1H , M), 1.23 (2H, m), 1.01 (1H, m), 0.83 (0,75) (3H, t, J = 8). MS (DC1 / NH3) m / e 575 (M + H +). Analysis estimates C33H38N207 · 0.5 H20: C, 07.91; H, 0.73; N, 4.80. Found 値: C, 67.78; H, 6.44; N, 4.55. Example 441 trans, trans ^ 1- (3-difluoro_4-methoxyphenyl) -4- (1,3-benzodifluorene ·

(2_ (N-Iso: 1-iso (pentanesulfonylamino) ethyl) pyrrolidine · 3-carboxylic acid The procedure of Example 66 was used to prepare the title compound. IH NMR (CD3OD, 300 MHz) d 0.76 (d, 3Η, J = 7), 0.84 (d, 3Η, 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 = 8), 6.88 (dd, 1H, J = 2.8), 7.00 (d, 1H, J = 2), 7.19 (t, 1H, J = 9), 7.35 (m, 2H) .MS (DC1 / NH3) m / e 593 (M + H) +. Analyzed and estimated C30H41N2O7F · 0.5 TFA: C, 57.31; H, 6.44; N, 4.31. Found 値: C, 57.08; H, 6.15; N, 3.95. Example 442 trans form, trans form · 4_α, 3 · modiofluorene · 5_yl) -2- (4-methoxyphenyl V1- (N-butyl-474-) This paper applies Chinese national standard ( CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling out this page) Order 581760 A7 B7 V. Description of the invention (472) -N- (3-fluoroaniline) carbonylmethyl) pyrrolidine 3-carboxylic acid The title compound was prepared using the procedure of Example 1. iH NMR (300 MHz, CD3OD) d 0.87 (t, J = 7 Hz, 3H), 1.10-1.30 (m, 4H), 2.70 · 2 · 90 (m, 2H), 3.13 (t, J = 8 Hz, 1H) , 3.40-3.90 (m, 6H), 3.79 (s, 3H), 5.93 (s, 2H), 6.75 (d, J = 8 Hz, 1H), 6.80-7.20 (m, 9H), 7.40 (m , 1H). MS (DC1) m / e 549 (M + H) +. Analyzed and estimated c3lH33N20F · 0.8 H20: C, 66.13; H, 6.19; N, 4.98. Found 値: C, 66.21; H, 5.83 N, 4.84. Example 443 trans, trans-4- (l, 3_benzyl-2-yin-5 · ylfluorophenylbutyl • N- (3-chloroaniline) carboxymethyl) Ethan _3_ The title compound can be prepared using the procedure of Example 1. iHNMR (300 MHz, CD3OD) d 0.87 (t, J = 7 Hz, 3H), 1.20-1.50 (m, 4H), 2.65 · 2 · 85 (m, 2H), 3.05-3.85 (m, 7H), 5.93 (s, 2H), 6.75 (d, J = 8Hz, 1H), 6.85 (dd, J = 8 Hz, 1H), 6.90-7.10 ( m, 4H), 7.10-7.25 (m, 3H), 7.33-7.45 (m, 2H). MS (DC1) m / e 553 (M + H) +. Analysis estimates C30H30N2O5FCl: C, 65.16; H, 5.47; N, 5.07. Found 値: C, 65 · 37; H, 5.41; N, 4.98. 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) Example 444 trans, trans-4- (1,3 ″ benzodioxin_5-based) _2- ( 4_methyl molybdenyl) _1 _ (((^ · butyl-N- (3,4-dimethyl & nonyl) amino) carbonyl) methyl) pyrrolidine The title compound can be prepared. ijj NMR (300 MHz, CDCI3) β (geometric isomer) 7.33 (1H, 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), -475 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) " Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs System 581760 A7 B7 V. Description of the invention (473) 5.93 (2H, m), 4.83 (4 · 09) (1H, d, J = 15), 4.45 (4.22) (1H, d, J = 15) ), 3.83 (3.86) (3H, s), 3.79 (1H, m), 3.77 (3.76) (3H, s), 3.75 (3.65) (3H, s), 3.60 (1H, m), 3.43 (2H, m), 3.28 (1H, 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 = 8). MS (DC1 / NH3) m / e 605 (M + H +). Analysis estimates C34H40N2O8 · · C, 67.53; H, 6.67; N, 4.63. Measured 値 ·· C, 67 · 28; H, 6.63; N, 4.38. Example 445 Gen formula, trans-4 · (1,3 · benzodifluorene, -5-yl) -2- (4-methoxyphenylyl-N- (2-methoxybenzyl) amine ) Carbonyl) methyl) pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. NMR (300 MHz, CDC13) d (geometric isomer) 7.33 (1H, d, J = 10), 7 u (2H, m), 7.03 (1H, dd J = 8, 3), 6.90-6.60 (7H, m), 5.93 (2H, m), 4.83 (4.15) (1H, d, J = 15), 4.47 (4.30) (1H, d, J = 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 (DC1 / NH3) m / e 575 (M + H +). Analysis estimates c33H38N207: C, 68.97; H, 6.66; N, 4.87. Found 値: C, 68 7〇; H, 6 56; N, 4 61. Example 446 trans'trans-di-K13-benzodiazine-5-ylmethoxyphenyl) peroxybenzyl) amino) carbonyl) methyl) pyrrolidine-3-carboxylic acid can be prepared using the procedure of Example 1 Title compound. iH Nmr (300 MHz, CDCl3) d (geometric isomers) 7.31 (1H, d, J = 10), 7.13 (1H, d, __-476-This paper is applicable to Chinese countries _ ^ 7 ^ §) A4 specification (210x297 mm) (Please read the notes on the back before filling this page) Order -f 581760 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7__ V. Description of the invention (474) J = 9), 7.16 ( 1H, dt, J = 8, 3), 7.03 (1H, dd, J = 10, 2), 6.90-6.60 (6H, m), 6.50 (1H, 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 (1H, m ), 3.75 (3.67) (3H, s), 3.59 (1H, m), 3.57-3.35 (2H, m), 3.25 (1H, 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 = 8 ”MS (DC1 / NH3) m / e 575 (M + H +) 〇 C33H38N207: C, 68.97; H, 6.66; N, 4.87. Found 値: C, 68.72; H, 6.55; N, 4.60. Example 447 trans'trans_2- (3-Ga-4-methoxyphenyl)- 4_ (l, 3-benzobenzo-5-yl) -1 _ (2- (N- (2-methoxyethyl-N- (3-fluoropropanesulfonyl) amino)) Ethyl) pyrrolidine-3-carboxylic acid The title compound was prepared using the procedure of Example 66. iH NMR (CD3OD, 300 MHz) d 2.15 (pentapeak, 2H, J = 7), 2.33 (m, 1Η), 2.81 ( m, 2H); 2.93 (t, 1H, J = 9); 3.1-3.6 (m, 10H), 3.24 (s, 3H); 3.65 (t, 2H, J = 6), 3.70 (d, 1H, J = 9), 3.87 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1H, J = 8), 6.84 (dd, 1H, J = 2, 8), 6.97 (d, 1H, J = 2), 7.07 (t, 1H, J = 9), 7.17 (m, 2H). MS (DC1 / NH3) m / e 601 (M + H) +. Analyzed and estimated C27H34N208C1FS: c, 53.95; H, 5.70; N, 4.66. Measured fluorene: c, 53 · 65; H, 5.49; N, 4.26 〇 Example 448 trans, trans-2- (3- ^ 4-methylamoyl) · 4_ (1,3_benzodifluorene- Hongji)-] · Methoxyethyl-Etosanylsulfonyl) amino) ethyl) pyrrolidine-3-carboxylic acid The title compound can be prepared by following the procedures of Example 66. ijj nmR (CD3〇D, -477-This paper size applies to Chinese national standards (21〇χ297) (please read the notes on the back before filling out this page) Order printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperative 581760 A7 B7 V. Description of the invention (475) 300 MHz) A 0.93 (m, 3H), 1.34 (m, 4H), 1.69 (m, 2H), 2.33 (m, 1H), 2.75-3.1 (m, 7H), 3.23 ( s, 3H), 3.3-3.6 (m, 6H), 3.70 (d, 1H, J = 9), 3.86 (s, 3H), 5_92 (s, 2H), 6.74 (d, 1H, J = 8), 6.84 (dd, 1H, J = 2, 8), 6.97 (d, 1H, J = 2), 7.07 (t, 1H, J = 9), 7.18 (m, 2H). MS (DC1 / NH3) m / e 595 (M + H) +. Analyzed and estimated C29H39N2O8FS: C, 58.57; H, 6.61; N, 4.71. Found 値: c 58.21; H, 6.29; N, 4.29. Example 449 trans form, Trans-4- (1,3-benzobisfluoren-5-yl) -2- (4-methylazine) _1 彳 ((^ _ 4-heptyl) -N- (4-fluoro-3 -Tolyl) carboxy) methyl)? Biloxidine_3_Lean acid The procedure of Example 1 was used to prepare the title compound. NMR (: 300 MZ, CD3OD) d 0.89 (m, 6Η), 1.18-1.36 (m, 8Η), 2.15 (bs, 1.5 (CH3 geometric isomer)), 2.28 (bs, I · 5 (CH3 Geometric isomers)), 2.64 (t, J = 14.9 Hz, 1H), 2.82 (m, 1H), 3.07-3.29 (m, 2H), 3.32_3 · 41 (m, 1H), 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 (m5 6H), 6.93-7.07 (m , 4H). MS (DC1 / NH3) m / e 605 (M + H.). Analysis estimates c35H41FN206: C, 69.52; H, 6.83; N, 4.63. Measured fluorene: C, 69.31; H, 6.78; N, 4.35. Example 450 trans, trans_4- (1,3-benzobenzofluoren-5-yl) -2 · (4.methylphenyl ( 5-Difyl) -N- (4-fluoro-3-methylphenyl) amino) carbonyl 1methyl) pyrrolidine-3_carboxylic acid The procedure of Example 1 was used to prepare the title compound. iH NMR (300 MHz, _ _ 478-^ Paper size applies Chinese National Standard (CNS) A4 specification (21〇X; 297 mm) " (Please read the notes on the back before filling this page)) Order _ 581760 A7 B7 V. Description of the invention (476) CD3OD) d 0.81-0.90 (m, 6H), 1.30 (m, 12H) 2 14 (s, i 5 (CH3 geometric isomer)), 2.30 (s, 1.5 (CH3 Geometric isomers)), 2 60 (t, J = 14.8 Hz, 1H), 2.80 (m, 1H), 3.09_3 · 24 (m, 2H), 3.33 · 3 · 42 (m, 1H ), 3.50-3.55 (m, 1H), 3.65-3.77 (m, ijj), 3 79 (s, 3H), 4.64 (m, 1H), 5.93 (m, 2H), 6.70-6.84 (m, 5H) , 6.91-7.13 (m, 5H). MS (DC1) m / e 633 (M + H +). Analysis estimates c37H45FN206: c 70.23; H, 7.17; N, 4.43. Measured fluorene: c, 7104. h, 7.13; N, 4.19 0 Example 451 trans, trans_4- (l, 3-benzodiazine_5.yl) -2- (4-methyl blue. Phenyl) -l-((N_ (5_nonamino) peptyl) methylpyridine_3_miao acid The title compound can be prepared using the procedure of Example 1. NMR (300 MHz, employee of the Central Standards Bureau of the Ministry of Economic Affairs Printed by a consumer cooperative (please read the precautions on the back before filling this page) CD3OD) d 0 · 80 (t, J = 7.0 Hz, 3H), 0.84 (t, J = 7.1 Hz, 3H), 1.15-1.55 ( m, 12H), 2.88 (d, J = 15.9 Hz, 1H), 3.07 (m, 2H), 3.26 (d, J = 16.3 Hz, 1H), 3.36 (dd, J = 4.4, 9.8 Hz, 1H), 3.64 (m, 1H), 3.76 (m, 1H), 3.79 (s, 3H), 3.98 (d, J = 9.5 Hz, 1H), 5.93 (m, 2H), 6.77 (d, J = 7.8 Hz, 1H ), 6.85 (dd, J = 1.7, 8.1 Hz, 1H), 6.93 (m, 2H), 6.99 (d, J = 1.7 Hz, 1H), 7.39 (m, 2H). MS (DC1) m / e 525 (M + H +). Analytical estimates of C3OH46N2O6 · 0.35 H20: C, 67.86; H, 7.73; N, 5.28. Found 値: C, 67.87; H, 7.63; N, 5.11. Example 452 Trans form , Trans-4- (1,3-benzobisfluoren-5-yl) -2- (4-methoxyphenyl) -1- (〇 ^ -butyl-N- (2-fluoro Phenyl) amino) carbonylmethyl) pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. iH NMR (300 MHz, -479-this paper is again applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) 581760 A7 B7 V. Description of the invention (477) CD3〇D) d 0.87 (dt, J = 7 Hz, 3H), 1.15-1.32 (m, 4H), 3.77 (d, J = 2Hz, 3H), 2.65-5.92 (m, 9H), 5.93 (d, J = 4Hz, 2H), 6.70-6.90 (m , 4H), 7.00 · 7 · 45 (m, 7H). MS (DC1) m / e 549 (M + H) +. Analytical estimates of C31H33N2 0 6 · 0 4 h2 0: c 66 99; H, 6 13; N, 5 04. Found 値: C, 67 · 01; H, 6.23; N, 4.68. Example 453 Well-formed 'transoxyphenyl) -4- (1,3-benzodiazine_5 · yl) _142-propyl-N_ (2- ^ thiazolyl) amino) ethyl 1 pyrrolidine The 3-carboxylic acid was prepared by the method of Example 418, but 2-bromopyrimidine was replaced with 2-chlorobenzopyridine. iH nmR (300 MHz, CDC1J β 0.88 (t, J = 7Hz, 3H), 1.59 (^ 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-9Hz? 1H)? 3.71 (s? 3H)? 5.87 (d, J = 2Hz? 1H), 5.91 (d, J = 2 Hz, m) , 6.57 (d, J = 8Hz, 1H), 6.73 (dd, J = 2Hz, 9Hz, 1H), 6.76 (d, J = 8Hz, 2H), 6.91 (d, J = 2Hz, 1H), 7.01 (t , J = 8Hz, 1H), 7.22 (t, J = 8Hz, 1H), 7.29 (d, J = 8Hz, 2H), 7.40 (d, J = 7Hz, 1H), 7.55 (d, J = 7Hz, 1H ) Example 454 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) _trans_trans-base) _4_α, 3_benzodipyrene_5base-XA Dimethyl a) pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. ijj nmR (CDC13, 300 MHz) ί 0.91 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 1.19 (t, J = 7.0 Hz, 3H), 1.24-1.38 (m, 5H), 1.46-1.60 (m, 4H), 2.03-2.12 (m, 2H), 3.07 (t, J = 8.0 Hz, 1H), 3.07-3.34 (m, 6H), -480- This paper The scale is applicable to China National Standards (CNS) A4 specification (21〇X a? Mm) 581760 A7 _____ B7 V. Description of the invention (478) 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 = 8.1 Hz, 1H), 6.79 (dd, J = 8.2 Hz, 1.7 Hz, 1H), 6.87 (d, J = 1.7 Hz, 1H). MS (DC1 / NH3) m / e 477 (M + H) +. Analysis estimates C26H40N2O6 · 0.4 TFA: C, 61.64; H, 7.80; N, 5.36. Found 値: C, 61.63; H, 7.84; N, 5.29. Example 455 trans, trans · 2 · (4 · methoxy · 3 · fluorophenyl) _4-Π, 3-benzodifluorene-5-cerium 1 · "2- (Ν-propyl_Ν · (2- (morpholin_4_ylethyl) continuous amine) ethyl ~ | p

Example 125 2- (4-methoxy-3-fluorophenyl) -4 · (1,3-benzobisfluoren_5_yl) -1_ [2 · (Ν · propyl-Ν_ [ 2-Vinylsulfonyl] amino) ethyl] pyrrolidin-3-ethyl benzate was reacted with an excess of morpholin for 4 hours at room temperature. Chromatography on silica gel and dissociation with EtOAc yielded the intermediate ethyl ester in 65% yield, which was then hydrolyzed with NaOH ethanol / water to the title compound. Printed by iji NMR, Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (please read the notes on the back before filling this page) (300 MHz, CDC13) d 0.81 (t, J = 7Hz, 3H), 1.46 (Six peaks, J = 7Hz, 2H), 2.43-2.52 (m, 4H), 2.70-2.92 (m, 5H), 2.97-3.33 (m, 6H), 3.60 (dd, J = 3Hz, 9Hz, 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 = 8Hz, 1H), 6.70 (dd, J = 2Hz, 8Hz, 1H) , 6.90 (t, J = 9Hz, 1H), 6.96 (d, J = 2Hz, 1H), 7.10 (d, J = 8Hz, 1H), 7.18 (dd, J = 2Hz, 12Hz, 1H). Example 456 Formula, trans-2- (3 • fluoro-4-methoxyphenyl) _4- (1,3_benzobiazine_5_yl) _Ί _ f2- (N-propyl_N _ ((W2 · Trifluoro ^ oxyethane) Sulfonyl) Amine) Ethyl sulfonate K-3-carboxylic acid-481-This paper size is applicable to China National Standard (CNS) A4 specifications (^^ Y97 public envy) ~ one- 581760 Α7 Β7 V. Description of the invention (479) Using the procedures of Example 6 6 to prepare the title compound and isolate it as a white solid. Mp 95-96X: .4 NMR (CD3OD, 300 ΜΗζ) β 0.80 (t, J = 7Hz, 3H), 1.35-1.48 (m, 2H), 3 · 07 (six peaks, = 7112,211), 3.23 · 3.55 (m, 8H), 3.80-3.87 (m, 2H), 3.93 (s, 3H), 3.94-4.02 (m, 4H), 4.66 (d, J = 12Hz, 1H), 5.96 (s, 2H), 6.83 (d, J = 8Hz, 1H), 6.94 (d, J = 8Hz, 1H), 7.06 (d, J = 2Hz, 1H), 7.23 (t , J = 9Hz, 1H), 7.43 (d, J = 9Hz, 1H), 7.49 (dd, J = 2Hz, J = 12Hz, 1H). MS (DC1 / NH3) m / e 63 5 (M + H) +. Example 457 trans, trans-4- (1,3-benzodifluoren-5-yl) -2_ (4-fluorophenyl) -1-〇 ^ -butyl 1 -N- (3-methyl Phenyl) aminocarbonylmethyl) pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. iH NMR (300 MHz, CD3OD) β 0.87 (t, J = 7Hz, 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 = 10Hz, 1H), 3.35-3.65 (m, 4H), 3.79 (d, J = 10 Hz, 1H), 5.93 (s, 2H), 6.74 (d, J = 7 Hz, 1H), 6.80-6.90 (m, 3H), 6.91-7.09 (m, 3H), 7.10-7.35 (m, 4H). MS (DCl) m / e 533 (M + H) +. Analysis estimates C31H33N205F: C, 69.91; H, 6.25; N, 5.26. Measured 値: C, 69 · 56; H, 6.26; N, 5.23 〇 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) Example 458 trans, trans- 2- (3-fluoro · 4-methylhydrophenyl) -4- (1,3-benzodifluoren-5-yl (2- (N- (2 · methoxy-4-yl (butanesulfonamido) ) Ethyl) pyrrolidine · 3- # 醢 The title compound was prepared using the procedure in Example 66. iH NMR (CD30D, 300 MHz) d0.94 (m, 3H), 1.23 (Six peaks, H , J = 8), 1.69 〇, 2H), _-482-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 public envy) 581760 A7 B7 V. Description of the invention (48〇) 3.08 (m, 2H), 3.20 (s, 3H), 3.3_3 · 5 (m, 10H), 3.77 (m, 2H), 3.92 (s, 3H), 4.60 (m, 1H), 5.96 (s, 2H ), 6.81 (d, 1H, J = 8), 6.88 (dd, 1H, J = 2, 8), 6.99 (d, 1H, J = 2), 7.22 (t, 1H, J = 9), 7.3 8 (m, 2H). MS (APC1) m / e 581 (M + H) +. Analyzed and estimated C28H37N208FS · 1.1 TFA: c, 51.37; H, 5.44; N, 3.97. Found 値: C, 51.27 H, 5.35; N, 4.11. Example 459 trans, trans-2- (3 · fluoro-4-methoxybenzene ) -4 · (ι, 3 · benzodifluoren-5-yl f2- (N-propyl-N- (2-methylpropane difluorenyl) amino) ethyl 1 pyrrolidine-3-carboxylic acid The title compound was prepared by the method of Example 66 and separated into a white solid. Mp 77-78 ° C. 4 NMR (CDC13, 300MHz) d 083 (t, J = 7Hz, 3H), 1.06 (d, J = 6Hz, 6H), 1.45 (q, J = 7Hz, 2H), 2.20 (seven peaks, J = 6Hz, 1H), 2.26-2.36 (m, 1H), 2.62-2.78 (m, 3H), 2.85-2.95 (m, 2H), 2.97_3 · 10 (m, 2H), 3.15-3.35 (m, 2H), 3.43 (dd, J = 3Hz, J = 9Hz, 1H), 3.53-3.62 (m, 1H), 3.66 (d , J = 9Hz, 1H), 3.88 (s, 3H), 5.95 (s, 2H), 6.74 (d, J = 8Hz, 1H), 6.82 (dd, J = 2Hz, J = 8Hz, 1H), 6.92 ( t, J = 8Hz, 1H), 6.97 (d, J = 2Hz, 1H), 7.12 (d, J = 9Hz, 1H), 7.18 (dd, J = 2Hz, J = 12Hz, 1H). MS (DC1 / NH3) m / e 565 (M + H) +. 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) Example 460 trans, trans-4- (1,3_benzodifluoren-5-ylmethoxyphenyl ) Butyl-N- (4-methylidene) amino) yl) methyl) p ratio ρgyodo-3-acid acid The title compound was prepared using the procedure of Example 1. 1H NMR (300 ΜΗζ, CDC13) d (geometric isomers) 8.11 (2Η, m), 7.32 (3Η, dd, J = 9, 2), -483- This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) 581760 A7 B7 V. Description of the invention (481) 7 · 16 (7 · 07) (1H, bd, J = 10), 6.98 (6 · 94) (1H, d, J = 2), 6.85 (2H, d, J = 9), 6.83-6.70 (2H, m), 5.99 (5 · 97) (2H, d, J = 2), 5.02 (4.18) (1H, d, J = 15), 4.63 (4.38) (1H, d, J = 15), 3.79 (3.77) (3H, s), 3.72 (1H, d, J = 10), 3.61 (1H, m), 3.48 (1H, bd, J = 15), 3.43-3.20 (2H, m), 3.06 (2H, m), 2.90 (1H, m), 3.79 (1H, bd, J = 14 ), 1.43 (1H, m), 1.23 (2H, m), 1.02 (1H, m), 0.84 (0.78) (3H, t, J = 8). MS (DCl / NH3) m / e 590 (M + H +). Analysis estimates C32H35N308: C, 65.18; H, 5.98; N, 7.13. Found 値: c, 65.89; H, 5.85; N, 6.85. Example 461 trans, trans-2_ (4-ethylphenyl) -4- (3,4-difluorophenyl) -1- (Team: ^-dibutylaminecarbonylmethyl) pyrrolidine-3- Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Carboxylic Acid Economy (please read the precautions on the back before filling this page). The title compound can be prepared by using the procedure of Example 1. iH NMR (CD3OD, 300 MHz) 0.78 (t, 3H, J = 7), 0.87 (t, 3H, J = 7), 1.02 (six peak, 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 (m, 3H), 3.44 (d, 1H, J = 14), 3.66 (m, 1H), 3.75 (d, 1H, 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 (DC1 / NH3) m / e 501 (M + H) +. Analysis estimates C29H38N203F2 · 0.6 H20: C, 68.11; H, 7.73; N, 5.48. Measured fluorene: C, 68.03; H, 7.53; N, 5.37 0 Example 462 each, trans-4_ (1,3-benzodihum-5-yl) -2- (4 • methylbenzyl Ding-484- This paper size is applicable _ National Standard of China (CNS) A4 (210 x 297 mm) '581760 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 ______B7 V. Description of Invention (482)-棊- N- (4-Gas_3-methylphenyl) aminomethylmethyl) was used to prepare the title compound using the procedure of Example 1. ijj NMR (300 MHz, CD3OD) d 0.87 (t, J = 7 Hz, 3H), 1.20-1.50 (m, 4H), 2.21 (d, J = 2 Hz, 3H), 2.64 (d, J = 14 Hz , 1H), 2.75 (dd, J = 10 Hz, 1H), 3.05 (t, J = 7 Hz, 1H), 3.25 (d, J = 15 Hz, 1H), 3.35-3.70 (m, 5H), 3.77 (s, 3H), 5.92 (s, 2H), 6.70-6.92 (m, 6H), 6.96-710 (m, 4H). MS (DC1) m / e 563 (M + H) +. Analytical estimates (: 32113 Office 06? · 0.5 HOAc: C, 67 · 24; H, 6.35; N, 4.90. Measured 値: C, 67.16; H, 6.06; N, 4.81 ° Example 463 Inverse Formula, trans form: _4_ (1,3_benzobisfluorene-5 · yl) -2- (4-methylphenyl) _1- (N-butyl-N-((3-isopropyl) benzene (Amino) amino) carbonylmethyl) pyrrolidine-3 -acid acid The procedure of Example 1 was used to prepare the title compound. ijj NMR (300 MΗζ, CD3OD) β0 · 87 (t, 3Η), 1.17 (d, J = 7 Ηζ, 6Η), 1.20-1.50 (m, 4H), 2.63 (d, J = 15 Hz, 1H), 2.75 (t, J = 7 Hz, 1H), 2.85 (m, 1H), 300 (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 = 7Hz, 3H), 7.07 (m, 3H), 7.20-7.35 (m, 2H). MS (DC1) m / e 573 (M + H) +. Analysis estimates C34H40N2O6 · 0.15 H3P04: C, 69.52; H, 6.94; N, 4.77. Found 値: C, 63 · 31; H, 6.72; N, 4.43. Example 464 trans, trans_4_ (1,3_benzobisfluoren_5_yl) -2- (4-methoxyphenylbutyl-N_ (3-ethylphenyl) aminocarbonylmethyl ) Pyrrolidine_3_carboxylic acid The procedure of Example 1 was used to prepare the title compound. iH NMR (300 MHz, -485- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling out this page). Order 581760 A7 B7 V. Description of the invention (483) CD3OD) d0.87 (m, J = 7Hz, 3H), 1.16 (t, J = 7Hz, 3H), 1.20-1.47 (m, 4H), 2.50 (q, J = 7 Hz, 2H), 2 · 70 · 2.85 (m, 2H), 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, 1H), 6.80-6.90 (m, 5H), 7.02-7.13 (m, 3H), 7.15-7.25 (m, 2H) 〇MS (DCl) m / e 559 (M + H) +. Analytical estimates: C33H38N2 06 · 0.3 · H20: C, 70.27; H, 6.90; N, 4.97. Found 値: C, 70.31; H, 6.63; N, 4.60. Example 465 trans, trans · 4- (1,3_benzodi-p-5-5-yl) -2- (4-ethylphenyl) (3-aminophenyl VN-butylamino) carbonyl) methyl Group) pyrrolidine-3.carboxylic acid The procedure of Example 1 was used to prepare the title compound. NMR (300 MHz, CDC13) Θ 0.87 (t, 3H, J = 7Hz), 1.23 (t, 3H, J = 7Hz), 1.28 (m, 2H), 1.41 (m, 2H), 2.63 (q, 2H , J = 7Hz), 2.67 (m, 1H), 2.92 (m, 1H), 3.20 (m, 2H), 3.42 (m, 1 H), 3.60 (q, 2H, J = 7Hz), 3.93 (m, 1H), 5.92 (s, 2H), 6.75 (d, 1H, J = 8Hz), 6.84 (m, 3H), 6.95 (br s, 1H), 7.02 (s, 1H), 7.10 (br s, 3H) , 7.25 (m, 2H). MS (APC1) m / e 563 (M + H) +. Analysis estimates C32H35N205a. 0.80 H3P04: C, 59.92; H, 5.88; N, 4,37. Found 値: C, 59.90; H, 5.83; N, 4.07. 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) Example 466 (4-Ethylphenylocta-1- (fluorene (N · (3-chlorophenyl) -N-butylamino) carbonyl) methyl) pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. NMR (300 ΜΗζ, CDC13) (J0.86 (t, 3Η, J = 7Hz), 1.23 (t, 3Η, J = 7Hz), 1.25 (m, 486-this paper size applies to Chinese National Standard (CNS) A4 specifications (210X 297mm) '581760 A7 B7 _ ^ ___ V. Description of the invention (484) 2H), 1.40 (m, 2H), 2.64 (q, 2H, J = 7Hz), 2.70 (m, 1H), 2.95 (m, 1H), 3.20 (m, 2H), 3.40 (m, 1 H), 3.57 (m, 3H), 3.90 (m, 1H), 4.25 (s, 4H), 6.80 (d, 1H, J = 8Hz), 6.95 (d, 1H, J = 2Hz), 6.95 (m, 2H), 7.07 (br s, 3H), 7.22 (m, 3H). MS (APC1) m / e 577 (M + H) + Analyze and estimate C33H37N205C1 · 0.85 H20: C, 66.90; H, 6.58; N, 4.73. Measured 値: C, 66.92; H, 6.25; N, 4.36. Example 467 trans, trans-4- Furan-5-yl) -2- (4-ethamoyl ν -((ΪN · (3 · chlorophenylbutylamino) carbonyl) methyl) pyrrolidine-3-carboxylic acid The title compound was prepared using the procedure of Example 1. iH NMR (300 MHz, CDC13) dO.85 (t , 3Η, J = 7Hz), 1.26 (t, 3Η, J = 7Hz), 1.30 (m, 2H), 1.40 (m, 2H), 2.60 (q, 2H, J = 7Hz), 2.72 (m, 1H) , 2.93 (m, 1H), 3.22 (m, 2H), 3.50 (m, 1H), 3.55 (m, 2H), 3.75 (m, 1H), 3.90 (br d, 1H), 6.75 (d, 1H, J = lHz), 6.80 (br d, 1H), 6.95 (br s, 1H), 7.08 (m, 4H), 7.20 (t, 1H, J = 8Hz), 7.28 (t, 1H, J = 8Hz), 7.42 (m, 2H), 7.58 (d, 1H, J = 1 Hz), 7.63 (s, 1H). MS (APC1) m / e 559 (M + H) +. Analysis estimates C33H35N204C1 · 0.45 H20: C, 69.88; H, 6.38; N, 4.94. Found 値: C, 69.83; H, 6.04; N, 4.87. 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) Example 468 trans'trans-2- (4-methoxy-3-fluorophenyl) -4- ( 7-methoxy-1.3-pack # difluorenyl_5_yl VI- 丨 2- (N-butyl · N-phenylamino) ethyl 1 pyrrolidine-3_ # _ 2 prepared in the procedure of Example 61A -(4-methoxy-3_fluorophenyl) · 4 · (7-methoxy-1,3-benzodifluoren-5-yl) -1- [2- (bromoethyl) -pyrrole Pyridine_3_ethyl carboxylate-487- This paper size applies to Chinese National Standard (CNS) A4 specification (2⑴X 297 mm) 1 '~ Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Description of the invention ( 485) (300 g) with N-butylaniline (190 mg) in 1 ml of Nisaki-yaki containing 130 mg of diisopropylethylamine. The hydrolysis of steel hydroxide can produce 148 mg of the title compound, White powder. 1η NMR (300 MHz, CDC13) d 0.90 (t, J = 9Hz, 3H), 1.28 (six peak, J = 7Hz, 2H), 1.46 (five peak, J = 7Hz, 2H) , 2.20 · 2 · 32 (m, 1H), 2.68-2.77 (m, 1H), 2.82-2.95 (m, 2H), 3.12-3.22 (m, 2H), 3.30-3.44 (m, 3H), 3.45-3.55 (m, 1H), 3.62 (d, J = 9Hz, 1H), 3.83 (s, 3H), 3.90 (s, 3H), 5.95 (s, 2H), 6.51 (d, J = 7Hz, 2H), 6.55-6.62 (m, 2H), 6.69 (d, J = 2Hz, 1H), 6.84 (t, J = 8Hz, 4H), 7.02-7.15 (m, 3H), 7.19 (dd, J = 2Hz, 12Hz, 1H). Example 469 trans, trans-4 · (1,4 · benzodioxane · 6-yl) -2- (4-ethylphenyl) _1 · (((ΝΝ , N_dibutylamino) carbonyl) methyl) pyrrolidine · 3-carboxylic acid The title compound was prepared using the procedure of Example 1. NMR (300 MHz, CDC13) β 0.78 (t, 3Η, J = 7Hz), 0.88 (t, 3Η, J = 7Hz), 1.05 (q, 2H, J = 7Hz), 1.23 (t, 3H, J = 7Hz), 1.28 (m, 2H), 1.45 (m, 2H), 2.64 (q, 2H, J = 7Hz), 2.78 (m, 1H), 2.9-3.2 (film, 4H), 3.30 (m, 1H), 3.40 (m, 3H), 3.60 (m, 1H), 3.80 (m, 1H) , 4.25 (s, 4H), 6.80 (d, 1H, J = 8Hz), 6.90 (m, 1H), 6.98 (d, 1H, J = 2Hz), 717 (d, 2H, J = 8Hz), 7.30 ( m, 2H) MS (APC1) m / e 523 (M + H) +. Analysis estimates C31H42N205 · 1.1 HOAc: C, 67.73; H, 7.94; N, 4.76. Found 値: c, 67.81; H, 7.55; N, 4.48. Example 470 trans, trans-4- (1,4-benzodifluorene-6_yl) -2- (4-methylbenzyl-488-This paper size applies to China National Standard (CNS) A4 specifications ( 210X297 mm) (Please read the precautions on the back before filling out this page) Order 581760 A7 ------- B7_____ V. Description of the invention (4 fats) A 暌) carbonyl) A certain) pyrrolidine-3- Carboxylic acid The procedure of Example 1 was used to prepare the title compound. 1H NMR (300 MHz, CD3OD) 6 0.87 (t, J = 7.1 Hz, 3H), 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, 1H), 3.33 (d, J = 10_2 Hz, 1H), 3.42-3.61 (m, 3H) , 3.79 (s, 3H), 3.91 (d, J = 9.8Hz, 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 (DCl) m / e 559 (M + H +). Analytical estimation: C33h38N2O6 · 〇4 ch3C02C2H5: C, 69 · 97; H, 6.99; N, 4.72. Found 値: c, 0.06; H, 6.66; N, 4.48. Example 471 trans, trans-bis 4- (1,4-benzodioxane · 6 · some methoxyphenyl) ((N-butyl-davinyl- (3 · chloroaniline, carbonyl) methyl) pyrrole Pyridine_3_carboxylic acid The title compound can be prepared using the procedure of Example 1. NMR (300 MHz, printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (please read the precautions on the back before filling this page) CD3OD) β 0.87 (t , J = 7.0 Hz, 3H), 1.25 (m, 2H), 1.40 (m, 2H), 2.78 (d, J = 14.6 Hz, 1H), 2.86 (t, J = 9.0 Hz, 1H), 3.16 (t , J = 9.5 Hz, 1H), 3.34-3.43 (m, 2H), 3.48 · 3 · 62 (m, 3H), 3.79 (s, 3H), 3.85 (d, J = 9.5 Hz, 1H), 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 (DCl) m / e 579 (M + H +). Analyzed and estimated c32H35C1N206 · 1.1 CH3C02C2H5 · 0 · 15 H3P〇4: C, 63.30; H, 6.46; N, 4.06. Found 値: C, 63.54; H, 6.09 N, 3.98. Example 472 trans, trans-4_ (1,3-benzodifluorene_5_ylmethoxyphenyl) _b (4_pyridine-489-Chinese paper standard (CNS) ) A4 size (2i × 297mm) 5817 60 A7 B7 V. Description of the Invention (487) Pyridinyl) pyrrolidine The title compound can be prepared using the procedure of Example 1. ijj NMR (300 MHz, (Please read the notes on the back before filling this page) CD3OD) β 2 · 84 (t, J = 9.6 Hz, 1H), 2.88 (dd, J = 9.6, 7.3 Hz, 1H), 3.09 (dd, J = 3.3, 9.6 Hz, 1H), 3.21 (d, J = 14.3 Hz , 1H), 3.53 (m, 1H), 3.78 (s, 3H), 3.81 (m, 2H), 5.92 (m, 2H), 6.73 (d, J = 8.1 Hz, 1H), 6.82 ( dd, J = 1.8, 8.1 Hz, 1H), 6.93 (m, 2H), 6.95 (d, J = 1.5 Hz, 1H), 7.43 (m, 4H), 8.44 (d, J = 5.2 Hz, 2H). MS (DC1) m / e 433 (M + H +). Analytical estimation: C25H24N205 · 03 C03C02C2H5: C, 68 · 57; H, 5.80; N, 6.10. Measured fluorene: c, 68.68; H, 5.60; N, 5.8 Example 473 trans, trans-4_ (1,3-benzodifluorene · 5-yl V2- (4 • methylphenyl) -N -(3 · Third-butylphenylamino) fluorenyl) methyl) r? P-P-Hydro-3-amino acid The procedure of Example 1 was used to prepare the title compound. iH NMR (300 MHz, CD3OD printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs) β 0.88 (t, J = 7.2 Hz, 3H), 1.23 (s, 9H), 1.26-1.45 (m, 4H), 2.74 (dd , J = 15.1 Hz, 1H), 2.84 (m, 1H), 3.13 (t, J = 9.0 Hz, 1H), 3.29 (d, J = 15.1 Hz, 1H), 3.50 · 3.66 (m, 4H) , 3.77 (s, 3H), 3.84 (d, J = 9.6 Hz, 1H), 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 Hz, 1H ), 7.42 (m, 1H). MS (DC1) m / e 587 (M + H +). Analysis estimates C35H42N206: C, 71.65; H, 7.22; N, 4.77. Measured 値: C, 71.56; H, 7.33; N, 4.69 ° -490- This paper size applies to Chinese National Standard (CNS) A4 specification (21 OX 297 mm) 581760 A7 B7 V. Description of the invention (488) Example 474 basis "Formula, base cover" di 唠 -5-some, formamidine 1, please read the precautions of Λ before filling in this page carbonyl) methyl) pyrrolidine-3-carboxylic acid The title compound can be prepared using the steps of Example 1 . 1H NMR (300 MHz, CD3OD) Θ 0.88 (t, J = 7.3 Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H), 1.23-1.59 〇, 8H), 2.58 (t, J = 7.6 Hz, 2H), 2.75 (d, J = 15.3 Hz, 1H), 2.80 (dd, J = 8.5, 9.5 Hz, 1H), 3.12 (t, J = 9.3 Hz, 1H), 3.29 (d, J = 15.6Hz, lH), 3.46 (dd, J = 4.9, 9.7Hz, lH), 3.52-3.64 (m, 3H), 3.78 (s, 3H), 3.83 (d, J = 9.8 Hz, 1H), 5.92 (s, 2H), 6.74 (d, J = 8.1 Hz, 1H), 6.79-6.87 (m, 4H), 7.05 (d, J = 1.7 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H) , 7.20 (d, 7.8 Hz), 7.29 (t, J = 7.6 Hz, 1H). MS (DC1 / NH3) m / e 587 (M + H +). Analysis estimates C35H42N206: C, 71.65; H, 7.22; N, 4.77. Found 値: C, 71.33; H, 7.28; N, 4.74. Example 475 Employees ’Cooperative Cooperatives of the Central Standards Bureau of the Ministry of Economy -3 · carboxylic acid The title compound was prepared using the procedure of Example 1. iH NMR (CD3OD, 300 MHz) θ 0 · 87 (t, 3H, J = 7), 1.19 (t, 3H, J = 7), 1.28 (m, 2H), 143 (m, 2H), 2.28 (s, 3H), 2.60 (q, 2H, J-2 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, J = 9), 6.80 (s, 2H), 7 · 06 (s, 4H), 7.18 (m, 4H), 7.45 (m, 1H). MS (APCl) m / e 535 (M + H) +. Analytical estimate C32H36N203F2 · 1.3 HOAc: C, 67.83; H, 6.78; N, 4.57. Measured -491-This paper size applies to the Chinese National Standard (CNS) A4 specification (21 × 297 mm) 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (489 ) 値: C, 67 · 83; H, 6.46; N, 4.70. Example 476 trans, trans-2- (4-ethylphenyl) -4- (3,4-dioxophenyl (n-butyl VN- (3-chlorophenyl) aminocarbonylmethyl) pyridine Pyridine_3_carboxylic acid The title compound was prepared using the procedure of Example 1. iH NMR (CD30D, 300 MHz) Γ 0.82 (t, 3H, J = 7), 1.16 (t, 3H, J = 7 ), 1.23 (m, 2H), 1.35 (m, 2H), 2.55 (q, 2H, J = 7), 2.66 (m, 2H), 3.01 (t, 1H, J = 9), 3.16 (d, 1H , J = 15), 3.32 (dd, 1H, J = 4, 9), 3.56 (m, 3H), 3.67 (d, 1H, J = 9), 6.94 (d, 1H, J = 7), 7.02 ( m, 5H), 7.14 (m, 2H), 7.32 (m, 3H). MS (APC1) m / e 555 (M + H) +. Analytical estimates C31H33N203C1F2 · 0.6 · TFA: C, 61.88; H, 5.42 N, 4.48. Measured C: C, 61 · 90; H, 5.62; N, 3.98. Example 477 trans, trans-4_ (1,4-benzyl-Nisaki-6-yl) -2- ( 4-fluorophenylbutyl-N- (3-chlorophenyl) aminocarbonylmethyl) pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. iH NMR (300 MHz, CD3OD) θ 0.87 (t, J = 7 Hz, 3H), 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, J = m Hz, 6H), 7 · 32_7 · 43 (m, 3H). MS (DCi) m / e 567 (M + H) +. Analysis estimates C31H32N205FC1 · 1.6 H20: C, 62 · 49; H, 5.95; N, 4.70. Found 値: C, 62.20; H, 5.54; N, 4.42. Example 478 trans'trans_4- (pyridinyl-5-yl) · 2 · (4-ethylphenyl) 1 (((Ν, Ν- 二 _ -492-) This paper is applicable to China Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back before filling out this page)-Order 581760 A7 __B7 V. Description of the invention (49〇) Butylamino) carbonyl) methyl) pyrrolidine -3- # _ The title compound was prepared using the procedure of Example 1. NMR (300 MHz, CDC13) d 0.78 (t, 3H, J = 7Hz), 0.84 (t, 3H, J = 7Hz), 1.05 (q, 2H, J = 7Hz), 1.21 (t, 3H, J = 7Hz ), 1.25 (m, 2H), 1.45 (m, 2H), 2.62 (q, 2H, J = 7Hz), 2.80 (d, 1H, J = 13Hz), 3.0 (m, 2H), 3.15 (m, 2H ), 3.35 (m, 1H), 3.43 (m, 2H), 3.52 (m, 1H), 4.40 (m, 2H), 6.73 (d, 1H, J = lHz), 7.14 (d, 2H, J = 8Hz ), 7.26 (s, 1H), 7.31 (d, 2H, J = 8Hz), 7.44 (s, 2H), 7.60 (d, 1H, J = lHz), 7.65 (s, 1H). MS (APC1) m / e 505 (M + H) +. Analysis estimates C31H40N2O4: C, 73.78; H, 7.99; N, 5.55. Measured fluorene: C, 73 · 69; H, 7.97; N, 5.21 〇 Example 479 Basic formula, trans · 2- (4-methylamido-3 · fluorophenyl) -4- (7-methoxy -1,3-Benzo-5-ylpropyl-N · (^ Yid-1 -Tanylmethyl) amino) ethyl 1 Outer halidine-3- Central acid bureau of the Ministry of Economic Affairs Printed by the employee consumer cooperative (please read the precautions on the back before filling this page) 2- (4-methoxy-3-fluorophenyl) -4- (7-methoxy-1) prepared according to the method of Example 61B , 3-Benzodifluoren-5-yl) -1- [2- (N-propylaminoethyl) • pyrrolidine-3-carboxylic acid ethyl ester (300 mg), N-bromoethylpyrrolidine ( 132 mg) and diisopropylethylamine (154 mg) were heated in 1 ml of acetonitrile at 50 ° C for 1 hour to form the intermediate ethyl ester. The ester was hydrolyzed to the title compound by the method of Example 1 D. 4 NMR (300 MHz , CDC13) d 0.88 (t, J = 7Hz, 3H), 1.30 · 1.45 (m, 2H), 1.75-1.92 (m, 4H), 2.30-2.40 (m, 1H), 2.47-2.58 (m, 2H), 2.70-3.00 (m, 5H), 3.24-3.45 (m, 6H), 3.50-3.70 (m, 2H), 3.83 (s, 3H), 3.86 (d, J = 9Hz, 1H), 3.88 ( s, 3H), 5.93 (s, 2H), 6.58 __ -493- This paper size applies to China National Standard (CNS) A4 specification (2.0 × 297 mm) 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (491) (d, J = 2Hz, 1H), 6.70 (d, J = 2Hz, 1H), 6.87 (t, J = 8Hz, 1H), 7.10 (d, J = 9Hz, 1H), 7_21 (dd, J = 2Hz, 12Hz, 1H). Example 480 trans-'trans- 2- (4-methylphenyl) -4- (1,3-benzodiazin-5-ylperhydroazacarbylcarbonyl, WDV leucoamido) amino, ethyl ^ pyrrolidine-3 -Carboxylic acid example 480A D-leucine 0-fluorenyl ester tosylate To D-leucine (5.0 g) and para-toluene dissolved in benzene (30 ml) of methanol (8.2 g) Sulfonic acid · hydrate (8.0g). The reaction was heated under reflux to remove it overnight. Once TLC showed that the starting material had been consumed, the reaction was cooled. The resulting solid was filtered off and washed with EtOAc to give a white powder. The title compound (14.26 g, 99%).

Example 480B N · perhydroazafluorenylcarbonyl_D · leucine 〇 芊 some ester To the compound of Example 4 80 A dissolved in chloroform (20 ml) was added triethylamine (0.4 Ml). The solution was cooled to zero. (:, Add carbonyldiimidine. After 1.5 hours, TLC shows that the starting material has been consumed, and then add hexamethyleneimine (0.3 27 ml). After 1 hour, add an additional amount of hexamethyleneimine (0.330 mL) and the reaction was stirred overnight at ambient temperature. The solution was washed with sodium bicarbonate (2 X 20 mL), 1 KHsPO4 (2 X 20 mL), and brine ', dried over NasSO4, decanted and evaporated. The residue The material was purified by silica gel flash chromatography, and was dissolved with 25_50% EtOAc / hexane to give the title compound as a crystalline solid (0.835 g, 89%). __________-494-This paper is a Chinese National Standard (CNS) M specification (21〇 > < 297 Meals) '--- ------------ (Please read the notes on the back before filling this page)

、 1T # 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (492)

480C N-perhydroazepine carbonyl-o-leucine The compound of Example 480B (200 mg) dissolved in absolute ethanol (1.0 ml) was added with 10% Pd / c (10 mg). After flushing with nitrogen, the reaction was stirred vigorously under a hydrogen atmosphere. The reaction was filtered through diatomaceous earth and evaporated to give the title compound (140 g).

Example 480D trans, trans-2_ (4_methylhydrogen 1) -4_ (1,3_benzodifluorene-5 · yl VI cyanomethyl a pyrrolidine_3_carboxylic acid Example 1 C compound (510 mg of a 50% wt solution in toluene) was dissolved in acetonitrile (2.0 ml) and diisopropylethylamine (0.24 ml) was added followed by bromoacetonitrile (0.072 ml). After 2 hours, TLC showed that the starting material was complete Consumption. The solvent was evaporated, and the residue was purified by flash chromatography on a chopped gum. The title compound was obtained as a colorless oil (0.28 g, 99%) by dissociation with 20-40% EtOAc / hexane.

Example 480E Trans'trans-2_ (4-methoxyphenyl) _4 · (1,3-benzodiain · 5-ylamineethyl V pyrrolidine-3-carboxylic acid ethyl ester Example 480D compound ( 275 mg) were dissolved in 10 ml of triethylamine and ethanol, and Raney nickel catalyst (0.2 g) was added. The reaction was placed under hydrogen atmosphere (4 atm) for 3 days. The reaction was filtered and evaporated. The residue was dissolved in dichloromethane (1 〇mL), and then extracted with 1 M HC1 (5 X 1ml). The mixed aqueous extract was tested and extracted with chloroform (5x2ml). The mixed organic extract was dried over MgS04 and passed through the oven Re-evaporation produces the title compound as an unstable oil (0.14 g). -495- This paper size applies Chinese National Standard (CNS) A4 (21 × 297 mm) (Please read the precautions on the back before filling this page) Order! Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 581760 A7 B7 V. Description of Invention (493)

Example 480F trans, trans-2- (4-methoxyphenyl) _4-Π, 3-benzodifluorene-5_a certain VW2-((N- (perhydroazinylcarbonyl) leucine carbonyl ) Amino) Ethyl Pyrrolidine I Acid Ethyl Example 4 8E Compound (0.10 g) was dissolved in dichloromethane (3.0 ml) and the compound from Example 480C (0.07 g) was added . The solution was cooled to 0 ° C and EDCI (0.052 g) was added. After 4 hours, the reaction was filtered and evaporated. The residue was dissolved in dichloromethane (10 liters) and extracted with 1 M Hcl (5 X 1 mL). The combined aqueous extracts were basified and extracted with dichloromethane (5 X 2 mL). The combined organic extracts were dried over MgS04, filtered and evaporated to give the title compound as an unstable oil (0.14 g).

Example 480F trans'trans-2- (4-methoxyphenyl) -4- (1,3-benzodi-17-l-5yl) -1-(2_ ((N- (perhydroazine Carbonyl) leukoamido) amine) ethyl V pyrrolidine-3-ethyl acid Example 4 8 0E Compound (0.10 g) was dissolved in dichloromethane (3.0 ml), and Example 4 8 was added. 0 C compound (0.07 g). The solution was cooled to 0 ° C and EDCI (0.052 g) was added. After 4 hours, the reaction was evaporated and partitioned between water (1 ml) and EtOAc (10 ml). The organic solution was water ( (1 ml) and brine (1 ml), dried over MgS04, filtered and evaporated. The residue was purified by flash chromatography on silica gel and dissolved with 50-60% EtOAc / hexane to give the title compound as a colorless oil. (0.075 g, 48%).

480G trans, trans-2- (4-methoxybenzyl) -4- (1,3-benzodiazine-5-yl) -1- (2- -496- This paper is applicable to China Standard (CNS) A4 specification (210X297 mm) ---------- ^-(Please read the notes on the back before filling out this page) Order 581760 A7 B7____ V. Description of invention (494) Order 氤Azathiocarbonylcarbonyl) Leucylamine) Amino) Ethyl) Pyrrolidine-3-carboxylic acid Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs To ethanol (1.0 ml) of Example 480F compound (0.75 g) was added 5 M NaOH (0.050 ml). After 2 hours, an additional 5 M NaOH (0.090 mL) was added. After another 3.5 hours, the reaction evaporated. The residue was dissolved in water (5 ml) and washed with diethyl ether (2 x 2 ml). The aqueous solution was acidified with 1 N H3P04 to pH = 3. The solid precipitated and was dissolved by extraction with chloroform (3 x 3 ml). The chloroform extract was washed with brine (2 ml) 'and dried over MgS04, filtered and evaporated to give the title compound as a brown solid (0.053 g). Dissolve with 10 ^ (: purified (¥ & (1 & (: 111 (: 18) in a gradient of 10-70% (: 11301 ^ at 0.10 / 〇TFA, suitable fraction (0.049g) can be freeze-dried) Generate the desired substance. 1H NMR (CDC13, 300 MHz) d 0.82 (dd, 6.4, 4.4 Hz, 6H), 0.87 (dd, J = 5.7, 5 · 7 Hz, 6H), 1.04 · 1 · 28 ( m, 3H), 1.34_1 · 65 (m, 19H), 2.95 (br m, 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 (s, 3H), 3.81 (s, 3H), 4.15 (br m, 2H), 5.10 (br m, 2H), 5.93 (s, 3H), 5. · 95 (s, 3H), 6.70-6.97 (m, 13H), 7.43-7.56 (br m, 3H), 8.2 (br s, 1H), 8.5 (br s, 1H). MS (DC1 / NH3) m / e 623 (M + H) +. Analyzed and estimated C34H46N407 · 2.00 TFA: C, 53.65; H, 5.69; N, 6_58. Measured 値: C, 53.66; H, 5.66; N, 6.54. Example 481 trans form, trans form _4- (1,3 · Benzodifluoren-5-yl V2- (4 · methoxyphenyl) · 1- (N, N-bis (n-hexyl) aminocarbonylmethyl) pyrrolidine_3-carboxyl The title compound can be prepared using the procedure of Example 1. NMR (300 MHz, -497 This paper is a Chinese national standard. (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (495) CD3OD) d 0.80-0.95 (m, 6H), 1.0 (m, 2H), 1.07 (1.55, J = m Hz, 14H) , 2.70 (d, J = 13 Hz, 1H), 2.85-3.15 (m, 4H), 3.20-3.60 (m, 9H), 3.64 (d, J = 10 Hz, 1H), 3.79 (s, 3H), 5.90 (m, 2H), 6.70 (d, 8H), 1, 6.80-6.93 (m, 3H), 7.05 (2, 1H), 7.35 (d, J = 10 Hz, 2H). Analysis estimates C33H46N206 · ι · 7 h20: C, 66.35; H, 8.34; N, 4.69. Measured 値 · C, 66.32; H, 8.04; N, 4.52. Example 482 Cong Li, trans-4- (1,4-benzodiurin-6-yl) -2_ (4-fluorophenyl) _1_〇 ^ _ 丁 盖 -N- (3-methylbenzene Benzenecarbonylmethyl) pyrrolidine-3_carboxylic acid The procedure of Example 1 was used to prepare the title compound. iH NMR (300 MHz, CD3OD) d0.87 (t, J = 7 Hz, 3H), 1.20-1.35 (m, 2H), 1.35-1.40 (m, 2H), 2.32 (s, 3H), 2.55 · 2 · 70 (m, 2H), 2.97 (t, J = 7 Hz, 1H), 3.22 (d, J = 14 Hz, 1H), 3.25-3.70 (m, 5H), 4.20 (m, 4H), 6.97 (d, J = 2 Hz, 1H), 7.09 (m, 2H), 7.15-7.35 (m, 2H). MS (DCl) m / e 547 (M + H) +. Analytical c32H35N205F · i 2 η2〇: c, 67 64; H, 6.63; N, 4.93. Found 値: c, 67 73; H, 6 37; N, 4 70. Example 483 Trans form, anti stand, 4 · (1,3 _ %% 二 唠 _5, _2 彳 4_methoxyphenyl 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) Iodo-N-bis (.3-nitrobenzyl-1amino) carbonyl) methyl) pyrrolidine-3_carboxylic acid The procedure of Example 1 was used to prepare the title compound. ιΗ NMR (300 Μ CDζ, CDCI3) d (geometric isomer) 8 μ (2H, m), 80 (5a) (m, 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 = 12), 4.75 (1H, bd, J = 15), 4.60-4.20 (2H, m), 4.10 (2H, m), 3.8Ό (3.76) (3H, s), 3.75-3.40 (3H, m), -498- This paper size applies to China Standard rate (CNS) A4 specification (21 οχ 297 male thin) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 ------------ B7 _ V. Description of invention U96) 3.20-2.80 (2H, m), 1.50 (1H, m), i3O (m, m), 12100 (2H, m), 0.91 (0.78) (3H, t, J = 8). MS (DC1 / NH3) m / e 590 (M + H +). Knife analysis estimates C32H35N308 · 2.1 tFA: c, 52 44; H 4 51; N 5 07. Found 値: C, 52.25; H, 4.83; N, 5.71. Example 484 trans-bis-trans-furan_5-yl) -2- (4-ethylphenyl) -1 · (ίϋ: Τ 基 -Ν (3, 立 立) amino) carbonyl) methyl) Pyrrolidine_3_guineaic acid The procedure of Example 1 was used to prepare the title compound. iH NMR (300 MHz, CDC13) (ί (geometric isomer) 7 4〇 (2H, m), 7 3007 1〇 (4H, m), 6.90-6.70 (3H, m), 6.48 ( 1H, m), 5.45 (1H, m), 4.65 (1H, d, J = 15), 4.57 (2H, dt, J = 9, 3), 4.40_4 · 00 (5H, m), 3.87 (3.85) (3H, s), 3.84 (1H, m), 3.83 (3.79) (3H, s), 3.56 (2H, m), 3.20 (2H, t, J = 10), 2.90 (1H, m), 2.64 (2H, q, J = 8), 1.52 (1H, m), 1.31 (2H, m), 1.22 (3H, dt, J = 9, 2), 1.07 (1H, m), 0.92 (0.78) (3H, t, J = 8). MS (DCl / NH3) m / e 601 (M + H +). Analytical estimate C36H44N206 · 1.35 TFA: C, 61.59; H, 6.06; N, 3 71. Measured fluorene: C, 61.69; H, 6.04; N, 3.63. Example 485 Basic formula, trans-4_α, 3_benzodihum-5-yl) 2_ (4 · methoxyphenylbutyl -N- (4-heptyl) amino) carbonyl) methyl) pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. 4 NMR (300 MHz, CD3OD) d 0.71-1.04 (m, 11H), 1.07-1.35 (m, 6H), 1.73-1.53 (m, 4H), 2.79-3.25 (m, 5H), 3.35 · 3 · 44 (m, 1H), 3.51-3.68 (m, -499-This paper size is applicable to China National Standard (CNS) A4 specification (21〇X 297 mm) ---------- ^- (Please read the precautions on the back before filling this page),?! Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 __B7 V. Description of the Invention (497) 3H), 3.78-3.89 (m, 1H), 3.79 ( s, 3H), 5.92 (m, 2H), 6.74 (dd, J = 1.7, 8.1 Hz, 1H), 6.85 (td, J = 1.7, 8.1 Hz, 1H), 6.93 (m, 2H) , 7.02 (dd, J = 1.7, 9.5 Hz, 1H), 7.36 (m, 2H). MS (C.I.) m / e 553 (M + H +). Analysis estimates C32H44N206: C, 69.54; H, 8.02; N, 5.07. Found 値: C, 69.31; H, 7.89; N, 5.06. Example 486 trans, trans-2 · (4-methylcyclohexyl molybdenyl · · 5_yl) -1- (N, N_dibutylaminopyrylmethyl) pbilodine_3_slim The title compound was prepared using the procedure of Example 1 as an amorphous solid. 1h NMR (CDC13, 300 MHz) J 0 · 88 (3H, d, J = 7Hz), 0.92 (3H, t, J = 7Hz), 0_96 (3H, t, J = 7Hz), 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, brm), 3.82 ( 1H, dd, J = 9Hz, 15Hz), 3.86 (1H, d, J = 15Hz), 5.93 (2H, s), 6.73 (1H, d, J = 8Hz), 6.78 ( 1H, dd, J = 2Hz, 8Hz), 6.88 (1H, d, J = 2Hz). MS (DC1 / NH3) m / e 501 (M + H) +. Analysis estimates C29H44N205 · 0.25 CF3C02H: C, 66 · 96; H, 8.43; N, 5.29. Found 値: C, 66.79; H, 8.60; N, 4.87. Example 487 Example of use of trans, trans-2- (2-propylpentyl) -4- (1,3-benzodifluorene · 5-yldibutylaminecarbonylmethyl) pyrrolidine-3-carboxylic acid Step 1 can prepare the title compound and isolate it into an amorphous solid. 4 NMR (CDC13, 300 ΜΗζ) β 0.85 (6H, m), 0.92 (3H, t, J = 7Hz), 0.97 (3H, t, J = 7Hz), 1.12-1.40 (13H, melon), 142 , 1.68 (6H, m), 2.90 (1H, m), 3.14-3.30 (2H, m), 3.33 (4H, m), -500- ____ This paper size applies to China National Standard (CNS) A4 specifications (210X 297 Mm) (Please read the notes on the back before filling this page) Order 581760 A7 B7 Printed by the Central Economic Bureau Standards Fee Cooperatives V. Invention Description (498 3 · 72 (1H, brm), 3.90 (1H, brm), 5.93 (2H, dd, J = 2Hz, 4Hz), 6.73 (1H, d, J = 8Hz), 6.78 (1H, dd, J = 2Hz, 8Hz), 6.88 (1H, d, J = 2Hz). MS (DCi / NH3) m / e 517 (M + H) +. Analyzed and estimated C30H48N2O5 · 0.35 CF3C02H: C, 66 · 24; H, 8.76; N, 5.03. Found: C, 66 · 26; H, 8 · 82; N, 4 · 98 ° Example 488 trans, trans_4- (1,4_benzodiphenyl-6-yl) _2- (4-aminophenyl) 1- (Ν, Ν- 二Butylaminocarbonylmethyl) pyrrolidine-3 · carboxylic acid The title compound was prepared using the procedure of Example 1. iH NMR (300 MHz, CD3OD) (^ 0.83 (t, J = 7Hz, 3H), 0.89 (t, J = 7Hz, 3H), 0. 90 · 1.17 (m, 4H), 1.20 · 1 · 65 (m, 5H), 2.77d (13, 1H), 2.87 (dd, J = 8, 2 Hz, 1H), 2.95-3.60 (m, 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 (DCl) m / e 513 (M + H) +. Analysis estimates C29H37N205F · 1.2C F3COOH: C, 58.07 H, 5.93; N, 4.31. Found 値: C, 57.94; H, 5.81; N, 4.56 o Example 489 trans, trans-2- (3-methylpentyl) -4_ (l , 3-Benzodifluorene · 5-a VI-HSLN-dibutylaminocarbonylmethyl) pyrrolidine-3-carboxylic acid ^ The title compound was prepared using the procedure in Example 1 and isolated as an amorphous solid. 4 NMR (CDC13, 300 MHz) d 0_83 (3H, t, J = 7Hz), 0.85 (3H, d, J = 7Hz), 0.91 (3H, t, J = 7 Hz), 0.97 (3H , T, J = 7Hz), 1.05-1.22 (2H, m), 1.22-1.41 (7H, m), 1.43 · 1 · 68 (5H, 501-This paper size applies to China National Standard (CNS) Α4 specifications (210X297 mm) (Please read the notes on the back before filling this page) 581760 A7 B7 V. Description of the invention () m), 1.89 (1H, m), 2.94 (1H, t, J = 6Hz ), 3.15-3.27 (3H, m), 3.29 · 3 · 60 (5H, m), 3.72 (1H, brd, J = 6Hz), 3.92 (1H, brd, J = 13.5Hz), 5.93 (2H, dd, J = 2Hz, 4Hz), 6.73 (1H, d, J = 8Hz), 6.78 (1H, dd, J = 2 Hz, 8Hz), 6.88 (1H, d, J = 2 Hz). MS (DC1 / NH3) m / e 489 (M + H) +. Analysis estimates C28H44N205 · 0.30 CF3C02H: C, 65.70; H, 8.54; N, 5.36. Found 値: C, 65.93; H, 8.81; N, 4.84. Example 490 trans, trans_2 · (2_ethylbutyl) · 4_ (1,3_benzodioxo-5-yl) _ 1 _ (N, N_dibutylaminocarbonylmethyl) Pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound and isolated as an amorphous solid. 4 NMR (CDC13, 300 MHz) d 0.85 (6H, m), 0.92 (3H, t, J = 7Hz), 0.97 (3H, t, J = 7Hz), 1.13-1.41 (13H, m) , 1.43_ 1.72 (6H, m), 2.96 (1H, brm), 3.12-3.52 (6H, m), 3.35 · 3 · 70 (1H, m), 3.70-3.86 (2H, m), 3.99 (1H, brm), 5.93 (2H, dd, J = 2Hz, 4Hz), 6.73 (1H, d, J = 8Hz), 6.78 (1H, dd, J = 2 Hz, 8Hz), 6.88 (1H, d, J = 2Hz). MS (DC1 / NH3) m / e 489 (M + H) +. Analysis estimates C28H44N205 · 0.45 CF3C02H: C, 64 · 28; H, 8.30; N, 5.19. Found 値: C, 64 · 16; 8.38; N, 5.08. 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) Example 491 trans'trans · 2_ (3-fluoro-4-methoxyphenyl) -4- (1, 3. Benzobisazin-5-yl (2- (N-isobutylbutanesulfonamido)) ethyl) pyrrolidine. 3-carboxylic acid The title compound was prepared by the method of Example 66. in NMR (CD3〇D, 300 MHz) β 0.74 (d, 3H, J = 7), 0.83 (d, 3H, J = 7), 0.94 (t, 3H, 502)-This paper is applicable to China National Standard (CNS> A4 specification (210X297 mm) '' Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 __B7 V. Description of the invention (500) J = 7), 1.44 (Liu Feng, 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 = 2), 7.22 (t, 1H, J = 9), 7.39 (m, 2H). MS (ESI) m / e 579 (M + H) +. Example 492 trans, trans-2- (4-form Oxy-3-fluorobenzyl > · 4-Π, 3-benzobisfluoren-5-yl \ 1- 丨 2- (N-propyl-N- 丨 4-ethylpyrimidine_2-yl 1 Amines) 1-dimethylamino · 1_pentene_3 · ketone prepared by the method described in Syn. Comm. 12 (1), 35 (I982), and Chem. · Ber · 97, 3397 (1964), using guanidine to convert to 2-amino-4-ethylpyrimidine. This material was NaN02 and HBr, using Helv. Chim. Acta 75, 1629 (199 2) method to convert 2-bromo-4 · ethyl-pyrimidine. This bromopyrimidine and 2- (4-methoxyphenyl) -4- (1,3-benzo-2-5-yl) -l- [2- (N-propylamino) propyl]-? bilodine-3 -acid acid (prepared by the method of Example 61B) was reacted by the method of Example 418 to give the title compound as a white powder. 1H NMR (300 MHz, CDC13) β 0.83 (t, J = 7Hz, 3H), 1.11 (t, J = 7Hz, 3H), 1.45 (six peak, J = 7Hz, 2H), 2.18-2.27 (m, 1H), 2.45 (q, J = 7Hz, 2H), 2.80-2.97 (m, 3H), 3.40-3.75 (m, 7H), 3.83 (s, 3H), 5.95 (s, 2H), 6.25 (d, J = 4HZ , 1H), 6.68 (d, J = 8Hz, 1H), 6.79 (dd, J = 2Hz, 8Hz, 1H), 6.82 (t, J = 9Hz, 1H), 6.92 (d, J = 2Hz, 1H), 7.05 (d, J = 9Hz, 1H), 7.15 (dd, J = 2Hz, 12Hz, 1H), 8.10 (d, J = 4Hz, 1H) 〇 Example 493 trans, trans-4- (1,3 • Benzenedifluorene-5 · Base-Acute Phenyl-503- This paper size is applicable to China National Standard (CNS) A4 (210X297 mmΊ) ------ IT ------ · (Please read first Note on the back, please fill out this page) 581760 A7 B7 V. Description of the invention (501) Butyl-N- (3,4-xylyl) amine Carbonyl) methyl) pyrrolidine-3-carboxylic acid The procedure of Example 1 was used to prepare the title compound. iH NMR (300 MHz, CD3OD) d0.87 (t, J = 7.3Hz, 3H), 1.23-1.36 (m, 2H), 1.38-1.43 (m, 2H), 2.22 (s, 3H), 2.29 (s, 3H), 2.79 (d, J = 14.9 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, 1H), 3.43-3.61 (m, 4H), 3.79 (s, 3H), 3.88 (d, J = 9.8 Hz, 1H), 5.93 (s, 2H), 6.74 (m, 3H), 6.83 ( m, 3H), 7.04 (d, T = 1.7 Hz, 1H), 7.11 (m, 3H). MS (C.I.) m / e 559 (MH +). Analytical estimates: C33H38N2 06 · 0.3 · H20: C, 70.27; H, 6.90; N, 4.97. Found 値: C, 70.24; H, 6.62; N, 4.58. Example 494 trans, trans-2_ (3_methylpent-3_en-1-yl V4_ (1.3_benzyl difluoren-5-yl) · Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please first Read the notes on the back and fill in this page again.) Dibutylamine carboxymethyl) pyrrolidine-3 · acid generator The title compound was prepared using the procedure of Example 1 and isolated into an amorphous solid.丄 !!!! NMR (CDC13, 300 MHz) d 0 · 92 (3H, t, J = 7 Hz), 0.97 (3H, t, J = 7Hz), 1.22-1.40 (5H, m), 1.44-1.61 (8H, m) , 1.82 (1H, brm), 2.02 (2H, m), 3.05-3.30 (4H, m), 3.3.8 (1H, m), 3.55 (1H, brm), 3.85 (2H, m), 4.12 (1H, brd, J = 15Hz), 5.11 (1H, dd, J = 6Hz, 12Hz), 5.93 (2H, s), 6.73 (1H, d, J = 8Hz), 6.78 (1H , Dd, J = 2Hz, 8Hz), 6.88 (1H, d, J = 2Hz). MS (DC1 / NH3) m / e 487 (M + H) +. Analytical estimation: C28H42N205 · 0.7 CF3C02H: C, 62.34; H, 7.60; N, 4.95. Measured 値: C, 62.49; H, 7.43; N, 4.73 o -504- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 581760 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the invention (502) Example 495 Example of (N-diphenylbicarbonylmethyl V2_ (4-methoxyphenyl) _4 · α, 3 · jasmine di ^ pyrrolidine-3-carboxylic acid example 495A Ν- Stirred solution of phenylbromoacetamide p-aniline (7.40 mmol) in dichloromethane (25 ml), and successively add N, N · diisopropylethylamine (1.58 ml, 8-14) at -50 ° C. Millimoles, 1.1 equivalents) and bromoethenyl bromide (0.72 ml, 7.40 millimoles, j equivalents), so that the temperature does not exceed -40 ° C. Once completely added, remove the cooling bath and allow the reaction mixture to add. Warm to room temperature. After stirring for another 30 minutes, the mixture is diluted with ether (70 ml) and poured into a sodium bisulfate solution. The phases are separated and the upper layer is washed successively with water and brine. The organic phase is dried (NasSO4) and the solvent was evaporated to half the volume, at which point the product could crystallize. The crystals were removed by suction filtration to give the title compound.

Example 495B Trans, trans-aniline carbonylmethyl V2- (4 · methoxybenzyl-V4-H benzodiamidin-5-yl) pyrrolidine-3-carboxylic acid The procedure of Example 1 and the compound of Example 495 A were used The title compound can be prepared. 4 NMR (300 MHz, CDC13) β 8.8 (bs, 1H), 7.49 (2H, d, J = 8Hz), 7.38 (4H, m), 7.11 (1H, tt, J = 8 & 2Hz) , 6.99 (1H, d, J = 2Hz), 6.91 (2H, d, J = 8Hz), 6.86 (1H, d, J = 2Hz), 6.81 (1H, d, J = 8Hz) , 5.99 (1H, d, J = 2Hz), 5.98 (1H, d, J = 2Hz), 3.94 (1H, d, J = 10Hz), 3.78 (3H, s), 3.70 (1H , Ddd, J = 6, 5 & 3Hz), 3.42 (1H, dd, J = 10 & 3Hz), 3.41 (1H, d, J = 16Hz), 3.18 (1H, dd, J = ll & -505- Paper size applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) ------------ (Please read the precautions on the back before filling this page}-Staff of the Central Bureau of Standards, Ministry of Economic Affairs Printed by the Consumer Cooperative 581760 A7 ____ — __B7_ V. Description of the invention (503) 9Hz), 3.01 (1H, t, J = 10Hz), 2.93 (1H, d, J = 16HZ). MS (Dd, NH3) m / e 475 (M + H +). Analyzed and estimated c27H26N206 · 1 H20 · · C, 65 · 85; H, 5.73; N, 5.69. Found 値: C, 65.95; H, 5.52; N, 5.38. Example 496 Trans'Hair A-Mθιί dimethylphenyl) aminocarbonylmethyl) _2_M-methylphenyl) _4- (1,3_benzene Dipyridine-5, pyrrolidine-3- # acid The title compound was prepared using the procedure of Example 1. iH NMR (300 MHz, CDC13) 4 8 · 68 (1H, bs), 7.64 9d, J = 8Hz), 7 · 38 (2H, d, J = 8Hz), 7.09 (1H, t, J = 8Hz), 6.97, (1H, d, J = 8Hz), 6.90 (1H, d, J = 2Hz), 6.88 (2H, d, J = 8Hz), 6.82 (1H, d, J = 8 & 3Hz), 6.76 (1H, d, J = 8Hz), 5.97 (1H, d, J = 2Hz), 5.96 (1H, d, J = 2Hz), 3.95 (1H, d, J = 10Hz), 3.80 (3H, s), 3.70 (1H, ddd, J = 6, 5 & 3Hz), 3.48 (1H , Dd, J = 10 & 3Hz), 3.44 (1H, d, J = 16Hz), 3.18 (1H, dd, J = ll & 9Hz), 3.06 (1H, t, J = 10Hz), 2.96 (1H , D, J = 16Hz), 2.31 (3H, s), 2.16 (3H, s). MS (DC1, NH3) m / e 503 (M + H +). Analytical estimates: C29H30N2 06 · 0.5 H20: C, 68.09; H, 6.11; N, 5.48. Found 値: C, 68.13; H, 5.91; N, 5.29. Example 497 trans, trans dimethylphenyl) aminocarbonylmethyl V2- (4-methoxy • phenyl) -4- (1,3-benzobisfluoren-5-yl) pyrrolidine_3_ The title compound was prepared from the carboxylic acid using the procedure of Example 1. 1H NMR (300 MHz, CDC13) d 8.60 (1Η, bs), 7.78 (d, J = 8Hz), 7.38 (2Η, d, J = 8Hz), 6.99 (1H, m), 6.95 (1H , D, J = 8Hz), 6.94 (1H, d, -506-This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) --------- Yes --- --- 1T ------ 0 (Please read the precautions on the back before filling this page) 581760 A7 ____ B7 V. Description of the invention (504) J = 2Hz), 6.88 (2H, d, J = 8Hz), 6.82 (1H, dd, J = 8 & 3Hz), 6.77 (1H, d, J = 8Hz), 5.97 (1H, d, J = 2Hz), 5.96 (1H, d, J = 2Hz), 3 · 92 (1H, d, J = 10 Hz), 3.79 (3H, s), 3.68 (1H, ddd, J = 6, 5 & 3Hz), 3.43 (1H, dd, J = 1 & 3Hz) , 3.42 (1H, d, J = 16Hz), 3.18 (1H, dd, J = ll & 9Hz), 3.04 (1H, t, J = 10Hz), 2.95 (1H, d, J = 16Hz), 2.29 (3H , S), 2.24 (3H, s). MS (DC1, NH3) m / e 503 (M + H +). Analytical estimates: C29H30N206. 0.75 H20: C, 67.50; H, 6.15; N, 5.43. Found 値: C, 67 · 42; H, 5.95; N, 5.13. Example 498 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 5-xylyl) aminocarbonylmethyl) -2- (4-methoxybenzene (4) (1.3-Benzodifluoren-5-yl) pyrrolidine-3-reading acid The procedure of Example 1 was used to prepare the title compound. 1H NMR (300 MHz, CDC13) d 8.62 (1Η, bs), 7.79 (1Η, bs), 7.38 (2Η, d, J = 8Hz), 7.03 (1H, d, J = 8Hz) , 6.95 (1H, d, J = 8Hz), 6.94 (1H, d, J = 2Hz), 6.88 (2H, d, J = 8Hz), 6.82 (1H, dd, J = 8 & 3Hz) , 6.77 (1H, d, J = 8Hz), 5.97 (2H, s), 3.92 (1H, d, J = 10Hz), 3.78 (3H, s), 3.70 (1H, ddd, J = 6, 5 & amp 3Hz), 3.48 (1H, dd, J = 10 & 3Hz), 3.42 (1H, d, J = 16Hz), 3.18 (1H, dd, J = 11 & 9Hz), 3.04 (1H, t, J = 10Hz), 2.95 (1H, d, J = 16Hz), 2.29 (3H, s), 2.24 (3H, s). MS (DCl, NH3) m / e 503 (M + H +). Analysis estimates C29H3ON206.0.5H20: C, 68.09; H, 6.11; N, 5.48. Found 値: c, 67 · 72; H, 5.89; N, 5.25. Example 499 trans, trans-1 · (N- (3,4-dimethylphenyl) amine carbonylmethylmethoxybenzene-507-This paper size is applicable to China National Standard (CNS) A4 (2 （〇χ297) ^ Cent) 581760 A7 B7 V. Description of the invention (5 05) group) -4- (1,3-benzodifluoren-5-yl) pyrrolidine-3-miao _ can be prepared by using the procedure of Example 1 Into the title compound. 1H NMR (300 MHz, CDC13) d 8.73 (1Η, bs), 7.38 (2Η, bd, J = 8Hz), 7.30 (1Η, d, J = 3Hz), 7.20 (1H, bs), 7.08 (1H , D, J = 8Hz), 7.01 (1H, bs), 6.90 (2H, d, J = 8Hz), 6.85 (1H, bs), 6.80 (1H, d, J = 8Hz), 5.99 (1H, d, J = 3Hz), 5.98 (1H, d, J = 3Hz), 3.92 (1H, d, J = 10Hz), 3.78 (3H, s), 3.70 (1H, ddd, J = 6,5 & 3Hz), 3.48 (1H, dd, J = 10 & 3Hz), 3.42 (1H, d, J = 16Hz), 3.18 (1H, dd, J = 11 & 9Hz), 3.04 (1H, t, J = 10Hz), 2.95 (1H, d, J = 16Hz), 2.25 (3H, s), 2.21 (3H, s). MS (DC1, NH3) m / e 503 (M + H +). Analysis estimates C29H30N2O6 · 0 · 75 H20: C, 67.50; H, 6.15; N, 5.43. Found 値: C, 67 · 24; H, 5.94; N, 5.20. Example 500 trans, trans 5-xylyl) aminocarbonylmethyl) -2- (4-methoxyphenyl) · 4- (1,3_benzhuangyi-5yl) Bilodol_ 3-Unsaturated acid was used to prepare the title compound using the procedure of Example 1. 1H NMR C300 Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (please read the notes on the back before filling this page) MHz, CDC13) β 8 · 75 (1Η, bs), 7.35, (2Η, d, J = 8Hz ), 7.10 (2Η, s), 7.02 (1H, d, J = 3Hz), 6.90 (2H, d, J = 8Hz), 6.84 (1H, d, J = 2Hz), 6.80 (1H, d, J = 8Hz), 6.76 (1H, bs), 5.99 (1H, d, J = 3Hz), 5.98 (1H, d, J = 3Hz), 3.92 (1H, d, J = 10Hz) , 3.79 (3H, s), 3.68 (1H, ddd, J = 6, 5 & 3Hz), 3.40 (2H, m), 3,18 (1H, dd, J = ll & 9Hz), 2.98 (1H, t , J = 10Hz), 2.88 (1H, d, J = 116Hz), 2.3 (6H, s). MS (DC1, NH3) m / e 503 (M + H +). Analytical estimates C29H30N205 · 0.5 · H20 ·· C, 68.09; H, 6.11; N, 5.48. Measured 値 ·· -508- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) ^ 581760 A7 ____ B7 V. Description of the invention (506) C, 67 · 93; H, 6.01; N, 5.19 . Example 501 (± 1 ^ formula, trans-di-n-butylaminocarbonyl methyl) -2- (4 • methyl on '(1,3-benzodifluoren-5-yl) pyrrolidin-3-carboxyl Hydrochloride

Example 501A A solution of N, N-dibutyl thiamine ethyl bromide (72.3 ml, 830 mmol) in toluene (500 ml) was cooled to 0 ° C. A solution of dibutylamine (28.0 ml, 1.66 moles) in toluene (220 ml) was added via an addition funnel. And the reaction temperature was maintained below 10C. Once the addition was complete, the reaction mixture was stirred at 0 ° C for 15 minutes. A 2.5% aqueous solution of P> 4 (500 ml) was slowly introduced, and the reaction mixture was warmed to room temperature again and stirred vigorously. The solution was 2 5% phosphoric acid by weight. The layers were separated and the organic layer was washed with water (500 ml), and concentrated to form bromoacetamide as a solution in toluene.

Example 501B 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) 5- (2-Nitrovinylbenzone Alkyl-piperaldehyde (15.55 kg, 103.5 mol) was added under mechanical stirring under nitrogen, ammonium acetate (13.4 kg, 173.8 mol), acetic acid (45.2 kg), and nitromethane (18.4 kg, 301.4 mol) were added sequentially The mixture was warmed to 70 ° C. After about 30 minutes, the yellow product began to crystallize. The reaction temperature was raised to 80 ° C and stirred for about 10 hours until a very small amount of piperaldehyde remained. A slightly thick reaction mixture Cool to 10 ° C and filter. The precipitate is washed with acetic acid (2 x 8 kg) and then with water (2 x 90 kg). The product is dried under a nitrogen flush and then dried in an air oven at 50 ° C for 2 days to form 15.94 kg (80%) _____- 509 -__ ^ The paper size applies the Chinese National Standard (CNS) A4 specification (210X ^ 97 mm) 'Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy 581760 A7 B7_________ (50.7) of the title compound as a pale yellow solid.

Example 501C 4-methylammonium acetate p-tertiary-valerate (25 wt%, 50.8 kg, 99.26 moles) in toluene (15.2 kg), cooled to 5 ° C, and mechanically stirred and Under nitrogen, a mixture of 4-methoxyacetophenone (6.755 kg, 44.98 mol) and diethyl carbonate (6.40 kg, 54.18 mol) in toluene was added for 1 hour and the temperature was maintained below 10 QC. The reaction mixture was heated to 60 ° C for 8 hours until 4-methoxyacetophenone was not detected by HPLC. The mixture was cooled to 20 ° C, and then a mixture of acetic acid (8 kg) and water (90 kg) was quenched for 30 minutes while maintaining the temperature at < 2 (TC. The layers were separated, and the organic layer was 5% hydrogen carbonate Sodium (41 kg) was washed and concentrated to 14.65 kg. The temperature was maintained at 50 ° C (in the steam residue). The yellow product concentrate was analyzed by HPLC and external standards were added and the yield was found to be 9.40 kg (94 %).

Example 501D Methacryl) -4_nitromethyl-3_π, 3-benzodifluorene_5_) Butyl ethyl ester Example 50 1B compound (7.5 kg, 37.9 moles) suspended in THF (56 Kg), under nitrogen and mechanical stirring, add the compound from Example C (8.4 kg, 37.9 moles). The mixture was cooled to 17 ° C, sodium ethoxide (6.4 g, 0.095 mole) was added, and the reaction was stirred for 30 minutes. After about μ minutes, the nitrostyrene was completely dissolved. Sodium ethoxide (64 g, 0,095 mol) was added and the mixture was stirred at 25 ° C until HPLC showed that the area of keto vinegar remaining was less than 1. The reaction was concentrated to 32.2 kg, determined by HPLC as -510- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ''---------- Shen Yi ------ 、 Order ------ 0 (Please read the notes on the back before filling out this page) 581760 A7 B7 V. Description of the invention (5〇8) ~ 14.9 kg (95%).

Example 501E Formula _2- (4 • methoxyphenyl) _4- (1,3-benzo ^ | _5_yl) pyridine_3-carboxylic acid ethyl ester Ruan nickel (20.0 g) (wherein ) Charge the device to a reheated, stirred hydrogenator. THF (20 mL), the crude compound of Example 50 (40.82 g, 0.0482 mol), and acetic acid (2.75 mL, 0.0482 mol) were added successively. The mixture was placed under a hydrogen atmosphere of 60 psi until the hydrogen was slowly absorbed. TFA was added and the mixture was hydrogenated at 2000 psi until jjPLC showed no residual imines and the nitroketone area% was less than 2. The catalyst was filtered and removed, and washed with 100 ml of methanol. The filtrate was analyzed by HPLC and found to contain 13.3 g (75% yield) of the cis, cis-pyrrolidine compound. The filtrate was concentrated and additional THF (200 mL) was added to produce a final volume of 100 mL. The mixture was neutralized with a 2 N NaOH solution (50 ml), diluted with water (200 ml), and extracted with ethyl acetate (2 x 100 ml). The mixed almost colorless ethyl acetate was analyzed by HPLC (plus external standards) and the title compound was found to be 13.0 g (73%).

Example 501F Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs-2_ (4-methylchloromolyl) -4- (1,3-benzodihen-5-a, pirodo_3_ ethyl carboxylate Example 501Ε The compound (38.1 g, 0.103 mole) was added with ethanol (200 ml) to a final volume of 100 ml, and sodium ethoxide (340 g, 5000 mole) was added. The mixture was heated to 75 ° C. When HPLC showed the remaining cis, cis isomers <3%, the mixture was cooled to room temperature. The product was analyzed by HPLC and added with -511-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) ) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. The external standard on the invention description (509) and found to contain 34.4 g (90% yield) of the title compound. The crude compound solution was concentrated and the residue was Isopropyl acetate absorption (400 ml). The organic layer was washed with water (2 X 150 ml) and extracted with 0.25 M acetic acid solution (2 X 400 ml). The mixed phosphoric acid layer and ethyl acetate (2 〇mL) Stir together, and then neutralize with sodium bicarbonate solid (21g) to pH 7. Have Layer was separated and found to contain 32.9 g (87%) of the title compound.

Example 501G (2R, 3R, 4S)-(+)-2- (4_methoxyphenylbenzodiazepine_5_ylpyrrolidin-3-carboxylic acid ethyl ester (SK +) The solution was supplemented with acetonitrile (110 ml) to obtain a final volume of 50 ml. (S)-(+)-mandelic acid (2.06 g, 0.0136 mmol) was added to dissolve it. The mixture was seeded with the product and allowed to dissolve in Stir for 16 hours at room temperature. The reaction mixture is cooled to 0 ° C and then expanded: stirred for 5 hours. The product is filtered and dried in an air oven, and then rushed with nitrogen at 50 ° C for 1 day to produce 5.65 g (40%). The title compound was determined by palm HPLC, using Chiralpak AS, and dissociated at a density of 95: 5: 0.05 hexane-ethanol-diethylamine at a flow rate of -1 ml / min; UV at 227 nm Detection. Retention time: (+)-enantiomer: 15.5 points (-)-enantiomer; 21.0 points.

Example 501H (! R, 3R, 4SW + V2- (4 · methoxyphenyl) -4- (1,3-benzobis-containing bi-5-yl group (N, N-dibutylaminomethyl) · ρ Biloxidan_3_Weic acid Example 501G compound (20_0 g, 0.0383 mol) was suspended in ethyl acetate (150 ¾ liter) and 5% sodium bicarbonate solution (150 ml). The mixture was stirred at room temperature until the salts dissolved And the carbon dioxide stops escaping. Organic layer -512- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) ------------ (Please read the precautions on the back first (Fill in this page again)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T. 581760 A7 _ B7 V. Description of the invention (51〇) Isolation and concentration. The residue was supplemented with acetonitrile (200 liters) to a final volume of 100 ml 'and cooled to 10. 〇. Diisopropylhexylamine (u.8 ml, 0.0574 mole) and the compound of Example A (10.5 g, 0.0421 mole) were added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and ethanol (200 ml) was added to a final volume of 100 ml. A sodium hydroxide solution (400/0, 20 liters, 0.200 moles) was added, and the mixture was heated at 60 ° C for 4 hours until HPLC showed that no starting material remained. The reaction mixture was poured into water (400 liters) and washed with hexane (2 x 50 ml). Wash the water layer with hexane (2 x 20 ml). The aqueous layer and ethyl acetate (400 ml) were stirred and the mixture was neutralized to pH 5 with concentrated HC1 (12 ml). The organic layer was separated and found to contain 183 g (94% yield) of the title compound. Example 5011 Methoxybenzyl V4-n, 3_benzodifluorene and its dibutylaminofluorenylmethyl) ^ Bilodoline_3-carboxylate_fluorene Example 501H compound in ethyl acetate, In a mechanically stirred tank with a thermocouple, add 39 4 ml of 1 N HC1 to ethanol (0.0394 mol) at room temperature. The resulting solution was filtered to remove foreign materials, concentrated under vacuum, and then ethyl acetate (400 ml) was added. The mixed solution was repeatedly seeded (when the solvent was removed) until crystallization started. The mixture was concentrated to 100 liters and the product was filtered and washed with ethyl acetate (25 mL). The resulting white solid was dried in an air oven, and 176 g (90%) of the title compound was formed under a 50 t nitrogen stream. Example 502 —Formula, trans-pentyl) · 4- (1 · 3-Benzodizakiji-513- This paper is a good degree for Shicai Guanjia County (---- ---------. 9 ^ — (Please read the notes on the back before filling this page) Order printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Description of the invention (511) Dibutylamine carbonylmethyl) _pyrrolidine_3-miao _

Example 502A (± V3-methylhexanoic acid ethyl ester to 60% sodium hydride (2.26 g, 57% millimolar) in 100 ml of hexane and 100 ml of diethyl ether were added to the slurry. (103 milliliters, 52 millimoles). Once the gas has stopped escaping, add 2-pentamidine (6.0 milliliter '64 millimoles). After 3 hours at room temperature, the reaction is quenched with water and then Partitioned in ether. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in 50 ml of ethanol, and 10% Pd / C (6.0 g) was added. The vessel was pressurized to 4 atmospheres of hydrogen and shaken at room temperature for 3 hours. The reaction was filtered and the solvent was removed under reduced pressure to produce 3.0 g of the title compound.

Example 502B (±). Ethyl 5-methyl-3-ketocaprylate. To a solution of ethyl 3-methylhexanoate in 150 ml of ethanol was added sodium hydroxide (2.3 g, 57.6 mmol). 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 diethyl ether, acidified with concentrated hydrochloric acid, and washed with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and filtered, and the solvent was removed under reduced pressure to produce 2.7 g of an equivalent acid. 3.9 g of the title compound.

Example 502C trans'trans_2- (2-methylpentyl) -4 · Π, 3 · benzobifluorene-5-m- (N, N- butylaminocarbonylmethylpyrridine- 3-carboxylic acid-514- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) ---------------- Order ------ IP— ( Please read the precautions on the back before filling this page) 581760 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (512) Use the procedure of Example 1 and use 5 · methyl-3-ketocaprylic acid Instead of ethyl (4-methoxybenzyl) ethyl acetate, ethyl ester can produce the title compound, which is then freeze-dried and separated from dilute TFk / CHsCN aqueous solution. Note that multiple signals in the aryl region of the NMR spectrum reflect the alkyl chain 1: 1 mixture of diastereoisomeric diastereomers. 1HNMR (CDCl3, 300 MHz) d0 · 8l · 0 (m, 12H), l · 2 1.4 (m 7H), 1.45-1.6 (m, 6H), 1.61-1.74 (m, 1H), 1.8-2.0 (m, 1H), 3.1-3.4 (m, 5H), 3.67 · 3.78 (m, 1H), 3 · 8_3 · 91 (m, 1H), 4.0 -4.2 (m, 2H), 4 · 2 · 4 · 5 (m, 2H), 5.93 (d, J = 1.5 Hz, 2H), 6.73 (dd, J = 8.1, 1.2 Hz, 1H), 6.79 (ddd , J = 7.8, 1.8, 1.8 Hz, 1 H), 6.86 (dd, J = 3.9, 1.5 Hz, 1H) 〇 MS (DC1 / NH3) m / e 489

V (M + H) +. Analysis estimates C28H44N205 · 1.0 TFA · 0.5 H20: C, 58.91; H, 7.58; N, 4.58. Found 値: C, 58.91; H, 7.58; N, 4.45. Example 503 trans, trans_2- (2,2-dimethylpentylbenzodifluoren-5-yl) -1- (N, N-dibutylaminecarbonylmethyl V pyrrolidine 3-3- _

Xin J used the general procedure of Cahiez et al., Tetrahedron Lett., 3i 7425 (1990) to prepare ethyl 3,3-dimethylhexanoate. Using the procedure of Example 502 and substituting 3,3-dimethylhexanoic acid ethyl 3-methylhexanoate for the title compound, the title compound can be formed by cold drying from a dilute TFA / CH3CN aqueous solution. 1η NMR (CDC13, 300 MHz) β 0.80-0.99 (m, 15Η), 1.10-1.37 (m, 8Η), 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 (s, 2H), 6.74 (d , J = 7.8 Hz, 1H), 6.8 (dd, J = 8.1, 1.5 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H). MS (DC1 / -515- This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) ------------ (Please read the precautions on the back before filling this page)) Order 581760 A7 B7 V. Description of the invention (513) NH3) m / e 503 (M + H) +. Analysis estimates C29H46N205 · 1.05 TFA: C, 60.01; H, 7.62; N, 4.50. Measured fluorene: C, 60.21; H, 7.37; N, 4.33 0 Example 504 trans'trans-2 · (2_ (1,3-diazaki-2-yl) ethyl) _4- (1,3-benzene # 二 阴 基） -1 · (Ν, Ν_Dibutylamine alkynylmethyl) · ρbilodine_3_ complex acid

Example 504A 5- (1,3-Difluorenyl) ethyl 3-ketovalerate The title compound was synthesized from ethyl acetate and 2-bromomethyl according to the method of Hukin and Weiler, Tetrahedron Lett. 3927, (1971) Base-l, 3-Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of Nisaki (Please read the precautions on the back before filling this page) Sodium hydride 4_97g (0.124 mol), showing a dispersed phase of 60% mineral oil It weighed in a 250 ml flask, and 80 ml of tetrahydrofuran was directly added thereto. The flask was capped with a septum cap, flushed with nitrogen, and then cooled in an ice bath. 15.0 ml (0. 118 mol) ethyl acetate. Once the addition is complete, the resulting mixture is stirred for an additional 10 minutes at 0.0%. The above mixture is added with 48.4 ml (0.121 mol) of n-butyllithium, and 2.50 M is added to it. Drop solution 'was added dropwise. The resulting orange solution was stirred for 0 minutes, 13.5 ml (0.130 mol) of bromomethyl-] L, and 3 · dioxane were added again. The reaction mixture was then warmed to room Warm and stir for another 120 minutes, and then slowly add 9.8 ml (0.12 mol) Concentrated hydrochloric acid was quenched. The biphasic mixture was poured into 50¾ liters of water and extracted with 15 liters of diethyl ether. The aqueous layer was extracted with additional ether. The ether extracts were mixed and washed with 2 x 50 ml of saturated brine. Dry on anhydrous magnesium sulfate, filter and evaporate under reduced pressure -516- This paper size is applicable to Chinese National Standard (CNS) A4 specifications --- 581760 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 514) into a brown oily residue. The crude product was purified by flash chromatography on silica gel and dissolved in 20% ether / hexane to yield 5.40 g (20%) of 6-ketoester as a pale yellow oil.

Example 504C

Trans, trans_2_ (2_ (1.3_diazaki-2-yl) ethyl V4- (l, 3 · benzobisfluoren-5-yl V1- (N, N-dibutylaminecarbonylmethyl V) The pyrrolidine-3-carboxylic acid was used in the procedure of Example 502, but 5- (1,3-difluorenyl) _2_ketovalerate was used instead of ethyl 3-methylhexanoate to give the title compound 1H NMR (CDC13, 300 MHz) β 0.93 (t, J = 7 · 2 Ηζ, 3Η), 0.95 (t, J = 7.2 Ηζ, 3Η), 1.23 · 1 · 38 (m, 4Η), 1.53 (Six peaks, J = 7.9 Ηζ, 4Η), 1.85 · 1.95 (m, 2Η), 2.02-2.17 (m, 2Η), 3.18 (dd, J = 6.0 Ηζ, 9.0 Ηζ, 2H), 3.30 (dd, J = 9.0 Hz, 18.0 Hz, 2H), 3.35 (m, 1H), 3.79 (dd, J = 3.6 Hz, 6.9 Hz, 1H), 3.83-3.88 (m, 3H), 3.97 (dd, J = 4.8 Hz, 6.0 Hz, 1H), 4.05 (q, J = 9.6 Hz, 2H), 4.30-4.40 (m, 1H), 4.37 (s, 2H), 4.87 (t, J = 3.6 Hz, 1H), 5.94 (s, 2H), 6 73 (d, J = 8.1 Hz, 1H), 6.79 (dd, J = 1.8 Hz, 8.1 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H). MS (APCl) (M + H) + m / e 505. Analytical estimation C27H40N2O7 · 1.2 TFA: C, 55.05; H, 6.47; N, 4.37. Measured値 · C, 55.12; H , 6.44; N, 4.27 ° Example 505 trans'trans-2- (2- (2-tetrazol-2H-p-biran) ethyl) -4- (1,3_Table 5- ) _L_〇SLN-dibutylaminecarbonylmethyl) pyrrolidine-3-carboxylic acid ^

Example 505A 5- (2_tetrahydro-2H-leaf bran) -3 · ketovaleric acid ethyl ester-517- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) &quot; ^^- ---------- (Please read the notes on the back before filling out this page) Order printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Invention Description (515) Use of Hukin and Weiler, Tetrahedron Lett. 3927, (1971). The title compound can be prepared from ethyl acetate and 2- (bromomethyl) tetrahydro-2H-p biran as a pale yellow oil.

Example 505B trans'trans-2- (2- (2-tetrazine · 2Η · lippyran) ethyl) -4_ (1,3 -benzodiρ No. 5-yldibutylaminecarbonylmethyl V pyrrolidine-3-borrow_ Using the procedure of Example 502 and replacing ethyl 3-methylhexanoate with 5- (2 · tetrahydro-2Η-pyran) -2-ketovalerate, it can be generated The title compound is an amorphous solid. 1H NMR (CDC13, 300 MHz) is a mixture of two diastereoisomeric forms: β 0.89 (t, J = 8.1 Hz, 3H), 0.89 (t, J = 8.1 Hz, 3H), 0.91 (t, J = 8.1Hz, 3H), 0.91 (t, J = 8.1Hz, 3H), 1.20 · 1.40 (m, 10H), 1.42-1.66 (m, 18H), 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 · 81 (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 (s, 1H) 〇MS (APCl) m / e 517 (M + H) +. Analyzed and estimated c29H44N206 · 1.4 TFA: C, 56 · 48; Η, 6.77; N, 4.14. Measured 値: c, 56.46; H, 6.99; N, 3.83. Example 506 Formula, trans-2 (2,2,4_trimethyl · 3 · pentyl) _4 彳 1,3-benzodi slogan_5_ group) -1- (N, N · dibutylamino Talking about methyl methyl acetic acid

Example 506A 3,3,5_trimethyl-4-hexenoic acid methyl ester-518- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) &quot; --- Order (please read the back first Note for refilling this page) 581760 A 7 __ B7 V. Description of the invention (516) p-Isopropyltriphenylscale (20_5g, 47mmol) Add n-butyl to 200ml of tetrahydrofuran slurry Lithium (27 ml of a 1.6 M solution in hexane, 43 mmol), and the solution was quickly warmed to 0 ° C. After recooling, 3,3 · dimethyl-4-ketobutenoic acid methyl ester (5.7 g '40¾ mol) in 10 ml of tetrahydrofuran (according to Hudlicky et al., Synth · Commun., 16_ 109 (I986)), and the reaction was warmed to 0 ° C for 30 minutes. The reaction was quenched with dilute hydrochloric acid and partitioned with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel and dissolved in 100/0 ethyl acetate in hexane to give 2.1 g (30%) of the title compound.

Example 506B 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 · (2,2,4-trimethyl · 3-pentenylbenzyl Benzodifluorenyl-5-yl) -1 · (N, N-dibutylaminecarbonylmethylpyrrolidine-3 · # acid uses the procedure of Example 502 and uses 3,3,5-trimethyl_4_ Methyl hexenoate replaces ethyl 3-methylhexenoate to generate the title compound, which is then freeze-dried and separated from a dilute TFA / CH3CN aqueous solution. 1η NMR (CDC13, 300 MHz "0 · 92 (t, wind 2 Hz , 3H), 0.94 (t, J = 7_2 Hz, 3H), 1.11 (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), 2.0-2.11 (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 (s, 1H), 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 (DC1 / NH3) m / e 515 (M + H) +. Analyze C30H46N2O5 · 1.05 TFA: C, 60.77; H, 7.48; • 519- this paper Degree applies to Chinese National Standard (CNS) A4 specification (210X297 mm) &quot; 581760 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (517) N, 4.42 〇 Actual measurement: C, 60.83; Η ， 7 · 20; N ， 4.43 ° Example 507 trans, trans_2- (2,2-dimethyl-2- (1,3-two-mouthed fe-2 -yl) Yimou (1,3 _Benzodihen-5-yl) _WN, N · Dibutylaminecarbonylmethyl

Example 507A 3 · 3-Dimethyl-3 · (1,3-dioxane-2-yl) propan 3,3-dimethyl-4-ketobutyric acid methyl ester (10 g, 70 mmol) Ear), prepared according to the method of Hudlicky et al., Synth. Commun., 16 169 (1986), dissolved in 40 ml of benzene, and then added ethylene glycol (20 liters) and para-toluenesulfonic acid-hydrate (1.3 g). The reaction was azeotropically removed under reflux for i hours. The reaction was poured into 200 ml of diethyl ether, washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give 12.4 g (94%) of the title compound.

Example 507B trans, -2- (2,2-- ψ Zj (1,3-benzodi ^ 7-deleted-5-yl) -1-(] ^,] ^-dibutylaminomethyl) -The procedure of using 502 for each carboxylic acid 3-carboxylic acid, and replacing methyl 3-methyl with 3,3-dimethyl · 3 · (ι, 3_diyin-2-yl) propionate Ethyl hexanoate, which yields the title compound, which is then freeze-dried from a dilute TFA / CH3CN aqueous solution. 4 NMR (CDC13, 300 MHz) d 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, 1H), 3.15-3.47 (m, 6H), 3.60- 3.70 (m, 3H), 3.74_3.95 (m, 5H), 4.48 (s, 1H), 5.94 (m, 2H), 6.72 (d, J = 8.0 Hz, 1H), 6.83 (dd, J = 8.0, 1.2 Hz, 1H), 6.94 (d, J = 1.2 Hz, 1H). MS (DC1 / NH3) m / e 533 -520- This paper size applies to China National Standard (CNS) A4 (210X297) (%) ---------- 0 ^-(Please read the notes on the back before filling this page) Order 581760 A7 B7___ V. Description of the invention (518) (M + H), analysis estimate C29H44N207 · 1.1 TFA 0.2 H2O: C, 56.63; Η, 6.93; Ν, 4.23. Measured 値: C, 56 · 60; Η, 6.96; Ν , 4.25. Example 508 trans, trans-2 · (2 · (1,3_diamidino-2-yl) ethyl V4-H-3-benzobisfluorene_5_yl) -1 • [丨 N-4-heptyl-N- (2-methyl-3-fluorophenylamine mesycarbonylmethyl 1 pyrrolidine-3-carboxylic acid example 508A 4-heptanol on 1.14 g (10.0 mmol) 4 · Heptanone was added to 20 ml of diethyl ether in an ice-cold solution, and 370 mg (10.0 mmol) of LiAlH4 was added in portions to keep the ether at a minimum reflux. After 45 minutes, 0.4 ml of H20 was added dropwise in order. 15 ml (w / v) NaOH (aqueous solution) and 1.2 ml of H20 were quenched. After stirring for another 45 minutes, MgS04 was added until the salt was free to flow, and the reaction was filtered. The salt was diethyl ether (3 X 5 ml) After washing, the filtrate and washings were concentrated to a colorless oil. The yield was 1.16 g (100%).

Example 508B 4-Methanesulfonyloxyheptane 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). To 5 ml of an ice-cold solution of CH2C12 was added 1.5 ml of triethylamine. Next, 0.7 ml (9 mmol) of methanesulfonium chloride was 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), 1 M HC1 (2 X 15 ml) and brine (1 X 15 ml). , Dried on MgS04, filtered and concentrated to an oil. Yield 1.31 g (94%). NMR (300 MHz, CDC13) d 0.96 (t, 6, J = 9), 1.43 (m, 4H), -521-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) ) 581760 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of Invention (519) 1.64 (m, 4), 3.00 (s, 3), 4.73 (Wufeng, 1 J = 5). Example 508C 4-argon-3-methylaniline To a solution of 20 g (129 mmol) of 2-fluoro-5-nitrotoluene in 400 ml of ethanol was added 2 g of 10% Pd / C. The mixture was shaken at 45 psi, H2 until hydrogen absorption ceased. The catalyst was filtered off and washed with ethanol, and the combined filtrate and washings were concentrated to 15.2 g (94%) of a colorless oil.

Example 508D A solution of 4.10 g (3.28 mmol) of 4-fluoro-3-methylaniline in 30 ml of acetonitrile was added to N-heptyl-4-gas-3 -methylaniline. 7.64 g (3.93 mmol) (Ear) 4-methanesulfonyloxyheptane and 3.4 g (4.1 mmol) NaHC03 (s). The mixture was stirred under reflux for 24 hours, poured into 150 ml of H20 and extracted with diethyl ether (2 x 30 ml). The combined ether layers were re-extracted with brine (1 X 30 mL), dried over MgS04 ', filtered and concentrated to an oil. This was purified by silica gel chromatography, and was separated with 97.5: 2.5 hexane · ethyl acetate, and 2.56 g (3 5%) of light yellow oil was produced.

Example 508E Heptyl)-(4-Ga-3-methyl) phenylthiazolamine 4.88 g (21.9 mmol) 1 ^-(4-heptyl) _4-fluoro-3_methylaniline and To an ice-cold solution of 4.9 ml (61 mmol) of pyridine in 100 ml of toluene was added a solution of 4.90 ml (56.2 mmol) of bromoacetamidine in 7 ml of toluene. The solution was stirred for 24 hours, warmed dropwise to 25 ° C, and extracted with 1 M HC1 (1 X 100 ml). The water layer was re-extracted with diethyl ether (丨 X 50 ml), the mixed organic layer was washed with Ηβ (2 X 50 ml), and then saturated with NaHC03 (water-soluble 々 ___ -522-). (CNS) 8 specifications (21 × 297 mm) — — — ϋ · — · 111 ^ — &gt; —1 ttMMm 111 «ϋ · ϋ ii ·· -— iMmmMmmmm I a ^ i— (Please read the back first Note for refilling this page) Order -m ϋϋ · 581760 A7 B7 V. Description of the invention (520) (2 X 50 ml) and brine (1 X 50 ml) Wash, dry on MgS04, filter, and empty Concentrated into an oil. This was purified by silica gel chromatography and dissolved in 90:10 hexane: ethyl acetate to yield 7.48 g (99%) of a light yellow oil. Ι NMR (300 MHz, CDC13) d 0.94 (t, 6, J = 5), 1.33 (m, 4), 1.43 (m, 4), 2.30 (s, 1.5), 2.31 (s, 1.5), 3.54 (s, 2), 4.72 (Five Peaks, 1, j = 5 ), 6.96-7.04 (m, 2), 7.07 (d, 1, J = 7).

Example 508F trans, trans-2- (2_ (1.3-bisaki-2-yl) ethyl) -4- (1,3-benzodifluoren-5-yl) -1- 丨 N-4 -Heptyl-N-Γ2-methyl-3-fluorophenylaminocarbonylmethyl 1 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 completing this Page) Using the procedure of Example 502, 5- (1,3-Difluorenyl) -2-ketovaleric acid ethyl ester was used instead of 3-methylhexanoic acid ethyl ester, and N, N- (4-heptyl ) (4_fluoro-3-methyl) phenyl-bromoacetamide replaces N, N-dibutylbromoacetamide to form the title compound as an amorphous solid. 1H NMR (CDC13, 300 MHz) d 0.93 (brt, 6H), 1.23-1.47 (m, 8H), 1.67-2.10 (m, 4H), 2.32 (s, 3H), 3.16 (t, J = 9.0 Hz, 1H), 3.52-3.67 (brm, 2H), 3.73 (t, J = 9.0 Hz, 1H), 3.81-4.02 (m, 6H), 4.13 (brm, 1H), 4.72 (five peaks, J = 6.9 Hz , 1H), 4.86 (t, J = 4.0 Hz, 1H), 5.93 (s, 2H), 6.72 (d, J = 8.1 Hz, 1H), 6.78 (dd, J = 1.8 Hz, 8.1 Hz , 1H), 6.85 (d, J = 1.8 Hz, 1H), 6.96 (m, 2H), 7.08 (t, J = 9.0 H, 1H). MS (DC1 / NH3) m / e 599 (M + H) +. Analysis estimates C33H43N207F · 0.8 TFA: C, 60.24; H, 6.40; N, 4.06. Found 値: C, 60.21; H, 6.14; N, 3.86. Example 509 trans, trans-di-2-yl) ethylbenzodifluorene-5- -523- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (521) yl) _1_ (N, N-dibutylaminecarbonylmethyl) -pyrrolidine-3-boron. Using the procedure in Example 502, 5- (1,3 · difluorenyl) _2-ketovaleric acid was used. The replacement of ethyl 3-methylhexanoate with ethyl ester and the replacement of piperonal with 6-methoxypiperonal gave the title compound as an amorphous solid. 1H NMR (CDC13, 300 MHz) d 0.93 (t, J = 7.8 Hz, 3H), 0.95 (t, J = 7.8 Hz, 3H), 1.31 (m, 4H), 1.53 ( m, 4H), 1.90 (m, 2H), 2.09 (m, 2H), 3.19 (dd, J = 8.4 Hz, 2H), 3.30 (q, J = 9.6 Hz, 2H), 3.25-3.42 (m , 1H), 3.73 (q, J = 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), 4.03 (dd , J = 3.0 Hz, 6.3 Hz, 2H), 4.33 (m, 3H), 4.87 (t, J = 3.6 Hz, 1H), 5.94 (s, 2H), 6.53 (d, J = 1.8 Hz, 1H ), 6.63 (d, J = 1.8 Hz, 1H). MS (DC1 / NH3) m / e 535 (M + H) +. Analysis estimates C28H42N208 · 1.05 TFA: C, 55.25; H, 6.63; N, 4.28. Found 値: C, 55.39; H, 6.66; N, 4.26. Example 510

Expansion type 'trans-2-((2-methoxyphenoxy) -methyl) -4- (1,3-benzodiainyl V1_ (N, N_dibutylaminecarbonylmethyl)- The pyrrolidine-3_carboxylic acid can be prepared as an amorphous solid by using the procedure of Example 502 and substituting ortho-methoxyphenoxyacetic acid for 3_methylhexanoic acid. 1H NMR Printed by the Consumers' Cooperative of the Central Standards Bureau, Ministry of Economic Affairs (Please read the precautions on the back before filling this page) (CDC13, 300 MHz) d 0.85 (t, J = 7Hz, 3Η), 0 · 90 (t, J = 7Hz, 3Η), 1.15-1.35 (m , 4H), 1.40-1.55 (m, 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 = 14Hz, 1H), 4.05-4.15 (m, 1H), 4.23-4.33 (m, 1H), 5.91 (s, 2H), 6.70 (d, J = 8Hz, 1H), 6.82-6.95 (m, 5H), 7.03 (s, 1H). MS (DC1 / NH3) m / e 541 (M + H) +. Analytical estimate -524- This paper standard applies to the Chinese National Standard (CNS ) A4 specification (2! 0 乂 297 mm) 581760 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (S22) C30H40N2O7: c, 66.65; H, 7.46; N, 5.18. Measured : C, 66.37; H, 7.61; N, 5.09. Example 511 (lg, 3R, 4S) _2 "2-2_Dimethyl fluorenyl) -4- (13-benzodifluorene (iidA group-N- (4-fluoro-3-methylbenzyl W aminocarbonylmethyl) pyrrolidine_3-carboxylic acid

Example 511A Well-formed, trans-N_third-butanecarbonylcarbonyl-2- (2,2-dimethylpentamyl V4- [1,3-benzodiazine_5_yl) _Ehadian- 3-Lean acid prepared according to Example 503 trans, trans_2- (2,2-dimethylpentyl) -4- (1,3-benzodifluoren-5-yl) -pyrrolidine_3 -Ethyl carboxylate (2.5 g, 6.9 mmol) was dissolved in 50 ml of dichloromethane, and di-tert-butyl dicarbonate (L5 g) was added. After stirring at room temperature overnight, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel at 100 /. Ethyl acetate / hexane dissociation yielded the title compound (2.8 g) as a colorless oil. The ester was dissolved in 50 ml of ethanol and sodium hydroxide (10 ml of a 5 M aqueous solution) was added. After stirring at room temperature for 20 hours, the solvent was removed under reduced pressure, and the residue was dissolved in 150 ml of water and acidified with concentrated phosphoric acid. The mixture was extracted with aerosol (3 X 50 ml), and the organic layer was washed with brine 'and dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give the title compound (2.4 g) as a white foam.

Example 511B poop-form, trans-2- (2,2-dimethylpentyl) _4-Π · 3-benzodihex-5-methylpyridin 1- (N-4-heptyl-N- (4 -Fluoro-3 · methylphenyl)) aminocarbonylmethyl) pyrrolidinecarboxylic acid methyl ester: as a single enantiomer -525- This paper is in accordance with China National Standard (CNS) A4 specification (21〇 &gt; &lt; 297 mm) ---------- clothing — (please read the precautions on the back before filling this page),? Τ 581760 A7 B7 V. Description of the invention (523) — Example 370A product (1.97 g , 4.5¾ mol) dissolved in 20 ml thf, (please read the precautions on the back before filling this page) and cool to (TC, then add DMF (0.017 ml, 5%) and monochloro chloride (〇 · 437 ml, 5.00 mmol). After hours, the solvent was removed under οχ and under a stream of nitrogen. The residue was dissolved in 5 ml of benzene and evaporated. In another flask, (S) -4- 芊Benzyl-2-, Junydone (12 g, 8 mmol) was dissolved in 30 ml of THF, and then added at 0. (: n-butyllithium (40 ml of 1.6 M in hexane was added below). Solution), and the slurry was stirred for 15 minutes. The methyl chloride was dissolved in 20 ml of THF and cooled to 0. (:, then The oxazolidine lithium suspension was added dropwise via a catheter. After 30 minutes, the reaction was partitioned between ether and saturated bicarbonate. The organic phase was washed with water and then brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed. Remove under reduced pressure. The residue is purified by flash chromatography on silica gel and dissolved in 15% ethyl acetate / hexane to form the undesired diastereoisomeric compound (1.17 g, 43%), and then 20%. Ethyl acetate / hexane dissociation produces the desired diastereoisomeric form (104 g, 38%). The desired diastereoisomeric form of N-fluorenazolidone (0 84 g) (1.42 moles) was dissolved in 2.5 ml of dichloromethane, and 2.5 ml of trifluoroacetic acid was added. After 30 minutes, the volatile matter was removed under a nitrogen stream, and the residue was dissolved in 5 ml of toluene and under reduced pressure. Evaporated a total of 2 times. The TFA salt printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs was mixed with 4 ml of acetonitrile, followed by diisopropylethylamine (10 ml '5.7¾ mole) and ν · 4_heptyl-N. -(4-fluoro-3 -methylphenyl) azetidine (589 mg '17 mmol), as a solution in 2 ml of acetonitrile. 2 1 小After that, the reaction was warmed to 50 ° C for 3 to 5 hours. The reaction was cooled, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel, which can be formed by dissociation with 20-30% ethyl acetate / hexane. 939 grams of ammonium, colorless oil. ____ -526- The paper size is suitable for Guancai County (CNS) A4 specification (21Gx297 public director) 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5. Description of the invention (524 ) The above amidine (200 ¾ g, 0.26 mole) was dissolved in 20 ml of THF and 0.7 ml of water. Lithium hydroxide · hydrate solid (22 mg, 0.53 mmol) was added at 0 ° F, and 30% hydrogen peroxide (500 ml, 55 mmol) was added. After 1 hour, the reaction was warmed to room temperature. After another 1 hour, the reaction was partitioned between 1 ·· 1 ethyl acetate ·· hexane and water, 0.5 g of sodium thiosulfate was added, and the mixture was mixed well. 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 residue was dissolved in 2 ml of ether, and 1 ml of methanol was added. A solution of (trimethylsilyl) azomethane in hexane was added dropwise until a yellow color remained. The reaction was quenched 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 and eluted with 15-20% ethyl acetate / hexane to give 70 mg of the title compound as a crystalline solid (mp 137.5 ° C).

Example 511C (2S, 3R, 4S) _trans, trans-2- (2.2-dimethylpentyl) · 4_Π, 3 · benzodiazine-5-yl) _1 · (N · 4 · heptyl · N "4 · Fluoro-3 · methylphenyl)) Aminocarbonylmethylpyridine-3_carboxylic acid ester Example 5 1 0B product (65 mg, 10.10 mmol) was dissolved in 1.0 ml of methanol and then added with hydroxide Sodium (0.1 ml of a 5 M 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 and acidified with concentrated phosphoric acid. The aqueous solution was chloroform Washed (3 X 5 ml), then brine, and dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The title compound was isolated from dilute TFA / CH3CN aqueous solution by freeze drying. 1H NMR (CDC13, 300 MHz) d 0.78-0.95 (m, 15H), 1.04 · 1 · 46 (m, 12H), 1.76-2.95 (m, 2H), 2.31 (s5 3H), 527- This paper size applies to Chinese national standards (CNS ) A4 size (210 X 297mm t) 1_1 'an— ϋϋ ϋϋ 1 ^ 1- In mi ϋϋ — ^ ϋ is—— temme m —ϋ mi, ^^ J (Please read the notes on the back before filling this page ) 581760 A7 B7 V. Description of the invention (525 ) 3.23-3.33 (m, lH), 3.47_3.58 (m, lH), 3.6-3.7 (m, 2H), 3.80 · 3.95 (m, 2H), 4.05-4.15 (m, 1H), 4.73 (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 (DC1 / NH3) m / e 597 (M + H) +. Analyzed and estimated c35H49N2F05 · 0.05 H20 · 0.8TFA: C, 63.81; H, 7.30; N, 4.07. Found 値: C, 63.84; H, 7.18; N, 3.94. [A ] g = + 46 ° (c 2 · 7 g / L, CHC13). Example 512 trans, trans-2 · (2- (2-ketopyrrolidin-1 · yl) ethyl) _4 · (1 , 3-Benzodizaki-5-yl) -1- (N, N · dibutylaminomethyl) _? Ratio. Each yttrium_3_ metaboic acid example 512A 2-amino pybilodine- 1-ylpropionic acid versus 5.0 ml (40.5 mmol) of 2-ketopyrrolidin-1-ylpropionitrile in a 5 liter liter of dinar roasting solution was added to 8.1 ml of a 6.0 M aqueous solution of hydrochloric acid. The mixture was refluxed overnight at 110 ° C. The reaction mixture was allowed to cool to room temperature and extracted twice with dichloromethane. The extracts were mixed and washed twice with saturated brine, dried over anhydrous sulfuric acid steel, filtered and evaporated under reduced pressure to yield 1.60 g (25%) of the acid as a brown oil.

Example 512B 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) 5- (2-pyridyl p-bilodine-1-yl) -3-ethoxyethyl acetate The title compound was prepared from the above acid using the method of Bram and Vilkas, Bui. Chem. Soc. Fr., 945 (1964).

Example 512C trans, trans-2- (2- (2-ketopyrrolidin-1-yl) ethyl) · 4_α, 3-jasamidin-5-yl V1- (N, N_dibutyl Aminocarbonylmethyl V pyrrolidine-3- # 醢 -528- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) '— 581760 A7 B7 V. Description of the invention (526) Use example 5 Procedure, but replacing ethyl 3-methylhexanoate with ethyl 5- (2-ketopyrrolidin-1-yl) -3-ketovalerate yields the title compound as an amorphous solid. 4 NMR ( CDC13, 300 MHz) d 0.91 (t, J = 7.5 Hz, 3H), 0.94 (t, J = 7.5Hz, 3H), 1.23_1.38 (m, 4H), 1.44 · 1.60 (m, 4H), 2.05 (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), 3.66 (t, J = 6.9 Hz, 1H), 3.96 (m, 2H), 4.14 (m, 1H), 4.38 (brs, 2H), 5.93 (s , 2H), 6.74 (d, J = 8.1 Hz, 1H), 6.89 (dd, J = 1.8 Hz, 8.1 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H). MS (DC1 / NH3) (M + H) + m / e 516. Analytical estimate C28H41N306 · 1.4 TFA: C, 54.78; H, 6.33; N, 6.22. Measured 値: C, 54.69 H, 6.33; N, 6.14. Example 513 trans, trans_2 · α, 3-difluoren-2-yl) ethoxy V4- (7-methoxy-1,3-benzodifluorene_ 5-yl) -1 · (N · 4_heptyl-N- (4 · Ga-3_methylphenyl)) aminocarbonylmethylpyrrolidin-3-carboxylic acid (Please read the precautions on the back before filling this page) Use the procedure in Example 5 02, but replace ethyl 3-methylhexanoate with 5- (1,3_dihumyl) -2 · ketovalerate Acetic acid, replacing N, N · dibutylbromoacetamide with N-4-heptyl-N- (4-fluoro-3-methylphenyl) bromoacetamide, and 6-methoxypiperonal Instead of piperonal, the title compound is formed as an amorphous solid. 1H NMR (CDCl3, 300 MHz) d0.93 (brt, 6H), 1.23-1.47 (m, 8H), 1.67-2 · 10 (m, 4H), 2.32 (s, 3H), 3.16 (t, J = 9 Hz, 1H), 3 · 60 · 4 · 03 (m, 8H), 3.88 (s, 3H), 4.21 (brs, 1H), 4.72 (Five Peaks, J = 6.6 Hz, -529- This paper is for China National Standard (CNS) A4 specification (210 X 297 mm) 581760 A7 ____ B7 V. Description of the invention (527) 1H), 4.86 (t, J = 3.6 HZ, 1H), 5.93 (s, 2H), 6.49 (s , 1H), 6.61 (s, 1H), 6.96 (m, 2H), 7.08 (t, J = 9 Hz, 1H). MS (DC1 / NH3) (M + H) + m / e 629 ° Analytical estimation c34H45N208F · 1.0 TFA: C, 58.21; H, 6.24; N, 3.77. Found 値: C, 58 11; H, 6 u; N, 3 58. Example 514 hydrazone, trans-2- (2,2 dimethylmethylpentylmethoxy-u · benzodifluoren-5-ylbutylaminecarbonylmethylpyrrolidine-3_carboxylic acid utilization example 50 2 method, but replacing ethyl 3-methylhexanoate with ethyl 5-methyl-3-ketocaprylate, and replacing piperonal with 6-methoxypiperonal, yielding the title compound as an amorphous solid. 1H NMR (CDC13, 300 MHz) 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) d0.81 (s, 3H), 0.84 (s, 3H), 0 · 86 (t, J = 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 (m, 4H), 1.84-2.00 (m, 2H), 3.15 (dd, J = 6.9 Hz, 10.0 Hz, 2H), 3.30-3.42 (m, 3H), 3.72 (t, J = 10 · 5 Hz, 1H), 3.86 (t, J = 10.5 Hz, 1H), 3.88 (s, 3H), 4.02 (q, J = 10.0 Hz, 1H), 4.12 (d, J = 16.8 Hz, 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, 1H). MS (DC1 / NH3) (M + H) + m / e 533. Analytical estimate C3OH48N20 6 · 0.9 TFA: C, 60.12; H, 7.76; N, 4.41. Measured 値: C, 60.18; H, 7.62; N, 4.33. Example 515 trans form, trans form 2-(2, 2 • 2 Methylpentyl) -4 · (2 · 3 · Dibenzobenzofuran-5-yl) · 1 · (N, N · Dibutylaminecarbonylmethyl) -pyrrolidine-UfeU Using the procedure of Example 502, but Use 3,3-dimethylhexanoic acid ethyl ester instead of 3 _A-530 · This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) '' ~ Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 581760 A7 B7 V. Description of the invention (528) Ethylhexanoate, and 2,3-dihydrobenzofuran-5-aldehyde instead of piperonal, can produce the title compound, which is an amorphous solid, which is based on CH3CN / TFA / H2〇 freeze-dried. 4 NMR (300 MHz, CDC13) d 0.83 (s, 3H), 0.85 (s, 3H), 086 (t, J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H), 1.09-1.39 (m, 8H), 1.44-1.59 (m, 4H), 1.88 (dd, J = 15.0, 7.2 Hz, 1H), 2.00 (d, J = 15.0 Hz, 1H), 3.09 (m, 2H), 3.18 (t, J = 9.0 Hz, 2H), 3.27-3.38 (m, 3H), 3.65-3.95 (m, 2H), 4.05 (q, J = l 〇Hz, 1H), 4.18 (d, J = 16.8 Hz, 1H), 4.30-4.45 (m, 2H), 4.55 (t, J = 9.0 Hz, 2H), 6.70 (d, J = 8.4 Hz, 1H), 7.04 (dd, J = 8.4, 2.1 Hz, 1H), 7.23 (brs, 1H). MS (DC1 / NH3) m / e 501 (M + H) +. Analysis estimates C30H48N204 / 1.05 TFA: c, 62.14; H, 7.97; N, 4.51. Found 値: C, 62.19; H, 8.00; N, 4.43. Example 516 trans, trans-2- (2,2-dimethyl_2_ (L3_dioxane · 2 · yl) ethyl) · 4_ (1-methoxy-1,3-benzodi唠 · 5-yl V1- (N, N-dibutylaminecarbonylmethyl) · pyrrolidine-3-carboxylic acid The procedure of Example 502 was used, but 3,3-dimethyl-3_ (1,3_di Hexan-2-yl) methyl propionate replaces ethyl 3 methylhexanoate, and 6-methoxypiperonal replaces piperonal. The title compound is formed as an amorphous solid, frozen in CH3CN / TFA / H20 Dry. 1H NMR (CDC13, 300 ΜΗζ) β 0 · 93 (t, J = 7.2 Ηζ, 3Η), 0.94 (t, J = 7.2 Ηζ, 3Η), 0.95 (s, 3Η), 0.96 (s, 3Η), 1.31 (six peaks, J = 7.2 Ηζ, 4Η), 1.45 (m, 4Η), 1.93 (dd, J = 15.9, 6.0 Hz, 1Η), 2.13 (d, J = 15.9 Hz, 1Η), 3.20 (dd, -531-This paper size applies to Chinese National Standard (CNS) A4 specification (210x297 mm) ------ Order ------ (Please read the precautions on the back before filling in this page) 581760 A7 B7 V. Description of the invention (529) J = 7.7, 7.7Hz, lH), 3.26-3.40 (m, 3H), 3.60 (m, lH), 3.75-3.86 (m, 3H), 3.88 (s, 3H) , 3.93 · 4 · 01 (m, 3H), 4.00-4.11 (m, 1 H), 4.23 (d, J = 15.9 Hz, 1H), 4.37-4.48 (m, 2H), 4.49 (s, 1H), 5.94 (s, 2H), 6.51 (d, J = 2.1 Hz, 1H ), 6.64 (d, J = 2.1 Hz, 1H). MS (DC1 / NH3) m / e 563 (M + H) +. Analyzed and estimated c30H46N2O8 · 0.9 · TFA: C, 57.41; H, 7.11; N, 4.21. Measured 値: C, 57.35; H, 6.86; N, 4.05. Example 517 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) trans, trans- 2- (2- (2-Methoxyphenylmosakizaki-5-yl VI- (N, N-dibutylamine carbonylmethyl V pyrrolidine_3_carboxylic acid uses the procedure of Example 502, but -Methoxyphenylpropionic acid refers to 3-methylhexanoic acid, and the above compound is prepared as an amorphous solid. IH NMR (CDC13, 300 MHz) cy 0.85 (t, J = 7Hz, 3H), 0.91 ( t, J = 7Hz, 3H), 1.10 · 1.27 (m, 4H), 1.42-1.60 (m, 4H), 1.72-1.89 (m, 1H), 1.91-2.02 (m, 1H), 2.55-2.77 (m , 2H), 2.94 (t, J = 6Hz, 1H), 3.05-330 (m, 6H), 3.59-3.82 (m, 3H), 3.73 (d, J = 14Hz, 1H), 3.77 (s, 3H) , 5.91 (s, 2H), 6.70 (d, J = 8Hz, 1H), 6.78 · 6 · 88 (m, 3H), 6.92 (d, J = 2Hz, 1H), 7.08-7.19 (m, 2H). MS (DC1 / NH3) (M + H) + m / e 539. Analysis estimates C31H42N206: C, 69.12; H, 7.86; N, 5.20. Measured tritium: C, 68.89; H, 7.70; N, 4.99 ° Example 518 trans, trans_2 · (2 · (2-dimethyl-3 · (Ε) · pentamyl methyl chloride) Certain -1,3-benzobisfluoren-5-yl) _1- (N, N · dibutylaminecarbonylmethyl) pyrrolidine-3_ # 醢 -532- This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 581760 A7 B7_ V. Description of the invention (530) Example 518A 4-methyl-3-penten-2-ol p. 3-methyl-2_butenal (8.7 g, 103 mmol) Methyl bromide (38 ml of a 3.0 M solution in diethyl ether, 114 mol) was added dropwise to 100 ml of a tetrahydrofuran stirring solution at N2 and 0 ° C. The mixture was allowed to warm to room temperature, stirred at room temperature for 1 hour, and then quenched with 25 ml of saturated NH4C1. The resulting two-phase mixture was partitioned between diethyl ether and water. The organic layer was washed with brine and dried over anhydrous It was dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure to produce 8.4 g (81%) of alcohol as a colorless oil.

Example 518B 3,3-dimethyl-4-pentenoic acid trans-ethyl ester 4-methyl-3-penten-2-ol (7.4 g, 74 mmol), triethyl orthoacetate (13.6 Ml, 74 millimoles) and propionic acid (0.28 ml, 3.7 millimoles), heated at 150 ° C for 7 hours. The product was distilled under normal pressure (200-220 ° C) to give 5.0 g of crude ester as a colorless oil.

Example 518C 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-2 彳 2.2_dimethyl-3- (E) -pentenylmethyl gas A -1,3-benzobisfluorene-5-D-1-OSLN-dibutylaminecarbonylmethylpyrrolidine-3-carboxylic acid was used in the procedure of Example 502 to trans 3,3 · dimethyl- Ethyl 4-pentenoate replaces ethyl 3-methylhexanoate and 6-methoxypiperonal replaces piperonal. The title compound is formed as an amorphous solid, which is freeze-dried from a dilute TFA / CH3CN aqueous solution. 1H NMR (CDC13, 300 MHz) 6 0.92 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H), 0.97 (s, 3H), 0.99 (s, 3H), 1.31 (Six peaks, J = 7.2 Hz, 4H), 1.52 (Five peaks, J = 7.2 Hz, 4H), 1.58 (d, -533 · This paper size applies to China National Standard (CNS) A4 specifications (210X 297 mm) 581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (531) J = 5.4 Hz, 3H), 1.92 (dd, J = 15.0, 6.6 Hz, 1H), 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, 3H), 5.29 (d, J = 15.6 Hz, 1H), 5.38 (dd, J 2 15.6, 6 Hz, 1H), 5.94 (s, 2H), 6.50 (d, J = 1.8 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H). MS (DC1 / NH3) m / e 531 (M + H) +. Analysis estimates c30H46N2O6 · 0.95 TFA: C, 59.95; H, 7.41; N, 4.38. Measured fluorene: c, 60.00; H, 7.33; N, 4.35. Example 519 trans, trans-2- (3- (2-pyridyl) ethyl V4_q.3-benzodizaki-5 -Yl) -1_ (N, N-dibutylaminecarbonylmethylpyrrolidine-3-carboxylic acid example 519A 3-(2-^ Bisynyl) · propionic acid 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). In this solution, stir to Add potassium permanganate (1.8 g, 11.3 mol) in 30 minutes while maintaining the reaction temperature at 50 ° C. Once the addition is complete, the mixture is kept at 50 ° C until the color of the reaction mixture turns brown. So far, it is heated at 80 ° C for 1 hour to filter. The mash is evaporated to dryness to produce (quantitatively) the desired acid (1.14 g), which is suitable for the next step without further purification. To prepare pure acid, the residue After being obtained, it was boiled in ethanol (10 ml), and there was the presence of activated carbon (0.1 g) for 5 minutes. It was passed through and cooled to form crystalline 3- (2-p ratio of yl) -propionic acid (0.88 G, 78%). -534- This paper size applies to China Standard (CNS) A4 specification (210X297 mm) ------------ (Please read the precautions on the back before filling out this page) Order printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperatives 581760 A7 B7 5 Description of the invention (532)

Example 519B trans'-trans- (3- (2-p-pyridyl) ethyl) -4- (1,3-benzodi-$-5 · yl) -1_ (Hepta-butylaminecarbonylmethylpyrrole Pyridin-3-carboxylic acid can be freeze-dried from the dilute TFA / CH3CN aqueous solution in the step of Example 502 to form an amorphous solid. 1H NMR (CDC13, 300 MHz) 6 8.65 (d, J = 6.0 Hz, 1H), 8.06 (t, J = 6.91 Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.51 (t, 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, J = 20.1, 10.5 Hz, 1 H), 3.84 (t, J = 12.6 Hz, 1 H) , 3.62 (dd, J = 13.8, 9.6 Hz, 1H), 3.46-3.13 (m, 7H), 2.51 (width s, 2H), 1.60-1.43 (m, 4H), 1.37-1.22 (m, 4H), 0.91 (t, J = 8.4 Hz, 6H) 〇MS (DC1 / NH3) m / e 510 (M + H) +. Analyzed and estimated c29H39N305 · 1.75 TFA: C, 55.04; H, 5.79; N, 5.92. Measured 値: C, 55.08; H, 5.64; N, 5.81. Example 520 (2S, 3R, 4S) _2- (2_ (2-keto p-biloline_1-yl) ethyl) _4_ (i, 3 _Benzodiz-5-yl) -l_ (N, N_dibutylamine methyl) -p-bilodine-3-chinic acid

Example 520A (2S, 3R, 4S) -ethyl-2- (2- (2-keto-exo-?-Yodo-1-yl) ethyl 3-benzyl-ortho-depleted · 5 · yl) ρbilo -3-3_ End version-(S) -Almondate Example 5 Racemic amine ester (3.45 g, 8.98 mmol) in 10 liters of ethyl acetate to (S) _ (+ ) Mandelic acid treatment (0.75 g, 4.93 mol). Once a clear solution was formed, hexane was slowly dropped with stirring until the solution became slightly cloudy. The solution was allowed to stir overnight at room temperature. The crystals were collected according to the data and recrystallized twice from ethyl acetate / hexane to produce 800 mg-535. This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) (please read the back first) For the matters needing attention, please fill in this tribute) -5-ΤΪ i 581760 A7 B7 V. Pure salt of invention description (533) (17%).

Example 520B (2S, 3R, 4S). Ethyl-2_ (2_ (2-ketopyrrolidin-1-yl) ethyl) _4-Π.3_benzodifluoren-5-yl) -1- (N , N-dibutylamine carbonylmethyl V pyrrolidine-3- # acid ester pure almond salt in a stirred solution of CH3CN, and N, N-dibutyl bromoacetamide (84 g, 0.34 mmol) ) And diisopropylethylamine (98 μl, 0.56 mmol). The resulting mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica gel. Yields 140 mg (90% yield) of the title compound.

Example 520C Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (please read the precautions on the back before filling this page) (2S, 3R, 4S) _2- (2_ (2 · (ketopyrrolidin-1-yl)) Benzenedifluorene-5_yldibutylaminecarbonylmethylpyrrolidine_3_carboxylic acid. The title compound was prepared as an amorphous solid by the procedure of Example 502, and was freeze-dried with CH3CN / TFA / H20. 1H NMR (CDC13 , 300 MHz) d 0.91 (t, J = 7.5 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H), 1.23 · 1 · 38 (m, 4H), L44_1.60 (m, 4H), 2.05 (t, J = 6.9Hz, 2H), 2.12-2.15 (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), 3.66 (t, J = 6.9 Hz, 1H), 3.96 (m, 2H), 4.14 (m, 1H), 4.38 (brs, 2H), 5.93 (s, 2H), 6.74 ( d, J = 8.1 Hz, 1H), 6.89 (dd, J = 1.8 Hz, 8.1 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H) 0 MS (DC1 / NH3 ) (M + H) + m / e 516. Analyzed and estimated C28H42N306 · 0.85 TFA: C, 58.23; H, 6.89; N, 6 .86. Measured 値: C, 58.37; H, 6.90; -536- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 581760 A7 Ν, 6.84 Example 521 (2S, 3R, 4S) -2- (2- (2-ketoerlotin-1-yl) ethyl) _4_ (ι, 3_benzodifluoren-5-yl) _1_ (Ν · 4-heptyl_N_ ( 4 · Fluorine · 3 · Tolylamine, a carbonylmethyl group) _Pirodoline-3-sulfonic acid Using the method of Example 520, N, N_ (4-heptyl) _ (4_fluoro-3_methyl) Phenyl-bromoacetamide replaces N, N · dibutylbromoacetamide to form the title compound as an amorphous solid, which was freeze-dried with CH3CN / TFA / H20.! H NMR (CDC13? 300 MHz) δ 0.85-0.98 (m? 6Η)? 1.22-1.55 (m 8Η), 2.04 (five peaks, J = 7.9 Ηζ, 4Η), 2.32 (s, 3Η), 2.36 (t, J = 7.9 Hz, 2H) , 2.61 (m, 1H), 3.14 (m, 1H), 3.25-3.61 (m5 5H), 3.66_ 3.77 (m, 1H), 3.79 · 3 · 90 (m, 2H), 3.92-4.03 (m, 1H ), 4.69 (five peaks, J = 6.8 Hz, 1H), 5.95 (s, 2H), 6.71 (s, 2H), 6.78 (s, 1H) 6.93-7.13 (m, 3H). MS (DCI / NH3) m / e 610 (M + H) +. Analytical estimates 1.45 TFA: C, 57.18; H, 5.91; N, 5.42. Measured radon: C, 57.20; H, 5.62; N, 5.52. Example 522 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- (2- (1-p 比 Junki) ethyl) -4- (1,3-Benzodiphenyl p_5_yl) 1- (N, N-dibutylaminecarbonylmethyl) _pyrrolidine_3_carboxyt Example 522A 3_ (1_pyrazolyl V propionic acid- In a 10 ml round-bottomed flask equipped with a condenser tube and a stir bar, add pyrazole (0.50 g, 7.3 mmol), acrylic acid (0.50 ml, 7.3 mmol), and triethylamine (3 ml). Reaction The mixture was refluxed for 6 hours. Triethylamine-537- 581760 was removed and printed by A7 B7 in the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. After the description of the invention (535), the viscous oil was dried for 1 to 2 hours under high altitude, and it could be quantified. The desired acid (1.0 g) was formed and suitable for the next step without further purification.

522B trans, trans-2- (2- (1-p than benzyl) ethyl) -4- (1,3-benzodiazine-5_yl) -1- (N, N-dibutyl Aminocarbonylmethyl V pyrrolidine · 3-carboxylic acid was isolated from the dilute TFA / CH3CN aqueous solution using the procedure of Example 502 to isolate the title compound. 1HNMR (CDC13, 300 MHz) d 7.56 (d, J = 3.0 Hz, 1H ), 7.50 (d, J = 3 Hz, 1Η), 6.83-6.66 (m, 3H), 6.28 (t, J = 3 Hz, 1H), 5.91 (s, 2H), 4.55-3.98 ( m, 6H), 3.83 planes 3.72 (t, J = 10.5 Hz, 1H), 3.61-3.40 (t, J = 10.5 Hz, 1 H), 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 (DC1 / NH3) m / e 499 (M + H) +. Analyze C27H38N405 · 0 · 75 TFA: C, 58.60; H, 6.69; N, 9.59. Found 値: C, 58.53; H, 6.45; N, 9.67. Example 523 trans, trans-2- (4-methoxyphenyl) -4 · (1,3-benzodiazin-5-yl [丨 butyl is propyl) amino) carbonylmethylμpyrrolidine-3- # Acid Example 523Α Ν- Butyl-N- (3-hydroxypropyl) amine in 1.59 g (100 mmol) of 3-N- (n-butyl) aminopropionate in 150 ml of diethyl ether , 50 ml (0.35 mmol) · 1 M LiAlH4 in diethyl ether billion, kept at reflux for a minimum of 0 ° c. The mixture was dropped at 2.50 hours, and then 1.9 ml of η20, 1.9 ml of 15% w / v NaOH (aqueous solution), and 5.7 ml of Η20 were added dropwise in order to quench. Stir for 30 minutes -538- This paper size applies Chinese National Standard (CNS) Α4 specification (2! 〇 × 297mm) '----------- (Please read the precautions on the back before filling in this Page), 11 L # Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 _ B7 V. Description of the invention (536) After the salt was filtered and washed with diethyl ether, the filtrate was concentrated to U.3 g (86%) light yellow Oily.

Example 523B: Butylhydroxypropyl V chloroacetamide in 1.31 g (10.0 mol) of N-butyl, v- (3-hydroxypropyl) amine in 20 ml of ethyl acetate in an ice-cold solution Then, a solution of L71 g (10.0 mmol) of chloroacetic anhydride in 10 ml of ethyl acetate was added. The mixture was stirred and gradually warmed to room temperature over 18 hours. The reaction was extracted with H20 (1 X 50 ml), saturated NaHC03 (aqueous solution) (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 dissolved in 80:20 hexane: ethyl acetate to produce 723 mg (35%) of a light yellow oil.

Example 523C Basic formula, trans-2- (4-methoxyphenyl) -4- (1,3-benzodifluorene-5 · yl V: L-"(N-meryl-N_ (3-hydroxypropyl A) Amine) Carbonylmethylpyrrolidine-3_carboxylic acid uses the procedure of Example 1D, but replaces N-propylbromoacetamidine with N-butyl-N_ (3 · hydroxypropyl) -chloroacetamide Amine and DMSO as a latent solvent can generate the title compound, freeze-dried and separated with dilute TFA / CH3CN aqueous solution. 1Η NMR (CD3OD, 300 MHz) β0 · 78 · 0 · 95 (m, 3Η), 1.00-1.80 (m , 4H), 2.80-3.65 (m, 15H), 3.80 (d, J = 15 Hz, 2H), 5.93 (s, 2H), 6.72-7.05 (m, 5H), 7.33-7.40 (m, 2H). MS (DC1 / NH3) m / e 513 (M + H) +. Analyzed and estimated c28H36N207 · 1.6 H20: C, 62.12; H, 7.30; N, 5.17. Found 値: c, 62.04; H, 7.21; N , 4.88. -539-This paper size is applicable to China National Standard (CNS) A4 specification (210X 297mm) ----------- (Please read the precautions on the back before filling this page) Order 581760 A7 B7____ 5. Description of the invention (537) Example 524 trans' trans-2_ (4 · methylbenzyl) -4- (1,3-benzo one-bit loss _5_yl) -1_ 丨 propyl- N-Propanylamino) carbonyl Bihar acid l_p

Example 524A N-Boc-N-propylpropyl was dissolved in THF (15 ml) via amine ortho-allyl hydroxylamine hydrochloride hydrochloride (5.0 g). The solution was cooled to 0 ° C in an ice bath. Diisopropylethylamine (8 ml) and di-tert-butyl dicarbonate (10.0 g) were added. The mixture was stirred at 0X: for J hours, at which time the water bath was removed and the reaction was warmed to room temperature and stirred overnight. The THF was removed under vacuum, and the residue was taken up with EtO Ac (25 ml), and with water (lx 50 ml), saturated bicarbonate steel solution (3x50 ml), in phosphoric acid (3 x 50 ml) and brine (1 X 50 liters) wash. The organic layer was dried over sodium sulfate and evaporated to give a pale yellow oil (6.5 g), which was used without further purification.

Example 524B 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) N-Boc-N-propyl-0- 晞 propylation N_Boc-0 from the previous step Allyl hydroxylamine (6.5 g) was dissolved in anhydrous THF (25 ml), and the solution was cooled to 0 ° C in an ice bath. Sodium hydride (1.5 g, 60% dispersed phase in oil was added in portions over 5 minutes. The resulting mixture was stirred for 30 minutes (at 0 ° C). 1-iodopropane (38 ml) was added dropwise. Reaction Stir at 0C; let it stand for 1 hour 'and mix with sandalwood overnight at room temperature. Thf is removed under sacrifice, the residue is taken up in EtO Ac (50 ml), and then saturated with water (j χ 50 耄 L), saturated Sodium bicarbonate solution (3 x 50 ml), 1 N brick acid (3 x 50 ml) and brine (l x 50 ml). The organic layer was dried over sodium sulfate-540 _ This paper size applies to Chinese national standards ( CNS) M specifications (210x297 mm) ----— 581760 A7 ________B7 V. Description of the invention (538) Dry and re-evaporate to produce a light-colored oil. Purify by flash gel chromatography and dissolve in 5% EtOAc / hexane. The title compound was formed as a colorless oil (60 g).

Example 524C N-Boc_N-propyl-N-propoxyamine N-Boc-N-propyl_0-allylhydroxylamine (6.0 g) was dissolved in EtoAc (100 ml). Another 10% Pd / C (0.5 g) was added, the mixture was flushed with nitrogen and replaced with hydrogen balloon, and the mixture was stirred at room temperature for 6 hours. The catalyst was removed by filtration through a Celite disk to give a yellow oil, which was purified by flash chromatography with crushed gel, and was isolated with 5% EtOAc / hexane to give the title compound (5.8 g) as a colorless oil. Example 524D Propyl-N-propoxyamine N-Boc-N-propyl-N-propoxyamine (5.8 g) was dissolved in 4N HC1 / dioxane (10 ml), and then at room temperature Beat for 7 hours. The solvent was removed under emptiness. The residue was triturated with diethyl ether. The resulting yellow solid (21 g) was collected by filtration and washed with diethyl ether.

Example 524E Propylpropoxy bromide ^ Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs N-propyl-N-propoxyamine hydrochloride (0.30 g) was dissolved in acetonitrile and cooled to -20X :. Pyridine (0.2 mL) was added. Bromoethenyl bromide (0.15 g) was added dropwise over 5 minutes. Spring liquid was stirred at -20 C; dropped for 30 minutes. The cooling bath was removed and the solution was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, and the residue was taken up in EtOAc (50 ml), and washed with water (1 x 25 ml), 1N phosphoric acid (3 x 25 ml) and brine (1 x 25 ml). The organic layer is dried with sodium phosphate -541-This paper size applies Chinese National Standard (CNS) A4 (210 X297 mm) 581760 A7 B7 V. Description of the invention (540) Printed and sealed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs . The resulting solution brought it to 50. (: Heated in an oil bath for 18 hours. Unreacted reagents were evaporated to remove the title compound. Example 525B I-butyl-N · (2-azidoethylchloroacetamidine to 500 mg N · butyl In N-2-hydroxyethylamine, 2 liters of thiosulfinyl chloride was added dropwise. After the initial reaction was stopped, the reaction was stirred for 10 minutes and then concentrated to an oil. Diethyl ether was added and evaporated to help sulfinous sulfonium Dichloromethane was removed. The residue was absorbed 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, and then poured into 50 ml of 0.6M NaHC03 (aqueous solution> ; And extracted with diethyl ether (3 X 15 ml). The mixed ether layer was extracted with brine (1 X 15 ml), dried over MgS04, and filtered. 850 ¾ g (4.97¾) was added to the ether solution. Mol) chloroacetic acid. The reaction was allowed to take for 10 minutes, and then concentrated to an oil. This was absorbed in 10 ml of saturated NaHC03 (transfer), and extracted with diethyl ether (3 x 5 ml). The mixed ether layer was then brine Extraction (5 x liters), dried over MgSO4, filtered and concentrated to an oil. Purified by silica gel chromatography with 30% ethyl acetate: hexane Dissolves to give 161 mg (17%) of oil. Example 525C _trans'trans_2- (4-methoxyphenylbenzylindion. 5-ylbutyl-N- (2-aminoethyl) amine (Methylidene) methyl Biloxidine According to the procedure of Example 523C, N-butyl_N · (2-azidoethyl) -chloroacetamide and 2- (4-methoxybenzene Ethyl) -4- (1,3-benzodifluorenyl-5-yl) _pyrrolidin_3_carboxylic acid ethyl acetate coupling. The crude product was chromatographed on a crushed gel and dissolved with 40% EtOAc / hexane. Product Soluble in ethanol and 2 · 5 N sodium hydroxide aqueous solution, and 543- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) I-(Please read the precautions on the back before filling this page }

I order 丨 钃

I. 581760 A7 B7 V. Description of the invention (54. Stir at room temperature for 3 hours. Concentrate the solution and add water. The mixture is extracted with ether; the aqueous layer is acidified to pH 4 with IN H3P04 and extracted with EtOAc. The organic extract was washed with brine and dried over Na 2 SO 4. To 100 mg (0.10 mmol) of azide was added 1 ml of 1M HC1 (aqueous solution). 0.5 ml of dioxane and 5 mg of 10% Pd / C. The suspension was stirred for 5 hours under 1 atmosphere h2 pressure, and then filtered and concentrated to a white solid. The product was purified by hplc and dissolved in a gradient of 0-70 CHgCN in a 0.1% TFA aqueous solution to form the title compound 'as its TFA salt Form: 1H NMR (CDC13, 300 MHz) ί 0.92 (t, J = 7.0 Hz, 3H), 0.96 (t, geometric isomer), 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, 2H), 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 (DC1 / NH3) m / e 498 (M + H). Analyzed and estimated C27H35N3〇6 · 3.15 TFA: C, 46.68; H, 4.49; N, 4.90. Found 値: C, 46.61; H, 4.73; N, 4.79. Example 526 trans, trans_2 · (4 · methoxyphenyl) · 4 · (1 · 3_stupid and two 55_based Vl-ΓΓΝ- 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) Gongye-N_ (3-aminopropyl ) Amino) Carboxymethyl ιρρο 洛 ΙοΙ · 3_ 醴 醴 To the compound of Example 523C (100 mg, 019 mmol) in 1 ml of dichloromethane in ice-cold solution was added 17 ml of methanesulfonyl chloride and 3 9 liters of triethylamine. The mixture was stirred for 20 minutes, then diluted with 1.5 ml of dichloromethane and extracted once with 5 ml. To this was added i drop of 85% Η3ρ〇4, followed by 5 0 / 〇 ammonium hydroxide ( lx 2.5ml) and brine (1x25ml), dried on MgSCU, filtered, and concentrated to an oil. At 8 丨 mg (〇13mmol-544-) This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) ---- printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 581760 A7 ------------- B7 V. Description of the invention (542) Ear) Mesylate on 1 Ml DMFi Was added 65 mg (1〇 mmol) of sodium azide. The mixture was stirred at 5 (rc for 1 hour, then poured into 10 liters of water and extracted with diethyl ether (3 x 5 liters). The mixed ether layer was extracted with brine (1 X 5 Φ liter) and dried over MgS04. , Filtered, and concentrated to an oil. This was purified by silica gel chromatography and separated with 60:40 hexane: ethyl acetate to produce 57¾ g of a colorless oil. The product was dissolved in ethanol and 2N aqueous sodium hydroxide solution, and the mixture Stir at room temperature for 3 hours. Concentrate under reduced pressure and add water. The mixture is extracted with ether; the aqueous layer is acidified to pH 4 with 1NH3po4 and extracted with EtOAc. The organic extract is washed with brine and dried over Na2SO4. To this azide, 1 ml of 1M Ηα (aqueous solution), 0.05 ml of dioxane 'and 5¾ g of i0% Pd / C were added. The suspension was stirred at 1 atm% for 5 hours, then passed through and concentrated It became a white solid. The product was purified by Hplc, and was separated by a gradient of 0-70% CHsCN / Ol% TFA aqueous solution to produce the title compound as its TFA salt form. 1H NMR (D6-DMSO, 300 MHz) d 0 · 85 ( Obviously, q, J = 6.8 Hz, 3H), 1.17 (m, 2H), 1.30 (m, 2H), 1.67 (m, 2H), 2.71 (m, 2 H), 3.04 (m, 1H), 3.21 (m, 3H), 3.45 (m, 1H), 3.75 (m, 3H), 3.97 (s, 3H), 3.85-4.80 (width m, 3H), 6.03 (m, 2H), 6.87 (dd, J = 1.4, 8.1 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 7.01 (m, 2H), 7.16 (m, 1H) , 7.55 (m, 2H), 7.72 (m, 2H), 7.85 (m, 1H); MS (DC1 / NH3) (M + H) + m / e 512. Analysis estimates C28H37N406 · 3.0 TFA: C, 47.84; H, 4.72; N, 4.92. Found 値: C, 47 · 86; H, 4.75; N, 4.97 ° Example 527 trans, trans-2_ (4-methoxyphenyl) -4- (1,3-benzodifluorene_5-yl) _1- 丨 〇 ^ _ -545- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm ----- ---- · Installation-(Please read the notes on the back before filling this page) Order_ Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Description of the invention (543) Butyl-N- (3 -Dimethylaminopropyl) amino) Talkylmethyl〗 _p 比 略 Lake_3_ margin acid

Example 527A N-Butyl-N- (3-bromopropyl) brimide was added to 1.5 g (II · 4 mmol) of N-butyl_N_ (3-hydroxy)) propylamine to 3 Ml of 48% HBr (aqueous solution) and 1.5 ml of concentrated HJO4. The reaction was refluxed and stirred for 3 hours, then cooled to room temperature and stirred for 2 2 hours. The mixture was poured into 50 liters of ice, and the bath solution was added with 50 liters. Treated with 2M NaOH (aqueous solution). The test solution was extracted with ethyl acetate (3 x 25 ml), and the combined ethyl acetate layers were extracted with brine (1 x 25 ml), dried, and filtered. In an ice-cold solution of ethyl acetate Add 3 ml of triethylamine, and then add 1.5 ml of bromoacetamidine as a solution in 35 ml of ethyl acetate. The reaction was stirred at 0 ° C for 30 minutes, and then 1M HC1 (aqueous solution) (2 X 25 ml) 'Saturated NaHC03 (aqueous) (1 x 25 mL) and brine (1 x 25 mL) were extracted. The organic layer was dried over MgS04, filtered and concentrated to an oil. This was purified by silica gel chromatography with 30% ethyl acetate. Vinegar is dissolved in hexane, which can produce 1.47 g of colorless oil.

Example 527B trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzobisfluoren-5-ylbutyl-N_ (3-bromopropyl) amino) carbonyl 1-pyrrolidine-3 · carboxylic acid ethyl ester according to the procedure of Example 523C, N-butyl-N- (3-bromopropyl-bromoacetamide and 2- (4 · methoxyphenyl) -4_ (1, 3-Benzodi-p--5-yl) -p-bilodine-3-leic acid ethyl ester coupling. The crude product was chromatographed on crushed gel and dissolved in hexane at 40% EtOAc.

Example 527C trans'trans-2- (4-methoxybenzyl) -4- (1,3-benzodiazin-5-ylbutyl-N- (3-dimethylaminopropyl) amino ） Carbonylmethylpyrrolidine_3_ Ji acid -546- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) Note for this page, please fill in this page),?! 581760 A7

To 400 mg (0.663 mmol) of the compound of Example 5 2 7 B in 4 ml of absolute EtOH 'was added 1.2 ml of 2.0 M Me2NH in THF. The reaction was heated at 50 ° C for 3 hours and stirred at room temperature for 18 hours. The mixture was concentrated and re-concentrated from CHgCN to remove most of the trimethylamine. The product was purified by silica gel chromatography and dissolved in about 20 ml of silica gel with 9: 1 CHAh: MeOH to produce ethyl acetate. The product was dissolved in ethanol and a 2.5 N sodium hydroxide solution and stirred at room temperature for 3 hours. The solution was concentrated under reduced pressure and water was added. The mixture was extracted with ethyl acetate, the aqueous layer was acidified to pH 4 with IN HsPO4, and the product was purified by preparative formula jjPLc. NMR (CD3OD, 300 MHz) d 0.92 (t, J = 7.0 Hz, 3H) 1.22 (m, 2H), 1.39 (m, 2H), 1.90 (m, 2H), 2.87 (s, 6H ), 3.07 (m, 4H), 3.24 (m, 1H), 3.43 (m, 1H), 3.62 (m, 1H), 3.84 (s 3H), 3.88 (m, 3H), 4.07 (m, 1H), 4.17 (m, 1H), 4.97 (m, 1H), 5.97 (s, 2H), 6.83 (d, J = 8.1 Hz, 1H), 6.93 (dd, J = 1.7, 8 i jjz 1H), 7.05 (m, 3H), 7.53 (m, 2H). MS (DC1 / NH3) m / e 540 (M + H) +. Analysis estimates C30H41N3O6 · 2.95 TFA: C, 49.22; H, 5.06; N, 4.80. Found 値: C, 49.16; H, 5.11; N, 4.62. Example 528 trans, trans_2- (4_methoxyphenyl) _4- (1,3_benzodiazine-5-yl) -1- 丨 (1 &lt; [-butyl-N · (3 -Trimethylammonium propyl) amino) carbonylmethyl μpyrrolidine · 3-carboxylic acid was prepared according to the method of Example 5 2 7 C, and Me3N was used instead of Me2NH. 4 NMR (CD3OD, 300 MHz) d 0.91 (m, 3H), 1.24 (m, 2H), 1.40 (m, 2H), 1.99 (m, 2H), 3.13 (s, 9H), 3.18 (s, Geometric isomers), 3.20 (m, 3H), 3.39 (m, 4H), 3.72 (m, 1H), 3.84 (s, 3H), 4.03 (m, 3H), 4.35 (m, 1H ), 5.19 (m, 1H), 5.97 (s, 2H), 6.84 (d, -547-) This paper size applies to China National Standard (CNS) A4 (210X297 mm) I 11 (Please read the back Please fill in this page for the matters needing attention)-Order · Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Description of the invention (545) J = 81 Hz, 1H), 6.96 (dd, J = 1.7, 7.9 Hz, 1H ), 7.10 (m, 3H), 7.62 (m, 2H). MS (DC1 / NH3) m / e 554 (M + H) +. Analysis estimates C3iH44N306 · 0.1 H2 · · 1.65 TFA: C, 47.25; H, 4.96; N, 4.32. Found 値: C, 47 · 25; H, 4.74; N, 4.75. Example 529 Cong Li, trans-2 · (4-methylamoyl) · 4_ (1,3_benzodifluoren-5-yl) V14 (N-_butyl-N- (4-aminobutyl) Amino) carbonylmethyl1-pyrrolidine-3- # acid

Example 529A A solution of N-butyl-N- (4-hydroxybutyl) · amine 8.1 g (110 mmol) n-butylamine and 8-6 g of butyrolactone in 50 ml of toluene, which was refluxed under a nitrogen atmosphere 50 hours. Remove the volatile solvent in the air. To a solution of 3.18 g (20 mmol) of N-butyl-4-hydroxybutyramine in 50 mL of toluene was added 120 mL (120 mmol) of DIBAL (25% W). The solution was heated with stirring at 70 ° C for 18 hours. After cooling to 0, the reaction was quenched with methanol (1/3 DIB AL), and a saturated solution of ROChelle, s salt was added. The mixture was extracted twice with EtOAc; the organic extract was washed with brine and dried over Na2S04.

Example 529B 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) 58 grams (4 millimoles) of N-butyl_N_ (4-hydroxybutyl) amine in 10 ml of EtOAc in an ice-cold solution. In this solution, 0.769 g (4.5 mmol) of chloroacetic anhydride was added in a small portion. The reaction mixture was allowed to expand downward: stirred for 5 hours' and allowed to warm to room temperature. Bicarbonate was added and the resulting mixture was extracted with EtOAc. The organic layer was washed with water and brine. Coarse material ____- 548-_ This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) '------ 581760 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 546) was purified by column chromatography. Example 529C trans_2_ (4_methoxyphenyl) -4- (1,3-benzodifluoren-5-ylidioyl-N- (4 · butyl-amino) amino) fluorenylmethyl The ratio of each of the _3_ leptate ethyl esters according to the procedure of Example 5 23 C, N · butyl · N- (4-hydroxybutylchloroacetamide and 2- (4-methoxyphenyl) -4- (1,3-Benzodiazin-5-yl) -P-bilodine_3_ Acetylacetate coupling. The crude product was chromatographed on silica gel. Phenyl) -4- (1,3-benzodiazine_5_yl) -1- 丨 (1 &lt; [_ butyl-N- (4-lacylbutyl) amino) fluorenylmethylpyridine _3. Ethyl carboxylate versus 0.180 g (0.33 mol) of the compound of Example 529C in 2 ml of DMF was added with 0.086 g (1 mmol) of lithium bromide and 012 mmol (0 66 mmol) (Ear) PBr. The reaction mixture was stirred at 0 ° C for 2 hours, and then slowly warmed to room temperature. Bicarbonate was added, and the resulting mixture was extracted with EtOAc. The organic layer was washed with water and brine, and the crude material was columned. Chromatographic purification. Example 529E trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodiazin-5-yl) -1_ 丨 (^ _butyl-N -(4-Aminobutyl) amino) carbonylmethyl _3_READ_ To 0.135 g (0.21 mmol) of the compound of Example 529D was added 0.1 g of sodium azide to a solution of 2 l of DMF. The reaction was stirred at room temperature for 18 hours (nitrogen atmosphere). Bottom). After adding water, the product was extracted with EtO Ac. The crude product (117 mg) was dissolved in 10 ml of ethanol (under nitrogen atmosphere). To this was added 10% Pd / C catalyst, the nitrogen in the reaction flask was evacuated, and Washed with hydrogen, placed with a balloon filled with chlorine. The reaction was done in the wind for 4 hours, and then passed -549- This paper size applies to t_ 家 鲜 (CNS) A4 size (training> ^ 97mm) &quot; (Please read the precautions on the back before filling out this page). Order. «1 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Description of Invention (547)

Celite dish filtering. The product was dissolved in ethanol and a 25 n aqueous sodium hydroxide solution and stirred at room temperature for 8 hours. The solution was concentrated under vacuum and water was added. The mixture was extracted with diethyl ether, the aqueous layer was acidified to pH 4 with IN HjO4, and the product was purified by preparative HPLC. ^ NMR (CD3OD, 300 MHz) j 0.90 (t, J = 7 Hz, 3H), 1.10-1.65 (m, 6H), 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 (DC1 / NH3) m / e 526 (M + H) +. Analysis estimates C29H39N306 · 2.2 TFA: C, 51.75; H, 5.35; N, 5.41. Measured 値: C, 51.75; H, 5.31; N, 5.30. Example 530 trans, trans_2_Γ4 · methoxyphenyl) -4 (l, 3-benzodifluoren-5-yl) -l_ms ^ butyl-N- (4, dimethylaminobutyl) amino ) The title compound, carbonylmethyl l-pyrrolidin-3-carboxylic acid, was prepared from the compound of Example 529D using the procedure of Example 527C. 4 NMR (CD3OD, 300 MHz) d 0.90 (dt, J = 7Hz, 3Η), 1.1- 1.75 (m, 8H), 2.75 (d, J = 7 Hz, 6H), 3.0-4.25 (m, 16H), 5.97 (s, 2H), 6.83 (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 (DC1 / NH3) m / e 554 (M + H) +. Analysis estimates C31H43N306 · 2.1 TFA: C, 53.31; H, 5.73; N, 5.30. Measured 値 · C, 53.50; H, 5.38; N, 5.34. Example 531 trans, trans-2- (4-methoxyphenylbenzodiazin-5-ylbutyl-N- (3 · ρ ratio) amino) hydroxymethyl 1-erodoline -3 -Thin fei -550- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 4 ^ clothing ------ Aw 2f Read the precautions on the back before filling in this page} 581760 A7 _____ B7 V. Description of the invention (548)

Example 531A Butylpyridine and Vamine (please read the precautions on the back before filling this page) A solution of 941¾g (10¾mol) of 3-aminopyridine and 0.9ml of butyric acid in 30ml of CHsOH 10 ml of glacial acetic acid was added. The mixture was stirred at room temperature for 1 hour, and the reaction was cooled in an ice bath, and 65.0 g (10.3 mmol) of sodium cyanoborohydride was added. The ice bath was removed and the reaction was allowed to stir at room temperature for 4.5 hours. The mixture was poured into 300 ml of 67M NaOH (aqueous solution) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were extracted with brine (1 X 50 ml), dried over MgS04, filtered, and concentrated to an oil. The product was separated by silica gel chromatography and dissolved in 3: 1 ethyl acetate · hexane to give 1-18 g (79%) of a colorless solid.

Example 531B trans, trans-2- (4-methylaminophenyl) -4_ (1,3_benzodiazin-5-yl) · 1 · | ΥN-butyl-N- (3-pyridyl ) Amine) Carbonylmethyl μpyrrolidine_3_ Carboxamidine Example 531A Compound was reacted according to the method of Example 523 to produce the title compound printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 4 NMR (D6_DMSO, 300 MHz) 0.80 (t, J = 6.4 Ηζ, 3H), 1.15-1.99 (m, 4H), 2.59 (m, 1H), 3.05 (m, 2H), 3.26 (m, 2H), 3.49 (m, 2H), 3.56 (t, J = 7.1 Hz, 2H), 3.73 (s, 3H), 6.00 (s, 2H), 6.80 (m, 3H), 6.85 (d, J = 8.1 Hz , 1H), 6.98 (m, 2H), 7.04 (m, 1H), 7.41 (dd, J = 1, 4.7 Hz, 8.1H), 7.58 (m, 1H), 8.36 (bs, 1H), 8.54 (bs , 1H), 12.24 (bs, 1H). MS (DC1 / NH3) m / e 532 (M + H) +. Analysis estimates C3OH33N3O6.0.1H3P04: C, 66.55; H, 6.20; N, 7.76. Found 値: C, 66.59; H, 6.06; N, 7.60. -551-This paper size applies the Chinese national standard CNS) A4 size (210x297 mm) 581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (549) Example 532 trans, trans-2_ ( 4_methoxybenzyl) _4-ΠBenzodifluoren-5-yl V1-KN-butyl-N- (3-diaminomethylphenyl) amino) carbonylmethyl ^ Billotian_3 · Example of Carboxylic Acid 532A &amp; butyl-N- (3-hydroxymethyl) acetic acid to a solution of 3.69 g (30 mmol) of 3-aminomethyl alcohol in 20 ml of DMSO, 3.78 g (45 mmol) ) Solid NaHC03 and 2.91 ml (27 mmol) of 1 · bromobutane. The reaction was stirred at 50 ° C for 18 hours (overnight). The reaction was treated with 250 ml of water, and the product was extracted with ethyl acetate. Water was added. The resulting mixture was extracted with EtOAc. The organic layer was washed with water and brine.

Example 532B Butyl-N-Π-hydroxymethylphenylbromoacetamide To 3.42 g (19.2 mmol) of the compound of Example 532A in 20 ml of toluene was added 2.42 ml (30 mmol) of pyridine. The mixture was cooled to 0 ° C, and 4.025 g (20.0 mmol) of bromoacetamidine (diluted in 5 ml of toluene) was added dropwise. The reaction mixture was allowed to stir at 0 ° C for 5 hours, and then allowed to warm to room temperature. A saturated solution of carbonic acid was added, and the mixture was vigorously searched for 2 hours. The mixture was extracted with EtOAc; the organic layer was washed with IN HJO4, water and brine.

Example 532C is _I_Formula-2- (4-methoxyphenyl) _4- (1,3-benzodiazine-5-yl) -1 • 丨 butyl-N · (3-chloromethyl Methylbenzyl) amine) carbonylmethylpyrrosis_3_Lean acid according to the procedure of Example 523C, N-butyl · N_ (3 · hydroxymethylphenyl) · bromoethiamine and 2- (4_ Methoxyphenyl) _4_ (r, 3 · benzodifluorenyl &gt; pyrrolidine-chinoic acid-552- This paper size is applicable to China National Standard (CNS) A4 size (210X297 mm) Please fill out this page again)-Binding · Binding 581760 A7 B7 V. Description of the invention (55〇) Ethyl coupling. The crude product (129 mg) was dissolved in 0.5 ml DMF and cooled to 0 ° C. 19 mg was added LiCl, and then 85 microliters of thionyl chloride were added. The mixture was stirred for 30 minutes; water was added, and the mixture was extracted with EtOAc again. The organic extract was washed with water and brine, and dried over Na 2 SO 4.

Example 532D trans, trans-2- (4-methylhydroceryl) · 4_ (fluorene, 3_benzodifluorene_5_some Vl_ 丨 (N-butyl-N_ (3 · aminomethyl molybdenum) An amine group) carbonylmethyl μpyrrolidin-3-boronic acid Example 5 3 2 C Compound (182 mg) was dissolved in 1 ml of DMF, 2 drops of water were added, and then 126 mg (2.0 mmol, 6.5 equivalents) was added Sodium azide. The resulting solution was heated at 115 ° C for 3 hours. Water was added and the mixture was extracted with EtO Ac. The organic extract was washed with water and brine, and dried over Na2S04.

Example 532E 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- (4_ 甲 气 笨 基) -4 · (1,3benzo Difluorenyl_5_yl) -1- [〇 ^ -butyl-N- (3-aminetolyl) amino) carbonylmethyl μpyrrolidine_3_carboxylic acid in a 50 ml round bottom flask, put 0.090 Tin (II) chloride was suspended in 1 ml of acetonitrile. Triethylamine (0.2 ml) was added followed by 0.19 ml of thiophenol; the reaction mixture turned yellow. The reaction flask was cooled in an ice bath to 0 ° C; a solution of 0.185 g of the compound of Example 532D in 2 ml of acetonitrile was added. The mixture was stirred for 30 minutes. Ether (10 ml) was added, followed by 10 ml of 2N HC1. The aqueous extract was basified with 4N NaOH and extracted with dichloromethane. The organic layer was washed with water and brine. The crude product was dissolved in ethanol and a 2.5 N aqueous sodium hydroxide solution and stirred at room temperature for 8 hours. The solution was concentrated under vacuum and water was added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N3PO4, and the product was purified by preparative HPLC. NMR (CD30D, 300 MHz) d 0.88 (t, -553-) This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) 581760 A7 B7 V. Description of the invention (551) 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 (DC1 / NH3) m / e 560 (M + H) +. Analysis estimates C32H37N306 · 4.2 TFA: C, 46.72; H, 4.0; N, 4.05. Measured pyrene: C, 46.66; H, 4.06; N, 4.00. Example 533 trans, trans-2_ (4-methoxyphenyl) -4- (1,3_benzodifluorene-5- Base group: N_ (3-trimethylammoniummethylphenyl) amino group, a certain 1, 1-pyrimidine Tibetan acid, 0.128 g of Example 5 3 2C compound in 0.5 ml of methanol, and 0.25 ml of trimethyl Amine solution in water. The mixture was stirred at room temperature and under nitrogen for 4 hours. 11 <[11 (: 1; water layer was washed with ether to extract organic impurities. The water layer was removed azeotropically with toluene and the residue was removed. Drying under high vacuum. Yield 0.115 g. 1H NMR (300 MHz, D6-DMSO) d 0.83 (t, J = 7 Hz, 3H), 1.15-1.40 (m, 4H), 2.62 (s, 2H), 3.35 (s, 9H), 3.40_3.80 (m, 10H) 54.47 (s, 2H), 6.00 (s, J = 3Hz, 2H), 6.75-6.90 (m, 3H), 7.25-7.37 (m, 2H) , 7.45 · 7 · 60 (m, 3H). MS (DC1 / NH3) m / e 602 (M + H) + 0 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back first) (Fill in this page) Example 534 (2R, 3R, 4S) -2- (3-Ga-4 -methoxyphenyl) -4_ (l, 3_benzodiazine-5-yl (2_ (N · propyl- N-amylamine ) Ethyl Billot shout -3-acid

Example 534A (3-fluoro-4-methoxy) ethyl acetate Acetyl acetate Sodium trioxide (17 g of a 60% suspension in mineral oil) was washed three times with toluene. Powder -554 This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 _______B7 V. Description of the invention (5¾) Suspended in 138 ml of toluene, then add 3 5 ml of diethyl carbonate. The mixture was heated to 90 C ', and a solution of 25 g of 3-fluoro-4-methoxyacetophenone and 50 g of carbon fe: -ethyl acetate in 50 ml of toluene was added dropwise. Heating was continued for 30 minutes, and the reaction was cooled to room temperature. 50 ml of concentrated HC1 was slowly added to 75 ml of ice water, and the mixture was stirred again. The mixture was extracted with toluene; the combined organic extracts were washed with brine and bicarbonate. The product was dried with Na2S04 and decolorized with activated carbon to give 34.5 g (97%) of the title compound.

Example 534B Fluoro-4-methyllactylphenyl) _4- (1,3-benzodiain-5 · yl) -P ratio p_3_Ethyl pivalate ethyl ester 534A compound (I2 · 5 g) and 5- (Nitrovinyl) 4,3-benzobisindro (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. Additional 0.1 g of DBU was added and the solution was stirred for 1 hour. The solvent was removed under vacuum; toluene was added, and brine containing 3 ml of concentrated HC1 was added. The mixture was extracted twice with toluene; the organic layer was dried over tritium. The residue was rinsed on silica gel and dissolved with Cl ^ Ch. This substance (17.4 grams) is mixed with 35 grams of Ruanlai Nickel (washed) in 25 ml jgt〇 Ac 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). The mixture was shaken for 4 hours at atmospheric pressure. The solution was concentrated under vacuum; the residue was chromatographed on silica and dissolved in 4% EtOAc / CH2Cl2. Yield 10.13 grams = 66%. The product was mixed with 26 ml of THF and 50 ml of EtOH; 2.18 g of NaBH ^ CN was added, and a trace amount of mocresol green was used as an indicator. A 1: 2 concentrated HCl / EtOH solution was added dropwise to maintain the pH at a greenish yellow color; after the color persisted, the reaction mixture was stirred for another 20 minutes. Solvent in 555-This paper size applies Chinese National Standard (CNS) A4 specification (21 × 297 mm) --- Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 B7 V. Description of invention (553) ; The residue was stirred with a mixture of toluene and khco3 solution. The organic phase was washed with water and brine and dried over MgS04. The crude product was purified by flash chromatography on crushed stone and dissolved with 2: 1 EtOAc / hexane. This gave 5.92 g (58%) of a mixture of trans-trans and cis-trans isomers of 2: 1.

Example 534C (2R, 3R, 4S) -2- (3 • Fluoro_4_methoxyphenyl) -4- (1,3-benzo-2-hexyl) -exopyrrolidine-3-carboxylic acid Ethyl acetate was dissolved in the racemic amino ester (15.0 g, 38.8 mmol) into 7 5 ml of dichloromethane and cooled in an ice bath. Boc anhydride (9.30 g, 42.7 mmol) was added. . After stirring at room temperature for 2 hours, the solution was concentrated under vacuum; the residue was dissolved in 50 ml of ethanol and treated with a solution of 3,75 g of sodium hydroxide in 19 ml of water. The solution is warmed until everything is soluble. After stirring for an additional 2 hours at room temperature, the solution was concentrated and redissolved in 2000 ml of water. This was extracted with 75 ml of diethyl ether. The ether layer was extracted with 40 ml of water. The mixed aqueous phase was acidified with 7.5 g of acetic acid; the mixture was stirred until a solid formed. The solid was filtered, washed with water and redissolved in dichloromethane. After drying over sodium sulfate, the solution was concentrated and the residue was crystallized from 1: 1 ether: hexane to give 15.99 g of product, m.p. 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 (8)-(-) 4-methylammonium amine. After dissolving the acid by heating, 80 ml of acetic acid was added. Take a glass rod to take out the product to crystallize. The solid particles were filtered off and washed with ether / ethyl acetate to yield 8.22 g (81% yield, subject to 50% maximum recovery) of the salt, m.p. 165-168 C. After one recrystallization, use Regis whelk- __________- 556-_ This paper size is applicable to China National Standard (CNS) A4 specification (210 × 297 mm) ---------- ^ 冬-(please first Read the notes on the back and fill in this page), ιτο Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 581760 A7 _____B7 V. Description of the invention (554) 〇 Column analysis of grassy HPLC analysis' display> 99.5% ee Soluble in 500 ml of 36% HC1 in ethanol; a white solid can be formed. The resulting suspension was heated at 52 C for 16 hours. After concentrating under agitation, the residue was mixed with toluene and stirred with potassium bicarbonate in water for 30 minutes. The toluene was separated, dried (NajCU) and concentrated. The residue was chromatographed on silica gel and eluted with 33% hexane-67-0 ethyl acetate to give 6.9 g (99%) of the resolved amino ester.

Example 534D (2R, 3R, 4S) -2- (3 4 _4_methoxyphenyl) -4_ (1,3_mobibis_5_yl VI- (g- (N-propylamino) ethyl) -Say g of each pyridin-3-acetic acid ethylamidine Example 5 3 4 C The compound is dissolved in 1,2-dibromoethane (100 liters / 1 g of starting material); further diisopropyl is added Ethylamine (1ml / g of starting material) and NaI (100¾g / 1g of starting material), and the mixture was allowed to fall at 100 ° C for 1 hour. Toluene was added and the mixture was washed with bicarbonate. Solvent Concentrated, the resulting black residue was chromatographed on silica gel and dissolved in 4: 1 hexane-EtOAc to give N- (2-bromoethyl) pyrrolidine (85-92%). This compound was mixed with n-propylamine (3.5 Equivalent) and Nal (10% by weight of bromine) in ethanol (5 ml / 1 g of bromide), and then heated at 80 ° C for 2 hours. Toluene was added, the mixture was washed with bicarbonate, dried (NaJO4) and Concentrate. Add more toluene and remove under stern air to form primary amine. The residue is dissolved in heptane and filtered to remove a small amount of insoluble material. The solvent is evaporated to produce the desired product (86-93% yield), which can be used in the next No further purification is required.

Example 534E Sodium salt of 1-pentanesulfonylpyrene 1-pentanesulfonic acid (10 g, 57.5 millimoles) was charged in a 250 ml round bottom _-557-^ Zhang scale applicable to Chinese National Standard (CNS) A4 Specifications (21〇ίΪ97mm) &quot; '------------ (Please read the notes on the back before filling this page) Order 581760

Printed in a bottle (in the hot room) by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Add gas of thionyl chloride (20 liters) to dissipate and form a white solid. The mixture was heated at 6 ° C for 3 hours. The solvent was removed under vacuum; toluene was added and removed under vacuum to remove the socl2 I residue. The residue was partitioned between CH2C12 and ice water; the organic layer was dried over NkSO4. Crude The product was distilled off (leaf 54_56τ @ 〇5mmHg) to produce a clear oil) 61% yield,

Example 534F ^^ 4S) -2_ (3_fluorodimethoxyphenyl) -4- (1,3-mocdodiyl) _; [_propyl-N-sulfonamido) ethyl) _pyrrole The carboxylic acid example 534D compound (200 mg, 043 mol) was dissolved in 5 ml of CHWN, 110 g (2 equivalents) of N, N diisopropylethylamine and 72 8 mg (1.2 equivalents) of 1 -Pentanesulfonyl chloride is added sequentially, and the resulting solution is allowed to stir for 30 minutes at high temperature. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc. The solution was saturated with NaHC0s solution 1N H3po4, and washed with brine 'on NaJCU and evaporated to give a slightly yellow oil, which was then purified by flash chromatography on crushed gel and dissolved in 40% EtOAc / hexane to produce 220 mg of product (85%). This solution was dissolved in 5¾ liters of EtOH, and a solution of NaOH (4 6 耄 g '3 equivalents) in 2¾ liters of H: 20 was added thereto. This mixture was stirred at room temperature for 3 hours. The solution was concentrated under vacuum and performed with low heat (&lt; 40t). Water (10 ml) and ether (50 ml) were added; the ether layer was extracted with 5 ml of water. The mixed aqueous mixture was extracted with ether and neutralized with acetic acid. This solution was extracted twice with ether. The ether was dried (Na2SO4) and concentrated under air. EtoAc (1 ml) and diethyl ether (1 ml) were added to dissolve the product, and hexane was added dropwise to give a white solid. The solids were collected and dried in the air to produce 125 mg-558- This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) ---- t Please read the weeping matter on the back and fill in this document ) tr 581760 A7 B7 V. Description of the invention (556) The title compound.

Example 534H (2 feet, 3 &amp;, 48) -2- (3-Ga-4-methyllactylbenzyl) _4- (1,3_benzyl two-depleted _5_yl) -1- (2- ( N-propyl-N-pentanesulfonamidoamino) ethylpyrrolidine-3 · • carboxylic acid hydrochloride free state amine in iPrOH; a slight excess of HC1 was added to iPrOH, and the solution was concentrated in the air Add more IP A, dissolve and concentrate. The resulting viscous material was stirred with ether overnight to produce a white powder. It was collected by filtration and dried overnight at 60 ° C under a vacuum. Yield 95%. Example 535 The compound of Table 3 C can be prepared by the method of the above examples. (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economy A4 specification (210X 297 mm) 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (557)

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-688- This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) 581760 A7 B7 V. Description of the Invention (6 volumes) As shown, the compounds described here can be bound to the endothelin receptor via Instead, compounds have been evaluated for their ability to replace endothelin from receptors. A membrane was prepared from MMQ cells in combination with the analysis method: MMQ [MacLeod / MacQueen / Login cell line (prolactin-secreting rat pituitary cells)], collected by centrifugation (1000xg, 10 minutes) from a 150 ml culture flask, Then in 25 ml of 10 mM Hepes (pH 7.4), containing 0.25 molose and a protease inhibitor [3 mM EDTA, 0.1 mM PMSF, and 5 μg / ml aprotin A] in microsonic cells Disintegrator (Kontes) homogenizes it. The mixture was centrifuged at 1000 × g for 10 minutes. The supernatant was collected and centrifuged at 60,000xg for 60 minutes. The pellet was resuspended in 20 mM Tris, pH 7.4 (containing the protease inhibitor described above) and centrifuged again. The final pellet was resuspended in 20 mM Tris, pH 7.4 (with protease inhibitor) and stored at -80 ° C until use. Bio-Rad dye-binding protein analysis was used to determine the protein content. [125η-Ετ · ι bonded to the membrane: 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). 〇〇ι〇 / 〇 BSA pretreated. The membrane prepared from the cells was treated with a B buffer solution (20 mM Tris, 100 mM NaCl, 10 mM MgCl, pH 7.4, plus 0.2% BSA, 0.1 mM PMSF, 5 μg / ml aprotin A, 0.025% bacitracin and 3 mM EDTA, diluted about 150-fold to a final concentration of 0.2 mg / ml protein. In a competitive study, the membrane (0.02 mg) and 0.1 nM [125I] ET- -689- Table paper size applies Chinese National Standards (CNS) A4 specifications (210X297 mm)-581760 A7 B7 V. Description of the invention (687) 1 Co-cultivate in B buffer solution (final volume: 0.2 ml), and add an unlabeled ET · 1 or an increased concentration The test compound was incubated at 25 ° C for 4 hours. After incubation, unbound ligand was separated from the bound ligand by air filtration, and glass fiber filter strips (Caambridge Technology, Inc., MA), and the filter strip was washed three times with saline (1 ml). Non-specific binding was determined in the presence of 1 // M ET_1. Data are shown in Table 4. Percent inhibition was shown at a concentration of 1 ml. The data show that the compounds of the present invention can bind to the endothelin receptor. (Please read first Please fill in this page again)) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs-690- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 581760 A7 B7 V. Description of Invention (688) Examples Table 4 Combined data Inhibition of ETa instances in ImM% Inhibition of ETa at 1 mM Printed by Employee Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs

1D 2 3 4 5 6B 7 8 9 10 14 15 16 17 18 19 20 21 22 23 26 27 28 29 30 31B 96.4 58.4 42.2 78.2 95.1 34.9 63.4 53.7 69.2 66.1 86.6 84.8 96.0 73.9 97.3 90.3 80.9 56.3 86.3 85.9 83.0 61.2 63.8 85.3 80.0 93.6 -691-34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 52 54 55 56 57 58 59 60 61C 62 63 95.5 91.8 94.5 47.9 100.0 83.6 94.8 89.9 95.2 99.2 91.3 85.4 90.4 95.1 96.3 84.0 64.6 50.5 34.3 93.2 81.9 70.8 42.8 90.6 94.1 92.0 (Please read the precautions on the back before filling in this page) Custom paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of invention (689) Ministry of Economic Affairs Printed by the Central Bureau of Standards Consumer Cooperatives Example ETa at 1 mM Example Inhibition% of ETa at 1 mM 64 95.0 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 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 (Please read the notes on the back before filling this page)

、 1T f -692- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 581760 A7 B7 V. Description of invention (69) Example printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs ETa at 1 mM Example% Inhibition of ETa at 1 mM% 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 93.6 133 88.6 162B 91.5 134 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 84.6 301 150 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 -693- (Please read the precautions on the back before filling this page)

、 1T f This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) 581760 A7 B7 V. Description of invention (691) Printed by Central Consumers Bureau of the Ministry of Economic Affairs Example of the printed sample of Eta under ImM. % Inhibition of ETa at 1 mM 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 59.2 323 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 89.9 373 92.9 343 98.7 374 91.4 344 95.6 375 97.8 375 97.8 86.6 376 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 -694- This paper size applies to China National Standard (CNS) A4 (210X 297 mm) (Please read the notes on the back before filling This page) Order P. 581760 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 692) Example% inhibition of ETa under ImM Example% inhibition of ETa under 1 mM 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 97.8 422 96.6 395 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 (Please read the notes on the back before filling this page) Order ^ 1. -695- this Paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (693) Examples of inhibition of ETa under ImM% Examples at 1 mM % Inhibition of ETa 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 10 0 465 95.1 443 100 466 94.2 444 100 467 93.6 445 98.1 468 88.7 446 97.8 469 98.7 447 96.9 470 100 448 97.4 471 100 449 100.0 475 91.6 450 99.7 476 82.3 451 100 477 80.1 452 100 479 96.5 453 94.4 495 95.9 454 96.8 496 92.7 455 99.1 497 83.7 456 95.3 498 81.6 457 88.9 499 68.5 458 93.4 500 55.7 -696-(Please read the notes on the back before filling this page)

、 1T f. This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 581760 A7 B7 V. Description of the invention (694) The printed example of the staff consumer cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs suppresses ETa at 1 mM % 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 99.0 524 99.2 525 100 526 100 527 96.6 528 98.3 529 98.1 531 99.8 532 100 533 97.9 -697- (Please read the notes on the back before filling this page)

、 1T f. This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of invention (695) (Please read the notes on the back before filling this page) To further prove the compound Acting as an endothelin with a functional antagonist effect, the ability of the compound to inhibit the ET-1 · induced phospholipids inositol hydrolysis was examined. Determination of Phospholipid Inositol (PI) Hydrolysis MMQ cells (0.4 X 106 cells / ml) were labeled with 10 // Ci / mL [3H] -inositol in RPMI for 16 hours. The cells were washed with PBS and incubated with a buffer solution of protease inhibitor and 10 mM LiCl for 60 minutes. The cells were incubated with the test compound for another 5 minutes, and platooned at 1 nM ET_1, and 1.5 ml of 1: 2 (v / v) chloroform-methanol was used to terminate the ET-1 battle. Subtract the total inositol phosphate after adding chloroform and water to produce a final ratio of 1: 1: 0.9 (v / v / v) chloroform-methanol-water, such as Berridge (Biochem. J. 206 587-595 (1982) ). The upper aqueous phase (1 ml) was retained and a small portion was counted (100 µl). The remaining aqueous samples were analyzed by batch chromatography using an anion-exchange resin AG1-X8 (Bio-Rad). IC5G is the concentration of test compound required to inhibit a 50% increase in ET-defense during PI conversion. The results of the above studies clearly show that the compounds can act as functional E T antagonists. Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs -698- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 581760 A7 B7 Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs ) Table 5 Example of hydrolysis of phosphoinositide inositol IC50 mM 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 Table 6 ETA / ETB selectivity MMQ cells, pig cerebellar tissue (known to contain ETB receptors) and Chinese hamster egg cells (CHO), are permanently transfected with human ETA * ETB receptors, and then homogenized in 25 ml of 10 mM Hepes (pH 7.4). It contains 0.25 M sucrose and a protease inhibitor [50 nM EDTA, 0.1 mM PMSF, 5 μg / ml aprotinin A, and 0.025% bacitracin], using a small amount of ultrasonic cell tiles -699- Applicable to this paper size China National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling out this page) 581760 A7 B7 V. Description of invention (697) The resolver is performed. The mixture was centrifuged at 1000xg for 10 minutes. The supernatant was collected and centrifuged at 60,000xg for 60 minutes. The pellet was resuspended in 20 mM Tris, pH 7.4 (containing protease inhibitors) and centrifuged again. The final membrane pellet was resuspended in 20 mM Tris, pH 7.4 (with protease inhibitor) and stored at -80 ° C until use. 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 out this page). Bio-Rad dye-conjugated protein analysis method to determine the protein content in a 96-well microtiter plate for combined analysis. It was pretreated with 0.1% BSA. Membrane prepared from cells was diluted approximately 100-fold in buffer solution B (20 mM Tris, 100 mM Naa, 10 mMMgCl2, pH 7.4, plus 0.2% BSA, 0.1 mM PMSF, 5 μg / ml aprotinin A, 0.025% Bacillus Peptide, and 50 mM EDTA) to a final concentration of 0.2 mg / ml protein. In competitive binding studies, membranes (0.02 mg) and 0.1 nM of [125I] ET-1 (for ETA analysis, MMQ or CHO cells transfected with human ETA receptors) or [125Ι] ΕΤ · 3 (in In ETB analysis, porcine cerebellum or CHO cells were transfected with human ETB receptors and co-cultured in a B buffer solution (final volume: 0.2 ml) with the presence of increasing concentrations of the test compound at 25 ° C for 3 hour. After incubation, the unbound ligand was separated from the bound ligand by suction filtration, and glass fiber strips (Cambridge Technology, Inc., MA) were used in a PHD cell recoverer with saline (1 ml). Wash three times. Non-specific binding was determined in the presence of 1 &quot; M ET-1. IC50 is estimated using the average of at least two separately determined 値. The data show the selectivity of the compounds of the invention for binding to the endothelin receptor. -700- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 581760 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (698) Table 6 Example number mET-A (% 1 @ 1μΜ) 502 95.7 mET-A IC50 (nM) 3.0 pET-B IC50 (nM) 71,000 selectivity (mA / pB ratio) 23,000 hET-A IC50 (nM) hET-B IC50 (nM) selectivity (hA / hB Ratio) 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; 100,000 &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 24,000 509 100 0.56 30,000 53,000 0.5t 23,000 45,000 510 100 0.50 35,000 68,000 1.0 11,000 11,000 511 99.2 0.81 ND 0.60 15,000 25,000 5t2 98.9 0.42 &gt; 80,000 &gt; 190,000 0.58 60,000 &gt; 102,000 513 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 29,000 515 99.1 1.6 &gt; 62,000 &gt; 37,0 00 6.7 &gt; 100,000 &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 (please read the precautions of V? Before filling out this page)

、 1T -701 This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) 581760 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (699) 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 1,700 2,100 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 3,200 630 533 97.9 76 7,900 100 40 22,000 560 534 0.12 0.36 3.0 0.08 0.28 3.5 Determination of plasma protein binding test Compounds were diluted 10X in 50% ethanol (2 mg / ml) in PBS. A 0.4 ml sample of this secondary stock solution was added to 3.6 ml of fresh plasma -702- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T. 581760 A7 B7 5. In the description of the invention (700), incubate for 1 hour at room temperature. Take this incubation mixture for 1 hour and transfer it to a Centrifree ultracentrifuge tube. Centrifuge the sample in a stationary hanging rotor for about 2 minutes, then discard the filter and liquid. Centrifuge the sample for another 15-30 minutes. A 100 microliter sample of ultrafiltration was transferred to a micro HPLC sample vial containing 150 microliters of HPLC mobile phase and mixed well. 50 microliters were injected, and the concentration of the drug in the ultra-speed filtrate was determined by HPLC analysis. The standard sample prepared in the absence of plasma was used. Estimate the concentration of ultrafiltration filtrate from the calibration curve. The protein binding was estimated according to the following formula:% PB = [l- (Cu / Ci)] * 100% where Cu is the ultrafiltration filtrate concentration and Ci is the initial plasma concentration. Data Example # 43 &gt; 99.5% Example # 532 96.8% Example 533 82.6% The ability of the compounds of the present invention to lower blood pressure can be determined according to Matsimmra, et al., Eur. J. Pharmacol. 185 103 (1990) Takata, et al.? Clin. Exp. Pharmacol. Physiol · 1Q_131 (1983). The ability of the compounds of the present invention to treat congestive heart failure can be demonstrated according to the method of Margulies, et al., Circulation ϋ 2226 (1990). The ability of the compounds of the present invention to treat myocardial hemorrhage can be proved by the method of Watanabe, et al., Nature Ml 114 (1990). The ability of the compound of the present invention to treat coronary angina pectoris can be proved according to Heistad, et and 1., (^ 1 ^ .1 ^ 8.11 711 (1984). The ability of the compound of the present invention to treat cerebral vasospasm can be according to Nakagomi, -703 -This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page)

1T f 581760 A7 B7 V. Description of the invention (701) et al.? J. Neurosurg. 66. 915 (1987) or Matsumura, et al., Life Sci. £ 841-848 (1991). The ability of the compound of the present invention to treat cerebral hemorrhage can be proved according to the method of Hara et al., European. J. Pharmacol. 197: 75-82, (1991). 0 The ability of the compound of the present invention to treat acute renal failure can be determined according to Kon, et al., J. Clin. Invest, ϋ 1762 (1989). The ability of the compounds of the present invention to treat chronic renal failure can be demonstrated by the method of Benigni, et al., Kidney Int. 41 440-444 (1993). The ability of the compound of the present invention to treat gastric ulcer can be proved according to the method of Wallace, et al., Am. J. Physiol. 256 G661 (1989). The ability of the compounds of the present invention to treat cyclosporine-splenic kidney poisoning can be proved by the method of Kon, et al., Kidney Int. U 1487 (1990). The compounds of the present invention for treating endotoxin and toxic poisoning (shock) can be proved according to the method of Takahashi, et al., Clinical Sci_79 619 (1990). 0 The ability of the compounds of the present invention to treat asthma can be determined according to Potvin and Varma, Can. J · Physiol. And Pharmacol. Red 1213 (1989). The ability of the compound of the present invention to treat transplant-deficient atherosclerotic arteriosclerosis can be proved by the method of Foegh, et al., Atherosclerosis 78_229-236 (1989). 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) The ability of the compound of the present invention to treat atherosclerosis can be determined according to Bobik, et al ·, Am. J. Physiol. 258 C408 (1990) and Chobanian, et al., Hypertension 327 (1990). The ability of the compounds of the present invention to treat LPL-associated lipoprotein disorders can be according to Ishida, et al., Biochem. Pharmacol. 44. 143 1-1436 (1992) -704- This paper standard is applicable to the Chinese National Standard (CNS) A4 specification (2 丨 0'〆297mm) 581760 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (702) Method certification. The ability of the compounds of the present invention to treat proliferative diseases can be 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 Shichiri, et al., J. Clin. Invest. 1867-1871 (1991). Proliferative diseases include smooth muscle proliferation, systemic sclerosis, liver cirrhosis, respiratory distress symptoms in adults, spontaneous cardiomyopathy, lupus erythematosus, diabetic nephropathy or other kidney diseases, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, Restenosis after arterial injury or pathological stenosis of other blood vessels. The ability of the compounds of the present invention to treat acute or chronic pulmonary hypertension can be demonstrated by Bonvallet et al.? Am. J. Physiol. 266 H1327 (1994). Pulmonary hypertension is associated with the following diseases: congestive heart failure, mitral stenosis, pulmonary embolism, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), altitude sickness, chemicals Exposure may be spontaneous. The ability of the compounds of the present invention to treat platelet aggregation and thrombosis can be demonstrated by the method of McMurdo et al. Eu. J. Phamacol. 259 51 (1994). The method for treating cancer of the compound of the present invention can be proved according to the method of Shichiri, et al., J. Clin. Invest. 52 1867 (1991). The ability of the compounds of the present invention to treat IL_2 (and other cytokines) -mediated cardiotoxicity and vascular permeability disorders can be proved by the method of Klemmetal ·, PΓOc · Nat · Acad. Sci .. £ 1 2691 (1995). -705- (Please read the precautions on the back before filling this page)-Γ-This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (7〇3) The ability of the compounds of the present invention to treat nociception can be proved by the method of Yamamoto et al.? J. Pharmacol. Exp. Therap. 271 156 (1994). The ability of the compounds of the present invention to treat colitis can be demonstrated according to the method of Hogaboam et al (EUR. J. Pharmacol. 1996, 309? 261-269). The ability of the compound of the present invention to treat the hemorrhage-defamation reinfusion injury in kidney transplantation can be treated according to Aktan et al (Transplant Int 1996, £, 201_207). 0 The compound of the present invention can treat angina pectoris, pulmonary hypertension, Raynaud's disease and partial The ability of headache can be proved by Ferro and Webb's method (Dmgs 1996, 5_L? 12-27) ° 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 compound of the present invention can Derived and used in the form of salts of inorganic or organic acids. These salts include but are not limited to the following: acetate, caproate, alginate, citrate, aspartate, benzoate, benzenesulfonate, hydrogen sulfate, butyrate, camphor Salt, camphor sulfonate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethane sulfonate, glucoheptanoate, glyceryl phosphate, hemisulfate, heptanoate Salt, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodate, 2 · hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate 2,2-sulfonate, oxalate, dihydroxygallate, pectate, persulfate, 3-phenylpropionate, picrate, trimethylacetate, propionate, amber Acid salt, tartrate salt, thiocyanate salt, p-toluenesulfonate and undecyl carbonate. At the same time, experimental nitrogen-containing groups can be quaternized, such as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromine and iodine; dialkyl sulfates, and sulfuric acid Dimethyl ester, diethyl ester, dibutyl ester and dipentyl ester, long-chain autochemicals, such as decyl, lauryl, myristyl, and stearyl chloride, -706- This paper size applies to Chinese national standards ( CNS) A4 specification (210X297 mm) 581760 Member of the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Metallurgical A7 B7 V. Description of the invention (704) Bromine and others. This results in water- or oil-soluble dispersible products. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Basic addition salts can be prepared in situ in the isolation and purification of compounds of formula I, or they can be separately reacted from a carboxylic acid functional group with a suitable base, such as a pharmaceutically acceptable metal cation hydroxide, carbonate or Bicarbonate, or react with ammonia, or organic primary, secondary or tertiary amines. This pharmaceutically acceptable salt includes, but is not limited to, cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, etc., and non-toxic 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 alkali addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, hexahydropyrine, and the like. The compounds of the invention are useful for antagonizing endothelin in humans or other mammals. In addition, the compounds of the present invention are useful in the treatment of hypertension (in humans or other mammals), acute or chronic pulmonary hypertension, Raynaud's disease, congestive heart failure, myocardial hemorrhage, reinfusion injury, coronary angina pectoris, cerebral hemorrhage, Cerebral vasospasm, chronic or acute renal failure, non-steroidal anti-inflammatory drugs ulcerative gastric ulcer, cyclosporine toxicative kidney toxicant, endotoxin-toxicant toxicant, asthma, fibrous or proliferative diseases, including smooth muscle proliferation, Systemic sclerosis, liver cirrhosis, respiratory distress syndrome in adults, spontaneous cardiomyopathy, lupus erythematosus, diabetic nephropathy or other kidney disease, psoriasis, scleroderma, prostate proliferation, cardiac hyperplasia, restenosis after primary vein injury or vascular Other diseases -707- This paper size applies to Chinese National Standard (CNS) A4 specification (2ι〇 × 297mm) (Please read the precautions on the back before filling this page) Order-581760 A7 B7 V. Description of Invention (705) Rationality Stenosis, LPL-associated lipoprotein disorders, transplanted atherosclerotic or general atherosclerosis, platelet aggregation, thrombosis, Disease, such as prostate cancer, IL-2 and other cells mediating the toxic core and the movable element through the force coated disorders, nociceptive and, in particular, to treat bone pain related with the bone. The total daily dose administered to the host in a single or divided dose may range from 0.001 to 1000 mg / kg body weight / day, and preferably from 0.001 to 100 g / kg for oral administration, or from 0.01 to 10 mg / Kg for parenteral administration. The dosage unit composition may contain the second largest amount of this dose to achieve a daily dose ^ The active principal ingredient dose that can be mixed with the carrier substance to produce a single dose depends on the host being treated and the particular mode of administration. However, it should be understood that the specific dosage level for any particular patient depends on various factors, including the activity of the specific compound applied, the patient's age, weight, general health, gender, diet, time of administration, route of administration, rate of excretion, medication Match the contraindications and the severity of the particular disease being treated. The compounds of the present invention can be administered orally, parenterally, sublingually, or by inhalation spray, administered rectally or locally, in the form of a dosage unit blend, containing traditional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles, Add as needed. Topical administration also involves transdermal administration, such as transdermal patches or iontophoresis devices. By so-called parenteral, such methods include subcutaneous injection, intravenous, intramuscular, intrasternal injection, or infusion techniques. Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be blended according to known techniques using suitable dispersing or wetting agents and suspending agents. None __ -708- This paper size applies to China National Standard (CNS) A4 (21GX 297mm) '(Please read the precautions on the back before filling this page)

、 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs M1760 A7 --------- B7 V. Description of the invention (704) The injectable preparation of bacteria can also be a sterile injectable solution or suspension. Toxicity (in parenterally acceptable diluents or solvents, such as &quot;. Propylene Glycol &gt; Losinner. In acceptable solvents and solvents, the applicable ones are: water, Ringer's, etc. A solution of sodium chloride. In addition, the fixed oil of Pseudomonas can be used as a solvent or a suspension medium. Combined fixed oil can be used, including synthetic mono- or diglycerol vinegar; Acids such as oleic acid can be used to make injectables. Suppositories for transanal administration of drugs can be prepared by mixing the drug with suitable non-irritating excipients, such as cocoa butter and polyethylene glycol, which are solid at ordinary temperatures but It is liquid at warm temperature and therefore can be melted and released in the anus. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In this solid dosage form, the active compound can be diluted with at least one inert Agent blends, such as sucrose, Sugar or starch. This dosage form may also contain additional substances (in addition to inert diluents), such as lubricants, such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. Tablets and Pills can also be prepared in additional casings. 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)% 1. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, Solutions, suspensions, syrups, and elixirs contain inert diluents commonly used in the art, such as water. This composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, and sweeteners. , Fragrances, and fragrances. The compounds of the present invention can also be administered in liposomal form. As is known in the art, liposomes are usually derived from phospholipids or other lipid substances. Liposomes are formed from mono- or multi-layered hydrated lipid crystals, which are dispersed In water-based medium, the paper size of -709- I is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 581760 A7 B7 V. Description of the invention (704) How non-toxic and physiologically Accepted and metabolizable lipids can be used as long as they can form liposomes. The composition of the present invention in the form of liposomes can contain stabilizers, preservatives, excipients, etc. in addition to the compounds of the present invention. The preferred lipids are Phospholipids and phosphatidylcholine (lecithin) can be natural and synthetic. Methods for forming liposomes are known in the art, see, for example, Prescott, Ed., Methods in Cell Biology. Volume XIV, Academic Press, New York, NY (1976), p. 33 et seq 0 Representative solid dosage forms, such as lozenges or capsules, which may contain: Compounds of the invention: 35% w / w starch, pregelatinized, NF 50% w / w microcrystalline cellulose, NF 10% w / w talc, powder, USP 5% w / w Although the compound of the present invention can be used alone as an active drug, it can also be used in combination with more than one cardiovascular agent, independently selected from Diuretics, adrenergic blockers, vasodilators, calcium tract blockers, renal enzyme inhibitors, vasopressin converting enzyme (ACE) inhibitors, vasopressin II antagonists, _ channel activators and Other cardiovascular agents. Representative diuretics include: p-chlorochloropyrimide, chloropyrimide, acetazolamide, ammonium chloride, p-butyric acid, benzophenone, wells, diuretic acid, diuretic amine, and mantazone ( indacrinone), mexalone, spironolactone, ampicillin, chloracetone, etc. or their pharmaceutically acceptable salts. Representative adrenergic blockers include phentolamine, phenoxybenzamine, prazolam, trimethylazol, torazol, amoxolol, metoprolol, -710- Applicable to this paper size China National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling out this page) Order f Printed by the Central Consumers Bureau of the Ministry of Economic Affairs's Consumer Cooperatives 581760 A7 B7 The Ministry of Economy ’s sample rate bureau employees ’consumption Cooperatives V. Description of the invention (708) 荇 心 心 安, propranolol, timolol, catamolol, etc., or a pharmaceutically acceptable salt thereof. Representative vasodilators include: hydrazine, long pressure, diazepam, nitroprusside, etc., or a pharmaceutically acceptable salt thereof. Representative calcium tract blockers include: amdiione, benzylcycloheptan, diltiazem, phenethylamphetamine, fluphenazine, nicardipine, and mormodine ( nimodipine), Xinshuning, Yibodian, Gallrpamil, nifedipine p-spin, etc., or a pharmaceutically acceptable salt thereof. Representative renal enzyme inhibitors include: enalkiren, zankiren, RO 42-5892, PD-134672, etc., or a pharmaceutically acceptable salt thereof. Representative vasopressin II antagonists include DUP 753, A-81988 and others. Representative ACE inhibitors include: captopril, enalapril, lisinopril, etc., or their pharmaceutically acceptable salts. Representative potassium activators include: Pinacidil, etc., or a pharmaceutically acceptable salt thereof. Other representative cardiovascular agents include sympathetic blockers such as methyldopa, antihypertensive tablets, guanabenz, reserpine, or a pharmaceutically acceptable salt thereof. The compounds of the present invention and cardiovascular agents can be administered at the recommended maximum clinical dose or minimum dose. Dosage of active compound in the composition of the present invention-711-This paper XjtJt uses Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page), 1T- 581760 A7 B7 V. Description of the invention (709) It can be changed according to the route of administration, the severity of the disease and the response of the patient. The composition may be administered as separate compositions or in a single dosage form containing two types of agents. When administered as a composition, the therapeutic agent can be adjusted to separate composition types, administered at the same or different times, or the therapeutic agent is given as a single composition type. The above is only for illustration of the present invention, and is not intended to limit the present invention to Disclosed compounds, methods, compositions and processes. The obvious changes for the artisans are within the scope and essence of the patent application park of the present invention. (Please read the precautions on the back before filling out this page) Printed by the Employees 'Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -712-This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 2 !: Too A mouth' ^ w Application date 86. 3. 24 — case number 86103710 — category (fill in the above columns by this Office) j # i 1 supplement «Α4 C4 sub-year 丨

A Chinese Manual Correction Page (10/87) 581760 Invention ^ ~ Bibian Patent Specification Chinese Invention New Name English Name Last Name Nationality Endothelin-antagonistic Saurox Complex Acid Derivative

PYRROLIDINE CARBOXYLIC ACID DERIVATIVES HAVING ENDOTHELIN ANTAGONISM I. Inventor ’s residence and residence 1. Ma T. Win 3. I W. Hu Chengsi 5. Android S. Teske 7. Jeffrey A. Xunst H Cao, G. Sus Pangeway 11. Liu Gen 13. Shi Wen A. Jin 11. Yu Jun of the Chinese mainland, No. 1263, Carlisle Square, Erfide City, State 2. Mendlin, Illinois No.410, Lakeside Road, Shanghai 3. No. 4120, Ogsby Road, Gaoli, Illinois f f No. 477 Wolland Avenue, Grank City, Illinois gf No. 6251 Eagle Mill Road, Guni City, Linn. $ Yang Guo No. 4209 West Solan Road, Richmond, Illinois I. No. 680 Sharplin Lane, Dilfield, Illinois 8. 262 North Levis Road, Wokken, Illinois | 337 No. 33720, Royal Oak Lane, Geki Lake, Yinlino. Yang Guo, No. 1047, Southwest Avenue, Wukgen, Linuo, No. 11. Vuke, Illinois, 520; No. 2LΗ. # Gf 317 North Amore Road, Mondland, Linn. 3. No. 6713 Orchard Road, Lenny, Illinois, Wong 2. Steven A. Byrd 4. Huang- Su Jie 6. Thomas W. Wenger Climbing 8. Dropping ic. Going to Rayson 10. Kenneth J. Henry II 12. Steven J. Whitberg Binding Name (Name) Printed by US Consumer Abbott Laboratories Central Standards Bureau Employees Consumer Cooperative Line Nationality American Applicant's Residence, Domicile (Office) Representative Name Charlie M. Brook, 100 Apel Park Road, Apel Park, Illinois, USA This paper is sized to the Chinese National Standard (CNS) A4 (210X297) (%) 581760 A7 B7 Patent Application No. 086103710 Patent Application Replacement Page (Year Years 丨 丨 Month) V. Description of Invention () ___— 447 7 (-修 玉 本 卞 ^ (&&amp; * Supplement CD3OD) 5 2.97 (dd, J = 7.9, 9 · 7 Ηζ, Γη), 3.04 (t, J = 9.6 Ηζ, 1Η), 3.18 (dd, J = 4.4 Ηζ, 9 · 9Η), 3.47 (d, J = 14.0 Ηζ, 1Η ), 3.59 (m, 1H), 3.78 (s, 3H), 3.96 (d, J = 9.9 Hz, 1H), 3.97 (d, J = 13.6 Hz, 1H), 5.90 (m, 2H), 6.73 (d, J = 8.1 Hz, 1H), 6.83 (dd, J spit 7, 7.9 Hz, 1H), 6.92 (m, 2H), 6.96 (d, &gt; 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 (DCL) m / e 433 (M + H +) ° Analytical estimation C25H24N2 0 5 · 0 35 h2 0: c, 68 · 43; H, 5.67; N, 6.38. Measured values: c, 68 · 44; H, 5.61; N, 6.24. Example 392 Plexus "trans-form # Erkou et al.-5_ group) _ (v · N-N-dimethylpyrimidine_3 · carboxylic acid The title compound can be prepared using the procedure of Example 1. lR [nmr (CDC13 , 300 MHz) (5 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), 3.65-3.76 (m, 1H), 3.82-3.90 (m, 1H), 3.96-4.10 (m, 1H), 5 92 (s, 2H), 6 71 (d, J = 8.1 Hz, 1H), 6.77 (dd, J = 8.1, 1.5 Hz, 1H), 6.86 (d, J = 1.2 Hz, 1H ), 7.10-7.28 (m, 5H). MS (DCL / NH3) m / e 523 (M + H). Analyzed and estimated C31H42N205.0.6 tfa: C, 65.43; H, 7.26; N, 4.74. Measured value: C, 65 · 28; H, 7.29; N, 4.50. I Example 393 trans, trans U4 dimethylamino-lk benzodihumidyl) .. :: υαυι ^ Ξ: χ ^ χ ^ Ι ^) carbonylcarbonyl] pyridine-450-

581760 No. 086103710 Patent Application Chinese Specification Replacement Page (January 1992) ------- 丨 revised supplement η, invention description (re-evaporation to produce dark orange oil (0 · 35 g). The product is chlorine -And bromoacetamide ~ 3: 1 mixture.

Example 524F Spread-2- (4-methyli-benzyl ν4-π.3-molyldifluorene-5-a certain Vl-lΎN-: fluorenyl-N- (3-hydroxypropanyl) amino group) Carboxymethylpyrrolidine-3-carboxylic acid was prepared according to Step 5 2 3 C using N-propyl-N-propoxy-bromoacetamide and 2- (4-methoxyphenyl) -4- ( 1,3-Benzenedi-5-yl) -pyrrolidine-3-carboxylic acid ethyl acetate. The crude product was purified by preparative HPLC (Vydac mC 1 8) and eluted with a gradient of 10-70% CH3CN in 0.1% TFA. Suitable fractions are freeze-dried to give the product as a white solid. iH NMR (CDC13, 300 MHz) 5 0.87 (m, 6H, J = 8Hz), 1.49 (m, 2H, J = 8Hz), 1.61 (m, 2H, J = 8Hz), 3.55 (m, 6H), 3.80 (m, 2H), 3.81 (s, 3H), 4.00 (m, 2H), 4.13 (d, 2H, J = 17Hz), 5.96 (s, 2H), 6.77 (d, 1H, J = 9Hz), 6.90 (m, 3H), 7.05 (d, 1H, J = 1 Hz), 7.44 (d, 2H, J = 9Hz). MS (DCL / NH3) m / e 499 (M + H) +. Analysis estimates c27H34N207 · 1.20 DFA: c, 55.57; H, 5.58; N, 4.41. Found: c, 55.59; H, 5.58; N, 4.55. Example 525 is in the form of trans-2- (4-fluorenylbenzyl) -4- (1,3-benzono_5_yl1 _ "(N-

) Aminocarbonylmethyl 1-pyridine: Example of 3-rollic acid 525A N-butyl-N- (2-hydroxyethyl V% in a thick-walled glass test tube, 5 ml (100 mmol) epoxy Ethane is condensed at _78 ° C. To this is added 12.5 ml (120 millimolar) of butylamine, and then -542- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Claims (1)

A8 B8 C8 D8 Qing Nian, _ 丨 ^ 1760 Patent Application No. 086103710 1 Replacement of the scope of patent application (February 1993, Patent Application Fan Huang ^ Bulletin 丨 — Heavy Objects Where ZS_C (R18) (Rl9)-, where R18 and R19 are hydrogen; η is 0; R is-(CH2) mW, where m is 0, and W is -C (0) 2-G, where G is hydrogen ; Ri is a phenyl substituted by a (: 1-alkoxy substituent; R3 is R4-C (0) -R5-, where ^ is d-alkyl, and R4 is (Rh) (R12) N-, where Rn and r12 are independently selected from the group consisting of: C4- Alkyl, di (Ci-alkyl) amino-c3-c4-alkyl, amine-C4-alkyl, and tri (C3-alkyl) amino-C3-C4-alkyl, or pharmaceutically acceptable Accepted salt. 2. Compounds according to the following formula: O: \ 46 \ 46585-930217 (CLAIM) .DOC \ 3 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 581760 2-3. A pharmaceutical composition capable of antagonizing endothelin, which contains a therapeutically effective dose of a compound according to item 丨 of the scope of patent application and a pharmaceutically acceptable carrier. 4. A pharmaceutical composition capable of antagonizing endothelin, which contains a therapeutically effective agent f according to item 2 of the patent application scope and a pharmaceutically acceptable carrier. 5. The compound according to item 丨 or 2 of the scope of patent application, which is selected from the group consisting of: trans'trans-2- (4-methoxyphenyl) _4_ (1,3-benzodifluorene -5-ylbutyl-N-2-aminoethyl) aminocarbonylmethyl] -pyrrolidine-3-carboxylic acid; trans'trans-2- (4-methoxyphenyl) -4- ( 1,3-benzobisfluoren-5-yl-butyl-N- (3-aminopropyl) amino) carbonylmethyl] -pyrrole-3 -unacid; trans'trans-2- ( 4-methoxyphenyl) -4- (1,3-benzodolin-5-yl) -1 _ [(N-butyl-N- (3-dimethylaminopropyl) amino) carbonylmethyl Group] -pyrrolidine_3-carboxylic acid; trans'trans-2- (4-methoxyphenyl) _4- (1,3-benzobenzo-5-yl) -1-[(N- Butyl-N- (3-trimethylaminopropyl) amino) carbonylmethylpyrrolidine-3-carboxylic acid; and trans, trans- 2- (4-methoxyphenyl) -4- (1 , 3-Benzodifluoren-5-ylbutyl-N- (4-aminobutyl) amino) carbonylmethyl] -pyrrolidin-3-carboxylic acid; or a pharmaceutically acceptable salt thereof. O: \ 46 \ 46585-930217 (CLAIM) .D〇C \ 3 This paper size applies the Chinese national standard ⑴ ^^ print A4 specification (21〇297mm) Binding 581760 A8 B8 C8 _ D8 6. Scope of patent application 6. Trans, trans-2- (2,2-Dimethylpentyl) -4- (7-methoxy-1,3_benzodifluorene · 5-kib b (N, N-bis (η-butyl) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 7 · trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) -1-((N-butyl-N- (4-dimethylaminobutyl) amino) ) Carbonylcarbonyl) -pyridine-3 -antamic acid or a pharmaceutically acceptable salt thereof. 8. (2R, 3R, 4S) -l- (2- (N -propyl- N- (n -pentyl) Keystone yellowyl) amino) ethyl) -2- (3-fluoro-4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) pyrrolidine-3-carboxylic acid or A pharmaceutically acceptable salt thereof. 9. A pharmaceutical composition for antagonizing an endothelin receptor, comprising a therapeutically effective amount of trans, trans- 2- (2,2-diamylpentyl) -4 -(7-fluorenoxy-1,3-benzobenzofluoren-5-yl) -b (N, N-bis (η-butyl) aminocarbonylmethyl) -pyrrolidine-3 -carboxylic acid or Its pharmaceutically acceptable salt and pharmaceutically acceptable carrier. 10 · — a kind of medicine for anti-endothelin receptor A composition comprising a therapeutically effective amount of trans, 2- (4--oxophenyl) -4- (1,3-benzodifluoren-5-yl) -1 _ ((N-butyl -N- (4-dimethylaminobutyl) amino) carbonylmethyl) -pyrrolidine-3 -carboxylic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 11 · One use A pharmaceutical composition for antagonizing an endothelin receptor, comprising a therapeutically effective amount of (211,311,43) -1- (2- (1 ^ -propyl-: ^-(11-pentylsulfo) amine ) Ethyl) -2- (3-fluoro-4 -fluorenyloxyphenyl) -4- (1,3-benzobisfluoren-5-yl) pyrrolidine-3 -carboxylic acid or a pharmaceutically acceptable Salt and pharmaceutically acceptable carrier. O: \ 46 \ 46585-930217 (CLAIM) .DOC \ 3 &quot; ^-This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 581760 ABCD 6 2. Patent application range 12 · —A pharmaceutical composition for treating cancer ', which includes a therapeutically effective amount of a trans-effective, trans-2_ (2,2-dimethylpentyl) -4- ( 7_ methoxy-1,3-benzobisfluoren-5-yl-bis (n-butyl) aminocarbonylfluorenyl) -pyrrolidine-3 -carboxylic acid or a medicament thereof Accepted salts and pharmaceutically acceptable carriers. 13 · —A pharmaceutical composition for treating cancer 'which includes a therapeutically effective amount of (211,311,43) -1- (2- ( 1 ^ -propyl-; ^-(n-pentylpyridyl) amino) ethyl) -2- (3-fluoro-4-methoxybenzyl) -4- (1,3-benzobenzodine -5-yl) pyrrolidine-3 -like acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 14. · A pharmaceutical composition for treating prostate cancer, comprising a therapeutically effective amount of trans, trans- 2- (4-methoxybenzyl) -4- (1,3-benzodifluorene -5-yl) -1- (N, N-bis (η, butyl) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt 15 A pharmaceutical composition for treating prostate cancer, comprising a therapeutically effective amount of (211,351,43)-(+)-2- (4-methoxyphenyl) -4- (1, 3-Benzenedi-5-yl) -1- (third-butoxycarbonyl-aminocarbonylfluorenyl) -pyrrolidine-3 -carboxylic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof Carrier. 16. —A pharmaceutical composition for treating prostate cancer, comprising a therapeutically effective amount of trans, trans-1- (2- (N-propyl-N- (n-pentylsulfo)) Amino) ethyl) -2- (3-fluoro-4-methoxyphenyl) -4- (1,3-benzobenzoxyl-5-yl) pyrrolidin-3-carboxylic acid or a pharmaceutically acceptable compound thereof Accepted salts and pharmaceutically acceptable carriers. O: \ 46 \ 46585-930217 (CLAIM) .DOC \ 3 _ 4-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 6. Application for patent scope 17. — A kind of therapeutic photography A pharmaceutical composition for prostate cancer, comprising a therapeutically effective amount of trans, trans-2- (2,2-dimethylpentyl) -4_ (7_methoxy-1,3-benzodifluorene -5-yl) -1_ (than 1 bis (11-butyl) aminocarbonylmethyl) -pyrimidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 18 · —A pharmaceutical composition for treating prostate cancer, which comprises a therapeutically effective amount of trans-, trans-2- (4-pyroxybenzyl) _4_ (1,3_benzodi-4- 5-yl) -1-((N-butyldimethylaminobutyl) amino) carbamoylmethyl) each bite-3-protective acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable Carrier. 19. A pharmaceutical composition for treating prostate cancer, comprising a therapeutically effective amount of (2 R, 3 R, 4 S)-1 _ (2-(Ν -propyl- Ν -(η -pentylcontinyl) amino) ethyl) -2_ (3-fluoro-4-methoxyphenyl) -4-(1,3-benzodihum-5-yl) pyrrolidine-3 -A carboxylic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 20 · —A pharmaceutical composition for treating pain sensation (η 〇cicepti ο η), which comprises a therapeutically effective amount of trans, trans- 2- (2,2-dimethylpentyl) -4- ( 7-fluorenoxy-1,3-benzobisfluoren-5-yl) -1- (N, N_bis (η-butyl) aminocarbonylmethyl) -pyrrolidine-3 -carboxylic acid or its Pharmaceutically acceptable salts and pharmaceutically acceptable carriers. 21. —A pharmaceutical composition for treating painful sensations, comprising a therapeutically effective amount of trans, trans- 2- (4-methoxyphenyl) -4- (1,3-benzodihum- 5-yl) -1-((N-butyl-N- (4-dimethylaminobutyl) amino) carbonylmethyl) -pyrrolidin-3-carboxylic acid or a pharmaceutically acceptable salt thereof HEYI-5- O: \ 46 \ 46585-930217 (CLAIM) .DOC \ 3 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) AB c D 581760 6. Application scope Accepted carrier. 22. A pharmaceutical composition for the treatment of pain, comprising a therapeutically effective amount of (2 feet, 311, 48) -1_ (2-(&gt; ^ propyl-1 ^-(11-pentylsulfonate (Amino) amino) ethyl) -2- (3-fluoro-4-methoxyphenyl) -4- (1,3-benzodihum-5-yl) pyrrolidine-3 -carboxylic acid or its medicine Acceptable salts and pharmaceutically acceptable carriers. 23. —A pharmaceutical composition for treating bone pain caused by bone cancer, comprising a therapeutically effective amount of trans, trans- 2- (4-methoxyphenyl) _4- (1,3- Benzodifluoren-5-yl) -1_ (N, N-bis (η-butyl) aminocarbonylmethyl) -pyrrolidin-3-carboxylic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable Carrier. 24. —A pharmaceutical composition for treating bone pain caused by bone cancer, comprising a therapeutically effective amount of (2R, 3R, 4S)-(+)-2- (4-methoxyphenyl)- 4- (1,3-Benzodifluoren-5-yl) -1- (tertiary-butoxycarbonyl-aminocarbonylmethyl) -pyridine-3-carboxylic acid or a pharmaceutically acceptable salt thereof And pharmaceutically acceptable carriers. 25. A pharmaceutical composition for treating skeletal pain caused by bone cancer, comprising a therapeutically effective amount of trans, trans-1- (2- (N-propyl-N- (n-pentan Sulfo) amino) ethyl) -2- (3-fluoro-4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) pyrrolidine-3 -carboxylic acid or Its pharmaceutically acceptable salt and pharmaceutically acceptable carrier. 26. —A pharmaceutical composition for treating bone pain caused by bone cancer, comprising a therapeutically effective amount of trans-trans, trans- 2- (2,2-dimethylpentyl) -4- (7 -Methoxy-1,3 -benzodihum-5-O: \ 46 \ 46585-930217 (CLAIM) .DOC \ 3 * 6-This paper size applies to Chinese National Standard (CNS) A4 Specifications (210 x 297 mm) 581760 A BCD, patent application Fan Yuanji) turn 1 sleep (N, N face di (n-butyl) aminocarbonylmethylpyrrolidine-3 erchiic acid or its pharmaceutically acceptable salt and pharmaceutically acceptable Carrier 27. A pharmaceutical composition for treating bone pain caused by bone cancer, comprising a therapeutically effective amount of trans, trans- 2- (4-methoxyphenyl) -4- (l , 3-Benzodifluoren-5-yl) -b ((N-butyl_N- (4-dimethylaminobutyl) amino) carbonylmethyl) -pyrrolidine-3 -carboxylic acid or Its pharmaceutically acceptable salt and pharmaceutically acceptable carrier. 28 · —A pharmaceutical composition for treating bone pain caused by bone cancer, which comprises a therapeutically effective amount of (2R, 3R, 4S) -1_ (2- (N -propyl-N- (n -pentylsulfo) amino) ethyl) -2- (3-fluoro-4-methoxyphenyl) -4- ( 1,3 -Benzodifluoren-5-yl) exordinol-3-carboxylic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. O: \ 46 \ 46585-930217 (CLAIM). DOC \ 3 scale is applicable to China National Standard (CNS) A4 specification (210 x 297 mm)