CA2297894A1 - Pyrrolidine-3-carboxylic acid derivatives and their use as endothelin antagonists - Google Patents

Pyrrolidine-3-carboxylic acid derivatives and their use as endothelin antagonists Download PDF

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CA2297894A1
CA2297894A1 CA002297894A CA2297894A CA2297894A1 CA 2297894 A1 CA2297894 A1 CA 2297894A1 CA 002297894 A CA002297894 A CA 002297894A CA 2297894 A CA2297894 A CA 2297894A CA 2297894 A1 CA2297894 A1 CA 2297894A1
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loweralkyl
hydrogen
aryl
haloalkyl
methoxyphenyl
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Inventor
Martin Winn
Steven A. Boyd
Charles W. Hutchins
Hwan-Soo Jae
Andrew S. Tasker
Thomas W. Von Geldern
Jeffrey A. Kester
Bryan K. Sorensen
Bruce G. Szczepankiewicz
Kenneth J. Henry
Gang Liu
Steven J. Wittenberger
Steven A. King
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Abbott Laboratories
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
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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

DEMANDES OU BREVETS VOLUMINEUX
L.A PRESENTS PARTiE DE CETTE DEMANDS OU CE BREVET
COMPREND PLUS 17'UN TOME_ CECI EST LE TOME ~ DE
NOTE. Pour les tomes additionels, veuiilez contacter !e Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THiS SECTION OF THE APPLICAT10N/PATENT CONTAINS MORE
THAN ONE VOLUME
. THtS tS VOLUME L ~ OF
NOTi': For additional volumes-phase contact the Canadian Patent Office . i' ENDOTHELIN ANTAGONISTS
This is continuation-in-part application of U.S. patent application s Serial No. 081905,913, filed August 4, 1997 which is a continuation-in-part of U.S. patent application Serial No. 08/794,50fi, filed February 4, 1997 which is a continuation-in-part of U.S. patent application Serial No. 08/600,625, filed February 13, 1996, which is a continuation-in-part of U.S. patent application Serial No. 08/497,998, filed August 2, i o 1995, which is a continuation-in-part of U.S. patent application Serial No. 08/442,575, filed May 30, 1995, which is a continuation-in-part of U.S. patent application Serial No. 08/334,717, filed November 4, 1994, which is a continuation-in-part of U.S. patent application Serial No.
08/293,349, filed August 19, 1994.
Technical Field The present invention relates to compounds which are endothelia antagonists, processes for making such compounds, synthetic intermediates employed in these processes and methods and 2o compositions for antagonizing endothelia.
Background of the invention Endothelia (ET) is a 21 amino acid peptide that is produced by endothelial cells. ET is produced by enzymatic cleavage of a Trp-Val 25 bond in the precursor peptide big endothelia (Big ET). This cleavage is caused by an endothelia converting enzyme (ECE). Endothelia has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility i n vitro, stimulate mitogenesis in vascular smooth muscle cells in vitro, ao contract non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in vi ro, increase airway resistance i n viv , induce formation of gastric ulcers, stimulate release of atrial natriuretic factor i n vitro and i n vivo, increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release 3s of renin i n vitr and stimulate release of gonadotropins i n vi ro.
It has been shown that vasoconstriction is caused by binding of endothelia to its receptors on vascular smooth muscle (Nature 3 2 411 (1988), FEBS Letters x,31 440 (1988) and Biochem. Biophys. Res.
Commun. 1 54 868 (1988)). An agent which suppresses endothelia production or an agent which binds to endothelia or which inhibits the binding of endothelia to an endothelia receptor will produce beneficial s effects in a variety of therapeutic areas. In fact, an anti-endothelia antibody has been shown, upon intrarenal infusion, to ameliorate the adverse effects of renal ischemia on renal vascular resistance and glomerular filtration rate (Kon, et al., J. Clin. Invest. 83 1762 (1989)).
In addition, an anti-endothelia antibody attenuated the nephrotoxic o effects of intravenously administered cyclosporin (Kon, et al., Kidney Int. 37 1487 {1990)) and attenuated infarct size in a coronary artery ligation-induced myocardial infarction model (Watanabe, et al., Nature 344 114 (1990)).
Clozel et al. (Nature ~5_: 759-761 (1993)) report that Ro 46-15 2005, a nonpeptide ET-A/B antagonist, prevents post-ischaemic renal vasoconstriction in rats, prevents the decrease in cerebral blood flow due to subarachnoid hemorrhage (SAH) in rats, and decreases MAP in sodium-depleted squirrel monkeys when dosed orally. A similar effect of a linear tripeptide-like ET-A antagonist, BQ-485, on arterial caliber 2o after SAH has also been recently reported (S.Itoh, T. Sasaki, K. Ide, K.
Ishikawa, M. Nishikibe, and M. Yano, Biochem. Biophys. Res. Comm. , 195:
969-75 (1993). These results indicate that agents which antagonize ETIET receptor binding will provide therapeutic benefit in the indicated disease states.
Agents with the ability to antagonize ET/ET receptor binding have been shown to be active in a number of animal models of human disease.
For example, Hogaboam et al (EUR. J. Pharmacoi. 1996, X09, 261-269), have shown that an endothelia receptor antagonist reduced injury in a rat model of colitis. Aktan et al (Transplant Int 1996, 9_, 201-207) have so demonstrated that a similar agent prevents ischemia-reperfusion injury in kidney transplantation. Similar studies have suggested the use of endothelia antagonists in the treatment of angina, pulmonary hypertension, Raynaud's disease, and migraine. (Ferro and Webb, Drugs 1996, 51,12-27).
35 Abnormal levels of endothelia or endothelia receptors have also been associated with a number of disease states, including prostate cancer (Nelson et al, Nature Medicine 1995, 1, 944-949), suggesting a rote of endothelin in the pathophysiology of these diseases.
Wu-Wong et al (Lfe Sciences 1996, 58, 1839-1847) have shown that both endothelin and endothelin antagonists bind tightly to plasma s proteins, e.g., serum albumin. This plasma protein binding can decrease the effectiveness with which the antagonists inhibit endothelin's action. Thus, endothelin antagonists with reduced plasma protein binding may be more effective than highly bound congeners.
~ o Disclosure of the Invention In accordance with the present invention there are compounds of the formula (I):
R2 Z~ ~ Ra N
~CH2)n R
R' (I) ~s wherein Z is -C(R18)(R19)-or -C(O)-wherein R18 and R1g are independently selected from hydrogen and loweralkyl;

n is 0 or 1;

R is -(CH2)m-W
wherein m is an integer from 0 to 6 and W is 20 (a) -C(O)2-G wherein G is hydrogen or a carboxy protecting gro up, (b) -P03H2, (c) -P(O){OH)E wherein E is hydrogen, loweralkyl or arylalkyl, (d) -CN, 2s (e) -C(O)NHR1 ~ wherein R~ 7 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, so (j) alkoxy, (k) sulfonamido, (I) -C(O)NHS(O)2R16 wherein R1s is loweralkyl, haloalkyl, ary l or dialkylamino, WO 99/06397 ' 4- PCTIUS98/15479 (m) -S(O)2NHC(O)R~6 wherein R16 is defined as above, Ho 0 NH

(n) O
s.S' O
(0) HO O
OH
~N
i (p) o , O
NH
O
(q) ° , .~~ N. o N
~~H
(r~ O , ~O
~S= O
N
(S) H
~N
~~-- CFs N
(t) ~ H , Or - ~ ~ NHS02CF3 (U) ;
i o R 1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl,. dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, afkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(R~b)N-Roy- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and R~~ is afkylene, with the proviso that one or both of R1 and s R2 is other than hydrogen;
R3 is (a) R4-C(O)-R5- , R4-R5a- ~ R4-C(O)- R5-N{Rs}- , Rs-S{O)2-R7_ or R26-S(O)-R27-wherein R5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R2o)-R8- or -R$a-N(R2o)-R8-wherein R8 and R8a are independently selected from the group consisting of alkylene and alkenylene and R2p is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyl or (v) -O-R9- or -R9a-O-R9- wherein Rg and Rga are 1 s independently selected from alkyiene;
R5a is (i) alkylene or (ii) alkenylene;
R7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R21 )-R~ o- or -R1 oa-N( R2~ )-R~ o- wherein R1 o and R 1 oa are independently selected from the group 2o consisting of alkylene and alkenylene and R21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl;
R4 and R6 are independently selected from the group consisting of 25 (i) (R11)(R12)N- wherein R11 and R12 are independently selected from ( 1 ) hydrogen, {2) loweralkyl, (3} haloalkyl, so (4) -alkoxyalkyl, (5} haloalkoxyalkyl, (6) alkenyi, (7) alkynyl, (8) cycloalkyl, 35 (9) cycloalkylalkyl, (10} aryl, (11) heterocyclic, (12) arylalkyl, (13) (heterocyclic)alkyl, { 14) hydroxyalkyl, ( 15) alkoxy, (16) aminoalkyl, (17) trialkylaminoalkyl, (18) aikylaminoalkyl, (19) dialkylaminoalkyl, and (20) carboxyalkyl, ~o (ii) loweralkyl, (iii) alkenyl, (iv) alkynyl, {v) cycloalkyl, (vi) cycloalkylalkyl, i5 (vii) aryl, (viii) aryialkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) aikoxyalkyl, 20 (xii) hydroxyalkyl, (x i i i ) haloalkyl, (xiv) haloalkenyl, (xv) haloalkoxyalkyl, (xvi) haloalkoxy, 25 (xvii) alkoxyhaloalkyl, (xviii) alkylaminoalkyl, (xix) dialkylaminoalkyl, (xx) alkoxy, and H
N \ R7a (XXI) wherein z is 0-5 and Rya is alkylene;
R26 is (i) loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy-substituted haloalkyl;
and R27 is aikylene or alkenylene;

(b) R22-O-C(O)-R23- wherein R22 a carboxy protecting is group or heterocyclic and R23 i) a covalent bond, is ( (ii) alkylene, (iii) alkenyleneor (iv) -N(R24)-R25-wherein R25 is afkylene and R24 is hydrogen or loweralkyl, (c) loweralkyl, (d} alkenyl, (e} alkynyl, (f) cycloalkyl, (g) cycloalkylalkyl, (h) aryl, ~s (i) arylalkyl, ( j ) aryloxyalkyl, (k) heterocyclic, (I) (heterocyclic)alkyl, (m) alkoxyalkyl, (n) alkoxyalkoxyalkyl, or (o) R13-C(O)-CH(R14}-wherein R13 is amino, alkylaminoor dialkylamino and is aryl or R~ 5-C(O)- wherein is amino, alkylamino R15 or dialkylamino;
or a pharmaceutically acceptable salt thereof.
A preferred embodiment of the invention is a compound of formula R2 Z~ ~ R3 N
R'~~~,. (CH2)n 3o R1 *rB

wherein the substituents -R2, -R and -R1 exist in a traps, traps relationship and Z, n, R, R1, R2, and R3 are as defined above.
Another preferred embodiment of the invention is a compound of s formula (I) or (II) wherein n is 0 and Z is -CH2-.
Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 1 and Z is -CH2-.
~ o Another preferred embodiment of the invention is a compound of formula (I) or (11) wherein n is 0, Z is -CH2-, and R3 is R4-C(O)-R5- , Rs-S(O)2-R~- or R26-S(O)-R27- wherein R4, R~, R6, R~, R26 and R2~ are as defined above.
7 s Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is alkoxyalkyl or alkoxyalkoxyalkyl.
A more preferred embodiment of the invention is a compound of 2o formula {I) or (II) wherein n is 0, Z is -CH2-, and R3 is R4-C(O)-R5-wherein R4 is (R1~){R12)N- as defined above and R5 is alkylene or R3 is R6-S(O)2-R~- or R26-S(O)-R27- wherein R7 is alkylene, R2~ is alkylene and R6 and R~6 are defined as above.
25 Another more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2- and R3 is R4-C(O)-N(R2o)-R$- or R6-S(O)2-N(R21)-Rio- wherein R8 and R1o are alkylene and R4, R6, R2o and R21 are defined as above.
so An even more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is. 0, R is tetrazolyi or -C(O)2-G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is ss -CH2-, R 1 and R2 are independently selected from (i) loweralkyl, (ii) cycloaikyl, (iii) substituted aryl wherein aryl is phenyl substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy, (iv) substituted or unsubstituted heterocyclic, (v) alkenyl, (vi} heterocyclic (alkyl), (vii) arylalkyl, (viii) aryloxyalkyl, (ix) (N-alkanoyl-N-alkyl)aminoalkyl and (x) alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5-wherein R4 is (R~1)(R12)N- wherein R~1 and R~2 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyciic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl, and R5 is alkylene; or R3 is R4-C(O)-N(R2p)-R$- or 1o R6-S(O)2-N(R21)-R1 o- wherein R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R6 is foweralkyl, haloalkyl, alkoxyaikyl, haloalkoxyalkyl, aryl or arylafkyl, R8 and R1 o are alkyiene and R2o and R21 are loweralkyl; or R3 is R6-S(O)2-R~- or R2s-S(O)-R2~-wherein R6 is loweralkyl or haloalkyl, R~ is alkylene, R26 is loweralkyl i s and R2~ is aikylene.
A yet more preferred embodiment of the invention is a compound of formula (i) or (il} wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R ~ 6 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 is (i) loweraikyl, (ii) alkenyl, (iii} alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methyiphenyl, 2s 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyi wherein the substituent is selected from alkoxy, so alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (x) arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alkyl)aminoalkyi, or (xiii) alkylsulfonyiamidoalkyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 35 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(O)-N(RZO)-R$- or R6-S(O)2-N(R21 )-R10- wherein R$ and R10 are alkylene, R2o and R21 are loweralkyl, R4 is foweraikyl, aryl, alkoxy, WO 99/06397 - 1 ~- PCT/US98/15479 alkylamino, aryloxy or arylalkoxy and R6 is loweralkyl, hafoalkyl, alkoxyalkyl, aryl or arylalkyl.
Another yet more preferred embodiment of the invention is a s compound of formula (I) or (II} wherein n is 0, R is -C(~)2-G wherein G
is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R~6 wherein R1s is loweralkyl, haloalkyl or aryl, Z is -CH2-, Ri is (i) loweralkyl, (ii) alkenyi, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl, ~ o (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fiuoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 1 ~ 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (x) arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 20 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R12)N-wherein R11 and R~ 2 are independently selected from loweralkyl, 2s haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl.
Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G
so is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2Rls wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 is (i) loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyl, (vi) aryl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, or (viii) alkyisulfonylamidoalkyl, R2 is substituted or ss unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or WO 99/06397 - ~ 1 - PCT/US98/15479 difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R~y)(R12)N- wherein R11 is loweralkyl and Rt2 is aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkyiaminoalkyl, or heterocyclic.
Another yet more preferred embodiment of the invention is a compound of formula (I) or {II) wherein n is 0, R is -C(O)2-G wherein G
is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 o is (i) loweralkyl, (ii) alkenyl, (iii) heterocyciic (alkyl), (iv) aryloxyalkyl, (v) arylalkyl, (vi) (N-alkanoyl-N-alkyl)aminoalkyl, or (vii) alkylsulfonylamidoalkyl,(vii) phenyl, or (ix) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-ffuorophenyl, i 5 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxoiyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 20 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-rnethoxyphenyf, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R6-S(O)2-N(R21)-Rio- wherein R1 fl is alkylene, R6 is loweralkyl, 25 haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl.
Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G
so is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R j6 wherein R16 is loweralkyl, haioalkyl or aryl, Z is -CH2-, R~
is (i) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyi, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl s5 o r 1,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy and alkoxyalkoxy, (ii} loweralkyl, (iii) alkenyl, {iv) *rB

heterocyclic (alkyl), {v) aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, (viii) alkyisulfonylamidoalkyl,or (ix) phenyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, s 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fiuorophenyl or difluorophenyl wherein the substituent is selected from loweralkyi, alkoxy and halogen and R3 is alkoxycarbonyl or R6-S(O)2-N{R21 }-R~ o- wherein R j o is alkylene, R6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R21 is ~ o loweralkyl, haloalkyl, alkoxyalkyl or haloaikoxyalkyl.
Another yet more preferred embodiment of the invention is a =
compound of formula (I} or (II) wherein n is 0, R is -C(O)2-G wherein G
is hydrogen or a carboxy protecting group, tetrazolyl or -C(O}-15 NHS(O)2R~6 wherein Ris is loweralkyl or haloalkyl, Z is -CH2-, R1 is loweralkyl,aikenyl, heterocyclic (allkyf), aryloxyalkyl, aryaikyi, aryl, (N-alkanoyl-N-alkyl)aminoalkyl" or alkylsulfonylamidoalkyl, and R3 is R4-C(O)-RS- wherein R5 is alkylene and R4 is (R~1)(R~2)N- wherein R1y and R~ 2 are independently selected from alkyl, aryl, hydroxyalkyl, 2o alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
A stilt more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)ZRy6 wherein 25 R~ 6 is loweralkyf or haloalkyl, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methyiphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyi, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodioxoiyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the so substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ii) foweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), (v) aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, (viii) alkylsulfonyfamidoalkyl,or (ix) phenyl, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-s~ methoxyphenyi, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C{O)-R5- wherein R5 is alkylene and R4 is (R~ 1 )(R~ 2)N- wherein WO 99/06397 - 'I 3- PCT/US98/15479 R 11 and R12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.
Another still more preferred embodiment of the invention is a s compound of formula (I) or (li) wherein n is 0, R is -C(O)2-G wherein G
is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R~6 is loweralkyl or haloalkyl, Z is -CH2-, R1 is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, arylalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkyisulfonylamidoalkyl, phenyl, or i o alkoxyalkyl, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(O)-R~- wherein R5 is alkylene and R4 is (R11 )(R12)N- wherein R11 and R12 are independently selected from foweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, 15 aminoalkyl, trialkylaminoalkyl, or heterocyclic.
A most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G
is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted 20 or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 2s is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyi or difluorophenyl and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R~1 and R~2 are independently selected from loweralkyl.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G
is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 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 and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is s (R11)(R~2)N- wherein R11 is loweralkyl and R12 is aryl.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G
is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted ~ o or unsubstituted 4-methoxyphenyl, 3-fluoro-4-rnethoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzadioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is i~ substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-~ ,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is 2o R6-S(O)2-N(R21)-Rio- wherein R1o is alkylene, R6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R21 is ioweraikyl, haloalkyl or alkoxyalkyl.
Another most highly preferred embodiment of the invention is a 2s compound of formula (!) or (ll) wherein n is 0, R is -C(O)2-G wherein G
is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or so dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl ss or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(O)-R~- wherein R5 is alkylene and R4 is (R11)(R~2)N- wherein R1 j is alkyl and R12 is selected from aryl, aminoalkyl, trialkyiaminoalkyl, and heterocyciic.
Another most highly preferred embodiment of the invention is a s compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G
is hydrogen or a carboxy protecting group, Z is -CH2-, R~ is loweralkyi,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyi, or alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R~2)N- wherein R1 ~
i o and R12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R11 and Ry2 is alkyl.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is R4-C(O)-R5- wherein R4 is (R1i)(R12)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a 2o compound of formula (() or (II) wherein n is 0, Z is -CH2-, R~ is loweralkyl, and R3 is R4-C(O)-RS- wherein R4 is (R11)(R12)N- as defined therein and R~ is alkylene.
Another most highly preferred embodiment of the invention is a 25 compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R1 is alkenyl, and R3 is R4-C(O)-R~- wherein R4 is (R~1)(R~2)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a so compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R~ is heterocyclic (alkyl), and R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N-as defined therein and R~ is alkylene.
Another most highly preferred embodiment of the invention is a 3s compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R1 is aryloxyalkyl, and R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N- as defined therein and R~ is alkylene.

WO 99/46397 1 6 PCTlUS98/15479 Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R~ is arylalkyl, and R3 is R4-C(O)-Rs- wherein _R4 is (R11)(R12)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R1 is aryl, and R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N- as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R~ is (N-alkanoyi-N-alkyl)aminoalkyl, and R3 is R4-C(O)-R5- wherein R4 is ~s (R11)(Ry2)N- as defined therein and RS is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CHZ-, R1 is alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5- wherein R4 is 2o (R11)(R~2)N- as defined therein and R~ is alkylene.
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 inventian also relates to a method of antagonizing endothelia in a mammal (preferably, a human) in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or (tl).
The invention further relates to endothelia antagonizing compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of 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 WO 99106397 1 7 ~ PCTJUS98/15479 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, Pure Appl. Chem. (1976) 45, 13 - 30.
The term "carboxy protecting group" as used herein refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis"
pp. 152-188 (1981 ), which is hereby incorporated herein by reference.
In addition, a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo , for example by enzymatic hydrolysis, to release the biologically active parent. T.
Higuchi and V. Stella provide a thorough discussion of the prodrug y 5 concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S.
Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference. Such carboxy protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin 2o fields, as described in U.S. Pat. No. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference.
Examples of 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 2s Press, New York (1987), which is hereby incorporated herein by reference. Representative carboxy protecting groups are C~ to C8 alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl;
cycioalkyl and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives so thereof such as cyclohexylmethyi, cylcopentylmethyl 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-indanyl and the like;
as dialkylaminoalkyl (e.g., dimethylaminoethyl and the like);
alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1-WO 99/06397 - 1$- PCTlUS98/15479 (propionyloxy)-1-ethyl, 1-(pivaloyloxyl)-1-ethyl, 1-methyl-1-(propionyloxy)-1-ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, s cyclopentyfcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2-benzylcarbonyioxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-~o methoxycarbonyl-1-ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1-ethoxycarbonyloxy-1-ethyl, 1-cyclohexyloxycarbonyloxy-1-ethyl and the like;
alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and 15 the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like;
dialkyfaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, 2o diethyiaminocarbonylmethyl and the like; (5-(loweralkyl)-2-oxo-1 ,3-dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-1,3-dioxolen-4-y1)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 2s refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," {John Whey & Sons, New York (1981 )), which is hereby ao incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaioyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichioroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like;
ss sulfonyl groups such as benzenesulfonyl, p-tofuenesulfonyl and the like;
carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, s 2-vitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyi, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, 1 o ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, 7 5 triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyf, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The term "alkanoyl" as used herein refers to an alkyl group as 2o previously defined appended to the parent molecular moiety through a carbonyl (-C(O)-) group. Examples of alkanoyl include acetyl, propionyl and the like.
The term "alkanoylamino" as used herein refers to an alkanoyl group as previously defined appended to an amino group. Examples alkanoylamino include acetamido, propionylamido and the like.
The term "alkanoylaminoalkyl" as used herein refers to R43-NH-R44- wherein R43 is an alkanoyl group and R44 is an alkylene group.
The term "alkanoyloxyalkyl" as used herein refers to Rgp-O-R3i-so wherein R3p is an alkanoyl group and R3~ is an alkylene group. Examples of alkanoyloxyalkyl include acetoxymethyl, acetoxyethyl and the like.
The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. Alkenyl groups ss include, for example, vinyl (ethenyl), allyi (propenyl), butenyl, 1-methyl-2-buten-1-yl and the like.

WO 99/06397 - 2 ~ - PCT/US98/15479 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-, -s CH2CH=CHCH2-, and the like.
The term "alkenyfoxy" as used herein refers to an alkenyl group, as previously defined, connected to the parent molecular moiety through an oxygen (-O-) linkage. Examples of alkenyloxy include allyloxy, butenyloxy and the like.
i o The term "alkoxy" as used herein refers to R41 O- wherein R41 is a loweralkyl group, as defined herein. Examples of alkoxy include, but are not limited to, ethoxy, tert-butoxy, and the like.
The term "alkoxyalkoxy" as used herein refers to R8p0-R$IO-wherein R8o is loweralkyl as defined above and R81 is alkyfene.
15 Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
The term "alkoxyalkoxyalkyl" as used herein refers to an alkoxyalkoxy group as previously defined appended to an alkyl radical.
Representative examples of alkoxyalkoxyalkyl groups include 2o methoxyethoxyethyl, methoxymethoxymethyl, and the like.
The term "alkoxyalkyl" as used herein refers to an alkoxy group as previously defined appended to an alkyl radical as previously defined.
Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.
25 The term "alkoxycarbonyl" as used herein refers to an alkoxyl group as previously defined appended 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 3o alkoxycarbonyl group as previously defined appended to an alkenyl radical. Examples of alkoxycarbonylalkenyl include methoxycarbonylethenyl, ethoxycarbonylethenyl and the like.
The term "alkoxycarbonylalkyl" as used herein refers to R34-C(O)-R3s- wherein R34 is an alkoxy group and R3s is an alkyfene 35 group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyl and the like.

WO 99106397 - 2'I - PCT/US98115479 The term "alkoxycarbonylaminoalkyi" as used herein refers to R3$-C(O)-NH-R3g- wherein R38 is an alkoxy group and R3g is an alkylene group.
The term "alkoxycarbonyloxyalkyl" as used herein refers to s R3s-C(O)-O-R3~- wherein R36 is an alkoxy group and R3~ is an alkylene group.
The term "(alkoxycarbonyl)thioalkoxy" as used herein refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy radical. Examples of (alkoxycarbonyl)thioalkoxy include ~ o methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like.
The term "alkoxyhaioalkyl" as used herein refers to a haloalkyl radical to which is appended an alkoxy group.
The terms "alkyl" and "loweralkyl" as used herein refer to straight or branched chain alkyl radicals containing from 1 to 75 carbon atoms 1 s 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-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term "(N-alkanoyl-N-alkyl}aminoalkyl" as used herein refers 2o to RgSC(O)N(Rgs)Rg7- wherein Rg5 is an alkanoyl as previously defined, Rgg is loweralkyl, and Rg7 is alkylene.
The term "alkyiamino" as used herein refers to R5~ NH- wherein R51 is a loweralkyl group, for example, ethylamino, butylamino, and the Pike.
25 The term "alkylaminoalkyf" as used herein refers to a loweralkyl radical to which is appended an alkylamino group.
The term "alkylaminocarbonyl" as used herein refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (-C(O)-) linkage. Examples of ao alkyiaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl and the like.
The term "alkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an alkylaminocarbonyl group.
The term "alkylaminocarbonylalkyl" as used herein refers to a 35 loweralkyl radical to which is appended an alkylaminocarbonyl group.

The term "alkylaminocarbonylaminoalkyl" as used herein refers to R4o-C(O)-NH-R41- wherein R4~ 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 "alkylsulfonylamidoaikyl" as used herein refers RggS(O)2NHRgg- wherein Rgg is loweralkyl and Rgg is alkylene.
o The term "alkylsulfonylamino" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino (-S(O)2-NH-) group. Examples of alkylsulfonylamino include methylsulfonylamino, ethyisulfonylamino, isopropylsulfonylamino and the like.
i s The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of aikynyl include -C--__C-H, H-C-_-C-CH2-, H-C--_C-CH(CH3)- and the like.
The term "alkynylene" refers to a divalent group derived by the 2o removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing from 2 to 15 carbon atoms and also containing a carbon-carbon triple bond. Examples of alkynylene include -C--_C-, -C=C-CH2-, -C--_C-CH(CH3)- and the like.
The term "aminoalkyl" as used herein refers to a -NH2, alkylamino, 25 or dialkylamino group appended to the parent molecular moiety through an alkylene.
The term "aminocarbonyl" as used herein refers to H2N-C(O}- .
The term "aminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an aminocarbonyl (NH2C(O}-) group.
so The term "aminocarbonylalkoxy" as used herein refers to H2N-C(O)- appended to an alkoxy group as previously defined. Examples of aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like.
The term "aminocarbonylalkyl" as used herein refers to a 35 loweralkyl radical to which is appended an aminocarbonyl (NH2C(O)-}
group.

WO 99/06397 ' 23- PCT/US98/15479 The term "trialkylaminoalkyl" as used herein refers to (Rgp)(Rg1)(Rg2)N(Rg3)- wherein Rgp, Rg~, and Rg2 are independently selected from loweralkyl and Rg 3 is alkylene.
The term "aroyloxyalkyl" as used herein refers to R32-C(O)-O-R33-s wherein R32 is an aryl group and R33 is an alkylene group. Examples of aroyioxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.
The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl 1 o and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyi, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, i 5 trialkylaminoalkyl, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy, mercapto, cyano, vitro, carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cyanoalkoxy, {heterocyclic)alkoxy, hydroxy, hydroxalkoxy, phenyl and tetrazolylaikoxy. In addition, substituted aryl 2o groups include tetrafluorophenyl and pentafluorophenyl.
The term "arylalkenyl" as used herein refers to an alkenyl radical to which is appended an aryl group, for example, phenylethenyl and the like.
The term "arylalkoxy" as used herein refers to R42O- wherein R42 2s is an arylalkyl group, for exampie, benzyloxy, and the like.
The term "arylalkoxyalkyl" as used herein refers to a loweralkyl radical to which is appended an arylalkoxy group, for example, benzyloxymethyl and the like.
The term "arylalkyl" as used herein refers to an aryl group as so previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
The term "aryloxy" as used herein refers to R45O- wherein R45 is an aryl group, for example, phenoxy, and the like.
The term "arylalkylcarbonyloxyalkyl" as used herein refers to a ss loweralkyl radical to which is appended an arylalkylcarbonyloxy group (i.e., R62C(O)O- wherein R62 is an arylalkyl group).

The term "aryloxyalkyl" refers to an aryloxy group as previously defined 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 s radical, -C(O)H.
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 previously defined appended to an alkenyl radical as previously i o defined. Examples of carboxyalkenyl include 2-carboxyethenyl, 3-carboxy-1-ethenyl and the Pike.
The term "carboxyalkoxy" as used herein refers to a carboxy group as previously defined appended to an alkoxy radical as previously defined. Examples of carboxyalkoxy include carboxymethoxy, 1 s carboxyethoxy and the like.
The term "cyanoaikoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a cyano (-CN) group.
Examples of cyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like.
2o The term "cycloalkanoyloxyalkyl" as used herein refers to a loweralkyi radical to which is appended a cycloalkanoyloxy group (i.e., R6o-C(O)-O- wherein R6o is a cycloalkyl group).
The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not 25 limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyi, and the like. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, vitro, carboxaldehyde, carboxy, alkoxycarbonyl and so carboxamide.
The term "cycioalkylalkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
The term "dialkylamino" as used herein refers to R56R5~N-ss wherein R56 and R5~ are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.

The term "dialkylaminoaiky(" as used herein refers to a loweralkyl radical to which is appended a dialkylamino group.
The term "dialkylaminocarbonyl" as used herein refers to a dialkylamino group, as previously defined, appended to the parent s molecular moiety through a carbonyl (-C(O)-) linkage. Examples of dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl and the like.
The term "dialkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended a dialkylaminocarbonyl group.
7 o The term "dialkylaminocarbonyialkyl" as used herein refers to R5o-C(O)-R5~- wherein R5o is a dialkylamino group and R51 is an alkylene group.
The term "halo" or "halogen" as used herein refers to I, Br, CI or F.
The term "haloalkenyl" as used herein refars to an alkenyl radical to which is appended at least one halogen substituent.
The term "haloalkoxy" as used herein refers to an alkoxy radical as defined above, bearing at least one halogen substituent, for example, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3-pentafluoropropoxy and the like.
2o The term "haioalkoxyalkyl" as used herein refers to a loweralkyl radical to which is appended a haloalkoxy group.
The term "haloalkyl" as used herein refers to a lower alkyl radical, as defined above, to which is appended at least one halogen substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl or 2s pentafluoroethyl and the like.
The term "heterocycfic ring" or "heterocyclic" or "heterocycle" as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen so atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The ss nitrogen heteroatoms can be optionally quaternized. The term "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinoiyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like). Heterocyclics include: aziridinyl, s azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazoiyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyi, ~ o isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyi, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl.
x~
;.
i~

Heterocyclics also include compounds of the formula 1 s where X* is -CHZ- or -O- and Y* is -C(O)- or [-C(R")2-lv where R" is hydrogen or C1-C4-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 quinuclidinyl and the like.
Heterocyclics can be unsubstituted or monosubstituted or 2o disubstituted with substituents independently selected from hydroxy, halo, oxo (=O), alkylimino (R*N= wherein R* is a loweralkyi group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -S03H, alkoxycarbonyl, vitro, cyano and loweralkyl. In addition, nitrogen 2s containing heterocycles can be N-protected.
The term "(heterocyclic)alkoxy" as used herein refers to a heterocyclic group as defined above appended to an alkoxy radical as defined above. Examples of (heterocyclic)alkoxy include 4-pyridylmethoxy, 2-pyridylmethoxy and the like.
ao The term "(heterocyclic)alkyl" as used herein refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.

WO 99106397 ' 27- PCT/US98115479 The term "heterocycliccarbonyloxyalkyl" as used herein refers to R46-C(O)-O-R4~- wherein R46 is a heterocyclic group and R4~ is an alkylene group.
The term "hydroxy" as used herein refers to -OH.
s The term "hydroxyalkenyl" as used herein refers to an alkenyl radical to which is appended a hydroxy group.
The term "hydroxyalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a hydroxy (-OH) group. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4-o hydroxybutoxy and the like.
The term "hydroxyalkyl" as used herein refers to a loweralkyl radical to which is appended a hydroxy group.
The term "leaving group" as used herein refers to a halide (for example, Cl, Br or I) or a sulfonate (for example, mesylate, tosylate, ~ s triflate and the like).
The term "mercapto" as used herein refers to -SH.
The terms "methyienedioxy" and "ethylenedioxy" refer to one or two carbon chains attached to the parent molecular moiety through two oxygen atoms. In the case of methylenedioxy, a fused 5 membered ring 2o is formed. In the case of ethylenedioxy, a fused 6 membered ring is formed. Methylenedixoy substituted on a phenyl ring results in the formation of a benzodioxolyl radical. . Ethylenedioxy substituted on a phenyl ring results in the formation of a benzodioxanyl radical .
25 The term "substantially pure" as used herein means 95% or more of the specified compound.
The term "tetrazolyl" as used herein refers to a radical of the formula H
N- N
or a tautomer thereof.

The term "tetrazolylalkoxy" as used herein refers to a tetrazolyl radical as defined above appended to an alkoxy group as defined above.
Examples of tetrazolylalkoxy include tetrazolylmethoxy, tetrazofylethoxy and the like.
s The term "thioalkoxy" as used herein refers to R7pS- wherein Rip is loweralkyl. Examples of thioalkoxy include, but are not limited to, methyithio, ethylthio and the like.
The term "thioalkoxyalkoxy" as used herein refers to RgpS-RglO-wherein R$p is loweralkyl as defined above and R81 is alkylene.
~ o Representative examples of alkoxyalkoxy groups include CH3SCH20-, EtSCH20-, t-BuSCH20- and the like.
The term "thioalkoxyalkoxyalkyl" as used herein refers to a thioalkoxyalkoxy group appended to an alkyl radical. Representative examples of alkoxyalkoxyalkyl groups include CH3SCH2CH20CH2CH2-, 7 s CH3SCH20CH2-, and the like.
The term "trans,trans" as used herein refers to the orientation of substituents (R1 and R2) relative to the central substituent R as shown R2 Z~ ~ Rs N
i R''~,.. (CH2)n 2o The term "trans,cis" as used herein refers to the orientation of substituents (R1 and R2) relative to the central substituent R as shown R2y.... Z~NiR3 2 Z Rs R ~N/
R~~.~' (CH2)n R~~.~w (CN2)n R' or R' . This definition encompasses both the case where R and R2 are cis and R and R1 are trans and the case where R2 and R are traps and R and R j are cis.
25 The term "cis,cis" as used herein refers to the orientation of substituents (R1 and R2) relative to the central substituent R as shown R2io,, ZwN/Rs (CH2)n ~1 Preferred compounds of the invention are selected from the group consisting of:
frans-frans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1-[3-(N
propyl-N-n-pentanesulfonylamino)propyl]-pyrrolidine-3 carboxylic acid;
traps,traps-2-(4-Methoxymethoxyphenyl)-4-(1,3-benzodioxol-5-yl)--(2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-~o carboxylic acid;
traps, traps-2-(3,4-Dimethoxyphenyl)-4-(1,3-benzodioxol -5-yl)-1-[2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid;
traps, traps-2-(3,4-Dimethoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1-[2-~ s (N-propyl-N-n-hexanesulfonylamino)ethyl]pyrroiidine-3-carboxylic acid;
traps, traps-2-(4-Propoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid;
2o traps,traps-2-(3,4-Difluorophenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(3,4-Difluorophenyl)-4-(1 ,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-pentanesuifonylamino)ethyl]pyrrolidine-3-carboxylic acid;
25 traps,traps-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid;
traps, traps-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-(3-chloropropanesuifonyl)amino)ethyl)-so pyrrolidine-3-carboxylic acid;
traps, traps-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-isobutyl-N-(3-chloropropanesulfonyl)amino)ethyl)pyrroiidine-3-carboxylic acid;

WO 99/06397 - 3 ~- PCT/US98/15479 traps, traps-2-(3-Fluoro-4-methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl}-1-[2-(N-propyl-N-(4-methylbutanesulfonyl)amino)ethyl]pyrroiidine-3-carboxylic acid;
traps, traps-2-(4-Methoxy-3-fl uorophen.yl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-[2-{N-propyl-N-(n-pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid;
traps,traps-2-(3-Fiuoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl) 1-[2-(N-propyl-N-{2,2,3,3,3-pentafluoropropoxyethanesulfonyl}-amino)ethyl]pyrrolidine-3-carboxylic acid;
io trans,trans-2-(1 ,4-Benzodioxan-6-yl)-4-{7-methoxy-1 ,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(n-pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid;
traps,traps-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl) 1-(2-(N-isobutyl-N-(pentanesulfonylamino)ethyl)pyrrolidine-3-75 carboxylic acid;
traps,traps-2-(3-Fluoro-4-methoxyphenyi}-4-(1 ,3-benzodioxol-5-yl)-1-(2-(N-(2-methoxyethyl)-N-(3-chioropropanesulfonyl)amino)-ethyl)pyrrolidine-3-carboxylic acid;
traps,traps-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-20 1-(2-{N-(2-methoxyethyl}-N-(pentanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid;
traps,traps-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl) 1-(2-(N-propyl-N-((2,2,2-trifluoroethoxyethane)sulfonyl)amino)-ethyl]pyrrolidine-3-carboxylic acid;
2s traps,traps-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-(2-methoxyethyl}-N-{butanesulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid;
traps,traps-2-(3-Fluoro-4-methoxyphenyl}-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(2-3o methylpropanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid;
traps,traps-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl}-1-(2-(N-isobutyl-N-(butanesulfonylamino))ethyl)pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-Methylpentyl)-4-( 1,3-benzodioxoi-5-yl}-1-(N,N-di (n-35 butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2,2-D imethylpentyl)-4-( 1,3-benzodioxol-5-yl)-1-(N, N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;

WO 99/06397 3 ~ - PCT/US98/15479 traps, traps-2-(2-( 1,3-Dioxo-2-yl)ethyl)-4-(1 ,3-benzodioxo I-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(2-Tetrahydro-2H-pyran)ethyl}-4-(1 ,3-benzodioxol-5-yl)-1-(N, N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2,2,4-Trimethyl-3-pentenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
~o traps,traps-2-(2,2,-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl}-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(1 ,3-Dioxo-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-[[N-4-heptyl-N(2 methyl-3-fluorophenyl}] amino carbonylmethyl]-i s pyrrolidine-3-carboxylic acid;
traps, traps-2-{2-(1 ,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps,traps-2-((2-Methoxyphenoxy)-methyl)-4-(i ,3-benzodioxol-5-yl)-20 1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S, 3R, 4S)-2-(2,2-Dimethyipentyl)-4-(1,3-benzodioxo I-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
25 traps,traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-{N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-( 1 ,3-Dioxo!-2-yl)ethyl)-4-{7-methoxy-1 ,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-ao methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl}-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
ss traps,traps-2-(2,2-dimethylpentyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-(N,N-di{n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;

traps, traps-2-(2,2,-Dimethyi-2-(1 ,3-dioxolan-2-yl)ethyl)-4-{7-methoxy-1,3-benzodioxol-5-yi)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Methoxyphenyl)-ethyl)-4-( 1 ,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps,traps-2-{2,2-Dimethyl-3-(E)-pentenyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
io traps,traps-2-(2-(2-pyridyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S, 3R, 4S)-2-(2-{2-oxopyrrolidin-1-yl)ethy!)-4-(1 ,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
i5 (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-( 1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N, N-2o di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-j(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
(2R,3R,4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)1-25 (2-(N-propyl-N-pentanesu Ifonylamino)ethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2,2-Dimethylpentyl}-4-{ 1,3-benzodioxol-5-yl)-1-((N-butyl-N-{4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
so traps,traps-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-35 yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acrd;
*rB

traps,traps-2-(2,2-Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonyfmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2,2-Dimethylpent-3-enyl}-4-(1,3-benzodioxol-5-yl}-1-s ((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2,2-Dimethy!pent-3-enyl}-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N, N-di{n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
~o traps,traps-2-(2,2-Dimethy!pent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2,2-Dimethy!pent-3-enyl)-4-(7-methoxy-1,3-~ s benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonyimethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2,2,4-Trimethylpent-3-enyl)-4-(1 ,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-2o methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2,2,4-Trimethylpent-3-enyl)-4-(1 ,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
2s traps,traps-2-(2,2,4-Trimethy!pent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2,2,4-Trimethylpe nt-3-enyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-so methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2,2,4-Trimethy!pent-3-enyl)-4-(7-methoxy-1 ,3-be nzodioxol-5-yl)-1-{(N-butyl-N-(4-dimethylamino)butyl)aminocarbony!methyl}-pyrrolidine-3-ss carboxylic acid;

traps, traps-2-(2-( 1,3-Dioxol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 [(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]
pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrofidine-3-carboxylic acid;
traps, traps-2-(2,2,-Dimethy I-2-.(1 ,3-Dioxol-2-yi)ethyl)-4-( 1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3 ~o methylphenyl)}aminocarbonylmethyl)-pyrrofidine-3-carboxylic acid;
traps,traps-2-(2,2-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-1 s carboxylic acid;
traps,traps-2-(2,2,-Dimethyl-2-(1 ,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonyfmethyl)-pyrrolidine-3-carboxylic acid;
2o traps,traps-2-(2,2-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))amino)carbonylmethy(]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-so pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1- (N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-1 ,3-ss benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;

traps, traps-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methcxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-((2-Methoxyphenoxy)-methyl)-4-( 1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-i o 1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-((2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1- (N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
15 traps,traps-2-((2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methyiphenyl})amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1,3-2o benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-{2-Oxo 1,2-dihydro pyridin-i -yl)-ethyl)-4-{1 ,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl}aminocarbonylmethyl)-25 pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
so traps,traps-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopyridin-i -yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-35 pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-((N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2(-2-Oxopiperidin-1-yi)-ethyl)-4-(1 ,3-benzodioxol-5 yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid;
1o traps,traps-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1 ,3-1s benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
2o traps, traps-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1 ,3 benzodioxol-5-yl)-1-j(N-4-heptyl-N-(4-fluoro-3 methyiphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1 ,3-2s benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethyiaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-so pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1 ,3-benzodioxol-5-35 yl)-1-[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;

CA 02297894~4~2000-O1-21 traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-trimethylammoniobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl}-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl}-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-~ o hydroxypropyl}amino)carbonylmethyl]-pyrroiidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonyimethyl]-pyrrolidine-3-carboxylic i s acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1 ,3-2o benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylis acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-trimethylammoniobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
so traps,traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyi]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl}-4-(2,3-dihydro-ss benzofuran-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
*rB

WO 99/06397 - 38- PCTlUS98/15479 traps,traps-2-(2-(3,3-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-yrrolidine-3-carboxylic acid;
traps, traps-2-(2-(3,3-Dimethyl-2-oxopyrrol idin-1-yl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(3,3-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-1 o dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
is traps,traps-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-{1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-{2-{4,4-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1 ,3-2o benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-{1-propanesuitamyl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic 25 acid;
traps, traps-2-(2-( 1-propa n esu lta my l) ethy l)-4-( 1 , 3-be nzodioxo l-5-y l)-1-[{N-4-heptyl-N-(4-fl uo ro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
so traps,traps-2-(2-(1-propanesultamyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonyl methyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-{2-{ 1-propanesultamyl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)-1 -[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-ss carboxylic acid;
*rB

WO 99/06397 - 3g- PCTIUS98/15479 traps,traps-2-(2-{1-propanesultamyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4 dimethyiaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(1-propanesultamyl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps,traps-2-{2-(1-propanesultamyl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethylJ-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(1-propanesultamyl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(1-propanesultamyl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl}-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(1-propanesultamyl)ethyl)-4-(2,3-dihydro benzofuran-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3 2o methylphenyl)amino)carbonylmethylJ-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(1-propanesultamyl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethylj-pyrrolidine-3-25 carboxylic acid;
traps,traps-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl}-1-j(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonyfmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-so butyl-N-{3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(1-pyrazo lyl)ethyl)-4-(1,3-be nzodioxol-5-yl)-1-(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
35 traps,traps-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;

WO 99/06397 - 4~- PCT/US98115479 traps, traps-2-(2-( 1-pyrazolyl)ethyl)-4-(7-methoxy-1 ,3-benzodioxo l 5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid;
traps,traps-2-(2-(1-pyrazolyl)ethyl)-4-(7-rnethoxy-1 ,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(1-pyrazolyl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-~ o dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(1-pyrazolyl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
i5 traps,traps-2-(2-(1-pyrazolyl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-( (N-4-h eptyl-N-(4-fl a o ro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(1-pyrazolyl)ethyl}-4-(2,3-dihydro-benzofuran-5-yl)-2o i -j(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(2-oxazolyl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(Oxazol-2-yl)ethyl)-4-( 1 ,3-benzodioxol-5-yl)-1 -[(N-25 4-heptyl-N-(4-fluoro-3-methyiphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(Oxazol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-i -[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethylj-pyrrolidine-3-carboxylic acid;
3o traps, traps-2-(2-(Oxazol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[(N-butyl-N-(~propoxy)amino)carbonylmethylJ-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(Oxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-35 pyrrolidine-3-carboxylic acid;

traps, traps-2-(2-(Oxazol-2-yl)ethyl)-4-{7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(Oxazol-2-yi)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl}amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(Oxazol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N-butyl-N-{4-~o dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-{2-(5-Methyrloxazol-2-yl)ethyl}-4-( 1 ,3-benzodioxol-5 yl)-1-{N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid;
1~ traps,traps-2-(2-(5-Methyloxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(5-Methyloxazol-2-yl)ethyl)-4-( i ,3-benzodioxol-5-2o yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
2s traps,traps-2-{2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-so 5-yl)-1-[(N-butyl-N-{3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2, 5-Dioxopyrro lidin-1-yl) ethyl)-4-( 1,3-benzodioxol-5-yl)-1-[{N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
ss traps,traps-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[{N-butyl-N-(4-dimethylaminobutyl) amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;

WO 99/06397 - 4'2- PCTJUS98115479 traps, traps-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1 ,3 benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl) pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-{Pyridin-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-~ o pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(Pyridin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethylj-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(Pyridin-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-[(N-15 butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(Pyridin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
2o traps,traps-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-i ,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-2s methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-so carboxylic acid;
traps, traps-2-(2-(Pyrimidin-2-yl)ethyl)-4-( 1,3-benzodioxol-5-yl)-1-(N,N-di{n-butyl)aminocarbonyfmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(Pyrimidin-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-35 [(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;

trans, traps-2-(2-(Pyrimidin-2-yl)ethyl)-4-( 7 ,3-benzodioxol-5-yl)-1 [(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]
pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-( 1, 3-be nzod ioxo I-4-yl)ethy I }-4-{ 1,3-be nzod ioxo I-5 yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid;
traps,traps-2-(2-(1,3-benzodioxol-4-yl)ethyl}-4-(1,3-benzodioxol- 5-yl)-1-[(N-4-heptyl-N-(4-fiuoro-3-methyiphenyl)amino}carbonylmethyl]-pyrrolidine-3-carboxylic 1 o acid; and traps, traps-2-(2-(1,3-benzodioxol-4-yl}ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-((N-butyl-N-(4 dirnethylaminobutyl}amino)carbonyfmethyl]-pyrrolidine-3-carboxylic acid;
(2S,3R,4S}-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-~s di(n-butyl)aminocarbonylmethyl}-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(1 ,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-1 ,3-2o benzodioxol-5-yl}-1-(N,N-di{n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl}-4-(1,3-benzodioxol-5-yi)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
2s (2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4-(1,3-benzodioxol-5-yl}-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
or a pharmaceutically acceptable salt.
so Most preferred compounds of the invention are selected from the group consisting of:
traps,traps-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl}-1-(N,N-di(n-butyl)aminocarbonylmethyi)-pyrrofidine-3-carboxylic 35 acid;

traps,traps-2-(2,2,-Dimethyl-2-(1 ,3-dioxoian-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrroiidine-3-carboxylic acid;
traps, traps-2-(2-( 1 ,3-Dioxol-2-y ()ethyl)-4-( 1 , 3-benzodioxol-5-yl)--1-[[N-4-heptyl-N-(2-methyl-3-fluorophenyl)]
aminocarbonylmethyl]-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(1,3-Dioxo!-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
7 o traps, traps-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5 yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 i ~ carboxylic acid;
traps, traps-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
2o traps,traps-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-25 butyl)aminocarbonylmethyl) -pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-(2-Methoxyphenyl)-ethyl)-4-( 1,3-benzodioxol-5-yl}-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrroiidine-3-carboxylic acid;
traps, traps-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-(7-methoxy-1,3-ao benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps,traps-2-(2-(2-pyridyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yi)ethyl)-4-(1,3-benzodioxoi-5-35 yl}-1-(N,N-di(n-butyl)aminocarbonyfmethyl)-pyrrolidine-3-carboxylic acid;

(2S, 3R, 4S}-2-(2,2 Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyfmethyl)-pyrrolidine-3-carboxylic acid;
(2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-s yl)-1-(N-4-heptyl-N-{4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
traps, traps-2-(2-( 1-pyrazolyl)ethyl)-4-( 1,3-benzodioxol-5-yl)-1-(N, N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
~o (2R, 3R, 4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[((N-propyl-N-pentanesulfonyl}amino)ethyl]-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-(2,2-Dimethylpentyl}-4-(1,3-benzodioxol-5-yl)-1-(N,N
di(n-butyl)aminocarbonyimethyl}-pyrrolidine-3-carboxylic acid;
i5 (2S,3R,4S)-2-{2,2-Dimethylpent-(E)-3-enyl)-4-(1,3-benzodioxol-5-yl) 1-(N,N-di(n-butyl}aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-{2,2-Dimethylpent-(E)-3-enyl}-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyi)-2o pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl)-4-(1 ,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyi)-pyrrolidine-3-carboxylic acid; and (2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-2s (N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
or a pharmaceutically acceptable salt thereof.
Methods for preparing the compounds of the invention are shown in Schemes I-XV.
Scheme I illustrates the general procedure for preparing the compounds of the invention when n and m are 0, Z is -CH2- and W is -C02H. A [i-ketoester ~, where E is loweralkyl or a carboxy protecting group is reacted with a vitro vinyl compound ~, in the presence of a base (for example, 1,8-diazabicyclo[5.4.0]undec-7-eve (DBU) or sodium ethoxide or sodium hydride and the like) in an inert solvent such as s toluene, benzene, tetrahydrofuran or ethanol and the like. The condensation product $ is reduced (for example, hydrogenation using a Raney nickel or platinum catalyst). The resulting amine cyclizes to give the dihydro pyrrole 4_. Reduction of 4_ (for example, sodium cyanoborohydride or catalytic hydrogenation and the like) in a erotic 1 o solvent such as ethanol or methanol and the like gives the pyrrolidine compound $ as a mixture of cis-cis, traps, traps and cis, traps products.
Chromatographic separation removes the cis-cis isomer leaving a mixture of the trans,trans and cis,trans isomers which is further elaborated. The cis-cis isomer can be epimerized (for example, using 1 ~ sodium ethoxide in ethanol) to give the traps, traps isomer and then carried on as described below. The pyrrolidine nitrogen is (1) acylated or sulfonylated with R3-X (R3 is R4-C(O)- or Rs-S(O)2- and X is a leaving group such as a halide {CI is preferred) or X taken together with R4-C(O)- or R6-S(O)2- forms an activated ester including esters or 2o anhydrides derived from formic acid, acetic acid and the like, alkoxycarbonyl halides, N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazoie, N-hydroxy-5-norbornene-2,3-dicarboxamide, 2,4,5-trichlorophenol and the like) or (2) alkylated with R3-X where X is a leaving group (for example, X is a halide (for example, CI, Br or I) or X
25 is a leaving group such as a sulfonate (for example, mesylate, tosylate, triflate and the like)) in the presence of a base such as diisopropyl ethylamine or triethyiamine and the like to give the N-derivatized pyrrolidine $ which is still a mixture of traps, traps and cis, traps isomers. Hydrolysis of the ester $ {for example, using a base such a ao sodium hydroxide in EtOHIH20) selectively hydrolyzes the trans,trans ester to give a mixture of 7 and $, which are readily separated.
Scheme II illustrates a general procedure for preparing the compounds of the invention when n is 1, m is 0, Z is -CH2- and W is -C02H. A substituted benzyl chloride $ is reacted with a lithio dithiane 35 1~ in an inert solvent such as THF or dimethoxyethane to give the alkylated adduct j 1. The anion of compound 1 1 is formed using a base such as n-butyliithium and then reacted with R1-CH2-X' wherein X' is a leaving group such as a halide or sulfonate to give compound 1 2. The dithiane protecting group is cleaved (for example, using a mercuric salt in water) to give the keto compound 1 3. Reaction of ketone 1 3 with benzyl amine and formaldehyde gives the keto piperidine compound 1 4.
s Treatment of compound 14 with an activated nitrite such as trimethylsilyl cyanide followed by a dehydrating agent such as phosphorous oxychloride provides the isomeric ene nitrites 1_~.
Reduction of the double bond (for example, using sodium borohydride) affords the piperidinyl nitrite 16. Hydrolysis of the nitrite using hydrochloric acid in the presence of a carboxy protecting reagent (for example, an alkyl alcohol) affords ester 17 (where E is a carboxy protecting group). Debenzylation by catalytic hydrogenation under acidic conditions affords the free piperidine compound 1 8. Compound 1 8 is further elaborated by the procedures described in Scheme I for 15 compound 5_ to give the final product compound 1 9.
Scheme III illustrates a general procedure for preparing the compounds of the invention when m and n are 0, Z is -C(O)- and W is -C02H. ~i-Keto ester 20 (wherein E is loweralkyl or a carboxy protecting group) is reacted with an a-haloester ~ 1_ (where J is lower 2o alkyl or a carboxy protecting group and the halogen is bromine, iodine or chlorine) in the presence of a base such as NaH or potassium tert-butoxide or lithium diisopropylamide in an inert solvent such as THF or dimethoxyethane to give diester 22. Treating compound 22 with R3-NH2 and heating in acetic acid gives the cyclic compound ~ 3. The double 2s bond is reduced (for example, by catalytic hydrogenation using a palladium on carbon catalyst or sodium cyanoborohydride reduction) to give pyrrolidone 24. Epimerization with sodium ethoxide in ethanol to give the desired trans,trans configuration, followed by sodium hydroxide hydrolysis of the ester, affords the desired trans,trans so carboxylic acid 25.
Scheme IV illustrates a general procedure for preparing the compounds of the invention when n is 0, m is 1, Z is -CH2- and W is -C02H. The trans,trans compound 7, prepared in Scheme I, is homologated by the Arndt-Eistert synthesis. The carboxy terminus is as activated (for example, by making the acid chloride using thionyl chloride) to give compound 52, where L is a leaving group (in the case of an acid chloride, L is CI). Compound ,5~ is treated with diazomethane to WO 99/06397 - 4g- PCT/US98115479 give the diazo ketone ,~3. Rearrangement of compound 5 3 (for example, using water or an alcohol and silver oxide or silver benzoate and triethylamine, or heating or photolysis in the presence of water or an alcohol) affords the acetic acid compound 54 or an ester which may be s hydrolyzed. Compounds where m is from 2 to 6 can be obtained by repetition of the above described process.
A preferred embodiment is shown in Schemes V and Vl. A benzoyl acetate ~ is reacted with a vitro vinyl benzodioxolyl compound 27 using 1,8-diazabicyclo[5.4.0]undec-7-eve (DBU) as the base in toluene to give compound 2 8. Catalytic hydrogenation using Raney nickel leads to reduction of the vitro group to an amine and subsequent cyclization to give the dihydropyrrole ~. The double bond is reduced with sodium cyanoborohydride to give the pyrrolidine compound 3~( as a mixture of cis-cis, traps, traps and cis, traps isomers. Chromatography separates ~ s out the cis-cis isomer, leaving a mixture of the traps, traps and cis, traps isomers (31 ).
Scheme VI illustrates the further elaboration of the traps, traps isomer. The mixture (31 ) of traps, traps and cis, traps pyrrolidines described in Scheme IV is reacted with N-propyl bromoacetamide in 2o acetonitrile in the presence of ethyldiisopropylamine to give the alkyiated pyrroiidine compound 32, still as a mixture of trans,trans and cis,trans isomers. Sodium hydroxide in ethanol-water hydrolyzes the ethyl ester of the traps, traps compound but leaves the ethyl ester of the cis,trans compound untouched, thus allowing separation of the 25 traps, traps carboxylic acid 3 3 from the cis, traps ester 3 4.
Scheme V!I illustrates the preparation of a specific piperidinyl compound. Benzodioxolyl methyl chloride 3 5 is reacted with lithio dithiane ~ to give the alkylated compound ~7. Treatment of compound ~7 with 4-methoxybenzyl chloride in the presence of lithium 3o diisopropylamide gives compound ~$,. Cleavage of the dithiane protecting group using a mercuric salt in aqueous solution gives ketone 3 9. Treatment of 3 9 with benzylamine and formaldehyde gives the keto piperidine 4Q. Treatment of compound 40 with trimethylsilyl cyanide followed by phosphorous oxychloride gives the eve nitrite as a mixture 35 Of isomers 41. Sodium borohydride reduction of the double bond gives the piperidinyi nitrite 42. Hydrochloric acid hydrolysis in the presence of ethanol gives ethyl ester 43. The N-benzyl protecting group is removed by catalytic hydrogenation to give the free piperidine compound 44. Compound 44 is further elaborated by the procedures described in Scheme V for compound 31 resulting in the formation of the N-derivatized carboxylic acid ~.
s A preferred embodiment of the process shown in Scheme III is shown in Scheme VIII. 4-Methoxybenzoylacetate 4_C (wherein E is loweralkyl or a carboxy protecting group) is reacted with an benzodioxolyl a-bromoacetate 47 (wherein E is lower alkyl or a carboxy protecting group) in the presence of NaH in THF to give diester 4 $,.
i o Treating compound 4~ with ethoxypropylamine and heating in acetic acid gives the cyclic compound 49. The double bond is reduced by catalytic hydrogenation using a palladium on carbon catalyst to give pyrrolidone ,5~. Epimerization with sodium ethoxide in ethanol to give the desired traps, traps configuration is followed by sodium hydroxide 1 s hydrolysis of the ester to afford the desired traps, traps carboxylic acid 51.
Scheme IX illustrates the preparation of compounds where n is 0, Z is -CH2-, and W is other than carboxylic acid. Compound 5 5, which can be prepared by the procedures described in Scheme IV, is converted (for 2o example, using peptide coupling condition, e.g. N-methylmorpholine, EDCI and HOBt, in the presence of ammonia or other amide forming reactions} to give carboxamide 56. The carboxamide is dehydrated (for example, using phosphorus oxychloride in pyridine) to give nitrite ,~7.
Nitrite ~7 under standard tetrazole forming conditions (sodium azide 2s and triethylamine hydrochloride or trimethylsilylazide and fin oxide) is reacted to give tetrazole 58. Alternatively nitrite 57 is reacted with hydroxylamine hydrochloride in the presence of a base (for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH) in a solvent such as DMF, so DMSO, or dimethylacetamide to give amidoxime ~9. The amidoxime is allowed to react with a methyl or ethyl chloroformate in a conventional organic solvent (such as, chloroform, methylene chloride, dioxane, THF, acetonitrile or pyridine) in the presence of a base (for example, triethylamine, pyridine, potassium carbonate and sodium ss carbonate) to give an O-acyl compound. Heating of the O-acyl amidoxime in an inert solvent (such as benzene, toluene, xylene, dioxane, THF, dichloroethane, or chloroform and the like) results in WO 99/06397 - 5 ~ ' PCTIUS98115479 cycfization to compound 6 0. Alternatively reacting the amidoxime with thionyl chloride in an inert solvent (for example, chloroform, dichloromethane, dixoane and THF and the Pike) affords the oxathiadiazoie F 1_.
Scheme X illustrates the preparation of compounds in which R3 is an acylmethylene group. A carboxylic acid 6 2 (where R4 is as previously defined herein) is treated with oxalyl chloride in a solution of methylene chloride containing a catalytic amount of N,N-dimethylformamide to give the acid chloride. Treatment of the acid 1 o chloride with excess ethereal diazomethane affords a diazoketone, and then treatment with anhydrous HCI in dioxane gives the a-chloroketone 6 3. Pyrrolidine ester 5_ where E is lower alkyl or a carboxy protecting group, prepared in Scheme I, is alkylated with the a-chloroketone 6 3 to provide alkylated pyrrolidine 6 4. Carboxy deprotection (for example, i s hydrolysis of an alkyl ester using lithium or sodium hydroxide in ethanol-water) gives the alkylated pyrrolidine acid 6 5.
Scheme XI illustrates the preparation of "reverse amides and sulfonamides". The carboxy protected pyrrolidine 5_, prepared in Scheme I, is reacted with a difunctionalized compound X-R$-X where R8 is 2o alkylene and X is a leaving group (for example a halide where Br is preferred) to give N-alkylated compound 6 6. Treatment of C~6 with an amine (R2pNH2) affords secondary amine 67. This amine (67) can be reacted with an activated acyl compound (for example, R4-C(O)-CI) and then carboxy deprotected (for example, hydrolysis of an ester or 25 hydrogenation of a benzyl moiety) to afford amide 68. Alternatively amine ~7 can be reacted with an activated sulfonyl compound (for example, R6-S(O)2-CI) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford sulfonamide ~9.
so Scheme XII illustrates a method for synthesizing pyrrolidines by an azomethine yfide type [3+2]-cycloaddition to an acryiate. General structures such as compound 70 are known to add to unsaturated esters such as 71 to provide pyrrolidines such as compound 72 (O. Tsuge, S.
Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983), O. Tsuge, S.
ss Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem. 5 2 2523-30 (1987), and S. Kanemasa, K. Skamoto, O. Tsuge, Bull. Chem. Soc. Jpn. ~ 1960-68 (1989)). A specific example is also shown in Scheme XII. Sifyiimine 73 7 ' S1 ' PCT/US98115479 is reacted with acrylate 74 in the presence of trimethylsilyl triflate and tetrabutylammonium fluoride to give the desired pyrrolidine 7 5 as a mixture of isomers. This method can be modified to provide the N-acetamido derivatives directly by reacting ~ and 7 4 with the s appropriate bromoacetamide (for example, dibutyl bromoacetamide) in the presence of tetrabutylammonium iodide and cesium fluoride to give compound 7~.
Scheme XI11 illustrates a method for producing an enantiomerically pure pyrrolidine $_0, which can be further elaborated io on the pyrrofidine nitrogen. intermediate racemic pyrrolidine ester 77 (for example, prepared by the procedure described in Scheme V) is Boc-nitrogen protected (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 ~ s ~. The carboxylic acid is converted to its (+)-cinchonine salt, which can be recrystallized (for example from ethyl acetate and hexane or chloroform and hexane} to afford the diastereomerically pure salt. This diastereomerically pure salt can be neutralized (for example, with sodium carbonate or citric acid) to afford enantiomerically pure 2o carboxylic acid 79. The pyrrolidine nitrogen can be deprotected (for example, using trifluoroacetic acid} and the ester reformed by the use of ethanolic hydrochloric acid to give salt 8 0. Alternatively one can use ethanol HCI to cleave the protecting group and form the ester in one step. The pyrrolidine nitrogen can be further elaborated (for example, 2s by treatment with the dibutyl amide of bromoacetamide in acetonitrile in the presence of diisopropylethylamine) to give optically active compound ~1,. The use of (-)-cinchonine will give the opposite enantiomer.
Scheme XIV describes another procedure for preparation of so pyrrolidines. Pyrrolidines may be synthesized by the use of an azomethine ylide cycloaddition to an acrylate derivative as described by Cottrell, I. F., et.al., J. Chem. Soc., Perkin Trans. 1, 5: 1091-97 (1991 ).
Thus, the azomethine ylide precursor ~2 (where R55 is hydrogen or methyl) is condensed with a substituted acryfate ~3 (wherein R2 is as 35 described herein and R~s is loweralkyl) under acidic conditions to afford the substituted pyrrolidine ~4. The N-protecting group can be removed (for example, by hydrogenolysis of an N-benzyl group) to give $_5, which can be alkylated under the conditions described above to provide the N-substituted pyrrolidine $6. Standard ester hydrolysis of 86 produces the desired pyrrolidine carboxylic acid $,7.
A preferred process is shown in Scheme XV. Nitro vinyl compound s (8 8) is reacted with beta-keto ester 8 9 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 1 o temperature of from about 0° C to about 100° C for a period of time from about 15 minutes to overnight to give compound ~0. Reduction of the vitro group followed by cyclization was effected for example by catalytic hydrogenation with a hydrogen pressure of from about atmospheric pressure to 300 p.s.i. over from about 1 hour to about 1 day 15 Of compound ~0_ in an inert solvent such as THF, ethyl acetate, toluene, ethanol, isopropanol, DMF or acetonitrile and the like, using a hydrogenation catalyst such as Raney nickel, palladium on carbon, a platinum catalyst, such as platinum oxide, platinum on carbon or platinum on alumina and the like, or a rhodium catalyst, such as rhodium 20 on carbon or rhodium on alumina and the like, and the like affords intermediate nitrone 9~ or a mixture of nitrone 91 a and imine 91 b.
The reaction mixture comprising the nitrone or nitrone/imine mixture is treated with an acid such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methanesulfonic acid and the like, 2s and the hydrogenation is continued to give pyrrolidine compound 92 as the cis,cis-isomer. Epimerization at C-3 is effected by treatment of compound ~2 with a base such as sodium ethoxide, potassium t-butoxide, lithium t-butoxide or potassium t-amyloxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the so like or an amidine such as DBU and the like in an inert solvent such as ethanol, ethyl acetate, isopropyl acetate, THF, toluene or DMF and the like at a temperature of from about -20° C to about 120° C to give the traps, traps compound ~3. Compound 9 3 itself can optionally be resolved into enantiomers prior to reacting with X-R3. The substantially pure 3s (i.e., at feast 95% of the desired isomer} optically active (+)-isomer of compound ~3 is obtained by treatment of a mixture of the (+)-isomer and the (-)-isomer of 9 3 with S-(+)-mandelic acid, D-tartaric acid or WO 99106397 - ~3- PCT/US98115479 D-dibenzoyl tartaric acid and the like in a solvent such as acetonitrile, ethyl acetate, isopropyl acetate, ethanol or isopropanol and the like.
The (+)-isomer of 9 3 selectively crystallizes as the salt, leaving the (-)-isomer of ~ in solution. Alternatively, the substantially pure (i.e., s at least 95% of the desired isomer) optically active (-)-isomer of compound 9 3 can be selectively crystallized by reaction of a mixture of the (+)-isomer and the (-)-isomer of ~ 3 with L-tartaric acid, L-dibenzoyl tartaric acid or L-pyroglutamic acid and the like, leaving the desired i o (+)-isomer of compound ~3, in solution.
Compound ~3, (racemic or optically active) is reacted with X-R3 {where X is a leaving group (for example, 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 i s in an inert solvent such as acetonitrile, THF, toluene, DMF or ethanol and the like at a temperature of from about 0° C to about 100° C to give the intermediate ester ~4. The ester can be isolated or converted in situ to the carboxylic acid {9~5 using hydrolysis conditions such as a base such as sodium hydroxide or lithium hydroxide or potassium hydroxide 2o and the like in a solvent such as ethanol-water or THF-ethanol and the like.
A more detailed description of the preparation of some specific analogs is provided in Schemes XVI-XX1. Aliphatic p-ketoesters (Scheme XVl) may be prepared by copper-catalyzed addition of a 25 Grignard reagent (for example, propylmagnesium bromide) to an unsaturated ester, for example, ethyl 3,3-dimethylacrylate. The resultant ester is hydrolyzed, for example with sodium hydroxide in aqueous alcohol, and is homologated in stepwise fashion to the corresponding ~3-ketoester, for example by activation using so carbonyldiimidazole and condensation with magnesio-ethoxymalonate.
Alternatively, olefinic (i-ketoesters may be prepared by Claisen rearangement of the corresponding allylic alcohols; hydrolysis and homologation as described above produce the desired ~i-ketoester.
N-alkyl,0-alkyl bromohydraxamates are prepared according to $s Scheme XVII. N-Boc-O-aliyl hydroxylamine is alkylated with and alkyl halide, for example using sodium hydride as base; the double bond is selectively reduced, for example using hydrogen and a palladium WO 99/06397 54 PCTlUS98115479 catalyst. After removal of the Boc protecting group, for example with TFA, the resultant amine is acylated, for example using bromoacetyl bromide.
The ~i-ketoesters described in Scheme XVI may be converted to s pyrroiidine derivatives as described in Scheme XVIII. Michael addition onto a nitrostyrene derivative can be catalyzed with base, for example DBU or potassium t-butoxide; the resultant adduct is hydrogenated, for example using Raney Nickel as catalyst, to give an imine, which is reduced further, for example using sodium cyanoborohydride under 1 o controlled pH. A mixture of isomers are generated, in which the trans-trans is generally preferred.
Scheme XIX describes several strategies for resolving the racemic pyrrolidines described above. Treatment with a chiral acid, for example (S)-(+)-mandelic acid, may provide a crystalline derivative, which can 15 be further enriched through recrystallization. The salt may be washed with base to extract the resolving agent and return the optically active pyrrolidine product. Alternatively, the amino ester can be N-protected (for example with Boc-anhydride) and hydrolyzed (for example with sodium hydroxide) to give the corresponding N-protected amino acid.
2o Activation of the acid, for example as the pentafluorophenyl ester, followed by coupling with a chiral nonracemic oxazolidinone anion, provides the corresponding acyloxazolidinone diastereomers, which may be separated chromatographically. Alcoholysis of one acyloxazolidinone diastereomer, followed by cleavage of the N-protecting group, returns 2s an optically enriched amino ester. A similar transformation may be accomplished through coupling of the protected amino acid with a chiral nonracemic amino alcohol. After chromatographic separation of the resultant diastereomers, the amide is cleaved and the protecting group is removed to provide optically enriched product.
so Optically active amino esters prepared as described above may be alkylated (Scheme XX) with a variety of electrophiles, for example dibutyl bromoacetamide, N-butyl,N-alkoxy bromoacetamide, N-(4-heptyl)-N-(3-methyl-4-fluorophenyl} bromoacetamide, or N-(S2-hydroxyalkyl)-N-alkyl haloacetamide. Hydrolysis of the resultant ester, 35 for example using sodium hydroxide in aqueous alcohol, provides the product.

For one particular class of electrophile, N-(S2-hydroxyalkyl)-N-alkyl haloacetamides, further transformations of the alkylation product are possible (Scheme XXI). Activation (for example using methanesulfonyl chloride) of the alcohol, followed by displacement with halogen (for example, using lithium bromide) provides the corresponding halide. Displacement of halide with an amine, for example dimethylamine, provides the corresponding amino ester, which may be hydrolyzed as previously described to provide product.

- 5s-Scheme I
R' p R2~N02 R C02E
~J/~ C02E

[HJ
~H
N N
R
R~

Mixture of 4 Cis-Cis Traps-Traps Cis-Traps X_Rs iRs N
R2~'~-R~ 7 N
R 1 Trans~Trar~s [ H20J
$ C02E
,Ra Mixture of N
Traps-Traps Cis-Traps C02E _B
Cis-Traps Scheme 11 S _ S
R2~C1 +
R
Li S Z~S

O~ S
Rz~R' ~ Rz S
R~

I \ N Rz ~ \ N ~ Rz ---a- 1~
/ O ~ CN
R~ R~
+ ISOMER
\ N R2 \ N R2 C02E ~ I / C N
R~ R~

1~
R2 Rs,N R2 HN
C02E ~''C02H
R~ R~

Scheme Halo R O R2~OJ C02E
t~C02E '~ O ,~ R1 J02C _ R2 Hafo = CI, Br, or I 22 O
R N~ ~- N.Rs Rt R2 i C02E Rt O .Rs N
R2 Rt Trar>.s-Trans WO 99/06397 PCTlUS98/15479 Scheme IV
N ERs N ERs R2'~-R~ --.-T R2~'R~

N ~R3 N ERs R2 R~ . R2~R~
~ CO H O ~CHN2 5;i Scheme V
O ~ N OZ O
cH3o ~ ~ + ~ ~ ~ ~ cooEt Et02C O ~ D-~ ~ ~

a Np2 N~ r O N
/ ~ / OCR O ~ / ~ / OC
COOEt ~ COOEt fVaCNBH3 Mixture of Cis-Cis Traps Traps Chromatographic separation Cis-Traps Cis-Cis + Mixture of Traps-Traps and Cis-Traps WO 99/06397 PCTlUS98/15479 -fi1 Scheme VI
r0 . H
N- _ O ~ ~ "" ~ ~ OCH3 O
COOEt O ~ N H CsH~
Cis Traps ~ N
~ BrCH2CONHC~7 O ~ ~ OCH
and O H iPr2fV Et COO Et N Traps-Traps and Cis-Traps O ~ ~ ~ ~ OCH3 3Z
COOEt Trar~Trans NaOH , H20, EtOH
O O
NHC3H7 ~NHC3H~
00 N 00 .. N
OCH3 + ~ ~ " ~ ~ OCH3 U
COOH COOEt Traps-Traps Cis-Traps Scheme VII
C~ + S --~ ~ I \ S
o ~ o ~ S
Li~S
~'1 OMe O ~ O ~ .~----O
M
O
O
ISOMER
OMe OMe w Scheme VII cont.
O ~ ~ o I/ I/
OMe -- OMe HN ~ O I ~ N ~ /O
C02Et / C02Et ~I ~ ~l _4~
OMe ~ OMe O' OMe *rB

/ ~ O

9~
Scheme VII!
_- CH3 Br - o'/
OE
o O ~O/''_CH3 r0 O ~O/~CH3 O
C02E ~ / OCH CO E OCH3 ~-CHa ~O
/~/O
O
O /
~OCH3 C02 ~H
Traps-Traps Scheme IX
iRs ~R3 N N
R R2~R
~

2 ~
R~

(CH2)m (CH2)m iRs iRs N N
R2~Ri RZ--~.R~
(CH2)m ~Ct"~2)m CN
~ NH
N=N
~1 N~R3 ~R3 N~Rs /~ ~ /- N
R2_'~-R~ R2._( 1 R~ R2'~-Ri (CH2)m -E- (CH2~)m ---~... (CHz)m ~N ~NOH "N
HN , H2N HN~ , g-O
p~~ ~ O
fit *rB

WO 99!06397 PCTIt3S98/15479 Scheme X
R, O H o R ~
+ Cyc~ R°~CI HN
O '' ---- C02E
o O +

R~
Rs l1 N i O C02H R4' ~N

Scheme XI
NCH NLRB-X
Rs ~ R2 O
/ Rd N,Rs-~ NLRB-NHR2o R2 R ~ E----- R2 R t O.SiRs i Rs / 00 N
R2 R~

-ss-Scheme XIl R~ COZEt R~
N+ + ' R3 ~ C02Et CHZ ' Me Si~N~ ~ \ O \ \ C02Et / _ f3u2N' ~N C02Et ~O
~ O
O
7~

WO 99!06397 PCT/US98/15479 - s9-Scheme XIII

/ \
1. BOCpO
C02Et ~N
2. NaOH, EtOH -C02H
HZO
/
'O~
(t) ZZ (~) 1$
t . (+)-cinchonine 2. recrystallize fro EtOAc/hexane 3. Na2C03 / \ / \
HCI ~ ~ -C02Et BocN -C02H
HCI
EtOH
-_ O 1 O
of of (+) ~ (+) z~
Bu2NC(O)CH2Br EtNiPr2, CH~CN

/ \

O
O
(+) ~t o-J

Scheme X!V

R2~CO2R5s ~~N
Ph~N ~O M a C02R5s TFA, CH2CI2 R2 Me3SiJ
H R3Br Pd(OH)21C H N BuaNl or Nal COzRSs NaOH or LiOH R
R3 ~ CO R EtOH, H20 3 \N CO2H

$L

_71_ Scheme XV
R2~ N02 + EO
~$
O
N N
R2 1 R~ R2 1 R~ 02N O
f C02E C02E R2 R~

NH NH
R2 R~ ~ R2~ Ri R3 /Rs N~ N
R2i..~R~
R2~R~

SCHEME XVI
O. M
COOEt ~pr~ NaOH i - CDI ~OEt .-,ate ----~ .~.nr ....rr O
cat CuCI HOOC
EtOOC
a M$~
OH ~pEt NaOH ~ CDI O~oEt --..~. -~.
-s --~ ...girl 1 H+, heat HOOC O
EtOOC
SCHEME XVII
BrCH2COBr p BocHN'O~ N--~ --Y BocN'O~ TFA ~ --~. Br~N.O~
R-X p~-C R
F
SCHEME XVIII
~~~u p w~~u + OpN / ( ~ p DBU H2 Na8H3CN HN .,nCOOEt _ _ or cat. KOtBu Ra-N pH4-5 EtOOC R
R O

SCHEME XIX
R (s)-(+)_ R
HN mandelic ~~nCOOEt acid recrystallization neutralization HN ~nCOOEt / \ O / \
v o R=
~..p ~~n (racemic) %~' 1 ''~ (single enantiomer) 1. EDAC, F5-pheno~ R
R
i N 0 1. NaOMe, HN
HN *,COOEt Z ~ Boc20 '~ ~ MeOH wiCOOMe 2. NaOH 3. separate 2. TFA
diastereomers ~ \
_ O

(racemic) R = (single enantiomer) ..nr ~~ar w. ~
I~ I
-~ N 1. EDAC, HOOBt : N

HN .nCOOEt ~- B°c20 w ~ H N OH 1. HCI, heat HN ~nCOOEt 2. NaOH 3. separate 2. HCl, EtOH
diastereomers / \
O
J o~

(racemic) (single enantiomer) SCHEME XX
O
Br~ ~ R~
R2 NaOH R~
NR~H2 -R3~O.~, ~ ~-SCHEME XXI
O
R
~ . nnsci HN .",COOEt 2. Liar _ O
~R of ~cl-NaOH /
~1 ~R
'N~N~N ..nCOOH
O
O
.R _ J

Compounds which are useful as intermediates for the preparation of compounds of the invention are:

NH
(CH2)n (CH2)m W Ri (III) wherein n is 0 or 1;
m is 0 to 6;
to W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -P03H2, (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR~7 where R17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, 20 (k), sulfonamido, (I) -C(O)NHS(O)2R ~ s where R~ 6 is loweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(O)2NHC(O)R~s.
Ho 0 NH
(n) ° , s.l" o 25 (~) HO

OH
\ N
i (p) o , O
' NH
O
(q) .~~NwO
N
~~H
(r) O , N, O
~S=O
N
(S) H , N
~~-- CF3 N
(t) H , Or - ~ ~ NHSOpCF3 (u) ; and R ~ and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyaikyl, ~o cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonyialkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonyialkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, ~s alkylsulfonylamidoalkyi, heterocyclic, (heterocyclic)aikyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or atkanoyl and Rcc is alkylene, with the proviso that one or both of R ~ and R2 is other than hydrogen;
or a salt thereof;
20 or a compound of the formula:

R2 i~.,. NH
R2 ~H
y (CH2)n w (CH2)n (CH2)m (CH2)m W Rt or W R
t (IV) (U) wherein n is 0 or 1;
s m is 0 to 6;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -P03H2, (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, ~o (e) -C(O)NHR» where R~~ is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyi, (h) tetrazolyl, (i) hydroxy, i 5 (j) alkoxy, (k) sulfonamido, (1) -C(O)NHS(O)2R~6 where R16 is loweralkyl, haloalkyl, phenyl or dialkyfamino, (m) -S(O)ZNHC(O)R~s, HO O
NH
20 (n) O
s.5' O
(O) HO O
OH
~N
(p) O , -7g-O
' NH
O
(q) O
.~~NwO
N--r( ~~H
( r) N,. O
~S=O
N
(S) H
N
N
(t) ~ H
or NHSO2cF3 (u) ; and R ~ and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyi, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyaikoxyalkyl, . thioaikoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyi, ~o alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylarninocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, aikylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and R~~ is alkyfene, with the proviso that one or both of R~ and R2 is other than hydrogen;
or a salt thereof.
Preferred intermediates include compounds of formula (lll), (IV) 2o and (V) wherein m is zero or 1;
W is -C02-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+).- or (-)-isomer thereof.

Particularly preferred intermediates are compounds of formula (III), (lV) and (V) wherein n and m are both 0;
W is -C02-G wherein G is hydrogen or a carboxy protecting group;
s and R~ is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furany! or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl; 4-ethoxyphenyl, 4-ethylphenyl, 4-~o methylphenyl, 4-trifluoromethylphenyl, 4-pentafiuoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, and (xiii) alkylsulfonyfamidoalkyl, and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-2o benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fiuorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or 2s the substantially pure (+)- or (-)-isomer thereof.
Other compounds which are useful as intermediates for the preparation of compounds of the invention are:
( W R, (VI) ~Rsb-D
'N
(CH2)n CH2)m wherein n is 0 or 1;
m is 0 to 6;
R 5b is alkylene;
D is a leaving group;
s W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -P03H2, (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHRi~ where R~7 is loweralkyi, ~o (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, ~ s (k) sulfonamido, (I) -C(O)NHS(O)2R i s where Ri 6 is loweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(O)2NHC(O)R~6, Ho 0 NH
(n) o , s.S' o 20 (O) HO O
OH
~~ \ N
i (p) O , O
_~ ' NH
O
(q) O , .~~ Nw O
N
~~H
{r) O , N~ O
~S= O
N
{s) " , ~N
~~-- CFA
N
{t) H , Or - ~ ~ NHSOzCF~
{u) ; and s R~ and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyf, dialkylaminocarbonylalkyl, ~o aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkytsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and {Raa){Rbb)N-Rcc- wherein Raa is aryl or arylafkyl, Rbb is hydrogen or ~ s alkanoyl and Rcc is alkylene, with the proviso that one or both of R 1 and R2 is other than hydrogen;
or a salt thereof;
or a compound of the formula:
R2 ~RSb-Q R2y.... N~R5b-O
'N
(Cl"'~2)n (CH2)n v (CH2)m (CH2)m W R, or W R~
(Vll) (VIII) wherein n is 0 or 1;
m is 0 to 6;

Rsb is alkylene;
Q is a leaving group;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -P03H2, s (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR~7 where R» is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, ~o (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (I} -C(O)NHS{O)2R ~ 6 where Ri s is loweralkyl, haloalkyl, ~ s phenyl or dialkylamino, (m} -S{O)2NHC(O)R~6, HO O
NH
(n) O , O
(~) HO O
OH
~N
{p) O
O
' NH
O
20 (q) O
N\ ' O
N--r( ~~H
( r) *rB

N, O
~S= O
N
(S) H , N
~>-- CFA
N
(t) H , Or - ~ ~ NHS02CF3 (u) ; and R ~ and R2 are independently selected from hydrogen, loweralkyl, s alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, ~o dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(R~b)N-R~~- wherein Raa is aryl or arylalkyl, Rib is hydrogen or alkanoyl and R~~ is aikylene, with the proviso that one or both of R j and ~s R2 is other than hydrogen;
or a salt thereof.
Preferred intermediates include compounds of formula (VI), (VII) and (VIII) wherein m is zero or 1;
2o R5b is alkylene;
Q is a leaving group;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and R~ and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
2s Particularly preferred intermediates are compounds of formula (Vi), (Vil) and (Vl.ll) wherein n and m are both 0;
R 5b is alkylene;
Q is a leaving group;
3o W is -C02-G wherein G is hydrogen or a carboxy protecting group;

and Ri is (i) loweralkyl, (ii) alkenyi, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-s methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyf, 1,3-benzodioxolyl, 1,4-benzodioxanyl ~o or dihydrobenzofuranyl wherein the substituent -'ss selected from loweralkyl, haloalkyl, aikoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryioxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-atkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-~s benzodioxolyi, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or 2o the substantially pure (+)- or (-)-isomer thereof.
Other compounds which are useful as intermediates for the preparation of compounds of the invention are:
R2 N~ Rsb - NHR2oa (CFi2)n ~C~"~2)m R~
W
2s (IX) wherein n is 0 or 7 ;
m is 0 to 6;
Rsb is alkylene;
ao Rzoa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyaikyl, cycloaikyl, cycloalkylalkyl, aryl or aryfalkyl;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -POgH2, *rB

WO 99106397 PCT/US981154?9 (c) -P(O){OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR~~ where Rig is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, o (I) -C(O)NHS(O)2Ry6 where R~6 is toweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(O)2NHC(O)Ris, Ho 0 NH
(n) O , O
(O) HO O
OH
~N
i (p~ O
15 , O
O
(q) o , .~~ Nw O
N
~~H
( r) O , ~O
~S= O
H
(S) , *rB

N' ~
-- CFy N
(t) ~ H , Or - ~ ~ NHSOZCF3 (u) ; and R ~ and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyaikyl, s haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloatkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonyfalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, ~o aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and R~~ is alkylene, with the proviso that one or both of R 1 and R2 is other than hydrogen;
~ s or a salt thereof;
or a compound of the formula:
R2 N~RSb - NHR2oa R2~n... NiRSb - NHR~a w (CH2)n w (CH2)n (CH2)m (CH2)m W R
W R~ or ' (X) (XI) wherein n is 0 or 1;
m is 0 to 6;
R5b is aikylene;
R2oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -P03H2, (c) -P(O)(OH)E where E is hydrogen, foweralkyl or arylalkyl, (d) -CN, (e) -C(U)NHRi7 where R» is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (I) -C(O)NHS(O)2Ri6 where R~6 is loweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(O)2NHC(O)R~s, HO O
NH
I
(n) o , S.s' o (o) Ho 0 OH
~N
i (p) o , O
_~ NH
O'' (q) o ' .~~ Nw O
N
~~H
O
(r) , ~O
~S= O
N
(g) H , ~. N
~~-- CF3 N
(t) H , Or - ~ ~ NHS02CF3 (u) ; and R ~ and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyfalkyi, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, s cycloalkyl, cycloalkylatkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylaikyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, ~o aikylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyf and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and R~~ is alkyiene, with the proviso that one or both of Ri and R2 is other than hydrogen;
or a salt thereof.
~s Preferred intermediates include compounds of formula (lX), (X) and (XI) wherein m is zero or 1;
R5b is alkylene;
R2oa is hydrogen, loweralkyi, alkenyl, haloalkyl, alkoxyalkyl, 2o haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
W is -C02-G wherein G is hydrogen or a carboxy protecting group, and R~ and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
Particularly preferred intermediates are compounds of formula 25 (1X), (X) and (XI) wherein n and m are both 0;
R5b is alkylene;
R2oa is hydrogen, loweralkyl, alkenyl, haloalkyl, aikoxyalkyl, hatoalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
so W is -C02-G wherein G is hydrogen or a carboxy protecting group;
and R1 is (i) loweralkyl, (ii) alkenyl, (iii) atkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-triffuoromethylphenyl, ss 4-pentafluoroethyiphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-_ 89_ ethoxyphenyi, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyi, 1,4-benzodioxanyl or dihydrobenzofuranyf wherein the substituent is selected from loweralkyl; haloalkyl, alkoxy, alkoxyalkoxy and carboxyatkoxy, (ix) s aryalkyi, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)arninoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof.
The foregoing may be better understood by reference to the following examples which are provided for illustration and not intended ~ s 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-ethylcarbodiimide hydrochloride, EtOAc for ethyl acetate, EtOH for ethanol, HOBt for 1-hydroxybenzotriazote, Et3N
2o for triethyiamine, TFA for trifluoroacetic acid and THF for tet rahyd rofu ran.
_Examole 1 2s r n r n - 2- 4-Methox h n I -4- 1 nz i x I- I -1-r ~(aminocarbonvlmethvl) avrrolidine-3-carboxylic acid Example 1 A
h I - 4-m h n I -4-nitr meth I- - 1 nz i x I - I r so To ethyl (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-nitrovinyf)-1,3-benzodioxole (17.0 g, 0.088 mol) dissolved in 180 mL of toluene and heated to 80 °C was added 1,8-diazabicyclo[5,4,0] undec-7-ene (DBU, 0.65 g) with stirring. The mixture was heated until all the 3s vitro starting material dissolved. The solution was stirred without heating for 30 minutes (min) and then an additional 0.65 g of DBU was added. After stirring an additional 45 minutes, thin layer chromatography (5% ethyl acetate in methylene chloride) indicated the absence of vitro starting material. Toluene (200 mL) was added, and the organic phase was washed with dilute hydrochloric acid and NaCI
solution. The organic phase was dried over sodium sulfate and then s concentrated under reduced pressure. The residue obtained 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 recovered ethyl (4-methoxybenzoyl}acetate.
Example 1 B
~h_yl 2-y4-m ethoxypheny~-4-( 1.3-benzodioxol-5-yl)-4.5-dihyrdro-3H-ovrrole-3 ~arboxylate The compound resulting from Example 1A (21 g) in 500 mL of ethanol was hydrogenated under 4 atmospheres of hydrogen pressure ~ s using a Raney nickel 2800 catalyst (51 g). (The Raney nickel was washed with ethanol three times before use.) 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 2o the desired product.
Example 1 C
Ethyl 2-(4-methoxyphenyl-4-(1 3-benzodioxol-5-yl)-pvrrolidine-3-carbox~ate~
~~ a mixture of cis-cis: trans.trans: and cfs.trans-isomers 25 The compound resulting from Example 1 B (11.89 g, 0.324 mol) was dissolved in 27 mL of tetrahydrofuran and 54 mL of ethanol. Sodium cyanoborohydride (2.35 g, 0.374 mot) and 5 mg bromocresol green were added. To this blue solution was added dropwise a solution of 1:2 concentrated HCI in ethanol at such a rate that the color was kept at so fight yellow-green. After the yellow color persisted without additional HCI, the solution was stirred 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 3s pressure. The residue was chromatographed on silica gel eluting with 85:15 ethyl acetate-hexane to give 5.96 g. of a mixture of 64%
traps, traps-compound and 34% cis, traps-compound. Further elution with pure ethyl acetate gave 0.505 g of an unknown solid followed by 3.044 g of pure cis,cis-compound.
Example 1 D
~rans irans 2 {_4 Methoxvpheny_I)-4-l1 3-benzodioxol-5-vll-1-~ro~ylaminocarbonvlmethy~-oyrrolidine-3-carboxylic acid The mixture of 64% irans,trans- and 34% cis,trans-pyrrolidines (the mixture resulting from Example i C) (5.72 g, 15.50 mmol}, ethyldiisopropylamine (4.20 g, 32.56 mmol), and N-propyl ~ o bromoacetamide (3.42 g, 19.0 mmol), prepared by.-the method of Weaver, W.E. and Whaley, W.M., J. Amer. Chem. Soc., ~~: 515 (1947), 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, shaken with potassium bicarbonate solution, dried over sodium sulfate and t s concentrated in vacuo to give 7.16 g of product as a mixture of traps, traps- and cis, traps- ethyl esters.
This mixture was dissolved in a solution of 50 mL 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 20 60 mL of water added. The mixture was extracted with ether to remove the unreacted cis,irans- ethyl ester. The aqueous phase was treated with hydrochloric acid until slightly cloudy. It was then further neutralized with acetic acid to give the crude acid product. The crude product was filtered and purified by dissolving it in tetrahydrofuran, zs drying over sodium sulfate, concentrating in vacuo, and crystallizing from ether to give 3.230 g of the title compound. m.p. 15i-'153 °C. ~ H
NMR (CD30D, 300 MHz) 8 0.87 (t, J = 7 Hz, 3H), 1.49 (sextet, J = 7 Hz, 2H), 2.84 ( d, J = 16 Hz, 1 H), 2.95-3.20 (m, 4H), 3.20 (d, J = i 6 Hz, 1 H), 3.34-3.42 (m, i H), 3.58-3.66 (m, 1 H), 3.78 (s, 3H), 3.88 (d, J = 10 Hz, so 1 H), 5.92 (s, 2H), 6.75 (d, J = 8 Hz, 1 H), 6.86 (dd, J= 8 Hz, J = 1 Hz, 1 H), 6.90 (d, J = 9 Hz, 2H), 7.02 (d, J = 1 Hz, 1 H), 7.40 (d, J = 9 Hz, 2H}.
Examale 2 r n r n - - 4-M hox hen I -4- 1 nzo i x !- I -1- min r n Im h i -s5 p~rrrolidine-3-carboxylic acid Using the method described in Example 1 D, 300 mg of the mixture of 64% trans,trans- and 34% cis,trans-pyrrolidines (the mixture _ g2_ resulting from Example 1 C), 220 mg of diisopropylethylarnine and 184 mg iodoacetamide were reacted at 45 °C in 1 mL acetonitrile to give 291 mg of a mixture of mans, traps- and cis, traps- N-alkylated esters.
A portion (270 mg.) was hydrolyzed with 200 mg NaOH in 1 mL of water s and 3 mL of ethanol; a chloroform extraction was used to remove the unreacted cis,rrans- ethyl ester. The isolation and purification procedures described in Example 1 D were used to give 134 mg of the title compound. m.p. 246-248 °C. 1 H NMR (DMSO-ds, 300 MHz) 8 2.61 (d, J = 16 Hz, 1 H), 2.71 (t, J = 9 Hz, 1 H), 2.90 (t, J = 9 Hz, 1 H), 2.98 (d, J
=
~ 0 16 Hz, 1 H),3.25-3.35 (m, 1 H), 3.45-3.55 (m, 1 H), 3:71 (s, 3H), 3.75 (d, J =
Hz, 1 H), 6.00 (s, 2H), 6.81 (s, 2H), 6.90 (d, J = 8 Hz, 2H), 7.10 (s, 1 H), ?.17 (s, 1 H), 7.34 (s, 1 H), 7.38 (d, J = 8 Hz, 2H).
Example 3 ~s traps.traps-2-~-Methoxynhenyl~-4-(1.3-benzodioxQl-5-YIL1-(4-fluorobenz~,L
p_vrrolidine-3-carbolic acid Using the method described in Example 1 D, 300 mg of the mixture of 64% trans,l'rans- and 34% cis,trans- pyrrolidines (the mixture resulting from Example 1 C), 220 mg of diisopropylethylamine and 185 2o mg of 4-fluorobenzyl bromide were reacted at room temperature for 3 hours in 1 mL of acetonitrile to give 387 mg of a mixture of trans,trans- and cis,trans-N-alkylated esters. A portion (360 mg) was hydrolyzed with 250 mg NaOH in 7 mL of water and 4 mL of ethanol to give 160 mg of the title compound as an amorphous powder. iH NMR
2s (CDC13, 300 MHz) 8 2.74 (t, J = 9 Hz, 1H), 2.95 (t, J = 7 Hz, 1H), 2.98 (d, J
= 14, 1 H), 3.07 (dd, J = 9 Hz, 1 Hz, 1 H), 3.42-3.53 (m, 1 H), 3.70 (d, J = 9 Hz, 1 H), 3.78 (d, J = 14, 1 H), 3.81 (s, 3H), 5.92 (s, 2H), 6.70 (d, J = 8 Hz, 1 H), 6.77 (dd, J = 8 Hz, 1 Hz, 1 H), 6.91 (d, J = 9 Hz, 2H), 6.94 -7.00 (m, 3H), 7.20 - 7.25 (M, 1 H), 7.44 (d, J = 9 Hz, 2H).
Exam lp a 4 frans. frans-2-(4-Methox,~~phen~l-4-(1. 3-ben zodioxol-5-vl)-1-(2-eth oxyethvll ~yrrolidine-3-carbox~rlic acid Using the method described in Example 1 D, 300 mg. of the mixture 3s of 64% traps, traps- and 34% cis, traps-pyrrolidines (the mixture resulting from Example 1 C), 220 mg of diisopropylethylamine and 152 mg of 2-bromoethyl ethyl ether were refiuxed in 1.5 mL acetonitrile fog 3 hours (bath temperature at 95 °C) to give 346 mg of a mixture of traps, irans- and cis, traps-esters. Hydrolysis with 250 mg NaOH in 1 mL of water and 3 mL of ethanol afforded 14'0 mg of the title compound.
m.p. 88 - 90 °C. ~H NMR (CDC13, 300 MHz) 8 1.25 (t, J = 7 Hz, 3H), 2.21-2.32 (m, 1 H), 2.70-2.80 (m, 1 H), 2.85-2,94 (m, 2H), 3.38-3.55 (m, 6H), 3.67 (d, J = 10 Hz, 1 H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, J = 8 Hz, 1 H), 6.84 (m, 1 H), 6.84 (d, J = 9 Hz, 2H), 7.08 (d, J = 1 Hz, 1 H), 7.33 (d, J = 9 Hz, 2H).
1 o Exarnale 5 --r n r n - - 4-M hox hen 1 -4- 1 -b nz i x I- i -1- 2- r x h I
pyrrolidine-3-carboxylic acid Using the method described in Example 1 D, 520 mg of the mixture resulting from Example 1 C, 364 mg of diisopropylethylamine, 50 mg ~ s potassium iodide and 350 mg 2-chloroethyl propyl ether were reacted at 125 °C in 0.5 mL acetonitrile for 4 hours to give 517 mg of a mixture of trans,trans- and cis,trans-esters. A portion (500 mg) was hydrolyzed with 315 mg NaOH in 1 mL of water and 4 mt_ of ethanol to give 225 mg of the title compound as an amorphous powder. ~H NMR
20 (CDC13, 300 MHz) 8 0.87 (t, J = 7 Hz, 3H), 1.53 (sextet, J = 7 Hz, 2H), 2.28-2.41 (m, 1H), 2.71-2.83 {m, iH), 2.92-3.08 (m, 2H), 3.30 (t, J = 7 Hz, 2H), 3.40-3.60 {m, 4H), 3.72-3.83 (m, 1 H), 3.76 (s, 3H), 5.92 (s, 2H), 6.71 (d, J = 8 Hz, 2H), 6.74 (dd, J = 8 Hz, 1 Hz), 6.71 (d, J = 9 Hz, 2H), 7.07 (d, J = 9 Hz, 2H), 7.73 (d, J = 9 Hz, 2H).
Example 6 ~rans;raps 2 f4 Methoxvaheny~-4-(1 3-benzodioxol-5-vl)-1-f2-f2 methoxyethoxy~eth~lt-a_ ry rolidine-3-carboxylic acid so ExamRle 6A
~Jhyl traps traps 2 (4 methoxvohenyl)-4-ji 3-benzodioxol-5-vl) savrrolidine-3-carboxvlate_ To the pure cis,cis-compound resulting from Example 1C (3.02 g) dissolved in 10 mL of ethanol was added 20 drops of a solution of 21 ss sodium ethoxide in ethanol. The reaction mixture was refluxed overnight, at which time thin layer chromatography in ethyl acetate indicated the absence of starting material. The NaOEt was neutralized with HCi in ethanol, and the solution was concentrated in vacuo. The residue was taken up in toluene and extracted with potassium bicarbonate in water. The toluene was dried over sodium sutfate and concentrated under reduced pressure to give 2.775 of the title compound s which was pure by TLC (ethyl acetate).
Example 68 ~rartc traps 2 (4 Methoxvohenyl-Z 4-(1 3-benzodioxol-5-vll-1-f2-(2 methoxvethoxy~ethyll-oyrrolidine-3-carboxylic acid s o Using the method described in Example 1 D, .250 mg of the compound resulting from Example 6A, 150 mg of 2-(2-methoxyethoxy)ethyl bromide and 175 mg diisopropyl-ethylamine in 1 mL acetonitrile were heated at 100 °C for 3 hours to give 229 mg of the irans, traps-ester. A portion (200 mg) was hydrolyzed with 125 mg ~ s NaOH in 1 mL of water and 2 ml- of ethanol to give 151 mg of the title compound as an amorphous powder. iH NMR (CD30D, 300 MHz) 8 2.9-3.9 (m, 13H), 3.81 (s, 3H), 4.49 (d, J = 10 Hz, 1 H}, 5.94 (s, 2H), 8.79 (d, J = 8 Hz, 1 H}, 6.89 (dd, J = 8 Hz, 1 Hz, 1 H), 7.00 (d, J = 9 Hz, 2H), 7.05 (d, J =

Hz, 1 H), 7.49 (d, J = 9 Hz, 2H).
Example 7 traps frans 2 (4 Methoxyphenyl)-4-(7 3-benzodioxo(-5-vl)-1-f2-(2-ovridvllethvll ~y-rrolidine-3-carboxylic acid The compound resulting from Example 6A (250 mg), 2-vinyl pyridine (355 mg) and one drop of acetic acid were dissolved in 2-methoxyethanol, and stirred at 100 °C for 2.5 hours. Toluene was added, and the solution was washed with potassium bicarbonate solution. The solution was dried over potassium bicarbonate and concentrated in vacuo. Toluene was added and the solution re-concentrated. This was so done until the odor of 2-vinylpyridine was gone. The residue was taken up in hot heptane, filtered to remove a small amount of insoluble impurity, and concentrated in vacuo to give 225 mg of intermediate ester. The ester was hydrolyzed by the method described in Example 1 D
to give 202 mg of the title compound as the dihydrate. m.p. 77-80 °C.
1H NMR (CD30D, 300 MHz) S 2.8 - 3.3 (m, 6H), 3.55-3.70 (m, 2H}. 3.76 (s, 3H}, 3.99 (d, J = 10 Hz, 1 H), 5.92 (d, J = 1 Hz, 2H), 6.72 (d, J = 8 Hz, 1 H), R Rc7 ldd. J = 8 Hz. 1 Hz), 6.85 (d, J = 9 Hz, 2H), 6.92 (d, J = 1 Hz, 1 H}, *rB

7.20 (d, J = 9 Hz, 2H), 7.20-7.32 (m, 2H), 7.70-7.80 (m, 2H), 8.40 (d, J =
4 Hz, 1 H).
Exam I
~~'nC traps 2 f4 Methoxvvhenvll 4 f1 3-benzodioxol-5-vl?-i-(morpholin-4 ylcarbonvll-c"rrolidine-3-carboxylic acid To the compound resulting from Example 6A (300 mg) and 164 mg triethylamine dissolved in 2 mL of methylene chloride and cooled in an ice bath was added 146 mg 1-morpholinocarbonyl chloride. The mixture was stirred 3 hours at room temperature. Toluene was added and the solution was washed with potassium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to give the intermediate ester. The ester was hydrolyzed by the method described in Example 1 D
to give 288 mg of the title compound. m.p. 244-246 °C. i H NMR (DMSO-~ s ds, 300 MHz) 8 2.96 (dd, J = l2.Hz, 13 Hz, 1 H), 3.03-3.13 (m, 2H), 3.20-3.30 {m, 2H), 3.40-3.60 (m, 5H), 3.74 {s, 3H), 3.70-3.85 (m, 3H), 5.10 {d, J = 10 Hz, 1 H), 5.99 (d, J = 1 Hz, 2H), 6.80-6.90 (m, 2H), 6.87 (d, J = 9 Hz, 2H), 7.07 (s, 1 H), 7.25 (d, J = 9 Hz, 2H).
Example 9 ran raps-2- 4-M thox hen ( -4- 1 3-benzodiox le-5- I -1- bu lamin c r n I
~rrolidine-3-carboxylic acid To the compound resulting from Example 6A (300 mg) dissolved in 2 mL tetrahydrofuran and cooled in an ice bath was added 88 mg of butyl 25 isocyanate. After 40 minutes at room temperature, toluene was added, ' and the solution was concentrated in vacuo to give the intermediate ester. The ester was hydrolyzed by the method described in Example 1 D
to give 232 mg of the title compound. m.p. 220-221 °C. ~ H NMR (DMSO-d6, 300 MHz) 8 0.78 (t, J = 7 Hz, 3H), 1.10 (sextet, J = 7 Hz, 2H), 1.22 30 (quintet, J = 7 Hz, 2H), 2.78-3.05 (m, 3H), 3.40-3.56 (m, 2H), 3.74 (s, 3H), 3.95-4.05 (m, 1 H), 4.93 (d, J = 9 Hz, 1 H), 5.80 (t, broad, J = 7 Hz, 1 H), 5.99 (s, 2H), 6.78-6.86 (m, 2H), 6.88 (d, J = 9 Hz. 2H), 7.00 {d, J = 1 Hz, 1 H), 7.12 (d, J = 9 Hz, 2H).

Example 1 mans traps 2 (4 Methoxy~henvl) 4- 1 3-benzodioxol-5-v!)-1-(4-methoxX~.henylaminocarbon,~l~-3-~yrrolidine-3-c ra boxvlic acid The compound resulting from Example 6A (300 mg) was treated s with 133 mg of 4-methoxyphenyl isocyanate by the procedure described in Example 9. The resulting ester was hydrolyzed with NaOH using the method described in Example 1 D to give 279 mg of the title compound.
m.p. 185-187 °C. ~ H NMR (CDC13, 300 MHz) b 3.23 (dd, J = 12 Hz, 13 Hz, 1 H), 3.55-3.68 (m, 2H), 3.72 (s, 3H), 3.83 (s, 3H), 4.50-4.65 (m, 1 H), s o 5.06 (d, J = 10 Hz, 1 H), 5.90 (s, 1 H), 5.95 (s, 1 H~f 6.72 (d, J = 9 Hz, 2H), 6.7-6.8 (m, 3H), 6.92 (d, J = 9 Hz, 2H), 6.97 (d, J = 9 Hz, 2H), 7.37 (d, J =
9 Hz, 2H).
Example 11 is traps traps 2 (4 Methoxvphenyl) 4 (1 3 benzodioxol-5-vl)-1-acetvlovrrolidine-3-carboxylic acid The compound resulting from Example 6A (250 mg) in 0.5 mL of toluene was treated with 200 mg of acetic anhydride. After stirring 2 hours at room temperature, water was added and the acetic acid 2o neutralized with potassium bicarbonate. The mixture was extracted with toluene to give 273 mg of the intermediate ester. A portion of the ester (200 mg) was hydrolyzed using the method of Example 1 D to give 211 mg of the title compound. m.p. 248-250 °C. Rotational isomers are seen in the NMR. ~ H NMR (DMSO-d6, 300 MHz) S 1.55 and 2.00 (s, 3H), zs 2.94 and 3.03 (dd, J = 12 Hz, 13 Hz, 1 H), 3.3-3.6 (m, 2H), 3.72 and 3.76 (s, 3H), 4.12 and 4.28 (dd, J = 12 Hz, 7 Hz, 1 H), 4.95 and 5.04 (d, J =
1 OHz, 1 H), 6.00 (s, 2H), 6.75-6.87 (m, 3H), 6.95 and 7.04 (d, J = 9 Hz, 2H), 7.18 and 7.32 (d, J = 9 Hz, 2H).
3o Examale 12 r n raps- - 4-Methox hen ! -4- 1 3-benzodioxol- L -1- 2-f ro I - rr 1i in carboxyfic acid To the compound resulting from Example 6A (300 mg) and 164 mg triethylamine dissolved in 2 mL methylene chloride and cooled in an ice 3s bath was added 138 mg of 2-furoyl chloride. The mixture was stirred 30 minutes at room temperature and then worked up by the procedures described in Example 8 to give the intermediare ester. The ester was hydrolyzed by the procedure described in Example 1 D to give 269 mg of the title compound as an amorphous powder. ~ H NMR (DMSO-d6, 300 MHz} b 3.06 (dd, J = 12 Hz, 13 Hz, 1 H), 3.3-3.6 {m, 2H}, 4.25 (m, 1 H), 5.19 ( d, J = 10 Hz, 1 H), 6.67.4 (m, 8H), 7.8-7.9 (m, 1 H).
Example 13 traps frans 2 t4 MethoxvohenvlL4-!1 3-benzodioxol-5-vll-1 ~ph~nylaminocarbonvll t~vrrolidine-3-carboxylic acid Starting with the compound resulting from Example 6A, phenyl ~ o isocyanate and the procedures described in Exana~ple 9, the title compound was prepared. m.p. 209-211 °C. ~ H NMR (DMSO-ds, 300 MHz) 8 3.03 (dd, 1 H), 3.55 (m, 1 H), 3.70 (m, 1 H), 3.72 (s, 3H), 4.15 (m, 1 H), 5.13 (d, 1 H), 6.00 (s, 2H), 6.88 (m, 5H), 7.07-7.20 (m, 3H), 7.30 (d, 2H), 7.38 (d, 2H), 8.20 (bs, 1 H).
is Example 14 _trans traps 2 (4 Methoxvohenvl)-4-(1 3-benzodioxol-5-vl)-1 ~ ll laminocarbonvlmethvl)-ovrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound 2o was prepared. m.p. 138-140 °C. i H NMR {CDC13, 300 MHz) 8 2.84 (d, 1 H), 2.90-3.i 0 (dt, 2H), 3.28 (d, 1 H), 3.35 (dd, 1 H), 3.62 {m, 1 H), 3.72-3.97 (m, 3H), 3.80 {s, 3H), 5.13 {bd, 2H), 5.80 (m, 1 H), 5.97 (s, 2H), 6.74-6.97 (m, 5H), 7.38 (d, 2H).
25 Exam-ple 1 r n. - - 4-M thox h n I -4- 1 n i x i- I -1- n-bntvlaminocarbonkmeth~rl)-nyrrolidine-3-~arboxvlic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 105-107 °C. ~ H NMR (CDC13, 300 MHz) 8 0.90 (t, 3H), 30 1.30 (m, 2H), 1.45 (m, 2H), 2.80 (d, 1 H), 2.87-3.35 (m, 6H), 3.62 (m, 1 H), 3.80 (s, 3H), 5.97 (s, 2H), 6.75-6.92 (m, 5H), 7.28 (d, 2H).
Example 16 r n . - 4-M th x h n I -4- 1 nzo i x (- I -1- N- n- r I -N-35 methvlaminocar nklmeth~l-~yrrolidine-3-carboxylic acid Using the procedures described ire Example 1 the title compound was prepared as an amorphous solid. Rotational isomers are seen in the - 98_ NMR. ~ H NMR (CDC13, 300 MHz) S 0.73, 0.84 (2t, 3H), 1.49 (m, 2H), 2.80 (dd, 1 H), 2.85 (2s, 3H), 2.95-3.20 (m, 3H), 3.20-3.40 (m, 1 H), 3.40 (d, 1 H), 3.60 (m, 1 H), 3.79 (s, 3H), 5.93 (s, 2H), 6.73 (d, 1 H), 6.86 (m. 2H), 7.03 (m, 1 H), 7.32 (d, 2H).
s Example 17 r n r n - - 4-M th x h n I -4- 1 en odiox 1- I -1- rr li in-1 ~r r~a bonvlmethyl_)-ovrro(idine-3-carboxylic acid Using the procedures described in Example 1 the title compound ~ o was prepared as an amorphous solid. ~ H NMR (CLlCl3, 300 MHz) s 1.40-1.70 (m, 6H), 2.80 {d, 1 H), 3.00 (m, 2H), 3.24-3.43 (m, 5H), 3.60 (m, 2H), 3.73 (d, 1 H), 3.80 (s, 3H), 5.95 (s, 2H), 6.74 (d, 1 H), 6.80-6.90 {m, 3H), 7.04 (d, 1 H), 7.30 (d, 2H).
~ s Examc~le 18 ~~ns irans 2 (4 Methoxvohenyl)-4~1 3-benzodioxol-5-vl)-1-~isobutylaminocarbonylmethxl~yrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 175-177 °C. 1 H NMR (CD30D, 300 MHz) 8 0.87 (dd, 20 6H), 1.75 (septet, 1 H), 2.85 (d, 1 H), 2.90-3.10 (m, 4H), 3.23 (d, 1 H), 3.40 (m, 1 H), 3.58-3.67 (m, 1 H), 3.78 (s, 3H), 3.89 (d, 1 H), 5.92 (s, 2H), 6.76 (d, 1 H), 6.86 (dd, 1 H), 6.91 (d, 2H), 7.02 (d, 1 H), 7.40 (d, 2H).
Example 19 25 ~r~.ns trans-2-(4-Methoxvohenyi)-4-(1 3-benzodioxoi-5-yl)-1-(cvclooentvlaminocarbonKlmethvl)-ovrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 137-139 °C. ~ H NMR (CDC13, 300 MHz) 8 1.34 (m, 2H), 1.62 (m, 4H), 1.90 (m, 2H), 2.76 (d, 1 H), 2.90 (t, 1 H), 3.04 (dd, 1 H), 30 3.22 (d, 1 H), 3.28 (dd, 1 H), 3.40 (m; 1 H), 3.80 (s, 3H), 4.15, (m, 1 H), 5.97 (d, 2H), 6.75-6.95 (m, 5H), 7.27 (m, 2H).

_ 99_ Fxamnle 20 r n r n - - 4-M h x h n I -4- 1 n i x I- I -1- m h lip-4 yl~minocarbonylmethvll-ovrrofidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. ~ H NMR (CDC13, 300 MHz) b 2.82 (d, 1 H), 3.00 (m, 2H}, 3.24 (m, 1 H), 3.30-3.52 (m, 4H), 3.52-3.75 (m, 8H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, 1 H), 6.84 (d, 3H), 7.00 (s, 1 H), 7.28 (d, 2H).
Example 21 --r ~ n r n - - 4-Methox h n I -4- 1 -benzodi x I- ! -1- 2- h n x h I
gyrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared as an amorphous solid. ~ H NMR (CD30D, 300 MHz) 8 2.82 ~ s (m, 1 H), 2.96 (dd, 1 H), 3.13 (m, 1 H), 3.32 (m, 1 H), 3.51-3.70 (m, 2H), 3.77 (s, 3H), 4.00 (d, 1 H), 4.07 (m, 2H), 5.91 (s, 2H), 6.72 (d, 1 H), 6.80-6.95 (m, 6H), 7.03 (d, 1 H), 7:22 {dd, 2H), 7.39 (d, 2H).
Example 22 2o frans traps 2 (4 Me hoxyphenvl)-4- 1 3-benzodioxo~vl)-1-(2-methoxvethyl_aminocarbonvlmethvl)-avrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 107-109 °C. ~ H NMR (CD30D, 300 MHz) b 2.82 (d, 1 H); 2.97 (q, 2H), 3.21 (d, 1 H), 3.38 (m, 1 H), 3.32 (s, 3H), 3.44 (m, 4H), 3.62 (m, 1 H), 3.79 (s, 3H), 3.86 (d, 1 H), 5.93 (s, 2H), 6.76 (d, 1 H), 6.85 (dd, 1 H}, 6.91 (d, 2H), 7.01 (d, 1 H), 7.38 (d, 2H).
Example 23 r n r n - - 4-M thox hen 1 -4- 1 -b n i x I- I -1- x h l -so gyrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared. m.p. 53-55 °C. ~ H NMR (CDC13, 300 MHz) b 0.88 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 1.50 (pentet, J=7Hz, 2H), 2.27 (tt, J=6Hz, 6Hz, 1 H), 2.92 (q, J=1 OHz, 2H), 3.35 (t, J=7Hz, 2H), 3.42-3.56 (m, 4H), 3.68 (d, J=lOHz, 1 H), 3.78 (s, 3H), 5.94 (s, 2H}, 6.73 (d, J=8Hz, 1 H), 6.83 (d, J=9Hz, 2H), 6.82-6.87 (m, 1 H), 7.06 (d, J=2Hz, 1 H), 7.32 (d, J=9Hz, 2H}. MS m/e 442 {M+H)+.

Examofe 24 traps traps 2 ( 1 3 Benzodioxol-5-vl1-4-(4-methoxvphenvll-1 (propvlaminocarbon~lmethvl)-ovrrolidine-3-carboxviic acid Using the procedures described in Example 1 and substituting ethyl {1,3-benzodioxol-5-ylcarbonyl)acetate for ethyl (4-methoxybenzoyl)acetate and 4-(2-nitrovinyl)anisote for 5-(2-nitrovinyl)-1,3-benzodioxol-5yl afforded the title compound. m.p. 97-99 °C. 1 H NMR (CDC13, 300 MHz) 8 0.78 (t, J=7Hz, 3H), 1.39 (sextet, ~ o J=7Hz, 2H), 2.72 (d, J=16Hz, 1 H), 2.74 (t, J=1 OHz; 1 H), 2.80-3.10 (m, 4H), 3.26-3.38 (m, 1 H), 3.53 {m, 1 H), 3.73 (s, 3H), 3.80 (d, J=1 OHz, 2H), 7.80 (t, J=6Hz,. 1 H). MS (DCI/NH3) mle 441 (M+H)+.
Example 25 n r n - - 1 -B n i x I- I -4- 4-m h x h n I -1- r x h I -pyrroiidine-3-carboxylic acid Using the procedures described in Example 5 and substituting ethyl (1,3-benzodioxol-5-ylcarbonyl)acetate for ethyl (4-methoxybenzoyl)acetate and 4-(2-nitrovinyl}anisole for 5-(2-2o nitrovinyl)-1,3-benzodioxol-5yl afforded the title compound. m.p. 67-69 °C. ~ H NMR (CDC13, 300 MHz) S 0.89 (t, J=7Hz, 3H), 1.56 (sextet, J=7Hz, 2H), 2.33 (m, 1 H), 2.78-3.00 (m, 3H), 3.32 (t, J=7Hz, 2H), 3.45-3.57 (m, 4H), 3.73 (m, i H), 3.79 (s, 3H), 5.93 (s, 2H), 6.22 (d, J=8Hz, 1 H), 6.85 (d, J=8Hz, 3H), 6.98 (s, 1 H}, 7.37 (d, J=8Hz, 2H). MS (DCIlNH3) m/e 2s 428 {M+H)+.
Example 26 traps traps 2 l1 3 Benzodioxol-5-vl)-4-f4-methoxvohenvll-1-f2-(2 methoxvethoxv)ethyl)Lpvrrolidine-3-carboxylic acid so Using the procedures . described in Example 4 and substituting the starting materials described in Example 25 and using 2-(2-methoxyethoxy)ethylbromide to alkylate the pyrrolidine nitrogen afforded the title compound. m.p. 85-86 °C. ~ H NMR (CD30D, 300 MHz) 8 3.18-3.90 (m, 15H), 3.79 (s, 3H), 4.57 (d, J=1 OHz, 1 H), 6.02 (s, 2H), 6.91 35 (d, J=BHz, 1 H), 6.95 (d, J=9Hz, 2H), .7.06 (dd, J=8Hz, 1 H), 7.12 (dd, J=1 Hz, 1 H), 7.37 (d, J=9Hz, 2H). MS (DCIINH3) mle 444 (M+H)+.

Example 27 r n r n -2- 1 3-Ben odioxol- I -4- 4-meth h n 1 -1- x th I
pyrrolidine-3-carboxylic acid Using the procedures described in Example 4, substituting the starting materials described in Example 25 and using 2-ethoxyethylbromide to alkylate the pyrrolidine nitrogen afforded the title compound. m.p. 54-56 °C. 1 H NMR (CDC13. 300 MHz) b 0.89 (t, J-7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 1.52 (pentet, J=7Hz, 2H), 2.40 (m, ~0 1H), 2.74-2.98 (m, 3H), 3.46 (t, J=7Hz, 2H), 3.42-3.56 (m, 4H), 3.68 {d, J=1 OHz, 1 H), 3.80 (s, 3H), 5.93 (dd, J=6Hz, 1 Hz, 2H), 6.72 (d, J=8Hz, 1 H), 6.74 {dd, J=9Hz, 3H), 6.96 (s, 1 H), 7.36 (d, J=9Hz, 2H).
Example 28 ~r ns traps 2 (4 Methoxvohenvl)-4-(1 4-benzodioxan-6-vl)-1-~proavlaminocarbon~rlmeth~)-pvrrolidine-3-carboxylic acid Using the procedures described in Example 1 and substituting 6-(2-nitrovinyl)-1,4-benzodioxane. for 5-(2-nitrovinyl)-1,3-benzodioxole afforded the title compound. m.p. 80-81 °C. ~ H NMR (CDC13, 300 MHz) 8 20 0.89 (t, J-7Hz, 3H), 1.49 (sextet, J=7Hz, 2H), 2.78 (d, J=16Hz, 1 H), 2.92 (t, J=1 OHz, 1 H), 3.05-3.43 (m, 5H), 3.24 (d, J=16Hz, 1 H}, 3.52-3.62 (m, 1 H), 3.80 (s, 3H), 3.80 (t, J=1 OHz, 1 H), 4.27 (s, 4H), 6.74-6.93 (m, 5H), 7.29 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 455 (M+H)+.
25 Exam~~lg 29 ~rans traps 2 (4 Methoxyphenvl) 4 (1 4 benzodioxan-6-vll-1-(N-methyl-N
~rogylaminocarbonylmethKl~-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, substituting 6-(2-nitrovinyl)-1,4-benzodioxane for 5-(2-nitrovinyl)-1,3-benzodioxole and so alkylating the pyrrolidine nitrogen with N-methyl-N-propyl bromoacetamide afforded the title compound. m.p. 74-76 °C.
Rotational isomers are seen in the NMR. ~ H NMR (CDCl3, 300 MHz) 8 0.73, 0.83 {2t, J=7Hz, 3H), 1.48 (m, 2H), 2.78 (dd, 1 H), 2.85 {2s, 3H), 2.96-3.15 (m, 3H), 3.27-3.42 (m, 3H), 3.52-3.60 {m, 1 H), 3.75 (d, 1 H), 35 3.78 (s, ~ 3H), 4.22 (s, 4H), 6.80-6.98 (m, 5H), 7.32 (d, 2H}. MS (DClINH3) mle 469 (M+H)+.

FYamole 30 r -4- i I- -1- - h _N
but~nlaminocarbonvlmethvl)-oy_rrolidine-3-cari~o_ ~ li ' Using the procedures described in Example 1, the title compound s was prepared. Rotational isomers are seen in the NMR. ~ H NMR (CD30D, 300 MHz) 8 0.86 (2t, 3H), 1.04-1.50 (m, 4H}, 2.85 (2s, 3H), 2.93-3.20 (m, 4H), 3.40 (m, 2H), 3.52 (dd, 1 H), 3.60 (m, 1 H), 3.80 (s, 3H}, 3.85 (m, 1 H), 5.91 (s, 2H), 6.74 {d, 1 H), 6.83-6.95 (m, 3H), 7.03 (dd, 1 H), 7.35 (dd, 2H).
Fxamole 31 -4- I-4-1 n i I- I-1-N-I- 1 my n I h 1 - rr li in - r li i F_xam Qle 31 A
1 s h I - 4- h h m h h n I-4- 1 i x I- i - rr li in -~,-carbox Iv atel Using the procedures described in Examples 1 A and 1 B and substituting ethyl (4-methoxy-2-methoxymethoxybenzoyl)acetate for ethyl (4-methoxybenzoyl)acetate afforded ethyl 2-(4-methoxy-2-2o methoxymethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4,5-dihydro-3H-pyrroie-3-carboxylate.
The above dihydro pyrrole carboxylate (3.0 g, 7.0 rnmol) was dissolved in 20 mL of methanol, treated with 500 mg of 10% PdIC and placed under hydrogen atmosphere for 32 hours. The catalyst was 25 removed by filtration and the filtrate was concentrated under reduced pressure and chromatographed on silica gel eluting with ethyl acetate to afford the title compound (1.9 g, 63%) as the cis-cis isomer.
~Ya_mgle 31 B
ao r n r n - - 4- h x - -m m .~h x h n I -4- 1 n x I- I -1- N-methyl N butvlaminocarbonvlmethvl) ovrrolidine-3-carboxylic acid The compound resulting from Example 31 A was epimerized by the procedure described in Example 6A. The resulting rrans, traps compound (100 mg, 0.23 mmol) was then reacted by the procedures described in ss Example 1 D substituting N-methyl-N-butyl bromoacetamide for N-propyl bromoacetamide to give the title compound (75 mg, 62%). m.p.
65-67 °C. Rotational isomers are seen in the NMR. ~ H NMR (CDC13. 300 MHz) 8 0.64, 0.68 (2t, J=7Hz,3H),1.14, 1.12 (2 sextet, J=7Hz, 2H), 1.40-1.48 (m, 2H), 2.86, 2.89 3H),2.95-3.42 (m, 6H), 3.50 (s, 3H), (2s, 3.43-3.65 (m, 2H), 3.78 (s, 3H), J=7Hz, 1 H), 5.09 (q, J=7Hz, 2H), 4.30 (t, 5.92 (s, 2H), 6.55 (dd, J=3Hz, 6.68(s, 1 H), 6.72 (s, 1 H), 6.85 1 H), (2t, J=1 Hz, 1 H), 7.04 (t, (dd,J=3Hz, 1 H).
J=1 Hz, 1 H), 7.42 Example 32 ran r n - - 4-M h h n I -4- 1 -benz i xol- I -1- tho ro I
pyrrrolidin-~-one-3-carbaxvlic acid ~o Example 32A
_Ethvl 2 (4 methoxvbenzovl) 3 c rbomethoxv-1 3-benzodioxole-5-propionate To ethyl (4-methoxybenzoyl)acetate (4.44 g, 0.02 mmol) dissolved in 20 mL of anhydrous THF was added in portions 480 mg of NaH. The mixture was stirred .for 30 minutes under nitrogen at ambient temperature. Methyl (1,3-benzodioxol-5-yl) bromoacetate (5.46 g, 0.02 mol) in 5 mL of THF was added. The mixture was stirred overnight at ambient temperature, diluted with 200 mL of EtOAc, and washed with water and brine. The organic phase was dried over sodium sulfate and 2o concentrated in vacuo to afford the title compound (7.67 g, 92%) which .
was used without further purification.
_Examole 32B
Eth I 1- 3- ho r ! -2- 4- h h n I -4- 1 -benzodi xol- I -4 5-dih dro-2s 5-oxo-1 H-pyrrole-3-carboxylate A mixture of the compound resulting from Example 32A {700 mg, 1.69 mmol), 3-ethoxypropytamine (348 mg, 3.38 mmol) and 1 mL of acetic acid in a sealed tube was heated for 18 hours at 125 °C. After cooling the contents of the tube to ambient temperature, 5 mL of water so was added and the mixture extracted with ethyl acetate (2x100 mL).
The. combined organic extracts were washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 3:2 hexane-ethyl acetate to s~ give 330 mg (42%) of the title compound:

_Fxamnle 32C
- 4- n I -4- 1 I - rr li in-nnca-~-carb0 The compound resulting from Example 328 (300 mg, 0.64 mmol) in s 15 mL of methanol was reduced with 100 mg of 10% Pd/C under hydrogen for 3 hours at ambient temperature. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound.
Example 32D
r rn--4- h I-4-1 n i x I- I-1- r I
~yrrolidin-5-one-:~-carboxylic acid To the compound resulting from Example 32C (100 mg, 0.21 mmol) dissolved in 1 mL of ethanol was added 3 drops of a solution of 21 ~ s sodium ethoxide in ethanol. The mixture was heated to 70-80 °C for hours, and then a solution of sodium hydroxide (100 mg) in 1 mL of water was added and heating was continued for 1 additional hour. The reaction mixture was cooled to ambient temperature, the ethanol was removed under reduced pressure, and water was added to the residue 2o which was washed with ether. The aqueous layer was neutralized with 3 M HCI and allowed to stand overnight. The white crystalline solid was collected by filtration to give the title compound (60 mg, 64%). m.p.
134-140 °C. ~ H NMR (DMSO-ds, 300 MHz) 8 1.04 (t, J=7Hz, 3H), 1.55 (sextet, J=7Hz, 2H), 2.48-2.56 (m, 1 H), 2.93 (dd, J=9Hz, 1 H), 3.25 {t, 2s J=7Hz, 2H), 3.28-3.40 (m, 2H), 3.48-3.57 (m, 1 H), 3.78 {s, 3H), 3.88 (d, J=1 OHz, 1 H), 4.72 (d, J=1 OHz, 1 H), 6.02 (s, 2H), 6.74 (dd, J=8Hz, 1 Hz, 1 H), 6.87 (d, J=BHz, 2H), 6.98 (d, J=SHz, 2H), 7.38 (d, J=BHz, 2H). MS
(DCIlNH3) m/e 442 (M+H)+.
3o Example 33 _trans traps 2 (4 Methoxyphenvll 4 t1 3 benzodioxol-5-vll-1-f3-methoxvbenzvl)-pyrrolidin-5-one-3-carboxylic acid Following the procedures described in Example 32 and substituting 3-methoxybenzylamine for 3-ethoxypropylamine afforded 35 the title compound (123 mg, 65%). m.p. 150-152 °C. 1H NMR (CD30D, 300 MHz) 8 2.96 (dd, J=SHz, 1 OHz, 1 H), 3.72 (s, 3H), 3.80 _ (s, 3H), 4.06 (d, . nu_ , w .t gist « .WRH~ 1 Hl. 4.92 (4. J=l6Hz, 2H), 5.92 (s, 2H), "_ "" ,~, .. .,, ..__ ,_, _ . , *rB

6.55-6.63 (m, 2H), 6.82 (d, J=8Hz, 4H), fi.94 {d, J=8Hz, 2H), 7.15-7.22 {m, 3H). MS (DCI/NH3) mle 475 (M+H)+.
FYamole 34 - 4- h n I -4- n i x I- I -1- N N-ii yl_aminocarbonvtmethvl)-~ inP ~~ar ooYlic acid The title compound was prepared as an amorphous soiid using the procedures described in Example 1. ~ H NMR (CDC13, 300 MHz) 8 0.70 -0.90 (m, 12H), 1.10-1.60 (m, 1 OH), 2.75 (d, J=13Hz, 1 H), 2.90-3.10 (m, 4H), 3.15 - 3.30 (m, 2H), 3.40 (d, J=lOHz, 1 H), 3.40 - 3.52 (m, 2H), 3.55 - 3.62 (m, 1 H), 3.75 (d, J=12 Hz, 1 H), 3.79 (s, 3H), 5.93 (dd, J =1 Hz, 3 Hz, 2H), 6.72 (d, J=BHz, 1 H), 6.82-6.90 (m, 3H), 7.03 (d, J=2Hz, 1 H), 7.30 (d, J=9Hz, 2H).
t s F.xamole 35 r - 4_ -4_ n i I- -1- N N
~~~~~tvlaminocarbonvlmethvl) Ryrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. i H NMR (CDC13, 300 MHz) b 0.82 (t, J
20 = 7Hz, 6H), 0.95-1.03 (m, 2H), 1.10-1.30 (m, 8H), 1.40-1.51 (m, 2H), 2.72 (d, J=13Hz, 1 H), 2.90-3.08 (m, 4H), 3.25-3.50 (m, 3H), 3.37 (d, J=13Hz, 1 H), 3.52-3,60 (m, 1 H), 3.70 ( J=1 OHz, 1 H), 3.75 (s, 3H), 5.92 (dd, J=2Hz, SHz, 2H), 6.72 (d, J=BHz, 7 H), 6.80-6.88 (m, 3H), 7.03 (d, J=2Hz, 1 H), 7.30 (d, J=9Hz, 2H).
F.xam~le 36 r n ~ -4- h h n 1-4-1 i x 1-1-NN- i h h i in r n I h I - rr i in - li i The title compound was prepared using the procedures described so in Example 1. m.p. 120-122 °C. ~ H NMR (CDCl3, 300 MHz) S 2.82 {d, J=13, 1 H), 2.94-3.08 (m, 2H), 3.12 (s, 3H), 3.23 (s, 3H), 3.20-3.70 (m, 11 H), 3.73 (d, J=I OHz, 1 H), 3.79 (s, 3H), 5.92 (dd, J= 2Hz. 2Hz, 2H), 6.72 (d, J=BHz, 1 H), 6.80-6.90 (m, 3H), 7.04 (d, J=2Hz, 1 H), 7.30 (d, J=9Hz, 2H).

Fxamole 37 - 4- i 1 - r I' i r r '~-carboxv is acid Using the procedures described in Example 4, 200 mg. of the pure s trans,trans isomer, the compound resulting from Example 6A was reacted with 109 mg of 1-bromo-2-hexyne, prepared by the method described in Perkin i, , 2004 (1987), for 1 hour at 55 °C, to give 226 rng of the intermediate ester. The ester was hydrolyzed using NaOH in ethanol-water for 3 hours at room temperature to give 175 mg of the i o title compound. t H NMR (CDCI3, 300 MHz) 8 1.OOr(t, J=7Hz, 3H), 1.54 (m, 2H), 2.14-2.22 (m, 2H), 2.96 (dd, J=7Hz, 13Hz, 1 H), 3.07 (dd, J=18Hz, 2Hz, 1 H), 3.15 (dd, J=9Hz, 2Hz, 1 H), 3.26 (t, J=9Hz, 1 H), 3.36 (dd, J = 18 Hz, 2Hz, 1 H), 3.47-3.55 (m, 1 H), 3.79 (s, 3H), 3.88 (d, J=9Hz, 1 H), 5.95 (s, 2H), 6.72 (d, J=8Hz, 1 H), 6.80-6.88 (m, 3H), 7.03 (d, J=2Hz, 1 H), 7.22 (d, J=9Hz, 2H).
Fxamole 38 r n r - 4- h h n I -4- 1 nz i x I- I -1- N- 1 r Im h i-,~ o,~o~~~~a~ninocarbonvlmethyll-ovrrolidine-3-carboxylic 2o The title compound was prepared using the procedures described in Example 1. m.p. 167-169 °C. Rotational isomers were seen in the NMR. ~ H NMR (CDC13, 300 MHz) b -0.1 (m), 0.05 (m), 0.12-0.25 (m), 0.32-0.51 (m), 0.67 and 0.74 (2 triplets, 3H), 0.90-1.00 (m), 1.20-1.55 (m), 2.72 {d, J=13Hz, 1 H), 2.85--3.29 (m, 4H), 3.30-3.50 (m, 3H), 3.52-3.62 2s (m, 1 H), 3.65-3.73 (2 doublets, J=1 OHz, 2Hz, i H), 3.78 (s, 3H), 5.95 (2 singlets, 2H), 6.72 (2 doublets, 2H), 6.80-6.90 (m, 3H), 7.00 and 7.05 (2 doublets, J=9Hz, 2H).
Exams so r n r n - - 4-M h x h n I -4- 1 nz i x I- 1 -1- N-m h I-N-p~ntvlaminocarbonvlmethvll-ayrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. ~ H NMR (CDC13, 300 MHz) b 0.85 (t, J=7Hz, 3H), 1.00-1.08 (m), 3s 1.13-1.32 (m), 1.35-1,50 (m), 2.72-2.82 (2 doublets, J=13Hz, 1 H), 2.83 and 2.86 (2 singlets, 3H), 2.92-3.20 (m, 3H), 3.22-3.45 (m, 3H), 3.52 .... ,_ a m n -» /~ .~1.",hlotc ~ H~ 3.75 and 3.76 (2 singlets, 3H), 5.92 J.OG ~~~~, ~~ ~~, v.. ~ ~.... .....-.,...._, .. ."

(2 singlets, 2H), 6.72 (d, J=BHz, 1 H), 6.80-6.87 (m, 3H), 7.03 (2 doublets, J=2Hz, 1 H), 7.30 (d, J=9Hz, 2H).
Fxamole 40 h x h -4- n i I- 1 -1- N N-_di~sobutvlaminocarbonylmethvll Qyrroiidine-3- r oocylic acid The title compound was prepared using the procedures described in Example 1. m.p. 141-143 °C. ~ H NMR (CDCI3, 300 MHz) s 0.54 (d, J=7Hz, 3H), 0.70-0.90 (3 doublets, J=7Hz, 9H), 1.60-1.75 (m, 1 H), 1.90-2.02 (m, 1 H), 2.67 (d, J=l3Hz, 1 H), 2.70 (d, J=13Hz, 1 H), 2.84 (dd, J=6Hz, lSHz, 1 H), 2.96-3.06 (m, 2H), 3.20 (dd, J=9Hz, 1 SHz, 1 H), 3.35 (dd, J=2Hz, 1 OHz, 1 H), 3.44-3.60 (m, 4H), 3.70 (d, J=9Hz, 1 H), 3.79 (s, 3H), 5.94 (dd, J=2Hz, 2Hz, 2H), 6.72 (d, J=9Hz, 1 H), 6.82-6.90 (m, 3H), 7.03 (d, J=2Hz, 1 H), 7.31 {d, J=9Hz, 2H).
~s FxamDle 41 r n I -4- 1 n i x 1 - - N-m h l-N-p~gynvl)aminocarbonkmeth~)-uyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the 2o procedures described in Example 1. Rotational isomers were seen in the NMR. ~ H NMR (CDCI3, 300 MHz) 8 2.09 and 2.32 (2 triplets, J=2Hz, 1 H), 2.80-3.10 (m, 3H), 2.90 and 2.99 (2 singlets, 3H), 3.35-3.50 (m, 2H), 3.52-3.fi2 (m, 1 H), 3.78 (s, 3H), 4.03 (d, J=13Hz, 1 H), 4.00-4.30 (m, 3H), 5.93 (s, 2H), 6.72 (2 doublets, J=BHz, 1 H), 6.80-6.90 (m, 3H), 7.02 and 2s 7.11 (2 doublets, J = 2Hz, 1 H), 7.30 (2 doublets, J=9Hz, 2H).
Example 42 traps traps 2 (4 Methoxv~henvl) 4 (1 3-benzodioxol-5-vl)-1-(N-methyl-N-(n h~PY~I)aminocarbonvimethvl)-oyrroiidine-3-carboxylic acid 3o The title compound was prepared as an amorphous solid using the procedures described in Example 1. ~ H NMR (CDCl3, 300 MHz) 8 0.85 (2 triplets, J=7Hz, 3H), 1.00-1.50 (m, 8H), 2.72-2.82 (2 doublets, J=l3Hz, 1 H), 2.81 and 2.86 (2 singlets, 3H), 2.92-3.20 (m, 3H), 3.22-3.45 (m, 3H), 3.52-3.fi2 (m, 1 H), 3.72 {2 doublets, 1 H), 3.75 and 3.76 (2 singlets ss 3H), 5.94 (2 singlets, 2H), 6.72 (d, J=8Hz, 1 H), 6.80-6.87 (m, 3H), 7.03 (2 doublets, J=2Hz, 1 H), 7.30 (d, J=9~Hz, 1 H).

Fxamnle 43 n i x I- I- -NN- in-b~c tX!)aminoc r~ bonvlmet~yrrolidine-3-carboxylic acid The title compound was prepared using the procedures described s in Example 1. m.p. 123-125 °C. ~ H NMR (CDC13, 300 MHz) b 0.79 (t, J=7Hz, 3H), 0.85 (t, J=7Hz, 3H), 7.00-1.50 (m, 8H), 2.74 (d, J=13Hz, 1 H), 2.90-3.09 (m, 4H), 3.23-3.50 (m, 3H), 3.38 (d, J=13Hz, 1 H), 3.52-3.62 (m, 1 H), 3.75 (d, J=10 Hz, 1 H), 3.78 (s, 3H), 5.93 (dd, J=2Hz, 4Hz), 6.71 (d, J=8Hz, 1 H), 6.81-6.89 (m, 3H), 7.03 (d, J=2Hz, 1 H), 7.30 (d, J=9 Hz, ~0 2H). MS (DCUNH3) m/e 511 (M+H)+. Anal calcd for C29H3sN2Os: C, 68.21; H, 7.50; N, 5.49. Found: C, 68.07; H, 7.47; N, 5.40.
Example 44 traps traps 2 (4-Methox Iphenvl~-4-i;1 3-benzodioxol-5-vll-1-(N,N-~ s diethvlaminocarbonylmethvl)-p~rrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 132-134 °C. ~ H NMR (CDC13, 300 MHz) 8 0.98 (t, J=7Hz, 3H), 1.06 (t, J=7Hz, 3H), 2.78 (d, J=13 Hz, 1 H), 2.95-3.20 (m, 4H), 3.30-3.50 (m, 4H), 3.55-3.65 (m, i H), 3.76 (d, J=12 Hz, 1 H), 3.79 20 (s, 3H), 5.93 (s, 2H), 6.72 (d, J=BHz, 1 H), 6.80-6.90 (m, 3H), 7.02 (d, J=2Hz, 1 H), 7.32 (d, J=9Hz, 2H).
Example 45 tr_ans irans 2 (4 Methoxvoheny~ 4 (1 3 benzodioxol-5-yrl)-1-(N-methyl-N-2s QhP~,nvlaminocarbonyrlmethx~~-RYrro(idine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. t H NMR (CD30D, 300 MHz) 8 2.75-2.85 (m, 2H), 3.05-3.13 (m, 1 H), 3. i 8 (s, 3H), 3.40-3.58 (m, 2H), 3.78 (s, 3H), 3.88 (d, J=l2Hz, 1 H), 5.92 (s, 2H), 6.72 (d, J=BHz, 1 H), 6.75-30 6.85 (m, 3H), 7.00-7.12 (m, 5H), 7.82-7.92 (m, 3H).
Example 46 ~r~nS irans 2 (4 Methoxy,Rhenvf)-4-(1 3-benzodioxol-5-vl)-1-(N-methyl-N
~y 1c ohexyiaminocarbonvimethvl)-~yrrolidine-3-carboxylic acid 35 The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the mn~A ~ H NrUA IC;D~OD. 300 MHz) 8 1.00-1.85 (m, 1 OH), 2.72 and 2.78 (2 singlets, 3H), 2.75-2.82 (2 doublets, J=l2Hz, 1 H), 2.96-3.22 (m, 3H), 3.40-3.65 (m, 3H), 3.68 and 3.82 (2 doublets, J=1 OHz, 1 H), 3.77 and 3.78 (2 singiets, 3H), 5.92 (s, 2H), 6.72 (2 doublets. J=BHz, 1 H), 6.82-6.88 (m, 3H), 7.02 (2 doublets, J=2Hz, 1 H), 7.30-7.40 (2 doublets, J=9Hz, s 2H).
~xamole 47 rn rn- n -1 n i I- I-1-NN- in-nronvllaminocarbonKmethvl) nvrrolidine-3-carbo i t The title compound was prepared using the-procedures described in Example 1. m.p. 170-172 °C. ~ H NMR (CDC13, 300 MHz) 8 0.69 (t, J=7Hz, 3H), 0.85 (t, J=7Hz, 3H), 1.20-1.55 (m, 4H), 2.72 (d, J=13Hz, 1 H), 2.90-3.10 (m, 4H), 3.25-3.47 (m, 4H), 3.35-3.62 (m, 1 H), 3.72 (d, J=9Hz, 1 H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, d, J=8Hz, 1 H), 6.80-6.90 (m, 3H), ~ s 7.02 (d, J=2Hz, 1 H), 7.30 (d, J=9Hz, 2H).
Example 48 r - 4- h x h n I -4- 1 -be i I- -1- N-m h I-N
~sob ~tvia~ninocarb~nylmeth I -~yr_rolidine-3-carboxylic acid 2o The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. ~ H NMR (CD30D, 300 MHz) S 0.65-0.85 (4 doublets, J=7Hz, 6H), 1.75-1.95 (m, 1 H), 2.80 and 2.90 (2 singlets, 3H), 2.90-3.10 (m, 4H), 3.10-3.65 (m, 4H), 3.74 9S, 3H), 3.81 and 3,88 (2 doublets, J=1 OHz, 1 H), 2s 5.93 (s, 2H), 6.72 (d, J=BHz, 1 H), 6.80-6.90 (m, 3H), 7.02 (2 doublets, J=2Hz, 1 H), 7.80-7.90 (2 doublets, J=9Hz, 2H).
F~xamole 49 Alternate Pre~~ration of ao Ethyl 2 L methoxvbenzovl) 4 nitromethvl-3-(1 3-benzodioxole-5-vl)butvrate Example 49A
E 2 (3 4 Methvlenedioxvnhenvl)-1-nitroethene To a stirred solution of piperonal (75g, 500 mmol) in methanol (120 mL) at 10 °C was added nitromethane (27.1 mL, 500 mmol, 1 eq) followed by the dropwise addition of sodium hydroxide (21 g, 525 mmol, 1.05 eq) in sufficient water to achieve a total volume of 50 mL while *rB

WO 99/06397 PCTlUS98/15479 maintaining the temperature between 10-15 °C. The reaction mixture became cloudy, turning to a thick paste. The mixture was stirred for 30 minutes upon completion of the addition, and the mixture was then diluted with ice-water 0350 mL) maintaining the temperature below 5 s °C, until solution was achieved. The resultant solution was poured in a narrow stream (such that it just failed to break into drops) into a rapidly stirred solution of 36% hydrochloric acid (100 mL) in water (150 mL). A yellow solid precipitated (nitrostyrene), and this was collected by filtration, washed with water (1.5 L) until the filtrate was neutral. The filter cake was air dried and then.-fecrystallized from hot ethanol (3 L) to yield E-2-(3,4-methylenedioxy)-nitrostyrene as yellow needles (53 g, 55%). ~ H NMR (300MHz, CDCI3) 8 7.94 (1 H, d, J=13.5Hz), 7.47 (1 H, d, J=13.5Hz), 7.09 (1 H, dd, J=7.5&2Hz), 7.01 (i H, d, J=2Hz), 6.87 (1 H, d, J=7.5Hz), 6.06 (2H, s). MS (DCIINH3) mle 194 (M+H)+, 211 (M+H+NH3)+.
Exam lie 49B
Ethyl 2 (4 methoxvohenvl)oxo 4 vitro-3-(:3 4-methvlenedioxvohenvllbutvrate 2o To a stirred solution of the nitrostyrene resulting from Example 49A (14.17 g, ?3.34 mmol, 1.2 eq) in a mixture of propan-2-of (75 mL) and tetrahydrofuran (175 mL) at room temperature was added successively a solution of ethyl (4-methoxybenzoyl)acetate (11.5 g, 51.7 mmol) in THF (50 mL) followed by 1,8-diazabicyclo[5,4,0)undec-7-2s eve (DBU) (0.45 mL, 3.0 mmol, 0.05 eq). The resultant mixture was stirred at room temperature for 1 hour, then additional DBU (0.45 mL, 3.0 mmol, 0.05 eq) was added. The mixture was stirred a further 1 hour, then the volatiles were removed in vacuo and the residue purified by flash chromatography on 500 g silica gel, eluting with 20% ethy4 so acetate-hexanes changing to 25% ethyl acetate-hexanes as the product eluted. The solvents were removed in vacuo to yield the nitroketoester {19.36 g, 76%) as a viscous oil. Diastereomers were seen in the NMR.
~ H NMR (300 MHz, CDC13,) s 8.06 (2H, d, J=9Hz), 7.89 (2H, d, J=9Hz), 6.96 (2H, d, J=9Hz), 6.91 (2H, d, J=9Hz), 6.77 (1 H, dd, J=9Hz,3Hz), 6.73 (1 H, d, ss J=9Hz), 6.65 (1 H, d, J=3Hz), 5.95 {2H, s), 5.89 (1 H, d, J=4Hz), 5.88 (1 H, d, J=4Hz), 4.90-4.60 (3H, m}, 4.39 (1H, m), 4.18 (2H, q, J=7Hz), 3.94 (2H, WO 9910b397 PCT/US98/15479 -1i1-m), 3.80 {3H,- s), 3.78 (3H, s), 1.19 (3H, t, J=7Hz), 0.99 (3H, t, J=7Hz), MS
(DCIlNH3) m/e 416 (M+H)+, 433 (M+H+NH3)+.
FYam~le 50 r - 4- t -4- 1 n i I- - I -1 _ ~~~ ,r~~~ on~ethl~l)-ovrrolidine-3-, r~ boxvi'~c acid To a stirred solution of the compound resulting from Example 1 C
(100 mg, 0.27 mmol) in acetonitrile (2 mL) was added successively diisopropylethylamine (70 ~L, 0.40 mmol, 1.5 eq) and t-butyl ~ o bromoacetate (48 ~L, 0.29 mmol, 1.1 eq). The mixture was stirred 2 hours, then the solvent was removed in vacuo to yield the crude diester.
To a stirred solution of the diester in ethanol (1 mL) at room temperature was added 50% w/w sodium hydroxide (300 mg, 3.75mmol) in water. The mixture was stirred 2 hours; then the volatiles were 1 s removed in vacuo. The residue was dissolved in water (5 mL), and the solution was washed with ether. The aqueous phase was acidified with acetic acid (300 ~L), and then extracted with ethyl acetate (2x). The combined organic extracts were dried (Na2S04), filtered, and concentrated to yield the title compound (74 mg, 60%) as a white solid.
2o j H NMR (300 MHz, CDC13) 8 7.36 (2H, d, J=8Hz), 7.13 (1 H, d, J=3Hz), 6.90 (1 H, dt, J=3Hz, 8Hz), 6.88 (2H, d, J=8Hz), 6.76 (1 H, d, J=8Hz), 5.96 (2H, s), 3.96 (1 H, d, J=9Hz), 3.81 (3H, s), 3.58 (1 H, ddd, J=12, 10Hz,3Hz), 3.52 (1 H, dd, J=9Hz,3Hz), 3.32 (1 H, d, J=i 7Hz), 3.08 (1 H, t, J=i 0Hz), 2.92 (1H, dd, J=9Hz,7Hz), 2.83 (1H, d, J=l7Hz). MS (DCllNH3) mle 456 2s (M+H)+.
Anal calc for C2sH29N0~ - 0.3 H20: C, 65.07; H, 6.48; N, 3.04. Found: C, 65.02; H, 6.42; N, 2.93.
Exa_mgle 51 so r -M I -4- 1-n h h I - -m I-oroovl)aminoc~vlmeth~cE~-~~~rr~~~~~~p_~.car oxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthalene-1-carboxatdehyde for piperonyt in Example 49A. Rotational isomers are seen in the NMR. ~ H
ss NMR (300 MHz, CDCI3) 8 8.29 (1 H, bd, J=8Hz), 7.86 (2H, d, J=8Hz),7.75 (1 H, d, J=8Hz), 7.49 (3H, m), 7.34 (2H, dd, J=3Hz,9Hz), 6.83 (2H, dd, J=9Hz,2Hz), 4.50 {1,H, m), 3.94 (1H, dd, J=9Hz,2Hz), 3.78 (3H, s), 3.65 s (1 H, m), 3.49 (1 H, d, J=l4Hz), 3.40-2:93 (5H, m), 2.91, 2.83 (3H, s), 1.48 (2H, sept, J=7Hz), 0.83, 0.77 (3H, t, J=7Hz}. MS (DCUNH3) mle 461 (M+H)+. Anal caicd for C2sH29N0~ - 0.5 HOAc: C, 71.00; H, 6.99; N, 5.71.
Found: C, 70.95; H, 7.00; N, 5.46.
~~amole 52 -4- r I - I-N-orow!~~minocarbonvlmethvll oyrroiidine-3-carboxvlic acid o ~xam~le 52A
3 Dihvdrobe zof~ran-5-carboxaiaenvae To a stirred solution of a,a-dichloromethyl methyl ether (2.15 g, 19 mmol, 1.35 eq) in methylene chloride (30 mL) at -40 °C was added successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes ~s later, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH2C12 (5 mL) maintaining the temperature at or below -35 °C. The mixture was warmed to 0 °C, stirred 1 hour, then poured into ice-water, and stirred a further 30 minutes. The mixture was diluted with ether, and the phases separated. The organic phase was concentrated in vacuo, and 2o the residue purified by vacuum distillation to yield the title compound (1.25 g, 60%) as a colorless liquid. b.p. 119-121 °C at 0.3 mm Hg.
FY~m~le 52B
r n - x h n I -4- ih r n f r n- I -1- N-m h I-N-2s ~ proovllarriinocarbon~lmethvl oyrrolidine-3-carboxvli~ acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the compound resulting from Example 52A for piperonal in Example 49A. Rotational isomers are seen in the NMR. ~ H NMR (300 MHz, CDCI3) S 7.33 (1H, d, J=8Hz), 7.28 (1 H, m), 7.19 30 (1 H, m), 6.87 ( 1 H, d, J=8Hz}, 6.73 (1 H, d, J=8Hz), 4.56 ( 1 H, t, J=8Hz), 3.83 (1 H, d, J=lOHz), 3.80 (3H, s), 3.63 (1 H, m), 3.4-3.0 (9H, m), 2.87, 2.84 (3H, s), 1.51 (2H, septet, J=7Hz), 0.88, 0.78 (3H, t, J=7Hz). MS
(DCIINH3) mle 453 (M+H)+. Anal calc for C2sHs2N20s - 0.25 H20: C, 68.33; H, 7.17; N, 6.13. Found: C, 68.60; H, 6.88; N, 5.80.

~mnle 53 4- n I- I h I -pyrrrolidine-3-carbox lic aci The title compound was prepared by the procedures described in s Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. ~ H NMR (300 MHz, CDC13) 8 7.37 (2H, d, J=7.5 Hz), 7.32 (2H, d, J=7.5 Hz), 6.86 (4H, m), 3.83 (1 H, m), 3.81 (3H, s), 3.79 (3H, s), 3.64 (1 H, m), 3.48-2.97 (6H, m), 2.87, 2.83 (3H, s), 2.85 (1H, m), 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz).
o MS (DCI/NH3) mle 441 (M+H)+. Anal calc for C25ki32N2~s ~ 0.5 H20: C , 66.80; H, 7.40; N, 6.23. Found: C, 67.15; H, 7.31; N, 6.00.
Fxamole 54 n - - 4- n I -4- 4- im h h n I - - N- h I-N-~roov~~aminocnrbonxlmethvl)~-oyrrolid~ir e-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-dimethoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. ~ H
NMR (300 MHz, CDCI3) b 7.33 (2H, d, J=7.5 Hz), 7.07 (1H, d, J=2.0 Hz), Zo 6.98 {1 H, m), 6.85 (1 H, d, 7.5 Hz), 6.82 (2H, d, 7.5 Hz), 3.91 (3H, s), 3.86 (3H, s), 3.83 (i H, m), 3.79 (3H, s), 3.64 (1 H, m), 3.50-2.95 (6H, m), 2.87 (1 H, m), 2.85, 2.83 (3H, s), 1.45 {2H, m), 0.84, 0.74 {3H, t, J=7.5 Hz). MS
(DCI/NH3) mle 471 (M+H)+. Anal calc for C2gH34N2~6 ~ 0.5 H20: C, 65.12; H, 7.36; N, 5.84. Found: C, 65.22; H, 7.27; N, 5.59.
Fxample 55 _ 4- h I -4- h h -1- N- h -N-QroQyrllaminocarbonlrlmethy~-oyrrolidine-3-carboxvli i The title compound was prepared by the procedures described in 3o Examples 1 and 49 substituting 3-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDC13) 8 7.33 (2H, d, J=7.5 Hz), 7.24 (1 H, t, J=7.5 Hz), 7.05 (2H, m), 6.85 {2H, dd, J=7.5&2 Hz), 6.76 (1 H, m), 3.83 (1 H, rn), 3.81 (3H, s), 3.79 (3H, s), 3.64 {1 H, m), 3.48-2.97 (6H, m), 2.87, 2.83 (3H, s), 2.85 ( 1 H, m), 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz): MS (DCI/NH3) mle 441 (M+H)+.

-i14-Anal calc for C25H32N20s ~ 0.5 H20: C, 66.80; H, 7.40; N, 6.23. Found: C, 66.76; H, 7.36; N, 6.05.
Example 56 s ~rwrans rrans-2-(4-Methoxvohen~)-4-(2-naohthy!_)-1-(N-methvl-N-proQyl)aminocarbonvlmethvll~,oyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthylene-2-carboxaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. ~ H
o NMR (300 MHz, CDCI3) S 7.82 (4H, m), 7.69 (1 H, m~, 7.47 (2H, m), 7.37 (2H, dd. J=7.5&2 Hz), 6.85 (2H, dd, J=7.5&2 Hz), 3.90 (1H, d, J=8 Hz), 3.78 (3H, s), 3.57 (1 H, m), 3.52-2.97 (6H, m), 2.93, 2.85 (3H, s), 2.90 (1 H, m), 1.52 (2H, m), 0.86, 0.76 (3H, t, J=7.5 Hz). MS (DCIlNH3) mle 461 (M+H)+.
Anal calc for C2sH32N2O4 - 0.5 H2O: C, 71.62; H, 7.08; N, 5.97. Found: C, 1 s 71.58; H, 7.11; N, 6.01.
~xamcle 57 r - 4- l -4- 1 i x I- I - h lfin I I -p~yrrrolidine-3-carboxylic acid zo To the compound resulting from Example 1 C (100 mg, 0.27 mmol) and 2-chloroethyl ethyl sulfide (67.5 mg, 0.5 mmol, 2 equivalents}
dissolved in 6 mL of acetonitrile was added 10 mg of KI and 0.5 ml_ of diisopropylethylamine. The mixture was refiuxed for 4 hours and then concentrated in vacuo. The residue obtained was purified by flash 2s chromatography on silica gel eluting with 4:1 hexane-ethyl acetate to afford 93 mg (75%) of the ethylthioethyl compound.
To the sulfide (90 mg, 0.2 mmol) dissolved in 5 mL of CH2C12 in an ice bath was added 68 mg of 3-chloroperoxybenzoic acid. The mixture was stirred for 40 minutes in the ice bath and for 3 hours at room ao temperature. A 10% solution of sodium hydroxide (2 mL) was added, and the mixture was extracted with EtOAc (2 x 50 mL.). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue obtained was chromatographed on silica gel eluting with EtOAc and 10% MeOH in ss CHzCl2 to afford the sulfoxide (62 mg, 65%).
The ethyl ester was hydrolyzed by the procedure described in FYamnlP 1 D to afford the title compound as a diastereomeric mixture.

m.p. 61-fi3 °C. MS (DClINH3) mle 446 (M+H)+. ~H NMR (CDC13, 300 MHz) 8 1.25, 1.32 (t, J=9Hz, 3H), 2.45-2.75 (m, 4H), 2.84-2.96 (m, 3H), 3.02-3.08 (m, 1 H), 3.32, 3.36 (d, J=3Hz, 1 H), 3.47-3.58 (m, 2H), 3.65, 3.68 (d, J=7.5Hz, 1 H), 3.76, 3.80 (s, 3H), 5.94 (s, 2H), 6.72 (d, J=7.5Hz, 1 H), 3.84-s 3.89 (m, 3H), 7.02 (d, J=6Hz, 1 H), 7.30, 7.34 (d, J=7.5Hz, 2H).
Example h -4- 1 n I- I -1-~j"SQ~~roovlsulfonvlaminolethvl) pyrrolidine-3-carboxvlic acrd To 2-bromoethylamine hydrobromide (1 mm''ol) suspended in anhydrous CH3CN was added 1 equivalent of Et3N. The mixture was stirred for 30 minutes and then 1 equivalent of isopropyl sulfonyl chloride and 1 equivalent of EtsN were added. The resulting mixture was stirred for 2 hours at room temperature and then added to. a s solution of the compound resulting from Example 1 C (185 mg, 0.5 mmol) in 3 mt_ of CH3CN. The mixture was warmed at 50-60 °C for 2 hours, cooled to room temperature, treated with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried and concentrated in vacuo. The residue obtained was 2o chromatographed on silica gel eluting with 3:2 hexane-EtOAc to give 195 mg (75%) of the ethyl ester. The ethyl ester (160 mg, 0.31 mmol) was hydrolyzed by the procedure described in Example 1 D to afford the title compound (133 mg, 88%). m.p. 94-96 °C. 1 H NMR (CD30D, 300 MHz) S 1.2fi (d, J=6Hz, 6H}, 1.97 {s, i H), 2.38 (m, 1 H), 2.77 {m, 1 H}, 2.88 (t, J=9Hz, 1 H), 3.04 (m, 1 H), 3.14 (t, J=7.5Hz, 2H), 3.35 {m, 2H), 3.46 {m, 1 H), 3.58 (m, 1 H), 3.78 (s, 3H), 5.92 {s, 2H), 6.74 (d, J=9Hz, 1 H), 6.86 {dd, J=9Hz,3Hz, 1 H), 6.92 (d, J=9Hz, 2H), 7.00 (d, J=3Hz, 1 H), 7.36 (d, J=9Hz, 2H). MS {DCl/NH3) mle (M+H)+.
3o Example ~9_ rn r -4- x n -1 n i x I- I-1- -i h~l' p~,rrrolidine-3-carboxyrlic acid The title compound was prepared by the procedures described in Example 1 D from the compound resulting from Example 1 C and 2-35 (isobutoxy)ethyl bromide. m.p. 68-70 °C. ~ H NMR (CDC13, 300 MHz) S
0.88 (d, J=6Hz, 6H), 1.82 (quintet, J=6Hz, 1 H), 2:22 (m, 2H), 2.72-2.79 -11 s-(m, 1 H), 2.86-2.95 (m, 2H), 3.13 (d, J=6Hz, 2H), 3.45-3.56 (m, 4H), 3.68 (d, J=9Hz, 1 H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, J=7.5Hz, 1 H}, 6.85 (dd, J=9Hz, 7.5 Hz, 3H), 7.08 (s, 1 H), 7.34 (d, J=9Hz, 2H}. MS (DC11NH3) mle 442 (M+H)+.
Example 60 tr n r ns-2- 4-Me ho h n I -4- 1 nz diox I- I -1- ut Isulf n 1 ,pyrrolidine-3-carboxylic acid To 100 mg (0.271 mmol) of the compound resulting from Example 1 C dissolved in 10 mL of THF was added 1-butanesulfonyl chloride {46.7 mg, 1.1 equivalents) and diisopropylethylamine (53 mg, 1.5 equivalents).
The resulting mixture was stirred for 2.5 hours at room temperature and then the solvent evaporated. The crude product was purified by flash chromatography on silica gel eluting with 3:2 hexane-EtOAc to 1 s afford 120 mg (90%) of the ethyl ester.
The ester (120 mg, 0.244 mmol) was dissolved in 1 mL of EtOH, and a solution of 100 mg of NaOH in 1 mL of water was added. The mixture was stirred for 3 hours at room temperature and then concentrated under reduced pressure. Water (5 mL) was added and the 2o solution was washed with ether to remove any unhydrolyzed traps-cis isomer. The aqueous solution was acidified to pH--6 with acetic acid and then extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the pure title compound 25 (60 mg, 53%) as a white solid. m.p. 67-69 °C. 1 H NMR (CDC13, 300 MHz) b 0.82 (t, J=7.5Hz, 3H), 1.20-1.33 (m, 2H), 1.58-1.68 (m, 2H), 2.48-2.69 (m, 2H), 3.28 (dd, J=9Hz, 1 H), 3.49 (t, J=12Hz, 1 H), 3.65 (dd, J=12Hz, 1 H), 3.82 (s, 3H), 4.32 (dd, J=l2Hz, 1 H), 5.17 (d, J=9Hz, 2H), 5.95 (s, 2H), 6.70-6.78 (m, 3H), 6.92 (d, J=9Hz, 2H), 7.35 (d, J=9Hz, 2H). MS (DCIINH3) 3o m/e 462 (M+H)+.
Fxamole 61 r n n - - 4- h x h n -4- n i x I- I -1- - N-m h I-N
i~ooropyl ~! carbon~Lamino)ethvll-R~rolidine-3-carboxylic acid Example ~1 A
r n - 4-M x h n I -4- i n i I- I -i - m h 1 o~~~rrolidine 3 carboY~~~~r arid ethyl ester To the mixture of cis,trans and traps, traps pyrroiidines resulting s from Example 1 C (400 mg) dissolved in 9 mL of 1,2-dibromoethane was added 0.7 mL of diisopropylethylamine and 30 mg of sodium iodide. The resultant mixture was heated at 100 °C for 1 hour, and then the solvents were removed in vacuo. The residue was taken up in EtOAc and washed sequentially with water and brine, dried and concentrated under ~ o reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 4:1 hexane-EtOAc to give 470 mg of the title product.
IExamQle 61 B
1s I - n I_ _1_ _ m h I in wrrolidin°-~-~~~hoxvlic acid ethyl ester To the compound resulting from Example 61 A (450 mg) dissolved in 10 mL of EtOH was added 0.5 mL of 40% aqueous methylamine and 50 mg of sodium iodide. The mixture was heated at 80 °C for 1 hour, and zo then the solvents were removed in vacuo. The residue was taken up in EtOAc and' washed sequentially with water and brine, dried and concentrated in vacuo. The resultant product was carried on without further purification.
2 s -~
r _ : 4- h -4- I_ . I _.1- _ N_m h I-N-j,°~~»tvrvlamino~ethvll nvrrolidine-3-carboxvli t To the compound resulting from Example 61 B (--150 mg) dissolved in 5 mL of 1,2-dichloroethane was added 0.3 mL of so diisopropylethylamine. The solution was cooled to -40 °C, isobutyryl chloride (0.17 mL) was added, the bath was removed, and the solution was allowed to warm to ambient temperature and stirred for 15 hours.
The solvent was removed in vacuo; the residue was taken up in EtOAc and washed sequentially with 1:1 sodium bicarbonate solutionlwater 3s and brine, dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel eluting with a gradient 1:1 EtOAc-hexanes going to EtOAc and finally using 10% MeOH-EtOAc.

WO 99/Ob397 PCT/US98/15479 The ester was dissolved in 1.5 mL of EtOH; 0.75 mL of a 17%
aqueous NaOH solution was added, and the resultant mixture was stirred at ambient temperature for 3 hours. The solvents were removed in vacuo; the residue was taken up in water and washed with ether. The s aqueous phase was acidified with 1 N H3P04 to pH 3 and extracted twice with ether. The combined organic extracts were washed with brine and dried over NazS04. The solvents were removed in vacuo to provide 82 mg of the title compound as a white foam. Rotamers were seen in the NMR. ~ H NMR (CDC13. 300 MHz) of the major rotamer b 1.06 (d, 3H, .
~ o J=1 OHz), 1.12 (d, 3H, J=1 OHz), 2.15 (m, 1 H), 2.5-3:0 (m, 3H), 2.91 (s, 3H), 3.32 (m, 2H), 3.50 (m, 2H), 3.65 (m, 2H), 3.77 (s, 3H), 5.92 (s, 2H), 6.73 (d, 1 H, J=8Hz), 6.75-6.9 (m, 4H), 6.96 (d, 1 H, J=2Hz), 7.29 (m, 1 H). MS
(DCI/NH3) mlz 469 (M+H)+. Analysis calcd for C2sHs2N20s ~ 0.3 TFA: C, 63.55; H, 6.48; N, 5.57. Found: C, 63.44; H, 6.71; N, 5.24.
Example 62 trans traps 2 l4 Methoxy,~,henvl)-4-(1 3-benzodioxol-5-vl)-1-(2-(N-methyl-N
propionvlamino)ethyl_~oyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in 2o Example 61 substituting propionyi chloride for isobutyryl chloride in Example 61 C. ~ H NMR (CDC13, 300 MHz) of the major rotamer 8 1.13 (t, 3H, J=8Hz), 2.19 (m, 1 H), 2.30 (m, 2H), 2.65-3.0 (m, 3H), 2.85 (s, 3H), 3.25-3.4 (m, 2H), 3.5-3.7 (m, 3H), 3.79 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1 H, J=SHz), 6.75-6.9 (m, 4H), 7.00 (bd s, 1 H), 7.29 (bd s, 1 H). MS (DCI/NH3) mlz 455 (M+H)+. Analysis calcd for C25H3pN20s ~ 1.0 H20: C, 63.55; H, 6.83; N, 5.93 . Found: C, 63.55; H, 6.52; N, 5.73.
Example 63 r - 4-M h n I -4- 1 n i I- I -1- N-m h I-N-so benzvlaminocarbonvlmethvl)-~yrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMR {CDC13, 300 MHz) of the major rotamer 8 2.79 (s, 3H), 2.8-3.2 (m, 2H), 3.48 (m, 2H), 3.61 (m, 2H), 3.77 {s, 3H), 3.78 (m, 1 H), 4.3-4.5 (m, 2H), 5.95 (d, 2H, J=2Hz), 6.7-6.9 {m, 4H), 7.00 (m, 1 H), 3s 7.15-7.35 (m, 7H). MS (FA8/NBA) m/z 503 (M+H)+. Anal calcd for C29H3oN2Os ~ 0.5 H20: C, 68.36; H,5.74; N, 5.50. Found: C,68.41; H, 5.74;
N, 5.36 .

Fxam~le 64 I _ _ 1 i x - -1- N- h I-N-r ~~tylaminocarbonY m thyll wrrolidine-3-carboxvl~c acid s Using the procedures described in Example 1 the title compound was prepared. i H NMR (CDC13, 300 MHz) of the major rotamer 8 0.88 (t, .3H, J=7Hz), 1.06 (t, 3H, J=7Hz), 1.27 (m, 2H), 1.45 (m, 2H), 2.8-3.6 (m, 11 H), 3.79 (s,3H), 3.80 (m, 1 H), 5.92 (bd s, 2H), 6.75 (d, 1 H, J=8Hz), 6.85 (d, 1 H, J=8Hz), 6.92 (d, 2H, J=SHz), 7.03 (s, 1 H), 7.33 (d, 1 H, J=8Hz). MS
~o (DCllNH3) mlz 483 (M+H)+. Anal calcd for C27H34~12C6 - 0.5 HOAc: C, 65.61; H,7.08; N, 5.46. Found: C,65.51; H, 6.70; N, 5.66.
~xam~le 65 n n - - 4-M n -4- 1 i x I- - N-m h I-N-~ s im h I r t min r n im h I - rr 1' in - r li i Using the procedures described in Example 1 the title compound was prepared. ~H NMR (CDCl3, 300 MHz) of the major rotamer S 0.90 (s, 9H), 2.8-3.1 (m, 4H), 2.94 (s, 3H), 3.3-3.5 (m, 3H), 3.61 (m, 1 H), 3.80 (s, 3H), 3.82 (m, 1 H), 5.94 (bd s, 2H), 6.74 (d, 1 H, J=8Hz), 6.86 (d, 2H, 2o J=8Hz), 6.87 (m, 1 H), 7.03 (d, 1 H, J=2Hz), 7.33 (d, 2H, J=8Hz). MS
(DCIINH3) m/z 483 (M+H)+.
Fxamnle 66 r r I . _ 1 n I- I -1- - N- I-N-2s l~~,yl°~ulfonvtamino)ethvll ovrrolidine-3-carboxylic acid To the compound resulting from Example 61 B (60 mg, 0.13 mmol) dissolved in 5 ml. of CH3CN was added 0.2 mL of Et3N and 22 mg (0.143 mmol, 1.1 equivalents) of 1-butanesulfonyl chloride. The mixture was stirred for 1 hour at room temperature and then concentrated in vacuo.
so The crude product was purified by column chromatography on silica get eluting with 1:1 EtOAc-hexane to yield 64 mg (90%) of the ester. Ester hydrolysis by the procedure described in Example 1 D afforded the title compound. m.p. 64-66 °C. j H NMR (CDC13, 300 MHz) 8 0.92 (t, J=7.5Hz, 3H), 1.39 (hexad, J=7.5Hz, 2H), 1.68-1.76 (m, 2H), 2.16-2.25 (m, 1 H), ss 2.72 (s, 3H), 2.75-2.92 (m, 5H), 3.12-3.20 (m, 1 H), 3.25-3.34 (m, 1 H), 3.46-3.55 (m, 2H), 3.65 (d, J=9Hz, 1 H), 3.78 (s, 3H), 5.53 (s, 2H), 6.72 (d, J=7.5Hz, 1 H), 6.82 (dd, J=7.5Hz,3Hz, 1 H), 6.86 (d, J=9Hz, 2H), 7.02 (d, J=3Hz, 1 H), 7.34 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 519 (M+H}+.
~,~,~nole s7 s p~oovh, sulfonylamino)ethyl.)-oyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example fib substituting 1-propanesulfonyl chloride for 1-butanesulfonyl chloride. m.p. 69-70 °C. ~ H NMR (CDCI3. 300 MHz) b 1.02 ~ o (t, J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.18-2:26 (m, 1 H), 2.72 (s, 3H}, 2.75-2.95 (m, 6H), 3.13-3.22 (m, 1H), 3.25-3.35 (m, 1 H), 3.47-3.58 (m, 2H), 3.66 (d, J=9Hz, 1 H), 3.80 (s, 3H), 5.96 (s, 2H}, 6.74 (d, J=7.5Hz, 1 H), 6.84 (d,d, J=7.5Hz, 3Hz, 1 H), 6.87 (d, J=9Hz, 2H), 7.04 (d, J=3Hz, 1 H), 7.43 (d, J=9Hz, 2H). MS (DCI/NH3) mle 505 (M+H)+.
is Fxam~lg 68 rr~na traps-2-(4-0.",e h~~yo~~ylZ-4-(1.3-benzodioxol-5-vl)-1-(2 ~~ronvlsulfonyl)ethyl)-Ryrrolidine-3-carboxylic acid To 1-propanethiol (3.5 g, 46.05 mmol) dissolved in 10 mL of 2o anhydrous THF was added 632 mg (26.32 mmol) of NaH in portions under a nitrogen atmosphere. The mixture was heated at 60-70 °C for 1 hours.
To this mixture was added the compound resulting from Example 61 A
(180 mg, 0.38 mmol} in 2 mL THF. Heating was continued at 60-70 °C
for an additional 2 hours, and then the volatiles were removed under 2s reduced pressure. The crude propylthioethyl adduct was purified by flash chromatography on silica gel eluting with 3:2 hexane-EtOAc to give 170 mg (95%).
To a solution of 170 mg (0.36 mmol) of the sulfide and 93 mg (0.8 mmol) of N-methyimorpholine N-oxide (NMO) in a mixture of 20 mL of so acetone and 5 mL of H20 was added a solution of osmium tetroxide (10 mg) in 0.3 mL of t-butanol. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was partitioned between EtOAc and H20. The organic phase was washed with brine, dried over Na2SOa and concentrated in vacuo. Flash s5 chromatography afforded i77 mg (98%) of the ethyl ester which was hydrolyzed by the procedures described in Example 1 D to afford the title compound. m.p. 73-75 °C. ~ H NMR (CDC13, 300 MHz) 8 1.04 (t, J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.59-2.66 (m, 1 H), 2.84-3.08 (m, 7H), 3.43 (dd, J=9Hz, 3Hz, 1 H), 3.53-3.60 (m, 1 H), 3.68 (d, J=9Hz, 1 H),, 3.82 (s, 3H), 5.96 (s, 2H), 6.75 (d, J=7.5Hz, 1 H), 6.82 (dd, J=7.5Hz, 3Hz, 1 H), 6.88 s (d, J=9Hz, 2H), 6.99 (d, J=3Hz, 1 H), 7.32 (d, J=9Hz, 2H}. MS (DCI/NH3) m/e 476 (M+H)+.
_EZcamp~e fig r - 4- I -4- I- ! -1-N- r n -m Ih 2-enyy-wrrolidine-3-carboxylic acid Exam I~~e 69A
fans-5-Methylhex-2-encZc acid ethy_I ester Oil dispersion sodium hydride (0.85 g} was washed with hexanes and suspended in THF (20 mL), and the mixture was cooled in an ice bath to 0 °C. Diisopropyl(ethoxycarbonylmethyl) phosphonate (5.0 mL) was added slowly and the mixture stirred for 20 minutes at 0 °C.
Isovaleraldehyde (2.0 mL) in THF (5 mL) was added dropwise over five minutes. The ice bath was removed and the mixture stirred for 18 hours 2o at ambient temperature. Saturated ammonium chloride solution (50 mL) was added and the mixture extracted with diethyl ether (3 x 50 mL).
The ether extracts were combined, dried with Na2S04, and evaporated to give a colorless oil which was purified by flash chromatography on silica gel eluting with hexanes. The title compound was isolated as a 2s colorless oil (2.1 g).
Example 69B
traps-5-Methylhex-2-en-1-of The compound resulting from Example fi9A (2.0 g) was dissolved in 3o toluene and cooled to 0 °C in an ice bath. Diisobutylaluminum hydride (1.5 N in toluene, 20 mL) was added dropwise and the solution stirred at 0 °C for two hours. Citric acid solution (25 mL) was added very slowly to the cooled solution. The resulting mixture was stirred for 18 hours at ambient temperature. Diethyl ether (50 mL) was added, the solids ss removed by filtration and washed with additional ether (2 x 25 mL).
The filtrate was extracted with ether (2 x 25 mL). The ether ~...~.,..+c.,.,e onri Wachinas were combined, dried, and evaported to give a W111.aW .v..v ~..~ .. _.

colorless oil which was purified by flash chromatography on silica gel eluting with 25% EtOAc-hexanes. The title compound was isolated as a colorless oil (1.25 g).
Example 69C
traps-1-Bromo-5-methylhex-2-ene The compound resulting from Example 69B (1.0 g) was dissolved in diethyl ether and cooled to 0 °C in an ice bath. Phosphorus tribromide (2.5 g, 0.87 mL) was added dropwise and the solution stirred at 0 °C
for ~ o two hours. The solution was poured onto ice, the.-layers separated, and the aqueous layer extracted with additional ether (3 x 25 m~). The ether layers were combined, dried, and evaporated to give a colorless oil which was used without further purification (0.95 g).
- 4- n - 1 i x I h x-2-enYl_1-pYrrolidine-3-carboxylic acid The title compound was synthesized using the methods detailed in Example 1 D but substituting the compound resulting from Example 69C
2o for N-propyl bromoacetamide. ~ H NMR (CDC13, 300 MHz) b 0.84 {d, 6H, J=8Hz), 1.57 (heptet, 1 H, J=8Hz), 1.87 (t, 2H, J=6Hz), 2.60 (dd, 1 H, J=8Hz,14Hz), 2.86 (t, 1 H, J=1 OHz), 2.96 (dd, 1 H, J=BHz, lOHz), 3.20 (dd, 1 H, J= 5Hz,14Hz), 3.29 (dd, 1 H, J=3Hz,10Hz), 3.50 (m, 1 H), 3.70 (d, 1 H, J=1 OHz), 3.78 (s, 3H), 5.47 (m, 2H), 5.93 (s, 2H), 6.71 (d, 1 H, J=8Hz), 6.83 (d, 3H, J=9Hz), 7.05 (s, 1 H), 7.32 {d, 2H, J=9Hz). MS (DCIINH3) m/e 438 (M+H)~. Anal calcd for C26H3t NO~: C, 71.37; H, 7.14; N, 3.20. Found:
C, 71.16; H, 7.24; N, 3.17.
Example 70 3o r - 4- h h n I -4- 1 n i I- I -1-N- r n -dimethyhex-2-enyil-oKrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in _ Example 69 but substituting 4-methyl-2-pentanone for isovaleraldehyde in Example 69A, which gave -7:1 mixture of trans/cis s5 olefins. The crude product was purified by preparative HPLC (Vydac uC i 8) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The ~ ____.:...... ...crc Imnnh;li7afl tn f7iVe, the product (and its 11CJ11GU W avaw"" ....... .~..r......._ _ - ~

diastereomer) as a white solid. ~ H NMR of the major (traps) isomer:
{CDC13. 300 MHz) 8 0.83 (d, 6H, J=8Hz), 1.56 (s,3H), 1.74 (m, 1 H), 1.92 {d, 2H, J=6Hz), 3.3-3.5 (m, 3H), 3.6-3.8 (m,4H), 3.78 (s, 3H), 3.9-4.0 (m, 1 H), 5.22 (m, 1 H), 5.90 (d, 2H, J=l2Hz), 6.63 (m, 1 H), 6.78 (m, 3H), 6.95 (s, s 1 H), 7.45 (d, 3H, J=8Hz). MS (DCI/NH3) m/e 438 (M+H)+. Anal calcd for C2~H33NO5 ~ 1.0 TFA: C, 61.59; H, 6.06; N, 2.48. Found: C, 61.36; H, 6.10;
N, 2.34.
mole 71 lrans traps-2-{4-Methoxvoheny~,l-4-{1 3 benzodioxol-5-vl)-1-~4 h~eotvlcarbon~,~lmethyrll-o~rrrolidine-3-carboxyrlic acid Example 71 A
1-Chloro-3-ps~vi-2-hexanone is To 2-propylpentanoic acid (156.6 pl, 1.00 mmol) dissolved in anhydrous dichloromethane (2 mL) was added DMF (3 pL, 4 mole %), and the solution was cooled to 0 °C under a nitrogen atmosphere. To the solution was added oxalyl chloride (94.3 p.L, 1.08 mmol) dropwise over a few minutes. The reaction was stirred 18 hours while warming to 2o ambient temperature. The mixture was cooled to 0 °C and excess -0.3 f~
ethereal diazomethane solution was added. The reaction mixture was stirred 18 hours while warming to ambient temperature. The reaction mixture was washed with 1 ~, aqueous sodium carbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated 2s under reduced pressure. The residue was dissolved in ether (2 mL) and cooled to 0 °C under a nitrogen atmosphere. Hydrogen chloride as a 4 N
solution in dioxane (275 ~.L, 1.10 mmol} was added dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. The reaction mixture was concentrated under reduced 3o pressure and the residual oil was used in the next step without further purification.
Exampe 71 B
n I - 4-m h h n I -4- 1 i x I- 1 -1- 4-ss Jl~gp~,ylcarbon,~,rlmethyrl)-oyrrolidine-3-carboxy Ir ate To the compound resulting from Example 71A (1.00 mmol, maximum theoretical yield) was added a solution of the traps, traps ethyl carboxylate from Example 1 C (295 mg, 0.80 mmol as a 50 solution in toluene), diisopropylethylamine (700 p.L, 4.00 mmol) and acetonitrile (4 mL). To the resulting solution was added sodium iodide (12 mg, 10 mole %), and the reaction mixture was stirred 18 hours s under a nitrogen atmosphere at ambient temperature. Additional sodium iodide (24 mg, 20 mole %) and acetonitrile (4 mL) were added, and the reaction mixture was heated at 45-50 °C with stirring for 18 hours.
The reaction mixture was concentrated under reduced pressure, and the residue was chromatographed on silica gel eluting with 1:9 ethyl ~ o acetate-hexane to give 237 mg (46%) of the title -compound as a yellow oil.
Exam~~e 71~
Lran~.trans-2-(4-Methoxyr~ henyl)-4-(1.3-benzodioxol-5-~rly-1-j4-~s hep~,yricarbonyyl)-pyrrolidine-3-carboxxlic acid To the compound resulting from Example 71 B (231 mg, 0.4532 mmol) dissolved in ethanol (10 mL) was added a solution of lithium hydroxide (38 mg, 0.9065 mmol) in water (2.5 mL). The solution was stirred for 18 hours under a nitrogen atmosphere, additional lithium 2o hydroxide (19 mg, 0.4532 mmol) in water (0.5 mL) was added, and stirring was continued 24 hours. The reaction mixture was concentrated under reduced pressure to remove the ethanol, and the aqueous residue was diluted with water (45 mL) and washed with ether (50 mL). The aqueous layer was neutralized with 1 N hydrochloric acid 2s to cloudiness and then 10% aqueous citric acid was added to adjust the pH to -5. This solution was then extracted with 10% ethanol in chloroform (4 x 25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel 3o eluted with 1:1 ethyl acetate-hexane to give 86 mg (39%) of the title compound as an off white powder. ~ H NMR (CDCi3, 300 MHz) b 0.73-0.97 (m, 6H), 1.03-1.33 (m, 6H), 1.36-1.58 (m, 2H), 2.46 (m, 1 H), 2.80-2.98 (m, 3H), 3.38-3.64 (m, 3H), 3.75-3.90 (m, 1 H), 3.79 (s, 3H), 5.94 {s, 2H), 6.75 (d, 1 H), 6.86 (d, 2H), 6.92 (d, 1 H), 7.7 2 (s, 1 H), 7.32 (d, 2H). MS
35 (FAB) m/e 482 (M+H)+. Ana! calcd for C28H3$NO6: C, 69.83; H, 7.32; N, 2.91. Found: C, 69.57; H, 7.41; N, 2.73.

Example 72 traps tran~2 ~~4 Methoxvohenyrl 4 j1 3 benzodioxol 5 y1 -1-lvalP~lmethvf) Qyrrrolidine-3-carbox~rlic acid Example 72A
1-rhloro-2-hexanone Using the procedure described in Example 71 A and substituting pentanoic acid for 2-propylpentanoic acid afforded the title compound as an oil which was used in the next step without further purification.
~o Example 72B
Lrans traps-Ethyl, 2-~4-methoxvoTh,enyl~-4-~(1.3-benzodioxole-5-vl)-1 ~valervimethyrl)-ovrrolidine-3-carboxyrlate Substituting the compound resulting from Example 72A for i ~ s ~chloro-3-propyl-2-hexanone and using the procedure described in Example 71 B, except deleting the first addition of sodium iodide, stirring 18 hours at ambient temperature and purifying by silica gel chromatography eluting with 3:17 ethyl acetate-hexane, the title compound 305 mg (65%) was obtained as a yellow oil.
Examp~ 7?
fr~n~ traps 2-~-Methox~rohen~)~-4-(1.3-benzodioxol-5-vll-1-~,valeryl_m~thy[~rrroli inP,~ 3-cartzoxyrlic acid By substituting the compound resulting from Example 72B for traps, traps-Ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(4-heptylcarbonylmethyl)-pyrrolidine-3-carboxylate and using the procedure described in Example 71 C, except only one solution of lithiurrr hydroxide (81.5 mg, 1.942 mmol) in water (3.5 mL) was added followed by stirring for 18 hours, the title compound 130 mg (46%) was obtained as an off white powder. ~H NMR (CDC13, 300 MHz) b 0.87 (t, 3H), 1.26 (m, 2H), 1.49 (m, 2H), 2.37 (m, 2H), 2.79-2.98 (m, 3H), 3.31-3.49 (m, 2H), 3.56 (m, 1 H), 3.77, 3.79 {d,s, 4H), 5.94 (s, 2H), 6.75 (d, 1 H), 3s 6.81-6.93 (m, 3H), 7.09 (d, 1 H), 7.33 (d, 2H). MS (FAB) m/e 440 (M+H)+.
Anal. calcd for C2sH29NO6: C, 68.32; H, 6.65; N, 3.19. Found:
C. 67.95: H. 6.64; N, 3.05.

FYample 73 _trans aans-2 (4 Methoxvt~henvll-4-(1 3-benzodioxol-5-vll-1-(N-(3.4 rlmethoxvb~nz~l N-methylaminocarbonlrlmethvl)ovrrolidine-3-carboxylic acid Exam~ie 73A
h I -4- 1 n i kt~~,(3 4-dimethoxybenzyrl)aminocarbonylmethvl)ovrrolidine-3-~ ra boxyiic acid ethyrt ester Using the procedure of Example 1 D, paragfaph 1, substituting 3,4-dimethoxybenzyl bromoacetamide for dipropyl brornoacetamide, the desired product mixture was obtained as a white foam in 81 % yield.
E, xam-ole 73B
t5 t;an s cans- and cis trans 2-l~-Methoxymhenyrl)-4-(1.3-benzodioxol-5-yl)-1-~(N~(3 4-dimethoxybenzyrl)-N-methylaminocarbonvlmethvl)nvrrolidine-3-carboxylic acid ethyl ester The resultant product from Example 73A (220 mg, 0.404 mmol) was dissolved in 2 mL dry THF and added dropwise to a stirred, cooled 20 (0 °C) suspension of sodium hydride (23 mg of a 60% by weight mineral oil suspension, 16.5 mg, 0.69 mmol) in 0.2 mL THF, under an argon atmosphere. The resulting mixture was stirred at 0 °C for 1 hour, then methyl iodide (28 pL, 64 mg, 0.45 mmo!) was added. The reaction mixture was stirred at 0 °C for 45 minutes. TLC (Et20) indicated 25 incomplete reaction. An additional portion of methyl iodide (28 pL, 64 mg, 0.45 mmol) and dry 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)pyrimidinone (50 pL, 0.41 mmol) were added. The reaction mixture was stirred at ambient temperature for 2 days. The reaction was poured into 25 mL of 0.5 M aqueous citric acid and extracted with 2 so x 25 mL EtOAc. The combined organic extrracts were washed sequentially with 30 mL water and 30 mL brine, then dried (Na2S04), filtered and concentrated under reduced pressure to produce 270 mg of crude material. Flash chromatography on silica gel eluting with Et20 gave the title compounds as an inseparable mixture in 43% yield. ~ H
ss NMR (CDC13, 300 MHz) S 2.79 (s) and 2.81 (s), for the N-CHa signals. MS
mlz 591 (M+H)+.

WO 99/06397 PC'TIUS98/15479 Example 73C
dimeth~~cvbenzyll-N-methylaminocarbonyrlm~ hvllovrrolidine-3 carboxyrlic acid s To the resultant compound from Example 73B (98 mg, 0.17 mmol) dissolved in 1 ml_ EtOH and cooled to 0 °C was added a solution of lithium hydroxide monohydroxide (17 mg, 0.41 mmol) in 0.5 mL H20. The resulting solution was stirred under a nitrogen atmosphere for 16 hours. The solution was concentrated in vacuo, and the residue was ~ o partitioned between i 5 mL H20 and 15 mL Et20. ~'he aqueous phase was extracted with 5 mL Et20, then the aqueous phase was acidified with 10% aqueous citric acid. The acidic aqueous phase was saturated with NaCI and extracted with 3 x 15 mL EtOAc. The EtOAc extracts were combined, dried (Na2S04), then filtered and concentrated in vacuo to ~ s give 40 mg (42%) of the title compound as a white foam. ~ H NMR
(CD30D, 300 MHz, two rotameric forms) 8 2.85 (s, 3H), 2.94-3.25 (br m, 3H), 3.35-3.70 (br m) and 3.64 (s, 4 H total), 3.70-3.97 (br m), 3.74 (s), 3.76 (s), 3.78 (s), 3.79 (s), 3.81 (s), and 4.03 (br d, J=i 4 Hz, 8H total), 4.43 (AB, 1 H), 5.91 (s) and 5.93 (s, 2H total), 6.50-6.60 (m, 1 H), 6.67-20 7.02 (br m, 6H), 7.29 (br d) and 7.35 (br d, 2H total). HRMS calcd for C3~ H35N2O8 {M+H)+: 563.2393. Found: 563.2385.
example 74 franc franc-~-{ -Methoxvuhe~~ nvl~-4-~1 ~ benz2dioxol-girl)-1-(N-(3_.4-2s dimethoxvbenzvl)~aminocarbonylmethvl)wrrolidine-3-carboxylic acid The procedure of Example 73C was used, with the substitution of the resultant compound from Example 73A for the resultant compound from Example 738, to provide the title compound. ~ H NMR (CD30D, 300 MHz) 8 2.85 (d, J=16Hz, 1 H), 2.92 (br t, J=9Hz, 1 H), 2.98 (br t, J=1 OHz, so 1 H), 3.32-3.39 (br m, 2H), 3.54-3.65 (br m, 1 H), 3.67 (s, 3H), 3.78 (s, 3H), 3.80 (s, 3H), 3.85 (d, J=10 Hz, 1 H), 4.21 (d, J=1 SHz, 1 H), 4.41 (d, J
=
l5Hz, 1 H), 5.91 (s, 2H), 6.67 (d, J=8Hz, 1 H), 6.75-6.95 (m, 7H), 7.33-7.40 (m, 2H). HRMS calcd for C3oHs2N208 (M+H)+: 549.2237. Found:
549.2224.

i xample 75 , j2R 3R 4R)-~l4-Methoxvo'~~lly~~L1 3-benzodioxol-5-vl)-1-((iR)-1-IN.N
diQrooviaminocarbonyly-1-butvl)nvrrolidine-3-carboxylic acid IExamnle 75A_ traps traps-2-(4- etho~ohenvl)-4-(1.3-benzodioxol-5 vl)-1-lli R)~, ~benzyloxvcarbonvl)buityl)ovrrolidine-3-carboxylic acid ethyl ester The procedure of Fung, et. at., J. Med. Chem., 35(10): 1722-34 (1992) was adapted. The resultant compound from Example 6A (103 mg, ~ 0 0.279 mmol) was dissolved in 0.7 mL of nitromethane and 0.7 mL of H20 , and ammonium carbonate (34 mg, 0.35 mmol) and (2S)-benzyl 2-bromopentanoate (78 mg, 0.30 mmol) were added. The reaction was refluxed for 24 hours. The reaction was partitioned between 15 mL of 1 M aqueous Na2C03 and 25 mL of CH2C12. The aqueous phase was 1 s extracted with 2 x 10 mL CH2CI2, and the combined organic phases were washed with 15 mL brine, dried (Na2S04), then filtered and concentrated under reduced pressure to a brown oil (169 mg). The crude product was purified by silica gel chromatography eluting with 3:1 CH2C12-hexane to produce 106 mg (68%) of the title compound as a waxy zo solid. ~ H NMR indicated the presence of two diastereomeric products.
xama~le 75B
Ir~3ns traps-2-~4-Methoxy~henyl)-4-~1 3-benzodioxol-5-vl)-1-lllR)-1-IN.N-~p~~yrlaminocarbonyrl~~-1-butyl)ovrrolidine-3-carboxylic acid ethyl ester .
2s The resultant compound from Example 75A (101 mg, O.i80 mmol) and 30 mg of. 10°l° palladium on charcoal were stirred in 2 mL
EtOAc under 1 atmosphere of H2 for 4 hours. The reaction mixture was filtered through a plug of Celite, using 15 mL MeOH to wash the catalyst., The combined filtrate and wash were concentrated in vacuo to 3o give 81.4 mg (96%) of the crude acid as a white solid.
The above crude acid was combined with HOBt hydrate (41 mg, 0.27 mmol), dipropylamine (26 mg, 0.26 mmot), and 4-methylmorpholine (37 mg, 0.37 mmol) in 2 mL dry DMF. The solution was cooled to -15 °C, then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochioride (44 as mg, 0.23 mmol) was added. The mixture was stirred at -15 °C and allowed to warm slowly to room temperature overnight. The solvent was removed by distillation under reduced pressure, and the residue was partitioned between 20 mL EtOAc and 10 mL of 1 M aqueous Na2C03.
The organic phase was washed with 10 mL of brine, dried (Na2S04), then filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 1:2 Et20-hexane.
s Further purification of overlap fractions by preparative TLC eluting with 1:2 Et20-hexane yielded 32 mg (34%) of a less polar product, and 44 mg (46%) of a more polar product.
Example 75C
~0 2R R 4R - - 4- h h n I -4- 1 n x I- t -1- 1 R -1-,~N N dipropylaminocarbonyl)-1-butyl)pvrrolidine-3-carboxylic acid The procedure of Example 73C was followed, with the substitution of the less polar isomer from Example 75B for the resultant product from Example 73B, to provide the title compound in 94% yield. [a]p = -i s 52° (c=0.235, CH30H). 1 H NMR {CD3OD, 300 MHz) 8 0.55 (t, J=7Hz, 3H), 0.87 (t, J=7Hz) and 0.87-0.94 (m, 6H total), 1.03-1.25 (br m, 2H), 1.25-1.68 (br m, 4H), 1.90-2.07 (br m, 1 H), 2.75-2.94 (br m, 2H), 2.94-3.02 (br m, 2H), 3.20-3.40 (m, overlapping with CD2HOD signal), 3.40-3.60 (br m, 2H), 3.79 (s, 3H), 4.04 (br d, J=9 Hz, 1 H), 5.92 (dd, J=3,5 Hz, 2H), 6.72 20 (d, J=8 Hz, 1 H), 6.79 (dd, J=1.5,8 Hz, 1 H), 6.92-6.98 (br m, 3H), 7.29-7.39 (m, 2H). MS m/z 525 {M+H)+.
Example 76 ~2S 3S 4S) 2 ~~4 Methoxvohenyl)-4-(1 3-benzodioxol-5-vl)-1-((1 R)-1-2s {N N dioroQyrlaminocarbonvl~-1-butyl_)pyrrolidine-3-carboxylic acid The procedure of Example 73C was followed, with the substitution of the more polar isomer from Example 75B for the resultant product from Example 73B, to provide the title compound in 88% yield. [a]p =
+58° (c=0.37, CH30H). ~ H NMR (CD30D, 300 MHz) S 0.57 (br t, J=7Hz, 3H), 3a 0.88-0.98 (m, 6H), 1.08-1.35 (br m, 2H), 1.35-1.68 (br m, 4H), 1.75-1.90 {br m, 1 H), 2.75-2.86 (br m, 2H), 3.10-3.30 (br m, 2H), 3.51-3.65 (br m, 2 H), 3.69 (s, 3H), 4.03-4.16 (br m, 2H), 5.91 (s, 2H), 6.71-6.83 (m, 2H), 6.86-6.97 (m, 3H), 7.32 (br d, J=9Hz, 2H). MS mlz 525 (M+H)+.
*rB

F,xam~le 77 - 4- -4- n i I- _ 1- N-~nroovlaminocarbonyl_)-1-butyl)pyrroJidine-3-carboxylic acid Examol~ 77A
#~ans tram-2-~(~-Methox~!-4-~1 3-benzodioxoLS-vl)-1-l(1 S)-1 jN N-di~ron I~amin~,rarbonyrl)-1-butyrl)~yrrrolidine-3-carboxyrlic acid ethXl ester (2R)-N,N-dipropyl 2-hydroxypentanamide (106 mg, 0.528 mmol, ~ o made by standard procedure) was dissolved in 2 rgL THF under an argon atmosphere, diisopropylethytamine (75 mg, 0.58 mmol) was added, then the solution was cooled to -20 °C. Trifluoromethanesulfonic anhydride (95 pL, 159 mg, 0.565 mmol) was added to the cooled solution over 1 minute, and the reaction mixture was stirred at -20 °C for 1 hour, and ~ s at room temperature for an additional 1 hour. The resulting slurry was recooled to 0 °C, and a solution of the resultant compound from Example 6A (195 mg, 0.528 mmol) and diisopropylethylamine (101 ~.L, 75 mg, 0.58 mmol) in 3 mL of CH2C12 was added. The reaction was stirred at 0 °C for 3 hours and for an additional 2 days at room temperature. TLC
zo (Et20-hexane 1:2) indicated starting materials remained, so the mixture was warmed to reflux for 4 hours. The reaction was cooled, then partitioned between 30 mL EtOAc and 15 mL of 1 M aqueous Na2C03. The aqueous phase was extracted with 15 mL EtOAc, then the combined organic phases were washed with 20 mL brine, dried (Na2S04), filtered zs and concentrated in vacuo to a yellowish oil. Purification by flash chromatography on silica gel eluting with 1:2 Et20-hexane gave 19.9 mg (7%) of a less polar product and 20.1 mg (7%) of a more polar product.
~ H NMR spectra and MS were the same as those of Example 76B.
so Exam Ip a 77B
4 - 4-M I -4- 1 n i x I- I -1- 1 -1- N N-ioroQy~aminocarbonSrl)-1-butvl~gyrrolidine-3-carboxylic acid The procedure of Example 73C was followed, with the substitution of the less polar isomer from Example 77A for the resultant product 35 from Example 73B, to provide the title compound in 100% yield. i H NMR
(CD30D, 300 MHz) and MS identical to those of Example 75C.

F_xamole 78 (~R 3R 4R) 2 (~ Mpthoxvohenvil-4-(1 3-benzodioxol-5-vl)-1-((1S -1- N
di~ro~,~laminocarbony~_ -butvl)Ryrrolidine-3-carb~~~rlic acid The procedure of Example 73C was followed, with the substitution s of the more polar isomer from Example 77A for the resultant product from Example 73B, to provide the title compound in 88% yield. ~ H NMR
(CD30D, 300 MHz) and MS identical to those of Example 76.
~;~amote 79 o prd:,s aran~s-2 ~4 Methoxv~gn~~4-(1 3-benzor~ioxol-5-yl)-1-lN.N-di~n-hr~yJ),~minocarbon I~~~I~ 3-(5-tetr I I rrolidin Carbonyldiimidazole (510 mg, 3.148 mmol) was added to i .020 g (2.00 mmol) of the compound resulting from Example 43 in 2.7 mL THI=, and the mixture was heated for 40 minutes at 50 °C. The reaction ~ s mixture was cooled in an ice bath, and 25% solution of ammonia in methanol was added. After 30 minutes, the solid which had formed was filtered, washed with ethanol and finally with ether to yield 850 mg (83%) of the 3-carboxamide compound. m.p. 194-196 °C.
Phosphorus oxychloride (1.06 g) was added to this amide in 7 mL
20 of pyridine, and the mixture was stirred 1 hour at room temperature.
Dichloromethane was added, and the solution was washed with potassium bicarbonate solution, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with 2:1 hexane-ethyl acetate to give 790 mg (96%) of the 3-2s carbonitrile compound.
To this nitrite in 5 mL toluene was added 385 mg of trimethyl tin chloride and 126 mg sodium azide. The mixture was heated 20 hours at 125 °C (bath temp). After cooling, methanol (5 mL ) was added, and the solution was concentrated in vacuo. To the resulting residue was so added 6 mL of methanol and f mL of water containing 0.2 g phosphoric acid. After stirring 1 hour at room temperature, water was added and the mixture extracted with dichtoromethane. The combined organic extracts were dried and concentrated, and the resulting residue was crystallized from ether to give a solid. The solid was dissolved in as sodium hydroxide solution, filtered from insoluble material and acidified with acetic acid to get 532 mg (62%) of the title compound.
m.p. 165-167 °C. i H NMR (CDC13, 300 MHz) b 0.85 (t, J=7Hz, 3H), 0.87 WO 99!06397 PCT/US98/15479 (t, J=7Hz, 3H), 1.10-1.50 (m, 8H), 3.0-3.6 (m, 8H), 3.70 (s, 3H), 3.7-3.8 (m, 7 H), 3.90 (t, J=9Hz, 1 H), 4.37 (d, J=9Hz, 1 H), 5.86 (s, 2H), 6.62 (d, J=BHz, 1 H), 6.65-6.73 (m, 3H), 6.95 (d, J=2Hz, 1 H), 7.11 (d, J=9Hz, 2H).
Example 80 traps traps-2-~4-Fl~;,oro~n_yjl-4-l1 3-benzodioxol-5-vl)-1-IN.N-di~n b~r ~rl)aminoc~,rbonvlmethyl_lpyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid from methyl (4-flourobenzoyl) acetate and 5-(2-nitrovinyl)-1,3-benzodioxole using the procedures described in Examples 1 and .43. ~ H NMR (CDC13, 300 MHz) 8 0.8i (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.0-1.55 (m, 8H), 2.81 (d, J=13 Hz, 1 H), 2.90-3.10 (m, 4H), 3.15-3.30 (m, 1 H), 3.32-3.45 (m, 3H), 3.55-3.65 (m, 1 H), 3.86 (d, J=lOHz, 1 H), 5.94 (dd, J=2Hz, 4Hz, 2H), 6.72 (d, J=8 Hz, 1 H), 6.86 (d, J= 8 Hz, 1 H), 6.95-7.07 (m, 3H}, 7.32-~ s 7.45 (m, 2H).
Exam I~e 81 - 4- h n ! -4- 1 nz x I- f -1- N N- ' n-b_~t~)aminocarbon~l_methyl)nvrrolidine-3-carboxyrlic acid 2o N,N-Dibutyl glycine (150 mg, 0.813 mmol), prepared by the method of Bowman, R.E., J. Chem. Soc. 1346 (1950), in 0.7 mL of THF was treated with 138 mg (0.852 mmol) carbonyldiimidazole and heated for 30 minutes at 50 °C. After cooling to room temperature, 250 mg (0.678 mmol) of ethyl traps,traps-2-(4-methoxyphenyl)-4-(1,3-2s benzodioxol-5-yl)-pyrrolidine-3-carboxylate, the compound resulting from Example 6A, was added, and the mixture was heated at 45 °C for 30 minutes. The product was chromatographed on silica gel, eluting with 1:1 hexane-ethyl acetate to give 306 mg of the intermediate ethyl ester.
3o The ester was hydrolyzed with sodiumhydroxide in waterand ethanol as a white powder.~ H
to give 265 mg of the title compound NMR (CDC13, 300 MHz) 8 rotational isomers0.75 and 0.85 J=7Hz, - (2 t, 3H), 1.05-1.5 (m, 8H}, 2.65-3.20 (m, (s, 3H), 6H) 3.43-3.70 (m, 3H}, 3.72 3.87 (d, J=l5Hz, 1 H), 4.49 (dd, J=12Hz,and 5.23 (dd, z, 8Hz}
6Hz) J=l2H

35 2H, 5.90 (dd, J=2Hz, 4Hz, 2H), 6.63-6.783H), 6.86 and (d, (m, 7.04 J=9H z, 2H), 7.22 (d, J=9Hz, 2H).

FxamDIe 82 ans traps-2-(,4-Methoxy h~n~~)~~ 3-benzodioxol-5-yll-1-lN-n-butyl)-N-(n Qroovl)amin~ar~onvimet vl)~oyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described s in Example 1. m.p. 160-162 °C. ~ H NMR (CDC13, 300 MHz) rotational isomers 8 0.69, 0.80, 0.84, 0.87 (four triplets, J=7Hz, 6H), 1.00-1.52 (m, 6H), 2.63 and 2.66 (two doublets, J=13Hz, 1 H), 2.90-3.10 (m, 4H), 3.23-3.61 (m, 5H), 3.71 and 3.75 (two doublets, J=1 OHz, 1 H), 3.78 (s, 3H), 5.92-5.96 (m, 2H), 6.72 (d, J=8Hz, 1 H), 6.83-8.89 (m, 3H), 7.03 (d, J=2Hz, ~ 0 1 H), 7.81 (d, J=9Hz, 2H).
Exarn 1~3_ traps traps-2 (4 Methoxvnhenyl~ 4-~(,1 3-benzodioxol-5-yrl)-1-j,?~N N-diln ~Ryrllaminoc3rbonyllethvllovrr li in -~sarboxylic acid ~ s The compound resulting from Example 6A (250 mg, 0.677 mmol), 205 mg (1.36 mmol) dialtyl acrylamide (Polysciences, Inc.), and 10 mg acetic acid were heated at 85 °C in 0.75 mL of methoxyethanol for one hour. Toluene was added, and the solution was washed with bicarbonate solution, dried, and concentrated. Chromatography on silica gel eluting zo with 3:1 hexane-ethyl acetate gave 283 mg (80%) of the diallyl compound.
The diallyl compound was hydrogenated using 10% Pd/C catalyst (27 mg) in ethyl acetate (25 mL) under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated 2s to afford the dipropyl amide ethyl ester in 100% yield.
The ester was hydrolyzed to the title compound by the method of Example 1 D in 83% yield. ~ H NMR (CDCl3, 300 MHz) b 0.82 and 0.83 (two triplets, J=7Hz, 6H), 1.39-1.54 (m, 4H), 2.35-2.60 (m, 3H), 2.80-3.07 (m, 5H), 3.14-3.21 (m, 2H), 3.31-3.38 (m, 1H), 3.51-3.61 (m, 1H), 3.73 (d, so J=12H, 1 H), 3.75 (s, 3H), 5.94 (s, 2H), 6,71 (d, J=9Hz, 1 H), 6.79-6.85 (m, 3H), 7.04. (d, J=2Hz, 1 H)< 7.32 (d, J=9Hz, 2H).

Exa P~,84 traps.traps-2-(4-Methox~tR~pyrl -~4-(1.3-benzodioxol-5-yrl)-~N.N-di(n b~l)a~ninoca~bo~r y~,Ryrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in s Example 8 using dibutyl carbamoyl chloride, prepared by the method of Hoshino et al., Syn. Comm., 17: 1887-1892 (1987), as a starting material. ~ H NMR (CDC13, 300 MHz) 8 0.86 (t, J=7Hz, 6H), 1.14-1.28 (m, 4H), 1.35-1.48 (m, 4H), 2.81-2.94 (m, 2H), 3.11 (t, J=l2Hz, 1 H), 3.30-3.41 (m, 2H), 3.59-3.68 (m, 2H}, 3.76 (s, 3H), 3.78-3.85 (m, 1 H), 5.81 (d, ~ o J=9Hz, 1 H), 5.94 (s, 2H), 6.73-6.86 (m, 5H), 7.24 (d, J=9Hz, 2H}.
Exam I~~ a 8_5 traps.traps-2-~(4-Methoxvohenyl~-4-(1.3-benzodioxol-5-yl}-1-(N N-dijn-butyl~aminocarbonvlmethvl,~yrrrolidin~-3-carboxv(ic acid s~ium sad, ~ s Sodium hydroxide (48.2 mg of 98.3% pure, 1.184 mmol) in 2 mL of MeOH was added to the compound resulting from Example 43 (610 mg, 1.196 mmol.) in 5 mL MeOH. The solution was concentrated to dryness, and the resulting powder was stirred with heptane. The heptane was removed in vacuo to give a powder which was dried in the vacuum oven 2o for 2 hours at 60 °C to yield 627.5 mg of the title compound.
ExamRle 86 traps.traps-2-(4-Methoxvc~henyr~-4~(1 3-benzodioxol-5-y~-1-[2-(N N-di(n butyrllamino)ethyrl]~~rrrolidine-3-carboxyrlirt acid 2s A solution of the bromoethyl compound resulting from Example 61A (150 mg), dibutylamine (150 mg} and sodium iodide (18 mg) in 0.75 mL ethanol was heated at 80 °C for 1 hour. After cooling, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na2S04 and concentrated. More toluene was added, so and the solution was again concentrated to get rid ~of excess dibutylamine. The residue was dissolved in warn°S heptane and filtered from a small amount of insoluble material. The hepane was removed in vacuo to give 143 mg (87%) of the intermediate ethyl ester.
The ester was hydrolyzed by the method of Example 1 D to give the 35 title compound as a white powder. ~ H NMR (CD30D, 300 MHz) 8 0.89 (t, J=7Hz, 6H}, 1.16-1.30 (m, 4H), 1.44-1.56 (m, 4H), 2.48-2.57 (m, 1 H), 2.80-3.08 (m, 8H), 3.14-3.25 (m, 1 H), 3.31-3.38 (m, 7 H), 3.59-3.60 (m, 1 H), 3.74 (s, 3H), 3.75 (d, J=lOHz, 1 H), 5.89 (s, 2H), 6.71 (d, J=9Hz, 1 H), 6.81 (dd, J=9Hz, 2Hz, 1 H), 6.90 (d, J=1 OHz, 2H), 6.96 (d, J=2Hz, 1 H), 7.37 (d, J=lOHz, 2H).
s F,,~~ olc a 87 traps.traps-2-(4-Methoxy~heny~-4-(1.3-benzodioxo!-5- I)-~, 1-~2-jN-IN.N-di n-butyl)aminocarbonyJl~-N-met~rlaminoj.~thyl)gyrrolidine-3-carboxyriic acid Dibutyl carbamoyl chloride (135 mg) was added to the compound resulting from Example 6i B (250 mg) and 150 mg triethylamine in 1 mL
~ o dichloromethane. After stirring 1 hour at room temperature, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na2S04 and concentrated. The residue was chromatographed on silica gel, eluting with a mixture of 38% EtOAc and 62% hexane to give 194 mg of the ethyl ester intermediate.
~ s The ester was hydrolyzed by the method of Example 1 D to afford i41 mg of the title compound. ~H NMR (CD30D, 300 MHz) 8 0.92 (t, J=7Hz, 6H), 1.21-1.32 (m, 4H), 1.42-1.53 (m, 4H), 2.62 (s, 3H), 2.65-2.7fi (m, 1 H), 3.00-3.20 (m, 8H), 3.44-3.55 (m, 1 H), 3.62-3.78 (m, 2H), 3.80 (s, 3H), 4.07 (d, J=12 Hz, 1 H), 5.93 (s, 2H), 6.75 (d, J=9Hz, 1 H), 6.87 (dd, 2o J=9Hz, 2Hz, 1 H), 6.94 (d, J=10 Hz, 2H), 7.04 (d, J=2Hz, 1 H), 7.40 (d, J=lOHz, 2H).
Exam I
traps. traps-2-(4-Methoxvohen~rl)-4-X1.3-benzodioxol-5-,yrl)-1-(N. N-diln-2s butyl)aminocarbonylmethyl, rrolidine-3- N-methanesulfonvl)carboxamide Carbonyldiimidazole (75 mg, 0.463 mmol) was added to 150 mg (0.294 mmol) of the compound resulting from Example 43 in 0.4 mL of tetrahydrofuran, and the solution was stirred at 60 °C for 2 hours.
After cooling, 50 mg (0.52fi mmol) of methanesulfonamide and 68 mg 3~ (0.447 mmol) of DBU in 0.3 mL of THF were added. The mixture was stirred at 45 °C for 2 hours. The solvents were removed in vacuo, and the residue was dissolved in water. A few drops of acetic acid were added, and the solution was lyophilized to give 121 mg (70%} of the title compound. m.p. 170-173 °C. ~ H NMR (CDC13, 300 MHz) 8 0.82 (t, ss J=7Hz, 31-i), 0.88 (t, J=7Hz, 3H), 1.05-1.51, (m, 8H), 2.75-2.86 (m, 2H), 2.83-3.25 (m, 4H}, 3.17 (s, 3H), 3.32-.3.50 (m, 3H), 3.70-3.78 (m, 1 H), 3.80 (s, 3H), 3.87 (d, J=1 OHz, 1 H), 5.96 (dd, J=2Hz, 4Hz, 2H), 6.74 (d, J=9Hz, 1 H), 6.84 (dd, J=9Hz, 2Hz, 1 H), 6.90 (d, J=10 Hz, 2H), 7.01 (d, J=2Hz, 1 H), 7.34 {d, J=lOHz, 2H).
Example 89 s trans.tran~2-(4-Methoxvo, henyl)-4-(1.3-benzodioxol5~rl)-1- .N-diln-butK)aminocarbonxlmethlrl)~yrrolidine-3-lN-benzenesulfonyljcarboxamide The compound resulting from Example 43 was converted to the title compound by the method of Example 88 substituting benzenesulfonamide for methanesuifonamide. m.p. 169-171 °C for a ~ o sample recrystallized from acetonitrile. ~ H NMR ~CDC13, 300 MHz) S
0.81 (t, J=7 Hz, 3H), 0.89 (t, J=7Hz, 3H), 1.02-1.50 {m, 8H), 2.65-2.80 (m, 2H), 2.90-3.25 (m, 4H), 3.80-3.95 (m, 3H), 3.50-3.60 (m, 1 H), 3.65 (d, J=1 OHz, 1 H), 3.81 (s, 3H), 5.94 (s, 2H), 6.70 (s, 2H), 6.81-6.90 (m, 3H), 7.17 (d, J=lOHz, 2H), 7.55 (t, J=7 Hz, 2H), 7.66 (t, J=7Hz, 1 H), 8.95 (d, ~ s J=7Hz, 2H).
Exam~fe 90 traps.traps-2-y4-Methoxvohenvl)-4-(i.3-benzodioxol-5_yll-1-[N.N-di(n~t-~tyrl~~
aminosulfon I,~,yl)-~yrrolidine-3-carboxylic acid 2o Chloromethyl sulfenyl chloride, prepared by the method of Brintzinger et. al., Chem. Ber. $~: 455-457 (1952), is reacted with dibutylamine by the method of E. Vilsmaier described in Liebigs Ann.
Chem. 1055-1063 (1980) to give N,N-dibutyl chloromethyl sulfenyl chloride. Alternatively dimethyl(methylthio)sulfonium 2s tetraflouroborate is reacted with dibutylamine to give N,N-dibutyl methylsulfenyl chloride which is chlorinated with N-chlorosuccinimide to give chloromethyl sulfenyl chloride by the method of E. Vilsmaier, described in the above reference.
The N,N-dibutyl chloromethyl sulfenyl chloride is reacted with the so compound resulting from Example 6A to give ethyl traps, traps-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1-[N, N-di(n-butyl)aminosulfenylmethylJ-pyrrolidine-3-carboxylate. This is oxidized with osmium tetroxide and N-methyl morpholine N-oxide by the method of S. Kaldor and M. Hammond, Tet. Lett. ~?: 5043-5045 (1991) to give 35 the title compound after hydrolysis of the ethyl ester.

exam to a 91 ~~ns. traps-2-t 4=Methoxvohenyl)-4-(,1.3-benzodioxol-5-vl)-1-((N. N-di (n b~tyrl)aminocarbonyl-i-,~?~~-ethyl~Qyrrolidine-3-carboxylic acid ~QIp 91 A
{~)-_Dibutyl 2-bromoorooanamide 2-Bromopropanoic acid (510 mg, 3.33 mmol) and 4-methyimorphoiine (0.74 mL, 6.73 mmol) were dissolved in 10 mL of CH2Ci2, the solution was cooled to 0 °C
under a N2 atmosphere, and then treated dropwise with isobutyl chloroformate ~ o (0.45 mL , 3.5 mmol). After 10 minutes at 0 °C, dibutytam~ne (0.57 mL, 3.4 mmol) was added. The reaction was stirred at 0 °C for i hour and for an additional 16 hours at room temperature. The mixture was partitioned with 25 mL of 1.0 M
aqueous Na2C03 solution, then the organic phase was washed sequentially with 25 mL of i LVI aqueous NaHS04 and 25 mL brine, dried (Na2S04), filtered, and ~ s concentrated under reduced pressure to afford 698 mg (2.64 mmol, 79 %) of the crude bromoamide as a colorless oil. ~ H NMR (CDC13, 300 MHz) 8 0.93 (t, J=7Hz) and 0.97 (t, J=7.5Hz, 6H total}, 1.26-1.60 (m, 7H), 1.60-1.78 (m, 1 H), 1.82 (d, J=6Hz, 3H), 3.04-3.27 {m, 2H}, 3.42-3.64 (m, 2H), 4.54 (q, J=7H, 1 H). MS (DC11NH3) m/e 264 and 266 (M+H)+.
Example 91 B
h I -4- 1 I -1-~(n-buty~a~r irlo)Ecarbon~-1-L S1-ethyl) rrolidine-3-carboxyrlic acid ethyrl ester A solution of the resultant mixture of trans,irans and cis,trans compounds 2s from Example 1 C (232 mg, 0.628 mmol) and the resultant compound from Example 91A {183 mg, 0.693 mmol) in 2 mL of CH3CN was treated with diisopropylethylamine (0.22 mL, 1.3 mmol). The solution was stirred at 60-80 °C
under a N2 atmosphere for 16 hours. The reaction was concentrated under reduced pressure, then the residue was partitioned between 30 mL Et20 and 10 mL
so of 1 ~I aqueous Na2C03 solution. The organic phase was washed with 20 mL
water and 20 mL brine, dried over Na2S0a, filtered and concentrated under reduced pressure to afford the crude amino amide as a brown oil (339 mg, 98%
crude). The product was obtained by flash chromatography on silica gel eluting with 20% EtOAc-hexane to provide 224 mg (70%) of the title compounds as a mixture of 35 4 diastereomers. ~ H NMR {CDC13, 300 MHz) 8 0.66-1.55 (several m, i 9H), 2.63-3.00 (m, 3H), 3.05-3.39 (m, 2H), 3.40-3.76 (m, 4H), 3.78-3.80 (4 s, 3H), 3.84-4.25 (m, 2.6H), 4.38 (d, J=10.5Hz. 0.2H) and 4.58 (d, J=10.5Hz, 0.2H), 5.90-5.97 (m, 2H), 6.68-6.96 (m, 5H). 7.38-7.43 (m, 2H). MS (DCI/NH3) m/e 553 (M+H)+.
Example 91C
s #rans traps-2-~4~Methoxvnheny~-4-(1.3-benzodioxol-5-vl)-1-l(N.N
dibutyfamino)carbonyl-1-{RSV-ethyl)pyrrolidine-3-carboxylic acid The procedure of Example 73C was used, substituting the resultant compound from Example 91 B for the resultant compound from Example 738 to give the title compound in 61 °~ yield. ~ H NMR (CD30D, 300 MHz) 8 0.70-1.05 (several ~ o m, 8H), 1.14 (d, J=6Hz, 2H), 1.17-1.55 (m, 6H), 2.79-3.031m, 3.5H), 3.20-3.65 (br m, 4.6H plus CD2HOD), 3.70-3.78 (m, 0.4H), 3.79 (s, 3H), 3.98 (d, J=BHz, 0.6H), 4.06 (t, J=7.5Hz, 0.4H), 4.25 (d, J=BHz, 0.4H), 5.92 (s) and 5.94 (s, 2H total 6H), 6.73 (d, J=2.5Hz) and 6.75 (d, J=3Hz, 1 H total), 6.78-6.85 (m, 1 H), 6.91-7.00 (m, 3H), 7.30-7.38 (m, 2H). MS {DCI/NH3) m/e 525 {M+H)+. Anal calcd for C3oHaoN20s~0.5H20:
~ s C, 67.52; H, 7.74; N, 5.25. Found: C, 67.63; H, 7.65; N, 5.21.
traps traps-2-(Penl~ll-4-(1.~'oenzodioxol-5-yl)-1-{N.N-di(n-~~rllaminocarbonyrlmeth"",~,~I~-yrrolidine-3-carboxyrlic acid Example 92A
Methyl 2-(4-hexenoyll-4-nitro-3-L .3-benzodioxole-5-yl)but~ rr ate A solution of methyl 3-oxo-6-octenoate (502 mg, 2.95 mmol) in 10 mL of isopropanol was added to a solution of 5-(2-nitrovinyl}-1,3-benzodioxole (712 mg, 2s 3.69 mmol) in 10 mL THF, then DBU (22 ~L, 0.15 mmol) was added. The resulting reddish solution was stirred at room temperature for 20 minutes. TLC {ethyl acetate-hexane, 1:3) indicated complete consumption of ketoester. The solution was concentrated in vacuo and flash chromatographed on silica gel eluting with 18% ethyl acetate in hexane to produce 879 mg {2.42 mmof, 82%} of the title so compound as a mixture of diastereomers in a 1:1 ratio. ~H NMR (CDC13, 300 MHz) 8 1.55-1.66 (m, 3H), 2.02-2.17 (br m, 1 H), 2.20-2.37 (m, 1.5H), 2.49-2.76 (m, 1.5H), 3.57 (s, 1.5H}, 3.74 (s, 1.5H), 3.97 (d, J=7.5H, 0.5H) and 4.05 (d, J =BHz, 0.5H), 4.10-4.20 (m, 1 H), 4.68-4.82 (m, 2H), 5.06-5.52 (m, 2H), 5.95 {2s, 2H), 6.65 (m, 1 H), 6.68 (br s, 1 H), 6.75 (d, 7.5Hz, 1 H). MS (DCI/NH3) mle 381 (M+NH4)+. Anal calcd 35 for C~8H2~N0~: C, 59.50; H, 5.82; N, 3.85. Found: C, 59.32; H, 5.71; N, 3.72.

Example 92B
i I- rr i in - I
The procedures of Example 18 and Example 1 C were followed, with the substitution of the resultant compound from Example 92A for the resultant s compound from Example 1 A, and the substitution of the this resultant compound for the resultant compound from Example 1 B, to provide the title compound in crude form as a yellow oil. This crude compound was epimerized under the following conditions. A solution of the crude compound (660 mg, 2.07 mmol) in 3 mL
methanol was treated with a solution of sodium rnethoxide (made by the addition of ~o sodium metal (14 mg, 0.61 mmol) to 1 mL of methanol). T_he resultant solution was heated at reflux for 18 hours. The reaction was concentrated under reduced pressure, and the residue was partitioned between 25 ml- saturated NaHC03 diluted with 70 mL water and 30 mL of CH2C12. The aqueous phase was extracted (2 x 30 mL CHZC12), then the combined organic phases were washed with 20 mt-i s brine, dried over Na2S04, filtered and the filtrate concentrated under reduced pressure to afford the crude product. Purification by flash chromatography on silica gel eluting with 3.5% methanol in CH2C12 gave 336 mg (57%) the title compound as a yellow oil. ~ H NMR (CDCI3, 300 MHz) b 0.90 (br t, 3H), 1.25-1.70 (br m, 8H), 1.83-2.02 (br s, 2H), 2.58 (dd, J=8,9Hz, 1 H), 2.99 (dd, J=8,14Hz, 1 H), 3.34-3.45 (m, zo 2H), 3.53 (q, J=9Hz, 1 H), 3.66 (s, 3H), 5.94 (s, 2H), 6.65-6.75 (m, 3H).
MS
(DCI/NH3) m/e 320 (M+H)+. Anal calcd for Ci 8H25N04: C, 67.69; H, 7.89; N, 4.39.
Found: C, 67.39; H, 7.84; N, 4.37.
fix. ample 92C
25 traps tran~2-(Penty~)-4-(~ 3-benzodioxol-5-yrl)-1-(N.N-di(n-~~yll,~~minoc rbonKmeth~lyrrrolidine-3-carboxylic acid The procedures of Exampte 1 B-1 D were used, with the substitution of the resultant compound from Example 92A for the resultant compound from Example 1 B, to provide the title compound as a white foam. ~ H NMR (CDCI3, 300 MHz) 8 30 0.87 (br t) and 0.89 (br t, 6H total), 0.97 (t, J=7.5Hz, 3H), 1.21-1.42 (br m, 10), 1.43-1.78 (br m, 6H), 2.76 (t, J=7Hz, 1 H), 3.02-3.30 (br m, 6H), 3.40-3.60 (m, 3H), 3.73 (d, J=l4Hz, 1 H), 5.98 (AB, 2H), 6.70 (d, J=7Hz, 1 H), 6.77 (dd, J=1.5,7Hz, 1 H), 6.89 (d, J=1.SHz, 1 H). MS (DCIINH3) mle 475 (M+H)+. Anal cafcd for C2~H42N205-0.5H20:
C, 67.05; H, 8.96; N, 5.79. Found: C, 67.30; H, 8.77; N, 5.68.

~s.;~.m I~e 93.
tranc tran~~.lPentvl)~-j1.3-benzodioxol-5-yl)-1-j2-(N-orooyrl-N
QroQ,ylsulfonylamiyolethvt~vrrolidine-3-carboxyrlic acid ~~ple 93A
Methyl trans.traps-2-~(penty~-4-y1.3-benz ioxol-5-yrl)-1-(2-bromoethyl)oyrrolidine 3-carboxvlate The procedure of Example 61 A was used, with the substitution of the resultant compound from Example 92B for the resultant compound from Example ~ 0 1 C, to provide the title compound as a yellow oil. ~ H NMR (CDCl3, 300 MHz) 8 0.89 (br t, J=7Hz, 3H), 1.24-1.40 (br m, 6H), 1.fi0-1.80 (br m, 2H), 2.61-2.75 (m, 2H), 2.76-2.91 (m, 2H), 3.i0-3.22 (m, 2H), 3.36-3.47 (m, 2H), 3.68 (s, 3H), 5.92 (s, 2H), 6.69-6.77 (m, 2H), 6.90-6.94 (m, 1 H). MS (DCI/NH3) m/e 426, 428 (M+H)+.
~ s Exam I
Methvl traps ns-2-(Pent)-4-(1_,3-benzodioxol-5-yl)-1-(~N-orooyrl-N-~r"~ylsutfonylamino~t~,~lj~yrrolidine-3-carboxy_late A solution of the resultant compound from Example 93A (102 mg, 0.24 mmol) and tetrabutylammonium iodide (6 mg, 16 pmol) in 1 mL EtOH was treated with 2o propylamine (60 ~L, 0.73 mmol). The solution was warmed to 80 °C for 4 hours.
The reaction was concentrated under reduced pressure, then the residue was dissolved in 35 mL ethyl acetate and extracted with 2 x 15 mL of 1 M aqueous Na2C03. The organic phase was washed with 15 mL brine, then dried over Na2S04, filtered and concentrated under reduced pressure to provide the crude 2s secondary amine as a yellow oil (94.2 mg). The crude amine was dissolved in 1 m ~L
of CH2C12, diiosopropylethylamine (65 ~zL, 0.373 mmol) was added, followed by propylsulfonyl chloride (29 ~L, 0.26 mmol}. The solution was stirred at room temperature for 4 hours. The reaction was quenched with 10% aqueous citric acid (to pH 4), and the mixture was extracted with 2 x 3 m~ CH2C12. The combined so organic extracts were washed with 2 mL brine, then dried over Na2S04, filtered, concentrated in vacuo. Purification by flash chromatography eluting with 20%
ethyl acetate in hexane provided 65.0 mg (53%} of the title compound as a waxy solid. Rt = 0.17 (20%EtOAc-hexane). MS (DCI/NH3) m/e 511 (M~H)+.

Example 93C
tr~n~ franc ~ (p~yj~1 3-benzodio~~,-yl)-1-[~(,N-orooyl-N
Qroovl,~sutfonylamino}ethy~]ovrrolidine-3-carboxylic acid The procedure of Example 71 C was followed, with the substitution of the s resultant compound from Example 93B for the resultant compound from Example 71 B, to provide the title compound as a white foam (47 mg, 80%), Rf = 0.14 (5%MeOH-CH2C12). ~ H NMR (CDC13, 300 MHz) S 0.88 (br t) and 0.92 (t, J=7Hz, 6H
total), 1.22-1.52 (br m, 6H), 1.63 (sextet, J=BHz, 2H), 1.75-2.10 (br m, 4H), 2.89-2.98 (m, 2H}, 3.05 (br t, J=9Hz, 1 H), 3.10-3.30 (m, 3H), 3.30-3.80 (br m, 7H), 5.94 (s, 2H), ~ 0 6.71 (t, J=BHz, 1 H), 6.77 (dd, J=1.5,8Hz, 1 H), 6.89 (d, J=1.SHz, 1 H).
MS (DCI/NH3) m/e 497 (M+H)+.
Example 94 ~rans traps-2-(]Proovl}-4 ~(1 3-benzodioxol-5-yl)-1-(N.N-di(n-~ 5 ~~!)aminocarbonXlmeth,~,I)ovrrolidine-3-carboxylic acid Exam l~ 94A
Fthy~4-butanQyl)-4-nitro-3-(1 3-benzodinxole-5-yrl)butyrrate The procedure of Example 92A was followed, with the substitution of ethyl 2o butyryl acetate for methyl 3-oxo-6-octenoate, to provide the title compound as a mixture of traps and cis isomers (47 mg, 80%), Rf = 0.28 (25%EtOAc-hexane). ~
H
NMR (CDCl3, 300 MHz) S 0.74 (t, J=7.5Hz) and 0.91 (t, J=7.5Hz, 3H total), 1.08 (t, J=7Hz) and 1.28 (t, J=7Hz. 3H total), 1.45 (sextet, J=7Hz, 1.5H), 1.63 (sextet, J=7Hz, approx. 1.5H}, 2.77 (t, J=7Hz) and 2.24 (t, J=7Hz, 0.5H total)2.40-2.54 (m, 1H), 2.60 2s (t, J=7.5Hz) and 2.67 (t, J=7.5Hz, 0.5H total), 3.93-4.09 (m, 2H), 4.10-4.20 (br m, 1 H), 4.23 (q, J=7Hz, 1 H), 4.67-4.85 9m, 2H), 5.94 (s, 2H), 6.62-6.75 (m, 3H). MS
(DCIINH3) m/e 369 (M+NH4)+. Anal calcd for C»H2~N0~: C, 58.11; H, 6.02; N, 3.99. Found: G, 58.21; H, 5.98; N, 3.81.
3a ExamQle 94B
I I -4- nz x I- I rr li i r i The procedure of Example 92B was followed, with the substitution of the resultant compound from Example 94A for the resultant compound from Example 92A, to afford the title compound. MS (DCI/NH3) mle 306 (M+H)+.

,~xamole 94C
mans. traps-2-(proRyrl)-4-{1.3-benzodioxol-5-yll-1-f (N. N-diln-b~yl[}aminocarbon, lyr m~th,ypyrrolidine-3-carbom,rlic acid The procedure of Example 92C was followed, with the substitution of the s resultant product from Example 94B for the resultant product from Example 92B, to give the title compound. ~H NMR {CDCI3, 300 MHz) b 0.89 (t, J=7.5Hz), 0.92 (t, J=7.5Hz), and 0.97 {t, J=7.5H, 9H total), 1.22-1.80 {br m, 12H), 2.83 {t, J=7.5Hz, 1 H), 3.40-3.55 (br m, 2H), 3.55-3.68 (m, 1 H), 3.78 (d, J=1 SHz, 1 H), 5.92 (q, J=1 Hz, 2H), 6.70 (d, J=BHz, 1 H), 6.79 (dd, J=1 Hz,BHz, 1 H), 6.90 (d, J=1 Hz, H). MS
(DC1/NH3) ~ o mle 447 (M+H)+. Anal calcd for C25H38N205~0.5 HZO: CJ 65.91; H, 8.63; N, 6.15.
Found: C, 65.91; H, 8.68; N, 5.94.
Exams ~
~( R.2 3R.4,~~-f+)-2-(4-Methoxvohenyl}-4-(I.3-benzodioxol-5-yl}-1-(tert-~ s fly,~o_xycarbonyl-aminocarbonyrlmeth5r(}-pyrrQlidine-3-carboxylic acid ~x~mr~Ie 95A
traris.tran_~2_~4-Methoxyphenyl)-4-(1.3-benzodioxoi-5-yl)-1-(jtert butylo~,rcarbony~aminocarbonylmethyllpyrrolidine-3-carboxylic acid 2o The resulting mixture of 64% traps, traps- and cis, trans-pyrrolidines resulting from Example 1 C (3.01 g, 8.15 mmol) was dissolved in 50 mL of methylene chloride. To this was added dropwise a solution of di-tert-butyl Bicarbonate (1.96 g, 8.97 mmol) in 20 mL
methylene chloride under a nitrogen atmosphere, and the resulting is solution was stirred 30 minutes at which point TLC (ethyl acetate:hexane, 1:1 ) indicated that all of the starting material was consumed. The reaction mixture was concentrated and dried under high vacuum to give 3.94 g of the ethyl ester as a yellow-brown oil. ~ H NMR
(CDCL3, 300 MHz) 8 0.99, 1.07 (br t, br t, J=7 Hz, 3H), 1.11-1.62 (several 3o br m, 9H), 3.05 (br m, 1 H), 3.44-3.95 (m, 3H), 3.81 (s, 3H), 4.04 (q, J=7 Hz, 1 H), 4.14-4.28 (br m, 1 H), 4.89-5.24 (br m, 1 H), 5.94 (d, J=3 Hz, 2H), 6.69-6.90 (m, 5H), 7.06-7.20 (m, 2H). MS (DCI/NH3) m/e 470 (M+H)+.
To the ethyl ester dissolved in 170 mL of ethanol was added a solution of lithium hydroxide (1.06 g, 25.17 mmol) in 60 mL of water.
3s The reaction mixture was vigorously stirred for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated to remove ethanol, diluted with 250 mL of water and extracted three times with 250 mL of ether. The organic phase acidified to slight cloudiness (pH
-7) with 1 ~ hydrochloric acid, then to pH 4 with 10 % citric acid and extracted with 5 % ethanol in methylene chloride (3 x 100 mL). The combined organic layers dried (NazS04), filtered, concentrated and dried on high vacuum to give the title compound as a white foam (2.19 g, 60 }. ~ H NMR (CDC13, 300 MHz) 8 1.16 (v br s, 9H), 3.11 (br m, 1 H), 3.50-3.64 (m, 2H), 3.81 (s, 3H), 4.24 (br m, 1 H), 4.96 (br m, 1 H), 5.94 (s, 2H), 6.71-6.79 (m, 3H), 6.84-6.91 (m, 2H), 7.19 (d, J=9 Hz, 2H). MS (DCI/NH3) m/e 442 (M+H)+.
~o F,xample 95B
(2R.3R,4Sy-(+1-2-~(4-Methoxy~henyl)-4-y1.3-benzodioxol-5-yl)-1-(tert-butyloxyc~3r onylaminocarbonvlmethyILQyrrolidine-3-carboxylic acid The compound resulting from Example 95A (2.15 g, 4.86 mmol) and ~5 (+)-cinchonine (1.43 g, 4.86 mmol) were added to 100 mL of methylene chloride; this suspension was swirled with warming as necessary to get all solids to dissolve. The solution was then concentrated and dried on high vacuum to a white foam. This material was crystallized from a mixture of refluxing chloroform (64 mL) and hexane (360 mL). The 2o resulting crystals were isolated by filtration and recrystallized under the same conditions seven additional times. Each time the resulting crystals and filtrate were monitored by ~ H NMR and chiral HPLC. The amount of (2S,3S,4R)-(-)- enantiomer decreased first in the crystals and then in the filtrate with the predetermined endpoint achieved when z5 the (2S,3S,4R)-(-)- enantiomer could no longer be detected in the filtrate. The pure (2R,3R,4S)-(+}- enantiomer thus obtained was partitioned between 100 mL of 10% citric acid and 100 mL of ether.
The aqueous layer was further extracted twice with 100 mL of ether.
The combined ether layers were washed with brine, dried (Na2S04}, 3o filtered, concentrated and dried on high vacuum to a white powder (550 mg, 55 % of theoretical 50 % maximum; >99.5 ee). ~ H NMR (CDC13, 300 MHz) 8 1.05-1.50 (br m, 9H), 3.12 (br m, 1 H), 3.50-3.65 (m, 2H), 3.81 (s, 3H), 4.24 (m, 1 H), 4.96 (br m, 1 H), 5.95 (s, 2H), 6.70-6.79 (m, 3H), 6.86 (d, J=9 Hz, 2H), 7.19. (d, J=9 Hz, 2H). MS (DCI/NH3) m/e 442 (M+H)+.

Example 95C
ii carbo gate The compound resulting from Example 95B (251 mg, 0.568 mmol}
s was dissolved in 20 mL of a saturated solution of anhydrous HCl(g) in anhydrous ethanol. The resulting solution was heated at 50 °C. with stirring for 18 hours at which point all of the precipitated solid had dissolved. The reaction mixture was concentrated to a solid which was partitioned between 0.8 1~1 aqueous sodium carbonate (50 mL) and ~ o . methylene chloride {50 mL). The aqueous layer was further extracted with methylene chloride (2 x 50 mL). The combined organic layers were dried (Na2S04), filtered, concentrated and dried under high vacuum to give the title compound as an almost colorless oil (158 mg, 69%). ~ H
NMR {CDC13, 300MHz) S 1.11 (t, J=7 Hz, 3H), 2.18 (v br s, 1 H), 2.93 (t, J=
9 Hz, 1 H), 3.19,3.22 (dd, J=7 Hz, 1 H), 3.50-3.69 (m, 2H), 3.80 (s, 3H), 4.07 (q, J=7 Hz, 2H), 4.49 (d, J=9 Hz, 1 H), 5.94 (s, 2H), 6.73 (d, J=2 Hz, 2H), 6.81-6.92 (m, 3H), 7.34-7.41 (m, 2H). MS (DCI/NH3) m/e 370 (M+H)+.
2o Example 95D
{,2R.3R.4S)-l+)-2-y4_-Methoxyrphenyl)-4-(1.3-benzodioxol-5-y1)-1-(tert-butyrl~,ycarbonyl-aminocarbonyrtmethyl)-~yrrolidine-3-carboxvriic acid To the resulting compound from Example 95C (131 mg, 0.355 mmot) was added, diisopropylethylamine (137 mg, 185 p.L, 1.06 mmot).
2s acetonitrile (2 mL), N,N-di-(n-butyl)bromoacetarnide (133 mg, 0.531 mmol), and the mixture was heated at 50 °C. for 1.5 hours. The reaction mixture was concentrated to a solid, dried under high vacuum, and purified by chromatography on silica gel eluting with 1:3 ethyl acetate-hexane to give pure ester as a colorless oil. ~ H NMR (CDC13, 300MHz) S
so 0.81 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H), 1.10 (t, J=7 Hz, 3H), 1.00-1.52 (m, 8H), 2.78 (d, J=14 Hz, 1 H), 2.89-3.10 (m, 4H), 3.23-3.61 (m, 5H), 3.71 (d, J=9 Hz, 1 H), 3.80 (s, 3H), 4.04 (q, J=7 Hz, 2H), 5.94 (dd, J=1.5 Hz, 2H), 6.74 (d, J=9 Hz, 1 H), 6.83-6.90 (m, 3H), 7.03 (d, J=2 Hz, 1 H), 7.30 (d, J=9 Hz, 2H). MS (DCI/NH3) m/e 539 (M+H)+.
To the ethyl ester dissolved in 7 mL of ethanol was added a solution of lithium hydroxide (45 mg, 1.06 mmol) in water (2.5 mL). The mixture was stirred for 1 hour at ambient temperature and then warmed slowly to 40 °C. over 2.5 hours at which point all of the starting material had been consumed. The reaction mixture was concentrated to remove the ethanol, diluted with 60 mL water and extracted with ether (3 x 40 mL). The aqueous solution was treated with 1 N aqueous s hydrochloric acid until cloudy, and the pH was then adjusted to -4-5 with 10% aqueous citric acid. This mixture was extracted with 1:19 ethanol-methylene chloride {3 x 50 mL). The combined extracts were dried (Na2S04), filtered, concentrated and dried under high vacuum to give the title compound as a white foam (150 mg, 83%}. ~ H NMR (CDC13, ~ 0 300MHz) 8 0.80 {t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3.ki), 1.08 (m, 2H), 1.28 (m, 3H), 1.44 (m, 3H), 2.70-3.77 (svr br m, 12H), 3.79 (s, 3H), 5.95 (m, 2H), 6.75 (d, J=8 Hz, 1 H), 6.87 (br d, J=8 Hz, 3H), 7.05 ( br s, 1 H), 7.33 (v br s, 2H). MS (DCI/NH3) m/e 511 (M+H}+. (a)22 = +74.42°. Anal calcd for C29H38N206 ~ 0.5 H20: C ,67.03; H, 7.56; N, 5.39. Found: C, 67.03; H, ~ s 7.59; N, 5.33.
~xamole 95E
A_ Iternate Preparation of l2R 3R 4S)~+)-2-(4-Methoxvohenv!?-4-(1.3-benzodioxol-5 ~~;tert butyloxvc~rbonvlamingcarbon~methy!)-oyrroiidine-3-carboxylic acid 2o The product of Example 95A (2.858 g) was suspended in 10 mL of EtOAc. 0.7833 g of R (+) alpha methyl benzylamine in 3 mL ethyl acetate was added. On swirling all of the solids were dissolved. The ethyl acetate was removed in vacuum. Ether (13 ml) was added to the residue. When all of the residue had .dissolved, 5 mg of seed crystals 2s were added and these crystals were crushed with a metal spatula while cooling in ice. The product crystallized very slowly. After 1 hour the solid was filtered and washed with ether giving 1.4213 g, m.p. 163-167°. The filtrate was concentrated, cooled and scratched with a spatula to give a second crop 0.1313 g, m.p. i 64-i 68°. The filtrate so was concentrated again and put in the refrigerator and let stand overnight giving 1.6906 g, m.p. 102-110°. (HPLC of this showed 20%of the desired enantiomer and 80% of the unwanted enantiomer.) The first two batches of crystallized material were combined and suspended in 20 mL dichloromethane (Note: the unwanted isomer is more 3s soluble in dichloromethane) and stirred for 2 minutes. The mixture was concentrated, but not to dryness, and ether (10 mL) was added. After WO 99!06397 PCT/US98/15479 stirring for a few minutes the crystals were filtered. Yield: 1.401 g, m.p. 164-172°.
Treatment of the crystalline product with 10% citric acid and ether according the method described in Example 95B provided the title s compound.
Example 96 ~tyrvl__-ar~inyettayllQyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61 B and butyryl chloride for isobutyryl chloride in Example 61 C. The product was purified by preparative HPLC (Vydac ~C18) eluting with a 15 10-70% gradient of CH3CN in 0.1 % TFA. The desired fractions were lyophilized to give the product as a white solid. ~ H NMR (CDC13, 300 MHz) b 0.80 (m, 3H), 0.90 {t, 3H, J=8Hz), 1.42 (m, 2H), 1.58 (heptet, 2H, J=8Hz), 2.20 (t, 3H, J=8Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.48 (br m, 4H), 3.76 (br m, 2H), 3.78 (s, 3H), 4.30 (br s, 1 H), 5.95 (s, 2H), 6.75 (d, 20 1 H, J=8Hz), 6.84 (m, 1 H), 6.85 (d, 2H, J=8Hz), 7.04 ~(d, 1 H, J=1 Hz), 7.40 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 497 (M+H)+. Anal calcd for .
C28Hs6N206 ~ 1.0 TFA: C, 58.82; H, 6.42; N, 4.57. Found: C, 58.77; H, 6.30;
N, 4.42.
Exam! to a 97 tranc rranG~-~4-Methoxvohen~rll-4;~1.3-benzodioxo!-5-yl)~-1-[2-(N-oroovl-N
jgth,~rlaminocarbonyl)amino)ethyl]~yrroiidine-3-carboxvlic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61 B and ethyl isocyanate for isobutyryl chloride in Example 67 C. The 3o crude product was purified by trituration with 1:1 diethyl ether-hexane.
The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. i H NMR (CDC13, 300 MHz) mixture of rotamers s o.80 (t, J=8Hz) and 1.05 (t, J=8Hz) and 1.20 (m) and 1.42 (m) total of SH for the four peaks, 2.35 (br s, 1 H), 2.70 (m, 1 H), 3.0 (m, 3H), 3s 3.2 (m, 3H), 3.25 (dq, 1 H, J=l,8Hz), 3.42 (m, 1 H), 3.6 (m, 1 H), 3.75 (m, 1 H), 3.78 (s, 3H), 4.8 (br s, 1 H), 5.95 (s, 2H), 6.74 (d, 1 H, J=8Hz), 6.85 (m, 3H), 7.00 (s, 1 H), 7.30 (d. 2H, J=8Hz). MS (DCI/NH3) mle 498 (M+H)ø.

WO 99/06397 PC'T/US98/15479 Anal calcd for C27H35N3O6 ~ 0.75 H20: C, 63.45; H, 7.20; N, 8.22. Found: C, 63.38; H, 7.29; N, 8.44.
exam In a 98 s ::a~s ara ~a-2-(4-Methoxyloheny~~-4-(1 3-benzodioxol-5-yl)-1-!2-(N-butyl-N-~,y~r l~ amin~~thvllovrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 6iB and butyryl chloride for isobutyryl chloride in Example 61C. The ~ o crude product was purified by trituration with 1:.~ diethyl ether-hexane.
The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDC13, 300 MHz) 8 0.80 (m, 3H), 0.90 (t, 3H, J=8Hz), 1.45 (m, 4H), 1.6 (m, 2H), 2.20 (t, 3H, J=8Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.5 (br m, 4H), 3.80 (br m, 2H), 3.82 (s, t s 3H), 4.30 (br s, 1 H), 5.95 (s, 2H), 6.75 (d, 1 H, J=8Hz), 6.84 (m, 1 H), 6.85 (d, 2H, J=8Hz), 7.04 (d, 1 H, J=1 Hz), 7.40 (d, 2H, J=8Hz). MS (DCIINH3) ' mle 511 (M+H)+. HRMS calcd for C2sH3aN206: 511.2808. Found:
511 .2809 2o Exam I~e 99 n I- I -1- r (-ethoxy a~rbonylamino)ethy_llpyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Exampte 61, but substituting propylamine for methylamine in Example 2s 61 B and ethyl chloroformate for isobutyryl chloride in Example 61 C.
The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. ~ H NMR (CDC13, 300 MHz) 8 0.80 (t, 3H, J=8Hz), i .05 (m, 2H), 1.22 (m, 3H), 1.45 (m, 3H), 2.08 so (br s, 1 H), 2.75 (m, 1 H), 2.88 (br q, 2H, J=8Hz), 3.08 (br rn, 2H), 3.27 (br m, 2H), 3.44 (m, 1 H), 3.54 (dt, 1 H, J=1,BHz), 3.63 (d, 1 H, J=8Hz), 3.78 (s, 3H), 4.02 (br d, 2H), 5.93 (s, 2H), 6.72 (d, 1 H, J=8Hz), 6.81 (dd, 1 H, J=1,BHz), 6.85 (d, 2H, J=8Hz), 7.00 (s; 1 H), 7.30 (d, 2H, J=SHz). MS
(DCIlNH3) mle 499 (M+H)+. Anal calcd for C27H34N2O7 ~ 0.5 H20: C, ~s 63.89; H, ~ 6.95; N, 5.52. Found: C, 64.03; H, 6.71; N, 5.30.

-'148-Examnl g~,yr uty~~,rl)amino)ethX[ioyrrolidine-3-carboxylic acid To the compound resulting from Example 61 B (190 mg) dissolved s in THF (2 mL) was added HOBt (60 mg), EDCI (85 mg), N-methylmorpholine (50 pL), and DMF (2 mL). 2-Ethylbutyric acid was added and the solution stirred overnight at ambient temperature. Water (10 mL) was added, and the mixture was extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution, 1 ~. H3P04, and brine, dried with Na2S04, and evaporated to give an oil which was purified by flash chromatography on silica gel eluting with 1:3 EtOAc-hexane. The resulting ethyl ester was saponified by the procedure described in Example 61 C. The crude product was dissolved in CH3CN and water and ~ s lyophilized to give the product as a white solid. 1 H NMR (CDC13, 300 MHz) (mixture of rotamers) 8 0.66, 0.74, 0.80, 0.88 (all triplets, total of 6H, J=8Hz), 1.05 (m, 2H), 1.25-1.75 (m, 5H), 2.16 (m, 1 H), 2.32 (m, 1 H), 2.45 (m, 1 H), 2.70 (m, 1 H), 2.86, 2.94 (s, total 3H), 2.95 (m, 1 H), 3.35 (m, 1 H), 3.52 (m, 2H), 3.65 (m, 1 H), 3.80 (s, 3H), 5.94, 5.96 (s, total 2H), Zo 6.73 (m, 1 H), 6.84 (m, 3H), 6.97 (m, 1 H), 7.30 (m, 2H). MS (DCIINH3) m/e 497 (M+H)+. Ana( calcd for CZ8H36N206 ~ 0.25 H20: C, 67.11; H, 7.34; N, 5.59. Found: C, 67.13; H, 7.24; N, 5.56.
Example 101 2s r - 4- I - i I -1- - N-m h I-N-oropylvalery_I)amino)ethyllpyrrolidine-3-carboxylic acid The title compound was prepared by the procedure described in Example 100, but substituting 2-propylpentanoic acid for 2-ethylbutyric acid. The crude product was purified by preparative HPLC
ao (Vydac pCl8) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The desired fractions were lyophilized to give the product as a white solid.
~ H NMR (CDCi3, 300 MHz) 8 0.79 {t, 3H, J=8Hz), 0.82 (t, 3H, J=8Hz), 1.10 (m, 4H), 1.2-1.5 (m, 4H), 2.55 (m, 1 H), 2.96 (s, 3H), 3.15 (br m, 1 H), 3.32 (br m, 1 H), 3.56 (m, 2H), 3.68 (m, 1 H) 3.68 (s, 3H), 3.70 (m, 1 H), 3.80 (m, 3s 2H), 4.65 (br d, 1 H), 5.92 (s, 2H), 6.75 (d, 1 H, J=8Hz), 6.84 (m, 1 H), 6.85 (d, 2H, J=8Hz), 7.05 (s, 1 H), 7.42 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 525 (M+H)~. Anal calcd for C3oH4oN2O6 ~ 1.25 TFA: C, 58.51; H, 6.23; N, 4.20.
Found: C, 58.52; H, 6.28; N, 4.33. .
Example 102 I - I-~yj~ ac rbor~,ylmethvl)amino,}~ t~ hvlloyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 618 and t-butyl bromoacetate for isobutyryl chloride in Example 61 C.
~o The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. ~ H NMR (CDC13, 300 MHz) 8 0.82 (t, 3H, J=8Hz), 1.18 (m, 2H), 1.19 (s, 9H), 2.12 (m, 1 H), 2.46 (m, 2H), 2.70 (m, 3H), 2.85 (m, 2H), 3.20 (s, 2H), 3.40 (dd, 1 H, J=2,8Hz), ~ s 3.50 (dt, 1 H, J=2,8Hz), 3.62 (d, 1 H, J=8Hz), 3.78 (s, 3H), 5.95 (s, 2H), 6.72 (d, 1 H, J=8Hz), 6.84 (m, 1 H), 6.85 (d, 2H, J=8Hz), 7.05 (s, 1 H), 7.16 (d, 2H, J=8Hz). MS (DCIlNH3) m/e 541 (M+H)+. Anal calcd for C3oHaoN207 ~ 1.0 H20: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.75; H, 7.35;
N, 4.86.
Exams a 103 - 4- h -4- i I- I -1- r I-N- n-oroQyl~lnocarbony~methy,~~amin~~~ethyrllQ~rrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61 B and N-propyl bromoacetamide for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac ~C 18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The desired fractions were lyophilized to give the product as a white solid. ~ H NMR
so (CDC13, 300 MHz) 8 0.78 (t, 3H, J=8Hz), 0.88 (t, 3H, J=8Hz), 1.45 (m, 2H), 1.48 (m, 3H, J=8Hz), 2.55-2.7 (m, 2H), 2.90 (m, 1 H), 3.04 (m, 1 Hj, 3.15 (m, 3H), 3.28 (t, 1 H, J=8Hz), 3.45 (t, 1 H, J=8Hz}, 3.60 (m, 2H), 3.70 (d, 2H, J=8Hz), 3.75 (m, 1 H), 3.80 (s, 3H), 4.25 (d, 1 H, J=8Hz), 5.95 (s, 2H), 6.75(d, 1 H, J=8Hz), 6.86 (dt, 1 H, J=1,BHz), 6.88 (d, 2H, J=8Hz), 7.04 (d, 3s 1 H, J=1 Hz), 7.40 (d, 2H, J=8Hz). MS (DCILNH3) m/e 526 (M+H)+. Anal calcd for C2gH3gN3Og ~ 1.85 TFA: C, 53.32; H, 5.59; N, 5.70. Found: C, 53.45; H, 5.62; N, 5.63.

Example 104 I- - 4_ ~,gthoxvo,~ heno~,rcarboniy)~~amino~,yllQyrrolidine-3-carboxylic acid s The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61 B and 4-methoxyphenylchloroformate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and ~o water and lyophilized to give the product as a while solid. ~H NMR
(CD30D, 300 MHz) mixture of rotamers 8 0.88 (m,3H), 1.57 (m, 2H), 2.45 (br s) and 2.60 (br s, total of 1 H), 2.90-3.15 (m, 4H), 3.42-3.7 (m, 5H), 3.78 (s, 3H), 3.80 (s, 3H), 3.85 (m) and 4.0 {m, total of 1 H), 5.95 (s) and 5.98 (s, total of 2H), 6.63(m, 1 H), 6.72 (d, 1 H, J=8Hz), 6.81 (m, 2H), 6.93 ~ s (m, 5H), 7.40 (m, 2H). MS {DCt/NH3) m/e 577 (M+H)+. Anal calcd for C32H3sN2O8 ~ 1.0 H2O: C, 64.63; H, 6.44; N, 4.7i . Found: C, 64.70; H, 6.38;
N, 4.63.
Example 105 2o tram tran.~~-f4-Methoxl_ -~4-.(1 3-benzodioxo(-5-yll-1-(2-fN-~rooyl-N- 4-methoxybenzoyE),aminoleth~Q~,yrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61 B and anisoyl chloride for isobutyryl chloride in Example 61 C. The is crude product was purified by trituration with 1:1 diethyl ether-hexane.
The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. ~H NMR (CDC13, 300 MHz) mixture of rotamers 8 0.78 (m) and 0.98 (t, J=8Hz) total of 3H, 1.47 (m) and 1.52 (q, J=8Hz) total of 2H, 2.25 (br s, 1 H), 2.78 (br s, 1 H), 2.90 (br t, 2H), 3.12-so 3.68 (m, 7H), 3.80 (s, 3H), 3.82 (s, 3H), 5.94 (s, 2H), 6.75(d, 1 H, J=8Hz), 6.83 (m, 5H), 6.94 (m, 1 H), 7.22 (m, 4H). MS (FAB) m/e 561 (M+H)+. Anal calcd for C32HssN247 ~ 0.75 H20: C, 66.94; H, 6.58; N, 4.88. Found: C, 67.00; H, 6.38; N, 4.59.
*rB

WO 99/Ob397 PCT/US98/15479 Fxam 1 I - r I-benzovlamino)ethy[lwrrolidine-3-carboxylic acid The title compound was prepared by the methods described in s Example 61, but substituting propylamine for methylamine in Example 61 B and benzoyl chloride for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1:1 diethyl ether-hexane.
The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. ~ H NMR (CDC13, 300 MHz) mixture of 1 o rotamers & 0.65 and 0.9 (m, total of 3H) , 1.4 and 1.55 (m, total of 2H), 2.05 and 2.15 (m, total of 1 H), 2.6 - 3.6 {m, 8H), 5.92 (s, 2H), 6.70(d, 1 H, J=8Hz), 6.82 (m, 4H), 7.2 - 7.4 (m, 6H). MS (DCI/NH3) mle 531 (M+H)+.
Anal calcd for Cgt H34N2~6 ~ 0.3 H20: C, 69.46; H, 6.51; N, 5.23. Found: C, 69.48; H, 6.19; N, 4.84.
example 107 fans frans-2 y-~f ",ethoxy~l-4-~,~I 3-benzodioxol-5-vl)-1-f2-(N-oroovl-N
ben7,~loxvcarbonylamino~~ethylloyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in 2o Example 61, but substituting propylamine for methylamine in Example 61 B and benzyl chloroformate for isobutyryl chloride in Example 61 C.
The crude product was purified by preparative HPLC (Vydac ~C 18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The desired fractions were lyophilized to give the product as a white solid. ~ H NMR
{CDC13, 300 MHz) 8 0.8 {m, 3H) 1.45 (m, 2H), 2.20 (br m, 1H), 2.75 (m, 1 H), 2.93 (m, 1 H), 3.15 (m, 2H), 3.32 (m, 3H), 3.52 (m, 2H), 3.66 (m, 1 H), 3.78 (s, 3H), 5.00 (m, 2H), 5.94 (s, 2H), 6.72(d, 1 H, J=8Hz), 6.82 (m, 3H), 7.0 (br d, 1 H, J= 15Hz), 7.2 {s, 4H), 7.30 {m, 3H). MS (FAB) m/e 561 (M+H)+. Anal calcd for C32H36N2~7 ~ 1.0 TFA: C, 60.53; H, 5.53; N, 4.i5.
3o Found: C, 60.66; H, 5.34; N, 4.28.
~xamote 108 r n r - 4- h n I -4- 1 n i I- I -1- - N- I-N- 4 methox enzvloxy~arbonyl~rniPolethYllwrrolidine-3-carboxylic acid The title compound is prepared by the methods described in Example 61, substituting propylamine for methylamine in Example 61 B

and 4-methoxybenzyl chloroformate for isobutyryl chloride in Example 61 C.
Example 109 s - 1 i-~thoxvcarbonvlamino)eth~lovrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 61 B and ethyl chloroformate for isobutyryl chloride in Example 61 C.
~ o The crude product was purified by preparative HPLC (Vydac ~.C 18) eluting with a 10-70°/° gradient of CH3CN in 0.1 % TFA. The desired fractions were lyophilized to give the product as a white solid. ~ H NMR
{CDC13, 300 MHz) 8 0.82 (t, 3H, J=8Hz), 1.20 (m, 5H), 1.34 (m, 2H), 3.08 (m, 2H), 3.17 (m, 2H), 3.52 (m, 2H), 3.75 {m, 2H), 3.78 (s, 3H), 4.06 {q, ~ s 2H, J=8Hz), 4.35 (br s, 1 H), 5.94 (s, 2H), 6.76 (d, 1 H, J=8Hz), 6.92 (d, 2H, J=8Hz), 7.03 (br s, 1 H), 7.17 (br s, 1 H), 7.7 (br s, 2H). MS (FAB) mle 513 (M+H)+. Anal calcd for C28H3sN20~ ~ 0.5 TFA: C, 61.15; H, 6.46; N, 4.92.
Found: C, 60.99; H, 6.80; N, 4.93.
20 ~,xamQle 110 I -4- 1 i I -1- - N- I-N-! ra ODOXycarb nyr mino)eth~~rrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 6i; but substituting butylamine for rnethyiamine in Example 2s 61 B and propyl chloroformate for isobutyryl chloride in Example 61 C.
The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. ~ H NMR (CDC13, 300 MHz) 8 0.80 (br s, 1 H), 0.85 (t, 3H, J=8Hz), 0.92 (br s, 1 H), 1.22 (m, 3H), 30 1.40 (m, 3H), 1.62 (br m, 1 H), 2.15 (br s, 1 H), 2.72 (m, 1 H), 2.87 {m, 1 H), 3.1-3.45 (m, 5H), 3.55 (m, 1 H), 3.64 (d, 1 H, J=8Hz), 3.79 (s, 3H), 3.88 (br s, 1 H), 3.97 (br s, 1 H), 5.95 (s, 2H), 6.73(d, 1 H, J=8Hz), 6.85 (m, 3H, 7.0 (s, 1 H), 7.30 (d, 2H, J=8Hz). MS (FAB) m/e 527 (M+H)+. Anal calcd for C29Hs8N20~ ~ 0.15 H20: C, 65.80; H, 7.29; N, 5.29. Found: C, 65.79; H, 35 7.30; N, 5.21.

Example 111 r -4- 1 n -N
ploDOXV ac rbon_yrl_~lmino~~thyljRyrrrolidine-3-carboxylic acid .
The title compound was prepared by the methods described in s Example 61, but substituting propylamine for methylamine in Example 61 B and propyl chloroformate for isobutyryl chloride in Example 61 C.
The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. ~ H NMR (CDC13, 300 ~o MHz) S 0.80 (t, 3H, J=8Hz), 093 (m, 3H), 1.43 (m, 3H), 1.62 (m, 1H), 2.15 (br s,. 1 H), 2.68-3.45 {m, 8H), 3.54 (m, 1 H), 3.66 (m, 1 H), 3.78 (s, 3H), 3.94 (m, 2H), 5.94 (s, 2H), 6.72 (d, 1 H, J=8Hz), 6.82 (m, 7 H), 6.84 (d, 2H, J=8Hz), 7.00 (br s, 1 H), 7.33 (m, 2H). MS (DCUNH3) m/e 513 (M+H)+.
Anal calcd for C28H36N20~ ~ 0.15 H20: C, 65.26; H, 7.10; N, 5.44. Found:
~ s C, 65.22; H, 6.74; N, 5.06.
Fxamole 112 n I - 4- i 1 i I-y_I~Qyrrolidine-3-carboxylic acid 2o Ethyl (3,4-methylenedioxybenzoyl)acetate, prepared by the method of Krapcho et al., Org. Syn. ~, 20 (1967) starting with 3,4-methylenedioxyacetophenone instead of 4-methoxyacetophenone, was reacted by the procedures described in Example 1 to give the title compound as a white solid. m.p. 58-60 °C. 1 H NMR (CDC13, 300 MHz) 8 25 0.87 (quintet, J=6Hz, 6H), 1.12 (sextet, J=6Hz, 2H), 1.24-1.51 (m, 6H), 2.80 (d, J=13Hz, 1 H), 2.94-3.12 (m, 4H), 3.28-3.50 (m, 4H), 3.58-3.62 (m, 1 H}, 3.78 (d, J=9Hz, 1 H), 5.95 (s, 4H), 6.73 (dd, J=8Hz, 3Hz, 2H), 6.84-6.89 (m, 2H), 6.92 (d, J=1 Hz, 1 H), 7.01 (d, H=1 Hz, 1 H). MS
(DCI/NH3) m!e 525 (M+H)+.
Examgle 113 r n r n - 1 -N- r I if mi I - - 4-m h h n I -4 ,(1_ 3 benzodioxol-5-~~ovrrofidine-3-carboxylic acid Using the procedures described in Example 66, the title compound 3s was prepared as a white solid. m.p. 64-65 °C. ~ H NMR (CDC(3, 300 MHz) b 0.83 (t, J=7Hz, 3H), 0.98 (t, J=7Hz, 3H), 1.12-1.25 (m, 2H}, 1.32-1.41 (m, 2H), 1.75 (sextet, J=7Hz, 2H), 2.23-2.31 (m, 2H}, 2.72-3.32 (m, 8H), 3.43 (dd, J=9Hz, 3Hz, 1 H), 3.53-3.59 (m, 1 H), 3.65 (d, J=9Hz, 1 H}, 3.80 (s, 3H), 5.95 (s, 2H), fi.73 (d, J=BHz, 1 H), 6.83 (dd, J=BHz, 1 Hz, 1 H), 6.88 (d, J=9Hz, 2H), 7.02 (d, J=7 Hz, 1 H}, 7.33 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 547 (M+H)+.
s Example 114 .
r n 1- N N- i n- I min car on Im h I -2- 4-me h hen I -4- 1 benzodioxol-5-vi)pvrrolidine-3-carboxylic acid Using the procedures described in Examples 28 and 43, the title compound was prepared as a white solid. m.p. 74;]6 °C. ~ H NMR
(CDC13, 300 MHz) b 0.80 (t, J=6Hz, 3H}, 0.88 (t, J=BHz, 3H), 1.08 (sextet, J=SHz, 2H}, 1.21-1.48 (m, 6H), 2.75 (d, J=l2Hz, 1 H), 2.95-3.09 (m, 4H), 3.26-3.59 (m, 5H), 3.75 (d, J=9Hz, 1 H), 3.79 (s, 3H), 4.28 (s, 4H), 6.78 (d, J=9Hz, 1 H), 6.85 (d, J=9Hz, 2H), 6.91 (d,d, J=3Hz, 9Hz, 1 H}, 6.98 (d, v s J=3Hz, 1 H), 7.32 (d, J=9Hz, 2H). MS (DCIlNH3) m/e 525 (M+H)+.
Example 115 r n r 1- I- r 1 If n I min h I - - 4- h x h n 1 -4 L1 ,'~-benzodi2xol-5-vl~ovrroiidine-3-carboxylic acid 2o Using the procedures described in Exampie 66, the title compound was prepared as a white solid. m.p. 72-73 °C. ~ H NMR (CDC13, 300 MHz) S 0.79 (t, J=SHz, 3H), 0.98 (t, J=8Hz, 3H), 1.43 (sextet, J=8Hz, 2H), 1.75 (sextet, J=BHz, 2H), 2.22-2.32 (m, 1 H), 2.69-3.32 (m, 9H), 3.42 (dd, J=3Hz, 12Hz, 1 H), 3.52-3.58 (m, 1 H), 3.64 (d, J=12Hz, 1 H), 3.80 (s, 3H), 2s 5.95 (s, 2H}, 6.73 (d, J=11 Hz, 1 H), 6.83 (dd, J=1 Hz, 1 i Hz, 1 H}, 6.87 (d, J=11 Hz, 2H), 7.0 (d, J=2Hz, 1 H), 7.32 (d, J=11 Hz, 2H). MS (DCIINH3) m/e 533 (M+H)+.
Example 116 so ~ traps traps 1 (2 LN Butyl-N-butvlsulfonylamino)ethyl)-2-(4-methoxvphenvl)-4-(1.3-benzodioxoi-5-vl)wrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 62-63 °C. ~ H NMR (CDC13, 300 MHz) b 0.82 (t, J=6Hz, 3H), 0.9i )t, J=6Hz, 3H), 1.20 (sextet, J=6Hz, 2H), 1.33-35 1.42 (m, 4H), 1.68 (quintet, J=6Hz, 3H),2.23-2.32 (m, 1 H), 2.70-3.28 (m, 9H), 3.41 (d, J=BHz, 1 H), 3.52-3.58 (m, i H), 3.65 (d, J=BHz, 1 H), 3.79 (s, 3H), 5.95 (s, 2H), 6.72 (d, J=BHz, 1 H), 6.82 (d, J=8Hz, 1 H), 6.87 (d, J=8Hz, 2H), 7.01 (s, 1 H), 7.32 (d, J=BHz, 2H). MS (DCI/NH3} m/e 561 (M+H)+.
Example 117 s trans.tran~l -(2-(N.N-Dln-butyljaminocarbonylmethyl)-2-(4-methoxvmetho~ynhenvl)-4-r(1.3-benzodioxol-5-yl)~y~olidine-3-carboxylic acid 4-Hydroxyacetophenone was treated with chloromethyl methyl ether and triethylamine in THF at room temperature to give ethyl 4-methoxymethoxybenzoylacetate which was treated by the procedures ~ o described in Example 1 to afford the title compotmd as a white solid.
m.p. 48-49 °C. ~ H NMR (CDC13, 300 MHz) 8 0.81 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.06 (sextet, J=7Hz, 2H), 1.20-1.35 {m, 4H), 1.44 (quintet, J=7Hz, 2H), 2.75 (d, J=l2Hz, 1 H), 2.94-3.10 (m, 4H), 3.25-3.35 (m, 1 H), 3.40 (d, J=l2Hz, 1 H), 3.43-3.52 (m, 2H), 3.47 (s, 3H), 3.55-3.62 (m, 1 H), ~ s 3.77 (d, J=9Hz, 1 H), 5.15 (s, 2H), 5.94 (m, 2H), 6.73 (d, J=8Hz, 1 H), 6.86 (dd, J=1 Hz, BHz, 1 H), 7.0 (d, J=BHz, 2H), 7.04 (d, J=1 Hz, 1 H), 7.32 (d, J=SHz, 2H). MS (DCIlNH3) m/e 541 (M+H)+.
Example 118 2o r n - N i n- 1 mi r n Im h - 4-h r h n I -4- 1 benzor~li~ol-5-yl~yrrolidine-3-carboxylic acid hydrochloride salt The compound resulting from Example 116 was treated with concentrated HCI in 1:1 THF-isopropanol to give the title compound as a white solid. m.p. 211-212 °C. ~H NMR (CD30D, 300 MHz) S 0.90 (t, 2s J=BHz, 6H), 1.12-1.27 (m, 6H), 1.36-1.45 (m, 2H), 3.04 (bs, 1 H}, 3.14-3.35 (t, J=9Hz, 1 H), 3.90 (bs, 3H), 4.17 (d, J=1 SHz, 1 H), 5.96 (s, 2H), 6.82-6.93 (m, 4H), 7.03 (d, J=1 Hz, 1 H), 7.42 (bs, 2H). MS (DCIlNH3) m/e 497 (M+H)+.
so Example 119 r n r 1- r If n I I - - 4- h h n I -4 (1.3-benzodioxol-5-yl),~yrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 73-74 °C. ~ H NMR {CDC13, 300 MHz) 8 0.80 (d, J=6Hz, 6H), 0.98 (t, J=BHz, 3H), 1.62 (sextet, J=6Hz, 1 H), 1.74 {sextet, J=8Hz, 2H), 2.23-2:34 (m, 1 H), 2.68-2.98 {m, 7H), 3.08-3.18 (m, 1 H), 3.26-3.42 (m, 2H), 3.52-3.58 (m, 1 H), 3.65 (d, J=9Hz, 1 H), 3.80 (s, 3H), 5.90 (s, 2H), 6.74 (d, J=8Hz, 1 H), 6.82 {d, J=BHz, 1 H), 6.86 (d, J=BHz, 2H), 6.98 .(d, J=1 Hz, 1 H), 7.33 {d, J=SHz, 2H). MS (DCI/NH3) mle 547 {M+H)+.
Exampl-a 120 #~ans rran~t-(2-~,N-Benzenesulfonyi-N~ropylamino}ethyl)-2-(4-methoxwhenvi)-4 ~1 3-benzodioxol-5 yi)ovrrotidine-3-carboxylic acid Using the procedures described in Example 66, the title compound to was prepared as a white solid. m.p. 89-91 °C. ~H-NMR (CDCI3, 300 MHz) b 0.74 (t, J=6Hz, 3H), 1.33 (sextet, J=6Hz, 2H), 2.20-2.30 (m, 1 H), 2.62-2.72 (m, 1 H), 2.85-3.05 (m, 4H), 3.12-3.22 (m, 1 H), 3.38 {dd, J=3Hz, 9Hz, 1 H), 3.49-3.57 (m, 1 H), 3.62 (d, J=9Hz, 1 H), 3.82 (s, 3H), 5.96 (s, 2H), 6.73 (d, J=8Hz, 1 H), 6.84 (dd, J=1 Hz, BHz, 1 H), 6.85 (d, J=9Hz, 2H), 7.02 ~ s (d, J=7 Hz, 1 H), 7.28 (d, J=9Hz, 2H), 7.39-7.54 (m, 3H}, 7.70 (d, J=7Hz, 2H). MS (DCI/NH3) m/e 567 (M+H)+.
Exam Ip a 121 r n r n - 4- h x n If n I -N- r I m in h I - - 4-2o methoxvohen~}-4-(13-benzodioxol-~yl)~~rrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 96-97 °C. ~ H NMR (CDCl3, 300 MHz) 8 0.73 (t, J=7Hz, 3H), 1.34 (sextet, J=7Hz, 2H), 2.20-2.30 (m, 1 H), 2.62-2.71 (m, 1 H), 2.82-3.03 (m, 4H), 3.08-3.18 (m, 2H), 3.38 (dd, J=3Hz, 9Hz, 25 1 H), 3.48-3.56 (m, 1 H), 3.62 (d, J=9Hz, 1 H), 3.81 (s, 3H), 3.86 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=BHz, 1 H), 6.81-6.89 (m, 5H), 7.01 (d, J=1 Hz, 1 H), 7.28 {d, J=8Hz, 2H), 7.62 (d, J=BHz, 2H). MS (DCt/NH3) m/e 597 (M+H)+.
Example 122 ao r~,r~s trans-1-SIN N-Di,L-buty~)aminocarbonyilmeth~)-~ -methoxyrethoxy-4-n -4- 1 z x I- I rr i in - r li i 2-Hydroxy-5-methoxyacetophenone was treated with sodium hydride and bromoethyl methyl ether in THF at 70 °C to provide ethyl 2-methoxyethoxy-4-methoxybenzoylacetate which was treated by the 35 procedures described in Example 7 . to provide the title compound as a white solid. m.p. 63-65 °C. ~H NMR (CDC13, 300 MHz} s 0.84 (t, J=7Hz, 3H), 0.89 (t, J=7Hz, 3H), 1.16 (sextet, J=7Hz, 2H), 1.28 (sextet, J=7Hz, 2H), 1.45-1.52 (m, 4H), 2.87-2.94 (m, 2H), 3.00-3.16 (m, 3H), 3.26-3.36 (m, 2H), 3.43 (s, 3H), 3.47-3.54 (m, 3H), 3.66-3.72 (m, 2H), 3.78 (s, 3H), 3.76-3.84 (m, 1 H), 4.02-4.10 (m, 2H), 4.25 (d, J=9Hz, 1 H), 5.92 (s, 2H), s 6.40 {d, J=2Hz, 1 H), 6.52 (dd, J=2Hz, 9Hz, 1 H), 6.70 (d, J=8Hz, 1 H), 6.B3 (dd, J=1 Hz, 8Hz, 1 H), 5.98 (d, J=2Hz, 1 H), 7.53 (d, J=9Hz, 1 H). MS
(DCIINH3) mle 585 (M+H)+.
ExamQle 123 l0 4- i I 1- -4-etho yD~ hEnVl),~(~benzodioxol-5-yl)Qyr~tidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 88-90 °C. ~ H NMR (CDCi3, 300 MHz) b 0.69 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.12-2.20 (m, 1 H), 2.32 ~ s (s, 3H), 2.47 (s, 3H), 2.62-2.69 (m, 1 H), 2.78 (t, J=9Hz, 1 H), 2.89 {dd, J=8Hz, 1 H), 3.02 {sextet, J=9Hz, 2H), 3.15-3.32 (m, 3H), 3.46-3.55 (m, 1 H), 3.60 (d, J=9Hz, 1 H), 3.82 (s, 3H), 5.96 (s, 2H), 6.72 {d, J=7Hz, 1 H}, 6.80 (dd, J=1 Hz, 9Hz, 1 H), 6.86 (d, J=9Hz, 2H), 6.97 (d, J=1 Hz, 1 H), 7.03 (bs, 2H}, 7.29 (d, J=9Hz, 1 H). MS (DCIINH3) m/e 595 (M+H)+.
ExamplP"124 trans.trans-1-(2-(N-Propyl-N- ~ ~hlorooroo) Isr ulfonvl)amino]ethyl)-2-(4-methoxvohenyl~l,;~-ben,~odioxol-5-yl)~yrrolidine-3-carboxSLc acid Using the procedures described in Example 66, the title compound 2s was prepared as a white solid. m.p. 75-76 °C. ~ H NMR (CDCI3, 300 MHz}
b 0.80 (t, J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.15-2.31 (m, 3H), 2.70-2.80 (m, 1 H), 2.85-3.10 {m, 6H), 3.23-3.31 (m, 2H), 3.43 (bd, J=9Hz, 1 H), 3.55-3.66 (m, 4H), 3.81 (s, 3H), 5.94 {s, 2H), 6.73 {d, J=BHz, 1 H), 6.82 (d, J=BHz, 1 H), 6.86 (d, J=8Hz, 2H), 7.00 (s, 1 H), 7.33 (d, J=BHz, 2H). MS
so (DCI/NH3) mle 567 (M+H)+.
ExamQ"le 125 r n r n -1- - N- I- -m th h I If n I mi I - - 4-methox~yll-4-11.3-benzodioxol-5-yl)~Qyrrolidine-3-carboxylic acid 35 Using the procedures described in Example 66, trans,trans-1-{2-(N-Propyl-N-(vinylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl}-4-(1 ,3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid was prepared. Ester hydrolysis using aqueous sodium hydroxide in methanol afforded the title compound as a white solid. m.p. 62-64 °C. ~ H NMR (CDC13, 300 MHz) S 0.78 (t, J=7Hz, 3H), 1.42 (sextet, J=7Hz, 2H), 2.23-2.32 (m, 1 H), s 2.72-2.79 (m, 1 H). 2.86-3.05 (m, 4H), 3.10-3.27 (m, 4H), 3.32 (s, 3H), 3.43 (dd, J=3Hz, 9Hz, 1 H), 3.53-3.58 (m, 1 H), 3.65 (d, J=9Hz, 1 H), 3.69 (t, J=6Hz, 2H), 3.80 (s, 3H), 5.94 (s, 2H), 6.73 (d, J=8Hz, 1 H), 6.82 (dd, J=1 Hz, BHz, 1 H), 6.87 (d, J=BHz, 2H), 7.02 (d, J=1 Hz, 1 H), 7.33 (d, J=BHz, 2H). MS (DCIINH3) m/e 549 (M+H)+.
~o Examale-126 ~,rans traps-1 ~2~lN-Prowl-N- 2-ethoxvethylsulfonyl)amino)ethvl)-2-(4-metho,~,~hen~)-4-(1 3-benzodioxol-5-ylhyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound ~ s was prepared as a white solid. m.p. 58-60 °C. ~ H NMR (CDC13, 300 MHz) b 0.78 (t, J=7Hz, 3H), 1.18 {t, J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2H), 2.24-2.33 (m, 1 H), 2.70-2.80 (m, 1 H), 2.87-3.05 (m, 4H), 3.13-3.20 (m, 2H), 3.22-3.32 (m, 2H), 3.42 (dd, J=2Hz, 9Hz, 1 H), 3.46 (q, J=7Hz, 2H), 3.52-3.58 (m, 1 H), 3.65 {d J=9Hz, 1 H), 3.72 (t, J=6Hz, 2H), 3.80 (s, 3H), 5.95 20 (s, 2H), 6.73 (d, J=7Hz, 1 H), 6.83 {dd, J=1 Hz, 7Hz, 1 H), 6.8? (d, J=8Hz, 2H), 7.00 (d, J=1 Hz, 1 H), 7.32 {d, J=BHz, 2H). MS (DC1/NH3) m/e 563 (M+H)+.
xam lp a 127 2s traps tran~l (2 (N-Proovl-N-(5-dimethylamino-1-naohthylsulfonyllamino)ethyl)-2-j4-methoxvohenvl)-4-{1 3-benzodioxo!-5-yl)oyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a yellow solid. m.p. 102-104 °C. 1 H NMR {CDC13, 300 MHz) S 0.62 (t, J=7Hz, 3H), 1.28 (sextet, J=7Hz, 2H), 2.12-2.20 (m, 1 H), 30 2.78 (t, J=9Hz, 1 H), 2.88 {s, 6H), 2.72-2.89 (m, 1 H), 3.05-3.12 (m, 2H), 3.26-3.45 (m, 3H), 3.45-3.52 (m, 1 H), 3.58 (d, J=9Hz, 1 H), 6.97 (d, J=1 Hz, 1 H), 7.13 (d, J=7Hz, 1 H), 7.26 (d, J=8Hz, 1 H), 7.42-7.50 (m, 2H), 8.08 (dd, J=1 Hz, 7Hz, 1 H), 8.20 (d, J=BHz, i H), 8.48 (d, J=8Hz, 1 H). MS (DCIINH3) mle 660 (M+H)+.

Example 128 r I I -4-m h I-Li 3-benzodioxol-5-vl)wrrolidine-3-carboxyrlic acid Using the procedures described in Example 66, the title compound s was prepared as a white solid. m.p. 70-72 °C. 1 H NMR (CDCl3, 300 MHz) 8 0.79 (t, J=8Hz, 3H), 1.28 (t, J=7Hz, 3H}, 1.43 (q, J=8Hz, 2H), 2.22-2.30 (m, 1 H), 2.71-2.80 (m, 1 H), 2.82-3.10 (m, 6H), 3.18-3.32 (m, 2H}, 3.43 (dd, J=3Hz, 9Hz, 1 H), 3.53-3.60 (m, 1 H), 3.65 (d, J=9Hz, 1 H), 3.80 (s, 3H), 5.96 (s, 2H), 6.73 (d, J=7Hz, 1 H), 6.82 (dd, J=1 Hz, 7Hz, 1 H), 6.88 (d, ~o J=BHz, 2H), 7.00 (d, J=1 Hz, 1 H),. 7.32 (d, J=BHz, 2~!). MS (DCIINH3) mle i 9 (M+H)+.
Example 129 trarra tran~l_(2-~N-Pro~rl-N-,L,4-methylbenzenesulfonyrl)amino)ethvl)-2-(4-~s ' metho~rhen~yrl)-4-(1 3-benzodioxo(-5-vl)ovrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 78-79 °C. 'H NMR (CDCI3, 300 MHz) 8 0.73 (t, J=7Hz, 3H), 1.33 (sextet, J=7Hz, 2H), 2.20-2.30 (m, 1 H}, 2.40 {s, 3H), 2.61-2.72 (m, 1H), 2.83-3.05 (m, 4H), 3.08-3.i9 (m, 2H), 3.48 20 (dd, J=3Hz, 9Hz, 1 H), 3.49-3.57 (m, 1 H), 3.62 (d, J=9Hz, 1 H), 3.81 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, 1 H), 6.82 (d, J=8Hz, 1 H), 6.87 (d, J=8Hz, 2H), 7.00 (s, 1 H), 7.21 (d, J=BHz, 2H), 7.29 (d, J=8Hz, 2H), 7.57 (d, J=BHz, 2H).
MS (DCIlNH3) m/e 581 (M+H)+.
2s Example 130 r~~4.t~ns- -(~! N-Di(n-butyl)aminocarbonylmethy()-2-(3-oyrid~rll-4-11.3 ~ nzo I~xol-5-v,Vovrrolidine-3-carboxylic acid Methyl nicotinoyl acetate was prepared by the method of Wenkert, et al., J. Org. Chem. 48: 5006 (1983) and treated by the procedures so described in Example 1 to provide the title compound as a white solid.
m.p. 167-168 °C. 1 H NMR (CDCl3. 300 MHz) 8 0.82 (t, J-7Hz, 3H}, 0.89 (t, J=7Hz, 3H), 1.14 (sextet, J=7Hz, 2H), 1.23-1.48 (m, 6H), 2.86-3.20 (m, 6H}, 3.34-3.43 (m, 2H), 3.57 (dd, J=3Hz, 9Hz, 1 H), 3.75-3.83 (m, 1 H), 4.08 (d, J=9Hz, 1 H), 5.93 (s, 2H), 6.73 (d, J=8Hz, 1 H), 6.90 (dd, J=2Hz, 3s 8Hz, 1 H), 7.03 (d, J=2Hz, 1 H), 7.38 (dd, J=4Hz, SHz, 1 H), 8.04 (d, J=BHz, 1 H), 8.48 (dd, J=2Hz, 4Hz, 2H). MS (DCIlNH3) m/e 482 (M+H)+.

Example 131 I If h h n ,~1 3-benzodioxol-5-y~ovrrolidine-3-carboxylic acid s Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 65-66 °C. ~ H NMR (CDCI3, 300 MHz) 8 0.78 (t, J=7Hz, 3H), 0.92 (t, J=7Hz, 3H), 1.3'1-1.46 (m, 4H}, 1.68 (quintet, J=7Hz, 2H), 2.21-2.32 (m, 1 H), 2.70-3.08 (m, 7H), 3.12-3.23 (m, 2H), 3.42 (dd, J=2Hz, 9Hz, 1 H), 3.52-3.58 (m, 1 H), 3.64 (d, J=9Hz, 1 H), ~ 0 3.80 (s, 3H), 5.96 (s, 2H), 6.72 (d, J=7Hz, 1 H), 6.83- (dd, J=1 Hz, 7Hz, 1 H), 6.86 (d, J=SHz, 2H), 7.00 (d, J=1 Hz, 1 H), 7.32 (d, J=BHz, 2H). MS
(DCI/NH3) mle 547 (M+H)+.
,~xamc~le 132 r -4- h If n I i I- -4-methoxvc~heny~,Z-4-(1 3-benzodioxol-5-yl~~oyrrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 105-106 °C. ~ H NMR (CDC13, 300 MHz) b 0.72 (t, J=7Hz, 3H), 1.34 (sextet, J=7Hzm 2H), 2.56-2.62 (m, 1 H), 20 2.78-2.86 (m, 1 H), 2.96-3.03 (m, 3H), 3.13-3.26 (rn, 3H), 3.51 (dd, J=SHz, 9Hz, 1 H), 3.62-3.68 (m, 1 H), 3.80 (s, 3H), 3.94 {d, J=9Hz, 1 H), 5.92 (s, 2H), 6.75 (d, J=8Hz, 1 H), 6.84 (dd, J=2Hz, 8Hz, 1 H), 6.94 (d, J=8Hz, 2H), 6.98 (d, J=2Hz, 1 H), 7.36 (d, J=BHz, 1 H), 7.49 (d, J=8Hz, 1 H}, 7.68 (d, J=8Hz, 1 H). MS (DCIINHs) m/e 601 (M+H)+.
2s Example 133 traps traps-1-(2-(N-Proayl-N-(benz,~ Is~ ulfon,yllamino)ethoil-2-(4-methoxvphenvl)-4 L 3-benzodioxol-S~IIp_yrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound 3o was prepared as a white solid. m.p. 88-89 °C. ~ H NMR (CDC13, 300 MHz) S 0.72 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.06-2.16 (m, 1 H), 2.56-2.67 (m, 1 H), 2.75-3.10 (m, 6H), 3.30 (dd, J=2Hz, 9Hz, 1 H), 5.95 (s, 2H), 6.73 (d, J=7Hz, 1 H), 6.80 (dd, J=1 Hz, 7Hz, 1 H), 6.86 (d, J=8Hz, 2H), 6.97 (d, J=1 Hz, 1 H), 7.27-7.35 (m, 7H). MS (DCI/NH3) mle 581 {M+H)+.

Fxam~le 134 r I- - 4- f I m i I - - 4-methoxy~~~ 4 (1.3 benzodioxol-5-vl)~y~rolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 91-93 °C. ~ H NMR {CDC13, 300 MHz) b 0.73 (t, J=7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 2.18-2.27 (m, 1 H}, 2.56-2.67 (m, 1H), 2.78-2.87 (m, 2H), 2.97 {septet, J=8Hz, 2H), 3.11-3.16 {m, 2H), 3.33 {dd, J=2Hz, 9Hz, 1 H), 3.43-3.50 (m. 1 H), 3.57 (d, J=9Hz, 1 H), 3.78 (s, 3H), 7.08 (t, J=BHz, 2H), 7.24 (d, J=BHz, 2H), 7.69 (dd, J=SHz, ~0 8Hz, 2H). MS (DCI/NH3) mle 585 {M+H}+.
Example 135 traps transl-[N-Methyl-N- r~op.~rlaminocarbonylmethyl)-2-(4-methoxvuhenvi)-4-(4 benzofuran~)ovrrolidine-3-carboxylic acid example 135A
Benzofuran-4-carboxaldehyde To a suspension of 60% sodium hydride in mineral oil (4.00 g, Z 00 mmol, 1.25 eq) in DMF (60 mL} at 0 °C was added a solution of 3-2o bromophenol (13.8 g, 80 mmol} in DMF (5 mL). After 10 minutes, bromoacetaldehyde diethyl acetal { 14.9 mL, 96.6 mmol, 1.24 eq) was added, and the resultant mixture then heated at 120 °C for 2.5 hours.
The mixture was cooled to room temperature and was poured into water, and extracted once with ether. The organic solution was dried 2s over MgS04, filtered, evaporated and vacuum distilled to yield a colorless liquid (17.1 g, 74%). b.p. 160-163 °C at 0.4 mm Hg.
To warm polyphosphoric acid (15.3 g) was added a solution of the above compound (17.1 g, 59.3 mmol) in benzene (50 mL). The resultant mixture was heated under reflux with vigorous stirring for 4 hours, so after which time the benzene layer was carefully decanted off, and the lower layer washed once with hexanes. The combined organic solutions were concentrated in vacuo, and then vacuum distilled to yieid a colorless liquid (8.13 g, 70%). b.p. 62-72 °C at 0.6 mm Hg.
To a solution of the above compounds (8.11 g, 41.5 mmol) in ether (80 mL) at -78 °C was added 1.7 M t-butyllithium (48.8 mL, 83 mmol, 2 eq) such that the temperature did not exceed -70 °C. After stirring for ~ ~ man"to~, a c~lntion of DMF (6.5 mL, 83 mmol, 2 eq) in ether (20 mL}

was added, and the mixture allowed to warm to room temperaure over 2 hours. The mixture was poured into water and the phases separated.
The organic solution was dried over MgS04 and concentated in vacuo.
The residue was purified by flash chromatography on silica gel eluting s with 10% ether in hexanes to yield benzofuran-6-carboxaldehyde {1.22 g) and benzofuran-4-carboxaldehyde (1.86 g), both as colorless oils.
Example 1358 ~rans tran~l-(N-Methyl-N-orooylaminocarbQ,~~ylmethyrlZ~4-methoxyphenyl,)-4-l4-~ o ~enzofurany,~m~rrrolidine-3-carboxvli~c acid The title compound was prepared using the procedures described in Examples 1 and 49 substituting the compound resulting from Example 135A in Example 49A for piperonal. ~ H NMR (300 MHz, CDCl3) {minor rotamer) 8 7.59 ( 1 H, t, J=3Hz), 7.4-7.2 (6H, m), 6.8 {2H, d, J=8Hz), 4.03 ~ s (1 H, m), 3.94 {1 H, dd, J=8Hz, 3Hz), 3.77 (3H, s), 3.61 (1 H, dd, J=8Hz, 3Hz), 3.42 {1 H, dd, J=11 Hz, 5Hz), 3.40-2.90 {5H, m), 2.82 (2.81 ) (3H, s), 1.50 (2H, septet, J=7Hz), 0.82 (0.75) (3H, t. J=7Hz). MS (DCI/NH3) mle 451 {M+H)+. Anal.calc. for C26H3oN205 ~ AcOH: C, 65.87; H, 6.71; N ,5.49.
Found: C, 66.04; H, 6.42; N, 5.60. s example 136 traps tr~n_~N-Meth_yr1-N-Q~flSrlaminocarbon,~rlmethvl)- S4-methoxyr~yl)-4-(6 benzofuranvllovrr2idine-3-carboxvis; acid The title compound was prepared using the procedures described 2s in Examples 1 and 49 substituting benzofuran-6-carboxaldehyde, prepared as described in Example 135A, in Example 49A for piperonal.
~ H NMR (300 MHz, CDC13) (minor rotamer) S 7.65 (1 H, bd), 7.60 (1 H, d, J=2Hz), 7.55 (1 H, d, J=8Hz), 7.35 {3H, m), 6.85 {2H, dd, J=BHz, 3Hz), 6.75 (1 H, dd, J=3Hz, 2Hz), 3.83 (2H, m), 3.79 (3H, s), 3.60-3.0 (7H, m), 2.91 ao {2.83) (s, 3H), 1.51 (2H, septet, J=7Hz), 0.83 (0.78) (3H, t, J=7Hz). MS
(DCI/NH3) m/e 451 (M+H)+. Anal.caic. for C26H3oN2O5 ~ 0.5 H20: C, 67.96; H, 6.80; N, 6.10. Found: C, 67.90; H, 6.71; N, 6.07.

Example 137 benzo-2 3-dihydrofuranvllovrrolidine-3-carboxvlic~acid_ The title compound was prepared by catalytic hydrogenation (4 s atmospheres of H2 in AcOH, followed by preparative hplc) of the compound resulting from Example 136 ~H NMR (300 MHz, CDC13) (minor rotamer) b 7.49 (7.47) (2H, d, J=8Hz), 7.19 (iH, d, J=8Hz), 7.00 (1H, m), 7.82 (3H, m), 5.40 (1 H, dd, J=11 Hz, 7Hz), 4.58 {2H, t, J=8Hz), 4.18 (1 H, m), 4.10 (1 H, m), 3.88 (1 H, m), 3.79 (3H, s), 3.fi0 (1 H, m}, 3.35 (1 H, m), io 3.19 (2H, t, J=8Hz), 3.00 (4H, m), 2.91 (2.78) (s, 3t-i), 1.53 (1.40) (2H, septet, J=7Hz), 0.88 (0.78) (3H, t, J=7Hz). MS (DCIINH3} mle 453 (M+H)+.
Anal.calc. for C2sHs2N20s - 1.25 TFA: C, 57.53; H, 5.63; N, 4.71. Found:
C, 57.fi8; H, 5.68; N, 4.70.
f5 traps traps-LAN N-Di(n-bu~yyaminocarbonyimethyf -u4-methoxvohenvl?-4-(4 ~benzofuranyl_lovrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-4-carboxaldehyde in 2o Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide for N-methyl-N-propyl bromoacetamide. 1 H NMR. (300 MHz, CDC13) 8 7.62 (1 H, d, J=3Hz), 7.39 (1 H, dt, J=8Hz, 2Hz), 7.34 {3H, m), 7.26 (1 H, d, J=2Hz), 7.23 (1 H, d, J=8Hz), 6.84 (2H, d, J=8Hz), 4.02 (1 H, ddd, J=8, 6Hz,4Hz), 3.89 (1 H, d, J=9Hz) 3.79 (3H, s), 3.67 (1 H, dd, J=lOHz, 3Hz), 25 3.44 (2H, m), 3.35-3.15 (3H, m), 3.00 (2H, m), 2.84 (1 H, d, J=l4Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 507 (M+H)+. Anal.calc. for C3oH38N205: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.86; H, 7.45; N, 5:24.
3o Examp el 13_9 r n -1- N N- i r I - 4- h n I -4- 4 b~nzof~ranarl~~rrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-5-carboxaldehyde, prepared s5 by the procedures described in Example 135A substituted 4-bromophenol for 3-bromophenol, in Example 49A for piperonal and w w J:~...a,.t Lwnmn~notwmlf~P fir N-methyl-N-propel SuU~.'UIlUlilllJ, lv,W -u,u..~ .. ".......,_...

bromoacetamide. ~ H NMR (300 MHz, CDCI3) S 7.64 (1 H, bd), 7.59 (1 H, d, J=2Hz), 7.43 (2H, m), 7.33 (2H, d, J=SHz), 6.85 (2H, d. J=8Hz), 6.73 (1 H, dd, J=3Hz, 1 Hz), 3.82 ( 1 H, d, J=11 Hz), 3.89 ( 1 H, d, J=9Hz) 3.79 (3H, s), 3.53 (1H, dd, J=lOHz, 3Hz), 3.44 (2H, m), 3.30 (1H, m), 3.20-2.95 (5H, m), s 2.82 (1 H, d, J=l4Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz}, 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 507 (M+H)+. Anal.calc.
for C3pHggN205: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.73; H, 7.45; N, 5.29.
Exams ' traps traps-1 JJ .N N-Di(n-bu~y(laiminocarbonximethyl)-2_(4-methoxvohenvll-4-(6 benzofuranYl,)p~rrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-6-carboxaldehyde in ~s Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide for N-methyl-N-propyl bromoacetamide. ~ H NMR (300 MHz, CDC13) S
7.63 (1H, bd), 7.59 (1H, d, J=2Hz), 7.53 (1H, d, J=8Hz), 7.36 (3H, m), 6.85 (2H, d, J=8Hz), 6.73 (1 H, dd, J=3Hz, 1 Hz), 3.82 (1 H, d, J=11 Hz), 3.89 (iH, d, J=9Hz) 3.79 (3H, s), 3.53 {iH, dd, J=lOHz, 3Hz), 3.44 (2H, m), 20 3.30 (1H, m), 3.20-2.95 (5H, m), 2.80 (iH, d, J=l4Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS
(DCI/NH3) m/e 507 (M+H)+. Anal.calc. for C3oH38N2O5 - 0.75 H20: C, 69.28; H, 7.65; N, 5.39. Found: C, 69.11; H, 7.33; N, 5.32.
2s Example 141 traps traps-1~,N N-Di(n-butyl}aminocarbonylmethyl)-2~,4-methoxyphemL-4-(6 han7o-2 3-dihydrofuranyl)pyrrolidine-3-carboxviic acid The title compound was prepared by catalytic hydrogenation of the compound resulting from Example 140 (4 atmospheres of H2 in AcOH, so followed by preparative hp!c). ~ H NMR (300 MHz, CDC13} 8 7.40 (2H, d, J=8Hz}, 7.16 (1 H, d, J=8Hz), 6.97 (1 H, dd, J=8Hz, 2Hz), 6.89 (3H, m), 5.90 (1 H, bs) 4.57 (2H, t, J=9Hz}, 4.93 (2H, m), 3.80 (3H, s), 3.70-3.58 (2H, m), 3.40 (i H, m), 3.30-2.90 (8H, m), 1.40 (2H, m), 1.29 (3H, m), 1.08 (2H, m}, 0.92 (3H, t, J=7Hz), . 0.82 (3H, t, J=7Hz). MS (DCI/NH3) s5 m/e 509 (M+H)+. Anal.calc. for C3oHaoN2~s - 0.85 TFA: C, 62.88; H, 6.80; N, 4.fi3. Found: C, 63.04; H, 6.66; N, 4.60.

-1 s5-Exam I
r n r n 1- h r min r n 1 -m h n I -4-j~danvl)oyrrrQ~~,ine-3-carboxvfic acid Example 142A
jpd~3~,P-,~ 5-ca_rlboxaldehvde Indane-5-carboxaldehyde was prepared by formylation of indane under the conditions described for 2,3-dihydrobenzofuran in Example ~ 0 52A. The resultant mixture of 4- and 5-carboxahiehydes was purified as follows: to a 6:1 mixture of indane-4-carboxaldehyde and indane-5-carboxaldehyde (3.46 g, 23 mmol) was added aniline (2.20 g, 23 mmol, 1 eq). The resultant solution slowly solidfied to a mixture of imines which was recrystallized from hot acetonitrile to yield the 5-aldimine ~ s as a white solid. The aldimine (2.65 g) was suspended in water (6 mL), and treated with 4 N hydrochloric dioxane (10 mL). The mixture was boiled for 1 hour, cooled to room temperature, and poured into ether.
The organic solution was dried over MgS04, filtered, and concentated in vacuo. Vacuum distillation of the residue afforded indane-5-2o carboxaldehyde (1.54 g, 88%) as a colorless liquid. b.p. 88-90 °C at 0.9 mm Hg.
~xam~le 1,~2B
n 1- -N- I min I h I - - 4- h h n I -4-2s indanvlloyrrrolidine-3-carboxyrlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting indane-5-carboxaldehyde for piperonat in Example 49A. ~ H NMR (300 MHz, CDC13) (minor rotamer) S 7.25-7.1 (5H, m), 6.78 (2H, d, J=8Hz), 3.89 (1H, d, J=8Hz), 3.75 (3H, s), 3.50-so 2.90 (6H, m), 2.88 (6H, t, J=6Hz), 2.82 (2.80) (3H, s), 2.04 (2H, t, J=8Hz), 1.48 (2H, septet, J=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS (DC1/NHg) m/e 451 (M+H)+, 473 (M+Na)+. Anal.calc. for C2~H34N204 - 2.5 H20 ; C, 65.44;
H, 7.93; N, 5.65. Found: C, 65.36; H, 7.45; N, 5.53.

Example 143 ~ran~ tra~~1-~(N-Methyt-N-or~vlaminocarbonyrlme yrl)-2-{4-methoxwhenvl)-4-(6 ~ndolyrl)Qyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in s Examples 1 and 49 substituting indole-6-carboxaldehyde, prepared by the method of Rapoport, J. Org. Chem. 51: 5106 (1986), for piperonal in Example 49A. ~ H NMR (300 MHz, CDC13) (minor rotamer) 8 8.43 (1 H, brs), 7.57 ( 1 H, d, J=8Hz), 7.43 (1 H, s), 7.31 (2H, dd, J=6Hz, 3Hz), 7.22 (t H, d, J=8Hz), 7.1 (1 H, t, J=3Hz), 6.78 (2H,dd, J=6Hz, 3Hz), 6.45 (1 H, m), 3.93 ~ o ( t H, dd, J=6Hz, 3Hz), 3.80 {1 H, m), 3.73 (3H, s), 3.60-2.90 (6H, m), 2.86 (2.82) {3H, s), 1.47 (2H, septet, J=7Hz), 0.83 (0.73 (3H, t, J=7Hz). MS
(DCI/NH3) m/e 450 (M+H)+. Anal.calc. for C26H3i N3O4 ~ 0.75 H20: C, 67.44; H, 7.07; N, 9.07. Found: C, 67.42; H, 7.09; N, 8.91.
~ s xam~le 144 ~an~ rans_1-(N-Met(~,yl-N-~oovlaminocarbonyr-Imethyl~~-2-(4-methoxvchenvll-4 (3 4-difluorotahenv!)ovrrolir~ine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-difluorobenzatdehyde for piperonal 2o in Example 49A. ~ H NMR (300 MHz, CDC13) (minor rotamer) 8 7.60-7.3 (4H, m), 7.13 (1 H, q, J=9Hz), 6.90 (2H, d, J=8Hz}, 3.90 (1 H, m), 3.79 (3H, s), 3.60-2.95 (6H, m), 2.92 (2.78) (3H, s), 1.55 (2H, septet, J=7Hz), 0.88 (0.73) (3H, t, J=7Hz). MS (DCI/NH3) mle 447 (M+H)+. Anal.caic. for C24H2aF2N204 ~ 1.80 H20: C, 60.19; H, 6.fi5; N, 5.85. Found: C, 60.13; H, 2s 6.34; N, 5.84.
ExamQle 145 r n r n -1- N- I-N- I min r n Im h I - - 4-m h x h n I -4 (oheny~~Ry_rrolidine-3-carboxxli~ acid, 3o The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzaldehyde for piperonal in Exampie 49A. ~ H NMR (300 MHz, CDC13) (minor rotamer) 8 7.53 (4H, d, J=6Hz), 7.40-7.20 (3H, m), 6.88 (2H, d, J=8Hz), 3.90 ( 1 H, m), 3.79 (3H, s), 3.70-2.95 (8H, m), 2.90 (2.79) (3H, s}, 1.50 (2H, sept, J=7Hz), 0.87 (0.72) (3H, 35 t, J=7Hz}. MS (DCIlNH3) mle 411 (M+H)+. Anal.calc. for C24H3oN2~a 2.00 H20: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.37; H, 7.43; N, 6.29.

- i 67-Example 146 i -4. 4_ ~,vdroxyoheny,~ovrrolidi -3-carboxy i acid s The title compound was prepared by the procedures described in .
Examples 1 and 49 substituting 4-hydroxybenzaldehyde for piperonat in Example 49A. ~ H NMR (300 MHz, CDC13-CD30D) (minor rotamer) 8 7.35 (2H, d, J=8Hz), 7.28 (2H, dd, J=7Hz, 3Hz), 6.90 (2H, dd, J=7Hz, 3Hz), 6.89 (2H, d, J=8Hz), 3.8i (3H, s), 3.65 (i H, d, J=8Hz), 3.70-3.00 (8H, m), 2.92 ~ o (2.83) (3H, s), 1.50 {2H, septet, J=7Hz), 0.87 (0.77). {3H, t, J=7Hz). MS
{DCi/NH3) mle 427 (M+H)+. Anal.calc. for C24H3oN2O5 - 1.00 H20: C, 64.85; H, 7.26; N, 6.30. Found: C, 64.82; H, 7.39; N, 6.46.
Examele 147 -N- r m'n r n Im h 1 - - 4-m n I -4-,(2 4-dimethoxv~,ohenyl)ovrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,4-dimethoxybenzaldehyde for piperonal in Example 49A. ~ H NMR (300 MHz, CDCl3-CD30D) (minor 2o rotamer) S 7.61 (i H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.82 (2H, d, J=8Hz}, 6.55 (1 H, d, J=8Hz), 6.45 (1 H, d, J=3Hz), 3.90 {1 H, m), 3.81 (3H, s), 3.79 (3H, s), 3.77 {3H, s), 3.70-2.90 (8H, m), 2.85 (3H, s}, 1.50 (2H, sept, J=7Hz), 0.87 (0.77) (3H, t, J=?Hz). MS (DCIINH3) m/e 471 (M+H)+.
Anal.calc. for C26H34N20s - 0.75 H20: C, 64.51; H, 7.39; N, 5.79. Found:
2s C, 64.65; H, 7.07; N, 5.75.
F.xam~le~l 48 h - 4-m n 1 -4-b~n~-2-~dihvdro,_ furanyl~rrolidine-3-carboxylic acid so The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. ~ H NMR (300 MHz, CDC13) 8 7.31 (2H, d, J=8Hz), 7.27 (1 H, d, J=2Hz), 7.18 (1 H, dd, J=7Hz, 3Hz}, 6.86 (2H, d, J=8Hz), 6.72 (1 H, d, J=8Hz), 4.56 (2H, t, J=7Hz), 3.78 {3H, s);
35 3.62 (i H, m), 3.50-3.25 (4H, m), 3.17 (2f-!, t, J=7Hz), 3.15-2.90 (5H, m), 2.79 (1 H, d, J=l4Hz), 1.43 {3H, m), i .26 (3H, m), 1.08 (2H, m), 0.87 (3H, WO 99/06397 PCTlUS98/15479 t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCIlNH3) mle 509 (M+H)+. Anal.calc.
for C3oH4pN205 - 0.25 H20: C, 70.22; H, 7.95; N, 5.46. Found: C, 70.21; H, 7.92; N, 5.36.
f=Yamnle 149 ~,rans traps-1 IN N-Di(n,-bu aminocarbony~mP !~yr~-.2_-~4-methox~rohenvl)-4-f4 methoxvt~henvtl~ rrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in ~o Example 49A. ~H NMR (300 MHz, CDCI3) 8 7.38 (2~i, d, J=8Hz), 7.30 (2H, d, J=SHz), 6.87 (4H, dd, J=7Hz, 3Hz), 3.78 (3H, s), 3.76 (3H, s), 3.63 (1 H, m), 3.50-3.20 {4H, m), 3.15-2.90 (5H, m), 2.78 (1H, d, J=l4Hz), 1.43 (3H, m), 1.27 {3H, m), 1.09 (2H, m), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH3) mle 497 (M+H)+. Anal.calc. for C29H4oN205: C, ~ s 70.13; H, 8.12; N, 5.64. Found: C, 69.78; H, 8.10; N, 5.54.
Example 150 - N I r n m I - - 4- h n I -4- 4-difluorophen,~)pvrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-difluorobenzaldehyde for piperonal in Example 49A: ~H NMR (300 MHz, CDC13) S 7.35 (1H, m), 7.30 (2H, d, J=8Hz), 7.20-7.00 (2H, m), 6.87 (2H, d, J=8Hz), 3.78 (3H, s), 3.79 (1H, m), 3.62 (1 H, m), 3.50-3.30 (3H, m), 3.23 (1 H, m), 3.15-2.90 {4H, m), 2s 2.78 (1 H, d, J=l4Hz), 1.43 (2H, m), 1.27 (4H, m), 1.08 {2H, m), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCIINH3) mle 503 (M+H)+. Anal.calc.
for C28H36F2N204- ~ 1 H20: C, 64.60; H, 7.36; N, 5.38. Found: C, 64.59; H, 7.20; N, 5.35.
so Example 151 rn rn-1-NN- in- I min c r n I h I- -4-m h x h n 1-4-24 ~limethoxxph~n_~)ovrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,4-dirnethoxybenzaldehyde for 35 piperonal in Example 49A. ~ H NMR (300 MHz, CDC13) S 7.37 (2H, d, J=8Hz), 7.20 (1H, d, J=8Hz), 6.92 (2H, d, J=8Hz), 6.60 (1H, d, J=3Hz), WO 99/0639? PCT/US98/15479 6.49 (1 H, dd, J=6Hz, 2Hz), 5.35 (1 H, d, J=8Hz), 4.20 (3H, m), 4.10 (3H, s), 3.83 (3H, s), 3.81 (3H, s), 3.75 (3H, m), 3.17 (2H, hep, J=7Hz), 3.05 (2H, t, J=7Hz), 1.30 (4H, m), 1.07 (4H, m), 0.87 {3H, t, J=7Hz}, 0.80 (3H, t, J=7Hz). MS (DCI/NH3) m!e 527 (M+H)+. AnaLcalc. for C3oHa2N2~s - 1.30 s TFA: C, 58.02; H, 6.47; N, 4.15. Found: C, 57.92; H, 6.43; N, 4.07.
ExamQle 7 52 n y~~yrrrolidine-3-carboxyrlic acid ~ o The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B.
~ H NMR (300 MHz, CDCI3) b 7.50-7.25 (5H, m), 7.04 (1 H, d, J=3Hz), 6.87 (1 H, dd, J=7Hz, 3Hz), 6.74 (1 H, d, J=8Hz), 5.94 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.85 (1H, d, J=8Hz), 3.64 (1H, m), 3.42 (3H, m), 3.27 (2H, m), ~s 3.20-2.90 (5H, m), 2.81 (1H, d, J=l4Hz), 1.43 (2H, m), 1.27 (4H, m), 1.05 (2H, m), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS {DCIINH3) m/e 481 (M+H)+. Anal.calc. for C28H3sN2O5: C, 69.98; H, 7.55; N, 5.83.
Found: C, 69.69; H, 7.63; N, 5.71.
r n 1- N I min car n Im h I - h n I-4- n -2 dihydrofurany,~,ovrrolidine-3-carboxlrlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B
2s and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. t H NMR (300 MHz, CDCI3) b 7.53 (2H, m), 7.40 (4H, m), 7.13 (1 H, dd, J=7Hz, 3Hz), 6.72 (1H, d, J=8Hz), 5.40 (1H, d, J=lOHz), 4.56 (2H, t, J=8Hz), 4.18 {1 H, d, J=l4Hz), 4.07 (2H, m), 3.79 (2H, m), 3.48 {1 H, d, J=l4Hz), 3.35 (1 H, m), 3.28 (3H, m), 2.95 (2H, m), 1.47 (2H, m), 1.28 (4H, m), 1.10 (2H, m), 0.93 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). MS
(DCI/NH3) m/e 479 (M+H)+. Anal.calc. for C2gH38N204 - 1.10 TFA: C, 62.04; H, 6.52; N, 4.64. Found: C, 61.89; H, 6.44; N, 4.57.

Fxam~le 154 2s3 dihvdrof~ranyf)ovrrolidine-3-carb~xvlic acid The title compound was prepared by the procedures described in s Examples 1 and 49 substituting t-butyl benzoylacetate, prepared by the method of Krapcho et al., Org. Syn. 47:20 (1967} starting from 4-t-butylacetophenone, in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. ~ H NMR (300 MHz, CDCl3) b 7.60-7.30 (6H, m), 6.90 (1 H, m), 4.50 (2H, m), 3.95 (1 H, m}, 3.85-2.95 ~ o (11 H, m), 2.90 (1 H, d, J=14Hz), 1..58 (2H, m), 1 ~0 (7H, m), 1.41 {6H, s), 1.10 (2H, m), 1.00 (3H, t, J=7Hz), 0.90 (3H, t, J=7Hz). MS (DCI/NH3) m/e 535 (M+H)+. Anal.calc. for C33H46N2~4 ~ 0.25 H20: C, 73.50; H, 8.69;
N, 5.19. Found: C, 73.57; H, 8.58; N, 5.14.
15 ~xamole 155 r r N- in 1 h - 4-m h n i -4- 4-fluoroohenyrl)oyrrrolidine-3-carboxvlic~acid_ The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-fluorobenzaldehyde far piperonal in 2o Example 49A. ~H NMR (300 MHz, CDCI3) 8 7.50 (1H, m), 7.42 (1H, dd, J=7Hz, 3Hz), 7.36 (2H, d, J=8Hz), 7.01 (3H, t, J=8Hz), 6.87 (1 H, d, J=8Hz), 3.83 (1 H, m), 3.8 (3H, s), 3.67 (1 H, m), 3.47 (3H, m), 3.30-2.90 (5H, m), 2.82 (1 H, d, J=l4Hz), 1.43 (2H, m), 1.28 {4H, m), 1.08 (2H, m), 0.90 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCIlNH3) mle 485 (M+H)+. Anal.calc.
25 for C28H3~FN204: C, 69.40; H, 7.70; N, 5.78. Found: C, 69.03; H, 8.00; N, 5.74.
Example 156 r r - N ' n- min r n im I - -f r I -4- 1 n t x 1-30 ~y!)~ovrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting p-oxo-3-furanpropionate in Example 498. ~ H NMR (300 MHz, CDC13) 8 7.41 (2H, m), 6.97 (1 H, d, J=3Hz), 6.85 (1 H, dd, J=7Hz, 3Hz), 6.72 (1 H, d, J=8Hz), 6.42 (1 H, s), 5.94 (1 H, d, 3s J=4Hz), 5.92 (1 H, d, J=4Hz), 3.90 (1 H, m), 3.70-3.25 (5H, m), 3.20-2.90 {4H, m), 2.85 (1 H, d, J=l4Hz), 1.43 (2H, m), 1.40-1.05 (6H, m), 0.90 (6H, m). MS (DCIINH3) m/e 471 (M+H)+. Anal.calc. for C26H3aN20s: C, 66.36;
H, 7.28; N, 5.95. Found: C, 66.09; H, 7.24; N, 5.87.
Exam !e 157 r i m i n r -4-benzodioxol-5-vl)wrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B.
~ H NMR {300 MHz, CDCI3) 8 6.85 (1 H, d, J=2Hz), 6.76 (1 H, dd, J=6Hz, 2Hz), 6.71 (1 H, d, J=8Hz), 5.92 (2H, s), 3.75 (1 H, d, J=141-Iz), 3.66 (1 H, q, J=7Hz). 3.42 (3H, m), 3.25 (3H, m), 3.11 {2H,m), 2.83 (1 H, t, J=7Hz), 1.88 (1 H, m), 1.55 (4H, m), 1.32 {4H, m), 0.92 (12H, m). MS {DCI/NH3) m/e 447 (M+H)+. Anal.calc. for C2~H3gN2O5 ~ 0.50 H20: C, 65.91; H, 8.63; N, 6.15. Found: C, 66.07; H, 8.10; N, 6.03.
Exams h - 4- - I h n 1 -4-b~n,~odioxof-5-vl)ovrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in zo Examples 1 and 49 substituting ethyl 4-t-butylbenzoyiacetate, prepared by the method of Krapcho et al., Org. Syn. 47: 20 {1967) starting with 4-t-butylacetophenone), in Example 498. ~ H NMR (300 MHz, CDC13) 8 7.32 {4H, d, J=3Hz), 7.04 (1 H, d, J=2Hz), 6.87 {1 H, dd, J=8Hz, 3Hz), 6.74 (1 H, d, J=9Hz), 5.94 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.77 (1 H, d, J=l4Hz), 2s 3.65-3.25 (5H, m), 3.15-2.85 (4H, m), 2.73 (1 H, d, J=l4Hz), 1.45 (2H, m), 1.29 (13H, s), 1.00 (2H, m), 0.86 (3H, t, J=7Hz), 0.76 (3H, t, J=7Hz). MS
(DCI/NH3) mle 537 (M+H)+. Anal.calc. for Cs2HaaN205: C, 71.61; H, 8.26;
N, 5.22. Found: C, 71.43; H, 8.09; N, 5.11.
3o ExamQle 159 r n n 1- I mi n Im - 4-- h n I -4-~,~-dihvdrofuranylhyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B
35 and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. i H NMR {300 MHz, CDCI3) 8 7.30 (1 H, s), 7.13 (1 H, dd, J=7Hz, 2Hz), *rB

6.82 (1 H, d, J=8Hz), 4.68 (2H, t, J=8Hz), 4.48 (1 H, s), 3.19 (3H, m), 3.80 (3H, m), 3.48 {2H, m), 3.3 (5H, m), 2.41 (1H, m), 1.65 {4H, m), 1.44 (4H, m), 1.21 (3H, d, J=5Hz), 1.17 (3H, d, J=5Hz), 1.05 (6H, m). MS (DCI/NH~) m/e 445 (M+H)+. Anal.calc. for C26HaoN2~4 ~ 1.2 TFA: C, 58.67; H, 7.14;
s N, 4.8.2 Found: C, 58.54; H, 7.25; N, 4.74.
Exam p,[e 160 traps tran~l-(N N~Di(n-butyl)aminocarbonlrlmethyr_[)~(anti-4-metho,~c_yrclo 4-~1 3-benzodioxol-5-yl)Qyrrolidine-3-carboxylic acid Syn, anti-4-Methoxycyclohexane carboxylic acid (5.00 g, 31.6 mmol) and carbonyldiimidazole (6.15 g, 37.9 mmol, 1.2 eq) were stirred 1 s in anhydrous tetrahydrofuran (50 mL) for 6 hours at room temperature.
At the same time, magnesium chloride (3.01 g, 31.6 mmoi) and ethyl malonate potassium salt (7.52 g, 44.2 mmol, 1.4 equivalents) were stirred in anhydrous tetrahydrofuran (75 mL) for 6 hours at 50 °C. The mixture was cooled to room temperature, and the imidazole-acid 2o mixture added to it. The reaction stirred overnight at room temerature.
The solvents were removed under reduced pressure, and the residue was taken up in chloroform/water. The organic phase washed with 5%
potassium bisulfate, water, and brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was 2s purified by flash chromatography on 175 g silica gel, eluting with 20%
ethyl acetate in hexanes. Pure fractions of the syn and anti methoxycyclohexyl ~-keto esters were obtained. The solvents were removed under reduced pressure to yield the traps-4-methoxycyclohexyl ~-keto ester (914 mg) as a colorless oil and the cis 4-3o methoxycyclohexyl ~ keto ester (1.07 g) as a colorless oil.
Exam I~e.160B
n r N- i I i r n Im h I - n '-4- h I h I -35 ~;~1 ~-ben~ndinxol-5-yl)nyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Fxamoles 1 and 49 substituting the anti-compound resulting from Example 160A in Example 49B. ~ H NMR (300 MHz, CDC13) 8 6.84 (1 H, d, J=2Hz), 6.76 (1 H, dd, J=7Hz, 2Hz), 6.61 (1 H, d, J=8Hz), 5.92 (2H, s), 3.69 (2H, m), 3.50-3.27 (5H, m), 3.26 (3H, s), 3.25-3.00 (3H, m), 2.88 (1 H, m), 1.95 (2H, m), 1.62 (7H, m), 1.33 (9H, m), 0.97 (3H, t, J=7Hz), 0.92 (3H, t, s J=7Hz). MS (DCI/NH3) mle 517 (M+H}+. Anal.calc. for C2sH44N2Os - 0.50 H20: C, 66.26; H, 8.63; N, 5.33. Found: C, 66.27; H, 8.50; N, 5.13.
Example 161 n r n - i i r n m h -4- I h I -0 4-j,~3-benzodioxol-5-X("~vrrolidine-3-cartroxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the syn-compound resulting from Example 160A in Example 498. ~H NMR (300 MHz, CDC13) b 6.84 (1H, d, J=2Hz), 6.77 (1 H, dd, J=6Hz, 2Hz), 6.61 (1 H, d, J=8Hz), 5.92 (2H, s), 3.65 ~ s (2H, m), 3.42 (2H, m), 3.32 (3H, s), 3.30-3.00 (6H, m), 2.82 (1 H, m), 2.10 (2H, m), 1.83 (2H, m}, 1.52 (6H, m), 1.33 (4H, m), 1.20-1.00 (4H, m), 0.96 (3H, t, J=7Hz), 0.91 (3H, t, J=7Hz). MS (DCI/NH3) m/e 517 (M+H)+.
Anal.calc. for C2gH44N2Og ~ 0.30 H20: C, 66.72; H, 8.61; N, 5.37. Found:
C, 66.76; H, 8.65; N, 5.28.
Example 162 ~rans iran~l-fN N-Di(n-bu rllaminocarbonylmethyrl~-2.4-di(5-benzo-2.3 ~ihvdrofuranyl~ovrrolidine-3-carboxyrtic acid ~xam~lg 162A
5-Acetvl-2.3-dihydrobenzofuran To a 0 °C solution of acetyl chloride (1.64. mL, 23.0 mmol, 1.3 equivalents) in methylene chloride (30 mL) was added stannic chloride (2.49 mL, 21.3 mmol, 1.2 equivalents), maintaining the temperature ao below 5 °C. The solution was stirred 15 minutes at 0 °C, and then a solution of 2,3-dihydrofuran (2.00 mL, 17.7 mmol) in methylene chloride (5 mL) was added dropwise while maintaining the temperature below 8 °C. The dark red solution was stirred 1 hour at 2 °C and then poured into 50 mL of ice water. The reaction was stirred an additional 30 ss minutes, and the layers were separated. The organic layer was washed with water and aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash .chromatography on 150 g silica gel, eluting with 18% ethyl acetate in hexanes. The solvents were removed under reduced pressure ~to yield the title compound (2.68 g, 93%) as a yellow solid.
xa ale 1628 ~rans traps-1 (jjN-Diln-butyl)aminocarbonytmethytl-?.4-di(,~-benzo-2.3 dihydrofurany~yvrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in ~ o Examples 1 and 49 substituting the compound resulting from Example 162A in Example 498 and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCl3) 8 7.43 {1H, s), 7.38 (1 H, s), 7.06 (2H, m), 6.75 {1 H, d, J=6Hz), 6.70 (1 H, d, J=6Hz), 5.40 (1 H, d, J=9Hz), 4.58 (4H, q, J=7Hz), 4.16 (1 H, d, J=l4Hz), 4.09 {2H, m), 3.82 ~ s (2H, m), 3.57 (1 H, d, J=l4Hz), 3.38 (1 H, m), 3.30-3.05 {6H, m), 2.95 (2H, q, J=6Hz), 1.50 (2H, m), 1.30 (4H, m), 1.15 (2H, m), 0.94 (3H, t. J=7Hz), 0.83 (3H, t, J=7Hz). MS (DCIINH3) mle 521 (M+H)+. Anal.calc. for C3~ H4oN2O5 - 1.25 TFA: C, 60.67; H, 6.27; N, 4.22. Found: C, 60.49; H, 6.18; N, 4.13.
ExamQle 163 r 1- ' n- I min n im I - -f -4- nz -~,ihvd~rofu_rany~ovrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in 2s Examples 1 and 49 substituting ethyl p-oxo-3-furanpropionate in Example 498 and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. ~ H NMR (300 MHz, CDC13) 8 7.42 (1 H, m), 7.38 (1 H, m), 7.13 (1H, s), 7.16 (1H, dd, J=7Hz, 3Hz), 6.70 (1H, d, J=8Hz), 6.41 (1H, m), 4.57 {2H, t, J=7Hz), 3.95 (1 H, d, J=8Hz), 3.63 (1 H, m), 3.55 (1 H, d, J=14), so 3.50-3.25 {4H, m), 3.18 (2H, t, J=6Hz), 3.15-2.95 {3H, m), 2.87 (1 H, d, J=l4Hz), i .45 (4H, m), 1.35-1.10 (4H, m), 0.85 (6H, m). MS (DCI/NH3) mle 469 {M+H)+. Anai.calc. for C27H3gN2O5 ~ 0.25 H20: C, 68.55; H, 7.78;
N, 5.92. Found: C, 68.62; H, 7.68; N, 5.82.

Fxamole 164 I I I-fluoro~t~,Q~yl~yrrolidine-3-carbox~rlic acid The title compound was prepared by the procedures described in s Examples 1 and 49 substituting 3-fluorobenzenecarboxaldehyde for piperonal in Example 49A. ~ H NMR (300 MHz, CDCI3} b 7.30 (2H, d, J=8Hz), 7.22 (2H, m}, 6.91 (1 H, m), 6.86 (2H, d, J=8Hz), 3.79 (1 H, m), 3.78 (3H, s), 3.68 (1 H, m}, 3.55-3.37 (3H, m), 3.29 (1 H, m), 3.15-2.90 (5H, m), 2.78 (1 H, d, J=l4Hz), 1.43 (2H, m), 1.25 (4H, m), 1.07 (2H, m}, 0 0.87 (3H, t, J=7Hz}, 0.80 (3H, t, J=7Hz). MS (DCtLNH3) mle 485 (M+H)+.
Anal.calc. for C2gH37FN2O4 ~ 0.25 H20: C, 68.76; H, 7.73; N, 5.73. Found:
C, 68.87; H, 7.69; N, 5.67.
,~xamflle 165 ~ s N- min n I h f - - 4-m h I -4-p~,rrl~yrl)~Qyrrotidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-pyridinecarboxaldehyde for piperonat in Example 49A. The vitro styrene was prepared by the method of o Bourguignon ,et at., Can. J. Chem. 63:.2354 (1985). ~ H NMR (300 MHz, CDC13) 8 8.82 (1 H, bs), 8.73 (1 H, bd, J=9Hz), 8.62 (1 H, bd, J=7Hz), 7.78 (i H, bdd, J=9Hz, 3Hz}, 7.38 (2H, d, J=1 OHz), 6.90 (2H, d, J=1 OHz), 4.39 ( 1 H, d, J=12Hz), 3.95 ( 1 H, m), 3.80 (3H, s), 3.79 ( 1 H, m}, 3.68 ( 1 H, d, J=l8Hz), 3.50-3.30 (3H, m), 3.25-2.90 (6H, m}, 1.47 (2H, m), 1.31 (4H, 2s m), 1.20 (2H, m), 0.92 (3H, t, J=7Hz), 0.83 (3H, t, J=7Hz). MS (DCIlNH3) m/e 468 (M+H)+. Anal.catc. for C27H37N304 ~ 1.65 TFA: C, 55.50; H, 5.94;
N, 6.41. Found: C, 55.53; H, 5.90; N, 6.27.
ExamQle 166 so traps tran~l_(N N-Di(n-buy(lam'nocarbonvlmethyly-2-(2-fluorooh~n~rJ~l,_1~
~enzodioxol-5-y~~,ovrrolidine-3-carbox~~lic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 2-ftuorobenzoytacetate in Example 498. ~ H NMR (300 MHz, CDCl3) S 7.52 (1 H, dt, J=7Hz, 3Hz), 7.25 ss (1 H, m), 7.13 (1 H, dt, J=7Hz, 3Hz), 7.02 (2H, m), 6.88 (1 H, dd, J=7Hz, 3Hz), 6.73 (1 H, d, J=8Hz), 5.93 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 4.25 ( 1 H, d, J=9Hz), 3.68 ( 1 H, m), 3.42 (3H, m), 3.39 ( i H, m), 3.20-2.95 (4H, m), 2.91 (1 H, d, J=l4Hz), 1.45 (3H, m), 1.26 {3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCIlNH3) mle 499 (M+H)+.
Anal.caic. for C28H35FN205 ~ 0.25 H20: C, 66.85; H, 7.11; N, 5.57. Found:
C, 66.51; H, 6.67; N, 5.18.
s Exam 1 -f benz, ~'ioxol-5-yj~ovrrolidine-3-ca oxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 3-fiuorobenzoyiacetate in Example 49B. ~H NMR (300 MHz, CDCI3) 8 7.38 (1H, m), 7.18 (1H, d, J=7Hz), 7.15 (1 H, m), 7.00 {1 H, d, J=2Hz), 6.95 (1 H, m), 6.86 (1 H, dd, J=7Hz, 2Hz), 6.75 (1 H, d, J=8Hz), 5.93 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.94 (1 H, d, J=l4Hz), 3.63 (1 H, m), 3.42 (3H, m)~ 3.35-2.95 (5H, m), 2.87 ~ s {1 H, d, J=14Hz), 1.44 (3H, m), 1.27 (3H, m), 1. i 0 (2H, m), 0.88 (3H, t, J=7Hz), 0.81 {3H, t, J=7Hz). MS (DCIINH3) m/e 499 (M+H)+. Anal.calc.
for C28H35FN20$: C, 67.45; H, 7.08; N, 5.62. Found: C, 67.32; H, 7.05; N, 5.40.
franc.traps-1-(4-N.N-Di(n-butyl)amino~henyly-2-(4-methoxvohenyl -4-(1.3 benzodioxol-5-yl)yXrrolidine-3-carboxylic acid 4-Nitro-1-fiuorobenzene, ethyl irans,irans-2-(4-methoxyphenyl)-4-{1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate is (the compound resulting from Example 6A), and diisopropylethylamine are heated in dioxane to give ethyl traps,mans-2-(4-methoxyphenyl)-4~
( 1, 3-benzodioxol-5-yl)-1-(4-nitrophenyi)-pyrrolidine-3-carboxylate.
The vitro compound is hydrogenated to give the corresponding aminophenyl compound. The aminophenyl compound is reacted with so butyraldehyde and sodium cyanoborohydride according to the method of Borch, J. Am Chem. Soc. 93: 2897 (1971) to give the corresponding N,N-dibutylaminophenyl compound. Hydrolysis with sodium hydroxide using the method of Example 1 D affords the title compound.

Example 169 traps tran~l-~Dibutylamino~yrimidi.-4-yl)-2-(4-methomrphenvl)-4-(1.3 benzodioxol-5-y~~yrrolidine-3-carboxlrlic acid 2-(Dibutylamino)-4-chloropyrimidine is prepared from 2,4 s dichloropyrimidine according to the method of Gershon, J. Heterocyclic Chem. 24: 205 (1987) and reacted with ethyl trans,trans-2-(4-methoxyphenyl}-4-(i ,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate (the compound resulting from Example 6A} and diisoproplyethylamine in dioxane with heating to give the intermediate ethyl ester, which is ~ o hydrolyzed with sodium hydroxide using the method of Example 1 D to the title compound.
Exann~les 70-266 Using the procedures described in Examples 1, 4, 5, 7, 8 and 9 and ~ s Scheme X, the following compounds can be prepared.
Ex. No. Name 170 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(isopropylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
i71 traps,traps-2-{4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(ethylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
172 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-( 1-methylpropylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
173 traps,irans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
174 traps, traps-2-{4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1-(piperidinylcarbonylmethyl)-pyrrolidine-3-carboxylic acid;

175 traps,traps-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yi)-1-( 1-(propylaminocarbonyl)ethyl)-pyrrolidine-3-carboxylic acid;
176 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(a-(propylaminocarbonyl)benzyl)-pyrrolidine-3-carboxylic acid;
177 traps,traps-2-(4-Methoxyphenyl}-4-(1,3-benzodioxol-5-yl)-1-(bis-(propylaminocarbonyl)methyl)-pyrrolidine-3-carboxytic acid;
178 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(propylaminocarbonyl)ethyl)-pyrrolidine-3-carboxylic acid;
179 traps, traps-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1-(propylaminosulfonylmethyl)-pyrrolidine-3-carboxylic acid;
180 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-phenethyl}-pyrrolidine-3-carboxylic acid;
181 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(pentan.oylmethyl)-pyrrolidine-3-carboxylic acid;
182 traps,traps-2-(4-Methoxyphenyl}-4-(1,3-benzodioxol-5-yl)-1-(benzoylmethyi)-pyrrolidine-3-carboxylic acid;
183 traps,frans-2-(4-Methoxyphenyl)-4-(1,3~
benzodioxol-5-yl)-1-(hexyl)-pyrrolidine-3-carboxylic acid;
184 traps, traps-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1-(2-hexynyl)-pyrrolidine-3-carboxylic acid;
185 traps,traps-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1-(propoxymethylcarbonyl-pyrrolidine-3-carboxylic acid;

18fi traps,traps-2-(4-Methoxyphenyi)-4-(1,3-benzodioxol-5-yl)-1-(phenyl acetyl)-pyrrolidine-3-carboxylic acid;
187 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(anilinylcarbonyl)-pyrrolidine-3-carboxylic acid;
188 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-acetylaminoethyl)-pyrrolidine-3-carboxylic acid;
189 traps, traps-2-(4-Methoxyphenyl)-4-( 1,.3-benzodioxol-5-yl)-1-{2-phenoxyethyi)-pyrrolidine-3-carboxylic acid;
190 traps,traps-2-(4-Methoxyphenyl)-4-{1,3-benzodioxol-5-yl)-1-(2-benzodioxanylmethyl)-pyrrolidine-3-carboxylic acid;
191 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-tetrahydrofuranylmethyl)-pyrrolidine-3-carboxylic acid;
192 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(propylaminocarbonylamino)ethenyl)-pyrrolidine-3-carboxylic acid;
193 traps,traps-2-{4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(propylaminocarbonylamino)ethyl)-pyrrolidine-3-carboxylic acid;
194 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-y!)-1-(3-oxohex-1-enyi)-pyrrolidine-3-carboxylic acid;
195 traps,traps-2-(2,4-Dimethoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1-(propylaminocarbonyimethyl)-pyrrolidine-3-carboxylic acid;
196 traps,traps-2-(2-Carboxy-4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;

- i 80-i 97 traps,traps-2-(2-Aminocarbonyl-4-methoxyph.enyl)-4-( i ,3-benzodioxol-5-yl)-1-(propylaminocarbonyimethyl)-pyrrolidine-3-carboxylic acid;
198 traps,traps-2-(2-Methanesulfonamido-4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl}-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
199 traps,traps-2-(2-Aminocarbonyimethoxy-4-methoxyphenyl)-4-( i ,3-benzodioxol-5:.y1)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
200 traps,traps-2-(2-Methoxyethoxy-4-methoxyphenyl)-4-( 1, 3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
201 traps,traps-2-(2-Carboxymethoxy-4-methoxyphenyl}-4-( 1, 3-benzodioxol-5-yl)-1-{propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
202 trans,trans-2-(4-Methoxy-2-tetrazolylmethoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)-1-~propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
203 traps,traps-2-(2-Atlyloxy-4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1-(propyiaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
204 trans,trans 2,4-Bis(4-methoxyphenyl)-1-(propylaminocarbonyl methyl)-pyrrolidine-3-carboxylic acid;
205 trans,trans 2,4-Bis(1,3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;

206 traps, traps-2-(4-Methoxyphenyl)-4-( 7 ,3-benzodioxol-5-yl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
207 traps, traps-2-(4-Methoxyphenyl)-4-{ 1,3-benzodioxole-5-yl)-1-(N-methyl-N-butylaminocarbonyl)-pyrrolidine-3-carboxylic acid;
208 traps,traps-2-(4-Methoxyphenyl)-4-{1,3-benzodioxol-5-yl)-1-(N-methyl-N-(4-methoxyphenyl)aminocarbonyl)-3-pyrralidine-3-carboxylic acid;
209 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-phenylaminocarbonyl)-pyrrolidine-3-carboxylic acid;
210 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-allylaminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid;
21 i traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
2 7 2 traps,traps-2-{4-Methoxyphenyl)-4-{ 1,3-benzodioxol-5-yt)-1-(N-methyl-N-isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
213 traps,traps-2-(4-Methoxyphenyl)-4-{ 1,3-benzodioxol-5-yl)-1-(N-methyl-N-cyclopentylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
214 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(2-methoxyethyl)aminocarbonyl)-pyrroiidine-3-carboxylic acid;

215 traps,traps-2-(4-Methoxyphenyi)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-butoxyethyiaminocarbonyl)-pyrrolidine-3-carboxylic acid;
216 traps,traps-2-(1,3-Benzodioxol-5-yi)-4-(4-methoxyphenyl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; .
217 traps,traps-2-(4-Methoxyphenyl)-4-(1,4-benzodioxan-6-yl)-1-(N-methyl-N-propylaminocarbonylmethyf)-pyrrolidine-3-carboxylic acid;
218 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-isopropylaminocarbonylmethyl)-pyrrolidine-3-carboxytic acid;
219 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-ethylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
220 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(1-methylpropyl)aminocarbonylmethyi)-pyrroiidine-3-carboxylic acid;
221 traps,traps-2-(4-Methoxyphenyl)-4-( 1.3 benzodioxol-5-yl)-1-(N-methyl-N
phenylaminocarbonylmethyi)-pyrrolidine-3-carboxylic acid;
222 franc,traps-2-(4-Methoxyphenyl)-4-{1,3-benzodioxol-5-yl)-i -( 1-(N-methyl-N-propylaminocarbonyl)ethyl)-pyrrolidine-3-carboxylic acid;
223 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(a-(N-methyl-N-propylaminocarbonyl)benzyl)-pyrrolidine-3-carboxylic acid;

224 traps,traps-2-(4-Methoxyphenyl}-4-(1,3-benzodioxol-5-yl)-1-(N-ethyl-N-propylaminocarbony!methyl}-pyrrolidine-3-carboxylic acid;
225 traps,traps-2-{4-Methoxyphenyl}-4-(1,3-benzodioxole-5-yl}-1-( N-ethyl-N-butylaminocarbonyl)-pyrrolidine-3-carboxylic acid;
226 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl}-1-(N-ethyl-N-(4-methoxyphenyl)aminocarbonyl)-3-pyrr~lidine-3-carboxylic acid;
227 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yi)-1-(N-ethyl-N-phenylaminocarbonyl)-pyrrolidine-3-carboxylic acid;
228 traps,traps-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1-{N-ethyl-N-allylaminocarbony!methyl)-pyrrolidine-3-carboxylic acid;
229 traps,traps-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1-{N-ethyl-N-isobutylaminocarbony!methyl)-pyrrolidine-3-carboxylic acid;
230 traps,traps-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1-(N-ethyl-N
cyclopentylaminocarbony!methyl)-pyrrotidine-3-carboxylic acid;
231 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl}-1-(N-ethyl-N-methoxyethylaminocarbonyl)-pyrrolidine-3-carboxylic acid;
232 . traps,traps-2-(4-Methoxypheny()-4-(1,3-benzodioxoi-5-yl)-1-(N-ethyl-N-butoxyethylaminocarbonyl)-pyrrolidine-3-carboxylic acid;

233 traps,!raps-2-(1,3-Benzodioxol-5-yl)-4-(4-methoxyphenyl)-1-(N-ethyl-N-propylaminocarbonyfmethyl)-pyrrolidine-3-carboxylic acid;
234 irans,traps-2-(4-Methoxyphenyl)-4-( 1,4-benzodioxan-6-yl)-1-(N-ethyl-N-propylaminocarbonylmethyl)-pyrroiidine-3-carboxylic acid;
235 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-i -(N-ethyl-N-isopropylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
236 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-diethylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
237 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-ethyl-N-( 1-methylpropyl)aminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid;
238 traps,traps-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1-(N-ethyl-N-phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
239 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-( 1-(N-ethyl-N-propylaminocarbonyl)ethyl)-pyrrolidine-3-carboxylic acid;
240 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(a-(N-ethyl-N-propylaminocarbonyl)benzyl)-pyrrolidine-3-carboxyiic acid;
241 traps,traps-2-(4-Methoxyphenyl)-4-{1,3-benzodioxol-5-yl)-1-(N-methyl-N-isobutylaminocarbonylmethy!)-pyrrolidine-3-carboxylic acid;
*rB

242 traps,traps-2-{4-Methoxyphenyl}-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-cyclohexylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
243 traps.traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-dipropylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
244 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl}-1-(isobutyloxyethyL}-pyrrolidine-3-carboxylic acid;
245 irans,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(butylsuifonyl)-pyrrolidine-3-carboxylic acid;
246 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(isopropylsulfonylaminoethyl)-pyrrolidine-3-carboxylic acid;
247 traps,traps-2-{4-Methoxyphenyl)-4-(i,3-benzodioxol-5-yl)-1-(ethoxymethylcarbonylmethyl)-pyrrolidine-3-carboxyiic acid;
248 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-ethylbutyrylmethyl)-pyrrolidine-3-carboxylic acid;
249 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(3,4-dimethoxybenzyl}aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
250 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[(1 R)-1-(N-methyl-N-propylaminocarbonyl)butyl]-pyrrotidine-3-carboxylic acid;
251 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl}-1-[( i S)-1-(N-methyl-N-propylaminocarbonyf)butyl]-pyrrolidine-3-carboxylic acid;

-~as-252 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yt)-1-(3-isopropoxypropyl)-pyrrolidine-3-carboxylic acid;
253 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxot-5-yl)-1-(5-methylhexyl)-pyrrolidine-3-carboxylic acid;
254 traps,traps-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1-(5-methyl-2-hexenyl)-pyrrotidine-3-carboxylic acid;
255 traps, traps-2-(4-Methoxyphenyl)-4-( i ,.3-benzodioxol-5-yl)-1-(5-methyl-4-hexenyl)-pyrrolidine-3-carboxylic acid;
256 irans,traps-2-(4-Methoxyphenyi)-4-(1,3-benzodioxol-5-yl)-1-(3,5-dimethyl-2-hexenyl)-pyrrolidine-3-carboxylic acid;
257 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-methyl-N-isobutyrytamino)ethyl)-pyrrolidine-3-carboxylic acid;
258 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(2,2-dimethylpropyl)aminocarbony!methyl)-pyrrolidine-3-carboxylic acid;
259 traps,traps-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1-(N-ethyl-N
butylaminocarbony!methyl)-pyrrolidine-3-carboxylic acid;
260 traps,traps-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-benzylaminocarbony!methyl)-pyrrolidine-3-carboxylic acid;
262 traps,traps-2-(4-Methoxyphenyl)-4-{5-indanyl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;

262 traps,traps-2-(4-Methoxyphenyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
263 traps,irans-2-(4-Methoxyphenyl)-4-(1-methylindoi-5-yl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
264 traps,traps-2-(4-Methoxyphenyl)-4-{2-naphthyl)-1-(N-methyl-N-propylaminocarbonylmathyl)-pyrrolidine-3-carboxylic acid;
265 traps,traps-2-(4-Methoxyphenyl)-4-(1,2-dimethoxy-4-phenyl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
266 traps,traps-2-(4-Methoxyphenyl)-4-(1-methoxy-3-phenyl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
,exam iii es 267-288 Following the procedures described in Example 1 and Scheme II, s the following compounds can be prepared.
267 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-i-(propylaminocarbonylmethyl)-piperidine-4-carboxylic acid;
268 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(aminocarbonylmethyl)-piperidine-4-carboxylic acid;
269 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(4-fluorobenzyl)-piperidine-4-carboxylic acid;
270 traps,traps-3-(4-Methoxyphenyl)-5-( 1,3-benzodioxol-5-yl)-1-(2-ethoxyethyl)-piperidine-4-carboxylic acid;

271 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-y!)-1-(2-propoxyethyl)-piperidine-4-carboxylic acid;
272 traps,traps-3-(4-Methoxyphenyl)-5-( 1,3-benzodioxol-5-yl)-1-[2-(2-methoxyethoxy)ethyl)-.
piperidine-4-carboxylic acid;
273 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-[2-(2-pyridyl)ethyl}-piperidine-4-carboxylic acid;
274 traps,traps-3-(4-Methoxyphenyl)-5-(1,~-benzodioxol-5-yl)-1-(morpholin-4-ylcarbonyl)-piperidine-4-carboxylic acid;
275 traps,traps-3-(4-Methoxyphenyl}-5-(1,3-benzodioxole-5-yl)-1-(butylaminocarbonyl}-piperidine-4-carboxylic acid;
276 traps,traps-3-(4-Methoxyphenyl)-5-( 1,3-benzodioxol-5-yl)-1-(4-methoxyphenytaminocarbonyl)-3-piperidine-4-carboxyiic acid;
277 traps,traps-3-{4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl}-1-acetylpiperidine-3-carboxylic acid;
278 traps,traps-3-(4-Methoxyphenyl)-5-( 1,3-benzodioxol-5-yl)-1-(2-furoyl)-piperidine-3-carboxylic acid;
279 traps,irans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(phenylaminocarbonyl)-piperidine-4-carboxylic acid;
280 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(allylaminocarbonylmethyl)-piperidine-4-carboxylic acid;
281 traps,traps-3-{4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(n-butylaminocarbonylmethyl)-piperidine-4-carboxylic acid;

WO 99/0639? PCTIUS98115479 282 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(N-n-butyl-N-methylaminocarbonylmethyl)-piperidine-4-carboxylic acid;
283 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(pyrrolidin-1-ylcarbonylmethyl)-piperidine-4-carboxylic acid;
284 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(isobutylaminocarbonylmethyl)-piperid~ne-4-carboxyiic acid;
285 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(cyclopentylaminocarbonylmethyl)-piperidine-4-carboxylic acid;
286 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(morpholin-4-ylaminocarbonylmethyl)-piperidine-4-carboxylic acid;
287 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(2-phenoxyethyl)-piperidine-4-carboxylic acid;
288 traps,traps-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(methoxyethylaminocarbonyl)-piperidine-4-carboxylic acid.
Example 289 traps traps= 2-(4-MethoxX~he-n~11-4-x(1.3-benzodioxol-5-yrl)-1- (4 dibutXlaminoQhenyll-nvrrolidine-3-carboxylic acid s 4-Nitro-fluorobenzene, ethyl traps,traps-2-(4-methoxyphenyl)-4-(1,3-benzodioxoi-5-yl)-pyrrolidine-3-carboxylate (example 6A) and di-isopropyl ethyfamine are heated in dioxane to give ethyl traps, irans-2-(4-methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)-1-(4-nitrophenyl)-pyrrolidine-3-carboxylate. The vitro compound is hydrogenated to the ~ o corresponding aminophenyl compound. This is reacted with butyraldehyde and sodium cyanoborohydride according to the method of Borch (J. Am Chem. Soc., 93, 2897, 1971 ) to' give the corresponding N,N-dibutylaminophenyl compound, which is hydrolyzed with sodium hydroxide using the method of example 1 D to give the title compound.
Example 290 s fans rrans-~~4-MetI~Q~y~yl)-4-(1.3-benzodioxol-5-yl)-1-(2-ct~~~ ino-ovrimidine-4-yl)-Qyrrolidine-3-carboxvlic acid 2-(Dibutylamino) 4-chloropyrimidine is prepared from 2-4-dichloropyrimidine according to the method of Gershon (J. Heterocyclic Chem. 24, 205, 1987). This compound, ethyl traps, irans-2-(4-so methoxyphenyt)-4-(1,3-benzodioxol-5-yl)-pyrroJdine-3-carboxylate (example 6A), and di-isopropyl ethylamine are heated in dioxane to give the intermediate ethyl ester, which is hydrolyzed with sodium hydroxide using the method of example 1 D to give the title compound.
~ s (Exam I
traps.traps-2-(4-Methoxyrhenyl)-4-(1.3-benzodioxol-5-yl)-1-lN-butyl-N-phenviaminocarbonylmeth~rl)-~,yrrrolidine-3-carboxylic acid The title compound was prepared according to the general procedure of Example 1. ~H NMR (CD30D) : b 0.87 (t,3H,J=8); 1.2-1.35 20 (m,2H}; 1.35-1.5 (m,2H); 2.78 (m, 2H); 3.10 (t,1 H, J=9}; 3.26 (d,1 H,J=15}:
3.44 (dd,1 H,J=5,10); 3.5-3.7 (m,3H); 3.77 (m,1 H); 3.78 (s,3H); 5.93 (s,2H); 6.7-6.9 (m,4H); 7.0-7.2 (m,SH); 7.4 (m,3H). MS (DCilNH3): mle 531 (M+H)+. Anal calcd for C3~H3aN2~s: C, 70.17; H, 6.46; N, 5.28.
Found: C,70.36; H, 6.52; N, 4.99.
~xameg 292 Sodium traps frans-2-~4-Methoxyahenvl)-4-~1.3-benzodioxot-5-~~-1-~N.N-di~n ~srfvl)aminocarbonylmefhyl)-pyrrolidine-3-carboxylate so Example 292A
Ethyl 3-(4-methoxyphenyl)-3-oxopropionate Simultaneous reactions were run in both a 65-L reactor and a 35-L reactor that share the same reflux system. A nitrogen atmosphere was maintained in both. 4.0 kg (100 moles} of 60% sodium hydride in ss mineral oil and 32 L toluene were charged into the ambient temperature reactors. The mixture was agitated for 5 minutes and an~wPd to settle. 20 L of the toluene solution was aspirated. 28 L of toluene was added, agitated for 5 minutes, allowed to settle and 28 L
of the toluene solution was aspirated. 68 L of toluene and 8.4 L (69.7 moles) diethyl carbonate were added. The agitation was begun and the flow of Syltherm (Note 4) in reactor jackets was initiated. A solution s of 5.0 kg (33.3 moles) 4-methoxyacetophenone in 12 L toluene was added over 20 minutes. When additions were complete, the jacket temperaturewas reduced to 10° C and stirring continued for 16 hours.
A solution of 6.7 L (117 moles) glacial acetic acid in 23 L deionized water was fed at the same rate that was previously used for the to acetophenone solution. When addition was complete, agitation was stopped and the layers separated. The aqueous Payer was washed once with 13 L toluene. The combined organic layers were washed twice with 6.7 L portions of 7% (w:w) aqueous sodium bicarbonate. The toluene solution was washed once with 6.7 L of 23% (w:w) aqueous 1 s sodium chloride . The organic solution was dried over 10 kg sodium sulfate, filtered, and the solvent removed on the rotary evaporator to provide the desired product.
Example 2928 20 3 4- P,~hylenedioxv-1-(,2-nitroethenyl)-benzene In a 45-L cryogenic reactor with a contoured, anchor stirrer was dissolved 5.537 kg (36.9 moles) piperonal in 9 L methanol and 2.252 kg (36.9 moles) nitromethane at 15°-20° C. The jacket temperature was set to -5° C and the reaction solution cooled to a temperature of +3.5°
25 C. A 21 ° C solution of 3.10 kg (38.8 moles) 50% (w:w) aquous sodium hydroxide diluted with 3.7 L water was pumped in. The reaction temperature was maintained between 10°-15° C. When addition was complete, the jacket temperature was reset to 1 ° C and stirring continued for 30 minutes. A mixture of 7 kg ice in 19 L water was so added to dissolve most of the solid. The reaction mixture was filtered through canvas and then a 27R10SV Honeycomb filter. The filtered solution was metered into a 21 ° C mixture of 7.4 L concentrated hydrochloric acid in 11.1 L deionized water. The final reaction temperature was 26° C. The resulting product was centrifuged and as washed until the wash pH rose to at least 6 (by pH indicating paper).
The crude product was dissolved in . 92 L dichloromethane and the layers separated. The aqueous layer was washed once with 8 L

dichtoromethane. The combined organics were dried over 1.32 kg magnesium sulfate and filtered through Whatman #1 paper. The volume was reduced to 20% and the solution cooled to 4° C. Filtration through Whatman #t paper, followed by ambient temperature drying in vacuo s with an air leak afforded 1.584 kg (22%) of a first crop Concentration of the MLS to 25% followed by similar cooling, filtration, and drying afforded 0.262 kg (4%) of a second crop. The yellow product darkened on standing in light and air.
~o ~,kl 2-y4-methoxK en~oyl)~-3-{1.3-benzodioxol-5-yl)-4-nitro butanoate Into a 45-L stirred reactor at ambient temperature were charged 5.819 kg (30.1 moles) 3,4-methylenedioxy-1-(2-nitroethenyl)-benzene 1 s and 24 L ethyl acetate . A solution of 5.355 kg (24.1 motes) ethyl 3-(4 methoxyphenyl)-3-oxopropionate in 16 L ethyl acetate was added. 280 g (275 ml, 1.84 moles) of 1,8-diaza-bicyclo[5.4.OJundec-7-ene in four equal portions was added over a 2.5 hour period. The reaction mixture was filtered through dicalite and the resulting filtered solution was 2o used in the next step without any further purification.
Example 292D
~h~,rl 2-(4-methox~rohenyl)-4-~( 1.3-benzodioxol-5-yll-4.5-dihyrdro-3H
~yrrol-3-carboxyl ate 2s The product of Example 292C (1316 ml solution consisting of 300 g Ethyl 2-(4-methoxybenzoyl)-3-(3,4-methylenedioxyphenyl)-4 nitrobutanoate in ethyl acetate) was added to a glass reactor containing RaNi # 28 (300 g). The reaction mixture was shaken under a hydrogen environment of 4 atm at room temperature for 18 hoursand so filtered through a nylon 0.20 micron 47 mm millipore.
The filtrate was concentrated to 1.4 kg of dark solution and purified by normal phase silica gel chromatography eluting with 85:15, hexanes: ethyl acetate. The pure fractions were combined and concentrated (as above) until crystals formed. The solution was cooled as to 0° C and filtered. The solid was washed with 2 L of 85:15, hexane:
ethyl acetate (0° C). The solids were dried in vacuo at 50° C to a constant weight of 193.4 g (21 % yield, melting point 80-81 ° C) of the title compound. A further 200 g (23% yield) of product was obtained from the mother liquors.
Fxam~le 292E
s '~,t vl 2 (4 methox~y11~4-~. ~-h°~'~~ioxol-5-vll-ovrrolidine S-car o riate Into a 12-L flask equipped with magnetic stirring, addition funnel, temperature probe, and nitrogen inlet was charged 0.460 kg ethyl 2-(4-methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-4,5-dihydro-3H -~ o pyrrole-3-carboxylate (1.25 mol). The reaction vessel was degassed with nitrogen. Absolute 3.7 L ethanol and 1.12 L of THF were added. 31 mg bromocresol green and 94.268 sodium cyanoborohydride (1.5 moI) were added. A solution containing 400 mL absolute ethanol and 200 mL
of 12 M HCI was then added. The reaction mixture was stirred for 30 ~ s minutes after addition was complete. After the starting material was consumed, 0.5 L of 7% aq. NaHC03 was added. The reaction mixture was concentrated and diluted with 5 L ethyl acetate. The organic layer was washed twice with 2 L of 7% aq. NaHC03 and once with 2.5 L of 23% aq.
NaCI, the dried over 1908 MgS04, filtered, and concentrated to give 447 2o g of the title compound as a thick yellow oil.
Examohe 292F
~hyl 2-( -methoxvo~ heny,~-4-~ 3-benzodioxol-5-yll-1-IN.N-di(n-l ino~arbo lyrlmethvll pvrrolidine 3-carboxvlate zs Into a 22-L flask equipped with overhead stirring, nitrogen inlet, and condenser was charged ethyl 2-(4-methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-pyrrolidine-3-carboxylate (2.223 kg,6.02 mol).
The reaction vessel was degassed with nitrogen. 13.2 L ofacetonitriie, 3.66 L diisopropylethylamine (2.71 kg, 20.9 mol), and 1.567 kg so dibutylamidomethyl bromide (6.26 mol) were added. The mixture was refluxed at 78° C for 17 hrs. After the disappearance of starting material , the mixture was concentrated until crystals formed. The solid was filtered and washed with 4 L ethyl acetate (0° C).
Concentrating of the filtrate was continued as above until all volatiles ss were removed. The residue was diluted with 40 L ethyl acetate and washed with 20 L deionized water. The organic layer was washed with 8 L of 23% aq. NaCI nad dried over 0.399 kg MgS04 and filtered.

Concentration as above provided 3.112 kg (96 % yield) of the title compound as a dark oil.
Example 2 ~12G
3-ca~b"Y~ ata and ~gnaration of tran,~. frans 2-(4-methoxvohenvl)-4 ~3 4-dioxvohenkl,l-olrrrolLdine-3-carboxylic acid ethv( ester Into a 35-L reactor equipped with overhead stirring, nitrogen inlet, and condenser was charged 3.112 kg ethyl 2-(4-methoxyphenyl)-~0 4-(3,4-methylenedioxyphenyl)-pyrrolidine 3-carboxylate (5.78 mol).
16.4 L of absolute ethanol was added and the reaction vessel was degassed with nitrogen. 0.115 kg of sodium ethoxide (1.69 mol) was added and the mixture was refluxed at 79° C for 1 hr. The mixture was cooled to 15° C and 5 L of 7.6 M NaOH solution (38.1 mol) was added.
The ~ s mixture was stirred at 15° C for 18 hrs. The solvent was evaporated and the residue dissolved in 15.8 L of deionized water and extracted with 28 L of ether. The ether solution was washed with 9.5 L deionized water. The aqueous wash was extracted with 3 L ether. 0.340 L of 12 M
HCI was added to the aqueous layer. The aqueous layer was extracted 2o with 24 L of ethyl acetate. The organic layer was washed with 9 L of 23% aq. NaCI, dried with 0.298 kg MgS04 , filtered, and concentrated to give 2.132 kg of a dark oil. The oil was triturated with 18 L ether. The undesired solids were filtered and saved for later use. The mother liquors were concentrated to obtain i .102 kg of tight foam. The foam zs was dissolved in 5.5 L ethyl acetate with heating to 65° C. 14 L
hexane was added slowly enough to keep the solution refluxing. The reaction mixture was cooled to 10° C and filtered. The crystals were washed with 2 L ether (0° C) and dried to constant weight in vacuo at 50° C to give 0.846 kg (43% yield, melting point 119-120) of crude product, 3o which was further purified by normal phase silica gel chromatography.
Examr~le 292H
Sodium rrans rrans-2-~4-mpthoxyr~henyll-4-( 1 .3-benzodioxol-5-vl)-1 (N N-di(n- utx_Ilaminocarbonylmethyll Dyrrolidine 3-carboxvlate 35 Into a 20-L flask was charged rrans,trans 2-(4-methoxyphenyf)-4-(3,4-methyledioxyphenyl)-1-,(N,N-dibutylamino- carbonyl methyl) i-U 1 ~ viiGi . r~ ~Wuuvm ~, pyrrotidine 3-carboxyic ac~o (u.9~7 icy, ' ""' ') " '"'""' "' 0.0720 kg NaOH (1.80 mol) dissolved in 4.65 L methanol was added. The reaction mixture was concentrated to an oil. Pentane (4 L) was added and the solution concentrated again. Pentane {4 L) was added again and concentration of this solution gave a tight tan foam. The foam was dried s in vacuo at 50° C to a constant weight of 0.937 kg (97% yield) of the title compound.
~xamp~e 293 ~r an s arans-2 ~4 Mei~hoxvohenvll-4-(1 3-benzodioxol-5-vll-1-[~ ecahysiroisoa,uinolin-2- carbonyimethvll-ovrroJidine-3-carboxylic acid:
The title compound was prepared using the procedures described in example 1. NMR (CD30D, 300 MHz) shows a mixture of isomers. MS
(DCl/NH3) mlz 521. Anal calcd for C3oH3sN2Os ~. 1.3 TFA: C, 58.54; H, ~ s 6.62; N, 4.19 . Found: C, 58.34; H, 5.58; N, 4.00 .
Examohe 294 n h I - I -1_ dimethvloioeridinyl- carbonylmethyl~-~yrrolidine-3-carboxylic acid.
zo The title compound was prepared using the procedures described in example 1. NMR (CD30D, 300 MHz) indicates presence of rotamers. &
0.84 (s, 3H), 0.86 (s, 3H), 1.35-1.6 (m, 4H), 3.83 (s, 3H), 5.96 (s, 2H), 6.81 (d, 1 H, J=8), 6.90 (dd, 1 H, J=1,8), 7.01 (d, 2H, J=9), 7.03 (s, 1 H), 7.47 (d, 2H, J=9). MS (DC11NH3) m/z 495. Anal calcd for C28Hs4N24s .
25 1.4 TFA: C, 56.55; H, 5.45; N, 4.28 . Found: C, 56.52; H, 5.83; N, 4.26 .
~xamDle~29-5 traps traps 2 ~(,4 Methoxvo.~henyl?-4-~1 3-ben~odioxol-5-yrll-1-f2-(N
prnnvl-N-iso-butoxycarbonvlaminolethylj-~yrrolidine-3-carboxylic acid ao The title compound was prepared by the methods detailed in Example 61, but substituting propyiamine for methylamine in Example 61 B and isobutyl chloroformate for isobutyryl chloride in Example 61 C.
The crude product was purified by trituration with 1:1 diethyl ether/
hexane. The resulting solid was dissolved in CH3CN and water and 35 lyophilized to give the product as a white solid. ~ H NMR (CDC13, 300 MHz) 8 0.80 (t, 3H, J=7), 0.92 (m, 3H), 1.43 (h, 2H, J=7Hz), 1.7-1.9 (m, 1 H), 2.72 (m, 1 H), 2.90 (m, 2H), 3.10 (m, 2H), 3.25 (m, 2H), 3.40 (m, 1 H), WO 99/06397 PC'T/US98/15479 3.55 (m, 1 H), 3.62 (m, 1 H), 3.7-3.9 (m, 2H) 3.78 (s, 3H), 5.95 (s, 2H), 6.72 (d, 1 H, J= 8Hz), 6.82 (m, 3H), 7.00 (s, 1 H), 7.30 {d, 2H, J=8Hz). MS
(DCIINH3) m/e 527 (M+H)+. Anal calcd for C29H38N2O6 ~ 0.5 H20: C, 65.03; H, 7.34; N, 5.23. Found: C, 65.13; H, 6.96; N, 4.95.
s FxamQle 296 _1-tetrahKdroiso~«innlin-2- carbonylmethvll-wrrolidine-3-carboxylic acid.
z o The title compound was prepared using therprocedures described in example 1. NMR (CD30D, 300 MHz) indicates presence of rotamers. S
2.97 (m, 2H), 4.68 (s, 3H), 5.97 {s, 2H), 6.83 (d, 1 H, J=8), 6.9-7.0 {m, 3H), 7.03 (d, 1 H, J=2), 7.1-7.3 (m, 4H), 7.4-7.5 (m, 2H). MS (DCI/NHa) m/z 515.
~s Example 297 Lrans traps-2-~4-Methoxvohenyh(~. 3-benzodioxol-5-vll-1-f2-(N
~~,Ryl N dimethy,~aminoc~rbonyrlaminoyethylj-pvrrolidine-3-carboxylic acid 2o The title compound was prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 61 B and dimethylcarbamyf chloride for isobutyryl chloride in Example 61 C. The crude product ~ was purified by preparative HPLC (Vydac p.C 18) eluting with a 10-70% gradient of CHgCN in O.i% TFA. The desired Zs fractions were lyophilized to give the product as a white solid. ~ H NMR
(CDC13, 300 MHz) S 0.70 (t, 3H, J=7), 1.28 (m, 2H), 2.75 {s, 3H), 2.82 (m, 2H), 3.1-3.45 (m, 4H), 3.70 (m, 1 H), 3.80 (s, 3H), 3.90 (m, 3H), 4.72 (m, 1 H), 5.95 (s, 2H), 6.75 (d, 1 H, J= 8Hz), 6.87 (m, 3H), 7.05 (s, 1 H), 7.40 (d, 2H, J=8Hz). MS (DCIINH3) m/e 498 (M+H)+. Anal calcd for C27Hg5N3Og 30 1.25 TFA: C, 55.35; H, 5.71; N, 6.56. Found: C, 55.41; H, 5.71; N, fi.41.
Example 298 I~rans traps-2 (4 Methox~ohenvl)-4-y1 3-benzodioxol-5-vll-1-(2-(N
Qrgp~rl N (4-nitrobenzenesulfonyl amino ethyll-oyrrolidine-3 35 Sarboxvlic acid Using the procedures described in Eample 66, the title compound ....,~. n~cnarc~ ac a vPllow solid. m.p. 85-87°C. 1 H NMR (CDC13, 300 MHz) .. aw ~,.. ..,,..... _ _ _. _ , 8 0.77 (t, J=7.5Hz, 3H), 1.38 (sextet, J=7.5Hz, 2H), 2.20-2.29 (m, 1 H), 2.57-2.66 {m, 1 H), 2.82-3.15 (m, 4H), 3.22 (t, J=7.5Hz, 2H) 3.38 (dd, J=3Hz,J=9Hz, 1 H), 3.49-3.57 (m, i H), 3.59 (d, J=9Hz, 1 H), 3.83 (s, 3H), 5.96 (s, 2H), 6.73 (d, J=BHz, 1 H), 6.82 (dd, J=i Hz,J=8Hz, 1 H), 6.87 (d, s J=9Hz, 2H), 6.98 (d, J=1 Hz, 1 H), 7.27 (d, J=9Hz, 2H), 7.82 (d, J=9Hz, 2H), 8.23 (d, J=9Hz,2H). MS (DCIlNH3) mle 612 (M+H)+~
Example 299 traps tran~2-(,4-Methoxyphenvl~-4-( 1 3-benzodioxol-5-vl)-1-(2-(N-~o Q~ov'~'I N n pentanesulfonylaminolethkl)-ovrrolidine-3-carbox5rlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 59-61 °C i H NMR (CDC13, 300MHz) 8 0.79 (t, J=7.5Hz, 3H), 0.90 (t, J=6Hz, 3H), 1.26-1.32 (m, 4H), 1.43 (sextet, J=7.5Hz, 2H), 1.67-1.76 (m, 2H), 2.23-2.32 (m, 1 H), 2.70-3.08 i s (m, 7H), 3.15-3.32 (m,2H), 3.42 (dd, J=3Hz,J=9Hz, 1 H), 3.52-3.57 (m, i H), 3.63 (d, J=9Hz, 1 H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=7.5Hz, 1 H), 6.83 (dd, J=1 Hz,J=7.5Hz, 1 H), 6.87(d, J=8Hz, 2H), 7.00 (d, J=1 Hz, 1 H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 561 (M+H)+~
2o Example 300 traps traps-2-(4-Methoxy~henyl~-4-(i.3-benzodioxol-5-vl)-1-(2-lN
~r Q,yrl-N-~(4-trifluoromethoxKbenzenesulfonyl)amino)ethvl) Qyrrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound 2s was prepared as a white solid. m.p.122-124°C. 1 H NMR (CD30D, 300MHz}
& 0.75 (t, J=7.5Hz, 3H), 1.26-1.45 (m, 2H), 2.96-3.08 (m, 2H), 3.23 (bs, 2H), 3.35-3.45 (m, 2H), 3.52 (t, J=1 OHz, 1 H), 3.81 (d, J=9Hz, 2H), 3.86 (s, 3H), 3.92 (t, J=9Hz, 1 H), 4.63 (d, J=1 OHz, 1 H), 5.97 {s, 2H), 6.82 {d, J=9Hz, 1 H), 6.93 (dd, J=3Hz,J=9Hz, 1 H), 7.06-7.08 (m, 3H}, 7.46 (d, 3o J=9Hz, 2H), 7.56 (d, J=9Hz, 2H), 7.89 (d, J=9Hz, 2H). MS (DCIINHs), m/e 651 (M+H)+.

Example 301 aranj trany2 ~4-Methoxvohenv_I)=4-(1 3-benzodioxol-5-vl)-1-(2-(N
~,~,~~2~methart-2-orooenesulfony~,)amin0,~~~ethvl)-ovrrolidine-3 carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 69-71 °C.. 1 H NMR (CDCfs, 300MHz) 0.79 (t, J=7.5Hz, 3H), 1.93 (sextet, J+7.5Hz, 2H), 1.92 (s, 3H), 2:25-2.35 (m, 1 H), 2.68-2.77 (m, 1 H), 2.85-3.28 (m, 7H), 3.40 (d, J=9Hz, 1 H), 3.52-3.68 (m, 2H), 3.66 (d, J=9Hz, 1 H), 3.80 (s, 3H), 4.92 (s, 1 H), 5.07 (s, 1 H), 5.97 (s, 2H), 6.74 (d, J=7Hz, 1 H), 6.82-6.89 (m,3H), 7.01 (s,1 H), 7.33 (d, J=9Hz, 2H). MS (DCllNH3), m/e 545 (M+H)+.
Example 302 traps-trarz~2-~(4-MethoxVD~y_I)-4-(1 .3-benzodioxol-5-yll-1-i2 15 ~thytQioeridin~-carbony,Imethylj-Ryrrolidine-3-carboxylic acid.
The title compound was prepared using the procedures described in example 1. NMR (CD30D, 300 MHz) shows a mixture of isomers. 8 0.75 (t, 3H, J=7), 1.4-1.7 (m, SH), 3.84 (s, 3H), 5.96 (s, 2H), 6.83 (d, 1 H, J=8), 6.91 (d, 1 H, J=8), 7.0-7.1 (m, 3H), 7.52 (d, 2H, J=9). MS (DCl/NH3) 2o m/z 495. Anal calcd for C28H34N2Os . 1.6 TFA: C, 55.35; H, 5.30; N, 4.14.
Found: C, 55.26; H, 5.37; N, 4.01 .
Exam i!~ a 303 ~rans tran~2 ~4-Methoxy,~h~n_yll-4S1 3-benzodioxol-5-yrll-1-l2-tN-25 Qr~t -m th~rlorooanesutfon~~)amino ethlrl)-ovrrolidine-3-~arboxy,~ic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 72-73°C. 1 H NMR (CDC13, 300 MHz) 8 0.82 (t, J=7.5Hz, 3H),1.04 (d, J=6Hz, 6H), 1.44(q, J=7.5Hz, 2H), 2.15-2.33 30 (m,2H), 2.57-2.75 (m, 2H), 2.84-3.08 (m, 3H), 3.12-3.21 (m, 1 H), 3.23-3.45 (m, 1 H), 3.43 (d, J=11 Hz, 1 H), 3.55-3.62 (m, 1 H), 3.66 (d, J=9Hz, 1 H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 {d, J=9Hz, 1 H), 6.83 (dd, J=1 Hz,J=9Hz, 1 H), 6.87(d, J=9Hz, 2H), 7.02 (d, J=1 Hz, 1 H), 7.33 (d, J=9Hz, 2H). MS
(DC1/NH3) mle 547 M+H)+.

Fxam~le 304 traps irans-2 ~4 Methoxvo~henKl) 4-(1 3-benzodaoxol-5-yl)-1-(2-f N-r -h n If n f min I - rr li r ti i Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.58-59°C. 1 H NMR (CDC13, 300MHz) 8 0.80(t, J=7.5Hz, 3H), 0:88 (t, J=7Hz, 3H), 1.23-1.36 (m, SH), 1.94 (q, J=7.5Hz, 2H), 1.71 (quintet, J=7Hz, 2H), 2.23-2.32 (m, 1 H), 2.70-3.09(m, 7H), 3.13-3.32 (m,2H), 3.43(dd, J=3Hz,J=9Hz, 1 H), 3.52-3.58(m,1 H), 3.65(d, J=9Hz, 1 H), 3.80 (s, 3H), 5.96(s, 2H), 6.73 (d, J=7Hz, 1 H), 6.83 (dd, J=1 Hz, J=7Hz, 1 H), 6.87(d, J=9Hz, 2H), 7.01 (d; J=1 Hz, 1 H), 7.32(d, J=9Hz, 2H). MS (DC1/NH3) m/e 589 M+H)+.
~,xam Ip a 305 tram-traps-~-(4-Methox~yl)-4- 1 3-benzodioxol-5-y1)-1-f2-(N
~s ethyl-N-ethoxycarbonylamino)ethyl-oyrrrolidine-3-carboxylic acid Prepared by the methods detailed in Example 61, but substituting ethylamine for methylamine in Example 61 B and ethyl chloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac ~C18) eluting with a 10-70% gradient of CH3C N
2o in 0.1 % TFA. The desired fractions were lyophilized to give the product as a white solid. ~H NMR (CDC13, 300 MHz) 8 0.90 (t, 3H, J=7), 1.22 (m, 3H), 3.0-3.2 (m, 4H), 3.42 (m, 2H), 3.78 (s, 3H), 3.82 (m, 4H), 4.10 (q, 2H, J=7Hz), 3.5 (br s, 1 H), 5.97 (dd, 2H, J=1,7Hz), 6.72 (d, 1 H, J= 8Hz), 6.84 (m, 3H), 7.00 (s, 1 H), 7.42 (d, 2H, J=8Hz). MS (DCIlNH3) mle 485 (M+H)+.
2s Anal calcd for C26H32N20~ ~ 1.2 TFA: C, 54.90; H, 5.39; N, 4.51. Found: C, 55.01; H, 5.36; N, 4.56.
ExamQle 306 Lran~ tr~n~~_~4-MethoxVD~,~ h2nyr_t)~-4-l1 .3-benzodioxol-5-vl)-1-(3'f N-3o r I n I 'n h I - r i i r x li. i Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.59-60°C. 1 H NMR (CDCIs, 300MHz) 8 0.80(t, J=7.5Hz,3H), 0.89(t, J=7Hz, 3H), 1.25-1.36(m, 6H), 1.53(sextet, J=7.5Hz; 2H), 1.72(quintet, J=7Hz, 2H), 2.23-2.32(m, 1 H), 2.72-3.08(m, 35 7H), 3.15-3.32(m, 2H), 3.43(d, J=9Hz, 1 H), 3.55-3.62(m, 1 H), 3.65 (d, J=lOHz, 1 H), 3.80(s, 3H), 5.96(s, 2H), 6.74(d, J=7.5Hz,1 H), 6.82(d, J=7.5Hz,1 H), 6.87(d, J=9Hz, 2H), 7.01 (s,1 H), 7.32(d, J=9Hz,2H). MS
(DCIINHs), m/e 575 (M+H)+.
~xamnle 307 s traps traps-2 ~4 Eth~,rt~he~rl)-4-(1 3-benzodioxol-5-yl)-1-fN N-diln-1Q,~ tyrl)aminocarbonylmethyl]-~yrrrolidine-3-carboxylic acid.
The title compound was prepared using the procedures described in examples 1 and 49, substituting ethyl 4-ethylbenzoylacetate (prepared by the method of Krapcho et al., Org. Syn. 47, 20 (1967) ~o starting with 4'-ethylacetophenone) in procedure 49B. NMR (CDCI3, 300 MHz) b 7.31 (2H, d, J=8Hz), 7.16 (2H, d, J=8Hz), 7.03 (1 H, d, J=3Hz), 6.86 (1 H, dd, J=8&3Hz), 6.73 (1 H, d, J=9Hz), 5.94 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.77 (1 H, d, J=9Hz), 3.60 (1 H, m), 3.53-3.23 (5H, m), 3.13-2.90 (4H, m), 2.73 (1 H, d, J=l4Hz), 2.62 (2H, q, J=9Hz), 1.45 (2H, m), 1.40-~ s 1.10 (6H, m), 1.02 (2H, m), 0.87 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). mle (DCI, NH3) 509 (MH+) AnaLcalc. for C3oHaoN2~s C 70.84, H 7.93, N 5.51.
Found C 70.80, H 7.85, N 5.25 .
Example 308 tr~ns-traps-2-j4-Methox~rphen~,rl)-4-(1.3-benzodioxol-5-yl)-1-f2-(N
prop_yl-N-y2-chloroethoxyycarbonylamino)ethyl]-pyrrofidine-3 carboxxlic acid Prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 618 and 2-chloroethyl 2s chloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1:1 diethyl ether/ hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. ~ H NMR (CDC13, 300 MHz) S 0.80 (t, 3H, J=7), 1.22 (m, 3H), 2.15 (m, 1 H), 2.75 (m, 1 H), 2.85 (m, 1 H), 3.1 (m, 2H), 3.25 so (m, 2H), 3.5 (m, 3H), 3.65 (m, 2H), 3.80 (s, 3H), 4.18 (m, 1 H), 4.30 (m, 1 H), 5.98 (s, 2H), 6.72 (m, 1 H), 6.82 (m, 3H), 7.00 (m, 1 H), 7.30(m, 2H).
MS (DCIlNH3) mle 533 (M+H)+. Anal calcd for C27H33N2O7C1: C, 60.84; H, 6.24; N, 5.26. Found: C, 60.48; H, 6.04; N, 5.10.

Fxam~le 309 r _ h I - 1 i - N N- i n ~~t~llaminoc ra bonXlmethvll"~oyrrrolidine~3-carboxylic acid.
The title compound was prepared using the procedures described in s example 1, substituting ethyl 5-methoxy-3-oxopentanoate for ethyl 4-methoxybenzoylacetate in Example 1 A. The title compound is a yellow foam. ~ H
NMR {CDC13, 300 MHz) b 0.91 (t, J=7Hz) and 0.95 (t, J=7Hz, 6H total), 1.28-1.41 (br m, 4H), 1.45-1.63 (br m, 4H), 2.00-2.20 (br m, 2H), 3.06 (br t, J=9Hz, 1 H), 3.30 (s) and 3.20-3.68 (br m, 11 H total), 3.72-4.10 (br m, 4H), 5.92 {s, 2H), 6.72 (d, J=8.5Hz, ~ 0 1 H), 6.82 (dd, J=1.5, 8.5Hz, 1 H), 6.91 (d, J=1.SHz, 1 H); M~S (FAB) m/e 463 (M+H)+.
Anal calcd for C25H3gN205~H2O: C, 62.48; H, 8.39; N, 5.83. Found: C, 62.13; H, 8.15; N, 5.69.
~xamr~le 310 ~s r h n -4- 1 n x I- -1- N
~th~ri N n nentanesulfony_lamino)ethyll-pvrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.57-58°C. 1 H NMR (CDCIs, 300MHz) b 0.89(t, J=7Hz, 3H), 1.06(t, J=7.5Hz, 3H), 1.26-1.37(m, 4H), 1.72(quintet, 2o J=7.5Hz, 2H), 2.22-2.32(m,iH), 2.71-2.96{m,SH), 3.08-3.30{m,4H), 3.95(d, J=9Hz, 1 H), 3.53-3.60(m, 1 H), 3.67{d, J=9Hz,1 H), 3.80(s, 1 H), 5.97{s, 2H), 6.73(d, J=9Hz, 1 H), 6.82(d, J=9Hz,1 H), 6.88(d, J=9Hz, 2H),7.02(s,lH), 7.33(d, J=9Hz, 2H). MS (CDI/NH3) mle 547 (M+H)+.
is Example 311 r n - 4- h n I -4- 1 n i x i- -1- N-din~,vcl, ohexylamino carbonvlmethvll-oyrrrolidine-3-carboxylic acid.
The title compound was prepared using the procedures described in example 1. ~ NMR (CD30D, 300 MHz) 8 1.0-2.0 (m, 20H), 3.0-3.1 (m, 2H), 30 3.80 (s, 3H}, 5.95 (s, 2H), 6.75 (d, 1 H, J=8), 6.86 (dd, 1 H, J=2,8), 6.95 (d, 2H, J=9), 7.04 (d, 1 H, J=2), 7.38 (d, 2H, J=9). MS (DCI/NH3) m/z 563.
Anal calcd for CssH42N2Os . 0.5 H20: C, 69.33; H, 7.58; N, 4.90 . Found: C, 69.42; H, 7.29; N, 4.78.
*rB

Example 312 !ra~s-mans-2-(4-Methoxvo, henyrl)-4-(1.3-benzodioxo(-5-vl)-1-f2-(N
Q~,~k,~-N-tert-butoyc~rbonXfamino ethyrll-oyrrrolidine-3-carboxylic s The title compound was prepared using the procedures described in example 61, substituting propylamine for aqueous methylamine in Example 61 B and di-tert-butyldicarbonate for isobutyryl chloride in Example 61C. NMR (CD30D, 300 MHz} suggests presence of rotamers 8 0.81 (t, 3H, J=7), 1.2-1.5 (m, 11 H), 3.78 (s, 3H), 5.92 (dd, 2H, J=1,2), ~ 0 6.74 (d, 1 H, J=8), 6.84 (dd, 1 H, J=2,8), 6.92 (d, 2H; J=9), 6.99 (bd s, 1 H), 7.35 (d, 2H, J=9}. MS (DCtlNH3} m/z 527. Anal calcd for C2gH3gN2O7 : C, 66.14; H, 7.27; N, 5.32 . Found: C, 66.,05; H, 7.36; N, 5.15.
Example 313 ~s traps-traps-2-(4-Methoxy-3-fluoronhenyrl)-4-(1.3-benzodtoxol-5-vl) 1-fN N-di(n-butyrilaminocarbonyrlmethvtl-Ryrrofidine-3-carboxlrlic acid.
The title compound was prepared using the methods described in examples 1 and 43, using 4-methoxy-3-fluoro acetophenone in place of 4-methoxy acetophenone. m.p. 142-143 °C. NMR (CDC13, 300 MHz) 8 0.82 20 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.03-1.50 (m, 8H), 2.82 (d, J=l3Hz, 1 H), 2.90-3.13 (m, 4H), 3.20-3.50 (m, 3H), 3.39 (d, J=13H, 1 H), 3.55-3.65 (m, 1 H), 3.82 (d, J=1 OHz, 1 H), 3.87 (s, 3H), 5.91 (dd, J=2Hz, 4Hz, 2H), 6.72 (d, J=8Hz, 1 H), 6.83-6.91 (m, 2H), 6.99 (d, J=2Hz, 1 H), 7.06 (m, 2H).
Anal calcd for C29H3~N206F : C, 65.89; H, 7.06; N, 5.30 . Found: C, 65.82;
2s H, 7.13; N, 5.29.
Exam~,IP,~314 traps traps-2-~ProQyll-4- j.3-benzodioxol-5-yl)-1-(2-(N-orooYl_ oentanesulfonvl~minolethyl)pyrrolidine-3-carboxylic acid Example 314A
Proovl ioentanesulfonamide Pentane sulfonyl chloride (687 mg, 4.03 mmol) was dissolved in 5 mL
CHZC12 and added to an ice-cooled solution of n-propylamine (0.40 mL, 4.82 mmol) as and ethyldiisopropylamine (0.85 mL, 4.88 mmol) in 5 mt_ CH2C12 under a nitrogen atmosphere. The reaction was stirred at 0 °C for 30 min, then at 25 °C for 4 h. The .......".,., ~n ".,i ~f ~ n M ananiic NaH~I~~ anti 25 mL
SOIUt~Ul1 wd5 EJG~VUVmu vcv..cc." ~... ...~ ... .-- - , CH2CI2. The organic phase was washed sequentially with 25 mL H20 and 25 mL
brine, then dried (Na2S04), filtered, and concentrated in vacuo to provide 739 mg (3.83 mmot, 95%) of the title compound as a white solid. TLC (25% EtOAc-hexane) Rf 0.23; ~H NMR (CDCi3, 300 MHz) 8 0.92 (t, J=7Hz, 3H), 0.97 (t, J=7Hz, 3H), 1.28-s 1.50 (br m, 4H), 1.52-1.68 (m, 2H), 1.75-1.90 (br m, 2H), 2.98-3.06 (m, 2H), 3.08 (q, J=6Hz, 2H), 4.10-4.23 (br m, 1 H); MS (DCI/NH3) mle 211 (M+NH4)+.
Example 31498 h I -4- n i x I- I -1- r h I - r I rr li in -carboxvlate The title compound was prepared according the procedure of Example 61 A, substituting the compound of Example 948 for the pyrrolidine mixture.
,~"xampfe 314C
t5 ,~y~tl8l7c trana_~_(~~y~(1 3-..-.benZOdIOXQI-5-yl)-1-(2-(N-DfOI?yl-~entanesutfonyll~,mino)eth~)Qyrrolidine-3-carboxvtate A solution of the compound of Example 314A (6.6 mg, 34 pmol) in 0.1 mL
DMF was treated with sodium hydride (2 mg, 60% oil dispersion, 1.2 mg NaH, 50 ~mol). The resulting mixture was stirred at room temperature for 15 min, then a 2o solution of the compound of Example 1898 (9.0 mg, 22 ~.mol) in 0.1 mL DMF
was added, followed b y 0.5 mg of tetra-n-butylammonium iodide. The reaction was sealed under argon and stirred at 60 °C overnight. The reaction was concentrated under high vacuum, and the residue was partitioned between 2 mL of saturated aqueous NaHC03, 1 mL water and 5 mL EtOAc. The organic phase was washed 2s with 1 mL brine, dried by passing through a plug of Na2S04, and the filtrate concentrated in vacuo to an pit. The crude product was purified by preparative TLC
(silica gel, 8 x 20 cm, 0.25 mm thickness, eluting with 20% EtOAc-hexane, providing 8.4 mg (73%) of the title compound as a wax.
so . ExamQ a 314D
trar,~ tranG4:(1 3-benzodioxol-5-yl)-2-(ProDVI)-1-(2-(N-oroovl pentanesulfonylamino)ethyl)oyrrotidine-3-carboxylic acid The title compound was prepared according to the procedure of Example 71C. ~H NMR (CDCl3, 300 MHz) s 0.88-1.00 (m, 9H), 1.20-1.55 35 (br m, 6H), 1.55-1.68 (m, 3H), 1.70-1.85 .(br m, 2H), 1.90-2.16 (br m, 2H), 2.84-3.26 (br m, 6H), 3.26-3.90 (br m, 6H), 5.95 (s, 2H), 6.76 (d, J=8Hz, 1 H), 6.79 (m, 1 H), 6.93 (br s, 1 H); HRMS (FAB} calcd for C25H4~ N2OsS
(M+H)+ 497.2685, found 497.2679.
Exarr~~le 315 s r - 4- n t ~ 1 n i xol- I -1- N-pro~,rt-N-dimethylsulfamoylaminolethyl)-ovrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was preapred as a white solid. m.p.59-61°C. 1 H NMR (CDCIs, 300MHz) 8 0..79 (t, J=7.5Hz, 3H}, 1.45(sextet, J=7.5Hz, 2H), 2.22-2.31 (m,1 H), 2.65(s, 6H), 2.70-2.79(m, 1 H), 2.85-3.04(m, 4H), 3.09-3.32(m, 2H), 3.40(d, J=9Hz, 1 H),3.55 (t, J=9Hz,1 H), 3.65(d, J=9Hz,1 H), 3.81 (s, 3H), 5.96(s,2H), 6.75(d, J=9Hz, 1 H), 6.83{d, J=9Hz, 1 H), 6.88(d, J=9Hz, 2H), 7.02{s, 1 H), 7.34(d, J=9Hz, 2H). MS (DCilNHs) m1e534 (M+H)+.
ExamQle 316 fans-traps-2-y4-Methoxohenyly-4-{1.3-benzodioxot-5-vll-1-f2-(N
r~~yrl-N-[4-methoxVD~, h2nyrl]sulfonyrlaminoloroovll-ovrrolidine-3 carboxvlic acid ~thvl traps-traps and cis-traps 2-~4-Methoxyr~ohenyrll-4-(1.3-benzodiox 5-yll -1-(3-brom~QyILoyrrolidine-3-carboxvlate A 2:1 mixture of frans-traps and cis-traps ethyl 2-(4 methoxyphenyl)-4-(1,3-benzodiox-5-yl) -pyrrolidine-3-carboxyl ate 2s {4.00 g; prepared according to example 1C), 32 ml dibromopropane, and 200 mg sodium iodide, were heated at 100° for 1.25 hrs. The excess dibromopropane was removed in vacuo and the residue was dissolved in toluene. After shaking with potassium bicarbonate, the solution was dried (Na2S04) and the solution concentrated. The residue was ao chromatographed on silica gel elufing with 5:1 hexane:EtOAc. yielding 5.22 (98%) of the title compound.

~xamnle 3168 h n - r - 4-M h . I -4- i ~yp~ (3 proQylaminoprooyl~yrrolidine-3-carboxvtate The compound described in Example 316A (5.22 g) was heated at s 80° for 2 hrs.with 35 ml. ethanol, 2.5 g. propylamine and 35 mg.
sodium iodide. The solvents were removed in vacuo. The residue was dissolved in toluene, shaken with potassium bicarbonate solution and dried ( Na~S04). The soilution was concentated in vacuum to give 4.96 g of the title compound as an orange oil. This was used in the next step without ~o purification.
xampl_e 316C
traps tran~2 (4 Methoxph null-4-(1 3-benzodioxol-5-vll-1-f2-lN-per Qyl N [4 methoxy~henyllsulfonylamino)oroovll-ovrrolidine-3-ls sarboxkic acid Using the method described in example 66, the compound prepared in Example 3168 was reacted with 4-methoxybenzenesulfonyl chloride in acetonitrile containing diisopropylethylamine. The resulting product was chromatographed on silica gel (30% EtOAc in hexane), and 2o hydrolyzed to the title compound by the method of example 1D. NMR
(CDC13, 300 MHz) 8 0.83 (t, J=7Hz, 3H), 1.40-1.52 (m, 2H), 1.56-1.70 {m, 2H), 2.00-2.11 (m, 1 H), 2.40-2.51 (m, 1 H), 2.69-2.78 (m, 1 H), 2.84-3.03 (m, 4H), 3.19-3.34 (m, 2H), 3.48-3.59 (m, 2H), 3.80 {s, 3H), 3.86 (s, 3H), 5.95 (s, 2H), 6.74 (d, J=BHz, 1 H), 6.85 (d, J=BHz, 3H), 6.93 (d, J=SHz, 2H), 2s 7.02 (d, J=2Hz, 1H), 7.29 (d, J=BHz, 2H), 7.69 (d, J=BHz, 2H). Anal calcd for C32H38N20aS : C, 62.93; H, 6.27; N, 4.59. Found: C, 62.97; H, 6.39; N, 4.45.
~,xam,ple 317 3o tr_ans traps-2 l4 Metho~hen~rll-4-(1 3-bertzodioxol-5-yll-1-f2-(N
~,~y~~r~Q, I nXlaminol r~ooyl)-oyrrolidine-3-carboxylic acid Using the method described in example 66, the propylamino compound prepared in Example 3168 was reacted with propanesulfonyl chloride in acetonitrile containing diisopropylethylamine. The residing ss product wias chromatographed on silica gel (30% EtOAc in hexane) and hydrolyzed to the title compound by the method of example 1 D. N1~1R
(CDC13, 300 MHz) 8 0.85 (t, J=7Hz, 3H), 1.02 (t, J=7Hz, 3H), 1.47-1.60 (m, 2H), 1.65-1.85 (m, 4H), 2.04-2.16 (m, 1 H), 2.42-2.57 (m, 1 H), 2.72-3.11 (m, 5H), 3.25-3.41 (m, 2H), 3.50-3.62 (m, 2H), 3.80 {s, 3H), 5.85 {s, 2H), 6.72 .(d, J=BHz, 1 H), 6.80-6.90 (m, 3H), 7.02 (d, J=2Hz, 1 H), 7.30 (d, J=9Hz, 2H). Anal calcd for C2gH3gN2O7S: C, 61.52; H, 7.01; N, 5.12 .
s Found: C, 6 i .32; H, 7.01; N, 5.0 i .
Example 318 ,~r~»~ r~~j ~_2-~~-Fluoro-4-me,~ o~,yr~yl)-4-(i.3-benzodioxol-5--2 (N-~oovl-N-oentanesulfony,~laminolethvl)-ovrrolidine-3-~ o carboxylic acid Using the procedures described in Example 313 and Example 66, the title compound was prepared as a white solid. m.p.66-68°C. 1 H NMR
(CDC13, 300MHz) S 0.81(t,J=7.5Hz, 3H), 0.89(t, J=7Hz, 3H), 1.26-1.35(m, 4H), 1.45(sextet, J=7.5Hz, 2H), 1.68-1.76(m, 2H), 2.25-2.33(m, i H), zs 2.72-2.92(m, 5H), 2.97-3.12(m, 2H), 3.16-3.33(m,2H), 3.43(dd, J=3Hz,J=9Hz,1 H), 3.53-3.60(m, 1 H), 3.66(d, J=1 OHz, 1 H), 3.88(s, 3H), 5.95(s, 2H), 6.74(d, J=BHz, 1 H), 6.82(dd, J=1 Hz,J=BHz,1 H), 6.92(t, J=BHz,1 H), 6.97(d, J=1 Hz, 1 H), 7. i 2(d, J=BHz, 1 H), 7.18(dd, J=1 Hz,J=l2Hz, 1 H). MS (DC1/NH3) m/e 579 (M+H)+.
Example 319 trans-traps-2-(4-Pvridinyll-4-~1.3-benzodioxol-5-yl)-1-fN.N-di(n ~~rl~minocarbonylmethyrll-ovrrolidine-3-carboxylic acid.
The title compound was prepared using the methods described in 2s examples 1 and 43, using methyl 3-oxo-3-(4-pyridyl)propanoate (J. Am.
Chem. Soc. 7 993, t t 5, 11705) in place of ethyl (4-methoxybenzoyl)acetate. m.p. 131-132 °C. NMR (CDC13, 300 MHz) & 0.82 (t, J+7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.05-1.50 (m, 8H), 2.90 (dd, J= 7Hz, 9Hz, 1 H), 2.97~(d, J=13Hz, 1 H), 3.00-3.25 (m, 4H), 3.32 (m, 1 H), 3.39 (d, 3o J=l3Hz, 1 H), 3.45-3.52 (m, 1 H), 3.67-3.78 (m, 1 H), 4.10 (d, J=9Hz, 1 H), 5.92 {dd, J=2Hz, 4 Hz, 2H), 6.75 (d, J=9Hz, 1 H), 6.90 (dd, J=9Hz, 2Hz, 1 H), 7.02 (d, J=2Hz, 1 H), 7.45 (d, J=BHz, 2H), 8.50 (d, J=8Hz, 2H). Anai calcd for G27H3~N3~5 : C, 67.34; H, 7.33; N, 8.73 . Found: C, 67.39; H, 7.45; N, a.si.

~xamole 320 I -4- i I -1-Rrcmvi N diethkaminocarbonvl~minolethvll-ovrrolidine-3-carboxylic acid.
The title compound was prepared using the procedures described in example 61, substituting propylamine for aqueous methylamine in Example 61 B and diethylcarbamyl chloride for' isobutyryl chloride in Example 61C. NMR (CD30D, 300 MHz) b 0.74 (t, 3H, J=7), 1.09 (t, 6H, J=7}, 1.33 (m, 2H), 3.17 (q, 4H, J=7), 3.78 (s, 3H), 4.04 (m, 1 H), 5.93 (s, ~ 0 2H), 6.86 (d, 1 H, J=8}, 7.06 (dd, 1 H, J=2,8), 6.94 (d-, 2H, J=9), 7.04 (d, 1 H, J=2}, 7.40 (d, 2H, J=9). MS (DCIINH3) mlz 526. Anal cafcd for C29H39N3O6 . 0.1 TFA: C, 65.31; H, 7.34; N, 7.82 . Found: C, 65.33; H, 7.43;
N, 8.14.
is ~rans-traps-2-(,4-Methoxvoheny~,L4~ 1.3-benzodioxol-5-vl )-1-f 3.5-dim t ~~ ridi ri- carbonxlmeth~l-oyrrolidine-3-carboxylic acid.
The title compound was prepared using the procedures described in example 1. NMR {CD300, 300 MHz) shows mixture of isomers. 8 0.88 20 (d, 3H, J=7), 0.93 (d, 3H, J=7), 3.82 (s, 3H), 5.95 (s, 2H), 6.82 (d, 1 H, J=8}, 6.89 (dd, 1 H, J=1,8), 7.00 d, 2H, J=9), 7.03 (m, 1 H), 7.47 (d, 2H, J=9). MS {DCIINH3) mlz 495.
FxamRle 322 2s ~r an s-ar an r2 ~4 Methox~,mhenyrll-4-L1 3-benzodioxol-5-vl)-1-fN.N-in n I 1 - r li in - x The title compound was prepared using the procedures described in example 1. NMR (CD30D, 300 MHz} suggests a mixture of isomers. 8 O.B3 {t, 6H, J=8), 1.27 (d, 6H, J=7), 1.6 (m, 2H), 3.79 (s, 3H}, 5.93 (s, 2H), 30 6.75 (d, 1 H, J=6}, 6.86 (d, 1 H, J=8), 6.94 (d, 2H, J=9}, 7.03 (d, 1 H, J=2), 7.35 (d, 2H, J=9). MS (DCI/NH3) m/z 511.

Exam$le 323 I- i i m I- r acid.
s The title compound was prepared using the procedures described in example 1. MS (DCIlNH3) mlz 545. Anal calcd for C32HssN24s . 0.9 H20: C, 68.53; H, 6.79; N, 4.99 . Found: C, 68.56; H, 6.62; N, 4.71.
Exannnle 324 ~o ~rans-traps-2-(4-Metho~yrohe XI_~(1.3-benz-odioxol-5-vl)-1-fN-(3 MethX'i[D~y -N-butlrlamino carbonylmeth~)-oyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in example 1. NMR (CD30D, 300 MHz) d 0.88 (t, 3H, J=7), 1.2-1.5 (m, 4H), ~ s 2.31 (s, 3H), 2.8 (m, 2H), 3.14 (t, 1 H, J=10), 3.3 {m, 1 H), 3.44 (dd, 1 H, J=5,10), 3.53 (m, 1 H), 3.60 (t, 2H, J=7), 3.79 (s, 3H), 3.82 (m, 1 H), 5.93 {s, ~2H), 6.74 (d, 1 H, J=8), 6.8-6.9 (m, 5H), 7.06 (d, 1 H, J=2), 7.09 (d, 2H, J=9), 7.18 (d, 1 H, J=7), 7.27 (t, 1 H, J=7). MS (DCIINH3) mlz 545. Anal calcd for Cg2H36N2~6 . 0.8 H20: C, 68.75; H, 6.78; N, 5.01 . Found: C, 20 68.70; H, 6.67; N, 4.85.
Exam~e 325 ~ran° mans-4-(1 3-Benzodioxoi-5-v,f~-2-(benzyloxymethyl)-1-((N.N
dibutYaminoc rbonylmethvllRyrrolidine-3-~t ra boxvlic acid E~xam~te 325A
h I r 4-1 n i x I- n I x m h I-1- NN- in-b_~llyllam inocarbonyrlm~~hyiloyrrolidine-3-carboxvlate The procedures of Example 1 A-1 D were followed, substituting ethyl 4-3o benzyloxy-3-oxobutyrate for 4-methoxybenzoylacetate in Example 1 A, to afford the title compound as a colorless oil. TLC (30% EtOAc-hexane) Rf 0.18; ~ H NMR
(CDCi3, 300 MHz) S 0.88 (t, J=7Hz, 6H), 1.17 {t, J=7Hz, 3H), 1.20-1.34 (br m, 4H), 1.40-1.56 (br m, 3H), 2.85 (t, J=BHz, 1 H), 2.98-3.30 (m, 5H), 3.39-3.60 (m, 3H), 3.64-3.75 (m, 2H), 3.92 (d, J-14Hz, 1 H), 4.10 {two overlapping q, J=6.5Hz, 2H), 4.53 (s, 3s 2H), 5.91 (m, 2H), 6.69 (d, J=9Hz, 1 H), 6.77 (dd, J=1.5. 9Hz, 1 H), 6.91 (d, J=1.SHz, 1 H); MS (DCI/NH3) mle 553 (M+H)+.

Fxamole 3258 I -1- N i b~t~)a,. minocarbony~m~~t_flyl)Qyrrolidine-3-carboxylic acid The title compound was prepared according to the procedure of Example s 71C, as a colorless glass. TLC (5% MeOH-CH2CI2) Rf 0.13; 1H NMR (CDC13, 300 MHz) S 0.86 (t. J=7Hz), and 0.90 (t, J=7Hz, 6H total), 1.15-1.52 (br m, 8H), 2.96-3.35 (br m, 5H), 3.50-3.75 (br m, 2H), 3.80 (dd, J=3, l3Hz, 1 H), 3.88-4.40 (br m, 6H), 4.45 (AB, 2H), 5.90 (s, 2H), 6.70 (d, J=8Hz, i H), 6.84 (dd, J=1,8Hz, 1 H), 6.93 (d, J=1 Hz, 1 H), 7.28-7.39 (m, 5H); MS (DCIINH3) m/e 524 (M+H)+.

Exam i ~~rt~frans-4 (1 3 Benzodioxol-5-vi)-2-(~vdroxvmethyl)-1-j(N N-di(n _b~ty~aminocarbonylmethy,~yrrolidine-3-carboxylic acid ~~-yttrans,trans-4-(,1 3-Benzodioxol-5~,rl~~hydf roxymethyrl)-1-(IN.N-di(n ~ty[)am inocarbonylmethyl)pyrrolidine-3-carboxvlate The resultant product from Example 325A (128 mg, 0.232 mmol) and 25 mg of 20% Pd(OH)2 on charcoal in 7 mL EtOH was stirred under 1 atm hydrogen for 2o h. The mixture was filtered through a plug of celite, and the catalyst was washed with 2 x 10 mL EtOH, then the combined filtrate and washes were concentrated under reduced pressure to afford the crude product. Purification by flash chromatography (40%EtOAc-hexane) provided the title compound.
Example 3268 has franc-4-y 3-Benzodioxol-5-yll-2-(h, dy roxymethvl)-1-((N.N
di{butyl)aminocarl~r~ylmethy!)ovrrolidine-3-carboxr~rlic acid The title compound was prepared according to the procedure of Example 71 C.
(Example 327 I - - N-m h I I -1- N N- i n-bsty~aminocarbony~methy_i},pXrrolidine-3-carboxylic acid Fly,~trans.traps--4-(1.3-Benzodioxol-5-y1l-2-~(, or yrl)~-1-(,(N.N-di(n butyl)~aminocarbonyrlmet yJ[)~p~rrolidine-3-carboxyrlate The title compound is made by selective oxidation (e.g. using the Swern s oxidation with DMSO, oxalyl chloride, ethyldiisopropylamine or using the Dess-Martin periodinane) of the compound of Example 326A.
I~,xamole 3278 Ethyrl traps.traps--4-(1.3-Benzodioxol-5-yrl)-2-(O-tert-butyl~rooenoat-3-yl)-1-{lN.N-~ o di(n-but~~~aminocarbonylmeth~~)Ryrrolidine-3-carbo~,vlate The title compound is produced by condensing the compound of Example 327A with tert-butyl triphenylphosphoranylidine acetate in CH2C12 solution.
Exan~nle 327C
~s ~tby~ traps.traps--4-(1.3-Benzodioxol-5-vl)-2-(~oenoic acid-3-y~-1-~(N.N-di(n-butyrl)aminocarbon I~_m_ethyrllpyrrrolidine-3-rarboxy,rlate The title compound is produced by reacting the compound of Example 327B
with trifluoacetic acid in CH2C12 (1:1).
2o Examc~le 27D
Ethyl traps.traps--4-11.3-Benzodioxol-5-vl)-2-(N-methylorocenamid-3-yr~-1_(N.N
di(n-buty~)am inocarbonylmethy)pyrrolidine-3-carboxylate The title compound is produced by condensing the compound of Example 327C with methylamine hydrochloride in the presence of a carbodiimide (e.g. N-2s ethyl-N-(3-dimethylamino)propylcarbodiimide, DCC).
Example 327E
traps.franc--4-~(,~~enzodioxol-5-y~,)-2-(N-mP,~hvlnrooenamid-3-yl)-1-~ N-di,(n bui~yl)aminocarbonylmethyll~yrrrolidine-3-carboxylic a~id_ 3o The title compound is produced by reacting the compound of Example 327D
with lithium hydroxide according to the procedure of Example 71 C.
Examl to a 328 traps.traps--4-r(1.3-Benzodioxol-5-yl)-2-(1-hydroxy-2~oen-3-vl)-1-(N N-diL
35 ~ I aminocarbon~rlmethvl)wrrolidine-3-c~rboxvlic acid *rB

example 328A
I- I-1-NN- in-~,~tvl)am inocarbonyrlmethy~)pyrrolidine-3-carboxvlate The title compound is produced by reacting the compound of Example 327C
s with borane methyl sulfide complex.
example 3288 traps. traps--4-( 1.3-Benzodioxol-5-yrly-~ 1-hydrox-2-orooen-3-yl)~-1-(N . N-di(n ~~yrf~minocarbon~rlmethyl}pyrrolidine-3-carboxylic acid ~ o The title compound is produced by condensing the compound of Example 328A with lithium hydroxide according to the procedure of Example 71 C.
~,le 329 traps.traps--4-~1.3-Benzodioxol-5-yl)-~N-benzyiaminomethyl)-~N.N-di(n-~ s bui~yrl~aminocarbonylmethyrl)~yrrrolidine-3-carboxylic acid Examr~le 329A
Ethyl traps.traps--4-(1.3-Benzodioxol-5-yl)-2-(N-benzyrlaminomethyl)~-1-(N.N-di(n butyrl)~aminocarbonyrlmethyrl,~~Ryrrrolidine-3-carboxylate 2o The title compound is produced by condensing the compound of Example 327A with benzylamine in the presence of sodium cyanoborohydride in ethanol.
Example 3298 traps.tram-4-(7.,~I~enzor,~joxol-5-yl~~-2 ~N-benzyrlaminomethvi)-1-(N.N-di(n 2s bul~yllaminocayQ,gyimethyl~~rrrolidine-3-carboxyrlic acid The title compound is produced by reacting the compound of Example 329A
with lithium hydroxide according to the procedure of Example 71 C.
Example 330 so irans.traps--4-~(~.3-Benzodioxol-5-yrl)-2-(N-acetyrl-N-benzyrlaminomet~rl)-1 jN.N-~(i(n-butyl)~aminocarbonyrlmethyrl)Ryrrolidine-3-carboxylic acid Exammle 330A
i I- I- -N- 1 min m h 1-1-35 (N.N-di(n-bu yl)~aminocarbon~ li methyrl)pyrrrolidine-3-carboxvlate The title compound is produced by reacting the compound of Example 3294A
with acetic anhydride in the presence of pyridine or triethylamine.

Examc~le 3308 traps.traps--4~~.3-Benzodioxol-5-yl)-2-(N-acel~yl- -benzylaminomethyrl)-1-(N.N
dl(n-butyl)aminocarbonylmethy~,Qynrolidine-3-carboxylic acid s The title compound is produced by reacting the compound of Example 330A
with lithium hydroxide according to the procedure of Example 71 C.
Exa~nle 33i traps. tram-4-(1.3-Benzodioxol-5-yrl)-2-(ethy~yt)-1-(N. N-dE,(n-~ o butyl)~aminocarbonyrlmeth)tl)pyrrrolidine-3-carboxyriic acid Exam~nle 331 A
Ethyl traps.tram-4-~(1.3-Benzodioxol-5-vIL2_~ethynv~-1-(N.N-di(,n-1 s b~t~~)aminocarbon, ly methyrllovrrolidine-3-carboxy to The title compound is made by employing the procedure of Corey and Fuchs (Tetrahedron Lett. 1972, 3769-72), using the compound of Example 327A.
Example 331 B
2o traps. traps--4-( 1.3-Benzodioxol-5-yl)-2-(eth~rnyl)-1-(N.N-di~n-butyf)~aminocarbonylmethyllpyrr~olidin~ 3-carboxylic aci The title compound is produced by reacting the compound of Example 331 A
with lithium hydroxide according to the procedure of Example 71C.
2s Exam I
traps.traps--4-(1.3-Benzodioxol-5-yrl)-2 ji-pent~~n_yl)~-1-~N.N-di n-butyrl)aminocarbonylmethyl)pyrrrolidine-3-carboxylic acid Exam I~A
3o Ethyrl traps.traps--4-l1.3-Benzodioxol-5-yr()-2-~ entynvi)-1~N N-di(n-bu;yl)aminocarbonylmethyri)~pyrrolidine-3-cart,~2yrlate The title compound is made by palladium-catalyzed coupling of the compound of Example 206A and propyl iodide, employing the procedure of Taylor, et. al. (J. Org. Chem. 1989, 54(15), 3618-24).
*rB

Example 3328 ~ra~~s traps--4-~ 3-Benzodioxol-5-y~-2-i(1-penty!~.yrl)-1-(N.N-di(n b~tyl_)aminocarbonkmethvl)ovrrolidine-3-carboxylic acid The title compound is produced by reacting the compound of s Example 332A with lithium hydroxide according to the procedure of Example 71 C.
Example 333 ~~ans-irana2-~,4-Methoxohenvl?-4-(1 3-benzodioxol-5-vl)-1-f2-(2:6 dioxoQ,ioe,~ ridinyl) eth~l~-~yrrolidine-3-carboxylic acid -The compound of example 61 A is added to a solution of the sodium salt of glutarimide in dimethylformamide. After stirring 24 hours, water is added and the mixture is extracted with ether. The resultant glutarimide is hydrolyzed to the title compound by the method of ~ s example 1 D.
Example 334 rrans-tran~~-(4-Methox h nvl ~-4-~~1 .3-benzodioxol-5-yl)-1-f N.N-di~>LaminocaL~nylmethxl]-Qyrrolidine-3-carboxylic acid.
2o The title compound was prepared according to the procedures described in Example 1. ~ H NMR (300 MHz, CD30D} S 2.83 (dd, 1, J = 8.1, 9.7), 2.99 (d, 1, J = 15.4), 3.19 (t, 1, J = 9.5), 3.49 (d, 1, J = 7 5.3}, 3.51 (dd, 1, J = 4.6, 9.5), 3.57 (m, 1 ), 3.79 (s, 3), 3.85 (d, 1, J = 9.5), 5.90 (s, 2), 6.71 (d, 1, J = 8.0), 6.84 (m, 3), 7.04 (d, 1, J = 1.6), 7.14-7.16 (m, 6), 25 7.19-7.34 (m, 6); MS (DCIINH3) m!z 551; Anal Calcd for C33H3oN2~s~0.65H20Ø35C2H50COCH3: C, 69.77, H, 5.77, N, 4.76. Found:
C, 69.75, H, 5.55, N, 4.64.
Example 335 so traps-traps 2-(4-Methoxvnhenyl)-4-(1.3-benzodioxol-5-yrl)-1-(N.N-diisooroQyrlaminocarbony methy_f]-~yrrolidine-3-carboxyrlic acid.
The title compound was prepared according to the procedures described in Example 1. ~ H NMR (300 MHz, CD30D) b 0.95 (d, 3, J = 6.5), 1.24 (d, 3, J = 6.4), 1.30 (d, 6, J = 6.8), 2.85 (d, 1, J = 12.5), 3.04 (dd, 1, s~ J = 8.1, 9.8), 3.14 (t, 1, J = 9.7), 3.32-3.55 (m, 3), 3.63 (m, 1 ), 5.92 (s, 2), 6.75 (d, 1, J = 8.1 ), 6.85 {dd, 1, J = 1.7, 8.1 ), 6.93 {m, 2), 7.02 (d, 1, J = 1.7), 7.35 (m, 2). MS (DCI/NH3} mlz 483. Anal Calcd for C27Hs4N20s ~ 0.65 EtOAc: C, 65.86, H, 7.32, N, 5.19. Found: C, 5.74, H, 7.26, N, 5.52.
Example 336 irans,traps-2-(3-Fluoro-4-methoxyrhhenyrl)~-4-( 1.3-benzodioxol-5-yrty-~2-N-~r_~vl-N-butar~esulfonvlar minx)ethyrl,)-pyrrrofidine-3-carboxyrlic acid Using the procedures described in Example 313 and Example 66, the title compound was prepared as a white solid. m.p.65-66°C. 1 H NMR
(CDC13, 300MHz) 8 0.82(t, J=7.5Hz, 3H), 0.92(t, J=7.5Hz, 3H}, 1.34-1.52(m, 4H), 1.72(quintet, J=7.5Hz,2H), 2.25-2.35(m,1 H), 2.72-2.94(m, 5H), 2.97-3.12(m, 2H}, 3.19-3.46(m, 2H}, 3.44(d, J=9Hz,lH), 3.53-3.60(m, '1 H), 3.67(d, J=9Hz, 1 H), 3.89(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, 1 H), 6.82(d, J=BHz, 1 H), 6.92(t, J=9Hz, 1 H), 6.97(s, 1 H), 7.12(d, J=9Hz, 1 H), 7.18(d, J=12Hz, 1 H). MS (DCIINHs) mle 565 (M+H)+.
Exam !p a 337 Using methods described in the above examples, the compounds 2o disclosed in Table 1 can be prepared.
Table 1 R R R
"Z
~ I~
1. 2. 3.

Table 1 cost.
R R R
J
4. J
s. s.
~I
I N OH~~ H3CO.F OS.ON~ ~S.ON~
7. 8. 9.
os 0 0 0'' o 10. 11. 12.
o c Or . s / I
I ~ s. ~
O .O

14. 18.
13.
w i ~ w I .S!"~'~
o'o~ do 16. 17. 1 S.
oz 19. 20. 21.

-2~s-Table 1 cont.
R R R

~

s~~ ~ cue:
~

o"''o 0 0 0 o 22. 23. 24.

H~

H

3 a ~ O O

O~rO O O

25. 26. 27.

Fa~;~ FH2C~~S~~ FHZC~~S~

O O O O O O

28. 29~ 30.

FHzC. ~ FH2C'C~S I~.~ F2HG
F ~'~'O~ F2 O O FZ OH'.
31. 32. 33.
F2HC. ~ . N~ FCC. . N~/.~ F3C. ~~' t~,~.~
FZ p~' O F O ~~O F2 O O
34. 35. 36.
~S; ~ .S. F3C~, O O ~ O O O
37. 38. 39.

Table 1 cont.
R R R
F CO F3~
FsC~~~ w I ~ w I ..
On O ..'~J~O ~ O O
O
40. 41. 42.
Ha~ ~ ~ ~ N, N~ ~ N~ S.'N
Os~p~ O ~ O 04 O
43. 44. 45.
N I / N~ N
O
46. 47. 48.
N
49. 51.
50.
N N
O ~ ~[ TO
52. 53.
54.
55. 56. 57.
w.o~~ n.o ~ ~o 58. 59. 60.

Table 1 coot.
R R R

O
61. 62.
63.

64. 65. 66.
w w " ~ ~ °~ ~ ~ . °~ N
°
° °
67. 68. 69.
O O '~i N O
70. 7 i . 72.
°1(N~
o ~%~ o 73. 74. 75.

wN

76. 77. 78.

Tabie 1 cont.
R R

Ct~° ~ CI~° N
79. 80~ 81.
O N O N
~O~N~ ~ o ~ CI~

82. 83. 84.
~~N~/'~ /~°~Nw/'~ Ct'~°~N~
85. 86. 87.

88. 89. 90.
I I
° ° o 91. 92. 93.
~°~N~ ~° O N~ CI~° O N
'O' 94. 95~ 96.
*rB

Table 1 cont.
R R R
J..

99.
97. 98.
o ~o 0 100. 101. 102.
~.'~lf'~'~

103. 104. 105.
W N II
p 106. 107, 1 OB.
CHs ~_ CH3 a Q' o 109. 110. 111.
"~'~ i v " ~ i '''l~ ~

112. 113. 114.
Cilia ~ C(Ha W O.$~O ~ 1 i O ~O
O
115. 1 i 6. 117.

Table 1 cont.
R
I, o 118. 119 120.
w I, o I., o 121. 122. 123.
o I ~ ~' F O F
F
124. 125. 126.
i~ o c 128. 129.
127.
I ~ li ~ y p~ 0 OCH3 OCH H~CO

130. 131. 132.
w I I~ 0 0 o ~I ~I
133. 134. 135.

Table 1 cont.
R R R
p E ~ ,i 136. 137. ~ 38~
U\/~ N_ ~ ~SN~
O Oa Q ~ p O
139. i Q0. 141.

142. 143. 144.
Oy$.'O ~ Fa~.~ ~ OJ' O O
145. 146. 147.
~~~3 Ow O O O O O
148. 149. i 50.
H
FhGr NS~~ \ \ N
0 0 ~ ,N o ' ~ o 151. 152. 153.

Table 1 cont.
R R R
° I ~ '~'~ O
154. 155, 15s.
o ° -~ o 157. 158, 159.
I ~ ~ i ~, I ° ~ o 160. 161. 162.
I
O O
i 63. 164. 165.
Fa~ ~ Faw~gf ~
O O FF O O O O
166. 167. 168.

Tabie 1 coot.
R R R
"1 Y Y
F3~0~~
O O O p O O
169. 170. 171.
0 0 0'"0 ~ o' o 172. 173. 174.
Y Y Y
Fad ~ ~./' Fa ~ ~/'' P~/' S ~S.
O" 'O F F. O O
175. 176. 177.
_Y F _Y
F3~0 O O~~ F3~0 p'~'~'O~~ F3~,,~ ~
FF O p 178. 179. 180.
FawO~ ~/' F F O ~ H3C" I
O~. p ~ F3~
18i. 182. 183.
H~CO
C1~~~~ H3C~ ~ H3C' O' O
184. d ° ~o" o~~
185. 186.
H~CO~ H3C~ H3C0 ~~~O~~ Fa~~ ~/'~ Fa- F ' .~/' O'SO
187. 1 g8. 189.

Table 1 cont.
R R
,,w,,~~~ H CO~ F ~_3~
FaCv~g~~ Fa~° O .O
O O
190. 191. 192.
o G~i' s; ~ ~~ s,;
o' 0 0 0 193. 194. 195.
p p O~O ~ Fa~gO
196. 197.
198.
Fa~ ~~ ~
F~O~ ~y~0~ FaCv~
O~ ~O
199. 200.
201.
F
Fa~~ .~° ' f' G ~ Ct 202. ~ ° I
203.
204.
G
CI
° / ° I / O
205. 2~. 207.

WO 99106397 PCT/tJS98115479 Table 1 cont.
R R R
I ~''~ I ~'.,~ "

208. 209. 210.
ci I o I~ ~ I~
211. 212. 213.
H
H
o I ~ ~ f o 214. 215. 216.
H/~ OH ~ H
\ r~
r~
I I ~ I\

217. 218. 219.
H
CF3 ~ CF3 I ~~ o I \ Nl~'~ o I \
O ~O
220. 221, 222.

Table 1 coot.
R R R
~F3 ~r~ O~~r~
223. ~4, X225.
CF

o I ~~: I~ ~~ !~
226. 227. 228' I

229. 230. 231.
cF~~~ ci i 232. 233.
234.
ci CF~ ~r~
jl~J O
235. 23fi. 237.

WO 9910b397 PCTIUS98115479 Table 1 cont.
R R R
I
o ~ o 238. 239.
240.
O I .~ I
O O
241.
242. 243.
F I/ ~.~ I
F O
245. 24fi.
F I ~.~ I ~~ F I
247. 248. 249.
I / O ( / O
F ~~ N~~f : N I
O
250. 251.
252.

Table 1 cont.
R R R
N N
''~'~ I ~ '''1r'.~ "
o ~ o ~ o 253. 254.
255.
N ~ r~
''l~' ~~~
I.N o 256. 257.
258.
259. 260. 261.
F F
i 2~, 263.
264.
I ~~,~
F N O F
265. 2ss. 2s~.

Table 1 coat.
R
Fa ~r ~r I N I
268. 269. 270.
c ~'~ P I
O F
271.
272. 273.
N
' o I '~''~' I
N O rL
274. F N
275.
276.
I ~~
N o I
I ~~
277.
278. 279.
~'lY~~t I ~~ .N o 280. 282.
281.

Table 1 cont.
R R R
p 283. 284. 285.
~ .N o 286.
287- 288.
N O
289. 290. 291.
i~~~ i~
292.
293. 294.
,~
~'~"N°' ' ~N O ~N
295.
296. 297.

Table 1 cont.
R R
''~N~'~ ,''~'"~
N O
298. 299. 300.
~r ,~
~N ''' o ' ~"' N "' or'' ~gN O
301. 302. 303.
I ~"~'v ~N O ~N O
304. 305.
306.
~~N~ I ~ N
~N O
307. 308. 309.
p ~N O
310. 311. 312.

Table 1 cont.
R R R

313. 314. 315.
°
316. 317. 318.
° ~,~-.~
'°
319.
320. 321.

322.
323. 324.
. '''~'~
r~ o ~g~ 326. 327.

Table 1 coot.
R R R
i o ~ o 328~ 329. 330.

1 ~ 332. 333.

334. 335.
336.
r o r,,~~ r . o 337. 338. 339.
~ ~ N.~.~
~N ~N
340. 341. 342.

WO 99106397 PC'T/EJS98/15479 Table 1 cont.
R R R
N
343. 344. 345.
I ~1'"~'~
iN F iN
346. 347. 348.
I n~ N'~..,~ I
F
349. 350. 351.
F I ~~ I ~Y~.~ I ~'l1'~~
F F N
352. 353. 354.
N
I ~ ~~ I ~~ ~r~
N iN ( 355. 356.
357.
*rB

Table 1 coot.
R R R
N I ~~-~ i ~t'~,4 355. N
359. 360.
'~ I "h' ~ I ''~'~,~
iN
361. 362.
363.
N
I iN ~r~ I NyY~''~
iN
364. 365.
366.
N
I ~~'~ I ~Y~'~
N ~N I ,T
iN
367. 368.
368.
I i N I N '~' ( Y N~.r~r ~N
370. 371.
372.

Table 1 cont.
R R R
~N ~N
373.
374.
375.
376. 377. 378.
N ~N
379. 380. 381.
E
382. 383. 384.
385. 386. 387.

Table 1 coot.
R R R
I N
388.
389. 390.
I ~ ~~
'~ N
391. 392.
393.
I r~N'',.~
N ~/'~ ~/'~
394. 395.
396.
397. 398.
399.
00.
401. 402.

Table 1 cost.
R R
N w/' N
403. 404. 405.
40fi. 407. 408.
N..,.~
409. 410. -411.
G
vl 4i2. 413.
414.
r 415. 416. 417.

Table 1 cont.
R R R
COOEt - _v 'COOEt 418. 419. 420.
'~ I'~
,~~ Nv 'COOEt Cv _NO
~COOEt 421. 422. 423.
I ~ I ~.~ I
~~ NO
z ~~ NO N
2 Op 424. 425. 426.

CN ~ CN I
~~

CN

427. 428. 429.

i CN Oz Oz 430. 431. 432.

-24'i-Table 1 cont.
R R R
I .~ N~.~ ~~.~
o K~ I ~ °
2 °21~~~
433. 434. 435.
N
o °
436. 437. 438.
I o 439. 440. 441.
I ° 1 ~ I~ o 442. 443. 444.
I o I
o ~ ~ o 445.
446. 447.

Table 1 cont.
R R p F~ ~ O
F
448. 449. 450.
w F~ O F ~ / ~ ~ r~
F
451. 452. 453.
Me0 ~ M
MeOI v v ~~' Me0 I / r~
F~ O O
O
454. 455. 456.
Ma0 ~ Mep ~ Me0 Me0' v v ~ ~
Me0_ y v ~ ~
O ~ Me0 457. ° o 458. 459.
Me0 ~/~ Me ~ ~ Me0 MeO~ ~ MeO~ r~: w Me0 r~
O
4so. 4s ~ . 4s2.

Table i cont.
R R R
~I - ~ ~
Ma0- v v ~ Me0 I ~ r~ MeO~ r~
463. 464. 465.
~(~ ~ ~~
Me0- v v r~ Me0_ 466. 467- 468.
~I i I
Moo ~ ,,~ I ~
M.o "~' ,~

469. 470. 47 i .
372. 473. 474.
I 1~
,~ ,~ I
475. 476. 477.

WO 9910b397 PCT/US98/15479 Table 1 cont.
R R R
ci c~
cl ~'~ ~~
478. 0 479.

480.
ci ~ cl ~~ cl c~~ ~ I ~ I ~
cl ~~ cl~~~
481. 482. ° o 483.
cl cl i cl ~'~~ c r~.,~
O O CI
484. 485. °
486.
F ~ F
~I ~ F
F '''~-~' I
F~ r~
° F r~
487. 488.
489.
F ~~ F ~J ' ~~ F W
F I ~ rC~ F' v v ~ F I ~ iL
490. 491. 492.

Table 1 cont.
R R R
F
~( F
F
493. 494. 0 495. ~
~'~' I
w 496. o 497. 498.
I
,~ .~
'''~' 499. 500. 501.
w w I I I
,,,~' 502. 503. 504.
,4 I
M.o' o~
505. 506.
507.

Tabte 1 cont.
R R R
I
MaO~~~ Me0 ~ I
Me0 r~
OMB O
OMe O . OMa O
508. 509.
510.
I
Moo ~ M~ ~ ,t I
Ma0 r~
OMo ~ OMe O
OMe 511. 512. 513.
Me0 Me MaO~ ~~ ( ~ I ~' OMa O OMe O OMe O
514. 515. 516.
Mo0 ~ Me0 M
t ~ I ~ ~: I
i OMo O OMe OMe 517. 518. 51 g.
Mo ~ Ma0 I ~ Me0 .~ y I
OMo O OMe OMe O
520. 521.
522.

Table 1 cont.
R R R
Ma H
I H i ~ H~'~ I H
Mop Ma0 0~ O
523. 524. 525.
Ma I H
r~ Br ~ N~r~ Br 0../i. p I / ~O[
526. 527.
528.
Br~H~~ Br~ ~ gr~~~r I ~o )I~i' . (~ 1~5(i 529. 530. 531.
Br Br I ~.~r I f' Br , ~~, O
532. 533. 534.
I w ~~
FO FO
535. 536. 537.

Table 1 cont.
R R R
I F I~ Fo I o r~
~F
538. 539.
540.
o I ~ ~ a I ~ .
540. 542. 543.
o B
B
544. 545. 546.
I "~'~ I w ~~.~ w ~.4 e~ ° a~ ° B I ~ o 547. 54g. 549.
a~~ F I ~ ,~~ I
c F~ C1 °
550.
551. 552.

Tabie 1 cont.
R R R
"~' I
F CIO / CIO F~CIO
553. 554. 555.
I w ~.r:
F , ~O F / CIC F I / CIO
556. 557. 558.
8r~Br~~~ Br i F F FF
559. 560. 561.
Br Br y r~
Br O
F
562. 563.
564.
F
8r~~.~r Br i ~ 1~,~ CI I ~'~
FF'' ~~ ~O F ~O~ F / O
565. 566. 567.
*rB

Tabie 1 cont.
R R R
F
F
CI ~ Ct I ~ ~~r C~ ~r~r F F
568. 569. 570.
F ~ F F
C
C~ ~ ~~ C1 ~r~r O
O ~ O
F ~ F
57 ~ . 572. 573.
F
Ci~~~r 574. 575. 576.

° 578. 579.
577.
w 580. 581. 582. o o ~
583. 584. 585.

WO 99!06397 PCT/US98115479 Table 1 cont.
R R R

586. 587. 588.
592. 593. 594.
595. 596. 597.
598. 599. 600.
so 1. sot. so3.

Table 1 cont.
R R
H
° i '''~.~' I
l 604.
605. 606.
H
~ I ~.
i o ~ o soy. soa. sos.
f ! H~'r'- I ~~. I ~.
° ° . o 610. 611. 612.
H H
l ~: l , '''~'~ p ''' 613. 614' 615.
H H H
l I ~ N~, I ~
O
616. 617' 618.
H
H
l y '~'~ . ~~ H
o l 619. ~ o 620.
621.

Tabie 1 cont.
R R R
o~ ~
H O H N II ' ' ~ O ' O
622. 623, 624.
1 ~ ~ ~ I
o I~ 0 0 625. 626. 627.
J
H H
H
I i O i O
_ O
628. 629. 630.

O H
'''1~ I " ot'~
I ~~ o 631. 632. 633, 634. 635. 636.
o ~~ o 637. 638' 639.

- 2 54-.
Table 1 cont.
R R R

%~ 0 0 640. ~1. 642.

643. 644 ~ 645.

- 646. 647.
ci I ~.~ c t ~.~
o ~ o ~ o 649. 650. 651.
I ~ ci ci o I w .~ I w o ~ o 652.
653. 654.

Table 1 cont.
R R R
655. 656. 657.
,~ I w o I o 0 658. 659. 660.
I ''~ I I
o ~ o 661. 662. 663.
b b-ss5. sss.
I ~~ i o ~o ~o ss7. s6a. sss.

Table 7 cont.
R R R
I 1 '4 I
o a 670. 671. 672.
o I ~ o .4 F F I / O
673. 674.
675.
I '~ I '~
o i F
s7s. 677 s78.
FI o I~ o 679. 680' 681.
682. 683. 684.

Table 1 cont.
R
w O F
ss5. sas, ss7.
i ~ ~~
O F~ O I
O
688. 689.
690.
y F~ . F~ O ~ O
691. 692. 693.
t F~ ° E o ~ o 694. 695. 696.
H ~ H
Me0 ~~' Ma0 N'~r~
O O O
698. 699.
607.

WO 99/06397 PCTlIJS98/15479 Table 1 cont.
R R R
H
AAoO ' H ~ Me0 ' ~~ ~ H ~r O Ma0 O O
701. 702.
700.
Moo "~~~ ~ ~ ,t o ~ o /F O
703. 704.
705.
pO ~FO O
706. 707. 708.
~~~'~ O r~
O O
709. 710. 711.
W ~~ F3C~S'~r~
O ~ O O'~O
712. 713. 714.
F3~,S: ~~
O O
715.

~xamole 338 Using methods described in the above examples, compounds comprising a parent structure selected from those disclosed in Table 2A
and an R substituent selected from those disclosed in Table 2B can be s prepared.
Table 2A
F
F
1. L. 3.
F
~,COOH
R-r \ O
4.
F
v. ...
7.

Table 2A cont, H~
~,.COOH
~ OCH3 . _. ~ ~ . 12.
F F
~,,COOH
R-OCH~

t 3. 14. 15.
F
,,COON
R-i O
OCH3 OCHy 1 O.
17. 18.

~COOH
20. ~ o Table 2A coot.

~,,COOH ~'~H
R- R-23. 0 24.
F
GI.
cv.
F
a ,,,COON
R-F
w~
29. ~ 30.
28.

,~COpH ~COOH
R-N
r r 31. ~ 32. 33.

Table 2A cont.
CHI
MOM
~~H ~COOH R_ ,,.COON
R_ R_ ~ 1 1 I 36.
34. 35.

MOM
\ /
~,,COOH
",COON R-N O
R-I
37. ~ I . 38. ~H3 MOM CHI
\ / \
,,"COON ~N ,.COON
~I
OCH
OCH3 42.
40.~ 41. _ OMOM OCH~
\ \ \ /
~COOH ",COON R- ,,.COON
R-N ~ 1 R' ~ ..
v1 v1 wI

43. 44. 45.

Table 2A cont.
F

\
xCOOH
~,COOH
R-R- ~ 1 ~ - 1 \~ \!
47. 48.
\ / 1 ~cooH ~cooH
R-! ~ i 50. ~ 51.

R- ~..COOH ~ ~,,COOH
\ O f \
"" , 53. 54.
\~
~~H ~.COOH ~ ,,.COOH
R' 55.0 56. i ~ F 57. ocH

- 2fi4-Table 2A cont.
~~H ~COOH
R- R-O
O
5s. so.
58.
,~COOH
R-I \
62. vo.
61.
...
~,COOH ~ ,,.COOH
' \ OCH3 sa. ~ s5. ' o~H3 .....
v y ~,,COOH ~ ~,,COOH
r \ ~ \ 0 s7. ' o ss.

Table 2A cont.
,~cooH
F
F
71 . ~ F r ~.. vvn3 '\ / O~ COON
O~ COON
~_COOH
73. ~o~ r -~. 75.

\ O~ COON \ O~' COON \ / O~ COON
~~H R- ~,.COOH ~ ,,,COON
R-! o I
! '~ ~ 77. ~ 78.
76.
CH3 CH3 .
O~ COON \ O~ COON
- ~,cooH ~ ~cooH
! F ! \ OCH3 ~ F 8O. ' OCH3 *rB

WO 99!06397 PCT/US98/15479 Table 2A cont.

NOH
O
,,COOH
r 83. o _ ..

OH
O~
~,COOH
R' r F
7.
vv.
OCH~

NOH , O~OCH3 O
~COOH F ~ ~,,COOH
r \
r OCH3 .

88. 89. 90.
93.
91.

Table 2A cont.

F
Ff-'~ 3 'J' 7. w.n3 96.

F F F

~OCH3 ' ~ ~ CH3 ,,.COOH ,,.COOH
R' R- F

\ ~ ~ w 97. 98.

F F F

~OCH3 ' -NOCH3 ~

~COOH r,, COOH

F R' R-F
~

1 101. ~ 102.

F

F

F

103. l U4. ~ vv.

Table 2A cont.
. ,,".,.

111. JcH, 1 ~9. . . ".
",,COOH ,,,COOH
R R- ,.cooH
~,' i ~ v o 112. 113. 114.
R- ,~cooH R-N ,,~cooH
o) 115. 116.
,,cooH
R- ,~cooH
R-118. 119. ' 120.

Table 2A cont.
R- ,,cooH R_ ~.cooH R- ,,cooH

121. ~ o~ 122. 123. !

,, COOH
R-! w o i 126.
125.

~COOH .,C~H R_ ,,.COON
R R ! ~ o ! ° ! v o~
0 128. ~ ° 129. ~ °
127.

,~COOH
~COOH R-R-132.
130. , Table 2A cont.
~~3 ~.cooH F
R-o, 135.
133. ' "'~' F
1:iti.
137.
H OCH~

~COOH ,~COOH
R-N
l ' N .-...
139. F 140. ' o ~,COOH ,a~H
R_ R_ H,co w ~
143. °"' 144.

WO 99!06397 PCTlUS98115479 Table 2A coot.

~,COOH
R- F
F

146. ~H3 145.
F F
1 / ~ /
~,.COOH ~ ~,.COOH
F ~ \ \ o H3C0 I ~ OCH 1 i s 148. 150.
149.
F F
,"COON
R- F
I ~
152.
OMOM
,.COON
I \
H3C0 ~' OCH

156.
154. 155.

Table 2A cont.
MOM
~,cooH F
R-N
F
I
158.
" °cH~ .

". ° 162.
161.

a O~
,,COOH ~COOii F ~N R-w:n3 164. ~ F 165.
163.
..,.... 1~/. IDG7.

Table 2A cont.
F F
H
K
..
169. ~O .
.... ~ r v.
F MOMO
~N.N ' ~ N .
~' N ~ ~ N
o I w 173. ' ~ 174.
! /L.
F
F
K
~ N
~~N
I~ F
177. ~~F
175. _ F
H
~N
s w.n3 ~ OcH3 11 ts. 179. 18~.

Table 2A cont.
H
t NH
..... 182. ~ iVV.
MOMO
0 0 - ~ ~ ,p r..
H S,CH3 R-~ H S.CH3 1 s~. ~0 18s.
~...
MOMO
~0..~ ~' ~~,0 ~~,~.S.CH3 ~ ~ ~ S'CH3 ~ ~'CH3 H
l ~ ~ l ~
187. I o 188. ~ 0 189.
o't o p . . ~ osp ~ .,~ _ H ~CH3 ~~ ~H S.CS3 ~ H~ CH3 t 91. 192.
190.

WO 99/06397 PCT/US98l15479 Table 2A cont.
F
F MOM
1 ~ O~ O
O O
a0 ~~"~ N CH a ~~ S'CHa R_ ~~CH3 ~' H
~F
j '~\
F
193. 194. 195.
-' ~g,p ' ~oao H ~'CH3 R- H'S~CHa R- J~H S.CHa F ~ \ OCHa ' \ OCHa i 196. 197. °cHa 198. °cHa °~ a_o ~ ~ o o - ~ o, o s H'S CHa R- H~S.CHa R- H CFa ° ~\ °
i 99. ~ 200. °~ 201.
00 ~°°
p a z a ~ ~~ CH2CFa f~" H ~ H(CHa)z H S' CH CH
O
202. ~ Q~ 203. ' ° 204.

Table 2A cont.
r"COOH ~ ~,,COOH
,,cooH l q o ' o, ' o~
I g o- 206. 207.
205.
~Ha N, CH3 ~,COOH ~H
r j \ ) ~O
p i 208. 209. 210.
y 212. ocH, 213. ocH~
zip. -ocH, ~~ 5. "'"3 216. ocH
214.

Table 2A cont.
217. 218. 219.
221. 222.
220.

223. 224. 225.
226. 227.

Table 2A cont.
229. 230. 231. ocH, 232.
233. 234.
235. 236. 237.
ocH3 239. 240.
238.

WO 99/06397 PCT/US9$115479 Table 2A cont.
241. 242. 243.
244. 245, ocH3 246.
248. 249.
247.
252. ocH3 250. 251.

Tabte 2A cont.
F F F F
rpppH ~,COOH ~COOH
O ~ ~ O
253. 254. 255.
F
\ \
'~H fcooH
R' ~ o R'H
1 1 /~
257. 258.
~COOH fCOOH
R' ' O
z59. 2so. 2s i .
~COOH ~COOH ~,COOH
R' ' O R'N ' / / R' N , O
262. 263. 264.
~,COOH
R' 265. ~..... 267, Table 2A cont.
268. 269. 270.
~COOH
R' \
273. "''"' 271. 272.
~COOH ,~H ~,COOH
\ ~ f1 \
o ~ / o 274. 275. 276.
fCOOH ~COOH ~CC~H
' R' t R'N
277. 278. 279 ,~.
*rB

Table 2A cont.
~,OOOH
~,COOH fCOOH
w O ~ , O
280. ~cH' 281. 282.
~~H ~,COOH ~COOH
R- ~ O R. O

283. 284, 285.
~COOH ~COOH ~COOH
R' v ~

28s. 28~. ~~H3 2ss.
~COOH ~COOH ~COOH
~ O
R' ~ O R' 1 w O 1 / /
289. 290. 291.
~COOH ~COOH
y R' y / O

292. 293. 294.

Table 2A cont.
~COOH ~COOH
R' 1 R' 1 0 1 295. ~ 296. 297.
p" ~COOH rCOOH
R. ~ o R~ ~ o R_ ~t~
t 1 / 1~/
298' 2gg. 300.
~COOH ,,~H ~CC~OH
R' R' w ~N

301. °~H' 302. 303.
v COOH ~ ~.~H ,,COOH
_ R' r R'N ~ R'N I / / N 1 ~O
306.
304.

Table 2A coot.
~COOH ,~~H
R

307. ocH 309.
308. z ~COOH ~CCiOH iCOOH
R R' ~ R_ ~ o 310. i ~ 1 311. 312.
~COOH O ~ COOH ~,COOH
R_ 1 w o R' 1,. ~ R_ ~ o~
i o 1 313. 314. 315.
~CC?OH ,COOH ~,COOH
R 1 R' ~ ~ R' ..
316. 1~~ 1 i 7 317. 318.
,~cooH
rCOOH ~COOH
R, 1 i / R_ ~ o R_ ~ o , 319. 320. 1 / 32 i .

WO 99!06397 PCT/US98115479 Table 2A cont.
.o t r ICppH ICOOH ~,COOH
w ~ w ~ / O
322. °°H' 323. 324.
t ~ t cooH
I~H ICOOH r O
t /
O
325. 32fi. 327.
t/
ICOOH ~,COOH
O
329. ocH, 328. .~~u.
~,COOH .COOH rCOOH
R" ~ R- t \ O R' v /
° 333.
331. 332.
IOOOH I~H ~,COOH
v ~ w ~O
334. 335. 33fi.

Table 2A cont.
'o iCOOH
~C°OH ~,COOH
R' ' O
O ~ O ~ / /
337. 338, 339.

,~cooH r ~H ,COOH
1~- o R. R' ~.
1 t / ~ t / o 340. 341. 342. ocH3 ~~H , ~COOH ~COOH
R. O
w ~ R' O ~~ ~ / O
343. 344. 345.

~COOH ~,COOH
O R-/ O
346. 347. Wig.
E
O
~ / o o. ° ~ / oo,~~
a Hs-CH3 ~H CH3 f;' ~O~
/ O ~ / O
349. ocH3 350.
351.

Table 2A cont.
_ o - ~o O Oi9-CH3 ~ O NS~CH3 ~ ~N~ CH3 ' ~N ~-H H
H R. w O R' ~ Ov R' ~ ~ / O ~ / O
O
ocH3 354. ocH3 352. ~ 353.

' / O
356. 357.
355. ocH3 358. 359. 360.
o / ono CH3 ~HS-CH3 H .~ a 4 .~ ~O_ - ~ . v--362. 363.
av i .

Table 2A cont.
H3C H~ . .,,_ / o ;~g-CH' ° 4 o O °ss-CH3 ~N ~ rS'CH3 H H ~ O.
R" 1 O R' I ,.. O ~O.
364. 365. 366.
H H3C Ha O N~CH3 ~ / '~NH / ~~NH
,L.H
/ / ~ ~ /
367. 368. 369.
HOC
H~ H~
ty ~ / ~~ NH
~~NH ~ / ' NH I N
I ~'N
R' ~ R' ~ ~ ~ / O
O ~ / O
370. 371. 372.
v / ~~ ~ / ° °'s-cH / ° °;~~-cH
I' N1NH N a ~ N a H H
R- w R- w F ~ / O ~ / /
373. 374. 375.

WO 99/Ob397 PCT/US98/15479 Table 2A cont.
o mss. \ / o°'s-cH3 / ° °, CH3 ~H ~H CH3 O ~ ~ O
376. 3n. 378.
° °r$CH \ / ° °'SrCH3 \ 'HNH
,L H / N
ft' ~. R' w F (~-F
379. 380. 381.
Na~'l \ / N'nINH N%N
,~NNH /LAN ,' ~NH
R- R' ~~ R-~ / ~ / O
382. 383. 384.
NH '~NH
' ~'NNH / N !~N
~ F
O ~ /
385. 386. 387.

Table 2A cont.

s Ors" CH ~~NH ~ H CH3 ~N ~ ~/~N O
R, H o~ R~ ~~o~ R' 1 0 ~'' 0 388. 3gg, 390.
F Fa ~NH \ / ~COOH
/~N , COON
..O ~ 1 ~ / O
/ 0 393.
391. 392.

\ /
~COOH sCOOH ~,COOH
R-N R'N w O F.;.N ~. O
O ~ / ~ ~ /
394. 395. 396.

397. 398. 399.

Table 2A cont.
F2CF3 FzCF3 F2CF3 ~,COOH ~COOH ~,COOH
R. R. w. R- ' 400. ~ 401. ~ 402.
403. 404. 405.
~COOH ~COOH
_ 1 '~ R' 1 ' 407. 408.
40fi.
~,,COOH
~~H ~,COOH ~ ' O
R' F~' -w IV\~O
411.
409. 410.
f --/
~COOH ~COOH ,,,COON
1' 412. 413. 414.

Table 2A cant.
-~o ~o ~COOH ~,COOH ~COOH
_ R. o R_K~~ R . 1 417:
415. 416.
~COOH ~,COOH ~COOH
R_ 1 0, R, 1 / o, R.
418. 419. 424.
~COOH ~H ~COOH
R.~ R..N ~ 1 R_nt 1 / O
421. 422. 423.
rCOOH ,COOH rC00H
R_N O R'H
1 p O ~O
424. 425. 42fi.
f~H ,COOH sGOOH
R.N ~ R,.N ~ O

/O /o 427. 428. 429.

WO 99/Ob397 PCTNS98/15479 Table 2A coot.
~,COOH COOH
~~H O ~N O
R
430. 431. 432.
~o ~,COOH
~COOH ~COOH O
_N ~ O R_ .~ O R' w R 1 / ~ > > ~ / o 433. 435.
434.
~o ~COOH ~,COOH rCOOH
R. o~
l R
436. 437. 438.
~,~H ~COOH
439. 440. 441.
~~H ~COOH ~COOH
O
R' ~ , ~ R 1 / O~ R.N~O
442. 443. ~4' WO 99106397 PCT/US98/i5479 Table 2A cont.
~,COOH ~,COOH lCOOH
R-~l~°o 447 0.
445. 446.
,r~H dCOOH ~COOH
448. 450.
449.
O ~,COOH
~COOH ,~COOH
f3' R'N~ R'N 1~ ' / O
O
451. 452. 453.
\ /
~,COOH
~ O
/ O
454. 455. 456.

Table 2A cont.
o~

~,COOH ~ COOH ~COOH
/ O , / O ' O
457. 458. 459.

~COOH ~COOH
jCOOH
O
w ~ w ~ w O ~t,~'/ 'O ~ / O
~J- 461. 462.
460.
fcooH

463. 464. 465.

- 2ss-Table 28 R , R R
w 1. 2~ 3.
l o g s~ ~' 4. 5.
6.
8. s.
°'1 °
10. 11. 12.
cW°~

13. 14. 15.

w I w N~.
p v ~' p O
1fi. 17. 18.
cW',s~ "~'~
~o~ os~''o 00 19. 20. 21.

Table 2B cost.
R R R

H3C0.~ H3C
i ~ ~
' 'S.
p O O

22. 23. 24.

~ 0~ F
H ~
' H'O 3 s N~ ~y/ ~O
~ O

O O

25. 26. 27.

F FH
N.

3 ~~0~ N~ z O~'O
FHzC~~

O
O

28. 29. 30.

FH ~ ' C.
/' z N~ FzHC
F O~~O ~ FHzC. ~ C
~

Fz O O Fz O O

31. 32. 33.

z ~ N
F HC.~ F
.
~

_~
4$ F3~ a0'G~S,.' O ~ ~
z0 F20~ O Fz0 O

34.
35. 36.

N

~ ~ ~
O ~ ..
O O

O O
! O

37. 38. 39.

N

S,.'N~ /~ . ~ S
'~' O

O O O
O

40. 41. 42.

*rB

Table 2B cont.
R R
F~
F3~a~r~ Fa~.~~ W I
O O O O O~' O
43. 44. 45.
F3~ H3 ~ ( .s; ~~

46. 47. 48.
w o I~ o I~ o 49. 50. 51.
w o I~ o i~
52. 53. 54.
I~ ~ I~ ~ I~
F
F
55. 56. 57.
I
ci i ~ o 58. c~ 59. 60.

DEMANDES OU BREVETS VOLUMlNEUX
LA PRESENTS PARTiE DE CETTE DEMANDS OU CE BREVET
COMPREND PLUS D'UN TOME.
CECI EST LE TOME ~ DE
NOTE. Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets THiS SECTION Of= THE APP~ICATION/PATENT CONTAINS MORE
THAN ONE VOLUME
THIS IS VOLUME ~ I - OF
NOTE: For additional volumes-pf~ase contact the Canadian Patent Ofific~ . I'

Claims (98)

What is claimed is:
1. A compound of the formula:
wherein Z is -C(R18)(R19)- or -C(O)- wherein R18 and R19 are independently selected from hydrogen and loweralkyl;
n is 0 or 1;
R is -(CH2)m-W 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, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR17 wherein R17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (l) -C(O)NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl, aryl or dialkylamino, (m) -S(O)2NHC(O)R16 wherein R16 is defined as above, (n) , R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (R aa)(R bb)N-R cc- wherein R aa is aryl or arylalkyl, R bb is hydrogen or alkanoyl and R cc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen;

R3 is (a)R4-C(O)-R5-, R4-R5a-, R4-C(O)-R5- N(R6)-, R6-S(O)2-R7- or R26-S(O)-R27-wherein R5 is (i) -a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R20)-R8- or -R8a-N(R20)-R8-wherein R8 and R8a are independently selected from the group consisting of alkylene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyl or (v) -O-R9- or -R9a-O-R9- wherein R9 and R9a are independently selected from alkylene;
R5a is (i) alkylene or (ii) alkenylene;
R7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R21)-R10- or -R10a-N(R21)-R10- wherein R10 and R10a are independently selected from the group consisting of alkylene and alkenylene and R21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl;
R4 and R6 are independently selected from the group consisting of (i) (R11)(R12)N- wherein R11 and R12 are independently selected from (1) hydrogen, (2) loweralkyl, (3) haloalkyl, (4) alkoxyalkyl, (5) haloalkoxyalkyl, (6) alkenyl, (7) alkynyl, (8) cycloalkyl, (9) cycloalkylalkyl, (10) aryl, (11) heterocyclic, (12) arylalkyl, (13) (heterocyclic)alkyl, (14) hydroxyalkyl, (15) alkoxy, (16) aminoalkyl, (17) trialkylaminoalkyl, (18) alkylaminoalkyl, (19) dialkylaminoalkyl, and (20) carboxyalkyl (ii) loweralkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl, (xii) hydroxyalkyl, (xiii) haloalkyl, (xiv) haloalkenyl, (xv) haloalkoxyalkyl, (xvi) haloalkoxy, (xvii) alkoxyhaloalkyl, (xviii) alkylaminoalkyl, (xix) dialkylaminoalkyl, (xx) alkoxy, and wherein z is 0-5 and R7a is alkylene;
R26 is (i) loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x} (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy-substituted haloalkyl; and R27 is alkylene or alkenylene;
(b) R22-O-C(O)-R23- wherein R22 is a carboxy protecting group or heterocyclic and R23 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R24)-R25- wherein R25 is alkylene and R24 is hydrogen or loweralkyl, (c) loweralkyl, (d) alkenyl, (e) alkynyl, (f) cycloalkyl, (g) cycloalkylalkyl, (h) aryl, (i) arylalkyl, (j) aryloxyalkyl, (k) heterocyclic, (l) (heterocyclic)alkyl, (m) alkoxyalkyl, (n) alkoxyalkoxyalkyl, or (o) R13-C(O)-CH(R14)-wherein R13 is amino, alkylamino or dialkylamino and R14 is aryl or R15-C(O)- wherein R15 is amino, alkylamino or dialkylamino;
or a pharmaceutically acceptable salt thereof.
2. The compound according to Claim 1 wherein n is 0 and Z is -CH2-,
3. The compound according to Claim 1 wherein n is 1 and Z is -CH2-.
4. The compound according to Claim 1 wherein n is 0, Z is -CH2-, and R3 is R4-C(O)-R5- , R6-SO2-R7- or R26-S(O)-R27- wherein R4, R5, R6, R7, R26 and R27 are as defined therein.
5. The compound according to Claim 1 wherein n. is 0, Z is -CH2-, and R3 is alkoxyalkyl or alkoxyalkoxyalkyl.
6. The compound according to Claim 1 wherein n is 0, Z is -CH2-, and R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N- as defined therein and R5 is alkylene or R3 is R6-S(O)2-R7- or R26-S(O)-R27-wherein R7 is alkylene, R27 is alkylene and R6 and R26 are as defined therein.
7. The compound according to Claim 1 wherein n is 0, Z is -CH2- and R3 is R4-C(O)-N(R20)-R8- or R6-S(O)2-N(R21)-R10- wherein R8 and R10 are alkylene and R4, R6, R20 and R21 are as defined therein.
8. The compound according to Claim 1 wherein n is 0, R is tetrazolyl or -C(O)2-G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 and R2 are independently selected from (i) loweralkyl, (ii) cycloalkyl, (iii) substituted and unsubstituted aryl wherein aryl is phenyl substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy, (iv) substituted or unsubstituted heterocyclic, (v) alkenyl, (vi) heterocyclic (alkyl), (vii) aryloxyalkyl, (viii) arylalkyl, (ix) (N-alkanoyl-N-alkyl)aminoalkyl, and (x) alkylsulfonylamidoaikyl, and R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N- wherein R11 and R12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, aryl and arylalkyl and R5 is alkylene; or R3 is R4-C(O)-N(R20)-R8- or R6-S(O)2-N(R21)-R10- wherein R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl, R7 and R26 are alkylene and R20 and R21 are loweralkyl; or R3 is Rs-S(O)2-R~- or R26-S(O)-R2~-wherein R6 is loweralkyl or haloalkyl, R~ is alkylene, R26 is loweralkyl and R2~ is alkylene.
9. The compound according to Claim 1 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(~)2R~6 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 is (i) loweralkyl, {ii) alkenyl, (iii) alkoxyalkyl, (iv) cycfoalkyl,~ (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl., 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl., 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) arylalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl, or difluorophenyl, and R3 is R4-C(O)-N(R20)-R8- or R6-S(O)2-N(R21)-R10- wherein R8 and R10 are alkylene, R20 and R21 are loweralkyl, R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R6 is loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl.
10. The compound according to Claim 1 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) arylalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl or (xiii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-i,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl, or difluorophenyl, and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R12)N-wherein R11 and R12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl.
11. The compound according to Claim 1 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 is (i) loweralkyl (ii) alkenyl, (iii) arylalkyl, (iv) aryloxyalkyl, (v) heterocyclic, (vi) heterocyclic (alkyl), (vii) aryl, (viii) (N-alkanoyl-N-alkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11 )(R12)N- wherein R11 is loweralkyl, and R12 is aryl or arylalkyl.
12. The compound according to Claim 1 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 is (i) phenyl or (ii) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy, and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R6-S(O)2-N(R21)-R10- wherein R10 is alkylene, R6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl.
13. The compound according to Claim 1 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl or 1,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy and alkoxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is alkoxycarbonyl or R6-S(O)2-N(R21)-R10- wherein R10 is alkylene, R6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl.
14. The compound according to Claim 1 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl or haloalkyl, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 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 and R3 is R4-C(O)-R5-wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R11 and R12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
15. The compound according to Claim 1 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl or haloalkyl, Z is -CH2-, R1 is loweralkyl, alkoxyalkyl, or alkenyl, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11) (R12)N- wherein R11 and R12 are independently selected from loweralkyl, aryl hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, heterocyclic, and arylalkyl.
16. The compound according to Claim 1 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 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 and R3 is R4-C(O)-R5-wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R11 and R12 are independently selected from loweralkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, aryl, and heterocyclic.
17. The compound according to Claim 1 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 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 and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R11 is loweralkyl and R12 is aryl.
18. The compound according to Claim 1 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R11 is alkyl and R12 is selected from aryl, aminoalkyl; trialkylaminoalkyl, and heterocyclic.
19. A compound according to Claim 1 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -C H2-, R1 is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R11 and R12 are independently selected from alkyl, aryl, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
20. A compound according to Claim 1 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R11 and R12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R11 and R12 is alkyl.
21. The compound according to Claim 1 of the formula:
wherein Z is -C(R18) (R19)- or -C(O)- wherein R18 and R19 are independently selected from hydrogen and loweralkyl;
n is 0 or 1;

R is -(CH2)m-W 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, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR17 wherein R17is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (l) -C(O)NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl, aryl or dialkylamino, (m) -S(O)2NHC(O)R16 wherein R16 is defined as above, R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (R aa)(R bb)N-R cc- wherein R aa is aryl or arylalkyl, R bb is hydrogen or alkanoyl and R cc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen;
R3 is (a) R4-C(O)-R5-, R4-R5a-, R6-S(O)2-R7- or R26-S(O)-R27-wherein R5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R20)-R8- or -R8a-N(R20)-R8-wherein R8 and R8a are independently selected from the group consisting of alkylene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl or cycloalkylalkyl or (v) -O-R9- or -R9a-O-R9-wherein R9 and R9a are independently selected from alkylene;
R5a is (i) alkylene or (ii) alkenylene;
R7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R21)-R10- or -R10a-N(R21)-R10-wherein R10 and R10a are independently selected from the group consisting of alkylene and alkenylene and R21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl;
R4 and R6 are independently selected from the group consisting of (i) (R11)(R12)N- wherein R11 and R12 are independently selected from (1) hydrogen, (2) loweralkyl, (3) haloalkyl, (4) alkoxyalkyl, (5) haloalkoxyalkyl, (6) alkenyl, (7) alkynyl, (8) cycloalkyl, (9) cycloalkylalkyl, (10) aryl, (11) heterocyclic, (12) arylalkyl, (13) (heterocyclic)alkyl, (14) hydroxyalkyl, (15) alkoxy, (16) aminoalkyl, and (17) trialkylaminoalkyl, (ii) loweralkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl, (xii) hydroxyalkyl, (xiii) haloalkyl, (xiv) haloalkenyl, (xv) haloalkoxyalkyl, (xvi) haloalkoxy, (xvii) alkoxyhaloalkyl, (xviii) alkylaminoalkyl, (xix) dialkylaminoalkyl, (xx) alkoxy, and wherein z is 0-5 and R7a is alkylene;
R 26 is (i) loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy-substituted haloalkyl; and R27 is alkylene or alkenylene;
(b) R22-O-C(O)-R23- wherein R22 is a carboxy protecting group or heterocyclic and R23 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R24)-R25- wherein R25 is alkylene and R24 is hydrogen or loweralkyl, (c) loweralkyl, (d) alkenyl, (e) alkynyl, (f) cycloalkyl, (g) cycloalkylalkyl, (h) aryl, (i) arylalkyl, (j) aryloxyalkyl, (k) heterocyclic, (l) (heterocyclic)alkyl, (m) alkoxyalkyl, (n) alkoxyalkoxyalkyl, or (o) R13-C(O)-CH(R14)-wherein R13 is amino, alkylamino or dialkylamino and R14 is aryl or R15-C(O)- wherein R15 is amino, alkylamino or dialkylamino;
or a pharmaceutically acceptable salt thereof.
22. The compound according to Claim 21 wherein n is 0 and Z is -CH2-.
23. The compound according to Claim 21 wherein n is 1 and Z is -CH2-.
24. The compound according to Claim 21 wherein n is 0, Z is -CH2-, and R3 is R4-C(O)-R5- , R6-SO2-R7- or R26-S(O)-R27- wherein R4, R5, R6, R7, R26 and R27 are as defined therein.
25. The compound according to Claim 21 wherein n is 0, Z is -CH2-, and R3 is alkoxyalkyl or alkoxyalkoxyalkyl.
26. The compound according to Claim 21 wherein n is 0, Z is -CH2-, and R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N- as defined therein and R5 is alkylene or R3 is R6-S(O)2-R7- or R26-S(O)-R27- wherein R7 is alkylene, R27 is alkylene and R6 and R26 are as defined therein.
27. The compound according to Claim 21 wherein n is 0, Z is -CH2- and R3 is R4-C(O)-N(R20)-R6- or R6-S(O)2-N(R21)-R10- wherein R8 and R10 are alkylene and R4, R6, R20 and R21 are as defined therein.
28. The compound according to Claim 21 wherein n is 0, R is tetrazolyl or -C(O)2-G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 and R2 are independently selected from (i) loweralkyl, (ii) cycloalkyl, (iii) substituted and unsubstituted aryl wherein aryl is phenyl substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy and (iv) substituted or unsubstituted heterocyclic, (v) alkenyl, (vi) heterocyclic (alkyl), (vii) aryloxyalkyl, (viii) aryalkyl, (ix) (N-alkanoyl-N-alkyl)aminoalkyl, and (x) alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N- wherein R11 and R12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, aryl and arylalkyl and R5 is alkylene; or R3 is R4-C(O)-N(R20)-R8- or R6-S(O)2-N(R21)-R10-wherein R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl, R8 and R10 are alkylene and R20 and R21 are loweralkyl; or R3 is R6-S(O)2-R7- or R26-S(O)-R27-wherein R6 is loweralkyl or haloalkyl, R7 is alkylene, R26 is loweralkyl and R27 is alkylene.
29. The compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryoxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(O)-N(R20)-R8- or R6-S(O)2-N(R21)-R10-wherein R8 and R10 are alkylene, R20 and R21 are loweralkyl, R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R6 is loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl.
30. The compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryoxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonyfamidoalkyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl , and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R11 and R12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl and arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl.
31. The compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 is (i) loweralkyl or (ii) alkenyl, (iii) aryalkyl, (iv) aryoxyalkyl, (v) heterocyclic (alkyl), (vi) aryl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl,R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R11 is loweralkyl and R12 is aryl or arylalkyl.
32. The compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 is (i) phenyl or (ii) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R6-S(O)2-N(R21)-R10- wherein R10 is alkylene, R6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl.
33 The compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl or 1,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy and alkoxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is alkoxycarbonyl or R6-S(O)2-N(R21)-R10- wherein R10 is alkylene, R6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl.
34. The compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl or haloalkyl, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 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 and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R11 and R12 are independently selected from loweralkyl, aryl arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
35. The compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O)2R16 wherein R16 is loweralkyl or haloalkyl, Z is -CH2-, R1 is loweralkyl, alkoxyalkyl or alkenyl, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R11 and R12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
36. The compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 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 and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11) (R12)N- wherein R11 and R12 are independently selected from loweralkyl.
37. The compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 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 and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R11 is loweralkyl and R12 is aryl.
38. The compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl, 1,4- benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R6-S(O)2-N(R21)-R10- wherein R10 is alkylene, R6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R21 is loweralkyl, haloalkyl or alkoxyalkyl.
39. The compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R11 and R12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, and heterocyclic.
40. A compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R11 and R12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R11 and R12 is alkyl
41. A compound selected from the group consisting of trans-trans-2-(4-Methoxphenyl)-4-(1,3-benzodioxol-5-yl)-1-[3-(N-propyl-N-n-pentanesulfonylamino)propyl]-pyrrolidine-3-carboxylic acid;
trans, trans-2-(4-Methoxymethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid;
trans, trans-2-(3,4-Dimethoxyphenyl)-4-(1,3-benzodioxol -5-yl)-1-[2-(N- propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid;
trans, trans-2-(3,4-Dimethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-( 4-Propoxyphenyl)-4-(1,3-benzodioxol-5-yl}-1-[2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-(3,4-Difluorophenyl)-4-(1,3-benzodioxol-5-yl)-1-(((N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans, trans-2-(3,4-Difluorophenyl}-4-(1 ,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid;
trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid;

trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl) 1-(2-(N-propyl-N-(3-chloropropanesulfonyl)amino)ethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-isobutyl-N-(3-chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(4-methylbutanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acrd;
trans, trans-2-(4-Methoxy-3-fluorophenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(n-pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid;
trans,trapns-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl) 1-[2-(N-propyl-N-(2,2,3,3,3-pentafluoropropoxyethanesulfonyl)-amino)ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-(1,4-Benzodioxan-6-yl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(n-pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-isobutyl-N-(pentanesulfonylamino)ethyl)pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-(2-methoxyethyl)-N-(3-chloropropanesulfonyl)amino)-ethyl)pyrrolidine-3-carboxylic acid;
trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-(2-methoxyethyl)-N-(pentanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-((2,2,2-trifluoroethoxyethane)sulfonyl)amino)-ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-(2-methoxyethyl)-N-(butanesuffonylamino)ethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(2-methylpropanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; and trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-isobutyl-N-(butanesulfonylamino))ethyl)pyrrolidine-3-carboxylic acid;
trans, trans-2-(2-Methylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans, trans-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1,3-Dioxo-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1 (N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans, trans-2-(2-(2-Tetrahydro-2H-pyran)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N, N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans, trans-2-(2,2,4-Trimethyl-3-pentenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbony!methyl)-pyrrolidine-3-carboxylic acid;
trans, trans-2-(2,2,-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans, trans-2-(2-(1,3-Dioxo-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[[N-4-heptyl-N-(2-methyl-3-fluorophenyl)]
aminocarbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid trans,trans-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyimethyl)-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans, trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;

(2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid trans, trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans, trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-dimethylpentyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2,-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-pyridyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;

trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
(2R,3R,4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-pentanesutfonylamino)ethyl)-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; and (2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl}aminocarbonylmethyl)pyrrolidine-3-carboxylic acid;
or a pharmaceutically acceptable salt thereof.
42: A compound of the formula:
wherein n is 0 or 1;
m is 0 to 6;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(O)(OH)E where E is hydrogen, loweralKy or aryalkyl, (d) -CN, (e) -C(O)NHR17 where R17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (I) -C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(O)2NHC(O)R16, , or R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-aikyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (R aa)(R bb)N-R cc- wherein R aa is aryl or arylalkyl, R bb is hydrogen or alkanoyl and R cc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen; or a salt thereof.
43. The compound of Claim 42 wherein m is zero or 1;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)-isomer thereof.
44. The compound of Claim 42 wherein n and m are both 0;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group;
and R1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoafkyl, or (xiii) alkysulfonylamidoalkyl, and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof.
45. The compound according to Claim 42 of the formula:
wherein n is 0 or 1;
m is 0 to 6;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR17 where R17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (I) -C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(O)2NHC(O)R16, R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (R aa)(R bb) N-R cc- wherein R aa is aryl or arylalkyl, R bb is hydrogen or alkanoyl and R cc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen;
or a salt thereof.
46. The compound according to Claim 45 wherein m is zero or 1;

W is -CO2-G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)-isomer thereof.
47. The compound according to Claim 45 wherein n and. m are both 0;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group;
and R1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl, and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof.
48. The substantially pure compound (+)-trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxo-5-lyl)pyrrolidine-3-carboxylic acid; or a salt or ester thereof.
49. The substantially pure compound (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; or a salt or ester thereof.
50. A compound of the formula wherein n is 0 or 1;
m is 0 to 6;
R5b is alkylene;
Q is a leaving group;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR17 where R17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (I) -C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(O)2NHC(O)R16, R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (R aa)(R bb)N-R cc- wherein R aa is aryl or arylalkyl, R bb is hydrogen or alkanoyl and R cc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen;
or a salt thereof.
51. The compound according to Claim 50 wherein m is zero or 1;
R5b is alkylene;
Q is a leaving group; and W is -CO2-G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)-isomer thereof.
52. The compound according to Claim 50 wherein n and m are both 0;
R5b is alkylene;
Q is a leaving group;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group;
and R1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methyl phenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl; or the substantially pure (+)- or (-)-isomer thereof.
53. The compound according to Claim 50 of the formula wherein n is 0 or 1;
m is O to 6;
R5b is alkylene;
Q is a leaving group;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR17 where R17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (I) -C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(O)2NHC(O)R16, R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloaikoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkyiaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (R aa)(R bb)N-R cc- wherein R aa is aryl or arylalkyl, R bb is hydrogen or alkanoyl and R cc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen; or a salt thereof.
54. The compound according to Claim 53 wherein m is zero or 1;
R5b is alkylene; Q is a leaving group; W is -CO2-G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)-isomer thereof.
55. The compound according to Claim 53 wherein n and m are both 0; R5b is alkylene; Q is a leaving group;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group;
and R1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, B-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl; or the substantially pure (+)- or (-)-isomer thereof.
56. A compound of the formula wherein n is 0 or 1; m is 0 to 6; R5b is alkylene;
R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR17 where R17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (I) -C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(O)2NHC(O)R16, R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (R aa)(R bb)N-R cc- wherein R aa is aryl or arylalkyl, R bb is hydrogen or alkanoyl and R cc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen;
or a salt thereof.
57. The compound according to Claim 56 wherein m is zero or 1;
R5b is alkylene;
R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; and W is -CO2-G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)-isomer thereof.
58. The compound according to Claim 56 wherein n and m are both 0;
R5b is alkylene;
R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
W is -CO2-G wherein G is hydrogen or a carboxy protecting group;
and R1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl; (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-aikyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl, and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof.
59. The compound according to Claim 56 of the formula wherein n is 0 or 1; m is 0 to 6; R5b is alkylene; R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR17 where R17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (I) -C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(O)2NHC(O)R16, R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (R aa)(R bb)N-R cc wherein R aa is aryl or arylalkyl, R bb is hydrogen or alkanoyl and R cc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen; or a salt thereof.
60. The compound according to Claim 59 wherein m is zero or 1;
R5b is alkylene;
R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; and W is -CO2-G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)-isomer thereof.
61. The compound according to Claim 58 wherein n and m are both 0; R5b is alkylene; R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
W is -CO2-G
wherein G is hydrogen or a carboxy protecting group; and R1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl, and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof.
62. A pharmaceutical composition for antagonizing the action of endothelin comprising a therapeutically effective amount of the compound of Claim 1 and a pharmaceutically acceptable carrier.
63. A pharmaceutical composition for antagonizing the action of endothelin comprising a therapeutically effective amount of the compound of Claim 21 and a pharmaceutically acceptable carrier.
64. A pharmaceutical composition for antagonizing the action of endothelia comprising a therapeutically effective amount of (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N, N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid and a pharmaceutically acceptable carrier.
65. A pharmaceutical composition for antagonizing the action of endothelin comprising a therapeutically effective amount of (2S,3R,4S)-2-3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-pentanesulfonyl)ethyl)-pyrrolidine-3-carboxylic acid and a pharmaceutically acceptable carrier.
66. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
67. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 21.
68. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically affective amount of (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid.
69. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically affective amount of (2S,3R,4S)-2-3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-pentanesulfonyl)ethyl)-pyrrolidine-3-carboxylic acid.
70. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfusion injury, angina, pulmonary hypertension, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
71. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxicity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.
72. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfusion injury, angina, pulmonary hypertension, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 21.
73. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfursion injury, angina, pulmonary hypertension, prostatic hyperplasia, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid.
74. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfursion injury, angina, pulmonary hypertension, prostatic hyperplasia, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of (2S,3R,4S)-2-3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-pentanesulfonyl)ethyl)-pyrrolidine-3-carboxylic acid.
75. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxicity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 21.
76. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxocity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid.
77. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxocity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of (2S,3R,4S)-2-3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-pentanesulfonyl)ethyl)-pyrrolidine-3-carboxylic acid.
78. A method for treating treating hypertension, congestive heart failure, restenosis following arterial injury, cerebral or myocardial ischemia or atherosclerosis 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 agents.
79. A method for treating treating hypertension, congestive heart failure, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 21 in combination with one or more cardiovascular agents.
80. A method for treating treating hypertension, congestive heart failure, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid in combination with one or more cardiovascular agents.
81. A process for the preparation of a compound of the formula:

wherein E is a carboxy-protecting group and R1 and R2 are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonytalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic and (heterocyclic)alkyl; or a salt thereof, comprising a) catalytic hydrogenation of a compound of the formula:

wherein E, R1 and R2 are defined as above and b) catalytic hydrogenation of the product of step a) in the presence of an acid or a mixture of acids.
82. The process of Claim 71 wherein E is loweralkyl, R1 is aryl and R2 is heterocyclic.
83. The process of Claim 71 wherein the hydrogenation catalyst is Raney nickel and the acid is a mixture of acetic acid and trifluoroacetic acid.
84. The process of Claim 71 wherein E is loweralkyl, R1 is 4-methoxyphenyl and R2 is 1,3-benzodioxol-5-yl.
85. A process for the preparation of a compound of the formula:

wherein E is a carboxy-protecting group and R1 and R2 are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic and (heterocyclic)alkyl; or a salt thereof, comprising a) catalytic hydrogenation of a compound of the formula:

wherein E, R1 and R2 are defined as above, b) catalytic hydrogenation of the product of step a) in the presence of an acid or a mixture of acids, and c) epimerization of the product of step b) with a base.
86. The process of Claim 75 wherein E is loweralkyl, R1 is aryl and R2 is heterocyclic.
87. The process of Claim 75 wherein the hydrogenation catalyst is Raney nickel and the acid is a mixture of acetic acid and trifluoroacetic acid.
88. The process of Claim 75 wherein E is loweralkyl, R1 is 4-methoxyphenyl and R2 is 1,3-benzodioxol-5-yl.
89. A process for the preparation of a compound of the formula:

wherein E is a carboxy-protecting group, R1 and R2 are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkyiaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic and (heterocyclic)alkyl and R3 is R4-C(O)-R5-wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R11 and R12 are independently selected from (1) loweralkyl, (2)haloalkyl, (3)alkoxyalkyl, (4)haloalkoxyalkyl, (5) alkenyl, (6) alkynyl, (7) cycloalkyl, (8) cycloalkylalkyl, (9) aryl, (10) heterocyclic, (11) arylalkyl and (12) (heterocyclic)alkyl;
(13) hydroxyalkyl, (14) alkoxy, (15) aminoalkyl, and (16) trialkylaminoalkyl, or a salt thereof, comprising a) catalytic hydrogenation of a compound of the formula:

wherein E, R1 and R2 are defined as above, b) catalytic hydrogenation of the product of step a) in the presence of an acid or a mixture of acids, c) epimerization of the product of step b) with a base and d) alkyation of the product of step c) with a compound of the formula R3-X
wherein X
is a leaving group and R3 is defined as above.
90. The process of Claim 79 wherein E is loweralkyl, R1 is aryl, R2 is heterocyclic and R3 is -CH2C(O)NR11R12 wherein R11 and R12 are independently selected from the group consisting of loweralkyl.
91. The process of Claim 79 wherein the hydrogenation catalyst is Raney nickel and the acid is a mixture of acetic acid and trifluoroacetic acid.
92. The process of Claim 79 wherein E is loweralkyl, R1 is 4-methoxyphenyl, R2 is 1,3-benzodioxol-5-yl, R3 is -CH2C(O)N(n-Bu)2 and X is a halogen or sulfonate leaving group.
93. A process for the preparation of the substantially pure (+)-trans,trans optical isomer of the compound of the formula:

wherein E is loweralkyl, R1 is 4-rnethoxyphenyl and R2 is 1,3-benzodioxol-5-yl, or a salt thereof, comprising reacting a mixture of the (+) and (-) enantiomers of the compound of the formula:

wherein E is loweralkyl, R1 is 4-methoxyphenyl and R2 is 1,3-benzodioxol-5-yl with S-(+)- mandelic acid and separating the mandelate salt of the (+)-trans,trans optical isomer.
94. A compound of the formula:

wherein Z is -C(R19)(R19)- or -C(O)- wherein R18 and R19 are independently selected from hydrogen and loweralkyl;
n is 0 or 1;
R is -(CH2)m-W 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, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR17 wherein R17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (l) -C(O)NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl, aryl or dialkylamino, (m) -S(O)2NHC(O)R16 wherein R16 is defined as above;

R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (R aa)(R bb)N-R cc wherein R aa is aryl or arylalkyl, R bb is hydrogen or alkanoyl and R cc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen;
R3 is (a)R4-C(O)-R5-, R4-C(O)-R5-N(R6)-, wherein R5 is (i) a covalent band, (ii) alkylene, (iii) alkenylene, (iv) -N(R20)-R8- or -R8a-N(R20)-R8- wherein R8 and R8a are independently selected from the group consisting of alkylene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl or cycloalkylalkyl or (v) -O-R9- or -R9a-O-R9- wherein R9 and R9a are independently selected from alkylene;
R4 and R6 are (R11)(R12)N- wherein R11 and R12 are independently selected from (1) hydrogen, (2) loweralkyl, (3) haloalkyl, (4) alkoxyalkyl, (5) haloalkoxyalkyl, (6) alkenyl, (7) alkynyl, (8) cycloalkyl, (9) cycloalkylalkyl, (10) aryl, (11) heterocyclic, (12) arylalkyl, (13) (heterocyclic)alkyl, (14) hydroxyalkyl, (15) alkoxy, (16) aminoalkyl, (17) trialkylaminoalkyl, (18) alkylaminoalkyl, (19) dialkylaminoalkyl, (20) carboxyalkyl, (21) (cycloalkyl)aminoalkyl, (22) (cycloalkyl)alkylaminoalkyl, (23) (heterocyclic)aminoalkyl, and (24) (heterocyclic)aminoalkyl, with the proviso that at least one of R11 and R12 is selected from heterocyclic, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, (cycloalkyl)aminoalkyl, (cycloalkyl)alkylaminoalkyl, (heterocyclic)aminoalkyl, and (heterocyclic)alkylaminoalkyl;
or a pharmaceutically acceptable salt thereof.
95. A compound selected from the group consisting of:

wherein R is selected from the group consisting of:

96. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfusion injury, angina, pulmonary hypertension, migraine, cerebral or myocardial ischemia, atherosclerosis, coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxicity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising a therapeutically effective amount of a compound of claim 94, wherein said compound has an attached charged functionality which reduces the degree of plasma protein binding of the compound.
97. A method of improving the in vivo activity of compounds by reducing the amount of compound bound to protein by attaching a charged functionality to the compound.
98. A method of claim 97 wherein the charged functionality carries a positive charge at physiological pH.
CA002297894A 1997-08-04 1998-07-27 Pyrrolidine-3-carboxylic acid derivatives and their use as endothelin antagonists Abandoned CA2297894A1 (en)

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