MXPA99012052A

MXPA99012052A - Pyrrolidine carboxylic acid derivatives as endothelin antagonists

Info

Publication number: MXPA99012052A
Application number: MXPA/A/1999/012052A
Authority: MX
Inventors: Winn Martin; W Von Geldern Thomas; S Tasker Andrew; A Boyd Steven; Jae Hwansoo; K Sorensen Bryan; J Henry Kenneth
Original assignee: Abbott Laboratories
Priority date: 1997-06-17
Filing date: 1999-12-17
Publication date: 2000-06-01

Abstract

A compound of formula (I), or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.

Description

DERIVATIVES OF CARBOXYLIC ACID OF PIRROLIDINE AS ENDOTHELIN ANTAGONISTS Technical Field 5 The present invention relates to compounds that are endothelin antagonists, processes for forming said compounds, synthetic intermediates employed in these processes, and methods and compositions for antagonizing endothelin. Background of the Invention 10 Endothelin (ET) is a peptide of 21 amino acids that are produced by endothelial cells. ET is produced by enzymatic cleavage of a Trp-Val ligation in the large endothelin of the * -I peptide precursor (Large ET). This division is caused by an endothelin conversion enzyme (ECE). -r 15 Endothelin has been shown to restrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility in vitro, stimulate mitogenesis in vascular smooth muscle cells in vitro, contract smooth muscle not vascular including guinea pig trachea from India, 6 20 separates the urinary bladder from human and rat uteri in vitro, increases the resistance of the respiratory tract im vivo, induces the formation of gastric ulcers, stimulates the release of atrial natriuretic factor in vitro, and in vivo, increases plasma levels of vasopressin, aldosterone and catecholamines, inhibits the release renin in vitro and stimulates the release of gonadotropins in vitro.

It has been shown that vasoconstriction is caused by the binding of endothelin to its receptors in vascular smooth muscle (Nature 332 411 (1988), FEBS Letters 231440 (1988) and Biochem, Biophys. Res. Commun. 154 868 (1988)). An agent that suppresses the production of endothelin or an agent that binds to endothelin or that inhibits the binding of endothelin to an endothelin receptor will produce beneficial effects in a variety of therapeutic areas. In fact, it has been shown that an anti-endothelin antibody, by intrarenal infusion, improves the adverse effects of renal ischemia or renal vascular resistance and glomerular filtration rate (Kon, and »Others, J. Clin. Invest. 83. 1762 (1989)). In addition, an anti-endothelin antibody attenuates the nephrotoxic effects of cyclosporin intravenously administered (Kon, et al., Kidney Int. 37. 14787 (1990) and attenuates the infarct dimension of a coronary artery.15 Clozel et al. (Nature 365: 759-761 (1993)) report that Ro 46-2005, an ET-A / B antagonist without peptides, avoids V * post-ischemic renal vasoconstriction in rats, prevents the decrease in cerebral blood flow due to subarachnoid hemorrhage (SAH) in rats and decreases MAP in squirrel monkeys that has exhausted sodium when dosed orally. A similar effect of a linear tpeptide similar to the ET-A antagonist, BQ-485, on the arterial f-caliber after SAH, has also been recently reported (S. Itoh, T. Sasaki, K. Ide, K. Ishikawa, M. Nishikibe and Yano.

Z, Biochem. Biophys. Res. Commn. 195: 969-75 (1993). The results 4 25 indicate that agents that antagonize the ET / ET receptor bound J will provide therapeutic benefit in the indicated disease states. Two structurally related endothelin receptors have been cloned, sequenced and characterized (Hosada, K .; Nakao, K .; Arai, 5; Suga, S.; Ogawa, Y .; Mukoyama, M .; Shirakami, G .; Saito, Y .; Nakasnishi, S .; Imura, H. FEBS Lett., 1991, 187, 27-26; Sakamoto, A.; Yanagisawa, M .; Sakurai, T .; Takuwa, Y .; Yanagisawa, H .; Masaki, T. Biochem, Biophys, Res. Commun. 1991, 178, 565-663). Each one binds the three endothelin isopeptides with different affinities; the ETA receptor exhibits affinity for ET-1 and ET-2- on ET-3, whereas the ETB receptor is not a selective isopeptide. It was originally described as a vasodilator receptor due to its mediation of nitric oxide release (DeNucci, G., Thomas, R., D'Orleans-Juste, P., Antunes, E., Walder, C.; Warner, T.D .; Vane, J.R. Proc. Nati Acad. Sci. U.S. A. 1988, 85, 9797-9800) it will now be evident that the ETB receptor is responsible for a greater diversity of physiological function. Current research suggests a role for ETB-mediated responses in certain disease states including established pulmonary hypertension (McCulloch, KM; MacLean, MR; J. Cardiovasc, Pharmacol, 1995, 26 (Suppl 3), S169-S176), contractile dysfunction associated with benign prostatic hyperplasia (Weeb ML, Chao, C.-C; Rizzo , M .; Shapiro, RA; Naubauer, M .; Liu, ECK; Aversa, CR; Brittaín, RJ; Treiger, B. Mol., Pharmacol., 1995; 47, 730-737; Webb, ML; Meek, T.D. Med. Res. Rev. 1997, 17, 17-67), myocardial infarction (Vitola, IH "JV; Forman, MB; Holsinger, JP; Kawana, M .; Atkinson, JB; Quatermous, T .; Jackson, EK; Murray, JJJ Cardiovasc. Pharmacol., 1996, 28, 774-783) and arteriosclerosis (Dagassan, PH, Breu, V, Clozel, M., Kunzli, A., Vogt, P, Turina, M., Kiowski, Clozel, J. -PJ Cardiovasc, Pharmacol., 1996, 27, 147-153.) Our group has previously reported the discovery of a series of pyrrolidine-3-carboxylic acids which bind potently and selectively to the ETA receptor subtype (Winn, M .; von Geldern, TW; Opgenorth, TJ; Jae, H. -S .; Tasker, AS, Boyd, SA, Kester, JA, Mantei, RA, Bal, RB, Sorensen, BK, Wu-Wong, JR, Chiou, WJ, Dixon, DB, Novosand, EI, Hernandez, L., Marsh, KCJ Med. Chem. 1996, 39, 1039-1048) The related compounds in the present invention differ from those previously described and are unique in that they bind potently and selectively to the ETB subtype, blocking the actions of endothelin on cough receptors. In this way, they can find utility in the treatment of diseases that are mediated by the ETB receptor. Description of the Invention According to the present invention there are those of the formula (I): (I) wherein R is - (CH2) mW wherein m is an integer from 0 to 6 and W is (a) -C (O) 2-G wherein G is hydrogen or a carboxy protecting group, (b) - PO3H2, (c) -P (O) (OH) E wherein E is hydrogen, lower alkyl or arylalkyl, (d) -CN, (e) -C (O) NHR17 wherein R17 is lower alkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy (j) alkoxy, (k) sulfonamido (I) -C (O) NHS (O) 2RIT wherein R16 is lower alkyl, haloalkyl, aryl or dialkylamino , (m) -S (O) 2NHC (O) R16 wherein R16 is as defined above, • ~ - -NHSOaCFg R1 and R2 are independently selected from hydrogen, lower alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbyalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkyl, , dialkylaminocarbonyalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic, (heterocyclic) alkyl and (Raa) (Rbb) N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with provided that one or both of R1 and R2 are different from hydrogen; R3 is R4-C (O) -R5- or R6-S (O) 2-R7-, wherein R5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (v) -N (R2o) -Rs- or -R8a-N (R20) -R8- wherein R8 and R a are independently selected from the group consisting of alkylene and alkenylene; and R20 is hydrogen, lower alkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl or cycloalkylalkyl or (v) -O-R9- or -Rga- wherein R9 and R9a are independently selected from alkylene; R7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N (R21) -R10- or -R? > a-N (R2?) - R? o- wherein R10 and RIOA are independently selected from the group consisting of alkylene or alkenylene and R21 is hydrogen, lower alkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl; wherein R4 and R6 are wherein Rn and R12 are independently selected from the group consisting of lower alkyl, cyano, alkoxy, halo, haloalkyl and phenyl and R13, R14 and R15 are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy, amino, alkoxy, aryl, heterocyclic, halo, carboxy, nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy, or cyano; or (ii) heterocyclic (amino), or a pharmaceutically acceptable salt thereof. A preferred embodiment of the invention is a compound of the formula (II) (ll) wherein the substituents -R2, -R and Ri exist in a trans, trans and R, R1f R2 and R3 ratio are as defined above. A more preferred embodiment of the invention is a compound of the formula (I) or (II) wherein R3 is R4-C (O) -R5, wherein R4 is as defined above and R5 is alkylene or R3 is R6- S (O) 2-R-, wherein R7 is alkylene and R6 is as defined above.

An even more preferred embodiment of the invention is a compound of the formula (I) or (II) wherein R is -C (0) 2 -G- wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or is -C (O) -NHS (O) 2R? 6 wherein R16 is lower alkyl, haloalkyl or aryl, Ri and R2 independently are selected from (i) lower alkyl, (ii) cycloalkyl, (iii) substituted or unsubstituted aryl and (iv) substituted or unsubstituted heterocyclic and R3 is R -C (O) -Rs- wherein R4 is as defined above and R5 is alkylene or R3 is R6-S (0) 2-R7-, wherein R7 is alkylene and R6 is as defined above. An even more preferred embodiment of the invention is a compound of the formula (I) or (II) wherein R is -C (O) 2-G, wherein G is hydrogen or a carboxy, tetrazolyl or -C ( O) -NHS (O) 2R? E wherein R? 6 is lower alkyl, haloalkyl or aryl, Ri is (i) alkoxyalkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furanyl or (vi) 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 2-fluoro-4-ethoxyphenyl, 3-f Io- 4- methoxy phenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxyphoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2 -ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl substituted or unsubstituted, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is 1, 3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1, 4-benzodioxanil, 8-methoxy-1,4-benzodioxanil, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl substituted or unsubstituted and R3 is R4-C (0) -Rs-, where R4 is as defined above and R 5 is alkylene or R 3 is R 6 -S (O) 2 -R-, wherein R 7 is alkylene and R 6 is as defined above. Another still more preferred embodiment of the invention is a compound of the formula (I) or (II) wherein R is -C (O) 2 -G, wherein G is hydrogen or a carboxy, tetrazolyl or C-protecting group ( O) -NHS (O) 2R16, wherein R-? 6 is lower alkyl, haloalkyl or aryl, R- is (i) alkoxyalkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furanyl or (vi) 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl 4-propoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 2-f-U-4-ethoxy phenyl, 3-fluoro 4-methoxy phenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- ( 2-ethoxyethoxy) phenyl, 1,4-benzodioxanyl or dihydrobenzofuranyl substituted or unsubstituted, wherein the substituent is selected from alkoxy, alcolialkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, , 4-benzodioxanil, 8-m ethoxy-1,4-benzodioxanil, dihydroben zofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C (O) -R5-, wherein R4 is as defined above and R5 is alkylene. An even more preferred embodiment of the invention is a compound of the formula (I) or (II) wherein R is -C (O) 2-G, wherein G is hydrogen or a carboxy, tetrazolyl or -C ( O) - NHS (O) 2R16, wherein R-? 6 is lower alkyl, haloalkyl, Ri is 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl 4-isopropoxyphenyl, 3-fluoro- 4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl substituted or unsubstituted, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R -C (0) -R5-, wherein R is as defined above and R5 is alkylene. A more highly preferred embodiment of the invention is a compound of the formula (I) or (II) wherein R is -C (O) 2 -G, wherein G is hydrogen or a carboxy protective group, R ^ is 4- methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro- 4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 4-methoxymethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-propoxyethoxy) phenyl, 4-hydroxyphenyl, , Substituted or unsubstituted 3-benzodioxolyl, 1,4-benzodioxanil or dihydrobenzofuranyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy,, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanil, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R -C (O) -R5-, where R4 is wherein R n and R 2 independently are selected from lower alkyl and R 3, R 1 and R 5 independently are selected from the group consisting of hydrogen, lower alkyl, hydroxy, amino, alkoxy, aryl, heterocycle, halo, carboxy , nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy or cyano and R5 is alkylene. A more highly preferred embodiment of the invention is a compound of the formula (I) or (II) wherein R is -C (O) 2-G, wherein G is hydrogen or a carboxy protective group, i is 4-methoxyphenyl , 4-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4 -propoxyphenyl, 3-methoxy-4-propoxyphenyl, 4-methoxymethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) phenyl, 4-hydroxyphonyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or substituted or unsubstituted dihydrobenzofuranyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, , 4-benzodioxanil, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R -C (O) -R5-, wherein R4 is wherein R n and R 12 independently are selected from the group consisting of lower alkyl, alkoxy and halo and R 13, R? and R15 independently are selected from the group consisting of hydrogen, lower alkyl, hydroxy, amino, alkoxy, aryl, heterocyclic, halo, carboxy, nitro, alkylsulfonyl, aryisulfonyl, thioalkoxy, thioaryloxy or cyano and R5 is alkylene. Another more highly preferred embodiment of the invention is a compound of the formula (I) or (II) wherein R is -C (O) 2-G, wherein G is hydrogen or a carboxy protective group, Ri is 4-methoxyphenyl , 4-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4 -propoxyphenyl, 3-methoxy-4-propoxyphenyl, 4-methoxymethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) phenyl, 4-hydroxyphenyl, 1,3- substituted or unsubstituted benzodioxolyl, 1,4-benzodioxanil or dihydrobenzofuranyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzo dioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4- benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C (O) -R5-, wherein R4 is wherein Rn and R12 are independently selected from the group consisting of lower alkyl, alkoxy and halo and R13, Ru and R15 are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy, amino, alkoxy, aryl, heterocyclic, halo, carboxy, nitro, alkylsulfonyl, aryisulfonyl, thioalkoxy, thioaryloxy or cyano and R5 is methylene. Another more highly preferred embodiment of the invention is a compound of the formula (I) or (II) wherein R is -C (0) 2-G, wherein G is hydrogen or a carboxy protective group, R ^ is 4- methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro- 4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 4-methoxymethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) phenyl, 4-hydroxyphenyl, 1,3 -benzodioxolyl, 1,4-benzodioxanyl or substituted or unsubstituted dihydrobenzofuranyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4- benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R -C (O) -Rs-, wherein R is wherein R n and R 2 independently are selected from the group consisting of lower alkyl, alkoxy and halo and R 13, R 4 and R 15 independently are selected from the group consisting of hydrogen, lower alkyl, hydroxy, amino, alkoxy, aryl, heterocyclic, halo, carboxy, nitro, alkylsulfonyl, aryisulfonyl, thioalkoxy, thioaryloxy or cyano and R5 is methylene. The present invention also relates to processes for preparing the compounds of formula (I) and (II) and to the synthetic intermediates employed in these processes. The present invention also relates to a method for antagonizing endothelin in a mammal (preferably a human) in need of such treatment, comprising administering to a mammal a therapeutically effective amount of a compound of the formula (I) or (II). The invention further relates to endothelin antagonizing compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the formula (I) or (II). The compounds of the invention comprise two or more asymmetrically substituted carbon atoms. As a result, racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention. The terms "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Puré Appl. Chem. (1976) 45, 13-30. The term "carboxy protecting group" as used herein, refers to an ester group that protects the carboxylic acid used to block or protect the functionality of the carboxylic acid while the reactions imply other sites functionalities of the compound carried out. Carboxy protecting groups are described in Greene, "Protective Groups in Organic Synthesis" p. 152-186 (1981), which are incorporated herein by reference. In addition, a carboxy protective group can be used as a prodrug whereby the carboxy protective group can be rapidly divided in vivo, for example by enzymatic hydrolysis to release the biologically active parent compound. T. Higuchi and V. Stella provide through the discussion of the prodrug the concept in "Por-drugs as Novel Delivery systems", Vol 14 of the A. C.S. Symposium Series, American Chemical society (1975), which are incorporated herein by reference. Said carboxy protecting groups are well known to those skilled in the art, which has been used extensively in the protection of the carboxyl groups in the penicillin and cephalosporin fields, as described in the U.S. Patent. No. 3,840,556 and 3,719,667, the descriptions of which are incorporated herein by reference. Examples of the esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E.B. Roche, Pergamon Press, New York (1987), which are incorporated herein by reference. Representative carboxy protecting groups are alkyl of d to C8 (e.g., methyl, ethyl or tertiary butyl and the like) haloalkyl; alkenyl, cycloalkyl and substituted derivatives thereof such as cyclohexyl, cyclopentyl and the like; substituted cycloalkylalkyl and derivatives thereof such as cyclohexylmethyl, cyclopentylmethyl and the like, arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indenyl and the like; dialkylaminoalkyl (e.g., dimethylaminomethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1- (propionyloxy) -l-ethyl, 1- (pivaloyloxy) -1-ethyl, 1-methyl-1- (propionyloxy) -1-ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2-phenylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-1-ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1-ethoxycarbonyloxy-1-ethyl, 1-cyclohexyloxycarbonyl-1-ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like; (5- (lower alkyl) -2-oxo-1,3-dioxolen-4-yl) alkyl, such as (5-t-butyl-2-oxo-1,3-dioxolen-4-yl) methyl and the like; and (5-phenyl-2-oxo-1,3-dioxolen-4-yl) alkyl, such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl and the like. The term "N-protecting group" or "N-protected" as used herein, refers to those groups intended to protect the N-terminus of an amino acid or peptides or to protect an amino group against undesirable reactions during synthetic procedures. . Commonly the N-protecting groups used are described in Greene, "Protective Groups In Organic Synthesis", (John Wiley &Sons, New York (1981), which is incorporated herein by reference.) The N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and similar: sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxy benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitro benzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4 -di methoxy benzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-bi fe nil il) -1-methyl-ethyl-rboni, a, ad-methyl-3,5-di methoxy-benzyloxycarbonyl, benzylhydri-1-oxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2, -trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorophenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethyl Isyl i lo and the like. The preferred N-protecting groups are formyl, acetyl, benzolyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). The term "alkanoyl" as used herein refers to an alkyl group as defined herein in the parent molecular moiety through a carbonyl group (-C (O) -). Examples of alkanoyl include acetyl, propionyl and the like. The term "alkanoylamino" as used herein refers to an alkanoyl group as previously defined attached to an amino group. Examples of alkolamino include acetamido, propionamido and the like. The term "alkanoylaminoalkyl" as used herein refers to R 3 -NH-R44, wherein R 3 is an alkanoyl group and R is an alkylene group. The term "alkanoyloxyalkyl" as used herein refers to R 30 -O-R 31- wherein R 30 is an alkanoyl group and R 31 is an alkylene group. Examples of the alkanoyloxyalkyl include acetoxymethyl, acetoxyethyl, and the like. The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon radical of 2 to 16 carbon atoms and also contain at least one carbon-carbon double bond. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1-methyl-2-buten-1-yl and the like. The term "alkenylene" denotes a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. Examples of alkenylene include -CH-CH-, -CH2CH = CH-, -C (CH3) = CH-, -CH2CH = CHCH2- and the like. The term "alkenyloxy" as used herein refers to an alkenyl group, as previously defined, connected to the parent molecular moiety through an oxygen ligature (-O-). Examples of alkenyloxy and include allyloxy, butenyloxy and the like.

The term "alkoxy" as used herein refers to R42O- wherein R42 is a lower alkyl group, as defined herein. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isobutoxy, tert-butoxy and the like. The term "alkoxyalkoxy" as used herein refers to R8oO-R8? O- wherein R8o is lower alkyl as defined above and R8? It is alkylene. Representative examples of the alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like. The term "alkoxyalkoxyalkoxy" as used herein refers to R82O-R83? -R8 O- wherein R82 is lower alkyl as defined above and R83 and R8 are alkylene. Representative examples of the alkoxyalkoxyalkoxy groups include methoxyethoxymethoxy, ethoxymethoxymethoxy, t-butoxymethoxymethoxy and the like. The term "(akoxyalkyl) sulfonyl" as used herein refers to Rs5-O-R86-S (O) 2-, wherein R85 is lower alkyl and R86 is alkylene.

The term "alkoxyalkoxyalkyl" as used herein refers to an alkoxyalkoxy group as previously defined attached to an alkyl radical. Representative examples of the alkoxyalkoxyalkyl groups include methoxyethoxyethyl, methoxymethyioxymethyl and the like. The term "alkoxyalkyl" as used herein refers to an alkoxy group as previously defined attached to an alkyl radical as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like. The term "alkoxycarbonyl" as used herein refers to an alkoxy group as previously defined attached to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, and the like. The term "alkoxycarbonylalkenyl" as used herein refers to an alkoxycarbonyl group as previously defined attached to an alkenyl radical. Examples of alkoxycarbonylalkenyl include methoxycarbonyletenyl, ethoxycarbonyletenyl and the like. The term "alkoxycarbonylalkyl" as used herein refers to R 3 -C (O) -R 3s- wherein R 3 is an alkoxy group and R 35 is an alkylene group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl and the like.

The term "alkoxycarbonylaminoalkyl" as used herein refers to R38-C (O) -NH-R39- wherein R38 is an alkoxy group and R39 is an alkylene group. Examples of alkoxycarbonylaminoalkyl include methoxycarbonylaminoethyl and the like. The term "alkoxycarbonyloxyalkyl" as used herein refers to R36-C (O) -O-R37- wherein R36 is an alkoxy group and R37 is an alkylene group. Examples of alkoxycarbonyloxyalkyl include (ethoxycarbonyloxy) methyl and the like. The term "(alkoxycarbonyl) thioalkoxy" as used herein refers to an alkoxycarbonyl group as previously defined attached to a thioalkoxy radical. Examples of (alkoxycarbonyl) thioalkoxy include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like. The terms "alkyl" and "lower alkyl" as used herein refers to straight or branched chain alkyl radicals having from 1 to 15 carbon atoms including, but not limited to, methyl, ethyl, n-propyl , iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyryl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like . The term "alkylamino" as used herein refers to R5 NH- wherein R51 is a lower alkyl group, for example, ethylamino, butylamino and the like.

The term "(alkylamino) alkoxy" as used herein refers to Rs2NH-R53-O- wherein R52 is lower alkyl and R53 is alkylene. The term "alkylaminocarbonyl" as used herein refers to an alkylamino group, as previously defined, appended to a parent molecular moiety through a carbonyl bond (-C (O) -). Examples of alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl and the like. The term "alkylamlocarbonylalkenyl" as used herein refers to an alkenyl radical to which an alkylammocarbonyl group is attached. The term "alkylaminocarbonylalkyl" as used herein refers to an alkyl radical to which an alkylaminocarbonyl group is attached. The term "alkylaminocarbonylaminoalkyl" as used herein refers to R40-C (O) -NH-R1 wherein R40 is an alkylamino group and R41 is an alkylene group. The term "alkylene" denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 15 carbon atoms by the removal of two hydrogen atoms, for example -CH2-, -CH2CH2-, -CH ( CH3) -, -CH2CH2CH2-, CH2C (CH3) 2CH2- and the like. The term "alkylsulfonyl" refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group -S (O) 2-. Examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, and the like. The term "(alkylsulfonyl) amino" as used herein refers to an alkyl group as previously defined attached to the parent molecular moiety through a sulphinylamino group (-S (O) 2-NH-). Examples of (alkylsulfonyl) amino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like. The term "(alkylsulfonyl) alkoxy" as used herein refers to an alkylsulfonyl group as previously defined attached to the parent molecular moiety through an alkoxy group.

Examples of (alkylsulfonyl) alkoxy include methylsulfonylmethoxy, ethylsulphonylethoxy, isopropylsulfonylisopropoxy and the like. The term "(alkylthio) alkoxy" as used herein refers to R5 -S-R55-O-, wherein R54 is lower alkyl and R55 is alkylene. The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also contains at least one triple carbon-carbon bond. Examples of alkynyl include -C = C-H, H-C = C-CH2-, H-C = C-CH (CH3) -, CH3-C = C-CH2- and the like. The term "aminocarbonyl" as used herein refers to H2N-C (O) -.

The term "aminocarbonylalkenyl" as used herein refers to an alkenyl radical to which an aminocarbonyl group (NH2C (O) -) is attached. The term "aminocarbonylalkoxy" as used herein refers to H2N-C (O) - attached to an alkoxy group as previously defined. Examples of aminocarbonylalkoxy include amiocarbonylmethoxy, aminocarbonylethoxy and the like. The term "aminocarbonylalkyl" as used herein refers to an alkyl radical to which is attached an aminocarbonyl group (NH2C (O) -). The term "aminocarbonylalkyl" as used herein refers to a lower alkyl radical to which is added an aminocarbonyl group (NH2C (O) -). The term "aroyloxyalkyl" as used herein refers to R32-C (O) -O-R33- wherein R32 is an aryl group and R33 is an alkylene group. Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl, and the like. The term "aryl" as used herein refers to a monocyclic or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. The aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxyalkoxyalkoxy, (cycloalkyl) alkoxy, cycloalkoxy, (alkylamino) alkoxy, (alkylthio) alkoxy, alkoxycarbonylalkenyl, (alkoxycarbonyl) thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, (dialkylamino) alkyl, (dialkylamino) alkoxy, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy, mercapto, cyano, nitro, carboxyaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy, carboxyamide, alkylsulfonyl, (alkylsulfonyl) amino, (alkylsulfonyl) alkoxy, (alkoxyalkyl) sulfonyl, cyanoalkoxy, (heterocyclic) alkoxy, hydroxy, hydroxyalkoxy, phenyl and tetrazolylakoxy, further, the substituted aryl groups include tetrafluorophenyl and pentafluorophenyl. The term "arylalkenyl" as used herein refers to an alkenyl radical to which is added an aryl group, for example, phenylethenyl and the like. The term "arylalkoxy" as used herein refers to R 45 O- wherein R 45 is an arylalkyl group, for example benzyloxy, and the like. The term "arylalkoxyalkyl" as used herein refers to a lower alkyl radical to which is added an arylalkoxy group, for example, benzyloxymethyl and the like. The term "arylalkyl" as used herein refers to an aryl group as previously defined, even an alkyl radical I have added, for example, benzyl and the like.

The term "aryloxy" as used herein refers to R46O- wherein R46 is an aryl group, for example, phenoxy, and the like. The term "arylalkylcarbonyloxy" as used herein refers to R62C (O) O-, wherein R62 is an arylalkyl group. The term "arylalkylcarbonyloxyalkyl" as used herein refers to a lower alkyl radical appended to an arylalkylcarbonyloxy group. The term "aryloxyalkyl" refers to an aryloxy group as defined previously appended to an alkyl radical. Examples of aryloxyalkyl include phenoxymethyl, 2-phenoxyethyl and the like. The term "carboxaldehyde" as used herein refers to a formaldehyde radical, -C (O) H. The term "carboxyamide" as used in the representation refers to NH2-C (O) -. The term "carboxy" as used herein refers to a carboxylic acid radical, -C (O) OH. The term "carboxyalkenyl" as used herein refers to a carboxy group as defined previously appended to an alkenyl radical as previously defined. Examples of carboxyalkenyl include 2-carboxylethenyl, 3-carboxy-1-propenyl and the like. The term "carboxyalkoxy" as used herein refers to a carboxy group as defined previously appended to an alkoxy radical as previously defined. Examples of carboxyalkoxy include carboxymethoxy, carboxyethoxy and the like. The term "cyanoalkoxy" as used herein refers to an alkoxy radical as previously defined attached to a cyano group (-CN). Examples of cyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like. The term "cycloalkanoyloxy" as used herein refers to R60-C (O) -O- wherein R6o is a cycloalkyl group. The term "cycloalkanoyloxyalkyl" as used herein refers to a lower alkyl radical appended to a cycloalkanoyloxy group. The term "cycloalkyl" as used herein, refers to an aliphatic ring system having from 3 to 10 carbon atoms and 1 to 3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl , and similar. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxyamide. The term "cycloalkyloxy" refers herein to R6? -O- where R6-? is a cycloalkyl group, examples of cycloalkyloxy include cyclohexyloxy and the like. The term "(cycloalkyl) alkoxy" in the present R63-R64-O-, wherein R63 is a cycloalkyl as defined above and is added to the parent molecular moiety through an alkoxy radical wherein R6 is an alkylene group. Examples of (cycloalkyl) alkoxy include (cyclopropyl) ethoxy and the like. The term "cycloalkyl" as used herein refers to a cycloalkyl group added to a lower alkyl radical, including but not limited to cyclohexylmethyl. The term "dialkylamino" as used herein refers to (R56) (Rs) - wherein R5e and R57 are independently selected from lower alkyl, for example diethylamino, methyl, propylamino and the like. The term "(dialkylamino) alkyl" as used herein refers to a lower alkyl radical to which a dialkylamino group is added. The term "(dialkylamino) alkoxy" as used herein refers to an alkoxy radical to which a dialkylamino group is added. The term "dialkylaminocarbonyl" as used herein refers to a dialkylamino group, as previously defined, added to the parent molecular moiety through a carbonyl bond (-C (O) -). Examples of dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl and the like. The term "dialkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which a dialkylaminocarbonyl group is added.

The term "dialkylaminocarbonylalkyl" as used herein refers to R5β-C (O) -R59-, wherein R58 is a dialkylamino group and R59 is an alkylene group. The term "halo" or "halogen" as used herein refers to I, Br, Cl, or F. The term "haloalkenyl" as used herein refers to an alkenyl radical to which it is added at minus one halogen substituent. The term "haloalkenyl" as used herein refers to alkenyl radical to which at least one halogen substituent is added. The term "haloalkoxy" as used herein refers to an alkoxy radical as defined above, having at least one halogen substituent, for example, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2, 2,3,3,3-pentafluoropropoxy and the like. The term "haloalkoxyalkyl" as used herein refers to a lower alkyl radical to which a haloalkoxy group is added. The term "haloalkyl" as used herein refers to a lower alkyl radical, as defined above, to which is added at least one halogen substituent, for example chloromethyl, fluoroethyl, trifluoromethyl or pentafluoroethyl. The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as used herein refers to any 3 or 4 member ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a ring of 5, 6 or 7 members containing one, two or three nitrogen atoms; an oxygen atom; a sulfur atom; a nitrogen atom and a sulfur atom; a nitrogen atom and an oxygen atom; in non-adjacent positions; or two sulfur atoms in non-adjacent positions. The 5-membered ring has double bonds 0-2 and the 6 and 7-membered rings have double 0-3 ligature. The nitrogen heteroatoms can optionally be quaternized. The terms "heterocyclic" or "heterocycle" also include bicyclic groups in which any of the above rings are fused to a benzene ring, or a cycloalkane ring or other heterocyclic ring (e.g., indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroquinolyl, dehydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl, and the like). Heterocyclics include; aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, ixazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl , itazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxatanyl, furyl, tetrahydrofuranyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyridyl and benzothienyl.

Heterocyclics also include compounds of the formula wherein X * is -CH2- or -O- and Y * is -C (O) - or [-C (R ") 2-] V wherein R" is hydrogen or CrC alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. Heterocyclics also include bicyclic rings such as quinolidinyl and the like. The above can be unsubstituted, monosubstituted, disubstituted, or trisubstituted with substituents independently selected from hydroxy, halo, oxo (= O), alkylamino (R * N = where R * is a lower alkyl group), amino, alkylamino, dialkylamino , alkoxy, alkoxyalkoxy, haloalkyl, cycloalkyl, aryl, phenyl, arylalkyl, -COOH; -SO 3 H, alkoxycarbonyl, nitro, cyano and lower alkyl. In addition, nitrogen containing heterocycles can be N-protected. The term "(heterocyclic) alkoxy" as used herein refers to a heterocyclic group as defined by an alkoxy radical added as defined above. Examples of (heterocyclic) alkoxy include 4-pyridinylmethoxy, 2-pyridinylmethoxy and the like. The term "(heterocyclic) alkyl" as used herein refers to a heterocyclic group as defined above added to a lower alkyl radical as defined above. Examples of (heterocyclic) alkyl include 2-pyridinylmethyl and the like. The term "heterocyclic (amino)" refers to R77-NH- where R77 is a heterocyclic group as defined above to which an amino group is added. The aromatic heterocyclic is substituted with substituents R75 and R76 that bind to the aromatic heterocycle atoms that are directly adjacent to the nitrogen. R75 and R7e are substituents independently selected from hydroxy, halo, oxo (= O), alkylimino (R * N = wherein R * is a lower alkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, haloalkyl, cycloalkyl, aryl, phenyl, arylalkyl, COOH, -SO3H, alkoxycarbonyl, nitro, cyano and lower alkyl. The aromatic heterocycle may also optionally be substituted with a third substituent selected from the group hydroxy, halo, oxo (= O), alkylimino (R * N = wherein R * is a lower alkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, haloalkyl, cycloalkyl, aryl, phenol, arylalkyl, -COOH, -SO 3 H, alkoxycarbonyl, nitro, cyano and lower alkyl. Examples of heterocyclic (amino) include 2,4-diethylpyridine-3-amino, 2,4-diethylthiophene-3-amino, 2,4-deitypyridine-2-amino and the like. The term "heterocyclocarbonyloxyalkyl" as used herein refers to R -C (O) -O-R48- wherein R47 is a heterocycle group and R8 is an alkylene group. The term "hydroxy" as used herein refers to -OH.

The term "hydroxyalkenyl" as used herein refers to an alkenyl radical to which a hydroxy group is added. The term "hydroxyalkoxy" as used herein refers to an alkoxy radical as previously defined to which a hydroxy group (-OH) is added. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4-hydroxybutoxy and the like. The term "hydroxyalkyl" as used herein refers to a lower alkyl radical to which a hydroxy group is added. The term "mercapto" as used herein refers to -SH. The terms "methylenedioxy" and "ethylenedioxy" refer to one or two carbon chains respectively attached to the parent molecular moiety through two oxygen atoms. In the case of methylenedioxy, a ring of 5 fused members is formed. In the case of ethylenedioxy, a fused 6-membered ring is formed. The substituted methylenedioxy on a phenyl ring results in the formation of a benzodioxolyl radical.

The substituted ethylenedioxy on a phenyl ring results in the formation of a benzodioxanyl radical The term "substantially pure" as used herein means 90% or more of the specific compound. The term "tetrazolyl" as used herein refers to a radical of the formula. 1 N- N -VVN or a tautomer thereof. The term "tetrazolylalkoxy" as used herein refers to a tetrazolyl radical as defined above added to an alkoxy group as defined above. Examples of tetrazolylalkoxy include teterazolylmethoxy, tetrazolylethoxy and the like.

The term "thioalkoxy" as used herein refers to R70S- wherein R70 is lower alkyl. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like. The term "thioalkoxyalkoxy" as used herein refers to R7? S-R72O-, wherein R71 is lower alkyl as defined above and R72 is alkylene. Representative examples of the thioalkoxyalkoxy groups include CH3SCH2O-, CH3CH2SCH2O- t-BuSCH20- and the like.

The term "thioalkoxicalcoxyalkyl" as used herein refers to a thioalkoxyalkoxy group added to an alkyl radical. Examples of tialkoxyalkoxyalkyl include CH3SCH2CH2OCH2CH2-, CH3SCH2OCH2-, and the like. The term "trans, trans" as used herein refers to the orientation of R3 substituents "* & Rt (Ri and R2) in relation to the central substituent R as shown. The term "trans, cis" as used herein refers to the orientation of the substituents (RT and R2) in relation to the R substituent central as shown or .. This definition covers both cases where R and R2 are cis and R and Rt are trans and the case where R2 and R are trans and R and R-i are cis. The term "cis, cis" as used herein refers to the orientation of the substituents (Ri and R2) in relation to the substituent R as shown.

Representative compounds of the invention include: trans acid, tra ns-2- (4-methoxy-enyl) -4- (1,3-benzodioxol-5-yl) -1- ((2,4,5-trimethyl)) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid tra ns, tra ns-2 - (3-fluoro-4-methoxy in en) -4- (1,3-benzodioxol-5-yl) -1 - ((2, 4,5-trimethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, trans-2- (4-Propoxyp in yl) -4- (1,3-benzodioxol-5-yl) -1 - ((2, 4,5-trimethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, tra /? S-2- (4-methoxy-en-l) -4- (1,3-benzodioxol-5-yl) -1 - ( (2,6-dimethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, t rans acid, tra ns-2- (4- Pro-poxy) -4- (1,3-be nzod i oxo l-5-i I) - 1- ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans-acid, tra / 7s-2- (3-Fluoro-4-methoxy fe nyl) -4- (1,3-benzodioxol- 5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, rra / 7S, tta / 7S-2- (3-Fluoro-4-ethoxyphenyl) -4- (1, 3-benzodioxol-5-yl) -1- ((2 , 6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans acid, trans-2- (3-F oo-4-methoxyp eni I) -4- (7-methoxy-1 -3-benzodioxol-5-yl) -1 - ((2,6- diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid tra ns, tra A? s-2- (3-met oxy-4-propoxife nyl) -4- (1,3-benzodi oxol-5-yl) -1 - ((2,6-diethylphenyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans-acid, trans-2- (3-methoxy-4-prop oxy) f) -4- (1,3-benzodioxole-5) -yl) -1 - ((2,6-diethylphenyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, ira ns-2- (4- ethoxy in il) -4- (1, 3- benzodioxol-5-yl) -1 - ((2,6-diethylphenyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, tra ns, tra /? s-2- (4-methoxyphenyl) -4- (1, 3- benzodioxol-5-yl) -1 - ((2,6-diethylphenyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans acid, frar7S-2- (4-propoxyphenol) -4- (7- methoxy-1,3-benzodioxol-5-yl) -1 - ((2,6-diethylphenyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, irra / 7S-2- (3-methoxy-4-) propoxyphenyl) -4- (7-methoxy-1,3-benzodioxol-5-yl) -1 - ((2,6-die tylphenyll) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans acid, fraps-2- (4-methoxy-en-yl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6- dib romo) phenylamino carbonylmethyl) -pyrrolidine-3-carboxylic acid, "/ 2 -3R, S7-2- (4-Methoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - (( 2,6-di bromo) f enyl amine carbon i I me ti I) -pyrrole id i na- 3-carboxylic acid, iaps-frans-2- (4-methoxyphenyl) -4- (1, 3- benzodioxol-5-yl) -1 - ((2,6-dimethoxy) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, urans, uraps-2- (4-methoxyphenyl) -4- (1,3-benzodioxol- 5-yl) -1 - ((4-bromo-2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans acid, frar? S-2- (4-methoxy-en-l) -4- ( 1,3-benzodioxol-5-yl) -1 - ((2-ethyl-6-methyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans acid, fra7s-2- (4- methoxyf in yl) -4- ( 1,3-benzodioxol-5-yl) -1 - ((2,4,6-triethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, f2 / =? - 3R, RS72- (4-Propoxyphenol) ) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phen ilaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, trans-2- (4-methoxy f en il) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diisopropyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans-acid, frar-s-2- (4- methoxy-en-yl)) - 4- (1,3-benzodioxol-5-yl) -1 - ((2,6-methyl) ) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, r2R-3fl, RS / -2- (4-ethoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2, 6-dimethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, t-rr? S-2- (4-methoxy-en-yl) -4- (1,3-benzodioxol-5-yl) -1 - ((4 -carboxy-2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans acid, frar / s-2- (4- methoxyf in yl) -4- (1,3-benzodioxol-5-yl) -1 - ((4-Nitro-2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans-acid, r ?s-2- (4- methoxy in) -4- (1,3-benzodioxole) -5-yl) -1 - ((2-isopropyl-6-methyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, frar? S, fra / 7s-2- (4-methoxyphenol) - 4- (1,3-benzodioxol-5-yl) -1 - ((2, ethyl-6-methoxy) feni laminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, fra / 7s-2- (4-isopropoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1- (2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine- 3-carboxylic acid tra ns, trans-2 - (2-f I uoro-4- prop oxy f en il) -4- (1,3-benzodioxol-5-yl) -1- (2,6-diethylphenylaminocarbonylmethyl) ) -pyrrolidine-3-carboxylic acid, trans-acid, tra ns-2- (4- (2-methoxy-ethoxy) -4- (1,3-benzodioxol-5-yl) -1- (2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans acid, trans-2- (4- (2-ethoxy ethoxy) f en yl) -4- (1,3-benzodioxol-5-yl) -1- (2,6-diethylphenylaminocarbonylmethyl) ) -pyrrolidine-3-carboxylic acid, [2R-3R, RS / -2- (4- (2-Methoxyethoxy) f eni I) -4- (1,3-benzodioxol-5-yl) -1- (2) , 6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, [2R-3R, RS] -2- (4- (2-Ethoxyethoxy) phen \) - 4 - (- \, 3-ber \ zodioxo \ -5 - \) - - (2,6-Diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans acid, frar7s-2- (4- (2-isopropoxyethoxy) phenyl) -4- (1,3-benzodioxol- 5-i I) - 1 - (2, 6-diethylf in i lam i noca rboni I me ti I) -pyrrole id ina-3-carboxylic acid, or a pharmaceutically acceptable salt thereof. The preferred compounds of this invention are selected from the group consisting of: tra ns acid, tra r / s-2- (4- Methoxy-enyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-dimethyl) phenylaminocarbonylmethyl) -pyrrolidine-3 -carboxylic acid, trans-acid, tra ns-2- (4- Pro-poxy) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid , trans acid, frarís-2- (3-Fluoro-4-methoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid , acid frar / s, frar >; s-2- (3-Fuoro-4-ethoxy in en) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans acid, fra / 7s-2- (3-Fluoro-4-methoxy-enyl) -4- (7-methoxy-1 -3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) ) -pyrrolidine-3-carboxylic acid, trans acid, irra-2- (3-methoxy-4-propoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) ) -pyrrolidine-3-carboxylic acid, trans, ira r / s-2- (3-methoxy-4- pro pox if en il) -4- (1,3-benzodioxol-5-yl) - 1 - (( 2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, trans-2- (4-ethoxyf in yl) -4- (1,3-benzodioxol-5-yl) -1 - ((2 , 6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, frar / s, fra / 7s-2- (4-propoxyf in yl) -4- (7-methoxy-1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans acid, ura7s-2- (4- (2-ethoxyethoxy) phenyl) -4- (1,3-benzodioxol-5-yl) ) -1 - ((2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, fido / 7S acid, urea-2- (3-methoxy-4-propoxyphenyl) -4- (7-methoxy-1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) ) -pyrrolidine-3-carboxylic acid, f2R-3R, fiS72- (4-Methoxyphenyl) -4- (1,3-benzodoloxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, acid / * 2 / "? - 3fi, /"? S72- (4-Propoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6- diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid [2R-3R, RS / -2- (4-ethoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6) -dimethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, fra / 7S-2- (4-isopropoxy in yl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6 -diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, / ra / 7S; ia / 7s-2- (2-fluoro-4-propoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - (( 2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, fra? S, rans-2- (4- (2-methoxyethoxy) phenyl) -4- (1,3-benzodioxol-5-yl) -1- ( (2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, urn? S, fra7s-2- (4 - (ethoxyethoxy) phenyl) -4- (1,3-benzodioxol-5-yl) -1- ((2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, acid * 2 /? - 3 / ?,? S72 - (4- (2-Mα-toxophenyl) -4- (1 -3-benzodoloxol-5-yl) -1 - ((2, β-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid / " 2R-3R, S72- (4- (2-Ethoxyethoxy) phenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid) / 7s, Ira / 7s-2- (4- (2-isopropoxyethoxy) phenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxyl Co, or a pharmaceutically acceptable salt thereof. The most preferred compounds are: frans acid, frans-2- (4- Propoxyp in yl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine- 3-carboxylic acid, / "2R-3R, RS72- (4-Methoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3- carboxylic acid, [2R-3R, RSJ2- (4- Pro poxif eni l) -4- (1,3-be nzod i oxo I-5- i I) - 1- ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, [2R-3R, RS72- (4- (2-ethoxyethoxy) f in yl) -4- (1,3-benzodioxol-5-i) - 1 - ((2,6 -diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, irra / 7s-2- (4- (2-methoxyethoxy) -4- (1,3-benzodioxol-5-yl) -1- ((2, 6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans-acid, frar / s-2- (4- (2-methoxyethoxy) f eni l) -4- (1,3-benzodioxol-5-yl) -1- ( (2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans-acid, r ?s-2- (4- (Ethoxy ethoxy) f en il) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethylphenollaminocarbonylmethyl) -pyrroli dina-3-carboxylic acid, [2R-3R, RS72- (4- (2-M ethoxy ethoxy) f eni I) -4- (1,3-be nzod-oxol-5-yl) -1 - ((2 , 6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, [2R-3R, RSJ2- (4- (2-ethoxyethoxy) f enyl) -4- (1,3- be nzod i oxo I-5- i I) - 1 - ((2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, fra / 7s, ia / 7s-2- (4- (2-isopropoxyethoxy) phenyl) -4- (1,3-benzodioxole) -5-yl) -1 - ((2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof. The methods for preparing the compounds of the invention are shown in Schemes I-VII. Scheme I illustrates the general procedure for preparing the compounds of the invention when m is 0 and W is -C02H. A ß-cetoester! wherein E is lower alkyl or a carboxy protective group, it is reacted with a nitro vinyl compound 2., in the presence of a base (for example 1, 8-diazabicyclo [5.4.0] undec-7-ene (DUB) or sodium ethoxide or sodium hydride and the like) in an inert solvent such as toluene, benzene, tetrahydrofuran or ethanol and the like. The condensation product 3_ is reduced (for example, by hydrogenation using a nickel catalyst or Raney platinum). The resulting amine cyclized to give the pyrrole dihydro 4. Reduction of 4 (eg, sodium cyanoborohydrate or catalytic hydrogenation and the like) in the THF solvent or the like given the pyrrolidine compound 5 as a mixture of cis-cis products, trans, trans and cis, trans. The chromatographic separation removes the cis-cis isomer giving a mixture of the trans, trans and cis, trans isomers that were also prepared. The cis-cis isomer can be epimerized (for example, using sodium ethoxide in ethanol or DBU in toluene) to give the trans, trans isomer and then carried out as described below. The pyrrilidine nitrogen is (1) acylated or sulfonylated with R3-X (R3 is R -C (0) - or R6-S (0) 2 and x is a group such as halide (Cl is preferred) or X is formed together with R -C (0) - or R6-S (0) 2 forming an activated ester including esters or anhydrides derived from formic acid, acetic acid and the like, alkoxycarbonyl halides, N-hydrosuccinimide, N-hydroxyphthalamide, N-hydrobenzotriazole, N -hydroxy-5-norbornene-2,3-dicarboxyamide, 2,4-5-trichlorophenyl and the like) or (2) alkylated with R3.x where x is a leaving group (for example, X is a halide (e.g. , Cl, Br or I) is a leaving group such as a sulfate (eg, mesylate, tosylate, triflate and the like) in the presence of a base such as diisopropyl ethylamine or triethylamine and the like to give the N-derivatized pyrrolidine 6 which is still a mixture of trans, trans and cis, trans isomers. Hydrolysis of ester 6 (for example, using a base such as a sodium hydroxide in EtOH / H20) selectively hydrolyzes the trans, trans ester to give a mixture of 7 and 8, which is rapidly separated. Many of the β-ketoester starting materials used in the preparation of the compounds of the present invention are commercially available. They can also be prepared using the methods indicated in Scheme VIII. In the method of Scheme VI 11 (a) an aromatic, heteroaromatic or a-quaternary methyl ketone deprotonated (e.g., with sodium hydride or lithium diisopropylamide) and treated with a reagent capable of transferring a carboxyalkoxy group (v. ., diethyl carbonate, methyl chloroformate or di-tert-butyldicarbonate). Alternatively, as shown in Scheme Vlll (b), a carboxylic acid (e.g., with carbonidiimidazole or oxalyl chloride) can be activated and treated with an equivalent acetate (e.g., ethyl lithium acetate, methylmalonate magnesium or Meldrum acid followed by thermal alcoholism). A preferred embodiment is shown in Schemes II and II. A benzoyl acetate such as 26 or 4- (2-methoxyethoxy) benzoyl acetate is reacted with a vinyl benzodioxolyl compound 27. using 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) as the base n the toluene to give the compound 28. Catalytic hydrogenation using charges of Raney nickel for the reduction of the nitro group in an amines and subsequent cyclization to give the dihydropyrrole 29 .. The double ligation is reduced with sodium cyanoborohydrate for give the pillolidine compound 30. as a mixture of cis-cis, trans, trans and cis isomers, after. The chromatography separates the isomer of cis-cis, giving a mixture of the trans, trans and cis, trans isomers (31). Scheme Ill illustrates the further elaboration of the trans, trans isomer. The mixture (31_) of trans, trans and cis, trans pyrrolidines described in Scheme IV is reacted with Br-CH 2 C (O) NHR 4 in acetonitrile in the presence of ethyldiisopropylamine to give the alkylated pyrrolidine compound 32., even as a mixture of trans, trans and cis, trans isomers. Sodium hydroxide in ethanol-water hydrolyzes the ethyl ester of the trans, trans compound but allows the ethyl ester of the cis, trans intact compound, thereby allowing the separation of the trans, trans, carboxylic acid from the cis, trans, ester. .

Scheme IV illustrates the preparation of the compounds wherein w is different from the carboxylic acid. The compound 5_5, can be prepared by the procedures described in Scheme I, is converted (for example, using peptide coupling condition, e.g., N-methylmorpholine, EDCI and HOBt in the presence of ammonia or other amide forming the reactions ) to give carboxyamide 56. The carboxyamide is dehydrated (for example, using phosphorous oxychloride in pyridine) to give nitrile 57_. Nitrile 57 under normal tetrazole formation conditions (sodium azide and triethylamine hydrochloride and tin oxide) are reacted to give tetrazole 5_8. Alternatively, the nitrite 5_7 is reacted with hydroxylamine hydrochloride in the presence of a salt (for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH) in a solvent such as DMF, DMSO or dimethylacetamide. to give amidoxime 5_9. Amidoxime 5_9 is allowed to react with methyl or ethyl chloroformate in a conventional organic solvent (such as, chloroform, methylene chloride, dioxane, THF, acetonitrile pyridine) in the presence of a base (eg, triethylamine, pyridine, potassium carbonate and sodium carbonate) to give an O-acyl compound. Heating from the O-acyl amidoxime in an inert solvent (such as benzene, toluene, xylene, dioxane, THF, dichloroethane, or chloroform and the like) results in the cyclization of compound 60. Alternatively, by reacting amidoxime 59 with chloride of thionyl in an inert solvent (for example, chloroform, dichloromethane, dioxane and THF and the like) gives oxathiadiazole 61_. Scheme V illustrates a method for synthesizing pyrrolidines by a [3 + 2] -zomethin halide-type cycloaddition to a carboxylate. General structures such as compound 70. are known to give an unsaturated ester such as 71_ to provide pyridines such as compound 72. (O. Tsuge, S. Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983 ), or Tsuge, S. Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem. 52. 2523-30 (1987) and S. Kanemasa, K. Skamoto, O. Tsuge, Bull. Chem. Soc. Jpn 62.1960-68 (1989)). The silyimine 73 is reacted with acrylate 74. in the presence of tri-methyl triflate Isyl i lo and tetrabutylammonium fluoride to give the desired pyrrolidine 75 as a mixture of isomers. This method can be modified to provide the N-acetamide derivatives directly by reacting 73. and 74. with the appropriate bromoacetamide (e.g., dibutylbromoacetamide) in the presence of tetrabuylmonium iodide and cesium fluoride to give compound 76. Scheme VI illustrates a method for the production of an enantiomerically pure pyrrolidine 80, which can be further elaborated with the pyrrolidine nitrogen. The intermediate racemic pyrrolidine ester 77. (for example, prepared by the procedure described in Scheme V) is protected Boc-nitrogen (for example, by treatment with Boc20) and then the ester is hydrolyzed (for example, using sodium or lithium hydroxide in ethanol and water) to give t-butyl carbamoyl pyrrolidine carboxylic acid 78. The carboxylic acid is converted to its (+) - a-methylbenzylamine salt, which can be recrystallized (for example from ethyl acetate and hexane or chloroform and hexane) to give the diastereomerically pure salt. This diastereomerically pure salt can be neutralized (for example, with sodium carbonate or citric acid) to give the enentiomerically pure carboxylic acid 79_. The pyrrolidine nitrogen can be deprotected (for example, using trichloroacetic acid) and the ester reformed by the use of ethanolic hydrochloric acid to give the salt 80. Alternatively one can use ethanolic HCl to partition the protecting group and form the ester in a just happened. The pyrrolidine nitrogen can also be further processed (for example, by treatment with 2,6-diethylbenzamide of bromoacetic acid in acetonitrile in the presence of diisopropylethylamine) to give the optically active compound 81. The use of (-) - a-methylbenzylamine could give the opposite enantiomer. Other optically active amines can be used. The preferred process is shown in Scheme VII. The nitro vinyl compound (88) is reacted with the β-keto ester 89. in the presence of a base such as sodium ethoxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as THF, toluene, DMF, acetonitrile, ethyl acetate, isopropyl acetate or methylene chloride and the like at a temperature from about 0 ° C to about 100 ° C for a period of about 15 minutes overnight to give compound 90. The reduction of the nitro group followed by cyclization can be effected for example by catalytic hydrogenation with a hydrogen pressure of about atmospheric pressure at 21.09 kg / cm2 for about 1 hour to about 1 day of compound 90. in an inert solvent such as THF, ethyl acetate, toluene, ethane, isopropanol, DMF or acetonitrile and the like, using a hydrogenation catalyst such as Raney nickel, palladium or carbon, a platinum catalyst, such as platinum oxide, platinum or carbon or platinum or alumina and the like, or rhodium catalyst such as rhodium or carbon or rhodium on alumina and the like giving the intermediate nitro 91a or a mixture of nitrone 91a and imina 91b. The reaction mixture comprising the mixture of nitrona or nitrone / imine was treated with an acid such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methanesulfonic acid and the like and the hydrogenation was continued to give the pyrrolidine compound 92. as the cis isomer, cis. The epimerization at c-3 was effected by the treatment of compound 92 with a base such as sodium ethoxide, potassium t-butoxide, lithium t-butoxide or potassium t-amyloxide and the like or a trialkylamino such as triethylamine or diisopropylethylamine and or an amidine such as DBU and similes in an inert solvent such as ethanol, ethyl acetate, isopropyl acetate, THF, toluene or DMF and the like at a temperature from about -20 ° C to about 10 ° C to give the trans compound, trans 93. Compound 93. itself optionally can be converted to enantiomers before reacting with X-R3. The substantially pure (i.e. to at least 95% of the desired isomer) optically active isomer of compound 93. is obtained by the treatment of a mixture of the (+) - isomer and the (-) - isomer of with S - (+) - mandelic acid. D-tartaric acid or D-dibenzoyl tartaric acid or the like in a solvent such as acetonitrile, ethyl acetate, isopropyl acetate, ethanol or isopropanol and the like. The (+) - isomer of 93. selectively crystallizes the salt, allowing the (-) - isomer of 93. in a solution. Alternatively, the substantially pure optically active (-) isomer (that is to say at least 95% of the desired isomer) of compound 93. can be selectively crystallized by the reaction of a mixture of the (-t -) - isomer and the (- ) -isomer of 93. with L-tartaric acid, L-dibenzoyl tartaric acid or L-pyroglutamic acid and the like, giving the desired (+) - isomer of compound 93. in solution. Compound 93. (racemic or optically active) is reacted as X-R3 (wherein x is a leaving group (eg, a halide or a sulfonate) and R3 is as previously defined) using a base such as diisopropylethylamine, triethylamine, sodium bicarbonate or potassium carbonate and the like in an inert solvent such as acetonitrile, THF, toluene, DMF or ethanol and the like at a temperature from about 0 ° C to about 100 ° C to give the intermediate ester 94_. The ether can be isolated or converted in situ to the carboxylic acid (95) using hydrolysis conditions such as a base such as sodium hydroxide or lithium hydroxide or potassium hydroxide and the like in a solvent such as ethanol-water or THF-ethanol and Similar. Scheme I [H] Mix of Cis-Cis Trans-Trans Cis-Trans Cis-Trans Mix of Trans-Trans Cis-Trans Scheme Mixture of Cis-Cis Trans-Trans Chromatographic separation Cis-Trans Cis-Cis + Mix of Trans-Trans and Cis-Trans Scheme lll Trans-Trans Cis-Trans sa 34 Scheme IV CONH2 SB. 5 £ I N "= N & ffi.

Scheme V 24 Scheme VI 1. (+) a-methylbenzylamine 2. recrystallize from EtO 3. H2PO4 1N R4HNC (0) CH2Br EtN (iPr) 2, CH3CN 20 25 Scheme Vil aa aa 22 aa a = ai Scheme VIII Scheme Vlla.

Aryl, heteroaryl, or a-quaternary Scheme Vllb.

R-COOH R Kz .COOR The compounds that are useful as intermediates for the preparation of the compounds of the invention are: (III) where m is 0 to 6; W is (a) -C (O) 2-G wherein G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P (O) (OH) E wherein E is hydrogen, alkyl lower or arylalkyl, (d) -CN, (e) -C (O) NHR 7 wherein R 7 is lower alkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy (j) alkoxy, (k) sulfonamido (I) -C (O) NHS (O) 2R? e wherein R16 is lower alkyl, haloalkyl, aryl or dialkylamino, and R and R2 are independently selected from hydrogen, lower alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbyalkyl, amiocarbonylalkenyl, alkylaminocarbyalkenyl, dialkylaminocarbonyalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic, (heterocyclic) alkyl and (Raa) (Rbb) N-Rcc- wherein Raa is aryl or arylalkyl, R b is hydrogen or alkanoyl and Roc is alkylene, with the provthat one or both of and R2 are different from hydrogen; or a salt thereof; and a compound of the formula: (ll!) where n is 0 or 1; m is 0 to 6; W is (a) -C (O) 2-G wherein G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P (O) (OH) E wherein E is hydrogen, alkyl lower or arylalkyl, (d) -CN, (e) -C (O) NHR17 wherein R17 is lower alkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy (j) alkoxy, (k) sulfonamido (I) -C (O) NHS (O) 2R16 wherein r16 is lower alkyl, haloalkyl, aryl or dialkylamino, (m) -S (O) 2NHC (O) R16, CFa N (t) R 2 and R 2 are independently selected from hydrogen, lower alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbyalkyl, aminocarbonylalkenyl, alkylaminocarbyalkenyl, dialkylaminocarbonylalkyl , hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic, (heterocyclic) alkyl, and (Raa) (Rbb) N-R0o- wherein Raa is aryl or arylalkyl, R b is hydrogen or alkanoyl, and Rcc is alkylene, as provided that one or both of R ^ and R2 are different from hydrogen; or a salt of them. Preferred intermediates include compounds of formulas (II), (IV) and (V) wherein m is 0; is -CO2-G, wherein G is hydrogen or a carboxy protective group; and Ri is (i) alkoxyalkylalkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridinyl, (v) furanyl or (vi) 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-trifluoromethylphenyl, 4-ethoxyphenyl , 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 4-propoxyphenyl, 4-ropoxyphenyl, 2-fluoro-4-ethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl , 4- (2-ropoxyethoxy) phenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 7-methoxy-1, 3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl; or the (+) - or (-) - substantially pure isomer thereof. The foregoing should be better understood by reference to the following examples that are provided for the illustration and are not intended to limit the scope of the inventive concept. The following abbreviations are used: Boc for tert-butyloxycarbonyl, Cbz for benzyloxycarbonyl, DBU for 1,8-diazabicyclo [5.4.0] undec-7-ene, EDCI for 1- (3-dimethylaminopropyl-3-ethylenecarbodimide hydrochloride, EtOAc for ethyl acetate, EtOH for ethanol, HOBt for 1-hydroxybenzotriazole, Et3N for triethylamine, TFA for trifluoroacetic acid and THF for tetrahydrofuran.

Example 1 Trans acid, frans-2- (4-methoxyf in yl) -4- (1,3-benzodioxol-5-yl) -1 - ((21416-trimethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carbox ? lico EXAMPLE 1A 2- (4-methoxy-benzoyl) -4-nor-trom eti-3- (1.S-benzodioxol-S-i-ethylbutyrate ethyl A (4-methoxybenzoyl) -acetate (23.0 g, 0.104 mol), prepared by the method of Krapcho et al., Org. Syn. 47., 20 (1967) and 5- (2-nitrovinyl) -1,3-benzodioxol (17.0 g, 0.88 mol) dissolved in 180 mL of toluene and heated to 80 ° C was added 1,8-diazabicylo [5.4.0] undec-7-ene (DBU, 0.65 g) with stirring, the mixture was heated until all the nitro starting material was dissolved. heating for 30 minutes and then an additional 0.65 g of DBU was added.After stirring for an additional 45 minutes, thin layer chromatography (5% ethyl acetate in methylene chloride) indicated the absence of nitro starting material. Toluene (200 mL) was added and the organic phase was poured in with dilute hydrochloric acid and a solution of NaCl, The organic phase was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was chromatographed on silica gel eluting with 3: 1 hexane-ethyl acetate to give 21.22 g of the desired product as a mixture of isomers and 9.98 g of ethyl (4-methoxybenzoyl) acetate. Example 1 B 2- (4-Methoxyphenyl) -4- (1,3-benzodioxol-5-yl) -4-dihydro-3 H-pyrrol-3-carboxylate sodium The resulting compound of Example 1A (21 g) in 500 mL of ethanol was hydrogenated under 4 atmospheres of hydrogen pressure using a 2800 Raney nickel catalyst (51 g). Nickel Raney was washed with ethanol three times before being used). The catalyst was removed by filtration and the solution was concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 8.5% ethyl acetate in methylene chloride to give 12.34 g of the desired product. Example 1 Ethyl 2- (4-methoxyphenyl-4- (1,3-benzodioxol-5-yl) -pyrrolidine-3-carboxylate as a mixture of cis-cis, trans, trans, and cis isomers The compound resulting from Example 1B (11.89 g, 0.325 mol) was dissolved in 27 mL of tetrahydrofuran and 54 mL of ethanol, sodium cyanoborohydrate (2.35 g, 0.374 mol) and 5 mg of green bromocresol were added. At this time, a 1: 2 concentrated HCl solution in ethanol was added dropwise to said regime so that the color was maintained in yellow-green light.After the yellow color persisted without additional HCl, the solution was stirred for an additional 20 minutes. The solution was concentrated in vacuo and then partitioned between chloroform and an aqueous potassium bicarbonate solution.The organic phase was separated, dried over sodium sulfate and concentrated under reduced pressure, the residue was chromatographed on silica gel eluting with 85:15 ethyl acetate-hexane to give 5.96 g of a mixture of 65% of the trans, trans and 35% of the cis-trans compound. The additional solution with pure ethyl acetate gave 0.505 g of an unknown solid followed by 3.044 g of the pure cis, cis compound. EXAMPLE 1 D N- (2,4,6-Trifenyl) Bromoacetamide To a stirred solution of 2,5-6-trimethylaniline (1 g, 7.40 mmol) in methylene chloride (25 mL) at -50 ° C was added. successively added?,? / - diisopropylethylamine (1.58 mL, 8.14 mmol), 1.1 eq) and bromoethyl bromide (0.72 mL, 7.40 mmol, 1 eq.) so that it did not exceed -40 ° C. Upon completion of the addition, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. After stirring for an additional 30 minutes, the mixture was diluted with ether (70 mL) and poured into a 1 N sodium bisulfate solution. The phases were separated, and the upper layer was washed successively with water and brine. The organic phase was dried (Na2SO4) and the solvent was evaporated to half the volume, at which point the product crystallized. The crystals were removed by vacuum filtration to give the title compound (1.51 g, 80%). EXAMPLE 1 E Rra /? S acid, fra / 7S-2- (4-Methoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,4,6-trimethyl) phenylaminocarbonylmethyl) - pyrrolidine-3-carboxylic acid The mixture of trans pyrrolidines, 64% trans and cis, trans 35% (the resulting mixture of Example 1c) 5.72 g, 15.50 mmol), of tridiisopropylamine (4.20 g, 3256 mmoles) and the resulting compound of Example 1D (19.0 mmoles) in 30 mL of acetonitrile was heated at 50 ° C for 1 hour the solution was concentrated in vacuo. The residue was dissolved in toluene, absorbed with potassium bicarbonate solution and dried over sodium sulfate and concentrated in vacuo to give the product as a mixture of trans, trans and cis rans ethyl esters. The mixture was dissolved in a 50 mL solution of ethanol and 15 mL of water containing 5.00 g of sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and 60 mL of water were added. The mixture was extracted with ether to remove the unreacted cis, trans ethyl ester. The aqueous phase was treated with hydrochloric acid until it became slightly cloudy. It was then neutralized with acetic acid to give the crude acid product. The crude product was filtered and purified by dissolving in tetrahydrofuran, drying over sodium sulfate, concentrating in vacuo and crystallizing from ether to the title compound. 1 H NMR (300 MHz, CDCl 3) d 8.2 (1H, bs), 7.78 (2H, d, J = 8Hz), 6.95 (5H, m), 6.82 (1H, bd, J = 8Hz), 6.77 (1H; d, J = 8Hz), 5.96 (2H, s), 3.97 (1H, bd, J = 10Hz), 3.81 (3H, s), 3.70 (1H, ddd, 6, 5 and 3Hz), 3.57 (bbb, 10 and 3Hz), 3.45 (1H, d, J = 1ß.Hz), 3.13 (2H, m), 2.24 (3H, s), 2.06 (6H, s), MS (DCI, NH3) m / e 517 (M + H +). Anal. Cale, for C30H32N2O6'0.5H2O: C, 68.56, H, 6.33, N.5.33. Found: C68.84, H, 6.20, N, 5.31. EXAMPLE 2 Trans, trans-2- (3-fluoro-4-methoxy in) -4- (1,3-benzodioxol-5-yl) -1 - ((2,4,6-trimetyl) ) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d 8.22 (1H, bs), 7.21 (1H, dd, J = 12 and 2Hz), 7.12 (1H, bd, J = 8Hz), 6.95 (1H, t, 8Hz), 6.90 (2H, bs), 6.84 (1H, d, J = 2Hz), 6.80 (1H, dd, J = 8 and 3Hz), 6.79 (1H, d, J = 8Hz), 85.93 (2H, s), 3.96 (1H, d, J = 10Hz), 3.89 (3H, s), 3.70 (1H, ddd, 6, 5 and 3Hz), 3.69 (1H, dd, 11 and 5 Hz), 3.45 (1H, d, J = 16Hz), 3.10 (1H, t, J = 10Hz), 3.07 (1H, dd, 8 and 6Hz), 3.02 (1H, d, J = 16Hz), 2.17 (3H, s), 2.07 (6H, s). MS (DCI, NH3) m / e 535 (M + H +). Anal. Cale. for C30H31FN2O60.75H2O: C, 65.75, H, 5.98, N, 5.11. Found: C, 65.96, H, 5.88, N, 5.16. Example 3 Trans acid, tra ns-2- (4-Proooxy in 1) -4- (1, 3-benzodioxol-5-yl) -1- ((2,4,6-tri-methyl) phenylaminocarbonylmethyl) ) -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d 8.21 (1H, bs), 7.38 (2H, d, J = 8Hz), 6.90 (2H, d, J = 88Hz), 6.89 (2H, d, 3Hz), 7.83 (1H, dd, J = 8 and 2Hz), 6.75 (1H, d, J = 8Hz), 5.95 (1H , d, J = 3Hz), 5.93 (1H, d, J = 3Hz), 3.96 (1H, d J = 10Hz), 3.85 82H, 1, J = 7Hz), 3.70 (1h, dd, 6, 5 and 3Hz) ), 3.58 (1H, dd, 11 and 5 Hz), 3.48 (1H, d, J = 16 Hz), 3.15 (1H, dd, 8y 6Hz), 3.13 (1H, t, J = 10 Hz), 2.99 ( 1H, d, J = 16Hz), 2.25 (3H, s), 2.05 (6H, s), 1.81 (2H, sixth, J = 7Hz), 1.04 (3H, t, J = 7Hz). MS (DCI, NH3) m / e 545 (M + H +). Anal. Cale, for C32H36N2O6O.33H2O: C, 69.79, 6.71, N 5.09. Found: C, 69.78, H, 6.73, N, 4.81. EXAMPLE 4 Trans, trans-2- (4-M-ethoxy f en-yl) -4- (1,3-benzodoloxol-5-yl) -1 - ((2,4,6-trimethyl) phenylamide Nocarbonylmethyl) -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d 8.24 (1H, bs), 7.39 (2H, d, J = 8Hz), 7.21 (1H, dd, 8 and 6Hz), 7.11 (2H, d, J = 8Hz), 6.92 (2H, d, 8Hz), 7.89 (1H, d, J = 3Hz), 7.82 (1H , dd, J = 8 and 2Hz), 6.75 (1H, dJ = 8Hz), 5.94 (1H, d, J = 3Hz), 5.93 (1H, d, J = 3Hz), 3.96 (1H, dJ = 10Hz), 3.82 (3H, s), 3.70 (1H, ddd, 6, 5 and 3Hz), 3.56 (1H, dd, 11 and 5Hz), 3.45 (1H, d, J = 16Hz), 3.15 (1H, dd, 8 and 6 Hz), 3.13 (1H, t, J = 10 Hz), 3.01 (1H, d, J = 16Hz), 2.42 (4H, 1, J = 7Hz), 1.08 (6H, t, J = 7Hz), MS (INN, NH3) m / e 559 (M + H4 +), 531 (M + H +). Anal. Cale, for C3-? H34N2O6: C..70.17, H, 6.46, N 5.28. Found: C, 69.88, H, 6.42, N, 5.09. Example 5 Trans acid, fra /? S-2- (4-Propoxyphenyl) -4- (1,3-benzodolox-5-M) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d 8.27 (1H, bs), 7.37 (2H, d, J = 8Hz), 7.21 (1H, ddd, 8 and 6Hz), 7.1 (2H, d, J = 8Hz), 6.0 (2H, d, 8Hz), 7.86 (1H, d, J = 3Hz), 7.83 (1H, dd, J = 8 and 2Hz), 6.75 (1H, d, J = 8Hz) 5.93 (1H, d, J = 3Hz), 5.92 (1H, d, J = 3Hz), 3.96 (1h, d, J = 10Hz), 3.85 82H, 1, J = 7Hz), 3.70 (1H, dd, 6, 5y 3Hz), 3.55 (1H, dd, 11 and 5 Hz), 3.48 (1H, d , J = 16Hz), 3.15 (1H, dd, 8 and 6 Hz), 3.13 (1H, t, J = 10 Hz), 3.01 (1H, d, J = 16Hz), 2.43 (4H, 1, J = 7Hz ), 1.82 (2H, sixth, J = 7H), 1.08 (6H, t, J = 7Hz) MS (DCI, NH3) m / e 549 (M + H +). Anal. Cale. for C31H33N2FN2O60.5H2O: C, 66.78, H, 61.5, N 5.02. found; C, 66.81, H, 5.89, N, 4.87. Example 7 Acid / tar / S, tYa / 7S-2- (3-Fluoro-4-ethoxy-phenyl) -4-d, 3-benzodioxol-5-yl) -1- ((2,6-d) Ethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d 8.23 (1H, bs), 7.23 (1H, d, J = 2Hz), 7.20 (1H, dd, J = 8 and 3 Hz), 7.11 (3H, m), 6.96 (1H, t, J = 8Hz), 6.83 (1H, dd, J = 8 and 2Hz ), 6.80 (1H, d, J = 3Hz), 6.76 (1H, d, J = 8Hz), 5.93 (1H, d, J = 3Hz), 5.92 (1H, d, J = 3Hz), 4.11 (2H, t, J = 7Hz), 3.97 (1H, d, J = 10Hz), 3.72 (1H, dd, 6, 5 and 3Hz), 3.55 (1H, dd, 11 and 5 Hz), 3.47 (1H, d, J = 16 Hz), 3.14 (1H, t, J = 10Hz), 3.12 (1H, dd, 8 and 6 Hz), 3.04 (1H, d, J = 16Hz), 2.45 (4H, q, J = 7Hz), 1.47 (3H, t, J = 7Hz), 1.09 (6H, t, J = 7Hz). MS (DCI, NH3) m / e 563 (M + H +). Anal. Cale, for C32H35FN2O60.1TFA: C, 66.92, H, 6.11, 4.83. Found: C, 67.19, H, 5.75, N, 4.69. EXAMPLE 8 Trans, Fra / 7s-2- (3-Fluoro-4-methoxy in en) -4- (, 3-benzodioxol-5-yl) -1 - ((2,6-d¡etl) phenyl carbonylcarbonyl) -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d 8.24 (1H, s), 7.25 (1H , t, J = 3Hz), 7.21 (1H, bd), 7.14 (1H, m), 7.08 (2H, d, J = 8Hz), 6.96 (1H, t, J = 8Hz), 6.56 (1H, d, J = 3Hz), 6.50 (1H, d, J = 3Hz), 5.93 (1H, d, J = 2Hz), 5.91 (1H, d, J = 2Hz), 3.97 (1H, d, J = 10Hz), 3.90 (3H, s), 3.72 (1H, ddd, 6, 5 and 3 Hz), 3.58 (1H, dd, 11 and 5 Hz), 3.46 (1H, d, J = 16Hz), 3.14 (1H, t, J = 10Hz), 3.13 (1H, dd, 8 and 6 Hz), 3.05 (1H, d, J = 16 Hz), 2.45 (4H, 1, J = 7Hz), 1.09 (6H, t, J = 7Hz). MS (DCI, NH3) m / e 579 (M + H +). Anal. Cale. for C32H35FN2O7'1.5H2O: C, 63.64, H, 6.31, N 4.64. Found: C, 64.00, H, 6.29, N, 4.26. Example 9 Trans acid frar / s-2- (3-methoxy-4- rooxif in i D-4-H, 3-benzodioxol-5-yl) - 1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d 8.22 (1H, s), 7.21 (1H, m), 7.12 (2H, d, J = 10Hz), 7.02 (1H, dd, J = 9 and 3 Hz), 6.93 (1H, d, J = 2Hz), 6.88 (1H, d, J = 2Hz), 6.85 (1H, m), 6.82 (1H, d, J = 2Hz), 6.75 (1H, d, J = 9Hz), 5.95 (1H, d, J = 2Hz), 5.93 (1H, d, J = 2Hz), 3.97 (2H, 1, J = 9Hz), 3.84 (3H, s), 3.72 (2H, m), 3.60-3.45 (2H, m), 3.15 (2H, m), 3.03 (1H, d, J = 18 Hz), 2.43 (4H , 1, J = 9Hz), 1.87 (2H, m), 1.08 (6H, t, J = 9Hz), 1.04 (3H, t, J = 9Hz), MS (DCI, NH3) m / e 589 (M + H +). Anal. Cale, for C34H40N2O70.45H2O: C, 68.43, H, 6.91, N, 4.69. Found: C, 68.45, H, 6.91, N, 4.62.

Example 10 Trans acid, tra / s-2- (4-ethoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3- carboxylic acid The title compound was prepared by the procedures described in Example 1. H NMR (300 MHz, CDCl 3) d 8.26 (1H, bs), 7.36 (2H, d, J = 9Hz), 7.21, (1H, m) , 7.11 (2H, d, J = 10Hz), 6.90 (2H, d, J = 9Hz), 6.86 (1H, d, J = 2Hz), 6.83 (1H, dd, J = 8 and 2Hz), 6.73 (1H , d, J = 9Hz), 5.94 (1H, d, J = 2Hz), 5.92 (1H, d, J = 2Hz), 4.10-3.90 (3H, m), 3.71 (1H, m), 3.60-3.40 ( 2H, m), 3.15 (2H, m), 3.02 (1H, d, J = 18 Hz), 2.43 84H, q, J = 9Hz), 1.42 (3H, t, J = 9Hz), 1.08 (6H, t , J = 9Hz). MS (DCI, NH3) m / e 545 (M + H +). Anal. Cale, for C32H36N2O60.5H2O: C.69.42, H, 6.74, N, 5.06. Found: C, 69.52, H, 6.52, N, 4.89. Example 11 Acid ra? S, frans-2-0-4- (1, 3-be nzod i oxo I-5- i D-1- ((2, 6-dimethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d 8.32 (1H, bs), 7.37 (2H, d, J = 9Hz), 7.08 (3H, m), 6.91 (2H, d, J = 9Hz), 6.88 (1H, d, J = 2Hz), 6.82 (1H, dd, J = 8 and 2Hz), 6.75 (1H, d, J = 9Hz), 5.95 (1H, d, J = 2Hz), 6.92 (1H, d, J = 2Hz), 3.95 (1H, d, J = 10Hz), 3.81 (3H, s), 3.72 (1H, m), 3.55 (1H, dd, J = 10 and 5 Hz), 3.46 (1H, d J = 18 Hz), 3.13 (2H, m), 3.00 (1H, d, J = 18Hz), 2.10 (6H, s). MS (DCI, NH 3) m / e 502 (M + H +). Anal. Cale, for C29H3oN2O60.5H2O: C, 68.09, H, 6.11, N, 5.48. Found: C, 67.98, H, 6.02, N, 5.33. EXAMPLE 12 Acid Rr / s, trans-2- (4-propoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolid Na-3-carboxylic acid The title compound was prepared by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d 8.30 (1H, bs), 7.36 (2H, d, J = 9Hz), 7.21 ( 1H, m), 7.09 (2H, d, J = 10Hz), 6.91 (2H, d, J = 9Hz), 6.59 (1H, d, J = 2Hz), 6.51 (1H, d, J = 2Hz), 5.93 (1H, d, J = 2Hz), 5.91 (1H, d, J = 2Hz), 3.93 (3H, m), 3.80 (3H, s), 3.72 (1H, m), 3.60-3.50 (2H, m) , 3.15 (2H, m); 3.02 (1H, d, J = 18 Hz), 2.43 (4H, 1, J = 9Hz), 1.82 (2H, m), 1.08 (6H, t, J = 9Hz), 1.05 (3H, t, J = 9Hz ). MS (DCI, NH3) m / e 589 (M + H +). Anal. Cale, for C34H40N2O7O.25H2O: C, 68.84, H, 6.88, N, 4.72. Found: C, 68.80, H, 6.59, N, 4.52. Example 13 Frans acid, f ra / 7s-2- (3-methoxy-4-propoxy in y) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylamide nocarbonylmethyl) -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d 8.22 (1H, s), 7.21 (1H, m) 7.09 (2H, d , J = 10Hz), 7.02 (1H, dd, J = 9 and 3 Hz), 6.93 (1H, d, J = 2Hz), 6.87 (1H, d, J = 9Hz), 6.61 (1H, d, J = 2Hz), 6.53 (1H, dJ = 2Hz), 6.93 (1H, d, J = 2Hz), 6.91 (1H, d, J = 2Hz), 3.97 (3H, 1, J = 9Hz), 3.84 (3H, s ), 3.82 (3H, s), 3.70 (1H, m), 3.60-3.45 (2H, m), 3.15 (2H, m), 3.02 (1H, d, J = 18Hz), 2.42 (4H, 1, J = 9Hz), 1.85 (2H, m), 1.08 (6H, t, J = 9Hz), 1.05 (3H, t, J = 9Hz). MS (DC1, NH3) m / e 619 (M + H +). Anal. Cale, for C35H42N2O8: C, 67.94, H, 6.84, N, 4.53. Found: C, 667.54. H, 6.98, N, 4.44. Example 14 Trans acid, raps-2- (4-methoxy-in-yl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid prepared the title compound by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d 8.58 (1H, bs), 7.58 (2H, d, J = 9Hz), 7.40 (2H, bd, J = 10Hz ), 7.02 (1H, t, J = 9Hz), 6.91 (2H, d, J = 9Hz), 6.89 (1H, m), 6.76 (1H, d, J = 9Hz), 5.93 (2H, s), 3.98 (1H, bd, J = 10Hz), 3.81 (3H, s), 3.973 (2H, m), 3.55 (1H, bd, J = 15Hz), 3.13 (2H, m), 3.01 (1H, bd, J = 18Hz). MS (DC1, NH3) m / e 633 (M + H +). Anal. Cale, for C27H24Br2N2O60.3H2O: C, 50.85, H, 3.89, N, 4.39. Found: C, 50.45, H, 3.48, N, 4.22. Example 15 Acid? 2R-3R. RS 72- (4-Methoxy-enyl D-4-M .3-benzod-oxol-5-yl) -1 - ((2,6-dietl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid Example 15A-E Alternative preparation of frar / s-fra /? S-2- (4-methoxy-phenyl-4- (1,3-benzodioxol-5-yl) -pyrrolidine-3-ethyl carboxylate) Example 15A 5- (Nitrovinyl) -1, 3- nzod i oxo l Piperonal (15.55 kg, 103.5 moles) under mechanical stirring and under nitrogen was added ammonium acetate (13.4 kg, 173.8 moles), acetic acid (45.2 kg) ), and nitromethane (18.4 kg, 301.4 moles) sequentially. The mixture was heated to 70 ° C. After about 30 minutes, the yellow product was recrystallized. The reaction temperature was stirred at 180 ° C and stirred for approximately 10 hours until minimum piperonal remained. The coarse reaction mixture was sometimes cooled to 10 ° C and filtered. The precipitate was washed with acetic acid (2 x 8 kg) and then with water (2 x 90 kg). The product was dried under a nitrogen purge and then in an oven and vacuum at 50 ° C for 2 days to give 15.94 kg (80%) of the title compound as a light yellow solid. Example 15B (4-Methoxybenzoyl) ethyl acetate To potassium t-amylate (25% by weight, 60.8 kg, 99.26 moles) in toluene (15.2 kg) cooled to 5 ° C under mechanical stirring and under nitrogen a mixture was added of 4-methoxyacetophenone (6.755 kg, 44.9 mmol) and dethyl carbonate (6.40 kg, 64.18 mol) in toluene for 1 hour keeping the temperature below 10 ° C. The reaction mixture was heated at 60 ° C for 8 hours when 4-methoxyacetophenone was not detected by HPLC. The mixture was cooled to 20 ° C and washed added to 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 5% sodium bicarbonate solution (41 kg) and concentrated to 15.65 kg. The temperature was maintained below 50 ° C during the distillation. The concentrated yellow product analyzed by CLAR against an external normal and the yield was found to be 9.40 kg (94%). Example 15C 2- (4-Methoxybenzoyl) -4-nitromethyl-3- (1,3-benzodioxol-5-M) -ethyl ester ethyl ester To the resultant compound of example 15a (7.5 kg, 379 mol) suspended in THF (56 kg) with mechanical stirring under nitrogen was added the compound resulting from Example 15B (8.4 kg, 37.9 moles). The mixture was cooled to 17 ° C, sodium ethoxide (6.4 g, 0.095 mol) was added and the reaction was stirred for 30 minutes. After approximately 15 minutes, the nitrostyrene dissolved completely. Sodium ethoxide (6.4 g, 0.095 mol) was added and the mixture was stirred at 25 ° C until CLAR showed less than 1 percentage area of remaining ketoster. The reaction was concentrated to 32.2 kg which was determined by the HPLC analysis to be approximately 14.9 kg (95%). Example 15D cis Carboxylate, c / s-2- (4-methoxyphenyl) -4- (1,3-benzodioxol-5-yl) -pyrrolidine-3-ethyl Raney nickel (20.0 g), from which it was decanted The water was charged to a stirred hydrogenator equipped with a thermocouple. THF (20 mL), the crude compound resulting from Example 15C 840.82 g, 0.0482 mol) and acetic acid (2.75 mL, 0.0482 mol) were added sequentially. The mixture was placed under a hydrogen atmosphere at 4.2 kg / cm2 until hydrogen was dramatically absorbed slowly. TFA was added and the mixture was hydrogenated at 14.06 kg / cm2 until CLAR showed non-residual imine and < 2 percent area of nitrone. The catalyst was filtered and washed with 100 mL of methanol. The filtrate was analyzed by HPLC and found to contain 13.3 g (75% yield of the cis compound, cis-pyrrolidine.) The filtrate was concentrated and exchanged with additional THF (200 mL) to give a final volume of 100 mL. The mixture was neutralized with 2N NaOH solution, diluted with water (200 mL) and extracted with ethyl acetate (2 x 100 mL) The combined colorless ethyl acetate layers were analyzed again in an external normal by HPLC to be 12.0 g (73%) of the title compound Example 15E Transcarboxylate, trans-2- (4-methoxy-in-yl) -4- (1,3-benzodioxol-5-yl) -pyrrolidine-3 ethyl The solution of the resultant compound was added Example 15d (38.1 g, 0.103 mol) was mixed with ethanol (200 mL) to a final volume of 100 mL and sodium ethoxide (3.40 g, 0.050 mol) The mixture was heated at 75 ° C, when CLAR showed <3% of the remaining cis, cis isomer, the mixture was cooled to room temperature. The product was analyzed by CLAR against an external normal and found to contain 3.44 g (90% yield) of the title compound. The crude compound solution was concentrated and the residue was taken up in isopropyl acetate (400 mL). The organic layer was washed with water (2 x 150 mL) and then extracted with phosphoric acid solution M. (2 x 400 mL). The combined phosphate layers were stirred with ethyl acetate (200 mL) and neutralized to pH 7 with solid sodium bicarbonate (21 g). The organic layer was separated and found to contain 32.9 g (87%) of the title compound. Example 15F Carboxylate of IR2R-3R. RS72- (4-Methoxy in 1 L) -4- (1,3-benzodioxol-5-yl) -pyrrolidine-3-ethyl The racemic amino ester of Example 1 (32.9 g) was dissolved in 50 mL of acetonitrile. Acid (S) - (+) - Mandélico (2.06 g, 0.0136 mmol) was added and allowed to dissolve. The mixture was seeded with the product and allowed to stir at room temperature for 16 hours. The reaction mixture was cooled to 0 ° C and stirred for 5 hours. The product was filtered and dried in a vacuum oven with a nitrogen purge for 1 day at 50 ° C. The resulting salt (20.0 g, 0.0383 mole) was suspended in ethyl acetate (150 mL) and 5% sodium bicarbonate solution (150 mL). The mixture was stirred at room temperature until the salt dissolved and the evolution pad of carbon dioxide was rinsed. The organic layer was separated and concentrated. Example 15G, IR2R-3R acid. RS72- (4-Methoxy-enyl) -4-M.3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid The title compound was prepared from Example 15F according to the procedures of Example 1E. EXAMPLE 15H Salt of hydrochloride of acid / 2R-3R.RS72- (4-Methoxyphenyl) -4- (1, 3-benzodolox-5-yl) -1 - ((2,6-di-ethyl) ) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid The compound of Example 15G (450 mg) was dissolved in 10 mL of isopropanol. A slight excess of HCl in ethanol was added, the resulting solution was stirred for 10 minutes. The solvents were removed in vacuo, and the excess HCl was washed with isopropanol. The residue was taken up in ether and filtered to give 448 mg of the title compound. MS (DC1, NH3) m / e 531 (M + H +). Anal. Cale, for C31H35N2O6CI: C, 65.66 H, 6.22; N, 4.94. Found: C, 65.72; H, 6.39; N, 4.65. EXAMPLE 16 Frans acid, frar / s-2- (4-methoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((216- d¡methoxy) phenylaminocarbonylmethyl) -pyrrolidine-3 -carboxylic To a stirred solution of 2,6-dimethoxybenzoic acid (2.00 g, 11. 0 mmol) in 1,2-dichloroethane (45 mL) at room temperature was added successively N-methylmofoline (1.45 mL, 13.2 mmol) and diphenylphosphoryl azide (2.60 mL, 12.1 mmol). After heating the mixture for 2 hours at 75 ° C, copper iodide (150 mg) and benzyl alcohol (2.27 mL, 22. 0 mmol) were added and heating continued overnight. The solvents were removed in vacuo and the residue was chromatographed on silica gel, eluting with 4: 1 hexane-ethyl acetate to give the intermediate carbamate (1.50 g, 48% yield) as a white crystalline solid. The solid was dissolved in methanol (15 mL) and added to a flask purge with nitrogen containing 10% palladium in charcoal (500 mg). The mixture was placed under a hydrogen balloon and stirred for 4 hours at room temperature. The mixture was filtered through a pad of Celite and the solvents were removed in vacuo to give the title compound (800 mg, 485 yield). Example 16B Cold acid, rr / s-2- (4-methoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-dimethoxy) phenylaminocarbonylmethyl ) -pyrrolidine-3-carboxylic acid The compound was prepared by the procedures described in Example 1, substituting the compound of Example 16A for 2,5-6-trimethylaniline in Example 1D. 1 H NMR (300 MHz, CDCl 3) d, 8.18 (1 H, bs), 7.39 (2 H, bd, J = 9 Hz), 7.17 (1 H, t, J = 9 Hz, 6.99 (1 H, d, J = 2 Hz), 6.90 (2H, d, J = 9Hz), 6.89 (1H, d, J = 2Hz), 6.75 (1H, d, J = 9Hz), 6.56 (2H, d, J = 9Hz), 5.93 (2H, s), 3.88 (1H, bd, J = 10Hz), 3.81 (3H, s), 3.71 (6H, s), 3.70 (2H, m), 3.49 (1H, bd, J = 15 Hz), 3.03 (2H, m) 2.85 (1H, bd, J = 18 Hz) NMR (DCl, NH3) MS (DCl, NH3) m / e 535 (M + H +) Anal.Cal, for C29H30N2O80.75 AcOH: C, 63.20, H, 5.74, N, 4,838. Found: C, C, 63.18, H, 5.34, N, 4.79 .. Example 17 Frans.fran? S-2- (4-methoxyphenyl) -4- (1,3-benzodioxole) acid -5-yl) -1 - ((4-bromo-2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid To a stirred solution of 2,6-diethylaniline (10.0 g, 67.0 mmol) in acetylic acid (50 mg). mL) at room temperature, bromide (10.4 mL, 201 mmol) was added The reaction was stirred overnight at room temperature The reaction mixture was diluted with diethyl ether (200 mL) and washed with 5% bisulfite sodium (4 x 50 mL) and brine. The organic phase was dried with sodium sulfate and the solvents were removed in vacuo. The residue was chromatographed on silica gel, eluting with 9: 1 hexane-ethyl acetate to give the title compound (3.28 g, 21% yield). Example 17B Fraps.frar / s-2- (4-methoxyphenyl) -4- (1 l3-benzodioxol-5-yl) -1 - ((4-bromo-2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3 acid -carboxylic The title compound was prepared by the procedures described in Example 1, substituting the compound of Example 17A by 2,4,6-trimethylamine in Example 1D. 1 H NMR (300 MHz, CDCl 3) d, 8.21 (1 H, bs), 7.38 (2 H, d, J = 9 Hz), 7.23 (2 H, s), 6.92 (2 H, d, J =) Hz), 6.88 (1 H , d, J = 2Hz), 6.82 (1H, dd, J = 8 and 2 Hz), 6.75 (1H, d, J = 9Hz), 5.93 (1H, d, J = 2Hz), 5.91 (1H, d, J = 2Hz), 3.95 (1H, dm J = 9Hz), 3.82 (3H, s), 3.72 (1H, m), 3.62 (1H, m), 3.45 (1H, d, J = 18Hz), 3.14 (2H , m); 3.00 (1H, d, J = 18Hz), 2.39 (4H, 1, J = 9Hz), 1.07 (6H, t, J = 9Hz). MS (DC1, NH3) m / e 609 (M + H +). Anal. Cale, for C31H33BrN2O7: C, 61.09, H, 5.46, N, 4.60. Found: C, 60.80, H, 5.35, N, 4.54.

Example 18 Frar / s acid, frar < s-2- (4-methoxy-in-yl) -4- (1,3-benzodioxol-5-yl) -1 - ((2-3-ethyl-6-methyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d 8.32 (1H, bs), 7.38 (2H, d, J = 9Hz), 7.20-7.10 (3H, m) , 6.92 (2H, d, J = 9Hz), 6.87 (1H, d, J = 2Hz), 6.82 (1H, dd, J = 8 and 2Hz), 6.76 (1H, d, J = 9Hz), 5.94 (1H , d, J = 2Hz), 5.92 (1H, d, J = 2Hz), 3.95 (1H, d, J = 9Hz), 3.82 (3H, s), 3.73 (1H, m); 3.55 (1H, dd, J = 12 and 6), 3.57 (1H, d, J = 18 Hz), 3.14 (2H, m), 3.02 (1H, d, J = 18 Hz), 2.44 (2H, 1, J = 9Hz), 2.10 (3H, s), 1.10 (3H, t, J = 9Hz). MS (DC1, NH3) m / e 517 (M + H +). Anal. Cale, for C30H32N2O6 .5H2O: C, 68.56, H, 6.33, N, 5.33. Found: C, C, 68.58, H, 6.29, N, 5.13. Example 19 Trans acid, frans-2- (4-methoxy-in-yl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,4,6-tricyl) phenol Nocarbonylmethyl) -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1.

Example 19A Trans carboxylate, frans-2- (4-methoxy-in-yl) -4- (1,3-benzodioxol-5-i0- 1 - ((2,4,6-triethyl) phenylaminocarbonylmethyl) -p rrolidine-3-ethyl To a mixture (purged with nitrogen) of [1,1-bis (phenylphosphonium) ferrocene] dichloropalladium (II) 1: 1 complex with dichloromethane) (13 mg) and cesium carbonate (307 mg, 0.942 mmol) in anhydrous N, N-dimethiformamide (2 mL) at room temperature was added frar / s carboxylate, írarís-2- (4-methoxyphenl) -4- (1,3-benzodioxol-5-yl) -1 - (4-Bromo-2,6-diethylpheni) aminocarbonylmethyl) -pyridinidine-3-ethyl (200 mg, 0.314 mmol, prepared in Example 17) in tetrahydrofuran anhydride (8 mL). After stirring the mixture for 10 minutes at room temperature, 1.0 M Triethylborane (0.471 mL, 0.471 mmol) in tetrahydrofuran was added. The reaction was stirred overnight at 65 ° C under nitrogen. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2 x 30 mL) and brine. The organic phase was dried with sodium sulfate and the solvents were removed in vacuo. The residue was chromatographed on silica gel eluting with 3: 1 hexane-ethyl acetate to give the title compound (110 mg, 60% yield). Example 19B Trans acid. frans-2- (4- methoxy-in-yl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,4,6-triethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid was prepared the title compound by the procedures described in Example 1E. 1 H NMR (300 MHz, CDCl 3) d 8.22 (1H, bs), 7.38 (2H, d, J = 9Hz), 6.95 (2H, s), 6.91 (2H, d, J = Hz), 6.84 (1H, d , J = 2Hz), 6.82 (1H, dd, J = 8 and 2Hz), 6.75 (1H, d, J = 9Hz), 5.93 (1H, d, J = 2Hz), 5.91 (1H, d, J = 2Hz ); 3.95 (1H, d, J = 10Hz), 3.82 (3H, s), 3.71 (1H, m), 3.52 (1H, dd, J = 9 and 2 Hz); 3.46 (1H, d J = 18 Hz), 3.13 (2H, m), 3.00 (1H, d, J = 18Hz), 2.60 (2H, 1, J = 9Hz), 2.40 (4H, 1, J = 9Hz) , 1.22 (3H, t, J = 9Hz), 1.08 (6H, t, J = 9Hz). MS (DC1, NH3) m / e 559 (M + H +). Anal. Cale. for C33H38N2O60.25H2O: C, 70.38, H, 6.89, N, 4.97. Found: C, 70.18, H, 7.14, N, 4.63. Example 20 Acid / 2R, 34, 4 S72- (4-propoxy in) -4-M, 3-benzodioxol-5-i I) -1- (n - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid EXAMPLE 20A Acid R 2, 4 S, 4 S 72- (4 -) -4- (1, 3-benzyl oxo I-5-yl) -1-tert-butoxycarbonyl-1-hydroxydole-3-carboxylic acid combined the racemic amino ester of Example 3 (8.00 g) with 4.45 g of di-tert-butyl bicarbonate in 100 mL of THF; 10 mL of triethylamine were added and the resulting solution was stirred at room temperature for 3 hours. The solvents were removed in vacuo: the residue was taken up in EtOAc and washed sequentially with aqueous H 3 PO, bicarbonate and brine. The crude product was dissolved in 30 mL of ethanol, 12 mL of 2.5 N NaOH solution were added, the mixture was stirred overnight at room temperature, heated at 50 ° C for 2 hours. The solvents were removed in vacuo; the residue was divided into water and ether. The aqueous extract was acidified with aqueous H 3 PO 1N and extracted twice with EtOAc. The organic extracts were washed with brine, dried over Na2SO to give 9.2 g of frans acid, fra / 7S-2- (4-propoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1-tert-butoxycarbonyl -pyrrolidine-3-carboxylic acid. this material was dissolved in 30 mL of EtOAc, and 1.3 mL of (R) - (+) -a-methylbenzylamide were added. The solution was stirred for 10 minutes; The solvents were removed in vacuo, 50 mL of ether was added and the resulting solution was seeded. After stirring overnight, the solvents were removed in vacuo; The residue was taken up in 70 mL of ether and filtered. The solid product was recrystallized with EtOAc / ether. The crystalline material was vigorously stirred in a two phase mixture of 1N H3P0 and EtOAc; the organic layer was decanted, then washed with brine and dried over Na2SO4. EXAMPLE 20B Carboxylate of 22R.34.4S72- (4-Propoxy in) -4- (1.3-be nzod-oxol-5-yl) -pyrrolidine-3-ethyl The compound of Example 20A was dissolved in ethanol and cooled in a thread bath. HCl gas was bubbled through a saturated solution; The resulting solution was warmed to room temperature and allowed to stir overnight under a bed of nitrogen. The solvents were removed in vacuo; The residue was taken up in bicarbonate and extracted with EtOAc. The organic layer was decanted, then washed with brine and dried over Na2SO4. EXAMPLE 20C Acid i2R.34.4S72- (4- Propoxyfine D-4-M, 3-benzodioxol-5-yl) -1 - ((2,6-diethylphenyl) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid compound of the compound of Example 20B according to the procedures of Example 1E. MS (DC1, NH3) m / e 559 (M + H +). Anal. Cale, for C 33 H 38 N 2 O 7 .2 H 2 O: C, 70.49; H, 6.88; N, 4.98. Found: C, 70.52; H, 6.78; N, 4.85. EXAMPLE 21 Trans, frans-2- (4-methoxy-3-yl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6- d¡¡-propyl) phenylaminocarbonylmethyl) -pyrrole Dina-3-carboxylic acid The title compound was prepared by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d, 8.29 (1 H, bs), 7.39 (2 H, d, J = 9 Hz) , 7.29 (1H, 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 and 2Hz), 6.74 (1H, d, J = 9Hz), 5.93 (1h, d, J = 2Hz), 5.91 (1H, d, J = 2Hz), 3.96 (1H, d, J = 10Hz), 3.83 ( 3H, s), 3.73 (1H, m), 3.55 (1H, dd, J = 12 and 6), 3.50 (1H, d, J = 18Hz), 3.14 (2H, m), 3.01 (1H, d, J = 18Hz), 2.84 (2H, m), 1.16 (6H, d, J = 8Hz), 1.05 (6H, d, J = 8Hz). MS (DC1, NH3) m / e 559 (M + H +). Anal. Cale. for C 33 H 38 N 2 O 6 .5H 2 O: C, 69.82; H, 6.92, N, 4.93. Found: C, 69.69, H, 6.63, N, 4.89. EXAMPLE 22 Tra ns acid, trans-2- (4-methoxyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl-4-methyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 19. 1 H NMR (300 MHz, CDCl 3) d 8.20 (1H, bs), 7.38 (2H, d, J = 9Hz ), 6.92 (4H, m), 6.86 (1H, d, J = 2Hz), 6.82 (1H, dd, J = 8 and 2Hz), 6.75 (1H, d, J = 9Hz), 5.93 (1H, d, J = 2Hz), 5.91 (1H, d, J = 2Hz), 3.95 (1H, d, J = 10 Hz), 3.81 (3H, s), 3.72 (1H, m), 3.55 (1H, dd, J = 9 and 2Hz), 3.45 (1H, d, J = 18 Hz), 3.13 (2H, m), 3.00 (1H, d, J = 18 Hz), 2.39 (4H , 1, J = 9Hz), 2.28 (3H, s), 1.07 (6H, t, J = 9Hz). MS (DC1, NH3) m / e 545 (M + H +). Anal. Cale, for C32H36N2O60.5H2O: C, 69.42, H, 6.74, N, 5.06. Found: C, 69.43, H, 6.57, N, 4.94. Example 23 Acid (2R, 34.4S) -2- (4-Ethoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) faith n -laminocarbonylmethyl) -pyrrolidine-3-carboxylic acid prepared the racemic amino ester compound of Example 10 according to the procedures of Example 20. 1 H NMR (300 MHz, CDCl 3) d 8.32 (1H, bs), 7.38 (2H, d, J = 9Hz), 7.21 (1H, m ), 7.12 (2H, d, J = 10Hz), 6.90 (3H, m), 6.83 (1H, dd, J = 8 and 2 Hz), 6.74 (1H, d, J = 9Hz), 5.94 (1H, d , J = 2Hz), 5.92 (1H, d, J = 2Hz), 4.05 (2H, m), 3.96 (1H, d, J = 10Hz), 3.72 (1H, m), 3.53 (1H, dd, J = 10 and 3 Hz), 3.47 (1H, d, J = 18Hz), 3.13 (2H, m), 3.02 (1H, d, J = 18Hz), 2.44 (4H, 1, J = 9Hz), 1.42 (3H, t, J = 9Hz), 1.08 (6H, t, J = 9Hz), MS (DCl, NH3) m / e 545 (M + H +). Anal. Cale, for C32H36N2O6O.5H20: C, 69.42, H, 6.74, N, 5.06. Found: C, 69.67, H, 6.73, N, 4.98. Example 24 Trans acid tra r? s-2- (4- methoxy-in-yl) -4- (1,3-benzodioxol-5-yl) -1 - ((4-carboxy-2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine- 3-carboxylic acid The title compound was prepared by the procedures described in Example 19. 1 H NMR (300 MHz, CDCl 3) d 7.68 (2H, bs), 7.54 (2H, d, J = 9Hz), 7.27 (2H, m), 6.93 (2H, d, J = 9Hz), 6.83 (2H, m), 5.98 (2H, s), 3.92 (1H, d, J = 9Hz), 3.76 (3H, s), 3.62 (1H, m), 3.45-3.00 (2H, m), 3.00-2.80 (3H, m), 2.44 (4H, 1, J = 9Hz), 1.04 (6H, t, J = 9Hz). MS (DC1, NH3) m / e 575 (M + H +). Anal. Cale, for C32H34N2O80.5H2O: C, 65.85, H, 6.04, N, 4.80. Found: C, 6.03, H, 5.84, N, 4.67. Example 25 Trans acid, tra rs-2- (4-methoxy-in-yl) -4- (1,3-benzodioxol-5-yl) -1 - ((4-n-tetra-2,6-diethyl) phen laminocarbonylmethyl) -pyrrolidine-3-carboxylic acid Example 25A 2,6-Diethyl-4-nitroaniline to a stirred solution of 2,6-diethylaniline (5.0 g, 34 mmol) in concentrated sulfuric acid (30 mL) at 0 ° C was added acidic drip Concentrated nitric acid (15.9 M, 2.10 mL, 34 mmol). The cooling bath was stirred and the reaction was stirred for 3 hours at room temperature. After pouring the reaction mixture into ice, the solution was neutralized using 4N sodium hydroxide and extracted with methylene chloride (3 x 50 mL). The extracts were dried with sodium sulfate and the solvents were removed in vacuo to give the title compound. Example 25B Fra / 7s acid, fya /? S-2- (4-methoxyphenol) -4- (1,3-benzodioxol-5-yl) -1 - ((4-nitro-2,6-diethyl) phenylamide nocarbonylmethyl) -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1, substituting the compound of Example 25a for 2,4,6-triethylaniline in Example 1D. 1 H NMR (300 MHz, CDCl 3) d 8.38 (1H, bs), 7.77 (1H, d, J = 9Hz), 7.38 (2H, d, J = 9Hz); 7.24 (1H, d, J = 9Hz), 6.92 (2H, d, J = 9Hz), 6.88 (1H, d, J = 2Hz), 6.82 (1H, dd, J = 8 and 2Hz), 6.75 (1H, dm J = 9 Hz), 5.93 (1H, d, J = 2Hz), 5.91 (1H, d, J = 2Hz), 3.97 (1H, d, J = 9Hz), 3.83 (3H, s), 3.74 (1H , m), 3.48 (2H, m), 3.18 (2H, m), 3.04 (1H, d, J = 18 Hz), 2.3 (2H, m), 2.44 (2H, 1, J = 9Hz), 1.10 ( 3H, t, J = 9Hz), 1.08 (3H, t, J = 9Hz). MS (DC1, NH3) m / e 576 (M + H +). Anal. Cale, for C3? H33N3O8 .75H2O: C, 63.20, H, 5.90, N, 7.13. Found: C, 63.30, H, 5.81, N, 7.14. EXAMPLE 26 Frap? S.frans-2- (4-methoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2-isopropyl-6-methyl) fe nylaminocarbonylmethyl) -pyrrolidine acid -3- carboxylic The title compound was prepared by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d 8.35 (1H, bs), 7.39 (2H, d, J = 9Hz), 7.18 (2H, m), 7.07 (1H, dd, J = 9 and 2 Hz), 6.92 (2H, d, J = 9Hz), 6.86 (1H, d, J = 2Hz), 6.82 (1H, dd, J = 8 and 2 Hz), 6.75 (1H, d, J = 9Hz), 594 (1H, d, J = 2Hz), 5.92 (1H, d, J = 2Hz), 396 (1H, d, J = 10Hz), 3.83 (3H, s), 3.72 (1H, m), 3.50 (2H, m), 315 (2H, m), 3.02 (1H, d, J = 18Hz), 2.86 (1H, m), 2.09 (3H, s), 1.16 (3H, d, J = 8Hz), 1.07 (3H, d, J = 8Hz). MS (DC1, NH3) m / e 531 (M + H +). Anal. Cale, for C31H34N2O6 .5H2O: C, 69.00, H, 6.54, N, 5.19. Found: C, 69.27, H, 6.67, N, 5.21. EXAMPLE 27 Cold acid, frans-2- (4-methoxyienyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2-ethyl-6-methoxy) phenylaminocarbonyl) ) -pyrrolidine-3-carboxylic acid Example 27a Ethyl 3-oxo-4- (3-methoxy-2-nitrophenyl) propionate Potassium ethyl malonate (3.68 g) was combined with 2.29 g of magnesium chloride in 12 mL of DMF; the reaction mixture was heated at 60 ° C for 4 hours. The resulting mixture was cooled to room temperature. 3-methoxy-2-nitrobenzoic acid (3.4 g) was dissolved simultaneously in 12 mL of DMF; 3.06 g of 1,1-carbonyldiimidazole (evolved gas) were added and the resulting solution (after stirring at room temperature for 4 hours) was added to the malonate mixture. The resulting slurry was stirred at room temperature for 14 hours. The solvents were removed in vacuo; the residue was taken up in EtOAc and washed sequentially with 1N H3PO4, bicarbonate and brine and concentrated in vacuo. Example 27B 2-Nitro-3- (1-hydroxyethyl) anol The compound of Example 27A (3.2 g) was dissolved in 50 mL of concentrated sulfuric acid and stirred at room temperature for 48 hours. The reaction mixture was poured into 300 mL of ice and extracted twice with EtOAc. The organic extracts were washed sequentially with water, bicarbonate and brine and concentrated in vacuo. The crude product was heated at 160 ° C for 3 hours. The resulting dark brown residue was extracted with EtOAc. The organic extracts were concentrated. The crude product was dissolved in 15 mL of ethanol; Sodium borohydrate (450 mg) were added and the resulting solution was stirred at room temperature for 2 hours. The solvents were removed in vacuo; the residue was taken up in 10% aqueous HCl and stirred for 15 minutes. The mixture was extracted with EtOAc; the organic extracts were washed sequentially with bicarbonate and brine and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 1: 1 EtOAc / hexanes, to give 1.08 g (32% overall) of the title compound as a colorless oil.

Example 27C 2-Ethyl-6-methoxyaniline The compound of Example 27B (310 mg) was dissolved in 10 mL of THF, 1.5 mL of H3PO3 were added, followed by 50 mg palladium on 10% charcoal. The resulting mixture was purged with nitrogen, then placed under a hydrogen balloon and stirred overnight. Bicarbonate was added carefully and the mixture was filtered through a pad of Celite. The filtrate was extracted with EtOAc; the organic extracts were washed with bicarbonate and brine and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 1: 1 ether / hexanes, to give 102 mg (43% yield) of the title compound as a colorless oil. EXAMPLE 27D Acid t ra ns, trans-2- (4-methoxy) -4- (1,3-benzodioxol-5-yl) -1 - ((2-etl! -6-methoxy) phenylaminocarbonylmethyl) - pyrrolidine-3-carboxylic acid The title compound was prepared according to the procedures of the Example, substituting the compound of Example 27C for 2,4,6-trimethylaniline. 1 H NMR (300 MHz, CDCl 3) d 1.10 (t, J = 8 Hz, 3H9, 2? B (d, j = 8 Hz, 2H), 3.4-3.9 (m, 7H), 3.73 (s, 3H), 3.824 (s, 3H9, 5.93 (s, 2H9, 6.80 (d, J = 8 Hz, 1H), 6.86 (d, J = 8 Hz, 2H), 6.93 (dd, J = 2.8 Hz, 1H9, 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). DCl, NH3) m / e 533 (M + H +) Anal.Cal, for C30H32N2O70.7 TFA: C, 61.59, H, 5.38; N, 4.57. Found: C, 61.27, H, 5.44; N, 4.61 Example 28 Frar acid / S, fYar? S-2- (4- / so-Propoxyphenl) -4- (1,3-benzodioxol-5-yl) -1- ((2,6-diethyl) phenylamide Nocarbonylmethyl) -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d 7.51 (2H, bd d, J = 9Hz), 7.22 (1H, dd , J = 8.9Hz), 7.13 (1H, s), 7.11 (1H, dd, J = 1.8Hz), 7.05 (1H, d, J = 2Hz), 6.99 (2H, bd d, J = 9Hz) , 6.91 (1H, dd, J = 2.8 Hz), 6.78 (1H, d, J = 8Hz), 5.93 (1H, d, J = 3Hz), 5.92 (1H, d, J = 3Hz), 4.64 (1H, septet, J = 7Hz), 3.80 (3H, m), 3.55 (2H, m), 2.47 (4H, 1, J = 7Hz), 1.33 (6H, dd, J = 2.7 Hz), 1.09 (6H, t, J = 7Hz). MS (DC1, NH3) m / e 559 (M + H +). Anal. Cale, for C33H38N2O60.7TFA: C, 64.71, H, 6.11, N, 4.39. Found: C, 64.54, H, 5.78, N, 4.121. EXAMPLE 29 Trans, trans-2- (2-F? -4-Propoxyp in yl) -4- (1,3-benzodioxol-5-yl) -1- ((2,6-diethyl nylaminocarbonylmethyl)) - pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d 1.06 (t, 3 H, J = 7 Hz), 1.09 (t, 6 H, J = 7Hz), 1.83 (m, 2H), 2.44 (q, 4H, J = 7Hz), 3.4-3.9 (m, 5H), 3.99 (t, 2H, J = 6Hz), 5.95 (dd, 2H, J = 1.2 Hz), 6.8-6.9 (m, 4H), 7.03 (d, 1H, J = 2Hz), 7.11 (d, 1H, J = 8Hz), 7.13 (s, 1H), 7.22 (dd, 1H, J = 7 , 9Hz), 7.63 (t, 1H, J = 9Hz) MS (DCl, NH3) m / e 577 (M + H +) Anal.Cal, for C33H37N2O6F'1.0TFA: C, 60.87, H, 5.55, N , 4.06 Found: C, 5.61, N, 3.97 Example 30 Trans acid, fra /? S-2- (4- (2-methoxyethoxy) f en yl) -4- (1,3-benzodioxol-5-yl); l) -1- ((2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1. 1 H NMR (300 MHz, CDCl 3) d 1.08 (t , J = 7Hz, 6H), 2.43 (q, J = 7Hz, 4H), 3.00 (d, J = 11 Hz, 1H), 3.05-3.15 (m, 2H), 3.44 (s, 3H), 3.46 (d, J = 11Hz, 1H), 3.45-3.55 (m , 1H), 3.65-3.75 (m, 1H9, 3.75-3.80 (m, 2H), 3.93 (d, J = 7Hz, 1H9, 4.12-4.17 (m, 2H), 5.94 (dd, J = 2Hz, 4Hz, 2H), 6.75 (d, J = 8Hz, 1H), 6.82 (d, J = 2Hz, 9Hz, 1H), 6.87 (d, J = 2Hz, 1H), 6.95 (d, J = 8Hz, 1H), 7.10 (d, J = 6Hz, 2H), 7.19-7.24 (m, 1H), 7.37 (d = 8Hz, 2H), 8.29 (s, 1H). MS (DC1, NH3) m / e 575 (M + H +). Anal. Cale, for C33H38N2O7: C, 68.97, H, 6.67, N, 4.87. Found: C, 68.92, H, 6.83, N, 4.77. Example 30A r4- (ethoxyethoxy) benzoin-ethyl acetate Methyl 4-hydroxybenzoate was reacted with 1-bromo-2-methoxyethane and potassium carbonate in dimethylformamide. The resulting ester was hydrolyzed to the acid with NaOH in alcohol. The acid was reacted with carbonyl diimidazole in THF; the resulting imidazole was reacted with potassium salt of mono ethyl ester of malonic acid and magnesium chloride, to give the title compound as a colorless oil. Example 30B Trans acid, trans-2- (4- (2-Methoxyethoxy) f) yl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethylphenylaminocarbonylmethyl) pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1, using b-ketoester described above as the starting material: 1 H NMR (300 MHz, CDCl 3) of 1.08 ( t, J = 7Hz, 6H), 2.43 (q, J = 7Hz, 4H), 3.00 (d, J = 11Hz, 1H), 3.05-3.15 (m, 2h), 3.44 (s, 3H), 3.46 (d , J = 11Hz, 1H), 3.45-3.55 (M, 2H), 3.65-3.75 (m, 1H9, 3.75-3.80 (m, 2H, 3.93 (d, J = 7Hz, 1H9, 4.12-417 (m, 2H ), 5.94 (dd, J = 2H, 4Hz, 2H), 6.75 (d, J = 8Hz, 1H, 6.82 (dd, J = 2H, 9Hz, 1H9, 6.87 (d, d = 8Hz, 2H), 8.29 ( s, 1H) .MS (APCI +) m / e 575 (M + H +).

Anal. Cale, for C33H38N2O7: C, 68.97, H, 6.67, N, 4.87. Found: C, 68.92, H, 6.83, N, 4.77. The following Examples 31-857 can be prepared using the methods described in the previous examples. 31 32 33 59 60 62 63 4 65 66 0 71 72 3 74 75 80 81 92 93 100 101 102 103 104 105 124 125 126 136 137 138 139 140 141 142 143 1 4 145 146 147 25 149 150 152 153 155 156 158 159 161 162 164 165 167 168 170 171 173 174 176 177 179 180 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 25 208 209 210 21 1 212 213 214 215 216 217 218 219 25 221 222 233 234 236 237 239 240 242 243 244 245 246 247 248 249 255 257 259 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 281 282 284 285 287 288 289 290 291 292 293 294 295 296 297 298 299 300 25 307 308 309 310 311 312 313 314 315 316 317 318 326 327 329 330 332 333 335 336 340 341 342 343 344 345 346 347 348 25 349 350 351 352 353 354 358 359 360 25 368 369 379 380 381 382 383 384 25 388 389 390 397 398 399 400 401 402 25 406 407 408 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 445 446 25 457 458 459 460 461 462 463 464 465 472 473 474 475 476 25 477 478 481 482 483 484 485 486 490 491 492 493 494 495 496 497 498 503 504 505 506 507 508 509 510 511 512 513 514 515 516 523 524 525 526 528 530 532 534 536 538 540 542 543 544 545 546 550 551 552 553 554 555 1 * 5 580 581 582 583 584 585 586 587 588 25 592 593 594 597 598 600 602 603 605 606 608 609 610 611 612 613 614 615 616 617 618. 622 623 624 625 626 627 628 629 630 25 632 633 635 636 638 639 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 25 67 668 669 697 698 699 20 25 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 20 25 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 25 748 749 750 751 752 753 754 755 756 7 758 759 0 761 762 3 764 765 766 767 768 769 770 771 772 773 774 20 25 776 777 781 783 785 786 788 789 791 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 25 813 814 815 816 817 818 819 820 821 822 25 824 825 827 828 830 831 833 834 836 837 839 840 842 843 845 846 848 849 851 852 Example 858 Trans, trans-2- (4-Methoxy) f) yl) -4- (1,3-benzodioxo! -5-yl) -1 - ((? / - 2,6-d¡et) lphenyl) aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid Example 858A 3-carbopylate of rt / 7s, tVa / 7S-2- (4-methoxy) -4- (1,3-benzodioxol-5-yl) -1-amino-pyrrole-dina-eti or A solution of 1.00 g (2.7 mmol) trans-3-carboxylate, fraA7S-2- (4-methoxy) phenyl-4- (1,3-benzodioxoI-5-yl) -1-pyrrolidine ethyl in 6 mL of acetonitrile is he added a solution of 1.18 g (10.4 mmoles) of hiroxylamine-O-sulfonic acid in 2 mL of H2O. The homogeneous reaction mixture was heated spontaneously and stirred for 20 minutes, then concentrated in vacuo. The residue was dissolved in 15 mL of ethyl acetate and extracted with 0.7M NaHCO3 82 x 25 mL), then with brine (2 x 10 mL), dried over MgSO, filtered and concentrated as a thick oil. This consisted of a mixture of starting pyrrolidine and the corresponding 1-aminopyrrolidine. To a solution of 892 mg (2.2 m moles) of this oil in 10 mL of ethyl acetate was added 7000 mg (3.21 mmoles) of di-tert.-butoxycarbonic anhydride. The mixture was stirred at room temperature for 30 minutes, then concentrated empty. Chromatography on silica gel eluting with 30% EtOAc / Hex gave 360 mg of frans, fra / 7s-2- (4-methoxy) phenyl-4, (1,3-benzodioxol-5-yl) - 1- (tert-butoxycarbonyl) amine-pyrrolidine-3-carboxylate ethyl as a colorless oil. The desired product was slightly more polar than terbutoxycarbonylpyrrolidine. To 360 mg (0.768 mmoles) of Boc hydrazine was added 2 mL of trifluoroacetic acid. After stirring for 2 hours at room temperature, the solvent was removed in vacuo. The residue was taken up in 10 mL of 0.6M NaHCO3 and extracted with ethyl acetate (3 x mL). The combined ethyl acetate layers were dark and extracted with brine (1 x 3 mL), dried over MgSO, filtered and concentrated to 249 mg of the clearly colorless oil. Example 858B Trans acid. tra ns-2- (4-Methoxy) phen \ -4- (1,3-ber \ zod \ oxo \ -5- \) - '\ - ((N -2,6- dieti fen¡l) am¡ nocarbonylmethyl) -pyrrolidine-3-carboxylic acid To an ice-cooled solution of 100 mg (0.670 mmol) of 2,6-diethyliniline in 2 mL of THF and 0.4 mL of? /,? / - diisopropyl-? / - ethylamine was added 66 mg (0.223 mmol) of triphosgene. The suspension was stirred at 0 ° C for 10 minutes, then a solution of 249 mg (0.645 mmol) of fraA7s, rans-2- (4-methoxy) phenyl-4- (1,3-benzodioxol-5-yl) - Ethyl 1-amino-pyrrolidine-3-carboxylate in 2 mL of THF were added. The mixture was stirred for 1.5 hours, then a solution of 0.6 NaHCO3 was added. The suspension was extracted from ethyl acetate (3 x 5 mL), dried over MgSO 4, filtered and concentrated in an oil that was recrystallized. This was absorbed in a small amount of ethylene acétate, allowed to crystallize and filtered to give 108 mg (305 of the hydrazine) of trans, tra / 7S-2- (4-Methoxy) f in i l-4- ( , Ethyl 3-benzodioxol-5-yl) -1 - ((? - 2,6-diethylphenyl) aminocarbonyl) amino-pyrrolidine-3-carbcxylate. The hydrolysis of the ester was carried out as described for the examples to give the title compound as a white solid. 1 H NMR (300 MHz, d6-DMSO) d 1.00 (t, JJ = 7.4, 6H), 2.33 (br t, J = 7.0Hz, 4H), 2.90 (t, J = 9.9Hz, 1H), 3.38-3.50 (m, 2H), 3.59 (m, 1H), 3.75 (s, 3H), 4.11 (d, J = 10.3Hz, 1H), 5.98 (d, J = 0.7Hz, 1H), 5.99 (d, J = 1.1 Hz, 1H), 6.92 (m, 2H), 6.89 (d, J = 8.4Hz, 2H), 7.03 (d, J = 7.0Hz, 2H), 7.12 (m, 1H), 7.33 (d, J = 1.5 Hz, 1H), 7.38 (s, 1H), 7.53 (d, J = 8.8Hz, 2H), 8.02 (s, 1H), 12.3 (s, 1H), MS (DCl, m / z) 531 (MH + ). Anal. Cale, for C30H33N32O6: C, 67.78, H, 6.29, N, 7.90. Found: C, 67.71, H, 6.42, N, 7.82. EXAMPLE 859 Acid R 2, 34, 4S 7-2- (4- (2-methoxyethoxy) f en yl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) -laminocarbonylmethyl ) -pyrrolidine-3-carboxylic acid Example 859A Carboxylate of f2f ~, 34,4S7-2- (4- (2-methoxyethoxy) -4- (1, 3-benzodioxol-5-yl) -pyrrodidine-3-ethyl It was reacted to taA7s, fra / 7s-2- [4- (2-methoxyethoxy)] - ethyl 4- (1, 3-benzodioxol-5-yl) -pyrrylidene-3-carboxylic acid of example 30 with di-ferf-butyl dicarbonate and the resulting product was hydrolyzed with NaOH to give fra /? S, fra / 7s-2- [4- (2-methoxyethyl)] - 4- (1,3-benzodioxol-yl) -1- (tert-butyloxycarbonyl) -pyrrolidine-3-benzylamine. The acid was resolved by salt formation with R - (+) - alpha methyl benzylamine. The dissolved salt was washed with aqueous HCl to remove the resulting agent, then heated with HCl in ethanol at 70 ° C for 18 hours to yield [2R, 34.4S] -2- (4 -) - 4- (1, 3-benzodioxol-5-yl) -pyrrolidine-3-carbcxylate, which was purified by chromatography on silica gel, eluting with ethyl acetate. Example 859B Acid / "2R, 34,4S7-2- (4-methoxyethoxy) phenan-4- (1,3-benzodioxol-5-iQ-1- ((2,6-diethyl) -laminocarbonylmethyl-pyrrolidine -3-carboxylic acid The compound was prepared as described in Example 30, using the compound of Example 859A as a starting material: 1 H NMR (300 MHz, CDCl 3) d 1.08 (t, J = 7Hz, 6H), 2.43 ( 1, J = 7Hz, 4H), 3.00 (d, J = 11Hz, 1H), 3.05-3.15 (m, 2H), 3.44 (s, 3H), 3.45 (d, J = 11Hz, 1H), 3.45-3.55 (m, 1H), 3.65-3.75 (m, 1H), 3.75-3.80 (m, 2H), 3.93 (d, J = 7Hz, 1H), 4.12-4.17 (m, 2H), 5.94 (dd, J = 2Hz, JHz, 2H), 6.75 (d, J = 8Hz, 1H), 6.82 (dd, J = 2Hz, 9Hz, 1H), 6.87 (d, J = 2Hz, 1H), 6.95 (d, J = 8Hz) , 7.10 (d, J = 6Hz, 2H), 7.19-7.24 (m, 1H), 7.37 (d, d = 8Hz, 2H), 8.29 (s, 1H) Example 860 Acid f ra /? S, frans- 2- (4- (2-ethoxyethoxy)) -4- (, 3-benzodioxol-5- i I) -1- (2,6-detho-phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid was prepared the title compound by the procedures described in Example 30. 1 H NMR (3 00 MHz, CD3OD) d 1.09 (t, J = 7Hz, 6H), 1.23 (t, J = 7Hz, 3H), 2.47 (q, J = 7Hz, 4H), 3.4-3.55 (wide, 2H), 3.62 ( q, J = 7Hz, 2H), 3.6-3.9 (broad, 4H), 3.82 (m, 2H), 4.16 (m, 2H), 4.4 (wide, 1H), 5.93 (dd, J = 1Hz, 2Hz, 2H ), 6.77 (d, J = 8Hz, 1H), 6.90 (dd, J = 2Hz, 8Hz, 1H), 7.04 (m, 3H), 7.12 (m, 2H), 7.22 (dd, J = 7Hz, 9Hz, 2H), 7.44 (m, 2H). MS (ESI +) m / e 589 (M + H +). Anal. Cale, for C34H4oH2O7.0.5TFA: C, 65.11, H, 6.32, N 4.34. Found: C, 64.81, H, 6.36, N, 4.25. Example 861 T rans acid, trans-2- (4- (2- i or propoxy ethoxy)) -4- (1, 3-benzodioxo! -5-i!) -1- (2,6-detho-phenylaminocarbonylmethyl) - pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 30. 1H-NMR (300 MHz, CD3OD) d 1.10 (t, J = 7Hz, 6H), 1.18 (2, J = 7Hz, 6H) , 2.47 (q, J = 7Hz, 4H), 3.4-3.55 (broad, 2H), 3.6-3.9 (broad, 4H), 3.75 (Hept.1H, J = 7Hz), 3.82 (m, 2H), 4.17 ( m, 2H), 4.4-4.5 (broad, 1H), 5.93 (broad, s, 2H), 6.78 (d, J = 8Hz, 1H), 6.90 (dd, J = 2Hz, 8Hz, 1H), 7.05 (m , 3H), 7.12 (m 2H), 7.20 (dd, J = 7Hz, 9Hz, 2H), 7.56 (m, 2H). MS (ESI +) m / e 603 (M + H +). Anal. Street, for C35H42H2O7.0.6TFA: C, 64.79, H, 6.40, N, 4.17. Found: C, 64.40, H, 6.53, N, 4.20. Eiemplp 862 Acid fa /? S, f / 'a / 7S-2- (4- (2-Propoxy) -4- (1,3-benzodoxox-5-i0-1- (2,6-diethylphenylaminocarbon) 1-methoxyprolidine-3-carboxylic acid The title cempuestp was prepared by IPSprops described in Example 1. 1H NMR (300 MHz, CD3OD) d 1.06 (t, J = 7Hz, 3H), 1.09 (t, J = 7Hz, 6H), 1.81 (m 2H), 2.46 (q, J = 7Hz, 4H), 3. 3 (m, 2H), 3.4-3.5 (broad, 2H), 3.6-3.9 (broad, 4H), 3.95 (t, J = 6Hz, 2H9, 4.22 (s, 4H), 4.4 (wide, 1H9, 6.80 (d, J = 8Hz, 1H), 6.92 (dd, J = 2Hz, (hz, 1H), 6.99 (m, 3H), 7.13 (m, 2H), 7.22 (dd, J = 7Hz, 9Hz, 2H), 7.44 (m, 2H). MS (ESI +) m / e 573 (M + H +), 595 (M + Na +). Anal. Cale, for C34H48N2O60.6TFA: C, 65.95, H, 6.38, N, 4.37. Found: C, 65.83, H, 6.40, N, 4.31. EXAMPLE 863 F ra /? S Acid, f RaA7s-2 - '(4-butoxif in i I) 1-4- (1,3-benzodioxol-5-iQ-1- (2,6-diethylphenylaminocarbonylmethi-pyrrolidine-3 carboxyl The title compound was prepared using the method of Example 30, substituting 1-bromobutane for 1-bromo-2-methoxyethane, 1 H NMR (300 MHz, CDCl 3) d 0.99 (t, J = 7Hz, 3H), 1.08 ( t, J = 7Hz, 6H, 1.42-1.57 (m, 2H), 1.73-1.82 (m, 2H), 2.42 (1, J = 7Hz, 4H9, 3.00 (d, J = 11Hz, 1H), 3.05-3.15 (m, 2H), 3.45 (d, J = 11Hz, 1H), 3.50-3.55 (m, 2H), 3.65-3-75 (m, 1H), 3.93-4.00 (m, 3H), 5.94 (dd, J = 2H, 4Hz, 2H), 6.75 (d, J = 8Hz, 1H), 6.82 (dd, J = 2Hz, 9Hz, 1H), 6.97 (d, J = 2Hz, 1H), 693 (d, J = 8Hz, 1H), 7.10 (d, J = 7Hz, 2H), 7.19-7.24 (m, 1H), 7.87 (d, H = 8Hz, 2H), 8.30 (s, 1H) MS (APCI +) m / e (M + H +) Anal Cale, for C34H40N2O6: C, 71.31 H, 7.04 N, 4.89 Found: C, 71.05 H, 7.09 N, 4.83 Example 864 Acid tra rs.f / -a /? s- 2-r4-- ~ (2-methoxyethoxy) ethoxy) f in i H-4- (1,3- be nzod i oxo I-5-yl) -1 - ((2,6-diethyl) phenylaminocarboni Methyl) -pyrrolidine-3-carboxylic acid The title compound was prepared using the method of Example 30, by substitution of 1-bromo-2- (2-methoxyethoxy) ethane ppr 1-bromo-2-methoxyethane. 1 H NMR (300 MHz, CDCI3) d 1.08 (t, J = 7Hz, 6H), 2.43 (q, J = 7Hz, 4h), 3.00 (d, J = 11 Hz, 1H), 3.05-3.15 (m, 2H), 3.40 (s, 3H), 3.46 (d, J = 11Hz, 1H), 3.44-3.55 (m, 1H), 3.57-3.62 (m, 2H), 3.65-3.75 (m, 1H), 3.70-3.75 (m, 2H), 3.88 (t, J = 6Hz, 2H), 3.93 (d, J = 7Hz, 1H), 4.15 (t, J = 7Hz, 2H), 5.94 (dd, J = 2Hz, 4Hz, 2H), 6.75 (d, J = 8Hz, 1H), 6.82 (dd, J = 2Hz, 9Hz, 1H), 6.87 (d, J = 2Hz, 1H), 6.93 (d, J = 8Hz, 1H), 7.10 (d, J = 7Hz , 2H), 7.19.7.24 (m, 1H), 7.37 (d, H = 8Hz, 2H), 8.30 (s, 1H). MS (APCI +) m / e 619 (M + H +). Anal. Cale, for C35H42N2O8: C, 67.94, H, 6.84, N, 4.53. Found: C, 67.49, H, 6.90, N, 4.41. Eiemplp 865 frans acid, fraA7S-2-r (3-propoxyphene-1-4- (1, 3-benzodioxol-5-yl) -1 - ((2,6- dethyl) phenylaminocarboni metip-pyrrolid) Na-3-carboxylic acid The title compound was prepared using the method of Example 30, by substitution of 1-bromopropane with 1-bromo-2-methoxyethane and methyl 3-hydrobenzoate ppr 4-hydrobenzoate. 1 H NMR (300 MHz, CDCI3) d, 1.02 (t, J = 7Hz, 3H), 1.08 (t, J = 7Hz, 6H), 1.75-1.87 (m, 2H), 2.43 (1, J = 7Hz, 4H), 3.02 (d, J = 11Hz, 1H), 3.09-3.20 (m, 3H), 3.48 -3.56 (m, 2H), 3.65-3.75 (m, 1H), 3.90 (t, J = 7Hz, 2H), 3.98 (d, J = 8Hz, 1H), 5.94 (dd, J = 2Hz, 4Hz, 2H), 6.75 (d, J = 8Hz, 1H), 6.80-6.89 (m, 3H), 6.98-7.05 (m, 2H), 7.10 ( d, J = 8Hz, 2H), 7.19-7.32 (m, 2H), 8.30 (s, 1H), MS APCI +) m / e 559 (M + H +), Anal.Cal, for C33H38N2O: C, 70.94, H, 6.86 M, 5.01 Found: C, 70.65 H, 6.63 N, 4.92 Example 866 Fra / is acid, R a / 7 S-2- (4- (2-methoxy) f in i I-4-H, 3-benzodioxol-5-yl) -1 - ((? / - 2,6-diethylphenyl) aminocarbonyl! Metip-pyrrolidine-3-) carbexyl Example 866a 5- (2-Methoxyethylbenzoic acid) A 50 ml 3-necked flask made to measure with two sections and a nitrogen balloon was added 800 mg (20 mmol) to 60% NaH was dispersed in mineral oil. The oil was removed by washing and decanted with hexanes (3 x 5 mL) of THF, the suspension was cooled on an ice bath, then a solution of 2.01 g (10.0 mmol) of 4-bromophenoethane in 5 mL of THF was added. via a cannula. The yarn bath was stirred and the mixture was stirred for 10 minutes, then 700 mL (11 mmol) of iodomethane were added. The mixture was stirred at room temperature for 1 hpra. Then 1 mL of H2O was added for the excess of NaH. The reaction was poured into 50 mL of H2O, then extracted with diethyl ether (3 x 20 mL). The combined ether layers were extracted in the dark with brine (1 x 20 mL), dried over MgSO 4, filtered and concentrated to 2.08 g (97%) of colorless oil. To a solution of 1.03 g (4.78 mmol) of above 4- (2-methoxy) ethylbromobenzene in 10 mL of THF was added 400 mg of magnesium turns, and a crystal of 12. The mixture was refluxed under N2 for 5 minutes, then cooled to room temperature. The Grignard reagent was transferred via a syringe into a 3-neck flask of 50 mL under N2. A CO2 balloon was opened over the reaction and quickly fed red to yellow. After stirring for 1 hour at room temperature, the reaction was concentrated in vacuo. The residue was taken up in 20 mL of H2O and acidified with 12M HCl to pH = 1, then extracted as diethyl ether (3 x 10 mL). The combined ether layers were extracted in the dark with 2M NaOH (3 x 5 mL), then the combined NaOH layers were extracted with diethyl ether (2 x 5 mL). The basic layers were treated with 12M HCl until pH = 1, then the product was extracted with ethyl acetate (2 x 5 mL). The combined ethyl acetate layers were extracted in the dark with brine (1 x 5 mL), dried over MgSO 4, filtered and concentrated to 427 mg (50%) of 4- (2-methoxy) ethylbenzoic acid as a solid yellow. The impurity of the yellow did not interfere with the no subsequent reaction. Example 866B f / -a / 7S acid, frar7S-2- (4- (2-methoxetim-4- (1,3-benzodioxol-5-M) -1 - ((? / - 2,6-diethylphenyl) aminocarboni Methyl) -pyridine-3-carboxylic acid Prepared according to the procedures of Example 1.

H-NMR (300 MHz, CDCl 3) d 1.00 (t, J = 7.5Hz, 6H), 2.40 (q, J = 7.5 Hz, 4H), 2.66 (t, J = 8.3 Hz, 1H), 2.79 (t, JP) = 6.8Hz, 2H), 2.87 (d, J = 15.6Hz, 1H), 3.00 (t, J = 9.2Hz, 1H), 3.20 (d, J = 15.9Hz, 1H), 3.24 (s, 3H), 3.42-3.47 (m, 1H), 3.53 (t, J = 6.9Hz, 1H), 3.60 (m, 1H), 3.91 (d, J = 9.5Hz, 1H), 5.94 (s, 2H), 6.76 (d) , J = 7.8Hz, 1H), 6.84 (dd, J = 1.4 Hz, 8.1Hz, 1H), 7.08 (d, J = 7.5Hz, 2H), 7.127 (d, J = 6.4Hz, 3H), 7.22 ( d, J = 1.4Hz, 1H), 7.51 (d, J = 8.1Hz, 2H), 9.21 (s, 1H) MS (CDI m / z) (M + H +) M Anal. Cale, for C33H38N2O6 «0.20 H3PO4: C, 68.54, H, 6.73, N, 4.84. Found: C, 68.28, H, 6.46, N, 4.82. EXAMPLE 867 Trans, trans-2- {3- (2-methoxy-ethoxy) -phenol- (3-benzodioxol-5-p-1- (2,6-diethylphenylaminocarbonylmethi) -pyr idine-3-carboxylic acid The title compound was prepared using the method of example 30 by substituting methyl 3-hydroxybenzoate for methyl 4-hydrobenzoate, 1 H NMR (300 MHz, CDCl 3) d 1.08 (t, J = 7Hz, 6H). , 2.43 (q, J = 7Hz, 4H), 3.00-3.20 (m, 3H), 3.42 (s, 3H), 3.50 (d, J = 11Hz, 1H), 3.53-3.59 (m, 1H), 3.65- 3.75 (m, 1H), 3.75 (t, J = 6Hz, 2H), 3.98 (d, J = 8Hz, 1H), 4.11 (t, J = 6Hz, 2H), 65.94 (dd, J = 2Hz, 4Hz, 2H), 6.75 (d, J = 8Hz, 1H), 6.80-6.89 (m, 3H), 7.05-7.10 (m, 2H), 7.20 (d, J = 8Hz, 2H), 7.19-7.32 (m, 2H) ), 8.30 (s, 1H) MS (APCI +) m / e 575 (M + H +) Anal.Cal, for C33H38N2O7: C, 68.97, H, 6.67, N, 4.87 Found: C, 58.78 H, 6.84 N, 472. EXAMPLE 868 Trans, trans-2 - (2- m ethi-4-prppoxyphen i I) 1-4-M, 3- benzodi oxo 1-5- D-1- (2 , 6-diphenylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid Example 858A (4-prop? I-2-methylbenzyl) acetatic acid ethyl ester 4-Hydroxy-2-methylacetophenone was reacted with 1-bromopropane and potassium carbonate in dimethylformamide to give 4-propoxy-2-methylacetophenone. This compound was reacted with diethyl carbonate, using the method described in Example 15B to provide the title compound. Example 868B Trans, trans-2- {3- (4- (1,3-benzodioxol-5-yl) -1- (2,6-diethylphenylaminocarbonylmethyl-pyrrolidine-3-carboxylic acid Prepared using the procedures described in Example 20 , using the compound of Example 868A as the starting material, 1 H-NMR (300 MHz, CDCl 3) d 1.02 (t, J = 7 Hz, 3 H), 1.08 (t, J = 7 Hz, 6 H), 1.75-1.85 (m, 2 H). ), 2.33 (s, 3H), 2.40-2.48 (q, J = 7Hz, 4H), 2.98 (d, J = 11Hz, 1H), 3.06-3.18 (m, 2H), 3.39 (d, J = 11Hz, 1H), 3.50-3.58 (m, 1H), 3.65-3.75 (m, 1H), 3.90 (t, J = 7Hz, 2H), 4.28 (d, J = 8Hz, 1H), 5.94 (dd, J = 2Hz , 4Hz, 2H), 6.70-6.88 (m, 5H), 7.08-7.25 (m, 3H), 7.48 (d, J = 8Hz, 1H), 8.28 (s, 1H) MS (APCI +) m / e 773 (M + H +) Anal Cale, for C34H5oN2O6: C, 70.56 H, 7.79 N, 4.33 Found: C, 70.16, H, 7.70 N, 4.26 Example 869 Fra /? S acid, fra /? S- 2- (4- (3-methoxy-propyl) phenyl-4- (1,3-benzodioxol-5-yl) -1- (T? -2,6-d.ethylphenylaminocarbonylmethio-pyrrolidine-3-carboxylic acid) Example 869A Acide 4- (3-methoxy-propylbenzoic acid) To a mixture of 10. Og (46.5 mmoles) of methyl 4-bromobenzoate, 325 mg (1.45 mmoles) of palladium (II) acetate, 15.1 g (51.0 mmoles) of tetrabutylammonium chloride and 13.7 g (140 mmol) of potassium acetate was added 200 mL of DMF.The mixture was degassed and filled in the dark with N2 twice, then 10 mL of allyl methyl ether was added. The reaction was stirred at 50 ° C for 6 hours, then at room temperature for 66 hours The reaction was monitored by CLF (20% ethyl acetate / hexanes) The additional Pd catalyst (319 mg) was added after this time, as some remaining bromoester After heating at 50 ° C under N2 for 2 hours, the reaction was poured into 1 liter of water, and this suspension was divided into two portions to facilitate heating. diethyl ether (3 x 100 mL), then each layer group was extracted in the dark with water (1 x 110 mL), saturated NaHCO3 solution (1 x 100 mL), and brine (1 x 100 mL), dried over MgSO4, filtered and concentrated in vacuo. The combined crude yield of methyl 4- (3-methoxy-1-propenyl) benzoate and methyl 4- (3-methoxy-2-propenyl) benzoate was 9.17 g. To a mixture of 8.57 g (41.6 moles) of the above and 400 mg of 10% of Pd-C were added 75 mL of THF. The mixture was stirred at room temperature under 1 atmosphere of H2 for 2 hours, then the catalyst was filtered and the solvent was removed in vacuo. Purification via 15% ethyl acetate / hexanes column gave 3.35 g (39%) of methyl 4- (3-methoxypropyl) benzoate as a colorless oil. This material was combined with 20 mL of 1.39M NaOH in 5: 1 ethanol: H2O. The reaction was refluxed for 30 minutes, then concentrated in vacuo. The residue was absorbed in 25 mL of H2O then 40 mL of 1M HCl was added. The mixture was drawn with diethyl ether (3 x 25 mL), then the combined ether layers were extracted in the dark with brine (1 x 25 mL), dried over MgSO 4, filtered and concentrated in vacuo to 3.03 g ( 97%) of 4- (3-methoxy) propylbenzoic acid as a white solid. Example 869 Fra n acid, rans-2- (4- (3-methoxy) propyl) phenyl-4- (1,3-benzodioxol-5-yl) -1 - ((γ) -2,6-diethylphenyl) aminocarbonyl ) methylpyrrolidine-3-carboxylic acid Prepared according to the procedures of Example 1. 1H-NMR (300 MHz, d6-DMSO) d 1.00 (t, J = 7.5Hz, 6H), 1.80 (m, 2H), 2.41 (1, J = 7.5Hz, 4H), 2.62 (t, J = 7.7Hz, 2H), 2.86 (t, J = 9.7Hz, 1H), 2.93 (d, J = 15.8Hz, 1H), 3.11 (t , J = 9.6Hz, 1H), 3.18 (d, J = 16.2Hz, 1H), 3.23 (s, 3H), 3.31-3.40 (m, 2H), 3.50 (m, 1H), 3.53 (m, 1H) , 3.95 (d, J = 9.9Hz, 1H), 5.98 (s, 2H), 6.80 (dd, J = 1.5Hz, 8.1Hz, 1H), 6.85 (dd, J = 1.5Hz, 8.1Hz, 1H), 7.10 (d, J = 7.0Hz, 2H), 7.18 (m, 3H), 7.28 (d, J = 1.5Hz, 1H), 7.53 (d, J = 8.1Hz, 1H), 9.28 (s, 1H); MS (CDI m / 1) (MH +). Anal. Cale, for C34H40N2O6 »0.05H3PO4: C, 70.70, h, 7.00, N, 4.85. Found: C, 70.68, h, 691, N, 4.52. As an indication of the compounds described herein that act through the binding of endothelin receptors, the compounds have been evaluated for their ability to exhibit endothelin from their receptor. ETR Receptor Binding Analysis Preparation of porcine cerebellum membranes: The portion cerebellum was homogenized in 25 volumes (w / v) of 10 mM Hepes (pH 7.4) containing 0.25M sucrose and prptease inhibitors (3 mM EDTA, 0.1 mM of PMSF and 5 ug / ml of Pepstantin A) for 3-10 seconds of polytron at 13,500 rpm with intervals of 10 seconds. The mixture was centrifuged at 1000xg for 10 minutes. The supernatant was recovered and centrifuged 30,000xg for 30 minutes. The precipitate was resuspended in pH A buffer (20 mM Tris, 100 mM NaCl, 10 mM MgCl 2, pH 7.4) containing the aforementioned protease inhibitors and again centrifuged. The final pellet was resuspended in buffer containing the protease inhibitors and stored at -80 ° C until used. The protein content was determined by Bio-Rad dye binding protein analysis. Binding of "125I1ET to membranes: Binding analysis was carried out in 96-well microtiter plates pretreated with 0.1% BSA.The membranes prepared from cells were diluted ~ 100-fold in buffer B (20 mM. mM of NaCI, 10 mM of MgCl2, pH 7.4, with 0.2% BSA, 0.1 mM of PMSF, 5 μg / mL of Pepstantin a, 0.025% of bacitracin and 3 mM of EDTA) at a final concentration of 0.2 mg / mL protein In the competition studies, the membranes (0.02 mg) were incubated with 0.1 nM of [12Sl] ET-3 in buffer B (final volume: 0.2 mL) in the presence of increasing concentrations of ET- 3 unlabelled or a purge compound for 4 hours at 25 ° C. After incubation, the unbound ligands were separated from bound ligands by a vacuum filtration method using glass fiber filter strips in cell cultures of PHD (Cambridge Technology, Inc., MA), followed by ppr washing the filtrp tips with saline (1 mL) d for three times. The specific np binding was determined in the presence of 1 μM ET-1. The datps are shown in Table 1. The pprcentual inhibition at a concentration of 1 μM is shown. LPS data show that the compounds of the invention bind to the endothelin receptor. Table 1 Junction Dips% inhibition of Example Inhibition ETB at μM Example ETB at 1 μM 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 28 97.2 29 94.7 30 97.4 858 98.3 859 95.6 860 93.0 861 96.7 862 92.8 863 92.7 864 96.3 865 92.1 866 92.0 867 93.5 868 96.1 869 98.9 The ability of the compounds of the invention at lower blood pressure can be demonstrated according to the methods described in Matsumura, et al., Eur. J. Pharmacol. 185 103 (1990) and Takata, et al., Clin. Exp. Pharmacol. Physiol. 1_0 131 (1983). The ability of the compounds of the invention to treat congestive heart failure can be demonstrated according to the method described in Margulies, et al., Circulation 82.2226 (1990). The ability of the compounds of the invention to treat myocardial ischemia can be demonstrated according to the method described in Watanabe et al., Nature 344 114 (1990). The ability of the compounds of the invention to treat coronary angina can be demonstrated according to the method described in Heistad et al., Circ. Res. 5_4711 (1984). The ability of the compounds of the invention to treat cerebral vasospasm can be demonstrated according to the methods described in Nakagomi, and others, J. Neurosurge. 66. 915 (1987) or Matsumura, et al., Life Sci. 49,841-848 (1991). The ability of the compounds of the invention to treat cerebral ischemia can be demonstrated according to the method described in Hara et al., European, J. Pharmacol, 197: 76-82, (1991). The ability of the compounds of the invention to treat watery renal failure can be demonstrated according to the methods described in Kon, et al., J. Clin. Invest. 83 1962 (1989). The ability of the compounds of the invention to treat chronic renal failure can be demonstrated according to the method described in Benigni, et al., Kidney Int. 44,440-444 (1993). The ability of the compounds of the invention to treat gastric ulceration can be demonstrated according to the method described in Wallace, and others, Am. J. Physipl. 256 G661 (1989). The ability of the compounds of the invention to treat cyclosporin-induced nephrotoxicity can be demonstrated according to the method described in Kon, and others Kidney Int. 37. 1487 (1990). The ability of the compounds of the invention to treat induced toxicity ppr endetpxine (check) can be assayed according to the method described in Takahashi, et al., Clinical Sci. 79619 (1990).

The ability of the compounds of the invention to treat asthma can be demonstrated according to the method described in Potvin and Varma, Can. J. Physiol, and Pharmacol. 67 1213 (1989). The ability of the compounds of the invention to treat arteriosclerosis induced by transplants can be demonstrated according to the method described in Foegh, et al., Atherosclerosis 78. 229-236 (1989). The ability of the compounds of the invention to treat arteriosclerosis can be demonstrated according to the methods described in Bobik, et al., Am. J. Physiol. 258 C408 (1990) and Chobanian, and others, Hypertension 1327 (1990). The ability of the compounds of the invention to treat lipoprotein disorders related to LPL can be demonstrated according to the method described in Ishida, et al., Biochem. Pharmacol. 44 1431-1436 (1992). The ability of the compounds of the invention to treat proliferative diseases can be demonstrated according to the methods described in Bunchman ET and CA Brookshire, Trnsplantation Proceed, 23967-968 (1991); Yamagishi, and others, Biochem. Biophys. Res. Cemm. 191 840-846 (1993); and Shichiri et al., J. Clin. Invest. 87 1867-1871 (1991). Proliferative diseases include smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythomasus, diabetic retinopathy or retinopathies, psoriasis, scleroderma, prosthetic hyperplasia, cardiac hyperplasia, restenosis followed by arterial damage or other pathological stenosis in blood vessels. The ability of the compounds of the invention to treat acute or chronic pulmonary hypertension can be demonstrated according to the method described in Bonvallet et al., Am. J. Physiol. 266 H 1327 (1994). Pulmonary hypertension may be associated with congestive heart damage, mitral valve stenosis, emphysema, lung fibrosis, obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), altitude sickness, chemical exposure or may be idiepathic. The ability of the methods of the invention to treat platelet aggregation and thrombosis can be demonstrated according to the method described in McMurdo et al. Eu J. Pharmacol. 259 51 (1994). The ability of the compounds of the invention to treat cancers can be demonstrated according to the method described in Shichiri, et al., J. Clin. Invest. 87 1867 (1991). The ability of the compounds of the invention to treat adenocarcinoma can be demonstrated according to the method described in Nelson, et al., Nature Medicine, 1_, (9), 944 (1995). The ability of the compounds of the invention to treat I L-2 (and other cytokines) mediated by cardiotoxicity and vascular permeability disorders can be demonstrated according to the method described in Klemm et al. Proc. Nat. Acad. Sci. 92. 2691 (1995).

The ability of the compounds of the invention to treat nociception can be demonstrated according to the method described in Yamamoto et al., J. Pharmacol. Exp. Therap. 271 156 (1994). The ability of the compounds of the invention to treat colitis can be demonstrated according to the method described in Hogaboam and bulls (EUR J. Pharmacol 1996, 309261-269). The ability of the compounds of the invention to treat reperfusion injury of ischemia in kidney transplantation is demonstrated according to the method described in Aktan et al. (Transplant Int 1996, 51, 12-27). The compounds of the present invention can be used in the form of salt flakes derived from inorganic or organic acids. These salts include, but are not limited to the following, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentaneprppipnat, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanpate, fumarate, hydrochloride, bromohydrate, iodohydrate, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocinate, p-toluenesulfonate and undecanoate, also the basic nitrogen-containing groups can be quaternized with said agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides, iodides, dialkyl sulfates similar to dimethyl, diethyl , dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stear chlorides ilo, bromides and iodides, alkyl halides similar to benzyl and phenethyl bromides and others. The splubble and dispersible prpductcs in water and oil are thus obtained. Exemplary 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 basic addition salts can be prepared in situ during the final isolation and purification of the compounds of the formula (I), or separately by the reaction the function of the carboxylic acid with a suitable base such as hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or a primary, secondary or tertiary organic amine. Said pharmaceutically acceptable salts include, but are not limited to, cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as non-toxic ammonium, quaternary ammonium, amine cations , including, but not limited to ammonium, tetramethylammonium, tetramethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. Other representative organic amines useful for the formation of the base addition salts include dimethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

The compounds of the invention are useful for antagonizing endothelin in a human or other mammal. In addition, the compounds of the present invention are useful (in humans or other mammals) for the treatment of hypertension, acute or chronic pulmonary hypertension, Raynaud's disease, congestive heart failure, myocardial ischemia, reperfusion injury, coronary angina, cerebral ischemia. , cerebral vasospasm, chronic or acute renal failure, gastric ulceration induced by non-spheroidal anti-inflammatory drugs, cyclosporine-induced nephrotoxicity, endotoxin-induced toxicity, asthma, fibrotic or proliferative diseases, including smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver , adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prosthetic hyperplasia, cardiac hyperplasia, restenosis followed by arterial damage or other pathological retenosis of blood vessels. Lipoprotein disorders related to LPL, arteriosclerosis induced by transplantation or arteriosclerosis in general, platelet aggregation, thrombosis, cancers, adenocarcinoma, I L-2 and other cardiotoxicidas mediated by cytokine and permeability disorders, coli migraine and nociception. The daily dose administered to a host in a single or divided dose may be in amounts, for example, from 0.001 to 1000 mg / kg. of body weight daily and even more usually from 0.1 to 100 mg / kg. for oral administration or from 0.01 to 10mg / kg. for parenteral administration. The unit dose compositions may contain said submultiple amounts thereof to form a daily dose. The amount of active ingredient can be combined with carrier materials to produce a single dose which can vary depending on the host to be treated and the particular mode of administration. It should be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration , excretion regimen, drug combination and severity of the particular disease of the therapy. The compounds of the present invention can be administered orally, parenterally, sublingually, by dew inhalation, rectally or topically in unit dose formulations containing pharmaceutically acceptable non-toxic carriers, adjuvants and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral, as used herein, includes subcutaneous, intravenous, intramuscular, intrasternal injection, or infusion techniques.

Exemplary injectable preparations, sterile injectable aqueous or oleaginous suspensions may be formulated in accordance with the known method using dispersion or suitable wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable selution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution of 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspension medium. For this purpose any of soft fixed oil can be employed including mono or synthetic diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Suppositories for rectal administration of drug can be formed according to the known technique. The title compound can be prepared by mixing the drug with a suitable irritating np excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and therefore melt in the rectum and release the drug. Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose or starch lactose.

Said dosage forms also comprise, as a normal practice, additional substances differ from inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may comprise regulating solution agents. The tablets and pills can be further prepared with enteric coatings. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Said compositions may also comprise adjuvants, such as before emulsifying humectants and suspending agents and sweetening, flavoring and perfume agents. The compounds of the present invention can also be administered in liposome fprma. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by liquid crystals mono or multilayer hydrates that are dispersed in an aqueous medium. Any physiologically acceptable and non-toxic metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form may further contain a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.

Methods for forming liposomes are well known in the art. See, for example, Prescott, De., Methods in Cell Biology, Volume XIV. Academic Press, New York, N.Y. (1976), p. 33 et seq. A representative solid dosage form, e.g., a tablet or capsule, comprises: Compound of the invention: 35% w / w Starch, Pregelatinized, NF 50% w / w Microcrystalline Cellulose, NF 10% w / w TTaallccoo ,, ppoollvvoo ,, UUSSPP 5% w / w While the compounds of the invention can be administered as the sole active pharmaceutical agent, it can also be used in combination with one or more cardiovascular agents, independently selected from diuretics, adrenergic block agents, vaspdilatadpres, blpqueaderes of calcium channel, renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angietensin II antagonists, pptasip channel activators and other cardiovascular agents. Representative diuretics include hydrochlorothiazide, chlorithiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, metolazone, spironolactone, triamterone, chlorothalidone and the like or a pharmaceutically acceptable salt thereof. Representative adrenergic blocking agents include pentolaine, phenoxybenzamine, prozosin, tarazosin, tolazine, atenolol, metoprolol, nadolol, propanolol, timolol, carteolol and the like or a pharmaceutically acceptable salt thereof. Representative vasodilators include hydralazine, mixoxidilp, diazpxidp, nitrofrusid and the like p a pharmaceutically acceptable salt thereof. Representative calcium channel blockers include amrinone, benziclan, diltiazem, fendiline, flunarizine, nicardipine, nimodipine, perhexylene, verapamil, gallopamil, nifedipine and the like or a pharmaceutically acceptable salt thereof. Representative renin inhibitors include enalkiren, zakiren, RO 42-5892, PD-134672 and the like or a pharmaceutically acceptable salt thereof. Representative angiotensin II antagonists include DUP 753-A-81988 and the like. ACE inhibitors representativps include captcprilp enalapril, lysonopril and the like or a pharmaceutically acceptable salt thereof. Representative potassium activators include pinacidyl and the like or a pharmaceutically acceptable salt thereof. Other representative cardiovascular agents include sympatholytic agents such as methyldopa, clonidine, guanabenz, reseprin and the like or a pharmaceutically acceptable salt thereof. The compounds of the invention and the cardiovascular agent can be administered at the maximum recommended clinical dose or at lower doses. The dose levels of the active compounds in the compositions of the invention can be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient. The combination can be administered with separate compositions or as a single dose containing both agents. When administered as a combination, the therapeutic agents can be formulated with separate compositions that give at the same time or at different times or the therapeutic agents can give a single composition. The foregoing is merely illustrative of the invention and is not intended to limit the invention of the compounds, process, compositions and methods described. Variations and changes that are obvious to one skilled in the art will be understood to be within the scope and nature of the invention as defined in the appended claims.

Claims

CLAIMS 1. A compound of the formula: wherein R is - (CH2) mW where m is an integer number from 0 to 6 and W is (a) -C (O) 2 -G where G is hydrogen or a carboxy protecting group, (b) - PO3H2, (c) -P (O) (OH) E wherein E is hydrogen, lower alkyl or arylalkyl, (d) -CN, (e) -C (O) NHR17 wherein R17 is lower alkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy (j) alkoxy, (k) sulfonamido (I) -C (O) NHS (O) 2R? e wherein R16 is lower alkyl, haloalkyl, aryl or dialkylamino, (m) -S (O) 2NHC (O) R? ß wherein R16 is as defined above, Ri and R2 are independently selected from hydrogen, lower alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbyalkyl, aminocarbonylalkenyl, alkylaminocarbonyalkenyl, dialkylaminocarbyalkenyl, hydroxyalkenyl , aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic, (heterocyclic) alkyl and (Raa) (Rbb) N-Roc- where Raa is aryl or arylalkyl, R b is hydrogen or alkanoyl and R00 is alkylene, with the proviso that one or both of Ri and R2 are different from hydrogen; R3 is R4-C (O) -R5- or R6-S (O) 2-R7-, wherein R5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N ( R20) -R8- c-Rsa-N (R2o) -R8- wherein R8 and R8a are independently selected from the group consisting of alkylene and alkenylene; and R20 is hydrogen, lower alkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl or cycloalkylalkyl or (v) -O-R9- or -R9a-wherein R9 and R9a are independently selected from alkylene; R7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N (R2?) -R10- or -R? Or -N (R21) -R10-wherein R10 and R- IOA independently are selected from the group consisting of alkylene or alkenylene and R2? is hydrogen, lower alkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl; where R4 and R6 are (i) wherein Rn and R12 are independently selected from the group consisting of lower alkyl, cyano, alkoxy, halo, haloalkyl and phenyl and R13, R1 and R15 are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy, amino , alkoxy, aryl, heterocyclic, halo, carboxy, nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy, or cyano; or (ii) heterocyclic (amino), or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R3 is R -C (O) -R5, wherein R4 is as defined herein and R5 is alkylene or R3 is R6-S (O) 2-R7 -, wherein R7 is alkylene and R6 is as defined herein.
3. The compound according to claim 1, wherein R is -C (O) 2 -G- wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is -C (O) -NHS (O ) 2R6 where R16 is lower alkyl, haloalkyl or aryl, Ri and R2 independently are selected from (i) lower alkyl, (ii) cycloalkyl, (iii) substituted or unsubstituted aryl and (iv) substituted or unsubstituted heterocyclic , and R3 is R -C (O) -R5- wherein R4 is as defined herein and R5 is alkylene or R3 is R6-S (O) 2-R7-, wherein R7 is alkylene and R6 is as It was defined in the present.
4. The compound according to claim 1, wherein: R is -C (O) 2-G, wherein G is hydrogen or a carboxy, tetrazolyl or -C (O) -NHS (O) 2R16 protecting group in where R 6 is lower alkyl, haloalkyl or aryl, Ri is (i) alkoxyalkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furanyl or (vi) 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 3- fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) phenyl, -hydroxyphenyl, 1,3-benzodioxolyl, 4-benzodioxanyl or dihydrobenzofuranyl substituted or unsubstituted, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy,R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-m-ethoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl substituted or unsubstituted and R3 is R -C (O) -Rd-, wherein R is as defined herein and R5 is alkylene or R3 is R6-S (O) 2-R7-, wherein R is alkylene and R6 it is as defined in the present.
5. The compound according to claim 1, wherein: R is -C (O) 2-G, wherein G is hydrogen or a carboxy, tetrazolyl or -C (O) -NHS (O) 2R16 protecting group in where R16 is lower alkyl, haloalkyl or aryl, Rt is selected from the group consisting of (i) alkoxyalkyl, (i) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furanyl or (vi) 4-methoxyphenyl , 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-penta fluoroethylphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxy phenyl, 3- fluoro-4-ethoxyphenyl, 3-fluoro-4-prppoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, - (2-isopropoxyethoxy) phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or substituted or unsubstituted dihydrobenzofuranyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is, 3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-b 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl substituted or unsubstituted and R3 is R4-C (O) -Rs-, wherein R4 is as defined in the present and R5 is alkylene.
6. The compound according to claim 1, wherein: R is -C (O) 2-G, wherein G is hydrogen or a carboxy, tetrazolyl or -C (O) -NHS (O) 2R? 6 protecting group in where R16 is lower alkyl, haloalkyl or aryl, Ri is 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 2-fluoro-4- ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl substituted or unsubstituted, wherein the substituent is selected from alkoxy , alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl od substituted or unsubstituted ifluorophenyl and R3 is R -C (O) -R5-, wherein R4 is as defined herein and R5 is alkylene. The compound according to claim 1, wherein: R is -C (O) 2-G, wherein G is hydrogen or a carboxy protecting group, Ri is 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethyl phenyl, 2-f Ioro-4-ethoxy phenyl, 3-fluoro-4-methoxy and phenyl, 3-fluoro-4-ethoxyphene , 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or substituted or unsubstituted dihydrobenzofuranyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy- 1, 3-benzodioxolyl, 1,4-benzodioxanil, 8-m ethoxy-1,4-benzodioxanil, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl substituted or unsubstituted and R3 is R4-C (O) - R5-, in do Nde R4 is wherein R n and R 2 independently are selected from lower alkyl and R 13, R -? and R15 independently are selected from the group consisting of hydrogen, lower alkyl, hydroxy, amino, alkoxy, aryl, heterocycle, halo, carboxy, nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy or cyano and R5 is alkylene. 2. 9. The compound according to claim 1, wherein: R is -C (O) 2-G, wherein G is hydrogen or a carboxy protecting group, R ^ is 4-methoxyphenyl, 4-fluorophenyl, 3- fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethyl phenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxy phenyl, 3-fluoro-4-ethoxyphenyl, -fluprp-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or substituted or unsubstituted dihydrobenzofuranyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3 -benzodioxolyl, 1,4-benzodioxanil, 8-methoxy-1,4-benzodioxanil, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl substituted or unsubstituted and R3 is R -C (O) -R5-, where R 4 is wherein Rn and R12 are independently selected from lower alkyl and R13, R14 and R5 independently are selected from the group consisting of hydrogen, lower alkyl, hydroxy, amino, alkoxy, aryl, heterocycle, halo, carboxy, nitro, alkylsulfonyl, aryisulfonyl , thioalkoxy, thioaryloxy or cyano and R 5 is alkylene. 9. The compound according to claim 1, wherein: R is -C (O) 2-G, wherein G is hydrogen or a carboxy protecting group, Rt is 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4- propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- (2-methoxy ethoxy) f enyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) phenyl, 4- hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or substituted or unsubstituted dihydrobenzofuranyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl substituted or unsubstituted and R3 is R4-C (O) -R5-, where R4 is wherein R n and R 12 are independently selected from methyl, ethyl and isopropyl and R 3, R 14 and R 15 independently are selected from the group consisting of hydrogen, lower alkyl, hydroxy, amino, alkoxy, aryl, heterocycle, halo, carboxy, nitro , alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy or cyano and R5 is alkylene. The compound according to claim 1, wherein: R is -C (O) 2-G, wherein G is hydrogen or a carboxy protecting group, Ri is 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethyl phenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro- 4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) phenyl, 4- hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl substituted or unsubstituted, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl substituted or not substituted and R3 is R4-C (O) -R5-, wherein R4 is wherein RM and R12 are independently selected from methyl, ethyl and isopropyl and R13, R14 and R15 are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy, amino, alkoxy, aryl, heterocycle, halo, carboxy, nitro, alkylsulfonyl , arylsulphonyl, thioalkoxy, thioaryloxy or cyano and R5 is methylene. 11. The compound according to claim 1 of the formula wherein R is - (CH2) mW where m is an integer number from 0 to 6 and W is (a) -C (O) 2 -G where G is hydrogen or a carboxy protecting group, (b) - PO3H2, (c) -P (O) (OH) E wherein E is hydrogen, lower alkyl or arylalkyl, (d) -CN, (e) -C (O) NHR-? wherein R17 is lower alkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy (j) alkoxy, (k) sulfonamido (I) -C (O) NHS (O) 2R16 wherein R16 is lower alkyl, haloalkyl, aryl or dialkylamino, (m) -S (O) 2NHC (O) Ri6 wherein R16 is as defined above, Ri and R2 are independently selected from hydrogen, lower alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbyalkyl, aminocarbonylalkenyl, alkylaminocarbyalkenyl, dialkylaminocarbonylalkyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic, (heterocyclic) alkyl and (Raa) (Rbb) N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of Rt and R2 are different from hydrogen; R3 is R4-C (O) -R5- or R6-S (O) 2-R7-, wherein R5 is (i) a covalent bond, (ii) alkylene, (ii) alkenylene, (iv) -N (R20) -R8- or -R8g-N (R2o) -R8- wherein R8 and R8a are independently selected from the group consisting of alkylene and alkenylene; and R20 is hydrogen, lower alkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl or cycloalkylalkyl or (v) -O-R9- or -R9a- wherein R9 and R9a are independently selected from alkylene; R7 is (i) a covalent bond, (i) alkylene, (iii) alkenylene or (iv) -N (R2?) -R10- or -R? Or -N (R21) -R? O-wherein R10 and RIOA independently are selected from the group consisting of alkylene or alkenylene and R2? is hydrogen, lower alkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl; where R and R6 are (i) wherein Rn and R12 are independently selected from the group consisting of lower alkyl, cyano, alkoxy, halo, haloalkyl and phenyl and R13, R14 and R15 are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy, amino , alkoxy, aryl, heterocyclic, halo, carboxy, nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy, or cyano; or (ii) heterocyclic (amino), or a pharmaceutically acceptable salt thereof. The compound according to claim 11, wherein R3 is R4-C (O) -R5, wherein R4 is as defined herein and R5 is alkylene or R3 is R6-S (O) 2-R -, wherein R7 is alkylene and R6 is as defined herein. The compound according to claim 11, wherein R is -C (O) 2 -G- wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is -C (O) -NHS (O ) 2R6 where R16 is lower alkyl, haloalkyl or aryl, Ri and R2 independently are selected from (i) lower alkyl, (ii) cycloalkyl, (iii) substituted or unsubstituted aryl and (iv) substituted or unsubstituted heterocyclic , and R3 is R -C (O) -R5- wherein R4 is as defined herein and R5 is alkylene or R3 is R6-S (O) 2-R7-, wherein R is alkylene and R6 is as It was defined in the present. 14. The compound according to claim 11, wherein: R is -C (O) 2-G, wherein G is hydrogen or a carboxy, tetrazolyl or -C (O) -NHS (O) 2R? 6 protecting group in where R16 is lower alkyl, haloalkyl or aryl, Ri is (i) alkoxyalkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furanyl or (vi) 4-methoxyphenyl, 4-fluorophenyl, 3- fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro -4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) f enyl, 4-hydroxyphenyl, 1,3-benzodiox- yl, 1,4-benzodioxanyl or dihydrobenzofuranyl substituted or unsubstituted, wherein the substituent is selected from alkoxy, alkoxy alkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl substituted or not substituted and R3 is R4-C (O) -R5-, wherein R is as defined herein and R5 is alkylene or R3 is R6-S (O) 2-R-, wherein R is alkylene and R6 is as defined in the present. 15. The compound according to claim 11, wherein: R is -C (O) 2-G, wherein G is hydrogen or a carboxy, tetrazolyl or -C (O) -NHS (O) 2R? 6 protecting group wherein R16 is lower alkyl, haloalkyl or aryl, RT is selects from the group consisting of (i) alkoxyalkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, (v) furanyl or (vi) 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-iopropoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 2-fluoro-4-ethoxyphenyl, 3-f Ioro-4-methoxy phenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4- propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) phenyl, 4-hydroxyphenyl, , Substituted or unsubstituted 3-benzodioxolyl, 1,4-benzodioxanil or dihydrobenzofuranyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1, 4-benzodioxanil, 8-m ethoxy-1,4-benzodioxanil, dihydrobenzof uranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl substituted or unsubstituted and R3 is R4-C (O) -R5-, wherein R4 is as defined herein and R5 is alkylene. 16. The compound according to claim 11, wherein: R is -C (O) 2-G, wherein G is hydrogen or a carboxy, tetrazolyl or -C (O) -NHS (O) 2R protecting group? 6 wherein R- | 6 is lower alkyl, haloalkyl or aryl, RT is 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, -fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- ( 2-methoxy ethoxy) f enyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl substituted or unsubstituted, in where the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-m ethoxy -1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl , 4-methoxyphenyl, dimethoxyphenyl, fluo substituted or unsubstituted rofenyl or difluorophenyl and R3 is R4-C (O) -R5-, wherein R is as defined herein and R5 is alkylene. 17. The compound according to claim 11, wherein: R is -C (O) 2-G, wherein G is hydrogen or a carboxy protecting group, Ri is 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4- propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-propoxyethoxy) phenyl, 4-hydroxyphenyl, 1, 3-benzodioxolyl, 1,4-benzodioxanyl or substituted or unsubstituted dihydrobenzofuranyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is, 3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1, 4-benzodioxanil, 8-m ethoxy-1,4-benzodioxanil, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl substituted or unsubstituted and R3 is R4-C (O) -R5-, wherein R4 is s wherein R-n and R12 independently are selected from lower alkyl and R13, R14 and R15 are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy, amino, alkoxy, aryl, heterocycle, halo, carboxy, nitro, alkylsulfonyl, aryisulfonyl, thioalkoxy, thioaryloxy or cyano and R5 is alkylene. The compound according to claim 11, wherein: R is -C (O) 2-G, wherein G is hydrogen or a carboxy protecting group, Ri is 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethyl phenyl, 2-fluoro-4-ethoxyphenyl, 3-f Io-4-methoxy phenyl, 3-phenyl-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) phenyl , 4-hydroxyphene, 1,3-benzodioxolyl, 1,4-benzodioxanyl or substituted or unsubstituted dihydrobenzofuranyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1, 3-Benzodioxolyl, 1,4-benzodioxanil, 8-m ethoxy-1,4-benzodioxanil, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl substituted or unsubstituted and R3 is R -C (O) -R5- , in where R is wherein R n and R 2 independently are selected from lower alkyl, alkoxy and halo, and R 13, R 14 and R 15 independently are selected from the group consisting of hydrogen, lower alkyl, hydroxy, amino, alkoxy, aryl, heterocycle, halo, carboxy , nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy or cyano and R5 is alkylene. 19. The compound according to claim 11, wherein: R is -C (O) 2-G, wherein G is hydrogen or a carboxy protective group, RT is 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-iopropoxyphenyl, -trifluoromethylphenyl, 4-pentafluoroethyl phenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2 -fluorophenyl, 4-methoxymethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) phenyl, 4-hydroxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or substituted or unsubstituted dihydrobenzofuranyl, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1, 4-benzodioxanil, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl substituted or unsubstituted and R3 is R -C (O) -R5-, where R is wherein Rn and R12 are independently selected from methyl, ethyl and isopropyl and R 3, R 14 and R 15 independently are selected from the group consisting of hydrogen, lower alkyl, hydroxy, amino, alkoxy, aryl, heterocycle, halo, carboxy, nitro, Alkylsulfophenyl, arylsulfonyl, thioalkoxy, thioaryloxy or cyano and R 5 is alkylene. The compost according to claim 11, wherein: R is -C (O) 2-G, wherein G is hydrogen or a carboxy protective group, RT is 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 2-fluoro-4-ethoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 3-fluoro-4- propoxyphenyl, 3-methoxy-4-propoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- (2-methoxyethoxy) phenyl, 4- (2-ethoxyethoxy) phenyl, 4- (2-isopropoxyethoxy) phenyl, 4-hydroxyphenyl, 1, 3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl substituted or unsubstituted, wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl substituted or not substituted and R3 is R4-C (O) -R5-, wherein R4 is wherein R n and R 2 are independently selected from methyl, ethyl and isopropyl and R 13, R 4 and R 15 independently are selected from the group consisting of hydrogen, lower alkyl, hydroxy, amino, alkoxy, aryl, heterocycle, halo, carboxy , nitro, alkylsulfonyl, arylsulfonyl, thioalkoxy, thioaryloxy or cyano and R5 is methylene. 21. A compound is selected from the group consisting of fra / 7s, fra / 7s-2- (4-Methoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6- diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, fra / 7s, fra / 7s-2- (4-Propoxyphenyl) -4- (, 3-benzodioxol-5-yl) -1 - ((2 , 6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans-acid, frar / s-2- (3-IFo-4-methoxy-en-yl) -4- (1,3-benzodioxol-5-) il) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, tra ns-2- (3-Fluoro-4-ethoxy-enyl) -4- (1, 3- benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans acid, fra / 7S-2- (3-Fluoro-4-methoxy-en-1) -4- (7-methoxy-1 -3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, trans-2- (3- m -toxy-4- p ro poxif en il) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethylphenyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, rra / 7S, RRA /? s-2- (4-ethoxyphenyl) -4- (, 3-benzodioxol-5-yl) -1 - ((2, 6-diethylphenyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans, fra / 7S-2- (4-methoxy-enyl) -4- (1,3-benzodioxol-5-yl) -1- ( (2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, fra / 7s, fra / 7S-2- (4-propoxyphenyl) -4- (7-methoxy-1,3-benzodioxol-5-yl) ) -1 - ((2, 6-d ieti I) nylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, fraps, ura7s-2- (3-methoxy-4-propoxyphenyl) -4- (7-methoxy-1, 3-benzodioxol-5-yl) -1 - ((2,6-diethylphenyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, / -2 / "" - 3r "?, /"? S / -2- (4 Methoxyphenyl) -4- (1,3-benzodoloxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, Jf2 -5f?, /;? S72- (4-Propoxyphenyl) -4- (1,3-benzodoloxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid (2 / " ? -3R, / "? S -2- (4-ethoxypheni) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid , trans acid, rraA7S-2- (4-isopropoxy in yl) -4- (1,3-benzodioxol-5-yl) -1- (2,6-diethyl Ifenylamide and nocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans acid, trans-2- (2-f urea-4-propoxy in en) -4- (1,3-benzodioxol-5-yl) -1- (2,6-diethylphenylaminocarbonylmethyl) -pyrrolidin-3 -carboxylic acid, trans acid, uraps-2- (4- (2-methoxyethoxy) phenyl) -4- (1,3-benzodioxol-5-yl) -1- (2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxyl Co, trans acid, trans-2-. {4- (2-ethoxyethoxy) f in yl) -4- (1,3-benzodioxol-5-yl) -1- (2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine -3-carboxylic acid, [2R-3R, f? S / -2- (4- (2-Methoxyethoxy) phenyl) -4- (1,3-benzodioxol-5-yl) -1- (2,6- diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, acid * 2 -3R, RS7-2- (4- (2-Ethoxyethyl) oxy) phenyl) -4- (1,3-benzodioxol-5-yl) -1- (2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, trans acid, t ra / 7S-2- (4- (2-iso-propoxy ethoxy) f en yl) -4- (1,3-benzodioxol-5-yl) -1- (2,6-diethylphenylaminocarbcnilmethyl) -pyrrplidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof . 22. A compound of claim 21, wherein said compound is acid rans, ura / 7s-2- (4-Propoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6 -diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof. 23. A compound of claim 21, wherein said compound is 2 / "? - 3r"? / "? Sy2- (4-Methoxyphenyl) -4- (1,3-benzodioxol-5-yl) - acid. 1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof 24. A compound of claim 21, wherein said compound is acid / "2"? -3f " ?, r "? Sy2- (4-Propoxyphenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethyl) phenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, or A pharmaceutically acceptable salt thereof thereof 25. A compound of claim 21, wherein the compound is / 2"? - 3 /"?, / '? S7-2- (4-ethoxy-phenyl) -4- (1,3-benzodioxol-5-yl) -1 - ((2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof) 26. A compound of claim 21, wherein said compound is trans, fra / 7s-2- (4-methoxyethoxy) phenyl) -4- (1,3-benzodioxol-5-yl) -1- (2,6-diethylphenylaminocarbonylmethyl) -pyrrolidine-3-carboxylic acid , or a salt pharmaceutically acceptable thereof. 27. A pharmaceutical composition for antagonizing endothelin comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. 28. A pharmaceutical composition for antagonizing endothelin comprising a therapeutically effective amount of the compound of claim 11 and a pharmaceutically acceptable carrier. 29. A method for antagonizing endothelin which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1. 30. A method for antagonizing endothelin which comprises administering to a mammal in need of such treatment an amount Therapeutically effective of a compound of claim 1. 31. A method for treating hypertension, congestive heart failure, restenosis followed by arterial, cerebral, myocardial ischemia or arterioclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1. 32. A method for treating hypertension, congestive heart failure, restenosis followed by arterial, cerebral, myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 11. 33. A method to treat coronary angina, cerebral vasospasm, acute and chronic pulmonary hypertension, watery and chronic renal failure, gastric ulceration, cyclosporine-induced nephrotoxicity, toxicity induced by endotoxicity, asthma, LPL-related lipoprotein disorders. Fibrotic or proliferative diseases, platelet aggregation, trpmbosis, ppr IL-2 mediated cardiotoxicity, npciception, cclitis, vascular permeability disorder, reperfusion injury of ischemia, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy , lupus erythematosus, diabetic retinopathy or other renopathies, psoriasis, scleroderma, prosthetic hyperplasia, cardiac hyperplasia, Raynaud's disease, cancers, adenocarcinomas, angina, transplant-induced arteriosclerosis, and migraine which comprises administering to a mammal in need of said treatment an amount Therapeutically effective of a compound of claim 1. 34. A method for treating coronary angina, cerebral vasospasm, acute and chronic pulmonary hypertension, acute and chronic renal failure, gastric ulceration, cyclosporine-induced nephrotoxicity, toxicity induced by endotoxicity, asthma, ipoproteinics related to LPL. Fibrotic or proliferative diseases, platelet aggregation, thrombosis, I-L-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorder, ischemia reperfusion injury, symmetric sclerosis, liver cirrhosis, adult respiratory distress syndrome, cardiomyopathy idiopathic, lupus erythematosus, diabetic retinopathy or other renopathies, psoriasis, scleroderma, prosthetic hyperplasia, cardiac hyperplasia, Raynaud's disease, cancers, adenocarcinomas, angina, atherosclerosis induced by transplants, and migraine which comprises administering to a mammal in need of said treatment a Therapeutically effective amount of a compound of claim 11. 35. A method for treating hypertension, congestive heart failure, restenosis followed by arterial damage, cerebral or myocardial ischemia or arteriosclerosis comprising administering to a mammal in need of such treatment a therapeutic amount. effective composition of a compound of claim 1, in combination with one or more cardiovascular agents. 36. A method for treating hypertension, congestive heart failure, restenosis followed by arterial damage, cerebral or myocardial ischaemia or arteriosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1, in combination with one or more cardiovascular people.