TW502018B - Pyrrolidine compounds having endothelin antagonism and their pharmaceutical compositions - Google Patents

Abstract

A compound of the 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. A compound of the formula: wherein R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is -CO2G wherein G is hydrogen; R1 is phenyl, wherein the phenyl can be oprionally substituted with 1, 2, or 3 substitucents independently selected from C1-C6-alkyl, C1-C6-alkoxy, and halo; R2 is benzodioxolyl, wherein the benzodioxolyl can be optionally substituted with 1, 2, or 3 substituents independently selected from C1-C6-alkyl, C1-C6-alkoxy, and halo; R3 is R4-C(O)-R5- wherein R5 is C1-alkylene and R4 is phenyl amino, wherein the phenyl can be optionally substituted with 1, 2, or 3 substituents independently selected from C1-C6-alkyl, C1-C6-alkoxy, carboxy, halo, and nitro.

Description

502018 A7 B7 V. Description of the invention (2) Relieve the side effects of renal hemorrhage on renal vascular resistance and vascular filtration rate (Kon. Et al.? J. Clin. Invest. M. 1762 (1989)). In addition, anti-endothelin antibodies attenuate the renal toxic effects of intravenous administration of cyclosporine (Kon. Et al., Kidney Int. 11 1487 (1990)) and can be used in a coronary myocardial infarction model. Reduce infarct size (Watanabe, et al., Nature 344 114 (1990))

Clozel et al. (Nature 3 65: 759-761 (1993)) reported that Ro 46_ 2005, a nine-peptide ET-A / B antagonist, can prevent renal vasoconstriction after hemorrhage in rats. Avoiding slowing of cerebral blood flow (S AH) due to subarachnoid hemorrhage in rats and reducing the MAP of sodium-depleted weird monkeys (when taken orally). Recently, it has been reported that a similar linear tripeptide ET-A antagonist, BQ-485, has a similar effect on the arterial caliber 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 benefits in the disease states shown Disclosure of the Invention According to the present invention, a compound of formula (I) is proposed: Please read the notice on the back and then load it on page b. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs.

Where R is-(CH2) mW, where m is an integer from 0 to 6, and W is -5- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 502018 A7 __B7 _ V. Description of the invention (3) (a) -C (0) 2_G, where G is hydrogen or a carboxy protecting group, (b) -P03H2, (c) -P (0) (0H) E, where E is hydrogen, lower alkyl Or arylalkyl, (d) -CN, (e) -C (0) NHR17, where R17 is a lower alkyl group, (f) an alkylaminocarbonyl group, 彳 g) dialkylamino group, ( h) Tetracyl-, (i) hydroxyl, 'fluorenyloxy,. (k) sulfonamido, (l) -C (0) NHS (0) 2R16, where r16 is lower alkyl, 卣Alkyl, aryl or diamine, (m) -S (0) 2NHC (0) R16, where R16 is as defined above, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 502018 A7 B7 V. Description of the invention (4) (r) (t) t hT0s or nhso2cf3 (Please read the notes on the back before filling in the page) -Loaded ·

Ri and R2 are independently selected from the group consisting of hydrogen, lower alkyl, fluorenyl, alkynyl, alkoxyalkyl, oxoalkyl, alkyl, odonyl, odonyl, odonyl Alkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkyl Aminocarbonylalkenyl, dialkylaminocarbonylfluorenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, aralkyloxyalkyl, heterocyclyl, (heterocyclic) alkyl and (Raa) (IUb) NR. . -, Wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkylalkyl, and R. . Is an alkylene group, and the restrictions are 1 and 112—or both are not hydrogen; R3 is R4-C (0) R5, or R6-S (0) 2-R7-, where R5 is (i) a covalent bond, (Ii) Shen Yu * base, (iii) Shen Fu base, (^)-1 ^ (& 2.)-Hua 8_ or -1 ^ -1 ^ (仏 2.)-Hua 8- 'Rr, Wherein Rs and R8a are independently selected from the following including alkylene and alkenyl; and R20 is hydrogen, lower alkyl, alkenyl, fluorenyl, alkoxyalkyl, haloalkoxy, cycloalkyl or Cycloalkynyl 'or 〇〇-〇-119_ or -foot 93-〇 * ^ 9-, where R9 and R9a are independently selected from the alkylene group; this paper size applies Chinese National Standard (CNS) A4 specification (210X297 (Mm) Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy 502018 A7 B7 V. Description of the invention (5) Anti 7 is (i) a covalent bond, (ii) an alkylene group, (iii) an alkenyl group, or ( iv) -N (R2 small Rio- or -RwNdD-Rw, wherein R10 and R10a are independently selected from the group consisting of alkenyl and alkenyl, and RS1 is hydrogen, lower alkyl, alkenyl, alkane Alkyl, alkoxyalkyl, alkoxyalkyl, aryl or arylalkyl; wherein R4 and trans 6 are

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs where Ri and R1S are independently selected from the group consisting of lower alkyl, cyano, alkoxy ', fluorenyl and phenyl, and R13 is hydrogen, lower alkyl, From carboxy'nitro or cyano; or (ii) heterocyclic (amino); or a pharmaceutically acceptable salt thereof. Preferred specific examples of the present invention are compounds of formula (Π)

Vf r2 (10 where the substituents -R2, -R, and -Ri exist in trans and trans relationships, and r, R1, R2, and r3 are as defined above. A preferred specific example of the present invention is formula (1 ) Or a compound of (11), wherein ruler 3 is K (c0-R5_, where and 4 are as defined above and ~ is an alkylene group, or ~ is rps (〇) 2-H7-, where r7 is an alkylene group And 116 is defined as above. -—— ^ ——.-8-This paper is from the applicable Zhongguanjiazheng Standard (CNS) A4 specification (21GX297 public) 502018 A7 B7 V. Description of the invention (6) The invention is even better Specific examples are compounds of formula (I) or (II), where R is -C (0) 2_G 'where g is hydrogen or a carboxy protecting group, or r is a tetrazolyl group, or R is -C (0) -NHS ( 0) 2R16, wherein R16 is lower alkyl, haloalkyl or aryl, and Xinyi is independently selected from (i) lower alkyl, (ii) cycloalkyl, (iii) substituted aryl ' Wherein the aryl group is substituted with 1, 2 or 3 phenyl groups, and is independently selected from the group consisting of low-carbon alkyl, alkoxy, amidine, alkoxyalkoxy and carboxyalkoxy, and (iv) substituted Or unsubstituted heterocyclic ring, and Chi 3 is K (〇) -Κ5_, where r4 is as above And Rs is an alkylene group or R.sub.3 is R6_s (〇) 2_R7 •, where R7 is an R.sub.2 and R.sub.6 is as defined above. Also, a preferred embodiment of the present invention is Formula (1) or ( 11) Compound, wherein R is -C (0) 2_G, where G is hydrogen or carboxy protecting group, tetrazolyl or _c (0 > NHSCOhRi6, wherein R10 is lower alkyl, haloalkyl or aryl, Ri Is (0) oxyalkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furyl or (vi) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4- Methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4_propoxyphenyl, 2-fluorophenyl, 4-methoxy Fluorenyloxyphenyl, 4-hydroxyphenyl, 13-benzodifluorenyl, benzobenzofluorenyl, or dihydrobenzofuranyl, wherein the substituent is selected from alkoxy, alkoxy R2 is substituted or unsubstituted, and R2 is substituted or unsubstituted, 3-benzobenzozinyl, 7-methoxy-1,3-benzodiacinyl, benzodihumane 8_ methoxy -1,4-benzodifluorenyl-dihydrobenzofuranmethyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl, and R3 It is R6-S (0) 2_R7 ·, where r7 is an alkylene group and trans 6 is defined as above. 9- This paper size applies the Chinese National Standard (CNS) A4 size (210X 297 cm) Please read the 5 Matters are printed on the page. Printed by the Consumer Cooperative of the Central Procurement Bureau of the Ministry of Economic Affairs. 502018 A7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Printed by B7. 5. Description of the invention (7) Or (11) a compound wherein R is -C (0) 2_G, where G is hydrogen or a carboxyl protecting group, tetrazolyl or -c (0) -NIIS (0) 2R16, where; ^ 16 is low Alkynyl, haloalkyl or aryl, ^^ is ^) alkynyl '(ii) cycloalkyl, (iii) phenyl, (iv) p-pyridyl, (v) p-furanyl, Or (vi) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-trifluoromethyl Phenyl, 4-pentafluoroethylphenyl, 3-fluoro-4_methoxyphenyl, 3-fluoro-4- Ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl'cardiomethoxymethoxyphenyl, renylhydroxyphenyl , Benzodialyl, 1,4-benzodifluorenyl or dihydrobenzofuranyl, wherein the substituent is selected from alkoxy'alkoxyalkoxy and carboxyalkoxy, and r2 is substituted Or unsubstituted 1,3-benzodiamyl, 7-methoxy4,3-benzodiazyl, I # -benzodiazyl, 8-methoxy4,4-benzene Benzodiazyl, dihydrobenzofuran'benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl, and trans 3 is r4_C (〇) _R5_, where R4 is as defined above and r5 is an alkylene group. And a preferred specific example of the present invention is a compound of formula () or (H), wherein r is -C (0) 2_G, where G is hydrogen or carboxy protecting group, tetrazolyl or _C (0) _νβ ^ ( ο) 2ιι16, where R16 is a low carbon or halogenated group, and Ri is a substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-ethoxyphenyl group '4-propoxyphenyl, 3-fluoromethoxyphenyl,% fluoro_4-ethoxyphenyl, 3-fluoropropoxyphenyl, 3-methoxy-4 -propoxyphenyl, 4-trifluoro Methylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, hydroxyphenyl '1,3-% and 1-p-phenylene' 1,4-benzyl Or dihydrobenzo bitan-10- This paper is a standard paper towel (CNS) (21 ^ x297mm) ^ ~ ~ (Please read the precautions on the back before you install-page) Thread A7 B7 V. Description of the invention (8) The group 'wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy' and 2 is 1,3-benzodifluorenyl, 7-methoxyq , 3-benzodifluorenyl, 1,4-benzodifluorenyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorine Or difluorophenyl group, and the heart is ^^ C (0) -R5 · 'wherein I as defined above, and & is an alkylene group. The most preferred embodiment of the present invention is a compound of formula (1) or (11), wherein r is -C (0) 2_G, where G is hydrogen or a carboxy protecting group, and & is a substituted or unsubstituted 4-formaldehyde. Oxy.phenyl, fluorophenyl, 2-fluorophenyl, 3-fluoro_4-ethoxyphenyl '3-fluoro_4-methoxyphenyl, 4-ethoxyphenyl, 4-propane- Oxy.phenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy_4-propoxyphenyl, 4-methoxyoxymethoxyphenyl '4- # benzyl, 4-ethyl Phenyl, U_benzodifluorenyl, benzobenzyl, or dihydrobenzofuranyl, wherein the substituents are selected from the group consisting of alkoxy, alkoxyalkoxy, and carboxyalkoxy, Benzodiaphthyl, 7-methoxy-1,3-benzodifluorenyl, 14-benzodifluorenyl, dihydrobenzofuryl'benzofuranyl, 4-methoxyphenyl, Dimethoxyphenyl, fluorophenyl or difluorophenyl and R3SR4-C (〇) -R5-, where 114 is

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economics where RuKRu is independently selected from the group consisting of lower alkyl groups, and r13 is hydrogen, low carbon alkyl, halogen, carboxyl, nitro, or cyano, and r5 is methylene. The preferred compounds of the present invention include compounds of formula G) or (Π), where R is -C (〇) 2-G, where G is hydrogen or a carboxy protecting group, and Ri is substituted or unselected. The scale is applicable to the Chinese National Standard (CNS) grid (210X297 mm) 502018 A7 B7 V. Description of the invention (9-generation 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 3_fluoro_ 4-ethoxyphenyl, 3-fluoro-4_methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4 _Propoxyphenyl, 4-methoxymethoxyphenyl, 4-triphenyl, 4-ethylphenyl, 1,3-benzodifluorenyl, ι, 4-benzobenzodine Alkyl or dihydrobenzofuranyl, wherein the substituent is selected from alkoxy, alkoxy, and quinoloxy 'is 1,3-benzodiazyl, 7 · methoxy_1, 3-benzodifluorenyl, ι, 4-benzodifluorenyl, dihydrobenzoxanyl, benzofuranyl, .4-methoxyphenyl, dimethoxyphenyl, fluorobenzene Or difluorophenyl, and R3 is R4_C (0) -R5, of which 仏 4 is-, please read the note and then b page

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs where ^^ and! ^ 2 are independently selected from the following including alkoxy and halogen, and r13 is hydrogen, lower alkyl, halogen, carboxy, nitro or cyano, and R5 is methylene. Another preferred embodiment of the present invention is a compound of formula (I) or (II), wherein the ruler is -C (0) 2-G ', where G is hydrogen or a tether protecting group, and Ri is substituted or unsubstituted. 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4- Ethylphenyl, 1,3-benzodiazyl, 1,4-benzodiamidyl or dihydrobenzofuranyl, wherein the substituents are selected from alkoxy, alkoxyalkoxy and carboxy Alkoxy, R2 is 1,3-benzodifluorenyl, 7-methoxy-1,3-benzodifluorenyl, 1,4-benzodifluorenyl, dihydrobenzofuranyl, 12- This paper size applies Chinese National Standard (CNS) A4 specification (21〇 < 297 mm) 502018 A7 B7 V. Description of the invention (10) Benzofuranyl, 4-methoxyphenyl, di Ethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4c (0) -R5-, where H 4 is

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs where Ru & R1: 2 is independently selected from the following including methyl, ethyl, and isopropyl, and is hydrogen, low alkyl, halogen, carboxy, nitro, or cyano And R5 is methylene. Another preferred embodiment of the present invention is a compound of formula (I) or (π), wherein R is -C (0) 2-G ', where G is hydrogen or a protecting group of a group, and Ri is substituted or unsubstituted. 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluoro-4 -ethoxyphenyl, 3-fluoro-4 -methoxyphenyl, 4-ethoxyphenyl, 4 -Propoxyphenyl, 3-fluoro-4 -propoxyphenyl, 3-methoxy-4 -propoxyphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylbenzene Group, 1,3-benzodifluorenyl, ι, 4-benzodifluorenyl or dihydrobenzofuranyl 'wherein the substituent is selected from the group consisting of alkoxy, alkoxyalkoxy and carboxyalkoxy , R2 is 1,3-benzodifluorenyl, 7-methoxy-1,3-benzodihumenyl, Γ, 4-benzodifluorenyl, dihydrobenzofuranyl, benzofuran , 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 疋 R4_C (0) -R5- 'wherein trans 4 is

1½ -13- This paper size applies Chinese National Standard (CNS) A4 specification (2i × 297mm) (Please read the notes on the back before filling in the page) Γ 502018 A7 B7 V. Description of the invention () RuKRu is independently selected from The following includes halo and alkoxy, and R13 is hydrogen, lower alkyl, halo, carboxy, nitro or cyano, and R5 is methylene. The present invention also relates to processes for preparing compounds of formulae (I) and (II), and to synthetic intermediates used in these processes. The present invention also relates to a method for antagonizing endothelin in mammals (preferably humans) in need of the therapy. The method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or (II). The invention further relates to an endothelin antagonistic composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective dose of a compound of formula (I) or (π). -^ The compound of the present invention contains two or more asymmetric substituted carbon atoms. As a result, racemic mixtures, mixtures of diastereoisomers, and single diastereoisomers of the compounds of the present invention are included in the present invention. The so-called "S " and " R" configuration is defined by the IUPAC 1974 Recommendations of Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30. The so-called "n-carboxy protecting group" as used herein means that a carboxylic acid-protecting ester group is used to block or protect a carboxylic acid functional group, and a reaction involving the position of another functional group of a compound proceeds. Several protecting groups are disclosed in Greene, " Protective Groups in Organic Synthesis " pp. 152-186 (1981), which is listed as a reference in this case. In addition, the carboxy-protecting group can be used as a prodrug, because the carboxy-protecting group can be easily dissociated in vivo, such as using enzyme hydrolysis to release a biologically active parent. T. Higuchi and V. Stella provide a full discussion of the concept of prodrugs in "Pro-drugs as Novel Delivery Systems", Vol 14 of the ACS Symposium Series, American Chemical -14- Standard (CNS) Α4 size (210X29 * 7mm) (Please read the precautions on the back before loading —

1T Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs.

Society (1975), which is incorporated herein by reference. This carboxy protecting group is well known to those skilled in the art, and has been sufficiently used to protect carboxyl groups in the fields of penicillin and cephalosporins, as disclosed by U.S. Pet, No. 3,840,556 and 3,719,667, which is incorporated herein by reference. An example of an ester containing a carboxyl group that can be used as a prodrug of a compound can be found in " Bioreversible Carriers in Drug Design: Theory and Application ", edited by E. B. Roche, Pergamon Press, New York (198), which is listed as a reference in this case. Typical carboxy protecting groups are Cl_c8 alkyl (such as methyl, ethyl or tertiary, butyl, etc.); haloalkyl; alkenyl; cycloalkyl and its substituted derivatives, such as cyclohexyl, cyclopentyl Groups, etc .; 'Cycloalkylalkyl and its substituted derivatives such as cyclohexylmethyl, cyclopentylmethyl, etc .; ; Aryl or nitrofluorenyl, etc .; arylalkenyl, such as phenethyl, etc .; aryl and its substituted derivatives, such as 5-hydroindenyl, etc .; dialkylaminoalkyl (such as dimethylamino Ethyl, etc.); alkoxyalkyl groups such as ethoxymethyl; butyloxymethyl, pentyloxymethyl, isobutyloxymethyl, isopentyloxymethyl, 1_ (Propanyloxy) -1-ethyl, 1- (pentamyloxy) ethyl, 1β > methyl_1β (propanyloxy) -1-ethyl, pentamyloxymethyl, propylamidine oxygen Methyl groups, etc .; cycloalkanoyloxy groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentaquinoxymethyl 'cyclohexyloxymethyl, etc .; arylmethyloxy Alkyl groups, such as alkoxycarbonyl, + ethoxyethyl, etc .; aryl carbonyloxy fluorenyl, such as carbonyloxymethyl '2-benzylcarboxyoxyethyl, etc .; alkoxycarbonylamino , Such as methoxycarbonylfluorenyl, cyclohexyloxycarbonylfluorenyl, 1-methoxycarbonylβ1-ethyl, etc .; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, third, butoxycarbonyloxymethyl , Buethoxycarbonyloxy-1-ethyl, 1-cyclohexyloxycarbonyloxy-I ethyl, etc .; Alkoxycarbonylamine 15- This paper size applies to Chinese National Standard (CNS) A4 size (21〇X297) ) (Please read the precautions on the back first). Pack. 502018 A7 B7 V. Description of the invention (13) Alkyl, such as third, butoxycarbonylaminomethyl, etc .; alkylaminocarbonylamino alkyl, such as Methylaminocarbonylaminomethyl, etc .; alkylaminoaminoalkyl, such as ethylaminoaminomethyl; etc .; heterocyclic carbonyloxyalkyl, such as 4-methylhexahydrogen p ratio, arylmethyloxy, etc. ; Dialkylaminocarbonylalkyl, such as dimethylaminocarbonyl Methyl, diethylaminocarbonylfluorenyl, etc .; (5- (lower alkyl) -2-keto-1,3-dioxocene-4-yl) alkyl, such as (5-third, Butyl-2-keto_1,3-dioxocen-4-yl) methyl, etc .; and (5-phenyl_2-keto-1,3-difluorenocen-4-yl) Alkyl, such as (5-phenyl-2-keto-1,3-dioxocen-4-yl) methyl etc. The so-called " N-protecting group "or ffN-protected." As used herein, it is meant to protect the N-terminus of the amino acid or peptide, or to protect the amino acid from antagonizing non-desirable reactions in the synthetic step. Commonly used N-protecting groups are disclosed in Greene, " Protective Groups In Organic Synthesis, " (John Wiley & Sons, New York (1981)), which is listed as a reference in this case. N-protecting groups include fluorenyl groups such as formamyl, ethenyl, propionyl, pentamyl, tertiary, butylethylfluorenyl, 2-chloroethylfluorenyl, 2-bromoethylfluorenyl, trifluoroethyl Fluorenyl, tris (1,4-ethyl) phenyl, phthalofluorenyl, z-nitrophenoxyethylfluorenyl, chlorobutylfluorenyl, benzylfluorenyl, 4-chlorobenzylfluorenyl, 4-bromobenzylfluorenyl, 4-nitrobenzyl Fluorenyl groups, etc .; sulfonyl groups such as benzenesulfonyl groups, para-toluene fluorenyl groups, etc .; carbamate forming groups such as benzyloxycarboxyl groups, para-chlorofluorenoxycarbonyl groups, para-fluorenyloxycarbonyl Carbonyl, para-nitrophosphonium oxycarbonyl '2-nitrooneoxycarbonyl, para-bromobenzyloxycarboxyl, 3,4-dioxobenzyloxycarboxyl' 3,5-dimethoxyloxy, 2,4-dimethoxybenzyloxycarboxyl, 4-methoxymethoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarboxyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (para-biphenylmethylethoxycarbonyl, α, pan-dimethyl-3,5-dimethoxyfluorenyloxycarbonyl, diphenylmethyloxycarbonyl, third, -16 · this paper Dimensions are applicable to Chinese National Standard (CNS) Α4 specifications (210 × 297 mm) ~ ^ (Please read the precautions on the back before loading. 5 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China 502018 A7 B7 5. Description of the Invention (14) Butoxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxy Carbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl '4-nitrophenoxycarbonyl, fluorenylmethoxycarboxyl, cyclopentyloxycarboxyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylsulfide Carbonyl groups, etc .; alkyl groups such as benzyl, benzyl, benzyloxymethyl, and the like; and stilbenzyl groups such as trimethylstilbenzyl and the like. Preferred N-protecting groups such as methyl ethyl group, ethyl ethyl group, and the like Alkyl 'pentyl' is tris, butyl ethylsulfonyl, phenylsulfonyl, fluorenyl, tertiary, butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). The so-called "fluorenyl" is as follows The fluorenyl group used, as previously described, is added to the parent molecular moiety through a carbonyl group (-C (O)-). Examples of the alkyl fluorenyl group include ethenyl, propionyl and the like. "Amidino" as used herein refers to an amidino group, as previously defined, added to an amine group. Examples of alkylamino groups include acetamido, propylamido, and the like. Referred to as π alkylaminoalkyl alkyl •• as used herein refers to r43_NH-R44-where r43 is alkyl alkyl and R44 is alkylene. The so-called H alkyl alkoxyalkyl " as used herein refers to R3 ( r〇-R3i_, where R30 is a methyl group and an RnS group is exemplified. Examples of the oxyalkyl group include ethoxymethyl, ethoxyethyl, etc. Employee Cooperatives, Central Standards Bureau, Ministry of Economic Affairs The so-called "alkenyl" is used to refer to a straight or branched hydrocarbon group containing 2 to 15 carbon atoms, and also contains at least one carbon-carbon double bond. Examples of alkenyl groups include ethenyl, propenyl, butylene Alkenyl, 1-methyl-2-butan-1-yl and the like. The term " endenyl " means a divalent radical derived from a straight or branched chain hydrocarbon containing 2 to 15 carbon atoms, and also contains at least one post-carbon double bond. Example of an alkenyl-17 · This ^ Zhang scale is applicable to the Chinese National Standard (CNS) A4 * m (210X 297¾) — '" " 502018 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 ____ B7 V. Invention Explanation (15) includes -CH = CH-, -ch2ch = ch «·, -c (ch3) = ch-, -ch2ch = chch2-, and so on. The so-called "alkenyloxy" refers to a fluorenyl group, as defined above, connected to the parent molecular moiety through an oxygen (-0-) link. Examples of alkenyloxy include allyloxy, butenyloxy and the like. As used herein, "alkoxy" refers to R41-, where R41 is a lower alkyl group, as defined herein. Examples of the alkoxy group include, but are not limited to, methoxy, ethoxy, propoxy, tertiary, butoxy, and the like. " Methoxyalkoxy " as used herein refers to R80〇-Rsi〇 ^, and its punching rule ⑽ is a low-carbon alkynyl group, as defined above, and ^^ is an elongation group. Representative of oxyoxyalkoxy group Examples include methoxymethoxy, ethoxymethoxy, tertiary, butoxymethoxy, etc. The so-called πalkoxyalkoxyalkyl, as used herein refers to alkoxyalkoxy Group, as previously defined, is added to the alkyl group. Representative examples of alkoxyalkoxyalkyl groups include methoxyethoxyethyl, methoxyfluorenylmethyl, etc. The so-called " alkane An oxyalkyl group, as used herein, refers to an alkoxy group, as previously defined, is added to an alkyl group. Examples of alkoxyalkyl groups are methoxyfluorenyl, methoxyethyl 'isopropoxymethyl Etc. It is stated that the "fluorenyloxy group" refers to an alkoxy group, as defined previously, which is added to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl groups include methoxyalkyl, ethoxycarbonyl , Isopropyloxycarbonyl, etc. The so-called "fluorenylcarbonyl" refers to an alkoxycarbonyl group, as previously defined, added to a fluorenyl group. Examples of alkoxycarbonylalkenyl include methoxycarbonylvinyl, ethoxycarboxyvinyl, and others. (Please read the precautions on the back first, then the page) • Binding and Threading --- -18-This paper size is suitable for financial and family care_ (CNS) 8 4 Na (2iGX297 mm) " 502018 Central Bureau of Standards, Ministry of Economic Affairs Printed by employees' consumer cooperatives A7 _ _B7 V. Description of the invention (16) The so-called alkoxycarbonylalkyl, as used herein, refers to R34_c (〇) inferior π, where R34 is an alkoxy group and Kb is an alkylene group. Examples of the alkoxycarbonylalkyl group include methoxycarboxymethyl'methoxymethyl, ethoxycarbonylmethyl and the like. The so-called "alkoxycarbonylaminoalkyl group", as used herein, refers to R3s_q0> NH-R39_, where R38 is an alkoxy group and r39 is an alkylene group. The so-called "alkoxycarbonyloxyalkyl group, as used herein, means R36_C (〇 > 〇-R37-, where R36 is an alkoxy group and r37 is an alkylene group. The so-called " (alkoxycarbonyl) thioalkoxy " as used herein refers to an alkoxycarbonyl group, as defined before It is added to the thioalkoxy group. Examples of the (alkoxycarbonyl) thioalkoxy group include a methoxycarbonylthiomethoxy group, an ethoxycarbonylthiomethoxy group, and the like. The so-called " carbon group " and " low carbon appearance "" Means herein a straight or branched alkyl group containing 1 to 15 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second, butyl, Third, butyl, n-pentyl, methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and others. "Amine group" as used herein refers to R51NH-, where R51 is a low-carbon alkyl group such as ethylamino, butylamine, etc. The so-called "alkylaminocarbonyl group" as used herein refers to an alkylamino group, as previously defined It is added to the parent molecular moiety via a carbonyl (-c (o)-) chain. Examples of the alkylaminocarbonyl group include methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, etc. The so-called "alkylaminocarbonylene" "Alkyl" as used herein refers to an alkenyl group with an alkylamine carbonyl group. The so-called "alkylaminocarbonylamino group" refers to a lower alkyl group with an alkylamine carbonyl group. (Please read the note on the back first Matters re-installation · page) _

-19- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm T 502018 A 7 B7 V. Description of the invention (17) "Alkylaminocarbonylaminoalkyl" as used herein refers to R4 (rC (0 ) -R41-, where r40 is an amine group and R41 is an alkynyl group. The so-called "alkylene" refers to the removal of two hydrogen atoms from a straight or branched saturated hydrocarbon containing 1 to 15 carbon atoms. Derived divalent groups, W-CH2-, -CH2- CH2-, -CHCCBb)-, -ch2ch2ch2-, -ch2c (ch3) 2ch2-, etc. The so-called "alkylsulfonamido" refers to The alkyl group, as previously defined, is added to the parent molecular moiety through a sulfaminino group (s (o) 2-nh). Examples of the alkylsulfonamido group include methylsulfonamido, ethylsulfonamido, isopropyl

Glycerol and other amino groups. -I so-called " alkynyl " as used herein refers to a straight or branched hydrocarbon group containing 2 to 15 carbon atoms, and also contains at least one carbon-carbon triple bond. Examples of alkynyl groups include _c tri CH, HC s C-CH2-, HC tri-C-CH (CH3)-, etc. The so-called "aminocarbonyl π" as used herein refers to H2N-C (; 0;)-. The so-called "amine postalkenyl" refers to a fluorenyl group, which is added to an amine carbonyl group (NH2C (0)-). The term "aminocarbonylalkoxy" as used herein refers to Η2N-(:( 0)-, added to an alkoxy group, as previously defined. Examples of aminecarbonylalkoxy groups include aminecarbonylalkoxy'amino groups Ethylethoxy and others. The so-called "aminocarbonylalkyl" is defined as a lower alkyl group, in which an aminecarbonyl group (NH2C (0)-) is added. The so-called " arylaminooxyalkyl group " As used herein, it refers to R32_C (0) _0_R33_, where R32 is an aryl group and R „is an alkylene group. Examples of aralkyloxyalkyl groups include alkoxymethyl, alkoxyethyl, etc. The so-called & quot Aromatic, as used in this case refers to a sheet with-or two aromatic rings -20- (Please read the precautions on the back before printing), τ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy-ί-502018 A7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs_B7 V. Description of the Invention (18) One or two ring carbocyclic ring systems, but not limited to phenyl, fluorenyl, tetrahydrolanyl, indenyl, indenyl, etc. .Aryl may be unsubstituted or substituted with 2 or 3 substituents independently selected from the group consisting of Alkyl, haloalkoxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkynyl '(alkoxyalkyl) sulfanyloxy, sulfanyloxy Group, amino group, alkylamino group, dialkylamino group, aminocarbonyl group, aminocarbonylalkoxy group, alkylamino group'arylalkyloxy group, aryloxy group, mirror group, cyano group, nitro group, bond group Acid, several groups, carboxyalkenyl, carboxyalkoxy, alkyl sulfonylamino, cyanofluorenyl, (heterosynthetic) peroxy, phenyl and tetra-4 In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl groups. The so-called " arylfluorenyl " refers to alkenyl groups, which are added with aryl groups, such as styryl, etc. The so-called "arylalkoxy" refers to R42-, where R42 is an aryl group such as benzyloxy. The so-called "arylalkoxyalkyl" refers to a low carbon Alkyl, which is added with arylalkoxy, such as benzyloxymethyl, etc. The so-called "aralkyl" as used herein refers to an aryl group, as previously defined, added to a lower alkyl group, such as fluorenyl, etc. . The so-called "aryl oxygen" "As used herein means R45〇-, where R45 is an aryl group, such as phenoxy, etc. The so-called" arylalkylcarbonyloxyalkyl "as used herein refers to a lower alkyl group, which is added with an arylalkyl group Carbonyloxy (ie, R62C (〇) (> where arylalkyl is an arylalkyl group). The so-called " aryloxyalkyl " refers to an aryloxy group, as previously defined, added to an alkane ___ -21 -This paper size is applicable to China National Standard (CNS) A4 specification (210X2 ^ 7mm)-" " ~ (Please read the precautions on the back before loading. Page) Order 502018 A7 B7 V. Description of the invention (19 ) Base. Examples of aryloxyalkyl include phenoxymethyl, 2-phenoxyethyl and the like. The so-called " carboxaldehyde " as used herein refers to a formaldehyde group, _c (〇) H. "So-called " carboxy" as used herein refers to a carboxylic acid group, _c (〇) 〇H. So-called " carboxyalkenyl "as used herein refers to a carboxyl group, as previously defined, added to a fluorenyl group, as previously defined . Examples of the quinenyl group include 2- quinvinyl '3 -multil-1-ethenyl and the like. The so-called π-carboxyalkoxy " refers to a carboxyl group, as previously defined, added to a mesoxy group, as previously defined. Examples of carboxyalkoxy include carboxyfluorenyloxy, carboxyethoxy, and the like. The so-called "cyanoalkoxy" as used herein refers to an alkoxy group, as defined previously, which is added to a cyano group (-CN). Examples of cyanoethoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like. The so-called " cycloalkanoyloxyalkyl " as used herein refers to a lower alkyl group to which a cycloalkanoyloxy group (ie, R6〇-C (0) -0-, where r6〇 is a cycloalkane) is added. base). The so-called " cycloalkyl group " 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-hostinyl, and 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 Group, amino group, alkylamino group, dialkylamino group, hydroxyl group, fluorenyl group, nitro group, carboxylic acid, carboxyl group, alkoxycarbonyl group and carboxamido. The so-called " cycloalkylalkyl " Refers to a cycloalkyl group, added to a lower alkyl group, including cyclohexylmethyl, but is not limited thereto. So-called, a dialkylamino group " refers to R56R57N- as used herein, wherein R56 and R57 are independently selected from lower alkyl groups Base, such as diethylamino, methpropylamino, etc. • 22-_ This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before loading. • Central of the Ministry of Economic Affairs Printed by the Standards Bureau Consumer Cooperatives 502018 A7 B7 V. Description of the Invention (20) The so-called " dialkylaminoalkyl group " Used refers to a lower alkyl group which is added with a dialkylamino group. The so-called "dialkylaminocarbonyl group" as used herein refers to a dialkylamino group, as previously defined, via a carboxyl (-C (O)-) chain Junction is added to the parent molecular moiety. Examples of dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl, etc. The so-called "dialkylaminocarbonylfluorenyl" as used herein refers to alkenyl groups, which are added to Dialkylaminocarbonyl. The so-called "dialkylaminocarbonylalkyl" refers to r50-C (0) -R51- as used herein, where R50 is a dialkylamino group and R51 is an alkylene group.-»The so-called " Halo " as used herein refers to I, Br, C1 or F. The so-called " from alkenyl " as used herein refers to a fluorenyl group that adds at least one halogen substituent. The so-called "_alkoxyπ is as such As used above, it refers to an alkoxy group, as defined above, which carries at least one halogen substituent, such as 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2,2 , 3,3,3-pentafluoropropoxy, etc. The so-called " fluorenyl group " as used herein refers to a low-carbon alkynyl group, which is added with a haloalkoxy group. The so-called "self-calcined group" as used in this A low-carbon alkyl group, as defined above, adds at least one functional substituent, such as chloromethyl, fluoroethyl, trifluorofluorenyl, or pentafluoroethyl, etc. The so-called "heterocyclic" as used herein means containing Heteroatoms are selected from any 3- or 4-membered ring of oxygen, nitrogen and sulfur; or contain 1, 2 or 3 nitrogen atoms; 1 oxygen atom; 1 sulfur atom; 1 nitrogen and 1 sulfur atom; 1 1 nitrogen and 1 oxygen atom · 2 oxygen atoms are at non-adjacent positions; 1 oxygen and 1 sulfur atom are at non-adjacent positions -23- This paper applies the Chinese National Standard (CNS) A4 · (210X ^ 57 (Please read the precautions on the back first, then true) Printed by the Consumers 'Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs and Printing 502018 A7 B7 V. Invention Description (21) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs; or 2 sulfur Atoms in non-adjacent positions, 6 • or 7-membered rings. The $ member ring has 0_2 double bonds, and the 6_ and 7_ member rings have 0_3 double bonds. The nitrogen heteroatom can be quaternized as needed. The so-called " heterocycle " also includes bicyclic groups, in which one of the above heterocycles is fused with a benzene ring or a cycloalkane ring or another heterocyclic ring (eg, indolyl, = indolyl, quinolinyl, Isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl 'decahydro-4linyl, decahydroisoquinolinyl, benzofuranyl, dihydrobenzocranyl or benzothienyl, etc.) . Heterocyclics include: aziridinyl, azetidinyl, errolyl, · pyrrolidinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, hydrazone, imidazolyl, imidazolinyl, · imidazolyl , Morphinyl, hexahydropyridyl, homohexahydropyridyl, pyrimidinyl, hexahydropyridyl, pyrimidinyl, dacrotyl, oxazolyl, oxazolyl, isoxazolyl, isoxazole Pyridinyl, morpholinyl, thiomorpholinyl, Psarzolyl, oxazolyl, isoxazolyl, isoxazolyl, indolyl, oxolinyl, isoquinolinyl, benzo Imidazolyl, benzopyridyl, benzopyridyl, ethoxycarbyl, succinyl, tetrahydrosuccinyl, cetylenyl, styrenyl, isoTTY, styrenyl, Tetrabenzyl, isoxazolyl, oxadiazolyl, Padiazolyl, pyrrolyl, pyrimidinyl and benzofluorenyl. Heterocycles also include compounds of formula 0, where X * is -CHr or _0_, and Y * is -c (0) or [-C (R ") r] v, where R " is hydrogen or CVC4 alkyl, and v is 1, 2 or 3, such as 1,3-benzodioxanyl, 1,4-benzodioxanyl and the like. Heterocycles also include bicyclic systems, such as 17 Kundian.

-24 This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the notes on the back before loading-page) Order 502018 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 2. Description of the invention (22) The heterocyclic ring may be unsubstituted, mono-substituted, di-substituted, or tri-substituted. The substituent is independently selected from the group consisting of light group, keto group (= 〇), alkylimine group, (R * N =, Where R is a low-carbon alkyl group) 'amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, haloalkyl, cycloalkyl, aryl, phenyl, aryl Alkyl, -COOH, -SO3H, alkoxycarbonyl, nitro, cyano and lower alkyl. In addition, nitrogen-containing heterocycles may be N-protected. By "(heterocyclic) alkoxy" as used herein is meant a heterocyclic group, as defined above, added to an alkoxy group, as defined above. Examples of (heterocyclic) alkoxy groups include 4-pyridylmethyl Oxygen, 2-pyridyl · methoxy, etc.-, "(heterocyclic) alkyl" as used herein refers to a heterocyclic ring, as defined above, added to the bottom carbon alkyl group, as defined above. The so-called "heterocycle (amino group)" refers to RtNH-, where R77 is an aromatic heterocyclic group, as defined above, which is added to the amine group. The aromatic heterocyclic ring may be substituted by a substituent or ^^ Both of them are bonded to the atom of the aromatic heterocyclic ring, and they are directly added to the nitrogen. R75 and R76 are substituents independently selected from a hydroxyl group, a halogen, a keto group (= 〇), and an alkylimide group (R * N = where R * is a lower alkyl group), amine, alkylamino, dialkylamine, alkoxy, alkoxyalkoxy, alkyl, cycloalkyl, aryl, phenyl, aromatic Alkyl, -COOH, -S03H, alkoxycarbonyl, nitro, cyano, and lower fluorenyl. The aromatic heterocyclic ring can also be substituted by a third substituent, which is selected from hydroxy, halo, and ketone. (= 〇), alkylimine, (R * N = where R * is a lower alkyl group), amine, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, From alkyl, cycloalkyl, aryl, phenyl, arylalkyl, -COOH, -SO3H, alkoxycarbonyl, nitro, cyano and lower alkyl groups. "As used herein refers to r46-C (〇) _〇_Rw, its -25- Applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back first-pack-^^ 4 pages) Line 2018 2018 A7 B7 V. Description of the invention (R46 in 23 is a heterocyclic group, and r47 is an elongation group. The so-called "hydroxy" is referred to as -OH. The so-called "alkenyl" refers to a fluorenyl group, which adheres to a light group. The so-called "arylene" "Alkyl" as used herein refers to alkoxy, which is added to a hydroxyl (-OH) group as previously defined. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4-¾ylbutoxy, etc. The so-called & quot "Suialkyl" refers to a lower-carbon alkyl group, which is added with a hydroxyl group 0--i as described in "woven group" refers to -S Η 0 so-called "methylenedioxy group" and "Ethylenedioxy" refers to the attachment of i or 2 carbon chains to the parent molecular moiety through two oxygen atoms. In the case of methylenedioxy, a fused 5-membered ring is formed. In the case of oxygen, a fused 6-membered ring is formed. Methylenedioxy substitution on the benzene ring causes the formation of benzodioxo. (Please read the note on the back first Matters then - loaded - page) book

Ethylenedioxy substituted on the benzene ring, resulting in the formation of benzodioxanyl

The so-called "essentially pure" means that more than 95% of the indicated compounds are used. The term "tetrazolyl" as used herein refers to a group of the formula or a tautomer thereof.

Vn

1 vV 26- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297mm line printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 502018)

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (24) The so-called "four-junky alkoxy group" refers to four-junky group, as defined above, added to alkoxy As defined above. Examples of tetrazolylalkoxy groups include tetradecylmethoxy, tetramodal ethoxy, etc. The so-called "thioalkoxy" means as used herein, wherein R70 is a lower alkyl base. Examples of thioalkoxy include methylthio, ethylthio, and the like, but are not limited thereto. The so-called " thioalkoxyalkoxy " as used herein refers to R80S-Rsi, in which Chi 80 is a lower alkyl group as defined above, and Rsi is an alkylene group. Representative examples of the alkoxyalkoxy group include CH3SCH20-, EtSCH20-, > BuSCH20_, and the like. The so-called "thioalkoxyalkoxyalkyl" refers to a thioalkoxyalkoxy group as used herein, and is added to the alkyl group. Representative examples of the alkoxyalkoxyalkyl group include CH3SCH2CH2OCH2CH2-, CH3SCH2OCH2- , Etc. The so-called " trans, trans " as used herein refers to the direction of substituents (Ri & R2) compared to the central substituent R, as shown: The so-called " trans, cis " The direction (1 and 2) of the substituents used in this case compared to the central substituent R is as shown:

This definition includes two examples where R and R2 are cis and R and I are trans, and H2 and R are trans and R and Ri are cis. -27- This paper size applies the Chinese National Standard (CMS) A4 specification (210x297 public holidays) (please read the precautions on the back first),-! 502018 Α7 Β7 V. Description of the invention (25) The so-called cis 'Cis' refers to the direction of the substituents (Ri and R2), as compared to the central substituent R, as shown in R Ri. Representative compounds of the invention include: trans, trans_2 -(4-fluorenoxyphenyl) -4- (1,3-benzobenzoin-5-yl) -bu ((2,4,6-trimethyl) phenylaminocarbonylmethyl) _pyrrole Pyridinecarboxylic acid, trans'trans-2- (3-fluoro-4-methoxyphenyl) -4- (1,3_benzo-dizaki f-5-yl) * " Bu ((2 , 4,6-Main methyl) phenylaminecarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, trans-2- (4 • propoxyphenyl) -4- (1,3-benzene Hydrazaki-5-yl) -1-((2,4,6-trimethyl) phenylaminecarbonylmethyl) -pyrrolidine-3 · carboxylic acid, trans, trans_2_ (4-form Oxyphenyl) _4_ (1,3_benzodifluoren-5-yl) -1 _ ((2,6-diethyl) phenylamine carbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, Trans-2- (4-propoxyphenyl) -4- (1,3-benzodifluoren-5-yl) -1 _ ((2,6_diethyl) benzene Aminoamine carbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, trans-2- (3-fluoro-4-methoxyphenyl) -4- (1,3-benzodihum-5- Base is 1 mono ((2,6-diethyl) phenylamine carbonylmethyl) -pyrrolidine-3-carboxylic acid, printed by trans-'trans-2- (3 -Ga-4-ethoxygenyl) -4- (1,3 -pyridobis-β-dethio-5-yl) ((2,6-diethyl) anilinecarbonylfluorenyl) -pyrrolidine-3- Carboxylic acid, trans, trans-2- (3-fluoro-4-methoxyphenyl) -4- (7-methoxy-I, 3-benzodiyl) -1-((2,6- Diethyl) anilinecarbonylmethyl) -pyrrolidine-3-carboxylic acid 'trans, trans-2- (3-methoxy-4-propoxyphenyl) -4- (1,3-benzo Di-Hen-5-yl) -1-((2,6-diethylphenyl) amine chitomethyl) -Ehadian-3-treason 'This paper size applies to China National Standard (CNS) M specifications (210X297 mm) -28- __ 502018 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the invention (26) trans'trans-2- (4 • ethoxyphenyl) -4- (1 , 3-Benzodizaki 5-yl) -1-((2,6-diethylphenyl) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, trans-2- (4 - Oxyphenyl) -4- (1,3-benzodiazine-5-yl) -1-((2,6-xylyl) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans , Trans-2- (4-propoxyphenyl) -4- (7-methoxy-1,3-benzodiazine-% yl) -1-((2,6-diethylphenyl) Amino-Ethyl-Methyl)-7-pyrrolidine-3-acid 'trans, trans-2- (4-methoxy-4-propoxyphenyl) -4- (7-fluorenyl- 1,3-Benzodiazepine-5 -yl) -1-((2,6-diethylphenyl) aminomethyl) -r-pylonol-3-carboxylic acid, i trans, trans Formula 2- (4-methoxyphenyl) _4- (l, 3-benzodiaphthm-5-yl) -l-((2,6-dibromo) anilinemethyl) biloline- 3-carboxylic acid, [2R, 3R, 4S] -2- (4-methoxyphenyl) _4- (1,3-benzodi 4-5 -yl) -1- (N- (2,6- Diethyl) aniline carbonylmethylpyrrole-3-polyacid, trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) -1-((2,6-xylyl) phenylamine carboxyfluorenyl) -erodoline-3-acid, trans, trans-2- (4-methoxyphenyl) -4_ (1 , 3-Benzodi-4-5-yl) -1-((4-bromo-2,6 · diethylmethyl) anilinecarbonylfluorenyl) -pyrrolidine-3-carboxylic acid, trans, trans- 2- (4-methoxyphenyl) -4- (1,3-Benzobenzo-5-yl) -1-((2-ethyl-6-methyl) anilinomethylbiloline-3-chinic acid, trans, trans Formula 2- (4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) -1-((2,4,6-triethyl) anilinecarbonylmethyl)- Pyrrolidine-3-carboxylic acid, [2R, 3R, 4S] -2- (4-propoxyphenyl) -4- (1,3-benzodolin-5-yl) -1- (N- ( 2,6--ethyl) epiaminomethyl) -orbiorox-3_retevic acid, trans, trans_2- (4-methoxyphenyl) _4_ (1,3_benzo Nisaki-ji)-] L-((2,6- _ -29- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before-installation-page) Order 502018 A7 ____B7 _ — 5. Description of the invention (27) Diisopropyl) aniline carbonylmethyl) _pyrrolidine_3 _carboxylic acid, trans, trans-2- (4-methoxyphenyl) -4 -(1,3-benzodihen-5-yl) small ((2,6-diethyl-4-methyl) anilinecarbonylmethyl) -pyrrolidine-3-carboxylic acid, (211,311, 48) _2_ (4_ethoxyphenyl) -4- (1,3-benzodifluoren-5-yl) small ((2,6-^ ethyl) aniline chinomethyl) -ρbilo Nine-3-Chinic acid, trans, trans-2- (4-_oxophenyl) -4- (1 , 3-Benzodilin-5-yl) -1 _ ((4-carboxy-2,6-diethyl) anilinecarbonylmethylpyrrolidine-3-carboxylic acid, trans, trans-2- (4 -Methoxyphenyl) -4- (1,3-benzodiazine-5-yl) -1-((4-nitro-2,6-diethyl) anilinecarbonylmethylpyrrolidine_3- Onconic acid; trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodifluoren-5-yl) -1-((2-isopropyl-6- Methyl) anilinecarbonylmethylpyrrolidine_3_carboxylic acid, trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodioxin-5-yl) -1 -(N- (2-ethyl-6-methoxy) anilinecarbonylmethyl) -pyrrolidin-3-carboxylic acid, or a pharmaceutically acceptable salt thereof. Preferred compounds of the present invention are selected from the group consisting of: trans'trans-2- (4-fluorenoxyphenyl) -4- (1,3 -epidithio-5-yl ((2 6 · diethyl ) Aniline (phenylfluorenyl)-!? Pyrrolidine-3-metanoic acid, trans'trans-2- (4-propionylphenyl) -4- (1,3-wood and di 17 _ 5 -Methyl-6 monoethyl) aniline and phenylmethyl) -exo-b-Hadine-3-acid, transgenic, trans-2_ (3_fluoro_4_methoxy) Phenyl) -4_ (1,3-benzobenzoinyl) i ((2,6-diethyl) anilinecarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, trans-2- ( 3-fluoro-4-ethoxyphenyl) -4- (1,3-benzodifluorenyl) and ((2,6-diethyl) anilinecarbonylmethyl) -pyrrolidine-3-carboxylic acid, -Trans, trans-2- (3-fluoro-4-methoxyphenyl) -4- (7-methoxy-1,3-benzidobi, -30- This paper size applies to Chinese national standards ( CNS) A4 specification (210 × 297 mm) 502018 A7 B7 V. Description of the invention (28). C Please read the precautions on the back before 5-yl) -1-((2,6-diethyl) aniline carbonylmethyl Pyrrolidine-3-carboxylic acid, trans, trans-2- (3-methoxy-4-propoxyphenyl) -4- (1,3-benzodifluorenyl -1-((2,6-monoethyl) aniline methyl) _I? Billoven_ 3-polyacid, trans, trans-2- (4-ethoxyphenyl), benzene Benzodifluorenyl-5-yl)-] L _ ((2,6_diethyl) anilinemethyl) -Epgoline_3_guinic acid, trans, trans-2- (4-propoxy Phenyl) -4- (7-methoxy-1,3-benzodifluorenyl) -1-((2,6-diethyl) anilinecarbonylmethyl) _pyrrolidine-3_carboxylic acid, Trans, trans_2- (3-methoxy-4-propoxyphenyl) -4- (7-fluorenyl-1,3-benzyl-2-inyl) -1-(( 2,6-diethyl) anilinecarbonylmethylpyrrolidine_3-carboxylic acid, [2R, 3R, 4S] 2- (4-methoxyphenyl) -4- (l, 3-benzodifluorene- 5-yl) -l- (N_ (2,6-diethyl) aniline carbonylmethyl) 4 than pyridin-3- | acid,-° [2R, 3R, 4S] 2- (4-propoxy Phenyl) -4- (l, 3-benzodiain-5-yl) -l- (N- (2,6-monoethyl) anilinemethyl) -bamboo (: Luodian-3- Diacid; and (2R, 3R, 4S) -2- (4-ethoxyphenyl) -4- (1,3-benzobenzo-5-yl) -1-((2,6-diethyl ) Aniline carbonylmethyl) -pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. The preferred compound is trans, trans-2- (4-propoxyphenyl) -4- (1,3-benzodiazine-5-yl) -1-((2,6-diethyl) Anilinecarbonylmethyl) -pyrrolidine-3-carboxylic acid; [2R, 3R, 4S] 2- (4-methoxyphenyl) _4- (1,3-benzodihum-5-yl) -1- (N- (2,6-monoethyl) aniline carboxymethyl) β-pyridine-3-carboxylic acid, [2R, 3R, 4S] 2- (4-propoxyphenyl) -4- (1, 3-benzodihum-5-yl) -1- (N- (2,6-diethyl) anilinecarbonylmethyl) _pyrrolidine_3_carboxylic acid; and. (2R, 3R, 4S)- 2- (4 • Ethoxyphenyl) -4- (1,3_benzodizaki-5- Basic paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 502018 Α7 Β7 Central Ministry of Economic Affairs Printed by the Standards Bureau Consumer Cooperatives V. Description of the Invention (29) Diethyl) aniline carbonylmethyl) -pyrrolidinecarboxylic acid; or a pharmaceutically acceptable salt thereof. The method for preparing the compounds of the present invention is shown in Scheme I_v11. Chengyi I illustrates the general procedure for preparing compounds of the present invention, where m is 0 and w is -C02n, a ketoester λ, where £ is a lower alkyl or carboxy protecting group, and reacted with a nitrovinyl compound 2- In the presence of the test (such as 丨, 8-diazodicyclo [5.4.0] undecane 7-ene (13) 81;) or sodium ethoxide or sodium hydride, etc., in an inert solvent such as toluene, benzene, Tetrahydrofuran or ethanol. Reduce the condensation product 2_ (such as the use of Raney nickel or platinum catalyst for hydrogenation. Widely cyclize the generated amine to form dihydropyrrole i. I in THF solvent reduction (such as sodium cyanoborohydride or catalytic Hydrogenation, etc.), can produce pyrrolidine compounds, as a mixture of cis-cis, trans, trans and cis, trans products. Chromatographic separation can remove the cis-cis isomers, leaving The lower trans, trans and cis, trans isomer mixtures, which are further tried to complete. The cis-cis isomer can be epimerized (eg, sodium ethoxide in ethanol) The trans and trans isomers are formed, and then proceed as follows. Pyrrolidine nitrogen (i) is tritiated or further tritiated using Rr * X (R3 is ^ (0) _ or ^ (〇) 2 and X is ion Deradicals such as self compounds (C1 is preferred) or X plus ^ (〇) _ or R6_s (〇) 2_ together form activated esters, including esters or anhydrides derived from formic acid, acetic acid, etc. N_ light-based perhydroimine 'N-#-based sulfanimine, N-Yaoylbenzotrimethylene, mesityl-5-n-pinene-2,3_dicarboxamide, 2,4,5 -Three gas phenol, etc.) or (2) calcined with r3-X, Where X is a leaving group (eg, X is a functional compound (such as Ci, Bγ, or I) or X is a leaving group, such as a sulfonate (such as mesylate, tosylate, trifluorosulfonate, etc.) )) In the presence of the test, such as diisopropylethylamine or triethylamine, the paper size applies to the Chinese National Standard (CNS) A4 size (210X297 male thin) to -32- (Please read the note on the back first) Matters re-installation-page), 1T printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economics of 1T; *---B7 V. Description of the invention (3〇) Is N-derivatized pyrrolidine produced? Formula, trans and cis, trans octamer mixture. Hydrolysis of ester L (such as the use of a base, such as sodium hydroxide in EtOH / H2O), can selectively hydrolyze the trans form, trans ester formation A mixture of 1 and I that can be easily separated. Many of the luketone ester starting materials used in the preparation of the compounds of the present invention are commercially available. They can also use the method described in Scheme Vln Preparation: In the method of private VIII (a), the aromatic, heteroaryl, or quaternary methyl ketones are removed, and chemically modified (such as by using sodium titanate or monoisopropyl amine). Chain) and treated with 4 doses of transferable methyl groups (such as diethyl carbonate, methyl chloroformate, di-tertiary, butyl dicarbonate). In addition, as described in Scheme VIII (b), The acid can be activated (such as with carbonyldiimidazole or grass gas) and treated with the equivalent of acetate (such as lithium ethyl acetate, magnesium methylmalonate or Meldrum, s acid and then thermal alcoholysis). Specific examples are shown in the scheme and ^〗. Benzyl acetoacetate plexes, reacted with nitrovinylbenzodiazyl compounds & using L 8 _ diazinebicyclo [5 · 4 · 0] 11 Carbon-7-ene (DBU) is a base in toluene to generate compound 28. Nitrogen nickel can be used to catalyze hydrogenation to reduce the nitro group to an amine, and then cyclization to form dihydrohelogen 2i. The double bond is reduced with sodium cyanoborohydride to form the pyrrolidine compound ϋ, which is a mixture of cis-cis, trans, trans and cis, trans isomers. The cis-cis isomer was separated by chromatography, leaving a mixture of the trans, trans and cis, trans isomers (2H). Scheme III illustrates the further completion of the trans, isomer. The trans-trans and cis-trans-pyrrolidine mixture (11) described in the scheme is reacted with Br-CH2C (0) NHR4 in acetonitrile in the presence of ethyl diisopropylamine to form alkylated pyrrolidines. Compound ϋ, still in trans, trans and cis-trans-33- This paper size applies to China National Standard (CNS), 8 4 ^ grid (21 0X 297 mm) (Please read the precautions on the back before • Pack-Page)

1T line 502018 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (31); Figure / Sodium silk dissolves trans-form in ethanol, trans-ethyl acetate 'but leaves cis-trans' The ethyl acetate of the compound of the formula is immobile, so the trans-, trans-carboxylic acid U can be separated from the cis-trans-ester 1 ^. Scheme IV illustrates the preparation of compounds where w is not a carboxylic acid. Compound U, which can be prepared by the method of Scheme IV, can be transformed (e.g., using peptide coupling conditions such as methylmorphine, EDCmHOBt, in the presence of ammonia or other amine formation reactions) to generate & amine. Betamine is dehydrated (for example, by using dichloromethane to pyridine) to form nitrile pyrene. Nitrile ^^ is reacted under standard tetrazole formation conditions (sodium azide and monoethylamine hydrochloride or trimethylsilyl azide and tin oxide) to form tetrazole U. In addition, nitrile & reacts with hydroxylamine hydrochloride in the presence of a base (such as potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH) in a solvent, such as D MF, DMSO or monomethylacetamide To form the amidine rib n. The amidoxime reacts with methyl formate or ethyl formate in conventional organic solvents (such as chloroform, dichloromethane, dioxane, THF, acetonitrile or pyridine) and in the presence of a base (such as monoethylamine 'P ratio lake 'Carbonic acid and carbonic acid steel) can form O-fluorenyl compounds. 0 -Bromoamine may be heated in an inert solvent (such as benzene, toluene, xylene, di'THF, dichloroethane, or chloroform, etc.) to cause cyclization to form compounds. In addition, amine and sulfinium disulfide The reaction in an inert solvent (such as chloroform, dichloromethane, dioxane and THF, etc.) can generate oxadierine ridge 61. Scheme V illustrates that via methylimine alkoxide type [3 + 2 Bu cycloaddition to acrylic acid _ Synthesis of esters of pyrrolidines. Like the general structure of compound 70, it is known that it can be added to unsaturated esters, such as 2X, to generate pyrrolidines such as compound 72 (0. Tsuge, S. Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983 ), -34- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) tf ^ —. --I— —I * · 1-1 -i --- = I—-i — -i -Three-1i · -.........- f (Please read the back of vg: 1 matter and then this page) Order 502018 Α7 Β7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Explanation (32) 〇, Tsuge, S. Kanemasa, T. Yamada, K. Matsuda, J. 〇rg Chem 12 2523-30 (1987), and S. Kanemasa, K. Skamoto, 〇. Tsuge Bull Chem · Soc · Jpn, Pull, 1960-68 (1989)). Silylimine reacts with propionate in the presence of dimethylethylsilyl trifluorosulfonate and tetrabutylammonium fluoride to form the desired pyrrolidine u as a mixture of isomers. This method can be changed to form an acetoamido derivative, which is a combination of red and 74 with an appropriate acetoamidoamine (such as dibutyl bromoacetamide) in the presence of tetrabutylammonium and fluorinated ginger. The direct reaction produces compound 2A. Scheme VI illustrates the method for producing pure pyrrolidine on the enantiomers, which can be done further on the pyrrolidine nitrogen. The middle racemic pyrrolidin ester & (prepared by the procedure described in Scheme v) is protected by nitrogen with Boc (as reacted with b0C2O), and re-hydrolyzed (such as with steel hydroxide or Zhongyu Ethanol and water) to form a third butylaminomethylpyrrolidinecarboxylic acid 2_ ^. The carboxylic acid is converted into its (+ methylammonium salt, which can be recrystallized (eg from ethyl acetate and hexane or chloroform and hexane) to form a diastereoisomerically pure salt. This diastereoisomeric The structurally pure salt can be re-neutralized (such as with sodium carbonate or citric acid) to generate the enantiomerically pure carboxylic acid Zi. It is said that slightly nitrogen can be deprotected (such as with trifluoroacetic acid) and use ethanol Hydrochloric acid re-forms the ester to form a salt ^ In addition, we can use ethanolic H C1 to dissociate the protecting group and form the ester in one step. Pyrrolidine nitrogen can be further exhausted (such as dibutylphosphonium bromide) The amine is treated in acetonitrile in the presence of diisopropylethylamine) to produce optically active compounds. The use of (-)-α-methylbenzylamine produces the opposite enantiomer. A preferred method is shown in Scheme VII. Nitrovinyl compound (8-8) reacts with β-ketoester in the presence of a base (such as sodium ethoxide or trialkylamine such as triethyl-35- (please read the note on the back first) Re-installation-page) The size of the paper used in the book is applicable to the Chinese National Standard (CNS) Α4 specification (210 × 297 mm) 5020 18 A7 ______ B7 V. Description of the invention (33) Employees of the Central Bureau of Standards of the Ministry of Economic Affairs print amines, diisopropylethylamine, etc. or 脒 such as DBU, etc. in an inert solvent (such as THF, toluene, DMF, B) Moon paste, ethyl acetate, isopropyl acetate or dichloromethane, etc.) The temperature is from about 0τ to about 100. (:, about 15 minutes to overnight can produce compounds. Reduction of nitro followed by cyclization can be This is achieved by using the catalytic hydride n with a hydrogen pressure from about atmospheric pressure to 300 psi for about 1 hour to about 1 day in an inert solvent (such as THF, ethyl acetate, toluene, ethanol, isopropyl Propanol, DMF or acetonitrile, etc.), using hydrogenation catalysts such as Raney nickel, palladium / carbon, platinum catalysts such as platinum oxide, platinum / carbon or platinum / alumina, etc., or germanium catalysts such as germanium / carbon or thorium / alumina. Intermediate nitrate or a mixture of nitrone and imine is formed. The reaction mixture containing nitrone or a mixture of nitrone / imine reacts with an acid, such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methyl alcohol, and continues Hydrogenation produces erlotidine compounds & _Isomers. The epimerization at C_3 can be accomplished by chemical treatment of compounds, such as ethoxylated steel, third, butyrate, third, butyrate or third, potassium pentoxide, etc. , Or trialkylamine such as triethylamine or diisopropylethylamine, etc., or hydrazine such as p BU, etc., in an inert solvent such as ethanol, ethyl acetate, isopropyl acetate, THF, toluene or DMF, etc. , The temperature from -20 ° C to about 12 (TC can generate trans, trans compound Er 1. The compound itself can be resolved into enantiomers, if necessary, and then react with x_Rs. Compound & is essentially pure (ie At least 95% of the desired isomers) optical activity (+) _ isomers obtained 'can be (+) _ isomers and (_) _ isomer mixtures with § _ (+)-mandelic acid D-tartaric acid or D-dimethyltartaric acid is treated in a solvent, such as acetonitrile, ethyl acetate, isopropyl acetate, ethanol or isopropanol. il · (+) _ isomers are selectively crystallized into salts, leaving (-) _ isomers at __ -36- ----- This paper size is applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm) 502018 A7 B7 V. Description of the invention (34) In solution. In addition, the optically active (-)-isomers of the desired isomers that are substantially pure (ie, at least 95% / 0) can be selectively crystallized, that is, the (+)-isomers and (-)-isomers of 1 The mixture of the substances reacts with 2-tartaric acid, 2_dibenzylidene tartaric acid or L_pyroglutamic acid, etc., leaving the desired (+ dipper compound in solution. Compound £! _ (Racemic or optically active ) And x_Rs (where χ is a leaving group (such as a halide or sulfonate) and I is as previously defined), using diisopropylethylamine, diethylamine, sodium bicarbonate, or potassium carbonate, etc., In an inert solvent such as acetonitrile, THF, toluene, DMF or ethanol, etc., the temperature can be from about οχ to about 100 ° C, the intermediate ester can be formed. The ester can be separated in situ or converted into carboxylic acid (0, using hydrolysis Conditions such as alkali, such as sodium hydroxide or lithium hydroxide or hydroxide, etc., in solvents such as ethanol_water or THF-ethanol, etc. (Please read the precautions on the back before loading-page) Central of the Ministry of Economics Printed by the Standards Bureau's Consumer Cooperatives 37- Flat i τ, J /? I, ~ Μ 公 7 9 2 ο02 5

CC A7 B7 V. Description of Invention (35)

Process I R2 co2e

IH]

r2

co2e (read. Read the notes on the back first) -Pack-cis-cis trans-trans-cis-trans mixture i order x-r3

§ c〇2e R2 " " ^ y ^ -Rl Z co2h trans-trans · line [H2〇] The Central Consumers Bureau of the Ministry of Economic Affairs prints trans-trans, trans-cis-trans. 4 *

-38- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 502018 A7 B7 V. Description of invention (36)

Process II ch3o

+

COOEt cis-cis, 32 trans-trans, \ chromatographic mixture OCH3

och3 NaCNBH3 Mixture of cis-cis + cis-trans-trans and cis-trans 21 (Please read the precautions on the back before loading-page) This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 502018 A7 B7 V. Description of invention (37

Process III ^ t) " ... COOEt · cis-trans and 31 och3

iPrsNB OCH3

och3

Trans-trans and 樨 -trans

NaOH f H2〇, EtOH Please read the following 5 items before installing

och3 +

〇CH3 Order trans-trans-cis-trans M \ Printed by the Central Consumers Bureau of the Ministry of Economic Affairs, Consumer Cooperatives 40- This paper size applies to Chinese National Standard (CNS) Α4 specifications (210 X 297 mm) 502018 A7 B7 V. Description of the invention (38)

Process IV

co2h m

Ra.Rl (CH2) m I CONHi

Ra

NH CN

Hi n ^ n League

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

5Z

(CH2) m R3 Rl

HN S-〇

O

£ L -41-This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 502018 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (39)

Process V

--.------ Installation-(Please read the precautions on the back first

、 TT -42- This paper size is applicable to China National Standard (CNS) A4 specification (210X297mm) 1 × ο 02 5 A7 B7 V. Description of invention (40

Process VI

(Taxi) 22 C02Et

J --- * ------ install-- (Please read the precautions on the back first

HCI ΒΟΗ

Order

R4HNC (0) CH2ar EtN (iPr) 2, CH3CN Printed by the Consumer Consumption Cooperative of the Central Standards Bureau of the Ministry of Economy 〇CH3

43- This paper size applies to Chinese National Standard (CNS) Α4 specification (210X297 mm) 502018 A7 B7 V. Description of invention (41

Flow VII

This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 502018 A7 B7 V. Description of invention (42)

Cheng VIII Scheme vma. 0 ^ CH3 aryl, heteroaryl or quaternary aryl

COOR J., --------- install-(Please read the precautions on the back first and then the page vnib.

R-COOH

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs. 45 This paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm). The compounds are:

m is 0 to 6; W is (a) -C (0) 2-G, where G is hydrogen or a carboxy protecting group, (b) -P03H2,-(c) -P (0) (0H) E, Where E is hydrogen, lower alkyl or aralkyl, (d) -CN, (e) -C (0) NHR17, where R17 is lower alkyl, (f) alkylaminocarbonyl, (g) di Alkylaminocarbonyl, (h) Tetrabenzyl, Perylene, Alkoxy, (k) Sulfonamido, printed by (l) -C (0) NHS (0 ) 2R16, where R16 is lower alkyl, haloalkyl, phenyl or dialkylamino, (m) -S (0) 2NHC (0) R16,

-46- ㈣ This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 502018 A7 B7 V. Description of invention (44) (〇)

HO

〇. Nh (q) pity. Η (r) s = * o (t) ⑻, or nhs〇2cf3 and the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy Oxygens 1 and 112 are independently selected from hydrogen, lower alkyl alkoxycarbonylalkyl, hydroxyalkyl, alkenylalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, amine Carbonylalkyl, alkylaminecarbonylalkyl, dialkylaminecarbonylalkyl, aminecarbonylalkenyl, alkylaminecarbonylalkenyl, dialkylaminecarbonylalkenyl, hydroxyalkenyl, aryl, aralkyl, aryloxyalkyl , Aralkyloxyalkyl, heterocyclic, (heterocyclic) alkyl, and 47 paper sizes applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm) --- CC IXο 02, A7 B7 V. Description of the invention ( 45) (Raa) (Rbb) N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkyl, and R. . Is an elongation group, with the limitation that one or both of ^ and ^ are not hydrogen; or a salt thereof; and a compound of the formula

Or (iv)

Please read the notes of δ first and then print it out printed by the Consumer Cooperatives of the Central Bureau of Standards 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) -P03H2, (c) -P (0) (0H) E, where E is hydrogen, lower alkyl or arylalkyl, (d) -CN , (E) -C (0) NHR17, where R17 is lower alkyl, (f) dialkylamine carbonyl, (g) alkylamine carbonyl, (h) tetradecyl, fluorenyl hydroxyl, fluorenyl alkoxy, ( k). Amido group, (1) -C (0) NHS (0) 2R16, where R16 is lower alkyl, haloalkyl, phenyl or dialkylamine, (m) -S (0) 2NHC (0) R16, 48- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297mm) Thread 502018 A7 B7 V. Description of invention (46) (Π) (〇)

〇

HO

Ο · Ο

OH

(Please read the precautions on the back before loading. (P) page) 〇

0 CF ^ ⑹, or NHS ° 2CF3 (ϋ); and 1 ^ and 112 are independently selected from hydrogen, lower alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, # Alkyl, from alkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, di Alkyl carbonyl alkyl, amine carbonyl ene 49- This paper size applies Chinese National Standard (CNS) A4 size (21 × 297 mm) Printed by the Central Consumers ’Cooperative of the Ministry of Economic Affairs 502018 A7 B7 Central Standards Bureau of the Ministry of Economic Affairs Printed by Employee Consumer Cooperatives 5. Description of the Invention (47), Alkylaminocarbonylalkenyl, Dialkylaminecarbonylalkenyl, Hydroxylenyl, Aryl, Arylamino, Aryloxyalkyl, Aryloxyalkyl , Heterocyclyl, (heterocyclyl) alkyl, and (Raa) (Rbb) NR. . -'Wherein Raa is an aryl group or an aryl group, Rbb is a hydrogen or a fluorenyl group, and R. . It is alkylene, the limitation is mindfulness! One or both of them is not hydrogen; or a salt thereof. 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 protecting group, * and 1 ^ And 112 are as defined above; or a substantially pure (+)-or (-)-isomer thereof. Particularly preferred compounds are compounds of formulae (III), (IV) and (V), where m is 0; W is -C02-G, where G is hydrogen or a protecting group; and Ri is (i) alkoxy Alkylhexyl, (ii) cycloalkyl, (iii) phenyl, (ίν) fluorenyl, (ν) furyl or (vi) substituted or unsubstituted 4-methoxyphenyl, 4 -Fluorophenyl, 2-fluorophenyl, 4-trifluoromethylphenyl, 4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl '3-fluoro-4-ethoxyphenyl, 4 -Propoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 1,3-benzodialinyl, 7-fluorenyl-1,3-benzodiyl, 4-benzobenzozyl or dihydrobenzoyl Wherein, the substituents are selected from the group consisting of alkoxy, alkoxyalkoxy, and carboxyalkoxy, and r2 is 1,3-benzodiazyl, 14-benzodiazyl, and dihydrobenzo Furyl'benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl ~~~~ -—__- 50 -_ This paper size applies to China National Standard (CNS) A4 specifications (210X297mm) (Please read the back Precautions Reload-page), tr 502018 A7 B7 V. Description of the invention (48) or difluorophenyl; or its substantially pure (+)-or (_) _ isomer. The above can be understood more with reference to the following examples, which are presented for illustration only and are not intended to limit the present invention. The following abbreviations are used: Boc in the third, butoxycarbonyl, cbz in the fluorenyloxycarbonyl group, DBU in the fluorene, diazabicyclo [5 乂 0] deca-7-ene; 1- (3-Dimethylaminopropyl-3_ethylcarbodiimide hydrochloride, EtOAc in ethyl acetate, EtOH in ethanol, HOBt in hydroxybenzotriazole, Et3N in triethylamine, TFA In trifluoroacetic acid and THF in tetrahydrofuran. Example 1-! Cong Li, trans-2- (4-methoxybenzyl H3-benzodifluorene VI-((1,4,6, -trimethyl ) Aniline · A certain methylpyrrolidine-3-moxinium · Example 1 A llil-fluorenyl $ Si Some 14-nitromethyl-3-Π.3-jasmine # dioxin butyric acid ethyl ester (please first (Read the precautions on the back again-back page)

'1T The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed 4- (methoxymethoxy) ethyl acetate (230 g, 0104 mol) to Krapcho et al ·, Org. Syn · II , 20 (1967), and 5- (2-nitrovinyl) -1,3-benzodioxo (ΐ7.0 g, 0.088 mole) dissolved in 180 ml of toluene, It was heated to 88, and 丨, 8-diazodicyclo [5 · 4 · 0] undec-7-ene (DBU, 0.65 g) was added in a stirring manner. 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 methane gas) showed no nitro starting material. Toluene (200¾ liters) was added and the organic phase was washed with dilute hydrochloric acid and Naci solution. The organic phase was dried over sulfuric acid steel and concentrated under reduced pressure. The obtained residue is on the upper layer of silicon rubber -51-This paper size applies the Chinese National Standard (CNS) A4 specification (210X297mm) line 502018 A7 B7 V. Description of the invention (49) Analysis with 3: 1 hexane-ethyl acetate The ester was lysed to give 21.22 g of the desired product as a mixture of 9.98 g of recovered (4-methoxyfluorenyl) ethyl acetate. Example 1 Beta-methoxyphenyl) -4- (1,3-benzodiazine difluorene-3Η-p-drol-3-3-carboxylic acid ethyl ester in 500 ml of ethanol obtained from the example compound (21 g ) Hydrogenation at 4 atmospheric hydrogen pressure using Ruanlai nickel 2800 catalyst (51g). (Ranlai nickel was washed twice with ethanol before use). The catalyst was removed by filtration, and the solution was shrunk under reduced pressure. The resulting residue was in silicone It was chromatographed and dissolved in 85% ethyl acetate in dichloromethane to give 12.34 g of the desired product.

Example 1 C Methoxyphenyl) -4- (1,3-benzodioxin-5-yl) -pyrrolidine_3_ acid-formula, trans and cis, trans iso-hibiscus mixture The compound from Example 13 (11.89 g, 0.324 moles) was dissolved in 27 ml of tetrahydrofuran and 54 ml of ethanol. Add sodium cyanoborohydride (235g, 0374 mol) and 5mg bromocresol green. In this blue solution, add 1: 1: 2 H C1 in ethanol solution dropwise, keeping the color at a light yellow-green color. After the yellow color continued without adding HC1, the solution was stirred for another 20 minutes. The solution was concentrated under vacuum. Partitioned between chloroform and aqueous potassium hydrogen carbonate. The organic phase was dried, dried over sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel and dissolved in 85:15 ethyl acetate-hexane to produce 5% g of 64% trans-trans-compound and 34% cis-trans-compound mixture. 52-Paper Standards apply to China ^ (CNS) (Please read the precautions on the back before loading. | Printed by A7, Staff Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs

A / ^. Further dissociation with pure ethyl acetate yielded 0.505 g of an unknown solid, followed by 3.044 g of a pure cis- and cis-compound.

Example 1D Methylphenyl) bromoacetamide p-2,4,6-trimethylaniline (1 g, 74.0 mol) in a stirred solution of dichloromethane (25 ml) at -55 ° C, Add n, n-diisopropylethylamine (1.58¾ liter, 8.14 mmol, 1; 1 equivalent) and bromoethenyl bromide (〇72 ml '7.40¾ Mol' 1 equivalent) successively, so the temperature is not Will exceed -40. 〇. Once all was added, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. After stirring for another 30 minutes, the mixture was diluted with ether (70 ml) and poured into a 1 N sodium hydrogen sulfate solution. The phases were separated and the upper layer was washed successively with water and brine. The organic phase was dried (NkSCXO, and the solvent was evaporated to half the volume, at which point the product could crystallize. The catalyst was removed by suction filtration to yield the title compound (151 g, 80%).

Example 1 E 'trans-2- (4-methoxyphenyl) _4-ί1_3-benzodiazin-5-yl) -1- (£ 2; > 4,6-dimethyl) fluorenamine Amidinomethyl is 64% trans, trans-, and 34% cis-trans-pyrrolidine (derived from Example 1 (:) and mixture) (5.72 g, 5.50 mol) ), Ethyldiisopropylamine (42 g, ^ 2 :: 56¾ mole), and a mixture of the compound from Example 10 (190 mmol) in 30 liters of acetonitrile at 50 ° C Heat for 1 hour. The solution was condensed in air. The residue was dissolved in toluene, shaken with potassium carbonate, dried over sodium sulfate and concentrated under vacuum to produce a mixture of trans, trans and cis, trans-ethyl esters. ———_____-53-This paper size is applicable to China National Standard (CNS) A4 specification (210X297). (Please read the precautions on the back before printing--·, τ Economy, 员工 Printed by the Central Standards Bureau Consumer Cooperatives. 502018 A7 Consumption printed by employees of the Central Government Bureau of the Ministry of Economic Affairs and Cooperatives ___ B7… 丨 丨 ........................ V. Description of the invention (59) Piperonal (15.55 kg (103.5 mol) under mechanical stirring and 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 ×: After about 30 minutes, the color-developing product began to crystallize. The reaction temperature was increased to 80 t, and stirred for about 10 hours until a minimum amount of piperic acid was left. Slightly thick The reaction mixture was cooled to 10 ° C and then filtered. The precipitate was washed with acetic acid (2 x 8 kg), and then washed with water (2 x 90 kg). The product was dried under a nitrogen flush and then dried in an air oven at 50 ° C. 2 days to produce 15.94 kg (80%) of the title compound as a pale yellow solid.-, Example 15 B L4-form Methyl ethyl) third ethyl acetate in toluene (15. 2 kg), potassium valeraldehyde (25 wt% / 5.0 kg, 99.26 moles), cooled to 5 ° C, mechanically Add a mixture of 4_methoxyacetophenone (6.755 kg, 44.98 moles) and diethyl carbonate (64 kg, 54.18 moles) in toluene under stirring under nitrogen for 1 hour while maintaining the temperature at Below 10 ° C. The reaction mixture was heated to 600 for 8 hours until 4-methoxyacetophenone was not detected by HpLC. The mixture was cooled to 20 and quenched by adding a mixture of acetic acid (8 kg) and water (90 kg) for 30 minutes while maintaining the temperature at < 20 ° C. The layers were separated and the organic layer was washed with a 5% sodium bicarbonate solution (41 kg) and concentrated to 14.65 kg. The temperature was maintained at 50 during the distillation. ^ Below. The yellow product concentrate was analyzed by HPLC based on an external standard and a yield of 9.40 kg (94%) was found. Example 1 5 C U4 -methyllactinoyl) -4-nitromethyl_3_ (1,3_benzodiyin_5_yl) butyrin — _ · 62-This paper size applies to Chinese National Standard (CNS) A4 Specifications (21GX297mm) ~ — —- (Please read the precautions on the back before you install-^ 1 ^ 4 pages) Line 502018 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (60) Ethyl ester · The compound obtained from Example 15A (7.5 kg, 37.9 mol) was suspended in THF (56 kg) with mechanical stirring, and the product of Example 15B (84 kg, 37.9 mol) was added under nitrogen. ear). The mixture was cooled to 17. 〇, Sodium ethoxide was added, and the reaction was stirred for 30 minutes. After about 15 minutes, the nitrostyrene was completely dissolved. Sodium ethoxide (6.4 g, 0.095 mole) was added and the mixture was stirred at 25 t until HPLC showed that the area percentage of the keto ester residue was less than}. The reaction was concentrated to 32.2 kg, which was determined by HPLC analysis to be ~ 14.9 kg (95%).

Example 1 5 D-I Calendar 'cis-2- (4-methoxyphenyl) -4- (1.3-benzodihum-5-yl) -pyrrolidine-3-carboxylic acid ethyl ester The decanted Ruanlai nickel (20.0 g) was added to a stirred hydrogenator with a thermocouple. THF (20 ml), the crude compound of Example uc (40.82 g, 0.0482 mole) and acetic acid (2.75 ml, 0.0482 mole) were added sequentially. The mixture was under a hydrogen pressure of 60 psi until the intake of hydrogen was drastically slowed. TFA was added and the mixture was hydrogenated at 200 psi until HPLC showed no residual imines and the area percentage of the azetone was less than 2. The catalyst was filtered off and washed with 100 liters of methanol. The filtrate was analyzed by HPLC and was found to contain 13.3 g (75% yield) of the cis, cis-pyrrolidine compound. The filtrate was concentrated and removed with additional THF (200 ml) so that the final volume was 100 ml. The mixture was neutralized with 2NNaOH solution (50 ml), diluted with water (200 ml), and extracted with ethyl acetate (2 x 100 ml). The mixed almost colorless ethyl acetate layer was analyzed by HPLC with additional standards to give 13.0 g (73%) of the title compound. ____ -63- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297mm) (please read the notes on the back before p. 014). · ______67 __502018 A7 V. Description of the invention (61) Example 1 5 E trans, transmethoxyphenyl) 4_π, 3_benzyl _5 _some) _pyrimidin-3-acetic acid ethyl alcohol solution of the compound from Example 15D (38 1 g, 〇103) Mohr) was chased with ethanol (200 ¾ liters) to a final volume of 100 ml, followed by sodium ethoxide (340 g, 0.050 Molar). The mixture was heated to 75 ° C. When HPLC showed cis, less than 3% of the cis isomer was left ', the mixture was cooled to room temperature. The product was analyzed by HPLC with additional standards and was found to contain 344 g (90% yield) of the title compound. The crude compound solution was concentrated, and the residue was collected with isopropyl acetate (400 liters). The organic layer was washed with water (2 X 150 ml) and extracted with 0.25 M phosphoric acid solution (2 X 400 ml). The mixed phosphoric acid layer was co-stirred with ethyl acetate (200 liters) and neutralized with solid sodium carbonate to pH 7 (21 g). The organic layer was separated and found to contain 32.9 g (87%) of the title compound. Example 1 5 FI ^, iR, 4S] 2- (4-methoxyphenyl molybdenum 4-5 雠 A certain UW into 々 • carboxylic acid (Please read the precautions on the back before loading-page) Order the Ministry of Economy Consumption cooperation with employees of the Central Bureau of Standards, printed racemic amine ester (32.9 g) of Example 1 was dissolved in 50 ml of acetonitrile. (8)-(+)-mandelic acid (2.06 g, 0.0136 mol) ) And let it dissolve. Add the product 'to the mixture and let it stir at room temperature for 16 hours. The reaction mixture was cooled to 10 ° C and stirred for 5 hours. The product was filtered and placed in an air oven under a nitrogen stream and 50Ό Dry for 1 day. The resulting salt (20.0 g, 0.0383 moles) was suspended in ethyl acetate (150 ml) and 5% sodium bicarbonate solution (15 ml). The mixture was stirred at room temperature until Until the salt is dissolved and the escape of carbon dioxide is stopped. The organic layer is separated and concentrated. -64- LINE 'standard [豕 T-, 〆r Gage A4 Aigong 7 9 2 502018 Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Preparing A7 ______ B7 _ V. Description of the Invention — Example 1 5 G [H3R, 4gjK ^ methoxybenzyl) _4_ (13_benzodihum-5_yl) ^ Group) benzylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid The title compound was prepared from the compound of Example 15] and was carried out according to the procedure of Example 1E. / Example 1 5 Η H1,3R? 4S1 ^^ methoxyphenyl) -4_ (1,3-benzyldioxin_5-some ("/ -monoethyl) benzylaminocarbonylmethyl)-Erow disease The 3-carboxylic acid hydrochloride example 15G compound (450 mg) was dissolved in 10 ml of isopropanol. A slight excess of saturated HC1 in ethanol was added, and the resulting solution was stirred for 10 minutes. The eluent was removed under vacuum, and the excess HC1 was removed with isopropanol. The residue was taken up by Otsuki and filtered, leaving 448 mg of the title compound as a white solid. MS (DCimH3) m / e 531 (M + H) +, analysis estimated C31H35N2O6Cl: C, 65.66; H, 6.22; N, 4.94. Measured 値 ·· C, 65.72; Η, 6.39; Ν, 4.65. Example 1 6-based, formula, trans-2- (4-methoxyphenyl) -4- (1.3- 笨 # 二 唠 · ................... II, 丨 II „((2,6-—Methoxy) amidinomethylmethyl bihadine-3-guinic acid Example 1 6 A 2,6 -dimethoxymoscarmine pair 2,6 · Di To a stirred solution of methoxybenzoic acid (2.0 g, mol, Yu Gong, 2. dioxane (45¾ liters) at ambient temperature, N-methylmorpholine (1 · 45 ml, 13.2 mmoles) and diphenylphosphonium nitrogen (260 mg / L '2.1 mmoles). After heating the mixture at 75 ° C for 2 hours, decomposed ketene (150 mg) was added. And alcohol (2.27 ml, 22.0 millimoles), and continue to add ____- 65- This paper size applies to China National Standards (CNS) A4 specifications (210; < 297 mm) Γ% Read the back first Note-Repacking--Ordering-Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, F 502018 A7 B7 V. Description of the Invention (63) 1 ~ One night. The solvent is removed under the sky, and the residue is on the upper layer of silicone Analyze and dissolve in 4 · 1 hexane-ethyl acetate to form the intermediate carbamate (15 g, 4 8% yield) as a white crystalline solid. The solid was dissolved in methanol (15 ml) and added to a flask with nitrogen rush and containing 10% pd / c (500 mg). The mixture was under hydrogen Stir under a balloon for 4 hours at ambient temperature. The mixture was filtered through a Cehte dish and the solvent was removed under vacuum to yield the title compound (800 mg, 48% yield).

Example 1 6 B group-formula 'trans-2_ (4-methoxyphenyl) _4_Π · 3_benzodifluorenyl) -1-C (2,6-dimethoxy) aniline carbonylmethylpyrrole The title compound was prepared according to the procedure described in Example 1 except that the compound of Example i 6 A was used instead of 2,4,6-trimethylaniline in Example 1D. NMR (300MHz, CDC13) d 8.18 (1Η, bs), 7.39 (2Η, bd, J = 9Hz), 7.17 (1Η, t, J = 9Hz), 6.99 (1Η, d , J = 2Hz), 6.90 (2Η, d, J = 9Hz), 6.86 (1Η, d, J = 2Hz), 6.75 (1Η, d, J = 9Hz), 6.56 (2H, d , J = 9Hz), 5.93 (2Η, s), 3.88 (1H, bd, J = 10Hz), 3.81 (3Η, s), 3.71 (6Η, s), 3.70 (2H, m) , 3.49 (1H, bd, J = 15Hz), 3.03 (2H, m), 2.85 (1Η, bd, J = 18Hz). MS (DC1, NH3) m / e 535 (MH +). Analysis estimates C29H30N2O8 · 0.75 AcOH: C, 63.20, Η, 5.74, Ν, 4.83. Measured 値 ·· C, 63.18, Η, 5.34, Ν, 4.79. Example 17 7, trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodihum-5-yl) -1-((4- > odor_2, 6_diethyl) benzylamine condensed methyl bilobitan-3-pic acid

Example 17A -66-This paper size applies to China National Standard (CNS) A4 (21〇297mm)

Hr. M! »It .............. ----- -Ξιi =-In I * 一 1 -_ * 一 ilii I (Please read the precautions on the back before reading Page) Thread 502018 A7 V. Description of the invention (64) Health " Xi-2,6-diethylaniline p-2,6-diethylaniline (100 g, 67.0 mol) in acetic acid ( 50 ml) of a stirred solution, and bromine (104 ml, 201 mmol) was added at ambient temperature. The reaction was stirred off at ambient temperature overnight. The reaction mixture was diluted with diethyl ether (200 ml) and washed with 5% sodium bisulfite (4 x 50 ml) and brine. The organic phase was dried over sulfuric acid steel and the solvent was removed under vacuum. The residue was chromatographed on silica gel and eluted with 9: 1 hexane-ethyl acetate to give the title compound (3.28 g, 21% yield). Example 17B: Basic formula, trans-2- (4-fluorenylbenzyl) -4- (1,3-benzodihum-5-yl) -1-L (4-bromo., -Diethyl Benzylamine, pyridylamine, pyridoxine ^-printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs .......... I .............. ............- --1_ * IC Please read the notes on the back first The title compound was prepared by the procedure described in Example 1, but replaced by the compound of Example 7A in place of 2,4,6-trimethylaniline of Example 1D. 4 NMR (300MHz, CDC13) d 8 · 21 (1Η, bs), 7.38 (2Η, d, J = 9Hz), 7.23 (2H, s), 6.92 (2H, d, J = 9Hz), 6 · 88 (1Η, d, J = 2Hz), 6.82 (1H, dd, J = 8 & 2Hz), 6.75 (1H, d, J = 9Hz), 5.93 (1Η, d, J = 2Hz), 5. · 91 (1Η, d, J = 2Hz), 3.95 (1H, d, J = 9Hz), 3.82 (3Η, s), 3.72 (21Η, m), 3.52 (1Η, m), 3 45 (1Η, d, J = 18Hz), 3.14 (2Η, m), 3.00 (1Η, d, J = 18Hz), 2.39 (4H, q, J = 9Hz), 1.07 (6H, t , J = 9Hz). MS (DC1, NH3) m / e 609 (MH +). Analysis estimates C3iH33BrN206: C, 61.09, H, 5.46, N, 4.60. Measured 値: C, 60.80, Η, 5.35, Ν, 4.54. '' Example 1 8 trans, trans-2- (4-methylbenzyl) -4- (1,3-benzodiazine-5-yl) -1-((2-ethyl-6-methyl Base) Benzoylaminomethylpyrrolidine-3-carboxylic acid ___- 67- This paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) 502018 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7__ V. Description of the invention (65) The title compound was prepared according to the procedure of Example 1. 4 NMR (300 MHz, CDC13) J8.32 (1H, bs), 7.38 (2Η, d, J = 9Hz), 7.20 -7 · 10 (3Η, m), 6.92 (2Η, d, J = 9Hz), 6.87 (1H, d, J = 2Hz), 6.82 (1Η, dd, J = 8 & 2Hz), 6 76 (1Η, d, J = 9Hz), 5.94 (1Η, d, J = 2Hz), 5.92 (1Η, d, J = 2Hz), 3.95 (1Η, d, J = 9Hz) , 3.82 (3Η, s), 3.73 (1Η, m), 3.55 (1H, dd, J = 12 & 6), 3.47 (1Η, d, J = 18Hz), 3.14 (2Η, m), 3.02 (1Η, d, J = 18Hz), 2.44 (2Η, q, J = 9Hz), 2.10 (3Η, s), 1 · 10 (3Η, t, J = 9Hz). MS (DC1, NH3) m / e 517 (M + H +). Analyzed and estimated C30H32N2 0 6 · 5 · 20: C, 68.56, Η, 6.33, N, 533-Measured 値 · C, 68.58, Η, 6.29, Ν, 5.13. Example 1 9 Trans, trans-2- (4 · methoxyphenyl) -4- (1,3 · benzodifluoren-5-yl 1α ?,, 6-triethyl) anilinecarbonylmethylpyrrolidine-3 _ Example of carboxylic acid 19A trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodiz-5-yl) -1-((2,4,6-tri Ethyl) anilinecarbonylmethylpyrrolidine-3-carboxylic acid ethyl ester [i, r-bis (diphenylphosphino) ferrocene] dichloropalladium (11) (1: 1) and a complex of dichloromethane ) (13 mg) and cesium carbonate (3 07 g, 0.942 mmol) in a mixture of anhydrous N, N-dipyridamidine (12 ml) (nitrogen flush), add reaction at ambient temperature Formula, trans-2- (4-methoxyphenyl) -4- (1,3-benzobis # thio-5 -yl) -1- (4-brook-2,6-diethylphenyl ) Amidomethyl bihadine_ ethyl 3-carbonyl (200 mg, 0.314 mmol, prepared in Example 17) in anhydrous tetrahydrooctane (8 ml). The mixture was allowed to fall at ambient temperature. After 10 minutes, add 1.0M triethylborane (0.471 ml, 0.471 mmol) to Siyi _-68- This standard applies to Chinese National Standard (€ milk) 64 (210/297) (Centi) scales Please read the back Notes and then install • · page) Order 502018 A7 B7 V. description of the invention (66) (read first read the back of the Hong Notes then hydrogen alas furans. The reaction was stirred at 65 ° C under nitrogen overnight. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (2 × 30 mL) and brine. The organic layer was dried over sodium sulfate, and the solvent was removed under vacuum. The residue was chromatographed on silica gel and eluted with 3: 1 hexane-ethyl acetate to give the title compound (110 g, 60% yield).

Example 1 9 B trans'trans' 2 sided (4-methoxybenzyl) 4 sided (1,3-benzobenzoyl-5-yl) -1- ~ ((2,4,6 · The title compound of triethyl) aniline carbonylmethyl V pyrrolidine-3-carboxylic acid was prepared by the procedure of Example 1 E. 4 NMRJ (300 MHz, CDCl3) d 8 · 22 (1Η, bs), 7.38 (2Η, d , J = 9Hz), 6.95 (2Η, s), 6.91 (2H, d, J = 9Hz), 6.84 (1Η, d, J = 2Hz), 6.82 (1Η, dd, J = 8 & 2Hz), 6.75 (1Η, d, J = 9Hz), 5.93 (1Η, d, J = 2Hz), 5.91 (1Η, d, J = 2Hz), 3.95 (1Η , D, J = 10Hz), 3.82 (3H, s), 3.71 (1Η, m), 3.52 (1Η, dd, J = 9 & 2Hz), 3.46 (m, d, J = 18Hz), 3.13 (2H, m), 3.00 (1H, d, J = 18Hz), 2.60 (2H, q, J = 9Hz), 2.40 (4H, q, J = 9Hz), 1.22 (3Η, t, J = 9Hz), 1.08 (6H, t, J = 9Hz). MS (DC1, NH3) m / e 559 (MH +). Analyzed and estimated C33H38N206 · 0 · 25Η20 ·· C, 70.38, Η, 6.89, Ν, 4 · 97. Measured ，: C, 70.18, Η, 7.14, Ν, 4.63. Example printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 2 0

"211,311,4812- (4-propoxyphenyl) -4- (1,3-benzodifluoren-5-yl) -1- (1 ^-((2,6-diethyl) aniline Carbonylmethyl V pyrrolidine-3- # acid, Example 2 0 A "2 feet, 3 feet, 4812 彳 4-propoxyphenyl) -4- (1,3-benzodolin-5-yl > ) -1-Third, Butoxycarboxyl-Sorcoline-3-Acid Acid-69- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 502018 A7 B7 Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed 5. Description of the invention (67) Example 3 Racemic amine ester (800 g) and 4 45 g of dicarbonate di-tertiary. Butyl vinegar was mixed in 100 亳 THF; i 〇 亳 liter Triethylamine, the resulting solution was stirred at ambient temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was taken up with EtOAc and washed successively with 1 n H3P04 aqueous solution, bicarbonate and brine. The crude product was dissolved In 30 liters of ethanol; 2 liters of 2.5N NaOH solution was added, and the mixture was stirred at ambient temperature overnight, and then heated to 5 (rc for 2 hours. The solvent was removed under empty space; the residue was partitioned into water And ether._ The aqueous extract was acidified with lNHsPCU aqueous solution. Then drying on Na2S04 can produce ^ g of trans'trans'propoxyphenylpropionyl '^^^ benzodiazine-% group) -1-third, butoxycarbonyl-pyrrolidine_ 3-Carboxylic acid. This material was dissolved in 30 ml of EtOAc, and then 1.3 ml (trans) _ (+) _ "methylmethylamine was added. The solution was stirred for 10 minutes; the solvent was removed under empty space, and 5 was added. 0 ml of diethyl ether, and the I solution was seeded. After standing overnight, the solvent was removed under vacuum; the residue was taken up in 70 ml of diethyl ether and refiltered. The solid product was recrystallized from EtoAc / ether. Crystals The material was stirred vigorously in a two-phase mixture of 1NHjO4 and EtOAc; the organic layer was decanted, washed with brine and dried over Na2SO4. Example 20B JH3R? 4S12- (4_propoxy, 3_benzodifluorene_ 5 -Example 20 A compound of pirocid-3-carboxylic acid ethyl ester was dissolved in ethanol, and then cooled in an ice bath. Hci gas was foamed through the solution until saturation. The resulting solution was heated to ambient temperature, and then Let it stir overnight under a nitrogen blanket. The solvent was removed under sacrifice; the residue was taken up with bicarbonate and extracted with Et0Ac. The organic layer was decanted and washed with salt: Dried on Na2S04. Solitary

(Read the precautions on the back before .........-...... mm · -........ .............. .. · · Loading page) Line A7 B7 V. Description of invention (68)

Example 2 0 C {Please read the precautions on the back and then% oxyphenyl) _4_ (13_benzodifluorene_5-some (2, --_ · k cumyl) amine carboxymethyl)-Eho The bite-3-boronic acid title compound was prepared from the compound of Example 20B, following the procedure of Example 1E. MS (DC1 / NH3) m / e 559 (M + H +). Analyze and estimate ^ to receive… · 〇 · 2Η20: C, 70.49, Η, 6.88, N, 4.98. Found 値: c, 70.52, H, 6.78, N, 4.85. Example 2 1 Basic formula, trans-2- (4-methoxybenzyl) -4- (1,3-benzodifluorene-5, yl) -1-((2,6-monoisopropyl) The title compound, aniline methylbilolide-3-acid, was prepared according to the procedure of Example 1. iH NMR (300 MHz, τ CDC13) d 8 · 29 (1Η, bs), 7.39 (2Η, d, J = 9Hz), 7.29 (1Η, m), 7.15 (2H, d, J = 9Hz), 6.93 (2H? D, J = 9Hz), 6.85 (1H? D, J = 2Hz), 6.83 (1H? dd, J = 8 & 2Hz), 6.74 (1H, d, J = 9Hz), 5.93 (1H, d, economy * The printed product of the Central Consumers ’Union Consumer Cooperatives J = 2Hz), 5.91 (1H, d, J = 2Hz), 3.96 (1H, d5 J = 10Hz), 3.83 (3H, s), 3.73 (1Η, m), 3.55 (1Η, dd, J = 12 & 6), 3.50 (1Η , D, J = 18Hz), 3.14 (2Η, m), 3.01 (1Η, d, J = 18Hz), 2.84 (2Η, m), 1.16 (6H, d, J = 8Hz), 1.05 (6H, d, J = 8Hz). MS (DC1, NH3) m / e 559 (MH +). Analyzed and estimated C33H38N206 · 0.5 · 2Η · · C, 69.82, Η, 6.92, N, 4.93. Measured erbium: C, 69.69, erbium, 6.63, Ν, 4.89. Example 2 2 Trans, trans, trans-2- (4-methoxyphenyl) · 4-Π, 3-mobi hydrazone -5-yl) -1-Li 2,6-diethyl-4-methyl) anilinecarbonylmethylpyridine-3- The title compound was prepared according to the procedure of Example 19. ifi NMR (300MHz, -71-This paper size applies the Chinese national standard CNS) A4 specification (210X297 mm) 502018 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (69) CDC13) d 8 · 20 (1Η, bs), 7.38 (2Η, d, J = 9Hz), 6.92 (4Η, m), 6.86 (1H, d, J = 2Hz), 6.82 (1Η, dd, J = 8 & 2Hz), 6.75 (1Η, d, J = 9Hz), 5.93 (1H? D, J = 2Hz), 5.91 (1H, d, J = 2Hz)? 3.95 (1H, d5 J = 10Hz), 3.81 (3Η, s), 3.72 (1Η, m), 3.55 (1H, dd, J = 9 & 2Hz), 3.45 (1Η, d, J = 18Hz), 3.13 (2H, m) , 3.00 (1Η, d, J = 18Hz), 2.39 (4Η, q, J = 9Hz), 2.28 (3H, s), 1.07 (6Η, t, J = 9Hz). NMR (DC1, NH3) 545 m / e (MH +). Analyze and estimate c32H36N206 · 0 · 5Η20: C, 69.42, Η, 6.74, N, 5.06. Found 値: c, 69.43, ,, 6.57, Ν, 4.94. Example 2 3-qua (2R, 3R, 4S) -2- (4-ethoxyphenyl) _4_ (1 · 3-benzodifluoren-5-yl) -1-((2,6-diethyl ) Aniline carbonylmethyl V pyrrolidine-3-carboxylic acid title compound Preparation Example 10 Racemic amine ester, prepared according to the procedure of Example 20. 4 NMR (300MHz, CDC13) J8.32 (1H, bs) , 7.38 (2Η, d, J = 9Hz), 7.21 (2H, m), 7.12 (2Η, d, J = 10Hz), 6.90 (3Η, m), 6.83 (1Η, dd , J = 8 & 2Hz), 6.74 (1Η, d, J = 9Hz), 5.94 (1Η, d, J = 2Hz), 5.92 (1Η, d, J = 2Hz), 4.05 (2Η, m), 3.96 (1Η, d, J = 10Hz), 3.72 (1H, m), 3.53 (1H, dd, J = 10 & 3Hz), 3.47 (1H, d, J = 18Hz), 3.13 (2H, m), 3.02 (1Η, d, J = 18Hz), 2.44 (4H, q, J = 9Hz), 1.42 (3Η, t, J = 9Hz), 1.08 (6Η, t, J = 9Hz). MS (DC1, NH3) m / e 545 (MH +). Analyzed and estimated C32H36N206 · 0 · 5Η20: C, 69.42, Η, 6.74, N, 5.06. Measured 値: C, 69.67, pyrene, 6.73, N, 4.98. 'Example 24 trans, trans-2- (4-methylphenyl V4- (l, 3-benzodifluoren-5-yl VI- ( (4-Carboxy-2,6-diethyl) aniline carbonylmethylpyrrolidine-3-carboxylic acid ______- 72- _ This paper Applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before loading-page) Thread 502018 A7 __B7 V. Description of the invention (70) The steps of the title compound are shown in Example 1 9 Preparation: iH NMR (300MHz, DMSO) β 7 · 68 (2Η, bs), 7.54 (2Η, d, J = 9Hz), 7.27 (2Η, m), 6.93 (2H, d, J = 9Hz ), 6.83 (2H, m), 5.98 (2H, s), 3.92 (lH, d, J-9Hz), 3.76 (3H, s), 3.62 (lH, m), 3.45-3.00 (2H, m), 3.00-2 · 80 (3Η, m), 2.44 (4Η, q, J = 9Hz), 1.04 (6Η, t, J = 9Hz). NMR (DC1, NH3) m / e 575 (MH + ). The analysis estimates c32h34N206 · 0.5H2O: C, 65.85, Η, 6.04, N, 4.80. Found 値: c, 66.03, H, 5.84, Ν, 4.67. Example 2 5 Mao-type, trans-2- (4-methoxyphenylbenzodiazine-Shi Xiao Juan_di 2,6-monoethyl) benzylmethyl-pyrrolidine_3 _ Number acid

Example 2 A solution of 5 A 2,6-monoethyl-4-nitroaniline p-2,6-diethylaniline (5.0 g, 34 mmol) in concentrated sulfuric acid (30 ml) at 0 C In the process, concentrated nitric acid (15.9 m, 20 ml, 34 mmol) was added dropwise. The cooling bath was removed and the reaction was stirred at ambient temperature for 3 hours. After the reaction mixture was poured into ice, the solution was neutralized with 4 N sodium hydroxide and extracted with dichloromethane (3 × 50 ml). The extract was dried over sodium sulfate and the solvent was removed under vacuum to give the title compound.

Example 2 5 B is shown in the formula 'trans-2_ (4-methoxyphenylbenzodiyin_5 -some, _ 1 · diethyl) benzylaminocarbonylmethylpyrrolidine-I. The title compound is given as an example. !! The method is prepared, but the compound of Example 8 is used to replace the 2,4,6-trimethylaniline of Example 1D. Ifj NMR (300MHz, CDC13) ^ 8.38 (1H5 bs)? 7.77 (1H, d, J = 9Hz)? 7.38 (2Η? D, ____- 73- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before-installation-page) Staff of the Central Bureau of Standards, Ministry of Economic Affairs Printed by Consumer Cooperatives 502018 A7 B7 V. Description of the invention (71) J = 9Hz), 7.24 (1Η, d, J = 9Hz), 6.92 (2Η, d, J = 9Hz), 6.88 (1Η , D, J = 2Hz), 6.82 (1Η, dd, J = 8 & 2Hz), 6.75 (1Η, d, J = 9Hz), 5.93 (1H, d, J = 2Hz), 5.91 (1Η, d, J = 2Hz), 3.97 (1Η, d, J = 9Hz), 3.83 (3H, s) 5 3.74 (1Η, m), 3.48 (2Η, m), 3. · 18 (2Η, m), 3.04 (1Η, d, J = 18Hz), 2.63 (2Η, m), 2.44 (2Η, q, J = 9Hz), 1.10 (3H, t, J = 9Hz), 1.08 (3H, t, J = 9Hz). MS (DC1, NH3) m / e 578 (MH +). Analysis estimates C3iH33N308 · 0 · 75Η20: C, 63.20, Η, 5.90, N, 7.13. Measured 値: C, 63.30, Η, 5.81, N, 7.14. Example 2 6 ^ Trans-trans, trans-2- (4-methoxyphenyl) -4_ (1,3-benzodig-5 -yl) _ 1 _ ((2 -isopropyl-6- The methyl) anilinecarbonylmethyl) -erogenline-3-folic acid title compound was prepared by the procedure described in Example 1. 1H NMR (300MHz, CDC13) $ 8.35 (1Η, bs), 7.39 (2Η, d, J = 9Hz), 7.18 (2Η, m), 7.07 (1Η, dd, J = 9 & amp 2Hz), 6.92 (2Η, d, J = 9Hz), 6.86 (1Η, d, J = 2Hz), 6.82 (1H, dd, J = 8 & 2Hz), 6.75 (1H, d, J = 9Hz), 5.94 (1H, printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs d5 J = 2Hz), 5.92 (1Η, d, J = 2Hz), 3.96 (1H, d, J = 10Hz), 3.83 ( 3H, s), 3.72 (1Η, m), 3.50 (2Η, m), 315 (2H, m), 3.02 (1H, d, J = 18Hz), 2.86 (1Η, m), 2.09 (3Η, s), 1.16 (3H, d, J = 8Hz), 1.07 (3H, d, J = 8Hz). MS (DC1, NH3) m / e 531 (MH +). Analysis estimates C31H34N206 · 0.5 · 20Η: C, 69.00 yen, 6.54, N, 5.19. Measured fluorene: C, 69.27, hydrazone, 6.67, Ν, 5.21 〇 ^ Example 27 * trans'trans-2- (4-methoxyphenyl) -4- (1,3-benzodizaki- 5 -yl) -1 _ (N- (2-ethyl-6-methoxy) aniline-methylmethylbiloline-3-polyacid; ___- 74- This paper size applies to Chinese National Standards (CNS) A4 specifications (210X297 mm) 502018 A7 _ B7 V. Description of the invention (72)

Example 27A (Please read the precautions on the back first, then 3-keto-4- (3-dioxy-2-nitrofluorenyl) ethyl propionate, ethyl potassium malonate (3.68 g) and 2.29 G of gadolinium chloride was mixed in 12 ml of D MF; the reaction mixture was heated at 60 ° C for 4 hours. The resulting mixture was cooled to ambient temperature. At the same time, 3-methoxy-2-nitrobenzoic acid (3.4 g) Dissolved in 12 liters of DMF; 3.06 g of 1,1-carbonyldiimidazole (gas overflow) was added, and the resulting solution (after stirring at ambient temperature for 4 hours) was added to the malonate mixture. The resulting sludge was stirred at ambient temperature for 14 hours. The solvent was removed under vacuum; the residue was taken up in EtOAc, washed with 1N Η3ρ〇4, bicarbonate and brine successively, and concentrated under vacuum. Example 27B 2 -Nitro-3-Π -Hydroxyethyl) -Anthony_ Example 27A Compound (3.2g) was printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, and dissolved in 50 liters of concentrated sulfuric acid, then in the environment Stir at temperature for 48 hours. The reaction mixture was poured into 300 ml of ice and extracted twice with EtO Ac. The organic extract was washed successively with water, bicarbonate, and brine, and then concentrated under vacuum. The crude product was at 160. (: Net heat for 3 hours. The resulting dark brown residue was extracted with EtOAc. The organic extract was re-condensed. The crude product was dissolved in 15¾ liters of ethanol; mg of sodium hydrolysate was added), and the resulting solution was at ambient temperature Stir for 2 hours. The solvent was removed under vacuum; the residue was taken up in 10% aqueous HC1 solution and stirred for 15 minutes. The mixture was extracted with EtOAc. The organic extract was washed successively with bicarbonate and brine, and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel and eluted with i: ^ EtOAc / hexane to give 1.08 g (32% overall) of the title compound as a colorless oil. -75-

502018 A7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs ____ B7_ V. Description of the Invention (73) Example 2 7 C-Based 6-methoxybenzylamine Example 27B Compound (310 g) dissolved in 10 ml tHf; add L5 ml of HJO4 and 50 mg of 10% pd / G. The resulting mixture was flushed 'under a hydrogen balloon' with nitrogen and stirred overnight. Bicarbonate was carefully added and the mixture was filtered through a celery pan. The filtrate was extracted with EtoAc; the organic extract was washed with bicarbonate and brine, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel and eluted with i: i diethyl ether / hexane to give 102 mg (43% yield) of the title compound as a colorless oil. ^ Example 27D at the cluster -_ 'Negotiation formula " 2- (4 · methoxyphenyl) -4 turn (1,3-benzodizaki surface 5-based) is shown 1-(N-(top Ethylenedi) aniline carbonylmethyl V pyrrolidine-3 -carboxylic acid The title compound was prepared according to the procedure of the example, but the compound of Example 2 7 C was used instead of 2,4,6-dimethylaniline. IH NMR (3〇_ Ηζ, J = 8Hz, 3Η), 2.48 (d, J = 8 Ηζ, 2Η), 3.4-3.9 (m, 7Η), 3.73 (s, 3Η), 3.84 (s, 3H), 5.93 (s5 2H), 6.80 (d, J = 8 Hz, 1H), 6.86 (d, J = 8 Hz, 2H), 6.93L (dd, J = 2,8 Hz, 1H), 7.03 (bd d, J = 9 Hz, 2H ), 7.07 (d, J = 2 Hz, 1H), 7.23 (t, J = 8 Hz, 1H), 7.53 (bd, d, J = 9 Hz, 2H) 〇MS (APCl) m / e 533 (M + H +). The analysis estimates c30H32N2O7 · 0.7TFA: C, 61.59, Η, 5.38, N, 4.57. Measured 値: c, 61.27, Η, 5.44, Ν, 4.61. As shown in 'here The compound mentioned above works by binding to the endothelin receptor, and the compound is evaluated for its ability to replace the endothelin in the endothelin receptor. Binding points (please read the precautions on the back first and then install the page) ___ _-76- This paper size applies to China National Standards (CNS) specifications (training Paojia sauce 502018 Α7 B7 V. Description of the invention (74) Preparation of membranes from porcine cerebellum by EIb receptor The porcine cerebellum contains 0.25 μM sucrose and protease inhibitors, (3 mM EDTA, 0.1 mM DMSF and 5 μg / ml aprotinin A ) At 25 times volume (w / v) in 10 mM Hepes (pH 7.4), homogenized using a 3-10 second polytron at 13,500 rpm, with an interval of 10 seconds. The mixture was centrifuged at 1,000 xg for 10 minutes. The supernatant was collected and centrifuged at 30,000xg for 30 minutes. The pellet was resuspended in buffer solution A (20 mM Tris, 100 mM NaCl, 10 mM MgCl2, pH 7.4), which contained the above-mentioned * protease inhibitor, and again Centrifuge. The final pellet is resuspended in buffer solution A containing protease inhibitor and stored at -80 ° C until use. The protein content is determined by Bio-Rad dye-bound protein analysis. F125IlET-3 Binding to the membrane: A 96-well microtiter plate was pretreated with 0.1% BSA for binding analysis. Membrane prepared from cells diluted ~ 100 times in buffer solution B (20 mM Tris, 100 mM NaCl, 10 mM MgCl2, pH 7.4, plus 0.2% BSA, 0.1 mM PMSF, 5 μg / ml aprotinin A, 0.025% nystatin, and 3 mM EDTA) to a final protein concentration of 0.2 mg / ml. In the competition study, the membrane (0.02 mg) was co-cultured with 0.1 nM [125I] ET-3 in buffer solution B (final volume ·· 0 · 2 ml) and tested in unlabeled E-3 or test In the presence of increasing concentrations of the compound, 4 hours at 25 ° C. After incubation, the unbound ligands were separated from the bound ligands by a vacuum filtration method. Here, glass-fiber filter strips were used in a PHD cell recoverer (Cambridge Technology, Inc., ΜΑ), and then saline was added. (1ml) Wash 3 times 0 _-77-_ This paper size applies to China National Standard (CNS) Α4 size (210X297 mm), (Please read the precautions on the back before loading-page) Central Standard of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperatives 502018

A

7 B V. Description of the invention (75) Non-specific binding is determined in the presence of 1 # M ET-1. The data are shown in Table 1. The percentage of inhibition at 1 βM concentration is shown. The data show that the compounds of the invention bind to endothelin receptors. Table 1 Combined data Example 1% inhibition of ETB under Μ Example 1 //% inhibition of ETB under Μ _ 1 96.4 2 91.5 3 82.1 4 94.0 5 96.5 6 ~ * 92.9 7 94.5 8 93.6 9 94.8 10 95.2 11 96.0 12 96.7 13 91.3 14 96.6 15 93.4 16 92.3 17 97.1 18 94.9 19 94.9 20 95.5 21 97.1 22 95.3 23 99.1 24 93.3 25 95.7 26 98.0 27 98.8 (Please read the precautions on the back before loading the pages) Order the Central Bureau of Standards of the Ministry of Economic Affairs The ability of employees' cooperatives to print compounds of the present invention to lower blood pressure can be determined by Matsumura, et al ·, Eur. J. Pharmacol. 185 103 (1990) and Takata, et al ·, Clin. Exp ·

The method described in Pharmacol. Physiol. U 131 (1983) expressly expresses the ability of the compound of the present invention to treat congestive heart failure, which can be expressed according to the method described in Margulies, et al., Circulation ϋ 2226 (1990). -78- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm), printed by the consumer cooperation of the China Standards Bureau of the Ministry of Economic Affairs, and printed 502018 A7 B7 V. Description of the invention (76) Capability can be explicitly stated as described in Watanabe, et al., Nature 344 114 (1990). The ability of the compound of the present invention to treat coronary angina pectoris can be clearly demonstrated according to the method described in Heistad, et al., Circ. Res. M 711 (1984). The ability of the compounds of the present invention to treat cerebral vasospasm can be clearly demonstrated by the method of Nakagomi, et al., J. Neurosurg. M. 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 shown according to the method of Hara et al., European. J. Phamacol. 197: 75-82, (1991). The ability of the compound of the present invention to treat acute renal failure can be Expressed according to the method described by 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 clearly demonstrated by the method described in Benignl, et al. Kidney Int. 44 440-444 (1993). The ability of the compound of the present invention to treat gastric ulcer can be clearly demonstrated according to the method described by Wallace, et al., Am. J. Physiol. 256 G661 (1989). The ability of the compounds of the present invention to treat nephrotoxicity due to cyclosporine-biosynthesis can be clearly demonstrated according to the method described by Kon, et al., Kidney Int. II 1487 (1990). The ability of the compounds of the present invention to treat endotoxin-deficient toxicity (shock) can be clearly demonstrated by the method of Takahashi, etal., Clinical Sci. Ϋ 619 (1990). The ability of the compounds of the present invention to treat asthma can be clearly stated in accordance with the method of Potvin and Varma, Can J. Physiol, and Pharmacol, 1213 (1989). The ability of the compound of the present invention to treat graft-induced atherosclerotic atherosclerosis can be clearly stated in accordance with the method of Foegh, et al., Atheroscierosis 78. 229-236 (1989) — _ -79 -___ This paper standard applies to Chinese national standards ( CNS) A4 specification (210X297 mm) ΙΓ. ............! | V. · _sI— I--8.---.............. ......... III .......- II (Please read the precautions on the back before ^ 1 ^ 4 pages) Order 502018 A7 B7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Description of the invention (77) 0 The ability of the compound of the present invention to treat atherosclerosis can be according to Bobik, et al., Am. J. Physiol. 258 C408 (1990) and Chobanian, et al., Hypertension 15 327 (1990) The method is explicitly stated. The ability of the compounds of the present invention to treat LPL-associated lipoprotein disorders can be clearly demonstrated by the method described in Ishida, et al., Biochem. Pharmacol. 44. 1431-1436 (1992). -The ability of the compound 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 the method described by 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, systemic lupus erythematosus, diabetic nephropathy or other kidney lesions, psoriasis, scleroderma, prostate proliferation , Cardiac hypertrophy, restenosis after arterial injury or other pathological stenosis of blood vessels. The ability of the compounds of the present invention to treat acute or chronic pulmonary hypertension can be clearly demonstrated by the method described in Bonvallet et al. Am. J. Physiol. 266 H1327 (1994). Pulmonary hypertension can be associated with congestive heart failure, mitral stenosis, emphysema, pulmonary fibrosis, chronic obstructive pulmonary disease (CopD), acute respiratory distress syndrome (ARDS), altitude sickness, and chemical exposure, Or it may be spontaneous. The ability of the compounds of the present invention to treat platelet aggregation and thrombosis can be determined according to the method described in McMurdo et al. Eu J. Phamacol. 259 51 (1994) --- 80-_ This paper is applicable to Chinese national standards (CNS) M specifications (21QX: 297 mm) (Please read the precautions on the back before you install-page) Printed by the Central Consumer Bureau of the Ministry of Economic Affairs, Printed by the Consumer Consumption Cooperative 502018 A7 B7 V. Description of Invention (78) 0 The ability of the compound of the present invention to treat cancer can be clearly demonstrated according to the method described by Shichiri, et al., J. Clin. Invest · ϋ 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 described by Klemm et al., Proc. Nat. Acad. Sci. Ϋ 2691 (1995) The method is express. The ability of the compound of the present invention to treat receptor injury can be explicitly expressed according to the method described in Yamamoto et al :, J. Pharmacol. Exp. Therap. 271 156 (1994). 0 The ability of the compound of the present invention to treat colitis can be determined according to Hogaboam et al. The method described in al (EUR. J. Pharmacol, 1996, 309 · 261-269) expressly 0 The ability of the compound of the present invention to treat hemorrhage-reinfusion injury in kidney transplantation can be determined according to Aktan et (Transplant Int 1996, £ _ , 201-207). The ability of the compounds of the present invention to treat angina pectoris, pulmonary hypertension, Raynaud's disease, and migraine pain can be explicitly expressed according to the method described by Ferro and Webb (Drugs 1996, II, 12-27). The compounds of the invention can be used in the form of salts derived from inorganic or organic acids. These salts include, but are not limited to the following: acetate, hexanoate, alginate, citrate, aspartate, benzoate, benzenesulfonate, hydrogen sulfate, butyrate Salt, camphor salt, camphor sulfonate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glyceryl phosphate, hemisulfate , Heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, argonate, 2-caproyl-ethanoate, lactate, maleate, methanesulfonic acid Salt, nicotinic acid salt, 2-ammonium sulfonate, oxalate, dihydroxygallate, pectin ester, peroxodisulfate, -81-This paper size applies to China National Standard (CNS) A4 (210X297 mm)

It— «1 .....» —1 111 —I ........ —I! 1 ....... I ..... ....... I (please read the Note Boxing on the back first)

、 1T like υΐ 8 Α7 Β7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (79) 3-phenylpropionate, picrate, third valerate, propionate, succinate, tartaric acid Salt, thiocyanate, p-toluenesulfonate and undecanoate. At the same time, the experimental nitrogen-containing group can be quaternized, and the used substances such as lower alkyl groups such as methyl, ethyl, propyl and butyl chloride, bromine and iodine; dialkyl sulfates such as sulfuric acid Dimethyl, diethyl, dibutyl and dipentyl, long chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromine and iodine, aralkyl groups such as benzyl and Phenethyl bromide, and others. This results in water or oil soluble or dispersible products. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. The addition salt can be prepared in situ during the final isolation and purification of the compound of formula (〗), or the double acid functional group can be separately reacted with a suitable test, pharmaceutically acceptable metal cation hydroxide, carbonic acid Salt or bicarbonate, react with ammonia or organic primary, secondary or tertiary amines. Such pharmaceutically acceptable salts include the following, but are not limited thereto, such as soil metal and basic <cations, such as steel, bell, unloading, dance, iron, salt, etc., and non-toxic ammonium, quaternary ammonium , And amine cations, including but not limited to the following, such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines that can be used to form test addition salts include diethylamine 'ethylenediamine, ethanolamine, diethanolamine, hexahydropyridine, and the like. The compounds of the present invention can be used to antagonize endothelin j in humans or other mammals. The compounds of the present invention can be used (in humans or other mammals). Exhausted muscle, blood, reinfusion injury, coronary angina, cerebral hemorrhage, brain

(Please read the precautions on the back first-installation-page) Order line 502018 A7 Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs V. Description of the invention (80) Vasospasm, chronic or acute renal failure, non-steroidal anti-inflammatory Gastric ulcers caused by drugs, kidney poisons caused by cyclosporine, toxic effects of endotoxin-biosynthesis, asthma, fibrotic or proliferative diseases, including smooth muscle proliferation, systemic disease, pulmonary sclerosis, adult respiratory distress syndrome, Spontaneous cardiomyopathy, systemic lupus erythematosus, diabetic retinopathy or other retinopathy, psoriasis, scleroderma, prostatic hypertrophy, cardiac hypertrophy, restenosis after arterial damage or other pathological stenosis of blood vessels, LDL-related lipids Protein Disorders, Transplantation-Blasting Atherosclerosis or General Atherosclerosis, Platelet Agglutination, Thrombosis, Cancer, Prostate Cancer, Jiang 2 and Other Cytokines Mediated Heart Toxicity and Osmotic Disorders And device injuries, especially for bone pain associated with gastric cancer. The total daily dose of a single or divided dose administered to the host can range from, for example, 0.001 to 1000 mg / kg body weight per day, and is usually 0.001 to 100 mg / kg for oral administration or 0.001 to 10 mg. G / kg for parenteral administration. A dosage unit composition may contain multiple sub-doses of this dose to the daily dose. The dosage of the active ingredient which can be mixed with the carrier substance to produce a single dose may vary depending on the host treated and the particular mode of administration. However, it should be understood that the specific dose for any particular patient may depend on various factors, including the activity of the particular compound applied, the age, weight of the patient, general health, gender, diet, time of administration, administration, route, excretion rate, Contraindications to medication and the severity of the particular disease being treated. ^ The compound of the invention can be administered parenterally, sublingually, or by inhalation spray, transrectally, or locally, in a unit dosage form, containing a traditional non-toxic pharmaceutically acceptable carrier, adjuvant and Demand solvent. Partial _______- 83- This paper size is applicable to Chinese National Standard (CNS) M specification (21〇 &gt; &lt; 297 cm) (Please read the precautions on the back before-installation) Order 502018 A7 B7 V. Description of the invention (81) For transdermal administration, transdermal administration is also available, such as transdermal patch or video game player penetrating into the clothes. The term parenteral, as used herein, includes subcutaneous injections, intravenous, intramuscular, intrasternal injections, 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. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution of i, 3 • propylene glycol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium vaporized solution. In addition, sterile solidified oils have traditionally been used as solvents or suspension media. For this purpose, any fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are also found in injectable preparations. Suppositories for rectal administration of the drug can be mixed with suitable non-irritating excipients, such as cocoa butter and polyethylene glycol, which are solid at ordinary temperatures, but will liquefy at the temperature of the anus. It melts and releases the drug. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In this solid dosage form, the active compound may be blended with at least one inert diluent, such as sucrose, lactose or starch. This dosage form also contains (as general practice) additional substances other than 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. Bonding agents and pills can additionally be prepared as enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs, containing inert diluents, such as water commonly used in technology. This composition may also contain adjuvants, such as moisturizers, milk: and help 502018 A7 B7 V. Description of the invention (82) Suspensions, and sweeteners, fragrances and fragrances. The compounds of the invention may also be administered in the form of liposomes. As is known in the art, liposomes are usually derived from phospholipids or other lipid substances. Liposomes can be formed from single or multiple hydrated liquid crystals, which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid-forming lipid can be used. If the composition is in the form of a liposome, it may contain a stabilizer, a preservative, an excipient, etc. in addition to the compound of the present invention. Preferred lipids are phospholipids and phospholipids choline, which can be natural and synthetic. Methods for forming liposomes are known in the art. See 3 Prescott, Ed. Methods in Cell Biology, Volume XIV, Academic Press, New York, N.A. (1976), p. 33 et seq. Representative solid dosage forms, such as lozenges or capsules, containing: 35% w / w starch of the compound of the present invention, pregelatinized, NF 50% w / w microcrystalline cellulose, NF 10% w / w talc, powder , USP 5% w / w IP printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs.-^ ------- install-(please read the notes on the back first and then the page). Although the present invention can be presented separately Active agent administration, which can also be used in combination with more than one cardiovascular agent, independently selected from diuretics, adrenergic blockers, vasodilators, calcium channel blockers, renal hormone inhibitors, vasopressors ACE inhibitors, vasopressin II antagonists, potassium activators, and other cardiovascular agents. Representative diuretics include dihydrochloride, saponin, chloramidine, acetazolamide, amlodipine, bupropion acid, hydrazone, diuretic acid, diurethamide, indacrinone, metolazone, amphetamine, Triammin, chloracetone-85- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 502018 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 _ ^ __ 5. Description of the invention (83), etc., or a pharmaceutically acceptable salt thereof. Representative adrenergic blockers include test tolamine, shamming, Lujun spray, terazosin, tolajun sentinel 1, amoxicillin, methoxyethoxan, hydrazine, xinxinan, timolol, carteolol Etc., or a pharmaceutically acceptable salt thereof. Representative vasodilators include hydralazine, longanidine, diazepine, nitroprusside, etc., or a pharmaceutically acceptable salt thereof. Typical trip blockers include amrinone, epoxigenol, diltiazem, phenethylamphetamine, fluorophenazine, nicardipine, nimodipine, Xinshuning, isotebotine, gallopamil, nitrate-benzene pideline, etc. Or a pharmaceutically acceptable salt thereof. Representative renal hormone inhibitors include enalkiren, zankiren, RO 42-5892, PD-134672, and the like, or a pharmaceutically acceptable salt thereof. Representative vasopressin II antagonists include DUP 753, A · 81988, and the like. Representative ACE inhibitors include captopril, enalapril, lisinopril, etc., or a pharmaceutically acceptable salt thereof. Representative potassium activators include pinacidil, etc., or their pharmaceutically acceptable salts. 0 Other representative cardiovascular agents include sympathetic blockers such as methyldopa, cotonin, guanabenz, reserpine, or Its pharmaceutically acceptable salt. The compounds of the present invention and cardiovascular agents can be administered at the recommended maximum clinical dose or minimum dose. The dosage level of the active compound in the composition of the present invention can be changed to obtain the desired therapeutic response, which varies depending on the route of administration, the severity of the disease and the response of the patient. The combination can be presented in separate compositions. __ · 86-Degree Applicable to China (CNS> A4 Specifications (2) [〇 &gt; &lt; 297gong ^ ~ (Please read the precautions on the back before-installation · page)

1T line A7 B7 V. Description of the invention (84) It may be in a single dosage form and contains two kinds of agents. When administered in combination, the therapeutic agents can be adjusted to separate compositions which are administered at the same or different times or the therapeutic agents can be administered as a single composition. The foregoing merely illustrates the present invention, and is not intended to limit the present invention to the disclosed method of humanizing, the composition. The obvious changes to the artisan are within the scope of the present invention, and the essence of the present invention is covered by the following patent applications: 疋 0

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs-Order ------ line -87- This paper size applies to China National Standards (CNS) 8 4 specifications (2 丨 0X 297 mm) 8ΠΤ26 repair king application 1 86. 3. 24. Case No. 86103700 Category 〇fil &quot; V] λΊ ίίψ t ') 4〇 Chinese manual revision page (October 8th)

502018 Employees' cooperation of the Central Government Bureau of the Ministry of Economic Affairs, printed by the company 11 Patent Specification Invention I. Name Chinese pyrrolidine compound with endothelin antagonistic effect and its pharmaceutical composition English COMPOUNDS ENDOTiMjN- SSSs — τ dirty PHARMAC —, Creator; name nationality residence, residence 1. Andrews S. Tasker 2. Martin Wayne 3. Chomas W. Wengerden_ 4. Steven A. Uncle 5. Note-Sue and 6. Ken Nice J. Henry 7. Brian K. Surowson L. United Kingdom 2-7. Both are American _ | _ and! Divide 63 No. 1 __Examination 1. f 1 Envy, Xin, F, K, F, and Drow Road 477 Wen Ke Ji Ji 11¾¾¾ warm name (name) American business Abbott company Nationality US III. Applicant's residence, residence (office) No. 00 Yappei Park Road, Aberdeen Park, Illinois, USA This paper is suitable for $ Person name ^ National standard april Charles M. Brooke -1- ^ (CNS) Ad4f 44r (1 \ r \\ y λπ-7. \ \ Binding line installation 502018 No. 86103700 Patent Application Chinese Specification Correction Page ( October 87) A7 B7 0. V. Description of the invention (1) This case is US series No. 〇8 / 6〇0,7 Part 24 continued the application, which was filed on February 13, 1996. (Please read the notes on the back before filling this page) TECHNICAL FIELD The present invention relates to a compound, which is an endothelin antagonist. Methods of compounds, synthetic intermediates used in these methods and methods and compositions that antagonize endothelin. BACKGROUND OF THE INVENTION Endothelin (ET) is a peptide of 21 amino acids produced by endothelial cells. Enzymatic dissociation of the Trp-Val bond in the body peptide big endothelin (Big ET). This dissociation is caused by endothelin converting enzyme (ECE). Endothelin has been shown to contract arteries and veins, increasing mean arterial blood pressure, Decreasing cardiac output 'increases intracardiac contractility, stimulates mitosis in vascular smooth muscle cells in the test tube, and contracts non-vascular smooth muscle, including guinea pig trachea, human urethral bladder strips, and rat uterus (in test tubes), increasing the respiratory Resistance, defame the formation of gastric ulcers, stimulate the release of atrial steeluria factors in test tubes and in vivo, increase vasopressin, aldosterone and catecholamines Plasma levels inhibit the release of renal hormones in the test tube and stimulate the release of gonadotrophins in the test tube. The 'vasoconstriction is caused by the binding of endothelin to receptors on vascular smooth muscle (Nature 21141 1 (1988) , FEBS Letters 440 (1988) and Biochem. Biophys. Res. Commun. 154 868 (1988)). If the agent can inhibit the production of endothelin or bind to endothelin, or it can inhibit the binding of endothelin and endothelin receptor, it will be beneficial in various therapeutic fields. Consistently, once the anti-endothelin antibody is fused in the kidney, it has been shown that it can be -4-paper scale Yaozhou Chinese National Standard (CNS) A4 specification (210X297 mm) 502018 No. 86103700 patent application Chinese description Book revision page (October 1987) A7 B7 May 5, description of the invention (This mixture was dissolved in 50 亳 L of ethanol and 15 ml of an aqueous solution containing 5,000 grams of sodium hydroxide, and stirred at room temperature for 3 hours. The solution was Concentrate under reduced pressure and add 60 ml of water. The mixture is extracted with ether to remove unreacted cis, trans-ethyl ester. The aqueous phase is treated with hydrochloric acid until slightly turbid. It is further neutralized with acetic acid to form a crude acid. The crude product was filtered and dissolved in tetrahydrofuran for purification, dried over sodium sulfate, concentrated under vacuum, and then crystallized from ether to give the title compound. 1H NMR (300MHz, CDC13) d 8.22 (1H, bs), 7.78 (2Η, d, J = 8Hz), 6.95 (5Η, m), 6,82 (1H, bd, J = 8Hz), 6.77 (1Η, d, J = 8Hz), 5.96 ( 2H, s), 3.97 (1Η, bd, J = 10Hz), 3.81 (3Η, s), 3.70 (1H, ddd, 6, 5 &amp; 3Hz), 3.57 (bdd, 10 &amp; 3 Hz), 3.45 (1Η, d, J = 16Hz), 3.13 (2Η, m), 2.24 (3H, s), 2.06 (6H, s). MS (DC1, NH3) m / e 517 ( M + H +). Analyze C30H32N2〇6 · 0.5H2O: C, 68.56, H, 6.33, N, 5.33. Measured 値: C, 6S.84, Η, 6.20, Ν, 5.31. Examples 1 \ -T eliminator in 2 parts (please read the precautions on the back before filling this page) trans, trans-2- (3-fluoro-4-methoxyphenyl 3-benzodi The hum-5-yl Vl-((2,4,6-trimethyl) anilinecarbonylmethylpyrrolidine-3-carboxylic acid title compound was prepared by the procedure described in Example 1. 1H NMR (300MHz, CDC13) 0 ' 8.22 (1H, bs), 7.21 (1H, dd, J 12 &amp; 2Hz), 7.12 (1H, bd, J = 8Hz), 6.95 (1Η, t, 8Hz), 6.90 (2Η, bs), 6.84 (1Η, d, J = 2Hz), 6.80 (1Η, d, J = 8% 3Hz), 6.76 (1Η, d, J = 8Hz), 5.93 (2Η, s), 3.96 (1Η, d, J = 10Hz), 3.89 (3H, s), 3.70 (1Η, ddd, 6, 5 &amp; 3Hz), 3.56 (1H, dd, 11 &amp; 5Ηζ), 3.45 ( 1Η, d, J = 16Hz), 3.10 (1H, t, J = 10Hz), 3.07 (1H, dd, 8 &amp; 6Hz), 3.02 (1H, d, J = 16Hz), 2.17 (3H, -54 sheets Standards apply Chinese national standards ( CNS) A4 Specification (210X297 mm) 502018 No. 86103700 Patent Application Chinese Manual Revised Page (October 1987) A. B7 V. Description of Invention (Jk il Eliminate Bamboo in the Gas Department), 2.07 (6H , S). MS (DC1, NH3) m / e 535 (M + H +). Analysis estimates C30H31FN2O6 · 0.75H2O: C, 65.74, Η, 5.98, Ν, 5.11. Measured 値: C, 65.96, Η, 5.88, Ν, 5.16. Example 3 trans'-2- (4-propoxybenzyl) -4-Π, 3-benzodifluorene-5-its H ((2,4,6-trimethyl) aniline carboxymethyl The title compound was prepared by the procedure described in Example 1. 1H NMR (300MHz, CDC13H 8.21 (1H, bs), 7.38 (2Η, d J = 8Hz), 6.90 (2H, d, J = 8Hz), 6.89 (2Η, d, 3Hz), 7 · 83 (1Η, dd, J = 8 &amp; 2Hz), 6.75 (1H, d, J = 8Hz), 5.94 (1Η, d, J = 3Hz), 5.93 (1H, d, J = 3Hz), 3.96 ( 1H, d, J = 10 Hz), 3.85 (2Η, q, J = 7Hz), 3.70 (1H, ddd, 6, 5 & 3Hz), 3.58 (1Η, dd, 11 &amp; 5Ηζ), 3.48 (1Η, d, J = 16Hz), 3.15 (1H, dd, 8 &amp; 6Hz), 3.13 (1Η, t, J = 10Hz), 2.99 (1Η, d, J = 16Hz), 2.25 (3H, s), 2.05 (6Η, s), 1.81 (2Η, sext, J = 7Hz), 1.04 (3Η, t, J = 7Hz). MS (DC1, NH3) m / e 545 (M + H +). Analyzed and estimated C32H36N2 06 · 0.33H2O: C, 69.79, H, 6.71, N, 5.09. Found 値: C, 69.78, Η, 6.73, Ν, 4.81. Example 4 trans, trans-2- (4-methoxybenzyl) -4- (1.3-benzodifluoren-5-yl) -1-((2,6-diethyl) aniline methyl ) Ο Bitong Lake _ 3 _ leptin title compound was prepared according to the procedure described in Example 1. 1h NMR (300MHz, CDC13) β 8 · 24 (1Η, bs), 7.39 (2H, d, J = 8Hz), 7.21 ( 1H, dd5 8 &amp; 6Hz), 7.11 (2Η, d, J = 8Hz), 6.92 (2H, d, 8 Hz), 7.89 (1Η, d, J = 3Hz) 5 7.82 (1H? Dd? J = 8 &amp; 2Hz), 6.75 (1H, d, J = 8Hz), 5.94 (1H, d, J = 3Hz) , 5.93 (1H, d, J = 3Hz), 3.96 (1H, d, J = 10Hz), 3.82 (3Η, -55) This paper size applies to China National Standard (CNS) A4 (210X297 mm) (please Read the precautions on the back before filling this page) d Order d No. 86103700 Patent Application Chinese Specification Correction Page (October 1987): &gt; A7 B7 V. Description of the invention (please read the note on the back first Please fill in this page for matters) s), 3.70 (1Η, ddd, 6, 5 &amp; 3Ηζ), 3.56 (1Η, dd, 11 &amp; 5Ηζ), 3.45 (1Η, d, J = 16Hz), 3.15 ( 1H, dd, 8 &amp; 6Hz), 3.13 (1Η, t, J = l'0Hz), 3.01 (1Η, d, J = 16Hz), 2.42 (4Η, q, J = 7Hz), 1.08 (6Η, t, J = 7Hz). MS (DC1, NH3) m / e 559 (M + H4 +), 53 1 (M + H +). Analysis estimates C31H34N206: C, 70.17, 17, 6.46, N, 5.28. Found 値: C, 69.88, H, 6.42, N, 5.09. Example 5 Eliminating 1V 々 卬% trans, trans-2- (4-propoxyphenyl) -4- (1,3-benzodiazin-5-yl) -1-((2,6 -Diethyl) anilinecarbonylmethyl) -pyrrolidine-3-carboxylic acid The title compound was prepared according to the procedure described in Example 1. 1H NMR (300MHz, CDC13) θ 8.27 (1Η, bs), 7.37 (2Η, d, J = 8Hz), 7.21 (1Η, dd, 8 &amp; 6Ηζ), 7.11 (2Η, d , J = 8Hz), 6.90 (2Η, d, 8Hz), 7.86 (1Η, d, J = 3Hz), 7.83 (1Η, dd, J = 8 &amp; 2Hz), 6.75 (1Η, d, J = 8Hz), 5.93 (1Η, d, J = 3Hz), 5.92 (1H, d, J = 3Hz), 3.96 (1Η, d, J = 10Hz), 3.85 (2Η, q, J = 7Hz), 3.70 (1H, ddd, 6, 5 &amp; 3Hz), 3.55 (1Η, dd, ll &amp; 5Hz), 3.48 (1H, d, J = 16Hz), 3.15 (1Η, dd, 8 &amp; 6Hz), 3.13 (1H, t5 J = 10Hz), 3.01 (1H, d, J = 16Hz), 2.43 (4Η, q, J = 7Hz), 1.82 (2H, sext, J = 7Hz), 1.08 (6H, t, J = 7Hz), 1.04 (3H, t, J = 7Hz). MS (DC1, NH3) m / e 559 (M + H.). Analyze C33H38N206 · 0.25 · 2 0 · · C, 70.38, H, 6.89, N, 4.97. Found 値: C, 70.49, H, 6.85, Ν, 4.68. Example 6 trans, trans-2- (3-fluoro-4-methoxyphenyl 3-benzodiazine-5-yl) -1-((2,6-diethyl) aniline carbonyl Pyrrolidine-3-carboxylic acid-56- The paper size is the national standard of China (CNS) A4 specification (210X297 mm) 502018 No. 86103700 Patent application Chinese manual amendment page (October 87) A7 B7 noon h Wu Bu Zhong il J Xiao 1V Hezhu a 卬, description of the invention (4 (Please read the notes on the back before filling this page) The title compound was prepared according to the procedure described in Example 1. 1H NMR (300MHz, CDC13) d 8.21 (1H, bs), 7.22 (1Η, dt, J = 8 &amp; 2Hz), 7.20 (1Η, d, J = 8Hz), 7.17 (1H, dt, J = 8 &amp; 2Hz), 7.10 (2Η, d, J = 8Hz), 6.96 (1H, t, J = 8Hz), 6.83 (1H, dd, J = 8 &amp; 2Hz), 6.80 (1H, d, J = 3Hz), 6.76 (1H, d , J = 8Hz), 5.94 (1Η, d, J = 3Hz), 5.93 (1Η, d, J = 3Hz), 3.97 (1H, d, J = 10Hz), 3.90 (3Η, s ), 3.72 (1Η, ddd, 6, 5 &amp; 3Hz), 3.58 (1Η, dd, ll &amp; 5Hz), 3.46 (1H, d, J = 16Hz), 3.14 (1H, t, J = 10Hz ), 3.12 (1H, dd, 8 &amp; 6Hz), 3.05 (1H, d, J = 16Hz), 2.45 (4 q, q, J = 7Hz), 1.09 (6H, t, J = 7Hz). MS (DC1, NH3) m / e 549 (M + H +). Analysis estimates C31H33FN206 · 0.5 · 2Η: C, 66.78, Η, 6.15, N, 5.02. Measured fluorene: C, 66.81, hydrazone, 5.89, N, 4.87. Example 7 trans, trans-2-Π-fluoro-4-ethoxyphenyl) -4-Π, 3-benzodizaki- 5-yl) -1-((2,6-diethyl) anilinecarbonylmethylpyrrolidine-3-carboxylic acid The title compound was prepared according to the procedure described in Example 1. 1H NMR (300MHz, CDC13) ό '8 · 23 (1Η, bs), 7.23 (1Η, d, J = 2Hz), 7.20 (1Η, dd5 J = 8 &amp; 3Hz), 7.11 (3H, m), 6.96 (1H, t, J = 8Hz), 6.83 (1Η, dd, J = 8% 2H2〇, 6.80 (1H, d, J = 3Hz), 6.76 (1Η, d, J = 8Hz), 5.93 (1H, d, J = 3Hz), 5.92 (1Η, d, J = 3Hz), 4.11 (2Η, t5 J = 7Hz), 3.97 (1H, d, J = 10Hz), 3.72 (1Η, ddd, 6, 5 &amp; 3Hz) , 3.55 (1H, dd, 11 & 5Hz), 3.47 (1 (, d, J = 16Hz), 3.14 (1H, t, J = 10Hz), 3.12 (1H, dd, 8 &amp; 6Hz), 3.04 (1 , D, J = 16Hz), 2.45 (4H, q, J = 7Hz), 1.47 (3Η, t, J = 7Hz), 1.09 (6Η, t, J = 7Hz). MS (DC1, NH3) m / e 563 (M + IT). Analysis estimates C32H35FN206 · 0.15TFA: C, 66.92,., 6.11, N, 4.83. -57 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 502018 No. 86103700 Patent Application Chinese Manual Correction Page (October 87) A7 B7% m, 19 month of amendment a V. Description of the invention (3 Measured tritium: C, 67.19, tritium, 5.75, N, 4.69. Examples (Please read the precautions on the back before filling out this page) Trans, trans 2- 2- (3-fluoro-4 -A Oxyphenyl) -4- (7-methylamino-1,3-benzodioxin-5-yldiethyl) benzylamine carboxymethyl) _pyrrolidin Prepared as described. iH NMR (300MHz, CDC13) 8.24 (1Η, S), 7.25 (1Η, t, J = 3Hz), 7.21 (1H, bd), 7.14 (1H? m), 7.08 (2H, d, J = 8Hz), 6.96 (1H, t? J = 8Hz) 5 6.56 (1H, d, J = 3Hz), 6.50 (1Η, d, J = 3Hz), 5.93 (1H, d, J = 2Hz), 5.91 (1Η, d, J = 2Hz), 3.97 (1H, d, J = 10Hz), 3.90 (3Η, s), 3.72 (1H, ddd, 6, 5 &amp; 3Hz), 3.58 ( 1Η, dd, ll &amp; 5Hz), 3.46 (1H, d, J = 16Hz), 3.14 (1Η, t, J = 10Hz), 3.12 (1Η, dd, 8 &amp; 6Hz), 3.05 ( 1Η, d, J = 16Hz), 2.45 (4Η, q, J = 7Hz), 1 · 09 (6Η, t, J = 7Hz). MS (DC1, NH3) m / e 579 (M + H +). Analysis estimates C32H35FN207 · 1.5 · 20: C, 63.65, H, 6.31, N, 4.64. Found 値: C, 64.00, H, 6.29, N, 6:26. Example 9 trans, trans-2- (3-methoxy-4 -propoxybenzyl) -4- (1,3-benzodi-5-5 · yl) -1-((2,6- The title compound of diethyl) anilinemethylbihazate-3-multiacid was prepared according to the procedure described in Example 1. 1H NMR (300MHz, CDC13) β 8 · 22 (1Η, s), 7.21 (1Η M), 7 · 12 (2Η, d, J = 10Hz), 7.02 (1Η, dd, J = 9 &amp; 3Hz), 6.93 (1Η, d, J = 2Hz), 6.88 (1Η, d, J 2Hz), 6.85 (1Η, m), 6.82 (1Η, d, J = 2Hz), 6.75 (1Η, d, J = 9Hz), 5.95 (1H, d, J = 2Hz), 5.93 (1Η, d, J = 2Hz), 3.97 (2Η, q, J = 9Hz), 3.84 (3H, s), 3.72 (2H, m), 3.60-3 · 45 (2Η, m), 3.15 (2Η, m), 3.03 (1H, d, J = 18Hz), 2.43 (4H, q, J = 9Hz), 1.87 (2H, m), -58 National Standard (CNS) A4 Specification (210X 297 mm) 7502018 No. 86103700 Patent Application Chinese Specification Correction Page (10/87) V. Invention Description (Please read the precautions on the back before filling this page) 1.08 (6Η, t, J = 9Hz), 1.04 (3Η, t5 J = 9Hz). MS (DC1, NH3) m / e 589 (MH +). Analysis estimates C34H4〇N207 · 0.45H2O: C , 68.43, H, 6.91, N, 4.69. Measured C: C, 68.45, H, 6.91, N, 4.62. Example 1 0 trans, trans-2- (4-ethoxybenzyl) -4- (1, 3-Benzenedi-5-yl VI-((2,6-diethyl) anilinecarbonylmethylpyrrolidine-3-carboxylic acid The title compound was prepared according to the procedure described in Example 1. 1H NMR (300MHz, CDC13 ) β 8.26 (1H, bs), 7.36 (2Η, d, J = 9Hz), 7.21 (1Η, m), 7.11 (2H, d, J = 10Hz), 6.90 (2Η, d, J = 9Hz), 6.86 (1Η, d, J = 2Hz), 6.83 (1H, dd, J = 8 &amp; 2Hz), 6.73 (1H, d, J = 9Hz), 5.94 (1Η, d, J = 2Hz), 5.92 (1Η, d, J = 2Hz), 4.10-3.90 (3H, m), 3.71 (1H, m), 3.60-3 · 40 (2Η, m), 3.15 (2Η, m), 3.02 (1Η, d, J = 18Hz), 2.43 (4H, q, J = 9Hz), 1.42 (3Η, t5 J = 9Hz), 1.08 (6Η, t, J = 9Hz). MS (DC1, NH3) m / e 545 (MH +). Analysis estimates C32H36N206 · 0.5H2O: C, 69.42,., 6.74, Ν, 5.06. Measured 値: C, 69.52, Η, 6.52, N, 4.89. Example 1 1 trans'trans-2- (4-methoxyphenyl) -4- (1,3-benzodi 4- 5-yl) -1-((2,6-dimethyl) aniline The title compound of the carbonyl amidinopyrrolidin-3-carboxylic acid was prepared according to the procedure described in Example 1. i; H NMR (300 MHz, CDC13) d 8 · 32 (1Η, bs), 7.37 (2Η, d, J = 9Hz), 7.08 (3H, m), 6.91 (2H, d, J = 9Hz), 6.88 (1Η, d, J = 2Hz), 6.82 (1H, dd, J2 8 &amp; 2Hz), 6.75 (1Η, d, J = 9Hz), 5.95 (1Η, d, J = 2Hz), 5.93 (1H, d, J = 2Hz), 3.95 (1H, d, J = 10Hz), 3.81 (3H, s ), 3.72 (1H, m), 3.55 (1H, dd, J = 10 &amp; 5Hz), 3.46 (1Η, d, J = 18Hz), 3.13 (2Η, m), -59- This paper size Shizhou Chinese National Standard (CNS) A4 Specification (210X297 mm) ^ 2018 A7 B7 No. 86103700 Patent Application Chinese Manual Correction Page (October 87) V. Description of Invention (55 · (Please read the note on the back first) Please fill in this page again for matters) 3.00 (1H, d, J = 18Hz), 2.10 (6Η, s). MS (DC1, NH3) m / e 502 (MH +). Analyze and estimate C29H30N2〇6 · 0 · 5Η20: C, 68.09, Η, 6.11, N, 5.48. Measured 値: C, 66.98, H, 6.02, N, 5.33. Example 1 2 Formula one, -trans-2- (4-propoxyphenyl) -4- (7-methylamino-1,3-benzodihum-5-yl) -1 _ ((2,6-diethyl Group) Aniline carbonylmethyl erogenide-3 -chinoic acid The title compound was prepared according to the procedure described in Example 1. 1η NMR (300MHz, CDC13) d 8 · 30 (1Η, bs), 7.36 (2Η, d, J = 9Hz), 7.21 (1Η, m), 7.09 (2H, d, J = 10Hz), 6.91 (2Η, d5 J = 9Hz), 6.59 (1H, d, J = 2Hz), 6.51 ( 1H, d, J = 2Hz), 5.93 (1Η, d, J = 2Hz), 5.91 (1Η, d, J = 2Hz), 3.93 (3Η, m), 3.80 (3H, s) , 3.72 (1Η, m), 3.60_3 · 50 (2Η, m), 3.15 (2Η, m), 3.02 (1H, d, J = 18Hz), 2.43 (4Η, q, J = 9Hz), 1.82 (2H, m), 1.08 (6Η, t, J = 9Hz), 1.05 (3H, t, J = 9Hz). MS (DC1, NH3) m / e 589 (MH +). Analytical estimation C34H4ON207 · 0.25 · 20: C, 68.84, H, 6.88, N, 4.72. Measured 値 ·· C, 68.80, H, 6.59, Ν, 4.52. Example 1 3 trans, transmethoxy-4 -propoxyphenyl) -4- (7-methoxy-1,3-benzodifluoren-5-yl) -M (2,6 · di Ethyl) phenylaminecarbonylmethyl) -pyrrolidine-3-chicanic acid was digested with ^ ii. ^-^ M in the Ministry of Commerce. ^ The title compound was prepared according to the procedure described in Example 1. 1H NMR (300MHz, CDC13) θ 8 · 22 (1Η, S), 7.21 (1Η, m), 7.09 (2Η, d, J = 10Hz), 7.02 (1Η, dd, J = 9 &amp; 3Hz ), 6.93 (1Η, d, J = 2Hz), 6.87 (1Η, d, J = 9Hz), 6.61 (1H, d, J = 2Hz), 6.53 (1H, d, J = 2Hz), 5.93 ( 1H, d, J = 2Hz), 5.91 (1Η, d5 J = 2Hz), 3.97 (3H, q, J = 9Hz), 3.84 (3Η, s), -60-^^ Chinese National Standard (CNS) A4 Specification (210X297mm) Chuan 2018 A7 B7 No. 86103700 Patent Application Chinese Specification Revised Page (October 1987) 5. Description of Invention (Door ......... ......-I ........ ——I I- = 1_---.............. ----- Ξ: — Hi n (Read the precautions on the back before filling this page) 3.82 (3H, s), 3.70 (1H, m), 3.60-3 · 45 (2Η, m), 3.15 (2Η, m), 3 02 (1Η, d, J = 18Hz), 2.42 (4H, q, J = 9Hz), 1.85 (2H, m), 1.08 (6H, t, J = 9Hz), 1.05 (3Η, t, J = 9Hz). MS (DC1, NH3) m / e 619 (MH +). Analyzed and estimated C35H42N208: C, 67.94, H, 6.84, N, 4.53. Measured 値 ·· C, 67.65, Η, 6.98, Ν, 4.44 〇 Example 1 4 trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzene The benzodiamidin-5-yl) -1-((2,6-dibromo) anilinecarbonylmethylpyrrolidine-3-carboxylic acid title compound was prepared by the procedure of Example 1. 4 NMR (300MHz, CDC13) β 8 · 58 (1Η, bs), 7.58 (2Η, d, J = 9Hz), 7.40 (2Η, bd, J = 10Hz), 7.02 (1Η, t, J = 9Hz), 6.91 ( 2Η, d, J = 9Hz), 6.86 (1H, m), 6.76 (1H, d, J = 9Hz), 5.93 (2H, s), 3.98 (1H, bd, J = 10Hz), 3.81 (3Η, s), 3.73 (2H, m) 3.55 (1H, bd, J = 15Hz), 3.13 (2Η, m), 3.01 (1Η, bd, J = 18Hz). MS (DC1, NH3 ) m / e 633 (MH +). Analyzed and estimated C27H24Br2N206 · 0.3H2O: C, 50.85, Η, 3.89, N, 4.39. Measured 値: C, 50.45, H, 3, 48, N, 4.22. Example 1 5 [2R, 3R, 4S ~ | 2- (4-methoxyphenyl) -4- (1,3-benzodiazin-5-yl) _ 1 w · (g, 6-diethyl ) Aniline carbonyl methyl pyrrolidine _ 3 -carboxylic acid hydrochloride _

Example 1 5 A-E

Example of another method for preparing 'trans-2- (4--oxophenyl) -4- (1.3-benzodi-4--5-yl) · ^^^ pyridine-3 -carboxylic acid ethyl ester in roll form 15A 5 -(2-Nitrovinyl) -L3 -Benzodizaki Mao 61-11 This paper is the state standard of the state of China (Yang ^ Shanjiange ^ ^ ^ Lu)

Claims (1)

502018 Patent Application No. 86103700 Amended Chinese Patent Application Range (April 91) A8 B8 C8 D8 Scope of patent application1.A compound of the following formula Where R is-(CH2) mW, where m is an integer from 0 to 6, and W is -C (0) 2-G, where G is hydrogen; R 1 is phenyl, wherein the phenyl is optionally Substituted by 1,2 or 3 independently selected from CrC6-alkyl, alkoxy and halogen substituents; R2 is benzodiazolyl, wherein the benzodiaxazolyl can be optionally Or 3 independently selected from Ci-Cr alkyl, alkoxy and halogen substituents; R3 is R4_C (0) -R5_ 'where R 5 is C 1-benzyl and R 4 is aniline' where The phenyl group may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of a group, a Ci-C6-alkoxy group, a carboxyl group, a halogen, and a nitro group; or a pharmaceutically acceptable salt thereof. 2. The compound according to item 1 of the scope of patent application, wherein R is-(CH2) mW, where m is 0, W is -C02G, and G is hydrogen; R! Is selected from 4-methoxyphenyl, 3- Fluoro-4 -ethoxyphenyl, 3-fluoro-4 -methoxyfungyl '4 -ethoxyphenyl' 4-propoxyphenyl and 3-methoxy-4-propoxyphenyl; R2 is optional From 1,3-benzodioxazolyl and 7-methoxy-1,3-benzodioxy; and this paper size applies to China National Standard (CNS) A4 specification (210X 297 mm). Han 3 is R4-C (0) -R5-, where R4 is Wherein RnKRu is independently selected from Ci-C3-alkyl, C "alkoxy and halogen and Rn is selected from hydrogen, C! -Alkyl, halogen, carboxy and nitro, and 5 is methylene. 3. According to The compound in the scope of patent application No. 1 has the following formula: ~ · / 1 where R is-(CH2) mW, where] !! is an integer from 0 to 6, and w is -C (0) 2-G 'Where G is hydrogen; I is a phenyl group, wherein the phenyl group can be optionally substituted with 1, 2 or 3 independently selected alkyl groups, Ci-Cs-fluorenyloxy group and a halogen substituent; R2 is benzobis Oxazolyl, wherein the benzobisoxazolyl can be optionally substituted with 1, 2 or 3 independently selected from Ci-Cs-alkyl, CVCV alkoxy and halogen substituents; R3 is R4-C ( 0) -R5-, in which R ^ Clr · alkylene and 114 are aniline, wherein the phenyl group can be optionally selected from 1, 2 or 3 independently selected from the group consisting of Ci-C ^ alkoxy, carboxyl, Substituted by self-priming and nitro substituents; -2- This paper size applies to China National Standard (CNS) A4 specifications (210x297 public love) A8 B8 C8 D8 scope of patent application or its pharmaceutically acceptable salt. 4. The compound according to item 3 of the patent application, wherein R is-(CH2) mW, where m is 0, W is -C02G, and G is hydrogen; R1 is selected from the group consisting of renylmethoxyphenyl and 3-fluoro -4 -Ethoxyphenyl, 3-fluoro-4 -methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl and 3-methoxy-4 -propoxyethyl; Inverse 2-series selection From 1,3-benzodioxazolyl and 7-methoxy-1,3-benzodioxazolyl; and R3 is R4-C (0) -r5-, where trans-4 is Wherein Ru and R12 are independently selected from C ^ C ^ -alkyl, CV alkoxy and halogen 'and R13 is selected from hydrogen, Cl-alkyl, halogen, carboxyl and nitro, and R5 is methylene. 5. The compound according to item 1 of the scope of patent application, which is selected from the group consisting of trans, trans-2- (4-methoxyphenyl) -4- (1,3-benzodihum-5-yl) -1- (2,6-diethyl) anilinecarbonylmethylpyrrolidine-3-carboxylic acid; trans, trans-2- (4-propoxyphenyl) -4- (1,3-benzo Diaz-5-yl) -1- (2,6-diethyl) anilinecarbonylmethyl) _pyrrolidin-3-carboxylic acid; trans, trans-2- (3-fluoro-4-methoxy Phenyl) -4- (1,3-benzodifluoren-5-yl) -1-((2,6-diethyl) aniline carbonylmethyl) -pyrrolidine-3-carboxylic acid; trans, Trans-2- (3-fluoro-4-ethoxyphenyl) -4- (1,3-benzodioxin-5-) This paper size applies to China National Standard (CMS) A4 specifications (210X 297 public love) 502018 A8 B8 C8 _______ D8 VI. Range of patent application)-Bu ((2,6-diethyl) aniline carbonylmethyl) _ p Bihadian_ 3 -carboxylic acid; trans, trans-2- ( 3-fluoro-4-methoxyphenyl) -4- (7-methoxy-1,3-benzodihum-5-yl) -1-((2,6-diethyl) anilinecarbonylmethyl ) _Pyrrolidincarboxylic acid; trans, trans-2- (3-methoxy-4-propoxyphenyl) -4- (1,3-benzodioxin-5-yl) -1- ((2,6-diethyl) aniline carbonyl methyl Ratio p each fluorene_3_carboxylic acid; trans, trans-2- (4_ethoxyphenyl) -4- (1,3-benzodifluoren-5-yl) _fluorene-((2,6 Ethyl) epiaminocarbonylmethyl) -erodoline-3-leic acid; trans, trans-2- (4-propoxyphenyl) -4- (7-methoxy-1,3-benzene Hexaclopyridine-5-yl) -bu ((2,6-diethyl) aniline carbonylmethyl) · Syringosis-3-metarate; trans, trans-2- (3-methoxy- 4-propanylphenyl) -4- (7-methoxy-1,3-benzo-"-5-yl) -1-((2,6-diethyl) anilinecarbonylmethyl)- ? Bi-Hydro-3 -polyacid; [21 ^, 31 ^, 48] 2- (4-methoxyethenyl) -4- (1,3-benzobis'7-5-yl) -1 -(^^-((2,6-diethyl) anilinecarbonylmethyl) -pyrrolidine-3-carboxylic acid; [211,311,48] 2- (4-propoxyphenyl) -4- ( 1,3-benzodi-17-5-yl) small (1 ^-(2,6-diethyl) anilinecarbonylmethyl) -pyrrolidinecarboxylic acid; and (2R, 3R, 4S) -2- (4-ethoxyphenyl) _4- (1,3_benzodolin-5-yl) small (2,6_monoethyl) aniline peptidylmethyl bihalide-3-polyacid, or Pharmaceutically acceptable salts. 6. The compound according to item 5 of the scope of patent application, wherein the compound is trans, trans-2- ( 4-propoxyphenyl) -4- (1., 3-benzodiazine-5-yl) -1-((2,6-diethyl) aniline carbonylmethyl) _pyrrolidine_3-carboxyl Acid;-or a pharmaceutically acceptable salt thereof. -4- This paper size is applicable to @ ® 家 料 (CNS) A4 specification (210 X 297 public directors) Application scope 7. The compound according to item 5 of the application scope, wherein the compound is [2R, 3R, 4S] 2- (4-methoxyphenyl) -4 · (1,3-benzodi 4-5 -(N- (2,6 · diethyl) anilinecarbonylmethyl) -pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof. 8. The compound according to item 5 of the scope of patent application, wherein This compound is [2R, 3R, 4S] 2- (4-propoxyphenyl) -4- (1,3-benzobenzoz-5-yl (N _ ((2,6-diethyl) aniline carbonyl Methyl pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof. 9. The compound according to item 5 of the scope of patent application, wherein the compound is (2R, 3R, 4S) -2- (4-acetamidine) Phenyl) -4- (1,3-benzodihum-5-yl) -1- (N- (2,6-diethyl) anilinecarbonylmethyl) -p-pyrrolidinecarboxylic acid; or a pharmacy thereof 10 · —A pharmaceutical composition that antagonizes endothelin, which contains a therapeutically effective dose of the compound according to item 1 of the patent application scope, and a pharmaceutically acceptable carrier. 11. · An antagonist of endothelin Pharmaceutical composition containing a therapeutically effective dose Compounds of 3, and pharmaceutically acceptable carriers. 12 · —A pharmaceutical composition for treating hypertension, congestive heart failure, restenosis after arterial damage, cerebral or myocardial hemorrhage or atherosclerosis Substance, which contains a therapeutically effective dose of the compound according to item 1 of the patent application 〇13 ·-a kind of treatment for 咼 blood pressure, congestive heart failure, restenosis after arterial damage, cerebral or myocardial hemorrhage or atherosclerosis Hardened pharmaceutical composition, its -5- 502018 A BCD 6. The scope of the patent application contains a therapeutically effective dose of a compound according to item 3 of the scope of the patent application. 14. · It is used to treat coronary angina pectoris, cerebral vasospasm, acute and chronic pulmonary hypertension, acute and chronic renal failure, gastric ulcer, renal toxicity of cyclosporine, toxicity of endotoxin, asthma, L p L _ Related Lipoprotein Disorders, Proliferative Diseases, Platelet Agglutination, Thrombosis, Cardiotoxicity Mediated by IL_2, Receiver Injury, Colitis, Vascular Penetration Disorders, Repeated Infusion of Wounds, Raynaud's Disease, Cancer and A migraine pharmaceutical composition 'contains a therapeutically effective dose of a compound according to item 1 of the patent application. 15 · It is used for "oral treatment of angina pectoris, cerebrovascular spasm, acute and chronic pulmonary hypertension, acute and chronic renal failure, gastric itch, renal toxicity caused by cyclosporine, toxicity of endotoxin, and asthma , LP l -related lipoprotein disorders, proliferative diseases, platelet aggregation, thrombosis, L 2 -mediated cardiotoxicity, receptor injury, colitis, vascular permeability disorder, repeated infusion injury from hemostasis, A pharmaceutical composition of Raynaud's disease, cancer and migraine, which contains a therapeutically effective dose of a compound according to item 3 of the scope of the patent application. 16. The compound according to item 2 of the scope of the patent application, wherein r4 is selected from 2,6 · xylamino; 2,6-diethylaniline; 2,6-dimethoxyaniline; 2,6_di Cumanilide; 2,6-dibromoaniline; 2-ethyl-6-methylbenzylamino; 2,4,6-trimethylamino; 2,4 ,. 6-triethylaniline; 2 ,, 6-diethyl-4-tolylamino; 4-carboxy-diethylaniline; 4-nitro. 2,6-diethylaniline; and 2-isopropyl-6-toluidine. This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 502018 8 8 8 8 AB c D VI. Patent application scope 17. According to the 4th patent application scope compound, where R4 is selected from 2, 6-xylamino; 2,6-diethylaniline; 2,6-dimethoxyaniline; 2,6-diisopropylaniline; 2,6-dibromoaniline; 2-ethyl- 6-tolylamino; 2,4,6-tritolylamino; 2,4,6-triethylanilyl; 2,6-diethyl-4-tolylamino; 4-carboxy-2,6-di Ethylanilide; 4-nitro-2,6-diethylaniline; and 2-isopropyl-6-toluidine. This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)