AU781355B2 - Novel benzo-1,3-dioxolyl-and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists - Google Patents

Description

S&F Ref: 425370D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name and Address of Applicant: Actual Inventor(s): Address for Service: Abbott Laboratories CHAD 0377/AP6D-2 100 Abbott Park Road Abbott Park Illinois 60064-3500 United States of America Martin Winn, Steven A. Boyd, Charles W. Hutchins, Hwan-Soo Jae, Andrew Tasker, Thomas W. von Geldern, Jeffrey A. Kester, Bryan K. Sorensen, Bruce G.

Szczepankiewicz, Kenneth J. Henry Jr., Gang Liu, Steven J. Wittenberger and Steven A. King Spruson Ferguson St Martins Tower,Level 31 Market Street Sydney NSW 2000 Novel Benzo-1,3-dioxolyl- and Benzofuranyl Substituted Pyrrolidine Derivatives as Endothelin Antagonists Invention Title: The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c NOVEL BENZO-13-DIOXOLYL- AND BENZOFURANYL SUBSTITUTED PYRROLIDINE DERIVATIVES AS ENDOTHELIN ANTAGONISTS Technical Field The present invention relates to compounds which are endothelin 015 antagonists, processes for making such compounds, synthetic intermediates employed in these processes and methods and compositions for antagonizing endothelin.

Background of the Invention Endothelin (ET) is a 21 amino acid peptide that is produced by endothelial cells. ET is produced by enzymatic cleavage of a Trp-Val bond in the precursor peptide big endothelin (Big ET). This cleavage is caused by an endothelin converting enzyme (ECE). Endothelin has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility in vitro, stimulate mitogenesis in vascular smooth muscle cells in vitro, contract non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in vitro, increase airway resistance in vivo, induce formation of gastric ulcers, stimulate release of atrial natriuretic factor in vitro and in vivo, increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release of renin in vitro and stimulate release of gonadotropins in vitro.

It has been shown that vasoconstriction is caused by binding of endothelin to its receptors on vascular smooth muscle (Nature 332 411 (1988), FEBS Letters 231 440 (1988) and Biochem. Biophys. Res.

Commun. 154 868 (1988)). An agent which suppresses endothelin production or an agent which binds to endothelin or which inhibits the -2binding of endothelin to an endothelin receptor will produce beneficial effects in a variety of therapeutic areas. In fact, an anti-endothelin 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-endothelin antibody attenuated the nephrotoxic 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 365: 759-761 (1993)) report that Ro 46- 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 after SAH has also been recently reported (S.ltoh, 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 ET/ET 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. Pharmacol. 1996, 309, 261-269), have shown that an endothelin receptor antagonist reduced injury in a rat model of colitis. Aktan et al (Transplant Int 1996, 9, 201-207) have demonstrated that a similar agent prevents ischemia-repurfusion injury in kidney transplantation. Similar studies have suggested the use of endothelin antagonists in the treatment of angina, pulmonary hypertension, raynaud's disease, and migraine. (Ferro and Webb, Drugs 1996, 51,12-27).

Abnormal levels of endothelin or endothelin 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 role 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 -3proteins, 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.

Disclosure of the Invention In accordance with the present invention there are compounds of the formula

R

2 ZN ,R 3

(CH

2 )n R

S.R

1

(I)

wherein Z is -C(R18)(R19)- or wherein R 18 and R19 are independently selected from hydrogen and loweralkyl; n is 0 or 1; i: R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is -C(0) 2 -G wherein G is hydrogen or a carboxy protecting group, -P0 3

H

2 -P(0)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl, -CN, -C(O)NHR1 7 wherein R 17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(0)NHS(0)2Ri6 wherein Re1 is loweralkyl, haloalkyl, aryl or dialkylamino, -S(0) 2 NHC(0)R 6 l wherein R 16 is defined as above, -4- HO 0 0 (HO 0

OH

N: H

N**

0,

H*

JC>-CF3 Mt H ,or

NHSO

2

CF

3 Ri and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hyd roxyalkyl, 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 (Raa)(Rbb)N-Rcc- wherein Raa is ary or a rylalkyl, Rbb is hydrogen or alkanoyl and RC is alkylene, with the proviso that one or both of R, and

R

2 is other than hydrogen;

R

3 is R4-C(O)-R5- Rv-Rsa- R6-S(O) 2

-R

7 or

R

26

-S(O)-R

27 wherein R 5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 2 o)-R 8 or -R 8 a-N(R 2 0

)-R

8 wherein R 8 and R8a are independently selected from the group consisting of alkylene and alkenylene and R 20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyl or -O-Rq- or -R 9 a-O-R 9 wherein Rg and R9a are independently selected from alkylene; is alkylene or (ii) alkenylene;

R

7 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 2 1)-Rio- or -Rj 0 8

-N(R

2 19-R 1 0 wherein R1o and Rioa are independently selected from the group consisting of alkylene and alkenylene and R 21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl;

R

4 and R 6 are independently selected from the group consisting of (Rll)(Rl 2 wherein R1 1 and R 12 are independently selected from hydrogen, loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, (11) heterocyclic, -6- (12) aryl 4 (13) (het (14) hydr alko: (16) amin (17) triall alkyl, erocyclic)alkyl, oxyalkyl, Ky, oalkyl, and (ylaminoalkyl, (i i) loweralkyl, (iii) alkenyl, (iv) alkynyl, cycloalkyl, (v i) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (i x) heterocyclic, (heterocyclic)alkyl, (x i) alkoxyalkyl, (xii) hydroxyalkyl, (xiii) haloalkyl, (xiv) haloalkenyl, (xv) haloalkoxyalkyl, (xv i) haloalkoxy, (xv ii) alkoxyhaloalkyl, (xviii) alkylamninoalkyl, (xix) dialkylaminoalkyl, (xx) alkoxy, and

H

N2Nz N

R

7 a (Xxi) 0 wherein z is 0-5 and R7a is alkylene;

R

26 is loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, alkynyl, -7- (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxysubstituted haloalkyl; and

R

2 7 is alkylene or alkenylene;

R

22

-O-C(O)-R

23 wherein R 22 is a carboxy protecting group or heterocyclic and R 23 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 24

)-R

25 wherein R 25 is alkylene and R 2 4 is hydrogen or loweralkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclic,: (heterocyclic)alkyl, (in) alkoxyalkyl, alkoxyalkoxyalkyl, or R13-C(O)-CH(Rl 4 wherein R 13 is amino, alkylamino or dialkylamino and R 14 is aryl or R15-C(O)- wherein R 1 5 is amino, alkylamino or dialkylamino; or a pharmaceutically acceptable salt thereof.

A preferred embodiment of the invention is a compound of formida

(II)

(CH

2 )n

R

(11) -8wherein the substituents -R 2 -R and -R1 exist in a trans,trans relationship and Z, n, R, Ri, R 2 and R 3 are as defined above.

Another preferred embodiment of the invention is a compound of formula or (II) wherein n is 0 and Z is -CH 2 Another preferred embodiment of the invention is a compound of formula or (II) wherein n is 1 and Z is -CH 2 0o Another preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 and R 3 is R4-C(O)-Rs-

R

6 -S(0) 2

-R

7 or R 2 6

-S(O)-R

2 7 wherein R 4

R

5

R

6

R

7

R

2 6 and R 2 7 are as defined above. Another preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 and R 3 is alkoxyalkyl or alkoxyalkoxyalkyl.

A more preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 and R 3 is R 4

-C(O)-R

5 wherein R 4 is (R11)(R1 2 as defined above and R5 is alkylene or R 3 is 2 -R7- or R 2 6

-S(O)-R

2 7 wherein R 7 is alkylene, R 2 7 is alkylene and R6 and R 26 are defined as above. Another more preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 and R 3 is R4-C(O)-N(R 2 0

)-R

8 or R6-S(0) 2

-N(R

2 1 )-R10- wherein R 8 and Rio are alkylene and R 4 R6, R 2 0 and R 2 1 are defined as above.

An even more preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, R is tetrazolyl or -C(0)2-G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is -C(O)-NHS(0) 2

R

1 6 wherein R 1 6 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 and R 2 are independently selected from loweralkyl, (ii) cycloalkyl, 9 (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, alkenyl, (vi) heterocyclic (alkyl), (vii) arylalkyl, (viii) aryloxyalkyl, (ix) (N-alkanoyl-N-alkyl)aminoalkyl and (x) alkylsulfonylamidoalkyl, and R 3 is R 4 5 wherein R 4 is

(R

1 ,)(Rl 2 wherein R 11 and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl, and R 5 is alkylene; or R 3 is R4-C(O)-N(R 20

)-R

8 or

R

6

-S(O)

2

-N(R

21 )-Rl 0 wherein R 4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R 6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl, R 8 and Rio are alkylene p and R 20 and R 21 are loweralkyl; or R 3 is R6-S(O) 2

-R

7 or R 26

-S(O)-R

27 wherein R 6 is loweralkyl or haloalkyl, R 7 is alkylene, R 26 is -loweralkyl and R 27 is alkylene.

A yet more preferred embodiment of the invention is a compound of formula or (11) 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) 2 Rl 6 wherein

R

16 is loweralkyl, haloalkyl or aryl, Z is -OH 2

R

1 is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 0 0% 3-f luorophenyl, 4-ethoxyphenyl, 4-ethyiphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-Nalkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R 2 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 and

R

3 is R 4

-C(O)-N(R

2 0)-R8- or R 6

-S(O)

2

-N(R

2 1 )-Rjo- wherein R 8 and R1o are alkylene, R 20 and R21 are loweralkyl, R 4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R 6 is loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl.

Another yet more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or

NHS(O)

2 Rl 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2

R

1 is loweralkyl, (ii) alkenyl, VeS (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl, 0S (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, *see 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4methoxyphenyl, 0.0.

3-f luoro-4-ethoxyphenyl, 2-f luorophenyl, 4-methoxymethoxyphenyl,SIO 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-N- 0:.

alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihyd robenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and

R

3 is R 4

-C(O)-R

5 wherein R 5 is alkylene and R 4 is (Rll)(Rl 2

)N-

wherein R 11 and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl.

Another yet more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or

NHS(O)

2

R

1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2

R

1 is loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, arylalkyl, (vi) aryl, (vii) (N-alkanoyl-N- 11 alkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl,

R

2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy- 1,3-benzodioxolyl, 1 ,4benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofumnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or dif luorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is R 4

-C(O)-R

5 wherein R 5 is alkylene and R 4 is (R 1 i)(R 12 wherein R 1 1 is loweralkyl and R 12 is aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.

Another yet more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or

NHS(O)

2

R

1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2

R

1 is loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, arylalkyl, (vi) (N-alkanoyl-N-alkyl)aminoalkyl, or (vii) alkylsulfonylamidoalkyl,(vii) phenyl, or (ix) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3fluorophenyl, 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, R 2 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 R 3 is

R

6

-S(O)

2

-N(R

2 1 )-Rl 0 wherein R 10 is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R 21 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl.

Another yet more preferred embodiment of the invention is a compound of formula or (HI) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or

NHS(O)

2

R

16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2

R

1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, -12- 3-fluoro-4-ethoxyphenyl, 4-rnethoxymethoxyphenyl, 1 ,3-benzodioxolyi or 1 ,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy and alkoxyalkoxy, (ii) loweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-Nalkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl,or (ix) phenyl, R 2 iS substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy- 1,3-benzodioxolyl, 1,4-be nzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is alkoxycarbonyl or R6-S(O)2-N(R 2 1)-Rlo- wherein R1o is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R 2 1 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl.

Another yet more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or NHS(0 2

R

16 wherein R 1 is loweralkyl or haloalkyl, Z is -CH 2

R

1 is loweralkyl,alkenyl, heterocyclic (alikyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl,, or alkylsulfonylamidoalkyl, and R 3 is- R4-C(0)-Rs5- wherein R 5 is alkylene and R4 is (Rll)(Ri 2 wherein R 11 and R 1 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trial kylami noal kyl, and heterocyclic.

A still more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0) 2 Rl 6 whereinl

R

1 6 is loweralkyl or haloalkyl, Z is -CH 2

R

1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methyiphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hyd roxyphenyl, 4-ethylphenyl, 1,3benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ii) loweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), aryloxyalkyl, -13- (vi) arylalkyl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl,or (ix) phenyl, R 2 is 1,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4methoxyph enyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4

-C(O)-R

5 wherein IRS is alkylene and R1 4 is (Rii)(Ri 2 wherein

R

11 and R 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, tnialkylaminoalkyl, or heterocyclic.

Another still more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or

NHS(O)

2

R

16 wherein R 16 is loweralkyl or haloalkyl, Z is -CH 2

R

1 is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, arylalkyl, (Nalkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, phenyl, or alkoxyalkyl, R 2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and

R

3 is R 4

-C(O)-R

5 wherein R 5 is alkylene and Rl 4 is (Rii)(Ri2)N- wherein R 11 and R 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trial kylamin oalkyl, or heterocycl ic.* A most highly preferred embodiment of the invention is compound of formula or (11) wherein n is 0, Rl is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 R, is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3berizodioxolyl, 1 ,4-benzodioxanyl or di hyd robe nzof uranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1 ,3-benzodioxolyl, 1,4-berizodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4

-C(O)-R

5 wherein R 5 is alkylene and R4 is (Rl )(Ri2)N- wherein

R

1 .j and R 12 are independently selected from loweralkyl.

-14- Another most highly preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 R, is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methyiphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethyiphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3benzodioxolyl, 1 ,4-benzodioxanyl or di hyd robe nzof uranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4

-C(O)-R

5 wherein R, 5 is alkylene and R 4 is (Rll)(Rl 2 wherein

R

11 is loweralkyl and R 12 is aryl. Another most highly preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2

R

1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3fluorophenyl, 2-f luorophenyl, 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, R 2 is substituted or unsubstituted 1,3benzodioxolyl, 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 R 3 is- R6-S(O) 2

-N(R

21 )-Rio- wherein R1o is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R 21 is loweralkyl, haloalkyl or alkoxyalkyl.

Another most highly preferred embodiment of the invention is a compound o1 formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, 7 is -CH 2 R, 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,

R

2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3benzodioxolyl, 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 R 3 is R 4

-C(O)-R

5 wherein R5 is alkylene and R 4 is (R11)(R12)Nwherein R 1 1 is alkyl and R 12 is selected from aryl, aminoalkyl, trialkylaminoalkyl, and heterocyclic.

Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, R is -C(0) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2

R

1 is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (Nalkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R 3 is R4-C(O)-R 5 wherein Rs is alkylene and R 4 is (R1I)(R12)N- wherein R 11 and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, amrninoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R 11 and R 12 is alkyl. Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 and R 3 is R4-C(Q)-R 5 wherein R 4 is (R11)(R1 2 as defined therein and Rs is alkylene.

Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is loweralkyl, and R 3 is R4-C(O)-R 5 wherein R 4 is (Ri1)(R 12 as defined therein and R 5 is alkylene.

Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is alkenyl, and R3 is R 4 wherein R 4 is (R11)(R12)N- as defined therein and

R

5 is alkylene.

-16- Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is heterocyclic (alkyl), and R 3 is R 4 wherein R 4 is (R11)(R 12

)N-

as defined therein and Rs is alkylene.

Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is aryloxyalkyl, and R 3 is R 4 wherein R 4 is (R11)(R 12 as defined therein and R 5 is alkylene.

Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is arylalkyl, and R 3 is R 4 wherein R 4 is (R11)(R 12 as defined therein and Rs is alkylene. Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is aryl, and R 3 is R 4

-C(O)-R

5 wherein R 4 is (R11)(R12)N- as defined therein and

R

5 is alkylene.

Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is alkanoyl-N-alkyl)aminoalkyl, and R 3 is R 4

-C(O)-R

5 wherein R 4 is (R11)(R 12 as defined therein and R 5 is alkylene. Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is alkylsulfonylamidoalkyl, and R 3 is R 4 wherein R 4 is (Rli)(R12)N- as defined therein and R 5 is alkylene.

The present invention also relates to processes for preparing the compounds of formula and (II) and to the synthetic intermediates employed in these processes.

The present invention also relates to a method of antagonizing endothelin in a mammal (preferably, a human) in need of such 17 treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula or (11).

The invention further relates to endothelin antagonizing compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of formula or (11).

According to one embodiment of this invention there is provided use of a compound having formula:

(CH

2 )n

R

RI

wherein is -C(R 18 wherein R 18 and Rig are hydrogen; n isO0; *R is -(CH 2 wherein m is 0 and W is

-C(O)

2 wherein G is hydrogen, 15 I -P0 3

H

2 wherein E is hydrogen, loweralkyl, or arylalkyl, tetrazolyl, -C(O)NHS(O) 2 RI6 wherein R 16 is loweralkyl, haloalkyl, aryl, or dialkylamino, 20 or

-S(O)

2 NHC(O)R16; R, and R 2 are independently selected hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylamninocarbonylalkyl, dial kylamninocarbonyl al kyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, aryl alkoxyalkyl, (N-alkanoyl-Nalkyl)aminoalkyl, alkylsulonylamidoalkyl, heterocyclic, (heterocyclic)alkyl, or (Raa)(Rbb)N-R~n, wherein Ra, is aryl or arylalkyl, Rbb is hydrogen or alkanoyl, and is alkylene; [R:\LIBXXj1O9I6.doc:aak 1 7a

R

3 is loweralkyl, alkenyl, akynyl, cycloalkyl, (e) cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclic,() (heterocyclic)alkyl, alkoxyalkyl, alkoxyalkoxyalkYl, (in) R 4 wherein R4 is loweralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, or (R I 1

I

2 wherein RI, and R 12 are independently selected loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclic, i0 arylalkyl (heterocyclic)alkyl, hydroxyalky, or alkoxy, and R 5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 2 wherein R 8 is alkylene or alkenylene, and R 2 0 is hydrogen, 15i loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycicoalkyl, or cycloalkylalkyl, -R~aN(R2o)-R8-, wherein R8a is alkylene or alkenylene, or (vi) -O-R 9 or -R 9 aO0R 9 wherein R 9 and R 9 a are independently selected 2 alkylne; (n RtR~awherein

R

5 a is alkylene or alkenylene, wherein -:R 6 is (RI j)(R I 2

R

6

-S(O)

2 wherein R 7 is a covalent bond, alkylene, alkenylene,

-N(R

2 j)-Rio-, or -RIOaN(R21)-R10, wherein Rio and Rjca are independently selected alkylene or alkenylene and R21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, or arylalkyl; R26-S(O)-R27-, wherein

R

26 is loweralkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, or alkoxy-substituted haloalkyl, and R 27 is alkylene or alkenylene,

R

22 -O-C(O)-R23- wherein

R

22 is heterocyclic and R 2 3 is a covalent bond, alkylene, alkenylene, or

-N(R

24 wherein R 25 is alkylene and R 24 is hydrogen or loweralkyl, or

R

13 wherein

R

13 is amino, alkylamino, or dialkylamino and R1 4 is aryl or R 15 wherein

R

15 is amino, alkylamino, or dialkylamino, or a [R:\LIBXX10491I6.doc:aak 17b pharmaceutically acceptable salt thereof, for the preparation of a medicament for treatment of bone pain associated with bone cancer.

According to another embodiment of this invention there is provided use of (2R,3R,4S)-2-(4-methoxyphenyl)- 4 -(1,3-benzodioxol-5-yl)- -(N,N-di(nbutyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treatment of bone pain associated with bone cancer.

According to a further embodiment of this invention there is provided use of (2R,3R,4S)-2-(4-methoxyphenyl)- 4 -(1,3-benzodioxol-5-yl)- -(N,N-di(n- 0o butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid hydrochloride for the preparation of a medicament for treatment of bone pain associated with bone cancer.

According to yet a further embodiment of this invention there is provided a compound having formula:

Y

R

Ri R1 s wherein Z is -C(Rs 8 wherein R 18 and RI9 are hydrogen; n is 0; R is -(CH 2 wherein m is 0, W is -C(0) 2 and G is hydrogen;

R

1 is alkyl, alkenyl, or phenyl substituted with one or two independently selected 20 halo or alkoxy substituents; S

X.*

I /Y*

R

2 is 0 wherein X* is and Y* is -CH2- and is substituted with one or two independently selected alkoxy and halo substituents;

R

3 is R 4 wherein Rs is alkylene; and R4 is (Ri 1

)(R

12 wherein R 11 is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or trialkylaminoalkyl and R 1 2 is alkyl, haloalkyl, haloalkoxyalkyl, or alkoxy; or a pharmaceutically acceptable salt thereof.

According to yet another embodiment of this invention there is provided the compound trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)- -((N-butyl-N-(4- [R:\LIBXX104916.doc:aak 1 7c dimethylaminobutyl)amino)carboflylmethyl)pyTrolidine- 3 -carboxylic acid, or a pharmaceutically acceptable salt thereof.

According to another embodiment of this invention there is provided the compound trans, trans-2-(2,2-dimethylpentyl)- 4 1,3 -benzodioxol-5-yl)- I -(N,N-di(nbutyl)aminocarbonylmethyl)pyrrolidine- 3 -carboxylic acid, or a pharmaceutically acceptable salt thereof.

According to a further embodiment of this invention there is provided a method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mamnmal. a therapeutically effective amount of a compound having formula:

(CH

2 )n

R

::R1 wherein Z is -C(R 18 wherein R 18 and Rig are hydrogen; n isO0; R is -CH 2 )mW, wherein mn is 0 and W is

-C(O)

2 wherein G is hydrogen, -P0 3

H

2 wherein E is hydrogen, loweralkyl, or arylalkyl, tetrazolyl, 20 -C(O)NHS(O) 2 R16 wherein R 16 is loweralkyl, haloalkyl, aryl, or dialkylamino, or

-S(O)

2 NHC(O)R16; R, and R 2 are independently selected hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarboflylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-Nalkyl) amino al kyl, alkylsulonyl amidoalkyl, heterocycl ic, (heterocyclic)alkyl, [R:\LIBxX1O491I6.doc:aak 1 7d wherein is aryl or arylalkyl, Rbb is hydrogen or alkanoyl, and is alkylene;

R

3 is loweralkyl, alkenyl, akynyl, cycloalkyl, cycloalkylalkyl, (f) aryl, arylalkyl, aryloxyalkyl, heterocyclic, (heterocyclic)alkyl, (k) s alkoxyalkyl, alkoxyalkoxyalkyl, (in) R 4 wherein

R

4 is loweralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkylaminoalkyl, dialkylamninoalkyl, alkoxy, or (RI 1

)(R

12 wherein

R

11 and R 12 are independently selected loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclic, arylalkyl (heterocyclic)alkyl, hydroxyalky, or alkoxy, and R 5 is a covalent bond, (ii) alkylene, 15i (iii) alkenylene, (iv) -N(R 2 o-R8-, wherein R 8 is alkylene or alkenylene, and R 20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl, or cycloalkylalkyl, (V -R 8 a-N(R 20 wherein R 8 a is alkylene or alkenylene, 20 or

-O-R

9 or -R9a-O-R9-, wherein R 9 and R9a are independently selected alkylene; 9:n) Pt4R 5 a- wherein R 5 a is alkylene or alkenylene, R4-C(O-R5-N(R6)-, wherein

R

6 is (R 1 1

)(R

12

R

6

-S(O)

2 wherein R 7 is a covalent bond, alkylene, alkenylene,

-N(R

21 or -RIOaN(R21>-R10, wherein RIO and Rica are independently selected alkylene or alkenylene and R 21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, or arylalkyl;

R

26 wherein R 26 is loweralkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, or alkoxy-substituted haloalkyl, and R 27 is alkylene or alkenylene,

R

22 -O-C(O)-R23- wherein R 22 is heterocyclic and R 23 is a covalent bond, alkylene, alkenylene, or -N(R 24 wherein R 25 is alkylene and R 24 is hydrogen or loweralkyl, or j R:\LIBXXj491 6.doc:aak 17e

RI

3 wherein R 13 is amino, alkylamino, or dialkylamino and Ri 4 is aryl or Ris-C(O)-, wherein Ris is amino, alkylamino, or dialkylamino, or a pharmaceutically acceptable salt thereof.

According to another embodiment of this invention there is provided a method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of (2R,3R,4S)-2-(4-methoxyphenyl)- 4 -(1,3-benzodioxol-5-yl)- -(N,N-di(nbutyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.

According to a further embodiment of this invention there is provided a method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of (2R,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)- I-(N,N-di(nbutyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid hydrochloride.

S: 15 According to a further embodiment of this invention there is provided a method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound having formula: R2 Z R3

(CH

2 )n

R

R

1 wherein Z is -C(R 1 i)(RI9)- wherein R 18 and RI9 are hydrogen; n is 0; R is -(CH 2 wherein m is 0, W is -C(0) 2 and G is hydrogen; R, is alkyl, alkenyl, or phenyl substituted with one or two independently selected halo or alkoxy substituents; x*

SY*

R

2 is wherein X* is and Y* is -CH 2 and is substituted with one or two independently selected alkoxy and halo substituents;

R

3 is R 4 wherein Rs is alkylene; and [R:\LIBXX10491 6.doc:aak 17f

R

4 is (RjI)(R 1 2 wherein R 1 1 is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or trialkylaminoalkyl and Ri 2 is alkyl, haloalkyl, haloalkoxyalkyl, or alkoxy; or a pharmaceutically acceptable salt thereof.

According to another embodiment of this invention there is provided a method of s treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of trans,trans-2-(4-methoxyphenyl)- 4 -(1,3-benzodioxol-5-yl)- I-((N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.

According to a further embodiment of this invention there is provided a method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of trans, S**trans-2-(2,2-dimethylpentyl)-4-(1,3-benzodioxol-5-yl)- -(N,N-di(nbutyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically S: 15 acceptable salt thereof.

.i According to another embodiment of this invention there is provided a method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a S pharmaceutical composition comprising compound having formula:

S

R 2 Z R3 c(CH 2 )n

.R

Ri wherein Z is -C(R 1 8 wherein Ri 8 and R 1 9 are hydrogen; n is O; R is -(CH 2 wherein m is 0 and W is -C(0) 2 wherein G is hydrogen, -P0 3

H

2 wherein E is hydrogen, loweralkyl, or arylalkyl, tetrazolyl, -C(O)NHS(0)2RI6 wherein Ri 6 is loweralkyl, haloalkyl, aryl, or dialkylamino, fR:\LIBXX104916 .doc:aak 1 7g or

-S(O)

2 NHC(O)RI6; RI and R 2 are independently selected hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarboflylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkYl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, arninocarbonylalkyl, alkylaminocarbonYlalkYl, dialkylaminocarboflYlalkYl, aminocarbonylalkenYl, alkylaminocarbonylalkell dialkylaminocarbonYlalkenYl, hydroxyalkeflyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-Nalkyl)aminoalkyl, alkylsulonylamidoalkyl, heterocyclic, (heterocyclic)alkyl, or(Raj)(Rbb)N-Rcc,, wherein Ra, is aryl or arylalkyl, Rbb is hydrogen or alkanoyl, and Rc is alkylene;

R

3 is loweralkyl, alkenyl, akynyl, cycloalkyl, cycloalkylalkyl, (f) aryl, arylalkyl, aryloxyalkyl, heterocyclic, (heterocyclic)alkyl, (k) C alkoxyalkyl, alkoxyalkoxyalkyl, (in) Rt-C(O)-R5-, wherein

R

4 is loweralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkylamninoalkyl, dialkylaminoalkyl, C C Calkoxy, or (RI 1 2 wherein o 20R 11 and R 12 are independently selected loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclic, arylalkyl (heterocyclic)alkyl, hydroxyalky, or alkoxy, and R 5 is C' C' C(i) a covalent bond, C' C.(ii) alkylene, (iii) alkenylene, (iv) -N(R 20 wherein R 8 is alkylene or alkenylene, and R 2 0 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl, or cycloalkylalkyl., -R8.N(R 2 o)R8-, wherein R 8 a is alkylene or alkenylene, or

-O-R

9 or -R9aO0R9-, wherein

R

9 and R9a are independently selected alkylene;

R

4 wherein R~a is alkylene or alkenylene,

R

4 wherein

R

6 is (RI 1

)(R

12

R

6

-S(O)

2 -R7-, [R:\LIBXX1O491I6.doc~aak 17h wherein R 7 is a covalent bond, alkylene, alkenylene, -N(R 21 or -Rioa-N(R21)- RIO-, wherein Rio and Rioa are independently selected alkylene or alkenylene and R 21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, or arylalkyl;

R

26 wherein

R

26 is loweralkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, or alkoxy-substituted haloalkyl, and R 27 is alkylene or alkenylene,

R

22 -O-C(O)-R23- wherein

R

2 2 is heterocyclic and R 2 3 is a covalent bond, alkylene, alkenylene, or -N(R24)-R25-, to wherein R 2 5 is alkylene and R 24 is hydrogen or loweralkyl, or

R

1 3 wherein Ri3 is amino, alkylamino, or dialkylamino and RI 4 is aryl or Ri 5 wherein Ri5 is amino, alkylamino, or dialkylamino, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable 5s carrier.

According to a further embodiment of this invention there is provided a method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of pharmaceutical composition comprising (2R,3R,4S)-2-(4-methoxyphenyl)- 4 20 benzodioxol- 5 -yl)-l-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

1. According to another embodiment of this invention there is provided a method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising (2R,3R,4S)-2-(4-methoxyphenyl)- 4 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid hydrochloride and a pharmaceutically acceptable carrier.

According to another embodiment of this invention there is provided a method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising a compound having formula: [R:\LIBXXjO49I6.doc:aak R2 Z R3

(CH

2 )n

R

wherein Z is -C(Rs 8 wherein R 18 and RI9 are hydrogen; n is 0; R is -(CH 2 wherein m is 0, W is -C(0) 2 and G is hydrogen; RI is alkyl, alkenyl, or phenyl substituted with one or two independently selected halo or alkoxy substituents; 0

Y*

o1 R 2 is wherein X* is and Y* is -CH 2 and is substituted with one or two independently selected alkoxy and halo substituents;

R

3 is R4-C(0)-R5-, wherein Rs is alkylene; and

R

4 is (RI)(RI2)N-, wherein Ril is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or trialkylaminoalkyl and R,2 is alkyl, haloalkyl, haloalkoxyalkyl, or alkoxy; s5 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

According to another embodiment of this invention there is provided a method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising trans,trans-2-(4-methoxyphenyl)-4-(1,3- -((N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

According to another embodiment of this invention there is provided a method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a pharmaceutically acceptable composition comprising trans, trans-2-(2,2-dimethylpentyl)- 4-(1,3-benzodioxol-5-yl)-l-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3fR:\LIBXXj049 6.doc:aak I 7j carboxylic acid, or a pharmaceutically acceptable salt thereof;, and a pharmaceutically acceptable carrier.

According to another embodiment of this invention there is provided a compound having formula: R2 z"N "-R3

(CH

2 )n

RT

wherein Z is -C(R 18 wherein R 18 and Rig are hydrogen; n isO0; R is -CH 2 )ngW, wherein m is 0 and W is

-C(O)

2 wherein G is hydrogen, 0: 0% -P0 3

H

2 wherein E is hydrogen, loweralkyl, or arylalkyl, tetrazolyl,

-C(O)NHS(O)

2 R[6 wherein R 16 is loweralkyl, haloalkyl, aryl, or dialkylamino, or

-S(O)

2

NH-C(O)R

1 6; and R 2 are independently selected hydrogen, loweralkyl, alkenyl, alkynl :*alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, 0: 20 alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylamninocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-Nalkyl)aminoalkyl, alkylsulonylamidoalkyl, heterocyclic, (heterocyclic)alkyl, or(R.)(Rbb)N-RcC-, wherein Ra, is aryl or arylalkyl, Rbb is hydrogen or alkanoyl, and R, is alkylene;

R

3 is loweralkyl, alkenyl, akynyl, cycloalkyl, cycloalkylalkyl, (f) aryl, arylalkyl, aryloxyalkyl, heterocyclic, (heterocyclic)alkyl, (k) alkoxyalkyl, alkoxyalkoxyalkyl, (in) R 4

-C(O)-R

5 wherein

R

4 is loweralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, IR:\LIBXXIO49I 6-doc:aak 17k haloalkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, or (RI 1

)(R

12 wherein RI, and R 12 are independently selected loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclic, arylalkyl (heterocyclic)alkyl, hydroxyalky, or alkoxy, and R 5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 2 o)-R 8 wherein R 8 is alkylene or alkenylene, and

R

20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl, or cycloalkylalkyl,

-R

8 aN(R 20

)R

8 wherein Rga is alkylene or alkenylene, S or

-O-R

9 or -R 9 a0R 9 wherein R 9 and R 9 a are independently selected 1 5 alkylene;

R

4

-R

5 wherein R 5 a is alkylene or alkenylene,

R

1

-C(O)-R

5

-N(R

6 wherein

PR

6 is (R 1

I

2

R

6

-S(O)

2

-R

7 :wherein

R

7 is a covalent bond, alkylene, alkenylene, -N(R 2 or -RiOa-N(R 2 *S 20 Rio-, wherein Rio and Rio,, are independently selected alkylene or alkenylene and R.

2 1 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, or arylalkyl; S

R

26

-S(O)-R

27 wherein R26 is loweralkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, or alkoxy-substituted haloalkyl, and R 27 is alkylene or alkenylene,

R

22 -O-C(O)-R 23 wherein R22 is heterocyclic and R 23 is a covalent bond, alkylene, alkenylene, or NR4-2, wherein R 2 5 is alkylene and R 24 is hydrogen or loweralkyl, or

R

13

-C(O)-CH(R

1 4 wherein R 13 is amino, alkylamino, or dialkylamino and R 14 is aryl or R, 5 wherein R 15 is amino, alkylamino, or dialkylamino, or a pharmaceutically acceptable salt thereof, when used in a therapeutically acceptable amount for the treatment of bone pain associated with bone cancer in a mammal.

rR:\LIBXXj0491 6.dOC:aak 171 According to another embodiment of this invention there is provided (2R,3R,4S)-2- (4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(nbutyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof, when used in a therapeutically effective amount for treatment of bone pain associated with bone cancer in a mammal.

According to another embodiment of this invention there is provided (2R,3R,4S)-2- (4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)- -(N,N-di(nbutyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid hydrochloride when used in a therapeutically effective amount for treatment of bone pain associated with bone cancer in a mammal.

According to another embodiment of this invention there is provided a compound having formula: R2 Z. /R3

I

(CH2)n

'R

R1 wherein S. 15 Z is -C(Ri 8

)(R

19 wherein Rg 8 and R 1 9 are hydrogen; n is 0; R is -(CH 2 wherein m is 0, W is -C(0) 2 and G is hydrogen; R, is alkyl, alkenyl, or phenyl substituted with one or two independently selected halo or alkoxy substituents; [I

Y*

R

2 is 0 wherein X* is and Y* is -CH 2 and is substituted with one or two independently selected alkoxy and halo substituents;

R

3 is R 4 wherein R 5 is alkylene; and R4 is (RI )(RI 2 wherein RI, is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or trialkylaminoalkyl and R 1 2 is alkyl, haloalkyl, haloalkoxyalkyl, or alkoxy; or a pharmaceutically acceptable salt thereof when used in a therapeutically effective amount for treatment of bone pain associated with bone cancer in a mammal.

According to another embodiment of this invention there is provided the compound trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-l-((N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl)pyrrolidine-3-carboxylic acid, or a [R:\LIBXX104916.doc:aak 17m pharmaceutically acceptable salt thereof when used in a therapeutically effective amount for treatment of bone pain associated with bone cancer in a mammal.

According to another embodiment of this invention there is provided the compound trans, trans-2-(2,2-dimethylpentyl)- 4 -benzodioxol-5-yl)- I-(N,N-di(nbutyl)aminocarbonylmethyl)pyrrolidine- 3 -carboxylic acid, or a pharmaceutically acceptable salt thereof when used in a therapeutically effective amount for treatment of bone pain associated with bone cancer in a mammal.

The compounds of the invention comprises two or more asymmetrically substituted carbon atoms. As a result, racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention.

The term and configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem.

(1976) 45, 13 The term "carboxy protecting group" as used herein refers to a carboxylic acid is 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. 152-186 (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 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 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 Press, New York (1987), which is hereby incorporated herein by reference. Representative carboxy protecting groups are C, to C 8 alkyl methyl, ethyl or tertiary butyl and the IR:\LIBXX04916.doc:aak -18like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cylcopentylmethyl and the like; arylalkyl, for example, phenethyl or s 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, indanyl and the like; dialkylaminoalkyl dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1- (propionyloxy)-1 -ethyl, 1 -(pivaloyloxyl)-1 -ethyl, 1-methyl-i- (propionyloxy)-1 -ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1methoxycarbonyl-1 -ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1ethoxycarbonyloxy-1 -ethyl, 1 -cyclohexyloxycarbonyloxy-1 -ethyl and the like; alkoxycarbony laminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonyl methyl and the like; (5-(Ioweralkyl)-2-oxo-1,3dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-1 ,3-dioxolen-4yl)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 ON-protecting group" or "N-protected" as used herein 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 -19groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chioroacetyl, 2-bromoacetyl, trifluoroacetyl, trichioroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chl orobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulf onyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-n it robe nzyl oxyca rbonyl1, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, is 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5trimethoxybenzyloxycarbonyl, 1 b ip he n yIy1) 1 met hylIet hoxy c arb onyl1, benzhydryloxycarbonyl, t-butyloxycarbonyl, dilsopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichioroethoxycarbonyl, phenoxycarbonyl,: 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenyithiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl,'benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

The term "alkanoyl m as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a carbonyl 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

R

4 3

-NH-R

4 4 wherein R 4 3 is an alkanoyl group and R 4 4 is an alkylene group.

The term "alkanoyloxyalkyl" as used herein refers to R 3 0

-O-R

3 1s wherein R30 is an alkanoyl group and R 3 1 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 io include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1methyl-2-buten-l-yl and the like. The term "alkenylene" denotes a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. Examples of alkenylene include -CH=CH-, -CH2CH=CH-, -C(CH 3

-CH

2

CH=CHCH

2 and the like.

The term "alkenyloxy" as used herein refers to an alkenyl group, as previously defined, connected to the parent molecular moiety through an oxygen linkage. Examples of alkenyloxy include allyloxy, butenyloxy and the like. The term "alkoxy" as used herein refers to R 4 1 0- wherein R4 1 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 R 80 0-R 8 1 0- i:wherein R80 is loweralkyl as defined above and R81 is alkylene.

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 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.

The term "alkoxycarbonyl" as used herein refers to an alkoxyl group as previously defined appended to the parent molecular moiety -21through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.

The term Oalkoxycarbonylalkenyl" as used herein refers to an alkoxycarbonyl group as previously defined appended to an alkenyl radical. Examples of alkoxycarbonylalkenyl include methoxycarbonylethenyl, ethoxycarbonylethenyl and the like.

The term malkoxycarbonylalkyl" as used herein refers to

R

3 4

-C(O)-R

35 wherein R 34 is an alkoxy group and R 35 is an alkylene group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyl and the like. The term Oalkoxycarbonylaminoalkyl' as used herein refers to

R

3 8-C(O)-NH-R 39 wherein R 38 is an alkoxy group and R 39 is an alkylene group.

The term ualkoxycarbonyloxyalky!" as used herein refers to R3 6

-C(O)-O-R

3 7 wherein R 36 is an alkoxy group and R 37 is an alkylene group.

The term 0(alkoxycarbonyl)thioalkoxyg as used herein refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy radical. Examples of (alkoxycarbonyl)thioalkoxy include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like. The term "alkoxyhaloalkylo as used herein refers to a haloalkyl radical to which is appended an alkoxy group.

The terms Nalkyl" and Oloweralkyl" as used herein refer to straight or branched chain alkyl radicals containing from 1 to 15 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, nbutyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.

The term "(N-alkanoyl-N-alkyl)aminoalkyl' as used herein refers to R85C(O)N(R86)R87- wherein R85 is an alkanoyl as previously defined, R86 is loweralkyl, and R87 is alkylene.

The term Oalkylamino" as used herein refers to R51NH- wherein

R

51 is a loweralkyl group, for example, ethylamino, butylamino, and the like.

The term "alkylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended an alkylamino group.

-22- The term "alkylaminocarbonyl" as used herein refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl linkage. Examples of alkylaminocarbonyl 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 loweralkyl radical to which is appended an alkylaminocarbonyl group.

The term *alkylaminocarbonylaminoalkyl" as used herein refers to

R

4 0-C(O)-NH-R 4 1- wherein R 4 0 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 is carbon atoms by the removal of two hydrogen atoms, for example -CH 2

-CH

2

CH

2

-CH(CH

3

-CH

2

CHCH

2

-CH

2

C(CH

3 2

CH

2 and the like.

The term "alkylsulfonylamidoalkyl" as used herein refers R88S(0)2NHR89- wherein R88 is loweralkyl and R89 is alkylene. The term "alkylsulfonylamino" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino 2 group. Examples of alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like. 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 alkynyl include H-CsC-CH 2

H-C=C-CH(CH

3 and the like.

The term "alkynylene" refers to a divalent group derived by the 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 -CsC-CH 2

-C=C-CH(CH

3 and the like.

The term "aminoalkyl" as used herein refers to a -NH2, alkylamino, or dialkylamino group appended to the parent molecular moiety through an alkylene.

The term "aminocarbonyl" as used herein refers to H2N-C(O)- -23- The term "aminocarbonylakenyl" as used herein refers to an alkenyl radical to which is appended an aminocarbonyl (NH 2 group.

The term "aminocarbonylalkoxy" as used herein refers to

H

2 appended to an alkoxy group as previously defined. Examples s of aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like.

The term "aminocarbonylalkylr as used herein refers to a loweralkyl radical to which is appended an aminocarbonyl

(NH

2 group.

The term atrialkylaminoalkylo as used herein refers to (R90)(R91)(R92)N(R93)- wherein R90, R91, and R92 are independently selected from loweralkyl and R93 is alkylene.

The term 'aroyloxyalkyl" as used herein refers to R3 2 -C(0)-O-R 3 3 wherein R 3 2 is an aryl group and R 3 3 is an alkylene group. Examples of aroyloxyalkyl 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 and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, trialkylaminoalkyl, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy, mercapto, cyano, nitro, carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cyanoalkoxy, (heterocyclic)alkoxy, hydroxy, hydroxalkoxy, phenyl and tetrazolylalkoxy. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.

The term marylalkenyl" as used herein refers to an alkenyl radical to which is appended an aryl group, for example, phenylethenyl and the like.

The term Oarylalkoxy" as used herein refers to R 4 2 0- wherein R 42 is an arylalkyl group, for example, benzyloxy, and the like.

-24- The term "arylalkoxyalkyl" as used herein refers to a loweralkyi 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 previously defined, appended to a loweralkyl radical, for example, benzyl and the like.

The term "aryloxy" as used herein refers to R4 5 0- wherein R 4 5 is an aryl group, for example, phenoxy, and the like.

The term "arylalkylcarbonyloxyalkyl" as used herein refers to a loweralkyl radical to which is appended an arylalkylcarbonyloxy group

R

6 2C(0)O- wherein R 62 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 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 defined. Examples of carboxyalkenyl include 2-carboxyethenyl, 3- carboxy-l-ethenyl and the like. 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, carboxyethoxy and the like.

The term "cyanoalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a cyano group.

Examples of cyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like.

The term "cycloalkanoyloxyalkyl" as used herein refers to a loweralkyl radical to which is appended a cycloalkanoyloxy group

R

6 0 wherein R 6 0 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 limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, 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, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.

s The term "cycloalkylalkyl" 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 Rs 6

R

5 7

N-

wherein R 56 and R57 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.

The term "dialkylaminoalkyl" 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 is molecular moiety through a carbonyl 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.

The term "dialkylaminocarbonylalkyl" as used herein refers to 5 i- wherein R 5 0 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 refers to an alkenyl radical to which is appended at least one halogen substituent.

SThe 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.

The term "haloalkoxyalkyl" 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 pentafluoroethyl and the like.

The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as used herein refers to any 3- or 4-membered ring containing a -26heteroatom selected from oxygen, nitrogen and sulfur; or a 6- or 7membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one s 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 nitrogen heteroatoms can be optionally quatemrnized. The term aheterocyclic" 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, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like). Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, iSOthiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl.

is

/Y

Heterocyclics also include compounds of the formula where X* is -CH 2 or and Y* is or 2 -v where RO 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 disubstituted with substituents independently selected from hydroxy, halo, oxo alkylimino wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -SO 3

H,

-27alkoxycarbonyl, nitro, cyano and loweralkyl. In addition, nitrogen 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 4pyridylmethoxy, 2-pyridylmethoxy and the like.

The term "(heterocyclic)alkyl" as used herein refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.

The term "heterocycliccarbonyloxyalkyl" as used herein refers to

R

4 6-C(O)-O-R 4 7 wherein R 4 6 is a heterocyclic group and R 4 7 is an alkylene group..

The term "hydroxy" as used herein refers to -OH.

The term "hydroxyalkenyl" as used herein refers to an alkenyl is 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 group. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4- 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, CI, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like). The term "mercapto" as used herein refers to -SH.

The terms "methylenedioxy" 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 is formed. In the case of ethylenedioxy, a fused 6 membered ring is so formed. Methylenedixoy substituted on a phenyl ring results in the S. ar0 formation of a Denzodioxoyi radical. thyenedioxy -28substituted on a phenyl ring results in the formation of a benzodioxanyl radical 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, tetrazolylethoxy and the like. The term "thioalkoxy" as used herein refers to R 7 0 S- wherein R 7 0 is loweralkyl. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like. The term "thioalkoxyalkoxy" as used herein refers to RsoS-R 8 1 0wherein R 8 0 is loweralkyl as defined above and R 8 1 is alkylene. Representative examples of alkoxyalkoxy groups include CH 3 SCH20-, t-BuSCH20- and the like. The term "thioalkoxyalkoxyalkyl" as used herein refers to a thioalkoxyalkoxy group appended to an alkyl radical. Representative S examples of alkoxyalkoxyalkyl groups include CH 3

SCH

2

CH

2 0CH 2

CH

2

CH

3

SCH

2 0CH 2 and the like.

The term "trans,trans" as used herein refers to the orientation of substituents (R 1 and R 2 relative to the central substituent R as shown R2 ZI. N R3

N

I

(CH

2 )n

RR

The term "trans,cis' as used herein refers to the orientation of substituents (R 1 and R 2 relative to the central substituent R as shown -29- R3N Rior HI This definition encompasses both the case where R and R 2 are cis and R and R1 are trans and the case where R 2 and R are trans and R and R 1 are cis.

The term cis,cis2 as used herein refers to the orientation of substituents (Rj and R 2 relative to the central substituent R as shown

RR

Prefrre copond Nfteivninaeseetdfo h ru consising of Prefe-rreopound of te inentane l n in are selected from the grou cosstn crof:li acd 10trans,-trans-2-(34-DMethoxyphenyl)-4-(1,3-benzodioxo-l- (propyl-N-n-pentanesulfonylamino)opyl]pyrrolidine-3carboxylic acid; trans, trans-2-(4-etoxm ethoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-- 2 20-(N-propyl-N-n-etanesulfonylamino)ethyl]pyrrolidine-3carboxylic acid; trans,trans-2-(3,4-Dimetoxyphenyl)-4-(1 ,3-benzodioxol (Npro pyl -N -n-pentan e suIf on ylamino) ethyl] py rrolid in e-3-roy acrid; cacd trans, trans-2-(3,4-Dimetoxphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 dbtlmncabnlmty)proiie3carboxylic acid; trans, trans-2-(3,4-Pr loophenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 p ropyl- N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3- Flu oro-4-methoxyp hen yl)-4-(1 1 -[2-(N-propyl-N-n- hexanesulfonylamino)ethyl]pyrrolidine-3carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-propyl-N-(3-chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxypheny)-4-(1 1 -(2-(N-isobutyl-N-(3chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluo ro-4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yt)- I ropyl-N-(4- methyl butanesulf onyl) amino) ethyl] py rrol idi ne- 3- carboxyli c acid; *trans, trans-2-(4- Meth oxy-3-f Iuoro ph enyl)-4- met hoxy- 1,3 benzodioxol-5-yI)-1 -[2-(N-propyl-N-(npentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -[2-(N-propyl-N-(2,2,3,3,3-pentafluoropropoxyethanesufonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(1 ,4-Benzodioxan-6-yl)-4-(7-methoxy- 1,3-benzodioxol- 5-yI)-1-[2-(N-propyl-N-(n- pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3- Fl uoro-4 -m ethoxyphenyl) (1 benzodioxo 1 (2 is obu ty I- N -(pe n tan e sulIf onyIa m in o) et hyl1)py rroIi din e -3 carboxylic acid; trans, trans-2-(3-F uoro-4-methoxyphenyl)-4-(1 *1 -(2-(N-(2-methoxyethyl)-N-(3-chloropropanesulfonyl)amino)ethyl) py rroli di ne-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-(2-methoxyethyl)-N- (pentanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -[2-(N-propyl-N-((2,2,2-triftuoroethoxyethane)sulfonyl)amino)ethyl]jpy rro Iidi ne-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1-(2-(N-(2-mettioxyethyl)-N-(butanesulfonylamino)ethyl)pyrrolidine-3-carboxylic acid; -31trans, trans-2-(3-Fluoro-4-methoxyp hen 1,3-benzod yi)-1 -[2-(N-propyl-N-(2mettiylpropanesulfonyI)amino)ethy]pyrroidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-isobutyl-N-(butanesulfonylamino))ethyl)pyrrolidine-3 carboxylic acid; trans, trans-2-(2- Methyl pentyl)-4- (1 be nzodioxol -5-yI1)- 1 dibutylaminocarbonylmethyi)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2 -Dim ethylpentyl)-4-(1 ,3-benzod ioxol -5-y)-1I Ndibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxo-2-yI)ethyl)-4-(1 ,3-benzodioxol-5-yI)- 1 (NN-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Tetrahydro-2 H-pyran)ethyl)-4-( 1,3-benzodioxol- 5-yI)-l1-(N, N-dibutylaminocarbonyi methyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(2,2,4-Trimethyl-3-pentenyl)-4-(1 1 -(NN-dibutylaminocarbonylmethyI)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(1 ,3benzodioxol-5-yl)- N-d ibutylami nocarbonyl methyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2- (1 Di oxo-2 -yI)ethyl) (1 ,3-benz odioxol- 5-yI)- 1 [[N-4-heptyl-N(2 methyl-3-fluorophenyl)] amino carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1,3-Dioxol-2-yI)ethyl)-4-(7-methoxy- 1,3benzodioxo 1-5-yt)- 1 N-d ibutylami nocarbonylm ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-((2-M ethoxyphenoxy)-m ethyl)-4-( 1,3-benzodioxol-5-yI)- 1 -(NN-dibutyaminocarbonylmethyI)-pyrrolidine-3-carboxylic acid; (2S, 3R, 4S)-2- D imethyl pentyl1)-4-( 1,3- be nzod ioxol-5-yI)- 1 heptyl- N-(4-flIuo ro-3-m ethyl phe nyl))am inoca rb onyl methyl).

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyi)-4-( 1,3-benzodioxol-5yI)-l1-(N, N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; -32trans, trans-2-(2-( 1,3-DioxolI-2-yI)ethyl)-4-(7-methoxy- 1,3- 1 he ptyl-N-(4-flIuoro-3methyl ph enyl) )am in oca rbo nylmnethyl) -py rroli din e-3- carboxyl ic acid; trans, trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1, yI)-1 N-dibutylaminocarbonylmethyl)-pyrro Ii din e-3-carboxylic acid; trans, trans-2-(2 ,2-dimethylIpentyl)-4-(2 ,3-dihydro-benzof uran 1 N-dib utyl am inocarbonyl methyl) -pyrro lid ine- 3-carboxylic acid; trans, trans-2- -D im ethyl-2-(1 di oxol an-2-yl) ethyl) mne th oxy -1 ,3 -b e nzo d io xoI- 5 -yI1) -1 (N,IN dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1 ,3-benzodioxol-5-yI)- 1 -(N,N-dibutylaminocarbonylmethyl)-pyrrolidine.3-carboxylic acid; trans, trans-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-(7-methoxy- 1,3benzodi oxoI- 5-yl)- N-dibutylami nocarbonyl methyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-pyridyl)ethyl)-4-( 1,3-benzodioxol-5-yI)-1 N- d ibutyl amino carb onyl methyl)- py rrol idi ne-3-carboxyli c acid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yI)ethyl)-4-(1 yI)-l -(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-( 1,3-benzodioxol-5yI)-l-(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2- 1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxol-5-y)-1 ,Ndibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 b utyl- N-(4-di methyl am inobutyl)am ino) carbonyl methyl] pyrrolidine-3-carboxylic acid; (2R, 3R, Flu oro-4-methoxypheny)-4- (1 ,3-benzodi oxol 1 (2-(N-propyl- N-pe ntan esulf onyla m ino) ethyl) -pyrrolidi ne-3carboxylic acid; -33trans, trans-2-(2,2-Dimethy Ipentyl)-4-( 1 3-benzodioxol-5-yl)- 1 b utyl -N im ethyla min o) butyl) am n ocarbon yl methy 1) pyrrolidine-3-carboxylic acid; trans, trans-2- Dim ethyl pentyI) et hoxy. 1, 3-benz od ioxol yI)-1-(N-4-heptyl-N-(4-fluoro-3methyIphenyI))aminocarbonyimethy)-pyrroitdine.3.carboxylic acid; trans, trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy- 1 yI)- 1-((N-butyl-N-(4dimethyiamino)butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; trans, trans-2-(2,2-Di methyl pent-3-e ny ,3-benz odi oxol 1

(N-

4 -heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl). pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpent-3-enyl)-4-(1 ,3-benzodioxoI-5-yi)- 1 ((N-butyl-N-(4 dimethylami no) butyl)ami noca rbonyl methyl)- pyrrolidine-3-carboxylic acid; trans, trans-2 D imethyl pent-3-e ny)4(7-.met hoxy.1, ,3benzodioxol-5-yI)-1 ,N-dibutyI)aminocarbonylmethyI)pyrrolidine-3-carboxylic acid;:.* trans, trans-2-(2,2- Dim ethyl pent- 3-eny)-4- (7-metho xy.1, ,3 1 -(N-4-heptyl-N-(4-fluo ro-3methylphenyI))aminocarbonylmethyI)-pyrrolidine-3carboxylic acid; trans, trans-2 D imethyl pent- 3-e nyl)-4 ethoxy- 1, 3benzodioxol-5-yI)-1 -((N-butyl-N-(4dimethylamino)butyl)aminocarbonylmethyl).pyrrolidine.3 carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent-3-eny)-4.(1 1-(N-4-heptyl-N-(4-fluoro-3methyiphenyl) )aminocarbonylmethy)-pyrroidine-3.carboxyI ic acid; trans, trans-2-(2,2,4-Trimethylpent-3-enyl)-4-( 1 1 -((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethy).

pyrrolidine-3-carboxylic acid; -34trans, trans-2-(2,2 ,4-Trim ethyl pent-3-enyI)-4-(7-methoxy- 1,3benzodioxol-5-yi)-1 ,N-dibutyI)aminocarbonylmethyl)yrrolidine-3-carboxylic acid; trans, trans-2-(2 ,2 ,4-Trim ethyl pent-3-enyl)-4- (7-m ethoxy-1, ,3benzodioxol-5-yI)-1-(N-4-heptyl-N-(4-fluoro-3methylphenyI))aminocarbonylmethy)-pyrroidine-3-carboxylic acid; trans, trans-2-(2,2,4-Tri methyl pent-3-eny)-4- (7-m ethoxy- 1,3- 1 N-butyl-N-(4dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2 (1 Dioxot-2-yI) ethyl) (1 ,3-benzodi oxol-5-yI)- 1 [(N-butyl-N-(4-dimethylaminobutyl)amino)carbonytmethyl]pyrrolidine-3-carboxylic acid; tans tras-2(2-(,3-ioxo-2-l~etyl)4-(7metoxy-1..

benzodioxol-5-yI)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonymethyl]-pyrrolidine-3carboxylic acid; trans,'trans-2 -Dim ethy1-2- (1 D ioxol -2-y1) ethyl) (1 ,3benzodioxol-5-yI)-1-(N-4-heptyl-N-(4-fluoro-3-: m e th y Iph e ny1)) amin o c arb on y Ime t hy1) -p yr r oIi d ine 3- ca r b o x y Ic acid; trans, trans-2-(2,2-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(1 ,3benzodioxol-5-yi)-1 N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-Dioxol-2-yI)ethyt)-4-(7methoxy-1 ,3-benzodioxol-5-yI)-1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2 D imet hyl (1 ,3-di oxolan-2-yI)ethyl)-4-(7methoxy-1, ,3-benzodi oxol-5-yi)- 1 -[(N-butyl-N-(4dimethylaminobutyl)ami no)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-( 1 1 -(N-4-heptyl-N-(4-fluoro-3m ethylphe nyl))am ino) carbo ny m ethyl]-pyrro lid in e-3-ca rboxyli c acid; trans, trans-2-(2-(2- Methoxyphenyl)-ethyl)-4-( 1,3-benzodioxol-5-yi)- 1 utyl- N-(4-di methylami nobutyl)am ino)ca rbonylm ethyl)-.

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy- 1 .3benzodioxol-5-yI)-l1-[((N .N-dibutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxyl 1,3- be nz od io xolI- 5 -yI1)- 1 (N -4 -h ep t yI- N -flIu oro -3 m ethyl ph enyI)) am ino) carbo ny m ethyl ]-pyrrolid in e-3carboxy i c acid; trans, trans-2- Methoxyp henyl)-ethyl) (7-m ethcxy. 1, 3b e nz od io xolI-5 -yI1)- 1 -b ut yI- N d im e th yIa m in obuty1) am in o) c arbo nylI m e th y Ip y rroIi d ine 3 carboxylic acid; trans, trans-2- Methoxyph enoxy)-methyl)-4-(1 ,3-benzodi oxol 1 -(N-4-heptyl-N-(4-f luoro-3- m e th yIp he ny arn in o)ca rb o ny Ime t hy I p yrroIi d in'e- 3 -c arb oxy Ii c acid; trans, trans-2- Methoxyph enoxy)-methyl) ,3-benzod ioxol- 1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-((2-M ethoxyphenoxy)-methyl)-4- (7-methoxy 1, ,3benzodioxol-5-yI)-l1-[(( N, N-dibutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl)-4-(7-methoxy 1, ,3benzodioxol-5-yl)-1 -(N-4-heptyl-N-(4-fluoro-3methylphenyI))amino)carbonylmethy]-pyrroidine-3-carboxylic acid; trans, trans-2-(2-(2-Methoxyphenoxy)-methyl)-4-(7-methoxy- ,3benzodioxol-5-yf)-l1-[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3.

carboxylic acid; -36trans, trans-2-(2-(2-Oxo 1 ,2-dihydro pyridin-l -yI)-ethyl)-4-(1 ,3benzodioxol-5-yI)-1 N-dibutyl)amino)carbonylmethyi]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyridin-1 -yI)-ethyl)-4-( 1,3-benzodioxol-5yl)-l1 -[(N-4-heptyl-N-(4-f luoro-3methyIphenyI)amino)carbonylmethyl-pyrroidine-3carboxylic acid; trans, trans-2-(2-(2-Oxopyrid in-i1 -yI)-ethyl).4-( 1,3-benzodioxol-5yI)-l1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl].

pyrrolidine-3-carboxylic acid; trans, trans-2- (2-0Oxopy ri din- 1 -yI) -ethyl)-4-(7-meth oxy- 1,3- benzodioxol-5-yi)-1 -[((N,N-dibutyl)amino)carbonylmethyl].

p pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyridin- 1 -yI)-ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1-[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine.3carboxylic acid;* trans, trans-2- (2-Oxopy ri din- 1 -yI)-ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yi)-1 -[(N-butyl-N-(4d im ethyl am i no butyl) am i no) ca rbonyl methyl] -pyrrol idi ne-3- carboxylic acid; trans, trans-2- (2 -Oxo pip eri din- 1 -yI) -ethyl) (1 ,3-benzod ioxol-5- yI1)-l1 N- d ib uty1) am in o) c arb on ylImethy I p y rro Ii d ine -3 carboxylic acid; trans, trans-2-(2- (2-Oxopipe ridin- 1 -y1) -ethyl) (1 ,3-benzodi y1)-1 4-h ept y I- N -fIu o ro -3 m eth y Ip h en y1) am ino) c arb on y Imethy I p yrr oi d in e 3 c arb oxy Ii c acid; trans, trans-2 Oxo pi peridi n- 1 -yi)-ethyl) ethoxy-1, ,3b en zo d io xo1- 5 -yI1)- 1 N- d ib uty1) am in o) c arbon ylIm e th ylpyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin- 1 -yI)-ethyl)-4-(7-methoxy- 1,3benzodioxol-5-yI)-l1-[((N, N-dibutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin-1 -yI)-ethyl)-4-(7-methoxy- 1,3benzodioxol-5-yI)-l1-[(N-4-heptyl-N-(4-fluoro-3- -37m ethy lphenyl) amino) ca rbonyl met hyl]-py rro lid in e-3- carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin- 1 -yl)-ethyl)-4-(7-methoxy-1 ,3- 1 -[(N-butyl-N-(4dim ethyl amino butyI) amino) carbon yl methyl]- py rro lid in e-3carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-( 1,3-benzodioxol-5yl)-l1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(1 yI)-1 -[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-. carboxylic acid; p trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(1 yI)-1 -[(N-butyl-N-(4 dim ethylaminobutyl)amino)carbonylmethyl].

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2 -Oxo py rrol idin- 1 -yl) ethyl) (1 be nzo d yl)- 1-[(N-butyl-N-(4trimethyla'mmoniobutyl)amino)carbonylmethyl]-pyrrolidine.3carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl) ethyl) methoxy-1, benzodioxol-5-yi)-1 N-dib utylami nocarbonyIm ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrol idin- 1 -yl) ethyl) methoxy-1, ,3benzodioxol-5-yl)-l1-[(N-butyl-N-(3hyd roxyp ropyl) am ino)carbonyl met hy] -pyrrol idin e-3-carboxyhi c I~ acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-l1-[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(7-methoxy-1 ,3- 1 -[(N-butyl-N- (propoxy)amino) carbonyl methyl] -pyrrol idi ne-3-carboxylic acid; trans, trans-2- (2-Oxopyrrol idi n- 1 -yl) ethyl) methoxy-1, ,3benzodioxol-5-yl)-1 -[(N-butyl-N-(4dimethylam inobutyl)amino)carbonyl methyl]-pyrrolidine-3carboxylic acid; -38trans, trans-2-(2-(2-OxopyrrolIidin-1 -yI) ethyl) -4-(7-methoxy- 193be nzodioxolI-5-yI) 1 N-butylI-N-(4t rim ethyl am mm oni obuty y1) ami no) ca.rbon yI met hyl] pyr rro I i di ne -3carboxylic acid; trans, trans-2 -(2-(2-Oxopy rroIi di n-1 -yl) ethyl) (2,3-d ihyd robenzofuran-5-yI)-1 N-dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopy rrol idi n- 1 -yl[)ethyl) ihydrobenzofuran-5-yl)-l1-I(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin- 1 -yl) ethyl) ihyd rop benzofuran-5-yl)-1-[(N-butyl-N-(4d im et h yIa m in obuty1) am in o) carb on yIme t hy I p yrro Ii d ine -3 carboxylic acid; trans, trans-2-(2-(3,3-Dimethyl-2-oxopyrrolidin- 1 -yI)ethyl)-4-(1 ,3benzodi oxoI- 5-yl)- 1 N-dib utyla mi noca rbonylm ethyl)yrrolidine-3-carboxylic acid; trans, trans-2-(2-(3,3-Dimethyl-2-oxopyrrolidi n- 1 -yI)ethyl)-4-(1 ,3benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3- m et hy Iph en y1) a m ino)c arb on y Imet hyI p yrroIi d in e- 3 -ca rb oxy Ii c acid; trans, trans-2-(2-(3,3-Dimethyl-2-oxopyrrolidi n- 1 -yl)ethyl)-4-(1 ,3b e nzo d io xo I-5 -yl1)- 1 -b u tyI- N d im et hy Iamni n ob uty1) am in o)car b on y Im e t hyIpy rro Ii din e -3 P carboxylic acid; trans, trans-2-(2-(4,4-Dimethyl-2-oxopyrrolidin- 1 -yl)ethyl)-4-( 1,3benzodioxol-5-yl)-1 -(N,N-dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(4,4-Dimethyl-2-oxopyrrolidin- 1 -yl)ethyl)-4-( 1,3benzodioxol-5-yl)-l1-[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(2-(4,4-Dimethyl-2-oxopyrrolidi n- 1 -yl)ethyl)-4-(1 .3benzodioxol-5-yi)-1 -[(N-butyl-N-(4dimethylaminobutyl)ami no)carbonyl methyl]-pyrrolidine-3carboxylic acid; -39trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(-1,3-benzodioxoi-5-yI)- 1 -(NN-dibutylaminocarbonylmethyl)-pyrroidine-3..carboxylic acid; trans, trans-2-(2-( 1 -propanesuttamyl)ethyl)-4-(1 1 -[(N-4-heptyl-N-(4-f luoro-3methyIphenyI)amino)carbonylmethy]-pyrrolidine.3.carboxylic acid; trans, trans-2-(2-( 1 -propanesultamyl)ethyl)-4-(1 1 N-butyl-N-(3-hydroxypropyl)am ino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -pro pan esu ltamyl) et hyl)- 4- (l 3-benz odioxoI- 5-yi) 1 -[(N-butyl -N ropoxy)ami no)carbony Im ethyl] -pyrrol idi ne-3 carboxylic acid; trans, trans-2-(2-( 1 -pro panes ultamyl) ethyl)-4-(1 1 3-be nzod ioxoI- 1 -[(N-butyl-N-(4 dimethylamiriobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2- (1 -p ropan esulItamnyl) ethyl) (7-meth oxy-1, ,3be nzodi oxol1-5-yi)- 1 N-dibutyaminoca rbonylm ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethy1)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-l1-[(N-4-heptyl-N-(4-fluoro-3. methylphenyl)amino)carbonylmethyl]-pyrrolidine3carboxylic acid; trans, trans-2-(2-(1 -propanes ultamnyl) ethyl) (7-meth oxy-1, ,3benzodioxol-5-y)-1-[(N-butyl-N-(4dimethylaminobutyI)amino)carbonylmethy]-pyrrolidine.3 carboxylic acid; trans, trans-2-(2-( 1 -propanesultamyl)ethyl)-4-(2,3-dihydrobenzof uran-5-yI)- 1 N-dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1 -propanesultamyl)ethyl)-4-(2,3-cfihydrobenzofuran-5-yI)-l1-[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl-pyrrolidine-3..carboxylic acid; trans, trans-2-(2-( 1 -propanesultamyl)ethyl)-4-.(2,3-dihydro- Sbenzof uran-5-yl)- 1-[(N-butyl-N-(4dimethylaminobutyl)am ino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-( 1 -pyrazo lyl) ethyl)-4-( 1,3-benzodi oxol-5-yI)- 1 4-heptyl- N-(4-f Iuo ro-3- methyl phenyl) am ino)ca rbonylmethyl].

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl)ethyl)-4-( 1,3-benzodioxol-5-yI)- 1 butyl-N-(3-hydroxypropyl)ami no)carbonylmethyi]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1 butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl)ethyl)-4-( 1,3-benzodioxol-5-yI)- 1 butyl-N- (4-di methyl am inobutyl)am ino)carbonylm ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl) ethyl) -4-(7-methoxy- 1, 3-benzodioxol- -yI1) -1 N -d ib utylIamin o c arb on yIm et hy1) -py rroIi d in e -3carboxylic acid; trans, trans-2- (1 -py razo lyl) ethyl) -4-(7-metho xy- 1, 3-b enzod ioxol 5-yI)-l1-[(N-4-heptyl-N-(4-fluoro-3- m eth y Ip h e ny1) am ino) ca rbo n y Imet h y IpyrroIi d in e- 3 -carb oxy Ii c acid; trans, trans-2-(2- (1 -py razolyl) ethyl) -4-(7-methoxy- 1, 3-be nzod ioxoi 5-yI -1 N -bu t y I-N d im et hy Ia min o b uty1) am ino) ca rb on ylIme t h y Ipyrro Ii d ine -3 carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl)ethyl)-4-(2,3-dihydro-benzof yl)-1 N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl)ethyl)-4-(2 ,3-dihydro-benzof yI)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2- (1 pyrazo lyl) ethyl) (2,3-di hyd ro-be nzof yI)- 1 butyl-N- (4-di methyl aminobutyl)am ino) ca rbonyl methyl]pyrrolidine-3-carboxylic acid; -41trans, trans-2-(2-(2-oxazolyl) ethyl) 1,3- be nzodioxol-5-yI)- 1 Ndibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2 -(Oxazo1-2-y1) ethyl) (1 ,3-be nzod ioxol-5-yI)- 1 4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl].

pyrrolidine-3-carboxylic acid; trans, trans-2- (2 -(Oxazo1-2-y) ethyl) (1 be nzod ioxol 1 butyI-N-(3-hydroxypropy)amino)carbonyImethyJ-pyrroidine.3 carboxylic acid; trans, trans-2-(2-(Oxazol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1 butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(Oxazol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yI)- 1 butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; is trans, trans-2-(2-(Oxazol-2-y)ethyl)-4-(7-methoxy- 1,3-benzodioxol- -l1 N-d ibutyl ami nocarbonyl met hyl)- py rrolid ine-3carboxylic acid; trans, trans-2-(2-(Oxazol-2-y)ethy)-4-(7-methoxy- 1 ,3-benzodioxol- 5-yi)-l1-[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Oxazol-2-yI)ethyl)-4-(7-methoxy- 1 ,3-benzodioxol- N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2- Methyl oxazol-2-yI) ethyl)-4- (1 benzodi oxo yI)-l1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2- Methyl oxazol-2-yI)ethyl)-4-( 1,3-benzodioxoi-5yI)-1-[(N-4-heptyl-N-(4-fluoro-3methyiphenyl) amino)carbonylmethyi]-pyrrolidine-3-carboxylic acid; trans, trans-2- Methyl oxazol-2-yI)ethyl)-4-( 1,3-benzodioxot-5yl)-l -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl>pyrrolidine-3-carboxylic acid; -42trans, trans-2-(2-(2,5-Dioxopyrrolid in -1 -yl) ethyl) ,3-benzodioxol- 1 N-dibutyl am inocarbonylmethy)-pyrrolidine.3 carboxylic acid; trans, trans-2-(2- Di oxopy rro li din- 1 -yI) ethyl) (1 benzodi oxol- 5-yI)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyI)amino)carbonylmethy]-pyrrolidine.3carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrroli din- 1 -yI) ethyl)-4-(1 ,3-benzodioxol- 1 -[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyq..

pyrrolidine-3-carboxylic acid; trans, trans-2-(2- Di oxo py rro lidi n- 1 -yI) ethyl) (1 ,3-benzodi oxoj- 5-yl)-1 -[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine.

p 3-carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrroli din.1 -yI)ethyl)-4-(1 ,3-benzodioxol- 5-yI)- 1 -[(N-butyl-N-(4-dimethylaminobutyl) amino)carbonylmethyi]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2- (2,5-Dioxopyrroli din- 1 -yI)ethyi)-4- (7-meth oxy- 1,3benzodioxol-5-yI)-1 -(N,N-dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrrolidin- 1 -yI)ethyl)-4-(7-methoxy- 1,3benzodioxol-5-yI)-l1-[(N-4-heptyl- N-(4-fluo ro-3-: methylp heny1) amino) ca rbo ny m ethyl]- pyrroli din e-3carb oxyli c acid; trans, trans-2-(2-(Pyridi n-2-yI)ethyl)-4-( 1,3-benzodioxol-5-yi)- 1 4 -heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl].

I pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Pyridin-2-yI)ethyl)-4-( 1,3-benzodioxol-5-yI)-1 butyl-N-(3-hyd roxyp ropyl )amino) carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(Pyridi n-2-yI)ethyl)-4-( 1,3-benzodioxol-5-yI)- 1 butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine.3 carboxylic acid; transtrans-2-(2-(Pyridin-2-yI)ethyl)-4-( 1,3-benzodioxol-5-yI)- 1 butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl].

pyrrolidine-3-carboxylic acid; -43trans, trans-2-(2-(Pyridin-2-y I) ethyl) -4-(7-methoxy- 1,3-benzodioxol- N-dibutylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2 (Pyri d in-2-y1) ethyl) -4 eth oxy-1, ,3-benzodi oxolI- 5-yl)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2 -(Pyri din-2-yl)ethyl) -4 -(7-methoxy-1, ,3-benzodi oxo I- 1 -[(N-butyl-N-(4dim ethyl am inob utyl)ami no)carbonyl methyl]-pyrrol idine-3carboxylic acid; trans, trans-2-(2-(Pyrimidin-2-yI)ethyl)-4-(1 ,3-benzodioxol-5-yl)- 1 (N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxyic acid; trans, trans-2-(2-(Pyrimidin-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)- 1 [(N-4-heptyl-N-(4-fluoro-3- mnet h y Iph e ny1) ami no)ca rb onylImeth ylI p yrroIi d in e-3 -c arb oxy Ii c acid; trans, trans-2-(2-(Pyri m idin-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)- 1 (N -b ut yI- N -di m et hyIam in ob uty1) a m ino) ca rb onylImeth y1] pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1,3-benzodioxol-4-yl)ethyl)-4-(1 yl)-l -(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1,3-benzodioxol-4-yl)ethyl)-4-(1 ,3-benzodioxol- yl)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; and trans, trans-2- (2 ,3-benzod ioxol-4-yl) ethyl) (1 ,3-benzod yl)- 1-[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt.

Most preferred compounds: of the invention are selected from the group consisting of: trans, trans-2-(2-( 1,3-Dioxol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)- 1 (N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; -44trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-dioxolIan -2-yI)ethyl)-4-(1 ,3benzodioxol-5-yi)-1 N-dibutylaminocarbonylm ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxol-2-yI)ethyl)-4-(1 [[N-4-heptyl-N-(2-methyl-3-fluorophenyl)] aminocarbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxol-2-yI)ethyl)-4-(7-methoxy- 1,3benzodioxol-5-yl)-1 -(N,N-dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl)-4-(1 ,3-benzodi 1 ,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin- 1 -yI)ethyl)-4-( 1,3-benzodioxol-5yI)-1 N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1,3-Dioxol-2-yI)ethyl)-4-(7-methoxy- 1,3benzodioxo I-5-yI)-1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans,trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1 ,3-benzodioxol-5- yI)-1 -(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(7methoxy-1 ,3-benzodioxol-5-yI)-1 dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1 1 N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2- (2,2-D imet hyl (E)-pe nteny1) -4 ethoxy- 1 3benzodioxol-5-yI)-1 -(N,N-dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-pyridyl)ethyl)-4-( 1,3-benzodioxol-5-yi)- 1 dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yI)ethyl)-4-(1 yi)-l -(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3carboxylicacid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5yl)-1-(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1 dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; and (2S, 3R, 4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)- 1 -[((N-propyl-N-pentanesulfonyl)amino)ethyl]-pyrrolidine-3carboxylic acid; or a pharmaceutically acceptable salt thereof.

Methods for preparing the compounds of the invention are shown is 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 -CH 2 and W is

-CO

2 H. A 0-ketoester 1, where E is loweralkyl or a carboxy protecting group is reacted with a nitro vinyl compound 2, in the presence of a base (for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium..

ethoxide or sodium hydride and the like) in an inert solvent such as toluene, benzene, tetrahydrofuran or ethanol and the like. The condensation product 3 is reduced (for example, hydrogenation using a Raney nickel or platinum catalyst). The resulting amine cyclizes to O give the dihydro pyrrole 4. Reduction of 4 (for example, sodium cyanoborohydride or catalytic hydrogenation and the like) in a protic solvent such as ethanol or methanol and the like gives the pyrrolidine compound 5 as a mixture of cis-cis, trans,trans and cis,trans 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 sodium ethoxide in ethanol) to give the trans,trans isomer and then carried on as described below. The pyrrolidine nitrogen is acylated or sulfonylated with R3-X (Rs is R4-C(O)- or R 6 -S(0) 2 and X is a leaving group such as a halide (CI is preferred) or X taken together with

R

4 or Re-S(0) 2 forms an activated ester including esters or -46anhydrides derived from formic acid, acetic acid and the like, alkoxycarbonyl halides, N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboxamide, 2,4,5-trichlorophenol and the like) or alkylated with R 3 -X where X is a leaving group (for example, X is a halide (for example, Cl, Br or I) or X 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 triethylamine and the like to give the Nderivatized pyrrolidine 6 which is still a mixture of trans,trans and cis,trans isomers. Hydrolysis of the ester 6 (for example, using a base such a sodium hydroxide in EtOH/H 2 0) selectively hydrolyzes the trans,trans ester to give a mixture of 7 and 8, which are readily p separated.

Scheme II illustrates a general procedure for preparing the compounds of the invention when n is 1, m is 0, Z is -CH 2 and W is -C02H. A substituted benzyl chloride 9 is reacted with a lithio dithiane 1. in an inert solvent such as THF or dimethoxyethane to give the alkylated adduct 11. The anion of compound 11 is formed using a base such as n-butyllithium and then reacted with R 1

-CH

2 wherein X' is a leaving group such as a halide or sulfonate to give compound 12. The dithiane protecting group is cleaved (for example, using a mercuric salt in water) to give the keto compound 13. Reaction of ketone 13 with benzyl amine and formaldehyde gives the keto piperidine compound 14.

Treatment, of compound 14 with an activated nitrile such as trimethylsilyl cyanide followed by a dehydrating agent such as phosphorous oxychloride provides the isomeric ene nitriles Reduction of the double bond (for example, using sodium borohydride) affords the piperidinyl nitrile 16. Hydrolysis of the nitrile 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 18. Compound 18 is further elaborated by the procedures described in Scheme I for compound 5 to give the final product compound 19.

Scheme III illustrates a general procedure for preparing the compounds of the invention when m and n are 0, Z is and W is -C02H. O-Keto ester 20 (wherein E is loweralkyl or a carboxy -47protecting group) is reacted with an a-haloester 21 (where J is lower 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 tertbutoxide or lithium diisopropylamide in an inert solvent such as THF or s dimethoxyethane to give diester 22. Treating compound 22 with R 3

-NH

2 and heating in acetic acid gives the cyclic compound 23. The double 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 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 -CH 2 and W is

-CO

2 H. The trans,trans compound 7, prepared in Scheme I, is homologated by the Amdt-Eistert synthesis. The carboxy terminus is 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 Cl). Compound 52 is treated with diazomethane to give the diazo ketone 53. Rearrangement of compound 53 (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 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 VI. A benzoyl acetate 26 is reacted with a nitro vinyl benzodioxolyl compound 27 using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base in toluene to give compound 28. Catalytic hydrogenation using Raney nickel leads to reduction of the nitro group to an amine and subsequent cyclization to give the dihydropyrrole 29. The double bond is reduced with sodium cyanoborohydride to give the pyrrolidine compound 30 as a mixture of cis-cis, trans,trans and cis,trans isomers. Chromatography separates out the cis-cis isomer, leaving a mixture of the trans,trans and cis,trans isomers (31).

Scheme VI illustrates the further elaboration of the trans,trans isomer. The mixture (31) of trans,trans and cis,trans pyrrolidines -48described in Scheme IV is reacted with N-propyl bromoacetamide in acetonitrile in the presence of ethyldiisopropylamine to give the alkylated pyrrolidine compound 2, still as a mixture of trans,trans and cis,trans isomers. Sodium hydroxide in ethanol-water hydrolyzes the ethyl ester of the trans,trans compound but leaves the ethyl ester of the cis,trans compound untouched, thus allowing separation of the trans,trans carboxylic acid 3 from the cis,trans ester 34.

Scheme VII illustrates the preparation of a specific piperidinyl compound. Benzodioxolyl methyl chloride 5 is reacted with lithio 1o dithiane 36 to give the alkylated compound 37. Treatment of compound Z3 with 4-methoxybenzyl chloride in the presence of lithium diisopropylamide gives compound 38. Cleavage of the dithiane protecting group using a mercuric salt in aqueous solution gives ketone 39. Treatment of 39 with benzylamine and formaldehyde gives the keto piperidine 40. Treatment of compound 40 with trimethylsilyl cyanide followed by phosphorous oxychloride gives the ene nitrile as a mixture of isomers 4.1. Sodium borohydride reduction of the double bond gives the piperidinyl nitrile 42. Hydrochloric acid hydrolysis in the presence i* 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 45. A preferred embodiment of the process shown in Scheme III is shown in Scheme VIII. 4-Methoxybenzoylacetate 4. (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 48.

Treating compound 48 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 50. Epimerization with sodium ethoxide in ethanol to give the desired trans,trans configuration is followed by sodium hydroxide hydrolysis of the ester to afford the desired trans,trans carboxylic acid 51.

Scheme IX illustrates the preparation of compounds where n is 0, Z is -CH 2 and W is other than carboxylic acid. Compound 55, which -49can be prepared by the procedures described in Scheme IV, is converted (for 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 nitrile 57.

Nitrile 57 under standard tetrazole forming conditions (sodium azide and triethylamine hydrochloride or trimethylsilylazide and tin oxide) is reacted to give tetrazole 58. Alternatively nitrile 57 is reacted with hydroxylamine hydrochloride in the presence of a base (for example, 1o potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH) in a solvent such as DMF, DMSO, or dimethylacetamide to give amidoxime 59. The amidoxime S 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 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 cyclization to'compound 6Q. Altematively reacting the amidoxime 59 with thionyl chloride in an inert solvent (for example, chloroform, dichloromethane, dixoane and THF and the like) affords the oxathiadiazole 61. Scheme X illustrates the preparation of compounds in which R3 is an acylmethylene group. A carboxylic acid 62 (where R 4 is as previously defined herein) is treated with oxalyl chloride in a solution of methylene chloride containing a catalytic amount of N,Ndimethylformamide to give the acid chloride. Treatment of the acid chloride with excess ethereal diazomethane affords a diazoketone, and so then treatment with anhydrous HCI in dioxane gives the a-chloroketone Ea. Pyrrolidine ester 5 where E is lower alkyl or a carboxy protecting group, prepared in Scheme I, is alkylated with the a-chloroketone 6 to provide alkylated pyrrolidine 64. Carboxy deprotection (for example, hydrolysis of an alkyl ester using lithium or sodium hydroxide in ethanol-water) gives the alkylated pyrrolidine acid 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 8 -X where R 8 is alkylene and X is a leaving group (for example a halide where Br is preferred) to give N-alkylated compound 66. Treatment of 66 with an amine (R2oNH 2 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 hydrogenation of a benzyl moiety) to afford amide 68. Alternatively amine 67 can be reacted with an activated sulfonyl compound (for example, R6-S(0) 2 -CI) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford sulfonamide Scheme XII illustrates a method for synthesizing pyrrolidines by an azomethine ylide type [3+2]-cycloaddition to an acrylate. General structures such as compound 70 are known to add to unsaturated esters such as 71 to provide pyrrolidines such as compound 72 Tsuge, S. Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983), 0. Tsuge, S.

Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem. 52 2523-30 (1987), and S. Kanemasa, K. Skamoto, O. Tsuge, Bull. Chem. Soc. Jpn. 62 1960-68 (1989)). A specific example is also shown in Scheme XII. Silylimine 73 is reacted with acrylate 74 in the presence of trimethylsilyl triflate and tetrabutylammonium fluoride to give the desired pyrrolidine 75 as a mixture of isomers. This method can be modified to provide the N- acetamido derivatives directly by reacting 73 and 74 with the appropriate bromoacetamide (for example, dibutyl bromoacetamide) in i" the presence of tetrabutylammonium iodide and cesium fluoride to give compound 76.

Scheme XIII illustrates a method for producing an enantiomerically pure pyrrolidine B0, which can be further elaborated on the pyrrolidine nitrogen. Intermediate racemic pyrrolidine ester 77 (for example, prepared by the procedure described in Scheme V) is Bocnitrogen protected (for example, by treatment with Boc 2 0) 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 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 -51sodium carbonate or citric acid) to afford enantiomerically pure 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 M8. 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, by treatment with the dibutyl amide of bromoacetamide in acetonitrile in the presence of diisopropylethylamine) to give optically active compound 81. The use of (-)-cinchonine will give the opposite enantiomer.

Scheme XIV describes another procedure for preparation of pyrrolidines. Pyrrolidines may be synthesized by the use of an S azomethine ylide cycloaddition to an acrylate derivative as described by Cottrell, I. et.al., J. Chem. Soc., Perkin Trans. 1, 5: 1091-97 (1991). Thus, the azomethine ylide precursor 82 (where R 5 5 is hydrogen or methyl) is condensed with a substituted acrylate 83 (wherein R 2 is as described herein and R5 6 is loweralkyl) under acidic conditions to afford the substituted pyrrolidine 84. The N-protecting group can be removed (for example, by hydrogenolysis of an N-benzyl group) to give 85, which can be alkylated under the conditions described above to provide the N-substituted pyrrolidine 86. Standard ester hydrolysis of 86 produces the desired pyrrolidine carboxylic acid 87. A preferred process is shown in Scheme XV. Nitro vinyl compound is reacted with beta-keto ester 89 in the presence of a base such i": as sodium ethoxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as THF, toluene, DMF, acetonitrile, ethyl acetate, isopropyl acetate or methylene chloride and the like at a temperature of from about 0° C to about 1000 C for a period of time from about 15 minutes to ovemight to give compound 9Q.

Reduction of the nitro 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 of compound Q9 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 -52platinum on alumina and the like, or a rhodium catalyst, such as rhodium on carbon or rhodium on alumina and the like, and the like affords intermediate nitrone 91a or a mixture of nitrone 91a and imine 91b. 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, 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 92 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 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 -200 C to about 1200 C to give the is trans,trans compound 93. Compound 93 itself can optionally be resolved into enantiomers prior to reacting with X-R 3 The substantially pure at least 95% of the desired isomer) optically *a active (+)-isomer of compound 93 is obtained by treatment of a mixture of the (+)-isomer and the (-)-isomer of 93 with S-(+)-mandelic acid, Dtartaric acid or 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 93 selectively crystallizes as the salt, leaving the "i" (-)-isomer of 93 in solution. Alternatively, the substantially pure i" at least 95% of the desired isomer) optically active (-)-isomer of compound a3 can be selectively crystallized by reaction of a mixture of the (+)-isomer and the (-)-isomer of 93 with L-tartaric acid, L-dibenzoyl tartaric acid or L-pyroglutamic acid and the like, leaving the desired (+)-isomer of compound 93 in solution.

Compound a3 (racemic or optically active) is reacted with X-R 3 (where X is a leaving group (for example, a halide or a sulfonate) and R 3 is as previously defined) using a base such as diisopropylethylamine, triethylamine, sodium bicarbonate or potassium carbonate and the like in an inert solvent such as acetonitrile, THF, toluene, DMF or ethanol and the like at a temperature of from about 0° C to about 1000 C to give the intermediate ester 94. The ester can be isolated or converted in -53situ to the carboxylic acid (95) using hydrolysis conditions such as a base such as sodium hydroxide or lithium hydroxide or potassium hydroxide and the like in a solvent such as ethanol-water or THFethanol and the like.

Scheme I 0 2

E

,_CO2E R2 NO2 ACO2E R C f< R2

NO

2

[H]

H

R2- R,

CO

2

E

Mixture of Cis-Cis Trans-Trans Cis-Trans

X-R

3 N R3 6 C0 2

E

Mixture of Trans-Trans Cis-Trans R2 N R1 C0 2

E

4 R3 R2- R

CO

2

H

Trans-Trans 2

E

R2@" c

RI

CO2E 0 0 0 S. S 0 oo oo oo o

[H

2 0 Cis-Trans -54- Scheme II cI 9 L Q Li 0 R

,S

Rn~I 0 R1 2 1JL R, /13 'i rN ~R2 14

R

Or N R2 y C02E N ,R 2

+CN

*r

C

ISOMER

O- R2 y CN R3,.N R 2 y.C0 2

H

Scheme III Halo R2 y

J

0 C0 2 E R, C0 2

E

J0 2 C R 2 21- Halo Cl, Br, or I

R

2

R

C0 2

E

24

N

R2 1 C0 2

E

N

C0 2

H

Trans-Trans -56- Scheme IV

R

3 2

H

R2 ~C0 2

H

0 L 52 iCH 2

N

2 N4R 3 R2-LR, 0 CHN 2 a.

4* -57- Scheme V C H0 N 0 N 2 EtO 2 C 0 m a 27 H2 N

_N

0 I OCH 3 COOIEt

OCH

3 NaCBH 4 Mixture of M Cis-Cis Trans-Trans Chro matographic separation Cis-Trans Cis-Cis Mixture of Trans-Trans and Cis-Trans -58- Scheme VI

COQE

Cis-Trans and B rCH 2 CO N HC 0 H ei

\/OCH

3 Trans-Trans 2 NEt COQEt Trans-Trans and Cis-Trans NaGH H 2 0, EtOH 0 rl-l N H 3

H

7 N HC 3

H

7

I

C H3 COQEt Trans-TransCs-rn Cis-Trans Scheme ViI 0o DI C J,

D

0 <0 QsQ o ~e 0i% J a. a

ISOMER

Scheme VII cont.

I

oo, OMe OMe

-CO

2 Et 44 'C0 2 Et 43 OMe OMe -61- Scheme VIII 2

E

Br

/-CH

3 C02E

OCH

3 C0 2

E

A

C

Tans-Trarm -62- Scheme IX R3

N'

(CHi 2 )m

I

NIN

R

3

(CH

2 )m

IN

S. RR3

(CH

2 )m H N 1,N

I~-

I 4eR 3

H

2 N INOH 59

(CH

2 )m HN

N

S-0 0 -63- Scheme X

R

4 )rOH cI "A y cI 0 0 'C0 2

E

-C0 2

H

C0 2

E

S S. S.

S

*SSS.S

-64- Scheme X1

H

R

2 R C0 2

E

0 \>-R4 N8- C0 2

H

C0 2

E

N'

R

8 -NHR 20 C0 2

E

Scheme XII

R,

R3,, "i

N+

I

CH2 C0 2 Et R2 C

R,

R3, NL

CO

2 Et Me 3 Si

OCH

3 Io oI C0~ 2

E

CO

2 Et -66- Scheme XIII

OCH

3 C 2 Et 2. NaOH, EtOH 0 2 0-i -j Z7 W± 7E 1. (+)-cinchonine 2. recrystallize fron EtOActhexane 3. Na 2

CO

3 ocd

-C

HCI

EtOH

HCI

9* /-0 80 Z2

BU

2

NC(O)CH

2 Br EtNiPr 2

CH

3

CN

0 a' -67- Scheme XIV Me, 3 Si

H

2 Pd(OH) 2

/C

R2 C02RS6 83 TFA, 0H 2 C1 2 Ph NQ _C0 2

R

56

R

2

R

3 Br

BU

4 NI or Nal

CH

3

CN

H Nq _C0 2

R

56

R

2 S

S.

S

S

C0 2 Rs 6 NaGH or UGH EtCH, H 2 0 1

C

2

H

-68- Scheme XV .,NO 2 0 0 E L- 0 C02

RU

2 C0 2

E

2

N

C0 2

E

9 9 9* 9 .9 .9 9 9**9 9 9 9 9 9.

9 9 99 9 9* 99 9 C0 2

E

R2 R C0 2

E

C0 2

E

-69- Compounds which are useful as intermediates for the preparafion of compounds of the invention are:

R

2

NH

IC

2 (CHH2)m w R wherein n isO0 or 1; m is 0 to 6; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3

H

2 -P(O)(OH)E where E is hydrogen, toweralkyl or arylalkyl,

-CN,

-C(O)NHR1 7 where R 17 is loweralkyl, alkylaminocarbonyl,V04 dialkylaminocarbonyl, tetrazolyl, hydroxy,.

alkoxy, sulfonamido,

-C(O)NHS(O)

2 Rl6 where R16 is loweralkyl, haloalkyl, phenyl or dialkytamino, (in) -S(O) 2

NHC(O)RI

6 HO 0 0 HO 0 (0)

OH

(p) 0 0 H 0 kPN

SCF

3 Mt ,or NHso 2

CF

3 and

R

1 and R 2 are independently selected from hydrogen, loweralkyl, S alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, o cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyi-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is a ryl or aryIalkl, Rbb is hydrogen or alkanoyl and RC is alkylene, with the proviso that one or both of R 1 and

R

2 is other than hydrogen; or a salt thereof; or a compound of the formula: -71- R2NH R2NH

(CH

2 )m(CH 2 )m W R 1 or W R (I V)

(V

wherein n is 0 or 1; m is 0to 6; W is -C(O)2-G where G is hydrogen or a carboxy protecting group, -P0 3 1- 2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

-CN,

-C(O)NHFI

17 where R 17 is loweralkyl, alkylamninocarbonyl, dial kylami nocarbonyl, tetrazolyl, hydroxy, U) alkoxy, sulfonamido,

V

-C(O)NHS(O)

2 Rl6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl 6

HO

0

HO

OH

-72- 0 (r) 0 (q J.

NHSFCF

,HQ2F and Ri and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hyd roxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylamninocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rc- wherein Ra is ary o rylalkyl, Rbb is hydrogen or alkanoyl and RC is alkylene, with the proviso that one or both of R, and

R

2 is other than hydrogen; or a salt thereof.

Preferred intermediates include compounds of formula (1ll), (IV) and wherein m is zero or 1; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group, and Rl and R 2 are as defined above; or the substantially pure or (+)isomer thereof.

-73- Particularly preferred intermediates are compounds of formula (1ll), (IV) and wherein n and m are both 0; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; and R, is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1,4benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy (ix) aryalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R 2 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.

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

(CH

2 )n

(CH

2 )m W R

(VI)

-74wherein n is 0 or 1; m is 0 to 6; Rs-b is alkylene; 0 is a leaving group; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3

H

2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

-CN,

-C(O)NHR1 7 where R 17 is loweralkyl, alkylamninocarbonyl, dialkylamninocarbonyl, hydroxy, ()alkoxy, sulfonmi,

-C(O)NH-S(O)

2 Rl 6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl 6 HO* 0 0 H 0

OH

(p) 0 0 (r) 0 A-JL-

N

H

%-CF 3 MH ,or

NHSO

2 cF 3 and

R

1 and R 2 are independently selected from -hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkyamincaronyllkyl dilkylminoarbnylakyl,: aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rb)RcwhrnRa is aryl or a rylalkyl, Rb is hydrogen or alkanoyl and RC 0 is alkylene, with the proviso that one or both of R, 1 and

R

2 is other than hydrogen; or a salt thereof; or a compound of the formula:

R

2 RSb Q

R

2 R~b -Q II

I

(CH

2 W (H) (CH2)m\ (CH 2 )m W or W R (ViI) (VilI) wherein n is 0 or 1; m is 0 to 6; -76- Rsb is alkylene; Q is W is a leaving group;

-C(O)

2 -G where G is hydrogen or a carboxy protecting group, -P0 3

H-

2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

-CN,

-C(O)NHR

17 where R 17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido,

-C(O)NHS(O)

2 Rl 6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl 6 HO 0 0 tn) (p)

~~NH

0- 0 -77- 0

H

CF

3 MH ,or -a NHSO 2

CF

3 an RI and R 2 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 (Raa)(Rbb)N-Rcc wherein Raa is a ryl or a rylalkyl, Rbb is hydrogen or alkanoyl and RC is alkylene, with the proviso that one or both of R, and

R

2 is other than hydrogen; or a salt thereof.

Preferred intermediates include compounds of formula (VII) and (ViII). wherein m is zero or 1; ko R 5 b is alkylene; Q is a leaving group; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group, and RI and R 2 are as defined above; or the substantially pure or (+)isomer thereof.

Particularly preferred intermediates are compounds of formula (VII) and (ViIl) wherein n and m are both 0; Rsb is alkylene; Q is a leaving group; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; -78and R 1 is loweraikyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4methyiphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4methoxyphenyl, 3-f luoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyt, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1,4benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R 2 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.

Other compounds which are useful as intermediates for the preparation of compounds of the invention are: N RftbNHR2Oa (0 2 )m

(IX)

wherein n is 0 or 1; m is 0 to 6;

R

5 b is alkylene; R2Oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; -79- W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3

H

2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

-CN,

-C(O)NHR1 7 where R 17 is loweralkyl, alkylamninocarbonyl, dial kyl aminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido,

-C(O)NHS(O)

2 Rl 6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl 6 HO 0 0 HO 0

OH

S~N

0 0 0

H

JC>- CF 3 MH ,or

NHSO

2

CF

3 an

R

1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, aikynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioal koxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylatkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, p dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, 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 RC is alkylene, with the proviso that one or both of R, and

R

2 is other than hydrogen; or a salt thereof; or a compound of the formula: R2 RbNHR

R

2 N R bNHR20a I I (H CH)m (CH2)(H 2 n W R or W R

(XI)

wherein n is 0 or 1; m is 0 to 6; Rsb is alkylene; R2Oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3

H

2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, -C N, -81- -C(O)NHR1 7 where R 17 is loweralkyl, alkylaminocarbonyl, dial kylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O)2Rl6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino,

-S(O)

2 NHC(O)Rl 6 HO 0 0 H OH Ia.

b (q)0 (r) 0

H

F

H =or -82-

NHSO

2

CF

3 an R, and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyI, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl,aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, 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 RC is alkylene, with the proviso that one or both of R, and

R

2 is other than hydrogen; or a salt thereof.

Preferred intermediates include compounds of formula (X) and (XI) whereinmn is zero or 1; Rsb is alkylene;

R

2 0a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group, and R1 and R 2 are as defined above; or the substantially pure or (-)isomner thereof.

Particularly preferred intermediates are compounds of formula and (Xl) wherein n and mn are both 0; Rsb is alkylene; R2Oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; and R 1 is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4ethoxyphenyl, 4-ethyiphenyt, 4-methyiphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- -83ethoxyphenyl, 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, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl.Nalkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R 2 is substituted or unsubstituted 1, 3-benzodioxolyl, 7-methoxy- 1,3benzodioxolyl, 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 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-(3dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, EtOAc for ethyl acetate, EtOH for ethanol, HOBt for 1-hydroxybenzotriazole, Et 3

N

for triethylamine, TFA for trifluoroacetic acid and THE for tetrahydrofuran. tran. tans 2-Example 1 Ethyl 2-(4-methoxybenzoyl-4-nitromethyl-3-(1 To ethyl (4-methoxybenzoyl) acetate (23.0 g, 0.104 mol), prepared by the method of Krapcho et al., Org. Syn. 47Z, 20 (1967), and 5-(2nitrovinyl)-1,3-benzodioxole (17.0 g, 0.088 mol) dissolved in 180 mL of toluene and heated to 80 OC was added 1 ,8-diazabicyclo[5,4,0] undec-7ene (DBU, 0.65 g) with stirring. The mixture was heated until all the nitro 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 -84chromatography ethyl acetate in methylene chloride) indicated the absence of nitro 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 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 1B Ethyl 2-(4-methoxvDhenvl)-4-(1.3-benzodioxol-5-vl)-4.5-dihvdro-3H-Pvrrole-3carboxvlate I The compound resulting from Example 1A (21 g) in 500 mL of ethanol was hydrogenated under 4 atmospheres of hydrogen pressure using a Raney nickel 2800 catalyst (51 (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 the desired product.

66 Example 1C Ethyl 2-(4-methoxyvhenyl-4-(1.3-benzodioxol-5-yl)-yvrrolidine-3-carboxylate as a mixture of cis-cis: trans.trans: and cis.trans-isomers The compound resulting from Example 1B (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 mol) 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 light 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 pressure. The residue was chromatographed on silica gel eluting with 85:15 ethyl acetate-hexane to give 5.96 g. of a mixture of 64% trans, trans-compound and 34% cis,trans-compound. Further elution with pure ethyl acetate gave 0.505 g of an unknown solid followed by 3.044 g of pure cis,cis-compound.

ExamDle 1D trans.trans-2-(4-Methoxvyhenvl)-4-(1.3-benzodioxol-5-vl)-1- (DroDvlaminocarbonvlmethvl)-ovrrolidine-3-carboxvlic acid The mixture of 64% trans,trans- and 34% cis,trans-pyrrolidines (the mixture resulting from Example 1C) (5.72 g, 15.50 mmol), ethyldiisopropylamine (4.20 g, 32.56 mmol), and N-propyl bromoacetamide (3.42 g, 19.0 mmol), prepared by the method of Weaver, W.E. and Whaley, J. Amer. Chem. Soc., 61: 515 (1947), in 30 mL of acetonitrile was heated at 50 °C for 1 hour. The solution was S concentrated in vacuo. The residue was dissolved in toluene, shaken with potassium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to give 7.16 g of product as a mixture of trans,trans- and cis, trans- ethyl esters. This mixture was dissolved in a solution of 50 mL of ethanol and mL of water containing 5.00 g of sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and 60 mL of water added. The mixture was extracted with ether to remove the unreacted cis,trans- 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, drying over sodium sulfate, concentrating in vacuo, and crystallizing from ether to give 3.230 g of the title compound. m.p. 151-153 OC. 1H NMR (CD 3 OD, 300 MHz) 8 0.87 J 7 Hz, 3H), 1.49 (sextet, J 7 Hz, 2H), 2.84 d, J 16 Hz, 1H), 2.95-3.20 4H), 3.20 J 16 Hz, 1H), 3.34-3.42 1H), 3.58-3.66 1H), 3.78 3H), 3.88 J 10 Hz, 1H), 5.92 2H), 6.75 J 8 Hz, 1H), 6.86 (dd, J= 8 Hz, J 1 Hz, 1H), 6.90 J 9 Hz, 2H), 7.02 J 1 Hz, 1H), 7.40 J 9 Hz, 2H).

Example 2 trans.trans-2-(4-Methoxvohenvl-41 .3-benzodioxol-5-vl- 1- (aminocarbonvlmethvl)-ovrrolidine-3-carboxylic acid Using the method described in Example 1D, 300 mg of the mixture of 64% trans,trans- and 34% cis,trans-pyrrolidines (the mixture -86resulting from Example 1C), 220 mg of diisopropylethylamine and 184 mg iodoacetamide were reacted at 45 "C in 1 mL acetonitnile to give 291 mg of a mixture of trans, trans- and cis, trans- N-alkylated esters.

A portion (270 mg.) was hydrolyzed with 200 mg NaOH in 1 mL of water and 3 mL of ethanol; a chloroform extraction was used to remove the unreacted cis, trans- 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 1 H NMR (DMSO-d 6 300 MHz) 8 2.61 (d, J 16 Hz, 1 2.71 J 9 Hz, 1 2.90 J 9 Hz, I1H), 2.98 J 16 Hz, 1H),3.25-3.35 (in, 1H), 3.45-3.55 (in, 1H), 3.71 3H), 3.75 J 10 Hz, 1 6.00 2H), 6.81 2H), 6.90 J 8 Hz, 2H), 7. 10 (s, 1 7.17 1 7.34 1 7.38 J 8 Hz, 2H). Example 3 trans, trans-2- (4-Methoxv~henyl)-4-( 1.3-benzodioxol-5-yl- 1- 44-fluorobenzyl)-:7 12yrrolidine-3-carboxylic acid Using the method described in Example 1D, 300 mng of the mixture of 64% trans,trans- and 34% cis,trans- pyrrolidines (the mixture resulting from Example 1C), 220 mg of diisopropylethylamine and 185 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 1 mL of water and 4 mL of ethanol to give 160 mng of the title compound as an amorphous powder. 1 H NMR (CDC1 3 300 MHz) 8 2.74 J 9 Hz, 1 2.95 J 7 Hz, 1 2.98 J 14, 1 3.07 (dd, J 9 Hz, 1 Hz, 1 3.42-3.53 (mn, 1 3.70 J 9 Hz, I1H), 3.78 J 14, 1 3.81 3H), 5.92 2H), 6.70 J 8 Hz, 1 6.77 (dd, J 8 Hz, 1 Hz, 1 6.91 J 9 Hz, 2H), 6.94 -7.00 (mn, 3H), 7.20 7.25 1H), 7.44 J 9 Hz, 2H).

Example 4 trans, tra ns-2- Meth oxyh en (1 ben zod ioxol-5-Yfl- 1 -(2-ethoxyethyl)- 12vrrolidine-3-carboxylic acid Using the method described in Example 1D, 300 mg. of the mixture of 64% trans,trans- and 34% cis, trans-pyrrolidines (the mixture resulting from Example 1C), 220 mng of diisopropylethylainine and 152 mng of 2-bromoethyl ethyl ether were refluxed in 1.5 mL acetonitrile for -87- 3 hours (bath temperature at 95 OC) to give 346 mg of a mixture of trans,trans- and cis,trans-esters. Hydrolysis with 250 mg NaOH in 1 mL of water and 3 mL of ethanol afforded 140 mg of the title compound.

m.p. 88 90 OC. 1 H NMR (ODC1 3 300 MHz) 8 1.25 J 7 Hz, 3H), 2.21- 2.32 (in, 11H), 2.70-2.80 (in, 1H), 2.85-2,94 (in, 2H), 3.38-3.55 (in, 6H), 3.67 J 10 Hz, 1H), 3.79 3H), 5.94 2H), 6.72 J 8 Hz, 1H), 6.84 (in, 1 6.84 J 9 Hz, 2H), 7.08 J 1 Hz, 1KH), 7.33 J =9 Hz, 2H).

Examp~le trans, trans-2-(4-Methoxvlhenyl)-4-( 1.3-benzodioxol-5-yfl)-1 -(2-Droooxyethyl-L: D2yrrolidine-3-carboxylic acid Using the method described in Example I D, 520 mg of the mixture resulting from Example 1C, 364 mng of diisopropylethylamine, 50 mng potassium iodide and 350 mg 2-chloroethyl propyl ether were reacted:: at 125 OC 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 mng) was hydrolyzed with 315 mg NaOH in 1 mL of water and 4 mL of ethanol to give 225 mng of the title compound as an amorphous powder. 1H NMR

(CDC

3 300 MHz) 8 0.87 J 7 Hz, 3H), 1.53 (sextet, J 7 Hz, 2H), 2.28-2.41 (in, 1KH), 2.71-2.83 (in, 1KH), 2.92-3.08 (mn, 2H), 3.30 J 7 Hz, 3.40-3.60 (in, 4H), 3.72-3.83 (in, 1 3.76 3H), 5.92 2H), 6.71 J =8 Hz, 2H), 6.74 (dd, J 8 Hz, 1 Hz), 6.71 J 9 Hz, 2K), 7.07 J =9 Hz, 2H), 7.73 J 9 Hz, 2H).

Exam~le 6 trans. tran-2(-Methoxyohenyfl-4-( 1.3-benzodioxol-5-yl)- 1 -i2-2methoxyethoxy~ethyl1Dyrrolidine-3-carboxylic acid Examlle 6A Ethyl trans. trans-2-(4-methoxvrhenyl-4-(1 .3-benzodioxol-5-yl' [2yrrolid ine-3ca rboxylate To the pure cis,cis-coinpound resulting from Example 1C (3.02 g) dissolved in 10 mL of ethanol was added 20 drops of a solution of 21% 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 NaQEt was neutralized -88with 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 sulfate and concentrated under reduced pressure to give 2.775 of the title compound which was pure by TLC (ethyl acetate).

Examole 6B trans, trans-2-(4-Methoxvyhenvy)-4-(1.3-benzodioxol-5-vl)-1 methoxyethoxyvethyll-yrrolidine-3-carboxylic acid Using the method described in Example 1D, 250 mg of the compound resulting from Example 6A, 150 mg of 2-(2methoxyethoxy)ethyl bromide and 175 mg diisopropyl-ethylamine in 1 S mL acetonitrile were heated at 100 °C for 3 hours to give 229 mg of the trans,trans-ester. A portion (200 mg) was hydrolyzed with 125 mg NaOH in 1 mL of water and 2 mL of ethanol to give 151 mg of the title compound as an amorphous powder. 1 H NMR (CD 3 OD, 300 MHz) 8 2.9-3.9 13H), 3.81 3H), 4.49 J 10 Hz, 1H), 5.94 2H), 6.79 J 8 Hz, 1H), 6.89 (dd, J 8 Hz, 1 Hz, 1H), 7.00 J 9 Hz, 2H), 7.05 J 1 Hz, 1H), 7.49 J 9 Hz, 2H).

Examole 7 trans trans-2-(4-MethoxvDhenvl)-4- 1 .3-benzodioxol-5-vl- 1 -12-(2-Dvridvl)ethyl]- Dyrrolidine-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 2methoxyethanol, and stirred at 100 OC 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 reconcentrated. This was 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 1D to give 202 mg of the title compound as the dihydrate. m.p. 77-80 1 H NMR (CD3OD, 300 MHz) 8 2.8 3.3 6H), 3.55-3.70 2H), 3.76 3H), 3.99 J 10 Hz, 1H), 5.92 J 1 Hz, 2H), 6.72 J 8 Hz, 1H), 6.80 (dd, J 8 Hz, 1 Hz), 6.85 J 9 Hz, -89- 2H), 6.92 J 1 Hz, 1H), 7.20 J 9 Hz, 2H), 7.20-7.32 2H), 7.70-7.80 2H), 8.40 J 4 Hz, 1H).

ExamDle 8 trans trans-2-(4-Methoxyphenvl)-4-(1.3-benzodioxol-5-vl-1 -(moroholin-4ylcarbonyl)-Dyrrolidine-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 1D to give 288 mg of the title compound. m.p. 244-246 0C. 1 H NMR (DMSOd 6 300 MHz) 8 2.96 (dd, J 12,Hz, 13 Hz, 1H), 3.03-3.13 2H), 3.20- 3.30 2H), 3.40-3.60 5H), 3.74 3H), 3.70-3.85 3H), 5.10 (d, J 10 Hz, 1H), 5.99 J 1 Hz, 2H), 6.80-6.90 2H), 6.87 J 9 Hz, 2H), 7.07 1H), 7.25 J 9 Hz, 2H). Example 9 trans. trans-2-(4-MethoxvDhenvl)-4-(1.3-benzodioxole-5-v)-1 -(butvlaminocarbonvl)- Dvrrolidine-3-carboxvylic 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 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 1D to give 232 mg of the title compound. m.p. 220-221 °C.

'H NMR (DMSO-d6, 300 MHz) 5 0.78 J 7 Hz, 3H), 1.10 (sextet, J 7 Hz, 2H), 1.22 (quintet, J 7 Hz, 2H), 2.78-3.05 3H), 3.40-3.56 (m, 2H), 3.74 3H), 3.95-4.05 1H), 4.93 J 9 Hz, 1H), 5.80 broad, J 7 Hz, 1H), 5.99 2H), 6.78-6.86 2H), 6.88 J 9 Hz, 2H), 7.00 J 1 Hz, 1H), 7.12 J 9 Hz, 2H).

Example trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)- 1 methoxvyhenylaminocarbonyl)-3-Dvrrolidine-3-carboxlic acid The compound resulting from Example 6A (300 mg) was treated 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 1D to give 279 mg of the title compound.

m.p. 185-187 'H NMR (CDC13, 300 MHz) 8 3.23 (dd, J 12 Hz, 13 Hz, 1H), 3.55-3.68 2H), 3.72 3H), 3.83 3H), 4.50-4.65 1H), 5.06 J 10 Hz, 1H), 5.90 1H), 5.95 1H), 6.72 J 9 Hz, 2H), 6.7-6.8 3H), 6.92 J 9 Hz, 2H), 6.97 J 9 Hz, 2H), 7.37 J 9 Hz, 2H).

Example 11 trans. trans-2-(4-MethoxyDhenvl)-4-(1.3-benzodioxol-5-yl)-1 -acetylpyrrolidine-3carboxylic 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 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 1D to give 211 mg of the title compound. m.p. 248-250 Rotational isomers are seen in the NMR. 1 H NMR (DMSO-d6, 300 MHz) S 1.55 and.: 2.00 3H), 2.94 and 3.03 (dd, J 12 Hz, 13 Hz, 1H), 3.3-3.6 2H), 3.72 and 3.76 3H), 4.12 and 4.28 (dd, J 12 Hz, 7 Hz, 1H), 4.95 and 5.04 J 10Hz, 1H), 6.00 2H), 6.75-6.87 3H), 6.95 and 7.04 (d, J 9 Hz, 2H), 7.18 and 7.32 J 9 Hz, 2H).

Example 12 trans. trans-2-(4-MethoxvDhenyl)-4-(1.3-benzodioxol-5-l)- 1 -(2-furoyl)-Dyrrolidine-3carboxylic 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 bath was added 138 mg of 2-furoyl chloride. The mixture was stirred minutes at room temperature and then worked up by the procedures described in Example 8 to give the intermediare ester. The ester was -91hydrolyzed by the procedure described in Example- 1 D to give 269 mg of the title compound as an amorphous powder. 'H NMR (DMSO-dr,, 300 MHz) 8 3.06 (dd, J 12 Hz, 13 Hz, I 3.3-3.6 (in, 2H), 4.25 (in, I1H), 5.19 d, J 10 Hz, 1 6.67.4 (in, 8H), 7.8-7.9 (in, 1 H).

Example 13 trans. trans-2-(4-Methoxy~henvl)-4- (1 .3-benzodioxol-5-yl)- 1- (phenylam inocarbonyl)-oyrrolidine-3-carboxylic acid Starting with the compound resulting from Example 6A, phenyl isocyanate and the procedures described in Example 9, the title compound was prepared. m.p. 209-211 0 C. IH NMR (DMS0-cl 6 300 MHz) 8 3.03 (dd, 1 3.55 (in, 1 3.70 (mn, 1 3.72 3H), 4.15 (in, 1 H), 5.13 1 6.00 2H), 6.88 (in, 5H), 7.07-7.20 (in, 3H), 7.30 2H), 7.38 2H), 8.20 (bs, 1 H).

was 1 H), 3.97 6.97 was 3H-), 1 H), Example 14 trans, trans-2-(4-Methoxyohenl)-4-(1 .3-benzodioxol-5-vl)- (allviam inoca rbonvlmethyl)-o2yrrolidine-3-carboxvlic acid Using the procedures described in Example 1 the title compound prepared. in.p. 138-140 OC. 1 H NMR (ODC1 3 300 MHz) 8 2.84 (d, 2.90-3.10 (dt, 2H), 3.28 1H), 3.35 (dd, 1H), 3.62 (in, 1H), 3.72- (in, 3H), 3.80 3H), 5.13 (bd, 2H), 5.80 (in, 1 5.97 2H), 6.74- (in, 5H), 7.38 2H).

Exam Dle trans. trans-2-(4-Methoxyhenyfl-4-( 1. 3-benzodioxol-5-yl)- 1 butylaminocarbonylmethyl)-Dyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound prepared. m.p. 105-107 OC. 'H NMR (CDC1 3 300 MHz) 8 0.90 (t, 1.30 (mn, 2H), 1.45 (in, 2H), 2.80 1 2.87-3.35 (in, 6H), 3.62 (in, 3.80 3H), 5.97 2H), 6.75-6.92 (in, 5H), 7.28 2H).

Examgle 16 trans, trans-2- (4-Methoxyhenfl)-4-( 1.3-benzodioxol-5-yl)- 1 -(N-(n-lnroDyl)-Nm ethyl am i noca rbony m ethyl)-gyrrol id ine-3-ca rboXylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. Rotational isomers are seen in the -92- NMR. 'H NMR (CDCI 3 300 MHz) 8 0.73, 0.84 (2t, 3H), 1.49 (in, 2H), 2.80 (dd, 1 2.85 (2s, 3H), 2.95-3.20 (in, 3H), 3.20-3.40 (in, 1 3.40 (d, 1 3.60 (in, 1 3.79 3H), 5.93 2H), 6.73 1 6.86 (in, 2H), 7.03 (in, 1 7.32 2H).

Example 17 trans, trans-2-(4-Methoxyrhenyl)-4-( 1.3-benzodioxol-5-yl)- 1 -(pvrrolidin- 1ylcarbonylmethyl)-Dyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. 1 H NMR (CDCI 3 300 MHz) 8 1.40- 1.70 (in, 6H), 2.80 1 3.00 (in, 2H), 3.24-3.43 (mn, 5H), 3.60 (mn, 2H), 3.73 1 3.80 3H), 5.95 2H), 6.74 1 6.80-6.90 (in, 3H), 7.04 1 7.30 2H).

Example 18 trans. trans-2- M eth oxyhenyl)-4- 3-ben zod ioxol- 5-yl)- 1 (isobutylaminocarbonlmethyl)-Dyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 175-177 OC. 1 H NMR (CD 3 OD, 300 MHz) 8 0.87 (dd, 6H), 1.75 (septet, I1H), 2.85 1 2.90-3.10 (in, 4H), 3.23 1IH), 3.40 (in, 1 3.58-3.67 (in, 1 3.78 3H), 3.89 I1H), 5.92 2H), 6.76: 1H), 6.86 (dd, 1H), 6.91 2H), 7.02 1H), 7.40 2H1).

Examp~le 19 trans. trans-2-(4- Methoxyphenyr)-4-( 1.3-benzodioxol-5-y)- 1- (cvclopgntylaminocarbonylmethyl)-n2yrrolidine-3-carbogylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 137-139 OC. 1 H NMR (CDC1 3 300 MHz) 8 1.34 (in, 2H), 1.62 (in, 4H), 1.90 (mn, 2H), 2.76 1H), 2.90 1H), 3.04 (dd, 11H), 3.22 I1H), 3.28 (dd, 1 3.40 (in, 1 3.80 3H), 4.15 (in, 1 5.97 2H), 6.75-6.95 (in, 5H), 7.27 (mn, 2H).

Exam ole trans. trans-2-(4-Methoxvphenyl)-4-( 1.3-benzodioxol-5-yl)-1 -(morgholin-4ylaminocarbonylmethyl-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. 1 NMR (CDCI 3 300 MHz) 8 2.82 (d, -93- 1H), 3.00 (in, 2H), 3.24 (in, 1H), 3.30-3.52 (in, 4H), 3.52-3.75 (mn, 8H), 3.80 3H), 5.95 2H), 6.75 I 6.84 3H), 7.00 1 7.28 (d, 2H).

Examlle 21 trans. trans-2-(4-Methoxyrhenyl)-4-( 1.3-benzodioxol-5-yfl- 1 -(2-nhenoxyethyflpyrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared as an amorphous solid. 1 H NMVR (CD 3 OD, 300 MHz) 8 2.82 o (in, 11H), 2.96 (dd, 1H), 3.13 (in, 1H), 3.32 (in, 1H), 3.51-3.70 (in, 2H), 3.77 3H), 4.00 1 4.07 (in, 5.91 2H), 6.72 1 6.80- 6.95 (in, 6H), 7.03 1 7.22 (dd, 2H), 7.39 2H). Examlle 22 tra ns, trans-2- (4-M eth oxoh enyl)-4(1 .3-ben zod ioxoI- 5-yi) 1 methoxyethylam inocarbonylmethyl)-Dyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. in.p. 107-109 OC. 1 H NMR (CD 3 OD, 300 MHz) 8 2.82 (d, 1KH), 2.97 2H), 3.21 1KH), 3.38 (mn, 1KH), 3.32 3H), 3.44 (mn, 4H), 3.62 (in, I1H), 3.79 3H), 3.86 I1H), 5.93 2H), 6.76 1KH), 6.85 (dd, 1H), 6.91 2H), 7.01 7.38 Example 23 trans. trans-2-(4- Meth oxyDhenyI)-4-(1 ben zod ioxo 1-5-yi)- 1 -butoxyethyl- 12yrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared. in.p. 53-55 0 C. I H NMR (CDC1 3 300 MHz) 8 0.88 (t, J=7Kz, 3H), 1.32 (sextet, J=7Hz, 2H), 1.50 (pentet, J=7Hz, 2H), 2.27 (ft, J=6Kz, 6Hz, 11H), 2.92 J=lOHz, 3.35 J=7Hz, 2H), 3.42-3.56 (in, 4H), 3.68 J=lOHz, 1H), 3.78 5.94 2H), 6.73 J=8Hz, 1H), 6.83 J=9Hz, 2H), 6.82-6.87 (in, 11H), 7.06 J=2Hz, 1H), 7.32 (d, J=9Hz, 2H). MS in/e 442 -94- Examole 24 trans. tra ns-2- (1 Ben zod ioxo 1-5-yl)-4- (4-M eth oxyhenyl)- 1- (D2rooylam inocarbonylm ethyfl)-pyrrolidine-3-cp rboxylic acid Using the procedures described in Example 1 and substituting ethyl (1,3-benzodioxol-5-ylcarbonyl)acetate for ethyl (4methoxybenzoyi) acetate and 4 -(2-nitrovinyl)anisole for 5-(2nitrovinyl)-1 ,3-benzodioxol-5yi afforded the title compound. m.p. 97- 99 OC. 1 NMVR (CDC1 3 300 MHz) 8 0.78 J=7Hz, 3H), 1.39 (sextet, J=7Hz, 2H), 2.72 J=l6Hz, 1H), 2.74 J=lOHz, 1H), 2.80-3.10 (in, 4H), 3.26-3.38 (in, 1H), 3.53 (in, 1H), 3.73 3H), 3.80 J=lOHz, 2H), 7.80 J=6Hz, 1H). MS (DCI/NH 3 mWe 441 Examole trans. trans-2- (1 .3-Ben zodi oxol-5-yl)-4-(4-meth oxyh enyl)-1 1-(2-proloxyethyr)- .pyrrolidine-3-carboxylic acid Using the procedures described in Example 5 and substituting ethyl (1 ,3-benzodioxol-5-ylcarbonyi) acetate for ethyl (4methoxybenzoyl) acetate and 4-(2-nitrovinyl)anisole for 5-(2nitrovinyl)-1 ,3-benzodioxol-5yi afforded the title compound. m.p. 67- 69 OC. 1 H NMVR (CDCI 3 300 MHz) 8 0.89 J=7Hz, 3H), 1.56 (sextet, J=7Hz, 2H), 2.33 (mn, 1 2.78-3.00 (in, 3H), 3.32 J=7Hz, 2H), 3.45- 3.57 (mn, 4H), 3.73 (in, I1H), 3.79 3H), 5.93 2H), 6.22 J=8Hz, 1 H), 6.85 J=8Hz, 3H), 6.98 1H), 7.37 J=8Hz, 2H). MVS (DCI/NH 3 mle*.

428 Exam ole 26 trans, trans-2-( 1.3-Benzodioxol-5-yi)-4-(4-methoXvohenyl.. 1 -r2-(2methoxyethoxy)ethy)1-o2yrrolidine.3-carboxylic acid Using the procedures described in Example 4 and substituting the starting materials described in Example 25 and using 2-(2methoxyethoxy)ethylbroide to alkylate the pyrrolidine nitrogen afforded the title compound. m.p. 85-86 1 H NMR (CD 3 OD, 300 MHz) 8 3.18-3.90 (in, 15H), 3.79 3H), 4.57 J=lOHz, 1H), 6.02 2H), 6.91 J=8Hz, 1H), 6.95 J=9Hz, 2H), 7.06 (dd, J=8Hz, 1H), 7.12 (dd, J=lHz, 1H), 7.37 J=9Hz, 2H), MS (DCI/NH 3 in/e 444 Exam Die 27 trans, trans-2-( 1. 3-Benzodioxol-5-y)-4-(4-methoypheny)- 1 -(butogyethyflpyrrolidine-3-carboXylic acid Using the procedures described in Example 4, substituting the starting materials described in Example .25 and using 2ethoxyethylbromide to alkylate the pyrrolidine nitrogen afforded the title compound. m.p. 54-56 00. I H NMR (CDC1 3 300 MHz) 8 0.89 J- 7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 1.52 (pentet, J=7Hz, 2H), 2.40 (in, 1H), 2.74-2.98 (in, 3H), 3.46 J=7Hz, 2H), 3.42-3.56 (in, 4H), 3.68 (d, J=lOHz, 1H), 3.80 3H), 5.93 (dd, J=6Hz, 1Hz, 2H), 6.72 J=8Hz, 1H), 6.74 (dd, J=9Hz, 3H), 6.96 1H), 7.36 J=9Hz, 2H).

Example 28 trans. trans-2-(4-Methoxyhenyl)-4-( 1. 4-benzodioxan-6-yl)- 1 (prolylam inocarbonylm ethyl)-pyrrolidine-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 OC. 1 H NMR (CDC1 3 300 MHz) 8 0.89 J-7Hz, 3H), 1.49 (sextet, J=7Hz, 2H), 2.78 J=l6Hz, 1H), 2.92 J=lOHz, 1H), 3.05-3.43 (mn, 5H), 3.24 J=l6Hz, 1H), 3.52-3.62 (in, 1H), 3.80 3H), 3.80 J=lOHz, 11H), 4.27 4H), 6.74-6.93 (mn, 5H), 7.29 J=9Hz, 2H). MS (DCI/NH 3 m/e 455 Example 29 trans. trans-2-(4- Metho2yrh enyl) (1 .4-benzod ioxan-6-Yl) 1 eth yl- NpropylamninocarbonylmethyI)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, substituting 6-(2nitrovinyl)-1 ,4-benzodioxane for 5-(2-nitrovinyl)- 1,3-benzodioxole and alkylating the pyrrolidine nitrogen with N-m ethyl- N-p ropyl broinoacetainide afforded the title compound. in.p. 74-76 00.

Rotational isomers are seen in the NMR. 1 H NMR (ODC1 3 300 MHz) 0.73, 0.83 (2t, J=7Hz, 3H), 1.48 (in, 2H), 2.78 (dd, 1H), 2.85 (2s, 3H), 2.96-3.15 (mn, 3H), 3.27-3.42 (mn, 3.52-3.60 (mn, 1H), 3.75 1H), 3.78 3H), 4.22 4H), 6.80-6.98 (mn, 5H), 7.32 2H). MS (DCI/NH 3 m/e 469 -96- Examole trans, trans-2- (4-Methoxyphenyl)-4-( 1. 3-benzodioxol-5-yl)- 1 -(N-methyl-Nbutyla m inoca rbonylm ethyl) -pyrro lidine-3-carboxcylic acid Using the procedures described in Example 1, the title compound was prepared. Rotational isomers are seen in the NMR. 1H NMR (CD 3

OD,

300 MHz) 8 0.86 (2t, 3H), 1.04-1.50 (in, 4H), 2.85 (2s, 3H), 2.93-3.20 (in, 4H), 3.40 (in, 2H), 3.52 (dd, 1 3.60 (in, 1 3.80 3H), 3.85 (in, I1H), 5.91 2H), 6.74 I 6.83-6.95 (in, 3H), 7.03 (dd, 1 7.35 (dd, 2H).

Examlle 31 trans. trans-2-(4-Methoxy-2-methoxym ethoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 m ethyl- N-b utylam in ocarbonylm ethyl)-yrrol id ine-3-ca rboxylic acid: Examlle 31 A Ethyl 2-(4-methoxy-2-methoxymethoxyphenyl-4-( 1.3-benzodioxol-5-y)-pyrrolidine- 3-carboxylate) Using the procedures described in Examples 1 A and 1 B and substituting ethyl (4-methoxy-2-methoxymethoxybenzoyl)acetate for ethyl (4-inethoxyb enzoyl) acetate afforded ethyl 2-(4-methoxy-2methoxymethoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-4,5-dihydro-3H-

V

pyrrol e-3-carboxyl ate. The above dihydro pyrrole carboxylate (3.0 g, 7.0 inmol) was dissolved in 20 mL of methanol, treated with. 500 mng of 10% Pd/C and placed under hydrogen atmosphere for 32 hours. The catalyst was 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.

Examgle 31 B tras trn-2-(4-Methoxcy-2-methoxymethoxyhenyl)4( 1.bezdol--yl)-l1-(Nm ethyl- N-butylam in ocarbonyl methyl)-pyrrol id ine-3-carboxylic acid The compound resulting from Example 31A was epimerized by the procedure described in Example 6A. The resulting trans,trans compound (100 mg, 0.23 inmol) was then reacted by the procedures described in Example 1 D substituting N -inethyl- N-butyl broinoacetainide for Npropyl bromoacetainide to give the title compound (75 mng, in.p.

65-67 OC. Rotational isomers are seen in the NMR. 1 H NMR (CDC13, 300 -97- MHz) 5 0.64, 0.68 (2t, J=7Hz, 3H), 1.14, 1.12 (2 sextet, J=7Hz, 2H), 1.40- 1.48 2H), 2.86, 2.89 (2s, 3H), 2.95-3.42 6H), 3.50 3H), 3.43- 3.65 2H), 3.78 3H), 4.30 J=7Hz, 1H), 5.09 J=7Hz, 2H), 5.92 2H), 6.55 (dd, J=3Hz, 1H), 6.68 1H), 6.72 1H), 6.85 (2t, J=lHz, 1H), 7.04 J=1Hz, 1H), 7.42 (dd, J=3Hz, 1H).

Example 32 trans. trans-2-(4-Methoxvohenyl)-4-( 1.3-benzodioxol-5-vl- 1- (3-ethoxvYroD;)- Dvrrolidin-5-one-3-carboxylic acid Example 32A Ethyl 2-(4-methoxvbenzoyl)-3-carbomethoxv- 1.3-benzodioxole-5-DroDionate 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 concentrated in vacuo to afford the title compound (7.67 g, 92%) which was used without further purification.

Example 32B Ethyl 1-(3-ethoxvDropyl)-2-(4-methoxvDhenvl)-4-(1.3-benzodioxol-5-vl)-4.5-dihvdro- 5-oxo-1 H-Dyrrole-3-carboxylate A mixture of the compound resulting from Example 32A (700 mg, 1.69 mmol), 3-ethoxypropylamine (348 mg, 3.38 mmol) and 1 mL of acetic acid in a sealed tube was heated for 18 hours at 125 After cooling the contents of the tube to ambient temperature, 5 mL of water 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 give 330 mg of the title compound.

-98- Example 320 Ethyl 1 -(3-ethoxyp ropyl)-2-(4-methoxyphenyl)-4-(1 .3-benzodioxol-5-yl-pyrrolidin-5one-3-carboxylate The compound resulting from Example 32B (300 mg, 0.64 mmol) in 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 trans. trans-2-(4-MethoxyphenylI-4-( 1.3-benzodioxol-5-yl)- 1 -(3-ethoxygrogyL'pyrrolidin-5-one-3-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 sodium ethoxide in ethanol. The mixture was heated to 70-80 00 for 3 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 which was washed with ether. The aqueous layer was neutralized with 3 MA HCl and allowed to stand overnight. The white crystalline solid was collected by filtration to give the title compound (60 mg, m.p.

134-140 00. 1 H NMR (DMSO-d 6 300 MHz) 8 1.04 J=7Hz, 3H), 1.55 (sextet, J=7Hz, 2H), 2.48-2.56 (in, 1H), 2.93 (dd, J=9Hz, 1H), 3.25 (t, J=7Hz, 2H), 3.28-3.40 (in, 2H), 3.48-3.57 (mn, 1H), 3.78 3H), 3.88 (d, J=lOHz, 1H), 4.72 J=lOHz, 1H), 6.02 2H), 6.74 (dd, J=8Hz, 1Hz, 1H), 6.87 J=8Hz, 2H), 6.98 J=8Hz, 2H), 7.38 J=8Hz, 2H). MS-

(DCI/NH

3 m/e 442 Examlle 33 trans. trans-2 Methoxyph en yl-4- (1 ben zod ioxoI- 5-yfl- 1 meth oxyben zyl)pyrrolidin-5-one-3-carboxylic acid Following the procedures described in Example 32 and substituting 3-methoxybenzylamine for 3-ethoxypropylamine afforded the title compound (123 mg, m.p. 150-152 00. 1 H NMR (CD3OD, 300 MHz) 8 2.96 (dd, J=8Hz, 10Hz, 1H), 3.72 3H), 3.80 3H), 4.06 (d, J=lOHz, 1H), 4.58 J=8Hz, 1H), 4.92 J=l6Hz, 2H), 5.92 2H), -99- 6.55-6.63 (in, 2H), 6.82 J=8Hz, 6.94 J=8Hz, 2H), 7.15-7.22 (in, 3H). MS (DCI/NH 3 m/e 475 Examgfe 34 trans. trans-2-(4- Methoxynhenvl)-4-( 1.3-benzodioxol-5-yI)- 1 Ndiisoam yi m inoca rbonylmethl)-D2yrrolidine-3cp rboxvlic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMVR (CDCI 3 300 MHz) 8 0.70 -0.90 (mn, 12H), 1.10-1.60 (mn, 10H), 2.75 J=l3Hz, 1H), 2.90-3.10 (in, 4H), 3.15 3.30 (in, 2H), 3.40 J=lOHz, 1H), 3.40 3.52 (in, 2H), 3.55 3.62 (in, 1H), 3.75 J=12 Hz, 1H), 3.79 3H), 5.93 (dd, J =1 Hz, 3 V Hz, 2H), 6.72 J=8Hz, 1H), 6.82-6.90 (in, 3H), 7.03 J=2Hz, 1H),: 7.30 J=9Hz, 2H).

Example trns trn--(4-Methoxyohenyl)-4-( 1.3-benzodioxol-5-yI)-l1-(N.

N-

digentylam inocarbonymethyl)-Dyrrolidine-3-carbpxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (CDCI 3 300 MHz) 8 0.82 J 7Hz, 6H), 0.95-1.03 (mn, 2H), 1.10-1.30 (in, 8H), 1.40-1.51 (in, 2H), 2.72 J=l3Hz, 1H), 2.90-3.08 (in, 4H), 3.25-3.50 (in, 3H), 3.37 J=13Hz, 1H), 3.52-3,60 (in, 1H), 3.70 J=lOHz, 1H), 3.75 3H), 5.92 (dd, J=2Hz, 5Hz, 2H), 6.72 J=8Hz, 1H), 6.80-6.88 (in, 3H), 7.03 (d, J=2Hz, 1H), 7.30 J=9Hz, 2H).

Example 36 trans, trans-2-(4-Methoxyohenyl)-4- (1 .3-benzodioxol-5-y)- 1 N-di(2methoxyethyfl am inocarbonylmethyl-pyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 120-122 OC. 1 H NMR (CDC1 3 300 MHz) 8 2.82 (d, J=13, 1H), 2.94-3.08 (mn, 2H), 3.12 3H), 3.23 3H), 3.20-3.70 (in, 11 3.73 J=1lOHz, 1 3.79 3H), 5.92 (dd, J= 2Hz, 2Hz, 2H), 6.72 J=8Hz, 1H), 6.80-6.90 (in, 3H), 7.04 J=2Hz, 1H), 7.30 J=9H-z, 2H).

-100- Example 37 trans. trans-2-(4-Methoxyhenyfl-4-( 1.3-benzodioxol-5-yl)- 1 -(2-heny!)-Dyrrolidine- 3-carboxylic acid Using the procedures described in Example 4, 200 mg. of the pure 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 1, 2004 (1987), for 1 hour at 55 OC, to give 226 mg 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 title compound. 1 H NMR (CDCI 3 300 MHz) 8 1.00 J=7Hz, 3H), 1.54 (in, 2H), 2.14-2.22 (in, 2H), 2.96 (dd, J=7Hz, 13Hz, 1H), 3.07 (dd, J=l8Hz, 2Hz, 1H), 3.15 (dd, J=9Hz, 2Hz, 1H), 3.26 J=9Hz, 1H), 3.36 (dd, J 18 Hz, 2Hz, 1H), 3.47-3.55 (in, 1H), 3.79 3H), 3.88 J=9Hz, 1H), 5.95 2H), 6.72 J=8Hz, 1H), 6.80-6.88 (in, 3H), 7.03 J=2Hz, 1H), 7.22 is J=9Hz, 2H).

Example 38 trans, trans-2-(4-Methoxyphenyfl)4-( 1.3-benzodioxol-5-yl)- 1 -(N-cyclopropylmethy;.

N-propylam inoca rbonylmethyl)-pyrro lid ine- 3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 167-169 OC. Rotational isomers were seen in the NMR. 1 H NMR (ODC1 3 300 MHz) 5 -0.1 0.05 0.12-0.25 0.32- 0.51 0.67 and 0.74 (2 triplets, 3H), 0.90-1.00 (),1.20-1.55 (in), 2.72 J=l3Hz, 1H), 2.85--3.29 (in, 4H), 3.30-3.50 (in, 3H), 3.52-3.62 (in, 1H), 3.65-3.73 (2 doublets, J=lOHz, 2Hz, 1H1), 3.78 3H), 5.95 (2 singlets, 2H), 6.72 (2 doublets, 2H), 6.80-6.90 (in, 3H), 7.00 and 7.05 (2 doublets, J=9Hz, 2H).

Example 39 trans, trans-2- (4-Methoxyohenyl)-4-( 1. 3-benzodioxol-5-yfl- 1 -(N-methyl-Npentylam inoca rbonylmethyl)-pyrrolidine-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. 1 H NMR (CDC1 3 300 MHz) 8 0.85 J=7Hz, 3H), 1.00-1.08 (in), 1.13-1.32 1.35-1,50 2.72-2.82 (2 doublets, J=l3Hz, 1H), 2.83 and 2.86 (2 singlets, 3H), 2.92-3.20 (in, 3H), 3.22-3.45 (in, 3H), 3.52- 3.62 (in, 1H), 3.72 (2 doublets, 1H), 3.75 and 3.76 (2 singlets, 3H), 5.92 -101- (2 singlets, 2H), 6.72 J=8Hz, 1 6.80-6.87 (in, 3H), 7.03 (2 doublets, J=2Hz, 1 7.30 J=9Hz, 2H).

Example trans. trans-2-(4-Methoxy=henvl)-4- 3-benzodioxol-5-yf)l1-(N.

N-

diisobutylam inoca rbonylmethyfl)-Drrolidine-3-ca rboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 141-143 OC. 'H NMR (CDCI 3 300 MHz) 5 0.54 (d, J=7Hz, 3H), 0.70-0.90 (3 doublets, J=7Hz, 9H), 1.60-1.75 (in, 1H), 1.90- 2.02 (in, 1H), 2.67 J=l3Hz, 1H), 2.70 J=l3Hz, 1H), 2.84 (dd, J=6Hz, 15Hz, 1H), 2.96-3.06 (mn, 2H), 3.20 (dd, J=9Hz, 15Hz, 1H), 3.35 (dd, J=2Hz, 10Hz, 1H), 3.44-3.60 (in, 4H), 3.70 J=9Hz, 1H), 3.79 (s, 3H), 5.94 (dd, J=2Hz, 2Hz, 2H), 6.72 J=9Hz, 1H), 6.82-6.90 (in, 3H), 7.03 J=2Hz, 1H), 7.31 J=9Hz, 2H). Example 41 ee trans. trans-2-(4-Methoxyghenyl-4-( 1.3-benzodioxol-5-y)- 1 -(N-methyl-N-(2- *0 p ropynyl) am in ocarbonylm ethyfl)-ovrro lid ine-3-ca rboXyl ic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. 1 H NMR (ODC1 3 300 MHz) 8 2.09 and 2.32 (2 triplets, J=2Hz, 1 H), 2.80-3.10 (mn, 3H), 2.90 and 2.99 (2 singlets, 3H), 3.35-3.50 (in, 2H), 3.52-3.62 (in, 1H), 3.78 3H), 4.03 J=l3Hz, 1H), 4.00-4.30 (in, 3H), 0 5.93 2H), 6.72 (2 doublets, J=8Hz, 1H), 6.80-6.90 (in, 3H), 7.02 and *O 7.11 (2 doublets, J 2Hz, 1 7.30 (2 doublets, J=9Hz, 2H).

S

Exam DIG 42 trans. trans-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-yl)-l1-(N-methyl-N-(nhexyflam inocarbonylm ethyl)-oyrarolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1H NMR (CDCI 3 300 MHz) 8 0.85 (2 triplets, J=7Hz, 3H), 1.00-1.50 (in, 8H), 2.72-2.82 (2 doublets, J=l3Hz, 1H), 2.81 and 2.86 (2 singlets, 3H), 2.92-3.20 (in, 3H), 3.22-3.45 (in, 3H). 3.52-3.62 (in, 1 3.72 (2 doublets, 1 3.75 and 3.76 (2 singlets 3H), 5.94 (2 singlets, 2H), 6.72 J=8Hz, 1H), 6.80-6.87 (in, 3H), 7.03 (2 doublets, J=2Hz, 1 7.30 J=9Hz, 1 H).

-102- Examlle 43 trans, trans-2-(4-Methoxyhenyl)-4-( 1. 3-benzod ioxol-5-yfl-1 1-(N.Ndybutvylaminocarbon-Lmethvl y)-pyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Example m.p. 123-125 I H NMR (CDCI 3 300 MHz) 8 0.79 (t, J=7Hz, 3H), 0.85 J=7Hz, 3H), 1.00-1.50 (in, 8H), 2.74 J=l3Hz, 1H), 2.90-3.09 (in, 4H), 3.23-3.50 (in, 3H), 3.38 J=l3Hz, 1H), 3.52-3.62 (in, 1H), 3.75 J=10 Hz, 1H), 3.78 3H), 5.93 (dd, J=2Hz, 4Hz), 6.71 J=8Hz, 1H), 6.81-6.89 (in, 3H), 7.03 J=2Hz, 1H), 7.30 J=9 Hz, 2H). MS (DCI/NH 3 m/~e 511 Anal calcd for C29H 3 8

N

2 0 6

C,

68.21; H, 7.50; N, 5.49. Found: C, 68.07; H, 7.47; N, 5.40.

Example 44 tra ns. trans-2-(4-Methoxyphenyl)-4-( 1. 3-benzodioxol-5-yl)- 1 Ndiethylam inocarbonylmethyF)-pyrrolidihe-3-ca rboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 132-134 1 H NMR (CDC1 3 300 MHz). 5 0.98 (t, J=7Hz, 3H), 1.06 J=7Hz, 3H), 2.78 J=13 Hz, 1H), 2.95-3.20 (in, 4H), 3.30-3.50 (in, 4H), 3.55-3.65 (in, 1H), 3.76 J=12 Hz, 1H), 3.79V00 3H), 5.93 2H), 6.72 J=8Hz, 1H), 6.80-6.90 (in, 3H), 7.02 (d, J=2Hz, 1H), 7.32 J=9Hz, 2H). Example trans. trans-2-(4-Methoxyphenyl)-4-( 1. 3-benzodioxol-5-yfl)-1 -(N-methyl-Nphenylam inoca rbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. IH NMR (CD 3 OD, 300 MHz) 8 2.75- 2.85 (in, 2H), 3.05-3.13 (in, 1 3.18 3H), 3.40-3.58 (in, 2H), 3.78- 3H), 3.88 J=l2Hz, 1H), 5.92 2H), 6.72 J=8Hz, 1H), 6.75- 6.85 (mn, 3H), 7.00-7.12 (in, 5H), 7.82-7.92 (in, 3H).

Example 46 trans. trans-2 Meth oxyp hen yl)-4- 3-b enzod ioxo 1-5-yi)- 1 -m eth yl-N ccl oh exylain in oca rbonylm ethyl) -pyrrol id ine-3- ca rboxyl ic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. I H NMR (CD 3 OD, 300 MHz) 8 1.00-1.85 (mn, 10H), 2.72 and 2.78 (2 -103singlets, 3H), 2.75-2.82 (2 doublets, J=l2Hz, 1H), 2.96-3.22 (in, 3H), 3.40-3.65 (in, 3H), 3.68 and 3.82 (2 doublets, J=lOHz, 3.77 and 3.78 (2 singlets, 3H), 5.92 2H), 6.72 (2 doublets, J=8Hz, 1H), 6.82-6.88 (in, 3H), 7.02 (2 doublets, J=2Hz, 1 7.30-7.40 (2 doublets, J=9Hz, 2H).

Exampl~e 47 trans. trans-2-(4-Methoxvphenvl)-4- (1 .3-benzodioxol-5-F)-1 N-di(n- D2ropvflam inocarbonylmehy)-Dvrrolidine-3-carboxvlic -acid The title compound was prepared using the procedures described in Example 1. m.p. 170-172 00. 1 H NMR (CDC1 3 300 MHz) 8 0.69 (t, J=7Hz, 3H), 0.85 J=7Hz, 3H), 1.20-1.55 (in, 4H), 2.72 J=l3Hz, 1H), 2.90-3.10 (in, 4H), 3.25-3.47 (mn, 4H), 3.35-3.62 (in, 1lH), 3.72 J=9Hz, 1H), 3.79 3H), 5.94 2H), 6.72 d, J=8Hz, 1H), 6.80-6.90 (in, 3H), 7.02 J=2Hz, 1 7.30 J=9Hz, 2H).

Examlle 48 trans, trans-2-(4-Methoxvghenyl)-4-( 1.3-benzodioxol-5-y)- 1 -(N-methyl-Nisobutylam inocarbonylmethyl)-Dyrrolidine-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 (CD 3 OD, 300 MHz) 8 0.65-0.85 (4 doublets, J=7Hz, 6H), 1.75-1.95 (in, 1H), 2.80 and 2.90 (2 singlets, 3H), 2.90-3.10 (in, 4H), 3.10-3.65 (in, 4H), 3.74 9S, 3H), 3.81 and 3,88 (2 doublets, J=lOHz, 1H), 5.93 2H), 6.72 J=8Hz, 1 6.80-6.90 (in, 3H), 7.02 (2 doublets, J=2Hz, 1 7.80-7.90 (2 doublets, J=9Hz, 2H).

Examgle 49 Alternate Prepration of Ethyl 2-(4-nethoybenzofl-4-nitromethyl-3-( 1.3-benzodioxole-5-vl~butyrate Example 49A E-2-(3.4-Methylenedioxyohenvl)-l1-nitroethene To a stirred solution of piperonal (75g, 500 minol) in methanol (120 mL) at 10 00 was added nitroinethane (27.1 inL, 500 inmol, 1 eq) followed by the dropwise addition of sodium hydroxide (21 g, 525 minol, 1.05 eq) in sufficient water to achieve a total volume of 50 mL while -104maintaining the temperature between 10-15 The reaction mixture became cloudy, turning to a thick paste. The mixture was stirred for minutes upon completion of the addition, and the mixture was then diluted with ice-water (-350 mL) maintaining the temperature below s 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 recrystallized from hot ethanol (3 L) to yield E-2-(3,4-methylenedioxy)-nitrostyrene as yellow needles (53 g, 1 H NMR (300MHz, CDC13) 8 7.94 (1H, d, J=13.5Hz), 7.47 (1H, d, J=13.5Hz), 7.09 (1H, dd, J=7.5&2Hz), 7.01 (1H, d, J=2Hz), 6.87 (1H, d, J=7.5Hz), 6.06 (2H, MS (DCI/NH 3 m/e 194 (M+H) 211

(M+H+NH

3 Example 49B Ethyl 2 4 -methoxyhenyl)oxo-4-nitro-3-(3.4-methylenedioxyDhenyl)butyrate i To a stirred solution of the nitrostyrene resulting from Example 49A (14.17 g, 73.34 mmol, 1.2 eq) in a mixture of propan-2-ol (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-7ene (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% ethyl 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.

1 H NMR (300 MHz, CDC 3 8 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 (1H, dd, J=9Hz,3Hz), 6.73 (1H, d, J=9Hz), 6.65 (1H, d, J=3Hz), 5.95 (2H, 5.89 (1H, d, J=4Hz), 5.88 (1H, d, J=4Hz), 4.90-4.60 (3H, 4.39 (1H, 4.18 (2H, q, J=7Hz), 3.94 (2H, -1 in), 3.80 (3H, 3.78 (3H, 1. 19 (3H, t, J=7Hz), 0.99 (3H, t, J=7H-z), MS

(DCIINH

3 mWe 416 433 (M+H+NH 3 Examlle trans. trans-2-(4-Methoxyohenyl)-4- (1 .3-benzodioxol-5-yi)- 1 butyloxvca rbonylm ethyl)- Dyrrolidine-3-ca-rboyl ic acid To a stirred solution of the compound resulting from Example 1C (100 mng, 0.27 inmol) in acetonitrile (2 ml-) was added successively diisopropylethylamine (70 il-, 0.40 mmol, 1.5 eq) and t-butyl bromoacetate (48 iL-, 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 V temperature was added 50% w/w sodium hydroxide (300 mng, 3.7Smmol) in water. The mixture was stirred 2 hours, then the volatiles were removed in vacua. The residue was dissolved in water (5 mL), and the solution was washed with ether. The aqueous phase was acidified with acetic acid (300 jiL), and then extracted with ethyl acetate The combined organic extracts were dried (Na 2

SO

4 filtered, and concentrated to yield the title compound (74 mng, 60%) as a white solid.

1 H NMR (300 MHz, CDCI 3 8 7.36 (2H, d, J=8H-z), 7.13 (1 H, d, J=3Hz), 6.90 (1H, dt, J=3Hz, 8Hz), 6.88 (2H, d, J=8Hz), 6.76 (1H, d, J=8Hz), 5.96 (2H, 3.96 (1H, d, J=9Hz), 3.81 (3H, 3.58 (1H, ddd, J=12,: lOHz,3Hz), 3.52 (1H, dd, J=9Hz,3Hz), 3.32 (1H, d, J=l7Hz), 3.08 (1H, t, J=lOHz), 2.92 (1H, dd, J=9Hz,7Hz), 2.83 (1H, d, J=l7Hz). MS (DCI/NH 3 m/e 456 Anal calc for C 2 9

H

2 9 N0 7 0.3 H 2 0: C, 65.07; H, 6.48; N, 3.04. Found: C, 65.02; H, 6.42; N, 2.93.

Examlle 51 trans, trans-2-(4-Methoxyghenyl)-4-( -naDhthyfl- 1 -(N-methyl-No2roo~yl)am in ocarbonylm ethyfl-oyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthalene- 1-carboxaldehyde for piperonyl in Example 49A. Rotational isomers are seen in the NMR. 1H NMR (300 MHz, CDCI3) B 8.29 (1 H, bd, J=8Hz), 7.86 (2H, d, J=8Hz),7.75 (1H, d, J=8Hz), 7.49 (3H, in), 7.34 (2H, dd, J=3Hz,9Hz), 6.83 (2H, dd, J=9Hz,2Hz), 4.50 (1H, in), 3.94 (1H, dd, J=9Hz,2Hz), 3.78 (3H, 3.65 -106- (1H, in), 3.49 (11H, d, J=l4Hz), 3.40-2.93 (5H, in), 2.91, 2.83 (3H, 1.48 (2H, sept, J=7Hz), 0.83, 0.77 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 461 Anal calcd for C 2 9

H

29 N07 0.5 HOAc: C, 71.00; H, 6.99; N, 5.71.

Found: C, 70.95; H, 7.00; N, 5.46.

Exam Die 52 trans. trans-2-(4-Methoxyhenyl)-4-(2.3-dihydrobenzofuran-5-yi) 1-(N-methyl-N- 2roo~yflam inocarbonyim ethyl)-D2yrrolidine-3-carboxylic acid Example 52A 2. 3-Dihydrobenzof uran-5-carboxa Idehyde To a stirred solution of czjz-dichloromethyl methyl ether (2.15 g, 19 mmol, 1.35 eq) in methylene chloride (30 mL) at -40 0 C was added successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes later, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH 2

CI

2 mL) maintaining the temperature at or below -35 0 C. The mixture was warmed to 0 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 vacua, and the residue purified by vacuum distillation to yield the title compound (1.25 g, 60%) as a colorless liquid. b.p. 119-121 OC at 0.3 mm Hg.

Examlle 52B trans, trans-2- Meth oxyh enyfl-4- (2.3-dihyd roben zof uran- 5-yl- 1 -m eth Yl-N D2rolyI)am inocarbonylmethyl)-pyrrolidine-3-carboxylic 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. 1 H NMR (300 MHz, CDCI 3 8 7.33 (1H, d, J=8Hz), 7.28 (1H, in), 7.19 (1iH, in), 6.87 (1 H, d, J=8Hz), 6.73 (1iH, d, J=8Hz), 4.56 (1iH, t, J=8Hz), 3.83 (1 H, d, J=lOHz), 3.80 (3H, 3.63 (1H, in), 3.4-3.0 (9H, in), 2.87, 2.84 (3H, 1.51 (2H, septet, J=7Hz), 0.88, 0.78 (3H, t, J=7Hz). MS

(DCI/NH

3 m/e 453 Anal calc for C26H 32

N

2 0 5 0.25 H 2 0: C, 68.33; H, 7.17; N, 6.13. Found: C, 68.60; H, 6.88; N, 5.80.

-107- Example 53 trans. trans-2 .4-Bis(4-m ethoxylhenyl)- 1-N-methyl-N-propyl)-am inocarbonyim ethyl'pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-methoxybenzaldehycie for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDCI 3 8 7.37 d, J=7.5 Hz), 7.32 (2H, d, J=7.5 Hz), 6.86 (4H, in), 3.83 (1 H, mn), 3.81 (3H, 3.79 (3H, 3.64 (1 H, mn), 3.48-2.97 (6H, in), 2.87, 2.83 (3H, 2.85 (1 H, in), 1.45 (2H, in), 0.84, 0.74 (3H, t, J=7.5 Hz).

MS (DCI/NH 3 in/e 441 Anal caic for C25H 32

N

2 0 5 0.5 H 2 0: C, 66.80; H, 7.40; N, 6.23. Found: C, 67.15; H, 7.31; N, 6.00.

trans, trans-2- Meth oXyh enyfl-4- (3.4-dim etho2=Dheny). 1 methyl- N- Dropyl')am inocarbonylmethyl)-D2yrrolidine-3-cprboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-dimethoxybenzaidehycje for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1

H

NMR (300 MHz, CDCI 3 8 7.33 (2H, d, J=7.5 Hz), 7.07 (1H, d, J=2.0 Hz), 6.98 (1 H, in), 6.85 (1 H, d, 7.5 Hz), 6.82 (2H, d, 7.5 Hz), 3.91 (3H, 3.86 (3H, 3.83 (1 H, mn), 3.79 (3H, 3.64 (1 H, mn), 3.50-2.95 (6H, in), 2.87 (1 H, in), 2.85, 2.83 (3H, 1.45 (2H, mn), 0.84, 0.74 (3H, t, J=7.5 Hz). MS

(DCI/NH

3 m/e 471 Anal caic for C26H34N 2 0 6 0.5 H 2 0: C, 65.12; H, 7.36; N, 5.84. Found: C, 65.22; H, 7.27; N, 5.59.

trans. trans-2- Methoxylhenl)-4-(3-m eth oyhenyl).. 1 (N-m ethyl- N- D2rogyl')am inocarbonylmethyl)-Dyrrolidine-3-cprboxlic acid- The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1H NMR (300 MHz, CDCI 3 8 7.33 (2H, d, J=7.5 Hz), 7.24 (1H, t, J=7.5 Hz), 7.05 (2H, in), 6.85 (2H, dd, J=7.5&2 Hz), 6.76 (1 H, in), 3.83 (1 H, in), 3.81 (3H, 3.79 3.64 (1H, in), 3.48-2.97 (6H, mn), 2.87, 2.83 2.85 (1H, in), 1.45 (2H, in), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH 3 nWe 441 Anal caic for C 25

H

32

N

2 05 0.5 H 2 0: C, 66.80; H, 7.40; N, 6.23. Found: C, 66.76; H, 7.36; N, 6.05.

-108- Example 56 trans. trans-2-(4-MethoxyDhenyl)-4-(2-naDhthyi)-1 -(N-methyl-N- DroDvl)aminocarbonvlmethvl)-Dvrrolidine-3-carboxylic acid s 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. 1H NMR (300 MHz, CDCI 3 8 7.82 (4H, 7.69 (1H, 7.47 (2H, 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, 3.57 (1H, 3.52-2.97 (6H, 2.93, 2.85 (3H, 2.90 (1H, 1.52 (2H, 0.86, 0.76 (3H, t, J=7.5 Hz). MS (DCI/NH 3 m/e 461 (M+H) Anal calc for C 2 8

H

3 2

N

2 0 4 0.5 H 2 0: C, 71.62; H, 7.08; N, 5.97. Found: C, 71.58; H, 7.11; N, 6.01.

Example 57 trans. trans-2-(4-MethoxvDhenyl)-4- (1.3-benzodioxol-5-vl)-1 -(2-(ethvlsuffinvl)ethyl- Dyrrolidine-3-carboxylic acid To the compound resulting from Example 1C (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 refluxed for 4 hours and then concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel eluting with 4:1 hexane-ethyl acetate to afford 93 mg of the ethylthioethyl compound. i:* To the sulfide (90 mg, 0.2 mmol) dissolved in 5 mL of CH 2

CI

2 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 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

CH

2

CI

2 to afford the sulfoxide (62 mg, The ethyl ester was hydrolyzed by the procedure described in Example 1D to afford the title compound as a diastereomeric mixture.

m.p. 61-63 MS (DCI/NH 3 m/e 446 (M+H) 1 H NMR (CDCi 3 300 MHz) 8 1.25, 1.32 J=9Hz, 3H), 2.45-2.75 4H), 2.84-2.96 3H), 3.02- -109- 3.08 (in, 1 3.32, 3.36 J=3Hz, 1 3.47-3.58 (in, 2H), 3.65, 3.68 (d, 1 3.76, 3.80 5.94 2H), 6.72 J=7.5Hz, 1 3.84- 3.89 (in, 7.02 J=6Hz, 1 7.30, 7.34 J=7.5Hz, 2H).

Examrle 58 trans. trans-2-(4-Meth ox~h enfl)-4- (1 .3-benzod ioxol-5-yl)-1 -42- (isolrolylsulfonylam ino?ethyl)-D2yrrolidine-3-ca rboxylic acid To 2-bromoethylamine hydrobromide (1 mmol) suspended in anhydrous CH 3 CN was added 1 equivalent of Et 3 N. The mixture was stirred for 30 minutes and then 1 equivalent of isopropyl sulfonyl chloride and 1 equivalent of Et 3 N were added. The resulting mixture was stirred for 2 hours at room temperature and then added to a solution of the compound resulting from Example 1C (185 mg, 0.5 minol) in 3 mL of CH 3 CN. The mixture was warmed at 50-60 OC 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 chroinatographed on silica gel eluting with 3:2 hexane-EtOAc to give 195 mg of the ethyl ester. The ethyl ester (160 mg, 0.31 mmol) was hydrolyzed by the procedure described in Example 1D to afford the title compound (133 mg, m.p. 94-96 OC. I H NMR (CD 3 OD, 300 MHz) 8 1.26 J=6Hz, 6H), 1.97 1H), 2.38 (in, 1H), 2.77 (in, 1H), 2.88 J=9Hz, 1 3.04 (mn, 1 3.14 J=7.5Hz, 2H), 3.35 (mn, 2H), 3.46 (mn 1 3.58. (mn, 1 3.78 3H), 5.92 2H), 6.74 J=9Hz, 1 6.86 (dd, J=9Hz,3Hz, 1H), 6.92 J=9H-z, 2H), 7.00 J=3Hz, 1H), 7.36 J=9Hz, 2H). MS (DCI/NH 3 Wne Examn~le 59 tra ns. trans-2- Meth oxyhe nyl-4- (1 ben zod ioxoI- 5-yi)- 1 Q sobutoxy)ethyl)- D2yrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Example ID from the compound resulting from Example 1C and 2- (isobutoxy)ethyl bromide. m.p. 68-70 OC. I H NMVR (ODC1 3 300 MHz) 8 0.88 J=6Hz, 6H), 1.82 (quintet, J=6Hz, 1H), 2.22 (in, 2H), 2.72-2.79 (in, 1H), 2.86-2.95 (in, 2H), 3.13 J=6Hz, 2H), 3.45-3.56 (in, 3.68 J=9Hz, 1H), 3.79 3H), 5.94 2H), 6.72 J=7.5Hz, 1H), 6.85 (dd, -110- J=9Hz, 7.5 Hz, 3H), 7.08 1H), 7.34 J=9Hz, 2H). MS (DCl/NH 3 m/e 442 (M+H) Example trans.trans-2-(4-MethoxyDhenyl)-4-(1.3-benzodioxol-5-vl)-1 -(butvlsulfonvl.- Dyrrolidine-3-carboxvlic acid To 100 mg (0.271 mmol) of the compound resulting from Example 1C 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 afford 120 mg of the ethyl ester.

The ester (120 mg, 0.244 mmol) was dissolved in 1 mL of EtOH, is 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 solution was washed with ether to remove any unhydrolyzed trans-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 mg, 53%) as a white solid. m.p. 67-69 1 H NMR (CDCl 3 300 MHz) 8 0.82 J=7.5Hz, 3H), 1.20-1.33 2H), 1.58-1.68 2H), 2.48-2.69 2H), 3.28 (dd, J=9Hz, 1H), 3.49 J=12Hz, 1H), 3.65 (dd, J=12Hz, 1H), 3.82 3H), 4.32 (dd, J=12Hz, 1H), 5.17 J=9Hz, 2H), 5.95 2H), 6.70-6.78 3H), 6.92 J=9Hz, 2H), 7.35 J=9Hz, 2H). MS

(DCI/NH

3 m/e 462 (M+H) Example 61 trans. trans-2-(4-Methoxyvhenvl)-4-(1.3-benzodioxol-5-yv)-1-(2-(N-methyl-NisoDroDvlcarbonylamino)ethyl)-Dyrrolidine-3-carboxylic acid -111- Example 61A trans.trans-2-(4-Methoxvyhenvl)-4-(1.3-benzodioxol-5l)- 1 -(2-bromoethyl) vyrrolidine-3-carboxvlic acid ethyl ester To the mixture of cis,trans and trans,trans pyrrolidines resulting from Example 1C (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 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. Example 61 B trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)- 1 (methylam ino)ethyl)- Dvrrolidine-3-carboxvlic acid ethyl ester To the compound resulting from Example 61A (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 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. Example 61C trans, trans-2-(4-MethoxvDhenyl)-4-(1.3-benzodioxol-5-yl)-1 -(2-(N-methyl-Nisobutvrvlamino)ethyl)-Dvrrolidine-3-carboxylic acid To the compound resulting from Example 61B (-150 mg) dissolved in 5 mL of 1,2-dichloroethane was added 0.3 mL of diisopropylethylamine. The solution was cooled to -40 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 solution/water and brine, dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel eluting with a gradient 1:1 EtOAchexanes going to EtOAc and finally using 10% MeOH-EtOAc.

-112- The ester was dissolved in 1.5 rnL 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 aqueous phase was acidified with 1 Ni H 3 P0 4 to pH 3 and extracted twice with ether. The combined organic extracts were washed with brine and dried over Na 2

SO

4 The solvents were removed in vacuo to provide 82 mg of the title compound as a white foam. Rotamers were seen in the NMR. 1 H NMR (CDCI: 3 300 MHz) of the major rotamer 8 1.06 3H-, J=lOHz), 1.12 3H, J=lOHz), 2.15 (in, 2.5-3.0 (in, 3H), 2.91 3.32 (in, 2H), 3.50 (in, 3.65 (in, 2H), 3.77 3H), 5.92 (s, 2H), 6.73 11H, J=8Hz), 6.75-6.9 (in, 4H), 6.96 1H, J=2Hz), 7.29 (in, 1H). MS (DCI/NH 3 m/z 469 Analysis calcd for C 2 6H 32

N

2 0 6 0.3 TFA: C, 63.55; H, 6.48; N, 5.57. Found: C, 63.44; H, 6.71; N, 5.24.

Examrfle 62 trans, trans-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-yl)-1 (2-(N-inethyl-N- Drogionylamino)ethyl)-D2yrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 61 substituting propionyl chloride for isobutyryl chloride in Example 61C. 1 H NMR (CDCI 3 300 MHz) of the major rotainer 8 1.13 3H, J=8Hz), 2.19 (mn, 1H), 2.30 (in, 2H), 2.65-3.0 (in, 3H), 2.85 3H), 3.25-3.4 (in, 2H), 3.5-3.7 (in, 3H), 3.79 3H), 5.92 2H), 6.74 1H, J=8Hz), 6.75-6.9 (in, 4H), 7.00 (bd s, 7.29 (bd s, 1H). MS (DCI/NH 3 m/z 455 Analysis caicd for C 2 5H 3

ON

2

O

6 .10H: C, 63.55; H, 6.83; N, 5.93 Found: C, 63.55; H, 6.52; N, 5.73.

Examlle 63 trans. trans-2-(4-Methoyrhenvfl-4-( 1. -benzodioxol-5-v1)- 1 -(N-methyl-Nbenzvlam inoca rbonylmethyl)-Dvrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. 1H NMR (CDCI 3 300 MHz) of the major rotamer 8 2.79 (s, 3H), 2.8-3.2 (mn, 2H), 3.48 (in, 3.61 (in, 2H), 3.77 3H), 3.78 (in, 11H), 4.3-4.5 (in, 2H), 5.95 2H, J=2Hz), 6.7-6.9 (in, 4H), 7.00 (mn, 1H), 7.15-7.35 (in, 7H). MS (FAB/NBA) m/z 503 Anal calcd for C29H 3 oN 2 0 6 -0.5 H 2 0: C, 68.36; H,5.74; N, 5.50. Found: C,68.41; H, 5.74; N, 5.36 -113trans, trans-2-(4-Methoxyhenyl)-4-( 1. 3-benzodioxol-5-y)- 1 -(N-ethyl-Nbutylam inoca rbonylm ethvl)-Dvyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMR (CDC1 3 300 MHz) of the major rotamer 8 0.88 (t, 3H, J=7Hz), 1.06 3H, J=7Hz), 1.27 (in, 2H), 1.45 (in, 2H), 2.8-3.6- (in, 11H), 3.79 3.80 (in, 1H), 5.92 (bd s, 2H), 6.75 1H, J=8Hz), 6.85 1 H, J=8Hz), 6.92 2H, J=8Hz), 7.03 1 7.33 1 H, J=8Hz). MS

(DCI/NH

3 mlz 483 Anal calcd for C27H3 4

N

2 0 6 -0.5 HOAc: C, 65.61; H.7.08; N, 5.46. Found: 0,65.51; H, 6.70; N, 5.66.

Example t-rans. trans-2-(4-Methoxylhenyl)-4-(1 .3-benzodioxol-5-yl)- I-(N-methvl-N-(2.2dimethylrroovyl)am inoca rbonylmethvl)-D2yrrolidine-3..carboxylic acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMR (ODC1 3 300 MHz) of the major rotamer 8 0.90 (s, 9H), 2.8-3.1 (in, 4H), 2.94 3H), 3.3-3.5 (in, 3H), 3.61 (in, 1H), 3.80 (s, 3H), 3.82 (in, 1 5.94 (bd s, 2H), 6.74 1 H, J=8Hz), 6.86 2H, J=8Hz), 6.87 (in, 1H), 7.03 1H, J=2Hz), 7.33 2H, J=8Hz). MS

(DCI/NH

3 m/z 483 Example 66 trans. trans-2-(4-Methoxyohenyl)-4-( 1.3-benzodioxol-5-vfl- 1 -(2-(N-methyl-Nbutylsulfonvlam ino)ethyl)-D2yrrolidine-3-carboxylic acid To the compound resulting from Example 61 B (60 mg, 0.13 inmol) dissolved in 5 mL of CH 3 CN was added 0.2 mL of Et 3 N and 22 mng (0.143 inmol, 1.1 equivalents) of 1 -butanesulfonyl chloride. The mixture wasstirred for 1 hour at room temperature and then concentrated in vacuo.

The crude product was purified by column chromatography on silica gel eluting with 1:1 EtOAc-hexane to yield 64 mng of the ester. Ester hydrolysis by the procedure described in Example 1 D afforded the title compound. m.p. 64-66 00. IH NMR (CDC1 3 300 MHz) 6 0.92 2.72 3H), 2.75-2.92 (in, 5H), 3.12-3.20 (in, 1H), 3.25-3.34 (mn, 1H), 3.46-3.55 (mn, 2H), 3.65 J=9Hz, 1H), 3.78 3H), 5.53 2H), 6.72 (d, -114- J=7.SHz, 1H), 6.82 (dd, J=7.5Hz,3Hz, 1H), 6.86 J=9Hz, 2H), 7.02 (d, J=3Hz, 1H), 7.34 J=9Hz, 2H). MS (DCI/NH 3 mWe 519 Exam Die 67 trans. trans-2-(4-Methoxy~henyl)-4-( 1.3-benzodioxol-5-vfl)-1-(2-(N-methyl-N- 12ropvlsu Ifonylam ino)ethyl)-Dvyrrolidine-3..ca rboxylic acid The title compound was prepared by the procedures described in Example 66 substituting 1-propanesulfonyl chloride for 1butanesulfonyl chloride. m.p. 69-70 OC. 1H NMR (CDCI 3 300 MHz) 8 1.02 J=7.5H-z, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.18-2.26 (in, 1H), 2.72 (s, 3H), 2.75-2.95 (in, 6H), 3.13-3.22 (in, 1H), 3.25-3.35 (in, 1H), 3.47-3.58 (in, 2H), 3.66 J=9Hz, 1H), 3.80 3H), 5.96 2H), 6.74 J=7.5Hz, 1 6.84 J=7.5Hz, 3Hz, 1 6.87 J=9Hz, 2H), 7.04 J=3Hz, 1H), 7.43 J=9Hz, 2H). MS (DCI/NH 3 mn/e 505 Examlle 68 trans. trans-2-(4-MethoXyvhenyfl-4- (1 .3-benzodioxol-5-yl)-l1-(2- (Drogylsulfonvl)ethyl)-pyrrolicdine--3-carbo~lic acid To 1-propanethiol (3.5 g, 46.05 mmol) dissolved in 10 mL of anhydrous THF was added 632 mg (26.32 mmol) of NaH in portions under a nitrogen atmosphere. The mixture was heated at 60-70 00 for 1 hours. To this mixture was added the compound resulting from Example 61A (180 mg, 0.38 minol) in 2 mL THF. Heating was continued at 60-70 00 for an additional 2 hours, and then the volatiles were removed under reduced pressure. The crude propylthioethyl adduct was purified by flash chromatography on silica gel eluting with 3:2 hexane- EtOAc to give 170 mng To a solution of 170 mng (0.36 minol) of the sulffide and 93 mg (0.8 iniol) of N-methylmorpholine N-oxide (NMO) in a mixture of 20 mL of acetone and 5 mL of H 2 0 was added a solution of osmium tetroxide mng) 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 H 2 0. The organic phase was washed with brine, dried over Na 2

SO

4 and concentrated in vacua. Flash chromatography afforded 177 mng 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 1 H NMR (CDC1 3 300 MHz) 8 1.04 (t, -115- 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.59-2.66 1H), 2.84-3.08 (m, 7H), 3.43 (dd, J=9Hz, 3Hz, 1H), 3.53-3.60 1H), 3.68 J=9Hz, 1H), 3.82 3H), 5.96 2H), 6.75 J=7.5Hz, 1H), 6.82 (dd, J=7.5Hz, 3Hz, 1H), 6.88 J=9Hz, 2H), 6.99 J=3Hz, 1H), 7.32 J=9Hz, 2H). MS

(DCI/NH

3 m/e 476 (M+H) Example 69 trans, trans-2-(4-MethoxvDhenvl)-4-(1.3-benzodioxol-5-vl- 1 2-enyl)-Dyrrolidine-3-carboxylic acid Example 69A trans-5-Methylhex-2-enoic acid ethyl 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 Diisopropyl(ethoxycarbonylmethyl) phosphonate (5.0 mL) was added slowly and the mixture stirred for 20 minutes at 0 OC.

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 i hours 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 Na 2

SO

4 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 colorless oil (2.1 P Example 69B trans-5-Methylhex-2-en-1 -ol The compound resulting from Example 69A (2.0 g) was dissolved in 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 removed by filtration and washed with additional ether (2 x 25 mL).

The filtrate was extracted with ether (2 x 25 mL). The ether extractions and washings were combined, dried, and evaported to give a colorless oil which was purified by flash chromatography on silica gel -116eluting with 25% EtOAc-hexanes. The title compound was isolated as a colorless oil (1.25 g).

Example 69C trans-i -Bromo-5-methylhex-2-ene The compound resulting from Example 69B (1.0 g) was dissolved in diethyl ether and cooled to 0 00 in an ice bath. Phosphorus tribromide g, 0.87 mL) was added dropwise and the solution stirred at 0 00 for two hours. The solution was poured onto ice, the layers separated, and the aqueous layer extracted with additional ether (3 x 25 mL). The ether layers were combined, dried, and evaporated to give a colorless oil which was used without further purification (0.95 .0 Exampl~e 69D trans. trans-2-(4-MethoXyo~henvl)-4-( 1.3-benzodioxo-5-y)- 1 2-enyl)-Dyrrolidine-3-carboxylic acid The title compound was synthesized using the methods detailed in Example 1D but substituting the compound resulting from Example 690 o* for N-propyl bromoacetamide. 1 H NMR (ODC1 3 300 MHz) 5 0.84 6H, J=-8Hz), 1.57 (heptet, 1H, J=8Hz), 1.87 2H, J=6Hz), 2.60 (dd, 1H, J=8Hz,l4Hz), 2.86 1H, J=lOHz), 2.96 (dd, 1H, J=8Hz,lOHz), 3.20 (dd, o. 1H, J= 5Hz,l4Hz), 3.29 (dd, 1H, J=3Hz,lOHz)', 3.50 (in, 1H), 3.70 1H, J=lOHz), 3.78 3H), 5.47 (in, 2H), 5.93 2H), 6.71 1H, J=8HIz), 6.83 3H, J=9Hz), 7.05 1H), 7.32 2H, J=9Hz). MS (DCI/NH 3 m/e 438 Anal calcd for C 26

H

31 NOS: C, 71.37; H, 7.14; N, 3.20. Found: C, 71.16; H, 7.24; N, 3.17.

Examlle trans, trans-2-(4-Methoxy~henyl)-4-( 1.3-benzodioxol-5-y)-1 dim ethylhex-2-enyl)-pyrrolidine-3-carboxvlic 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 olefins. The crude product was purified by preparative HPLC (Vydac p.018) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were lyophilized to give the product (and its diastereomer) as a white solid. 1 H NMR of the major (trans) isomer: -117- (CDCi 3 300 MHz) 8 0.83 6H, J=8Hz), 1.56 1.74 1H), 1.92 (d, 2H, J=6Hz), 3.3-3.5 3H), 3.6-3.8 3.78 3H), 3.9-4.0 1H), 5.22 1H), 5.90 2H, J=12Hz), 6.63 1H), 6.78 3H), 6.95 (s, 1H), 7.45 3H, J=8Hz). MS (DCI/NH 3 m/e 438 Anal calcd for

C

2 7 H33NO5 1.0 TFA: C, 61.59; H, 6.06; N, 2.48. Found: C, 61.36; H, 6.10; N, 2.34.

Example 71 trans. trans-2-(4-Methoxyphenvl)-4-(1.3-benzodioxol-5-yl)-1 heDtylcarbonvlmethyl)-pyrrolidine-3-carboxylic acid Example 71A 1 -Chloro-3-proDyl-2-hexanone To 2-propylpentanoic acid (156.6 il, 1.00 mmol) dissolved in S*.

anhydrous dichloromethane (2 mL) was added DMF (3 4±L, 4 mole and the solution was cooled to 0 OC under a nitrogen atmosphere. To the solution was added oxalyl chloride (94.3 gL, 1.08 mmol) dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. The mixture was cooled to 0 oC and excess -0.3 M ethereal diazomethane solution was added. The reaction mixture was stirred 18 hours while warming to ambient temperature. The reaction mixture was washed with 1 M aqueous sodium carbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated 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 gpL, 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 pressure and the residual oil was used in the next step without further purification.

Example 71B trans,trans-Ethyl 2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l- (4-heptylcarbonylmethyl)-pyrrolidine-3-carboxylate To the compound resulting from Example 71A (1.00 mmol, maximum theoretical yield) was added a solution of the trans,trans ethyl carboxylate from Example 1C (295 mg, 0.80 mmol as a 50 -118solution in toluene), diisopropylethylamine (700 gL, 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 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 OC 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 acetate-hexane to give 237 mg of the title compound as a yellow oil.

Example 71C rans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 heDtylcarbonylmethyl)-pyrrolidine-3-carboxylic acid To the compound resulting from Example 71B (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 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 mL). The aqueous layer was neutralized with 1 N hydrochloric acid to cloudiness and then 10% aqueous citric acid was added to adjust the 2s pH to 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 eluted with 1:1 ethyl acetate-hexane to give 86 mg of the title compound as an off white powder. 1 H NMR (CDCI 3 300 MHz) 8 0.73-0.97 6H), 1.03-1.33 6H), 1.36-1.58 2H), 2.46 1H), 2.80-2.98 3H), 3.38-3.64 3H), 3.75-3.90 1H), 3.79 3H), 5.94 2H), 6.75 1H), 6.86 2H), 6.92 1H), 7.12 1H), 7.32 2H). MS (FAB) m/e 482 (M+H) Anal calcd for C28H 35

NO

6 C, 69.83; H, 7.32; N, 2.91. Found: C, 69.57; H, 7.41; N, 2.73.

-119- ExamlDie 72 trans, trans-2-(4- Methoxyrhenyl)-4-(1 .3-benzodioxol-5-y)- 1 -(vale!YlmnethYflp~yrrolidine-3-carbogylic acid Examlle 72A 1 -Ch loro-2-hexanone Using the procedure described in Example 71A 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.

Examlle 72B: trans, trans-Ethyl 2-(4-methoxy henyl)-4-(1 .3-benzodioxole-5-yl)-1 (val erylmethyl)-Dyrrolidine-3-carboxyI ate Substituting the compound resulting from Example 72A for 1chiloro-3-pro pyl-2-hexanone and using the procedure described in Example 71B, 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 was obtained as a yellow oil.

Exampl 72C BsusiuigtecmonreunfrmExample 72 for.

trans trans- yI2-(4-methoxyphenyl)-4-(1 3-benzodioxol-5-y)- (4-heptylcarbonylmethyl)-pyrrolidine-3-carboxylate and using the procedure described in Example 71C, except only one solution of lithium 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 was obtained as an off white powder. 1 H NMVR (CDC1 3 300 MVHz) 8 0.87 (t, 3H), 1.26 (in, 1.49 (mn, 2.37 (in, 2H), 2.79-2.98 (mn, 3.31- 3.49 (mn, 3.56 (in, 1 3.77, 3.79 5.94 6.75 1 H), 6.81-6.93 (mn, 7.09 11H), 7.33 MS (FAB) in/e 440 Anal. calcd for C 25

H-

29 N0 6 C, 68.32; H, 6.65; N, 3.19. Found: C, 67.95; H, 6.64; N, 3.05.

-120- Example 73 trans. trans-2-(4-Methoxyhenyl-4-(1 .3-benzodioxol-5-yfl- 1 4dim eth oxyben zyl) -N -meth yl am in oca rbonvim ethyl) gyrro lid in e-3-ca rbo~ylica acid Example 73A trans~trans- and cis, trans-2-(4-Methoxylhenyl)-4-(1 yl)-l .4-dimethoxybenzyl)aminocarbonylmethyflpy2rrolidine-3 carboxylic acid ethyl ester Using the procedure of Example 1 D, paragraph 1, substituting 3,4dimethoxybenzyl bromoacetamide for dipropyl bromoacetamide, the desired product mixture was obtained as a white foam in 81% yield.

S

trans~trans- and cis, trans-2 -(4-Meth oxyh e nyp) ben zodi oxol yi)-1 -(N-(3.4-dimethoxybenzyl)-Nmethylaminocarbonylmethyflpyrrolidine-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 (0 00) 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 *e atmosphere. The resulting mixture was stirred at 0 00 for 1 hour, then 0 methyl iodide (28 pL, 64 mg, 0.45 mmol) was added. The reaction mixture was stirred at 0 00 for 45 minutes. TLC (Et 2 O) indicated incomplete reaction. An additional portion of methyl iodide (28 p1L, 64 mg, 0.45 mmol) and dry 1 ,3-dimethyl-3,4,5,6-tetrahydro- 2(1 H)pyrimidinone (50 giL, 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 Mi aqueous citric acid and extracted with 2 x 25 mL EtOAc. The combined organic extrracts were washed sequentially with 30 mL water and 30 mL brine, then dried (Na 2

SO

4 filtered and concentrated under reduced pressure to produce 270 mg of crude material. Flash chromatography on silica gel eluting with Et 2

O

gave the title compounds as an inseparable mixture in 43% yield. 1H NMR (CDC1 3 300 MHz) 8 2.79 and 2.81 for the N-OH 3 signals. MS m/z 591 -121- Examlle 73C trans. trans-2 -Met ho xy h enyr)-4-(1 be nzodi oxol -5-yb-1 dimethoxybenzyl)-N-methylaminocarbonylmethyloyrrolidine.3.

carboxylic acid To the resultant compound from Example 73B (98 mg, 0.17 mmol) dissolved in 1 mL EtOH and cooled to 0 0 C was added a solution of lithium hydroxide monohydroxide (17 mg, 0.41 mmol) in 0.5 mL H 2 0. The resulting solution was stirred under a nitrogen atmosphere for 16 hours. The solution was concentrated in vacuo, and the residue was partitioned between 15 mL H20 and 15 mL Et 2 O. The aqueous phase was extracted with 5 mL Et2O, then the aqueous phase was acidified with 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 (Na2SO 4 then filtered and concentrated in vacua to give 40 mg of the title compound as a white foam. 1H NMR

(CD

3 OD, 300 MHz, two rotameric forms) 8 2.85 3H), 2.94-3.25 (br m, 3H), 3.35-3.70 (br m) and 3.64 4 H total), 3.70-3.97 (br in), 3.74 3.76 3.78 3.79 3.81 and 4.03 (br d, J=14 Hz, 8H total), 4.43 (AB, 1H), 5.91 and 5.93 2H total), 6.50-6.60 (in, 1H), 6.67- 7.02 (br mn, 6H), 7.29 (br d) and 7.35 (br d, 2H total). HRMS calcd for

C

3 1 H 35

N

2 0 8 563.2393. Found: 563.2385.

Examp~le 74 trn.tans-2-(4-MethoxyohenI)-4-( benzodioxol-5y)- 1 dimethoxvbenzyflaminocarbonylmethylkvrrolidine-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 73B3, to provide the title compound. 1 H NMR (CD 3 OD, 300- M Hz) 8 2.85 J=l16Hz, 1 2.92 (b r t, J=9Hz, 1 2.98 (b r t, J=l1OHz, 1 3.32-3.39 (br in, 2H), 3.54-3.65 (br mn, 1 3.67 3H), 3.78 (s, 3H), 3.80 3H), 3.85 J=10 Hz, 1H), 4.21 J=l5Hz, 1H), 4.41 J= 1H), 5.91 2H), 6.67 J=8Hz, 1H), 6.75-6.95 (mn, 7H), 7.33-7.40 (in, 2H). HRMS calcd for C 3 0

H

3 2

N

2

O

8 549.2237. Found: 549.2224.

-122- ExamDle (2R.3R.4R)-2-(4-Methoxyhenyl)-4-(1.3-benzodioxol-5-y)-1-((1R)-1-(N.Ndipropylaminocarbonyl)-l-butyl)pyrrolidine-3-carboxylic acid s Example trans. trans-2-(4-MethoxyDhenyl)-4-(1.3-benzodioxol-5-vl-1-((1 R)-1- (benzyloxvcarbonvl)butyl)Dvrrolidine-3-carboxylic acid ethyl ester The procedure of Fung, et. al., J. Med. Chem., 35(10): 1722-34 (1992) was adapted. The resultant compound from Example 6A (103 mg, 0.279 mmol) was dissolved in 0.7 mL of nitromethane and 0.7 mL of

H

2 0, and ammonium carbonate (34 mg, 0.35 mmol) and (2S)-benzyl 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 Na 2

CO

3 and 25 mL of CH 2

CI

2 The aqueous phase was is extracted with 2 x 10 mL CH 2

CI

2 and the combined organic phases were washed with 15 mL brine, dried (Na 2

SO

4 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 CH2Cl2-hexane to produce 106 mg of the title compound as a waxy solid. 1 H NMR indicated the presence of two diastereomeric products. Example frans.trans-2-(4-Methoxhenyl)-4-(1.3-benzodioxol-5-yl)-1-((1 dipropylaminocarbonyl)-l-butyl)vDrrolidine-3-carboxylic acid ethyl ester The resultant compound from Example 75A (101 mg, 0.180 mmol) and 30 mg of 10% palladium on charcoal were stirred in 2 mL EtOAc under 1 atmosphere of H 2 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 give 81.4 mg 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 mmol), and 4-methylmorpholine (37 mg, 0.37 mmol) in 2 mL dry DMF. The solution was cooled to -15 OC, then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) was added. The mixture was stirred at -15 OC and allowed to warm slowly to room temperature overnight. The solvent -123was removed by distillation under reduced pressure, and the residue was partitioned between 20 mL EtOAc and 10 ML of 1 M aqueous Na 2 C 03.

The organic phase was washed with 10 mL of brine, dried (Na2SO 4 then filtered and concentrated in vacua. The crude product was purified by flash chromatography on silica gel, eluting with 1:2 Et2O-hexane.

Further purification of overlap fractions by preparative TLC eluting with 1:2 Et2O-hexane yielded 32 mg of a less polar product, and 44 mg of a more polar product.

Example 75C (2R.3R.4R)-2-(4-Methoxypheny)-4-(1 .3-benzodioxol-5-yfl)-1-((1 R)-1 N-dip2ropy Iam inocarbonyl)- 1 -butyflpyrrol idin e-3-carboxyl ic acid The procedure of Example 730 was followed, with the substitution of the less polar isomer from Example 75B for the resultant product from Example 73B3, to provide the title compound in 94% yield. [aID 52O (c=0.235, CH 3 QH). 1 H NMR (CD3OD, 300 MHz) 8 0.55 J=7Hz, 3H), 0.87 J=7Hz) and 0.87-0.94 (in, 6H total), 1.03- 1.25 (br m, 2H), 1.25-1.68 (br mn, 4H), 1.90-2.07 (br m, 1 2.75-2.94 oo (br mn, 2H), 2.94-3.02 (br in, 2H), 3.20-3.40 (mn, overlapping with CD 2

HOD

signal), 3.40-3.60 (br m, 2H), 3.79 3H), 4.04 (br d, J=9 Hz, 1 5.92 (dd, J=3,5 Hz, 2H), 6.72 J=8 Hz, 1H), 6.79 (dd, J=1.5,8 Hz, 6.92- 6.98 (br m, 3H), 7.29-7.39 (in, 2H). MS m/z 525 Exain~le 76 (2S.3S.4S)-2-(4-Methoxyphenyl-4-(1 .3-benzodioxol-5-yl-1 R)-1 (N.N-dipropylaminocarbonyl)-1-butyflp1yrrolidine-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. [al +580 CH 3 OH). 1 H NMR (CD30D, 300 MHz) 80.57 (br t, J=7Hz, 3H), 0.88-0.98 (in, 6H), 1.08-1.35 (br mn, 2H), 1.35-1.68 (br mn, 4H), 1.75-1.90 (br mn, 1H), 2.75-2.86 (br mn, 2H), 3.10-3.30 (br in, 2H), 3.51-3.65 (br in, 2 3.69 3H), 4.03-4.16 (br m, 2H), 5.91 2H), 6.71-6.83 (in, 2H), 6.86-6.97 (in, 3H), 7.32 (br d, J=9H-z, 2H). MS m/z 525 -124- Example 77 (2S.3S.4S)-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-vl)-1-((1 dipropvlaminocarbonyvl- 1-butvl)pDrrolidine-3-carboxylic acid Example 77A trans, trans-2-(4-Methoxyvheny)-4-(1 .3-benzodioxol-5-l)- 1 1 (N.N-diDropylaminocarbonvy)-1 -butvl)pyrrolidine-3-carboxylic acid ethyl ester (2R)-N,N-dipropyl 2-hydroxypentanamide (106 mg, 0.528 mmol, made by standard procedure) was dissolved in 2 mL THF under an argon atmosphere, diisopropylethylamine (75 mg, 0.58 mmol) was added, then the solution was cooled to -20 Trifluoromethanesulfonic anhydride IL, 159 mg, 0.565 mmol) was added to the cooled solution over 1 minute, and the reaction mixture was stirred at -20 OC for 1 hour, and at room temperature for an additional 1 hour. The resulting slurry was recooled to 0 OC, and a solution of the resultant compound from Example 6A (195 mg, 0.528 mmol) and diisopropylethylamine (101 uL, 75 mg, 0.58 mmol) in 3 mL of CH 2

CI

2 was added. The reaction was stirred at 0 OC for 3 hours and for an additional 2 days at room temperature. TLC (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 Na 2

CO

3 The aqueous phase was extracted with 15 mL EtOAc, then the combined organic phases were washed with 20 mL brine, dried (Na2SO 4 filtered 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 of a less polar product and 20.1 mg of a more polar product.

1H NMR spectra and MS were the same as those of Example 76B.

Example 77B (2S.3S.4S)-2-(4-MethoxyDhenyl)-4-(1.3-benzodioxol-5-yl)-

N-

dipropylaminocarbonvl)-1-butylvDvrrolidine-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 from Example 73B, to provide the title compound in 100% yield. 1 H NMR (CD 3 OD, 300 MHz) and MS identical to those of Example -125- ExamDle 78 2R.3R.4R)-2-(4-MethoxMhenyl)-4-(1.3-benzodioxol-5-yl)-1

N-

diDroDylaminocarbonyl)-l-butyl)ovrrolidine-3-carboxylic acid s The procedure of Example 73C was followed, with the substitution of the more polar isomer from Example 77A for the resultant product from Example 73B, to provide the title compound in 88% yield. 1 H NMR (CD30D, 300 MHz) and MS identical to those of Example 76.

Example 79 trans.trans-2-(4-MethoxvDhenvl)-4-(1.3-benzodioxol-5-vl)-1

N-

Carbonyldiimidazole (510 mg, 3.148 mmol) was added to 1.020 g (2.00 mmol) of the compound resulting from Example 43 in 2.7 mL THF, and the mixture was heated for 40 minutes at 50 OC. The reaction 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 of the 3-carboxamide compound. m.p. 194-196 Phosphorus oxychloride (1.06 g) was added to this amide in 7 mL 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 of the 3carbonitrile compound.

To this nitrile 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 OC (bath temp). After cooling, methanol (5 mL was added, and the solution was concentrated in vacuo. To the resulting residue was added 6 mL of methanol and 6 mL of water containing 0.2 g phosphoric acid. After stirring 1 hour at room temperature, water was added and the mixture extracted with dichloromethane. 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 sodium hydroxide solution, filtered from insoluble material and -126acidified with acetic acid to get 532 mg of the title compound.

m.p. 165-167 OC 1 H NMR (CDC1 3 300 MHz) 8 0.85 J=7Hz, 3H), 0.87 J=7Hz, 3H), 1.10-1.50 (in, 8H), 3.0-3.6 (in, 8H), 3.70 3H), 3.7-3.8 (in, 1H), 3.90 J=9Hz, 1H), 4.37 J=9Hz, 1H), 5.86 2H), 6.62 (d, J=8Hz, 1H), 6.65-6.73 (in, 3H), 6.95 J=2Hz, 1H), 7.11 J=9Hz, 2H).

Exam Die trans, trans-2-(4-Fluorophenyl)-4-(1 .3-benzodioxpl-5-vl)- 1- (N.Ndibutylamncro vlehvrrolidine-3-.ca rbox lc acid The title compound was prepared as an amorphous solid from methyl (4-f lourobenzoyl) acetate and 5-(2-nitrovinyl)-1 ,3benzodioxole using the procedures described in Examples 1 and 43. 1H NMR (CDCI 3 300 MHz) 8 0.81 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.0-1.55 (mn, 8H), 2.81 J=13 Hz, 1H), 2.90-3.10 (in, 4H), 3.15-3.30 (in, 1H), 0153.32-3.45 (in, 3H), 3.55-3.65 (mn, 1H), 3.86 J=lOHz, 1H), 5.94 (dd, J=2H[z, 4Hz, 2H), 6.72 J=8 Hz, 1 6.86 J= 8 Hz, 1IH), 6.95-7.07 (in, 3H), 7.32-7.45 (in, 2H).

Examlle 81 trans. trans-2-(4-Methoxyihenyl)-4.( 1.3-benzodioxol-5-yl)- 1 N-di(nbutyl~am inomethylcarbonyfl1yrrolidine.3carbolic acid N,N-Dibutyl glycine (150 mng, 0.813 mmol), prepared by the method of Bowman, J. Chem. Soc. 1346 (1950), in 0.7 mL of THF was treated with 138 mng (0.852 mmol) carbonyldiimidazole and heated for 30 minutes at 50 0 C. After cooling to room temperature, 250 mg (0.678 inmol) of ethyl trans, trans-2-(4-methoxyphenyl)4-(1,3benzodioxol-5-yl)-pyrrolidine-3-carboxylate, the compound resulting from Example 6A, was added, and the mixture was heated at 45 *C for minutes. The product was chromatographed on silica gel, eluting with 1:1 hexane-ethyl acetate to give 306 mg of the intermediate ethyl ester.

The ester was hydrolyzed with sodium hydroxide in water and ethanol to give 265 mng of the title compound as a white powder. 1H NMR (CDC1 3 300 MHz) 8 rotational isomers 0.75 and 0.85 (2 t, J=7Hz, 3H), 1.05-1.5 (in, 8H), 2.65-3.20 (mn, 6H) 3.43-3.70 (mn, 3H), 3.72 3H), 3.87 J=l5Hz, 1H), 4.49 (dd, J=l2Hz, 6Hz) and 5.23 (dd, J=l2Hz, 8Hz) -127- 2H, 5.90 (dd, J=2Hz, 4Hz, 2H), 6.63-6.78 (in, 3H), 6.86 and 7.04 (d, J=9Hz, 2H), 7.22 J=9Hz, 2H).

Example 82 trans-2-(4-Methoxyphenyl)-4-( 1 3-benzodioxol-5-vl)- 1 -(N-n-butyl)-N-(n- D2rolyl)am inocarbonylmethyflgyrrolidine-3..carbo~,ic acid The title compound was prepared using the procedures described in Example m.p. 160-162 1 H NMVR (CDCI 3 300 MHz) rotational isomers 6 0.69, 0.80, 0.84, 0.87 (four triplets, J=7Hz, 6H), 1.00-1.52 (in, 6H), 2.63 and 2.66 (two doublets, J=l3Hz, 1H), 2.90-3.10 (in, 4H), 3.23- 3.61 (in, 5H), 3.71 and 3.75 (two doublets, J=lQHz, 1H), 3.78 3H), 5.92-5.96 (in, 2H), 6.72 J=8Hz, 1H), 6.83-6.89 (in, 3H), 7.03 (d, J=2Hz, 1H), 7.81 J=9Hz, 2H).

Examile 83 trans. trans-2-(4-Methoxyhenyl)-4-( 1.3-benzodioxol-5-yl)-l1-r2-(N .N-di(n- Dropyl)aminocarbonyl)ethyflDrrolidine3carbolic acid The compound resulting from Example 6A (250 mg, 0.677 mmol), 205 mg (1.36 mmol) diallyl acrylamide (Polysciences, Inc.), and 10 mg acetic acid were heated at 85 OC 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 with 3:1 hexane-ethyl acetate gave 283 mng 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 to afford the dipropyl amnide ethyl ester in 100% yield.

The ester was hydrolyzed to the title compound by the method of Example 1ID in 83% yield. 1 H NMVR (CDC1 3 300 MHz) 8 0.82 and 0.83 (two triplets, J=7Hz, 6H), 1.39-1.54 (in, 4H), 2.35-2.60 (in, 3H), 2.80-3.07 (in, 3.14-3.21 (mn, 2H), 3.31-3.38 (in, 1H), 3.51-3.61 (mn, 1H), 3.73 (d, J=12H, 1H), 3.75 3H), 5.94 2H), 6,71 J=9Hz, 1H), 6.79-6.85 (in, 3H), 7.04 J=2Hz, 1H)< 7.32 J=9Hz, 2H).

-128- Exam Die 84 trans. trans-2-(4-Methoxyohenyl)b4-( 1. 3-benzodioxol-5-yl)-l1-(N. N-di(nbutyI~am inocarbonyflpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 8 using dibutyl carbamoyl chloride, prepared by the method of Hoshino et al., Syn. Comm., 17: 1887-1892 (1987), as a starting material. 1 H NMR (CDCI 3 300 MHz) 8 0.86 J=7Hz, 6H), 1. 14-1.28 (in, 4H), 1.35-1.48 (in, 4H), 2.81-2.94 (in, 2H), 3.11 J=l2H1z, 1H), 3.30- 3.41 (in, 2H), 3.59-3.68 (in, 2H), 3.76 3H), 3.78-3.85 (in, 1H), 5.81 (d, J=9Hz, 11H), 5.94 2H), 6.73-6.86 (mn, 5H), 7.24 J=9Hz, 2H).

trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)-1 1-(NNdfibutvyLaminocarbonlmethl)pyrrolidine-3-carboxylic acid sodium salt 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 inmol.) 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 for 2 hours at 60 0 C to yield 627.5 mng of the title compound.: Example 86 trans, trans-2-(4-Methoxyphenyl)-4-( 1. 3-benzodioxol-5-yi)- 1 .N-di(nbutyl~ aiino)-ehyl]pyrrolidine-3-carboxylic acid A solution of the bromoethyl compound resulting from Example 61A (150 mng), dibutylamine (150 mg) and sodium iodide (18 mg) in 0.75 mL ethanol was heated at 80 0 C for 1 hour. After cooling, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na2SO 4 and concentrated. More toluene was added, and the solution was again concentrated to get rid of excess dibutylamine. The residue was dissolved in warm heptane and filtered from a small amount of insoluble material. The hepane was removed in vacuo to give 143 mng of the intermediate ethyl ester.

The ester was hydrolyzed by the method of Example 1 D to give the title compound as a white powder. 1 H NMR (CD 3 OD, 300 MHz) 8 0.89 (t, J=7H-z, 6H1), 1.16-1.30 (in, 4H), 1.44-1.56 (mn, 4H), 2.48-2.57 (mn, 1H), 2.80-3.08 (mn, 8H), 3.14-3.25 (mn, 1H), 3.31-3.38 (mn, 3.59-3.60 (mn, -129- 1H), 3.74 3H), 3.75 J=lOHz, 1H), 5.89 2H), 6.71 J=9Hz, 1H), 6.81 (dd, J=9Hz, 2Hz, 1H), 6.90 J=lOHz, 2H), 6.96 J=2Hz, 1H), 7.37 J=lOHz, 2H).

Examlle 87 trans. trans-2-(4-Methoxyohenfl)-4-(1 .3-benzodioxol--5-yl.. 1 2-[N-4N. N-di(nbutyl~am inoca rbonfl-N-methylam inolethylDvrplidine-3-carboxylic acid Dibutyl carbamoyl chloride (135 mg) was added to the compound resulting from Example 61B (250 mg) and 150 mg triethylamine in 1 mL dichloromethane. After stirring 1 hour at room temperature, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na 2

SO

4 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.

The ester was hydrolyzed by the method of Example ID to afford 141 mg of the title compound. 1 H NMR (CD 3 OD, 300 MHz) 8 0.92 J=7Hz, 6H), 1.21-1.32 (in, 4H), 1.42-1.53 (mn, 4H), 2.62 3H), 2.65-2.76 (in, 1H), 3.00-3.20 (in, 8H), 3.44-3.55 (in, 1H), 3.62-3.78 (in, 2H), 3.80 3H), 4.07 J=12 Hz, 1H), 5.93 2H), 6.75 J=9Hz, 1H), 6.87 (dd, J=9HZ, 2Hz, 1H), 6.94 J=10 Hz, 2H), 7.04 J=2Hz, 1H), 7.40 (d, J=1lOHz, 2H).

Example 88 trans. trans-2-(4-Methoxyheny)-4-( 1.3-benzodioxol-5-y)-I N-di(nb-utyl) am inocarbonyflmethyfl)1yrrolidine-3-(N-inethanesulfonyl~cprboxam ide Carbonyldiimidazole (75 mng, 0.463 inmol) was added to 150 mng 9 (0.294 minol) of the compound resulting from Example 43 in 0.4 mL of tetrahydrofuran, and the solution was stirred at 60 OC for 2 hours.

After cooling, 50 mg (0.526 inmol) of methanesulfonainide and 68 mg (0.447 minol) of DBU in 0.3 mL of THF were added. The mixture was stirred at 45 0 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 mng of the title compound. m.p. 170-173 IC. 1 H NMR (CDC1 3 300 MHz) 8 0.82 (t, J=7HZ, 3H), 0.88 J=7HZ, 3H), 1.05-1.51 (in, 8H), 2.75-2.86 (mn, 2H), 2.83-3.25 (in, 4H), 3.17 3H), 3.32-3.50 (in, 3H), 3.70-3.78 (mn, 11-), 3.80 3H), 3.87 J=lOHz, 1H), 5.96 (dd, J=2Hz, 4Hz, 2H), 6.74 (d, -130- J=91-lz, 1H), 6.84 (dd, J=9Hz, 2Hz, 1H), 6.90 J=10 Hz, 2H), 7.01 (d, J=2Hz, 1H), 7.34 J=lOHz, 2H).

Example 89 trans. trans-2-(4-Methoyghenl)-4-(1 .3-benzodioxol-5-y)- 1 N-di(nbutvl)aminocarbonyl)methyl)1yrrolidine-3-(N-benzenesulfonyl)carboxam ide The compound resulting from Example 43 was converted to the title compound by the method of Example 88 substituting benzenesulfonamide for methanesulfonamide. m.p. 169-171 'IC for a sample recrystallized from acetonitrile. 1H NMR (ODC1 3 300 MHz) 8 0.81(t, J=7 Hz, 3H), 0.89 J=7Hz, 3H), 1.02-1.50 (in, 8H), 2.65-2.80 (in, 2H), 2.90-3.25 (in, 4H), 3.80-3.95 (in, 3H), 3.50-3.60 (mn, 1H), 3.65 (d, J=lOHz, 1H), 3.81 3H), 5.94 2H), 6.70 2H), 6.81-6.90 (in, 3H), 7.17 J=lOHz, 2H), 7.55 J=7 Hz, 2H), 7.66 J=7Hz, 1H), 8.95 (d, J=7Hz, 2H).

Examgle trans. trans-2-(4-Methoyhenyl)-4-(1 .3-benzodioxol-5-yl)-1 -rN. N-di(n-butyI aminosulfonylmethyll-gyrrolidine-3-carboxcylic acid Chloromethyl sulfenyl chloride, prepared by the method of Bnintzinger et. al., Chem. Ber. D5.: 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 tetraf lou robo rate 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 chloroinethyl sulfenyl chloride is reacted with the compound resulting from Example 6A to give ethyl trans,trans-2- (4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-l1-[N,N-di(nbutyl)aminosulfenylmethyl]-pyrrolidine-3-carboxylate. This is oxidized with osmium tetroxide and N-methyl inorpholine N-oxide by the method of S. Kaldor and M. Hammond, Tet. Lett. 5043-5045 (1991) to give the title compound after hydrolysis of the ethyl ester.

-131- Example 91 trans. trans-2- (4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-

N-

dibutvlamino)carbonvl- 1 -(RS)-ethvllvrrolidine-3-carboxvlic acid Example 91A (+)-Dibutyl 2-bromoproDanamide 2-Bromopropanoic acid (510 mg, 3.33 mmol) and 4-methylmorpholine (0.74 mL, 6.73 mmol) were dissolved in 10 mL of CH 2

CI

2 the solution was cooled to 0 °C under a N 2 atmosphere, and then treated dropwise with isobutyl chloroformate (0.45 mL 3.5 mmol). After 10 minutes at 0 OC, dibutylamine (0.57 mL, 3.4 mmol) was added. The reaction was stirred at 0 OC for 1 hour and for an additional 16 hours at room temperature. The mixture was partitioned with 25 mL of 1.0 M aqueous Na 2

CO

3 solution, then the organic phase was washed sequentially with mL of 1 M aqueous NaHSO 4 and 25 mL brine, dried (Na 2

SO

4 filtered, and concentrated under reduced pressure to afford 698 mg (2.64 mmol, 79 of the crude bromoamide as a colorless oil. 1 H NMR (CDCI 3 300 MHz) 8 0.93 J=7Hz) and 0.97 J=7.5Hz, 6H total), 1.26-1.60 7H), 1.60-1.78 1H), 1.82 J=6Hz, 3H), 3.04-3.27 2H), 3.42-3.64 2H), 4.54 J=7H, 1H). MS (DCI/NH 3 m/e 264 and 266 Example 91B trans.trans- and cis.trans-2-(4-Methoxvyhenvl)-4-(1.3-benzodioxol-5-vl)-1 dibutylam ino)carbonl- 1 -(RS)-ethyl)Dvrrolidine-3-carboxvlic acid ethyl ester A solution of the resultant mixture of trans,trans and cis,trans compounds:from Example 1C (232 mg, 0.628 mmol) and the resultant compound from Example O 91A (183 mg, 0.693 mmol) in 2 mL of CH 3 CN was treated with diisopropylethylamine (0.22 mL, 1.3 mmol). The solution was stirred at 60-80 °C under a N 2 atmosphere for 16 hours. The reaction was concentrated under reduced pressure, then the residue was partitioned between 30 mL Et 2 0 and mL of 1 M aqueous Na2CO3 solution. The organic phase was washed with 20 mL water and 20 mL brine, dried over Na 2

SO

4 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 EtOAc-hexane to provide 224 mg of the title compounds as a mixture of 4 diastereomers. 1 H NMR (CDCl 3 300 MHz) 8 0.66-1.55 (several m, 19H), 2.63- 3.00 3H), 3.05-3.39 2H), 3.40-3.76 4H), 3.78-3.80 (4 s, 3H), 3.84-4.25 -132- (in, 2.6H), 4.38 J= 10.5Hz, 0.2H) and 4.58 J= 10.5 Hz, 0.2H), 5.90-5.97 (in, 2H), 6.68-6.96 (in, 5H), 7.38-7.43 (in, 2H). MS (DCI/NH 3 mle 553 ExamDile 910 trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 Ndibutylam ino)carbonyl-l1-(RS)-ethyl)pyrrolidine-3-carboxylic acid The procedure of Example 730 was used, substituting the resultant compound from Example 91 B for the resultant compound from Example 73B to give the title compound in 61% yield. 1 H NMR (CD 3 OD, 300 MHz) 8 0.70-1.05 (teveral m, 8H), 1. 14 J--6Hz, 2H), 1. 17-1.55 (in, 6H), 2.79-3.03 (in, 3.5H), 3.20-3.65 (br m, 4.6H plus CD 2 HOD), 3.70-3.78 (in, 0.4H), 3.79 3H), 3.98 J=8Hz, 0.6H), 4.06 J=7.5Hz, 0.4H), 4.25 J=8Hz, 0.4H), 5.92 and 5.94 2H total 6H), 6.73 and 6.75 J=3Hz, 1 H total), 6.78-6.85 (in, 1 6.91-7.00 (in, 3H), 7.30- 7.38 (in,2H). MS (DCI/NH 3 mle525 Anal calcd for 03 0

H

40

N

2 0 6 -0.5H 2 0: ,67.52; H, 7.74; N, 5.25. Found: 0,67.63; H, 7.65; N, 5.21. 00 trans. trans-2-(Pentyl)-4-( 1.3-benzodioxol-5-y)- 1 N- dibutylam inocarbonylmethyl)pyrrolidine-3-carboxylic acidVa* A Example 92A Methyl 2-(4-hexen oyfl-4-nitro-3-( 1. Asolution of methyl 3-oxo-6-octenoate (502 mng; 2.95 mmol) in 10 m L of isopropanol was added to a solution of 5-(2-nitrovinyl)-1,3-benzodioxole (712 mg, 3.69 inmol) in 10 mL THF, then DBU (22 iL-, 0.15 inmol) 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 vacua and flash chroinatographed on silica gel eluting with- 18% ethyl acetate in hexane to produce 879 ing (2.42 minol, 82%) of the title compound as a mixture of diastereomers in a 1:1 ratio. 1 H NMR (CDC1 3 300 MHz) 8 1.55-1.66 (mn, 3H), 2.02-2.17 (br m, 1 2.20-2.37 (mn, 1.5H), 2.49-2.76 (in, 3.57 1.5H), 3.74 1.5H), 3.97 J=7.5H, 0.5H) and 4.05 J =8Hz, 4.10-4.20 (in, 1 4.68-4.82 (in, 2H), 5.06-5.52 (in, 2H), 5.95 (2s, 2H), 6.65 (in, I1H), 6.68 (br s, 1 6.75 7.5Hz, 1 MS (DC I/N H 3 Wne 381 (M+NH 4 Anal calcd for C 18

H

21 N0 7 C, 59.50; H, 5.82; N, 3.85. Found: C, 59.32; H, 5.71; N, 3.72.

-133- Example 92B Methyl trans trans-2-(Dentyl)-4-(1.3-benzodioxol-5-l) pyrrolidine-3-carboxvlate The procedures of Example 1B and Example 1C were followed, with the substitution of the resultant compound from Example 92A for the resultant s compound from Example 1A, and the substitution of the this resultant compound for the resultant compound from Example 1B, 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 methoxide (made by the addition of 1o sodium metal (14 mg, 0.61 mmol) to 1 mL of methanol). The 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 NaHCO s diluted with 10 mL water and 30 mL of CH 2

CI

2 The aqueous phase was extracted (2 x 30 mL CH 2 C1 2 then the combined organic phases were washed with 20 mL brine, dried over Na 2

SO

4 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 CH 2

CI

2 gave 336 mg the title compound as a yellow oil. 1 H NMR (CDC 3 300 MHz) 8 0.90 (br t, 3H), 1.25-1.70 (br m, 8H), 1.83-2.02 (br s, 2H), 2.58 (dd, J=8,9Hz, 1H), 2.99 (dd, J=8,14Hz, 1H), 3.34-3.45 2H), 3.53 J=9Hz, 1H), 3.66 3H), 5.94 2H), 6.65-6.75 3H). MS

(DCI/NH

3 m/e 320 Anal calcd for C 18

H

25 N0 4 C, 67.69; H, 7.89; N, 4.39. Found: C, 67.39; H, 7.84; N, 4.37.

S

Example 92C .00* trans.trans-2-(Pentyl)-4-(1.3-benzodioxol-5-l)-1 dibutylaminocarbonvlmethyl)Dvrrolidine-3-carboxvlic acid I The procedures of Example 1B-1D were used, with the substitution of the resultant compound from Example 92A for the resultant compound from Example 1B, to provide the title compound as a white foam. 1 H NMR (CDCI 3 300 MHz) 0.87 (br t) and 0.89 (br t, 6H total), 0.97 J=7.5Hz, 3H), 1.21-1.42 (br m, 10), 1.43- 1.78 (br m, 6H), 2.76 J=7Hz, 1H), 3.02-3.30 (br m, 6H), 3.40-3.60 3H), 3.73 (d, J=14Hz, 1H), 5.98 (AB, 2H), 6.70 J=7Hz, 1H), 6.77 (dd, J=1.5,7Hz, 1H), 6.89 (d, 1H). MS (DCI/NH 3 m/e 475 Anal calcd for C 2 7H 42

N

2 05-0.5H 2 0: C, 67.05; H, 8.96; N, 5.79. Found: C, 67.30; H, 8.77; N, 5.68.

-134- Example 93 trans, trans-2-(Pentyl)-4- (1.3-benzodioxol-5-yl)- 1 -[2-(N-propyl-NoroDvlsulfonvlamino)ethyllDvrrolidine-3-carboxylic acid Example 93A Methyl trans.trans-2-(pentl)-4-(1 .3-benzodioxol-5-yl)- -(2-bromoethyl)Dvrrolidine- 3-carboxylate The procedure of Example 61A was used, with the substitution of the resultant compound from Example 92B for the resultant compound from Example o1 1C, to provide the title compound as a yellow oil. 1H NMR (CDCI 3 300 MHz) 8 0.89 (br t, J=7Hz, 3H), 1.24-1.40 (br m, 6H), 1.60-1.80 (br m, 2H), 2.61-2.75 2H), 2.76-2.91 2H), 3.10-3.22 2H), 3.36-3.47 2H), 3.68 3H), 5.92 2H), 6.69-6.77 2H), 6.90-6.94 1H). MS (DCI/NH 3 m/e 426, 428 Example 93B Methyl trans trans-2-(Pentvl)-4-(1.3-benzodioxol-5-yv)- -(2-(N-proDyl-N- propylsulfonvlam ino)ethyl]pyrrolidine-3-carboxylate A solution of the resultant compound from Example 93A (102 mg, 0.24 mmol) and tetrabutylammonium iodide (6 mg, 16 nimol) in 1 mL EtOH was treated with propylamine (60 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 Na 2

CO

3 The organic phase was washed with 15 mL brine, then dried over Na 2

SO

4 filtered and concentrated under reduced pressure to provide the crude secondary amine as a yellow oil (94.2 mg). The crude amine was dissolved in 1 mL of CH 2

CI

2 diiosopropylethylamine (65 gLL, 0.373 mmol) was added, followed by propylsulfonyl chloride (29 gL, 0.26 mmol). The solution was stirred at room temperature for 4 hours. The reaction was quenched with 10% aqueous citric acid (to pH and the mixture was extracted with 2 x 3 mL CH 2 C12. The combined organic extracts were washed with 2 mL brine, then dried over Na 2

SO

4 filtered, concentrated in vacuo. Purification by flash chromatography eluting with 20% ethyl acetate in hexane provided 65.0 mg of the title compound as a waxy solid. Rf 0.17 (20%EtOAc-hexane). MS (DCI/NH 3 m/e 511 -135- Example 93 trans. trans-2-(Pentyfl-4.( 1.3-benzodioxol-5-yW -1 -[2-(N-oropyl-N- 12ropyls uffonyl am in o)ethyllpyrro lid ine-3-ca rboxyl ic acid The procedure of Example 710 was followed, with the substitution of the resultant compound from Example 93B for the resultant compound from Example 71 B, to provide the title compound as a white foam (47 mg, Rf 0. 14 2

CI

2 1 H NMR (ODC1 3 300 MHz) 8 0.88 (br t) and 0.92 J=7Hz, 6H total), 1.22-1.52 (br m, 6H), 1.63 (sextet, J=8Hz, 2H), 1.75-2.10 (br m, 4H), 2.89-2.98 (in, 2H), 3.05 (br t, J=9Hz, 1 3.10-3.30 (in, 3H), 3.30-3.80 (br m, 7H), 5.94 2H), 6.71 J=8Hz, 1 6.77 (dd, J=1.5,8Hz, 1 6.89 J=1.5Hz, 1 MS (DCI/NH 3 ine 497 Example 94 trans. trans-2- (PropyW)4- 1.3-ben zod ioxol-5-yl- 1 N dibutylam inocarbonylmethyl)yrrolidin-3carbo~lic acid Example 94A Ethyl 2-(4-buta noyl)-4-nitro-3-( 1.3-benzodioxole-5-ylobutyrate The procedure of Example 92A was followed, with the substitution of ethyl butyryl acetate for methyl 3-oxo-6-octenoate, to provide the title compound as a mixture of trans and cis isomers (47 mg, Rf 0.28 (25%EtOAc-hexane). 1

H

NMR (CDC1 3 300 MHz) 8 0.74 J=7.5Hz) and 0.91 J=7.5Hz, 3H total), 1.08 (t, J=7Hz) and 1.28 J=7Hz, 3H total), 1.45 (sextet, J=7Hz, 1 1.63 (sextet, J=7Hz, approx. 1.5H), 2.17 J=7Hz) and 2*.24 J=7Hz, 0.5H total)2.40-2.54 (in, 1 2.60 J=7.5Hz) and 2.67 J=7.5Hz, 0.5H total), 3.93-4.09 (in, 2H), 4.10G-4.20 (br m, 1 4.23 J=7Hz, 1 4.67-4.85 9mn, 2H), 5.94 2H), 6.62-6.75 (in, 3H). MS

(DCL/NH

3 ine 369 (M+NH 4 Anal calcd for C17H 21 N0 7 0, 58.11; H, 6.02; N, 3.99. Found: C, 58.21; H, 5.98; N, 3.81.

Examiole 94B Ehltans. trans-2-(propyl)-4-( 1. 3-benzod ioxol-5-yl)pyrrolid ine-3-carboxyte 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/NH 3 in/e 306 -136- Example 94C trans.trans--Propyl)-4-(1 .3-benzodioxol-5-yl)-i dibutylam in o)carbonyl)methylpyrrolidine-3-carboxylic acid The procedure of Example 920 was followed, with the substitution of the resultant product from Example 94B for the resultant product from Example 92B, to give the title compound. 1 H NMR (CDC1 3 300 MHz) 8 0.89 J=7.5Hz), 0.92 (t, and 0.97 J=7.5H, 9H total), 1.22-1.80 (br m, 12H), 2.83 J=7.5Hz, 1 H), 3.40-3.55 (br m, 2H), 3.55-3.68 (in, 1 3.78 J=l15Hz, 1 5.92 J=1 Hz, 2H), 6.70 J=8Hz, 1 6.79 (dd, J=1lHz,8Hz, 1 6.90 J=1 Hz, MS (DCI/NH 3 m/e 447 Anal calcd for C 25

H

3 8N 2 0 5 -0.5 H 2 0: C, 65.91; H, 8.63; N, 6.15.

Found: C, 65.91; H, 8.68; N, 5.94.

Example 0 ~(2R .3R (+)-2-(4-Methoxyphenyl)-4.( 1.3-benzod ioxol-5-yfl- 1 -(tertbutyloxycarbonyl-am inocarbonylinethyl)-D2yrrolidine-3-carboxlic acid: Examn~le trans. trans-2- (4-Methoxcylhenyl)-4- (1 butyloxycarbonylaminocarbonylmethyllpyrrolidine3!carboxylic acid The resulting mixture of 64% trans,trans- and cis, transpyrrolidines resulting from Example 10C (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 dicarbonate (1.96 g, 8.97 inmol) in 20 mL methylene chloride under a nitrogen atmosphere, and the resulting 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. 1 H NMR

(CDCL

3 300 MHz) 8 0.99, 1.07 (br t, br t, J=7 Hz, 3H), 1.11-1.62 (several br m, 9H), 3.05 (br m, 1 3.44-3.95 (in, 3H), 3.81 3H), 4.04 J=7 Hz, 1 4.14-4.28 (br mn, 1 4.89-5.24 (br m, 1 5.94 J=3 Hz, 2H), 6.69-6.90 (mn, 5H), 7.06-7.20 (mn, 2H). MS (DCI/NH 3 in/e 470 To the ethyl ester dissolved in 170 mL of ethanol was added a solution of lithium hydroxide (1.06 g, 25.17 inmol) in 60 mL of water.

The reaction mixture was vigorously stirred for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated to remove -137ethanol, diluted with 250 mL of water and extracted three times with 250 mL of ether. The organic phase acidified to slight cloudiness (pH with 1 N 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 (Na 2

SO

4 filtered, concentrated and dried on high vacuum to give the title compound as a white foam (2.19 g, 60 1 H NMR (CDCI 3 300 MHz) 8 1.16 (v br s, 9H), 3.11 (br m, 1H), 3.50-3.64 2H), 3.81 3H), 4.24 (br m, 1H), 4.96 (br m, 1H), 5.94 (s, 2H), 6.71-6.79 3H), 6.84-6.91 2H), 7.19 J=9 Hz, 2H). MS

(DCI/NH

3 m/e 442 (M+H) Example (2R.3R.4S)-(+)-2-(4-Methoxyvhenvl)-4-(1.3-benzodioxol-5-vl)-1-(tert- butvloxvcarbonvlaminocarbonvlmethvl)-Dvrrolidine-3-carboxvlic acid The compound resulting from Example 95A (2.15 g, 4.86 mmol) and (+)-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 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 1H NMR and chiral HPLC. The amount of enantiomer decreased first in the crystals and then in the filtrate with the predetermined endpoint achieved when the enantiomer could no longer be detected in the filtrate. The pure 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 (Na 2

SO

4 filtered, concentrated and dried on high vacuum to a white powder (550 mg, 55 of theoretical 50 maximum, >99.5 ee). 1 H NMR (CDCI 3 300 MHz) 5 1.05-1.50 (br m, 9H), 3.12 (br m, 1H), 3.50-3.65 2H), 3.81 (s, 3H), 4.24 1H), 4.96 (br m, 1H), 5.95 2H), 6.70-6.79 3H), 6.86 J=9 Hz, 2H), 7.19 J=9 Hz, 2H). MS (DCI/NH 3 m/e 442 -138- Example (2R.3R.4S)-(+)-Ethyl 2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-Dvrrolidine-3carboxylate The compound resulting from Example 95B (251 mg, 0.568 mmol) was dissolved in 20 mL of a saturated solution of anhydrous HCI(g) in anhydrous ethanol. The resulting solution was heated at 50 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 M aqueous sodium carbonate (50 mL) and methylene chloride (50 mL). The aqueous layer was further extracted with methylene chloride (2 x 50 mL). The combined organic layers were dried (Na 2

SO

4 filtered, concentrated and dried under high vacuum to give the title compound as an almost colorless oil (158 mg, 1

H..

NMR (CDCis, 300MHz) 8 1.11 J=7 Hz, 3H), 2.18 (v br s, 1H), 2.93 J= 9 Hz, 1H), 3.19,3.22 (dd, J=7 Hz, 1H), 3.50-3.69 2H), 3.80 3H), 4.07 J=7 Hz, 2H), 4.49 J=9 Hz, 1H), 5.94 2H), 6.73 J=2 Hz, 2H), 6.81-6.92 3H), 7.34-7.41 2H). MS (DCI/NH 3 m/e 370 Example (2R.3R.4S)-(+)-2-(4-Methoxphenyl)-4-(1.3-benzodioxol-5-yl)-1-(tert-:' butvloxvcarbonyl-aminocarbonylmethyl)-yvrrolidine-3-carboxylic acid To the resulting compound from Example 95C (131 mg, 0.355 mmol) was added, diisopropylethylamine (137 mg, 185 gL, 1.06 mmol), acetonitrile (2 mL), N,N-di-(n-butyl)bromoacetamide (133 mg, 0.531 •e i mmol), and the mixture was heated at 50 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. 1 H NMR (CDCI 3 300MHz) 8 0.81 J=7 Hz, 3H), 0.88 J=7 Hz, 3H), 1.10 J=7 Hz, 3H), 1.00-1.52 8H), 2.78 J=14 Hz, 1H), 2.89-3.10 4H), 3.23-3.61 5H), 3.71 J=9 Hz, 1H), 3.80 3H), 4.04 J=7 Hz, 2H), 5.94 (dd, Hz, 2H), 6.74 J=9 Hz, 1H), 6.83-6.90 3H), 7.03 J=2 Hz, 1H), 7.30 J=9 Hz, 2H). MS (DCI/NH 3 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 -139warmed slowly to 40 oC. 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 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 (Na 2

SO

4 filtered, concentrated and dried under high vacuum to give the title compound as a white foam (150 mg, 1 H NMR (CDC13, 300MHz) 8 0.80 J=7 Hz, 3H), 0.88 J=7 Hz, 3H), 1.08 2H), 1.28 3H), 1.44 3H), 2.70-3.77 (svr br m, 12H), 3.79 3H), 5.95 2H), 6.75 J=8 Hz, 1H), 6.87 (br d, J=8 Hz, 3H), 7.05 br s, 1H), 7.33 (v br s, 2H). MS (DCI/NH 3 m/e 511 [a] 2 2 +74.420. Anal calcd for C29H 3 8N 2 0 6 -0.5 H 2 0: C ,67.03; H, 7.56; N, 5.39. Found: C, 67.03; H, 7.59; N, 5.33. ExamDle Alternate Preparation of (2R.3R.4S)-(+)-2-(4-Methox3henyl)-4-(1.3-benzodioxol-5- yl)-l-(tert-butyloxvcarbonvlaminocarbonylmethyl)- rrotidine-3-carboxylic acid 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 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- 1670. The filtrate was concentrated, cooled and scratched with a spatula to give a second crop 0.1313 g, m.p. 164-1680. The filtrate was concentrated again and put in the refrigerator and let stand overnight giving 1.6906 g, m.p. 102-1100. (HPLC of this showed 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 soluble in dichloromethane) and stirred for 2 minutes. The mixture was concentrated, but not to dryness, and ether (10 mL) was -140added. After stirring for a few minutes the crystals were filtered.

Yield: 1.401 g, m.p. 164-1720.

Treatment of the crystalline product with 10% citric acid and ether according the method described in Example 95B provided the title compound.

Examole 96 trans. trans-2-(4-Methoxyohenyl)-4-( 1.3-benzodioxol-5-yi)- 1 -r2-(N-Droo~yl-Nbutvrylam ino')ethylloyrrolidine-3-carboxylic -acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and butyryl chloride for isobutyryl chloride in Example 61C. The product was purified by preparative HPLC (Vydac giC18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TEA. The desired fractions were lyophilized to give the product as a white solid. 1 H NMR (CDC1 3 300 MHz) 8 0.80 (in, 3H), 0.90 3H, J=8Hz), 1.42 (in, 2H), 1.58 (heptet, 2H, J=81-z), 2.20 3H, J=8Hz), 2.94 (br mn, 2H), 3.10 (br m, 2H), 3.48 (br in, S 4H), 3.76 (br m, 2H), 3.78 3H), 4.30 (br s, 1 5.95 2H), 6.75 (d, 1 H, J=8Hz), 6.84 (in, 1 6.85 2H, J=8Hz), 7.04 1 H, J=1lHz), 7.40 2H, J=8Hz). MVS (DCI/NH 3 rn/e 497 Anal calcd for

C

28

H

3 6

N

2 0 6 -1.0 TEA: C, 58.82; H, 6.42; N, 4.57. Found: C, 58.77; H, 6.30; N, 4.42.

Exainole 97 trans. trans-2-(4-Methoxyghenyl)-4-( 1.3-benzodioxol-5yl-1 -[2-(N-orooyl-N- (ethylaininocarbonyl~ am ino)ethyllo~yrrolidine-3-ca rboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylainine for inethylainine in Example 61B and ethyl isocyanate 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 CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDC13, 300 MHz) mixture of rotainers 8 0.80 J=8Hz) and 1.05 J=8Hz) and 1.20 (in) and 1.42 (in) total of 8H for the four peaks, 2.35 (br s, 1H), 2.70 (in, 1H), 3.0 (in, 3H), 3.2 (in, 3H), 3.25 (dq, 1H, J=1,8Hz), 3.42 (in, 1H), 3.6 (mn, 1H), 3.75 (mn, 1H), 3.78 3H), 4.8 (br s, 1H), 5.95 2H), 6.74 1H, J=BHz), 6.85 (in, 3H), 7.00 1H), 7.30 2H, J=8Hz). MS (DCI/NH 3 m/e 498 -141- Anal calcd for C2 7

H

35

N

3 0 6 -0.75 H 2 0: C, 63.45; H, 7.20; N, 8.22. Found: C, 63.38; H, 7.29; N, 8.44.

Exam Die 98a trans. trans-2-(4-Methoxy~henyl-4-(1 .3-benzodioxol-5-yl)-i 1 2-(N-butyl-Nbutyryamino)ethylIl~vrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 618 and butyryl chloride 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 CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDC1 3 300 MHz) 8 0.80 (in, 3H), 0.90 3H, J=8Hz), 1.45 (mn, 4H), 1.6 (in, 2H), 2.20 3H1, J=8Hz), 2.94 (br m, 2H), 3.10 (br mn, 2H), 3.5 (br m, 4H), 3.80 (br m, 2H), 3.82 (s, 3H), 4.30 (br s, I1H), 5.95 2H), 6.75 1 H, J=8Hz), 6.84 (in, 1 6.85 2H, J=8Hz), 7.04 IH, J=lHz), 7.40 2H, J=8Hz). MS (DCI/NH 3 mWe 511 HRMS calcd for C2 9 H38N 2 0 6 511.2808. Found: 511.2809 Examlle 99 trans. trans-2-(4-Methoxyhenyl-4-( 1.3-benzodioxol-5-yfl)- -[2-(N-Qroo2Yl-Nethoxycarbonylam ino)ethylloyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and ethyl chioroformate for isobutyryl chloride in Example 61C.

The crude product was purified by trituration with 1:1 diethyl etherhexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1H NMR (CDC1 3 300 MHz) 5 0.80 3H, J=8Hz), 1.05 (mn, 2H), 1.22 (in, 3H), 1.45 (mn, 3H), 2.08 (br s, 1H), 2.75 (mn, 1H), 2.88 (br q, 2H, J=8Hz), 3.08 (br in, 2H), 3.27 (br mn, 2H), 3.44 (in, 1H), 3.54 (dt, 1H, J=1,8Hz), 3.63 1H, J=8Hz), 3.78 (s, 3H), 4.02 (br 5.93 2H), 6.72 1H, J=8Hz), 6.81 (dd, 1H, J=1,8Hz), 6.85 2H, J=8Hz), 7.00 7.30 2H, J=8Hz). MS

(DCI/NH

3 W/e 499 Anal calcd for C27H34N 2

O

7 -0.5 H 2 0: C, 63.89; H, 6.95; N, 5.52. Found: C, 64.03; H, 6.71; N, 5.30.

-142- Example 100 trans. trans-2-(4-Methoxy~henvl)-4-(I .3-benzodioxol-5-yi)- 1 -[2-(N-methyl.N-( .2ethylbutyryfl am ino)ethylllyrrolidine-3-carboxylic acid To the compound resulting from Example 61B (190 mg) dissolved in THE (2 mL) was added HQBt (60 mg), EDCI (85 mg), Nmethylmorpholine (50 giL), and DMF (2 mL). 2-Ethylbutyric acid was added and the solution stirred overnight at ambient temperature. Water mL) was added, and the mixture was extracted with EtOAc (2 x mL). The combined organic extracts were washed with saturated sodium bicarbonate solution, 1 N H3P0 4 and brine, dried with Na 2

SO

4 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 61C. The crude product was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDCI 3 300 MHz) (mixture of rotamers) 8 0.66, 0.74, 0.80, 0.88 (all triplets, total of 6H, J=8Hz), 1.05 (in, 2H), 1.25-1.75 (in, 5H), 2.16 (in, 1 2.32 (mn, 1 H), 2.45 (in, 1 2.70 (mn, 1 2.86, 2.94 total 3H), 2.95 (in, 1 3.35 (mn, 1 3.52 (in, 2H), 3.65 (in, 1 3.80 3H), 5.94, 5.96 total 2H), 6.73 (mn, 1H), 6.84 (in, 3H), 6.97 (in, 1H), 7.30 (in, 2H). MS (DCI/NH 3 in/e 497 Anal calcd for C 28

H

36

N

2 0 6 -0.25 H 2 0: C, 67.11; H, 7.34; N, 5.59. Found: C, 67.13; H, 7.24; N, 5.56. Example 101 trans. trns-2-(4-Methoxyphenyl-4-( 1.3-benzodioxol-5-y)-l1 2-(N-methyl- N-(2propylvaleryl)amino)ethyllpyrrolidine-3-carboxylic acid The title compound was prepared by the procedure described in- Example 100, but substituting 2-propylpentanoic acid for 2ethylbutyric acid. The crude product was purified by preparative HPLC (Vydac g±C18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid.

1 H NMR (CDC1 3 300 MHz) 6 0.79 3H, J=8Hz), 0.82 31-, J=8Hz), 1. (in, 4H), 1.2-1.5 (in, 4H), 2.55 (in, 1 2.96 3H), 3.15 (br mn, 1 3.32 (br mn, 1H), 3.56 (in, 2H), 3.68 (in, 1H) 3.68 3H), 3.70 (mn, 1H), 3.80 (in, 2H), 4.65 (br d, I1H), 5.92 2H), 6.75 1 H, J=8Hz), 6.84 (in, 1 6.85 2H, J=8Hz), 7.05 1 7.42 2H, J=8Hz). MS (DCI/NH 3 in/e 525 -143- Anal calcd for C3 0 1- 40

N

2 0 6 -1.25 TFA: C, 58.51; H, 6.23; N, 4.20.

Found: C, 58.52; H, 6.28; N, 4.33.

Examlle 102 trans. trans-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-yfl- 1 -[2-(N-grolvl.N-(tertbutyl oxyca rbonyl methyl) amin o)ethvll pyrrol idi ne- 3-ca rboyl ic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and t-butyl bromoacetate for isobutyryl chloride in Example 61C.

The crude product was purified by trituration with 1:1 diethyl etherhexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDCI 3 300 MHz) 8 0.82 3H, J=8Hz), 1.18 (in, 2H), 1.19 9H), 2.12 (mn, 2.46 (in, 2H), 2.70 (in, 3H), 2.85 (in, 2H), 3.20 3.40 (dd, 1 H, J=2,8Hz), 153.50 (dt, 1 H, J=2,8Hz), 3.62 1 H, J=8Hz), 3.78 3H), 5.95 2H), 6.72 I1H, J=8Hz), 6.84 (mn, 1 6.85 2H-, J=8Hz), 7.05 1 7.16 2H, J=8Hz). .MS (DCI/NH 3 m/e 541 Anal calcd for

C

3 oH 4

ON

2

O

7 -1.0 H 2 0: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.75; H, 7.35; N, 4.86.

Example 103 trans. trans-2-(4-Methoxyohenyl)-4-( 1.3-benzodioxol-5-yIY -lr2-(N-1Drooyl-N-(n- Drol~viam in oca rbonylm ethyl) am in o)ethya 12yrrolid ine-3-ca rboyl ic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for inethylamine in Example 61B and N-propyl broinoacetamide for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac iC 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. 1 H NMR (CDC1 3 300 M1-z) 8 0.78 3H, J=8Hz), 0.88 3H, J=BHz), 1.45 (mn, 2H), 1.48 (in, 3H, J=8Hz), 2.55-2.7 (in, 2H), 2.90 (in, 1 3.04 (in, I1H), 3.15 (mn, 3H), 3.28 1 H, J=8Hz), 3.45 1 H, J=8Hz), 3.60 (in, 3.70 (d, 2H, J=8Hz), 3.75 (in, 1 3.80 3H), 4.25 1 H, J=8Hz), 5.95 2H), 6.75(d, 1 H, J=8Hz), 6.86 (dt, 1 H, J=1,8Hz), 6.88 2H-, J=8Hz), 7.04 (d, 1H, J=lHz), 7.40 2H, J=8Hz). MS (DCI/NH 3 m/e 526 Anal calcd for C 2 9

H

39 N30 6 -1.85 TEA: C, 53.32; H, 5.59; N, 5.70. Found: C, 53.45; H, 5.62; N, 5.63.

-144- Examile 104 trans, trans-2- (4-Methoxyihenvl)-4-(1 .3-benzodioxol-5-fl)- 1 -r2-(N-Droj2Yl-N-(4methoxyhenocycarbonyl)am ino)ethyllpyrrolidine-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 4-methoxyphenylchioroformate 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 CH 3 CN and 1o water and lyophilized to give the product as a white solid. 1H NMR

(CD

3 OD, 300 MHz) mixture of rotamers 8 0.88 1.57 (in, 2H), 2.45 (br s) and 2.60 (br s, total of 1 2.90-3.15 (in, 4H), 3.42-3.7 (in, 3.78 3H), 3.80 3H), 3.85 (in) and 4.0 (in, total of 1 5.95 and 5.98 total of 2H), 6.63(m, 1H), 6.72 1H, J=8Hz), 6.81 (in, 2H), 6.93 (in, 5H), 7.40 (in, 2H). MS (DCI/NH 3 mWe 577 Anal calcd for:: C3 2

H

36

N

2 0 8 1.0 H 2 0: C, 64.63; H, 6.44; N, 4.71. Found: C, 64.70; H, 6.38; N, 4.63.

Examgle 105 tans. tr n--4Mtoyhnl.- 3-be zodioxol-5-yl)-l1-r2-(N-D2rolyl-N-(- methoxybenzoylam ino~ethyll1Drrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and anisoyl chloride for isobutyry chloride in Example 61C. The crude product was purified by trituration with 1:1 diethyl ether-hexane.

The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDC1 3 300 MHz) mixture ofrotamers 6 0.78 (in) and 0.98 J=8Hz) total of 3H, 1.47 (in) and 1.52 (q, J=BHz) total of 2H, 2.25 (br s, 1 2.78 (br s, 1 2.90 (br t, 3.12- 3.68 (mn, 7H), 3.80 3H), 3.82 3H), 5.94 2H), 6.75(d, 1H, J=8Hz), 6.83 (mn, 5H), 6.94 (mn, 1H), 7.22 (mn, 4H). MS (FAB) mWe 561 Anal calcd for C 32

H

36

N

2 0 7 -0.75 H 2 0: C, 66.94; H, 6.58; N, 4.88. Found: C, 67.00; H, 6.38; N, 4.59.

-145- Examlle 106 trans. trans-2-(4-Methoxyphe nyl-4- (1 .3-benzodioxol-5-yl)- 1 -[2-(N-Oropyl- Nbenzoylam ino)ethyllpyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and benzoyl chloride 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 CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDCI 3 300 MHz) mixture of rotamers 5 0.65 and 0.9 (in, total of 3H) 1.4 and 1.55 (mn, total of 2H), 2.05 and 2.15 (in, total of 1H), 2.6 3.6 (in, 8H), 5.92 2H), 6.70(d, 1H, J=8Hz), 6.82 (in, 4H), 7.2 7.4 (in, 6H). MS (DCI/NH 3 m/e 531 Anal calcd for C 3 1

H

3 4

N

2 0 6 -0.3 H 2 0: C, 69.46; H, 6.51; N, 5.23. Found: C, 69.48; H, 6.19; N, 4.84.

Example 107 trans. trans-2-(4-MethoxyphenyF)-4-( 1.3-benzodioxol-5-yl)- 1 -(2-(N-propyl-Nbenzyloxycarbonylamino)ethyllpyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamnine for methylamine in Example 61B and benzyl chioroformate for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac .C 18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TEA. The desired fractions were lyophilized to give the product as a white solid. 1H NMR (ODC1 3 300 MHz) 8 0.8 (in, 3H) 1.45 (in, 2H), 2.20 (br m, 1 2.75 (in, I1H), 2.93 (mn, 1 3.15 (mn, 2H), 3.32 (in, 3H), 3.52 (mn, 2H), 3.66 (in, 1 H), 3.78 3H), 5.00 (mn, 2H), 5.94 2H), 6.72(d, 1 H, J=8Hz), 6.82 (mn, 3H)-, (br d, 1 H, J= 15Hz), 7.2 4H), 7.30 (in, 3H). MS (FAB) W/e 561 Anal calcd for C 32

H

3 6

N

2 0 7 -1.0 TEA: C, 60.53; H, 5.53; N, 4.15.

Found: C, 60.66; H, 5.34; N, 4.28.

Example 108 trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yF- 1 -12-(N-propyl-N-(4methoybenzyloycarbonylamino~ethyllpyrrolidine-3-carboxylic acid The title compound is prepared by the methods described in Example 61, substituting propylainine for methylamine in Example 61 B -146and 4-methoxybenzyl chioroformate for isobutyryl chloride in Example 610C.

Examlle 109 trans.trans-2-(4-Methoxvohenvl)-4-(1 .3-benzodioxol-5-vl)-l1-f2-(N-butyl-Nethoxycarbonviam ino)ethyfll~vrrolidine,-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 61B and ethyl chioroformate for isobutyryl chloride in Example 61C.

The crude product was purified by preparative HPLC (Vydac gC 18) eluting with a 10-70% gradient of CH3CN in 0.1% TEA. The desired fractions were lyophilized to give the product as a white solid. 1 H NMR (CDC1 3 300 MHz) 8 0.82 3H, J=8Hz), 1.20 (in, 5H), 1.34 (mn, 2H), 3.08 (in, 2H), 3.17 (in, 2H), 3.52 (in, 2H), 3.75 (in, 3.78 3H), 4.06 (q, 2H, J=-8Hz), 4.35 (br s, 1 5.94 2H), 6.76 1 H, J=8Hz), 6.92 2H, J=8Hz), 7.03 (br s, 1H), 7.17 (br s, 1H), 7.7 (br s, 2H). MS (FAB) in/e 513 Anal calcd for C 2 8H3 6

N

2 0 7 -0.5 TFA: C, 61.15; H, 6.46; N, 4.92.

Found: C, 60.99; H, 6.80; N, 4.93.

Examile 110 trans. trans-2-(4-Methoxy~henyl)-4-( 1.3-benzodioxol-5-y)- 1 -r2-(N-butyl-N- Droloxycarbonylamino)ethylliyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example .61, but substituting butylamine for methylamine in Example 61B and propyl chloroforinate for isobutyryl chloride in Example 61C.

The crude product was purified by trituration with 1:1 diethyl etherhexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1H NMR (ODC13, 300 MHz) 8 0.80 (br s, 1H), 0.85 3H, J=8Hz), 0.92 (br s, 1H), 1.22 (in, 3H), 1.40 (in, 3H), 1.62 (br mn, 1 2.15 (br s, 1 2.72 (in, 1 2.87 (in, I1H), 3.1-3.45 (mn, 5H), 3.55 (mn, 1 3.64 1 H, J=8Hz), 3.79 3H), 3.88 (br s, 1H), 3.97 (br s, 1H), 5.95 2H), 6-73(d, 1H, J=8Hz), 6.85 (in, 3H, 1H), 7.30 2H, J=8Hz). MS (FAB) m/e 527 Anal calcd for C29H 38

N

2 0 7 0.15 H 2 0: C, 65.80; H, 7.29; N, 5.29. Found: C, 65.79; H, 7.30; N, 5.2 1.

-147- Examlle 111 trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 -f2-(N-prol2Yl-Npropoxycarbonylamino)ethyllyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and propyl chloroformate for isobutyryl chloride in Example 61C.

The crude product was purified by trituration with 1:1 diethyl etherhexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1H NMR (CDC1 3 300 MHz) 8 0.80 3H, J=8Hz), 093 (in, 3H), 1.43 (in, 3H), 1.62 (in, 1H), 2.15 (br s, 1H), 2.68-3.45 (in, 8H), 3.54 (in, 1H), 3.66 (in, 1H), 3.78 3H), 3.94 (mn, 2H), 5.94 2H), 6.72 1H, J=8Hz), 6.82 (in, 1H), 6.84 2H, J=8H-z), 7.00 (br s, 1H), 7.33 (in, 2H). MS (DCI/NH 3 m/e 513 Anal calcd for C 2 8

H

3 6

N

2 0 7 -0.15 H 2 0: C, 65.26; H, 7.10; N, 5.44. Found: C, 65.22; H, 6.74; N, 5.06.

Examlle 112 trans, trans-i1 N- Di(n-butyl)aminocarbonyflmethyl-2. 4-di (1 yl)pyrrolidine-3-carboxylic acid Ethyl methyl ene di oxybe nzoyl) acetate, prepared by the method of Krapcho et al., Org. Syn. 47, 20 (1967) starting with 3,4- methylenedioxyacetophenone instead of 4-m ethoxyacetophen one, was reacted by the procedures described in Example 1 to give the title compound as a white solid. m.p. 58-60 1 H NMR (ODC1 3 300 MHz) 8 0.87 (quintet, J=6Hz, 6H), 1.12 (sextet, J=6Hz, 2H), 1.24-1.51 (in, 6H), 2.80 J=l3Hz, 1H), 2.94-3.12 (in, 4H), 3.28-3.50 (in, 4H), 3.58-3.62 (mn, 1H), 3.78 J=9Hz, 1H), 5.95 4H), 6.73 (dd, J=8Hz, 3Hz, 2H), 6.84-6.89 (mn, 2H), 6.92 J=lHz, 1H), 7.01 H=lHz, 1H). MS

(DCI/NH

3 m/e 525 Examle 113 trans. trans-i1 -(2-(N-(n-Butyl)-N-propylsulfonylam ino~ethyl)-2-(4-methoxyhenYl)-4- (1 .3-benzodioxol-5-ylpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 64-65 CC. 1 H NMR (CDCI 3 300 MHz) 8 0.83 J=7Hz, 3H), 0.98 J=7Hz, 3H), 1.12-1.25 (mn, 2H), 1.32-1.41 (in, 2H), 1.75 (sextet, J=7Hz, 2H), 2.23-2.31 (in, 2H), 2.72-3.32 (mn, 8H), -148- 3.43 (dd, J=9Hz, 3Hz, 1 3.53-3.59 (in, 1 3.65 J=9Hz, 1 3.80 3H), 5.95 2H), 6.73 J=8Hz, 1 6.83 (dd, J=8Hz, 1 Hz, 1 6.88 J=9Hz, 2H), 7.02 J=lHz, 1H), 7.33 J=9Hz, 2H). MS (DCI/NH 3 W/e 547 Examlle 114 mrans. trans-i1 N-Di(n-butvflaminocarbonylmethyl)-2-(4methoxyhenY;) 4 ben zodioxo 1-5-y)D2yrro lid ine-3-carbpxlic acid Using the procedures described in Examples 28 and 43, the title compound was prepared as a white solid. m.p. 74-76 00. 1 HNMR (ODC1 3 300 MHz) 8 0.80 J=6Hz, 3H), 0.88 J=8Hz, 3H), 1.08 (sextet, J=8Hz, 2H), 1.21-1.48 (in, 6H), 2.75 J=l2Hz, 1H), 2.95-3.09 (in, 4H), 3.26-3.59 (in, 5H), 3.75 J=9Hz, 1H), 3.79 3H), 4.28 4H), 6.78 (d, J=9Hz, 1H), 6.85 J=9Hz, 2H), 6.91 J=3Hz, 9Hz, 1H), 6.98 (d, J=3Hz, 1H), 7.32 J=9Hz, 2H). MS (DCI/NH 3 W/e 525 Examlle 115 trans. trans-i -(2-(N-Proryl-N-D2rolylsu fonylamino~ethfl-2-(4-methoxyThenyn)4.

(1 .3-benzodioxol-5-vl~rDyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 72-73 00. 1H NMR (ODC1 3 300 MHz): 8 0.79 J=8Hz, 3H), 0.98 J=8Hz, 3H), 1.43 (sextet, J=8Hz, 2H), 1.75 (sextet, J=8Hz, 2H), 2.22-2.32 (in, 1H), 2.69-3.32 (in, 3.42 (dd, J=3Hz, 12Hz, 1H), 3.52-3.58 (in, 1H), 3.64 J=l2Hz, 1H), 3.80 3H), 5.95 2H), 6.73 J=llHz, 1H), 6.83 (dd, J=lHz, 11Hz, 1H), 6.87 (d, J=llHz, 2H), 7.0 J=2Hz, 1H), 7.32 J=llHz, 2H). MS (DCI/NH 3 in/e 533 Examole 116 trans. trans-i1 -(2-(N-Butyl-N-butylsulfonylam ino~ethyfl-2-(4-methoxymheny)-4-(1 .3ben zodioxol-5-yfln1yrro lidine-3-ca rboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 62-63 OC. 1H NMR (ODCI 3 300 MHz) 0.82 J=6Hz, 3H), 0.91 J=6Hz, 3H), 1.20 (sextet, J=6Hz, 2H), 1.33- 1.42 (mn, 4H), 1.68 (quintet, J=6Hz, 3H),2.23-2.32 (mn, 1H), 2.70-3.28 (in, 9H), 3.41 J=8Hz, 1H), 3.52-3.58 (in, 1H), 3.65 J=8Hz, 1H), 3.79 (s, -149- 3H), 5.95 2H), 6.72 J=8Hz, 1H), 6.82 J=8Hz, 1H), 6.87 J=8Hz, 2H), 7.01 1 7.32 J=8Hz, 2H). MS (DCI/NH 3 m/e 561 Examlle 117 trans. trans-i1 N-Dibutylam inaca rbonylmethyl)-2-(4-methoxymethoyhenYL-.

4- (1.3-be nzod ioxol-5-yflpyrro lid ine-3-ca rboxylic acid 4-Hydroxyacetophenone was treated with chloromethyl methyl ether and triethylamine in THF at room temperature to give ethyl 4methoxym ethoxybenzoyl acetate which was treated by the procedures described in Example 1 to afford the title compound as a white solid.

m.p. 48-4901C 1 H NMR (ODC1 3 300 MHz) 8 0.81 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.06 (sextet, J=7Hz, 2H), 1.20-1.35 (in, 4H), 1.44 (quintet,: p J=7Hz, 2H), 2.75 J=l2Hz, 1H), 2.94-3.10 (in, 4H), 3.25-3.35 (in, 1H), 3.40 J=l2Hz, 1H), 3.43-3.52 (in, 2H), 3.47 3H), 3.55-3.62 (in, 1H), is 3.77 J=9Hz, 1 5.15 2H), 5.94 (in, 2H), 6.73 J=8Hz, 11-H), 6.86 (dd, J=1 Hz, 8Hz, 1H), 7.0 J=8Hz, 2H), 7.04 J=lHz, 1H), 7.32 J=BHz, 2H). MS (DCI/NH 3 m/e 541 Examgle 118 trans, trans-i1 N-Dib utylam inocarbonylmethvl')-2-(4-hydroxyhenyl)-4-(1.3- ben zodioxol-5-yfl) yrroi dine-3-carboxyl ic acid hydrochloride salt The compound resulting from Example 116 was treated with concentrated HCl in 1:1 THE-isopropanol to give the title compound as a white solid. in.p. 211-212 0C. 1 H NMR (CD 3 OD, 300 MHz) 8 0.90 (t,0 J=8Hz, 6H), 1.12-1.27 (in, 6H), 1.36-1.45 (in, 2H), 3.04 (bs, 1H), 3.14- 1 3.35 J=9Hz, 1H), 3.90 (bs, 3H), 4.17 J=l5Hz, 1H), 5.96 2H-), 6.82-6.93 (mn, 4H), 7.03 J=lHz, 1H), 7.42 (bs, 2H). MS (DCI/NH 3 m/e 497 Exain~le 119 trans. trans-i1 I sobulyl-N-D)ropysulfonylam ino~ethyl)-2- (4-methoxyph enyl)-4 (1 .3-benzodioxol-5-l)oyrrolicdine-3-carboxlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 73-74 OC I H NMR (ODC1 3 300 MHz) 8 0.80 J=6Hz, 6H), 0.98 J=8Hz, 3H), 1.62 (sextet, J=6Hz, 1H), 1.74 (sextet, J=8Hz, 2H), 2.23-2.34 (in, 1H), 2.68-2.98 (mn, 7H), 3.08-3.18 (in, 1H), 3.26-3.42 (in, 2H), 3.52-3.58 (in, 1H), 3.65 J=9Hz, 1H), 3.80 (s, -150- 3H), 5.90 2H), 6.74 J=8Hz, 1 6.82 J=8Hz, 1HM), 6.86 J=8Hz, 2H), 6.98 J=1lHz, 1 7.33 J=8Hz, 2H). MS (DCI/NH 3 mn/e 547 Examile 120 trans, trans-i1 Ben zenesu fonyl-N-Dropylam in o)ethyl)-2-(4-m ethoy~h enyl..4 (1 .3-benzodioxol-5-vl)1yrrolidine-3-carbpXylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 89-91 OC 1H NMR (CDCI 3 300 MHz) 8 0.74 J=6Hz, 3H), 1.33 (sextet, J=6Hz, 2H), 2.20-2.30 (in, 1H), 2.62- 2.72 (in, 1H), 2.85-3.05 (in, 4H), 3.12-3.22 (in, 1H), 3.38 (dd, J=3Hz, 9Hz, I1H), 3.49-3.57 (in, 1 3.62 J=9Hz, I1H), 3.82 3H), 5.96 2H), 6.73 (d J=8Hz, 1H), 6.84 (dd, J=lHz, 8Hz, 1H), 6.85 J=9Hz, 2H), 7.02 J=lHz, 1H), 7.28 J=9Hz, 2H), 7.39-7.54 (in, 3H), 7.70 J=71-Z, 2H). MS (DCI/NH 3 m/e 567 Example 121 trans, trans-I1 Methoxybenzenesulfonyl-N-Droolplm ino)ethyfl-2-(4. methoxyhenyl)-4-(1 .3-benzodioxol-5-yl)oyrErolidine-3-ca rboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 96-97 1 H NMR (CDC1 3 300 MHz) 8 0.73 J=7Hz, 3H), 1.34 (sextet, J=7Hz, 2H), 2.20-2.30 (mn, 1 2.62- 0* 2.71 (in, 1 2.82-3.03 (in, 4H), 3.08-3.18 (in, 2H), 3.38 (dd, J=3Hz, 9Hz, 1iH), 3.48-3.56 (in, 1 3.62 J=9Hz, 1iH), 3.81 3H), 3.86 3H), 5.95 2H), 6.73 J=8Hz, 1H), 6.81-6.89 (mn, 5H1), 7.01 J=lHz, 1H), 7.28 J=8Hz, 2H), 7.62 J=8Hz, 2H). MS (DCI/NH 3 mn/e 597 Examole 122 trans. trans-i1 N-Di(n-butyflam inocarbonylmethyl)-2-(2-m ethoxyethoxy-4m ethoxyghenyl)-4- (1 ben zodioxoI- 5-yfl yrro Iidine -3-ca rboul ic acid was treated with sodium hydride and bromoethyl methyl ether in THF at 70 00 to provide ethyl 2-methoxyethoxy-4-methoxybenzoylacetate which was treated by the procedures described in Example 1 to provide the title compound as a white solid. m.p. 63-65 00. 1 H NMR (CDC1 3 300 MHz) 8 0.84 J=7Hz, 3H), 0.89 J=7Hz, 3H), 1.16 (sextet, J=7Hz, 2H), 1.28 (sextet, J=7Hz, 2H), 1.45-1.52 (in, 4H), 2.87-2.94 (mn, 2H), 3.00-3.16 (in, 3H), 3.26-3.36 -151- (in, 2H), 3.43 3H), 3.47-3.54 (in, 3H), 3.66-3.72 (in, 2H), 3.78 3H), 3.76-3.84 (in, 1H), 4.02-4.10 (in, 2H), 4.25 J=9Kz, 1H), 5.92 2H), 6.40 J=2Hz, 1H), 6.52 (dd, J=2H-z, 9Hz, 1H), 6.70 J=8Hz, 1H), 6.83 (dd, J=l1-z, 8Hz, 1H), 5.98 J=2Hz, 1H), 7.53 J=9Hz, 1H). MS

(DCI/NH

3 m/e 585 Examlle 123 trans, trans-i1 (N-Prolyl-N-(2.4-dimethylbenzenesulfonyl)pin ino)ethfl)-2-(4inethoxy~henyP)-4-( 1.

3 -benzodioxol-5-yl)Dvyrolidine..3.carboxyl ic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 88-90 OC. 'H NMR (CDCI 3 300 MHz) 0.69 J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.12-2.20 (in, 1 2.32 3H), 2.47 3H), 2.62-2.69 (in, 1H), 2.78 J=9Hz, 1H), 2.89 (dd, J=8Hz, 1H), 3.02 (sextet, J=9Hz, 2H), 3.15-3.32 (in, 3H), 3.46-3.55 (in, 015 1KH), 3.60 J=9Hz, 1 3.82 3H), 5.96 2H), 6.72 J=7Hz, 1KH), 6.80 (dd, J=lHz, 9Hz, 1H), 6.86 J=9Hz, 2H), 6.97 J=lHz, 1H), 7.03 (bs, 2H), 7.29 J=9Hz, 1H). MS (DCI/NH 3 m/e 595 Example 124 trans. trans- 1-(2-(N-Pror)y-N(-chlororoysulfonv)m ino~ethYl')-2.( 4 m eth oXyvhen yl) (1 ben zod ioxo- 5-yi) oyrrol idmn e-3-cp rb oXyl ic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 75-76 OC. 1 H NMR (CDC1 3 300 MHz) 8 0.80 J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.15-2.31 (mn, 3H), 2.70- 2.80 (in, 1KH), 2.85-3.10 (in, 3.23-3.31 (in, 2H), 3.43 (bd, J=9Hz, 1KH), 3.55-3.66 (in, 4H), 3.81 3H), 5.94 2H), 6.73 J=8Hz, 1 6.82 (d, J=8Hz, 1 6.86 J=8Hz, 2H), 7.00 1KH), 7.33 J=8Hz, 2H). MS

(DCI/NH

3 m/e 567 ExaMDle 125 trans. trans-i1 (2-f N-Propyl-N-(2-methoxyethylsulfonyljam ino~ethyfl-2-(4inethoxvohenvl)-4- (1 .3-benzodioxol-5-yl~Dyrrolidine-3-carboXylic acid Using the procedures described in Example 66, trans, trans- 1-(2- Propyl -N-(vi nyl suf onyl) amino) ethyl)-2(4-meth oxypheny 1) 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 00. 1 H NMR (CDC1 3 300 -152- MI-z) 8 0.78 J=7Hz, 1.42 (sextet, J=7Hz, 2.23-2.32 (in, 1 H), 2.72-2.79 (in, 1 2.86-3.05 (mn, 3.10-3.27 (in, 4H), 3.32 3H-), 3.43 (dd, J=3Hz, 9Hz, 1 3.53-3.58 (in, 1 3.65 J=9Hz, 1 3.69 (t, J=6Hz, 3.80 5.94 2H), 6.73 J=8Hz, 1 6.82 (dd, J=1lHz, 8Hz, 1 6.87 J=8Hz, 7.02 J=1lHz, 1 7.33 J=8Hz, 2H). MS (DCI/NH 3 mn/e 549 Examgle 126 trans, trans-i1 (2-(N-Propyl-N- (2-ethonvethylsulf onyl)am ino~ethvl)-2-(4methoxyo~henyl)-4-( 1. 3-benzodioxol-5-yl~pyrrolidine-3-ca rboxcylic acid Using the procedures described in Example 66, the title compound was .prepared as a white solid. m.p. 58-60 00. 1 H N MR (ODC1 3 300 M Hz) 8 0.78 J=7Hz, 3H), 1.18 J=7Hz, 1.43 (sextet, J=7Hz, 2.24- 2.33 (mn, 1H), 2.70-2.80 (in, 1H), 2.87-3.05 (in, 3.13-3.20 (mn, 2H), 3.22-3.32 (in, 2H), 3.42 (dd, J=2Hz, 9Hz, 1H), 3.46 J=7Hz, 3.52- 3.58 (in, 1 3.65 (d J=9Hz, 1 3.72 J=6Hz, 3.80 3H), 5.95 6.73 J=7Hz, 6.83 (dd, J=1 Hz, 7Hz, 11H), 6.87 J=8Hz, 2H), 7.00 J=lHz, 1H), 7.32 J=8Hz, 2H). MS (DCI/NH 3 m/e 563 Examlle 127 trans. trans-i1 -(2-(N-Propyl-N-(5-dimethylamino-i -nalhthylsulfonyl)am ino)ethyl)-2- (4-rnethoxylhenyl)-4-(1 .3-benzodioxol-5-yl) pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a yellow solid. m.p. 102-104 00. 1 H NMR (CDCI 3 300 MHz) 8 0.62 J=7Hz, 3H), 1.28 (sextet, J=7Hz, 2H), 2.12-2.20 (in, 1H),_ 2.78 J=9Hz, 1H), 2.88 2.72-2.89 (mn, 1H), 3.05-3.12 (in, 2H), 3.26-3.45 (mn, 3H), 3.45-3.52 (mn, 11H), 3.58 J=9Hz, 1H), 6.97 (d, J=lHz, 1H), 7.13 J=7Hz, 1H), 7.26 J=8Hz, 1H), 7.42-7.50 (in, 2H), 8.08 (dd, J=1 Hz, 7Hz, 11H), 8.20 J=8Hz, 1H), 8.48 J=8Hz, 1H). MS

(DCI/NH

3 mn/e 660 Example 128 trans. trans-i1 -(2-(N-Propyl-N-(Iethylsufonyl~amino)-ethyfl-2-( 4-methoxcyphenyl)-4- (1 .3-benzodioxol-5-yl~pyrrolidine-3-carboyilic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 70-72 00. I H NMR (CDC13, 300 MHz) -153- 8 0.79 J=8Hz, 3H), 1.28 J=7Hz, 3H), 1.43 J=8Hz, 2H), 2.22-2.30 (in, 11H), 2.71-2.80 (in, 1H), 2.82-3.10 (in, 6H), 3.18-3.32 (in, 2H), 3.43 (dd, J=3Hz, 9Hz, 1H), 3.53-3.60 (in, 1H), 3.65 J=9Hz, 1H), 3.80 3H), 5.96 2H), 6.73 J=7Hz, 11H), 6.82 (dd, J=lHz, 7Hz, 1H), 6.88 (d, J=8Hz, 2H), 7.00 J=lHz, 7.32 J=8H-z, 2H). MS (DCI/NH: 3 m/e 519 Examole 129 trans, trans-i1 -(2-(N-Prory-N-(4-methlbenzenesuIf onyflam ino)ethfl)-2-(4methoxy~henyfl-4- (1 .3-benzodioxol-5-yI)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 78-79 0 C. I H NMR (CDC1 3 300 MHz) 8 0.73 J=7Hz, 3H), 1.33 (sextet, J=7Hz, 2H), 2.20-2.30 (in, 1H), 2.40 3H), 2.61-2.72 (in, 1H), 2.83-3.05 (mn, 4H), 3.08-3.19 (in, 2H), 3.48 (dd, J=3Hz, 9Hz, 1H), 3.49-3.57 (in, 1H), 3.62 J=9Hz, 1H), 3.81 3H), 5.95 2H), 6.73 J=8Hz, 1H), 6.82 J=8Hz, 1H), 6.87 J=8Hz, 2H), 7.00 1 7.21 J=8Hz, 2H), 7.29 J=8Hz, 2H), 7.57 J=8Hz, 2H).

MS (DCI/NH 3 mle 581 Example 130 trans. trans-i1 N- Di(n-butyl)am in oca rbonyim ethyl) (3-yridyl)-4(1 .3benzodioxol-5-yfl)1yrro lid ine-3-ca rboxcyl ic acid Methyl nicotinoyl acetate was prepared by the method of Wenkert, 0 et al., J. Org. Chem. 48: 5006 (1983) and treated by the procedures described in Example 1 to provide the title compound as a white solid.

m.p. 167-168 OC. 1 H NMR (ODC1 3 300 MHz) 8 0.82 J-7Hz, 3H), 0.89- J=7Hz, 3H), 1.14 (sextet, J=7Hz, 2H), 1.23-1.48 (mn, 6H), 2.86-3.20 (in, 6H), 3.34-3.43 (in, 2H), 3.57 (dd, J=3Hz, 9Hz, 1H), 3.75-3.83 (in, 1H), 4.08 J=9Hz, 1H), 5.93 2H), 6.73 J=8Hz, 1H), 6.90 (dd, J=2Hz, 8Hz, 7.03 J=2Hz, 1H), 7.38 (dd, J=4Hz, 8Hz, 1H), 8.04 J=8Hz, 1H), 8.48 (dd, J=2Hz, 4Hz, 2H). MS (DCI/NH 3 m/e 482 Example 131 trans. trans-i -(2-(N-Propyl-N-(n-butylsulfonyflam ino)-ethyl)-2-(4-methoxyphenyl)-4- (1 .3-benzodioxol-5-yl) Dyrrolidine-3-carboxcylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 65-66 00. 1 H NMR (ODCII, 300 MHz) -154- 80.78 J=7Hz, 0.92 J=7Hz, 3H), 1.31-1.46 (in. 4H), 1.68 (quintet, J=7Hz, 2H), 2.21-2.32 (in, 1H), 2.70-3.08 (in, 7H), 3.12-3.23 (in, 2H), 3.42 (dd, J=2Hz, 9Hz, 3.52-3.58 (in, 1H), 3.64 J=9Hz, 1H), 3.80 3H), 5.96 2H), 6.72 J=7Hz, 1H), 6.83 (dd, J=lHz, 7Hz, 1H), 6.86 J=8Hz, 2H), 7.00 J=lHz, 1H), 7.32 J=8Hz, 2H). MS

(DCI/NH

3 mle 547 Examle 132 trans, trans-i1 Pro pyl- N- (4-ch lo roben zenesulIf onyl)am ino)ethyl)-2-(4oLxyhen yl) (1 3 ben zod ioxoI- 5-yl) pyrro id ine3ca rboal ic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 105-106 0C. 1 H NMR (CDC1 3 300 MHz) 8 0.72 J=7Hz, 3H), 1.34 (sextet, J=7Hzm 2H), 2.56-2.62 (in, 1H), 2.78-2.86 (in, 1H), 2.96-3.03 (in, 3.13-3.26 (in, 3H), 3.51 (dd, J=5Hz, 9Hz, 1H), 3.62-3.68 (in, 1H), 3.80 3H), 3.94 J=9Hz, 1H), 5.92 2H), 6.75 J=8Hz, 1 6.84 (dd, J=2Hz, 8Hz, 1 6.94 (d, J=8Hz, 2H), 6.98 J=2Hz, 1 7.36 J=8Hz, 1 7.49 J=8Hz, 1 H), 7.68 J=8Hz, 1 MS (DCI/NH 3 m/e 601 Example 133 trans. trans-i1 -(2-(N-Propyl-N (benzylsulfonyflam ino)ethyfl-2-(4-methoyhenyl).4- (1 .3-benzodioxol-5-yl)pyrrolidine-3-carboxlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 88-89 00. 'H NMR (ODC1 3 300 MHz) 8 0.72 J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.06-2.16 (mn, 1H), 2.56- 2.67 (in, 1 2.75-3.10 (in, 6H), 3.30 (dd, J=2Hz, 9Hz, 1 5.95 2H).

6.73 J=7Hz, 1 6.80 (dd, J=1lHz, 7Hz, 1 6.86 J=8Hz, 2H), 6.97 J=lHz, 1H), 7.27-7.35 (in, 7H). MS (DCI/NH 3 m/e 581 Examlle 134 trans. trans-i1 -(2-(N-Propyl- N-(4-fluorobenzenesufonyl)am ino)ethyl)-2-(4methoXyphenyl)-4- (1 .3-benzodioxol-5-ylpyrroliine3cabo~clic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 91-93 00. 1 H NMR (CDC1 3 300 MHz) 8 0.73 J=7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 2.18-2.27 (in, 1H), 2.56- 2.67 (mn, 1H), 2.78-2.87 (mn, 2H), 2.97 (septet, J=8Hz, 2H), 3.11-3.16 (in, 2H), 3.33 (dd, J=2Hz,- 9Hz, 1H), 3.43-3.50 (in, 1H), 3.57 J=9Hz, 1H), -155- 3.78 3H), 7.08 J=8Hz, 2H), 7.24 J=8Hz, 2H), 7.69 (dd, 8Hz, 2H). MS (DCI/NH 3 m/e 585 (M+H) Example 135 trans.trans-1 -(N-Methyl-N-DroDylaminocarbonylmethyl)-2- (4-methoxvDhenvl)-4-(4benzofuranyl)vyrrolidine-3-carboxylic acid Example 135A Benzofuran-4-carboxa dehyde To a suspension of 60% sodium hydride in mineral oil (4.00 g, 100 mmol, 1.25 eq) in DMF (60 mL) at 0 °C was added a solution of 3- bromophenol (13.8 g, 80 mmol) in DMF (5 mL). After 10 minutes," S bromoacetaldehyde diethyl acetal (14.9 mL, 96.6 mmol, 1.24 eq) was added, and the resultant mixture then heated at 120 OC 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 over MgSO 4 filtered, evaporated and vacuum distilled to yield a colorless liquid (17.1 g, 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, 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 yield a colorless liquid (8.13 g, 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 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 After stirring for minutes, a solution 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 MgSO 4 and concentated in vacuo.

The residue was purified by flash chromatography on silica gel eluting with 10% ether in hexanes to yield benzofuran-6-carboxaldehyde (1.22 g) and benzofuran-4-carboxaldehyde (1.86 both as colorless oils.

-156- Examlle 135B trans. trns-i -(N-Methyl-N-D~rooylam inocarbonylmethyl)-2- (4-methoxyhenyl).4-(4be nzof ura nyl) pyrro lid in e-3-ca rboxylic 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. 1 H NMR (300 MHz, ODC1 3 (minor rotamer) 8 7.59 (1H, t, J=3Hz), 7.4-7.2 (6H, in), 6.8 (2H, d, J=8Hz), 4.03 (1 H, in), 3.94 (1 H, dd, J=8Hz, 3Hz), 3.77 (3H, 3.61 (1 H, dd, J=8Hz, 7 3Hz), 3.42 (1H, dd, J=llHz, 5Hz), 3.40-2.90 (5H, in), 2.82 (2.81) (3H, s), 1.50 (2H, septet, J=7Hz), 0.82 (0.75) (3H, t, J=7Hz). MS (DCI/NH 3 m/e 451 Anal.calc. for C26H3oN2O 5 -AcOH: C, 65.87; H, 6.71; N p5.49. Found: C, 66.04; H, 6.42; N, 5.60. s Example 136 trans- 1-(N-Methyl-N-Uropylam inocarbonylmethyl)2. (4-rn ethoxyohenyfl-4-(6- Thetilecompound was prepared using the procedures described in Examples 1 and 49 substituting benzofuran-6-carboxalciehyde, prepared as described in Example 135A, in Example 49A for piperonal.

1 H NMR (300 MHz, ODC1 3 (minor rotainer) 8 7.65 (1H, bd), 7.60 (1H, d, J=2Hz), 7.55 (1H, d, J=8Hz), 7.35 (3H, in), 6.85 (2H, dd, J=8Hz, 3Hz), 6.75 (1H, dd, J=3Hz, 2Hz), 3.83 (2H, mn), 3.79 (3H, 3.60-3.0 (7H, in), 2.91 (2.83) 3H), 1.51 (2H, septet, J=7Hz), 0.83 (0.78) (3H, t, J=7Hz). MS

(DCI/NH

3 m/e 451 Anal.calc. for C26H 30

N

2

O

5 0.5 H 2 0: C, 67.96; H, 6.80; N, 6.10. Found: C, 67.90; H, 6.71; N, 6.07.

Examlle 137 trans, trans-i1 -(N-Methyl-N-oropylam inocarbonylmethyl)-2-(4-methoxyhenyl)..4-(6 ben zo-2 .3-d ihyd rof ura nyfl pyrroIid in e-3-ca rboxylic acid The title compound was prepared by catalytic hydrogenation (4 atmospheres of H 2 in AcOH, followed by preparative hplc) of the compound resulting from Example 136 1 H NMR (300 MHz, CDCI 3 (minor rotamer) 8 7.49 (7.47) (2H, d, J=8Hz), 7.19 (1H, d, J=8Hz), 7.00 (1H, in), 7.82 (3H, in), 5.40 (1H, dd, J=llHz, 7Hz), 4.58 (2H, t, J=8Hz), 4.18 (1H, in), 4. 10 (1 H, in), 3.88 (1 H, in), 3.79 (3H, 3.60 (1 H, mn), 3.35 (1 H, in), 3.19 (2H, t, J=8Hz), 3.00 (4H, in), 2.91 (2.78) 3H), 1.53 (1.40) (2H, septet, J=7Hz), 0.88 (0.78) (3H, t, J=7Hz). MS (DCI/NH 3 in/e 453 -157- Anal caic. for C 26

H

32

N

2 0.

5 1.25 TFA: C, 57.53; H, 5.63; N, 4.71.

Found: C, 57.68; H, 5.68; N, 4.70.

Example 138 trans. trans-i1 N-Dibutylamn inocarbonylmethyl)-2-(4-mn eth oxyhenyfl-4-(4benzofuranyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-4-carboxaldehyde in Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide for N-methyl-N-propyl bromoacetamide. 1 H NMR (300 MHz, CDC1 3 8 7.62 (1 H, d, J=3Hz), 7.39 (1 H, dt, J=8Hz, 2Hz), 7.34 (3H, in), 7.26 (1 H, d, J=2Hz), 7.23 (1 H, d, J=8Hz), 6.84 d, J=8Hz), 4.02 (1 H, ddd, J=8, C 6Hz,4Hz), 3.89 (1H, d, J=9Hz) 3.79 (3H, 3.67 (1H, dd, J=lOHz, 3Hz), 3.44 (2H, in), 3.35-3.15 (3H, in), 3.00 (2H, in), 2.84 (1H, d, J=l4Hz), 1.43 15(3H-, mn), 1.23 (3H, in), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 507 Anal.calc. for C 3 oH 38

N

2

O

5

C,

71.12; H, 7.56; N, 5.53. Found: C, 70.86; H, 7.45; N, 5.24.

Example 139 trans. trans-i1 N-Dibutylain inocarbonylinethyfl-2- (4-methoxyphenyl)-4-(4benzofu ranyl~Dyrrolidine-3-carboxylic acid V.

The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-5-carboxaldehyde, prepared by the procedures described in Example 1 35A substituted 4broinophenol for 3-bromophenol, in Example 49A for piperonal and substituting N,N-dibutyl broinoacetainide for N-inethyl-N-propyl broinoacetamide. 1 H NMR (300 MHz, CDCI 3 8 7.64 (1H, bd), 7.59 (1H, d, J=2Hz), 7.43 (2H, in), 7.33 (2H, d, J=8Hz), 6.85 (2H, d, J=8Hz), 6.73 (1H, dd, J=3Hz, 1Hz), 3.82 (1H, d, J=ll11z), 3.89 (1H, d, J=9Hz) 3.79 (3H, s), 3.53 (1H, dd, J=lQHz, 3Hz), 3.44 (2H1, in), 3.30 (1H, in), 3.20-2.95 in), 2.82 (1H, d, J=l4Hz), 1.43 in), 1.23 (3H, in), 1.08 (2H, in), 0.87 t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH 3 rn/e 507 Anal.calc. for C 30

H-

38

N

2 0 5 C, 71.12; H, 7.56; N, 5.53. Found: C, 70.73; H, 7.45; N, 5.29.

-158- Example 140 trans. trans-i1 N-Dibutylam inocarbonylmethyl)-2-m etho yhenyf I( benzofuranyl)pyrrolidine-3-carboxcylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-6-carboxaldehyde in Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide for N-methyl-N-propyl bromoacetamide. 1 H NMR (300 MHz, CDC1 3 8 7.63 (1H, bd), 7.59 (1H, d, J=2Hz), 7.53 (1H, d, J=8Hz), 7.36 (3H, in), 6.85 (2H, d, J=8Hz), 6.73 (1H, dd, J=3H-z, 1Hz), 3.82 (1H, d, J=llHz), 3.89 (1H, d, J=9Hz) 3.79 (3H, 3.53 (1H, dd, J=lOHz, 3Hz), 3.44 (2H, in), 3.30 (1H, in), 3.20-2.95 (5H, in), 2.80 (1H, d, J=l4Hz), 1.43 (3H, in), 1.23 (3H, in), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), .0.82 (3H, t, J=7Hz). MS (DC I/NH 3 m/e 507 Anal-calc. for C30H 38

N

2 0O 5 -0.75 H 2 0: C, 1 69.28; H, 7.65; N, 5.39. Found: 0, 69.11; H, 7.33; N, 5.32.

Example 141 trans. trans-i1 N-Dibutylam inocarbonylmethyl)-2-(4-methoxyphenyl)-4 (6-benzo- 2.3-dihydrofuranyl pyrrolidine-3-ca rboxylic acid The title compound was prepared by catalytic hydrogenation of the compound resulting from Example 140 (4 atmospheres of H 2 in: AcOH, followed by preparative hplc). 1 H NMR (300 MHz, CDC1 3 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, mn), 5.90 (1 H, bs) 4.57 (2H, t, J=9Hz), 4.93 (2H, in), 3.80 (3H, 3.70- 3.58 (2H, in), 3.40 (1 H, in), 3.30-2.90 (8H, in), 1.40 (2H, in), 1.29 (3H, in), 1.08 (2H, in), 0.92 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) in/e 509 AnaI.calc. for C3 0

H

40

N

2 0 5 .0.85 TFA: C, 62.88; H, 6.80; N, 4.63. Found: C, 63.04; H, 6.66; N, 4.60.

Examlle 142 trans. trans- 1 -(N-Methvl-N-Drolylain inocarbonylmethyrl-2-(4-m eth indanyl~pyrrolidine-3-carboxlic acid Exam Dle 1 42A I lndane-5-carboxaldehyde was prepared by forinylation of indane under the conditions described for 2,3-dihydrobenzofuran in Example 52A. The resultant mixture of 4- and 5-carboxaldehydes was purified -159as follows: to a 6:1 mixture of indane-4-carboxaldehyde and 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 as a white solid. The aldimine (2.65 g) was suspended in water (6 mL), and treated with 4 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 MgSO 4 filtered, and concentated in vacua. Vacuum distillation of the residue afforded carboxaldehyde (1.54 g, 88%) as a colorless liquid. b.p. 88-900~C at 0.9 mm Hg.

tran. trExample 142B trn.tans-i -(N-Methyl-N-propylam inocarbonylmethyl)-2-(4-m 1s indanyt)12yrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting indane-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 (minor rotamer) 8 7.25-7.1 in), 6.78 (2H, d, J=8Hz), 3.89 (1H, d, J=8Hz), 3.75 (3H, 3.50- 2.90 (6H, in), 2.88 (6H, t, J=6Hz), 2.82 (2.80) (3H, 2.04 (2H, t, J=8Hz), V..

1.48 (2H, septet, J=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS (DCI/NH 3 m/e 451 473 Anal.calc. for C27H 3 4

N

2 0 4 -2.5 H 2 0 C, 65.44; H, 7.93; N, 5.65. Found: C, 65.36; H, 7.45; N, 5.53.

Examp~le 143 trans. trans-i Methvl-N-Droryla m i nocarbonyl methyfl-2- (4-m eth oK= hen yl)-4- (6indolvflgrrolidine-3-carboxyiic acid The title compound was prepared by the procedures described in 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. 1 H NMR (300 MHz, CDCI 3 (minor rotamer) 8 8.43 (1H, brs), 7.57 (1 H, d, J=8Hz), 7.43 (1H, 7.31 (2H, dd, J=6Hz, 3Hz), 7.22 (1H, d, J=8Hz), 7.1 (1H, t, J=3Hz), 6.78 (2H,dd, J=6Hz, 3Hz), 6.45 (1H, in), 3.93 (1H, dd, J=6Hz, 3Hz), 3.80 (1H, in), 3.73 (3H, 3.60-2.90 (6H, in), 2.86 (2.82) (3H, 1.47 (2H, septet, J=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS

(DCI/NH

3 mWe 450 Anal.calc. for C2 6

H

3 1 N 3 0 4 0.75 H 2 0: C, 67.44; H, 7.07; N, 9.07. Found: C, 67.42; H, 7.09; N, 8.91.

-160- Examlle 144 trans, trans-i1 -(N-Methyl-N-12ropylam inoca rbonylmethvl)-2-(4-methoxvphenvl).4- (3 .4-difluorophenyl)Dvyrrolidine-3-carboxcylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-difluorobenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 (minor rotamer) 8 7.60-7.3 (4H, in), 7.13 (1 H, q, J=9Hz), 6.90 (2H, d, J=8Hz), 3.90 (1 H, mn), 3.79 (3H, 3.60-2.95 (6H, in), 2.92 (2.78) (3H, 1.55 (2H, septet, J=7Hz), 0.88 (0.73) (3H, t, J=7Hz). MS (DCI/NH 3 m/e 447 Anal.calc. for

C

24

H

28

F

2

N

2 0 4 -1.80 H 2 0: C, 60.19; H, 6.65; N, 5.85. Found: C, 60.13; H, 6.34; N, 5.84.

Examgle 145 trans, trans-i1 (N -Methyl- N -Dropvlam inoca rbon yl methyl)-2 eth ovphenyl)-4- (1Dhenyfl1yrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 (minor rotamer) 5 7.53 (4H, d, J=6Hz), 7.40-7.20 (3H, in), 6.88 (2H, d, J=8Hz), 3.90 (1H, in), 3.79 (3H, 3.70- V..

2.95 (8H, in), 2.90 (2.79) (3H, 1.50 (2H, sept, J=7Hz), 0.87 (0.72) (3H, t, J=7Hz). MS (DCI/NH 3 m/e 411 Anal.calc. for C 24

H

30

N

2 0 4 2.00 H 2 0: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.37; H, 7.43; N, 6.29.

Examp~le 146 trans, trans-i1 (N -Methyl- N-12ro~yl am i noca rbonylmethyl 1-2- (4-m eth oxyhenyl)-4- (4hydroxyo~henyl)o2yrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-hydroxybenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3-CD 3 QD) (minor rotainer) 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), 3.81 (3H, 3.65 (1H, d, J=8Hz), 3.70-3.00 (8H, in), 2.92 (2.83) (3H, 1.50 (2H, septet, J=7Hz), 0.87 (0.77) (3H, t, J=7Hz). MS

(DCI/NH

3 mWe 427 Anal.calc. for C 24

H

30

N

2 0 5 1.00 H 2 0: C, 64.85; H, 7.26; N, 6.30. Found: C, 64.82; H, 7.39; N, 6.46.

-161- Examlle 147 trans. rans-i -(N-Methyl-N-propylaminocarbonylmethyl)Y2-(4-methoxyphenvyfl4 4-d im ethoxyp hen yl)yrrol id ine-3-ca rboyl ic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,4-dimethoxybenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3

-CD

3 OD) (minor rotamer) 8 7.61 (1H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.82 (PH, d, J=8Hz), 6.55 (1 H, d, J=8Hz), 6.45 (1 H, d, J=3Hz), 3.90 (1 H, in), 3.81 (3H, 3.79 (3H, 3.77 (3H, 3.70-2.90 (8H, in), 2.85 (3H, 1.50 (2H, sept, J=7Hz), 0.87 (0.77) (3H, t, J=7Hz). MS (DCIINH 3 m/e 471 Anal.calc. for C 26

H

34

N

2 0 6 -0.75 H 2 0: C, 64.51; H, 7.39; N, 5.79. Found: C, 64.65; H, 7.07; N, 5.75.

Example 148 trans, trans-i1 N-Dibutylam in ocarbonlmethyl)-2-(4-methoxyphenyl)-4-(5-benzp..

2.3-dihydrofuranyflpyrrolidine-3-carboxylic aci The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,3-dihydrobenzofuran-5carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 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, 3.62 (1H, in), 3.50-3.25 (4H, in), 3.17 (2H, t, J=7Hz), 3.15-2.90 (5H, in), 2.79 (1H, d, J=l4Hz), 1.43 (3H, in), 1.26 (3H, mn), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 509 Anal.calc. for C 30

H

40

N

2 0 5 0.25 H20: C, 70.22; H, 7.95; N, 5.46. Found: C, 70.21; H, 7.92; N, 5.36.

Examgle 149 trans, trans-i1 N-Dibutvlam inocarbonylmethyfl-2-(4-m ethoxyohenyl)-4-(4methoxcyphenyl)Dvrrolidine-3-carboxcylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, ODC1 3 8 7.38 (2H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.87 (4H, dd, J=7Hz, 3Hz), 3.78 (3H, 3.76 (3H, 3.63 (1H, in), 3.50-3.20 (4H, in), 3.15-2.90 (5H, in), 2.78 (1H, d, J=l4Hz), 1.43 (3H1, in), 1.27 (3H, in), 1.09 (2H, in), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, -162- J=7Hz). MS (DCI/NH 3 m/e 497 Anal.calc. for C2 9

H

40

N

2

O

5

C,

70.13; H, 8.12; N, 5.64. Found: C, 69.78; H, 8.10; N, 5.54.

Example 150 trans. trns-i N-Dibutylam inocarbonylmethyl)-2-(4-methoxvrhenyI)-4(3 difluorophenyflpyrrolidine-3-ca rboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-difluorobenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 8 7.35 (1 H, in), 7.30 (2H, d, J=8Hz), 7.20-7.00 (2H, mn), 6.87 (2H, d, J=8Hz), 3.78 (3H, 3.79 (1H, mn), 3.62 (1H, mn), 3.50-3.30 (3H, in), 3.23 (1H, in), 3.15-2.90 (4H, in), 2.78 (1H, d, J=l4Hz), 1.43 (2H, in), 1.27 (4H, in), 1.08 (2H, mn), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 503 Anal.calc.

for C 28

H

36

F

2

N

2

O

4 1 H 2 0: C, 64.60; H, 7.36; N, 5.38. Found: C, 64.59; H, 7.20; N, 5.35.

Examlle 151 trans. trans-i1 N-Dibutylam inocarbonylmethyfl-2-(4-methoxyohenyF.-4-(2.4dimethoxyghenyflpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,4-diinethoxybenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 8 7.37 (2H, d, J=8Hz), 7.20 (1H, d, J=8Hz), 6.92 (2H, d, J=8Hz), 6.60 (1H, d, J=3Hz), 6.49 (1H, dd, J=6Hz, 2Hz), 5.35 (1H, d, J=8Hz), 4.20 (3H, in), 4.10 s), 3.83 (3H, 3.81 (3H, 3.75 (3H, in), 3.17 (2H, hep, J=7Hz), 3.05 (2H, t, J=7Hz), 1.30 (4H, in), 1.07 (4H, in), 0.87 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 527 Anal.calc. for C30H 42

N

2 0 6 1.30 TFA: C, 58.02; H, 6.47; N, 4.15. Found: C, 57.92; H, 6.43; N, 4.07.

Exaingle 152 trans, trans-i1 N-Dibutylam inocarbonyim ethvl)-2-phenvl-4-( 1. yfl1yrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B.

1 H NMR (300 MHz, CDC1 3 8 7.50-7.25 (5H, in), 7.04 (1H, d, J=3Hz), 6.87 (1H, dd, J=7Hz, 3Hz), 6.74 (1H, d, J=8Hz), 5.94 (1H, d, J=4Hz), 5.92 (1H, -163d, J=4Hz), 3.85 (1 H, d, J=8Hz), 3.64 (1 H, in), 3.42 in), 3.27 (2H, i) 3.20-2.90 (5H, mn), 2.81 (1H, d, J=l4Hz), 1.43 (2H, in), 1.27 (4H, in), 1.05 (2H, in), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 481 AnaI.calc. for C 2 8

H

3 6

N

2 0 5 C, 69.98; H, 7.55; N, 5.83.

Found: C, 69.69; H, 7.63; N, 5.71.

Example 153 trans. trans-i1 N-Dibutylam inocarbonvim ethvfl)-2-ohenyl-4-(5-benzo-2 .3dihydrofuranvl)12yrrolidine-3-ca rboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B and 2,3- dihyd robe nzofu ran-5-ca rboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 8 7.53 (2H, in), 7.40 (4H, in), 7.13 (IH, se dd, J=7Hz, 3Hz), 6.72 (1H, d, J=8Hz), 5.40 (1H, d, J=lOHz), 4.56 (2H, t9 J=8Hz), 4.18 (1H, d, J=l4Hz), 4.07 (2H, in), 3.79 (2H, mn), 3.48 (1H, d, J=l4Hz), 3.35 (1H, in), 3.28 (3H, in), 2.95 (2H, in), 1.47 (2H, in), 1.28 (4H, in), 1.10 (2H, in), 0.93 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). MS

(DCI/NH

3 m/e 479 Anal.calc. for C 29

H

3 8

N

2 0 4 1.10 TFA: C, 62.04; H, 6.52; N, 4.64. Found: C, 61.89; H, 6.44; N, 4.57.

Example 154 trans, trans- 1 N- Dib utylam inocarbonylm ethyfl-2-(4-t-butyl phenyl)-4- ben zo- 2.3-dihyd rofuranyl)D2yrrolidine-3-carboxylic acid The. title compound was prepared by the procedures described in Examples 1 and 49 substituting t-butyl benzoylacetate, prepared by the method of Krapcho et al., Org. Syn. 47:20 (1967) starting from 4-tbutylacetophenone, in Example 49B and 2,3-dihydrobenzofuran-5carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 8 7.60-7.30 (6H, in), 6.90 (1H, in), 4.50 (2H, in), 3.95 (1H, in), 3.85-2.95 (11H, mn), 2.90 (1H, d, J=l4Hz), 1-.58 (2H, mn), 1.50 (7H, mn), 1.41 (6H, 1.10 (2H, in), 1.00 (3H, t, J=7Hz), 0.90 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 535 Anal.calc. for C 3 3

H

4 6

N

2 0 4 0.25 H 2 0: C, 73.50; H, 8.69; N, 5.19. Found: C, 73.57; H, 8.58; N, 5.14.

-164- Example 155 trans. trans-2-(N .N-Dibutylam inocarbonylmethyfl-2-(4-m ethoxyhenyfl-4-(4f luorophenyl)D2yrro lid ine-3-carboxyl ic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-fluorobenzaldehyde for piperonal in Example 49A. I H NMR (300 MHz, CDCI 3 8 7.50 (1H, in), 7.42 (1H, dd, J=7Hz, 3Hz), 7.36 (2H, d, J=8Hz), 7.01 (3H, t, J=8Hz), 6.87 (1H, d, J=8Hz), 3.83 (1H, in), 3.8 (3H, 3.67 (1H, in), 3.47 (3H, mn), 3.30-2.90 (5H1, m), 2.82 (1H, d, J=l4Hz), 1.43 (2H, in), 1.28 (4H, in), 1.08 (2H, mn), 0.90 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH 3 in/e 485 Anal.calc.

for C 2 8

H

3 7

FN

2 0 4 C, 69.40; H, 7.70; N, 5.78. Found: C, 69.03; H, 8.00; N, 5.74. Example 156 1 5 trans. trans-i N-Dibutylaminocarbonylmethyl)-2-(3-f uryfl-4-( 1.3-benzodioxol-5yflpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting f-oxo-3-furanpropionate in Example*0 49B. 1 H NMR (300 MHz, CDC1 3 5 7.41 (2H, in), 6.97 (1H, d, J=3Hz), 6.85 (1H, dd, J=7Hz, 3Hz), 6.72 (1 H, d, J=8Hz), 6.42 (1 H, 5.94 (1 H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.90 (1H, in), 3.70-3.25 (5H, in), 3.20-2.90 (4H, in), 2.85 (1H, d, J=l4Hz), 1.43 (2H, in), 1.40-1.05 (6H, in), 0.90 (6H, 0 inMS (DCI/NH 3 in/e 471 Anal.calc. for C 2 6

H

3 4

N

2 0 6 C, 66.36; o H, 7.28; N, 5.95. Found: C, 66.09; H, 7.24; N, 5.87.

Examlle 157 trans, trans-1 N- Dibutyla m inoca rbonyl methyl) -2 sorolyl-4- (1 .3-be nzod ioxol- 5-vlhr~vrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B.

1 H NMR (300 MHz, ODC1 3 8 6.85 (1H, d, J=2Hz), 6.76 (1H, dd, J=6Hz, 2Hz), 6.71 (1H, d, J=8Hz), 5.92 (2H, 3.75 (1H, d, J=l4Hz), 3.66 (1H1, q, J=7Hz), 3.42 (3H, in), 3.25 (3H, in), 3.11 (2H,in), 2.83 (1H, t, J=7Hz), 1.88 (1H, in), 1.55 (4H, in), 1.32 (4H, in), 0.92 (12H, in). MS (DCI/NH 3 Wne 447 Anal-calc. for C 2 5H 3 8N 2 0 5 0.50 H 2 0: C, 65.91; H, 8.63; N, 6.15. Found: C, 66.07; H, 8.10; N, 6.03.

-165- Exam Die 158 trans. trans-i1 N-Dibutylam inocarbonylmethyl)-2-(4-t-butylph enyfl-4-(l1.3benzodioxol-5-y)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 4-t-butylbenzoyl acetate, prepared by the method of Krapcho et al., Org. Syn. 47: 20 (1967) starting with 4t-butylacetophenone), in Example 49B. 1 H NMR (300 MHz, CDC1 3 8 7.32 (4H, d, J=3Hz), 7.04 (1H, d, J=2Hz), 6.87 (1H, dd, J=8Hz, 3Hz), 6.74 (1H, d, J=9Hz), 5.94 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.77 (1H, d, J=l4Hz), 3.65-3.25 (5H, in), 3.15-2.85 (4H, mn), 2.73 (1H, d, J=l4Hz), 1.45 (2H, mn), 1.29 (13H, 1.00 (2H, rn), 0.86 (3H, t, J=7Hz), 0.76 (3H, t, J=7Hz).

MS (DCI/NH 3 m/e 537 Anal.calc. for C 3 2H 44

N

2 0 5 C, 71.61; H, 8.26; N, 5.22. Found: C, 71.43; H, 8.09; N, 5.11.

Examlle 159 trans, trans-i1 N -D ibutyl am in oca rbonylm eth yfl-2- butyl phen yl-4-(5- benzo- 2.3-dihydrofuranyfloyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B and 2,3-di hyd robe nzof uran-5-carboxal dehyde for piperonal in Example 49A. 1 H NMR (300 MHz, ODC1 3 8 7.30 (1H, 7.13 (1H, dd, J=7Hz, 2Hz), 6.82 (1 H, d, J=8Hz), 4.68 (2H, t, J=8Hz), 4.48 (1 H, 3.19 (3H, in), 3.80 (3H, in), 3.48 (2H, in), 3.3 (5H, mn), 2.41 (1 H, in), 1.65 (4H, in), 1.44 (4H, in), 1.21 (3H, d, J=5Hz), 1.17 (3H, d, J=5Hz), 1.05 (6H, in). MS (DCI/NH 3 Wne 445 Anal.calc. for C 2 6H 4

ON

2 0 4 1.2 TEA: C, 58.67; H, 7.14; N, 4.8.2 Found: C, 58.54; H, 7.25; N, 4.74.

Examole 160 trans. trans-i1 N-Dibutylam inocarbonylmethyl)-2-(anti-4-methoxyyclohexvr)-4- (1 .3-benzodioxol-5-yl)Dyrrolidine-3-carboxylic acid Exam Die 1 svn and anti Ethyl 4-methoXycyclohexanoylacetate Syn, anti-4-Methoxycyclohexane carboxylic acid (5.00 g, 31.6 inmol) and carbonyldiimidazole (6.15 g, 37.9 minol, 1.2 eq) were stirred in anhydrous tetrahydrofuran (50 ml-) for 6 hours at room temperature.

At the same time, magnesium chloride (3.01 g, 31.6 inmol) and ethyl -166malonate potassium salt (7.52 g, 44.2 mmol, 1.4 equivalents) were stirred in anhydrous tetrahydrofuran (75 mL) for 6 hours at 50 OC. The mixture was cooled to room temperature, and the imidazole-acid mixture added to it. The reaction stirred overnight at room temerature.

s The solvents were removed under reduced pressure, and the residue was taken up in chloroform/water. The organic phase washed with potassium bisulfate, water, and brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 175 g silica gel, eluting with o1 ethyl acetate in hexanes. Pure fractions of the syn and anti methoxycyclohexyl P-keto esters were obtained. The solvents were removed under reduced pressure to yield the trans-4- S methoxycyclohexyl 3-keto ester (914 mg) as a colorless oil and the cis 4-methoxycyclohexyl P keto ester (1.07 g) as a colorless oil. Example 160B trans, trans- N-Dibutylaminocarbonylmethvl)-2-(anti-4-methoxvcyclohexvl)-4- (1.

3 -benzodioxol-5-vl)Dvrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the anti-compound resulting from Example 160A in Example 49B. 1 H NMR (300 MHz, CDCs 3 8 6.84 (1H, d, J=2Hz), 6.76 (1H, dd, J=7Hz, 2Hz), 6.61 (1H, d, J=8Hz), 5.92 (2H, 3.69 (2H, 3.50-3.27 (5H, 3.26 (3H, 3.25-3.00 (3H, 2.88 (1H, 1.95 (2H, 1.62 (7H, 1.33 (9H, 0.97 (3H, t, J=7Hz), 0.92 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 517 (M+H) Anal.calc. for C29H 44

N

2 0 6 S0.50 H 2 0: C, 66.26; H, 8.63; N, 5.33. Found: C, 66.27; H, 8.50; N, 5.13.

Example 161 trans. trans-1 N-Dibutvlaminocarbonvlmethvl)-2-(svn-4-methoxvcvclohexl)-4- (1.

3 -benzodioxol-5-vl)oyrrolidine-3-carboxylic 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 49B. 1 H NMR (300 MHz, CDCI 3 8 6.84 (1H, d, as J=2Hz), 6.77 (1H, dd, J=6Hz, 2Hz), 6.61 (1H, d, J=8Hz), 5.92 (2H, 3.65 (2H, 3.42 (2H, 3.32 (3H, 3.30-3.00 (6H, 2.82 (1H, 2.10 (2H, 1.83 (2H, 1.52 (6H, 1.33 (4H, 1.20-1.00 (4H, 0.96 -167- (3H, t, J=7Hz), 0.91 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 517 (M+H) Anal.calc. for C2 9

H

4 4

N

2 0 6 0.30 H 2 0: C, 66.72; H, 8.61; N, 5.37. Found: C, 66.76; H, 8.65; N, 5.28.

Example 162 trans. trans- N-Dibutylaminocarbonylmethyl)-2.4-di(5-benzo2.3dihydrofuranyl)oyrrolidine-3-carboxylic acid Example 162A 5-Acetyl-2.3-dihydrobenzofu ran 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 below 5 The solution was stirred 15 minutes at 0 oC, 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 OC. 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 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.

Example 162B trans. trans- 1 -(N.N-Dibutylaminocarbonylmethyl)-2.4-di(5-benzo-2.3dihydrofuranyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the compound resulting from Example 162A in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 8 7.43 (1H, 7.38 (1H, 7.06 (2H, 6.75 (1H, d, J=6Hz), 6.70 (1H, d, J=6Hz), 5.40 (1H, d, J=9Hz), 4.58 (4H, q, J=7Hz), 4.16 (1H, d, J=14Hz), 4.09 (2H, 3.82 (2H, 3.57 (1H, d, J=14Hz), 3.38 (1H, 3.30-3.05 (6H, 2.95 (2H, q, J=6Hz), 1.50 (2H, 1.30 (4H, 1.15 (2H, 0.94 (3H, t, J=7Hz), ee -168- 0.83 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 521 Anal.calc. for C3 1

H

40

N

2 0 5 -1.25 TFA: C, 60,67; H, 6.27; N, 4.22. Found: C, 60.49; H, 6.18; N, 4.13.

Examlle 163 trans, trans-i1 N- Dibutyl am in oca rbon yl methyl) (3-f u yfl-4- 5-benzo-2.3dihydrofuranyl)Dyr~rolidine-3-ca rboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl P-oxo-3-furanpropionate in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, ODC1 3 b 7.42 (1H1, in), 7.38 in), 7.13 (1H, 7.16 (1H, dd, J=7Hz, 3Hz), 6.70 (1H, d, J=8Hz), 6.41 (1H, mn), 4.57 (2H, t, J=71-1z), 3.95 (1H, d, J=8Hz), 3.63 (1H, in), 3.55 (1H, d, J=14), 3.50-3.25 (4H, in), 3.18 (2H, t, J=6Hz), 3.15-2.95 (3H, mn), 2.87 (1H, d, J=l4Hz), 1.45 (4H1, in), 1.35-1.10 (4H, in), 0.85 (6H, in). MS (DCI/NH 3 m/e 469 AnaI.calc. for C 27

H

36

N

2 0 5 -0.25 H 2 0: C, 68.55; H, 7.78; K..

N, 5.92. Found: C, 68.62; H, 7.68; N, 5.82.

Examgle 164 trans. trans-i1 N -Dibutylam inocarbonylm-ethyl)-2-(4-m ethoXyphenYlb-44p.

fluoroo~henyl)Dyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-fluorobenzenecarboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDC1 3 5 7.30 (2H, d, J=8Hz), 7.22 (2H, in), 6.91 (1H, in), 6.86 (2H, d, J=8Hz), 3.79 (1H, in), 3.78 (3H, 3.68 (1H, in), 3.55-3.37 (3H, in), 3.29 (1H, mn), 3.15-2.90 in), 2.78 (1H, d, J=l4Hz), 1.43 (2H, in), 1.25 (4H1, in), 1.07 (2H1, in),_ 0.87 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 485 Anal.calc. for C 28

H

37

FN

2 0 4 0.25 H 2 0: C, 68.76; H, 7.73; N, 5.73. Found: C, 68.87; H, 7.69; N, 5.67.

Examgle 165 trans. trans-i1 N-Dibutylam inocarbonylmethyll-2- (4-rn ethoxyohenyl)-4-(3- 12yridyl)12yrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-pyridinecarboxaldehyde for piperonal -169in Example 49A. The nitro styrene was prepared by the method of Bourguignon ,et aL, Can. J. Chem. 63: 2354 (1985). 1 H NMR (300 MHz, CDCI3) 8 8.82 (1 H, bs), 8.73 (1 H, bd, J=9Hz), 8.62 (1 H, bd, J=7Hz), 7.78 (1H, bdd, J=9Hz, 3Hz), 7.38 (2H, d, J=lOHz), 6.90 (2H, d, J=lOHz), 4.39 (1H, d, J=l2Hz), 3.95 (1H, in), 3.80 (3H, 3.79 (1H, in), 3.68 (1H, d, J=l8Hz), 3.50-3.30 (3H, in), 3.25-2.90 (6H, in), 1.47 (2H, mn), 1.31 (4H, in), 1.20 (2H, in), 0.92 (3H, t, J=7Hz), 0.83 (3H, t, J=7Hz). MS

(DCIINH

3 m/e 468 Anal.calc. for C 27

H

3 7

N

3 0 4 1.65 TEA: C, 55.50; H, 5.94; N, 6.41. Found: C, 55.53; H, 5.90; N, 6.27.

Examlle 166 trans. trans-i1 N-Dibutylam inocarbonylmethyl-2-(2-fluorophenyl)-4-( 1.3- benzodioxol-5-yl)oyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 2-flIuorobenzoyl acetate in Example 49B. 1 H NMR (300 MHz, CDCI 3 8 7.52 (1H, dt, J=7Hz, 3Hz), 7.25 (1H, in), 7.13 (1H, dt, J=7Hz, 3Hz), 7.02 (211, in), 6.88 (1H, dd, J=7Hz, 3Hz), 6.73 (1H, d, J=8Hz), 5.93 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 4.25 (1H, d, J=9Hz), 3.68 (11H, in), 3.42 (3H, in), 3.39 (1H, mn), 3.20-2.95 (4H,V.

in), 2.91 (1H, d, J=l4Hz), 1.45 (3H, in), 1.26 (3H, in), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH 3 in/e 499 AnaI.ca~c. for C 2 8

H

3 5

FN

2 0 5 0.25 H 2 0: C, 66.85; H, 7.11; N, 5.57. Found: C, 66.51; H, 6.67; N, 5.18.* Examn~le 167% trans. trans-i N-Dibutylaminocarbonylmethyl-2-(3-fluorolhenyl)-4-( 1.3ben zod ioxol-5-yl)12rro lid in e-3-ca rboyl ic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 3-flIu orobe nzoyl acetate in Example 49B. 1H NMR *(300 MHz, CDC1 3 8 7.38 (1H, in), 7.18 (1H, d, J=7Hz), 7.15 (1H, in), 7.00 (1H, d, J=2Hz), 6.95 (1H, in), 6.86 (1H, dd, J=7Hz, 2Hz), 6.75 (111, d, J=8Hz), 5.93 (1H1, d, J=4Hz), 5.92 O1H, d, J=4Hz), 3.94 (1H, d, J=l4Hz), 3.63 (1H, in), 3.42 (3H, in), 3.35-2.95 (5H, in), 2.87 (1H, d, J=l4Hz), 1.44 (3H, in), 1.27 (3H, in), 1.10 (2H, in), 0.88 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH 3 rTI/e 499 Anal.calc.

for C 28

H

3 5

FN

2 0 5 C, 67.45; H, 7.08; N, 5.62. Found: C, 67.32; H, 7.05; N, 5.40.

-170- Example 168 trans. trans-I1 N-Dibutylaminoo~henyfl-2-(4-m etho yhenyl)-4- (1.3benzodioxol-5-yl)Dyrrolidine-3-carboxylic acid 4-Nitro-l1-fluorobenzene, ethyl trans, trans-2-(4methoxyphenyl)-4-(1 3 -benzodioxol-5y)pyrrolidine3carboxylate (the compound resulting from Example 6A), and diisopropylethylamine are heated in dioxane to give ethyl trans, trans-2-(4-methoxyphenyl)- 4 3-benzodi oxol1-5-yl)- 1 4 -nitrophenyl)- py rro lidi ne3ca rboxyl ate.

The nitro compound is hydrogenated to give the corresponding aminophenyl compound. The aminophenyl compound is reacted with butyraldehyde and sodium cyanoborohyd ride 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.:*.* Examole 169 Mrans. trans- N-Dibutvlam inoyrim idin-4-yi)-2-(4-methoxyghenyl)..4.1.3benzodioxol-5-yl)12yrrolidine-3-carbpxnlic acid i2-(Dibutylamino)-4-chloropyrimidine is prprdfrom 2,4- dichioropyrimidine according to the method of Gershon, J. Heterocyclic Chem. 24: 205 (1987) and reacted with ethyl trans, trans-2-(4methoxyphenyl)-4-(1 3 -benzodioxol-5y)pyrrolidine3carboxylate (the compound resulting from Example 6A) and diisoproplyethylamine in dioxane with heating to give the intermediate ethyl ester, which is hydrolyzed with sodium hydroxide using the method of Example 1 D to the title compound.

Examl~ies 170-266 Using the procedures described in Examples 1, 4, 5, 7, 8 and 9 and Scheme X, the following compounds can be prepared.

Ex. No. Name 170 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-1 (isopropylaminocarbonylmethyl)-pyrrolidine.3 carboxylic acid; 171 trans, trans-2-(4-Methoxyphenyl)-4-(1 13- 1 -(ethylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; 172 trans, trans-2-(4-Methoxyphenyl)-4-(1 13benzodioxol-5-yl)-l1-(1methylpropylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 173 trans, trans-2-(4-M ethoxyphenyl)-4-(1 ,3benzodioxol-5-yI)-l1-(phenylaminocarbonyl methyl)pyrrolidine-3-carboxylic acid; 174 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodi oxol-5-yI)- 1 (pipe ridi nyl carbonyl methyl)- pyrrolidine-3-carboxylic acid; 175 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-1 (propylaminocarbonyl)ethyl)-pyrrolidine-3-: carboxylic acid; 176 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3- 1 (pro pylIam in oca rbo nyl1) b enzy p yrrolIi d in e-3 carboxylic acid; 177 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yI)-l1-(bis- (propylaminocarbonyl)methyl)-pyrrolidine-3carboxylic acid; 178 trans, trans-2-(4-M ethoxyphenyl)-4-( 1,3benzodioxol-5-yI)-1 (propylaminocarbonyl)ethyl)-pyrrolidine-3carboxylic acid; 179 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-1 ropyl am inosuIf onylm ethyl)pyrrolidine-3-carboxylic acid; 180 trans, trans-2-(4-Methoxyphenyl)-4-(1 13benzodioxol-5-yl)-1 -(2-phenethyl)-pyrrolidine-3carboxylic acid; -172- 181 trans, trans-2-(4-Methoxyphenyl)-4-(1 13- 1 -(pentanoylmethyl)pyrrolidine-3-carboxylic acid; 182 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-l1-(benzoyt methyl)-pyrrolidine- 3-carboxylic acid; 183 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzod ioxol 1 (hexyl) -pyrrol idine- 3carboxylic acid; 184 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-l1-(2-hexynyl)-pyrrolidine-3- carboxylic acid; 185 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-1 -(propoxymethylcarbonyl-9 pyrrolidine-3-carboxylic acid; 186 trans, trans-2- Methoxyphenyl)-4-(1 ,3b e n zodio x olI- 5 1 (ph en yIa c ety1) -p yr rolIi d in e 3 carboxylic acid; 1 87 trans, trans-2- Met hoxy ph enyl)-4-( 1,3benzodioxol-5-yI)-1 -(anilinylcarbonyl)- pyrrolidine-3-carboxylic acid; 188 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-l1-(2-acetylarninoethyl)pyrrolidine-3-carboxylic acid; 1 89 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3- )-l1-(2-phenoxyethyl)-pyrrolidi ne- 3-carboxylic acid; 1 90 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzo dioxol 1 -(2-be nzo di oxanyl methyl)pyrrolidine-3-carboxylic acid; 191 trans, trans2-(4-Methoxyphenyl)-4-(1 13benzodioxol-5-yI)-l1-(2-tetrahydrofuranylmethyl)pyrrolidine-3-carboxylic acid; 1 92 trans, trans-2-(4-Methoxyphenyl)-4-(1 13benzodioxol-5-yl)-1 (p ropyl amino carbon yl ami no) et hen yl py r rol lidine 3-carboxylic acid; -173- 193 trans, trans-2-(4-M ethoxyphe nyl)-4-(1 13be nzodioxol-5-yi)- 1 (p ropyl am inocarbonyl amino) ethyl) -py rrolid in e- 3carboxylic acid; 194 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yI)-1 -(3-oxohex-l1-enyl)pyrrolidine-3-carboxylic acid; 195 trans, trans-2-(2,4-Di methoxyp henyl)-4-(1 ,3- 1 ropyl ami nocarbonyl methyl)pyrrolidine-3-carboxylic acid; 1 96 trans, trans-2-(2-Carboxy-4-methoxyphenyl)-4- (1 ,3-benzodioxol-5-yi)-1 (propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 197 trans, trans-2-(2-Aminocarbonyl-4-:eg.

methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1- (propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 1 98 trans, trans-2-(2-Methanesulf onamido-4methoxyphenyl)-4-(1 ,3-benzodioxol-5-yi)-1 (p ro pyIam in o c arb on y Imethy 1) -p y rro i d ine -3 carboxylic acid;* 199 trans, trans-2- (2-Am inocarbo nylIm eth oxy-4me t ho xyp h e ny1) -4 en z od io xolI- 5 -yI1) -I- (pr op y Iam ino c arb o n yImeth y1) -p y rroIi d in e -3 carboxylic acid; 200 trans, trans-2 Met ho xyet hoxy-4methoxyphenyl)-4-(1 ,3-benzodioxol-5-yi)- 1- (propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 201 trans, trans-2-(2-Carboxymethoxy-4methoxyphenyl)-4-( 1,3-benzodioxol-5-yi)- 1- (propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; -174- 202 trans, trans-2-(4-Methoxy-2tet raz olyl methoxyph eny l)-4 ,3 -benzo djioxol yi)-1 -(propylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 203 trans, trans-2-(2-Allyloxy-4-methoxyphenyl)-4 (1 ,3-benzodioxol-5-yl)-1 (propylaminocarbonylmethyl)-pyrrolidine.3 carboxylic acid; 204 trans, trans 2A4-Bis(4-methoxyp henyl) -1 (p ropy Ia mi nocarbo nyl methyl)- py rro Ii di ne-3 carboxylic acid; 205 trans, trans 2,4- Bis 3-benzod ioxol-5-yI)- 1 (p ropyl am in ocarbo nyl methyl)- py rro Ii di ne-3 carboxylic acid; 206 trans, trans-2-(4-Methoxyphenyl)-4-(1 13- 1 -(N-methyl-Npropylaminocarbonylmethy)-pyrrolidine-3carboxylic acid; 207 trans, trans-2-(4-Methoxyphenyl)-4-(1,3benzodioxole-5-yi)-1 -(N-methyl-N- butylaminocarbonyl)-pyrrolidine-3-carboxylic acid; 208 trans, trans-2-(4-Methoxyphenyl)-4-(1 benzodioxol-5-yl)-1 -(N-methyl-N-(4m e th oxy ph enyl1) am ino c arbo nyt1) -3 -p y rroI i d ine -3 carboxylic acid; 209 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benz od ioxol 1 -m ethyl- Nphenylaminocarbonyl)-pyrrolidine-3-carboxylic acid; 21 0 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-l1-(N-methyl-Nallylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 211 trans, trans-2-(4-Methoxyphenyl)-4-(1,3benzodioxol-5-yl)-l1-(N-methyl-N-(nbutyl)aminocarbonylmethyl)-pyrro lidine-3carboxylic acid; -1 212 trans, trans -2-(4-Methoxyp he nyl)-4-( 1,3- 1 -(N-methyl-Nisobutyl am inocarbonylmethyl)-pyrrolidi ne-3carboxylic acid; 213 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-l1-(N-methyl-Ncyclopentylaminocarbonylmethyl )-pyrrol idine-3carboxylic acid; 214 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-1 -(N-methyl-N-(2methoxyethyl)aminocarbonyl)-pyrrolidine-3- carboxylic acid; 215 tra nstrans -2 et h oxyp he ny1) 4- 3 benzod ioxol1-5-yl)- 1 -m ethyl- Nb uto xyet hylIa m in oca rb ony1) py rroIi d ine-3 carboxylic acid; 216 trans, trans-2-(1 ,3-Benzodioxol-5-yl)-4-(4methoxyphenyl)- 1 methyl- Npropylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 217 trans, trans-2-(4-Methoxyphenyl)-4- (1 .4benzodioxan-6-yI)-l1-(N-methyl-N.propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 218 tra ns, trans -2 Met h oxy ph enyl)-4- (1,3 benzodioxol-5-yI)-1 -(N-inethyl-Nisopropylaminocarbonyl methyl)-py rrolidine-3carboxylic acid; 21 9 trans, trans -2 Met h oxyph enyl1)-4-( 1,3benzodioxol-5-yl)-1 -(N-methyl-Nethylaminocarbo nyl methyl)- pyrrolIi din e- 3carboxylic acid; 220 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-1 -(N-methyl-N-( 1methylpropyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; -176- 221 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3- 1 -(N-methyl-Nph eny lam inoca rbo nyl methyl) -py rrol d ine- 3carboxylic acid; 222 trans, trans-2-(4-Methoxyphenyl)-4-(1,3benzodioxol-5-yi)-1 -(N-rnethyl-Npropylaminocarbonyl)ethyl)-pyrrolidine.3 carboxylic acid; 223 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-1 -(c-(N-methyl-Npropylaminocarbonyl)benzyl)-pyrrolidi ne-3- carboxylic acid; 224 trans, trans-2-(4- Met hoxyp heny (1,3b en zo d iox olI- 5-yl1)- 1 (N -eth ylI-N p ro pyIa m i no c arb on y Imet hy 1) -py rroIi d ine -3 carboxylic acid; 225 trans, trans-2-(4-Methoxyphenyl)-4-(1,3benzodioxoie-5-yl)-1 -(N-ethyl-Nbutylaminocarbonyl)-pyrrolidine-3-carboxylic acid; 226 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3- 1 -(N-ethyl-N-(4-: methoxyphenyl)aminocarbonyl)-3-pyrrolidine-3.

carboxylic acid; 227 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3- 1-(N-ethyl-Nphenylaminocarbonyl)-pyrrolidine-3-carboxylic acid; 228 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3- 1-(N-ethyl-Nallylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 229 trans, trans-2 Methoxyphenyl)-4-( 1,3benzodioxol-5-yI)-1 -(N-ethyl-Nisobutylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; -177- 230 trans, trans -2-(4-Methoxyphenyl)-4-( 1,3be nzodioxol-5-yI)- 1 -(N-ethyl-Ncycl opentylami nocarbonylmethyl) -pyrro id in e-3 carboxylic acid; 231 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-l1-(N-ethyl-Nmethoxyethylaminocarbonyl)-pyrrolidine-3carboxylic acid; 232 trans, trans-2-(4-Methoxyphenyl)-4.( 1,3- 1-(N-ethyl-Nbutoxyethylaminocarbonyl)-pyrrolidine-3carboxylic acid; 233 trans, trans-2-(1 ,3-Benzodioxol1-5-yl)-4-(4methoxyphenyl)-l1-(N-ethyl-Npropylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 234 trans, trans-2-(4- Met h oxyphenyl1)-*4- (1,4benzodi oxan-6-yl)- 1 ethyl- Np rop ylIam in o ca rb on y Ime t hy1) -py rrolIi d ine -3 carboxylic acid; 235 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-1 -(N-ethyl-N- isopropylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 236 trans, trans-2-(4- Met hoxyphe nyl)-4-(1 ,3benzodioxol-5-yl)-1 Nd iethyl am inocarbonylm ethyl)-pyrrol id ine-3carboxylic acid; 237 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-l1-(N-ethyl-N-( 1methylpropyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 238 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3- 1-(N-ethyl-Nphenylam inocarbo nyl methyl) -py rrol id ine-3carboxylic acid; -178- 239 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3- 1 -(N-ethyl-Npropylaminocarbonyl)ethyl)-pyrrolidine-3carboxylic acid; 240 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodi oxol-5-yl)- 1 (N -ethyl- Npropylaminocarbonyl)benzyl)-pyrrolidine-3carboxylic acid; 241 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol 1 -(N-rn ethyl- Nisobutylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 242 trans, trans-2- Met hoxyp he nyl)-4-( 1,3b en zo d iox olI- 5-y1) 1 (N -m eth ylI-N cyc I ohe xyIa m in o carb o nylIme thyl1) -p yr ro I i d ine -3 carboxylic acid; 243 trans, trans -2 Methoxyp heny1) (1,3benzodioxol-5-yl)-1 Ndipropylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 244 trans, trans-2-(4-Methoxyphenyl)-4-(1 b en zo d io x olI- 5-y1)- 1 (i s ob ut yIo xy e t hyl1) pyrrolidine-3-carboxylic acid; 245 trans, trans-2-(4- Methoxyp henyl)-4- (1 ,3be nz o d ioxoI- 5 -y 1) -1 (but yIs u If o ny1) py rroIi d in e 3-carboxylic acid; 246 trans, trans-2-(4-Methoxyphenyl)-4-(1 13- 1- (isopropylsulfonylaminoethyt)-pyrrolidine-3carboxylic acid; 247 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3- 1- (eth oxymethylcarbonylmethyl)-pyrrolidine-3carboxylic acid; 248 trans, trans -2 Methoxyp heny1) (1 ,3benzodioxol-5-yl)-1 -(2-ethylbutyryi m ethyl)pyrrolidine-3-carboxylic acid; -179- 249 trans, trans-2-(4- Met hoxyphenyl)-4-( 1,3- 1 -met hyl-N-(3,4di methoxybenzyl)ami nocarbo nyl methyl) pyrrolidine-3-carboxylic acid; 250 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodi oxol-5-yI)- 1 1 -(N-rn ethyl- Npropylaminocarbonyl)butyl]-pyrrolidine-3carboxylic acid; 251 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-l1-[(1 S)-1 -(N-methyl-Npropylaminocarbonyl)butyl]-pyrrolidine-3- carboxylic acid; 252 trans, trans-2-(4- Met hoxyphenyl)-4-( 1,3be nzodioxol-5-yl)- 1 -(3-isop rop oxyp ropyl)pyrrolidine-3-carboxylic acid; 253 trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3- 1 -(5-methylhexyl)-pyrroli dine- 3-carboxylic acid; 254 trans, trans -2 Metho xyp henyl)-4- (1 ,3benzodioxol-5-yl)-l1-(5-methyl-2-hexenyl)- pyrrolidine-3-carboxylic acid; 255 trans, trans-2 Met hoxyphe ny1) 1,3-* b en z od ioxolI- 5- y1) 1 met hyI- 4 he xe ny1)pyrrolidine-3-carboxyiic acid; 256 trans, trans-2- Methoxyp he ny1)-4 1,3b en z od io xolI- 5 1 5- d irme th yI- 2- he xe ny1)pyrrolidine-3-carboxylic acid; 257 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-1 ethyl-Nisobutyrylamino)ethyl)-pyrrolidine-3-carboxylic acid; 258 trans, trans-2-(4-Methoxyphenyl)-4-(1,3benzodioxol-5-yl)-1 -(N-methyl-N-(2,2dimethylpropyl)arninocarbonylmethyl)-pyrrolidine- 3-carboxylic acid; -180- 259 trans, trans-2 Met hoxyp he nyl)-4-(1 ,3be nzodioxol-5-yl1) -1 -(N-ethyl-Nbutyl aminocarbonyl methyl)-pyrrolidi ne-3carboxylic acid; 260 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3- 1 -(N-rnethyl-Nbenzylaminocarbonylmethyl)-pyrrolidine.3 carboxylic acid; 262 trans, trans-2-(4-Methoxyphenyl)-4-(5-indanyl).1 (N-methyl-N-propylaminocarbonylmethyl)py rro li dine- 3- carboxylic acid;* 262 trans, trans-2 Methoxyp he ny1) (2,3d ih yd ro be n zof uran 5-y1) -1 (N -rn eth ylI-N p r op yIamni n oc a rb on ylIme thy1) p yrro Ii d ine -3 carboxylic acid; 263 trans, trans-2-(4-Methoxyphenyl)-4-(1 1 -(N-methyl-Np ro pyIa m in oca rb on ylImeth y1) -p y rrolIi d ine -3 carboxylic acid; 264 trans, trans-2-(4-Methoxyphenyl)-4-(2-naphthyl).

1 -(N-methyl-N-propylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; 265 trans, trans-2-(4-Methoxyphenyl)-4-( 1,2dimethoxy-4-phenyl)-1 -(N-methyl-Nprop yl am i no carbon yl m ethyl) py rro lid in e-3carboxylic acid; 266 trans, trans-2-(4-Methoxyphenyl)-4-( -methoxy-3.

phenyl)-l1-(N-rnethyl-Np ropyl am inocarbonyl methyl) -pyrrol idi ne-3carboxylic acid; Examgles 267-288 Following the procedures described in Example 1 and Scheme 11, the following compounds can be prepared.

-181- 267 trans, trans-3-(4-Methoxyp he nyl)-5-( 1,3- 1 -(propylaminocarbonylmethyl)pipe ridine-4-carboxylic acid; 268 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3- 1 -(am in ocarbonyl methyl)piperidine-4-carboxytic acid; 269 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3benzodioxoi-5-yI)-l1-(4-fluorobenzyl)-piperidine- 4-carboxylic acid; 270 trans, trans-3-(4- Met hoxyp he nyl)-5- (1 3benzodioxol-5-yI)-1 -(2-ethoxyethyl)-piperidine-4carboxylic acid; 271 trans, trans-3-(4- Methoxyphenyl)-5- (1,3b e nzo d io xolI-5 -y 1 (2 -p ro p oxyet hy1) -p ip eri d ine 4-carboxylic acid; 272 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3- 1 -[2-(2-methoxyethoxy) ethyl]pipe ridine-4-carboxylic acid; 273 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3benzodioxol-5-yi)-1 -[2-(2-pyridyl)ethyl]piperidine-4-carboxylic acid;* 274 trans, trans-3-(4- Methoxyp he ny1) benzodioxol-5-yl)-1 -(morpholin-4-ylcarbonyl)piperidine-4-carboxylic acid; 275 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3benzodioxole-5-yI)-l1-(butylaminocarbonyl)piperidine-4-carboxylic acid; 276 trans, trans-3-(4-Methoxyphenyl)-5-(1 .3benzodioxol-5-yi)-1 methoxyphenylam inoca rbo nyt) -3-pi pe rid ine-4carboxylic acid; 277 trans, trans-3-(4-Methoxyphenyl)-5-(1,3benzodi oxol-5-yi) 1 -acetyl p ipe rid in e-3-ca rboxyl ic acid; 278 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3benzodioxol-5-yl)-l1-(2-f uroyl)-piperidine-3carboxylic acid; -182- 279 trans, trans-3-(4-Methoxyp he nyl)-5-( 1,3- 1 -(phenylamin ocarbonyl)piperidine-4-carboxylic acid; 280 trans, trans-3-(4-Methoxypheny)-5-(1,3- 1 -(al lylam inocarbonyl methyl)piperidine-4-carboxylic acid; 281 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3benzodioxol-5-yI)-l1-(nbutyl aminocarbonylmethyI)-piperidine-4carboxylic acid; 282 trans, trans-3-(4-Methoxyphenyl)-5.(1 ,3benzodioxol-5-yI)-1 -(N-n-butyl-N- methylaminocarbonyl methyl) -pi peri di ne-4 carboxylic acid; 283 trans, trans-3-(4-Methoxyphenyl)-5-(1 benzodioxol-5-yl)-1 -(pyrrolidin- 1ylcarbonylmethyl)-piperidine-4-carboxylic acid; 284 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3- 1 (isobutylaminocarbonylmethyl)-piperidine-4carboxylic acid;* 285 trans, trans-3 -(4-Methoxyphenyl)-5-(1 1-* (cyclopentylami nocarbonylmethyl)-piperidine-4carboxylic acid; 286 trans, trans-3-(4-Methoxyphenyl)-5-(1,3benzodioxol-5-yI)-l1-(morpholin-4ylaminocarbonylmethyl)-piperidine-4-carboxylic acid; 287 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3benzodioxol-5-yI)-l1-(2-phenoxyethyl)-piperidine- 4-carboxylic acid; 288 trans, trans (4-M ethoxyp henyi)- 1,3benzodioxol-5-yI)-1 -(methoxyethylaminocarbonyl)piperidine-4-carboxylic acid.

-183- Example 289 trans. trans- 2-(4-Methoxylhenyl)-4-(1 .3-benzodioxol-5-yl)-1 (4dibutylaminolhenyl)-pyrrolidine-3-carboxylic acid 4-Nitro-fluorobenzene, ethyl trans, trans-2-(4-methoxyphenyl)-4- (1 ,3-benzodioxol-5-yI)-pyrrolidine-3-carboxylate (example 6A) and diisopropyl ethylamine are heated in dioxane to give ethyl trans,trans-2- (4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(4-nitrophenyl)pyrrol idine-3-carboxyl ate. The nitro compound is hydrogenated to the corresponding aminophenyl compound. This is reacted with butyraldehyde and sodium cyanoborohyd ride according to the method of Borch 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 trans, trans-2 Methoxyp henyfl-4-(1 .3-benzodi oxo I-5-yl)- 1 (2dibutyl-amino-oyrimidine-4-yfl)-yrrolidine-3-carboxylic acid 2-(Dibutylamino) 4-chioropyrimidine is prepared from 2-4dichloropyrimidine according to the method of Gershon Heterocyclic Chem. 24, 205, 1987). This compound, ethyl trans, trans-2-(4- m et ho xyp h eny1) -4 ,3 -ben z odio x o I- 5-y 1) -p yr r oIid ine -3 -c a rb oxy Iat e (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 1D to give the title compound.

Example 291 trans. trans-2-(4-Methoxyhenyl)-4-(1 .3-benzodioxo-5-yl)- 1 -(N-butyl-N- D2henylam inoca rbonylmethyl)-ovrrolidine-3-carboxylic acid The title compound was prepared according to the general procedure of Example 1. 1 H NMVR (CD 3 OD) 8 0.87 1.2-1.35 1.35-1.5 2.78 (in, 2H); 3.10 (t,1H, 3.26 (d,1H,J=15); 3.44 (dd,1H,J=5,10); 3.5-3.7 3.77 3.78 5.93 6.7-6.9 7.0-7.2 7.4 MS (DCI/NH 3 mn/e 531 Anal calcd for C 3 1

H

34

N

2 0 6 C, 70.17; H, 6.46; N, 5.28.

Found: C,70.36; H, 6.52; N, 4.99.

-184- Example 292 Sodium trans. trans-2-(4-MethoxyDhenyl)-4-(1.3-benzodioxol-5-yl)-1 dibutylaminocarbonylmethyl)-Dyrrolidine-3-carboxylate Example 292A Ethyl 3-(4-methoxyphenyl)-3-oxopropionate Simultaneous reactions were run in both a 65-L reactor and a 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 mineral oil and 32 L toluene were charged into the ambient temperature reactors. The mixture was agitated for 5 minutes and allowed 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 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 100 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 acetophenone solution. When addition was complete, agitation was stopped and the layers separated. The aqueous layer was washed once with 13 L toluene. The combined organic layers were washed twice with 6.7 L portions of 7% aqueous sodium bicarbonate. The toluene solution was washed once with 6.7 L of 23% aqueous 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 292B 3.4-Methylenedioxy- 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 150-200 C. The jacket temperature was set to -50 C and the reaction solution cooled to a temperature of +3.50 C. A 210 C solution of 3.10 kg (38.8 moles) 50% aquous sodium -185hydroxide diluted with 3.7 L water was pumped in. The reaction temperature was maintained between 10°-150 C. When addition was complete, the jacket temperature was reset to 10 C and stirring continued for 30 minutes. A mixture of 7 kg ice in 19 L water was 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 210 C mixture of 7.4 L concentrated hydrochloric acid in 11.1 L deionized water. The final reaction temperature was 260 C. The resulting product was centrifuged and 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 dichloromethane. 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 40 C. Filtration through Whatman #1 paper, followed by ambient temperature drying in vacuo with an air leak afforded 1.584 kg of a first crop Concentration of the MLS to 25% followed by similar cooling, filtration, and drying afforded 0.262 kg of a second crop. The yellow product darkened on standing in light and air. Example 292C Ethyl 2-(4-methoxybenzoyl)-3-(1.3-benzodioxol-5-yl)-4-nitrobutanoate Into a 45-L stirred reactor at ambient temperature were charged 5.819 kg (30.1 moles) 3,4-methylenedioxy-1-(2-nitroethenyl)-benzene and 24 L ethyl acetate A solution of 5.355 kg (24.1 moles) ethyl 3-(4methoxyphenyl)-3-oxopropionate in 16 L ethyl acetate was added. 280 g (275 ml, 1.84 moles) of 1,8-diaza-bicyclo[5.4.0]undec-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 used in the next step without any further purification.

-186- Example 292D Ethyl 2-(4-methoxyDhenvl)-4-(1.3-benzodioxol-5-yl)-4.5-dihydro-3Hpyrrol-3-carboxylate 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 The reaction mixture was shaken under a hydrogen environment of 4 atm at room temperature for 18 hoursand 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 to 0° C and filtered. The solid was washed with 2 L of 85:15, hexane: ethyl acetate The solids were dried in vacuo at 500 C to a constant weight of 193.4 g (21% yield, melting point 80-810 C) of the title compound. A further 200 g (23% yield) of product was obtained from the mother liquors. Example 292 E Ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine 3- carboxylate 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- I 3H -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 94.26g sodium cyanoborohydride mol) 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 minutes after addition was complete. After the starting material was consumed, 0.5 L of 7% aq. NaHCO3 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. NaHCO3 and once with 2.5 L of 23% aq. NaCI, the dried over 190g MgSO4, filtered, and concentrated to give 447 g of the title compound as a thick yellow oil.

187- Example 292 F Ethyl 2-(4-methoxvDheny)-4-(1.3-benzodioxol-5-l)-1 dibutylaminocarbonyl methyl) pyrrolidine 3-carboxylate Into a 22-L flask equipped with overhead stirring, nitrogen inlet, and condenser was charged ethyl 2-(4-methoxyphenyl)-4-(3,4methylenedioxyphenyl)-pyrrolidine-3-carboxylate (2.223 kg,6.02 mol).

The reaction vessel was degassed with nitrogen. 13.2 L ofacetonitrile, 3.66 L diisopropylethylamine (2.71 kg, 20.9 mol), and 1.567 kg dibutylamidomethyl bromide (6.26 mol) were added. The mixture was refluxed at 780 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 (00 Concentrating of the filtrate was continued as above until all volatiles 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 MgSO4 and filtered.

Concentration as above provided 3.112 kg (96 yield) of the title compound as a dark oil. Example 292G trans.trans-2-(4-Methoxyphenyl)-4-(1 3-benzodioxol-5-yl)-pyrrolidine 3-carboxylate and preparation of trans.trans 2-(4-methoxyphenyl)-4- (3.4-dioxyphenyl)-pyrrolidine-3-carboxylic acid ethyl ester Into a 35-L reactor equipped with overhead stirring, nitrogen inlet, and condenser was charged 3.112 kg ethyl 2-(4-methoxyphenyl)- 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 790 C for 1 hr. The mixture was cooled to 150 C and 5 L of 7.6 M NaOH solution (38.1 mol) was added. The mixture was stirred at 150 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 with 24 L of ethyl acetate. The organic layer was washed with 9 L of 23% aq. NaCI, dried with 0.298 kg MgSO4 filtered, and concentrated to -188give 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 1.102 kg of light foam. The foam was dissolved in 5.5 L ethyl acetate with heating to 650 C. 14 L hexane s was added slowly enough to keep the solution refluxing. The reaction mixture was cooled to 100 C and filtered. The crystals were washed with 2 L ether (00 C) and dried to constant weight in vacuo at 500 C to give 0.846 kg (43% yield, melting point 119-120) of crude product, which was further purified by normal phase silica gel chromatography.

Example 292H Sodium trans. trans-2-(4-methoxyvhenyl)-4-(1.3-benzodioxol-5-yl)-- S(N.N-dibutylaminocarbonyl methyl) pyrrolidine 3-carboxylate Into a 20-L flask was charged trans,trans 2-(4-methoxyphenyl)- 4-(3,4-methyledioxyphenyl)-1-(N,N-dibutylamino- carbonyl methyl) pyrrolidine 3-carboxylic acid (0.927 kg, 1.819 mol). A solution of 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 light tan foam. The foam was dried in vacuo at 50° C to a constant weight of 0.937 kg (97% yield) of the title compound.

0 Example 293 i*o trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 [decahydroisoquinolin-2- carbonylmethyll-pyrrolidine-3-carboxylic acid.

The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) shows a mixture of isomers. MS

(DCI/NH

3 m/z 521. Anal calcd for C 3 oH 3 6

N

2 0 6 1.3 TFA: C, 58.54; H, 6.62; N, 4.19 Found: C, 58.34; H, 5.58; N, 4.00 -189- Example 294 trans-trans-2-(4-Methoxylhenyl)-4-(1 .3-benzodioxol-5-yfl-1 43.3dimethylpiperidinyl- carbonylmethyll-12yrrolidine-3-carboxylic acid.

The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) indicates presence of rotarners. 8 0.84 3H), 0.86 3H), 1.35-1.6 (in, 4H), 3.83 3H), 5.96 2H), 6.81 1H, 6.90 (dd, 1H, 7.01 2H, 7.03 1H), 7.47 2H, MS (DCI/NH 3 m/z 495. Anal calcd for C283H3N 2

OG.-

1.4 TEA: C, 56.55; H, 5.45; N, 4.28 Found: C, 56.52; H, 5.83; N, 4.26.

Examole 295 trans-trans-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-yf)l- N- 12rop~yl-N-iso-butoxycarbonylamino~ethyl1pyrrolidine-3-carboxylic acid The title compound was prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 61B and isobutyl chioroformate 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 CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDCI 3 300 MHz) 8 0.80 3H, 0.92 (in, 3H), 1.43 2H, J=7Hz), 1.7-1.9 (in, 1IH), 2.72 (in, 1H), 2.90 (in, 2H), 3.10 (in, 2H), 3.25 (mn, 2H), 3.40 (in, 1H), 3.55 (mn, 1 3.62 (in, 1 3.7-3.9 (in, 2H) 3.78 3H), 5.95 2H), 6.72 1 H, J= 8Hz), 6.82 (in, 3H), 7.00 1 7.30 2H, J=8Hz). MS

(DCI/NH

3 m/e 527 Anal calcd for C 2 9 H3 8 N20 6 -0.5 H 2 0: C, 65.03; H, 7.34; N, 5.23. Found: C, 65.13; H, 6.96; N, 4.95.

Example 296 trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yfl)-1ri .2.3.4-tetrahydroisoguinolin-2- carbonylmethyll-p2yrrolidine-3carboxylic a cid.

The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) indicates presence of rotamers. 8 2.97 (mn, 2H), 4.68 3H), 5.97 2H), 6.83 1 H, 6.9-7.0 (in, 3H), 7.03 1H, 7.1-7.3 (in, 4H), 7.4-7.5 (in, 2H). MS (DCI/NH 3 m/z 515.

-190- Example 297 trans- trans-2- Methoxyph enyfl)-4- (1 .3-benz od ioxoI- 5-yi)- 1 -r2-(Npropyl-N-dimethylaminocarbonylamino)ethl-Dyrrolidine-3p.carboxylic The title compound was prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 61iB and dim ethyl carbamyl chloride for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac iC 18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid. 1 NMR

(CDCI

3 300 MHz) 5 0.70 3H, 1.28 (in, 2H), 2.75 3H), 2.82 (in, 2H), 3.1-3.45 (mn, 4H), 3.70 (in, 1 3.80 3H), 3.90 (in, 3H), 4.72 (in, 1 1H), 5.95 2H), 6.75 1 H, J= 8Hz), 6.87 (mn, 3H), 7.05 1 7.40 (d, 2H, J=8Hz). MS (DCI/NH 3 m/e 498 Anal calcd for C2 7

H

3 5

N

3 0 6 1.25 TEA: C, 55.35; H, 5.71; N, 6.56. Found: C, 55.41; H, 5.71; N, 6.41.

Example 298 trans. trans-2-(4- Methoxyhenyl-4- 1 .3-benzodioxol-5-ylb- 1 propyl- N- (4-n it robenzen esuIf onyflainno)ethyfl-oyrrolidi ne-3 carboxylic acid Using the procedures described in Eainple 66, the title compound was prepared as a yellow solid. in.p. 85-870C. I1 NMR (CDCI3, 300 MHz) 8 0.77 J=7.5Hz, 3H), 1.38 (sextet, J=7.5Hz, 2H), 2.20-2.29 (mn, 1H), 2.57-2.66 (in, 1H), 2.82-3.15 (in, 4H), 3.22 J=7.5Hz, 2H) 3.38 (dd, J=3Hz,J=9Hz, 1H), 3.49-3.57 (in, 1H), 3.59 J=9Hz, 1H), 3.83 3H), 5.96 2H), 6.73 J=8Hz, 1H), 6.82 (dd, J=lHz,J=8Hz, 1H), 6.87 (d, J=9Hz, 2H), 6.98 J=lHz, 1H), 7.27 J=9Hz, 2H), 7.82 J=9Hz, 2H), 8.23 J=9Hz,2H). MS (DCI/NH3) m/e 612 Exainple 299 trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 propyl-N-n-pentanesulfonylainino)ethyl)-pyrrolidine-3--carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 59-61 OC 1 H NMR (CDC1 3 300MHz) 8 0.79 J=7.5Hz, 3H), 0.90 J=6Hz, 3H), 1.26-1.32 (in, 411), 1.43 (sextet, J=7.5Hz, 2H), 1.67-1.76 (mn, 2H), 2.23-2.32 (in, 1 2.70-3.08 (in, 7H), 3.15-3.32 3.42 (dd, J=3Hz,J=9Hz, 1H), 3.52-3.57 (in, -191- 1H), 3.63 J=9Hz, 1H), 3.80 3H), 5.95 2H), 6.73 J=7.5Hz, 1H), 6.83 (dd, J=lHz,J=7.5Hz, 1H), 6.87(d, J=8Hz, 2H), 7.00 J=lHz, 11-), 7.32 J=8Hz, 2H). MS (DCI/NH 3 m/e 561 Example 300 trans, trans-2-(4-Methoxyrphenyl)-4-(1 .3-benzodioxol-5-yi)-1 Dropyl-N-(4-trifl uoromethoxybenzenesufonl)amino)ethyl,)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound prepared as a white solid. m.p.122-124-C. 1 H NMR (CD3OD, 300MHz) 50.75 J=7.5Hz, 3H), 1.26-1.45 (in, 2H), 2.96-3.08 (in, 2H), 3.23 (bs, 2H), 3.35-3.45 (in, 2H), 3.52 J=lOHz, 1H), 3.81 J=9Hz, 2H), 3.86 (s, 3H), 3.92 J=9Hz, 1H), 4.63 J=lOHz, 1H), 5.97 2H), 6.82 J=9Hz, 1H), 6.93 (dd, J=3Hz,J=9Hz, 1H), 7.06-7.08 (in, 3H), 7.46 J=9Hz, 2H), 7.56 J=9Hz, 2H), 7.89 J=9Hz, 2H). MS (DCI/NH3), m/e 651 Example 301 trans, trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-y)- 1 12ropyl- N- methyl-2- propenesuIf onyflamino) ethyl) p1yrrolidi ne-3 carboxylic -acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 69-71 1 H NMR (CDCI3, 300MHz) 8: 0.79 J=7.5Hz, 3H1), 1.93 (sextet, J+7.5Hz, 2H), 1.92 3H), 2.25-2.35 (mn, 11H), 2.,68-2.77 (in, 1H), 2.85-3.28 (mn, 7H), 3.40 J=9Hz, 1H), 3.52- 3.68 (in, 211), 3.66 J=9Hz, 1 3.80 3H), 4.92 1 5.07 1 H), 5.97 2H), 6.74 J=7Hz, 1H), 6.82-6.89 7.01 7.33 (d, J=-9Hz, 2H). MS (DCIINH3), in/e 545 -192- Example 302 trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yf)l- ethyloiieridinyl-carbonylmethyll-pyrrolidine-3-_carboxylic acid.

The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) shows a mixture of isomers. 8 0.75 3H, 1.4-1.7 (in, 8H), 3.84 3H), 5.96 2H), 6.83 1 H, 6.91 1H, 7.0-7.1 (in, 3H), 7.52 2H, MS (DCI/NH 3 m/z 495. Anal calcd for C2 8

H

34

N

2 0 6 1.6 TEA: C, 55.35; H, 5.30; N, 4.14 Found: C, 55.26; H, 5.37; N, 4.01 Example 303 trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-be-nzodioxol-5-yfl)-1 prop~yl-N-(2-methylpropanesulfonyflamino'~ethyn)-pyrrolidine-3 carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 72-73 0 C. 1 H NMR (CDC13, 300 MHz) a 0.82 J=7.5Hz, 3H),1.04 J=6Hz, 6H), 1.44(q, J=7.5Hz, 2H), 2.15-2.33 2.57-2.75 (in, 2H), 2.84-3.08 (mn, 3H), 3.12-3.21 (mn, 1H), 3.23- 3.45 (mn, 1H), 3.43 J=llHz, 1H), 3.55-3.62 (mn, 1H), 3.66 (d,'J=9Hz, 1 3.80 3H), 5.95 2H), 6.75 J=9Hz, 1 6.83 (dd, J=lHz,J=9Hz, 1H), 6.87(d, J=9Hz, 2H1), 7.02 J=lHz, 1H), 7.33 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 547 Example 304 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)- 1 propyI-N-heptanesulfonylamino~~ethyfl-pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p.58-59 0 C. 1H NMR (CDCI3, 300MHz) 8 0.80(t, J=7.5Hz, 3H), 0.88 J=7Hz, 3H), 1.23-1.36 (in, 8H), 1.94 (q, J=7.5Hz, 2H), 1.71(quintet, J=7H-z, 2H), 2.23-2.32 (in, 1H), 2.70-3.09(mn, 7H), 3.13-3.32 (m,2H1), 3.43(dd, J=3Hz,J=9Hz, 1H), 3.52-3.58(m,1H), 3.65(d, J=9Hz, 1H), 3.80 3H), 5.96(s, 2H), 6.73 J=7Hz, 1H), 6.83 (dd, J=lHz, J=7Hz, 1H), 6.87(d, J=9Hz, 2H), 7.01(d, J=lHz, 1H), 7.32(d, J=9Hz, 2H). MS (DCI/NH3) rn/e 589 .a 1 9 3 Example 305 trans -trans-2 Meth oxyp henyfl-4- (1 .3-be nzod ioxol 1 -l2-(Nethyl-N-ethoxycarbonylamino~ethyll-pyrrolidine-3-carboxylic acid Prepared by the methods detailed in Example 61, but substituting ethylamine for methylamine in Example 61 B and ethyl chioroformate for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac gCl8) eluting with a 10-70% gradient of

CH

3 CN in 0.1% TEA. The desired fractions were lyophilized to give the product as a white solid. 'H NMR (CDCI 3 300 MHz) 8 0.90 3H, J=7)1 1.22 (in, 3H), 3.0-3.2 (in, 4H), 3.42 (in, 2H), 3.78 3H), 3.82 (in, 4H), 4.10 2H, J=7Hz), 3.5 (br s, 1H), 5.97 (dd, 2H, J=1,7Hz), 6.72 1H, J= 8Hz), 6.84 (in, 3H), 7.00 1 7.42 2H, J=8Hz). MS, (DCI/NH 3 m/e Ip 485 Anal calcd for C26H 32

N

2 0 7 -1.2 TFA: C, 54.90; H, 5.39; N, 4.51. Found: C, 55.01; H, 5.36; N, 4.56.

trans, trans-2-(4-Methoxyphenyfl-4-(1 .3-benz odioxol-5-yI)-1 propyl-N-hexanesulfonylamino)ethyfl-pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.59-60 0 C. 1 H NMR (CDCI3, 300MHz) 8 0.80(t, J=7.5Hz,3H), 0.89(t, J=7Hz, 3H), 1.25-1.36(m, 6H), 1.53(sextet, 2H), 1.72(quintet, J=7Hz, 2H), 2.23-2.32(m, 1H), 2.72-3.08(mn, 7H), 3.15-3.32(m, 2H), 3.43(d, J=9Hz, 3.55-3.62(m, 1H), 3.65 J=lOHz, 1H), 3.80(s, 3H), 5.96(s, 2H), 6-74(d, J=7.5Hz,1H), 6.82(d, J=7.5Hz,1H), 6.87(d, J=9Hz, 2H), 7.01(s,1H), 7.32(d, J=9Hz,2H). MS (DCI/NH3), mle 575 ExamrnQe trans-trans-2- Ethyl ph enyfl-4-(1 .3-benzodi oxol Iyl- -r N. N-di(nbutyl)aininocarbonylmethyll-pyrrolidine-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) starting with 4'-ethylacetophenone) in procedure 49B. NMR (CDCI 3 300 MHz) 8 7.31 (211, d, J=8Hz), 7.16 (2H, d, J=8Hz), 7.03 (1 H, d, J=3Hz), 6.86 (1H, dd, J=8&3Hz), 6.73 (1H, d, J=9Hz), 5.94 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.77 (OH, d, J=9Hz), 3.60 (1H, in), 3.53-3.23 (5H, in), 3.13-2.90 -194- (4H, in), 2.73 (1H, d, J=l4Hz), 2.62 (2H, q, J=9Hz), 1.45 (2H, in), 1.40- 1.10 (6H, in), 1.02 (2H, in), 0.87 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). m/e (DCI, NH 3 509 Anal.calc. for C 30

H

4 oN 2

O

5 C 70.84, H 7.93, N 5.51.

Found C 70.80, H 7.85, N 5.25 Example 308 trans-trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yb)-l1-r2-(Nprop~yl-N-(2-chloroethoxy)carbonylamino)ethyll-pyrrolidine.3 carboxylic acid Prepared by the methods detailed in Example 61, but substituting propylainine for inethylainine in Example 61 B and 2-chioroethyl chloroformate for isobutyryl chloride in Example 610. The crude product p was purified by trituration with 1:1 diethyl ether! hexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDCI 3 300 MHz) 8 0.80 (t, 3H, 1.22 (in, 3H), 2.15 (in, 1 2.75 (in, 1 2.85 (in, 1 3.1 (in, 2H), 3.25 (in, 2H), 3.5 (in, 3H), 3.65 (in, 2H), 3.80 3H), 4.18 (in, 1H), 4.30 (in, 1 5.98 2H), 6.72 (in, 1 6.82 (in, 3H), 7.00 (in, 1 H), 7.30(m, 2H). MS (DCI/NH 3 W/e 533 Anal calcd for C27H 33

N

2 0 7 CI: C, 60.84; H, 6.24; N, 5.26. Found: C, 60.48; H, 6.04; N, 5.10.

Exainole 309 trans-trans-2-(2-Methoxyethyl-4-(1 .3-benzodioxol-5-yfl)-1-rN.N-diun- butyl)amino carbonylmethyll-pyrrolidine-3-carboxylic acid.

The title compound was prepared using the procedures described in P example 1, substituting ethyl 5-methoxy-3-oxopentanoate for ethyl 4inethoxybenzoylacetate in Example 1lA. The title compound is a yellow foam. 1

H

NMR (CDCI 3 300 MHz) 8 0.91 J=7Hz) and 0.95 J=7Hz, 6H total), 1.28-1.41 (br in, 1.45-1.63 (br mn, 4H), 2.00-2.20 (br in, 3.06 (br t, J=9Hz, 1 3.30 (s) and 3.20-3.68 (br in, 11 H total), 3.72-4. 10 (br m, 4H), 5.92 2H), 6.72 I1H), 6.82 (dd, J=1.5, 8.5Hz, 1 6.91 J= 1.5H-z, 1 MS (FAB) W/e 463 Anal calcd for C 25 H38N 2 0 5

-H

2 O: C, 62.48; H, 8.39; N, 5.83. Found: C, 62.13; H, 8.15; N, 5.69.

-195- Example 310 trans, trans-2-(4- Methoxyphenyfl-4-(1 .3-b-enzodioxol-5-yi)- 1 ethyI-N-n-pentanesulfony amino~ethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.57-58 0 C. 1H NMR (CDC13, 300MHz) 8 0.89(t, J=7Hz, 3H), 1.06(t, J=7.5Hz, 3H), 1.26-1.37(m, 4H), 1.72(quintet, 2H), 2.22-2.32(m,l1H), 2.71 -2.96(m,5H), 3.08-3.30(m,4H), 3.95(d, J=9Hz, 1H), 3.53-3.60(m, 1H), 3.67(d, J=9Hz,1H), 3.80(s, 1H), 5.97(s, 2H), 6.73(d, J=9Hz, 1H), 6.82(d, J=9Hz,1H), 6.88(d, J=9Hz, 2H),7.02(s,1H), 7.33(d, J=9Hz, 2H). MS (CDI/NH3) m/e 547 Example 311 trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)- 1 4rN.N- 0 dicyclohexylamino carbonylmethyll-pyrrolidine-3-carboxylic acid.

is The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) 5 1.0-2.0 (in, 20H), 3.0-3.1 (mn, 2H), 3.80 3H), 5.95 2H), 6.75 1 H, 6.86 (dd, 1 H, 6.95 (d, 2H, 7.04 1 H, 7.38 2H, MS (DCI/NH 3 m/z 563.

Anal calcd for C 3 3H 4 2

N

2 0 6 0.5 H 2 0: C, 69.33; H, 7.58; N, 4.90 Found: C, 69.42; H, 7.29; N, 4.78.

Example 312 trans-trans-2-(4-Methoxylhenyl)-4-(1 .3-benzodioxol-5-yli-1 -r2-(N- 1Propyl-N-tert-butoxycarbonylamino~ethyl-pyrrolidine3carboxylic The title compound was prepared using the procedures described in example 61, substituting propylamine for aqueous methylamine in Example 61 B and di -tert-b utyldi carbonate for isobutyryl chloride in Example 61C. NMR (CD3OD, 300 MHz) suggests presence of rotamers 8 0.81 3H, 1.2-1.5 (in, 11 3.78 3H), 5.92 (dd, 2H, J=1,2), 6.74 1 H, 6.84 (dd, 1 H, 6.92 2H, 6.99 (bd s, 1 H), 7.35 2H, MS (DCI/NH 3 m/z 527. Anal calcd for C 2 9

H

3 8

N

2 0 7

C,

66.14; H, 7.27; N, 5.32 Found: C, 66.,05; H, 7.36; N, 5.15.

-196- Examole 313 trans-trans-2-(4-Methoxy-3-fluorophenyfl-4-(1 1 -rN. N-di(n-butyl) amino carbonylmethyll-pyrrolidine-3-carboxylic 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 0 C. NMR (CDCI 3 300 MHz) 8 0.82 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.03-1.50 (in, 8H), 2.82 (d, J=l3Hz, 1H), 2.90-3.13 (in, 4H), 3.20-3.50 (in, 3H), 3.39 J=13H, 1H), 3.55-3.65 (in, 1H), 3.82 J=lOHz, 1H), 3.87 3H), 5.91 (dd, J=2Hz, 4Htz, 2H), 6.72 J=8Hz, 1H), 6.83-6.91 (in, 2H), 6.99 J=2Hz, 1H), 7.06 (mn, 2H1). Anal calcd for C29H37N 2 0 6 F: C, 65.89; H, 7.06; N, 5.30 Found: C, 65.82; H, 7.13; N, 5.29. Example 314 trans, trans-2-(Progvll-4-(1 .3-benzodioxol-5-yl)- 1 -(2-(N-D2rogvI- Dentanesultonylam ino~ethyl~cyrrolidine-3-carboxylic acid Examole 314A Prooyl ggntanesulfonamide Pentane sulfonyl chloride (687 mg, 4.03 minol) was dissolved in 5 mL

CH

2

CI

2 and added to an ice-cooled solution of n-propylamine (0.40 mL, 4.82 minol) and ethyldiisopropylamine (0.85 mL, 4.88 mmcl) in 5 mL CH 2

CI

2 under a nitrogen atmosphere. The reaction was stirred at 0 OC for 30 min, then at 25 0 C for 4 h. The solution was partitioned between 20 mL of 1.0 M aqeous NaHSO 4 and mL CH 2

CI

2 The organic phase was washed sequentially with 25 mL H 2 0 and mL brine, then dried (Na 2

SO

4 filtered, and concentrated in vacuo to provide 739 mg (3.83 mmcl, 95%) of the title compound as a white solid. TLC (25% EtOAchexane) Rf 0.23; 1 HNMR (CDCI 3 300 MHz) 5 0.92 J=7Hz, 3H), 0.97 J=7Hz, 3H), 1.28-1.50 (br m, 4H), 1.52-1.68 (in, 2H), 1.75-1.90 (br mn, 2H), 2.98-3.06 (in, 2H), 3.08 J=-6Hz, 2H), 4.10-4.23 (binm, 1 MS (DCI/NH 3 m/e 211 (M+NH 4 Examgle 3149B Ethyl trans. trans--4- (1 ben zod ioxol-5-yl)- 1 (2 -b rom oeth yl-2- rolyl 1vrro li din e-3ca rboxvlate The title compound was prepared according the procedure of Example 61A, substituting the compound of Example 94B for the pyrrolidine mixture.

-197- Example 314C Ethyl trans, trans-2-(Propyfl-4-( 1.3-benzodioxol-5-yl)- 1 (N-propylpentanesulfonylam ino)ethyl~pyrrolidine-3-ca rboxylate A solution of the compound of Example 314A (6.6 mg, 34 pimoI) in 0.1 mL DMF was treated with sodium hydride (2 mg, 60% oil dispersion, 1.2 mg NaH, pmol). The resulting mixture was stirred at room temperature for 15 min, then a solution of the compound of Example 189B (9.0 mg, 22 t~mol) in 0.1 mL DMVF was added, followed b y 0.5 mg of tetra-n-butylammonium iodide. The reaction was sealed under argon and stirred at 60 00 overnight. The reaction was concentrated under high vacuum, and the residue was partitioned between 2 mL of saturated aqueous NaHCO 3 1 mL water and 5 mL EtOAc. The organic phase was washed with 1 mL brine, dried by passing through a plug of Na 2 SO4, and the filtrate:.* concentrated in vacuo to an oil. 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 of the title compound as a wax.

Example 314D trans. trans-4-(1 .3-benzodioxol-5-yl)-2-(Propyl)- 1 -(2-(N-propylpentanesuIf onylam ino~ethyl)pyrrolidine-3-carboxylic acid The title compound was prepared according to the procedure of Example 710C. 1 H NMR (CDC1 3 300 MHz) 8 0.88-1.00 (in, 9H), 1.20-1.55 (br m, 6H), 1.55-1.68 (mn, 3H), 1.70-1.85 (br m, 2H), 1.90-2.16 (br mn, 2H), 2.84-3.26 (br m, 6H), 3.26-3.90 (br mn, 6H), 5.95 2H), 6.76 (d, J=-8Hz, 1H), 6.79 (in, 1H), 6.93 (br s, 1H); HIRMS (FAB) calcd for

C

25

H

4 jN 2 0 6 S 497.2685, found 497.2679.

Example 315 trans, trans-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-yb)- 1 propyl-N-dimethylsulfainoylamino~ethyfl-yrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was preapred as a white solid. m.p.59-61 0 C. 1 H NMR (CDC13, 300MHz) 8 0.79 J=7.5Hz, 3H), 1.45(sextet, J=7.5Hz, 2H), 2.22-2.31(m,1H), 2.65(s, 6H), 2.70-2.79(m, 1H), 2.85-3.04(m, 4H), 3.09-3.32(m, 2H), 3.40(d, J=9Hz, 1H),3.55 J=9Hz,1H), 3.65(d, J=9Hz,1H), 3.81(s, 3H), 5.96(s,2H), 6.75(d, J=9Hz, 1H), 6.83(d, J=9Hz, 1H), 6.88(d, J=9Hz, 2H), 7.02(s, 1H), 7.34(d, J=9Hz, 2H). MS (DCI/NH3) m/e534 -198- Example 316 trans-trans-2-(4-Methoxphenyb-4-( 1.3-benzodioxol-5-yfl-1 -r2-(Npropyl-N-r4-methoxyphenyllsulfonylamino) propyll-pyrrolidine-3carboxylic acid Example 316A Ethyl trans-trans and cis-trans 2-(4-Methoxyjhenyfl-4-( 1.3- -1 -(3-bromopropyfl p2yrrolidine-3-carboxylate A 2:1 mixture of trans-trans and cis-trans ethyl 2-(4methoxyphenyl)-4-(1 ,3-benzodiox-5-yl) -pyrrolidine-3-carboxylate (4.00 g; prepared according to example 1C), 32 ml dibromopropane, and 200 mg sodium iodide, were heated at 1000 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 (Na 2

SO

4 and the solution concentrated. The residue was chromatographed on silica gel eluting with 5:1 hexane:EtOAc. yielding*. 5.22 of the title compound.

Example 316B Ethyl trans-trans and cis-trans 2-(4-Methoxyphenyfl-4-(1 .3- -1-(3-propylaminopropyfl pyrrolidine-3-carboxylate The compound described in Example 316A (5.22 g) was heated at 800 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 (Na2SO 4 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 purification.

Example 316C trans-trans-2-(4-Methoxphenyl)-4-( 1.3-benzodioxol-5-yfl-1 -l2-(Np2ropyl-N-r4-methoxyphenyllsulfonylaminorrolyll-pyrrolidine- carboxylic acid Using the method described in example 66, the compound prepared in Example 316B was reacted with 4-methoxybenzenesulfonyl chloride in acetonitrile containing di isop ropylethylamine. The resulting product was chromatographed on silica gel (30% EtOAc in hexane), and -199hydrolyzed to the title *compound by the method of example 1D. NMR (ODC1 3 300 MHz) 8 0.83 J=7Hz, 3H), 1.40-1.52 (in, 2H), 1.56-1.70 (in, 2H), 2.00-2.11 (in, 1H), 2.40-2.51 (mn, 1H), 2.69-2.78 (in, 1H), 2.84-3.03 (in, 4H), 3.19-3.34 (in, 2H), 3.48-3.59 (mn, 2H), 3.80 3H), 3.86 3H), 5.95 2H), 6.74 J=8Hz, 1H), 6.85 J=8Hz, 3H), 6.93 J=8Hz, 2H), 7.02 J=2Hz, 1H), 7.29 J=8Hz, 2H), 7.69 J=8Hz, 2H). Anal calcd for C 32

H

38

N

2 0 8 S: C, 62.93; H, 6.27; N, 4.59. Found: C, 62.97; H, 6.39; N, 4.45.

Example 317 trans-trans-2-(4-Methoxohenyfl-4-( 1.3-benzodioxol-5-yl)-1 -r2-(Np2ropyl-N-propylsulfonylamino~propyll1Dyrrolidine-3-carboxylic acid Using the method described in example 66, the propylamino compound prepared in Example 31 6B was reacted with propanesulfonyl a chloride in acetonitrile containing diisopropylethylainine. The resuling product was chromatographed on silica gel (30% EtOAc in hexane) and hydrolyzed to the title compound by the method of example 1D. NMR

(CDCI

3 300 MHz) 8 0.85 J=7Hz, 3H), 1.02 J=7Hz, 3H), 1.47-1.60 (in, 2H), 1.65-1.85 (in, 4H), 2.04-2.16 (in, 1H), 2.42-2.57 (in, 1H), 2.72- 3.11 (in, 5H), 3.25-3.41 (mn, 2H), 3.50-3.62 (in, 2H), 3.80 3H), 5.85 (s, 2H), 6.72 J=8Hz, 1H), 6.80-6.90 (in, 3H), 7.02 J=2Hz, 1H), 7.30 (d, J=9Hz, 2H). Anal calcd for C 28

H

38

N

2 0 7 S: C, 61.52; H, 7.01; N, 5.12.

Found: C, 61.32; H, 7.01; N, 5.01.

Examp~le 318 0~ trans, trans--2-(3-Fluoro-4-methoxyphenyl)-4-(1 yl)1 -(2-(N-prop~yl-N-pentanesutfonylainino'iethyl)-o2yrrolidine-3.

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 0 C. 1 NMR (CDC13, 300MHz) 8 0.81(t,J=7.5Hz, 3H), 0-89(t, J=7Hz, 3H), 1.26-1.35(mn, 4H), 1.45(sextet, J=7.5Hz, 2H), 1.68-1-76(m, 2H), 2.25-2.33(m, 1H), 2.72-2-92(mn, 5H), 2.97-3.1 2(m, 2H), 3.1 6-3.33(m,2H), 3.43(.dd, J=3Hz,J=9Hz,1H), 3.53-3.60(m, 1H), 3-66(d, J=lOHz, 1H), 3.88(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, 1H), 6.82(dd, J=lHz,J=8Hz,1 6.92(t, J=8Hz,1H), 6.97(d, J=lHz, 1H), 7.12(d, J=8Hz, IH), 7.18(dd, J=lHz,J=l2Hz, 1H). MS (DCI/NH3) m/e 579 -200- Example 319 trans-trang-2-(4-Pyridinyl)-4-(1 .3-benzodioxol-5-yfl-1 -rN.N-di(nbutyflamino carbonylmethyll-12yrrolidine-3-ca-rboxylic acid.

The title compound was prepared using the methods described in examples 1 and 43, using methyl 3 -oxo- 3 4 -pyridyl)propanoate Am.

Chem. Soc. 1993, 115, 11705) in place of ethyl (4methoxybenzoyl)acetate. m.p. 131-132 0 C. NMR (CDCI 3 300 MHz) 8 0.82 J+7Hz, 3H), 0.88 J=7Hz, 1.05-1.50 (in, 8H), 2.90 (dd, J= 7Hz, 9Hz, 1H), 2.97 J=l3Hz, 1H), 3.00-3.25 (mn, 4H), 3.32 (in, 1H), 3.39 (d, J=l3Hz, 1H), 3.45-3.52 (in, 1H), 3.67-3.78 (in, 1H), 4.10 J=9Hz, 1H), 5.92 (dd, J=2Hz, 4 Hz, 2H), 6.75 J=9Hz, 1 6.90 (dd, J=9Hz, 2Hz, 1 7.02 J=2Hz, 1H), 7.45 J=8Hz, 2H), 8.50 J=8Hz, 2H). Anal calcd for C 2 7H 3 5

N

3 0 5 C, 67.34; H, 7.33; N, 8.73 Found: C, 67.39; H, 7.45; N, 8.61. Example 320 trans-trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yi)-1-r2-(Np-ropyl-N-diethvlaininocarbonylainino'~ethywlpyrrolidine-3carboxyljc Ag:. The title compound was prepared using the procedures described in example 61, substituting propylamine for aqueous methylamine in Example 61 B and diethylcarbanyl chloride for isobutyryl chloride in Example 61C. NMR (CD 3 OD, 300 MHz) 8 0.74 3H, 1.09 6H, 1.33 (in, 2H), 3.17 4H, 3.78 3H), 4.04 (in, 1 5.93 (s, 2H), 6.86 1 H, 7.06 (dd, 1 H, 6.94 2H, 7.04 1 H, 7.40 2H, MS (DCI/NH 3 m/z 526. Anal calcd for C29H 3 9

N

3 0 6 0.1 TEA: C, 65.31; H, 7.34; N, 7.82 Found: C, 65.33; H, 7.43; N, 8.14.

Example 321 trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yll- dimethylpiperidinyl- carbonylmethyll-pyrrolidine-3-carboxylic acid.

The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) shows mixture of isomers. 8 0.88 3H, 0.93 3H, 3.82 3H), 5.95 2H), 6.82 1H, -201- 6.89 (dd, 1H, 7.00 d, 2H, 7.03 (in, 1H), 7.47 21-, MS (DCI/NH3) m/z 495.

Example 322 trans- tra ns-2-(4- Meth oxyphenyI)-4-(1 .3-b enz od ioxol-5-yl)- I -fN. Ndi(s-butyfl)amino carbonylmethyll-pyrrolidine-3-carboxylic acid.

The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) suggests a mixture of isomers. 8 0.83 6H, 1.27 6H, 1.6 (in, 3.79 3H), 5.93 2H), 6.75 1 H, 6.86 1 H, 6.94 2H, 7.03 I1H, J=2), 7.35 2H, MS (DCI/NH 3 m/z 511.

Example 323 tra ns -tra ns- 2 -M et h oxyp he ny 1) .3 -b en zo d io xo-I-y1) 1 -[fN is Methylphenyl)-N-butylamino carbonylmethyll-pyrrolidine-3-carboxylic The title compound was prepared using the procedures described in example 1. MS (DCI/NH 3 m/z 545. Anal calcd for C3 2

H

3 6

N

2 0 6 0.9

H

2 0: C, 68.53; H, 6.79;, N, 4.99 Found: C, 68.56; H, 6.62; N, 4.71.

Example 324: tran s -tra ns -2 e th oxyp h eny 1) -4 .3 -be n zod io x oI- 5 y 1-I -rN Methylphenyl)-N-butylamino carbonylmethyl]-pyrrolidine-3-carboxylic acid.

The title compound was prepared using the procedures described in example 1. NMR (CD 3 QD, 300 MHz) d 0.88 3H, 1.2-1.5 (in, 4H), 2.31 3H), 2.8 (in, 2H), 3.14 1 H, J=1 3.3 (in, 1 3.44 (dd, 1 H, J=5,10), 3.53 (in, 1IH), 3.60 2H, 3.79 3H 3.82 (in, 1 5.93 2H), 6.74 1 H, 6.8-6.9 (in, 5H), 7.06 1 H, 7.09 2H, 7.18 1 H, 7.27 1 H, MS (DCI/NH 3 m/z 545. Anal calcd for C 32

H

3 6N206 0.8 H 2 0: C, 68.75; H, 6.78; N, 5.01 Found: C, 68.70; H, 6.67; N, 4.85.

-202- Example 325 trans, trans-4-( 1.3-Benzodioxol-5-yl)-2-(benzlomety-1

N-

dibutylam inoca rbonylmethyl)c2yrrolidine-3-carboxylic aci Example 325A Ethyl trans, trans-4- (1 Ben zod ioxo1-5-yl)-2- (ben zyloXym eth yl). 1 Ndibutylam inoca rbonylmethyl)pyr-rolidine-3-car..,pyjpte The procedures of Example lA-iD were followed, substituting ethyl 4benzyloxy-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; 1 H NMR

(CDCI.

3 300 MHz) 5 0.88 J=7Hz, 6H), 1.17 J=7Hz, 3H), 1.20-1.34 (br m, 4H), 1.40-1.56 (br m, 3H), 2.85 J=8Hz, 1 2.98-3.30 (in, 5H), 3.39-3.60 (in, 3H), 3.64- 3.75 (in, 2H), 3.92 J-l4Hz, 4.10 (two overlapping q, J=6.5Hz, 2H), 4.53 2H), 5.91 (in, 2H), 6.69 J=9Hz, 1 6.77 (dd, J=1.5, 9Hz, 1 6.91 1 MS (DCIINH 3 m/e 553 Example 325B trans. trans-4- (1 Benzo d ioxo (ben zyboLym etyl- 1 Ndibutylam inocarbonylmethyl)pyrrolidine-3-cartboxylic acid The title compound was prepared according to the procedure of Example 71C, as a colorless glass. TLC MeOH-CH 2

CI

2 Rf 0.13; 'H NMR (CDCI 3 300 MHz) 8 0.86 J=7Hz), and 0.90 J=7Hz, 6H total), 1. 15-1.52 (br mn, 8H), 2.96-3.35 (br mn, 5H), 3.50-3.75 (br m, 2H), 3.80 (dd, J=3, 13Hz, 1 3.88-4.40 (br m, 6H), 4.45 (AB, 2H), 5.90 2H), 6.70 J=8Hz, 1 6.84 (dd, J=1 ,8Hz, 1 6.93 J=1 Hz, 1H), 7.28-7.39 (in, 5H); MS (DCI/NH 3 W/e 524 Example 326 trans, tras4( -ezdool-5-y)-2-( hyd roxmethyl)-

N-

dibutylam inoca rb-onylmethyl)pyrrolidine-3-carboxylic acid Example 326A Etltrans, trans-4- 3 -Benzodioxol-5-yl)-2-(hyd roxymethyl). 1 Ndibutylaminocarbonylmethyl)pyrrolidine3carbolate The resultant product from Example 325A (128 mg, 0.232 minol) and 25 mg of 20% Pd(OH) 2 on charcoal in 7 mL EtOH was stirred under 1 atm hydrogen for 48 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 -203under reduced pressure to afford the crude product. Purification by flash chromatography (40%EtOAc-hexane) provided the title compound.

Example 326B trans. trans-4- 3- Ben zodioxol- 5-yl)-2- (hydroxymethyl)- 1 N dibutylam in o)carbo ~methylpyrrolidine-3-carboxylic acid The title compound was prepared according to the procedure of Example 710C.

Example 327 trans. trans-4-( 1. 3-Benzodioxol-5-yl)-2- (N-methylpropenam id-3-yl)- 1 Ndibutylam inoca rbonylmethyfl)1yrrolidine-3-carboxylic acid h ~Example 327A..: Ethyl trans. trans--4- (1 Ben zod ioxol-5-yl)-2- (form yl)- 1 Ndibutylaminocarbonylmethyl)pyrrolidine-3-ca rboxylate The title compound is made by selective oxidation using the Swemn oxidation with DM50S, oxalyl chloride, ethyldiisopropylamine or using the Dess- Martin periodinane) of the compound of Example 326A.

Example 327B Ethyl tras trn-4(1.-Ben zod ioxol-5-yl)-2- (0-te rt- butyl prope noat-3-yl)- 1 N dibutylaminoca rbonylmethyfloyrrolidine-3-cprboxylate The title compound is produced by condensing the compound of Example 327A with tert-butyl triphenylphosphoranylidine acetate in CH 2

CI

2 solution.

Examlle 3270 Ethyl trans. trans-4-(1 .3-Benzodioxol-5-yfl-2-(D2ropenoic acid-3-yl)- Ndibutylaminocarbonylmethyl)o2yrrolidine-3-carboxylate The title compound is produced by reacting the compound of Example 327B with trifluoacetic acid in CH 2

CI

2 -204- Example 327D Ethyl trans. trans-4- 1.3-Benzod ioxol-5-yfl-2-(N-m ethyl progena m id-3-yl)- 1 Ndibutylaminocarbonylmethyflp1yrrolidine-3-carboxylate The title compound is produced by condensing the compound of Example 3270 with methylamine hydrochloride in the presence of a carbodiimide Nethyl-N-(3-dimethylam ino)propylcarbodiim ide, DCC).

Example 327E trans. trans--4-( 1. 3-Benzodioxol-5-yl)-2-(N-methyllropenam id-3-yl)-1 Ndib utyl am inoca rbonylmnethyflpyrro Iidi ne-3-ca rboxylic acid The title compound is produced by reacting the compound of Example 327D with lithium hydroxide according to the procedure of Example 710C. Examlle 328 trans.trans--4-( 1.3-Benzodioxol-5-yl)-2-(1 -hydroxy-2-propen-3-yl)-l1-((N. N- dibutylam inocarbonylmethyl)pyrrolidine-3-carboxylic acid Example 328A Ethyl trans. trans--4-( 1.3-Benzodioxol-5-yl)-2-(1 -hydroXY-2-propen-3-yl)- 1 Ndibutylam inocarbonylmethyflo1yrrolidine-3-carboxcylate o. o The title compound is produced by reacting the compound of Example 3270C with borane methyl sulfide complex.

Example 328B trans. trans--4-( 1.3-Benzodioxol-5-y)-2-(1 -hydrox-2-p2ropen-3-yi)- 1 Ndibutylam inoca rbonylmethyflpyrrolidine-3-carboxcylic acid The title compound is produced by condensing the compound of Example- 328A with lithium hydroxide according to the procedure of Example 710.

Example 329 trans. trans--4- (1 .3-Benzodioxol-5-yl)-2- (N-benzylam inomnethyl)- 1 Ndibutylam inocarbonylmethyl)gyrrolidine-3-carboxylic acid -2 Example 329A Ehltans. trans--4- (1 Ben zodioxol-5-yl)-2- (N-benzylam inomethyl)- 1-(.N dibutylam indca rbonylmethyl)pyrrolidine-3-ca rboxylate The title compound is produced by condensing the compound of Example 327A with benzylamine in the presence of sodium cyanoborohydride in ethanol.

Examrole 329B trans. trans--4-( 1.

3 -Benzodioxol-5-yl)-2-(N-benZylpminom ethyl)- 1 Ndibutylaminoca rbonylmethyljpyrrolidine-3-carboxylic acid The title compound is produced by reacting the compound of Example 329A with lithium hydroxide according to the procedure of Example 71C.

Example 330: k ~trans. trans--4-( 1.3- Benzodioxol-5-yfl-2-(N-acetyl-N..benzylam inomethyli- 1 Ndibutylaminocarbonylmethyl)oyrrolidine-3carbpxylIcad Example 330A Ethyl trans. trans--4-( 1.3-Benzodioxol-5-yl)-2-(N-acetyl-N-benzylam inomethyl)- 1- N -dibutylam in oca rbonydm ethyl) pyrrolid ine-3-carboxylate The title compound is produced by reacting the compound of Example 3294A with acetic anhydride in the presence of pyridine or triethylamine. Example 330B trans, trans--4-( 1.3- Benzodioxol-5-yl)-2-(N-acetyl-N-benzylam inomethyl)- 1 Ndibutylam inocarbonylmethyl)pyrrolidine-3-carboxylic acid The title compound is produced by reacting the compound of Example 330A with lithium hydroxide according to the procedure of Example 71C.

Example 331 trans. trans--4-( 1. 3-Benzodioxol-5-yl)-2-(ethynyl)- 1 Ndibutylam inoca rbonylmethyflpyrrolidine-3-carboxylic acid -206- Example 331 A Ethyl trans, trans--4-( 1.3-Benzodioxo-5-vl)-2-(ethynyl)- 1 Ndibutylaminoca rbonylmethyflpyrrolidine-3-carboxylate The title compound is made by employing the procedure of Corey and Fuchs (Tetrahedron Lett. 1972, 3769-72), using the compound of Example 327A.

Examlle 331 B trans. trans--4-( 1. 3-Benzodioxol-5-yl)-2-(ethynyfl- 1 Nd ib utylam i noca rbonylmrnethyl) yrrol i din e-3 -ca rboxyLcacid The title compound is produced by reacting the compound of Example 331 A with lithium hydroxide according to the procedure of Example 710C.

Example 332 trans. trans-4-(1 .3-Benzodioxol-5-yF)-2-( 1 -pentynyl'-l1-((N. N- 115 dibutylam inocarbonylmethyflpyrrolidine-3-carboxylic acid Example 332A Ethyl trans. trans--4-( 1. 3-Benzodioxol-5-yl)-2-(pentvnyl)- 1 Ndibuiylamnin oca rbon ylmethyl) pyrro Iid ine-3-ca rboxcyl ate 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. Org. Chem. 1989, 54(15), 3618-24). Examlle 3328 trans. trans--4-( 1.3- Benzodi oxol-5-yP)-2- (1 -pentynyl) 1 N dibutylaminocarbonylmethyi)pyrrolidine-3-carboxcylic acid The title compound is produced by reacting the compound of Example 332A with lithium hydroxide according to the procedure of- Example 71 C.

Example 333 trans-trans-2-(4-Methoxphenyl)-4-( 1.3-benzodioxol-5-yl)-l1-[2-(2.6dioxopiperidinyl) ethyll-pyrrolidine-3-carboxylic acid The compound of example 61A 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 -207glutarimide is hydrolyzed to the title compound by the method of example I D.

Examlle 334 trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yfl)-1-rN.Ndi~h enylaminoca rbo nyl methyll-12yrroi din e-3-carboxyl ic acid.

The title compound was prepared according to the procedures described in Example 1. 1 H NMR (300 MHz, CD 3 OD) 5 2.83 (dd, 1, J 8.1, 2.99 1, J 15.4), 3.19 1, J 3.49 1, J 15.3), 3.51 (dd, 1, J 4.6, 3.57 (in, 3.79 3.85 1, J 5.90 (s, 6.71 1, J 6.84 (mn, 7.04 1, J 7.14-7.16 (in, 6), 7.19-7.34 (in, MS (DCI/NH 3 m/z 551; Anal Calcd for C33H30N2O6.0.65H20.0.35C 2 H5OCOCH 3 C, 69.77, H, 5.77, N, 4.76. Found:: C, 69.75, H, 5.55, N, 4.64.

Examn~le 335 tran s -tra ns-2 -M et h oxy12h en y1)- 4 .3 -b en z o d i0xo1- 5 -y I -TfN. .N diisopropylaminocarbonylmethyll-pyrrolidine-3-carboxylic acid.

The title compound was prepared according to the procedures described in Example 1. 1 H NMR (300 MHz, CD 3 OD) 8 0.95 3, J 1.24 3, J 1.30 6, J 2.85 1, J 12.5), 3.04 (dd, 1, J 8.1, 3.14 1, J 3.32-3.55 (in, 3.63 (mn, 5.92 6.75 1, J 6.85 (dd, 1, J 1.7, 6.93 (in, 7.02 (d, 1, J 7.35 (in, MS (DCIINH 3 in/z 483. Anal Calcd for C27H34N 2

Q

6 .0.65 EtOAc: 65.86, H, 7.32, N, 5.19. Found: C, 5.74, H, 7.26, N, 5.52.

Example 336 trans, trans-2-(3-Fluo ro-4-m ethoxyphenyl)-4- 1 .3-benzodi 1 -(2-N-propyl-N-butanesulfonylainino)ethyl)-pyrrolidine-3-carboxylic Using the procedures described in Example 313 and Example 66, the title compound was prepared as a white solid. in.p.65-66 0 C. 1H NMR (CDCI3, 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 2.72-2.94(m, 2.97-3.12(m, 2H), 3.19-3.46(m, 2H), 3.44(d, J=9Hz,1H), 3.53- 3.60(m, 1H), 3.67(d, J=9Hz, 1H), 3.89(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, -208- I1H), 6.82(d, J=8Hz, 1 6.92(t, J=9Hz, 1 6.97(s, I1H), 7.12(d, J=9Hz, 1H), 7.18(d, J=l2Hz, 1H). MS (DCI/NH3) m/e 565 Example 337 Using methods described in the above examples, the compounds disclosed in Table 1 can be prepared.

Table 1 1 2. 3.

-209- 0 Table 1 cont.

R

HCF2 *r'.OT 8.

HccO 6.

9.

12.

15.

18.

02N,,:: 14.

0 16.

co0 19.

17.

20. 21.

-210- 0 0 22.

F3C~~ 28.

FH

2 N,,o;

F

2 0 0 31.

F

2

H-IC...S,

F

2 0 0 34.

Table 1 cont.

R

0 0 23.

26.

29.

FH

2

C.

F

2 0- 0 32.

F

3 C.

F

2 0 0 35.

0 0 24.

F

3

C.L

0 0 27.

F

2 H '0 33.

F.

3 C-

D-

F

2 0 0'" 36.

looh o o*o.

38. 39.

-211- Table 1 cont.

R

F

3 H3C~r 6'o 43.

41.

0 44.

F00~ 91% zsc 42.

H3C s r ocy 0 46.

49.

52.

01C 0 47.

48.

NV

53.

56.

0 59.

p 54.

N"~C

57.

0 -212- Table 1 cont.

R

0 0~" crw", 64.

olw- 0 67.

0ro, 65.

0 oy" 68.

71.

0 66.

69.

72.

~0 0 78.

CC

C

C

C. C C. a

C

0 0 74.

0 77.

A6 76.

-213cr'-Y-' 79.

o0 0 82.

88.

Table 1 cont.

R

80.

0 83.

(K

86.

89.

H

3Colo 81.

87.

a a a.

a. a -92. 93. 96.

-2 14- 97.

100.

0 103.

0 106.

CH

3 109.

112.

Table 1 cont.

R

0 98.

101.

0o 0 104.

H roo 107.

CH

3 r 110.

113.

qH3 <o 60 0 99.

oy 102.

0 105.

H (NNY 108.

111.

114.

YH3 crY-0 0

OS

0 0 0 0 00006S 0 0

OS

0@ 0 0060 00 00 0 0060 1 115.

116.

117.

-215- -Th0 118.

121.

124.

127.

130.

133.

Table 1 cont.

R

119.

1 PP 122.

0

F

125.

cl 128.

OCH

3 131.

120.

123.

126.

crOC 129.

H3C0Q 0 132.

C

C

GC

C C

*CC.

CC CC 134. 135.

-216- Table 1 cont.

R

137.

1N8 138.

136.

139.

-Th o~ 142.

o0 145.

148.

H

3 C 0 0 d' o 140.

-Th 143.

146.

CH3 149.

141.

144.

147.

r 150.

0N~ 151.

152. 153.

-217- Table 1 cont.

R

GrY~oo

R

9 Cr-- 0 154.

155.

R

0 156.

0 159.

0 157.

0 7N 0 158.

161.

16 162.

160.

163. 164.

2;Lpo 165. r r 0 166.

F3 FF6o 167.

168.

-218- F3 O 0, 169.

Y

0 0 172.

175.

0 0 178.

181.

0 0 187.

Table 1 cont.

R

170.

0 0 173.

Y

F

3

C-.N%

F F 0 0 176.

179.

0 0 18.

0 *0 18.

Y

0 0 171.

00 174.

177.

FF 0 o 180.

*0 183.

0 0 186.

H3Ca,>,

F

3

C%N..

F F 0 '*0 189.

so -219t- 190.

193.

196.

FF 6-0 199.

F F F3 202.

Table 1 cont.

R

H

3 Cc(>,

F

3 S- 191.

0 0 194.

197.

200.

R

F F H 3 Cal-*, 6 ,0 192.

195.

F3C~~ "o 198.

201.

r r r r 203.

204.

y y 205.

206.

207.

-220-

R

208.

y 211.

Table 1 cont.

R

KYNC

209.

212.

215.

OH

Y

218.

CF

3 221.

R

210.

Ccy- 213.

216.

K

219.

F

3 222.

214.

I-Crhr OH0 217.

OH V 220.

r r

E

-221-

R

qF3"r 223.

226.

229.

%cNv 232.

235.

Table 1 cont.

R

F

3 Y

OQNC

224.

227.

y 230.

233.

y 236.

R

CF

3 225.

228.

Kr 231.

234.

237.

4* -222- Table 1 cont.

R R 238.

y 241.

Ptr244 244.

239.

242.

F 245 245.

240.

K

243.

246.

K

249.

252.

r r r r r 247.

V

250.

248.

251.

-223-

R

253.

256.

:LN O 259.

Table 1 cont.

R

y 254.

257.

R

NCN/

255.

Cd-N 0kx 258.

K

261.

264.

y 267.

260.

262.

265.

263.

y 266.

-224- 268.

271.

NC 274.

274.

Table 1 cont.

R

OH>

269.

272.

0 275.

278.

281.

cF3 270.

273.

F 7N 276.

y N 0 279.

277.

282.

282.

280.

-225- Table 1 cont.

R

R

283. r 283.

284.

286.

289.

C.N 0 292.

y 295.

y 287.

290.

293.

296.

.N 0 285.

'N 0 288.

l~ 4 Tir N 0 291.

y 294.

297.

298.

301.

304.

307.

-226- Table 1 cont.

R

N0 299.

ly 302.

JlNO 305.

308.

y >JNMor 300.

y 303.

v 306.

309.

312.

S

S.

a S

S

555 y 310.

311.

-227- Table 1 cont.

.R

v -jxra r N 0 313. 314.

N 0 316.

317.

319.

315.

318.

0 321.

o 324.

327.

a a. a.

a a a a.

a.

a a a a.

a..

a *aa.

320.

323.

322.

325.

326.

-228- 328.

331.

Table 1 cont.

R

329.

332.

Ir 335.

330.

)I)

kl o 333.

336.

336.

a a a. a a a. 334.

337.

340.

338.

339.

)I)

341.

342.

-229- Table 1 cont.

R

343.

346.

349.

344.

347.

v 350.

y 353.

R

y

-CN

345.

348.

y 351.

354.

y

A"

357.

9O 4 *4 4 4*a* *4* 352.

355.

355.

356.

-230- Table 1 cont.

358.

359.

360.

361.

362.

363.

K-

364.

Iy

-N

365.

9e..

366.

367.

370.

368.

N

371.

94 368.~ SS 372..

-231- Table 1 cont.

R

y 373.

374.

376. 377.

375.

378.

y 381.

y 380.

379.

0 0*

S

S

0

S

6. S

S

S.

0S 50 *555 55 S *005 382.

383.

N U-1-A~ 384.

JN

385.

386. 387.

-232-

R

y o1lN 388.

391.

Jl#N 394.

"*I

397.

400.

Table 1 cont.

R

y 389.

392.

395.

R

390.

393.

396.

to It I t o to to: t

*S.*S

398.

399.

401. 402.

-233- Table 1 cont.

R R 403.

406.

409.

412.

415.

404.

407.

410.

413.

416.

405.

408.

411.

V

414.

417.

o oo o *o o* o -234- Table 1 cont.

R

7-/ FL~-r~ 418.

419.

'COOEt 421. 422.

-NO

2 424.

A,

427.

v

CN

430.

NO

2 425.

cN 428.

02."1~ COOEt 420.

NO

2 423.

NO

2 426.

42cN 429.

r r u 431. 432.

-235- Table 1 cont.

R

O32NO#r 433.

0 436.

)-Ir 439.

442.

445.

434.

0 437.

N0 440.

435.

0 438.

441.

444.

Axyv a-r r r ro 443.

446. 447.

448.

F&O

451.

454.

-236- Table 1 cont.

R

'c? 449.

452.y 452.

r 450.

4C 453.

moo 456.

456.

r r 455.

0 457.

MeO N o 0 458.

MeO 0 459.

460. 461. 462.

-237- Table 1 cont.

R

463.

464. 465.

466. 467.

468.

M4 0 470.

469.

471.

372. 473.

474.

ZOCY

475.

476.

476. 477.

-238- Table 1 cont.

r" iIVT 0 478.

cl lik~ 0 481.

0 484.

487.

490.

490.

Ca 479.0 0 482.

485.

F

0 488.

0 0 480.

ci) y 483.

486.

r 489.

F~L~n/0 491. 492.

-239- 493.

496.

Table 1 cont.

R

0 494.

497.

500.

500.

0 495.

0 498.

501.

504.

499.

r r r ri r 502. 503.

0 505.

506. 0 MeO o 507.

507.

OMe 0 508.

-240- Table 1 cont.

R

OMe 0 509.

OMe 0 512.

OMe 0 510.

513. 511.

OMe 0 OMe 514. 515.

OMe 0 516.

m eooq OMe 0 mo%~ OMe 0

V.

517. 518.

OMe 519.

OMe 0 OMe 0 ome 521. 520.

522.

-241- MOQN14 523.

OMe 0 526.

529.

532.

Table 1 cont.

R

0_ 0 524.

527.

y 530.

533.

525.

528.

531.

BrN<r 534.

r 535 535.

F 0* 536. 537.

-242y 0~Z~ 538.

540.

544.

Kr "Or 547.

V

B)QOO

550.

Table 1 cont.

R

539.

542.

545.

)I)

548.

551.

543.

y 546.

549.

552.

-243- 553.

N

556.

F)OYNC

559.

y 562.

565.

Table 1 cont.

R

y 554.

557.

BryY 560.

563.

v Br~is y 555.

558.

Br~y~ 561.

Br yN{ 564.

F

566. 567.

-244- Table 1 cont.

R R 568.

FY'-

571.

F

574.

0 577.

0 580.

(2c 0 583.

569.

572.

0 575.

y 0 578.

0 581.

&rr 0 584.

FY

570.

F'

573.

0 576.

0 579.

v 0 582.

0 585.

9* -245- Table 1 cont.

R R 0 586.

589.

y 592.

595.

Sr? 598.

601.

0 587.

590.

593.

596.

'rV 599.

602.

0 588.

591.

594.

597.

y

OTV

600.

603.

-246- Table 1 cont.

R

H

SH

0 14.5 604.

605.

H

0 606.

Ht~ 607.

608.

611.

614.

609.

0~ 610.

612.

H

615.

S

S.

S. S 613.

H

ON_

616.

617.

618.

619.

6H 0 Jo,

H

620.

621.

-247- Table 1 cont.

R

623.

623.

H

6&4.

624.

622.

625.

625.

628.

631.

634.

y 637.

626.

H

629.

632.

635.

638.

627.

H

630.

633.

636.

639.

a a a. a a. a 640.

ulr 0 643.

0 646.

-248- Table 1 cont.

R

0 641.

NcXr 0 644.

642.

0 645.

0 648.

647.

9r

C

C

C. C C. C 9***C 650.

649.

652.

651.

0 653.

654.

-249- Table 1 cont.

R

655.

656.

657.

658.

659.

660.

9. 4 S 9 9*

S

9* S.

S

9.5.

Se 9 9 *995 9 99 S S S 99 59 S 9 *695 *9 6 @9 @9 9

S

661. 662.

663.

666.

664. 665.

4 Q#NrfY 667. 67.668. 669.

-250- Table 1 cont.

R

R

0 yx~ 670.

673.

676.

0 679.

6 682.

671.

672.

k~QrY0 675.

674.

goes 0 0

V.

0 0

S

0 0 *0

S

0 0S 0 0 S. 0 0 0S

S

@0555 0 677.

678.

680.

681.

683.

684.

-251- Table 1 cont.

R

y 685.

688.

691.

694.

607.

607.

686.

687.

690.

689.

oo :o::2 o ooo 1.

692.

693.

695.

698.

696.

69MeO 9.

699.

-252- Table 1 cont.

R

7 701.

700.

0 703.

706.

0 709.

0 702.

704.

707.

0 710.

0 713.

705.

0 708.

00 711.

-0 712.

0 0 714.

6*> 715.

-253- Example 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 prepared.

Table 2A

,COOH

OCH

3 R-

,.COOH

3.

3

COOH

4.

.COOH

F

,COOH

R-6.

6.

r r

MOMO

SCOOH

7.

1 7.

F

,COOH

8.

-254-

F

R-

.COOH

Table 2A cont,

MOMO

-ICOOH

F

MOMO

j\OCH,

OCH

3

.COOH

COOH

OCH

3

'OCH:

MOMO

,COOH

OCH3 fl-N

CO

0

OCH

3

F

ICOOH

0>

OCH

3 18.

OMOM

fl-N 40CO0H 0 19. OCH 3 -255omom

.COOH

0 22. 0 0

OMOM

R- *COOH 0 28.

OMOM

,.COOH

Table 2A cont.

0CH 3 R-

OCOOH

23. 0

OCH

3 R- *COOH 26. 0

OCH-

3 1,

_COOH

29.

F

R-

COOH

a

OCH

3

F

R-N *.COOH qI 32. 33.

-256- R-

ICOOH

*COOH

R- OO

OCH

3 omom R-N 0

OCH

3 Table 2A cont.

CH

3

.*COOH

R-

OCH

3 R-N 0 38. OCH,

F

R-

36.

OCH

3

.COOH

IOCH

3

F

R-N 0

OCH

3 42.

F

S. S.

.COOH

MOMO

.COOH

49. .I -257- Table 2A cont.

OCH

3 %.C00

R-

47.

R- COOH 0 50. 0>

,.COOH

R-/

53.

F

R- .eCOOHj 48.

.COOH

.cooH *00N 3 -258- Table 2A cont.

63.

R-N

\%OCH

3

OCH

3

-COOH

68.

.COOH

67.

-259-

~,COOH

0

I

OCH

3

~COOH

73.-) Table 2A cont.

,COOH

71. F

OCH

3

COOH

,*COOH

R-

74. 0

COOH

R-

OICOOH

77.

H

3

COOH

COOH

75. 0

OCH

3 0 '-CO0H 78.)

OCH

3

.OH

81.

S.

OCH

3

Q'COOH

R-

OOOH

79.

-2 Table 2A cont.

OCH

3

OH

R-

.COOH

84.

OCH

3

OH

1- R-

,COOH

0 00HH

OICOOH

86.

OCH

3 0OCH 3 0CM0 -261- Table 2A cont.

OCH,

F

ocl OH 3

OCH

3 0 0 R- 01 Z: PF-N OCOOH R-

COOH

F 1

NOCH

3 0N 94. 95. OCH 3 96. 0i' F F F /c~OCH3 /H

O'CH/

*.COOH ,CCOOH A- *COOH 0 F F F OC301

OCH

3 H0 3 eC00H OCOOH .COOH R-

R

100. -101. U102.

F 143C0 H300c .COOH

COOOO

A-R PN 103.10.15 104. 105.

-262-

H

3 F 106. 0 Table 2A cont.

H

3

CO

R

*COOH

107.

H

3 CO

F

,.COOH

110.

F

.OOH

113.

H

3 00

F

0cO 108.

H

3 CO

F

R-

,COOH

OCH

3 111. OCH3 109.

R- ICOOH 112.

IOOOH

115.

R-N

CO

117. 0 R-

.COOH

IN

,COOH

118. 18.119. 120.

-263- Table 2A cont.

.COOH

CH

3 R-

-*COOH

124. 0 1'COOH 127. 0

,COOH

130.

OCH

3 R-

COOH

1 0 125.

OOCH

3 R-

*PCOOH

128. 0 0 131. 0

OCH

3 R-

,COOH

126.

OOCH3 R-

#COOH

1 0 129. 0

OH

R-N

,.COOH

1 0 132. 0

S

S.

SCH 3 133.

OCH

3 R-N

OCO

136.

0CH 3 4PCOOH 139.

.OCOOH

142. 0-- -2 64- Table 2A cont.

HC,.

PH,

N

R *.COOH 134. 0>

OH

3

O.

137.

0CH 3 5 COOH R-N 140. o

OCH

3 R-0 143. N 0CM 3 R-

COOH

135.

0CH 3 138.

OCH

3 R-

M.COOH

141. 01

OCH

3

R-C

H

3 00 N 144.

a a a, a. a a a.

a a a a -265- Table 2A cont.

'COOH

145.

F

4,COOI4 148.

F

A- *CJOOH 151. OC13 146. trH

CH,

F

O- ICOOH

H

3 C0

OCH,

149.

F

A-N 'GOOH 152.

F

R-

OPCOOH

147.

F

*,COOH

R- N 150.

OMOM

A-

OIPCOOH

153. *s

S.

S

S

S. 55

S.

55

S

55.555 S S

SO

S S 55.5

OMOM

4.OOOH

R-

OMOM

*.OOH

RCR

156.

154. 15 155.

-266- Table 2A cont.

157. OCH 3

CHI

3 k CH3 3 A-0 160.

OCH

3 0H pr I.CO0H 163.

OCH

3 A-N COOH 158. F

OCH

3 R-

#OCOOH

159. 0

,CCH

R-N

OCOOH

H

3 C

CH

161.

162.

164.

H3C 165. OCH 3

MOMO

H

R-N

168. 0 es S S. 0 0@ 0

S.

SS OS 5@5*

S

S

*0 @5 06 0 Sees

S

OSSe*e

S

IO S S S

SO

0@ S S @0 0 S S 5* 5 OS@e 0

S

OOSOO.

166. 17 167.

-267- Table 2A cont.

F

H

N

169.

H

172. 0

F

H

~fN 176.

F

H

171.

MOMO

174.

F

R-

N

177.

C

MOMO

H

'iC N R-

N

178.

IN

Rjk.

OCH

3 180.

0OCH 3 179.

-268- Table 2A cont.

MOMO

H

3 R-N

H

j.0% 0) 31. 0) 182. -183. 0~ F MOMO iN- 0 H R-H H- H 3 04 0 MOMO

F

RN N CH 3 N H

HH

37. 0 188.18. F MOMO ~0 00

CH

3

C

NNe-CH 3 F- H N H

H

190. 191. 192.

-269- Table 2A cont.

0 0

S.

N( Cl-H 3

H

0 0 N CH 3

H

193.

194.

195.

IN OCH, 197.

MOMO

200.

A

A

H

3 00 -O trH 2

CH

3

H

202. 0 203. 24 204.

U-

Table 2A cont.

0> 207.

?H3 os' hkCH, 206.

205.

208.

H3

,COOH

0 211. OCH 3

H

3 C

OCH

3 k\h0

*,.COOH

214. 00H 3 209.

210.

F

q*.COOH $0 212. OCH 3

COOH

215. OCH 3

H

3

C

1

OCOOH

0 213. OCH 3 0* 0

C

0*00*C 216.

-271- 217.

EtO F

.COOH

Ft- 220.

EDO F 223.

Table 2A cont.

DtO F

.*.OOOH

218.

EDO F

COOH

221.

EtO F

COOH

OCH

3 224.

EtO F:

.COOH

'0 219.

EtO F

,.COOH

222.

0 225.

*,COOH

C

227' o 228.

226.

-zlz Table 2A cont.

0 0 COO

H

229.

H

3 0CH 3

,COO

0 232.

H

3 0CH 3 e.COOH 235.

H

3

COCH

3

.,COOH

238.

OCH

3 0 0 .c0H 231. OCH 3 230.

H

3 C 0CH 3 4 0 233.

H

3 C 00)IOH 3 236.

0,0 qC> i, 0 239.

H

3 c OCH 3 'd0 234.

H

3 C 0CH 3

.,COOH

237.

*0 0 0 0,0

*.COOH

'~0 240.

-2 73- Table 2A cont.

00

.*COOH

242.

241.

244.

245.

OCH

3 0,0 .*COOH 0 0C 243.

H

3 1CF F h 246.

H

3

C

R-N

249.

H

3 -hF

COOH

252. OCH 3

H

3

F

4

,COOH

R'0

H

3 C F

COOH

z 0 V 247.

248.

H

3

F

*bCOOH

R-N

250. 251.

-274- Table 2A cont.

F F '0 253.

F F

.COOH

256.

F F

.COOH

R-N 0 '00 259. OCH3 F F q

.COOH

254.

F F

COOH

~0 257.

F F q

,COOH

255.

F F

,,COOH

258.

COOH

RN

0 261.

a 260.

262.

*.COOH

263.

q.COOH '0 265. 267.

264.

265. 267.

-2

F

,,COOH

R-

N

'0 268.

II.COOH

271.

Table 2A cont.

CH

'0 269. 270.

273.

OCH

3 272.

4 ,COOH *COOH

R-

0 ,0 274. 275.

276.

J

COOH

279.

277.

277. 278.

-276- Table 2A cont.

280.

281.

JCOOH

R-

'0 282.

PPOOH

A- 285.

283.

eCOOH 286.

COOH

R-

289.

284.

5 #COOH

R-

287. OCH3

**COOH

288.

290.

#COOH

R-~

291.

COOH

R-

OCH,

294.

a.

JCOOH

292. 23 293.

-277- Table 2A cont.

ECOOH

K-a 296.

4

.PCOOH

R' ~0

J#OOOH

297.

295.

298.

299. 300.

.,COOH

R-N

303.

301.

OCH

3 302.

FCOOH

Ft- 304.

R-N,:3.:COOH

ZO

306. a..

305.

-278- Table 2A cont.

cOOH .CflO OOO 0 Pr R-309.

307. 308. OCH 3 .COOH ,,COOH ,C0 R- R R 310 311 312 ~.COOH -C00H ,COOH ,,COOH 0 -~R0 R- R

R-

31. 31. 318. *C O H_ C 0H CoO H 321.

319. 30 320.

-2 79- ~~0 7b,.COOH

R'

CO

'0 325.

Table 2A cont.

a h

.COOH

323.

326.

328.

,.COOH

0 331.

'I'

329.

OH

~.COOH

'0 332.

335.

0

RI

324.

327.

O*COOH

330.

OCH

3

.OCOOH

333. ~~i

OOH

336. 334.

.bCOOH ',0 337.

-2 Table 2A cont.

4pCOOH '0 338.

339.

,0 0 '0 342. ocHM 3 340.

341.

'0 343.

S. 345.

344.

347. 348.

346.

OCOOH

'0 349.

H

3

H

3

CF

h 0 ,9 ti 3-CH 3 Ho '0 350.

51.HC -281o 0 0 ,9

CH,

H

352.

-0 h 0 0 0

-CH

3 H C 0 '~0 355. OCH 3 0

/H

0 358.

o 0 W

~NH

361.

OCH

3 Table 2A cont.

HC F 0

H

OCH

3 353.

H

3 C F A l NH 0 356.

H

3

F

0

OCH

3 359.

H

3 0 N- S-CH 3 H 1 0 362.

EtO0 0'CH~

H

3 35.

OH

EtO F

OCH

3 57.

3L.CH 3 H3H 0 363.

-2 82-

H

3 h 0 SCH 3 N4.

Table 2A cont.

H

3

C

0 h 0 Q

H

~0 365.

H

3 368.

H

3 c 1~0 371.

SCH

3 5H 366.

367.

H

3

C

h -_NH '0 370.

H

3 LgNH

H

3

C

h NH 369.

H

3 372.

0 k h 0 0

CH

3

H

Ft 0'it*

S

S.

S

a 9 9 S S a. a 4

S

373.37.35 374.

375.

-283- Table 2A cont.

H

F~r0 378.

376.

377.

379.

380.

381.

382.

383.

N-

~NH

384.

L NH 387.

@6 6 6

S.

6* 66 6 6*6* 6@ 666@

S

S

*6 9 S 6 *5 56 *6 6 66 66@S 6 I S 656*69 _tNH x 0 385. 386.

Table 2A cont.

388. 389.

*NH

391.

F

3

,.COOH

394.

~CH3 H 0 '0 390.

F

3

J,COOH

R--

393.

F

3

,,COOH

R-N

396.

392.

0O 0 0* 0 00 0 00 6@ SO 0000

S

55.5

S

OS

51 0

S

S. 0 *5 55 0O S 5.5.

05 S 0@ 5S 0

SOSI

0500 0

S

000005 0 395.

397. 398.

399.

F

2

CF

3

COOH

0 400.

F

2

CF

3 403.

kF 2

CF

3

OOOH

'0

OCH

3 406.

-285- Table 2A cont.

F

2

CF

3

OOH

'0 401.

F

2

CF

3 C0-H 00 407.

,,COOH

410.

F

2

F

3

*.COOH

402. o0 405.

408.

411.

409.

412.

412. 413. 44 414.

-286- Table 2A cont.

COOH

~0 416.

I,

COOH

415.

417.

_COOH

420. 418.

419.

421.

422.

423.

.COOH

R-N 0 ~0 425.

424.

426.

427. 427. 428. 49 429.

-287- 4p COOH '0 430.

JCOOH

R- 436.

Table 2A cont.

0O 432.

431.

00 435.

434.

437.

438.

J

COOH

'0 441.

439.

440.

442. 42.443. 444.

-288- Table 2A cont.

445.

446.

,.COOH

'0 447.

4

,COOH

450.

'~0 448.

449.

451.

0 452.

C00H '00 453.

S

.5555.

COOH

R-9 N -s ,~00 454.

455. 46 456.

-289- Table 2A cont.

~,COOH

459.

458.

457.

462.

460.

461.

S.

4*

S

S S 463.

465.

464.

-290- 0 1.

0 4.

0 7.

0 0 Table 2B

R

o 0 2.

5.

YY8? 8.

00~ oy" 0 11.

14.

H3C Q 0" 0 3.

6.

N

9.

00 12.

r r r 0 0 18.

0 -Thi~ 00o 0 f -291- 22.

H

3 N%, 00 28.

F

2 6' 0 31.

F

2 0 34.

Table 2B cont.

R

H

3

C

23.

0 0 26.

FH

2

C>.L$

6. o 29.

FH

2 C 4

F

2 0 0 32.

HCQ(%

24.

27.

FH2r-,NSr 0 30.

F

2 6* o 33.

F

3 C l S

F

2 6-0

F

3

C..

F

2 0 0 36.

-11" 0 39.

-292- 0 0 43.

F3OQ%.

1 c 3 0 46.

Table 2B cont.

R

0 0 44.

00 47.

F

3

CQ~

0 0 H3 o 4 48.

49.

52.

58.

50.

53.

00 51.

54.

57.

-611o r r 59. -293- Table 2B cont.

R

61.

OCH

62.

HC 0d- 63.

64.

orf 67.

9H3 73.

o 68.

YH

3 r' 71.

o0 74.

~s-Th 66.

69.

72.

r o r 0 O* 0 78.

-294-

R

6'o 79.

do 82.

F F 0 0 88.

F

3 Q, 00 91.

F3C 94.

97.

97.

Table 2B cont.

R

0 0 80.

F

3

C&

F F 0 83.

00 86.

0 0 89.

Y

F3%~L- F F 92.

00 95.

F F 98.

R

doo 81.

F

3 CO0-.s 0O 0b 84.

Y 0 87.

y 0 0 93.

-Th FF S96.

H

3

COO>

99.

a -295- H3Cal'*) 100.

o* 0 103.

H

3

CO->

Table 28 cont.

R

H

3 C0n 00 101.

00 104.

H

C0> F3C-..Io~ 0' 106.

107.

109.

112.

F F 00 102.

FH

3 C0'T F F 0-0o 105.

0 0 108.

0 0 111.

F,

00 114.

00 00 110.

00 113.

A~s"~ 115.

116.

117.

-296-

R

0 118.

121.

124.

y 127.

127.

Table 2B cont.

R

)y 119.

y ONOaC 122.

125.

avos0 128.

OH

130. 132.

R

CK"a 120.

y 123.

126.

K

129.

129.

130.

132.

-297- 133.

136.

F*'

ovrA Table 2B cont.

R

134.

ICF

3 137.

FF3 Y 1 ovcr-r4

OH

135.

138.

£F3 Yr 141.

144.

04 0* 139.

140.

142.

NQJAVr CACr 143.

y y-l 0 145. 16 146.

147.

R

148.

151.

154.

y 157.

160.

-298- Table 2B cont.

R

149.

y 152.

155.

158.

R

150.

153.

Pt rAc 156.

159.

162.

p. 6 p 9 9*

S

p 66 p p *0 p p *9 p *9 p* p p. PP P *6P9

P

161.

-299- Table 2B cont.

R

1 163.

1 164.

166.

NCVNr 167.

y 170.

R

y 165.

168.

NC Nr 171.

NC'

169.

S.

S

S

0

S

S

0 0

OSSS

0

S

172.

173.

174.

C i-,Y' y Y: N 0

K

175.

176.

177.

-300- Table 2B cont.

R

Vi 179. 178.

F0 180.

183.

181.

182.

184.

OH

185.

188.

186.

~x~rV 187.

189.

192.

190.

191.

-301- Table 2B cont.

R R R 193. 194. 195.

'NO

196. 197. 198.

7VNV 199. 200. 201.

y K) 202.203. 204.

N,

205. r-

~IJI

-302- I-IcN 0 208.

y 211.

V

r,'-YN-r-l 214.

KtN 0 217.

220.

Table 2B cont.

R

209.

212.

r 215.

218.

K&0 y 210.

213.

216.

y

LAV

219.

V

LX>Y%

221.

222.

-303- Table 2B cont.

R

N le 6^yN;"~r 223. 224.

y 0 y cN 0 226.

227.

225.

AITI-

228.

231.

234.

229.

232.

N 0 230.

233.

r 235.

?r~h' 236.

237.

-304- Table 2B cont.

R

240.

238.

239.

241.

242.

243.

244.

247.

245.

v 248.

246.

249.

a. .t a 250.

252. 252.

252. 252.

-305- Table 2B cont.

253.

254.

255.

256.

257.

259.

y 262.

265.

260.

258.

y

-CN

261.

264.

'00X 263.

266. 267.

-306- Table'2B cont.

R

X'N

269.

270.

268.

271.

272.

273.

274.

a 275.

%r A

N

276.

N

277. 278.

279.

280.

20.281. 282.

-307- Table 28 cont.

R

283.

286.

y 289.

292.

295.

284.

287.

290.

293.

296.

285.

288.

291.

294.

297.

297.

r r r r -308- Table 2B cont.

298.

299.

LWN

301.

y 304.

>j

N

307.

310.

302.

305.

305.

R

KLN

300.

303.

306.

309.

312.

r r 308.

311.

-309- Table 2B cont.

R

313.

316.

315.

314.

317. 318.

319.

yv 320.

323.

v 326.

321.

322.

325.

K-4 I 324. 327.

-310- Table 28 cont.

R

328.

331.

334.

329.

332.

v 330.

333.

335.

336.

N0 2 'COOEt 'COOEt 337. 338.

339.

NO3 340.

NO3 341.

NO

2 342.

-311- Table 2B cont.

R

343.

346.

349.

0 352.

344.

347.

350.

0 353.

345.

348.

0 351.

0 354.

0r 355. 356.

357.

-312- 358.

361.

364.

367.

3 370.

Table 2B cont.

R

-7NC 359.

362.

y 0 360.

363.

366.

y 369.

365.

y 368.

S

S

SO

S

S

S.

0* 0 S. S 0. 0 0 371. 372.

-31 3- Table 2B cont.

R

0 374.

moo 0 373.

0 376.

0 379.

mweois N- 1

MOO

Mo~yo 0 375.

moo 0 378.

0 381.

377.

moo J 0 380.

9*

I

I

*1

I

I I I. 384. 383.

382.

0 385.

0 386.

0 389.

0 387.

0 390.

I I I. I

I

SII Ie 388.

-314- Table 2B cont.

R

0 392.

0 391.

0 394.

393.

395.

CIc 396.

0 399.

397.

CI

0 398.

0 401.

0 400.

S

6*

S

S

00 b 0 *000 0 0a.

S

00 0 0* 0 Se 402.

403.

404.

405.

FI

0 407. 408.

406.

-315-

F

0 409.

0 412.

0 415.

Table 2B cont.

R

0 410.

0 413.

416.

416.

411.

414.

A o 417.

418.

419. 420.

0 421.

OMe 0 424.

Me OMe O 423.

422.

MeOMe 0 OMe O 425. 426.

426.

-316- Table 2B cont.

R

OMe 0 427.

428.

R

MeOr OMe 0 429.

OMe 0 432.

OMe 0 430.

OMe 0 433.

431.

OMe 0 434.

Meo~~< OMe 0 435.

OMe 0 438.

436. 437.

H

439.

H

440.

443.

441.

444.

442.

-317- 445.

448.

451.

y 454.

457.

Table 2B cont.

R

y 446.

449.

452.

y 455.

O

y 447.

v 450.

453.

456.

458. 459.

-318- 460.

Table 2B cont.

R

461.

464.

F~acI~ 0 467.

y 462.

8 ~Q 0

A

465.

F~a ll 468.

463.

466.

469.

470.

471.

FO c 472.

473. 474.

-319- Table 2B cont.

R

475.

476.

477.

478.

479.

481.

484.

y 487.

Br~y 482.

BYA

480.

F

483.

F Y 486.

489.

489.

c r 485.

488.

-320-

R

F

490.

ri 0 493.

O1 x 0 496.

0 499.

0 502.

505.

505.

Table 2B cont.

R

491.

0 494.

0 497.

500.

500.

R

0 492.

0 495.

O

0 498.

0 501.

N-rA o 504.

507.

507.

r 0 506.

-321-

R

y 508.

511.

514.

517.

H

N6 520.

Table 2B cont.

R

0 509.

512.

N2 515, 518.

R

510.

513.

y 516.

519.

521.

522.

-322- Table 2B cont.

R

H~~

0

H

-o- 523.

526.

526.

524.

-o 527.

530.

525.

528.

H

531.

r 529.

H

532.

535.

H

533.

536.

534.

537.

-323- Table 2B cont.

R

of-) r 0 540.

540. 538. 539.

541.

H

o544.

544.

H

542.

H

545.

548.

548.

YY0

H

0 543.

o* :00.: 0 546.

547.

H

&N-

549.

r aN"r/ aN-rA 550. 551. 552.

y 553.

>rY~ -324- Table 2B cont.

R

554.

v 0Js 555.

556.

557. 558.

559.

560. 561.

564.

562.

0 565.

563.

566. 567.

-325- Table 2B cont.

R

568.

569.

ci~c 571. 572.

570.

573.

KVx 576.

4 574.

575.

577. 578.

579.

580.58.5 581.

582.

-326- Table 2B cont.

R R R A)

V,

9 rk 583. 584. 585.

585.

*c 586.

586. 587. 588. F O a 589. 590.5 591.

592. 593. 594.

592. 593. 594 595.

596.

597.

-327- Table 2B cont.

R R R 598. 599. 600.

yK 601. 602. 603.

608. F 609.

FVO

F fo o, 607. 608.

609.

610. F 611.

612.

-328- Table 2B cont.

A'0 613.

616.

0 619.

MeOo~y 614.

617.

R

H

615.

0 618.

620.

621.

S.

S S S. S

S

S

622. 623.

624.

0 0 00 625.

626. 627.

-329- Table 2B cont.

R

H

629.

H

628.

0 630.

0 631.

F

3

C~S~

60 632.

SS 0 0 0@

S

iS S. SO

S

S

0@ 5@ @6

S

0 SS 0 5 0

SS

*5 S S 5e S 05 0@

SO..

0

S

eSOSO) 0 Example 339 Using methods described in the above examples, compounds comprising a parent structure selected from those disclosed in Table 3A and an R substituent selected from those disclosed in Table 3B can be prepared.

-330- Table 3A

F

*COOH

1.

OCH

3

-COOH

4.

F

.COOH

3. 0

OCH

3 R+-N

,CO

6. F

CH

3

VCOOH

8. 0

OCH

3 OCH3 R -N

CO

9. 0 331

-N

R-

COOH

13.

0CH 3 R- 4COOH

OCH

3 16.

Table 3A cont.

H

3

,,COOH

14. 0

N'CH

3

,COOH

0> 21.

-332- Table 3B 0 1.

4.

A)

7.

".Oy 0 13.

0 0 2.

0 5.

8.

0 11.

_NC

3.

0 6.

9.

NLTh 12.

12.

cy" 0 14.

H3CQ 0 0 H3C% 18.

-Th4~ 00 -ThSEI 21.

6. 0 22.

0 28.

F H 2

C..C"

31.

-1h

F

2 0 34.

37.

-333- Table 3B cont.

R

0 23.

26.

0 29.

FH

2 Cr'

F

2 6 *0 32.

F3C-.

F

2 0 0 38.

24.

F3N 00o 27.

0 F2HC- o-

F

2 00 33.

F3C.

F

2 0 0 36.

39.

-Ioh 0 0 41.

6 0 42.

-334- 0 0 43.

F

3

CQP,

0 0 46.

Table 3B cont.

R

0 0 44.

H3QZ1 o 0 47.

0 0 H3cI 48.

48.

le 0s 49.

oc6r 52.

ozr 58.

58.

wrC 50.

53.

or 0 51.

0 54.

57.

nrcr r 59. -335- Table 3B cont.

R

61.

7

OCH

62.

H3C 0 63.

64.

913 r 73.

76.

68.

H13 r 71.

74.

00 66.

69.

72.

00~f 77. 78.

79.

doo 82.

FF

00 88.

00 91.

F3 q, 94.

97.

-336- Table 3B cont.

R

-Th 80.

F F 83.

00 86.

00 89.

y F3 F F d6 0 92.

95.

do~d o 0 81.

F3C-,,/ 00 84.

y 0 0 87.

00 93.

F F 96.

H

3 CeO'> 0 0 -337-

R

H3W00) 0 0 100.

103.

106.

109.

0 0 112.

F3A F F 0 115.

Table 3B cont.

R

60 101.

H

3

CO""'

1

F

3 Q-c S- 104.

107.

0 0 110.

R

0 102.

FH

3 CnrT 105.

F F HC 108.

A

113.

116.

0A 114.

AFC,-

0 0 117.

-338- 118.

~%cTr 121.

N'ri 124.

y 127.

Table 3B cont.

R

119.

y 122.

C

120.

Ncrv 123.

Lcrv0 126.

K

129.

5* 125.

128.

OH

I-cr 0 130.

131. 132.

-339-

R

133.

136.

139.

9F 3 142.

145.

Table 3B cont.

R

y 134.

9F 3 )-r

O-N~

137.

FF3 y

CF

3 o 140.

143.

y 146.

R

OH

135.

;F'

3 138.

9F 3 141.

144.

147.

-340-

R

148.

cX7Nv8 151.

154.

y 157.

1 160.

Table 3B cont.

R

149.

y CyyN 152.

155.

158 158.

R

150.

153.

Ptr8c 156.

K

159.

162.

9* 161.

-341- Table 3B cont.

R

163.

164.

167.

y NCV 170.

R

165.

168.

171.

166.

NCy.

169.

172.

175.

173.

y 176.

174.

K

177.

-342- 178.

181.

Table 38 cont.

R

179.

y N0 182.

OH

185.

188.

Nr 191.

180.

-N0 183.

S

S S S. 55

*SS.

S

S*

555* 186. 184.

N0 187.

190.

N

189.

F N 192.

55

S

0

S

-343- Table 3B cont.

R

193.

196.

y 195. 194.

198.

197.

0S 0 0 0 0I 0 0@ 0@ @0 0000

S

400S 4 4* 0S 00 *000 0 000000 0* 4 0 0 @0

S.

0 S OS 0 0 0* 0 0005 @500

S

0 000004

S

199.

200.

201.

202.

203.

204.

205.

205. 206. 27 207.

-344- 208.

y 211.

V

214.

N0 217.

A r -K 1-10 Table 3B cont.

R

209.

212.

N 0 215.

218.

218.

KtN y N 0 210.

213.

,N 0 216.

y 219.

V

KLN0 u r 220.

221.

222.

-345- Table 3B cont.

R

LAY'g 223. 224.

y 226.

229.

232.

y 227.

230.

233.

233.

225.

228.

231.

234.

Arr 23cr0 235.

236.

237.

-346- Table 3B cont.

R

240.

238.

239.

241.

244.

242.

245.

243.

246.

249.

v 252.

247.

248.

or 250.

252.

-347- Table 3B cont.

253.

254.

255.

257.

256.

259.

K-

258.

y 260.

261.

262. 263. 264.

267.

265.

266.

-348- Table 3B cont.

R

~!N

269.

y 268.

271.

272.

270.

y 273.

276.

A-r,

N

Ay.

N

274- S. 275.

277. 278.

279.

282.

280. 21 281.

-349- Table 3B cont.

R

283.

286.

y 289.

292.

N~

284.

287.

290.

293.

y

-N

285.

K

288.

291.

294.

297.

295.

296.

-350- Table 3B cont.

R

Lj~N 298. 299.

301.

304.

304.

302.

305.

305.

KN

300.

303.

306.

309.

r 307.

308.

310.

310.

k~a-- 311. 312.

-351- Table 3B cont.

R

313.

316.

314.

315.

317.

318.

319. 320.

323.

321.

322. 324.

N

327.

325.

326.

-352-

R

328.

331.

334.

Table 3B cont.

R

329.

332.

330.

333.

COOEt 335.

COOEt 338.

341.

336.

N0 2 339.

NOX

2 342.

337.

340.

-353- Table 3B cont.

R

343.

346.

349.

0 352.

355.

355.

SCN

344.

347.

350.

0 353.

345.

02A(> 348.

0 351.

354.

55555

S

356.

357.

Y-1 y~Ny' 358.

N-r 361.

364.

0 367.

3V 370.

-354- Table 3B cont.

R

359.

v 362.

365.

y 368.

R

y 360.

&O

363.

366.

src 369.

B.

B B B. B

*BB.

371. 372.

-355- MeO 0 373.

MGO~li 0 376.

0 379.

0 382.

Me0& 0 385.

Table 3B cont.

R

MoO O 0 374. 375.

377.

moo"Ji 0 380.

MO

0 383.

0 386.

0 m 'V MeO> 0 378.

0 381.

0 384.

0 387.

l rl' ~i 'r0 0*

*S..S

388. 389. 390.

-356- Table 3B cont.

R

0 391.

0 394.

0 393.

392.

395.

396.

397.

398.

CIc 0 399.

402.O 402.

0 400.

C'

0 401.

9* 0* 00 0 0 *000* 403. 404.

405.

F)2Z<- y 0

F

0 406.

407. 408.

-357- 0 409.

0 412.

0 415.

Table 3B cont.

R

0 410.

0 413.

411.

414.

0 417.

416.

a.

0 a 0 a a 05 0 00 a as sea.

CS a 00 so..

418.

419.

0 421.

OMe 0 424.

420.

MOO

OMe 0 423.

422.

OMe 0 425. 426.

-358- Table 3B cont.

R

OMe 0 OMe 427. 428.

ome 0 430.

OMe 0 431.

OMO OMe 0 ome 0 429.

m oo OMe 0 432.

CM. 0 435.

CMe 0 438.

CM.

441.

433. 434.

a a 436. 437.

m ooe D 439.

mo 440.

Me

H.

442.

0 443.

444.

445.

448.

451.

y 454.

A)"

-359- Table 3B cont.

R

y BF'%O~0 446.

I> 4 449.

452.

y 455.

if y 447.

450.

453.

456.

4.

457.

458. 459.

-360- Table 3B cont.

R

461 461.

y sr- 0 462.

460.

463.

464.

465.

BY

466.

4 467.

468.

471.

N 469.

470.

472.

473. 474.

-361- 4 475.

Table 3B cont.

R

476.

y 479.

Br482.

482.

477.

478.

480.

481.

484.

c 487.

F

483.

F Y 486.

489.

485.

488.

488.

-362-

R

F

490.

0 493.

496.

CI

0 499.

0 502.

0 505.

Table 38 cont.

R

)%.lN 0 491.

y 0 494.

I-X

0 497.

0 500.

R

0 492.

0 495.

0 498.

0 501.

Cy 0 504.

0 507.

r r 503.

506.

-363- Table 3B cont.

R

y-r y K-r 508. 509.

511.

r? 514.

517.

520.

520.

v 512.

515, 518.

.4 O 510.

513.

y 516.

519.

r r r r 521. 522.

-364- Table 3B cont.

H

523.

H

oN

H

o~V 524.

525.

J

H

526.

f&Y.

H

V

527.

530.

528.

S0531.

531.

r r 529.

H

0 532.

535.

533.

S 0 534. 537.

536.

-365-

R

538.

541.

Table 3B cont.

R

o-) 539.

H

0 542.

o 545.

548.

551.

R

540.

H

Vro 543.

544.

546.

547.

550.

549.

552.

y 553.

0r -366- Table 3B cont.

R

554.

vI 0TT 555.

556.

557. 558.

559.

560.

561.

564. 562.

0 565.

563.

566.

567.

-367- Table 3B cont.

R R R cl cK 0 CIay# 568.

569. 570.

ci 571. 572. 573.

*~74 5 574. 575. 576.

577. 578. 579.

580.

581. 582.

-368- Table 3B cont.

R R R 583. 584. 585.

586. 587. 588.

589. 590. 591.

9~~l

FF'

0 0..

592. 594. 94 596. rn DUD. UZ71.

369 Table 3B cont.

R R R

FV

598. 599. 600.

FVV0 FyL 601. 602. 603.

F 604 F V 60. 606. F 0 605.

606. "Sk* 607. 608. 609.

610. 612.

611.

612.

-370-

R

Vx 0 613.

IC r 0 616.

0 619.

622.

Table 3B cont.

R

H

614.

moo 617.

R

Moo,(r 615.

M6O 618.

620.

621.

S

5*555 S. S

S

S

55 0

S..

SSS

623.

624.

V

625.

626. 627.

371 Table 3B cont.

R

0 630. 628.

629.

0 631. 632.

*o 00 ***aS o 0 S O500 0 S 0e 0*000 Example 340 trans, trans-4-(1 .3-Benzodioxol-5-yI)-2-(4-methoxylhenyln-1-(N- (3-methylbut-1 -yl)-N-phenyflaminocarbonylmethyl)-pyrrolidine-p..

carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 5 0.85 J=6 Hz, 6H), 1.25 J=7 Hz, 2H), 1.42-1.56 (in, 1H), 3.43-3.85 (in, 9H), 3.88s 5.95 2H), 6.80 J=7 Hz, 1 6.86 (dd, J=9 Hz, 1 6.89-7.00 (mn, 2H), 6.97 J= 1 Hz, 1 7.04 J=9 Hz, 2H), 7.37 J=9 Hz, 2H), 7.40- 7.47 (mn, 3H). MS m/e C (53.12, 53.11), H (4.63, 4.80), N (3.33, 3.28).

-372- Example 341 trans. trans-4-(1 .3-Benzo-dioxol-5-yi)-2-(4-methoxyjhenyfl)-1-(Nbutyl-N-(4-methylp~henyflaminocarbonylmethyl)-oyrrolidine.3.

carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.47 (in, 4H), 2.37 3H), 2.83 J=7 Hz, 2H), 3.06-3.25 (in, 2H), 3.40- 3.50 (in, 1 3.51-3.63 (in, 3H), 3.80 3H), 3.87 J=9 Hz, 1 5.92 2H), 6.74 J=8 Hz, 1 6.80-6.86 (in, 3H), 6.89 J=8 Hz, 2H), 7.04 J=2 Hz, 1H), 7.12 J=8 Hz, 2H), 7.19 J=8 Hz, 2H). MS (DCI) m/e 545 Analysis calcd for C32H36N206: C, 70.57; H, 6.66; N, 5.14. Found: C, 70.20; H, 6.81; N, 5.03.

Example 342 tra nk. tra ns-4 .3-B e nz o d ioxoI- 5 y 1)-2 -(4-12r opo xy ph e n y1)-1 Ndibutylamino)carbonyflmethyl)pyrrolidine-3-carboxylic- acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 8 7.30 (2H, d, 7.03 (1 H, d, 6.83 (3H, in), 6.72 (1 H, d, 5.95 (1 H, d, 5.93 (1 H, d, J=2), 3.88 (2H, t, 3.73 (1H, d, J=12), 3.58 (1H, in), 3.53-3.20 (4H, in), 3.10-2.90 (4H, in), 2.72 (11H, d, J=15), 1.79 (2H, q, 1.50-1.05 (8H, in), 1.02 (3H, t, 0.87 (3H, t, 0.80 (3H, t, MS (DCI/NH3) mWe 539 Anal calcd for C31 H42N206 0.5H20: C, 67.98; H ,7.91; N, 5.11. Found: C,68.24; H, 7.70; N, 5.03.

Example 343 trans.trans-4-(1 .3-Benzodioxol-5-yi)-2-(4-propyl~henyl)-1 dibutylainino~carbonyflinethyflpyrrolidin-e-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 8 7.31(2H, d, 7.13 (2H, d, J=9), 7.03 (1 H, d, 6.84 (1H, dd, J=6, 6.73 (1 H, d, 5.95 (1 H, d, 5.93 (1H, d, 3.76 (1H, d, J=10), 3.60 (1H, in), 3.55-3.20 (4H, in), 3.13-2.88 (4H, in), 2.75 (1H, d, J=15), 2.55 (2H, t, J=8),1.62 (2H, q, 1.50-1.00 (8H, in), 0.92 (3H, t, 0.85 (3H, t, 0.78 (3H, t, MS (DCI/NH3) in/e 523 Anal calcd for C31 H42N205.0.25 C, 70.63; H, 8.13; N, 5.31. Found: C, 70.55; H, 8.08; N, 5.18.

-373- Example 344 trans-trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxl-5-yU)-i -r3-(Nprolyl-N-n-p2entanesulfonylamino)ropyllDyrrolidine-3-carboxylic acid Using the procedures described in Example 316, the title compound was prepared. 1 HNMR (300MHz, CDCI3) 8 0.85 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.3-1.4 (in, 4H), 1.5-1.6 (sextet, J=7, 2H), 1.65-1.8 (in, 4H), 2.05-2.15 (in, 1H), 2.43-2.56 (mn, 1H), 2.72-3.1 (mn, 7H), 3.27- 3.4 (in, 2H), 3.5-3.6 (mn, 2H), 3.80 3H), 5.95 2H), 6.73 J=8Hz, 1 0 1H), 6.8-6.9 (in, 1H), 6. 85 J= 9Hz, 2H), 7.02 J=2Hz, 1H), 7.80 (d, J=9Hz, 2H).

Example 345 trans. trans-4-(1 .2-Dihydrobenzof uran-5-yI-2-(4-ethylphenyl)-1 1 5 (((N.N-dibutylamino~carbonyflmethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 8 7.40 (3H, in), 7.22 (2H, d, J=8), 7.13 (1H, dd, J=8, 6.72 (1H, d, 5.28 (1H, d, J=12), 4.55 (2H, t, 4.15 (1H, d, J=18), 4.03 (2H, in), 3.75 (2H1, in), 3.40 (2H, in), 3.20 (2H, t, 3.15 (1 H, in), 3.10-2.90 (2H, in), 2.63 (2H, q, 1.47 (2H, mn), 1.31 (4H, in), 1.12 (3H, t, 1.10 (2H,in), 0.92 (3H, t, 0.80 (3H, t, MS (DCI/NH3) m/e 507 Anal calcd for C31 H42N204 TFA: C ,63.86 H, 6.98; N, 4.51. Found: C, 63.95; H, 7.12; N, 4.43.

Examp~le 346 trans. trans-4-(1 .3-Benzodioxol1-5-yfl-2-(4-methoxypheny)- 1 pentyl)-N-phenylamino)carbonyl)methyl'pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I NMR (300 MHz, CD3OD) 8 0.93 J=7.3 Hz, 3H), 0.94 J=7.3 Hz, 3H), 1.33 (mn, 4H), 2.72 J=15.2 Hz, 1H), 2.81 (in, 1H), 3.11-3.23 (in, 2H), 3.45-3.57 (in, 2H), 3.79 3H), 3.83 J=9.8 Hz, I1H), 4.54 (in, 1 5.92 2H), 6.73 J=7.8 Hz, 1 6.83 (mn, 3H), 6.98 (bs, 2H), 7.04 J=1.7 Hz, 1H), 7.07 7.37 (mn, 3H). MS (DCI) mWe 545 Anal calcd for C32H33N206 -0.35H20: C, 69.76; H, 6.71; N, 5.08. Found: C, 69.72; H, 6.66; N, 4.94.

-374- Example 347 trans. trans-4- (1 .3 -Benz odi oxol-5-yb)-2-(4-m et ho xyhenyl- 1 butyb)-N-(3-trifluoromethylphenyllamino)carbonyflmethyl)p2yrrolidine.

3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=6.6 Hz, 3H), 1. 17- 1.45 (in, 4H), 2.65 J= 16.5 Hz, 1 2.72 (in, 1 3.10 J=9.5 Hz, 1 3.21-3.27 (in, 1 3.40 (dd, J=4.1, 9.9 Hz, 1 3.54 (in, 1 3.61 3.74 (in, 3H), 3.77 3H), 5.93 2H), 6.73-6.85 (in, 4H), 7.02 (in, 3H), 7.33 J=7.5 Hz, 1 7.40 1 7.58 J=7.8 Hz, 1 7.69 Hz, 1H). MS (DCI) m/e 599 Anal calcd for C32H33F3N206: C, 64.21; H, 5.56; N, 4.68. Found: C, 64.09; H, 5.63; N, 4.57. Example 348 trans. trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-methoxyphenvyn-1-(Npropyl-N-(4-morpholinylcarbonyflaminocarbonyfmethyfl-pyrrolidine.3carboxylic acid Using the procedures described in Example 1, the title compound C..

was prepared. 1 HNMR (300 MHz, CD3OD) 8 0.78 J=7 Hz, 3H), 1.43 (q, J=7 Hz, 2H), 2.07-3.01 (in, 1 2.76 (dd, J=7, 9 Hz, 2H), 2.77-3.00 (in, 3.05 (3.70, J=m Hz, 11 3.76 3H), 5.88 2H), 6.67 J=8 Hz, 1H), 6.80 (dd, J=7 Hz, 1H), 6.83-6.90 (mn, 2H), 6.98 J=2 Hz, 1H), 7.32- 7.39 (mi, 2H). MS mWe calc'd for C29H39N307: 540.2710,.

Found 540.2713.

Examp~le 349 trans. trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-methoxyphenyl)- 1 -(cis- 2-.6-dimethylpiperidin-1 -yflcarbonylmethyfl-pyrrolidine-3-carboxylic Using the procedures described in Example 1, the title compound was prepared. IH NMR (300 MHz, CD3OD) 8 0.94 J=7 Hz, 3H), 1-15d 3H), 1.10-1.70 (mn, 6H), 1.70-1.90 (in, 1H), 2.9. J=13 Hz, 1H), 3.00-3.20 (in, 2H), 3.50 (3.70, J=m Hz, 2H), 3.79 3H), 3.80-4.00 (in, 1H), 4.10-4.65 (mn, 2H), 5.95 2H), 6.70 (7.10, J=m Hz, 5H), 7.35 (in, 2H). MS in/e calc'd for 028H35N206: 495.2495. Found 495.2493.

-375- Example 350 trans,. trans-2-(4-Methoxymethoxylhenyfl-4-(1 1 -(2-(N-nropyI-N-n-oentanesulfonylamino~ethyllpyrroI dinp-3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 57-59 OC. 1H NMR (CDCI3, 300 MHz) 8 0.78 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.28-1.36 (in, 4H), 1.93 (sextet, J=7Hz, 2H), 1.72 J=7Hz, 2H), 2.20-2.32 (in, 1H), 2.72-3.10 (mn, 7H), 3.18-3.41 (mn, 2H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.48 3H), 3.52-3.59 (mn, 1H), 3.68 J=9Hz, 1H), 5.15 2H), 5.94 (s,2H), 6.73 J=8Hz, 1H), 6.82 (dd, J=lHz, J=8Hz, 1H), 6.98-7.02 (mn, 3H), 7.32 J=9Hz, 2H). MS (DCI/NH3) m/e 591 Examp~le 351 trans. trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-methoxyphenyl)- 1 butyl)-N-phenylainino)carbonyl)methyflpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.79-0.89 (in, 6H), 1. 14-1.21 (in, 1 1.25-1.40 (in, 1 2.64 (dd, J=4.6, 15.4 Hz, 1 2.76 Hz, 1 3.05-3.13 (mn, 2H), 3.37-3.49 (in, 2H), 3.70 3H), 3.80 (d, J=9.8 Hz, 1 4.53 (in, 1 5.83 (in, 2H), 6.65 J=8.1 Hz, 1 6.72 6.76, J=m Hz, 3H), 6.87 (in, 2H), 6.95 J=1.7 Hz, 1 7.03 (mn, 2H), 2 7.29 (mn, 3H). MS (DCI) m/e 531 Anal calcd for C31 H34N206 0.4H20: C, 69.23; H, 6.52; N, 5.21. Found: C, 69.19; H, 6.52; N, 5.03.

Example 352 trans. trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-methoxyphenyl)- 1 propyl- N -phenyl amino) ca rbonyflmethyflyrrol id ine-3-ca rboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.99 J=6.8 Hz, 6H), 2.71 J=15.6 Hz, 1H), 2.84 (mn, 1H), 3.13-3.18 (in, 2H), 3.45-3.58 (mn, 2H), 3.79 3H), 3.88 J=9.8 Hz, 1 4.80 (mn, 1 5.92 2H), 6.74 (d, J=8.1 Hz, 1H), 6.83 (in, 3H), 6.96 (br s, 2H), 7.04 J=1.7 Hz, 1H), 7.13 (mn, 2H), 7.38 (mn, 3H). MS (DCI) in/e 517 Anal calcd for -376- C30H32N206 0.4H20 0.08CH3002C2H5: C, 68.65; H, 6.28; N, 5.28.

Found: C, 68.64; H, 6.35; N, 5.14.

Example 353 trans, trans-4-(4-Proloxyphenyl-2-(4-methoxYo2henyl)-1 dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 8 7.42 (2H, d, J=1lOHz), 7.38 (2H, d, J=lOHz), 6.92 (2H, d, J=lOHz), 6.88 (2H, d, J=l0Hz), 5.13 (1H, bd, 1 0 J=l2Hz), 4.02 (2H, in), 3.90 (2H, t, J=8Hz), 3.80 (3H, 3.71 (3H, in), 3.40 (2H, in), 3.19 (1H, in), 3.10-2.90 (2H, in), 1.80 (2H, in), 1.48 (2H, in), 1.29 (4H, in), 1.13 (2H, in), 1.03 (3H, t, J=8Hz), 0.92 (3H, t, J=9Hz), 0.82 (3H, t, J=9Hz). MS (DCI/NH3) m/e 525 Anal calcd for C31 H4N2O5. 1 TFA C, 62.06 H 7.10; N, 4.39 Found: C, 62.43; H, 7.28; N, 4.39. Example 354 trans. trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-methoxylhenyl)-1 .2.3.4-tetrahydroquinolin-1 -yfl ca rbonyl) methyfl) yrrol idin e-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 1.88 (quintet, J=6.5 Hz, 2H), 2.67 J=6.4 Hz, 2H), 2.87 J=8.6 Hz, 1 3.14 (in, 2H), 3.42 (dd, J=4.6, 9.7 Hz, 1 3.53-3.70 (in, 3H), 3.72-3.78 (in, 1 3.77 3H), 263.86 J=9.6 Hz, 1 5.91 2H), 6.73 J=8.1 Hz, 1 6.83 (in, 3H), W 6.98 J=1.1 Hz, 1H), 7.02-7.23 (mn, 6H). MS (DCI) m/e 515 Anal calcd for C30H30N206 -0.3H20 0.15 CH3002C2H5: C, 68.93; H, 6.01; N, 5.25. Found: C, 68.91; H, 5.86; N, 5.19.

Example 355 trans.t rans-2-(3.4-Dimethoxyphenyl)-4-(1 .3-benzodioxo-5-y)-1 (N.N-di(n-butyl)amino)carbonyI)methyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. in.p. 64-65 OC. 1 H NMR (CDC13, 300MHz) 8 0.79 J=7Hz, 3H), 0.88 J=7Hz, 3H),1.07 (sextet, J=7Hz, 2H), 1.20-1.35 (in, 4H), 1.43 (sextet, J=7Hz, 2H), 2.83 (d, -377- J=13.5Hz, 1H), 2.94-3.17 (in, 4H), 3.22-3.42 (in, 1H), 3.40-3.48 (in, 3H), 3.58-3.65 (in, 1H), 3.82 3H), 3.85 4H),5.92 2H), 6.73 J=8Hz, 6.81 J=8Hz, 1H), 6.86-6.96 (in, 3H), 7.07 J=3Hz, 1H). MS (DCl/NH3) m/e 541 Example 356 trans, trans-2- Di met hoxylheny benz od ioxol -5-yfl-14-2- (N-propyl-N-n-o2entanesulfonylamino~ehyll pyrrol idine-3-carboxyl c aid 1 0 Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 75-86 OC. 1 H NMR (CD3OD, 300 MHz) 8 0.75 J=7Hz, 3H), 0.82 J=7Hz, 3H), 1.32-1.43 (in, 6H), 1.65-1.77 (in, 2H), 3.0-3.09 (in, 4H), 3.23-3.27 (in, 2H), 3.44 (t, J=6Hz, 1 3.47-3.56 (in, 2H), 3.78 J=9Hz, 1 3.83-3.93 (in, 2H), is 3.87 3H), 3.92 3H), 4.63 J=l3Hz, 1H), 5.97 2H), 6.82 (d, J=7Hz, 1H), 6.93 J=7Hz, 11H), 7.06 J=7Hz, 1H), 7.08 J=3Hz, 1H), 7.16 (dd, J=3Hz, J=7Hz, I1H), 7.27 J=3Hz, 1 MS (DCI/NH3) m/e 591 Example 357 trans, trans-2-(3.4-Dimethoxyphenyfl-4-(1 .3-benzodioxol-5-yl)- 14-2- (N-1oropyl-N-n-hexanesulfonylamino'ethyllpyrrolidine-3-carboxy ic acid.

Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 65-66 OC. 1 H NMR (CDC13, 300 MHz) 8 0.80 J=7Hz, 3H), 0.89 J=7Hz, 3H), 1.23-1.48 (in, 6H), 1.43 (sextet, J=7Hz, 2H), 1.72 (sextet,J=7Hz, 2H), 2.25-2.35 (mn, IH), 2.73-3.10 (mn, 7H), 3.19-3.32 (mn, 2H), 3.45 (dd, J=3Hz, J=9Hz, 1H), 3.53-3.59 (in, 1H), 3.68 J=9Hz, 1H),3.87 6H), 5.95 2H), 6.74 J=8Hz, 1H), 6.79-6.86 (mn, 2H), 6.92-6.97 (in, 7.02 1H).

MS (DCI/NH3) in/e 605 -378- Example 358 trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 -r2.- (phthalimido~ethyll-pyrrolidine-3-carboxylic acid The compound of Example 10 (250 mg), N-bromoethylphthalimide (206 mg), and diisopropylethylamine (175 mg) were dissolved in 1 mL of acetonitnile and heated for 2.5 hours at 95 OC. Toluene was added, and the mixture was washed with KHCO3 solution. The solution was dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel eluting with 3:1 EtOAc-hexane to give 216 1 0 mg of an intermediate ethyl ester which was hydrolyzed by the method of Example 1 D to give 130 mg of the title compound as a white powder.

1 H NMR (300 MHz, CDC13) 8 3.12-3.26 (in, 2H), 3.60-3.75 (in, 2H), 3.70 3H), 3.98-4.12 (in, 2H), 4.45-4.55 (mn, 1H), 4.69 J=9Hz, 1H), 4.76- 4.88 (in, 1H), 5.96 2H), 6.55 J=8Hz, 1H), 6.60-6.70 (in, 3H), 6.79 J=8Hz, 1H), 7.05-7.45 (mn, 5H), 7.75 J=7Hz, 1H).

Example 359 trans, trans-4-( 1.3-Benzodioxol-5-yl)-2-(4-inethoxyphenyfl- 1 9.

pentyl)-N-phenylamino~carbonyflmethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.86-0.98 (in, 6H), 1.17-1.22 (in, 1H), 1.23-1.41 (in, 3H), 2.70 (dd, J=11.2, 15.3 Hz, 1H), 2.83 (in, 1H), 3.10-3.21 (in, 2H), 3.45-3.60 (in, 2H), 3.79 3H), 3.86 (in, 1H), 4.74 (in, 1H),,5.91 (in, 2H), 6.73 (dd, J=1.1, 7.7 Hz, 3H), 6.82 (mn, 2H), 7.04- 7.14 (in, 3H), 7.36 (in, 3H). MS (DCI) m/e 545 Anal calcd for C32H36NO6 0.25 CH3002C2H5: C, 69.95; H, 6.76; N, 4.94. Found: C,.

70.03; H, 6.54; N, 4.78.

Example 360 trans, trans-4- (1 Benz od io xol-5-y)-2- (4-m etho xyhe nyl) -1 (Nbutyl-N-(2-naphthyl)aininocarbonylinethyfl-pyrrolidine-3-carboxylic Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 8 0.83 J=7 Hz, 3H), 1.23- 1.39 (in, 4H), 1.40-1.55 (in, 3H), 2.60-2.72 (mn, 2H), 3.00-3.80 (mn, 3.66 3H), 5.87 2H), 6.39 J=9 Hz, 2H), 6.74-6.85 (in, 3H), 7.17 -379- J=2 Hz, 1 7.40 (dd, J=8 Hz, 1 7.52-7.62 (in, 7.80-7.90 (n 1H), 7.90-8.00 (in, 2H). MS (DCI) m/e 581 Analysis calcd for C35H36N206 .0.3 H20: C, 71.73; H, 6.29; N, 4.78. Found: C, 71.74; H, 6.26; N, 4.72.

Example 361 trans. trans-2-( 4-P roloxyphenyl)-4-(1 .3-benzodioxol-5-yf)l- Propyl-N-n-pentanesulfonylaminolethyllp~yrrolidine-3-carbo -xylic acid Using the procedures described in Example 66, the title compound 1 0 was prepared and isolated as a white solid. m.p. 53-54 OC. 1 HNMR (CDCI3, 300MHz) 8 0.79 J=7Hz, 3H), 0.89 J=7Hz, 1.03 (t, J=7Hz, 3H), 1.24-1.34 (in, 4H), 1.43 (sextet, J=7Hz, 2H), 1.67-1.75 (in, 2H), 1.80 (sextet, 2H), 2.23-2.33 (in, 1H), 2.72-2.93 (in, 5H), 3.05 (septet, J=7Hz, 2K), 3.15-3.35 (in, 2H), 3.42 J=9Hz, 1H), 3.54-3.62 1 5 (in, 1H), 3.67 J=9Hz, 1H), 4.90 J=7Hz, 2H), 5.95 2H), 6.73 (d, J=8Hz, 1H), 6.85 J=8Hz, 2H), 7.02 1H), 7.32 J=8Hz, 2H). MS (DCI/NH3) m/e 589 Examp~le 362 trans, trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-methoxypheny)- m ethyl indoli n- 1 -yfl carbonylhmethyl)py rrol id ine-3-ca rboxyli c acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 mixture of indole C2 diastereomers, 0.95 (in, 1.5 (CH3 1.05 6.3H, 1.5 2.62 (mn, 1K), 3.01 (in, 2H), 3.14-3.25 (in, 1K), 3.37-3.52 (mn, 1.5H), 3.56-3.80 (in 2H), 3.65 1.5 (CK3O)), 3.76 1.5 (CK3O)), 3.93 (in, 0.5K), 4.05-4.1-3 (in, 4.42 (in, 0.5K), 4.65-4.74 (in, 1K), 5.91 (in, 2H), 6.72 J=8.1 Hz, 0.5H), 6.75 (in, 0.5H), 6.85 (in, 2K), 6.92 J=8.5 Hz, 1K), 7.00-7.06 (in, 2H), 7.14 J=7.7 Hz, 1KH), 7.21 J=6.6 Hz, 1KH), 7.38 (in, 2H), 7.99 (in, I1H). MVS (DCI) m/e 515 Anal calcd for C30H30N206 0.35H20 -0.3 CK3CO2C2H5: C, 68.47; K, 6.10; N, 5.12. Found: C, 68.46; H, 5.97; N, 5.07.

-380- Example 363 trans, trans-4-( 1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)- 1 hyd roxy-3-p royl hex- 1 -yflpyrrol id ine-3-ca rboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 1.06 (in, 6H), 1.26-1.60 (mn, 9H), 3.16 (dd, J=1 0.9, 12.6 Hz, 1 3.18 J=1 1 Hz, 1 3.44 Hz, 1 3.61 J= 11 Hz, 1 3.73 J= 11.0 Hz, 1 3.85 (in, 11-H), 3.96-4.17 (in, 2H), 4.02 1.5 (CH3O diastereomer)), 4.03 1.5 (CH3O diastereomer)), 6.15 2H), 7.01 J=8.1 Hz, 0.5H), 7.00 J=8.1 Hz, 1 0 0.5H), 7.10 (in, 1H), 7.23 (in, 3H), 7.77 (in, 2H). MS (DCI.) m/e 484 Anal calcd for C28H37N06 -0.33 H3P04: C, 65.34; H, 7.44; N, 2.72. Found: C, 65.30; H, 7.40; N, 2.60.: Example 364 trans, trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)- heptyl)-N-(3.4-dimethoxybenzyl)amino~carbonyl)methylp1yrrouidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 81:1 mixture of rotamers, 0.61 J=7.1 Hz, 1.5H), 0.72 1.5H), 0.76 J=7.1, 1.5, 0.83, t, 7.3 Hz, 1.05-1.60 (in, 8H), 2.84-3.10 (in, J=2.5, 3.18, t, 9.7 Hz, 0.5H), V 3.41-3.52 (in, 2H), 3.47-3.69 (in, 2H), 3.66 1.5H), 3.73 1.5H), 3.77 1.5H), 3.78 1.5H), 3.79 1.5H), 3.86 J=9.8 Hz, 0.5H), 4.19 J=17.7 Hz, 0.5H), 4.29 J=15.2 Hz, 0.5H), 4.40-4.49 (in, 0.5H), 4.47 (d, J=15.3 Hz, 0.5H), 4.60 J=17.6 Hz, 0.5H), 5.93 (mn, 2H), 6.46 (dd, J=1.71 8.2 Hz, 0.5H), 6.52 J=2.0 Hz, 0.5H), 6.74 (in, 2.5H), 6.80 1H), 6.83- 6.88 (in, 1H), 6.92 (mn, 1.5H), 7.03 (dd, J=1.7, 6.8 Hz, 1H), 7.19 (in, 1H), 7.36 (mn, 1H). MS (DCI) m/e 647 Anal calcd for C37H46N208: C, 68.71; H, 7.17; N, 4.33. Found: C, 68.41; H, 7.26; N, 4.11.

Examn~le 365 trans, trans-4-( 1.3-Benzodioxol-5-yfl-2-(4-methoxyphenyfl)- ((indolin-1-yflcarbonyflmethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 82.97 (dd, J=8.1, 9.5 Hz, I1H), 3.10 J=8.1 Hz, 2H), 3.16-3.22 (in, 2H), 3.51-3.68 (mn, 3H), 3.73 (in, -381- 3H), 3.83-4.05 (in, 3H), 5.90 (in, 2H), 6.73 J=8.1 Hz, 1 6.86 (in, 6.99 (dt, J=1.1, 7.4 Hz, 1H), 7.08 J=0.7 Hz, 1H), 7.11 (in, 1H), 7.18 J=7.1 Hz, 1H), 7.38 J=8.5 Hz, 2H), 8.02 1H). MS W/e 501 Anal calcd for C29H28N206 -0.5 H20 0.15 CH3002C2H5: 0, 68.01; H, 5.82; N, 5.36. Found: 0, 68.03; H, 5.65; N, 5.25.

Examlle 366 trans, trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1 butyl-N-(2-chlorop~henyl)aminocarbonylmethyfl)1yrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 80.89 (dt, J=7 Hz, 3K), 1.23- 1.51 (in, 4K), 2.52-4.00 (in, 8H), 3.78 J=6 Hz, 3H), 5.92 J=6 Hz, 1 5 2H), 6.70-6.87 (in, 4H), 7.02-7.21 (in, 4H), 7.27-7.52 (in, 3H). MS (DCI) m/e 565 Analysis calcd for C31H32N2O6CI 0.61-20: C, 64.66; H, 5.99; N, 4.86. Found: C, 64.59; H, 6.00; N, 4.64.

Example 367 trans, trans-2-(4-Methoxphenyl)-4-( 1.3-benzodioxol-5-yl)-1 (3.4 .5-trimethoxybenzylI1pyrrolidine-3-carboxvlic acid: The compound resulting from Example 10 (0.25 g) was reacted..

with 0.169 g of 3,4,5-tfimethoxybenzyl chloride and 0.175 g of diisopropylethylamine in 1 mL of acetonitrile for 2 hours at room temperature. The resulting ester was isolated and then hydrolyzed by the method of Example 1D to give 0.193 g of the title compound. m.p.

108-110 OC 1 H NMR (300 MHz, CDCI3) 82.75 J=9Hz, 1KH), 2.95-3.05 (in, 2K), 3.20 J=11 Hz, 1H), 3.45-3.55 (mn, 1H), 3.7-3.8 (in, 2H), 3.84 3H), 5.95 (dd, J=2Hz, 6Hz, 2H), 6.55 6.70 J=8Hz, 1H), 6.30-6.35 (in, 1K), 6.90 J=9Hz, 2H), 7.13 J=2Hz, 7.43 (d, J=9Kz, 2H).

-382- Example 368 trans, trans-4-( 1.3- Benz odioxol -5-yb-2-(4-methoxyghenyl)- 1 (Nbutyl-N-(3-chlorophenyflaminocarbonylmethyl)-pyrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.89 J=7 Hz, 3H), 1.20- 1.42 (in, 4H), 3.42-3.87 (in, 9H), 3.9 3H), 5.96 2H), 6.75 (7.10, J=m Hz, 7H), 7.33-7.50 (in, 4H). MS m/~e 565(M+H). Analysis calcd for C31 H33N206C1*1.OCF3000H: C, 58.37; H, 5.05; N, 4.13. Found: C, 58.41; H, 4.99; N, 4.08.

Example 369 trans, trans-2-(4-Methoxphenyfl-4-( 1.3-benzodioxol-5-yfl-1 butyl amino) pyrimi d in-4-yll pyrrol idin e-3-ca rboxyl ic acid The compound resulting from Example 10 (0.25 g) was reacted with 0.11 g of 2,4-dichioropyrimidine and 0.175 g of..: dilsopropylethylamine in 1 mL of acetonitrile for 2 hours at room temperature to give 0.218 g of ethyl 2-(4-methoxphenyl)-4-(1,3- 1 -(2-chloro-4-py ri midyl)-py rrol idin e-3carboxylate. This compound was reacted with 1 mL of dibutylainine in 2 mL of toluene at 125 00 for 17 hours. The resulting ethyl ester was hydrolyzed by the method of Example 1D to give 0.142 g of the title comopund as a white powder. 1 H NMR (300 MHz, CDCI3) 80.75-0.90 (broad, 6H), 1.1-1.3 (br, 4H), 1.35-1.55 (br, 4H), 3.05 (mn, 1H), 3.3-3.5 (br, 2H), 3.55-3.67 (in, 2H), 3.75 3H), 4.6 (br, 1 5.2 (br, 1 5.45 (br, 1 5.87 6.3 (br, 1 6.67 J=8Hz, 1 6.7-6.85 (mn, 4H), 7.10 J=9Hz, 2H).

Example 370 trans. trans-4-( 1.3-Benzodioxol-5-yl)-2-(4-methoxyohenyfl- 1 methylbut-2-yfl-N-12henylamino~carbonyl)methyflpyrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.90 J=7.5 Hiz, 3H), 1.12 3H), 1.14 3H), 2.06 J=7.5 Hz, 2H), 2.73 J=15.3 Hz, 1H), 2.91 J=9.5 Hz, 1 3.11 J=1 5.6 Hz, 1IH), 3.21 J=8.8 Hz, 1 3.50- -383- 3.61 (in, 2H), 3.80 3H), 4.00 J=10.2 Hz, 1H), 5.91 2H), 6.74 (d, J=7.8 Hz, 1H), 6.85 (in, 3H), 6.93 (in, 1H), 6.98 (in, 1H), 7.03 J=1.7 Hz, 1H), 7.17 (in, 2H), 7.36 (in, 3H). MS (DCI) m/e 545 Anal calcd for C32H36N206: C, 70.57; H, 6.66; N, 5.14. Found: C, 70.17; H, 6.53; s N, 4.97.

Example 371 trans, trans-2-(4- Ethyl phenyl)-4- (5-i ndanyb- 1 Ndibutylamino'carbonylmethyl)p2yrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDCI3) 8 7.25 (3H, mn), 7.21 (1 H, d, 3Hz), 7.17 (3H, mn), 3.80 (1 H, d, 10OHz), 3.65 (1 H, ddd, 6, 5, 3Hz), 3.4 (4H, mn), 3.10 (2H, in), 2.98 (2H, in), 2.88 (5H, mn), 2.79 (1H, d, 16Hz), 2.62 (2H, q, 7Hz), 2.05 (2H, in), 1.42 (2H, mn), 1.32 (1 H, in), 1.21 (3H, t, 7Hz), 1.05 (2H, sext, 7Hz), 0.87 (3H, t, 7H-z), 0.79 (3H, t, 7Hz). MS (DCl, NH3) mWe 505 Anal calcd for C32H44N203: C, 76.15; H, 8.79; N 5.55. Found: C, 75.96; H, 8.75; N, 5.36.

Example 372 trans. rans-2-(3.4-Difluorophenyb)-4-(1 .3-benzodioxol-5-yb)-1-(((N.Ndibutylamino~carbonyl)methyfl-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 62-63 OC. 1 H NMR (CDC13, 300 MHz), 8 0.83 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.13 (sextet, J=7Hz, 2H),1.20-1.32 1.36-1.49 2.85-2.93 2.98-3.23 (in, 4H), 3.36-3.45 (in, 3H), 3.58-3.66 (m 1H), 3.94 (d, J=8Hz, 1H), 5.93 2H), 6.72 J=7.5Hz, 1H), 6.84 (dd, J=1 Hz, 1H), 6.98 J=7.5Hz, 1H), 7.08-7.15 (mn, 2H), 7.22-7.28 (mn, 1H). MS (CDI/NH3) m/e517 Exain~le 373 trans, trans-2-(3.4-Difluorophenyl)-4-(1 .3-benzodioxol-5-yi)- 1 prolyl-N-n-pentanesulfonylamino~ethyI)Dyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 71-72 0 C. 1 H NMR (CDC13, 300 MHz) 8 0.82 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.25-1.38 -384- (in, 4H), 1.46 (sextet, J=7Hz, 2H), 1.74 (quintett, J=7Hz, 2H), 2.26-2.36 (mn, 1H), 2.72-2.95 (mn, 5H), 2.98-3.12 (mn, 2H), 3.15-3.34 (in, 2H), 3.45 (dd, J=3Hz, J=9Hz, 1H), 3.53-3.60 (in, 1H), 3.71 J=9Hz, 1H), 5.96 (s, 2H), 6.75 J=9Hz, 1H), 3.82 J=2Hz, J=9Hz, 1H), 5.96 J=2Hz, 1H), 7.09-7.18 (in, 2H), 7.23-7.34 (in, 1H). MS (CDI/NH3) m/e567 Examile 374 trans, traris-4-(1 Be nzodi oxol -5-y 1)-2 -(etho xymnethyl)- 1 N- 1 0 dibutylamino)carbonyl)methy~pyrrolidine-3-carboxylic acid Using the procedures, described in Example 1, the title compound was prepared. TLC (10% MeOH-CH2CI2) Rf 0.53. 1 H NMR (CDCI3, 300 MHz, rotameric forms) 8 0.70 J=7Hz), 0.80 J=7Hz) and 0.96-1.04 (in, 6H total), 1.04-1.75 (in, 11H), 1.34-1.53 (br m, 4H), 2.65 (AB) and 2.80-3.08 (in, 2H total), 3.10-3.82 (br m, 12H), 4.03 (in) and 4.22-4.45 (br m, 2H total), 5.90 and 5.91 2H total), 6.65-6.84 (in) and 6.93 (in) and 6.99 (in, 3H total). MS (FAB) m/e 463 Anal calcd for C25H38N206 1.5 H20: C, 61.33; H, 8.44; N, 5.72. Found: C, 61.28; H, 7.78; N, 5.62.

Examlle 375 trans. trans-4-( 1.3-Benzodioxol-5-yfl-2-(n-butyl)-1 dibutylamino'carbonyflmethylpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a colorless wax. TLC (10% MeOH-CH2CI2) Rf 0.37. 1 H NMR (CDCI3, 300 MHz, rotamenic forms) 8 0.71 J=7Hz) and 0.77-1.05 (mn, 9H total), 1.05-1.20 (in, 2H), 1.20-1.72 (br in, 13H), 2.48-2.52 (in, 1H), 2.87-3.00 (in, 1H), 3.05-3.60 (in, 5H), 3.60-3.80 (br mn, 2H), 3.88-4.05 (br in, 1H), 4.28 (br d, J=l5Hz, 1H total), 5.90 and 5.92 2H total), 6.67-6.82 (in, 3H total). MS (FAB) mn/e 461 Anal calcd for C26H40N205 1.75 H20: C, 63.45; H, 8.90; N, 5.69.

Found: C, 63.18; H, 8.22; N, 5.60.

-385- Example 376 trans. trans-4-(1 Ben zo dioxol-5-yfl-2-(2- methyl butyfl)-1 N dibutylamino~carbonyl)methyl)1pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a colorless glass. TLC (10% MeOH- CH2CI2) Rf 0.49. 1 H NMR (CDCI3, 300 MHz, rotameric forms and mixture of diastereomers) 5 0.69 (br t, J=7Hz) and 0.75-2.15 (several br m, approx. 26H total), 2.48-2.65 (br m, 1H), 2.87-3.01 (br m, 1H), 3.06-3.82 (br m, 7H), 3.90-4.40 (br m, 2H), 5.90 and 5.92 2H 1 0 total), 6.67-6.90 (in, 3H total). MS (FAB) m/e 475 Example 377. trans. trans-4-(1 .3-Benzodioxol-5-yfl-2-(3-methylbutyl)-1 dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. TLC (10% MeOH-CH2CI2) Rf 0.41. 1 H NMR (CDCI3, 300 MHz, rotameric forms) 8 0.73 J=7Hz) and 0.77-1.05 (in, 12H total), 1.07-1.75 (mn, approx. 14H plus H20), 2.48-2.63 (in, 1H), 2.87-3.05 (mn, 1H), 3.05-3.60 (several br mn, 5H), 3.62-4.02 (br m, 2H), 4.29 (br d, J=l5Hz, 1H), 5.89 and 5.93 2H total), 6.65-6.90 (in, 3H total). MS (FAB) mn/e 475 Example 378 trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-y')-1 125 lproo~yl- N-((N-methyl-N-p ropyl ami no)s ulf onyflam ino~ethyllloyrrol idine-: 3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 58-59 00. 1 H NMR (CDC13, 300MHz) 8 0.78 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.27 (sextet, J=7Hz, 2H), 1.48 (mn, 4H), 2.22-2.30 (mn, 1H), 2.62 3H), 2.68-2.78 (in, 1H), 2.84-3.03 (mn, 5H), 3.08-3.31 (mn, 3H),3.39 (dd, J=3Hz, J=9Hz,1H), 3.50-3.58 (mn, 1H), 3.63 J=9H-z, 1H),3.79 3H), 5.95 2H), 3.73 (d, J=8HZ, 1H), 6.83 (dd, J=2Hz, J=8Hz, 1H), 3.87 J=9Hz, 2H), 7.01 (d, J=2Hz, 1H), 7.33 J=9Hz, 2H). MS (DCI/NH3) m/e 576 -386- Example 379 trans, trans-2.4-Di(3.4-difluorophenyn)- 1 Ndibutylamino~carbonyl)methyflp1yrrolidine.3.carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300MHz, CDC13 5 7.35 (2H, in), 7.18 (4H, in), 4.87 (1H, d, J=12), 4.00-3.60 (5H, in), 3.60-3.10 (3H, in), 3.10-2.90 (2H, mn), 1.45 (2H, in), 1.29 (4H, mn), 1.15 (2H, in), 0.91 (3H, t, 0.83 (3H, t, MS (DCI/NH3) mWe 509 Anal calcd for C27H32F4N20 3 0.75 TFA: C, 57.62; H, 5.56; N, 4.72. Found: C, 57.72; H, 5.67; N, 4.66.

Example 380 trans, trans-4- Dim ethyl phenyl).2- (4.meth oxyh eny N- Idibutylaminocarbonyl)methyl)pyrrolidine3ca-rboxylic -acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.43 (2H, d, 7.25 (1 H, bs), 7.18 (1H, dd, J=8, 7.11 (1H, d, 6.90 (2H, d, J=10), 5.48 (1H, d, J=12), 4.26 (IH, d, J=18), 4.16 (2H, in), 3.83 (2H, in), 3.81 (3H, s), 3.56 (1H, bd, J=18), 3.37 (1H, in), 3.20 (1H, in), 2.96 (2H, mn), 2.24 (3H, 2.22 (3H, 1.47 (2H, in), 1.27 (4H, in), 1.10 (2H, 0.93 (3H, t, 0.81 (3H, t, MS (DCI/NH3) in/e 495 Anal calcd for C30H42N204- 1.25 TFA: C, 61.26; H, 6.84; N, 4.40. Found: C, 61.16; H, 7.05; N, 4.38.

Example 381 trans, trans-2.4-Di(3-f luoro-4-methoxyphenyl)-1

N-

dibutylam ino)carbonyfl)methyloyrro lid ine-.3..carb oxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300MHz, CDC13 5 7.20 (2H, in), 7.17 (2H, in), 6.93 (2H, in), 5.48 (1 H, mn), 4.26 (1 H, in), 4.16 (2H, in), 3.83 (2H, in), 3.87 3.56 (1 H, mn), 3.37 (1 H, in), 3.20 (1 H, in), 2.96 (2H, mn), 1.47 (2H, in), 1.27 (4H, in), 1.10 (2H, in), 0.93 (3H, t, 0.81 (3H, t, MS (DCI/NH3) in/e 533 Anal calcd for C29H38F2N20 5 0.75 H20: C, 63.78; H, 7.29; N, 5.13. Found: C, 63.77; H, 7.08; N, 4.99.

-387- Exam le 382 trans, trans-4 .3 -Benz od io xol methoxyphenyl)- 1 p2entyfl .N-(3-methyltohenyI)amino~carbonyl)methylb1yrrolidine-3_ carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 5 0.90 (in, 3H), 0.95 J=7.3 Hz, 3H), 1.13-1.37 (in, 4H), 2.30 3H), 2.34 (s (CH3 rotamer)), 2.73- 2.91 (in, 2H), 3.17-3.26 (mn, 2H), 3.32-3.62 (in, 2H), 3.77-4.08 (mn, 1H), 3.80 3H), 4.71 (mn, 1H), 5.92 (in, 2H), 6.61-6.84 (mn, 6H), 7.04-7.16 1 0 (in, 3H), 7.23-7.29 (mn, 2H). MS (DCI) in/e 559 Anal calcd for C33H38N206 -0.35 H20 0.05 CH3002C2H5: C, 70.03; H, 6.92; N, 4.92.

Found: C, 70.08; H, 6.82; N, 4.95. Example 383 trans, trans-4-( 1.3-Benzodioxol-5-yI)-2-(4-nethoxyohenyl)-1 se butyl-N-(1 -naphthyl)aininocarbonylmethyfloyrrolidine-3-carboxyc Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 6 0.87 J=7 Hz, 3H), 1.20- 1.40 (in, 2H), 1.40-1.60 (in, 2H), 2.42-2.80 (in, 2H), 2.85-4.00 (in, 6H), 3.77 J=1.5 Hz, 3H), 4.05-4.20 (in, 1 5.94 J=2 Hz, 2H), 6.6 (dd, J=9, 10 Hz, 1H), 6.70-6.85 (mn, 4H), 6.95-7.02 (in, 2H), 7.17 (dd, 8H, 7.25 (dd, 8H, 7.38-7.60 (in, 4H), 7.87-8.00 (in, 2H). MIS m/e 581. Analysis calcd for C35H36N206 1.4 H20: C, 69.38; H, 6.45; N, 4.62. Found: C, 69.36; H, 6.07; N, 4.41.

Example 384 trans 'trans-2-(4-Methoxyphenyb)-4-(1 .3-benzodioxol-5-yfl-1 -r2-(N- DhenylI-N-n-hexanesulfonylaino&elhyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a tan solid. m.p. 67-68 OC. 1 HNMR (CD3OD, 300 MHz,) 8 0.88 J=7Hz, 3H), 1.25-1.40 (in, 6H), 1.73 (quintet, J=7Hz, 2H), 2.13-2.23 (in, 1H), 2.64-2.88 (in, 3H), 3.02 (sextet, J=BFtz, 2H), 3.44-3.53 (in, 2H), 3.58 J=9Hz, 1H), 3.56-3.75 (in, 1H), 3.78 3H), 3.88-3.98 (in, 1H), 5.93 2H), 6.72 J=9Hz, 1H), 5.78- -388- 5.84 (in, 6.96 J=2Hz, 1 7.20 J=9Hz, 2H), 7.27-7.36 (in, MS (DCI/NH3) m/e 609 Example 385 trans, trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-methoxyphenyl). 1 m ethyl-i 1.2.3.4-tetrahyd ro u inol in- 1 -yi) ca rbonyl methyl) 1yrrol id ine-..3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 1.03 (in, 3H), 1.10-1.45 (in, 1H), 2.10-2.85 (in, 4H), 2.90-4.00 (in, 7H), 3.76 1.5H), 3.77 isomer), 5.90 (mn, 2H), .6.70-7.40 (in, 11H). MS (DCI) m/e 529 Analysis calcd for 031 H32N206 -0.3 H20: C, 69.73; H, 6.15; N, 5.25.

Found: C, 69.74; H, 6.10; N, 5.01.

Example 386 ,4 trans. trans-4- (1 Benz odi oxol-5-ylb-2 met hoxyp henyl). 1(.eg butyl-hept-2-en-1 -yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound 041 was prepared. 1 HNMR (300 MHz, CD300) 8 0.86 J=7.0 Hz, 3H), 0.90 J=7.0 Hz, 3H), 1.20-1.41 (in, 8H), 1.95-2.06 (in, 4H), 3.24 J=11.0 Hz, I1H), 3.51-3.59 (in, 3H), 3.60-3.71 (in, 1 3.77-3.84 (in, 1 3.81 3H), 4.45 J=11.0 HIz, 1H), 5.52 J=7.4 Hz, 1H), 5.93 2H), 6.77 J=8.1 Hz, 1 6.87 (dd, J=1.8, 8.1 Hz, 1 6.99 (in, 3H), 7.46 (in, 2H).

MS (DCI) m/e 494 Anal calcd for C30H39N05: C, 72.99; 7.96; N, 2.84. Found: C, 72.73; H, 7.89; N, 2.64.

Example 387 trans. trans-2-(3-Fluoro-4-methoxyphenyn)-4-(1 1 -12- (N-12rolyl- N- n-hexanes ulf onyl amin o)ethyll pyrro lid ine-3 carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. in.p. 63-65 0 C. 1 H NMR (CDC13, 300MHz) 8 0.82 J=7Hz, 3H), 0.88 J=6Hz, 3H), 1.23-1.47 (in, 1.44 (sextet, J=7Hz, 2H), 1.71 (quintet, J=6Hz, 2H), 2.24-2.34 (in, 11H), 2.70-2.93 (mn, 2.96-3.12 (in, 2H), 3.15-3.35 (in, 2H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.52-3.59 (mn, 1H), 3.66 J=9Hz, 1H), 3.87 (s, -389- 3H), 5.95 2H), 6.74 J=8Hz, 1 6.82 J=8Hz, 1 6.42 (t, J=8Hz, 1H), 6.96 1H), 7.12 J=9Hz, 1H), 7.17 J=l2Hz, 1H). MS (DCI/NH3) mle 593 ~Examp le 388 trans, trans-4-( 1.3-Benzodioxol-5-ylb-2-(4-methoxylhenyl).1 pyridyfl)methyfl)pyrroli din e-3-carboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 8 2.87 (in, 2H), 3.04 (dd, J=3.29 9.7 Hz, 1H), 3.21 J=13.7 Hz, 1H), 3.51 (in, 1H), 3.76-3.85 (in, 2H), 3.79 3H), 5.90 (in, 2H), 6.71 (in, 1 6.79 (dd, J=1.7 Hz, 7.8H), 6.94 (in, 3H), 7.36-7.45 (in, 3H), 7.81 (in, 1 8.39 (in, 1 8.46 (dd, J=1.4 Hz, I1H). Anal calcd for C25H24N205 0.70 H20 -0.05 CH3CO2C2H5: C, 67.34; H, 5.79; N, 6.23. Found: C, 67.31; H, 5.63; N, 5.90.

Example 389 trans, trans-2-(n-Hexyl)-4-(1 .3-benzodioxol-5-yl)-1

N-

dibutylaminocarbonylmethyflpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CDC13, 300 MHz) 5 0.82-1.00 (in, 9H), 1.20-1.40 (in, 12H), 1.45-1.60 (in, 4H), 1.70-1.90 (br m, 2H), 3.10-3.46 (in, 6H), 3.65 J=10.8 Hz, 1H), 3.76 J=11.0 Hz, 1H), 3.92-4.06 (in, 2H), 4.14-4.34 (mn, 2H), 5.94 2H), 6.73 J=8.1 Hz, 1H), 6.79 (dd, J=8.1, 1.8 Hz, 1H), 6.87 J=1.8 Hz, 1H). MS(DCI/NH3) mle 489 Anal calcd for C28H44N205 0.9 TEA: C, 60.53; H, 7.65; N, 4.74. Found: C, 60.62; H, 7.69; N, 4.61.

Example 390 trans, trpns-4-(1 .3-Benzodioxol-5-yi)-2-(4..methOXYphenyl)-1 p enty I (4-flu oro -3m ethyl 1henyflami no~carbonyl)methyl) py rrol id ine.3-ca rboxylic aci-d Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 8 0.92 (mn, 3H), 0.97 J=7.1 Hz, 3H), 1.13-1.40 (mn, 4H), 2.22 (mn, 3H), 2.58-2.74 (mn, 1H), 2.78-2.87 (mn, 1H), 3.09-3.25 (mn, 2H), 3.39-3.60 (mn, 2H), 3.70-3.90 (in, 1H), 3.80 3H), 4.70 (mn, 11H), 5.93 (mn, 2H), 6.70-6.76 (in, 1H), 6.75 (dd, J=1.4, -390- 8.1 Hz, 1H), 6.80-6.94 (in, 4H), 6.96-7.13 (in, 4H). MS (DCI.) m/e 577 Anal calcd for C33H37FN206 0.25 H20: C, 68.20; H, 6.50; N, 4.82. Found: C, 68.21; H, 6.46; N, 4.74.

Example 391 trans, trans-4- Be nzodioxol -5-yfl-2 met h oxyp henyl)- 1-(2 pyridyflmethyflpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 2.97 (dd, J=7.9, 9.7 Hz, 1 H), 3.04 J=9.6 Hz, 1H), 3.18 (dd, J=4.4 Hz, 9.9H), 3.47 J=14.0 Hz, 1H), 3.59 (mn, 1IH), 3.78 3H), 3.96 J=9.9 Hz, 1H), 3.97 J=13.6 Hz, 1H), 5.90 (in, 2H), 6.73 J=8.1 Hz, 1H), 6.83 (dd, J=1.7, 7.9 Hz, 1H), 6.92 (in, 2H), 6.96 J=1.8 Hz, 1H), 7.28 (in, 1H), 7.44 (in, 2H), 7.53 J=8.1 Hz, 1 7.80 (dt, J= 1.8, 7.7 Hz, 1IH), 8.42 (in, 1 MS (DCI1) mn/e 433 1is Anal calcd for C25H24N205 -0.35 H20: C, 68.43; H, 5.67; N, 6.38.

Found: C, 68.44; H, 5.61; N, 6.24.

Examp le 392 trans. trans-2-(3-Phenylpropyl)-4-(1 .3-benzodioxol-5-yf)l1-(N.Ndibutylaminocarbonylinethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CDCI3, 300 MHz) 8 0.89-0.97 (in, 6H), 1.22-1.36 2 (mn, 4H), 1.41-1.55 (in, 4H), 1.63-1.95 (mn, 4H), 2.62 (dt, J=7.2, 2.1 Hz, 2H), 3.05-3.44 (mn, 7H), 3.53-3.60 (mn, 2H), 3.65-3.76 (mn, 1 3.82-3.90 (in, 1 3.96-4.10 (in, 1 5.92 2H), 6.71 J=8.1 Hz, 1 6.77 (dd, J=8.1, 1.5 Hz, 1H), 6.86(d, J=1.2 Hz, 1H), 7.10-7.28 (in, MS(DCI/NH3) m/e 523 Anal calcd for C31H42N205 0.6 TFA: C, 65.43; H, 7.26; N, 4.74. Found: C, 65.28; H, 7.29; N, 4.50.

Examp~le 393 trans-trans-2-(4-Methoxy-3-fluorophenyfl-4-r7-inethoxy- 1.3benzodioxol-5-yfl)-1-[(N. N-di(nbutyflamino)carbonylmethyll]Dyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. in.p. 115-1 17 0 C. 1 H NMR (300 MHz, CDCI3) 5 0.82 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.5 (in, -391- 8H), 2.85 J=l3Hz, 1H), 2.90-3.17 (in, 5H), 3.20-3.35 (mn, 1H), 3.35- 3.50 (mn, 3H), 3.55-3.65 (in, 1H), 3.84 J=lOHz, 1H), 3.87 3H), 3.92 3H), 5.94 (dd, J=4Hz, 2Hz, 2H), 6.62 1H), 6.70 1H), 6.90 (t, J=8Hz, IH), 7.05-7.20 (in, 2H).

Example 394 trans-trans-2-(l .4-Benzodioxan-6-yfl-4-(7-methoxy-1 .3benzodioxol-5-yfl)-1-r(N .N-di(nbutyflamino~carbonylmethyllpyrrolidine-3-carboxylic acid 1 0 Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 107-110 OC. 1H NMR (300 MHz, CDCI3) 0.82 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.50 (in, 8H), 2.75 J=l3Hz, 1H), 2.90-3.12 (in, 4H), 3.32-3.60 (in, 5H), 3.69 J= 8Hz, 1 3.90 3H), 4.23 4H), 5.95 (dd, J=4Hz, 2Hz, 2H), 6.62 1IH), 6.70 I1H), 6.78-6.93 (m Example 395 trans, trans-4- (1 .3-Benzodi oxol-5-yi)-2- (4-mnet hoxy12 henyfl)-1 b uty I- 2- f Iu oro -hep12t -2 -e n -1 -y 1)p2y rro Ii d in e -3 -c arb oxy Ii c acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 8 0.84 J=7.0 Hz, 3H), 0.88 J=7.0 Hz, 3H), 1.16-1.37 (in, 8H), 1.83 J=8.5 Hz, 2H), 2.03-2.08 (mn, 2H), 2.76-2.92 (mn, 2H), 3.02 J=9.3 Hz, 1H), 3.32-3.42 (in, 2H), 3.50 (in, 1H), 3.71 J=9.2 Hz, 1H), 3.78 3H), 5.91 (mn, 2H), 6.72 (d, J=7.8 Hz, 1 HY 6.83 (dd, J=1.7, 8.1 Hz, 1 6.90 (mn, 2H), 7.02 J=1.7 Hz, 1H), 7.34 (in, 2H). MS (DCI) m/e 512 Anal calcd for C30H38FN05: C, 70.43; H, 7.49; N, 2.74. Found: C, 70.58; H, 7.54; N, 2.66.

Example 396 trans. trans-2-(3-Fluoro-4-ethoxyohenyfl-4-( 1.3-benzodioxol-5-yfl)-1 [2-(N-12rolyl-N-n-p2entanesultonylamino~ethyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. in.p. 65-66 OC. I H NMR (CDCI3, 300 MHz) 5 0.82 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.26-1.36 -392- (in, 4H1), 1.41-1.52 (in, 5H), 1.73 (quintet, J=7Hz, 2H), 2.23-2.33 (in, 1H), 2.69-2.96 (in, 5H), 2.97-3.12 (in, 2H), 3.16-3.37 (in, 2H), 3.43 J=91-Iz, 1H), 3.52-3.59 (in, 1H), 3.66 J=9Hz, 1H), 4.08 J=7Hz, 2H), 5.95 (s, 2H), 6.74 J=8Hz, 1H), 6.82 J=8Hz, 1H), 6.92 J=8Hz, 1H), 6.97 1H), 7.07 J=8Hz, 1H), 7.15 J=l2Hz, 1H). MS.(DCI/NH3) m/e 593 Exam~le 397 trans. trans-2-(4-Methoxy-3-fluorophenyn)-4.(7-methoxy.1 .3benzodioxol-5-yl)-l1-f(N-butyl-N-_ propylamino)carbonylmethyllpyrrolidine-3-carbpxylic -acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 118-120 00. 1 H NMR (300 MHz, CDCI3) 8 0.70-0.90 (4 triplets, J=7Hz), 1.05-1.55 (in, 8H), 2.80-3.50 (in, 9H), 3.55-3.65 (in, 1H), 3.82 J= 10Hz, 1H), 3.85 3H), 3.92 3H), 5.96 2H), 6.62 1H), 6.70 1H), 6.90 J=8Hz, 1H), 7.08-7.22 (in, 2H).

Example 398 trans. trans-4-( 1.3-benzodioxol-5-yO)-2-(4-methoxyph-enyl)-1 butyl-N-(4-chlorophenyflaminocarbonylmethyl)pyrrolidine-3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.50 (mn, 4H), 2.66-4.00 (mn, 9H), 3.81 3H), 5.95 2H), 6.77 J=7 Hz, 1H), 6.85 J=8 Hz, 3H), 7.05 (in, 5H), 7.33-7.42 (in, 211). MS m/e 565 (MWH). Analysis calcd for 031 H33N206CI 0.25 H3P04: C, 63.16; H, 5.77; N, 4.75. Found: C, 63.14; H, 5.59; N, 4.53.

Example 399 trans. trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-methoxyphenyn.. 1 (4.

methyl-i .2 .3.4-tetrahydroauinolin-1 -yflcarbonylmethyfl)yrrouidine-3.

carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 5 1.27 J=7 Hz, 1.5H), 1.28 7H1, 1.5-diastereomer), 1.39-1.55 (mn, 1H), 2.02-2.15 (mn, 1H), 2.60- -393- 3.25 (in, 5H), 3.33-4.00 (in, 5H), 3.78 3H), 5.92 J=3 Hz, 2H), 6.73 (dd, J=8 Hz, 1H), 6.75-6.90 (in, 3H), 6.91-7.35 (in, 7H). MS (DCI) mie 529 Analysis calcd for C31 H32N206: C, 70.44; H, 6.10; N, 5.30.

Found: C, 70.16; H, 6.04; N, 5.04.

Example 400 trans, trans-2-(3-Fluoro-4-methoxyphenyl)P4-(1 1 -f2-(N-Dropyl-N-(2-(piDeridin-1

I

yflethanesulfonylamino)ethyllpyrrolidine-3-carboxylic acid 1 0 Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 95-96 00. 1 H NMR (CDCI3, 300MHz) 5 0.82 J=7Hz, 3H), 1.43-1.55 (in, 4H), 1.63-1.72 (in, 4H), 2.29-2.38 (in, 1H), 2.64-2.78 (in, 5H), 2.87 J=8Hz, 1H), 2.95- 3.04 (in, 5H), 3.20-3.30 (in, 1H), 3.32-3.43 (in, 4H), 3.54-3.63 (in, 1H), 3.78 J=8Hz, 1H), 3.87 3H), 5.92 2H), 6.72 J=8Hz, 6.78 (dd, J=2Hz, J=8Hz, 1H), 6.88 J=8Hz, 1H), 6.94 J=2Hz, 1H), 7.08- 7.20 (in, 2H). MS (DCI/NH3) m/e 620 Example 401 trans. trans-2-(n-Heptyb)-4-(1 .3-benzodioxol-5-yfl-1 ,dibutylaminocarbonylmethyflp1yrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CDCI3, 300 MHz) 8 0.83-0.98 9H), 1.18-1.40 (in, 14H), 1.44-1.60 (in, 4H), 1.72-1.96 (br m, 2H), 3.12-3.45 (in, 6H), 3.65 J 10.5 Hz, 1H), 3.76 J =11.2 3.90-4.06 (in, 2H), 4.13- 4.33 (in, 2H), 5.93 2H), 6.73 J =7.8 Hz, 1 6.79 (dd, J 7.8, 1.7.

Hz, 1H), 6.87 J 1.7 Hz, 1H). MS(DCI/NH3) in/e 503 Anal calcd for C29H46N205 .0.75 TFA: 0, 62.28; H, 8.01; N, 4.76. Found: C, 62.20; H, 7.99; N, 4.50.

Example 402 Ira ns. trans-4- (1 Benz odi oxoI- 5-yl)-2 etho xyp henyl)-1 methyl-i .2.3.4-tetrahydroguinolin-1 -ylbcarbonylmethyflo1yrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 8 0.99 1 1.03 J-6 -394- Hz, 1.5H, second diastereomer), 2.60-4.00m 3.78 1.5H), 3.79 (s, second diastereomer), 5.92 1H), 5.93 1H, diastereomer), 6.65-7.40 (in, 11H). MS (DCI) mle 529 Analysis calcd for C31 H32N206 0.8 H20: C, 68.57; H, 6.24; N, 5.16. Found: C, 70.44; H, 6. 10; N, 5.30.

Example 403 trans. trans-4-( 1.3-Benzodioxol-5-yb)-2-(4-methoxyphenyl)- 1 butyl-N-(4-fluorophenylbaminocarbonylmethylpyrrolidine.3 carboxylic acid Using the procedures described in Example 1, the title compound V was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.2-1.47 (mn, 4H), 2.7 J=12 Hz, 1H), 2.80 J=9 Hz, 1H), 3.09 J=9 Hz, 1H), 3.25 J=15 Hz, 1H), 3.40-3.47 (in, 1H), 3.49-3.65 (in, 3H), 3.75 J=12 Hz, 1H), 3.80 3H), 5.94 2H), 6.72-6.86 (in, 4H), 7.00-7.15 (in, 7H). MS (DCI) m/e 549 Analysis calcd for C31 H33N206F 0.4 C, 66.99; H, 6.13; N, 5.04. Found: C, 66.99; H, 5.94; N, 4.99.

Example 404 trans~trans-1 -(N-Butyl-N-(3-methylphenyI)aminocarbonylmethyI)-2-. (4-methoxyphenyl)-4-(5-benzofuranyflpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300MHz, CDCI3) 8 7.66 (1 H, bs), 7.60 (1 H, d, J=3Hz), 7.45 (2H1, 7.15 (411, in), 6.75 (5H, in), 3.96 (1H, d, J=lOHz), 3.78 (3H, 3.74 (1 H, in), 3.59 (3H, in), 3.21 (1 H, t, J=9Hz), 3. 19 01H, J=1l6Hz), 2.92 (1H, t, J=9Hz), 2.70 (1 H, d, J=1611z), 2.29 (3H, s), 1.41 (2H, in), 1.24 (211, in), 0.85 (3H, t, J=7Hz). MS (DCI, NH3) m/e 541 Anal. calcd for C33H34N20 1 H20: C, 71.21; H, 6.52; N 5.03.

Found: C, 71.3 1; H, 6.30; N, 4.98.

Example 405 trans, trans-i -(N-Butyl-N-(3-methylphenyflaininocarbonylmethyw)2.

(4-fluorophenyb)-4-(5-benzofuranyboryrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 7.67 (1 H, bs), 7.60 (1 H, d, J=3Hz), 7.45 (2H, in), 7.18 (3H, in), 7.12 (1H, d, J=7Hz), 6.93 (2H, in), -395- 6.76 (1H, d, J=3Hz), 6.70 (2H, bd), 4.02 (1H, in), 3.77 (1H, in), 3.59 (3H, mn), 3.29 (1 H, in), 3.19 (1 H, mn), 2.94 (1 H, in), 2.71 (1 H, in), 2.30 (3H, 1.45 (2H, in), 1.26 (2H, sext, J=7Hz), 0.84 (3H, t, J=7Hz). MS (DCI, NH3) in/e 529 Anal. calcd for C33H34N205 -0.2 HOAc: C, 71.98; H, 6.30; N 5.18. Found 71.68; H, 5.89; N, 5.25.

Example 406 trans. trans-4-(l .3-Benzodioxol-5-yi)-2-(4-methoxyphenyfl)-1

N-

(d i-(3-methy 112henyfl)am in o~carbonyl) met hyfl)pyrro lid ine-3-ca rboxylic ai Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3O1D) 8 2.27 6H), 2.81 (dd, J--8.1, Hz, 1H), 2.98 J=15.3 Hz, 1H), 3.20 J=16.6 Hz, 1H), 3.47-3.60 (in, 3H), 3.80 3H), 3.85 J=9.5 Hz, I1H), 5.91 2H), 6.73 J=7.8 Hz, 6.85 (in, 3H), 6.95 (in, 4H), 7.05 J=1.7 Hz, 1H), 7.06-7.24 (in, MS (DCI) in/e 579 Anal calcd for C35H34N2O6 0.15 0.20 CH3002C2H5: C, 71.79; H, 6.04; N, 4.68. Found: C, 71.81; H, 5.79; N, 4.51.V- Example 407 V trans. trans-4-( 1.2-Dihyd robenzof uran-5-yfl-2-(4-methoxyohenyn)-1 (((N-butyl-N-(3-methylphenyflamino~carbonyflmethyflp1yrrolidine-3. carboxylic acid Using the procedures described in Example 1, the title compound 125 was prepared. 1 H (300MHz, CDC13 8 7.73 (2H, 7.40-7.10 (4H, in), 6.92 in), 6.72 (2H, d, 6.63 (1 H, mn), 5.40 (1 H, in), 4.55 (2H, t, 4.30-4.10 (3H, in), 3.84 (3H, 3.82 (1H, in), 3.65 (1H, mn), 3.39 (1H, mn), 3.21 t, 3.10-2.90 (2H, in), 2.26 (3H, 1.55 (2H, in), 1.45 (2H, mn), 0.92 (3H, t, MS (DCI/NH3) in/e 543 Anal calcd for C33H38N205 0.65 H20: C, 71.50; H, 7.15; N, 5.05 Found: C, 71.47; H, 6.96; N, 4.83.

-396- Example 408 trans, trans-2-(3-Fluoro-4-methoxyphenyfl-4-(1 1 -f2-(N-propyl-N-[2-(N. Ndimethylamino)lethanesulfonylamino)ethylllDyrrolidine.3.carboy"lic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 81-82 00. 1H NMR (CDCI3, 300 MHz) 8 0.80 J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2H), 2.15- 2.24 (in, 1H), 2.36 6H), 2.66-2.76 (in, 1H), 2.83-3.04 (in, 6H), 3.18- 3.41 (in, 5H), 3.55-3.63 (in, 1H), 3.72 J=8Hz, 1H), 3.85 3H), 5.90 J=6Hz, 2H), 6.67 J=8Hz, 1H), 6.78 (dd, J=2Hz, J=8Hz, 1H), 6.84 (t, J=8Hz, 1H), 7.94 J=2Hz, 1H), 7.09 J=8Hz, 1H), 7.20 (dd, J=2Hz, J=l2Hz, 1 MS (DCI/NH3) mn/e 580 Example 409 trans, trans-i N-Dibutylaminocarbonylmethyl)-2-(4-f luorophenyn..

4-(5-benzofuranyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 5 7.88 (1 H, bs), 7.80 (2H, in), 7.61 (1H, d, J=3Hz), 7.55 (1H, bd, J=8Hz), 7.46 (1H, d, J=8Hz), 7.07 (2H1, t, J=8Hz), 6.76 (1H, d, J=3Hz), 5.53 (1H, bd, J=llHz), 4.18 (2H, rn), 3.91 (3H, mn), 3.55 (1H, d, J=l6Hz), 3.30 (3H, in), 3.12 (1H, dd, J=10&9Hz), 2.95 (1H, in), 1.51 (2H, in), 1.31 (4H, in), 1.12 (2H, in), 0.92 (3H, in), 0.83 (3H, t, J=7Hz). MS mn/e (DCI, NH3) 595 Example 410 trans. trans-4-(1 .2-Dihydrobenzof uran-5-ylb-2-(4-ethylphenyl)-1 butyl-N-(3-methylphenylanino~carbonyl)methyl)pyrrolidine.3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.35 (2H, in), 7.20-7.00 (7H, in), 6.70 (2H, d, 5.38 (1H, in), 4.55 (2H, t, 4.05 (1H, in), 3.64 (2H, in), 3.45 (1H, in), 3.21 (2H, t, 2.95 (1H, in), 2.75 (1 H, in), 2.63 (2H, q, 2.38 (2H, in), 2.27 (3H, 1.43 (2H, in), 1.30 (2H, in), 1.22 (3H, t, 0.89 (3H, t, MS (DCI/NH3) nile 541 Anal -397calcd for C34H4ON2O4 1.6 AcOH: C, 70.17; H, 7.34; N, 4.40. Found: C, 70.11; H, 7.06; N, 4.80.

Example 411 trans. trans-4-( 1.2-Dihyd robe nzof uran-5-yF)-2-(4-flIuorophenyl,)- (((N.N-dibutylamino~carbonyl)methyflo1yrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.40 (2H, in), 7.28 (1 H, bs), 7.18 (1 H, dd, J=8, 7.00 (2H, t, 6.72 (1 H, d, 4.53 (2H, t, 3.92 (1 H, in), 3.65 (1 H, in), 3.42 (3H, in), 3.19 (2H, t, 3.15- 2.90 (6H, in), 1.43 (3H, in), 1.25 (3H, in), 1.10 (2H, in), 0.90 (3H, t, 0.83 (3H, t, MS (DCI/NH3) m/e 497 Anal calcd for C29H37FN204 0.25 H20: C, 69.51; H, 7.54; N, 5.59. Found: C, 69.45; H, 7.60; N, 5.44. Example 412 trans, trans-4-( 1.2-Dihyd robenzof uran-5-yfl-2-(4-f luorophenyl)- 1 (((N-butyl-N-(3-methylphenyflamino~carbonyflmethyl)D2yrrolidine-3-.

carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 5 7.28 (1 H, bs), 7.25-7.00 in), 6.91 (2H, in), 6.72 (3H, d, 4.54 (2H, t, 4.00 (1 H, mn), 3.60 (3H, in), 3.45 (1 H, in), 3.19 (2H, t, 3.11 (2H, in), 2.84 (1KH, in), 2.67 (1H, bd, J=18), 2.26 1.42 (2H, in), 1.25 (2H, in), 0.88 (3H, t, J=8).

MS (DCI/NH3) mle 531 Anal calcd for C32H35FN204 0.25 C, 71.82; H, 6.69; N, 5.23. Found: C, 71.66; H, 6.55; N, 5.03.

Example 413 trans. trans-4-( lndan-5-yl)-2-(4-methoxyphenyfl- 1 dibutylamino)carbonyl)methyflpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CDC13 8 7.32 (3H, in), 7.18 (2H, in), 6.85 (2H, d, 3.83 (1H, in), 3.79 (3H, 3.67 (1H, in), 3.50-3.20 (4H, in), 3.20-2.92 (4H, in), 2.87 (5H, in), 2.79 (1H, bd, J=15), 2.06 (2H, mn), 1.43 (2H, in), 1.27 (4H, in), 1.08 (2H, in), 0.88 (3H, t, 0.82 (3H, t, -398- MS (DCI/NH3) m/e 507 Anal calcd for C31 H42N20 4

C,

73.49; H, 8.36; N, 5.53. Found: C, 73.18; H, 8.29; N, 5.17.

Example 414 trans, trans-2-(4-Methoxyphenyl)-4-(3.4-difluorophenyl)- 1 -f(N-butyl- N-(3-methylp~henybamino)carbonylmethyllpyrrolidine-3-cprboxylic Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300MHz, CDCI3) 8 0.86 J=7Hz, 3H), 1. 10-1.35 (in, 2H), 1.35-1.52 (mn, 2H), 2.29 3H), 2.63 J=13H-z, 1H), 2.76 (t, J=7Hz, 1 3.06-3.20 (in, 2H), 3.42-3.53 (in, 1 3.50-3.64 (in, 3H), 0 3.80 3H), 3.86 J=9Hz, 1 6.66-6.82 (in, 4H), 7.02-7.22 (in, 6H), V 7.30-7.40 (mn, 1H).

Example 415 trans. trans-i N-Butyl-N-(3-chlorophenyllaminocarbonylinethyl)-2- (4-fluorophenyl)-4-(5-benzofuranyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13) 8 7.64 (1 H, d, J=2Hz), 7.61 (1 H, d, J=3Hz), 7.47 (1H, d, J=8Hz), 7.41 (1H, dd, J=8&3Hz), 7.30 (1H, dt, J=8&2Hz), 7.21 (1H, d, J=8Hz), 7.19 (2H, in), 7.00 (1H, bs), 6.94 (2H, t, J=8Hz), 6.83 (1H, bd, J=8Hz), 6.74 (1H, dd, J=2&lHz), 3.96 (1H, d, J=1lOHz), 3.75 (1 H, ddd, 6, 5&3Hz), 3.59 (3H, in), 3.23 (1 H, t, J=1lOHz), 3.18 (1 J=1l6Hz), 2.92 (1 H, dd, J=1 0&9Hz), 2.69 (1iH, d, J=1l6Hz), s1.41 (2H, in), 1.23 (2H, in), 0.87 (3H, t, J=7Hz). MS (DCI, NH3) 549, 551 W Anal. calcd for C31 H30CIFN20: C, 67.82; H, 5.51; N, 5.10.

Found: C, 67.43; H, 5.33; N, 4.78.

Example 416 trans, trans-4-( 1.3- Ben zodi oxo 1-5-ylb-2 -(4-nethoxyph enyl) 1 propyl-N-(4-phenoxybenzyfl am ino)carbonyl )methyl)p2yrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CDC13 8 (rotamer) 7.40-7.20 in), 7.13 (2H, in), 6.98 (2H, in), 6.93-6.60 (7H, in), 5.93 (1 H, d, 5.88 (5.85) (1H, d, 4.90 (4.50) (1H, d, J=15), 4.10 (4.25) (11H, d, -399- 3.77 (3.73) (3H, 3.72 (1 H, in), 3.60 (1 H, in), 3.53-3.20 (3H, in), 3.15- 2.75 (4H, in), 1.60-1.20 (2H, in), 0.83 (0.64) (3H, t, MS (DCI/NH3) m/e 623 Anal calcd for C37H38N207 -0.25 H20: C, 70.85; H, 6.19; N, 4.47. Found: C, 70.68; H, 6.10; N, 4.42.

Example 417 trans, trans-4-(l .2-Dihydrobenzofuran-5-y)-2-(4-ethyllhenyl)..1-(((N- (2-pentyb)-N-(4-fluoro-3inethyllhenyflamino)carbonylbmethyflpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.30 (H s,72-.0(H in), 6.87 (1 H, in), 6.73 (2H, d, 6.57 (1 H, in), 4.81 (1IH, in), 4.55 (2H, t, 3.92 (1 H, bd, J=1 3.60 (1 H, in), 3.43 (1 H, in), 3.18 (2H, t, J=9), 3.17 (1 H, in), 3.06 (1 H, dd, J=1 5, 2.88 (1 H, dd, J=1 1, 2.61 (2H, q, 2.59 (1 H, in), 2.18 (3H, in), 1.40-1.10 (41H 1.22 (3H, t, J=9), 1.00-0.80 (6H1, in). MS (DCI/NH3) m/e 573 Anal calcd for C35H41FN204 0.75 H20: C, 71.71; H, 7.31; N, 4.78. Found: C, 71.56; H, 7.33; N, 4.56.

Example 418: trans, trans-2-(4-Methoxlhenyfl-4-( 1.3-benz odioxol-5-yfl- 1 -r2-(N- P2rolyl-N-[2-pyrimidinylamino~ethylpyrrolidine-3-carboxylic acid 999 Ethyl 2-(4-inethoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1 pro pylam~ro)p ropyl] pyrrolid ine-3-carboxyl ate, prepared by the procedures of Example 61B (300 mng), 138 mg of 2-bromopyrimidine, and 150 mg of diisopropylethylamine were heated at 95 00 for 15 hours in 2 mL of acetonitrile. The resulting intermediate trans-trans ethyl ester was isolated by chromatography on silica gel eluting with 5-10% ETOAc in CH12CI2 and hydrolyzed with NaOH in ethanol/water to give mg of the title compound. 1 H NMR (300 MHz, CDCl3) 5 0.82 J=7Hz, 31H), 1.50 (sextet, J=7Hz, 2H), 2.15-2.30 (in, 11H), 2.75-2.97 (mn, 3H), 3.40-3.55 (m 4H1), 3.60-3.70 (mn, 31H), 3.75 3H), 5.95 2H), 6.34 (t, J=-4Hz, 1H), 6.65 J=8Hz, 1H), 6.75-6.82 (in, 11H), 6.78 J=9Hz, 21H), 6.96 J=2Hz, 1H), 7.27 J=9Hz, 2H), 8.20 J=4Hz, 21H).

-400- Examlle 419 trans, trans-4-(l .3-Benzodioxol-5-yl)-2-(4-methoxylhenyl)- 1 butyl-2-chloro-hept-2-en-1 -yflpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 8 0.84 J=6.8 Hz, 3H), 0.88 J=6.7 Hz, 3H), 1.19-1.39 (in, 8H), 2.05-2.09 (in, 2H), 2.17-2.23 (in, 2H), 2.78 (dd, J=6.6, 9.2 Hz, 1 2.95 J=9.2 Hz, 1 3.32-3.37 (in, 2H), 3.49 (in, 1 3.70 J=9.2 Hz, 1 3.77 3H), 5.91 (in, 2H), 6.72 J=8.1 Hz, 1H), 6.85 (dd, J=1.9, 8.1 Hz, 1H), 6.89 (in, 2H), 7.08 (d, J=1.5 Hz, 1H), 7.36 (in, 2H). MS (DCI) mle 528 Anal calcd for C30H38CIN05 0.25 H20: C, 67.66; H, 7.29; N, 2.63. Found: C, 67.62; H,0 7.18; N, 2.40.

Example 420 trans, trans-4- (1 D ihyd robenzof uran -5-yI)-2-(4-meth oxyphenyl)- 1 (((N-(2-pentyfl-N-(4-fluoro-3methylp~henyflamin-o~carbonyl~inethylnpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 5 7.28 (1 H, bs), 7.15 (3H, in), 6.90 (1 H, mn), 6.77 (2H, dd, J=9, 6.71 (2H, d, 6.56 (1 H, in), 4.80 (I1H, in), 4.53 (2H, t, 3.92 (1 H, in), 3.79 (3H, 3.60 (1 H, in), 3.45 S* (1H, in), 3.19 (2H, t, 3.18 (1H, in), 3.03 (1H, dd, J=15, 2.85 O1H, mn), 2.55 (1H, in), 2.18 (3H, in), 1.40-1.05 (4H, in), 1.00-0.80 (6H, in). MS (DCI/NH3) in/e 575 Anal calcd for C34H39FN205 0.35 H20: C, 70.29; H, 6.89; N, 4.82. Found: C, 70.37; H, 6.92; N, 4.30.

Example 421 trans. trans-4- 1.2- D ihyd robenzof uran- 5-yl-2%(4- meth oxyh enyl).1 (((N-butyl-N-(3-chlorophenyliamino)carbonyl)methyl)ipyrrolidine.3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 5 7.29 (1 H, d, 7.25-7.05 in), 6.98 (1 H, bs), 6.80 (2H, in), 6.72 (2H, d, 4.53 (2H, t, J=9), 3.85 (1H, d, J=10), 3.79 (3H, 3.58 (3H, in), 3.42 (1H, dd, J=10, 6), 3.18 (4H, mn), 2.87 (1 H, mn), 2.66 (1 H, mn), 1.40 (2H, in), 1.25 (2H, in), 0.86 (311, t, MS (DCI/NH3) in/e 563 Anal calcd for -401- C32H35CIN205 .0.25 H20: C, 67.72; H, 6.30; N, 4.94. Found: C, 67.72; H, 6.2 1; N, 4.5 Examlle 422 trans. trans-4-(1 .3-Benzodioxol-5-yb)-2-(5-ethylf uran-2-yl)- I Ndibutylamino)carbonyflmethyl)p2yrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.77 (1 H, bs), 7.11 (1 H, d, 7.02 (1 H, dd, J=9, 6.82 (1 H, d, 6.52 (1 H, dl, 6.08 (1H, d, 5.98 (2H, 5.80 (1H, d, 4.70 (1H, bd, J=15), 4.37 (2H, in), 3.70 (2H, in), 3.39 (2H, in), 3.20 (1H, in), 3.10-2.82 (2H, in), 2.76 (2H, q, 1.45 (2H, mn), 1.32 (3H, t, 1.30-1.10 (6H, mn), 0.87 (3H, t, 0.85 (3H, t, MS (DCI/NH3) Wne 499 Anal calcd for C28H38N206 1.75 HOI: C, 59.80; H, 7.12; N, 4.98. Found: C, 59.51; H, 6.96; N, 4.88.

Example 423 trans. trans-4-( 1.2-Dihyd robenzof uran-5-ylb-2-(4-f luorophenyfl-1 (2-pentyl)~-N- (4-flu oro methylp~henyl)amino)carbonyflmethyl)p2yrrolidine-3-carboxylic acid Using the procedures described irT Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.30-7.10 (4H, in), 6.92 (3H, in), 6.73 (2H, d, 6.59 (1KH, in), 4.80 (1 H, in), 4.53 (2H, t, 4.00 (11, bd, J=10), 3.62 (1H, in), 3.45 (1H, in), 3.22 (1H, mn), 3.21 (2H, t, 3.02 (1H, dd, J=15, 3.85 (1H, t, J=10), 2.58 (1H, bd, J=18), 2.20 bs), 1.40-1.30 (3H, in), 1.15 (1H, in), 1.00-0.80 (6H, in). MS (DCI/NH3) m/e 563 Anal calcd for C33H36F2N204: C, 70.44; H, 6.45; N, 4.98. Found: C, 70.06; H, 6.47; N, 4.71.

Example 424 trans. trans-4-( 1.2-Dihyd robenzof uran- 5-yfl-2-(4-flIu orophenyl)- 1 (((N-butyl-N-(3-chlorophenyl)ainino)carbonyl)inethyl)p2yrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 7.30 (2H, in), 7.25-7.10 (4H, in), 6.95 (3H, in), 6.82 (1KH, bd, 6.73 (1KH, d, 4.55 (2H, t, J=9), -402- 3.92 (1H, bd, J=11), 3.60 (3H, in), 3.43 (1H, dd, J=9, 3.21 (2H, t, J=9), 3.16 (2H, in), 2.87 (1H, in), 2.69 (1H, in), 1.42 (2H, in), 1.26 (2H, in), 0.87 (3H, t, MS (DCI/NH3) m/e 551 Anal calcd for C31H32CIFN2O4 .0.25 H20: C, 67.02; H, 5.90; N, 5.04. Found: C, 66.98; H, 5.71; N, 4.76.

Example 425 trans, trans-4- (1 Di hyd rob enz of uran (4-etlphe nyll)1 butyl- N-(3-ch lo rop heny1) am in o)ca rbonyl m ethyl) 1yrrolidine.3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.30 (1H, in), 7.21 (1H, d, 7.15 (2H, in), 7.09 (4H, bs), 6.96 (1 H, bs), 6.80 (1 H, bd, 6.73 (1H, d, 4.54 (2H, t, 3.89 (1H, bd, J=11), 3.60 (3H, in), 3.43 (1 H, in), 3.22 (2H, t, 3.18 (2H, in), 2.92 (1 H, in), 2.72 (1 H, in), 2.62 q, 1.41 (2H, in), 1.26 (2H, in), 1.23 (3H, t, 0.87 (3H, t, MS (DCI/NH3) m/e 561 Anal calcd for C33H37CIN204 0.25 H20: C, 70.08; H, 6.68; N, 4.95. Found: C, 70.13; H, 6.59; N, 4.65.

Example 426 trans, trans- 1 Butyl- N-(3-cho rophe nyl) ca rboxam id omethyl2-(4inethoxyphenyfl-4 (5-benzofuranyl)yrrolidine.3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 7.67 (1H, bs), 7.60 (1H, d, J=3Hz), 7.48 (1H, d, J=8Hz), 7.42 (1H, dd, J=8&3Hz), 7.29 (1H, dt, J=8&3Hz), 7.21 (1H, d, J=8Hz), 7.14 (2H, in), 6.99 (1H, bs), 6.76 (4H,.

in), 3.88 (1H, d, J=lO1-z), 3.75 (1H, ddd, 5&3Hz), 3.59 (2H, in), 3.53 (1H, dd, J=10&3Hz), 3.22 (1H, t, J=9Hz), 3.19 (1H, mn), 2.96( 1H, in), 2.70 (1H, d, J=l6Hz), 1.42 (2H, in), 1.26 (2H, in), 0.87 (3H, t, J=7Hz). MS NH3) m/e 563, 561 Anal. calcd for C32H33CIN205 -0.5 H20: C, 67.42; H, 6.01; N, 4.91. Found: C, 67.45; H, 5.82; N, 4.68.

-4 03- Examlle 427 trans, trans-4- (1 .3 Benzodi oxol.5-yfl-2 -(4-met hoxyph-enyI)- 1 cycl ohexyl-N- bulyl amino) ca rbony 1)m ethyl)pyrroh id in e.3..crboxy ic Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) (rotamer) 8 0.78 (0.86) 3H, J=7Hz), 0.90-1.90 (envelope, 14H), 2.69 (2.80) 1H, J=l2Hz), 2.9-3.8 (envelope, 10H), 3.78 (3.80) 3H), 5.92 2H), 6.72 1H, J=9Hz) 6.86 (in, 3H) 7.03 I H, J=6Hz), 7.34 (in, 2H). MS (DCI/NH3) m/e 537 Anal. calc'd for C31 H40N206 1 H20: C, 67.13; H, 7.63; N, 5.05.

Found: C, 67.09; H, 7.34; N, 4.92. Example 428 trans, trans-4- (1 Benzod ioxol- 5yl-2- (4 -ethyl1h e nyl) 1 1 5 methylphenyl)- N-butylamino) ca rbonyl) methyl) pyrrol id ine..37carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13) 8 0.86 3H, J=7Hz), 1.22 (t, 3H, J=7Hz), 1.25 (mn, 2H), 1.43 (in, 2H), 2.26 3H), 2.6 2H, J=7Hz), 2.68 1H, J=12H-z), 2.86 1H, J=8Hz), 3.19 2H, J=7Hz), 3.44 (dd, 1 H, J= 3Hz,l1OHz), 3.59 (in, 3H), 3.94 1 H, 9Hz), 5.92 2H), 6.75 (in, 3H), 6.86 (dd, 1 H, J= 2Hz, 8Hz), 7.08 (mn, 6H), 7.17 1 H, J= 8Hz). MS (DCI/NH3) m/e 543 Anal. calc'd for C33H-38N205 0.60 H20: C, 71.61; H,'7.14; N, 5.06. Found: C, 71.57; H, 6.80; N, 4.87.

Examn~le 429 trans. trans-4-(Benzof u ran- 5-yfl-2-(4-ethylphenyl 1 methyl phenyl)- N-butyl ami noicarbonyflm ethyl)p1yrroi id ine.3.ca rboxyli11c acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13) 8 0.90 3H, J=7Hz), 1.30 (t, 3H-, J=7Hz), 1.31 (in, 2H), 1.43 (in, 2H), 2.27 3H), 2.73 2H, J=7Hz), 3.15 2H, J=l7Hz), 3.61 2H, J= 8Hz), 3.82 (in, 2H), 4.00 1 H, 12Hz), 4.26 (in, 2H), 5.53 (br d, 1 6.54 (br s, 2H), 6.76 1 H, J= 2Hz), 7.14 (mn, 3H), 7.28 1 7.40 (in, 3H), 7.48 1 H, J= 8Hz), 7.63 1 H, -404- J=2Hz), 7.73 1H). HRMS. calc'd for 034H39N204 539.2910.

Found: 539.2891 Example 430 trans. trans-4-(1 .4-Benzodioxan-6-yfl-2-(4-ethylphenyl)-l1-(((N-(3methylp~henyl)- N-butyl amino) carbonyl)methyl) pyrroidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 0.87 3H, J=7Hz), 1.22 (t, 3H, J=7Hz), 1.24 (in, 2H), 1.42 (in, 2H), 2.30 3H), 2.61 2H, J=7Hz), 2.67 1H, J=l4Hz), 2.86 1H, J= 8Hz), 3.18 2H, J=7Hz), 3.41 (dd, 1 H, J=4,1OF-z), 3.59 (in, 3H), 3.93 1H, J=l0Hz), 4.25 (in, 4H), 6.74 (br s, 2H), 6.80 1 H, J=8Hz), 6.93 (dd, 1 H, J=2Hz,8Hz), 6.99 1 H, J=2Hz), 7.07 (in, 5H), 7.17 1H, J=8Hz). MIS (DCI/NH3) m/e 557 Anal.

1 5 caic'd for C34H4ON2O5 0.40 H20: C, 72.42; H, 7.29; N, 4.97. Found: C, 72.49; H, 7.16; N, 4.62.

Example 431 trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -E2-(N-propyl-N-2-mesitylenesulfonylamino)ethyllpyrrolidine-3carboxylic acid: Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 80-82 OC. 1 H NMR (CDCI3, 300 MHz) 8 0.69 J=7Hz, 3H), 1.37 (sextet, J=7Hz, 2H), 2.09-% 2.17 (mn, 1H), 2.24 3H), 2.53 6H), 2.54-2.64 (in, 1H), 2.73-2.86 (in, 2H), 3.02 (sextet, J=7Hz, 2H), 3.13-3.28 (in, 3.44-3.53 (mn, 1H), 3.57 J=9Hz, 1H), 3.89 3H), 5.94 2H), 6.74 J=8Hz, 1H), 6.78 (dd, J=2Hz, J=8Hz, 1H), 6.85 2H), 6.92 J=8Hz, 1H), 9.94 J=2Hz, 1H), 7.06 J=8Hz, 1H), 7.13 (dd, J=2Hz, J=l2Hz, 1H). MIS (DCI/NH3) m/e 627 Example 432 trans. trans-2-(4-Methoxyphenyl)-4-(3 .4-dif luorophenyl)-1 -r(N-butyl- N-(3-chlorophenyl)amino)carbonylmethyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 5 0.86 J=7Hz, 3H), 1.18-1.32 -4 (in, 2H), 1.35-1.48 (in, 2K), 2.64 J=l3Hz, 2.71 J= 7Hz, 1H), 3.08-3.18 (in, 2H), 3.42-3.48 (mn, 1H), 3.53-3.64 (in, 3H), 3.77 3K), 3.80 J=9Kz, 1H), 6.73-6.85 (in, 3H), 6.94 1H), 7.04-7.40 (in, 7H).

s Example 433 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 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 0.80 3K, 1.47 (bd hex, 2K, 2.15 (pen, 2H, 2.32 (in, 1H), 2.7-3.2 (in, 9H), 3.46 V. (dd, 1H, J=4, 10), 3.57 (in, 1H), 3.64 2K-, 3.67 1K, 3.86 3H), 5.92 2H), 6.74 1KH, 6.84 (dd, 1KH, J=2, 6.96 1KH, 7.06 1KH, 7.18 (in, 2H). MS (DCI/NH3) m/e 585 1 5 3 5 587 37CI)+. Anal calcd for C27H34N207C1FS: C, 55.43; H, 5.86; N, 4.79. Found: C, 55.65; H, 5.81; N, 4.70.

Example 434 trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 4 1-2( .uy--3clrpo~nsloy~mn 1-2-Niout--3choorpaeufnylmn)ethyfl)pyrrolidine- 3-carboxylic acid: Using the procedures described in Example 66, the title compound was prepared. I H NMR (CD3OD, 300 MHz) 8 0.79 3H, 0.84 3H, J=7),1.68 (hept, 1K, 2.18 (pen, 2K, 2.8-3.4 (in, 10H), 3.5-3.8 41 (mn, 3H), 3.65 2K, 3.90 3H), 5.94 2H), 6.77 1H, J=8), 6.87 (dd, 1KH, J=2, 6.99 1KH, 7.13 1KH, 7.27 (in, 2H).

MS (DCI/NH3) mn/e 599 Anal calcd for C28H36N2O7CIFS 0.3 TEA: C, 54.24; K, 5.78; N, 4.42. Found: C, 54.19; K, 5.71; N, 4.01.

Example 435 trans, trans-2 -Pro poxyinethyl 1.3-b enzod ioxoI- 5-yl) -1 Ndibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. IH NMR (CDCI3, 300 MHz) 8 0.87-0.98 (in, 9K), 1.21-1.39 (in, 4K), 1.43-1.57 (mn, 4K), 1.58-1.70 (in, 2K), 3.13-3.29 (in, 4H), 3.34- 3.43 (in, 3H), 3.45-3.55 (in, 3K), 3.69 (dd, J 10.2, 4.5 Hz, 1KH), 3.80- -406- 4.20 (in, 4H), 5.93 2H), 6.73 J 7.8 Hz, 1 6.84 (dd, J 8.2, 1.7 Hz, 1H), 6.93 J 1.7 Hz, 1H). MS(DCIINH3) m/e 477 Anal.

calcd for C26H-40N206O.50 TFA: C, 60.77; H, 7.65; N, 5.25. Found: C, 60.73; H, 7.74; N, 5.22.

Example 436 trans, trans-2-(3-Fluoro-4-methoxyphenyfl-4-( 1.3-benzodioxol-5-yn 1 -r2-(N-propyl-N-(4-methylbutanesulfonylamino~ethyllpyrrolidine.3 carboxylic acid 1 0 Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 65-67 OC. 1 HNMR (CDCI3, 300MHz) 8 0.82 J=7Hz, 3H), 0.88 J=5Hz, 6H), 1.46 (sextet, J=7Hz, 2H), 1.56-1.64 (in, 3H), 2.24-2.33 (in, 1H), 2.68-2.93 (in, 2.98-3.12 (in, 2H), 3.15-3.35 (in, 2H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.52-. 3.58 1H), 3.65 J=l2Hz, 1H), 3.87 3H), 5.95 2H), 6.73 (d, J=8H[z, 1 6.82 (dd, J=2Hz, J=8Hz, 1 6.92 J=8Hz, 1 6.97 (d, J=2Hz, 1H), 7.10 J=9Hz, 1Hz) ,7.16 (dd, J=2Hz, J=l2Hz, 1H). MS (DCI/NH3) m/e 579 Example 437 trans, trans-2-(4-Methoxy-3-fluorophenyfl-4-(7-methoxy-1 .3benzodioxol-5-yi)l1 -12-(N-prolyl-N:n- p2entanesulfonyl)amino)ethyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMVR (300MHz, CDCI3) 5 0.81 J=7Hz, 3H), 0.90 (t, J=9Hz, 3H), 1.25-1.35 (mn, 4H), 1.44 (sextet, J=7Hz, 2H), 1.67-1.78 (in, 2H), 2.22-2.34 (in, 1H), 2.30-2.95 (in, 5H), 2.95-3.10 (mn, 2H), 3.15-3.33 (mn, 2H), 3.45 (dd, J=3Hz, 9Hz, 1H), 3.47-3.56 (in, 1H), 3.65 J=9Hz, 1H), 3.88 3H), 3.94 3H), 5.95 2H), 6.55 1H), 6.65 1H), 6.92 J=7H-, 1H), 7.11 J=9Hz,1H), 7.17 J=l2Hz, 1H).

-407- Examlle 438 trans. trans- 243- F Iu oro-4 -meth oxyph enyl)-4- (1 benzod ioxo 1-5-Y I)- 1 -r2-(N-propyl-N-(2.2.3.3.3pentafluoropropoxyethanesufonylamino~ethyllyrroidine.3 carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 63-64 OC. 1 HNMR (CDCI3, 300MHz) 8 0.82 J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.24- 2.33 (in, 1H), 2.70-2.82 (in, 1H), 2.85-3.09 (in, 5H), 3.14-3.28 (in, 4H), 1 0 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.52-3.58 (in, 1H), 3.65 J=9Hz, 1H), 3.87 3H), 3.92-3.98 (in, 3H), 5.94 2H), 6.74 J=8Hz, 1H), 6.82 (dd, J=2Hz, J=8Hz, 1H), 6.92 J=8Hz, 1H), 6.97 J=2Hz, 1H), 7.10 (d, J=9Hz, 1H), 7.17 (dd, J=2Hz, J=l2Hz, 1H). MS (DCI/NH3) m/e 685 Exain~e 439 trans. trans-2-(1 .4-Benzodioxan-6-yfl-4-(7-inethoxy- 1 .3-benzodioxol- 1 -r2-(N-propyl-N-(n-pentanesulfonyflamino~ethyllpyrrolidine-3 carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CDCI3) 8 0.81 J=7Hz, 3H), 0.90 J=7H-z, 3H), 1.23-1.36 (in, 4H), 1.45 (sextet, J=7Hz, 2H), 1.65-1.78 (in, 2H), 2.20- 2.30 (in, 1H), 2.30-2.95 (mn, 5H), 2.95-3.10 (in, 2H), 3.15-3.35 (in, 2H), 3.42 (dd, J=3Hz, 9Hz, 1H), 3.46-3.56 (mn, 1H), 3.59 J=9Hz, 1H), 3.91 3H), 4.24 4H), 5.95 2H), 6.57 1H), 6.68 1H), 6.82 (d, J=8Hz, 1H), 6.88 (dd, J=2Hz, 8Hz, 1H), 6.95 J=2Hz, 1H).

Example 440 trans, trans-4-( 1.3-Benzodioxol-5-yfl-2-(4-methoxyphenyl)-1 butyl- N- meth oxybe nzyflam ino) ca rbonyl)m ethyl) pyrrol idine-3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CDC13 8 (rotamer) 7.32 (1 H, d, 7.22 (1H, in), 7.10 (1H, d, 7.03 (6.98) (1H, d, 6.90-6.80 (4H, rn), 6.79 (2H, d, 6.77 (1H, t, 5.85 (2H, 4.92 (4.10) (1H, d, J=15), 4.42 (4.22) (11H, d, J=15), 3.81 (1H, in), 3.79 (3.78) (31H, 3.76 -408- (3H, 3.62 (1 H, in), 3.43 (2H, mn), 3.30-2.70 (5H, in), 1.42 (1 H, in), 1.23 (2H, in), 1.01 (1H, in), 0.83 (0.75) (3H, t, MS (DCI/NH3) m/e 575 Anal calcd for C33H38N207 -0.5 H20: C, 67.91; H, 6.73; N, 4.80. Found: C, 67.78; H, 6.44; N, 4.55.

Exampl e 441 trans. trans-2- Fl uoro-4-meth oxyp heny (1 .3-b enz odi oxol -yn)- 1 (2 is o bu ty I- N -(pen tan e suIf o n y Ia m ino) et h y 1) 1yrro Ii d ine -3 carboxylic acid 1 0 Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 0.76 3H, 0.84 3H, 0.92 3H, 1.36 (in, 4H),1.70 (in, 3H), 2.90 (in, 2H), 3.02 (in, 2H), 3.1-3.8 (in, 7H), 3.84 2H, 3.91 3H), 5.96 2H), 6.80 (d, 1 H, 6.88 (dd, 1 H, J=2, 7.00 1 H, 7.19 1 H, 7.35 1 5 (in, 2H). MS (DCI/NH3) Wne 593 Anal calcd for C30H41 N207F TFA: C, 57.31; H, 6.44; N, 4.31. Found: C, 57.08; H, 6.15; N, 3.95.

Example 442 trans, trans-4-( 1.3-Benzodioxol-5-yl)-2-(4-inethoxyohenyl)- 1 (Nbutyl-N-(3-f lu orophenyl aino) carbonyl met hyfl) yrrolidi ne-3- carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1. 1.30 (mi, 4H), 2.70-2.90 (in, 2H), 3.13 J=8 Hz, 1H), 3.40-3.90 (in, 6H), 3.79 3H), 5.93 2H), 6.75 J=8 Hz, 1 6.80-7.20 (in, 9H), 7.40 (in, 1 MS (DCl) Wne 549 Anal calcd for C31 H33N206F 0.8 C, 66.13; H, 6.19; N, 4.98. Found: C, 66.21; H, 5.83; N, 4.84.

Example 443 trans. trans-4-( 1.3-Benzodioxol-5-yfl-2-(4-f luorophenyl)-l -(N-butyl- N-(3-chlorop~henylamino~carbonylinethyl~pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.50 (mn, 4H), 2.65-2.85 (mn, 2H), 3.05-3.85 (mn, 7H), 5.93 2H), 6.75 (d, J=8 Hz, 1H), 6.85 (dd, J=8 Hz, 1H), 6.90-7.10 (in, 4H), 7.10-7.25 (mn, 3H), 7.33-7.45 (in, 2H). MS (DCI) in/e 553 Anal calcd for -409- C30H3ON205FCI: C, 65.16; H, 5.47; N, 5.07. Found: C, 65.37; H, 5.41; N, 4.98.

Example 444 trans, trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-methoxyghenyl)- butyl- N- (3.4-d im eth oxybenzyfl)am ino~ca rb onyl) methyl) pyrrolid ine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 (rotamer) 7.33 (1 H, d, J=10), 7.23 (1H, in), 7.03 (6.97) (1H, d, 6.90-6.60 (6H, mn), 6.47 (1 H, in), 5.93 (2H, in), 4.83 (4.09) (1 H, d, J=15), 4.45 (4.22) (1 H, d, 3.83 (3.86) (3H, 3.79 (1H, mn), 3.77 (3.76) (3H, 3.75 (3.65) 0 (3H, 3.60 (1H, in), 3.43 (2H, mn), 3.28 (1 H, in), 3.20-2.70 (4H, in), 1.43 (1KH, 1.23 (2H, mn), 1.02 (1KH, mn), 0.84 (0.77) (3H, t, MIS (DCI/NH3) m/e 605 Anal calcd for C34H40N208: C, 67.53; H, 6.67; N, 4.63. Found: C, 67.28; H, 6.63; N, 4.38.

ExaMDle 445 trans, trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-methoxyphenyl)-1 butyl-N-(2-methoxybenzyl)amino~carbonyl)methyfloyrrolidine-3- carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 (rotamer) 7.33 (1KH, d, 7.11 (2H, mn), 7.03 (1H, dd, J=8, 6.90-6.60 (7H, in), 5.93 (2H,% in), 4.83 (4.15) (1H, d, J=15), 4.47 (4.30) (1H, d, J=f5), 3.81 (1H, in), 3.78 (3.73) (3H, 3.72 (3H, 3.59 (1KH, in), 3.43 (2K, mn), 3.30 (1KH, in), 3.20-2.70 (4H, in), 1.42 (1K, in), 1.23 (2H, in), 1.01 (1H, in), 0.83 (0.77) (3H, t, MS (DCI/NH3) m/e 575 Anal calcd for C33K38N207: C, 68.97; K, 6.66; N, 4.87. Found: C, 68.70; H, 6.56; N, 4.61.

-410- Examlle 446 trans, trans-4-( 1.3-Benzodioxol.5-yl)-2-(4-methoxylheny,)-1 butyI- N- (3-methoxybe nzyflam in o)ca rbonyl) methyl) 1yrrol id ine.3 carboxylic acid S Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MI-z, CDC13 8 (rotamer) 7.31 (1 H, d, 7.13 (OH, d, 7.16 (1H, dt, J=8, 7.03 (1H, dd, J=10, 2), 6.90-6.60 (6H, in), 6.50 (1H, in), 5.94 (2H, in), 4.82 (4.19) (1H, d, 4.50 (4.23) (1 H, d, J=15), 3.78 (3.76) (3H, 3.77 (1K, in), 3.75 (3.67) (3H, 3.59 (1H, in), 3.57-3.35 (2H, in), 3.25 (1H, in), 3.20-2.70 (4H, in), 1.43 (1H, in), 1.23 (2H, in), 1.02 (1H, in), 0.84 (0.77) (3H, t, MS (DCI/NH3) m/e 575 Anal calcd for C33H38N207: C, 68.97; H, 6.66; N, 4.87. Found: C, 68.72; H, 6.55; N, 4.60.

is Example 447 trans.trans-2-(3-Fluoro-4-methoxyphenyl-4-(1 1 -(2-(N-(2-methoxyethyl)-N-(3- chloroprooanesulfonyflamino)ethylpyrrolidine3carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 2.15 (pen, 2H, 2.33 (in, o 1H), 2.81 (in, 2H); 2.93 1H, 3.1-3.6 (in, 10H), 3.24 3H); 3.65 2H, 3.70 1 H, 3.87 3H), 5.92 2H), 6.74 1 H, 6.84 (dd, 1 H, J=2, 6.97 1 H, 7.07 1 H, 7.17 (mn 2H). MS (DCI/NH3) m/e 601 Anal calcd for C27H34N208ClFS: C, 53.95; H, 5.70; N, 4.66. Found: C, 53.65; H, 5.49; N, 4.26.

Example 448 trans. trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-(2-inethoxyethyfl-N- (12entanesulfonybamino)ethylbpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 0.93 (in, 3H), 1.34 (in, 4H), 1.69 (mn, 2H), 2.33 (in, 1H), 2.75-3.1 (in, 7H), 3.23 3H), 3.3-3.6 (in, 6H), 3.70 1 H, 3.86 3H), 5.92 2H), 6.74 I1H, 6.84 (dd, 1H, J=2, 6.97 I1H, 7.07 1H, 7.18 (in, 2H). MS -411- (DCI/NH3) mle 595 Anal calcd for C29H39N208FS: C, 58.57; H, 6.61; N, 4.71. Found: C, 58.21; H, 6.29; N, 4.29.

Example 449 trans, trans-4-(l Benz od i 0xol-5-yfl (4-m eth o xYphe ny) -1 heptyl)-N-(4-fluoro-3methylphenylaminoicarbonyflmethyflpyrroidine3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 5 0.89 (in, 6H), 1.18-1.36 (in, 8H), 2.15 (bs, 1.5 (CH3 rotamner)), 2.28 (bs, 1.5 (CH3 rotamer)), 2.64 (t, J=14.9 Hz, 1H), 2.82 (in, 1H), 3.07-3.29 (in, 2H), 3.32-3.41 (in, 1H), 3.53-3.60 (in, 1H), 3.70-3.79 (in, 1H), 3.79 3H), 4.68 (in, 1H), 5.92 (mn, 2H), 6.69-6.90 (in, 6H), 6.93-7.07 (in, 4H). MS (DCI) mle 605 Anal calcd for C35H41 FN206: C, 69.52; H, 6.83; N, 4.63. Found: C, 69.31; H, 6.78; N, 4.35. Example 450 trans. trans-4-(1 .3-Benzodioxol-5-yI)-2-(4-methOXYphenyl). 1 non yl (4-flu oro- 3m ethyl 12heny~a mi no~ca rbonyfl)methyfl)py rrol id ine.3-ca rb xyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.81 -0.90 (in, 6H), 1.30 (mn, 12H), 2.14 1.5 (CH3 rotamer)), 2.30 1.5 (CH3 rotamer)), 2.60 (t, J=14.8 Hz', 1H), 2.80 (in, 1H), 3.09-3.24 (in, 2H), 3.33-3.42 (in, 1H), 0j 3.50-3.55 (in, 1 3.65-3.77 (mn, 1 3.79 3H), 4.64 (in, 1 5.93 (in, 2H), 6.70-6.84 (in, 5H), 6.91-7.13 (in, 5H). MS (DCI) W/e 633 Anal calcd for C37H45FN206: C, 70.23; H, 7.17; N, 4.43. Found: C, 70.14; H, 7.13; N, 4.19.

Example 451 trans. trans-4-(1 .3-Benzodioxol-5-yl-2-(4-methoxyphenyl)- 1 nonylamino)carbonyl)methyl)p2yrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.80 J=7.0 Hz, 3H), 0.84 J=7.1 Hz, 3H), 1.15-1.55 (mn, 12H), 2.88 J=15.9 Hz, 1H), 3.07 (in, 2H), 3.26 J=1 6.3 Hz, 1 3.36 (dd, J=4-4, 9.8 Hz, 1 3.64 (mn, I1H), -412- 3.76 (in, 1 3.79 3H), 3.98 J=9.5 Hz, 1 5.93 (mn, 2H), 6.77 (d, J=7.8 Hz, 1H), 6.85 (dd, J=1.7, 8.1 Hz, 1H), 6.93 (in, 2H), 6.99 J=1.7 Hz, 1IH), 7.39 (mn, 2H). MS (DCI) m/e 525 Anal calcd for C30H46N206* 0.35 H20: C, 67.86; H, 7.73; N, 5.28. Found: C, 67.87; H, 7.63; N, 5.11.

Example 452 trans. trans-4-(l .3-Benzodioxol- 5-yfl-2-(4-methoxyphenyfl)-1-((Nbutyl- N-(2 -f Iuorop henyl)amino) ca rbonyl methyl) 1yrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 (dt, J=7 Hz, 3H), 1.15- 1.32 (in, 4H), 3.77 J=2 Hz, 3H), 2.65-5.92 (in, 9H), 5.93 J=4 Hz, 2H), 6.70-6.90 (in, 4H), 7.00-7.45 (in, 7H). MS (DCI) m/e 549 1s Anal caicd for C31 H33N206 -0.4 H20: C, 66.99; H, 6.13; N, 5.04. Found: C, 67.01; H, 6.23; N, 4.68.

Example 453 trans, trans-2-(4-Methoxphenyl)P4-(1 .3-benzodioxol-5-yfl-1 or2-(Npropyl-N-(2-benzothiazolyflamino)ethyllp~yrrolidine-3-carboxylic acid The title compound was prepared by the method of Example 418, substituting 2-ch lo robe nzothiazol e for 2-b rom opyri iidine. 1 H NMR (300 MHz, CDCI3) 8 0.88 J=7Hz, 3H), 1.59 (sextet, J=7Hz, 2H), 2.25- 2.37 (in,l 2.85-2.97 (in, 3H), 3.28-3.36 (in, 2H), 3.50-3.58 (in, 3H), 3.60-3.65 (in, 1 3.67 J=9Hz, 1 H),3.71 3H), 5.87 J=2Hz, 1 H), 5.91 (d J=2Hz, 1H), 6.57 J=8Hz, 1H), 6.73 (dd, J=2Hz, 9Hz, 1H), 6.76 J=8 Hz, 2H), 6.91 J=2Hz, I1H), 7.01 J=8Hz, 1 7.22 J=8Hz, I1H), 7.29 J=8Hz, 2H), 7.40 J=7Hz, 1 7.55 J=7Hz, 1 H).

Examlle 454 trans. trans-2-(2-Ethoxyethyl)-4-( 1.3-benzodioxol-5-yfl-1 dibutylaininocarbonylmethyfl)1yrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CDCI3, 300 MHz) 5 0.91 J 7.4 Hz, 3H), 0.94 J 7.4 Hz, 3H), 1.19 J 7.0 Hz, 3H), 1.24-1.38 (mn, 5H), 1.46-1.60 (mn, 4H), 2.03-2.12 (mn, 2H), 3.07 J 8.0 Hz, 1 3.07-3.34 (in, 6H), -413- 3.43-3.52 (in, 3H), 3.59-3.74 (in, 3H), 3.80-4.01 (in, 2H), 5.93 2H), 6.72 J 8.1 Hz, 1 6.79 (dd, J 8.2 Hz, 1.7 Hz, 1 6.87 J 1.7 Hz, I1H). MS(DCI/NH3) m/e 477 Anal calod for C26H40N206 0.4 TFA: C, 61.64; H, 7.80; N, 5.36. Found: C, 61.63; H, 7.84; N, 5.29.

Example 455 trans, trans-2-(4-Methoxy-3-f luorophenyl)-4-( 1.3-benzodioxol-5-yb)- 1 -r2-(N-propyl-N-(2-(morpholin-4ylethyflsulfonylamino)ethyllpyrrolidine-3-carboxylic acid Ethyl 2-(4-methoxy-3-fluorophenyl)-4-( 1,3-benzodioxol-5-yl)- 1 -[2-(N-propyl-N-[2-vinylsulfonyl]am ino)ethyl]pyrrolidine-3- carboxylic acid, prepared by the procedures of Example 125, was reacted with excess morpholine for 4 hours at room temperature.

Chromatography on silica gel eluting with EtOAc gave a 65% yield of an intermediate ethyl ester which was hydrolyzed to the title 0 compound with NaOH in ethanol/water. 1 H NMR (300 MHz, CDCI3) 8 0.81 J=7Hz, 3H), 1.46 (sextet, J=7Hz, 2H), 2.43-2.52 (in, 4H), 2.70-2.92 (in, 2.97-3.33 (mn, 6H), 3.60 (dd, J=3Hz, 9Hz, 1H), 3.51-3.59 (mn, 1H), 3.62- 3.70 (mn, 5H), 3.88 3H), 5.95 2H), 6.72 J=8Hz, 1 6.70 (dd, J=2Hz, 8Hz, 1H), 6.90 J=9Hz, 1H), 6.96 J=2Hz, 1H), 7.10 J=8Hz, 1H), 7.18 (dd, J=2Hz, 12Hz, 1H).

Example 456 trans.trains-2-(3-Fluoro-4-inethoxyphenyl)-4-( 1.3-benzodioxol-5-yfl- 1 -r2-(N-prolyl-N-((2.2 .2trif luoroethoxyethane)suIf onyflamnino~ ethyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. in.p. 95-96 OC. 1 HNMR (CD3OD, 300MHz) 8 0.80 J=7Hz, 3H), 1.35-1.48 (mn, 2H),3.07 (sextet, J=7Hz, 2H), 3.23-3.55 (in, 8H), 3.80-3.87 (mn, 2H), 3.93 3H), 3.94- 4.02 (in, 4H), 4.66 J=l2Hz, 1H), 5.96 2H), 6.83 J=8Hz, 1H), 6.94 J=8Hz, 1 H),7.06 J=2Hz, 1 7.23 J=9Hz, 1 7.43 J=9Hz, 1 7.49 (dd, J=2Hz,J=l2Hz, 1 MS (DCI/NH3) in/e 635 -414- Example 457 trans. trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-f luorophenyfl)- -(N-butylmethyl phenyl)am inoca rbonyl methyl) pyrrol id ine- 3-ca rboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MI-z, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.50 (in, 4H), 2.31 3H), 2.65-2.80 (in, 2H), 3.19 J=7 Hz, 1 3.25 J=10 Hz, 1H), 3.35-3.65 (mn, 4H), 3.79 J=10 Hz, 1H), 5.93 2H), 6.74 J=7 Hz, 1H), 6.80-6.90 (in, 3H), 6.91-7.09 (in, 3H), 7.10-7.35 (in, 4H). MS (DCI) m/e 533 Anal calcd for C31 H33N205F: C, 69.91; H, 6.25; N, 5.26. Found: C, 69.56; H, 6.26; N, 5.23.

Examp~le 458 trans, trans-2- Flu oro-4-meth oxy h enyl) -4 .3-ben zodi oxo 1-5-Y I- 1 ethoxy-ethyfl-N-(butan esuf onyl amin o)ethyl) yrrol id ine- 3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 .H NMR (CD3OD, 300 MHz) 8 0.94 (in, 3H), 1.23 (hex, 2H, 1.69 (mn, 2H), 3.08 3.20 3H), 3.3-3.5 (in, 10H), 3.77 (mn, 2H), 3.92 3H), 4.60 (in, 1 5.96 2H), 6.81 1 H, 6.88 (dd, 1 H, J=2, 6.99 1 H, 7.22 1 H, 7.38 (mn, 2H). MS (APCI) m/e 581 Anal calcd for C28H37N2O8FS 1.1 TFA: C, 51.37; H, 5.44; N, 3.97. Found: C, 51.27; H, 5.35; N, 4.11.

Example 459 trans, trans-2-(3-Fluoro-4-inethoxyphenyfl-4-(1 1 -r2-(N-propyl-N-(2-inethylpropanesulfonyflainino)ethyllpyrrolidine- 3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. in.p. 77-78 OC. 1 H NMR (CDCI3, 300MHz) 8 0.83 J=7Hz, 3H),1.06 J=6Hz, 6H),1.45 (q, J=7Hz, 2H), 2.20 (septet, J=6Hz, 1K), 2.26-2.36 (in, 1H), 2.62-2.78 (in, 3H), 2.85-2.95 (in, 2K), 2.97-3.10 (in, 2K), 3.15-3.35 (in, 2H), 3.43 (dd, J=3Hz, J=9Hz, 1K), 3.53-3.62 (in, 1H), 3.66 J=9Kz, 1H), 3.88 3K), 5.95 2H), 6.74 J=8Hz, 1H), 6.82 (dd, J=2Hz, J=8Hz, 1K), 6.92 (t, J=8Hz, 1H), 6.97 J=2Hz, 1H), 7.12 J=9Hz, 1H), 7.18 (dd, J=2Hz, J=l2Hz, 1H). MS (DCI/NH3) in/e 565 -415- Example 460 trans, trans-4-( 1.3-Benzodioxol-5-yl)-2-(4-methoyphenyl). 1 butyl-N-( 4 -nitrobenzyl)amino)carbonyl)methl)n2yrrolidine.3.

carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 5 (rotamer) 8.11 (2H, m),7.32 (3H, dd, J=9, 7.16 (7.07) (1H, bd, J=10), 6.98 (6.94) (1H, d, J=2), 6.85 (2H, d, 6.83-6.70 (2H, in), 5.99 (5.97) (2H, d, 5.02 (4.18) (1H, d, J=15), 4.63 (4.38) (1H, d, J=15), 3.79 (3.77) 3.72 (1 H, d, 3.61 (1H, in), 3.48 (1H, bd, J=15), 3.43-3.20 (2H, in), 3.06 (2H, in), 2.90 (1H, mn), 3.79 (1H, bd, J=14), 1.43 (1H, in), 1.23 (2H, in), 1.02 (1H, mn), 0.84 (0.78) (3H, t, MS (DCI/NH3) m/e 590 Anal calcd for C32H35N308: C, 65.18; H, 5.98; N, 7.13. Found: C, 65.89; H, 5.85; N, 6.85.

Example 461 trans, trans-2-(4-Ethylphenyl)-4-(3.4-dif luo rophenyln)- Ndibutylaminocarbonylmethyflo1yrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (CD3OD, 300 MHz) 8 0.78 3H, 0.87 3H, 1.02 (hex, 2H, 1.22 3H, 1.27 (in, 2H), 1.45 (in, 2H, 2.63 2H, 2.77 1H, J=14), 2.94 (dd, 11H, J=7, 3.05 (in, 3H), 3.3-3.5 mn, 3H), 3.44 1H, J=14), 3.66 (in, 1H), 3.75 1H, J=10), H 7.20 (td, 2H, 7.22 (in, 2H), 7.32 (td, 2H, 7.43 (ddd, 1H, F J=2,8,12). MS (DCI/NH3) mWe 501 Anal calcd for C29H38N2O3F2 0.6 H20: C, 68.11; H, 7.73; N, 5.48. Found: C, 68.03; H, 7.53; N, 5.37.

Example 462 trans, trans-4-( 1.3-Benzodioxol-5-yl-2-(4-methoxyphenyl).1 butyl-N-(4-fluoro-3-methyl phenyflaminocarbonylmethyl)p2yrrolidine- 3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 6 0.87 J=7 Hz, 3H), 1.20- 1.50 (mn, 4H), 2.21 J=2 Hz, 3H), 2.64 J=14 Hz, 2.75 (dd, -416- Hz, 1H), 3.05 J=7 Hz, 1H), 3.25 J=15 Hz, 1H), 3.35-3.70 (in, 3.77 3H), 5.92 2H), 6.70-6.92 (in, 6H), 6.96-7.10 (in, 4H). MS (DCI) m/e 563 Anal calcd for C32H35N206F 0.5 H20: C, 67.24; H, 6.35; N, 4.90. Found: C, 67.16; H, 6.06; N, 4.81.

Example 463 trans. trans-4-( 1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl butyl-N-((3-isopropyflphenyl)amino)carbonylmethyly-1pyrrolidine.3 carboxylic acid 1 0 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 3H), 1. 17 J=7 Hz, 61H), 1.20-1.50 (in, 4H), 2.63 J=15 Hz, 1H), 2.75 J=7 Hz, 1H), 2.85 (in, 1 3.00 J=7 Hz, 1 3.25 J= 15 Hz, 1 3.40-3.70 (in, 3.75 3H), 5.90 2H), 6.65-6.80 (mn, 3H), 6.71 (dt, J=7 Hz, 3H), 7.07 (in, 3H), 7.20-7.35 (in, 2H). MS (DCI) m/e 573 Anal calcd for C34H40N206 0.15 H3P04: C, 69.52; H, 6.94; N, 4.77. Found: C, 63.31; H, 6.72; N, 4.43. 9 Example 464 trans, trans-4-( 1.3- Benz odioxol-5-yfl-2-(4-metho xyphenyl)- 1 butyl-N-(3-ethylphenyl~aininocarbonylmethybp1yrrolidine-3-carboxylic acid9 Using the procedures described in Example 1, the title compound 9.

was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 (in, J=7 Hz, 3H), 1.16 (t, J=7 Hz, 3H), 1.20-1.47 (mn, 4H), 2.50 J=7 Hz, 2H), 2.70-2.85 (in, 2H), 3.13 J=7 Hz, I1H), 3.20-4.5 (in, 6H), 3.78 3H), 3.83 J=8 Hz, 1 H), 5.92 2H), 6.72 J=8 Hz, 1H), 6.80-6.90 (mn, 5H), 7.02-7.13 (in, 3H), 7.15-7.25 (mn, 2H). MS (DCI) m/e 559 Anal caicd for C33H38N206 -0.3 H20: C, 70.27; H, 6.90; N, 4.97. Found: C, 70.31; H, 6.63; N, 4.60.

-417- Example 465 trans. trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-ethyllhenyfl)- chlorolhenyfl-N-butylamino)carbonyl)methyfl)1yrrolidine-3-carboxylic Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 0.87 3H, J=7Hz), 1.23 (t, 3H, J=7Hz), 1.28 (in, 2H), 1.41 (in, 2H), 2.63 2H, J=7Hz), 2.67 (in, IH), 2.92 (in, 1IH), 3.20 (in, 2H), 3.42 (mn, 1 3.60 2H, J=7Hz), 3.93 (in, 1 5.92 2H), 6.75 1 H, J=8Hz), 6.84 (in, 3H), 6.95 (br s, 1 7.02 1 0 1H), 7.10 (br s, 3H), 7.25 (in, 2H). MS (APOI) m/e 563 Anal.

calc'd for C32H35N205CI 0.80 H3P04: C, 59.92; H, 5.88; N, 4.37. Found: C, 59.90; H, 5.83; N, 4.07. Examingl 466 trans, trans-4-(1 .4-Benzodioxan-6-yfl-2-(4-ethylphenyfl-1 chlorolhenyl N-butylamino)ca rbonyflmethyl ~pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CDCI3) 8 0.86 3H, J=7Hz), 1.23 (t, 3H, J=7H~z), 1.25 (in, 2H), 1.40 (in, 2H), 2.64 2H, J=7Hz), 2.70 (in, 1H), 2.95 (mn, 1 3.20 (in, 2H), 3.40 (in, 1 3.57 (in, 3H), 3.90 (in, 1 H), 4.25 4H), 6.80 1 H, J=8Hz), 6.95 1 H, J=2Hz), 6.95 (mn, 2H), 7.07 (br s, 3H), 7.22 (in, 3H). MS (APCI) mn/e 577. Anal. calc'd for C33H37N205CI 0.85 H20: C, 66.90; H, 6.58; N, 4.73. Found: C, 66.92; H, 6.25; N, 4.36.

Examn~le 467 trans, trans-4-(Benzofuran-5-yfl-2-(4-ethylphenyfl- 1 chloropheny)- N-butylamino~carbonyflinethyflp1yrrolidine-3-carboxylic ai Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 0.85 3H, J=7Hz), 1.26 (t, 3H, J=7Hz), 1.30 (in, 2H), 1.40 (mn, 2H), 2.60 21-, J=7Hz), 2.72 (mn, 1 H), 2.93 (mn, I1H), 3.22 (mn, 2H), 3.50 (mn, 1 3.55 (in, 2H), 3.75 (mn, 1 3.90 (br d, I1H), 6.75 1 H, J=1 Hz), 6.80 (br d, 1 6.95 (br s, 1 7.08 (in, 4H), 7.20 1 H, J=8Hz), 7.28 1 H, J=8Hz), 7.42 (mn, 2H), 7.58 1 H, -41 8- J=1 Hz), 7.63 1 MS (APCI) mle 559 Anal. calc'd for C33H35N204C1*- 0.45 H20: C, 69.88; H, 6.38; N, 4.94. Found: C, 69.83; H, 6.04; N, 4.87.

ExaMDle 468 trans, trans-2-(4-Methoxy-3-fluorophenyfl-4-(7-methoxy- 1.3benzodioxol-5-yi)l1 -r2-(N-butyl-N-p2henylamino~ethyllpyrrolidine-3carboxylic acid Ethyl 2-(4-methoxy-3-fluorophenyl)-4-(7-methoxy-1,3- 1 0 benzodioxol-5-yl)-1 -[2-(bromoethyl]-pyrrolidine-3-carboxylate, prepared using the procedures of Example 61A (300 mg), was reacted with N-butyl aniline (190 mg) in 1 mL of dioxane containing 130 mg of dilsopropylethylamine to give the ethyl ester. The ester was hydroyzed with sodium hydroxide to give 148 mg of the title compound as a white 0 powder. 1 H NMR (300 MHz, CDC13) 5 0.90 J=9Hz, 3H), 1.28 (sextet, J=7Hz, 2H), 1.46 (quintet, J=7Hz, 2H), 2.20-2.32 (in, 1H), 2.68-2.77 (in, 1H), 2.82-2.95 (mn, 2H), 3.12-3.22 (in, 2H), 3.30-3.44 (in, 3H), 3.45-3.55 0"0 (in 3.62 J=9Hz, 1 3.83 3H), 3.90 3H), 5.95 2H), 6.51 J=7Hz, 2H), 6.55-6.62 (in, 2H), 6.69 J=2Hz, 1H), 6.84 J=8Hz, 1H), 7.02-7.15 (mn, 3H), 7.19 (dd, J=2Hz, 12Hz, 1H). Example 469 trans, trans-4-(1 .4-Benzodioxan-6-yfl-2-(4-ethylphenyl)-1 d ibuitylam ino) ca rbonyl) m ethyl) yrro lidi ne-3-ca rboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 5 0.78 3H, J=7Hz), 0.88 (t, 3H, J=7Hz), 1.05 2H, J=7Hz), 1.23 3H, J=7Hz), 1.28 (in, 2H), 1.45 (in, 2H), 2.64 2H, J=7Hz), 2.78 (mn, 1H), 2.9-3.2 (envelope, 4H), 3.30 (mn, 1 3.40 (mn, 3H), 3.60 (mn, 1 3.80 (in, 1 4.25 4H), 6.80 (d, 1 H, J=8H~z), 6.90 (in, 1IH), 6.98 1 H, J=2Hz), 7.17 2H, J=8Hz), 7.30 (in, 2H). MS (APOI) in/e 523 Anal. calc'd for C31 H42N205 1 .1 HOAc: C, 67.73; H, 7.94; N, 4.76. Found: C, 67.81; H, 7.55; N, 4.48.

-419- Example 470 trans. trans-4-(l .4-Benzodioxan-6-yb)-2-(4-methoxyhenyl)-1 butyl- N- (3-m ethyl 1h enylam ino) carbonyfl)met hyl) yrrol id ine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 5 0.87 J=7.1 Hz, 3H), 1.30 (in, 2H), 1.44 (in, 2H), 2.30 3H), 2.80 J=15.2 Hz, 1H), 2.85 J=9.3 Hz, 1H), 3.19 J=9.3 Hz, 1H), 3.33 J=10.2 Hz, 1H), 3.42-3.61 (in, 3H), 3.79 3H), 3.91 J=9.8 Hz, 1H), 4.22 (mn, 4H), 6.75-6.86 (in, 6H), 1 0 6.95 J=2.0 Hz, 1H), 7.09 J=8.8 Hz, 2H), 7.22 J=10.2 Hz, 1H), 7.26 J=7.6 Hz, 1H). MS (DCI) m/e 559 Anal calcd for C33H38N206 0.4 CH3002C2H5: C, 69.97; H, 6.99; N, 4.72. Found: 0.06; H, 6.66; N, 4.48.

Example 471 0O SO trans, trans-4-(1 .4-Benzodioxan-6-yl)-2-(4-methoxyphenyl)-1 butyl-N-(3-ch Iorophenyl am ino~carbonyl) methyfl) yrrol idine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 5 0.87 J=7.0 Hz, 3H), 1.25 (in, 2H), 1.40 (in, 2H), 2.78 J=14.6 Hz, 1H), 2.86 J=9.0 Hz, 1H), 0 3.16 J=9.5 Hz, 1H), 3.34-3.43 (in, 2H), 3.48-3.62 (in, 3H), 3.79 (s, 3H), 3.85 J=9.5 Hz, 1H), 4.22 (mn, 4H), 6.78 J=8.5 Hz, 1H), 6.81- 6.86 (mn, 3H), 6.93-7.09 (in, 5H), 7.33-7.38 (in, 2H). MS (DCI) m/e 579 Anal calcd for C32H35CIN206 1 .1 CH3CO2C2H5 0.15 H3P04: C, 63.30; H, 6.46; N, 4.06. Found: C, 63.54; H, 6.09; N, 3.98.

Example 472 trans.trans-4-( 1.3-Benzodioxol-5-yfl-2-(4-inethoxyphenyl)-1 pyridylmethyflyrrolidine-3--carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 2.84 J=9.6 Hz, 1 2.88 (dd, J=9.6, 7.3 Hz, 1H), 3.09 (dd, J=3-3, 9.6 Hz, 1H), 3.21 J=14.3 Hz, 1 3.53 (in, I1H), 3.78 3H), 3.81 (mn, 2H), 5.92 (in, 2H), 6.73 J=8.1 Hz, 1H), 6.82 (dd, J=1.8, 8.1 Hz, 6.93 (in, 2H), 6.95 J=1.5 Hz, 1H), 7.43 (in, 4H), 8.44 J=5.2 Hz, 2H). MS (DCI) m/e 433 Anal -420caicd for C25H24N205 0.3 CH3002C2H5: C, 68.57; H, 5.80; N, 6.10.

Found: C, 68.68; H, 5.60; N, 5.81.

Examlle 473 trans. trans-4 Benz od ioxo 1-5-yl)-2-(4 -m eth oxyp he nyl)1 butyl-N-(3- tert-butylphenylamino~carbonyl methyl) Dyrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.88 J=7.2 Hz, 3H), 1.23 9H), 1.26-1.45 (in, 4H), 2.74 (dd, J=15.1 Hz, 1H), 2.84 (mn, 1H), 3.13 J=9.0 Hz, 1H), 3.29 J=15.1 Hz, 1H), 3.50-3.66 (in, 4H), 3.77 3H), 3.84 J=9.6 Hz, I1H), 5.92 2H), 6.74 J=7.7 Hz, 1 6.79- 6.85 (mn, 4H), 6.86-6.90 (in, 1H), 6.99 J=1.8 Hz, 1H), 7.06 J=1.8 Hz, 1H), 7.13 (in, 2H), 7.33 J=7.7 Hz, 1H), 7.42 (in, 1H). MS (DCl) m/e 587 Anal calcd for C35H42N206: C, 71.65; H, 7.22; N, 4.77. Found: C, 71.56; H, 7.33; N, 4.69.

Examole 474 trans. trans-4--(1 Ben zod ioxo 1-5-yl)-2-(4-m eth oxyl2heny)- 1 butyl-N-(3-n-butylphenylamino~carbonyl)methyl)p2yrrolidine.3-:* carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.88 J=7.3 Hz, 3H), 0.92 J=7.3 Hz, 3H), 1.23-1.59 (mn, 8H), 2.58 J=7.6 Hz, 2H), 2.75 (d, 5J=15.3 Hz, 1H), 2.80 (dd, J=8-5, 9.5 Hz, 1H), 3.12 J=9-3 Hz, 1H), 3.29 W J=15.6 Hz, 1H), 3.46 (dd, J=4.9, 9.7 Hz, 1H), 3.52-3.64 (mn, 3H), 3.78- 3H), 3.83 J=9.8 Hz, 1 5.92 2H), 6.74 J=8.1 Hz, 1 6.79- 6.87 (mn, 4H), 7.05 J=1.7 Hz, 1H), 7.10 J=8.8 Hz, 2H), 7.20 (d, 7.8H), 7.29 J=7.6 Hz, 1H). MS (DCI) m/e 587 Anal calcd for C:35H42N206: C, 71.65; H, 7.22; N, 4.77. Found: C, 71.33; H, 7.28; N, 4.74.

-421- Example 475 trans, trans-4- (3 .4-Dif lu orophenyb)-2-(4 -ethyl phe nyl) -1 -(N-(n-butyl)- N-(3-methylr~henyl)aminocarbonylmethyfl)1yrrolidine-3-carboxyIi-c acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 5 0.87 3H, 1.19 3H, 1.28 (in, 2H), 1.43 (in, 2H), 2.28 3H), 2.60 2H, 2.66 (in, 2H), 3.06 (in, 1H), 3.21 1H, J=15), 3.42 (dd, 1H, 3.58 (in, 3H), 3.71 1H, 6.80 2H), 7.06 4H), 7.18 (in, 4H), 7.45 (in, 1H).

MS (APCI) m/e 535 Anal calcd for C32H36N203F2 1.3 HOAc: 1 0 C, 67.83; H, 6.78; N, 4.57. Found: C, 67.83; H, 6.46; N, 4.70.

Example 476 trans, trans-2-(4-Ethyllhenyl)-4-(3.4-dif luorophenyl)- 1 -(N-(-n-butyfl- N-(3-chlorophenyflaminocarbonylmethyflp1yrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 0.82 3H, 1.16 3H, 1.23 (in, 2H), 1.35 (in, 2H), 2.55 2H, 2.66 (in, 2H), 3.01 (t, 1H, 3.16 1H, J=15), 3.32 (dd, 1H, 3.56 (in, 3H), 3.67 (d, 1 H, 6.94 1 H, 7.02 (in, 5H), 7.14 (in, 2H), 7.32 (in, 3H). MS (APCI) m/e 555 Anal calcd for C31 H33N203CIF2 0.6 TFA: C, 61.88; H, 5.42; N, 4.48. Found: C, 61.90; H, 5.62; N, 3.98.

Example 477 trans, trans-4-(1 .4-Benzodioxan-6-yfl-2-(4-fluorophenyl)-1 -(N-butyl- N-(3-chlorophenyl)aminocarbonylmelhyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compoundwas prepared. 1 H NMR (300 MHz, CD3O1D) 8 0.87 J=-7 Hz, 3H), 1.10G- 1.30 (mn, 4H), 2.60-2.75 (mn, 2H), 3.03 J=7 Hz, 1H), 3.15-3.75 (in, 6H), 4.02 (in, 4H), 6.75 J=6 Hz, 1 6.85 (dd, J=7 Hz, 1lH), 6.90 (7.19, J=m Hz, 6H), 7.32-7.43 (in, 3H). MS (DCI) m/e 567 Anal calcd for C31 H32N205FCI 1.6 H20: C, 62.49; H, 5.95; N, 4.70. Found: C, 62.20; H, 5.54; N, 4.42.

-422- Examlle 478 trans, trans-4-(Benzof uran-5-yl)-2-(4-ethylphenyl)-1 Ndibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CDCI3) 8 0.78 3H, J=7Hz), 0.84 (t, 3H, J=7Hz), 1.05 2H, J=7Hz), 1.21 3H, J=7Hz), 1.25 (in, 2H), 1.45 (in, 2H), 2.62 2H, J=7Hz), 2.80 1H, J=l3Hz), 3.0 (mn, 2H), 3.15 (in, 2H), 3.35 (in, 1 3.43 (in, 2H), 3.52 (mn, 1 4.40 (in, 2H), 6.73 1 H, J=lHz), 7.14 2H, J=8Hz), 7.26 1 7.31 2H, J=8Hz), 7.44 (s, 1 0 2H), 7.60 1 H, J=1 Hz), 7.65 1 MS (APOI) m/e 505 Anal.

calc'd for C31 H40N204: C, 73.78; H, 7.99; N, 5.55. Found: C, 73.69; H, 7.97; N, 5.2 1.

Example 479 trans, trans-2-(4-Methoxy-3-f luorophenyl)-4-(7-nethoxy- 1.3- 1 .42-(N-propyl-N-(pyrroli dine- 1 carbonylmethyflamino)ethyllpyrrolidine-3-carboxylic acid Ethyl 2-(4-methoxy-3-fluorophenyl)-4-(7-inethoxy-1 ,3benzodioxol-5-yl)-1 -12-(N-propyl-aiinoethyl]-pyrrolidine-3carboxylate, prepared according to the procedures of Example 61 B (300 mg), N-bromoacetyl pyrrrolidine (132 mng) and diisopropylethylamine (154 mng) were heated for 1 hour at 50 00 in 1 mL of acetonitrile to give the intermediate ethyl ester. The ester was hydrolyzed to the title compound by the method of Example 1iD. 1 H NMR (300 MHz, CDCI3) 8 0.88 J=7Hz, 3H), 1.30-1.45 (mn, 2H), 1.75-1.92 (in, 4H), 2.30-2.40 (in, 1H), 2.47-2.58 (mn, 2H), 2.70-3.00 (in, 5H), 3.24-3.45 (mn, 6H), 3.50-3.70 (mn, 2H), 3.83 3H), 3.86 J=9Hz, 1 3.88 3H), 5.93 2H), 6.58 J=2Hz, 1H), 6.70 J=2Hz, 1H), 6.87 J=8Hz, 1H), 7.10 J=9Hz, 1H), 7.21 (dd, J=2Hz, 12Hz, 1H-).

Example 480 trans, trans-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-yl)- 1 (perhydroazeinylcarbonyl-(D)-leucylamino~ethylboyrrolidine-3carboxy ic acid -423- Example 480A D-Leucine O-benzyl ester Tosylate salt To benzyl alcohol (8.2 g) dissolved in benzene (30 mL) was added D-leucine (5.0 g) and p-toluenesulfonic acid monohydrate (8.0 The reaction was warmed to reflux with removal of water overnight. Once TLC indicated consumption of starting material, the reaction was cooled, and the resulting solid was filtered and washed with EtOAc to give the title compound as a white powder (14.26 g, 99%).

Example 480B N-Perhydroazepinylcarbonyl-D-Leucine O-Benzvl ester'* To the compound resulting from Example 480A (1.0 g) dissolved in chloroform (20 mL) was added triethylamine (0.4 mL). The solution was cooled to 0 OC, and carbonyldiimidazole was added. After 1.5 hours, TLC indicated complete consumption of starting material, so *.i hexamethylene imine (0.327 mL) was added. After 1 hour, an additional amount of hexamethylene imine (0.330 mL) was added, and the reaction was stirred at ambient temperature overnight. The solution was washed with sodium bicarbonate (2 x 20 mL), 1 N H3PO4 (2 x 20 mL), and brine (20 mL), dried over Na2SO4, decanted and evaporated. The residue was purified by flash chromatography on silica gel eluting with 50% EtOAc in hexanes to give the title compound as a crystalline solid (0.835 g, 89%).

Example 480C N-Perhydroazepinylcarbonyl-D-Leucine To the compound resulting from Example 480B (200 mg) dissolved in dry ethanol (1.0 mL) was added 10% palladium on carbon (10 mg).

After flushing the flask with nitrogen, the reaction was stirred vigorously under an atmosphere of hydrogen for 1 hour. The reaction was filtered through infusorial earth and evaporated to give the title compound (140 mg).

-424- Example 480D trans, trans-2-(4-MethoxyDhenyl)-4-(1.3-benzodioxol-5-yl-1 (cyanomethyl)-pyrrolidine-3-carboxylic acid ethyl ester To the compound resulting from Example 1C (510 mg of a 50 wt.

solution in toluene) dissolved in acetonitrile (2.0 mL) was added diisopropylethylamine (0.24 mL), followed by bromoacetonitrile (0.072 mL). After 2 hours, TLC indicated complete comsumption of starting material. The solvent was evaporated, and the residue was purified by flash chromatography on silica gel eluting with 20 40% EtOAc in 1 o hexanes to give the title compound as a colorless oil (0.28 g, 99%).

Example 480E trans. trans-2-(4-MethoxvDhenvl)-4-(1.3-benzodioxol-5-vyl-1 aminoethyl)-pyrrolidine-3-carboxylic acid ethyl ester 1 5 To the compound resulting from Example 480D (275 mg) dissolved in 10 mL each of triethylamine and ethanol was added Raney nickel catalyst (0.2 and the reaction was placed under a hydrogen atmosphere (4 atmospheres) for 3 days. The reaction was filtered and evaporated. The residue was dissolved in methylene chloride (10 mL) and extracted with 1 M HCI (5 x 1 mL). The combined aqueous extracts were basified and then extracted with methylene chloride (5 x 2 mL). The combined organic extracts were dried with MgSO4, filtered and evaporated to give the title compound as an unstable oil (0.14 g).

Example 480F r trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 (Derhydroazepinylcarbony)leucvllamino)ethyl)-pyrrolidine-3carboxylic acid, ethyl ester The compound resulting from Example 480E (0.10 g) was dissolved in methylene chloride (3.0 mL), and the compound resulting from Example 480C (0.07 g) was added. The solution was cooled to 0 OC, and EDCI (0.052 g) was added. After 4 hours, the reaction was evaporated and partitioned between water (1 mL), and EtOAc (10 mL).

The orgainc solution was washed with water (1 mL) and brine (1 mL), dried over MgSO4, filtered and evaporated. The residue was purified by -425flash chromatography on silica gel eluting with 50 60% EtOAc in hexanes to give the title compound as a colorless oil (0.075 g, 48%).

Example 48OG transtrans-2-(4- Met hoxyphenyl)-4-(1 .3-benzod ioxol- 5-yi) -1 (perhyd ro azei nylca rbonyl) leucyfl)am ino) ethyfl)py rro Iid ine-3-ca rboxyic The compound resulting from Example 480F (0.75 g) was dissolved in ethanol (1.0 ml-) and 5 M NaOH (0.050 mL) was added. After 2 hours, additional 5 M NaOH (0.090 mL) was added. After an additional hours, the reaction was evaporated. The residue was dissolved in water (5 ml-) and washed with diethyl ether (2 x 2 mL). The aqueous solution was acidified with 1 N4 H3P04 to pH 3.I The solid which precipitated dissolved when the mixture was extracted with 1 5 chloroform (3 x 3 mL). The chloroform extracts were washed with brine (2 mL), dried with MgSO4, filtered and evaporated to give the title compound as a tan solid (0.053 Purification by HPLC (Vydac mnCl8) eluting with a 10 70% gradient of CH3CN in 0.1%TFA provided suitable material (0.049 g) after lyophilization of the desired fractions. 1H NMR (CDCI3, 300 MHz) 8 0.82 (dd, 6.4, 4.4 Hz, 6H), 0.87: (dd, J 5.7, 5.7 Hz, 6H), 1.04-1.28 (in, 3H), 1.34-1.65 (in, 19H), 2.95 (br mn, 2H), 3.15-3.40 (in, 14H), 3.40-3.55 (in, 4H), 3.58-3.68 (in, 2H), 3.70- 3.76 (br in, 3.80 3H), 3.81 3H), 4.15 (br m, 2H), 5.10 (br mn, 2H), 5.93, 3H), 5.95 3H), 6.70-6.97 (in, 13H), 7.43-7.56 (br m, 31H), 8.2 (br s, 1 8.5 (br s, I MS(DCI/NH3) m/e 623 Anal calcd for C34H46N407 2.00 TEA: C, 53.65; H, 5.69; N, 6.58. Found: C, 53.66; H, 5.66; N, 6.54.

Example 481 trans, trans-4-( 1.3-Benzodioxol-5-yfl-2-(4-inethoxyphenyl-1 di(n-hexyflaminocarbonylmethyl)p2yrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, 0030D) 8 0.80-0.95 (in, 6H), 1.0 (in, 21H), 1.07 (1.55, J=m Hz, 14H), 2.70 J=13 Hz, 1H), 2.85-3.15 (mn, 4H), 3.20-3.60 (in, 9H), 3.64 J=1 0 Hz, 1 3.79 3H), 5.90 (mn, 2H), 6.70 8H), 1, 6.80-6.93 (in, 3H), 7.05 1IH), 7.35 J=10 Hz, 2H). Anal -426calcd for C33H-46N206 1.7 H20: C, 66.35; H, 8.34; N, 4.69. Found: C, 66.32; H, 8.04; N, 4.52.

Example 482 trans, trans-4-(l .4-Benzodioxan-6-yfl-2-(4-f luorophenyl)-l -(N-butyl- N-(3-methyl phenyfl)am inoca rbonyl methyl) pyrrQ i d ine.3ca rboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20.

1.35 (in, 2H), 1.35-1.40 (in, 2H), 2.32 3H), 2.55-2.70 (in, 2H), 2.97 (t, J=7 Hz, 1H), 3.22 J=14 Hz, 1H), 3.25-3.70 (in, 5H), 4.20 (in, 4H), 6.97 J=2 Hz, 1H), 7.09 (in, 2H), 7.15-7.35 (in, 2H). MS (DCI) m/e 547~ Anal calcd for C32H35N205F 1.2 H20: C, 67.64; H, 6.63; N, 4.93., Found: C, 67.73; H, 6.37; N, 4.70.

Examp~le 483 trans. trans-4-( 1.3-Benzodioxol-5-ylF-2-(4-methoXyohenyl)- 1 butyl- N- (3-nitrobe nzyl) am ino) ca rbo nyl)mnethyl) pyrrol idine-3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 (rotamer) 8.14 (2H, in), 8.05 (7.83) (1H, in), 7.60-7.30 (3H, in), 7.13 (1H, in), 7.10-6.70 (5H, mn), 5.94 (2H, in), 5.43 (5.33) (1H, d, J=12), 4.75 (1H, bd, J=15), 4.60-4.20 (2H, in), 4.10 (2H, in), 3.80 (3.76) (3H, 3.75-3.40 (3H, in), 3.20-2.80 (2H, in), 1.50 (1H, in), 1.30 (1H, in), 1.20-1.00 (2H, in), 0.91 (0.78) (3H, t, MS (DCI/NH3) m/e 590 Anal calcd for C32H35N30 8 2.1 TFA: C, 52.44; H, 4.51; N, 5.07. Found: C, 52.25; H, 4.83; N, 5.71.

Example 484 trans. trans-4-(1 .2-Dihydrobenzof uran-5-yi)-2-(4-ethlphenyl)- 1 butyl- N-(3.4-dim ethoxybe nzyl) ainno~carbo nyl) methyl) pyrrolid ine.3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 5 (rotainer) 7.40 (2H, in), 7.30-7.10 (4H, in), 6.90-6.70 (3H, in), 6.48 (1 H, in), 5.45 (1 H, in), 4.65 (1 H, d, J=15), 4.57 (2H, dt, J=9, 4.40-4.00 (5H, in), 3.87 (3.85) (3H, 3.84 (1H, in), 3.83 (3.79) (3H, 3.56 (2H, in), 3.20 (2H, t, J=10), 2.90 (1H, -427in), 2.64 (2H, q, 1.52 (1 H, in), 1.31 (2H, in), 1.22 (3H, dt, J=9, 2), 1.07 (1H, mn), 0.92 (0.78) (3H, t, MS (DCI/NH3) m/e 601 Anal calcd for C36H44N206 -1.35 TFA: C, 61.59; H, 6.06; N, 3.71*.

Found: C, 61.69; H, 6.04; N, 3.63.

Examp e 485 trans, trans-4-(l .3-Benzodioxol-5-yfl-2-(4-methoxyrheny)- 1 butyl-N-(4-heptyflamino)carbonvl~methyfl pyrrolidine-3-carboxylic acid 1 0 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.71-1.04 (in, 11 1.07- 1*35 (in, 6H), 1.73-1.53 (in, 4H), 2.79-3.25 (in, 5H), 3.35-3.44 (in, 1H), 3.51-3.68 (mn, 3H), 3.78-3.89 (in, 1 3.79 3H), 5.92 (in, 2H), 6.74 (dd, J=1.7, 8.1 Hz, 1H), 6.85 (td, J=1.7, 8.1 Hz, 1H), 6.93 (in, 2H), 7.02 (dd, J=1.7, 9.5 Hz, 1H), 7.36 (in, 2H). MS m/e 553 Anal calcd for 032H44N206: C, 69.54; H, 8.02; N, 5.07. Found: C, 69.31; H, 7.89; N, 5.06.

Examp~le 486 trans, trans-2-(4-Methylcyclohexyfl-4-(1 .3-benzodioxol-5-yl)-I dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) 8 0.88 (3H, d, J 7Hz), 0.92 (3H, t, J 7Hz), 0.96 (3H, t, J 7Hz), 1.05 (1H, in), 1.22-1.40 (7H, in), 1.45-1.65 (6H, mn), 1.67-1.84 (4H, in), 3.17-3.45 (6H, in), 3.70 (1 H, brm), 3.82 (1 H, dd, J 9Hz, 15Hz), 3.86 (1H, d, J 15Hz), 5.93 (2H, 6.73 (1 H, d, J 8H1z), 6.78 (1 H, dd, J 2Hz, 8Hz), 6.88 (1 H, d, J 2Hz). MS (DCI/NH3) in/e 501 Anal calcd for C29H44N205 0.25 CF3CO2H C, 66.96; H, 8.43; N, 5.29.

Found: C, 66.79; H, 8.60; N, 4.87.

-428- Example 487 trans, trans-2-(2-Propyloentyl)-4-(1 .3-benzodioxol-5-yl1-(N.Ndibutylaminocarbonylmethyflp1yrrolidine.3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDC13, 300 MHz) 0.85 (6H, in), 0.92 (3H, t, J 7Hz), 0.97 (3H, t, J 7Hz), 1.12- 1.40 (13H, in), 1.42-1.68 (6H, in), 2.90 (1H, in), 3.14-3.30 (2H, in), 3.33 (4H, in), 3.72 (1H, brm), 3.90 (1H, bin), 5.93 (2H, dd, J 2Hz, 4Hz), 6.73 (1H, d, J 8Hz), 6.78 (1H, dd, J 2Hz, 8Hz), 6.88 (1H, d, J =2Hz). MS 1 0 (DCI/NH3) m/e 517 Anal calcd for C30H48N20 5 0.35 CF3C02H C, 66.24; H, 8.76; N, 5.03. Found: C, 66.26; H, 8.82; N, 4.98.

Example 488 trans, trans-4-(1 .4-Benzodioxan-6-yfl-2-(4-fluorophenyl).1

N-

dibutylaminocarbonylmethylpDyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 8 0.83 J=7 Hz, 3H), 0.89 (t, J=7 Hz, 3H), 0.9.0-1.17 (in, 4H), 1.20-1.65 (mn, 5H), 2.77d (13, 1H), 2.87 (dd, J=8, 2 Hz, 1 2.95-3.60 (in, 7H), 3.71 J=9 Hz, 1 4.21 4H), 6.72 1 6.91 (dd, J=8 Hz, 1 6.97 J=2 Hz, 1 7.05 J=7 Hz, 2H), 7.40-7.50 (in, MS (DCI) m/e 513 Anal calcd for C29H37N205F 1.20 F3000H: C, 58.07; H, 5.93; N, 4.31. Found: C, 57.94; H, 5.81; N, 4.56. Example 489 trans, trans-2-(3- Methyl pentyfl-4-(1 benzod ioxol1-5-yi)-1

N-

I dibutylamino-carbonylmethyloyrrolidine3carbpxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDC13, 300 MHz) 8 0.83 (3H, t, J 7H-z), 0.85 d, J= 7Hz), 0.91 (311, t, J 7Hz), 0.97 (3H, t, J 7Hz), 1.05-1.22 (2H, in), 1.22-1.41 (7H, in), 1.43-1.68 in), 1.89 (1 H, in), 2.94 (1 H, t, J 6H-z), 3.15-3.27 in), 3.29-3.60 in), 3.72 (1 H, brd, J 6Hz), 3.92 (1 H, brd, J 13.5Hz), 5.93 (2H, dd, J 2Hz, 4Hz), 6.73 (1 H, d, J 8Hz), 6.78 (1 H, dd, J 2Hz, 8Hz), 6.88 (1 H, d, J 2Hz). MVS (DCI/NH3) in/e 489 Anal calcd for C28H44N20 -429- 0.30 CF3CO2H: C, 65.70; H, 8.54; N, 5.36. Found: C, 65.93; H, 8.81; N, 4.84.

Example 490 trans, trans-2-(2-Ethylbutyl)-4-(1 .3-benzodioxol-5-yfl)-1-(N. Ndibutylaminocarbonylmethyl)Dyvrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.85 (6H, in), 0.92 (3H, t, J 7Hz), 0.97 (3H, t, J 7Hz), 1.13- 1 0 1.41 (13H, in), 1.43-1.72 (6H, in), 2.96 (1H, brm), 3.12-3.52 (6H, mn), 3.55-3.70 (1H, in), 3.70-3.86 (2H, in), 3.99 (1H, brm), 5.93 (2H, dd, J 2Hz, 4Hz), 6.73 (1 H, d, J 8Hz), 6.78 (1H, dd, J 2Hz, 8Hz), 6.88 (1H, d, J 2Hz). MS (DCI/NH3) m/e 489 Anal calcd for C28H44N20 5 0.45 CF3002H: C, 64.28; H, 8.30; N, 5.19. Found: C, 64.16; H, 8.38; N, 5.08.

Example 491 trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-isobutyl-N-(butanesulfonylamino))ethyl)prrolidine.3 carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 0.74 3H, 0.83 3H, 0.94 3H, 1.44 (hex, 2H), 1.67 (in, 4H), 2.91 2H, J=8), 3.04 (dd, -2H, J=8,10), 3.1-3.6 (in, 5H), 3.78 (in, 2H), 3.92 3H), 4.60 j 5 11-H), 5.97 2H), 6.82 1 H, 6.89 (dd, 1 H, J=2, 7.01 1 H, 7.22 1 H, 7.39 (in, 2H). MS (ESI) m/e 579 Exampole 492 trans, trans-2-(4-Methoxy-3-f IuorOpheny1) 1.3- ben zodioxo 1 r2- (N -propy -N-4-ethl pyri mid in-2-yll ami no)et hyll pyrrolid ine-3 carboxylic acid 1 -Diimethyl amino- 1 -pe ntene-3-one, prepared by the method described in Syn. Comm. 12 35 (1982), was converted to 2-amino- 4-ethylpyrimidine with guanidine by the method of Chem. Ber. 97, 3397 (1964). This material was converted to 2-bromo-4-ethyl-pyrimidine with NaNO2 and HBr, using the method of Helv. Chim. Acta 75, 1629 -430- (1992). This bromopyrimidine was reacted with ethyl 2-(4m ethoxph enyl)-4-(1 ,3-benzod ioxol-5-yl)- 1 -[2-(N-propylami no)p ropyl]pyrrolidine-3-carboxylate, prepared using the procedures of Example 61B, using the procedure for Example 418, to give the title compound as a white powder. 1 H NMR (300 MHz, CDC13) 8 0.83 J=7Hz, 3H), 1. 11 J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.18-2.27 (in, 1H), 2.45 (q, J=7Hz, 2H), 2.80-2.97 (in, 3H), 3.40-3.75 (in, 7H), 3.83 3H), 5.95 (s, 2H), 6.25 J=4Hz, 1H), 6.68 J=8Hz, 1H), 6.79 (dd, J=2Hz, 8Hz, 1H), 6.82 J=9Hz, 1H), 6.92 J=2Hz, 1H), 7.05 J=9Hz, 1H), 7.15 (dd, J=2Hz, 12Hz, 1H), 8.10 J=4Hz, 1H).

Example 493: trans, trans-4-(1 .3-Benzodioxol-5-yV)-2-(4-methoxylhenyfl-1 butyl-N-(3.4-dimethylphenylbaminocarbonyflmethyfl)1yrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7.3 Hz, 3H), 1.23- 1.36 (mn, 2H), 1.38-1.43 (in, 2H), 2.22 3H), 2.29 3H), 2.79 (d, J=14.9 Hz, 1H), 2.84 (dd, J=8.6, 9.7 Hz, 1H), 3.16 J=9.5 Hz, 1H), 3.32 J=15.3 Hz, 1H), 3.43-3.61 (in, 4H), 3.79 3H), 3.88 J=9.8 Hz, 11H), 5.93 2H), 6.74 (in, 3H), 6.83 (in, 3H), 7.04 J=1.7 Hz, 1H), 7.11 (in, 3H). MS m/e 559(MH+). Anal calcd for C33H38N206-0.3H20: C, 70.27; H, 6.90; N, 4.97. Found: C, 70.24; H, 6.62; N, 4.58.

Example 494 trans, trans-2-(3-Methylpent-3-en-1 (N.N-dibutylaiinocarbonylmethyflpyrrolidine-3-carboxylic acid Using the procedure described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.92 (3H, t, J 7Hz), 0.97 (3H, t, J 7Hz), 1.22-1.40 (5H, in), 1.44-1.61 (8H, in), 1.82 (1H, bin), 2.02 (2H, in), 3.05-3.30 (4H, in), 3.3.8 (1H, in), 3.55 (1H, brm), 3.85 (2H, in), 4.12 (1H, bind, J 15Hz), 5.11 (1H, dd, J 6Hz, 12Hz), 5.93 (2H, 6.73 (1 H, d, J 8Hz), 6.78 (1 H, dd, J 2Hz, 8Hz), 6.88 (1H, d, J 2Hz). MS (DCI/NH3) mWe 487 Anal calcd for C28H42N205 0.7 CF3002H 62.34; H, 7.60; N, 4.95.

Found: C, 62.49; H, 7.43; N, 4.73.

-431- Example 495 1 -(N-Phenylaminocarbonylmethyl-2-(4-methoxyphenyl)-4-(1 .3benzodioxol-5-yfl~yrrolidine-3-carboxylic acid Example 495A N -Ph enfylb ro moacet amid e To a stirred solution of aniline (7.40 mmol) in methylene chloride ml-) at -50 00 was added successively N,N-diisopropylethylamine (1.58 mL, 8.14 mmol, 1.1 eq) and bromoacetyl bromide (0.72 mL, 7.40 mmol, 1 eq) such that the temperature did not exceed -40 On completion of the addition, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. After stirring for a further 30 minutes, the mixture was diluted with ether 15(70 ml-) and poured into 1 N sodium bisulfate solution. The phases were separated, and the upper layer was washed successively with water and brine. The organic phase was dried (Na2SO4) and the solvent evaporated to half volume, at which point the product crystallized. The crystals were removed by vacuum filtration to afford the title compound. Example 495B trans, trans-i1 -(N-Phenylaminocarbonylmethyl)-2-(4-methoxyphenyfl- .3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example l and the compound F resulting from Exampe 495A, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 8.8 (bs, 1H) 7.49 (2H, d, J=8Hz), 7.38 (4H, in), 7.11 (I1H, tt, J=8&2Hz), 6.99 (1 H, d, J=2Hz), 6.91 (2H, d, J=8Hz), 6.86 (1 H, d, J=2Hz), 6.81 (1H, d, J=8Hz), 5.99 (1H, d, J=2Hz), 5.98 (1H, d, J=2Hz), 3.94 (1H, d, J=lOHz), 3.78 (3H, 3.70 (1H, ddd, J=6, 5&3Hz), 3.42 (1H, dd, J=10&3Hz), 3.41 (1H, d, J=l6Hz), 3.18 (1H, dd, J=11&9H-z), 3.01 (1H, t, J=lOHz), 2.93 (1H, d, J=l6Hz). MS (DCl, NH3) m/e 475 Anal. Caic for C27H26N2O6 1 H20: C, 65.85, H, 5.73, N 5.69, Found: C, 65.95, H, 5.52, N, 5.38.

-432- Example 496 trans, trans-i1 N-(2 .3-Dimethyllhenyl)aminoca rbonylmethyfl-2-(4methoxyphenyl)-4-(1 .3-benzodioxol-5-yfl~yrrolidine-3--carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 5 8.68 (1H, bs), 7.64 J=8Hz), 7.38, (2H, d, J=8Hz), 7.09 (1H, t, J=8Hz), 6.97, (1H, d, J=8Hz), 6.90 (1H, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 (1H, dd, J=8&3Hz), 6.76 (1H, d, J=8Hz), 5.97 (1H, d, J=2Hz), 5.96 (1H, d, J=2Hz), 3.95 (1H, d, J=lOHz), 3.80 (3H, 3.70 (1H, ddd, J-6, 5&3Hz), 3.48 (1H, dd, J=10&3Hz), 3.44 (1H, d, J=l6Hz), 3.18 (1H, dd, J=1.1&9Hz), 3.06 (1H, t, J=lOHz), 2.96 (1H, d, J=l6Hz), 2.31 (3H, 2.16 (3H, MS (DCI, NH3) m/e 503 Anal. Calc for C29H30N206 0.5 H20: C, 68.09, H, 6.11, N, 5.48. Found: C, 68.13, H, 5.91, N, 5.29.

Examlle 497 trans. trans-i1 .4-Dimethylphenyl)aminocarbonylmethyfl-2-(4rnethoxyphenyl)-4-(1 .3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13) 8 8.60 (1 H, bs), 7.78 (d, J=8Hz), 7.38, (2H, d, J=8Hz), 6.99 (1H, in), 6.95, (1H, d, J=8Hz), 6.94 (1H, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 (1H, dd, J=8&3Hz), 6.77 (1 H, d, J=8Hz), 5.97 (1H, d, J=2Hz), 5.96 (1H, d, J=2Hz), 3.92 (1H, d, 0* J=lOHz), 3.79 (3H, 3.68 (1H, ddd, J=6, 5&3Hz), 3.43 (1H, dd, J=10&3Hz), 3.42 (1H, d, J=l6Hz), 3.18 (1H, dd, J=11&9Hz), 3.04 (1 H, t, J=lOHz), 2.95 (1H, d, J=l6Hz), 2.29 (3H, 2.24 (3H, MS (DCI, NH3) m/e 503 Anal. Calc for C29H30N\206 -0.75 H20: C, 67.50, H, 6.15, N 5.43. Found: C, 67.42; H, 5.95; N, *5.13.

Example 498 trans. trans-i1 .5-Dimethylphenyl)aminocarbonytmethyb)-2-(4methoxyphenyfl-4-(1 .3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 8.62 (1H, bs), 7.79 (1H, bs), 7.38, (2H, d, J=8Hz), 7.03 (1 H, d, J=8Hz), 6.95, (1 H, d, J=8Hz), 6.94 (OH, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 O1H, dd, J=8&31-Iz), 6.77 (1H, d, J=8Hz), 5.97 (2H, 3.92 (1H, d, J=lOHz), 3.78 (3H, 3.70 (1H, -433ddd, 5&3Hz), 3.48 (1H, dd, J=10&3Hz), 3.42 (1H, d, J=l6Hz), 3.18 (OH, dd, J=11&9Hz), 3.04 (1H, t, J=lOHz), 2.95 (1H, d, J=l6Hz), 2.29 (3H, 2.24 (3H, MVS (DCl, NH3) m/e 503 Anal. Calc for C29H30N206 0.5 H20: C, 68.09; H, 6.11; N, 5.48. Found: C, 67.72; H, 5.89; N, 5.25.

Example 499 trans. trans- Dim ethyl phenyl) am inoca rbo ny Imethyl-2-( 4 methoxyphenyl)-4-(1 .3-benzodioxol-5-yfl)1yrrolidine-3-carboxyiic acid 1 0 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 8.73 (1 H, bs), 7.38 (2H, bd, J=8H-z), 7.30, (1H, d, J=3Hz), 7.20 (1H, bs), 7.08, (1H, d, J=8Hz), 7.01 (I1H, bs), 6.90 (2H, d, J=8Hz), 6.85 (1H, bs), 6.80 (1H, d, J=8Hz), 5.99 (1H, d, J=3Hz), 5.98 (1H, d, J=3Hz), 3.92 (1H, d, J=lOHz), 3.78 (3H, s), 3.70 (1H, ddd, 5&3Hz), 3.48 (1H, dd, J=10&3Hz), 3.42 (1H, d, J=l6Hz), 3.18 (1H, dd, J=11&9Hz), 3.04 (1H, t, J=lOHz), 2.95 (1H, d, J=l6Hz), 2.25 (3H, 2.21 (3H, MS (DCl, NH3) mn/e 503 Anal. Calc for C29H30N206 0.75 H20: C, 67.50; H, 6.15; N 5.43.

Found: C, 67.24; H, 5.94; N, 5.20.

Example 500 trans, trans-i1 Di methylp12he nybam i noca rbo nyl methyl)-2-(4methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 8.75 (1 H, bs), 7.35, (2H, d, J= 8Hz), 7.10 (2H, 7.02 (1H, d, J=3Hz), 6.90 (2H, d, J=8Hz), 6.84 (1H, d, J=2Hz), 6.80, (1K, d, J=8Hz), 6.76 (1H, bs), 5.99 (1H, d, J=3Hz), 5.98 (1H, d, J=3Kz), 3.92 (1H, d, J=lOHz), 3.79 (3H, 3.68 (1H, ddd, J=6, 5&3Hz), 3.40 (2H, in), 3.18 (1H, dd, J=11&9Hz), 2.98 (1H, t, J=lOHz), 2.88 (1H, d, J=l6Hz), 2.3 (6H, MS (DCI, NH3) m/e 503 Anal.

Caic for C29H30N206 -0.5 H20: C, 68.09; H, 6.11; N 5.48. Found: C, 67.93; H, 6.01; N, 5.19.

-434- Example 501 Alternate Preparation of (+)-trans. trans- -(N.N-Di-n-butylaminocarbonylmethyl)-2-(4methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Hydrochloride Salt Example 501A N. N-Dibutyl bromoacetamide To a solution of bromoacetyl bromide (72.3 mL, 830 mmol) in 1 o toluene (500 mL) cooled to 0 °C was added a solution of dibutylamine (280.0 mL, 1.66 mol) in toluene (220 mL) via an addition funnel maintaining the reaction temperature below 10 Upon completion of I the addition, the reaction mixture was stirred at 0 °C for 15 minutes.

A solution of 2.5% aqueous H3P04 (500 mL) was slowly introduced, and 1 5 the reaction mixture was allowed to warm to room temperature with vigorous stirring. The solution is 2.5% phosphoric acid by weight. The layers were separated and the organic phase washed with water (500 mL) and concentrated to provide the bromoacetamide as a solution in toluene.

Example 501B 5-(2-Nitrovinyl)-1.3-benzodioxole To piperonal (15.55 kg, 103.5 mol) under mechanical stirring and under nitrogen was added ammonium acetate (13.4 kg, 173.8 mol), acetic acid (45.2 kg), and nitromethane (18.4 kg, 301.4 mol) sequentially. The mixture was warmed to 70 After about minutes, the yellow product began to crystallize. The reaction temperature was raised to 80 °C and stirred for about 10 hours until minimal piperonal remains. The somewhat thick reaction mixture was cooled to 10 °C and filtered. The precipitate was washed with acetic acid (2 x 8 kg) and then water (2 x 90 kg). The product was dried under a nitrogen purge and then in a vacuum oven at 50 °C for 2 days to afford 15.94 kg of the title compound as a bright yellow solid.

-435- Example 501C 4-Methoxybenzoyl acetate To potassium t-amylate (25 wt 50.8 kg, 99.26 mol) in toluene (15.2 kg) cooled to 5 °C under mechanical stirring and under nitrogen was added a mixture of 4-methoxyacetophenone (6.755 kg, 44.98 mol) and diethyl carbonate (6.40 kg, 54.18 mol) in toluene over 1 hour maintaining the temperature below 10 The reaction mixture was heated to 60 °C for 8 hours until no 4-methoxyacetophenone was detected by HPLC. The mixture was cooled to 20 OC and quenched by 1 0 adding to a mixture of acetic acid (8 kg) and water (90 kg) over minutes while maintaining the temperature at <20 The layers were separated, and the organic layer was washed with 5% sodium bicarbonate solution (41 kg) and concentrated to 14.65 kg. The temperature is maintained below 50 °C during the distillation. The 1 5 yellow product concentrate was assayed by HPLC against an external standard and the yield was found to be 9.40 kg Example 501D Ethyl 2-(4-methoxybenzoyl)-4-nitromethyl-3-(1,3-benzodioxol-5-yl) butyrate To the compound resulting from Example 501B (7.5 kg, 37.9 mol) suspended in THF (56 kg) with mechanical stirring under nitrogen was added the compound resulting from Example C (8.4 kg, 37.9 mol). The mixture was cooled to 17 oC, sodium ethoxide (6.4 g, 0.095 mol) was added, and the reaction was stirred for 30 minutes. After about minutes, the nitrostyrene was completely dissolved. Soc ethoxide (6.4 g, 0.095 mol) was added, and the mixture was stirred at 25 °C until HPLC shows less than 1 area ketoester remaining. The reaction was concentrated to 32.2 kg which was determined by HPLC assay to be -14.9 kg Example 501E Ethyl cis, cis-2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl pyrrolidine-3-carboxylate Raney nickel (20.0 from which the water had been decanted, was charged to a stirred hydrogenator equipped with a thermocouple.

-436- THF (20 mL), the crude compound resulting from Example 501D (40.82 g, 0.0482 mol), and acetic acid (2.75 mL, 0.0482 mol) were added sequentially. The mixture was put under a hydrogen atmosphere at psi until the hydrogen uptake slowed dramatically. TFA was added, and the mixture was hydrogenated at 200 psi until HPLC shows no residual imine and <2 area nitrone. The catalyst was filtered away and washed with 100 mL of methanol. The filtrate was assayed by HPLC and found to contain 13.3 g (75% yield) of the cis, cis-pyrrolidine compound. The filtrate was concentrated and chased with additional 1 0 THF (200 mL) to give a final volume of 100 mL. The mixture was neutralized with 2 N NaOH solution (50 mL), diluted with water (200 mL), and extracted with ethyl acetate (2 x 100 mL). The combined nearly colorless ethyl acetate layers were assayed against an external standard by HPLC to be13.0 g of the title compound.

Example 501 F Ethyl trans, trans-2-(4-methoxyphenyl)-4-(1 pyrrolidine-3-carboxylate The solution of the compound resulting from Example 501E (38.1 g, 0.103 mol) was chased with ethanol (200 mL) to a final volume of 100 mL and sodium ethoxide (3.40 g, 0.050 mol) was added. The mixture was heated to 75 When HPLC shows of the cis,cis isomer remaining, the mixture was cooled to room temperature. The product was assayed by HPLC against an external standard and found to contain 34.4 g (90% yield) of the title compound. The crude compound solution was concentrated and the residue taken up in isopropyl acetate (400 mL). The organic layer was washed with water (2 x 150 mL) and then extracted with 0.25 M phosphoric acid solution (2 x 400 mL). The combined phosphate layers were stirred with ethyl acetate (200 mL) and neutralized to pH 7 with solid sodium bicarbonate (21 The organic layer was separated and found to contain 32.9 g of the title compound.

-437- Example 501G Ethyl (2R.3R. 4S)-(+)-2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl) pyrrolidine-3-carboxylate. mandelate salt The solution resulting from Example 501F was chased with acetonitrile (100 mL) to give a final volume of 50 mL. (S)-(+)-Mandelic acid (2.06 g, 0.0136 mmol) was added and allowed to dissolve. The mixture was seeded with the product and allowed to stir at room temperature for 16 hours. The reaction mixture was cooled to 0 °C and stirred for 5 hours. The product was filtered and dried in a vacuum 1 0 oven with a nitrogen purge for 1 day at 50 °C to give 5.65 g of the title compound. The purity of the product can be determined by chiral HPLC using Chiralpak AS, isocratic elution with 95:5:0.05 hexane-ethanol-diethylamine; flow 1 mL/min.; UV detection at 227 nm. Retention times: (+)-enantiomer: 15.5 min.; (-)-enantiomer: 21.0 min.

Example 501 H (2R.3R.4S)-(+)-2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-y)-1 dibutylaminocarbonylmethyl)- pyrrolidine-3-carboxylic acid The compound resulting from Example 501G (20.0 g, 0.0383 mol)..

was suspended in ethyl acetate (150 mL) and 5% sodium bicarbonate solution (150 mL). The mixture was stirred at room temperature until the salt dissolved and carbon dioxide evolution had ceased. The organic layer was separated and concentrated. The residue was chased with acetonitrile (200 mL) to a final volune of 100 mL and cooled to 10 OC.

Diisopropylethylamine (11.8 mL, 0.0574 mol) and the compound resulting from Example A (10.5 g, 0.0421 mol) were added, and the mixture was stirred for 12 hours at room temperature. The reaction mixture was concentrated and chased with ethanol (200 mL) to a final volume of 100 mL. Sodium hydroxide solution 20 mL, 0.200 mol) was added, and the mixture was heated at 60 °C for 4 hours until HPLC showed no starting material remaining. The reaction mixture was poured into water (400 mL) and washed with hexanes (2 x 50 mL). The aqueous layer was washed with hexane (2 x 20 mL). A stirred mixture of the aqueous layer and ethyl acetate (400 mL) was neutralized to pH -438with concentrated HCI (12 mL). The organic layer was separated and found to contain 18.3 g (94% yield) of the title compound.

Example 5011 (2R.3R.4S)-(+)-2-(4-methoxyphenyl)-4-(1 3-benzodioxol-5-yl)- 1-(N.Ndibutylaminocarbonylmethyl)- pyrrolidine-3-carboxylic acid hydrochloride salt To a solution of the compound of Example 501H in ethyl acetate at room temperature in a mechanically stirred vessel equipped with a 1 o thermocouple, was added 39.4 mL of 1 N HCI in ethanol (0.0394 mol) The resultant solution was filtered to remove foreign matter, concentrated in vacuo, and chased with ethyl acetate (400 mL). The solution was seeded repeatedly, as the solvent was removed, until crystallization was initiated. The mixture was concentrated to a volume of 100 mL, and the product was filtered and washed with ethyl acetate (25 mL). The resultant white solid was dried in a vacuum oven under a nitrogen purge at 50 °C to afford 17.6 g of the title compound. Example 502 trans, trans-2-(2-MethylDentyl)-4-(1.3-benzodioxol-5-yl-l1-(N. N- dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Example 502A (±)-Ethyl 3-methylhexanoate 2 To a slurry of 60% sodium hydride (2.26g, 57 mmol) in 10mL of hexanes and 100mL of diethyl ether was added triethylphosphonoacetate (10.3mL, 52mmol). Once gas evolution ceased, 2-pentanone (6.0mL, 64mmol) was added. After 3 hours at room temperature, the reaction was quenched with water, and partitioned into ether. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in of ethanol and 10% palladium on carbon (6.0g) was added. The vessel was pressurized to 4 atmosphere of hydrogen, and was shaken at room temperature for 3 hours. The reaction was filtered and the -439solvent was removed under reduced pressure to give 3.0g of the title compound.

Example 502B (±)-Ethyl 5-methyl-3-oxooctanoate To a solution of ethyl 3-methylhexanoate in 150mL of ethanol was added sodium hydroxide (2.3g, 57.6mmol). After 48 hours at room temperature, solvent was removed under reduced pressure, and the 1 residue was dissolved in 150mL of water. The solution was washed with ether, then acidified with concentrated hydrochloric acid and washed with methylene chloride. The organic layer was dried with.

S anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 2.7g of the corresponding acid from which 3.9g of the title compound was prepared by the method of Bram and Vilkas,- Bul. Chem. Soc. Fr., 945 (1964).

Example 502C trans, trans-2-(2-Methylpentyl)-4-(1.3-benzodioxol-5-yl-1l-(N.NdibutylaminocarbonylmethylI-pyrrolidine-3-carboxylic acid..

Using the procedures described in Example 1 and substituting ethyl 5-methyl-3-oxooctanoate for ethyl (4-methoxybenzoyl)acetate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. Note that the multiplicity of the signals in the aryl region of the NMR spectrum reflects a 1:1 mixture of diastereomers on the alkyl chain. 1H NMR (CDCI3, 300 MHz) 8 0.8-1.0 12H), 1.2-1.4 7H), 1.45-1.6 6H), 1.6-1.74 1H), 1.8-2.0 1H), 3.1-3.4 5H), 3.67-3.78 1H), 3.8-3.91 1H), 4.0-4.2 2H), 4.3-4.5 2H), 5.93 J=1.5 Hz, 2H), 6.73 (dd, J=8.1, 1.2 Hz, 1H), 6.79 (ddd, J=7.8, 1.8, 1.8 Hz, 1H), 6.86 (dd, J=3.9, 1.5 Hz, 1H). MS (DCI/NH3) m/e 489 (M+H) Anal calcd for C28H44N205*1.0 TFA- C, 58.91; H, 7.58; N, 4.58. Found: C, 58.91; H, 7.58; N, 4.45.

-440- Example 503 trans, trans-2-(2.2-Dimethylpentyl)-4-(1 .3-benzodioxol-5-yl)-1

-N.N-

dibutylaminocarbonylmethyl)-2yrrolidine-3-carboxyic acid Ethyl 3,3-dimethyihexanoate was prepared using the general procedure of Cahiez et al., Tetrahedron Left., 31, 7425 (1990). Using the procedures described in Example 502 and substituting ethyl 3,3dimethylhexanoate for ethyl 3- methyl hexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. 1 H NMR (CDCI3, 300 MHz) 5 0.80-0.99 (in, 15H), 1.10-1.37 (in, 8H), 1.43-1.58 (in, 4H), 1.77-1.97 (in, 2H), 3.48-3.12 (mn, 5H), 3.60- 3.69 (in, 1 3.75-3.86 (mn, 1 3.95-4.16 (in, 2H), 4.28-4.4 (in, 2H), 5.94 2H), 6.74 J=7.8 Hz, 1 6.8 (dd, J=8.1, 1.5 Hz, I1H), 6.87 (d, J=1.8 Hz, 1H). MS (DCI/NH3) in/e 503 Anal calcd for C29H46N205-1.05 TFA: C, 60.01; H, 7.62; N, 4.50. Found: C, 60.21; H, 7.37; N, 4.33.

Example 504 trans, trans-2-(2-(1 .3-Dioxo-2-yflethyfl-4--(1 .3-benzodioxol-5-yl)-1 N-dibutylaminocarbonylmethyl)-oyrrolidine-3-carboxylic acid Example 504A Ethyl 5-(1 .3-dioxolyfl-3-oxopentanoate title compound was synthesized from ethyl acetoacetate and F2-bromomethyl-1,3-clioxane, according to the procedure of Huckin and Weiler, Tetrahedron Lett. 3927, (1971).

Sodium hydride 4.97 g (0.124 mol), as a 60% mineral oil dispersion, was weighed into a 250 mL flask, into which 80 ml of tetrahydrofuran was directly added. The flask was capped with septum cap, flushed with nitrogen, and cooled in an ice bath. To above stirred slurry was added dropwise 15.0 mL (0.118 mol) ethyl acetoacetate.

After the addition was complete, the resulting mixture was stirred at 0 *C for additional 10 min. To above mixture was then added 48.4 mL (0.121 mol) n-butyl lithium, a 2.50 M solution in hexane, in a dropwise manner. The resulting orange color solution was stirred for 10 min -441before 13.5 mL (0.130 mol) bromomethyl-1,3-dioxane was added in one portion. The reaction mixture was then allowed to warm to room temperature and stirred for additional 120 min before it was then quenched by slow addition of 9.8 ml (ca. 0.12 mol) concentrated hydrochloric acid. The biphasic mixture was poured to 50 ml of water and extracted with 150 ml of ethyl ether. The aqueous layer was extracted thoroughly with additional ethyl ether. The ethereal extracts were combined, washed with 2x50 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced 1 0 pressure to give an brown oily residue. The crude product was purified using silica gel flash chromatography eluting with 20% ether/hexane to give 5.40 g of b-keto ester as a light yellow oil.

Example 5040 trans, trans-2-(2-(1 .3-Dioxo-2-yl)ethyl)-4-(1 .3-benzodioxol-5-yl)-1 (N.N-dibutylaminocarbonylmethyfl-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502 and substituting ethyl 5-(1 ,3-dioxolyl)-2-oxopentanoate for ethyl 3-m ethyl hexanoate afforded the title compound. 1 HNMR (CDCI3, 300 MHz) 8 0.93 J =7.2 Hz, 3H), 0.95 J 7.2 Hz, 3H), 1.23-1.38 (in, 4H), 1.52 (sextet, J =7.9 Hz, 4H), 1.85-1.95 (mn, 2H), 2.02-2.17 (in, 2H), 3.18 (dd, J 6.0 Hz, Hz, 2H), 3.30 (dd, J 9.0 Hz, 18.0 Hz, 2H), 3.35 (mn, 1 3.79 (dd, J 3.6% Hz, 6.9 Hz, 1 3.83-3.88 (mn, 3H), 3.97 (dd, J 4.8 Hz, 6.0 Hz, 1 4.05 J 9.6 Hz, 2H), 4.30-4.40 (mn, 1 4.37 2H), 4.87 J 3.6 Hz, 1H), 5.94 2H), 6.73 J 8.1 Hz, 1H), 6.79 (dd, J 1.8 Hz, 8.1 Hz, 1 6.87 J 1.8 Hz, 1 MS (APCI) at m/e 505. Anal calcd for C27H40N207-1.2 TEA: C, 55.05; H, 6.47; N, 4.37. Found: C, 55.12; H, 6.44; N, 4.27.

Examgle 505 trans, trans (2-Tetrahydro-2 H-pyran) ethyfl-4- (1 .3-benzod ioxol- 5-yfl)-1 N-di butyl ami nocarbonyl methyl)-py rrolid i ne-3-carboxyli c acid -442- Examlle 505A Ethyl 5-(2-tetrahydro-2H-p2yran)-3-oxooegntanopte Using the procedure of Huckin and Weiler, Tetrahedron Lett. 3927, (1971), the title compound was prepared from ethyl acetoacetate and 2-(bromomethyl)tetrahydro-2H-pyran as a light yellow oil.

Example 505B trans. trans-2 -(2-Tet rahyd ro- 2H-pyran) ethyl) (1 benz od ioxol- 5-yb)-i-(N .N-dibutylaminocarbonylmethyb-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502 and substituting ethyl 5-(2-tetrahydro-2 H-pyran)-2-oxopentanoate for ethyl 3- 1 5 methylhexanoate afforded the title compound as an amorphous solid. 1H NMR (CDCI3, 300 MHz) as a mixture of two diastereoisomers: 8 0.89 J =8.1 Hz, 3H), 0.89 J 8.1 Hz, 3H), 0.91 J 8.1 Hz, 3H), 0.91 J =8.1 Hz, 3H), 1.20-1.40 (in, 10H), 1.42-1.66 (in, 18H), 1.71 (brm, 2H), 1.85 (brm, 2H), 1.96-2.23 (bin, 4H), 3.10-3.29 (in. 8H), 3.29-3.52 (in, 6H), 3.54-3.81 (in, 6H), 4.01 J 9 Hz, 2H), 4.12-4.25 (in, 4.43 J 9 Hz, 2H), 4.50 J 2.7 Hz, 2H), 5.94 2H), 5.95 2H), 6.76 2H), 6.76 2H), 6.81 1H), 6.81 1H). MS (APCI) at m/e 517. Anal calcd for C29H44N206-1.4 TFA:. C, 56.48; H, 6.77; N, 4.14. Found: C, 56.46; H, 6.99; N, 3.83.% Example 506 trans. trans-2-(2 .2.4-Trimethyl-3-p2entenyb)-4-(1 yl)-1 N-dibutylaminocarbonylinethyl)-pyrrolicline-3-carboxylic acid Example 506A Methyl 3.3.5-trimethyl-4-hexenoate To a slurry of isopropyltripenylphosphonium iodide (20-5g, 47mmol) in 200rnL of tetrahydrofuran was added n-butyllithiumn (27inL of a 1.6M solution in hexane, 43mmol), and the solution was briefly warmed to 000. After recooling, a solution of methyl 3,3-dimethyl-4- -44 3oxobutenoate (5.7g, 4Ommol), prepared according to the procedure of Hudlicky et al., Synth. Commun., 16. 169 (1986) in l0mL- of tetrahydrofuran was added, and the reaction was warmed to 0 0 C for The reaction was quenched with dilute hydrochloric acid, and partitioned with ethyl acetate. The organic layer was washed with water, and brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate in hexanes to give 2.1g of the title compound.

Example 506B trans. trans-2-(2.2.4-Trimethyl-3-pentenyfl-4-(1 yl)-l -(N.N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic- acid Using the procedures described in Example 502 and substituting methyl 3,3,5-t rimethyl-4-hexe no ate for ethyl 3-m ethylihe xanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFAICH3CN. 1 NMR (CDCI3, 300 MHz) 8 0.92 J=7.2 Hz, 3H), 0.94 J=7.2 Hz, 3H), 1.11 3H),-1.13 3H), 1.24-1.37 (in, 4H), 1.46-1.59 (in, 4H), 1.61 J=1.2 Hz, 3H), 1.69 J=1.2 Hz, 3H), 2.04-2.11 (mn, 2H), 3.10-3.20 (in, 2H), 3.30-3.39 (in, 3H), 3.67-3.82 (in 2H), 3.95-4.08 (mn, 1H), 4.32 (in, 2H), 4.37-4.47 (mn, 1H), 4.99 1H), 5.95 2H), 6.73 J=7.8 Hz, 1 6.78 (dd, J=8.4, 1.2 Hz, 1 6.84 (d, J=1.2 Hz,' 1H). MS (DCI/NH3) m/e 515 Anal calcd for 4025 CH4N01.5TFA: C, 60.77; H, 7.48; N, 4.42. Found: C, 60.83; H, 7.20; N, 4.43.

Example 507 trans, trans-2- -Dim ethyl -2 .3-d ioxol an-2 -yflet hyl-4-(1 .3benzodioxol-5-yi)-1 N-dibutylaminocarbonylmethyfl-pyrrolidine-3carboxylic acid -444- Examole 507A Methyl 3.3-dimethyl-3-(1 3 -dioxolan-2-yflopropanoate Methyl 3,3-dimethyl-4-oxobutanoate (l0g, 7Ommol), prepared according to the procedure of Hudlicky et al., Synth. Commun., .jj 169 (1986), was dissolved in 4Oml- of benzene, followed by addition of ethylene glycol (2OmL-), and p-toiuenesulfonic acid monohyd rate (1 .3g).

The reaction was ref luxed with azeotropic removal of water for 1 hour.

The reaction was poured into 200ml- of ether, washed with saturated 1 0 sodium bicarbonate, water and brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 12.4g of the title compound.

Examole 507B trans, trans-2-(2.2.-Dimethyl-2-(l .3-dioxolan-2-yljethyfl-4-(1 .3- N-dibutylaminocarbonylmethyl)-12yrrolidine-3 carboxylic acid Using the procedures described in Example 502 and substituting methyl 3,3-dimethyl-3-(1,3-dioxolan-2-yl)propanoate for ethyl 3- methyihexanoate afforded the title compound, which was isolated by* lyophilization from dilute aqueous TFAICH3CN. H NMVR (CDCI3, 300 MHz) 8 0.82-1.00 (in, 12H), 1.24-1.40 (in, 4H), 1.43-1.64 (in, 5H), 1.76- e 1.84 (in, 1H), 2.93-3.00 (mn, 1H), 3.15-3.47 (mn, 6H), 3.60-3.70 (mn, 3H), 253.74-3.95 (in, 5H), 4.48 1H), 5.94 (in, 2H), 6.72 J=8.0 Hz, 1H), 6.83 P (dd, J=8.0, 1.2 Hz, 6.94 J=1.2 Hz, 1H). MS (DCI/NH3) in/e 533 Anal calcd for C29H-441\207 -1.1 TFA-0.2 H20: C, 56.63; H, 6.93; N, 4.23. Found: C, 56.60; H, 6.96; N, 4.25.

Exain~le 508 trans, trans-2-(2-(1 .3-Dioxo-2-yl~ethyfl-4-(1 .3-benzodioxol-5-y)-1 rrN-4-heptyl-N-(2-methyl-3-fluoroohenyfll amino carbonymethyllpyrrolidine-3-carboxylic acid -445- Example 508A 4-Heptanol To an ice cooled solution of 1.14g (10.0 mmol) of 4-heptanone in 20 mL of diethyl ether was added 370 mg (10.0 mmol) of LiAIH4, in portions to keep ether reflux at a minimum. After 45 minutes, the reaction was quenched by sequential dropwise addition of 0.4 mL 0.4 mL 15% NaOH(aq), and 1.2 mL H20. After stirring another minutes, MgSO4 was added until the salts were free flowing, then the 1 o reaction was filtered. The salts were washed with diethyl ether (3 x mL), then the filtrate and washings were concentrated to a colorless oil. Yield 1.16g Example 508B 4-Methanesulfonyloxyheptane To an ice cooled solution of 834 mg (7.19 mmol) of 4-heptanol in mL of CH2CI2 was added 1.5 mL of triethylamine. Next, 0.7 mL (9 mmol) of methanesulfonyl chloride was added, dropwise, over 1 minute.

The mixture was stirred at 0 °C for 30 minutes, then extracted with (1 x 15 mL), 5% NH40H (2 x 15 mL), 1M HCI (2 x 15 mL), and brine (1 x 15 mL), dried over MgSO4, filtered, and concentrated to an oil.

Yield 1.31g 1 H NMR (300 MHz, CDCI3) d 0.96 6, J 1.43 1.64 3.00 4.73 (quintet, 1 J Example 508C 4-Fluoro-3-methylaniline To a solution of 20g (129 mmol) of 2-fluoro-5-nitrotoluene in 400 mL of ethanol was added 2g of 10% Pd-C. The mixture was shaken under 45 P.S.I. H2 until hydrogen uptake ceased. The catalyst was filtered away and washed with ethanol, then the combined filtrate and washings were concentrated to 15.2 g of a colorless oil.

-446- Example 508D N-Heptyl-4-fluoro-3-methylaniline To a solution of 4.10 g (3.28 mmol) of 4-fluoro-3-methylaniline in 30 mL of acetonitrile was added 7.64 g (3.93 mmol) of 4methanesulfonyloxyheptane, and 3.4 g (4.1 mmol) of NaHCO3(s). The mixture was stirred at reflux for 24 hours, then poured into 150 mL of and extracted with diethyl ether (2 x 30 mL). The combined ether layers were back extracted with brine (1 x 30 mL), dried over MgSO4, 1 0 filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 97.5: 2.5 hexanes: ethyl acetate, to give 2.56g of a pale yellow oil.

Example 508E N,N-(4-Heptyl)-(4-fluoro-3-methyl)phenylbromoacetamide To an ice cooled solution of 4.88g (21.9 mmol) of N-(4-heptyl)-4fluoro-3-methylaniline and 4.9 mL (61 mmol) of pyridine in 100 mL of toluene was added a solution of 4.90 mL (56.2 mmol) of bromoacetyl bromide in 7 mL of toluene. The solution was stirred for 24 hours, gradually warming to 25 then extracted with 1M HCI (1 x 100 mL).

The aqueous layer was back extracted with diethyl ether (1 x 50 mL), then the combined organic layers were washed with H20 (2 x 50 mL), saturated NaHCO3(aq) (2 x 50 mL), and brine (1 x 50 mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. This was purified via silica gel chromatography, eluting with 90:10 hexanes: ethyl acetate to give 7.48g of a light yellow oil. 1H NMR (300 MHz, CDCI3) d 0.94 6, J 1.33 1.43 2.30 2.31 (s, 3.54 4.72 (quintet, 1, J 6.96-7.04 7.07(d, 1, J 7).

-447- Example 508F trans, trans Dio xol -2-yi) ethyfl-4- (1 be nzodio xo 1-5-Yl)- 1 [[N-4-heptyl-N-(2-methyl-3-fluorophenyfll amino carbonylmethyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting ethyl 1,3-dioxolyl)-2-oxopentanoate for ethyl 3-m ethylihexan oate and N, N-(4 -h eptyl)-(4-flIu oro-3- methyl) phenyl-b rom oaceta mid e for N,N-dibutylbromoacetamide afforded the title compound as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) 8 0.93 (brt, 6H), 1.23-1.47 (in, 8H), 1.67-2.10 (in, 4H), 2.32 3H), 3.16 J 9.0 Hz, 1 3.52- 3.67 (brm, 2H), 3.73 J 9.0 Hz, 1 3.81-4.02 (in, 6H), 4.13 (brm, 1H), 4.72 (quintet, J 6.9 Hz, 1H), 4.86 J 4.0 Hz, 1H), 5.93 2H), 6.72 J 8.1 Hz, 1 6.78 (dd, J 1.8 Hz, 8.1 Hz, 1 6.85 J 1.8 Hz, 1H), 6.96 (in, 2H), 7.08 J 9.0 Hz, 1H). MS (DCI/NH3) at m/e 599. Anal Calcd for C33H43N207F-0.8 TEA: C, 60.24; H, 6.40; N, 4.06. Found: C, 60.21; H, 6.14; N, 3.86.

Example 509 trans, trans-2-(2- (1 .3-Dioxol-2-yl)ethyV-4-(1 .3-benzodioxol-5-yl)- 1 (N.N-dibutylaminocarbonylmethyl')-p2yrrolidine-3-carboxylic acid,:: Using the procedures described in Example 502, substituting ethyl 5- (1 ,3-dioxolyl)-2-oxopentanoate for ethyl 3-m ethyl hexano ate and 6methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1 H NMR (CDC13, 300 MHz) 8 0.93 J 7.8 Hz, 3H), 0.95 J 7.8 Hz, 3H), 1.31 (in, 4H), 1.53 (in, 4H), 1.90 (in, 2H), 2.09 (in, 2H), 3.19 (dd, J 8.4 Hz, 8.4 Hz, 2H), 3.30 J 9.6 Hz, 2H), 3.25- 3.42 (in, 1H), 3.73 J 10.5 Hz, 1H), 3.78-3.94 (in, 4H), 3.88 3H), 3.96 (dd, J 5.1 Hz, 6.0 Hz, 1H), 4.03 (dd, J 3.0 Hz, 6.3 Hz, 2H), 4.33 (in, 4.87 J 3.6 Hz, 1 5.94 2H), 6.53 J 1.8 Hz, 1 H), 6.63 J 1.8 Hz, I1H). MS (DCI/NH3) at m/e 535. Anal calcd for C28H42N208.1.05 TEA: C, 55.25; H, 6.63; N, 4.28. Found: C, 55.39; H, 6.66; N, 4.26.

-448- Example 510 trans. trans-2 Meth oxyp he no xy)-methyfl)-4- (13 be nzod ioxol-5-y h- 1 N-dibutyl amin oca rbo nyl methyfl-pyrroli din e-3-carboxylic acid Using the procedures described in Example 502, substituting omethoxyphenoxyacetic acid for 3-m ethylihexanoic acid, the above compound was prepared as an amorphous solid. 1 HNMR (CDCI3, 300 MHz) 8 0.85 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.15-1.35 (in, 4H), 1.40- 1.55 (in, 4H), 3.05-3.25 (in, 4H), 3.28-3.55 (in, 4H), 3.58-3.68 (in, 1H), 3.75-3.80 (in, 1H), 3.82 3H), 3.91 J=l4Hz, 1H), 4.05-4.15 (in, 1H), 4.23-4.33 (in, 1H),5.91 2H), 6.70 J=8Hz, 1H), 6.82-6.95 (mn, 7.03 1H). MS (DCI/NH3) at m/e 541. Anal calcd for C30H40N207: C, 66.65; H, 7.46; N, 5.18. Found: C, 66.37; H, 7.61; N, 5.09.

Example 511 (2S 3P. 4S)-2 -f2.2- Di methyl pentyl)-4-( 1.3-benzodi oxol 1 h e ptyI- N f Iu oro -3 -m et hy I phe ny 1))a m in oc arb o n y Imethby Ipyrrolidine-3-carboxylic acid Example 511A trans, trans-N-tert-Butoxycarbonyl-2-(2.2-dimethylpentyl)-4-(1 .3yl)-py rrolidine-3-carboxy lic acid Ethyl trans, trans-2-(2,2 -dimnethyl pe ntyl) be nzo yi)-pyrrolidine-3-carboxyl ate (2.5g, 6.9mmol), prepared according to Example 503, was dissolved in 5OmL of methylene chloride and di-tertbutyldicarbonate (1 .5g) was added. After stirring overnight at room temperature, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexanes to give the ethyl ester of the title compound (2.8g) as a colorless oil. The ester was dissolved in 5OmL of ethanol followed by addition of sodium hydroxide (l1inL of a aqueous solution). After stirring for 20 hours at room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in l5OinL of water, and acidified with concentrated -449phosphoric acid. The mixture was extracted with chloroform (3X50mL), and the organic layers were washed wiith brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give the title compound (2.4g) as a white foam.

Example 511B Methyl trans, trans-2-(2,2-dimethylpentyl)-4-(1.3-benzodioxol-5-yl)- 1 -(N-4-heDtyl-N-(4-fluoro-3-methylDhenyl))aminocarbonylmethylpyrrolidine-3-carboxylate: As a single enantiomer The product from Example 510A (1.97g, 4.5 mmol) was dissolved in 20mL of THF and cooled to 0°C, followed by addition of DMF (0.017mL, and oxalyl chloride (0.437mL, 5.00mmol). After 1 hour, solvent was removed at 0°C under a stream of nitrogen. The residue 1 5 was dissolved in 5mL of benzene and evaporated. In a separate flask, (S)-4-benzyl-2-oxazolidinone (1.2g, 6.8mmol) was dissolved in 30mL of THF followed by addition of n-butyllithium (4.0mL of a 1.6M solution in hexanes) at 0°C, and the slurry was stirred for 15min. The acid chloride was dissolved in 20mL of THF and cooled to 0°C, followed by dropwise addition of the lithium oxazolide suspension via cannula. After 30min, the reaction was partitioned between ether and saturated bicarbonate. The organic phase was washed with water then brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 15% ethyl acetate/hexanes to give the undesired diastereomer (1.17g, then elution with ethyl acetate/hexanes gave the desired diastereomer (1.04g, 38%).

The desired diastereomer of the N-acyloxazolidinone (0.84g, 1.42mmol) was dissolved in 2.5mL of dichloromethane, and 2.5mL of trifluoroacetic acid was added. After 30min, the. volatiles were removed under a stream of nitrogen, and the residue was twice dissolved in 5mL of toluene and evaporated under reduced pressure.

The TFA salt was stirred with 4mL of acetonitrile followed by addition of diisopropylethyl amine (1.0mL, 5.7mmol), and N-4-heptyl- N-(4-fluoro-3-methylphenyl)bromoacetamide (589mg, 1.7mmol) as a solution in 2mL of acetonitrile. After 21 hours, the reaction was -450warmed to 50°C for 3.5 hours. The reaction was cooled, the solvent removed under reduced pressure, and the residue was purified by flash chromatography on silica gel eluting with 20-30% ethyl acetate/hexanes to give 0.939g of amide as a colorless oil.

The above amide (200mg, 0.26mmol) was dissolved in 2.0mL of THF and 0.7mL of water. Solid lithium hydroxide monohydrate (22mg, 0.53mmol) was added at 0°C, followed by 30% hydrogen peroxide (0.050mL, 0.55mmol). After 1 hour, the reaction was warmed to room temperature. After an additional hour, the reaction was partitioned between 1:1 ethyl acetate:hexanes and water, 0.15g of sodium thiosulfate was added and the mixture was mixed thoroughly. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The crude residue was dissolved in 2mL of ether, and 1mL of methanol. A solution of (trimethylsilyl)diazomethane in hexanes was added dropwise until the yellow color remained. The reaction was quenched by addition of 2 drops of glacial acetic acid, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on 10g of silica gel eluting with 20% ethyl acetate/hexanes to give 70mg of the title compound as a crystalline solid (mp137.5 0 Example 511C (2S.3R.4S)-trans, trans-2-(2.2-Dimethylpentyl)-4-(1,3-benzodioxol-..:.

5-yl)-1-(N-4-heptyl-N-(4-fluoro-3- Smethylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylate The product from Example 510B (65mg, 0.10mmol) was dissolved in 1.OmL of methanol and sodium hydroxide (0.1mL of a 5M aqueous solution) was added. After 2 hours, the reaction was warmed to reflux.

After 6 hours, the reaction was cooled, and the solvent was removed under reduced pressure. The residue was dissolved in water and acidified with concentrated phosphoric acid. The aqueous solution was washed with chloroform (3X5mL), which was then washed with brine, dried with anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The title compound was isolated by lyophilization -451from dilute aqueous TFN/CH3CN. 1 H NMR (CDCI3, 300 MHz) d 0.78-0.95 (in, 15H), 1.04-1.46 (in, 12H), 1.76-2.95 (in, 2H), 2.31 3H), 3.23-3.33 (in, 1H), 3.47-3.58 (mn, 1H), 3.6-3.75 (in, 2H), 3.80-3.95 (in, 2H), 4.05- 4.15 (in, 1H), 4.73 (in, 1H), 5.94 2H), 6.70-6.80 (in, 2H), 6.82-6.93 (in, 2H), 6.96-7.14 (in, 2H). MS (DCI/NH3) m/e 597 Anal calcd for C35H4gN2FO5 -0.05H20 -0.8TFA: C, 63.81; H, 7.30; N, 4.07. Found: C, 63.84; H, 7.18; N, 3.94. 2 =+460 (c 2.7g/L, CHCI3) Example 512 trans, trans-2- (2 -(2-Oxopy rroIidi n- 1 -yfl ethyl) (1 benzod ioxol-5- yli-1 -(N.N-dibutylaininocarbonylmethyl)-pyrrolidine-3-carboxylic acid Example 512A 2-Oxopyrrolidin-1 -ylpropionic acid:7 To a stirred solution of 5.0 mL (40.5 mmol) 2-oxopyrrolidin-1 ylpropionitrile in 15 mL of dioxane was added 8.1 mL of hydrochloric acid, a 6.0 M aqueous solution. The resulting mixture was then refluxed at 110 00C over night. The reaction mixture was then allowed to cool to room temperature, extracted with mnethylene chloride three times. The extracts were combined and washed with saturated brine solution once, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 1.60 g of acid as a brown oil.

Examp~le 512B Ethyl 5-(2-oxopyrrolidin- 1-yl)-3-oxopentanoate The title compound was prepared from the above acid by adapting the method of Brain and Vilkas, Bul. Chem. Soc. Fr., 945 (1964).

Example 512C trans, trans-2-(2- (2-Oxopyrrolidin- 1 -yl) ethyfl)-4-( 1 yl)-1 -(N.N-dibutylaminocarbonylmethyfl-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting ethyl 5-(2-oxopyrrolidin-1-yl)-3-oxopentanoate for ethyl 3- -452methyihexanoate afforded the title compound as an amorphous solid.

I H NMR (CDCI3, 300 MHz) 6 0.91 J 7.5 Hz, 3H), 0.94 J 7.5 Hz, 3H), 1.23-1.38 (in, 4H), 1.44-1.60 (m 2.05 J 6.9 Hz, 2H), 2.12- 2.25 (in, 1H), 2.38 (td, J 4.2 Hz, 8.4 Hz, 2H), 2.47-2.61 (in, 1H), 3.17 (dd, J 6.0 Hz, 8.7 Hz, 2H), 3.24 J 9 Hz, 1 3.32 J 7.8 Hz, 2H), 3.38-3.48 (in, 3H), 3.52 J 9 Hz, 1 3.66 J 6.9 Hz, 1 3.96 (in, 2H), 4.14 (in, 1H), 4.38 (brs, 2H), 5.93 2H), 6.74 J 8.1 Hz, I 6.89 (dd, J 1.8 Hz, 8.1 Hz, 1 6.87 J 1.8 Hz, 1 MS (DCI/NH3) at m/e 516. Anal calcd for C28H411N306-1.4 TFA: C, 1 0 54.78; H, 6.33; N, 6.22. Found: C, 54.69; H, 6.33; N, 6.14.

Example 513 trans.trans-2-(2-(1 .3-Dioxol-2-yflethyfl-4-(7-methoxy.1 .3benzodioxol-5-yl)-l1-(N-4-heptyl-N-(4-fluoro-3- 1 5 methylphenyl))aminocarbonylmethyl)-pyrrolidmne-3--carboxvlic acid Using the procedures described in Example 502, substituting ethyl 5-(1 ,3-dioxolyl)-2-oxopentanoate for ethyl 3-methyihexanoate, N-4-heptyl-N-(4-fluoro-3-methylphenyl) bromoacetamide for N,Ndibutyl bromoacetamide and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) 6 0.93 (br t, 6H), 1.23-1.47 (in, 8H), 1.67-2.10 (in, 4H), 2.32 3H), 3.16 J 9 Hz, 1 3.60-4.03 (in, 8H), 3.88 3H), 4.21 (brs, 1 4.72 ,2 (quintet, J 6.6 Hz, 1 4.86 J 3.6 Hz, 1 5.93 2H), 6.49 1H), 6.61 1H), 6.96 (in, 2H), 7.08 J 9 Hz, 1H). MS (DCI/NH3) at mWe 629. Anal calcd for C34H45N208F.1.0 TEA: C, 58.21; H 6.24; N, 3.77. Found: C, 58.11; H, 6.11; N, 3.58.

Example 514 trans.trans-2-(2.2-Diinethyllenty)-4-(7-methoxy-1.3-benzodioxol-5yl)- -(N.N-dibutylaminocarbonylmethyfl-pyrrolidine.3carboxylic acid Using the procedures described in Example 502, substituting ethyl 5-m ethyl -3-oxo octan oate for ethyl 3-methylhexanoate and 6methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1 HNMR (CDC13, 300 MHz) 8 0.81 3H), 0.84 3H), -453- 0.86 J 6.9 Hz, 3H), 0.93 J 6.9 Hz, 3H), 0.96 J 6.9 Hz, 3H), 1.09-1.38 (in, 8H), 1.45-1.59 (in, 4H), 1.84-2.00 (in, 2H), 3.15 (dd, J 6.9 Hz, 10.0 Hz, 2H), 3.30-3.42 (in, 3H), 3.72 J 10.5 Hz, 1H), 3.86 (t, J 10.5 Hz, 1H), 3.88 3H), 4.02 J 10.0 Hz, 1H), 4.12 J 16.8 Hz, 1 4.29 J 16.8 Hz, 1 4.41 (brm, 1 5.94 1 6.52 J 1.8 Hz, 1H), 6.67 J 1.8 Hz, 1H). MS (DCI/NH3) at m/e 533.

Anal calcd for C30H48N206-0.9 TFA: C, 60.12; H, 7.76; N, 4.41. Found: C, 60.18; H, 7.62; N, 4.33.

Example 515 trans, trans-2-(2.2-d im ethyl pentyb-4- (2.3-d ihyd ro-benzof uran--yl)- 1 -(N.N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid: Using the procedures described in Example 502, substituting ethyl 3,3-dimethyihexanoate for ethyl 3-methylhexanoate and 2,3-:7 for piperonal afforded the title compound as an amorphous solid by lyophylization with CH3CN/TFA/H20. 1 H NMR (300 MHz, CDC13) 5 0.83 3H), 0.85 3H), 0.86 J=7.2 Hz, 3H), 0.92 J=7.2 Hz, 3H), 0.95 J=7.2 Hz, 3H), 1.09-1.39 (in, 8H), 1.44-1.59 (in, 4H), 1.88 (dd, J=15.0, 7.2 Hz, 1H), 2.00 J=15.0 Hz, 1H), 3.09 (in, 2H), 3.18 J=9.0 Hz, 2H), 3.27-3.38 (mn, 3H), 3.65-3.95 (in, 4.05 J=10.0 Hz, 1H), 4.18 J=16.8 Hz, 1H), 4.30-4.45 (in, 2H), 4.55 J=9.0 Hz, 2H), 6.70 J=8.4 Hz, 1H), 7.04 (dd, J=8.4, 2.1 Hz, 1H), 7.23 (brs, 1H). MS (DCI/NH3) at m/e 501 Anal calc'd for C30H48N204-1.05 TEA: C, 62.14; H, 7.97; N, 4.51.

Found: C, 62.19; H, 8.00; N, 4.43.

Example 516 trans, trans-2-(22.-Dimethyl-2-(1 .3-dioxolan-2-yl)ethyl)-4-(1 methoxy- 1.3-benzodioxol-5-y)-1 N-dibutylaminocarbonylinethyn)pyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting methyl 3,3-dimethyl-3-( 1,3-dioxolan-2-yl)propanoate for ethyl 3methylhexanoate and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid by lyophylization with -4 54- CH3CN/TFAIH2O. 1 H NMR (CDCI3, 300 MHz) S 0.93 J=7.2 Hz, 3H), 0.94 J=7.2 Hz, 3H), 0.95 3H), 0.96 3H), 1.31 (sextet, J=7.2 Hz, 4H), 1.45 (in, 4H), 1.93 (dd, J=15.9, 6.0 Hz, 1H), 2.13 J=15.9 Hz, 1H), 3.20 (dd, J=7.7, 7.7 Hz, 1H), 3.26-3.40 (in, 3H), 3.60 (in, 1H), 3.75-3.86 (in, 3H), 3.88 3H), 3.93-4.01 (in, 3H), 4.00-4.11 (in, 1H), 4.23 J=15.9 Hz, 1H), 4.37-4.48 (in, 2H), 4.49 1H), 5.94 2H), 6.51 J=2.1 Hz, IH), 6.64 J=2.1 Hz, 1H). MS (DCI/NH3) at m/e 563 Anal calcd for C30H46N208-0.9 TFA: C, 57.41; H, 7.11; N, 4.21; found: C, 57.35; H, 6.86; N, 4.05.

Example 517 trans, trans-2-(2-(2-Methoxyph enyb)-ethyl)-4-(1 benzod 1-(N.N-dibutylaminocarbonylmethyl).pyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting 0methoxyphenyipropionic acid for 3-methyihexanoic acid, the above compound was prepared. as an amorphous solid. 1 HNMR (CDCI3, 300 MHz) 8 0.85 J=7Hz, 3H), 0.91 J=7Hz, 3H), 1.10-1.27 (in, 4H), 1.42-% 1.60 (in, 4H), 1.72-1..89 (in, 1H), 1.91-2.02 (in, 1H), 2.55-2.77 (in, 2H), 2.94 J=6Hz, 1H), 3.05-330 (mn, 6H), 3.59-3.82 (in, 3H), 3.73 J=l4Hz, 1H), 3.77 3H), 5.91 2H), 6.70 J=8Hz, 1H), 6.78-6.88 (mn, 3H),6.92 J=2Hz, 1H), 7.08-7.19 (in, 2H). MS (DCI/NH3) at m/e 539. Anal calcd for C31H42N206: C, 69.12; H, 7.86; N, 5.20. Found: C, 68.89; H, 7.70; N, 4.99.

Example 518 trans. trans-2-(2.2-Diinethyl-3-(E)-pentenyl)-4-(l1-methoxy-1 .3- N-dibutylaminocarbonylmethyl)-pyrrolidine-3.

carboxylic acid Example 518A 4-Methyl-3-penten-2-ol To a stirred solution of 3-inethyl-2-butenal (8.7g, lO3minoI) in lO0inL of tetrahydrofuran under N2 at 0 00 was added -455methylmagnesium bromide (38mL of a 3.0M solution in ethyl ether, 114mmol) dropwise. The resulting mixture was allowed to warm to room temperature slowly and stirred at room temperature for 1 hour before it was quenched with 25mL of saturated NH4CI. The resulting biphasic mixture was partitioned between ethyl ether and water. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 8.4g of alcohol as a colorless oil.

1 Example 518B trans-Ethyl 3.3-dimethyl-4-pentenoate A mixture of 4-methyl-3-penten-2-ol (7.4g, 74mmol), triethyl orthoacetate (13.6mL, 74mmol) and propionic acid (0.28mL, 3.7mmol) was heated at 150 oC for 7 hours. The product was then distilled under normal pressure (200-220 oC) to give 5.0g of crude ester as a colorless oil.

Example 518C trans. trans-2-(2.2-Dimethyl-3-(E)-pentenyl)-4-(1-methoxy-1 .3benzodioxol-5-yl)-1-(N.N-dibutylaminocarbonylmethyl)-pyrrolidine-3- carboxylic acid Using the procedures described in Example 502, substituting trans-ethyl 3,3-dimethyl-4-pentenoate for ethyl 3-methylhexanoate and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid by lyophilization from dilute aqueous TFA/CH3CN. 1H NMR (CDCI3, 300 MHz) 8 0.92 J=7.2 Hz, 3H), 0.95 J=7.2 Hz, 3H), 0.97 3H), 0.99 3H), 1.31 (sextet, J=7.2 Hz, 4H), 1.52 (quintet, J=7.2 Hz, 4H), 1.58 J=5.4 Hz, 3H), 1.92 (dd, J=15.0, 6.6 Hz, 1H), 2.04 J=15.0 Hz, 1H), 3.15 (dd, J=7.8, 7.8 Hz, 1H), 3.30-3.40 3H), 3.75 2H), 3.87 3H), 3.99 J=9 Hz, 2H), 4.11-4.30 3H), 5.29 (d, J=15.6 Hz, 1H), 5.38 (dd, J=15.6, 6 Hz, 1H), 5.94 2H), 6.50 J=1.8 Hz, 1H), 6.63 J=1.8 Hz, 1H). MS (DCI/NH3) at m/e 531 Analysis calc'd for C30H46N206-0.95 TFA: C, 59.95; H, 7.41; N, 4.38; found: C, 60.00; H, 7.33; N, 4.35.

-4 56- Example 519 trans. trans-2-(3-(2-12yridyflethyl)-4-(1 .3-benzodio-xol-5-yl)-1 dibutylaminocarbonylmethyl)-p2yrrolidine-3-carboxylic acid Example 519A 3-(2-Pyridyfl)-propionic Acid In a 50 mL round-bottomed flask equipped with a stirring bar was 1 0 placed 3-(2-pyridyl)-propanol (1 g, 7.6 mmol), water (13 mL) and concentrated sulfuric acid (0.5 g, 5.1 mmol). To this stirred solution was added over a period of 30 min potassium permanganate (1.8 g, 11.3 mmol) while the reaction temperature was maintained at 50 00. After the addition was completed, the mixture was held at 50 00 until the 1 5 color of the reaction mixture turned brown, then heated at 80 O0 for 1 hour and filtered. The filtrate was evaporated to dryness to yield quantitatively the desired acid (1.14 g) suitable for next step without further purification. To prepare a pure acid, the residue thus obtained was boiled in ethanol (10 mL) in the presence of charcoal (0.1 g) for min, filtered and cooled to give crystalline 3- (2-pyridyl)-propionic acid (0.88 g, Example 51 9B trans, trans-2-(3-(2-pyridyflethyl)-4-(1 .3-benzodioxol-5-yb)-1-(N.Ndibutylaminocarbonylmethyfl-pyrrolidine-3-carboxylic acid Using the procedure described in Example 502, the title compound was isolated by lyophilization from dilute aqueous TFA/CH3CN as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) 8.65 J=6.0 Hz, 1 8.06 J=6.91 Hz, 1 7.70 J=9.0 Hz, 1 7.51 J=6.91 Hz, 1 6.82- 6.66 (in, 3H), 5.91 2H), 4.45 2H), 4.29-4.18 (in, 1H), 4.04 (dd, J=20.1, 10.5 Hz, 1 3.84 J=12.6 Hz, 1 3.62 (dd, J=13.8, 9.6 Hz, 1H), 3.46-3.13 (in, 7H), 2.51 (broad s, 2H), 1.60-1.43 (in, 4H), 1.37-1.22 4H), 0.91 J=8.4 Hz, 6H). MS (DCI/NH3) m/e 510 Anal caicd for C29H39N305*1.75 TFA: C, 55.04; H, 5.79; N, 5.92. Found: C, 55.08; H, 5.64; N, 5.8 1.

-457- Example 520 (2S. 3R,. 4S)-2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-(1 yb)-i-(N.N-dibutylaminocarbonylmethyfl)-yrrolidine-3-carboxylic acid Example 520A (2S, 3R. 4S)-Ethyl-2-(2-(2-oxolyrrolidin-1-ylbethyb)-4-(1 .3benzodioxol-5-yl)pyrrolidine-3-carboxylate-(S)- Mandel ate 1 0 The racemic amino ester from Example 512 (3.45g, 8.98mmol) in l0mL- of ethyl acetate was treated with (+)-mandelic acid (0.75g, 4.93mmol). Upon the formation of the clear solution, hexane was dropped in slowly with stirring till the solution became light cloudy. 0..

The solution was left stirred at room temperature over night. The 1is crystals was then collected by filtration, recrystalized from ethyl: acetate/hexane twice to give a yield of 800 mg of pure salt. too to Example 520B (2S, 3R, 4S)-Ethyl-2-(2-(2-oxopyrrolidin-1 -ylbethyfl-4-(1 .3benzod ioxol-5-yi)- 1 N-dibutyl am inoca rbonyl methyfl)-py rroli di ne-3- carboxylate To a stirred solution of pure mandelate (150 mg, 0.28 mmol) in CH3CN was added N,N-dibutylbromoacetamide(84 mg, 0.34 mmol) and diisopropylethylamine (98uL, 0.5Gmmol). The resulting mixture was stirred at room temperature over night. Solvent was then removed under reduced pressure and the crude product was purified by silica gel flash chromatography to give 140 mg (90% yield) of the title compound.

Example 5200 2S. 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yb~ethvl)-4-(1 y)-i1 N-d ibutyla min oca rbonyl methyfl)-pyrrolidi ne-3-ca rboxyli c acid Using the procedures described in Example 502, the title compound was prepared as an amorphous solid by lyophylization with CH3CN/TFA/H20. 1 HNMR (CDCI3, 300 MHz) 8 0.91 J 7.5 Hz, 3H), -458- 0.94 J =7.5 Hz, 3H), 1.23-1.38 (in, 4H), 1.44-1.60 (m 2.05 J 6.9 Hz, 2H), 2.12-2.25 (in, 1 2.38 (td, J 4.2 Hz, 8.4 Hz, 2H), 2.47- 2.61 (mn, 1 3.17 (dd, J 6.0 Hz, 8.7 Hz, 2H), 3.24 J 9 Hz, I1H), 3.32 J 7.8 Hz, 2H), 3.38-3.48 (in, 3H), 3.52 J 9 Hz, 1 3.66 J 6.9 Hz, 1 -3.96 (in, 2H), 4.14 (in, I1H), 4.38 (brs, 2H), 5.93 2H), 6.74 J 8.1 Hz, 1 6.89 (dd, J 1.8 Hz, 8.1 Hz, 1 6.87 J 1.8 Hz, 1 MS (DCI/NH3) at m/e 516. Anal calcd for C28H-41N306-0.85 TFA: C, 58.23; H, 6.89; N, 6.86. Found: C, 58.37; H, 6.90; N, 6.84.

Example 521 (2S. 3R. 4S)-2-(2-(2-oxopyrrolidin-1-yflethyn)-4-(1.3benzodioxol-5-yl)-l-(N-4-heltyl-N-(4-fluoro-3- 0 m ethyl phenyl))ami nocarbonyl methyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 520, substituting N,N- (4-heptyl)-(4-fluoro-3-methyl)phenyl-bromoacetamide for N,Ndibutylbromoacetamide afforded the title compound as an amorphous solid by lyophylization with CH3CN/TFAIH2O. 1H NMR (CDCI3, 300 MHz) 8 0.85-0.98 (in, 6H), 1.22-1.55 (in, 8H), 2.04 (quintet, J=7.9 Hz, 2.32 3H), 2.36 J=7.9 Hz, 2H), 2.61 (in, 1 3.14 (in, 1 3.25-3.61 (in, 5H), 3.66-3.77 (mn, 1H), 3.79-3.90 (in, 2H), 3.92-4.03 (mn, 1H), 4.69 (quintet, J=6.8 Hz, 1H), 5.95 2H), 6.71 2H), 6.78 1H), 6.93-7.13 (in, 3H); MS (DCI/NH3) at mn/e 610 Anal calc'd for C34H44N306F1.1.45 TFA: C, 57.18; H, 5.91; N, 5.42. Found: C, 57.20; H, 5.62; N, 5.52.

Examlle 522 trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1 .3-benzodioxol-5-yb)-1- N-dibutylaininocarbonylmethyfl)-yrrolidine-3-carboxylic acid Example 522A 3-(1-Pyrazolyfl)-orooionic Acid In a 10 mL round-bottomed flask equipped with a condenser and a stirring bar was placed pyrazole (0.50 g, 7.3 inmol), acrylic acid (0.50 -459mL, 7.3 mmol) and triethylamine (3 mL). The reaction mixture was refluxed for 6 hours. After removing triethylamine, the viscous oil was dried on high vacuo during 12 hours to yield quantitatively the desired acid (1.0 g) suitable for the next step without further purification.

Example 522B trans. trans-2-(2-(1 -Dyrazolyb~ethyl)-4-(1 .3-benzodioxol-5-yl)-1 (N.N-dibutylaminocarbonylmethyb)-pyrrolidine-3-carboxylic acid Using the procedure described in Example 502, the title compound was isolated by lyophilization from dilute aqueous TFAICH3CN as an amorphous solid 1 H NMR (CDCI3, 300 MHz) 8 7.56 J=3.0 Hz, 1 7.50 J=3 Hz, 1 6.83-6.66 (in, 3H), 6.28 J=3 Hz, 1 5.91 2H), 4.55-3.98 (in, 6H), 3.83-3.72 J=10.5 Hz, 1H), 3.61-3.40 J=10.5 Hz, 1 3.36-3.12 (in, 5H), 2.69-2.43 (in, 2H), 1.59-1.42 (mn, 4H), 1.38-1.21 (mn, 4H), 0.91 J=7.5 Hz, 6H). MS (DCI/NH3) at m/e 499 Anal calcd for C27H38N405'0.75 TFA: C, 58.60; H, 6.69; N, 9.59. Found: C, 58.53; H, 6.45; N, 9.67.

Examp~le 523 trans, trans-2-(4-Methoxyp~henyfl-4-(1 .3-benzodioxol-5-yb)-1-r(NbutyI-N-(3-hydroxypropyl)amilo~carbonylmethyll-pyrrolidine-3-, carboxylic acid Example 523A N-Butyl-N-(3-hydroxypropyfl-amine To a solution of 15.9g (100 iniol) of methyl 3-N-(nbutyl)aminopropionate in 150 mL of diethyl ether at 0 .0 was added mL (0.35 minol) of 1 .OMV LiAIH4 in diethyl ether, keeping reflux at a minimum. The mixture was stirred at 0 *C for 2.25 hours, the quenched by sequential dropwise addition of 1.9 mL H20, 1.9 mL NaOH(aq), and 5.7 mL H20. After stirring for 30 min, the salts were filtered and washed with diethyl ether, then the filtrate was concentrated to 11.3 g of a light yellow oil.

-460- Example 523B N-Butyl-N-(3-hydroxypropy)-chloroacetamide To an ice cooled solution of 1.31g (10.0 mmol) of N-butyl,N-(3hydroxypropyl)amine in 20 mL of ethyl acetate was added a solution of 1.71g (10.0 mmol) of chioroacetic anhydride in l0mL- of ethyl acetate.

The mixture was stirred, and gradually warmed to room termperature over 18 hours. The reaction was extracted with H20 (1 x 50 mL), 1 0 saturated NaHCO3 (aq) (2 x 50 mL), and brine (1 x 50 mL), dried over MgSO4, filtered, and concentrated to an oil. The product was purified via silica gel chromatography, eluting with 80:20 hexanes:ethyl acetate p to give 723 mg of a light yellow oil.

Example 5230 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yb)-1-[(N- butyl-N-(3-hyd roxypropyflamino~carbonylmethyll-pyrrolidine-3carboxylic acid Using the procedures described in Example 1 D, substituting N- butyl-N-(3-hydroxypropyl)-chloroacetamide for N-propyl bromoacetamide and adding DMSO as cosolvent, afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. 1 H NMR (CD3OD, 300 MHz) 8 0.78-0.95 (in, 3H), 1.00-1.80 4H), 2.80-3.65 (in, 15H), 3.80 J=1.5 Hz, 2H), 5.93 2H), 6.72- 7.05 (in, 5H), 7.33-7.40 (in, 2H). MS (DCI/NH3) at mle 513 Anal calc'd for C28H36N207-1.6 H20: C, 62.12; H, 7.30; N, 5.17. Found: C, 62.04; H, 7.2 1; N, 4.88.

Examp~le 524 trans, trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yb)-1-[(Noropvl-N-nror~oxvamino~carbonylnethyl-pyrroidine-3-carboxylic acid -461- Example 524A N-Boc-0-allylhydroxylamine O-Allylhydroxylamine hydrochloride hydrate (5.0g) was dissolved in THF (15 mL). The solution was cooled to 0°C in an ice bath.

Diisopropylethylamine (8mL) and di-t-butyldicarbonate (10.0g) were added. The mixture was stirred at 0°C for 1 hour at which point the bath was removed and the reaction allowed to warm to room temperature and stirred overnight. The THF was removed in vacuo and 1 o the residue taken up in EtOAc (25 mL), and washed with water (1 x mL), saturated sodium bicarbonate solution (3 x 50 mL), 1N phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil which was used without any further purification.

Example 524B N-Boc-N-propyl-0-allylhydroxylamine N-Boc-O-allylhydroxylamine (6.5g) from the above procedure was dissolved in dry THF (25 mL) and the solution cooled to 0°C in an ice bath. Sodium hydride (1.5g, 60% dispersion in oil) was added portionwise over 5 min. The resulting mixture was stirred for 30 min at 0°C. 1-lodopropane (3.8mL) was added dropwise to the mixture. The reaction was stirred at 0°C for 1 hour, then stirred overnight at room i"* temperature. The THF was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 50 mL), saturated sodium bicarbonate solution (3 x 50 mL), 1N phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil, which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give the title compound as a colorless oil -462- Example 524C N-Boc-N-prooyl-N-p ropoxyamine N-Boc-N-propyl-O-allylhydroxylamine (6.0g) was dissolved in EtOAc (100 mL). 10% Palladium-on-carbon (0.5g) was added, and the mixture was purged with nitrogen. The nitrogen line was exchanged for a balloon of hydrogen, and the mixture was stirred at room temperature for 6 hours. The catalyst was removed by filtration through a pad of Celite and the solvents were removed in vacuo to give a yellow oil 1 o which was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give the title compound as a colorless oil ee I Example 524D N-Propyl-N-propoxyamine hydrochloride N-Boc-N-propyl-N-propoxyamine (5.8g) was dissolved in 4N HCl/dioxane (10mL) and stirred at room temperature for 7 hours. The solvent was removed in vacuo and the residue triturated with diethyl i: ether. The resulting yellow solid (2.1g) was collected by filtration and washed with diethyl ether. Example 524E N-propyl-N-propoxy-bromoacetamide N-Propyl-N-propoxyamine hydrochloride (0.30 g) was dissolved in acetonitrile and cooled to -200C. Pyridine (0.2 mL) was added.

Bromoacetyl bromide (0.15g) was added dropwise over 5 min. The solution was stirred at -200C for 30 min. The bath was removed and the solution was stirred for 6 hours at room temperature. The solvent was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 25 mL), 1N phosphoric acid (3 x 25 mL), and brine (1 x 25 mL). The organic layer was dried with sodium sulfate and evaporated to give a dark orange oil (0.35g). The product is a mixture of chloro- and bromoacetamides in a ratio of -3:1.

-463- Example 524F trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-y)-l-f(Nbutyl-N-(3-hyd roxyp~rolylamino)carbonylmethyll-D2yrrolidine-3carboxylic acid Prepared according to the procedure of Example 523C, employing N-propyl-N-propoxy-bromoacetamide and ethyl 2-(4-methoxyphenyl)- 1,3- benz od ioxoI- 5-yl)-pyrrol id in e-3-carboxyl ate. The crude product was purified by preparative HPLC (Vydac mCl8) eluting with a 10-70% 1 0 gradient of CH3CN in 0.1% TEA. The appropriate fraction was lyophilized to give the product as a white solid. 1 H NMVR (CDC13, 300 MHz) 8 0.87 (in, 6H, J=8Hz), 1.49 (in, 2H-, J=8Hz), 1.61 (in, 2H, J=8Hz), 3.55 (in, 6H), 3.80 (in, 2H), 3.81 3H), 4.00 (in, 2H), 4.13 2H, J=l7Hz), 5.96 2H), 6.77 1H, J=9Hz), 6.90 (in, 3H), 7.05 11H, J=1 Hz), 7.44 2H, J=9Hz). MS (DCI/NH3) m/e 499 Anal calcd for C27H34N207 1.20 TEA: C, 55.57; H, 5.58; N, 4.41. Found: C, 55.59; H, 5.58; N, 4.55.

Example 525 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 -l(Nbutyl-N-propoxyamino~carbonylmethyll-pyrrolidine-3-carboxylic acid Example 525A N-butyl-N-(2-hydroxyethyfl-amine In a thick walled glass tube 5 ml (100 minol) of ethylene oxide was condensed at -78'C. To thisl12.5 ml (120 inmol) of butylamine was added and the tube was sealed. The resultant solution was allowed to heat in an oil bath at 50*C for 18 hours. Unreacted reagents were removed by evaporation to give the title compound.

-464- Example 525B N-Butyl-N-(2-azidoethyl)-chloroacetamide To 500 mg of N-butyl,N-2-hydroxyethylamine was added 2 mL of thinoyl chloride, dropwise. After the initial reaction had ceased, the reaction was stirred for 10 min, then concentrated to an oil. Diethyl ether was added and evaporated to aid in removal of the thionyl chloride. The residue was taken up in 10 mL of DMF, and 1.0g (16 mmol) of sodium azide was added. The reaction was stirred at 75 'C for 2 1 o hours, then poured into 50 mL of 0.6M NaHCO3(aq.) and extracted with diethyl ether (3 x 15 mL). The combined ether layers were back extracted with brine (1 x 15 mL), dried over MgSO4, and filtered. To S the ether solution was added 850 mg (4.97 mmol) of chloroacetic anhydride. The reaction was stirred for 10 min, then concentrated to an oil. This was taken up in 10 mL of saturated NaHCO3(aq.) and extracted with diethyl ether (3 x 5 mL). The combined ether layers were back extracted with brine (1 x 5 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 30% ethyl acetate: hexanes, to give 161 mg of an oil.

Example 525C trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-- butyl-N-(2-aminoethyl)amino)carbonylmethyll-pvrrolidine-3- carboxylic acid According to the procedure of Example 523C, N-butyl-N-(2azidoethyl)-chloroacetamide was coupled with ethyl 2-(4- Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate.

The crude product was chromatographed on silica, using 40% EtOAc in hexanes to elute. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and water added.

The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H3P04 and extracted with EtOAc. The latter organic extract was washed with brine and dried over Na2SO4. To 100 mg (0.10 -465mmol) of the azide was added 1mL of 1M HCI(aq.), 0.5 mL of dioxane, and 5 mg of 10% Pd-C. The suspension was stirred under 1 atm. of H2 for 5 hours, then filtered and concentrated to a white solid. The product was purified via HPLC, eluting with a 0 to 70 CH3CN in 0.1% aqueous TFA gradient to give the title compound as its TFA salt. 1H NMR (CD3OD, 300 MHz) 8 0.92 J=7.0 Hz, 3H), 0.96 rotamer), 1.23 2H), 1.41 2H), 3.06 4H), 3.39 2H), 3.69 2H), 3.84 (s, 3H), 3.94 3H), 4.18 2H), 5.05 (bd, J=10.7 Hz, 1H), 5.98 2H), 6.84 J=7.7 Hz, 1H), 6.93 (dd, J=1.8, 8.1 Hz, 1H), 7.05 3H), 7.56 (m, 2H). MS (DCI/NH3) at m/e 498 (M+H) Anal calcd for C27H35N306-3.15 TFA: C, 46.68. H, 4.49. N, 4.90. Found: C, 46.61; H, 4.73; N, 4.79. Example 526 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-[(Nbutyl-N-(3-aminopropyl)amino)carbonylmethyll-pyrrolidine-3carboxylic acid To and ice-cold solution of the compound of Example 523C (100 mg, 0.19 mmol) in 1 mL of dichloromethane was added 17mL of methanesulfonyl chloride, and 39 mL of triethylamine. The mixture was stirred for 20 min, then diluted with 1.5 mL of dichloromethane and extracted once with 5mL of water to which had been added 1 drop of 85% H3P04, then 5% ammonium hydroxide (1 x 2.5 mL), and brine (1 x mL), dried over MgSO4, filtered, and concentrated to an oil. To a solution of 81 mg (0.13 mmol) of the mesylate in 1mL of DMF was added 65 mg (10 mmol) of sodium azide. The mixture was stirred for 1 hour at 50 then poured into 10 mL of water and extracted with diethyl ether (3 x 5 mL). The combined ether layers were back extracted with brine (1 x 5 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 60:40 hexanes: ethyl acetate to give 57 mg of a colorless oil. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H3P04 and extracted with EtOAc. The latter -466organic extract was washed with brine and dried over Na2SO4. To this azide was added 1mL of 1M HCI(aq.), 0.5 mL of dioxane, and 5 mg of Pd-C. The suspension was stirred under 1 atm. of H2 for 5 hours, then filtered and concentrated to a white solid. The product was purified via HPLC, eluting with a 0 to 70 CH3CN in 0.1% aqueous TFA gradient to give the title compound as its TFA salt. 1H NMR (D6-DMSO, 300 MHz) 8 0.85 (apparent q, J=6.8 Hz, 3H), 1.17 2H), 1.30 2H), 1.67 2H), 2.71 2H), 3.04 1H), 3.21 3H), 3.45 1H), 3.75 3H), 3.97 3H), 3.85-4.80 (broad m, 3H), 6.03 2H), 6.87 (dd, J=1.4, 8.1 Hz, 1H), 6.92 J=7.8 Hz, 1H), 7.01 2H), 7.16 1H), 7.55 2H), 7.72 2H), 7.85 1H); MS (DCI/NH3) at m/e 512. Anal calcd for C28H37N306*3.0 TFA: C, 47.84. H, 4.72. N, 4.92. Found: C, 47.86; H, 4.75; N, 4.97.

Example 527 trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-l-r(Nbutvl-N-(3-dimethylaminoDrovpylamino)carbonvlmethyll-pyrrolidine- 3-carboxylic acid Example 527A N-butyl-N-(3-bromopropyl)bromoacetamide To 1.50g (11.4 mmol) of N-butyl-N-(3-hydroxy)propylamine was added 3 mL of 48% HBr(aq.), and 1.5 mL of conc. H2SO4. The reaction s was stirred at reflux for 3 hours, then cooled to room temperature and stirred for 22 hours. The mixture was poured over 50 mL of ice, and the solution was treated with 50 mL of 2M NaOH(aq.). The basic solution was extracted with ethyl acetate (3 x 25 mL), then the combined ethyl acetate layers were back extracted with brine (1 x mL), dried, and filtered. To the ice cooled ethyl acetate solution was added 3mL of triethylamine, then 1.5 mL of bromoacetyl bromide as a solution in 3.5 mL of ethyl acetate. The reaction was stirred at 0 'C for 30 min, then extracted with 1M HCI(aq.) (2 x 25 mL) saturated NaHCO3(aq.) (1 x 25 mL) and brine (1 x 25 mL). The organic layer was dried over MgSO4, filtered, and concentrated to an oil. This was -467purified via silica gel chromatography, eluting with 30% ethyl acetate in hexanes to give 1 .47g of a colorless oil.

Example 527B Ethyl trans, trans-2-(4-Methoxypheflyfl-4-( 1.3-benzodioxol-5-yl)-1 (N-butyl-N-(3-brornoproDl')amiflo~ca rbonylmethyll-pyrrolidine-3carboxylate According to the procedure of Example 5230, N-butyl-N-(3- 1 0 bromopropyl-bromoaCetamide was coupled with ethyl 2-(4- Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate.

The crude product was chromatographed on silica, using 40% EtOAc in hexanes to elute.

Example 5270 trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 b utyI -N Q3-d im e thy Ia m in op ropy1)a m in o)ca r b n yIm et h y II-py rroIi d in e- 3 -carboxy lic acid To 400 mg (0.663 mmol) of the compound of Example 527B in 4 mL of absolute EtOH was added 1.2 mL of 2.0 M Me2NH in THF. The reaction was heated at 50 *C for 3h, then stirred at room temperature for 18 hours. The mixture was concentrated, then reconcentrated from CH3CN to remove most of the trimethylamine. The product was purified via silica gel chromatography, eluting with 9:1 CH2012: MeOH over about 20 mL of silica gel to give the ethyl ester. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H13P04, and the product was purified by preparative HPLC. 1HNMR (CD3OD, 300 MHz) 8 0.92 J=7.0 Hz, 3H), 1.22 (in, 2H), 1.39 (in, 2H), 1.90 (mn, 2H), 2.87 6H), 3.07 (in, 4H), 3.24 (mn, 1 3.43 (in, 1 3.62 (in, 1 3.84 3H), 3.88 (in, 3H), 4.07 (mn, 1H), 4.17 (mn, 1H), 4.97 (in, 5.97 (s, 2H), 6.83 J=8.1 Hz, 1H), 6.93 (dd, J=1-7, 8.1 Hz, 1H), 7.05 (in, 3H), 7.53 (mn, 2H). MIS (DCI/NH3) at in/e 540 Anal calcd for -468- C30H41N306*2.95 TFA: C, 49.22. H, 5.06. N, 4.80. Found: C, 49.16; H, 5.11; N, 4.62.

Example 528 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-l1-r(Nbutyl- N -(3-tri methyl am mon iolroyl)am inocarbonyl methy1..

p2yrrolidine-3-carboxylic acid.

Prepared according to the procedures of Example 527C, substituting aqueous Me3N for Me2NH. 1H NMR (CD3OD, 300 MHz) 5 0.91 (in, 3H), 1.24 (in, 2H), 1.40 (in, 2H), 1.99 (in, 2H), 3.13 9H), 3.18 (s, rotamer), 3.20 (in, 3H), 3.39 (in, 4H), 3.72 (mn, 1 3.84 3H), 4.03 (in, I3H), 4.35 (in, 1 5.19 (in, I1H), 5.97 2H), 6.84 J=8-1 Hz, 1 6.96 (dd, J=1.7, 7.9 Hz, 1H), 7.10 (in, 3H), 7.62 (in, 2H). MS (DCI/NH3) at m/e 1s 554 Anal calcd for C31 H44N306-0.1 H20-1.65 TFA: C, 47.25. H, 4.96. N, 4.32. Found: C, 47.25; H, 4.74; N, 4.75.

Example 529 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-y)-1 bu ty I- N amnin ob u ty 1)a m ino)c a rbo ny Ime t hy 11- 12y rro Ii d in e -3 carboxylic acid Examlle 529A N-butyl-N-(4-hydroxybutyfl-amine A solution of 8.1 g (110 minol) of n-butylamine and 8.6 g of butyrolactone in 50 ml toluene was allowed to reflux under nitrogen atmosphere for 50 hours. Volatile solvents were removed in vacuo. To a solution of 3.18 gin (20 inmol) of the resultant N-butyl -4hydroxybutyramide in 50 ml of toluene were added 120 ml (120 inmol) The solution was heated with stirring at 70 *C for 18 hours. After cooling to O*C, the reaction was quenched with methanol (1/3 amount of DIBAL solution was used) followed by addition of saturated solution of Rochelle's salt. The mixture was extracted twice with EtOAc; the organic extracts were washed with brine and dried over Na2SO4.

-469- Example 529B N-butyl-N-(4-hytdroxybutyfl-chloroacetamfide Pyridine (2 ml) was added to an ice cold solution of 0.58 gm (4 mmol) of N-butyl-N-(4-hydroxybutyl)-amifle in 10 ml of EtOAc. To this solution 0.769 gm (4.5 mmol) chioroacetic anhydride was added in small portions. The reaction mixture was allowed to stir for 5 hours at 0.C, and then was allowed to warm to room temperature.

1 0 Bicarbonate was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine. The crude material was purified by column chromatography. Example 5290 1s Ethyl trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 r(N-uy -4hdoyuy~mn~croymtylproiie3 carboxylate According to the procedure of Example 5230, N-butyl-N-(4hydroxybutyl-chloroacetamide was coupled with ethyl M ethoxyphe nyl)-4 ,3-benzo d ioxol -5-yl)-pyrroIi difnle- 3-carb oxyl ate.

The crude product was chromatographed on silica gel.

Example 529D 2S Ethyl trans, trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yl)-1 [(N-butyI- N-(4b romobutyl) amino) carbonyl methyl]-py rro li din e- 3carboxylate To the solution of 0.180 gm (0.33 mmol) of the compound of Example 5290 in 2 ml DMF 0.086 gm (1 mmol) of lithium bromide and 0.120 ml (0.66 mmol) of PBr3 was added. The reaction mixture was allowed to stir at 0.0 for 2 hours and was slowly warmed to room temperature. Bicarbonate was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine. The crude material was purified by column chromatography.

-470- Example 529E trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-[(Nbutyl-N-(4-aminobutyl)amino)carbonylmethyll-pyrrolidine-3carboxylic acid To a solution of 0.135 gm (0.21 mmol) of the compound of Example 529D in 2 ml DMF was added 0.1 gm of sodium azide. Reaction was allowed to stir at room temperature for 18 hours under nitrogen atmosphere. After addition of water, the product was extracted into 1 EtOAc. The crude product (117 mg) was dissolved in 10 ml ethanol under nitrogen atmosphere. To this 45 mgs of 10% Pd/C catalyst was added, the nitrogen from the reaction flask was evacuated and was I flushed with hydrogen by placing a balloon filled with hydrogen.

The reaction was allowed to stir for 4 hours under hydrogen atmosphere, and was worked up by filtering through a Celite pad. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 8 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H3P04, and the product was purified by preparative HPLC. 1 H NMR (CD30D, 300 MHz) 8 0.90 J=7 Hz, 3H), 1.10-1.65 6H), 2.85-2.95 2H), 3.00- 4.10 14H), 5.50 J=3 Hz, 2H), 5.97 2H), 6.82 J=8 Hz, 6.91 (dd, J=7 Hz, 1H), 7.00-7.06 3H), 7.45-7.55 2H). MS (DCI/NH3) at m/e 526 (M+H) Anal calc'd for C29H39N306.2.2 TFA: C, 51.75; H, 5.35; N, 5.41. Found: C, 51.75; H, 5.31; N, 5.30.

Example 530 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-r(Nbutyl-N-(4-dimethylaminobutyl)amino)carbonylmethyll-pyrrolidine-3carboxylic acid The title compound was prepared from the compound of Example 529D, employing the procedures of Example 527C. 1 H NMR (CD30D, 300 MHz) 8 0.90 (dt, J=7Hz, 3H), 1.1-1.75 8H), 2.75 J=7 Hz, 6H), 4.25 16H), 5.97 2H), 6.83 J=8 Hz, 1H), 6.93 (dd, J=8 Hz, 1H), 7.02-7.08 3H), 7.49-7.56 2H). MS (DCI/NH3) at m/e 554 (M+H) -471- Anal calc'd for C31H431N306*2.1 TFA: C, 53.31; H, 5.73; N, 5.30. Found: C, 53.50; H, 5.38; N, 5.34.

Examlle 531 trans, trans-2-(4-Methoxyghenyl)-4-(1 butyl-N-(3-pyridyl'amino~carbonylmethyll-pyrrolidine-3-carboxylic acid Example 531A N-butyl-N-(3-pyridyfl-amime To a solution of 941 mg (10 mmol) of 3-aminopynidine and 0.9 mL U I of butyraldehyde in 30 mL of CH30H was added 10 mL of glacial acetic acid. The mixture was stirred at room temperature for 1 hour, then the is reaction was cooled with an ice bath, and 650 mg (10.3 mmol) of sodium cyanoborohyd ride was added. The ice bath was removed, and the reaction was stirred for 4.5 hours at room temperature. The mixture was poured into 300 mL of 0.67M NaOH(aq.), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were back extracted with brine (1 x 50 mL), dried over MgSO4, filtered, and concentrated to an oil. The product was isolated via silica gel chromatography, eluting with 3:1 ethyl acetate: hexanes to give 1.18g of a colorless solid.

Examlle 531 B trans, trans-2-(4-Methoxyphenyb)-4-(1 .3-benzodioxol-5-yl)-1 -r(Nbutyl-N-(3-pyridyl)amino~carbonylmethyll-pyrrolidine-3-carboxylic acid The compound of Example 531A was reacted according to the procedures of Example 523, to give the title compound. 1 H NMR (D6- DMS0, 300 MHz) 5 0.80 J=6.4 Hz, 1.15-1.99 (in, 4H), 2.59 (mn, 1H), 3.05 (in, 2H), 3.26 (in, 2H), 3.49 (in, 2H), 3.56 J=7.1 Hz, 2H), 3.73 (s, 3H), 6.00 2H), 6.80 (mn, 3H), 6.85 J=8.1 Hz, 1 6.98 (in, 2H), 7.04 (mn, 1 7.41 (dd, J=1, 4.7 Hz, 8.1 7.58 (in, 1 8.36 (bs, 1 8.54 (bs, 1H), 12.24 (bs, I1H). MS (DCI/NH3) at in/e 532 Anal calcd -472for C30H33N306*0.1 H3P04: C, 66.55. H, 6.20. N, 7.76. Found: C, 66.59; H, 6.06; N, 7.60.

Example 532 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yI)-1-[(Nbutvl-N-(3-aminomethylDhenyl)amino)carbonylmethyl-pyrrolidine-3carboxylic acid Example 532A 1 0 N-butyl-N-(3-hydroxymethylphenyl)-amine To a solution of 3.69 g (30 mmol) of 3-amino benzyl alcohol in ml DMSO was added 3.78 g (45 mmol) solid NaHCO3 and 2.91 ml (27 mmol) 1-bromobutane. The reaction was allowed to stir at 50 'C for 18 hours (overnight). Reaction was worked up by adding 250 ml water *.i and product was extracted in ethyl acetate. Water was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine. Example 532B N-butyl-N-(3-hydroxymethylphenyl)-bromoacetamide To a solution of 3.42 g (19.2 mmol) of the compound of Example 532A in 20 ml toluene, was added 2.42 ml (30 mmol) pyridine. The mixture was cooled to O'C; 4.025 gm (20.0 mmol) of bromoacetyl bromide (diluted with 5 ml toluene) was added in a dropwise fashion.

The reaction mixture was allowed to stir for 5 hours at O'C and then was allowed to warm to room temperature. Saturated potassium carbonate solution was added, and the mixture was stirred vigorously for 2 hours. The mixture was extracted with EtOAc; the organic layer was washed with 1N H3P04, water, and brine.

-473- Example 5320 Ethyl trans, trans-2-(4-Methoxyp~henyl)-4-(1 .3-benzodioxol-5-yfl-1 rUN-butyl-N-(3-chloromethyllhenyfl~amino~carbonyl methyll- 12yrrol idine-3-carboxyl ate According to the procedure of Example 5230, N-butyl-N-(3hydroxymethylphenyl)-bromoacetamide was coupled with ethyl 2-(4- Methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate.

The crude product (129 mg) was dissolved in 0.5 ml of DMF and cooled to 000; 19 mg of LiCI was added, followed by 85 il of thionyl chloride.

The mixture was allowed to stir for 30 min; water was added, and the mixture was extracted with EtOAc. The organic extracts were washed with water and brine, and dried over Na2SO4.

Example 532D trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yf)l- butyl-N-(3-aminomethylphenyflamino'carbonymethyll-oyrrolidine-3carboxylic acid The compound of Example 5320 (182 mg) was dissolved in 1 mL of U DMVF. Two drops of water were added, followed by 126 mg (2.0 mmol, eq) of sodium azide. The resultant solution was heated at 115 1C for 3 hours. Water was added, and the mixture was extracted with EtOAc. The organic extracts were washed with water and brine, and dried over Na2SO4.

Example 532E trans, trans-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-yl)-1 butyl- N-(3-ami nom ethyl phenyl) am ino) carbonyl m ethyll-p2yrrof id ine-3carboxylic acid In a 50 ml round bottom flask 0.090 gm Tin (11) chloride was suspended in 1 ml acetonitrile. Triethylamine (0.2 ml-) was added, followed by 0.19 ml of thiophenol the reaction mixture turned yellow.

Reaction flask was cooled to O*C in ice bath; a solution of 0.185 gm of the compound of Example 532D in 2 ml acetonitrile was added. The -474mixture was allowed to stir for 30 min. Ether (10 ml) was added, followed by addition of 10 ml 2N HCI The aqueous extract was basified with 4N NaOH and extracted with dichloromethane. The organic layer was washed with water and brine. The crude product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 8 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H3P04, and the product was purified by preparative HPLC. 1 H NMR (CD3OD, 300 MHz) 5 0.88 J=7 Hz, 3H), 1.15-1.45 4H), 3.40-4.20 14H), 5.97 2H), 6.82 J=8 Hz, 1H), 6.88 (dd, J=8 Hz, 1H), 6.97-7.20 5H), 7.40 J=9 Hz, 2H), 7.56 J=5 Hz, 2H). MS (DCI/NH3) at m/e 560 9 (M+H) Anal calcd for C32H37N306*4.2 TFA: C, 46.72; H, 4.00; N, 4.05.

Found: C, 46.66; H, 4.06; N, 4.00. Example 533 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-r(N- butyl-N-(3-trimethylammoniomethylphenyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid To a stirred solution of 0.128 gm of the compound of Example 532C in 0.5 ml methanol, 0.25 ml of an aqueous solution of trimethylamine was added. The mixture was allowed to stir at room temperature under nitrogen atmosphere for 4 hours. 1N HCI was added; 4F 5 the aqueous was washed with ether to extract organic impurities. The aqueous layer was dried azeotropically with toluene, and the residue was dried under high vacuum. Yield 0.115 gm. 1 H NMR (300 MHz, D6- DMSO) 8 0.83 J=7 Hz, 3H), 1.15-1.40 4H), 2.62 2H), 3.35 (s, 9H), 3.40-3.80 10H), 4.47 2H), 6.00 J=3 Hz, 2H), 6.75-6.90 (m, 3H), 7.25-7.37 2H), 7.45-7.60 3H). MS (DCI/NH3) at m/e 602

(M+H)

-475- Example 534 (2R.3R,4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl 1- (2-(N-propyl-N-pentanesulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid Example 534A Ethyl (3-fluoro-4-methoxy)benzoylacetate Sodium hydride (17g of a 60% suspension in mineral oil) is 1 washed three times with toluene. The powder is suspended in 138 mL of toluene, and 35 mL of diethyl carbonate is added. The mixture is heated to 90 OC, and a solution of 25 g of 3-fluoro-4- methoxyacetophenone and 50 ml of diethyl carbonate in 50 ml of toluene was added portionwise. Heating is continued for 30 min, then 1 5 the reaction is cooled to room temperature. A solution of 50 ml of concentrated HCI in 75 ml of ice water is added slowly, and the mixture is stirred. The mixture is extracted with toluene; the combined organic extracts are washed with brine and bicarbonate solutions. The product is dried over Na2SO4 and decolorized with charcoal to give 34.5 g of the title compound. Example 534B Ethyl 2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate The compound of Example 534A (12.5 g) and 5-(nitrovinyl)-1,3benzodioxote (13.1 g, 20% excess) were suspended in a mixture of ml of THF and 13 ml of iPrOH. DBU (0.25 g) was added, and the mixture was stirred at room temperature for 30 min. An additional 0.1 g of DBU was added, and the solution was stirred for 1 hour. The solvents were removed in vacuo; toluene was added, along with brine containing 3 mi of concentrated HCI. The mixture was extracted twice with toluene; the organics were dried over MgSO4. The residue was flashed on silica, using CH2CI2 to elute. Yield 75%. This material (17.4 g) is combined with 35 g of Raney Nickel (washed) in 250 mL of EtOAc. The mixture is shaken under 4 atm of hydrogen for 18 hours. The solution is -476concentrated in vacuo; the residue is chromatographed on silica, eluting with 4% EtOAc in CH2CI2. Yield 10.13 g 66%. The product is combined with 26 ml of THF and 50 ml of EtOH; 2.18 g of NaBH3CN are added, along with a trace of bromcresol green as indicator. A solution of 1:2 concentrated HCI/EtOH is added dropwise to maintain pH at green-yellow; after color persists, the reaction mixture is stirred for an additional 20 min. The solvents are removed in vacuo; the residue is stirred with mixture of toluene and KHCO3 solution. The organic phase is washed with water and brine, and dried over MgSO4. The crude product is purified by flash chromatography on silica, eluting with 2:1 EtOAc/hexanes. Yield 5.92 g of a 2:1 mixture of trans-trans and cis-trans isomers. 0. Example 534C Ethyl (2R.3R,4S)-2-(3-Fluoro-4-methoxyDhenyl)-4-(1,3-benzodioxol- 5-yl)-pyrrolidine-3-carboxylate o To the racemic amino ester above (15.0 g, 38.8 mmol), dissolved in 75 ml methylene chloride and cooled in an ice bath, was added Boc anhydride (9.30 g, 42.7 mmol). After stirring 2 hours at room temperature, the solution was concentrated in vacuo the residue was dissolved in 50 ml ethanol and treated with a solution of 3.75 g sodium hyroxide in 19 ml water. The solution was warmed until all was ao:* soluble. After stirring for 2 hours at room temperature, the solution i:* was concentrated and redissolved in 200 ml of water. This was extracted with 75 ml of diethyl ether. The ether layer was extracted with 40 ml of water. The combined aqueous phases were acidified with g acetic acid; the mixture was stirred until a solid formed. The solid was filtered, washed with water and dissolved in methylene chloride. After drying with sodium sulfate, the solution was concentrated and the residue crystallized from 1:1 ether:hexane to get 15.99 g of product, m.p. 200-203 (90% yield). The crude acid was suspended in 80 ml ethyl acetate and treated with 4.00 g (33.1 mmol) of (S)-(-)-a-methylbenzylamine. After heating to dissolve the acid, ml of ether was added. Scratching with a glass rod caused the product to crystallize. The solids were filtered and washed with ether-ethyl -477acetate solution to give 8.22 g (81% yield based on 50% maximum recovery) of salt, m.p. 165-1680C. After one recrystallization, chiral HPLC analysis, using a Regis Whelk-O column, indicated >99.5 e.e.

The salt was dissolved in 500 ml of 36% HCI in ethanol; a white solid forms. The resultant suspension was heated for 16 hours at 52 0

C.

After concentrating in vacuo, the residue was combined with toluene and stirred with potassium bicarbonate in water for 30 minutes. The toluene was separated, dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel, eluting with 33% hexane-67% ethyl 1 acetate to get 6.9 g of the resolved amino ester.

Example 534D Ethyl (2R,3R.4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol- 5-yl)1-(2-(N-propylamino)ethyl)-pyrrolidine-3-carboxylate The compound of Example 534C was dissolved in 1,2dibromoethane 10 mL per 1 g of starting material diisopropylethylamine (1 mL per 1 g of starting material and Nal 100 mg per 1 g of starting material) were added, and the mixture was stirred at 1000C for 1 hour. Toluene was added, and the mixture was washed with bicarbonate. The solvents were concentrated, and the resultant black residue was chromatographed on silica gel, eluting with 4:1 hexane-EtOAc to give the N-(2-bromoethyl)pyrrolidine This compound was combined with n-propylamine (3.5 eq.) and Nal (10% by weight of bromide) in ethanol 5 mL per 1 g of bromide), and was heated at 800C for 2 hours. Toluene was added, and the mixture was washed with bicarbonate, dried (Na2SO4), and concentrated. More toluene was added, and removed in vacuo, to get rid of the primary amine. The residue was dissolved in heptane and filtered to remove a small amount of insoluble material. Evaporation of the solvent gave the desired product (86-93% yield), which was used for the next step without further purification.

-478- Example 534E 1-Pentanesulfonyl chloride 1-Pentanesulfonic acid, sodium salt (10 g, 57.5 mmol) was charged into a 250 ml round bottom flask (allow headroom). Thionyl chloride (20 mL) is added; gas evolves, and a while solid forms. The mixture is heated at 60 °C for 3 hours. The solvents are removed in vacuo; toluene is added and removed in vacuo to remove residue of SOCI2. The residue is partitioned between CH2CI2 and ice water; the 1 0 organic layer is dried over Na2SO4 The crude product is purified by distillation (bp 54-56 oC 0.5 mm Hg) to give a clear oil, 61% yield. Example 534F (2R.3R.4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl)1- 1 (2-(N-propyl-N-Dentanesulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid The compound of Example 534D (200 mg, 0.43 mmol) was dissolved in 5 mL of CH3CN; 110 mg (2 eq) of N,Ndiisopropylethylamine and 72.8 mg (1.2 eq) of 1-pentanesulfonyl chloride were added sequentially, the resultant solution was allowed to stir at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc. The solution was washed with saturated NaHCO3 solution, 1N H3P04, and brine, dried over Na2SO4 and evaporated to give a yellowish oil which was purified by flash chromatography on silica gel eluting with EtOAc/hexane to give 220 mg of product This ester was dissolved in 5 mL of EtOH, to which was added NaOH (46 mg, 3 eq) solution in 2 mL of H20. This mixture was stirred for 3 hours at room temperature. The solution was concentrated in vacuo using low (<400C) heat. Water (10 mL) and ether (50 mL) were added; the ether layer was extracted with 5 mL of water. The combined aqueous mixture was back-extracted with ether and then neutralized with acetic acid. This solution was extracted twice with ether. The ether was dried (Na2SO4) and concentrated in vacuo. EtOAc (1 mL) and ether (1 mL) were added to dissolve the product, and hexane was added dropwise to produce a -479white solid. The solid was collected and dried in vacuo to give 125 mg of the title compound.

Example 534H (2R.3R.4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)1- (2-(N-propyl-N-pentanesulfonylamino)ethl)-pyrrolidine-3-carboxylic acid, hydrochloride salt The free amine is 1 0 iPrOH is added, and the added, and the solution material is stirred with is collected by filtration dissolved in iPrOH; a slight excess of HCI in solution is concentrated in vacuo. More IPA is is reconcentrated. The resultant sticky ether overnight to give a white powder, which and dried overnight in vacuo at 60 Yield Example 535 The compounds in Table 3C may be prepared using methods presented in the above Examples.

480 Table 3C.

*',ICOOH

0 0 0-J y .1COOH 0

C

3 0 0-i 6

-'ICOOH

00 0-i 7 N IC00H 0

C

0 0-i 11 12 0.ICOOH 0 0-i F 2 W N *.9COOH -4 0 0-i _o 94 0r0410 0 0CH 0 0 0 H00011 0 H01- 0 0 N N ZH N LZ 9z

SE

0 CHOO" f-0 r 0 HO~i.

o 0 0 g000u-- H00013- 0 r 3-- 0 N N :i N HN 0 0 0 H0001--- 00 N HOO0zb.

S6L 0 0 0 i 4 CHO 0 4 0

CH

H00 HOOO"j H0 i N H00Z- 0 L t L 9L 0O~i. CHOu. 0.Q 2 HCHO" 0 H003 9- 0H0 Ot 0H 31- 0 N, a NJ ~a O 0 I8V 0V I

ZH

0 H 0 H000t- 0 0 HOO311-- N JN"-N

H

0 H000i.- 0 0 et 483 N

'ICOOH

F 0 -0 46

**"COOH

0

C

0 -0-i 00 0 I0 H2 4 ~r *..ZCOOH 0 O-0 53

*."COOH

00 0-i 48 0 *.CO0H 0 0-i 51

OCOOH

0 I0-i 54 0

*'ZCOOH

0 0-i 57 0

'-ICOOH

0 Cl-I 0-i0

S

S 56 HN *iC0OH ~-0 0 -0-i r N "iCOOH 0C 59 0L 0 HOOD"l- N 0kJ~~ 99

CHO

HOO0i'. 0 99 0OOCHO 0 00 H00i.

HOOO"

CH

0 HOO031- 0 L9 01 HOOZie. 0 0 H000s- 0c vt7t 06 r 0 0 0 HN03 1l--

X

0 H OQO"" 0 0 H0O011-

N~J'

0 0 H000t- 0 6L 0 9L 0 0 H000z1- Li.

set 486

'RCOOH

00 91

COOH

0 94

*'ICOOH

00 0- 97

*,IICOOH-

0 0 95 96 S S 5*

S

S S S. 55

S

S.

S

S

S. S

S

55 5 55 5*

S

98 99 100 r N -1"COOH 0 0C-i 103 *nICOOH 0 O-0 101 0

*"ICOIOH

0

CH

3 0O 104 102

"ICOOH

0

CH

3 487

'ICOOH

0 0

CH

3 0- 106 0 ~N N 0 IICOOH 0 CF1 3 0O 107 011 0

CH

3 110 N NI ,iCOOH 0C 0 C14 3 n- N.ThCOO 00 112 0 CK3 115 I I f-N 'COOH 0 0 6 0,~ IN I' *iCOOH 0C 0 Cl-I.

114

H

2

NW'N

1 Nf -f3NCOOH 00 117CH 0 S S

S.

S

S S@ *O 0 0eee S 00 000@

S

*00*0S S. 0* S

S

S

S

116

N

119 120 488 123 124 125 126 127 .1"COOH 0 130 I N 12812 't2

."'COOH

0 132 QSL 61' L 0 00 0 H000i 0 N I,,o..0 9t, L.

K-,N

Z17 L i-i

I

0 H 0i,,..0 01' L 0 0 H00011- 0 N'-KN i H 0- 00 0 HOOOl-

N

68V' 490

.""COOH

0 0 Cl-b 151 0

C

0 01130 0- 154 *.sICOOH 0 0 c oj 3 155 0

-I

0

OH

3 153 0 'IC0O 0 156 00 159 00 162 157 6*

'-ICOOH

00 160 'jCOOH 0 0-5'.ICOOH 0 164 -165 491 0 166 168 171 169 170 ~Th

COOH

0 173 175 H O N -j r* C O O H 00 0 176 177 0f 0

C

0 0-i 179 180 492 0 '12 ll N 'C O O H 0 0 ~0-i 181 0 0 -o- 184 0 0 0 -131COJOH 0 0-i 187

N.~

I0 'I

COOH

0 190

H

2

N-.,N

1 N -Ia:C0OH 0 0 C 6F 3 0 193 0 182 0

N

**sCOOH 0 0-i 186 189 *d'IC00 0 00 00

CH

3 0-- 191 192 0 CH3 C 195 493 0f-I 0 -IC00H 0

CH

3 196 0

",COOH

00 199 H2N~>yf *iCOOH 00 202 0 *.tCOO 0 197 200 -1 ".CO0H 0 0 CI-I3- 198 0 NNTh

*"'ICOOH

201

-"OO

0 204 ~N 00 00 0 0 $O-4 205 0 0

COOH

0 206 ~-Th 209 210 0 HOOO"** 0 0 6 LZ 0 92L 92L 0 0 H ,0..0 LLz r-o- 0 0

KKZ

0L 0S HOOD""1 0Nkj~ 0 0 HOOD,-* 0 0 :)o tV6V 495 0 0 0-i 926 228 229 230 0- 232 0

,'?COOH

0 C 3 ~0- 235 0 **COOH 0 238 a.

a 233 ~0O 0 0 Cl-b 236 N

COOH

0 0 23908 234 0 0 237OH 0

C

0 C83e0' i 240 496 I -11COOH 0 0

C

3 0 0K~ Nfl 'tCOOH 0 243 244 246 a 247 0 250 248 249 N~Th 251

-"ICOOH

0 0

H

2

N-

252 253 23254 255 497 257 256 258 259 260 262 263 264 266 0 267 00 0 0- 270 26826 269 498 271 272 273 274 275 276

N

F 0 277 N

COOH

0 278C-b

H

2 N "'ICOOH 0

C

0

CH

3 0 9 9 9 9.

9 9* .9 9.

9 *9 99 9 9999 9 99 9 0 9. 9 9 9 99 9 *9.9 9 9 279 oL.

CI-1( 280 282 499 283 284 0

CH

286 289 285 0 0 288 0 I0 291

N,

290 0 0 0 *0 0 0* 00 00 0 0* 0000 0 .000

S

000000 S. 0 0

SO

5005 505000 292 294

H

2 295 25296 297 500 298 N~~Th 300 299 0* S 0

S.

S~

S. Sm 302 303

."JCOOH

304 N.~ThOCH.

""COOH

00 0 307 0",COOH 0 310 0

WS*S

0 5505

S

S* 1655

S

*0 0 I 0 0e 5*

S

05 0500 0 0 006000 0 305 306

CH

3

**"ICOOH

0 0-J 311 309

OCH

3 0

I"COOH

0 0-j 312 r0

CHO

0K

HOO'

CHOO

K 1.4 0 0 H00311-

CHOO

N ZNNH 6 LE: 0 1 ,O~N 0 H0O" H 0 0 0 i s N J LLE 9 LC r- 0 0 0

HOO

LOS 502 326

H

2 N- W "N

'H

0 -ntCOOHC

I

0 C~aO 0- 329 328 0 -ICOOHI Cl c 330

CH,

0

CH

3 0O 333 ~NrN' 332 N,

-COOH

334

OCH:

-iCOOH 0 0 337

H

3 335 336 0 338

CH

3

*-,"COOH

0

H

2

N

339

H~N.

503 340 CH3

H

2

CCOOH

w4

NYCN

344

-'COOH

0 347 342

*COOH

345

CM

3

M

2 N Ni N "COOH 0 346 V.* 350 351

?OCH

3 0 ~0 352 9

'OCH

3 0 0 0o-J 9

OCH

3 0 *::iCOOH 0

O-J

353

).-'OCH

3 0

-JIOO

QICH

0 H2 N lr L *.,C00)H 0 0

-J

504 355 356 357

*COOH

-3.,O

_COCH

359 zkJ 360 rNCH 0

OH

3 0 364 N

H

0 H2 N r N 0 0-J 362 0 N *COOH 365 363 366 367 9

CH

P-1CH ~N~fl~N{'COOP

OH

3 03 369 H,N N .,CH 0 'Co0 0 CF1 3 0 505 370 0 -COOH0

CH

3 0 05 CH 373 374 0 aN'rN.aaCOOHH 0 376CH 2OCH 3 00 379

Q'OCH

3 0 1 01N'r N *-iCO0H 0 382 3 0 N

COOH

0

'OCH

3 1 2 N 'r IaCOO 01 3 PO0CH 3 0

-NN

378 0 OCH 3 0 381 §;bCHt 0

H

2 384 4 380 9b;CH3

-*-COOH

0 383 0 I0 506 385 386 387 0 388 C0 0OCH3 a N'r N -COOH 3910 0 0 394

C~

00 COGH "l COOH -'Coc0 JbI4 390 0 0

C

0 392 0 0a-i 395 00 00 -0-i 398 2

*'COOH

0 0-i

CHI

0 393 396 00 0 0. 0- 399 397 00 0 -0-i 507- 400 401 0 .'COOH N *"COOH 00 "Co

CC

0-i 403 404 Fi 2 W _C N -r N "C O O H 0

CO-J

407 402 N~JA'J ~N COOH 0

'-J

405 0 0 -i 406 0 0 0* 409 410 0 "COOH 0 C0 413

H

2 NN COO 0

CH

3 0- 412 0 0 0 H001 c 0 HOOO',i..

04 zz7 .t,~I7 Let' ozt7 0 0 6 Lt 0 9 Lt' 0 /Lt7 80S 509 427 429 0 430 \o

-COOH

0 433 434 0 "ICOOH 00 438 436 Qo 0*.,"C0OH 00 -0-i 440 441 510 Noj o N .COOH H2NY ,ICOOH 0 0 0 442 443 0-1 44o-J ~NN~N ."COOH m*COOH "'COOW 0- 0i 0 446 0 445 446447 0 *'IC0H ~N .'COOH N "ICOIOH 0 0 0 0.

448 49450 ICO 0.I O 'COOH 0 0 0 0.-Co o.,OI J 451 452 453 N QO Y-'-NH Q N .COH"CO0H 0 F"OH 0 0 0

CH-

3 0c-s

CH

3 0 511 455 C0 0 457 0 0

O

0 460

H

2 Nl 458 456 0

C

0

OH

3 459

Q

0 OH1 3 o- 462 b** ,0-0 :0 to 09:5 463 464 465 466 46467 468 512 469 470 473 471

H

2 r

"'COOH

0 474 472 475 476 477 1 0 478 479 0yN Qo

H

2 N *"COOH 0 480 N *'IICOOH I0 513 N~Th 482 485 483 486 488 489 491 492 490 493 N

N

I 8*'iCOOH I 494 495

NN

514 496 N

,COOH

0 0

CH

3 0 499

I-

498 N Y

'-COOH

0 CH30 0 501 500 502 ~rN 0N N

'COOH

00

CH

3 0 505 0C 0 508CH 503 0 .1COOH 0 CH3 506

CN

**iCOOH 509 504

H

2 N~N~ rN-N 04 0

CH

3 507 a. a. a 510 515 511 514 0 0 512' 0 515 0 0 .ICO0H -0

CH

3

C

513 516 518 519 00 0 516 523 ~yN 526 524

H

2 N <N

"COOH

527 525 Qo- ~YY> *tiCOOH 528

*'COOH

0 a-_ 531 H 2 N N N C OH 00 00 0 534 530 a a a 532 533 0 L 537 535 536 NN o N4 0 N

N

6 -"OC

*.COOH

-0 517 541 539

H

2 N *"1COOH 0

'-J

542 1 0 540 543 545 546 0 548 549 0 552 551 518 553

."COOH

0 lI 555 556 557 558 0 0.

o o e* 559 560 562 563

~NZ~~~J'J

566 567 5ig

I-

0 0 N ,iCOOH C0

."COOH

0 569 N4 0 572 o-\N 570 0'00 0 571

N

0

ICOOH

574 573 576 S. S S

SS

0 S *5 0*55 0 05 555.

S

S

S. S

S

*S

55 S. S 5.55 .5 S S S. S

S

SS**S@

575 578 579 L 6S 999 069 69 L89 99 99 t'99 ~99 LBS 0gg 0zs 521 H2 r N *'obCOOH 00

CH

3 593 592 595 594 596 597 598 599 600

H

2 602 603 522 I

HO,~N

606 605 607 608 609 611 0 614 615 523 616 H2N 617 0 "COOH 0 0-J 620 "11COOH 00 0-i 623

N,

618 619

*~COOH

0 -0-i 622

N>

0 0KO0 00 0 625 N~N o 0 C0 0 628 0 624 0 0 0-i 627 4* 626 N 0 0 0-i 629 630 524 0"COIOH 0 0-i 631

*:COOH

C R3 a 634 H2N~N~..<N -COOH 0 0 CI-b 0-i 637

A

0 H0

ICOOH

0

CH

3 640 0 643 0

I

CH

3 0 632 0

CH

3

C

633 0

*"'COIOH

0 CH, n-i 635

H

0

-J

638 639 0.

-0

CH

641 642 Ni-o 0 ""ICOOIH H 2 <N CO'OH 0 644 c b645 Kb 099 699 999 L99 t799 999 -0 C99 HOO3t- 0 099 0 HOO31.-a.

Z99 0 HOO 0z;.- 0 H003**N-N 9t,9 0 0 SES f- L9 LL0 9 0- L9 N N-

Z

0 0 699 999 L99 000 0 0 0 HOO3iz.. HOD0i.. 0HO0~v'* 0999 999I9 0 0 0 0 0 HO~z.. N.J1 ZNH HOO0s.* HOO~il- E699 U99 1.99 9zs 527

N

'r

"ICOOH

00 673 ~~~INd 0 674 675 676 677 678 679 0 0 682 680 R2 W--_-NCOOH 00

CHI-

681 0

ICOOH

CF 0 683 684 528 0 (1IH0 -COOH 0 "COOH 0 0 0 685 CH, 01686 C~ 1687 CFI3

N

1 f<N IC0OH H 'COOH H N N .'.CoO 00 0 0H 3 CH, ii -i 688 C3689 3690 C3 0

"'C'COON

y 0 0

CH

3 O-0 691 692 693 0 -ICO H 0 -ICO H H N0COH 0, a 694 695 696 0 529 0 13COOH 0 697 00 0 700 0 0 699 698 701 4 703 704 "'COOH N ,.O 0 0 00 705 706 76707 708

OZL

0 0

LLL

0 tLL 6 LL

NN

9 LL 0 0 LL 0 Wo"

HL

0 r 0 0

N

OES 531 ~?Th 0

-I"COOH

0 o 721 ~Th 722 724 N0

*.COOH

0

CH

3 727 N 0 o -ltOO

-COOH

0 78O 728 ~N/V~N~6 -I0 731 732 Ot 0e ~0 L17LOt~L 66L 0 9SL 861L 9-13 0 H003".. NJ

NJ

HS :533 745 748 751

C.

C

C

*C.C

C

C C C 752 753 -Th

KN-

755 756 534 -oCOIOH 0 o-J 757 0 11co0 0 o-j 758 0

C

0 0oJ 761 760

C

C

a.

C

C.

C.

C C

CCC

CC..

763 766 764

NO

.ICOOH

0 0

CH

3 n- 767 765 768 533 H2

*"'COOH

0 0 cf* o 3 '-cOH 0 0 C IH 3 773 "'liCOOH 00 0

CH,

776 a:

N

0 -IC00H 00

CH

3

O

774 0 0 C143 Hi 2

W

780 S. S S

S.

S

9O S. 5.5.

S

S.

S

S

.55.5.

S

55 55 SS S .55.

S* S 55 05

S

F-J

782 783 536 HO~-~N **COOH 0C 784 785 786

-I

789 787 788 *0* 000 006 0 790 792

H

2

N~

793 93794 795 537 797 799 800 798 0 0 "1COOH 0 0- 801 p ""Icoo 0

JI

804 R<9 N 0 0 -soCOOH 0 0-J 803 802 0

N

805 85806 807 538 808 809 810 811 0CF o- 1c 814 or

.'ICOIOH

00 c-a, Oj 813 816 818 819 539 N 0 0 N IC 0OH 00

C

3 820 Iy rN gCO 0

CH

3 -0- 823 N 0

:ICOOIH

822

."COOH

00 825CH 826 827 828 829 89830 831 540 H2 N~ \R, 0 N0 0 0

N

0 0 0 0 835 836 837

N

0 00N*0 0 -COOH "CH I ,aCOOH 0 0 0 838 836 840

N

0 0 88842 843 541

HN

844 845

H

2 NW-N-N 0N

-COOH

I0 846 0 ,COIOH 0 849 oL 850 848 N~N 0 0

COOH

0 -0-i 851 852 2

N

853 83854 855 542 N o 857 N0 0.CO 0 C ol0 <N

*.ICOQOH

00

CH

3 862N

N

H2N*, N<IlN -ICOOH 0 0 CH3 865 860 863 858 N0 0 -tC010H 0 cH- 3 oj 861 0 .9COJOH 0 864 CH 3 0~-

C

866 867 543

N

U--

N~N 0 H2" N

"COOH

870CH 869 872 873 874 875 876 a.

877 87878 879 544 I 881

Q

884 883 ~Th 885 0 0

-ICOO

00 0 0-i 886 887 889 89890 891 545 892 {Vo

H

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2

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a.

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a. 1749 1747 1750 1751 1752 0 0 C0 cH 3 1754 1755 1753 607

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1756

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HN-S::

0 1780 1781 -609- As an indication that the compounds described herein act through binding to endothelin receptors, the compounds have been evaluated for their ability to displace endothelin from its receptor.

Binding Assay ETA Receptor Preparation of membranes from MMQ cells: MMQ [MacLeod/MacQueen/Login cell line (prolactin secreting rat pituitary cells)] cells from 150 mL culture flasks were collected by centrifugation (1000xg for 10 min) and then homogenized in 25 mL of mM Hepes (pH 7.4) containing 0.25 M sucrose and protease inhibitors [3 mM EDTA 0.1 mM PMSF, and 5 ltg/mL Pepstatin A] by a micro ultrasonic cell disruptor (Kontes). The mixture was centrifuged at 1000xg for 10 min. The supernatant was collected and centrifuged at 60,000xg for 60 min. The precipitate was resuspended in 20 mM Tris, pH 7.4 containing the above protease inhibitors and centrifuged again. The final pellet was resuspended in 20 mM Tris, pH 7.4 containing protease inhibitors and stored at -800C until used. Protein content was determined by the Bio-Rad dye-binding protein assay. 1 2 5 11ET-1 binding to membranes: Binding assays were performed in 96-well microtiter plates pretreated with 0.1% BSA. Membranes prepared from cells were diluted -100 fold in Buffer B (20 mM Tris, 100 mM NaCI, 10 mM MgCI2, pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 gg/mL Pepstatin A, 0.025% bacitracin, and 3 mM EDTA) to a final concentration of 0.2 mg/mL of protein. In competition studies, membranes (0.02 mg) were incubated with 0.1 nM of 1 2 5 1]ET-1 in Buffer B (final volume: 0.2 mL) in the presence of increasing concentrations of unlabeled ET-1 or a test compound for 4 hours at 25 After incubation, unbound ligands were separated from bound ligands by a vacuum filtration method using glass-fiber filter strips in PHD cell harvesters (Cambridge Technology, Inc., MA), followed by washing the filter strips with saline (1 mL) for three times.

Nonspecific binding was determined in the presence of 1 tM ET-1. The data are shown in Table 4. The per cent inhibition at a concentration of 1 mM is shown. The data show that the compounds of the invention bind to the endothelin receptor.

-610- Table 4 Binding Data Example Inhibition Example Inhibition of ETA at 1 of ETA at 1 mM mM 1D 96.4 34 95.5 2 58.4 35 91.8 3 42.2 36 94.5 4 78.2 37 47.9 95.1 38 100.0:.o 6GB 34.9 39 83.6 7 63.4 40 94.8 8 53.7 41 89.9 9 69.2 42 95.2 66.1 43 99.2 14 86.6 44 91.3 84.8 45 85.4 16 96.0 46 90.4 17 73.9 47 95.1 18 97.3 48 96.3 19 90.3 52 84.0 80.9 54 64.6 21 56.3 55 50.5 22 86.3 56 34.3 23 85.9 57 93.2 26 83.0 58 81.9 27 61.2 59 70.8 28 63.8 60 42.8 29 85.3 610C 90.6 80.0 62 94.1 31B 93.6 63 92.0 -611- Example Inhibition ETA at 1 mM Example 64 66 67 68 69D 71 72C 73C 74 76 79 82 83 84 86 87 88 89 91C 92C 93C 96 97 95.0 82.8 87.7 96.3 84.6 37.4 62.7 81.4 80.7 96.3 95.6 95.3 93.1 100.4 89.4 90.3 85.0 65.3 52.6 62.4 84.3 84.6 91.6 107.4 59.2 82.1 86.1 89.0 98 99 100 101 102 103 104 105 106 107 109 110 111 112 113 114 115 116 117 118 119 120 121 122 125 126 127 128 Inhibition ETA at 1 mM 86.8 92.1 76.8 89.2 75.2 69.0 98.0 98.6 90.0 97.2 96.8 94.4 101.8 94.9 94.3 86.2 88.4 79.3 95.2 93.2 86.6 99.5 98.6 95.3 97.2 91.7 91.4 95.4 -612- Example Inhibition ETA at 1 mM Example Inhibition ETA at 1 mM 123 124 129 130 131 132 133 134 135B 136 138 139 140 141 142B 143 144 145 146 147 148 149 150 151 152 153 154 155 89.7 91.0 100.1 91.0 89.5 90.0 88.6 92.2 77.7 79.4 83.0 98.6 106.3 92.8 78.7 20.6 78.2 32.4 25.0 73.0 94.7 84.6 93.6 80.5 86.9 97.1 80.2 92.7 156 157 158 159 160B 161 162B 163 164 165 166 167 291 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 92.6 83.8 91.8 36.2 80.3 93.6 91.5 90.6 98.6 54.1 91.6 94.4 100.0 89.8 77.7 93.0 87.1 84.4 93.3 90.4 96.1 96.7 86.6 87.2 89.7 87:4 93.3 92.2 r -613- Example Inhibition ETA at 1 mM Example Inhibition ETA at 1 mM 308 309 310 311 312 313 314 315 316 317 318 319 320 322 323 324 334 335 340 341 342 343 344 345 346 348 349 350 93.0 80.7 87.1 92.3 88.2 96.3 86.0 82.7 74.0 68.5 79.0 79.0 82.2 95.6 91.3 95.0 88.0 84.1 94.0 87.4 89.9 98.7 95.6 86.6 88.9 91.3 73.0 92.1 351 352 353 354 355 356 357 358 359 360 361 362 363 365 366 367 368 370 371 372 373 374 375 376 377 378 379 380 99.0 96.2 73.7 79.3 100 93.5 96.3 62.7 94.7 93.7 92.8 94.1 82.3 59.2 91.5 71.0 94.6 84.3 97.2 91.6 92.9 91.4 97.8 90.2 85.6 91.1 90.7 99.0 cc r -614- Example Inhibition Example Inhibition of ETA at 1 of ETA at 1 mM mM 381 95.7 408 100 382 96.8 409 89.4 383 91.4 410 91.4 384 79.4 411 93.5 385 86.2 412 86.4 386 47.8 413 99.5 387 98.7 414 91.4 388 69.2 415 87.3 389 100 416 86.4 390 98.2 417 98.7 391 45.6 418 100 392 93.7 420 100 393 100 421 100 394 97.8 422 96.6 395 79.8 423 89.1 396 98.7 424 85.8 397 100 425 90.8 398 90.0 426 97.2 399 59.9 427 100 400 93.0 428 100 401 96.5 429 100 402 80.5 430 94.1 403 96.1 431 99.1 404 95.4 432 95.5 405 86.4 433 99.6 406 94.5 434 100 407 100 435 97.8 -615- Example Inhibition of ETA at 1

M

Example Inhibition ETA at 1 mM 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 100 1 00 94.3 94.3 100 98.3 1 00 100 100 98.1 97.8 96.9 97.4 100.0 99.7 100 100 94.4 96.8 99.1 95.3 88.9 93.4 459 460 461 462 463 464 465 466 467 468 469 470 471 475 476 477 479 495 496 497 498 499 500 97.4 91.6 99.6 98.3 96.1 97.1 95.1 94.2 93.6 88.7 98.7 1 00 1 00 91.6 82.3 80.1 96.5 95.9 92.7 83.7 81.6 68.5 55.7 -616- Example. Inhibition of ETA at 1 mM 502 95.7 503 97.0 504 97.1 505 95.8 506 99.7 507 99.3 508 97.6 509 100 510 100 511 99.2 512 98.9 513 98.0 514 100 515 99.1 516 99.7 517 94.1 518 96.3 519 99.1 520 97.4 521 100 523 99.0 524 99.2 525 100 526 100 527 96.6 528 98.3 529 98.1 531 99.8 532 100 533 97.9 -617- As further demonstration of the efficacy of the described compounds as functional antagonists of endothelin, the ability of the described compounds to inhibit ET-1-induced phosphatidylinositol hydrolysis was measured.

Determination of PhosDhatidylinositol (PI) Hydrolysis MMQ cells (0.4 x 106 cells/mL) were labeled with 10 jRCi/mL of 3 H]myo-inositol in RPMI for 16 hours. The cells were washed with PBS, then incubated with Buffer A containing protease inhibitors and mM LiCI for 60 minutes. The cells were then incubated with test compounds for 5 minutes, and then challenged with 1 nM ET-1. ET-1..

challenge was terminated by the addition of 1.5 mL of 1:2 (v/v) chloroform-methanol. Total inositol phosphates were extracted after adding chloroform and water to give final proportions of 1:1:0.9 (v/v/v) chloroform-methanol-water as described by Berridge (Biochem. J. 206 587-595 (1982)). The upper aqueous phase (1 mL) was retained and a small portion (100 p.L) was counted. The rest of the aqueous sample was analyzed by batch chromatography using anion-exchange resin AG1- X8 (Bio-Rad). The IC50 is the concentration of test compound required to inhibit the ET-induced increase in PI turnover by 50%. The results of the above study clearly indicate that the compounds act as functional ET antagonists.

-618- Table Phosphatidylinositol Hydrolysis Example IC50 mM 1D 0.025 14 0.017 0.010 16 0.009 18 0.009 19 0.024 0.001 31B 0.002 43 0.0001 46 0.002 47 0.0005 48 0.0004 291 0.0098 300 0.0012 534 0.05 r r r r r r r Table 6 ETA/ETB Selectivity MMQ cells, porcine cerebellar tissues (known to contain ETB receptors) and chinese hamster ovary cells (CHO) permanently transfected with the human ETA or ETB receptor were homogenized in ml of 10 mM Hepes (pH 7.4) containing 0.25 M sucrose and a protease inhibitor [50 mM EDTA 0.1 mM PMSF, 5 Ig/ml Pepstatin A, and 0.025% Bacitracin] using a micro ultrasonic cell disruptor. The mixture was centrifuged at 1000xg for 10 min. The supernatant was collected and is centrifuged at 60,000xg for 60 min. The precipitate was resuspended in 20 mM Tris, pH 7.4 containing protease inhibitor and centrifuged again. The final membrane pellet was resuspended in 20 mM Tris, pH 7.4 containing protease inhibitors and stored at -80 °C until used.

-619- Protein content was determined by the Bio-Rad dye-binding protein assay.

Binding assays were performed in 96-well microtiter plates pretreated with 0.1% BSA. Membranes prepared from cells were diluted s -100 fold in Buffer B (20 mM Tris, 100 mM NaCI, 10 mM MgCI2, pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 gg/mL Pepstatin A, 0.025% bacitracin, and 50 mM EDTA) to a final concentration of 0.2 mg/mL of protein. In competition binding studies, membranes (0.02 mg) were incubated with 0.1 nM of [1251]ET-1 (for ETA assay in MMQ or CHO cells transfected with human ETA receptor) or [1251]ET-3 (for ETB assay in porcine cerebellum or CHO cells transfected with human ETB receptor) in Buffer B (final volume: 0.2 mL) in the presence of increasing concentrations of the test compound for 3 hours at 25 After incubation, unbound S ligands were separated from bound ligands by a vacuum filtration method using glass-fiber filter strips in PHD cell harvesters (Cambridge Technology, Inc., MA), washing the filter strips three times with saline (1 mL). Nonspecific binding was determined in the presence..

of 1 pM ET-1. IC50 values are calculated using an average of at least two separate determinations. The data shows the selectivity of the compounds of the invention in binding to the endothelin receptors.: Table 6 EXAMPLE mET-A mET-A pET-B Selectivity hET-A hET-B Selectivity NO. IC50 IC50 (mA/pB IC 5 0 IC50 (hA/hB 1.M) (nM) (nM) ratio) (nM) (nM) ratio) 502 95.7 3.0 71,000 23,000 503 97.0 1.4 50,000 35,000 0.92 52,000 56,000 504 97.1 3.1 >100,000 >32,000 4.6 >100,000 >21,000 505 95.8 2.0 60,000 30,000 5.7 68,000 12,000 506 99.7 3.2 >100,000 >31,000 3.0 61,000 20,000 -620- 507 99.3 3.0 >100,000 >33,000 1.63 >100,000 >60,000 508 97.6 1.9 45,000 23,000 2.1 51,000 24,000 509 100 0.56 30,000 53,000 0.51 23,000 45,000 510 100 0.50 35,000 68,000 1.0 11,000 11,000 511 99.2 0.81 N.D. 0.60 15,000 25,000 512 98.9 0.42 >80,000 >190,000 0.58 60,000 >102,000 513 98.0 0.30 8,800 29,000 0.36 14,000 37,000 514 100 1.0 26,000 26,000 0.36 9,800 29,000 515 99.1 1.6 >62,000 >37,000 6.7 >100,000 >15,000 516 99.7 0.71 29,000 40,000 1.8 37,000 21,000 517 94.1 1.0 30,000 30,000 0.43 12,000 29,000 518 96.3 1.3 85,000 63,000 0.31 38,000 124,000 519 99.1 0.38 14,000 36,000 0.23 19,000 83,000 520 97.4 0.20 28,000 130,000 521 100 0.67 37,000 54,000 523 99.0 0.42 360 880 0.33 290 880 524 99.2 0.79 1,700 2,100 0.82 890 1,100 525 100 8.2 560 SUBSTITUTE SHEET (RULE 26) -621- 526 527 528 529 531 532 533 534 100 96.6 98.3 98.1 99.8 100 97.9 17 7,400 440 10,000 11 43,000 1,300 3,800 1,700 3.6 1.2 5.1 76 0.12 6,300 0.71 870 1,200 3,200 7,900 0.36 630 100 3.0 40 0.08 22,000 0.28 560 Determination of Plasma Protein Binding 9 9 *9 9 9 9.99 A stock solution of the test compound in 50% ethanol (2 mg/mL) was diluted 10X into PBS. A 0.4 mL sample of this secondary stock solution was added to 3.6 mL of fresh plasma, and incubated at room temperature for 1 hour. A 1 mL sample of this incubation mixture was transferred to a Centrifree ultrafiltration tube. The sample was centrifuged in a fixed-bucket rotor for approximately 2 min and the S filtrate was discarded. The sample was centrifuged for another 15-30 min. A 100 gpL sample of the ultrafiltratewas transfered to a micro HPLC sample vial containing 150 ML of HPLC mobile phase and mixed thoroughly. A 50 gL sample was injected and the concentration of drug in the ultrafiltrate was determined by HPLC analysis compared against a standard sample prepared identically in the absence of plasma.

Ultrafiltrate concentrations are calculated from a calibration curve.

Protein binding is calculated according to the equation: %PB 100% -622where Cu is the ultrafiltrate concentration and Ci is the initial plasma concentration.

s Data: Example #43 99.5 Example #532 96.8% Example #533 82.6% O The ability of the compounds of the invention to lower blood s pressure can be demonstrated according to the methods described in Matsumura, et al., Eur. J. Pharmacol. 185 103 (1990) and Takata, et al., Clin. Exp. Pharmacol. Physiol. IQ 131 (1983). The ability of the compounds of the invention to treat congestive heart failure can be demonstrated according to the method described in o Margulies, et al., Circulation 82 2226 (1990). The ability of the compounds of the invention to treat myocardial ischemia can be demonstrated according to the method described in Watanabe, et al., Nature 344 114 (1990). The ability of the compounds of the invention to treat coronary 1 angina can be demonstrated according to the method described in Heistad, et al., Circ. Res. 54 711 (1984).

The ability of the compounds of the invention to treat cerebral vasospasm can be demonstrated according to the methods described in Nakagomi, et al., J. Neurosurg. 66 915 (1987) or Matsumura, et al., Life o Sci. 49. 841-848 (1991).

The ability of the compounds of the invention to treat cerebral ischemia can be demonstrated according to the method described in Hara et al., European. J. Pharmacol. 197: 75-82, (1991).

The ability of the compounds of the invention to treat acute renal failure can be demonstrated according to the method described in Kon, et al., J. Clin. Invest. 3 1762 (1989).

-623- The ability of the compounds of the invention to treat chronic renal failure can be demonstrated according to the method described in Benigni, et al., Kidney Int. 44 440-444 (1993).

The ability of the compounds of the invention to treat gastric s ulceration can be demonstrated according to the method described in Wallace, et al., Am. J. Physiol. 256 G661 (1989).

The ability of the compounds of the invention to treat cyclosporin-induced nephrotoxicity can be demonstrated according to the method described in Kon, et al., Kidney Int. 37 1487 (1990).

The ability of the compounds of the invention to treat endotoxininduced toxicity (shock) can be demonstrated according to the method described in Takahashi, et al., Clinical Sci. Z9 619 (1990). The ability of the compounds of the invention to treat asthma can be demonstrated according to the method described in Potvin and Varma, Can. J. Physiol. and Pharmacol. 6Z 1213 (1989). The ability of the compounds of the invention to treat transplantinduced atherosclerosis can be demonstrated according to the method described in Foegh, et al., Atherosclerosis Z. 229-236 (1989). The ability of the compounds of the invention to treat atherosclerosis can be demonstrated according to the methods.

described in Bobik, et al., Am. J. Physiol. 258 C408 (1990) and Chobanian, et al., Hypertension 15 327 (1990).

The ability of the compounds of the invention to treat LPL-related lipoprotein disorders can be demonstrated according to the method described in Ishida, et al., Biochem. Pharmacol. 44 1431-1436 (1992).

The ability of the compounds of the invention to treat proliferative diseases can be demonstrated according to the methods described in Bunchman ET and CA Brookshire, Transplantation Proceed.

23 967-968 (1991); Yamagishi, et al., Biochem. Biophys. Res. Comm. 191 840-846 (1993); and Shichiri, et al., J. Clin. Invest. 87 1867-1871 (1991). Proliferative diseases include smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels.

-624- The ability of the compounds of the invention to treat acute or chronic pulmonary hypertension can be demonstrated according to the method described in Bonvallet et al., Am. J. Physiol. 266 H1327 (1994).

Pulmonary hypertension can be associated with congestive heart failure, mitral valve stenosis, emphysema, lung fibrosis, chronic obstructive pulmonary disease (COPD), acute repiratory distress syndrome (ARDS), altitude sickness, chemical exposure, or may be idiopathic.

The ability of the compounds of the invention to treat plaletet aggregation, and thrombosis, can be demonstrated according to the method described in McMurdo et al. Eu. J. Pharmacol. 259 51 (1994). The ability of the compounds of the invention to treat cancers can be demonstrated according to the method described in Shichiri, et al., J.

Clin. Invest. 87 1867 (1991).

The ability of the compounds of the invention to treat IL-2 (and other cytokine) mediated cardiotoxicity and vascular permeability disorders can be demonstrated according to the method described in Klemm et al., Proc. Nat. Acad. Sci. 92 2691 (1995). The ability of the compounds of the invention to treat nociception can be demonstrated according to the method described in Yamamoto et al., J. Pharmacol. Exp. Therap. 271 156 (1994). The ability of the compounds of the invention to treat colitis can be demonstrated according to the method described in Hogaboam et al (EUR. J. Pharmacol. 1996, 309, 261-269). SThe ability of the compounds of the invention to treat ischemiarepurfusion injury in kidney transplantation can be demonstrated according to the method described in Aktan et al (Transplant Int 1996, 9, 201-207).

The ability of the compounds of the invention to treat angina, pulmonary hypertension, raynaud's disease, and migraine can be demonstrated according to the method described in Ferro and Webb (Drugs 1996, 51,12-27).

The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, -625camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quatemized with such agents as loweralkyl halides, such as methyl, to ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides..

such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others.

Water or oil-soluble or dispersible products are thereby obtained.

Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula or separately by reacting the carboxylic acid function with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, S secondary or tertiary amine. Such pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

The compounds of the invention are useful for antagonizing endothelin in a human or other mammal. In addition, the compounds of -626the present invention are useful (in a human or other mammal) for the treatment of hypertension, acute or chronic pulmonary hypertension, Raynaud's disease, congestive heart failure, myocardial ischemia, reperfusion injury, coronary angina, cerebral ischemia, cerebral vasospasm, chronic or acute renal failure, non-steroidal antiinflammatory drug induced gastric ulceration, cyclosporin induced nephrotoxicity, endotoxin-induced toxicity, asthma, fibrotic or proliferative diseases, including smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, S cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels, LPL-related lipoprotein disorders, transplantation-induced atherosclerosis or atherosclerosis in general, platelet aggregation, thrombosis, cancers, prostate cancer, IL-2 and other cytokine mediated cardiotoxicity and permeability disorders, and nociception, especially treatment of bone pain associated with bone cancer. Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg/kg body weight daily and more usually 0.1 to 100 mg/kg for oral administration or 0.01 to 10 mg/kg for parenteral administration. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.

The compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic -627pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.

The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, is sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules, 025 tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as -628wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances.

Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically aceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the S phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.

Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

A representative solid dosage form, for example, a tablet or a capsule, comprises: Compound of the invention: 35% w/w Starch, Pregelatinized, NF 50% w/w Microcrystalline Cellulose, NF 10% w/w Talc, Powder, USP 5% w/w While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more cardiovascular agents independently selected from diuretics, adrenergic blocking agents, vasodilators, calcium channel blockers, renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, potassium channel activators and other cardiovascular agents.

Representative diuretics include hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, metolazone, spironolactone, triamterene, chlorthalidone and the like or a pharmaceutically acceptable salt thereof.

Representative adrenergic blocking agents include phentolamine, phenoxybenzamine, prazosin, terazosin, tolazine, atenolol, metoprolol, -629nadolol, propranolol, timolol, carteoloi and the like or a pharmaceutically acceptable salt thereof.

Representative vasodilators include hydralazine, minoxidil, diazoxide, nitroprusside and the like or a pharmaceutically acceptable salt thereof.

Representative calcium channel blockers include amrinone, bencyclane, diltiazem, fendiline, flunarizine, nicardipine, nimodipine, perhexilene, verapamil, gallopamil, nifedipine and the like or a pharmaceutically acceptable salt thereof.

Representative renin inhibitors include enalkiren, zankiren, RO 42-5892, PD-134672 and the like or a pharmaceutically acceptable salt thereof. Representative angiotensin II antagonists include DUP 753, A-81988 and the like. Representative ACE inhibitors include captopril, enalapril, lisinopril and the like or a pharmaceutically acceptable salt thereof.

Representative potassium channel activators include pinacidil and the like or a pharmaceutically acceptable salt thereof. Other representative cardiovascular agents include sympatholytic agents such as methyldopa, clonidine, guanabenz, reserpine and the like or a pharmaceutically acceptable salt thereof. The compounds of the invention and the cardiovascular agent can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient. The combination can be administered as separate compositions or as a single dosage form containing both agents.

When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.

-630- The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds, processes, compositions and methods. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

*o

Claims (42)

1. Use of a compound having formula: R2 zN R3 (CH 2 )n R wherein Z is -C(R 18 wherein R 1 8 and Rig are hydrogen; n isO0; *R is -(CH 2 wherein m is 0 and W is -C(O) 2 wherein G is hydrogen, 10 -P0 3 1- 2 wherein E is hydrogen, loweralkyl, or arylalkyl, tetrazolyl, -C(O)NHS(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl, aryl, or dialkylamino, 15 or -S(O) 2 NHC(O)R 1 6 and R 2 are independently selected hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonyl alkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dial kylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N- alkyl)aminoalkyl, alkylsulonylamidoalkyl, heterocyclic, (heterocyclic)alkyl, or (R.)(Rbb)N-Rcc-, wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl, and is alkylene; R 3 is loweralkyl, alkenyl, akynyl, cycloalkyl, (e) cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclic,() (heterocyclic)alkyl, alkoxyalkyl, alkoxyalkoxyalkyl, (in) R 4 -C(O)-R 5 wherein [R:\LIBXX]425370d1 .doc:aak R 4 is lowerailcyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkylamninoalkyl, dialkylaminoalkyl, alkoxy, or (RI 1 )(R 12 wherein R 11 and R 12 are independently selected loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclic, arylalkyl (heterocyclic)alkyl, hydroxyalky, or alkoxy, and R 5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20 wherein R 8 is alkylene or alkenylene, and R 20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl, or cycloalkylalkyl, -R 8 a-N(R 2 0 wherein R 8 a is alkylene or alkenylene, (vi) -O-R 9 or -R9a-O-R9-, wherein R 9 and R9a are independently selected alkylene; R4-R 5 a, wherein R 5 a is alkylene or alkenylene, R 4 -C(O)-R 5 -N(R 6 wherein R 6 is (RI 1 )(R 12 R 6 -S(O) 2 -R 7 wherein R 7 is a covalent bond, alkylene, alkenylene, -N(R 21 )-R 10 or orRI~aN(R 2 )Rio, wherein Rio and RIO,, are independently selected alkylene or alkenylene and R 21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, or arylalkyl; R 26 -S(O)-R 27 wherein R 2 6 is loweralkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, or alkoxy-substituted haloalkyl, and R 27 is alkylene or alkenylene, R 22 -O-C(O)-R 23 wherein R 22 is heterocyclic and R 2 3 is a covalent bond, alkylene, alkenylene, or N(R 24 )-R 25 wherein R 25 is alkylene and R 24 is hydrogen or loweralkyl, or R 13 -C(O)-CH(R 1 4 wherein R 13 is amino, alkylamino, or dialkylamino and R 14 is aryl or R] 5 wherein R 15 is amino, alkylamino, or dialkylamino, or a [R:\LIBXX]425370d1 Idoc:aak 633 pharmaceutically acceptable salt thereof, for the preparation of a medicament for treatment of bone pain associated with bone cancer.

2. The use of the compound of claim 1 wherein the compound has formula R2 zN R3 (CH 2 )n

3. The use of claim 1 or 2 wherein R is -C(O) 2 -G and G is hydrogen.

4. The use of claim 1 or 2 wherein R, is 2,2-dimethylpentyl, 4-methoxyphenyl, or 3-fluoro-4-methoxyphenyl. The use of claim 1 or 2 wherein R 2 is I ,3-benzodioxolyl or 7-methoxy- 1,3- benzodioxolyl.

6. The use of claim I or 2 wherein R 3 is R 4 -C(O)-R 5 or R 6 -S0 2 -R 7 R 4 is (Rjj)(R 12 R 5 is methylene, R 7 is -N(R21)-R1O-, Rio is ethylene, and R 11 and R 12 and R(21 are propyl. The use of claim I or 2 wherein the compound is trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- 1- 15 (propylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- 1- (aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1-(4- fluorobenzyl)-pyrrolidine-3-carboxylic acid; trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1-(2- ethoxyethyl)-pyrrolidine-3-carboxylic acid; trans,trans-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yI)- 1 propoxyethyl)pyrrolidine-3 -carboxylic acid; trans,trans-2-(4-methoxyphenyl)-4-(1I,3-benzodioxol-5-yl)- methoxyethoxy)ethyl)pyrrolidine-3 -carboxylic acid; trans,trans-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)- 1 pyridyl)ethyl)-pyrrolidine-3 -carboxylic acid; [R:\LflBXX]425370d1 .doc:aak trans,trans-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)- 1-(morpholin- 4-ylcarbonyl)pyrrolidine-3-carboxylic acid; trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1- (butylaminocarbonyl)pyrrolidine-3-carboxylic acid; (10) trans,trans-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)- 1-(4- methoxyphenylaminocarbonyl)-3 -pyrrolidine-3 -carboxylic acid; (11) trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yI)- 1- acetylpyrrolidine-3-carboxylic acid; (12) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1 -(2-furoyl)- pyrrolidine-3-carboxylic acid; (13) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- I1- (phenylaminocarbonyl)pyrrolidine- 3 -carboxylic acid; (14) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- 1- (allylaminocarbonylmethyl)pyrrolidile-3-carboxylic acid; i (15) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-(n- butylaminocarbonylmethyl)pyrTolidifle- 3 -carboxylic acid; (16) trans,trans-2-(4-methoxypheflyl)- 4 1,3 -benzodioxol-5-yl)- :Th propyl)-N-methylaminocarbolmethy1)pyrrolidine 3 carboxylic acid; (17) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- 1 -(pyrrolidin- 1-ylcarbonylmethy1)pyrrolidile-3-caboxylic acid; (18) trans,trans-2-(4-methoxypheflyl)- 4 1,3 -benzodioxol-5-yl)- I1- (isobutylaminocarboflylmethyl)pyrTolidifle- 3 -carboxylic acid; (19) trans,trans-2-(4-methoxyphelyl)- 4 1,3 -benzodioxol-5-yI)- 1- (cyclopentylaminocarbonylmethyl)pyrTolidile- 3 -carboxylic acid; (20) trans,trans-2-(4-methoxyphelyl)4-( 1,3 -benzodioxol-5-yi)- 1-(morphol in- 4-ylcarbonylmethy1)pyrrolidifle-3-carboxylic acid; (2 1) trans,trans-2-(4-methoxypheflyl) 4 {l ,3-benzodioxol-5-yI)- 1 phenoxyethy)-pyrrolidine-3-carboxylic acid; (22) trans,trans-2-(4-methoxypheflyl)- 4 ,3-benzodioxol-5-yl)-1-( 2 methoxyethylaminocarbolylmethyl)pyrTolidifle- 3 -carboxylic acid; (23) trans,trans-2-(4-methoxypheflyl) 4 -(1,3-benzodioxol-5-yl)- 1-(2- butoxyethyl)-pyrrolidifle- 3 -carboxylic acid; [R:\LIBX )425 370d1 .doc:aak (24) tras,trans-2-( 1,3 -benzodioxol-5-yl)-4-(4-methoxyphenyl)- 1- (propylainiinocarbonylmethyl)pyrrolidie-3-carboxylic acid; trans,trans-2-( 1,3 -benzodioxol-5-yl)-4-(4-methoxyphenyl)- 1-(2- propoxyethyl)-pyrrolidine-3-carboxylic acid; (26) trans,trans- 2 1,3-benzodioxol-5-yl)-4-(4-methoxyphelyl)- 1 methoxyethoxy)ethyl))pyrolidile-3-carboxylic acid; (27) trans,trans-2-( 1,3 -benzodioxol-5-yl)-4-(4-methoxyphelyl)- 1- (butoxyethyl)- pyrrolidine-3-carboxylic acid; (2 8) trans,trans-2-(4-methoxypheflyl)- 4 1,4-benzodioxan-6-yl)- 1 (propylaminocarbonylmethyl)pyrTolidie3-carboxylic acid; see**:(29) trans,trans-2-(4-methoxypheflyl)A4(1I,4-benzodioxan-6-yl)- 1 -(N-methyl- N-propylaminocarbonylmethyl)pyrTolidifle- 3 -carboxylic acid; trans,trans-2-(4-methoxypheflyl)A4( 1,3 -benzodioxol-5-yl)- 1-(N-methyl- N-butylaminocarbonylmethy)pyrrolidile- 3 -carboxylic acid; 15 (3 1) trn~rn--4mtoy2mehx ehxpey)4(,3- I -(-ehlNbtlmncroymehlproiie3croyi acid; (32) trans,trans-2-(4-methoxyphelyl)- 4 -(1I,3-benzodioxol-5 -yl)-l ethoxypropyl)-pyrrolidif-5ofe3-carboxylic acid; 20 (33) trans,trans-2-(4-methoxyphelyl)A4( 1,3 -benzodioxol-5-yl)- 1-(3- methoxybenzyl)- pyrrolidin-5-one-3-carboxylic acid; (34) trans,trans-2-(4-methoxyphefl)ll( 1,3 -benzodioxol-5-yl)- 1-(N,N- di isoamylaminocarbonylmethyl)pyrrolidine- 3 -carboxyl ic acid; trans,trans-2-(4-methoxypheflyl)A4( 1,3 -benzodioxol-5-yI)- 1-(N,N- dipentylaminocarboflmethyl)pyrrolidine 3 carboxylic acid; (36) trans,trans-2-(4-methoxypheflyl) 4 -(1,3-benzodioxol-5-yl)- 1-(N,N-di(2- methoxyethyl)aminocarboflylmethyl)pyrrolidine- 3 -carboxylic acid; (37) trans,trans-2-(4-methoxypheflyl) 4 -benzodioxol-5 -yl)-l hexynyl)-pyrrolidine- 3 -carboxylic acid; (38) trans,trans-2-(4-methoxyphefl)A4(l,3-benzodioxol-5-yl)-l-(N- cyclopropylmethyl-N-propylaminocarbonylmethyl)pyrrolidine3carboxylic acid; [R:\[,IBXX]425370d I .doc:aak (39) trans,trans-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)- I-(N-methyl- N-pentylaminocarbonymethy)pyrTolidile-3-caboxylic acid; trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yI)- 1-(N,N- diisobutylaminocarbolylmethyl)pyrrolidifle- 3 -carboxylic acid; (4 1) trans,trans-2-(4-methoxypheflyl)- 4 1,3 -benzodioxol-5-yl)- 1 -(N-methyl- N-(2-propynyl) aminocarbonylmethyl)pyrrolidile-3-carboxylic acid; (42) trans,trans-2-(4-methoxyphelyl)- 4 1,3 -benzodioxol-5-yl)- 1-(N-methyl- N-(n-hexy1)aminocarboflmethyl)pyrTolidifle- 3 -carboxylic acid; (43) trans,trans-2-(4-methoxyphelyl)- 4 -(1I,3-benzodioxol-5-yl)- I -(N,N-di(n- butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; (44) trans,trans-2-(4-methoxypheflyl)- 4 1,3-benzodioxol-5-yl)- 1-(N,N- diethylaminocarbolylmethyl)pyrrolidine- 3 -carboxylic acid; (45) trans,trans-2-(4-methoxypheflyl)- 4 1,3 -benzodioxol-5-yl)- 1 -(N-methyl- N-phenylaminocarboflmethy1)pyrrolidine3carboxylic acid; 15 (46) trans,trans-2-(4-methoxypheflyl)- 4 1,3 -benzodioxol-5-yl)- 1 -(N-methyl- N-cyclohexylamiflocarboflYmethyl)pyroidine3carboxylic acid; trans,trans-2-(4-methoxypheflyl)- 4 -benzodioxol-5-yl)- 1-(N ,N-di(n- propyl)aminocarbolmfethyl)pyrrolidine- 3 -carboxylic acid; (48) trans,trans-2-(4-methoxyphenyl)- 4 ,3 -benzodioxol-5-yI)- 1 -(N-methyl- 2o N-isobutylaminocarboflmethy)pyrroidine3carboxylic acid; (50) trans,trans2-(4-methoxyphefl- 4 ,3 -benzodioxol-5-yl)- 1 butyloxycarbonylmethyl)pyrrolidife3carboxylic acid; 1) trans,trans-2-(4-methoxypheflyl)- 4 -naphthyl)- I -(N-methyl-N- propyl)aminocarbonylmethyl)pyrrolidine3carboxylic acid; (52) trans,trans-2-(4-methoxyphefl- 4 2 3 -dihydrobenzofurafl-S-yl)-l methy1-N-propy1)amiflocarboflYmethy)pyroidine3carboxylic acid; (53) trans,trans-2,4-bis(4-methoxyphenyl)l -(N-methyl-N- propyl)aminocarbonylmethyl)pyrrolidine-3carboxylic acid; (54) trans,trans-2-(4-methoxyphelyl) 4 3 ,4-dimethoxyphelyl)-1I-(N-methyl- N-propy1)aminocarboflylmethy)pyrroidine3carboxylic acid; trn~rn--4mehxpey)4(3mtoyhn (N-methyl-N- propyl)aminocarbonylmethyl)pyrrolidine3carboxyl ic acid; [R:\LIBXX]42537Od I.doc:aak (56) tras,trans-2-(4-methoxyphelyl)4(2-naphthyl)l -(N-methyl-N- propyl)aminocarboflmethyl)pyrroidine3carboxylic acid; (57) trans,trans-2-(4-methoxyphenyl)- 4 -(l,3-benzodioxol-5-yI> 1 (ethyl sulfinyl) ethyl)pyrrolidine-3-carboxylic acid; (58) trans,trafls-2-(4-methoxyphenyl)- 4 (l,3 -benzodioxol-5-yl)-l (isopropylsulfonylamilo)ethyl)pyrrolidine- 3 -carboxylic acid; (59) trans,trans-2-(4-methoxyphenyl)- 4 -benzodioxol-5-yI)-i (isobutoxy)ethyl)pyrrolidifle- 3 -carboxylic acid; trans,trans-2-(4-methoxyphenyl)- 4 (l,3-benzodioxol-5-yI)- 1- (butylsulfonyl)-pyrrolidine3carboxylic acid; (61) trans,trans-2-(4-methoxyphenyl)-4(1, 3 -benzodioxol-5-yi) I methl-Nisoroplcabonlamio~ehylpyroli 1,e3-croy acid; (62) trans,trans-2-(4-methoxyphenyl) 4 -(1,-benzodioxol-5-yl)- methyl-N-propioflaminno)efiy1)pyrroidine- 3 -carboxylic acid; i (63) trans,trans-2-(4-methoxyphenyl)- 4 ,3 N-bezylaminocarboflylmethyl)pyrrolidine3carboxylic acid; (64) trans,trans-2-(4-methoxyphenyl) 4 -benzodioxol-5-yI)- 1-(N-ethyl-N- butylaminocarboflylmethyl)pyrrolidine- 3 -carboxylic acid; (65) trans,trans2(4methoxyphenyl)- 4 (l,3 -benzodioxol-5-yl)- I -(N-methyl N-( 2 2 -dimethylpropyl)aminocarbonylmethyl)p /olidine 3 caoyl cd mehlNbtlufnlmn*thlproiie3croyi aci0d aid (66) trans,trans-2-(4-methoxyphenyl) 4 3 -benzodioxol-5-yi) 1 methyl-N-pbutylsulfonyamin)ethyl)pyrrolidine-3carboxylic acid; 25(67) trans,trans-2-(4-methoxyphenyl) 4 3 -benzodioxol-5-yI)- 1-(2-(N mpoysfnlethyl~N proPlSUf liinehlPI1o die3-carboxylic acid; 25(68) trans,trans-2-(4-methoxyphenyl) 4 3 -benzodioxol-S -yl)-l (peQpyhex-fonyl)hpyrrolidine3carboxylic acid; (69) trans,trans-2-(4-methoxyphenyl)A4(l ,3 -benzodioxol-5-yl)- 1 3 ,5-dimethylhex-2-eflY)pyrrolidine3carboxylic acid; (71) trans,trans-2-(4-methox)'phenyl) 4 -(l,3-benzodioxol- 5 -yl) 1-(4- heptylcarboflylmethylDpyrolidine3carboxylic acid; [R:\LII3XX]42537Od I.doc:aak (72) trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1- (valerylmethyl)-pyrrolidine-3-carboxylic acid; (73) trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yI)- ,4- dimethoxybenzy)-N-methyaminocarbonymethy)pyToidile-3-carboxyic acid; (74) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- ,4- dimethoxybenzyl)aminocarbonylmethyl)pyrrolidile-3-carboxylic acid; (2R,3R,4R)-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1- (N,N-dipropylaminocarbonyl)- 1 -butyl)pyrrolidine-3 -carboxylic acid; (76) (2S,3S,4S)-2-(4-methoxypheny)4-( 1,3-benzodioxol-5-yl)- 1 1 (N,N-dipropylaminocarbonyl)- 1 -butyl)pyrrolidine-3 -carboxylic acid; (77) (2S,3S,4S)-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)- 1- (N,N-dipropylaminocarbonyl)- 1-butyl)pyrrolidine-3 -carboxylic acid; (2R,3R,4R)-2-(4-methoxypheflyl)>4-(1,3-benzodioxol-5-yl)- 1 1 (N,N-dipropylaminocarboflyl)- 1-butyl)pyrrolidine-3 -carboxylic acid; (79) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-(N,N-di(n- butyl)aminocarbonylmethyl)- 3 trans,trans-2-(4-fluorophenyl)- 4 -(1I,3-benzodioxol-5-yI)- 1-(N,N-di(n- butyl)aminocarbonylmethyl)pyrrOlidifle- 3 carboxylic acid; (8 1) trans,trans-2-(4-methoxyphefyl) 4 -benzodioxol-5-yl)- 1-(N,N-di(n- 20 butyl)aminocarbonylmethyl)pyrrolidile- 3 -carboxylic acid; (82) trans,trans-2-(4-methoxypheflyl) 4 -(1,3-benzodioxol-5-yD- 1 butyI)-N-(n-propy1)aminocarboflmethyI)pyrrolidine 3 carboxylic acid; (83) trans,trans-2-(4-methoxypheflyl) 4 1,3 -benzodioxol-5-yl)- di(n-propy1)aminocarbony)ethyl)pyrrolidile- 3 -carboxylic acid; (84) trans,trans-2-(4-methoxypheflyl)- 4 -benzodioxol-5-yl)- 1-(N,N-di(n- butyl)aminocarbonyl)pyrrolidile-3-carboxylic acid; trans,trans-2-(4-methoxypheflyl)A4( 1,3 -benzodioxol-5-yl)- 1-(N,N-di(n- butyl)aminocarbonylmethyl)pyrTolidile- 3 -carboxylic acid; (86) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1 di(n-butyI)amino)ethy)pyrroidile-3-carboxylic acid; (87) trans,trans-2-(4-methoxyphenyl)- 4 -benzodioxol-5-yl)- (NNd -uy~mncronl--ehlmn~ty~proiie3croyi acid; (R:\LIBXX]42 5370d1 Idoc:aak (88) trans,trans-2-(4-methoxypheflyl)- 4 -benzodioxol-5-yl)- I-(N ,N-di(n- butyl)aminocarboflyl)methyl)pyrrolidine- 3 -(N-methanesulfofl)carboxamide; (89) trans,trans-2-(4-methoxypheflyl) 4 0 ,3-benzodioxol-5-yl)- 1-(N,N-di(n- butyl)aminocarboflyl)methyl)pyrrolidne3(N-benzenesul fonyl)carboxamide; (90) trans,trans-2-(4-methoxyphefl)> 4 -benzodioxol-5-yl)- 1-(N,N-di(n- butyl)-aminosulfonylmethy1)pyrrolidine3carboxylic acid; (91) trans,trans-2-(4-methoxypheflY 4 -benzodioxol-5-yl)- dibutylamino)carboll 1-(RS)-ethyl)pyrrolidifle- 3 -carboxylic acid; (92) trans,trans-2-(pentyl)A4( 1,3 -benzodioxol-5-yI)-1I-(N,N-di(n- butyl)aminocarboflylmethyl)pyrrolidine- 3 -carboxylic acid; (93) trans,trans-2-(pentyl) 4 -benzodioxol-5-yD)- I-(2-(N-propyl-N- propyisulfonylamino)etfli)pyrrolidune-3uuuaroyic acid; (94) trans,trans-2-(propyl) 4 -benzodioxol-5-yl)- 1-(N ,N-di(n- *.butyl)aminocarboflYlmethyl)pyiTolidine3-caboxylicacd Go: 15 (95) (2R,3R,4S)-(+)-2-(4-methoxypheflY) 4 O ,3-benzodioxol-5-yl)- I-(N,N- di(n-butylaminocarboflmethy1)pyrrolidine- 3 -carboxylic acid; (96) trans,trans-2-(4-methoxyphenyl) 4 O ,3-benzodioxol-5-yi)- 4~**propyI-N-butyrylamiflo)ethy)pyrroidine3carboxylic acid; Go. (97) trans,trans-2-(4-methoxyphenyl) 4 -benzodioxol-5-yl)- 20 propyl-N-(ethylaminocarbofl)amino)ethyl)pyrroidine3carboxylicacd (98) trans,trans2(4-methoxyphenyl) 4 (l,3-benzodioxol-5-yl> I 5:buty1-N-butyrylamino)ethyl)pyrrolidine- 3 -carboxylic acid; (99) trans,trans-2-(4-methoxyphenyl> 4 -benzodioxol-5-yl)- prplNehxcroyaioehlproiie3croyi acid; (100) trans,trans-2-(4-methoxyphenyl) 4 -benzodioxol- 5 methyl-N -(2-ethylbutyry1)amiflo)ethy)pyrroidine3carboxyl ic acid; 1) trans,trans-2-(4-methoxyphenyl) 4 -(l,3-benzodioxol- 5 I methyl-N-(2-propylvalery)amino)ethyl)pyrroidine3carboxylic acid; (102) trans,trans-2-(4-methoxyphenyl> 4 O ,3-benzodioxol- 5 1 propyl-N-(tert-butyoxycarboflmethyl)amino)ethyl)pyrroidine- 3 -carboxyl ic acid; (03 trans,trans-2-(4-methoxy'phenyl> 4 -benzodioxol- 5 I prplN(-rplmnoabnlehlaio ty~yrldn--carboxyl ic acid; [R:\LIBXX]42537OdI .doc:aak (104) trans,trans-2-(4-methoxypheflyl)- 4 1,3 -benzodioxol-5-yl)- propyI-N-(4-methoxyphenoxycarbony)amio)ethyl)pyrrolidie- 3 -caboxylic acid; (105) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- 1 propy1-N-(4-methoxybenzoyl)amilo)ethyl)pyrrolidifle- 3 -carboxylic acid; 106) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1 propyl-N-benzoylamino)ethy)pyrrolidifle 3 -carboxylic acid; (107) trans,trans-2-(4-methoxyphelyl)- 4 1,3-benzodioxol-5-yl)- 1 propy1-N-benzyloxycarbonylamino)ethyl)pyrrolidifle- 3 -carboxylic acid; (108) trans,trans-2-(4-methoxypheflyl)- 4 -(1I,3-benzodioxol-5-yl)- I i 0 propy1.N-(4-methoxybenzyloxycarbofl)amino)ethyl)pyrrolidine 3 carboxyI ic acid; (109) trans,trans-2-(4-methoxyphelyl)- 4 1,3 -benzodioxol-5-yI)- 1 butyl-N-ethoxycarbonylamilo)ethyl)pyrrolidifle- 3 -carboxylic acid; (1 10) trans,trans-2-(4-methoxypheflyl)- 4 -benzodioxol-5-yl)- 1 0* buty1-N-propoxycarbonylamiflo)ethy)pyrrolidine 3 carboxylic acid, 15 (111) trans,trans-2-(4-methoxypheflyl) 4 -benzodioxol-5-yl)- propy1-N-propoxycarbolamilo)ethy1)pyrrolidine- 3 -carboxylic acid; (112) trans,trans- 1 (N,N-di(n-buty1)amirnocarboflYmethyl)- 2 4 -di( 1,3- *Soo idine-3 -carboxylic acid; 0(13)) trans,trans- I 2-N(nbuy 20S methoxyphenyl)- 4 1,3 -benzodioxo1-5-y1)pyrTolidifle- 3 -carboxyl ic acid; *0000 Veo (114) trans,trans-l1 (N,N-di(n-butyl)aminocarbonflmethyl)- 2 4 methoxyphenyl)- 4 1,3 -benzodioxo1-5-y1)pyrrolidie3-carboxylic acid; (115) trans,trans-l 1 -roy--roysloylmn~thl--4 methoxyphenyl)- 4 -(1I,3-benzodioxo-5-y1)pyrTolidie3-carboxylic acid; (116) trans,trans-l 1 -utlNbtysloylmn~thl--4 methoxyphenyl)- 4 1,3 -benzodioxo1-5-y1)pyrrolidifle- 3 -carboxylic acid; (11 7) trans,trans- 1 (2-(N,N-di(n-buty)aminocarboflmethylY 2 4 methoxymethoxypheflyl)- 4 1,3-benzodioxol-5-y1)pyrTolidile-3-carboxylic acid; (11 8) trans,trans-lI (2-(N,N-di(n-buty1)amiflocarboflmethyl)Y 2 4 hydroxyphenyl)- 4 1,3-benzodioxo1-5-y1)pyrrolidifle- 3 -carboxylic acid; ER:\LIBXX]4253 70dI ldoc:aak (119) trans,trans- I (-souy--royslonlmn~thl--4 methoxyphenyl)- 4 1,3 -benzodioxo-5-y1)pyrrolidifle-3-carboxylic acid; (120) trans,trans-l1 (2-(N-benzenesulfony-N-propylamflifo)ethyl> 2 4 methoxyphenyl)-4-( 1,3 -benzodioxo-5-y)pyTolidifle-3-carboxylic acid; 12 1) trans,trans- I -(2-(N-(4-methoxybenzenesulfol)-N- propylamino)ethyl)-2-(4-methoxypheyl) 4 -benzodioxol-5-yl)pyrTolidifle- 3 carboxylic acid; (122) trans,trans-1I (N,N-di(n-butyl)aminocarbolmethyl)- 2 2 methoxyethoxy-4-methoxyphelyl)- 4 1,3 -benzodioxol-5-y1)pyrrolidifle- 3 -carboxylic acid; (12 23) trans,trans- 1 -(2-(N-propyl-N-(2, 4 dimethylbenzenesulfoflY)amiflo)ethyl) 2 4 -methoxyphenyl)-4(1 ,3 yl)pyrrolidine-3-carboxylic acid; (124) trans,trans-lI-(2-(N-propyl-N-(3 -chloropropylsulfony1)amliflo)ethyl)- 2 15 (4-methoxyphenyl)- 4 1,3-benzodioxo-5-y1)pyrrolidifle-3-carboxylic acid; (1 25) trans,trans- I 2(-rpl--2mtoythlufnlamn~ty)2 (4-methoxyphenyl)- 4 1,3-benzodioxo-5-y)pyrrolidifle- 3 -carboxylic acid; (126) trans,trans-l 1 -rpl--2ehxehysloy~mnoehl--4 methoxyphenyl)- 4 1,3 -benzodioxo-5-y1)pyrrolidifle-3-carboxylic acid; (127) trn~rn-I-2( poylN(-iehlaio naphthylsulfony)amino)ethy)2(4methoxyphenyl) 4 yl)pyrrolidine-3-carboxylic acid; (128) trans,trans- 1 -(-Npoy--ehlufnlaioehl--4 methoxyphenyl)- 4 1,3 -benzodioxol-5-y1)pyrrolidifle-3-caboxylic acid; 129) trans,trans- 1 -(2-(N-propy1-N-(4-methylbelzelesul fonyl)amino)ethyl)- 2-(4-methoxyphenyl)-4-( 1,3 -benzodioxo1-5-y1)pyrrolidile- 3 -carboxylic acid; (130) trans,trans- 1 -(N,N-di(n-buty1)aminocarbonylmethyl)- 2 3 -pyridyI)- 4 (1,3 -benzodioxo1-5-y)pyrrolidie-3-carboxylic acid; (13 1) trans,trans- 1 -(-Npoy--nbtlufnlaioehl--4 methoxyphenyl)- 4 1,3-benzodioxo1-5-yI)pyrTolidie3-caboxylic acid; (132) trans,trans- 1 (-Npoy--4clrbnznsloy~mn~ty)2 (4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-y1)pyrTolidiflC-3-carboxylic acid; [R:\LIBXX]425370d I .doc:aak (133) trans,trans-l 1 -roy--bnzlufny~mn~thl--4 methoxyphenyl)- 4 1,3 .benzodioxo1-5-y1)pyrrolidifle-3-carboxylic acid; (134) trans,trans-lI (2-(N-propy-N-(4-fluorobelzelesul fonyl)amino)ethyl)- 2 (4-methoxyphenyl)- 4 1,3-benzodioxol-5-y1)pyrrolidie 3 -carboxylic acid; 13 5) trans,trans- 1 -(N-methy1-N-propylamiflocarboflylmethyl) 2 4 methoxypheny)-4-(4-benflZfranl)pyrroidine3carboxylic acid; (136) trans,trans-l I ty-Npoyaincroymehl--4 methoxypheny)-4-(6-belzoftlranyl)pyrroidine3carboxylic acid; (137) trans,trans- 1 -(N-methy1-N-propylamiflocarboflylmethyl) 2 -(4 mehxpey)4(-ez-,-iyrfrnlproiie3croyi acid; (13 8) trans,trans- 1 -(N,N-di(n-buty1)anminocarboflylmethyl) 2 4 (139) trans,trans- 1 -(N,N-di(n-buty1)anfinocarbonylmethyl)- 2 4 3 -carboxylic acid; i (140) trans,trans-1I (N,N-di(n-buty)aminocarboflYmethyl) 2 4 mehxpey)4(-ezouay yrldn--carboxylic acid; 14 1) trans,trans- 1 -(NN-di(n-buty)aminocarboflylmethyl) 2 4 mehxpey)4(-ez-,-iyrfrnlproiie3croyi acid; trans,trans- 1 (-ehlNpoplmncroylehl-- methoxyphenyl)-4-(5-ifdal)pyrroidine3carboxylicacd trans,trans- I (N-methy1-N-propylamiflocarboflYmethyl) 2 4 methoxypheny1)-4-(6-ifdldY)pyrroidine3carboxylic acid; (144) trans,trans- 1 -(N-methy1-N-propylamiflocarboflylmethyl) 2 4 methoxyphenyl)- 4 3 ,4-difluoropheny1)pyrrolidie3-carboxylic acid; 145) trans,trans- I -(N-methy1-N-propylamiflocarbonlYmethyl) 2 4 mehxpey)4(hnlproiie3croyi acid; (146) trans,trans- 1 -(N-methy1-N-propylamiflocarbonylYmethyl) 2 4 methoxypheny)-4-(4-hydroxyphenyI)pyrroidine 3 carboxylic acid; (147) trans,trans-lI (N-methyl-N-propylamiflocarboflYmethyl) 2 4 methoxypheny1)-4-(2,4-dimethoxyphenyl)pyrroidine3carboxylic acid; (148) trans,trans-l1 (N,N-di(n-butyl)amiflocarboflylmethylY 2 4 methoxyphenyl)- 4 -benzo-2,3-dihydrofurafl)pyrrolidine- 3 -carboxylic acid; [R:\LIBXX]425370d I .doc:aak (149) trans,trans- 1 (N,N-di(n-buty)amTinocarbonlmethyl)- 2 4 methoxypheny)-4-(4-methoxyphefl)pyrrolidie3-caboxylic acid; 15 0) trans,trans- I -(N,N-di(n-buty1)aminocarboflmethyl)- 2 4 methoxypheny)-4-(3,4-difluorophely1)pyrrolidine3carlboxylic acid; 15 1) trans,trans- I (N,N-di(n-buty1)amiflocarbonylmethyl> 2 4 methoxypheny1)-4-(2,4-dimethoxypheny)pyroidine 3 carboxylic acid; (152) trans,trans-l1 (N,N-di(n-butyl)axninocarbonylmethy1)-2-pheflyl- 4 1,3 benzodioxo-5-y1)pyrrolidifle3-carboxylic acid; 3) trans,trans- 1 -(N,N-di(n-buty1)am-inocarboflmethy)- 2 -pheflyI-4-(S benzo-2,3-dihydrofiurafl)pyrrolidine3carboxylic acid; (154) trans,trans- 1 ,N-di(n-buty)amiflocarbofylYmethyl) 2 4 -t no23dhdouay~proiie3croy acid; 05)trans,trans-2-(N,N-dibutylamiflocarbonylmethy)2(4-methoxyphenyl)- 4-(4-tTluoropheny1)pyrTolidife-3-carboxylic acid; 15 (156) trans,trans- I -(N,N-dibutyaminocarbofylYmethy)2(3fiyl) 4 benzodioxol-5-y1)pyrrolidife3carboxylic acid; (157) trans,trans- I (N,N-dibutyaminocarbofylYmethy)2(isopropyl) 4 benzodioxo1-5-y1)pyrrolidife3carboxylic acid; 0(158) trans. trans- I (N,Ndibuty aminocarbofylYmethyl)2(4tbutylphenyI) 4 (1 ,3-benzodioxo1-5-y)pyrrolidine3carboxylic acid; (159) trans,trans- I (N,Ndi(nbuty)aminocarbofylYmethyl)- 2 4 t yl--5bez-,-dhdouanlproldn--croyi acid; (160) trans,trans- I -(N,N-dibutylaminocarboflYmethyl 2 anti- 4 methoxycyclohexyl) 4 -(1I,3-benzodioxo1-5-y)pyrrolidine3carboxylic acid; (161) trans,trans-lI (N,N-dibutylaninocarboflYmethyl) 2 (syn- 4 methoxycyclohexyl> 4 ,3-benzodioxo1-5-yI)pyrrolidine- 3 -carboxylic acid; (162) trans,trans- 1 N-dibutylaminocarbofylymethy)2,4di(5-benzo- 2 3 dihydroturaflyl)pyrrolidifle- 3 -carboxyl ic acid; (163) trans,trans-l1 (N,N-dibutylaminocarboflmethy) 2 3 benzo-2,3 -dihydrofuralyY1olidiflC3-carboxylic acid; (164) trans,trans-1I (N,N-dibutylamiflocarboflmethy1>-2(4-methoxyphenyl)- 4 -(3-fluoropheny1)pyrrolidifle-3carboxylic acid; [R:\LIBXX]425370d1 .doc :aak (165) trans,trans-l1-(N,N-di(n-butyl)aminocarbonylmethyl)-2-(4- methoxyphenyl)-4-(3 -pyridyl)pyrrolidine-3-carboxylic acid; (166) trans,trans-l1-(N,N-di(n-butyl)amninocarbonylmethyl)-2-(2- fluorophenyl)-4-( 1,3 -benzodioxol-5-yl)pyrrolidine-3-carboxylic acid; (1 66a) (trans. trans-i -(N,N-dibutylaminocarbonylmethyl)-2-(2-fluorophenyl)- 1, 3-benzodioxol-5-y1)pyrrolidine-3-carboxylic acid; (501 Ha) (2R,3 R,4S)-(+)-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yI)- 1- (N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; (167) trans,trans-lI-(N,N-di(n-butyl)aminocarbonylmethyl)-2-(3 fluorophenyl)-4-(1I,3-benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; (16 7a) trans,trans-l1-(N,N-dibutylaminocarbonylmethyl)-2-(3 -fluorophenyl)- 1, 3-benzodioxol-5-yl)pyrrolidine-3 -carboxylic acid; (168) trans,trans- 1-(4-N,N-di(n-butyl)aminophenyl)-2-(4-methoxyphenyl)-4- (1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid; (169) trans,trans- 1 -(2-N,N-dibutylaminopyrimidin-4-yl)-2-(4- methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid; :A (289) trans,trans- 2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yI)- 1-(4- dibutylaminophenyl)pyrrolidine-3-carboxylic acid; (290) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-(2- dibutylamino-pyrimidine-4-yl)pyrrolidine-3 -carboxylic acid; (291) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yI)- 1 -N-buty1- N-phenylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; (293) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1- (decahydroisoquinolin-2-carbonylmethyl)pyrrolidile-3-carboxylic acid; (294) trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1-(3,3- dimethylpiperidinylcarbonylmethyl)pyrrolidine-3-carboxylic acid; (295) trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yI)- propyl-N-iso-butoxycarbonylamino)ethyl)pyrrolidine-3-carboxylic acid; (296) trans,trans-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)- 1-(1,2,3,4- tetrahydroisoquinol in-2-carbonylmethyl)pyrrolidine-3-carboxylic acid; (297) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-y1)- propyl-N-dimethylaminocarbonylamino)ethyl)pyrrolidine-3-carboxylic acid; [R:\LIBXX]425370d L doc:aak (298) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- propyl-N-(4-nitrobenzenesufonyl)wmilo)ethyl)pyrrolidifle- 3 -carboxylic acid; (299) trans,trans-2-(4-methoxyphelyl)- 4 1,3 -benzodioxol-5-yl)- propyl-N-n-pentanesulfonylamiflo)ethyl)pyrTolidife3carboxylic acid; (300) trans,trans-2-(4-methoxyphel- 4 1,3 -benzodioxol-5-yI)- propy1-N-(4-trifluoromethoxybelzelfofl)amiflo)ethyl)pyrroidine3carboxylic acid; (301) trans,trans-2-(4-methoxypheflyl) 4 -benzodioxol-5-yl)- prplN(-ehl2poeeufnlaioehlproiie3croyi acid; (302) trans,trans-2-(4-methoxypheflyl)A4( 1,3 -benzodioxol-5-yl)- 1-(2- ethylpiperidinylcarbofylmethyl)pyrolidine- 3 carboxylc acid; (303) trans,trans-2-(4-methoxyphely) 4 -benzodioxol-5-yl)- 0acid; *SSpropyl-N-(2-methylpropalesulfofylY)amino)ethyl)pyroidine3carboxylicacd (304) trans,trans-2-(4-methoxyphelyl) 4 -benzodioxol-5-yl)- propy1-N-heptanesulfoflYamino)ethyl)pyrroidne3carboxylic acid; (305) trans,trans-2-(4-methoxypheflY 4 (l,3-benzodioxol-5-yl)- 1 ethyl-N-ethoxycarboflYamino)ethyl)pyrroidine3carboxylic acid; (306) trans,trans-2-(4-methoxypheflyl) 4 G ,3 -benzodioxol-5-yl)- propy1-N-hexanesulfoflamino)ethyl)pyrroidine3carboxyI ic acid; 20 (307) trans,trans-l1 (N,N-dibutylaminocarboflmethlY)L2-4-ethylpIeny)4 (1 ,3-benzodioxo1-5-yI)pyTrolidie3-carboxylic acid; (308) trans,trans-2-(4-methoxyphelyl) 4 (l,3 -benzodioxol-5-yl)-1I-(2-(N- prplN(-hootoycroyaioehlproiie3croyi acid; (309) trans,trans-2-(2-methoxyethyl 4 (l,3 -benzodioxol-5-yl)- I-(N ,N-di(n- buty1)aminocarbonylmethy1)pyrroidine3carboxylic acid; (3 10) trans,trans-2-(4-methoxyphenyl) 4 {l ,3-benzodioxol-5-yl)- ethy1-N-n-pentanesulfoflYamino)ehyl)pyrroidine- 3 -carboxylic acid; (3 11) trans,trans-2-(4-methoxyphenyl) 4 -(l,3-benzodioxol-5-Yl)- 1-(N,N- dicyclohexylamilo carbonylmethyl)pyITolidifle- 3 -carboxylic acid; (3 12) trans,trans-2-(4-methoxyphenyl) 4 (',3-benzodioxol-5-yi) 1 propyl-N-tert-butoxycarbonlamino)ethyO~pyrrolidine- 3 -carboxylic acid; IR:\LIBXX]42537Od I doc:aak (3 13) trans,trans-lI (N,N-dibutylaminocarbonylmethyO)- 2 3 -fluoro-4- methoxyphenyl)-4-( 1,3 -benzodioxo1-5-yI)pyrrolidile-3-carboxylic acid; (3 14) trans,trans-2-(propyl)- 4 -(1I,3-benzodioxol-5-yi)- 1-(2-(N-propyl- pentanesulfonylamino)ethyl)pyrrolidile- 3 -carboxylic acid; (315) trans,trans-2-(4-methoxypheflyl) 4 -benzodioxol-5-yl)- propy1-N-dimethylsulfamoylamiflo)ethyl)pyrrolidine- 3 -carboxylic acid; (3 16) trans,trans-2-(4-methoxypheflyl) 4 -benzodioxol-5-yl)-1I-(2-(N- propy1-N-(4-methoxyphel)sulfoflYamino)propy)pyrrolidine- 3 -carboxylic acid; (31 7) trans,trans-2-(4-methoxypheflyl) 4 -(1,3-benzodioxol-5-yl)- 1 prplNpoysufnlmn rpy~yrldn--carboxylic acid; (318) trans,trans- I -poy--(-etysloylannoehl-2-3 2" ~fluoro-4-methoxypheflyl)- 4 -(1I,3-benzodioxol-5-yl)pyrrolidie3-carboxylic acid; (319) trans,trans-2-(4-Pyridilyl)- 4 1,3-benzodioxol-5-yl)- 1-(N,N-di(n- butyl)aminocarboflmethyl)pyI1roidine3carboxylic acid; (320) trans,trans-2-(4-methoxypheflyl)- 4 ,3-benzodioxol-5-yl) 1 propyI-N-diethylamiflocarboflamino)ethyl)pyrroidine3carboxylic acid; (32 1) trans,trans-2-(4-methoxyphefl)lM}' ,3-benzodioxol-5-yI)- 1 dimethylpiperidilcarboflmethyl)pyrroidine- 3 -carboxylic acid; C (322) trans,trans-2-(4-methoxyphefl) 4 (l,3 -benzodioxol-5-yl)- 1-(N ,N-di(s- butyl)aminocarboflylmethyl)pyrrolidine- 3 -carboxylic acid; (323)) trans,trans-2-(4-methoxyphenyl)A4(l ,3 -benzodioxol-5-yI)-1I-(N-(2- methylphenyl)-N-butYlamino carbonylmethyl)pyrrolidie3-carboxylic acid; (324) trans,trans-2-(4-methoxypheflyl) 4 O ,3 -benzodioxol-5-yl)- 1 methylphenyl)-N-butylamilo carbonylmethyl)pyrrolidife3carboxylic acid; (325) trans,trans- 4 1,3bnoioo--i-2(ezlxyehl-((N,N- dibutylaminocarbonylmethyl)pyrrolidine- 3 -carboxylic acid; (326) trans,trans- 4 1,3-bnoixo--l-2(yrxyehl ,N-di(n- butyl)aminocarboflylmethyl)pyrrolidine- 3 -carboxylic acid; (327) trans,trans- 4 -(1,-ezIixl5y Nmehlrpeai- -y)l ((,-inbtlaioabnlehlproiie3croyi acid; (328) trans,trans- 4 1,3-benzodioxol-5-y) 2 I-hydroxy-2-propel- 3 1- (N,N-di(n-butyl)aminocarboylmethy)pyrr1olidine- 3 -carboxylic acid; [R:\LIBXX]42537OdI .doc:aak (329) trans,trans-4-( 1,3-benzodioxo1-5-yl)-2-(N-benzylamilomethyl)- I-(N,N- di(n-butyl)aminocarbonylmethyl)pyrrolidifle- 3 -carboxylic acid; (330) trans,trans-4-( 1,3-benzodioxol-5-yl)-2-(N-acetyl-N- benzylaminomethyl)- 1 ,N-di(n-butyl)aminocarboflmethyl)pyrrolidife3carboxylic acid; (3 3 1) trans,trans-4-(1I,3-benzodioxol-5-yl)-2-(ethynyl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)pyrrolidine3-carboxylic acid; (332) trans,trans- 4 1,3 -benzodioxol-5-yl)-2-( I-pentynyl)- I-(N,N-di(n- butyl)aminocarbonylmethyl)pylTolidifle- 3 -carboxylic acid; (333)) trans,trans-2-(4-methoxphenyl)- 4 1,3 -benzodioxol-5-yl)- dioxopiperidinyl) ethyl)pyrrolidine-3 -carboxylic acid; (334) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yI)- 1-(N,N- diphenylaminocarbonylmethyl)pyrrolidine 3 carboxylic acid; (335) trans,trans-2-(4-methoxyphenyl)- 4 ,3-benzodioxol-5-yl)- 1-(N,N- *C 15 diisopropylaminocarboflylmethyl)pyrolidine- 3 carboxyic acid; or (336) trans,trans-2-(3-fluoro-4-methoxyphenyl)H4-( 1,3 -benzodioxol-5-yl)- 1- 2 -N-propyl-N-butanesulfonylamino)ethyl)pyrrolidine3carboxylic acid; or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treatment of bone pain associated with bone cancer. 20

8. Use of (2,R4)2(-ehxpey)4(,-ezdoo--l--NN di(n-butyl)aminocarbonylmethy)pyI1~olidine- 3 -carboxylic acid, or a pharmaceutically *.:acceptable salt thereof, for the preparation of a medicament for treatment of bone pain associated with bone cancer.

9. Use of (2R,3R,4S)-2-(4-methoxyphenyl)- 4 -(1I,3-benzodioxol-5-yl)- 1-(N,N- di(n-butyl)aminocarbonylmethy1)pyrrolidine- 3 -carboxylic acid hydrochloride for the preparation of a medicament for treatment of bone pain associated with bone cancer. A compound having formula: (CH 2 )n wherein R:LIBXX )42 5370d1 .doc:aak 648 Z is -C(R 18 wherein R 18 and Rig are hydrogen; n is 0; R is -(CH 2 wherein m is 0, W is -C(O) 2 and G is hydrogen; R, is alkyl, alkenyl, or phenyl substituted with one or two independently selected halo or alkoxy substituents; R 2 is 0 ,wherein X* is and Y* is -GH 2 and is substituted with one or two independently selected alkoxy and halo substituents; R 3 is R4-C(O)-R 5 wherein R 5 is alkylene; and R 4 is (R 1 1 )(R 12 wherein RI, is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or trialkylaminoalkyl and R1 2 is alkyl, haloalkyl, haloalkoxyalkyl, or alkoxy; or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 having formula R2 Z R (CH 2 )n 2 15 12. A compound of claim 10 which is 2 CC. (525) trans,trans-2-(4-methoxphenyl)-4-(l ,3 -benzodioxol-5-yl)- I-((N-butyl- N-ethylamino)carbonylmethyl)pyrolidine3carboxylic acid; (526) trans,trans-2-(4-methoxphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1 -((N-butyl- N-(3-aminopropylamino)carbonylmethyl)pyITolidine- 3 -carboxylic acid; (527) trans,trans-2-(4-methoxphenyl)- 4 -benzodioxol-5-yl)- I-((N-butyl- N-3dmtyaiorplaio abnlmty~yrldn--carboxylic acid; 28) trn~rn--4mehxhn 1,3 -benzodioxol-5-yl)- I -((N-butyl- N-(3 jmethylammoniopropyl)amino)carbonylmethyl)pyrrouidine- 3 -carboxyl ic acid; (529) trans,trans-2-(4-methoxphenyl> 4 -benzodioxol-5-yl)- 1-((N-butyl- N-4aiouy~mn~abnlehlproiie3croyi acid; or (530) trans,trans-2-(4-methoxyphenyl)A4( 1,3 -benzodioxol-5-yl)- 1 -((N-butyl- N-(4-dirnethylaminobutyl)amino)carbonylmethyl)pyrroidine-3 -carboxylic acid; [R:\LIBXX]42 5370d I.doc:aak or a pharmaceutically acceptable salt thereof.

13. The compound trans,trans-2-(4-methoxyphenyl)- 4 -(1,3-benzodioxol-5-yl)-1- ((N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl)pyrrolidine- 3 -carboxylic acid, or a pharmaceutically acceptable salt thereof.

14. Use of a compound of claim 10, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treatment of bone pain associated with bone cancer. Use of a compound of claim 11, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treatment of bone pain associated with bone cancer.

16. Use of a compound of claim 12, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treatment of bone pain associated with bone S° cancer.

17. Use of a compound of claim 13, or a pharmaceutically acceptable salt thereof, 15 for the preparation of a medicament for treatment of bone pain associated with bone cancer.

18. The compound trans, trans-2-(2,2-dimethylpentyl)- 4 -(1,3-benzodioxol-5-yl)- 1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof. o* 20 19. A method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound having formula: Z N R3 I (CH 2 )n R wherein Z is -C(R 1 8 )(R 1 9 wherein R 1 8 and Ri 9 are hydrogen; n is 0; R is -CH 2 wherein m is 0 and W is -C(0) 2 wherein G is hydrogen, -PO 3 H 2 [R:\LBXX]425370d1 .doc:aak wherein E is hydrogen, loweralkyl, or arylalkyl, tetrazolyl, -C(O)NHS(O) 2 RI 6 wherein R 16 is loweralkyl, haloalkyl, aryl, or dialkylamino, or -S(O) 2 NHC(O)R] 6 R, and R 2 are independently selected hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, amninocarbonylalkyl, alkylamninocarbonylalkyl, dialkylamninocarbonylalkyl, amninocarbonylalkenyl, alkylamninocarbonylalkenyl, dialkylamninocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-al kanoyl-N- :::alkyl)aminoalkyl, alkylsulonylamidoalkyl, heterocyclic, (heterocyclic)alkyl, or(R.)(Rbb)N-Rc-, wherein is aryl or arylalkyl, Rbb is hydrogen or alkanoyl, and R,, 15 is alkylene; R 3 is loweralkyl, alkenyl, akynyl, cycloalkyl, (e) cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclic,() (heterocyclic)alkyl, alkoxyalkyl, alkoxyalkoxyalkyl, (in) R 4 -G(O)-R 5 wherein R 4 is loweralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, :20 heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, ~:haloalkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkylaminoalkyl, dialkylamninoalkyl, 00 0 alkoxy, or (RI 1 )(R 12 wherein RI, and R 12 are independently selected loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclic, arylalkyl (heterocyclic)alkyl, hydroxyalky, or alkoxy, and R 5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 2 o-Rs-, wherein R 8 is alkylene or alkenylene, and R 20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl, or cycloalkylalkyl, MV -R 8 a-N(R 20 )R 8 wherein R 8 is alkylene or alkenylene, [R:\LIBXX]425370d1 .doc:aak or -O-R 9 or wherein R 9 afld Rga are independently selected alkylene; R 4 -R 5 wherein R 5 a is alkylene or alkenylene, R4-C(O-R 5 N(& 6 wherein R 6 is (RI 1 )(R 12 R 6 -S(O) 2 -R 7 wherein R 7 is a covalent bond, alkylene, alkenylene, -N(R 2 1 or -Ri~a-N(R 2 wherein RIO and Rjoa are independently selected alkylene or alkenylene and R 21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, or arylalkyl; R 26 -S(O)-R 27 wherein R 26 is loweralkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, or alkoxy-substituted haloalkyl, and R 27 is alkylene or alkenylene, R 22 -O-C(O)-R23- wherein R 22 is heterocyclic and R 23 is a covalent bond, alkylene, alkenylene, or -N(R 24 )-R 25 wherein R 25 is alkylene and R 24 is hydrogen 15 or loweralkyl, or R 13 -C(O)-CH(R1 wherein R 1 3 is amino, alkylamino, or dialkylamino and R 14 is aryl or R 15 wherein R 15 is amino, alkylamino, or dialkylamino, or a pharmaceutically acceptable salt thereof.

20. The method of claim 19 wherein the compound has formula (CH 2 )n

21. The method of claim 19 or 20 wherein R is -C(O) 2 -G and G is hydrogen.

22. The method of claim 19 or 20 wherein R, is 2,2-dimethylpentyl, 4- methoxyphenyl, or 3-fluoro-4-methoxyphenyl.

23. The method of claim 19 or 20 wherein R 2 is l,3-benzodioxolyl or 7- methoxy- I ,3-benzodioxolyl. [R:\LIBXX]42 5370d1 Ldoc:aak

24. The method of claim 19 or 20 wherein R 3 is R 4 or R 6 -S0 2 -R 7 R 4 is (Rjj)(R 12 R 5 is methylene, R 7 is -N(R21)-RIO-, Rio is ethylene, and RI, and R 12 and R 21 are propyl. The method of claim 19 or 20 wherein the compound is trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- 1- (propylaminocarbonylmethyl)pyrrolidine- 3 -carboxylic acid; trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1- (aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans,trans-2-(4-methoxyphenyl)- 4 -(1I,3-benzodioxol-5-yl)- 1 fluorobenzyl)-pyrrolidine-3 -carboxylic acid; trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- 1-(2- ethoxyethyl)-pyrrolidine-3-carboxylic acid; trans,trans-2-(4-methoxypheflyl)- 4 ,3-benzodioxol-5-yI)- 1 propoxyethyl)pyrrolidine-3-carboxylic acid; trans,trans-2-(4-methoxyphenyl)- 4 ,3 -benzodioxol-5-yl)- 1 methoxyethoxy)ethyl)pyITolidine-3carboxylic acid; trans,trans-2-(4-methoxyphenyl) 4 -(1,3-benzodioxol-5-yl)- 1 pyridyl)ethyl)-pyr-rolidine-3-carboxylic acid; trans,trans-2-(4-methoxyphenyl)-4( 1,3 -benzodioxol-5-yl)- 1-(morpholin- 20 4-ylcarbonyl)pyrrolidile-3-carboxylic acid; trans,trans-2-(4-methoxyphenyl) 4 -benzodioxol-5-yl)- 1- (butylaminocarbonyl)pyrrolidine- 3 carboxylic acid; trans,trans-2-(4-methoxyphenyl)A4( 1,3 -benzodioxol-5-yl)- 1 methoxyphenylaminocarbonyl> 3 -pyrrolidine-3 -carboxylic acid; (11) trans,trans-2-(4-methoxyphenyl)- 4 ,3-benzodioxol-5-yl)- 1 acetylpyrrolidine- 3 -carboxylic acid; (12) trans,trans-2-(4-methoxyphenyl)- 4 ,3-benzodioxol-5-yI)-1I-(2-furoyl)- pyrrolidine-3-carboxylic acid; (13) trans,trans-2-(4-methoxyphenyl)- 4 ,3-benzodioxol-5-yl)- 1- (phenylaminocarbonyl)pyrrolidine- 3 -carboxylic acid; (14) trans,trans-2-(4-methoxyphenyl-4(l ,3-benzodioxol-5-yl)- 1- (allylaminocarbonylmethyl)pyrrolidine- 3 -carboxylic acid; [R:\LIBXX]425370d1 .doc:aak trans,trans-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yI)-1I-(n- butylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; (16) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5 -yl)-l propy1)-N-methylaminocarbonylmethy)pyrroidine-3-caboxylic acid; (17) trans,trans-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)- 1-(pyrrolidin- 1 -ylcarbonylmethyl)pyrrolidine-3-carboxylic acid; (18) trans,trans-2-(4-methoxyphenyl)- 4 ,3-benzodioxol-5-yl)- 1 (isobutylaminocarbonylmethyl)pyrrolidie-3-carboxylic acid; (19) trans,trans-2-(4-methoxyphenyl)- 4 ,3-benzodioxol-5-yI)- 1- (cyclopentylaminocarbonylmethyl)pyrolidile-3-carboxylic acid; trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5 -yl)-l -(morpholin- 8 4-ylcarbonylmethyl)pyrrolidifle- 3 -carboxylic acid; (21) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- 1-(2- :phenoxyethyl)-pyrrolidine-3-carboxylic acid; 15(22) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1 methoxyethylaminocarboflylmethyl)pyrrolidiflC 3 -carboxylic acid; (23) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yI)- 1-(2- butoxyethyl)-pyrrol idine-3-carboxylic acid; 20 (24) trans,trans-2-( 1,3 -benzodioxol-5-y)-4-(4-methoxyphelyl)-1- (propylaminocarbonylmethyl)pyrrolidifle- 3 -carboxylic acid; S. (25) trans,trans-2-( 1,3 -benzodioxo1-5-y1)-4-(4-methoxyphefl)>1 *propoxyethyl)-pyrrolidine-3-carboxylic acid; (26) trans,trans- 2 1,3 -benzodioxol-5-yl)-4-(4-methoxyphelyl)- 1 methoxyethoxy)ethyl))pyrrolidile-3-carboxylic acid; (27) trans,trans-2-( 1,3 -benzodioxol-5-yl)-4-(4-methoxyphelyl)- 1- (butoxyethy1)-pyrrolidine-3-carboxylic acid; (28) trans,trans-2-(4-methoxyphenyl)> 4 -(1,4-benzodioxan-6-yI)- 1- (propylaminocarbonylmethyl)pyrrolidifle- 3 -carboxyl ic acid; (29) trans,trans-2-(4-methoxypheflyl)- 4 -(1I,4-benzodioxan-6-yl)- I -(N-methyl- N-propylaminocarbonylmethyl)pyrrolidile- 3 -carboxylic acid; trans,trans-2-(4-methoxypheflyl)- 4 ,3-benzodioxol-5-yl)- 1-(N-methyl- N-butylaminocarbonylmethyl)pyrrolidifle- 3 -carboxylic acid; [R:\LIBXX]425370d1 ldoc:aak (3 1) trans,trans-2-(4-methoxy-2-methoxymethoxyphenyl)- 4 1,3- I -(N-methyl-N-butylaminocarbonylmethyl)pyrrolidine-3 -carboxylic acid; (32) trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1-(3- ethoxypropyl)-pyrrolidin-5-one- 3 -carboxylic acid; (33) trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1-(3- methoxybenzyl)-pyrrolidin-5-one-3-carboxylic acid; (34) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- 1-(N,N- diisoamylaminocarbonylmethyl)pyrTolidile-3-carboxylic acid; (35) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yI)- 1-(N,N- dipentylaminocarbonylmethyl)pyrrolidile- 3 -carboxylic acid; (36) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yI)- 1-(N,N-di(2- methoxyethyl)aminocarbonylmethyl)pyITolidifle- 3 carboxylic acid; 15 (37) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-(2- hexynyl)-pyrrolidine-3-carboxylic acid; 9 (38) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-(N- cyclopropylmethy1-N-propylamiflocarboflmethy)pyrrolidine- 3 -carboxylic acid; (39) trans,trans-2-(4-methoxyphenyl)- 4 ,3-benzodioxol-5-yI)- 1-(N-methyl- 20N-pentylaminocarbonylmethy)pyrrolidifle-3-carboxylic acid; 20(40) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-(N,N- diisobutylaminocarbonylmethyl)pyITolidile- 3 -carboxylic acid; (41) trans,trans-2-(4-methoxypheflyl)- 4 -(1I,3-benzodioxol-5-yl)- 1-(N-methyl- N-(2-propynyl) aminocarbonylmethyl)pyrrolidile- 3 carboxylic acid; (42) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-(N-methyl- N-(n-hexy1)aminocarbolmethy)pyrTolidile- 3 -carboxylic acid; (43) trans,trans-2-(4-methoxyphelyl)- 4 1,3 -benzodioxol-5-yI)- 1-(N ,N-di(n- butyl)aminocarbonylmethyl)pyrrolidile-3-carboxylic acid; (44) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- I diethylaminocarbonylmethyl)pyrTolidile- 3 -carboxylic acid; trans,trans-2-(4-methoxypheflyl)- 4 1,3 -benzodioxol-5-yl)- 1-(N-methyl- N-phenylaminocarbonylmethyl)pyrrolidie 3 -carboxylic acid; [R:\LIBXX]425370d1 .doc:aak (46) trans,trans-2-(4-methoxyphelyl)- 4 1,3-benzodioxol-5-yl)- 1 -(N-methyl- N-cyclohexylaminocarbolmethyl)pyrrolidine 3 -carboxylic acid; (47) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-(N,N-di(n- propyl)aminocarbonylmethyl)pyrTolidife 3 caboxylic acid; (48) trans,trans-2-(4-methoxypheflyl)-4( 1,3 -benzodioxol-5-yl)- 1-(N-methyl- N-isobutylaminocarbonylmethy1)pyrTolidie-3-carboxylic acid; trans,trans-2-(4-methoxyphelyl)- 4 1,3 -benzodioxol-5-yl)- 1-(t- butyloxycarbonylmethyl)pyITolidifle- 3 -carboxylic acid; 1) trans,trans-2-(4-methoxyphelyl)- 4 1 -naphthyl)- 1 -(N-methyl-N- propyl)aminocarbonylmethyl)pyrTolidine- 3 -carboxylic acid; (52) trans,trans-2-(4-methoxyphelYl)- 4 2 3 -dihydrobenzofiiran-5 -yl)-l methyl-N-propyl)amiflocarboflmethyl)pyrroidine3carboxylic acid; (53) trans,trans-2,4-bis(4-methoxyphelD- 1-(N-methyl-N- propyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; (54) trans,trans-2-(4-methoxypheflyl) 4 3 ,4-dimethoxyphenyl)- 1-(N-methyl- N-propy1)aminocarboflmethyl)pyrrolidine3caboxylic acid; (55) trans,trans-2-(4-methoxypheflyl)- 4 3 -methoxyphenyl)- 1-(N-methyl-N- propyl)amiflocarbonylmethyl)pyITolidine3carboxylic acid; 206 trans,trans2(4methoxyphel)4-(2-naphthy)-lI -(N-methyl-N- (57)tran~trns-2(4-ethoyphnyl)4-(,3 -benzodioxol-5-yI)-I-2 (ethyl sulfinyl)ethyl)pyrTolidifle-3 -carboxylic acid; (58) trans,trans-2-(4-methoxypheflyl)- 4 1,3 -benzodioxol-5-yl)- 1-(2- (isopropyisulfonylamiflo)ethy1)pyrrolidine3carboxylic acid; (59) trans,trans-2-(4-methoxyphelyl)- 4 1,3 -benzodioxol-5-yl)- 1-(2- (isobutoxy)ethyI)pyrrolidile-3-carboxylic acid; trans,trans-2-(4-methoxyphefl)> 4 -benzodioxol-5-yl)- 1- (butylsulfonyl)-pyrrolidifle-3-carboxylic acid; (61) trans,trans-2-(4-methoxypheflyl) 4 1,3-benzodioxol-5-y1)- methy1-N-isopropylcarboflamino)ethy1)pyITolidine- 3 -carboxylic acid; (62) trans,trans-2-(4-methoxypheflyl)A4( 1,3 -benzodioxol-5-yl)- methyl-N -propionylaminno)ethyl)pyrrolidifle- 3 -carboxylic acid; R:\LIBXX]42 5370d1 .doc:aak (63) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-(N-methyl N-benzylaminocarbonylmethy)pyrroidile-3-carboxylic acid; (64) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-(N-ethyl -N- butylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; (65) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- I-(N-methyl N-(2,2-dimethylpropy)aminocarboflmethy1)pyrrolidine- 3 -carioxylic acid; (66) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- methy1-N-butylsulfonylamino)ethy1)pyrrolidife 3 carboxylic acid; (67) trans,trans-2-(4-methoxypheflyl)- 4 -benzodioxol-5-yl)-1I-(2-(N- methyl-N-propyisulfonylamiflo)ethyl)pyrrolidie 3 -carboxylic acid; (68) trans,trans-2-(4-methoxypheflyl)- 4 1,3 -benzodioxol-5-yl)- 1-(2- (propylsulfonyl)ethyl)pyrrolidile-3-carboxylic acid; (69) trans,trans-2-(4-methoxypheflyl)A4( 1,3 -benzodioxol-5-yl)- 1 methylhex-2-enyl)pyrrolidifle- 3 -carboxylic acid; (70) trans,trans-2-(4-methoxypheflyl) 4 3,5-dimethylhex-2-eny1)pyrTolidile-3-carboxylic acid; h (7I) trans,trans2(4-methoxyphefyl) 4 (1,3-benzodioxol-5-y1)- 1-(4- heptylcarbonylmethyl)pyrrolidie3-carboxylic acid; (72) trans,trans-2-(4methoxyphefyl) 4 -(1,3-benzodioxol-5-yl)- 1- 20 (valerylmethy1)-pyrrolidile-3-carboxylic acid; (73) trans,trans-2-(4-methoxyphefyl) 4 -benzodioxol-5-yI)- ,4- diehxbny)Nmtyaiocroymty yrldn--carboxylic acid; (74) trans,trans-2-(4-methoxypheflyl)4( 1 ,3-benzodioxol-5-y1)- diehxbny~mncroymehlproiie3croyi acid; (75) (2R,3R,4R)-2-(4-methoxypheflyl)-4-( 1,3 -benzodioxol-5-yI)- 1- (N,N-dipropylaminocarboflyl)- 1 -butyl)pyrrolidine-3 -carboxylic acid; (76) (2S,3S,4S)-2-(4-methoxyphefly)4-( 1,3-benzodioxol-5-yl)- 1- (N,N-dipropylaminocarboflyl)- 1 -butyl)pyrrolidine-3 -carboxylic acid; (77) (2S,3S,4S)-2-(4-methoxypheflyl)-4-(1I,3-benzodioxol-5-yl)- 1- (N,N-dipropylaminocarboflyl)- I -butyl)pyrrolidine-3-carboxylic acid; (78) (2R,3R,4R)-2-(4-methoxypheflyl)- 4 -(1I,3-benzodioxol-5-yl)- 1 I (N,N-dipropylaminocarboflyl)- 1 -butyl)pyrrolidine-3 -carboxylic acid; [R:\LIBXX]425370d1 .doc:aak (79) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5 -yl)-lI -(N,N-di(n- butyl)aminocarbonylmethyl)-3 trans,trans-2-(4-fluorophenyl)- 4 1,3-benzodioxol-5-yl)- 1-(N,N-di(n- butyl)aminocarbonylmethy)pyrolidile- 3 -caboxylic acid; (8 1) trans,trans-2-(4-methoxypheflyl)- 4 1,3 -benzodioxol-5-yl)- I -(N,N-di(n- butyl)aminocarbonylmethyl)pyITolidifle3-carboxylic acid; (82) trans,trans-2-(4-methoxyphelyl)- 4 1,3 -benzodioxol-5-yl)-1I-(N-n- butyI)-N-(n-propy1)amilocarboflmethy)pyrrolidine 3 carboxylic acid; (83) trans,trans-2-(4-methoxypheflyl)- 4 ,3-benzodioxol-5-yl)- di(n-propy1)aminocarbofl)ethy1)pyrrolidine- 3 -carboxylic acid; (84) trans,trans-2-(4-methoxypheflyl)A4( 1,3 -benzodioxol-5 -yl)-l -(N,N-di(n- butyl)aminocarbonyl)pyrrolidie3-carboxylic acid; trans,trans-2-(4-methoxyphelyl)A4( 1,3 -benzodioxol-5-yl)- 1-(N ,N-di(n- butyl)aminocarbonylmethyl)pyrrolidine 3 carboxylic acid; (86) trans,trans2-(4-methoxypheflyl)A4( 1,3 -benzodioxol-5-yl)- di(n-buty1)amino)ethy1)pyrrolidife3carboxylic acid; (87) trans,trans-2-(4-methoxypheflyl) 4 {l,3 -benzodioxol-5-yl)- 1 (N,N-di(n- buty1)aminocarbony1)-N-methylamino)ethyl)pyrrolidine- 3 -carboxylic acid; 20(88) trans,trans-2-(4-methoxyphefyl) 4 -benzodioxol-5-yl)- 1-(N,N-di(n- butyl)aminocarbofl)methy)pyrrolidine 3 -KNmethanesulfonyl)carboxamide; (89) trans,trans-2-(4-methoxyphelyl) 4 -benzodioxol-5-yI)- 1-(N,N-di(n- *butyl)aminocarbol)methyl)pyrrolidine3KNbenzenesulfonyl)carboxamide; (90) trans,trans-2-(4-methoxyphelyl) 4 (',3-benzodioxol-5 -yI)-l -(N,N-di(n- butyl)-aminosul fonylmethyl)pyrrolidile-3-carboxylic acid; (9 1) trans,trans-2-(4-methoxyphelyl) 4 -benzodioxol-5 -yl)-lI dibutylamino)carbofll- (RS)-ethy1)pyrrolidifle- 3 -carboxylic acid; (92) trans,trans-2-(jpentyl)- 4 1,3 -benzodioxol-5-yI)- I-(N,N-di(n- butyl)aminocarbonylmethyl)pyrrolidine- 3 -carboxylic acid; (93) trans,trans-2-(pentyl)- 4 -(1I,3-benzodioxol-5-yl)- 1-(2-(N-propyl-N- propylsul fonylamino)ethyl)pyrTolidifle- 3 -carboxylic acid; (94) trans,trans-2-(propyl)- 4 1,3 -benzodioxol-5-yI)- I-(N,N -di(n- buty1)aminocarboflmethyl)pyrrolidine3carboxylic acid; [R:\LIBXX]425370d I .doc:aak (2R,3 R,4S)-(+)-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1-(N,N- di(n-butylaminocarbonylmethyl)pyrrolidifle- 3 -carboxylic acid; (96) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- propy1-N-butyrylamino)ethy)pyrrolidile- 3 -carboxylic acid; (97) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1 propy1-N-(ethylaminocarbony1)amilo)ethyI)pyrrolidifle3-carboxylic acid; (98) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- buty1-N-butyrylamino)ethy1)pyrrolidifle- 3 -carboxylic acid; (99) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- propyl-N-etboxycarbonylamiflo)ethy1)pyrrolidife 3 carboxylic acid; (100) trans,trans-2-(4-methoxypheflyl)- 4 1,3 -benzodioxol-5-yl)- methy1-N-(2-ethylbutyry1)amiflo)ethy)pyrrolidife 3 carboxylic acid; (101) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- 15methy1-N-(2-propylvalery1)amiflo)ethy)pyrroidine 3 carboxylic acid; (102) trans,trans-2-(4-methoxypheflyl)- 4 1,3 -benzodioxol-5-yl)- propy1-N-(tert-butyloxycarboflmethy1)8.liflo)ethyl)pyrrolidine- 3 -carboxylic acid; (103) trans,trans-2-(4-methoxypheflyl)- 4 1,3-benzodioxol-5-yl)- prplN(-ehxpeoyabnlaioehlproiie3croyi acid; 20(104) trans,trans-2-(4-methoxypheflyl)-4-l ,3-benzodioxol-5-yl)- 1 prplN(-ehxbnolaioehlproiie3croyi acid; (105) trans,trans-2-(4-methoxypheflyl) 4 1,3 -benzodioxol-5-yl)- 1 prplNbnolmn*tylproiie3croyi acidcid (106) trans,trans-2-(4-methoxypheflyl)4( 1 ,3-benzodioxol-5-yl)- propy1-N-benzyoxcoylamiflO~ethY1)PYITOliddine3carboxxlic acid; (107) trans,trans-2-(4-methoxypheflyl) 4 -(1,3-benzodioxol-5-yI)- 1 propy1-N-(b-eth yny loabfyafonety)PYino~iethycayrboiie3-blic acid; (108) trans,trans-2-(4-methoxypheflyl) 4 -(1,3-benzodioxol-5-yl)- propuyl-N(ethoxybe1Xcarbonlmfoeh lyrr)ainehY1)Pboxycaid;~abxYi cd (110) trans,trans-2-(4-methoxypheflyl) 4 1,3 -benzodioxol-5-yl)- 30buty1-N-etoxycarboflamiflo)ethyl)pyrrolidine- 3 carboxylic acid [R:\LIBXX]425370d1 .doc:aak (I111) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- propy1-N-propoxycarbonylamino)ethyl)pyrrolidifle- 3 -carboxylic acid; (112) trans,trans- 1 (N,N-di(n-buty1)aminocarbonylmethyl)-2,4-di( 1,3- benzodioxol-5-y)pyrrolidine-3-carboxylic acid; (113) trans,trans-l I -nbty)Npoysufnlmn~ehl--4 methoxyphenyl)-4-( 1,3 -benzodioxol-5-y)pyrTolidifle- 3 -carboxylic acid; (114) trans,trans-l1 (N,N-di(n-buty1)amiflocarbonylmethyl)- 2 4 methoxyphenyl)-4-( 1,3 -benzodioxo-5-y1)pyTolidifle-3-carboxylic acid; (115) trans,trans- I -(-Npoy--rpluloyaioehl--4 methoxyphenyl)-4-(1I,3-benzodioxol-5-y)pyrrolidifle-3-carboxylic acid; (116) trans,trans- 1 -(-NbtlNbtlufoyaioehl--4 methoxyphenyl)-4-( 1,3 -benzodioxo-5-y1)pyrTolidifle-3-carboxylic acid; (117) trans,trans- 1 (2(N,Ndi(nbuty1)aminocarboflmethyl)- 2 4 15 methoxymethoxyphenyl)- 4 1,3 -benzodioxo-5-y1)pyTolidifle-3-carboxylic acid; (118) trans,trans-l1-(2-(N ,N-di(n-buty1)aminocarboflmethyl)- 2 4 hydroxyphenyl)-4-( 1, 3-benzodioxo-5-yl)pyrTolidife3carboxylic acid; trans,trans-l I -sbty--rpluloya-n~ehl--4 methoxyphenyl)- 4 1,3 -benzodioxo1-5-y1)pyrrolidie3-carboxylic acid; (120) trans,trans-l I -ezeeufnlN-rplmn~ehl--4 20 methoxyphenyl)- 4 1,3 -benzodioxo1-5-y)pyrrolidne3-caboxyI ic acid; (12 1) trn~rn-I-2(-4mtoyeznsloy)N :propylamino)ethy1)-2-(4-methoxyphenyl) 4 ,3 -benzodioxo-5-y)pyrTolidifle- 3 carboxylic acid; (122) trans,trans- 1 -(N,N-di(n-buty1)amnhfocarboflYmethyl) 2 2 methoxyethoxy-4-methoxypheflYD 4 (l,3 -benzodioxo1-5-y)pyrolidie3-caboxylic acid; (123) trans,trans- 1-(2-(N-propyl-N-(2, 4 dimethylbenzenesulfoflyl)amiflo)ethyl)2(4methoxyphenyl) 4 yl)pyrrolidine-3-carboxylic acid; (124) trans,trans-l 1 -rpl--3clrpopiufnlamn~ty)2 (4-methoxyphenyl)- 4 -(1I,3-benzodioxo-5-y)pyrTolidifle- 3 -carboxylic acid; [R:\LIBXX]425370d I .doc:aak (125) trans,trans- 1 (-Npoy--2mehxehlufnl~nin~ty) (4-methoxypheflyl)-4-( 1,3-benzodioxol-5-yl)pyrrolidie3-caboxylic acid; (126) trans,trans- 1 (-Npoy--2etoytysloy~aioehl-- methoxyphenyl)-4-( 1,3 -benzodioxo1-5-yl)pyrrolidie3caboxylic acid; (127) trans,trans- 1 -poy--5dmty 1mn- naphthylsulfonyl)amiflo)ethyl)2(4-methoxyphenyl) 4 yl)pyrrolidine-3-carboxylic acid; (128) trans,trans-l I -rpy--ehluloy~mn~ehl--4 methoxyphenyl)- 4 1,3-benzodioxo1-5-y1)pyrrolidife 3 caboxylic acid; (129) trans,trans- 1 (-Npoy--4mtybnznsloy~mn~ty) 2-(4-methoxypheflyl)- 4 1,3-benzodioxo1-5-yl)pyrrolidifl3carboxylic acid; (130) trans,trans-l1-(N ,N-di(n-buty)amlilocrboflYmethyl)2( 3 -pyrdyl)- 4 (1 ,3-benzodioxo1-5-y1)pyrrolidife3carboxylic acid; 3 1) tra n s,tra n s- 1 N p o y n b t l u f n l a i o e h l 4 15 methoxyphenyl)- 4 1,3 -benzodioxo-5-y1)pyiTolidifle- 3 -carboxylic acid; (132) trans,trans- I -(-N-rpy--4clrbnznslfnlaioehl 2 :~.(4-methoxypheflyl)- 4 1,3-benzodioxo1-5-y)pyrrolidine3caboxylic acid; (133) trans,trans- 1 (-Npoy--bnyslfnlaioehl--4 methoxyphenyl)- 4 1,3 -benzodioxo1-5-y1)pyrrolidie3-carboxylic acid; (134) trans,trans- I -(-NpoylN(-lorbneeufonyl)amino)ethyl)- 2 0(4-methoxyphenyl)- 4 1,3 -benzodioxo1-5-yl)pyrrolidie3caboxylic acid; *0 5) trans,trans- 1 -(N-methyl-N-propylamiflocarbonylmethyl) 2 4 mehxpey)4(-bnouay yrliie3croyi acid; (136) trans,trans- 1 (-ehlNpoplmncroylehl-- mehxpey)4(-ezouay yrldn--carboxylic acid; 137) trans,trans- I1-(N-methyl-N-propylamiflocarboflYmethyl) 2 4 methoxyphenyl)-4-(6-be11zo 2 3 -dihydrofturany1)pyrrolidife3carboxylic acid; (13 8) trans,trans- 1 -(N,N-di(n-buty1)aminocarboflYmethyl) 2 4 methoxypheny1)-4-(4benfuraiy1)pyrrolidine- 3 -carboxylic acid; 139) trans,trans- 1 -(N,N-di(n-buty1)aminocarboflYmethyl) 2 4 methoxypheny1)-4-(5belzofurany)pyI7olidine- 3 -carboxylic acid; [R\LIB XX142 5370d1 .doc:aak (140) trans,trans-1I (N,N-di(n-buty1)aminocarbonylmethyl)- 2 4 methoxypheny)-4-(6-belzoftranl)pyrrolidife 3 caboxylic acid; (14 1) trans,trans- I1-(N,N-di(n-buty1)aminocarbonylmethyl)- 2 4 mehxpey)4(-ez-,-dhdouay yrldn--carboxylic acid; 142) trans,trans- I -{N-methyl-N-propylaminocarboflylmethyl) 2 4 3 -carboxylic acid; 143) trans,trans- 1 -(N-methy1-N-propylamiflocarboflylmethyl) 2 4 methoxypheny)-4-(6-indo1yl)pyrrolidine- 3 -carboxylic acid; (144) trans,trans-lI (N-methy1-N-propylaminocarbofylYmethyl) 2 4 methoxyphenyl)- 4 3 ,4-difluoropheny)pyrrolidifle-3carboxylic acid; (145) trans,trans- 1 (N-methy1-N-propylamiflocarboflylmethyl) 2 4 methoxyphenyl)-4-(pheflyYIolidine 3 carboxylic acid; (146) trans,trans- 1 (N-methy1-N-propylamiflocarboflylmethylY 2 4 methoxypheny)-4-(4-hydroxyphenyl)pyrrolidine- 3 -carboxylic acid; (147) trans,trans- 1 (N-methy1-N-propyamiflocarboflylmethyl) 2 4 methoxypheny)-4-(2,4-dimethoxyphenyl)pyrroidine3carboxylic acid; :(148) trans,trans-1I (N,N-di(n-buty)aminocarboflylmethyl)- 2 4 methoxyphenyl)- 4 benzo2,3dihydroftral)pyrroidine3carboxylic acid; (149) trans,trans-1I (N,Ndi(nbutyl)anminocarbofylmethyl) 2 4 trans,trans- 1 -(N,N-di(n-buty1)aminocarboflmethyl)- 2 4 00 *l methoxyphenyl)- 4 3 ,4-difluoropheny1)pyrrolidie3-carboxylic acid; (15 1) trans,trans- I -(N,N-di(n-buty1)aminocarboflYmethyl> 2 4 methoxypheny)-4-(2,4-dimethoxyphenyl)pyrroidine3carboxylic acid; (15 52) trans,trans- 1 ,N-di(n-buty)aminocarboflYmethyl 2 phenylA4(l ,3 3 -carboxylic acid; (1 53) trans,trans- 1 -(N,N-di(n-buty)aminocarbonylmethyl) 2 phenyl 4 benzo-2,3-dihydrofural)pyrrolidife 3 carboxylic acid; (154) trans,trans- 1 -(N,N-di(n-butyl)aminocarboflYmethyl) 2 4 -t buypey)4(-ez-,-iyrfrnlproiie3croyi acid; (155) trans,trans-2-(N,N-dibutylaminfocarbonylmethyl)2(4methoxyphenyI>- 4-(4-fluoropheny)pyr-rolidifle- 3 -carboxylic acid; [R:\LIBXX]42 5 370d1 ldoc:aak (156) trans,trans-l1-(N,N-dibutylaminocarbonylmethyl)-2-(3-furyl)- 4 1,3- benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; (157) trans,trans- 1-(N,N-dibutylaminocarbonylmethyl)-2-(isopropyl)- 4 1,3- benzodioxol-5-yl)pyrrolidine-3-carboxylic acid; 15 8) trans.trans- 1 -(N,N-dibutylaminocarbonylmethy)-2-(4-t-butylphel)- 4 (1 ,3-benzodioxol-5-y1)pyrrolidine-3-carboxylic acid; 15 9) trans,trans- 1 -(N,N-di(n-buty1)aminocarbonylmethyl)- 2 4 -t- buypey)4(-ez-,-iyrotrnlproiie3croyi acid; (160) trans,trans- I -(N,N-dibutylanminocarbonylmethy1)-2-(aflti- 4 methoxycyclohexyl)- 4 -(1I,3-benzodioxo-5-y)pyrrolidifle-3-carboxylic acid; (16 1) trans,trans- I -(N,N-dibutylaminocarbcrnylmethyl)- 2 -(syfl- 4 methoxycyclohexyl)- 4 1,3-benzodioxol-5-yI)pyrTolidifle-3 -carboxylic acid; 9: (162) trans,trans-lI-(N, N-dibutylaminocarbonylmethy1)-2,4-di(5-benzo- 2 3 :dihydroturanyl)pyrrolidifle- 3 -carboxylic acid; ~(163) trans,trans- 1 -(N,N-dibutylaminocarbonyimethyl)- 2 3 -uryiV. 4 benzo-2,3 -dihydrofurany)pyrrolidifle-3-carboxylic acid; (164) trans,trans- 1 (N,Ndibutylaminocarbonylmethyl)2(4-methoxyphenyl)- 4-(3-fluoropheny1)pyrTolidifle-3-carboxylic acid; 20 (165) trans,trans- 1 (N,Ndi(nbuty1)aminocarboflmethyl)- 2 4 methoxyphenyl)- 4 3 -pyridy1)pyrrolidine-3-carboxylic acid; (166) trans,trans-l1 (N,N-di(n-buty)amilocarboflmethyl)- 2 2 9. fluorophenyl)-4-( 1,3-benzodioxo-5-y1)pyITolidifle-3-carboxylic acid; (1 66a) (trans. trans-i I (N,N-dibutylaminocarbonylmethy1)-2-(2-fluorophenyl)- 4-(1I,3-benzodioxo1-5-y1)pyrrolidifle-3carboxylic acid; 167) trans,trans- 1 -(N,N-di(n-buty1)aminocarboflmethyI)- 2 3 fluorophenyl)-4-( 1,3-benzodioxo-5-y1)pyrrolidife3carboxylic acid; (1 67a) trans,trans- 1 (N,N-dibutylaminocarbonylmethyl)- 2 3 -fluorophenyl)- 1,3 -benzodioxo1-5-yl)pyrrolidiflC3-carboxylic acid; (168) trans,trans-1I (4-N,N-di(n-buty1)aminophel)-2-(4-methoxyphefl)-4 (1 ,3-benzodioxo1-5-y1)pyITrolidie3-carboxylic acid; (169) trans,trans-1I (2-N,N-dibutylaminopyrimidifl- 4 -yl)- 2 4 methoxyphenyl)- 4 1,3 -benzodioxo-5-y1)pyroidifle-3-carboxyhic acid; [R:\LIBXX]425370d1 doc:aak (289) trans,trans- 2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)- 1 dibutylaminophenyl)pyrrolidine-3-carboxylic acid; (290) trans,trans-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)- 1-(2- dibutylaniino-pyrimidine-4-yl)pyrrolidine-3-carboxylic acid; (291) trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- I-(N-butyl- N-phenylaminocarbonylmethyl)pyrrolidine-3-carboxyic acid; (501 Ha) (2R,3 R,4S)-(+)-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)- 1- (N,N-di(n-butyl)aminocarbonylmethy)pyrToidine-3-carboxyic acid; (293) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1- (decahydroisoquinoin-2-carbonylmethy1)pyrTolidifle-3carboxylic acid; (294) trajns,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-(3,3- dimethylpiperidinylcarbonylmethyl)pyrTolidile-3-carboxylic acid; (295) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- :0::propy1-N-iso-butoxycarbonylamino)ethyl)pyrrolidifle- 3 carboxylic acid; (296) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yI)- 1-(1,2,3,4- tetrahydroisoquinolin-2-carboflylmethyl)pyrTolidile- 3 -carboxylic acid; (297) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- propy1-N-dimethylaminocarbonylamilo)ethyl)pyrTolidifle- 3 -carboxylic acid; (298) trans,trans-2-(4-methoxyphenyl)- 4 -(1I,3-benzodioxol-5-yl)- 20 propy1-N-(4-nitrobenzenesufofl)amliflo)ethyl)pyrrolidine- 3 -carboxylic acid; (299) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yI)- 0, propy1-N-n-pentanesulfonylamiflo)ethyI)pyrrolidie 3 -carboxylic acid; (300) trans,trans-2-(4-methoxyphenyl)- 4 -(1I,3-benzodioxol-5-yl)- propyl-N-(4-tri fluoromethoxybenzenesulfonyl)amilo)ethyl)pyrrolidie 3 -carboxylic acid; (301) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- prplN(-ehl2poeeufnlaioehlproiie3croyi acid; (302) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-(2- ethylpiperidinycarbonylmethyl)pyrrolidifle- 3 -carboxylic acid; (303) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yI)- propyl-N-(2-methylpropanesulfonl)amiflo)ethy)pyrrolidine 3 carboxylic acid; IR:\LIBXX]425370d1 .doc:aak (304) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- propyl-N-heptanesulfonylamiflo)ethy1)pyrrolidife3-caboxylic acid; (305) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- ethyl-N-ethoxycarboflamiflo)ethy1)pyrrolidine- 3 -carboxylic acid; (306) trans,,trans-2-(4-methoxypheflyl)- 4 ,3-benzodioxol-5-yl)- propy1-N-hexanesulfonylamiflo)ethy)pyrrolidine3carboxylic acid; (307) trans,trans-l1 (N,N-dibutylaminocarbonylethy)-2-(4-ethylphefl)-4 (1 ,3-benzodioxo-5-y1)pyrrolidile-3-carboxylic acid; (308) trans,trans-2-(4-methoxypheflyl) 4 1,3-benzodioxol-5-yl)-1I-(2-(N- propyl-N-(2-chloroethoxy)carboflamiflo)ethyl)pyI1roidine 3 carboxylic acid; 9 (309) trans,trans-2-(2-methoxyethyl)- 4 ,3-benzodioxol-5-yl)- 1-(N ,N-di(n- butyl)aminocarlbonylmethyl)pyrTolidie3-caboxylic acid; (3 10) trans,trans-2-(4-methoxypheflyl) 4 (1,3 -benzodioxol-5-yl)- 1 15 ethy1-N-n-pentanesulfoflamiflo)ethylUpyrrolidine- 3 -carboxylic acid; (11) trans,trans-2-(4-methoxypheflyl) 4 1,3 -benzodioxol-5-yl)- 1-(N,N- dicyclohexylamino carbonylmethyl)pyrrolidile-3carboxylic acid; too: (3 12) trans,trans-2-(4-methoxypheflYl)A4( 1,3 -benzodioxol-5-yl)- apropy1-N-tert-butoxycarbonlamiflo)ethyl)pyrroidine 3 carboxylicacd V too.(3 1 3 trans,trans-I 1 (N,N-dibutylaminocarbonylmethy)- 2 3 -fluoro-4- methoxyphenyl)-4-( 1,3 -benzodioxo1-5-yI)py1Tolidile- 3 -carboxylic acid; (3 14) trans,trans-2-(propyl)- 4 -(1I,3-benzodioxol-5-yI)- I-(2-(N-propyl- *0 pentanesulfonylamino)ethyl)pyrrolidine 3 carboxyI ic acid; *0 0 (315) trans,,trans-2-(4-methoxypheflyl) 4 -benzodioxol-5-yl)- I propyl-N-dimethylsul famoylamino)ethyl)pyrrolidile-3-carboxylic acid; (316) trans,trans-2-(4-methoxypheflyl) 4 {l ,3-benzodioxol-5-yl)- propyl-N-(4-methoxyphel)sulfofylYamino)propyl)pyroidine3carboxylic acid; (317) trans,trans-2-(4-methoxyphelyl)A4( 1,3 -benzodioxol-5-yl)- propy1-N-propylsulfonylamilo)propyl)pyrrolidine- 3 -carboxylic acid; (3 18) trans,trans-l I -roy--npetlufny~mn~thl--3 fluoro-4-methoxypheflyl)- 4 ,3-benzodioxo1-5-y)pyrrolidifle- 3 -carboxylic acid; (319) trans,trans-2-(4-Pyridinyl)- 4 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)aminoc arbonylmethyl)pyrolidifle- 3 -carboxylic acid; [R:\LIBXX]425370d1 .doc:aak (320) trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- propy1-N-diethylaminocarbonyamino)ethy1)pyroidile-3-carboxylic acid; (32 1) trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yI)- 1 dimethylpiperidiny-carbonymethy1)pyrroidile-3-carboxylic acid; (322) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1 -(N,N-di(s- butyl)aminocarbonylmethyl)pyrrolidile-3-carboxylic acid; (323) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yI)- methylphenyl)-N-butylamino carbonylmethyl)pyrrolidine-3 -carboxylic acid; (324) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- methylphenyl)-N-butylamiflo carbonylmethyl)pyrrolidine-3-carboxylic acid; (325) trans,trans-4-( 1,3-benzodioxol-5-yl)-2-(benzyloxym~ethyl)- a dibutylaminocarbonylmethyl)pyrTOlidifle- 3 -carboxylic acid; (3 26) trans,trans-4-( 1,3 -benzodioxo1-5-y1)-2-(hydroxymethyl)- 1 3 carboxylic acid; (327) trans,trans-4-( 1,3 -benzodioxo1-5-yl)-2-(N-methyIpropefami- 3 -yl> 1- ((N,N-di(n-buty1)aminocarbonylmethy1)pyrrolidie 3 -caboxylic acid; 05. (328) trans,trans-4-(1I,3-benzodioxol-5-yl)-2-( I-hydroxy-2-propen-3-yI)- 1- (N ,N-di(n-buty1)aminocarbonylmethy1)pyrrolidie 3 -carboxylic acid; (329) trans,trans- 4 1,3 -benzodioxol-5-y1)-2-(N-belYamiflomethyl) 1 20 di(n-buty1)aminocarbonylmethy1)pyrrolidie 3 -caboxylic acid; (330) trans,trans- 4 1,3 -benzodioxo1-5-y1)-2-(N-acetyl-N- benzylaminomethyl)- I -(N,N-di(n-butyl)aminocarboflmethyI)pyflrolidie 3 -carboxylic acid; (33 1 trans,trans-4-(1I,3-benzodioxol-5-y)-2-(ethyflyl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)pyITolidifle- 3 -carboxylic acid; (332) trans,trans- 4 1,3-benzodioxol-5-yI)-2-( I-pentynyl)- 1-(N,N-di(n- butyl)aminocarbonylmethyl)pyrrolidile- 3 -carboxylic acid; (333) trans,trans-2-(4-methoxphel)l 4 1,3 -benzodioxol-5-yl)- dioxopiperidinyl) ethyl)pyrrolidine-3-carboxylic acid; (334) trans,trans-2-(4-methoxypheflyl)4( 1 ,3-benzodioxol-5-yI)- 1-(N,N- diphenylaminocarbonylmethyl)pyrrolidile-3-carboxylic acid; (R:\LIBXX]425370d I .doc:aak (335) trans,trans-2-(4-methoxypheflY) 4 G ,3.benzodioxol-5-yl)- 1-(N,N- diisopropylaminocarlbofylmethyl)pyrrolidine- 3 carboxylic acid; or (336) trans,trans-2-(3-fluoro-4methoxyphenyl) 4 O ,3-benzodioxol-5-yl)- 1- (2Npoy--uaeufnlmn~ty~y-oiie3croyi acid; or a pharmaceutically acceptable salt thereof.

26. A method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of (2R,3R,4S)-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- I -(N,N-di(n- butyl)aminocarbonylmethy)pyrrolidine3carboxylic acid, or a pharmaceutically acceptable salt thereof.

27. A method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammual a therapeutically effective ::.amount of (2R,3 R,4S)-2-(4-methoxyphenyl)- 4 -(1I,3-benzodioxol-5-yI)- I -(N,N-di(n- butyl)aminocarbonylmethyl)pyrrolidine 3 carboxyi~c acid hydrochloride.

28. A method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound having formula: (CH 2 )n R wherein Z is -C(R 18 wherein R1 8 and Rig are hydrogen; n isO0; R is (CH 2 wherein m is 0, W is -C(O) 2 and G is hydrogen; R, is alkyl, alkenyl, or phenyl substituted with one or two independently selected halo or alkoxy substituents; R 2 is 0o wherein X* is and Y* is -CH 2 and is substituted with one or two independently selected alkoxy and halo substituents; R 3 is R 4 wherein R 5 is alkylene; and [R:\LIBXX]425370d I doc:aak 667 R 4 is (R, 1 )RO 2 wherein RI, is aminoalkyl, alkylamninoalkyl, dialkylaminoalkyl, or trialkylaminoalkyl and R 12 is alkyl, haloalkyl, haloalkoxyalkyl, or alkoxy; or a pharmaceutically acceptable salt thereof.

29. The method of claim 28 wherein the compound has the formula (CH 2 )n, The method of claim 29 wherein the compound is (525) trans,trans-2-(4-methoxphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-((N-butyl- N-ethylamino)carbonylmethyl)pyroidine- 3 -carboxylic acid; 10 (526) trans,trans-2-(4-methoxphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-((N-butyl- N-(3-aminopropylamino)carbonylmethy1)pyrroidine3carboxylic acid; (527) trans,trans-2-(4-methoxphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-((N-butyl- N-(3-dimethylaminopropyl)amino)carbonyl)methyl)pyrrolidine- 3 -carboxyl ic acid; (528) trans,trans-2-(4-methoxphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-((N-butyl- N-(3-dimethylammoniopropy)amino)carbonylmethylDpyrrolidine- 3 -croy cd N-(4-aminobuty1)amino)carboflylmethyl)pyrrolidine- 3 -carboxylic acid; or (530) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- I -((N-butyl- N-(4-dimethylaminobutyl)amino)carbolylmethyl)pyrroI idine-3 -carboxylic acid; or a pharmaceutically acceptable salt thereof. 3 1. A method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of trans,trans-2-(4-methoxyphenyl)- 4 -(1I,3-benzodioxol-5-yl)- I-((N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl)pyrrolidine3carboxylic acid, or a pharmaceutically acceptable salt thereof.

32. A method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of trans, trans-2-(2,2-dimethylpentyl)- 4 -benzodioxol-5-yl)- 1-(N,N-di(n- [R:\LIBXX]425370d1 .doc:aak 668 butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.

33. A method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising compound having formula: R2Nz R3 (CH 2 )n R wherein Z is -C(R 18 wherein R 18 and Rig are hydrogen; n is 0; 10 R is -(CH 2 wherein m is 0 and W is -C(O) 2 wherein G is hydrogen, -PO31-2, wherein E is hydrogen, loweralkyl, or arylalkyl, tetrazolyl, -C(O)NHS(O) 2 RI 6 wherein R 16 is loweralkyl, haloalkyl, aryl, or dialkylamino, or .0 0 -S(O) 2 NHC(O)R 1 6 and R 2 are independently selected hydrogen, loweralkyl, alkenyl, alkynyl, 0.0 20 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, or(Ra~j(Rbb)N-R~c-, wherein is aryl or arylalkyl, Rbb is hydrogen or alkanoyl, and R, is alkylene; [R:\LIBXX]425370d1 doc:aak R 3 is loweralkyl, alkenyl, akynyl, cycloalkyl, (e) cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, alkoxyalkoxyalkyl, (in) R 1 -C(O)-R 5 wherein R 4 is loweralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkylamninoalkyl, dialkylamninoalkyl, alkoxy, or (R 1 1 )(R 12 wherein R 11 and R1 2 are independently selected loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclic, arylalkyl (heterocyclic)alkyl, hydroxyalky, or alkoxy, and R 5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20 )-R 8 wherein R 8 is alkylene or alkenylene, and R 20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl, or cycloalkylalkyl, -R 8 aN(R 20 )R 8 wherein R 8 is alkylene or alkenylene, *or -O-R 9 or -R9a-O-R9-, wherein R 9 and R9a are independently selected 20 alkylene; R 4 ~Ra whri 5 a is alkylene or alkenylene, wheei R 4 -G(O)-R 5 -N(R 6 wherein R 6 is (RI 1 )(R 12 R 6 -S(O) 2 -R 7 wherein R 7 is a covalent bond, alkylene, alkenylene, -N(R 21 or -RIOa-N(R21)- Rio-, wherein Rio and RIO,, are independently selected alkylene or alkenylene and R 21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, or arylalkyl; R 26 -S(O)-R 27 wherein R 26 is loweralkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, or alkoxy-substituted haloalkyl, and R 27 is alkylene or alkenylene, R22-O-C(O)-R23- wherein [R:\LIBXX]42 53 70d1 .doc:aak 670 R 22 is heterocyclic and R 23 is a covalent bond, alkylene, alkenylene, or N(R 24 )-R 25 wherein R 25 is alkylene and R 24 is hydrogen or loweralkyl, or R 13 -C(O)-CH(RI4O-, wherein R 13 is amino, alkylamino, or dialkylamino and R 1 4 is aryl or R 15 wherein R 15 is amino, alkylamino, or dialkylamino, or a pharmaceutically acceptable salt thereof;, and a pharmaceutically acceptable carrier.

34. The method of claim 33 wherein the compound has formula (CH 2 )n 0: 0% 10 35. The method of claim 33 or 34 wherein R is -C(O) 2 -G and G is hydrogen.

36. The method of claim 33 or 34 wherein R 1 is 2,2-dimethylpentyl, 4-methoxyphenyl, or 3-fluoro-4-methoxyphenyl.

37. The method of claim 33 or 34 wherein R 2 is l,3-benzodioxolyl or 7-methoxy- ,3-benzodioxolyl.

38. The method of claim 33 or 34 wherein R 3 is R 1 -C(O)-R 5 or R 6 -S0 2 -R 7 R 4 is (Ril)(R 12 R 5 is methylene, R 7 is -N(R 21 )-Ri 0 Rio is ethylene, and R 11 and R 1 2 and 1R21 are propyl. The method of claim 33 or 34 wherein the compound is 20 trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- I1- (propylaminocarbonylmethyl)pyrrolidine-3carboxylic acid; trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- I1- (aminocarbonylmethyl)pyrrolidine-3carboxylic acid; trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5 1-(4- fluorobenzyl)-pyrrolidine-3-carboxylic acid; trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- 1-(2- ethoxyethyl)-pyrrolidine- 3 -carboxylic acid; trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yI)- 1-(2- propoxyethyl)pyrrolidine- 3 -carboxylic acid; [R:\LIBXX]425370d1 Ldoc:aak trans,trans-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)- methoxyethoxy)ethyl)pyrrolidine-3-carboxylic acid; trans,trans-2-(4-methoxyphenyl)-4-(1I,3-benzodioxol-5-yI)- pyridyl)ethyl)-pyrrolidine-3-carboxylic acid; trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yI)-1I-(morpholin- 4-ylcarbonyl)pyrrolidine-3-carboxylic acid; trans,trans-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)- 1- (butylaminocarbonyl)pyrrolidine-3-carboxylic acid; trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1 methoxyphenylaminocarbonyl)-3 -pyrrolidine-3 -carboxylic acid; (11) trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1 acetylpyrrolidine-3-carboxylic acid; (1 2) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- I -(2-furoyl)- pyrrolidine-3-carboxylic acid; (hey (13) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1 (peyaminocarbonyl)pyrrolidine-3-carboxylic acid; (14) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1- (allylaminocarbonylmethyl)pyrrolidifle- 3 -carboxylic acid; trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yI)- 1 20 butylaminocarbonylmethyl)pyrrolidile-3-carboxylic acid; (16) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1 propy1)-N-methylaminocarbonylmethy1)pyrTolidifle-3-carboXylic acid; S(1 7) trans,trans-2-(4-methoxyphenyl)- 4 -(1I,3-benzodioxol-5-yI)- I -(pyrrolidin- 1 -ylcarbonylmethyl)pyrrolidine-3-carboxylic acid; 18) trans,trans-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yi)- 1 (isobutylaminocarbonylmethyl)pyrolidile-3-carboxylic acid; (19) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yI)- I1- (cyclopentylaminocarbonylmethyl)pyrrolidile-3-carboxylic acid; trans,trans-2-(4-methoxyphenyl)- 4 ,3-benzodioxol-5-yI)-1-(morpholin- 4-ylcarbonylmethyl)pyrrolidile-3-carboxylic acid (2 1) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yI)- 1-(2- phenoxyethyl)-pyrrolidine-3-carboxylic acid; [R:\LIBXX]425370d I .doc:aak (22) trans,trans-2-(4-methoxyphelyl)- 4 1,3 -benzodioxol-5-yl)- 1-(2- methoxyethylaminocarboflmethy1)pyf~lOidine3carboxylic acid; (23) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yI)- 1-(2- butoxyethy)-pyrroidile-3-carboxylic acid; (24) trans,trans- 2 1,3-benzodioxo-5-y1)-4-(4-methoxypheflyl)-1- (propylaminocarbonylmethyl)pyrrolidile- 3 -caboxylic acid; trans,trans- 2 1,3 -benzodioxo1-5-y1)-4-(4-methoxyphelyl) 1 propoxyethy)-pyrroidile-3-carboxylic acid; (26) trans,trans- 2 1,3 -benzodioxo1-5-yl)-4-(4-methoxyphefl) methoxyethoxy)ethyl))pyrTolidifle- 3 -carboxylic acid; (27) trans,trans- 2 1,3 -benzodioxo1.5-yI)-4-(4-methoxyphefl)- (butoxyethy)-pyrrolidifle-3-carboxylic acid; (28) trans,trans-2-(4-methoxypheflyl) 4 -(1,4-benzodioxan-6-yl)- 1- (propylaminocarbonylmethyl)pyrrolidie3-caboxylic acid; (29) trans,trans-2-(4-methoxypheflyl) 4 -(1,4-benzodioxan-6-yl)- 1 -(N-methyl- N-propylaminocarbolmethy1)pyrrolidine3caboxylic acid; (30) trans,trans-2-(4-methoxypheflyl) 4 (1,3-benzodioxol-5-yl)- 1-(N-methyl- N-butylaminocarbonylmethyl)pyrrolidile- 3 -carboxylic acid; 0(3 1) trn~rn--4mehx--ehxmehxpey)4 ,3- benzodioxol-5-yI)- 1 -(-ehlNbtlmncroymehlproiie3croyi acid; (32) trans,trans-2-(4-methoxypheflyl)A4( 1,3 -benzodioxol-5-yl)- 1-(3- 3 -carboxylic acid; (33) trans,trans-2-(4-methoxypheflyl) 4 1,3 -benzodioxol-5-yl)- 1 methoxybenzyl)-pyrrolidifl-5-0le- 3 -carboxylic acid; (34) trans,trans-2-(4-methoxypheflyl)A4(1I,3-benzodioxol-5-yl)- 1-(N,N- diisoamylaminocarbonylmethy1)pyrrolidine3carboxylic acid; trans,trans-2-(4-methoxyphelyl) 4 -benzodioxol-5-yl)- I-(N,N- dipentylaminocarbonylmethyl)py'ITolidine- 3 -carboxylic acid; (36) trans,trans-2-(4-methoxyphelyl)4( 1,3 -benzodioxol-5-yl)- 1-(N,N-di(2- methoxyethyl)aminocarboflylmethylDpy'lolidine- 3 -carboxylic acid; [R:\LIBXX]42 5370d1 .doc:aak (37) trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1-(2- hexynyl)-pyrrolidine-3-carboxylic acid; (3 8) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- I cyclopropylmethyl-N-propylaminocarbonymethyl)pyrTolidile- 3 -carboxylic acid; (39) trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- I-(N-methyl- N-pentylaminocarbonylmethy)pyrroidile- 3 -carboxylic acid; trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-(N,N- diisobutylaminocarbonylmethyl)pyrTolidile-3-carboxylic acid; (41) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- 1-(N-methyl- N-(2-propynyl) aminocarbonylmethyl)pyrrolidine- 3 -carboxylic acid; (42) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)-1I-(N-methyl- N-(n-hexy1)aminocarbonylmethy)pyrrolidifle- 3 -carboxylic acid; (43) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-(N,N-di(n- butyl)aminocarbonylmethyl)pyrTolidile- 3 -carboxylic acid; (44) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- 1-(N,N- diethylaminocarbonylmethYl)pyrTolidifle- 3 -carboxylic acid; :9 (45) trans,trans-2-(4-methoxypheflyl)- 4 1,3 -benzodioxol-5-yI)- 1-(N-methyl N-phenylaxninocarbonylmethyl)pyrroidile- 3 -carboxylic acid; 0 trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- I -(N-methyl- 20 N-cyclohexylaminocarboflylmethyl)pyrrolidifle- 3 -carboxylic acid; (47) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- I-(N,N-di(n- propyl)aminocarbonylmethyl)pyrrolidifle- 3 caboxylic acid; so0:(48) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-(N-methyl- N-isobutylaminocarbonylmethy)pyrrolidifle- 3 -carboxylic acid; (50) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1-(t- butyloxycarbonylmethyl)pyrrolidile-3-carboxylic acid; 1) trans,trans-2-(4-methoxyphenyl)- 4 1 -naphthyl)- I -(N-methyl-N- propyl)aminocarbonylmethyl)pyrrolidifle- 3 -carboxylic acid; (52) trans,trans-2-(4-methoxyphenyl)- 4 2 3 -dihydrobenzofuran-5-yl)- 1-(N- methy1-N-propyI)aminocarboflmethyl)pyrrolidine- 3 -carboxylic acid; (53) trans,trans-2,4-bis(4-methoxypheflyl) 1 -(N-methyl-N- propyl)aminocarbonylmethyl)pyrrolidifle- 3 carboxylic acid; [R:\LIBXX142537OdI ldoc:aak (54) trans,trans-2-(4-methoxyphenyD)- 4 3 ,4-dimethoxyphelyl)- 1-(N-methyl- N-propy1)aminocarboflmethy)pyrroidine3carboxylic acid; trans,trans-2-(4-methoxyphenyl)A-( 3 -methoxyphenyl)- 1-(N-methyl-N- propyl)aminocarboflylmethyl)pyrolidine-3carboxylic acid; (56) trn~rn--4mtoypey)4(-ahh (N-methyl-N- propyl)aminocarboflylmethyl)pyrroidine3carboxylic acid; (57) trans,trans-2-(4-methoxyphenyl)- 4 ,3 -benzodioxol-5-yI)- 1-(2- (ethylsulfinyl)ethyl)pyrTolidine3carboxylic acid; (58) trans,trans-2-(4-methoxyphefl- 4 ,3 -benzodioxol-5-yl)- 1-(2- (isopropylsulfonyamiflo)ethyl)pyrolidine3-caboxylic acid; *eae:(59) trans,trans-2-(4-methoxyphefl- 4 ,3 -benzodioxol-5-yl)- 1-(2- (isobutoxy)ethyl)pyrTolidife3carboxylic acid; (60) trans,trans2(4-methoxyphefl- 4 ,3 -benzodioxol-5-yl)- 1- @6 (butylsulfony1)-pyrrolidile-3-carboxylic acid; 15 (61) trans,trans-2-(4-methoxyphenyl)- 4 -O ,3-benzodioxol-5-yl)- mehlNiorpycroyaio ty~yrldie3croyi acid; (62) trans,trans-2-(4-methoxyphenyD) 4 -benzodioxol-5-yl)- *metnyl-N prop1iolai II1IuJyl11yroidine -carboxylic acid; (63) trans,trans-2-(4-methoxyphenyl)- 4 ,3 -benzodioxol-5-yl)- 1-(N-methyl- 1-ezlmncroymth\o11rdine--carboxyi~cacd Nbezylamnocarboylmeylpyrrldie3-aboy acid; (64) trans,trans-2-(4-methoxyphenyl)- 4 {l ,3 -benzodioxol-5-yI)- 1-(N-ethyl- N-(butyl moca rolYmli)Pcrboymy~roli1ulneJ-cauUAYyli acid; 25(6)trans,trans-2-(4-methoxypheflyl)- 4 O 1,3 -benzodioxol-5-yl)- I (-(N-ehl Net(y,-N-imethylroylamilnonyl~yroiethlP-3ld 3 -carboxylic acid; (66) trans,trans-2-(4-methoxyphenyl)- 4 ,3 -benzodioxol-5-yl)- methyl-N-pbuysulfoflamino)ethyl)pyrrolidine-3carboxylic acid; (68) trn~rn--4mehxpey)4 ,3 -benzodioxol-S -yl)-l (propylsulfonyl)ethyl)pyrrolidine3carboxylic acid; (69) trans,trans-2-(4-methoxyphenyl 4 -benzodioxol-5-yl)-l1-N-(trans-5 methylhex-2-efl)pyrrolidine- 3 -carboxylic acid; IR:\ IJRXX 142 5370d1 .doc:aak trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)-l1-N-(trans- 3, 5-dimethylhex-2-enyl)pyrrolidine-3-carboxylic acid; (7 1) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1 heptylcarbonylmethyl)pyrrolidile-3-carboxylic acid; (72) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- 1- (valerylmethyl)-pyrrolidine-3-carboxylic acid; (73) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yI)- ,4- dimethoxybenzy)-N-methylamilocarboflmethyl)pyrrolidine- 3 -carboxylic acid; (74) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- ,4- dimethoxybenzyl)aminocarboflylmethyl)pyrTolidine- 3 -carboxylic acid; (2R,3 R,4R)-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1 1 (N,N-dipropylaminocarboflyl)- 1 -buty1)pyrrolidine-3-carboxylic acid; (76) (2S,3S,4S)-2-(4-methoxyphefly)4(1I,3-benzodioxol-5-yl)- 1- (N,N-dipropylaminocarboflyl)- 1 -butyl)pyrrolidine-3 -carboxylic acid; (77) (2S,3S,4S)-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)- 1 1 dipropylaminocarbolyl)- 1 -butyl)pyrrolidine-3-carboxylic acid; NN-(78) (2R,3R,4R)-2-(4-methoxypheflyl)- 4 1,3-benzodioxol-5-yl)- 1 1 (,-dipropylaminocarbonyl)- 1 -butyl)pyrrolidine-3 -carboxylic acid; (79) trans,trans-2-(4-methoxypheflyl)4-( 1,3 -benzodioxol-5-yl)- 1-(N,N-di(n- 20 butyl)aminocarbonylmethyl)- 3 trans,trans-2-(4-fluorophelyl)A4-( 1,3-benzodioxol-5-yI)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)pyrrolidine3carboxylic acid; Se (81) trans,trans-2-(4-methoxyphefli)- 4 ,3-benzodioxol-5-yl)- 1-(N,N-di(n- butyl)aminocarbonylmethyl)pyITolidile3-carboxylic acid; (82) trans,trans-2-(4-methoxyphelyl)- 4 1,3 -benzodioxol-5-yl)- 1-(N-n- buy)N(-rplaioabnlehlproiie3croyi acid; (83) trans,trans-2-(4-methoxyphelyl)A4( 1,3 -benzodioxol-5-yl)- di(n-propy1)aminocarbony1)ethy1)pyrrolidine3carboxylic acid; (84) trans,trans-2-(4-methoxypheflyl)A4( 1,3 -benzodioxol-5-yl)- 1-(N,N-di(n- butyl)aminocarbonyl)pyTolidile-3-carboxylic acid; trans,trans-2-(4-methoxypheflyl) 4 -(1,3-benzodioxol-5-yl)- 1-(N,N-di(n- butyl)aminocarbonylmethyl)pyrrolidine- 3 -carboxyl ic acid; [R:\U,[BXX]425370d I doc:aak (86) trans,trans-2-(4-methoxypheflyl)- 4 1,3 -benzodioxol-5-yl)- di(n-buty1)amino)ethy)pyroidile-3-carboxylic acid; (87) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- (N,N-di(n-butyl)aminocarbony)-N-methylamiflo)ethy1)pyrrolidife 3 caboxylic acid; (88) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- I -(N,N-di(n- buy~mncroy~ehlproiin--Nmtaeufnlcroaie (89) trans,trans-2-(4-methoxyphelyl)- 4 1,3 -benzodioxol-5-yl)- 1-(N,N-di(n- butyl)aminocarbonyl)methyl)pyrrolidifle- 3 -(N-benzenesulfonyl)carboxamide; trans,trans-2-(4-methoxypheflyl) 4 -(1,3-benzodioxol-5-yI)- 1-(N,N-di(n- butyl)-aminosulfonylmethy)pyrrolidife 3 caboxylic acid; (91) trans,trans-2-(4-methoxypheflyl)-4(1I,3-benzodioxol-5-yl)- dibutylamino)carboflyl- 1 -(RS)-ethyl)pyrrolidine-3 -carboxylic acid; (92) trans,trans-2-(pentyl)- 4 1,3-benzodioxol-5-yI)- 1-(N,N-di(n- butyl)aminocarbonylmethyl)pyrTolidife 3 carboxylic acid; (93) trans,trans-2-(pentyl)- 4 1,3 -benzodioxol-5-yl)-1I-(2-(N-propyl-N- p roy*s l:o y(9 4 et yl1,rl d i e 3c r o y acid (9)trans,trans-2-(propyl)- 4 -(1,-benzodioxol-5-yl)- 1-(N,N-di(n- butyl)aminocarboflylmethyl)pyrTolidine3carboxylic acid; (95) (2R,3R,4S)-(+)-2-(4-methoxypheflyl) 4 -benzodioxol-5-yI)- 1-(N ,N- di(n-butylaminocarbonylmethyl)pyrrolidine- 3 -carboxylic acid; (96) trans,trans-2-(4-methoxypheflyl) 4 {l,3-benzodioxol-5-yl)- propyl.N-butyrylamino)ethyl)pyrrolidine3carboxylic acid; (97) trans,trans-2-(4-methoxypheflyl) 4 O ,3 -benzodioxol-5-yl)- propy1-N-(ethylaminocarbofl)amiflo)ethyl)pyrrolidine- 3 -carboxylic acid; (98) trans,trans-2-(4-methoxypheflyl) 4 0 ,3 -benzodioxol-5-yl)- buty1-N-butyrylamino)ethy1)pyrrolidifle- 3 -carboxylic acid; (99) trans,trans-2-(4-methoxypheflYD 4 -benzodioxol-5 -yI)-l propyl-N-ethoxycarbonylamiflo)ethyl)pyrrolidine- 3 -carboxylic acid; (100) trans,trans-2-(4-methoxyphefl)> 4 1 ,3-benzodioxol-5-yI)-1I-(2-(N- methy-N-(2-ethylbutyry)amiflo)ethyl)pyrroidine- 3 -carboxylic acid; 1) trans,trans-2-(4-methoxyphefl)l> 4 O ,3-benzodioxol-5-yl)- 1 mehlN(-rplaey~mn~ehlproiie3croyi acid; [R:\LIBXX]425370d1 .doc:aak (102) trans,trans-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)- propyl-N-(tert-butyloxycarbonylmethy)amino)ethy1)pyrroidile-3-carboxylic acid; (103) trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- propyl-N-(n-propylaminocabonylmethyI)amilo)ethyI)pyrrolidifle3-carboxylic acid; 104) trans,trans-2-(4-methoxyphenyl)- 4 ,3-benzodioxol-5-yl)- 1 propy1-N-(4-methoxyphenoxycarbony1)amilo)ethyl)pyrrolidifle- 3 -carboxylic acid; (105) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- propy1-N-(4-methoxybenzoy)amilo)ethy1)pyrTolidifle 3 -carboxylic acid; (106) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- propyl-N-benzoylamino)ethyl)pyITolidifle- 3 -carboxylic acid; (107) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- 1 propy1-N-benzyloxycarbonylamino)ethyI)pyrrolidifle- 3 -carboxylic acid; (108) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yI)- 1 prplN(-ehxbnyoyabnlaioehlproiie3croyi acid; (109) trans,trans-2-(4-methoxypheflyl)- 4 -(1I,3-benzodioxol-5-yl)- 1 buty1-N-ethoxycarbonylamilo)ethyl)pyrrolidifle- 3 -carboxylic acid; (110) trans,trans-2-(4-methoxypheflyl)- 4 1,3-benzodioxol-5-yl)- buy--rpxcroyaioehlproiie3croyi acid, (1I 11) trans,trans-2-(4-methoxypheflyl) 4 -(1,3-benzodioxol-5-y1)- propyI-N-propoxycarboflamiflo)ethyl)pyrrolidine- 3 -carboxylic acid; (112) trans,trans- 1 (N,N-di(n-buty1)aminocarboflmlethyl)- 2 4 -di( 1,3- benzodioxo-5-y1)pyrrolidifle-3-carboxylic acid; *(11 3) trans,trans-l 1 -nbty)Npoysufnlmn~ehl--4 methoxyphenyl)-4-(l ,3-benzodioxo-5-y1)pyrrolidie3-carboxylic acid; (1 14) trans,trans- 1 (N,N-di(n-buty1)aminocarboflmethyl)- 2 4 methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)pyrrolidifle-3 -carboxylic acid; (115) trans,trans- 1 (2-(N-propy1-N-propylsulfoflamiflo)ethyl> 2 4 methoxyphenyl)-4-( 1,3 -benzodioxo-5-y1)pyrrolidile-3-carboxylic acid; (116) trans,trans- 1 -(2-(N-buty1-N-butylsulfonylamino)ethyl)- 2 4 methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)pyrrolidifle- 3 -carboxylic acid; (117) trans,trans- 1 (2-(N,N-di(n-buty1)aminocarboflmethyI)- 2 4 methoxymethoxyphenyl)- 4 1,3-benzodioxo-5-y)pyrTolidiflC-3-carboxylic acid; [R:\LIBXX]425370d1 ldoc:aak (118) trans,trans-l1 (2-(N,N-di(n-buty1)aminocarbonylmethyl)-2-( 4 hydroxyphenyl)-4-( 1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid; (119) trans,trans-lI (2-(N-isobutyl-N-propylsulfonylamino)ethy1)-2-( 4 methoxyphenyl)-4-( 1,3-benzodioxo1-5-y)pyrrolidine-3-carboxylic acid; 120) trans,trans- 1 -(2-(N-benzenesulf'onyl-N-propylaliflo)ethyl)- 2 4 methoxyphenyl)-4-( 1,3 -benzodioxo1-5-yl)pyrrolidine-3-carboxylic acid; 12 1) trans,trans- 1 -(2-(N-(4-methoxybenzenesulfony1)-N- propylamino)ethyl)-2-(4-methoxypheflyl)- 4 -(1I,3-benzodioxol-5-yI)pyrrolidifle-3- carboxylic acid; (122) trans,trans- 1 (N,N-di(n-buty1)aminocarbonylmethy)- 2 2 methoxyethoxy-4-methoxypheflyl)- 4 -benzodioxol-5-yl)pyrrolidifle- 3 -carboxylic acid; (123) trans,trans- 1 -(2-(N-propyl-N-(2,4- dimethylbenzenesulfonyl)amilo)ehyl)2(4-mefioxyphenyl) 4 15 yl)pyrrolidine-3-carboxylic acid; 124) trans,trans- I -(-Npoy--3clrpoysloy~mn~ty)2 (4-methoxyphenyl)-4-( 1,3 -benzodioxo-5-y1)pyrrolidifle-3-carboxylic acid; (125) trans,trans- 1 (-Npoy--2-ehxehlufny~mn~ty) (4-methoxyphenyl)- 4 1,3-benzodioxo-5-y1)pyrTolidife3carboxylic acid; 20 (126) trans,trans-l I -rpl--2ehxehysloy~mnoehl--4 methoxyphenyl)- 4 1,3-benzodioxo1-5-y1)pyrrolidie3-carboxylic acid; (127) trans,trans- 1 -(2-(N-propyl-N-(5-dimethylamilo- 1- naphthylsulfonyI)amiflo)ehflY)L2(metuAypheniyl)Y4-I,3 yl)pyrrolidine-3-carboxylic acid; (12 8) trans,trans- I -(-Npoy--ehlufnlaioehl--4 methoxyphenyl)-4-(1I,3-benzodioxol-5-y1)pyrTolidie3-caboxylic acid; (129) trans,trans- 1 (-Npoy--4mtybnznsloy~mn~ty) 2-(4-methoxyphenyl)- 4 -(1I,3-benzodioxo-5-y1)pyrrolidile-3-carboxylic acid; (13 0) trans,trans- 1 -(N,N-di(n-buty1)aminocarboflmethyl> 2 3 -pyridyl)-4- (1 ,3-benzodioxo1-5-y1)pyrrolidie3-caboxylic acid; (13 1) trans,trans- I -(-Npoy--nbtlufnlaioehl--4 methoxyphenyl)-4-( 1,3 -benzodioxo-5-y1)pyrTolidie3-carboxylic acid; R:\LIBXX]4253 70d1 ldoc:aak (132) trans,trans- 1 -(2-(N-propy1-N-(4-chlorobenzenesulfony)amilo)ethyl)- 2 (4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)pyrrolidine-3 -carboxylic acid; 13 3) trans,trans- I -(2-(N-propyl-N-(benzylsulfonyl)amilo)ethyl)-2-(4- methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)pyrrolidie-3-carboxylic acid; 134) trans,trans- 1 -(2-(N-propyl-N-(4-fluorobenzenesul fonyl)amino)ethyl)-2- (4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)pyrrolidine- 3 -carboxylic acid; 13 5) trans,trans- 1 -(N-methy1-N-propylaminocarbonlmethyl)- 2 4 methoxyphenyl)-4-(4-benzofuralyl)pyrTolidifle- 3 -carboxylic acid; (136) trans,trans- I -(N-methy1-N-propylaminocarboflylmethyl)- 2 4 methoxypheny)-4-(6-benfurWafl)pyrrolidifle- 3 -carboxylic acid; (13 7) trans,trans- I -(N-methy1-N-propylaminocarboflylmethyI)- 2 4 methoxyphenyl)-4-(6-belzo- 2 3 -dihydrofurany)pyrrolidile-3-carboxylic acid; (13 8) trans,trans- 1 -(N,N-di(n-buty1)aminocarbolmethyI)- 2 4 methoxypheny)-4-(4-belzofuraflyl)pyrrolidine- 3 -carboxylic acid; (139) trans,trans- 1 (N,N-di(n-buty1)aminocarbolmethyl)- 2 4 methoxypheny)-4-(5-benzofuranl)pyrrolidife 3 carboxyi~c acid; 140) trans,trans- 1 -(N,N-di(n-buty1)aminocarboflmethyl)- 2 4 methoxypheny)-4-(6-belzofuranl)pyrroidine3carboxyhic acid; (14 1) trans,trans- 1 -(N,N-di(n-butyI)aminocarboflmethyl)- 2 4 20 mehxpey)4(-ez-,-iyrfrnlproiie3croyi acid; (142) trans,trans-l1 (N-methy1-N-propylamiflocarboflYmethyl> 2 4 methoxypheny)-4-(5-ifldafl)pyrroidine3carboxylic acid; (143) trans,trans- I -(N-methy1-N-propylamiflocarboflylmethyl) 2 4 *:methoxypheny)-4-(6-iflOy1)pyrrolidine3carboxylic acid; (144) trans,trans- 1 -(N-methy1-N-propylaminocarboflYmethyl) 2 4 methoxyphenyl)- 4 3 ,4-difluoropheny1)pyrrolidile-3-carboxylic acid; (145) trans,trans-1I (N-methy1-N-propylaminocarboflYmethyl) 2 4 methoxypheny)-4-(phefl)pyrrolidine3carboxylic acid; (146) trans,trans- 1-(N-methyl-N -propyaminocarbonylmethyl) 2 4 methoxypheny)-4-(4-hydroxypheflyl)pyrfolidine- 3 -carboxylic acid; (147) trans,trans- 1 (N-methy1-N-propylamiflocarboflylmethyl) 2 4 methoxyphenyl)-4-(2,4-dimethoxyphenyl)pyrroidine 3 carboxylic acid; f R:LIBXX142537Od I .doc:aak (148) trans,trans-l1 (N,N-di(n-buty1)aminocarbonylmethy1)- 2 4 methoxypheny)-4-(5-benzo-2,3-dihydrofurayl)pyrTolidine- 3 -carboxylic acid; (149) trans,trans-l1 (N,N-di(n-buty1)aminocarbonylmethyl)- 2 4 methoxypheny)4-(4-methoxyphel)pyrrolidife 3 carboxylic acid; 150) trans,trans- 1 -(N,N-di(n-buty1)aminocarbonylmethyl)- 2 4 methoxyphenyl)-4-(3 ,4-difluoropheny)pyroidile-3-caboxylic acid; 1) trans,trans-l1 (N,N-di(n-buty1)aminocarboflmethyl- 2 4 methoxypheny1)-4-(2,4-dimethoxyphenl)pyrroidine3carboxylic acid; 2) trans,trans- 1 -(N,N-di(n-buty1)aminocarbonylmethyl)- 2 -phenl-lAO ,3 benzodioxo-5-y1)pyrrolidifle3-carboxylic acid; (153) trans,trans- 1 -(N,N-di(n-butyI)aminocarbonylmethyl)- 2 phefll 4 benzo-2,3 -dihydrofuranyl)pyrrolidile-3-caboxylic acid; (154) trans,trans- 1 -(N,N-di(n-butyl)amiflocarboflYmethyl) 2 4 -t buypey)4(-ez-,-iyrfrnlproiie3croyi acid; 15(1 5 trans,trans-2-(N,N-dibutylamiflocarbonylmethyl)2(4-methoxyphenyI)- 4-(4-fluoropheny1)pyrrolidifle-3-carboxylic acid; (156) trans,trans- 1 -(N,N-dibutylaminocarbonlmethy)2( 3 -furyl)-4-(l ,3 benzodioxo1-5-y1)pyrrolidife3carboxylic acid; (157) trans,trans- I -(N,N-dibutylanminocarboflYmethy)2(isopropyl) 4 3- 20 benzodioxo1-5-y)pyrTolidie3carboxylic acid; (1589) trans~trans- 1 ,N-di~buty~aminocarbonymethy1)2(4t-~~eY) (1 ,3enodioxo15Y1)PY1o-23ihdofle raboylic acoidn--abxyi cd (159) trans,trans- I -(N,N-di~buty)aminocarboflylmethyl)- 2 (i 4 butyhpheny)l4(5hexylZO2-,3edidoxourany)pyrrolidine 3 -carboxylic acid; (1601) trans,trans- I -(N,N-dibutylamiflocarbofylYmethyl) 2 (ynti 4 methoxycyclohexyl)- 4 ,3-benzodioxo-5-y1)pyrrolidife3carboxylic acid; (161) trans,trans- I N-dibutylaminocarboflmethyl)- 2 ,4(SI1 4 o2, dihydroturanyl)pyTolidifle- 3 -carboxylic acid; (163 trans,trans- 1 -(N,N-dibutylaminocarboflYmethy)2( 3 -fryl) 4 benzo-2,3 -dihydrofuranyl)pyrrolidie3-carboxylic acid; [R:\LIBXX]425370d1 .doc:aak (164) trans,trans- 1 (N,N-dibutylaminocarbonylmethy1)-2-(4-methoxyphenyl)- 4-(3-fluorophenyl)pyrrolidine-3-carboxylic acid; (165) trans,trans-l1-(N,N-di(n-butyl)aminocarbonylmethyl)-2-(4- methoxyphenyl)-4-(3-pyridyl)pyrrolidile-3-carboxylic acid; 166) trans,trans- 1 -(N,N-di(n-butyl)aminocarbonylmethyl)-2-(2- fluorophenyl)-4-( 1,3-benzodioxol-5-yl)pyrrolidie-3-carboxylic acid; (I 66a) (trans. trans-i I (N,N-dibutylaminocarbonylmethy)-2-(2-fluoropheflyl)- 1,3-benzodioxol-5-yl)pyrrolidine-3 -carboxylic acid; (167) trans,trans- 1-(N,N-di(n-butyl)aminocarbonylmethyl)-2-(3- fluorophenyl)-4-( 1,3-benzodioxol-5-yl)pyrrolidile-3-carboxylic acid; (1 67a) trans,trans-l1-(N,N-dibutylaminocarbonylmethyl)-2-(3 -fluorophenyl)- 4-(1I,3-benzodioxol-5-yl)pyrrolidifle-3 -carboxylic acid; foes.:(168) trans,trans- 1 -(4-N,N-di(n-buty1)aminopheny)-2-(4-methoxyphelyl)- 4 (1 ,3-benzodioxo1-5-y1)pyrrolidifle-3-carboxylic acid; (169) trans,trans- 1-(2-N,N-dibutylaminopyrimidin-4-y1)-2-( 4 methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)pyrrolidifle-3 -carboxylic acid; so: ('289) trans,trans- 2-(4-methoxyphenyl)-4-(1I,3-benzodioxol-5-yI)- 1-(4- dibutylaminophenyl)pyrrolidile-3-carboxylic acid; (290) trans,trans-2-(4-methoxypheflyl)- 4 1,3-benzodioxol-5-yl)- 1-(2- dibutylamino-pyrimidine-4-y1)pyrTolidifle- 3 -carboxylic acid; 0 N-phenylaminocarbonylmethy1)py1Tolidifle- 3 -carboxylic acid; :00. (501 Ha) (2R,3R,4S)-(±)-2-(4-methoxyphelyl)-4-( 1,3-benzodioxol-5-yI)- 1- 00 (N,N-di(n-buty1)aminocarbonylmethy1)pyrrolidifle-3-carboxylic acid; (293) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yi)- 1- (decahydroisoquinolin-2-carbolmethy)pyrrolidife 3 carboxylic acid; (294) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yI)- 1-(3,3- dimethylpiperidinylcarbolylmethyl)pyrrolidile-3carboxylic acid; (295) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yl)- propy1-N-iso-butoxycarbonylamiflo)ethy1)pyrrolidine 3 carboxylic acid; [R:\LIB XX]425370d1 .docmaak (296) trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1-(1,2,3,4- tetrahydroisoquinolin-2-carbonylmethyl)pyrTolidifle- 3 -carboxylic acid; (297) trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- propyl-N-dimethylaminocarbonylamilo)ethy1)pyrrolidie 3 -carboxylic acid; (298) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-y1)-1I-(2-(N- propy1-N-(4-nitrobenzenesulfonyl)amiflo)ethyl)pyrrolidie3-caboxylic acid; (299) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- propy1-N-n-pentanesulfonylamino)ethyl)pyrrolidifle- 3 -carboxylic acid; (300) trans,trans-2-(4-methoxyphenyl)- 4 1,3 -benzodioxol-5-yI)-1I-(2-(N propy1-N-(4-trifluoromethoxybelzelfofl)amiflo)ethyl)pyrrolidine- 3 -carboxylic acid; (301I) trans,trans-2-(4-methoxypheflyl)- 4 1,3 -benzodioxol-5-yl)- prplN(-ehl2poeeufnlaioehlproiie3croyi acid; S (302) trans,trans-2-(4-methoxypheflyl)- 4 -benzodioxol-5-yl)- 1-(2- e15 ethylpiperidinylcarboflylmethyl)pyrrolidine 3 carboxylic acid; 5: (303) trans,trans-2-(4-methoxypheflyl)4-( 1,3 -benzodioxol-5-yi)-1I-(2-(N- prplN(-ehlrpnsloy~mioehlproiie3croyi acid; (304) trans,trans-2-(4-methoxyphelyl)- 4 1,3-benzodioxol-5-yl)- propy1-N-heptanesulfonylamilo)ethy1)pyI1rolidine- 3 -caboxylic acid; 20 (305) trans,trans-2-(4-methoxyphelyl)- 4 1,3 -benzodioxol-5-yl)- ethy1-N-ethoxycarbonyamiflo)ethyI)pyrroiOine-3carboxylic acid; (306) trans,trans-2-(4-methoxyphelyl)- 4 1,3 -benzodioxol-5-yl)- propy1-N-hexanesulfoflamiflo)ethylOpyrrolidine- 3 -carboxylic acid; 5: (307) trans,trans- 1 (N,N-dibutylaminocarboflylethyl)2( 4 -thylphel)- 4 (1 ,3-benzodioxo-5-y)pyTolidifle-3-carboxylic acid; (308) trans,trans-2-(4-methoxyphelyl)- 4 1,3-benzodioxol-5-yl)- propyI-N-(2-chloroethoxy)carboflamiflo)ethyl)pyrrolidine- 3 -carboxylic acid; (309) trans,trans-2-(2-methoxyethyl)- 4 -benzodioxol-5-yl)- 1-(N,N-di(n- butyl)aminocarbonylmethyl)pyfl7olidine- 3 -carboxylic acid; (3 10) trans,trans-2-(4-methoxypheflyl) 4 -benzodioxol-5-yI)- 1 ethy1-N-n-pentanesulfonlYamiflo)et1yl)pyroidine 3 caboxylic acid; [R:\LIBXX]425370d I .doc:aak (311) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- 1-(N,N- dicyclohexylamnino carbonylmethyl)pyrrolidile-3-carboxylic acid; (3 12) trans,trans-2-(4-methoxyphenyl)- 4 ,3-benzodioxol-5-yl)- propy1-N-tert-butoxycarbolamilo)ethyl)pyrrolidine3carboxylic acid; (313) trans,trans- 1 (N,N-dibutylaminocarbonylmethy1)-2-( 3 -fluoro- 4 methoxyphenyl)-4-( 1,3 -benzodioxo-5-y)pyTolidifle-3-carboxylic acid; (314) trans,trans-2-(propyl)- 4 1,3-benzodioxol-5-yl)- 1-(2-(N-propyl- pentanesulfonylamino)ethyl)pyrrolidifle3carboxylic acid; (315) trans,trans-2-(4-methoxypheflyl)4( 1 ,3-benzodioxol-5-yI)- propy1.N-dimethylsulfamoylamiflo)ethy)pyrroidine3carboxylic acid; (316) trans,trans-2-(4-methoxypheflyl)A4(',3 -benzodioxol-5-yI)- propyl-N-(4-methoxyphel)sulfoflYamino)propy)pyrroidine3carboxylic acid; (317) trans,trans-2-(4-methoxyphefl)> 4 -(l,3-benzodioxol-5-yl)-1I-(2-(N- propy1-N-propylsulfoflamiflo)propyl)pyrroli1One3-carboxylic acid; (318) trans,trans-l 1 -roy--n-etluloy~mioehl-2-3 S. fuoro-4-methoxypheflyl)4( 1 ,3-benzodioxo-5-y)pyrrolidile- 3 -carboxylic acid; (3 19) trans,trans-2-(4-PyridiflyI)-4AI,3-benzodioxol-5-yl)- 1 -(N,N-di(n- buty1)aminocarboflmethy)pyrroidine3carboxylic acid; (320) trans,trans-2-(4-methoxyphenyl) 4 O 1,3 -benzodioxol-5-yl)- dimethylpiperidinyl-carboflmethyl)pyrrolidine- 3 -carboxylic acid; (322) trans,trans-2-(4-methoxypheflY)AO -benzodioxol-5-yl)- 1-(N ,N-di(s- buty1)aminocarbonylmethyl)pyrrolidine3caboxylic acid; (323) trans,trans-2-(4-methoxypheflyl) 4 {l,3 -benzodioxol-5-yl)-1I-(N-(2- methylphenyl)-N-butylamilo carbonylmethyl)pyrrolidile3-carboxylic acid; (324) trn~rn--4mehxpey)4 ,3 -benzodioxol-5-yl)- methylpheny)-N-butyl aminlo carbonylmethyl)pyTrolidie3-carboxylic acid; (325) trans,trans- 4 1,3 -benzodioxo1-5-yl)-2-(belYoxymethyl)l ,N- dibutylaminocarboflmethy)pyrroidine3carboxylic acid; (3 26) trans,trans- 4 1,3bnoixl5y)2(yrxmt) I butyl)aminocarboflylmethyl)pyrrolidine3carboxylic acid; [R:\LIBXX]425370d1 doc:aak (327) trans,trans-4-( 1,3 -benzodioxol-5-yl)-2-(N-methylpropenamid-3 -yl)-l ((N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3 -carboxylic acid; (328) trans,trans-4-( 1,3 -benzodioxol-5-yl)-2-( 1-hydroxy-2-propen-3-yl)- 1- (N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidie-3-carboxylic acid; (329) trans,trans-4-( 1,3-benzodioxol-5-yl)-2-(N-benzylaminomethyl)- I-(N,N- di(n-buty1)aminocarbonylmethyl)pyIolidile-3-carboxylic acid; (330) trans,trans-4-( 1,3 -benzodioxol-5-yl)-2-(N-acetyl-N- benzylaminomethyl)- 1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrr01idile-3-carbxylic acid; (33 1) trans,trans-4-( 1,3-benzodioxol-5-yl)-2-(ethylyl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)pyrTolidifle- 3 -carboxylic acid; (332) trans,trans-4-( 1,3 -benzodioxol-5-yl)-2-( 1-pentynyl)- I-(N ,N-di(n- fee*&: C butyl)aminocarbonylmethyl)pyrTolidine- 3 -carboxylic acid; (333) trans,trans-2-(4-methoxphenyl)- 4 1,3 -benzodioxol-5-yl)- 15 dioxopiperidinyl) ethyl)pyrrolidine-3-carboxylic acid; ~(334) trans,trans-2-(4-methoxypheflyl)- 4 1,3 -benzodioxol-5-yl)- 1-(N,N- *diphenylaminocarbonylmethyl)pyrrolidine- 3 carboxylic acid; (335) trans,trans-2-(4-methoxyphenyl)- 4 ,3-benzodioxol-5-yl)- 1-(N,N- diisopropylaminocarboflylmethyl)pyrrolidine-3carboxylic acid; or (3 10) trans,trans-2-(3-fluoro-4-methoxyphelyl) 4 -(l,3-benzodioxol-5-yl)- 1 2 -N-propyl.N-butanesulfonylamino)ethyl)pyrolidine- 3 carboxylicacd or a pharmaceutically acceptable salt thereof.

40. A method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of pharmaceutical composition comprising (2R,3R,4S)-2-(4-methoxyphenyl)-4- (1 ,3-benzodioxol-5-yl)- 1 (N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine- 3 -carboxylic acid, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

41. A method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a pharmnaceutical composition comprising (2R,3R,4S)-2-(4-methoxyphenyl)-4- [R:\LIBXX]425370d I .doc :aak 685 (1,3-benzodioxol-5-yl)- 1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid hydrochloride and a pharmaceutically acceptable carrier.

42. A method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising a compound having formula: R2 Z R3 (CH 2 )n R1 wherein Z is -C(R 1 8 )(RI 9 wherein R 18 and R 1 9 are hydrogen; n is O; 10 R is -(CH 2 wherein m is 0, W is -C(0) 2 and G is hydrogen; RI is alkyl, alkenyl, or phenyl substituted with one or two independently selected halo or alkoxy substituents; X* Y* 1o•wh R 2 is ,wherein X* is and Y* is -CH 2 and is substituted "with one or two independently selected alkoxy and halo substituents; R 3 is R 4 wherein R 5 is alkylene; and R 4 is (R 1 I)(R 1 2 wherein RI, is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or trialkylaminoalkyl and R 12 is alkyl, haloalkyl, haloalkoxyalkyl, or alkoxy; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

43. The method of claim 42 wherein the compound has the formula R2 Z'N R3 [R:\LIBXX]425370d Ldoc:aak

44. The method of claim 43 wherein the compound is (525) trans,trans-2-(4-methoxphenyl)-4-( 1,3-benzodioxol-5-yl)- 1 -((N-butyl- N-ethylamino)carbonylmethy)pyrrolidine-3-carboxylic acid; (526) trans,trans-2-(4-methoxphenyl)-4-( 1,3-benzodioxol-5-yl)- 1 -((N-butyl- N-(3-aminopropylamino)carbonylmeth yl)p yrolidine- 3 -carboxylic acid; (527) trans,trans-2-(4-methoxphenyl)-4-( 1,3-benzodioxol-5-yl)- 1 -((N-butyl- N-(3-dimethylaminopropyl)amino)carbonyl)methyl)pyrrolidine- 3 -carboxylic acid; (528) trans,trans-2-(4-methoxphenyl)- 4 1,3-benzodioxol-5-yl)- I -((N-butyl- N-(3-dimethylammoniopropyl)amio)carbonylmethyl)pyrrolidine- 3 -carboxylic acid; (529) trans,trans-2-(4-methoxphenyl)- 4 1,3 -benzodioxol-5-yl)- I-((N-butyl- N-(4-aminobutyl)amino)carbonylmethyl)pyrrolidine-3-carboxylic acid; or (530) trans,trans-2-(4-methoxyphenyl)- 4 1,3-benzodioxol-5-yl)- 1-((N-butyl- N-(4-dimethylaminobutyl)amino)carbonylmethyl)pyrrolidine3carboxylic acid; or a pharmaceutically acceptable salt thereof.

45. A method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising trans,trans-2-(4-methoxyphenyI)- 4 (1 ,3-benzodioxol-5-yl)- 1 -((N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl) acid, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

46. A method of treating of bone pain associated with bone cancer in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a pharmaceutically acceptable composition comprising trans, trans-2-( 2 2 dimethylpentyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -(N,N-di(n- butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

47. The method of any one of claims 19 to 46 wherein the mammal is a human.

48. A compound having formula: R2 z R3 (CH 2 )n R) [R:\LIBXX]425370d1 .doc:aak 687 wherein Z is -C(R 18 wherein R 18 and R 1 9 are hydrogen; n isO0; R is -CH 2 wherein m is 0 and W is -C(O) 2 wherein G is hydrogen, -P0 3 11 2 wherein E is hydrogen, loweralkyl, or arylalkyl, tetrazolyl, -C(O)NHS(O) 2 R]6 wherein R 16 is loweralkyl, haloalkyl, aryl, or dialkylamino, or -S(O) 2 NHC(O)R] 6 R, and R 2 are independently selected hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylamninocarbonylalkyl, dialkylaminocarbonylalkyl, amninocarbonylalkenyl, alkylamninocarbonylalkenyl, dialkylamninocarbonylalkenyl, *hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N- *:alkyl)aminoalkyl, alkylsulonylamidoalkyl, heterocyclic, (heterocyclic)alkyl, or(R.)(Rbb)N-RC-, wherein &aa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl, and R,, is alkylene; R 3 is loweralkyl, alkenyl, akynyl, cycloalkyl, (e) cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclic,() (heterocyclic)alkyl, alkoxyalkyl, alkoxyalkoxyalkyl, (in) R4-C(O)-R 5 wherein R 4 is loweralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkylaminoalkyl, dialkylamninoalkyl, alkoxy, or (R I 1 12 wherein R 11 and R 12 are independently selected loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclic, arylalkyl (heterocyclic)alkyl, hydroxyalky, or alkoxy, and R 5 is a covalent bond, [R:\LIBXX]42S37Od L doc:aak 688 (ii) alkylene, (iii) alkenylene, (iv) -N(R 20 wherein R8~ is alkylene or alkenylene, and R 20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl, or cycloalkylalkyl, -RsaN(R20)R8-, wherein Rs,, is alkylene or alkenylene, or -O-R 9 or -R9aO0R9-, wherein R 9 and R9a are independently selected alkylene; Rr-R5a- wherein R5a is alkylene or alkenylene, R 1 -C(O)-R 5 -N(R 6 wherein R. 6 is (Ri 1 )(R 12 R 6 -S(O) 2 -R 7 wherein R 7 is a covalent bond, alkylene, alkenylene, -N(R 2 j)-R 10 or -Ia N(R 2 wherein Rio and Rjca are independently selected alkylene or alkenylene and 15 R 21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, or arylalkyl; R 26 -S(O)-R 27 wherein R 26 is loweralkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, alkoxyalkyl, or alkoxy-substituted 20 haloalkyl, and R 27 is alkylene or alkenylene, R 22 -O-C(O)-R 23 wherein R 22 is heterocyclic and R 23 is a covalent bond, alkylene, alkenylene, or- wherein R 25 is alkylene and R 24 is hydrogen or loweralkyl, or R 13 -C(O)-CH(R 1 4 wherein R 13 is amino, alkylamino, or dialkylamnino and R 14 is aryl or R, 5 wherein R 15 is amino, alkylamino, or dialkylamino, or a pharmaceutically acceptable salt thereof, when used in a therapeutically acceptable amount for the treatment of bone pain associated with bone cancer in a mammal.

49. The compound when used of claim 48 wherein the compound has formula [R:\LIBXX]425370d1 .doc:aak 689 R2 zN R3 (CH 2 )n (2R,3R,4S)-2-(4-methoxyphenyl)- 4 -(1I,3-benzodioxol-5-yl)- 1-(N,N-di(n- butyl)aminocarbonylmethyl)pyrrolidifle- 3 -carboxylic acid, or a pharmaceutically acceptable salt thereof, when used in a therapeutically effective amount for treatment of bone pain associated with bone cancer in a mammal.

51. (2R,3R,4S)-2-(4-methoxyphenyl)- 4 ,3-benzodioxol-5-yl)- 1-(N,N-di(n- butyl)aminocarbonylmethyl)pyrTolidine-3carboxylic acid hydrochloride when used in a therapeutically effective amount for treatment of bone pain associated with bone cancer in a mammal.

52. A compound having formula: R (CH 2 )n wherein Z is -C(R, 8 wherein R 1 8 and R 1 9 are hydrogen; n isO0; 15 R is -(CH 2 wherein m is 0, W is -C(O) 2 and G is hydrogen; R, is alkyl, alkenyl, or phenyl substituted with one or two independently selected halo or alkoxy substituents; R 2 is 0 ,wherein X* is -0Hn s-I 2 and is substituted with one or two independently selected alkoxy and halo substituents; R 3 is R 4 wherein R 5 is alkylene; and R 4 is (Rjj)(R 12 wherein R 11 is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or trialkylaminoalkyl and R 12 is alkyl, haloalkyl, haloalkoxyalkyl, or [R:\LIBXX]42 5370d1 .docaak 690 alkoxy; or a pharmaceutically acceptable salt thereof when used in a therapeutically effective amount for treatment of bone pain associated with bone cancer in a mammal.

53. The compound trans,trans-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1- ((N-buty1-N-(4dimethylaminobutyl)amino)carbonylmethyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof when used in a therapeutically effective amount for treatment of bone pain associated with bone cancer in a mammal.

54. The compound trans, trans-2-(2,2-dimethylpentyl)-4-( 1,3-benzodioxol-5-yl)- 1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof when used in a therapeutically effective amount for treatment of bone pain associated with bone cancer in a mammal. Dated 22 March, 2005 Abbott Laboratories Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON a.a [R:\LIBXX]425370d1 .doc:aak