AU2763602A

AU2763602A - Endothelin antagonists

Info

Publication number: AU2763602A
Application number: AU27636/02A
Authority: AU
Inventors: Steven A. Boyd; Kenneth J. Henry; Charles W Hutchins; Hwan-Soo Jae; Jeffrey A. Kester; Steven A. King; Gang Liu; Bryan K Sorensen; Bruce G. Szczepankiewicz; Andrew S. Tasker; Thomas W. Von Geldern; Martin Winn; Steven J. Wittenberger
Original assignee: Abbott Laboratories
Current assignee: Abbott Laboratories
Priority date: 1996-02-13
Filing date: 2002-03-25
Publication date: 2002-05-16
Also published as: AU2005201160B2; AU2005201160A1

Description

S&F Ref: 493447D1

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 S. Tasker, Thomas W. von Geldem, Jeffrey A. Kester, Bryan K. Sorensen, Bruce G.

Szczepankiewicz, Kenneth J. Henry, Gang Liu, Steven J.

Wittenberger, Steven A. King Spruson Ferguson St Martins Tower,Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Invention Title: Endothelin Antagonists The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c ENDOTHELIN ANTAGONISTS Technical Field The present invention relates to compounds which are endothelin antagonists, processes for making such compounds, synthetic intermediates employed in these processes and methods and compositions for antagonizing endothelin.

Background of the Invention oEndothelin (ET) is a 21 amino acid peptide that is produced by Sendothelial 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 5 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 invitro, increase airway 20 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 i vitro.

It has been shown that vasoconstriction is caused by binding of 25 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 binding 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- 15 2005, a nonpeptide ET-A/B antagonist, prevents post-ischaemic renal vasoconstriction in rats, prevents the decrease in cerebral blood flow due to subarachnoid hemorrhage (SAH) in rats, and decreases MAP in sodium-depleted squirrel monkeys when dosed orally. A similar effect of a linear tripeptide-like ET-A antagonist, BQ-485, on arterial caliber 20 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 S* ET/ET receptor binding will provide therapeutic benefit in the indicated disease states.

*25 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-reperfusion 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 s proteins, 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 a a.

'1 (I) wherein Z is -C(Ri 8

)(R

19 or wherein R 18 and R 1 9 are independently selected from hydrogen and loweralkyl; n is 0 or 1; R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is -C(0) 2 -G wherein G is hydrogen or a carboxy protecting group,

-PO

3

H

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

-CN,

-C(O)NHR

17 wherein R 17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(0) 2

R

16 wherein R 16 is loweralkyl, haloalkyl, aryl or dialkylamino, (in) -S(O) 2 NHC(O)Rl 6 wherein R 16 is defined as above, HO 0 0 HO 0

OH

0N 0 es 0 o* 0.0 5.5 (q)0 .oV(r) 0

S-

H

,goo JL CF 3 t H or NHS0 2

CF

3

R

1 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, d ialkyla min oc:arbonylalIkenyl, 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 RCC is alkylene, with the proviso that one or both of R, and

R

2 is other than hydrogen;

R

3 is R 4

-C(O)-R

5 R4-R~a- R 4

R

5

-N(R

6

R

6

-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 0)-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-R 9 or -R 9 a-O-R 9 wherein R 9 and R 9 a are independently selected from alkytene; is alkylene or (ii) alkenylene;

:R

7 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 2 1 )-Rio- or -RlOa-N(R21)-R1o- wherein Rio and joa 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 *25 (Rll)(Rl 2 wherein R 11 and R 12 are independently selected from (1 hydrogen, loweralkyl, haloalkyl, -alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, 011) heterocyclic, (12) arylalkyl, (13) (heterocyclic)alkyl, (14) hydroxyalkyl, alkoxy, (16) aminoalkyl, (17) trialkylaminoalkyl, (18) alkylaminoalkyl,.

(19) dialkylaminoalkyl, and carboxyalkyl, (i i) loweralkyl, (iii) alkenyl, v) alkynyl, cycloalkyl, i) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x (heterocyclic)alkyl, i) alkoxyalkyl, (xii) hydroxyalkyl, (xiii) haloalkyl, (xiv) haloalkenyl, haloalkoxyalkyl, (xvi) haloalkoxy, (xvii) alkoxyhaloalkyl, :(xviii) alkylaminoalkyl, (xix) dialkylaminoalkyl, (xx) alkoxy, and

H

(CH N R 7 a (xxi) 0 wherein z is 0-5 and R 7 a is alkylene;

R

2 6 is loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) -arylalkyl, (ix) heterocyclic, (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy-substituted haloalkyl; and

R

27 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

2 5 wherein R 25 is alkylene and R 24 is hydrogen or low~ralkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, -aryloxyalkyl, heterocyclic, 20(1) (heterocyclic)alkyl, (in) alkoxyalkyl, alkoxyalkoxyalkyl, o r

R

13 -C(O)-CH(Rl 4 wherein R13 is amino, alkylamino or dialkylamino and R 1 4~ is aryl or R 15 wherein R 15 is amino, alkylamino or or adial kylaurnmo; o pharmaceutically acceptable salt thereof.

A preferred embodiment of the invention is a compound of formula R2 z R 3

N

Rv'* (CH 2 )n

R

(11) wherein the substituents -R 2 -R and -R 1 exist in a trans,trans relationship and Z, n, R, R 1

R

2 and R 3 are as defined above.

Another preferred embodiment of the invention is a compound of s 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 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- R6-S(0) 2

-R

7 or R2 6

-S(O)-R

27 wherein R 4

R

5

R

6

R

7

R

2 6 and R 2 7 are as defined above.

15 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 20 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 (R 1 1

)(R

1 2 as defined above and Rs is alkylene or R 3 is

R

6 -S(0) 2

-R

7 or R 2 6

-S(O)-R

27 wherein R 7 is alkylene, R 2 7 is alkylene and R 6 and R 26 are defined as above.

25 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 )-Ro 0 wherein R 8 and Rio are alkylene and R 4

R

6

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

-CH

2

R

1 and R 2 are independently selected from loweralkyl, (ii) cycloalkyl, (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-Nalkyl)aminoalkyl and alkylsulfonylamidloalkyl, and R 3 is R 4 -C(O)-n 5 wherein R 4 is (Ril)(Rl2)N- 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 R 4

-C(O)-N(R

2 o)-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, hatoalkoxyalkyl, aryl or arylalkyl, R 8 and Rio are alkylene and R 20 and R 21 are loweralkyl; or R 3 is R 6

-S(O)

2

-R

7 or R 2 6

-S(O)-R

2 7 wherein R 6 is loweralkyl or haloalkyl, R 7 is alkylene, R 26 is loweralkyl and R 2 7 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 Ri 6 is loweralkyl, haloalkyl or aryl, Z is -CH 2

R

1 is loweralkyl, (ii) a Ike ny I, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methyiphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethyiphenyl, 3-fluoro-4methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidloalkyl, 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)-R 8 or R6-S(O) 2

-N(R

21 )-Rl 0 wherein R 8 and Rio are alkylene, R 2 0 and R 21 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

R

16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 Rl is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethyiphenyl, 4-methyiphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethyiphenyl, 3-fluoro-4methoxyphenyl, :::3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl :or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) :alkylsulfonylamidoalkyl,

R

2 is substituted or unsubstituted 20 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and

R

3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (Rii)(Rj 2

)N-

wherein Rjj and R 12 are independently selected from loweralkyl, :25 haloalkyl, aikoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl.

NHS(O)

2

R

1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R 1 is loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, arylalkyl, (vi) aryl, (vii) (N-alkanoyl-Nalkyl)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, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or 11 difluorophenyl 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 (Rli)(Ri 2 wherein Rl 11 is loweralkyl and Rl 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, Rl 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 Rl 1 io 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, 3- 3flu oro h ehxphn 2-fluorophenyl, 4-methoxymethoxyphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, Rl 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 Rl 3 is

R

6

-S(O)

2

-N(R

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

NHS(O)

2

R

16 wherein Rl 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 Fl 1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-mnethoxyphenyl, 3-fluorophenyl, 3-f luoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1 ,3-benzodioxolyl or 1 ,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy and alkoxyalkoxy, (ii) loweralkyl, (iii) alkenyl, (iv) -12heterocyclic (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-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 alkoxycarbonyl or R 6

-S(O)

2

-N(R

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

NHS(O)

2

R

16 wherein R 16 is loweralkyl or haloalkyl, Z is -OH 2 R1 is :loweralkyl ,alkenyl, heterocyclic (allkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl,, or alkylsulfonylamidoalkyl, and R 3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (Rj 1)(Rl 2 wherein R and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.

A 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 -C(O)-NHS(O) 2 Rl 6 wherein 16 is loweralkyl or haloalkyl, Z is -OH 2

R

1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, .2-fluorophenyl, 4methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4 -methoxymethoxyphenyl, 4-hydroxyphenyl, 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, (vi) arylalkyl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl,or (ix) phenyl, 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 -13-

R

11 and R 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, 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

1 6 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 R 4 is (Rll)(Rl 2 wherein R 11 and R 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, 15 aminoalkyl, trialkylaminoalkyl, or heterocyclic.

A 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 -OH 2

R

1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, RP is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, S **benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyi and R 3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (Rii)(Ri 2 wherein R 11 and R 12 are independently selected from loweralkyl.

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 -OH 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 ,3benzodioxolyl, 1 ,4-benzodioxanyl or di hyd robe nzof uranyl wherein the -14substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy,

R

2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4 -methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (Rii)(R 12 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 RI is substituted or unsubstituted 4-methoxyphenyl, 3 -fluoro-4-methoxyphenyl, 3fluorophenyl, 2-fluorophenyl, 3 -fluoro-4-ethoxyphenyl, 4methoxymethoxyphenyl, 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-i ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimet 'hoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is R6-S(O) 2

-N(R

2 1

)-R

10 wherein Rio is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R 2 1 is loweralkyl, haloalkyl or alkoxyalkyl.

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, 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 R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (R11)(R1 2 wherein R 1 1 is alkyl and R 1 2 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

R

4

-C(O)-R

5 wherein R 5 is alkylene and R 4 is (R 1 1

)(R

1 2 wherein R 11 and R 1 2 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R, and R 12 is alkyl.

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

R

4

-C(O)-R

5 wherein R4 is (R11)(R12)N- as defined therein and R5 is alkylene.

Another most highly preferred embodiment of the invention is a 20 compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is loweralkyl, and R3 is R 4

-C(O)-R

5 wherein R4 is (R11)(R 1 2 as defined therein and RS is alkylene.

*J Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH2-, R1 is alkenyl, and R3 is R 4 wherein R 4 is (R11)(R 1 2 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 heterocyclic (alkyl), and Rs is R 4 wherein R4 is (R11)(R 1 2)Nas 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 R3 is R4-C(O)-R 5 wherein R4 is (R11)(R 1 2 as defined therein and Rs 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 arylalkyl, and R 3 is R 4

-C(O)-R

5 wherein R 4 is (R11)(R 1 2 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 aryl, and

R

3 is R4-C(O)-R 5 wherein R 4 is (R 1 1

)(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 (Nalkanoyl-N-alkyl)aminoalkyl, 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 alkylsulfonylamidoalkyl, and R 3 is R 4 wherein R 4 is 20 (R1i)(R 1 2 as defined therein and R 5 is alkylene.

The present invention also relates to processes for preparing the Scompounds 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 treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula or (II).

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

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

The terms 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 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 15 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 20 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 1 to C 8 alkyl methyl, ethyl or tertiary butyl and the like); 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 benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1- -18- (propionyloxy)-1 -ethyl, 1 -(pivaloyloxyl)-l -ethyl, 1-methyl-l- (propionyloxy)- -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, -cyclohexyloxycarbonyloxy-1 -ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and 15 the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4 -methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like; (5-(loweralkyl)-2-oxo-1 ,3- 0* dioxolen-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, 0*55 such as (5-phenyl-2-oxo-1 ,3-dioxolen-4-yl)methyl and the like.

The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John 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-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, -19p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2 ,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2 -nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-l-methylethoxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, 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 benzyloxycarbo nyl (Cbz).

:The term "alkanoyl" 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

43

-NH-R

44 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 0-0-R 3 1wherein R 3 0 is an alkanoyl group and R 31 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 include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1methyl-2-buten-1-yl and the like.

The term "alkenylene" denotes a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond.

Examples of alkenylene include -CH=CH-, -CH 2 CH=CH-, -C(CH3)=CH-, CH2CH=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 R 4 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 8 00-R 8 1 0wherein R 80 is loweralkyl as defined above and R 81 is alkylene.

5s Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.

S" 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 20 methoxyethoxyethyl, methoxymethoxymethyl, and the like.

The term "alkoxyalkyl" as used herein refers to an alkoxy group as previously defined appended to an alkyl radical as previously defined.

Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.

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

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

The term "alkoxycarbonylalkyl" as used herein refers to

R

3 4

-C(O)-R

3 5 wherein R 34 is an alkoxy group and R 3 5 is an alkylene group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyl and the like.

-21- The term "alkoxycarbonylaminoalkyl" as used herein refers to

R

3 8

-C(O)-NH-R

3 9 wherein R 3 8 is an alkoxy group and R 39 is an alkylene group.

The term "alkoxycarbonyloxyalkyl" as used herein refers to

R

36

-C(O)-O-R

3 7 wherein R 3 6 is an alkoxy group and R 37 is an alkylene group.

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

The term "alkoxyhaloalkyl" as used herein refers to a haloalkyl radical to which is appended an alkoxy group.

The terms "alkyl" and "loweralkyl" as used herein refer to straight or branched chain alkyl radicals containing from 1 to 15 carbon atoms 15is 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 20 to R85C(O)N(R86)R87- wherein R85 is an alkanoyl as previously defined, e R8 6 is loweralkyl, and R87 is alkylene.

The term "alkylamino" as used herein refers to Rs 1 NH- wherein

R

5 1 is a loweralkyl group, for example, ethylamino, butylamino, and the like.

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

The term "alkylaminocarbonyl" as used herein refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl 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.

-22- The term "alkylaminocarbonylaminoalkyl" as used herein refers to 4 1 wherein R 4 0 is an alkylamino group and R 41 is an alkylene group.

The term "alkylene" denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to carbon atoms by the removal of two hydrogen atoms, for example -CH 2

-CH

2

CH

2

-CH(CH

3

-CH

2

CH

2

CH

2

-CH

2

C(CH

3 2

CH

2 and the like.

The term "alkylsulfonylamidoalkyl" as used herein refers R88S(0)2NHR 8 9 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.

15 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-C=C-CH 2

H-C=C-CH(CH

3 and the like.

The term "alkynylene" refers to a divalent group derived by the 20 removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing from 2 to 15 carbon atoms and also containing a carbon-carbon triple bond. Examples of alkynylene include -C=C-CH 2

-C=C-CH(CH

3 and the like.

The term "aminoalkyl" as used herein refers to a -NH2, alkylamino, 25 or dialkylamino group appended to the parent molecular moiety through an alkylene.

The term "aminocarbonyl" as used herein refers to H 2

N-C(O)-

The term "aminocarbonylalkenyl" 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 of aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like.

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

(NH

2 group.

-23- The term "trialkylaminoalkyl" as used herein refers to (R90)(R91)(R92)N(R9 3 wherein R90, R91, and R92 are independently selected from loweralkyl and R93 is alkylene.

The term "aroyloxyalkyl" as used herein -refers to R32-C(O)-O-R 3 3 wherein R 32 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, 15 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 20 groups include tetrafluorophenyl and pentafluorophenyl.

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

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

The term "arylalkoxyalkyl" as used herein refers to a loweralkyl radical to which is appended an arylalkoxy group, for example, benzyloxymethyl and the like.

The term "arylalkyl" as used herein refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.

The term "aryloxy" as used herein refers to R 4 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 2 C(0)O- wherein R 62 is an arylalkyl group).

-24- 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, 3carboxy-1-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, o 15 carboxyethoxy and the like.

s 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.

20 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 25 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.

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 R 5 6

R

5 7

N-

wherein R 5 6 and R 5 7 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 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 1 wherein Rso is a dialkylamino group and R 5 1 is an alkylene group.

The term "halo" or "halogen" as used herein refers to I, Br, CI or F.

SThe term "haloalkenyl" as used herein refers to an alkenyl radical s15 to which is appended at least one halogen substituent.

The term "haloalkoxy" as used herein refers to an alkoxy radical as defined above, bearing at least one halogen substituent, for example, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3-pentafluoropropoxy and the like.

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 S. 25 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 heteroatom 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 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 quaternized. The term "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or -26another 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.

Heterocyclics also include compounds of the formula 0 where X* is -CH 2 or and Y* is or 2 ]v where R" is hydrogen or C 1

-C

4 -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,

alkoxycarbonyl, 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.

-27- 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.

s The term "hydroxyalkenyl" as used herein refers to an alkenyl radical to which is appended a hydroxy group.

The term "hydroxyalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a hydroxy (-OH) group. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4hydroxybutoxy and the like.

The term "hydroxyalkyl" as used herein refers to a loweralkyl radical to which is appended a hydroxy group.

T. he term "leaving group" as used herein refers to a halide (for example, CI, Br or I) or a sulfonate (for example, mesylate, tosylate, is 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 formed. Methylenedixoy substituted on a phenyl ring results in the a\ formation of a benzodioxolyl radical. Ethylenedioxy substituted 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 or a tautomer thereof.

-28- 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 R70S- 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 Rso is loweralkyl as defined above and R 8 1 is alkylene.

Representative examples of alkoxyalkoxy groups include CH 3 SCHO2-, t-BuSCH 2 O- and the like.

The term "thioalkoxyalkoxyalkyl" as used herein refers to a thioalkoxyalkoxy group appended to an alkyl radical. Representative examples of alkoxyalkoxyalkyl groups include CH 3

SCH

2 CH20CCH 2

CH-,

15 CH 3

SCH

2 0CH 2 and the like.

The term "trans,trans" as used herein refers to the orientation of substituents (RI and R 2 relative to the central substituent R as shown

.R

2 Z R 3 (cH 2 )n o n" e R1 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

R

2 Z N R 3 R Z N R 3

*:N

R (CH2)n R" (H 2 n R1 or This definition encompasses both the case where R and R 2 are cis and R and R 1 are trans and the case where R 2 and R are trans and R and R 1 are cis.

The term "cis,cis" as used herein refers to the orientation of substituents (Ri and R 2 relative to the central substituent R as shown -29- Preferred compounds of the invention are selected from the group consisting of: trans-trans-2-(4-Methoxyphenyl)4-(l 1 3-benzodioxol-5-yl.1 prop yl-N- n-pe nta nes uIf onylam ino) pro pyl]-pyrro lidine- 3 carboxylic acid; trns trans-2-(4-Meth oxv meth oyp he n y)IiA(13bn trans, trn--34Dmtoyhnl--1 3-nzodioxoI -5.y)[2 ((N-propyNnpentanesulfonylamino)ethyl]pyrroidine 3 io carboxylic acid; trans, trans-2-(3,4-Dimethoxyphenyl)- 4 -(1,-ezdool5yl-2 (N-propyl-N-nhenane suf ony am ino)ethyI pyrroidi ne 3 carboxylic acid; :trans, trans-2-(4DimeoxyphenyI)-4-(l 3-benzodioxoI-5-y)1 1(propyNneanesulfonyamino)ethy]pyrroidine 3 croy dn-uyamncroymty)proiie3carboxylic acid; trans, trans-2-(34PD uropyhenyl)-4(,3-benzodioxol-5-y.1 propyI-Nnpentanesufonyamino)ethyIjpyrroidine-3-carboxylic acid; ~.20 trans, trans-2-(3,-Dfluoropmehenyph)4(1 1*[di(n-utyl-incarbonletylamnehpyrrolidine-3 carboxyicacid; trans, trans-2-(3-fluoropmehenyph)4(1 (,3-benzodioxol-5-y

[-N

1 2 -(N-propyl-N-3-hxooanesulfonyl no)ethyl)oldn-3 yrolin-3carboxylic acid; trans, trans- 2 -(3-Fluoro-4-methoxyphenyl)-4(1 1 -(2-(N-isobutyl-N-(3chloropropanesulfonyl)amino)ethyl)pyrrolidine-3carboxylic acid; trans, trans-2-(3-Fluo ro-4-methoxyp heny) 4-(1 ,3-benzod ioxol-5-y I)- 1 -[2-(N-propyl-N-(4methylbutanesulfonyl)amino)ethyl]pyrrolidine-3carboxylic acid; trans, trans-2-(4-Methoxy-3-fI uoropheny) 4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -[2-(N-propyl-N-(npentanesulfonyl)amino)ethyl]pyrrolidine-3carboxylic acid; trans, trans-2-(3-Fluoro-4.methoxyphenyl)-4(1 1 12 -(N-propy-N-(22333pentafluoropropoxyethanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; :10 trans, trans-2-(1 4 -Be nzodioxan-6-yI1)-4-(7- methoxy 1 ,3-benzodi oxolI- 5-yI)-l1-[2-(N-propyl-N-(n- *pentanesulfonyl)amino)ethyl]pyrrolidine-3carboxylic acid; trans, trans-2-(3-Fluoro..4-methoxyphenyl)-4(1 1 2 iso bu t yI- N -(pe nta ne sulIf o n y Iami n o)e t h y1)py rroIidin e -3 15 carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 2 2 methoxyethyl)-N-(3-.chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl 1,3-benzodioxol-5-yI)- 1 -(2-(N-(2-methoxyethyl)-N- .(pentanesulIfonyl)amino)ethyl)pyrro lid ine-3carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -[2-(N-propyl-N-((2,2 2 -trifluoroethoxyethane)sulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 2 2 -methoxyethyI)-N-(butanesulfonylamino)ethyl).

pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl).4.( 1 yI)-1 -[2-(N-propyl-N-(2methylpropanesulfonyl)amino)ethyllpyrrolidine-3.carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl).4-(1 1 2 -(N-isobutyl-N-(butanesulfonylamino))ethyl)pyrrolidine-3carboxylic acid; trans, trans-2-(2-Methylpentyl)4-( ,3-benzodioxol-5-yl)-l1-(N,N-di(n- .butyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(2,2-Dimethylpentyl)y4(1 ,3-benzodioxol-5-yI)-1 di(n-butyl)aminocarbonylmethyl).pyrrolidine-3-carboxylic acid; -31trans, trans 3 -Dioxo-2-y I) ethyl) ,3-benzodioxoI-5y N -d i(nb uty) am in ocarbon y Imeth y) pyrro Iid ine3ca rbxyI acid; trns trn--2(-erhdr- -ya~ty)4 ,3 -ben zodioxo I- 5 -y1) -1 (NNdi(nbuty I)am inocarbony Imet hyI) pyrro Iidine- 3 carboxylic acid; trans, trans2 -(2,2,4Tri meth y 3pe nte ny1) 4 .3-ben zod ioxoI- 5-y1) 1 ,N-di(nbuty)aminocarbony methy-pyrr roiiidincabx.i acid; trans, trans-2-(22-DimethyI2.(1 3-dioxolan-2-y)ethy)4(1 ,3benzodioxol-5-yl).1 N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2.(1 3 Dioxo-2-yI)ethyl).4.(1 ,3-benzodioxol-5y 1 [N-4-heptyl-N(2 methyl-3-fluorophenyl)] amino carbonylmethyl]pyrrolidine-3-carboxylic acid; tran~~~s, t 3 -DioxoI-2-vI'~ethyvI47-methoxy-,3benzodioxol-5-yy.1 -(NN-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-((2Methoxyphenoxy)methy)- 4 1 -~(NN-di(nbuty)aminocarbonymethy)pyrroidine3carboxyic acid; h e hpty I -N f Iu oro3 -m e thy Ip he ny1))a m in oca rbo ny Im et hy 1) pyrrolidine-3-carboxylic acid; carboxylic acid; 1-(N-4-heptyl-N-(4-fluo ro-3methylphenyl))aminocarbonylmethyl)pyrrolidine3carboxylic acid; trans, trans- 2 2 2 -DimethylpentyI)-4-(7-methoxy-1 y1) -1 N-di(n-b uty) amino carbon ylmethy)pyrrol idin e-3 carboxylic acid; trans trans2(22di methnyl)penty3-i)423yd r-e furanf 5 Iy)- 1 N-di(n-butyl)aminocarbonylmethyl)pyrrolidine 3 carboxylic acid; -32me thoxy-1 ,3 -ben zodioxol-5-y1) -1 -(N,N-di(nbutyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2(2Methoxyphenyl)ethyl)4(1 1 -(NN-di(n-buty)aminocarbonymethy)pyrroidine3carboxylic acid; trans, trans-2-(2,2-DimethyI3-(E)..penteny)4(7methoxy- 1,3- -(N,N-di(n-butyI)aminocarbonylmethyl).

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-pyridyl)ethyl)-4(1 ,3-benzodioxol-5-yI)- 1 Ndi(n-butyl)aminocarbonylmethyl)-pyrrolidine.3-carboxylic acid; 3P, 4S)-2- (2-(2-oxopy rrolIid in- 1 -y1) ethyl) ,3-ben zod iox yI)-1 -(N,N-di(n-butyl)aminocarbonyl methyl)-pyrrolidine-3carboxylic acid; i (2S, 3P, 4S)-2-(2-(2-oxo pyrrol id in- 1 -yI) ethyl) ,3-benzodioxol1-5yI)-1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbo nylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; **trans, trans-2 ethoxyph e nyl) -benzod ioxol-5-y 1) -1 b utylI- N -d imet h y Iam in o buty1) am in o) carbon y Im et h y I :pyrrolidine-3-carboxylic acid; 2 R,3R,4S)-2-(3-Fluoro-4-methoxyphenyl).4-(1 ,3-benzodioxol-5-yI) 1- 2 -(N-propyl-N-pentanesulfonylamino)ethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yI)-1 butyl-N-(4-dimethylamino) butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpentyl).4-(7-methoxy-1 yI)-l1-(N-4-heptyl-N-(4-fI uoro-3meth ylph e nyl))am in ocarbo nylm ethyl)-py rro lid ine-3-ca rboxyl ic acid; trans, trans-2-(2,2-Dimethylpentyl)4(7-methoxy-1,3-benzodioxol-5y)-l-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; 33trans, trans-2-(2,2-Di met hyIpent -3-eny) 3-benzodioxol-5-y 1) -1 (N-4-h eptyl-N-(4-flIuoro-3-methylIph enyl)) am inocarbony Ime thy I) pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpent-3.enyl)-4(1 ,3-benzodioxol-5-yI)-1 ((N-butyl-.N-(4-dimethylamino)butyl)amnocarbonylmethyl).

pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpent-3..enyI)-4.(7-methoxy-1,3benzodioxol-5-y)-1 -(N,N-di(n-butyl)aminocarbonylmethyl).

pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpent-3.e nyl)-4.(7.methoxy- 1,3- 1 -(N-4-heptyl-N-(4-fluo ro-3rnethylphenyl))aminocarbonylmethyl)-pyrroidine3carboxylic trans, trans-2-(2,2- Dimethylpe nt3-enyl)-4.(7-methoxyl 1,3be nzodioxol-5-yi)-1 -((N-butyt-N-(4d imethy la min o)butyl)ami n ocarbo nyl methylI)-pyrrol id ine-3- :carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent3enyl).4-(1 1 -(N-4-heptyl-N-(4-f Iuo ro-3methylphenyl))aminocarbonylmethyl)pyrrolidine3carboxylic acid; trans, trans-2-(2,2,4-Tri methy pent3-enyl)-4-(1 ,3-be nzod ioxoI- 5-y1) *1 utyl-N-(4-d imethytIa min o) butyl)ami noca rbonylImeth yl) pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent3enyl)..4-(7-methoxy-1,3benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent3enyl).4-(7-methoxy-1,3benzodioxol-5-yI)-l1-(N-4-heptyl-N-(4-fluoro-3meth ylph enyl))ami nocarbo nyl meth yl)-py rro lid ine3ca rboxyl ic acid; trans, trans-2-(2,2,4-Trimethylpent3enyl)4-(7-methoxy-1,3- -((N-butyl-N-(4dimethylamino)butyl)ami nocarbonylmethyl)-pyrrolidine-3carboxylic acid; -34trans, trans-2-(2-(1 1 3-DioxolI-2-yl)ethy1) ben zodioxolI-5-yI) 1 [(N-buty I N(4di methy a min obuty)amni no) carbon ylImethyl1] pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 3 -Dioxo-2.yl)ethyl).4-(7..methoxy-1 3ben zodioxol-5-yI)- 1 N-butylI-N dimethylaminobutyl)ami no)carbonylmethyl]-pyrrolidine-3carboxylic acid; benzodioxol-5-yl)-l1-(N-4-he ptyl-N-(4-fluoro-3-.

methyl ph enyl) )a mlnoca rbo nyl methyl)-p yrro lid in e-3-ca rboxyl ic acid; *trans, trans-2- (2,2-D imethy 1 3-d ioxola n-2-yl) eth yl)-4-(1 3- *.ben zodioxol-5-yl). 1 -butyl-N-(4dimethylaminobutyl)ami no)carbonylmethyl]-pyrrolidifle.3 carboxylic acid; trans, trans-2-(2,2-Dimethyl12-(1 ,3-Dioxol-2-yl)ethyl)-4-(7methoxy-1 3 -benzodioxol-5-yl)-l-(N4heptylN(4-fluoro- 3 methylphenyl))aminocarbonylmethyl)pyrroldne3carbolic acid; C20 trans, trans-2- (2,2-D imeth y I 2(1 ,3-d ioxol an-2-ylI)ethyl1).4-(7mnetho xy 3 -b e nz od io xo-5 y -1 -b ut y I-N d n de t h y Iam in ob uty1) a m ino)ca rbo ny m eth y py rro I id in e 3 carboxylic acid; trans, trans-2(2(2Methoxyphenyl)ethyl) 4 :25 1-(N-4-heptyl-N-(4-fluoro-3methylphenyl))amino)carbonylmethyllpyrroldine-3carboxylic acid; trans, trans-2 (2(2Meth oxy pheny )ethyl) 4 ,3-ben zod ioxol1-5-y1) 1 -[(N-butyl-N-(4-dimeth ylaminobutyl)amino)carbonylmethyl].

pyrrolidine-3-carboxylic acid; trans, trans2(2(2Methoxyphen-tyl)t4(7methy,3benzodioxol-5-yl).1 (N,N-di(n-butyl)aminocarbonylmethyl).

pyrrolidine-3-carboxylic acid; trans, trans2(2(2Methoxyphenyl)ethyl)4(7-methoxy- 1 3benzodioxo5yly1l(N-4.heptyIN-(4-fluor- 3 methylphenyl))amino)carbonylmethyl-pyrroldine-3carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethy)4(7-methcxy 1 ,3benzodioxol-5-yl)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl..pyrrolidine-3 carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl)-4(1 1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))amino)carbonylmethyl]-pyrrolidine3carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl)-4(1 1 -[(N-butyl-N-(4-dimethyiaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; .trans, trans-2-((2-Methoxyphenoxy)methyl)4(7-methoxy-1,3benzodioxol-5-yi)-1- (NN-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)methy)4-(7-methoxy-1 3- *...benzodioxol-5-yl)-1 -(N-4-heptyl-N-(4-fluoro-3- *methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; :20 trans, trans-2-(2-(2-Methoxyphenoxy)methyl)4(7-methoxy-1,3benzodioxol-5-yI)-1 -[(N-butyl-N-(4d im eth yIa m ino b uty1) ammin o) ca rbo nyl meth y 11pyrroIld ine -3carboxylic acid; trans, trans-2-(2-(2-Oxo 1 ,2-dihydro pyridin-1 -yl)-ethyl)-4-(1 .3benzodioxol-5-yl)-1 ,N-di (n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; :trans, trans-2-(2-(2-Oxo py rid in- 1 -yl)-ethyl)-4-(1 yl)-l1-[(N-4-h eptyl-N-(4-fluoro-3methyl phen yl )amino) carbon yl methyl] -p yrro lid in e-3-ca rbox yli c acid; trans, trans-2-(2-(2-Oxopyridin-1 -yl)-ethyl)-4-(1 yl)-1 -[(N-butyl-N-(4-dj methylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2- (2-Oxo py ridin- 1 -y I)-ethyl)-4-(7-meth oxy-1, ,3- ,N-di(N-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyridin-1 -yI)-ethyl)-4-(7-methoxy-1 .3benzodioxol-5-yl)-1 -[(N-4-heptyl-N-(4-fluoro-3- -36methylIph enyl) am ino) ca rbony Imeth yl]..pyrro id ine3carboxy I i acid; trans, trans-2-(2-(2-Oxopyridin-1 -y I) -ethyI) -4-(7-methoxy1 ,3benzodioxol-5-yI)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine- 3 carboxylic acid; trans, trans-2-(2(-2-Oxo pipe ridin -1 -yI) -eth yl)-4-(1 ,3-benzodioxo yI)-1 -(NN-di(N-butyl)aminocarbonylmethyl)-pyrrolidine- 3 carboxylic acid; trans, trans-2-(2-(2-Oxopipe rid in -1 -yI) -eth yl)-4- (1 ,3-benzodioxo yI)-l1-U(N-4-heptyl-N-(4-fluoro-3 m eth y Iphe nyl1) a m ino) ca rbon y Im e t h y Ipyrro i d in e 3ca rbox y Iic acid; trans, trans-2-(2-(2-Oxopiperidin.1 -yI)-ethyl)-4-(7-methoxy-1 ,3pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin-1 -yI)-ethyi)-4-(7-methoxy-1 ,3- ~~benzodioxol-5-y)- -di(-btylN-minloronymehy) mehlhnlaiocroymty]pyrrolidine-3-carboxyuiiaid trans, trans-2-(2-(2-Oxopiperidin-.1 -yI)-ethyl)-4-(7-methoxy-1 ,3- 2 benzodioxol-5-yI)-1 -[(N-4-htyl-N-(4-fur.

~dmethylahenouyl)amino)carbonylmethyl]-pyrrolidine-3-bxyi caid;icacd tralns, trans-2-(2-(2-Oxopyrperidin.1 -yI)-ethvl)-4-(1,-mehodiv-1 2 rns tas2(-2Ooyrldn1ylehl4(,3benzodioxol-5-yI--(btI( y I)-tyI [Nbt-Nobutyloxyamin o) carbonmetyl mtp -yrroI idi e 3 carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(1 ~yI)-1 -[(N-butyl-N-(3-hdroxypry lam amibny)arinonylmethylmehy] pyrrolidine-3-carboxylic acid; -37trans, trans-2-(2-(2-Oxopyrro lid in -1 -y I) ethy1) ben zodioxo1 yI1) -1 -[(N-butylI-N-(4trim ethylammoniobutyI) am ino)carbonylI methyl]-pyrro Iidine-.3carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(7-methoxyl ,3benzodioxol-5-yI)-l1-(N.N-di(N-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyt)-4-(7-methoxyl ,3- -[(N-butyl-N-(3hydroxypropyl)amino)carbonylmethyllpyrrolidine-3carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(7-methoxyl ,3- :..ben zodioxol-5-yI) -1 -[(N-4-heptyl- N-(4-f Iuo ro-3 methylphenyl)amino)carbonylmethyl-pyrroidine3carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(7-methoxy-j ,3benzodioxol-5-yI)-l1-[(N-butyl-N- (propoxy)amino)carbonylmethyl]lpyrrolidine-3-carboxylic acid; *:trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(7-methoxy-1,3benzodioxol-5-yl)-l -[(N-butyIN-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine- 3 carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -[(N-butyl-N-(4trimethylammoniobutyl)amno)carbonylmethyllpyrrolidine-3 carboxylic acid; trans, trans-2-(2-(2-Oxopyrroljdin-1 -yI)ethyl)-4-(2,3-dihydrobenzofuran-5-yI)-l1-(N, N-di(N-butyl)aminocarbonylmethyl).

pyrrolidine-3-carboxyljc acid; trans, trans-2-(2-(2Oxopyrroidin1 yl)ethyl)4(2,3dihydrobenzofuran-5-yi)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(2,3-dihydrobenzofuran-5-y)11-(N-butyIN-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrdlidine-3 carboxylic acid; -38trans, trans-2-(2(33-Di methy 12-oxopyrro lid in- -yI) ethyl) ,3 be nzodioxo I-5-yI).1 -(NN-di(N-butyI)aminocarbony[ me thy I) yrrolidine-3-carboxylic acid; trans, trans-2-(2(3,3DimethyI2-oxopyrrolidin-1 -yI)ethyl)-4-(1 ,3benzodioxol-Sy). 1-[(N-4-he ptyl-N-(4-fluoro-3..

methylPhenyl)amino)carbonylmethylpyrrolidine 3 aboy acid; trans, trans2(2(33-Dimethy-2oxopyrroidn- -YI)ethyl)-4-(1 ,3- -f(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]pyrrlidie 3 carboxylic acid; trans, trans-2(2-(4,4-Dimethy-2-oxopyrrolidin- -yI)ethyl)-4-(1 ,3benAodioxoJylf.. 1 (NlN-di(N-butyI)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2(2-(4,4Dimethy-2-oxopyrrolidin1 -y)ethyl)-4-(1 .3- 1-[(N-4-heptyl-N-(4-fluoro-3.

methylphenyl)amino)carbonylmethyl]pyrroli idin-cabxli *acid trans, trans-2-(2-(4,4-D imethy 12-oxopyrro idi -yl) ethyl) (1 ,3- *20 benzodioxol-5-yl)-l -[(N-butyI-N-(4dimethylaminobutyl)amino)carbonylmethyl]pyrroidie 3 carboxylic acid; *trans, trans2(2(prpautlesuthry)hyj) 4 1 3 boioxl 5 1 y)acid; -[(N-4-heptyl-N-(4-fluoro-3methy lphe nyl)a m ino)carbo nylmethyllpyrro lid ine 3 carbol i acid; trans, trans2(2-(1 -propanesultamyI)ethyl)-4(1 1 d(N-butyI-N-(3hydroxypropy)amino)carbonylmethyl] pyrrolidine-3-carboxylic acid; trans, trans2(2-(1 -propanesultamyI)ethyl).4.(1 1 -[(N-butyI-N(propoxy)amino)carbonymethytpyrroidie 3 carboxylic acid; -39trans, trans-2-(2-(1 -pro panes ulta myI) ethy1) ben zodioxol-5-y I) 1 -[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonymethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-l -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -propanesultamyI)ethyI)-4-(7-methoxy-1 ,3- 1 -[(N-4-heptyl-N-(4-f luoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2- (1 -propanesulItamyl)ethyl)-4-(7-methoxy-1, ,3benzodioxol-5-yI)-1 N-butyl-N-(4- .:..*dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3carboxylic acid; *15 trans, trans-2-(2-(1 -pro panesultamyl)ethyl)-4-(2,3-di hydrobenzofuran-5-y)-1 ,N-di(n-butyl)aminocarbonylmethyl)ranspyrrolidine- 3 carboxylic acid; trntrans-2-(2-(1 -propan esu Itamy1) ethyl)-4-(2,3-d ihyd rob en zo f uran -5 -yI1) -1 -4 -h ept ylI- N-(4 -f I u oro -3 m et h yIp he ny 1) am ino) ca rbon y Imet h y Ip yrroIi d in e-3-carbo xy Ii c acid; trans, trans-2-(2-(1 -propan esulItamy1) ethylI)-4-(2 .3-di hyd robenzofuran-5-yI)-1 -[(N-butyl-N-(4- 25 dimethylaminobutyl)amino)carbonylmethyll-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxol-5-yI)- 1 4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyllpyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxol-5-yl)- 1 butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxol-5-yI)-l butyl-N-(propoxy)amino)carbo nylmeth yI]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1 butyl-N- (4-dimethylaminobutyl) amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -pyrazolIyI) ethy1) met hoxy-1,3 -ben zodioxo I 1 N-dibutylaminocarbonylmethyl).pyrrolidine- 3 carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(7-methoxy-1,3-benzodioxol- 5 -yI)-l -[(N-4-heptyl-N-(4-fluoro-3 m ethy lphen yl) amino) carbo nyl methyl ]-py rro lid ine-3carboxyl i acid; trans, trans-2-(2-(l -pyrazoiyl)ethyl)-4-(7-methoxy-1,3-benzodioxol- 5-yI)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]pyrrdlidine- 3 carboxylic acid; *trans, trans-2-(2-(l -pyrazoly) ethyl) -4(2,3d ihyd robenzof 1 N-dib utyamninocarbony methyl) py rro lid in e3carbox ylic acid; is 1 trans, trans-2-(2-(1 -pyrazo ly)ethy) -4(2,3d ihydrobenzof uran 1 -f(N-4-heptyl-N-(4-fluoro-3meth ylphe nyl)a min o)carbonyl methyll-pyrrouIidin e3carboxyl ic acid; atrans, trans-2-(2-( 1 -pyrazo lyl)ethyl)-4-(2 ,3-d i hyd ro-benzof ura n- 5-y1) 1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-oxazolyl)ethyI)-4(1 ,3-benzodioxol-5-yI)-1

,N-

di(n-butyl)aminocarbonylmethyl)pyrrolidine-3carboxylic acid; trans, trans-2-(2-(Oxazo 2-yl)ethyl) 4-(1 ,3-benzod ioxol-5-yI)- 1 .25 4 -heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Oxazof-2yI)ethyl)-4(1 ,3-benzodioxol-5-yl)-l butyI-N-(3-hydroxypropyl)amino)carbonylmethylI-pyrrolidine-3 carboxylic acid; trans, trans-2- (2-(Oxazo 2-yI)ethyl)-4-(1 ,3-be nzod ioxol-5-yI) -1 butyl-N-(propoxy)amino)carbonylmethyllpyrrolidine3carboxylic acid; trans, trans-2-(2-(Oxazo 2-yI)ethyl)-4-(1 ,3-be nzod ioxol-5-yt) -1 butyl-N-(4-di methylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; -41trans, trans-2-(2-(Oxazol-2-y I) ethy1)-4(7-..met hoxy1 ,3 -ben zodioxolI- 5-y1) -1 N-di(n-buty I) am inocarbonyl met hyl)-pyrro Iidine-3 carboxylic acid; trans, trans- 2 -(2-(Oxazol-2-yI)ethyl)-4(7-methoxy-1 ,3-benzodioxol- 5-yI)-l1-[(N-4-heptyl-N-(4-fI uoro-3methylphenyI)amino)carbonylmethyl].pyrroidine-.3-carboxylic acid; trans, trans- 2 2 -(OxazoI-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol- 5-yI)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyll-pyrrolidine-3 carboxylic acid; *trans, trans-2- Methyl ox azo 1-2-y) ethyl)4-(1 ,3-be nzod yI1) -1 N-d i(n -b uty1) amni n oc arbon y Ime t hy1) -py rro Ii d in e -3 ***.carboxylic acid; trans, trans-2-(2-(5-Methyloxazol-2-yl)ethyl).4-(1 yI)-1 -[(N-4-heptyl-N-(4-fluoro-3- :methylphenyl)amino)carbonylmethyl]-pyrrolidine3carboxylic acid; trans, trans-2- (5-Methyloxazo 1-2-y) ethyl)-4-(1 yI)-l -1(N-butyl-N-(4-dimethylaminobutyl)am ino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrrolidin-1 -yI)ethyl)-4-(1 ,3-benzodioxol- N-di (n-butyl)amni nocarbo nyl met hyl)-py rrolid ine-3- :carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrrolidinl yI)ethyl) ,3-benzod ioxo I- 5-yI)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3.carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrrolidin.1 -yI)ethyl)-4-(1 ,3-benzodioxol- 5 -yI)-l1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl].

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrrolidin- -yI) ethyl) ,3-benzodioxo I- 1 -[(N-butyl-N-(propoxy)amino)carbon ylmeth yI]-pyrrolidine- 3-carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrrolidin- 1 -yI)ethyl)-4-(1 ,3-benzodioxol- 5-yI)-1 -[(N-butyl-N-(4-dimethylaminobutyl) amino)carbonylmethyl-pyrrolidine-3carboxylic acid; -42trans, trans-2-(2-(2,5-Dioxopyrro lid in-1 -y I) ethy1) met hoxy-1 ,3ben zodioxol-5-y1) -1 N-di(n-butyI) amino carbon ylmethy I).

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrrolidin-1 -yl)ethyl)-4-(7-methoxyi1 ,3benzodioxol-5-yI)-l epty.N-(4-fluoro-3methylphenyl)amino)carbonyl methyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Pyridin-2-yI)ethyl).4-(1 .3-benzodioxol-5-yI)-1 4 -he pty I-N-(4-f Iuo ro-3-meth ylphe n yg)amino)carbo nylme thyI]- **10 pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Pyridi n-2-y1) ethy 1)4-(1 .3-benzodioxol-5-yI1)- 1 b u btyI- N 3 -h y dro xy prop y1) a m ino) carb on y Imet h y I] pyrro Ii d in e 3 carboxylic acid; trans, trans-2-(2-(Pyridin-2-yI)ethyl).4-(1 ,3-benzodioxol-5-yl)-1 butyl-N-(propoxy)amino)carbonylmethyl].pyrrolidine3carboxylic acid; trans, trans-2-(2-(Pyridin-2-yl)ethyl).4-(1 ,3-benzodioxol-5-yI)-1 butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl].

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Pyridin-2-yI)ethyl)4(7-methoxy-1,3-benzodioxol- 5-yi)-1 N-di(n-butyl)ami nocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(Pyridin-2-yI)eth yl).4(7-methoxy-1 ,3-benzodioxol- :5-yI)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethylpyrrolidine3carboxylic acid; trans, trans-2-(2-(Pyridin-2-y)ethy)4(7-methoxy-1,3-benzodioxol- -yI)-l1-[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl].pyrrolidine-3.

carboxylic acid; trans, trans-2-(2-(Pyri midin-2-yI) ethyl) ,3-benzodioxol1-5-yI) -1 (N ,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine..3.carboxylic acid; trans, trans-2- (2-(Pyri mid in-2.yI) ethyl) (1 ben zod ioxol1-5-YI1)- 1 4 -hepty-N-(4-fluoro3-methylphenyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; -43trans, trans-2-(2-(Pyrimidin-2-yI) ethy1) 1,3- ben zodioxol-5-y1) -1 utyl-N- (4d imeth yam in obutyl) am ino) carbon yl meth y pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-benzodioxoI-4-yl)ethyl)-4-(1 yl)-l -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(1 ,3-benzodioxol-4-yl)ethyl)-4-( 1,3-benzodioxol- yI)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonyl methyll-pyrrolidine-3-carboxylic acid; and trans, trans-2-(2-(1 ,3-benzodioxol-4-yI)ethyl)-4-(1 yl)-1-[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]- ::*pyrrolidine-3-carboxylic acid; V....(2S,3R,4S)-2-(2,2-Dimethylpentyl)-4.(1 ,3-benzodioxol-5-yI)-1 :15 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3.carboxylic acid; 2 S,3R,4S)-2-(2,2-Dimethylpent(E)-.3-enyl).4.(1 1 -(NN-di(n-butyl)aminocarbonylmethyl)-pyrrolidine.3.carboxylic 0 go acid; too* 2

S,

3 R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl).4(7-methoxy.1 ,3benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)- ,~.pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl).4(1 -(.N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine3carboxylic :acid; (2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4(1 ,3-benzodioxol-5-yl)-1 (NN-di(n-butyl)aminocarbonylmethyl)-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-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-.3-carboxylic acid; -44trans, trans-2-(2,2,-Dimethyl-2.( 1 3-dioxolan-2-yl)ethyl)-4-(1 ,3benzodioxol-5-yI)-1

-(N

1 N-di(n-butyl)aminocarbonylmethyl).

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 .3-Dioxot-2-yI)ethy!)-4-(1 -1 -[[N-4-heptyl-N-(2-methy.-3-fluorophenyl)] aminocarbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 3 -Dioxol-2-yI)ethyl)-4-(7-methoxy-1,3benzodioxol-5-yI).1 N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl)-4(1 *1 -(,.d~-uy~mncroymty)proiie3croyi acid; *trans, trans-2-(2-(2-OxopyrrolIidin 1 -y1) ethyl) (1 ,3-be yi)-1 -(NN-di(n-butyl)a minocarbonylmethyl)-pyrrolidine-3- :15 carboxylic: acid; trans, trans-2-(2-(1 ,3-Dioxol-2-yl)ethyl)-4-(7-methoxyl ,3benzodioxol-5-yI)-l1-( N-4-h eptyl-N-(4-fI uoro-3methylphenyl))aminocarbony Imethyl)-pyrrolidine-3-carboxyl ic acid; trans, trafls-2-(2,2-DimethylpentyI).4-(7.methoxy-1 yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine.3.

carboxylic acid; **:trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yl)ethyl)-4-(7methoxy-1 .3-benzodioxol-5-y)-1 -(N,N-di(nbutyl)aminocarbonylmethyl).pyrrolidine-3-carboxylic acid; transtrans-2-(2-(2-Methoxyphenyl)-ethyI)-4.(1 1 -(N,N-di(n-butyl)ami nocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans- 2 -(2,2-Dimethyl-3-(Ey.pentenyl)4(7-methoxyl ,3benzodioxol-5-yI)-l -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-pyridy1) ethyl) ,3-be nzodioxolI-5-yI) -1 di(n-butyl)aminocarbonyimethyl)ypyrrolidine3carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yI)ethyl)-4-(1 y)-l -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3 carboxylic acid; (2S, 3R, 4S)-2-(2,2 Dimethylpentyl)-4-(7-methoxy-1 yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin- 1-yl)ethyl)-4-(1 yl)-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-yI)- 1 ,Nd i(n-butyl) ami nocarbo nyl met hy1) -pyrrol idi ne-3-ca rboxy lic acid; (213, 3R, 4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ropyl-N-pe nta nesuif on y 1) amino) ethyl]-pyrro lidi ne -3 carboxylic acid; :::.(2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-y)-1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; :15 (2S,3R,4S)-2-(2,2-Dimethylpent-(E)--enyl)-4-(1 1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-.3..carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-1 ,3- Sbe nzo d ioxol1- 5-yI1) -1 N -d i(n -b uty1) amni n oca rbon ylImet hy1) pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl)-4-(1 1 N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3..carboxylic acid; and (2 S, 3R,4S) (2-M eth oxyph en yl) ethyl) ,3-be nzod ioxoI- 5-yl)- 1 25 (N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-.carboxylic acid; or a pharmaceutically acceptable salt thereof.

Methods for preparing the compounds of the invention are shown in Schemes l-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 -46- -C0 2 H. A (-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 s 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 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 15 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 Rs-X (R 3 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 R4-C(O)- or R 6 -S(0) 2 forms an activated ester including esters or 20 anhydrides 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, CI, 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 N-derivatized 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 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 IQ in an inert solvent such as THF or dimethoxyethane to give the alkylated adduct 11. The anion of compound J1. is formed using a base such as n-butyllithium and then reacted with R 1

-CH

2 wherein X' is a -47leaving 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 1.3. Reaction of ketone 13 with benzyl amine and formaldehyde gives the keto piperidine compound 1 4.

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 i 18 is further elaborated by the procedures described in Scheme I for *15 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 -C0 2 H. P-Keto ester 20 (wherein E is loweralkyl or a carboxy protecting group) is reacted with an a-haloester 21 (where J is lower 20 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 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 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 Z, prepared in Scheme I, is homologated by the Arndt-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 CI). Compound 52 is treated with diazomethane to -48give the diazo ketone 5. Rearrangement of compound 5 (for example, using water or an alcohol and silver oxide or silver benzoate and triethylamine, or heating or photolysis in the presence of water or an alcohol) affords the acetic acid compound 54 or an ester which may be s hydrolyzed. Compounds where m is from 2 to 6 can be obtained by repetition of the above described process.

A preferred embodiment is shown in Schemes V and 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 3 as a mixture of cis-cis, trans,trans and cis,trans isomers. Chromatography separates s15 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 described in Scheme IV is reacted with N-propyl bromoacetamide in 20 acetonitrile in the presence of ethyldiisopropylamine to give the alkylated pyrrolidine compound 32, 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 35 is reacted with lithio dithiane 36 to give the alkylated compound 37. Treatment of compound 37 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 19. 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 41. Sodium borohydride reduction of the double bond gives the piperidinyl nitrile 42. Hydrochloric acid hydrolysis in the presence of ethanol gives ethyl ester 4A. The N-benzyl protecting group is -49removed by catalytic hydrogenation to give the free piperidine compound 44. Compound 44 is further elaborated by the procedures described in Scheme V for compound 31 resulting in the formation of the N-derivatized carboxylic acid s A preferred embodiment of the process shown in Scheme III is shown in Scheme VIII. 4-Methoxybenzoylacetate 46 (wherein E is loweralkyl or a carboxy protecting group) is reacted with an benzodioxolyl a-bromoacetate Z4 (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 The double bond is reduced by .catalytic hydrogenation using a palladium on carbon catalyst to give pyrrolidone 5. Epimerization with sodium ethoxide in ethanol to give the desired trans,trans configuration is followed by sodium hydroxide 15 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 can 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 25 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, 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 59 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 60. Alternatively reacting the amidoxime 59 with thionyl chloride in an inert solvent (for example, chloroform, dichloromethane, dixoane and THF and the like) affords the oxathiadiazole 6 1.

Scheme X illustrates the preparation of compounds in which R 3 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 then treatment with anhydrous HCI in dioxane gives the a-chloroketone o 63. Pyrrolidine ester 5 where E is lower alkyl or a carboxy protecting group, prepared in Scheme I, is alkylated with the a-chloroketone U 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 .o Scheme XI illustrates the preparation of "reverse amides and sulfonamides". The carboxy protected pyrrolidine 5, prepared in Scheme S, is reacted with a difunctionalized compound

X-R

8 -X where

R

8 is 20 alkylene and X is a leaving group (for example a halide where Br is preferred) to give N-alkylated compound 6. Treatment of 66 with an amine (R 2 0

NH

2 affords secondary amine 67. This amine (67) can be S. reacted with an activated acyl compound (for example, R4-C(O)-CI) and then carboxy deprotected (for example, hydrolysis of an ester or S. 25 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 69.

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. 2 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 -51is reacted with acrylate Z4 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 Nacetamido derivatives directly by reacting 73and 4 with the s appropriate bromoacetamide (for example, dibutyl bromoacetamide) in the presence of tetrabutylammonium iodide and cesium fluoride to give compound 76.

Scheme XIII illustrates a method for producing an enantiomerically pure pyrrolidine 80, 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 Boc20) and then the ester is hydrolyzed (for example, using sodium or lithium hydroxide in ethanol and water) to give t-butyl carbamoyl pyrrolidine carboxylic acid 78. The carboxylic acid is converted to its (+)-cinchonine salt, which can be recrystallized (for example from ethyl acetate and hexane or chloroform and hexane) to afford the diastereomerically pure salt. This diastereomerically pure salt can be neutralized (for example, with sodium carbonate or citric acid) to afford enantiomerically pure 20 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 80. 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, 25 by treatment with the dibutyl amide of bromoacetamide in acetonitrile in the presence of diisopropylethylamine) to give optically active compound 8 1. 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 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 R 5 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 -52- 8J, 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 (88) is reacted with beta-keto ester 89 in the presence of a base such as sodium ethoxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as THF, toluene, DMF, acetonitrile, ethyl acetate, isopropyl acetate or methylene chloride and the like at a 1o temperature of from about 0° C to about 1000 C for a period of time from about 15 minutes to ovemight to give compound 90. 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 U in an inert solvent such as THF, ethyl acetate, toluene, ethanol, isopropanol, DMF or acetonitrile and the like, using a hydrogenation catalyst such as Raney nickel, palladium on carbon, a platinum catalyst, such as platinum oxide, platinum on carbon or platinum on alumina and the like, or a rhodium catalyst, such as rhodium 20 on carbon or rhodium on alumina and the like, and the like affords intermediate nitrone 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, 25 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 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 active (+)-isomer of compound 9 is obtained by treatment of a mixture of the (+)-isomer and the (-)-isomer of 9 with S-(+)-mandelic acid, D-tartaric acid or -53- 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 (-)-isomer of 3 in solution. Alternatively, the substantially pure s at least 95% of the desired isomer) optically active (-)-isomer of compound 9 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 3 in solution.

Compound 3 (racemic or optically active) is reacted with X-R 3 S: (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 15 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 situ to the carboxylic acid (95) using hydrolysis conditions such as a base such as sodium hydroxide or lithium hydroxide or potassium hydroxide 20 and the like in a solvent such as ethanol-water or THF-ethanol and the like.

A more detailed description of the preparation of some specific analogs is provided in Schemes XVI-XXI. Aliphatic p-ketoesters S..o (Scheme XVI) may be prepared by copper-catalyzed addition of a 25 Grignard reagent (for example, propylmagnesium bromide) to an unsaturated ester, for example, ethyl 3,3-dimethylacrylate. The resultant ester is hydrolyzed, for example with sodium hydroxide in aqueous alcohol, and is homologated in stepwise fashion to the corresponding P-ketoester, for example by activation using carbonyldiimidazole and condensation with magnesio-ethoxymalonate.

Alternatively, olefinic P-ketoesters may be prepared by Claisen rearangement of the corresponding allylic alcohols; hydrolysis and homologation as described above produce the desired p-ketoester.

N-alkyl,O-alkyl bromohydroxamates are prepared according to Scheme XVII. N-Boc-O-allyl hydroxylamine is alkylated with and alkyl halide, for example using sodium hydride as base; the double bond is selectively reduced, for example using hydrogen and a palladium -54catalyst. After removal of the Boc protecting group, for example with TFA, the resultant amine is acylated, for example using bromoacetyl bromide.

The 3-ketoesters described in Scheme XVI may be converted to pyrrolidine derivatives as described in Scheme XVIII. Michael addition onto a nitrostyrene derivative can be catalyzed with base, for example DBU or potassium t-butoxide; the resultant adduct is hydrogenated, for example using Raney Nickel as catalyst, to give an imine, which is reduced further, for example using sodium cyanoborohydride under controlled pH. A mixture of isomers are generated, in which the transtrans is generally preferred.

Scheme XIX describes several strategies for resolving the racemic So pyrrolidines described above. Treatment with a chiral acid, for example (S)-(+)-mandelic acid, may provide a crystalline derivative, which can 15 be further enriched through recrystallization. The salt may be washed o with base to extract the resolving agent and return the optically active pyrrolidine product. Alternatively, the amino ester can be N-protected (for example with Boc-anhydride) and hydrolyzed (for example with sodium hydroxide) to give the corresponding N-protected amino acid.

20 Activation of the acid, for example as the pentafluorophenyl ester, followed by coupling with a chiral nonracemic oxazolidinone anion, provides the corresponding acyloxazolidinone diastereomers, which may be separated chromatographically. Alcoholysis of one acyloxazolidinone diastereomer, followed by cleavage of the N-protecting group, returns 25 an optically enriched amino ester. A similar transformation may be accomplished through coupling of the protected amino acid with a chiral nonracemic amino alcohol. After chromatographic separation of the resultant diastereomers, the amide is cleaved and the protecting group is removed to provide optically enriched product.

Optically active amino esters prepared as described above may be alkylated (Scheme XX) with a variety of electrophiles, for example dibutyl bromoacetamide, N-butyl,N-alkoxy bromoacetamide, N-(4heptyl)-N-(3-methyl-4-fluorophenyl) bromoacetamide, or N-(Khydroxyalkyl)-N-alkyl haloacetamide. Hydrolysis of the resultant ester, for example using sodium hydroxide in aqueous alcohol, provides the product.

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

-56- Scheme I

__,CO

2

E

R2 N 02 N0 2 a.

H

C0 2

E

[H)

C0 2

E

Mixture of Cis-Cis Trans-Tranvs Cis-Trans

R

3 0 C0 2

E

Mixture of Trans-Trans Cis-Trans

H

2 01

R

3 80 2

H

Trans-Trans

R

3 C0 2

E

Cis-Trans -57- Scheme II

R

2 9 R2 S 11 4 13

NC

R

1 14

R,

ISOMER

22 y CN

R,

R3,Nq R C0 2

H

19 19 -58- Scheme III Halo 0i C0 2

E

21 Halo =Cl. Br, or I C0 2

E

2

H

Trans-Trans -59- Scheme IV

R

3 C0 2

H

7 N R3

R

2 CJ. R 1 0 L 52

CH

2

N

2 20 3 SC0 2

H

R

3 o J CHN2 53 Scheme V

CH

3 0~C 0~

O

EtO 2 C DL

DB

0 COQEt C H 3 0 0 H2I 4* C.

C

C.

C

C. C C C C C

C.

C C

C.

C C. C C 0*

OCH

3 NaCNBH 3 b /C4 3 COQEt COQEt Mixture of 29 Cis-Cis Trans-Trans Crmatographic separation Cis-Trans Cis-Cis Mixture of Trans-Trans and Cis-Trans 31 -61- Scheme VI

*H

diD' 00H 3 COQEt Qs-Trans and 31 .BrCR 2 C0NHC3H 7 .00 H 3 0S 4*SS S. S I

S.

00

'OS.

S.

S

S. S 1*

S.

S. S

S.

55

S

\/CH

3 Trans-Trans 2N E COOEt Trans-Trans and Cis-Trans NaOH .H 2 0, EtOH 0 N H C 3

H

7 0 NI NC11H 7 00H3 COQEt Cis-Trans S 55 S. 5 SSS S S. 55

S.

Trans-Trans -62- Scheme ViI 0 -S K:OKQU Li S o e

ISOMER

OMe -63- Scheme Vii cont.

0

I>

O NI 0N

CN

ollN OMe -OMe 00 0 HN-i" 0 OMe -64- Scheme VIII C H **.Br

OE

0 0 0 r- 0 0 C N 0 O CH 3

CH

3 Tran-Trans Scheme IX /R 3

(CH

2

)M

I

NI N H

N=N

R

3 CO NH R3

R

2 (CHi 2 )m

(CH

2 )m HN I

R

3 (Cli 2

H

2 N INOH

(CH

2

)M

HN

N

I

s -66- Scheme X

R

4 )rOH 0 R4-1 cl 0 R4 )r N C0 2

E

0 -67- Scheme X1

H

R2 R, C0 2

E

0 C0 2

H

Re-X C0 2

E

R

8

-NHR

20

R

2 iR C0 2

E

67 0 %R 6 "o C0 2

H

1-68- Scheme X11

R

3 No+.

0H 2

CO

2 Et R3 C02Et Me 3 Si N 00H 3 7~3

OCH

3 O)D% C 2 Et 74

OCH

3

'CO

2 Et -69- Scheme XIII 1. Boc 2

O

2. NaOH. EtOH

H

2 0

OCH

3 BocN -C0 2

H

W± ZZ 1. (+)-Cinchonine 2. recrystallize frorri EtOAc/hexane 3. Na 2

CO

3

HOL

HCI

EtH

OCH

3 BocN CO2 0 O-j

~Q

Bu 2 NC(0)CH 2 Br EtNiPr 2

CH

3

CN

00 N+ fu 0- Scheme XIV Rss PhAN OMe MeSi

H

2 Pd(OH) 2

/C

R3, Nq

CO

2 Rs 6 TFA, CH 2

CI

2

HN

C0 2

R

56

R

2 0

R

56 83 Rss Ph" NQ C0 2

R

5 6

R

2

R

3 Br

BU

4 NI or Nal

CH

3

,CN

R

3 Q 02 NaOH or LiOH EtOH, H 2 0 -71- Scheme XV R2 NO 2 0 0

E'

0

N

C0 2

E

N

C0 2

E

0 2 N 0 C0 2

E

R

2

RI

C0 2

E

92 R3

N

C0 2

H

C0 2

E

93 C0 2

E

94 -72- SCHEME XVI COOEt nPrMgBr NaOH cat CuCI HOOC CDI 0K OEt -q 0 EtOOC

OH

-I

OEt/ OEt OEt NaOH H4-. heat

HOOC

CDI Oj'" OEt 0 EtOOC SCHEME XVII 0 NaH t- TFA BrCH 2 COBr 0I BocHN' BocN- -Br2 jO R-X Pd-C SCHEME XVIII 0 EtOOC 0 2 N ~DBU H 2 NaBH 3 CN HN -iO~ S0 or cat. KOtBu Ra-Ni

R

R 0 -73- SCHEME XIX

R

HNC -uCOQEt 0 0- (,acemnic) mandelic

HN

acid recrystallization neutralization -uCOOEt I, 0 (single enantiomer) .9 9 .9 *9 *9 9 9* 9.9.

9 .9 *9 9 9 9.

99 *99 9 *9 9 9* HN -*COOEt 0

CH

3 0 0 (racemnic)

-N

HN.CQ(OEt 0 1. EDAC.

2. FS-phenO6

R

1o 2 OK:i0 Me0H HN *IC00Me 2. Na0H 3. separate 2. TFA dia stereomers,

/CH

3 O0 0

NN

1. EDAC.HOOBt 1OHc 2 1. HCI. heat HN .aCoo[t 2. NaOH 3. separate 2. HCI. EIOH diastereomers 0 (racemic) (racmic)(single enantiomer) -74- SCHEME XX

R

HN -eCOOEt 0 'R 0- 0 A2 NaOH 9 .9 9.

9* 9* 9 .9 9 9999 9 9 9 .9 9 9 .9 9 9* 9S

NR

1

R

2 ~~R3-Cry- SCHEME XXI 0 R C)-0HR HN .K OO. 1. M sCI N 1CO 2. LiBr 0 C0E 0 'R 0

(CH

3 2 NH 0R O Na0H

R

*"iCOOH 0 0 Compounds which are useful as intermediates for the preparation of compounds of the invention are:

NH

(cH 2

(CH

2 )m q w

R

wherein n is 0 or 1; .Mmis 0 to 6; 10 i 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,

-ON,

-C(O)NHR1 7 where R 1 7 is loweralkyl, :15 alkylaminocarbonyl, dialkylaminocarbonyl, tetrazotyt, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O)2Rl6 where R16 is toweralkyl, haloalkyl, phenyl or dialkytamino, HO 0 0 -76-

OH

0 0 0 0 H 00 0 0= 0

H

Mt H ,or NS2F and and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hiydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, :10 cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, 1* 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; or a compound of the formula: -77- R 2 N H S (CH 2 )n

(CH

2 )m C w

(IV)

R2 NH S (CH 2 )n (CH 2

R,-

wherein n is 0 or 1; mnis 0to 6 W is

-C(O)

2 -G where G is hydrogen or a carb-oxy protecting group.

-P0 3

H

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

-ON.

10 -C(O)NHR17 where R17 is loweralkyl, alkylaminocarbonyl.

dialkylaminocarbonyl, tetrazolyl, hydroxy, 15 alkoxy, sulfonamido, -C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino.

(in) -S(O) 2 NHC(O)RI6.

HO 0 0 HO 0

OH

SS N -78-

~NH

0 (r 0

H

0*\ H o

NHSO

2

CF

3 Mu and R, 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, dilyaioaroyakn* *yrxaknl aryl, arylalkyl.

alkylsulIf onyl amid oalkyl, heterocyclic, (hete ro cyclic) al kyl 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 (1ll). (IV) and wherein m is zero or 1; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group, and R, and R 2 are as defined above; or the substantially pure or (+)isomer thereof.

-79- 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 RII is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl.

phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4metho xyp henyl, 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-benzodioxotll 1 ,4-benzodioxanyl or dihyd robe nzof uranYl 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, 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 *.25 the substantially pure or (+)isomer thereof.

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

(CH

2

(CH

2

W

(VI1) wherein n is 0 or 1; m is 0 to 6; Rsb is alkylefle Q is a leaving group; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P03H 2 -P(O)(OH)E where E is hydrogen, toweralkyl or arylalkyl,

-CN,

-C(O)NHR17 where R17 is loweralkyl, :10 alkylaminocarbonyl, dialkylaminocarbonyt, tetrazolyl, hydroxy, alkoxy, :is sulfonamido, -C(O)NHS(O)2Rl6 where R 1 6 is loweralkyt, haloalkyt, :phenyl or dialkylamino, (in) -S(O) 2 NHC(O)R16, HO 0

NH

0 HO 0

OH

(p)N 0 0 -81-

N

HA

NC

H o

NHSO

2

CF

3 and R, and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, *cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarboflylalkyl, aminocarbonylalkenyl, alkylaminocarboflylalkenyl, dialkylaminocarbOnylalkenyl. hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl. (N-alkanoyi-N-alkyl)amifloalkyl, 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: RN 'R 5b Q R2N S (CH 2 )n

(H

2 )n

(CH

2 )m (CH C C 26 w Ror W R (VII) (Vill) wherein n is 0 or 1; m is 0 to 6; -82- Rsb is alkytene; Q is a leaving group; 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,

-ON,

-C(O)NHR17 where R 17 is loweralkyl, alkylamninocarbonyl, dialkylaminocarbonYl, tetrazolyl, hydroxy, alkoxy, sutfonamido,

-C(O)NHS(O)

2 Rl6 where R 16 is loweralkyl, hatoalkyl, phenyl or dialkytamino,

-S(O)

2 NHC(O)Ri6, HO 0

NH

0 HO 0

H

OH

0 0

NH

0 -83-

H

IZNHSO

2 CF3 (u a NS2F and R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, *.haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alyaioaroyakl dilyaioaroyakl lyamino carbonylalkyl, alkylaminocarbonylalkyl, :10 dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, r(heterocyclic) alkyl and (Raa)(Rbb)N-Rcc- hri a is aryl orarylalkyl, 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 :20 m is zero or 1; Rab is alkylene;, 0 is a leaving group; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group, and R 1 and R 2 are as defined above; or the substantially pure or (+)isomer thereof.

Particularly preferred intermediates are compounds of formula (VI, (VII) and (Vill) wherein n and m are both 0; Rsb is alkylene; 0 is a leaving group; W is -C0 2 -G wherein- G is hydrogen or a carboxy protecting group; -84and R, is loweralkyl, (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, 4methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylpheny, 3-fluoro-4methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl :10 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 3is 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: R2 R5b -NHR 2 0a

(CH

2 )n

(CH

2 )m

(IX)

wherein n is 0 or 1; m is 0 to 6; Rsb is alkylene; R20a 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,

-CN,

-C(O)NHR17 where R17 is toweralkyl, al kytamiflocarboflyl, dialkylamiflocarboflyl.

tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O)2R16 where R 16 is toweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl6.

/NH

0

()HO

OH

*15

(P)

~NH

0q 0 0 (q)

HA

-86- WH ,or -a NHSO 2

CF

3 and

R

1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, halo alkoxyal kyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkyl amino carbonyl alkyl, aminocarbonylalkenyl, alkylaminocarbonylalkeflyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl.N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (hete ro cyclic) al kyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or :alkanoyl and Rcc is alkylene, with the proviso that one or both of R, and

R

2 is other than hydrogen; or a salt thereof; or a compound of the formula: R2IR~b -NHR 2 0a R2 R~b -NHR 2 a N

N

W(cHH))

(CH

2 )m 2 w R or w R NX (Xl) wherein n is 0 or 1; m is 0 to 6; Rsb is alkylene;

R

2 0a 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, -O N, -87- -C(O)NHR17 where R 1 7 is loweralkyl, alkylamnifocarboflyl, dialkylaminocarbofll tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamiflo, (in) -S(O) 2 NHC(O)Rl6.

HO 00 559V

NH

00 S. (n) HO 0

OH

I. SN 9* 0 N 0 0, (r)0 N -01

H

CF3 H ,or -88-

NHSO

2

CF

3 and R, and R 2 are independently selected from hydrogen, loweralkyl, alkenyl. alkynyl, alkoxyalkyl, alkoxycarbonylalkyl. hydroxyalkyl, haloalkyl. haloalkoxyalkyl. alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl.

cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl. dialkylaminocarboflylalkyl, arninocarbonylalkenyl, al kyl aminoca rbolyl al kenYl, dlialkylamiflocarbonylalkenyl, hydroxyalkerlyl. aryl1, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, alkanoyi-N-alkyl) aminloalkyl, alkylsulfonylamidoalkyl. heterocyclic, (heterocyclic) alkyl and (Raa)(Rbb)N-Rc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc 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 (Xl) wherein m 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 R 1 and R 2 are as defined above; or the substantially pure or (+)isomer thereof.

0. 00: Particularly preferred intermediates are compounds of formula and (XI) wherein n and m are both 0; Rsb is alkylene; 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 RI is loweralkyl, (6i) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4ethoxyphenyl, 4-ethylphenyl, 4-methylpheflyl, 4-trifluorom ethylphenyl, 4-pentafluoroethylphenyl, 3-loo4mtoyhnt 3-fluoro-4- -89ethoxyphenyl, 2-fluorophenyl, 4-methoxynmethoxyphefll 4hydroxyphenyl, 4-t-butylpheflyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuralYl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxy.lkoxy and carboxyalkoxy, (ix) aryalkyl. aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-Nalkyl)aminoalkyl, and (xiii) alkylsulfonylan'idoalkyl, 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-(3dim ethylarninopropyl-3-ethylcarbodiimide hydrochloride, EtOAc for ethyl acetate, EtOH for ethanol, HOBt for 1-hydroxybenzotriazole, Et 3

N

for triethylamine, TFA for trifluoroacetic acid and THF for tetrahydrofuran.

Example 1 25 trans. trans- 24Methoxyphen l0-4-( 1.3-benzdixl5y- 1- *(propVlami ocarbonlmethl-pyrrolidine3carbgxyig acid Ethyl 2(4metoxbnzol4-nitromethyl-3-(l.3benzodioole5Vl'bu vrat To ethyl (4.metho xybenzoyl) acetate (23.0 g, 0.104 mol), prepared by the method of Krapcho et al., Org. Syn. 47, 20 (1967), and 5-(2nitrovinyl)-1,3-benzodioxole (17.0 g, 0.088 mol) dissolved in 180 mL of toluene and-heated to 80 0 C was added 1 ,8-diazabicyclo[5, 4 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 chromatography 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-m ethoxyhenvl-4-1.3-benzodioxol-5-vl- 4 .5-dihydro-3H-Dyrrole-3carboxlate The compound resulting from Example 1A (21 g) in 500 mL of ethanol was hydrogenated under 4 atmospheres of hydrogen pressure 15 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 20 the desired product.

Example 1C Ethyl 2-(4-methoxyohenyl- 4 -(1.3-benzodioxol-5-vl)-prrolidine-3-carboxylate) as a mixture of cis-cis trans trans: and cis.trans-isomers 25 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 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 -91with pure ethyl acetate gave 0.505 g of an unknown solid followed by 3.044 g of pure cis,cis-compound.

Example 1D trans, trans-2-(4-Methoxyphenyl)- 4 -(1.3-benzodioxol-5-vl)-1- (prolvlaminocarbonvlmethyl)-pyrrolidine-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., 9: 515 (1947), in 30 mL of acetonitrile was heated at 50 °C for 1 hour. The solution was concentrated in vacuo. The residue was dissolved in toluene, shaken with potassium bicarbonate solution, dried over sodium sulfate and is concentrated in vacuo to give 7.16 g of product as a mixture of trans,trans- and cis,trans- ethyl esters.

S. 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 20 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, 25 drying over sodium sulfate, concentrating in vacuo, and crystallizing from ether to give 3.230 g of the title compound. m.p. 151-153 1

H

NMR (CD 3 0D, 300 MHz) 5 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-MethoxvDhenyl)-4-(1.3-benzodioxol-5-vl- 1 -(aminocarbonvlmethyl)pyrrolidine-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 -92resulting from Example IC), 220 mg of diisopropylethYlamifle and 184 mg jodoacetamide were reacted at 45 00 in 1 mL acetonitrile 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 ID were used to give 134 mg of the title compound. m.p. 246-248 1 H NMR (DMSO-d6, 300 MHz) 8 2.61 (d, J 16 Hz, 1H), 2.71 J 9 Hz, 1H), 2.90 J 9 Hz, 1H), 2.98 J 16 Hz, 1H),3.25-3.35 (in, 1H), 3.45-3.55 (in, 1H), 3-71 3H), 3.75 (ci, J= Hz, 1H), 6.00 2H), 6.81 2H), 6.90 J 8 Hz, 2H), 7.10 1H), 7.17 1 7.34 I1H), 7.38 J 8 Hz, 2H-).

Example 3 *15 trans, trans-2-(4- Metho xyphen yfl-44(1 .3-be nzodio xol-5-yl)- 1 (4-f Iuo robe nzyl) pvyrrolidine-3-carboxylic acid ofUsing 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 mng of diisopropylethylamnife and 185 *.20 mng of 4-fluorobenzyl bromide were reacted at room temperature for 3 hours in 1 mL of acetonitrile to give 387 mng of a mixture of trans,trans- and cis, trans-N-alkylated esters. A portion (360 mng) was hydrolyzed with 250 mng NaOH in 1 mL of water and 4 mL of ethanol to give 160 mg of the title compound as an amorphous powder. 'H NMR (ODC13, 300 MHz) 8 2.74 J 9 Hz, 1H), 2.95 J 7 Hz, 1H), 2.98 J 14, 1H), 3.07 (dd, J 9 Hz, 1 Hz, 1H), 3.42-3.53 (in, 1H), 3.70 J 9 1H), 3.78 J 14, 1H), 3.81 3H), 5.92 2H), 6.70 J 8 Hz, 1H), 6.77 (dd, J 8 Hz, 1 Hz, 1H), 6.91 J =9 Hz, 2H), 6.94 -7.00 (in, 3H), 7.20 7.25 1 7.44 J 9 Hz, 2H).

Examiple 4 trans. trans-2- (4 -Met hoxyghen l-4-0l.3-ben zodioxol-5 1- (2-eth oxvethfl)pyrrolidine-3-carboxlic acid Using the method described in Example 10, 300 mg. of the mixture of 64% trans,trans- and 34% cis, trans-pyrrolidifles (the mixture resulting from Example 10), 220 mng of diisop ropyl ethyl amine and 152 mg of 2-bromoethyl ethyl ether were refluxed in 1.5 mL acetonitrile for -93- 3 hours (bath temperature at 95 00) 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.

mn.p. 88 90 OC. 1H NMR (00013, 300 MHz) 8 1.25 J 7 Hz, 3H), 2.21 2.32 (in, 1H), 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 (mn, 1 6.84 J 9 Hz, 2H), 7.08 J 1 Hz, 1 7.33 J 9 Hz, 2H).

Examgle trans. trans-2-(4-Methoxyohenfl)-4-( 1.3-benzodioxol-5-yl1- 1 -(2-Proooxyethvl'th orrolidine- 3-carboxylic acid Using temethod described in Example 1D, 520 mng of the mixture resulting from Example 10, 364 mg of diisopropylethylainine, 50 mng potassium iodide and 350 mg 2-chioroethyl propyl ether were reacted at 125 00 in 0.5 mL acetonitrile for 4 hours to give 517 mg of a mixture of trans,trans- and cis,trans-esters. A portion (500 mg) was hydrolyzed with 315 mg NaOH in 1 mL of water and 4 mL of ethanol to 20 give 225 mg of the title compound as an amorphous powder. 'H NMR (00013, 300 MHz) 5 0.87 J =7 Hz, 3H), 1.53 (sextet, J 7 Hz, 2H), 2.28-2.41 (in, 1H), 2.71-2.83 (mn, IH), 2.92-3.08 (in, 2H), 3.30 J 7 Hz, 2H), 3.40-3.60 (in, 4H), 3.72-3.83 (in, 3.76 5.92 2H), *6.71 J 8Hz, 2H), 6.74 (dd, J 8Hz, 1 Hz), 6.71 J 9Hz, 2H), 7.07 J 9 Hz, 2H), 7.73 J 9 Hz, 2H).

Examole 6 ~trans, trans-2-(4-Methoxvohenyl)-4-( 1.3.benzodioxol-5-0f- 14-2-2methoxvethoxy)ethll-iovrrolidine-3-carbox~lic acid Example 6A Ethyl trans. trpns-2-(4-methoxyohenyl)-4- (1 .3-benzodioxol-5-vl) 12yrrolidine-3carboxylate To the pure cis, cis- compound resulting from Example 10 (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 chromratography in ethyl acetate indicated the absence of starting material. The NaQEt was neutralized -94with 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).

Example 6B trans.trans-2-(4-Methoxyohenyl)-4-(1.3-benzodioxol-5-yl)-1 methoxyethoxy)ethyll-pyrrolidine-3-carboxylic acid o1 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 mL acetonitrile were heated at 100 °C for 3 hours to give 229 mg of Sthe trans, trans-ester. A portion (200 mg) was hydrolyzed with 125 mg s15 NaOH in 1 mL of water and 2 mL of ethanol to give 151 mg of the title compound as an amorphous powder. 'H NMR (CD3OD, 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).

Example 7 trans. trans-2-(4-Methoxyphenyl)-4-( 13-benzodioxol-5-yl)- 2-pyridyl)ethyllpyrrolidine-3-carboxylic acid The compound resulting from Example 6A (250 mg), 2-vinyl 25 pyridine (355 mg) and one drop of acetic acid were dissolved in 2methoxyethanol, and stirred at 100 °C for 2.5 hours. Toluene was added, and the solution was washed with potassium bicarbonate solution. The solution was dried over potassium bicarbonate and concentrated in vacuo. Toluene was added and the solution re-concentrated. This was 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 °C.

'H NMR (CD3OD, 300 MHz) 5 2.8 3.3 6H), 3.55-3.70 2H), 3.76 (s, 3H), 3.99 J 10 Hz, 1H), 5.92 J 1 Hz, 2H), 6.72 J 8 Hz, 1H), (dd, J 8 Hz. 1 Hz). 6.85 J 9 Hz, 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).

Example 8 transtrans.2-(4-MethoxvDhenvyl- 4 -(1.3-benzodioxol-5-vl)- 1 -(morpholin-4ylcarbonyl)-ovrrolidine-3-carboxvlic 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 C. 1H NMR (DMSO- 15 d6, 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).

xamle 9 trans, trans-2-(4-Methoxyvhenyl)- 4 .3-benzodioxole-5-vl-1-(but laminoca rtonvl)pvrrolidine-3-carboxvlic acid To the compound resulting from Example 6A (300 mg) dissolved in 2 mL tetrahydrofuran and cooled in an ice bath was added 88 mg of butyl 25 isocyanate. After 40 minutes at room temperature, toluene was added, and the solution was concentrated in vacuo to give the intermediate ester. The ester was hydrolyzed by the method described in Example 1D to give 232 mg of the title compound. m.p. 220-221 OC. 'H NMR (DMSOd6, 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 2H), 3.74 (s, 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).

-96- Examole trans.trans-2-(4-Methoxvyhenvl)-4-(1 .3-benzodioxol-5-l-1 methoxvphenvlaminocarbonvl-3-ovrrolidine-3-carboxvlic 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 1 H NMR (CDCI3, 300 MHz) 5 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).

m.

Example 11 i trans. trans-2-(4-Methoxvyhenvl)- 4 .3-benzodioxol-5-vl-1 -acetvloDrrolidine-3carboxyvlic acid

S

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 OC. Rotational isomers are seen in the NMR. 1 H NMR (DMSO-d6, 300 MHz) 5 1.55 and 2.00 3H), 25 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 1H), 6.00 2H), 6.75-6.87 3H), 6.95 and 7.04 J 9 Hz, 2H), 7.18 and 7.32 J 9 Hz, 2H).

Examole 12 trans. trans-2-(4-Methoxvhenvl)-4-(1.3-benzodioxol-5-l)- 1 -(2-furoyl- rrlidi carboxylic 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 97hydrolyzed by the procedure described in Example 1D to give 269 mg of the title compound as an amorphous powder. 1H NMR (DMSO-d 6 300 MHz) 8 3.06 (dd, J 12 Hz, 13 Hz, 1H), 3.3-3.6 (in, 2H), 4.25 (in, 1H), 5.19 d, J 10 Hz, 1H), 6.67.4 (in, 8H), 7.8-7.9 (mn, 1H).

Example 13 trans, trans-2 -Met hoxygh en l)-4 1.3- benzodioxoI- 5-yO- 1 (ohenylaminoca rbonyvl-pyrrolidine-3-cprboxvlic acid Starting with the compound resulting from Example 6A, phenyl isocyanate and the procedures described in Examnple 9, the title compound was prepared. in.p. 209-211 1H NMR (DMSO-d 6 300 MHz) 3.03 (dd, 1H), 3.55 (in, 1H), 3.70 (in, 1H), 3.72 3H), 4.15 (in, 1H), 5.13 1H), 6.00 2H), 6.88 (in, 5H), 7.07-7.20 (in, 3H), 7.30 2H), 7.38 2H), 8.20 (bs, 1H).

Examole 14 trans, trans-2-(4-Methoxvohenvl)-4-( 1.3-benzodioxol-5-vl)- 1 (allylaminocarbonvlmethfl)-ovrrolidine-3-carboxvlic acid Using the procedures described in Example 1 the title compound :20 was prepared. in.p. 138-140 1 H NMR (C~DC 3 300 MHz) 852.84 (d, 1H), 2.90-3.10 (dt, 2H), 3.28 1H), 3.35 (dd, 1H), 3.62 (in, 1H). 3.72- 3.97 (in, 3H), 3.80 3H), 5.13 (bd, 2H), 5.80 (mn, 1H), 5.97 2H), 6.74- 6.97 (in, 5H), 7.38 2H).

Examgle tfrans. trns-2-(4-Methoxyohenyl)-4-( 1.3-benzodioxol-5-yl)-1 butylaminoca rbonylmethyfl)-yrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. in.p. 105-107 00. 1 H NMR (CD013, 300 MHz) 6 0.90 3H), 1.30 (in, 2H), 1.45 (in, 2H), 2.80 1H), 2.87-3.35 (in, 6H), 3.62 (mn, 1H), 3.80 3H), 5.97 2H), 6.75-6.92 (mn, 5H), 7.28 2H).

Example 16 trans. trans-2- (4-Methoxyo~henyl)-4-( 1 .3-benzodioxol-5-yfl- 1 (n-oroo2yjl- Nmethylaminocarbonylmethyl)-oyrrolidin-3-carbowclic acid Using the procedures described in, Example 1 the title compound was prepared as an amorphous solid. Rotational isomers are seen in the 9 *9 -98- NMR. 'H NMR (CDCI3, 300 MHz) 5 0.73, 0.84 (2t, 1.49 (in, 2.80 (dd, 2.85 (2s, 3H), 2.95-3.20 (in, 3H), 3.20-3.40 (in, 1H), 3.40 (d, IN), 3.60 (in, 3.79 3H1), 5.93 6.73 6.86 (in, 2H), 7.03 (in, 11H), 7.32 2H).

Example 17 trans, tran 4-MethoxY hfnY1'- 4 1 -3benzoioxl I-f- rrolidin- 1y~carbon ehl~~r~iiecrox tic acid Using the procedures described in Example I the title compound was prepared as an amorphous solid. 1 H NMR (CICI 3 300 MHz) 5 1.40- 1.70 (mn, 6H), 2.80 1H), 3.00 (in. 3.24-3.43 (mn, 5N), 3.60 (in, 2H), 3.73 1iN), 3.80 3H), 5.95 2H), 6.74 1 6.80-6.90 (in, 3H), 7.04 1N), 7 10 2H).

15 ExampI ej 8 tran s. trans.(4MtoVhnl-l 3benzodioxol-5-Yl- 1fisobuvanil-rbfpint~~ yrrolidine3carboxvlic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 175-177 0C. 1 H NMR (CD 3 OD, 300 MHz) 5 0.87 (dd, 20 6H), 1.75 (septet, 1 2.85 1 2.90-3.10 (in, 4H), 3.23 I 3.40 (mn, 3.58-3.67 (in, 1H), 3.78 3H), 3.89 1N), 5.92 6.76 11N), 6.86 (dd, 1H), 6.91 2H), 7.02 11H), 7.40 2H).

Example 19 25 trans. trans-24-MethoX~ev~( .3bnoioX-5yi (cvclooentylaminocarbonylmethyl)- rrolidine-L-carbox Vlicacid Using the procedures described in Example 1 the title compound was prepared. m.p. 137-139 OC. 'H NMR (00013. 300 MHz) 8 1.34 (in, 1.62 (mn, 4H), 1.90 (mn, 2.76 1H), 2.90 1H), 3.04 (dd, 1H), 3.22 3.28 (dd, 1H), 3.40 (in, 11N), 3.80 3H), 4.15. (in, 1H), 5.97 2H), 6.75-6.95 (in, 5N), 7.27 (mn, 2H).

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

-99- Example trans, trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 -(morgholin-4ylaminocarbonlmethyl-yrolidie-3-carboxlic 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 2.82 (d, 1H), 3.00 (in, 2H), 3.24 (in, 1H), 3.30-3.52 (mn, 3.52-3.75 (in, 8H), 3.80 3H), 5.95 2H), 6.75 1 6.84 7.00 1 7.28 (d, 2H).

Example 21 trans. trans-2-(4-Methoxyohenfl)-4-( 1 .3-benzodioxol-5-ll-(2-ohenoxyethvl)- 12yrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared as an amorphous solid. 'H NMR (CD 3 00, 300 MHz) 8 2.82 (in, 1H), 2.96 (dd, 1H), 3.13 (mn, 1H), 3.32 (in, 11H), 3.51-3.70 (in, 2H), 3.77 3H), 4.00 1 4.07 5.91 2H), 6.72 1 6.80-6.95 6H), 7.03 1 7T22 (dd, 7.39 2H).

Examplie 22 20 trans. trans-2-(4-Methoxyohenyl)-4-( 1. 3-benzodioxol-5-yl)- 1 f*e9~ methoxcyethlaninocarbonlnethylO-D2rrolidife3carboxlic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 107-109 00. I'H NMR (CD 3 OD, 300 MHz) 8 2.82 (d, 1H), 2.97 2H), 3.21 1H), 3.38 (in, 1H), 3.32 3H), 3.44 (mn, 4H), 3.62 (mn, 1H), 3.79 3H), 3.86 1H), 5.93 2H), 6.76 1H), 6.85 (dd, 1 6.91 2H), 7.01 1 7.38 2H).

Exa mple 23 trans, trans-2-(4-Methoxyphen vl)4-( 1 .3-benzodioxol-5-y')- 1 -(2-butgxyeth~f-vIcovrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared. 53-55 00. H N MR (ODC1 3 30.0 MHz) 8 0.88 J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 1.50 (pentet, J=7Hz, 2H), 2.27 (tt, J=6Hz, 6Hz, 1H), 2.92 J=lOHz, 2H), 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, 1H), 7.06 J=2Hz, 1H), 7.32 J=9Hz, 2H). MS in/e 442 -100- Example 24 trans, trans-2-(1 .3-Benzodioxol-5-yll-4-(4-metho~yphenyfl- 1- (oroovylam inocarbonlmethyl-yrrolidile-3-carboxliC acid Using the procedures described in Example 1 and substituting ethyl 3-benzodioxol -5-yl carbo nyl) acetate for ethyl (4meth oxyb enzoyl) acetate and 4-(2-nitrovinyl)anisole for 5-(2nitrovinyl)-1 ,3-benzodioxol-5yl afforded the title compound. m.p. 97- 99 'H NMR (CDCI 3 300 MHz) 8 0.78 J=7Hz, 3H), 1.39 (sextet, J=7Hz, 2H), 2.72 J=l6Hz, 1IH), 2.74 J=10Hz-,- IH), 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 m/e 441 Examlole trans. trans-2-(1.Bezdoo5-)4(-mtxyhnl1 -(-rpxyty) 0. teyrrolidine-3-carboxylic acid *Using teprocedures described in Example 5 and substituting "SOO ethyl 3-b enzodioxol -5-ylcarboly 1) acetate for ethyl (4methoxybenzoyl)acetate and 4-(2-nitrovinyl)anisole for 5-(2got** a20 nitrovinyl)-1.3-benzodioxol-5yl afforded the title compound. m.p. 67- 69 00. I H NMR (00013. 300 MHz) 5 0.89 J=7Hz, 3H), 1.56 (sextet, J=7Hz, 2H), 2.33 (in, 1IH), 2.78-3.00 (in, 3H), 3.32 J=7Hz, 2H), 3.45- 3.57 (in, 4H), 3.73 (mn, 1H), 3.79 3H), 5.93 2H), 6.22 J=8Hz, 1H), .5 6.85 J=8Hz, 3H), 6.98 1H), 7.37 J=8Hz, 2H). MS (DC1/NH 3 m/e 428 Example 26 frans. trans-2-( 1.3-Benzodioxol-5-l)4-(4-nethoxyiphenI')-1 4r2427 methoxyethoxvethlfl-gyrrolidine-3-carboxylic acid Using the procedures. described in Example 4 and substituting the starting materials described in Example 25 and using 2-(2methoxyethoxy)ethylbroinide to alkylate the pyrrolidine nitrogen afforded the title compound. in.p. 85-86 00. 'H NMR (00300, 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 (001/NH 3 m/e 444 -101- Examp-le 27 trans. trans-2- (1.3 Be o oo-5y)-4 toxlhnl -(butoxyethvl)- Sy rr olid in e-3-c a rbO-l acd 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 NMVR (00013. 300 MHz) 8 0.89 J- 7Hz, 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, IH), 3.80 3H). 5.93 (dd, J=6Hz, 1Hz, 21H), 6.72 J=8Hz, 1H), 6.74 (dd, J=9Hz, 3H), 6.96 1H), 7.36 J=9Hz,-2H).

EagMple 28 trans, trans-2-(4- Methoxvo~henfl)-4-( 1.4-benzodioxal-6-vl)- 1 (p~roo~ylaminocarboflylmethvlYO-.rrolidineaaoxlic acid 0.0 Using the procedures described in Example l and substituting 6- (2-nitrovinyl)-1 ,4-benzodioxane. for 5-(2-nitrovinyl)-1 ,3-benzodioxole :o afforded the. title compound. m.p. 80-81 00. 'H NMRi (00013, 300 MHz) 8 0.89 J-7Hz, 3H), 1.49 (sextet. J=7Hz, 2H), 2.78 J=l6Kz, 1K), 2.92 J=lO~z, 1H), 3.05-3.43 (in, 5H), 3.24 J=l6Kz, 1H), 3.52-3.62 (in, 1H), 3.80 3K), 3.80 J=lOHz, 1H), 4.27 4H), 6.74-6.93 (in, o 7.29 J=9Hz, 2H). MS (D01/NH 3 in/e 455 25 Example 29 trans. trans-2-(4-Methox oh n 1f- 4 1 .4-benzodioxan-6-yIY1 -(N-methy,-lpropyl ami noca rbonylm ethyl) yrroli dine-3carboxylic 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-methyl-N-propyI bromoacetamide afforded the title compound. in.p. 74-76 00.

Rotational isomers are seen in the NMR. 'H NMR (00013. 300 MHz) 0.73, 0.83 (2t, J=7 Hz, 3H), 1.48 (in, 2H), 2.78 (dd, 1H), 2.85 (2s, 3K), 2.96-3.15 (in, 3H), 3.27-3.42 (in, 3H), 3.52-3.60 (mn, 1H), 3.75 1K).

3.78 4.22 4H), 6.80-6.98 (in, 5H), 7.32 2K). MVS (001/NH 3 m/e 469 -102- Fxarnplam blitylaminocr~llehlProiiec~o i acn Using the procedures described in Example 1, the title compound was prepared. Rotational isomers are seen in the NMR. 'H 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 2H), 3.52 (dd, 1H), 3.60 (mn, 1H), 3.80 3H), 3.85 (in, 1H), 5.91 2H), 6.74 6.83-6.95 (in, 7.03 (dd, IH), 7.35 (dd, 2H).

Examole 31 trans. trans.

2 -(4-Methgx-2methio2=gmtho /ghenl'- 4 (1 mehlNbtlmnc o m ehyflD)r-liine- carbonlic acid Examp I1A 2 4 meh x~ ethoy igthoxy~henl 4 (l.3 bez di x I l~jV2rrDidine :3-car 2gx laej Using the procedures described in Examples 1A and 1B and substituting ethyl (4-iethoxy-2 -etoxy to ybe ola t o ethyl (4-methoxybeflzoyl) acetate afforded ethyl 2-(4-inethoxy-2 m eth oxym et h oxyph en yl)- 4 3 -be n zod i oxol 5 -yl)-4,5 -d ihyd ro- 3

H

p y rrole -3 -ca rb oxylate.

The above dihydro pyrrole carboxylate (3.0 g, 7.0 minol) was dissolved in 20 mL of methanol, treated with 500 mg 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 aff ord the title compound (1.9 g, 63%) as the cis-cis isomer.

Examiple-31B trns rn 4-Methxv-2-methoxame etho 1he WQI 4 535benzY x 15-Vll The compound resulting from Example 31A was epimerized by the procedure described in Example 6A. The resulting tranS,trafls compound (100 mg, 0.23 mmol) was then reacted by the procedures described in Example 10 substituting N-rnethyl-N-butyl bromoaCetainide for Npropyl bromoacetamide to give the title compound (75 mg, in.P.

65-67 OC. Rotational isomers are seen in the NMR. 'H NMR (CDC13, 300 -103- Ml-z) 8 0.64, 0.68 (2t, J=7Hz, 3H), 1.14, 1.12 (2 sextet, J=7Hz, 2H), 1.40- 1.48 (in, 2H), 2.86, 2.89 (2s, 3H), 2.95-3.42 (in, 3.50 3H), 3.43- 3.65 (in, 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 6.85 (2t, J=lHz, 1H), 7.04 J=ll-z, 1H), 7.42 (dd, J=3Hz, 1H).

Examp-le 32 trans. trans-2-(4-Methoxyphelyl)- 4 1.3-benzodioxol-5-vI)-l 1 -(-thoxyronvh'pyrrolidin-5-one-3-carboxlic acid Exam2Ple 32A Ethyl 2(4methoxybelzoyl)3carbomethox~y-1 To ethyl (4-methoxybeflzoyl)acetate (4.44 g, 0.02 mmol) dissolved in 20 mL of anhydrous THE was added in portions 480 mng 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 THE 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.

Examp-le 32 Ethyl 1 -to rpy)2(-eho ey)4(1 .3-benzodioxol5yl4.5:dih dro :25 A5-oxo-1 H-pyrrol-3-carbqnLa-te mixture of the compound resulting from Example 32A (700 ing, 1.69 inmol), 3-ethoxypropylan'ine (348 mg, 3.38 iniol) and 1 mL of acetic acid in a sealed tube was heated for 18 hours at 125 11C. After cooling the contents of the tube to ambient temperature, 5 mL of water was added and the mixture extracted with ethyl acetate (2x100 mQL.

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.

-104- Exml-2C Ethyl 1 -(3-ethoxy1orpyl-2-(4-methXo~henYl)- 4 1.3-benzodioxol-5-yfl-o rrlid one-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-Methoxv~heflyl)-4-( 1.3-benzodioxol-5-yl)- 1 -(3-ethoxyoro2Yfl)ac~id 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 OC 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 M 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. 'H NMR (DMSO-d6,, 300 MHz) 5 1.04 J=7Hz, 3H), 1.55 (sextet, J=7Hz, 2.48-2.56 (in, 1H), 2.93 (dd, J=9Hz, 1H), 3.25 (t, *:25 J=7Hz, 2H), 3.28-3.40 (mn, 2H), 3.48-3.57 (mn, 1H), 3.78 3.88 (d.

J=IOHz, 1H), 4.72 J=lOHz, 6.02 2H), 6.74 (dd, J=8Hz, 1Hz, 1H), 6.87 J=8Hz, 2H), 6.98 J=8Hz, 7.38 J=8Hz, 2H). MS (001/NH 3 m/e 442 Example 33 trans. trans-2-(4-Methoxyohel)-4-( 1.3-benzodioxol-5-yi')- 1 -(3-methoLxYbeflzyl)pyrrolidi-n-5-one-3-crboxlic acid Following the procedures described in Example 32 and substituting 3-methoxybenzylamine for 3-ethoxypropylanfe afforded the title compound (123 mg, in.p. 150-152 1 H NMR (00300, 300 MHz) 5 2.96 (dd, J=8Hz, 10Hz, 11H), 3.72 3.80 3H), 4.06 (d, O Id .I=RHI-h 4.92 J=l6Hz, 2H), 5.92 2H), -105- 6.55-6.63 (in, 2H), 6.82 J=8Hz, 4H), 6.94 J=8Hz, 2H). 7.15-7.22 (in.

MS (DCI/NH 3 mle 475 trans. trans-2 -(4-Methoxyhelyl)-4-( 1.3-b)enzodioxol-5-yl)- 1 .Ndiisoamylamino~abn~ehlDroiiecarbo) 2Mic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1H NMR (C~DC 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 (mn, 4H), 3.15 3.30 (mn, 2H), 3.40 J=l0Hz, 1H), 3.40 3.52 (in, 2H), 3.55 -3.62 (mn, 3.75 J=12 Hz, 1H), 3.79 3H), 5.93 (dd, J =1 Hz, 3 Hz, 2H), 6.72 J=8Hz, 1H), 6.82-6.90 (in, 3H), 7.03 J=--2Hz, I1H), 7.30 J=9Hz, 2H).

.*15 EaPle ~~trns. trans-2-(4- Methoxyjohenyl)- 4 -0 .3-benzdigxol--yIkl -N dipentylam inocarbonylm ethvI'i-Dvrroli in -3-c rOYic aid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (00013, 300 MHz) 8 0.82 J 7Hz, 6H), 0.95-1.03 (mn, 2H), 1.10-1.30 (mn, 8H), 1.40-1.51 (in, 2H), 2.72 J=l3Hz, 1H), 2.90-3.08 (mn, 4H), 3.25-3.50 (mn, 3H), 3.37 (d, J=l3Hz, 1H), 3.52-3,60 (mn, IH), 3.70 J=lOHz, 1H), 3.75 3H), 5.92 (dd, J=2Hz, 5Hz, 2H), 6.72 J=8Hz, 6.80-6.88 (mn, 3H), 7.03 (d, ~:J=2Hz, 1H), 7.30 J=9Hz, 2H).

ExammngJara tns.. trns- 4-M thoxvyhenvl-) 4 meth xeh I mainnn~rbn~netvl~roidnecab)- ai The title compound was prepared using the procedures described in Example 1. m.p. 120-122 OC. 'H NMR (00013, 300 MHz) 852.82 (d, J=13, 1H), 2.94-3.08 (in, 2H), 3.12 3H), 3.23 3H), 3.20-3.70 (in, 11H), 3.73 JlOHz, 1H), 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=9Hz, 2H).

-106- Examp le 3 trans, trans-2-(4-Methoxyphenl)f-4-( 1.3-benzodioxol-5-yl)- 1 -(2-hexynyl'l-oyrrolidine- 3-aboxylicacid Usi ng 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 l-bromo-2-hexyne, prepared by the method described. in Perkin 1, 2004 (1987), for 1 hour at 55 0 C, 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 (C~DC 3 300 MHz) 8 J=7Hz, 3H), 1.54 (in, 2H), 2.14-2.22 (in, 2H), 2.96 (dd, J=7Hz, 13Hz, IH), 3.07 (dd, J=18Hz, 2Hz, 11H), 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 :15 J=9Hz, 2H).

trans. trpns-2-(4-Methoxvpheflyfl-4(1 .3-benzodioxol-5-yi)-1 -(N-cvcloproovylmethvl N-12rooyliaminocarbonylmethyl)1Dyrrolidile-3-carboxvlic acid The title compound was prepared using the procedures described in Example 1. m.p. 167-169 0 C. Rotational isomers were seen in the NMR. 'H NMR (CDCI3, 300 MHz) 8 -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), 25 2.72 J=l3Hz, 1H), 2.85--3.29 (in, 4H), 3.30-3.50 (in, 3H), 3.52-3.62 (mn, 1H), 3.65-3.73 (2 doublets, J=lOHz, 2Hz, IH), 3.78 3H), 5.95 (2 singlets, 2H), 6.72 (2 doublets, 2H), 6.80-6.90 (mn, 3H), 7.00 and 7.05 (2 doublets, J=9Hz, 2H).

trans, trans-2-(4-Metho~yphenl)- 4 .3-benzodioxol-5-vyl- 1 ethyl-NoentylaininocarbonVyinethyfl)-0rroidine3carboxylic 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 (COCl 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 10 .72 (dutI) 1" 175 and 3.76 (2 singlets, 3H), 5.92 -107- (2 singlets. 2H), 6.72 J=8Hz, 1 6.80-6.87 (in, 3H). 7.03 (2 doublets, J=2Kz, 1H), 7.30 J=9Hz, 2H-).

trans. trans-2-(4-Methoxyhenfl)f-4-(l .3-benzodioxol-5-VO)-1

N-

diisobUtylaminocarbonl m ethyfl I-vrrolidi e- 3-crbo)l ic acid The title compound was prepared using the procedures described in Example 1. m.p. 141-143 1 H NMR (00013, 300 MHz) 8 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, 1K), 2.70 J=l3Hz, 1H), 2.84 (dd, J=6Hz, 15Hz, 1H), 2.96-3.06 (in, 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, I1H). 6.82-6.90 (in, 3H), 7.03 J=2Hz, 1H), 7.31 J=9Hz, 2H-).

Examlle 41 ~trans. trans-2-(4-MethgxvhenVI'I- 4 .3-benzodixol-5-Afl1-(N-methvl-N-(2 progynyflaminocarbonylm ehvlIk-yrrolidile-3-cabo~ylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMIR. 1 H NMR (00013, 300 MHz) 8 2.09 and 2.32 (2 triplets, J=2Kz, 1KH), 2.80-3.10 (in, 3H), 2.90 and 2.99 (2 singlets, 3H), 3.35-3.50 (in, 2K), 3.52-3.62 (in, 3.78 3H), 4.03 J=13Kz, 1K), 4.00-4.30 (in, 3K), 5.93 2K), 6.72 (2 doublets, J=BHz.,'1K), 6.80-6.90 (in, 3K), 7.02 and 7.11 (2 doublets, J 2Hz, 1K), 7.30 (2 doublets, J=9Kz, 2H).

Exampole 42 trans. trans-2-(4-Methoxyphenyl'I- 4 1.3-benzodioxol-5-V'l)- N-methyl-N-(nhexyl~aminocarbonylinethy)i~yVrrolidine3carbo(ylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. IK NMR (00013, 300 MHz) 8 0.85 (2 triplets, J=7Kz, 3H), 1.00-1.50 (mn, 8H), 2.72-2.82 (2 doublets, J=l3Kz, 1H), 2.81 and 2.86 (2 singlets. 3H), 2.92-3.20 (in, 3H), 3.22-3.45 (in, 3K), 3.52-3.62 (in, 1H), 3.72 (2 doublets, 1H), 3.75 and 3.76 (2 singlets 3H), 5.94 (2 singlets. 2K), 6.72 J=8Kz, 6.80-6.87 (in, 7.03 (2 doublets, J=2Kz, 1H), 7.30 J=9Hz, 1H).

-108trans, trans-2-(4-Methoxyo~henyfl-4-( 1. 3-benzodioxol-5--y')- 1 N-di(nbu(tvl aminocarbonlmevl)-yrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 123-125 I H NMVR (COCl 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=BHz, 1H), 6.81-6.89 (in, 3H), 7.03 J=2Hz, 1H), 7.30 J=9 Hz, 2H). MS (001/NH 3 in/e 511 Anal calcd for C 2 9

H

3 13N 2 0 6

C,

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

Example 44 trans, trans-2-(4-Methoy~heny'I-4-(1 .3-benzodioxol-5-l)- 1 diethylaminocarbonylmethl)-yrrolidifle-3-carboxlic acid The title compound was prepared using the procedures described in Example 1. m.p. 132-13400C 1 H NMR (00013, 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 (mn, 1H), 3.76 J=12 Hz, 1H), 3.79 3H), 5.93 2H), 6.72 J=8Hz, 1H), 6.80-6.90 (in, 3H), 7.02 (d, J=2Hz, I1H), 7.32, J=9Hz, 2H).

Exam Di .::trans. trans-2 ethoxyphelyfl-4-( 1.3ben zodioxol- 5-yi)- 1 ethyl-N o2henylaminocarbonymethyl-prrolidine-3-carbo)Cylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMVR (CD 3 OD, 300 MHz) 8 2.75- 2.85 (in, 2H), 3.05-3.13 (in, 1H), 3.18 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 (in, 3H), 7.00-7.12 (mn, 5H), 7.82-7.92 (mn, 3H).

tran trans-2-(4-Methoxyohelyl)-4-( 1.3benzodioxol-5-yl)-l1-(N-methyl-Ncyclohexylainocarbolylmethvl)-Ovrrolidifle-3-caltoxylic aci The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the

MR

1 H NmR mcnOD. 300 MHz)~ 8 1.00-1.85 (in, 10H), 2.72 and 2.78 (2 -109singlets, 3H), 2.75-2.82 (2 doublets, J=12Hz, 1H), 2.96-3.22 (in, 3H), 3.40-3.65 (in, 3H), 3.68 and 3.82 (2 doublets, J=lOHz, 1H), 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, 1H), 7.30-7.40 (2 doublets, J=9Hz, 2H).

ExamDle 47 trans, trans-2-(4-Methoxyghenl)-4-( 1.bezd0o-Vl1-(N-di(nproovfl~aminocarbonlmethyl)-Dyrrolidine cartg~c~icacid The title compound was prepared using the-procedures described in Example 1. in.p. 170-172 1 H NMR (00013, 300 MHz) 8 0.69 (t, 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 (in, 4H), 3.35-3.62 (in, 1H), 3.72 J=9Hz, 1H), 3.79 3H), 5.94 2H), 6.72 d, J=8Hz, IH), 6.80-6.90 (mn, 3H), 7.02 J=2Hz, 1H), 7.30 J=9Hz, 2H).

Exampole 48 trans. trans-2-(4-Methoxyo~hefl)f- 4 -(1.3-ben zodioxol-5-fl)- 1-(N-methyl-Nisobutylam inocarbonyimethyl)-pyrrol idine-3-carbX~y icaid 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 (00300, 300 MHz) 5 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 (mn, 4H), 25 3.10-3.65 (in, 4H), 3.74 9S, 3H), 3.81 and 3,88 (2 doublets, J=1lOHz, I1H), 5.93 2H), 6.72 J=8Hz, 1H), 6.80-6.90 (in, 3H), 7.02 (2 doublets, J=2Hz, 1H), 7.80-7.90 (2 doublets, J=9Hz, 2H).

Example 49 Alternate PIreaig o Ethyl 24me hox benzoyl)4fitr~iehI( )ezoi Example 49A E-2-(31.4-MethlenedioXVohenl)- 1 -nitroethene To a stirred solution of piperonal (75g, 500 inmol) in methanol (120 ml-) at 10 00 was added nitromethane (27.1 mL, 500 iniol, 1 eq) followed by the dropwise addition of sodium hydroxide (21 g, 525 mmol, 1.05 eq) in sufficient water to achieve a total volume of 50 mL while -110maintaining 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, CDCI3) 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) m/e 194 (M+H) 211 15 (M+H+NH 3 Example 498 Ethyl 2-(4-methoxvohenyl)oxo-4-nitro-3-(3.4-methvlenedioxvDhenyl'butyrate 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-7- 25 ene (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, 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, CDCl 3 5 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, 111in), 3.80 3.7 8 (3H, 1.19 (3H, t. J=7Hz), 0.99 (3H, t, J=7Hz),

MS

(DCI/NH3) m/e 416 433 (M+H+NH3)+.

trans. trans 7-(4-M ethoxyphenl 4 (.3enzdol-Yl

C-

butyloycr~Ymt~protiecro~lcai To a stirred solution of the compound resulting from Example 1C (100 mg, 0.27 mmol) in acetonitrile (2 mL) was added successively d i isopropyl ethyl amine (70 1 iL, 0.40 mmol, 1.5 eq) and t-butyl bromoacetate (48 giL, 0.29 mmol, 1.1 eq). The mixture was stirred 2 hours, then the solvent was removed in vacuo to yield the crude diester.

To a stirred solution of the diester in ethanol (1 mL) at room temperature was added 50% w/w sodium hydroxide (300 mg, 3.75min01) in water. The mixture was stirred 2 hours, then the volatiles were Is removed in vacuo. The residue was dissolved in water (5 mL), and the solution was washed with ether. The aqueous phase was acidified with **:acetic acid (300 iL), and then extracted with ethyl acetate The combined organic extracts were dried (Na 2 SO4), filtered, and :concentrated to yield the title compound (74 mg, 60%) as a white solid.

1 H NMR (300 MI-z, 00013) 8 7.36 (2H, d, J=8Hz), 7.13 (1 H, d, J=3Hz), 6.90 (1H, dt, J=3Hz, 8Hz), 6.88 (2H, d, J=BHz)., 6.76 (1H, d, J=8Hz), 5.96 (2H, 3.96 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=17Hz). MS (001/NH 3 m/e 456 Anal calc for C 29

H

29 NO7 0.3 H 2 0: C, 65.07; H, 6.48; N, 3.04. Found:

C,

65.02; H, 6.42; N, 2.93.

trans.t .1-naohh 1 -(N-mthv_-N- The title compound was prepared by the procedures described in Examples 1 and 49 substituting na~phthalene- I1carboxaldehyde for piperonyl in Example 49A. Rotational isomers are seen in the NMR. 1

H

NMR (300 MHz, CDCI3) 8 8.29 (1H, bd, J=8Hz), 7.86 (2H, d, J=8Hz),7.75 O1H, d, J=8Hz), 7.49 (3H, in), 7.34 (2H, dd, J=3Hz,9Hz), 6.83 (2H, dd, J=9Hz,2Hz), 4.50 in), 3.94 (1H, dd, J=9Hz,2Hz), 3.78 (3H, 3.65 -112in), 3.49 (111, d, J=l4Hz), 3.40-2;93 (5H, in), 2.91, 2.83 (3H, 1.48 sept, J=7Hz), 0.83, 0.77 (3H, t, J=7Hz).' MS (DCI/NH3) m/e 461- Anal calcd for C 29

H

2 9 N07 -0.5 HOAc: C, 71.00; H, 6.99; N, 5.71.

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

Examl trans. trans 2 4 Methoxy~hen l4(.di roiiezof uran-5-yI) acidmehypropyflam crollntYDrotiecro~lcai ExamapieaA 2 3 ~DihydrobenZ~f~rafca1olehe To a stirred solution of c,czdichloromethyl methyl ether (2.15 g.

minol, 1.35 eq) in methylene chloride (30 ML) at -40 IC was added **osuccessively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes later, a solution of 2,3-dihydrobenzofurafl (1.68 g, 14 inmol) in CH 2 CI2 mL) maintaining the temperature at or below -35 0 The mixture was warmed to 0 OC, stirred 1 hour, then poured into ice-water, and stirred a further 30 minutes. The mixture was diluted with ether, and 0: the phases separated. The organic phase was concentrated in vacuo, 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.

Examnple 52B3 f~a m hvl r ii rb xlc anci 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. 1H NMR (300 MHz, CDCI 3 8 7.33 d, J=8Hz), 7.28 (1H, in), 7.19 (1H, in), 6.87 (1H, d, J=8Hz), 6.73 (1H, d, J=8Hz), 4.56 (1H, t, J=8Hz).

3.83 (1H, d, J=lOHz), 3.80 (3H, 3.63 (1K, in), 3.4-3.0 (9H, in), 2.87, 2.84 (3H, 1.51 (2H, septet. J=7Hi), 0.88, 0.78 (3H, t, J=7Hz).

MS

(DC I/NH 3 m/e 453 Anal calc for C 26

H

32 N205 0.25 H 2 0: C,- 68.33; H, 7.17; N, 6.13. Found: C, 68.60; H, 6.88; N, 5.80.

-113trans. I-ns2 i(-ehxoelf- m(pmtylNDDl~amiflOCnrbrflvlmcethyp~yrrolidine-3-carboxykiCacid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the.NMR. 1 H NMR (300 MHz, C~DC 3 8 7.37 (2H, d. J=7.5 Hz), 7.32 (2H, d, J=7.5 Hz), 6.86 (4H, in), 3.83 (1 H, in), 3.81 (3H, 3.79 (3H, 3.64 (1 H, in), 3.48-2.97 (6H, in), 2.87, 2.83 (3H, 2.85 (1H, in), 1.45 (2H, in), 0.84, 0.74 (3H, t, J=7.5 Hz).

MS (DCI/NH 3 m/e 441 Anal calc for C 2 5Ei 32 N2O5 0.5 H 2 0: C, 66.80; H, 7.40; N, 6.23. Found: C, 67.15; H, 7.31; N, 6.00.

Example 54 *trans. trn--4Mtocpey)4(.-i etoyhey) -(N-rn ethyl-N is groSyl)am inoca rbonylmethl)-Dyrro lid ife3-carog(ylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-dimethoxybenzaldehyde for 20 piperonal in Example 49A. Rotational isomers are seen in the NMR. 1H 6.98 (1H, in), 6.85 (1H, d, 7.5 Hz), 6.82 (2H, d, 7.5 Hz), 3.91 (3H, 3.86 (3H. 3.83 (1 H, in), 3.79 (3H, 3.64 (1 H, in), 3.50-2.95 (6H, in), 2.87 (1H, in), 2.85, 2.83 (3H, 1.45 (2H, in), 0.84, 0.74 (3H, t, J=7.5 Hz). MS

(DCI/NH

3 m/e 471 Anal calc for C 26

H

34

N

2 O6 0.5 H 2 0: C, 65.12; H, 7.36; N, 5.84. Found: C, 65.22; H, 7.27; N, 5.59.

~~25 trans.trans- 5 24-Methpyhenyl)43eho~ey 1 m-nethyl-Npropyl)ami oca nylfl'ehyl-pyrrolidine~cro(lcai 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. 1 H NMR (300 MHz, CDC1 3 8 7.33 (2H, d, J=7.5 Hz), 7.24 (1 H, t. J=7.5 Hz), 7.05 (2H, in), 6.85 (2H. dd, J=7.5&2 Hz), 6.76 (1H, in), 3.83 (1H, in), 3.81 (3H, 3.79 (3H, 3.64 (1H, in), 3.48-2.97 (6H, mn). 2.87, 2.83 (3H, 2.85 (1H, in), 1.45 (2H, in), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (001/NH 3 W/e 441 -114- Anal calc for C 25

H

32 N205 0.5 H 2 0: C, 66.80; H, 7.40; N, 6.23. Found: C, 66.76; H, 7.36; N, 6.05.

Example 56 trans. trans-2-(4-Methoxyvhenyl)-4-(2-naphthyl-1 -(N-methyl-NproDyvlaminocarbonvlmethyl)-Drrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthylene-2-carboxaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1H NMR (300 MHz, CDC13) 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, m), 1.52 (2H, 0.86, 0.76 (3H, t, J=7.5 Hz). MS (DCl/NH3) 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, 15 71.58; H, 7.11; N, 6.01.

Example 57 traansrans-2-4-Methoxvhenv-4-(1.3-benzodioxol-5-vl-1-(2-(ethvlsulfinvl)ethyl)pyrrolidine-3-carboxylic acid 00 20 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 25 chromatography on silica gel eluting with 4:1 hexane-ethyl acetate to afford 93 mg of the ethylthioethyl compound.

To the sulfide (90 mg, 0.2 mmol) dissolved in 5 mL of CH 2 CI2 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 FvImnli 10 to afford the title compound as a diastereomeric mixture.

-115m.p. 61-63 OC. MS (001/NH 3 mle 446 I H NMR (COCl 3 300 MHz) 8 1.25, 1.32 J=9Hz, 3H1), 2.45-2.75 (in. 4H), 2.84-2.96 (in, 3H). 3.02- 3.08 (in, 1H), 3.32, 3.36 J=3Hz, 1H), 3.47-3.58 (in, 2H1), 3.65, 3.68 (d.

1H), 3.76, 3.80 3H), 5.94 2H), 6.72 J=7.5Hz, 1H), 3.84- 3.89 (in, 3H), 7.02 J=6H-z, 1 7.30, 7.34 J=7.5Hz, 21-).

trans, trans-2-(4-MethoXV=henyl- 4 3-benzodioxoI-5-ylI- 1 -isooropylsulfonylam ino~ethylI-Dyrolidie3-carbog-xy-icacid To 2-bromoethylamifle hydrobromide (1 mm-rol) 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 Et3N were added. The resulting mixture was stirred for 2 hours at room temperature and then added to a 15 solution of the compound resulting from Example IC (185 mng, 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 vacua. The residue obtained was chromatographed on silica gel eluting with 3:2 hexane-EtOAc to give 195 mng of the ethyl ester. The ethyl ester (160 mg, 0.31 mmol) was hydrolyzed by the procedure described in Example 10 to afford the title compound (133 mg, m.p. 94-96 00. 1 1 NMR (00300, 300 MHz) 8 1.26 J=6Hz, 6H), 1.97 2.38 (in, 1H), 2.77 (in, 2.88 25 J=9Hz, 111), 3.04 (in, 1H), 3.14 J=7.5Hz, 2H), 3.35 (in, 211), 3.46 (in, 1H), 3.58 (in, 1H), 3.78 311), 5.92 6.74 J=9Hz, 1H), 6.86 (dd, J=9Hz,3Hz, 1H), 6.92 J=9Hz, 2H1), 7.00 J=3Hz, 1H), 7.36 J=9Hz, 2H1). MS (001/NH 3 mWe (M+H) 4 Exa npJ-52 trans. trans-2-(4-Meth xY hefn l- 4 3-benzodioxol-5-_Yl'-l-p ~(~i3D~bIOXYV)e U11 p yrrol id in e--&arO-xy -iC acd The title compound was prepared by the procedures described in Example 1D from the compound resulting from Example 10 and 2- (is obut oxy) ethyl bromide. in.p-. 68-70 I H NMR (00013. 300 MHz) 0.88 J=6Hz, 6H), 1.82 (quintet. J=6Hz, 2.22 (in, 2H), 2.72-2.79 -116- (in, I1H), 2.86-2.95 (mn, 2H), 3.13 J=6Hz, 2H), 3.45-3.56 (in, 4H), 3.68 J=9Hz, 1H), 3.79 3H), 5.94 2H), 6.72 J=7.5Hz, 1H), 6.85 (dd, J=9Hz, 7.5 Hz, 3H), 7.08 1H), 7.34 J=9Hz, 2H). MS (DCI/NH 3 mn/e 442 fExam Die trans. trans-2-(4-Methoxvheflvl)-4-( 1.3-benzodioxpl-5-Vfl- 1 -(butvlsu Ifonvl)pvrrolidine-3-carboxylic acid To 100 mg (0.271 mmol) of the compound resulting from Example 1C dissolved in 10 mL. of THIF 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 iniol) was dissolved in 1 mL of EtOH, and a solution of 100 mng 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 inL). The combined organic extracts were washed with brine, dried over sodium sulfate and :concentrated under reduced pressure to afford the pure title compound :25 (60 ing, 53%) as a white solid. in.p. 67-69 0 C. 1 H NMR (CDC1 3 300 MHz) 8 0.82 J=7.5Hz, 3H), 1.20-1.33 (in, 2H), 1.58-1.68 (in, 2H), 2.48-2.69 (in, 2H), 3.28 (dd, J=9Hz, 1H), 3.49 J=l2Hz, 1H), 3.65 (dd, J=12Hz, 1H), 3.82 3H), 4.32 (dd. J=l2Hz, 1H), 5.17 J=9Hz, 2H), 5.95 2H), 6.70-6.78 (in, 3H), 6.92 J=9Hz, 7.35 J=9Hz, 2H). MS (DCI/NH3) in/e 462 Exampole 61 trans. trans-2-4-Methoxyo~heflyl)- 4 .3bnoiXl5V' (2-(N-mehisolorooylcarbonylainino) Ethyfl-prrolidine3carbowtLic acid -117- Exam le 6A rans.trans-2(4-MethoxyDhenyl) 4 .3.benzodioxol-5-vl-1 -(2-bromoethyl)pyrrolidine-3-carboxvli 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 61B n15 s. tran2.(4-Methox henyl-4.( 3-benzodioxol-5-vl-1 -(2-(methylamino)ethyl)vrrolidine-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 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-Methoxvhenyvl-4-(1 3-benzdioxyl-5-vl)-1 N-methyl-Nisobutvrvlaminolethvl-ovrrolidine-3-carboxyic 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 oC, 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.

-1 18- The ester was dissolved in 1.5 mL of EtOH; 0.75 mL of a 17% aqueous NaOH solution was added, and the resultant mixture was stirred at ambient temperature for 3 hours. The solvents were removed in vacuo; the residue was taken up in water and washed with ether. The aqueous phase was acidified with 1 N~ H 3 P04 to pH 3 and extracted twice with ether. The combined organic extracts were washed with brine and dried over Na 2 SO4. The solvents were removed in vacuo to provide 82 mg of the title compound as a white foam. Rotamers were seen in the NMR. 'H NMR (C~DC 3 300 MHz) of the major rotamer 8 1.06 3H, J=lO1-z), 1.12 3H, J=lOHz), 2.15 (in, IH), 2.5-3-.0 (in, 2.91 3H), 3.32 (in, 3.50 (mn, 3.65 (mn, 2H), 3.77 5.92 2H), 6.73 1H, J=8H-z), 6.75-6.9 (in, 6.96 1H, J=2H-z), 7.29 (mn, 1H). -MS (DCI/NH3) in/z 469 Analysis calod for C 2 6

H-

32

N

2 06 0.3 TEA: C, 15 63.55; H, 6.48; N, 5.57. Found: C, 63.44; H, 6.71; N, 5.24.

Example 62 trans, trans-2-(4-Methoxyphelyl)- 4 1.3-benzod ioxol-5-vl)- 1 ethyl-N progionylam in Oethyl)-pyrroli din e-3-carboX~lic acid The title compound was prepared by the procedures described in Example 61 substituting propionyl chloride for isobutyryl chloride in Example 61C.- IH NMR (C~DC 3 300 MHz) of the major rotamer 8 1.13 (t, 3H, J=8H-z), 2.19 (in, 11H), 2.30 (in, 2H), 2.65-3.0 (in, 2.85 3H), 3.25-3.4 (in, 3.5-3.7 (in, 3H), 3.79 5.92 2H), 6.74 1H, :J=8Hz), 6.75-6.9 (in, 4H), 7.00 (bd s, 1H), 7.29 (bd s, 11H). MS (DCI/NH 3 in/z 455 Analysis calcd for C 2 51H 3

ON

2 O6 1.0 H 2 0: C, 63.55; H, 6.83; N, 5.93 Found: C, 63.55; H, 6.52; N, 5.73.

trans. trans-2-(4-Methoxylheflyfl-4-( 1 -3-benzodioxol-5-yfl- 1 -(N-methyl-Nbenzyaminoca rn lm'ehyfL-pyrrolidine-3-carboxyic acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMVR (00013, 300 MHz) of the major rotamer 5 2.79 (S, 2.8-3.2 (in, 3.48 (in, 2H), 3.61 (in, 2H), 3.77 3H), 3.78 (in, 1H), 4.3-4.5 (mn, 2H), 5.95 2H1, J=2H-z), 6.7-6.9 (in, 4H), 7.00 (in, 1H-), 7.15-7.35 (in, MS (FAB/NBA) m/z 503 Anal calcd for

C

2 9

H-

30

N

2

O

6 0.5 H 2 0: C, 68.36; H,5.74; N, 5.50. Found: 0,68.41;- H, 5.74; N, 5.36.

-119- Exam2le 64 trans. trans-2-(4-Methoxyphelyl 4 .3-beanzodioxol-5-yl- 1 -(N-ethyl-Nbuyaioabnlehl-2roiie3croyi acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMR (CDCI3. 300 MHz) of the major rotamer 8 0.88 (t, .3H, J=7Hz), 1.06 3H, 1=711z), 1.27 (in, 2H), 1.45 (in, 2H), 2.8-3.6 (in, I11H), 3.79 (s,3H1), 3.80 (mn, 5.92 (bd s, 6.75 1H, J=8Hz), 6.85 1H, J=8Hz), 6.92 2H, J=8Hz), 7.03 7.33 1H, J=8Hz). MVS (DCI/NH3) mlz 483 Anal calcd for C 27

H-

34

N

2 O6 0.5 HOAc: C, 65.61; H,7.08; N, 5.46. Found: C,65.51; H, 6.70; N, 5.66.trans, trans-2-(4-Meth ovhe nvl) 4 (l.3-ben zodioxol-5-vl) 1 -meth vl-N- M.dim gthylpropP) aminocarbonvlm ethyfl)-Dyrroli difle-3-carbox~lic acid Using the procedures described in Example 1 the title compound *:was prepared. 1H NMR (CDC1 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. 3.80 (s, 3.82 (in, 1H), 5.94 (bd s, 6.74 I1H, J=8Hz), 6.86 2H, 1=8H-z), 6.87 (in, 1H), 7.03 1H, J=2Hz), 7.33 2H, J=8Hz). MS

(DCI/NH

3 in/z 483 trans. trans-2- 4-Metho henylI- 4 -(J1 3-bennodioxlYnl- 1-2Nmhyl-N- ~.25 butylsulfonylaino~ethyfl)-yrr:)idine- rx i ci To the compound resulting from Example 61B (60 ing, 0.13 iniol) dissolved in 5 mL of CH 3 CN was added 0.2 mL of Et 3 N and 22 mng (0.143 mmol, 1.1 equivalents) of 1 -butanesulfonyl chloride. The mixture was stirred for 1 hour at room temperature and then concentrated in vacuo.

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 1D afforded the title compound. in.p. 64-66 'H NMR (CDCI3. 300 MHz) 8 0.92 1.39 (hexad. J=7.5Hz, 2H), 1.68-1.76 (mn, 2H), 2.16-2.25 (in, 1H), 2.72 2.75-2.92 (mn, 5H), 3.12-3.20.(mn, 3.25-3.34 (in, 1H-), 3.46-3.55 (mn, 3.65 J=9Hz, 1H), 3.78 3H), 5.53 6.72 (d, -120- 1H), 6.82 (dd, J=7.5Hz,3Hz, lIH), 6.86 J=9Hz, 2H), 7.02 (d, J=3Hz, 1Hl), 7.34 J=9Hz, 2H). MS (DCI/NH3) m/e 519-(M+H)+.

ExampIl 6 trans, trans-2-(4-Metho Yhenfl)lV-(l.3.benzodioxol-5-VI)- 1 -(2-(N-methyl-N- PropylsuloIlaifOPthviflPrrolid-.Ine-carhnox-lic acid The title compound was prepared by the procedures described in Example 66 substituting I1-propane sulf ofyl chloride for 1butanesulfoflyl chloride. m.p. 69-70 'H NMR (CDCI3. 300 MHz) 8 1.02 J=7.5Hz, 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, lIH), 3.47-3.58 (in, 2H), 3.66 J=9Hz, 1H), 3.80 3H), 5.96 2H), 6.74 6.84 J=7.5Hz, 3Hz, 1H), 6.87 J=9Hz, 2H), 7.04 J=3Hz, 1H), 7.43 J=9Hz, 2H). MS (DCI/NH3) m/e 505 Examgle -68 trans. trans-2-(4-MethoXyrhenl)l 4 3-benzodioxol-5-lj-l :(oroovylsulfonyl'lethylVP1yrrolidie- 3 -ca rboxylc aci-d 1-propanethiol (3.5 g, 46.05 mnmol) dissolved in 10 mL of anhydrous THE was added 632 mg (26.32 mmol) of Nail in portions under a nitrogen aitmosphe re. The mixture was heated at 60-70 00 for 1 hours.

To this mixture was added the compound resulting from Example 61 A (180 mg, 0.38 inmol) in 2 mL THF. Heating was continued at 60-70 0

C

: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 mg To a solution of 170 mng (0.36 irnol) of the sulfide and 93 mg (0.8 inmol) 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 mg) in 0.3 mL of t-butanol. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was partitioned between EtOAc and H 2 0. The organic phase was washed with brine, dried over Na 2 SO4 and concentrated in vacuo. Flash chromatography afforded 177 mng of the ethyl ester which was hydrolyzed by the procedures described inl Example 1D to afford the title -121compound, m.p. 73-75 1 H NMR (CDCI3, 300 MHz) 5 1.04 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.59-2.66 1H), 2.84-3.08 7H), 3.43 (dd, J=9Hz, 3Hz, 1H), 3.53-3.60 1H), 3.68 J=9Hz, 3.82 (s, 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-Methoxvyhenl- 4 -(1.3-benzodioxol-5-vl)-1-N-(trans-5-methylhexo1 2-enyl)-Dvrrolidine-3-carboxvlic jcid Examde 69A trans-5-Methvlhex-2-enoic acid ethyl ester Oil dispersion sodium hydride (0.85 g) was washed with hexanes 15 and suspended in THF (20 mL), and the mixture was cooled in an ice bath to 0 oC. Diisopropyl(ethoxycarbonylmethyl) phosphonate (5.0 mL) was added slowly and the mixture stirred for 20 minutes at 0 °C.

Isovaleraldehyde (2.0 mL) in THF (5 mL) was added dropwise over five minutes. The ice bath was removed and the mixture stirred for 18 hours 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 Na2SO4, 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 25 colorless oil (2.1 g).

Example 69B trans-5-Methvlhex-2-en-l -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 N in toluene, 20 mL) was added dropwise and the solution stirred at 0 oC 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 ,nd washinns were combined, dried, and evaported to give a -122colorless oil which was purified by flash chromatography on silica gel eluting with 25% EtOAc-hexanes. The title compound was isolated as a colorless oil (1.25 g).

ExamQ1k 69C trans-i -Bromo-5-methylhex-2-efle The compound resulting from Example 69B (1.0 g) was dissolved in diethyl ether and cooled to 0 0 C in an ice bath. Phosphorus tribromide g, 0.87 mL) was added dropwise and the solution stirred at 0 CC 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 g).

xml69 trans. trans--2-(4-MethoXylhenyl'- 4 .3-benzodixol-5-l)- 1 N- (trans- -mn eh lh x- 2-enyl'I-Dvrrolidifle-3-carboxylic acid The title compound was synthesized using the methods detailed in Example ID but substituting the compound resulting from Example 690 for N-propyl bromoacetamide. 1 H NMR (CDCI3, 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,IOHz), 3.20 (dd, 1H, J= 5Hz,l4Hz), 3.29 (dd, 1H, J=3Hz,lOHz), 3.50 (in, 1H), 3.70 11-, :J=lOHz), 3.78 3H), 5.47 (in, 2H), 5.93 6.71 1H, J=8Hz), 6.83 3H, J=9Hz), 7.05 1H), 7.32 2H, J=9Hz). MS (DCI/NH3) m/e 438 Anal calcd for C 2 6

H

3 1NO5: C, 71.37; H, 7.14; N, 3.20. Found: 0, 71.16; H, 7.24; N, 3.17.

Example trans. trans-2-(4-M ,thoxylohenl)-4-( 1.3-benzodioxol-5-yi')- 1 idn aro i aid 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 olef ins. The crude product was purified by preparative HPLC (Vydac iiCl8) eluting with a 10-70% gradient of GH 3 CN in 0.1% TFA. The 1ir-1,hilized to nivethe product (and its -123diastereomer) as a white solid. 1H NMR of the major (trans) isomer: (CDCI3, 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-Methoxvyhenyl)-4-(1.3-benzodioxol-5-yl)-1 heotylcarbonylmethvl-ovrrolidine-3-carboxvlic acid Example 71A 1 l-Chloro-3-proyDl-2-hexanone is To 2-propylpentanoic acid (156.6 gl, 1.00 mmol) dissolved in anhydrous dichloromethane (2 mL) was added DMF (3 glL, 4 mole and the solution was cooled to 0 °C 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 20 ambient temperature. The mixture was cooled to 0 °C 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 mL), dried over anhydrous sodium sulfate, filtered and concentrated 25 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 IL, 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-methoxyphenvl)-4-(1.3-benzodioxol-5-vl)-1-(4heptylcarbonvlmethyl-pyrrolidine-3-carboxvlate To the compound resulting from Example 71A (1.00 mmol, maximum theoretical yield) was added a solution of the trans,trans -124ethyl carboxylate from Example 1C (295 mg, 0.80 mmol as a 50 solution in toluene), diisopropylethylamine (700 jiL, 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 trans.trans-2-(4-Methoxyohenvl)- 4 -(1.3-benzodioxol-5-vlI-1 15 heotylcarbonylmethvyl-ovrrolidine-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 25 to cloudiness and then 10% aqueous citric acid was added to adjust the 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 (CDCI3, 300 MHz) 5 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 Anal calcd for C 2 8

H

3 5

N

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

-125- ExampiedZa trans. trans-2-(4-Met ogyphenl v-44-( 1 benZodOXQ-5-YlI)i -(valerymethyfl- Example 72A 1 -Chloro-2-hexAnQne 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.

ran. trans-Ehyl _2(4methoxy phenyl)b 4 .3-benzodioxole-5-yl)-1 l rvlmethyflpyrrolidine3carboD lt Substituting the compound resulting from Example 72A for 1- -chiloro-3-p ropyl-2-h exanone 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.

Exml 72Q trans, trans-Ethyl 2-(4-methoxyphenyl) 4 -(l,3-benzodioxol-5-yl)l h pyc b y ty)-yrlii 3cr xlt and using the procedure described in Example 710, 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 NMR (CDCI3, 300 MHz) 8 0.87 (t, 3H), 1.26 (in, 2H), 1.49 (mn, 2H), 2.37 (mn, 2H), 2.79-2.98 (mn, 3H), 3.31- 3.49 (in, 2H), 3.56 (in, 1 3.77. 3.79 4H), 5.94 2H), 6.75 1 H), 6.81-6.93 (mn, 3H), 7.09 1H), 7.33 2H). MVS (FAB) m/e 440 Anal. calcd for C 25

H

2 9 N06: C. 68.32; H, 6.65: N, 3.19. Found: C. 67.95-, H. 6.64: N, 3.05.

-126trans. trans-2-(4-Methoxvohenvl)-4-(1 .3-benzodioxol-5-vfl)-1 4dim eth oxben zy)-N-m ethylaminocarboylmethl)2rrolidile-3-ca rboxy ic acid Eample 73A trAns.trans- and cis. trpns-2-(4- Meth oxyphenyl')-4-( 1.3-ben zod ioxol yfl- 1 .4-dimethoxybenzylam i nocarboflyl rnethyl) pyrrolidi ne-3carboxylic acid ethyl ester Using the procedure of Example 1D, paragFoph 1, substituting 3,4dimethoxybenzyl bromoacetamide for dipropyl bromoacetamide, the desired product mixture was obtained as a white foam in 81% yield.

Example -73B :15 trans.trans- and cis. trans.-2-(4-Methoxyphenyfl)-4-(1 .3-ben zod yf)l-(N-(3.4-dimethoxybenzyfl-NmethylaminocarbonymethlDyrrolidine-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 THE, under an argon atmosphere. The resulting mixture was stirred at 0 00 for 1 hour, then methyl iodide (28 jiL, 64 mg, 0.45 mmol) was added. The reaction mixture was stirred at 0 00 for 45 minutes. TLC (Et 2 O) in dicated .*25 incomplete reaction. An additional portion of methyl iodide (28 l 1 iL, 64 mg, 0.45 mmol) and dry 1 ,3-dimethyl-3,4,5,6-tetrahydro- 2(1 H)pyrimidinone (50 gL, 0.41 mmol) were added. The reaction mixture was stirred at ambient temperature for 2 days. The reaction was poured into 25 mL of 0.5 M aqueous citric acid and extracted with 2 x 25 mL EtOAc. The combined organic extrracts were washed sequentially with 30 mL water and 30 mL brine, then dried (Na2SO4).

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. 1

H

NMR (ODC1 3 300 MHz) 5 2.79 and 2.81 for the N-OH 3 signals. MS m/z 591 -127trExmpl 2 enC dieh -mel~lNeth lmin cr I hbYroldne-- To the resultant compound from Example 73B (98 mg, 0.17 mmol) dissolved in I mL EtOH and cooled to 0 oC 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 H 2 0 and 15 mL Et2O. She 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 (Na2SO4) then filtered and concentrated in vacuo to give 40 mg of the title compound as a white foam. 'H NMR (CD30D, 300 MHz, two rotameric forms) 2 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 (mn, 1H), 6.67- 7.02 (br m, 6H), 7.29 (br d) and 7.35 (br d, 2H total). HRMS calcd for

C

31

H

3 5N2O8 563.2393. Found: 563.2385.

Example 74 ~~trans trans7!2(4-Nlth xY h nv 4 t 1 3bn~i~~ N- (3.4 :25 dMeth xbnZ 'minnocarbonvlm ethvfllvrrolidine- xvclic ac'id 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. 'H NMR

(CD

3 OD, 300 MHz) 8 2.85 J=1l6Hz, 1 2.92 (br t, J=9Hz, I1H), 2.98 (br t, J=lIOHz, 1H), 3.32-3.39 (br m, 2H), 3.54-3.65 (br 1H), 3.67 3H), 3.78 (s, 3H), 3.80 3H), 3.85 J=10 Hz, 1H), 4.21 J=15Hz, 1H), 4.41.

J

1H), 5.91 (s 2H), 6.67 J=8Hz, 1H), 6.75-6.95 (in, 7H), 7.33-7.40 (in, 2H). HRMS calcd for C 3 0 H32N2O8 549.2237. Found: 549.2224.

128- Example (2R.3R.4R)-2-(4-Methoxyhenvl)-4-(1.3-benzodioxol-5-vl-1-((1 diprooylaminocarbonyvl- 1- butyllvrrolidine-3-carboxylic acid Example trans. trans2-f(4-Methoxyohenyl-4-( .3-benzodioxol-5-Y|)-1 R)-lbenzvloxvcarbonvlbutvovrrolidine-3-carb 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 2bromopentanoate (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 Na2CO3 and 25 mL of CH 2 C02. The aqueous phase was 15 extracted with 2 x 10 mL CH 2 CI2, and the combined organic phases were washed with 15 mL brine, dried (Na2SO4), 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

CH

2

CI

2 -hexane to produce 106 mg of the title compound as a waxy 20 solid. 1H NMR indicated the presence of two diastereomeric products.

Example trans. ran -2(4-Methnovhen v- 4 -1 3-b nz dioxl-5Yl 1R (N dipropylamincarbonvl.l.butylvyrrolidin-3-carboxylic acid thyl ester 25 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 was removed by distillation under reduced pressure, and the residue 129was partitioned between 20 mL EtOAc and 10 mL of 1 tdaqueous Na2003.

The organic phase was washed with 10 mL of brine, dried (Na2SO4), then filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 1:2 Et 2 O-hexane.

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

2

R.

R

4n2( Mtoyhen l 4 X3bn od1xl-5V- I R-1- (N.N~i~r Plmncarbon 1-lbutyliprrolidi -3carboxylic 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 7313, to provide the title compound in 94% yield. [czj 520 (c=0.235,

CH

3 OH). 1H NMR (CD300. 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 m, 4H), 1.90-2.07 (br m, 1H), 2.75-2.94 (br m, 2H), 2.94-3..02 (br m, 2H), 3.20-3.40 (in, overlapping with CD 2 HOD signal), 3.40-3.60 (br mn, 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, 1H), 6.92-6.98 (br m, 3H), 7.29-7.39 (in, 2H). MS mn/z 525 Example 76

(S.

3 4 SV~44ethXyDhenyl 4 .3-benzodioxo-5i)I'-((1 (N .Nd iDroDlamiinocarbony 'l bli)Dy2 lrrolidine3cabxv 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 7313, to provide the title compound in 88% yield. [(ctI +580 (c=0.37,

CH

3 OH). 1H NMR (00300. 300 MHz) 8 0.57 (br t, J=7Hz, 3H), 0.88-0.98 (in, 6H), 1.08-1.35 (br m, 2H), 1.35-1.68 (br in, 4H), 1.75-1.90 (br mn, 1H), 2.75-2.86 (br m, 2H), 3.10-3.30 (br m, 2H), 3.51-3.65 (br in, 2 3.69 3H), .4.03-4.16 (br in, 2H), 5.91 2H), 6.71-6.83 (in, 2H), 6.86-6.97 (mn, 3H), 7.32 (br d, J=9Hz, 2H). MS m/z 525 -130dirovlmil~ar~fhl 1-4 nb fpyr~difloaroxcai tra,gs, trans24eto hn 1 4 3~bn~iXl5V~ (1S- (N.N-diprop lminO rbn 11-1 butyflpyroliinle-3cArbX-XIc aId (2 R)-N ,N-dipropyl 2-hyd roxypentanamide (106 mg, 0.528 mmol, made by standard procedure) was dissolved in 2 mL THF under an argon 0*atmosphere, dii sop ropylethylamin e (75 mg, 0.58 mmol) was added, then the solution was cooled to -20 0 C. Trifluoromethaflesulfonic anhydride g.L, 159 mg, 0.565 mmol) was added to the cooled solution over 1 minute, and the reaction mixture was stirred at -20 0 C for 1 hour, and :ep. is at room temperature for an additional 1 hour. The resulting slurry was 0@*:recooled to 0 0 OC, and a solution of the resultant compound from Example 6A (195 mg, 0.528 mmol) and diisopropylethYlamifle (101 1 jl-, 75 mg.

:0.58 mmol) in 3 mL of CH 2 CI2 was added. The reaction was stirred at 0 0 IC for 3 hours and for an additional 2 days at room temperature.

TLC

(Et 2 O-hexafle 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 Maqueous Na2CO3. The aqueous phase was extracted with 15 mL EtOAc, then the combined **:organic phases were washed with 20 mL brine, dried (Na2SO4). filtered and concentrated in vacuo to a yellowish oil. Purification by flash 000 chromatography on silica gel eluting with 1:2 Et 2 O-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.

Examaple _77B 4S 4M-h he .3n i x'l-Vl: -1 S'-(NNdioroyl~mil~caronvl I ~btfrr iidlrne-3-carbox 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. 'H NMR

(CD

3 OD, 300 MHz) and MS identical to those of Example -131- ExamDle 78 R.3R.4R 4Meho h.3-benzdioxol-5-l-1 diDroDlaminocarbonv)-l -butvl)ovrrolidine--arbxlic acid The procedure of Example 73C was followed, with the substitution s of the more polar isomer from Example 77A for the resultant product from Example 73B, to provide the title compound in 88% yield. 1H NMR

(CD

3 OD, 300 MHz) and MS identical to those of Example 76.

Exmle 79 o trans.trans 2.(4-Mthoxvhenv-4-(1 .3-.benzodioxl-5-Vl N-dinbutvl)aminocarbonvlmeth 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 The reaction 15 mixture was cooled in an ice bath, and 25% solution of ammonia in 1 methanol was added. After 30 minutes, the solid which had formed was 0* filtered, washed with ethanol and finally with ether to yield 850 mg of the 3-carboxamide compound. m.p. 194-196

°C.

Phosphorus oxychloride (1.06 g) was added to this amide in 7 mL S 20 of pyridine, and the mixture was stirred 1 hour at room temperature.

Dichloromethane was added, and the solution was washed with potassium bicarbonate solution, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with 2:1 hexane-ethyl acetate to give 790 mg of the 3carbonitrile compound.

STo 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 °C (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 acidified with acetic acid to get 532 mg of the title compound.

m.p. 165-167 H NMR (CDC13, 300 MHz) 8 0.85 J=7Hz, 3H), 0.87 -132- 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, 7.11 J=9Hz, 2H).

trans, trans-2-(4-Fluoroghenl)lY 4 3- benzodioxol-5-yll N-dI nbutyI)amInocarbonW mthI prrolidine-3-cartmlic acid The title compound was prepared as an amorphous solid from methyl (4-flourobenzoyl) acetate and 5-(2-nitrovinyl)-l ,3-benzodioxole using the procedures described in Examples 1 and A43. 1 H NMR (CoDC 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 (mn, 3.15-3.30 (in, IH), 3.32-3.45 (in, 3H), 3.55-3.65 (in, 1H), 3.86 J=lOHz, 1H), 5.94 (dd, J=2Hz, 4Hz, 2H), 6.72 J=B Hz, 1H), 6.86 J= 8 Hz, 1H), 6.95-7.07 (mn, 3H), 7.32- 7.4 5 (in, 2H).

~trans. trans-2)44MethoXYghenyl 4 .3bezdiXI-Vl- inbu tyl) am in ocarbonl ethl pyrroli dinecar oxlc aci N,N-Dibutyl glycine (150 mg, 0.813 inmol), prepared by the method of Bowman, J. Chein. Soc. 1346 (1950), in 0.7 mL of THF was treated with 138 mg (0.852 mmol) carbonyldiimidazole and heated for minutes at 50 00. After cooling to room temperature, 250 ing :(0.678 mmol) of ethyl trns tas2(-ehxpny)41,3- *:25 bezdoo--i-yrldn--abxIae the compound resulting from Example 6A, was added, and the mixture was heated at 45 ad 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. 1 NMR (00013, 300 MHz) 5 rotational isomers 0.75 and 0.85 (2 t, J=7Hz, 3H), 1.05-1.5 (mn, 8H), 2.65-3.20 (mn, 6H) 3.43-3.70 (in, 3H), 3.72 3H), 3.87 J=l5Hz, 4.49 (dd, J=l2Hz, 6Hz) and 5.23 (dd, J=l2Hz, 8Hz) 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).

-133trans, trans-2-(4-Methogyphenl)l4-( 1.3-bez iOXI -5vy1)1 n -b utvfl-N-(f-1 p2ropyflam inoca rbpflylm ethyfl1yrrol idine-3-ca rbgXyli acid The title compound was prepared using the procedures described in Example 1. m.p. 160-162 OC. 1 H NMVR (CDCI 3 300 MHz) rotational isomers 8 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=lOHz, 1H), 3.78 3M), 5.92-5.96 (in, 2H), 6.72 J=8Hz, 1H), 6.83-6.89 (in, 3H), 7.03 J=2Hz, 1H), 7.81 J=9Hz, 2H).

Exammle 8 ~trans. trans-2-(4-Methox )henl)l 4 1.3-benzodi~xol-5-yll .N-di(ninoca bonyl~ethyl]Drl iinpab~clcai 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 00 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 mg of the diallyl compound.

~.The diallyl compound was hydrogenated using 10% Pd/C catalyst (27 mng) in ethyl acetate (25 mL) under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated *25 to afford the dipropyl amide ethyl ester in 100% yield.

The ester was hydrolyzed to the title compound by the method of Example 10D in 83% yield. H NMR (00013, 300 MHz) 6 0.82 and 0.83 (two triplets, J=7Hz, 6H), 1.39-1.54 (mn, 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 (in, 1H), 3.73 (d, J=12H, 1H), 3.75.(s, 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).

-134trans trans-2-(4-MethoXyphenyl)- 4 .3-benzodioxpl-5-yf)l--(N .N-di(nbutyflam inocarbonvfl)pyrro lidifle3-carboM&ylicWi 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. IH NMR (CDCI3, 300 MHz) 8 0.86 J=7Hz, 6H), 1.14-1.28 (in, 4H), 1.35-1.48 (in. 4H), 2.81-2.94 (mn, 2H), 3.11 J=12Hz, 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, 1H), 5.94 2H), 6.73-6.86 (mn, 5H), 7.24 J=9Hz, 2H-).

trans, trans-2-(4-MethoxYphenyl)- 4 (1 .3beBnzodioxol-5-yl)- 1 N-di(nbutvl~~~aIinocarpflimethV1)D~trr~fiin3qrbo cd oimsl is Sodium hydroxide (48.2 mg of 98.3% pure, 1.184 minol) in 2 mL of MeOH was added to the compound resulting from Example 43 (610 mng, 1.196 minol.) 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 00 to yield 627.5 mng of the title compound.

trans-24(4-MethoX=h n 1)- 4 1, -bnzodiol-y)l xr-N.-in bUtyfl)mino~pthyl1Dyrrolidife 3 -,arboxylic aid A solution of the bromoethyl compound resulting from Example 61 A (150 mg), dlibutylamine (150 mg) and sodium iodide (18 mg) in 0.75 mL ethanol was heated at 80 00 for 1 hour. After cooling. toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na 2 SO4 and concentrated. More toluene was added, and the solution was again concentrated to get rid-of excess dibutylamine. The residue was dissolved in warn') heptane and filtered from a small amount of insoluble material. The hepane was removed in vacuo to give 143 mng (870/) of the intermediate ethyl ester.

The ester was hydrolyzed by the method of Example I D to give the title compound as a white powder. 1 H NMR (CD 3 00, 300 MHz) 8 0.89 (t, J=7Hz, 6H), 1.16-1.30 (in, 4H), 1.44-1.56 (in, 4H), 2.48-2.57 (mn, 1H), 2.80-3.08 (in, 8H), 3.14-3.25 (in, 1H), 3.31-3.38 (mn, 1H), 3.59-3.60 (mn, -135- 1H), 3.74 3H), 3.75 J=lOHz, 111), 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).

7~~ trans. trans- 2-(4-M ethoxvo~henvl)-4- (1 .3-benzod ioxol1-5-fl)- 1 N-di (nhbutflaminocarbonl)-N-m ethylaminolethllpyrrlidile-3-crboxylic 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 !3emperature, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na2SO4 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 1D to afford 141 mg of the title compound. 'H NMR (00300, 300 MHz) 8 0.92 (t, J=7Hz, 6H), 1.21-1.32 (in, 4H), 1.42-1.53 (in, 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 (mn, 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=lOHz, 2H).

Examole 88 trans, trpns-2-(4-MethoxyohenlI-4-( 1.3-benzodioxol-5-Vi)- .N-di(n- Carbonytdiiinidazole (75 mg, 0.463 minol) was added to 150 mng (0.294 minol) of the compound resulting from Example 43 in 0.4 mL of tetrahydrofuran, and the solution was stirred at 60 00 for. 2 hours.

After cooling, 50 mg (0.526 mmol) of inethanesulfonainide and 68 mng (0.447 inmol) of DBU in 0.3 mL of THF were added. The mixture was stirred at 45 OC for 2 hours. The solvents were removed in vacuo, and the residue was dissolved in water. A few drops of acetic acid were added, and the solution was lyophilized to give 121 mg of the title compound. m.p. 170-1730 'C 1H NMR (00013, 300 MHz) 8 0.82 (t, J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.51 (in, 81H), 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, IIH), 3.80 3H), 3.87 J=lOHz, 1H), 5.96 (dd, J=2Hz, 4Hz, 2H), 6.74 (d, -136- J=9Hz, 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).

Examole 89 trans, trans-2-(4-Methoxyohenyfl-4-( 1.3-benzodioxol-5-yfl- 1I-(N N-di(nbutvl)aminocarbonylmethvfl)yrrolidine-3-(N-benzelesu lfonyl)carboxamide 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 00 for a sample recrystallized from acetonitrile. 1 H NMR (CDCI3, 300 MHz) 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, 7.55 J=7 Hz, 2H), 7.66 J=7Hz, 1H), 8.95 (d, J=7Hz, 2H).

Examiole trans. trans-2-(4-Methoxvohenfl)-4-(1 .3-benzodioxol-5-vl)- 1 N-di(n-butyl) inosyIf onylm ethyll-gvrrol idin e-3-ca rboxl ic acid Chloromethyl sulfenyl chloride, prepared by the method of Bnintzinger et. al., Chem. Ber. U: 455-457 (1952), is reacted with dibutylamine by the method of E. Vilsmaier described in Liebigs Ann.

Chemn. 1055-1063 (1980) to give N,N-dibutyl chloromethyl sulfenyl chloride. Alternatively dimethyl(methylthio)sulfonium :25 tetraflou robo rate is reacted with dibutylamine to give N,N-dibutyl methylsulfenyl chloride which is chlorinated with N-chlorosuccinimide to give chioroinethyl sulfenyl chloride by the method of E. Vilsinaier, described in the above reference.

The N,N-dibutyl chloromethyl 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)-1 -[N,N-di(nbutyl)aminosulfenylmethyl]-pyrrolidine-3-carboxylate. This is oxidized with osmium tetroxide and N-methyl morpholine N-oxide by the method of S. Kaldor and M. Hammond, Tet. Lett. 32: 5043-5045 (1991) to give the title compound after hydrolysis of the ethyl ester.

-137- Example 91 trans.trans-2-(4-Methoxyhenyl)-4-(1.3-benzodioxol-5-vl)- 1-(N.N-di(nbutvylaminocarbonvl-1 -(RS,-ethyloyrrolidine-3-carboxvlic acid Example 91A (±+-Dibutyl 2-bromoDrooanamide 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 o0 (0.45 mL, 3.5 mmol). After 10 minutes at 0 OC, dibutylamjne (0.57 mL, 3.4 mmol) was added. The reaction was stirred at 0 °C for 1 hour and for an additional 16 hours at room temperature. The mixture was partitioned with 25 mL of 1.0 M aqueous Na2CO3 solution, then the organic phase was washed sequentially with S* 25 mL of 1 M aqueous NaHSO4 and 25 mL brine, dried (Na2SO4), filtered, and 15 concentrated under reduced pressure to afford 698 mg (2.64 mmol, 79 of the crude bromoamide as a colorless oil. 'H NMR (CDCI3, 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)- di(n-butyl)aminolcarbonvl-1-(RS)-ethyl)Dvrrolidine-3-carboxvlic acid ethyl ester A solution of the resultant mixture of trans,trans and cis,trans compounds 25 from Example 1C (232 mg, 0.628 mmol) and the resultant compound from Example 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 10 mL of 1 M aqueous Na2CO3 solution. The organic phase was washed with 20 mL water and 20 mL brine, dried over Na 2 SO4, 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. 1H NMR (CDC 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 -138- (in, 2.6H), 4.38 J=10.5Hz, 0.2H) and 4.58 J=10.5Hz. 0.2H), 5.90-5.97 (in, 2H), 6.68-6.96 (mn. 5H), 7.38-7.43 (in, 2H). MVS (DCIINH 3 Wle 553 Ex mpg 91 trans. trAns-2-(4-Methoxylhenyll-4-( 1.3-benzodioxol-5-yl-1

N-

dibutylam 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) 860.70-1.05 (several mn, 8H), 1. 14 J=6Hz, 2H), 1. 17-1.55 (in, 6H), 2.79-3.03}rn. 3.5H), 3.20-3.65 (br in, 4.6H plus CD 2 HOD), 3.70-3.78 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 (d, J=2.5Hz) 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 mWe 525 Anal calcd for C 30

H

4 0

N

2 0 6 0.5H 2 0: is C, 67.52; H, 7.74; N, 5.25. Found: C, 67.63; H, 7.65; N, 5.21.

Examole_92 trans. trans-2-(Pentyl)-4-(1 .3-benzodioxol-5-vl)-1 .N-di(n- .butyll am inocarbonyl m ethyl)pyrrolidi ne-3-ca rbxylic acid Examp~le 92A Methyl 2-(4-hexenoyl)-4-nitro-3-( 1 A solution of methyl 3-oxo-6-octenoate (502 mg, 2.95 inmol) in 10 mL of isopropanol was added to a solution of 5-(2-nitrovinyl)-1 ,3-benzodioxole (712 ing, 3.69 iniol) in 10 mLTHF, then DBU (22 jlal, 0.15 minol) was added. The resulting reddish solution was stirred at room temperature for 20 minutes. TLC (ethyl acetate-hexane, 1:3) indicated complete consumption of ketoester. The solution was concentrated in vacuo and flash chromatographed on silica gel eluting with 18% ethyl acetate in hexane to produce 879 mg (2.42 inmol, 82%) of the title compound as a mixture of diastereoiners in a 1:1 ratio. 1 H NMR (00013, 300 MHz) 8 1.55-1.66 (in. 3H), 2.02-2.17 (br in, 1 2.20-2.37 (in, 1 2.49-2.76 (in, 1 3.57 1 3.74 1 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 (mn, 1 H), 6.68 (br s, 1 6.75 7.5Hz, 1 MS (DCI/NH 3 m/e 381 (M+NH 4 Anal calcd for C, 8

H

2 1 N0 7 0, 59.50; H, 5.82; N, 3.85. Found: C, 59.32; H, 5.71; N, 3.72.

-139- Example 92B Methyl trans.trans-2-(pentyl)-4-(1.3-benzodioxol-5-vylDvrrolidine-3-carboxylate The procedures of Example 1B and Example 1C were followed, with the substitution of the resultant compound from Example 92A for the resultant 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 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 NaHCO3 diluted with 10 mL water and 30 mL of CH 2

CI

2 The aqueous phase was extracted S(2 x 30 mL CH 2

CI

2 then the combined organic phases were washed with 20 mL 15 brine, dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford the crude product. Purification by flash chromatography on silica .i gel eluting with 3.5% methanol in CH 2 CI2 gave 336 mg the title compound as a yellow oil. 1 H NMR (CDCI3, 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 (m, 20 2H), 3.53 J=9Hz, 1H), 3.66 3H), 5.94 2H), 6.65-6.75 3H). MS

(DCI/NH

3 m/e 320 (M+H) Anal calcd for C18H25N04: C, 67.69; H, 7.89; N, 4.39.

Found: C, 67.39; H, 7.84; N, 4.37.

Example 92C trans. trans-2-(Pentvl)-4-(1.3-benzodioxol-5-yl-1-(N.N-di(nbutvlaminocarbonvlmethvl'Dvrrolidine-3-carboxvic acid 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/NH3) m/e 475 (M+H) Anal calcd for C 27

H

42

N

2 05-0.5H20: C, 67.05; H, 8.96; N, 5.79. Found: C, 67.30; H, 8.77; N, 5.68.

-140- E&IMPJle-2 trans. trans-2-(Pentyfl-4- (1 3-benzodioxol-5-yi)- 1 42-(N-gropyl-NW propylsulfonylamino)ethyllpyrrolidine-3-carboxylic acid Exam 9A Methyl trans, trans-2-(oentyl)l-4-( 1.3-benzodioxol-5-fl)-1 (2-bromoethyflo1yrrolidine- The procedure of Example 61A was used, with the substitution of the resultant compound from Example 92B for the resultant compound from Example 1C, to provide the title compound as a yellow oil. 1 H 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 (in, 2.76- 2.91 (in, 2H), 3.10-3.22 (in, 2H), 3.36-3.47 (in, 2H), 3.68 3H), 5.92 2H), 6.69- 6.77 (in, 2H), 6.90-6.94 (mn, 1H). MS (DCi/NH 3 m/e 426, 428 Example 9aB Methyl toans. trans-2-(Pentyfl-4-(1 .3-benzodioxol-5-yl-1 -12-(N-oropyl-N- *progylsulfonylpinino'~ethyl1Drrolidine-3carbogxylate A solution of the resultant compound from Example 93A (102 mng. 0.24 minol) and tetrabutylaminonium iodide (6 mng, 16 jimol) in 1 mL EtOH was treated with :20 propylainine (60 0.73 inmol). The solution was warmed to 80 OC 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 C03. The organic phase was washed with 15 mL brine, then dried over *:Na 2 SO4, 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 01 2 diiosopropylethylamine (65 il-, 0.373 minol) was added. followed by propylsulfonyl chloride (29 4iL, 0.26 minol). 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

CI

2 The combined organic extracts were washed with 2 mL brine, then dried over Na2SO4, filtered, concentrated in vacua. 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 (001/NH 3 m/e 511 -141- ExamMle 93 trans. trans-2-(Pentyl)-44(1. 3-beodOl5-I-1 -r(NropyI-Npropylsulfonylamino~ethyllyrrolidifle-3-carboxylic acid The procedure of Example 71 C was followed, with the substitution of the resultant compound from Example 93B for the resultant compound from Example 71B, to provide the title compound as a white foamn (47 mg, Rf 0.14 (5%MeOH-CH2CI2). IH 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, 1H), 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/NH3) m/e 497 Ex ml~le94 ~~~trans. trans-2-(Propyl)- 4 .3-benzodioxol-5-yfl-1 -N.-in o 15 'butyl~aminocarbonylinethyl)DYrrolidine3carboxylic acid o Exampl -94A The Ethyl 2-(4-butanoyfl-4-nitro-3- (1 0 0 h 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). 1H 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, 1.5H), 1.63 (sextet, J=7Hz, approx. 1.5H), 2.17 J=7Hz) and 2.24 J=7Hz, 0.5H total)2.40-2.

5 4 (in, 1 2.60 J=7.5Hz) and 2.67 J=7.5Hz, 0.5H total), 3.93-4.09 (in, 2H), 4.10-4.20 (br m, 1H), 4.23 J=7Hz, 1H), 4.67-4.85 9m, 2H), 5.94 2H), 6.62-6.75 (in, 3H). MS 0::(DCIIN

H

3 mWe 369 Anal calcd for C1 7

H

2 1NO7: C, 58.11; H, 6.02; N, 0: 3.99. Found: C, 58.21; H, 5.98; N, 3.81.

30Exml94 Ethyl trans. trpns-2-(oro- 4 ;-fiy ldne3cnQXl 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 m/e 306 -142- Exampile 4Q trans. trans-2-(Prooy'-4-(1 .3-benzodioxol-5-Vl')- 1 butyflamincarbonylmethyfl)yrrolidle-3-carboxylic acid The procedure of Example 92C was followed, with the substitution of the resultant product from Example 94B for the resultant product from Example 92B. to give the title compound. 1H NMR (CDCl3, 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, 1H), 3.40-3.55 (br 2H), 3.55-3.68 1 3.78 J=1l5Hz, 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 H38N2050.5 H 2 0: C, 65.91; H. 8.63; N, 6.15.

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

(2R.3R.4S)-(+)-2-(4-Methoxyohenl)-4-(1 .3-benzodioxol-5-yfl-1 -(tertbulyloxycarbgnyl-aminocarbollm ethyfl)-yrrol id ine-3-carbo(ylic acid Example 0. 0. trans. trans-2-(4-Methoxyphenyl)-4-( 1. 3-benzodioxol-5-ylI- 1 -iftertbutyloxycarboriylamlinocarbonylm ethvlloyrrolidine-3-carboul ic acid :20 The resulting mixture of 64% trans,trans- and cis,transpyrrolidines resulting from Example 10 (,3.01 g, 8.15 inmol) was oooodissolved in 50 mL of methylene chloride. To this was added dropwise a solution of di-tert-butyl dicarbonate (1.96 g, 8.97 minol) in 20 mL methylene chloride under a nitrogen atmosphere, and the resulting solution was stirred 30 minutes at which point TLC (ethyl 0 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. 1H 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 mn, 1H), 3.44-3.95 (in, 3H), 3.81 3H), 4.04 J=7 Hz, 1H), 4.14-4.28 (br m, 1 4.89-5.24 (br m, 1 5.94 J=3 Hz, 2H), 6.69-6.90 (in, 5H), 7.06-7.20 (mn, 2H). MS (DCI/NH 3 infe 470 (M+H) 4 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 ethanol, diluted with 250 mL of water and extracted three times with -143- 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 (Na2SO4), filtered, concentrated and dried on high vacuum to give the title compound as a white foam (2.19 g, 'H NMR (CDCI 3 300 MHz) 5 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 2H), 6.71-6.79 3H), 6.84-6.91 2H), 7.19 J=9 Hz, 2H). MS (DCI/NH3) m/e 442 ExamDle (2R.3R.4S)-(+)-2-(4-Methoxyhenyl)-4-1 .3-benzodioxol-5-vl)-1-(tertbutyloxvcarbonvlaminocarbonvlmethvl)-Dvrrolidine-3-carboxylic 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 i the same conditions seven additional times. Each time the resulting crystals and filtrate were monitored by 1 H 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 (Na2SO4), filtered, concentrated and dried on high vacuum to a white powder (550 mg, 55 of theoretical 50 maximum,' >99.5 ee). 'H NMR (CDC13, 300 MHz) 8 1.05-1.50 (br m, 9H), 3.12 (br m, 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.(d, J=9 Hz, 2H). MS (DCI/NH 3 m/e 442 -144- Examiple 950 (2R-3R 2-(4-mrethoxyohenvfl-4-(1 .3-benzodioxol-5-yl)-pyrrolidine-3- 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 yvas further extracted with methylene chloride (2 x 50 mL). The combined organic layers were dried (Na 2 SO4), filtered, concentrated and dried under high vacuum to :give the title compound as an almost colorless oil (158 mg, 1H NMR (CDC1 3 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 (in, 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 (in, 3H), 7.34-7.41 (in, 2H). MS (DCI/NH3) m/e 370 Examlple (2R.3R.4S)- &U-2-(4-Methoxvohenyl)-4-( 1 3-benzodioxol-5-yl)-1 -(tertbutyloxycarbolyl-amilocarbonylm ethyfl)-oyrrolidine-3-car--.xlic acid To the resulting compound from Example 95C (131 mg. 0.355 mmol) was added, diisopropylethylamirle (137 mg, 185 g.L, 1.06 mmol), acetonitrile (2 mL), N,N-di-(n-butyl)bromnoacetamnide (133 mg, 0.531 minol), and the mixture was heated at 5000C. 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 acetatehexane to give pure ester as a colorless oil. 1 H NMR (COCl 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 (in, 8H), 2.78 J=14 Hz, 1H), 2.89-3.10 (in, 4H), 3.23-3.61 (in, 5H), 3.71 J=9 Hz, 1H), 3.80 3H), 4.04 J=7 Hz, 2H), 5.94 (dd, J=1.5 Hz, 2H), 6.74 J=9 Hz, 1H), 6.83-6.90 (in, 3H), 7.03 J=2 Hz, 1H), 7.30 J=9 Hz, 2H). MS (DCI/NH 3 m/e 539 To the ethyl ester dissolved in 7 mL of ethanol was added a solution of lithium hydroxide (45 mg, 1.06 inmol) in water (2.5 mL). The mixture was stirred for 1 hour at ambient temperature and then warmed -145slowly to 40 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 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 SO4), filtered, concentrated and dried under high vacuum to give the title compound as a white foam (150 mg, 1 H NMR (CDCl 3 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 (m, 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 C 29

H

38

N

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.

Example Altemate Preparation of (2R.3R,4S)-(+)-2-(4-Methoxyhenl)-4-(1 yl)- -(tert.butyloxycarbonlaminocarbony lethvl)-pvrrolidine.3-carboylic acid 20 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 added. After -146stirring for a few minutes the crystals were filtered. Yield: 1.401 g, m.p. 164-172*.

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

Exali 9 trans. trans-2-(4-MethoxVmhenfl- 4 1.3-benzodioxol-5-VI)- 1 -r2-(N-QroDVIl-Nbutvrvamino~ethyl1D~yrrolidie3-carbo2X~li 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 pgC18) eluting with a is* 10-70% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) 8 0.80 (in, 3H), 0.90 3H, J=8Hz), 1.42 (in, 2H), 1.58 (heptet, 2H, J=8Hz), 2.20 3H, J=8Hz), 2.94 (br m, 2H), 3.10 (br mn, 2H), 3.48 (br m, 4H), 3.76 (br m, 2H), 3.78 3H), 4.30 (br s, 1H), 5.95 2H), 6.75 (d, :20 1H, J=8Hz), 6.84 (in, 1H), 6.85 2H, J=8Hz), 7.04'(d, 1H, J=1 Hz). 7.40 2H, J=8Hz). MS (DCI/NH3) in/e 497 Anal calcd for 0 28

H

36 N206 -1.0 TFA: C, 58.82; H, 6.42; N, 4.57. Found: C, 58.77; H, 6.30; Vol% N, 4.42.

Examl 7 trans. trans-244- ethoxypheyl)lV 4 1.3-benzodixol-5VlV 1 rnnyl-N- :(ethyl am in ocarb)oyl) amin o) ethvll pvrroidin e-3-carboXalic acid The title compound was prepared by the methods described in Example 61, but substituting propylamnine for inethylainine in Example 61B and ethyl isocyanate for isobutyryl chloride in Example 610. 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 rotamers 5 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 (in, 1H), 3.75 (in, 1H), 3.78 3H), 4.8 (br s, 1H), 5.95 2H), 6.74 1H, J=8Hz), 6.85 (in, 3H), 7.00 1H), 7.30 2H, J=8Hz). MS (001/NH 3 Wne 498 -147- Anal calcd for C 2 7

H

35

N

3 06 -0.75 H 2 0: C, 63.45; H, 7.20; N, 8.22. Found: C, 63.38; H, 7.29; N, 8.44.

Exa mple9 trans, trans-2-(4-Methoxypheyl)l- 4 1 3-benz.odioxol-5-yfl)-1 -T2-(N-butyl-Nbutyrylamino~ehylDyrrolidile-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 61B and butyryl chloride for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1:.4 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 (in, 3H), 0.90 3H, J=8Hz), 1.45 (in, 4H), 1.6 (in, 2H), 2.20 3H, J=8Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.5 (br m, 4H), 3.80 (br m, 2H), 3.82 (s, 3H), 4.30 (br s, 1H), 5.95 2H), 6.75 I1H, J=8Hz), 6.84 (in; 1H), 6.85 2H, J=8Hz), 7.04 1H. J=lHz), 7.40 2H, J=8Hz). MS (DCI/NH 3 mle 511 HRMS calcd for C 29

H

38

N

2 O6: 511.2808. Found: Examoplem9 trans. trans-2-(4-Methoxyphelyl-4-( 1.3-benzodioxol-5-yfl-1 -12-(N-propvl-Nethoxycarbonyla inoehylDvrrolidine-3-Carbox~lic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and ethyl 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. 1 H NMR (CDCI3, 300 MHz) 8 0.80 3H, J=8Hz), 1.05 (in, 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 m, 2H), 3.27 (br in, 2H), 3.44 (mn, IH), 3.54 (dt, 1H, J=1,8Hz), 3.63 1H, J=8Hz), 3.78 (s, 3H), 4.02 (br d, 2H), 5.93 2H), 6.72 1H, J=8Hz), 6.81 (dd, 1H, J=1,8Hz), 6.85 2H, J=8Hz), 7.00 1H), 7.30 2H, J=8H-z). MS (DC I/N H 3 m/e 499 Anal calcd for C 27 H1 3 4N207 0.5 H 2 0: C, 63.89; H, 6.95; N, 5.52. Found: C, 64.03; H,-6.71; N, 5.30.

-148- Exmple 100 trans. trans-2-(4-Methoxyhenyfl-4-( 1.3-benzodioxol-5-yfl- I -r2-(N-methYl-N- (2ethylbutyylamino~ethylOyrrplidifle-3-carboxylic acid To -the compound resulting from. Example 61B (190 mg) dissolved in THF (2 mL) was added HOBt (60 mg), EDCI (85 mg), Nmethylmorpholine (50 tLL), and DMVF (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 hlI H 3 P04, and brine, dried with Na2SO4, 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 (CDC1 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 (mn, 1H), 2.32 (in, IIH), *:2.45 (mn, 1 2.70 (in, 1 2.86, 2.94 total 3H), 2.95 (mn, 1 3.35 (in, 1 3.52 (in, 2H), 3.65 (in, 1 3.80 3H1), 5.94, 5.96 total 2H), 6.73 (in, 1 6.84 (in, 3H), 6.97 (in, 1H), 7.30 (in, 2H1). MS (DCI/NH 3 in/e 497 (M+H) 4 Anal calcd for C 2 8

H

3 6 N206 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. trans-2-(4-Methoxvlhenyl)-4-( 1.3-benzodioxol-5-vfl)-1 -r2-(N-m ethyl-N-42- Droo~ylvalerylanino~ethylDvrrolidine-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 liC18) 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.

H NMR (00013, 300 MHz) 850.79 3H, J=8Hz), 0.82 3H, J=8Hz), 1.10 (in, 4H), 1.2-1.5 (in, 4H), 2.55 (in, 1H), 2.96 3H), 3.15 (br in. 1H), 3.32 (br in, 1H), 3.56 (in, 2H1), 3.68 (mn, 1H) 3.68 3H), 3.70 (mn, 1H), 3.80 (in, 2H), 4.65 (br d, 1H), 5.92 2H), 6.75 1H, J=8Hz), 6.84 (in, 1H), 6.85 2H, J=8H1z), 7.05 1H1), 7.42 2H, J=8Hz). MS (DCI/NH3) in/e 525 -149- Anal calcd for C 3

OH

4

ON

2 O6 -1.25 TEA: C, 58.51; H, 6.23; N, 4.20.

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

ExamgJe-102 trans, trans-2-(4-Methoxylhenyl)-4-( 1.3-benzodioxol-5-yfl- 1 -12-(N-propyl-N-(terthi tyioxycarbofllm ethyflam ino~ethyllpyrrolidin e-3-ca rboxyl ic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine fo r 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 CH 3 CN and water and lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) 8 0.82 3H, J=8Hz), 1.18 (in, 2H), 1.19 9H), 2.12 (in, 1H), 2.46 2H), 2.70 (in, 3H), 2.85 (in, 2H), 3.20 2H), 3.40 (dd, 1 H, J=2,8Hz), 1 5 3.50 (dt, I H, J=2,8Hz), 3.62 1H, J=8Hz), 3.78 3H), 5.95 2H), 6.72 1H, J=8Hz), 6.84 (in, 1H), 6.85 2H, J=8Hz), 7.05 1H), 7.16 2H, J=8Hz). MS (DCI/NH 3 mWe 541 Anal calcd for

C

30

H

40

N

2 O7- 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, trpns-2-(4-Methonypheflyl)-4-( 1.3-ben zodi x I5f- 2-(N-DrODyl-N pro ylam inocarbonylmethyl)am ino'ethyllyrrolidine-3-carboXulic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and N-propyl broinoacetainide for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac gCi 8) 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 (CDC1 3 300 MHz) 8 0.78 3H, J=8Hz), 0.88 3H, J=8Hz), 1.45 (in, 2H), 1.48 (mn, 3H, J=8Hz), 2.55-2.7 (in, 2H), 2.90 (mn, 1H), 3.04 (in, 1H), 3.15 (mn, 3H), 3.28 1 H, J=8Hz), 3.45 I1H, J=8Hz), 3.60 (in, 2H), 3.70. (d, 2H, J=8Hz), 3.75 (mn, 1 3.80 3H), 4.25 I1H, 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 Wne 526 Anal calcd for C 29

H

39

N

3 O6 1.85 TEA: C, 53.32; H, 5.59; N, 5.70. Found: C, 53.45; H, 5.62; N, 5.63.

-150- Example 104 trans, trans-2.(4-Mgt11ox 01 ol vfl-4-( 1.3-ben 1io -5-0-l1 -l 2-(N-toroyl-N-(4methoxvohenpx rilvlmfO~tvlYrrolidi e3carbo~lic acid The title compound was prepared by the methods described in Example 61, but substituting propylanline for methylamine in Example 61 B and 4-methoxyphenylchloroformate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a wh.!e 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 1H), 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/NH3) m/e 577 Anal calcd for

C

32

H

36 N2O8 1.0 H 2 0: C, 64.63; H, 6.44; N, 4.71. Found: C, 64.70; H, 6.38; N, 4.63.

Example 105 *20 trans. trans-24-Meth xYphenl)- 4 -(l.3-beflzodioxol5-yl)- 42-(N-propyl-N-(4methoxybn Iflm inn)ethvllvrrol Min 3carboxvlt ac pid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61 B and anisoyl chloride for isobutyryl chloride in Example 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. IH NMR (00013, 300 MHz) mixture of rotamers 8 0.78 (in) and 0.98 J=8Hz) total of 3H, 1.47 (in) and 1 .52 (q.

J=8Hz) total of 2H, 2.25 (br s, 2.78 (br s, 1H), 2.90 (br t, 2H), 3.12- 3.68 (in, 3.80 3H), 3.82 3H), 5.94 2H), 6.75(d, 1H, J=8Hz), 6.83 (in, 6.94 (in, 1H), 7.22 (in, 4H). MS (FAB) W/e 561 Anal calcd for C 32

H

36 N207 -0.75 H 2 0: C, 66.94; H, 6.58; N, 4.88. Found: C, 67.00; H, 6.38; N, 4.59.

-151- Fxamp1eAQM benzoylamilo~ethyl]12,rrolidne3carboxlcai 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 NMIR (CDCI3. 300 MHz) mixture of rotamers 8 0.65 and 0.9 (in, total of 3H) 1.4 and 1.55 (in, total of 2H), 2.05 and 2.15 (in, total of 1 2.6 3.6 (mn, 8H), 5.92 2H), 6.70(d, 1 H, J=8Hz), 6.82 (in, 4H), 7.4 (in, 6H). MIS (DCI/NH3) Wne 531 Anal calcd for C 3 jH 34

N

2 06 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 :trans, trans-2-(4-Meth xV~eflY' 4 .3beflzodioxol-5-yl 1 -r2-(N-D-rO~yvlNbenzvloXycarboflvlaino)ethyllpyrrolidine3carboxvlic, The title compound was prepared by the methods described in Example 61, but substituting propylamine for inethylamine in Example 61 B and benzyl chloroforinate for isobutyryl chloride in Example 61C.

The crude product was purified by preparative HPLC (Vydac ltO 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. 'H NMR (CDC13, 300 MHz) 8 0.8 (in, 3H) 1.45 (in, 2H), 2.20 (br m, 1H), 2.75 (in, 1H), 2.93 (in, 1H), 3.15 (in, 2H), 3.32 (in, 3H), 3.52 (in, 2H), 3.66 (in, 1H), 3.78 3H), 5.00 (in, 2H), 5.94 2H), 6.72(d, 1H, J=8Hz), 6.82 (in, 3H), (br d, 1H, J= 15Hz), 7.2 4H), 7.30 (in, 3H). MIS (FAB) mWe 561

(M+H)

4 Anal calcd for C 32

H

3 6N207 1.0 TFA: C, 60.53; H, 5.53; N, 4.15.

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

rn. trn ~4-M thovheI 4 .3-enodil-5- 1 -1 r2- N- ronvlN-4mh xvbZloxvcarbonyl~ainnp~ethvl roiiecr acid The title compound is prepared by the methods described in Example 61. substituting propylamine for methylainine in Example 61 B -152and 4-methoxybelzyl chioroformate for isobutyryl chlooide in Example 61C.

Examol19 trans. trans-24-MethoxYmhenyl- 4 (l .3bn~iXl5V~ -f-(-Utyl-Ngtoyaboyaio a rl i3 cid The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 61B and ethyl chloroformate for isobutyryl chloride in Example 61C.

The crude product was purified by preparative HPLC (Vydac .Cl 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. 1H NMR (CDCI3, 300 MHz) 8 0.82 3H, J=8Hz), 1.20 (in. 5H), 1.34 (in, 2H), 3.08 (in, 2H), 3.17 (in, 2H), 3.52 (in, 2H), 3.75 (in, 2H), 3.78 311), 4.06 (q, *15 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) m/e 513 Anal calcd for C 28 H136N207 0.5 TFA: C, 61.15; H, 6.46;, N, 4.92.

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

trans. trans- 2-i4-Metho a~hen il 4 4( .3bnoiXl5V~l~2(N-12utyl-No roooxvcrbl lin ~eh I Drrolidine3caOrboUVYc acd- The title compound was prepared by the methods described in Example 61, but substituting butylainine for inethylamine. in Example **25 61B and propyl chloroforniate 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. 'H NMR (CDCI3. '300 MHz) 8 0.80 (br s, 1H), 0.85 3H, J=8H1z), 0.92 (br s, 1H), 1.22 (in, 3H), 1.40 (in, 311), 1.62 (br m, I1H), 2.15 (br s, I1H), 2.72 (mn, 11-H), 2.87 (mn, I1H), 3.1-3.45 (in, 5H1), 3.55 (mn, 1H1), 3.64 1H, J=8Hz), 3.79 3H), 3.88 (br s, 1H1), 3.97 (br s, 1H), 5.95 2H), 6.73(d, I1H, J=8Hz), 6.85 (in, 3H. 1H), 7.30 2H, J=8Hz). MS (FAB) m/e 527 Anal calcd for

C

29

H

3 8N2O7 0.15 H20: C, 65.80; H, 7.29; N, 5.29. Found: C, 65.79;

H,

7.30; N, 5.2 1.

-153- X EDlbe 111 pronnxyarbonylaming~ethy-~yrldn~abY ai The title compound was prepared by the methods described in Example 61, but substituting propylamifle for methylamifle in Example 61B3 and propyl 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. 'H NMR (C~DC 3 300 MHz) 8 0.80 3H, J=8Hz), 093 (in, 3H), 1.43 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 (in, 2H), 5.94 2H), 6.72 I1H, J=8Hz), 6.82 (in, 1H), 6.84 2H, J=8Hz), 7.00 (br s, 1H), 7.33 (in, 2H). MVS (DCI/NH3) m/e 513 Anal calcd for C 2

BH

3 6N207 -0.15 H 2 0: C, 65.26; H, 7.10;, N, 5.44. Found: C, 65.22; H, 6.74; N, 5.06.

Example 112 ~~~trans. trans- 1 .N-i(n-bty' in nO~rbh flvIinth-l.- di 1I 'I'llZ yflpyrrolidifle-3-CarbOxy-lic acid :20 Ethyl 3 4 -inethylenedioxybenzoyl)acetate, prepared by the method of Krapcho et al., Org. Syn. 41, 20 (1967) starting with 3,4m ethyl en edioxyacetop he none instead of 4-inethoxyacetophen one, was reacted by the procedures described Iin Example 1 to give the title compound as a white solid. m.p. 58-60 0 C. 1 H NMR (CDC13. 300 MHz) 8 0.87 (quintet, J=6Hz, 6H), 1.12 (sextet, J=6Hz, 1.24-1.51 (in, 6H), ~:2.80 J=1l3Hz, 1 2.94-3.12 (in, 3.28-3.50 (in, 4H), 3.58-3.62 (in, 1H), 3.78 J=9Hz, 1H), 5.95 41), 6.73 (dd, J=8Hz, 3Hz, 2H), 6.84-6.89 (in, 2H), 6.92 J=lHz, 1H), 7.01 H=lHz, 1H). MS (DCI/NH 3 Wne 525 trans.t trns-1- -nB I--r itlovannph l--4 fr~~ (1.

3 benzdiOx 1- l ~rrOiidin3--rbo~xYlic id Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 64-65 OC. 'H NMR (CDCI3, 300 MHz) 8 0.83 J=7Hz, 3H),.0.98 J=7Hz, 3H), 1.12-1.25 (mn, 2H), 1.32-1.41 (mn, 2H), 1.75 (sextet, J=7Hz, 2H), 2.23-2.31 (in, 2H), 2.72-3.32 (in, 8H), -154- 3.43 (dd, J=9Hz, 3Hz, 1IH), 3.53-3.59 (in, 1H). 3.65 J=9Hz, 1H), 3.80 (s.

3H), 5.95 2H), 6.73 J=8Hz, -1 6.83 (dd, J=8Hz, 1 Hz, I1H), 6.88 (d, J=9Hz, 2H), 7.02 J=11Hz, 1 7.33 J=9Hz, 2H). MS (DCI/NH3) mie 547 (M+H) 4 Example- 114 trans. trans-i -DiO-butyflaf'inocarbon Imieth 1 4-me hoxvv/henylh- 4 (l.3 ben oIOI~x l 5-Vl' rr Viifle rylc ai Using the procedures described in Examples 28 and 43, the title compound was prepared as a white solid. m.p. 74_-6 OC. I H NMR (CDCI3, 300 MHz) 8 0.80 J=6Hz, 3H), 0.88 J=8Hz, 3H), 1.08 (sextet, 0 J=8Hz, 2H), 1.21-1.48 (in, 6H), 2.75 J=l2Hz, 1H), 2.95-3.09 (in, 4H), et 3.26-3.59 (in, 5H), 3.75 J=9Hz, IH), 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 mWe 525 Example 115 trans. trans- 1 (-NP rIufnlmi ~l--4mhxoey)4 20(1 3 -benzodioxol-5- I D rroliine3carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 72-73 0 C. 'H NMR (CDCI3, 300 MHz) 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, 1 2.69-3.32 (mn, 9H), 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~11Hz, 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/NH3) m/e 533 Examn~Le 1 16 trans. trans- 1 .(-NBtlNbtluf yanin~tD 2L-ehxhnI--13ben zodioxo 1-5-VflD rrolidi e3carb ovlc ci Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 62-63 00. I'H NMR (CDCI3, 300 MHz) 0.82 J=6Hz, 3H), 0.91 J=6H-z, 3H), 1.20 (sextet, J=6Hz, 2H), 1.33- 351.42 (in, 4H), 1.68 (quintet, J=6H z, 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.

-155- 3H), 5.95 2H), 6.72 J=8Hz, 1H), 6.82 J=8Hz, 1H), 6.87 J=8Hz, 2H), 7.01 1H), 7.32 J=8Hz, 2H). MS (DCI/NH 3 mle 561 Examole 117 trans. trans-i N-Di(n-butyflaminocarboflylmethyl)- 2 4 methoxymethoxylheflyl)-4-(l .3-benzodioxol-5-ylPIDyrrolidifle-3-crboxylic acid 4- Hyd roxyacetophenonle was treated with chloromethyl methyl ether and triethylamine in THF at room temperature to give ethyl 4metho xymnethoxybe nzOyl acetate which was treated by the procedures described in Example 1 to afford the title compound as a white solid.

m.p. 48-49 0 C. 'H NMR (CDC 3 300 MHz) 5 0.81 J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.06 (sextet, J=7Hz, 2H), 1.20-1.35 (in, 4H), 1.44 (quintet.

J=7Hz, 2H), 2.75 J=l2Hz, 1H), 2.94-3. 10 (in, 41H), 3.25-3.35 (in, 1H), 3.40 J=l2Hz, 1H), 3.43-3.52 (in, 2H), 347 31H), 3.55-3.62 (in, 1H), 15 3.77 J=9Hz, 5.15 2H), 5.94 (in, 2H), 6.73 J=8Hz, 1IH), 6.86 (dd, J=lHz, 8Hz, 1H), 7.0 J=8Hz, 2H), 7.04 J=lHz, IH), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) W/e 541 :20 trans. trans-i -(2-tNN-D~-u ~mncroymty)2(-yrxlhn abenzodioxol-5-vfl)1yrrolidi ne-3-carboxvlic acid hydrochlorides The compound resulting from Example 11.6 was treated with concentrated HCI in 1:1 THF-isopropanol to give the title compound as a white solid. m.p. 211-212 I'H NMR (CD 3 0D. 300 MHz) 8 0.90 (t, J=8Hz, 61H), 1.12-1.27 (mn, 6H), 1.36-1.45 (in, 2H), 3.04 (bs, 11H), 3.14- :3.35 J=9Hz, 1H), 3.90 (bs, 3H), 4.17 J=l5Hz, 11H), 5.96 2H), 6.82-6.93 (in, 4H), 7.03 J=lHz, 11H), 7.42 (bs, 2H). MS (DCI/NH 3 m/e 497 Exainpe 119 trans. trans-i1 souy--2g~~uI nlmnoehl-.4mtoy~ey)4 (1 3 b noiX l -lhrrl n3-c rboxlic aid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 73-74 ad. H NMVR (CDCI3. 300 MHz) 8 0.80 J=6Hz, 6H), 0.98 J=8Hz, 3H), 1 .62 (sextet, J=6Hz, 1 1 .74 (sextet, J=8Hz, 2H), 2.23-2-34 (in, 1H), 2.68-2.98 (in, 71H), 3.08-3.18 (in, 156- 1H), 3.26-3.42 (in, 2H), 3.52-3.58 (in, 3.65 J=9Hz, 1H), 3.80 (s, 3H), 5.90 2H), 6.74 J=8Hz, 1H), 6.82 J=8Hz, 1H), 6.86 J=8Hz, 2H), 6.98 J= 1Hz, 1 7.33 J=8Hz, 2H). MS (DC I/NH 3 m/e 547 Example 120 trans~trans-1 -(-NBneeufnlNgo~lmioehl--4mtoY~ey)4 (1 .3-benzodioxol-5-fl~oyrrolidifle-3-cabog(lic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 89-91. I H-NMR (COCl 3 300 MHz) 0.74 J=6Hz, 3H), 1.33 (sextet, J=6H1z, 2H), 2.20-2.30 (in, 1H), 2.62- 2.72 (in, 1H), 2.85-3.05 (in, 4H), 3.12-3.22 (mn, 11H), 3.38 (dd, J=3Hz, 9Hz, 3.49-3.57 (mn, 1H), 3.62 J=9Hz, 1H), 3.82 3H), 5.96 2H), 15 6.73 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=7Hz, 2H). MS (DCI/NH 3 m/e 567 Examplge 121 trans. trans-i 1 (-N(-ehxbneeufoy)Npoya ino')ethyl)k2-(4- .20 methoxyghenyfl-4-(1 .3-benzodioxol-5-vflovrrolidile-3-carbo~lic acid **eg Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 96-97 0C. 1H NMR (00013. 300 MHz) S. *S 5 0.73 J=7Hz, 3H), 1.34 (sextet, J=7Hz, 2H), 2.20-2.30 (in, 1H), 2.62- 2.71.(m, 1H), 2.82-3.03 (in, 4H), 3.08-3.18 (in, 2H), 3.38 (dd, J=3Hz, 9Hz, ~.25 1H), 3.48-3.56 (mn, 1H), 3.62 J=9Hz, 1H), 3.81 3H), 3.86 3H), 5.95 2H), 6.73 J=8Hz, 1H), 6.81-6.89 (in, 5H), 7.01 J=lHz, 1H), 7.28 J=8Hz, 2H), 7.62 J=8Hz, MS (DCI/NH3) Wne 597 Examgle 122 trans, trans-i1 N-Di(n-bUtjyfl incrovm tyl2(2-methoxyethoxy- 4 methoxyoheny')-4-(1 .3-benzod ioxol.5-ylo1yrrolidile- 3-crOi acdid was treated with sodium hydride and broinoethyl methyl ether in THE at 70 00 to provide ethyl 2methoxyethoxy-4-methoxybeflzoyl acetate which was treated by the procedures described in Example 1 to provide the title compound as a white solid. m.p. 63-65 00. 'H NMVIR (00013. 300 MHz) 8 0.84 J=7Hz, -157- 3H), 0.89 J=7Hz, 3H), 1.16 (sextet, J=:7Hz, 1.28 (sextet, J=7Hz, 2H), 1.45-1.52 (in, 4H), 2.87-2.94 (in, 2H), 3.00-3.16 (in, 3H), 3.26-3.36 (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=9Hz, 1H), 5.92 2H), 6.40 J=2Hz. 1H), 6.52 (dd, J=2Hz, 9Hz, 1H), 6.70 J=8Hz, 1H), 6.83 (dd, J=11-z, 8Hz, 1H), 5.98 J=2Hz, 7.53 J=9Hz, 1H). MS

(DCI/NH

3 Wne 585 trans. trans-i 1 (N-Prooy-M-(24-i -tybneeU~lfann'ehI 2 4 methxy~efll'~ 4 I 3 bnoi x I-Y Orrliin -ar oIic aid 0SUsing the procedures described in Example 66, the title compound 66 .6*was prepared as a white solid. m.p. 88-90 'H NMR (CDCI3. 300 MHz) 58 0.69 J=7Hz, 3H), 1.32 (sextet. J=7Hz, 2H), 2.12-2.20 (in, 1H), 2.32 io 5 3H), 2.47 3H), 2.62-2.69 (in, 1H), 2.78 J=9Hz, 1H), 2.89 (dd, fee J=8Hz, 1H), 3.02 (sextet, J=9gHz, 3.15-3.32 (in, 3H), 3.46-3.55 (in.

'ls 1H), 3.60 J=9Hz, 1H), 3.82 3H), 5.96 2H), 6.72 J=7Hz, 1H), 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/NH3) m/e 595 0000 ExamQle 14 trans. trans-i -(2-(N-Pramin'ylth-(Y 2 4 0 methoxyohenl)-4-(l. 3 -benzodioxol 5-ylOpyrroidine3carbo~Lic aci-d Using the procedures described in Example 66, the title compound 0 0 25 was prepared as a white solid. in.p. 75-76 0 G. I NMR (C~DC 3 300 MHz) 8 0.80 J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.15-2.31 (in, 3H), 2.70- 2.80 (mn, 1H), 2.85-3.10 (mn, 6H), 3.23-3.31 (in, 2H), 3.43 (bd, J=9Hz, 1H), 3.55-3.66 (in, 4H), 3.81 3H), 5.94 2H), 6.73 J=8Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.86 J=8Hz, 2H), 7.00 1H), 7.33 J=8Hz, 2H). MS (DCI/NH3) in/e 567 trans, trans- 1 (-NPg~lN(-ehovthluinl mn rnethoxvohen Df- 4 1 bnz~dioxoi-5YflDuyrrOidine3-Carrbo)x-Iic acid Using the procedures described in Example 66, trans, tranlsl 2 (N-PropylN(vinylsulfo nY~ainn tyl)-2 (4inhoyetoyP)4(13- -158benzodioxol-5-yl)pyrrolidine3carboxylic acid was prepared. Ester hydrolysis using aqueous sodium hydroxide in methanol afforded the title compound as a white solid. m.p. 62-64 I1 NMR (CDC1 3 300 MHz) 8 0.78 J=7Hz, 3H), 1.42 (sextet, J=7Hz, 2H), 2.23-2.32 (in, 1H), 2.72-2.79 (in, IH), 2.86-3.05 (mn, 4H), 3.1 0-3.27 (in, 4H), 3.32 3H), 3.43 (dd, J=3Hz, 9Hz, 1H), 3.53-3.58 (in, 1H), 3.65 J=9Hz, 1H), 3.69 (t, J=6Hz, 2H), 3.80 3H), 5.94 2H), 6.73 J=8Hz, 1H1), 6.82 (dd, JlHz, 8Hz, 1H), 6.87 J=8Hz, 2H), 7.02 J=lHz, 1H), 7.33 J=8Hz, 2H). MS (DCI/NH3) mWe 549 *trans.trans-l1 2(-rly--2e io ehlufnla ioebj--Lmethoxytphenyl)-4-l -3 benzo I-X -5 flrriine3-carboxli aci Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 58-60 'H NMR (CDCI3. 300 MHz) 8 0.78 J=7Hz, 3H), 1.18 J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2H), 2.24- 2.33 (mn, 1H), 2.70-2.80 (in, 1H), 2.87-3.05 (mn, 4H), 3.13-3.20 (in, 2H), 3.22-3.32 (in, 2H), 3.42 (dd, J=2Hz, 9Hz, 1H), 3.46 J=7Hz, 2H), 3.52- 3.58 (in, 1 3.65 (d J=9Hz, 1 3.72 J=6Hz. 2H), 3.80 3H). 5.95 2H), 6.73 J=7Hz, 1 6.83 (dd, J= 1Hz, 7Hz, 1 6.87 J=8Hz, 2H), 7.00 J=lHz, 1H), 7.32 J=8Hz, 2H). MS (D01/NH 3 m/e 563 EMoleQ 127 trans, trans-i1-2( N im tysm -1,0-1t1011~~fpniO'eh~~ (4-methoxyohenll- 4 4(1 3 benzoixl5Y 0r~il3carbxjT' aId Using the procedures described in Example 66, the title compound was prepared as a yellow solid. in.p. 102-104 'H NMR (CDC1 3 300 MHz) 8 0.62 J=7Hz, 3H), 1.28 (sextet, J=7Hz, 2H), 2.12-2.20 (mn, 1H), 2.78 J=9Hz, 1H), 2.88 6H), 2.72-2.89 (in, 1H1), 3.05-3.12 (mn, 2H), 3.26-3.45 (in, 3H), 3.45-3.52 (in, 1H), 3.58 J=9Hz, 1H), 6.97 J1lHz, 1H), 7.13 J=7Hz, 1H), 7.26 J=8Hz, 1H), 7.42-7.50 (in, 2H), 8.08 (dd, J=lHz, 7Hz, 1H), 8.20 (d,-J=8Hz, 1H), 8.48 J=8Hz, 1H). MS (DCI/NH 3 m/e 660 -1 59- (1 3 -benzodoxl5yfDrliilcabyt ad Using the procedures described in Example 66, the title compound was prepared as a white solid. mn-p. 70-72 'H NMR (CDCI3, 300 MHz) 8 0.79 J=8Hz, 3H), 1.28 J=7Hz, 3H), 1.43 J=8Hz, 2H), 2.22-2.30 (in, 1H), 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 (mn, 1H), 3.65 J=9Hz, IH), 3.80 3H), 5.96 2H), 6.73 J=7Hz, 1H), 6.82 (dd, J=lHz, 7Hz, 1H), 6.88 (d.

J=8Hz, 2H), 7.00 J=lHz, 7.32 J=8Hz, 2H). MS (DCI/NH 3 m/e 519 Example-129 *trans. trans-i 1 (2-(N-ProDyl-N-(4-m eth lbenze-nesulfqnyl pnin ehl 4 methoxyphenvl')- 4 3 .benzodioxol-5-vlIoli e-3-carbO)(Ylc aci Using the procedures described in Example 66, the title compound was prepared as a white solid. mn.p. 78-79 'H NMR (C~DC 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 (mn, 1H), 2.83-3.05 (in, 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, 1 6.82 J=8Hz, 1 6.87 J=8Hz, 2H), 7.00 1H), 7.21 J=8Hz, 2H), 7.29 J=8Hz, 2H), 7.57 J=8Hz, 2H).

MS (DCI/NH3) m/e 581 :25 Exampl 3 trans, trans-i1 i n-butI'am inocarbonyliethl-2(312yi vI- 4 benz iOx I-5W- I rr li in 1-arboxvlic aidl Methyl nicotinoyl acetate was prepared by the method of Wenkert, et al., J. Org. Chein. 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 00. I H NMR (CDC13, 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 (mn, 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, 1H), 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 in/e 482 160trans trans-i-2(-rcy--nbtlufnlaio ty)24mtoyhnn4 (1 .3-benzodioxol-5-ylD12rrolidine-3-ca rboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 65-66 I NMR (CDC13, 300 MHz) 8 0.78 J=7Hz, 3H), 0.92 J=7Hz,*3K), 1.31-1.46 (in, 4H), 1.68 (quintet, J=7Hz, 2H), 2.21-2.32 (in, 1K), 2.70-3.08 (mn, 7H), 3.12-3.23 (mn, 2H), 3.42 (dd, J=2Hz, 9Hz, 1H), 3.52-3.58 (in, 1H), 3.64 J=9Hz, 11H), 3.80 3H), 5.96 2H), 6.72 J=7Hz, 1H), 6.83-(dd, J=lHz, 7Hz, 1K), 6.86 J=8Hz, 2H), 7.00 J=lHz, 1H), 7.32 J=8Hz, 2H). MS

(DCI/NK

3 m/e 547 (M+K)I.

trans. trans- 1 -(-NPoy-N(-horbneeufoy~ ino'~ethyfl-2-(4methoyhnf-4-( .3-hbendixIynVl' r ldil 3Cabolic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 105-1060 -C.IK NMR (CDCI 3 300 MHz) 5 0.72 J=-7Hz, 3H), 1.34 (sextet, J=7Kzm 2K), 2.56-2.62 (in, 1H), 2.78-2.86 (in, 1H), 2.96-3.03 (in, 3H), 3.13-3.26 (in, 3H), 3.51 (dd, 9Hz, 1H), 3.62-3.68 (in, 1H), 3.80 3H), 3.94 J=9Kz, 1K), 5.92 (s, 2H), 6.75 J=8Hz, 1H), 6.84 (dd. J=2Hz, 8Hz, 1K), 6.94 J=8Kz, 2K), 6.98 J=2Hz, 1K), 7.36 J=8Kz, 1H), 7.49 J=8Hz, 1K), 7.68 (d, 25 J=8Hz, 1K). MS (DCI/NH 3 m/~e 601 (M+H) 4 Example 133 trans. trans-i 1 (2-(N-ProovI-N-(ben~S lfnlanfl-ty)(4methoxvphenyl- 4 (1 .3-benzodioxol-5VlOrliieCbovc acid Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 88-89 00. 'K NMR (CDCI 3 300 MHz) 0.72 J=7Kz, 3K), 1.32 (sextet, J=7Kz, 2K), 2.06-2.16 (in, 1KH), 2.56- 2.67 (in, 1K), 2.75-3.10 (in, 6K), 3.30 (dd, J=2Kz, 9Hz, 1K), 5.95 2K), 6.73 J=7Hz, 1K), 6.80 (dd, J=l~z, 7Hz, 1K). 6.86 J=8Kz, 2H), 6.97 J=l~z, 1K), 7.27-7.35 (in, 7K). MS (DCI/NK3) in/e 581 -161- Example 134 trans.trans-1 -(2(N-Proviy-N-(4-iluorQ nenesulfonvlamino ethyl-2-4methoxvphenvl)-4-(1 3 -benzodioxol-5-vlrvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 91-93 1 H NMR (CDCI3, 300 MHz) 0.73 J=7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 2.18-2.27 1H), 2.56- 2.67 1H), 2.78-2.87 2H), 2.97 (septet, J=8Hz, 2H), 3.11-3.16 (m, 2H), 3.33 (dd, J=2Hz, 9Hz, 1H), 3.43-3.50 1H), 3.57 J=9Hz, 1H), 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- -(N-MethvlNDropylaminocarbonvlmethl-2-(4-methoxyphenyl)-4-( 4 benzofuranvl)ovrrolidine-3-carboxylic acid Example 135A Benzofuran-4-carboxaldehyde 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 3bromophenol (13.8 g, 80 mmol) in DMF (5 mL). After 10 minutes, bromoacetaldehyde diethyl acetal (14.9 mL, 96.6 mmol, 1.24 eq) was added, and the resultant mixture then heated at 120 °C for 2.5 hours.

The mixture was cooled to room temperature and was poured into water, and extracted once with ether. The organic solution was dried 25 over MgSO4, 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 (80 mL) at -78 °C was added 1.7 M t-butyllithium (48.8 mL, 83 mmol, 2 eq) such that the temperature did not exceed -70 After stirring for mint, qo nution of DMF (6.5 mL, 83 mmol, 2 eq) in ether (20 mL) -162was 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 MgSO4 and concentated in vacua.

The residue was purified by flash chromatography on silica gel eluting with 10% ether in hexanes to yield benflfuran-6-carboxaldehyde (1.22 g) and bezfrn4croadhd (1.86 both as colorless oils.

Pxamle135 trans. tran- -MhINooyaioabnlnthl--4mtoyhnl--4 henzofuran~lyawm idfl cro~ 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 NMIR (300 MHz, CDCI3) (minor rotamer) 8 7.59 t, J=31-Iz), 7.4-7.2 in), 6.8 d, J=8H-z), 4.03 (1 H, in), 3.94 dd, J=81-z, 3H-z), 3.77 3.61 (1H, dd, J=8Hz, 7 3.42 dd, J=1lHz, 5H-z), 3.40-2.90 (5H, in), 2.82 (2.81) s), 1 .50 (2H, septet. J=7Hz), 0.82 (0.75) t, J=7H-z). MIS (DC I/NH 3 m/e 451 Anal.calc. for C 2 6

H-

3 0

N

2 O5 AcON: C, 65.87; H, 6.71; N .5.49.

Found: C, 66.04; H, 6.42;, N, 5.60. s *trans. tran&-i I (N4Methy. rOlinfOpnI m e h I -4m t h ox vD h e yvI)-4% Q9 *The title compound was prepare d using the procedures described in Examples 1 and 49 substituting beflz 0 furan-6-carboxaldehyde, prepared as described in Example 1 35A, in Example 49A for pipe ronal.

1H NMR (300 MHz, CDCI3) (minor rotamer) 8 7.65 (1 H, bd), 7.60 (1IH, d, J=2H-z), 7.55 (1H, d, J=8H-z), 7.35 in), 6.85 dd, J=8Hz, 3H-z), 6.75 01H, dd, J=3Hz, 2H-z), 3.83 mn), 3.79 3.60-3.0 in), 2.91 (2.83) 3H), 1.51 septet, J=7H-z), 0.83 (0.78) t, J=7H-z).

MIS

(DCI/NH

3 m/e 451 Anal.calc. for C 2 6 H-30N205 .0.5 H20: C, 67.96; H. 6.80; N, 6.10. Found: C, 67.90; H, 6.71; N, 6.07.

-163- Example JaZ trans. trans-i -24 ben zo-2 .3-dihyd roturpflyl) Dyrrolidife3csa Qxrl cid 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 'H NMR (300 MHz, CDCI3) (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=1lIz, 7H-z), 4.58 (2H, t, J=8Hz), 4.18 (1H, in), 4.10 (1H, mn), 3.88 (1H, in), 3.79 (3H, 3.60 (1H, in), 3.35 (1H, 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 m/e 453 Anal.calc. for C 26

H

32 N205 1.25 TFA: C, 57.53; H, 5.63; N, 4.71. Found: C, 57.68; H, 5.68; N, 4.70.

trans.any tras- inN .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-inethyl-N-propyl broinoacetainide. 1H NMR.(300 MHz, CDCI3) 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 (1H, d, J=8Hz), 6.84 (2H, d, J=8Hz), 4.02 (1H, ddd, J=8, 25 6Hz,4Hz), 3.89 (1H, d, J=9Hz) 3.79 (3H, 3.67 (11H, dd, J=lOHz, 3Hz), 3.44 (2H, in), 3.35-3.15 (3H, in), 3.00 mn), 2.84 (IH, d, J=14H-z), 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 (DCI/NH3) m/e 507 Anal.calc. for C 30

H

38 N205: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.86: H, 7.45; N, 5.24.

Eapg-a trans. tran- Di(n butylalcarbonlYmeth _meto~~e~~ benzouaylyrldfeCbolc Id 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 135A substituted 4bromophenol for 3-broinophenol, in Example 49A for piperonal and subtiijiuji"'y Y brcmcacetamip. inr N-methl-N-propvI -164bromoa cetamide. IH NMR (300 MHz, CDCI 3 8 7.64 (1H, bd), 7.59 (17, d, J=2Hz), 7.43 (2H, in), 7.33 (2H, d, J=8Hz), 6.85 (2H, d, J=BHz), 6.73 (1H, dd, J=3Hz, 1Hz), 3.82 (1H, d, J=llHz), 3.89 (1H, d, J=9Hz) 3.79 (3H, s), 3.53 (1H, dd, J=lOHz, 3Hz), 3.44 (2H, in), 3.30 (1H, mn), 3.20-2.95 (5H, in), 2.82 (17, d, J=l4Hz), 1.43 (3H, in), 1.23 (3H, in), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.82 t, J=7Hz). MS (DCI/NH3) m/e 507 Anal.calc.

for C 30

H

38

N

2 05: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.73; H, 7.45; N, 5.29.

Eampile 140 *trans. trans-I1 -(N.NDi(nbutvfaminocrbonflmlethyl)2(4metho)(\tDhenyl- 4 6 ~benzofuranylo1yrrolidile-3-carbo(Ylic aid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-6-carboxaldehyde in 15 Example 49A for piperonal and substituting N,N-dibutyl broinoacetamide for N-inethyl-N-propyl broinoacetainide. 1H NMR (300 MHz, CDC1 3 ::i726 (1H, bd), 7.59(1H, d. J=2Hz), 7.53 (1H, d, J=8Hz), 7.36 (37, in), 6.85 (2H, d. J=8Hz), 6.73 (1 H, dd, J=3Hz, 1 Hz), 3.82 (1 H, d, J=ll1Hz), 3.89 (IH dJ=9z)3.7 3.3(1,dJ=lOHz, H)3.4(.m, 3.30 (1H, in), 3.20-2.95 (5H, in), 2.80 (17, d, J=l4Hz), 1.43 (3H, in), 1.23 (3H, in), 1.08 (27, mn), 0.87 (31H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS

(DCI/NH

3 m/e 507 (M+iH) 4 Anal.calc. for C 3 oI- 38

N

2 05 0.75 720: C, 69.28; H, 7.65; N, 5.39. Found: C, 69.11; H, 7.33; N, 5.32.

Examole 141 trans. trans-i I N-Di(n butl) am inocarbo ylm ethl)2 (4methoxY) hen yl) 4 6 benzo-2.3-dih ydrofuranVOOrr~lidine3carboxvlic acid The title compound was prepared by catalytic hydrogenation of the compound resulting from Example 140 (4 atmospheres of H2 in AcOH, followed by preparative hp'c). 1H NMR (300 MHz, CDC1 3 8 7.40 (2H, d, J=8Hz), 7.16 (1H, d, J=8Hz), 6.97 (1H, dd, J=8Hz. 2Hz), 6.89 (3H, in), 5.90 (1H, bs) 4.57 (2H, t, J=9Hz), 4.93 (2H, in), 3.80 (3H, 3.70-3.58 (2H, in), 3.40 (1H, in), 3.30-2.90 (87, in), 1.40 (2H, in), 1.29 (37, in), 1.08 (2H, in), 0.92 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH 3 Wne 509 Anal.calc. for C 3 oH 4 ON205 0.85 TFA: C, 62.88; H, 6.80; N. 4.63. Found: C, 63.04; 6.66; N, 4.60.

-1 Examlle 142 trans.trans-l-(-ehlN1rryaioabnle indanvl)oyrrolidine-3-carboXsyic acid Examle 142A Indane-5-carboxaIdehyd2 was prepared by formylation of indane under the conditions described for 2,3-dihydrobenzofuran in Example *10 52A. The resultant mixture of and 5-carboxaldehydes was purified *.as 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 aldimnine (2.65 g) was suspended in water (6 mL), and treated with 4 N hydrochloric dioxane (10 mL). The mixture was boiled for 1 hour, cooled to room temperature, and poured into ether.

The organic solution was dried over MgSO4, filtered, and concentated in vacuo. Vacuum distillation of the residue afforded carboxaldehyde (1.54 g, 88%) as a colorless liquid. b.p. 88-90 0 C at 0.9 mm Hg.

2 trns~ran- 1Examlole 142B 25indanyvpy~rrolidine-3-carbxiC ci 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, CoDC 3 (minor rotamner) 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), 1.48 (2H, septet, J=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS (DCI/NH3) m/e 451 473 Anal.calc. for C 27

H

34 N204 2.5 H 2 0: C, 65.44; H, 7.93; N, 5.65. Found: C, 65.36; H, 7.45; N, 5.53.

-166- Examlple 143 trans. tran- lethyl-N-propylamiflocaronYlmgfy h 4 indolyflpyrrolidile-3-carbgzyLC-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, CDCI3) (minor rotamer) 8 8.43 (1H, brs), 7.57 (1H, 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 t, J=7Hz).

MS

*.(DCI/NH3) W/e 450 Anal.calc. for C 26

H

3 1 N304 0.75 H 2 0: C, 67.44; H, 7.07; N, 9.07. Found: C, 67.42; H, 7.09; N, 8.91.

*.:trans. trans-i 1 (-ehlNpo~lmn 4 (3.-dilacid~en The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3 ,4-difluorobenzaldehyde for piperonal in Example 49A. IH NMR (300 MHz, CDC13) (minor rotamer) 8 7.60-7.3 (4H, in), 7.13 (1H, q, J=9Hz), 6.90 (2H, d, J=8Hz), 3.90 (1H, in), 3.79 (3H, 3.60-2.95 (6H, mn), 2.92 (2.78) (3H, 1.55 (2H, septet, J=7Hz), 0.88 (0.73) (3H, t, J=7Hz). MS (DCIINH3) Wne 447 Anal.calc. for .*C 24

H

28 F2N204 -1.80 H20: C, 60.19; H, 6.65; N, 5.85. Found: C, 60.13;,

H,

:25 6.34; N, 5.84.

Example 145 trans. trans- 1 (NM t r Imncroym tv)2(-phyrh

-,NA

The title compound was prepared by the procedures described in Examples I and 49 substituting benzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) (minor rotamer) 8 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- 2.95 (8H, in), 2.90 (2.79) (3H, 1.50 (2H1, sept, J=7Hz), 0.87 (0.72) (3H, t, J=7Hz). MS (DCI/NH3) Wne 411 Anal.calc. for C 24

H

30 N204 2.00 H 2 0: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.37; H, 7.43; N, 6.29.

-167tran-s trans,-NMty--rglm etohnl--4 hydroxyo~henyl)Dyvrrolidine3 car~oxyic acid The title compound was prepared by the procedures described in.

Examples 1 and 49 substituting 4-hydroxybeflzaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3-CD300) (minor rotamer) 6 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=BHz), 3.70-3.00 (8H, in), 2.92 (2.83) (3H, 1.50 (2H, septet, J=7Hz), 0.87 t, J=7Hz).

MS

(DCI/N'H

3 mWe 427 Analcaic. for C 2 4 H30N205 -1.00 H 2 0: C, 64.85;, H, 7.26; N, 6.30. Found: C, 64.82; H, 7.39; N, 6.46.

Example 147 15 trans. trans-i -(N-Methyl-N-poOylpminocarbonylm ethyl').2-(4-methoxy~bhefllt 4 .4-dimethoxvhefn IDrr li ine-3-carbpxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,4-dimethoxybenzaldehyde for piperonal in Example 49A. 1H NMR (300 MHz. CDC1 3 -CD3OD) (minor rotamer) 6 7.61 (1H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.82 (2H, d, J=8Hz), 6.55 (1 H, d, J=8Hz), 6.45 (1H, d, J=3Hz), 3.90 (1H, 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 (DCIINH3) m/e 471 Anal.calc. for C 26

H

34 N206 0.75 H 2 0: 0, 64.51; H, 7.39; N, 5.79. Found: *:25 C, 64.65; H, 7.07; N, 5.75.

Examnie-134 trans. trans- 1 N-Di(n-butyl)am inocarbonylmethy)-2-(4 r11eth OXYheLnl benzo-2.3-dh ~u~~lDrdiiec~x li acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,3-dihyd robenlzof u carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) 6 7.31 (2H, d, J=8Hz), 7.27 (1H, d, J=2Hz), 7.18 (1H, dd, J=7Hz, 3Hz), 6.86 (2H d, J=8Hz), 6.72 (1 H, d, J=8Hz), 4.56 (2H, t, J=7Hz), 3.78 (3H, s), 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, in), 1.08 (2H, in), 0.87 (3H, -168t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH3) mle 509 Anal.calc.

for C 3 0

H

4 0 N205 0.25 H20: C, 70.22; H, 7.95; N, 5.46. Found: C, 70.2.1;- H, 7.92; N, 5.36.

Exale l*A trans. trans-i ND~-uy~mncabnlehl--4-ehuhnl--4 The title compound was prepared by the procedures described in Examples 1 and 49- substituting 4-methoxybenzaldehyde for piperonal in Example 49A. IH NMR (300 MHz, CDCI3) 5 7.38 (2R, d, J=8Hz),.7.30 (2H, d, J=8Hz), 6.87 (4H, dd, J=7Hz, 3Hz), 3.78 (3H, 3.76 (3H, 3.63 (1 H, in), 3.50-3.20 (4H, mn), 3.15-2.90 (5H, in), 2.78 (1H, d, J=l4Hz), 1.43 0 (3H, in), 1.27 (3H, mn), 1.09 (2H, in), 0.87 (3H, t, J=7Kz), 0.81 (3H, t, 0 015 J=7Kz). MS (DCI/NH 3 m/e 497 Anal.calc. for C 2 9

H

40 N205: C, oo 15 70.13; H, 8.12; N, 5.64. Found: C, 69.78; H, 8.10; N, 5.54.

:oltrans. trans-i1 N-Di(n-butyflam inlocarbonvim ehl~2(-ehX~ell 4 difluorolheflyl)pyrrO liin cr0x fiC c *20 The title compound was prepared by the procedures described in 0 Examples 1 and 49 substituting 3,4-difluorobeflzaidehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 8 7.35 (1H, in), 7.30 (2H, d, J=BHz), 7.20-7.00 (2H, in), 6.87 (2H, d, J=8Hz), 3.78 (3H, 3.79 (1K, .2(H .033 3 ,r ,32 1-,m ,31-.0(H o. i) .2(K n,35-.0(Kn,32 1,i) .529 4,i) 2.78 (1H, d, J=l4Hz), 1.43 (2H, in), 1.27 (4H, mn), 1.08 (2H, mn). 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCIINH3) mWe 503 Anal.calc.

for C 28

H

3 6F 2 N2O4- 1 H 2 0: C. 64.60; K, 7.36; N, 5.38. Found: C, 64.59; H, 7.2 0; N, 5.3 Example 1 51 nl-4 trans. trans-I1 -(N.N-Di(n-butl) iinQcarbon Ineth l-2(4 m thovhnI 4 2 ditmeth xyhefl l')r o ld n ca r oxfi c aci 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, ODC1 3 8 7.37 (2K, d.

J=8Hz), 7.20 (11K1 d, J=BKz), 6.92 d, J=8Hz), 6.60 (1H, d, J=3Kz), -169- 6.49 (1 H, dd, J=6Hz, 2Hz), 5.35 (1 H. d, J=8Hz), 4.20 (3H, mn), 4.10 (3H, s), 3.83 (3H, 3.81 (3H, 3.75 (3H, mn), 3.17 (2H, hep, J=7Hz), 3.05 (2H, t, J=7Hz), 1.30 (4H, mn), 1.07 (4H, in), 0.87 (3H, t, J=7Hz),, 0.80 (3H, t, J=7Hz). MS (DCI/NH3) m/e 527 Anal.calc. for C 3

OH

4 2 N206 -1.30 TFA: C, 58.02; H, 6.47; N, 4.15. Found: C, 57.92; H, 6.43; N, 4.07.

Example 152 trans. trans- 1 N-Di (n-b utyI~am ino~carbonlm ethl)-2-pheflyl- 4 .3-ben yl)pyrroli ine--aro liC acid The title compound was prepared by the proc~edures 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, d, J=4Hz), 3.85 (1H, d, J=8Hz), 3.64 (1H, mn), 3.42 in), 3.27 (2H, mn).

3.20-2.90 (5H, in), 2.81 (1H, d, J=l4Hz), 1.43 (2H, in), 1.27 (4H, in), 1.05 (2H, mn), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH 3 ine 481 Anal.calc. for C 28

H

36 N205: C, 69.98;- H, 7.55; N, 5.83.

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

Examole 153 trans. trans- 1 .N-Di(n-butflanlocarbonvyinethyl'-2heyl4(5benzo- 2 .3dihydrofuranfl)1yrrlidine-3-crboXylic acid The title compound was prepared by the procedures described in *.:Examples I and 49 substituting ethyl benzoylacetate in Example 49B and 2,3-dihyd rob enzof uran- 5-ca rbo xal dehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDC13) 8 7.53 (2H, in), 7.40 (4H, in), 7.13 (1 H.

dd, J=7Hz, 3Hz), 6.72 (IH, d, J=8Hz), 5.40 (1H, d, J~10Hz), 4.56 (2H, t, J=8Hz), 4.18 O1H, d, J=l4Hz), 4.07 (2H, in), 3.79 (2H, in), 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 in/e 479 Anal.calc. for C 2 9H 3

BN

2 O4 1.10 TFA: C, 62.04; H, 6.52; N, 4.64. Found: C, 61.89; H, 6.44; N, 4.57.

-170trans. trans-i1 N-Di(n-butylaminocarbonli-metlb)L(4t-butylhenyI)- 4 -(S.benzo- 2.3-dihydrfuranyl)pyrrolidile-3-carbOgylic 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 498 and 2,3-dihyd rob enzof carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDC1 3 8 7.60-7.30 (6H, in), 6.90 (1H, mn), 4.50 (2H, in), 3.95 (11H, mn), 3.85-2.95 10l (11H, in), 2.90 (1H, d, J=l4H-z), 1-.58 in), 1.50 (7H, in), 1.41 (6H, 1.10 (2H, in), 1.00 (3H, t, J=7Hz), 0.90 (3H, t, J=7Hz). MS (DCI/NH 3 V. i/e 535 Anal.calc. for C 3 3H 46 N2O4 0.25 H 2 0: C, 73.50; H, 8.69; N, 5.19. Found: C, 73.57; H, 8.58; N, 5.14.

15Example 155 trans. trans-2(N N- D n-butyaminocarbgflvlm thvI')2-P ehXYhnl"- 4 The fluoroohenyl)ovrrolidine3-carboxylic acid Th title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-fluorobenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, C0013) 5 7.50 (1H, in), 7.42 (1H, dd, J=7Hz, 3Hz), 7.36 d, J=8Hz), 7.01 (3H, t, J=8Hz), 6.87 (1H, d, J=8Hz), 3.83 (1H, in), 3.8 (3H, 3.67 (11H, in), 3.47 in), 3.30-2.90 (5H, in), 2.82 (1H, d, J=l4Hz), 1.43 (2H, in), 1.28 (4H, mn), 1.08 (2H, in), 0.90 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (001/NH 3 We 485 Anal.calc.

for C 28

H

37

FN

2 04: C, 69.40; H, 7.70; NK 5.78. Found: C, 69.03; H, 8.00; N, 5.74.

Exampgle 156 trans, trans- 1 N-Di(n uyaiopbf~Ine-hfl2(3ur-l 4 1.3-benz-dionol- 5.yfloyrroidile-3-carbgxyiC aci The title compound was prepared by the procedures described in Examples 1 and 49 substituting P-oxo-3-furalpropionate in Example 498. H NMR (300 MHz, C0013) 8 7.41 (2H, in), 6.97 (1 H, d, J=3Hz), 6.85 (1 H, dd, J=7Hz, 3Hz), 6.72 (1 H, d, J=8Hz), 6.42 (1 H, 5.94 (1 H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.90 (1H1, in), 3.70-3.25 (5H, in), 3.20-2.90 in), 2.85 (1H, d, J=l4H1z), 1.43 (2H, in), 1.40-1.05 (6H, in), 0.90 (6H, in). MS (001/NH 3 Wie 471 Anal-calc. for C 2 6

H

34

N

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

Exam ole 157 trans. trans-i -(N.N-1D(n-butyl~aminocrbofllmethl-2-(isoropyl)- 4 4 l.3ben zodioxo.5-yl) yrrolidile3ca rbgniC acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl iso butyryl acetate in Example 49B.

1H NMR (300 MHz, CDC13) 8 6.85 (1H, dl, 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 (1H, q, J=7Hz), 3.42 (3H, in), 3.25 (3H, in), 3.11 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 ni/e 447 Anal.calc. for C 2 5

H

3 8

N

2 Os 0.50 H 2 0: C, 65.91; H. 8.63; N, -6.15. Found: C, 66.07; H, 8.10; N, 6.03.

.:Examgole 158 trans. trans-i -(N.NDn-uyamocbnletI -2_4 Ihvl41.3- :ben zodioxo 15-l) yrrolidifle-3-ca rbXafic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 4-t-butyl benzoyl acetate, prepared by the method of Krapcho et al., Org. Syn. 47: 20 (1967) starting with 4t-butylacetophenone), in Example 49B. NMR (300 MHz, COCl 3 8 7.32 (4H, d, J=3H 7.04 (1H, d, J=2Hz), 6.87 (1 H, dd, J=8Hz, 3Hz), 6.74 (1 H, d, 5.94 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.77 (1H, d, J=l4Hz), 25 3.65-3.25 (5H, in), 3.15-2.85 (4H, mn), 2.73 (1H, d, J=l4Hz), 1.45 (2H, in), 1.29 (13H, 1.00 (2H, mn), 0.86 (3H, t, J=7Hz), 0.76 (3H, t, J=7Hz). MS

(DCI/NH

3 Wie 537 Anat.calc. for 0 3 2

H

4 4N205: C, 71.61; H, 8.26; N, 5.22. Found: C, 71.43; H, 8.09; N, 5.11.

Examle 159 trans, trans-i1 N- Di(n-butylaminocarbonlmethy-2(4tbutlhenl-4(Sbe:nz 2.3-dihydrofurny~pyrrolidile-3-carboxylic cid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl iso buty ryt acetate in Example 49B and 2,3 -dihydrobenzofuran-5-carboxaldehyde for piperoh~al in Example 49A. 'H NMR (300 MHz, COCl 3 8 7.30 (1IH, 7.13 dd, J=7Hz, 2Hz), -172- 6.82 (1H, d, J=8Hz), 4.68 (2H, t, J=8Hz), 4.48 (1H, 3.19 (3H, in), 3.80 (3H, in), 3.48 (2H, in), 3.3 (5H, mn), 2.41 (1 H, in), 1.65 (4H, mn), 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 Analcalc. for C 26

H-

40

N

2 O4 -1.2 TFA: C, 58.67; H, 7.14; N, 4.8.2 Found: C, 58.54; H, 7.25; N, 4.74.

Examgle 160 trans, trans-I1 N-Di(n-bu tyl')am inocarbonlmethyl)2-(anti-4methoXycyclohecy)- 1.3.benzodioxol-5-yflyrroliine oxYic acid Exam aLe 16 syn and anti Ethyl 4methoxycyclohexanoviacetate Syn, anti-4-Methoxycyclohexane carboxylic acid (5.00 g, 31.6 mmol) and carbonyldiimidazole (6.15 g, 37.9 mmol, 1.2 eq) were stirred 15 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 malonate potassium salt (7.52 g, 44.2 mmol, 1.4 equivalents) were stirred in anhydrous tetrahydrofuran (75 mL) for 6 hours at 50 0 C. The mixture was cooled to room temperature, and the imidazole-acid mixture added to it. The reaction stirred overnight at room temerature.

The solvents were removed under reduced pressure, and the residue was taken up in chloroform/water. The organic. phase washed with 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 ethyl acetate in hexanes. Pure fractions of the syn and anti inethoxycyclohexyl 1-keto esters were obtained. 'The solvents were removed under reduced pressure to yield the trans-4-methoxycyclohexyl 0-keto ester (914 mg) as a colorless oil and the cis 4inethoxycycloheXyl 03 keto ester (1.07 g) as a colorless oil.

Example 160B trans. trans-i 1( n-inbtfpl Incroymethyfl-.(nnfi-4meth I vclh xvh- 4(13bezdol5yfl~rroliine3-crboxyjrg acid The title compound was prepared by the procedures described in Fxarnples 1 and 49 substituting the anti-compound resulting from -173- Example 160A in Example 49B. 1 H NMVR (300 MHz, CDC1 3 5 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, in), 3.50-3.27 (5H, in), 3.26 (3H, 3.25-3.00 (3H, in), 2.88 (1H, in), 1.95 (2H, in), 1.62 (7H, in), 1.33 (9H, mn), 0.97 (3H, t, J=7Hz), 0.92 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 517 Anal.calc. for C 2 9

H

44 N2O6 -0.50

H

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

Exam~i~e trans, trans-i 1 (N NDi(n-butflaminoca rbonylm ethyl)-2-(sy-4-methocycclohexyIj- 1.3-benzodioxol-5yl)1yrroidile.3-carb-oxyic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the syn-coinpound resulting from Example 160A in Example 49B. 1 H NMR (300 MHz, CDCI3) 8 6.84 (1H1, d, J=2Hz), 6.77 (1H, dd, J=6Hz, 2Hz), 6.61 d, J=8Hz), 5.92 (2H, 3.65 15 (2H, in), 3.42 (2H, in), 3.32 (3H, 3.30-3.00 (6H, mn), 2.82 (1H, in), 2.10 in), 1.83 (2H, in), 1.52 (6H, in), 1.33 (4H, in), 1.20-1.00 (4H, in), 0.96 (3H, t, J=7Hz), 0.91 (3H, t, J=7Hz). MS (DCI/NH 3 mWe 517 Anal.calc. for C 29

H

44

N

2 0 6 0.30 H 2 0: C, 66.72; H, 8.61; N, 5.37. Found: 22.C, 66.76; H, 8.65; N, 5.28.

Example 162 trans. trans-i N.Di(n-butflamninoc arbolylmethyl)-2.4-di(5-benzo- 2 3 :dihydrofu ranyfloiyrrolidine-3-caboxyic acid Example 162A 5-Acetyl-2.3- dihydrobenzof uranl To a 0 OC solution of acetyl chloride (1.64. mL, 23.0 iniol, 1.3 equivalents) in mnethylene chloride (30 mL) was added stannic chloride (2.49 inL, 21.3 mmol, 1.2 equivalents), maintaining the temperature below 5 00. The solution was stirred 15 minutes at 0 00, and then a solution of 2,3-dihydrofuran (2.00 inL, 17.7 iniol) in methylene chloride mQL was added. dropwise while maintaining the temperature below 8 The dark red solution was stirred 1 hour at 2 O0 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 -174sulfate, 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.

trans. trans-i N-Di(n-butvlam inocarbon lVmflethyfl)-2.4-di (5-beflzo-2.3dihydrofuranvflov2rrolidile-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 -dihyd ro ben zof uran -5-carboxald ehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) 8 7.43 (1 H, 7.38 (I1H, 7.06 (2H, in), 6.75 (1H, d, J=6Hz), 6.70 (1 H, d, J=6Hz), 5.40 (1 H, d, J=9Hz), 4.58 (4H, q, J=7Hz), 4.16 (1H, d, J=14Hz), 4.09 (2H, in). 3.82 :15 (2H, in), 3.57 (1H, d, J=l4Hz), 3.38 (1H, mn), 3.30-3.05 (6H, in), 2.95 (2H, q, J=6Hz), 1.50 (2H, in), 1.30 (4H, in), 1.15 (2H1, in), 0.94 (3H, t, J=7Hz), 0.83 (3H, t, J=7Hz). MS (DCI/NH 3 ine 521 Anal.calc. for 031 H 4 0

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.

Example 163 trans, trans-i1 .NDi(n-butyl'tam inocarboflylm ethyl)-2-(3-f uYfl-4-(5-ben zo-2 .3- :dihydrofuranvlkc~rrolidile--3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 5-oxo-3-furanpropionate in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDC1 3 8 7.42 (1H, in), 7.38 (1 H, in), 7.13 (1H, 7.16 (1H, dd, J=7Hz, 3Hz), 6.70 (1H, d, J=8Hz), 6.41 (1H, in), 4.57 (2H, t, J=7Hz), 3.95 (1H, d, J=8Hz), 3.63 (1H, in), 3.55 (1H, dl, J=14), 3.50-3.25 (4H, in), 3.18 (2H, t, J=6Hz), 3.15-2.95 (3H, in), 2.87 (1H, d, J=l4Hz), 1.45 (4H, in), 1.35-1.10 (4H, in), 0.85 in). MS (DCI/NH 3 Wne 469 Anal.calc. for C 2 7

H

3 6 N205 0.25 H 2 0: C, 68.55; H, 7.78; N, 5.92. Found: C, 68.62; H, 7.68; N, 5.82.

175- Examle164 tras~tan-l (NN-Di(n-butyl)aminocarbonylmethyD-2-(4-methogyphenl)f-4-(3fluorophenyl)pyrrolidine-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, C~DC 3 8 7.30 (2H, d, J=8Hz), 7.22 (2H, in), 6.91 (1H, in), 6.86 (2H, d, J=8Hz), 3.79 (1H, mn), 3.78 (3H, 3.68- (1 H, mn), 3.55-3.37 (3H, in), 3.29 (1 H, mn), 3.15-2.90 mn), 2.78 (1 H, d, J=l4Hz), 1.43 (2H, mn), 1.25 (4H, in), 1.07 (2H, in), 0.87 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCILNH 3 m/e 485 **Anal.calc. for C 28

H-

37

FN

2 04 0.25 H 2 0: C, 68.76; H, 7.73; N, 5.73. Found: C, 68.87; H, 7.69; N, 5.67.

Example 165 trans. trans-i1 N- Di(n-butyl)am inocarbonlm ethl)-2-(4-m ethouyghenyfl-4- (3- DvridvF2yrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-pyridinecarboxaldehyde for piperonal Example 49A. The nitro styrene was prepared by the method of Bourguignon ,et al., Can. J. Chemn. 63: 2354 (1985). 'H NMR (300 MHz, CDC1 3 8 8.82 (1H, bs), 8.73 (1H, bd, J=9Hz), 8.62 (1H, bd, J=7Hz), 7.78 (1H, bdd, J=9Hz, 3Hz), 7.38 (2H, d, J=lOHz), 6.90 d, J1lOHz), 4.39 (1H, d, J=l2Hz), 3.95 (1H, in), 3.80 (3H, 3.79 in), 3.68 (1H, d,' J=18Hz), 3.50-3.30 (3H, in), 3.25-2.90 (6H, in), 1.47 (2H, in), 1.31 (4H, 25 in), 1.20 (2H, in), 0.92 (3H, t, J=7Hz), 0.83 t, J=7Hz). MS (DCI/NH 3 Wne 468 Anal.calc. for C 2 7

H-

3 7

N

3 04 -1.65 TEA: C, 55.50; H, 5.94; N, 6.41. Found: C, 55.53; H, 5.90; N, 6.27.

Example 166 trans, trans-i1 (N .NDi(n-butylam inocarbonylm ethyl)-2-(2-fluorophenl)f- 4 .3ben zodioxo 1-5- vl) 1yrrol idine-3-carOxyk acd The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 2-fluorobenzoyl acetate in Example 49B. 1 H NMR (300 MHz, CDCI 3 8 7.52 (1 H, dt, J=7Hz, 3Hz), 7.25 (1H, in), 7.13 (1H, dt, J=7Hz, 3Hz), 7.02 (2H, in), 6.88 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 (1H, in), 3.42 (3H, in), 3.39 (1H, in), 3.20-2.95 (4H, Page(s). were not lodged with this application -177- Example 16 trans. trans- 1(2NNDitylaminopyrimidin-4-yl)-2-(4-methoxyohenyfl-4-( 1.3benzodioxol-5-yl)oyrrolidine-3-carboxylic acid 2-(Dibutylamino)-4-chloropyrimidine is prepared from 2,4dichtoropyrimidine according to the method of Gershon, J. Heterocyclic Chem. 24: 205 (1987) and reacted with ethyl trans, trans-2-(4methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-pyrrolidine-3-carboxylate (the compound resulting from Example GA) and diisoproplyethylamine in dioxane with heating to give the intermediate ethyl ester, which is hydrolyzed with sodium hydroxide using the methodl of Example 1 D to the title compound.

*Examjles 170-266 lost 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 lee.170 trans, trans-2-(4-Methoxyphenyl)-4-(1,3- *0000benzodioxol-5-yl)- 1- (isopropylaminocarbonylmethyl)-pyrrolidine- 3 171 carboxylic acid; 17 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-1 -(ethylami noca rbonylm ethyl) pyrrolidine-3-carboxylic acid; :172 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-1 methylpropylaminocarbonyl methyl)-pyrrolidine-3carboxylic acid; 173 trans, trans-2- (4-M et hoxyph enyI)-4-(1 ,3benzodioxol-5-yl)-l1-(phenylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; 1 74 trans, trans-2-(4-Metho xyphenyl)-4-(1 .3benzo di oxol-5-yl) 1 (pipe ridi nylcarbonyl methyl)pyrrolidine-3-carboxylic acid; -178- 1.75 trans, trans-2-(4-Methoxyphenyl)-4(1 .3benzodioxol-5.yi)-1 (propylaminocarbonyl)ethyl)-pyrro Iidine-3carboxylic acid; 1 76 tra ns, tr ans-2- Met ho xyp h enyl) -4 3b en zo d io x olI-5-yI)- 1 (cc- (p ropyl am in oca rb o nyl) be nzyl)- pyrro i d in e- 3 carboxylic acid; 177 trans, trans-2-(4-M ethoxyphenyl).4.(1 benzodioxol-5-yI)-l1-(bis- (propylaminocarbonyl)methyl)-pyrrolidine-3 carboxylic acid; 178 trans, trans-2-(4-Methoxyphenyl).4(1 .3benzodioxol-5-yi)-1 (propylaminocarbonyl)ethyl)-pyrrolidine.3- .carboxylic acid; 1 79 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3- :benzodioxol-5-yl)- 1 ropyl amino sulf onyl methyl) pyrrotidine-3-carboxylic acid; 180 trans, trans-2- Methoxyphe nyl) 1,3- *ben zod ioxol-5-yI)- 1 henethyl) -pyrrolidi ne-3carboxylic acid; 1 81 trans, trans-2-(4-Methoxyphenyl)-4.( 1 3- .be nzodioxol-5-yI)- 1 (pentanoytm ethyl)- :pyrrolidine-3-carboxylic acid; 182 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3ben zod ioxol-5-yl)- 1 -(ben zoylmethyl)-pyrrol idi ne- 3-carboxylic acid; 183 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-l1-(hexyl)-pyrrolidine-3carboxylic acid; 184 trans, trans-2-(4-Methoxyphenyl)-4-(1,3..

benzodioxol-5-yl)-1 -(2-hexynyl)-pyrrolidine-3carboxylic acid; 185 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3ben zodioxol-5-yI)- 1 -(pro poxymethylcarbonylpyrrolidine-3-carboxylic acid; -179- 186 trans, trans-2- (4-M etho xyphenyl)-4 3ben zodioxol-5-yt)- 1 hen ylIacetyl)-pyrrolIi dine-3carboxylic acid;, 1 87 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3ben zodio xol1-5-yI)- 1 -(anili nyl carbonyl) pyrrolidine-3-carboxylic acid; 188 trans, trans- 2- (4-M ethoxyp henyl) .3- 1-(2-acetytaminoethyl)pyrroli dine- 3-carboxylic acid; 1 89 trans, trans-2-(4-M ethoxyphenyl)-4-(l benzodioxol-5-yI)-1 -(2-phenoxyethyl)-pyrrolidine- 3-carboxylic acid; .190 trans, trans-2- Metho xyp henyl) -4 benzodioxol-5-yI)-l1-(2-benzodioxanytmethyl)pyrrolidine-3-carboxylic acid; .191 trans, trans-2-(4-Methoxyphenyl)-4-(l,3pyrrolidine-3-carboxylic acid; :192 trans, trans-2-(4-Methoxyphenyl)-4-(1,3benzodioxol-5-yI)- 1 (propylaminocarbonylamino)ethenyl)- pyrrolidine-3carboxylic acid; 1 93 trans, trans-2-(4-Methoxyphenyl 1 3- 1 (propylaminocarbonylami no~ethyl)-pyrrolidine-3carboxylic acid; 194 trans, trans-2-(4-M ethoxyphenyl)-4-( 1,3benzodioxol-5-yI)-l1-(3-oxohex-l1-enyl)pyrrolidine-3-carboxylic acid; 195 trans, trans-2-(2,4- Dimethoxyphenyl)-4-(1 ,3- 1-(propylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; 1 96 trans, trans-2-(2-Carboxy-4-methoxyphenyl)-4- (1 ,3-benzodioxol-5-yI)-1 (propylaminocarbonylmethyl)-pyrrolidifle-3carboxylic acid; -180- 197 trans, trans-2-(2- Amin ocarbonyl-4.

methoxyph.enyl)-4-(1 be nzodioxol-5-y)- 1 (pro pylami nocarbonyl methyl)-pyrro i din e-.3 carboxylic acid; 198 trans, trans-2-(2-Methanesulf onamid-4m ethoxyphe nyl)-4-(1 ben zodi oxolI-5-yI) -1 (propylaminocarbonylmethyl)..pyrrolidine-3 carboxylic acid; 199 trans, trans- 2- (2-Ami nocarb onylmrneth oxy-4 methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 (propylaminocarbonylmethy)-pyrroidine-3.

carboxylic acid; trans, trans-2 -Met hoxyet hoxy-4methoxyphenyl)-4-(1 .3-benzodioxol-5-yI)-1 (propylamin ocarbo nyl methyl) -pyrrol idin e-3 :carboxylic acid; 201 trans, trans-2-(2-Carboxym ethoxy-4methoxyphenyl)-4-( 1,3-benzodioxol-5-y)-1 (propylaminocarbonylmethyl)-pyrrolidine..3carboxylic acid; 202 trans, trans-2 Met hoxy- 2 .*te tra zolIyIm et h oxy phe nyl1) -4 -b e nzo d iox oI- 5 yI1) -1 (p ro p yIam in oc ar bo n y Imet hy 1) -p yrro Ii d in e-3 :carboxylic acid; 203 trans, trans-2-(2-AIlyloxy-4-methoxyphenyl) -4- ,3-benzodioxol-5-yt)-l (propylaminocarbonylmethyl)pyrrolidine.3 carboxylic acid; 204 trans, trans 2,4- Bis me thoxyp he nyl) -1 (pro pyIami n ocarbo ny Ime t hyl) -py rro i d in e 3 carboxylic acid; 205 trans, trans 2,4- Bis (1 3-b e nzod io xol-5-y) I (p ropyl amin o carb o nyl m et hyl) -py rrolIi d ine -3 carboxylic acid; -181- 206 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3- 1 -(N-methyl-Npropylaminocarbonylmethyl)-pyrrolidi ne-3carboxylic acid; 207 trans, trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxole-5-yl)-1 -(N-methyl-Nbutylaminocarbonyl)-pyrrolidine-3-carboxylic acid; 208 trans, trans-2-(4-Methoxyphenyl)-4-( 1 3benzodioxol-5-yi)-l1-(N-methyl-N-(4methoxyphenyl)aminocarbonyl )-3-pyrrol idine-3- ::carboxylic acid;, 209 trans, trans-2-(4- Methoxyphen yl)-4- (1 ,3benzo di oxol-5-yl) 1 ethyl- Nphenylaminocarbonyl)-pyrrolidine-3-carboxylic acid; *.:210 trans, trans Metho xyphen 1,3ben zodioxol-5-yl) 1 methyl-N- -allylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 211 trans, trans Metho xyphen yl)-4- (1 ,3benzodioxol-5-yl)-l1-(N-methyl-N-(nbutyl) am in oca rb onyl methyl)- p yrroIi d in e- 3carboxylic acid; trans, tra ns-2-(4- Methoxyphe nyl)-4- (1,3benzodioxol-5-yI)-l1-(N-methyl-Ni sobutyl ami noca rbonylm ethyl) -pyrro lidi ne-3carboxylic acid; 213 trans, trans-2-(4- Methoxyphe nyl)-4-( 1 3benzodioxol-5-yl)-1 -(N-methyl-Ncy ciop entyl amino carb onflImethyl) -p yr rolid in e-3carboxylic acid; 214 trans, trans-2-(4-Methoxyphenyl)-4-( 1 3benzodioxol-5-yl)-l1-(N-methyl-N-(2methoxyethyl)aminocarbonyl)-pyrrolidine-3carboxylic acid; -182- 215 trans, trans -2-(4-Methoxyphenyl)-4-( 1,3- 1 -(N-methyl-Nbutoxyethyt am inocarb onyl)-pyrroli di ne-3carboxylic acid; 216 trans, trans-2-(1 ,3-Benzodioxol-5-yI)-4-(4methoxyphenyl)-l1-(N-methyl-Npropylami nocarbonylm ethyl) -pyrrotidi ne-3carboxylic acid; 217 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,4ben zodioxan-6-yI)- 1-(N-methyl-N p ropyl ami nocarbonylm ethyl) -pyrroli dine-3- 28 carboxylic acid; 28 trans, trans-2-(4-Methoxyphenyl)-4-(1,3benzodioxol-5-yI)-l1-(N-methyl-Nisopropylaminocarbonylmethyl)-pyrrolidine-3- :carboxylic acid; 219 'trans, trans-2-(4-Methoxyphenyl)-4-(1,3benzodioxol-5-yl)- 1 -(N-methyl-Neth ylamin oc arbo nyl methyl) -pyrrol idi ne-3-.

carboxylic acid; 220 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3- 1-(N-methyl-N-( 1methylpropyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 221 trans, trans -2 Met hoxyp he nyl) 1,3benzodioxol-5-yl)-l1-(N-methyl-Nphenylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 222 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-1 -(N-methyl-Npropylaminocarbonyl)ethyl)-pyrrolidine-3carboxylic acid; 223 trans, trans-2-(4-Methoxyphenyl)-4-(1.3benzodioxol-5-yl)-l1-(a-(N -methyl-Npro pylamin ocarbonyl) be nzyl)-pyrroli dine-3carboxytic acid; -183- 224 trans, trans Methoxyp he nyl) (1,3ben zodioxol-5-yl)- 1 -(N-ethyl-Nprop ylami nocarbonylm ethyl) -pyrroli dine -3 carboxylic acid; 225 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxole-5-yt)-l1-(N-ethyl-Nbutylaminocarbonyl)-pyrrolidine-3-carboxylic acid; 226 trans, trans-2-(4-Methoxyphenyt)-4-(1,3ben zodioxol-5-yl)- 1 N-ethyl-N methoxyphenyl)aminocarbonyl)-3-pyrrolidine-3carboxylic acid; 227 trans, trans-2-(4-Methoxyphenyl)-4- (1 3benzodioxol-5-yl)-1 -(N-ethyl-Nphenylami nocarbonyl)-pyrrolidine-3-carboxylic 228 acid; 28 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3benzodioxol-5-yl)-1 -(N-ethyl-N :allylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 229 trans, trans-2- Metho xyp hen yl)-4-(1 .3benzodioxol-5-yi)- 1 -(N-ethyl-N- *isobutyl amino carbo nylm ethyl)-pyrrolidifle-3 carboxylic acid; :230 trans, trans-2-(4-Methoxyphenyl)-4-(1,3benzodioxol-5-yl)- 1-(N-ethyl-Ncyclopentylami nocarbonylmethyt)-pyrrolidine-3carboxylic acid; 231 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3- 1 -(N-ethyl-Nmethoxyethylaminocarbonyl)-pyrrolidifle-3carboxylic acid; 232 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3benzodioxol-5-yl)-1 -(N-ethyl-Nb uto xye thyl ami no carbo nyl) -py rrol i dine- -3carboxylic acid; -184- 233 trans, trans Ben zodioxol1-5-y1) -4 methoxyphenyl)-1 -(N-ethyl-Npropylaminocarbonylm ethyl)-pyrroli dine -3carboxylic acid; 234 trans, trans-2-(4-Methoxyphenyl)-4-( 1,4benzodioxan-6-yl)- 1-(N-ethyl-Nprop ylam ino carbon yl methyl) -p yr rol idine -3carboxylic acid; 235 trans, trans-2-(4-Methoxyphenyl)-4-(1,3benzodioxol-5-yl)-1 -(N-ethyl-Nisopropylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; :..236 trans, trans-2-(4-M et hoxyphenyl) (1,3 ****benzodioxol-5-yl)- 1 di ethylami no carbo nyl methyl)- pyrrol idi ne- 3- 237 carboxylic acid; 23 trans, trans-2-(4-M ethoxyphen 1,3- 1-(N-ethyl-N-( 1- *.:methylpropyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 238 trans, trans et hoxyphe nyl) (1.3benzodioxol-5-yl)- 1-(N-ethyl-Nphenylami nocarbonyim ethyl)-pyrrolidin e-3- 239 carboxylic acid; 23.trans, trans -2 et hoxyphe nyl)-4-( 1 3benzodioxol-5-yl)-l1-(1 -(N-ethyl-Npropylaminocarbonyl)ethyl)-pyrrolidine-3carboxylic acid; 240 trans, trans ethoxyphenyl)-4-(1 .3benzodioxol-5-yl)-l1-(a-(N-ethyl-Npro pylamin ocarbonyl) be nzyl)-pyrrolid in e-3carboxylic acid; 241 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3- 1 -(N-methyl-Nisobutylaminocarbonylmethyl )-pyrrolidine-3carboxylic acid; -185- 242 trans, trans etho xyp hen yl)-4- (1 3benzodioxol-5-yl)-1 -(N-methyl-Ncyclohexyl ami nocarbonylmethyl)-pyrroli dinle-3carboxylic acid; 243 trans, trans-2-(4-Methoxyphenyl)- 4 .3benzodioxol-5-yl)-1 ,Ndip ropylaminocarbonylmethyl)-pyrrolidifle-3carboxylic acid; 244 trans, trans Methoxyp he nyl)-4- (1,3- 1-(isobutyloxyethyL4pyrrolidine-3-carboxylic acid; *:245 trans, trans-2-(4- Met hoxyp hefnlyl)-4- I benzodioxol-5-yt)-l1-(butylsulfonyl)-pyrrolidifle-3carboxylic acid; *246 trans, trans -2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yi)- 1- (is opropylsulf on ylami noet hyl)-pyrro li dine -3 carboxylic acid; *247 trans,trans-2-(4-Methoxyphenyl)- 4 1,3- 1- *.t(hto xyme th ylIc arb on y Im et h y1)- p y r roIid ifne-3 carboxylic acid; 248 trans, trans Met hoxyphe nyl)-4- (1,3benzodioxol-5-yI)-l1-(2-ethylbutyrylmethyl)pyrrolidine-3-carboxylic acid; 249 trans, trans -2 ethoxyphe nyl) (1,3benzodioxot-5-yl)-l1-(N-methyl-N-(3,4dimethoxybenzyl)aminocarboflylmethyl)pyrrolidine-3-carboxylic acid; 250 trans, trans-2 -(4-Methoxypheflyl) 4 13benzodioxol-5-yl)-1 R)-1 -(N-methyl-Npropylaminocarbonyl)butyll-pyrrolidifle- 3 carboxylic acid; 251 trans, trans-2-(4-M ethoxyphenyl)- 4 (l 3benzodioxot-5-yl)-l1-[(1S)-l1-(N-methyl-Npropytaminocarbonyl)butyl]-pyrrolidile-3carboxylic acid; -186- 252 trans, trans eth oxyp hen 1,3ben zodioxol-5-yl)-1 -(3-isopropoxypropyt)pyrrolidine-3-carboxytic acid; 253 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3- 1 ethyl he xyl) -pyrro i di ne- 3-carboxylic acid; 254 trans, trans-2-(4-M ethoxyphenyl)-4-( 1,3benzod ioxol-5-yI)- 1 methyl hexenyl) pyrrolidine-3-carboxylic acid; 255 trans, trans-2-(4-Methoxyphenyl)-4-( 1 p3b enzodi oxol 1 methyl he xenyl)- 0: 0::pyrrolidine-3-carboxylic acid; 256 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3benzodioxol-5-yI)-l1-(3.5-dimethyl-2-hexenyl)pyrrolidine-3-carboxylic acid; 257 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yI)-l1-(2-(N-methyl-Nisobutyrytami1no)ethyl) -pyrrol idin e-3-carb oxyl ic 0 258 trans, trans-2 Metho xyp hen yl) (1,3b en zo d ioxoI- 5 -y 1) -1 (N -me t hyl -N .dimethyl propyl) ami nocarb onyl methyl)-pyrroli dine 3-carboxylic acid; 0 0 0 259 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yI)-1-(N-ethyl-Ncarboxylic acid;, 260 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3- 1 -met hyl-Nben zyl aminocarbonylm eth yl)-pyrrol idine- 3carboxylic acid; 262 trans, trans-2-(4-Methoxyphenyl)-4-(5-indanyl)-1 (N -m ethyl -N-propylami nocarbonyl methyl) pyrrolidine-3-carboxylic acid; -187- 262 trans, trans -2-(4-Methoxyphenyl)- 4 dihyd robe nzof uran-5-yl)- 1 -(N-methyl-Nprop ylam inocarbo nyl methyl)-pyrrolidi ne-3carboxylic acid; 263 trans, trans-2-(4-M ethoxyphenyl)-4-(1 methylindol-5-yl)-1 -(N-methyl-Npro pyl ami nocarbonyl met hyl) -pyrro lid i ne-3carboxylic acid; 264 trans, trans-2-(4-Methoxyphenyl)-4-(2-laphthyl)- 1 -(N-methyl- N-propylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; 265 trans, trans-2-(4-Methoxyphenyl)-4-( 1,2dimethoxy-4-phenyl)-l1-(N-methyl-Npropyl ami nocarbonyl meth yl) -pyrroli dinle-3carboxylic acid; :266 trans, trans-2-(4-Methoxyp he nyl)-4-(l -methoxy-3phenyl)-l1-(N-methyl-N- ~j propylaminocarbonylmethyl)-pyrrolidine-3cabyi acid Examples 267-288 Following the procedures described in Example I and Scheme 11, the following compounds can be prepared.

*267 trans, trans etho xyp henyl)-5- (l,3ben zodioxol-5-yl)- 1 ropyl ami nocarbonylm ethyl) piperidine-4-carboxylic acid; 268 trans, trans-3-(4- Methoxyphenyl)-5-(1 ,3- 1 -(aminocarbonylmethyl)piperidine-4-carboxylic acid; 269 trans, trans-3-(4-Methoxyphenyl)-5-(l ,3benzodioxol-5-yI)-l1-(4-fl uorobenzyl)-piperidine- 4-carboxylic acid; 270 trans, trans-3-(4-Methoxyphenyl)-5-(1 .3- 1 -(2-ethoxyethyl)-piperidine-4carboxylic acid; -188- 271 trans, trans -3-(4-Methoxyp he nyl)-5-(1 ,3ben zodioxol1-5-yi)- 1 -(2-propoxyethyl)-piperidine- 4-carboxylic acid; 272 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3ben zod ioxot-5-yI)- 1 -(2-(2-metho xyethoxy)ethyl]-.

piperidine-4-carboxylic acid; 273 trans, trans-3-(4-Methoxyphenyl)-5-(1 13- -py ridyl) ethyl] piperidine-4-carboxylic acid; 274 trans, trans Methoxyphenyl) 1 ,3benzodioxol-5-yI)-l1-(morpholin-4-ylcarbonyl)piperidine-4-carboxylic acid; 275 trans, trans-3-(4-Methoxyphenyl)-5-(1,3e. bn zo d ioxolIe-5 -y1) 1 (b utyIa m in ocarb o nyl) piperidine-4-carboxylic acid; 276 trans, trans-3-(4-M ethoxyphenyt)- 5-(1,3benzodioxol-5-yI)-l1-(4- :0 methoxyphenylaminocarbonyl)-3-piperidine-4cabxyi acid 277 trans, trans Met hoxyp he nyl) (193ben zodioxol-5-yI) 1 -acetyl pi peridine-3-carboxyli c 00~acid; 278 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3ben zod ioxol-5-yI) 1 uroyl)- pipe ridine-3- 279 carboxylic acid; 27 trans, trans-3-(4-Methoxyphenyl)-5-(1,3ben zodioxol-5-yI)- 1 -(phenylami nocarbonyl)piperidine-4-carboxylic acid; 280 trans, trans-3-(4-Methoxyphenyl)-5-(1 .3- 1-(allylaminocarbonytmethyl)piperidine-4-carboxylic acid; 281 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3- 1-(nb ut yI amino carbon yImet h y pipe ri di n e-4- ca rb o xy Ii c acid: -1 89- 282 trans, trans-3-(4-M ethoxyphenyl)-5- (1 3benzodioxol-5-yl)-1 -(N-n-butyl-Nmethyl amino carbon yl m ethyl) pipe ri din e -4carboxylic acid; 283 trans, trans-3-(4-Methoxyphenyl)-5-(1, 3 benzodioxol-5-yl)-l1-(pyrrolidin- 1ylcarbonylmethy)-piperidine-4-carboxylic acid; 284 trans, trans -3 Metho xyphe nyl)- 3- 1- (isobutylaminocarbonylmethyl) -pi peridi-ne-4carboxylic acid; 285 trans, trans..3-(4- Metho xyphe nyl) (1,3- (cyclopentylamninocarbonylmethyl)-pipe ridi ne- 4 I' 286 carboxytic acid; 26 trans, trans Met hoxyphefnlyl) .3benzodioxol-5-yl)-l1-(morpholin-4ylaminocarbonylmethyl)-piperidine-4-carboxylic ****acid; 287 trans, trans-3-(4- Meth oxyp hen yl)- b e nzo d ioxo I- 5 -yl) 1 (2 -phe n o xye thyl) p iperi din e 4-carboxylic acid-, 288 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3benzodioxol-5-yl)-l1-(methoxyethylaminocarbonyl)- .:piperidine-4-carboxylic acid.

trans. trans- 2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yfl- 1- (4dibutylaminophenyl)-pyrrtidile-3-carboxylic acid 4-Nitro-fluorobenzene, ethyl trans, trans-2-(4-methoxypheflyl)- 4 ,3benzodi oxol.5-yl)-pyrrolidifle-3-carboxyl ate (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)pyrrolidine-3-carboxyl ate. The nitro compound is hydrogenated to the io corresponding aminophenyl compound. This is reacted with butyraldehyde and sodium cyanoborohydride according to the method of Borch Am Chem. Soc., 93, 2897, 1971) to: give the corresponding N,N- 190dibutylaminophenyl compound, which is hydrolyzed with sodium hydroxide using the method of example 1D0 to give the- title compound.

Example 290 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yfl-1 dibutylamino- niidine-4-yfl-o2yrrolidine-3-carboxylic acid 2 -(Di butyl amino) 4-chi oropyri mi dine is prepared from 2-4dichioropyrimidine according to the method of Gershon Heterocyclic Chem. 24, 205, 1987). This compound, ethyl trans, trans-2-(4methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-pyrroljdine-3-caLrboxylate (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 10 to give the title compound.

Example 291 trans, trans-2-(4-Methoxyvohenyl)-4-( 1.3-benzodioxol-5-vI'- 1 -(N-butyl-Nphenylaminocarbonylmethl)-ovrrolidine-3-carboxylic acid :The title compound was prepared according to the general procedure of Example 1. 1H NMR (CD 3 00): 5 0.87 1.2-1.35 1.35-1.5 2.78 (in, 2H); 3.10 (t,IH, 3.26 (d,1H,J=15); 3.44 (ddI,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 m/e 531 Anal calcd for C 3 1

H

3 4

N

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

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

Example 292 Sodium trans. trans-2- MethoxUp h enyl)-4- 1,3- ben zodio xol 1 N-di(n butvl~amin ocarbonv~m eth vl)-pyrrol idin e- 3-c arbo xvlate Example 292A Ethyl 3-(4-methoxyohenfl-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 .qInowed to settle. 20 L of the toluene solution was aspirated. 28 L of -191toluene 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 is 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 20 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 15°-200 C. The jacket temperature was S**set to -50 C and the reaction solution cooled to a temperature of +3.50 25 C. A 210 C solution of 3.10 kg (38.8 moles) 50% aquous sodium S" hydroxide 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 -192dichloromethane. 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 s 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 15 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.

Example 292D Ethyl 2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl'-4.5-dihydro-3Hoyrrol-3-carboxylate 25 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 -193title compound. A further 200 g (23% yield) of product was obtained from the mother liquors.

Example 292E Ethyl 2-(4-methoxyphenvil-4-(1.3-benzodioxol-5-yl)-Dvrrolidine 3carboxylate Into a 12-L flask equipped with magnetic stirring, addition funnel, temperature probe, and nitrogen inlet was charged 0.460 kg ethyl 2-(4methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-4,5-dihydro- 3 H 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 (1.5 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 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.

Example 292F Ethyl 2-(4-methoxypheny)-4-(1.3-benzodioxol-5-yl)-1-(N.N-di(nbutylaminocarbonylmethyl) ovrrolidine 3-carboxylate 25 Into a 22-L flask equipped with overhead stirring, nitrogen inlet, and condenser was charged ethyl 2-(4-methoxyphenyl)-4-(3, 4 methylenedioxyphenyl)-pyrrolidine-3-carboxylate (2.223 kg,6.02 mol).

The reaction vessel was degassed with nitrogen. 13.2 L 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 C).

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.

-194- Concentration as above provided 3.112 kg (96 yield) of the title compound as a dark oil.

Example 292G trans. trans-2-(4-Methoxvohenylv-4-( 1.3-benzodioxol-5-yl)-Dvrrolidine 3-carboxylate and preparation of trans.trans 2-(4-methoxDhenyl)-4- (3.4-dioxyphenyl)-pyrrolidine-3-carboxvlic 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)- 10 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 is 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 give 2.132 kg of a dark oil. The oil was triturated with 18 L ether. The undesired solids were filtered and saved for later use. The mother liquors were concentrated to obtain 1.102 kg of light foam. The foam was dissolved in 5.5 L ethyl acetate with heating to 650 C. 14 L hexane 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-methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 (N.N-di(n-butyl)aminocarbonylmethvl) pyrrolidine 3-carboxvlate 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 acia (0.927 ky, i.G19 A soution of -195- 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 Q) was added again and concentration of this solution gave a light tan foam. The foam was dried in vacuo at 5Q0 C to a constant weight of 0.937 kg (97% yield) of the title compound.

Example 293 trans- trans-2-(4-Methoxyphenyfl- 4 1.3-benzodioxol-5-yl)- I idecahydroisoguinolin-2- carbonylmethyll-pyrrcdidine- -carboxyliCQ The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) shows a mixture of isomers. MS

(DCI/NH

3 mlz 521. Anal calcd for C 3 oH1 36

N

2 O6 1.3 TFA: C, 58.54; H, 6.62; N, 4.19 Found: C, 58.34; H, 5.58; N, 4.00 trans-trans-2-(4-Methoxyp~henyfl-4-(l .3-benzodioxol-5-yfl-1 -f3.3- *dimethylpiperidinyl- ca rbonvl met hyll-12rro i dine- 3-ca rboxyli c acid.

The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) indicates presence of rotamers. 8 0.84 3H), 0.86 3H), 1.35-1.6 (in, 4H1), 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 C 28

H

34

N

2 06 1.4 TEA: C, 56.55; H, 5.45; N, 4.28 Found: C, 56.52: H, 5.83; N, 4.26.

Example 295 trans- trpns-2-(4- Meth oxyg he nyfl- 4 1.3-b enzodioxo 1-5-yl 14 2(Nprolyl-N-iso-butoxycarbonylamino'~ethyibD1yrrolidine3carboxYlic acid The title compound was prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 61B and isobutyl chloroforinate 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) 8 0.80 3H, 0.92 (in, 3H), 1.43 2H, J=7Hz), 1.7-1.9 (in, 1H), 2.72 (mn, 1H), 2.90 (mn, 2H), 3.10 (in, 2H), 3.25 (mn, 2H), 3.40 (mn, 1H), -196- 3.55 (in, 1H), 3.62 (in, 1H), 3.7-3.9 (in, 2H) 3.78 3H), 5.95 2H), 6.72 IH, J= 8Hz), 6.82 (in, 3H), 7.00 1H), 7.30 2H, J=8Hz). MS

(DCI/NH

3 m/e 527 Anal calcd for C 29

H

3 8N206 -0.5 H 2 0: C, 65.03; H, 7.34; N, 5.23. Found: C, 65.13; H, 6.96; N, 4.95.

Exam~e 29 trans- trans-2-(4-M ethoxyphenyfl)-4-(1 .3-ben zodio xol-5-yl)- 1 -fi .2.3.4tetrahydroisoguinolin-2- carbonylmethyll-pyrrolidine-3-carboxyLicQ The title compound was prepared using the-.procedures described in example 1. NMR (CD 3 0D, 300 MHz) indicates presence of rotamers. 6 2.97 (in, 2H), 4.68 3H), 5.97 2H), 6.83 11-, 6.9-7.0 (in, 3H), 7.03 1 7.1-7.3 (in, 4H), 7.4-7.5 (mn, 2H). MS (DCI/NH3) m/z 515.

Examole 297 The title compound was prepared by-the methods detailed in Example 61, but substituting propylainine for inethylainine in Example 61B and diinethylcarbamyl chloride for isobutyryl chloride in Example 610. The crude product was purified by preparative HPLC (Vydac 4iC18) 25 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 (00013, 300 MHz) 5 0.70 3H, J=7),.1.28 (in, 2H), 2.75 3H), 2.82 (in, 2H), 3.1-3.45 (in, 4H), 3.70 (in, 1 3.80 3H), 3.90 (in, 3H), 4.72 (in, 1H), 5.95 2H), 6.75 1H, J= 8Hz), 6.87 (in. 3H), 7.05 1H), 7.40 (d, 2H, J=8Hz). MS (001/NH 3 Wne 498 Anal calcd for C 27 H3 5

N

3

O

6 1.25 TFA: C, 55.35; H, 5.71; N, 6.56. Found: C, 55.41; H, 5.71; N, 6.41.

Examgle 298 trans, trans-2-(4-Methoxyphenfl)-4-(1 .3-benzodioxol-5-vb)-1 propyl-N-(4-nitrobenzenesulfonyl)amino'lethyfl-pyrrolidine- 3 carboxylic acid Using the procedures described in Eample 66, the title compound w z prepard nc v yllow solid. 85-87-C. 1H NMR (00013. 300 MHz) -197- 8 0.77 J=7.5Hz, 3H), 1.38 (sextet, J=7.5Hz, 2H), 2.20-2.29 (in, I H), 2.57-2.66 (in, 1 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~gHz, 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 Example 299 trans, trans-2-(4-Methoxypheny')-4-(1 .3-benzodioxol-5-yl)-1 propyl-N-n-pentanesulfonylanino)ethyl-Dvrrolicdine-3-carboxylic acid Using the procedures described in Example 66, the title compound ~.was prepared as a white solid. m.p. 59-61 -C 1 H NMR (CDC13, 300MHz) 8 0.79 J=7.5Hz, 3H), 0.90 J=6Hz, 3H), 1.26-1.32 (in, 4H), 1.43 (sextet, J=7.5Hz, 2H), 1.67-1.76 (in, 2H), 2.23-2.32 (in, 2.70-3.08 (in, 7H), 3.15-3.32 3.42 (dd, J=3Hz,J=9Hz, 1H), 3.52-3.57 (in, 1H), 3.63 J=gHz, 1H), 3.80 3H), 5.95 2H), 6.73 J=7.5Hz, 1H), 6.83 (dd, J=lHz,J=7.5Hz, 11H), 6.87(d, J=8Hz, 2H), 7.00 J=1Hz, 1H), 7.32 J=8Hz, 2H). MS (DCI/NH 3 m/e 561 Example 300 *trans, trpns-2 Methoxyvohenyl)P4-(1 .3-benzodi oxol-5-yvO- 1 (2 Uingthe pyrrolidine-3-car boxylic acid Usig heprocedures described in Example 66, the title compound was prepared as a white solid. m.p.122-124*C. 1H NMR (CD3OD, 300MHz) 8 0.75 J=7.5Hz, 3H), 1.26-1.45 (in, 2H), 2.96-3.08 (in, 2H), 3.23 (bs, 2H), 3.35-3.45 (mn, 2H), 3.52 J=lOHz, 1H), 3.81 J=9Hz, 2H), 3.86 (s, 3H), 3.92 J=9Hz, 1H), 4.63 J=lOHz, 11H), 5.97 2H), 6.82 (d, J=9Hz, 1H), 6.93 (dd, J=3Hz,J=9Hz, 11H), 7.06-7.08 (mn, 3H), 7.46 (d, J=9Hz, 2H), 7.56 J=9Hz, 2H), 7.89 J=9Hz, 2H). MS (DCI/NH3),'m/e 651 -198- Example 301 trans, trans-2-(4-Methoxyghenyfl)4-( 1.3-benzodioxol-5-yl)- 1 propyl -N ethyl-2-12ro penes ulf ofylmi') ethyl) -Pyrro lid ife-3, cabxlcai Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 69-710C.. 1 H NMR (CDCI3, 300MHz) 0.79 J=7.5Hz, 3H), 1.93 (sextet, J+7.5Hz, 2H), 1.92 3H), 2.25-2.35 (in, 1H), 2.68-2.77 (in, 1H), 2.85-3.28 (in, 7H), 3.40 J=9Hz, 1H), 3.52- 3.68 (in, 2H), 3.66 J=9Hz, 1H), 3.80 3H), 4.92 1H), 5.07 1H), 5.97 2H), 6.74 J=7Hz, 1H), 6.82-6.89 7.01 7.33 (d, J=9Hz, 2H). MS (DCI/NH3), m/e 545 Example 302 t rans tra ns- 2 -Meth ox y phe ny 1) -4 (1.3 -b en z odio x oI- 5 y 1)-1 f2 ethyl 1i peridi nyl-carbonyl methyl- yrrolidifle-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. :0.75 3H, 1.4-1.7 (mn, 8H), 3.84 3H), 5.96 2H), 6.83 I1H, 6.91 1H, 7.0-7.1 (in, 3H), 7.52 2H, MS (DCI/NH 3 in/z 495. Anal calcd for C 2 8

H

3 4

N

2 06 1.6 TFA: C, 55.35; H, 5.30; N, 4.14.

Found: C, 55.26;, H, 5.37; N, 4.01 Examole 303 trans. trpns-2-(4- Methoxyphenyl)-4-(l .3-benzodi oxol-5-yi)- 1 (Ncarboxylic 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 (CDCI3, 300 MHz) 8 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 (mn, 2H), 2.84-3.08'(m, 3H), 3.12-3.21 (in, 1H), 3.23- 3.45 (mn, 1 3.43 J=1l1Hz, 1 3.55-3.62 (mn, 1 3.66 J=9Hz, 1H), 3.80 3H), 5.95 2H), 6.75 J=9Hz, 1H), 6.83 (dd, J=lHz,J=9Hz, 1H), 6.87(d, J=9Hz, 2H), 7.02 J=lHz, 1H), 7.33 J=9Hz, 2H). MS (DCI/NH3) m/e 547 -1 99- Example 304 trans, trans-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-yfl- 1 prooyl-N-heptanesulfonylamino~ethyl-yrrolidile-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.58-59 0 C. I H NMR (CDC13, 300MHz) 8 0.80(t, J=7.5Hz, 3H), 0.88 J=7Hz, 1.23-1.36 (in, 8H), 1.94 (q, 2H), 1.71(quintet, J=7Hz, 2H), 2.23-2.32 (in, 1H), 2.70-3.09(m, 71H), 3.13-3.32 3.43(dd, J=3Hz,J=9Hz, 3.52-3.58(m,1H), *3.65(d, J=9Hz, 1 3.80 3H), 5.96(s, 2H1), 6.73 J=7Hz, 1 6.83 (dd, J=lHz, J=7Hz, IHI), 6.87(d, J=9Hz, 2H), 7.01 J=lHz, 1H), 7.32(d, Example 305 15 trans-trans-2-(4-Methoxyghenyfl-4-( 1.3-benzodioxol-5-yf)l- Is ~ethvl-N-ethoxycarbonyl amino) ethyll -pyrrol id ine-3-ca rboxyl ic acid Prepared by the methods detailed in Example 61, but substituting ethylamine for methylainine in Example 61B and ethyl chioroformate for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac jiCl8) 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 NMVR (CDCI 3 300 MHz) 8 0.90 3H, 1.22 (in, 3H), 3.0-3.2 (in, 3.42 (in, 2H), 3.78 3.82 (in, 4H), 4.10 2H, 3.5 (br s, 1H), 5.97 (dd, 2H, J=1,7Hz), 6.72 I1H, J= 8Hz), 6.84 25 (mn, 3H), 7.00 1H), 7.42 2H, J=8H-z). MS (DCI/NH 3 m/e 485 Anal calcd for C 2 6H3 2 N2Or 1.2 TFA: C, 54.90; H, 5.39; N, 4.51. Found: C, 55.01; H, 5.36;, N, 4.56.

Exaingle 306 trans, trans-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-ylI- 1 N- 12ropyl-N-hexanesulfonylamino~ethyfl)-yrrolidine-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, 1.25-1.36(m, 6H), 1.53(sextet, 2H), 1.72(quintet, J=7Hz, 2.23-2.32(m, 1H), 2.72-3.08(m, 7H), 3.15-3.32(mn, 2H), 3.43(d, J=9Hz, 1H), 3.55-3.62(mn, 11H), 3.65 (d, J=lOHz, 1H), 3.80(s, 5.96(s, 2H), 6.74(d, J=7.5Hz,1H), 6.82(d, -2 00- J=7.5Hz,1H), 6.87(d, J=9Hz, 2H), 7.01(s,1H), 7.32(d, J=9Hz,2H). MS (DCI/NH3), m/e 575 Example 307 trans- trans- 244- Et hylph enyfl-4- (1 be nzodio xol -5-yi 1 -rN.N-di(nbutyflaminocarbonvlmethyll-pyrrolidine-3-carboxylic acid.

The title compound was prepared using the procedures described in examples 1 and 49, substituting ethyl 4-eth yl ben zoyl acetate (prepared by the method of Krapcho et al., Org. Syn. 47. 20 (1967) starting with 4'-ethyl acetophe none) in procedure 49B. NMR (ODC1 3 300 MHz) 8 7.31 (2H, 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=4H), .77 1Hd, J=9Hz), 3.60 (11H, in), 3.53-3.23 (5H, in), 3.13-2.90 (4H, in), 2.73 (1H, d, J=l4Hz), 2.62 q, J=9Hz), 1.45 (2H, in), 1.40- 15 1.10 (6H, mn), 1.02 (2H, in), 0.87 (3H. t, J=7Hz), 0.78 (3H, t, J=7Hz). m/e (DCI, NH 3 509*(MHW) Anal.calc. for C 30

H

40

N

2 0 5 C 70.84, H 7.93, N 5.51.

Found C 70.80, H 7.85, N 5.25.

Examp~le 308 trans-trans-2-(4-Methoxyphenyl)-4-( 1 3-benzodioxol-5-vl)-1 propyl-N-(2-chloroethoxy~carbolylanino~ethyll-pyrrolidine-3- S carboxylic acid Prepared by the methods detailed in Example 61, but substituting :propylamine for methylamine in Example 61B and 2-chioroethyl chloroformate for isobutyryl chloride in Example 610. 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 lyop hilized to give the product as a white solid. 1 H NMR (CDCI 3 300 MHz) 8 0.80 3H, J=7), 1.22 (in, 3H), 2.15 (in, 1H), 2.75 (mn, 2.85 (in, 1H), 3.1 (in, 2H), 3.25 (in, 2H), 3.5 (in, 3H), 3.65 (in, 2H), 3.80 3H), 4.18 (mn, 1 4.30 (in, 1H), 5.98 2H), 6.72 (mn, 1H), 6.82 (in, 3H), 7.00 (mn, 1H), 7.30(m, 2H).

MS (001/NH 3 Wne 533 Anal calcd for C 27

H

33

N

2 0 7 CI: C, 60.84; H, 6.24; N, 5.26. Found: C, 60.48; H. 6.04; N, 5. -201- Examgle 309 tran s-trans-2-(2-Methoxyethvi)- 4 1.3-benzodioxolI-5-y 1 .N-di(nbutyflaminocarbonlmethyll-pyrroidne-3-carboxylic acid.

The title compound was prepared using the procedures described in example 1, substituting ethyl 5-methoxy-3-oxopentafloate for ethyl 4methoxybenzoylacetate in Example 1A. The title compound is a yellow foam. IH NMR (CDCI 3 300 MHz) 850.91 J=7Hz) and 0.95 J=7Hz, 6H total), 1.28-1.41 (br m, 4H), 1.45-1.63 (br m, 4H), 2.00-2.20 (br m, 2H), 3.06 (br t, J=9Hz, 1 3.30 (s) and 3.20-3.68 (br m, 11 H total), 3.72-4.10 (br m, 4H), 5.92 2H), 6.72 J=8.5H z, 1H), 6.82 (dd, J=1.5, 8.5Hz, 1H), 6.91 J=1.5Hz, 1H); MS (FAB) Wle 463-(M+H)+.

file@. Anal calcd for C 25

H

38

N

2 05H20: C, 62.48; H, 8.39; N, 5.83. Found: C, 62.13; H, ,S8.15; N, 5.69.

Example 310trans-2-(4-Methoxyphenyl- 4 -(l.3-benzodioxol-5-yfl-l ety-N--pnaeufoyaio~ty)proiie3cr xli acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.57-58 0 C. 1 H NMR (CDCI3, 300MHz) 8 0-89(t. J=7Hz, 3H), 1.06(t, J=7.5Hz, 3H), 1.26-1.37(m, 4H), 1.72(quintet, J=7.5Hz, 2H), 2.22-2.32(m,1 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, 1-H), 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 (M+H) 4 9 *25 Example 311 trans -trpns-2-(4-M thoxyphenyl)- 4 -(l-.3-benzodioxol-5-yfl-l -fN.Ndicyclohexylamino carbonylmethyll12pyrrolidine-3-carboxylic acid.

The title compound was prepared using the procedures described in example 1. -NMR (CD 3 OD, 300 MHz) 8 1.0-2.0 (in, 20H), 3.0-3.1 (in, 2H), 3.80 3H), 5.95 2H), 6.75 I1H, 6.86 (dd, 1H, 6.95 (d, 2H, 7.04 1H, 7.38 2H, MS (001/NH 3 m/z 563.

Anal calcd for C 33

H

42

N

2 06 0.5 H 2 0: C, 69.33; H, 7.58; N, 4.90 Found: C, 69.42; H, 7.29; N, 4.78.

-202- Example- 312 trans -trans-2-(4-Methoxyphenfl)-4-( 1. 3-benzodioxol-5-yl)- 1 Np rogyl -N -tert- butoxycarbonyl am ino) ethyl 1-pyrrolid in e-3-ca rboxyl ic agJAL The title compound was prepared using the procedures described in example 61, substituting propylamine for aqueous methylamine in Example 61B and di-tert-butyldicarbonate for isobutyryl chloride in Example 610. NMR (CD 3 OD, 300 MHz) suggests presence of rotamers 8 0.81 3H, 1.2-1.5 (in, 11H), 3.78 3H), 5.92 (dd, 2H, J=1,2), 6.74 1H, 6.84 (dd, IH, 6.92 2H-rJ=9), 6.99 (bd s, 1H), 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.

15 Example 313 trans -trans-2-(4-M ethoxy-3-f Iuoro phenyl)-4-(1 .3-ben 6 1 -fN.N-di(n-butyflaminocarbonylmethyll-o2yrrolidine-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 00. NMVR (ODC1 3 300 MHz) 5 0.82 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.03-1.50 (in, 8H), 2.82 J=l3Hz, V".961H), 2.90-3.13 (mn, 4H), 3.20-3.50 (in, 3H), 3.39 J=13H, 1H), 3.55-3.65 0 (in, 1H), 3.82 J=lOHz, 1H), 3.87 3H), 5.91 (dd, J=2Hz, 4Hz, 2H), 6.72 J=8Hz, 1H), 6.83-6.91 (in, 2H), 6.99 J=2Hz, 1H), 7.06 (mn, 2H).

Anal calcd for C 2 9

H

37

N

2 0 6 F: 0, 65.89; H, 7.06; N, 5.30 Found: C, 65.82; H, 7.13; N, 5.2 9.

Example 314 trans. trans-2-(Proovyl)-4-( 1.3-benzodioxo-5-yfl- 1 -(2-(N-orooylo2entanesu lfonylamino)ethylhpvrrolidine-3-carboxvlic acid Example 314A Propyl Dentanesulfonamide Pentane sulfonyl chloride (687 mg, 4.03 minol) was dissolved in 5 mL

CH

2 01 2 and added to an ice-cooled solution of n-propylamine (0.40 mL, 4.82 minol) and ethyldiisopropylamine (0.85 mL, 4.88 mmol) in 5 mL 0H 2 C1 2 under a nitrogen atmosphere. The reaction was stirred at 0 OC for 30 min, then at 25 00 for 4 h. The solujiori wab pa,-IIcna d~ta 20mL of 1.n KA ne-nn NqI-4qC) ;ind 25 mL -203-

CH

2 CI2. The organic phase was washed sequentially with 25 mL H 2 0 and 25 mL brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide 739 mg (3.83 mmol, 95%) of the title compound as a white solid. TLC (25% EtOAc-hexane) Rf 0.23; 1 H NMR (COCl 3 300 MHz) 8 0.92 J=7Hz, 3H), 0.97 J=7Hz, 3H), 1.28- 1.50 (br m, 4H), 1.52-1.68 2H), 1.75-1.90 (br m, 2H), 2.98-3.06 2H), 3.08 (q, J=6Hz, 2H), 4.10-4.23 (br m, 1H): MS (DCI/NH3) m/e 211 (M+NH 4 Example 3149B Ethyl trans, trans--4-( 1.3-benzodioxol-5-yl)-1 -(2-bromoethfl)-2-oroovloyrrolidine-3cbOUDxyILte *.The title compound was prepared according the procedure of Example 61lA, substituting the compound of Example 94B for the pyrrolidine mixture.

Example 314C :is Ethyl transtrans-2-(Progyl)4(i.3-ben zodioxol-5-fl- 2 -(N-1ropyl A solution of the compound of Example 314A (6.6 mg, 34 pimol) in 0.1 mL :DMF was treated with sodium hydride (2 mg. 60% oil dispersion, 1.2 mg NaH, pimol). The resulting mixture was stirred at room temperature for 15 m, then a solution of the compound of Example 189B (9.0 mg, 22 i imol) in 0.1 mL DMF was added, followed b y 0.5 mg of tetra-n-butylammonium iodide. The reaction was sealed under argon and stirred at 60 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 .25 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 3140 trans. trans-4-.(1 3-benzodioxol-5-v')-2-(Propyfl-l -(2-(N-oroolY- Dentp ne su fonylam ino) e thvfl1rro lid in e-3-ca rboxylic acid The title compound was prepared according to the procedure of Example 710. 1 H NMR (00013, 300 MHz) 8 0.88-1.00 (in, 9H), 1.20-1.55 (br m, 6H), 1.55-1.68 1.70-1.85 (br m, 2H), 1.90-2.16 (br in, 2H), 2.84-3.26 (br m, 6H), 3.26-3.90 (br m, 6H), 5.95 2H), 6.76 J8BHz, -204- 1 6.79 (in, I 6.93 (br s, I1H); HRMS (FAB) calcd for C 2 sH 4 1

N

2 0 6

S

497.2685, found 497.2679.

Example 315 trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 proo~yt-N-dimethylsulfamovlamino)ethyfl-Dyrrolidine-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. 1H NMR (CDCI3, 300MHz) 8 0.79 J=7.5Hz, 3H), 1.45(sextet, J=7.5Hz, 2H), 2.22-2.31(m,11-), 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,IH), 3.65(d, J=9Hz,1H), 3.81(s, 3H), 5.96(s,2H), 6.75(d, J=9Hz, I1H), 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 (M+H) 4 trans-trans-2-(4-Methoxphenyl)-4-(1 .3-benzodioxol-5-yfl-1 ropyl-N-r4-methoxyohenyllsulfonylamino~prolyll-Dyrrolidine-3carboxylic acid Examp~le 316A Ethyl trans-trans and cis-trans 2-(4-Methoxyphenyll-4-( 1.3-benzodiox- -1 -(3-bromopropyl) pyrrolidine-3-carboxyl ate A 2:1 mixture of trans-trans and cis-trans ethyl 2-(4methoxyphenyl)-4-( 1,3-benzodiox-5-yl) -pyrrolidine-3-carboxyl ate (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 SO4) and the solution concentrated. The residue was chromatographed on silica gel eluting with 5:1 hexane:EtOAc. yielding 5.22 of the title compound.

-205- Exam le 316B Ethyl trans-trans and cis-trans 2-(4-Methoxvphenyfl-4-(1 .3-benzodiox- -i -(3-ropylaminopropyl) ryrr olidine-3-carboxylate The compound described in Example 316A (5.22 g) was heated at 800 for 2 hrs.with 35 mi. 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-M et hoxrhenyfl)-4-( 1.3-benzodioxol- 5-yh- 1 rror~yl 4-m etho xyhenyls uf onyl ami no)rolDyl-pyrroli din e-3carboxylic acid in Using the method described in example 66, the compound prepared in Example 3168 was reacted with 4-methoxybenzenesulfonyl chloride in acetonitrile containing diisopropylethylamine. The resulting product .:was chromatographed on silica gel (30% EtOAc in hexane), and hydrolyzed to the title compound by the method of example 1D. NMR (CDC1 3 300 MHz) 8 0.83 J=7Hz, 3H), 1.40-1.52 (in, 211), 1.56-1.70 (in, 2H), 2.00-2.11 (mn, 1H), 2.40-2.51 (in, 1H), 2.69-2.78 (in, 1H), 2.84-3.03 (in, 4H), 3.19-3.34 (in, 2H), 3.48-3.59 (in, 3.80 3H), 3.86 3H), 5.95 2H), 6.74 J=8Hz, 1H), 6.85 J=8Hz, 3H1), 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

3 8

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- Methoxph enl)- 4 (l.3-be nzodioxol- 5-yfl-1 [l2 1Dropvl-N-1roylsulfonylamino'iropyl-Drroidine 3 carboxylic _Sacid Using the method described in example 66, the propylamino compound prepared in Example 316B was reacted with propanesulfonyl 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. NNMR (CDC1 3 300 MHz) 8 0.85 J=7Hz, 3H), 1.02 J=7Hz, 3H), 1.47-1.60 -206- (in, 2H), 1.65-1.85 (in, 4H), 2.04-2.16 (in, 1H), 2.42-2.57 (mn, 1H), 2.72- 3.11 (in, 5H), 3.25-3.41 (in, 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

3 8N207S: C, 61.52; H, 7.01; N, 5.12.

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

Example 318 trans. trans- -Fluo ro-4-metho xyphenyfl-44(1 .3-ben zodi oxol yfl 1 (2-(N-propvI-N-pentanesulfonylaminoethyl-Oyrrolidine-3- 10 Uigtecarboxylic acid Usig heprocedures described in Example 313 and Example 66, the title compound was prepared as a white solid. m.p.66-68-C. 1 H NMR (CDCI3, 300MHz) 8 0.81(t,J=7.5Hz, 3H), 0.89(t, J=7Hz, 3H), 1.26-1.35(m, 4H), 1.45(sextet, J=7.5Hz, 2H), 1.68-1.76(m, 2H), 2.25-2.33(m, 1H), :15 2.72-2.92(m, 5H), 2.97-3.12(m, 2H), 3.16-3.33(m,2H), 3.43(dd, J=3Hz,J=9Hz,1H), 3.53-3.60(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,l H),6.2t J=lHz,J=l2Hz, 1H). MS (DCIINH3) m/e 579 Exampole 319 trans-trans-2-(4-Pyridinyfl-4-(1I.3-benzodioxol-5-yfl-1 -rN.N-di(nbutyflaminocarbonylmethyll-yrrolidine-3-carboxylic 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 (4m etho xybe nzoyl) acetate. m.p. 131-132 OC. NMR (00013, 300 MHz) 8 0.82 J+7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.50 (mn, 8H), 2.90 (dd, J= 7Hz, 9Hz, 1H), 2.97t(d, J=l3Hz, 1H), 3.00-3.25 (mn, 4H), 3.32 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, 1H), 6.90 (dd, J=9Hz, 2Hz, 1H), 7.02 J=2Hz, 1H), 7.45 J=8Hz, 2H), 8.50 J=8Hz, 2H). Anal calcd for C 27

H

35

N

3 0 5 C, 67.34; H, 7.33; N, 8.73 Found: C, 67.39; H, 7.45; N, 8.61.

-207- Example 320 trans- tran s-2 -M eth oxvphe nyfl-4-(l .3-ben zod io xol- 6- yfl -r2-(Npropyl-N-diethylaminocarbonylamino~ethyll-pyrrolidine-3-carboxvlic The title compound was prepared using the procedures described in example 61, substituting propylamine for aqueous methylamine in Example 61B and diethylcarbamyl chloride for' isobutyryl chloride in Example 610. NMVR (CD 3 OD, 300 MHz) 5 0.74 3H, 1.09 6H, 1.33 (in, 2H), 3.17 4H, 3.78 4.04 (in, 1H), 5.93 (s, 2H), 6.86 1H, 7.06 (dd, 1H, 6.94 2H, 7.04 1H, 7.40 2H, MS (D01/NH 3 m/z 526. Anal calcd for 0 2 9

H

3 9

N

3 0 6 0.1 TFA: C, 65.31; H, 7.34; N, 7.82 Found: C, 65.33; H, 7.43; Exmle3, trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yfl- 1-f3.5dimethylliperidinvi- carbonylmethyll-yrrolidine-3-carboxylic acid.

:The title compound was prepared using the procedures described in example 1. NMR (00300, 300 MHz) shows mixture of isomers. 8 0.88 3H, 0.93 3H, 3.82 5.95 2H), 6.82 1 H, 6.89 (dd, 1H, 7.00 d, 2H, 7.03 (in, 1H), 7.47 2H, MVS (001/NH 3 mlz 495.

:Example 322 trans-trans-2-(4-Methoxyphenyl)-4-(l .3-benzodioxol-5-yf)l- -N.Ndi(s-butyl'pmi nocarbonylm ethyl -yrrolidine-3-carboxylic acid.

The title compound was prepared using the procedures described in example 1. NMR (00300, 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 1H, 6.86 1H, 6.94 2H, 7.03 1H, J=2), 7.35 2H, MS (DCI/NH 3 MlZ 511.

-208- Example 323 trans-trans--(-Mtoxyohenyfl-4-(1 .3-benzodioxol-5-yfl-1 -rN-(2- Methylphenyl)-N-butylamino carbonylmethvll-gyrrolidine--3-c-arboxyicr The title compound was prepared using the procedures described in example 1. MS (DCI/NH 3 mlz 545. Anal calcd for C 3 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 trans-trans-2-(4-Methoxyphenyfl-4-(1 .3-benz-odioxoI 5-yfl)-1 M ethylph en yl)-N-butyl amino carbonylmethyll-pyrrolidine-3-carboxylic The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 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 (mn, 1H), 3.60 2H-, 3.79 3H), 3.82 (in, 1H), 5.93 2H), 6.74 1H, 6.8-6.9 (in, 5H), 7.06 1H, 7.09 2H, 7.18 I1H, 7.27 1 H, MS (DCI/NH 3 in/z 545. Anal calcd for C 32

H

3 6

N

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

Example 325 trans. trans-44(1 Ben zodio xol- 5-yl -2-(ben zloxymethyl)-1 N- :dibutvlaminocarbonylmethyl)o2yrrolidine-3-carboxvlic acid Example 325A Ethyl trans. trans-4-( 1.3-Benzodioxol-5-yl)-2-(benzloxymethyF)- 1 .N-di( nb utyfl)am inoca rbonyl m ethyl) yrrolid ine-3-carbo yl ate The procedures of Example 1lA-i1D were fol lowed, 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 (CDC1 3 300 MHz) 5 0.88 J=7Hz, 6H), 1. 17 J=7Hz, 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-l14Hz, 1 4. 10 (two overlapping q, J=6.5Hz, 2H), 4.53 (s, 2H), 5.91 (in, 2H), 6.69 J=9Hz, 1 6.77 (dd, J=1.5, 9Hz, 1 6.91 1H); MS (DCI/NH 3 m/e 553 -209- Examole 325B trans. trans-4-( 1.3-Benzodioxol-5-fl -2-(belzyloxymfethyfl-l1-((N.N-di(nbutyl~aminocarbonylmethflyrrolidife-3-carboxylic acid The title compound was prepared according to the procedure of Example 710C, as a colorless glass. TLC MeOH-CH2CI2) Rf 0. 13; 1 H NMR (CDC1 3 300 MHz) 8 0.86 J=7Hz), and 0.90 J=7Hz, 6H total), 1. 15-1.52 (br m, 8H), 2.96-3.35 (br m, 5H), 3.50-3.75 (br m, 2H), 3.80 (dd, J=3, 13Hz, 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=l1Hz, 1 7.28-7.39 (in, 5H); MS (DCI/NH 3 m/e 524 Example 326 trans, trans-44(1 .3-Ben zodioxol -5-yl-2-(hyd roxyfl'ethyl)- 1 N-di (nb butyflp min ocarbonylm ethyl) yrrol idifle-3-ca rboxyl ic acid Examgole 326A Ethl rastrans-4- (1 Benzod ioxo- 5-yl-2- (hydro~ym ethyl)- 1 .N-d inbutyl'Iam inoca rbonyl methyl) yrrolid ine-3-carboXylate ofThe resultant product from Example 325A (128 mg, 0.232 mmol) and 25 mg 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 -under reduced pressure to afford the crude product. Purification by flash chromatography (40%EtOAc-hexane) provided the title compound.

:25 Examlole 320B trans. trans-4-01.3-Benzodioxol-5-yl-2-(hydro~ymethyl)-l1-((N-Nd i(butyflam inoca rbonylmrnethyl) yrrol idine-3- carboxyl ic acid The title compound was prepared according to the procedure of Example 710C.

Examole 327 trans. trans-4-(1I.3-Benzodioxol-5-yl)-2-(N-methylrolenaid-3-yl')-l1-((N .N-di(n- Sbutvflaminocarbonlmethyloyrrolidine-3-carboxlic acid -210- Example 27A Ethyl trans. traris--4-(l 1 3-Benzodioxol-5-yl)-2-(formyfl- 1 .N-diknbutyflam inocarbonylmethyl)pyrrolidine-3-carboxylat The title compound is made by selective oxidation using the Swern oxidation with DMS0, oxalyl chloride, ethyidlisopropylamine or using the Dess- Martin periodinane) of the compound of Example 326A.

Example 327B Ethyl trans. trans--4-(1 .3-Benzodioxol-5-yl)-2-(O-tert-butylorooenoat.3-y)..

N-

di(n-butyflam inocarbonyim ethyl) Dyrrolidine-3-carboxylate The title compound is produced by condensing the compound of Example 327A with tert-butyl triphenylphosphoranylidine acetate in CH 2

CI

2 Solution.

.Example 327C 15 Ethyl trans. trans--4-( 1.3- Ben zodioxol-5-yl)-2- (proni ac-3-yl)- 1-(N.N-di(nbutyflaminocarbonylmethyl)oyrrolidine.3.carboxlate The title compound is produced by reacting the compound of Example 327B with trifluoacetic acid in CH 2 Cl 2 *20 Examnple MID~ Ethyl trans, trans--4-(1 .3-Benzodioxol-5-yl)-2-(N-m ethylpropenam id-3-yfl- 1 Ni(n -butyl) am inocarbo nyl methyl) yrrolid ine-3-ca rboxylate The title compound is produced by condensing the compound of Example 327C with methylamine hydrochloride in the presence of a carbodiimide N- :25 ethyl-N-(3-dimethylamino)propylcarbodiimide,

DCC).

Example 327E trans. trans--4-( 1.3-Benzodioxol-5-yfl-2-(N-methylprooenamid-3-yly 1 N-di(nbutyl)aminocarbonylmethyloyrrolidine-3-carboxlic acid The title compound is produced by reacting the compound of Example 327D with lithium hydroxide according to the procedure of Example 71C.

Example 328 trans, trans--4-(1 .3-Benzodioxol-5-yl-2-( 1 -hydroxy-2-propen-3-yi)- 1 N-di(nbutyl)aminocarbonylmethyl)pyrrolidine-a-ca rboxylic acid -211- ExampDie 328A Ethyl trans, trans--4-( 1.3-Benzodioxol-5-yl)-2-( 1 -hydroxy-2-propen-3-ylY. 1 N-di(nbutyl'am inocarbonylmethyl~pyrrolidine-3-carboxylate The title compound is produced by reacting the compound of Example 327C with borane methyl sulfide complex.

Example 328B trans. trans--4-( 1.3-Benzodioxol-5-yl)-2-( 1 -hydrox-2-propen-3-yfl)- .N-di(nbutyl)aminocarbonylmethylpyrrolidine-3-carboxylic acid The title compound is produced by condensing the compound of Example 328A with lithium hydroxide according to the procedure of Example 71C.

Example 29 .trans. trans--4- (1 Ben zod ioxol-5-yl-2-(N -benzylaminom ethyl)-1 N-di(nbutyflam inocarbonylm ethyl) 1yrrolidine-3-ca rboxyl ic acid Example 329A Ethyl trans, trans-4- Benzodioxol -5-yl-2- (N -ben zylam inom ethyl) 1 .N-di(n- *-butyl)am inocarbonyl meth yl)pyrrolid ine-3-ca rboxyl ate The title compound is produced by condensing the compound of Example 327A with benzylamine in the presence of sodium cyanoborohydride in ethanol.

Example 329B 25trans. trans--4-(1 .3-Benzodioxol-5-yfl-2-(N-benzylaminomethyl)- 1 N-di(n- Th butyflaminocarbonylmethyl)pyrrolidine-3-carboxylic acid Tetitle compound is produced by reacting the compound of Example 329A with lithium hydroxide according to the procedure of Example 71 C.

Example 330 trans-trans--4-(1 .3-Benzodioxol-5-yl)-2-(N-acetyl-N-benzylaminomethyll- 1 .Ndi (n-butyflam inocarbonylm ethyl) pyrrol idine-3- ca rboxylic acid Example 330A Ethyl trans, trans--4- (1 .3-Ben zodioxol- 5-yl)-2-(N-acetyl- N-benzylam ino methyfl)- 1- (N .N-di(n-butyl)am inocarbonylmethyl)pyrrolidine-3-carboxylate The title compound is produced by reacting the compound of Example 3294A with acetic anhydride in the presence of pyridine or triethylamine.

-212trans, trans--4-( 1.38noixl5y)2(-c ty- bnyam4 ty) 1 Ndi(n-butyl~am 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 N-di(nbutyflaminocarbonylmethyl)pyrrolidine-3-carboxyLic-acid Example 331 A Ethyl trans, trans--4-(1I.3-Benzodioxol-5-yl)-2-(ethynyl)-1 N-di(nbutyl)aminocarbonylmethyl)pyrrolidine-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.

trans. trans--4-( 1.3-Benzodioxol-5-yl-2-(ethynyl)-1 .N-di(nbutyl)aminocarbonylmethyl'pyrrolidine-3-carboxylic acid The title compound is produced by reacting the compound of Example 331 A with lithium hydroxide according to the procedure of Example 71C.

:25 Example 332 trans. trans--4-( 1 3-Benzodioxol-5-yl)-2-( 1 -pentynyl)-1 N-di(nbutvl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid Example 332A Ethyl trans, trans--4-( 1.3-Benzodioxol-5-yl'-2-(pentynyl)-1-(N .N-di(nb utyl) am inocarbgnylm ethyi)pyrrolid ine-3-carbo xyl ate The title compound is made by pal lad ium -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).

-213- Eample332 trans, trans--4-(1 .3-Benzodioxol-5-yl)-2- (1 -pentynyl)-l -(N.N-di(nbutyl)aminocarbonylmethyl~pyrrolidine-3-carboxylic acid The title compound is produced by reacting the compound of Example 332A with lithium hydroxide according to the procedure of Example 71C.

Example33 trans-trans-2-(4-Methoxphenl)-4-(1 .3-benzodioxol-5-yfl-1 -f2-(2.6dioxoloeridinyb) ethyl) -pyrrol idi ne-3-carboxyl ic acid_ The compound of example 61 A is added to a solution of the sodium salt of glutarimide in dimethylformamide. After stirring 24 hours, water is added and the mixture is extracted with ether. The resultant *..*glutarimide is hydrolyzed to the title compound by the method of example 1iD.

trans- trans-2-(4-Methoxyphe nyl)-4- (1 .3-benzodioxol-5-yi) -1 N. N- :*diphenylaminocarbonylmethyll-pytrrolidine-3-carboxylic acid.

The title compound was prepared according to the procedures described in Example 1. 1H NMR (300 MHz, CD 3 OD) 8 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 (in, 7.04 1, J 7.14-7.16 (in, 6), 7.19-7.34 (in, MS (DCI/NH 3 mn/z 551; Anal Calcd for C33H30N 2

O

6 .0.65H 2 0.O.35C 2

HSOCOCH

3 C, 69.77, H, 5.77, N, 4.76. Found: C, 69.75, H, 5.55, N, 4.64.

Examgle 335 trans -trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)- 1 -f N.Ndiisopropylaminocarbonylmethvll-pyrrolidine-3-carboxylic acid.

The title compound was prepared according to the procedures described in Example 1. 1 1- 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 (in, 5.92 (s, 6.75 1, J 6.85 (dd, 1, J 1.7, 6.93 (in, 7.02 1, -214- J 7.35 (in, MS (DCI/NH 3 mlz 483. Anal Calcd for C 2 7

H-

3 4

N

2 0 6 .0.65 EtOAc: C, 65.86, H, 7.32, N, 5.19. Found: C, 5.74, H, 7.26, N, 5.52.

Example 336 trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 2 -N-Drogyl-N-butanesulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 313 and Example 66, the title compound was prepared as a white solid. m.p.65-66 0 C. 1H NMVR (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,l1H), 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, 3.67(d, J=9Hz, 1H), 3.89(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, 1H), 6.82(d, J=8Hz, 1H), 6.92(t, J=9Hz, 6.97(s, 1H), 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.

H

3

C

jCOOH Table 1 R R R 1.2. 3.

-215- 4.

a a.

-sI~ 7.

10.

13.

rs" 16.

19.

Table 1 cont.

R

HCO S 8.

0 0 11.

H

3

CO

14.

17.

6.

9.

0 0 rol 0 18.

02N 6 0 0 0 22.

H3C-T 0 0 25.

0 0 28.

FHC .:i 31.

F

2 0 0 34.

0 0 -216- Table 1 cont.

R

00 23.

HCO1FI 0 0 26.

FH

2 C5.s..

0 0 29.

FH

2 C-c..csN.

F

2 0 *0 32.

F; 0 35.

P.71 0 0 24.

0 0 27.

FH

2

C~N~C

0 0

F

2

HC.

F

2 0 '0 33.

F

3

C.

F

2 0 0 36.

11,N

F

3 c, S 0 0 37. 38.

-217- Table I cont.

R

0 0000 0* 00 0 *0 0*00 0 I. 0 0 0 000 00 H3Q r" 43.

0ZQ 46.

49.

0 58.

41.

44.

47.

53.

56.

r'- 42.

H3C: r d'o 6+N 48.

51.

54.

57.

0 0 59.

4 4* 4,* .4, 4. 4, 44 4, 4,4, 4 44 4, 0 61.

64.

0 67.

0 yN -218- Table 1 cont.

R

QOyNY 62.

65.

68.

0 N, Q 0 71.

63.

0 66.

69.

72.

OyN 78.

73.

0 76.

o- 0 74.

A

77.

-2 19- Table 1 cont.

R

80.

-1h 79.

H

3

CO

81.

lb.

lb lb lb...

lbS lbs lb lb lb lb lb.

lb lb lb...

lb.

Olb** lb lb lb lb.

lb lb lb lb.

6*lblb lb lb...

lb. lb.

lb lb lb ,lb lb lb lb.

lb lb lb lb.. lb lb. lb lb lb lb lb.

82.

88.

83.

86.

89.

84.

87.

(k 92. 93.

94. -220- 9* 9. 9 9090 06 09 9 9 9* a. a *9b9 .9 .9 a 09 9 9.

9.

99 9 *9 99 9 @9 99 9.

0 0 99 9 9* @9 0 97.

0 100.

0 103.

0 106.

CH

3 0 109.

112.

0 115.

Table 1 cont.

R

0 98.

101.

ON J 0 104.

H rN 107.

CH

3 110.

0 113.

YH3 r' r N, _,oA 0 116.

99.

0 102.

"NyN%~ 0 105.

Hr 108.

111.

0 114.

YH

3 r"- 0 .0 117.

-221- 0@ 0

S.

0@ 0 55.5 0O 0055

S

*5 5

OS

0 0

OS

S S 118.

121.

124.

cl 127.

ocrI 130.

133.

Table 1 cont.

R

119.

122.

F

125.

01 120.

123.

FV$ 00 126.

.cft" 129.

H

3 CO 0 132.

Y

OCH

3 131.

Ill 134. 135.

-222- Table 1 cont.

R

136.

.o 139.

cro 142.

d 0 145.

148.

H,

3 0 0 137.

140.

143.

146.

0 149.

I- N 0 138.

141.

0 0 144.

147.

0.

150.

01 151. 152.

153.

PCTIUS98/1 5479 -223- Table 1 cont.

R

154.

0 157.

9 155.

0 158.

161.

0 156.

0 159.

162.

160.

163.

164.

165.

0 166.

F3 C xr F F 0 'o 167.

0 0 168.

-224- Table 1 cont.

R

FF

0 0 169.

Y

00 172.

F3 0 0 175.

y 00 178.

0 0 181.

H

3

CO#>

00 184.

0 0 170.

00 173.

Y

F F o 00 176'.

179.

FF

0 0 182.

H

3

CO*>

185.

0 0

Y

00 171.

174.

177.

F

3

C

F F 6 0 180.

H

3 CcI 183.

H

3

CI(

186.

FH

3 C0''n F F 0 '0 00

H

3

CG*K>

d o 187. 188.

189.

-225- Table 1 cont.

R

H

3 CO,,h

F

3 0*N 6 *o 190.

191.

00 193.

196.

F3C

N,

F F 6 6 199.

A

202.

A94 0.0 19.

0 0 200.

203.

y 206.

192.

195.

F3 198.

201.

204.

K

205.

207.

-226- Table 1 cont.

R

208.

y 211.

oo I-CrN1-14 209. 210.

214.

217.

v~ kA

V

212.

215.

OH Y 218.

CF,

"CN

3 213.

O1H 216.

P~y 219.

9F 3 ODyNF 220. 221.

222.

-227- S. 223.

CF

3 t oO~0 226.

229.

232.

Table 1 cont.

R

224.

227. 228.

pF 3 O~N{0 225.

NOc NIr y 230.

233.

y cxy 231.

cy 234.

cc 235. 236. 27 237.

-228a a

R

238.

y PKQ ,7r 241.

V

244.

Table 1 cont.

R

PKI' N{o 239.

242.

R

PV r 240.

243.

246.

249.

N C N U~ 252.

245.

247.

V

250.

248.

251.

-229-

R

r 253.

V

256.

259.

Table 1 cont.

R

y N),:N46 254.

257.

R

255.

,N 0 258.

K

261.

N 0 264.

K

267.

260.

N

263.

262.

X 0 265.

266.

-230-

S.

268.

C~~yN'A 271.

274.

0 277.

280.

Table 1 cont.

R

H>-N

269.

272.

275.

N 0 278.

281.

R

~F3 270.

273.

276.

y .N 0 279.

u N 0 282.

-231- Table 1 cont.

R

283.

NN 284.

285.

286.

Ic N 0 289.

0 292.

y 295.

287.

.N 0 288.

2N 0 290. 291.

N

293.

jN0o

K

294.

.,N

296.

297.

-232a. a.

v N 0 298.

N 0 301.

304.

307.

Table 1 cont.

R

NLNO

299.

y 302.

305.

KcN 0 ,N 0 300.

y 303.

V

306.

.&N

308. 309.

310.

y 311. 312.

-233-

C

CC C

C

CC**

C.

.C C C C

C

~N 0 313.

316.

319.

322.

Table 1 cont.

R

314.

317.

315.

318.

321.

324.

320.

323.

325. 326.

327.

-234- Table 1 cont.

R

328.

C

C. C c*

C.

331.

329.

V

332.

or 335.

338.

330.

NA)

333.

334.

336.

ir 0r 337.

v a 0o 340.

)y 0r 339.

Ar [Il. 341.

342.

-235- Table 1 cont.

R

9 @9 9. 9 9999

S.

*1 9* 9 9 9 999.

9 9* 9 999 9 99 9 99 343.

346.

349.

y 352.

344.

347.

y 345.

FX "N 348.

351.

354.

350.

y 353.

355. 356.

357.

-236- Table 1 cont.

R

358.

359.

360.

S.

S

S.

S

S.

C S 5S S 5 361.

362.

363.

S

OS S S S @5 364.

367.

lyN 370.

N

.N

365.

368.

371.

NN

366.

368.

372.

-237- Table 1 cont.

R

y 373.

374.

376. 377.

375.

378.

y 381.

JAN

379.

y 380.

382.

383.

1>a 384.

385. 386.

387.

-238- 388.

391.

I>-

394.

'Iy 397.

400.

Table 1 cont.

R

y 389.

392.

395.

N**-y 390.

393.

396.

398.

399.

401. 402.

-239- 403.

406.

409.

412.

415.

Table 1 cont.

R

404.

407.

410.

413.

416.

405.

408.

411.

414.

417.

-240- Table 1 cont.

R

V

4a 418.

419.

'COOEt 421.

cNO, 424.

c&A 4CN 427.

v r 422.

ANO

425.

420.

NO,

423.

NO,

426.

CN

429.

02N4 kCN 428.

02N'

I-

430. 431.

432.

-241- Table 1 cont.

R

433.

0 436.

439.

442.

434.

0 437.

0 440.

443.

N

435.

v 0 438.

441.

444.

445.

Fv0 F~aNo 446.

447.

-242a.

a a a a. a a a 448.

451.

V

454.

0 457.

Table 1 cont.

R

F&0o 449.

y F&0' 452.

450.

453.

0 456.

Meoi~ C>(z 0 459.

0 462.

455.

moo MoO___ 0 458.

460. 461.

-243- Table 1 cont.

R

463. 464. 465.

466. 467.

468.

470.

469.

471.

474.

372. 473.

CK~K

475. 476.

477.

-2 44-

S

S..

S. S x14 0 478.

:XXN-fA 0 481.

0 484.

0 487.

Table 1 cont.

R

cl C)C 0 485.

cll 0 48.

CIDC

0 480.

483.

cl J'~v 0 486.

489.

F

0 490. 491.

F)

0 492.

-245- Table 1 cant.

R

494.

493.

0* 0 496.

497.

0 500.

0 495.

0 498.

AlA 501.

0 504.

CMe 0 507.

499.

0 502.

0 505.

503.

1cKIVr 506. 0 -246- Table 1 cont.

R

OMO 0 509.

512.

I O r OMe 0 510.

508.

511. 513.

Vo4

OM,

514.

MO~Q

OMe 0 516.

515.

517.

MOO

OMO 0 518. 59 519.

MOQo, OMe 0 520.

521.

522.

-247-

MO-

523.

526.

529.

532.

Table 1 cont.

R

MoO 524.

527.

y 530.

53 533.

Me

H

525.

528.

K

Br QagA 531.

Br Ny 534.

535. 536. 537.

y

F

0 538.

540.

544.

547.

V

550.

-248- Table 1 cont.

R

y 539.

NaV- 542.

0 545.

548.

551.

540.

543.

y 2~QWO B~a"' 546.

549.

552.

-249- 0 .e 0 553.

556.

559.

y 562.

BYY

Table 1 cont.

R

y 554.

1> 557.

Br 560.

Bryy~ 563.

v Br5y 565. 567.

K

555.

so 558.

561.

Br> FW O 564.

Fi-A-Icl R~ r 565.

567.

-250- Table 1 cont.

R

S..

S

S.

S S

*SS.

5

S

S. S

S.

568.

F

571.

FV

574.

0 577.

0 580.

0 583.

569.

F>

572.

0 575.

y 0 578.

0 581.

I~rx 0 584.

Sk 570.

F'>

573.

0 576.

rN~ 0 579.

v "'NUrx 0 582.

(2L 0 585.

-251- Table 1 cant.

R

S.

S. S OS S.

S

SS

S

*S*S

S.

5555

S

S. S S. re

S

0* 5

S

56 0 586.

>Y'b0 589.

y 592.

595.

598.

601.

0 587.

N7rY* 590.

K

593.

v 596.

599.

602.

0 588.

591.

594.

597.

y 600.

0 603.

-252- Table 1 cont.

R

H

604.

@0 Oe 0

OS*S

0e 0* 0 0

S

Oe 0 0 000* *0 0@S0 0@ 0 0@ 1 00 @0 S 0 00 0000 605.

H

Nk 0 606.

6H 6^ 0 609.

607. 608.

610.

611.

612.

00 00 0 050 0 00 S 00

SO

H

0

H

614.

615.

613.

H

0 616.

619.

H

617.

620.

618.

621.

-253- Table 1 cont.

R

622.

624.

623.

H

0 625.

628.

631.

626.

r f H 629.

r 632.

635.

638.

627.

0 633.

636.

639.

630.

634.

y 637.

0* 0 640.

643.

0 -646.

-254-.

Table 1 cont.

R

v aN1r,4 641.

0 644.

0 642.

0 645.

0 648.

I 0

Y

651.

647.

650.

649.

C~oN 0 652.

653.

654.

-255- Table 1 cont.

R

655. 656.

657.

658.

659. 660.

C.

C

C. C C 661.

662.

663.

r4 664.

0 665.

666.

667. 668.

669.

-256- Table 1 cont.

R

670.

673.

671.

672.

4 674.

675.

677.

676.

678.

679.

680.

681.

A) 0 682. 683.

684.

-257- Table 1 cont.

4*

R

y 685.

\J)4 688.

691.

694.

607.

686. 687.

689.

690.

692.

693.

695. 696.

MO9 698.

699.

-258- Table 1 cont.

R

701.

700.

0 703.

706.

0 709.

0 702.

704.

705.

0 708.

707.

00 710.

711.

H

0 712.

H

0 713.

0 o 714.

00 715.

-2 59- 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 F mom 3 .*1.COOH *COO

OOOOH

1. 0 2. 0 0 ~CH, O R- ;.COOH #COON

.CO

4. 0 5. 06.CO *MOMQ F.MOMQ -260- Table 2A cont,

MOMO

eCOOH

F

~,COOH

OCH,

14.

H

3

~.COOH

N. 0H 3 12.

OCH

3 mom

OCOOH

16.

flN

COOH

19. OCH 3 0

CH

3

-COOH

R-N

V

0

OCH

3 17.

H

3 kH,COOH fl-N 20.

F

O.COOH

0

OCH

3 18.

F

F-

OCOOH

21. 0> -261- Table 2A cont.

MOM

22. 0

,COOH

Se..

C

C.

C

CC. C CC C C C

OCH

3

&.COOH

26. 0

CH

3

*COOH

R-

N)

F

ICOOH

R--

27. 0

F

.COOH

R-2

.COOH

29. 28.

OM CH 3 4POOOH R-CN

O

31. 32.

-262- .0e* C 2%OM R- 4COOH 37.

MOM

fl-N\_ 0

OCH

3

OMOM

fl- 0COOH N 0

OCH

3 43.

Table 2A cont.

CH

3 eCOOH

R-'

CH

3 Fl-N 0 :38. OCH 3

CH

3

,~COOH

f-N 0

OCH

3 41.

OCH

3 R-

ICOOH

44.

F

R-

COOH

36.N fN ,COOH 39.

OCH

3

IOCH

3 42.

,COOH

-263- 4.

4. 4 4* 4. 4 4 4 4 4* 4.

MOMO

46. F

MOMO

_COO

*.COOH

52.

Table 2A cant.

CH

3

COOH

R-

47.

Rr

COOH

0N

F

*COOH

R-

48.

.COOH

COOH

P-

0N 54.

e.COOH 56.

F

-264- Table 2A cont.

R- OCOOH F-

.OOO

0 59 58.

*0 61. 62.

64.. F:5 O

.COOH

69.

-265-

#COOH

7 0.

Table 2A cont.

%qPCOOH 71. F

OCH

3

OCH

3

COOH

OCOOH

75. 0

OCH

3

COOH

R-

78._1' D

S

S. tCH 3 R- ~O0 76.

CH

3 0 -'000H R-

OCOOH

79. F -266- Table 2A cont.

OH

R-

COOH

84.

S a S S

S

S.

9 5 .5*S 5.55 S. S

S*

S.

S. S

S

*5 S S S. S

OCH

3

OH

R-

COOH

86.'ij

OCH

3

-OCH

3 (.0 91.

OCH

3

OCH

3

.OOOH

93.

-267- Table 2A cont.

CH3 OCH

OCHHF

OCH

"k

OCH

3 .~OCH3 eCrvO

,.COOH

9 07. 98.

F F F .OOOH A *y

S.

S. 100. -101.

F H 3 00

-OCH

3 eCOOH

OCOOH

A 'k OH 3 0O kl-- 103. OCH3 104. 0 105.

-268-

H

3 F

,COOH

106. 0o a a a a. a a.

a Table 2A cant.

H

3

CO

.*COOH

107.

H

3 00

OI.COOH

JF

110.

F

.COOH

113.

COOH

116. 0 109.

a.

a a a. a a a a.

112.

H3O

F

,.COOH

N. CH

OCH

3 R-

.COOH

114.

R- .COOH

R--

117. 0) R-4'..C00H 120.

115.

R- #COOH

,.COOH

R- 118. 119.

-269- Table 2A cant.

.COOH

COOH

.9 4. 4 4* .4 4 4.

4 4 4.

4*4* 9* 4 .4 4

S

4* 9 4 4

OCH

3

*OCOOH

124. 0 IeCOOH 127. 0

~.COOH

0 130.

O0H 3

OCOOH

R-

125.

OOCH

3 .COO

H

R--

128. 0 0 R- eC0OH 123.e

OCH

3 R-

COOH

I%O

126.

OOCH

3 .COH3 "'0OH 129. 0

OCH

3 R- 8

.COOH

Vk 0 132. 0 131.

0* 6 0 @000 6* @0 0 0 0 @0 00 6060 6* 0 @0 @0 9 06 0900 O 0

SCH

3

.COOH

0) 133.

0CM 3 136.

H

3 R-

OCOOH

139.

F

-270- Table 2A cant.

H

3

M

.c0O 134. 0

CM

3

H

3

COO

H3CO1-1OCH 3 137.

0CM 3 R-N

CH

N

140. 0 0CM 3

*,.COOH

R-0 143. N 0CM 3 d 4COOH 135. 0 0CM 3 Ft

COOH

138.

0CM 3 R-

-COOH

1 0 141. 00 S 00. 0 0* 0 @0 00 0CM 3 R-

.COOH

3 CO N 144.

,COOM

142.

OH

3 CC00H 145.

-271- Table 2A cont.

OCH

3 A- ,COOH 146.

.CH

3

OH

3

F

40.OOH %H3C

OCH

3 149.

F

A-

#COOH

147.

@6 0@ 0 *6BO 00 0 0 0S S.

OSSO

S.

6 *0 0 S 6

SO

0O S 6@ 6@ 6S56 6 6@60 S. @6 S. S

S

S.

SO 0 0 *5 S 05 06 .000 H 148.

150.

A-

MCOOH

153. 0

.OCH

3

OMOM

Pr COO

H

F~3O

OCH

3 156.

154. 155.

-272- Table 2A cont.

'MOM

OCH

3

~CH

3 159. 0

OCH

3

JOCH

3 R-

ICOOH

H

3 C OC0H 3 161.

OCH

3

CH

Pr-N

OCOOH

164.

F

162.

CH

3

,.COOH

163.

OCH

3

H

3

C

R-N

COOH

165. OCH 3

MOMO

H

168. 0

.COOH

F

R-N

X

167. 0 166.

-273- Table 2A cont.

F

169.

F

H

1

N

174. 0 172.

MOMO

H

17 6.

MOMO

H

178.

OCH

3 179.

0CH 3 180.

-274- Table 2A cont.

F MOMO H 3

C

H H R- R-N H 181. 0 182. 183. 0

H

3

FMOMO

'CH 3

H-

H- HH 184. 0)185. 0 186 F MOMO F R- N: CH 3 H& 33-- N CH3 H H H 187. 0 188. 0 189. 0 MOMO F MOMO 0 00 0 p )tNSCA CH 3 3 CH 3

H

3 Pr- H 190. 191. 192.

-2 Table 2A cant.

f+ NCH 193.

N'0CH,

H

194.

195.

H

F

00N CH R-

H

199.

197. 198.

-OCH

3

MOMO

200.

H

3

C

~N:CF3

H

201. 0 202.20.24 203.

204.

-276- Table 2A cont.

206.

207.

205.

jVH3

U.OH

3 208.

H

3 h '0 211. OCH 3

H

3 O CR 3 h0 ,o0 214.

OCR

3 209.

F

*.COOH

212.

OCR

3

JCOOH

215. OCR 3

H

3

C

0 213. OCR 3 210.

216. OCR 3 -277- Table 2A cont.

217.

218.

F

COOH

'0 219.

Et0 F eCOOH Ft- 222.

D0 F

COOH

'0 220.

Et0 ,C\OOh EtC F 221.

EtO F

,COOH

OCH

3 224.

'0 223.

225.

0 .,CO0H '0 228.

226. 227.

-278- Table 2A cont.

S

S.

S

55 S S S *5 0 0 229.

H

3

COCH

3 4pCOOH 232.

H

3 C OCH 3

.COOH

235.

H

3 C OCH 3

,,COOH

/0 238.

OCH

3 230.

0 0 c00 231. OCH 3

H

3 C OCH, 233.

H

3 C OCH 3 c0H 236.

H

3

OCH

3 234.

,POOH

23.

0,0

.,COOH

'~0 240. 239.

-279- Table 2A cont.

241.

242.

C.

he ~9O* C9 Ce 4

S*

C C Ce *C C

CC

C.

C. C

CO

C.

C

CC..

C.

C C

C

OC

C C CC. C C. C

C.

0,0

,OOOH

244.

'C)OH

247.

H

3 C F F \h

,COOH

R-N

250.

0,0 1

COOH

R- *0 243.

HC

F

1E4COOH 246.

H

3 C F 249.

245. 0CH 3

H

3 C F .,cOOH

RWN

'0 248.

252. 0CH 3 251.

-280- Table -2A cont.

F

OCOOH

0 253.

Fq

,COOH

R-

256.

F

OCH

259.

OH

J \hCOOH _0 254.

Fq 257.

.COOH

R0) 258.

\LOh '0 261.

F F h cOOOH '0 255.

260.

262.

264.

263.

00 266. OCH 3 4 265.

267.

#.COOH

RN

0 268.

,*COOH

271.

*#COOH

0 274.

*COOH

277.

-281- Table 2A cont.

.'COOH

/0 269.

,OOH

272.

'0 275.

.COOH

278.

,ICOOH

0) ',0 273.

OCH

3 270.

276.

ICOOH

279.

-282c0H 280. 0OI*3 ~0 0 283.

4 C00 286.

Table 2A cont.

~0 281.

J

COOH

284.

eCOOH 287. OCH 3

J*COOH

'0 290.

ICOOH

/0 282.

C00- 285.

.COOH

Ft 288.

a a a a a a 289.

COOH

ft 291.

OCH

3 292. 293. 24 294.

~0) 295.

R-

I

-283- Table 2A cont.

.'COOH

0 00 296.

~0

,*COOH

297.

298.

299. 300.

301. 0CH 3

R-N

'0

,,COOH

302.

eOOH

RN

OCOOH

N

'/0 303.

,PCOOH

R-N

306.

304. 305.

307.

-284- Table 2A cont.

W9

COOH

308. OCH 3

A

R- FOOH 311.

0'0 314.

.,COOH

317.

310.

309.

A

R R 00 313.

.*COOH

316.

AA

312.

R-

OCA

315.

318.

OpCO0I- 321.

319.

320.

-285- 0 322.

OCH

3

,COOH

/0 325.

I,CO

0) 328.

Table 2A cont.

COOH

323.

326.

,.COO

H

/0 329. OCH 3 '0 332.

4 fCOOH 335.

324.

327.

41 COOH 33. OCH 3 331.

,COOH

334.

,COOH

RN 0 336.

-286- 337.

,.COQH

0 00 340.

00 343.

~~0 346.

COOH

"0 349.

OCH,

Table 2A cont.

00 /0 338.

COOH

341.

b#COOH /0 342. OCH,

,.COOH

'0 0 345.

O.COOH

348.

339.

344.

*#COOH

347.

H

3 C F 0 CH 3

H

~~0 '0 350.

351.

-287- 0 0 A 0 CH 3 N C'

H

352.

0 h 0 0-CH 3 H0 355. OCH 3 a.

a a a Table 2A cont.

H

3

C

0 H o

OCH

3

H

3 C F R 0 1/00 353.

H

3 C F h ~NH 0

OCH

3 359.

H.CO

EtO-0 0 OCH 3 '~0 35.

OH

EDO

0 '0

OCH

3 360.

358.

0 0 h/ 0)

K.

0 361.

OCH

3 363.

362.

-288- H3H 0~

R

3

C-

0 36.

HC

0HPCC

\/N

H

R-

'F

367.

Table 2A cont.

H

3 )~NfCH3

H

'0 365.

H

3 yNH 368.

H

3

'NH

0 371.

H

3

NH

369.

366.

372.

374. 35 375.

-289- Table 2A cont.

k A 0 4 S-CH 3 '0 0 377.

376.

a.

a. a.

a a a.

a.

a a a a a a. a a a a.

A 0 &CH3 H 0 379.

382.

380.

H0

R-S

'0 378.

NH

~NH

'0 38.

w NH Ft-- 387.

383.

W\/

A? i 385. 386.

-290- Table 2A cont.

388.

4 0 0 0S 09 0 0009 00 0 0 0 00 00 0000 00 0 0 0 0 0 000 0 00 0 00 00

ANH

389.

F

3

.,COOH

R- 0 '~0 392.

F

3

COOH

395.

NSH3 H 0 '~0 390.

F

3

.COOH

393.

391.

396.

394.

F

3 Z 0) 397.

OCH

3 399.

398.

-291- Table 2A cont.

ec ~0 6* *e 0 0 0 00 S 0

OS..

9@ .555

S

0@ S

SS

05 S S S @5

S

.S~S

OS ES

S

S.

5 0 550 05 55

S.

F

2

CF

3 h

,COOH

~,0 400.

F

2

CF

3

COOH

403.

kF 2

CF

3

A

eC00H

OCH

3 406.

F

2

CF

3

.,COOH

401.

F

2

CF

3 eCOOH 404.

0_ 407.

F

2

CF

3 2

CF

3

.COOH

0 408.

411.

410.

409.

ecooH R-0 0 412.

413. 44 414.

-292-

.,COOH

0 418.

,COOH

R/9 Table 2A cont.

*OOOH

0 R-0 419.

417.' 420.

421.

422.

423.

'~0 424.

425. 426.

IOO

COOH

WN~0) /0 428. 427.

429.

-293- Table 2A cont.

432.

430.

431.

COOH

Rw- 0 435.

433.

,COOH

R- 00' 436.

434.

1400 0 437.

438.

439.

440.

441 444.

442. 443.

-294- Table 2A cont.

h O 0H 445.

446.

C 0H 447.

",COOH

450.

448.

0 451.

449.

453.

452.

454.

4 55. 455. 456.

-295- Table 2A cont.

JCOOH

'0 457.

0

.COOH

0 46.cO 0 '0 463.

458.

459.

462.

461.

,.COOH

R- 0) ~0 464.

465.

-296-

R

0 1.

'o 0 4.

0 7.

0 13.

0 16.

Table 2B

R

0 2.

5.

8.

R

3.

6.

9.

0 11.

0 14.

0 17.

12.

0 c"O 0 18.

0 0 -0Th -Th 19. -2 97e 22.

H 60~N F3'-- 28.

F

2 0 0 31.

F

2 60 34.

37.

Table 2B cont.

R

0 23.

-Th

H

3 C0N-1^. N *'Ko 26.

29.

FH

2

F

2 0 C; 0 32.

F3Q..

F

2 0 6 0 38.

0 0 41.

H3C~ 24.

6' 0 27.

F

2

F

2 6o 0 33.

F

3 C-

F

2 36.

39.

42.

-298- Table 2B cont.

R

0 0 43.

0 0 F 3s:~~ 0 0 .0 0 0 0*@ 00 00 S.r 0 OS 0* *C 0 0 0 46.

0?s I

I

47.

49.

52.

-th C 50.

yr 0 53.

F

56.

48.

c0 51.

54.

0 57.

ciz v 0 ci 58. 59.

-299- Table 2B cont.

R

crocr 61.

OCH

3 62.

63.

64.Ni 64.

YH

3 Ni 0 0 73.

0 68.

cr o 71.

60 74.

pr 00 66.

69.

Nt ,N 0 72.

oO oo 0 79.

d o 82.

F,~T

0 0 88.

0 0 91.Y -300- Table 2B cont.

R

0 0 80.

83.

0 0

A

600 81.

00 84.

0' 0 0 0 89.

Y

F

3 y.

K%~

F F d' 0 0 0 93.

F3C,Q--I 94.

F 3 I 0 1 1

I

00 97.

F F 95.

F,3F 110") F 3 C FF6 0 96.

H

3 C0>, 0 0d\ -301a.

0 0 100.

0 0 103.

H3GO 0 0 106.

00 109.

00 112.

F F 0 Table 2B cont.

R

H3cal> 00 101.

3 C0 0 o 104. 105.

Hc0 102.

FF0 0

H

3 C0> 00 107.

00 110.

a.

a a a a. a.

a.

F F Hw- 00 00 ill.

0 0 114.

A>

00 117.

610 113.

A>0 115. 116.

-302- S. 118.

121.

124.

y 127.

Table 2B cont.

R

119.

y 122.

K;v 125.

0i 120.

123.

r 126.

ly ,-a 128. 129.

OH I-r0 130. 131. 132.

-303r 133.

V

136.

CF

3 139.

142.

145.

Table 2B cont.

R

y Z& V 134.

137.

CF

3

Y

140.

143.

y -a Rr-1 OH Y11r 135.

138.

141.

144.

147.

146.

304- 148.

151.

154.

y 157.

160.

Table 2B cont.

R

149.

y 152.

155.

CIX7{

F-

158.

CtyN

F

153.

156.

159.

161. 162.

-305- Table 28 cont.

R

y 164.

163.

166.

NQ y 169.

167.

y NC y- 170.

rcryr 165.

NCVyNA 168.

171.

174.

0 172.

a. a a.

N

176. 177.

175.

306- Table 2B cont.

R

Fi, 178. 180.

183 183.

9.

99

S

99** Sn.

99 9.

0 .0 5** 181.

182.

N

185.

N'hT 55 5 959 9. 99 187.

NC,,ya 190.

188.

li A)~b -307- Table 2B cont.

R

A-Ky 194.

193.

A~yv 195.

196. 197.

198.

199.

K1c 202.

N'r v 200.

y11, r 203.

201.

204.

205. 25.206. 207.

~N 0 208.

y 211.

v Ny0 214.

N0 217.

~WNO

-308- Table 213 cont.

R

r__N jN 0 209.

'1< jN 0 212.

4N 0 215.

y 0 218.

lNko NN0 213.

216.

y 219.

KtNO y 210.

220. 221. 222.

-309- 223.

226.

229.

0> Table 2B cont.

R

224.

y 227.

v3~~ Nr 225.

N 0 228.

r~6 230.

0 231.

I-lc-r 232.

0jyv 234.

235. 236.

237.

-310- Table 26 cont.

R

0 238.

240.

239.

241.

244.

247.

1> o 242.

245.

248.

K

243.

Ir 246.

al- 0 249.

250. 252.

-311- Table 2B cont.

R

253.

N- 0 254.

255.

V56

N

259.

N

262.

257. 258.

y 261.

N

264.

S)N

260.

263.

265. 266. 27 267.

-312- Table 2B cont

R

269.

272.

270. 268.

271.

274.

275.

y 273.

276.

279.

N yNIV 282.

277.

278.

281.

280.

-313- Table 2B cont.

a a.

a a a.

a

S

a.

a a a a. a a a a

R

283.

286.

y 289.

292.

295.

284.

287.

NJ

290.

293.

)lN 296.

R

285.

288.

291.

294.

y 297.

-314-

C

S.

C C

CC..

CC

C

OC 0

C

298.

301.

304.

307.

310.

Table 2B cont.

R

)jN 299.

1 302.

y 305.

V

300.

303.

>WN

306.

>jN 309.

312.

C.

CCC C C. c 308.

311.

-315- Table 2B cont.

R

313.

316.

314.

315.

317.

318.

319.

322.

325.

320.

323.

V

326.

321.

324.

327.

316- Table 2B cont.

R

328.

331.

V

334.

Ny 329.

332.

v 330.

-ri 3COOEI 3 335. 336.

337.

NO,

338.

339.

NO

2 342.

340. 341.

-317- 343.

346.

349.

0 352.

355.

Table 2B cont.

R

344.

A

347.

350.

Ar- 0 353.

0 356.

~CNA

345.

0 2 NY A 348.

351.

0 354.

357.

-318- 0 358.

Table 2B cont.

R

r-A 359.

V

362.

365.

361.

364.

367.

v F~a" y 360.

363.

366.

y 368.

MoO uY:, 369.

0 372.

370. 371.

a a a. a a.

MoO% 0 373.

M-0- .moo 376.

0 379.

M.O

QNYY

0 382.

0 385.

0 -319- Table 2B cont.

R

374.

MoO 0 377.

0 380.

0 383.

0 386.

Do~ 0 375.

Mo00 MoO 378.

0 381.

384.

387.

x 0 390.

388. 389.

0 391.

0 394.

0 397.

0 400.

0 403.

0 -320- Table 2B cont.

R

)alluTrx 0 392.

x 0 395.

398.

0 401.

0 404.

I

C

F'~L ~0 0 393.

396.

0 399.

0 402.

0 405.

FI

0 408.

406. 407.

-321- Table 2B cont.

R

0 410.

FP

0 409.

0 412.

0 415.

0 418.

0 421.

OMO 0 413. 414.

0 411.

0 416.

0 419.

422. 0 0MG 0 0 417.

0 420.

OMO 0 423.

Mo M. 0x OMo 0 424. 425.

426.

-322- OM. 0 427.

Table 2B cont.

R

OMO

428.

OMe 0 431.

OMe O 430.

OM. 0 433.

moo

OMO

436.

M.OoYNfA 439.

OM. 0 429.

moo OMe 0 432.

MyA~rx OMe 0 435.

OMe 0 438.

441.

434.

OMe 0 437.

440.

442.

4 443.

0-T' 444.

-323- 445.

B 0~y 448.

451.

y 454.

457.

Table 28 cont.

R

y 446.

449.

452.

455.

V

447.

V

450.

453.

456.

459.

458.

-324- Table 2B cont.

R

460.

461.

462.

p.

p p p.

9. 9 p p.

p. p pp p.

p pp pp V P p p.

p p p p. p p p.

463. 464.

467.

465.

468.

466.

FA

469.

472.

470.

471.

F

CA

474. 473.

-325- 475.

Table 2B cont.

R

476.

S

OSSO

0

S.

S

*0@*i *0

S

5. 0

OS

SO

S

S S 0 Sq..

478.

Br 481.

484.

FY

UxrlV 0~5 479.

482.

Br~y 477.

0 480.

F

483.

F Y 486.

FL

0 OS S 00 485.

F

II1Trl' 487. 488. 489.

-326- 0 .0 I. 0 0 0 0 0 0.: 490.

0 493.

C- x 0 496.

0 499.

0 502.

505.

Table 2B cont.

R

0 491.

0 494.

0 497.

Ei 0 500.

0A 503.

A

506.

R

0 492.

0 495.

0 498.

501.

0 504.

0 507.

-327- 4

R'

y 508.

511.

514.

K

517.

520.

Table 2B cont.

R

509.

512.

515, 518'.

H

521.

R

02Y 510.

513.

y 516.

519.

522.

-328- Table 2B cont.

R

H

5250 525.

523.

524.

526. 527.

H

0

H

530.

528.

531.

529.

H

532.

H

535.

H

o533.

533.

H

K&Ny?0 534.

K&YA

536.

537.

-329- Table 2B cont.

R

538.

541.

540.

539.

542.

H

545.

544.

VI-

547.

550.

543.

0 546.

549.

552.

548.

551.

-330y 553.

i 556.

559.

562.

0 Table 28 cont.

R

554.

V

557.

560.

563.

566.

555.

558.

561.

564.

567.

-331- Table 2B cont.

R

568.

569.

570.

571. 572.

573.

S

S. S 574.

575.

576.

577.

578.

579.

'-,crYx 580. 581. 52 582.

-332- Table 2B cont.

R

0cy 583.

586.

589.

584.

588.

0 585.

591.

593.

594.

592.

596. 597.

-333- Table 2B cont.

598.

601.

604.

607.

610.

599.

:y 602.

605.

600.

603.

606.

-608. S609.

611. 612.

R

613.

-334- Table 2B cont.

R

O)y

H

614.

DOSHN,17.

617.

R

615.

0 618.

616.

0 619.

622.

620.

is 621.

624.

623.

V

0 0 00 625. 626.

627.

-335- Table 213 cont.

R

0 0 630.

628.

FCP 0~j 631.

629.

00 632.

Example 339 Using methods described in the above examples, compounds comprising a par6nt structure selected from 'those disclosed in Table 3A and an R substituent selected from those disclosed in Table 3B can be prepared.

-336- Table 3A

F

CH33 _C0OOH 0 4.

CH,

,COOH

7. momo

COOH

I

F

3. 0

R-

6. F 00 9. 0 *COO H 0 8. 0 -337-

-N

VCOOH

13.

Table 3A cont.

H"

.ECOOH

14. 0o a. a a a.

a a a.

a. a .a a. a a a.

a

CH,

.COOH

IOCH,

16.

_COOH

0 19.

HC

pr H .0 18.

F

.COOH

0> a.

a. a a a. a a a.

a a.

-338- Table 38 6* b 6

OS

6* S 5 6 .5 8 66

R

0 1.

0 4.

0 7.

0 13.

0 16.

R

0 2.

0 5.

8.

14.

0 14.

0 17.

00

R

3.

0 6.

0 9.

12.

0 mlGOaSy" 0 18.

00 00 19.

S

0 S

OOS

0O 5.

S

0@ S 0* 22.

60 -Th SNi 28.

FH2C

F

2 6 0 31.

F

2 HC.Cr-*N 4

F

2 0 34.

c0 37.

-339- Table 3B cont.

R

d0 23.

60 26.

29.

I)

FH2CA NsCt F2 6 0 00 24.

27.

FH

2 6

F

2

HC

F

2 6~ 0 32. 33.

@5 5 555 5 0* 0

SO

Se F 0 0 35.

8' 38.

F

2 0 0 36.

39.

0 -T

I

0 0 00 43.

46.

-340- Table 3B cont.

R

0 0 44.

H,

0 0 47.

F,

00 48.

<Qy 49.

52.

55.

58.

50.

53.

F

56.

59.

0 51.

54.

57.

-341- Table 3B cont.

R

61.

64.

67.

0 0 73.

0 76.

(Vs" y 0

OCH,

62.

65.

68.

H A0 63.

66.

69.

72.

0 78.

78.

9H 3 r 71.

0~ 74.

00 77.

-342- 0..

0:: 00

R

79.

doo 82.

Y

00 88.

FJ"Y

00 91.

y

F

3 1~ 00 94.

97.

Table 36 cont.

R

-in 00 80.

83.

00 86.

00 89.

Y

F F 6' 0 92.

95.

98F.1-1) 98.

R

-Th 81.

F

3 1-% 00 84.

y 87.

Y

00 y 93.

Fd F F 'o 96.

H,C99.

99.

-343- 00 100.

00 103.

A>

106.

00 109.

112.

FF

0 Table 3B cont.

R

Hc01 00 101.

HC0> 00 104.

0 0 107.

0 0 110.

113.

A>PLTi 0 0 102.

F,

FFOF

105.

0-0 108.

111.

F,~

00 114.

00

C

115. 116.

-344- 118.

121.

CII-rl Table 3B cont.

R

119.

y *,aNO 122.

Kcry0 125.

128.

OHR

120.

123.

126.

129.

124.

y 127.

130. 131. 132.

-345- 133.

136.

139.

142.

145.

Table 3B cont

R

134.

137.

PF

3

Y

140.

143.

y 0cY 146.

135.

138.

141.

144.

147.

-346- 0* 148.

151.

154.

y 157.

V

PtaN,, Table 3B cont.

R

149.

y

FC'

152.

155.

158.

150.

153.

Ph.oN~ra 156.

159.

162.

163.

-347- Table 3B cont.

R

y ~cV 164.

167.

y 170.

165.

168.

NC1.N 171.

166.

169.

172.

0 173.

y "r-1i

Y"T

N

174.

K Mr 175.

176. 177.

-348- Table 3B cont.

R

179.

178. 180.

183.

0* 182.

185.

'VA 4* 184.

187.

NC~

186.

N

F I 192.

190.

-349- 193.

Table 38 cont.

R

194.

1yo~ 195.

196.

197.

199.

202.

200.

Iy 203.

201.

204.

205.

05.206. 207.

-350- 9*

C.

9 .9 99 9 9 .99 9 9. 9 9b 99 ciro .N 0 208.

y 211.

v 214.

217.

QtNOr Table 3B cont.

R

209.

212.

rir

N

215.

ly 218.

LJN 0 210.

WN0 213.

,N 0 216.

y 219.

Q.L"No 220. 221. 222.

-351- 0@ 0 0# 0 S 00 223.

226.

229.

0~ Table 3B cont.

R

224.

y 227.

v

AN

225.

228.

>Y0 230.

0 231.

0* 0 006 0 *0 0 S SO 232.

0v 233. 234.

236. 237.

-352- 238.

241.

244.

247.

250.

Table 3B cont.

R

0crr 239.

242.

y(N{A 245.

v 248.

252.

V

240.

243.

0> 246.

249.

252.

-353.

Table 3B cont.

R

253.

256.

259.

N

262.

265.

N~yN 0 254.

257.

255.

258.

y 261.

264.

260.

263.

266. 27 267.

-354- Table 3B cont.

R

V

270.

268.

269.

272.

271.

274.

275.

273.

V

276.

279.

N

282.

277.

K-

280.

278.

y1C 281.

-355- Table 3B cont.

R

283.

286.

y 289.

V

292.

295.

284.

287.

290.

293.

296.

285.

K

288.

291.

294.

y 297.

Uj'N 298.

-356- Table 3B cont.

R

299.

302.

y 305.

V

300.

301.

304.

>j'N 307.

310.

N

303.

306.

309.

312.

308.

311.

-357- Table 3B cont.

R

313.

316.

314. 315.

317. 318.

319.

320.

323.

321.

324.

322.

325.

v 326.

3 327.

-358- Table 3B cont.

R

328.

331.

V

334.

R

329.

332.

R

V

r 330.

333.

COOEt 336.

NO,

339.

3 342.

335.

'COOEt 337.

N0 2 340.

338.

341.

-359- 343.

Table 3B cont.

R

344.

O

2

N

347.

>6 350.

0 353.

346.

349.

0 352.

0

CN

345.

0, 348.

0 351.

354.

355.

356.

Y

0 357.

-360- 358.

361.

364.

367.

0 Table 3B cont.

R

359.

V

""q 362.

365.

y 368.

0 y 360.

363.

F~aKV0 366.

0 369.

0 370. 371.

-361- S. S 5*55 .5

S

eS

S.

5

S

*S

OS

*5 S

S

*5 5 S 55 MeO 0 373.

0 376.

0 379.

moo, IIN rA 0 382.

0 385.

Table 3B cont.

R

0 374.

0 377.

MOO 6 0 380.

0 383.

0 386.

0 375.

0 378.

M Lwo 0 381.

Me0 0 0 384.

0 387.

390.

388. 389.

-362- 0 391.

9@

S

S.

S

SOSS

S.

@555

S

5* 5 0 394.

0 397.

0 400.

0 403.

Table 3B cont.-

R

0 392.

0 395.

clc 0 398.

0 401.

F)C

0 404.

396.

0 393.

0 399.

402.

5S

S

S.

9SS S S. S

*S

S. 405.

I Cu 407 0 406. 407.

F)

408.

-363- Table 3B cont.

R

0 410.

S

S.

S. S F~t~ 0 409.

0 412.

0 415.

0 418.

0 421.

OMO 0 424.

413.

0 416.

0 419.

422. 0 OMO 0 425.

0 411.

0 414.

0 417.

0 420.

OMO 0 423.

OMO 0 OMo 0 427.

OMs 0 430.

-364- Table 3B cont.

R

OMO

428.

Mee CM. 0 431.

OMe 0 429.

moo OMe 0 432.

OMe 0 435.

OMe 0 433. 434.

moo-IQ

OMO

436.

mo0Ys N V 439.

OMO 0 437.

meoQ

N

440.

441.

Mo

A-

444.

442. 443.

-365- 445.

B0K 448.

451.

y 0cFr 454.

Table 3B cant.

R

y B, No-, 446.

449.

452.

455.

>1 447.

V

450.

453.

456.

457. 458. 49 459.

366- Table 3B cont.

460.

0 463.

461.

464.

467.

R

y 462.

465.

F a 468.

466.

469. 470.

471.

Fc~a

CA

474.

472. 473.

475.

-367- Table 3B cont.

R

476.

479.

482.

477.

K

1 481.

484.

FxrY CA 480.

F

F LT 483.

Fy 486.

F 489.

485.

F

0 487. 488.

R

490.

r -""K6rx 0 493.

0 496.

0 499.

0 502.

505.

368- Table 3B cont.

R

0 491.

0 494.

0 497.

500.

0 503.

506.

R

0 492.

NA(-

0 495.

0 498.

(2)L 0 501.

504.

507.

-369-

Y

508.

h 511.

514.

y 517.

520.

Table 3B cont.

R

509.

V

512.

515,

-A

518.

521.

N

510.

513.

y NOrY' 516.

519.

522.

-370- Table 3B cont.

R

0 523.

526.

529.

H

532.

535.

H

525.

528.

H

531.

527.

H

530.

533.

534.

&0 536.

537.

-371- Table 3B cont.

*9

R

538.

0 541.

H

0 544.

6r 547.

A-r 539.

540.

542.

H

%CrY? 545.

548.

0v

H

546.

549.

'O I au r-, 550. 551. 552.

-372- Table 3B cant.

R

y 553.

556.

559.

562.

0 565.

554.

v; 557.

560.

I 6uv8 563.

CI r 555.

558.

561.

564.

566. 567.

-373- Table 3B cont.

R

568.

571.

569.

570.

9 9 9 9 9*9 9 .9 9 9@ 9 99 572.

573.

574.

575. 576.

577.

578.

579.

580. 581. 52 582.

-374- Table 3B cont.

S

9 evot

S.

I..

S

S. 9 Sc

R

583.

586.

V

589.

584.

588.

585.

587.

591.

593.

594. @5 t o 0 5 9. S SO 592.

596.

597.

595.

-375- Table 38 cont.

R

FO

598.

y

FV

601.

FV

604.

607.

610.

599.

ly

F

602.

605.

600.

603.

606.

6 609.

608.

611. 612.

-376-

R

~soy 613.

Table 3B cont.

R

61-4.

617.

MOQS4 616.

0 619.

622.

R

M.0O.)A 615.

0 618.

0 621.

YI4 6 624.

620.

623.

Y

0 0 00 625. 626.

627.

-377- Table 3B cont.

R

629.

0 630.

628.

S

S. *5

S

*SSS

S

631.

00 632.

Examngle 340 trans, trans-4-( 1.3-Benzodioxol-5-vl)-2-(4-mTethoxyphelyl)- 1 -(N-(3-methylbut- 1 -yi)- N-phenyl)aminoca rbonylmethyl)-pvyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound 10 was prepared. 1 H NMR (300 MHz, CD 3 OD) 8 0.85 J=6 Hz, 6H), 1.25 (q, J=7 Hz, 2H), 1.42-1.56 (in, 1H), 3.43-3.85 (in, 9H), 3.88s 5.95 (s, 2H), 6.80 J=7 Hz, I 6.86 (dd, J=9 Hz, 1 6.89-7.00 (in, 2H), 6.97 J=1 Hz, 1 7.04 J=9 Hz, 2H), 7.37 J=9 Hz, 2H), 7.40-7.47 (in, 3H). MS Wle C (53.12, 53.11), H (4.63, 4.80), N (3.33, 3.28).

-378- Example 341 trans. trans-4-( 1.3-Benzodioxol-5-y)-2-(4-mlethoxyp~helyfl)-1-(Nbutyl-N-(4-methyllhenylaminocarbolylmethyl)-P~rrolidinle-3carboxylic 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- 1.47 (in, 4H), 2.37 3H), 2.83 J=7 Hz. 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, 1H), 6.80-6.86 (in, 3H), 6.89 J=8 Hz, 2H), 7.04 J=2 Hz, 1 7.12 J=8 Hz, 2H), 7.19 ;1=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 trans. trans-4-(1 .3-Benzodioxol-5-yl-2 -(4-roD~oxyVhenl)-'l :di(n-butyflamino)carbonylinethyfl)Dy rrolidife- 3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz. CDC13 8 7.30 d, 7.03 (1IH, 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, mn), 3.53-3.20 (4H1, in), 3.10-2.90 (4H, in), 2.72 (1H, d, J=15), 1.79 q, 1.50-1.05 (8H, in), 1.0 2 (3H, t, 0.87 t, 0.80 t, MS (DCI/NH3) me 539 Anal calcd for C31H-42N206 0.51-20: C, 67.98; H 2 .7.91; N, 5.11. Found: C,68.24; H, 7.70; N, 5.03.

0 0 Example 343 trans, trans-4-(1 .3Benzodioxol-5-fl)-2-(4-propylphenlfl .N-di-nbutyl) amin ocarboflylinethyflDprrol idin e3carbo xylic acid Using the procedures described in Example 1, the title compound was prepared. I 1 H (300MHz, CDC13 8 7.31(2H, d, 7.13 (2H, d, J=9), 7.03 (1 H, d. 6.84 (1 H. dd, J=6, 6.73 (1 H, d, 5.95 (1KH, d.

5.93 (1KH, d, 3.76 (1 H, d, J=1 3.60 (1KH, mn), 3.55-3.20 (41-, in), 3.13-2.88 in), 2.75 (1H, d, J=15), 2.55 t, J=8),1.62 (2H, q, 1.50-1.00 (8H, in), 0.92 t, 0.85 t, 0.78 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.

-379- Example 34-4 trans-trans-2-(4-Methoxyohenyll-4-(1 .3 -ben zodioxolI-5-yb)- -r3-(Ng ro pyl- N -r-pentanesuIf o nyl amino) pro pyllDyrrol idi ne-3-carboxyl ic acid Using the procedures described in Example 316, the title compound was prepared. I H NMR (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 (in, 11H), 2.72-3.1 (in, 7H1), 3.27- 3.4 (in, 2H), 3.5-3.6 (in, 2H), 3.80 3H), 5.95 2H1), 6.73 J=8Hz, 1H), 6.8-6.9 (in, 1H), 6. 85 J= 9Hz, 2H), 7.02 (Cd, J=2Hz, 1H), 7.80 (d, J=9Hz, 2H).

Example 345 trans, trans-4-(1 Dih yd robe nzof uran- 5-yi)-2-(4-ethyl phenyl)-1- (N.N-di(n-butyflaininocarbonylmethyfl)-oyrrolidine-3-carboxylic acid wsUsing the procedures described in Example 1, the title compound wsprepared. I H (300MHz, CDC13 8 7.40 (3H, in), 7.22 (2H, d, J=8), 7.13 (1 H, dd, J=8, 6.72 (1 H, d, 5.28 (1 H, d, J=1 4.55 (2H, t, 4.15 (1H, d, J=18), 4.03 (2H, in), 3.75 (2H, in), 3.40 (2H, mn), 3.20 (2H, t, 3.15 (1H, in), 3.10-2.90 (2H, mn), 2.63 (2H, q, 1.47 (2H, in), 1.31 (4H1, mn). 1.12 (3H, t, 1.10 (2H~in), 0.92 (3H, t, 0.80 (3H, t, MS (DCI/NH3) Wne 507 Anal calcd for C31 H42N204 TEA: C .63.86 H, 6.98; N, 4.51. Found: C, 63.95; H, 7.12; N, 4.43.

Example 346 trans. trans-4-(1 Benzodioxol ethoxyphelyfl)- 1 pentyfl-N-phenvlamino)carbonylmethyl)pyrrolidine-3-carboxylic acid- Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.93 J=7.3 Hz, 3H), 0.94 J=7.3 Hz, 3H1), 1.33 (in, 4H), 2.72 J=15.2 Hz, 1H), 2.81 (mn, 1H), 3.11-3.2 (in, 2H), 3.45-3.57 (in, 2H), 3.79 3H), 3.83 J=9.8 Hz, 4.54 (in, 1H), 5.92 2H1), 6.73 J=7.8 Hz, 1H), 6.83 (in, 3H), 6.98 (bs, 2H), 7.04 (di, J=1.7 Hz, 1H), 7.07 7.37 (in, 3H). MS (DCI) ine 545 Anal calcci for C32H33N206 0.35H20: C, 69.76; H, 6.71; N, 5.08. Found: C, 69.72; H, 6.66; N, 4.94.

-3 Example 347 trans, trans-4-(l .3.-Benzodioxol-5-yfl)2-(4-methoxyphenyl)-1 butyl)-N-(3-trif luoromethyl phenyl) amino) ca rbonylmethyflpyrrolidi 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=6.6 Hz, 3H), 1.17- 1.45 (in, 4H), 2.65 J=16.5 Hz, 1H), 2.72 (in, IH), 3.10 J=9.5 Hz, I1H), 3.21-3.27 (in, 1 3.40 (dd, J=4.1, 9.9 Hz, I1H), 3.54 (in, I1H), 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, 1H), 7.40 7.58 J=7.8-Hz, 1H), 7.69 Hz, 1H). MS (DCI) in/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 15 trans, trpns-4-(1 .3-enzodioxol-5-y)-2-(4.inethoxylhenvl-l propyl-N-(4-inorpholinylcar onlfamiflocarbonylinethvil-nvrrolidine- 3 carboxylic acid wasUsing the procedures described in Example 1, the title compound wsprepared. 1 H NMR (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, 11H), 3.76 5.88 2H), 6.67 J=8 Hz, 1H), 6.80 (dd, J=7 Hz, 1H), 6.83-6.90 (in, 2H), 6.98 J=2 Hz, 1H), 7.32- 7.39 (in, 2H). MS in/e calc'd for C29H39N307: 540.2710,.

Found 540.2713.

25Example 349 trans, trans-4-(l -ezdool5y)2(-etoyhnl- -(cis- 2.6-d imethylpipe ridil- I -l)carbonylmeth i)pyrrol idin e3-carboxyli c acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD 3 OD) 8 0.94 J=7 Hz, 3H), 1.15d 3H), 1.10-1.70 (in, 6H), 1.70-1.90 (in, 1H), 2.9. J=13 Hz, 1H), 3.00-3.20 (mn, 2H), 3.50 (3.70, J=m Hz, 2H), 3.79 3H), 3.80-4.00 (in, 1H), 4.10-4.65 (in, 2H), 5.95 2H). 6.70 (7.10, J=in Hz, 5H), 7.35 (in, 2H). MS ni/e calc'd for C28H35N206: 495.2495. Found 495.2493.

-381trans. trans-2-(4-MethoxymethoXYWhnl- 4 -j1 1 -(2-(N-prpn Nr pnae Ifnlmn~tylyrr-ie3 carboxylic -acid Using the procedures described in Example 1, the title compound Was prepared and isolated as a white solid. m.p. 57-59 0 OC. 1 HNMR (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 1H), 2.72-3.10 (in, 7H), 3.18-3.41 (in, 2H), 3.43 (dd, J=-3Hz, J=9Hz, IH), 3.48 3H), 3.52-3.59 (in, 1H), 3.68 J=9Hz, 1H), 5.15 2H), 5.94 (s,2H), 6.73 J=8Hz, 1H), 6.82 (dd, J=lHz, J=81-z, 1H). 6.98-7.02 (in, 3H), 7.32 J=9Hz, 2H). MS (DCI/NH3) m/e 591 Example 351 *trans. trans-44-(l 1 n x 15v)2_4mthxh-,x-(((1(1 *butyfl)-N -1h e nyami no)carb nyfl) methyl lpyrrlidi ne3-carboxyLig ci-d Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD300) 5 0.79-0.89 (in, 6H), 1.14-1.21 (in, 1H), 1.25-1.40 (in, 1H), 2.64 (dd, J=4.6, 15.4 Hz, 1H), 2.76 Hz, 1H), 3.05-3.13 (mn, 2H), 3.37-3.49 (in, 2H), 3.70 3H), 3.80 (d, J=9.8 Hz, 1H), 4.53 (mn, 1H), 5.83 (in, 2H), 6.65 J=8.1 Hz, 1IH), 6.72 6.76, J=in Hz, 3H), 6.87 (in, 2H), 6.95 J=1.7 Hz, 1H), 7.03 (mn, 2H), 7.29 (in, 3H). MS (DCI) mWe 531 Anal calcd for C31H34N206 0.4H20:. C. 69.23; H, 6.52;, N, 5.21. Found: C, 69.19; H, 6.52; N, 5.03.

Exainne 352 trans, trans-4-(1.3Bnoixl5y)2(-ehX~etl-: prop~yfl)-Nphenylamino)carbonyl)inethyli~nrrolidine3carboxlic-acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 6 0.99 J=6.8 Hz, 6H), 2.71 J=15.6 Hz, 1H), 2.84 (mn, 1H), 3.13-3.18 (mn, 2H), 3.45-3.58 (mn, 2H), 3.79 3H), 3.88 J=9.8 Hz, 1H), 4.80 (mn, 1H), 5.92 2H), 6.74 (d, J=8.1 Hz, 1H), 6.83 (mn, 3H), 6.96 (br s, 2H), 7.04 J=1.7 Hz, 1H), 7.13 (mn, 2H), 7.38 (mn, 3H). MS (DCI) mWe 517 Anal calcd for -382- C30H-32N206 0.41-20 0 .08CH3C02C2H5: C, 68.65; H, 6.28; N, 5.28.

Found: C, 68.64; H, 6.35; N, 5.14.

trans. trn-4(- rooy~)e toyhnl-(N.N-di(nbutyflamin crb nImeh l-nvrrolidinecA-nrbxyl c-d Using the procedures described in Exam ple 1, the title compound was prepared. I H (300MHz, CDC13 6 7.42 d, J=lO1-z), 7.38 d, J=lOHz), 6.92 d, J=1lO-z), 6.88 d, J=lOHz), 5.13 01H, bd, .10 J=l2H-z), 4.02 (2H, in), 3.90 t, J=8H-z), 3.80 (3H, 3.71 in), .*3.40 in), 3.19 in), 3.10-2.90 in), 1.80 mn), 1.48 in), *1.29 in), 1.13 in), 1.03 t, J=8H-z), 0.92 t, J=9H-z), 0.82 t, J=9H-z). MS (DCI/NH3) mn/e 525 Anal calcd for C311-40N205- 1 TFA C, 62.06 H 7.10; N, 4.39 Found: C, 62.43; H, 7.28; N, 4.39.

transtrans4-(lExam le 354 trns tas41. 3 -Benzodioxol5yl)2(4-m athoxyphen~yl~L- (1 .23. 4 -te t ra hy r in if- I y'crbonybineh I )D r rIine 3 carboxyliC acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3O1D) 8 1.88 (quintet, J=6.5 Hz, 2H), ~:2.67 J=6.4 Hz, 2H), 2.87 J=8.6 Hz, 3.14 (mn, 2H), 3.42 (dd, J=4.6, 9.7 Hz, 11H), 3.53-3.70 (in, 3H), 3.72-3.78 (in, 1H), 3.77 3H), 25 3.86 J=9.6 Hz, 5.91 2H), 6.73 J=8.1 Hz, 1H), 6.83 (mn, 3H), 6.98 J=1.1 Hz, 7.02-7.23 (mn, MS (DCI) Wne 515 Anal calcd for C 3 0H30N206 0.31-20 0.15 CH3C02C2H5- C, 68.93; H, 6.01; N, 5.25. Found: C, 68.91; H, 5.86; N, 5.19.

trans~t rns2-(3.4Dint Y~ev~(1 .3nz odiXl5vl-l (N .N-di(n-butyl)Zm ainiflOCrbn linh lDrri i ne car oxl ac id, Using the procedures described in Example 1, the title compoundu was prepared and isolated as a white solid. m.p. 64-65 OC. 1H NMR (CDCI3, 300MHz) 8 0.79 J=7Hz, 3H), 0.88 J=7Hz, 3H),1.07 (sextet, .17H-7 2H). 1.20-1.35 (mn, 4H), 1.43 (sextet, J=7Hz, 2H), 2.83 (d, -383- J=13.5Hz, 1H), 2.94-3.17 (in, 4H), 3.22-3.42 3.40-3.48 (in, 3H), 3.58-3.65 (in, 1 3.82 3H), 3.85 4H),5.!R2 2H), 6.73 J=8Hz, 1H), 6.81 J=8Hz, 1H), 6.86-6.96 (in, 3H), 7.07 J=3Hz, 1H). MS (DCI/NH3) m/e 541 trans. fra ns-2 -(3.4-Di metho xylh enyl)- 4 3- ben zod io xol 142- (N-Drooyi-N-ri~entanesul oflylainfo)ethylnyrrolidine 3 -carboxylic Using the procedures described in Example the title compound was prepared and isolated as a white solid. m.p. 75-86 1 H NMR (CD300. 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 (mn, 4H), 3.23-3.27 (mn, 2H), 3.44 (t.

J=6Hz, 1H), 3.47-3.56 (in, 2H), 3.78 J=9Hz, 1H), 3.83-3.93 (in, 2H), 3.87 3H), 3.92 3H), 4.63 J=l3Hz, 1H), 5.97 2H), 6.82 (d, *:J=7Hz, 1 6.93 J=7Hz, 1 7.06 J=7Hz, 1 7.08 J=3Hz, 1 H), 7.16 (dd, J=3Hz, J=7Hz, 1H), 7.27 J=3Hz, 1H). MS (DCI/NH3) m/e 591 ~20 MH).Example 357 trans, trans-2-(3.4- imethoxypheflyl) 4 .3-benzodioxol-5-yI"-l -12- ~:Using the procedures described In Example 1, the title compound was prepared and isolated as a white solid. m.p. 65-66 OC. 1 NMR (CDCI3, 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 (in, 1H), 2.73-3.10 (mn, 7H), 3.19-3.32 (in, 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 (d, J=8Hz, 1H), 6.79-6.86 (in, 2H), 6.92-6.97 (mn, 2H), 7.02 1H). MS (DCI/NH3) m/e 605 -384- Exam le 358 trns traenndixmL5-(4 1142- (phthalimidOehl ~r~iiecarboxylic acid The compound of Example 1IC (250 mg), N-bromoethylphthalimide (206 mg), and diisopropylethylamifle (175 mg) were dissolved in 1 mL of acetonitrite and heated for 2.5 hours at 95 OC. Toluene was added, and the mixture was washed with KHCO3 solution. -The solution was dried (Na2SQ4) and concentrated. The crude product was purified by chromatography on silica gel eluting with 3:1 EtOAc-hexafle to give 216 mg of an intermediate ethyl ester which was hydrolyzed by the method 4@**of Example 10D to give 130 mg of the title compound as a white powder.

.1 1 H NMR (300 MHz, 00013) 8 3.12-3.26 (in, 2H), 3.60-3.75 (in, 2H1), 3.70 3H1), 3.98-4.12 (in, 2H), 4.45-4.55 (in, 1H), 4.69 J=9Hz, 4.76- 4.88 (in, 1H), 5.96 2H), 6.55 J=8Hz, 1H), 6.60-6.70 (in, 3H). 6.79 is J=8Hz, 1H), 7.05-7.45 (in, 5H), 7.75 J=7Hz, 1H).

ExampjgaM e**;trans, trans-4-( 3 Be izodixol5y/fl2-(4- e hYh 1) 1 -1(-2 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD300) 8 0.86-0.98 (in, 6H), 1. 17-1.22 (in 1.23-1.41 (in, 3H), 2.70 (dd, J=1 1.2, 15.3 Hz, I1H), 2.83 (in, 1 H), 3.10-3.21 (in, 2H1), 3.45-3.60 (in, 2H1), 3.79 3H), 3.86 (in, 1H), 4.74 1H), 5.91 (mn, 2H), 6.73 (dd, J=1.1, 7.7 Hz, 3H), 6.82 (in, 2H), 7.04- 25 7.14 (in, 3H), 7.36 (in, 3H). MS (DCI) Wne 545 Anal calcd for C32H36N206 -0.25 CH 3 002C2H5: C, 69.95; H, 6.76; N, 4.94. Found:

C,

70.03; H, 6.54; N, 4.78.

Examp~le 360 tastrans- 4 3 Benzodioxol-5-- 12 4inethoxY~henyl 1 -Nbutyl N-( 2 lahth ainincabnvintyrlidine-3 cdin 3 Yl acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (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 (in, 2H), 3.00-3.80 (mn. 3.66 3H), 5.87 2H), 6.39 J=9 Hz, 2H), 6.74-6.85 (in. 7.17 -385- J=2 Hz, 1H), 7.40 (dd, J=8 Hz, 1H), 7.52-7.62 (in, 3H), 7.80-7.90 (in, 1H), 7.90-8.00 (in, 2H). MS (DCI) mWe 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, transw2-( 4-Pro oxyphenyfl-4-(1 .3-benzodioxol-5-yfl-l-l2-(Npropyl-N-rn-oentanesulfonylaino)ethyl1P~Yrrolidine 3 .carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 53-54 OC. 1 HNMR (CDCI3, 300MHz) 8 0.79 J=7Hz, 31H), 0.89 J=-7Hz, 3H), 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 (mn, I1H), 2.72-2.93 (in, 5H), 3.05 (septet, J=7Hz, 2H), 3.15-3.35 (mn, 2H), 3.42 J=9Hz, 1H), 3.54-3.62 (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 trans. trans-4-(1.3 Be zdio15y)2(-ehxlen)l-((2m ethyl in dol in-I -ylcarbonyfl)meth~jlDpyrrol idine3carboxvEWi acid **Using the procedures described in Example 1, the title compound *was prepared. 1 HNMR (300 MHz, CD3OD) 8 mixture of indole C2 diastereoiners, 0.95 (in, 1.5 (CH3 1.05 6.31-, 1.5 2.62 (in, 25 1H), 3.01 (in, 2H), 3.14-3.25 (in, 1H), '3.37-3.52 (mn, 1.5H), 3.56-3.80 (in, 2H), 3.65 1.5 (CH3O)), 3.76 1.5 (CH3O)), 3.93 (in, 0.5H), 4.05-4.13 (in, 4.42 (in, 0.5H), 4.65-4.74 (in, 1H), 5.91 (mn, 2H), 6.72 J=8.1 Hz, 0.5H), 6.75 (in, 0.5H), 6.85 (mn, 6.92 J=8.5 Hz, 1H), 7.00-7.06 (in, 2H), 7.14 J=7.7 Hz, 1H), 7.21 J=6.6 Hz, 1H), 7.38'(in, 2H), 7.99 (in, 1H). MS (DCI) in/e 515 Anal calcd for C 3 0H30N206 0-35H20 0.3 CH3CO2C2H5: C, 68.47; H, 6.10; N, 5.12. Found: C, 68.46; H,I 5.97; N, 5.07.

-386- ExampLe-I363 trans, trpns-4-(1 .3-Benzodioxol-5-fl)-2-(4-methoxyphen l-1 -i(2hydroxy-3-propylhex-1 -yflprrolidine-3-carboxylic -acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD300) 8 1.06 (in, 6H), 1.26-1.60 (in, 9H), 3.16 (dd, J=10.9, 12.6 Hz, 1H), 3.18 J=11 Hz, 1H), 3.44 Hz, I1H), 3.61 J= 11 Hz, 1 3.73 J=1 1.0 Hz, 1 3.85 (mn, 1 H), 3.96-4.17 (mn, 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, 0.5H), 7.10 (in, 1H), 7.23 (in, 3H), 7.77 (in, 2H). MS_ (DCI.) in/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.

Examlle 364 trans, trans-4- (1 Ben zodi oxol-5-fl)-2-(4- meth oxjoh enyl) -1 heotyfl-N-(3 .4-dimethoxybenzyl)ami no~carbonyl')methyl)oyrrolidine-3carboxylic acid :Using the procedures described in Example 1, the title compound was prepared. 1 H NMVR (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, 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 1.5H1), 3.79 1.5H), 3.86 J=9.8 Hz, 0.5H), 4.19 (d, J=17.7 Hz, 0.5H), 4.29 J=15.2 Hz, 0.5H), 4.40-4.49 (mn, 0.5H), 4.47 (d, 25 J=15.3 Hz, 0.5H), 4.60 J=17.6 Hz, 0.5H), 5.93 (mn, 2H), 6.46 (dd, J=1.7.

8.2 Hz, 0.5H), 6.52 J=2.0 Hz, 6.74 (mn, 2.5H), 6.80 1H), 6.83- 6.88 (in, 1H), 6.92 (en, 7.03 (dd, J=1.7, 6.8 Hz, 1H), 7.19 (in, 1H), 7.36 (in, 1H). MVS (DCI) Wne 647 Anal calcd for C37H46N208: C, 68.71; H, 7.17; N, 4.33. Found: C, 68.41; H, 7.26; N, 4.11.

Example 365 trans. trans-4-(1 .3.Benzodioxol-5-fl)-2-(4-methoxyphefll-J ((indolin-1 -yflcarbonyflmethylIprrlife3-abxic cd 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 (mn, 2H), 3.51-3.68 (in, 3H), 3.73 (in, -387- 3H), 3.83-4.05 (in, 3H1), 5.90.(in, 2H1), 6.73 J=8.1 Hz, 11H), 6.86 (in, 3H), 6.99 (dt, J=1.1, 7.4 Hz, IH), 7.08 J=0.7 Hz, 11H), 7.11 (in, 1H), 7.18 J=7.1 Hz, I1H), 7.38 J=8.5 Hz, 2H), 8.02 1, 1 MS mle 501 Anal calcd for C29H128N206 0.5 H20 -0.15 CH3CO2C2H5: C, 68.01; H, 5.82; N, 5.36. Found: C, 68.03; H, 5.65; N, 5.25.

Exmple 366 trans. trans-4-(1 .3.Benzodioxol-5-yl-2-(4-methoxyphenyfl)-1-(N- 1o butyl-N-(2-chlorophenyfl)aminocarbonyl methyflyrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound prepared. I 1 H NMR (300 MHz, CD3OD) 80.89 (dt, J=7 Hz, 3H), 1.23- 1.51 (in, 4H), 2.52-4.00 (in, 8H), 3.78 J=6 Hz, 3H), 5.92 J=6 Hz, 2H), 6.70-6.87 (in, 4H), 7.02-7.21 (in, 7.27-7.52 (in, 3H1). MS (DCI) *m/e 565 Analysis calcd for C31H32N206CI 0.6H20: C, 64.66; H, 5.99; N, 4.86. Found: C, 64.59; H, 6.00; N, 4.64.

Examgle 367 trans, trans-2-(4-Methoxphenyl 1-44(1 .3-benzodioxol-5-vfl-l 1 (3.4 .5-trimethoxybenzyl~pyrrolidile-3-carboxylic acid The compound resulting from Example IC (0.25 g) was reacted with 0.169 g of 3,4,5-trimethoxybenzyl chloride and 0.175 g of d iisop ropyl ethyl amine in 1 mL of acetonitrile for 2 hours at room temperature. The resulting ester was isolated and then hydrolyzed by the method of Example 10 to give 0.193 g of the title compound. m-p.

108-110 1H NMR (300 MHz, CDC13) 82.75 J=9Hz, 1H), 2.95-3.05 (in, 2H1), 3.20 J=11 Hz, 1H1), 3.45-3.55 (in, 3.7-3.8 (in, 2H), 3.84 3H1), 5.95 (dd, J=2Hz, 6Hz, 2H), 6.55 2H), 6.70 J=8Hz, 1H), 6.30-6.35 (mn, 1H), 6.90 J=9Hz, 2H), 7.13 J=2Hz, 1H), 7.43*(d, J='gHz, 211).

-388- Example 368 trans, trans-4-(l .3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)- 1 butyl-N-(3-chlorophenyl)aminocarbonylmethyl)-yrrolidine-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 W/e 565(M+H). Analysis calcd for C31 H33N2OGCIO1.OCF3COOH: C, 58.37; H, 5.05; N, 4.13. Found:. C, 58.41; H, 4.99; N, 4.08.

trans. trans-2-(4-MethoxphenyP)-4-(1 .3-benZodioxol-5-yf)l- -2-(di-rnbutyl amino) 1yrimidi n-4-yllgyrrol idine-3-carboxylic acid is The compound resulting from Example 1 C (0.25 g) was reacted :with 0.11 g of 2,4dichloropyrimidine and 0.175 g of diisopropylethylamine in 1 mL of acetonitrile for 2 hours at room :temperature to give 0.218 g of ethyl 2-(4-methoxphenyl)-4-(1,3b e nz o d io x oI-5 1 (2 -c hIo ro -4 pyrim id y1) py rr oIi d in e-3 carboxylate. This compound was reacted with 1 mL of dibutylamine in.

2 mL of toluene at 125 OC 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 4.6 (br, 1H), 5.2 (br, 1H), 5.45 (br, 1H), 5.87 2H), 6.3 (br, 1H), 6.67 J=8Hz, 1H), 6.7-6.85 (in, 41H), 7.10 J=9Hz, 2H).

Examnole 370 trpns.trpns-4-(1 .3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-l m ty t2y)Npeny m oab y)mehl yr) ~npcarboxylic- acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, 00300) 8 0.90 J=7.5 Hz, 3H), 1.12 3H), 1.14 3H), 2.06 J=7.5 Hz, 2H), 2.73 J=1 5.3 Hz, 1H). 2.91 J=9.5 Hz, 1H), 3.11 J=15.6 Hz, 1H), 3.21 J=8.8 Hz, 1IH), 3.50- -389- 3.61 (in, 3.8 3H), 4.00 j=10.2 Hz, 1H), 5.91 6.74 (d, J=7.8 Hz, 11H), 6.85 (in, 3H), 6.93 (in, 6.98 (in, 1H), 7.03 J=1.7 Hz, 1 7.17 (in, 2H), 7.36 (in, MS (DCI) W/e 545 Anal calcd for C32H36N206: C, 70.57; H, 6.66; N, 5.14. Found: C, 70.17; H, 6.53; N, 4.97.

Example 371 trans. trans-2-(4-Ethylphenyfl-4-(5-indanyl)-1 N-di(nbutyl~aininocarbonylmethyl-pyrrolidine-3-crboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDCI3) 8 7.25 (3H, in), 7.21 (1H, d, 3Hz), 7.17 (3H1, mn), 3.80 (1 H, d, 10OHz), 3.65 (1 H, ddd, 6. 5, 3H1z), 3.4 (4H1, mn), 3.10 (2H1, in), 2.98 (2H, mn), 2.88 (5H1, in), 2.79 (1H1, d, 16H-z), 2.62 (2H, q, 7Hz), 2.05 mn), 1.42 (2H, in), 1.32 (1 H, in), 1.21 (3H1, t, 7H-z), is 1.05 (2-,sx,7Hz), 0.87 (3H, t, 7H-z), 0.79 (3H, t, 7Hz). MS (DCI, NH3) in/e 505 Anal calcd for 032H44N203: C, 76.15; H, 8.79; N 5.55.

Found: C, 75.96; H, 8.75; N, 5.36.

Exml 372 20 trans. rpns-2-(3.4-DifluorophenyI)-4-(1 .3-benzodioxol-5-yfl)-1-(N .Ndi(n-butyflaminocarbonylmethyl-yrrolidine-3-carboxyic 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 (CDCI3, 300 MHz), 8 0.83 J=7Hz, 3H), 0.811 J=7Hz, 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, 3.58-3.66 (in 3.94 (d, J=8Hz, 5.93 6.72 J=7.5Hz, 6.84 (dd, J=lHz, 6.98 J=7.5Hz, 1H), 7.08-7.15 (in, 7.22-7.28 (in, MS (CDI/NH3) in/e517 Example 373 trans, trans-2-(3 .4-Dif Iuoroph enyfl)-4-( 1.3-be nzodioxol-5-yi)- 1 -f 2- (Npropyl-N-n-pentanesulfonylaino~ehyllpyrrolidine-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 OC. 1H NMVR (CDCI3, 300 MHz) 8 0.82 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.25-1.38 -390- (in, 4H), 1.46 (sextet, J=7Hz, 2H), 1.74 (quintett, J=7Hz, 2H), 2.26-2.36 (in, 1H), 2.72-2.95 (in, 5H), 2.98-3.12 (in, 211), 3.15-3.34 (in, 2H). 3.45 (dd, J=3Hz, J=9Hz, 1H), 3.53-3.60 (in, IH), 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 (mn, 2H), 7.23-7.34 (mn, 1H). MS (CDI/NH3) m/e567 Exam~le 374 trans, trans-4 Be nzodioxo I-5-yl) -2 -(eth oxyn ethyl)- 1 .N-d i(nbutyl) aino carbonyl meth l)-pyrrol idin e-3--a rboxli c acid Using the procedures described in Example 1, the title compound was prepared. TLC (10% MeOH-CH2CI2) Rf 0.53. 1 H NMR (CDC13, 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 15 2.80-3.08 (in, 2H total), 3.10-3.82 (br mn, 12H), 4.03 (in) and 4.22-4.45 (br in, 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) Wne 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.

trans, trans-4-(1 .3-Benzodioxol-5-yl-2-(l-butyl)-I di(n-butyflaminocarbonylmethyl-pyrrolidine-3-arboxylic acid wasUsing the procedures described in Example 1, the title compound wasprepared and isolated as a colorless wax. TLC (10% MeOH-CH2CI2) Rf 0.37. 1H NMR (CDCI3, 300 MHz, rotameric forms) 8 0.71 J=7Hz) and 0.77-1.05 (in, 9H t otal), 1.05-1.20 (mn, 2H), 1.20-1.72 (br mn, 13H), 2.48-2.52 1H), 2.87-3.00 (in, 1H), 3.05-3.60 (mn, 5H), 3.60-3.80 (br in, 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) W/e 461 Anal calcd for C26H40N2O5 1.75 H20: C, 63.45; H, 8.90; N, 5.69.

Found: C, 63.18; H, 8.22; N, 5.60.

-391- Example 376Q trans. trans-4-(l .3-Benzodioxol-5-vl)-2-(2-mlethylbutyfl-1 -(N.N-di(nbutflaminocarbonylmethy)-2rrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a colorless glass. TLC (10% MeOK- CH2CI2) Rf 0.49. 1 H NMR (CDCI3, 300 MHz, rotamneric forms and mixture of diastereomers) 8 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 total), i0 6.67-6.90 (in, 3H total). MS (FAB) W/e 475 Example 37.

*trans. trans-4-(1 Benzod! oxol methylbutyl -l1 N-d ijn- **.butyl~aminocarbonylmethl)-pyrrolidine- 3-carboxylic acid Is Using the procedures described in Example 1, the title compound was prepared. TLC (10% MeOH-CH2CI2) Rf 0.41. 1H NMR (CDCI3, 300 M~z roameicforms) 8 0.73 J=7Hz) ad0.77-1.05 (mn, 12H total), 1.07-1.75 (in, approx. 14H plus H20), 2.48-2.63 (mn, 1K), 2.87-3.05 (in, 1H), 3.05-3.60 (several br in, 5H), 3.62-4.02 (br in, 2H), 4.29 (b'r d, J=l5Hz, 1H), 5.89 and 5.93 2H total), 6.65-6.90 (in, 3H total). MS (FAB) m/e 475 25 trans, trpns-2-(4-Methoxyphenyl)- 4 .3-benzodioxol-5-yI L-l -r2-(LN- 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 1 H NMR (CDCI3, 300MHz) 5 0.78 J=7Hz, 0.90 J=7Hz, 3K), 1.27 (sextet, J=7Hz, 2H), 1.48 (in, 4H), 2.22-2.30 (in, 1H), 2.62 3H), 2.68-2.78 (in, 1H), 2.84-3.03 (in, 5H), 3.08-3.31 (in, 3H),3.39 (dd, J=3Hz, J=9Hz,1H), 3.50-3.58 (in, 1H), 3.63 J=9Kz, 1H),3.79 3H), 5.95 2H), 3.73 (d, J=8Hz, 1H), 6.83 (dd, J=2Hz, J=8Kz, 3.87 J=9Hz, 2H), 7.01 (d, J=2Hz, 1K), 7.33 J=9Hz, 2H). MS (DCI/NH3) m/e 576 -392- Example 379 trans, trans-2.4-Di(3 .4-difluorophefl)f- 1 -(N.N-di(nbutyflaminocarbonylmethyl-yrrolidifle3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300MHz, CDC13 8 7.35 (2H, in), 7.18 mn), 4.87 (1H, d, J=12), 4.00-3.60 (5H, mn), 3.60-3.10 in), 3.10-2.90 (2H, in), 1.45 (2H, mn), 1.29 (4H, in), 1.15 in), 0.91 (3H, t, 0.83 (3H, t, MS (DCI/NH3) mWe 509 Anal calcd for C27H32F4N2O3- 0.75 TFA: C, 57.62; H, 5.56; N, 4.72. Found: C, 57.72; H, 5.67; N, 4.66.

trans, trans-4- (3.4-Dinethyl 1h enl)-2-(4-m eho xyVh enyl)Il N-d i(nbutyl',aminocarbonylmethl)-12rrolidile-3-carboxlic- 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 d, J=18), 4.16 in), 3.83 (2H, mn), 3.81 s), *:3.56 (1H, bd, J=18), 3.37 in), 3.20 (1H, mn), 2.96 in), 2.24 (3H, 2.22 (3H, 1.47 (2H, mn), 1.27 (4H, in), 1.10 (2H, in), 0.93 (3H, t, 0.81 t, MS (DCI/NH3) Wne 495 Anal calod for C30H42N2O4- 1.25 TFA: C, 61.26; H, 6.84; N, 4.40. Found: C, 61.16; H, 7.05; N, 4.38.

:Example 381trans, trans-2.4-Di(3-fluoro-4-nethoxylhenl)l 1 -(N.N-di(nbutyI)aininocarbony)ethyl)-pyrrolidife3carboxY-ic -acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300MHz, CDC13 8 7.20 (2H, in), 7.17 (2H. in), 6.93 (2H, in), 5.48 (1H, in), 4.26 (1H, mn), 4.16 (2H, in), 3.83 (2H, in), 3.87 3.56 (1H, in), 3.37 (1H, in), 3.20 (1H, in), 2.96 (2H, in), 1.47 (2H, in), 1.27 (4H, in), 1.10 in), 0.93 (3H, t, 0.81 (3H, t, MS (DCI/NH3) W/e 533 Anal calcd for C 2 9H38F2N2O5- 0.75 H20: C, 63.78; H, 7.29; N, 5.13. Found: C, 63.77; H. 7.08; N, 4.99.

-393- Examlle 382 trans, trans-4-(l .3-Benzodioxol-5-yl)-2-(4-methoxyo~henyl)-1 pentyl).N-(3-methylphenyl)amino)carbonyl)methylpyrrolidine3.

carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 860.90 (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 (in, 2H), 3.32-3.62 (in, 2H), 3.77-4.08 (in, 1H), 3.80 3H), 4.71 (in, 1H), 5.92 (mn, 2H), 6.61-6.84 (in, 6H), 7.04-7.16 (mn, 3H), 7.23-7.29 (in, 2H). MS (DCI) mn/e 559 Anal calcd for C33H38N206 0.35 H20 -0.05 CH3CO2C2H5: C, 70.03; H, 6.92; N, 4.92.

**.*Found: C, 70.08; H, 6.82; N, 4.95.

trans. trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-methoxyohenyfl)-1-(Nbutyl-N-(l1-naphthyflaiinocarbonylmethylb1vrrolidine-3-carboxyIc 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 (mn, 2.85-4.00 (mn, 6H), 3.77 J=1.5 Hz, 3H), 4.05-4.20 (mn, 1H), 5.94 J=2 Hz, 2H), 6.6 (dd, J=9, 10 Hz, 1IH), 6.70-6.85 (in, 4H), 6.95-7.02 (mn, 2H), 7.17 (dd, 8H, 7.25 (dd, 8H, 7.38-7.60 (mn, 4H), 7.87-8.00 (in, 2H). MS m/e 581. Analysis calcd for C35H36N206 1.4 H20: C, :25 69.38; H, 6.45; N, 4.62. Found: C, 69.36; H, 6.07; N, 4.41.

Example 384 trans-trans-2-(4-Methoxyphenyl)-4- 1 .3-benzodioxol-5-yl'h -F2-(N- Dhe nvl -N-n-he xanesulf on yl amin o',th yllpyrroli din e-3-ca rboxyl ic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a tan solid. in.p. 67-68. OC. 1 H NMR (CD3OD, 300 MHz) 6 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 (mn, 3H), 3.02 (sextet, J=8Hz, 2H), 3.44-3.53 (in, 2H), 3.58 J=9Hz, 3.56-3.75 (mn, 1H), 3S 3.78 3H), 3.88-3.98 (mn, 1H), 5.93 2H), 6.72 J=9Hz, 1H), 5.78- -394- 5.84 (in, 3H), 6.96 J=2Hz, 1H), 7.20 J=9Hz, 2H), 7.27-7.36 (in, MS (DCI/NH3) in/e 609 trans, trans-4-(l .3-Benzodioxol-5-yfl-2-(4-nethoxyphenfl) 1 2 m ethyl-i .2.3.4-tetrahydrog ulfloli n-l1 -flcarbonylmethyl~pyrrolidifle-3carboxyvLic aci*d Using the procedures described in Example 1, the title compound was prepared. I 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 (s,1.511), 3.77 isomer), 5.90 2H), 6.70-7.40 (in, 1 1H). MS (DCI) m/e 529 Analysis calcd for C31H132N206 0.3 H20: C, 69.73; H, 6.15; N, 5.25.

Found: C, 69.74; H, 6.10; 5.0 1.

Example 386 butvl-hept-2-efl-l -vlyrrolidine-3-carboxylic acid :Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD300) 8 0.86 J=7.0 Hz, 3H), 0.90 J=7.0 Hz, 3H), 1.20-1.41 (mn, 1.95-2.06 (in, 4H), 3.24 J=1 Hz, 1 3.51-3.59 (in, 3H1), 3.60-3.71 (in, 1 3.77-3.84 (in, 1 3.81 3H), 4.45 J=11.0 Hz, 1H), 5.52 J=7.4 Hz, 1H), 5.93 2H), 6.77 J=8.1 Hz, 1H), 6.87 (dd, J=1.8, 8.1 Hz, 1H), 6.99 (in, 3H), 7.46 (in, 2H).

MS (DCI) W/e 494 Anal calcd for C30H39N05: C, 72.99; H. 7.96; .:25 N, 2.84. Found: C, 72.73; H, 7.89; N, 2.64.

Example 387 trans, trans2(3Fluoro-4-mfethoxyphefnyD- 4 .3-bendiXll' 1-f-N rp lNr-ex n s lo ya ioehylyrld~carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 63-65 1 H NMR (CDCI3, 300MHz) 8 0.82 J=7Hz, 3H), 0.88 J=6Hz, 1.23-1.47 (in, 6H). 1.44 (sextet, J=7Hz, 2H), 1.71 (quintet, J=6Hz, 2H), 2.24-2.34 (in, 1H), 2.70-2.93 (mn, 5H1), 2.96-3.12 (mn, 3.15-3.35 (in, 2H1), 3.43 (dd.

J1-17 I=qHz. 3.52-3.59 (in. 1H), 3.66 J=9Hz, 111), 3.87 3H), -395- 5.95 2H), 6.74 J=8Hz, 1H), 6.82 J=8Hz, 1H), 6.42 J=8Hz, 1H), 6.96 1 7.12 J=9Hz, 1 7.17 J=l 2Hz, 1 MS (DCI/NH3) mWe 593 Example 388 trans, trans-4-(l .3-Benzodioxol-5-yl)-2-(4-methoxyvohenfl)- 1 pyridvlimethl)Dyrrolidine-3-carboxylic 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=3.2, 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, 7.83H), 6.94 (in, 3H), 7.36-7.45 (mn, 3H), 7.81 (mn, 1H), 8.39 (in, 1H), 8.46 (dd, J=1.4 *Hz, 1H). 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.

.15 f rans. trans- 2 He xyl) .3-benzodi oxol- 5-yi)- 1 N-difrib butyflainocarbonyl methyl)- oyrroli din e-3-ca rbo xylic acid 20Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CDCI3, 300 MHz) 6 0.82-1.00 (in, 9H), 1.20-1.40 (in, 12H), 1.45-1.60 (in, 4H), 1.70-1.90 (br in, 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 (mn, 2H), 4.14- 4.34 (mn, 5.94 2H), 6.73 J=8.1 Hz, I1H), 6.79 (dd, J=8.1, 1.8 Hz, 1 6.87 J=1.8 Hz, 1H). MS(DCI/NH3) Wne 489 Anal calcd for C28H44N205 0.9 TFA: C, 60.53; H, 7.65; N, 4.74. Found: C, 60.62; H, 7.69; N,'4.61.

Exainole 390 trans, trpns-4-(1 .3-Benzodioxol-5-yl)-2-(4-methoxyphenyfl- 1 pent vi)- N-(4-flu oro -3inethylphenyl)amino)carbonyflmethylkpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.92 (mn, 3H), 0.97 J=7.1 Hz, 3H), .1.13-1.40 (mn, 4H), 2.22 (in, 2.58-2.74 (in, 1H), 2.78-2.87 3 5 (mn, 1H), 3.09-3.25 (in, 2H), 3.39-3.60 (in, 2H), 3.70-3.90 (mn, 1H), 3.80 3H), 4.70 (mn, 1H), 5.93 (in, 2H), 6.70-6.76 (mn, 1H), 6.75 (dd, J=1.4, -396- 8.1 Hz, 1H), 6.80-6.94 (in, 4H), 6.96-7.13 (in, 4H1). MS (DCI.) m/e 577 Anal calcd for C33H37FN206 0.25 H20: C, 68.20; H, 6.50; N, 4.82. Fou nd: C, 68.21; H, 6.46; N. 4.74.

Examla 91 trans. trans-74-(l .3.Benzodioxol-5-ylV-24-methoxyphenvl)- 1 pyridyl~methyflDprrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 5 2.97 (dd, J=7.9, 9.7 Hz, 1 H).

3.04 J=9.6 Hz, 1H1), 3.18 J=4.4 Hz, 9.9H), 3.47 J=14.0 Hz, I1H), 3.59 (mn, 1H), 3.78 3H), 3.96 J=9.9 Hz, 1H), 3.97 J=13.6 Hz, 1H1), 5.90 (mn, 2H), 6.73 J=8.1 Hz, 1 6.83 (dd, J=1.7, 7.9 Hz, I1H), 6.92 (in, 2H), 6.96 J=1.8 Hz, 1H), 7.28 (in, 1H1), 7.44 (mn, 2H), 7.53 J=8.1 Hz, 1H1), 7.80 (dt, J=1.8. 7.7 Hz, 1H), 8.42 (in, MS (DCI) W/e 433 is 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.

Example 392 trans, trans 2 (3Pheylolro 1 -4 1 3bnodioxolr--N-1(N.

di(n-butyl)aminocarb nlylmnethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. IH NMR (CDC13, 300 MHz) 8 0.89-0.97 (mn, 611), 1.22-1.36 (in, 4H), 1.41-1.55 (in, 4H1), 1.63-1.95 (in, 4H), 2.62 (dt, J=7.2, 2.1 Hz, 2H), 3.05-3.44 (mn, 7H), 3.53-3.60 (in, 2H), 3.65-3.76 (in, 1H), 3.82-3.90 *.25 (in, 1H), 3.96-4.10 (in, 1H), 5.92 6.71 J=8.1 Hz, 1H), 6.77 (dd.

J=8.1, 1.5 Hz, 1H), 6.86(d, J=1.2 Hz, 1H), 7.10-7.28-(M, MS(DCI/NH3) mle 523 Anal calcd for C31H142N205 0.6 TFA: C, 65.43; H, 7.26; N, 4.74. Found: C, 65.28; H, 7.29; N, 4.50.

Eamle 393 trans-trals-2-( 4Methox-3fluorphenyl'4(7methoQxy-l 3- 1-(N.N Nii(n-butyflpimifocarbonylinethy-L- Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. in-p. 115-117 OC. 1H NMR (300 MHz, CDC13) 5 0.82 J=7Hz, 3H), 0.88 J=7Hz, 3H). 1.05-1.5 (in, -397- 8H), 2.85 J=l3Hz, 1H), 2.90-3.17 (in, 5H), 3.20-3.35 (in, 1H), 3.35- 3.50 (in, 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, 1H), 7.05-7.20 (in, 2H).

Example 394 trans-trans,-2-(l .4-Benzodioxan-6-yfl-4-(7-methoxy-1 .3-benzodioxol- 5-vI)-l1-(N .N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 107-110 1 H NMR (300 MHz, CDCI3) 8 0.82 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.50 (mn, 8H), 2.75 J=l3Hz, 1H), 2.90-3.12 (in, 4H), 3.32-3.60 (in, 5H), 3.69 J= 8Hz, 1H), 3.90 3H), 4.23 4H), 5.95 (dd, J=4Hz, 2Hz, 2H), 6.62 1H), 6.70 1H), 6.78-6.93 (m ,3H).

Example 395 trans, trans-4-(1 .3-Benzodioxol-5-vl)-2-(4-methoxvlhenyl)- 1 .:butyl-2-fluoro-hept-2-en- 1-yl)o2yrrolidine-3-carboxylic acid 20 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.84 J=7.0 Hz, 3H), 0.88 V*AG J=7.0 Hz, 3H), 1.16-1.37 (mn, 8H), 1.83 J=8.5 Hz, 2H), 2.03-2.08 (in, 2H), 2.76-2.92 (in, 2H), 3.02 J=9.3 Hz, 1 3.32-3.42 (in, 2H), 3.50 (in, 1H), 3.71 J=9.2 Hz, 1H), 3.78 5.91 (in, 2H), 6.72 J=7.8 Hz, 1H), 6.83 (dd, J=1.7, 8.1 Hz, 1H), 6.90 (mn, 2H), 7.02 J=1.7 Hz, I1H), S. 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.

Examp~le 396 trans2.trans-2-(3-Fluoro-4-ethoxyphenylI-4-(1 .3-benzodioxol-5-yl)-1 -1ropyl-N-rn-Dentanesulfonylami no~ethyllpyrrolidine-3-carbxylic Using t he procedures described in Example 66, the title compound was prepared and isolated as a white solid.. i.p. 65-66 OC. 1H NMR (CDCI3, 300 MHz) 5 0.82 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.26-1.36 (mn, 4H), 1.41-1.52 (in, 5H), 1.73 (quintet, J=7Hz, 2H), 2.23-2.33 (mn, 1H).

-398- 2.69-2.96 (in, 5H), 2.97-3.12 (in, 2H), 3.16-3.37 (in, 2H), 3.43 J=9Hz, 1H), 3.52-3.59 (mn, 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 (s, 1H), 7.07 J=8Hz, 1H), 7.15 J=l2Hz, 1H). MS (DC VNH3) mn/e 593 Example 397 trans, trans-2-(4-Methoxy-3.fluorophenl)f-4(7-methoxy-1 3.

-f(N-butyA-Npropylainfo'~carbonylinethyllpyrrolidifle-3-carboxlic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. rn.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), is3.92 3H), 5.96 2H), 6.62 1H), 6.70 1H), 6.90 J=8Hz, 1H), 7.08-7.22 (in, 2H).

Examape 398 .trans, trans-4 .3 -be nzo dio xo I -5-yi-2- (4 -et hoxyphenyl) 20 butyl-N..(4..chlorophenylainocarboylethylliDyrrolidine- 3 carboxylic. acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 5 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 25 Hz, 1H), 6.85 J=8 Hz, 3H), 7.05 (in, 5H), 7.33-7.42 (mn, 2H). MS (0.1, ine 565 Analysis calcd for C31H33N206CV 0.25 H3P04: C.

63.16; H, 5.77; N, 4.75. Found: C. 63.14; H, 5.59; N, 4.53.

trpnstrpns-4-(1 .3.Benzodioxol..5.yI)-2-(4-methoxyVhen~y!L.. m ethyl-i1 .2.3.4-tetrahydr oin~lnl.v~abnlehfDr~iie carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 8 1.27 J=7 Hz, 1.5H), 1.28 7H, 1.5-diastereomer), 1.39-1.55 (in, 1H), 2.02-2.15 (in, 1H), 2.60- 3.25 (mn, 3.33-4.00 (mn, 3.78 3H)i, 5.92 .j=3 Hi 212), 5W.72 -399.

(dd, J=8 Hz, 1H1), 6.75-6.90 (in, 3H), 6.91-7.35 (in, 7H). MS (DCI) W/e 529 Analysis calcd for C31 H32N2Oa.: C, 70.44; H, 6.10; N, 5.30.

Found: C, 70.16; H, 6.04; N, 5.04.

ExaDmpJe 400 trans, trans-2-(3-Fluoro-4-methoxyghenyl)-4-(1 1 -r2-(N-propyl-N-(2-(piperidin-1 yflethanesulfonyaminoethyllpyrrolidine-3-carboxylic acid Using the procedures described-in Example 66, the title compound was prepared and isolated as a white solid. rn.p. 5-96 OC. 1H NMR (CDCI3, 300MHz) 8 0.82 J=7Hz, 3H), 1.43-1.55 (in, 4H), 1.63-1.72 (in, 4H), 2.29-2.38 1H), 2.64-2.78 (in, 5H), 2.87 J=8Hz, 1IH), 2.95-3.04 (in, 5H1), 3.20-3.30 (in, 1H), 3.32-3.43 (in, 4H), 3.54-3.63 (nm, 1H), 3.78 J=8Hz, 1 3.87 311), 5.92 2H), 6.72 J=8Hz, 1 6.78 (dd, J=2Hz, J=8Hz, 1H), 6.88 J=8Hz, 111). 6.94 J=2Hz, 1H), 7.08-7.20 (in, 2H). MS (DCI/NH3) in/e 620 Exampie 401 **trans. trans- 2 (-Hpptyfl-4-( 1.3-benzodioxol-5-yfl-l1 -(N.N-di(nbutyl)aininocarbonylmethy)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. IIH NMR (CDCI3,. 300 MHz) 8 0.83-0.98 9H), 1.18-1.40 (mn, 14H), 1.44-1.60 (in, 4H), 1.72-1.96 (br mn, 2H), 3.12-3.45 (in, 6H), 253.65 J 10.5 Hz, 1IH), 3.76 J =11.2 1H1), 3.90-4.06 (mn, 2H). 4.13- 4.33 (in, 2H1), 5.93 2H), 6.73 J =7.8 Hz, 1 6.79 (dd, J 7.8, 1.7 Hz, 1IH), 6.87 J 1.7 Hz, 11H). MS(DCI/NH3) Wne 503 Anal calcd for C29H46N205 0.75 TFA: C, 62.28; H, 8.01 N, 4.76. Found: C, 62.20; H, 7.99; N, 4.50.

Example 402 trans. trans-4-(1 .3-Benzodioxol-5-yl')-2-(4-methoxyohenyl)l1 mnethyl-i .2.3.4-tet rahyd roauinolil- 1 yl carbo nylm ethyl yrrolidine9- 3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. IH NMR (300 MHz, CD3OD)" 60.99 1.5H), 1.03 J=6 Hz, 1.5H, second diastereomer), 2.60-4.00mn 3.78 1.5H1), 3.79 (s, -400second diastereomer), 5.92 1H), 5.93 IH, diastereomer), 6.65-7.40 (in, 11H). MS (DCI) m/e 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. trpns-4-(1 .3-Benzodi oxol-5-yfl-2-(4-methoxylhenfl)- 1 butyl-N-(4-fluorophelylanocarboflylmethyl~ pyrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.2-1 .47 (in, 4H), 2.7 J=1 2 Hz, 1 2.80 J=9 Hz, 1 3.09 J=9 Hz, 1 H), 3.25 J=15 Hz, 1H), 3.40-3.47 (in, 1H), 3.49-3.65 (in, 3H), 3.75 (d, J=12 Hz, 1H), 3.80 3H), 5.94 2H), 6.72-6.86 (in, 4H), 7.00-7.15 (in, 7H). MS (DCI) Wne 549 Analysis calcd for C31 H33N206F 0.4 H20: C, 66.99; H, 6.13; N, 5.04. Found: C, 66.99; H, 5.94; N, 4.99.

:Example 404 trans, trans -1 BtlN 3me yp nl m cronlmty)-: (4-methoxyphenvfl)4-(5-benzofuranlIrhrrlidine 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 (2H, 7.15 (4H, in), 6.75 (5H, in), 3.96 (1H, d, J=lOHz), 3.78 (3H, 3.74 (1 H, in), 3.59 (3H, nm). 3.21 (1 H, t, J=9Hz), 3.19 (1 H, *25 d, J=l6Hz), 2.92 (1H, t, J=9Hz), 2.70 (1H, d, J=l6Hz), 2.29 (3H, s), 1.41 (2H, in), 1.24 (2H, in), 0.85 (3H, t, J=7Hz). MS (DCI, NH3) Wne 541 Anal. calcd for C33H34N20 -1 H20: C, 71.21; H, 6.52; N 5.03.

Found: C, 71.31; H, 6.30; N, 4.98.

Example 405 trans. trans-1 -(-uy--3mtylhnlaioabnl tL-- (4-fluoropheny)-4-(5-benzofuravl)D~vrrglidife3carbgxyli- acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz. CDCI3) 5 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), U AIH P, .37)6 hd). 4.02 (1H, in), 3.77 (1H, in), 3.59 (3H, -401in), 3.29 (1 H, mn), 3.19 (1 H, mn), 2.94 (1 H, mn), 2.71 (1 H, in), 2.30 (3 H, 1.45 (2H, mn). 1.26 (2H, sext, J=7Hz), 0.84 (3H, t, J=7Hz). MIS (DCI, NH3) mle 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-( 1.3-Benzodioxol-5-yfl-2-(4-methoxyphenyll- 1 N- (di-(3-m ethyl heny) aminocarboyl)'Methyfllyrrolidin e-3-carboxyl ic Using the procedures described in Examplel1, the title compound was prepared. 1 H NMR (300 MHz, CD300) 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 (mn, 3H), 3.80 3H), 3.85 J=9.5 Hz, 1 5.91 2H), 6.73 J=7.8 Hz, 1H), 6.85 (in, 3H), 6.95 (in, 4H), 7.05 J=1.7 Hz, 1H), 7.06-7.24 (in, 156H). MIS (DCI) in/e 579 Anal calcd for C35H34N206 0.15 H20 0.20 CH3CO2C2H5: C, 71.79; H, 6.04; N, 4.68. Found: C, 71.81; H, 5.79; N, 4.5 1.

Example 407 trans, trans-4-(1 .2-D ihyd roben zof uran-5yl -2 -(4-methoxyph enyl)~ Usng te pocedrescarboxylic acid Usn h poeue described in Example 1, the title compound was prepared. I H (300MHz, CDC13 8 7.73 in), 7.40-7.10 (4H, in), 6.92 (2H, m),.6.72 (2H, d, 6.63 (1 H, in), 5.40 (1H, in), 4.55 (2H. t, 4.30-4.10 (3H, in), 3.84 (3H, 3.82 (1H, mn), 3.65 (1H, in), 3.39 (OH, mn), 3.21 (2H, t, 3.10-2.90 (2H, in), 2.26 (3H, 1.55 (2H, in), 1 .45 (2H, in), 0.92 (3H, t, MS (DCI/NH3) mWe 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.

-402- E x amnple -408 trans, trans-2-(3-Fluoro-4-methOxY h-nvl- 4 14~2-(N-prop (I-N-f2-(N.Ndi met hylam in o)1eth afesulf onl amino ethylpyrrol idi ne 3 carb oxyli c S acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 81-82 0 C. 1 H NMR (CDCI3, 300 MHz) 8 0.80 J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2 2.15- 2.24 (in, 1 2.36 6H), 2.66-2.76 (in, .1 2.83-3.04 (in, 6H), 3.18- 3.41 (in, 5H), 3.55-3.63 (in, I1H), 3.72 J=8Hz, 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, IH). MS (DCI/NH3) in/e 580 ExamIQ 409 trans. trans-I .N-Dibutylaminocarbonylmethyl) -2-(4-fluorophenylY7 ranyl~pyrrolidine.-3carboxylic acid :Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, 00013) 5 7.88 (1H, bs), 7.80 (2H. in), 7.61 (1H, d, J=3Hz), 7.55 (1 H, bd, J=8Hz), 7.46 d, J=8Hz), 7.07 (2H, t, J=8Hz), 6.76 (1 H. d, J=3Hz), 5.53 (1IH, bd, J=1l1Hz), 4.18 (2H, in), 3.91 (3H, in), 3.55 (1H, d, J=l6Hz), 3.30 (3H, in), 3.12 (1H, dd, J=10&9Hz), 2.95 (1H, in), 1.51 (2H, mn), 1.31 (4H, in). 1.12 (2H, in), 0.92 (3H, in), 0.83 (3H, t. J=7Hz). MS m/e (DCI, NH3) 595 ExaMpLe 410 trans, trafls-4-(l 2Dihdrobenzofuran5y)2-(4-ethylphenyl.)-1 butyl-N-(3iehlhnlaI no.carbonyl)inethyflDprrolidine- 3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, 0DC13 8 7.35 (2H, in), 7.20-7.00 (7H.

mn), 6.70 (2H, d, 5.38 (1H, in), 4.55 (2H, t, 4.05 (1H. in), 3.64 (2H, in), 3.45 (1 H, in), 3.21 (2H, t, 2.95 (1 H, in), 2.75 (1 H. 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 (DCl/NH3) m/e 541 Anal -403calcd for C34H40N204 .1.6 AcOH: C, 70.17; H, 7.34; N, 4.40. Found: C, 70.11; H, 7.06;, N, 4.80.

Exampe 411 trans, trans-4(1 .2-Dihydrobenzof uran-5-yl)-2-(4-fluorophenyl)- 1 (N.N-di(n-butyflaminocarbonylmethyl)-Dyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CDC13 857.40 in), 7.28 (1 H, bs).

7.18 (1 H, dd, J=8, 7.00 t, 6.72 (1 H, d, 4.53 (2H, t, 1o 3.92 (11H, in), 3.65 in), 3.42 in), 3.19 t, 3.15- 2.90 (6H, in), 1.43 (3H, in), 1.25 in), 1.10 (2H, in), 0.90 (3H, t, J=8), 0.83 (3H, t, MS (DCI/NH-3) mWe 497 Anal calcd for ~:C29H37FN204 0.2.5 H20: C, 69.51; H, 7.54; N, 5.59. Found: C, 69.45; H, 7.60; N, 5.44.

Exml 4..2 trans, trans-4-(1 .2-Dihydrobenzofuran-5-yfl-2-(4-fluoroohenYfl-1 (((N-bUtyl-N-(3-methyl 12henyfl)amino) carbonyl)methyl) 1yrrol idine-3 carb2oxyjlic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.28 (1 H, bs), 7.25-7.00 (51-, 6.91 in), 6.72 (3H, d, 4.54 t, 4.00 (1 H, mn), 3.60 (3H, 3.45 (1 H, in), 3.19 (2H, t, 3.11 in), 2.84 in), 2.67 (1H, bd, J=18), 2.26 (3H-1s), 1.42 in), 1.25 (2H, Mn), 0.88 (3H, t, J=8).

:25 MS (DCI/NH3) m/e 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-;y l-2-(4-m ethoxyohenyfl)-1-(N. N-di(ributyl~aminocarbonylmgthyl)-ovrrolidine-3-carboxylic acid .Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.32 in), 7.18 (2H. in), 6.85 (2H, d, 3.83 (1H-1 in), 3.79 3.67 (11H, in), 3.50-3.20 (4H-, in), 3.20-2'.92 (41-1, in), 2.87 (5H, in), 2.79 bd, J=15), 2.06 (2H, in), 1.43 (2H, mn), 1.27 in), 1.08 mn), 0.88 t, 0.82 (3H. t, -404- MS (DCI/NH3) W/e 507 Anal calcd for C31H42N204: C, 73.49; H, 8.36; N, 5.53. Found: C, 73.18; H, 8.29; N, 5.17.

Example414 trans. trn72(-ehx ~ey)4(.-iluoroo~henyl).'l -r(N-butylmet hl 1henylami nIc rbonyl met hyI12rrol id n e- 3 carbo xylic ai Using the procedures described in Example 1, the title compound was prepared. IH NMR (300MHz, CDCI3) 5 0.86 J=7Hz, 3H), 1.10-1.35 (in, 2H), 1.35-1.52 (mn, 2H), 2.29 3H), 2.63 J=13Hz, 1H), 2.76 (t, *J=7Hz, 1 3.06-3.20 (in, 2H), 3.42-3.53 (in, 1H), 3.50-3.64 (in, 3H), 3.80 3H), 3.86 J=9Hz, I1H), 6.66-6.82 (in, 4H), 7.02-7.22 (in, 6H), 7.30-7.40 (in, 1H).

15 tran. trns-iExample 415 (4-f luoroghenyfl4-(5-belzof uranyl)pyrrolidine-3-carboxy ic -acid* Using the procedures described in Example 1, the- title compound was prepared. 1 H NMR (300 MHz, CDC13) 5 7.64 (1 H, d, J=2Hz), 7.61 (1 H, d, J=3Hz), 7.47 (1 H, d, J=8Hz), 7.41 (1H. dd, J=8&3Hz), 7.30 (1H, dt, 7.21 (1H1. 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=lOHz), 3.75 (1H, ddd, 6, 5&3Hz), 3.59 (3H, in), 3.23 (1H, t, J=lOHz), 25 3.18 (1H, d, J=l6Hz), 2.92 (1H, dd, J=10&9Hz), 2.69 (1H, d, J=l6Hz), 1.41 (2H, in), 1.23 (2H, in), 0.87 t, J=:7Hz). MS (DCl, NH3) 549, 551 Anal. calcd for C 3 1H30CIFN2O: C, 67.82; H, 5.51: N, 5.10.

Found: C, 67.43; H, 5.33; N, 4.78.

Exain~le 416 trigns, trans-4 Benz i x I- I)2(4-ethOXyvhonvl'l-(( carboxylic acid *Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDC13 8 (rotainer) 7.40-7.20 (5H, in), 7.13 (2H, in), 6.98 (2H1, in), 6.93-6.60 (7H1, in), 5.93 (1H, d, 5.88 (5.85) a, 4.90 15 .0 ('12A 11 l.1=15h.

-4 3.77 (3.73) (3H, 3.72 (1H, in), 3.60 (1 H, in), 3.53-3.20 (3H, mn), 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-(1 .2-Dihydrobenzofuran-5-yfl-2-(4-ethylghenyl)-1 (2-pentfl)- -(4-lU 3methylohenyllamino)carbonyl)iethYl~~Dyrrolidine 3 carboxyltc acid Using the procedures described in Example 1. the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.30 (1 H, bs), 7.20-7.00 .9 in), 6.87 (1H, in), 6.73 (2H, d, 6.57 (1H, in), 4.81 (1H, in), 4.55 (2H,.

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 (1H, in), 3.06 (1H, dd, J=15, 2.88 dd, J=11, 2.61 (2H, q, 2.59 (1H, in), 2.18 (3H, in), 1.40-1.10 (4H- mi), 1.22 (3H, t, J=9), 1.00-0.80 (6H, in). MS (DCI/NH3) Wle 573 Anal calcd for C35H41FN204 0.75 H20: C, 71.71; H, 7.31;, N, 4.78. Found: C, 71.56; H, :9 :7.33; N, 4.56.

Example 418 trans. trans-2-(4-MethoxphenYl- 4 -(l.3-benzodioxol-5-yfl-l1 -f 2-(Np pro pyl -N yri mindi nyl a m in oet hyl pyr ro idi ne3ca rbo xyLtc ai Ethyl 2-(4-inethoxyphenyl)-4-(l ,3-benzodioxol-5-YI)-(-2-(Np ropylamino)p ropyllpyrrolidine-3-carboxyl ate, prepared by the 25 procedures of Example 61B (300 ing), 138 mng of 2-broinopyriinidine, 99 and 150 mg of diisopropylethylanhine were heated at 95 OC 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 CH2CI2 and hydrolyzed with NaOH in ethanol/water to give mng of the title compound. 1 H NMR (300 MHz, CDCI3) 8 0.82 J=7Hz, 3H). 1.50 (sextet, J=7Hz, 2H), 2.15-2.30 (in, 1H), 2.75-2.97 (in, 3H), 3.40-3.55 (in 4H), 3.60-3.70 (in, 3H), 3.75 3H), 5.95 2H), 6.34 (t, J=4Hz, 1H), 6.65 J=8Hz, iH), 6.75-6.82 (in, 6.78 J=9Hz. 2H), 6.96 J=2Hz, 1H), 7.27 J=9Hz, 2H), 8.20 J=4Hz, 2H).

-4 06- Examgle 419 trans, trans-4-(l .3-Benzodioxol-5-yll2-4-meh_ x phel)-1 bUtyl-2-chloro-he -2-efl- ilDvrrnlidline-3-carbOX-iC aci Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD300) 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 (mn, 2H), 2.17-2.23 (in, 2H), 2.78 (dd, J=6.6, 9.2 Hz, 1H), 2.95 J=9.2 Hz, 1H), 3.32-3.37 (in, 2H), 3.49 (in, 1 3.70 J=9.2 Hz, I1H), 3.77 3H), 5.91 (in, 2H), 6.72 J=8.1 Hz, 1 6.85 (dd, J=1.9, 8.1 Hz, 1 6.89 (in, 2H), 7.08 (d, 1o J=1.5 Hz, 1N), 7.36 (mn, 2H). MS (DCI) m/e 528 Anal calcd for C30H38ClNO5 0.25 H20: C. 67.66; H, 7.29; N, 2.63. Found: C, 67.62; H, 7.18; N, 2.40.

E..rnnl. 420Q *is trans. trans-4-(l -iyrbnofrn5yl2(-mtoyhnl- .:(((N-(2-oentyfl-N-(4-flmprp- 3 methylphenyllaino~carbonYflinethyI'1Dyrroidine3-carboxylic acid wasUsing the procedures described in Example 1, the title compound wsprepared. 1 H NMR (300 MHz, CDC13 5 7.28 (1N, bs), 7.15 (3H, in), 6.90 (1 H, in), 6.77 (2H, dd, J=9, 6.71 (2H, d, 6.56 (1 H, in), 4.80 (1iH, in), 4.53 (2H, t, 3.92 (1iH, in), 3.79 3.60 (1 H, in), 3.45

V*.

(iN, in). 3.19 (2H, t, 3.18 (iN, in), 3.03.(1H, dd, J=15, 2.85 (1N, in), 2.55 (1H. in), 2.18 (3H, in), 1-40-1.05 (4H, in), 1.00-0.80 (6H, in). MS (DCI/NH3) m/e 575 Anal calcd for C 34 H39FN205 0.35 H20: C, :25 70.29; N, 6.89;, N, 4.82. Found: C, 70.37; H, 6.92: N, 4.30.

Example 421 trans. trans-4-(1.2Dhdoezfrn5y)?-4mto h c arboxyic aci Using the procedures described in Example 1, the title compound was prepared. I N NMR (300 MHz, CDC13 5 7.29 (1iN, d, 7.25-7.05 in), 6.98 (1iH, bs), 6.80 (2H, in), 6.72 (2H, d, 4.53 (2H, t, J=9), 3.85 (1H, d, J=10), 3.79 3.58 (3H, in), 3.42 (iN. dd, J=10, 3.18 (4H, mn), 2.87 (1N, in), 2.66 (iN. in), 1'.40 (2N, in), 1.25 (2H. in), 0.86 (3N, Page(s) were not lodged with this application -4 08in), 6.95 (3H, mn), 6.82 (1H, bd, 6.73 (1H, d, 4.55 (2H, t, J=9), 3.92 (1H, bd, J=11), 3.60 (3H, mn), 3.43 (1H, dd, J=9, 3.21 (2H, t, J=9), 3.16 (2H, in), 2.87 (1H, mn), 2.69 (1H, in), 1.42 (2H, in), 1.26 (2H, in), 0.87 (3H, t, MS (DCI/NH3) Wne 551 Anal calcd for C31 H32CIFN204 .0.25 H20: C, 67.02; H, 5.90; N, 5.04. Found: C, 66.98; H, 5.71; N, 4.76.

trans. trans-4-(l .2-Dihyd robe nzof uian 5fl5 -2-(4-ethyl phpny]L'-l Using the procedures described in Example 1, the title compound .was prepared. 1 H NMR (300 MHz, CDC13 5 7.30 Q-lH, in), 7.21 (1 H, d, 7.15 (2H, in), 7.09 (4H, bs), 6.96 (1H, bs), 6.80 (1H, bd, 6.73 0*15 (1H, d, 4.54 (2H, t, 3.89 (1H, bd, J=11), 3.60 (3H, in), 3.43 (I1H, in), 3.22 (2H, t, 3.18 (2H, in), 2.92 (1 H, in), 2.72 (1 H, in), 2.62 (2H, q, 1.41 (2H, in), 1.26 (2H, in), 1.23 (3H, t, 0.87 (3H, t, MS (DCI/NH3) Wne 561 Anal calcd for C 3 3H37ClN2O4 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 -(-uy--3clrpey~abxmdmt i--C inethoxy h 1 -benzfura ~~Proiiecrbovic acid Using the procedures described in Example 1, the title compound 025 was prepared. 1H NMR (300 MHz, CDC13) 5 7.67 (1 H, 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 O1H, d, J=lOHz), 3.75 (1H, ddd, J=6, 5&3Hz), 3.59 (2H, in), 3.53 (1H, dd, j=10&3Hz), 3.22 (1H, t, J=9Hz), 3.19 (1H, in), 2.96( 1H.

in), 2.70 O1H, d, J=l6Hz), 1.42 (2H, in), 1.26 (2H, in), 0.87 (3H. t, J=7Hz). MS (DCI, 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.

-409- Example 427 trans, trans-4-'(1 .3-Benzodioxol-5-yl-2-(4-methoxyv-hel)- 1 cyclohexyl-N-butlamino)carbonfl~fmethy)yrrolidile-3-carboxylic Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) (rotamer) 6 0.78 (0.86) 3H, J=7H-z), 0.90-1.90 (envelope, 14H), 2.69 (2.80) 1H, J=l2H-z), 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 1H, J=6H-z), 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.

transtrans4-(1Example 428 tras. ras-4-(.3-Ben zoodioxol-5-yl'l-2 -ethvyl he nyfl-I (3 is me t hyl ph e nyfl-N -but yl a m in o)carbo n ylmeth yl)y rrol idin e- 3 -ca rb o xy ic Li Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 0.86 3H1, J=7H-z), 1.22 (t.

*:3H1, J=7H-z), 1.25 (in, 2H1). 1.43 (in, 2H), 2.26 3H), 2.6 2H, J=7H-z), 2.68 1H, J=l2Hz), 2.86 1H, J=8H-z), 3.19 2H1, J=7Hz), 3.44 (dd.

1H. J= 3Hz,lOHz), 3.59 (mn, 3H), 3.94 1H, 9Hz), 5.92 2H), 6.75 (in, 3H), 6.86 (dd, I1H, J= 2H-z, 8H-z), 7.08 (in, 6H), 7.17 1 H, J= 8Hz). MS (DC l/NH3) mWe 543 Anal. calc'd for C33H38N205 0.'60 H20: C, 2571.61;.H, 7.14; N, 5.06. Found: C, 71.57; H, 6.80; N, 4.87.

Example 429 trans, trans-4-(13en zof u ran -5-yll-2 -(4-eth ylhel)-1(((N 3 methylphenyl)-N-butylamino)carbonyl)iethylyrrolidife3- arboxm." Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 6 0.90 3H, J=7Hz), 1.30 (t.

3H, J=7H-z), 1.31 (in, 2H), 1.43 (in, 2H1), 2.27 3H1), 2.73 2H. J=7HZ).

3.15 2H, J=l7H1z), 3.61 2H, J= 8Hz), 3.82 (mn, 2H1), 4.00 1 H, 12H-z), 4.26 (in, 2H), 5.53 (br d, 6.54 (br s, 2H1), 6.76 1H, J= 2H1z), 7.14 (in, 3H), 7.28 1H), 7.40 (in, 3H1), 7.48 I1H, J= 8H1z), 7.63 I1H.

-4 J=2H1z), 7.73 1H). HRMS. calc'd for C 3 4H39N204 539.2910.

Found: 539.2891 trans. trans-!4-(l .4-1Benzodioxan-6-yfl-2-(4-ethllhefl~l~-1 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 0.87 Q, 3H, J=7Hz). 1.22 (t, 1o 3H, J=7Hz), 1.24 (in, 1.42 (in, 2H), 2.30 3H), 2.61 2H, J=7Hz), :.2.67 1IH, J=l4Hz), 2.86 1H, J= 8Hz), 3.18 2H, J=7H1z), 3.41 (dd, 1 H, J=4,lOHz), 3.59 (mn, 3H), 3.93 1H, J=lOHz), 4.25 (in, 4H). 6.74 (br s, 2H), 6.80 1H, J8BHz), 6.93 (dd, IIH, J=2Hz,8Hz), 6.99 1H, J=2Hz), 7.07 (in, 5H), 7.17 1H, J=8Hz). MS (DCI/NH3) mWe 557 Anal.

i calc'd for 034H40N205 -0.40 H20: 0, 72.42; H, 7.29; N, 4.97. Found: C.

72.49; H. 7.16; N, 4.62.

trans. trpns 2(3-Fluoro-4-mlethoxytphelyl)- 4 1.3-benzodioxl5yl 1 v- e iy n s lo ya io tylyrldn carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 80-82 OC. 1H NMR :(CDCI3, 300 MHz) 8 0.69 J=7Hz, 3H), 1.37 (sextet, J=7Hz, 2K), 2.09- 2.17 (in, 1K), 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 (in, 1 H), 3.57 J=9Hz, 1KH), 3.89 3H), 5.94 2H), 6.74 J=8Kz, 1KH), 6.78 (dd, J=2Kz, J=8Hz, 1H), 6.85 2K), 6.92 J=8Hz, 1K), 9.94 J=2Hz, 1 7.06 J=8Hz, 1KH), 7.13 (dd, J=2Hz, J=1l2Hz, I1H). MS (DCI/NH3) m/e 627 E xale 43 tra ns. tra ns-2-(4 -M et ho xyph e l) -4 -d if u oro phe n yfl-1 -LCN-bUtYFI

N-(

3 -chlorophenyl)amin ))carbQn mehYI o r rli i ne crbXlc a Using the procedures described in Example 1, the title compound ia 1 U KIKAD vi'Wn tEAH- rflo) 8 0.86 J=7Hz. 3H), 1.18-1.32 -411- (in, 2H), 1.35-1.48 (mn, 2H), 2.64 J=l3Hz, 1H), 2.71 J= 7Hz, 1H), 3.08-3.18 (mn, 2H), 3.42-3.48 (in, 1H), 3.53-3.64 (in, 3H), 3.77 3H), 3.80 J=9Hz, 1H), 6.73-6.85 (in, 3H), 6.94 1H), 7.04-7.40 (in, 7H).

Example 433 trans. trn--3Fuoo4mtoypey 4(.3-benzodioxol-5y- 1-(2(-rplN(-hoprgnsf onlai!)ty)2roiie3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. IH NMR (CD300, 300 MHz) 5 0.80(t, 3H, 1.47 (bd hex, 2H, 2.15 (pen, 2H, 2.32 (in, 1H), 2.7-3.2 (in, 9H), 3.46 (dd, I1H, J=4, 10), 3.57 (in, 1H), 3.64 2H, 3.67 I1H, 3.86 3H), 5.92 2H), 6.74 1H, 6.84 (dd, I1H. J=2, 6.96 I1H, 7.06 I1H, 7.18 (in, 2H). MS (DCl/NH3) Wne 585 (M+H; 3 5 587 37 Anal calcd for C27H34N207CIFS: C, 55.43; H, :5.86; N, 4.79. Found: C, 55.65; H, 5.81; N, 4.70.

Example 434 trans. tr 1-2(-sbtlN(-hoorpnsufnlaioehlproidi 3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. I H NMR (CD3OD, 300 MHz) 5 0.79 3H, 0.84 3H, J=7),1.68 (hept, 1H, 2.18 (pen, 2H-, 2.8-3.4 (in, 10H), 3.5-3.8 (in, 3H), 3.65 2H, 3.90 3H), 5.94 2H), 6.77 1H, J=z8), 6.87 (dd, 1H, J=2, 6.99 1H, 7.13 1H, J=9),i 7.27 (in, 2H).

MS (DCIINH3) W/e 599 Anal calcd for C 28

H

3 6N2O7CIFS 0.3 TFA: C, 54.24; H, 5.78; N, 4.42. Found: C, 54.19; H, 5.71; N, 4.01.

E-xample 435 trans. trans-2-Prgpoxy mpth 11 4 .3-benoixN--l- d i nbutyflaminOc-arbonylinethyl)D1Yrr liinecrxli acid; Using the procedures described in Example 1, the title compound was prepared. IH NMR (CDCI3, 300 MHz) 5 0.87-0.98 (mn, 9H), 1.21-1.39 4H), 1.43-1.57 (mn, 4H). 1.58-1.70 (mn, 2H), 3.13-3.29 (in, 4H), 3.34- 3.43 (mn, 3H), 3.45-3.55 (in. 3H), 3.69 (dd, J 10.2, 4.5 Hz, I1H), 3.80- -412- 4.20 (in, 4H), 5.93 2H), 6.73 J 7.8 Hz, 1H), 6.84 (dd, J 8.2, 1.7 Hz, 6.93 J 1.7 Hz, MS(DCI/NH3) mle 477 Anal calcd f or C26H-40N206-0.50 TFA: C, 60.77; H. 7.65; N, 5.25. Found: C, 60.73; H, 7.74; N, 5.22.

Egample 43 trans, trans--2-(3-FIUoro-4methoxyhen6~( Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 65-67 OC. 1 H NMR (CDCI3, 300MHz) 8 0.82 J=7Hz, 3H), 0.88 J=5Hz, 6H), 1.46 (sextet, J=7Hz, 2H), 1.56-1.64 (mn, 3H), 2.24-2.33 (in, IH), 2.68-2.93 (in, 2.98-3.12 (mn, 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=8Hz, 1H), 6.82 (dd, J=2Hz, J=8Hz, 1H), 6.92 J=8Hz, 1H), 6.97 (d, J=2Hz, 1H), 7.10 J=9Hz, 1Hz) 7.16 (dd, J=2Hz, J=l2Hz, 1H). MS *:(DCI/NH3) in/e 579 Exainole 437 ***.trans. trans-24 t'Methox-3-fluoroDhenyl-4( 7 -methox 1 3 benzodioxol-5-yl')-l -r2-(N-nronyl-N-flpentanesulfonyflanino)ethyllpyrrolidine-3carb)xyliccid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (300MHz, CDCI3) 8 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 (mn, 2H), 2.22-2.34 (in, 1H), 2.30-2.95 (in, 5H), 2.9573.10 (mn, 2H), 3.15-3.33 (in, 2H), 3.45 (dd, J=3Hz, 9Hz, iH), 3.47-3.56 (mn, 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).

-4 13- Example 438 trans, trans-2-(3-Fluoro-4-methoxyphenl)l- 4 1 4l2-(N-propyl-N-(2.2.3 .3.3pentafluoroprODOxyethalesulfoflyl)amiflo)ethVylDiyrrolidine- 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 00. 1H NMR (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 (mn, 4H), 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, 1 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, I1H). MVS (DCI/NH3) mWe 685 trans, trans-2-(1 .4.Benzodioxan-6-yl-4-(7-methoxyl 1.3-benzodioxolcarboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CDCI3) 8 0.81 J=7Hz, 0.90 J=7Hz, 3H), 1.23-1.36 (mn, 4H), 1.45 (sextet, J=7Hz, 1.65-1.78 (in, 2H), 2.20- 2.30 (mn, 1H), 2.30-2.95 (in, 5H), 2.95-3.10 (mn, 2H), 3.15-3.35 (in, 2H), 3.42 (dd, J=3Hz, 9Hz, 1H), 3.46-3.56 3.59 J=9Hz, 1H), 3.91 3H), 4.24 4H), 5.95 2H), 6.57 I1H), 6.68 1 6.82 (d, J=8Hz, 1H), 6.88 (dd, J=2Hz, 8Hz, 1H), 6.95 J=2Hz, 1H).

trans. trans-4-(1 .3Benzodioxol-5-Vl)-2-(4-m ethoxyphenyl)-l-((-CC Using the procedures described in Example 1, the title compound was prepared. 1 H NMVR (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 (4H1, in), 6.79 (2H, d, 6.77 (1 H. t, 5.8.5 (2H, 4.92 10) (1 H, d, J=15), 4.42 (4.22) (1H, d. J=15), 3.81 .(11H, in), 3.79 (3.78) (3H, 3.76 (3H, 3.62 (1H, in), 3.43 (2H, in), 3.30-2.70 (5H, in), 1.42 (1H, in), 1.23 -414- (2H1, in), 1.01 (1 H, mn), 0.83 (0.75) 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.

Exam~e441 trans. trans-2(3Fluoro-4-methoxVghel)P- 4 1 -(2-(N-isobutyl.N-(pentanesulfolylamilo)ethyl)pyrrolidifle- 3 Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD300, 300 MHz) 8 0.76 3H, 0.84 3H, 0.92 3H, 1.36 (in, 4H),1.70 (in, 3H1), 2.90 (in, 2H), 3.02 (mn, 2H1), 3.1-3.8 (in, 7H), 3.84 2H, 3.91 3H), 5.96 2H1), 6.80 (d, 1H, 6.88 (dd, 1H, J=2, 7.00 1H, 7.19 IH, 7.35 (in, MS (DCI/NH3) m/e 593 Anal calcd for C30H41 N207F 0.5 TFA: C, 57.31; H, 6.44; N, 4.31. Found: C, 57.08; H, 6.15; N, 3.95.

trans, trans-4-(1 .3.BenzodioxoI-5-y)-2-(4-nethoxyphenyl').l-(NcarboXyLic aci:fd Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD300) 5 0.87 J=7 Hz, 3H), 1.10- 1.30 (in, 4H), 2.70-2.90 (in, 2H), 3.13 J=8 Hz, 3.40-3.90 (mn, 611), 25 3.79 3H), 5.93 2H), 6.75 J=8 Hz, 1 6.80-7.20 (in, 9H), 7.40 I1H). MS (DCI) m/e 549 Anal calcd for C 3 1 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-(1.3Bnoixl -l--4flgohni- -(N-but v- N-(3-chlorophenylaino~carbonylinethyl)pyrrolidine3carboxylicaci Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD300) 5 0.87 J=7 Hz, 3H), 1.20- 1.50 (in, 4H1), 2.65-2.85 (mn, 2H), 3.05-3.85 (in, 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, MS (DCI) m/e 553 Anal calcd for -4 C3OH3ON205FCl: C, 65.16; H, 5.47; N, 5.07. Found: C, 65.37; H, 5.41; N, 4.98.

Example44 tra ns.trans-44-( 3- Ben zodioxo-5-yllI-2 eth oxyphe nyfl-1 butyl- N-(3.4-dim etho xyben zyflamIn o~ca rbonyllmethyfl) yrroii*d in e-3- Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 (rotamner) 7.33 (1H, d, 7.23 (1IH, in), 7.03 (6.97) (1 H, d, 6.90-6.60 (6H, in), 6.47 (1 H, in), 5.93 (2H, rn), 4.83 (4.09) (1H, d, J=15), 4.45 (4.22) (1H, d, J=15), 3.83 (3.86) (3H, 3.79 (1H, in), 3.77 (3.76) (31H, 3.75 (3.65) (3H, 3.60 (1H, mn), 3.43 (2H, in), 3.28 (111, in), 3.20-2.70 mn), 1.43 (1H, in), 1.23 (2H, in), 1.02 (1 H, in), 0.84 (0.77) (3H, t, MS (DCIINH3) in/e 605 Anal catcd for C34H40N208: C, 67.53; H, 6.67; N, 4.63. Found: C, 67.28; H, 6.63; N, 4.38.

:Example 445 *trans, trans-44(1 Ben zodioxol- 5-yl-2-(4 -rn ethoxyp he nfl)- 1 butyl-N-(2 -iethoxybenzyl) amino) carbonyl)m ethyl)pyrrolidi ne-3theproceurescarboxylic acid *Using th rcdrsdescribed in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDC13 8 (rotainer) 7.33 (1 H, d, :7.11 (2H, in), 7.03 (1 H, dd, J=8, 6.90-6.60 in), 5.93 (2H, in), 4.83 25 (4.15) (1H, d, J=15), 4.47 (4.30) (1H, d, J=15), 3.81 (1H, in), 3.78 (3.73) (3H, 3.72 (3H, 3.59 (1 H, in), 3.43 (2H, in), 3.30 (1 H, in). 3.20-2.70 (4H, in), 1.42 (1H, in), 1.23 (2H, in), 1.01 (1H, in), 0.83 (0.77) (3H, t, J=8).

MS (DCI/NH3) in/e 575 Anal calcd for C33H38N207: C. 68.97; H, 6.66; N, 4.87. Found: C, 68.70; H. 6.56; N, 4.61.

-4 16- Examgle 446 trans. trans-4-( 1.3-Benzodioxol-5-yfl-2-(4-methoxyphenyl)-1 butyl-N-(3-methoxybenzyllamino)carbonyflmethyfloyrrolidine-3carboxylic acid Using the procedures described in Example 1. the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 (rotamer) 7.31 (1 H. d, J= 7.13 (1 H. d, 7.16 (1 H, dt, J=8, 7.03 (1 H. dd, J=1O0, 6.90-6.60.

(611, in), 6.50 (1H, mn), 5.94 in), 4.82 (4.19) d, J=15). 4.50 (4.23) d, J=15), 3.78 (3.76) (3H, 3.77 (1H, in), 3.75 (3.67) (311, 3.59 (111, mn), 3.57-3.35 (211, in), 3.25 (111, in), 3.20-2.70O (4H, mn), 1.43 (11H, in), 1.23 (2H1, mn), 1.02 (111, in), 0.84 (0.77) (3H, t. MS (DCI/NH3) W/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.

Example 47 :trans. trans- Fl uoro-4- meth oxylohenyfl)-4- (1 .3-ben zodi oxol 1 -(2-(N-(2-methoxyethyl)-N-(3- :ch lo rop ropanesulf onylamin o) ethylpyrro id ine-3-ca rbo xyl c acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 2.15 (pen, 2H1, 2.33 (in, 1H). 2.81 (in, 2H1); 2.93 111, 3.1-3.6 (in, 10H), 3.24 3H); 3.65 2H1, 3.70 1H, 3.87 3H), 5.92 2H), 6.74 11H, 6.84 (dd, 111, J=2, 6.97 1H, 7.07 111, 7.17 (in, MS (DCI/NH3) in/e 601 Anal calcd for C27H34N208C1FS: o 25 C, 53.95; H. 5.70; N, 4.66. Found: C, 53.65; H, 5.49; N. 4.26.

Example448 trans. trpns:2 (3-Flu o r-4-m eth oxyph enyl)-4- (1.3 -ben zo d iOI-l 1 -(2-(N-2mtoyty)N(etnsloy~mn I lrip 3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD300, 300 MHz) 8 0.93 (in, 3H), 1.34 (mn, 4H), 1.69 (mn, 2H), 2.33 (mn, 1H), 2.75-3.1 (mn, 7H), 3.23 3H), 3.3-3.6 (mn, 6H), 3.70 I1H, 3.86 3H), 5.92 2H), 6.74 1H, 6.84 (dd, 1H, J=2, 6.97 1H, 7.07 1H, 7.18 (mn, 2H). MS -4 17- (DCI/NH3) mWe 595 Anal calcd for C29H39N208FS: C, 58.57; H.

6.61; N, 4.71. Found: C, 58.21; H, 6.29; N, 4.29.

Example449 trans. trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-methoxylhelyfl- 1 hePtYl -N -(4-flu oro -3methylohenylamin)carbolylmethl)yrrolidfle-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. IH NMR (300 MHz, CD300) 8 0.89 (in, 6H), 1.18-1.36 (in, 8H), 2.15 (bs, 1.5 (CH3 rotamer)). 2.28 (bs, 1.5 (C5H3 rotamer)), 2.64 (t.

J=14.9 Hz, 1H), 2.82 (mn, 1H), 3.07-3.29 (in, 2H), 3.32-3.41 (mn, 1H), 3.53-3.60 (mn, 1H), 3.70-3.79 (in, 1H), 3.79 3H), 4.68 (in, 1H), 5.92 (in, 2H), 6.69-6.90 (in, 6H), 6.93-7.07 (in, 4H). MS (DCI) mWe 605 Anal calcd for C35H41 FN206: C, 69.52; H, 6.83; N, 4.63. Found: C, is 69.31; H, 6.78; N, 4.35.

Example 450 :trans. trans-4-(1 Benzodioxol-5-yi)-2-(4-m ethoxylhenyl)-l methylohenyl~aininolcarbonyPlinethyl~yrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.81-0.90 (in, 6H), 1.30 (in, 12H), 2.14 1.5 (CH3 rotainer)), 2.30 1.5 (CH3 rotainer)), 2.60 (t, J=14.8 Hz, 1H),.2.80 (mn, 1H), 3.09-3.24 (mn, 2H). 3.33-3.42 (in, 1H), 3.50-3.55 (in, 1H), 3.65-3.77 (in, 1H), 3.79 3H), 4.64 (mn, 1H), 5.93 (in, 2H), 6.70-6.84 (mn, 5H), 6.91-7.13 (in, 5H). MS (DCI) Wne 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.trpns-4-(1 .3-Benzodioxol-5-vI')-2-(4-inethoxyphenVyl nonylamino~IcarbonylinethFIDyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD300) 5 0.80 J=7.0 Hz, 3H), 0.84 J=7.1 Hz, 3H), 1.15-1.55 12H), 2.88 J=15.9 Hz, 1H), 3.07 (in, 2H), 3.26 J=1 6.3 Hz, I1H), 3.36 (dd, J=4.4, 9.8 Hz, I1H), 3.64 (mn, 1 H), -4 18- 3.76 (in, 1H), 3.79 3H), 3.98 J=9. '5 Hz, 1 5.93 (in, 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, 1H), 7.39 (in, 2H). MS (DCI) mWe 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.

trans. trans-4-(I 3 Ben odi O5yl)2(4-rnejhoxyjhenyl)- croylcai Using the procedures described in Example 1, the title compound was prepared. IH NMR (300 MHz, CD300) S 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) mWe 549 15 Anal calcd for C31H33N206 -0.4 H20: C, 66.99; H, 6.13; N, 5.04. Found: C, 67.01; H, 6.23; N. 4.68.

Examgle 453 trans. trans-2(.eto ef~~ -0l.3benz di xol-r I 1 prpl--2 n hl rldn-cabxf -acid The title compound was prepared by the method of Example 418, substituting 2-chlorobenzothiazole for 2-bromopyri midinle. 1 H NMR (300 MHz, CDC13) 8 0.88 J=7Hz, 3H), 1 .59 (sextet, J=7Hz, 2H), 2.25- 2.37 (in, 1H), 2.85-2.97 (in, 3H), 3.28-3.36 (in, 28), 3.50-3.58 (in, 3H), 25 3.60-3.65 (mn, 1H), 3.67 J=9Hz, 1H),3.71 3H), 5.87 J=2Hz, 1H), 5.91 J=2Hz, 1H), 6.57 J=8Hz, 1H), 6.73 (dd, J=2Hz, 9Hz, IH), 6.76 J=8 Hz, 2H), 6.91 J=2Hz, 11H), 7.01 J=8Hz, IH), 7.22 J=8Hz, 1H), 7.29 J=8Hz, 2H), 7.40 J=7Hz, 1H), 7.55 J=7Hz, 18).

ExaMgleQ 454 rasrans-2-(2-Ethoxyethyl- 4 1 3 benzodioxol-5fl1(N.dibutylami ab~~ieh I -rroldine3-carboxylic aci Using the procedures described in Example 1, the title compound was prepared. I H NMR (CDCI3, 300 MHz) 5 0.91 J 7.4 Hz, 3H), 0.94 J 7.4 Hz, 38), 1.19 J 7.0 Hz, 38), 1.24-1.38 (in, 5H), 1.46-1.60 (in, 48), 2.03-2.12 (mn, 2H), 3.07 J 8.0 Hz, 18H), 3.07-3.34 (in, 6H), -4 19- 3.43-3.52 (in, 3H), 3.59-3.74 (mn, 3H), 3.80-4.01 (in, 2H), 5.93 2H), 6.72 J 8.1 Hz, 1H), 6.79 (dd, J 8.2 Hz, 1.7 Hz, 1H), 6.87 J 1.7 Hz, 1H1). MS(DCI/NH3) mWe 477 Anal calcd for C26H4ON2O6 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.tran&724-Meth oxy-3furhey 4 .benzodioxol-S-vl) ylethyl~sulfonylainnO)eth Fl1Drroldie3&arboXvXicacQid Ethyl 2 -(4-inethoxy-3-fluoropheny')- 4 1.3-benzodioxol-5-yl)- 1 -1 2 (N-propyl-N1 2 -viflylsulfonyl] amino) ethyl1pyrroli dine- 3 carboxylic acid, prepared. by the procedures of Example 125, was reacted with excess morpholifle for 4 hours at room temperature.

Chromatography on silica gel eluting with EtOAc~gave a 65% yield of an intermediate ethyl ester whic h was hydrolyzed to the title compound :with NaOH in ethanol/water. 1H NMR (300 MHz, CDC13) 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 (in, 6H), 3.60 (dd, J=3Hz, 9Hz, 1H), 3.51-3.59 (in, 1H), 3.62- 3.70 (in, 5H1), 3.88 3H), 5.95 2H), 6.72 J=8Hz, 1H), 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. trans. 2 3 1F!lu r4flthx 'henvlI- 4 Cl .3-kbe-7 zi xI- :25 142-f N_ rpy-N-( (2.2.2triflur eh xehane)'sulfo idinginoZeUyltgurolid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 95-96 1 NMR (CD300, 300MHz) 8 0.80 J=7Hz, 3H), 1.35-1.48 (mn, 2H),3.07 (sextet, J=7Hz, 2H), 3.23-3.55 (mn, 8H), 3.80-3.87 (in, 2H), 3.93 3H), 3.94- 4.02 (in, 4H1), 4.66 J=l2Hz, 1H), 5.96 2H), 6.83 J=8Hz, 1H), 6.94 J=8Hz, 1H),7.06 J=2Hz, 1H), 7.23 J=9Hz, 1H), 7.43 J=9Hz, 111), 7.49 (dd, J=2Hz,J=l2Hz, 1H). MVS (DCI/NH3) W/e 635 -420- Example 457 trans, trans- 4- (13B'zdoo 5y)24-Iu rhey 1 -butyl N mty 2 nl m cronlmehl yrlid e3c bxl acid Using the procedures described in Example 1, the title compound s was prepared. I H NMR (300 MHz, CD300) 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 (mn, 4H). MS (DCI) in/e 533 Anal calcd for .C31H-33NS205F: C, 69.91; H, 6.25; N, 5.26. Found: C, 69.56; H, 6.26; N, 5.23.

3-carboxylic aci Using the procedures described in Example 66, the title compound 9* was prepared.

I

1 H NMR (CD3OD, 300 MHz) 8 0.94 (in, 3H), 1.23 (hex, 2H, 1.69 (in, 2H), 3.08 3.20 3.3-3.5 (mn, 101H), 3.77 (in, 2H), 3.92 3H), 4.60 (in, 1H), 5.96 6.81 1H, 6.88 (dd, 1H, J=2, 6.99 1H, 7.22 1H. 7.38 (in, MS (APCI) m/e 581 Anal calcd for C 2 8 H37N2O8FS 1.1 TFA: C, 51.37; H, 5.44; N, 3.97. Found: C, 51.27; H, 5.35; N, 4.11.

trans. trns i .3~L enzodi~olYn l>r-v) 3-carbo-xyliQ aId Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 77-78 0 C. I H NMR (CDCI3, 300MHZ) 5 0.83 J=7Hz, 3H),1.06 J=6Hz. 6H),1.45 J=7Hz.

2H), 2.20 (septet, J=6Hz, 2.26-2.36 (in, 2.62-2.78 (in, 3H).

2.85-2.95 (mn, 2H), 2.97-3.10 2H), 3.15-3.35 (in, 3.43 (dd.

J=3Hz, J=9Hz, 1H), 3.53-3.62 (in, 3.66 J=9Hz, 3.88 31-), 5.95 6.74 J=8Hz, 6.82 (dd, J=2Hz, J=8H-z, 1H), 6.92 (t.

J=8Hz. 1H), 6.97 J=2H-z, 1H), 7.12- J=9H-z, 1H), 7.18 (dd, J=2Hz, .1=12Hz. 11-1). MS (DCI/NH3) m/e 565 -421- Examlle 460 trans, trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1 butyl-N-(4-nitrobenzyl)amino)carbonyflmethyfloyrrolidine-3carboxylic- acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 (rotamner) 8.11 (2H, m),7.32 (3H, dd, J=9, 7.16 (7.07) (1H, bd. J=10), 6.98 (6.94) (1H, d, 6.85 (2H, 6.83-6.70 (2H, 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) (3H- 3.72 (1H, d, 3.61 (1H, in), 3.48 (IH, bd, J=15), 3.43-3.20 (2H, in), 3.06 (2H, in), 2.90 (1H, in), 3.79 (1H, bd, J=14), 1.43 (1H, mn), 1.23 (2H, in), 1.02 (1H, in), 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, is1 6.85.

Examlle 461 trans. trans-2-(4- Ethyl phenyfl-4-(3 .4-dif luorogohenyl)- 1 N-di (n- .:butyflaminocarbonylmethyfl)-oyrrolidine-3-carboxylic, acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 6 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 1IH, J=14), 2.94 (dd. 1H, J=7. 3.05 (in, 3H), 3.3-3.5 3H), 3.44 1H, J=14), 3.66 1H), 3.75 1H, 7.20 (td, 2H, 7.22 (in, 2H), 7.32 (td, 2H, 7.43 (ddd, 1H, J=2,8,12). MS (DCIINH3) mWe 501 Anal calcd for C29H38N203F2 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, trpns-4-(1 .3-Benzodioxol-5-yll-2-(4-methoxyphenyfl-1I butyl-N-(4-fluoro-3-methylo~henyl)aminocarbonylmethyflovrrolidifle- 3-carboxylic acid, Using the procedures described in Example 1. the title compound was prepared. 1 H NMR (300 MHz, CD3O1D) 8 0.87 J=7 Hz, 3H), 1.20- 1.50 (in, 4H), 2.21 J=2 Hz, 3H). 2.64 J=14 Hz, 1H), 2.75 (dd, -'422- Hz, 1H), 3.05 J=7 Hz, 1H), 3.25 J=15 Hz, IH), 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) W/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.

Examle403 trans, trans-4-(1I.3-.Benzodioxol5V)2(4iethogyphenyl)l Using the procedures described in Example the title compound was prepared. I1 NMR (300 MHz, CD300) 8 0.87 3H), 1.17 J=7 Hz, 6H), 1.20-1.50 (in, 4H), 2.63 J=15 Hz, 1H), 2.75 J=7 Hz, 1H), 2.85 (mn, 1H), 3.00 J=7 Hz, 1H), 3.25 J=15 Hz, 1H),,3.40-3.70 (in, 3.75 3H), 5.90 2H), 6.65-6.80 (nm, 3H), 6.71 (dt, J=7 Hz, 3H), 7.07 15 (mi, 3H), 7.20-7.35 (mn, 2H). MS (DCI) in/e 573 (M+H) 4 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.

Eamp-le 464 trans, trans744(l. 3 .Be nz di xol5vl2(4inethOXVDh-vl l-(-1 butyl-N-( 3 -ethylphenyflaino.arbo Iin vlDrrolidine3carboxYvic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD300) 8 0.87 (mn, J=7 Hz, 3H), 1.16 (t, J=7 Hz, 3H), 1.20-1.47 (in, 4H), 2.50 J=7 Hz, 2H), 2.70-2.85 (mn, 2H), 3.13 J=7 Hz, 1H), 3.20-4.5 (mn, 6H), 3.78 3.83 J=8 Hz, 1H), 5.92 2H), 6.72 J=8 Hz, 1H), 6.80-6.90 (in, 5H), 7.02-7.13 (in, 3H), 7.15-7.25 (in, 2H). MS (DCI) W/e 559 Anal calcd for C33H38N206 0.3 H20: C, 70.27; H, 6.90; N, 4.97. Found: C, 70.31; H.

6.63; N, 4.60.

-423- Examlle 465 transE.trans-4-(l .3-Benzodioxol-5-yl-2-(4-ethylphenyfl-l chl oro~h enyl)- N- butyl amino) carbonyllm ethyfl~yrrol idin e-3-ca rbo xyli c Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CDCI3) 8 0.87 3H, J=7Hz), 1.23 (t, 3H, J=7Hz), 1.28 (mn, 2H1), 1.41 (in, 2H), 2.63 2H1, J=7H1z), 2.67 (mn, I1H), 2.92 111), 3.20 (in, 2H1), 3.42 (in, 1 3.60 2H, J=7H1z), 3.93 (in, 1H), 5.92 2H), 6.75 I1H, J=8H1z), 6.84 (in, 6.95 (br s, 111), 7.02 1 7.10 (br s, 3H1), 7.25 (in, 2H1). MS (APOI) ni/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.

trans. trans-4-(1 Ben zod ioxan-6-yl)-2 (4-ethyl~henyfl-1 go 0 chlo roghenyl '-N-butyl amino) carbonyflmethvfloiyrrolidine-3-carboxylic Usingthe poceduesd cid i xml ,tettecmon wsprepared. I H NMR (300 MHz, CDCI3) 6 0.86 3H, J=7H1z), 1.23 (t, 203H, J=7Hz), 1.25 (in, 2H1), 1.40 (in, 2H), 2.64 2H, J=711z), 2.70 (in, 1 H), 2.95 (in. 1H), 3.20 (in, 2H), 3.40 (in, 1 3.57 (in, 3H), 3.90 (in, I1H), *4.25 4H), 6.80 111, J=8H1z), 6.95 11H, J=2Hz), 6.95 (in, 2H1), 7.07 (br 7.22 (in, 3H1). MS (APCI) Wie 577. Anal. calc'd for **:C33H37N205CI 0.85 H20: C, 66.90; H, 6.58; N, 4.73. Found: C, 66.92; :25 H, 6.25; N, 4.36.

Example 467 trans. trans-4- (Be nzof uran -5-yi) -2 -(4-ethylp henyl)- 1 (3 chi orophenyl)-N-butyl amino) carbonyl)inethyflpyrrolidine crox lie,

AJ

Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CDC13) 8 0.85 3H, J=7Hz), 1.26 (t, 3H, J=7Hz), 1.30 (mn, 2H), 1.40 (in, 2H), 2.60 2H. J=7Hz), 2.72 (mn, I1H), 2.93 (in, I 3.22 (mn, 2H), 3.50 (mn, I1H), 3.55 (mn, 2H), 3.75 (in, I1H), 3.90 (br d, I 6.75 1 H, J=l Hz), 6.80 (br d, 1 6.95 (br s, 1 7.08 (in, 4H). 7.20 1H, J=8Hz), 7.28 1H, J=8H-z), 7.42 (in, 2H), 7.58 1H, 424- J=1 Hz), 7.63 1H). MS (APCI) mWe 559 Anal. calc'd for C33H35N204CI 0.45 H20: C, 69.88; H, 6.38; N, 4.94. Found: C. 69.83; H, 6.04; N, 4-.87.

Exm~l 6 trans. trn--4Mtox--loohn l4(-ehx-.3f2-Nbtl -2eyamn~t lnyrldne-3- Ethyl 2 -(4-methoxy-3fluorophenyl)-4-(7-methoxy-1l 3benzodioxol-5-yl)-l 2 romoethyl1.pyrrolidi ne 3-carboxyl ate, 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 diisopropylethylamine to give the ethyl ester. The ester was hydroyzed with sodium hydroxide to give 148 mg of the title compound as a white powder. 1 H NMR (300 MHz, CDCI3) 8 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 (in, 2H), 3.12-3.22 (in, 2H), 3.30-3.44 (mn, 3H), 3.45-3.55 (in, 1H), 3.62 J=9Hz, 1H), 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 (in, 3H), 7.19 (dd. J=2Hz, 12Hz, IH).

Exampole 469 trans, trans-44-(l B izdoa--l--4ehtlhnl,

.N-

:di(n-butflai inocarbonylinethvl rrolidineq-arboxvl;c aid :25 Using the procedures described in Example 1, the title compound was prepared. I NMR (300 MHz, CDC13) 8 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 (mn, 2H), 2.64 2H, J=7Hz), 2.78 (nm, 2.9-3.2 (envelope. 4H), 3.30 (in, 1H), 3.40 (mn, 3H), 3.60 (in, 1H), 3.80 (in, 1H), 4.25 4H), 6.80 (d, 1 H, J=8Hz), 6.90 (in, -1 6.98 1 H, J=2H-z), 7.17 2H, J=8Hz), 7.30 (in, 2H). MS (APCI) ine 523 Anal. calc'd for C31H42N205 -1.1 HOAc: C, 67.73; H, 7.94; N, 4.76. Found: C, 67.81; H, 4.48.

-425- Examole 470 trans, trans- 4 Be odoa nl carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 J=7.1 Hz, 3H), 1.30 (in. 2H), 1.44 (mn, 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 (in, 4H), 6.75-6.86 (in, 6H), 6.95 J=2.0 Hz, lH), 7.09 J=8.8 Hz, 2H), 7.22(d, J=10.2 Hz, iN), 7.26 J=7.6 Hz, 1H). MS (DCI) W/e 559 Anal calcd for C33H38N206 .0.4 CH3002C2H5: C, 69.97; H, 6.99;, N, 4.72. Found: C, 0.06; H, 6.66; N, 4.48.

15Exampl1e 471 ~~~~trans. trans-4-(l 4 Benzodioxan-6-yl'2(4mehx hnl-(N .:carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 8 0.87 J=7.0 Hz, 3H), 1.25 S(in, 2H), 1.40 (in, 2H), 2.78 J=14.6 Hz, 1H), 2.86 J=9.0 Hz, 1H).

3.16 J=9.5 Hz, IH), 3.34-3.43 (in, 3.48-3.62 (in, 3H), 3.79 (s, 3.85 J=9.5 Hz, I1H), 4.22 (in 6.78 J=8.5 Hz, 1H), 6.81- 6.86 (in, 3H), 6.93-7.09 (in, 5H), 7.33-7.38 (in, MS (DCI) in/e 579 Anal calcd for C 3 2H35ClN2O6 1 .1 CH3CQ2C2H5 0.15 H3P04: C, 63.30; H, 6.46; N, 4.06. Found: C, 63.54; H, 6.09; N, 3.98.

Example 472 ttransr-4( -Bnoixl5y)2(-nt j hk L_1-(4pyri dyl methyl) pyrroli dine3 -garkoxy-lQ acid Using the procedures described in Example the title compound was prepared. IH NMR (300 MHz, CD3OD) 8 2.84 J=9.6 Hz, iH), 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, 1H), 3.53 (in, 1H), 3.78 3H), 3.81 2H), 5.92 (in, 2H), 6.73 J=8-1 Hz, 1H), 6.82 (dd, J=1.8. 8.1 Hz, 1H), 6.93 (mn, 6.95 J=1.5 Hz, 1H), 7.43 (mn. 4H). 8.44 J=5.2 Hz, 2H). MS (DCI) m/e 433 Anal '-426calcd for C25H24N205 -0.3 CH3CO2C2H5: C. 68.57; H, 5.80; N, 6.10.

Found: C, 68.68; H, 5.60; N, 5.81.

trans, trans-4-(l .3-Benzodioxol-5-yl)-2-(4-methgxyphel)- 1 butyl- 3-te rt-butylohenylamino~carbolyl)methyl)D2yrrolidifle-3- Scarboxylic acid Using the procedures described in Example 1, the title compound was prepared. I 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 (in, 1H), 3.13 J=9.0 Hz, 1H), 3.29 J=15.1 Hz, 1H), 3.50-3.66 (mn, 4H), 3.77 3H), 3.84 J=9.6 Hz, 1H), .5.92 2H), 6.74 J=7.7 Hz, 1H), 6.79-6.85 (in.

4H), 6.86-6.90 (mn, 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, I1H). MS (DCI) 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.

:trps~trns--(1Exaile 474 tras, rans--(.3-Benzod ioxol-5-yl-2- (4 -meth o xylhenyfl)-I carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMRP(30 MHz, CD300) 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, :25 J=15.3 Hz, 1H), 2.80 (dd, J=8.5, 9.5 Hz, 3.12 J=9.3 Hz, 1H), 3.29 J=1.5.6 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, 1H), 5.92 2H), 6.74 J=8.1 Hz, 1H), 6.79- 6.8-7 (mn, 4H), 7.05 J=1.7 Hz, 7.10 J=8.8 Hz, 2H), 7.20 (d, 7.8H), 7.29 J=7.6 Hz, 1H). MS (DCI) in/e 587 Anal calcd for C35H42N206: C, 71.65; H, 7.22; N, 4.77. Found: C, 71.33; H, 7.28; N, 4.7i4.

-427- Example 475 trans. trans-4-(3.4-D if Iuorophen yl -(.thlefy- (Nnbuy-

N-(

3 -rmethYlphenyflamiflOcarbonylmethYlpyrrolidine3carboxylic aidd Using the procedures described in Example 1, the title compound was prepared. I H NMR (CD3OD, 300 MHz) 8 0.87, 3H, 1.19 3H, 1.28 (in, 211), 1.43 (in, 2.28 2.60 2H, 2.66 (mn, 2H), 3.06 (in, 1 3.21 I1H, J=1 3.42 (dd, 1 H, 3.58 (in, 3H), 3.71 1H, 6.80 7.06 7.18 (mn, 4H), 7.45 (mn, I1H).

MS (APCI) m/e 535 Anal calcd for C 3 2H36N203F2 1.3 HOAc: C, 67.83; H, 6.78; N, 4.57. Found: C, 67.83; 6.46; N, 4.70.

Examp~le 476 *trans. trans-2 Ethyl phenyl 4 3 .4-difluorophgnyl)- butyl)-

N-(

3 -chlorO en mIani nabnvImth-"--^Prjiin~abxlc ai Using the procedures described in Example 1, the title compound .:was prepared. I H NMR (CD3OD, 300 MHz) 8 0.82 3H, 1.16 3H.

1.23 (in, 2H), 1.35 (in, 2H), 2.55 2H1, 2.66 (in, 2H1), 3.01 (t.

3.16 III. J=15), 3.32 (dd, 11H, 3.56 (mn, 3H), 3.67 (d, 1H, 6.94 I1H, 7.02 (mn, 5H), 7.14 7.32 (mn, 3H). MS (APCI) Wne 555 Anal calcd for C 3 1H33N203CIF2 -0.6 TEA: C, 61.88; H, 5.42; N, 4.48. Found: C, 61.90; H, 5.62; N, 3.98.

Examp~le 477 trans.trans-4-(l .4Bnzodioxan 6yfl-2(4luorolhenyl)l -(N-but-

N-(

3 -chloroDhenfaiOra rbo nvl mnthvl)PvrroIdA--Irne~abxlc a Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD300) 8 0.87 J=7 Hz, 3H1), 1.10- 1.30 (in, 4H1), 2.60-2.75 (in, 2H1), 3.03 J=7 Hz, 1H), 3.15-3.75 (mn, 611), 4.02 (in; 4H), 6.75 J=6 Hz, 1H), 6.85 (dd, J=7 Hz, 11H), 6.90 (7.19, J=in Hz, 6H), 7.32-7.43 (mn, 3H1). MS (DCI) mWe 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.

-428- Examlle 478 trns, tas4(Bno urn5y)2(-tylhnl- N-di(nbutyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I 1 H NMR (300 MHz, CDCI3) 8 0.78 3H, J=7Hz), 0.84 (t, 3H, 1=7Hz), 1.05 2H, J=7Hz), 1.21 3H, 1=7Hz), 1.25 (in, 2H), 1.45 (in, 2H), 2.62 2H, 1=7Hz), I1H, J=l 3Hz), 3.0 (in, 2H), 3.15 (in, 2H), 3.35 (in, 1H), 3.43 (in, 2H). 3.52 (in, 1H), 4.40 (in, 2H), 6.73'(d, 1H.

1=1Hz), 7.14 2H, J=8Hz), 7.26 1H), 7.31 2H, J=8Hz), 7.44 (s, 2H), 7.60 1 H, J=1 Hz), 7.65 I1H). MVS (APCI) &~ie 505 Anal.

calc'd for C31H40N204: C, 73.78; H, 7.99; N, 5.55. Found: C, 73.69; H, 7.97; N, 5.2 1.

benzodioxol-5-fl)-l1-f2-( N-propyl-N-(D2yrrolidine-1carbonylmethF~amino~ethyllpyrrolidine-3-carbox-yli acid **~Ethyl 2-(4-methoxy-3-fluorophenyl)-4-(7-methoxy-l ,3b e nzod io x oI- 5 -yl) 2.f- (Np ro pyl -a m in oet hylI-p yrro I id ine 3 carboxylate, prepared according to the procedures of Example 618B (300 ing), N-bromoacetyl pyrrrolidine (132 ing) and dilsop ropyl ethyl aiine (154 ing) were heated for 1 hour at 50 0 C in 1 mL of acetonitrile to give the intermediate ethyl ester. The ester was hydrolyzed to the title compound by the method of Example I D. I 1 H NMR (300 MHz, CDCI3) 8 0.88 1=7Hz, 3H), 1.30-1.45 (in, 2H), 1.75-1.92 (mn, 4H), 2.30-2.40 (mn, 1H), 2.47-2.58.(in, 2H), 2.70-3.00 (mn, 5H), 3.24-3.45 (in, 6H), 3.50-3.70 (mn, 2H), 3.83 3H), 3.86 1=9Hz, 1H), 3.88 3H), 5.93 2H), 6.58 (d, 1=2Hz, 1H), 6.70 1=2Hz, 1H), 6.87 1=8Hz, 1IH), 7.10 1=9Hz, 1H),, 7.21 (dd, 1=2Hz, 12Hz, 1H).

Example 480 trans, trpns-2-(4-Methoxyphenyfl- 4 -(l1.-benzo-dioxoI1-5-fl)-l (perhydroapiflycarbonyl(D)-eucyl~ainino~ethyl')oyrrolidine.- 3 carboxylic acid -429- 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-Perhydroazepinvlcarbonyl-D-Leucine O-Benzyl 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 and carbonyldiimidazole was added. After s15 hours, TLC indicated complete consumption of starting material, so 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 H3P04 (2 x 20 mL), 20 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%).

25 Example 480C N-Perhydroazepinylcarbonyl-D-Leucine To the compound resulting from Example 4808 (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).

-430- Example 480D trans, trans-2-(4-Methoxyvhenyl)-4-( 1.3-benzodioxol-5-y)- 1- (cyanomethvl-oyrrolidine-3-carboxylic acid ethyl ester To the compound resulting from Example 1C (510 mg of a 50 wt.

s 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 hexanes to give the title compound as a colorlessoil (0.28 g, 99%).

-Example 480E trans.trans-2-(4-Methoxvohenyl)-4-(1.3-benzodioxol-5-vl)-1-(2aminoethyl)-yvrrolidine-3-carboxylic acid" ethyl ester 15 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).

25 Example 480F trans, rans-2-(4-Methoxyphenyll-4-(1,3-benzodioxol-5-yl- 1 (Derhvdroazepihvlcarbonvl)leucvylamino)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 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 -431flash 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 480G trans, trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yfl- I (gerhyd ro azepi nylca rbo nylle ucylamino ethyfl)yrrolid ine-3-carbo xy ic acid 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 N H3P04 to pH The solid which ****precipitated dissolved when the mixture was extracted with 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 mCl8) eluting with a 10 70% gradient of CH3CN in 0.1%/TFA provided suitable material (0.049 g) after lyophilization of the desired f ractions. HNM (CC330Mz)50.82 (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 2H), 3.15-3.40 (in, 14H), 3.40-3.55 4H), 3.58-3.68 (mn, 2H), 3.70- 3.76 (br mn, 2H), 3.80 3H), 3.81 3H), 4.15 (br m, 2H), 5.10 (br m, 2H), 5.93 3H), 5.95 3H), 6.70-6.97 (in, 13H), 7.43-7.56 (br mn, 3H), 25 8.2 (br s, I1H), 8.5 (br s, 1H). MS(DCI/NH3) Wne 623 Anal calcd for C34H46N 407 -2.00 TFA: C, 53.65; H, 5.69; N, 6.58. Found: C, 53.66; H, 5.66; N, 6.54.

Examp~le 481 trans, trans-4-(1.3- Ben zod ioxoI- metho xY-henyl *di hexyflaminocarbonylnethylipvrrolidine- 3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD300) 5 0.80-0.95 (in, 6H), 1.0 (in, 2H), 1.07 (1.55, J=in Hz, 14H), 2.70 J=13 Hz, 1H), 2.85-3.15 (in, 4H), 3.20-3.60 (mn, 9H), 3.64 J=10 Hz, 1H), 3.79 3H), 5.90 (in, 2H), 6.70 8H), 1, 6.80-6.93 (mn, 3H), 7.05 1H), 7.35 J=10 Hz, 2H). Anal -432calcd for C33H46N2O6 1.7 H20: C, 66.35; H, 8.34; N, 4.69. Found: C, 66.32; H, 8.04; N, 4.52.

trans, trans-4-(1.4Beflzodioxa-6y)2(4fluorohenyl)- (N-butyl-

N-(

3 -methylphenllamiflocarbonylmethyIj)Dyrroidineacarboxylic aced Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD300) 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) W/e 547 4 Anal calcd for C 32 H35N2O5F 1.2 H20: C, 67.64; H, 6.63; N, 4.93. Found: C, 67.73; H, 6.37; N, 4.70.

15Example 483 trns ras4-1.3 B i Izod iO l-9Y44me- xoeY~ *Using the procedures described in Example 1, the title compound was prepared. I'H NMR (300 MHz, CDC13 8 (rotainer) 8.14 (2H, in), 8.05 (7.83) (1H, in), 7.60-7.30 (3H, in), 7.13 (IH, in), 7.10-6.70 (5H, in), 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, mn), 3.20-2.80 (2H, 25 1.50 (1H, mn), 1.30 (1H, mn), 1.20-1.00 (2H, in), 0.91 (0.78) (3H, t.

MS (DCI/NH3) Wne 590 (M+H 4 Anal calcd for C32H35N308 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-(l 2 Di hydrobe n zoturan5yl 2(4-eth I hen I) 1 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 8 (rotamer) 7.40 (2H, mn), 7.30-7.10 (4H, in), 6.90-6.70 (3H, in), 6.48 (1H, in), 5.45 (1H, mn), 4.65 (1H, d, J=15), 4.57 (2H, dt J=9, 4.40-4.00 (5H, in), 3.87 (3.85) (3H, 3.84 (1 tI, 3.053 (5.79 (Sr 3~ 2-,)20 t. J=1 2.90 (1 H, -433in), 2.64 (2H, q, 1.52 (1 H, mn), 1.31 (2H, in), 1.22 (3H, dt, J=9, 2), 1.07 (11H, in), 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.

Exml58 trans. trans-4- Ben zodioxol-5-yfl-2-(4 -m ethoxyphenyl)- 1 butyl-N-(4-heotyflainino'icarbonyflmethyfl oyrrolidine-3-carboxylic Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.71-1.04 (in, 11H), 1.07- 1.35 (mn, 6H), 1.73-1.53 (mn, 4H), 2.79-3.25 (in, 3.35-3.44 (in, 1 H), 3.51-3.68 (in, 3H), 3.78-3.89 (in, 1H1), 3.79 3H), 5.92 (in, 2H), 6.74 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 (mn, 2H). MS mWe 553 Anal calcd for C32H44N206: C, 69.54; H, 8.02; N, 5.07. Found: C, 69.31; H, 7.89; N, 5.06.

Example 486 trans. trans- 2-(4-M ethylcycl oh exyl) .3 -ben zodioxol 1 Ndi(n-butyl)aininocarbonylmethl)-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) 6 0.88 (3H, d, J 7Hz), 0.92 (3H, t, J 7Hz), 0.96 (3H, t, J 7Hz), 25 1.05 (1 H, in), 1.22-1.40 (7H, in), 1.45-1.65 (6H, in), 1.67-1.84 (4H, in), 3.17-3.45 (6H, in), 3.70 H, brm), 3.82 (1IH, dd, J 9Hz, 15Hz), 3.86 (1 H, d, J 15Hz), 5.93 (2H, 6.73 (1H, d, J 8Hz), 6.78 (1H, dd, J 2Hz, 8Hz), 6.88 (1 H, d, J 2Hz). MS (DCI/NH3) mWe 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.

-434- Examgle 487 trans, trans- Pro 12lge ntyl) -3-benzOdioxol-5-yfl-1 di(nbutvl)aminocarbonylmethyl',-ovrrolidine-3-carboxylic acid Using the procedures described in Example the title compound s was prepared and isolated as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) 8 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 (1 H, bin), 3.90 (1 H, brm), 5.93 (2H, dd, J 2Hz, 4Hz), 6.73 (I1H, d, J 8Hz), 6.78 (1 H, dd, J 2Hz, 8Hz), 6.88 (1H, d, J 2Hz). MS (DCI/NH3) W/e 517 Anal calcd for C30H48-N2O5 0 CF3CO2H: 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-f luoroo2henyl)-l -(N.N-di(nis butflaminocarbonylmethyfl-pyrrolidine-3-carboxylic acid wsUsing the procedures described in Example 1, the title compound wa* prepared. 1 HNMR (300 MHz, CD3OD) 8 0.83 J=7 Hz, 3H), 0.89 (t, J=7 Hz, 3H), 0.90-1.17 (in, 4H), 1.20-1.65 (in, 5H), 2.77d (13, 1H), 2.87 (dd, J=8, 2 Hz, 1H), 2.95-3.60 (in, 7H), 3.71 J=9 Hz, 1H), 4.21 4H), 6.72 I 6.91 (dd, J=8 Hz, 1 6.97 J=2 Hz, 1 7.05 J=7 Hz, 2H), 7.40-7.50 (in, 2H). MS (DCI) W/e 513 Anal calcd for C29H37N205F 1.2C F3COOH: C, 58.07; H, 5.93; N, 4.31. Found: C, 57.94; H, 5.81; N, 4.56.

Eampe Aa trans. trpns-2-(3-Methylopentyl)-4-( 1.3-benzodioxol-5-yl)I- -(NLN-dRifLbutyflaminocarbonylmethyl-pyrnolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1 H NMR (CDC13, 300 MHz) 8 0.83 (3H, t, J 7Hz), 0.85 d, J= 7Hz), 0.91 (3H, 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 (1H, t, J 6Hz), 3.15-3.27 (3H, in), 3.29-3.60 in), 3.72 (1H, brd, J 6Hz), 3.92 (1H, brd, J 13.5Hz), 5.93 (2H, dd, J 2Hz. 4Hz), 6.73 (1H, d, J 8Hz). 6.78 (1IH, dd, J 2Hz, 8Hz). 6.88 (1H, d, J 2Hz). MS (DCI/NH3) in/e 489 Anal calcd for C28H44N205 -4 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 Ethylb utyfl-4-(1 .3-b enzodioxol-5-yl)- 1 -N-d i (fbutyflaminocarbovlmethyl-yrrolidile-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. IH NMR (CDC13, 300 MHz) 8 0.85 (6H, in), 0.92 (3H, t, J 7Hz), 0.97 (3H, t, J 7Hz), 1.13- 1.41 (13H, mn), 1.43-1.72 (6H, mn), 2.96 (1H, brm), 3.12-3.52 (6H, in), 3.55-3.70 (1 H, in), 3.70-3.86 (2H, in), 3.99 (1 H, brm), 5.93 (2H, dd, J= 2Hz, 4Hz), 6.73 (1H, d, J 8Hz), 6.78 (1 H, dd, J 2Hz, 8Hz), 6.88 (1H, d, J 2Hz). MS (DCI/NH3) m/e 489 Anal calcd for C28H44N2O5~ 0.45 CF3CO2H: C, 64.28; H, 8.30; N, 5.19. Found: C, 64.16; H, 8.38; N, is1 5.08.

Examole 491 *.:trans, trans- 2 (3-Fl yoro-4 -met hoxyphenyfl) 4 (l .3-benzodi oxpl carboxylic acid Using the procedures described in Example 66, the title compound was prepared. I 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), 25 3.04 (dd, 2H, J=8,10), 3.1-3.6 (in, 5H), 3.78 (mn, 2H), 3.92 3H), 4.60 (in, 1H), 5.97 2H), 6.82 1H, 6.89 (dd, 1H. J=2, 7.01 1H, 7.22 1H, J=9),'7.39 (in, 2H). MS m/e 579 Example 492 trans. trans-2-(4-Methoxy-3-f luoinophenyl)- 4 1.3-benzodiol-YI 1-2(-rp-N4-typrmdn )-laioehlproLdn-3 carboxylic acid 1-Dimethylainino-1-pentene-3-one, prepared by the method described in Syn. Comm. 12 35 (1982), was converted to 2-amino- 4 -ethyl pyriinidi ne with guanidine by the method of Chem. Ber. 97, 3397 (1964). This material was converted to 2-b romo-4- ethyl -pyri mi dine with NaNO2 and HBr, using the method of Helv. Chum. Acta 75, 1629 -436- (1992). This bromopyrimidifle was reacted with ethyl 2-(4m etho xph enyl) 1,3- belzo di oxol-5-y)- I ropyl aminlo) prOPyI]pyrrolidine-3-carboxylate, prepared using the-procedures of Example 6113, using the procedure for Example 418, to give the title compound as a white powder. 1 NMR (300 MHz, CDCI3) 8 0.8-3 J=7Hz, 3H), 1.11 (t.

J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.18-2.27 (in, 1H), 2.45 J=7Hz, 2H), 2.80-2.97 (in, 3H), 3.40-3.75 (in, 7H), 3.83 3H), 5.95 2H), 6.25 J=4Hz, 1H), 6.68 J=8Hz, 1H), 6.79 (dd, J=2Hz, 8H1z, 1H), 6.82 J=9Hz, lH), 6.92 J=2Hz, 1H), 7.05 J=9Hz- 1H), 7.15 (dd, J=2Hz, goo*10 12Hz, 1H), 8.10 J=4Hz, 1H).

00 S Exaingle 493 :.trans.tra s-4-(l.-en hxnhn'--Pd butyl-N ety hnl mnoabnl ty~yrldie3 :15 arboxyIic_ acid Using the procedures described in Example the title compound :was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 J=7.3 Hz, 3H), 1.23- 1.36 (in, 2H), 1.38-1.43 (in, 2H), -2.22 3H), 2.29 3H), 2.79 (d, J=14.9 Hz, 1H1), 2.84 (dd, J=8.6, 9.7 Hz, 1H), 3.16 J=9.5 Hz, 1H), 3.32 5@20 J=15.3 Hz, 1H), 3.43-3.61 (in, 4H), 3.79 3H), 3.88 J=9.8 Hz, 1H), 5.93 2H), 6.74 (in, 3H), 6.83 (in, 3H), 7.04 J= 1.7 Hz, 1 7.11 (in, 311). MS W/e 559(MH+). Anal calcd for C 33 H38N206'0.3H20:

C,

~:70.27; H, 6.90; N, 4.97. Found: C, 70.24; H, 6.62; N, 4.58.

Example 494 trans. trans-24(3-Me thyl~en -3-en-l 1 (N.N-di(n-butylamiflocarbonylmethl)pyrrolidine3carboxlIic acid Using the procedure described in Example 1. the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDC13, 300 MHz) 8 0.92 (3H, t, J 7Hz), 0.97 (311, t, J 7Hz), 1.22-1.40 (5H, in), 1.44-1.61 (8H, in), 1.82 (1H, brm), 2.02 (2H, in), 3.05-3.30 (4H, in), 3.3.8 (1H1. in), 3.55 (1H, brm), 3.85 (2H, in). 4.12 (1H1, brd, J 15Hz), 5.11 (1H, dd, J 6Hz, 12Hz). 5.93 (2H1, 6.73 (11H, d, J 8Hz), 6.78 (1H, dd, J= 2Hz, 8Hz), 6.88 (1 H, d, J 2Hz). MS (DCI/NH3) Wne 487 (M+H) 4 Anal calod for C28H42N2O5 0.7 CF 3 CO2H 62.34; H, 7.60; N, 4.95.

Found: C, 62.49; H, 7.43; N, 4./U.

-437- Example 495 1-NPeya~ncroymty) benzodioxol-5VflDpyrrolidife3carboxylic acid Examp~le 495A N-PhenylbromoacetamideQ To a stirred solution of aniline (7.40 mmol) in methylene chloride ml-) at -50 0 C was added successively N,N-diisopropylethylamine (1.58 mL-, 8.14 mmol, 1.1 eq).and bromoacetyl bromhide (0.72 mL, 7.40 mmol, 1 eq) such that the temperature did not exceed -40 OC. 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 bisulf ate 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 0% 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. tran NPhenylaminocarbo iylmgthyl-2(4- eth x hen lI 0' 0 4-(1 3 benzodioxol5YflDyrrolidne3carboxylic acid Using the procedures described in Example 1 and the compound ~:resulting from Exampe 495A, the title compound was prepared. 1 H NMR (300 MHz, CDC13) 8 8.8 (bs, IH) 7.49 (2H, d, J=8Hz), 7.38 (4H, in), 7.11 (OH, tt, J=8&2Hz), 6.99 (1H, d, J=2Hz), 6.91 (2H, d, J=8Hz), 6.86 (1H, d, J=2Hz), 6.81 (1H, d, J=8Hz), 5.99 (1H, d, J=2Hz), 5.98 (1H, d, J=2Hz), 3.94 (1H, d, J=IOHz), 3.78 (3H, 3.70 (1H, ddd, J=6, 5&3Hz), 3.42 (1H, dd, J=1O&3Hz), 3.41 (1H, d, J=l6Hz), -3.18 (1H1, dd, J=11&9Hz), 3.01 O1H, t, J=lOHz), 2.93 (1H, d, J=16Hz). MS (DCl, NH3) mWe 475 Anal. Calc for C27H26N2O6 1 H20: C, 65.85, H, 5.73, N 5.69, Found: C. 65.95, H, 5.52, N, 5.38.

-438trans, trans-i1 .3-Dim ethylph enyl) am! noca rb onyl mthyl)-2 -(4 methoxyphenyl)-4-(1 .3-benzodioxol-5-yflpyrrolidine-3-carboxylic acid Using the procedures described In Example 1, the title compound was prepared. I1 NMR (300 MHz, CDCI3) 8 8.68 (1 H, bs), 7.64 J=8Hz), 7.38, (2H1. d, J=8Hz), 7.09 (1 H, t, J=BHz), 6.97, d, J=8H1z), 6.90 (11-1 d, J=2H-z), 6.88 (2H, d, J=8Hz), 6.82 (1H-1 dd, J=8&3Hz), 6.76 (1 H, d, J=8Hz), 5.97 d, J=2Hz), 5.96 d, J=2Hz), 3.95 d, J=lOHz), 3.80 3.70 ddd, J=6, 5&3Hz), 3.48'(1H. dd, J=1O&3Hz), 3.44 (1 H, d, J=1l6Hz), 3.18 (1 H, dd,- J=1 1 3.06 (1HA, t, J=1lOHz), 2.96 (1 H.

d, J=l6Hz), 2.31 2.16 MS (DCI, NH-3) m/e 503 Anal. Caic for C29H-30N206 -0.5 H20: C, 68.09, H, 6.11, N. 5.48. Found: C, 68.13, H, 5.91, N, 5.29.

Example 497 *trans. trans-i1 .4-Dimethyl ohenyflaminoca rbonvlmethyfl)-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, CDC13) 8 8.60 (1 H, bs), 7.78 (d, 20 J=8Hz), 7.38, (2H, d, J=8Hz), 6.99 (1H, in), 6.95, d, J=8Hz), 6.94 (1 H, d, J=2Hz), 6.88 d, J=8Hz), 6.82 (1 H, dd, J=8&3Hz), 6.77 (1 H.

d, J=8Hz), .5.97 (1H, d, J=2Hz), 5.96 d, J=2Hz), 3.92 (1 H, d, J=lOHz), 3.79 3.68 (11H, ddd,.J=6, 5&3Hz), 3.43 dd, *J=10&3Hz), 3.42 d, J=l6Hz), 3.18 dd, J=11&9Hz), 3.04 (1 H, t, J=lOHz), 2.95 d, J=l6Hz), 2.29 2.24 MS (DCI, NH-3) ~:mle 503 Anal. Caic for .C29H30N206 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- 1 -(N-(2.5-Dim ethyl 1henyflaminoca rbonylmnethyf- 2 4 4

A

methoxyphenyl)-4-( 1.3-benzodioxol-5-ylboyrrolidine-3-carboxyliC id Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDC13) 8 8.62 (1 H, bs). 7.79 bs), 7.38, J=8Hz), 7.03 d, J=8Hz), 6.95, d. J=8H-z), 6.94 (1H, d, J=2Hz), 6.88 d, J=8Hz), 6.82 dd, J=8&3Hz), 6.77 (1H-1 I..SHZ\,'R 07 OH 1 .92 d. J=lQHz), 3.78 (311, 3.70 (1 H, -439ddd, J=6, 5&3Hz), 3.48 (1 H. dd, J=1 0&3Hz), 3.42 (1 H. d, J=l 6Hz), 3.18 (1H, dd, J=11&9Hz), 3.04 (1H, t, J=lOHz), 2.95 (1H. d, J=l6Hz), 2.29 (3H, 2.24 (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, 67.72; H, 5.89; N, 5.25.

Examn~l 49 trans. trans- I .4-Dimethylphenyflaminocarbonylmethyl)-2-(4methoxyohenyfl-4-( 1.3-benzodioxol-5-yflo1yrrolidine-3-carboxylic acid 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=8Hz), 7.30, (1 H. d, J=3Hz), 7.20 (1 H, bs), 7.08, (1 H, 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 (I1H, d, J=3Hz), 5.98 (1 H, d, J=3Hz), 3.92 (1 H, d, J=l OHz), 3.78 (3H, s), is 3.70 (1H, ddd, 5&3Hz), 3.48 (1H, dd, J=10&3Hz), 3.42 (11H, d, ,,:J=1l6Hz), .3.18 (1 H, dd, J=11I&9Hz), 3.04 (1 H, t, J=l OHz), 2.95 (1 H, d, J=l6Hz), 2.25 (3H, 2.21 (3H, MS (DCI, NH-3) mWe 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.

trans. trans- .5-Dimethylphenyflaminocarbonylmethyl)- 2 4 methoxyphenyl)-4-(1.3.benzodioxol-5.ylpyrrolidine-3-carboxyLiC cidC' Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13) 8 8.75 (1 H, bs), 7.35, (2H, d, 7.10 (2H, 7.02 d, J=3Hz), 6.90 (2H, d, J=8Hz), 6.84 (1H, d, J=2Hz), 6:80, (1H, d, J=8Hz), 6.76 (1H, bs), 5.99 (1H, d, J=3Hz), 5.98 (1H, d, J=3Hz), 3.92 (1H, d, J=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.

Calc for C29H30N206 0.5 H20: C, 68.09; H, 6.11; N 5.48. Found: C, 67.93; H, 6.01; N, 5.19.

-440- Example 501 Alternate Preparation of (+)-trans.trans-1 -(NN-Di(n-butyl)aminocarbonvlmethyl)-2-(4methoxyDhenvl)-4-(1.3-benzodioxol-5-yl)ovrrolidine-3-carboxylic acid Hydrochloride Salt Example 501A N. N-Dibutyl bromoacetamide To a solution of bromoacetyl bromide (72.3 mL, 830 mmol) in toluene (500 mL) cooled to 0 °C was added a soTution 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 the addition, the reaction mixture was stirred at 0 OC for 15 minutes.

A solution of 2.5% aqueous H3P04 (500 mL) was slowly introduced, and .is 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-Nitrovi nyl)- 1.3-benzod i oxole 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 OC. 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.

-441- 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 °C and quenched by 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 15 yellow product concentrate was assayed by HPLC against an external standard and the yield was found to be 9.40 kg Example 501D S" Ethyl 2-(4-methoxybenzoyl)-4-nitromethvl- 3 -(1.3-benzodioxol-5-yli 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 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. Sodium 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.

-442- 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 THF (200 mL) to give a final volume of 100 mL. The mixture was neutralized with 2 f 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 501F Ethyl trans. trans-2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-Yl) 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 o 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.

-443- Example 501G Ethyl (2R.3R. 4S)-(+)-2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl) Dvrrolidine-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 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 hexaneethanol-diethylamine; flow 1 mL/min.; UV detection at 227 nm.

Retention times: (+)-enantiomer: 15.5 min.; (-)-enantiomer: 21.0 min.

Example 501H (2R.3R.4S)-(+)-2-(4-methoxyhenyl-4-( 1.3-benzodioxol-5-vl)- 1 -(NNdi(n-butyl)aminocarbonylmethyl)- 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 0

C.

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 5 with concentrated HCI (12 mL). The organic layer was separated and found to contain 18.3 g (94% yield) of the title compound.

-444- Example 5011 (2R.3R.4S)-(+)-2-(4-methoxvyhenyl)-4-(1.3-benzodioxol-5-vyl- 1-(N.Ndi(n-butyl)aminocarbonvlmethyl)- yDrrolidine-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 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 15 under a nitrogen purge at 50 OC to afford 17.6 g of the title compound.

Example 502 trans, trans-2-(2-Methylpentyl)- 4 -(1.3-benzodioxol-5-yl)-1-(N.Ndi(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Example 502A (±)-Ethyl 3-methylhexanoate .o To a slurry of 60% sodium hydride (2.26g, 57 mmol) in 10mL of 25 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 solvent was removed under reduced pressure to give 3.0g of the title nomnni Ind.

-445- 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 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 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- 1 Ndi(n-butyl)aminocarbonylmethyl)-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.

-446- Example 503 trans. trans-2-(2.2 -D im ethyl le ntyfl-4 .3-ben zod io d i(n-butyl) am inocarbonl methyl)-yrrol idie-3-carboKXyLCacid Ethyl 3,3-dimethylhexanoate was prepared using the general procedure of Cahiez et Tetrahedron Lett., 2.1. 7425 (1990). Using the procedures described in Example 502 and substituting ethyl 3,3dimethylhexanoate for ethyl 3-m ethyl hexano ate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFN/CH3CN. 1H NMR (CDCI3, 300 MHz) 8 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 (in, 5H), 3.60- 3.69 (mn, 1H), 3.75-3.86 (mn, 1H), 3.95-4.16 (in, 2H), 4.28-4.4 (in, 2H), 5.94 2H), 6.74 Hz, 1H), 6.8 (dd, J=8.1, 1,.5 Hz, 1H), 6.87 (d, *J=1.8 Hz, 1H). MS (DCI/NH3) m/e 503 Anal calcd for 15 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-yli-1 (N.N-di(n-butyl)aminocarbonvlmethyl-pyrrolidile-3-carboxylic acid Example 504A Ethyl 5-(1 .3-dioxolyl)-3-oxopentanoate The title compound was synthesized from ethyl acetoacetate and 2-broinomethyl-1 ,3-dioxane, 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 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 m;;nn-r- The resultina orancie color solution was stirred for 10 min -447before 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 o f 9.8 ml (ca. 0.12 mol) concentrated 6 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 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 504C trans, tra ns (24(1.3- D ioxo -2-yi) ethyl)-4-(1 .3-ben zodi oxol -5-yi) -1 .N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid :Using the procedures described in Example 502 and substituting *ethyl 5-(1 ,3-di oxo lyl)-2-oxope ntano ate for ethyl 3-m ethyl hexanoate afforded the title compound. 1 HNMR (CDCI3, 300 MHz) 8 0.93 J =7.2 .Hz, .0.95 J 7.2 Hz, 3H), 1.23-1.38 (in, 1.52 (sextet, J =7.9 Hz, 4H1), 1.85-1.95 (in, 2H), 2.02-2.17 (in, 2H), 3.18 (dd.J 6.0 Hz, Hz, 2H1), 3.30 (dd, J 9.0 Hz, 18.0 Hz, 2H), 3.35 (in, 1H), 3.79 (dd, J 3.6 Hz, 6.9 Hz, 3.83-3.88 (in, 3H), 3.97 (dd, J 4.8 Hz, 6.0 Hz, 1H), 4.05 J 9.6 Hz, 2H), 4.30-4.40 (in, I1H), 4.37 2H), 4.87 J 3.6 Hz, *1H1), 5.94 2H), 6.73 J 8.1 Hz, 11H), 6.79 (dd, J 1.8 Hz, 8.1 Hz, 6.87 J 1.8 Hz, 1H). MS (APCI) at mWe 505. Anal calcd for C27H140N207-1.2 TFA: C, 55.05; H, 6.47; N, 4.37. Found: C, 55.12; H, 6.44; N, 4.27.

30Exml50 trans. trans -2 (2-Tetra hydro-24p~cyran~ethyl-4- (1 .3-ben zodi oxol- N-di(n-butyl~amingcarbonylmethyfl-pyrrolidine-3carboxylic acid -448- Example Ethyl 5(-tetrahydro-2/H pyran) -3-oxoipentanoate 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 trans, transr 2 2 (2-Tetrahydro-2Fspyran~ethyl)-4.( 1.3-ben Zdiogxol- 5-yl)- lAN.N-di(n-butyflaminocrbonylehl.Droii carboxylic acid Using the procedures described in Example 502 and substituting .*ethyl 5-( 2 -tetrahydro-2H-pyran)-2oxopentanoate -for ethyl 3is1 methylhexanoate afforded the title compound as an amorphous solid.

*1 H 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, IOH), 1.42-1.66 (in, 18H), 1.71 (bin, 2H), 1.85 (brm, 2H), 1.96-2.23 (brm, 4H),'3.10-3.29 (in. 8H1), 3.29-3.52 (in, 6H1), 3.54-3.81 (in, 6H), 4.01 J 9 Hz, 2H), 4.12-4.25 (in, 4H), 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 '1H1). MS (APCI) at m/e 517. Anal calcd for C29H44N 2 0 6 -1.4 TFA: C, 56.48; H, 6.77; N, 4.14. Found: C, 56.46; H,1 6.99; N, 3.83.

Example 506 raps. rans- 2 2 24 rrimethyl-3-pntenyl-4- 1 enzoiooll :yl)-1 N-di(n-butyflaminocarbonI m ethyl) -pyrrolidine ca rboxyl ic Example 506A M ethyl _3 3 trdm ethyl-4-he xeno ate To a slurry of isopropyltripenylphosphonium iodide (20.5g, 47mmol) in 200mL of tetrahydrofura 'n was added n-butyllithium (27mL of a 1 .6M solution in hexane, 43mmol), and t he solution was briefly -449warmed to 0 0 C. After recooling, a solution of methyl 3.3-dimethyl-4oxobutenoate (5.7g, 4Ommol), prepared according to the procedure of Hudlicky et Synth. Commun., IE 169 (1986) in l0mL- of tetrahydrofuran was added, and the reaction was warmed to 0 0 C for 30mmn. 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-Triminethyl-3 pente nyl)4-(1I.3-be nzod io xol- yfl)-1-(N .N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502 and substituting methyl 3,3,5-trimethyl-4-hexenoate for ethyl 3-methylhexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFAICH3CN. 1 H NMR (CDCI3, 300 MHz) 8 0.92 J=7.2 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 (in, 2H), 3.10-3.20 (in, 2H), 3.30-3.39 (in, 3H), 3.67-3.82 (in, 3.95-4.08 (in, 1H), 4.32 (in, 2H), 4.37-4.47 (in, 1H), 4.99 1H), 5.95 2H), 6.73 J=7.8 Hz, 1 6.78 (dd, J=8.4, 1.2 Hz, I 6.84 (d, J=1.2 Hz, 1H). MS (DCI/NH3) W/e 515 Anal calcd for C3H4 6

N

2 0 5 .1.05 TFA: C, 60.77; H, 7.48; N, 4.42. Found: C, 60.83; H, 7.20; N, 4.43.

Exampole 507 'trans. trans-2-(2 .2.-Dimethyl-2-(i .3-dioxolan-2-yl)ethyfl-4-(1 .3be nzodi oxol- 5-yfl- 1 N-d i(n-butyfl)amino carbonylm ethyl)p2yrrolidine-3-carboxylic acid -450- Example 507A Methyl 3.3-dimethyl-3-(1 .3-dioxolan- 2-yfl~ropanoate Methyl 3,3-dimethyl-4-oxobutanoate (10g, 7Ommol), prepared according to the procedure of Hudlicky et al, Synth. Commun., 169 (1986), was dissolved in 4Oml- of benzene, followed by addition of ethylene glycol (2OmL-), and p-toluenesulfonic acid monohydrate (1 .3g).

The reaction was refluxed with azeotropic removal of water for 1 hour.

The reaction was poured Into 200ml- of ether, washed with saturated 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.

i' Examole 5078 trans. trans-2-(2.2.-Dim ethyl (1.3-d ioxol an-2-yflethyl)-4- (1 .3be nzodioxol -5-yi I N-d i(n-butyl) ami noca rbonyl methyfl)pyrrolidine-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- .com methylhexanoate afforded the title compound, which was isolated by Ses lyophilization from dilute aqueous TFAICH3CN. 1 H NMR (CDC13, 300 :*se MHz) 8 0.82-1.00 (in, 12H), 1.24-1.40 (in, 4H), 1.43-1.64 (mn, 5H), 1.76- 1.84 (mn, 1H). 2.93-3.00 (in, 1H), 3.15-3.47 (mn, 6H). 3.60-3.70 (in, 3H), 3.74-3.95 (in, 5H), 4.48 1H), 5.94 (mn, 2H), 6.72 J=8.0 Hz, 1H), 6.83 (dd, J=8.0, 1.2 Hz, 1H), 6.94 J=1.2 Hz, 1H). MS (DCI/NH3) Wle 533 Anal calcd for C29H44N207 e1.1 TFAMO.2 H20: C, 56.63; H, 6.93; N, 4.23. Found: C, 56.60; H, 6.96: N, 4.25.

Example 508 trans. trans 3-Dioxo-2-yi) ethyl)-4- (1 .3 -be nzodi oxol -5-Yl)IE ffN44-heot yl -N(2-methyl-3-fluorophenyfll amino carbonylmethyllpyrrolidine-3-carboxylic acid -451- 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 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 (100%).

*o 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 OC 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 ei* *1.31g 1 H NMR (300 MHz, CDCI3) d 0.96 6, J 1.43 4), 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.

-452- 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, 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 15 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 S. 20 bromide in 7 mL of toluene. The solution was stirred for 24 hours, gradually warming to 25 OC, 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 25 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).

-4 53- Example 508F trans, trans-2-(2-(1 .3-Dioxol-2-yl)ethyl)-4-(1 .3-benzodioxol-5-Yn)-1 ffN4-h e otyl-N-(2-methyl-3-fluorophenylUI amino carbonylmethyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting ethyl 5-(1,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate and N,N-(4-heptyl)-(4-fluoro-3-methyl)phenyl-bromoacetamide for N,Ndibutylbromoacetamide afforded the title compound as an amorphous solid. 1 H NMR (CDC13, 300 MHz) 8 0.93 (brt, 6H)-,l.23-1.47 (in, 8H-), 1.67-2.10 (mn, 4H), 2.32 3.16 J 9.0 Hz, 1H), 3.52-3.67 (brun, 3.73 J 9.0 Hz, 1H), 3.81-4.02 (in, 6H), 4.13 (brm, 4.72 (quintet, J 6.9 Hz, 1 4.86 J 4.0 Hz, 1 5.93 6.72 J =8.1 Hz, 1 6.78 (dd, J 1.8 Hz, 8.1 Hz, 111), 6.85 J 1.8 Hz, 1 H), 6.96 (mn, 7.08 J 9.0 Hz, I1H). MS (DC I/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.

20 trans.trans-2-(2-(1 .3-Dioxol-2-yl)ethyl)-4-(1 (N.N-di(n-butyflaminocarbonylinethyfl-pyrrolidine-3-carboxylic acid *o Using the procedures described in Example 502, substituting ethyl (1 ,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate and 6- 25 inethoxypiperonal for piperonal afforded the title compound as an .:amorphous solid. 1 H NMR (CDCI3, 300 MHz) 8 0.93 J 7.8 Hz, 31-), 0.95 J 7.8 Hz, 3H), 1.31 (mn, 4H), 1.53 (in, 4H), 1.90 (mn, 2H1), 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, 3.73 J 10.5 Hz, 1H1), 3.78-3.94 (in, 4H), 3.88 3H), 3.96 (dd, J 5.1 Hz, 6.0 Hz, 1 4.03 (dd, J 3.0 Hz, 6.3 Hz, 4.33 (in.

3H), 4.87 J 3.6 Hz, 1 5.94 21H), 6.53 J 1.8 Hz, 1 6.63 J 1.8 Hz, I1H). MVS (DCI/NH3) at in/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.

-454- Example 510 trans, trans-2 -((2-Methoxypheno xy) -meth 1 .3-benzodioxol 1 N-di(n-butyl~am inocarbonylm ethyl)- lyrroli din e-3-carboxyl ic 'acid Using the procedures described in Example 502. substituting omethoxyphenoxyacetic 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), 0.90 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, 1H1). 3.82 3H1), 3.91 J=l4Hz, TH), 4.05-4.15 (in, 1H), 4.23-4.33 (in, 1H).5.91 2H), 6.70 J=8Hz, 1H1), 6.82-6.95 (in, 1H). MS (DCI/NH3) at mWe 541. Anal calcd for C30H40N207: C, 66.65; H, 7.46; N, 5.18. Found: C, 66.37; H, 7.61; N, 5.09.

D imethylp e ntyfl)-4-(1 ben zod io xol -5-YI) -1 h e tylI- N lu pro -methylgohe ny I amino carbon ylm ethyl)~- :pyrrolidine-3-carboxylic acid Example 511iA trans, trans- N -tert-Butoxycarbonyl-2-(2.2-dimethylpentyl)-4-(1 .3benzodio xol -5-yl)-pyrro Ii dine -3-carbg xylic acid Ethyl trans, trans-2-(2,2-dim ethyl pentyl) yl)-pyrrolidine-3-carboxylate (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 50mL of ethanol followed by addition of sodium hydroxide (l0ml- of a SM aqueous solution). After stirring for 20 hours at room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in 1 5Oml of water, and acidified with concentrated phosphoric acid. The -455mixture 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 1 -N-4-heptvl-N-(4-fluoro-3-methylhenvyl))aminocarbonvlmethyl)pyrrolidine-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 15 was dissolved in 5mL of benzene and evaporated. In a separate flask, (S)-4-benzyl-2-oxazolidinone (1.2g, 6.8mmol) was dissolved in 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.

S. 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 -456warmed 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 20% ethyl acetate/hexanes to give 70mg of the title compound as a crystalline solid (mp137.5 0

C).

Example 511C (2S.3R.4S)- trans. trans-2-(2.2-Dimethylpentvl)-4-(1.3-benzodioxol-5- 25 yl)-1-(N-4-heDtvl-N-(4-fluoro-3methvlDhenyl)aminocarbonylmeth-prrolidinecarb ate The product from Example 510B (65mg, O.10mmol) was dissolved in 1.0mL 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 -4 57from dilute aqueous TFN/CH3CN. 1 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 (mn, 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 2H), 6.96-7.14 (in, 2H). MS (DCI/NH3) mn/e 597 (M+H) 4 Anal calcd' for C35-H49N2F05 -0.05H20 *0.8TFA: C, 63.81; H, 7.30; N, 4.07. Found: 21 C, 63.84; H, 7.18; N, 3.94. [a]D =4460 (c 2.7g/L, CHCI3) Examl 12 trans. trans-2-(2-2-Oxopyrrolidin-1 -yl~ethyfl-4-(1 yl)-l1-(N .N-di(n-butvl)aminocarbonylmethyl)poyrrolidine-3-carboxylic Example 512A 'is 2-Oxopyrrolidin-1-ylorpincad To a stirred solution of 5.0 mL (40.5 rnmol) 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 OC over night. The reaction mixture was then allowed to cool t o room temperature, extracted with inethylene 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.

:25 Example 512B Ethyl, 5- (2 -oxooyrrol idin- 1 oxope ntan oate The title compound was prepared from the above acid by adapting the method of Brain and Vilkas, Bul. Chem. Soc. Fr., 945 (1964).

-458- Example 5120 trans. trans-2-(2-(2-Oxogyrrolidin-1 -yflethyl)-4-( 1.3-benzodioxol-5yfl-l N-di(n-butyflamlnocarbonylmethyfl-pyrrolidin-3-carboxylic acid Using the procedures described in Example 502, substituting ethyl 5-(2-oxopyrrolidin-1 -yl)-3-oxopentanoate. for ethyl' 3methythexanoate afforded the title compound as an amorphous solid.

1 H NMR (CDCI3, 300 MHz) 8 0.91 J 7.5 Hz, 3H), 0.94 J 7.5 Hz, 3H), 1.23-1.38 (in, 4H), 1.44-1.60 (mn 4H1), 2.05 6.9 Hz, 2H), 2.12- 2.25 (mn, I1H), 2.38 (td, J 4.2 Hz, 8.4 Hz, 2H), 2.47-2.6 1 (mn, 1 3.17 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, I1H), 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, 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 C28H41 N306-1.4 TFA: C, 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-Dl oxo I-2-yi) ethyfl)-4-(7-m ethoxy-1 .3 be nz od io x o I-5 1 N-4 -h e pty I- N -f Iu or o -3 m ethyl 1he nyl)) am inocarbonylm ethyl)-pyrroli din e-3-carboxyl ic acid Using the procedures described in Example 502, substituting ethyl 5-(1,3-dioxolyl)-2-oxopentanoate for ethyl 3-inethylihexanoate, N-4- :heptyl-N-(4-fluoro-3-inethylphenyl) bromoacetamide for N,N-dibutyl bromoacetainide and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1 H NMR (CDC13, 300 MHz) 5 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, 1H), 3.60-4.03 (in, 8H), 3.88 3H), 4.21 (brs, 1H), 4.72 (quintet, J 6.6 Hz, 1 4.86 J 3.6 Hz, 1 5.93 2H1), 6.49 1 6.61 6.96 (in, 2H), 7.08 J 9 Hz, 1H). MS (DCI/NH3) at in/e 629. Anal calcd for C34H45N20 8 F.1.0 TFA: C, 58.21; H, 6.24; N, 3.77.

Found: C, 58.11; H, 6.11; N, 3.58.

-459- Example 514 trans, trans-2-(2.2- DimethyIentvyl)-4-7mehrr 3 bnoiooyl)-l1-(N .N-di(nbutyLgaminocarbonlmethyl).~yrrolidine 3 carboxyli acid Using the procedures described in Example 502, substituting ethyl 5-methyl-3-oxooctanoate for ethyl 3 -methylhexanoate and 6methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1 H NMVR (C~DC 3 300 MHz) 8 0.81 3H), 0.84 3H-), 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, 1.45-1.59 (in, 4H), 1.84-2.00 (in, 2H1), 3.15 (dd, J 6.9 Hz, 10.0 Hz, 211), 3.30-3.42 (in, 3.72 J 10.5 Hz, 3.86 (t, J 10.5 Hz, 1 3.88 3H1), 4.02 J 10.0 Hz- 1 4.12 J 16.8 :Hz, 1H), 4.29 J 16.8 Hz, 1 4.41 (brm, 1 5.94 1 6.52 J =1.8 Hz, 1H1), 6.67 J 1.8 Hz, 1H1). MS (DCI/NH3) at m/e 533.

Anal calcd for C30H148N20 6 .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.-dimethylpentyl)4(23dihydrobenzofurn5-i) 1 .N-d ~~uy~mnocarbonylmethyl)..pyrrolidine.3-carboxylic acid Using the procedures described, in Example 502, substituting ethyl 3,3-di methylhexanoate for ethyl 3-m ethyl hexanoate and 2 ,3-dihydrobenzofuran-5-carbaldehyde for piperonal afforded the title compound :as an amorphous solid by lyophylization with CH3CNITFA/H 2 0. I1 NMR (300 MHz, CDCI3) 8 0.83 3H). 0.85 0.86 J=7.2 Hz, 3H), 0.92 J=7.2 Hz, 3H1), 0.95 J=7.2 Hz, 1.09-1.39 (mn, 8H), 1.44-1.59 (in, 1.88 (dd, J=15.0. 7.2 Hz, 2.00 J=1 5.0 Hz, 1H1), 3.09 (in, 2H1), 3.18 J=9.0 Hz, 3.27-3.38 (mn, 3.65-3.95 (in, 4.05 (q, J=10-0 Hz, 1H1), 4.18 J=16-8 Hz, 4.30-4.45 (in, 2H), 4.55 Hz1,-21-), 6.70 J=8.4 Hz, 1H1), 7.04 (dd, J=8.4, 2.1 Hz, 1H), 7.23 (brs, MS (DCIINH3) at Wne 501 Anal calc'd for C30H- 48

N

2 O4.1.05 TFA: C, 62.14; H, 7.97; N, 4.51. Found: C, '62.19; H, 8.00; N, 4.43.

-460- Example 516 trans, trans- 2- (2.2 Dim ethvl -2 .3-dio xol an -2-yl) ethyfl)-4-( 1methoxy- 1.3-benzodioxol-5-yl1-(N.N-di(nbutyflarninocarbonylmethyI)-rpyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting methyl 3.3-di methyl ioxol an-2-yl)prop anoate for ethyl 3methyihexanoate and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid by lyophylization with CH3CNITFAIH2O. 1 H NMR (CDCI3, 300 MHz) 8 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, 1H1), 2.13 J=15.9 Hz, 1H1), 3.20 (dd, J=7.7, 7.7 Hz, I 3.26-3.40 (in, 3.60 (in, 1 3.75-3.86 (mn, 3H), 3.88 3H), 3.93-4.01 (mn, 3H), 4.00-4.11 (i 1H), 4.23 J=15.9 Hz, 1 4.37-4.48 (in, 2H), 4.49 1 5.94 2H), 6.51 J=2.1 Hz, 1IH), 6.64 J=2.1 Hz, 1H). MS (DCI/NH3) at m/e 563 Anal calcd ~for C30H46N208-0.9 TEA: C, 57.41; H, 7.11; N, 4.21; found: C, 57.35; H, 6.86; N, 4.05.

Example 517 0000 trans. trans-2-(2-(2-Methoxyphenyfl-ethyl)-4.(1 1 N-di (n-butyl) ainoca rb onylinethyfl)-pyrrolid in e-3-carbo xyl ic acid Using the procedures described in Example 502, substituting o- **25 inethoxyphenyipropionic acid for 3-inethylhexanoic acid,, the above 7. :compound was prepared as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.85 J=7Hz, 0.91 J=7Hz, 3H), 1.10-1.27 (mn, 4H), 1.42- 1.60 (mn, 4H), 1.72-1.89 (mn, 1H), 1.91-2.02 (in, 1H), 2.55-2.77 (mn, 2H), 2.94 J=6Hz, 1H), 3.05-330 (mn, 6H), 3.59-3.82 (in, 3H1), 3.73 (d, J=l4Hz, 1IH), 3.77 3H1), 5.91 2H1), 6.70 J=8Hz, 1H), 6.78-6.88 (mn, 3H),6.92 J=2Hz, 1IH), 7.08-7.19 (mn, 2H). MS (DCI/NH3) at Wne 539. Anal calcd for C31H42N206: C, 69.12; H, 7.86; N, 5.20. Found: C, 68.89; H, 7.70; N, 4.99.

-461- Examgle 518 trans, trans-2-(2.2-Dimethyl-3-(E-pentenyl)-4-( -methoxy-1 .3ben zodioxol-5-yfl1-1 N-di(n- butyl) ami noca rbonyl met hyl).

pvrrolidine-3-carboxylic acid Example 518A 4-M ethyl- 3-penten-2-ol To a stirred solution of 3-methyl-2-butenal (8.7g, 1O3mmol) in lOOmL of tetrahydrofuran under N2 at 0 OC was added methylmagnesium bromide (38mL of a I.OM solution in ethyl ether, 1 l4mmol) 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.

Example 518B trans-Ethyl 3.3-dimethyl-4-gentenoate A mixture of 4-methyl-3-penten-2-ol (7.4g, 74mmol), triethyl orthoacetate (13.6mL. 74mmol) and propionic acid (0.28mL. 3.7mmol) :25 was heated at 150 0 IC for 7 hours. The product was then distilled under *.:normal pressure (200-220 OC) to give 5.Og of crude ester as a colorless oil.

Exampl~e 518BC trans. trans-2(2 .2-D im ethyl- 3 -(E)-gentenyl)-4- (1 -methoxy- 1 .3benzodioxol-5-yl)-1 -(N.N-di(n-butyl)aminocarbonylmethyflpyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting trans-ethyl 3.3-dimethyl-4-penteno ate for ethyl 3-m ethyl hexanoate and 6-m ethoxypiperonal for piperonal afforded the title compound as an -462amorphous- solid by lyophilization from dilute. aqueous TFAICH3CN. 1H NMR (CDCI3, 300 MHz) 8 0.92 J=7.2 Hz, 0.95 J=7.2 Hz, 3H), 0.97 8H), 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 (in, 3H), 3.75 (in, 3.87 3H), 3.99 J=9 Hz, 2H), 4.11-4.30 (in, 3H), 5.29 (d, J=15.6 Hz, 1H), 5.38 (dd, J=15.6, 6 Hz, 11H), 5.94 2H), 6.50 J=1.8 Hz, I1H), 6'63 J=1.8 Hz, 1 MS (DCl/NH3) at mWe 531 Analysis calc'd for C30H-46N206.0.95 TFA: C, 59.95; H, 7.41; N, 4.38; found: C, 60.00; H, 7.33; N, 4.35.

Example 519 trans, trans-2-(3-(2-pvridyflethyl)-4-( 1.3-benzodioxol-5-yl)-l-(N.Ndi(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-pprbgxylic acid Example 519A 3-(2-Pyridvl)-propionic Acid :In a 50 mL round-bottomed flask equipped with a stirring bar was 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 inmol) while the reaction temperature was maintained at 50 OC. After the addition was completed, the mixture was held at 50 OC until the color of the reaction mixture turned brown, then heated at 80 OC 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)-p ro pion ic acid (0.88 g, 78%).

-4 63- Example 51913 trans, trans-2 -(3-(2-Dyri dyl) ethyl) 1.3-be nzodioxol- 5-yfl)-1 (N.N di(n-butyl)aminocaronylmethyl)-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 8.65 J=6.0 Hz, I 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 4.29-4.18 (in, 1 4.04 (dd, J=20.1. 10.5 Hz, 1 3.84 J=12.6 Hz, I 3.62 (dd, J=13.8, 9.6 Hz, I1H), 3.46-3.13 (in, 2.51 (broad s, 2H), 1.60-1.43 (in, 4H), 1.37-1.22 (in, 4H), 0.91 J=8.4 Hz, 6H). MS (DCI/NH3) m/e 510 Anal calcd for C29H39N305*1.75 TEA: C, 55.04; H, 5.79; N, 5.92. Found: C, 55.08; H, 5.64; N, 5.81.

(29. Example 520 12.3R. 4S)-2-(2-(2-oxopyrrolidin-1 -yl~ethyl)-4-(1 I N-di (n-butyflainnocarbonylm ethyfl)-pyrrol dine-3-ca rbo Ky"Ic acid Examiole 520A (2S. 3R. 40)-E th yl-2-(2- oxopyrrolidi n- 1 -yl) ethyl) (1 .3b en zo d ioxo I- 5-y p y-rroIi d in e- 3-ca rbo xyl at e M an delate 25 The racemic amino ester from Example 512 (3.45g, 8.98minol) in lOmL of ethyl acetate was treated with (S)-(+)-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.

The solution was left stirred at room temperature over night. The crystals was then collected by filtration, recrystalized from ethyl acetate/hexane twice to give a yield of 800 mg of pure salt.

-464- Examole 520B (2S. 3R. 4S2)-Ethyl-2-(2-(2-oxopyrrolidin- 1 -flethyl)-4-(1 .3benzod oxol-5-yD -l1 N-d i(n-butyfl)ami no carbonylmrnethyl Ipyrrolidine-3-carboxylate To a stirred solution of pure mandelate (150 mg. 0.28 mmol) in CH3CN was added NN-dibutylbromoacetamide(84 mg, 0.34 mmol) and diisopropylethylamine (98uL, 0.56mmol). The resulting mixture was stirred at room temperature over night. Solvent was then removed under reduced pressure and the .crude product wg s purified by silica gel flash chromatography to give 140 mg (90% yield) of the title compound.

Examdle 5200 (2S, 3R. 4S)-2 -(2-oxopyrrolidin- 1-yfl ethyl) .3-benzod is yfl- -(N.N-di(n-butyflaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid :Using the procedures described in Example 502, the title compound was prepared as an amorphous solid by lyophylization with 20 CH3CNITFAIH2O. 1 H NMR (CDCI3, 300 MHz) 8 0.91 J 7.5 Hz, 3H-), *0.94 J 7.5 Hz, 1.23-1.38 (in, 4H), 1.44-1. 60 (m 2.05 J 6.9 Hz, 2H), 2.12-2.25 (in, 2.38 (td, J 4.2 Hz, 8.4 Hz, 2H), 2.47- 2.61 (mn, 1H), 3.17 (dd, J 6.0 Hz, 8.7 Hz, 3.24 J 9 Hz, 3.32 J 7.8 Hz, 3.38-3.48 (mn, 3.52 J 9 Hz, 1H), 3.66 J= 6.9 Hz, 1H), 3.96 (in, 2H), 4.14 (in, 4.38 (brs, 5.93 6.74 J 8.1 Hz, 1 6.89 (dd, J 1.8 Hz, 8.1 Hz, 1 6.87 J 1.8 Hz, MS (DCI/NH3) at mn/e 516. Anal calcd for C28H41 N306-0.85 TEA: C, 58.23; H, 6.89; N, 6.86. Found: C, 58.37; H, 6.90; N, 6.84.

-465- Example 521 (2S. 3R. 45)-2-(2-(2-oxogyrrolidin-l -yllethyli-4-(1 .3ben zodioxol-5-y- 1 -(N-4-heptvl -N-(4-fluoro-3m ethyl phenyl))aminoca rbonlmethyl)-pyrrol idi ne-3carbo xylic acid Using the procedures described in Example 520, substituting NN- 4 -heptyl)-(4-fluoro-3-methyl)phenyl-bromoacetamide for N,Ndibutyibromoacetamide afforded the title compound as an amorphous solid by lyophylization with CH3CN/TFA/H20. 1 H NMVR (CDCI 3 300 MHz) 8 0.85 -0.98 (in, 6H), 1.22-1.55 (in, 8H), 2.04 (quiriliet, J=7.9 Hz, 4H), 2.32 3H), 2.36 J=7.9 Hz, 2H), 2.61 (in, 1H), 3.14 (in, 1H), 3.25-3.61 (mn, 5H), 3.66-3.77 (in, 1H), 3.79-3.90 (mn, 2H), 3.92-4.03 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 mWe 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.

Example 522 trans. trans-2-(2-(1-opyrazolyflethyl)-4-(1 .20 (N.N-di(n-butyl~aminocarbonylmethyfl)-Dyrrolidine-3-carboxylic acid Exaile 522A 3-(1 -Pyrazolyfl)-ropionic Acid In a 10 mL round-bottomed flask equipped with a condenser and a stirring bar was placed pyrazole (0.50 g, 7.3 minol), acrylic acid (0.50 iL, 7.3 inmol) and triethylamine (3 mL). The reaction mixture was refluxed for 6 hours. After removing triethylainine, 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.

-466- Example 5228 trans. trans-2-(2-(1 -Dyrazolflethyl)-4-(1 .3-benzodioxoL-Yvu.-- N-di(n-butyl) am inocarbonyl methyl)-pyrroli din e-3-artboxyi ic 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) 87.56 J=3.0 Hz, I1H), 7.50 J=3 Hz, 1H), 6.83-6.66 (in, 3H), 6.28 J=3 Hz, 1H), 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 (mn, 5H), 2.69-2.43 (in, 2H), 1.59-1.42 (in, 4H), 1.38-1.21 (in, 4H), 0.91 J=7.5 Hz, 6H). MVS (DCI/NH3) at m/e 499 Anal calcd for C27H38N40 5 O.75 TFA: C, 58.60; H, 6.69; N, 9.59. Found: C, 58.53; H, 6.45; N, 9.67.

Examlle 523 trans. trans-2-(4-Methoxyohenyl)-4-(l. 3-benzodioxol-5-yfl)-1-r(N- :butyl-N-(3-hvdroxyprooyl)amino)carbonylmethyllpyrrolidine-3 carboxylic acid Examole 523A N-Butyl-N-(3-hydroxy rooyl)-ainine a solution of 15.9g (100 inmol) of methyl 3-N.(nbutyl)aminopropion ate in 150 mL of diethyl ether at 0 *C was added mL (0.35 inmol) of 1.OM LiAIH4 in diethyl ether, keeping reflux at a 7. 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 NaQH(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.

Example 523B N-Butyl-- 3-hydroxypro"yf-chloroacetainide 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 -467- 1.71g (10.0 mmol) of chioroacetic anhydride in lOmL 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), 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 to give 723 mg of a light yellow oil.

Example 523C trans. trans-2-(4-Methoxychenyw4(-1 butyl-N-(3-hyd roxylrol~l)amino)carbonylmethyll-oy rolidine.

3 carboxylic acid :Using the procedures described in Example 'iD, substituting Nis 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. 1H NMR (CD3OD, 300 MHz) 8 0.78-0.95 (in, 1.00-1.80 (mn, 4H), 2.80-3.65 (mn, 15H), 3.80 J=1.5 Hz, 2H), 5.93 2H), 6.72- 207.05 (in, 5H), 7.33-7.40 (in, MS (DCI/NH3) at W/e 513 Anal calc'd for C28H36N2O 7 01.6 H20: C, 62.12; H, 7.30; N, 5.17. Found: C, 62.04; H, 7.21; N, 4.88.

Example 524 trans. tans..2.(4.Methoxyohenyl).4-(1 .3-benzodioxol5yl)i..1-r(Nn )croym.hl-yoldn--croyi acid Examole 524A N-Boc-0-allylhydrgxylamine 0-Allyihydroxylamine hydrochloride hydrate (5.0g) was dissolved in THF (15 inL. The solution was cooled to 0 0 C in an ice bath.

Diisopropylethylainine (8inL) and di-t-butyldicarbonate (10.0g) were added. The mixture was stirred at OOC for 1 hour at which point the bath was removed and the reaction allowed to warm to room -468temperature and stirred overnight. The THF was removed in vacuo and 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 s with sodium sulfate and evaporated to give a light yellow oil which was used without any further purification.

Example 524B N-Boc-N-proDyl-O-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 s: 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 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 20 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 Example 524C N-Boc-N-propyl-N- propoxyamine 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 which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give the title compound as a colorless oil (5.8g).

-469- Examlle 524D N-Prol-N- Droloxyamine hydrochloride N-Boc-N-propyl-N-propoxyamine (5.8g) was dissolved in 4N HCI/dioxane (l0mL-) and stirred at room temperature for 7 hours. the solvent was removed in vacuo and the residue triturated with diethyl ether. The resulting yellow solid (2.1g) was collected by filtration and washed with diethyl ether.

Example 524E N-1 ropyl-N-propoxy-bromoacetamide N-Propyl-N-propoxyamine hydrochloride (0.30 g) was dissolved in acetonitrile and cooled to -20 0 C. Pyridine (0.2 ml-) was added.

is1 Bromoacetyl bromide (0.15g) was added dropwise over 5 min. The solution was stirred at -20 0 C 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 20 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 chloroand bromoacetamides in a ratio of -3:1.

Example 524F trans. trans-2-(4-Methoxylhenyl)-4-( 1.3-benzodioxol-5-yfl-l1-r(Nbutyl-N-(3-hyd roxyproo~yl)amino)carbonylmethyll-o2yrrolidi ne-3- :carboxylic acid Prepared according to the procedure of Example 523C, employing N-propyl-N-propoxy-bromoacetamide and ethyl 2-(4-methoxyphenyl)- 4- ben zod ioxolI- 5- yl)-pyrroli din e-3-carboxyl ate. The crude product was purified by preparative HPLC (Vydac mCl8) eOuting with a 10-70% gradient of CH3CN in 0.1% TFA. The appropriate fraction was lyophilized. to give the product as a white solid. 1H NMR (CDCI3, 300 IAHz) 8 0.87 (in, 6H, J=8Hz), 1.49 (mn, 2H, J=8Hz), 1.61 (in, 2H, J=8Hz), 3.55 (mn, 6H), 3.80 (in, 2H), 3.81 3H), 4.00 (in, 2H), 4.13 2H, -470- J=17Hz), 5.96 2H), 6.77 1H, J=9Hz), 6.90 3H), 7.05 1H, J=1Hz), 7.44 2H, J=9Hz). MS (DCI/NH3) m/e 499 Anal calcd for C27H34N207 1.20 TFA: 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-MethoxyDhenyl)-4-(1.3-benzodioxol-5-yli-1l-rNbutyl-N-proDoxyamino)carbonylmethyll-pyrrolidine-3-carboxylic acid Example 525A N-butyl-N-(2-hydroxvethyl)-amine In a thick walled glass tube 5 ml (100 mmol) of ethylene oxide was condensed at -78'C. To this12.5 ml (120 mmol) of butylamine 15 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.

o.

Example 525B 20 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 Sreaction 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 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 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 -471chromatography, 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-aminoethylamino)carbonylmethyll-pyrrolidine-3carboxylic 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 15 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 mmol) of the azide was added 1mL of 1M HCl(aq.), 0.5 mL of dioxane, 20 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. 1 H 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.

-472- Example 526 trans. trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-vl-1 -r(Nbutyl-N-(3-aminopropyl)amino)carbonylmethyll-Dyrrolidine-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 ImL of DMF was added 65 mg (10 mmol) of sodium azide. The mixture was stirred for 1 hour 15 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 20 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 this 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 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 C28H37N30 6 -3.0 TFA: C, 47.84. H, 4.72. N, 4.92. Found: C, 47.86; H, 4.75; N, 4.97.

-473- Examole 527 trans. trans-2-(4-Methoxy phenyfl-4-(1 butyl-N-(3-di methyl ami nop ro pyflami no) carbonyl methy12jrro ictin e-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 mnL of 48% HBr(aq.), and 1.5 mL of conc. H2S04. The reaction 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 .0 :20 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 purified 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-Methoxyphenfl)-4-(1 .3-benzodioxol-5-yfl)-1f(N-butyl-N-(3-bromoprooflamino)carbonylmethyll-pyrrolidine-3carboxylate According to the procedure of Example 523C, N-butyl-N-(3bromopropyl-bromoacetamide was coupled with ethyl 2-(4- Methoxyphe nyl)-4- (1 ,3-ben zo diox ol-5-yl)-pyrrolidine-3-carboxyI ate.

The crude product was chromatographed on silica, using 40% EtOAc in hexanes to elute.

-474- Example 527C trans, trans-2-(4-Methoxyphenyl 1 .3-benzodioxol-5-yl)-1 butyl-N;.(3-dimethylaminopropyl) amino) carbonylmethy-Yo.yrrolidine-3carboxylic acid To 400 mg (0.663 mmol) of the compound of Example 5278 in 4 mL of absolute EtOH was added 1.2 mL of 2.0 M Me2NH in THF. The reaction was heated at 50 *0 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 CH2CI2: MeOH over about 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 H3P04, and the product :was purified by preparative HPLC. 1 HNMR (CID300D, 300 MHz) 8 0.92 (t, J=7.0 Hz, 3H), 1.22 (in, 1.39 (in, 1.90 (in, 2H), 2.87 6H), 3.07 (mn, 3.24 (in, 1 3.43 (in, I1H). 3.62 (in, 1 3.84 3.88 (in, :20 4.07 (mn, 11H), 4.17 (in, 1H), 4.97 5.97 6.83 J=8.1 Hz, 1H), 6.93 (dd, J=1.7, 8.1 Hz, 7.05 (in. 7.53 (in, MS (DC I/NH3) at W/e 540 Anal calcd for C30H-41 N306-2.95 TFA: C, 49.22. H, 5.06. N, 4.80. Found: C, 49.16; H, 5.11; N, 4.62.

Example 528 *.tans trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)-1 -r(N- *butyl-N-(3-tri methyl amnno ni o ropyfl amino) carbonyl m ethyll pyrrolidine-3-carboxyli-c acid Prepared according to the procedures of Example 527C, substituting aqueous Me3N for Me2NH. 1 H NMR (CD3OD, 300 MHz) 8 0.91 (in, 1.24 (mn, 1.40 (in, 2H), 1.99 (in, 2H), 3.13 3.18 (S.

rotainer), 3.20 (in, 3.39 (in, 4H), 3.72 (in, 3.84 4.03 (in, 4.35 (in, 1 5.19 (mn, 1 5.97 6.84 J=8.1 Hz, I1H), 6.96 (dd, J=1.7, 7.9 Hz, 7.10 (in, 7.62 (in, MS (DCI/NH3) at W/e -475- 554 (M+H) Anal calcd for C31H44N306-0.1 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-yl)-1-[(Nbutl-N-(4-minutyl)amino)carbonylmethyl-pyrrolidine-3carboxylic acid Example 529A N-butyl-N-(4-hydroxybutyl)-amine A solution of 8.1 g (110 mmol) of n-butylamine and 8.6 g of i* butyrolactone in 50 ml toluene was allowed to reflux under nitrogen atmosphere for 50 hours. Volatile solvents were removed in vacuo. To 15 a solution of 3.18 gm (20 mmol) of the resultant N-butyl -4hydroxybutyramide in 50 ml of toluene were added 120 ml (120 mmol) 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.

Example 5298 25 N-butyl-N-(4-hydroxybutyl)-chloroacetamide 0e Pyridine (2 ml) was added to an ice cold solution of 0.58 gm (4 mmol) of N-butyl-N-(4-hydroxybutyl)-amine in 10 ml of EtOAc. To this solution 0.769 gm (4.5 mmol) chloroacetic anhydride was added in small portions. The reaction mixture was allowed to stir for 5 hours at O'C, and then was allowed to warm 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.

-476- Exampole 529C Ethyl- trans, trans-2-(4-Methoxyphenvl)-4-(l1.3-benzodioxol-5-yfl- 1f(-uy--4hdoyuy~mnocroymtvIpr~iie3 carboxylate According to the procedure of Example 523C, N-butyl-N-(4hydroxybutyl-chloroacetamide was coupled with ethyl 2-(4- M etho xyph enyl) (1 ,3-b en zodi oxol-5-yl) -pyrroli dinle-3-carbo xylate.

The crude product was chromatographed on silica gel.

Example 529D Ethyl trans, trans-2-(4-Methoxypheflyfl- 4 V. r( N-butyl-N -(4-bromobutyflam ino~carbonyl methyll-pyrrolidine-3- *~**carboxylate To the solution of 0.180 gm (0.33 mmol) of the compound of Example 529C 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 O*C 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.

Example 529E :25 trans, trans-2-(4-Methoxyphenyl'l- 4 .3-benzodioxol-5-yfl-l -l(Ncarboxylic 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 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 flushed with hydrogen by placing a balloon filled with hydrogen.

-477- 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 1 N H3P04, and the product was purified by preparative HPLC. IH NMR (CD3OD, 300 MHz) 8 0.90 J=7 Hz, 3H), 1.10-1.65 (in, 6H1), 2.85-2.95 (in, 2H1), 3.00- 4.10 (in, 14H), 5.50 J=3 Hz, 2H), 5.97 2H1), 6.82 J=8 Hz, 1H), 6.91 (dd, J=7 Hz, 1H), 7.00-7.06 (mn, 3H), 7.45-7.55 2H). MS (DC I/N H3) at mWe 526 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.

Examp~le 530 trans, trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yi)l'-f (Nbutyl-N-(4-dim ethyl aminobutyl) am in o)ca rboyl miethyll -pyrrol idi ne-3carboxylic acid :The title compound was prepared from the compound of Example 529D, employing the procedures of Example 527C. 1H NMR (CD3OD, 300 MHz) 8 0.90 (dt, J=7Hz, 3H), 1.1-1.75 (mn, 8H), 2.75 J=7 Hz, 6H), 4.25 (mn, 16H), 5.97 2H), 6.83 J=8 Hz, 1H), 6.93 (dd, J=8 Hz, 1H), 7.02-7.08 (mn, 3H), 7.49-7.56 (mn, 2H). -MS (DCI/NH3) at mWe 554 Anal calc'd for C31H43N306*2.1 TFA: C, 53.31; H, 5.73; N, 5.30. Found: C, 53.50; H, 5.38; N, 5.34.

Example 531 trans, trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yl)-1-r(Nbuy--3prdlaiocroymtylproiie3c oyi ai Exampe 53A N -but yl -N yrid yI)i- amine To a solution of 941 mg (10 minol) of 3-aininopyridine and 0.9 mL of butyraldehyde in 30 mL of CH30H was added 10 mL of glacial acetic -478acid. The mixture was stirred at room temperature for 1 hour, then the reaction was cooled with an ice bath, and 650 mg (10.3 mmol) of sodium cyanob orohyd 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.

Example 531 B trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 -r(Nbutyl-N-(3-o2yridflamino~carbonylmethyll-pyrrolidine-3-carboxylic :0....acid .710 The compound of Example 531A was reacted according to the a a: procedures of Example 523, to give the title compound. 1 HNMR (D6- DMS0, 300 MHz) 8 0.80 J=6.4 Hz, 3H), 1.15-1.99 (in, 4H), 2.59 (in, 1H), 3.05 (in, 2H), 3.26 (in, 2H), 3.49 (in, 2H1), 3.56 J=7.1 Hz, 2H), 3.73 (s, *:20 3H), 6.00 2H), 6.80 (mn, 3H), 6.85 J=8.1 Hz, 1H), 6.98 (in, 2H), 7.04 (in, 1H), 7.41 (dd, J=1, 4.7 Hz, 8.1H), 7.58 (in, 1H), 8.36 (bs, 1H),,8.54 (bs, 1H), 12.24 (bs, 1H). MS (DCI/NH3) at m/e 532 Anal calcd for C301133N306-0.1 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-Methoxyo~henyl'i-4-( 1.3-be nzodioxol-5-yfl-1 -f(Nbutyl-N-(3-aminomethylphenyflamino)carbonylmethyll-pyrrolidine-3carboxylic acid Example 532A N-butyl-N-(3-hydroxymethylphenyl)-amine To a solution of 3.69 g (30 minol) of 3-amino benzyl alcohol in ml DMSO was added 3.78 g (45 mmol) solid NaHC03 and 2.91 ml (27 mmol) 1-bromobutane. The reaction was allowed to stir at 50 'C for -479- 18 hours (overnight). Reaction was worked up by adding 250 ml water 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-butvl-N-(3-hydroxymethvlDhenvl)-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 15 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.

Example 532C 20 Ethyl trans, trans-2-(4-MethoxyDhenyl)-4-(1.3-benzodioxol-5-yl)-1f(N-butyl-N-(3-chloromethylphenyl)amino)carbonylmethyll-pyrrolidine- 3-carboxylate According to the procedure of Example 523C, N-butyl-N-(3- 25 hydroxymethylphenyl)-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 0 C; 19 mg of LiCI was added, followed by 85 p~ 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.

-480- Example 532D trans, trans-2-(4-Methoxyphenyvl-4-(1.3-benzodioxol-5-yl)-1-(Nbutyl-N-(3-aminomethylphenyl)amino)carbonylmethyll-pyrrolidine-3carboxvlic acid The compound of Example 532C (182 mg) was dissolved in 1 mL of DMF. Two drops of water were added, followed by 126 mg (2.0 mmol, eq) of sodium azide. The resultant solution was heated at 115 °C 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-Methoxyphenyl)-4-(1.3-benzodioxol-5-yli-1-r[N- 15 butvl-N-(3-aminomethylphenyl)amino)carbonylmethyll-pyrrolidinecarboxylic acid In a 50 ml round bottom flask 0.090 gm Tin (II) chloride was suspended in 1 ml acetonitrile. Triethylamine (0.2 mL) was added, 20 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 mixture was allowed to stir for 30 min. Ether (10 ml) was added, followed by addition of 10 ml 2N HCI The aqueous extract was 25 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. 1H NMR (CD30D, 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 7.40 J=9 Hz, 2H), 7.56 J=5 Hz, 2H). MS (DCI/NH3) at m/e 560 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.

-481- Examole 533 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-vfl)-1-fNbutyl-N-(3-trimethylammoniomethylphenyflami no'Icarbonylmethyllpyrrolidine-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. 1 N HCI was added; 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 gin. 1 H NMVR (300 MHz, D6- 8 0.83 J=7 Hz, 3H), 1.15-1.40 (in, 4H), 2.62 2H), 3.35 (s, 15 9H), 3.40-3.80 (in, I0H), 4.47 2H), 6.00 J=3 Hz, 2H), 6.75-6.90 (in, V 3H), 7.25-7.37 (mn, 2H), 7.45-7.60 (mn, MVS (DCI/NH3) at me/& 602 Exampole 534 2R.3R.4S)-2-(3-Fluoro-4-methoxyrphenfl)-4-(1 .3-benzodioxol-5-yfll (2-(N-grooyl-N-2entanesulfonylamino'ethyfl)-oyrrolidine-3-carboxylic acid Example 534A Ethyl (3-f luoro-4-inethoxy~benzoyl acetate Sodium hydride (17g of a 60% suspension in mineral oil) is 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 0 C, and a solution of 25 g of 3-fluoro-4- z methoxyacetophenone and 50 ml of diethyl carbonate in 50 ml of toluene was added portionwise. Heating is continued for 30 min, then 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 -482is dried over Na2SO4 and decolorized with charcoal to give 34.5 g (97%) of the title compound.

Example 534B Ethyl 2-(3-Fluoro-4-methoxyDhenyl-4-(1 pyrrolidine-3-carboxylate The compound of Example 534A (12.5 g) and 5-(nitrovinyl)-1,3benzodioxole (13.1 g, 20% excess) were suspended in a mixture of 75 ml of THF and 13 ml of IPrOH. DBU (0.25 g) was added, and the mixture was stirred at room temperature for 30 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 ml of concentrated HCI. The mixture was extracted twice with toluene; 15 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 concentrated in vacuo; the residue is chromatographed on silica, eluting 20 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 greenyellow; after color persists, the reaction mixture is stirred for an 25 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.

-483- Examole 534C Ethyl (2R.3R.4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1.3-benzodioxol- 5-yl)-pyrrolidine-3-carboxylate 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 soluble. After stirring for 2 hours at room temperature, the solution 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 15 7.5 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 20 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 acetate solution to give 8.22 g (81% yield based on 50% maximum 25 recovery) of salt, m.p. 165-168°C. 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 520C.

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 acetate to get 6.9 g of the resolved amino ester.

-484- Example 534D Ethyl (2R.3R.4S)-2-(3-Fluoro-4-methoxyphenyl)-4-( 13-benzodioxol- 5-yl)1 -(-(-(N-proylamino)ethyl)-yrrolidine-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 100°C 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 (85-92%).

This compound was combined with n-propylamine (3.5 eq.) and Nal by weight of bromide) in ethanol 5 mL per 1 g of bromide), and was 15 heated at 80°C 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 S* amine. The residue was dissolved in heptane and filtered to remove a small amount of insoluble material. Evaporation of the solvent gave the 20 desired product (86-93% yield), which was used for the next step without further purification.

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 organic layer is dried over Na2SO4 The crude product is purified by distillation (bp 54-56 °C 0.5 mm Hg) to give a clear oil, 61% yield.

-485- Example 534F (2R.3R.4S)-2-(3-Fluoro-4-methoxyphenvyl-4-(1.3-benzodioxol-5-yl)1- (2-(N-propyl-N-pentanesulfonylamino)ethyl)-vprrolidine-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 NaHC03 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 15 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 (<40 0

C)

heat. Water (10 mL) and ether (50 mL) were added; the ether layer was 20 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 white solid. The solid was collected and dried in vacuo to give 125 mg of the title compound.

9.

Example 534H (2R.3R.4S)-2-(3-Fluoro-4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl1 (2-(N-Dropyl-N-pentanesulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid. hydrochloride salt The free amine is dissolved in iPrOH; a slight excess of HCI in iPrOH is. added, and the solution is concentrated in vacuo. More IPA is added, and the solution is reconcentrated. The resultant sticky 486 material is stirred with ether overnight to give a white powder, which is collected by filtration and dried overnight in vacuo at 60 00. Yield Exam 3 The compounds in Table 30 may be prepared using methods presented in the above Examples.

Table 3C.

1 2 *r -4COOH N IIN -uCOOH 0 0 N 0* 0 0 0j 3 4* *..COOH 1f .COOH 0 0 -487- 6 48IC001

ICOOH

0* 12 -488- 13 14 >r~r~rN COOH 16

.O

0 0 17 18 H4 0. 0 HOO~vs-1 1 1 r HO r HO 00

N*

NL,

oz 6L pZ O* 490 26

S

S.

S

S.

S. S

S.

S

S. S 5

S.

S

.5 5* 5

S

55 S S 0* S 50

S.

27

CH

3 32

H

2

N~~

-491- 0* 0 9..

*00 .00

HN"

38 39 41

H

2 N NQ NN .42 -492- 43 47 I "'0 493 O*o* o.* 57 494 58 59 0 0 0 C H 3 C H 61 *,OO H2WM II-r -"COOH

CH

3

CH

3 0 62 63 II .ICOOH yo .aCOO4 0 CC)0 0 0 0

CH

3

CH

3 495 66 67 1 0 -ICOOH

CH

3 68 69 -iCOOH 71

CH

3 72 "11COOH 496 o*.

0 a.

a.0

HNN.

H2N, N,

H

2

N-

N0 497

III

S. S

S

S S

S

S. S

SS

F00 HO,_ N 498 91 HNTh 93 96 N4" 97 -499- 98 99 ,eNe O c 100 101 0 0

COOHUCO

0* 0 01 H iC

H

0 ~0 CH

CH

3 104 105 500 106 107 109 a a. a a a a.

a a a. a a.

a a.

a a. a.

a a a a.

a a a a. a a a a.

108 110 112 501 114 FINrN a.

a. 116 a. a a a.

a a a 118 N~Th 120 502 122 123 124 125 H2N 7%l~ N~Th I 6 L 126 127 12812 129 -503 130 131 9 9.

9 9 99 9 9 9.99 .9 9* 9 99 99 *9 9999 9 *9 99 9 9 99 9 9 999 9 .9 9 99 99 132 133 N~Th 0 135 H 92N 136 504 138 139i

"MCOOH

@000N 140 141 0SS0 *6N

N.

I. N COOH H @0 *142 143

N

505 146 147 0 148 149

CH.

H2N 150 151 152 152 153 -506- 154 155

>I

156 157 157 159

H

2 N ~jN 16016 161 -507- 162 163 N "ICOOH 164 165 11C

H~

N 6OO

*-,COO

16 1 166 167 168 169 -508- 170 171 172 173 NH2N >f' .:0:0 S.i 174 175 IL~Jc *.'COOH 176 177

COOH

0 4 .J 509 178 179 181 180 182 183 18418 a rl

VIP

I..

-510- 186 187 0000 o.* 0 0* 188 189 190 0

-COOH

CH

193

-NICOOH

0

CH

3 192 I

N~I

-511 194

H

2

N*

195 196' 197 198 199 20020 201 6OZ 8OZ 0 HOOOio-. H0O'. LOZ H000it- H*3i HOO0H0004- 0 HOOO"" N N. sozI)-z -513- 210 211 212 213

S

S S

S*

214 215 21621 217 -514- 218 219 220 221 a a a.

a. a.

222 223 a.

a a a a. a a a 22425 225 -515- 226 227 0 '0 228 229

H~~N

0 *230 231 .5

'COOH

00 23 2 23 3 nucOO "Oy~0 -516- 234 236 235

I~T

237 239 238 24024 241

N

'N'

HOOOwN U 0-~ -518- 250 251 252 253 .t 254 255 256'25 257 -519- 258 259 260 261 262 263 H 2No

N

264 265 520 266 267 268 269 N

N*

-i 9O .9.270 271 +N N oii,'sCOOH H2N""N(' 0 272 273 0 -521- 274 275 276c IH 2770 N O H 2 N Y .10 0 .0 0 *278 279 *0 IOOH

.QCOO

0*0 CH1

CH

3 280 281 -522- 282 283

-K)OOH

284 285 H: N N Ny.ii .',COO CH 286 287 a 0 '.9 288 289 0 523 290 291 0 292 293

C

a. C 294

I

295 296 297 H N,-s Th 524 298 299 .'eKOOOH

.*COOH

NNY

300 301 lilA 4C00 nil' .aOO *302 303 525 306 307 H2Uytn 308 309 C. ~N 310 311 312 312 313 526 314 315

CH

3 IL JAS.aCOOH t 316 317 H*3 6 N 6 6

H

3 *.OOH fI 6* 0 318 31 527 322 323

H,

H2N% N

CH

0 CH CH;

S

S. *S

S

5 9 .55 S 55 S S 5* 324 326 325 o.COOH 0 327 C3 32832 329 528- 330 331

CH

3 H2

OCOOH

CH

3 332 333 H3

SN

*.ICO y* II *4ICOOH S.3 3373 N..o 529 338 339 I H 3

T

icOOH 340 341

C

6 'COH 2- 530 346 347 N~Th 348 349 0 4000 0* 00 0

S

*t 0 0000 0 00 0 0* 00 00

SO

00 0 000.

*0 0 0 0 00 0 0 000 0 00 0 Og 00 350 351

H

2

N-

352 *iGOH3 353 rN-COOH 0

C-J

-531- 354 355 0 0CH 356 357 S.<"CH 3 0 -dCOOH. J -iCOOH 99* .358 359 0 c3 *o C O

O.

99 0 0 0.

-i

CH

3 532 362 363

S

0 00 0 0 *000 S. 0

SO

*0 00

OS

0* *090 0 *500 364

CH

3

CH

366 365 367

S.

0 0 S. S 0@ 0 368 369 'nN -533- 370 371 H3 33

CH

3 O

CH.

372 373

~OH

3

§%OH

3 NeN SO 0 COOH N N -niCOOH 0 0*CH 3

CH

3 *374 375 H3 0; WH CH -3 3 37 377 4- -534-

S

S.

*S

S

S.

S

S.

S

SS

S.

378

QPOCH

3

'.COOH

380§Iba 3823

§'COCH

3 .aCQOH 384 379 0 iCOOH 383

*'COOH

385 535 386 387 oOOHaNT 388 389

.O

*COO

390 391h ,.iIII .CQ0 390 391

Q

N ,t oH 536 394 -rL 395 396 S S

S

S S S S

S

55

S

*S

397 399 398

NZ~-~N.

HN~T

0 400 401 No-COOH 0 537 402 403 0 404 405 0 H2N %r I~-N 'COOH 406 407 0

F

0

CH

3 408 409 a

M

HO,, N N o )fooo, oCCO 538- 410 SQo

H~NPHCOOH

CH-

412 Qo

**'ICOOH

0 0

CH

3 414

,C

411 413 a 0 N suCOOH 0 0 C H 3 415 41641 417 539 418 419 421

C.

C

CC..

C C C C C CCC C C. C C C 420 N

.COOH

CH

3 422 423 424 425 0 -540- 426 427 H2N~NvN 428 429 I-i 0 -*~4ICOOH 430 431 a o 432 433 N N K+ NtI

COO

Nt 541 434 435C H2I- .',co **436ia 437 0 lj -COOH oCO 438 439 0* 0 ~cOO

COOH

440 441 N~hQo 0~ Q H N NfN .ICOOH H2.,IN *CO( 0 o, 5 '0 542 442 443 444 445 446 447 448 449 Qo

H

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716 717 1 t 718 719 720 721 577 722 723 r 0

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724 725 726 727 -578- 728 729 4* a.

730 731 732 733 H2NIO' 734 It ,ICOOH 0 735 579 a.

736 738 740 737 739 0 741 742 0 -NOOOH 743 -580- 744 745 aOCOOH 746 747 *N

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0 or "COlOH 0 847 848 593 849 851 850 852 853 854 855

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0

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3 594 856 857 858 859 861 860 862 863 H2N,-" N~~Th -595- 864 865 Qo .0 866 867

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*O

.0 -710- 2 S.3R.

4 -2-(2.2-DimethvlDentvl-4-(7-methoxv-1.3-benzodioxol-5yl)- 1 N-di(n-butvl) aminocarbonylmethyvl-ovrrolidine-3-carb oxylic Example 536A Ethyl 5.5-dimethyl-3-oxooctanoate Ethyl 3,3-dimethylhexanoate was prepared using the general procedure of Cahiez et al., Tetrahedron Lett., 3, 7425 (1990). To a solution of 63.8 g (370 mmol) of this compound in 400 mL of ethanol, cooled to 0°C, was added a solution of 30 g of NaOH in 150 mL of water.

The resultant solution was warmed to ambient temperature and stirred overnight. Solvents were removed in vacuo; the residue was taken up in 15 700 mL of water, and extracted twice with 1:1 ether/hexanes. The aqueous layer was acidified to pH3 with 1N HCI and extracted twice with hexanes. The combined hexane extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. A 20.2 g (150 mmol) sample of the crude product is dissolved in 150 mL of THF; 27.3 g 20 of 1,1'-carbonyldiimidazole is added portionwise, to control gas evolution. In meantime, 33.4 g of potassium ethylmalonate and 13.4 g of magnesium chloride are combined in 350 mL of THF (overhead mechanical stirring) and warmed to 50 0 C for 3 hrs. This mixture is cooled to ambient temperature, and the above acid imidazolide -solution is added. The resultant slurry is stirred overnight. Ether (600 mL), o* hexanes (600 mL) and aqueous 1N phosphoric acid (500 mL) are added, and the mixture is sitrred for 30 min. The aqueous layer is separated; the organics are washed sequentially with bicarb water and brine.

The organics are dried over sodium sulfate, filtered and concentrated to give 30.2 g (95% yield) of a colorless liquid.

Example 536B 4-Methoxy-6-(2-nitrovinyl)-1.3-benzodioxole 3-Methoxypiperonal (50.0 g) is combined with 71.9 mL of nitromethane in 250 mL of acetic acid; 36 g of ammonium acetate is -711added, and the mixture is heated to 500C for 4 hrs. Solvents are removed in vacuo; the residue is taken up in water and stirred for min. The solution is filtered; the filtrate is washed with water, then ether, to give'51.8 g of a yellow solid.

Example 536C Ethyl trans, trans-2-(2.2-Dimethvloentvil-4-(7-methoxv-1.3benzodioxol-5-yl)-ovrrolidine-3-carboxvlate The compound of Example 536A (6.42 g, 30 mmol) was combined with 5.79 g of the compound of Example 536B in 40 mL of THF. DBU mL) was added, and the mixture was stirred at ambient temperature for 6 hrs, during which time it turns reddish brown, and homogeneous. The solvents were removed in vacuo; the residue was taken up in EtOAc and 15 washed sequentially with aqueous 1N phosphoric acid and brine. The organic phase was dried over sodium sulfate, filtered and concentrated.

The residue was dissolved in 50 mL of THF; 12 g of Raney Nickel catalyst (washed sequentially with water and ethanol) was added, followed by 10 mL of acetic acid. The resultant mixture was 20 hydrogenated under 4 atmospheres of hydrogen until hydrogen uptake ceased 3 hrs). The catalyst was removed by filtration; solvents were removed in vacuo. The residue was dissolved in 90 mL of 2:1 ethanol/THF; 30 mg of bromcresol green indicator was added, followed by 30 mL of 1N sodium cyanoborohydride in THF. Concentrated HCI was added dropwise to maintain pH at the indicator point, over 1 hr. The resultant solution was stirred ovemight at ambient temperature.

Bicarb was added, and the solvents were removed in vacuo; the residue was partitioned between water and EtOAc. The organic material was washed with water (2X) and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in 100 mL of acetonitrile; 10 mL of HOnig's base was added, and the solution was warmed to 40 0 C overnight. Removal of solvents in vacuo provided 5.0 g of a yellowish oil.

-712- Example 536D Ethyl (2S.3R.4S-2-(2.2-Dimethylpentyl)-4-(7-methox- 1.3benzodioxol-5-yl)-Dyrrolidine-3-carboxylate The crude compound of Example 536C (2.0 g) was combined with 4 mL of triethylamine in 40 mL of THF; 2.0 g of di-tert-butyldicarbonate was added, and the mixture was stirred at ambient temperature for hrs. Solvents were removed in vacuo, and the residue was taken up in mL of ethanol. Aqueous sodium hydroxide (10 mL of 2.5 N solution) was added, and the resultant solution was stirred overnight. Solvents were removed in vacuo; the residue was taken up in water and extracted with ether. The aqueous phase was acidified with aqueous 1N phosphoric acid and extracted with EtOAc. The organic extracts were washed with *5 brine, dried over sodium sulfate, filtered, and concentrated to give 1.0 g of a colorless oil. A sample of this material (0.734 g, 1.58 mmol) was combined with 0.35 g of pentafluorophenol and 0.364 g of EDAC in 5 mL fi°' of DMF. The resultant solution was stirred at ambient temperature for 1 hr, then was poured onto 50 mL of 0.6M sodium bicarbonate solution and extracted (3 X 15 mL) with ether. The combined ether extracts were 20 washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a foam, which was dissolved in 5 mL of THF and cooled to 0°C. Simultaneously, 0.418 g (2.37 mmol) of R-4benzyl-2-oxazolidinone was combined with -0.1 mg of pyreneacetic acid in 5 mL of THF and cooled to 0°C. N-butyllithium (1.6M in hexanes) was added to a red endpoint (persists -10 sec), and the solution was stirred for 10 min. The solution was transferred into the solution of the pentafluorophenyl ester, and the resultant solution was stirred at 0°C for 40 min. Solvents were removed in vacuo; the residue was taken up in bicarb and extracted with ether (3 X 10 mL). The combined ether extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture of diasteromeric products was separated by flash chromatography on silica gel, eluting with a gradient from hexanes/EtOAc, giving 423 mg of the faster-moving and 389 mg of the slower-moving diastereomer, respectively. The faster-moving diastereomer was dissolved in 2 mL of a 2.0M solution of sodium methoxide in methanol (freshly prepared, -713containing 5% methyl formate by volume) and stirred at ambient temperature for 16 hrs. Solvents were removed in vacuo, and the residue was partitioned .between ether and aqueous 1N sodium hydroxide.

The ether laypr was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 4:1 hexanes/EtOAc. The resultant material was dissolved in 5 mL of TFA and stirred at ambient temperature for 1 hr. Solvents were removed in vacuo; the residue was suspended in bicarb and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 98 mg of product.

Example 536E

[P

2 S.3R.4S--2.(2.2-Dimethylpentvl)-4-(7-methoxy-1.3- y1-(N.Ndi(n-butyvaminocarbonvmethl rrodine--rbYli The compound of Example 536D (48 mg) was combined with 35 mg of the compound of Example 501A in 3 mL of acetonitrile; 0.5 mL of 20 HOnig's base was added, and the solution was allowed to stir ovemight .at ambient temperature. Solvents were removed in vacuo; the residue was partitioned between EtOAc and aqueous 1N phosphoric acid: The organic layer was washed with bicarb. and brine, then dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 2:1 hexanes/EtOAc. The product was dissolved in 4 mL of ethanol; 1 mL of 2.5N aqueous sodium hydroxide was added, and the resultant solution was stirred overnight at ambient temperature. Solvents were removed in vacuo; the residue was taken up in water and extracted with ether. The aqueous phase was acidified to pH 3 with aqueous 1N phosphoric acid and extracted with EtOAc. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give a colorless oil. Lyophilization from acetonitrile/0.1% aqueous TFA gave 56 mg of a white solid.

1 H NMR (CDC1 3 300 MHz) d 0.81 3H), 0.84 3H), 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 8H), 1.45-1.59 4H), 1.84-2.00 2H), 3.15 (dd, J 6.9 Hz, 10.0 Hz, 2H), -714- 3.30-3.42 (in, 3H), 3.72 J 10.5 Hz, I1H), 3.86 J 10.5 Hz, 1 3.88 3H), 4.02 J 10.0 Hz, 1H), 4.12 J 16.8 Hz, 4.29 J= 16.8 Hz, I1H), 4.41 (brm, I1H), 5.94 1 6.52 J 1.8 Hz, 1 6.67 (d, J 1.8 Hz, 1 MS (ES I) at mWe 533. Anal calcd for

C

30

H-

48

N

2 0 6 .0.7 TFA: C, 61.57; H, 8.01; N, 4.57. Found: C, 61.59; H, 8.20; N, 4.63.

Examle53 r2S.3R.4S-2-(2.2-Dimethylpentyl)-4-(1 .3-benzodioxol-5-yfl-1 di(n-butyl)aminocarbonylmethyl)-pyrrolidie-3-carboxylic acid Ethyl trans, trans-2-(2.2-Dimethylpentyl)-4-(1 pyrrolidine-3-carb oxyl ate Prepared according to the procedures of Example 536C above, substituting the compound of Example 501B (5-(2-nitrovinyl)-1,3benxodioxole) for 4-methoxy-6-(2-nitrovinyl)-1 ,3-.benzodioxole.

Example 537B Ethyl [2S.3R4S-2-(2.2-Dimnethyl pentyfl)-4- (1 .3-ben zod io xol- 5-Yl) pyrrolidine-3-carboxylate .:The compound of Example 537A (6.8 g) was dissolved in 100 mL of *.:ether; a solution of 1.6 g of (S)-(+)-mandelic acid in 60 mL of ether was added, the total volume was made up to -200 mL, and the solution was seeded. The mixture was stirred slowly overnight. The resultant crystals were collected by filtration and recrystallized from ether/EtOAc to give 1.8 g of a white solid. Thsi material was partitioned between bicarb and ether; the ether layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the enantiomerically pure product -715- Example 537C rp-S 3R.4S1.2-(2.2-Dim ethyl pentyl)-4- (1 .3-benzodio xol- 5-yi)-1 di(n-butyflaminocarbonylmethyl)-pyrrolidie-3-carboxylic acid Prepared from the compound of Example 537B according to the procedures of Example 536E. 1 NMR (CDCI3, 300 MHz) d 0.80-0.99 (in, 1.10-1.37 (in, 8H), 1.43-1.58 (in, 4H), 1.77-1.97 (mn, 2H), 3.48-3.12 (in, 5H), 3.60-3.69 (in, 1H), 3.75-3.86 (in. 1H), 3.95-4.16 (in, 2H), 4.28- 4.4 (in, 2H), 5.94 2H),'6.74 J=7.8 Hz, 1H), 6.8 (dd, J=8.1. 1.5 Hz, 1H), 6.87 J=1.8 Hz, 1H). MS (APCI+) Wne 503 Example 538 r2S.3R.4S-2- Di methyl ge ntyfl-4- (1 .3-ben zod io xoI- 5-yfl -1 :propoxy. N-(n-b uty))ami nocarbonyl methyl)-pyrrol idin e-3-ca rOxlic Example 538A N -B oc-N -b u tyl aIIyIhdro xyl am in e *.20 0-Allylhydroxylamine hydrochloride hydrate (5.0g) was dissolved in* THF (15 mL). The solution was cooled to 0 0 C in an ice bath.

**Diisopropylethylamine (8mL) and di -t-butyl dicarbon ate (10.0g) were added. The mixture was stirred at 0 0 C for. one 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 the residue taken up in EtOAc (25 mL), and washed with water (1 x mL), saturated sodium bicarbonate solution (3 x 50 mL), 1IN 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 This crude product was dissolved in dry THF (25 mL) and the solution cooled to 01 0 C in an ice bath. Sodium hydride (1 .5g, 60% dispersion in oil) was added portionwise over five minutes. The resulting mixture was stirred for 30 minutes at 0 0 1C. 1-lodobutane (4.1 mL) was added dropwise to the mixture. The reaction was stirred at 01C. for one hour, then stirred overnight at room temperature. The THE was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 50 ML), -716saturated 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 EtOAc/hexanes to give the title compound as a colorless oil (6.0 g).

Example 538B N-butyl-N- ropoxyamine trifluoroacetate 10 The compound of Example 538A (6.0 g) was dissolved in EtOAc (100 mL). 10% Palladium-on-carbon (0.5 g) 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 15 and the solvents were removed in vacuo to give a yellow oil which was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give a colorless oil (5.8 A sample of the resultant material (1.15 g) was dissolved in CH 2

CI

2 (5 mL) and cooled in an ice bath. Trifluoroacetic acid (3mL) was added and the solution stirred cold for two hours. The solvent was removed in vacuo care being taken not to allow the solution to warm above room temperature. The residue contained considerable TFA and was used without further purification.

S. Example 538C N-butyl-N-propoxy-bromoacetamide The salt of Example 538B (0.60 g) was dissolved in acetonitrile mL) and cooled to -20 0 C. Hunig's base (5.5 mL) was added slowly.

Bromoacetyl bromide (0.5 mL) was added dropwise over five minutes.

The solution was stirred at -20 0 C for 30 minutes. The bath was removed and the solution was stirred for six 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 (0.65 g) which was used without further purification.

-717- Example53D r2S.3R.4s1-2- Dim ethylpe ntyfl-4-(1 .3-benzod ioxol-5-vfl- 1 propoxy. N-(n-butym)aminocarbonylmethyl)-pyrrolidine-3-carboxvlic acid The compound of Example 537B was reacted with the compound of Example 5380 according to the procedures of Example 536E.

.10 Example 539 r2S. 3R, 45 2 -D em ethy 112e n tyl) -4 .3 -b e nzo d iox o I-5 y1)-1 propoxy. N-(n-propyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic Eall-59 N-propyl-N-propoxy bromoacetamide Prepared according to the procedures of Example 538A-C, substituting iodopropane for iodobutane in Example 538A.

Example 539B r2S.3R.4s]-2-(2.2-Dimethylpentyl)-4-( 1.3-benzodioxol-5-yI)-1 propoxy. N-(n-propyl))aminocarbonylmethyl)-pyrrolidine-3-carboX~i The compound of Example 537B was reacted with the compound of Example 539A according to the procedures of Example 536E.

-718- Exampe 54 [2S,3R.451-2-(2 .2-Dimethylpent-yfl-4-(7-methoxy-1I.3-benzodioxo;-5yfl)-1-((N-propoxy, N-(n-butyl))ami noca rbonylm ethyl)- pyrrol* dfin e.3 carboxylic acid The compound of Example 536D was reacted with the compound of Example 538C according to the procedures of Example 536E., Exmple54 10 [2S.3R.4S1-2-(2.2-Dimethylpentyl)-4-(7-methoxy-1 yl)-j-((N-propoxy. N-(n-prop 1))aminocarbonylmethyn)-pyrrolidinep3 The compound of Example 536D was reacted with the compound of *:15 Example 539A according to the procedures of Example 536E.

:Example 542 2S.32R.4a 2 -D ime th yl pe nt -3 en y 1)-4 .3 -b e nzo d ioxo I- 5 Y)-1 ((N-propoxy. N-(n-butyl))aminocarbonylmethyl)-pyrrolidine--3carboxylic acid Example 542A trans-Ethyl 3.3-dimethyl-4-hexenoate A mixture of 4-m-ethyl-3-penten-2-ol (7.4 g, 74 mmol), triethyl orthoacetate (13.6 mL, 74mmol) and propionic acid (0.28 mL, 3.7 mmol) was heated at 150 0 C for 7 hr. The product was then distilled under normal pressure (200-220 OC) to give 5.0 g of crude ester as a colorless oil.

Exampe 42B Ethyl trans. trans-2-(2.2-Dimethyjpent-3-enyl-4-(l1.3-benzodioxol-5yil-o2yrrolidine-3-carboxylate.

The title compound is prepared according to the procedures of Examples 536A and 536C, substituting the compound of Example 542A -719for ethyl 3,3-dimethyihexanoate in Example 536A and the compound of Example 501 B (5-(2-nitrovinyl)-1 ,3-benxodioxole) for 4-methoxy-6-(2nitrovinyl)-1 ,3-benzodioxole in Example 536C.

Exmpl 52C Ethyl F2S.3R.4s-2-(2.2-Dim ethyl pent-3-enyl-4-(1.3-benzodioxol-5yl'I-pyrrolidine-3-carboxyl ate The compound of Example 542B was resolved according to the procedure described in Example 537B.

Examl 42D f 2S. 3R. 4a 2-(2 2 -D im e thyl pen t -3 eny1)- 4 3 -b en z odio xo I- 5 -yl1) -1 ((N-propoxy. -N-(n-butyfl)aminocarbonylmethyfl-pyrrolidine-3- 0. 10: 15 carboxylic acid The compound of Example 542C was reacted with the compound of Example 538C according to the procedures of Example 536E.

20Exml54 0 0 2S.3R.4s1-2-(2 .2-Dimethylpent-3-enyl)-4-( 1.3-benzodioxol-5-yl)- 1- ((N-propoxy, N-(n-propyl))aminocarbonylmethyl)-pyrrolidine-3- :carboxylic acid The compound of Example 542C was reacted with the compound of Example 539A according to the procedures of Example 536E.

Example 544 1.2S.3R.4s0-2-(2.2-Di methyl pent-3-enyl)-4- methoxy- 1 .3benzodioxol-5-yl)-1 -((N-propoxy. N-(n-butyl))aminocarbonylme-thy 12yrrolidine-3-carboxylic acid -720- Examl 44A Ethyl tranj. tran&-2 2.2 -Dim ethyl pent3-enyfl.4(7-methoxyl .3benzodioxol-5-yl)-pyrrolidine.3.carboxylate The title compound is prepared according to the procedures of Examples 536A and 536C, substituting the compound of Example 542A for ethyl 3,3-dimethyihexanoate in Example 536A.

Example 54B to 1 Ethyl 2 S.3R.4%9 Dim ethyl pent--enyl-4- (7methoxy 3b ben z odi oxo I- 5- yl) pyrroIi d in e- 3 -ca rb oxyl at e .The compound of Example 544A was resolved according to the procedure described in Example 5360.

Exampe 44C :[S3R.49-2-(2.2-Dimethylpent3-enyl)-4-(7-methoxy- 1 .3b be n z odioxo I- 5-y1)-1 (N -p ro poxy N-(n-butyl))am inoca rbonylm ethyl)pyrrolidine-3-crboxylic acid The compound of Example 544B was reacted with the compound of Example 538C according to the procedures of Example 536E.

Example 545 25 r2S.3R.4s1-2-(2.2-imethylpent-3-enyfl-447-methoxy-1 .3benzodioxol-5-yl)-1 -((N-propoxy. N-(n-propyl))aminocarbonyl methyl)pyrrolidine-3-carboxylic acid The compound of Example 544B was reacted with the compound ot Example 539A according to the procedures of Example 536E.

Example 546 f2S.3R.4S-2-(2-(2-pyridyl)ethyfl-4-(1 .3-benzodioxol-5-yfl)-1-f[N4heptyl-N4(2-methyl-3-fluorophenyn)1 amino carbonylmethyllpyrrolidine-3-carboxylic acid -721- Example 546A Ethyl trans.trans-2-(2-(2-pyridyl)ethyl)-4-(1.3-benzodioxo4-5-yl)pyrrolidine-3-carboxylate The title compound is prepared according to the procedures of Examples 536A and 536C, substituting the compound of Example 519A for 3,3-dimethylhexanoic acid in Example 536A.

Example 546B 10 Ethyl f2S.3R.4S-2-(2-(2-pyridyl)ethyl)-4-(1.3-benzodioxol-5-yl)pyrrolidine-3-carboxylate The compound of Example 546A (1.5 g) was dissolved in CH2CI2 mL). Di-t-butyldicarbonate (0.9 g) was added and the solution 15 stirred overnight at room temperature. The solvent was evaporated in vacuo and the residue taken up in EtOAc (50 mL), washed with water (1x50 mL), saturated sodium bicarbonate solution (3x50 mL), and brine (1x50 mL). The organic layer was dried with sodium sulfate and evaporated in vacuo to give an oil with was purified by flash chromatography on silica gel eluting with 1/10/10 EtOH/EtOAc/hexanes Sto give a colorless oil (1.5 The oil was dissolved in EtOH (10 mL) and NaOH solution (0.5 mL) and water (5 mL) were added. The mixture was stirred overnight at room temperature. The solvents were evaporated in vacuo and the residue taken up in EtOAc (25 mL) and acidified with 1 N H3P04 (10 mL). The layers were separated and the organic layer dried with sodium sulfate and evaporated to give a white semi-solid (1.3 A sample of the resultant Boc-protected amino acid (0.9 g) was dissolved in DMF (5 mL). (S)-Phenylalaninol (0.32 HOOBt (0.33 and EDCI (0.40 g) were added and the solution sitrred overnight at room temperature. Water (50 mL) was added and the mixture extracted with EtOAc (3x25 mL). The organic layers were combined, washed with water (2x50 mL), saturated sodium bicarbonate solution (3x50 mL), and brine (1x50 mL), and evaporated to give a yellow oil; tic indicated the presence of two diastereomeric products. The diastereomeric amides were separated by flash chromatography on silica gel eluting with 1/12/12 EtOH/EtOAc/hexanes to give faster- -722- (450 mng) and slower-moving isomers (400 mg). The faster-movin~g diastereomer (400 mg) was taken up in 6N HOI and heated at reflux overnight. The solvent was evaporated and the residue was taken up in toluene (75 riL) and evaporated. This was repeated two additional times to give a brown solid, which was dissolved in EtCH. (5Oml-). 4N HCVdioxane (10 ml-) was added and the solution heated at reflux overnight. The EtCH was evaporated and the residue taken up in EtOAc which was treated with saturated sodium bicarbonate solution (3x50 mL), and brine (1x50 mL), and evaporated to give a brown solid. Flash chromatography on silica gel eluting with 30% EtCH/EtOAc gave ~a mixture of products (130mg) which was approximately 70% desired material. This product was carried forward without additional :*Ogg* purification.

r2S.3R.4S]-2-(2-(2-pyridyl)ethyfl-4- 1 .3-benzodioxol-5-yi)l- 4[W 4 heptyl -N(2-methyl-3-fluorophenyl)I amino carbonylmethyllpyrrolidine-3-carboxylic acid The compound of Example 546B was reacted with the compound of Example 508E according to the procedures of Example 536E.

Example 547 2S.3R.4S1 -2 -(4-Methoxyphenyfl-4-(1 .3 -ben zodio xol-5-yfl -I -r(N -butyl N-(4-dimethylaminobutyflaminokcarbonylmethyll-pyrrolidine-3carboxylic acid Example 547A N-butyl-4-hydroxybutyramide To 30 mL (390 mmol) of g-butyrolactone was added 45 ml (455 mmol) of n-butylamine. The solution was heated at 85'C for 1 .5 hr. then the excess n-butylamine was removed in vacuo. The product crystallized on standing to give about 62 g of a colorless, low melting solid.

-723- Example 547B N-butyl-4-hydroxybutyl chloroacetamide To an ice cooled solution of 3.40 g (91.9 mmol) of LIAIH4 in 90 mL of THF was added 2.4 mL of 98% H2S04, dropwise, with stirring. After bubbling had ceased, a solution of 4.7 g of the compound of Example 547A in 10mL of THF was added. The mixture was stirred at reflux for 24 hr, then cooled with an ice bath and quenched by sequential dropwise addition of 1.7 mL H20, and 17 mL of 25% w/v aqueous NaOH. The white precipitate was filtered, and washed with about 50 mL of THF. The combined filtrate and washings were concentrated to 3.85 g of an oil.

To an ice cooled solution of this material in 35 mL of ethyl acetate was added a solution of 5.0 g (29.2 mmol) of chloroacetic anhydride in 10 mL of ethyl acetate. The solution was stirred at 0 C for 30 min, then extracted with saturated aqueous NaHCO3 solution (1 x 25 mL), 2M NaOH (1 x 25 mL), 5% NH40H (1 x 25 mL), 1M HCI (1 x 25 mL), and brine (1 x mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. The product was purified via silica gel chromatography, eluting with 98:2 diethyl ether: methanol, to give 1.52 g of a colorless oil.

Example 547C Ethyl (2S.3R.4S1-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)- 1-(Nbutvl-N-(4-hydroxvbutyl)amino)carbonylmethyll-pyrrolidine-3carboxylate To 1.52 g (6.85 mmol) of the compound of Example 547B was added 2.75 g (7.44 mmol) of the ethyl [2S,3R,4S]-2-(4-Methoxyphenyl)-4-(1,3benzodioxol-5-yl)-pyrrolidine-3-carboxylate (prepared by neutralization of the compound of Example 501G), 10 mL of DMSO, and 2 mL of N,N-diisopropylethylamine. The solution was stirred -at ambient temperature for 22 h, then poured into 100 mL of water and extracted with diethyl ether (3 x 25 mL). The combined ether layers were washed with water (1 x 25 mL), 4% H3PO4 (1 x 25 mL), saturated aqueous NaHCO 3 solution (1 x 25 mL), and brine (1 x 25 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel -724chromatography, eluting with 98:2 diethyl ether: methanol to give of a colorless oil.

Example 547D Ethyl r2S.3R.4SI-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl- 1-r(Nbutyl-N-(4-bromobutyllamino carbonylmethyll-Dyrrolidine-3carboxylate To an ice cooled solution of 2.80 g (5.05 mmol) of the compound of Example 547C in 27 mL of diethyl ether was added 1.4 mL (10 mmol) of S: triethylamine, then 0.58 mL of methanesulfonyl chloride. A white precipitate formed, and the suspension was stirred at 0 °C for 20 min.

The reaction was diluted with 75 mL of diethyl. ether, then extracted with saturated aqueous NaHCO3 solution (2 x 25 mL), 5% NH40H (2 x mL), and brine (1 x 25 mL), dried over MgSO4, filtered, and concentrated to 3.0 g of a colorless oil. To this material in 45 mL of DMF was added 6.0 g (69 mmol) of LiBr. The reaction warmed to about 50 then gradually cooled. The solution was stirred at ambient temperature for 4h, then poured into 450 mL of water, and extracted with diethyl ether 20 (3 x 100 mL). The combined ether layers were back extracted with water (1 x 100 mL), and brine (1 x 100 mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. The product was purified via silica gel chromatography, eluting with 3:1 diethyl ether: petroleum ether, to give 2.65 g of a colorless oil.

Example 547E f2S.3R.4S-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -l(N-but l- N-(4-dimethylaminobutyl)amino)carbonvlmethyll-pyrrolidine- 3 carboxylic acid To a solution of the compound of Example 547D (0.825 g, 1.34 mmol) in 3 mL of ethanol was added 5 mL of 4.07M dimethylamine in ethanol; the resultant solution was heated at reflux for 75 min.

Solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 9:1 dichloromethane/methanol. I he resuitant maieriai was iakn, up 5

L

-725of IA4N NaOH in 5:1 ethanol/water and stirred at ambient temperature for 14 hrs. Solvents were removed in vacuo; the residue was taken up in water, then adjusted to pH 6-7 with I M HCI mL required). The mixture was extracted with EtOAc the aqueous layer was concentrated in vacuo. The residue was washed 3X with acetonitrile; the combined washes were filtered through Celite and concentrated to give 596 mg of a white foam.

Exampe 48 10 r2S.3R.4S-2-(2.2-DimethylpentylI-4-(1 .3-benzodioxol-5-yl).-1 -fN-.

butyl- N-(4-dim ethyl aminobutyl)amino) carbonylmethyl1yrrolidin e-3carboxylic acid Prepared according to the procedures of Example 547, substituting *:15 the compound of Example 537B (ethyl [2S,3R,4S]-2-(2,2- D imethyl pe ntyl) (1 ,3be nzodi oxol1-5-yl) -pyrro Iidi ne-3-carb oxyl ate) :in Example 547C.

r2S.3R.4s1-2-(2.2-Dimethylpentyl)-4-(7-methoxy'-1 yl)-1 -[(N-butyl-N-(4-dimethylaminobutyl)aminocarbonyln'ethYI1pyrrolidine-3-cairboxylic acid Prepared according to the procedures of Example 547, substituting the compound of Example 5360 (ethyl (2S,3R,4S]-2-(2,2- Dimethylpentyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-pyrrolidine-3carboxylate) in Example 547C.

Examle550 f 2S.3R.4s1-2- (2.2-Di methyl pent- 3-enyfl-4- (1 .3-be nzod i oxol- 5-Yf- 1 r(N-butyl-N-(4-dimethylaminobutyflamino)carbonylmethyl]-pyrrolidine- 3-carboxYlic acdd Prepared according to the procedures of Example 547, substituting the compound of Example 542C (ethyl [2S,3R,4S]-2-(2,2- -726- Di1meth yl pent-3-e nyl)-4- (1 .3-ben zod 1o xol- 5-yI) -pyrroIi d in e-3carboxylate) in Example 547C.

r2s.3R.'4sl-2-(2 .2-Dimethylpent-3-enyfl-4-(7-methoxy- 1.3benzodioxol-5-yl)-1 -r(N-butyl-N-(4dimethylaminobutyl)aminoicarbonylmethyfl-pyrrolidine-3-carboxylic Prepared according to the procedures of Example 547, substituting the compound of Example 544A (ethyl [2S,3R,4S]-2-(2,2- D imet hyl p ent- 3 -enyl) (7 -m et h oxy-1, ,3-b en z odi oxolI- 5 -y1) pyrrolidine-3-carboxylate) in Example 547C.

:15 Example 552 ezdoo--lr(N.N-di(nbutyl)amino)carbonylmethyll-pyrrolidine-3-carboxylic -acid Prepared according to the procedures of Example 1, substituting the compound of Example 541 C (ethyl[2S,3R,4S1-2-(2,2-Dimethylpent-3- *enyl)-4-( 1,3 -ben zodi oxol-5-yl)-pyrrol idine-3- carbo xylate).

:Example 553 r28.3R4S-2-(2.2-Dimethylpent-3-enyfl-4-(7-methoxy-1 .3- .:25 benzodioxol-5-yl)-l -r(N.N-di(n-butyl)amino)carbonylmethyllpyrrolidine-3-carboxylic acid Prepared according to the procesures of. Example 1, substituting the compound of Example 544B (ethyl [2S,3R,4S1-2-(2,2-Dimethylpent-3enyl)-4- (7-methoxy-1, ,3-be nzodi oxol-5-yl) -pyrrol idi ne-3-'carboxyl ate).

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.

-727- 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 .ig/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 15 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 -80°C 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 mMMgCI2, pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 gg/mL Pepstatin A, 0.025% bacitracin, :25 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 [1251]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 iM 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.

-72 8- Table 4 Binding Data Example Inhibition of ETA at 1 Example Inhibition of ETA at 1 gim 1D 2 3 4 5

GB

7 8 9 14 16 17 18 19 21 22 23 26 27 28 29 31 B 96.4 58.4 42.2 78.2 95.1 34.9 63.4 53.7 69.2 66.1 86.6 84.8 96.0 73.9 97.3 90.3 80.9 56.3 86.3 85.9* 83.0 61.2 63.8 85.3 80.0 93.6 34 35 36 37 38 39 40 41 42 43 44 45 46 47, 48 52 54 55 56 57 58 59 60 610C 62 63 95.5 91.8 94.5 47.9 100.0 83.6 94.8 89.9 95.2 99.2 91.3 85.4 90.4 95.1 96.3 84.0 64.6 50.5 34.3 93.2 81.9 70.8 42.8 90.6 94.1 92.0 -729- Example Inhibition Example Inhibition of ETA atl1 of ETA atl1 64 95.0 98 86.8 82.8 99 92.1 66 87.7 100 76.8 67 96.3 101 89.2 68 84.6 102 75.2 ::69D3 37.4 103 69.0 62.7 104 98.0 71 81.4 105 98.6 :72C 80.7 106 90.0 73C 96.3 107 97.2 :74 95.6 109 96.8 95.3 110 94.4 76 93.1 ill 101.8 ::79 100.4 112 94.9 89.4 113 94.3 90.3 114 86.2 :83 85.0 115 88.4 84 65.3 116 79.3 86 52.6 117 95.2 87 62.4 118 93.2 88 84.3 119 86.6 89 84.6 120 99.5 91 C 91.6 121 98.6 92C 107.4 122 95.3 93C 59.2 125 97.2 82.1 126 91.7 96 86.1 127 91.4 9-7 89.0 128 95.4 -730- Example Inhibition ETA at I 123 124 129 130 131 132 133 1 34 135B 136 138 139 140 141 142B 143 144 145 146 147 148 149 150 151 1 52 1 53 1 54 155 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 Example 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 Inhibition of ETA at 1 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 -73 1- Example Inhibition Example Inhibition of ETA atl1 of ETA atlI 308 93.0 351 99.0 309 80.7 352 96.2 310 87.1 353 73.7 311 92.3 354 79.3 **.312 88.2 355 100 313 96.3 356 93.5 314 86.0 357 96.3 315 82.7 358 62.7 316 74.0 359 94.7 *317 68.5 360 93.7 *318 79.0 361 92.8 319 79.0 362 94.1 320 82.2 3.63 82.3 322 95.6 365 59.2 S323 91.3 366 91.5 95.0 367 71.0 334 88.0 368 94.6 335 84.1 370 84.3 340 94.0 371 97.2 341 87.4 372 91.6 342 89.9 373 92.9 343 98.7 374 91.4 344 95.6 375 97.8 345 86.6 376 90.2 346 88.9 377 85.6 348 91.3. 378 91.1 349 73.0 379 90.7 350 92.1 380 99.0 -73 2- Example Inhibition Example Inhibition of ETA atl1 of ETA atl1 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 0391 45.6 418 100 392 93.7 420 100 100 421 100 394 97.8 422 96.6 395 79.8 423 89.1 0. 00: 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 -733- Example Inhibition ETA at 1 gim Example Inhibition ETA at 1 jiM

I...I

4.

*too** 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 100 100 94.3 94.3 100 98.3 100 100 100 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 98.7 100 100 91.6 82.3 80.1 96.5 95.9 92.7 83.7 81.6 68.5 55.7 44 4 444 4 4* 4 9* 4 9* -734- 0* 0 OOeS S. 00 0 0 0 4* 4 9 *00e 0* p 0* *0 S. S @4 4 4* Example.

502 503 504 505 506 507- 508 509 510 511 512 513 514 515 516 517 518 519 520 521 523 524 525 526 527 528 529 531 532 533 536 537 Inhibition of ETA at 1 95.7 97.0 97.1 95.8 99.7 99.3 97.6 100 100 99.2 98.9 98.0 100 99.1 99.7 94.1 96.3 99.1 97.4 100 99.0 99.2 100 100 96.6 98.3 98.1 99.8 100 97.9 100 97.2 00 S S 0 OS S 4.

S.

-735- 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 Phosphatidvlinositol (PI) Hydrolysis MMQ cells (0.4 x 106 cells/mL) were labeled with 10 tCi/mL of 3 H]myo-inositol in RPMI for 16 hours. The cells were washed with to 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 15 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. 2.6 587-595 (1982)). The upper aqueous phase (1 mL) was retained and a small portion (100 giL) 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.

00: -736- Table Phosphatidylinositol Hydrolysis Example IC50 iM 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 0.05 553 0.0004 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 gg/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 centrifuged at 60,000xg for 60 min. The precipitate was resuspended in mM Tris, pH 7.4 containing protease inhibitor and centrifuged again.

The final membrane pellet was resuspended in 20 mM Tris, pH 7.4 -737- containing protease inhibitors and stored at -80 °C until used. 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 diluied -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 g/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 ligands were separated from bound ligands by a vacuum filtration 15 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 CIM ET-1. IC50 values are calculated using an average of at least two separate determinations. The data shows the selectivity of the 20 compounds of the invention in binding to the endothelin receptors.

Table 6 .o EXAMPLE rET-A rET-A pET-B Selectivity hET-A hET-B Selectivity NO. IC50 IC50 (rA/pB IC50 IC 5 0 (hA/hB S" .1M) (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 -738- 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 e o 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 -739- 100 96.6 98.3 98.1 10,000 43,000 6,300 1,300 3.800 1,700 17 7,400 531 99.8 1.2 532 100 5.1 3,200 0.71 630 1,200 97.9 76 7,900 100 40 22,000 0.08 a 560 56,000 8,200 100 0.52 17,000 33,000 0.92 52,000 97.2 0.96 5,900 6,200 1,900 97.3 0.78 7100,000 7125,000 1.0 >96,000 >96,000 100 0.26 42,400 160,000 0.29 39,500 136,000 Determination of Plasma Protein Binding 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 filtrate was discarded. The sample was centrifuged for another 15-30 min. A 100 pL sample of the ultrafiltrate was transfered to a micro HPLC sample vial containing 150 ML of HPLC mobile phase and mixed thoroughly. A 50 pL 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: -740- %PB 100% where Cu is the ultrafiltrate concentration and Ci is the initial plasma concentration. The percent of bound compound is listed in Table 7.

Table 7.

Example #43 99.5 bound Example #530 78% bound Example #531 92% bound Example #532 96.8% bound Example #533 82.6% bound It has been demonstrated in the literature (Wu-Wong, et al., Life Sci. 1996, 58, 1839-1847, and references contained therein) that compounds which are highly protein bound show decreased potency in vitro in the presence of plasma proteins. A decrease in in vitro potency may correspondingly result in reduced in vivo potency. An endothelin antagonist which has reduced protein binding might be expected to be less susceptible to this effect; and thus be more potent as an in vivo agent.

The ability of "reduced protein binding" endothelin antagonists to exhibit enhance activity in the presence of serum albumin has been demonstrated through the following study: A series of binding curves is recorded for a given antagonist, each experiment 25 performed in the presence of increasing concentrations of serum albumin.

Protocol for Albumin-induced binding shift studies: Binding assays were performed in 96-well microtiter plates precoated with 0.1 BSA unless otherwise indicated. Membranes were diluted in Buffer B (20mM Tris, 100mM NaCI, 10mM MgCI2, pH 7.4, 0.1 mM PMSF, 5mg/mL Pepstatin A, 0.025% bacitracin and 3 mM EDTA) to a final concentration of 0.05 mg/ml of protein.

Varying concentrations of human serum albumin (HSA) were added as indicated.

In competition studies, membranes were incubated with 0.1 nM of [1 2 5 1]ET in 741 Buffer B (final volume: 0.2 ml) in the presence of increasing concentrations of unlabeled test ligands for 4 hours at 25 0 OC. After incubation, unbound ligands were separated from bound ligands by vacuum filtration using glass-fiber filter strips -in PHD cell harvesters (Cambridge Technology, Inc., Watertown, MA), followed by washing the filter strips with saline (1 ml) for three times.

Nonspecific binding was determined in the presence of 1 pjM ET-1.

Figure 1A.

16. 16- c [Example 43], M >98% Protein Bound Figure 1B.

20.

001 80- 3 C50 3 nM 3.1 n M 0.15 5.5 nM Figure IC.

120 100 0.

0 2 0 0 20.

0 -20 1 Or, 1c50 SA 5.5 nM 0.2% 6.5 nM 1% 4 10"l 101. 10"2 10" 104 rExample 531], M 92% protein bound 10' 10. 10.1 10-W Pample 5 30],u M 7T/% Prtein Bound 10' Figure 1 Inhibition of 25 1 ]ET-1 binding to human ETA receptor by ETA antagonists. Each curve was determined in the presence of either 1 or 5% HSA, and -742assays were performed as described above. The results are expressed as of control binding, with [t 25 1]ET-1 binding in the absence of antagonist defining 100%. Each point represents the mean of three determinations.

As observed in Figure 1A, a compound which is highly protein bound (Example 4 >98% bound) shows a rightward shift of the binding curve (toward decreasing potency in the presence of increasing albumin levels. The compound of Example 531 (Figure 1B in which protein binding is reduced to 92%, shows a substantial diminution of this rightward shift; the shift is completely eliminated with the compound of Example 530 (Figure 1C), in which protein binding is reduced to 78%. This experiment demonstrates that a reduction in protein binding translates into increased potency in the presence of plasma proteins, and suggests that such compounds may exhibit enhanced in vivo activity.

The observed reduction in protein binding, in compounds which rethin high affinit 15 for endothelin receptors, appears linked to the placement of "basic" functionality (group which carry a positive charge at physiological pH).

Such compounds also exhibit improved solubility in aqueous solutions, as demonstrated below (Table 1) in an experiment in which maximum solubility was measured in aqueous media at varying pH at about 25 0 C. These results indicate that compounds that contain charged groups on the amide sidechain exhibit increased solubility over a significant range of pH. Such increased aqueous solubility, coupled wit the enhanced potency resulting from decreased protein binding, might make such compounds preferred for development as parenteral agents. Table 8 presents the pH- Solubility profiles for representative compounds of the present invention.

Table 8.

pH [Example 43] (mg/m (Example 531] (mg/ 5.1 0.08 >3.3 0.51 >3.4 7.1 0.99 3.54 7.6 1.14 3.55 -743- The present invention provides less protein bound compounds having improved in vitro and in vivo activity as pharmaceutical agents. The present invention also provides compounds that show that the affinity of hydrophobic acids for plasma protein may be reduced by attaching a counterbalanced charge at a biologically acceptab site. For example, protein binding is reduced by attaching a "basic" functionality (group which carry a positive charge at physiological pH) on the amide sidechain (see Formula wherein R 3 has an amide sidechain).

The present invention covers compounds having the formula XII: Z R3 S* CH)n

R)

XII

wherein Z is -C(R 18 or wherein R18 and R 1 9 are independently selected from hydrogen and loweralkyl; 20 n is 0 or 1; S: 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 carbdxy protecting group, -P0 3

H

2 -P(0)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl,

-CN,

-C(0)NHR 1 7 wherein R 1 7 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(0)NHS(0)2R16 wherein R 1 6 is loweralkyl, haloalkyl, aryl or dialkylamino, 744 (in) -S(O) 2 NHC(O)Rl 6 wherein R 1 6 is-defined as above,

HO

NH

0 (HO 0

OH

N

0

NH

WN

-a

(U)

R n R are) neednl eetdfo hdoelwrlyakn **ynl *.oyakl N-Oy ab nllkl y rx akyh lakl haoloxakl *loyloxakl tholoylkxakl cycloalky cylakyakl amNoabnllyakam ocr nyay dilklamincrbnla kl mnoab nlaknl aklmnoabnHaknl 15 **lya io ab n lleyl y rx ak nl rl ayak l rlx ak :.:akxylkl :Nakny--ly~mnakl Nlyslnlmdakl 745 heterocyclic, (heterocyclic) alIkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and RC is al kylene, with the proviso that one or both of R, and R 2 is other than hydrogen;

R

3 is (a)34 -C(O)-R1 5 R4-C(O)-R 5 N(R6)-, wherein R 5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20 8 or

-R

8 a-N(R 20

V-R

8 wherein R 8 and R 8 a are independently selected from the group consisting of alkylene and alkenylene and R 20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl or cycloalkylalkyl or -O-R3 9 or -R 9 a-O-R 9 wherein R 9 and R9a are independently selected from alkylene;

R

4 and R 6 are (Rll)(Rl 2 wherein Rjj and R 12 are independently selected from hydrogen,.

15(2) loweralkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclic, (12) arylalkyl, (13) (heterocyclic) alIkyl, (14) hydroxyalkyl, alkoxy, aminoalkyl, (17) trial kylaminoal kyl, alkylaminoalkyl, (1 9) dial kylami noal kyl, carboxyalkyl, (21) (cycloalkyl)aminoalkyl, (22) (cycloalkyl)alkylaminoalkyl, (23) (heterocyclic) amin oal kyl, and (24) (heterocyclic) amin oal kyl, with the proviso that at least one of R 11 and R, 2 is selected from heterocyclic, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, trial kylani noalkyl, alkylaminoalkyl, dial kylaminoalkyl, carboxyalkyl, (cycloalkyl)aminoalkyl, (cycloalkyl)al kylaminoalkyl, (heterocyclic) aminoalkyl, and (heterocyclic) al kylami noal kyl; or a pharmaceutically acceptable salt thereof.

746 Preferred compounds having reduced protein binding are Ishown in Table 9A wherein R may be selected from the substituents shown in Table 9B.

Table 9A.

1

CO

I. S ce em C C

C

S.

S S

SOS.

OS

*OOS

*0 S

IC

I Yb SO 0 55 *0

*CCS

0 @505 tO

C

5

SC

S S OC* S 00 5 O0

OCH,

R.

N

COOH

0 0-i

OCH,

R.N.."COOH

ci 2 b- R.

N

COOH

0 5 c 0o

COOH

-0 8 o~

COOH

-0 C01

OCH

3 R.

N

COOH

0

CC

R.

N

COOH

-0 CH30 0-J 747 N COOH

CI

D 0 15 CH 3 O 0- R.N0

**"COOH

18 o

-N

R.N

"VOOH

0 2101 R.N o~

CO

24

CI

-N

R.N

_-COOH

0

CH

3 0 0-i

R.N

"COOH

0 23 RN

COOH

0 O-j 0 R. N

COOH

t 0

CO

oj 25 -748- 28

R.N

N-NH

0 0 31

CH

3 o 0-i

RN

0 0-i Table 9B.

fSCNH Ny 0

H

3

CNH-,-_N

4 0 7 7 0 2 0 5 H

H

8 0 H II 1 N 14 0 HCNH

~N<

3 0 6 0 9 H 0

H

12 0

H

15 0 18 0--a 10 0 13 H 0

H

16 0 17 0 -749- 19 2 0 22 0 20 0.

23 H 0 0 0 0 0 31 0 0 34 37 N) 0 43 0 46~ HN 0 49 0 32 0 0 35 0 38 41 0 47 0 50 HN,_)

CH

3 N 0 53 21 H 0 24-f 0 27 0 30 0 0 33 0 36 39 0 420 0 0O 0 480.1) HN0 51 0 -750c H 3N 0 0 o

N~~Q

5 6 cH 3 N) 5 7 K2 "0 58 H59 60 H 61oNU4 62 H 63 H0 64 For the purposes of this disclosure, the term "(cycloalkyl)aminoalkyl" as used ***herein refers a cycloalkyl moiety attached to the parent compound through an aminoalkyl. Examples of (cycloalkyl)aminoalkyl include (cyclohexane)aminopropyl, (cyclohexane)aminoethyl, and the like.

10 The term "(heterocyclic)aminoalkyl" as used herein refers to a heterocyclic moiety attached to the parent compound through an aminoalkyl. Examples of (heterocyclic)aminoalkyl include (pyridine)aminopropyl, (benzofuran)aminopropyl, (tetrahydopyran)aminoethyl, and the like.

The term "(cycloalkyl)alkylaminoalkyl" refers to a cycloalkyl moiety attached to the parent compound through an alkylaminoalkyl. Examples of (cycloalkyl)alkylaminoalkyl include (cyclohexane)ethylaminomethyl, (cyclopentane)methylaminoisopropyl, and the like.

The term "(heterocyclic)alkylaminoalkyl" as used herein refers to a heterocyclic moiety attached to the parent compound through an alkylaminoalkyl.

Examples of (heterocyclic)alkylaminoalkyl include (pyridine)ethylaminopropyl, (benzofuran)methylaminoisobutyl, (tetrahydopyran)methylaminoethyl, and the like.

The ability of the compounds of the invention to lower blood pressure can be demonstrated according to the methods described in Matsumura, et al., Eur. J.

Pharmacol. 185 103 (1990) and Takata, et al., Clin. Exp. Pharmacol. Physiol. 1i 131 (1983).

The ability of the compounds of the invention to treat congestive heart failure can be demonstrated according to the method described in Margulies, et al., Circulation 82 2226 (1990).

-751- The ability of the compounds of the invention to treat myocardial ischemia can be demonstrated according to the method described in Watanabe, et al., Nature 344 114(1990).

The ability of the compounds of the invention to treat coronary angina can be demonstrated according to the method described in Heistad, et al., Circ. Res. 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. 66915 (1987) or Matsumura, et al., Life Sci. 49 841-848 (1991).

The ability of the compounds of the invention to treat cerebral ischemia can be demonstrated according to the method described in Hara et al., European. J.

Pharmacol. 197: 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. 83 1762(1989).

The ability of the compounds of the invention to treat chronic renal failure can be demonstrated according to the method described in Benigni, et al., Kidney Int. 44 440-444 (1993).

The ability of the compounds of the invention to treat gastric ulceration can be demonstrated according to the method described in Wallace, 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).

25 The ability of the compounds of the invention to treat endotoxin-induced toxicity (shock) can be demonstrated according to the method described in Takahashi, et al., Clinical Sci. 79 619 (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. 67 1213 (1989).

The ability of the compounds of the invention to treat transplant-induced atherosclerosis can be demonstrated according to the method described in Foegh, et al., Atherosclerosis 78 229-236 (1989).

The ability of the compounds of the invention to treat 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).

-752- 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.

The ability of the compounds of the invention to treat acute or chronic oo 15 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 25 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).

-753- The ability of the compounds of the invention to treat ischemia-repurfusion 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, camphorsulfonate, 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, 15 persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogencontaining groups can be quaternized with such agents as loweralkyl halides, such as methyl, 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, 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, quatemary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other -754representative 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 the 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, 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.

25 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 pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use -755of transdermal administration such as transdermal patches or iontophoresis devices.

The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal 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 10 solution, and isotonic sodium chloride solution. In addition, 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, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be 20 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, lubricating agents such as magnesium stearate. In the case i 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 wetting 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 multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any nontoxic, 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 -'756 like. The preferred lipids are the 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 15 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, nadolol, propranolol, timolol, carteolol 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.

-757- 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.

The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds, processes, compositions and methods.

S. 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

1. A compound of the formula: R2 zNR3 (CH 2 )n RI wherein Z is -C(R 18 )(R 19 or wherein R 18 and R 19 are independently selected from hydrogen and loweralkyl; n is 0 or 1; :R is -(CH2)M-W wherein m is an integer from 0 to 6 and W i! -C(O) 2 -G wherein G is hydrogen or a carboxy protecting -P0 3 1- 2 -P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl, -CN, -C(O)NHR 17 wherein R 1 7 is loweralkyl, alkylaminocarbonyl, dial kylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O) 2 Rl 6 wherein R 1 6 is loweralkyl, haloalkyl, aryl or dial kylImin o, (in) -S(O) 2 NHC(O)Rl 6 wherein R 16 is defined as above, HO 0 0 -759- (HO ):0 OH (p) NH H9 S. N CZ CF SN 6*O H M o r NHS02C* (r)0 RI an02aeidpnetyslctdfo yrgn oeakl alenl (s)xalyl Hloyabnllyl yrxak hlakl aoakxakl loyakxakl hoakxakxakl cylakl 9ylakllyamnc royakl alya iocroyakydakya ioaboyakl amncrb.llknl jlylmnoaboyllenl *ilya ioaroyaknl hyrxaknl Hrl ryak R2 and ohr tae indpenetyslce;rmhyrgn oeakl -760- R 3 is (a)R 4 -C(O)-R 5 Rc4-R5a-, R4-C(O)-R 5 N(R 6 R6S02R-or R26-S(O)-R 27 wherein R 5 is -a covalent bond, (ii) alkylene, (iii.) alkenylene, (iv) -N(R 2 0 )-R 8 or -R 8 a-N(R 20 )-R 8 wherein R 8 and Rea are independently selected from the group consisting of alkylene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyl or -O-R 9 or -R 9 a-O-R 9 wherein R 9 and R9a are independently selected from alkylene; R~a is alkylene or (ii) alkenylene; R7 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 21 )-Rlo- or -RlOa-N(R21)-R1O- wherein R 10 and Rioa are independently selected from the group consisting of alkylene and alkenylene and R 21 is hydrogen, loweralkyl, alkenyl, haloalkyl, haloalkoxyalkyl, aryl or arylalkyl; 6o R 4 and R 6 are independently selected from the group consisting of (Ri 1)(Rl 2 wherein Ru and R 1 2 are independently selected from hydrogen, loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, (11) heterocyclic, (12) arylalkyl, (13) (heterocyclic)alkyl, (14) hydroxyalkyl, alkoxy, (16) aminoalkyl, (17) trialkylaminoalkyl, (18) alkylaminoalkyl, -76 1- (19) dial kylam inoalkyl, and carboxyalkyl (i i) loweralkyl, (iii) alkenyl, alkynyl, cycloalkyl, (v i) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x (heterocyclic)alkyl, i) alkoxyalkyl, *(xii) hydroxyalkyl, (xiii) haloalkyl, (xiv) haloalkenyl, (xv) haloalkoxyalkyl, haloalkoxy, *(xv ii) alkoxyhaloalkyl, (xviii) alkylamninoalkyl, 100 (x ix) dialkylaminoalkyl, alkoxy, and H NR7,a (xxi) 0 wherein z is 0-5 and R7a is alkylene; 105 R 2 6 is loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy- substituted haloalkyl; and R 27 is alkylene or alkenylene; 110 R 22 -O-C(O)-R 2 3 wherein R22 is a carboxy protecting group or heterocyclic and R 2 3 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R24)-R25- wherein R2 5 is alkylene and R 2 4 is hydrogen or loweralkyl, loweralkyl, -76 2- alkenyl, alkynyl, Mf cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, (k heterocyclic, (heterocyclic)alkyl, (in) alkoxyalkyl, alkoxyalkoxyalkyl, R, 3 -C(O)-CH(R 4)- wherein R 13 is amino, alkylamino Ri 5 wherein R 15 is amino, or a pharmaceutically acceptable o r or dialkylamino and R 14 is aryl or alkylamino or dialkylamino; salt thereof.

2. The compound according to Claim 1 wherein n is 0 and Z is -C H 2

3. The compound according to Claim 1 wherein n is 1 and Z is -C H 2

4. -CH 2 and R 4 R 5 R 6 The compound according to, Claim 1 wherein n is 0, Z is R 3 is R 4 -C(O)-R 5 R 6 -S0 2 -R 7 or R2 6 -S(O)-R 27 wherein R 7 R 26 and R 27 are as defined therein. The compound according to Claim 1 wherein n. is 0, Z is -OH 2 and R 3 is alkoxyalkyl or alkoxyalkoxyalkyl.

6. The compound according to Claim 1 wherein n is 0, Z is -CH 2 and R 3 is R 4 wherein R 4 is (Rll)(Rl 2 as defined therein and R 5 is alkylene or R 3 is R6-S(O) 2 -R 7 or R2 6 -S(O)-R 2 7 wherein R 7 is alkylene, R 27 is alkylene and R 6 and R 26 are as defined therein. -763-

7. The compound according to Claim 1 wherein n is 0, Z is -OH 2 and R 3 -is R 4 -C(O)-N(R 2 0)-R 8 or R 6 -S(O) 2 -N(R 21 )-Rlo- wherein R8 and Rio are alkylene and R 4 R 6 R 2 0 and R 21 are as defined therein. The compound according to Claim 1 wherein n is 0, R is tetrazolyl or -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is -C(O)-NHS(O) 2 Rl 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 R 1 and R 2 are independently selected from loweralkyl, (ii) cycloalkyl, (iii) substituted and unsubstituted aryl wherein aryl is phenyl substituted with one, two or ::.three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy, (iv) substituted or unsubstituted ****heterocyclic, alkenyl, (vi) heterocyclic (alkyl), (vii) aryloxyalkyl, (viii) arylalkyl, (ix) (N-alkanoyl-N-alkyl)aminoalkyl, and (x) alkylsulfonylamidoalkyl, and R 3 is R 4 -C(O)-R 5 wherein R 4 is (Ri 1)(R12)N- wherein R 11 and R 12 are independently selected from :loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, heterocyclic, alkoxy, aminoal kyl, trial kylam inoalkyl, aryl and arylalkyl R 5 is alkylene; or R 3 is R 4 -C(O)-N(R 20 )-R 8 or R 6 -S(O) 2 -N(R 2 1 )-R 1 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 Rj 0 are alkylene 20 and R 20 and R 21 are loweralkyl; or R 3 is R 6 -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.

9. The compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 Rl 6 wherein R 16 is loweralkyl, haloalkyl or aryl, -Z is -OH 2 RI is loweralkyl, (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, 4-methylphenyl., 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl., 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl -764- or dihydrobenzofuranyl whe .rein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) arylalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkano'yl-N-alkyl)aiminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1,3- benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 1 4-benzodioxanyl, 8- methoxy-1 .4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4- methoxyphenyl, dimethoxyphenyl, fluorophenyl, or difluorophenyl, and R 3 is R4-C(O)-N(R 2 0 )-R 8 or R6-S(O) 2 -N(R 2 l)-Rio- wherein R 8 and R 10 are alkylene, R 2 o and R 21 are loweralkyl, R 4 is loweralkyl, aryl, alkoxy, alkylarnino, aryloxy or arylalkoxy and R 6 is loweralkyl, haloalkyl, :::.alkoxyalkyl, aryl or arylalkyl. The compound according to Claim 1 wherein n is Of 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 -CH 2 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, 4- ethoxyphenyl, 4-ethyiphenyl, 4-methyiphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethyiphenyl, 3 -fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, -1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) arylalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl or (xiii) alkylsutfonylamidoalkyl, R 2 is substituted or unsubstituted 1,3- benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8- methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4- methoxyphenyl, dimethoxyphenyl, fluorophenyl, or difluorophenyl, and 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.

11. The compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, -76 tetrazolyl or -C(O)-NHS(O) 2 Rl 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 R, is loweralkyl (ii) alkenyl, (iii) arylalkyl, (iv) aryloxyalkyl, heterocyclic, (vi) heterocyclic (alkyl), (vii) aryl, (viii) (N-alkanoyl-N-alkyl)aminoalkyl, or (viii) alkylsulfonylamidloalkyl, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (Ril)(RI2)N- wherein R 11 is loweralkyl, and R 12 is aryl or arylalkyl. .12. The compound according to Claim 1 wherein n isO0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, :tetrazolyl or -C(O)-NHS(O) 2 R 1 wherein R 1 is loweralkyl, haloalkyl or aryl, Z is -OH 2 R 1 is phenyl or (ii) substituted or unsubstituted 4- :5 methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro- 4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 1,3- benzodioxolyl, 1 ,4-benzodioxanyl or dihyd robe nzof uranyl 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 R6-S(O) 2 -N(R 2 l)-Rlo- wherein R1o is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl. 1 3. The compound according to Claim 1 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 1 6 is loweralkyl, haloalkyl or aryl, Z is -OH 2 R 1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1 ,3-benzodioxolyl or 1 ,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy -76 6- and alkoxyalkoxy, R 2 is Substituted or unsubstituted 1 3 -benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 1 4-benzodioxanyl, 8-methoxy..i,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 l)-Rio- wherein Rj 0 is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R2 1 is loweralkyl, -haloalkyl, alkoxyalkyl or haloalkoxyalkyl.

14. The compound according to Claim 1 wherein n is 0, R is 0 -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl or haloalkyl, Z is -OH 2 RI is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methyiphenyl, 4 -trifluoromethylphenyl, 4 -pentafluoroethylphenyl, 4 -methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3-benzodioxolyl, 1 .4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 iS 1 .3-benzodioxolyl, 1 ,4- benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (Rll)(Rl 2 wherein R 11 and R 12 are independently selected from loweralkyl, aryl,' arylalkyl, hydroxyalkyl, 00% alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic. 1 5. The compound according to Claim 1 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R.,6 wherein R 16 is loweralkyl or haloalkyl, Z is -OH 2 RI is loweralkyl, alkoxyalkyl, or alkenyl, R 2 is l,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 R 4 is (Rll1)(R12)N- wherein R, 1 and R 12 are independently selected from loweralkyl, aryl hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, heterocyclic, and arylalkyl. -767-

16. The compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -OH 2 R1 is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-flUorophenyl, 4-methyiphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent 'is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1 ,3-benzodioxolyl, 1,4- benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-R 5 :::wherein R5 is alkylene and R 4 is (Rii)(Rl 2 wherein Rjj and R 12 are .*:independently selected from loweralkyl, hydroxyalkyl, alkoxy, :::aminoalkyl, trialkylaminoalkyl, aryl, and heterocyclic.

17. -The compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -OH 2 R, is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methyiphenyl, 4-trifluoromethyiphenyl, *5 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, :10 dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 wherin 5 i alklen an R4is (Rll)(Rl 2 wherein R 11 is loweralkyl and R 12 is aryl. 1 8. The compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -OH 2 R 1 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 ca'rboxyalkoxy, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7- methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4- -768- benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (R11)(R2)N- wherein R 11 is alkyl and R 12 is selected from aryl, aminoalkyl; trialkylaminoalkyl, and heterocyclic.

19. A compound according to Claim 1 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, 20 aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or .alkylsulfonylamidoalkyl, and R 3 is R 4 -C(O)-R 5 wherein R 5 is alkylene and R 4 is (R11)(R 2 wherein R 1 1 and R 1 2 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, 25and heterocyclic. A compound according to Claim 1 wherein n is 0, R is S*-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, (N-alkanoyl-N-alkyl)aminoalkyl, or 30 alkylsulfonylamidoalkyl, and R 3 is R 4 -C(O)-R 5 wherein R 5 is alkylene and R 4 is (R11)(R 1 2 wherein R 11 and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R 11 and R 12 is alkyl.

21. The compound according to Claim 1 of the formula: R2 Z R3 S (CH 2 )n RI wherein Z is -C(R 18 )(Rl 9 or wherein R 18 and R 1 9 are independently selected from hydrogen and loweralkyl; n is 0 or 1; -769- S. S. *5 S S S S. S S S S 555 5 S. S S S S. R is -(CH2)m-W wherein mn is an integer from 0 to 6 and W is. -C(O)2-G wherein G is hydrogen or a carboxy protecting group, -P0 3 H 2 -P(O)(OH)E wherein E is hydrogen, ioweralkyl or arylalkyl, -ON, -C(O)NHR1 7 wherein R17i is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O) 2 Rl 6 wherein R 16 is loweralkyl, haloalkyl, aryl or dial kylImin 0, (in) -S(O) 2 NHC(O)Rl 6 wherein R 16 is defined as above, HO 0 HO 0 OH 0 NH 0 -770- 0 H (tM~ ifI F or R 1 and R 2 are independently selected from hydrogen, loweralkyl, .9 alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, 0999 haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, **35 cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalIke nyl, alkylaminocarbonylalkenyl, 99 9.dlalkylaminocarbonylalkenyl, 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 0 is alkylene, with the proviso that one or both of R, and R 2 is other than hydrogen; R 3 is R4-C(O)-R 5 R4-R5a-, R6-S(O) 2 -R 7 or R26-S(O)-R 27 wherein R 5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) 99*-N(R 2 0 )-R 8 or RaN20R8 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, cycloalkyl or cycloalkylalkyl or -0-Rl 9 or -R 9 a-0-R9- wherein R 9 and R9a are independently selected from alkylene; is alkylene or (ii) alkenylene; R 7 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) or -R Oa-N(R21 )R o- wherein Rj 0 and R10a are independently selected from the group consisting of alkylene and alkenylene and R 2 1 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl; R 4 and R 6 are independently selected from the group consisting of -77 1- (Rii)(R 12 wherein R11 and R1 2 are independently selected from hydrogen, loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, CO cycloalkylalkyl, (10) aryl, (11) heterocyclic, -Oat(12) arylalkyl, 0* 0(13) (heterocyclic)alkyl, (14) hydroxyalkyl, (15) alkoxy, 0(16) aminoalkyl, and (17) trialkylaminoalkyl, (i i) loweralkyl, *(iii) alkenyl, (i v) alkynyl, (v i) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (i x) heterocyclic, Mx (heterocyclic)alkyl, (x i) alkoxyalkyl, (xii) hydroxyalkyl, (xiii) haloalkyl, (xiv) haloalkenyl, (xv) haloalkoxyalkyl, (xvi) haloalkoxy, (xvii) alkoxyhaloalkyl, (xviii) alkylaminoalkyl, -772- (Xix) dialkylaminoalkyl, (xx) alkoxy, and (CH2 N R 7 a (xxi) 0 100 wherein z is 0-5 and R7a is alkylene; R 26 is loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy- substituted haloalkyl; and 105 R 27 is alkylene or alkenylene; R22-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 2 4 )-R 25 wherein R 25 is alkylene adR 24 is hydrogen or loweralkyl, 110 loweralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylaikyl, 115 aryl, arylalkyl, aryloxyalkyl, heterocyclic, (heterocyclic)alkyl, 120 (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 15 is amino, alkylamino or 125 dialkylamino; or a pharmaceutically acceptable salt thereof. -773-

22. The compound according to Claim 21 wherein n is 0 and Z is -CH 2

23. The compound according to Claim 21 wherein n is 1 and Z is -CH 2

24. The compound according to Claim 21 wherein n is 0, Z is -CH 2 and R 3 is R 4 -C(O)-R 5 R 6 -SO2-R 7 or R26-S(O)-R 2 7 wherein R 4 R 5 R 6 R 7 R 2 6 and R 2 7 are as defined therein. The compound according to Claim 21 wherein n is 0, Z is -CH 2 and R 3 is alkoxyalkyl or alkoxyalkoxyalkyl.

26. The compound according to Claim 21 wherein n is 0, Z is -CH 2 and R 3 is R4-C(O)-R 5 wherein R 4 is (R11)(R 1 2 as defined therein and Rs is alkylene or R 3 is R 6 -S(0) 2 -R 7 or R 2 6 -S(O)-R 2 7 wherein R 7 is alkylene, R 2 7 is alkylene and R 6 and R 2 6 are as defined 5 therein.

27. The compound according to Claim 21 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 )-Ro 0 wherein R 8 and Rio are alkylene and R 4 R 6 R 2 0 and R 2 1 are as defined .therein.

28. The compound according to Claim 21 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(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 R 1 and R 2 are independently selected from loweralkyl, (ii) cycloalkyl, (iii) substituted and unsubstituted aryl wherein aryl is phenyl substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy and (iv) substituted or unsubstituted heterocyclic, alkenyl, (vi) heterocyclic (alkyl), (vii) aryloxyalkyl, (viii) aryalkyl, (ix) (N-alkanoyl-N-alkyl)aminoalkyl, and alkylsulfonylamidoalkyl, and R 3 is R 4 -C(O)-R 5 wherein R 4 is (R11)(R12)N- wherein R 1 1 and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, -774- heterocyclic, hydroxyalkyl, 'alkoxy, aminoalkyl, trialkylaminoalkyl, aryl and arylalkyl and R 5 is alkylene; or R 3 is R4-C(O)-N(R 20 )R 8 or wherein R 4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R 6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or a rylIa1k yI, R 8 and R 10 are alkylene and R 20 and R 21 are loweralkyl; or R 3 is R 6 -S(O) 2 -R 7 or R2 6 -S(O)-R 2 7 wherein R 6 is loweralkyl or haloalkyl, R 7 is alkylene, R 26 is loweralkyl and 27 is alkylene.

29. The compound according to Claim 21 wherein n is 0, R is 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 RI is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) *5 cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4mehxpny 4-fluorophenyl, 3-fluorophenyl, 4- ethoxyphenyl, 4-ethyiphenyl, 4-methyiphenyl,' 4 -trifluoromethylphenyl, V. 4 -pentafluoroethylphenyl, 3 -fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4 -methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, l,3-benzodioxolyl, l,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, aryoxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1 ,3- benzodioxolyl, 7-methoxy-i .3-benzodioxolyl, 1 .4-benzodioxanyl, 8- methoxy- 1 4 -benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4- methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-N(R 20 )-R 8 or R6-S(O) 2 -N(R 2 1 )-Rl 0 wherein R 8 and R 10 are alkylene, R 20 and R 21 are loweralkyl, R 4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and -775- R 6 is loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl. The compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 Rl 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 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, 4- ethoxyphenyl, 4-ethylphenyl, 4-methyiphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethyiphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, aryoxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) R 2 is substituted or unsubstituted 1,3- 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8- methoxy-1 .4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4- i~i methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 wherein R 5 is alkylene and R4 is (Rli)(Rl 2 wherein R 11 and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl and arylalkyl, heterocyclic, *hydroxyalkyl, alkoxy, amino alkyl, and trialkylaminoalkyl.

31. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 Rl 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -OH 2 R 1 is loweralkyl or (ii) alkenyl, (iii) aryalkyl, (iv) aryoxyalkyl, heterocyclic (alkyl), (vi) aryl, (vii) (N-alkanoyl-N- alkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl ,R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is R 4 wherein R 5 is alkylene and R 4 'is (Ri i)(Rl 2 wherein R 11 is loweralkyl and R 12 is aryl or arylalkyl. -776-

32. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(o) 2 Rl 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -OH 2 RI is phenyl or (ii) substituted or unsubstituted 4- methoxyphenyl, 3 -fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro- 4-ethoxyphenyl, 2-fluorophenyl, 4 -methoxymethoxyphenyl, 1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl or dihyd robe nzof uranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is substituted or unsubstituted 1,3- benzodioxolyl, 7-methoxy-i 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 15R6-S(O) 2 -N(R 2 1 )-Rl 1 0 wherein Rio is alkylene, R 6 is loweralkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R 21 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl. 33 The compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 RI 6 wherein R 16 is loweralkyl, haloalkyl *or aryl, Z is -OH 2 R 1 is substituted or unsubstituted 4-methoxyphenyl, 3 fluoro-4-methoxyphenyl, 3-fluorophenyl, 3 -fluoro-4-ethoxyphenyl, 4 -methoxymethoxyphenyl, 1 ,3-benzodioxolyl or 1 ,4-benzodioxanyl **wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy and alkoxyalkoxy, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy- 1,3-benzodioxolyl, 1 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 alkoxycarbonyl or R6-S(O) 2 -N(R 21 )-R 10 wherein Rio is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R 21 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl.

34. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, -77 7- tetrazolyl or -C(O)-NHS(O) 2 RI 6 wherein R 16 is loweralkyl or haloalkyl, Z is -CH 2 Rl is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethyiphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1 ,3-benzodioxolyl, 1,4- benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-R 5 wherein R5 is alkylene and R 4 is (R 11 )(Rl 2 wherein RI, and R 12 are independently selected from loweralkyl, aryl arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.

35. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 1 wherein R 1 is loweralkyl or haloalkyl, :Z is -OH 2 R 1 is loweralkyl, alkoxyalkyl or alkenyl, R 2 is 1,3- benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (Rii)(Ri 2 )N- wherein R 1 1 and R 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyt, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.

36. The compound according to Claim 21 wherein n is 0, R is 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -OH 2 R 1 is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methyiphenyl, 4-trifluor omethyiphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, 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 R 4 is (Rii)(R 1 2 wherein R 11 and R 12 are independently selected from loweralkyl. -778-

37. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 RI is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, '2-fluorophenyl, 4-methylphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, 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 R 4 is (Rii)(Rl2)N- wherein R 11 is loweralkyl and R 12 is aryl.

38. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -OH 2 R 1 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 ,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 21 )-R 1 0 wherein R 10 is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R 21 is loweralkyl, haloalkyl or alkoxyalkyl.

39. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -OH 2 R 1 is Ioweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R 3 is R 4 -C(O)-R 5 wherein R 5 is alkylene -7797 and R 4 is (Rll)(Rl 2 wherein R 11 and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, and heterocyclic.

40. A compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -OH 2 Ri is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R 3 is R4-C(O)-Rs- wherein R 5 is alkylene and R 4 is (Rli)(Rl 2 wherein R 11 and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R 1 1 and R 12 is alkyl

41. A compound selected from the group consisting of trans-trans-2- Meth oxp hen y1)-4-(1 ben zodioxol1-5-yl1)- 1 propyl-N-n-"pentanesulfo nylam ino)propyl]-pyrrolidine-3-. carboxylic acid; trans, trans- 2 (4-Meth oxy meth oxyphenyl)4-(1 ,3 -ben zod ioxol -5-yl) 1 -(-Npoy---enansuI n a o ty~yroiie3 carboxylic acid; trans, trans-2- Di meth oxyp hen yl)-4-(1 ben zod ioxolI -5-yI)-1 (N p ro pyI- N npen ta n e suIf on yl ami no)eth y1)pyr ro Iid in e-3 carboxylic acid; trans, trans-2-(3,4-Dimethoxyphenyl)-4.(1 ,3-benzodioxol-5-yl)- 1 -Nnhxneufnlaioehy~yrliie3 carboxylic acid; 0**otrans,trans-2-( 4-Propoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 *15 p ropy I- N-n-pentanes u If ony la mino)ethyl]pyrrol idine-3..carboxyg ic acid; trans, trans-2-(3,4-Dif luorophenyl)-4(1 ,3-benzodioxol-5-yl)-1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3carbxylic acid; trans, trans-2-(3,4-Dif luorophenyl)-4(1 ,3-benzodioxol-5-yl)-1 propy I-N-n-pen tan es ulfon ylam in o)ethyl] py rro lid in e-3-ca rboxyIi c acid; trans, trans-2-(3-Fluoro-4-methoxyphenyI)-4(1 1 2 -(N-propyl-N-nhexanesulfonylamino)ethyIlpyrrolidine-3 carboxylic acid; -780- trans, trans-2-(3-Fl uoro-4-methoxyp he ny1) be 1 -(2-(N-propyl-N-(3-chloropropanesuIf onyl) am ino)ethyl)- pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 .1 -(2-(N-isobutyl-N-(3- chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 1 -[2-(N-propyl-N-(4- methylbutanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxy-3-fluorophenyl)-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-Fluoro-4-methoxyphenyl)-4-(1 1 -[2-(N-propyl-N-(2,2,3,3,3-pentafluoropropoxyethanesulfonyl)- amino)ethyllpyrrolidine-3-carboxylic acid; trans, trans-2-(1 ,4-Benzodioxan-6-yI)-4-(7-methoxy-1 ,3-benzodioxol- 5-yI)-1 ropylI-N-(n- pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; :trans, trans-2-(3-Fluoro-4-rnethoxyphenyl)-4-(i,3-benzodioxol-5-yI)- carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-(2-methoxyethyl)-N-(3-chloropropanesulfonyl)amino)- ethyl) py rrol idi ne-3-carboxyl ic acid; trans, trans-2-(3- FIu oro-4-nethoxyp henyl)-4-(1 ,3-be (pentanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -[2-(N-propyl-N-((2,2,2-trifluoroethoxyethane)sulfonyl)amino)- ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-(2-methoxyethyl)-N-(butanesulfonylamino)ethyl)- pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -[2-(N-propyl-N-(2- -781- me thy I propan esu If o nyI)am ino) ethyl] pyrroid ine3-carboxylic acid; and trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3 1 (N-isob'utyl-N utan esuf on ylamino))e thy) pyrrol idine-3. carboxylic acid; trans, trans-2-(2-Methylpentyl)-4-(1 ,3-benzodioxol-5-yI)-1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yI)-1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxo-2-yI)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1 (NN-di(n-butyl)aminocarbonylmethyl)-pyrrolidine3carboxylic acid; **trans, trans-2-(2-(2-Tetrahydro-2H-pyran)ethyl)4(1 ,3-benzodioxol- 5-yI)-l1-(N, N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; trans, trans-2-(2,2,4-Trimethyl-3-pentenyl)-4-(1 yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidin-3- carboxylic acid; trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(1 ,3- :benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxo-2-yI)ethyl)-4-(1 ,3-benzodioxol-5-yI)- 1 [[N-4-heptyl-N-(2-methyl-3-fI uoroph enyl)] aminocarbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxol-2-yI)ethyl)-4-(7-methoxy- 1,3- benzodioxol-5-yI)- 1 N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid trans, trans-2-((2-Methoxyphenoxy)-.methyl)-4(1 1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yI)-1 heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl). pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrroljdin- 1 -yI)ethyl)-4-( 1,3-benzodioxol-5- yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)..pyrrolidine-3- carboxylic acid; -782- (2S, 3R, 4S)-2- (2,2-Dimethylpentyl)-4-(7-methoxy- 1,3-benzodjoxol1-5- yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid trans, trans-2-(2-('1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1 ,3- 100 benzodioxol-5-yi)-1 -(N-4-heptyl-N-(4-fluoro-3 methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-.carboxylic acid; trans, trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy.1 yl)-l -(N,N-di(n-butyl)aminocarbonylmethyl)-,pyrrolidine-3-

105. carboxylic acid; trans, trans-2-(2 ,2-dimethylpentyl)-4-(2,3-dihydro-benzof uran-.5-y 1 -(N,N-di(n-butyl)aminocarbonymethyl).pyrrolidine-3- carboxylic acid; trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(7- **110 methoxy-1 ,3-benzodioxol-5-yI)-1 -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid- trans, trans-2-(2-(2- Methoxyph eny )-eth yl)4-(7-methoxy- 1, 3- benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; 115 trans, trans-2-(2,2-Dimethyl-3-(E)-pentenyl)4(7-methoxy-1,3- benzodioxol-5-yl)-l -(N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-pyridyl)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 120 (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yI)ethyl)-4-(1 1 N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; (2S, 3R, 4 S)- 2 -(2-(2-oxopyrrolidin-1 -yI)ethyl)-4-(1 yI)-l1-(N-4-heptyl-N-(4-fluoro-3- 125 methylphenyl))aminocarbonylmethyl)pyrrolidine3carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1 N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; -783- 130 trans, trans-2-(4- Methoxyp hen 1 ,3-benzodioxol-5-yl)-1 butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]. pyrrolidine-3-carboxylic acid; (2R,3F,4S)-2-(3-Fluoro-4-methoxyphenyl)-4.(1 2 -(N-propyl-N-pentanesulfonylamino)ethyl)-pyrrolidine-3 135 carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yl)-1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine3carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(1 yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 140 carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-1 ,3- benzodioxol-5-yl)-1 N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-((2-Methoxyphenoxy)-methy)4-(1,3-benzodioxok5-yl)- acid; and 09.0: (2S, 3R, 4S)-2- (2-(2-Meth oxyp he nyl) ethyl)..4(1 ,3-be nzodioxolI-5-yI1) -1 N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3..carboxylic o. :acid; .0 0 150 or a pharmaceutically acceptable salt thereof. :0,0.042:, A compound of the formula: ~.NH (CH 2 )n 0 (CH 2 )m C w R wherein n is 0ori1; m is 0 to 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, -784- -C(O)NHR 17 where R 17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O) 2 RI 6 where R 16 is loweralkyl, haloalkyl, phenyl or dialIky lam in a, (in) -S(O)2NHC(O)Rl6, HO 0 0 .3 0. HO 9 0 OH SS(N 0 NH 0 rN N (s H o -785- M NHS0 2 CF 3 an R 1 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 aryl or arlalkyI, Rbb is hydrogen or alkanoyl and RC 0 is alkylene, with the proviso that one or both of R, and R 2 is other than hydrogen; or a salt thereof. *2 *43. The compound of Claim 42 wherein mn is zero or 1; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; or the substantially pure or (+)isomer thereof. The compound of Claim 42 wherein n and m are both 0; 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, 4- :ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N- alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl, and R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or -786- difluorophenyl wherein the substituent is selected from loWeralkyl, alkoxy and halogen; or the substantially pure or (+)isomer thereof. The compound according to Claim 42 of the formula: R2NH R 2 NH 2 6 (CH 2 )m w RI ~or w R 5 wherein nis 0ori1; V, m is 0 to 6; W i s -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, d ialIkyla min oca rbo nyl1, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(o) 2 Rl 6 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl 6 HO 0 _NH 0 -787- OH S&N (p) 0 NH (q) ()0 0 H (t or NH0.F and *9Sv R 1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, *lk la9.oabnlakl ilyaincroyak :alyaminocarbonylalkyl, alkylaminocarbonylalkyl, 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 RCC is alkylene, with the proviso that one or both -of R, and R 2 is other than hydrogen; or a salt thereof. 46. The compound according to Claim 45 wherein m is zero or 1; -788- W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; or the substantially pure or (+)isomer thereof. 47. The co mpound according to Claim 45 wherein n and. m are both 0; 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, 4- ethoxyphenyl, 4-ethylphenyl, 4-methyiphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl dihydrobenzofuranyl wherein the substituent is selected from erlkl haolkl alo alkoxyalkoxy adcarboxyalkoxy, (x aryalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N- 15alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl, and R 2 is substituted unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4- benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or *****difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure or (+)isomer thereof. 48. The substantially pure compound (+)-trans,trans-2-(4- :5.:Methoxyphenyl)-4-(1 3 -benzodioxo-5-lyl)pyrrolidine-3-carboxylic acid; or a salt or ester thereof. 49. The substantially pure compound (2S,3R,4S)-2-(2,2- Dimethylpentyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yI)-1 -(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; or a salt or ester thereof. -789- A compound of the formula R2 (H 2 )n (C 2 )m I R I I. wherein n is 0 or 1; m is 0 to 6; R. 5 b is alkylene; 0 is a leaving group; 10 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, -ON, -C(O)NHR 17 where R 17 is loweralkyl, 15 alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, 20 sulfonamido, -C(O)NHS(O) 2 Rl6 where R 1 6 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl 6 HO 0 f 0 )EC HO 0 (0) -790- OH (p) 0 0 0 *N H N .J.L'>F3 Mt H .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, :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 a rylalkyl, Rbb is hydrogen or alkanoyl and IRC is alkylene, with the proviso that one or both of R, and R 2 is other than hydrogen; or a salt thereof. -791- 51. The compound according to Claim 50 wherein m is zero or 1; b is alkylene; Q is a leaving group; and W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; or the substantially pure or (+)isomer thereof. 52. The compound according to Claim 50 wherein n and m are both 0; it alkylene; 0 is a leaving group; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; and RI is loweralkyl, (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-ethyiphenyl, 4-methyiphenyl, 4-trifluoromethyiphenyl, l1 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from **.loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy and R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3- benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen, (ix) aryalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl; or the substantially pure or (+)isomer thereof. 53. The compound according to Claim 50 of the formula RN 'R5b -Q R2N lR5b -Q %CH 2 )m)(cH2)n W R or w R -792- wherein n is 0ori1; m is 0 to 6; Rsb is alkylene; Q is a leaving group; 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)NHR 17 where R 17 is loweralkyl, alkylamninocarbonyl, dialkylamninocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, 20 -C(O)NHS(O) 2 Rl 6 where R 16 is loweralkyl, haloalkyl, phenyl or dial kylImin o, 4HO 0 *S 0* HO 9 0, 0NH I -793- N* 0 ~N 5 Q H N N /S Ho NHSO 2 ,CF 3 and Ri an 2are 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 40 (Ra)bbNcwhriRa is aryl or a rylalkyl, Rb is hydrogen or alkanoyl and RCC is alkylene, with the proviso that one or both of R, and ~.R 2 is other than hydrogen; or a salt thereof. 54. The compound according to Claim 53 wherein m is zero or 1; Rsb is alkylene; Q is a leaving group; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; or the substantially pure or isomer thereof. The compound according to Claim 53 wherein n and m are both 0; R.5b is alkylene; Q is a leaving group; 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, 4- -794- ethoxyphenyl, 4-ethyiphenyl, 4-methyiphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethyiphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy and R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen, (ix) aryalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl; or the substantially pure (+)isomer thereof. -795- 56. A compound of the formula R2 R~b -NHR2Oa (CH 2 )n (C 2 )m wherein n is 0 or 1; m is 0 to 6; R5b 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 1- 2 10 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, -CN, -C(O)NHR 17 where R 17 is loweralkyl, alkylaminocarbonyl, d ialkyla min ocarbonyl, 15 tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O) 2 Rl 6 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl 6 HO 0 0 OH -796- 0 0, NI 0 H N H 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, alkylaminocarbonytalkyl, 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 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. 57. The compound according to Claim 56 wherein m is zero or 1; Rsb is alkylene; R2Oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; and -797- W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; or the substantially pure or (+)isomer thereof. 58. The compound according to Claim 56 wherein n and, m are both 0; 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 Ri is loweralkyl, (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, 4-methylphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethyiphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl,. alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N- alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl, and R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1,4- benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure or (-)isomer thereof. 59. The compound according to Claim 56 of the formula R2Sb -NH R 2 0a R2N. R5b NH R2Oa C 2) VIH (CH 2 (CH 2 )mG( M w R1or w R -798- wherein n is 0 or 1; m is 0 to 6; R5b is alkylene; R20a is hydrogen, loweralkyl, alkenyl, haloalkyl' alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -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 R 1 6 where R 16 is loweralkyl, haloalkyl, phenyl or :020 dialkylamino, (in) -S(O) 2 NHC(O)Rl 6 00:H 0 0 *N 0 00,* 00 *0 .00(o) HO 0 :OH *00 0 0 0 N 0 -799- S=0 H ~~CF3 Mt H or M NHS0 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, dialkylamninocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkytaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N- alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (aa)(RbbNc hri a is aryl or arylalkyl, Rb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R, and R 2 is other than hydrogen; or a salt thereof. :60. The compound according to Claim,59 wherein .:mmis zero or 1; R 5 b is alkylene; R2Oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; and W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; or the substantially pure or (+)isomer thereof. -800- 61. The compound according to Claim 58 wherein n and m are both 0; R 5 b is alkylene; R20a 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 RI is loweralkyl, (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, 4-methylphenyl, 4-trifluoromethylphenyl, 4- pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2- fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3- benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl, and R 2 is substituted or unsubstituted 1,3- benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4- benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure or (-)-isomer thereof. 62. A pharmaceutical composition for antagonizing the action of endothelin comprising a therapeutically effective amount of the compound of Claim 1 and a pharmaceutically acceptable carrier. 63. A pharmaceutical composition for antagonizing the action of endothelin comprising a therapeutically effective amount of the compound of Claim 21 and a pharmaceutically acceptable carrier. 64. A pharmaceutical composition for antagonizing the action of endothelin comprising a therapeutically effective amount of 2 S,3R,4S)-2-(2,2-Dimethylpentyl)- -801- 4 -(7-methoxy-1,3-benzodioxol-5-yl)-1-(N, N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid and a pharmaceutically acceptable carrier. 65. A pharmaceutical composition for antagonizing the action of endothelin comprising a therapeutically effective amount of (2S,3R,4S)-2-3-Fluoro-4- methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-( 2 -(N-propyl-N-pentanesulfonyl)ethyl)- pyrrolidine-3-carboxylic acid and a pharmaceutically acceptable carrier. 66. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1. 67. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 21. 68. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically affective amount of (2S,3R, 4 S)- 2 -(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1- (N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid. 69. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically affective amount of (2S,3R, 4 S)- 2 -3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2- (N-propyl-N-pentanesulfonyl)ethyl)-pyrrolidine-3-carboxylic acid. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfusion injury, angina, -802- pulmonary hypertension, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1. 71. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxicity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1. 72. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfusion injury, angina, pulmonary hypertension, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a 5 therapeutically effective amount of a compound of Claim 21. 73. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfursion injury, angina, pulmonary hypertension, prostatic hyperplasia, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4- (7-methoxy- ,3-benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid. 74. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfursion injury, angina, -803- pulmonary hypertension, prostatic hyperplasia, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of (2S,3R,4S)-2-3-Fluoro-4- methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-pentanesulfonyl)ethyl)- pyrrolidine-3-carboxylic acid. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxicity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative 5 diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 21. 76. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxocity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, 15 IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy- 1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid. 77. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxocity, erldotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative -804- diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of (2S,3R,4S)-2-3-Fluoro-4-methoxyphenyl)-4-(1,3- benzodioxol-5-yl)-1 2 -(N-propyl-N-pentanesulfonyl)ethyl)-pyrrolidine-3-carboxylic acid. 78. A method for treating treating hypertension, congestive heart failure, restenosis following arterial injury, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a 5 therapeutically effective amount of a compound of Claim 1 in combination with one or more cardiovascular agents. 79. A method for treating treating hypertension, congestive heart failure, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 21 in combination with one or more cardiovascular agents. A method for treating treating hypertension, congestive heart failure, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of (2S,3R, 4 S)- 2 -(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)- 1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid in combination with one or more cardiovascular agents. -805- 81. A process for the preparation of a compound of the formula: R2 RI CO 2 E wherein E is a carboxy-protecting group and R 1 and R 2 are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic and (heterocyclic)alkyl; or a salt thereof, *comprising a) catalytic hydrogenation of a compound of the formula: 0 2 N R, *0 CO 2 E wherein E, R 1 and R2 are defined as above and b) catalytic hydrogenation of the product of step a) in the presence of an acid or a mixture of acids. 82. The process of Claim 71 wherein E is loweralkyl, R 1 is aryl and R 2 is heterocyclic. 83. The process of Claim 71 wherein the hydrogenation catalyst is Raney nickel and the acid is a mixture of acetic acid and trifluoroacetic acid. -806- 84. The process of Claim 71 wherein E is loweralkyl, R, is 4-methoxyphenyl and R 2 is 1 A process for the preparation of a compound of the formula: C0 2 E wherein E is a carboxy-protecting group and R 1 and R 2 are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, am n c r o y ak l i oc r o y aky ,d aky a i o a bo y ak l .:aminocarbonylalkeyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkeyl, arl :10 arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic and (heterocyclic)alkyl; or a salt thereof, comprising a) catalytic hydrogenation of a compound of the formula: 0 2 N C0 2 E wherein E, R, and R 2 are defined as above, b) catalytic hydrogenation of the product of step a) in the presence of an acid or a mixture of acids, and c) epimerization of the product of step b) with a base. -807- 86. The process of Claim 75 wherein E is loweralkyl, R, is aryl and R 2 is heterocyclic. 87. The process of Claim 75 wherein the hydrogenation catalyst is Raney nickel and the acid is a mixture of acetic acid-and trifluoroacetic acid. 88. The process of Claim 75 wherein E is loweralkyl, R, is 4-methoxyphenyl and R 2 is 1 A process for the preparation of a compound of the formula: /R3 N R* *C02E whri sacrox-rtciggop R*n*2aeidpndnl eetdfo :oeakl aloxalyl /loyabnllyhdoylyl aolyhlakxak aloylkxakytiolo47> xalycylakycclaklakl hrenEi acroy-rtctn rup 1 ad 2 aeindependently selected from )loweralkyl,akoakyakycroyakhdryayhaokyhoaoyayl 1 aoyakxalioalkoxakxakyccolkl ylalyakl amiocr)nyalkenylalkylamncroyaknl ilylmncroyaknl rl haloalkolyl, -808- alkenyl, alkynyl, 6 cycloalkyl, cycloalkylalkyl, aryl, heterocyclic, (11) arylalkyl and (12) (heterocyclic)alkyl; (13) hydroxyalkyl, (14) alkoxy, (15) aminoalkyl, and (16) trialkylaminoalkyl, or a salt thereof, comprising a) catalytic hydrogenation of a compound of the formula: *0 2 N J R2 Ri CO 2 E 99e 35 wherein E, R 1 and R 2 are defined as above, b) catalytic hydrogenation of the product of step a) in the presence of an acid or a mixture of acids, c) epimerization of the product of step b) with a base and d) alkyation of the product of step c) with a compound of the formula R 3 -X wherein X is a leaving group and R 3 is defined as above. The process of Claim 79 wherein E is loweralkyl, R 1 is aryl, R 2 is heterocyclic and R 3 is -CH 2 C(O)NR 1 1 R 12 wherein R 11 and R 12 are independently selected from the group consisting of loweralkyl. -809- 91. The process of Claim 79 wherein the hydrogenation catalyst is Raney nickel and the acid is a mixture of acetic acid and trifluoroacetic acid. 92. The process of Claim 79 wherein E is loweralkyl, R, is 4-methoxyphenyl, R 2 is 1,3-benzodioxol-5-yl, R 3 is -CH 2 C(O)N(n-Bu) 2 and X is a halogen or sulfonate leaving group. 93. A process for the preparation of the substantially pure (+)-trans,trans optical isomer of the compound of the formula: S R2 R, wherein E is loweralkyl, R, is 4-methoxyphenyl and R 2 is 1,3-benzodioxol-5-yl, or a salt thereof, comprising reacting a mixture of the and enantiomers of the I\ 1 compound of the formula: R2 R, CO2E wherein E is loweralkyl, R 1 is 4-methoxyphenyl and R 2 is 1,3-benzodioxol-5-yl with mandelic acid and separating the mandelate salt of the (+)-trans,trans optical isomer. -810- 94. A compound -of the formula: (CH 2 )n R wherein Z is -C(Rl 8 )(Rl 9 or wherein R 18 and R 19 are independently selected *.:from hydrogen and loweralkyl; n is 0ori1; R is -(CH2)mW wherein mn is an integer from 0 to 6 and W is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, -P0 3 H 2 -P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl, -CN, -C(O)NHR 17 wherein R 1 7 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, Wk sulfonamido, -C(O)NHS(O) 2 Rl 6 wherein R 16 is loweralkyl, haloalkyl, aryl or dialkylamino, -S(O) 2 NHC(O)Rl 6 wherein R 16 is defined as above, -811- HO N H 0 0 HO 0 OH N 0. k 0 IKNZ 0 0 N \C NS=O H WN j -CF 3 N H or NHS0 2 CF 3 R 1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonytalkyl, hydroxyalkyl, haloalkyl, -812- haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylal kyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dial kylaminocarbonyl alkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyal kyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-.Rcc- wherein Raa is aryl or arylalkyl, R"i~ hydrogen or alkanoyl and Ris alkylene, with the proviso that one or both of R, 1 and R 2 is other than hydrogen; R 3 is (a)R 4 -C(O)-R 5 R 4 -C(O)-R 5 N(R 6 wherein R 5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20 )-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, cycloalkyl or cycloalkylalkyl or -0-13 9 or -R9a-O- R 9 wherein R 9 and R9a are independently selected from alkylene; R 4 and R 6 are (Rj j)(R 1 2 wherein Rl 1 and R 1 2 are independently selected from hydrogen, loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, -813- (11) heterocyclic, (12) arylalkyl, (13) (heterocyclic)alkyl, (14) hydroxyalkyl, alkoxy, (16) aminoalkyl, (1 7) trialkylaminoalkyl, (18) alkylaminoalkyl, (1 9) dial kylaminoal kyl, carboxyalkyl, (21 .o lkla inakl (21) (cycloalkyl)alkminoalkyl, (heterocyclic) aminoalkyl, and (24) (heterocyclic)aminoalkyl, with the proviso that at least one of R 1 1 and R 12 is selected from heterocyclic, aminoalkyl, alkylaminoalkyl, dial kyl aminoal kyl, trialkylaminoalkyl, alkylaminoalkyl, dial kyl aminoal kyl, carboxyalkyl, :(cycloalkyl)aminoalkyl, (cycloalkyl)alkylaminoalkyl, :(heterocyclic) aminoalkyl, and (heterocyclic)alkylaminoalkyl; or a pharmaceutically acceptable salt thereof. -814- A compound selected from the group consisting of: OCH 3 00113 R.N R*~0 R. COOH COOHL -0 1 ~2 0 3 R. R. R. N N N **COOH **C00H...c CC 4 CA5 CH 3 0 0 R. R.N *N N R N 0 R .N. 0 0* C3 0 -1 020 -815- R.N R. R. COOH N C00H 0 CI 13 14 cI 15 CH N 0 R R. N COOH R.N...COOHR. 0 16 o17 0 18 0A N 0 -N N R. R. "COOH N....COOH :00. 0 cl 19 cI 20 CH 3 0 0 21 0. -N -N R.N CO R.N R. -0 22 0 23 OJ24 RR -816- a R.N NN R.N N=N NNH N NH 0 0 31 CH 3 0 0) and 32 0-1 wherein R is selected from the group consisting of: bCNH N H 3 N/ 0 2 0 H 3 CNH N N N" N N 4 0 5 0 H N NN 7 8 10 N N )rl N 0 1 N 13 H 14 0, H6 H I i T 16 0 ,17 H 0 H 3 CNH .N<A 3 0 N~- 6 0 9 H H 12 0 H H5 0 18 0 L- -817- 19 0 22 0 HN r 20 0 23 H0 H2N 0 0 (HjC>N N 0 H 2 N 28 0 31 0 0 34 1-1) 0 37 0 0 NN 49 0 52 N 32 0 0 0 38 0 41 0 5 0 HNI) CH 3 N 0 53 111 21 0 N +Hy~ 24 0 H 2 N~r/ 27 0 30 0 0 (CHiJ 3 N 33 0 39 0 0 42o~ 0 48-- -818- CH 3 N" 0 0 0 N 5 6 H 3 N 57 58 H 59 K r 60 H H 0 0' 0 H 61o 62 H 6 3 0 ,and oa H O *64 96. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfusion injury, angina, pulmonary hypertension, migraine, cerebral or myocardial ischemia, atherosclerosis, coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxicity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising a therapeutically effective amount of a compound of claim 94, wherein said compound has an attached charged functionality which reduces the degree of plasma protein binding of the compound. 97. A method of improving the in vivo activity of compounds by reducing the amount of compound bound to protein by attaching a charged functionality to the compound. -819- 98. A method of claim 97 wherein the charged functionality carries a positive charge at physiological pH. Dated 18 March, 2002 Abbott Laboratories Patenit Attorneys for the Applican t/Nomiiiated P~erson SPRUSON FERGUSON